stesura seveso archivio italiano di urologia e andrologia 2016; 88, 176 original paper dietary treatment of urinary risk factors for renal stone formation. a review of clu working group domenico prezioso 1, pasquale strazzullo 1, tullio lotti 1, giampaolo bianchi 2, loris borghi 3, paolo caione 4, marco carini 5, renata caudarella 6, manuel ferraro 7, giovanni gambaro 7, marco gelosa 8, andrea guttilla 9, ester illiano 1, marangella martino 10, tiziana meschi 3, piergiorgio messa 8, roberto miano 11, giorgio napodano 12, antonio nouvenne 3, domenico rendina 1, francesco rocco 8, marco rosa 2, roberto sanseverino 12, annamaria salerno 13, sebastiano spatafora 14, andrea tasca 15, andrea ticinesi 3, fabrizio travaglini 5, alberto trinchieri 16, giuseppe vespasiani 11, filiberto zattoni 9 1 università federico ii napoli; 2 azienda ospedaliera-policlinico di modena; 3 università degli studi di parma; 4 ospedale pediatrico bambino gesù di roma; 5 azienda ospedaliero universitaria di careggi, firenze; 6 casa di cura villalba, bologna; 7 università cattolica sacro cuore di roma; 8 fondazione irccs ca' granda ospedale maggiore policlinico, milano; 9 università degli studi di padova; 10 a.o. ordine mauriziano di torino; 11 fondazione irccs ca' granda ospedale maggiore policlinico, milano; 11 università di roma tor vergata; 12 ospedale umberto i, nocera inferiore, salerno; 13 università campus biomedico, roma; 14 arcispedale santa maria nuova, reggio emilia; 15 ospedale san bartolo di vicenza; 16 ospedale a. manzoni di lecco. doi: 10.4081/aiua.2016.1.76 due to a technical error, dr. manuel ferraro was omitted from the author list of this article. the correct author details appear above. archivio italiano di urologia e andrologia doi: 10.4081/aiua.2015.2.105 erratum: erratum_stesura seveso 08/04/16 11:34 pagina 76 77archivio italiano di urologia e andrologia 2016; 88, 1 doi: 10.4081/aiua.2016.1.77 original paper current approach for urinary system stone disease in pregnant women orcun celik, hakan türk, rahmi gokhan ekin, ozgur cakmak, salih budak, mehmet zeynel keskin, guner yildiz, yusuf ozlem ilbey urology department, tepecik educational and research hospital, i̇zmir, turkey. due to a technical error, dr. salih budak was omitted from the author list of this article. the correct author details and order appear above. archivio italiano di urologia e andrologia doi: 10.4081/aiua.2015.4.280 erratum: erratum_stesura seveso 08/04/16 11:34 pagina 77 stesura seveso 171archivio italiano di urologia e andrologia 2015; 87, 2 case report penile plaque as predictor of an advanced anorectal carcinoma: a case report andrea fabiani 1, alessandra filosa 2, fabrizio fioretti 1, gabriele mammana 1 1 unit of urology, surgical department, 2 section of pathological anatomy, department of clinical pathology, macerata hospital, area vasta 3, asur marche, italy. the secondary involvement of the penis by tumors from others organs is a rare event representing only 0.8% of overall metastasis in the genitourinary tract. the most frequent clinical findings is priapism, but occasionally, solitary metastases to the penile skin, mucosa of the glans, corpus spongiosum or lesions of the albuginea mimicking an induratio penis have been reported. we report a case of penile plaque predicting the relapse of an anorectal carcinoma. the precise etiology of this particular manifestation is not well understood and the prognosis is poor. there are no individual treatments with curative intent. key words: penile induration; metastasis; penile neoplasms; anorectal carcinoma. submitted 1 september 2014; accepted 20 december 2014 summary no conflict of interest declared. doi: 10.4081/aiua.2015.2.171 case report a 78 year old man came to our attention presenting with a fast growing painless nodular lesion of the lateral surface of the root of the left corpus cavernosum of the penis. medical history included an anorectal carcinoma for which the patient had undergone surgical resection and complementary radiation therapy 5 years before. many years before, the patient underwent a surgical debridement of scrotal tissue due to a necrotizing fasciitis. penile ultrasound evaluation revealed a nodular thickening of albuginea, inhomogeneous for echo pattern, containing hyperechoic spots with posterior shadowing and hypoechoic areas, sized 30 mm x 27,5 mm x 13,5 mm, with minimal presence of color signal at ecocolor ultrasound assessment (figures 1-2). excisional biopsy was performed with local anhestesia (penile ring block technique with a mixture of 5 ml of 1% lidocaine and 5 ml of plain 0.25% bupivacaine). frozen section examination revealed a malignant lesion figure 1. transversal ultrasound image of circumscribed nodule within the root of left corpus cavernosum showing an inhomogeneous echostructural pattern consisting in hyperechoic spots with posterior shadowing and hypoechoic areas with minimal presence of color signal at ecocolor ultrasound assessment. tunica albuginea is interrupted. figure 2. longitudinal ultrasound image of the nodule. cavernous tissue is infiltrated by the solid nodule. tunica albuginea is non remarkable. fabiani_stesura seveso 02/07/15 11:35 pagina 171 archivio italiano di urologia e andrologia 2015; 87, 2 a. fabiani, a. filosa, f. fioretti, g. mammana 172 traceable to an adenocarcinoma (figure 3). patient was studied with a total body computed tomography (ct) scan and a recto-colonscopy with evidence of relapsed colorectal neoplasm. two months later, the patient underwent a surgical ileostomy because of occlusion from rectal cancer recurrence. he died after 17 months after chemotherapy administration. discussion penis is rarely involved by metastatic spread of tumors from others organs. in a report of more than 600 tumors with metastases to the genitourinary tract, only 0.8% were located in this organ (1). the most frequent clinical findings is priapism but occasionally, solitary metastases to the penile skin, mucosa of the glans, corpus spongiosum or lesions of the albuginea mimicking an induratio penis have been reported. the urinary bladder and the prostate gland represent about the 70% of the primary tumors who give metastases to the penis (3). most of the remaining metastases originate from tumors of the gastrointestinal tract, usually the rectosigmoid tract (2). in this case, the metastatic tumor was localized in the tunica albuginea in absence of documented widely disseminated disease. at least prior to our clinic evaluation, the patient had no signs of recurrence of primitive disease. only the examinations subsequently performed highlighted a recurrence of the anorectal carcinoma. retrograde venous spread from the pudendal venous system appears to be the most probable way of spreading (2-3). another mechanism may be a retrograde lymphatic dissemination into penile lymphatic channels after obstruction of inguinal and hypogastric nodes determined by anatomical disruption of lymphatic drainage after surgery or radiotherapy. the diagnosis could be difficult due to the non specific clinical and instrumental features. only an histological evaluation of the biopsy could confirm the suspect. in cancer patients penile metastasis tends to be associated with a poor prognosis because its presence tends to be part of a widely disseminated disease. the majority of patients dies within one year. there are no treatment of choice and the combination treatment with radiotherapy and chemotherapy in such advanced disease produces only occasional responses (2). conclusion despite the metastatic penile involvement can be considered a rare occurrence in visceral tumours, in cases of fast-growing penile induration with anamnesis of neoplasms and suspected ultrasonographic findings, an early histological assessment of penile lesion should be performed to avoid a misdiagnosis. evaluation of progression of primitive tumor is mandatory because metastasis to the penis, in most cases, tends to be part of a widely disseminated disease. references 1. bates aw, baithun si. secondary tumours of the penis. j r soc med. 2002; 95:162-3. 2. yuta kimura, dai shida, keiichi nasu, et al. metachronous penile metastasis from rectal cancer after total pelvic exenteration. world j gastroenterol. 2012; 18:5476-5478; 3. chaux a, amin m, cubilla al, et al. metastatic tumors to the penis: a report of 17 cases and review of the literature. int j surg pathol. 2011; 19:597-606. figure 3. hystopathologic features of metastatic nodule excisional biopsy. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md, phd fa.fioretti@libero.it gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3, macerata hospital, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy fabiani_stesura seveso 02/07/15 11:35 pagina 172 stesura seveso 175archivio italiano di urologia e andrologia 2015; 87, 2 case report a rare complication after renal transplantation: forgotten stent mustafa karabıcak, tumay ipekci, cemal selcuk isoglu, mehmet zeynel keskin, rahmi gokhan ekin, salih budak, hakan turk, orcun celik, yusuf ozlem ilbey tepecik education and research hospital, urology clinic, izmir, turkey. in renal transplantation surgery, double j stents (djs) are often used to reduce complications, protect the anastomosis between ureter and bladder, provide drainage in ureteral obstructions and enhance healing if there is an ureter injury. urinary tract infections, hematuria and irritative voiding symptoms are the early complications of djs. migration, fragmantation, encrustation and rarely sepsis are among the late complications of djs. in this report we describe a renal transplantation case whose djs stent was forgotten because the patient did not attend the regular follow-up and noticed 5 years after surgery. key words: double j stent (djs); urinary tract infection (uti); extracorporal shockwave lithotripsy (eswl); ureterorenoscopy (urs); oercutaneous nephrolithotomy (pnl). submitted 5 january 2015; accepted 15 march 2015 summary no conflict of interest declared. ture. at ultrasonography, patient’s native kidneys were athropic and the transplanted kidney was seen in the right lower quadrant. parenchymal thickness of the transplanted kidney was normal but mild pyelectasis was detected. djs was seen in the bladder also with x-ray. patient was informed about the procedure and informed consent was obtained. djs was removed endoscopically.the patient was discharged after antibiotic treatment without any problem. doi: 10.4081/aiua.2015.2.175 introduction double j stent is an useful tool that is commonly used in many urological procedures. in renal transplantation surgery, double j stents (djs) are often used to reduce complications, protect the anastomosis between ureter and bladder, provide drainage in ureteral obstructions and enhance healing if there is an ureter injury (1, 2). complications caused by djs are seen with a rate of 2.2% in renal transplant patients (1). complications like migration, fragmentation and encrustation can cause obstructive nephropathy (3). in this report we described a renal transplantation case whose djs stent was forgotten becasue of not attending the regular follow-up and noticed 5 years after surgery. case report a 55 years old male patient presented to the hospital with recurrent urinary tract infection.patient had a renal transplantation surgery 5 years before due to chronic kidney disease caused by high blood pressure and did not apply for regular follow up. physical examination was normal except the suprapubic pain. laboratory tests were in normal ranges but escherichia coli was detected in urine culfigure 1. cytoscopic view of double j stent. figure 2. double j stent removed from the patient karabıcak_stesura seveso 02/07/15 11:38 pagina 175 problems in renal transplanted patients. multimodal urological approach is necessary for treatment. all patients should be evaluated carefully for uti and sepsis because of the immunosupression and antibiotics are recommended for prophlaxy. patients should be informed about the complications of djs and the importance of regular follow-up (7). in cases of recurrent uti after renal transplantation, possible retention of djs should always be kept in mind. references 1. nicol dl, p'ng k, hardie dr, et al. routine use of indwelling ureteral stents in renal transplantation. j urol. 1993; 150:1375-9. 2. aravantinos e, graves s, karatzas ad, et al. forgotten, encrusted ureteral stents: a challenge problem with an endourologic solution. j endourol. 2006; 20:1045-9. 3. monga m, klei e, castaneda-zuniga wr, et al. the forgotten indwelling ureteral stent: a urological dilemma. j urol. 1995; 153:1817-9. 4-verma bs, bhandari m, srivastava a, et al. optimum duration of j.j. stenting in live related renal transplantation. indian j urol. 2002; 19:54-7. 5. singh v, srinivastava a, kapoor r, kumar, a. can the complicated forgotten indwelling ureteric stents be lethal? int urol nephrol. 2005; 37:541-6. 6-vanderbrink ba, rastinehad ar, ost mc, smith ad. encrusted urinary stents: evaluation and endourologic management. j endourol. 2008; 22:905-12. 7. shaheel bhuva, steven j, kennish, tze m wah. forgotten indwelling stent in a transplanted kidney. cases journal. 2009; 2:27. archivio italiano di urologia e andrologia 2015; 87, 2 m. karabıcak, t. ipekci, c. selcuk isoglu, m. zeynel keskin, r. gokhan ekin, s. budak, h. turk, o. celik, y. ozlem ilbey 176 discussion there is no consensus about the removal time of djs in renal transplanted patients. the removal time varies around 1-12 weeks in different studies (4). however it is prudent to remove the stent in 2-4 weeks after transplantation for preventing the possible complications (5). there is no clear definition for forgotten djs but in some studies the stent was defined as forgotten when was retained more than 6 months (2). complications caused by djs are observed with a rate of 2.2% in renal transplant patients (1). urinary tract infections (uti), hematuria and irritative voiding symptoms are the early complications of djs. migration, fragmentation, encrustation and rarely sepsis are among the late complications of djs. our patient was suffering from recurrent uti and irritative voiding symptoms. a biofilm layer covers long-term retained stents and it can cause uti by contact with urine. urine ph can increases due to urea splitting bacterias that decompose urea and cause magnesium-calcium-phosphate cyristals accumulation on the djs. encrustation is highly related with urine composition, bacterial colonisation and duration of staying of the stent (6). there is no proofed gold standard treatment for encrusted stents. extracorporeal shock wave lithotripsy and percutanous nephrolithotomy are recommended for proximal encrustation, ureterore noscopy is recommended for distal encrustations. because of the immunosupression, all patients should be assessed for uti and after removal should be carefully evaluated for sepsis, urinary tract injury and uti (7). in our case, djs was seen with cystoscope and removed with foreign body forseps. in conclusion, forgotten djs can cause severe urological correspondence mustafa karabıcak, md bicak_7@hotmail.com tumay ipekci, md cemal selcuk isoglu, md mehmet zeynel keskin, md rahmi gokhan ekin, md salih budak, md hakan turk, md orcun celik, md yusuf ozlem ilbey, md tepecik education and research hospital, urology clinic izmir, turkey karabıcak_stesura seveso 02/07/15 11:38 pagina 176 stesura seveso 173archivio italiano di urologia e andrologia 2015; 87, 2 case report patch bulging after plaque incision and grafting procedure for peyronie’s disease. surgical repair with a collagen fleece andrea fabiani 1, fabrizio fioretti 1, alessandra filosa 2, lucilla servi 1, gabriele mammana 1 1 unit of urology, surgical department, 2 section of pathological anatomy, department of clinical pathology, macerata hospital, area vasta 3, asur marche, italy. the incision/excision and grafting techniques (pig) for surgical therapy of peyronie’s disease (pd) have gained popularity in recent years. several different graft materials have been used but the ideal graft has yet to be established. the use of grafting materials could cause complications. in the daily clinical practice it will always be more frequent to manage complications arising from their use. we present herein the case of a patch bulging repaired with a ready-to-use collagen fleece (tachosil®, takeda, linz, austria, europe) in a 61 years old man subjected to intervention of geometric corporoplasty with paulo egydio technique using an acellular collagen material (xenform® patch, boston scientific, natick, ma, usa) as graft. we also discuss the possible implications of pig procedure. key words: patch bulging; corporoplasty; complication; collagen fleece; acellular collagen material. submitted 1 september 2014; accepted 20 december 2014 summary no conflict of interest declared. third medium of the penis. pathological remote history reported eight years before a clear cell renal carcinoma treated and adjuvant chemotherapy. from that period the patient begun to complain of moderate erectile dysfunction and a worsening left lateral and dorsal penile bowing of about 45°. elsewhere, patient underwent a geometric corporoplasty with paulo egydio technique using an acellular collagen material as graft (xenform® patch, boston scientific, natick, ma, usa). three months after surgery, the patient noted the gradual increase of an irregularity in the middle third of penile shaft and reported a complete deterioration in the ability to get a valid erection despite the absence of curvature of the penis. a non-reducible edema at the circumcision site coexisted. a basal ultrasound of the penis was performed (figures 1-2a-2b) with detection of a cystic image of the tunica albuginea of the corpus cavernosum. its echostructure was predominantly hypoechoic, the size was 14.1 mm x 8.6 mm x 8.4 mm. needle aspiration did not allow to get the resolution of the cystic dilatation. after discussing the case with the patient we decided to proceed to surgical correction of the anomaly. despite the erectile dysfunction, the patient refused the placement of a penile prosthesis. after penile shaft degloving (figures 3-4), surgical procedure consisted in cystic dilatation removal and replacement of the defect created with suitably shaped patch of collagen fleece (tachosil®, takeda, linz, austria, doi: 10.4081/aiua.2015.2.173 introduction peyronie’s disease (pd) is still a surgical disease. medical treatments have been plagued with flawed results, poorly designed studies, and conflicting data. surgery remains the mainstay in treatment (1). from the classic nesbit and modified nesbit operation, surgical treatment has evolved through penile plication procedures and incision/excision and grafting techniques (pig), combined or not with the inflatable penile prosthesis implants in case of patients with moderate to severe erectile dysfunction and complicated plaque defects. the pig procedures are the ideal treatment choice for pd in case of good erectile function with complex or > 60° curvatures, destabilizing hinge defects and/or shorter phallus (2). several different graft materials have been used but the ideal graft has yet to be established. the pig have gained popularity in recent years so that, in the daily clinical practice, it will always be more frequent to manage complications arising from the use of grafts. we present herein the case of a patch bulging repaired with a ready-to-use collagen fleece (tachosil®, takeda, linz, austria, europe). we discuss the possible implications of pig procedure. case report a 61 years old man presented at our urologic section for the appearance of a swelling in the dorsal left side of the figure 1. pre operative basal ultrasound evaluation of patch. fabiani2_stesura seveso 02/07/15 11:37 pagina 173 archivio italiano di urologia e andrologia 2015; 87, 2 a. fabiani, f. fioretti, a. filosa, l. servi, g. mammana 174 europe) without need of dorsal neurovascular bundle isolation. the fleece was manually compressed on the defect for 3 minutes and additional fixation by sutures was not performed. the procedure was concluded by reconstruction of buck's fascia. circumcision was revised. histological findings consisted in keloid dense fibrous tissue with chronic lymphocytic inflammation and giant cells containing birefrangent foreign material. the postoperative course was regular. the patient was discharged 48 hours after removal of the draped medication and of the bladder catheter. follow up at 15 days highlighted the disappearance of penile deformity and the normal healing of the skin at circumcision site. twenty four months later evaluation was performed with basal penile ultrasound and penile dynamic echo-color-doppler (figures 5-6a6b). after intracavernous injection (ici) with 10 µg of prostaglandin (pg) we observed an erection of type 3 according to erection hardness score (ehs) (3) without penile curvature. the patient referred a satisfactory sexual activity by 10 mcg pg ici. conclusions cystic dilation of the graft is a possible event that has become more frequently over time. the etiology may be related to an immediate post surgery bleeding or an implicit flaw of geometric technique used. the decision on the surgical treatment has to consider the clinic and the patient requests. the urologists involved in the andrological field must be aware of possible complications related to pig procedures. in our experience tachosil® may be a good material of choice to restore the corpus cavernosum defect. discussion and supplementary references are posted on www.aiua.it references 1. martinez d, parker j, carrion r. peyronie’s disease: lessons learned and recent advances in minimally invasive therapy, aua news. 2012; 17:5-6. 2. egydio ph. surgical treatment of peyronie’s disease: choosing the best approach to improve patient satisfaction. j androl. 2008; 10:158-166. 3. mulhall jp, goldstein i, bushmakin ag, et al. validation of the erection hardness score. j sex med. 2007; 4:1626-1634. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md, phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3, macerata hospital, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy figure 2a. cystic anechoic lesion of patch, transversal view. figure 2b. cystic anechoic lesion of the patch, longitudinal view. figure 3. intraoperative aspect of patch bulging after penile degloving. figure 4. intraoperative aspect of patch bulging after penile degloving. the dorsal neurovascular bundle wasn’t isolated.. fabiani2_stesura seveso 02/07/15 11:37 pagina 174 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2142 case report idiopathic spontaneous perforation of the upper urinary tract. a presentation of 4 cases ioannis katafigiotis 1, ioannis adamakis 2, alexandra zormpala 3, christos pournaras 1, konstantinos stravodimos 2 1 resident in urology, university of athens medical school, athens, greece; 2 assistant professor in urology, university of athens medical school, athens, greece; 3 radiologist, radiology department, laikon general hospital, athens, greece. spontaneous perforation of the collecting system constitutes a rare entity masked by the presentation of a typical renal colic. however, it should not be forgotten when managing patients with colic, since missed diagnoses may carry significant morbidity. we herein present a series of spontaneous perforation of the collecting system without an apparent obstruction site evident in helical ct urography. four consecutive patients who presented with typical renal colic were initially subjected to kub and renal ultrasound imaging and were ultimately diagnosed with perforation of the collecting system via contrast enhancedhelical ct urography. despite thorough evaluation, the cause responsible obstructive was not discovered and an exclusion diagnosis of idiopathic collecting system perforation was assigned to all patients. due to the rarity of a spontaneous perforation traditional retrograde urography was performed in an effort to identify the possible cause but was also unrevealing. all patients were successfully treated with endourological means. perforation of the collecting system without an evident obstructive cause is a rare entity with obscure etiology. a reasonable but yet unconfirmed speculation is that of a transient obstruction capable of a significant increase of intraluminal pressures. key words: spontaneous ureter rupture; idiopathic upper urinary tract perforation. submitted 28 april 2014; accepted 31 may 2014 summary introduction spontaneous perforation of the collecting system is a rather rare disease entity with relevant reports dating back to the 60s. several latter reports presented a variety of cases each within an individual clinical setting. in fact, spontaneous perforation of the ureter has been encountered as a complication of cystectomy with orthotopic ileal neobladder formation (1) or lupus vasculitis (2). even though these reports have termed respective cases no conflict of interest declared of upper tract perforation as spontaneous, it is reasonable to assume that ureteral rupture with impaction of a ureteral calculus as the triggering event would represent the most common scenario. interestingly, certain cases with no obvious cause (excluding even calculus disease) have also been reported (3). helical computed tomography (ct) urography is currently considered the standard of practice in the evaluation of an episode of renal colic. delayed scans are already reported as the optimum for the diagnosis of traumatic ureteral rupture and respective urine leaks (4). even though no data have been published on their value in diagnosis of spontaneous upper tract rupture, it seems reasonable to apply the technique in this setting. after thorough evaluation with the above mentioned techniques in 4 cases of persistent renal colic with confirmed urinoma formation an obstructive cause was not revealed. therefore a diagnosis of spontaneous rupture of the upper tract was set and respective data and comments are herein presented. materials and methods during a 14 month period, from may 2011 to july 2012, 4 patients (2 male, 2 female, mean age 71.5 years, age range 67-79 years) presented with signs and symptoms of acute renal colic in 3 different urological departments (2 to an urban university referral centre-university of athens, athens, greece and 2 to rural county-affiliated hospitals). patients underwent the conventional diagnostic work-up routinely performed in such cases including blood and urine tests (urinalysis with urine culture, blood cell counts and biochemical panel). imaging studies all patients underwent renal ultrasonography and kidneys, ureters and bladder (kub) x-ray. in all patients abdominal helical ct urography was performed using a helical scanner from the level of the kidneys to the pubic symphysis, in breath-hold status, with a slice thickness of 5 mm and a pitch of i.5. intravenous non-ionic contrast was administered at a rate of 3 ml per second for a doi: 10.4081/aiua.2014.2.142 143archivio italiano di urologia e andrologia 2014; 86, 2 idiopathic perforation of the upper urinary total volume of 100-130 ml. the ct scans were obtained as part of a ct renal protocol that included nonenhanced imaging and imaging in both nephrographic and delayed excretory phases. delayed excretory phase scans of the urinary tract were acquired 10-15 minutes after the injection. in order to obtain a more accurate view of the urinary tract and increase the sensitivity of the work-up, retrograde urography was also used. the latter was used after the patient had undergone evaluation with delayed ct scan, so the conclusions based on ct imaging were minimally biased. results ultrasound findings raised the suspicion for urinary tract continuity disruption with perinephric fluid collection of mixed echogenic characteristics in all cases. delayed scans of helical ct-urography set the diagnosis of upper tract disruption in all four patients. contrast medium leakage in the periureteral and perirenal space was the main finding (figures 1, 2). retrograde pyelography (performed during stent insertion) confirmed the point of extravasation at the ureteropelvic junction in three patients and the upper third of the ureter in the remaining. an obvious obstructive cause was not demonstrated in either case. all patients were then managed by endourological approaches using a double j stent under fluoroscopic guidance. drainage of the urinoma was eventually required in one patient who developed septic complications rendering the case an absolute emergency. discussion and full list of references are posted in supplementary materials on www.aiua.it references 1. deliveliotis ch, chrisofos m, argyropoulos v, et al. spontaneous rupture of the ureter after cystectomy and creation of orthotopic ileal neobladder: treatment with percutaneous nephrostomy and drainage. j endourol. 2003; 17:33-5. 2. benson ch, pennebaker jb, harisdangkul v, songcharoen s. spontaneous ureteral rupture in a patient with systemic lupus erythematosus. south med j. 1983; 76:1053-5. 3. ertugrul a, yücel s, ilker y, akdas a. use of double j stent in a case of spontaneous ureteral extravasation of urine. arch esp urol. 2000; 53:491-3. correspondence ioannis katafigiotis, md (corresponding author) katafigiotis@yahoo.com christos pournaras, md christpourn@gmail.com ioannis adamakis, md yianton@hotmail.com konstantinos stravodimos, md kgstravod@yahoo.com alexandra zormpala, md azormpala@med.uoa.gr department of urology, athens university medical school laiko hospital, 17 agiou thoma str., 11527 athens, greece figures 1, 2. delayed excretory ct scans demonstrating contrast medium leakage in the perirenal and periureteral space compatible with urinary tract disruption. stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3256 case report contralateral tumor seeding of renal cell carcinoma mimicking late metastasis of liver after laparoscopic nephrectomy: a case report with review of the literature özgür haki yüksel, caglar yildirim, ahmet ürkmez, serkan akan, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey. laparoscopic surgery has been increasingly used every day in the management of urologic malignancies. even though it seems as a minimally invasive surgery, during these interventions tumor seeding, as seen in open surgery, confronts us as a rarely seen serious risk. herein, we have reported a case who demonstrated peritoneal tumor implantation at 12 month postoperative follow up after laparoscopic radical nephrectomy (lrn) performed for furhman grade 1 (t2n0m0) renal cell cancer. key words: laparoscopic radical nephrectomy; tumor seeding; peritoneal implant; renal cell cancer. submitted 9 march 2015; accepted 30 april 2015 summary no conflict of interest declared. tic biopsy with the aid of transrectal ultrasound. histopathological report indicated prostate cancer (pca) with gleason score 3+3 in 6 out of 12 core biopsy specimens. magnetic resonance imaging (mri) performed for tumor grading incidentally disclosed a mass lesion radiologically suggesting rcc located in the mid-portion of the left kidney with exophytic extension and measuring 45 mm in its largest diameter. with this indication, the patient underwent laparoscopic renal nephrectomy (lrn) in december 2012. his histopathological report indicated the lesion to be furhman grade 1 (t2n0m0) rcc (figure 1). afterwards, we performed radical retropubic prostatectomy and lymph node dissection with the indication of pca in march 2013 and penile prosthesis was implanted to treat his erectile dysfunction. up to that time, laboratory and radiological controls did not reveal the presence of rcc and pca recurrences or metastases. control mri performed at 12 month follow up postlrn, disclosed a perihepatic mass lesion with dimensions of 20x18x12 mm consistent with metastasis or tumor seeding located on the anterior segment of the right lobe of the liver (figure 2). then, the patient underwent laparotomy in february 2014 in the department of general surgery and the lesion visualized during mri was revealed to be a peritoneal tumor implant. the implant was excised and consulted during the perioperative period to the department of histopathology for frozen section. histopathological report indicated the lesion to be a rcc implant (figure 3). the patient is still at post-lrn 24. months. all abdominal mri, thoracic ct and bone scans could not reveal any evidence of clinically significant rcc and pca recurrence or metastases. conclusions in conclusion, following oncologic laparoscopic interventions, not only local recurrence and distant metastases, but also peritoneal implantation should be also considered and atypical abdominal small lesions away from trocar access site should be also taken into consideration as for implantation metastases. discussion and supplementary references are posted in supplementary materials on www.aiua.it doi: 10.4081/aiua.2015.3.256 introduction during removal of malignant tumours by means of open surgery or laparoscopic resection, direct inoculation of neoplastic cells can occur. this inoculation is generally seen along the port access route which is known as portsite metastasis (1). in laparoscopic surgeries applied for the management of urologic malignancies, peritoneal implants or port-site metastases have been rarely (0.090.03%) seen up to now (2). although etiological factors of this phenomenon have not been completely understood, tumor aggressivity, laparoscopy-related factors, immune system of the patient and local characteristics of the surgical site have been implicated. among all urologic malignancies, peritoneal tumor seeding and portsite metastasis are extremely rarely seen in renal cell cancer (rcc). very scarce number of case reports have been reported in the literature (3). herein, we presented a case who demonstrated peritoneal tumor implantation at postoperative 12 month follow up after laparoscopic radical nephrectomy (lrn) performed for furhman grade 1 (t2n0m0) renal cell cancer (rcc). case report a 68-year-old male patient consulted to our outpatient clinic in december 2012 with complaints of dysuria and pollakiuria. his medical evaluation revealed a high serum psa level (10.5 ng/ml) which necessitated prostayuksel_stesura seveso 23/09/15 12:46 pagina 256 257archivio italiano di urologia e andrologia 2015; 87, 3 contralateral tumor seeding of renal cell carcinoma mimicking late metastasis of liver after laparoscopic nephrectomy references 1. lee br, tan bj, smith ad. laparoscopic port site metastases: incidence, risk factors, and potential preventive measures. urology. 2005; 65:639-644. 2. tanaka k, hara i, takenaka a, et al. incidence of local and port site recurrence of urologic cancer after laparoscopic surgery. urology. 2008; 71:728-734. 3. castillo oa, vitagliano g. port site metastasis and tumor seeding in oncologic laparoscopic urology. urology. 2008; 1:372-378. figure 1. hematoxylin and eosin stain of the left kidney: renal cell carcinoma (40x). figure 3. hematoxylin and eosin stain of the peritoneal renal cell carcinoma implant (100x). figure 2. mr image: a perihepatic mass lesion measuring 20x18x12 mm located on the anterior segment of the right lobe of the liver. correspondence özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com caglar yildirim, md ahmet ürkmez, md serkan akan, md ayhan verit, md. prof. fatih sultan mehmet research and training hospital, dept. of urology, içerenköy/ataşehir, tr34752 istanbul, turkey yuksel_stesura seveso 23/09/15 12:46 pagina 257 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 160 notes on surgical technique a novel cannulation technique for difficult urethral catheterization mehmet kaynar, murat akand, serdar goktas department of urology, selcuk university, faculty of medicine, konya, turkey. introduction: to propose a novel cannulation technique for difficult urethral catheterization procedures. technique: the sheath tip of an intravenous catheter is cut off, replaced to the needle tip and pushed through the distal drainage side hole to foley catheter tip, and finally withdrawn for cannulation. in situations making urethral catheterization difficult, a guide wire is placed under direct vision. the modified foley catheter is slid successfully over the guide wire from its distal end throughout the urethral passage into the bladder. results: the modified foley catheter was used successfully in our clinic in cases requiring difficult urethral catheterization. conclusions: this easy and rapid modification of a foley catheter may minimize the potential complications of blind catheter placement in standard catheterization. key words: technique; difficult; urethral catheterization. submitted 5 october 2015; accepted 11 november 2015 summary no conflict of interest declared. foley catheter (rüsch gold tmgermany), and a scalpel are the necessary tools (figure 1a). the tip of the iv catheter sheath is cut off up to 4 mm and replaced to the needle tip (figures 1b, 1c).the iv catheter with the cut and replaced sheath tip is pushed through the distal drainage side hole of the urethral catheter to the center of the foley catheter tip. the intravenous catheter needle and proximal sheath are withdrawn (figure 2a). upon withdrawal, the 4 mm cut sheath remains spontaneously in the foley catheter tip. yet, the length of the tip of the sheath cannula sticking out of the foley catheter may be 1 mm or less. in the present manuscripts it is longer in order to depict the technique (figure 2b). depending on the situation present, the guide wire is fed past the undermining bladder trigone and placed into the bladder under direct vision using a resectoscope. after the placement of the guide wire, the modified foley catheter with the 4 mm sheath tip for cannulation is slid successfully over the guide wire from its distal end throughout the urethral passage into the bladder (figure 2c). finally, the balloon is filled and the guide wire is removed. the modified foley catheter with the sheath tip for cannulation was used successfully in our clinic in cases requiring difficult urethral catheterization such as after internal urethrotomy in urethral strictures, flexible cystoscopy and cystourethroscopy in false passages, and transurethral resection of the prostate with emergent undermining of bladder trigone. discussion urologist develop their own ways with time and experience to dwell a catheter in challenging situations using different tools and methods as there is not a standard procedure. the present manuscript describes the use of a foley catheter minimizing urethral trauma and that can be placed easily and safely into the bladder using a guide wire. the use short rigid ureteroscope placed into foley catheter in urethral catheterization may not be suitable with small size foley catheters and in case of hemorrhagy disturbing the view of the urethral passage (3). peel-away sheath may not be a routine tool as in extreme urethral strictures hindering the placement of cystoscopy or resectoscope (2). blitz has defined a similar technique using an iv catheter placed into a foley catheter to enable easy passage of hydrophilic guide wire. however, in nondoi: 10.4081/aiua.2016.1.60 introduction despite the developments in minimally invasive techniques and invention of novel endourological instruments, difficulties and failures in urethral catheterization may be unavoidable especially in male patients. urologist may have difficulties in urethral catheterization caused by urethral strictures, iatrogenic false passages, large obstructive prostates, and especially in the presence of a large median lobe that may associated to undermining of the bladder trigone after an excessive transurethral resection of the bladder neck. several techniques and instrument have been described in the literature in case of misdirection or misplacement of an indwelling urethral catheter (1-3). the present manuscript is about a novel, alternative, simple, and safe cannulation technique to be used in difficult urethral catheterization. technique and material a 16-gauge intravenous (iv) catheter, a 0.038 inch ptfe-nitinol guidewire with hydrophilic floppy tip (sensortm boston scientific corporation) or any other teflon coated spiral wound guide wire, pc guide wire and double j guide wire, an indwelling 22 f three-way kainar_stesura seveso 05/04/16 15:25 pagina 60 61archivio italiano di urologia e andrologia 2016; 88, 1 cannulation technique for catheterization hand, makes the foley catheter more disposed to deformation of the catheter tip and balloon as well as snagging, during urethral passage (1). yet, our modified foley catheter enables permanent cannulation with all type of guide wires minimizing guide wire buckling and foley catheter snagging due to the lack of friction in impacted conditions; since the catheter tip is not deformed, gait will become less resistant to advancement enabling easy passage through the urethral catheter and into the bladder. the proposed technique can be used successfully with all type of guide wires and catheters varying in size and type. it is rapidly and easily applied with common urological tools and it minimizes the potential complications of blind catheter placement in standard catheterization. acknowledgment we would like to express our gratitude to the medical assistant of the urology operation theatre mr. ennur civelek for his contribution. references 1. blitz bf. a simple method using hydrophilic guide wires for the difficult urethral catheterization. urology. 1995; 46:99-100. 2. lowe ma, defalco aj. endourologic technique for catheter placement after turp, prostatectomy, and difficult urethroscopy. urology. 1992; 40:461-63. 3. rozanski ta, salazar f, thompson im. direct vision bladder catheterization using a short rigid ureteroscope. urology. 1998; 51:827-28. correspondence mehmet kaynar, md (corresponding author) mekaynar@gmail.com selçuk üniversitesi alaeddin keykubat kampüsü 42075 selçuklu-konya, turkey murat akand, md serdar goktas, md department of urology, selcuk university, faculty of medicine konya, turkey figure 1. a: 16-gauge intravenous (iv) catheter, 0.038 in ptfenitinolguidewire with hydrophilic floppy tip, indwelling 22-f 3 way foley catheters, and bistoury. b: the tip of the iv catheter sheath is cut off up to 4 mm. c: replaced sheath to the needle tip. figure 2. a: the iv catheter with the cut and replaced sheath tip is pushed through the distal drainage side hole of the urethral catheter to the center of the foley catheter tip. b: the intravenous catheter needle and proximal sheath is withdrawn. sheath remains spontaneously in the foley catheter tip. c: the foley catheter with the sheath tip is slid over the guide wire into the bladder. a. b. c. c. b. a. hydrophilic guide wires, the friction between the guide wire and foley catheter makes the advancement of the catheter difficult. cutting the catheter tip on the other kainar_stesura seveso 05/04/16 15:25 pagina 61 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3222 case report bladder tumours in children: an interesting case report of tcc with a partial inverted growth pattern davide abed el rahman 1, giuseppe salvo 2, carlotta palumbo 3, bernardo rocco 3, francesco rocco 3 1 u.o.c. di urologia azienda ospedaliera “g. salvini”, presidio di rho, rho (mi), italy; 2 dipartimento universitario materno-infantile di andrologia ed urologia, università degli studi di palermo, italy; 3 istituto di urologia fondazione irccs ospedale maggiore policlinico “ca granda”, università degli studi di milano, italy. bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. there is debate and uncertainty in the literature regarding the clinicopathologic and prognostic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. we report on a 16 years old girl with transitional cell carcinoma of the bladder with a partial inverted growth pattern who presented with gross hematuria. ultrasonography revealed a papillary lesion in the bladder; cystoscopic evaluation showed a 15 mm papillary lesion with a thick stalk located in the left bladder wall. pathologic evaluation of the specimen was reported as “low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern”. key words: bladder cancer; young adults; inverted papilloma; pathology. submitted 24 april 2014; accepted 30 june 2014 summary no conflict of interest declared. introduction bladder urothelial cancer is predominately a disease of males and occurs mainly among the elderly adults (1), less than 1% of bladder urothelial cancer has been reported during the first four decades of life. reported cases of transitional cell carcinoma of the bladder in the pediatric population are less than 150. in 1969 javadpour and mostofi studied the records of 10,000 patients with urothelial malignancy and found that just 40 patients were younger than 20 years old. large series have described the characteristics of these tumours as low grade and seldom recurring (2). although the biologic behaviour and treatment of bladder cancer has been well studied, conflicting reports exist about clinical behavior and prognosis for patients under 40 years of age; whether younger patients have a better prognosis than their older counterparts has long been a subject of debate; indeed, some groups observed similar patterns of clinical behavior and prognosis for doi: 10.4081/aiua.2014.3.222 bladder cancer in young and older patients (3), whereas other investigators reported lower rates of disease recurrence and progression, and better survival, in younger patients (4). moreover even if inverted papilloma of the urinary bladder is not uncommon in adults this is not the case in the pediatric population in which tumors of the urinary bladder are rare and more commonly of mesenchymal origin. paschkis first described this lesion in 1927 and named it polypoid adenoma (5). later, potts and hirst designated it as inverted papilloma (6). this lesion exhibits a polypoid configuration with an inverted papillomatous architecture lined by transitional epithelium. it also may have submucosal cyst formation and brunn’s nests so some authors refer to this lesion as brunnian adenoma (7). this lesion is rare in children, with the first case described in 1979 (8) and the youngest case described in a 11-year-old boy in 2000 (9). furthermore, the exact biological behaviour of inverted papilloma of the urinary bladder remains uncertain. we report an additional case of a low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern in a 16 years old girl and emphasize the need for an intense and long-term follow-up of the pediatric population affected by bladder tumours (in its various histological types) to fully define its prognostic significance and potential biological behaviour in a near future. case report we report the case of a non-smoking 16 years old girl without a clinically significant pathologic anamnesis who referred to another urology department for a double episode of asymptomatic macrohematuria in two months spontaneously resolved. the patient underwent an ultrasound scan of urinary bladder showing an endovescical papillary lesion of 15 mm located on the left side of bladder without associated ureterohydronephrosis. cystoscopy demonstrated a 15 mm papillary lesion of the left bladder wall far from omolateral ureteral orifice; the lesion was connected to the bladder wall by a thin stalk. el rahman cr_stesura seveso 08/10/14 12:17 pagina 222 223archivio italiano di urologia e andrologia 2014; 86, 3 bladder tumours in children: an interesting case report of tcc with a partial inverted growth pattern the patient underwent a transurethral resection of the bladder (turb) and a 13 grams resection of newly formed tissue was performed. the hystopathologic examination performed by an expert urological pathologist revealed a “low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern in absence of subepithelial connective tissue infiltration”. after turb the patient underwent a contrast enhanced computed tomography (tc) that showed a normal high urinary tract. urologists gave indication for a “single shot” 40 ml mytomicin c instillation, but the patient refused the treatment. two months later the patient contacted our department and, considering the rarity of the case and the extension of the neoplasm, we gave the indication of a “2nd look” turb that was performed after a few days. preoperative cystoscopy showed the area of previous resection interested by edema and partially covered by fibrin; there were not instead secure signs of persistent disease. we performed a deep resection of the described area and a separate collection of resection margins (medial, lateral, anterior and posterior). the biopsied areas were sent to the same expert pathologist who had done the previous diagnosis that revealed the absence of any suspicious area for recurrence. the patient is now followed with cistoscopy and urinary citology every 3 months. conclusions younger patients with bladder cancer appear to have a more favourable prognosis, because they usually present with superficial stage and low-grade tumours. however, the risk of disease progression is the same, influenced by grade and stage at the time of presentation. patients younger than 40 years old diagnosed with bladder cancer should be offered the same stage and grade appropriate management as older ones. a diagnosis of bladder cancer should be considered in all patients with haematuria and bladder irritative symptoms, regardless of age. references 1. zhang zl, xiong yh, li yh, et al. reassessment of the predictive role of perivesical fat invasion in invasive bladder cancer prognosis in 151 chinese patients. chin med j. 2011; 124:2915-2919. 2. javadpour n, mostofi fk. primary epithelial tumors of the bladder in the first two decades of life. j urol. 1969; 101:706-710. 3. johnson de, hillis s. carcinoma of the bladder in patients less than 40 years old. j urol. 1978; 120:172-3. 4. witjes ja, debruyne fm. bladder carcinoma in patients less than 40 years of age. urol int. 1989; 44:81-3. 5. paschkis r. uber adenoma der harnblase. z urol chir. 1927; 21:315-325. 6. potts if, hirst e. inverted papilloma of the bladder. j urol. 1963; 90:175-179. 7. kim yh, reiner l. brunnian adenoma (inverted papilloma) of the urinary bladder: report of a case. hum pathol. 1978; 9:229. 8. lorentzen m, rohr n. urinary bladder tumours in children. scand j urol nephrol. 1979; 13:323-327. 9. isaac j, lowicik a, et al. inverted papilloma of the urinary bladder in children: case report and review of prognostic significance and biological potential behavior j pediatr surg. 35:1514-1516. correspondence davide abed el rahman, md (corresponding author) davide.adel@libero.it u.o.c. di urologia azienda ospedaliera “g. salvini” presidio di rho, viale europa, 250 rho (mi) giuseppe salvo, md dipartimento universitario materno-infantile di andrologia ed urologia, università degli studi di palermo, palermo, italy carlotta palumbo, md bernardo rocco, md francesco rocco, md istituto di urologia fondazione irccs ospedale maggiore policlinico “ca granda”, università degli studi di milano via delle forze armate, 260 20152 milan, italy el rahman cr_stesura seveso 08/10/14 12:17 pagina 223 stesura seveso 229archivio italiano di urologia e andrologia 2014; 86, 3 case report a rare cause of renal colic pain: chilaiditi syndrome murat tuncer, cahit sahin, ozgur yazici, alper kafkaslı, kemal sarica dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey. chilaiditi syndrome, first described in 1910 by the radiologist chilaiditi from vienna, is the interposition of right colon between liver and right hemi diaphragm. it occurs most often in males and its incidence increases with age. it is often detected incidentally during radiological examination. it’s rarely symptomatic; symptoms can differ from mild abdominal pain to severe acute intestinal obstruction. our case applied to emergency service with right flank pain. there was no calculus or dilatation in the urinary system at non-contrast abdominopelvic computerized tomography. ascending colon was interposed between liver and diaphragm so that the patient was diagnosed as chiliaditi syndrome. the patient was treated conservatively and discharged with dietary suggestions by the gastroenterology consultant. the conclusion of this report is that the chilaiditi syndrome must be considered in differential diagnosis for patients presenting with urinary colic pain symptoms with no urinary pathology on radiologic imaging. key words: chilaiditi syndrome; renal colic; hepatodiaphragmatic interposition. submitted 3 february 2014; accepted 30 june 2014 summary case report we present a patient with chilaiditi syndrome referred to emergency department for severe right renal colic pain, who was diagnosed with the help of radiological examinations and treated conservatively. case report details in supplementary materials posted on www.aiua.it discussion as in the majority of the cases of asymptomatic anatomical abnormalities, chilaiditi’s sign is a characteristic radiological finding of hepatodiaphragmatic interposition of bowel segment. as chiladiti syndrome has no specific clinical finding(s) which will let the clinician to consider the pathology at once and make the diagnosis, this pathology is usually incidentally diagnosed during a routine chest and/or abdominal plain film (4) whereas ct and/or ultrasonography examination have been reported to be necessary for the differential diagnosis. although no conflict of interest declared. the majority of the cases are clinically symptom free, in case of associated symptoms (abdominal pain, nausea, vomiting, distension, anorexia, constipation, respiratory distress and chest pain (2, 6, 7) it is called chilaiditi syndrome (8). the pathology is extremely rare and up to now approximately a total of 160 cases have been reported in the literature (9). in our present case radiological images were not obtained during an asymptomatic period but ct evaluation done during symptomatic period confirmed the diagnosis. hepatodiaphragmatic interposition of right colon is the most common radiological sign of chiliaditi syndrome. although an anterior interposition is the most common radiologic finding; posterior interposition is also possible in a certain percent of the cases (7). on the other hand, ileal or gastric form of interpositions have also been described in the literature (7). this condition may be permanent or temporary (10). although the precise underlying causes of this pathologic interposition are still to be clarified, some liver (small or ptotic liver, cirrhosis, abnormal or deficient falciform ligament), diaphragm (diaphragmatic muscle degeneration, phrenic nerve palsy, and intrathoracic pressure increase due to tuberculosis or emphysema) and lastly colon related factors (abnormal dilatation of colon, abnormal or deficient suspensory ligament and congenital malposition or malrotation of colon, chronic constipation, aerophagia) could be responsible for this anatomical abnormal location of the colon (2, 11). the differential diagnoses of chilaiditi syndrome can also include bowel obstruction, volvulus, intussusception, ischemic bowel, or inflammatory conditions (eg, appendicitis or diverticulitis) and diaphragmatic hernia (2) pneumoperitoneum and subphrenic abcesses (12). in our case, at physical examination, lung auscultation was normal and there was no rebound or defence during abdominal palpation. furthermore there were no signs of infection like fever and leucocytosis. in the light of the present clinical signs, symptoms and laboratory findings along with the normal anatomy of the gallbladder on ct (which may cause right upper quadrant abdominal pain), and absence of other characteristic radiologic signs which may be attributed to other well known pathologies (volvulus, intussusception, ischemic bowel or inflammatory conditions such as appendicitis or diverticulitis, etc.) and should be considered in differential diagnosis we took in consideration this syndrome. colonic doi: 10.4081/aiua.2014.3.229 tuncer cr_stesura seveso 08/10/14 12:19 pagina 229 archivio italiano di urologia e andrologia 2014; 86, 3 m.tuncer, c. sahin, o. yazici, a. kafkaslı, k. sarica 230 interposition between liver and diaphragm and the presence of aforementioned symptoms, made us to diagnose the case as a chilaiditi syndrome. this syndrome is generally asymptomatic however patients can refer with symptoms of abdominal pain, nausea, vomiting, distension, anorexia, constipation, respiratory distress, cardiac arrhythmia (12). occasionally, it may be associated with some severe complications such as internal hernias, colonic volvulus and acute intestinal obstruction (7). treatment of chilaiditi syndrome is generally conservative. this approach requires bed rest, nasogastric and/or rectal decompression, high fiber diet, fluid supplementation and stool softeners in symptomatic cases (7). although conservative management is successful to relieve the existing symptoms in the majority of the cases, surgical treatment (such as subtotal colectomy, peritoneal fixation of colon, and hepatopexy) may be necessary in cases with persistent pain, refractory ileus, colonic volvulus or bowel ischemia (10, 13). conservative management was successful in our case and the clinical course was uneventful without any serious complication. chilaiditi syndrome generally presents with gastrointestinal, respiratory and cardiac symptoms. however, patients can rarely refer with symptoms mimicking renal colic pain as shown in our present case. to our knowledge there is only one case with this syndrome reported in the literature referring with renal colic symptoms (14) although another case has been reported to have urological problems such as complaints of prostatism and right renal stone (15). references 1. chilaiditi d. on the question of the hepatoptosis ptosis and generally in the exclusion of three cases of temporary partial liver displacement. progr field roentgenst. 1910; 11:173-208. 2. moaven o, hodin ra. chilaiditi syndrome: a rare entity with important differential diagnoses. gastroenterol hepatol. 2012; 4: 276-8. 3. mcnamara rf, cusack s, hallihan p. chilaiditi’s syndrome. west j emerg med. 2009; 10:250. 4. chen sy, liu ct, tsai yc, et al. sigmoid volvulus associated chilaiditi’s syndrome. rev esp enferm dig. 2007; 99:482-3. 5. dogu f, reisli i, ikinciogullari a, et al. unusual cause of respiratory distress: chilaiditi syndrome. pediatrics international. 2004; 46:188-190. 6. angulo cuesta j, gonzález zorraquino a, unda urzaiz m, flores corral n. chilaiditi syndrome in the differential diagnosis of renal colic. arch esp urol. 1991; 44:300-1. 7. qubenaıssa a, perrault lp, ridoux g, et al. hepatodiaphragmatic interposition of the colon: an unusual case of combined anterior and posterior types treated with an original operative technique. dis colon rectum. 1999; 42:278-80. 8. sorrentino d, bazzocchi m, badano l, et al. heart-touching chilaiditi’s syndrome. world j gastroenterol. 2005; 11:4607-9. 9. yagnik vd. chilaiditi syndrome with carcinoma rectum. saudi j gastroenterol. 2011; 17:85-6. 10. haddad cj, lacle j. chilaiditi’s syndrome: a diagnostic challange. postgrad med. 1991; 89:249-52. 11. white jj, chavez ep, macon sj. internal hernia of the transverse colon chilaiditi syndrome in a child. j pediatr surg. 2002; 37:802-4. 12. dogu f, reisli i, ikinciogullari a, et al. unusual cause of respiratory distress: chilaiditi syndrome. pediatr int. 2004; 46:188-90. 13. hsu hl, liu kl. hepatodiphragmatic interposition of the colon.cmaj. 2011; 183:132. 14. alva s, shetty-alva n, longo we. image of the month. chilaiditi sign or syndrome.arch surg 2008; 143:93-4. 15. özer c, zenger s. chilaiditi syndrome in a patient with urological problems: incidental diagnosis on computed tomography. can urol assoc j. 2012; 6:75-6. interposition of colon between diaphragm and liver: the chilaiditi sign. correspondence murat tuncer, md (corresponding author) murattuncer77@hotmail.com. cahit sahin, md cahitsahin129@hotmail.com ozgur yazici, md md.ozguryazici@yahoo.com.tr alper kafkaslı, md alpkafkasli@hotmail.com kemal sarıca, md professor saricakemal@gmail.com altunizade mah.atif bey sok.gokdeniz sitesi e blok d:20 kosuyolu, istanbul, turkey tuncer cr_stesura seveso 08/10/14 12:19 pagina 230 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 162 case report spontaneous recurrent hematuria and hematospermia: unique manifestations of von willebrand disease type i. case report daniele minardi 1, anna rita scortechini 2, giulio milanese 1, pietro leoni 2, giovanni muzzonigro 1 1 department of clinic and specialistic sciences, urology; 2 department of clinic and molecular sciences, institue of hematology, polytechnic university of the marche region, a.o. ospedali riuniti, ancona, italy. in this report we describe the case of a patient with unrecognized von willebrand disease (vwd), in whom the only presenting symptoms were spontaneous and recurrent hematuria with bladder tamponade, associated with recurrent hematospermia. the diagnosis was made only after several admissions to the hospital. we suggest to include coagulopathies such as vwd as part of the evaluation in patients with unexplained genito-urinary bleeding. key words: von willebrand disease; hematuria; hematospermia. submitted 8 march 2015; accepted 21 may 2015 summary no conflict of interest declared. , the most common form, accounting for up to 80% of reported cases, and is generally transmitted as an autosomal dominant disorder. mucocutaneous bleeding is the most common symptom in these patients, and typically presents as epistaxis, easy bruising, menorrhagia, gingival bleeding and post-traumatic or postsurgical bleeding (4). to date very few cases of spontaneous hematuria and hematospermia have been reported (5, 6); they were secondary to trauma such as self-instrumentation, catheterization, falls or straddle injuries. in this report we describe a patient with unrecognized vwd, in whom the only presenting symptoms were spontaneous and persistent hematuria and hematospermia. case report a 34 years old male patient, with chronic adrenal failure under substitutive therapy, came to our observation because of spontaneous and persistent hematuria and hematospermia, recurring since a few years; the hematuria was so important that in few occasions he underwent to acute urinary retention and bladder tamponade. he was already been evaluated in other urologic units, where investigations were performed; he had renal, bladder, and prostatic ultrasound, abdominal ct scan and cystoscopy, that showed normal morphology and function of the urinary tract; urine and semen colture did not show any infection. in the family history, no hemorrhagic disease was present. he was admitted from emergency to our department of urology for further investigations and treatment, after another episode of hematuria with bladder tamponade and acute urinary retention. we performed routine blood exams, that were normal, and a urethrocystoscopy, that did not show any abnormality; renal and bladder ultrasound was normal, while prostatic ultrasound showed only a slight periurethral congestion and oedema, with symmetric seminal vesicles. an hematologic consultation was then requested; coagulation parameters pt, ptt, fibrinogen and platelet count were normal, as well as the platelet agglutination test with ristocetin; in the suspicion of an hematologic disorder further investigations were performed; it was posdoi: 10.4081/aiua.2016.1.62 introduction von willebrand disease is the most common congenital bleeding disorder in the usa; population-based prevalence studies suggest that the disorder affects more than 1% of individuals screened, with little difference among racial and ethnic groups (1). a prolonged bleeding time with a normal platelet count is the most important laboratory abnormality. while in 1926 von willebrand described a novel bleeding disorder, only in the 1950s it was demonstrated that the prolonged bleeding time is associated with reduced factor viii, and in the 1970s it was clarified that the deficiency of a new factor, called von willebrand factor and different from factor viii, was actually responsible for the disease. the disorders arises from qualitative (type 2 vwd) or quantitative (type 1 and 3 vwd) aberrations in the production or clearance of von willebrand factor (vwf)(3). this large multimeric glycoprotein is synthetized by endothelial cells and megakariocytes, and serves as a promoter of platelet aggregation and a carrier of coagulation factor viii:c. it is an extremely heterogeneous disorders with up to 20 distinct subtypes reported (2). vwf is essential for platelet-subendothelium adhesion and platelet-toplatelet interactions as well as platelet aggregation in vessels; vwf is the specific carrier of factor viii in plasma, in this way protecting it from proteolytic degradation, prolonging its half-life in circulation and efficiently localizing it at the site of vascular injury. type i vwd is minardi2_stesura seveso 05/04/16 16:37 pagina 62 63archivio italiano di urologia e andrologia 2016; 88, 1 spontaneous recurrent hematuria and hematospermia: unique manifestations of von w, italyillebrand disease type i. case report sible to detect a deficit of von willebrand factor (33%, with normal values being in between 70 and 150 u/dl) and of the ristocetinic factor (31% with normal values being in between 58 and 166 u/dl), while the factor viii resulted normal (86% with normal values being in between 70 and 200 u/dl). the diagnosis was confirmed by the desmopressin test; the positive response to it gave evidence of type i von willebrand disease. discussion von willebrand disease is a diagnostic entity recognized for at least 80 years, and considered the most common inherited disorder. mutations at the vwf locus on chromosome 12 leads to vwd (2, 7). although generally considered to be inherited as an autosomal dominant trait, vwd inheritance may be more complex, including compound heterozygosity, which may contribute to phenotypic variability seen in the disease (1). further, extragenic factors including abo blood groups (8), adrenergic states (9), hormones (10) and inflammatory states (11) may cause fluctuation in vwf levels and mask a vwd diagnosis. spontaneous genitourinary bleeding is very rare in the general population, and we did not find in the literature a description of cases of bladder tamponade as a presenting symptom of vwd. when spontaneous bleeding occurs, it is mild and in most cases the symptoms resolve spontaneously without the need of invasive treatment. we decided to publish this unusual case report of a patient presenting with recurrent gross hematuria and bladder tamponade; we want to draw attention to the presence of hematologic disorders in cases of unexplained recurrent genito-urinary bleeding; we stress the importance of including the evaluation for existing coagulopathies, such as vwd, in such cases. references 1. ziv o, ragni mv. bleeding manifestations in males with von willebrand disease. haemophilia. 2004; 10:162. 2. nichols wc, ginsburg d. willebrand disease. medicine 1993; 76:893. 3. rodeghiero f, castaman g. congenital von willebrand disease type i: definition, phenotypes, clinical and laboratory assessment. best pract res clin haematol. 2001; 14:321. 4. armenian s, raffel jl, nugent dj, young g. painless urethral bleeding: an unusual presentation of von willebrand disease. haemophilia. 2003; 9:332. 5. benton o, lazarchick j, orak jk, turner wr. use of a bleeding time determination in the evaluation of unexplained hematuria. j urol. 1987; 137:527. 6. lemesh ra. case report: recurrent hematuria and hematospermia due to prostatic teleangiectasia in classic von willebrand disease. am j med sci. 1993; 306:35. 7. ginsburg d, handin ri, bonthron dt, et al. human von willebrand factor (vwf): isolation of complementary dna (cdna) clones and chromosomal localization. science 1985; 228: 1401. 8. gill jc, endres-brooks j, bauer pj, et al. the effect of abo blood group on the diagnosis of von willebrand disease. blood. 1987; 69:1691. 9. rickles fr, hoyer lw, rick me, ahr dj. the effects of epinephrine infusion in patients with von willebrand disease. j clin invest. 1976; 57:1618. 10. liu l, wang x, lin z, wu h. elevated plasma levels of vwf:ag in hyperthyroidism ar mediated through adrenergic receptors. endocr res. 1993; 19:123. 11. bloom al. the biosynthesis of factor viii. clin haematol. 1979; 8:53. correspondence daniele minardi, md d.minardi@gostec.net giulio milanese, md giovanni muzzonigro, md department of clinic and specialistic sciences, urologic clinic polytechnic university of the marche region, a.o. ospedali riuniti via conca 71 60020 ancona, italy anna rita scortechini, md pietro leoni, md department of clinic and molecular sciences, institute of hematology polytechnic university of the marche region, a.o. ospedali riuniti via conca 71 60020 ancona, italy minardi2_stesura seveso 05/04/16 16:37 pagina 63 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3254 case report treatment of urethral strictures with balloon dilation: a forgotten tale konstantinos stamatiou 1, georgios christopoulos 1, hippocrates moschouris 2, dimitrios zavradinos 1, michalis kiltenis 2, athanasios marinis 1 1 urology dpt, general hospital "tzanio", piraeus, greece; 2 radiology & interventional radiology dpt, general hospital "tzanio", piraeus, greece. urethral stricture is a common condition that can lead to serious complications such as urinary infections and renal insufficiency secondary to urinary retention. treatment options include catheterization and dilation, urethroplasty and endoscopic internal urethrotomy as well. although treatment option depends on the type, length and aetiology of stricture, the choice can be influenced to varying degrees by the simplicity of the method, the preferences of the patient the available accoutrements and the patient health condition. both urethroplasty and endoscopic internal urethrotomy require anaesthesia and thus are not suitable for many elder and unfit for surgical treatment patients. on the other hand, dilations are easy to perform in every day clinical practice however they have been associated with iatrogenic urethral trauma. in contrast, balloon dilation under vision dilates by radial application of forces against the stricture, avoiding the potentially shearing forces associated with sequential rigid dilation. since it reduces the possibility of an iatrogenic urethral trauma and the subsequent spongiofibrosis may lead into improved therapeutic outcomes. in this report we describe a technique for the treatment of urethral strictures with balloon dilation in elder and unfit for surgical treatment patients. key words: urethral stricture; balloon dilation. submitted 14 march 2015; accepted 30 april 2015 summary no conflict of interest declared. the patient the available accoutrements and health conditions that can affect the decision and the outcome of surgery as well (2, 3). given that even minor procedures come with major risks, balloon dilation offers several theoretical advantages over dilatation. in fact, balloon dilatation is less traumatic due to its effective radial force during stricture dilatation, thus reduces extravasations and thus subsequent spongiofibrosis. 4 less urethral trauma may also make the procedure less painful, cause less bleeding, and be better tolerated under local anesthesia. case report/description of technique case 1 a 38-year old male patient, with history of polytrauma and long term hospitalisation in intensive care unit was presented with acute urinary retention and a mild disability in urination for the last six months. he reported decreased range of urination, nocturia up to 3 times and stranguria. since urethral catheterization was impossible, a suprapubic catheter was placed and residual urine of 500 cc was found. upon investigation a severe (> 3 cm), tortuous stricture of the penile urethra was detected in descending cystourethrogram (figure 1a). his laboratory exams were all normal except a mild neutrophilic leucocytosis. due to obvious malformations of the airway and column spine he wasn’t able to receive neither general anaesthesia nor spinal-epidural analgesia and he was treated with urethral balloon dilatation. via suprapubic cystostomy, the urinary bladder was filled with 300 ml of diluted iodinated contrast (contrast/normal saline: 1/3). a 0035” j-tip standard angiographic guide-wire was inserted into the urinary bladder through the suprapubic catheter. the latter was removed and exchanged with a short (11 cm), 5-french angiographic sheath. the angiographic guide-wire was subsequently withdrawn and an angiographic catheter loaded with a hydrophilic, j-tip guide-wire was inserted into the bladder. under fluoroscopy the catheter-guide-wire combination was guided towards the urethral orifice and subsequently into the urethra. the hydrophilic guidewire was finally advanced through the penile urethral orifice (figure 2a). the angiographic catheter was subsequently advanced through the stenosis, over the guidewire. assisted by the guide-wire, an angiographic stent with a dilation balloon (compliant balloon 14 atmdoi: 10.4081/aiua.2015.3.254 introduction urethral stricture causes a blocked or reduced flow of urine which can result in a range of manifestations, from an asymptomatic presentation to severe discomfort. moreover, it can lead to serious complications such as urinary infections and renal insufficiency secondary to urinary retention. the larger proportion is iatrogenic (secondary to instrumentation). of the remaining, blunt perineal trauma, chronic inflammatory disorders (such as lichen sclerosus et atrophicus) and sexually transmitted diseases are the most frequent causes of strictures (1). treatment of urethral strictures is often difficult because this condition is characterised by high recurrence rates and an important number of interventions are associated with poor outcomes. currently, three different interventions are used to treat urethral strictures: dilations, optical internal urethrotomy and open urethroplasty.1 although treatment option depends on the type, length and aetiology of stricture, the choice can be influenced to varying degrees by the simplicity of the method, the preferences of stamatiou_stesura seveso 23/09/15 13:28 pagina 254 255archivio italiano di urologia e andrologia 2015; 87, 3 treatment of urethral strictures with balloon dilation: a forgotten tale ing cystourethrogram, a short segment stricture (1 cm) of the penile urethra was detected (figure 1c). his laboratory exams were all normal. due to severe chronic heart failure, anaesthesia was denied to this patient and urethral balloon dilatation was finally decided. via suprapubic cystostomy, the urinary bladder was filled with 300 ml of diluted iodinated contrast (contrast/normal saline: 1/3). a 0035” j-tip standard angiographic guide-wire was inserted into the urinary bladder through the structured urethra. the guide wire was gently advanced through the stricture. the balloon dilating catheter was then advanced over the guide wire, and the balloon was guided to the area of narrowing under direct vision. then, the balloon was slowly inflated till 180 psi for 5 minutes under fluoroscopy till waist disappeared. when the balloon is subsequently deflated, the dilating catheter and guidewire were removed. the patient voided well immediately after treatment and he did not required auxiliary procedures at 6 months. conclusions in conclusion, balloon dilatation of the urethra is minimally invasive and effective therapeutic option for patients with short segment non-traumatic urethral stricture. regarding treatment of strictures > 2 cm, short-term success is also possible encouraging thus the management of elder and unfit for surgical treatment patients with strictures of such size. the fact that the procedure is performed under direct vision makes this technique to offer considerably improved safety compared to blind dilation methods. discussion and supplementary references are posted in supplementary materials on www.aiua.it references 1 tritschler s, roosen a, füllhase c, et al. urethral stricture: etiology, investigation and treatments. dtsch arztebl int. 2013; 110:220-6. 2 wani bn, jajoo sn, bhole am. outcome of urethral strictures managed by general surgeons in a rural setting of india. indian j surg. 2011; 73:336-40. 3 wong ss, aboumarzouk om, narahari r, et al. simple urethral dilatation, endoscopic urethrotomy, and urethroplasty for urethral stricture disease in adult men. cochrane database syst rev. 2012; 12:cd006934. 4. steenkamp jw, heyns cf, de kock ml. internal urethrotomy versus dilation as treatment for male urethral strictures: a prospective, randomized comparison. j urol 1997; 157:98-101. figure 1a,b,c. cystourethrograms showing stenosis of the penile urethra. figure 2. a. the angiographic catheter is advanced through the stenosis, over the guide-wire. b. a progressive dilation of 1‐2 min duration is performed. correspondence konstantinos stamatiou, md (corresponding author) georgios christopoulos, md drchristog@gmail.com dimitrios zavradinos, md athanasios marinis, md general hospital "tzaneio", zanni & afentouli 1 str, 18536, piraeus, greece hippocrates moschouris michalis kiltenis, md radiology & interventional radiology dpt, general hospital "tzanio", piraeus, greece 4.3mm) was advanced to the strictured part of the urethra. a progressive dilation of 1-2 min duration was performed followed by instillation of normal saline solution under pressure (figure 2b). an appropriately sized foley catheter was inserted through the repair into the urinary bladder. hospitalization lasted 2 days and the patient kept the catheter a few days. the patient was followed up at 1, 3, 6 and 12 months and was asymptomatic. case 2 a 87-year old male patient with history of focal prostate cancer treated with radiotherapy ten years before his admission was presented with symptoms of the lower urinary tract suggestive of bladder outlet obstruction. urinary flowmetry test revealed weak urinary stream and prolonged urination. urethro-cystoscopy showed a constriction ring caused by urethral stenosis and a compact (2 cm), stricture of the penile urethra was detected in ascending cystourethrogram (figure 1b). due to chronic airflow obstruction and destruction of parenchymal tissues, as a result of chronic inflammation he was treated with urethral balloon dilatation. the procedure started with an "on table" urethrogram to assess the precise site of stricture. a 0.038” hydrophilic guide wire was passed across the stricture. the hydrophilic property allowed the wire to negotiate the narrow portion. balloon dilatation of the stricture was done under fluoroscopic guidance. the disappearance of waisting indicated adequate dilatation. duration of the dilatation was 5 minutes. a 16 fr foley's catheter was inserted. postoperatively, qmax increased from 5.5 to 15.3 and pvr decreased from 120 to 70 cc. at 1, 3, and at 6 monthly follow-up, the patient was asymptomatic. case 3 a 56-year old male patient with history of recrudescent urethral stenosis and multiple direct visual internal urethrotomies was presented to our department with acute urinary retention. passage of a urethral catheter was impossible and a suprapubic catheter was placed. upon descendstamatiou_stesura seveso 23/09/15 13:28 pagina 255 stesura seveso 327archivio italiano di urologia e andrologia 2015; 87, 4 case report intraoperative presentation of bochdalek’s hernia in an adult during robotic-assisted partial nephrectomy: an uncommon situation and literature review luca cindolo 1, francesco berardinelli 1, arianna manzi 2, francesca spagnuolo 2, elisa fabbri 2, pietro castellan 1, flavia petrini 2, luigi schips 1 1 urology dept, robotic unit, asl abruzzo 2, italy; 2 uoc anestesia rianimazione e terapia intensiva, asl abruzzo 2, italy. bochdalek's diaphragmatic hernia (bdh) is a congenital defect of the diaphragm that usually present during the neonatal period and rarely remain silent until adulthood. we present a 45-year-old-female case with diagnosis of double left kidney tumor prepared for robot-assisted partial nephrectomy (rpn). during the preoperative procedure she had a reduction of inspiratory volumes and increased pulmonary pressures: the robotic camera revealed the incidental presence of the left diaphragmatic defect. we report a simultaneous nephron sparing surgery (nss) and left posterolateral bdh correction done by the da vinci surgical robot (intuitive surgical, sunnyvale, ca). key words: bochdalek’s hernia; diaphragmatic defect; renal tumor; partial nephrectomy; da vinci robot. submitted 30 june; accepted 30 september summary no conflict of interest declared. left posterolateral bdh in adult done by the da vinci surgical robot (intuitive surgical, sunnyvale, ca). case report a 45-year-old female was admitted in our clinic after an episode of acute flank pain and the ct scan revealed a double left renal masses. she refused a preliminary renal biopsy and opted for a robot-assisted partial nephrectomy (rpn). in her medical history there was absence of abdominal or thoracic trauma or previous surgery. during physical examination we inspected no respiratory symptoms and normal abdomen. the preoperative chest x-ray, the computed tomography (ct) (figure 1) and the magnetic resonance imaging (mri) (figure2) were negative for secondary malignancy or for diaphragmatic hernia. her hematological investigations were normal. during the initial preoperative workout of a rpn, she undergone general anesthesia, placed in flank position and pneumoperitoneum was established up to 12mmhg co2, nevertheless there was an immediate reduction of inspiratory volumes and an increased pulmonary pressures. haemodynamic parameters were steadily stable as well as peripheral arterial saturation. after checking the correct placement of the tube and evaluating the depth of anesthesia, the robotic camera revealed the presence of the left posterolateral bdh: the diaphragmatic defect was measured about 5 cm (figure 3). the chest was retracted and visible; the pleura and the peritoneum were “in continuum”, without herniation of organs. no hernia sac was found. after a consultation with thoracic surgeon, the urologist decided to continue the procedure by a pure robot-assisted approach. the hernia was repaired with interrupted nonabsorbable sutures with mersilene stitches and a single drainage was left in the thoracic cavity to avoid a pneumothorax (figure 4). then the planned rpn was done. the operative time was 170 min, the blood loss was 110 ml. the patient had an uncomplicated postoperative recovery; in the first post operative day (pod) the drain was clamped and removed in second pod. the pod 3 chest doi: 10.4081/aiua.2015.4.327 introduction congenital diaphragmatic hernia (cdh) is a developmental anomaly characterized by a failure to form a continuous sheet in order to separate the abdominal and thoracic cavities during the embryogenesis. bochdalek’s hernias (bdh) are the posterolateral hernias and they are the most frequent (80%) with a prevalence of left side (85%) among right side (13%) or bilateral (2%) (1). as a result, bdh represents a perinatal pathology associated with significant morbidity and mortality: infants are affected by a severe pulmonary hypoplasia and pulmonary hypertension. bdh in adult is a rarely clinical entity and it remains silent until the adulthood, usually discovered incidentally, without specific symptoms or signs (2). once diagnosed, the surgical repair is the recommended therapy and the use of laparoscopy and thoracoscopy are safe surgical approaches with low morbidity and shorter hospital stay. even more, with the evolution of surgical technology, new approaches for repairing these defects can be developed. we present the first report of abdominal robotic repair of archivio italiano di urologia e andrologia 2015; 87, 4 l. cindolo, f. berardinelli, a. manzi, f. spagnuolo, e. fabbri, p. castellan, f. petrini, l. schips 328 clear cytoplasm, absence of necrosis or atypia, low proliferative index mib-1, and negative surgical margins. the immunophenotype was: positive for aml on the epithelioid and vascular components; positive for hmb-45; focal positive for cd117; positive for melan-a; positive for < 1% ki67; negative for amacr and ck7. the clinical and radiological findings at 3-month follow-up were negative. discussion according to reported literature, vincent alexander bochdalek first described this hernia in 1848. the exactly etiology is still under study, but however the disease is due to the failure of closure of the canal between the septum transversum and the esophagus during the 8th week of gestation (1). bdh are the posterolateral hernias and they are the most frequent (80%) with a prevalence of left side (85%) among right side (13%) or bilateral (2%) (2). in 2557% of cases bhd are associated with other congenital anomalies and in 10-20% whit chromosomal disorders (3). as a result, bdh represents a perinatal pathology associated with significant morbidity and mortality: infants are affected by a severe pulmonary hypoplasia and pulmonary hypertension. bdh in adult is a rarely clinical entity and it remains silent until the adulthood, usually discovered incidentally, without specific symptoms or signs (4). in a retrospective review of 13.138 ct scans, mullins et al. found 22 patients with incidental, asymptomatic bdh, which represents an incidence of 0.17%, with a female-male ratio of 17:5 (77% woman) (5). in adults, the bdh diagnosis is difficult because of its rarity; moreover, the variety of symptoms and its asymptomatic presentation may be easily confused whit other diseases. the majority of patients present generic chronic gastrointestinal symptoms and/or respiratory symptoms related to dyspnea or breathlessness: presence of bowel sounds within the chest and the absence of breath sounds are typical findings (6). contrariwise acute presentation of bdh include severe cardiorespiratory distress with cyanosis, tachypnea, tachycardia, abdominal pain and it’s represent an emergency for the potential life threatening complications. the correct diagnosis is usually discovered as an incidental finding and the radiologic evaluation is required just to confirm. frontal and lateral x-ray chest are the common exams performed to assess the presence of any herniations or abnormality. if the radiography is indeterminate, ct-scan and mri offer a better visualization of the defect and help clinicians in the differential diagnosis. the management of bdh consist in the surgical reduction of the herniations in the abdominal cavity and the repair of the diaphragm defect as soon as possible. traditionally, it can be performed via laparotomy and/or thoracotomy, it depends from the scenario. recently, in order to inflicts minimal surgical trauma, thoracoscopic and laparoscopic repair of bdh have also been reported, with excellent results. figure 1. ct scan showed the left kidney tumor and the absence of any visceral herniations or collapsed lung. figure 2. rmi confirmed the diagnosis and showed no presence of the bdh. figure 3. intraoperative photo of the left diaphragmatic defect. figure 4. intraoperative photo showing the bochdalek diaphragmatic hernia repaired from the abdomen. x-ray showed a fully expanded left lung with no evidence of any herniated bowel loops in the thoracic cavity. the discharge occurred in pod 4 in good general clinical conditions. the histopathology revealed a double angiomyolipoma on the left kidney (4,1 x 3,5 cm and 3,3 x 2,6 cm) with focal areas of epithelioid cells with large transthoracic approach allows to examine the thoracic cavity and herniated organs in detail; to avoid ischemic change, necrosis and perforation, even in the case of bilateral hernia; to separate adhesions between the contents with a good control of bleeding; to confirm the presence of lung hypoplasia and to easily reduce the hernia sac, if present (7). at the opposite, transabdominal approach is preferred for the management of the possible complications (strangulation, malrotation, perforation, peritonitis), which are documented in many bdh, and it allows to examine the entire abdominal cavity, and easily repair the defect (8). in addition, several surgeons prefer to reinforce the suture whit some type of mesh. a recent literature search, showed only two reports of “robotic repair of bdh”. meehan described a case report of a newborn of 37 weeks and bethany presented a series of 8 consecutive newborns with diaphragmatic anomalies who underwent robotic repair (9, 10). we present the first report of patient underwent a pure robotic approach using the abdominal route and we noted that the articulating instruments offered an easy access to the posterolateral region. moreover, referred to newborns size, we didn’t have space problems and we could use the entire range of motion. we were able to close it primarily without any mesh, because there was sufficient diaphragmatic tissue to approximate. conclusions in adulthood, symptomatic bochdalek hernia is extremely rare and correct diagnosis and early treatment is significant to avoid the occurrence of morbidity and a higher complication rate. the application of robotic techniques to repair bochdalek hernia is an excellent option because it’s feasible, reduces the morbidity of surgery, allows a short hospitalization and may result in significant clinical improvement. consent written informed consent was obtained from the patient for publication of this case report and any accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal. references 1. brown sr, horton jd, trivette e, et al. bochdalek hernia in the adult: demographics, presentation, and surgical management. hernia 2011; 15:23-30. 2. greer, jj. current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. respir physiol neurobiol. 2013; 189:232-40. 3. zhou y, du h, che g. giant congenital diaphragmatic hernia in an adult. j cardiothorac surg. 2014; 9:31. 4. kesieme eb, kesieme cm. congenital diaphragmatic hernia: review of current concept in surgical management. isrn surgery. 2011; 2011:974041. 5. mullins, me, jeffrey s, sanjay ss, mueller pr. prevalence of incidental bochdalek’s hernia in a large adult population. ajr am j roentgenol. 2001; 177:363-66. 6. hamid, ks, rai ss, rodriguez ja. symptomatic bochdalek hernia in an adult. jsls. 2010; 14:279-81. 7. tokumoto n, tanabe k, yamamoto h, et al. thoracoscopic-assisted repair of a bochdalek hernia in an adult: a case report. j med case rep. 2010; 4:366. 8. patle nm, tantia o, prasad p, et al. laparoscopic repair of right sided bochdalek hernia a case report. indian j surg. 2013; 75:303-4. 9. meehan jj, sandler a. robotic repair of a bochdalek congenital diaphragmatic hernia in a small neonate: robotic advantages and limitations. j pediatr surg. 2007; 42:1757-60. 10. slater bj, meehan jj. robotic repair of congenital diaphragmatic anomalies. j laparoendosc adv surg tech a. 2009; 19:s123-7. 329archivio italiano di urologia e andrologia 2015; 87, 4 intraoperative presentation of bochdalek’s hernia in an adult during robotic-assisted partial nephrectomy: an uncommon situation and literature review correspondence luca cindolo, md francesco berardinelli, md pietro castellan, md (corresponding author) castellanpietro@gmail.com luigi schips, md urology dept, via s. camillo de lellis 1 – 66054 vasto, italy arianna manzi, md francesca spagnuolo, md elisa fabbri, md flavia petrini, md uoc anestesia rianimazione e terapia intensiva, asl abruzzo 2, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3214 original paper sexual activity and the risk of prostate cancer: review article ahmed fouad kotb, ahmad beltagy, asmaa mohamed ismail, mohamed mohie hashad urology department, faculty of medicine, alexandria university, alexandria, egypt. introduction: sexual activity can affect prostate cancer pathogenesis in a variety of ways; including the proposed high androgen status, risk of sexually transmitted infections and the potential effect of retained carcinogens within the prostatic cells. methods: pubmed review of all publications concerning sexual activity and the risk of prostate cancer was done by two researchers. results: few publications could be detected and data were classified as a prostate cancer risk in association with either heterosexual or homosexual activities. conclusion: frequent ejaculation seems to be protective from the development of prostate cancer. multiple sexual partners may be protective from prostate cancer, excluding the risk of sexually transmitted infections. homosexual men are at a greater risk for the diagnosis of prostate cancer. key words: prostate cancer; ejaculation; homosexuality; heterosexuality. submitted 16 january 2015; accepted 31 march 2015 summary no conflict of interest declared. female sexual partner was observed during most age periods, and was associated with increased exposure to sexually transmitted diseases. a meta-analysis in 2002 confirmed the positive association between multiple female sexual partners, stds and the resulting higher risk of prostate cancer (rr 1.2) (5) fernández et al. (6) found that men who had sexual intercourse more than 7 times per week had a significant positive risk of having prostate cancer. included men were in the old age group, with only 7% of men younger than 55 years, and that was associated with the risk of having stds. giles et al. (7) studied 2.338 men and found no association of prostate cancer with the number of sexual partners and argued against infection as a cause of prostate cancer. they, however, could detect that men who averaged 5 or more ejaculations weekly in their 20s had a relative risk of 0.66 compared to those who ejaculated less frequently. spence et al. (8) reported a protective effect of having several female sexual partners over the lifetime. in their study, they found that those men having > 20 female sexual partners had a reduced risk of overall (or 0.72) and less aggressive pca (or 0.68) compared to men reporting having had only one female sexual partner over the lifetime. they explained this protective effect may be related to higher ejaculation frequency which is supposed to be pca protective. frequent ejaculation is thought to reduce the concentration of carcinogenic substances within prostatic fluid (3) or reduce production of intraluminal prostatic crystalloids (9). early on 1986, a study found that the average ejaculatory frequency in pca patients was significantly lower than in the control group and mentioned that reduced ejaculatory frequency appears to promote the pathogenesis of pca by retained prostatic secretions promoting dysplasia of the prostatic gland epithelium (10). age of the first intercourse was a factor that was also studied in the literatures. ahmadi et al. (11) found that early age of first marriage was significantly associated with a lower risk of prostate cancer. a study in 1993 detected that pca patients were significantly older at the time of their first marriage, compared with men who first married under the age of 25 years (12). doi: 10.4081/aiua.2015.3.214 sexual activity is hypothesized to affect prostate cancer (pca) pathogenesis through numerous etiologic pathways. one of the proposed mechanism associates increased sexual activity to higher androgenic activity that may be an indicator for a higher pca risk (1). another mechanism proposes that sexual activity increase exposure to sexually transmitted infectious diseases (stds), which have been hypothesized to play a role in pca development (2). a different hypothesis suggests that a reduced ejaculation frequency in otherwise normal men might be an etiologic risk factor for pca. such proposition is based on the theory that infrequent ejaculation causes carcinogenic secretions to be retained within the prostatic acini (3). heterosexuality and pca several studies were found concerning the heterosexual activity and prostate cancer risk. rosenblatt et al. (4) suggested that there is a direct positive correlation between the number of lifetime female sexual partners and the risk of prostate cancer in middle-aged men. the increased risk associated with having more than one kotb_stesura seveso 23/09/15 12:35 pagina 214 215archivio italiano di urologia e andrologia 2015; 87, 3 sexuality and prostate cancer in 2004, a large prospective study on 29.342 men by leitzmann et al. (13) concluded that higher ejaculation frequency was related to decreased risk of total and organ confined prostate cancer. the relative risk for men reporting 21 or more ejaculations per month across a lifetime was 0.67 (33% lower risk) compared to 0.89 for men reporting 4 to 7 ejaculations per month across a lifetime. chavez et al. (14) conducted a retrospective study on 4,974 men with erectile dysfunction (ed). they could find that men treated for ed with phosphodiesterase inhibitors (47.5%) had a significantly lower risk for prostate cancer than non-treated patients that could be attributed to more frequent ejaculations and retaining of sexual activities. homosexuality and pca sexual orientation and pca has received little attention in the literature. a published study in 2002 found no association between sexual orientation and pca. (4) potential mechanisms underlying a possible greater risk of pca among men having had several male partners or bisexuals are still unclear. homosexual men have been found to report more often a diagnosis of prostate cancer than heterosexual men (15). hiv is more in homosexual men and being immunosuppressed, making them more vulnerable to develop cancer (15). another potential mechanism attributes physical trauma to the prostate. receptive anal intercourse, significantly result in increased serum psa levels causing higher pca diagnosis rates (16). potentially, the physical pounding of the prostate gland itself may possibly lead to a greater risk of pca like previous studies have linked the receipt of physical trauma to with breast and testicular cancers. spence et al. (8) found that men who ever had 2-3 male sexual partners over their lifetime were at a significantly greater risk of less aggressive pca compared to men who never had male partners (or 3.01). conclusion frequent ejaculation seems to be a protective factor for the development of prostate cancer. homosexual men may be at a higher risk of being diagnosed with prostate cancer, during their lifetime, more than heterosexual men. references 1. krain ls. some epidemiologic variables in prostatic carcinoma in california. prev med. 1974; 3:1549. 2. taylor ml, mainous ag 3rd, wells bj. prostate cancer and sexually transmitted diseases: a meta-analysis. fam med. 2005; 37:506-12. 3. isaacs jt. prostatic structure and function in relation to the etiology of prostatic cancer. prostate. 1983; 4:351-66. 4. rosenblatt ka, wicklund kg, stanford jl. sexual factors and the risk of prostate cancer. am j epidemiol. 2001; 153:1152-8. 5. dennis lk, dawson dv. meta-analysis of measures of sexual activity and prostate cancer. epidemiology. 2002; 13:72-9. 6. fernández l, galán y, jiménez r, et al. sexual behaviour, history of sexually transmitted diseases, and the risk of prostate cancer: a case-control study in cuba. int j epidemiol. 2005; 34:193-7. 7. giles gg, severi g, english dr, et al. sexual factors and prostate cancer. bju int. 2003; 92:211-6. 8. spence ar, rousseau mc, parent mé. sexual partners, sexually transmitted infections, and prostate cancer risk. cancer epidemiol. 2014; 38:700-7. 9. del rosario ad, bui hx, abdulla m, ross js. sulfur-rich prostatic intraluminal crystalloids: a surgical pathologic and electron probe x-ray microanalytic study. hum pathol. 1993; 24:1159-67. 10. banerjee ak. carcinoma of prostate and sexual activity. urology. 1986; 28:159. 11. ahmadi h, allameh f, baradaran n, et al. circulating sex hormones play no role in the association between sexual activity and the risk of prostate cancer. j sex med. 2011; 8:905-13. 12. la vecchia c, franceschi s, talamini r, et al. marital status, indicators of sexual activity and prostatic cancer. j epidemiol community health. 1993; 47:4503. 13. leitzmann mf, platz ea, stampfer mj, willett wc, giovannucci e. ejaculation frequency and subsequent risk of prostate cancer. jama. 2004; 291:157886. 14. chavez ah, coffield ks, rajab mh, jo c. incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors: retrospective analysis. asian j androl 2013; 15:246-248. 15. boehmer u, miao x, ozonoff a. cancer survivorship and sexual orientation. cancer. 2011; 117:3796-804. 16. stephan c, jung k, diamandis ep, et al. prostate-specific antigen, its molecular forms, and other kallikrein markers for detection of prostate cancer. urology. 2002; 59:2-8. correspondence ahmed fouad kotb; m.d, phd, mrcs, febu drahmedfali@gmail.com ahmad beltagy, md bil_doctor@hotmail.com asmaa mohamed ismail, md asmaaismail@rocketmail.com urology department, faculty of medicine, alexandria university, azarita, sultan hussein street, alexandria, egypt kotb_stesura seveso 23/09/15 12:35 pagina 215 stesura seveso 219archivio italiano di urologia e andrologia 2014; 86, 3 short communication self and partner satisfaction rates after 3 part inflatable penile prosthesis implantation abdulmuttalip simsek, onur kucuktopcu, faruk ozgor, unsal ozkuvanci, murat baykal, omer sarilar, zafer gokhan gurbuz haseki research and training hospital, department of urology, turkey. objective: to evaluate and present satisfaction rates of our patients and their partners after 3 part inflatable penile prosthesis implantation. materials and methods: we searched our hospital electronic data for patients who underwent inflatable penile prosthesis implantation between january 2008 and july 2013. computer and archived file data were used to get information and reach the patients. we made telephone calls to patients and asked questionnaires about self and partner satisfaction rates. results: 36 patients underwent prosthesis implantation during the 5 year period. we were able to reach by telephone call 18 of them. the mean age of 18 patients was 55.7 ± 9.4 years and mean body mass index was 24.6 ± 2.1 kg/m2. the etiology was diabetes mellitus on 14 (77.8%) and radical pelvic surgery on 4 (22.2%) patients. 14 of 18 patients had penile doppler ultrasound test. doppler ultrasound demonstrated venous insufficiency in 8 and arterial insufficiency in 6 patients. mean time from implantation to study was 20.8 ± 13.9 months. out of 18 patients 2 had prosthesis removal operation because of infection in one patient and perforation in the other. satisfaction rate was 88.9%, and recommendation rate was 94.4%. causes of dissatisfaction were pain in one patient and insufficient rigidity plus shortening of the penis in the other one. partner satisfaction rate was 94.4%. conclusion: penile prosthesis implantation (ppi) is the gold standard treatment of erectile dysfunction (ed) irresponsive to medical treatment. infection and mechanical failure rates are going to be less according to the improvements in synthetic materials and coverings of the prosthesis, so patient and partner satisfaction rates will be higher. key words: penile prosthesis; erectile dysfunction; satisfaction rate. submitted 30 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction erectile dysfunction (ed) affects more than half of men between 40 and 70 years of age. oral phosphodiesterase type-5 inhibitors and intracavernosal injections (ici) are doi: 10.4081/aiua.2014.3.219 first and second line therapies respectively. penile vascular surgery is indicated for healthy men with acquired ed due to isolated stenosis of extra penile arteries without any kind of generalized vascular disease (1). phosphodiesterase type 5 inhibitors will fail in approximately 25-30% of patients and they will therefore be offered intracavernosal injection. since most patients drop out ici treatment, around 10-15% of patients with ed will be candidate for penile prosthesis implantation (ppi) (2). prosthetic implants for ed have been used successfully for many years. scott et al in 1973 introduced the inflatable penile prosthesis (ipp) and initiated the modern treatment of erectile dysfunction (3). 5-year survival rate is greater than 90% and more than 90% of patients are satisfied with the function of their prosthesis (4). in this retrospective study using a non-validated questionnaire, we aimed to evaluate the satisfaction rates of the patients and their partners, reasons of unsatisfaction and need for sexual partner change. materials and methods between january 2008 and july 2013, three part ipp implantation was performed in 36 patients. patient data was obtained by searching of computer data base of our hospital and archived files of the patients. computer data base is searched for the term of “penile prosthesis”. so we could find the patients who underwent penile prosthesis implantation or penile prosthesis removal. patients data were evaluated for the etiologies and for prosthesis removal in the same hospital or not. all patients were interviewed by phone using number which were recorded in the archived files or in the computer data base. if we could reach the patients by the recorded telephone number we asked several questions to evaluate the use of prosthesis. the questions are shown in table 1 (supplementary materials). patient and partner satisfaction rates, co morbidities, etiology of ed, penile doppler ultrasound results, time between start of complaints and implantation, prosthesis failure rates and causes, and need for partner change were evaluated. all the parameters were evaluated as means, standard deviations, percentages and number of patients. simsek sc_stesura seveso 08/10/14 12:16 pagina 219 archivio italiano di urologia e andrologia 2014; 86, 3 a. simsek, o. kucuktopcu, f. ozgor, u. ozkuvanci, m. baykal, o. sarilar, z. gokhan gurbuz 220 results between january 2008 and july 2013, we implanted three-part ipp to 36 patients depending on computer database search results. according to the data from computer and archived files of patients, the etiology of erectile dysfunction was diabetes mellitus in 18, priapism in 1, radical pelvic surgery in 9 and unknown in 8 patients. of these 36 patients 4 were recorded for removal of prosthesis. the cause of prosthesis removal was infection in 3 patients and perforation in 1 patient. out of 36 patients recorded on computer, we could reach only 18 patients by telephone. all of them answered our questionnaire. the mean age of 18 patients was 55.7 ± 9.4 years and mean body mass index was 24.6 ± 2.1 kg/m2. the etiology was diabetes mellitus in 14 (77.8%) and radical pelvic surgery in 4 (22.2%). fourteen of 18 patients had penile doppler ultrasound test which demonstrated venous insufficiency in 8 and arterial insufficiency in 6 patients. the patients suffered from erectile dysfunction from a mean of 4 ± 3 years. mean time from implantation to study was 20.8 ± 13.9 months. patients used their prosthesis on a mean of 8 ± 3.1 times per month. of these 18 patients 2 had prosthesis removal operation because of infection in one case and perforation in another case. sixteen (88.9%) patients were satisfied with their prosthesis and 2 (11.1%) were dissatisfied. causes of dissatisfaction were pain in one patient and insufficient rigidity and shortening of penis in the other one. surprisingly 5 patients reported shortening of penis but 4 of them did not complain about and only one of them was dissatisfied because of shortening. none of them reported cosmetic problems and none of the patients needed to change their sexual partners after implantation. patients reported 17/18 (94.4%) partner satisfaction rate. but the unsatisfaction cause of this one partner was urinary incontinence of the male because of radical prostatectomy rather than the erection status. only one patient that was dissatisfied because of insufficient rigidity and penile length reported that he could not recommend the implantation. the recommendation rate was 94.4%. discussion ppi surgery is the treatment method in patients with end stage ed when oral and ici treatments are ineffective or contraindicated (5). arterial and venous dysfunctions caused by systemic diseases (6) or non nerve sparing surgery on bladder, prostate or rectum can cause ed needing prosthesis implantation (7, 8). inflatable devices have been initially introduced by scott in 1973 (3) and now are available in a two and three pieces version. ipp can be deflated mimicking the flaccid penile state. they are associated with higher patient and partner satisfaction rates than malleable prosthesis as they allow expansion of penis, thus preventing the risk of “pencil penis” syndrome and cosmetic problems (9). none of our patients in this study reported occurrence of such cosmetic problems after implantation. reliability of the device has been significantly improved and mechanical failure rates declined from 61% to 1020% at approximately 5-10 years of follow up (10). if the failure occurs in the early months, it is not necessary to remove the entire device and the identification and exchange of the faulty component usually suffices. if the mechanical failure occurs after 2 years instead, it is advisable to exchange the entire device (9). in this study prosthesis removal surgery was done for 2 (6%) patients in the total group of 36 patients and for one (6%) patient out of 18 patients interviewed by phone because of perforation of prosthesis. infection ranges from 1.8% to 10% and is an important complication which could cause the revision or the removal of the device (11). infections are generally caused by staphylococcus epidermidis and s. aureus, followed by gram-negative bacteria and anaerobic organisms (12). in our study infection rates was 6 % for both the total group and the group of interviewed patients. patients who have already undergone this kind of treatment defined really high rates of satisfaction, up to 97% of cases (9, 13). satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits)(14-15). the edits questionnaire was first validated in 1999 as an instrument by which patients’ and partners’ satisfaction with treatments for erectile dysfunction could be assessed (15). satisfaction can be affected by many variables. partner behavior plays a role (16) and patient expectations can have a great impact (17). satisfied patients have favorable partner sexual function compared to that of unsatisfied patients. the correlation observed suggests that patients not satisfied with their inflatable penile prosthesis (ipp) are likely to have female partners at high risk for female satisfaction. also female satisfaction rate correlates satisfaction rates of the patients. studies suggested a direct linear correlation of satisfaction between the sexual partners (16). also in our study, patient and partner satisfaction rates were 88.9% and 94.4% respectively, similarly to the literature. none of our patients defined dissatisfaction due to bad partner sexual performance and none of them needed to change their partners. of the 8% who were unsatisfied in the bettocchi et al. paper, the main reasons given were insufficient rigidity and penile length (9). moreover, the same could be said for the garber’s study where 8% were dissatisfied with penile length. one of our patients dissatisfied because of pain, and one patient (5.6%) was dissatisfied because of insufficient rigidity and shortening of the penis. five patients (27.8%) had shortening problem but only one of them was dissatisfied. one limitation in this study is that we did not use validated questionnaires for evaluating the satisfaction of patients and partners. we asked only if the patient was satisfied and if he recommended this treatment to another patient or not. according to our questionnaire our satisfaction rate was 88.9% and this was compatible with the literature. seventeen (94.4%) patients recommended ppi treatment. one patient who was dissatisfied because of pain also recommended this treatment because of good rigidity of penis. another limitation of our study was a low patient number. bettocchi et al. studied 79 patients between 2004-2008. in simsek sc_stesura seveso 08/10/14 12:16 pagina 220 their study 92% of patients defined improvement in sex and 97% would recommend the same surgery to others (9). montorsi et al. studied 200 patients between 19861997 and 92% patients had satisfactory sexual activity (18). goldstein et al. studied 234 patients between 19891993 and 86% of patients recommended surgery to others (19). our results correlate with rate reported on literature. conclusion today, ppi is the gold standard treatment of ed irresponsive to medical treatment. patient and partner satisfaction rates are high. infection and mechanical failure rates are going to be less according to the improvements in synthetic materials and coverings of prosthesis. more studies about factors effecting dissatisfaction after surgery, especially about female factors resulting in partner changes, should be done. references 1.montague dk, jarow jp, broderick ga, et al. erectile dysfunction guideline update panel. chapter i: the management of erectile dysfunction: an aua update. j urol. 2005; 174:230-239. 2. montague dk. penile prosthesis implantation in the era of medical treatment for erectile dysfunction. urol clin north am. 2011; 38:217-25. 3. scott fb, bradley we, timm gw. management of erectile impotence: use of implantable inflatable prosthesis. urology. 1973; 2:80. 4. carson cc, mulcahy jj, govier fe. efficacy, safety, and patient satisfaction outcomes of an ams 700 cx inflatable penile prosthesis: results of a long term multicenter study. j urol. 2000; 164:376-382. 5. montorsi f, deho f, salonia a, et al. penile implants in the era of oral drug treatment for erectile dysfunction. bju int. 2004; 94:745-51. 6. hatzimouratidis k, hatzichristou dg. treatment options for erectile dysfunction in patientsfailing oral drug therapy. eau updates series. 2004; 2:75. 7. meuleman ej, mulders pf. erectile function after radical prostatectomy: a review. eur urol. 2003; 43:95-101. 8. bettocchi c, palumbo f, spilotros m, et al. penile prostheses. ther adv urol. 2010; 2:35-40. 9. bettocchi c, palumbo f, spilotros m, et al. long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis. j sex med. 2010; 7:304-9. 10. kim sc mechanical reliability of ams hydraulic penile prostheses. j korean med sci. 1995; 10:422-425. 11. al-enezi a, al-khadhari s, al-shaiji tf. three-piece inflatable penile prosthesis: surgical techniques and pitfalls. j surg tech case rep. 2011; 3:76-83 12. evans c. the use of penile prostheses in the treatment of impotence. bju. 2001; 81:591-598. 13. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-1512. 14. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-1433. 15. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-9. 16. gittens p, moskovic dj, avila d jr, et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2008; 8:1996-2001. 17. kramer ac, schweber a. patient expectations prior to coloplast titan penile prosthesis implant predicts postoperative satisfaction, j sex med. 2010; 7:2261-2266. 18. montorsi f, rigatti p, carmignani g, et al. ams three-piece inflatable implants for erectile dysfunction: a long-term multi institutional study in 200 consecutive patients. eur urol. 2000; 37:50-55. 19. goldstein i, newman l, baum, et al. safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment. j urol, 1997; 157:833-839. 221archivio italiano di urologia e andrologia 2014; 86, 3 satisfaction rates of penile prosthesis implantation correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com onur kucuktopcu, md faruk ozgor, md unsal ozkuvanci, md murat baykal, md omer sarilar, md zafer gokhan gurbuz, md haseki training and research hospital,department of urology, millet cad. no: 11, 34000 fatih, istanbul, turkey simsek sc_stesura seveso 08/10/14 12:16 pagina 221 39archivio italiano di urologia e andrologia 2017; 89, 1 original paper blue light cystoscopy with hexylaminolevulinate: our 7 years experience vito lacetera 1, ubaldo cantoro 1, lorenzo montesi 1, daniele cantoro 2, bernardo cervelli 1, antonio cicetti 1, giuliana gabrielloni 1, domenico milella 1, michele montesi 1, roberto morcellini 1, gianni parri 1, emilio recanatini 1, valerio beatrici 1 1 azienda ospedaliera ospedali riuniti marche nord, pesaro-fano, italy; 2 ospedale di ascoli piceno, ascoli piceno, italy. aim: the objective of the present study is to evaluate the diagnostic accuracy of hexylaminolevulinate (hal) blue light cystoscopy compared with standard white light cystoscopy (wlc) in daily practice. materials and methods: an observational, comparative, controlled (within patient) study was carried out at our center. 61 consecutive patients with suspected or confirmed bladder cancer were recruited for the study from january 2008 until january 2015. patients with suspected bladder cancer (positive cytology with negative wlc) or history of previous high-grade nmibc or cis were included in the study. biopsies/resection of each positive lesion/suspicious areas were always taken after the bladder was inspected under wlc and blc. diagnoses of bladder tumor or cis were considered as positive results, and the presence of normal urothelium in the biopsy specimen as negative result. results: 61 blc were performed. 15/61 (24.5%) with suspected initial diagnosis of nmibc and 46/61 (75.5%) with a history of high-risk non-muscle invasive bladder cancer (nmibc). we performed a total of 173 biopsies/turbt of suspicious areas: 129 positive only to the blc and 44 both positive to wlc and blc. 84/173 biopsies/turbt were positive for cancer. all 84 nmibc were positive to the blc, while 35/84 were positive to the wlc with a sensitivity of blc and wlc respectively of 100% and 41.7%. sensitivity of wlc for highgrade nmibc and cis was 34.1% and 39% respectively while sensitivity of blc for high-grade nmibc and cis was 100%. the specificity of the wlc was 79.9% compared to 48.5% of the blc. the positive predictive value of blc and wlc were respectively 48% (95% ci: 0.447-0.523) and 79% (95% ci: 0.856-0.734). conclusions: our data confirm those reported in the literature: blc increases the detection rate of nmibc particularly in high risk patients (history of cis or high grade). blc is a powerful diagnostic tool in the diagnosis of bladder cancer if malignancy is suspected (positive urine cytology) and if conventional wlc is negative. key words: blue light cystoscopy; hexaminolevulinate. submitted 7 february 2016; accepted 3 june 2016 summary no conflict of interest declared. photoactive porphyrins that are preferentially taken up by dysplastic cells, which emit red fluorescence after exposure to blue light (blue-light cystoscopy, blc) (1, 2). blue light turbt or biopsies has been shown to reduce the risk of early recurrence compared with wlturbt improving the diagnostic accuracy of conventional cystoscopy for detecting bladder tumors and particularly carcinoma in situ (cis) (1). carcinoma in situ (cis) of the urinary bladder is defined as a flat highgrade noninvasive transitional cell carcinoma (3). cis is generally associated with a high risk of tumor progression. bladder wash cytology should be positive in over 90% of patients with cis, whereas conventional white light cystoscopy (wlc) may fail to detect cis in up to 50% of cases. a full understanding of the presence and extent of cis is crucial to treatment planning and followup, and may lead to improved treatment outcomes. from a quality of-life point of view it is also important to diagnose superficial flat lesions that will become evident in a few months, needing further transurethral resection. however, according to the 2011 european association of urology (eau) guidelines, pdd cystoscopy should be restricted to those patients who are suspected of harboring a high-grade tumor, particularly cis, and should not be used on a regular basis (1). to date, few studies have presented results of pdd cystoscopy compared with wlc in daily practice. the objective of the present study is to evaluate the diagnostic accuracy of hal hydrochloride (hexvix) pdd cystoscopy compared with standard wlc in daily practice. materials and methods 61 consecutive patients with suspected or confirmed bladder cancer were recruited for the study from january 2008 until january 2015 (table 1). patients with suspected bladder cancer (positive cytology with negative wlc) or history of previous high-grade malignancy or cis were included in the study. exclusion criteria were gross hematuria, porphyria, known allergy to hal, pregnancy or lactation, and intravesical bacillus calmetteguerin (bcg) or chemotherapy within 3 months before hal instillation. an observational, comparative, condoi: 10.4081/aiua.2017.1.39 introduction white-light cystoscopy (wlc) is the current standard for bladder cancer diagnosis and follow-up. 5-aminolaevulinic acid (5-ala) or hexylaminolevulinate (hal) are lacetera_stesura seveso 04/04/17 09:15 pagina 39 archivio italiano di urologia e andrologia 2017; 89, 1 v. lacetera, u. cantoro, l. montesi, et al. 40 trolled (within patient) study was carried out at our center. all the data provided were collected as part of a routine clinical procedure. in addition, all patients gave their written informed consent to have their clinical records included in a dedicated database, and they were aware that their data, after having been made anonymous, would be used for clinical research purposes. the principles of the declaration of helsinki were followed. hal hydrochloride (hexvix®) in phosphate-buffered saline solution (50 ml of 2.0 mg/ml (8 nm) solution) was instilled into the bladder via a standard catheter 1 hour before cystoscopy. the bladder was evacuated and inspected by white-light cystoscopy. a band filter on the lamp was then used to supply blue light (wavelength 380-450 nm) for fluorescence cystoscopy. one dedicated and wellexperienced endourologist recorded the presence and number of positive lesions/suspicious areas compared with surrounding urothelium detected using white-light and blue-light cystoscopy. biopsies/resection of each positive lesion/suspicious areas were always taken after the bladder was inspected under white and blue light. random biopsies from normal-appearing urothelium were never taken. all procedures were performed under local or spinal anesthesia. the safety of hal was evaluated by clinical examination at hal instillation, during surgery, and in the postoperative period until discharge. all papillary lesions/biopsies were collected and sent separately for histological analysis. each biopsy was reviewed by a dedicated uropathologist blinded to detection method and patient history. all samples were evaluated and classified as normal urothelium, cis, or urothelial neoplasia. tumor stage was assigned according to the 2009 tumornode-metastasis (tnm) classification (4). grading of papillary lesions was assigned using the 1973 world health organization (who) classification (5). diagnoses of bladder tumor or cis were considered as positive results, and the presence of normal urothelium in the biopsy specimen as negative result. sensitivity, specificity and positive predictive value for each method were calculated. we compared the results per biopsy specimen for wlc and blc using the mcnemar test. data was analyzed using spss for windows version 17.0 (spss inc., chicago, il, usa). results analysis of wlc and blc findings is presented in table 2. 61 blc (54 men and 7 women; mean age 77 years) were performed. 15/61 (24.5%) with suspected initial diagnosis of nmibc (positive cytology and negative wlc) and 46/61 (75.5%) with a history of high-risk nmibc. we performed a total of 173 biopsies/turbt of suspicious areas: 129 positive only to the blc and 44 both positive to wlc and blc. 84/173 biopsies/turbt were positive for cancer with the following histology: 44 cis, 17 tag1, 2tag3, 21 t1g3. all 84 nmibc were positive to the blc, while 35/84 of them were positive to the wlc with a sensitivity of blc and wlc respectively of 100% and 41.7%. the 49 lesions detected only by the blc had the following histology: 29 cis, 14 tag3, 6 t1g3. sensitivity of wlc for high-grade nmibc and cis was 34.1% and 39% respectively while sensitivity of blc for high-grade nmibc and cis was 100%. the specificity of the wlc was 79.9% compared to 48.5% of the blc. the positive predictive value of blc and wlc were respectively 48% (95% ci 0.447-0.523) and 79% (95% ci 0.856-0.734). discussion as expected, our findings were consistent with the reports of previous studies that hal was more sensitive for detection of cis than wlc (1, 6-8). this is important as the data were consistent between studies performed in north america and europe, where this technology has been approved by regulatory authorities in 27 countries. hal also received us food and drug administration approval in may, 2010. the ability of hal to detect both visible and occult cis could provide a more accurate, site-directed approach to the identification of cis. blc detected more cis lesions than did wlc in patients with primary cancer. these data showed that the addition of blc improved detection of cis and might have resulted in a more complete determination of the extent of cis. in addition, some patients who appeared normal by wlc were found to have cis by blc only. these data support an approach utilizing both wlc and blc in order to optimize detection of cis and determine the extent of cis. in the present study we evaluated the diagnostic accuracy of hal pdd versus wlc for diagnosis of cis and bladder tumors in daily practice. the sensitivity of blc table 1. characteristics of the sample. number of patients 61 male/female 54/7 mean age 77 suspected cis 15 history of previous high-risk nmibc 46 number of biopsies 173 positive biopsies to both blc and wlc 44 positive biopsies only to blc 173 positive biopsies only to wlc 0 table 2. results. positive biopsies 129/173 tag1 17 tag3 2 t1g3 21 cis 44 sensibility of blc for cis 100% sensibility of wlc for cis 39% specificity wlc/blc 80%/48.5% predictive positive value blc/wlc 48%/79% lacetera_stesura seveso 04/04/17 09:15 pagina 40 biopsies was significantly higher than sensitivity of wlc technique. fradet et al. compared hexvix fluorescence cystoscopy with wlc for detecting cis in a multicenter study on 298 patients (6). overall, more cis were found by hexvix than by wlc: of a total of 113 cis lesions diagnosed in 58 patients, 104 (92 %) were detected by hal cystoscopy and 77 (68 %) by wlc, thus leading to the conclusion that blc can diagnose cis that may be missed with wlc (6). similar conclusions were reached by lerner et al. (7) in a recently published study using hal in 551 patients. presence of cis is associated with higher risk of tumor progression and can significantly change the follow-up schedule and treatment algorithm toward bcg instillations instead of farmorubicin if associated with a papillary tumor confined to the mucosa (pta) or toward cystectomy if its diagnosis is associated with recurrent highgrade papillary tumor invading the subepithelial connective tissue (pt1). there are no data, however, regarding detection of cis in extravesical sites using hal. these sites can be a reservoir for cis and explain, at least in part, the failure of bcg to completely clear the lower urinary tract of cis in some patients. this represents an important gap in our detection armamentarium that could possibly be addressed by further clinical trials of florescence cystoscopy or other novel imaging systems for detection of cis in the upper urinary tract and prostatic urethra (9). references 1. babjuk m, oosterlinck w, sylvester r, et al. eau guidelines on nonmuscle-invasive urothelial carcinoma of the bladder, the 2011 update. eur urol. 2011; 59:997-1008. 2. jocham d, stepp h, waidelich r. photodynamic diagnosis in urology: state of the art. eur urol. 2008; 53:1138-1150. 3. epstein ji, amin mb, reuter, vr, et al. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998; 22:1435-48. 4. sobin lh, gospodarowicz mk, wittekind c, eds tnm classification of malignant tumors (uicc international union against cancer), 7th edn. wiley-blackwell, new york 2009, p. 262-5. 5. mostofi fk, sobin lh, torloni h. histopathological typing of urinary bladder tumours. in: international histological classification of tumours. world health organisation, geneva 1973. 6. fradet y, grossman hb, gomella l, et al. a comparison of hexaminolevulinatefluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase iii, multicenter study. j urol. 2007; 178:68-73. 7. lerner sp, liu h, wu m-f, et al. fluorescence and white light cystoscopy for detection of carcinoma in situ of the urinary bladder. urol oncol. 2012; 30:285-289. 8. schmidbauer j, witjes f, schmeller n, et al. improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. j urol. 2004; 171:135-138. 9. goh ac, lerner sp. application of new technology in bladder cancer diagnosis and treatment. world j urol. 2009; 27:301-7. 41archivio italiano di urologia e andrologia 2017; 89, 1 blue light vs with light cistoscopy correspondence vito lacetera, md, urologist vlacetera@gmail.com ubaldo cantoro, md, urologist (corresponding author) ubaldocantoro@tiscali.it lorenzo montesi, md, resident in urology lorenzomontesi@yahoo.it bernardo cervelli, md, urologist bernardino.cervelli@ospedalimarchenord.it antonio cicetti, md, urologist antonio.cicetti@ospedalimarchenord.it giuliana gabrielloni, md, urologist giuliana.gabrielloni@ospedalimarchenord.it domenico milella, md, urologist domenico.milella@ospedalimarchenord.it michele montesi, md, urologist michele.montesi@ospedalimarchenord.it roberto morcellini, md, urologist roberto.morcellini@ospedalimarchenord.it gianni parri, md, urologist gianni.parri@ospedalimarchenord.it emilio recanatini, md, urologist emilio.recanatini@ospedalimarchenord.it valerio beatrici, md, urologist beatrici@libero.it azienda ospedaliera ospedali riuniti marche nord piazzale cinelli 4 61121 pesaro, italy daniele cantoro, md, urologist danidoc2580@alice.it ospedale di ascoli piceno, ascoli piceno, italy lacetera_stesura seveso 04/04/17 09:15 pagina 41 archivio italiano di urologia e andrologia 2013; 85, 124 introduction squamous cell carcinoma of the penis (scc), which represents a rare condition in western europe and north america, accounting for less than 1% of all male malignancies, is slightly more common in the developing countries, where it has an incidence up to 20 per 100,000 people (1, 2). the traditional treatment of scc has been radical penectomy, which guarantees excellent local control rates at the expense of a complete loss of sexual and urinary function with consequent severe psychological morbidity (3). although there is little dispute that radical surgery is necessary for t3 and t4 disease, the need to perform this type of surgery in patients with t1 and t2 disease limited to the glans penis and the prepuce and the belief that a 2 cm margin is required to guarantee an adequate oncological clearance have been questioned in recent studies. original paper glans reconstruction with the use of an inverted urethral flap after distal penile amputation for carcinoma salvatore sansalone 1, giulio garaffa 2, giuseppe vespasiani 1, alessandro zucchi 3, franklin emmanuel kuehhas 4, ralf herwig 4, mauro silvani 5, stefano pecoraro 6, carla loreto 7, rosario leonardi 8 1 department of experimental medicine and surgery, tor vergata university of rome, rome, italy; 2 st peter’s andrology, university college london hospitals, london, uk; 3 department of urology and andrology, university of perugia, perugia, italy; 4 department of urology, medical university of vienna, vienna, austria; 5 department of urology, general hospital, biella, italy; 6 department of nephro-urology, malzoni medical center avellino, avellino, italy; 7 department of bio-medical sciences, anatomy section, university of catania, catania, italy; 8 musumeci gecas clinic of catania, catania, italy. restoration of adequate cosmesis and preservation of sexual and urinary function are the main goals of penile reconstructive surgery following amputation for carcinoma. split thickness skin grafts and oral mucosa grafts have been widely used for the creation of a pseudoglans with excellent cosmetic and functional results. the main drawbacks associated with the use of grafts are donor site morbidity, the lack of engorgement of the pseudoglans and the risk of poor graft take, which may lead to contracture and poor cosmetic results. in the present series the long term cosmetic and functional outcomes of glans reconstruction with an inverted distal urethral flap are described. key words: glans reconstruction; urethral flap; penile cancer. submitted 12 february 2013; accepted 28 february 2013 no conflict of interest declared summary in particular, a more conservative organ sparing approach is suggested by the fact that more than 80% of scc arises from the glans and prepuce and that margins of few millimeters may be adequate for the clearance of most tumours. moreover, the penis is easy to inspect and therefore local recurrences can be immediately identified and treated (4-8). current eau guidelines recommend a penile preserving approach for carcinoma in situ, ta, t1 and t2 scc with involvement of the glans only in patients committed to a regular surveillance program (2). in particular, patients with t1 and t2 disease limited to the glans penis should be offered glansectomy with or without corporeal tips amputation followed by construction of a pseudoglans (9, 10). herein the long-term outcome of a series of patients who sansalone_stesura seveso 18/04/13 11:01 pagina 24 25archivio italiano di urologia e andrologia 2013; 85, 1 glans reconstruction with the use of an inverted urethral flap after distal penile amputation for carcinoma heads and the distal aspect of the urethra and frozen sections were collected form the corporeal heads and the distal urethral margin in all patients, as previously described by various authors (5, 8, 10-15). two patients presented positive corporeal margins at the frozen section and underwent distal corporectomy with reconstruction of the corporeal heads. the shaft penis was then completely degloved in all patients in order to allow a complete dissection of the urethra off the corpora cavernosa down to the crura (figure 1). the distal aspect of the urethra was then spatulated ventrally for approximately 2.5 cm, everted and used to cover the corporeal heads in order to form a pseudoglans (figure 2). the urethral edges were sutured to the underlying corpora cavernosa with interrupted 4-0 polyglactin sutures (vicryl®, ethicon, somerville, new jersey, usa) in order to form the ridge of the pseudoglans. the penile shaft skin was also approximated to the edge of the urethral flap using interrupted 4-0 polyglactin sutures in order to recreate the coronal grove (figure 3). a light compressive dressing was applied on the penile shaft to prevent haematoma formation and a 16 french foley catheter left in situ for 24 hours. patients were usually discharged on postoperative day one on broad-spectrum oral antibiotics for 1 week. patients were reviewed on postoperative week 2, after 3 months and then on a 6 monthly basis and instructed to regularly inspect the genitalia in order to identify early signs of recurrence. a physical examination was routinely performed at each visit while a computerized tomography (ct) scan of chest, abdomen and pelvis with contrast was carried out on a yearly basis. patients with histology of pt1 g3 and pt2 and/or palpable groin disease have been then managed with groin node dissection according to the eau guidelines (2). cosmetic and functional outcome of the glans reconstruction, patients’ satisfaction, complications, recurrence of the disease and eventual need for revision surgery were recorded in the postoperative follow-up visit. figure 1. a circumferential subcoronal incision is carried out and the penile disassembly is performed. figure 2. the urethra is divided and then spatulated ventrally. have undergone organ-sparing surgery for the management of t1 and t2 scc of the glans penis followed by reconstruction of a pseudoglans with the use of urethral flaps is reported. materials and methods in our institution, between march 2007 and may 2011, 34 patients have undergone organ-sparing surgery for the management of t1 and t2 scc of the glans penis followed by pseudoglans reconstruction with the use of an inverted distal urethral flap. all patients gave their informed consent prior to their inclusion in the study. preoperatively, 22 patients reported good quality erection and 19 reported to be sexually active. prior to surgery all patients have undergone local stadiation based on clinical examination and on magnetic resonance imaging (mri) findings. in particular, contrast enhanced t1 and t2 weighted mri images in combination with an artificial erection with prostaglandin e1 (pge1) were used to identify invasion of the tumour through the tunica albuginea into the corpora cavernosa. only sexually active patients committed to a regular surveillance program with clinical t1 and t2 disease arising from the glans and without involvement of the corpora cavernosa were included in the series. patients with a history of urethral stricture or of previous urethral surgery were excluded from this series and underwent glans reconstruction with split thickness skin grafts as previously described by various authors (5, 8, 10-12). this because glans reconstruction with the use of urethral flap relies on an adequate blood supply form the proximal aspect of the urethra, and this might be severely compromised in patients with spongiofibrosis. after a circumferential subcoronal incision has been carried out in the shaft skin and deepened down to the level of buck’s fascia, the glans was dissected off the corporeal sansalone_stesura seveso 18/04/13 11:01 pagina 25 archivio italiano di urologia e andrologia 2013; 85, 1 s. sansalone, g. garaffa, g. vespasiani, a. zucchi, f.e. kuehhas, r. herwig, m. silvani, s. pecoraro, c. loreto, r. leonardi 26 all patients who did not require further local surgery were able to maintain physiological urinary function and considered the cosmetic result of the urethral flap satisfactory. all 22 patients who preoperatively had good quality erections reported no reduction in rigidity after surgery. overall, 14 of the patients who were preoperatively sexually active have resumed sexual activity postoperatively (74%). of the remainder, 4 had required a delayed partial penectomy due to malignant infiltration of the corporeal heads and one, who had undergone glansectomy followed by bilateral radical lymph node dissection of the groin, had a residual penile length insufficient for penetration. it is likely that the prepubic and scrotal lymphoedema consequence of the bilateral lymph node dissection was the cause of the perceived loss of penile length in this patient. a ventral penile curvature during erection was noticed by 2 patients (9%) and was consequence of a relatively short urethra, which was acting as a ventral chordee. this occurred despite of a meticulous intraoperative dissection of the urethra proximally down to its bulbar aspect. in both cases the curvature was less than 20 degrees, and, although ventral, did not interfere significantly with sexual activity. at 6 months postoperative follow up, all patients who have not required further local surgery have reported pseudo glans sensation and a degree of urethral flap engorgement. discussion reconstruction of the glans penis following glansectomy or distal corporectomy for carcinoma of the penis represents a challenge for the reconstructive surgeon. this because the aim of surgery is to achieve complete oncological clearance and to guarantee adequate cosmetic and functional results to allow the patient to resume sexual and urinary function with confidence (5-15). after the initial technique description in 2004, split thickness skin grafts, usually harvested from the inner thigh, have been widely used for glans resurfacing and pseudoglans construction for both benign and malignant conditions (5, 8-18). a recent series has also described the use of oral mucosa grafts for glans reconstruction.18 although glans reconstruction with the use of grafts yields adequate cosmetic and functional results in the hands of experienced surgeons, it is associated with donor site morbidity and the risk of poor graft take, which can lead to contracture and poor cosmesis. despite a good cosmetic result, the pseudoglans fashioned with this technique does not engorge like the native one (8). furthermore, oral infection with human papillomavirus (hpv), which can have a prevalence as high as 31%, can lead to the development of hpv related carcinomas arising from the oral mucosa grafts, although the literature has not provided any indication of the actual risk after genital reconstruction (20). this series confirms that a distal urethral flap is a good alternative to a split thickness skin graft for the reconstruction of the glans penis following amputation for carcinoma, as previously described in 1 series of 14 patients (21). this technique is not associated with donor site sensation of the urethral flap and patient’s satisfaction were assessed by direct questioning the patient and no objective test or validated questionnaire has been employed. results mean age at the time of surgery was 60 years (range 3673) and the final histo-pathological results are reported in table 1. infiltration of the proximal surgical margin, which had resulted clear in the initial frozen section, was present in 4 patients with pt2 disease (17%) and was managed with a distal corporectomy followed by glans reconstruction with the use of split thickness skin grafts, as the distal urethra had already been used (5). after a median follow-up of 27 months (range 6-48 months) none of the patients has succumbed because of the disease. the urethral flap survived in all patients and a penile hematoma occurred in 2 (6%) patients and required surgical evacuation in one case. a local recurrence occurred in one of the patients who had pt2 disease (3%) and was noticed at the 6 months follow up visit. eventually the patient was managed with partial penectomy and was local recurrence free at the 18 months follow up visit. figure 3. the final results after the eversion of the urethral flap and the creation of the pseudoglans table 1. histology results. histology result n. of patients g2 pt1 12 g3 pt1 15 pt2 7 sansalone_stesura seveso 18/04/13 11:01 pagina 26 27archivio italiano di urologia e andrologia 2013; 85, 1 glans reconstruction with the use of an inverted urethral flap after distal penile amputation for carcinoma morbidity, as it does not require the harvesting of a graft, and as the spongy tissue engorges during the erection, it leads to tumescence of the pseudo glans and therefore produces a more physiological outcome. regardless to the reconstructive technique used, glansectomy and distal corporectomy needs to be carried out as previously described in the literature.8 in particular, frozen sections of the corporeal and urethral margins are required to assess whether a complete clearance of the malignancy has been achieved (8, 22). only patients with a good blood supply to the distal urethra can be offered glans reconstruction with the use of distal urethral flap and therefore in presence of history of urethral strictures and/or previous urethral surgery reconstruction should be performed with the use of skin grafts. patients need to be warned that even with adequate preparation of the urethra, which should be dissected proximally down to its bulbar portion, a minor ventral penile curvature during erection is not an uncommon finding. conclusions the present series confirms that urethral flaps represent an excellent alternative to split thickness skin grafts for pseudoglans reconstruction following glansectomy and partial corporectomy for penile carcinoma in carefully selected patients. references 1. mistry t, jones rw, dannat e, pet al. a 10-year retrospective audit of penile cancer management in the uk. bju int. 2007; 100:1277-81. 2. pizzocaro g, algaba f, horenblas s, et al. eau penile cancer guidelines 2009. eur urol. 2010; 57:1002-12. 3. opjordsmoen s, fossa sd. quality of life in patients treated with for penile cancer. a follow-up study. br j urol. 1994; 74:652-7. 4. hegarty pk, shabbir m, hughes b, et al. penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the united kingdom experience. world j urol. 2009; 27:179-87. 5. pietrzak p, corbishley c, watkin n. organ sparing surgery for invasive penile cancer: early follow-up data. bju int. 2004; 94:1253-7. 6. hoffman ma, renshaw aa, loughlin kr. squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure? cancer. 1999; 85:1555-68. 7. minhas s, kayes o, hegarty p, et al. what surgical resection margins are required to achieve oncological control in men with primary penile cancer? bju int. 2005; 96:1040-3. 8. smith y, hadway p, biedrzycki o, et al. reconstructive surgery for invasive squamous carcinoma of the glans penis. eur urol. 2007; 52:1179-85. 9. lont ap, gallee mp, meinhardt w, et al. penis conserving treatment for t1 and t2 penile carcinoma: clinical implications of a local recurrence. j urol. 2006; 176:575-80. 10. palminteri e, berdondini e, lazzari m, barbagli g. resurfacing and reconstruction of the glans penis. eur urol. 2007; 52:893-900. 11. barbagli g, sansalone s, djinovic r, et al. current controversies in reconstructive surgery of the anterior urethra: a clinical overview. int braz j urol. 2012; 38:307-16. 12. bracka a. grans resection and plastic repair. bju int. 2010; 105:136-44. 13. ralph dj, garaffa g, garcia ma. reconstructive surgery of the penis. curr opin urol. 2006, 16:396-400. 14. garaffa g, sansalone s, ralph dj. penile reconstruction. asian j androl. 2013; 15:16-9. 15. loreto c, garaffa g, djinovic r, et al. penile disassembly: anatomical surgical steps. bju int. 2013; (in press). 16. garaffa g, shabbir m, christopher an, et al. the surgical management of lichen sclerosus of the glans penis: our experience and review of the literature. j sex med. 2011; 8:1246-53. 17. shabbir m, muneer a, kalsi j, et al. glans resurfacing for the treatment of carcinoma in situ of the glans: surgical technique and outcomes. eur urol. 2011; 59:142-7. 18. morelli g, pagni r, mariani c, et al. glansectomy with split thickness skin graft for the treatment of penile carcinoma. int j imp res. 2009; 21:311-4. 19. venkov g, laaser mk. reconstruction of tissue defects of the glans penis by transplantation of buccal mucosa. aktuelle urol. 2008; 39:219-24. 20. barbagli g, sansalone s, lazzeri m. oral mucosa and urethroplasty: it is time to change. eur urol 2012; 62:1071-3. 21. gulino g, sasso f, falabella r, bassi pf. distal urethral reconstruction of the glans for penile carcinoma: results of a novel technique at 1 year follow up. j urol. 2007; 178:941-4. 22. algaba f, arce y, lopez-beltran a, et al. intraoperative frozen section diagnosis in urological oncology. review. eur urol. 2005; 47:129-36. correspondence salvatore sansalone, md (corresponding author) salvatore.sansalone@yahoo.it giuseppe vespasiani, md department of experimental medicine and surgery tor vergata university of rome 00133 rome, italy giulio garaffa, md st peter’s andrology university college london hospitals w1g 6bj london, uk alessandro zucchi, md department of urology and andrology university of perugia 06123 perugia, italy franklin emmanuel kuehhas, md ralf herwig, md department of urology medical university of vienna 1040 vienna, austria mauro silvani, md department of urology – biella general hospital 13900 biella 13900, italy stefano pecoraro, md department of nephro-urology, malzoni medical center avellino, 83100 avellino, italy carla loreto, md department of bio-medical sciences anatomy section university of catania 95100 catania, italy rosario leonardi, md musumeci gecas clinic of catania 95100 catania. italy sansalone_stesura seveso 18/04/13 11:01 pagina 27 51archivio italiano di urologia e andrologia 2017; 89, 1 original paper blood platelet activity in men with vasculogenic erectile dysfunction zeki bayraktar, selami albayrak istanbul medipol university, school of medicine, department of urology, istanbul, turkey. objective: the aim of this study was to investigate the platelet activity in patients with vasculogenic erectile dysfunction (ed). materials and methods: the total blood count, including hemoglobin (hgb), white blood cell (wbc), red blood cell (rbc), platelet (plt) and mean platelet volume (mpv) parameters were measured in the patient (n = 70) and control groups (n = 50). results: the average age was 48.1 ± 11.7 and 47.6 ± 12.3 in the patient and control groups (p = 0.8217), respectively. mpv was higher in the patient group and there was a statistically significant difference between two groups (11.27 ± 0.56 and 9.8 ± 0.91, p < 0.0001). plt counts were lower in the patient group but there was not a statistically significant difference (196.23 ± 37.01 and 209.07 ± 36.71, p = 0.0626). in terms of haemoglobin, wbc and rbc values, there was no difference in the patient and control groups. conclusions: finding high mpv, which reflects the platelet activity, in the patient group shows that platelets also have a role in the ved etiopathogenesis. in the case of the confirmation of this result with additional studies, the efficiency of anti-platelet therapy in the vasculogenic ed should also be researched. key words: erectile dysfunction; platelet; mean platelet volume. submitted 18 august 2017; accepted 14 january 2017 summary no conflict of interest declared. most potent vasoconstrictor agent. therefore increased platelet activity play an important role in the atherosclerosis formation through mechanisms such as thrombocyte gathering, tromboxan synthesis, and expression of adhesion molecules (10-13). increased platelet activity probably plays a role in the etiopathogenesis of vasculogenic ed with such atherothrombotic process. the relationship between vasculogenic ed and platelet activity has been investigated in some studies (4-9). but these studies contain some conflicting results. for example, while çiftçi et al. (8) stated that both platelet count (plt) and mean platelet volume (mpv) increased in vasculogenic ed, aldemir et al. (9) reported that platelet count was normal. in this study, it was aimed to investigate some hematological parameters such as hemoglobin (hgb), white blood cell (wbc), red blood cell (rbc), plt and mpv in patients with vasculogenic ed. materials and methods the study protocol was approved by the institutional ethics committee of the school of medicine, istanbul medipol university, turkey. all of the individuals gave their informed consent. 70 patients in total who came to the urology polyclinic between may 2015 and june 2016 with the ed complaint and were diagnosed with vasculogenic ed (arterial insufficiency) were included in this study. all the patients in this group were subjected to the detailed history (anamnesis), physical examination, erectile function examination, laboratory evaluations and penile colour doppler ultrasonography (pdus). the ed level was questioned by international index of erectile function (iief) which had 6 questions consisting of the 1-5 and 15th questions of the iief questionnaire (14, 15). according to this, those whose iief-ed score was < 26 were regarded to have ed. the patients were grouped according to their erectile function area scores (q1-5 and q15) as mild ed (17-25), moderate ed (1116) and severe ed (6-10). penile color doppler evaluation was conducted on the basis of the criteria proposed by la vignera et al. (16). the patients were classified according to the peak systolic velocity (psv) value obtained. according to these, psv ≥ 35 cm/s values were assumed as normal (no arterial insufficiency). psv < 25 cm/s, between 25 and 29 cm/s, and between 30-34 cm/s values were consdered as severe, moderate, and mild arterial insufficiency, respectively. all patients with psv values < 35 cm/s were condoi: 10.4081/aiua.2017.1.51 introduction erectile dysfunction (ed) is defined as the inability to attain or maintain the penile erection required for sufficient sexual performance for at least 6 months (1, 2). ed is a multifactorial disease in the pathophysiology of which vascular, neurogenic, hormonal, psychogenic, cavernosal, iatrogenic, and anatomic causes play a role (3). ed may affect physical and psychosocial health and may have a significant impact on the quality of life of sufferers and their partners. additionaly, ed can be an early manifestation of coronary artery and peripheral vascular disease (2). in recent years, there have been some studies which report that mean platelet volume (mpv) increases in patients with vasculogenic ed (4-9). mpv is a marker of platelet size that is easily measured by automated blood counters and routinely available at a relatively low cost and reflects indirectly platelet activity. increased production of large platelets could conribute to the pathogenesis of atherotrombosis, because large platelets are metabolically and enzymatically more active than small platelets and produce more thromboxane, known as the bayraktar _stesura seveso 04/04/17 09:21 pagina 51 archivio italiano di urologia e andrologia 2017; 89, 1 z. bayraktar, s. albayrak 52 sidered to have vasculogenic ed and were included in the study. by contrast, patients with ed, the vasculogenic ed diagnosis of which was not confirmed with usg (with peak systolic velocity ≥ 35 cm/s), were excluded from this study, even if their iief-ed score was < 26. additionally patients who used anti-platelet and/or anticoagulant medication, patients with neurogenic or endocrinological ed, history of pelvic surgery and pelvic trauma, prostatectomy, history of other vascular risk factors for ed such as diabetes, smoking, or hypertension, patients recently diagnosed with coronary artery disease (cad) or hematological disorder, active infectious disease, malignancy, immunological disease, or renal or hepatic failure were excluded from this study. the control group consisted of 50 volunteering men who came to the urology polyclinic during the same period with the complaints different from ed such as hydrocele, varicocele, inguinal hernia, and epididymis cyst, which were sexually active, married and whose ed domain score was ≥ 26. those who did not apply with the ed complaint but had an iief-ed score < 26 and/or had a kind of disease that may affect hemogram parameters were not included in the control group. the patients in the control group were also subjected to the detailed sexual anamnesis, physical examination, iief-ed examination and laboratory evaluations as in the patient group. however, penile doppler ultrasonography was not performed in the control group. the total blood count, including hemoglobin (hgb), white blood cell (wbc), red blood cell (rbc), platelet (plt), and mean platelet volume (mpv) parameters were measured in the patient and control groups. all parameters were measured by using commercially available assay kits (sysmex europe gmbh, norderstedt, germany) with an autoanalyzer (sysmex xt 200i, hamburg, germany). blood samples were drawn from the antecubital vein and analyzed immediately (without freezing) after an overnight fasting period. the blood samples were collected in tubes containing dipotassium ethylenediaminetetraacetic acid. all the measurements were performed immediately after venipuncture to prevent in vitro platelet activation (within 1 h of sampling). statistical analyses were performed with medcalc statistical software (version16.4.3, medcalc software bvba, ostend, belgium). student t-test was used for comparison of two groups (vasculogenic ed and control). p < 0.05 was used as a threshold for statistical significance. data were presented as mean±standard deviation. results the findings are shown in table 1 and table 2. the average age in the patient group was 48.1 ± 11.7 (range 2969), the average age in the control group was 47.6 ± 12.3 (range 18-68) (p = 0.8217). the iief scores were 13.2 ± 0.5 and 27.3 ± 1.7 in the patient and control groups, respectively, and there was a significant difference between two groups (p < 0.0001). total platelet count was lower in the patient group than the control group (196.23 ± 37.01 and 209.07 ± 36.71, respectively) but there was not a statistically significant difference (p.=.0.0626). the mpv values were higher in the patient group than in the control group (11.27 ± 0.56 and 9.8 ± 0.91, respectively) and there was a statistically significant difference (p < 0.0001) (figure 1). by contrast with this, there was not a significant difference between the patient and control groups in terms of wbc, rbc and hemoglobin values. discussion the findings obtained show that mpv values in the patients with vasculogenic ed were significantly increased when compared to the patients in the control group, however, any increase in the platelet count did not take place. these results are compatible with the previous similar studies in terms of mpv values (4-9)., but not in terms of platelet count. according to aldemir et al. (9), mpv values in the patients with vasculogenic ed increased significantly when compared to the control group but there was no change in the platelet count. by contrast, according to çiftçi et al. (8), both mpv value and platelet count increased significantly in the patients with vasculogenic ed. in this study as well, mpv values were significantly higher in the patients with vasculogenic ed compared to the control group. this result (in terms of mpv) is compatible with other table 1. patients’ characteristics in vasculogenic ed (n = 70). age 29-69 (48.1 ± 11.7) psv, n (%) severe (< 25 cm/s), 23 (32.8%) moderate (25-29 cm/s), 26 (37.1%) mil (30-34 cm/s), 21 (30%) iief-ed 13.2 ± 0.5 ed severity, n (%) severe (iief 17-25), 27 (38.5%) moderat (iief 11-16), 27 (38.5%) mild (iief 6-10), 16 (22.8%) wbc 8.07 ± 2.77 rbc 5.16 ± 0.04 hgb 14.89 ± 0.86 plt 196.23 ± 37.01 mpv 11.27 ± 0.56 ed, erectile dysfunction; iief, international index of erectile function; psv, peak systolic velocity. table 2. study parameters and results in vasculogenic ed and control group (t test, p < 0.05, statistically significant). vasculogenic ed control p values stastical (no = 70) (n = 50) result age 48.1 ± 11.7 47.6 ± 12.3 p = 0.8217 ns iief 13.2 ± 0.5 27.3 ± 1.7 p < 0.0001 s wbc 8.07 ± 2.77 7.67 ± 0.21 p = 0.3109 ns rbc 5.16 ± 0.04 5.23 ± 0.53 p = 0.5510 ns hgb 14.89 ± 0.86 14.98 ± 0.98 p = 0.5950 ns plt 196.23 ± 37.01 209.07 ± 36.71 p = 0.0626 ns mpv 11.27 ± 0.56 9.8 ± 0.91 p < 0.0001 s ed, erectile dysfunction; iief, international index of erectile function; wbc, white blood cells; rbc, red blood cells; hgb, hemoglobin; plt, platelet; mpv, mean platelet volume; ns, stastically nonsignificant; s, stastically significant. bayraktar _stesura seveso 04/04/17 09:21 pagina 52 similar studies. however, platelet counts in this study were lower in the patient group. even though this difference is not statistically significant, this result is partially compatible with the study carried out by aldemir et al. (9) (in terms of platelet count) and contradictory with the study carried out by çiftçi et al. (8). this contradiction may have resulted from the number of patients and/or the age difference of the patients since the average age of the patients in this study was 48.1 ± 11.7 years, and it was 53.70 ± 12.39 years in the study carried out by çiftçi et al. (8). nevertheless, the mpv level was found to be high in all studies including the present study. what does the high mpv value indicate? platelet size has been shown to reflect platelet activity. mpv is a parameter which states platelet size and indirectly proves its activity. large platelets are metabolically and enzymatically more active than small platelets and produce more thromboxane. they show greater aggregability in response to adp and decreased inhibition of aggregation by prostacyclin in vitro. larger platelets are denser and contain more α-granules, which can release prothrombotic substances, including platelet factor 4, p-selectin, and platelet-derived growth factor, a chemotactic and mitogenic factor contributing to vascular neointimal proliferation. finally, larger platelets are more often reticulated, and this is an independent predictor of poor response to dual antiplatelet therapy (10, 11). there is evidence showing an association between mpv and cardiovascular disease, peripheric artery disease (pad) and stroke (11, 16). berger et al. reported that platelets play a pivotal role in the pathogenesis of atherosclerosis and pad. mpv, a measure of platelet size available in every blood count, is increasingly recognized as an important marker of platelet activity. large platelet size is an independent predictor of increased risk for peripheral artery disease (17). increased production of large platelets can contribute to the pathogenesis of atherothrombosis (18). additionally, platelet aggregation plays an important role in the pathogenesis of acute myocardial infarction. mpv, an indicator of platelet activation, has been reported to be higher in patients with coronary artery disease compared to healthy individuals, and as a possible independent risk factor for myocardial infarction (19). mpv can be examined in patient with erectile dysfunction because large platelets may be an indicator of the peripheral artery disease and vascular ed. because mpv is a marker of platelet size that is easily measured by automated blood counters and routinely available at a relatively low cost (4-9, 17-19). conclusions consequently, mpv values which demonstrate the thrombocyte activity were found to be high in the patients with vasculogenic ed. however, these data found in the limited number of patient groups with ed should be confirmed with additional studies. furthermore, the efficiency of the anti-platelet therapy to be performed individually or combined in the patients with vasculogenic ed who have high mpv values can also be investigated. references 1. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 2. hatzimouratidis k, amar e, eardley, et al. european association 53archivio italiano di urologia e andrologia 2017; 89, 1 erectile dysfunction and platelet activity figure 1. comparison of iief-ed and mpv values between vasculogenic ed and control group. bayraktar _stesura seveso 04/04/17 09:21 pagina 53 archivio italiano di urologia e andrologia 2017; 89, 1 z. bayraktar, s. albayrak 54 of urology. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol. 2010; 57:804-14. 3. chew kk, bremner a, stuckey b, et al. is the relationship between cigarette smoking and male erectile dysfunction independent of cardiovascular disease? findings from a populationbased cross-sectional study. j sex med. 2009; 6:222-31. 4. sönmez mg, göger ye, sönmez lö, et al. can eosinophil count, platelet count, and mean platelet volume be a positive predictive factor in penile arteriogenic erectile dysfunction etiopathogenesis? am j mens health. 2016 nov 28. pii: 1557988316679575. [epub ahead of print]. 5. otunctemur a, bozkurt m, besiroglu h, et al. erectile dysfunction is positively correlated with mean platelet volume and platelet count, but not with eosinophil count in peripheral blood. urol j. 2015; 12:2347-52. 6. choi h, kim jh, shim js, et al. comparison of the efficacy and safety of 5-mg once-daily versus 5-mg alternate-day tadalafil in men with erectile dysfunction and lower urinary tract symptoms. int j impot res. 2015; 27:33-7. 7. la vignera s, condorelli ra, burgio g, et al. functional characterization of platelets in patients with arterial erectile dysfunction. andrology. 2014; 2:709-15. 8. ciftci h, gumus k, yagmur i, et al. assessment of mean platelet volume in men with vasculogenic and nonvasculogenic erectile dysfunction. int j imp research. 2015; 27:38-40. 9. aldemir m, akdemir f, okulu e, et al. evaluation of blood platelet count and function in patients with erectile dysfunction. andrologia. 2016; 48:189-92. 10. abdel-rahman tm. mean platelet volume and prognosis of unstable angina, world j cardiovasc dis. 2015: 5:32-41. 11. chu sg, becker rc, berger pb, et al. mean platelet volume as a predictor of cardiovascular risk: a systematic review and metaanalysis. j thromb haemost. 2010; 8:148-56. 12. clappers n, brouwer ma, verheugt fwa. antiplatelet treatment for coronary heart disease. heart 2007; 93:258-265. 13. dong jy, zhang yh, qin lq. erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. j am coll cardiol. 2011; 58, 1378-1385. 14. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for the assessment of erectile dysfunction. urology 1997; 49:822-830. 15. bayraktar z, atun ai. despite some comprehension problems the international index of erectile function is a reliable questionnaire in erectile dysfunction. urol int. 2012; 88:170-6. 16. la vignera s, vicari e, condorelli ra, et al. arterial erectile dysfunction: reliability of penile doppler evaluation integrated with serum concentrations of late endothelial progenitor cells and endothelial microparticles. j androl. 2012; 33:412-9. 17. berger js, eraso lh, xie d, et al, iii. mean platelet volume and prevalence of peripheral artery disease, the national health and nutrition examination survey, 1999-2004 atherosclerosis. 2010; 213:586-591. 18. davi g, patrono c. platelet activation and atherothrombosis. n engl j med. 2007; 357:2482-94. 19. endler g, klimesch a, sunder-plassmann h, et al. mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. br j haematol. 2002; 117:399-404. correspondence zeki bayraktar, md, urologist, assoc. prof. dr. (corresponding author) zbayraktar@medipol.edu.tr istanbul medipol university, school of medicine, department of urology, çamlık mah. piri reis cad. papatya sitesi no:48 34890, pendik istanbul, turkey selami albayrak, md, urologist, prof. dr. salbayrak@medipol.edu.tr istanbul medipol university, school of medicine, department of urology, istanbul, turkey bayraktar _stesura seveso 04/04/17 09:21 pagina 54 stesura seveso 95archivio italiano di urologia e andrologia 2014; 86, 2 original paper musculoskeletal disorders among robotic surgeons: a questionnaire analysis claudio giberti 1, fabrizio gallo 1, luca francini 2, alessio signori 3, marco testa 2 1 department of surgery, division of urology, san paolo hospital, savona, italy; 2 department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health, university of genova, campus of savona, italy; 3 department of health science biostatistics unit, university of genoa, italy. objective: robotic surgical systems offer better workplace in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes. however, robotic surgery could produce musculoskeletal disorders due to the prolonged sitting position of the operator, the fixed position of the console viewer and the movements of the limbs. until today, no one study has been reported concerning the association between robotics and musculoskeletal pain. the aim of this work was verify the prevalence of musculoskeletal disorders among italian robotic surgeons. material and methods: between july 2011 and april 2012 a modified standardized nordic questionnaire was delivered to thirty-nine italian robotic centres. twentytwo surgeons (56%) returned the questionnaires but only seventeen questionnaires (43.5%) were evaluable. results: seven surgeons (41.2%) reported musculoskeletal disorders, by since their first use of the robot which significantly persisted during the daily surgical activity (p < 0.001). regarding the body parts affected, musculoskeletal disorders were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on their surgical procedures. conclusions: in spite of some important limitations, our data showed musculoskeletal disorders due to posture discomfort with negative impact on daily surgical activity among robotic surgeons. these aspects could be due to the lack of ergonomic seat and to the fixed position of the console viewer which could have produced an inadequate spinal posture. the evaluation of these postural factors, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes. key words: robotics; musculoskeletal diseases; pain; neck pain; posture; ergonomics. submitted 26 august 2014; accepted 15 january 2014 summary no conflict of interest declared. introduction the implementation of advanced robotic instruments today offers operators minimally invasive options for a wide range of complex surgical procedures (1-2). in fact, the use of the robot allows the surgeon to operate on small areas with an improved technical accuracy reducing the size of the surgical wound and providing many advantages in the postoperative recovery of the patient (3). as with all the newer working technologies, robotic surgical systems also offer better workplaces in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes (4). in fact, when using the robot, the surgeon operates seated at the console with the arms and elbows placed on a soft plane in order to allow free movement of the wrists and fingers which grasp two master controls located below the display. however, in spite of this more comfortable workplace, compared to traditional surgical approaches, robotic surgery can also produce many musculoskeletal disorders due to the prolonged sitting position of the operator who needs to maintain the image of the operative area through a semi-vertically oriented binocular viewer and adequately coordinate arm, wrist and lower limb movements (5-9). to date, no previous study has investigated the association between robotic surgery and musculoskeletal pain, probably due to the recent introduction of this technology. the aim of this work is to verify, using a specific questionnaire, the development of recurrent musculoskeletal disorders in a sample of italian robotic surgeons. materials and methods in the period between july 2011 and april 2012, a simplified version of the validated standardized nordic questionnaire was prepared and delivered to thirty-nine italian robotic centers (10-11). the questionnaire focused on the pain reported by the surgeon from the beginning of his robotic experience and during his daily robotic activity. in particular, the items took into consideration the amount of robotic experience achieved by each surgeon, the weekly use of the robot, the development of any recurrent musculoskeletal pain during the doi: 10.4081/aiua.2014.2.95 archivio italiano di urologia e andrologia 2014; 86, 2 c. giberti, f. gallo, l. francini, a. signori, m. testa 96 robotic procedures and the possible influence of this pain on daily surgical activity. lastly, a self reported ergonomic evaluation of the comfort feeling during robotic surgery was also included. twenty-two surgeons (56%) returned the questionnaires. five questionnaires were excluded due to incomplete or inaccurate compilation. in total, seventeen questionnaires (43.5%) received from different italian robotic centers were deemed evaluable (table 1). in december 2011, all questionnaire data were analyzed anonymously and statistically evaluated. statistical analysis the data was analyzed using the median and 25th-75th percentile for numerical variables and counts, and percentages for categorical variables were also reported. the fisher test was used in order to evaluate the association between the development of pain from the first use of the robot and its persistence during subsequent daily surgical activities and the association between the comfort posture and the development of musculoskeletal disorders. a non-parametric mann-whitney test was performed to evaluate any differences between groups with and without musculoskeletal pain regarding the number of months and hours per week spent at the robotic console. a p-value of 0.05 was considered statistically significant. the analyses were performed using spss (version 18.0; ibm corporation). results the questionnaire data reported by the seventeen robotic surgeons are shown in table 2. all of the surgeons were expert robotic operators and none of them reported any musculoskeletal pain before starting robotic surgery. seven operators (41.2%) declared having recurrent musculoskeletal pain which started with the first use of the robot, while six surgeons (35.3%) reported feeling pain during their daily surgical activities. as regards the association between these data, among the surgeons who reported the onset of pain from the first robotic procedure, a significant amount (85.7%) declared its persistence during the following daily surgical activities (p < 0.001). concerning the association between musculoskeletal pain and the duration of robot use, although both the median values related to the time spent from the first robotic procedure and the weekly use of the robot resulted higher among those surgeons who declared musculoskeletal pain, no statistically significant difference was assessed between these data (figures 1 and 2). as regards the body parts affected by musculoskeletal disorders, they were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). concerning the self-reported ergonomic evaluation of the comfort feeling during robotic surgery, six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on the surgical procedures. with regard to the association between comfort posture evaluation and the development of musculoskeletal disorders, despite 8 out of 10 surgeons who didn’t report any musculoskeletal disorder defining the robot console as comfortable while 4 out of 7 surgeons affected by musculoskeletal pain number (n) 17 age (years) 51.3 (32-61) gender male 16/17 (94%) female 1/17 (6%) italian geographical area (n -%-) north-west 5/17 (29.6%) north-east 6/17 (35.2%) middle 6/17 (35.2%) duration of robot use/surgeon’s robotic experience (months) 36 (12-63) weekly use of the robot (hours) 6 (5-7) weekly number of robotic procedures (n) 2.2 (2-3) robotic surgery (n -%-) urology 12/17 (70.5%) general surgery 4/17 (23.5%) gynaecology 1/17 (6%) concomitant standard laparoscopy (n -%-) 3/17 (17.6%) table 1. surgeons’ characteristics. the data regarding the age, duration of robot use and number of procedures are reported as mean with range between parentheses. the data concerning the gender, geographical area and type of robotic surgery are reported as percentages. questionnaire n° of patients (%) musculoskeletal pain before the first robotic operation no 17/17 (100%) yes 0/17 (0%) recurrent musculoskeletal pain since the first robotic operation no 10/17 (58.8%) yes 7/17 (41.2%) recurrent musculoskeletal pain during daily surgical activity no 9/17 (52.9%) yes 6/17 (35.3%) non-responders 2/17 (11.8%) body parts affected by pain* cervical spine 5/17 (29.4%) thoracic spine 2/17 (11.8%) upper limbs 4/17 (23.5%) lower limbs 1/17 (5.9%) lombar spine 1/17 (5.9%) none 10/17 (58.8%) console posture evaluation less comfortable 2/17 (11.8%) neither comfortable nor uncomfortable 4/17 (23.5%) comfortable 11/17 (64.7%) interference with surgical procedures no 6/17 (35.3%) yes 6/17 (35.3%) non-responders 5/17 (29.4%) table 1. answers to the questionnaire items reported by the robotic surgeons. the data shows the number of patients with percentages in parentheses. *: each operator could mark more than one answer. defined the robotic console as less comfortable or neither comfortable/uncomfortable, no statistical association (p = 0.16) was assessed between these two data. discussion work related musculoskeletal disorders represent a frequent problem among the general population with a prevalence ranging from 13.5 and 47% (12-14). many studies have also investigated this aspect among the health workforce showing musculoskeletal pain between 17-66%, 81.5-82.9% and 28-70% in dental operators, open and laparoscopic surgeons, respectively (15-18). robotic surgical systems offer better workplaces which should relieve surgeons from prolonged physical efforts and decrease the incidence of musculoskeletal pain. however, until today, no one study has been available in literature concerning the association between robotic surgery and musculoskeletal pain. the aim of this study was to verify the development of recurrent musculoskeletal disorders among surgeons who usually work with this new and high-tech surgical system. we also focused our attention on the robotic surgeons’ feeling of comfort during the operations and the possible interference of any discomfort on their daily surgical activity. in our study, 41.2% of surgeons reported a recurrent musculoskeletal disorder, mainly neck pain, which started from the beginning of the robotic experience and substantially continued to impact negatively on the daily surgical activity (p < 0.001). furthermore, 35.3% of surgeons defined the robotic console as rather uncomfortable with a negative influence on the surgical procedures. these data seem to point out the presence of some ergonomic problems at the robotic workstation. actually, the correlation between the sitting working position and the presence of musculoskeletal discomfort or neck pain has already been reported in literature by many authors, especially among those workers who need to maintain an even gaze, only 20° below the horizontal line, for at least one hour, like robotic surgeons (19-21). in fact, as recommended by the united states department of labor’s occupational safety and health administration (osha), a correct working sitting position requires many conditions including an appropriate positioning of the upper and lower limbs and a relaxed spinal posture with less inclination of the cervical region and adequate lumbar support (22). in spite of the fact that robotic workplaces allow good positioning of the upper arms with alignment of the forearms and hands, moderate relaxation of the arms and shoulders and bending of the elbows between 90 and 120 degrees, they don’t provide similar attention to the positioning of the spine or the lower limbs. in fact, because a chair is not usually sold together with the robotic console, surgeons often resort to using a simple stool which doesn’t provide any support to the hips or the lumbar spine (figure 3). furthermore, although all the da vinci surgical systems provide the opportunity to adapt the height of the console binocular viewer, only the newest model also allows the surgeon to modify its inclination, the height of the forearm supports and the position of the pedals (23). in our study, none of the robotic surgeons reported using this latest version of the da vinci system and this aspect could contribute to explaining the posture discomforts derived from the questionnaire data. further studies will certainly verify the impact of the newest surgical robotic system on surgeons’ postural pain. however, a more correct design of the sitting workstation remains a crucial point in order to respect the posture of the spine and to reduce neck and shoulder pain among people working with a protracted or retracted head position (20, 24-26). as regards the da vinci robotic system, an integrated and more ergonomic seat could further improve the comfort of the surgeon, thus minimizing the risk of musculoskeletal pain. this study has some important limitations: it is a retrospective, not comparative, study and it is based on a low number of questionnaires. these aspects could decrease the reliability of our statistical evaluation especially since surgeons who reported musculoskeletal pain after robotic surgery may have been more likely to join the study than those who experienced no pain. this is mainly due to the presence of few robotic centers in italy and, in particular, 97archivio italiano di urologia e andrologia 2014; 86, 2 musculoskeletal disorders and robotics figure 1. the figure shows the association between musculoskeletal pain and the time spent from the first robotic procedure. figure 2. the figure shows the association between musculoskeletal pain and the weekly use of the robot. archivio italiano di urologia e andrologia 2014; 86, 2 c. giberti, f. gallo, l. francini, a. signori, m. testa 98 few surgeons who use the da vinci robot regularly. in this setting, the aim of this study was to present our preliminary data which strongly needs to be confirmed by a larger study among all european robotic surgeons. conclusion in spite of the new workplaces, our data showed recurrent musculoskeletal disorders and posture discomfort with a negative impact on daily activity in 41.2% and 35.3% of robotic surgeons, respectively. these aspects could be due to the lack of an ergonomic seat and to the fixed position of the console binocular viewer which could have produced an inadequate spinal posture with consequent musculoskeletal disorders. the evaluation of these postural aspects, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes. acknowledgements we thank dr. jennifer mcdermott for the language revision. references 1. jayaraman s, quan d, al-ghamdi i, et al. 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[homepage on the internet] washington. available from: http://www.osha.gov/sltc/etools/computerworkstations/positions.html 23. matthew, lux mm, marshall m, erturk e, joseph jv. ergonomic evaluation and guidelines for use of the davinci robot system.j endourol. 2010; 24:371-375. 24. rempel dm, wang pc, janowitz i, et al. a randomized controlled trial evaluating the effects of new task chairs on shoulder and neck pain among sewing machine operators: the los angeles garment study. spine. 2007; 32:931-938. 25. stuart j. horton gillian m. johnson, margot a. skinner. changes in head and neck posture using an office chair with and without lumbar roll support. spine. 2010; 35:e542-548 26. falla d, o’leary s, fagan a, jull g. recruitment of the deep cervical flexor muscles during a postural-correction exercise performed in sitting. manual therapy. 2007; 12:139-143. correspondence claudio giberti, md fabrizio gallo, md (corresponding author) fabrizio.gallo@fastwebmail.it department of surgery, division of urology, san paolo hospital via genova, 30 -17100 savona, italy luca francini, md marco testa, md department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health, university of genova, campus of savona, savona, italy alessio signori, md department of health science biostatistics unit, university of genoa, genova, italy stesura seveso archivio italiano di urologia e andrologia 2014; 86, 146 case report use of inflatable penile prostheses ams cx with momentary squeeze in a patient with peyronie’s disease after removal of two previously implanted penile prostheses patrizio vicini 1, ferdinando de marco 1, gabriele antonini 2, ettore de berardinis 2, riccardo giovannone 2, stefano pecoraro 3, luigi azzarri 1, vincenzo gentile 2 1 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 2 department of urology, “sapienza” rome university, rome, italy; 3 department of urology, malzoni institute avellino, italy. objective: peyronie's disease (pd) is a fibrotic wound-healing condition of the tunica albuginea that results in penile deformity, curvature, hinging, narrowing and shortening, penile pain, and in some cases, erectile dysfunction (ed). surgery remains the gold standard treatment option, ensuring the faster and trustworthy treatment. for those patients who have erectile dysfunction and pd, penile prosthesis placement with straightening procedure is the best method to solve both diseases. the aim of this article is to present the use of hydraulic penile prostheses ams cx with momentary squeeze associated with a complete isolation of the neurovascular bundle in a complex case after removal of two previously implanted prostheses in a man suffering from peyronie’s disease and erectile dysfunction. material and method: a 50 year-old patient underwent two previous prosthetic implants in another hospital. the first implantation was performed using an infrapubic approach followed by placement of a three-component hydraulic penile prosthesis. after six months the prosthesis was removed using an infra-pubic approach and two soft prosthesis virilis ii were implanted during the same surgery. one year after the second operation we implanted a hydraulic penile prosthesis ams cx with mo mentary squeeze after complete isolation of the neurovascular bundle, fixing the two crural tips at the same level of albuginea of the two corpora cavernosa. result: twelve months after surgery the penis was completely straight without penile shortening and the patient was fully satisfied with his sexual life. conclusion: the procedure enabled a perfect alignment of the cylinders along the longitudinal axis and penile prosthetic symmetry to obtain a good penile rigidity and a perfect penile straightening. key words: inflatable penile prosthesis; peyronie’s disease; erectile dysfunction; isolation of the neurovascular bundle. submitted 17 september 2013; accepted 5 october 2013 summary introduction peyronie's disease (pd) is a fibrotic wound-healing condition of the tunica albuginea that results in penile deformity, curvature, hinging, narrowing and shortening, penile pain, and in some cases, erectile dysfunction (ed) (1-3). although a lot of non-surgical options have been proposed, none to date offers a trustworthy and effective correction of the penile curvature. as a result, surgery remains the gold standard treatment option, ensuring the faster and trustworthy treatment (4). tunica albuginea plication is the recommended method of straightening for patients with adequate rigidity and less severe deformity described as curvature less than 70° without narrowing/hinging (5-7). patients who have more serious, complex peyronie’s disease, but maintain good preoperative erectile function should be submitted to a straightening consisting in plaque incision or partial excision and grafting (5-7). in the end, for those patients who have erectile dysfunction and pd, penile prosthesis placement with straightening procedure is the best method to solve both diseases (5, 6, 8, 9). the aim of this article is to present the use of hydraulic penile prostheses ams cx with momentary squeeze associated with a complete isolation of the neurovascular bundle in a complex case after removal of two previous prostheses in a man suffering from pd and ed. after insertion of two crural tips, both tips have been attached symmetrically at the same level of the albuginea of the two corpora cavernosa. this has enabled a perfect alignment of the cylinders along the longitudinal axis and penile prosthetic symmetry to obtain a good penile rigidity and a perfect penile straightening. case report and figures are posted in suppementary materials on www.aiua.it. discussion the first and the second surgery did not correct penile curvature as the isolation of neurovascular bundle was no conflict of interest declared doi: 10.4081/aiua.2014.1.46 vicini cr_stesura seveso 26/03/14 10:44 pagina 46 47archivio italiano di urologia e andrologia 2014; 86, 1 use of inflatable penile prostheses ams cx with momentary squeeze in a patient with peyronie’s disease... not done. before surgery we planned to make a geometrical incision of relaxation as well as application of a-cellular collagen matrix graft in order to allow better lengthening and straightening of the penis; this was not necessary, as the complete isolation of neurovascular bundle has allowed a good penile straightening by itself. we performed an apical dilation of the right corpus cavernosum to correctly reposition the right prosthetic cylinder, we fixed the crural tips of the two prosthetic cylinders with prolene 2/0 at the same crural level in order to obtain the alignment of the cylinders along the longitudinal axis and the symmetry of both cylinders of penile prosthesis (figures 4-5). as described in literature, the most common postoperative complaint from men who have undergone the penile implant is the length loss, for these reason we suggest an early activation of penile prostheses to avoid penile shortening (10-11). references 1. rosen r, catania j, lue t, et al. impact of peyronie’s disease on sexual and psychological functioning: qualitative findings in patients in patients and controls. j sex med. 2008; 5:1997-84. 2. smith jf, walsh tj, conti s, et al. risk factors for emotional and relationship problems in peyronie’s disease. j sex med. 2008; 5: 2179-84. 3. el-sakka ai, hassoba hm, chui rm, et al. an animal model of peyronie’s like condition associated with an increase of transforming growth factor beta mrna and protein expression. j urol. 1997; 158:2284-90. 4. larsen sm, levine la. review of non surgical treatment options for peyronie’s disease. int j impot res. 2012; 24:1-10. 5. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie’s disease and erectile dysfunction. functional and satisfaction outcomes. j sex med. 2005; 2:132-8. 6. levine la, lenting el. a surgical algorithm for the treatment of peyronie’s disease. j urol. 1997; 158:2149-52. 7.ralph dj, minhas s. the management of peyronie’s disease bju int. 2004; 93:208-15. 8. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie’s disease and erectile dysfunction. functional and satisfaction outcomes. j sex med. 2005; 2:132-8 9. levine la, dimitriou rj, a surgical algorithm for penile prosthesis placement in men with erectile failure and peyronie’s disease. int j impot res. 2000; 12:147-51. 10. montague dk. penile prostheses implantation: size matters. eur urol. 2007; 51:887-8. 11. wang r, howard ge, hoang a, et al. prospective and long-term evaluation of erectile penile length obtained with inflatable penile prostheses to that induced by intracavernosal injection. asian j androl. 2009; 411-5. correspondence patrizio vicini, md (corresponding author) patriziovicini@gmail.com ferdinando de marco, md luigi azzarri, md department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy gabriele antonini, md ettore de berardinis, md riccardo giovannone, md vincenzo gentile, md department of urology, “sapienza” rome university, rome, italy stefano pecoraro, md department of urology, malzoni institute avellino, italy vicini cr_stesura seveso 26/03/14 10:44 pagina 47 201archivio italiano di urologia e andrologia 2016; 88, 3 original paper emergency management of ureteral stones: evaluation of two different approaches with an emphasis on patients’ life quality kemal sarica 1, bilal eryildirim 1, cahit sahin 1, özlem kolçak türkoğlu 1, murat tuncer 1, alper coskun 1, hakan akdere 2 1 dr. lütfi kirdar training and research hospital urology clinic, istanbul, turkey; 2 trakya university, faculty of medicine, urology clinic, edirne, turkey. objectives: to evaluate the emergency management of obstructing ureteral calculi with two different techniques (swl and urs) with an emphasis on patients life quality. methods: a total of 80 patients presenting with acute colic pain due to a single obstructing ureteral stone were treated within 24 hours following the onset of pain with two different approaches in a randomized manner. patients requiring dj stent placement and/or auxiliary measures after both procedures were excluded and the remaining 65 patients were evaluated [group1: eswl (n = 34); group 2: urs (n = 31)]. patients were followed during 4-weeks period with respect to the analgesic requirement, number of renal colic attacks and emergency department visits along with the hrqol scores. results: while 26 patients treated with urs (83.9%) were stone-free, 24 cases in swl were stone-free (70.6%) after 4 weeks. evaluation of the cases during this follow-up period demonstrated that cases undergoing swl required significantly higher amount of analgesics when compared with urs group (p < 0.001). in addition to the lower mean number of renal colic attacks and emergency department visits in urs group; both the mean hrqol in terms of eq-5d index and mean eq-5d vas values were also significantly higher in these cases when compared with the cases tretaed with swl. conclusions: due to the negative impact of stone related events after emergency swl on patients hrqol, emergency urs may be applied more effectively with the advantages of prompt fragmentation of the calculi along with the immediate relief of obstruction and pain. key words: emergency treatment; ureteral stone; ureteroscopy; swl; hrqol. submitted 6 july 2016; accepted 19 july 2016 summary no conflict of interest declared. obstruction and colic related distressing symptoms necessitating analgesic use and emergency department (ed) visits which could have significant effects on the healthrelated quality of life (hrqol) (2-8). placement of an ureteral stent or percutaneous nephrostomy tube are the alternatives when conservative medical management does not resolve symptoms (3-5). currently shock wave lithotripsy (swl) and ureterorenoscopy (urs) are commonly performed procedures and while eau/aua treatment guidelines accepted both approaches as preferred options (4). stone free (sf) rates after swl is probably lower, especially for mid and distal ureteral stones (4, 6). although both methods were performed successfully in an elective manner; accumulated data so far in demonstrated that emergency disintegration with swl (management of the obstructing stones within 24 hours after the first colic attack) and also emergency removal with urs (where swl system is unavailable or has been unsuccessful) may also be effective alternatives (3, 4). each approach has its own advantages and disadvatages and although emergency swl has been performed with acceptable stone free rates (9, 10); uretersocopic lithotripsy has been found to be more effective in the quick and complete relief of acute obstruction and related pain (11-13). hrqol is an estimate of freedom from impairment, disability or handicap (14). the concept of hrqol is multidimensional and includes psychosocial, physical and emotional status, as well as patient autonomy and is applicable to a wide variety of medical conditions (1517). this brings the issue into the agenda that irrespective of the stone related factors, urologists should not solely focus on the stone free rates obtained but also on the possible effects of the procedure induced psychological and social life of the patients (14, 15). related with this subject, although various studies focused on the stone free rates and stone related problems to some extent after treatment; to our knowledge no study so far has investigated the hrqol of the patients after undergoing certain ureteral stone management procedures. in this present prospective controlled study, in addition doi: 10.4081/aiua.2016.3.201 introduction as a worldwide common pathology, urolithiasis affects about 5 to 10% of the general population (1). despite the asymptomatic clinical course in a certain percent of the cases; ureteral calculi may cause obstruction and colic pain requiring an immediate management. stone removal is often needed for relatively larger stones to remove the sarica2_stesura seveso 21/09/16 08:53 pagina 201 archivio italiano di urologia e andrologia 2016; 88, 3 k. sarica, b. eryildirim, c. sahin, ö. kolçak türkoğlu, m. tuncer, a. coskun, h. akdere 202 to outline the efficacy of swl and urs approaches performed in an emergent manner; we also aimed to evaluate the possible treatment related changes in the hrqol of the patients undergoing these procedures. patients and methods between october 2014 and may 2015, 80 adult patients (54 male and 26 female; m/f: 2.07) with acute colic pain due to a single obstructing opaque upper ureteral stone (5 to 10 mm) were evaluated. patients with multiple stones, previous stone surgery including stent placement and auxiliary procedures, congenital anomalies, active urinary tract infection, pregnancy or renal insufficiency were excluded. following acute pain management, emergency treatment of the stones within 24 hours after the onset of pain was performed. in addition to a detailed history and uro-genital examination, biochemical evaluation and urinalysis were performed. the study protocol has been approved by ethics committee of the institution. although a noncontrast computed tomography (ncct) was performed in all cases during colic attack; plain x-ray of the kidney, ureter and bladder (kub), ultrasound and excretory urography were also done when necessary. all cases were treated within 24 hours following the onset of pain with two different approaches (swl and urs) in a randomized manner. although medical expulsive therapy (met)), observation or a planned elective therapy were offered; due to the distressing colic pain none has accepted these alternatives. patients requiring dj stent placement and/or auxiliary measures after both procedures were excluded due to the possible effects of these procedures on the hrqol of the cases which may affect to interprete our final data. the remaining 65 patients were included in the study (group 1: swl (n = 34); group 2: urs (n = 31)). randomization was done by a simple method by generating a random digit (0-60 in each group). while even numbers were used for swl, odd numbers used for urs. the advantages, disadvantages and possible complications of both procedures were explained and a written informed consent has been obtained. swl was performed with an electromagnetic lithotriptor (compact sigma, dornier medtech, wessling, germany) under analgesia. semirigid ureteroscopy was performed with 8 fr ureteroscope (karl storz, tuttlingen, germany) under general anesthesia. in addition to the stone free and possible complication rates; patients were followed during 4weeks period (by accepting every week) with respect to the analgesic requirement (mg of diclofenac sodium applied), number of renal colic attacks and emergency department visits. lastly, as an important parameter the hrqol of all cases were assessed by using euroqol 5d (eq-5d) scale ((comprising two different scales namely eq5d index scale and the eq-5d visual analogue scale (vas)) which has been devaloped in 1987 by an international team, the european quality of life group at the end of 4-weeks period (18). data are presented as mean ± standard error of mean. by using prism 5.0 (graphpad software, san diego, ca), unpaired t test was used to evaluate the overall statistical significance between subgroups; p < 0.05 was considered to be significant. results a total of 65 patients were included and further evaluated (47 men and 18 women; m/f: 2.61), (group 1: eswl (n = 34); group 2: urs (n = 31)). the overall mean stone burden was 51.50 ± 2.78 mm2 (30-96 mm2). patient as well as stone related characteristics in the whole group are being summarized in table 1. evaluation of our results after 4-weeks period revealed the following findings. of all the 31 cases treated with urs: 26 cases (83.9%) became completely stone free (sf), residual fragments (rf) were present in 5 cases (16.1%). rf were removed by flexible urs. on the other hand, of the 34 cases undergoing swl: 24 cases were completely sf (70.6%), one case (2.9%) had rf (< 4 mm), the procedure was unsuccessful in the remaining 9 cases (26.5%) (table 2). ureteroscopic stone disintegration was performed in all the unsuccessful swl treatments. on the other hand, cases undergoing swl required statistically significant higher amount of analgesics (mean value of analgesic requirement was 351.0 ± 60.25 mg (01200 mg) and 75.00 ± 20.27 mg (0-525 mg) respectively, p < 0.001). additionally, the mean value of visual analog scores during pain was also significantly higher in these cases (p = 0.0212). same findings were true for the mean number of renal colic attacks and ed visits with significantly higher values in favour of swl (< 0.001 and 0.0097 respectively) (table 3). regarding the possible negative impact of above mentioned parameters on the hrqol of the cases after 4 weeks; the life quality scores in both groups were well evaluated (by using the mean index values of eq-5d and overall eswl urs p n = 65 n = 34 n = 31 age (year) 40.50 ± 1.73 38.73 ± 2.48 42.27 ± 2.41 0.3109 stone burden (mm2) 51.50 ± 2.78 47.40 ± 2.84 55.60 ± 4.71 0.1416 hu (hounsfield unit) 764.4 ± 37.59 707.5 ± 46.72 821.3 ± 57.82 0.1312 degree of hydronephrosis (grade) 1.71 ± 0,10 1.53 ± 0.14 1.90 ± 0.13 0.0773 table 1. evaluation of patient and stone characteristics in both groups. stone free 24 70.6 26 83.9 residüel stone ≤ 4 mm 1 2.9 0 0 not stone free (requiring intervention) 9 26.5 5 16.1 table 2. stone passage rates and required interventions after 4-weeks in both groups. sarica2_stesura seveso 21/09/16 08:53 pagina 202 mean values of eq-5d vas methods) after 4-weeks. our results showed that cases undergoing swl tended to have significantly lower scores indicating the negative effects of spontaneous passage of rf and additional procedures. evaluation of the hrqol scores in terms of eq-5d instrument diemensions again demonstrated that the “pain/discomfort” and “anxiety/depression” dimensions were the most commonly and meaningfully affected dimensions (expressions as “some problems”). our data revealed the mean indices of eq-5d to be 0.77 ± 0.02 (0.36-1.00) vs 0.87 ± 0.01 (0.76-1.00), (p = 0.004) in cases undergoing swl and urs respectively. lastly, evaluation of mean eq-5d vas values demonstrated higher mean values in patients undergoing urs (p < 0.001) (table 4). these findings indicated the meaningful adverse effects of swl related events on the qol of the cases treated for ureteral calculi. comparative evaluation of our results with pooled european data of comparable age group did show similar mean index values for the dimensions evaluated (19). discussion as a result of obstruction and colic pain requiring an emergency management in the majority of the cases, upper ureteral stones may significantly affect the life quality of the patients (1, 2). currently both swl and urs with different lithotriptor systems are acceptable alternatives in the management of these stones (20, 21). although swl seems to be the preferred method with its effective and safe nature; repeated treatments may prolong the total duration of the treatment during which fragment passage may cause obstruction, colic pain and urinary symptoms (22-25). in addition to distressing symptoms; severe obstruction will require a rapid stone removal in at least a certain subset of patients with relatively harder stones (1, 2, 4, 5). on the other hand, clinical use of the smaller scopes has led the endourologists to remove the ureteral calculi in a safe, quick and more cost-effective manner with urs (26, 27). however; despite the advantage of an immediate decompression of the obstruction in one session, general anesthesia and hospitalization will be required in these cases (4, 11). due to the prolonged obstruction along with the impact of repeated colic attacks requring analgesic medication and emergency department referral, emergency management of ureteral stones during or immediately after the first acute renal colic attack has been applied as a more reasonable alternative in selected cases (3, 10, 28). available limited data demostrated that both “swl” and “ureteroscopic lithotripsy” could be performed in an “emergent manner” to relieve the present obstruction and related colicky pain. however it is hard for the responsible endourologist to select and also offer one procedure as more advantageous than the other one depending solely on these similar outcomes. lastly, such stones could be a serious health problem due to the obstruction induced colic pain and associated distressing symptoms with significant adverse effects on the hrqol of the cases (7, 8). health related quality of life assessment is an increasingly important aspect of contemporary medical practice which can be measured by general and/or disease-specific instruments (14). the concept of hrqol is multidimensional and includes psychosocial, physical and emotional status, as well as patient autonomy and is applicable to a wide variety of medical conditions (15-17). among the instruments used so far; as a generic, hrqol instrument to measure health outcomes; eq-5d scale has been devaloped in 1987 by an international team, the european quality of life group. the validity of the eq-5d has been assessed within a number of different patient groups and within the general population in different countries. currently there are 170 official language versions of eq-5d (18). one of them is the turkish version of eq-5d, which was obtained from euroqol (www.euroqol.org) and used in our study. this instrument comprises two different scales namely eq-5d index scale and the eq-5d visual analogue scale (vas). the eq-5d index scale currently comprises a questionnaire with five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). each dimension of the eq-5d is divided into three degrees of severity as “no problem”, “some problems”, or “major problems”. a single index score can be produced using information from these five dimensions. the eq-5d index score range from -0.59 to 1 and includes a worse than death measure (negative score), outside the range of 0 (dead) to 1 (perfect health). second scale is the eq-5d vas scale and it is a 20-cm visual analogue scale where the respondent is asked to mark his or her own current state of health on a thermometer-like line calibrated from 0 to 100. in light of the data given above, we may claim that emergency removal of ureteral calculi following pain manage203archivio italiano di urologia e andrologia 2016; 88, 3 emergency management of ureteral stones overall eswl urs p n = 65 n = 34 n = 31 no. of renal colic 2.55 ± 0.36 4.30 ± 0.54 0.80 ± 0.20 < 0.001 no. of ed visit 0.68 ± 0.13 1.03 ± 0.23 0.33 ± 0.11 0.0097 analgesic required (mg) 213.3 ± 36.30 351.0 ± 60.25 75.00 ± 20.27 < 0.001 vas during pain 4.90 ± 0.35 5.70 ± 0.38 4.10 ± 0.55 0.0212 table 3. evaluation of the mean number of colic attacks, analgesic requirement, ed visits and vas in both groups during 4-weeks follow-up period. overall eswl urs p n = 65 n = 34 n = 31 mean eq-5d index 0.82 ± 0.13 0.77 ± 0.02 0.87 ± 0.01 0.004 mean eq-5d vas value 78.92 ± 1.35 73.17 ± 1.72 84.67 ± 1.49 < 0.001 vas during pain 4.90 ± 0.35 5.70 ± 0.38 4.10 ± 0.55 0.0212 table 4. evaluation of the mean eq-5d index values and eq-5d vas values in both groups, during 4-weeks follow-up period. sarica2_stesura seveso 21/09/16 08:53 pagina 203 archivio italiano di urologia e andrologia 2016; 88, 3 k. sarica, b. eryildirim, c. sahin, ö. kolçak türkoğlu, m. tuncer, a. coskun, h. akdere 204 ment after first colic attack will further be advantageous by diminishing the negative effects of the stone induced symptoms on the hrqol of the cases and this observation will further strengthen the judicious emergency application of both procedures in such cases. with this concept, we may realize that urologists should not solely focus on the sf rates obtained but also on the possible effects of the stone-induced distressing symptoms on the psychological and social life of the patients (14, 15). to our knowledge, no study so far has investigated hrqol in patients with ureteral calculi undergoing swl as well as urs in an emergent manner. regarding the possible changes in hrqol in patients with stone disease penniston and nakada reported that these patients showed decreased hrqol when compared to healthy adults. using the sf-36 validated qol questionnaire, they found that stone-bearing patients had lower scores on the general health and bodily pain domains, and female stone formers reported lower average qol scores than male respondents (17). in 2009, again, bensalah et al. reported multiple factors affecting hrqol in such patients, including bmi, age and the number of surgical procedures performed (15). lastly, rabah et al. examined hrqol of patients after lithotripsy procedure and stated that hrqol of these cases was similar to the healthy controls (8). in this present study, we aimed to evaluate the possible effects of two different ureteral stone management options (swl vs urs) performed in an emergent manner on the hrqol of the treated patients. our results have clearly demonstrated that contrary to swl application; ureteroscopic ho-yag disintegration of ureteral stones were found to be associated with higher sf rates after a single session with limited or no additional procedures which significantly lowered the mean number of both renal colics and ed visits along with the total amount of analgesic used. relatively lower sf rates after a single session of swl coupled with higher rates of additional procedures for rf removal may have a negative impact on patients life quality during this period. evaluation of the data reported in the literature on this aspect so far did show that although 5-10% of the patients reported “extreme problems”; most of the patients had reported “no problem” for all domains. our findings were in accordance with these data where most of the cases after swl showed “some problems” related with two main dimensions (“pain/discomfort” and “anxiety/depression”). thus our data indicate that in addition to the higher sf rates and limited additional procedures, emergency ureteroscopy may have certain advantages mentioned above which will definitely have positive effects on the hrqol of treated cases. our findings again seem to be further valuable by giving the chance for the practising urologists to offer this approach reliably based on the objective advantages of the procedure that will inevitably preferred by the patients. our current study has only one certain limitation; the number of the cases evaluated in this study might be small, but in light of the highly limited data available in the literature, we believe that our current findings will be contributive enough to a considerable extent. furthermore to our knowledge this is the first report focusing on the life quality changes in cases undergoing two different stone treatment modalities (swl vs urs). conclusion emergency ureteroscopic management of obstructive ureteral stones appears to be an effective treatment modality with comparable success as well as complication rates with swl performed in the same manner. however, taking the statistically significant negative impact of stone related distressing events induced by the fragments after emergency swl on the hrqol of the treated cases, we believe that in skilled hands, emergent urs approach may be a better option than emergency swl. we believe that further studies with larger series of patients including other indicative parameters are certainly needed. references 1. teichman jm. clinical practice. acute renal colic from ureteral calculus. n engl j med. 2004; 350:684-93. 2. doublet jd, tchala k, tligui m, et al. in situ extracorporeal shock wave lithotripsy for acute colic due to obstructing ureteral stones. scand j urol nephrol. 1997; 31:137-9. 3. gettman mt, segura jw. management of ureteric stones: issues and controversies. bju int. 2005; 95:85-93. 4. preminger gm, tiselius hg, assimos dg, et al. eau/aua: nephrolithiasis guideline panel. 2007 guideline for the management of ureteral calculi. j urol. 2007; 178:2418-34. 5. joshi hb, obadeyi oo, rao pn. a comparative analysis of nephrostomy, jj stent and urgent in situ extracorporeal shock wave lithotripsy for obstructing ureteric stones. bju int. 1999; 84:264-9. 6. bierkens af, hendrikx aj, de la rosette jj, et al. treatment of midand lower ureteric calculi: extracorporeal shock-wave lithotripsy vs laser ureteroscopy. a comparison of cost, morbidity and effectiveness. br j urol. 1998; 81:31-7. 7. roehrborn cg. acute relief or future prevention. is urology ready for preventive health care? urology 2000; 56:12-9. 8. rabah dm, alomar m, binsaleh s. health related quality of life in ureteral stone patients: post-ureterolithiasis. urol res. 2011; 39:385-8. 9. peschel r, janetschek g, bartsch g. extracorporeal shock wave lithotripsy versus ureteroscopy for distal ureteral calculi: a prospective randomized study. j urol. 1999; 162:1909-12. 10.tiglui m, el khadime mr, tchala k, et al. emergency extracorporeal lithotripsy (eswl) for obstructing ureteral stones. eur urol. 2003; 43:552-5. 11. jiang h, wu z, ding q. ureteroscopy and holmium yag laser lithotripsy as emergency treatment for acute renal failure caused by impacted ureteral calculi. urology 2008; 72:504-7. 12. conort p, doré b, saussine c. comité lithiase de l'association françaised'urologie (guidelines for the urological management of renal and ureteric stones in adults) progurol. 2004; 14:1095-1102. 13. kijvikai k, haleblian ge, preminger gm, et al. shockwave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an old discussion revisited. j urol. 2007; 178:1157-63. sarica2_stesura seveso 21/09/16 08:53 pagina 204 14. last jm, spasoff ra, harris ss. a dictionary of epidemiology. new york, oxford university press. 2001; vol 4: p.148. 15. bensalah k, tuncel a, gupta a, et al. determinants of quality of life for patients with kidney stones. j urol. 2008; 179:2238-43. 16. alonso j, ferrer m, gandek b, et al. iqola project group. health-related quality of life associated with chronic conditions in eight countries: results from the internation. qual life res. 2004; 13:283-98. 17. penniston kl, nakada sy. health related quality of life differs between male and female stone formers. j urol. 2007; 178:2435-40. 18. euroqol group (20-5-2008) eq-5d available versions. http://www.euroqol.org/web/users/language_a.php. 19. szende a, williams a. measuring self-reported population health: an international perspective based on eq-5d. springmed publishing, (budapest) hungary; 2004. 20. tiselius h.g. removal of ureteral stones with extracorporeal shock wave lithotripsy and ureteroscopic procedures. what can we learn from the literature in terms of results and treatment efforts. urol res. 2005; 33:185-90. 21. stewart gd, bariol sv, moussa sa, et al. matched pair analysis of ureteroscopy vs. shock wave lithotripsy for the treatment of upper ureteric calculi. int j clin pract. 2007; 61:784-8. 22. turna b, akbay k, ekren f, et al. comparative study of extracorporeal shock wave lithotripsy outcomes for proximal and distal ureteric stones. int urol nephrol. 2008; 40:23-9. 23. ziaee sa, halimiasl p, aminsharifi a, et al. management of 1015 mm proximal ureteral stones: ureteroscopy or extracorporeal shockwave lithotripsy? urology 2008; 71:28-31. 24. karlsen sj, renkel j, tahir ar, et al. extracorporeal shockwave lithotripsy versus ureteroscopy for 5to 10-mm stones in the proximal ureter: prospective effectiveness patient-preference trial. j endourol. 2007; 21:28-33. 25. bagley dh. expanding role of ureteroscopy and laser lithotripsy for treatment of proximal ureteral and intrarenal calculi. curr opin urol. 2002; 12:277-80. 26. lee yh, tsai jy, jiaan bp, et al. prospective randomized trial comparing shock wave lithotripsy and ureteroscopic lithotripsy for management of large upper third ureteral stones. urology 2006; 67:480-4. 27. yencilek f, erturhan s, sarıca k. treatment of ureteral calculi with semi-rigid ureteroscopy: where should we stop? urol int. 2010; 84:260-4. 28. sarica k, tanrıverdi o, aydın m, et al. emergency ureteroscopic removal of ureteral calculi after first colic attack: is there any advantage? urology 2011; 78:516-20. 205archivio italiano di urologia e andrologia 2016; 88, 3 emergency management of ureteral stones correspondence kemal sarica, md saricakemal@gmail.com bilal eryildirim, md bilaleryildirim@yahoo.com cahit sahin, md cahitsahin129@gmail.com murat tuncer, md murattuncer77@hotmail.com alper coskun, md dr.alper05@gmail.com dr. lütfi kirdar training and research hospital urology clinic tecerdagi cad. yakutlar sitesi g/11 kartal/istanbul, turkey özlem kolçak türkoğlu, md ozlemkolcak@hotmail.com dr. lütfi kirdar training and research hospital radiology clinic, istanbul, turkey hakan akdere, md hakdere@yahoo.com trakya university, faculty of medicine, urology clinic, edirne, turkey sarica2_stesura seveso 21/09/16 08:53 pagina 205 stesura seveso 177archivio italiano di urologia e andrologia 2015; 87, 2 case report extraintestinal gastrointestinal stromal tumor of undetermined origin: is the mass resection a wrong approach? a case report and review of the literature özgür haki yüksel, serkan akan, çaglar yildirim, ahmet ürkmez, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey gastrointestinal stromal tumor (gist) was first defined by mazur et al. in 1983. gist is evaluated among tumoral lesions that can be acquired or congenital. those not associated with gastrointestinal system are termed as extragastrointestinal stromal tumor (egist). egists can develop on intraperitoneal spaces as omentum, mesenterium and gallbladder and they can occur on retroperitoneum, extraperitoneal (prostate) and intrapelvic organs. herein, we present a case with egist in a 65-year-old male patient located in intrapelvic and retroprostatic area which had no connection with gastrointestinal system as assessed by radiological methods and we discuss its treatment. we reviewed the literature and observed that ours is the first case report on a patient in which the mass was only extirpated rather than performing radical surgery. he is still at the 2. year of his follow-up period without any disease recurrence. key words: extragastrointestinal stromal tumor; prostate; mass extirpation. submitted 10 january 2015; accepted 19 march 2015 summary no conflict of interest declared. case report a 60 year-old male patient presented to the clinic of general surgery with complaints of epigastric pain, jaundice and difficulty in defecation. when radiological evidence of intrapelvic retroprostatic mass was found, he was referred to our clinic. he had undergone hypophysectomy 16 years before with the diagnosis of pituitary adenoma. his laboratory test results were as follows: hematocrit: 36%, platelet count: 373.000/mm3, serum creatinine: 0.67 mg/dl, total testosterone: 0.24 ng/ml, prolactin: 0.8 ng/ml, baseline cortisol: 9 mcg/dl, total psa < 0.01 ng/ml. decreased luteinizing hormone levels were detected, while t3, t4, follicle stimulating hormone and results of complete urinalysis were within normal limits. the patient was receiving daily doses of 0.1 mg levothyroxine and 2.5 mg bromocriptine. general physical examination revealed a slight rebound tenderness (murphy’s sign positivity). scrotal examination revealed decreased bilateral testicular volumes. during digital rectal examination, a rectal fibrotic mass in the prostatic lodge that could be partially palpated and presumably extending up to the proximal part of the rectum was palpated. magnetic resonance imaging (mri) of the abdomen revealed a mass lesion measuring nearly 65x68x95 mm with a central cystic and necrotic area. this mass was located on the left posterolateral part of the prostate gland associated with a decrease in the prostatic volume and its post-contrast images demonstrated a space-occupying lesion with an intense contrast uptake (figure 1). the lesion was adjacent to the left posterolateral wall of the bladder. demarcation line between some part of the mass and layers of the bladder walls was disrupted and also the lesion extended to the mesorectum. the adipose tissue interposed between the lesion and the rectum was effaced and the mass compressed the rectum. multiple reactive lymph nodes were observed in bilateral inguinal regions. degenerative changes consistent with the patient’s age were observed in bony structures, which did not suggest metastases. report of the flexible colonoscopic examination performed by the department of gastroenterology denied the presence of a macroscopic mass lesion. positron emission tomography (pet/ct) disclosed a left paramedian mass lesion with a soft-tissue density over the prostatic lodge with its largest doi: 10.4081/aiua.2015.2.177 introduction interstitial cells of cajal (iccs) have been defined by ramon cajal nearly 120 years ago as primitive neurons of the intestines (1). various studies have shown that iccs are pacemaker cells which ensure control of peristaltism in the gastrointestinal system (gis) (2). presence of iccs in the urinary system was firstly demonstrated in 1999 (3). in two separate studies performed by exintaris and shafik, the authors proposed the presence of spontaneous contractile activity in the stromal layers of the prostate of guinea pigs and dogs (4, 5). similarly presence of c-kit positive staining interstitial cells in the human prostate has been shown (6). it has been demonstrated that these cells can be pacemaker cells triggering slow-wave spontaneous electrical activity. it has been also suggested that they can be responsible for the transport of glandular secretion from prostatic acinar cells into its major and minor ducts and finally into urethra (4). herein, a case of egist located in retroprostatic area without any association with gastrointestinal system was discussed and evaluated in the light of the literature. yuksel_stesura seveso 02/07/15 11:40 pagina 177 archivio italiano di urologia e andrologia 2015; 87, 2 özgür haki yüksel, serkan akan, çaglar yildirim, ahmet ürkmez, ayhan verit 178 dimensions reaching 87 x 61 mm. on pet/ct, effacement of fat planes interposed between the mass and the rectum posteriorly, and left obturator internus muscle laterally was observed. the result of transrectal ultrasound guided biopsy was reported as gastrointestinal stromal tumor. with the aid of these data, surgical intervention was planned and realized under general anesthesia. intraoperatively, a mass measuring nearly 8 cm posterior to the left side of the bladder without any association with genitourinary system and rectum was detected and resected as an intact mass from its suitable surgical cleavage and sent to pathology. pecimens excised from the anterior wall of the rectum and retroprostatic region were sent for frozen section evaluation. frozen section examination was reported as tumor-negative, so we also excised tissues from surgical margin and sent them for histopathological examination. immunohistochemical evaluations of the specimen were reported as follows: cd-34, cd-117 (c-kit), vimentin positive; s-100, desmin, sma, hhf-35, panceratinine negative and ki-67 score was 11-12%. histopathological and immunohistochemical findings were evaluated as high-risk malignant gastrointestinal stromal tumor (figure 2). postoperatively, imatinib treatment was planned. at 2 year follow-up period no radiologically detected metastasis was observed. discussion and supplementary references are posted on www.aiua.it references 1. cajal sr. sur les ganglions et plexus nerveux d’intestin (abstract). cr soc bio. 1893; 5:217-223. 2. rumessen j, thuneberg l. pacemaker cells in the gastrointestinal tract: interstitial cells of cajal. scand j gastroenterol. 1996; 216:82-94. 3. klemm mf, exintaris b, lang rj. �dentification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. j physiol. 1999; 519:867-884 4. exintaris b, klemm fm, lang jr. spontanous slow wave and concractile activity of the guinea pig prostate. j urol. 2002; 168:315-322. correspondence özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com serkan akan, md çaglar yildirim, md ahmet ürkmez, md ayhan verit, md. prof, dept. of urology, fatih sultan mehmet research & training hospital içerenköy/ataşehir tr34752 istanbul, turkey figure 1. magnetic resonance imaging of the mass lesion measuring nearly 65 x 68 x 95 mm. figure 2. histopathological appearance of the mass lesion. yuksel_stesura seveso 02/07/15 11:40 pagina 178 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2132 note on surgical technique preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: a technical modification to improve the early recovery of continence eugenio brunocilla, riccardo schiavina, marco borghesi, cristian pultrone, matteo cevenini, valerio vagnoni, giuseppe martorana university of bologna s. orsola-malpighi hospital, bologna, italy. objective: we describe our technique for preservation of the smooth muscular internal (vesical) sphincter and proximal urethra during radical retropubic prostatectomy (rrp) and present our preliminary clinical results. materials and methods: the first steps of the prostatectomy reflect the standard rrp, while for the final phases the procedure continues in an anterograde manner with incision of the fibers of the detrusor muscle at the insertion of the ventral surface of the base of the prostate. at this level, the inner circular muscle of the bladder neck forms a sphincteric ring of smooth muscle that covers the longitudinally oriented smooth muscle component of the urethral musculature that extends distally to the verumontanum. these two proximal structures represent the internal sphincter that envelops and locks the proximal urethra. a blunt dissection is continued until the ring shaped vesical sphincter is separated from the prostate and the longitudinally oriented smooth muscle component of the urethral musculature is identified. the base of the prostate is then gently separated from the urethra and from the bladder until the maximal length of the urethral musculature is isolated and preserved. results: after 30 initial set-up procedures, 40 consecutive patients with organ confined prostate cancer were submitted to radical retropubic prostatectomy with the preservation of muscular internal sphincter and the proximal urethra and compared to 40 patients submitted to standard procedure who served as control group. the group of patients submitted to our technical modification had a faster recovery of early continence than control group at 3 and 7 days. conclusions: the described technique is a feasible and safe method for preservation of the internal urethral sphincter and allows improving the early recovery of urinary continence. the technique does not increase the rate of positive margins and the duration of the procedure. key words: radical prostatectomy; urinary continence; internal sphincter; proximal urethra; surgical margins. submitted 9 september 2013; accepted 31 march 2014 summary no conflict of interest declared. introduction retropubic radical prostatectomy (rrp) is one of the standard surgical methods for the treatment of clinically localised prostate cancer (pca). the preservation of urinary continence is one of the most important endpoints of the procedure. numerous mechanisms have been advocated as responsible for male postoperative urinary continence but the preservation of the integrity of the external urethral sphincter muscle, of the pelvic floor as well as anterior and posterior urethral support seem to play the most important role (1). young age and nervesparing procedure have been proposed as additional protective factors (2). during the last few decades, many technical modifications have been described in order to improve clinical results (3-6). in particular, the rocco stitch has shown an important potential role for the early recovery of continence (5, 6). in this paper, we describe our approach of preservation of the smooth muscular internal (vesical) sphincter (mis) as well as of the proximal urethra (pa) during bladder neck dissection as part of the conservation of the full functional length of the urinary sphincter and we present our preliminary results. materials and methods anatomic considerations and surgical technique the first part of the procedure is similar to the standard rrp described by walsh and co-workers (7) concerning the maintenance of the anterior and posterior urethral supports. in all cases we preserve the pubourethral and puboprostatic ligaments and we reconstruct the posterior musculofascial plate as described by rocco (6); great attention is made in preserving the integrity of the external urethral sphincter muscle, with clear visualization of the circular orientated horseshoe-shaped urethral sphincter (with its striated and smooth components, the rabdomyosphincter) and with the preservation of the maximal part of the longitudinally oriented smooth muscle of the urethra (the intrinsic sphincter or lissosphincter) that is close to the urethral lumen. doi: 10.4081/aiua.2014.2.132 133archivio italiano di urologia e andrologia 2014; 86, 2 internal sphincter and radical prostatectomy in the second part of the prostatectomy, the procedure becomes antegrade, with the aim of preserving the internal vesical sphincter and the pa. we cut the fibers of the detrusor muscle at the insertion of the ventral aspect of the base of the prostate; at this level, the inner circular smooth muscle of the bladder neck forms a sphincteric ring of smooth muscle that extend distally to the verumontanum and covers the longitudinally oriented smooth muscle component of the urethral musculature (the cranial prolongation of the lissosphincter). these structures represent the internal (vesical) sphincter that covers the pa (figure 1). presence of nodules of benign prostatic hyperplasia within the wall of the internal sphincter, previous surgery for benign prostatic obstruction (bpo) as well as loss of the integrity of the circular smooth muscle during radical prostatectomy may impair the function of the internal sphincter. a blunt dissection is continued till the ring shaped vesical sphincter is separated from the prostate and the longitudinally-oriented smooth muscle component of the urethral musculature is identified. thus, the base of the prostate is gently separated from the urethra till the maximal length of the internal (vesical) sphincter is preserved and the urethra is incised to remove the catheter. finally, the anastomotic sutures are placed through the distal urethral stump of external sphincter and the pa structure and are fixed to the circular fibers of the bladder neck. to assess the oncologic safety of our surgical technique, we perform circumferential biopsies of the pa and of the base of the prostate during the dissection in all cases. case-control study after 30 initial set-up procedures, we performed a prospective case-control study to assess the impact of our technique on urinary continence (8, 9): 40 consecutive patients with organ confined pca were submitted to radical retropubic prostatectomy with the preservation of muscular internal sphincter (mis) and the pa and compared to 40 patients submitted to standard procedure who served as control group. exclusion criteria were large mid lobe prostate or large prostate volume (> 80 cc) and high-risk pca (defined as psa > 20 ng/ml or clinical t3 or clinical gleason score > 7). the same surgeon with 25 years experience in rrp performed all surgical procedures. in all cases the catheter was removed after 12 days. continence rates were assessed using a self-administrated questionnaire at 3, 7, 30 days and 3, 12 months after removal of the catheter. results the group of patients submitted to our technical modification had a faster recovery of early continence than control group at 3 days (45% vs. 22%; p = 0.029) and at 7 days (75% vs. 50%; p = 0.018); considering the number of pads, group 1 had faster recovery of continence at 3, 7 and 30 days and a minor incidence of severe incontinence. there were no statistically difference in terms of continence at 3 and 12 months among the two groups. multivariate logistic regression analysis of continence in relation to the clinical, pathological and surgical characteristics showed that surgical technique and young age were significantly associated with earlier time to continence at 3 and 7 days, while there were no significant correlations with continence at 30 days, 3 and 12 months. the two groups had no significant differences in terms of positive surgical margins. there were no cases of bladder neck sclerosis/stricture or acute urinary retention. discussion recently others authors described the first clinical trial with the same technique, with optimal results in terms of early recovery of the continence (10). they demonstrated significantly lower urine loss, higher objective and social continence rates and higher qol-scores in patients who underwent this technique, thus confirming the positive impact of this technique in urinary incontinence after radical prostatectomy. conclusion in conclusion, in well-selected patients, our modified technique may accelerate the recovery of urinary continence and may improve the continence when the rabdosphincter has not been perfectly preserved. no additional positive margins were noted in both the two clinical trials and we look forward for the follow-up data to confirm its oncological safety. our preliminary results show optimal rates of recovery of urinary continence after surgery. however, because of the small number of patients who underwent this technique, further evaluation and comparative studies are needed to confirm these encouraging initial results. figure 1. identification and isolation of about 10 mm of proximal urethra during the dissection of the dorsal surface of the prostate from the bladder neck, with the preservation of the internal vesical sphincter. archivio italiano di urologia e andrologia 2014; 86, 2 e. brunocilla, r. schiavina, m. borghesi, c. pultrone, m. cevenini, v. vagnoni, g. martorana 134 references 1. xylinas e, ploussard g, durand x, et al. evaluation of combined oncological and functional outcomes after radical prostatectomy: trifecta rate of achieving continence, potency and cancer control a literature review. urology. 2010; 76:1194-8. 2. walz j, burnett al, costello aj, et al. a critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy. eur urol. 2010; 57:179-92. 3. licht mr, klein ea, tuason l, et al. impact of bladder neck preservation during radical prostatectomy on continence and cancer control. urology. 1994; 44:883-7. 4. schlomm t, heinzer h, steuber t, et al. full functional-length urethral sphincter preservation during radical prostatectomy. eur urol. 2011; 60:320-9. 5. rocco f, carmignani l, acquati p, et al. restoration of posterior aspect of rhabdosphincter shortens continence time after radical retropubic prostatectomy. j urol 2006; 175:2201-6. 6. gautam g, rocco b, patel vr, et al. posterior rhabdosphincter reconstruction during robot-assisted radical prostatectomy: critical analysis of techniques and outcomes. urology. 2010; 76:734-41. 7. walsh pc, lepor h, eggleston jc, et al. radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. prostate. 1983; 4:473-85. 8. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 9. brunocilla e, schiavina r, pultrone cv, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. int j urol. 2013 jun 26. 10. nyarangi-dix jn, radtke jp, hadaschik b, et al. impact of complete bladder-neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomised controlled single-blind trial. j urol. published on line: 24 sep 2012. correspondence eugenio brunocilla, md riccardo schiavina, md (corresponding author) rschiavina@yahoo.it marco borghesi, md cristian pultrone, md matteo cevenini, md valerio vagnoni, md giuseppe martorana, md university of bologna s. orsola-malpighi hospital, bologna, via palagi 9 40134 bologna, italy archivio italiano di urologia e andrologia 2013; 85, 296 introduction rupture of an aneurysm of the retroperitoneal or pelvic vessels represents an extremely rare cause of macroscopic haematuria (1, 2). the diagnosis is difficult but should be considered whereas conditions as neoplasms, lithiasis or infections have been excluded and there is a history of retroperitoneal/pelvic surgical treatment. case report in the present report, we describe the case of a 65 yearsold-woman who underwent a diagnostic laparoscopy for a suspected ovarian cancer. the procedure consisted in a peritoneal washing, right oophorectomy and multiple biopsies of the right and left diaphragmatic dome of the peritoneum with an intraoperative diagnosis of peritoneal carcinomatosis. the histological examination confirmed the presence of an ovarian serous carcinoma. the patient underwent an operative laparoscopy with extrafascial radical isterectomy, left oophorectomy, pelvic peritonectomy and pelvic-lomboaortic lymphadenectomy. during the procedure the right ureter was accidencase report massive hematuria due to ruptured iatrogenic aortic pseudoaneurysm: a case report valerio vagnoni 1, caterina gaudiano 2, giovanni passaretti 1, riccardo schiavina 1, eugenio brunocilla 1, cristian vincenzo pultrone 1, marco borghesi 1, giuseppe martorana 1 1 department of urology, university of bologna, s. orsola-malpighi hospital, bologna, italy; 2 department of radiology, bologna, s. orsola-malpighi hospital, bologna, italy. we report an interesting case of massive haematuria secondary to a rupture of a pseudoaneurysm of the abdominal aorta below the renal vessels. a 65-year-old woman presented at our institution with a painful massive haematuria and anaemia. two months before, she undergone a pelvic surgery complicated by an accidental injury of the right ureter sutured with a end-to-end anastomosis. an abdominal computed tomography (ct) scan with intravenous contrast showed a right-sided hydronephrosis with clots in the lumen of the right pelvis with a massive retroperitoneal hematoma due to a rupture of a iatrogenic pseudoaneurysm of the abdominal aorta below the origin of the renal arteries. key words: haematuria; aortic pseudoaneurysm; pelvic surgery. submitted 25 october 2012; accepted 31 december 2012 no conflict of interest declared summary tally injured; therefore a laparotomic surgery has been required and an end-to-end ureteral anastomosis with placement of a renovesical “jj stent” was performed. the stent was removed after 45 days and after 65 days from surgery the patient presented at our institution with massive haematuria and severe anaemia (haemoglobin 7.6 g/dl, haematocrit 23%). bladder irrigation was initiated and cystoscopy showed a little clot from the right ureteric orifice in the absence of urothelial bladder lesions: a right ureteral catheter was inserted, some clots were removed from the right pelvis and a right retrograde pyelography showed the dehiscence of the uretheral anastomosis with a mild passage of contrast medium in the left retroperitoneum; thereafter, a second renovesical “jj stent” was inserted. an abdominal computed tomography (ct) scan was performed: we noted a right-sided hydronephrosis with clots in the lumen of the right pelvis and the presence of a massive hematoma between the abdominal aorta and the vena cava, ahead the ileo-psoas muscle in the left retroperitoneum (figure 1); after the administration of vagnoni_stesura seveso 24/06/13 11:07 pagina 96 97archivio italiano di urologia e andrologia 2013; 85, 2 hematuria after ruptured aortic pseudoaneurysm la due to the rupture of a iatrogenic pseudoaneurysm of the abdominal aorta was diagnosed and, after consulting the vascular surgeon, the patient underwent an urgent placement of aortic endoprothesis. afterwards, the hematuria was controlled. a further ct exam showed the correct positioning of the prosthesis and the patient was discharged with ureteral stent. discussion we described an extremely rare cause of macroscopic hematuria due to the rupture of a iatrogenic pseudoaneurysm of the abdominal aorta. the recent ureterouretero-anastomosis due to the accidental injury of the ureter was the obligatory condition in order to have an aorto-ureteric fistula after the rupture of the aneurysm. the iatrogenic injury of the aortic wall during the lymphadenectomy may explain the pseudoaneurysm. surgical treatment procedures like vascular reconstructive surgery or retroperitoneal/pelvic surgery for urogynecolocic or abdominal malignancies represent conditions with a potential risk for a hemorrhagic fistula from an artery into the urinary outflow tract; furthermore, previous radiation therapy or presence of aortic or iliac aneurysm may represent a potential risk conditions for the development of a fistula between an artery and the urinary tract; in the latter cases the pathophysiology is unclear but seems to be related to the inflammatory reaction around the aneurysm caused by surgery, radiation, malignancy, pulsatile trauma with the fixation and subsequent perforation of ureteral or bladder wall (1, 2). also the endourological treatment such as holmium laser endoureterothomy or acucise ballon endopielotomy for ureteropelvic junction obstruction may represent a rare cause of iatrogenic arterio-urinary fistula (3). in the present case, hematuria represented the sole symptom. however the passage of the clots in the renal pelvis and ureter could have been the cause of the abdominal pain. in literature is anecdotally reported that, in the absence of the intravenous contrast (arterial phase), we noted the presence of a breach of the right wall of the abdominal aorta, 4 cm below the origin of the renal arteries, with a large loculated pseudoaneurysm (axial diameters 37 x 22 mm) (figures 2-3) in the right retroperitoneum with a massive hematoma due to a recent rupture of the aneurysm. hematuria caused by an aorto-ureteral fistufigure 1. non-enhanced abdominal ct scan in the axial plane showing a right-sided hydronephrosis with clots in the lumen of the right pelvis. figure 2. contrast enhanced abdominal ct scan in arterial phase (mpr-reconstruction in oblique axial plane) showing the abdominal aortic pseudoaneurysm in the context of a massive retroperitoneal hematoma. note the metallic clip utilized during pre-aortic lymphadenectomy and the right ureteral stent (red arrow). figure 3. contrast enhanced abdominal ct scan in arterial phase (mip-reconstruction in oblique coronal plane) showing the pseudoaneurysm below the right renal artery in the context of a massive retroperitoneal hematoma. vagnoni_stesura seveso 24/06/13 11:07 pagina 97 archivio italiano di urologia e andrologia 2013; 85, 2 v. vagnoni, c. gaudiano, g. passaretti, r. schiavina, e. brunocilla, c.v. pultrone, m. borghesi, g. martorana 98 references 1. honma i, takagi y, shigyo m, et al. massive hematuria after cystoscopy in a patient with an internal iliac artery aneurysm. int j urol. 2002; 9:407-409. 2. bergqvist d, parsson h, sherif a. arterio-ureteral fistula a systematic review. eur j vasc endovasc surg. 2001; 22:191-196. 3. preminger gm, clayman rv, nakada sy, et al. a multicenter clinical trial investigating the use of a fluoroscopically controlled cutting balloon catheter for the management of ureteral and ureteropelvic junction obstruction. j urol. 1997; 157:1625-1629. 4. levi n, sonksen jr, iversen p, helgstrand u. rupture of an iliac artery pseudo-aneurysm into a ureter case report. eur j vasc endovasc surg. 1999; 17:264-265. a correct diagnosis of the arterio-ureteral fistula, a nephroureterectomy has often been performed, in emergency and life-threatening cases (2, 4); however, it is clear that the goal of the treatment is to solve the vascular lesion. open or endovascular procedures generally allow to stop the hematuria even if postoperative morbidity and mortality still remains high but less than thirty years ago. in conclusion, the present case report represents a rare cause of massive hematuria due to a double iatrogenic surgical injury of the aortic wall and the right ureter. after the initial rupture of the pseudoaneurysm (with subsequent spontaneous closing), a massive hemorrhage of the retroperitoneum and the dehiscence of a recent uretero-ureteral anastomosis caused a massive aortoureteral fistula that was promptly corrected by the placement of aortic endoprothesis. correspondence valerio vagnoni, md (corresponding author) vagno07@libero.it giovanni passaretti, md giovannipassaretti@hotmail.it riccardo schiavina, md rschiavina@yahoo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it cristian vincenzo pultrone, md cristian28@libero.it marco borghesi, md mark.borghesi@gmail.com giuseppe martorana, md giuseppe.martorana@unibo.it department of urology, university of bologna, s. orsola-malpighi hospital, via p. palagi 9 40138, bologna, italy caterina gaudiano, md department of radiology, bologna, s. orsola-malpighi hospital, via p. palagi 9 40138, bologna, italy caterina.gaudiano@aosp.bo.it vagnoni_stesura seveso 24/06/13 11:07 pagina 98 archivio italiano di urologia e andrologia 2017; 89, 2102 original paper effectivity of intravescical thermo-chemotherapy prophylaxis for patients with high recurrence and progression risk for non-muscle invasive bladder cancer ali serdar gözen 1, paolo umari 2, walter scheitlin 1, fuat ernis su 3, yigit akin 4, jens rassweiler 1 1 department of urology, slk-kliniken, university of heidelberg, heilbronn, germany; 2 department of urology, cattinara hospital, university of trieste, italy; 3 department of urology, kanuni sultan süleyman education and research hospital, istanbul, turkey; 4 department of urology, harran university school of medicine, sanliurfa, turkey. background&aim: high grade non-muscle invasive bladder cancer (nmibc) is common in urological practice. most of these cancers are or become refractory to intravesical immunotherapy and chemotherapy. here we evaluated the efficacy of combined local bladder hyperthermia and intravesical mitomycin-c (mmc) instillation in patients with high-risk recurrent nmibc. materials and methods: between february 2014 and december 2015, 18 patients with high risk nmibc were enrolled. patients were treated in an outpatient basis with 6 weekly induction sessions followed by monthly maintenance sessions with intravesical mmc in local hyperthermia with bladder wall thermo-chemotherapy (bwt) system (pelvixtt system, elmedical ltd., hod hasharon, israel). the follow-up regimen included cystoscopy after the induction cycle and thereafter with regular intervals. time to disease recurrence was defined as time from the first intravesical treatment to endoscopic or histological documentation of a new bladder tumour. adverse events were recorded according to ctc 4.0 (common toxicity criteria) score system. results: mean age was 72 (32-87) years. 10 patients had multifocal disease, 9 had cis, 6 had recurrent disease and 2 had highly recurrent disease (> 3 recurrences in a 24 months period). 6 patients underwent previous intravesical chemotherapy with mmc. the average number of maintenance sessions per patient was 7.6. after a mean follow-up of 433 days, 15 patients (83.3%) were recurrence-free. 3 patients had tumour recurrence after a mean period of 248 days without progression. side effects were limited to grade 1 in 2 patients and grade 2 in 1 patient. conclusions: bwt seems to be feasible and safe in high grade nmibc. more studies are needed to identify the subgroup of patients who may benefit more from this treatment. key words: bladder cancer; mitomycin-c; regional perfusion cancer chemotherapy. submitted 12 august 2016; accepted 11 january 2017 summary no conflict of interest declared. muscle invasive disease at the diagnosis (2). the mean characteristics of this cancer are high recurrence rates after transurethral resection and high risk of progression to muscle invasive disease (3). although, intravesical chemotherapy and immunotherapy can significantly decrease the recurrence and progression rates, they still represent the main challenge in this field and more effective therapies are needed (4). particularly challenging is the treatment of patients with high-risk tumours according to the european organization for research and treatment of cancer (eortc) scoring system and those who are refractory to intravescical bacillus calmetteguérin (bcg) instillation (1). moreover, there has been a shortage of bcg in europe. many approaches have been used to enhance the antitumor effects of intravesical chemotherapy (5). several studies have shown promising results combining intravesical mitomycin-c (mmc) with hyperthermia. it was demonstrated that hyperthermia of the bladder wall improves mmc penetration into the deep bladder wall and can offer anticancer advantages over chemotherapy instillation alone (6). the aim of this study was to evaluate the efficacy of combined intravesical mmc instillation and bladder hyperthermia in a selected group of patients with high-risk recurrent nmibc in whom radical surgery was not an option or bcg treatment was contraindicated. materials and methods this was a retrospective evaluation of prospectively collected data. the ethics commitee of our institution approved the present study. all patients read, understood, and signed the consents forms. all procedures performed were in accordante with the helsinky declaration or comparable ethical standards. patient and data collection between, february 2014 and december 2015, 24 patients with high risk nmibc underwent adjuvant thermo-chemotherapy with mmc at our department. the exclusion criteria were patients with muscle invasive doi: 10.4081/aiua.2017.2.102 introduction the non-muscle invasive bladder cancer (nmibc) is the 4th most common cancer in men and 12th in women with a great impact on health care system in europe (1). nearly 80% of the patients with bladder cancer present with nongozen new_stesura seveso 22/06/17 17:12 pagina 102 103archivio italiano di urologia e andrologia 2017; 89, 2 thermo-chemotherapy in nmibc bladder cancer, low risk bladder cancer, histology different than transitional, tumours involving the urethra or upper urinary tract, large bladder diverticulum (> 1 cm), patients underwent previous partial cystectomy and impossibility to undergone catheterisation with a 20 french catheter. 18 patients were eligible for the analysis and were included in the study. the other 6 patients did not meet the inclusion criteria, because 2 of them had incomplete data, 1 had muscle invasive disease, 1 had squamous tumour at histology, 1 had multiple tumours involving the urethra and 1 withdrew treatment at 3rd instillation because of his personal decision. we used tumour node metastasis (tnm) classification of 2009 for defining levels of nmibc in the study (7). treatment patients were treated on an outpatient basis with 6 weekly induction sessions followed by monthly maintenance sessions of intravesical mmc and bladder thermochemotherapy (bwt). the maintenance treatment was prosecuted for up to 1 year and patients with no recurrences underwent to an additional maintenance cycle every 3 months thereafter. the unithermia system (pelvix tt system, elmedical ltd., hod hasharon, israel) was used to heat the bladder wall, in all patients. this system is composed of a compact console with a peristaltic pump and a heat exchanger that delivers intravesical mmc through a 3-way silicon 20 french catheter. it allows to obtain a uniform hyperthermia all over the bladder by continuous flow of the heated mmc solution. according to previous studies, patients received 80 mg of mmc in 50 ml 0.9% saline, heated at 45°c in continuous circulation for 50 minutes (8) (figure 1). follow-up the follow-up regimen included cystoscopy after the induction cycle and after that every 3 months for a period of 2 years. thereafter the follow-up was conducted every 6 months. all lesions that were detected by cystoscopy during follow-up underwent biopsy. the recurrence was evaluated by histological examination. patients without tumour in the bladder and positive cytology underwent bladder mapping to exclude the presence of a carcinoma in-situ (cis). the transitional cell carcinoma of the upper urinary tract was also rolled out with appropriate imaging in these cases. time to disease recurrence was defined as the time from the first intravesical treatment to endoscopic or histological documentation of a new bladder tumour. adverse events were recorded regarding the common toxicity criteria (ctc) 4.0 score system (9). results description the mean age was 72 years (range 32-87). there were 16 male and 2 female patients. in total, 10 patients had multifocal disease, 9 had cis, 7 had recurrent diseases and 2 of them had a highly recurrent disease (> 3 recurrences in a 24 months period). both of last 2 patients had also a concurrent t1g3 disease. stage before starting the bwt treatment was ta in 5 patients, and t1 in 12 patients and all the patients had high grade (g2-3) disease. 6 patients have undergone previous intravesical therapy with mmc. the average number of maintenance sessions per patient was 7.6. all patients conducted the treatment during the induction and maintenance period with no significant side effects due to mmc and no physical complaints due to bladder hyperthermia. table 1 summarizes patients’ characteristics. table 1. patients characteristics. patients characteristics number of patients (total) 24 number of patients (included) 18 age mean (range) 72 (32-87) gender male 16 female 2 recurrence history recurrent 7 highly recurrent 2 number of tumours before bwt unifocal 8 multifocal 10 tumor stage prior bwt ta 5 t1 12 cis 9 prior intravescical therapy bcg 0 mmc 6 none 12 bcg: bacillus calmette-guérin; bwt: bladder wall thermo-chemotherapy; mmc: mitomycin c. figure 1. the unithermia system (pelvix tt system, elmedical ltd., hod hasharon, israel) used to heat the bladder wall. it is composed from a compact console with a peristaltic pump and a heat exchanger that delivers intravesical chemotherapy through a 3-way silicon 20 french catheter. the uniform hyperthermia at 45°c of 80 mg mmc in 50 ml 0.9% saline solution is mantained for 50 minutes by the continuous flow. gozen new_stesura seveso 22/06/17 17:12 pagina 103 archivio italiano di urologia e andrologia 2017; 89, 2 a. serdar gözen, p. umari, w. scheitlin, f. ernis su, y. akin, j. rassweiler 104 treatment results after a mean follow-up of 433 days, 15 patients (83.3%) were recurrence-free. besides, no patient had recurrence at the first cystoscopy after the induction cycle. 3 patients had tumour recurrence after a mean period of 248 days (range 191-339 days). however there was no disease progression, in fact staging and grading of these patients prior the treatment and at the time of reccurence were: t1g3+cis, tag2, cis and t1g3, tag1, cis respectively. 2 of them had multifocal disease recurrence. none among the 2 patients with highly recurrent disease relapsed during a mean follow-up of 655 days. these results are summarized in table 2. side effects side effects according to ctc 4.0 were limited to grade 1 in 2 patients (skin allergy and haematuria) and grade 2 in 1 patient (pain and bladder spasm during induction treatment sessions treated with intravesical oxybutynin). grade 1 complications were treated with oral analgesics and antiistaminics respectively. discussion the nmibc is characterised by a high recurrence rate (30-85%) after primary transurethral resection of the tumour (2). thus, intravesical immunotherapy with bcg or mmc is used for preventing recurrence (1). it is well known that bcg can significantly reduce the disease progression and recurrence rate but at the same time can also produce serious side effects such as voiding problems, urinary infection, haematuria up to miliary tubercolosis (10, 11). in these cases only mmc can be used as intravescical therapy (12). on the other hand, since more than hundred years ago, many experiments have shown that cancer cells are more susceptible to hyperthermia than normal healthy cells (13). local hyperthermia has a therapeutic potential for the treatment of many solid tumours, especially if used in combination with other treatments, such as radiation (radio hyperthermia) and chemotherapy (chemo hyperthermia) (14). lammers et al. reported a systematic review of 15 original articles and concluded that mmc+hyperthermia reduces the risk of nmibc recurrence by 59% when compared to mmc alone despite a limited number of randomized trials in current literature (15). the bladder is particularly suitable for the application of local hyperthermia because its wall could be heated by the irrigation of warm fluid (15). until now, several chemotherapeutics in various dosages and different regimens (adjuvant and neo-adjuvant) have been used in association with hyperthermia (16). intravesical mmc was recently used for preventing the recurrence and the progression of nmibc (17). it was demonstrated, that mmc associated with hyperthermia could have promising effects on a well selected subgroup of patients (18). it has been shown that hyperthermia interferes with dna, rna and protein synthesis of cancer cells. moreover intravescical mmc can inactivate cell repair mechanisms by increasing tumour cell apoptosis (19). for these reasons intravescical mmc associated with thermotherapy may be used as prophylaxis for recurrence and progression in high grade nmibc. heating of the bladder can be achieved, by radiofrequency, by magnetic nanoparticles in magnetic field or by circulation of externally heated fluid into the bladder (19). the most used systems are the synergo system (sbts 101 ± 1 system introduced by colombo r et al. in 1996) and the more recently unithermia system (20, 21). the former is based on direct irradiation of the bladder lumen by a 915-mhz intravesical microwave applicator and the latter comprises a console with a peristaltic pump and a heat exchanger that delivers intravesical chemotherapy through a 3-way silicon catheter (8). another method was recently proposed and consists on regional hyperthermia therapy using an array of 70 to 120 mhz antennas that are positioned around the patient, resulting in high homogenous temperatures of the target organ (22). we used the unitherma system in the current study because of its easy applicability. in our study thermo-chemotherapy with mmc provided promising results with low recurrence rate and no disease progression in patients with high grade nmibc at a medium-term follow-up period. the overall rate of side effects was low and the acceptance of the treatment by the patient was high. the main limitation of the current study is the small number of patients and therefore the impossibility to perform an accurate statistical analysis. the favorable factors are the only inclusion of patient with a high risk disease according to eortc classification in whom radical surgery was not an option or bcg treatment was containdicated. moreover all patients followed stricty the therapy plan and the follow-up schedule. conclusions according to these data thermo-chemotherapy seems to be a feasible, safe and promising approach for prophylactic treatment in patients with high risk nmibc. more studies are needed to identify the subgroup of patients who may benefit more from this treatment (ex. old patients with short life expectancy, those who are not candidates for anestesia due to high comorbidities or not suited for bcg therapy, those who refuse radical surgery and prefer conservative treatment to keep the bladder in situ). these preliminary results encourage further studies to define the limits and prospects of this regimen. table 2. review of the current series results. parameters mean follow-up (days) 433 recurrence free rate 15/18 (83,3%) mean recurrence time (days) 248 (191-339) disease progression 0/18 (0%) side effects (according to ctc) grade 1 2 (11,1%) grade 2 1 (5,6%) grade 3 0 (0%) grade 4 0 (0%) grade 5 0 (0%) ctc: common toxicity criteria. gozen new_stesura seveso 22/06/17 17:12 pagina 104 105archivio italiano di urologia e andrologia 2017; 89, 2 thermo-chemotherapy in nmibc references 1. http://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/ accessed june.16.2016. 2. aldousari s, kassouf w. update on the management of non-muscle invasive bladder cancer. can urol assoc j. 2010; 4:56-64. 3. van rhijn bw, burger m, lotan y, et al. recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. eur urol. 2009; 56:430-442. 4. geijsen ed, de reijke tm, koning cc, et al. combining mitomycin c and regional 70 mhz hyperthermia in patients with nonmuscle invasive bladder cancer: a pilot study. j urol. 2015; 194:1202-1208. 5. arends tj, falke j, lammers rj, et al. urinary cytokines in patients treated with intravesical mitomycin-c with and without hyperthermia. world j urol. 2015; 33:1411-1417. 6. maffezzini m, campodonico f, canepa g, et al. intravesical mitomycin c combined with local microwave hyperthermia in nonmuscle-invasive bladder cancer with increased european organization for research and treatment of cancer (eortc) score risk of recurrence and progression. cancer chemother pharmacol 2014; 73:925-930. 7. uicc international union against cancer. in: sobin lh, gospodariwicz m, wittekind c, editors. 7th ed. oxford: wileyblackwell tnm classification of malignant tumours. 2009; p.262265. 8. http://www.elmedical-group.com/home/doc.aspx?mcatid=13636. accessed june.16.2016. 9. https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-0614_quickreference_5x7.pdf. accessed june.16.2016. 10. holz s, sotorres cabanillas jl, legrand f, et al. evaluation of adverse events caused by intravesical bcg instillations: has the strain used a potential implication? prog urol. 2016; 26:73-78. 11. rosati y, fabiani a, taccari t, et al. intravesical bcg therapy as cause of miliary pulmonary tuberculosis. urologia. 2016; 82:49-53. 12. porten sp, leapman ms, greene kl. intravesical chemotherapy in non-muscle-invasive bladder cancer. indian j urol. 2015; 31:297303. 13. edwards mj. apoptosis, the heat shock response, hyperthermia, birth defects, disease and cancer. where are the common links? cell stress chaperones. 1998; 3:213-220. 14. hurwitz m, stauffer p. hyperthermia,radiationandchemotherapy: the role of heat in multidisciplinary cancer care. semin oncol. 2014; 41:714-729. 15. lammers rj, witjes ja, inman ba, et al. the role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review. eur urol. 2011; 60:81-93. 16. colombo r. combined treatment with local thermo-chemotherapy for non muscle invasive bladder cancer. the present role in the light of acquired data and preliminary cumulative clinical experiences. arch ital urol androl. 2008; 80:149-156. 17. milla p, fiorito c, soria f, et al. intravesicalthermo-chemotherapy based on conductive heat: a first pharmacokinetic study with mitomycin c in superficial transitional cell carcinoma patients. cancer chemother pharmacol. 2014; 73:503-509. 18. owusu ra, abern mr, inman ba. hyperthermia as adjunct to intravesical chemotherapy for bladder cancer. biomed res int. 2013; 262313. 19. slater se, patel p, viney r, et al. the effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer. ann r coll surg engl. 2014; 96:415-419. 20. kiss b, schneider s, thalmann gn, roth b. is thermochemotherapy with the synergo system a viable treatment option in patients with recurrent non-muscle-invasive bladder cancer? int j urol. 2015; 22:158-162. 21. soria f, milla p, fiorito c, et al. efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 bcg recurrent nmibc: a phase i-ii study. world j urol. 2016; 34:189-195. 22. geijsen ed, de reijke tm, koning cc, et al. combining mitomycin c and regional 70 mhz hyperthermia in patients with nonmuscle invasive bladder cancer: a pilot study. j urol. 2015; 194:1202-1208. correspondence ali serdar gözen, md, febu. associate professor of urology (corresponding author) asgozen@yahoo.com walter scheitlin, md jens rassweiler, md department of urology slk-kliniken heilbronn am gesundbrunnen 20-26, d-74078 heilbronn, germany paolo umari, md department of urology, cattinara hospital, university of trieste trieste, italy fuat ernis su, md department of urology, kanuni sultan süleyman education and research hospital, istanbul, turkey yigit akin, md department of urology, harran university school of medicine sanliurfa, turkey gozen new_stesura seveso 22/06/17 17:12 pagina 105 stesura seveso 227archivio italiano di urologia e andrologia 2015; 87, 3 original paper stone size and quality of life: a critical evaluation after extracorporeal shock wave lithotripsy cahit sahin, a. cihangir cetinel, bilal eryildirim, murat tuncer, gokhan faydaci, kemal sarica dr. lutfi kirdar training and research hospital, departments of urology, istanbul, turkey. objectives: to evaluate the quality of life (qol) of the patients after extracorporeal shockwave lithotripsy (eswl) on a treated stone size related basis. methods: 90 patients undergoing eswl for kidney stones were divided into three groups; group 1 (n: 30, ≤ 10 mm), group 2 (n: 28, 11 mm≤ 20 mm) and group 3 (n: 32, 2025 mm). during 3months follow-up, outcome of the procedure, number of cases with emergency department visits, analgesic required, re-tretatment rates, additional procedures and the changes in the qol were evaluated. results: the number of emergency department visits and mean analgesic need; re-treatment rates and additional procedures were significantly higher in group 3. evaluation of the qol scores in three groups showed that cases with larger stone still had lower scores during 3-month evaluation. conclusions: stone size could help us to predict the possible impact of eswl on the qol and depending on the size of the stone treated, a well planned indication and effective management possibly by an experienced urologist could limit the changes in the qol of the patients. key words: extracorporeal shockwave lithotripsy; quality of life; kidney stones; stone size. submitted 24 january 2015; accepted 30 april 2015 summary no conflict of interest declared. expected (33-65%) (10). in their original study, abe et al. reported that of the 267 patients undergoing eswl for stones sizing between 20 and 30 mm.,46% were sf, while residual fragment were present in 54% (11). thus, despite a safe and successful disintegration, depending on the stone size, sfr could vary in a considerable percent of the cases (6, 12). the associated symptoms and morbidity during the passage of disintegrated fragments might have significant effects on these patients’ qol (4, 13, 14). thus, it becomes more important that endourologists should not solely focus on the sf obtained but also on the changes in psychological, functional, social and economic life of the patients after eswl which may possibly change well during the clinical course and the repeated sessions and/or additional procedures after eswl (4, 5, 15). qol is an estimate of freedom from impairement, disability or handicap (16). the quantification of qol has been extensively reported in patients with a wide variety of diseases and well assessed in many health problems as well as after certain medications and/or procedures (17). however, to our knowledge highly limited data regarding the qol of the stone formers after certain endourological procedures could be derived from the literature (13, 14, 18) and our current study is the first study focusing solely on the qol changes in cases undergoing eswl in a standardized and detailed manner. in this prospective study we aimed to evaluate the changes in the qol of the patients after eswl on a treated stone size based manner. materials and methods between may 2012 and december 2012, a total of 90 patients (53 men, 37 women; m/f: 1.4) undergoing eswl for solitary radioopaque renal pelvis stones were included into this prospective study program. patients with established contraindications for eswl were excluded. a detailed information about the procedure were given to all cases with an informed consent prior to eswl. patients were divided into three subgroups with respect to the treated stone size. group 1 (n:30) patients with stones sizing ≤ 10 mm, group 2 (n: 28) 11 mm-≤ 20 mm, and group 3 (n:32) 21-25 mm. following routine biochemical tests; plain kub, sonography and noncontrast computed tomography (ncct) were perdoi: 10.4081/aiua.2015.3.227 introduction urolithiasis is a worldwide health problem (1, 2) which typically affects the social life of the patients during their most active and productive age between 20 and 50 years (3, 4). in addition to the distressing pain, obstruction and recurrent infections, decreased productivity, loss of work time are the adverse outcomes of stone disease (5, 6). regarding the treatment, although eswl has revolutionized the management of urinary calculi with its highly effective results (2), a considerable percentage of the patients may require additional procedures (7, 8). success as well as re-treatment rates after eswl are related to some certain patient and stone related factors among which the stone sizeis the most crucial one (8, 9). as the stone burden increases (> 20 mm), the sf-rate (sfr) decreases in a considerable extent with high reretreatment rates (6). sfr after eswl monotherapy in patients with larger stones (20-30 mm) are lower than sahin_stesura seveso 30/09/15 09:36 pagina 227 archivio italiano di urologia e andrologia 2015; 87, 3 c. sahin, a. cihangir cetinel, b. eryildirim, m. tuncer, g. faydaci, k. sarica 228 formed. stone size has been assessed by ncct in all cases. eswl was performed by an electromagnetic (dornier compact sigma, dornier medtech germany) lithotriptor with a maximum shockwave number of 3000 in a session at 120 kv values. outcome of eswl was assessed after 1-week and depending on the size of fragments further sessions have been performed with a 1-week interval between each eswl session. the overall outcome of eswl was evaluated 3 months after the last session and while the cases with no fragment(s) were accepted as sf, cases with fragments as well as with no documented disintegration after 3 successful sessions were accepted as not sf.to evaluate the cases first plain kub and sonography were performed in all cases and ncct was performed in a case dependant manner when needed to assess the presence and size of fragments. spontaneous passage rates, cases referring to ed visits, analgesic required (diclofenac sodium 75 mg im at each referral); additional procedures and also the changes in the qol were assessed during 1 and 3 months after eswl. changes in qol were evaluated by giving sf36® questionnaire filled at hospital conditions. first the overall baseline qol scores before the procedure were evaluated and noted then the qol scores after swl were obtained and compared with the baseline scores before making an inter sub-group comparison. the medical outcome study sf-36 turkish version 1.0 was used to assess qol (19). this questionnaire consists of 36 self-administered questions that quantify qol using eight multi-item scales: general health (gh), physical functioning (pf), role physical (rp), bodily pain (bp), vitality (vt), social functioning (sf), mental health (mh) and role emotional (re) (20). the eight scales were scored separately from 0 to 100, with a higher score being indicative of a better result, and these scores were used for analyses of the comparisons among the groups. statistical analysis all analyses were performed by using ncss 2007&pass 2008 statistical software program. sf-36 domains were compared among three subgroups by one-way anova. tukey hsd test was performed to evaluate post hoc analysis of the parameters found to be significant. while mann whitney u test was used for the comparison of nonnormally distributed parameters, kruskal wallis test was used for the nonnormally distributed parameters. overall ≤ 10 mm 11-≤ 20 mm 21-25 mm p (n = 90) (n = 30) (n = 28) (n = 32) no of patients n (%) 90 (100) 30 (33.3%) 28 (31.2%) 32 (35.5%) gender female n (%) 37 (41.1%) 12 (40%) 12 (42.9%) 13 (40.6%) a1.000 male n (%) 53 (58.9%) 18 (60%) 16 (57.1%) 19 (59.45) mean stone size (mm) 15.68 ± 6.45 8.34 ± 1.18 14.95 ± 2.33 23.19 ± 1.62 mean age (years) 41.47 ± 9.44 41.87 ± 9.06 40.21 ± 9.15 42.19 ± 10.19 b0.698 overall evaluation after 3 months 1.stone free (sf) 1.1 sf after eswl (n,%) 58 (67.8%) 22 (73.3%) 19 (67.9%) 17 (53.1%) a0.227 first session 29 (32.2%) 13 (43.3%) 10 (35.7%) 6 (18.8%) a0.325 second session 16 (17.8%) 7 (23.3%) 5 (17.9%) 4 (12.5%) c0.873 third session 10 (11.1%) 2 (6.6%) 4 (14.3%) 4 (12.5%) a0.097 more than 4 sessions 3 (3.3%) none none 3 (9.3%) a0.022* mean no of eswl session 2.04 (1-5) 1.67 (1-3) 1.79 (1-3) 2.63 (1-5) d0.001** 1.2 sf after additional procedures for fragments symptomatic and obstructive fragments (n,%) 12 (13.3%) 2 (6.6%) 3 (10.7%) 7 (21.9%) c1.000 urs 9 (10.0%) 2 (6.6%) 2 (7.1%) 5 (15.6%) c1.000 dj 3 (3.3%) none 1 (3.6%) 2 (6.2%) 2. not stone free 2.1. patients under follow-up with asymptomatic fragments, (n,%) 17 (18.9%) 6 (20.0%) 5 (17.9%) 6 (18.8%) a0.978 ≤ 2 mm (n,%) 5 (5.6%) 3 (10.0%) 2 (7.1%) none c0.178 2-≤ 4 mm (n,%) 6 (6.6%) 3 (10.0%) 2 (7.1%) 1 (3.1%) c0.576 4-< 5 mm (n,%) 6 (6.6%) none 1 (3.6%) 5 (15.6%) c0.006** mean fragment size overall (mm) 3.9 (1.5-4.8) 2.5 (1.5-3.7) 3.2 (2.0-4.8) 4.5 (3.8-4.9) d0.009** 2.2. unsuccessful [cases unresponsive to eswl (n,%)] 3 (3.3%) none 1 (3.6%) 2 (6.2%) c1.000 secondary procedures, (n,%) 3 (3.3%) none 1 (3.6%) 2 (6.2%) c1.000 flexble urs 1 (1.1%) none 1 (3.6%) none c0.333 pnl 2 (2.2%) none none 2 (6.2%) 3. complications (overall), (n,%) 25 (27.7%) 3 (10.0%) 6 (21.4%) 15 (46.9%) a0.003** hematuria 7 (7.7%) 1 (3.3%) 2 (7.1%) 4 (12.5%) c1.000 fever (> 38.5 ₒ) 4 (4.4%) none 1 (3.6%) 3 (9.3%) c1.000 obstruction 14 (14.4%) 2 (6.6%) 3 (10.7%) 8 (25.0%)* c1.000 *spontaneous resolution witout any intervention in 1 cases, apearson ki-kare test, boneway anova test, cfisher-freeman-halton test, dkruskal wallis test. **p<0.01 table 1. evaluation of the patient, stone characteristics, success rates, additional proceures and complications in all sub-groups. sahin_stesura seveso 30/09/15 09:36 pagina 228 mann whitney u test was performed to evaluate post hoc analysis of the parameters found to be significant. analysis of qualitative data was performed by pearson chi-square test and fisher-freeman-halton exact test. significance was considered as p < 0.05. results while the mean age of the cases was 41.5 years (24-67) in the study group; overall mean stone size was 15.7mm (6–25 mm). stone characteristics in all subgroups are given in table 1. stone analysis data was available in 61 patients and majority of them had calcium containing stones [calcium oxalate monohydrate in 36 (59%), calcium oxalate dihydrate in 15 (24.6%), and mixed calcium stones in 10 (16.4%)]. evaluation of our data revealed following findings: patients with stones ≤ 10 mm although stones were successfully disintegrated in all cases; 22 cases (73.3%) became completely sf within 3months. of the remaining 8 cases, while 6 cases (20%) had asymptomatic fragments requiring no further management, ureteroscopic (urs) stone removal was performed in 2 cases (6.7%) with symptomatic fragments (table 1). patients with stones 11 mm≤ 20 mm stones were successfully disintegrated in 27 of 28 cases (96.4%). while 19 cases (67.9%) became sf within 3months, remaining 8 cases demonstrated asymptomatic fragments requiring no further management in 5 cases (17.9%). two cases became sf after urs stone removal (7.1%); double-j (dj) stent was inserted in 1 case (3.6%) for obstructing fragments. lastly no disintegration at all was observed in 1 case (3.6%) and flexible urs stone disintegration was performed (table 1). patients with stones sizing 21 mm-25 mm stones were successfully disintegrated in 30 of 32 cases (93.7%). however only 17 cases (53.1%) became completely sf within 3-months. of the remaining 13 cases, 6 (18.8%) had asymptomatic rf requiring no further management; 7 cases were sf after urs stone removal in 5 cases (15.6%) and dj stent insertion in 2 case (6.2%). lastly eswlproduced no disintegration at all in 2 cases (6.2%). minipercutaneous nephrolithotomy (pnl) procedure was performed in these cases. the size of the fragments in all subgroups are being given in table 1. analgesic use and ed visits while the mean amount of analgesic use was higher in group 3, these values were relatively less in the second and the first group [p 1-2 = 0.785, p 1-3 = 0.001, p 2-3 = 0.001]. similarly while 15 cases (46.9%) in group 3 referred to ed, 5 cases (17.9%) in group 2 and only 4 cases (13.3%) in group 1 referred to ed [p 1-2 = 0.726, p 1-3 = 0.010, p 2-3 = 0.035] (table 2). data on qol evaluated by sf-36 survey data obtained at 1-month evaluation demonstrated significantly lower scores in all 8 subdomains (gh, pf, rp, bp, vt, sf, mh and re) in three subgroups. however this evaluation at 3-month follow-up period clearly showed that this difference was significantly lower for only 5 subdomains (gh, pf, rp, sf and re) at 3 month evaluation (table 3). additionally and more importantly this evaluation was performed in all subgroups and statistically significant mean lower scores with respect 229archivio italiano di urologia e andrologia 2015; 87, 3 stone size and quality of life: a critical evaluation after extracorporeal shock wave lithotripsy table 2. evaluation of the mean analgesic requirement and emergency department visit in all sub-groups. table 3. evaluation of the qol scores between baseline (before eswl) and overall values of the whole group during 1 and 3 months. group ≤ 10 mm 11-≤20 mm 21-25 mm p n: 30 n: 28 n: 32 mean no of ed visit no 26 (86.7%) 23 (82.1%) 17 (53.1%) ap1-2:0.726 ap1-3:0.010* ap2-3:0.035* yes 4 (13.3%) 5 (17.9%) 15 (46.9%) mean analgesic required (mg) mean ± sd 22.50 ± 52.67 32.14 ± 71.96 133.59 ± 123.07 bp1-2:0.785 bp1-3:0.001** bp2-3:0.001** group 1 = 1, group 2 = 2, group 3 =3, apearson ki-kare test, bkruskal wallis test, **p < 0.01. overall group scores (n = 90) baseline (before eswl) scores (n = 90) p mean ± sd mean ± sd gh 1.month 32.67 ± 16.27 56.89 ± 9.90 0.001** 3.month 46.67 ± 14.38 56.89 ± 9.90 0.001** pf 1.month 58.33 ± 18.74 75.00 ± 17.97 0.001** 3.month 70.28 ± 11.18 75.00 ± 17.97 0.049* rp 1.month 53.61 ± 19.67 75.83 ± 16.10 0.001** 3.month 68.06 ± 15.91 75.83 ± 16.10 0.004** bp 1.month 43.56 ± 18.62 67.11 ± 13.51 0.001** 3.month 67.78 ± 16.06 67.11 ± 13.51 0.060 vt 1.month 38.61 ± 19.53 64.44 ± 12.97 0.001** 3.month 60.83 ± 17.19 64.44 ± 12.97 0.314 sf 1.month 53.06 ± 20.12 77.50 ± 16.78 0.001** 3.month 65.83 ± 13.74 77.50 ± 16.78 0.001** mh 1.month 48.89 ± 18.70 68.33 ± 17.09 0.001** 3.month 69.44 ± 10.45 68.33 ± 17.09 0.315 re 1.month 48.33 ± 19.40 77.50 ± 13.01 0.001** 3.month 66.94 ± 16.26 77.50 ± 13.01 0.001** mann whitney u test, *p < 0,05, **p < 0,01 gh, general health. pf, physical functioning. rp, role-physical. bp, bodily pain. vt, vitality. sf, social functioning. mh, mental health. re, role-emotional. sahin_stesura seveso 30/09/15 09:36 pagina 229 archivio italiano di urologia e andrologia 2015; 87, 3 c. sahin, a. cihangir cetinel, b. eryildirim, m. tuncer, g. faydaci, k. sarica 230 to all 8 subdomains were present in all of them during 1month follow-up (figure 1 a). however, at 3-month follow-up this evaluation showed an evident improvement in the mean qol scores of the first group (≤ 10 mm) where the values found to be similar to baseline (before eswl) data. in the second group again (11 mm≤ 20 mm) these scores improved in a considerable extent where there was a significant difference with respect to only one subdomain (gh, p = 0.018). lastly the improvement of qol scores in cases with larger stones (> 20 mm) has been found to be highly limited with statistically significant differences in the mean values of 6 subdomains [gh (p = 0.001), pf (p = 0.006), rp (p = 0.001), vt (p = 0.001), sf (p = 0.001), re (p = 0.001)] (figure 1 b). discussion urolithiasis is a major problem particularly in endemic countries (1, 2). in addition to the disease related bothersome symptoms; fragments forming after certain stone removal procedure(s) and related interventions can also be associated with a variety of distressing symptoms which may worsen over time (15). among these symptoms colic pain, obstruction and recurrent infections resulting in decreased productivity, loss of work time or employment are the most prominent ones (5, 6). currently eswl, urs and pnl are well-established procedures for stone removal. regarding the procedure related advantages and disadvantages; selection should be based on certain stone and patient related factors (2). although eswl is the management of choice for most stones with its efficient and safe natüre (2); studies demonstrated that despite an effective disintegration, spon ta neous passage and in some cases removal of the fragments may be needed for a completely sf status. long-term follow-up data in large number of patients has clearly shown that 23% to 54% of the cases undergoing eswl may have residing fragments after this procedure (11, 12). regarding the clinical course after eswl although majority of disintegrated stone particles may pass spontaneously or stay in situ asymptomatic; they may be symptomatic and/or obstructive in a certain percent of the cases. obstruction induced symptoms and morbidity casued by these fragments could cause significant changes in patients’ qol (4, 13, 14). furthermore, they may necessitate pain management, ed visits, hospitalization, or even additional procedures that may further worsen the long-term qol. regarding the success rates, data in the literature show that while the sfafter eswl monotherapy are meaningfully higher in stones sizing < 20 mm (80-85%) (2, 6) figure 1a. evaluation of qol scores during 1-month evaluation in all sub-groups. figure 1b. evaluation of the qol scores during 3-month evaluation in all sub-groups mann whitney u test, p < 0,05, gh, general health. pf, physical functioning. rp, role-physical. bp, bodily pain. vt, vitality. sf, social functioning. mh, mental health. re, role-emotional. mann whitney u test, p < 0,05, gh, general health. pf, physical functioning. rp, role-physical. bp, bodily pain. vt, vitality. sf, social functioning. mh, mental health. re, role-emotional. sahin_stesura seveso 30/09/15 09:36 pagina 230 these rates are reasonably lower (33-65%) in larger stones (20-30 mm) (10). additionally such stones may require retreatment due to incomplete disintegration resulting in a risk of partial obstruction in 19-50% of the cases.[8] psihramis et al. reported 52% sf after eswl in 674 cases with renal stones sizing > 20 mm with a retreatment rate of 18.6% (22). again, lingeman et al. showed that the re-treatment rates increased from 10% to 33% for stones sizing of 10–20 mm and 20-30 mm, respectively (23). additionally, abe et al. reported that of the 267 cases undergoing swl monotherapy for larger stones (20-30 mm), while 46% of the cases became sf, 54% did still have rf during follow-up (11). lastly “the american urological association nephrolithiasis clinical guidelines panel” data emphasized that the re-retreatment rates increases from 12% for stones < 10 mm up to 46% for stones > 30 mm (24). finally, recommendation made by nih consensus conference indicated that patients with stones > 20 mm were offered pnl initially due to the higher re-treatment rates and the need for auxiliary procedures (10). thus, the stone size is an important parameter to predict the re-treatment rates and auxiliary procedures after eswl. however endourologists so far, followed the patients solely with respect to the success rates without giving any attention for the changes in patient’s qol. procedure itself, stone fragments resided as well as the additional procedures required could affect the qol and the endourologists should not solely focus on the final outcome but also on these important changes (4, 5, 15). such a perspective is particularly true in socially active aged cases undergoing eswl (13, 14). to our knowledge detailed data focusing on the qol changes after eswl therapy particularly on a treated stone size based manner is reasonably lacking. in the limited number of studies published so far the authors either evaluated qol changes after different procedures in a comparative manner or focused on the patient preferences in the treatment of urinary stones (14, 15, 26). in this present study, apart from the evaluation of the efficacy of eswl, we aimed to evaluate the changes in the qol of the patients with an emphasis on the treated stone size during 1 and 3month follow-up period. patients with larger stones (> 20 mm) tended to have an impaired qol as a result of the higher re-treatment rates as well as colic pain requiring ed visits forrelatively larger fragments. again, mean qol scores in such patients were compared with baseline (before eswl) scores during both 1 and 3 month follow-up and while significantly lower scores for all 8 subdomains were noted in all sub groups during 1month period; during 3-months however values in the first group were similar to baseline (before eswl) data. again qol scores improved in the second group with lower values only for one subdomain (gh). however the improvement of qol scores in cases with larger stones (> 20 mm) was highly limited with statistically significant lower mean scores in 6 subdomains. to support these findings further, mean analgesic use and the ed visits were significantly higher in patients with such stones. thu, although eswl is considered as the least invasive alternative for the majority of the stones, in the light of our data evaluation of the qol of in these cases gains a meaningful importance by bringing the question in front of the endorologists as “obtaining a completely sf status after eswl at the expense of what?” clinical studies published so far focused mainly on success rates in terms of sf status; possible changes in the qol of these cases have not been subjected to any of these studies in an attempt to outline the certain factors affecting such changes. these possible changes should be kept in mind and monitored with as much attention as given for the evaluation of the final outcome of the procedure. again, the evident qol changes in patients with larger stones (> 20 mm) may let the endourologists to consider a proper tretament plan in favour of other minimal invasive procedures in these cases. concerning the limitations, limited the number of cases could be the only certain drawback of our study. however, as this one is the first in the literature evaluating the qol after eswl in a stone size based manner; we believe that our study will certainly give an idea in defining the importance of changes in qol a topic which was not evaluated in detail so far. conclusions although eswl is a safe and effective procedure; despite a successful stone disintegration, higher re-treatment rates, residing fragments and additional procedures particularly in cases with relatively larger stones (> 20 mm) could significantly affect the qol of these cases. depending on the stone size, a proper indication and effective management possibly by an experienced urologist could limit the possibility of factors responsible for the changes in the qol. references 1. bartoletti r, cai t, mondaini n, et al. epidemiology and risk factors in urolithiasis. urol int. 2007; 79:3-7. 2. miller nl, lingeman je. management of kidney stones. bmj. 2007; 334:468-72. 3. tiselius hg. epidemiology and medical management of stone disease. bju int. 2003; 91:758-67. 4. gambaro g, reis-santos jm, rao n. nephrolithiasis: why doesn't our "learning" progress? eur urol. 2004; 45:547-56. 5. pearle ms, calhoun ea, curhan gc. urologic diseases in america project: urolithiasis. j urol. 2005; 173:848-57. 6. khalil mm. which is more important in predicting the outcome of extracorporeal shockwave lithotripsy of solitary renal stones: stone location or stone burden? j endourol. 2012; 26:535-9. 7. el-nahas ar, el-assmy am, mansour o, et al. a prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. eur urol. 2007; 51:1688-93. 8. lingeman je, coury ta, newman dm, et al. comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy. j urol. 1987; 138:485-90. 9. raynal g, petit j, saint f. which efficiency index for urinary stones treatment? urol res. 2009; 37:237-9. 231archivio italiano di urologia e andrologia 2015; 87, 3 stone size and quality of life: a critical evaluation after extracorporeal shock wave lithotripsy sahin_stesura seveso 30/09/15 09:36 pagina 231 archivio italiano di urologia e andrologia 2015; 87, 3 c. sahin, a. cihangir cetinel, b. eryildirim, m. tuncer, g. faydaci, k. sarica 232 10. lingeman je, lifshitz da, and evan ap: surgical management of urinary lithiasis, in walsh pc (ed): campbell's urology, 8th ed. philadelphia, wb saunders, 2002; vol 4, pp 3361-3451. 11. abe t, akakura k, kawaguchi m, et al. outcomes of shockwave lithotripsy for upper urinary-tract stones: a large-scale study at a single institution. j endourol. 2005; 19:768-73. 12. el-assmy a, el-nahas ar, abo-elghar me, et al. predictors of success after extracorporeal shock wave lithotripsy (eswl) for renal calculi between 20-30 mm: a multivariate analysis model. scientific world journal. 2006; 23:2388-95. 13. bensalah k, tuncel a, gupta a, et al. determinants of quality of life for patients with kidney stones. j urol. 2008; 179:2238-43. 14. arafa ma, rabah dm. study of quality of life and its determinants in patients after urinary stone fragmentation. health qual life outcomes. 2010; 19:119. 15. diniz dh, blay sl, schor n. anxiety and depression symptoms in recurrent painful renal lithiasis colic. braz j med biol res. 2007; 40:949-55. 16. last jm, spasoff ra, harris ss. a dictionary of epidemiology. new york, oxford university press. 2001, vol 4, p. 148. 17. alonso j, ferrer m, gandek b, et al. health-related quality of life associated withchronic conditions in eight countries: results from the internation quality of life assessment (iqola) project. qual life res. 2004; 13:283-98. 18. penniston kl, nakada sy. health related quality of life differs between male and female stone formers. j urol. 2007; 178:2435-40. 19. kocyigit h, aydemir o, fisek g, et al. validity and reliability of turkish version of short form 36: a study of a patients with romatoid disorder. journal of drug and therapy (in turkish) 1999; 12:102. 20. ware je, kosinski m, gandek b. reliability, precision, and data quality. in: sf36® health survey manual & interpretation guide. lincoln, rhode island, qualitymetric incorporated 1993, pp 7:17:17. 21. lingeman je, newman d, mertz jh, et al. extracorporeal shock wave lithotripsy: the methodist hospital of indiana experience. j urol. 1986; 135:1134-7. 22. psihramis ke, jewett ma, bombardier c, et al. lithostar extracorporeal shock wave lithotripsy: the first 1,000 patients. toronto lithotripsy associates. j urol. 1992; 147:1006-9. 23. lingeman, j.e. non-staghorn renal calculi. in urinary calculi. lingeman, j.e., smith, l.h., woods, j.r., and newman, d.m., eds. lea and febiger, philadelphia. 1989, pp. 149-162. 24. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasisclinical guidelines panel. j urol 1994; 151:1648-51. 25. mays nb, petruckevitch a, snowdon c. patients' quality of life following extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy for renal calculi. int j technol assess health care. 1990; 6:633-42. 26. kurahashi t, miyake h, shinozaki m, et al. health-related quality of life in patients undergoing lithotripsy for urinary stones. int urol nephrol 2008; 40:39-43. correspondence cahit sahin, md (corresponding author) cahitsahin129@gmail.com gömeç sok. sabancı -2 sitesi a1 kat 4 daire 24 acıbadem/kadıköy istanbul, turkey a. cihangir cetinel, md cihangircetinel@gmail.com bilal eryildirim, md bilaleryildirim@yahoo.com murat tuncer, md murattuncer77@hotmail.com gokhan faydaci, md faydacig@yahoo.com kemal sarica, md kemalsarica@superonline.com dr. lutfi kirdar training and research hospital, departments of urology istanbul, turkey sahin_stesura seveso 30/09/15 09:36 pagina 232 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3222 original paper androgen deprivation therapy (castration therapy) and pedophilia: what’s new mauro silvani, nicola mondaini, alessandro zucchi 1 urologist in chief, urology dept. “degli infermi” hospital, biella, italy; 2 urologist, urology unit, santa maria annunziata hospital, firenze, italy; 3 urologist, urology and andrology dept. university of perugia, perugia, italy. andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. with regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. at present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. international legislation primarily aims to defend childhood, but does not provide for compulsory treatment. we reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. current opinions on chemical castration for pedophilia are discordant. some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. on the other hand, some authors report that chemical castration does not modify the pedophile’s personality. in our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects. key words: pedophilia; chemical castration; andrology. submitted 30 april 2015; accepted 30 july 2015 summary no conflict of interest declared. are usually taken from the dms-v (4). international legislation primarily aims to defend childhood, but does not provide for compulsory treatment. pharmacological solutions with andrological implications, such as “chemical castration” (androgen deprivation therapy – adt), have been proposed for the clinical management of pedophiles. inevitably, this therapeutic option poses major legal and moral implications (5), but current literature does not provide any indications. for this reason, we reviewed international literature that, at present, only comprises a few reports on research concerning adt in pedophilic patients, considering the psychological aspect of the disease and leaving out the crucial role of the andrologist. furthermore, we performed a revision of current legislation in more developed western countries. materials and methods we performed a detailed review of literature about chemical castration using adt, also examining the effects of each of these drugs and the side effects of androgen deprivation. rationale for chemical castration in pedophiles in all probability the term “castration” derives from the latin word castor or beaver. the therapeutic benefits of beaver testicles were described by galen and pliny, who urged people to hunt this animal. today, this term implies a therapeutic approach designed to inhibit sexual impulses or block them with specific chemical compounds. chemical castration is therefore the common term, but it would be more appropriate to speak of “testosterone antagonist pharmacological therapy”. the effects of pharmacological castration are a reduction in libido, sexual fantasies, frequency of masturbation and pleasure, erections (both nocturnal and induced by erotic stimuli), blood testosterone, fsh and lh, and an increase in prolactin (6). there are a number of different reasons for androgen deprivation therapy (adt) in pedophile patients: – reduction and elimination of the most significant symptoms of the sexual malaise; – controlling the ideational, repetitive and aggressive threat to minors; – reducing sexual attitudes and urges to the point of eliminating them; doi: 10.4081/aiua.2015.3.222 introduction andrology is a constantly evolving discipline, embracing social and legal problems such as pedophilia. there is no clear-cut definition of pedophilia: it is not easy to place it within a conceptual framework due to the difficulty in bringing the two orientations – socio-anthropological and clinical – together in a “single concept”. in socio-anthropological terms, pedophilia is a form of social perversion that is only classed as such in certain civilizations and during certain periods of history (1); child sexual abuse has always existed in all populations. it is not a phenomenon associated with so-called “complex societies”, nor can it be linked to modernity. however, to date, there are no known specific chromosomal, genetic, hormonal alterations or neurological diseases associated with pedophilia, though some authors suggest a genetic predisposition (2, 3). the criteria used for the clinical diagnosis of pedophilia silvani_stesura seveso 23/09/15 12:38 pagina 222 223archivio italiano di urologia e andrologia 2015; 87, 3 andrologist and pedophilia – easier application of psychotherapy and cognitive behavioral therapy; – low percentage (just 3-5%) of pedophile recovery with psychotherapy alone; – possible association with other paraphilias (such as sadomasochism) (6-10). however, certain currents of thought are completely opposed to this procedure. moige (an italian parents’ movement – www.moige.it) has a negative view of chemical castration, claiming that it leads to more aggression in the subject when therapy is suspended and that it does not change the pedophile’s personality. moreover, the pedophile may accept it simply to avoid detention. lastly, in particular cases, it is contraindicated due to potential side effects (anemia, osteoporosis, etc.). it is also important to consider other fundamental aspects. long-term treatment is intended to reduce the symptoms and is not a cure. moreover, no controlled studies have been conducted on the long-term efficacy of androgen deprivation therapy. the pedophile commits the crime for reasons that go beyond pure sexual gratification; as a result, reducing libido does not necessarily mean eliminating the risk of repeat offences (10). furthermore the pedophilic act does not necessarily require an erection or penetration. the following drugs are used in chemical castration: 1. cyproterone acetate; 2. diethylstilboestrol (no longer in use); 3. medroxyprogesterone acetate; 4. lhrh analogues: particularly leuprolide acetate (11-13). medroxyprogesterone acetate (mpa) was first used in pedophilia therapy in 1990 by cooper at al. (14). the drug was administered at a dose of 300 mg per day for a period of two years. after two weeks of treatment, the authors observed a 73% reduction in total blood testosterone, a 300% increase in blood prolactin, and a noticeable reduction in nocturnal and stimulation-induced erections that persisted even two months after stopping treatment and the recovery of physiological blood testosterone levels. however, this study is limited due the fact that it involved just six patients. maletzky carried out a broader study in 2003, with essentially comparable results (8, 15). the risks associated with the prolonged use of this drug, as emphasized by kruger et al. in a recent study conducted in 2006, are metabolic in nature. in fact, over time a reduction in carbohydrate tolerance is observed due to an increase in basal insulin levels. the drug also stimulates lipoprotein lipase, producing a tendency to obesity and, by reducing hdl levels, it significantly increases atherogenic risk. moreover, a reduction in the effects of aldosterone on the renal tubules is described, with diminished sodium reabsorption and increased secretion of glucocorticoids by the adrenal cortex. cases of cushing’s syndrome and adrenocortical insufficiency have been described. the drug also increases the mitotic activity of the acinar epithelium of the breast, leading to a risk of gynecomastia and breast cancer (16). another drug used was cyproterone acetate (cpa). despite the fact that they date back to 1992 (17), the studies conducted by cooper et al. provide interesting data. the study used a dose of 100 mg/day over an average period of 28 months. after two weeks of taking the drug, a reduction in testosterone, fsh and lh, and an increase in prolactin were observed. sexual urges were also reduced in parallel with testosterone levels. the effect on diurnal erections varied from subject to subject. when therapy was suspended, testosterone levels rose rapidly. the authors also conducted a controlled double-blind study to assess the effects of cpa and mpa, and found that they were comparable and dose-dependent. another study by lasket (18) shows that the broadest studies of the drug occurred in germany, where benefits in 100 male pedophiles, sadists and exhibitionists included decreased sexual drive, lower frequency of orgasms and less frequent erections. the drug most commonly used today is an lhrh agonist: leuprolide acetate (11, 12). published studies demonstrate that analogues are more effective on the sexual sphere than mpa and cpa, and on sexual urges, desire, ejaculation, and erections and orgasms, but with fewer side effects (13, 14, 16, 17, 19). the literature only includes a very small number of case studies regarding the use of leuprolide in the treatment of pedophiles. one of the most significant studies is the one conducted by briken et al., which recruited eleven men aged between 41 and 63, all of whom repeat offenders. all the subjects were treated for one year, with a reduction in aggressive sexual behavior, erections and masturbation. one of the subjects committed suicide (20). another interesting study is the one conducted by schober et al. (21), assessing five pedophiles treated for a year with quarterly leuprolide acetate. the reduction in testosterone, fsh and lh was rapid, as was the increase in blood prolactin. there was a reduction in urges, erotic fantasies and nocturnal erections assessed with the rigiscan test. after one year of therapy, the penile circumference at the base of the shaft had decreased from an average of 9.7 to 8 cm. the number of case studies is noticeably larger if we also consider patients with different paraphilias. in fact, the work carried out by briken et al. in 2003 (20) assesses 118 patients treated for 6-24 months and affected by different types of paraphilias. in some cases, ssris (selective serotonin reuptake inhibitors) were also used without any evidence of better success. literature also includes an interesting study conducted by almeida et al. in 2004, which demonstrates that the drastic reduction in testosterone levels leads to a highly neurotoxic increase in beta-amyloid protein associated with the pathophysiology of alzheimer’s disease. (22). finally no randomised controlled trials have yet been published (23). as to non-androgen deprivation pharmacological therapy designed to treat the psychiatric disorder, various categories of psychoactive drugs can be used (24, 25): – tricyclic antidepressants (clomipramine and desipramine); – ssris, paroxetine, sertraline, etc.; – typical and atypical neuroleptics, benperidol, haloperidol, thioridazine; – benzodiazepines (diazepam, clonazepam, etc.); – lithium salts, lithium carbonate; – antiepileptics, carbamazepine. antidepressants can be used to reduce libido and delay ejaculation to the point of anorgasmy, especially in the event of comorbidity with mood disorders and obsessilvani_stesura seveso 23/09/15 12:38 pagina 223 archivio italiano di urologia e andrologia 2015; 87, 3 mauro silvani, nicola mondaini, alessandro zucchi 224 sive-compulsive disorder. ssris offer advantages in the treatment of paraphilia because they permit simple monitoring of the patient, even on an outpatient basis, and form a valid option together in combination with psychotherapy. possible pharmacological therapies pertaining to the andrologist in definitive terms, pedophilia therapy is comparable to medical therapy for prostate cancer and andrologists usually work with therapy for the male sex, including androgen deprivation. it should be remembered that the therapy can obviously be combined: androgen deprivation and ssris, benzodiazepine (clonazepam) or carbamazepine. these combinations must obviously come after psychological and/or psychiatric assessment. current legislation in italy the first official italian proposal regarding chemical castration was made in milan on 17 february 1997 during the trial of a man accused of repeat rape. since then, there has been much disagreement about the process. however, it should be remembered that in italy no one can be forced to receive medical treatment unless so ruled by law. moreover, the law cannot violate the limits imposed by the need to respect the individual, as enshrined in article 32 of the italian constitution, paragraph ii. the national bioethics committee specifies that “the infrangibility of the human body is always valid even in convicted criminals, unless expressly requested by the individual concerned”. in italy, crimes linked to pedophilia are governed by law 269/98, as updated in 2006, which regulates against pedophilia, the exploitation of prostitution, pornography, sex tourism involving minors and new offences of slavery. this law exclusively regards means for repressing crime linked to pedophilia, but excludes the possibility of intervening with suitable pharmacological therapy. in greater detail, the primary objective of the law is to protect children against all forms of sexual exploitation and violence, safeguarding their physical, psychological, moral and social development. in addition to the cited law, crimes of pedophilia are regulated by law 66/96 containing the new regulations against sexual violence. this law finally repealed the provisions of the rocco code, meaning that the crime of sexual violence is no longer considered a crime against public morality and decency, but is instead a crime against a person. law 66/96 finally interprets the sexual act objectively for the first time: assessed in relation to the objectifying nature of the sexual act, determined according to medical-psychological and anthropological-sociological indications. therefore, sexual relevance is configured in relation to the local customs. chemical castration and legislation in other european countries in germany, chemical castration has been legal since 1969. it is only permitted in individuals aged over 25, once a final sentence has been passed and after they have undergone clinical assessment regarding their suitability for treatment. in denmark the provision has been in place since 1973 and has replaced surgical castration, approved since 1929. those who undergo this treatment benefit from early release or a shorter sentence. social services monitor the implementation of the pharmacological castration program. in sweden it has been in place since 1993 and is only applicable if requested by the person concerned, in the case of a high risk of recidivism. those who undergo the treatment receive certain benefits and shorter sentences. in france it has been permitted under state law since 1997, but only for those who volunteer to receive it; it was first applied in 2005. nicolas sarkozy adopted a very restrictive position regarding the phenomenon of pedophilia over recent years, according to which a significant role is filled by androgen deprivation therapy together with more severe prison sentences (26, 27). the first european pedophile center was slated to open in lyon in 2009. pedophiles are assessed by a panel of specialists, responsible for examining the risk level posed by each individual on a case by case basis. in the united kingdom chemical castration can be administered on the direct request of those convicted of crimes of pedophilia. since 7 january 2008, all those condemned for sexual abuse offences have been informed of the possibility of receiving chemical castration at their own request. however, there is no monitoring to ensure that these patients comply with the oral or injection therapy, which has led to many objections being raised by various associations, both for and against chemical castration. in norway, pharmacological treatment of those convicted of sex crimes has been possible, subject to consent, since 2004, together with group psychological therapy. in this case, castration does not lead to reduced sentences or other privileges. in spain, research is being carried out into psychological and pharmacological measures other than chemical castration that could reduce libido in pedophile patients. chemical castration: legislation in the usa on 17 september 1996, california became the first american state to issue a law providing for chemical castration of pedophiles. the drug authorized for this purpose is medroxyprogesterone acetate (mpa). the state pays only half of the cost of therapy, while the offender is responsible for the other half. the treatment is not subject to any age limits. the patient is informed of the side effects of the treatment, but the therapy can only be authorized at the discretion of the ruling court. in the state of florida, the law on chemical castration came into effect on 1 october 1997. the treatment is administered after the second pedophilia offence and the court decides the duration of the treatment. the offender is not informed of the therapy he is receiving, nor of the side effects. instead, the suitability of treatment is decided by a medical team. chemical castration: legislation in korea in 2011 the ministry of justice of korea enacted legislation requiring chemical castration of paraphilic sexual offenders over the age of 19 and/or those at high risk of recidivism. the current chemical castration legislation calls for the psychiatric evaluation of sex offenders and silvani_stesura seveso 23/09/15 12:38 pagina 224 225archivio italiano di urologia e andrologia 2015; 87, 3 andrologist and pedophilia chemical castration is performed 3 months prior to probation so that the treatment may effectively change the behavior of the offender (28). discussion a scientific publication such as this one on pedophilia may seem unusual but, in fact, statistical data, such as the findings of 1994 (caffarra et al.) and censis data (1999), reveal that 470 cases of child sexual abuse are reported every year in italy, including 64 by unknown offenders (www.pacse.censis.it) (29, 30). the most commonly involved age bracket is between 11 and 14 years (9). the estimated annual incidence of sexual abuse is: – 1 case per 400 minors; – 1 case per 4 schools; – 1 case per 500 families. official italian news reports indicate a constant and considerable rise in the number of reported cases of child abuse on a yearly basis (26). in the first half of 2003, compared to the same period in 2002, this type of violence saw a 62.7% increase in victims in the 11-14 age bracket and a 43.9% increase in the age bracket of 10 and under (www.etica2001.com/ monitoraggio castelfranco.asp), with the overall number of victims rising from 296 to 438. it should also be borne in mind that the ratio of reported to non-reported offences is 1 to 100. the research carried out by laederach at 68 schools in geneva on a sample of 1,193 adolescents concluded that 20.4% of girls and 3.3% of boys had experienced abuse of a sexual nature before the age of 14 (31). the problem of pedophilia is certainly being placed increasingly in the spotlight. the media constantly brings reported cases to public attention and it is therefore a subject of discussion on all levels, legal, social, moral, medical, and scientific alike. what role can the andrologist play in the treatment of pedophiles? it should be remembered that over the last twenty years the treatment of pedophiles has been entrusted to psychiatrists, psychologists, and sexologists: this is certainly a multidisciplinary approach. however, the andrologist has detailed knowledge of the mechanisms of action and the side effects of the drugs used in androgen deprivation, which are the same drugs used to treat prostate cancer. obviously, this does not exclude the assessment of suitability for pharmacological castration formulated by other medical figures, endocrinologists, psychiatrists, criminologists, and so on. the threshold below which androgen deprivation therapy should not be administered could be set at 25 because, at this age, the hypothalamic-pituitary-gonadal axis has reached maturity. castration should be continued for a sufficiently long period of time – at least two or three years – in combination with psychotherapy or ssri therapy, until the subject’s obsessive-compulsive disorder and/or repetitive sexual ideations are under control. as clearly shown in a recent paper by amelung et al. (32), there are few randomized study about chemical castration with adt and this retrospective study presents initial data on self-motivated, help-seeking pedohebephiles choosing adt in the course of a psychotherapy program. furthermore, this study clearly showed a decrease in paraphilic sexual behavior and offense-supportive cognition under combined psychotherapy and adt, although only 15 patients agreed this therapy out of a total of 111 patients. unfortunately, there were different factors leading to discontinuation/non-acceptance of therapy: in this study, both the intended and the adverse effects of the medication seemed to influence compliance. in daily practice, only a small number of pedophiles voluntarily request treatment and they reach this decision because they experience anxiety or depression associated with this perversion; otherwise they do not spontaneously renounce their sexual orientations. for these reasons, careful education and monitoring of patients interested in adt regarding the potential effects and side effects is fundamental. in any case, as noted, the medical therapy used for androgen deprivation in pedophiles is the same therapy used to treat prostate cancer: it is important to consider the effects of therapy with lhrh super-agonists on a systemic level, such as osteoporosis, increased physical fatigue, gynecomastia, depression. and anemia. though some of these adverse effects occur regardless of the means of castration, gnrh agonists may achieve lower testosterone levels while having fewer side-effects than cpa and mpa; however, the risk of bone demineralization remains and may require additional treatment (23). nevertheless, according to the world federation of societies of biological psychiatry (wfsbp), when properly administered, with an appropriate protocol in place to detect and treat side effects should they develop, gnrh agonist treatments constitute no more or less of a risk than other pharmacological agents and represent the most promising treatment in pedophilic patients (23). from this point of view the andrologist is a highly specialized professional figure in a position to assess any indication/contraindications present in pedophile candidates for androgen deprivation therapy, as part of a team of specialists. however, it is important to examine certain considerations regarding the treatment of pedophiles: many believe that the behavior they have adopted is innocuous and they only agree to treatment to avoid detention. moreover, during their lives they have found an erotic solution to their problems and, as a result, they are rarely interested in giving it up. many psychiatrists believe that the most valid approach is insight-oriented psychotherapy; through these processes the patients become aware of the dynamics and events that caused the pedophilia to develop, improving their self-esteem and interpersonal skills, and helping them find more acceptable methods of sexual gratification. in any case, the current legislation of western countries is deficient and is primarily focused on protecting younger victims of sexual abuse. as a result, it does not support the clinical activity of the clinicians (andrologists, psychiatrists, etc.) but merely places ethical restrictions. conclusions pedophilia is an illness as well as a legal and social phenomenon with criminal implications. detention and psychotherapy alone are not sufficient to control the phenomenon and prevent repeat offences, as detention is not long enough to counteract the phenomenon. in patients who have been sentenced and have a psychosilvani_stesura seveso 23/09/15 12:38 pagina 225 archivio italiano di urologia e andrologia 2015; 87, 3 mauro silvani, nicola mondaini, alessandro zucchi 226 logical profile strongly suggestive of potential recidivism, chemical castration could provide a significant therapeutic option. aside from the severity of the phenomenon in the face of public opinion, a political class and a scientific world largely divided between those for and those against chemical castration, there are questions that every doctor who deals with the problem must ask. would it be desirable to have a law that provides for compulsory pharmacological treatment without the consent of the person concerned? lastly, prevention plays a significant role in the phenomenon of pedophilia, necessarily involving the institution, the family and, above all, schools; children spend many hours at school and teachers need to be able to interpret any signs of discomfort that may be manifested. science and institutions remain strongly divided regarding the issue of androgen deprivation in pedophiles, partly because its adoption would certainly open up a significant precedent for application in all other forms of sexual violence, especially against women. references 1. de masi f. the paedophile and his inner world: theoretical and clinical considerations on the analysis of a patient. int j psychoanal. 2007; 88:147-65. 2. alanko k, salo b, mokros a, santtila p. evidence for heritability of adult men's sexual interest in youth under age 16 from a populationbased extended twin design. j sex med. 2013, 10:1090-9. 3. mendez m1, shapira js. pedophilic behavior from brain disease. j sex med. 2011; 8:1092-100. 4. american psychiatric association. dsm v diagnostic and statistical manual disorders. washington, dc: american psychiatric publishing, inc. 2013. 5. berti a, maberino c. pedophilia: do effective treatments exist? giorn it psicopat. 2002; 8:14-8. 6. houts fw, taller i, tucker de, berlin fs. androgen deprivation treatment of sexual behavior. adv psychosom med. 20121; 31:149-63. 7. drapeau m, korner a, granger l, et al. a plan analysis of pedophile sexual abusers’ motivation for treatment. a qualitative pilot study. int j offender ther comp criminol. 2995; 49:308-24. 8. maletzky bm. the biological treatment of dangerous sex offenders. a review and preliminary report of the oregon pilot depo-provera program. arch sex behav. 2003; 8:391-412. 9. heim n. sexual behavior of castrated sex offenders. arch sex behav. 2005; 10:9-11. 10. hughes jr. review of medical reports on paedophilia. clin pediatr phil. 2007; 14:342-55. 11. iustine m, schober l, peter m. leuprolide acetate is a eamiliar drug that may modify sex-offender behaviour: the urologist’s role. bju international. 2006; 97:684-6. 12. schober jm, kuhn pj, kovacs pg, et al. leuprolide acetate suppresses pedophilic urges and arousability. arch sex behav. 2005; 34:691-705. 13. briken p, nika e, berner w. treatment of paraphilia with luteinizing hormone-releasing hormone agonist. j sex marital ther. 2001; 27:45-55. 14. cooper aj, sandhu s, losztyn s. a double-blind placebo controlled trial of mpa and cpa with seven pedophiles. can j. psychiatry. 1992; 37:687-93. 15. hill a, briken p, kraus c, et al. differential pharmacological treatment of paraphilias and sex offenders. int j offender ther comp criminol. 2003; 47:407-421. 16. krueger rb, hembree w, hill m. prescription of medroxyprogesterone acetate to a patient with pedophilia, resulting in cushing’s syndrome and adrenal insufficiency. sex abuse. 2006; 18:227-8. 17. cooper aj, cernovovsky z. the effects of cpa on sleeping and waking penile erections in pedophiles: possible implications for treatment. can j psychiatry. 1992; 37:33-9. 18. laschet v, laschet l. psychopharmacotherapy in sex offenders with cpa. pharmakopsychiatr neuropsychopharmakol 2001;4:99-104. 19. vanderschueren dm. hormone treatment of pedophilia. geneeskd belg. 1997; 59:371-8. 20. briken p, hill a, berner w. pharmacotherapy of paraphilias with long-term agonist of luteinizing hormone-releasing hormone: a systematic review. j clin psychiatry. 2003; 64:890-7. 21. schober jm, kuhn pj, kovacs pg, et al. leuprolide acetate suppresses pedophilic urges and arousability. arch sex behav. 2005; 34:691-705. 22. almeida op, waterreus a, spry n, et al. one year follow-up study of the association between chemical castration, sex hormones, betaamyloid, memory and depression in men. psychoneuroendocrinology. 2004; 29:1071-81. 23. thibaut f, de la barra f, gordon h, et al. the world federation of societies of biological psychiatry (wfsbp) guidelines for the biological treatment of paraphilias. the world journal biol psychiatry. 2010; 11:604-655. 24. prahlada rao n, chand pk, murthy p. a case of late-onset pedophilia and response to sertraline. prim care companion j clin psychiatry. 2007; 9:235-6. 25. cantor jm, kabani n, christensen bk, et al. cerebral white matter deficiencies in pedophilic men. j psychiatric res. 2008; 42:167-83. 26. pellai a, castelli b, scyvlowska g, bassoli l, et al. child sexual abuse primary prevention: outcome evaluation of a health education project implemented in milan’s elementary schools. ann ig. 2003; 15:529-39. 27. nau jy. nicolas sarkozy and pedophilia. rev med suisse 2007; 3:1980. 28. koo kc, ahn jh, hong sj, et al. effects of chemical castration on sex offenders in relation to the kinetics of serum testosterone recovery: implications for dosing schedule. j sex med. 2014; 11:1316-24. 29. caffarra d. uscire dal silenzio. gli abusi sessuali e l’incesto. asper; censis, 1998. 30. centro studi investimenti sociali (censis). sfruttamento sessuale e minori: nuove linee di tutela. un progetto contro l’abuso sessuale, c.r. 11641. rome 1998. 31. bouvier p, halpérin d, rey h, et al. typology and correlates of sexual abuse in children and youth: multivariate analyses in a prevalence study in geneva. child abuse negl. 1999; 23:779-90. 32. amelung t, kuhle lf, konrad a, et al. androgen deprivation therapy of self-identifying, help-seeking pedophiles in the dunkelfeld. int j law psychiatry 2012; 35:176-84. correspondence mauro silvani, md urologist in chief urology dept. “degli infermi” hospital, biella, italy nicola mondaini, md urologist mondatre@hotmail.com urology unit, santa maria annunziata hospital, firenze, italy alessandro zucchi, md urologist urology and andrology dept. university of perugia, perugia, italy silvani_stesura seveso 23/09/15 12:38 pagina 226 stesura seveso 217archivio italiano di urologia e andrologia 2014; 86, 3 short communication comparison of individuals consuming natural spring water and tap water in terms of urinary tract stone disease mustafa resorlu 1, muhammet arslan 2, eylem burcu resorlu 3, murat tolga gulpinar 4, gurhan adam 1, eyup burak sancak 4, alpaslan akbas 4, nilufer aylanc 1, huseyin ozdemir 1 1 department of radiology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey; 2 department of radiology, vefa hospital, manisa, turkey; 3 department of radiology, canakkale state hospital, canakkale, turkey; 4 department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey. objectives: to compare individuals consuming natural spring water and tap water in terms of presence of urinary tract stone disease. patients and methods: patients were divided into two groups on the basis of the type of water: tap water (group i) vs natural spring water consumers (group ii). the two groups were compared in terms of presence of urolithiasis. in addition to the type of water consumed, participants were investigated in terms of age, sex, occupation, body mass index (bmi) and presence of hypertension (ht) and diabetes mellitus in order to evaluate if they constituted a risk factor for urolithiasis. results: two hundred fifty-nine patients consuming tap water and 254 consuming natural spring water were included in this study. presence of urinary stone disease was determined in 27% of patients in group i and 26% of group ii (p = 0.794). at multivariate analysis involving all variables that might be correlated with the presence of urolithiasis; male gender, high bmi and presence of ht emerged as being significantly associated with urolithiasis. conclusions: although we showed that male gender, presence of ht and high bmi affect stone formation, no difference was demonstated in terms of presence of stone among patients consuming tap or natural spring water key words: tap water; natural spring water; ultrasound; urolithiasis. submitted 3 july 2014; accepted 14 july 2014 summary no conflict of interest declared. introduction urinary system stone disease is a common pathology, with a lifetime prevalence across the world of between 1% and 15% (1). the disease is more common in some geographical regions probably in relation with various genetic and environmental factors. considering environmental factors alone, stone disease is more common in mountaineous areas and in people living in dry and hot climatic conditions, such as deserts and tropical re gions (2). studies have implicated temperature-related fluid loss from the body and rise in vitamin d stimulated by solar rays as the main reasons for this (3,4). doi: 10.4081/aiua.2014.3.217 several studies have proved that increasing daily fluid intake plays a protective role against stone formation by leading to diuresis and preventing supersaturation of stone components in urine (5-7). as much as the amount of fluid consumed, however, several studies have also considered the effect on stone formation of mineral content, electrolyte level, hardness and ph level of water consumed (8-15). however, no studies to date have investigated the widespread popular idea that consumption of chlorinated tap water can lead to stone disease. in order to answer that question, we used renal ultrasound (us) to compare individuals consuming natural spring water or tap water in terms of presence of stone in the urinary system. materials and methods study population five hundred thirteen patients aged over 18 who underwent urinary system us due to abdominal or flank pain and meet study conditions were included in the study following approval of its design by the çanakkale onsekiz mart university ethical committee. subjects with renal malformation that might constitute a risk factor for urinary stone formation (horseshoe kidney, polycystic renal disease, malrotated or ectopic kidney, ureteropelvic junction obstruction etc.), with known glomerular or tubular renal disease or a family predisposition (with stone first detected in childhood) to stone disease were excluded from the study. patients were divided into two groups on the basis of the type of water they had principally consumed in the previous 2 years: those consuming tap water (group i) and those consuming natural spring water (group ii). patients drinking both types of water or had changed the type of low urine volume urine supersaturation high urine concentration crystal aggregation high fluid intake tiselius oxalate-calcium crystallization risk index: 1.9 x (ca)0.84 x (ox) x (mg)-0.12 x (cit)-0.22 x urine volume-1.03 stone formation resorlu sc_stesura seveso 08/10/14 12:15 pagina 217 archivio italiano di urologia e andrologia 2014; 86, 3 m. resorlu, m. arslan, e. burcu resorlu, m. tolga gulpinar, g. adam, e. burak sancak, a. akbas, n. aylanc, h. ozdemir 218 water consumed over the preceding 2 years or stating to consumed less than 7 glasses of water a day (< 1.5 l/day) were excluded. in addition to the type of water consumed, demographic data such as participants’ age, sex, occupation, body mass index (bmi) and presence of chronic diseases such as hypertension (ht) and diabetes mellitus (dm) were recorded. all these variables were investigated in terms of whether or not they constituted a risk factor for presence of stone in the urinary system. ultrasound measurements all examinations were performed by radiologists with experience of ultrasound. sonographic examinations were performed with gray scale ultrasound machines (toshiba aplio xg and general electric logiq 9) using two convex transducers with 3.5 mhz, 4.0 mhz frequency. the presence of the stone was defined as presence of an echogenic image with or without posterior acoustic shadowing, clearly located within the urinary tract. statistical analysis all statistical analyses were performed using spss, version 16.0. all values are shown as mean ± standard deviation. comparisons were performed using the chi-square test. differences between groups were considered statistically significant at p < 0.05. results two hundred fifty-nine patients consuming tap water (group i) and 254 consuming natural spring water (group ii) were included in the study. in terms of gender, 52% of males stated that they used to drink tap water and 48% natural spring water, while 49% of women used to drink tap water and 51% natural spring water. mean age of patients was 52.2 (18-88) years in group i and 48.6 (1886) in group ii (p = 0.75). mean bmi values were 25.7 kg/m2 in group i and 26.2 kg/m2 in group ii (p = 0.58). in terms of chronic diseases, ht was determined in 22% and dm in 17% of patients in group i, and in 16% and 12%, respectively, of those in group ii. stone was detected in 26% (n = 145) of the patients in the study, in 33% of men and 18% of women (p < 0.001). presence of stone in the urinary system was determined in 27% of patients in group i and 26% of group ii (p = 0.794). mean bmi of the patients with stone in the urinary system was 27.2 kg/m2 whereas it was 25.5 kg/m2 in those with no stone. dm was observed in 17% and ht in 31% of the patients with stone and in 14% and 15%, respectively, in those with no stone. at multivariate analysis involving all variables that might be correlated with the presence of a stone in the urinary system, male gender and presence of ht emerged as being significantly associated with urolithiasis. variables such as age, occupation, type of water consumed and presence of dm were not risk factors for development of stone. conclusions in this study we therefore investigated whether there is any association between consumption of tap or natural spring water and urolithiasis in patients receiving us due to abdominal or flank pain. although we showed that male gender, presence of ht and high bmi affect the risk of stone formation, no difference was determined in terms of presence of stone among patients consuming tap versus natural spring water. references 1. curhan gc. epidemiology of stone disease. urol clin north am. 2007; 34:287-93. 2. soucie jm, thun mj, coates rj, et al. demographics and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-9. 3. curhan gc, willett wc, rimm eb, et al. a prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. n engl j med. 1993; 328:833-8. 4. urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. j urol. 1996; 155:839-43. 5. borghi l, meschi t, amato f, et al. urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. j urol. 1996; 155:839-43. 6. lotan y, daudon m, bruye f, et al. impact of fluid intake in the prevention of urinary system diseases: a brief review. curr opin nephrol hypertens. 2013; 22(suppl):1-10. 7. parks jh, goldfischer er, coe fl. changes in urine volüme accomplished by physicians treating nephrolithisis. j urol. 2003; 169:863-6. 8. aras b, kalfazade n, tugcu v, et al. can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? a prospective randomized study. urol res. 2008; 36:313-7. 9. koff sg, paquette el, cullen j, et al. comparison between lemonade and potassium citrate and impact on urine ph and 24-hour urine parameters in patients with kidney stone formation. urology. 2007; 69:1013-6. 10. penniston kl, steele th, nakada sy. lemonade therapy increases urinary citrate and urine volumes in patients with recurrent calcium oxalate stone formation. urology. 2007; 70:856-60. 11. goldfarb ds, asplin jr. effect of grapefruit juice on urinary lithogenicity. j urol. 2001; 166:263-7. 12. shuster j, finlayson b, scheaffer r, et al. water hardness and urinary stone disease. j urol. 1982; 128:422-5. 13. bellizi v, de nicola l, minutolo r, et al. effects of water hardness on urinary risk factors for kidney stones in patients with idiopathic nephrolithiasis. nephron 1999; 81(suppl1):66-70. 14. rodgers al. effect of mineral water containing calcium and magnesium on calcium oxalate urolithiasis risk factors. urol int. 1997; 58:93-9. 15. massey lk, sutton ra. acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers. j urol. 2004; 172:555-8. correspondence mustafa resorlu, md (corresponding author) mustafaresorlu77@gmail.com gurhan adam, md huseyin ozdemir, md nilufer aylanc, md department of radiology, canakkale onsekiz mart university, faculty of medicine, canakkale onsekiz mart universitesi, terzioglu yerleskesi barbaros mh, 17100, canakkale, turkey muhammet arslan, md department of radiology, vefa hospital, manisa, turkey eylem burcu resorlu, md department of radiology, canakkale state hospital, canakkale, turkey murat tolga gulpinar, md eyup burak sancak, md alpaslan akbas, md department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey resorlu sc_stesura seveso 08/10/14 12:15 pagina 218 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 2144 case report robot-assisted laparoscopic resection of a huge pelvic tumor: a case report zhuomin jia 1*, xiangjun lyu 2*, yong xu 2, rosario leonardi 3*, xu zhang 2 1 department of urology, military general hospital of beijing pla, beijing, 100700, china; 2 department of urology/state key laboratory of kidney diseases, chinese pla general hospital/pla medical school, beijing 100853, china; 3 department of urology, musumeci gecas clinic, gravina di catania 95030, italy. *contributed equally. the traditional open surgery, for the treatment of huge tumor in the narrow space of pelvic cavity and in close proximity to pelvic organs and neurovascular structures, is very difficult and challenging. we report a case of huge neurilemmoma operated using the robot-assisted laparoscopy. we used interventional pre-operation embolization to control blood supply of tumor because mri showed the tumor had a sufficient blood supply. key words: huge pelvic neurilemmoma; pelvic robot-assisted laparoscopic surgery; mini-invasive surgery for pelvic tumor. submitted 29 april 2016; accepted 8 may 2016 summary no conflict of interest declared. cation. a month ago, magnetic resonance imaging (mri) (figure 1) showed a huge pelvic solid neoplasm (10 x 9.7 x 9.0 cm) with sufficient blood supply. type b ultrasound guided puncture biopsy was performed and pathology confirmed neurilemmoma. electrocardiogram, chest x-ray, abdominal and urological type b ultrasound were normal. during physical examination, a sharply demarcated hard and smooth neoplasm with no margin and tenderness was found above the prostate by digital rectum examination. we decide to candidate the patient for a robot-assisted laparoscopic resection surgery. one day before the operation, interventional embolization (figure 2) was performed to control the blood supply of the tumor. the mri showed that the tumor had a sufficient blood supply. during the angiography dilated right internal iliac artery was found, meaning that the tumor received its blood supply mainly from right internal iliac artery. besides, middle sacral artery was another blood supplier for the tumor. these blood supply arteries were embolized by gelatin sponge particles as well. six-hour bed rest was suggested after embolization and no uncomfortable reactions were reported. doi: 10.4081/aiua.2016.2.144 introduction pelvic cavity, is a narrow space closely surrounded by muscular skeletal structures. in this space urogenital organs, intestine, sigmoid colon and rectum are located. patients with huge space-occupying lesions in this cavity may suffer from voiding or defecation dysfunctions because of rectum or bladder compression. due to the ultra narrow space and close proximity to pelvic organs and neurovascular structures, traditional open surgery in this cavity is very difficult and challenging (1). convalescence is usually prolonged. operation using robot da vinci because of the advantage of high-definition (hd) vision and great surgical precision can reduce the difficulty and risk of the surgical treatment. recently, we successfully resected a huge pelvic neurilemmoma by using robot-assisted laparoscopy. case report a 33-year-old male was referred to the department of urology of the general hospital of people’s liberation army in february 2016 as a case of huge pelvic tumor. the tumor was found one and a half year before and wasn’t treated for personal decision of the patient. during the intercurring period, the tumor stayed with no growth, although the patient was suffering from frequent difficulty in urination and defefigure 1. mri. figure 2. interventional embolization. leonardi figura rifatta_stesura seveso 13/07/16 19:37 pagina 144 145archivio italiano di urologia e andrologia 2016; 88, 2 robotic resection of pelvic tumor surgical procedure under general anesthesia, patient was placed in supine position, with a urinary catheter placed before the surgery. the insertion of trans umbilical scar veress needle was used to create pneumoperitoneum. co2 pressure was raised to 14mmhg. a 1 cm incision was made about 2 cm up to the the umbilicus. a 12 mm trocar was placed in this incision for camera. two 8 mm trocar were placed 8 cm away from the umbilicus on the left and right at umbilicus transverse line for the second and the first robotic arm, respectively. another 8 mm trocar was placed 8 cm laterally from the right trocar for the third robotic arm. a 12 mm trocar was placed in the left upper abdomen as an assistant port (figure 3). the patient was then placed in a 30 degree trendelenburg position. following the docking of the robotic arms, the 3-dimensional zerodegree stereoscopic endoscope, monopolar scissors (the first arm), meryland bipolar forceps (the second arm), progasp forceps (the third arm) were placed for the the surgeon. aspirator and other assistant instruments were then used by assistant through the no robotic ports. the surgeon then moved to the console to remotely control the robot.the tumor was located in the pelvic floor, with a size of 11 x 7 x 7 cm. pelvic floor peritoneal was opened and the edge of the tumor was exposed. first was dissected the ventral surface of the tumor (figure 4), then the left surface (figures 5). we performed a tight dissection of left surface of tumor, along the capsula, with a high attention to not interrupt it, with an accurate hemostasis using bipolar forceps and hem-o-lok clips as well. the right surface (figures 6) of the tumor was closely adhesive to adjacent tissues, with sufficient blood supply. hem-o-lok clips were used for hemostasis whereas blunt and sharp dissection was used to expose the tumor. the space between tumor and the back wall of bladder (figure 7), tumor and the anterior rectum wall (figure 8) was then dissected. the tumor was slight adherent to the rectum. the tumor was then successfully excised en bloc, with no rectum or bladder injury. after thorough hemostasis, silicon drainage tube was placed in the pelvic cavity, and pelvic peritoneum was closed by using hem-o-lok clips. all robotic arms and trocars were then removed. umbilicus incision was elongated upwards to remove the tumor. incisions were sutured layer by layer. total blood loss was 200 ml, total operative time, defined as the time from skin incision to skin closure was 100 minutes. post-operative data the catheter was removed and patient was encouraged to get out bed one day post-operation, the gastric tube was removed 2 days post-operation, pelvic drainage tube was removed 3 days post-operation. the patient was discharged 5 days post-operation. postoperative pathologic examination showed neurilemmoma (figure 10). discussion neurilemmoma, solitary fibrous tumor, teratoma, seminoma and extra-gastrointestinal stromal tumor are the most common pelvic tumors among males (2). the histological type of this case was neurilemmoma, which is a kind of benign tumor belong to nerve sheath tumor; another two kinds of nerve sheath tumor are neurofibroma and malignant peripheral nerve sheath tumor. these tumors are usually seen in head, neck, mediastinum, and upper limbs, but rarely, about 0.5%-3%, in retroperitoneal space. pelvic neurilemmoma is even more rare, usually located in presacral space and peri-lumbosacral vertebral region, sometimes arising from pelvic wall, bladder and bowel wall (3). deep location, narrow space, multiple adjacent organs and bony structure of pelvic wall add difficulties to open surgery for treatment of pelvic tumors. besides, open surgery has the disadvantage of severe operation trauma, which leads to slow recovery. in this case, the robotic surgical system davincisi was used, because this system could provide surgeons with enhanced visual control and dexterity. the 3-dimensional monitor system provides us figure 3. trocars’ position. figure 4. ventral surface of the tumor. figure 6. right surface of the tumor. figure 7. the space between tumor and the back wall of bladder. figure 8. the space between tumor and the anterior rectum wall. figure 9. the tumor. figure 10. pathologic picture of the neurilemmoma. figure 5. left surface of the tumor. leonardi figura rifatta_stesura seveso 13/07/16 19:37 pagina 145 archivio italiano di urologia e andrologia 2016; 88, 2 z. jia, x. lyu, y. xu, r. leonardi, x. zhang 146 high-definition, magnified images to better observe tissue boundaries and vessels, which adds the possibility of sharp dissection and the possibility to remove all the tumor without interruption of the capsule and without leaving tumoral tissue that could give a relapse of pathology. the robotic arms of the system are more flexible than human hands, especially for deep-space surgeries, and the third arm works as an assistant and can be manipulated by the surgeon, making the cooperation closer. less trauma and fast recovery are the other advantages of this system. the huge pelvic tumor of this patient was closely adjacent to bladder and rectum, and had sufficient blood supply. thus we first controlled its blood supply prior operation by using interventional embolization to reduce the risk of intra-operative bleeding. during the operation, the relationship between the tumor and adjacent tissues could be divided into five steps, that are abdominal, left pelvic wall, right pelvic wall, back bladder wall and front rectum wall. robotic assisted laparoscopic surgery has the advantages of enhanced dexterity, high-definition 3-dimentional magnified images, less trauma and fast post-operative recovery in resection of huge pelvic tumor, and could be considered as an alternative procedure for treatment of huge pelvic tumor. references 1. wong kc, sze ky, wong io, et al. patient-specific instrument can achieve same accuracy with less resection time than navigation assistance in periacetabular pelvic tumor surgery: a cadaveric study. int j comput assist radiol surg. 2016; 11:307-16. 2. daneshmand s, youssefzadeh d, chamie k, et al. benign retroperitoneal schwannoma: a case series and review of the literature. urology. 2003; 62:993-7. 3. hoarau n, slim k, da id. ct and mr imaging of retroperitoneal schwannoma. diagn interv imaging. 2013; 94:1133-9. correspondence zhuomin jia, md department of urology, military general hospital of beijing pla, beijing 100700, china xiangjun lyu, md yong xu, md xu zhang, md (corresponding author) xzhang@foxmail.com department of urology/state key laboratory of kidney diseases, chinese pla general hospital/pla medical school, beijing 100853, china rosario leonardi, md leonardi.r@me.com department of urology, musumeci gecas clinic, gravina di catania 95030, italy leonardi figura rifatta_stesura seveso 13/07/16 19:37 pagina 146 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4266 original paper spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy: two centers experiences abdulmuttalip simsek 1, faruk ozgor 1, bahar yuksel 2, ercan bastu 2, mehmet fatih akbulut 1, onur kucuktopcu 1, omer sarilar 1, ahmet yalcin berberoglu 1, zafer gokhan gurbuz 1 1 haseki research and training hospital, department of urology; 2 istanbul university, school of medicine, department of obstetrics and gynecology. background: to analyze the characteristics of the patients with diagnosis of spontaneous retroperitoneal hematoma associated with anticoagulation therapy and antiplatet therapy. methods: from january 2006 to march 2013, 9 patients (6 from haseki training and research hospital urology department and 3 from istanbul medical faculty gynecology and obstetric department) were included in the study. patients charts including sex, age, comorbidities, main complaint, and medication intake were examined. also initial hemoglobin level, initial international normalized ratio level, red blood cells and fresh frozen plasma units transfused were evaluated. results: median age was 60 year-old. abdominal pain and flank pain were common symptoms. eight patients were taking only anticoagulation therapy, 2 only antiplatet therapy and 1 both anticoagulation and antiplatet therapy. median initial hemoglobin value was 9,0 g/dl and median international normalized ratio level was 3.2 patients were evaluated by abdominal ultrasonography or abdominal computer tomography. seven patients were treated conservatively. only one patient died because of septic shock with a mortality ratio of 11%. conclusion: despite benefits of anticoagulation and antiplatet theraphy these agents have serious side-affects as retroperitoneal hemorrhage in elderly patients taking multi-drug medication. key words: spontaneous retroperitoneal hematoma; anticoagulation therapy; antiplatet therapy. submitted 14 january 2014; accepted 30 june 2014 summary no conflict of interest declared. (act) and antiplatet theraphy (apt) were well described in stroke, deep vein thrombosis and pulmonary embolism, these agent may be cause of bleeding anywhere in the human body (3). once when retroperitoneal haemorrhage occurs, the patient’s condition abruptly deteriorates requiring assistance in emergency due to hypotension, weakness and flank pain. also hematoma induce symptoms due to the compression of adjacent structures. in this paper we aim to present the exprience of two center (haseki training and research hospital urology department and istanbul medical faculty gynecology and obstetric department) about srh associated with act and apt. materials and methods in two academic tertiary care center with high volume emergency department, patients charts were evaluated retrospectively. from january 1, 2006 to march 31, 2013; 6 patients in haseki training and research hospital urology department (hsku) and 3 patients in istanbul medical faculty gynecology and obstetric department (imfgo) with diagnosis of srh associated with act and apt were included study. sex and age of patients, comorbidities, main complaint and medication intake were analyzed. also history of trauma and surgical manipulation was investigated carefully. patients with history of surgical manipulation up to three months prior to the time of application were excluded from the study. initial hemoglobin level, initial international normalized ratio (inr) level, red blood cells (rbc) and fresh frozen plasma (ffp) units transfused were evaluated. additionally diagnostic imaging methods were recorded. all patients charts were rewieved by two authors for variables defined before data collection. microsoft excel 2010 software (microsoft corporation, redmond, wa) was used for data entry. results nine patients were included in the study (table 1). four were males and five were females with median age 60 years (range from 37 to 77 years). abdominal and flank doi: 10.4081/aiua.2014.4.266 introduction spontaneous retroperitoneal hematoma (srh) is a rare but serious clinical condition described as bleeding into the retroperitoneal area without associated trauma or surgical manipulation (1). the most common causes of srh are renal tumors, vascular diseases and anticoagulation treatments (2). despite the benefits of anticoagulation theraphy simsek2_stesura seveso 22/01/15 09:56 pagina 266 267archivio italiano di urologia e andrologia 2014; 86, 4 spontaneous retroperitoneal hematoma pain, weakness, dizziness were the most common symptoms. also acute dyspnea and dyspepsia were described. abdominal mass and flank discoloration was seen only in one patient. one patient (11%) was taking a combination of act and apt (acetylsalicylic acid plus warfarin). six patients were taking only act includig warfarin or heparin. two patients were taking only apt (acetylsalicylic acid). almost all patients (88%) were receiving multiple medication simultaneously. initial mean hemoglobin value was 9.05 g/dl and ranged 5.9-12.1 g/dl. median international normalized ratio (inr) level was 3.2 (range 1.2-5.8) with supratherapeutic level (> 3) in 5 patients. the diagnosis was based on imaging method but two patients (22%) were initially misdiagnosed. the first diagnosis of these two patient was endometrioma and pelvic mass respectively, depending on abdominal ultrasonography. abdominal ultrasonography was performed in all patients and contrast-enhanced abdominal ct was performed in 7 of 9 patients. due to the high creatinine level two patients were evaluated by non-contrast enhanced computer tomography. angiography was performed in 3 patients but no pathological finding was described. magnetic resonance imaging was not used. seven patients were treated conservatively. six patients were transfused with red blood cells, ranging from 2 to 9 units, to elevate hemoglobin level. median number of packed red blood cells transfused was 2.7 unit per patient. two patients did not require blood transfusion. vitamin k and ffp was used to correct coagulopathy in 7 patients. ffp was used in one patients to avoid side effects of rbc transfusion. one patient underwent surgery in emergency deparment because of continuous decrease of hemoglobin level. the patient had chronic renal failure with non-functional hydronephrotic kidney and underwent dialysis programme. nephrectomy and clot evacuation was performed (figure 1). perioperative and post operative period were uneventful. one patient underwent elective surgery after hemodynamic stabilisation. despite the normal hemoglobin level, patient fever was elevated > 38º c a week after the hospitalisation even on broad-spectrum age gender symptoms drug initial inr rbc ffp surgery co-morbidities type hgb level transfusion transfusion (number (number of pocket) of pocket) p-1* 64 f pain, weakness act 9.8 3,2 2 + ht, dm p-2* 53 f pain, weakness act+ apt 12.1 5 + cve, ht p-3* 71 f pain,weakness, dizziness act 7.4 3,6 2 + p.ulcus, ht p-4 60 f pain act 8.2 1,2 2 + dm,cve p-5 48 m pain, weakness, dyspnea act 5.9 2 9 + ht, ckd p-6 43 m pain, abdominal maas, flank coloration act 7.6 3,5 3 + p-7 77 m pain, weakness apt 11.4 1,4 dvt p-8 64 m pain,weakness, dizziness apt 10.1 1,3 4 + + ht, ckd p-9 37 f pain, dyspepsia act 9.0 5,8 6 + + le, ht *: patients treated in istanbul medical faculty – gynecology and obstetric department; rbc: red blood cell; ffp: fresh frozen plasma; act: anticoagulation theraphy; apt: antiplatet theraphy; ht: hypertension; dm: diabetes mellitus; cve: cerebrovasculer event; le: lupus erythematosus; ckd: chronic kidney disease; dvt: deep vein thrombosis. table 1. characteristics of mine patients. figure 1. massive retroperitoneal hematoma: patient underwent unsuccesful clot evacuation. figure 2. retroperitoneal hematoma in a patient who underwent a dialysis programme because of cystic disease. simsek2_stesura seveso 15/01/15 13:04 pagina 267 archivio italiano di urologia e andrologia 2014; 86, 4 a. simsek, f. ozgor, b. yuksel, e. bastu, m. fatih akbulut, o. kucuktopcu, o. sarilar, a. yalcin berberoglu, z. gokhan gurbuz 268 antibiotics. after achievement of normal inr level, clot evacuation, abscess drainage and, if necessary, nephrectomy was planned. clots covered all the retroperitoneal area including aorta and superior mesenteric artery. despite consultation of the general surgeon clot evaculation failed (figure 2) and on the sixth day after surgery septic shock developed and the patient died. after achievement of stable hemoglobin and coagulation levels, patients were discharged. mean hospitalisation was 5.8 day ranging from 3 to 18 days. follow up with imaging modalities was performed in 8 patients exluding the patient who underwent nephrectomy. size of hematoma was decreased in 6 patients and stable in 2 patients at the discharge. discussion spontaneous retroperitoneal hematoma (srh) is a well defined lethal entity but the pathogenetic mechanism is not clearly understood due to the rarity of the disease (4). the underlying pathology of srh could be ignored by physicians because of its fatality and the requirement of emergency intervention. certainly rupture of organs or vessels causes bleeding in to the retroperitoneal space without trauma or surgical manupilation. the definitive pathology is still unkown but several hypotheses have been proposed including small vessel arteriosclerosis, anticoagulation induced immune microangiopathy and forceful vascular strain (5). dougal and collegues investigated etiology of srh and renal tumors including renal cell cancer and angiomyolipomas were identified as the reason of 58% of all cases. vascular pathologies and infectious diseases played second and third role with 18% and 10% respectively (6). these findings were supported by zhang et al. who review the english literature from 1985 to 1999 (7). differently sunga reported a study about srh including 89 cases and 64% of patients were on anticoagulation therapy (8). anticoagulation treatment and antiplatet treatment has a essantial role for prevention of thrombosis and thromboembolism in acute myocardial infarctus, deep vein thrombosis and pulmonary embolism. warfarin is the most widely preferred anticoagulation agent that interfere on blood caogulation by inhibiting vitamin k epoxide reductase. during the initial stage of treatment, checking of inr may be required daily and frequent testing can be prolonged until the patient has stable therapeutic inr levels on an unchanged warfarin dose. by the fact warfarin interact with many commonly used medications and foods particularly vegetables. also kidney failure or liver failure modify the effect of warfarin (9). acetylsalicylic acid inhibit on cyclooxigenase and have antipyretic, anti inflammatory and analgesic affect. most common side affects are seen in gastrointestinal tract but prolonged bleeding time and thrombocytopenia are other side affect especially in high dose use (10). drug interaction is common for both drugs and we believe that is critical for hemorragic events. in our study 10 of our patients received multidrug treatment for hypertension, diabetes mellitus, cerebrovasculer event, lupus erythematosus and gastric ulcer. on the other hand our population mean age was 57.44 ± 13.20 years and five patients were older than 60. senile systemic changes affect on drug metabolism. reduced intestinal passage, atrophy of intestinal villi, chronic liver disease or chronic kidney disease alter the metabolism of drugs. also systemic diseases as hypertension, diabetes mellitus, and hyperlipidemia disrupt the structure of the vascular wall and facilitate hemorrhage. diagnosis of srh mostly depends on presentation symptoms and radiological studies (11). although lenk triad including acute flank pain, tenderness and symptoms of internal bleeding was described for srh, symptoms may show a wide range from hip-leg pain to cardiovascular collapse. generalized weakness, headache, dyspnea, syncope and altered mental status are less common symptoms associated with the degree and the duration of bleeding. particularly in patients with stable cardiovascular status, the mass of the hematoma develops a pressure on adjacent structures such as small intestine or stomach causing constipation and dyspepsia (12). abdominal computer tomography and ultrasonography are the most common radiological modalities for define srh (13). although its non invasive, rapid and reproducible nature, ultrasonography is operator dependent and has limited capacity to define hematoma and its relation with adjacent organs. diagnostic accuracy of ct scan is higher and give more valuable information about size, relation with adjacent organs and also underlying pathology of hematoma. magnetic resonance imaging is helpful to differentiate blood from tumor but is performed only for patients in stable condition (14). managament of srh is mostly depending on degree of bleeding and underlying pathology. if the patient’s condition was deteriated or underlying pathology was renal tumor, nephrectomy was suggested (15), but clinical condition is much more complicate if srh is associated with act or apt. decision is challenging for physician because on one side there is a patient with bleeding requiring surgical intervention, on the other side surgical intervention can contribute to further bleeding. conservative treatment is also supported in patients with a stable condition. bosniak et al. demonstrated that operative exploration is not essential for all unexplained cases (16). also hematoma evacuation is performed only for patients if hematoma become focus of infection or with significant compressive symptoms. conclusion in this paper we report experience about srh associated with act and apt in two high volume tertiary centers. particularly in elderly patients taking multidrug medication, side effects of act and apt are more frequent. physicians must be aware about bleeding complications and have a good knowledge of its clinical presentations and treatment. if the patient’s condition is stable in retroperitoneal hemorrhage, conservative treatment is a feasible method to protect patient from unnecessary surgical manipulation. simsek2_stesura seveso 15/01/15 13:04 pagina 268 269archivio italiano di urologia e andrologia 2014; 86, 4 spontaneous retroperitoneal hematoma references 1. melde sl. enoxaparin induced retroperitoneal hematoma. ann pharmacother. 2003; 37:822824. 2. daskalopoulos g, karyotis i, heretis i, et al. spontaneous perirenal hamorrhage:a 10-year exprience at our institution. int urol and nephr. 2004; 36:15-9. 3. moudouni sm, en-nia i, patard jj, et al. spontaneous subcapsular renal hematoma: diagnosis and treatment. two case reports. ann urol. 2002; 36:29. 4. koo v, duggan b, lennon g. spontaneous rupture of kidney with peri-renal haematoma: a conservative approach. ulster med j. 2004; 73:53-6. 5. srinivasan v, turner ag, blackford hn. massive intraperitoneal hemorrhage associated with renal pathology. j urol. 1994; 151:980-1. 6. mc dougal ws, kursh ed, persky l. spontaneous rupture of the kidney with perirenal hematoma. j urol. 1975; 114:181-184. 7. zhang jq, fieling jr, zou kh. etiology of spontaneous perirenal haemorrhage: a meta-analysis. j urol. 2002; 167:1593-1596. 8. sunga kl, bellolio mf, gilmore rm, cabrera d. spontaneous retroperitoneal hematoma: etiology, characteristics, managament and outcome. j emer med. 2012; 43:e157-e161. 9. mabjeesh nj, matzkin h. spontaneous subcapsular renal hematoma secondary to anticoagulant theraphy. j urol 2001; 165:1201. 10. zhu jp, davidsen mb, meyhoff hh. aspirin, a silent risk factor in urology. scand j urol. nephrol. 1995; 29:369-74 11. mrug m, mishra pv, lusane hc, et al. hemothorax and retroperitoneal hematoma after anticoagulation with enoxaparin. south med. j 2002; 110:69-71. 12. boumdin h, ameur a, lezrek m, et al. spontaneous subcapsular hematoma of the kidney. report of six cases. ann urol. 2002; 36:357. 13. zissin r, ellis m, gayer c. the ct findings abdominal anticoagulant-related hematomas. semin ultrasound ct mr 2006; 27:117-25. 14) balci nc, sirvanci m, tufek i, et al. spontaneous retroperitoneal hemorrhage secondary to subcapsular renal hematoma: mri findings. magn reson imaging. 2001; 19:1145. 15. morgentaler a, belville js, tumeh ss, et al. rational approach to evalution and management of spontaneous perirenal hemorrhage. surg gynecol obstet. 1990; 170:121-5 16. bosniak ma. spontaneous subcapsular and perirenal hematomas. radiology. 1989; 172:601-2. correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com faruk ozgor, md mehmet fatih akbulut, md onur kucuktopcu, md omer sarilar, md ahmet yalcin berberoglu, md zafer gokhan gurbuz, md haseki training and research hospital, department of urology, millet cad. no: 11, 34000 fatih, istanbul, turkey bahar yuksel, md ercan bastu, md istanbul university, school of medicine, department of obstetrics and gynecology, istanbul, turkey simsek2_stesura seveso 15/01/15 13:04 pagina 269 stesura seveso 299archivio italiano di urologia e andrologia 2015; 87, 4 original paper male sexual dysfunction in patients with chronic end-stage renal insufficiency and in renal transplant recipients michele antonucci 1, giuseppe palermo 1, salvatore marco recupero 1, riccardo bientinesi 1, fabrizio presicce 2, nazario foschi 1, pierfrancesco bassi 1, gaetano gulino 1 1 department of urology clinic, catholic university of s. heart, rome, italy; 2 urology, policlinico s. andrea, “la sapienza” university, rome, italy. materials and methods: the study was conducted from december 2011 to december 2012 on 95 patients between the ages of 20 and 65 years: 44 of which had been undergoing dialysis for over a year and 51 of whom had undergone kidney transplants more than 6 months before. comorbidities were carefully recorded, erectile function was evaluated the with iief5 questionnaire and serum levels of total testosterone / free and prolactin were tested at early morning (7 am). to assess the relationship between erectile dysfunction (ed) and clinical laboratory tests, student's t-test statistical (quantitative variables), chi-square (qualitative variables), the uni and multivariate analysis were used. results: in patients undergoing dialysis and in recently transplanted patients a higher instance of ed was found (70% and 65% of cases respectively). amongst dialyzed patients, patients aged over 50 suffer from ed more frequently. patients aged over 50s represent 61% of the total number of patients suffering from ed, and just 31% of patients not suffering from ed, (p = 0.006); hyperprolactinemia was found in 23% and 20% of both groups respectively. fifty nine % of the dialyzed patients presented values of testosterone serum levels of less than 250 ng/dl with a significant difference between those who were suffering from ed and those who were not (65% of ed patients vs. 46%,of patients not affected from ed p = 0.019). this was found in only 37% of transplanted patients and there does not appear to be a statistically significant correlation with the onset of ed (p = 0.12). in patients over the age of 50, diabetes and a condition of hypotestosteronemia were significantly correlated with ed at univariate and multivariate analyses. conclusions: the ed in patients with end stage chronic kidney failure (ckf) continues to have a strong prevalence, either in the patients who are undergoing dialysis or in those who have received transplants. in literature this issue is not sufficiently considered if not at all. hypotestosteronemia is a risk factor for the onset of ed in end stage ckf patients. a significantly lower prevalence of hypogonadism among dialyzed patents and transplant recipients suggests that renal transplantation may be protective for the sexual capabilities of these patients. key words: chronic renal failure; kidney transplant; erectile dysfunction; hypogonadism; pathophysiology; risk factors. submitted 18 january 2015; accepted 30 april 2015 summary no conflict of interest declared. introduction patients with end-stage chronic kidney failure (ckf) who undergo hemodialysis experience a significant deterioration in their quality of life, due both to a treatment requiring patients to attend dialysis sessions of 3-4 hours duration 3 days a week, and for the comorbidity associated with it. among comorbidities, it is important to highlight erectile dysfunction due to its high frequency. in 1975, the first scientific studies documenting a close link between erectile dysfunction and chronic renal failure came to light (1). erectile dysfunction (ed) is an inability to obtain or maintain an erection sufficient for satisfactory sexual activity. with the examination of several studies, its prevalence in this group of patients becomes apparent with a leveling off between 50 and 80% (1, 2). several factors may contribute to the onset of erectile dysfunction and its progression over time. these could include: abnormalities in the neuro-endocrine control system of the hypothalamic-pituitary-gonadal axis; secondary hyperparathyroidism; peripheral neuropathy; changes in smooth muscle of the corpora cavernosa of the penis, structural alterations of the arterial wall, damage of the veno-occlusive cavernosal mechanism, drug therapies consequential to ckf, stress and depression. pathophysiology of erectile dysfunction in chronic renal failure numerous scientific evidence shows that the pulsatile release of gonadotrophic hormones in uremic patients is dramatically compromised until reaching a stage of clear hypogonadism (3). in the plasma of patients with severe ckf, a decrease in the concentration of testosterone and increased levels of fsh and lh it is often noted (4). the decrease of concentration of testosterone in plasma is attributed to several mechanisms: increased testosterone excretion during the dialysis treatment (5), reduction of its production by the leydig cells (6), poor response to gonadotropin stimulation probably induced, at least in part, by cytokine changes resulting from the chronic systemic disease. low levels of testosterone stimulate a feedback mechanism with the secretion of lh, whose concentration is further elevated as a result of its reduced renal excretion. fsh levels are high because of the atrophy of doi: 10.4081/aiua.2015.4.299 archivio italiano di urologia e andrologia 2015; 87, 4 m. antonucci, g. palermo, s.m. recupero, r. bientinesi, f. presicce, n. foschi, p.f. bassi, g. gulino 300 the sertoli cells, normally responsible for its inhibition through the secretion of inhibin peptide (7). hyperprolactinemia was present in 25-57% of male patients with ckf and was indicated by some authors as a possible associated cause of impotence, hypogonadism and decreased libido (8). hyperprolactinemia interferes with normal gonadal response to gonadotropins, thus resulting in a reduction in testicular steroidogenesis. the reasons for the occurence of this remain disputed. erectile dysfunction may, however, be the earliest clinical manifestation of diabetes based on autonomic neuropathy. diabetes is in fact the most frequent factor which determines a condition of end-stage chronic renal failure. studies of tissue biopsy samples of uremic patients with diabetes and erectile dysfunction documented a weakening of neurogenic and endothelial mechanisms that allows the relaxation of smooth muscles of the corpora cavernosa (9). in those patients the simultaneous diagnosis of neurogenic bladder supports a neuropathic etiology of erectile dysfunction (10). the peripheral neuropathies are the most frequent, in particular a sensorymotor polyneuropathy that appears with numbness, burning pain, and a reduction or disappearance of deep tendon reflexes. restless legs syndrome is frequent, characterized by continuous movement of the legs during sleep and caused by impaired neuromuscular conduction velocity. the autonomic nervous system may also be compromised, leading to alterations in blood pressure control and erectile dysfunction on a neuropathic basis. the basis of the neuropathy is probably a block of nerve transmission mediated by so-called “uremic toxins” (urea, creatinine, parathyroid hormone, myoinositol and b2microglobulin). in particular, some substances with a molecular weight between 300 and 12,000 dalton are suspected of being responsible for the neuropathy. studies have also shown a slowing of nerve conduction in the segments not affected clinically. in patients with chronic kidney disease an abnormal metabolism of carbohydrates, lipids and proteins is often observed. due to these reasons, and also to the state of inflammation that accompanies the chronic kidney diseases, the uremic patient is particularly predisposed to atherosclerosis and therefore to ischemic disease especially in the coronary artery, but also in the arterial penile district, determining an artery based erectile dysfunction. diabetes together with hypertension, another condition extremely common in dialyzed patients, often determines a significant acceleration of atherosclerotic processes and therefore a vascular based erectile dysfunction (11). in a large proportion of end-stage ckf patients (78%), in fact, an occlusion was found in blood vessels in the pelvic arteries and their tributaries (12). a high percentage of patients with ckf, due to the occurrence of cardiovascular comorbidities, take medications such as beta-blockers and diuretics whose most common side effect is erectile dysfunction. but, replacing it with other types of drugs does not appear to result in significant improvements of erectile function (13). an impaired synthesis of erythropoietin, very common in end-stage ckf patients, as is well known, produces anemia, causing, among other side effects, a low flow of oxygen in the corpora cavernosa; this results in a reduced synthesis of nitric oxide and increased production of contractile factors of endothelial origin, leading to an augmentation of smooth muscle tone and consequently a possible impairment of the mechanism of erection (14). finally, the psychogenic component must not be ignored since patients on dialysis often suffer from anxiety, low self-esteem and chronic fatigue: these factors can lead to a reduction in sexual interest (15, 16). due to all of the aforementioned possibilities, it is not surprising that the prevalence rate of erectile dysfunction in dialyzed patients could be as high as 80%. in kidney transplanted patients, the prevalence of erectile dysfunction remains high, occurring in around 65% of cases and hypogonadism is also a frequent occurrence. the protracted uremic condition before the transplant is not only due to a functional damage but also to an anatomical damage to the delicate hypothalamic-pituitary-gonadal axis (17, 18). biopsies performed on transplanted patients in testicular tissue, showed abnormalities of number and morphology of leydig cells (17). other authors, instead, have focused their attention on immunosuppressive therapy: a study by lee showed that the sirolimus (an immunosuppressant drug often used in combination with calcineurin inhibitors in renal transplant) results in a significant decrease in serum concentrations of testosterone (18). it was also postulated that the cyclosporin forms adversely affect the production of nitric oxide, an essential substrate in the complex mechanism of erection (19). so it is possible that the immunosuppressive therapy in transplant patients helps to maintain the endothelial and gonadic dysfunction that the previous uremic state had produced. a final possible explanation for the ed in the transplanted patients is related to surgical transplant procedures: according to a study published by elbahnasawy one internal iliac artery ligation without further external iliac artery terminal anastomosis results in a significant reduction of blood flow, negatively impacting penile erectile function (20). objective the objectives of this study are as follows: – the evaluation of the prevalence of sexual dysfunction (erectile dysfunction and hypogonadism) in male patients with end stage chronic renal failure on hemodialysis; – the evaluation of the prevalence of sexual dysfunction (erectile dysfunction and hypogonadism) in male patients with end stage renal failure after kidney transplantation; – the searching for factors predisposing to erectile dysfunction, with particular attention to hormones, in male patients with end stage chronic renal failure, on dialysis or after renal transplantation. materials and methods the study was conducted during the period between december 2010 to december 2011, at the university hospital a. gemelli, in the department of urology, department of transplant surgery and center for hemodialysis. it involved a total of 95 patients aged between 20 and 65 years with severe chronic renal failure, divided into two groups: one group of 44 patients who had been undergoing dialysis for more than a year and another consisting of 51 patients that recevied a kideny transplant more than 6 months before. clinical information for patients in both groups was recorded (age, start of dialysis treatment/duration of transplantation, pathology that led to the ckf, comorbidity, drug treatment). all patients were given iief5 questionnaire, consisting of 5 questions. this was proposed by rosen in 1997 and is widely known and used for the evaluation of the degree of erectile dysfunction (ed) (21). the score is recorded between a range of 2 and 30. four categories can be identified depending on the score: the absence of disease (score 26-30), mild ed (17-25), moderate ed (11-16), severe ed (< 10). the study considered all patients with ed with a score less than or equal to 25. we also performed a blood test on all patients in order to measure total and free testosterone and prolactin. a normal range of prolactin was defined as 3.5-15.5 ng/ml; from 2.50 to 8.4 ng/ml for total testosterone; from 2.50 to 8.4 ng/ml for free testosterone. an informed consent was obtained from all patients. statistical analysis for both groups we calculated the prevalence of hypogonadism and ed, which was in turn stratified by age and severity. then, within the two groups (post-dialysis and transplant patients), some clinical features were compared along with laboratory records among patients presenting ed and those who did not presented it. the statistical relationships between ed and clinical-laboratory characteristics were evaluated with student t test for quantitative variables and chi-square test for qualitative variables. a p value < 0.05 was considered statistically significant. only those statistically significant factors at univariate analysis were further studied in a multivariate analysis. statistical analysis was performed using the spss 14.0 system. results in the group of dialyzed patients 44 men in total were recruited, the average age of the sample was 49 years. the ed was found in 31 patients, representing 70% of the sample. of these patients 7 (16%) reported mild ed, 10 (22%) moderate ed, and 14 (32%) severe ed (figure 1). patients older than 50 represent 61% of the total number of patients suffering from ed while representing just 31% of patients not suffering from ed, p = 0.006. there is also a high prevalence of diabetes in those who suffer from ed compared with those who do not (39% of the total number of patients suffering from ed versus 15%,of the total number of patients not suffering, p = 0.014). the other clinical characteristics (duration of dialysis, use of beta-blockers), although presenting minimal difference between the two subgroups examined, do not reach the threshold of statistical significance. among the laboratory parameters, hyperprolactinemia is present in 23% of patients, but without significant differences between the two subgroups. with regard to testosterone, as many as 59% of the patients had serum values below 250 ng/dl with a significant difference between those suffering from ed and those not (65% of the total number of patients suffering from ed versus 46%,of the total number of patients not suffering, p = 0.019) (table 1). among the considered factors, those which significantly correlated with ed based on a univariate analysis were the following: being older than 50 years of age, diabetes and a condition of hypotestosteronemia. these considerations are confirmed after a multivariate analysis (table 2). 301archivio italiano di urologia e andrologia 2015; 87, 4 sexual dysfunctions in kidney transplant recipients figure 1. prevalence of ed in patients with ckf on dialysis. clinical-laboratory total patients patients with ed patients without ed p characteristics n = 44 n = 31 n = 13 age > 50 years 23 (52%) 19 (61% of ed 4 (31% of no-ed 0.006 patients) patients) diabetes 14 (31%) 12 (39% of ed 2 (15% of no-ed 0.014 patients) patients) duration of dialysis in months * 65.2 (52.4) 63.1 (50.9) 67.3 (54.3) 0.72 taking beta-blockers 33 (75%) 24 (77% of ed 9 (69% of no-ed 0.66 patients) patients) hypotestosteronemia 26 (59%) 20 (65% of ed 6 (46% of no-ed 0.019 (free t < 40 pg/ml) patients) patients) hyperprolactinemia 11 (25%) 8 (26% of ed 3 (23% of no-ed 0.53 (prl > 15.5 ng/ml) patients) patients) * standard deviation in brackets. table 1. clinical and laboratory characteristics of the sample. risk factors for ed or ic 95% p age > 50 years 7.221 1.826 to 29.385 0.004 diabetes 6.139 1.298 to 31.659 0.023 hypotestosteronemia (ft < 40 pg/ml) 6.456 1.437 to 40.871 0.031 or: odds ratio; ic: interval confidence 95%. table 2. results of multivariate analysis for risk factors for ed in patients with ckf on dialysis. severe (2-10) 32% absent (iief 5: 26-30) 29% mild (17-25) 16%moderate (11-16) 23% archivio italiano di urologia e andrologia 2015; 87, 4 m. antonucci, g. palermo, s.m. recupero, r. bientinesi, f. presicce, n. foschi, p.f. bassi, g. gulino 302 in the group of 51 patients with end stage ckf, who received renal transplantation from over a year, the average age stood at 47 years, de was found in 33 patients (65%). out of them in 9 (18%) de proved to be mild, in 10 (20%) moderate ed and in 14 (27%) severe ed (figure 2). through the evaluation of the clinical and laboratory characteristics of this second group of patients, it becomes clear that in the cases older than 50 years of age (51% of the sample) there is a significant risk factor for the emergence of ed. there are 22 (67%) who are over fifty, while in this subgroup four are not affected, accounting for only 22% (p = 0.004). diabetes, that in the dialysis group continues to be a statistically significant factor for the onset of ed (p = 0.01), seems to play a significant role in the etiopathogenesis of ed in post-transplant, that did not depend on duration of transplantation and the possible use of betablockers. turning to the evaluation of the hormone profile, hyperprolactinemia was present in 20% of the sample without significant differences between the two subgroups. however the most interesting result is that relative to the hypotestosteronemia which is predicated on having a prevalence of less than or equal to the group of dialysis 37% and also does not appear statistically significant correlated with the onset of ed (p = 0.12) (table 3). age > 50 years and diabetes remain as the only statistically significant risk factors for the onset of ed in the group of transplant patients. the data was also confirmed after performing a 'multivariate analysis (table 4). discussion erectile dysfunction in patients treated with dialysis for end-stage chronic kidney failure has a particularly high prevalence. the first epidemiological studies have been carried on since the early 70's by abram (22). over the years many others have been conducted, including fletcher’s (23), all of which indicated a prevalence rate above 50%, varying between 63% and 81%. in our study the prevalence of ed amongst patients on dialysis amounted to 70%. this shows that despite the clear improvement of therapy for end-stage kidney failure over the years, the prevalence of ed has remained high. age was always considered as the major risk factor for the onset of ed and the concept is also valid for the patients on dialysis .in our study the mean age of patients without ed stands at 43 years. on the other hand, the average age is 54 in patients with ed. in this study therefore, patients over fifty have a 7.2 times greater risk of developing ed than younger individuals. however, if the data obtained in this study were to be compared with the data from other studies, in a sample of individuals in apparent good health, the average age of onset of ed is 5 years lower (54 vs 59 years) and severe forms of ed are 50% more. therefore the end-stage chronic renal failure has to be considered a factor that accelerates and exacerbates the pathological mechanisms responsible for the appearance of ed that develops normally with age. in our study, as previously published (24), another significant risk factor is diabetes, which is the cause that leads a kidney disease patient to dialysis, and also the main responsible for the onset of ed. it is important to point out that diabetes is able to determine the onset of ed regardless of the presence or absence of diabetic nephropathy. in patients with end-stage crf and diabetes, it is still uncertain whether the ed appears before or after the beginning of dialysis treatment. with regard to the duration of dialysis treatment in our clinical-laboratory total patients patients with ed patients without ed p characteristics n = 51 n = 33 n = 18 age > 50 years 26 (51%) 22 (61% of ed 4 (22% of no-ed 0.004 patients) patients) diabetes 15 (29%) 13 (39% of ed 2 (11% of no-ed 0.010 patients) patients) duration of transplantation in years * 7.2 (5.6) 7.4 (5.9) 7.0 (5.4) 0.82 taking beta-blockers 35 (69%) 24 (72% of ed 11 (61% of no-ed 0.57 patients) patients) hypotestosteronemia 19 (37%) 13 (39% of ed 6 (33% of no-ed 0.012 (free t < 40 pg/ml) patients) patients) hyperprolactinemia 10 (20%) 7 (21% of ed 3 (17% of no-ed 0.36 (prl> 15.5 ng/ml) patients) patients) * standard deviation in brackets. table 3. characteristics of clinical laboratory sample. risk factors for ed or ic 95% p age> 50 years 7.823 1.724 to 26.384 0.005 diabetes 6.755 1.128 to 30.054 0.019 or: odds ratio; ic: interval confidence 95%. table 4. results of multivariate analysis for risk factors for ed in crf patients after kidney transplantation. figure 2. prevalence of ed in ckf patients after kidney transplantation. severe (2-10) 27% absent (iief 5: 26-30) 35% mild (17-25) 18% moderate (11-16) 20% study, it affects neither the appearance nor the development of ed. this conclusion is supported by numerous studies in the literature (25). there is, however, a prospective study carried out by capotondo in 1990, which shows an improvement of ed in the first three months of dialysis treatment, before returning to previous levels (26). wein and van arsdalen have identified a list of drugs most commonly used by the general population that may be able to determine ed, some of which are frequently used in dialysis patients (27). in our study, the focus was on beta-blockers, but no significant correlation between drug intake and onset of ed was found. in the literature there is only one study that demonstrates that the use of beta blockers is a significant risk factor for developing ed in dialyzed patients. as for the evaluation of the hormone profile, a condition of hyperprolactinemia was found in 25% of the sample, according with the data in the literature ranging between 20 and 40%. this however does not seem to affect the appearance of ed, but we need to point out the existence of studies which show that there exists a connection between the condition of hyperprolactinemia and decreased libido (28). a condition of important hypotestosteronemia (t < 250 ng/dl) was seen in almost 60% of the sample, which is quite concordant with the literature (29). however, it remains disputed why this condition appears. according to some authors, the reason might be the uremia, that, like with other organs (eg, uremic cardiomyopathy, uremic gastritis), leads to a dysfunction of the complex mechanisms of regulation of the hypothalamic-pituitary-gonadal axis, caused especially by changes in the opioid pathway (30); according to other authors the substances used in dialysis membranes produce a functional and histological change in the gonads (31). a third hypothesis is based on the loss of most steroid precursors during dialysis procedures. finally there is one last hypothesis that claims that the decreased blood level of zinc may be the cause (32). our study also shows that hypotestosteronemia is an effective risk factor for the onset of ed. the data in the literature concerning this statement are very discordant and very often this is determined by the different value of testosterone serum concentrations considered pathological by different authors. in recent years, however, the tendency is to reaffirm an important role of testosterone in erectile mechanisms: in fact, there are frequent cases of ed refractory to pde-5 inhibitors that happen to be cases of unknown hypogonadism (33). the records obtained from end-stage ckd patients treated with renal transplantation, are similar to those obtained from the group of patients undergoing dialysis. also in this group the prevalence of ed is higher, it appears earlier and is more severe than in the group of patients not affected by ckf. we would underline that there is a slightly lower prevalence (65% vs 70%) of ed in transplanted patients compared with dialyzed ones, but the difference is not so blatant and numerous comparative studies showed that the prevalence of ed before and after renal transplantation remains the same or the improvement is only limited to a small percentage of cases (34, 35). as well as in dialyzed patients, in transplanted patients advanced age and diabetes are major risk factors for the development of ed. beta blockers intake and hyperprolactinemy do not seem to affect the onset of ed. the new element is represented by a reduction in the prevalence of hypotestosteronemia (37% vs 59%). this may suggest, on one hand, that the uremia improvement obtained by transplant solves at least in part the condition of hypogonadism, and on the other hand that dialysis treatment is actually one of the causes of the hypotestosteronemia. hypotestosteronemia still has a much higher prevalence in these patients rather than in subjects in apparent good health (37% vs 12%) of the same age. this is probably due to the fact that uremia and dialysis treatment produce not only a functional damage, but also an anatomic chronic damage at gonads. another hypothesis is that the immunosuppressive therapy to which the transplanted patients are subjected, determines a disendocrine disease preventing at least in part, the resolution of the hypogonadism. in the end, the hypotestosteronemia does not appear to be a significant risk factor for the onset of ed in the transplanted patients therefore, probably, the ed is caused by the vascular and neuropathic chronic damage produced by pre-existing chronic uremia. many recent publications have pointed out the usefulness and the safety of the treatment. a study by sharma in 2006 and one by cofan in 2002 have shown effectiveness of therapy in approximately 85% of the subjects and at the same time no change in blood concentration of calcineurin inhibitors (36, 37). in patients on hemodialysis, as well as in transplanted patients, the elective drugs for treatment of ed are the pde5 inhibitors. a review of the 2006 shows their effectiveness and safety. however, the number of patients not responding to the therapy is higher than that found in transplant recipients. as our study demonstrated, hypogonadism is a major risk factor for ed in dialyzed patients. for this reason, in refractory cases in which the hypo testosteronemia is diagnosed, it is necessary to support a pde5 inhibitor therapy with transdermal hormone replacement therapy (5 mg/day) or intramuscular (250 mg every 3-6 weeks). recent studies in fact show a synergistic role of testosterone and pde-5 inhibitors: in fact, testosterone induces an increased expression of inos in the corpora cavernosa. conclusions ed in patients with end stage ckf continues to have a strong prevalence, in cases both where the patients are undergoing dialysis or have received transplants. in the literature this issue is often not considered, or sufficiently so, with the direct consequence that the ed often ends up being misunderstood and therefore not treated in these patients. in our experience during this study it is evident that both patients and their physicians maintain a certain reticence on this issue, even though the patients affected by ed say that this condition greatly impacts their quality of life. our advice therefore would be to practice all the strate303archivio italiano di urologia e andrologia 2015; 87, 4 sexual dysfunctions in kidney transplant recipients archivio italiano di urologia e andrologia 2015; 87, 4 m. antonucci, g. palermo, s.m. recupero, r. bientinesi, f. presicce, n. foschi, p.f. bassi, g. gulino 304 gies (reduction of risk factors and pharmacological approach) that could counteract the ed. age, obviously, is not a modifiable factor, but an effective diabetic control is possible, and both the kidney basic functionality and erection would benefits from that. our study also shows that the hypotestosteronemia is a genuine risk factor for the onset of ed in patients with end-stage chronic renal failure. based on the records of prevalence of hypogonadism which is significantly lower among transplant recipients, the kidney transplantation appears to have a protective role of the sexual capabilities of these patients. this may suggest, on one hand that the improvement of uremia obtained by transplant solves at least in part the condition of hypogonadism, or on the other, that dialysis treatment is actually one of the causes of the hypotestosteronemia. finally, we pointed out that the therapy of hypogonadism, not only helps to solve the ed so improving the quality of life for patients, but also could increase life expectancy. in fact, there is increasingly more scientific evidence indicating that low testosterone serum level correlates with increased cardiovascular accidents, increased central obesity, metabolic syndrome, bone fragility which would reduce life expectancy. references 1. leny nb. sexual adjustments to maintenance dialysis and renal transplantation. national survey by questionnaire. preliminary results. trans am soc artif int organs. 1973; 19:138-143. 2. procci wr, goldstein dd, adelstein j, massry sg. sexual dysfunction in the male patient with uremia. a reappraisal. kidney int. 1981; 19:317-323. 3. toorans awft, janssen e, laan e, et al. chronic renal failure and sexual functioning: clinical status versus objectively assessed sexual response. nephrol dial transplant. 1997; 12:2654-2663. 4. bergandahl m, evans ws, veldhuis jd. current concepts on ultradian rhythms of luteinizing hormone secretion in the human. hum reprod update. 1996; 2:507-518. 5. steward-bentley m, gans d, horton r. regulation of gonadal function in uremia. metabolism 1974; 23:1065-1072. 6. coppola a, cuomo g. pituitary testicular evaluation in patients with chronic renal insufficiency in haemodialysis treatment. minerva med. 1990; 81f 461-464. 7. handelsman dj, dong q. hypothalamic-pituitary-gonadal axis in chronic renal failure. endocr metab clin north am. 1993; 22:145-161. 8. chryssicopoulos a, koutsikos d, kapetanaki a, et al. evaluation of the hypothalamic-pituitary axis in uraemic males using dynamic tests. the possible role of testicular inhibin. a preliminary report. renal fail. 1996; 18:911-921. 9. bancroft j. human sexuality and its problems, ed 2. churchill livingstone, edinburgh, 1989; 12-145. 10. saenz de tejada i, goldstein i, azadzoi k, et al. impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence n engl j med. 1989; 320:1025-1030. 11. campese vm, procci wr, levitan d, et al. autonomic nervous system dysfunction and impotence in uremia. am j nephrol. 1982; 2:140-143. 12. linder a, charra b, sherrar d, et al. accelerated atherosclerosis and prolonged maintenance hemodialysis. n engl j med. 1974; 290:697-701. 13. kaufman jm, hatzichristou dg, mulhall j, et al. impotence and chronic renal failure. a study of the hemodynamic pathophysiology. j urol, 1994; 151:612-618. 14. virag r, bouilly p, frydman d. is impotence an arterial disease? lancet. 1985; 1:181-184. 15. kim n, vardi y, padma-nathan h, et al. oxygen tension regulates the nitric oxide pathway. physiological role in penile erection. j clin invest. 1993; 19:437-442. 16. janssen. e, everaerd w, van lunsen et al. validation of a psychophysiological waking erectile assessment (wea) for the diagnosis of the male erectile disorder. urology. 1994; 43:686-695. 17. lim vs. reproduction function in patients with renal insufficiency. am j kidney dis. 1987; 9:363-367. 18. rebollo p, ortega f, valdes c, et al. factors associated with erectile dysfunction in male kidney transplant recipients. int j impot res. 2003; 15:433. 19. wong ja, lawen j, kiberd b, et al. prevalence and prognostic factors for erectile dysfunction in renal transplant recipients can urol assoc j. 2007; 1:383-387. 20. el-bahnasawy ms, el-assmy a, el-sawy e, et al. critical evaluation of the factors influencing erectile function after renal transplantation. int j impot res. 2004; 16:521-6. 21. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an 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1984; 39:63-70. 28. perryman rl, thorner mo. the effects of hyperprolactinemia on sexual and reproductive function in men. j androl. 1981; 5:233. 29. handelsman d. hypothalamic-pituitary gonadal dysfunction in renal failure, dialysis and renal transplantation. endocr rev. 1985; 6:151-82. 30. lim v, fang v. gonadal dysfunction in uremic men. a study of the hypothalamo-pituitary-tisticular axis before and after renal transplantation. am j med. 1975; 58:655-62 31. palmer bf. sexual dysfunction in uraemia. j am soc nephrol. 1999; 10:1381-8. 32. hakim r, depner t, parker t. adequacy of haemodialysis. am j kidney dis. 1992; 20:107-123. 33. penson df, ng c, cai l, et al. androgen and pituitary control of penile nitric oxide synthase and erectile function in the rat. biol reprod.1996; 55:567-574. 34. peskircioglu l, tekin mi, demirag a, et al. evaluation of erectile function in renal transplant recipients. transplant proc. 1998; 30:747-749. 35. malavaud b, rostaing l, rischmann p, et al. high prevalence of erectile dysfunction after renal transplantation. transplantation. 2000; 69:2121-2124. 36. sharma rk, prasad n, gupta a, kapoor r. treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial. am j kidney dis. 2006; 48:128-33. 37. cofán f, gutiérrez r, beardo p, et al. interaction between sildenafil and calcineurin inhibitors in renal transplant recipients with erectile dysfunction nefrologia. 2002; 22:470-6. 305archivio italiano di urologia e andrologia 2015; 87, 4 sexual dysfunctions in kidney transplant recipients correspondence michele antonucci, md (corresponding autor) mic.antonucci@yahoo.it giuseppe palermo, md salvatore marco recupero, md riccardo bientinesi, md nazario foschi, md pierfrancesco bassi, md gaetano gulino, md department of urology clinic, catholic university of s. heart, rome largo a. gemelli 8, 00168 rome, italy fabrizio presicce, md urology, policlinico s. andrea, “la sapienza” university, rome stesura seveso 171archivio italiano di urologia e andrologia 2014; 86, 3 original paper impact of cystic fibrosis transmembrane regulator (cftr) gene mutations on male infertility jlenia elia 1, rossella mazzilli 1, michele delfino 1, maria piane 2, cristina bozzao 2, vincenzo spinosa 1, luciana chessa 2, fernando mazzilli 1 1 sant’andrea hospital, unità di andrologia, department of clinical and molecular medicine, university of rome “sapienza”, rome, italy; 2 sant’andrea hospital, unità di genetica medica, university of rome “sapienza”, rome, italy. objective. the aim of this study was to evaluate the prevalence of most common mutations and intron 8 5t (ivs8-5t) polymorphism of cftr gene in italian: a) azoospermic males; b) non azoospermic subjects, male partners of infertile couples enrolled in assisted reproductive technology (art) programs. material and methods. we studied 242 subjects attending our andrology unit (44 azoospermic subjects and 198 non azoospermic subjects, male partners of infertile couples enrolled in art programs). semen analysis, molecular analysis for cftr gene mutations and genomic variant of ivs8-5t polymorphic tract, karyotype and chromosome y microdeletions, hormonal profile (lh, fsh, testosterone) and seminal biochemical markers (fructose, citric acid and l-carnitine) were carried out. results. the prevalence of the common cftr mutations and/or the ivs8-5t polymorphism was 12.9% (4/31 cases) in secretory azoospermia, while in obstructive azoospermia was 84.6% (11/13 cases; in these, the most frequent mutations were the f508del, r117h and w1282x). regarding the non azoospermic subjects, the prevalence of the cftr and/or the ivs8-5t polymorphism was 11.1% (11/99 cases) in severe dyspermia, 8.1% (6/74 cases) in moderate dyspermia and finally 4.0% (1/25 cases) in normospermic subjects. conclusions. this study confirms the highly significant prevalence of cftr mutations in males with bilateral absence of the vas deferens or ejaculatory ducts obstruction compared with subjects with secretory azoospermia. moreover, the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of cftr even in the spermatogenic process. this could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. key words: semen analysis; azoospermia; male infertility; molecular analysis; cftr gene mutations; ivs8-5t polymorphic tract. submitted 27 december 2013; accepted 15 may 2014 summary no conflict of interest declared. introduction in recent years, increasing attention has been paid to the pathogenesis of dyspermia with a genetic basis (1, 2). in particular, after the development of assisted reproductive techniques (art), genetic screening has taken on an important role in the diagnostic approach to couple infertility. regarding the male factor, in addition to the usual genetic investigations in clinical practice to identify factors, such as karyotype and chromosome y microdeletions, the study of cystic fibrosis transmembrane regulator (cftr) gene mutations, implicated in the genesis of cystic fibrosis (cf) (3), has acquired a great significance. beyond the classic aspects (pulmonary and pancreatic involvement) there are also atypical forms of cf. these atypical forms include male reproductive disorders. to date, a clear correlation with cftr mutations has been demonstrated only in obstructive azoospermia due to congenital bilateral absence of the vas deferens (cbavd) (4-8). it has also been suggested that there is the direct involvement of the cftr on spermatogenesis (9-15), and on pathogenesis of seminal hyperviscosity (17), as well as its having a potential action on the maturation of spermatozoa in vitro (16). the aim of this study was to evaluate the prevalence of the common mutations and the ivs8-5t polymorphism of the cftr gene in: a) azoospermic males and b) non azoospermic male partners of infertile couples enrolled in art programs. material and methods subjects we studied 242 males attending our andrology unit from january 2005 to december 2012. among these there were 44 azoospermic and 198 non azoospermic subjects, male partners of infertile couples taking part in art programs. semen analysis semen analysis was performed in all the subjects at least twice at a distance of 30 days; the mean values were doi: 10.4081/aiua.2014.3.171 elia_stesura seveso 08/10/14 12:06 pagina 171 archivio italiano di urologia e andrologia 2014; 86, 3 j. elia, r. mazzilli, m. delfino, m. piane, c. bozzao, v. spinosa, l. chessa, f.mazzilli 172 recorded and analyzed. the semen samples were collected by masturbation after 3-5 days of sexual abstinence. the samples were stored in a controlled incubator (37°c). after liquefaction, semen samples were analyzed according to world health organization (who) guidelines (18). the superimposed image analysis system (sias) was used to assess sperm motility parameters (19, 20). in azoospermic males three further tests, fructose, l-carnitine and citric acid were also carried out. molecular analysis written informed consent was obtained from each subject enrolled in this study. genomic dna was extracted from peripheral blood, according the standard procedure. molecular analysis of the most frequent mutations of cftr and the ivs8-5t polymorphic tract was performed by inno-lipa cftr 19, cftr 17+tn update and cftr italian regional kits (innogenetics, belgium), providing a screening for 57 cftr gene mutations and following the manufactures instructions. other analyses the hormonal profile was studied in all the subjects (lh, fsh, testosterone), as well as karyotype and chromosome y microdeletions. statistical analysis statistical analysis was performed using the chi-square test on frequency differences between two samples. a p value < 0.05 was considered significant. results prevalence of mutations and polymorphism of cftr gene in subjects with azoospermia. azoospermic males (n. 44) were divided into two groups: a) subjects with secretory azoospermia (n. 31); b) subjects with obstructive azoospermia (n. 13). the clinical examination, the hormonal profile, the biochemical study of seminal plasma (fructose, l-carnitine and citric acid as markers respectively of prostate, vesicles and epididymis), genetic screening, ultrasound examination and, when indicated, cytomorphological study by testicular needle aspiration permitted the differential diagnosis between secretory and obstructive azoospermia. secretive azoospermia (31 subjects) was due to: a) spermatogenic arrest (n.4); b) bilateral cryptorchidism, epididymo-orchitis and radioor chemo-therapy (n.20); c) chromosomal anomalies (klinefelter's and robertsonian translocations) (5 cases); d) y chromosome microdeletions (2 cases). altogether in 4 of these 31 subjects (12.9%) a classic mutation of cftr and/or the ivs8-5t polymorphism were identified. in particular, one male (3.2%) with previous cryptorchidism showed the most common mutation of the cftr gene (f508 del), while in the other 3 subjects (9.7%) was detected the ivs8-5t polymorphism. obstructive azoospermia (n. 13 subjects) was due to: a) obstruction of the vas deferens (n. 2); b) obstruction of the ejaculatory ducts (n. 10); epididymal obstruction, seen at surgery (n. 1). altogether 11 of these 13 subjects (84.6%) were affected by a classic mutation of the cftr and/or the ivs8-5t polimorphysm. in particular, in 9 cases (69.2%; p < 0.01 vs secretory azoospermia) a classical mutation was found; in the remaining 2 cases (15.4%) the ivs8-5t variant allele was found. the mutations found are listed in table 1. prevalence of mutations and 5t polymorphism of cftr gene in non azoospermic males genetic screening was carried out in 198 male partners of subfertile couples enrolled in programs of art. according to the seminal profile, the subjects were subdivided into: a) severe dyspermia (n. 99) (seminal parameters: n/ml !5 x 106, ! 5 progressive motility; atypical forms " 85%); b) moderate dyspermia (74); c) normospermia (n. 25) (who guidelines 1999) (18). hormonal profile biochemistry subjects cftr site karyotype microdel fsh lh test. ph vol eiac. fructose l-carnitine citric acid genotype of obstruction crom y mu/ml mu/ml ng/ml (ml) (mg/dl) (mg/dl) (mg/dl) 1 f508del/n ejaculatory duct 46,xy negative 4.9 3.2 5.1 6.3 0.4 10 0.4 1100 2 f508del/n ejaculatory duct 46,xy negative 4.8 5.4 5.6 6.7 0.5 20 0.2 1200 3 f508del/n ejaculatory duct 46,xy negative 5.3 2.8 6.7 6.5 0.4 10 0.3 1100 4 f508del/5t ejaculatory duct 46,xy negative 6.4 5.8 2.9 6.5 0.3 30 0.3 > 1200 5 f508del/5t vas deferens 46,xy negative 5.6 4.9 3.9 6.5 0.4 20 0.4 > 1200 6 r117h/n vas deferens 46,xy negative 6.5 4.7 4.9 6.5 0.5 210 0.1 1100 7 d1152h/n ejaculatory duct 46,xy negative 5.2 3.9 3.8 6.5 0.4 10 0.1 1200 8 l1065p/n intra-epididymal 46,xy del azf b 11.3 9.8 3.4 6.7 0.3 10 0.4 1200 9 w1282x/n ejaculatory duct 46,xy negative 4.7 5.1 5.8 7.4 2.1 180 0.1 450 10 5t/n ejaculatory duct 46,xy negative 3.9 2.8 6.5 6.0 0.2 20 0.3 > 1200 11 5t/n ejaculatory duct 46,xy negative 4.2 7.1 2.8 6.7 0.3 10 0.2 > 1200 table 1. genotype-phenotype correlation in males with obstructive azoospermia. elia_stesura seveso 08/10/14 12:06 pagina 172 in subjects with severe dyspermia (n. 99), 11 cases (11.1%) showed a classic mutation and/or the ivs8-5t polymorphism. in particular, 7 subjects (7.1%; p = 0.465 vs moderate dyspermia) had a classic mutation (one of them was compound heterozygous f508del/5t), 1 male was homozygote 5t/5t (0.9%), and finally 3 subjects (2.7%) were heterozygotes for the 5t polymorphism (table 2). in subjects with moderate dyspermia (n. 74), 6 subjects (8.1%) had a classic mutation of the cftr gene and/or the ivs8-5t polymorphism; in particular, 2 subjects (2.7%) were heterozygous w1282x/n and the r117h/n) and 4 subjects (5.4%) had the 5t polymorphism. in normospermic subjects (n. 25), only one moresubject (4.0%) with 5t polymorphism was found. discussion after the introduction of the art programs, genetic screening gradually took on a leading role in the diagnostic process of infertility counselling. in fact, such techniques have “put in play” also couples with high genetic risk. regarding genetic screening of the male partner, the search for mutations in the cftr gene has become increasingly important. in this study we evaluated the prevalence of mutations in the cftr gene in subjects with seminal tract obstructions as well as in subjects with varying degrees of dyspermia. regarding the first group, our study confirmed the high prevalence of cftr mutations in subjects with bilateral absence of the vas deferens or ejaculatory ducts obstruction. the most frequent mutations were, according to the literature, f508del, r117h and w1282x. with regard to the male d1152h/n, his partner carried the heterozygous genotype 621+3a>g/n. this opened a debate between operators on the opportunities and possibilities of using pre-implantation diagnosis as part of a program of assisted reproduction. in disagreement with karpman et al. (21), who reported significant association of cftr mutations with y chromosome microdeletion, in our study we found such association only in one case. on the other hand, the prevalence of mutations in subjects with classical secretory azoospermia was significantly lower compared with obstructive azoospermia. the second part of the study was conducted on the prevalence of mutations and/or genomic variants in a population of male partners (dyspermic and normospermic) of subfertile couples enrolled in art programs. there are sharply conflicting reports in the literature. according to some authors (9-11) there are no significant changes in the prevalence of mutations or genomic variants of cftr in subjects affected by moderate dyspermia and population controls. in partial agreement with other authors (12-15) this study highlights a significant prevalence of mutations in the cftr gene in males with severe dyspermia compared to normospermic ones. conclusions in conclusion, this study confirms the direct involvement of the cftr gene in the pathogenesis of seminal tract obstructions. the significant prevalence of mutations in severely dyspermic subjects may suggest the possible involvement of cftr even in the spermatogenic process. this could explain the unsatisfactory recovery of sperm from testicular fine needle aspiration in patients affected by genital tract blockage. references 1. mak v, jarvi ka. the genetics of male infertility. j urol. 1996; 156:1245-56. 2. lee jy, dada r, carpi a, et al. role of genetics in azoospermia. urology, 2011; 77:598-601. 3. knowles mr, durie pr. what is cystic fibrosis? n engl j med, 2002; 347:439-42. 173archivio italiano di urologia e andrologia 2014; 86, 3 cftr gene and male infertility hormonal profile biochemistry subjects cftr karyotype microdel fsh lh test. n/ml progressive atypical genotype crom y mu/ml mu/ml ng/ml (x 106/ml) motility (%) form (%) 1 n1303k/n 46,xy negative 14.3 5.2 7.6 2 5 87 2 621+3 a>g/n 46,xy negative 13.8 4.2 5.3 1 < 5 98 3 w1282x/n 46,xy negative 12.9 4.5 3.8 0.5 < 5 94 4 f508del/n 46,xy negative 18.3 2.8 6.5 < 0.1 < 5 96 5 3120+1g>a/n 46,xy negative 3.8 6.3 4.2 5 5 89 6 r117h/n 46,xy negative 14.1 3.9 5.6 1 < 5 96 7 f508del/5t 46,xy negative 11.8 5.4 5.4 < 0.1 < 5 97 8 5t/5t 46,xy negative 11.4 3.6 5.8 0.2 < 5 98 9 5t/n 46,xy negative 6.8 3.8 6.3 3 5 87 10 5t/n 46,xy negative 4.6 4.1 5.0 4 5 86 11 5t/n 46,xy negative 15.6 4.2 4.6 2 5 88 table 2. genotype-phenotype correlation in males with severe dyspermia. elia_stesura seveso 08/10/14 12:06 pagina 173 archivio italiano di urologia e andrologia 2014; 86, 3 j. elia, r. mazzilli, m. delfino, m. piane, c. bozzao, v. spinosa, l. chessa, f.mazzilli 174 4. dohle gr, veeze hj, overbeek se, et al. the complex relationships between cystic fibrosis and congenital bilateral absence of the vas deferens: clinical, electrophysiological and genetic data. hum reprod. 1999; 14:371-4. 5. chillon m, casals t, mercier b, et al. mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferent. n eng j med. 1995; 332:1475-80. 6. jarzabek k, zbucka m, pepinski w, et al. cystic fibrosis as a cause of infertility. reprod biol. 2004; 4:119-29. 7. chen h, ruan yc, xu wm, et al. regulation of male fertility by cftr and implications in male infertility. hum reprod update. 2012; 18:703-13. 8. mocanu e, shattock r, barton d, et al. all azoospermic males should be screened for cystic fibrosis mutations before intracytoplasmic sperm injection. fertil steril. 2010; 94:2448-50. 9. riccaboni a, lalatta f, caliari i, et al. genetic screening in 2,710 infertile candidate couples for assisted reproductive techniques: results of application of italian guidelines for the appropriate use of genetic tests. fertil steril. 2008; 89:800-8. 10. larriba s, bonache s, sarquella j, et al. molecular evaluation of cftr sequence variants in male infertility of testicular origin. int j androl. 2005; 28:284-90. 11. foresta c, garolla a, bartoloni l, et al. genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. j clin endocrinol metab. 2005; 90:152-6. 12. mennicke k, klingenberg rd, bals-pratsch, et al. rational approach to genetic testing of cystic fibrosis (cf) in infertile men. andrologia. 2005; 37:1-9. 13. schulz s, jakubicza s, kropf s, et al. increased frequency of cystic fibrosis transmembrane conductance regulator gene mutations in infertile males. fertil steril. 2006; 85:135-8. 14. tamburino l, guglielmino a, venti e, et al. molecular analysis of mutations and polymorphisms in the cftr gene in male infertility. reprod biomed online. 2008; 17:27-35. 15. chan hc, ruan yc, he q, et al. the cystic fibrosis transmembrane conductance regulator in reproductive health and disease. j physiol. 2009; 587:2187-95. 16. li cy, jiang ly, chen wy, et al. cftr is essential for sperm fertilizing capacity and is correlated with sperm quality in human. hum reprod. 2010; 25:317-27. 17. rossi t, grandoni f, mazzilli f, et al. high frequency of (tg)m tn variant tracts in the cystic fibrosis transmenbrane conductance regulator gene in men with high semen viscosity. fertil steril. 2004; 82:1316-22. 18. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4th ed. cambridge uk; new york ny; 1999. 19. mazzilli f, rossi t, sabatini l, et al. superimposed image analysis system (sias) software: a new approach to sperm motility assessment. fertil steril. 1995; 64:653-6. 20. mazzilli f, rossi t, delfino m, et al. application of the upgraded image superimposition system (sias) to the assessment of sperm kinematics. andrologia. 1999; 31:187-94. 21. karpman e, williams dh, wilberforce s, et al. compound genetic abnormalities in patients with cystic fibrosis transmembrane regulator gene mutation. fertil steril. 2007; 87:1468.e5-8. correspondence jlenia elia, md. rossella mazzilli, md michele delfino, md vincenzo spinosa, md fernando mazzilli, md (corresponding author) fernando.mazzilli@uniroma1.it sant’andrea hospital, unit of andrology, university of rome, “sapienza” via di grottarossa 1035 00189 roma, italy maria piane, md cristina bozzao, md luciana chessa, md sant’andrea hospital, unità genetica medica, university of rome, “sapienza” via di grottarossa 1035 00189 roma, italy elia_stesura seveso 08/10/14 12:06 pagina 174 249archivio italiano di urologia e andrologia 2016; 88, 4 original paper factors affecting the course of body and kidney growth in infants with urolithiasis: a critical long-term evaluation kemal sarica 1, fatma narter 2, kubilay sabuncu 1, ahmet akca 3, utku can 1, ayşe buz 1, h. nese sarica 4, bilal eryildirim 1 1 dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey; 2 dr. lutfi kirdar training and research hospital pediatric clinic, istanbul, turkey; 3 dr. lutfi kirdar training and research hospital radiology clinic, istanbul, turkey; 4 medistate hospital, istanbul, turkey. objective: to investigate the possible effects of dietary, patient and stone related factors on the clinical course of the stone disease as well as the body and renal growth status of the infants. patients and methods: a total of 50 children with an history of stone disease during infancy period were studied. patient (anatomical abnormalities, urinary tract infection uti, associated morbidities), stone (obstruction, uti and required interventions) and lastly dietary (duration of sole breast feeding, formula feeding) related factors which may affect the clinical course of the disease were all evaluated for their effects on the body and renal growth during long-term follow-up. results: mean age of the children was 2.40 ± 2.65 years. our findings demonstrated that infants receiving longer period of breast feeding without formula addition seemed to have a higher rate of normal growth percentile values when compared with the other children. again, higher frequency of uti and stone attacks affected the growth status of the infants in a remarkable manner than the other cases. our findings also demonstrated that thorough a close follow-up and appropriately taken measures; the possible growth retardation as well as renal growth problems could be avoided in children beginning to suffer from stone disease during infancy period. conclusions: duration of breast feeding, frequency of uti, number of stone attacks and stone removal procedures are crucial factors for the clinical course of stone disease in infants that may affect the body as well as kidney growth during long-term follow-up. key words: urinary calculi; kidney; stone related factors; infant. submitted 7 june 2016; accepted 19 july 2016 summary no conflict of interest declared. follow-up of every stone forming infant in an individual basis (3-5, 12, 13). regarding the clinical course of the disease; while overall recurrence rates range widely from 6.5 to 44% without follow-up and appropriate management, these rates have been reported to be as high as 50% within 5 or 6 years (2, 13-16). the rate of stone recurrence in one of our previous reports was 4% during a 5-year follow-up period (17). in the light of these data, it is clear that a close follow-up of the clinical course as well as the natural history of urolithiasis in these cases merit great attention. there are sufficient data reported in the literature dealing with the incidence, metabolic abnormalities, recurrence rates and that of spontaneous passage rates in adults (14, 18-20). however, evaluation of the current literature clearly shows the lack of reliable data on the clinical course of urolithiasis particularly in infants with highly limited data concerning the possible crucial factors affecting the disease course in this highly specific population. on the other hand again, the susceptibility of growing body as well as the kidneys of these cases increases the importance of some certain patient and disease related factors which makes the careful monitorization of all children mandatory after the first stone attack. the aim of the present study is to evaluate the natural course of the stone disease in infants from different perspectives in order to outline the possible adverse affects of certain factors on the body as well as kidney growth. patients and methods a total of 50 infants (28 boys and 22 girls; m/f: 1.27) with an established primary single calcium oxalate urinary stone (when a calculus was diagnosed by a renal ultrasonography or a spontaneous passage was present) were included and the follow-up file notes were evaluated in detail. metabolic abnormalities which may significantly affect the clinical course of the disease were noted based on serum and urine related risk factors basically depending on spot urine evaluations. all children with anatomic obstruction, neurogenic disorders and urinary diversions noted in their files were excluded from the doi: 10.4081/aiua.2016.4.249 introduction although the overall incidence of pediatric urinary stone disease is relatively rare (1-2%) (1, 2); infantile nephrolithiasis has been reported to be common in countries like iran, turkey, armenia, united kingdom, iceland, iraq, and italy (3-11). taking the commonly detected metabolic as well as genitourinary abnormalities and other certain crucial factors that can lead to recurrent stone episodes into account, published data have clearly shown that the disease may reveal morphologic and functional changes in the kidneys indicating the importance of a thorough evaluation as well as close sarica1_stesura seveso 09/01/17 09:46 pagina 249 archivio italiano di urologia e andrologia 2016; 88, 4 k. sarica, f. narter, k. sabuncu, a. akca, u. can, a buz, h. nese sarica, b. eryildirim 250 study program in the beginning. additionally, infants with kidney failure and genitourinary anomalies and those who were taking drugs that could affect mineral metabolism (corticosteroids, diuretics, and anticonvulsants) were also excluded. in the absence of urinary tract obstruction, infection and hematuria, depending on the size of the stones no child among these 50 cases required an intervention at first referral and they were all taken on a close follow-up program. although the majority of the children were followed-up regularly in our center; data of the children coming from other cities were obtained from the referring physicians. additionally, some of the data concerning the clinical symptomatology, spontaneously passed stones, procedures performed for stone removal were obtained from the parents by way of phone call interviews. the clinical course of the disease in all children with solitary stones located in renal pelvis were assessed and noted. in addition to the age at first presentation, stone size, positive family history and the results of metabolic evaluation; feeding status of the children (the total duration of breast feeding, beginning of formula feeding), was also carefully recorded. all children were again well evaluated with respect to spontaneous passage rates, required interventions, urinary tract infections and lastly and more importantly the physical as well as the renal growth rates. after obtaining the past history (including positive family anamnesis); a careful physical examination was performed and biochemical analysis including blood and urine examinations (including culture sensitivity test) were performed in all children. additionally, they underwent thorough a radio-sonographic investigation of the urinary tract to detect the possible anatomic abnormalities, the presence and the degree of obstruction caused by the stone, and to determine and locate other possible stones. in the majority of the cases, a plain film (kub) and/or urinary sonography were the initial radiological method to image the stone. non-contrast helical computerized tomography (ncct) was performed rarely when necessary (especially in cases with relatively smaller stones and ureteral calculi). as metioned above, as no child among these 50 cases required an intervention at first referral, they were all taken on a close follow-up program with regular visits and necassary evaluations. growth retardation was defined as a height z score below the 2 sd for age and sex and/or below 2 sd than mid-parenteral height sd (21, 22). at the same time all of the cases with defined growth retardation were also found to have weight percentiles under 10. measurement of renal size (length and width) and parenchymal thickness values were done with renal sonography and comparatively evaluated with respect to the nomograms of renal parenchymal thickness and renal lenght in healthy children. reduced renal size and/or renal parenchymal thickness were defined with the values obtained below 2sd (23). the study protocol was approved by the ethics committee of the institution. written informed consent from the children’s parents was obtained before performing any examination or treatment. ncss (numbercruncher statistical system) 2007&pass (power analysis and sample size) 2008 statistical software (utah, usa) program has been used for staistical analysis. in addition to the definitive statistical methods (mean, standard deviation, median, frequency, rate, minimum and maximum) used during the evaluation of the data obtained, mann whitney u test has also been used for the evaluation of the abnormally distributed parameters between two groups to compare the quantitative data. lastly, pearson chi-square test, fisher’s exact test, fisher-freeman-halton test and yates continuity correction tests (yates corrected chi-square) were used in the evaluation and comparison of qualitative parameters between the groups. statistical significance was defined with the levels of p < 0.01 and p < 0.05. results in this present study we mainly aimed to evaluate the possible effects of feeding status, urinary tract infections, number of new stone attacks and additional stone removal procedures on the physical as well as renal growth of infants during a long term follow-up period. data obtained from a total of 50 infants (28 boys and 22 girls, m/f: 1.27, aged 15 days-11,5 years) were recorded. all children had a single radiopaque stone located in renal pelvis at first referral. stone analysis was done after obtaining a stone sample either after a stone removal procedure (40 cases) or after spontaneous passage of the fragments (10 cases) during close follow-up. evaluation of the stone composition revealed that the vast majority of the stones were calcium containing ones. evaluation of the stone size in both groups revealed similar values with an average value of 3.4 mm (2-9 mm). basic characteristic and clinical variables of the patients evaluated in both groups are shown in table 1. taking the difficulty of 24-h urine collection in these cases into account, metabolic evaluation depended mainly on a spot urine examination. urinary metabolic data were present in 38 cases. hypocitraturia alone with hypercalciuria were the most common abnormalities detected. table 2 summarizes the outcomes on this aspect. overall follow-up period in all cases ranged from 4 to 75 months birthweight (g) (mean ± sd) (range) 3027 ± 767 980-5000 birthweight < 10 p (n,%) 8 16 male sex (n,%) 22 44 female sex (n,%) 28 56 duration of breastfeeding (month) (mean ± sd) (range) 5.9 ± 6.2 (0-24) time of starting solid food (month) (mean ± sd) (range) 8.6 ± 4.8 (4-24) duration of breastfeeding (month) (mean ± sd) (range) 14.0 ± 10.1 (1-42) additional disease (n,%) 9 18 hypertension (n,%) 0 0 family history of nephrolitiasis 37 74 growth retardation 11 22 table 1. basic characteristic and clinical variables of cases (n = 50). sarica1_stesura seveso 09/01/17 09:46 pagina 250 with an average period of 25 months. children were divided into two groups depending on the growth percentiles and renal growth status as follows: group 1 (n:11) = infants demonstrating growth retardation and/or renal growth failure (1a; growth retardation and 1b; renal growth retardation), group 2 (n:39) = infants with normal growth percentile as well kidney size values. all relevant parameters mentioned above were comparatively evaluated in these two groups. patient characteristics and the follow-up period in both groups are summarized in tables 3-5. during the long-term follow up of these cases, a total of 40 children (80%) required stone removal procedures due to the obstruction related problems (pain, infection and hematuria). while 32 cases underwent shock wave lithotripsy (swl) (80%), a total of 8 cases (20%) required ureteroscopy for the removal of symptomatic stones. the remaining 10 cases passed the stone spontaneously without any intervention. evaluation of our obtained data revealed the following findings: 1. feeding status of the infants: a careful assessment of the duration of breast feeding and the timing of initiation of formula feeding in infants showed that cases with evident growth retardation status (height z score below to 2 sds for age and sex and/or below to 2 sds than mid-parenteral height sd) seemed to have a shorter total breast feeding time along with longer formula feeding (12 vs 11 month; 75% vs 56.5% respectively) (table 3). in other words, stone disease in infants with shorter period of breast feeding seemed to be more complicated with higher number of stone as well as urinary tract infection attacks than the cases with normal growth percentiles (> 1 stone attack frequency 18.2% vs 15.4%; ≥ 3 urinary tract infection attack frequency 54.5% vs 30.8% respectively) (table 3). infants in whom the formula feeding has been initiated in an earlier manner tended to have more frequent stone and uti attacks which may affect the growth status of the children during long-term follow-up. on the other hand again, evaluation of the renal growth status (kidney size as well as renal parenchymal thickness) on this aspect clearly demonstrated the positive effects of breast feeding where children with reduced kidney size and renal parenchymal thickness had a shorter period of sole breast feeding along with an earlier initiation of formula feeding (median exclusively breast feeding duration 6 vs 1 month, median total breast feeding duration 12 vs 8.5 month, formula initiation 56.5% vs 75% respectively in children having normal and reduced renal size) (table 4), (median exclusively breast feeding duration 6 vs 3 month, median total breast feeding duration 14.5 vs 8 month, formula initiation 51.5% vs 70.6% respectively in children having normal and reduced renal parenchymal thickness) (table 5). 2. frequency of urinary tract infections: urinary tract infection (uti) is a certain risk factor which may affect the body and as a result renal growth of the children. careful assessment of the frequency of uti attacks in infants clearly showed the negative effect of higher number of uti’s on the growth percentile values where infants demonstrating a normal body growth course had lower number of uti attacks when compared with cases demonstrating evident retardation (≥ 3 urinary tract infections 54.5% vs 30.8%) (table 3). in other words infants with frequent stone related uti attacks tended to have lower percentile values during long-term follow-up. on the other hand again, evaluation of the renal growth status (kidney size) on this aspect clearly showed the evident negative effects of uti attacks where children with reduced kidney size had more frequent urinary tract infections than the ones with normal values (≥ 3 urinary tract infections 75% vs 32.6% respectively) (table 4). however, we found the rate of the frequency of urinary tract infections to be similar among cases with decreased and normal renal parenchymal thickness (35.3% vs 36.4% respectively) (table 5). 3. frequency of stone attacks and age at the diagnosis of stone disease: close follow-up and careful assessment of 251archivio italiano di urologia e andrologia 2016; 88, 4 factors affecting the course kidney growth in infants with urolithiasis normal growth retarded growth p (n = 39) (n = 11) growth retardation at birth (n,%) 6 (15.4) 1 (9.1) 1.000 duration of breastfeeding (month) mean ± sd 5.1 ± 5.04 8.5 ± 9.1 0.508 range (median) 0-24 (6) 0-24 (6) formula use (n,%) 22 (56.4) 7 (63.6) 0.741 time of starting solid food (month) mean ± sd 8.0 ± 3.7 10.7 ± 7.5 0.722 range (median) 4-24 (6) 5-24(6) duration of breastfeeding (month) mean ± sd 14.3 ± 10.4 13.0 ± 9.7 0.777 range (median) 1-42 (12) 1-30 (11) urinary tract infections (n,%) none 14 (35.9) 4 (36.4) 0.202 1 14 (37.3) 1 (9.1) ≥ 3 12 (30.8) 6 (54.5) age of first stone (month) mean ± sd 32.8 ± 3.45 14.9 ± 12.60 0.078 range (median) 0-138 (24) 0-36 (7) stone attack (n,%) none 15 (38.5) 6 (54.5) 0.594 1 18 (15.0) 3 (27.3)) > 1 6 (54.5) 2 (18.2) additional treatment need none 7 (17.9) 3 (27.3) 0.888 eswl 26 (66.8) 6 (54.5) eswl+ other 6 (15.4) 2 (18.2) additional disease (n,%) 6 (15.4) 3 (27.3) 0.392 metabolic abnormality normal values n % decreased urine output > 20 ml/kg/day 20/38 52.6 hypocitraturia > 400 mg/g cre/day 22/38 57.8 hypercalciuria < 4 mg/kg/day 17/38 44.7 hyperoxaluria < 45 mg/1.73 m2 3/38 7.8 table 2. metabolic abnormalities in terms of urinary risk factors detected in 38 children. table 3. evaluation of some risk factors according to the growth percentile of the cases. sarica1_stesura seveso 09/01/17 09:46 pagina 251 archivio italiano di urologia e andrologia 2016; 88, 4 k. sarica, f. narter, k. sabuncu, a. akca, u. can, a buz, h. nese sarica, b. eryildirim 252 the frequency of stone attacks in infants clearly demonstrated that higher number of stone attacks had also a negative effect on the growth percentile values of the cases. infants demonstrating a normal body growth course had lower number stone attacks when compared with cases demonstrating evident retardation (> 1 stone attack 18.2% vs 15.4%). age at the first diagnosis stone disease in growth retarded children was remarkably lower than the ones demonstrating normal growth (median 7 vs 24 months) (table 3). in orther words, infants with frequent stone attacks beginning at early ages tended to have lower percentile values during long-term follow-up. on the other hand again, evaluation of the renal growth status (kidney size) on this aspect clearly showed the evident negative effect of frequent stone attacks where children with reduced kidney size had higher new stone attacks than the ones with normal values (25% vs 15.8% (table 4). in the same way, frequent stone attacks were associated with reduced renal parenchymal thickness size (> 1 urinary stone attacks 29.4% vs 9.1% respectively) (table 5). last but not least, our results showed that children presenting with stone disease at relatively younger ages (median 5 vs 24 months, median 12 vs 24 months respectively) tended to have lower kidney size as well as renal parenchymal thickness values when compared with the older ones (tables 4, 5). 4. additional stone removal procedures: evaluation of the children with stone removal procedures (40 cases, 80%) did not reveal and difference with respect to the body as well as renal growth status in both groups. the interventions seemed to have no negative effect on these values and we may quote that removal of the stone from the kidney may have a protective effect on this aspect by lowering risk of obstruction and infection during the course of the disease. but the procedures themselves did not seem to affect the growth status of these children (tables 3-5). discussion with an incidence of 1-5%, children constitute only a small number of all patients with urolithiasis. however, pediatric urolithiasis is still an endemic problem in developing countries where the composition of stones depends mainly on socioeconomic conditions, geography and dietary habits (1, 2, 15). thus, at least in these regions, pediatric stone disease is an important health care problem because of the high recurrence rate and the subsequent threat on renal function and possible decrease in the quality of life (24-27). infantile nephrolithiasis is not a rare situation and the diagnosis of small calculi by well defined pediatric ultrasonography has been increasing in recent years. there are several studies on pediatric stone disease which include children younger than 1 year. majority of these studies have been reported from countries like turkey, armenia, united kingdom, iceland, iran, iraq, and italy where the disease is still relatively common (3-11, 21, 26). published data showed that like in adults, greater than 75% of all urinormal renal size reduced renal size p (> 2sd) (n = 46) (< 2sd) (n = 4) duration of breastfeeding (month) mean ± sd 5.8 ± 5.7 6.5 ± 11.7 0.406 range (median) 0-24 (6) 0-24 (1) formula use (n,%) 26 (56.5) 3 (75) 0.630 time of starting solid food (month) mean ± sd 6.5 ± 4.4 10.5 ± 9 0.808 range (median) 4-24 (6) 6-24 (6.5) duration of breastfeeding (month) mean ± sd 14.2 ± 10.0 12.0 ± 12.7 0.517 range (median) 1-42 (12) 1-30 (8.5) frequency of uti’s (n,%) none 17 (37.0) 1 (25.0) 0.432 1 14 (30.4) 0 (0.0) ≥ 3 15 (32.6) 3 (75) age of first stone (month) mean ± sd 30.5 ± 4.8 8.5 ± 10.7 0.064 range (median) 0-138 (24) 0-24 (5) frequency of stone attack (n,%) none 20 (43.5) 6 (25) 0.812 1 19 (41.3) 3 (50) > 1 7 (15.8) 2 (25) growth retardation (n,%) 8 (17.4) 3 (75) 0.029 additional treatment need (n,%) none 9 (19.6) 1 (25) 1.000 eswl 29 (63) 3 (75) eswl+ 8 (17.4) 0 (0) table 4. evaluation of some risk factors according to the renal size of the cases. normal renal reduced renal p parenchymal parenchymal thickness thickness (n = 33) (< 2sd) (n = 17) duration of breastfeeding (month) mean ± sd 6.3 ± 6.2 5.1 ± 6.3 0.426 range (median) 0-24 (6) 0-24 (3) formula use (n,%) 17 (51.5) 12 (70.6) 0.321 time of starting solid food (month) mean ± sd 9.0 ± 5.7 7.7 ± 2.1 0.668 range (median) 4-24 (6) 6-12 (7.7) duration of breastfeeding (month) mean ± sd 14.6 ± 8.8 12.9 ± 12.6 0.228 range (median) 1-32 (14.5) 1-42 (8) frequency of uti’s (n,%) none 10 (30.3) 8 (47.1) 0.427 1 11 (33.3) 3 (17.6) ≥ 3 12 (36.4) 6 (35.3) age of first stone (month) mean ± sd 30.7 ± 31.5 25.2 ± 32.9 0.281 range (median) 0-138 (24) 0-132 (12) frequency of stone attack (n,%) none 15 (45.5) 6 (25) 0.229 1 15 (45.5) 3 (50) > 1 3 (9.1) 5 (29.4) growth retardation (n,%) 5 (15.2) 6 (35.3) 0.151 additional treatment need none 6 (18.2) 4 (23.5) 0.913 eswl 21 (63.6) 11 (64.7) eswl+ other 6 (18.2) 2 (11.8) table 5. evaluation of some risk factors according to the renal parenchyma size of the cases. sarica1_stesura seveso 09/01/17 09:46 pagina 252 nary tract calculi in children are composed of calcium oxalate or calcium phosphate (3, 6, 7, 28-30). the objective of stone management in children should include complete stone clearance, prevention of new stone formation and re-growth, preservation of renal function, control of urinary tract infection, and correction of both the anatomic abnormalities and underlying metabolic disorders (1, 3, 13, 28). long-term post-operative follow-up is mandatory, especially after using newer stone management modalities due to the higher stone recurrence rates in this specific population (18-20, 31-33). regarding this issue; the disease has been found to be associated with considerable morbidity, with recurrence rates ranging from 6.5 to 44% with a mean recurrence interval of 3-6 years (3, 13, 31, 34). without follow-up and medical intervention, stone recurrence rates have been reported to be as high as 50% within 5 or 6 years (13, 31). in our previous study, we were able to evaluate 91 children with a mean follow-up of 38.2 months and report a 4.2% recurrence rate (17). in their original study, rivzi et al. evaluated a huge number of children (n:1440) and demonstrated a 2% recurrence rate during a 13-year follow-up period (35). taking high incidence of metabolic abnormalities, anatomical anomalies and other certain problems into account; stone disease may have a recurrent course in most of the children and unfortunately there are limited data published in the literature evaluating the natural course of pediatric urinary stone disease on this aspect on a long-term basis (18-20, 31-33). on the other hand, by giving a special emphasis on the risk factors for stone recurrence in children, schwarz and dwyer concluded that children with upper urinary stones have a risk of recurrence similar to the risk reported in adult series (20). they also concluded that no specific risk reduction was related to the outcomes of metabolic risk evaluation tests. regarding the impact of stone disease on renal growth and pysical development again; the authors could not observe any evidence regarding the negative impact of these factors. on the other hand, as a chronic disease and stress for the growing body of children, stone disease and related disorders (infection, obstruction, colic pain attacks etc.) may well affect the physical growth of the children suffering from this problem. recurrent urinary tract infections with or without obstruction are the most important parameters affecting body growth. in this present study, regarding the impact of uti on the growth status of children; while 54.5% of the children with growth retardation demonstrated recurrent uti; of the 39 cases with normal growth status only 30.8% demonstrated recurrent uti (≥ 3 attacks) which might pose a possible additional adverse effect on the clinical course of stone disease in these children during long-term follow-up. evaluation of our current findings clearly showed the evident effects of some certain factors on the physical as well as renal growth status of the infants which should be monitored in a close manner. our data demonstrated that thorough a very close follow-up and approptiately taken measures, the possible growth retardation (which has been reported in limited number of studies) as well as renal growth problems could be avoided in a successful manner. in our group, infants receiving longer period of breast feeding without formula addition did seem to have a higher rate of normal growth percentile values then compared with the other children. again, higher frequency of uti as well as stone attacks affected the growth status of the infants with stones in a remarkable manner than the others. taking the limited data published in the literature so far into account; we believe that our study contains valuable and important information regarding the natural clinical course of stone disease in infants, with an emphasis on the feeding status that may closely affect this course with lower frequency of uti and stone attacks. delayed or later initiation of the formula with long-lasting breast feeding seemed to be highly relevant with these events that may affect the growth status of infants. this special effect of breast feeding could be explained by its possible reducing effect on the urinary tract infections. ajetunmobi et al. found a greater risk of hospitalization for all infections including utis among formula-fed infants compared with breastfed ones (36). marild et al. showed that longer duration of exclusive breast feeding was associated with a lower risk of febrile uti in children (37). it was suggested that the antiadhesive oligosaccharides, unspecific antibacterial lactoferrin, secretory immunoglobulin antibodies in breast milk could be effective in these special protective effects supplied by human milk (37, 38). our study may have some limitations. one major limitation of the study may be the relatively small number of children included in both groups. again, the possible individual effect of medical management on the correction of above mentioned parameters could also have been evaluated during the long-term follow-up. however taking the highly limited data reported in the literature on this subject paticularly in this specific population into account, we believe that our current findings will be contributive enough on this aspect. conclusions accumulated data in the literature so far demonstrate that due to the high likelihood of predisposing factors resulting in higher stone recurrence and re-growth rates; all children with urinary stone disease should be followed closely with regular visits. in the light of our findings we may implicate that all infants with stone disease should be followed closely with respect to the body as well as kidney growth status. breast feeding is a critical factor that may affect the child’s growth status by lowering the risk of uti as well as new stone attacks. however, we believe that further studies with larger number of cases are certainly needed in order to outline the possible effects of the parameters evaluated in this study on the clinical course of urolithiasis in this specific group of cases. ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. 253archivio italiano di urologia e andrologia 2016; 88, 4 factors affecting the course kidney growth in infants with urolithiasis sarica1_stesura seveso 09/01/17 09:46 pagina 253 archivio italiano di urologia e andrologia 2016; 88, 4 k. sarica, f. narter, k. sabuncu, a. akca, u. can, a buz, h. nese sarica, b. eryildirim 254 references 1. faerber gj. pediatric urolithiasis. review curr opin urol. 2001; 1:385-9. 2. sarica k. medical aspect and minimal invasivetreatment of urinary stones in children. arch ital urol androl. 2008; 80:43-9. 3. bastug f, gunduz z, tulpar s, et al. urolithiasis in infants: evaluation of risk factors. world j urol. 2013; 31:1117-22. 4. guven ag, koyun m, baysal ye, et al. urolithiasis in the first year of life. pediatr nephrol. 2010; 25:129-34. 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36. ajetunmobi om, whyte b, chalmers j, et al. breastfeeding is associated with reduced childhood hospitalization: evidence from scottish birth cohort (1997-2009). j pediatr. 2015; 166:620-5. 37. marild s, hansso u, jodal u, et al. protective effect of breast feeding against urinary tract infection. acta paediatr. 2004; 93:164-8. 38. coppa g, gabrielli o, giorgi p, et al. preliminary study of breastfeeding and bacterial adhesion to uroepithelial cells. lancet 1990; 335:569-71. correspondence kemal sarica, md saricakemal@gmail.com kubilay sabuncu, md kubilaysabuncu@yahoo.com utku can, md utkucan99@yahoo.com ayş e buz, nurse aysebuz@hotmail.com bilal eryildirim, md (corresponding author) ilaleryildirim@yahoo.com dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey tecerdagi cad. yakutlar sitesi g/11 kartal, istanbul, turkey fatma narter, md fatmakaya06@yahoo.com.tr dr. lutfi kirdar training and research hospital pediatric clinic, istanbul, turkey ahmet akca, md ahmtakca@yahoo.com dr. lutfi kirdar training and research hospital radiology clinic, istanbul, turkey h. nese sarica, md nesesarica@yahoo.com pediatrician, medistate hospital, istanbul, turkey sarica1_stesura seveso 09/01/17 09:46 pagina 254 217archivio italiano di urologia e andrologia 2016; 88, 3 original paper chylous ascites as a complication of left sided robot-assisted laparoscopic partial nephrectomy gaurav pahouja 1, kalpit patel 1, daniel j. ricchiuti 2 1 northeast ohio medical university, akron general medical center department of urology, akron, ohio, united states; 2 st. elizabeth health center, division of urology, youngstown, ohio, united states. objective: the aim of the study was to present a case series of the sparsely reported complication of chylous ascites (ca) after left sided robot-assisted laparoscopic partial nephrectomy (ralpn), identify possible risk factors for the development of postoperative ca, and explore current recommendations for identification, management and prevention of ca. material and methods: a retrospective review of patients that were treated with a ralpn during a one year time period (august 2012 to august 2013) by one surgeon at our institution was conducted. a total of 12 patients were included in the study. demographics, tumor characteristics, and perioperative outcomes were assessed. results: three patients in the study experienced postoperative ca. all three patients had left sided surgery. the initial clinical suspicion for ca was raised due to complaints of abdominal pain with increased milky appearance of jp fluid. jp triglycerides were elevated in all three patients. the patients responded to conservative measures, with two patients treated with medium chain triglyceride diets and one patient treated with total parenteral nutrition (tpn). among the patients treated with ralpn, the group that was diagnosed with postoperative ca (ca group) was found to have a statistically significant lower average body mass index (bmi) as compared to the group that did not have ca (non-ca group) (24.67 kg/m2 in the ca group versus 31.77 kg/m2 in the non-ca group; p = 0.026). other demographic data, tumor characteristics, and perioperative outcomes were similar in both groups. conclusions: ca as a result of ralpn is a newly reported and rare postoperative complication. as utilization of ralpn continues to increase, urologists should be aware of this possible complication and be adept at diagnosing and managing ca. we suggest that left sided retroperitoneal surgery and a lower bmi preoperatively be considered risk factors for developing this complication. key words: chylous ascites; left; robotics; laparoscopy; partial nephrectomy; body mass index. submitted 11 april 2016; accepted 22 may 2016 summary no conflict of interest declared. compared to many other types of cancer, ranking as the 9th most common type of cancer in the united states and comprising approximately 3.7% of all new cancer cases in the united states (1-2). the incidence of renal cell carcinoma has been rising on average 1.4% each year over the past 10 years while death rates have been falling on average of 0.7% each year (1). current surgical management values favorable oncologic outcomes paired with a nephron sparing approach. partial nephrectomy is emerging as a minimally invasive nephron sparing approach for renal cancers, with the options of an open, laparoscopic, or robotic approach (3-4). robotic partial nephrectomy is gaining popularity secondary to acceptable safety and outcomes (5-6). advantages of the robotic approach to partial nephrectomy as compared to the open approach include decreased blood loss, decreased pain, shorter length of hospital stay, improved cosmesis, and more rapid convalescence (7-8). as the robotic approach to partial nephrectomy continues to gain support, possible complications must be explored. chylous ascites (ca), also known as chyloperitoneum, is a rare complication of retroperitoneal surgery that can often go undiagnosed and untreated (9-11). ca is an accumulation of lymphatic fluid within the peritoneal cavity. in the surgical setting, it is hypothesized that disruption of the retroperitoneal lymph vessels leads to lymphoperitoneal fistula formation (12-13). analysis of peritoneal fluid is diagnostic and will produce a milky, sterile, odorless fluid with an alkaline ph, total protein > 3 g/dl, total fat between 0.4 and 4.0g/dl and predominance of lymphocytes on the differential white blood cell count (14). historically, ca was most commonly reported as a complication of abdominal aortic surgery. ca has been reported in the literature after urologic surgeries including retroperitoneal lymphadenectomy for testis and renal cancers, wilm’s tumor resection, and laparoscopic radical and donor nephrectomy (15-31). chylous leakage and ascites has only been reported in very rare instances in operative techniques and surgical outcomes in robot-assisted laparoscopic partial nephrectomy (ralpn) (32-34). our objective is to present a case series of this rare complication after left sided ralpn, identify possible risk factors for the development of postoperative ca, and explore current recommendations for identification, management, and prevention of ca. doi: 10.4081/aiua.2016.3.217 introduction the incidence of renal cell carcinoma in the united states is estimated to be approximately 15.6 per 100,000 men and women per year (1-2). the lifetime risk of developing renal cell carcinoma is estimated to be 1.6% (1-2). renal cell and renal pelvis cancer is fairly common pahouja_stesura seveso 21/09/16 09:00 pagina 217 archivio italiano di urologia e andrologia 2016; 88, 3 g. pahouja, k. patel, d.j. ricchiuti 218 material and methods study population a retrospective review of patients that were treated with a ralpn during a one year time period (august 2012 to august 2013) by one surgeon at our institution was conducted. the medical records of these patients were gathered and analyzed. data collected included diagnosis of postoperative ca, demographics, tumor characteristics, and perioperative outcomes. inclusion criteria included the presence of a renal mass or lesion, as confirmed by radiologic imaging, and subsequent ralpn performed by the same surgeon. surgical technique standard approach to left sided robot-assisted partial nephrectomy was performed (35-36). all operations were performed using the da vinci surgical system through a retroperitoneal approach. briefly, the aorta is identified and the left renal artery is dissected at the level of the takeoff from the aorta. any lymphatic channels identified are secured with surgical clips. once the hilum is fully dissected, the renal artery is clamped. in some cases, the renal vein may also be clamped. tumor excision and renorrhaphy are then performed. statistical analysis for descriptive statistics, data is presented as mean with standard deviations. categorical variables are presented as the percentage of total patients and the total number of patients. the between group comparisons were done utilizing two-tailed t-test or fisher’s exact test with significance defined as p < 0.05. results chylous ascites case series patient 1 a 46-year-old man with a past medical history of hypertension and gastroesophageal reflux disease and past surgical history of hernia repair was found to have a complex cystic lesion. he also had a 20 pack-year smoking history. his preoperative computed tomography (ct) scan revealed inflammatory changes around the kidney suggestive of a soft tissue mass or complex cyst. subsequently, he underwent a left sided ralpn. intraoperatively, the patient was noted to have two renal arteries and one renal vein. the lesion was identified and removed from gerota’s fascia. a jackson pratt (jp) drain was placed and monitored postoperatively. his pathology revealed a 7 cm by 6 cm by 4.5 cm benign cortical cyst. on postoperative day (pod) 1, the patient complained of epigastric, left upper quadrant (luq), and left lower quadrant (llq) abdominal tenderness but has no evidence of abdominal distention. his vital signs were within normal limits at the time. in addition, the patient had high output drainage (302 ml) of pink tinged, milky white fluid. evaluation of the drain fluid revealed that the drain fluid and serum creatinine were equivalent. in addition, jp drain fluid lipase and amylase were within normal limits. however, jp drain fluid triglycerides were elevated (> 1,100 mg/dl) and the patient was subsequently diagnosed with ca. the patient was treated with total parenteral nutrition (tpn). on pod 3, jp drain fluid triglycerides decreased to 212 ml. besides complaints of luq and llq abdominal pain, the patient remained clinically stable and his abdominal exam was unremarkable with normal bowel sounds throughout the hospital stay. by pod 4, the drainage had decreased considerably (< 50 ml/day). after his diet was advanced without increased jp drainage, the jp drain was removed and he was discharged home on pod 7 with resolution of his symptoms. patient 2 a 56-year-old male with a past medical history of asthma and gastrointestinal reflux disease and no past surgical history presented with a left sided renal lesion. his ct scan revealed an enhancing lesion on the lower pole of his left kidney suggestive of renal cell carcinoma or angiomyolipoma and also showed perihilar lymphadenopathy. he underwent a left sided ralpn and periaortic lymph node resection for the enhancing lesion and lymphadenopathy. the patient was noted to have a solitary renal artery and solitary renal vein. a 1.5 cm by 1.5 cm by 1.2 cm tumor was identified and successfully removed. pathology revealed a grade 3 clear cell renal cell carcinoma (rcc). in addition, six periaortic lymph nodes removed during surgery were negative for malignancy. on pod 1, the patient complained of left sided flank pain and mild abdominal distension was noted. his vital signs were within normal limits. by pod 2, a low volume milky leakage was identified in the jp drain. jp drain fluid evaluation revealed an elevated triglyceride count (> 1100 mg/dl), with normal amylase, lipase, and creatinine levels. he was diagnosed with ca, and started on a low fat medium chain triglyceride diet. on pod 3, he was discharged home with his jp drain in place on a low fat medium chain triglyceride diet. after two weeks, his jp drain output had decreased considerably, and his jp drain was removed as an outpatient without any further issues. patient 3 a 54-year-old male with a past medical history of degenerative disc disease and chronic back pain and past surgical history of hernia repair, appendectomy, left elbow surgery, right hand surgery, and right foot surgery presented for evaluation of a left renal mass. he also had a 75 pack-year smoking history. his preoperative ct scan revealed a posterior superior 3 cm left renal mass. he was treated with a left sided ralpn. intraoperatively, he had a large amount of lymphatic vessels that needed to be transected to access the renal artery which were cauterized as best as possible. he was noted to have a solitary renal artery and vein. his tumor was identified, removed, and sent for pathological evaluation which revealed a 3 cm by 3 cm by 2.5 cm tumor composed of clear cell rcc. on pod 3, his jp drain was draining a pink tinged, milky fluid. laboratory analysis of the jp drain fluid showed normal jp drain fluid creatinine, lipase, and amylase but elevated jp drain fluid triglycerides (> 1,100 mg/dl). ca was identified, and the patient was started on a medium chain fatty acid diet. by pod 5, he was doing well clinipahouja_stesura seveso 21/09/16 09:00 pagina 218 cally but persisted to have elevated drain output. he was discharged home on pod 5 with his jp drain in place. the patient returned 7 days after discharge (pod 12) with a chills, fatigue, cough, and abdominal pain. his vital signs revealed a blood pressure of 124/70 mmhg, respiratory rate of 16, tachycardia with a heart rate of 124 beats per minute, and fever of 38.44ºc. his abdomen was moderately tender in the llq and was mildly distended. in addition, his jp drain was in place and draining minimal serous cream tinged fluid. his white blood cell count was elevated (> 12,000 mm3). the patient had a ct scan which was negative for a pelvic abscess. a gram stain of the jp drain fluid revealed group a streptococcus pyogenes and severe sepsis was identified. he was treated with fluid resuscitation and broad spectrum antibiotics. in addition, he was placed on tpn. the patient improved clinically and was started on a clear liquid diet on pod 16. on pod 17, his tpn was weaned and he was started on a low fat medium chain fatty acid diet. on pod 18, the jp drain output decreased to 10 ml over 24 hours and the jp drain was removed. the patient was again discharged in stable condition on pod 20 without any further complications. demographics a total of 12 patients had a ralpn by one surgeon during a one year long time period and were included in the study. three of the patients in the study experienced postoperative ca. all three patients had underwent a left sided ralpn. among the patients treated with ralpn, the group that was diagnosed with postoperative ca (ca group) was found to have a statistically significant lower average body mass index (bmi) as compared to the group that did not have ca (non-ca group) (24.67 kg/m2 in the ca group versus 31.77 kg/m2 in the non-ca group; p = 0.026). the ca and non-ca groups were comparable in terms of other demographic data (table 1). perioperative outcomes when the ca group is compared to the non-ca group, there were no significant differences in tumor characteristics including tumor size, tumor location, and final pathologic findings (table 2). in terms of perioperative outcomes, the ca group was comparable to the non-ca group (table 3). there were no statistically significant differences in operative duration, estimated blood loss, and variations in renal anatomy. 219archivio italiano di urologia e andrologia 2016; 88, 3 chylous ascites as a complication of left sided robot-assisted laparoscopic partial nephrectomy variable ca after ralpn no ca after ralpn p value* (n = 3) (n = 9) operative duration (min) 249.67 (12.74) 279.78 (43.73) 0.28 estimated blood loss (ml) 333.33 (236.29) 500 (446.51) 0.56 greater than 2 renal vessels on side of surgery (%) 33.33 (1) 44.44 (4) 1 2 or more renal arteries on side of surgery (%) 33.33 (1) 22.22 (2) 1 2 or more renal veins on side of surgery (%) 0 (0) 22.22 (2) 1 table 3. perioperative outcomes of ralpn patients – ca group versus non-ca group. ralpn = robot-assisted laparoscopic partial nephrectomy; ca = chylous ascites. data presented as mean, with standard deviation in parenthesis, for operative duration and estimated blood loss. data presented as percentage of patients, with number of patients in parenthesis, for greater than 2 renal vessels on side of surgery, 2 or more renal arteries on side of surgery, and 2 or more renal veins on side of surgery. * group comparison p value performed using two-tailed t-test and fisher’s exact test with statistical significance set to p < 0.05. variable ca after ralpn no ca after ralpn p value* (n = 3) (n = 9) age (years) 51.67 (5.86) 53.44 (9.44) 0.77 bmi (kg/m2) 24.67 (2.43) 31.77 (4.39) 0.026 males (%) 100 (3) 55.56 (5) 0.49 caucasian (%) 100 (3) 100 (9) 1 prior abdominal surgery (%) 66.67 (2) 66.67 (6) 1 left sided surgery (%) 100 (3) 55.56 (5) 0.49 table 1. demographic data and intraoperative findings of patient in center a and center b included in this study. ralpn = robot-assisted laparoscopic partial nephrectomy; ca = chylous ascites; bmi = body mass index. data presented as mean, with standard deviation in parenthesis, for age and bmi. data presented as percentage of patients, with number of patients in parenthesis, for males, caucasian, prior abdominal surgery, and left sided surgery. * group comparison p value performed using two-tailed t-test for age and bmi and fisher’s exact test for males, caucasian, prior abdominal surgery, and left sided surgery with statistical significance set to p < 0.05. variable ca after ralpn no ca after ralpn p value* (n = 3) (n = 9) tumor size (cm) 3.83 (2.84) 4.07 (1.71) 0.86 tumor location (%) upper pole 33.33 (1) 44.44 (4) 1 middle pole 0 (0) 11.11 (1) 1 lower pole 33.33 (1) 33.33 (3) 1 gerota’s fascia 33.33 (1) 0 (0) 0.25 perihilar 0 (0) 11.11 (1) 1 pathologic findings (%) clear cell rcc 66.67 (2) 77.78 (7) 1 chromophobe rcc 0 (0) 11.11 (1) 1 benign cortical cyst 33.33 (1) 0 (0) 0.25 angiomyolipoma 0 (0) 11.11 (1) 1 table 2. tumor characteristics of ralpn patients – ca group versus non-ca group. ralpn = robot-assisted laparoscopic partial nephrectomy; ca = chylous ascites; rcc = renal cell carcinoma. data presented as mean, with standard deviation in parenthesis, for tumor size. data presented as percentage of patients, with number of patients in parenthesis, for tumor location and pathologic findings. * group comparison p value performed using two-tailed t-test for tumor size and fisher’s exact test for tumor location and pathologic findings with statistical significance set to p < 0.05. pahouja_stesura seveso 21/09/16 09:00 pagina 219 archivio italiano di urologia e andrologia 2016; 88, 3 g. pahouja, k. patel, d.j. ricchiuti 220 discussion chylous fluid accumulation has been reported to arise from disruption of the lymphatic system secondary to traumatic injury or obstruction (37). the lymphatic system consists of a linear network of lymphatic vessels and lymphoid organs. lymph, a collection of tissue fluids, cells and extracellular molecules, are drained into lymphatic capillaries and then into lymphatic vessels, lymph nodes, and lymph trunks and then returned to the blood circulation (38-39). classically, the renal lymphatic system follows along a similar pathway as the renal venous drainage. renal lymphatics coalesce to form lymphatic trunks that exit the renal hilum. the right renal lymphatic trunks drain to the paracaval, precaval, retrocaval, and interaortocaval lymph nodes which extend from the diaphragm to the right common iliac artery (40-41). the left renal lymphatic drainage is to the paraaortic, preaortic, and retroaortic lymph nodes which extend from the diaphragm to the inferior mesenteric artery (40-41). most of the efferent vessels from these groups of lymph nodes then converge to form the right and left lumbar trunks which subsequently drain to the cisterna chyli (40-41). it is important for urologists performing ralpn to be aware of the clinical presentation, diagnosis, and treatment of ca, as ca may lead to serious complications. the most common clinical manifestations of ca are abdominal distention and nonspecific pain (42). additional findings may include pleural effusions, lower extremity edema, dyspnea, cachexia, malnutrition, lymphadenopathy, hernia, fevers, and night sweats (9, 37, 42-43). ca results in a loss of chyle to the peritoneal cavity which can progress to nutritional deficiency with loss of crucial electrolytes, proteins, immunoglobulins, lymphocytes, vitamins, lipids, and water (44). additionally, the continued loss of lymphocyte-rich lymph to the peritoneal cavity paired with loss of protein can cause hypogammaglobulinemia and a resultant immunodeficiency with increased susceptibility to infection (45). finally, the bioavailability of drugs can be severely deteriorated with ca (46-47). in the postoperative setting, these losses can lead to an increased morbidity and mortality rate (48). ca is routinely diagnosed using peritoneocentesis. on analysis, the triglyceride level in the milky appearing ascitic fluid sample will be elevated the standard is greater than 110 mg/dl (37). rather than using an absolute level, the ratio of ascitic triglyceride to plasma triglyceride can be used as well. a ratio between 2:1 and 8:1 is associated with ca (43). to further confirm suspicion, lymphoscintigraphy, lymphography with ct, abdominal ultrasound, as well as magnetic resonance imaging can be utilized to explore the possibility of a chyloperitoneum. most of the treatment for ca is supportive in nature. nutritional support is essential to replenish vitamin, electrolyte, and fluid deficiencies. to achieve symptomatic relief, the fluid must be removed via diuretics, elevation of legs, supportive stockings, dietary changes, and also repeated paracentesis (37). since chyle is made up of long-chain fatty acids, minimizing high fat foods paired with medium chain triglyceride supplementation may decrease chyle development (49). in cases of resistant or postsurgical ca, a more vigorous treatment regimen of bowel rest and tpn may be warranted (50). somatostatin therapy in addition to tpn has also proven beneficial in several instances in decreasing chyloperitoneum and alleviating symptoms (50-51). in cases where the ca continues despite adequate mechanical and pharmacological therapy, there are several possible surgical options. if the leak is discovered early, then it can be managed with staples or clips (52). another possibility is peritoneovenous shunting in order to prevent nutritional depletion (53). some success has also been seen with using fibrin glue applications with and without mesh after careful dissection of the leakage area (52, 54). as ca remains a rare complication, there is yet to be a standard surgical approach. it has been identified in the literature that during laparoscopic donor nephrectomy (ldn), the incidence of ca increases when attempting to preserve the length of the renal artery and vein. in order to do so, a more extensive dissection of the renal hilum is necessary. in ldn, there has been a higher incidence of ca following the removal of the left donor kidney (22-24). the higher incidence of ca associated with left sided ldn versus the right has been attributed to the lymphatic anatomy as well as the higher frequency of extraction of the left kidney, as the left kidney is anatomically preferred for transplantation. the ascending vertical lymphatic channels parallel the aorta into the retroperitoneum and merge posterior and medial to the aorta forming the cisterna chyli. this saclike dilatation of the ascending vertical lymphatic channels is located anterior to the first and second lumbar vertebrae (22). however, there are many anatomical variants of the lymphatic channels (14). the location of the cisterna chyli is thought to be the anatomic cause of the increased incidence of ca following left sided ldn. of note, ca does not appear to be a complication of open nephrectomy. this finding is attributed to the pneumoperitoneum which decreases the leakage of the low pressure lymph vessels. on the contrary, in the absence of pneumoperitoneum during an open surgery, these lymphatics are more readily identified and ligated (34). ca as a result of partial nephrectomy is a rare postoperative complication that has been sparsely reported. weiser et al. reported one incidence of ca after an open partial nephrectomy for wilms tumor (30). wan et al. reported five patients out of 39 experiencing ca after upper-pole heminephrectomy for duplex kidney (31). even fewer reports of ca after ralpn have been published. tanagho et al. reported one case of ca out of 886 patients treated with robotic-assisted partial nephrectomy for a renal mass (32). hillyer et al. reported one case of ca out of nine patients that underwent bilateral robot-assisted partial nephrectomy for renal masses (33). in both instances, the side of the ca was not specified. in reviewing the patients, this study found that three out of 12 patients that had a ralpn by a single surgeon over the span of a year had the postoperative complication of ca. all three patients had their procedures done on the left side. this study found that bmi was a statistically significant variable between patients that had ca and those that did not. this may suggest that patients with a lower pahouja_stesura seveso 21/09/16 09:00 pagina 220 bmi have a higher risk of developing ca after a ralpn, and those with a higher bmi have a lower risk of developing ca after a ralpn. finally, the patient series of this study paired with the reports in the literature discussed may suggest that ralpn, especially on the left side, is a risk factor for developing the complication of postoperative ca. urologists should be well aware of techniques to prevent ca during a ralpn. as mentioned, an extensive renal hilar dissection during robotic surgery may increase the risk of ca, especially on the left side. the length and position of the left kidney make it necessary to perform a dissection close to the aorta. as described, many lymph vessels and major lymph trunks are concentrated along the paraaortic region. therefore, during dissection of the renal vessels, care should be taken to identify and avoid, if possible, the paraaortic lymphatic channels. in addition, caution should be utilized when identifying and dissecting any possible accessory renal vessels. over dissection while trying to locate such accessory vessels may result in higher risk of postoperative ca. of note, with ralpn and pure laparoscopic cases, monopolor and bipolar coagulation are often used to perform dissections and achieve lymphostasis. therefore, it is critical to be aware of lymphatics and the cisterna chyli that lie in close proximity to the aorta during left ralpn and utilize laparoscopic clipping of major lymphatics around the perihilar and retroperitoneal tissue during renal pedical dissection. this technique may help prospectively prevent ca. limitations of this study should be discussed. the limitations of the study included the retrospective nature and small sample size which partially limit the significance of the outcome assessments. a multivariate analysis may validate the findings of this study. however, the sample size is small. in addition, aside from the possible risk factors of left sided surgery and bmi, the study was unable to identify the exact risk factors and etiology of ca following ralpn. large, prospective, randomized studies are still needed to better study the complication of ca following ralpn and definitively characterize the possible risk factors and etiologies. nevertheless, this study was able to identify the postoperative complication of ca after ralpn which has not been widely reported in the literature. conclusions ca as a result of ralpn is a newly reported and rare postoperative complication. as utilization of ralpn continues to increase, urologists performing the case should be aware of this possible complication and be adept at diagnosing and managing ca. a patient with a lower bmi preoperatively may be at a higher risk of developing postoperative ca. in addition, 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and parenteral nutrition. transplant proc. 2008; 40:320-321. 52. jensen eh, weiss ca 3rd. management of chylous ascites after laparoscopic cholecystectomy using minimally invasive techniques: a case report and literature review. am surg. 2006; 72:60-63. 53. matsufuji h, nishio t, hosoya r. successful treatment for intractable chylous ascites in a child using a peritoneovenous shunt. pediatr surg int. 2006; 22:471-473. 54. zeidan s, delarue a, rome a, roquelaure b. fibrin glue application in the management of refractory chylous ascites in children. j pediatr gastroenterol nutr. 2008; 46:478-481. correspondence gaurav pahouja, md (corresponding author) gpahouja@neomed.edu kalpit patel, md kalpatel428@gmail.com northeast ohio medical university, akron general medical center department of urology, akron, ohio, united states daniel j. ricchiuti, md dricchiuti@yahoo.com st. elizabeth health center, division of urology, youngstown, ohio, united states pahouja_stesura seveso 21/09/16 09:00 pagina 222 stesura seveso 1archivio italiano di urologia e andrologia 2016; 88, 1 original paper patient’s satisfaction after 2-piece inflatable penile prosthesis implantation: an italian multicentric study giorgio gentile 1-2, alessandro franceschelli 1, paolo massenio 3, agostino tuccio 4, andrea cocci 4, lucia divenuto 5, daniele romagnoli 2, alessandro natali 4, antonio vitarelli 5, luigi cormio 3, fulvio colombo 1 1 andrology-unit, university hospital s.orsola-malpighi, bologna, italy; 2 department of urology, university of bologna, bologna, italy; 3 department of urology and kidney transplant center, university of foggia, italy; 4 department of urology and oncology, aou careggi, university of florence, italy; 5 department of urology, university of bari “aldo moro”, italy. introduction: penile prosthesis implant represents a valuable solution for pts with severe erectile dysfunction (ed), non-responders to medical management. the aim of our study was to evaluate the satisfaction of patients (pts) after 2-pieces inflatable penile prosthesis (ipp). aim of the study: to evaluate safety, reliability and post-operative patient’s satisfaction after implantation of two-pieces ipp. materials and methods: this retrospective multicentric analysis concerns a group of 42 patients undergone 2-pieces ipp implantation from november 2005 to november 2013, in four centers of proven experience. as a first step, a detailed review of all clinical reports was performed. secondly, every patient was asked to fill the erectile dysfunction inventory of treatment satisfaction (edits) specifically modified, in order to assess their own satisfaction after surgery and, its impact on patient’s quality of sexual life. results: 42 pts were evaluated (ams-ambicor: 28; coloplastexcell: 14); mean age, at time of operation: 60,7 years; mean follow up: 27,6 months; etiology of ed: vascular 23,8%, diabetes 19%, la peyronie d. 7,1%, consequence of radical prostatectomy 31%, consequence of other pelvic surgery 11,9%, spinal trauma 7%. mean operative time: 117 ± 58 min, mean postoperative hospital stay 3 ± 1,6 days. post operative short-term complications: 4 pts (9,5%). post operative long-term complications: 4 pts (9,5%). long-term functional results (questionnaire): 71% of pts (30) reported regular use of the prosthesis, at least 1 time/week, the satisfaction was good in 42% of pts (18), quite good in 33,3% (14), quite bad in 2,4% (1), very bad in 7,1% (3), 6 pts (14,4%) didn’t answer. conclusions: 2 pieces ipp appears to be associated with a low complication rate and good satisfaction of pts especially in the elderly. it also assures satisfactory rates of aesthetics and functional results. key words: erectyle dysfunction; patient satisfaction. submitted 5 february 2016; accepted 15 february 2016 summary no conflict of interest declared. based upon different options, ranging from oral administration to intracavernousal injections (2). in patients (pts) not responsive to medical therapies, penile prosthesis implant is the only chance (3). since their first appearance in 1970, penile prosthetic devices have progressively improved, thus becoming not only more reliable but also easier to be implanted and to be used (4). the 2-piece ipp is often considered a “second option” for these pts, although there are only few studies focused on their impact in patients’ quality of life (5-9). aims the aim of this study was to evaluate the clinical safety and reliability of two-pieces ipp implantation, and the level of acceptance and satisfaction in operated pts under different points of view: functional, sexual, behavioral and personal. materials and methods this paper reports a retrospective multicentric study regarding 42 patients undergone 2-pieces ipp from november 2005 to november 2013, in four different centers of proven experience. patients’ age, cause of ed and possible cardiovascular risk factors were collected. indication for surgery was given in case of severe organic ed refractory to any medical treatment. each patient received a detailed explanation about any possible risk related to the procedure, and a specific informed consent was obtained. exclusion criteria were psychiatric illness, genital or systemic infections and any comorbidity affecting wound healing. ams ambicor device was implanted in 29 cases (69%), since a coloplast excel model was chosen in the remaining 13 (31%). in all pts a peno-scrotal approach was applied. a detailed review of all clinical reports was performed and data were collected. each patient was then contacted by phone and asked to return to the referring hospital, for long-term clinical examination. in this occasion, every patient was asked to fill a specific questionnaire, a modified version of the valdoi: 10.4081/aiua.2016.1.1 introduction erectile dysfunction (ed) is defined as “the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance” (1). the prevalence of this condition is about 19%, and its medical treatment is colombo_stesura seveso 08/04/16 11:21 pagina 1 archivio italiano di urologia e andrologia 2016; 88, 1 g. gentile, a. franceschelli, p. massenio, a. tuccio, a. cocci, l. divenuto, d. romagnoli, a. natali, a. vitarelli, l. cormio, f. colombo 2 idated questionnaire “erectile dysfunction inventory of treatment satisfaction (edits)” (5-6), probing on four fundamental items: frequency of use of the implant, its impact on patient’s quality of sexual life, personal evaluation of the outcomes of the operation, from both the functional and aesthetic point of view. reponses were classified according to a five-point scale, in most cases ranging from “extremely satisfied (1)” to “totally unsatisfied (5)”. each interview was conducted by the same physician (one for each institution). during the interview, the patient and his partner were placed in different areas. results a total of 42 pts were implanted using 2-pieces ipp between november 2005 and november 2013. mean age at the time of surgery was 61 ± 10, ranging from 33 to 80. 50% of patients were smokers, 30% were affected by hypertension, 19% had type 2 diabetes mellitus (in effective pharmacological treatment) and 1% had dyslipidemia (table 1). none of the patients had been previously implanted. etiology of ed was: radical prostatectomy (33%), vascular abnormalities (24%), diabetes mellitus (19%), other pelvic surgery (12%), peyronie’s disease (7%), spinal trauma (5%) figure 1. in 29 cases (69%) the ams ambicor device was implanted, since a coloplast excel model was placed in the remaining 13 (31%). mean operative time recorded was of 117 ± 58 minutes, no intra-operatory complications had been reported. antibiotic prophylaxis was administered in the operatory room, and each patient (100%) was given systemic therapy with third generation cephalosporines (cephuroxime) until the hospital discharge. mean hospital stay was 3 ± 1.6 days. during hospitalization one patient presented hyperpyrexia, while two required prolonged analgesic therapy for post-operative pain. no blood transfusion was required, and there was no need of surgical revision in any case. considering long term complications, two patients had prosthesis extrusion due to infection, one patients complained persistent loss of glans sensitivity, one patient presented prosthetic malfunction. in the remaining 37 cases (88%), no late onset complication was documented. mean follow up time was 27 months. at the follow up no patient was lost: 31 (73%) patients were found to routinely use the prosthesis, 6 (14%) didn’t have a partner to use it with, 3 (7%) lost interest in using (two of them because affected by oncological disease, the remaining one because of poor manageability of the implant), and two (4.8%) reported pain at the activation of implant. when asked about the frequency of sexual activity, the response was 2 intercourse per week, average. analyzing overall patients’ satisfaction following the operation, 42% were extremely satisfied, 33% referred to be almost satisfied, the remaining 25% were substantially indifferent to the result. there were no case of total unsatisfaction. 29 pts (70%) found almost full realization of their preoperative expectations, with 67% stated they were ready to use the device. in 90% of cases the operation granted the sexual self confidence the patients were searching for, and 73% of the partners interviewed resulted to be fully satisfied. the device was found to be “user-friendly” in 76% of the pts and only one patient defined the implant as “extremely difficult to use”. 27 out of 42 pts (64%) reported to be fully satisfied by the device, once activated, and the majority of pts reported fully satisfaction about the aesthetic appearance of the prosthesis when deactivated. only three pts complained for the incomplete concealing of the prosthesis. if considering the filling system, only two pts reported a certain “delay” in the activation process. one was not satisfied for the insufficient girth of the shaft, another one referred shortening of the penis and one was unsatisfied for incomplete penile rigidity with full-activated implant. under the aestethical point of view the overall percentage of appreciation was 95% (40 pts). only two pts were dissatisfied due to the aspect of the penis when inflated (one for the girth, one for the lenght); moreover, one of them referred to be “not personally satisfied” by the overall appearance of the prosthesis. the length of the penis was reported to be increased in 13 of patients, reduced in 8 pts, and unmodified in the remaining 21. discussion ipp is the final option for the treatment of pts with ed (1). this is the only reliable solution for this population. according to our data the 2 piece ipp seems still to play a role in this field. in our multicentric study no patient was lost during the follow up. the rate of satisfaction results consistent with data of literature (9). it is important to notice that, in our study, there were 15 patients (36%) who were older than 65 years and all of them reported to be almost or very satisfied by the 2-piece ipp function (figure 2), belonging the low rate of dissatisfaction only to patients younger than 65 age (mean ± sd) (years) 61 ± 10 age range 33-80 smokers 50% hypertension 30% dyslipidemia 1% diabetes 19% table 1. characteristics of the population enrolled. figure 1. etiology of ed in the population of the study. pelvic surgery 12% radical prostatectomy 33% diabetes mellitus 19% peyronie’s disease 7% vascular abnormalities 24% ed: ethiology spinal trauma 5% colombo_stesura seveso 08/04/16 11:21 pagina 2 years (figure 3). these data agree with many works about ppi (10-12). explanation could be the lower expectations among elder pts. the low rate of complications observed (both early and late onset) confirms the reliability of the 2 piece-ipp. interestingly, this kind of implant seems to do not affect penile length (maybe due to the incomplete state of flaccidity of the penile shaft, typically provided by the 2pieces ipp when deactivated), thus dismantling one of those myths which prevents people affected by ed from undergoing ipp (11). the aesthetical aspects of the prosthesis have substantially gained widespread appreciation, with acceptable concealing of the device. conclusions ipp is a feasible solution to treat severe ed. the 2-pieces models are a valid option of choice, especially in the elder patient, and has low rates of intra and postoperative complications. it also offers satisfactory rates of aesthetics and functional results. references 1. lue tf, giuliano f, montorsi f, et al. summary of the recommendations on sexual dysfunctions in men. j sex med. 2004; 1:6-23. 2. hatzimouratidis k, amar e, eardley i, et al. eau guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation, eur urol. 2010; 57:804-814. 3. montague dk. penile prosthesis implantation in the era of medical treatment for erectile dysfunction. urol clin north am. 2011; 38:217-25. 4. jarow jp. risk factors for penile prosthesis infection, j urol. 1996; 156:402-404. 5. altof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for ed. urology. 1999; 53:793. 6. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece prosthesis, j urol. 2007; 177:262-266. 7. levine la, estrada cr, morgentaler a. mechanical reliability and safety of, and patient satisfaction with the ambicor inflatable penile prosthesis: results of a 2 center study, j urol. 2001; 166:932-937. 8. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-1433. 9. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfaction after ams inflatable penile prosthesis implant. j sex med. 2010; 7:304-309. 10. villareal hg, jones l. outcomes and satisfaction with the inflatable penile prosthesis in the elderly male. adv urol. 2012; 240963. 11. al-najar a, naumann cm, kaufmann s, et al. should being aged over 70 years hinder penile prosthesis implantation? bju int. 2009; 104:834-837. 12. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece prosthesis. j urol. 2007; 177:262-6. 3archivio italiano di urologia e andrologia 2016; 88, 1 patient’s satisfaction after 2-piece inflatable penile prosthesis implantation: an italian multicentric study figure 2. satisfaction rate (%) in patients older than 65 years (15 pts). figure 3. satisfaction rate (%) in patients younger than 65 years (27 pts). correspondence giorgio gentile, md dr.giorgio.gentile@gmail.com alessandro franceschelli, md alessandro.franceschelli@aosp.bo.it fulvio colombo, md fulvio.colombo@aosp.bo.it andrology unit, university hospital s.orsola-malpighi, bologna, italy paolo massenio, md p.massenio@alice.it luigi cormio, md luigi.cormio@unifg.it department of urology and kidney transplant center, university of foggia, foggia, italy agostino tuccio, md agostinotuccio@yahoo.it andrea cocci, md cocci.andrea@gmail.com alessandro natali, md anatali@dada.it department of urology and oncology, aou careggi, university of florence firenze, italy lucia divenuto, md luciadivenuto@hotmail.it antonio vitarelli, md antoniovitarelli@hotmail.com department of urology, university of bari “aldo moro”, bari, italy daniele romagnoli, md danieleromagnoli@hotmail.it department of urology, university of bologna, bologna, italy very almost satisfied a few not at all satisfied satisfied satisfied satisfied very almost satisfied a few not at all satisfied satisfied satisfied satisfied colombo_stesura seveso 08/04/16 11:21 pagina 3 introduction the suprapubic cystostomy (spc) is a common urological procedure to drain the bladder in a wide variety of pathological processes. suprapubic catheter can be placed either through a punch trocar, after localization of the bladder by palpation, or by using other safer techniques like the application of the lowsley retractor, seldinger technique using peel away sheath introducer or image guidance using ultrasonography (usg) guidance. local anesthesia is usually enough in most cases of spc insertion except some special circumstances, like in patients with spinal cord injuries, in which general or regional anesthesia is indicated (1). additionally, in uncooperative or agitated patients, sedation might be necessary along with local anesthesia (2). although the spc is a safe procedure, it is not devoid of complications such as site bleeding, catheter blockade, malpositioning, dislodgment, or bowel injury. bowel perforation is the most dreaded complication of spc insertion with an incidence rate of 2.4 to 2.7% in two 101archivio italiano di urologia e andrologia 2013; 85, 2 case report iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (spc) insertion and its laparoscopic management rakesh rajmohan, bernardo aguilar-davidov, theodoros tokas, jens rassweiler, ali serdar gözen department of urology, slk-kliniken, university of heidelberg, heilbronn, germany. suprapubic cystostomy (spc) is commonly used, instead of indwelling urethral catheterization, as indicated in many pathological conditions. although considered to be a safe procedure that can be easily performed in an outpatient basis several complications have been reported in international literature. bowel injury can be a serious complication with the small intestine affected in the majority of cases. we present a case of an accidental rectal injury by a suprapubic catheter misplacement, in a 76 year old demented patient with prostatic hyperplasia and chronic urinary retention. the injury was confirmed by cystography and injection of contrast meterial through the suprapubic catheter, and successfully treated laparoscopically by an extraperitoneal approach. the patient was discharged after 10 days without any complications. the above method, in experienced hands, can be an effective primary treatment option for such rare but devastating complications. the case and management is unique as, to our knowledge, as no similar cases have been presented. key words: suprapubic cystostomy (spc); ultrasonography (usg); benign prostatic hyperplasia (bph). submitted 11 february 2013; accepted 30 april 2013 no conflict of interest declared summary different series (3, 4), the most commonly affected part is the small bowel and several cases have been reported (5, 6). in contrast, only a single case of rectal injury has been reported in international literature (7). it is of utmost importance to recognize a bowel injury immediately, since primary repair represents the best therapeutic option (8, 9). laproscopic radical prostatectomy is a well established operative therapy for localized prostate cancer in the era of minimally invasive surgery. rectal injuries during laparoscopic radical prostatectomy can be managed successfully intraoperatively without requiring any conversion to open surgery (10, 11). we present a case of rectal injury during spc insertion, as well as its subsequent management by laparoscopy using an extra peritoneal approach. its presentation and successful management is unique as, to our knowledge, as no similar cases have been presented. rajmohan_stesura seveso 24/06/13 11:09 pagina 101 archivio italiano di urologia e andrologia 2013; 85, 2 r. rajmohan, b. aguilar-davidov, t. tokas, j. rassweiler, a. serdar gözen 102 pyrexia during the first two days. the parenteral antibiotic combination was administered for 7 days and the total parenteral nutrition for 5 days. the drain and rectal tube was removed on 3rd and 5th. postoperative day respectively. the patient was discharged on the 10th day. discussion supra pubic cystostomy using a punch trocar, with localization of the bladder by palpation, is a well established interventional procedure for urinary drainage. the technique is usually safe when done in a well distended bladder. it is never a safe method to do, in a non distended bladder, or when bladder cannot be distended adequately, to a minimum of 300 ml of urine (12). it may not be feasible to fill the bladder adequately in some cases of neurogenic bladder due to low capcity or incontinence. there are safer techniques described for complicated cases, like using the lowsley retractor (13), seldinger technique with a peel away sheath introducer (14) or image guidance using usg (15) or fluroscopy (16). abdominal wall adhesions can be found in up to 59% of patients with previous midline laparotomy scars (17). in such cases with history of previous abdominal surgery open spc insertion is a safer option (1). usg guidance is advisable for safety, even in cases with adequate bladder distention, since there is always a risk of deep peritoneal fold or adhesions, as seen in patients with previous abdominal surgery. in one study by levrant et al., it was noted that when the distance between the upper border of the pubic symphysis and the umbilicus is less than 19 cm, there is a high risk for bowel inter positioning at spc trocar site due to deep peritoneal folding (18). the seldinger technique using a peel away trocar under local anesthesia is a safe method when a minimal bladder distention of 300 ml is achieved and none of the aforementioned risk factors are present (19). another key factor for a safe spc insertion is an adequate anesthesia, so that the patient should be comfortable and stable during the procedure. although different methods like general anesthesia and regional anesthesia have been used for spc insertion, the most preferred choice is local anesthesia. a sedo-analgesia, a technique combining adequate local anaesthesia with sedation, is recommended, especase report a 76 year old patient with bph and chronic urinary retention was under chronic indwelling urethral catheter, since he was unsuitable for definite operative treatment due to co-morbidities like senile dementia, diabetic neuropathy, coxarthrosis, osteoporosis and poor general heath. an insertion of a spc was decided due to recurrent urinary tract infections and urethral discomfort. an elective spc insertion, under local anesthesia, using a 12 f catheter through a punch trocar was performed in an outpatient basis. after filling the bladder with 300 cc saline, a 12 fr catheter was introduced under local anesthesia through a punch trocar. no ultrasound guidance was used. due to senile dementia the patient was uncooperative and moving during the procedure. the spc did not function satisfactorily after placement and a feculent catheter discharge was noted. the patient was admitted to our department immediately thereafter. cystography was done after reintroducing the urethral catheter, which showed an intact bladder outline with spc outside the bladder. when contrast was injected through the spc, it filled the rectal lumen without signs of extravasation (figure 1). we decided to perform a primary repair of the rectum using our described five port laparoscopic extraperitoneal approach as in our extraperitoneal laparoscopic radical prostatectomy technique under general anesthesia (14). a preoperative broad-spectrum intravenous antibiotic combination consisting of ceftriaxone and metronidazole was administered. a cautious dissection, initially around the spc and then downwards, following the catheter towards the rectum, was performed. the cystography findings were confirmed intraoperatively, with the bladder wall being almost intact and the spc placed directly into rectum (figure 2). two stay sutures were placed on the rectal wall, after an adequate dissection, and the catheter was removed. the rectum was then closed in 3 layers, with interrupted 3/0 vicryl sutures followed by a running 3/0 v-loc suture, and tested for the absence of leakage. finally, a drain was left in place and a rectal tube was placed. the patient was kept on intensive care unit for 2 days and the postoperative course was uneventful apart from mild figure 1. figure 2. rajmohan_stesura seveso 24/06/13 11:09 pagina 102 103archivio italiano di urologia e andrologia 2013; 85, 2 iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (spc) insertion and its laparoscopic management catheterisation: clinical outcome and satisfaction survey. spinal cord. 1998; 36:171-176. 5. noller kl, pratt jh, symmonds r. bowel perforation with suprapubic cystostomy. report of two cases. obstet gynecol. 1976; 48:675-695. 6. cundiff g, bent ae. suprapubic catheterization complicated by bowel perforation. int urogynecol j pelvic floor dysfunct. 1995; 6:110-113. 7. ahmed sj, mehta a, rimington p. delayed bowel perforation following suprapubic catheter insertion. bmc urol. 2004; 4:16-18. 8. bostick pj, johnson da, heard jf, et al. management of extraperitoneal rectal injuries. j natl med assoc. 1993; 85:460-463. 9. gümüs m, böyük a, kapan m, et al. unusual extraperitoneal rectal injuries: a retrospective study. eur j trauma emerg surg. 2012; 38:295-299. 10. rassweiler j, schulze m, teber d, et al. laparoscopic radical prostatectomy with the heilbronn technique: oncological results in the first 500 patients. j urol. 2005; 173:761-764. 11. guillonneau b, gupta r, el fettouh h, et al. laparoscopic management of rectal injury during laparoscopic radical prostatectomy. j urol. 2003; 169:1694-1696. 12. k. albrecht, oelke m, schultheiss d, tröger hd. the relevance of urinary bladder filling in suprapubic bladder catheterization. urologe. 2004; 43:178-183. 13. zeidman ej, chiang h, alarcon a, raz s. suprapubic cystostomy using lowsley retractor. urology. 1998; 32:54-55. 14. o’brien wm. percutaneous placement of a suprapubic tube with peel away sheath introducer. j urol. 1991; 145:1015-1016. 15. røhl l, rasmussen os. ultrasound-guided percutaneous suprapubic cystostomy. eur j ultrasound. 1997; 6:57-61. 16. lee mj, papanicolaou n, nocks bn, et al. fluoroscopically guided percutaneous suprapubic cystotomy for long-term bladder drainage: an alternative to surgical cystotomy. radiology. 1993; 188:787-789. 17. levrant sg, bieber ej, barnes rb. anterior abdominal wall adhesions after laparotomy or laparoscopy. j am assoc gynecol laparosc. 1997; 4:353-356. 18. cho kh, doo sw, yang wj, et al. suprapubic cystostomy: risk analysis of possible bowel interposition through the percutaneous tract by computed tomography. korean j urol. 2010; 51:709-712. 19. morey af, iverson aj, swan a, et al. bladder rupture after blunt trauma: guidelines for diagnostic imaging. j trauma. 2001; 51:683-686. 20. khan a, abrams p. suprapubic catheter insertion is an outpatient procedure: cost savings resultant on closing an audit loop. bju int. 2008; 103:640-644. cially in case of uncooperative or agitated patients to ensure patient safety during the procedure (2). when the patient is restless during a punch trocar spc insertion without image guidance and adequate sedation, the procedure is always complicated. in this case the patient moved during the trocar insertion which, most probably, resulted in an accidental placement of the spc to the rectum. it may have been avoidable if he was adequately sedated and stabilized. murphy’s law “if anything can go wrong, it will”, explains that complications like these can occur even in ideal conditions. those who are doing these procedures should be vigilant and aware of these potential complications. if any misplacement or iatrogenic injury is suspected, imaging modalities like usg, cystogram, catheterogram, or flexible cystoscopy may be useful. in doubtful cases computer tomography or mri can be performed (19). we have performed usg, cystogram, catheterogram to localize the spc. in case of an iatrogenic rectal injury, a primary repair with or without diversion is the treatment of choice. in extraperitoneal injuries a diversion colostomy is not usually necessary. open surgery has been the treatment of choice in such cases, presenting good results (8, 9). laparoscopic repair has proven to be effective in intraoperative rectal injuries during laparoscopic radical prostatectomy (lrp) (10, 11). since our department is a high volume laparoscopic center, where the extraperitoneal approach for lrp is routinely performed, we could manage this case laparoscopically. the extraperitoneal approach allowed an adequate primary repair of the rectal injury without intraperitoneal contamination. previous papers present good results using a double-layered closure of the rectal wall. in this case we have performed a 3 layer closure reinforced by a 3rd layer with a v-loc barbed suture, which resulted in an uneventful recovery. conclusion image guidance; adequate anesthesia and stabilization of the patient are key factors for a safe spc placement in complicated cases. in case of an iatrogenic rectal injury, early recognition is of utmost importance and primary repair without diversion is the treatment of choice. laparoscopic extraperitoneal surgery, in experienced hands, is an effective minimal invasive treatment option. references 1. harrison scw, lawrence wt, morley r, et al. british association of urological surgeons’ suprapubic catheter practice guidelines. bju int. 2010; 107:77-85. 2. birch br, anson k, gelister j, et al. the role of midazolam and flumazenil in urology. acta anaesthesiol scand suppl. 1990; 92:25-32. 3. ahluwalia rs, johal n, kouriefs c, et al. the surgical risk of suprapubic catheter insertion and long-term sequelae. ann r coll surg engl. 2006; 88:210-213. 4. sheriff mk, foley s, mcfarlane j, et al. long-term suprapubic correspondence rakesh rajmohan, md, ms, mch bernardo aguilar-davidov, md theodoros tokas, md jens rassweiler, md ali serdar gözen, md, febu (corresponding author) asgozen@yahoo.com department of urology, slk-kliniken heilbronn am gesundbrunnen 20-26 d-74078 heilbronn, germany rajmohan_stesura seveso 24/06/13 11:09 pagina 103 stesura seveso 135archivio italiano di urologia e andrologia 2014; 86, 2 note on surgical technique pseudo-capsule “coffin effect”: how to prevent penile retraction after implant of three-piece inflatable prosthesis enrico caraceni 1, lilia utizi 2, giovanni angelozzi 3 department of urology, civitanova marche hospital, italy. objective: following three-component implantation of a penile prosthesis, some patients are dissatisfied with their penile length. this may be due to the procedure by itself or pre-existing risk factors or psychological reasons. we supposed that formation of a restricted pseudo-capsule due to a late prosthesis activation can inhibit later system expansion. we aimed to identify the presence or absence of penile retraction after implant and to prevent it by immediate prosthesis activation after implantation. material and methods. forty-six patients operated with three-piece inflatable penile prosthesis (ams 700 cx o lgx) were enrolled. in 27 patients prosthesis was first activated four weeks after surgery (nea group) and in 19 patients prosthesis was activated immediately after surgery (dea group). length and girth of the penis was evaluated before (in dea group) and after the surgical procedure. results. the average post implant dorsal length of the erect penis in group nea was found 3.28 cm shorter than in group with early activation (dea). in dea group there was no lenght difference between pre-operative stretching (14.57 cm) and post operative erection (14.98 cm). when early activation was not performed, the clinical result was a smaller penis in erect phase. conclusion. reduced lenght of the penis after implantation can be caused by the presence of a pseudo-capsule that limits the elongation of the prosthesis and of the penis (“coffin effect”). timing of first activation seems to be the key in order to prevent the risk of penile retraction after implantation. early activation is identified as the best measure to maintain the length of the pre implant erect penis after the prosthetic hydraulic implant. key words: penile prosthesis length; penile retraction; early activation; lgx penile prosthesis; ams 700 cx penile prosthesis; coffin effect, three piece penile prosthesis; size of the penis; shortening of the penis. submitted 23 december 2013; accepted 29 march 2014 summary no conflict of interest declared pointment can be severe and in some cases can lead to loss of use of the prosthesis even when it is working well. first montorsi et al. in 2000 (4) reported that about 30% of patients complained a decrease in penile size after three-piece prosthesis implantation. the authors explained the finding as follows: this dissatisfaction is linked with the loss of engorgement of the glans or to the recall of the natural preexisting erection, or to the pre-operatory penis size loss. deveci et al. in 2007 (5) wrote there were no statistically significant differences in penile length after the surgery compared to preoperative measurements in a group of 56 patients affected of erectyle dysfunction (ed) of various nature, excluding peyronie’s disease. patients had the penile length measured at the beginning of the operation prior to device implantation (stretched flaccid length), and at 1 and 6 months postoperatively (dorsal length with activated prosthesis). length was measured from the pubic bone to meatus along the dorsum of the shaft. they did not find significative difference in preoperative stretched penis and postoperative penile length with the activated device. in their experience about two of three patients (72%) surprisingly complained decreased in penile length. they explained that this feeling might be related to a comparison with their penile length before the onset of ed, or to pre-implant penile length reduction related to radical prostatectomy or other penile fibrotics changes. they concluded that patient and partner education from the beginning may limit unrealistic expectations after implantation. patient should be advised that penile implants may not restore the full length once achieved by natural erections. treatment satisfaction appears not to be fully dependent on subjective penile length and then the failure in sizing (told by 72% of their patients) is not real but subjective. montague (6) in 2007 published a review of literature on the penis size matter after penile implants. he recognized that it is likely that inflatable penile prosthesis implantation does not provide a prosthetic erection quite as long as a natural erection. he believed that the loss of penile sizing could be attributed to the fact that prosthetic erection does not include glans tumescence or to penile retraction due to preoperatory factors, like radical prostatectomy. however, he concluded it is necessary to speak to the patient telling him: “your preoperative doi: 10.4081/aiua.2014.2.135 introduction following implants of a penile prosthesis some couples are dissatisfied with penile length and girth (1-3). this may be one reason for implant dissatisfaction: disaparchivio italiano di urologia e andrologia 2014; 86, 2 e. caraceni, l. utizi, g. angelozzi 136 stretched penile length will approximately be like your erect length after prosthetic surgery”. shaeer et al. (7) in a recent paper published in sexual medicine in 2010 about his surgical technique to improve penile size after inflatable prosthesis implantation, classified the possible causes of the loss of penis size after implantation. they wrote “decrease in size may sometimes be a mental impression due to unrealistic expectations, poor counseling, or dysmorphophobia”. alternatively, diminished phallic size may be real and due to the inherent nature of the procedure or to a preexisting pathology. the latter includes cases of fibrosis following radiotherapy, neglected priapism, and peyronie’s disease, all of which exhibit shortening and/or narrowing, or cases with overhanging suprapubic fat leading to concealment. in such cases, diminished size is not a result of the procedure itself, but rather due to an ignored preexisting complaint of undersized phallus, shadowed by erectile dysfunction (ed), a complaint that the physician failed to recognize and address. on the other hand, actual diminution in size may be iatrogenic, caused by the procedure itself. shaeer and al recognized that there is a real loss of penis size after implantation techniques and proposes expansion to correct the defect and improve patient and partner’s satisfaction. however, he lacked the demonstration of his statements about the real loss in size after installation. his work is only about the surgical technique to supersize the penis following penile prosthesis implantation. levine and rybak in 2011 (8) concluded that there is not recognised reliable technique to gain length once the device is placed and proposed the use of external traction therapy prior to inflatable penile prosthesis placement to solve the problem. moskovic (9) obtained the same results in a case treated using the same method of levine. finally, other authors proposed preoperatory vacuum device treatment (10, 11). we believe the loss of length and girth of the penis after prosthetic hydraulic implant is a multi-factorial phenomenon: preexisting factors like obesity, penile fibrosis (post priapism or post induratio penis plastica), pelvic surgery (radical prostatectomy, cystectomy or abdominal amputation of the rectus) can reduce “per se” penile size (12, 13), but in addition to these factors pseudo-capsule formation could play an important role in reducing the penis after implant. in fact in case of late activation of the prosthetic device a pseudo-capsule can form around the deactivated empty implant that is smaller in size with respect to the fully activated implant. when the prosthesis is activated after three or four weeks, as recommended by the manufacturers (14, 15), it cannot expand further due to the resistance of pseudo-capsule, which is so far fully formed. in other words the pseudo-capsule prevents the full prosthesis expansion, thus determining a reduction of the true size of the penis working like an inextensible wall. we have called this phenomenon “coffin effect” of pseudo capsule. the “coffin effect” should be added to other predisposing factors of penile size reduction and it is always present. if the prosthesis is not left inflated immediately after the surgery and for subsequent two or three weeks the result will be a smaller penis with similar dimensions to the non activated prosthesis. aim of this study was to identify the presence or absence of penile retraction after implant with three-component prosthesis and to evaluate the possibility to prevent it by immediate activation of the prosthesis after the surgical procedure without use of other device or other surgical strategies before or after the operation (16-19). conclusions according to our observations we confirmed the occurrence of a “true” penile shortening after prosthetic implant (11.70 cm in the nea group). this can be caused by the formation of a pseudo capsule, that develops around the non activated implant that acts as a “wall” that subsequently prevents the prostesis expansion and the potential elongation of the penis after implantation. the pseudo capsule limits the dimension of the penis and the prosthesis can only move like a “sliding door” inside it forward during activation and backward when it is deactivated. the result is a larger penis in flaccid state but smaller in erect phase expecially when early activation was not performed. the implant can work like an expander, if well used, but the size of the penis is limited by the pseudocapsule. this “coffin effect” explains the retraction and the lower elasticity of the penis that can occur after implantation as a consequence of the formation of the pseudo capsule. the decreased elastic capacity of the penis after penile prosthesis implantation involves a lower difference between penile length in flaccid and erect state and larger length and girth of the flaccid penis. this is confirmed by the observation that early activation as an effective measure to prevent penile shortening after implantation. lgx implant can improve the length (15.35 in dea group versus 11.90 in nea group) and girth (12.43 in dea group versus 11.90 in nea group) of the penis only if early activated. in conclusions early activation is a measure to prevent the loss of length of the erect penis after implantation. materials and methods, results, tables and discussion are fully described in supple mentary materials posted on www.aiua.it length preoperative girth preoperative (available with fic in 12 patients, with str. in 14 patients) group δ δ1 ici str 2.61 3.23 dea (lgx and cx) 2.75 length postoperative girth postoperative group �δ �δ1 nea (lgx and cx) 1.55 1.02 dea (lgx and cx) 1.65 1.69 table. penile elasticity (δ and δ 1). references 1. candela jv, hellstrom wj. three-piece inflatable penile prosthesis implantation: a comparison of the penoscrotal and infrapubic surgical approaches. j la state med soc. 1996; 148:296-301. 2. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. adv urol. 2012; 2012:707321. 3. trost lw, baum n, hellstrom wj. managing the difficult penile prosthesis patient. j sex med. 2013; 10:893-906. 4. montorsi f, rigatti p, carmignani g, et al. ams three-piece inflatable implants for erectile dysfunction: a long-term multi-institutional study in 200 consecutive patients. eur urol. 2000; 37:50-55. 5. deveci s, martin d, parker m, mulhall jp. penile length alterations following penile prosthesis surgery. eur urol. 2007; 51:1128. 6. montague dk. penile prosthesis implantation: size matters. europ urol. 2007; 51:887-888. 7. shaeer o. supersizing the penis following penile prosthesis implantation. j sex med. 2010; 7:2608-16. 8. levine la, rybak j. traction therapy for men with shortened penis prior to penile prosthesis implantation: a pilot study. j sex med. 2011; 2112-7. 9. moskovic dj, pastuszak aw, lipshultz l, khera m. revision of penile prosthesis surgery after use of the penile traction therapy to increase erect penile length: case report and review of the literature. j sex med. 2011; 8:607-11. 10. raheem aa, garaffa g, raheem ta, et al. the role of vacuum pump therapy to mechanically straighten the penis in peyronie's disease. bju int. 2010; 106:1178-80. 11. soderdahl dw, petroski ra, mode d, et al. the use of an external vacuum device to augment a penile prosthesis. tech urol. 1997; 3:100-2. 12. montague dk, angermeier kw. increasing size with penile implants. curr urol rep. 2008; 9:483-486. 13. sansalone s, garaffa g, djinovic r, et al. simultaneous total corporal reconstruction and implantation of a penile prosthesis in patients with erectile dysfunction and severe fibrosis of the corpora cavernosa. j sex med. 2012; 9:1937-44. 14. american medical system (ams). available at the website: http://www.americanmedicalsystems.com 15. henry gd, brinkman mj, mead sf, et al. a survey of patient with inflatable penile prostheses: assessment of timing and frequency of intercourse and analysis of implant durability. j sex med. 2012; 9:1715-21. 16. borges f, hakim l, kline c. surgical technique to maintain penile length after insertion of an infatable penile prosthesis via infrapubic approach. j sex med. 2006; 3:550-3. 17. henry g, houghton l, culkin d, et al. comparison of a new length measurement technique for inflatable penile prosthesis implantation to standard techniques: outcomes and patient satisfaction. j sex med. 2011; 8:2640-6. 18. hakky ts, suber j, henry g, et al. penile enhancement procedures with simultaneous penile prosthesis placement. adv urol. 20123; 314-612. 19. rolle l, ceruti c, timpano m, et al. a new, innovative, lengthening surgical procedure for peyronie’s disease by penile prosthesis implantation with double dorsal-ventral patch graft: the “sliding technique”. j sex med. 2012;9:2389-95. 137archivio italiano di urologia e andrologia 2014; 86, 2 early activation to prevent penile retraction after prosthesis implant correspondence enrico caraceni, md director of department of urology civitanova marche hospital civitanova marche, italy ecarace@libero.it lilia utizi, clinical psychologist (corresponding author) sexual behavior consultant department of urology civitanova marche hospital civitanova marche, italy l.utizi@libero.it. giovanni angelozzi, md department of urology civitanova marche hospital civitanova marche, italy giovauro@yahoo.it archivio italiano di urologia e andrologia 2013; 85, 278 introduction modern medicine uses increasingly innovative techniques that require more and more capabilities in order to be acquired. consequently an objective is try to make easier the surgical technique to better manage the surgical procedure and consequently the postoperative patient's course. technical training in any surgical procedure involves three elements: didactic learning, supervised hands-on training and unsupervised experienced. original paper resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure alessandro del rosso, stefano masciovecchio, giuseppe paradiso galatioto, carlo vicentini university of l’aquila, department of health science, mazzini hospital, urology department, teramo, italy. introduction: modern medicine uses increasingly innovative techniques that require more and more capabilities for acquisition. in the urological department is increasing the presence of patients with lower urinary tract symptoms (luts) and transurethral resection of the prostate (turp) is the standard of care in their surgical treatment. we report our surgical experience and learning curve of using bipolar plasmakinetic devices in the training of urological residents to benign prostatic hyperplasia (bph) treatment. materials and methods: 80 patients with benign prostatic enlargement due to bph were enrolled in the study. turp has been performed by three urological residents and by an experienced urologist. patients were evaluated before and 6 months after the endoscopic bipolar plasmakinetic resection using the international prostate symptom score (ipss), maximum urinary flow rate (qmax), postvoid residual urine (pvr) and prostate specific antigen (psa). results: overall 60 procedures were performed, 18 plasmakinetic (pk)-turp procedures were completed by the three residents. in the other 42 cases the procedures were completed by the experienced urologist. in eight cases there was a capsular perforation and the experienced urologist replaced the resident to complete the resection. no complications have been reported in the procedures completed by the senior urologist. all complications caused by the residents were managed intraoperatively without changing the course of the procedure. statistical differences were observed regarding ipss, quality of life (qol), and pvr at 6-month follow-up when procedures completed by urological residents were compared to those completed by the senior urologist. conclusion: bipolar device represents appropriate tools to acquire endoscopic skills. it is safe and it can be used at the first experience of bph treatment by a resident who has not previously approached this endoscopic surgical procedure. key words: bph; resident; surgical skills; turp. submitted 5 october 2012; accepted 31 december 2012 no conflict of interest declared summary the current organization of university departments and the new standards require that the trainees may demonstrate at least the minimum standards of competence. this would be to ensure uniform standards of training and allow comparisons among different institutions (1). in the urological departments is increasing the affluence of patients with lower urinary tract symptoms (luts) and benign prostatic hyperplasia (bph) parallel to the del rosso_stesura seveso 24/06/13 11:27 pagina 78 79archivio italiano di urologia e andrologia 2013; 85, 2 resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure gation. after the introduction of the resectoscope, the surgeon always provided to mark the ureteral orifices. the incision at 6 o’clock position was the first step of the endoscopic procedure with a cut extended from bladder neck to the veru montanum, deep to the surgical capsule. thereafter the incision at the 12 o’clock position was performed, involving a 180° rotation of the sheath being careful to the adequate depth and length of the incision. finally we proceeded to resection of the prostatic lateral lobes. at the end of the procedure a 20 ch 3-way catheter was inserted. postoperatively a continuous saline bladder irrigation was used until the efflux was sufficiently clear, with subsequent catheter removal and patient discharge when urine were clear. residents training prior to perform endoscopic procedures in the operating room, the urological residents were given didactic lessons on the surgical technique at an academic teaching hospital (3). following these lessons, the residents practiced the surgical device and, once the attending surgeon determined that the residents were able to perform the procedure safely, they performed a surgical endoscopic resection on the patient in the operating room, always with the senior urologist supervision. results baseline and immediate postoperative parameters are reported in table 1. all patients completed the sixmonths follow-up. overall 80 procedures performed, the three residents completed a mean of 6 pk-turp for each one, without any intervention of the experienced urologist, but only with his supervision. in the first 14 cases for each resident, the procedures were completed by the experienced urologist due to different reasons (loss of orientation, low speed of resection, bleeding, capsular perforation). out of all the endoscopic pkturp treatments, a capsular perforation was observed in increase of the age of patients. the impact on quality of life (qol) and health care cost justifies additional research about the use of therapeutic resources. transurethral resection of the prostate (turp) is the standard of care in surgical management of luts due to bladder outlet obstruction for prostate of 30-80 ml (2). different type of resectoscope are actually available, roughly divided in monopolar and bipolar devices. today is currently more widespread the use of the bipolar plasmakinetic (pk) turp that appears to offer many advantages compared to the monopolar resection. we report here our surgical experience and learning curve of using bipolar plasmakinetic devices in the training of urological residents for bph treatment. materials and methods patients from january 2009 to august 2011, a total of 80 patients with benign prostatic enlargement due to bph were enrolled in the study. all patients undergo pkturp. the study included all patients candidates for transurethral resection with a prostate volume at least of 80 ml, luts causing a ipss of 15 or greater, qol index of 2 or greater and qmax less than 15 ml/s. all patients were older than 50 years with symptomatic benign prostatic hyperplasia of at least 3-months duration of and who did not benefit of medical therapy with persistence or progression of urinary symptoms. exclusion criteria included patients with urinary tract infections and patients who reported a neurogenic bladder dysfunction, abnormal digital rectal examination (dre) findings or known prostate cancer, previous prostatic or urethral surgery or bladder stones. written informed consent has been obtained from all subjects. anticoagulant drugs have been discontinued at least 7 days before surgery. patients were evaluated before and 6 months after the endoscopic resection using the ipss bother score, the measurements of the qmax, pvr and psa. we reported the experience and technical progress in treating patients with the plasmakinetic bipolar endoscopic device and evaluated the difficulties in carrying out the surgical procedures, considering patients outcome in the immediate postoperative and after six-months follow-up. spss for windows (version 10.0.7) computer package was used for statistical analysis of the data. the wilcoxon test was used and p < 0.05 was considered as a level of statistical significance. surgical technique all the procedures were performed under spinal anesthesia, in lithotomic position and after a preoperative antibiotic prophylaxis. the endoscopic procedures were performed by three urological residents (20 procedures for each) and an experienced urologist (20 procedures). pk-turp has been performed using the gyrus plasmakinetic tissue management system (gyrus medical ltd., cardiff, uk) with a 27 ch continuous flow resectoscope and a u-shaped cutting loop. once connected, the generator was automatically set to 160 w for cutting and 80 w for coagulation. saline solution was used for irrimean range age (years) 66.3 51-78 total prostate volume (g) 51.6 32-68 transitional zone volume (g) 28.5 18-44 resection time (min) 55 26-105 resection weight (g) 31 22-40 preoperative psa (ng/ml) 3.45 0.8-6.3 preoperative mean qmax (ml/s) 7.2 2.6-12.4 preoperative mean pvr (ml) 160 50-280 catheterization time (day) 2.4 2-4 hospital stay (day) 3.2 3-5 hemoglobin decrease (g/dl) 1.7 0.7-2.7 blood transfusion none tur syndrome none table 1. baseline and immediate postoperative parameters of the patients. del rosso_stesura seveso 24/06/13 11:27 pagina 79 archivio italiano di urologia e andrologia 2013; 85, 2 a. del rosso, s. masciovecchio, g. paradiso galatioto, c. vicentini 80 all professionals (1). although didactic training methods can accelerate the evolution of procedural skills, they cannot substitute the other elements, considering the hands-on experience through which technical skills, including three-dimensional awareness and hand-eye coordination, develop (5, 6). currently, the most frequently used models are the synthetic organ models for ureterorenoscopy and transurethral resection of the prostate. however the use of these tools has a limited value due to the lack of bleeding and the unrealistic force feedback. furthermore local and national regulation in relation to the use of animal organs in the hospital and use of instruments in animal urinary tracts must be also considered. as a consequence the main way to gain experience remains the real contact with the patient and the surgical treatment of his pathology (7). currently bph is one of the most common disease that affect men beyond middle age and turp is the standard of care in the surgical management of luts due to bladder outlet obstruction. regarding this endoscopic procedure, significant technical improvements during the past 15 years have been introduced and the bipolar technology has become a safe and effective procedure in alternative to conventional monopolar turp (8). our training course allowed us to learn and approach the endoscopic surgical technique with the new endoscopic modern devices. our data showed that there is a greater ease of training with the bipolar instrument, also confirmed by the increasing number of resections that have been completed by the residents alone with onlly supervision of an expert. in addition, only minor complications occurred during the endoscopic procedures confirming the easier handling for the pk device. in fact the learning curve seems to confirm that already an approximate number of about 20 procedures resulted in a good capacity of surgical management. in fact the latest procedures of this series were substantially completed by the residents who could complete them autonomously, although under the supervision of an experienced urologist. a six-months follow-up, although still limited, seems adequate to confirm the success of the procedure even in cases in which the resident has completed the eight cases. in these cases, the experienced urologist replaced the resident in order to complete the resection (table 2). all the complications caused by the residents were managed intraoperatively without changing the course of the procedure. comparing endourological procedures carried out by the resident alone with those performed by the senior urologist, the latter showed no problems or complications of the resection. mean catheterization time was 2.4 days in the pk-turp and mean hospital stay was 3.2 days. no cases of tur syndrome have been observed. considering the immediate postoperative and 6 months follow-up, in all cases there was a normal course of the patient both in the time of catheterization that in hospitalization. after 6 months, comparing the three groups: 1) procedures not completed by the resident, 2) procedures completed alone with supervision and 3) procedures completed by the experienced urologist, qmax value was significantly different between group 1 and 3 (p < 0.05), no significant differences have been reported between the other two groups. no differences were observed regarding ipss, qol, pvr and preoperative and postoperative 6-months psa. moreover, we report significant differences (p < 0.05) in the resected weight between group 2 and group 3. discussion endourology is one of the most difficult techniques to learn. safe and effective performance of diagnostic and therapeutic endourological procedures requires longterm practical experience. training opportunities for residents and urologists are the way to increase their experience in the surgical approach (4). as just reported, the technical training in any procedure involves three elements: 1) didactic learning, 2) supervised hands-on training and 3) unsupervised experience. obviously the third parameter continues throughout the individual professional career, and so, the first two elements are basic for proper growth of a resident. nowadays, the standardization of education is increasingly important for the education of procedures not completed procedures completed procedures completed by residents alone by residents alone (with supervision) by experienced urologist group 1 group 2 group 3 no. of procedures 42/60 (70%) 18/60 (30%) 20/20 (100%) capsular perforation 3/60 (5%) 5/60 (8.3%) 0/20 (-) mean qmax, ml/s* 20.1 (15.3-26.2) 22.7 (17.4-32.6) 25.6 (19.5-34.2) mean ipss 2.8 (1-3) 3.1 (2-3) 2.8 (2-3) mean qol 2.3 (1-3) 2.4 (1-3) 2.2 (0-3) mean pvr, ml 15 (0-40) 20 (0 -50) 10 (0-30) mean psa, ng/ml 1.5 (0.4-2.3) 1.5 (0.9-2.1) 1.2 (0.6-1.7) mean resected weight (g)** 32 (27-38) 27 (22-36) 42 (28-48) table 2. perioperative, immediate complications and postoperative characteristics at 6-months follow-up of the different type of procedures and surgeon. * p < 0.05 group 1 vs group 3; ** p < 0.05 group 2 vs group 3. del rosso_stesura seveso 24/06/13 11:27 pagina 80 81archivio italiano di urologia e andrologia 2013; 85, 2 resident training in urology: bipolar transurethral resection of the prostate a safe method in learning endoscopic surgical procedure resection alone by himself, without needing any direct aid for proper management of the endoscopic procedure. clearly, results cannot be comparable to the surgical management obtained by an experienced urologist, because significant differences in terms of mean qmax and resected weight were observed between the procedures entirely performed by residents and those performed by an experienced urologist. these results suggests that the bipolar resector seems to be a good tool for training because it is easy to handle and speeds the learning process. conclusions in our experience, bipolar devices represent a very important and appropriate way to acquire the endoscopic skills. it is possible to use this endoscopic device by residents even at their first experience of bph treatment. references 1. le cq, lightner dj, vanderlei l, et al. the current role of medical simulation in american urological residency training programs: an assessment by program directors. j urol. 2007; 177:288-91. 2. yu x, elliott sp, wilt tj, et al. practice patterns in benign prostatic hyperplasia surgical therapy: the dramatic increase in minimally invasive technologies. j urol. 2008; 180:241-5. 3. alley jr, stucky cc, moncure m. teaching surgical residents dome-down laparoscopic cholecystectomy in an academic medical center. j soc laparoendoscopic surg. 2008; 12:368-371. 4. schreuder hw, oei g, maas m, et al. implementation of simulation in surgical practice: minimally invasive surgery has taken the lead: the dutch experience. med teacher. 2011; 33:105-15. 5. el-hakim a, elhilali mm. holmium laser enucleation of the prostate can be taught: the first learning experience. bju international. 2002; 90:863-869. 6. kössi j, luostarinen m. virtual reality laparoscopic simulator as an aid in surgical resident education: two years’ experience. scand j surg. 2009; 98:48-54. 7. rodríguez-sanjuán jc, palazuelos cm, fernández-díez mj. et al. assessment of resident training in laparoscopic surgery based on a digestive system anastomosis model in the laboratory. cir esp. 2010; 87:20-25. 8. rassweiller j, schlze m, stock c, et al. bipolar transurethral resection of the prostate-technical modifications and early clinical experience. minim invasive ther allied technol. 2007; 16:11-21. correspondence alessandro del rosso, md (corresponding author) delrossoa@tiscali.it stefano masciovecchio, md giuseppe paradiso galatioto, md carlo vicentini, md mazzini hospital, department of urology, italy square, teramo, italy del rosso_stesura seveso 24/06/13 11:27 pagina 81 archivio italiano di urologia e andrologia 2016; 88, 2128 original paper a survey on the experience of 136 italian urologists in the treatment of erectile dysfunction with pde5 inhibitors and recommendations for the use of avanafil in the clinical practice vincenzo mirone 1, ferdinando fusco 1, fabio parazzini 2, alessandro zucchi 3 1 dipartimento ostetricia, ginecologia, urologia clinica urologica università di napoli federico ii, italy; 2 i clinica ginecologica, fondazione irccs ca' granda, ospedale maggiore policlinico, università di milano, italy; 3 clinica urologica ed andrologica, università di perugia, italy. introduction: pde5 inhibitors are the firstline treatment for erectile dysfunction. although all these drugs share the same mechanism of action, each agent could have different characteristics in terms of selectivity, pharmacokinetics and tolerability profile. materials and methods: this manuscript illustrates a project, undertaken by the italian society of urology in order to obtain a “snapshot” of the experience of italian urologists with the use of pde5 inhibitors in the clinical practice. this project included a survey, targeting a sample of 136 italian urologists experienced in the treatment of ed, and the organization of a conference of experts who, based on the findings of the survey, the scientific literature and the clinical experience, would define some recommendations for the use of pde5 inhibitors in clinical practice with a particular focus on avanafil, the most recent drug in this class. results: the following recommendations on the use of avanafil were issued: 1) in patients who are candidates for the use of avanafil, it is advisable to use the 200-mg dose from the first administration; 2) when used at the highest dose (200 mg), avanafil shows a favourable tolerability profile with an efficacy similar to that of other agents; 3) the patient should be instructed to take avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal; 4) the efficacy window of avanafil is between 30 minutes and 6 hours after dosing, which qualifies this molecule as a new drug with an intermediate duration of action; 5) avanafil at a dose of 50-100 mg/day may be a therapeutic option in chronic rehabilitation. conclusions: among pde5 inhibitors, avanafil is a new agent with an intermediate duration of action, characterized by high efficacy and good tolerability even at the highest dose (200 mg). key words: erectile dysfunction; pde5 inhibitors; avanafil; italian survey; recommendations; dosage. submitted 1 june 2016; accepted 10 june 2016 summary no conflict of interest declared. tion with a high prevalence worldwide; it has been estimated that 5-20% of men are affected by moderate-tosevere ed at some time during their sexual life (1). the introduction in the clinical practice of phosphodiesterase type 5 inhibitors (pde5is), in the early 1990s, represented a milestone in the treatment of ed. penile erection is a complex neurovascular event that occurs due to relaxation of cavernosal helicine arteries and smooth muscle of corpora cavernosa in combination with a coincident veno-occlusion, leading to blood distension of the corporal sinusoid and resultant penile rigidity (2). the primary mediator of this process is the nitric oxide (no)/cyclic guanosin-monophosphate (cgmp) pathway. phosphodiesterase type 5 (pde5), the enzyme which breakdowns cgmp in the corpus cavernosum, regulates the no-mediated relaxation of smooth muscle cells. the mechanism of action of pde5is consists precisely in the inhibition of pde5, which results in increased cgmp concentrations with continued activation of the no/cgmp pathway and subsequent increase in blood flow into the corpora cavernosa (3). the efficacy of pde5 inhibitors is independent of patient age, etiology of ed (organic, psychogenic, mixed), and baseline severity of the condition (4). four pde5is (sildenafil, tadalafil, vardenafil, and avanafil) have so far been approved for clinical use in italy. avanafil, the most recently marketed molecule, differs pharmacologically from the other agents of the same class due to its higher selectivity for the pde5 isoenzyme. indeed, pde5 inhibitors have different selectivities for this isoenzyme, as they may exert inhibitory effects on other pde isoforms resulting in potential side effects, sometimes serious enough to require treatment discontinuation. on the other end, the greater the selectivity for the pde5 isoenzyme, the less likely is the occurrence of adverse events potentially related to the inhibition of other pde isoforms (5). experimental studies have shown that avanafil has higher selectivity for pde5 than for other isoenzymes. it is generally believed that the high selectivity of avanafil results in better tolerability compared with other less selective agents (5, 6). doi: 10.4081/aiua.2016.2.128 introduction erectile dysfunction (ed), defined as the consistent or recurrent inability to attain and maintain an erection sufficient for satisfactory sexual performance, is a condimirone_stesura seveso 01/07/16 11:08 pagina 128 129archivio italiano di urologia e andrologia 2016; 88, 2 avanafil and ed: a survey on italian urologists the efficacy of avanafil in the treatment of ed is confirmed by a number of double-blind, placebo-controlled, randomized clinical trials, conducted both in the general population (7) and in “difficult” patient subgroups, such as those with diabetes mellitus (8) or those who have undergone nerve-sparing radical prostatectomy (9). in these clinical trials, avanafil demonstrated a rapid onset of action, often as early as 15 minutes after dosing, a prolonged therapeutic effect (in some cases up to 6 hours after administration), and a good tolerability (10). after approximately two years from the avanafil launch in italy, urologists have now developed a specific clinical experience with the use of this drug. however, there are still some “uncertainties” about the best use of avanafil, particularly with regard to dosage, efficacy, and safety profile compared with older pde5is. in order to obtain a “snapshot” of the use of avanafil in the clinical practice, and to make recommendations for its “best” use, the italian society of urology (siu, società italiana di urologia) started a project involving: 1) a survey, targeting a sample of italian urologists experienced in the treatment of ed, with a particular focus on their clinical experience with the use of avanafil; and 2) the organization of a conference of experts who, based on the findings of the survey and the scientific literature, would define some recommendations for the use of avanafil in clinical practice. this paper describes, in its first part, the preliminary results of the survey, and subsequently presents the recommendations made by the conference of experts. material and methods this research was conducted from february to april 2016 through an online survey. siu members were invited to answer anonymously a number of questions included in a questionnaire. in particular, siu local chairpersons and physicians experienced in the treatment of ed were invited to participate. the questionnaire investigated the number of ed patients treated over the past 12 months, and the proportion of them treated with avanafil. physicians were also asked to indicate, based on their clinical experience, the characteristics of the patients (expressed in percentage) who had been treated with avanafil 100 mg and 200 mg. the aim of this survey was to collect information on physicians' experience in this context; therefore, detailed information on individual patients was not collected. a total of 136 urologists responded to the survey (88.2% male; mean age 47 years, range 26-71 years; 48.5% of the respondents stated they worked mainly in a hospital setting). overall, urologists who participated in this survey stated that they had treated 17.856 patients during the 12 months prior to the completion of the questionnaire. of these, 13% were treated with avanafil 100 mg, and 26% with avanafil 200 mg (the same patient could have been treated, at different times, with both doses of avanafil). table 1 shows the characteristics of the patients treated with avanafil 100 mg and 200 mg, the patient satisfaction, and the frequency of side effects. patients treated with avanafil 200 mg were on average older and were more likely to report comorbid diabetes mellitus. the use of avanafil 100 mg was more common in treatment-naïve patients. patient satisfaction was greater in those treated with avanafil 200 mg. likewise, the frequency of side effects was slightly higher in individuals treated with the higher dose of avanafil: overall, the observed difference in the frequency of side effects was essentially due to a higher frequency of headaches. the methodology chosen for the production of recommendations was that of the “consensus conference”, which involves the drafting of recommendations by a “jury” at the end of a presentation and consultation of experts summapatient characteristics patients treated with avanafil 100 mg (%) patients treated with avanafil 200 mg (%) age (years) > 50/< 50 61.6/38.4 65.7/34.3 organic-based ed 56.6 51.1 comorbid diabetes mellitus 28.6 36.2 first treatment (treatment-naïve pts) 45.7 40.4 on-demand use 65.4 63 patient satisfaction (yes/no) 54.2/45.8 58.4/41.6 frequency of side effects any side effects 15.9 22.4 headache* 12.6 16.5 hot flushes 5.5 4.1 back ache 2.5 1.1 rash/itching 2.6 2 * only the side effects reported in more than 2% of the patients in at least one of the two groups are listed. the percentages shown are mean percentages, weighted by the number of patients treated by each physician. table 1. characteristics of patients receiving avanafil 100 mg and 200 mg as reported by physicians participating in the siu survey. mirone_stesura seveso 01/07/16 11:08 pagina 129 archivio italiano di urologia e andrologia 2016; 88, 2 v. mirone, f. fusco, f. parazzini, a. zucchi 130 rizing scientific knowledge on a given topic. the critical analysis of the literature enables the “jury” to compare the available evidence with expert opinions or reports. this method implies the following steps: 1. the definition of the themes of the recommendations; 2. the search for relevant literature; 3. the preparation of the first draft of the consensus statement by a drafting group; 4. the discussion by a “jury” of experts, and the preparation of the final document. in march 2016, the drafting group identified the themes of the recommendations, searched pubmed using the key words “avanafil, erectile dysfunction, treatment”, and then prepared a first draft of the recommendations. the experts invited to take part in the production of the recommendations participated in a workshop that was held on april 21-22, 2016. during this workshop, the results of the literature review and the findings of the siu survey, reported in the introduction of this paper, were presented. subsequently, the recommendations prepared by the drafting group were also presented. the expert panel was composed of 16 siu local chairpersons and 32 experts (2 per local area) in the treatment of ed, identified among the siu members by the local chairpersons of the association. results all the experts discussed, amended, and approved in plenary session the recommendations that are presented herein, with comments illustrating their rationale and relevance for the clinical practice. 1. in patients who are candidates for the use of avanafil, it is advisable to use the 200-mg dose from the first administration. the data of this survey indicate that the 200-mg dose of avanafil is the most commonly used in clinical practice. this practice is supported at least partly by scientific literature. corona et al. (11) have recently published a systematic review of the literature on randomized controlled trials (rcts), evaluating avanafil versus placebo in the treatment of erectile dysfunction. this systematic review included five placebo-controlled rcts, showing that avanafil was superior to placebo in improving vaginal penetration and achieving a successful sexual intercourse. this review of the literature concluded that both the 100and 200-mg doses of avanafil were effective and well tolerated. actually, the single most commonly reported adverse effect with avanafil 200 mg was an increased frequency of headache compared to avanafil 100 mg, although this difference was not statistically significant (this finding has also been reported in the present survey on the clinical practice in italy). no differences were observed between the two groups in the rate of treatment continuation. with regard to efficacy, the analysis of published studies indicates a greater efficacy (although not statistically significant) of the treatment with the 200-mg dose. the effect of avanafil 100 mg was also lower in elderly subjects, while no differences were observed with avanafil 200 mg. the observation that the 200-mg dose of avanafil shows greater efficacy in all patient categories, while having a substantially similar tolerability profile, clearly supports the recommendations of our working group. 2. when used at the highest dose (200 mg), avanafil shows a favourable tolerability profile with an efficacy similar to that of other agents. chen et al. (12) have recently published a “network metaanalysis” that included rcts evaluating the efficacy of sildenafil, tadalafil, vardenafil, and avanafil, usually in comparison with placebo. overall, the authors included 82 rcts (for a total of 47626 patients) for the efficacy analysis, and 72 rcts (20325 patients) for the tolerability analysis. the authors concluded that there were no significant differences between avanafil, sildenafil, tadalafil, and vardenafil, when the maximum recommended doses of these drugs (200, 100, 20 and 20 mg, respectively) were administered. with regard to tolerability, avanafil was significantly associated with a lower incidence of adverse effects when drugs were given at the maximum recommended dosage patients were treated with the maximum recommended doses of these drugs (200, 100, 20, and 20 mg, respectively). 3. the patient should be instructed to take avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal. it is important to adequately educate the patient about the fact that avanafil should be taken on an empty stomach. in fact, the median time to maximum plasma concentration (tmax) is obtained within 30-45 minutes after dosing, and the concomitant intake with food causes a delay in median tmax of 1 hour and 25 minutes , as reported in the summary of product characteristics (spc) of avanafil (13). 4. the efficacy window of avanafil is between 30 minutes and 6 hours after dosing, which qualifies this molecule as a new drug with an intermediate duration of action. table 2 shows the median tmax and the plasma half-life (in hours) of the four pde5 inhibitors available today in italy for the treatment of ed (13-17). with regard to avanafil, discordant data about half-life have been presented in the literature. its terminal half-life is 6-17 h, as reported in the spc, while the apparent t1/2 is 1.20 to parameter avanafil sildenafil vardenafil tadalafil tmax (median) 30-45 min 1 h 1 h 2 h plasmatic half-life 1.20-5 h 3–5 h 4–5 h 17.5 h (mean) table 2. tmax and plasmatic half-life of pde5-inhibitors (13-17). mirone_stesura seveso 01/07/16 11:08 pagina 130 131archivio italiano di urologia e andrologia 2016; 88, 2 avanafil and ed: a survey on italian urologists 5 hours (17), in line with the duration of the therapeutic effect observed in clinical trials. it is quite clear from above that avanafil can be qualified as a new agent with an intermediate duration of action, as compared with other active substances. 5. avanafil at a dose of 50-100 mg/day may be a therapeutic option in chronic rehabilitation. there is scientific evidence supporting the use of pde5 inhibitors as on-demand or chronic (daily) treatment for penile rehabilitation following radical prostatectomy. the fibrosis of cavernous bodies has been associated with reduced penile length: experimental studies have demonstrated that, following bilateral cavernous nerve injury, there is a significant reduction in the cavernosal smooth muscle/collagen ratio. chronic use of pde5is has been specifically studied with the aim to improve this clinical problem. avanafil has been shown to be effective in the treatment of patients with ed following radical prostatectomy. when prescribed for chronic use, these agents are usually given at the lowest dose available (18), and increasing their dose does not seem to improve their efficacy (19). discussion as emphasized by the recent guidelines of the european association of urology (eau), pde5is are the first-line therapeutic option for most men with ed. currently available pde5is (sildenafil, tadalafil, vardenafil, and avanafil) have the same mechanism of action; therefore, their efficacy is substantially similar at comparable doses. there are, however, relevant differences in the pharmacokinetic profile and degree of selectivity between different agents, and this should be taken in account in the therapeutic decision-making process. the high selectivity of avanafil, in particular, gives this agent a very satisfactory tolerability profile, as pointed out also by one of the recommendations in this paper, which suggests that good tolerability is one of the main “strengths” of avanafil compared to other molecules. the prevailing opinion among the participants in this survey is that, in patients who are candidates for the use of avanafil, the 200-mg dose should be used from the start of the treatment; in fact, this dose provides an appropriate balance between the efficacy and tolerability of pde5is, in combination with satisfactory response and compliance rates. according to the findings of this survey, there seem to be no significant differences in terms of efficacy between avanafil, sildenafil, tadalafil, and vardenafil when the maximum recommended doses of these drugs are used (200, 100, 20, and 20 mg, respectively); moreover, avanafil shows a favourable tolerability profile when used at the highest dose (200 mg), with an efficacy similar to that of other agents. a crucial point for the successful treatment of ed with pde5is is the effectiveness of doctor-patient communication in relation to the proper administration of prescribed medications and the outcomes to be expected, both in terms of efficacy and response times. in fact, if these issues are not adequately explained to the patients, they may mistakenly believe that the treatment prescribed is ineffective and/or may inappropriately stop or change their medications on their own initiative. in particular, the patient should be instructed to take avanafil on an empty stomach, i.e., 30-45 minutes before or 2 hours after a meal, in order to obtain an optimal therapeutic effect; it is also necessary to explain that the efficacy window of avanafil is between 30 minutes and 6 hours after dosing, which qualifies this new pde5i as an agent with intermediate duration of action. finally, a topic of great interest that has emerged from this survey is that avanafil, used at a dose of 50-100 mg/day, can be a therapeutic option for long-term penile rehabilitation, confirming the literature data that support the use of pde5-inhibitors as on-demand or chronic treatment for penile rehabilitation after radical prostatectomy (20). conclusions avanafil, a highly selective pde5 inhibitor, characterized by rapid onset of action and prolonged therapeutic effect, is an effective and well tolerated option for the treatment of ed. the present survey, conducted by siu among italian urologists, largely confirms the clinical efficacy and tolerability of avanafil in a real-life setting, even at the highest dose (200 mg), in line with the results of previous international clinical trials conducted to evaluate this pde5 inhibitor. references 1. hatzimouratidis k, eardley i, giuliano f, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. european association of urology web site. http://uroweb.org/guideline/male-sexual-dysfunction/. updated 2015. 2. ali w, besarani d, kirby r. modern treatment of erectile dysfunction. br j diabetes vasc dis. 2002; 2:255. 3. limin m, johnsen n, hellstrom wj. avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. expert opin investig drugs. 2010; 19:1427. 4. bruzziches r, francomano d, gareri p, et al. an update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. expert opin pharmacother. 2013; 14:1333. 5. gupta r, kumar g, kumar rs. an update on cyclic nucleotide phosphodiesterase (pde) inhibitors: phosphodiesterases and drug selectivity. methods find exp clin pharmacol. 2005; 27:101. 6. omori k, kotera j. overview of pdes and their regulation. circ res. 2007; 100:309. 7. goldstein i, mccullough ar, jones la, et al. a randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction. j sex med. 2012; 9:1122. 8. goldstein i, jones la, belkoff lh, et al. avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus. mayo clin proc. 2012; 87:843. 9. mulhall jp, burnett al, wang r, et al. a phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. j urol. 2012; 189:2229. mirone_stesura seveso 01/07/16 11:08 pagina 131 archivio italiano di urologia e andrologia 2016; 88, 2 v. mirone, f. fusco, f. parazzini, a. zucchi 132 10. belkoff lh, mccullough a, goldstein i, et al. an open-label, longterm evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction. int j clin pract. 2013; 67:333. 11. corona g, rastrelli g, burri a, et al. the safety and efficacy of avanafil, a new 2(nd) generation pde5i: comprehensive review and meta-analysis. expert opin drug saf. 2016; 15:237. 12. chen l, staubli se, schneider mp, et al. phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. eur urol. 2015; 68:674. 13. avanafil summary of product characteristics (spc). 14. sildenafil summary of product characteristics (spc). 15. vardenafil summary of product characteristics (spc). 16. tadalafil summary of product characteristics (spc). 17. kedia gt, ückert s, assadi-pour f, et al. avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. ther adv urol. 2013; 5:35. 18. bannowsky a, van ahlen h, loch t. increasing the dose of vardenafil on a daily basis does not improve erectile function after unilateral nerve-sparing radical prostatectomy. j sex med. 2012; 9:1448. 19. bannowsky a, schulze h, van der horst c, et al. recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. bju int. 2008; 101:1279. 20. cui ys, li n, zong ht, et al. avanafil for male erectile dysfunction: a systematic review and meta-analysis. asian journal of andrology. 2014; 16:472. correspondence vincenzo mirone, md mirone@unina.it ferdinando fusco, md (corresponding author) ferdinando-fusco@libero.it dipartimento ostetricia, ginecologia, urologia clinica urologica università di napoli federico ii, italy fabio parazzini, md fabio.parazzini@unimi.it i clinica ginecologica, fondazione irccs ca' granda ospedale maggiore policlinico, università di milano, italy alessandro zucchi, md zucchi.urologia@gmail.com clinica urologica ed andrologica, università di perugia, italy mirone_stesura seveso 01/07/16 11:08 pagina 132 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3252 case report 10-year survival of a patient with metastatic prostate cancer: case report and literature review kristian krpina, dean markić, dražen rahelić, juraj ahel, nino rubinić, josip španjol department of urology, clinical hospital center rijeka, rijeka, croatia. prostate cancer is the most common malignancy in men. the 5-year relative survival for all stages combined is 98.8%. patients diagnosed with metastatic prostate cancer have median survival from 2 to 3 years. we describe a case of 64-year old man who clinically presented with inguinal lymphadenopathy. because of elevated psa levels biopsy of prostate was done and adenocarcinoma was diagnosed. biopsy of inguinal lymph nodes confirmed the diagnosis of prostate cancer. hormonal treatment was started and at the most recent follow-up, 10 years later, the patient is asymptomatic with no clinical signs of disseminated disease. key words: generalized lymphadenopathy; prostate cancer: survival: treatment. submitted 1 february 2015; accepted 31 march 2015 summary no conflict of interest declared. the prostate which partially ocluded the rectum. psa level was 152 ng/ml. transrectal ultrasound (trus) showed prostatic enlargement with multiple hypoechoic peripheral lesions. chest x ray showed no pathological findings. computed tomography (ct) of the abdomen and pelvis was remarkable for an enlarged retroperitoneal and inguinal lymph nodes with dislocation of the left ureter and bladder to the right side (figure 1). cystography showed bladder dislocated to the projection of the right iliac bone. the bone scan showed metastasis in the fifth thoracic vertebra. transrectal biopsy of the prostate demonstrated adenocarcinoma (gleason score 5+5, “signet ring”). biopsy of the left inguinal lymph node also revealed adenocarcinoma with immunohistochemical staining that was strongly positive for psa. the patient underwent castration and therapy was continued with flutamide. afterwards, during time, his psa level reached 0.16 ng/ml. in 2008, the patient was lost to follow-up. he was again referred to urology consultant in december 2012. the patient stated that he stopped talking medications in 2008, because of the adverse effects. his psa level was 3.8 ng/ml and bicalutamide treatment was started. at the most recent check-up in september 2014, ct of the abdomen and pelvis showed no evidence of disease. his psa level is 0.32 ng/ml and he is asymptomatic. discussion despite advances in the treatment of prostate cancer, nearly 260,000 men worldwide will die from the disease this year, and the vast majority will have metastatic disease at the time of death. while in patients with metastatic prostate cancer median survival is approximately 30 months when treated with hormonal therapy, there is substantial inter patient variation. why this disease has such a divergent response to hormonal therapy is a fundamental question of urologic oncology. given the heterogeneity of prognoses in patients with metastatic prostate cancer, the ability to accurately predict survival is vital for optimal patient counseling, selection of treatments, clinical trial design, and interpretation of clinical data. over the past 20 years, several prognostic models have been developed in an attempt to refine the clinician's predictive ability. glass et al. through their clinical data analysis identified doi: 10.4081/aiua.2015.3.252 introduction prostate cancer is the most common malignancy in men. the median age at diagnosis of prostate cancer is 68 years. prostate cancer does not alter life expectancy for most of these men as the 5-year relative survival for all stages combined is 98.8%. those who present with metastatic disease have a median survival of approximately 30 months, however a small proportion of men diagnosed with metastatic prostate cancer will live substantially longer. one of the rare presentations of metastatic prostate cancer are generalized lymphatic metastases (1). we report a case of prostate cancer patient who clinically manifested as generalized lymphadenopathy with concomitant minimal bone metastases and subsequent ten years follow up. case report in march 2004, a 64-year-old male was referred to clinical hospital center rijeka for a constipation. the patient reported swelling of the left leg and suprapubic fullness. he denied any voiding difficulties. the patient’s past medical and surgical history were not contributory. physical examination of the patient showed palpabile suprapubic fullness, enlarged lymph nodes in left inguinum and left leg oedema. digital rectal examination (dre) revealed nodular induration in the lateral lobes of krpina _stesura seveso 23/09/15 12:45 pagina 252 253archivio italiano di urologia e andrologia 2015; 87, 3 metastatic prostate cancer 10-year survival four prognostic factors which have a major impact on outcome of metastatic prostate cancer patients (2). namely those are appendicular versus axial disease, performance status 0 versus 1 to 3, psa less than 65 versus 65 ng/ml or greater and gleason score less than 8 versus 8 or greater. using these criteria three prognostic groups can be made, including a good, intermediate and poor group. for example, estimation of five-year survival in the poor prognostic group is only 9%. authors concluded that risk stratification according to these factors is helpful for individual patient treatment. the eortc conducted two randomized phase iii trials (trial 30,843 and trial 30,853) of maximal androgen blockade in 695 patients with metastatic prostate cancer. these trials showed discrepancy of results according to overall survival of treated patients. in order to determine whether differences in patient characteristics could explain these possibly contradictory results, sylvester at al used a statistical model to identify prognostic factors for survival. their model revealed six prognostic factors such as alkaline phosphatase, hemoglobin, performance status, pain score, t category and g grade. by using these factors patients can be divided into two risk groups (good or poor prognosis with 3.5 and 1.75 years' median survival, respectively). in conclusion, authors underline the importance of taking into account patient characteristics when treatment strategy is planned. montgomery study revealed higher body mass index to be associated with better overall and progression-free survival in patients with androgen dependent metastatic prostate cancer. the question remains what is real clinical application of these study-results in every day clinical setting. on example of our case-presentation it is possible to see that the same patient would be grouped differently according to different authors. for example, glass criteria would group the presented patient in poor prognostic group whereas sylvester model would group him in good prognosis group. on the other hand one of the peculiarities of this case is clinical presentation. although many cases have been reported of prostate cancer metastasizing to inguinal nodes many years after diagnosis only one case has been reported in which inguinal lymphadenopathy was the presenting sign (3). the patient presented here had not undergone any previous local surgery that might have distorted the lymphatic drainage of the prostate. one possible explanation of such metastasis is that he might have had some aberrant lymphatic drainage of the prostate. uncommon routes of pelvic lymphatic drainage that have been reported include the gonadal vessels, mesenteric and mesocolic nodes, posterior iliac crest nodes and inferior phrenic nodes. as prostate cancer specific mortality has fallen to low levels for many men prostate cancer is a chronic disease. survivorship research has defined many risks and factors unique to this population but further work to identify novel prognostic markers is needed. current efforts to better classify the molecular phenotypes of metastatic clones of cells may provide essential information in predicting the clinical behaviour of the disease. references 1. moura fm, garcia lt, castro lpf, ferrari tca. prostate adenocarcinoma manifesting as generalized lymphadenopathy. urol oncol. 2006; 24:216-9. 2. glass tr, tangen cm, crawford ed, thompson i. metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning. j urol. 2003; 169:164-9. 3. slavis sa, golji h, miller jb. carcinoma of the prostate presenting as inguinal adenopathy. cleve clin j med. 1990; 57:97. figure 1. ct of the abdomen showing enlarged retroperitoneal lymphnodes. correspondence kristian krpina, md, phd, febu (corresponding author) kristiank@net.hr dean markić, md, phd, febu dražen rahelić, md juraj ahel, md nino rubinić, md josip španjol, md, phd department of urology, clinical hospital center rijeka tome strižića 3, 51000 rijeka, croatia krpina _stesura seveso 23/09/15 12:45 pagina 253 235archivio italiano di urologia e andrologia 2016; 88, 3 case report priapism and glucose-6-phosphate dehydrogenase deficiency: an underestimated correlation? aldo franco de rose 1, guglielmo mantica 1, mattia tosi 1, giulio bovio 2, carlo terrone 1 1 department of urology, irccs san martino hospital, university of genova, genova, italy; 2 department of radiology, irccs san martino hospital, university of genova, genova, italy. priapism is a rare clinical condition characterized by a persistent erection unrelated to sexual excitement. often the etiology is idiopathic. three cases of priapism in glucose-6-phosphate dehydrogenase (g6pd) deficiency patients have been described in literature. we present the case of a 39-year-old man with glucose-6-phosphate dehydrogenase deficiency, who reached out to our department for the arising of a non-ischemic priapism without arteriolacunar fistula. we suggest that the glucose-6-phosphate dehydrogenase deficiency could be an underestimated risk factor for priapism. key words: non-ischemic; glucose-6-phosphate dehydrogenase (g6pd) deficiency. submitted 14 may 2016; accepted 30 may 2016 summary no conflict of interest declared. obliged him to go to the emergency department. he reported a normal and spontaneous erectile function before the arising of the disease. he denied having any gender of trauma and he admitted to have a g6pd deficiency, documented by laboratory tests. he denied having taken any drugs, phosphodiesterase type 5 (pde5) inhibitors, intracavernosal agents or any other pharmacological agents. he denied any other risk factor for priapism. at clinical examination he presented a painless erection. systemic hemoglobin was 13.6 g/dl. intracorporal blood resulted as arterial at gas analysis (p02 = 76 mmhg; pc02 = 44.5 mmhg; ph = 7.35). the color doppler ultrasonography didn’t point out any arterocavernosa fistula. after a period of observation in which there wasn’t the resolution of the priapism, we decided to submit him to a pelvic arteriography (figure 1). panoramic arteriography of the aorto-iliac and selective of internal pudendal artery showed a bilateral increase of the arterial level of the corpora cavernosa, higher in the left one, without a fistula. we performed a temporary embolization with spongostantm of the distal left internal pudendal artery. a complete detumescence was obtained and the next arteriography confirmed the procedure was a success. the patient was released. after 2 weeks of a state of good health, he presented a new episode of prolonged erection, after which he returned to the emergency department of our institute. doi: 10.4081/aiua.2016.3.235 figure 1. pelvic arteriography showing a bilateral increase of the arterial level of the corpora cavernosa, higher in the left one, without a fistula. introduction there are three types of priapism with different pathophysiological causes: the ischemic priapism (or “low flow”), which is a dolorous and prolonged erection with a tissue ischemia, the non-ischemic (or “high flow”) priapism, which is usually due to a perineal injury with the formation of an arteriolacunar fistula, and the stuttering (intermittent) priapism, which is a recurrent form of ischemic priapism in which unwanted painful erections occur repeatedly with intervening periods of detumescence. all types of priapisms can lead to an erectile dysfunction (1), not only the ischemic one. for that reason, it is important to treat it in time and in correct way, but also to identify the possible risk factors. three cases of priapism in patients with g6pd deficiency have been described in literature (2). we report an unique case of “high flow” priapism without fistula in a patient with g6pd deficiency. case presentation in october 2015, a 39-year-old man reached to our observation for an intermittent, painless erection, everyday, for about one month. he reported erections lasting about 4-6 hours during the first days of the month. these erections stopped in the following days, then he had another erection lasting more than 17 hours, which mantica_stesura seveso 21/09/16 09:06 pagina 235 archivio italiano di urologia e andrologia 2016; 88, 3 a.f. de rose, g. mantica, m. tosi, g. bovio, c. terrone 236 this time the erection was higher and mildly painful. he still denied having taken drugs or medications. we performed a gas analysis (p02 = 21.3 mmhg; pc02 = 56.4; mmhg; ph = 7.34). we carried out an evacuation of blood from the cavernosa corpora through transglandular cannula and injection of etilefrine which lead to a detumescence. after an observation time of 24 hours without erections, we decided to discharge the patient from our department. three months later he affirmed to have preserved a sufficient erectile function (iief-5: 18). conclusions the number of priapisms, classified as idiopathic, both ischemic and not-ischemic, continues to be high. among the clinically significant enzymatic defects, g6pd deficiency is the most common (3), with hundreds and millions of affected people. with the proliferation of the g6pd deficiency, especially in some countries, we suggest it could be a casual factor or a co-factor, responsible for some cases of priapism classified as idiopathic. therefore, now we consider the g6pd deficiency as a underestimated risk factor for the emergence of priapism. discussion priapism can be associated with some hematologic, coagulative and enzymatic disorders (4-5) such as leukemia and sickle cell anemia. hematologic diseases are usually associated with a “low flow” priapism, but some associations have also been reported between “high flow” priapism and sickle cell anemia (6). both type of priapism are also associated with fabry disease (7, 8). nowadays, few cases of priapism, related to a g6pd deficiency, are present in literature, even if the correlation between the two disorders has been discovered (2, 9, 10). the cases, which have emerged until now, showed a link between the g6pd deficiency and the “low flow” priapism. in our case, the patient initially showed a “high flow” priapism, without the presence of other risk factors for the disorder. the interesting thing was the absence of fistula at the arteriography, but the presence of an increase of the blood flow in the corpora cavernosa. although the arrangements are unknown, the g6pd deficiency could be responsible for that increase of blood flow and it could lead to a not-ischemic priapism other than an ischemic one, as it’s already documented and assumed for the other enzymatic and hematologic defects (6-8). references 1. zacharakis e, ralph david j, walkden m, et al. distal corpus cavernosum fibrosis and erectile dysfunction secondary to nonischaemic priapism. arch it urol androl. 2015; 87:258-9. 2. morrison bf, thompson eb, shah sd. ischaemic priapism and glucose-6-phosphate dehydrogenase deficiency: a mechanism of increased oxidative stress? west indian med j. 2014; 63:658-60. 3. who working group. glucose-6-phosphate dehydrogenase deficiency. bull world health organ. 1989; 67:601-11. 4. kalathia j, agrawal s, sudirchipde s, agrawal r. homo cysteinemia: a rare cause of priapism. urol ann 2016; 8:118-21. 5. morrison bf, burnett al. priapism in hematological and coagulative disorders: an update. nat rev urol. 2011; 8:223-230. 6. ramos ce, park js, ritchey ml, benson gs. high flow priapism associated with sickle cell disease. j urol. 1995; 153:1619-1621. 7. foda mm, mahmood k, rasuli p, et al. high-flow priapism associated with fabry’s disease in a child: a case report and review of the literature. urology. 1996; 48:949-952. 8. backenroth r, landau eh, goren m, raas-rothschild a. fabry disease and g6pd in three family members with priapism: is the nitric oxide pathway to blame? j sex med. 2010; 7:1588-1591. 9. burnett al, bivalacqua tj. glucose-6-phosphate dehydrogenase deficiency: an etiology for idiopathic priapism? j sex med. 2008; 5:237-240. 10. finley ds. glucose-6-phosphate dehydrogenase deficiency associated stuttering priapism: report of a case. j sex med. 2008; 5:2963-2966. correspondence aldo franco de rose, md aldofrancoderose@gmail.com guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com 3383699431 mattia tosi, md matti.grifone@hotmail.it carlo terrone, md department of urology, irccs san martino hospital, university of genova largo rosanna benzi 10 16131, genova, italy giulio bovio, md giulio.bovio@hsanmartino.it department of radiology, irccs san martino hospital, university of genova largo rosanna benzi 10 16131, genova, italy mantica_stesura seveso 21/09/16 09:06 pagina 236 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4304 letter to editor about: penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri) reply by authors we read with interest the paper “penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri)” by antonini et al. in your journal (2014; 86(1) 39-40). the statement “early surgical exploration is paramount” does not take into consideration the excellent results reported for delayed repair of the fracture (1). delayed repair also makes clinical identification of the fracture site more accurate since, when the acute swelling settles, the rolling sign (caused by clot at the torn cavernosum) becomes even more obvious. this is even more evident in late delayed repair (2). the authors correctly point out that “degloving a bruised edematous penis can be quite challenging” especially since most fractures are in the proximal shaft. the peno scrotal incision is also easier to perform in a delayed repair as much of the swelling and deformity are reduced. thus, we believe that in most cases, the fracture site can be accurately identified by the rolling sign on presentation (3). if, however, this is not evident, a delay of 712 days makes accurate identification and repair via a penoscrotal incision much easier (1). thus, we do not share the view that “mri should be the first choice modality of investigation” since it is both costly and unnecessary. it should be reserved for cases of suspected urethral rupture, bilateral cavernosal injury or doubtful diagnosis. references 1. nasser ta, mostafa t. delayed surgical repair of penile fracture under local anesthesia. j sex med. 2008; 5:2464-9. 2. naraynsingh v, hariharan s, goetz l, dan d. late delayed repair of fractured penis. j androl. 2010; 31:231-3. 3. naraynsingh v, raju gc. fracture of the penis. br j surg. 1985; 72:305-6. vijay naraynsingh, ravi maharaj, shamir cawich department of clinical surgical sciences, the university of the west indies, eric williams medical sciences complex, mount hope trinidad w.i. magnetic resonance imaging (mri) scan of the penis is highly sensitive at detecting the exact location of the tunical tear and allows the surgeon to chose the best surgical approach. as 2/3 of fractures occur all the way down on the proximal aspect of the shaft, a complete degloving becomes an unnecessary procedure, as a penoscrotal approach would guarantee adequate exposure in these patients (1-4). magnetic resonance imaging or uss of the penis play therefore a pivotal role for the identification of the exact location of the tear and therefore allow the surgeon to adequately choose the most appropriate surgical approach. surgery should be immediate, in order to preserve as much cavernosal tissue as possible and to minimize the formation of corporeal fibrosis, which would lead to ed, penile shortening and curvature (5-7). when readily available, mri should be the first choice modality of investigation due to its superior sensitivity in detecting tunical injuries (8). references 1. ozcan s, akpinar e. diagnosis of penile fracture in primary care: a case report. cases j. 2009; 2:8065. 2. kowalczyk j, athens a, grimaldi a. penile fracture: an unusual presentation with lacerations of bilateral corpora cavernosa and partial disruption of the urethra. urology. 1994; 44:599-601. 3. dever dp, saraf pg, catanese rp, feinstein mj, davis rs. penile fracture: operative management and cavernosography. urology. 1983; 22:394-6. 4. srinivas bv, vasan ss, mohammed s. a case of penile fracture at the crura of the penis witout urethral involvement.indian j urol. 2012; 28:335-337. 5. garaffa g, raheem aa, ralph dj. penile fracture and penile reconstruction. curr urol rep. 2011; 12:427-31. 6. sharma mb, singh ts, khumucham s, chito t, sharma bb. fracture of the penis – report of seven cases. j indian med assoc. 2011; 109:45-6. 7. hatzichristodoulou g, dorstewitz a, gschwend je, herkommer, zantl n. surgical management of penile fracture and long-term outcome on erectile and voiding. j sex med. 2013; 10:1424-30. 8. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-4575. gabriele antonini 1, patrizio vicini 3, salvatore sansalone 4, giulio garaffa 4, antonio vitarelli 5, ettore de berardinis 1, magnus von heland 1, riccardo giovannone 1, emanuele casciani 2, vincenzo gentile 1 1 department of urology, “sapienza” rome university, rome, italy; 2 department of radiology, “sapienza” rome university, rome, italy; 3 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 4 department of experimental medicine and surgery, “tor vergata” rome university, rome, italy; 5 department of urology, bari university, bari, italy. doi: 10.4081/aiua.2014.4.304 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2146 case report post-renal acute renal failure due to a huge bladder stone orcun celik, tufan suelozgen, salih budak, yusuf ozlem ilbey tepecik educational and research hospital urology department, 35140, izmir, turkey a 63-year old male was referred to our emergency unit due to acute renal failure. the level of serum renal function tests levels, blood urea nitrogen (bun)/creatinine, were 63 mmol/l/848 µmol/l. ct (computarised tomography) scan showed a huge bladder stone (5 cm x 6 cm x 5 cm) with increased bladder wall thickness. post-renal acute renal failure due to bilateral ureterohydronephrosis was diagnosed. the huge bladder stone was considered to be the cause of ureterohydronephrosis and renal failure. the patient was catheterised and received haemodialysis immediately. he received haemodialysis four times during ten days of hospitalization and the level of serum renal function tests levels (bun/ creatinine) decreased 18 mmol/l/123 µmol/l. after improvement of renal function, we performed cystoscopy that demonstrated normal prostatic urethra and bladder neck and bilaterally normal ureteral orifices. bladder wall was roughly trabeculated and bladder outlet was completely obstructed by a huge bladder stone. after cystoscopy open, cystolithotomy was performed to remove calcium phosphate and magnesium ammonium phosphate stone weighing 200 g removed. four days after operation the patient was discharged uneventfully and urethral catheter was removed on the seventh day. post-renal acute renal failure due to large bladder stones is rare in literature. according to the our knowledge; early diagnosis of the stone avoid growth to large size and prevent renal failure. key words: bladder calculus; acute renal failure; open cystolithotomy; ureterohydronephrosis. submitted 28 april 2014; accepted 31 may 2014 summary introduction the pathogenesis of bladder stones has not been well studied (1). bladder stones account for 5% of urinary stones and occur in association with urinary tract infection, foreign bodies and neurogenic voiding dysfunction (2). in our recent urology practice, massive bladder stone is a rare entity. the association between bladder calculi and urinary stasis is not completely clear. unlike studies of upper urinary tract stone disease, factors contributing no conflict of interest declared to the pathogenesis of bladder calculi have not been well explored. although, bladder stones are usually associated to ureteral or renal stones, they may occasionally occur alone in absence of stones of the supravesical tract, as in our case (3). case report we present a 63-year-old man referred to our emergency unit for recurrent urinary tract infection , lower abdominal pain, oliguria and weight loss since six months. hepresented lower urinary tract symptoms including weak urine stream, urgency, urinary frequency, voiding difficulty and urinary intermittency. at physical examination he was anorexic and weak. blood urea nitrogen (bun) and serum creatinine levels were 63 mmol/l and 848 µmol/l respectively. ct (computerised tomography) scan showed a huge bladder stone (6 cm x 6 cm x 5 cm) with increased bladder wall thickness and bilateral ureterohydronephrosis (figures 1-2). neurologic examination was normal, therefore urodynamic evaluation was not indicated pre and post-operatively. haemodialysis and urethral catheterization improved renal function, whereas we simultaneously treated urinary tract infection with intravenous antibiotics during ten days hospitalization. we planned cystoscopy and open cystolithotomy. doi: 10.4081/aiua.2014.2.146 figures 1. the huge pelvic calculi seen in ct scan. 147archivio italiano di urologia e andrologia 2014; 86, 2 a huge bladder stone of bladder cystoscopic examination and open procedure were done together on the same operative day. no anatomic urethral obstruction was observed and prostatic urethra and bladder neck were normal too. cystoscopy normal demonstrated bilaterally normal ureteral orifices and a bladder stone which completely obstructed the bladder outlet as it was severely adherent to the bladder mucosa. the stone weighed 200 g and measured 5.0 cm x 6.0 cm x 5.0 cm in size (figure 3). post-operative period was uneventful. the patient was discharged on fourth post-operative day and urethral catheter was removed on the seventh day. at the first month post-operative outpatient control, no residual bladder stone or ureterohydronephrosis was present. discussion the presence of a huge bladder calculus is a rare cause of acute renal failure. according to the recent study from komeya et al, it was reported that, according to english literature of the last several decades, only six papers reported acute renal failure caused by stones (4). the median age of patients was 62 years and the heavier weight was 200 g. the level of serum creatinine on admission was higher than 672 µmol/l whereas in our patient was 848 µmol/l. nygaard et al reported that their patient’s serum creatinine level was 1264 µmol/l on admission and the stone weighted 1640 g which was the largest stone ever removed by open cystolithotomy in literature(5). additionally, in this patient an inoperable carcinoma of the bladder was detected more than four years later after cystolithotomy. in these papers, limited information was provided about the underlying disease which caused voiding disorder and bladder stones before admission. patients usually complained recurrent urinary tract infection and long-term persistent urinary symptoms. our patient had urinary tract infection on admission and we detected 100.000 e.coli cfu/ml in urine culture that was treated by intravenous antibiotics before surgical operation. conclusions in order to summarize about our case report, although single huge bladder stones rarely cause acute renal failure with respect to upper tract urinary stones, we should always remember this rare condition. we need to carefully consider two important aspects: 1) long-term urinary symptoms and recurrent urinary tract infections especially in men may cause huge bladder stone and acute renal failure 2) a 2-fold increase in bladder cancer risk was observed in association with a history of bladder stones in a case-control study (6). therefore the long delay in diagnosis of giant stones can cause squamous cell carcinoma of bladder. we should strictly follow-up patients with huge bladder stones for the risk of bladder cancer after operation. references 1. childs ma, mynderse la, rangel lj, et al. pathogenesis of bladder calculi in the presence of urinary stasis j urol. 2013; 189:1347-1351. 2. aydogdu o, telli o, burgu b, beduk y. infravesical obstruction results as giant bladder calculi, can urol asoc j. 2011; 5:77-78. 3. hammad ft, kaya m, kazim e. bladder calculi: did the clinical picture change? urology 2006; 67:1154-8. 4. komeya m, sahoda t, sugiura s, et al. a huge bladder calculus causing acute renal failure urolithiasis 2012; 12:517-8. 5. nygaard e, terjesen t. giant vesical calculas and anuria scand j urol nephrol. 1976; 10:88-90. 6. kantor af, hartge p, hoover rn, et al. urinary tract infection and risk of bladder cancer. am j epidemiol. 1984; 119:510-5. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com tufan suelozgen, md salih budak, md yusuf ozlem ilbey, md associate professor endourology section urology department, tepecik educational and research hospital gaziler cd.no:468, yenisehir 35140, izmir, turkey figures 2. bilateral ureterohydronephrosis that cause of acute renal failure seen in ct scan. figures 3. a 6 x 5 cm bladder stone was extracted by open cystolithotomy. stesura seveso 197archivio italiano di urologia e andrologia 2014; 86, 3 review to evaluate the etiology of erectile dysfunction: what should we know currently? orcun celik 1, tumay ipekci 2, ilker akarken 1, gokhan ekin 1, turker koksal 2 1 tepecik education and research hospital, urology clinic, 35140, izmir, turkey; 2 akdeniz university, faculty of medicine, department of urology, 07070, antalya, turkey. erectile dysfunction (ed) is the inability to develop normal erection or an hardening problem at various extent that causes inability to maintain the erection for the sufficient time required for a complete sexual activity. it can be the result of neurologic, psychogenic, vascular, urogenital and hormonal abnormalities. it is reported that it affects 52-67% of men between 40 and 70 years old. numerous theories and opinions are issued in the literature in order to explain the hemodynamic changea that occur during erection and detumescence. especially the effects of chronic diseases and psychogenic factors on the pathophysiology of erectile dysfunction are common matters of discussion in recent years. in this review, we will evaluate the current developments in the literature about the etiology of erectile dysfunction. key words: erectile dysfunction; ethiology; erection. submitted 13 june 2014; accepted 30 june 2014 summary no conflict of interest declared. as aterial muscular bolsters (von enbner, 1990; kiss, 1921), arterial and venous bolsters (conti, 1952), duct theory (deysach, 1939), arteriovenous shunt (newman et al., 1964; wagner et al., 1982) and cavernous smooth muscle contraction (goldstein et al., 1982) (3). most of the information regarding to erection physiology is obtained along 1980s and 1990s. in addition to the role of smooth muscles that regulate arterial and venous blood stream, the role of three dimensional structure of the tunica albuginea and its role in venous occlusion are explained. an important stage for understanding the nervous control was to determine that nitric oxide (no) is the primary neurotransmitter for erection and that phosphodiesterases turns penis back to its flask condition for the adjustment of smooth muscle tone. furthermore it was revelead the role of endothelium and the connection between the cells by “gap junctions” (3). prevalence of erectile dysfunction ed is one of the primary problems that affect the quality of life of people and its incidence is gradually increasng. in 2025, it is estimated that more than 322 million men will be affected from ed (4). on the basis of the epidemiological data, patient population and definition of ed, it has been shown that ed prevalence is between 16-25% (5). the overall prevalence of erectile dysfunction in men aged > 20 years was 18.4% suggesting that erectile dysfunction affects 18 million men aged 16-20 in the us (6). according to the results of this studies about ed prevalence, it has been shown that ed prevalence increases with age. ed prevalence ratios in the study of “national health and social life survey” (nhsls) is found as 7% between the ages 18 and 29, 11% between the ages 40 and 49 and 18% between the ages 50 and 59 (7). the prevalence of sexual activity declined with age to 73% among respondents who were 57 to 64 years of age, 53% among respondents who were 65 to 74 years of age, and 26% among respondents who were 75 to 85 years of age. among men, the most prevalentsexual problems were erectile difficulties (37%). fourteen percent of all men reported using medication or supplements to improve sexual function (8). in a study performed in our country, it was determined that in men over 40 years old mild ed is foun in 35.7%, doi: 10.4081/aiua.2014.3.197 introduction erectile dysfunction (ed) is defined as not providing or not continuing, when provided, the required penis hardening in order to perform a successful sexual intercourse (1). various aspects have been introduced in order to explain the mechanism of erection. in 19th century, it has been hypothesized that the essential factor for the success of erection could be venous occlusion. in 1933, howell revealed the role of the arterial system and, in the same years, oswald lowsey showed that there was no erection in dogs after ischiocavernous and bulbocavernous muscles ablation and that erection easily occurred as the result of separated plication of these muscles by catgut stiches and more plication caused priapism (2). newman et al. (1964) have shown that erection may occur in volunteers and human cadavers simply by isotonic solution infusion without venous construction (3). shiari et al. (1978) concluded that despite the increase of venous drainage, arterial flux was excessively increased to overtop venous drainage. wagner (1981) demonstrated that arterial flux was increased and, in return, venous drainage was decreased. various theories were developed celik4_stesura seveso 08/10/14 12:11 pagina 197 archivio italiano di urologia e andrologia 2014; 86, 3 o. celik, t. ipekci, i. akarken, g. ekin, turker koksal 198 moderate ed in 23% and severe ed in 6%. in this study, it was determined that the factors increasing ed prevalence are advanced age, low educational level, diabetes mellitus (dm), hypertension, psychological stress and prostate diseases (9). in another study; ed prevalence in turkey was measured as 69.2% and it was shown that especially the moderate-severe level of ed prevalence increased by age (10). in the study of massachusetts men aging (mmas), it was shown that 9.6% of men between the ages 40 and 70 have severe, 25.2% moderate and 17.2% mild ed. rate of complete ed increased from 5.1% in 40-year-old to 15% in 70-year old (9). this and similar studies have obviously shown that ed increases by age and libido possibly decreases by loss of erections. there are some evidences showing that decrement rate of erection is related to the frequency of sexual activities and that men with more active sexual lives are better protected (10). in various studies, it was observed that there is a strong relationship between diabetes and ed. ed incidence in diabetics treated at mmas is about 28% (11). according to a study, more than 6% of usa population is diabetic and ed is present in approximately 8 million of them (13). ed is observed in 32% of men with type 1 dm and in 46% of men with type 2 dm (14). ed occurs in 50% of men with dm within 10 years and 12% of men with dm are diagnosed after they have applied for ed (15). ed in patients with dm is seen three times more frequently than in the normal population (11). cardiovascular diseases may affect potency with various mechanisms. although ed has occurred up to 45% in men after myocardial infarction, there are also evidences that there is a high incidence in the period before having a cardiac attack. in a recent cross-sectional multicentered survey study among randomly selected males visiting a cardiologist, overall, 56% had ed, with up to 86% in patients with heart failure (16). oaks and moyer reported that 8 ± 10% of all untreated hypertensive patients had ed at the diagnosis of hypertension (17). a recent study using the validated international index of erectile function questionnaire reported a higher incidence of severe ed amongst hypertensive men than in the general population (18). in spite of the fact that hypertension causes ed by itself, frequently used antihypertensive drugs can also be a cause of ed (19). ed is more frequent after cerebrovascular events with up to 85% incidence of ed reported. there is strong relationship between various neurological diseases and ed. it is reported that ed incidence is high in men with multiple sclerosis (about 70-80%) and that more than 50% of such men have also complaint about decreased libido. such effects are not only based on autonomic and somatic neuropathies that affect men with multiple sclerosis, but they are also related to concomitant psychological factors such as depression and anxiety. chronic renal insufficiency (cri) is related to a decrease in erectile function, decrease of libido and infertility. ed incidence in men with cri is about 40%. it is thought that occlusion of cavernous arteries, veno-occlusive dysfunction, lack of testosterone, increase in prolactin levels, various drugs used, autonomic and somatic neuropathy and especially psychological factors are the reasons for ed in patients with renal insufficiency (20, 21). after a successful renal transplantation, 50-80% of the patients may return to their potency levels before the disease (22, 23). the relationship between ed and psychiatric diseases, chronic alcohol usage and chronic liver disease, malignancies, trauma and smoking was shown in various studies (24). psychogenic reasons psychogenic ed generally occurs in young adults under the age of 40. although psychogenic ed rate in men over the age of 50 is approximately 10%, 45% of all ed patients have psychogenic problems (25). sexual behaviors and penile erection are controlled by hypothalamus, limbic system and cerebral cortex. thus stimulating or inhibiting messages may be transferred to spinal erection centers in order to ease or prohibit erection. psychogenic reasons may be emotional problems such as depression and anxiety, previous traumatic sexual experiences, lack of self-confidence, suspicions in sexual roles, physical disorders in spouses and lack of attraction and also interparental conflicts or cultural differences, sexual myths or socioeconomical factors such as job stress. two possible mechanisms explaining the inhibition of erection in psychogenic ed are the direct inhibition of the spinal erection center of the brain by excessive normal suprasacral inhibition or over sympathetic discharge and the increased peripheral catecholamine levels that inhibit the relaxation required for erection by increasing the penis smooth muscle tonus (26). clinically it is reported that serum norepinephrine level is higher in patients with psychogenic ed when compared to normal controls or patients with vasculogenic ed (27). organic reasons 1. vascular pathologies in middle aged men, ed is generally vascular-derived accounting for 40-50% of all the etiological factors. according to the general population, pudendal artery lesions are seen more frequently in men with ed (28). apart from that, ed is frequently seen in men with atherosclerotic diseases such as ischemic heart disease and arterial foot disease. furthermore ed and cardiovascular diseases have similar risk factors such as hypertension, diabetes mellitus, hypercholesterolemia and smoking (29). such findings show that ed is a different form of vascular diseases. in a study it was observed that low penile brachial pressure index can be a predictive factor for myocardial infarction and cerebrovascular events (30). arterial diseases causing atherosclerotic or traumatic occlusion in hypogastric-cavernous-helix arterial branching decrease perfusion pressure and arterial blood flow through sinusoidal gaps, prolong time to maximum erection and reduce the rigidity of the erected penis. in most of arteriogenic ed patients, the decrease in penile perfusion is common. at arteriography of atherosclerotic ed patients, it was observed bilateral diffuse pathologic involvement of penile and cavernous arteries. focal stenosis in penile or cavernous arteries is mostly observed in young patients who have been exposed to pelvic or perineal blunt trauma (31). long-distance bicycle riding is a risk factor for neurogenic and vascular ed (32). in cavernous arteries of old men and men with dm, it were frequently observed fibrotic lesions together with intimal celik4_stesura seveso 08/10/14 12:11 pagina 198 proliferation, calcification or lumen stenosis. nicotine does not only reduce the blood flow of the penis but also inhibits the corporeal smooth muscle relaxation and thus the normal venous occlusion and may affect negatively erectile function. it was reported that ed rate is about 70% at 30 year age in patients who are consuming 1 package of cigarettes per day and at 15 year age in patients who are consuming 2 packages of cigarettes per day (33). as a result of uncontrolled venous leak, blood cannot be maintained in the cavernous bodies and erection cannot be obtained. such group of pathologies account for 2025% of all ed cases. veno-occlusive dysfunction that is an important reason of ed may occur following the below mentioned pathophysiological conditions: 1. presence or development of wide venous channels that drains corpus cavernosum 2. insufficient compression of subtunical and emissary veins that are formed after degenerative changes in tunica albuginea (peyronie’s disease, advanced age, dm) or traumatic damage (penile fracture). in fat tunica albuginea that has lost its elasticity during peyronie’s disease may inhibit the obstruction of emissary veins 107,108. tunica albuginea alteration may contribute to ed in men due to the reduction in elastic fibers and modification of its micro structure. although rare, in patients who underwent to surgery for peyronie’s disease, changes in the subtunical aerolar layer may violate the veno-occlusive mechanism. 3. structural changes in the fibroelastic content of trabecula, cavernous smooth muscle and endothelium may also cause venous leakage. 4. individuals with anxiety may have insufficient neurotransmitter release or excess adrenergic tonus; insufficient smooth muscle relaxation and subsequent insufficient expansion of sinusoids and insufficient compression of subtunical venules may result in ed. it is shown that the changes in ! adrenergic receptors or the decrease of nno release may increase smooth muscle tonus and reduce the relaxation related to endogenous muscle relaxants (34). 5. acquired venous shunts, operative correction of priapism, permanent shunts between glans/cavernosal body or cavernous body/spongiform body may cause ed. 2. neurogenic reasons neurogenic reasons explain approximately 10-20% of ed cases. medial preoptic area (mpoa), paraventricular nucleus and hippocampus are important integration centers for penile erection and sexual drive. pathological situations that affect these regions such as parkinson’s disease, stroke, encephalitis or temporal lobe epilepsy are generally associated with ed. the negative effect of parkinson’s disease on erectile function may occur as a result of the imbalance in dopaminergic pathways. tumor, dementia, alzheimer’s disease, shy-drager syndrome and trauma are other important brain lesions accompanying ed. the grade of erectile function in spinal cord traumatic patients is mostly related to the quality, location and prevalence of the spinal lesion. while reflex in the upper motor neuron complete lesions of spinal cord is conserved at about 95%, erection can be provided in only 25% in the lower motor neuron complete lesions (35). it is known that sacral parasympathetic neurons have an important role in the protection of reflex of erection. furthermore thoracolumbar pathway may compensate the losses related to sacral lesion via synaptic connections. other diseases at spinal level (spina bifida, discal hernia, syringomyelia, tumor, transverse myelitis and multiple sclerosis etc.) may affect the afferent or efferent nerve pathways similarly (36). 3. post-trauma and post-surgery ed the mechanism of ed that develops after radical prostatectomy or cystoprostatectomy is generally neurogenic but ed may also be due to vascular reasons. after radical surgery, neurogenic lesion may generally develop in the cavernosal nerves in the posterolateral of prostate or in the pelvic plexus. in the past ed frequency after radical prostatectomy or urinary bladder surgeries was estimated about 100%; today this ratio varies between 35% and 68% depending on the surgical clinic, clinical and pathological stage and age of the patient as the result of the development of neuroprotective techniques (37, 38). ed prevalence in the patients exposed to transurethral prostate resection (tur-p) due to benign prostate hyperplasia (bph) varies between 4-10% (39). cavernous nerve progresses at 5 and 7 o’ clock at prostatic urethra level, 3 and 9 o’clock at membranous urethra level and 11 and 1 o’clock at penile urethra level. during tur-p, the nerves may be damaged due to the energy released. deep resection and coagulation at cavernous nerve transition points may cause the loss of erection. it is reported that ed develops in 59% after abdominoperineal resections performed for rectum cancer (40). after retroperitoneal lymph node dissection and lumber symphatectomy, and during aorta-iliac and aorta-femoral surgery, ed develops in 10-20% due to the damage of nerves who regulate the reflex of erection (41). due to the surgeries performed for head trauma and intracranial pathologies, influence of limbic system, destruction of hypothalamo-hypophyseal axis and modification of hormonal control may cause ed. like perineal trauma (like overriding) and penis fracture, ed may develop after the traumas causing amendments in the anatomic structure of the penis. additionally traumas causing posterior urethra ruptures destruct the reflex pathways of erection and may cause ed development at a rate of 10-50%. 4. endocrinologic reasons hypogonadism in ed patients is a commonly seen pathology. any disorder in hypothalamo-hypophyseal axis may result in hypogonadism. as hypogonadotropic hypogonadism can be congenital, it may also develop depending on a tumor or trauma. hypergonadotropic hypogonadism develops as a result of various causes such as tumor, trauma, surgery or mumps orchitis. hypophysis adenoma or drug-induced hyperprolactinemy can also cause ed. in hyperprolactinemy cases, symptoms such as decrease in libido, ed, galactorrhea, gyneacomastia and infertility may occur. high serum prolactin levels suppress the releasing hormone levels and reduce the testosterone levels. ed can be seen together with hyperthroidism and hypothyroidism. hyperthyroidism is associated to loss of libido that may be caused by the increase of levels of cir199archivio italiano di urologia e andrologia 2014; 86, 3 current evaluation of erectile dysfunction celik4_stesura seveso 08/10/14 12:11 pagina 199 archivio italiano di urologia e andrologia 2014; 86, 3 o. celik, t. ipekci, i. akarken, g. ekin, turker koksal 200 culating estrogen and rarely with ed. in hypothyroidism, plasma testosterone is decreased because of the reduced testosterone binding globulin. as a result, hypothyroidism may participate in ed pathogenesis by causing low testosterone release and high prolactin level. 5. diabetes mellitus and ed dm is a chronic disease that is commonly seen throughout the world with a prevalence ranging 0.5-2%. ed prevalence is three times more frequent in diabetic men (%28/%9,6). diabetic ed occurs in young age and its incidence is the course of the disease. although ed is seen more frequently in patients with neuropathic complications, its relationship with vascular damage is not yet clear. dm causes ed due to various physiopathologic mechanisms involving psychological functions, central nervous system functions, androgen release, peripheral nerve activation, endothelial cell proliferation and smooth muscle cell contraction (42). in comparison to non-diabetic men, major atherosclerotic vascular lesions are seen 40 times more frequently in diabetic men and frequently dm accompanies ed. in men with dm, it was demonstrated that there is a decrease in the quantity and rigidity of night erections during sleep. again some studies have specified that penile arterial insufficiency occurred in men with dm with rate ranging 75-100% (43). the presence of ultra-structural changes is seen in the cavernosal tissues of diabetic men. these can be summarized as increased collagen ratio at smooth muscle level, thickening in basal lamina and loss of endothelial cells (41). it was also shown that there is a significant decrease in the relaxation responses to endothelial and neuronal no. it was observed that neurogenic no formation was significantly decreased in men with vascular ed when compared to patients with non-vascular ed and controls. a possible etiology that explains all these findings is the advanced stage of glycation end products (age) levels that are seen in diabetics. in various studies there are evidences showing alterations of the mechanisms causing no release in relation to the increase of free oxygen radical production in diabetes that causes the decrease of vasodilatator response. 6. ed related to ageing and chronic diseases in the literature, it is shown that there is a progressive deterioration in sexual functions due to ageing in healthy men. changes, as prolongation of time to erection, erection weakening, strong loss of ejaculation, decrease in the ejaculate volume and prolongation in the resting period between two sexual intercourses have been described in association with ageing. hypertension is an independent risk factor in the development of ed (44) and ed is seen more frequently in the patients who are treated for hypertension. complications developed after hypertension such as ischemic heart disease and renal insufficiency increase the prevalence of ed. severe ed prevalence in men submitted to hemodialysis for chronic renal insufficiency (cri) is reported as high as 45% (45) and risk increases with increasing age, dm and not using angiotensin-converting enzyme (ace) inhibitors. various physiopathological effects such as permanent uremia, deterioration in the hypothalamus-hypophysis-testis sex hormone axis, hyperprolactinemia, increase in atheromatous diseases and psychological diseases cause ed development (46). chronical diseases such as tuberculosis, tumors, leukemia can also cause loss of libido and ed. in scleroderma the rate of ed is about 60% due to thin penile arteries. in a study performed in brucella patients it is reported a ed rate of 68% in parallel with the duration of disease. 7. ed related to priapism and peyronie’s disease priapism is a pathological penile erection that is not related to sexual stimulation or that continues after sexual stimulation. sickle cell anemia, trauma, neuoplasias, leukemia, intracavernosal injection, total parenteral nutrition and drugs (anti-depressants, anti-psychotics, ! blockers as prazosin, heparin, warfarin, cocaine, etc.) are the agents that cause priapism. ed is observed in patients with priapism at a rate of about 11% (47). peyronie’s disease is one of the pathologies that affect the penis anatomy. ed incidence in peyronie’s disease is related to the severity of the disease. it is reported that anomalies due to the plaque have been observed at nocturnal penile tumescence in 5-7%. conclusion in historical literature erection physiology was explained by different mechanisms. aristo described 3 nerve fibers that carry spirit and energy to the penis and explained penile erection by air ingress (13), in 1504 leonardo da vinci showed that there is blood in the penis of men who were hung on (14), in 1573 varolio showed that ischiocavernous and bulbocavernous muscles constrict the penis stem to achieve erection. finally in 1585 in the book titled “ten books and production book about surgery”, ambroise pare described the penis as formed of concentric layers including nerves, veins, arteries,two ligament (corpora cavernosa), an urinary system and four muscles in 1585 in the book titled “ten books and production book about surgery” (11, 14). these observations show us that ed has been a popular research area throughout history. we suggest that researches will be effective in increasing the knowledge of the etiology and pathophysiology of ed especially at molecular level and will offer us a deeper insight in the future. references 1. consensus development conference statement. national institutes of health. impotence. december 7-9, 1992. int j impot res. 1993; 5:181-284. 2. boylu u, miroglu c. history of erectile dysfunction. bju inter national. 2002; 90:433-441. 3. walsh pc. campbell’s urology. 2005; 2:1591-2. 4. mckinlay jb. the worldwide prevalance and epidemiology of erectile dysfunction. int j impot res. 2000; 12(suppl 4):6-11. 5. rosen rc, fisher wa, eardeley i. the multinational mens’s attidues to life events and sexuality (males) study: prevalence of erectile dysfunction and related health concerns in the general population. curr med res opin. 2004; 20:607-17. 6. selvin e, burnett al, platz ea. prevalence and risk factors for erectile dysfunction in the us. am j med. 2007; 120:151-7. 7. laumann eo, paik a, rosen r. sexual dysfunction in the united states: prevelance and predictors. jama 1999; 21:537. celik4_stesura seveso 08/10/14 12:11 pagina 200 8. lindau st, schumm lp, laumann eo, et al. a study of sexuality and health among older adults in the united states. n engl j med. 2007; 357:762-74. 9. tellaloglu s, kadıoglu a. male sexual dysfunction. nobel medical, istanbul 2000. 10. akkus e, kadıoglu a, esen a. prevalence and correlates of erectile dysfunction in turkey: a population-based study. eur urol. 2002; 41:298-304. 11. feldman ha, goldstein i, hatzichristou dg. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 12. eardley i, sethia k. erectile dysfunction: current investigation and treatment. 1998:1-4. 13. costabile ra. optimizing treatment for diabetes mellitus induced erectile dysfunction. j urol. 2003; 170:35-38. 14. vickers ma, wright ea. erectile dysfunction in the patient with diabetes mellitus. am j manag care. 2004; 100(suppl 1):3-11. 15. lewis rw. epidemiology of erectile dysfunction. urol clin north am. 2001; 28:209-16. 16. nicolai mp, van bavel j, somsen ga, et al. erectile dysfunction in the cardiology practice-a patients' perspective. am heart j. 2014; 167:178-85. 17. oaks ww, moyer jh. sex and hypertension. med asp hum sex. 1972; 6:128-37. 18. burchardt m, burchardt t, baer l et al. hypertension is associated with severe erectile dysfunction. j urol. 2000; 164:1188-91. 19. silvestri a, galeta p, cerquetani e. report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and isreversed by placebo. eur heart j. 2003; 24:1928-32. 20. kaufman jm, hatzichristou dg, mulhall jp. impotence and chronic renal failure: a study of the hemodynamic pathophysiology. j urol. 1994; 151:612-8. 21. bellinghieri g, santoro d, mallamace a, savica v. sexual dysfunction in chronic renal failure. j nephrol. 2008; 21(suppl 13):s113-7. 22. salvatierra o, fortmann jl, bezler fo. sexual function of males before and after renal transplantation. urology. 1975; 5:64-6. 23. yavuz d, acar fn, yavuz r, et al. male sexual function in patients receiving different types of renal replacement therapy. transplant proc. 2013; 45:3494-7. 24. ko dt, hebert pr, coffey cs, et al. beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. jama. 2002; 288:351. 25. anafarta k ,özdiler e, aydos k. penile erection and impotance. in clinic andrology, ankara university publishing, ankara 2000, pp 337-377. 26. steers wd. neural control of penile erection. semin urol. 1990; 8:66-70. 27. kim sc, oh mm. norephinephrine involvement in response to intracorporeal injection of papaverine in psychogenic impotance. j urol. 1992; 147:1530-1532. 28. virag r, bouily p, frydman d. is impotance an arterial disorder: a study of arterial risk factors in 440 impotant men. lancet. 1985; 1:181-184. 29. greinstein a, chen j, miller h, et al. does severity of ischemic coronary disease correlate with erectile function? int j impot res. 1997; 9:123-126. 30. morley je, korenman sg, kaiser fe, et al. relationship of penile brachial pressure index to myocardial infarction and sesrebrovascular accidents in older men. am j med. 1988; 84:445-448. 31. levine fj, greenfield aj, goldstein i. arteriographigally determined occlusive disease within the hypogastric-cavernous bed in impotent patients following blunt perineal and pelvic trauma. j urol. 1990; 144:1147-1153. 32. ricchiuti vs, haas ca, sftel ad. pudental nevre injury associated with avid bicycling. j urol. 1999; 162:2099-2100. 33. rosen mp, greenfield aj, walker tg. cigarette smooking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotance. j urol. 1991; 145:759-763. 34. christ gj, maayani s, valvic m, melman a. pharmacologic studies of human erectile tissue: characteristics of spontaneous contractions and alterations in alpha adrenoceptor responsiveness with age and disease in isolated tissues. br pharmacol. 1990; 101:375-381. 35. eardley i, kirby rs. neurogenic impotence. in rs kirby, cc carson, cc webster,gd webster (eds.) impotence: diagnosis and management of male erectile dysfunction, oxford: butterworthheinemann 1991; pp 227-231. 36. courtois fj, mac dougal jc, sachs bd. erectile mechanism in paraplegia. physiol behav. 1993; 53:721-726. 37. quinlan dm, epstein ji, carter bs, walsh pc. sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. j urol. 1991; 145:998. 38. leach ge. potency evaluated after radical retropubic prostatectomy. clin perp. 1992; 5:1. 39. soderdahl dw, knight rw, hansberry kl. erectile dysfunction following transurethral resection of the prostate. j urol. 1996; 156:1354-1356. 40. nehra a, moreland rb. neurologic erectile dysfunction. urol clin north am. 2001; 28:289-308. 41. nusbaum mr. erectile dysfunction: prevelance, etiology and major risk factors. j am osteopath assoc. 2002; 102-1-6. 42. dunsmuir wd, holmes s. the etiology and management of erectile, ejaculatory and fertility problems in men with diabetes mellitus. diabet med. 1996; 13:700-708. 43. bemelmans blh, meuleman ejh, doesburg wh, notermans lh, debruyne fmj. erectile function in diabetic men: the neurological factor revisited. j urol. 1994; 151:884-889. 44. burchardt m, burchardt t, baer l, et al. hypertension is associated with severe erectile dysfunction. j urol. 2000; 164:1188-1191. 45. rosas se, joffe m, franklin e, et al. prevelance and determinants of erectile dysfunction in haemodialysis patient. kidney int. 2001; 59:2259-66. 46. ayub w, fletcher s. end stage renal disease and erectile dysfunction: is there any hope? nephrol dial transplant. 2000; 15:1525-28. 47. iacono f, bara s, de rosa g. microstructural disorders of tunika albuginea in patients affected by impotance. eur urol. 1994; 26:233-239. 201archivio italiano di urologia e andrologia 2014; 86, 3 current evaluation of erectile dysfunction correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com ilker akarken, md gokhan ekin, md tepecik education and research hospital, urology clinic, gaziler cd.no:468 35110, yenisehir, izmir, turkey i. turker koksal, md, prof tumay ipekci, md akdeniz university, faculty of medicine, department of urology 07070 antalya, turkey celik4_stesura seveso 08/10/14 12:11 pagina 201 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3204 original paper pde-5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction luis labairu-huerta 1, bárbara padilla-fernández 2, josé luis arrondo-arrondo 3, lauro sebastián valverde-martínez 4, agustín martín-rodríguez 4, juan miguel silva-abuín 5, maría begoña garcíacenador 6, josé antonio mirón-canelo 7, maría fernanda lorenzo-gómez 4, 6, 8 1 department of urology, university hospital of donostia, spain; 2 department of urology, university hospital of the canary islands, tenerife, spain; 3 department of urology, hospital of navarra, spain; 4 department of urology, university hospital of salamanca, spain; 5 department of urology, university hospital of san pedro, logroño, spain; 6 department of surgery, university of salamanca, spain; 7 department of preventive medicine and public health, university of salamanca, spain; 8 urological renal multidisciplinary research group of the biomedical research institute of salamanca (ibsal), spain. objectives: to compare the effectiveness in the treatment of erectile dysfunction when using pde-5 inhibitors (pde5i), alprostadil (pg-e1) and testosterone (tes) in monotherapy or combination therapy. material and methods: observational multicentre retrospective study of men diagnosed and treated for ed between january 2008 and january 2014. age, social and employment situation, pathological medical history, risk factors, usual treatments, iief-5 at the first consultation and at first and each 6 months follow-ups, physical examination, calculated total and free testosterone and received treatment were analysed. descriptive statistics, one-way anova analysis, chi2 for qualitative data, t-test, fisher's exact test and pearson's correlation coefficient were used; p < 0.05 is considered significant. results: average age was 58.61 years, sd5.02, average follow-up time 48.21 months, sd 6.21, range 6-174 months. out of the patients 76.12% were married, 9.81% divorced/separated, 10.04% single, 4.03% widowed; 85.14% of the total in stable partnership but 66.16% were not accompanied by their partners. in total 844 patients received monotherapy (597 pde5i; 62 pg-e1; 36 tes; 27 penile prosthesis; 121 psychotherapy/alternative therapies) and 357 combination therapy (167 pde5i+tes; 124 pde5i+pge1; 66 pg-e1+tes). there was a homogeneous distribution between risk factors and medical history groups. satisfactory response according to iief-5 was achieved for 72.33% of patients on pde5i monotherapy, 46.65% of patients on pde5i+pg-e1 combination therapy and 83.41% of patients on pde5i+tes. conclusions: the best therapeutic success for ed in this series was achieved through a combination of testosterone+pde-5 inhibitors without increasing morbidity and maintaining the response over time. larger studies with longer follow-up will corroborate these findings. key words: erectile dysfunction; combination therapy; pde-5 inhibitors; testosterone. submitted 8 january 2015; accepted 31 march 2015 summary no conflict of interest declared. introduction erectile dysfunction (ed) is defined as the persistent and/or recurrent inability to achieve and maintain sufficient rigidity of penis to allow satisfactory sexual performance (1), extended for at least three months, except for the cases secondary to trauma or surgery, or those cases problematically experienced by the patient (2). the world health organization expressly recognizes that sexual health is a basic right of the individual and that erectile dysfunction is a serious disease that changes the quality of life of those suffering it, their partners and families, and that can be framed in the group iii (3, 4). ed is currently considered a health indicator, i.e. an alarm signal that can predict the presence of serious cardiovascular diseases (5). however, most cases have a multifactorial origin and for almost all men, ed will be accompanied by some psychological disorder that is sometimes the only cause of the dysfunction perpetuation (6). the main objective of the treatment strategy for ed patients is to determine the aetiology of the disease, to treat it whenever possible and not to treat only the symptoms. on the 1st international consultation on ed, it was established that modifiable risk factors should be corrected for initial treatment, and that therapeutic proposals staggered from the least to the most aggressive and individualised for each patient should be provided (3). the first-line drug treatment is established with phosphodiesterase-5 inhibitors; testosterone should be used for patients with proved hypogonadism, and prosta glandin-e1 for those who don’t respond or cannot take pde5i (7). however, we postulate that monotherapy with pde-5 inhibitors (pde5i), prostaglandin e1 (pg-e1) and testosterone (tes) may be less effective than combination therapy with 2 or 3 components. doi: 10.4081/aiua.2015.3.204 labairu-huerta_stesura seveso 30/09/15 09:31 pagina 204 205archivio italiano di urologia e andrologia 2015; 87, 3 combination therapy in erectile dysfunction materials and methods a retrospective observational multicentre study was designed in order to assess the effectiveness of different therapeutic modalities for ed. medical records of men diagnosed and treated for ed between january 2008 and january 2014 at the andrology consultations of the university hospital of salamanca and the hospital of navarra were reviewed. age, social and employment situation, pathological medical history, risk factors, usual treatments, iief and iief5 questionnaire score at the first consultation and at first month and each 6 months follow-ups, physical examination, calculated total and free testosterone and received treatment were collected. a descriptive study of the distribution of the frequency of every studied qualitative variable, and the corresponding descriptive statistics (central tendency and dispersion measures) of the quantitative variables included in the study (univariate analysis) was carried out for the statistical treatment of the information. a variables association study (bivariate analysis) was then performed in order to assess the relationship, statistically significant, p < 0.05, among the variables included in the study. parametric and nonparametric tests based on the characteristics of the variables and the adequate procedures and tests have been used in this process. the response to the 5 questions iief questionnaire was classified as follows: no response (0): score between 5 and 16; partial/slight response (1): score between 17 and 21; satisfactory response (2): score between 22 and 25. results during the study period, 1200 men diagnosed and treated for ed were identified in salamanca and navarra (spain). the average age was 58.61, ranging between 43 and 75. the average follow-up time was 48.21 months, sd 6.21 with a minimum follow-up time of 6 months and a maximum of 174 months. out of all the patients 76.12% were married, 9.81% divorced or separated, 10.04% single and 4.03% widowed (figure 1). in general 85.14% of the total reported having a stable partner, but 66.16% were not accompanied by their partners. furthermore, 61.83% reported having normal ejaculations and 35.02% reported maintaining normal sexual desire. in total 844 patients were in treatment with monotherapy and 356 with combination therapy. eight groups were differentiated according to the drug received: group a: phosphodiesterase inhibitors 5; group b: alprostadil; group c: testosterone; group d: penile prosthesis; group e: other treatments (psychotherapy, alternative therapies); group f: pde5i and testosterone combination; group g: pde5i and alprostadil combination; group h: alprostadil and testosterone combination. table 1 shows the number of patients included in each group. table 2 shows a summary of the patients’ response to the iief-5 questionnaire in the different study groups. at the first visit, all patients have an unsatisfactory erectile function; then the percentage of intra-group patients regarding the satisfaction degree at first month and each 6 months follow-ups after establishing the different therapeutic measures is shown in percentage. regarding the medical history of men, 42.01% suffered from hypertension; 20.03% from diabetes mellitus; 30.42% from obesity (bmi > 30); 11.30% from some type of heart disease and 10.32% from psychiatric disorders. furthermore 64.33% were active smokers (5-40 cigarettes /day) and 69.39% reported alcohol consumption of 20 g or higher. the patients were on polypharmacy in 70.01%: 46.38% was taking anti-hypertensive drugs, 12.24% 5α-reductase inhibitors and 10.09% antidepressant. finally 6.52% of patients suffered from prostate cancer and 3.02% had undergone radical prostatectomy. no statistically significant differences between groups regarding these records were proved. satisfactory response was found for 72.33% of patients under pde5i monotherapy, 46.65% of patients under combination therapy with pde5i+ pg-e1 and 83.41% of patients under pde5i+tes. the mortality in the series was 2.01%, although these deaths were not related to ed. in fact there was no relation between death and erectile dysfunction or received treatment in any case. administration of tes was stopped in two cases due to figure 1. distribution of married, divorced or separated, single and widowed patients. treatment received number of patients monotherapy pde5i vardenafil 20 mg 272 sildenafil 25-50-100 mg 171 tadalafil 10-20 mg 154 alprostadil 62 testosterone 36 penile prosthesis 27 others 121 combination pde5i+tes 167 therapy pde5i+pg-e1 124 pg-e1+tes 66 table 1. distribution of patients included in each group. labairu-huerta_stesura seveso 30/09/15 09:31 pagina 205 archivio italiano di urologia e andrologia 2015; 87, 3 labairu-huerta, padilla-fernández, arrondo-arrondo, valverde-martínez, martín-rodríguez, silva-abuín, garcía-cenador, mirón-canelo, lorenzo-gómez 206 the increase in packed cell volume, in one case due to psa increase with no confirmation of prostate cancer after biopsy and in two other cases due to mood changes. the overall response to the treatment was satisfactory in 70.04%, partial in 16.09% and there was no response in 13.87%. no changes were seen in the annual follow-ups (p = 0.4836) after analysing the responses to the iief questionnaire. discussion a number of studies have shown the importance of sexual health and its direct influence on psychological wellbeing of individuals and their partners (4). society evolution is oriented towards a even greater importance of sexual health in the future (8). however, it is estimated that only 16.5% of patients with erectile dysfunction go to the doctor in order to be diagnosed and treated, mainly because both doctors and patients are still reluctant to treat sexual issues openly at the consultation. it is estimated that over 320 million men will suffer from ed in western countries, which means more than twice the observed prevalence 15 years ago. this invites us to reassess the therapeutic strategy of this pathology (9, 10). the main objective of the treatment strategy for patients with ed is to determine the aetiology of the disease, to treat it whenever possible and not to treat only the symptoms. it is very important to encourage changes in the patient’s lifestyle in order to decrease the incidence of cardiovascular diseases (11): doing regular exercise, stop smoking, healthy diet, drinking little alcohol. the potential benefits of lifestyle changes may be particularly important in patients with ed and selected concomitant cardiovascular or metabolic diseases such as diabetes or hypertension (12, 13). in fact, studies show that intensive changes in lifestyle not only improve erectile function, but can be also beneficial for overall cardiovascular and metabolic health (14). once risk factors are identified and corrected, the first-line drug treatment is established with phosphodiesterase-5 inhibitors in monotherapy, with a broad safety profile even in patients with multiple pathologies, considering combination therapy as second-line (15). the main reason why a patient does not use properly pde5i is the inadequate advice of the physician, who may encourage not using adequate sexual stimulation, not using the appropriate dose or not waiting enough time between the drug intake and the attempt of intercourse (16). a drug must be taken at least 6 times in order to test its effectiveness (17) and it must be taken at maximum dose. furthermore, the right patient education has been found to help achieving the effective response of a pde5 inhibitor without apparent previous response after underlining the importance of dose, the moment of intake and the necessary sexual stimulation (18, 19). a second-line setting was performed in one study and patients treated with tadalafil were advised to wait at least two hours; the patients treated with vardenafil were advised to use it fasting, rescuing patients with no apparent response (20). chronic therapy with pde5i is safe and is an alternative in the treatment of ed in any degree or aetiology, although no subpopulation of men with ed taking. greater advantages from chronic therapy has been identified, but it is promoted as the best alternative for men who seek for more naturalness and spontaneity. furthermore, chronic inhibition of pde-5 might be a treatment of endothelial dysfunction. tadalafil 5 mg is the only drug approved in this sense (21). two non-randomized trials have showed that daily intake of a pde5i can rescue some patients who do not respond to intermittent administration: in one study, some patients benefited from regular administration of vardenafil or tadalafil (22); in other study, daily administration of tadalafil rescued patients who had not responded to intermittent administration of a pde-5 inhibitor (23). tadalafil is the only drug approved for daily administration of a dose of 2.5 to 5 mgr. sildenafil, tadalafil and vardenafil can be nowadays considered equally effective and safe, therefore it is postulated that patients should have the opportunity of trying the three drugs and then select the one that best suits their sexual habits and is most effective (24). some authors have studied the pharmacological combination value in ed, especially in those cases refractory to conventional treatment (10, 25). in patients with testosterone deficiency, normalization of serum testosterone may improve the response to pde5i: shabsigh et al. (26) studied the administration of testosterone gel and sildenafil 100 mgr versus sildenafil 100mgr in a double-blind 1st v f/u 1st month f/u 12 months f/u 24 months f/u 36 months f/u 48 months f/u 72 months response to iief-5 0 (%) 0 (%) 1 (%) 2 (%) 0 (%) 1 (%) 2 (%) 0 (%) 1 (%) 2 (%) 0 (%) 1 (%) 2 (%) 0 (%) 1 (%) 2 (%) 0 (%) 1 (%) 2 (%) group a 100 12 14 74 13 15 72 14 15 71 15 15 70 15 16 69 14 15 66 group b 100 5 30 65 6 31 63 7 30 63 6 31 63 7 32 61 8 30 60 group c 100 47 6 47 42 14 44 40 16 44 38 18 44 36 18 46 33 19 47 group d 100 19 24 57 18 25 57 19 25 56 18 26 56 17 26 57 15 24 56 group e 100 54 18 28 50 20 30 51 21 28 52 22 26 55 23 22 53 21 20 group f 100 6 11 83 6 10 84 5 11 84 5 12 83 5 11 84 6 10 82 group g 100 20 36 44 19 37 44 18 38 44 19 36 45 20 36 44 21 33 40 group h 100 13 50 37 12 50 38 11 51 38 12 50 38 10 49 41 9 45 42 table 2. summary of the patients’ response to the iief-5 questionnaire in the different study groups. labairu-huerta_stesura seveso 30/09/15 09:31 pagina 206 207archivio italiano di urologia e andrologia 2015; 87, 3 combination therapy in erectile dysfunction study with 75 hypogonadal men with ed for 12 weeks. combination therapy group patients significantly improved the iief-ef domain (4.4 vs. 2.1) and better but not significant scores were observed in the iief-q3q4. one patient left the combination therapy due to adverse event. aversa et al. (27) assessed administration of patches of testosterone 5 mgr and sildenafil 100 mgr versus sildenafil 100 mgr in monotherapy. in this nonmasking study, 77 hypogonadal men with ed were studied for one month. the group under combination therapy had a significant improvement of the iief (21.8 vs. 14.2), of the number of intercourses (2.8 vs. 1.5), of satisfactory intercourses (12.1 vs. 7.7) and of erections (80% vs. 10%). the testosterone replacement therapy can be provided with gel at 1% achieving improvement from the first month in the iief, although with no statistical significance (26). the hypogonadal men can receive trt and add tadalafil with good response or receive vardenafil when they do not respond to testosterone undecanoate monotherapy, with good response in 88% and better satisfaction of their partners (26). in another case series published by greenstein et al. (28), it was observed that in 17 out of 49 hypogonadal patients in whom tes monotherapy had failed, a significant improvement of erectile function according to the iief questionnaire was achieved after combination with sildenafil. in addition, all the 49 patients reported to be satisfied with their erections under combination therapy. prevalence of total testosterone deficiency in men with ed is highly variable depending on the assessed studies, showing a broad range from 1.72% to 47.7%, although studies with largest number of patients set it at 5.7% (29), 6.65% (30) or 15% (31). a significant association between the decrease of free testosterone and insulin resistance has also been proved, which could justify the use of tes as combination therapy in diabetic patients without prostate cancer (32). tes replacement therapy is contraindicated in patients with history of prostate cancer or with prostatism symptoms. rectal examination and a psa test should be performed before starting this treatment. clinical response and emergence of liver disease or prostate condition (33) should be then controlled. there are no contraindications in the use of tes in men with coronary disease correctly diagnosed as hypogonadism or ed, although packed cell volume should be monitored and testosterone dose adjustment may be necessary, especially in patients with congestive heart failure. the pg-e1, marketed as alprostadil, is considered the second-line treatment, mainly administered as intracavernous injections at 5-40 mg doses (11). the right technique for the drug administration should be taught to the patient, which is also useful in order to verify successful response to the treatment. effectiveness’ rates are around 70%; sexual activity is presented after 94% of injections, with satisfaction rates ranging from 87 to 93.5% in patients and from 86 to 90.3% in their partners (11). intracavernous therapy is however accompanied by high dropout rates ranging from 41 to 68% and its compliance is limited (34). the first combination of intracavernous therapy was performed by zorgniotti in 1985 with papaverine and phentolamine (35). it is still indicated in patients with pg-e1 painful injections or when pg-e1 monotherapy becomes ineffective (36). a physiological study proves that this combination therapy of ici with trimix and sildenafil has better results in doppler ultrasound and higher increase of guanosine monophosphate (cgmp) and adenosine monophosphate (camp) in the corpus cavernosum (37). only two studies were published about this combination therapy in patients who did not report problems with priapism and referred difficulty in adjusting doses: the first study included 93 patients who did not responded to ici (trimix), of which 34% responded to sildenafil as rescue therapy; 48% of the rest had a good response to combination therapy, but had more side effects (38). the second study with 22 post-rp patients, in which better results were obtained by combination therapy (sildenafil + trimix) versus monotherapies (39). the use of sildenafil and alprostadil has been successful after failure of monotherapy with sildenafil, although success rates vary from 47 to 100% (25). this therapy has been used even in patients who had undergone retro-pubic radical prostatectomy with nerve preservation, with satisfactory results (39, 40). the key to the success of this association is the use of two different cavernous ways: pde5 inhibitors indirectly relax body’s smooth muscle by inhibiting the metabolism of cyclic guanosine monophosphate, for which nitric oxide is required; pge1 directly relaxes trabecular smooth muscle tissue through e-prostanoid receptors, which leads to an increase of cyclic adenosine monophosphate. therefore, the use in combination of these two drugs theoretically allows a therapeutic synergy to activate two different but inter-related ways (10, 41). in our series, patients did not report suffering severe adverse effects with this combination, and in particular no higher incidence of priapism compared to monotherapy group. there is no scientific evidence of previous use of pg-e1 and tes in combination therapy (10). in one study with 120 men who had not responded to sildenafil or intraurethral alprostadil monotherapy, it is assessed what happens when both are combined. none stopped the combination therapy due to adverse effects and they improved the iief score (42). other studies have reported the same with smaller series of patients (43), even in patients who had undergone radical prostatectomy who had not responded to monotherapy and in both studies with no increase of adverse effects after combination therapy (44). a metaanalysis with 515 men with ed and luts concluded that combination therapy is more effective than pde5i, with better scores on the iief questionnaires, ipss, and peak flow (45). a meta-analysis with 398 men showed better effectiveness and greater adherence to treatment when psychosexual therapy is combined with pde5i in comparison to simple administration of pde5i (46, 47). conclusions the best therapeutic success for ed in our series is achieved by combining testosterone and pde-5 inhibitors without increasing morbidity and keeping the response over time. waiting for the results of monotherapy instead of establishing a combination therapy initiallabairu-huerta_stesura seveso 30/09/15 09:31 pagina 207 archivio italiano di urologia e andrologia 2015; 87, 3 labairu-huerta, padilla-fernández, arrondo-arrondo, valverde-martínez, martín-rodríguez, silva-abuín, garcía-cenador, mirón-canelo, lorenzo-gómez 208 ly leads to lower success of therapy as well as to stop trying and a more negative attitude. it also increased anxiety of patients who did not have a satisfactory answer. we advise using combination drug therapies as the effects are well known and different in order to promote synergy of treatment by helping to solve the various mechanisms involved in erectile dysfunction. larger studies with longer follow-up will corroborate these findings. references 1. resel estévez l, silmi moyano a, moreno sierra j. disfunción eréctil. 2004. 2. ralph d, mcnicholas t. uk management guidelines for erectile dysfunction. bmj. 2000;32:499-503. 3. erectile dysfunction. world health organization, editor. oxford. united kingdom.: health publication ltd. plymouth.; 2000. 4. feldman h, goldstein i, hatzichristou d, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-6. 5. burchardt m, burchardt t, anastasiadis a, et al. erectile dysfuncion is a marker for cardiovascular complications and psychological functioning in men with hypertension. int j impot res. 2001; 13:276-81. 6. martín morales a, díaz f, garcía e. epidemología y etiopatogenia de la disfunción eréctil. in: rodríguez vela l, rioja sanz l, editors. actualización en andrología. barcelona: ediciones pulso; 2000. 7. eardley i, donatucci c, corbin j, et al. pharmacotherapy for erectile dysfunction. j sex med 2010; 7(1pt2):524-40. 8. fugl-meyer a, lodnert g, bräholm i, fugl-meyer k. on life satisfaction in male erectile dysfunction. int j impot res. 1997; 9:141-8. 9. mckinlay j. the worldwide prevalence and epidemiology of respective pdes, could achieve greater enhanceerectile dysfunction. int j impot res. 2000; 2(suppl 4):s6-11. 10. dhir rr, lin h-c, canfield se, wang r. combination therapy for erectile dysfunction: an update review. asian j androl. 2011; 13:382-90. 11. hatzimouratidis k, amar e, eardley i, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. european urology. 2010; 57:804-14. 12. moyad m, barada j, lue t, et al. sexual medicine society nutraceutical committee. prevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: what works and what is worthless, part i. urol clin north am. 2004; 31:249-57. 13. moyad m, barada j, lue t, et al. sexual medicine society nutraceutical committee. prevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: what works and what is worthless, part ii. urol clin north am. 2004; 31:259-73. 14. esposito k, giugliano f, di palo c, et al. effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. jama. 2004; 291:2978-84. 15. lue t. erectile dysfunction. n engl j med. 2000; 342(suppl. 24):1802-13. 16. hatzimouratidis k, amar e, eardley i, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol 2010; 57:804-14. 17. rajagopalan p, mazzu a, xia c, dawkins r, sundaresan p. effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. j clin parmacol 2003; 43:260-7. 18. mccullough ar, barada jh, fawzy a, et al. achieving treatment optimization with sildenafil citrate (viagra) in patients with erectile dysfunction. urology. 2002; 60(2 suppl 2):28-38. 19. gruenwald i, shenfeld o, chen j, et al. positive effect of counseling and dose adjustment in patients with erectile dysfunction who failed treatment with sildenafil. eur urol 2006; 50:134-40. 20. hatzichristou d, moysidis k, apostolidis a, et al. sildenafil failures may be due to inadequate patient instructions and follow-up: a study on 100 non-responders. eur urol 2005;47:518-22; discussion 22-3. 21. fusco f, razzoli e, imbimbo c, et al. a new era in the treatment of erectile dysfunction: chronic phosphodiesterase type 5 inhibition. bju international. 2010; 105:1634-9. 22. mcmahon c. efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. j sex med 2004; 1:292-300. 23. hatzimouratidis k, moysidis k, bekos a, et al. treatment strategy for "non-responders" to tadalafil and vardenafil: a real-life study. eur urol 2006; 50:126-32; discussion 32-3. 24. wespes e, eardley i, giuliano f, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature eyaculation. arnheim, the netherland, 2013. 25. sommer f, engelmann u. future options for combination therapy in the management of erectile dysfunction in older men. drugs & aging. 2004; 21:555-64. 26. shabsigh r, kaufman j, steidle c, padma-nathan h. randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. j urol. 2004; 172:658-63. 27. aversa a, isidori a, spera g, et al. androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. clin endocrinol (oxf). 2003; 58:632-8. 28. greenstein a, mabjeesh n, sofer m, et al. does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? urology. 2005; 173:530-2. 29. earle c, stuckey b. biochemical screening in the assessment of erectile dysfunction: what tests decide future therapy? urology. 2003; 62:727-31. 30. buvat j, lemaire a. endocrine screening in 1,022 men with erectile dysfunction: clinical significance and cost-effective strategy. j urol. 1997; 158:1764-7. 31. el-sakka a, hassoba h, sayed h, tayeb k. pattern of endocrinal changes in patients with sexual dysfunction. j sex med. 2005; 2:551-8. 32. guay a, jacobson j. the relationship between testosterone levels, the metabolic syndrome (by two criteria), and insulin resistance in a population of men with organic erectile dysfunction. j sex med. 2007; 4:1046-55. 33. morales a, heaton j. hormonal erectile dysfunction. evaluation and management. urol clin north am. 2001; 28:279-88. 34. flynn rj, williams g. long-term follow-up of patients with erectile dysfunction commenced on self injection with intracavernosal papaverine with or without phentolamine. br j urol. 1996; 78:628-31. 35. zorgniotti aw, lefleur rs. auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. j urol. 1985; 133:39-41. labairu-huerta_stesura seveso 30/09/15 09:31 pagina 208 209archivio italiano di urologia e andrologia 2015; 87, 3 combination therapy in erectile dysfunction 36. vozmediano r. tratamiento intracavernoso y dispositivos de vacío. in: cruz n, editor. tratado de andrología y medicina sexual 1. sevilla: editorial médica panamericana s.a.; 2011. p. 596-601. 37. park jk, park js, jeon sb, et al. why a combined intracavernosal injection with trimix and oral sildenafil is reliable therapy in the ultrasonographic evaluation of erectile dysfunction. bju international. 2008; 102:993-7. 38. mcmahon cg, samali r, johnson h. treatment of intracorporeal injection nonresponse with sildenafil alone or in combination with triple agent intracorporeal injection therapy. j urol. 1999; 162:1992-7; discussion 7-8. 39. nandipati k, raina r, agarwal a, zippe cd. early combination therapy: intracavernosal injections and sildenafil following radical prostatectomy increases sexual activity and the return of natural erections. int j impot res 2006; 18:446-51. 40. mydlo jh, viterbo r, crispen p. use of combined intracorporal injection and a phosphodiesterase-5 inhibitor therapy for men with a suboptimal response to sildenafil and/or vardenafil monotherapy after radical retropubic prostatectomy. bju international. 2005; 95:843-6. 41. kim n, huang y, moreland r, et al. cross-regulation of intracellular camp and cgmp in cultured human corpus cavernosum smooth muscle cells. mol cell biol res commun. 2000; 4:10-4. 42. mydlo jh, volpe ma, macchia rj. results from different patient populations using combined therapy with alprostadil and sildenafil: predictors of satisfaction. bju international. 2000; 86:469-73. 43. nehra a, blute ml, barrett dm, moreland rb. rationale for combination therapy of intraurethral prostaglandin e(1) and sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy. int j impot res 2002; 14 suppl 1:s38-42. 44. raina r, nandipati kc, agarwal a, et al. combination therapy: medicated urethral system for erection enhances sexual satisfaction in sildenafil citrate failure following nerve-sparing radical prostatectomy. j androl. 2005; 26:757-60. 45. yan h, zong h, cui y, et al. the efficacy of pde5 inhibitors alone or in combination with alpha-blockers for the treatment of erectile dysfunction and lower urinary tract symptoms due to benign prostatic hyperplasia: a systematic review and meta-analysis. j sex med 2014; 11:1539-45. 46. melnik t, soares bg, nasello ag. the effectiveness of psychological interventions for the treatment of erectile dysfunction: systematic review and meta-analysis, including comparisons to sildenafil treatment, intracavernosal injection, and vacuum devices. j sex med 2008; 5:2562-74. 47. schmidt hm, munder t, gerger h, et al. combination of psychological intervention and phosphodiesterase-5 inhibitors for erectile dysfunction: a narrative review and meta-analysis. j sex med 2014; 11:1376-91. correspondence labairu-huerta, luis (corresponding author) luislabairu@hotmail.com department of urology, university hospital of donostia, spain bárbara padilla fernández padillaf83@hotmail.com department of urology, university hospital of the canary islands, tenerife, spain arrondo-arrondo, josé luis jlarrondo@telefonica.es department of urology, hospital of navarra, spain valverde-martínez, lauro sebastián sebasv_2000@hotmail.com martín-rodríguez, agustín drmartinr@hotmail.com department of urology, university hospital of salamanca, spain silva-abuín, juan miguel elviso@usal.es department of urology, university hospital of san pedro, logroño, spain garcía-cenador, maría begoña mbgc@usal.es department of surgery, university of salamanca, spain mirón-canelo, josé antonio miroxx@usal.es department of preventive medicine and public health. university of salamanca, spain lorenzo-gómez, maría fernanda mflorenzogo@yahoo.es department of urology, university hospital of salamanca, spain department of surgery, university of salamanca, spain urological renal multidisciplinary research group of the biomedical research institute of salamanca (ibsal), spain labairu-huerta_stesura seveso 30/09/15 09:31 pagina 209 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4312 original paper comments concerning the real risk of sexual adverse events secondary to the use of 5-aris furio pirozzi farina, antonella pischedda andrological urology unit, aou di sassari. treatment-induced sexual dysfunctions (sd) are a recurrent and controversial topic in recent literature on the adverse events related to the use of 5-alpha-reductase inhibitors (5aris) (1, 2). in order to deal adequately with the various aspects of this topic, it is necessary to first cover some of the steps that allow a better definition and understanding of the subject. key words: 5-alpha-reductase inhibitors (5aris); sexual dysfunctions; benign prostatic hyperplasia (bph); androgenetic alopecia. submitted 9 november; accepted 15 december summary no conflict of interest declared. ondary to bph with a high risk of progression, in order to reduce the incidence of the risks connected with disease progression (10). these risks consist in acute urinary retention (aur) and in the need for surgical treatment for prostatic adenoma (11). over the years, a great number of patients have benefitted from treatment with 5aris, especially those with progressing bph (11). a number of studies performed on patients with bph treated with 5a-ris have reported positive effects such as a reduction in prostatic volume, an improvement in ipss questionnaire scores, an improvement in urinary flow, a reduction in the risk of acute urinary retention and, most importantly, a reduction in the number of patients having to undergo surgical treatment or other invasive or minimally-invasive treatments for bph (11, 12). however, these therapies allegedly have a high risk of important and irreversible side effects that also involve the sexual area (1). in addition to this, finasteride has also been approved for the treatment of androgenetic alopecia (aga) or male pattern baldness, which affects about 50% of males (13). sexual adverse events of treatment with 5a-r inhibitors (also known as post-finasteride syndrome) there are increasingly frequent reports of problems that the use of 5a-ris (finasteride and dutasteride) may cause to sexual health in a subgroup of patients; in some cases, these problems would appear to persist even after the discontinuation of treatment (14, 15). however, there are still very few studies on this subject and knowledge is based either on scientific concepts or on case reports submitted by general practitioners and based on reports by patients (16). in actual fact, a study by erdemir f, et al. (2008) reported that the 5aris used to treat bph, caused erectile dysfunction and/or a loss of libido with an incidence of less than 10%, for both monotherapy and combination therapy (dutasteride + tamsulosin). (17) in this same paper, the authors reported that finasterideand dutasterideinduced sexual dysfunction resolved completely when treatment was discontinued and that, in any case, in approximately 4% of patients, treatment was discontinued due to sexual adverse events. (17) the size of the problem was further put into perspective doi: 10.4081/aiua.2015.4.312 5-a-reductases and their inhibitors 5-a-reductases are enzymes able to reduce the 4,5 bond of c19 and c21 steroids, to create the 5a-reduced steroid of a precursor steroid (3). two of this type of isoenzyme are known: 5a-r type1 (5a-r1) and 5a-r type 2 (5a-r2) (3). both isoenzymes trigger the chain of events that lead to the synthesis of other steroids, of which the best known is 5a-dihydrotestosterone (5a-dht) (3). 5a-dht is the most active androgen in certain expressions of male sexuality (4) and it is also the most involved hormone in prostate gland function and dysfunction. (5) in addition, the many roles played by 5a-dht also include a direct involvement in the tone of the scalp’s piliferous bulbs (6). consequently, the induction of a reduction in the activity of 5-a-reductase, through the administration of 5aris, is a treatment approach useful in the treatment of benign prostatic hyperplasia (bph) (7) and androgenetic alopecia (8), as both diseases are related to 5a-dht. however, at the same time, this treatment also theoretically exposes the subject to repercussions in terms of various expressions of male sexuality. the 5a-ris used for therapy are finasteride and dutasteride. dutasteride is a selective inhibitor of 5a-r1 and 5a-r2 and reduces serum 5a-dht by approximately 90% (9). finasteride is above all an inhibitor of 5a-r2 and is approximately 50 times weaker in inhibiting 5ar1 than 5a-r2; for this reason, finasteride is able to reduce serum 5a-dht by about 70% (9). indications for treatment with 5a-r inhibitors the 5a-ris finasteride and dutasteride were developed for the treatment of patients with urinary disorders sec313archivio italiano di urologia e andrologia 2015; 87, 4 comments concerning the real risk of sexual adverse events secondary to the use of 5-aris by a recent literature review by abdulmaged mt, et al. (2011), in which the finding of sexual adverse events attributed to the use of 5a-ris is compared with data relating to the use of placebo (2). the findings of this review can be summarised as follows: erectile dysfunction 6%-8% vs. 4% with placebo; loss/reduction in libido 1.3%-4.4% vs. 1.8% with placebo and ejaculatory disorders 2.8% vs. 1% with placebo (2). as far as the persistence of sexual adverse events is concerned, an important finding was reported by the medicine health care products regulatory agency (mhra), which, in its 2009 report states, that “... in postmarketing experience, in certain patients the ed that appeared with the introduction of propecia is thought to persist even after discontinuation of the medicinal product”. (medicine health care products regulatory agency (mhra december 2009 sect. 4.8) however, again on the subject of alopecia, sato and takeda (2012) conducted a study on the efficacy and safety of finasteride 1 mg administered for 41 months in 3177 patients with androgenetic alopecia, concluding that the treatment allowed progressive hair growth without any side effects being observed (18). in this contradictory series of data, it can be said that the nature of the persistence of these disorders is still an active field of research. therefore, as a precautionary measure, both doctors prescribing 5a-ris, and patients taking this class of drugs, must be made aware of the potential permanent sexual adverse events that could, according to certain authors, be related to them (19). at this point, the question is: if the reduction in 5a-dht induced by 5a-ris is a sufficient condition to cause sexual dysfunction which, in some cases, can be permanent, why does this not occur in all patients treated, and in particular in those in whom normal sexual function was confirmed prior to treatment? amongst the various hypotheses, it is possible that the answer should be sought in the genetic differences existing between individuals, such as postulable 5a-reductase polymorphisms, which could contribute to an inter-individual variability in the response to 5a-ris (20). regardless of the cause and actual incidence of the risk of sexual adverse events in patients treated with 5a-ris, both clinical and ethical importance undoubtedly vary with the age of patients and the condition for which the 5a-ris are used. for this reason, it is believed that the chronic administration of finasteride 1 mg in young patients with androgenetic alopecia (aga) constitutes a “cosmetic” treatment, although it is also sometimes prescribed to minimise the relational psychological repercussions that hair loss can have. on the other hand, a comparison must be made between the risk of sexual adverse events deriving from the use of 5a-ris (alone or combined with alpha adrenergic blockers) in patients with lower urinary tract symptoms secondary to bph at a high risk of progression, and the far more pressing issue of important sexual and other adverse events deriving from the underlying prostatic condition (acute urinary retention, bph surgery-related symptoms and clinical progression), and the treatment options for bph that are alternative to 5a-ris. specifically, the awareness of all the potential adverse events related to invasive and minimally invasive treatments for bph is very important (21). this balance is well expressed in two pivotal studies conducted on a large number of patients with bph treated with dutasteride 0.5 mg + tamsulosina 4 mg (combat study) (22) and with finasteride 5 mg (pless study) (23). combat study (dutasteride 0.5 mg and tamsulosina 4 mg, in combination or monotherapy); 4844 pt (≥ 50 years) observed for 4 years. (22) the study was conducted to evaluate the efficacy of the therapy with dutasteride and tamsulosin, administered as monotherapy or in combination, in the prevention of major complications secondary to bph: disease progression, acute urinary retention (aur), bph-related surgery (22). this study showed that combination treatment with dutasteride + tamsulosin significantly reduces the relative risk of aur and bph-related surgery (primary endpoint at four years) compared to monotherapy with tamsulosin (22). this study also showed that the incidence of adverse events in the sexual field (ed) drops with the years of use of treatment (22 & avodart european summary of product characteristics february 2011). pless study (the proscar long-term efficacy and safety study); 3040 pt. (45-78 years), observed for 4 years, rct, finasteride vs. placebo (23). – at screening, 46% of patients in both groups said they had a history of sexual dysfunction (sd) (23) – the sexual side effects were only significant during the first year (15% vs. 7%) (23) – there were no significant differences between the second and the fourth year (7% in both groups) (23) – only 4% of patients treated with finasteride and 2% of patients treated with placebo interrupted the study due to sexual adverse events (23) • 50% of patients treated with finasteride said the sd persisted after the suspension of the treatment (23) • 59% of patients treated with placebo said the sd persisted after the suspension of the treatment (23) to conclude, on the subject of sexual adverse events, the results of this study can be summarised by stating that there is a low and equivalent prevalence of adverse events at 2-4 years with both finasteride and placebo, and that 59% of patients treated with placebo who suspended use due to sexual adverse events, reported persistent sexual dysfunction (23). the “nocebo” effect of treatment with 5a-r inhibitors the numerous contradictions that emerge from recent literature concerning the presumed sexual repercussions observed in certain groups of patients treated with 5aris, arouse doubts as to the methods used to investigate the parameters of sexual health in patients eligible for treatment with 5a-ris. specifically, this applies for an adequate definition of the parameters of sexual health (libido, erection, ejaculation) immediately prior to the start of treatment with 5a-ris. archivio italiano di urologia e andrologia 2015; 87, 4 f. pirozzi farina, a. pischedda 314 moreover, the sexual medicine society of north america has reported that treatment with 5a-ris is associated with sexual side effects that can persist even after the discontinuation of the treatment; however, it specifies that, at the current time, there are no proven causal connections between 5a-ris and the symptoms of sexual dysfunction reported by patients, and therefore further studies on the matter are required (24). this suggests that doctors could perceive a greater incidence of sexual adverse events in clinical practice than observed during clinical trials, although there is currently no objective evidence of this greater incidence. moreover, a potential “nocebo effect” has been proven that could be attributed to the ways in which patients are informed about the use of 5a-ris. to investigate this, mondaini n, et al. (2007) studied 120 patients with bph and iief-ef score ≥ 25 treated for one year with 5 mg of finasteride, masked as “compound x with proven efficacy for the treatment of bph”. patients were assigned to two groups (26). those in group 1 did not received information about the possible sexual repercussions of the drug; patients in group 2, on the other hand, were provided with the following information: “... may cause erectile dysfunction, loss of libido and ejaculation disorders, however these are not common’. (26) all the patients were evaluated at 6 and 12 months using the male sexual function questionnaire -4 (msf4). the authors’ results are provided below (table1) (26). on the basis of these results, the authors concluded that patients in group 2 simulate the side effects indicated in medical information and in the information leaflet, which would suggest that the information/illustration has a nocebo effect (26). how to optimise the medical treatment of bph and of the related urinary symptoms at the current time, the optimisation of medical treatment for lower urinary tract symptoms secondary to bph consists in knowing how to create the most individualised treatment plan possible. this means setting oneself the following objectives: minimising dysuria symptoms; stopping or slowing bph when at high risk of progression, avoiding or delaying the surgical solution; safeguarding the patient’s sexual health in the best way possible; as far as possible following the wishes of the patient, who must in any case receive comprehensible information on the mechanism of action of the drugs suggested, the incidence of any events that can be attributed to the various therapies and their reversibility before starting treatment. on this basis, at least three main patient classes can be summarised: patients with bph-related lower urinary tract symptoms at low risk of progression. in this type of patient, a first therapeutic approach could be a1a adrenergic blocker monotherapy when the urinary symptoms are not associated with pre-existent erectile dysfunction (ed). otherwise, it is possible to suggest treatment with the pde5-inhibitor tadalafil 5 mg once daily, a treatment regimen approved for patients with bph with obstructive symptoms of the lower urinary tract, with or without ed (27). patients with bph-related lower urinary tract symptoms at high risk of progression. in this class of patients the ideal treatment approach is 5a-ri prescription. the drugs can be administered as monotherapy or, in order to obtain a faster and more beneficial therapeutic result on symptoms, the 5a-ri dutasteride can be prescribed in combination with an a1a-adrenergic blocker (22). moreover, as the pde5inhibitor tadalafil 5 mg once daily has been approved for the treatment of obstructive lower urinary tract symptoms secondary to bhp (27), the 5a-ri dutasteride can, currently, be suggested in combination with tadalafil 5 mg once daily, with or without concomitant ed (28). patients with bph-related lower urinary tract symptoms at high risk of progression and concomitant ed. the simultaneous administration of tadalafil and finasteride would appear to allow a rapid improvement in obstructive and irritation symptoms of the lower unit urinary tract in men with bph (29). tadalafil co-administered with finasteride is also thought to improve erectile function in those men with concomitant erectile dysfunction (29). regardless of the treatment prescribed or proposed – as a general rule the fully reimbursed agents are prescribed and those not reimbursed are proposed – appropriately timed regular clinical monitoring is required (1-3-6-12 months). the aim of this is to monitor the results of treatment, evaluate any adverse events and, ultimately, prevent, approximately every 12 months, the incidental overlap of prostatic cancer. the evaluation of any adverse events and, in particular, sexual adverse ones, cannot exclude a careful investigation of the conditions of the patient before starting therapy and the implications that may be determined by the nocebo effect described above. in this sense, it is essential to administer dedicated questionnaires (e.g. iiefstudy patients (%) sae (%) sae (%) ed (%) ed (%) diminished (%) diminished (%) ejaculated (%) ejaculated at 6 months at 1 year at 6 months at 1 year libido at 6 months libido at 1 year disorder at 6 months disorder at 1 year all patients (n = 107) 24.3% 29.90 15.8% 20.5% 11.2% 15.8% 8.4% 11.2% group 1 (n = 52) 11.5% 15.3 5.7% 9.6 3.8% 7.7 5.7% 5.7 group 2 (n = 55) 36.3% 43.6 25.4% 30.9 18.1% 23.6 10.9% 16.3 mondaini n, et al. j sex med 2007; 4:1708-12. table 1. 315archivio italiano di urologia e andrologia 2015; 87, 4 comments concerning the real risk of sexual adverse events secondary to the use of 5-aris ipss) and to perform endocrinological tests before and during treatment. as with any other treatment, in the case of adverse events, in addition to reporting them to the appropriate authority, their relationship with the 5a-ris must be verified and, where appropriate, solutions must be devised. in addition to this, the patient must be reassured of the fact that he will in any case be helped to overcome the problem. conclusions the most recent literature review conducted by trost l et al. (2013) including over 62,827 patients, showed a slight increase in the rate of loss of libido, of ed, and ejaculatory disorders in patients taking 5a-ris and placebo (1.5% 1.6% 3.4%, and 1.3% respectively) (1). the authors of this review conclude that further studies are required using validated questionnaires, to establish the real prevalence, clinical relevance and potential longterm persistence of adverse effects related to the use of 5a-ris (1). as regards the information to be given to patients before starting treatment with 5a-ris, the doctor must illustrate, in a certainly comprehensible manner, the rationale and expected benefits of the therapy: a reduction in the risk of bph progression; a reduction in the risk of aur; an improvement in urinary symptoms; a reduction in the risk of the need for surgical treatment. the doctor must also illustrate the potential onset of side effects related to the use of 5a-ris. as far as the assessment of sexual adverse events is concerned, the doctor must thoroughly investigate the various aspects of the individual’s basic sexual function, before starting treatment. in addition to this, the doctor must always remember the importance of the documented nocebo effect and appropriate counselling must be provided in order to reassure the patient that he will receive help in overcoming any sexual problems that, for whatever reason, may arise during treatment. medical treatment for lower urinary tract symptoms associated with bph must be as individualised as possible. this ranges from monotherapy with a1a-adrenergic blockers, to that with 5a-ris when bph is at risk of progression. a beneficial synergetic therapeutic effect has been observed for combinations of 5aris and a1a-adrenergic blocker (tamsulosin and dutasteride). a new alternative to this solution is treatment with the pde5-inhibitor tadalafil that, both in monotherapy and in combination with the 5a-ris, provides advantages in the treatment of lower urinary tract symptoms secondary to bph, especially with concomitant ed and in the treatment of lower urinary tract symptoms secondary to bph at risk of progression, especially when associated with ed. references 1. trost l, saitz bs, hellstrom wjg. side effects of 5-alpha reductase inhibitors: a comprehensive review. sex med rev. 2013; 1:21-41. 2. abdulmaged mt, hassani jma, guay at, et al. adverse side effects of 5a-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients j sex med. 2011; 8:872-884. 3. russell dw, wilson jd. steroid 5 alpha-reductase: two genes/two enzymes. annu rev biochem. 1994; 63:25-61. 4. arteaga-silva m, vigueras-villaseñor rm, retana-márquez s, et al. testosterone, androstenedione, and 5a-dihydrotestosterone on male sexual behavior and penile spines in the hamster. physiology & behavior 2008; 94: 412-421. 5. bartsch g, rittmaster rs, klocker h. dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. world j urol. 2002; 19:413-25. 6. urysiak-czubatka i, kmiec ml, broniarczyk-dyła g. assessment of the usefulness of dihydrotestosterone in the diagnostics of patients with androgenetic alopecia. postepy dermatol alergol. 2014; 31:207-15. 7. park t, choi jy. efficacy and safety of dutasteride for the treatment of symptomatic benign prostatic hyperplasia (bph): a systematic review and meta-analysis. world j urol. 2014; 32:1093-105. 8. yim e, nole kl, tosti a. 5a-reductase inhibitors in androgenetic alopecia. curr opin endocrinol diabetes obes. 2014; 21:493-8. 9. bartsch g, rittmaster rs, klocker h. dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. world j urol. 2002; 19:413-25. 10. mcconnell jd, bruskewitz r, walsh p, et al. the effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. finasteride long-term efficacy and safety study group. n engl j med. 1998; 338:557-63. 11. roehrborn cg, boyle p, nickel jc, et al. efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. urology. 2002; 60:434-41. 12. mcconnell jd, bruskewitz r, walsh r, et al. the effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. finasteride long-term efficacy and safety study group. n engl j med. 1998; 338:557-63. 13. otberg n, finner am, shapiro j. androgenetic alopecia. endocrinol metab clin north am. 2007; 36:379-98. 14. traish am, hassani j, guay at, et al. adverse side effects of 5a-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. j sex med. 8:872-84. 15. irwig ms, kolukula s. persistent sexual side effects of finasteride for male pattern hair loss. j sex med. 2011; 8:1747-53. 16. trost l, saitz tr, hellstrom wjg. side effects of 5-alpha reductase inhibitors: a comprehensive review. sex med rev. 2013; 1:24-41. 17. erdemir f, harbin a, hellstrom wj. 5-alpha reductase inhibitors and erectile dysfunction: the connection. j sex med. 2008; 5:2917-24. 18. sato a, takeda a. evaluation of efficacy and safety of finasteride 1 mg in 3177 japanese men with androgenic alopecia. dermatol. 2012; 39:27-32. 19. irwing ms. persistent sexual side effects of finasteride: could they be permanent? j sex med. 2012; 9:2927-293. 20. elzanaty s, giwercman yl, giwercman a. significant impact of archivio italiano di urologia e andrologia 2015; 87, 4 f. pirozzi farina, a. pischedda 316 5alpha-reductase type 2 polymorphisms on sperm concentration and motility int. j androl. 2006; 29:414-420. 21. aua guideline: managemant of benign prostatic hyperplasia (bph); panel members: kt mcvary (chair), cg roehrborn (cochair), et al.; copyright 2010 american urological association education and research, inc®;1-496. 22. roehrborn cg, siami p, barkin j, et al. combat study group. the effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the combat study. eur urol. 2010; 57:123-31. 23. wessels h, roy j, bannow j, et al. incidence and severity of sexual adverse experiences in finasteride and placebo treated men with benign prostatic hyperplasia. urology. 2003; 61:579-84. 24. fda warns men of serious side effects from these drugs—but keeps them on the market (http://www.fda.gov/drugs/drugsafety/ informationbydrugclass/ucm299754.htm) 25. seftel a, rosen r, kuritzky l. physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (bph) symptoms and sexual side effects related to bph medications international journal of impotence research. 2007; 19:386-392. 26. mondaini n, gontero p, giubilei g, et al. bartoletti. finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon? j sex med. 2007; 4:1708-12. 27. european medicines agency. 18 october 2012 ema/647346/ 2012 committee for medicinal products for human use (chmp). assessment report cialis tadalafil procedure no. emea/h/c/ 000436/ii/0060 28. volkov aa, petrichko mi, budnik nv. correction of erectile dysfunction in patients with benign prostate hyperplasia using daily administration of tadalafil 5 mg against the background of combined drug therapy. urologiia. 2013; 54:50-2. 29. casabé a, roehrborn cg, da pozzo lf, et al. efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia. j urol. 2014; 191:727-33. correspondence antonella pischedda, md furio pirozzi farina, (corresponding autor) andro@tin.it associate professor of urology università di sassari specialist in urology and andrology director, department of andrological urology aou di sassari via matteotti, 14 sassari, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 138 original paper the effect of inclined position on stone free rates in patients with lower caliceal stones during swl session basri cakiroglu 1, orhun sinanoglu 2, tuncay tas 3, ismet aydin hazar 3, mustafa bahadir can balci 3 1 hisar intercontinental hospital department of urology, istanbul, turkey; 2 maltepe university medical school, department of urology, istanbul, turkey; 3 taksim training and research hospital, department of urology, istanbul, turkey. objective: to compare the outcomes of shock wave lithotripsy (swl) combined with inclined position and swl alone in patients with lower pole calyx stones. methods: seven hundred forty patients who underwent swl treatment for lower pole renal stones with a total diameter of 2 cm or less were prospectively randomized into two groups. they were comparable in terms of age, sex, and stone diameters. patients with lower calyceal stones (4-20 mm) were randomized to swl (368 patients) or swl with simultaneous inclination (372 patients) with 30o head down trendelenburg position). shock wave and session numbers were standardized according to stone size. additional standardized shock waves were given to patients with stone fragments determined by kidney urinary bladder film and ultrasound at weeks 1, 4, 10. results: the overall stone free rate (sfr) was 73% (268/368) in patients with swl alone and 81% (300/372) in swl with inclination at the end of 12th week (p = 0.015). no significant adverse events were noted in both treatment groups. conclusion: simultaneous inclination of patients during swl session increase sfr in lower caliceal stones significantly compared to swl treatment alone. key words: lower pole calyx stones; shock wave lithotripsy; inclined position; stone free rate. submitted 25 september 2014; accepted 30 november 2014 summary no conflict of interest declared. clearance of lower calyceal stones after swl seems difficult, swl still continues to be the first choice therapy for patients with lower calyceal stones of any sizes as it is the non-invasive and easily available treatment option (6, 7). investigators tried to increase stone-free rates in lower calyceal stones with some maneuvers, such as controlled inversion therapy with percussion after swl or irrigation during treatment (4, 5).when outcomes of these auxiliary procedures accompanying swl were classified by stone size (< 1 cm diameter, 1-2 cm, and > 2 cm),stonefree rates after swl treatment were found 74%, 56% and 33% respectively (8). contrast opinions also were reported in other studies claiming that controlled inversion therapy did not improve results for people who underwent shock wave lithotripsy for lower pole kidney stones, among them diuresis and inversion did not significantly improve stone free rates in a series (4, 9). despite several studies supporting the benefit of auxiliary procedures, there is limited evidence suggesting that percussion, diuresis and especially inversion therapy may be beneficial for patients with lower calyceal stones after shock wave lithotripsy. therefore, we compared the effectiveness of inclination to regular position during swl for eliminating lower calyx calculi. we suggest that a 30º head down inclination would overcome the gravitational effect of lower pole calyx that will eliminate residual fragments than usual session alone at 3 months without altering confort or hemodynamics of the patient. materials and methods seven hundred forty patients between august 2006october 2013 who underwent swl treatment for radiologically identified lower pole radiopaque renal calculi with a total diameter of 2 cm or less were prospectively randomized into two groups. the study protocol was reviewed and approved by the institutional ethics committee. participants were enrolled if they were 18 years of age or older having solitary renal calculi between 4 and 20 mm, and gave consent to randomization. exclusion criteria were non lower calyceal stones of the same side, renal anatomical deformities such as urethral stricture or ureteropelvic junction obstruction, concomitant distal doi: 10.4081/aiua.2015.1.38 introduction the prevalence of kidney stones is 2% to 3% in the general population), but the relative incidence of lower calyceal stones remains unclear (1). shock wave lithotripsy (swl) is widely accepted as the gold standard treatment for kidney stones less than 2 cm diameter. it is a non-invasive procedure, requires minimum anaesthesia, and with high patients preference. the incidence of lower calyceal kidney stones treated with swl has risen as time passed after the primitive swl devices came into use (2). afterwards various studies have suggested the use swl for these stones (2-5), however, although the cakiroglu_stesura seveso 02/04/15 10:21 pagina 38 39archivio italiano di urologia e andrologia 2015; 87, 1 lower caliceal stones with swl obstruction, renal insufficiency or gross hydronephrosis of the affected kidney, pregnancy, bleeding diathesis, significant cardiac conditions that does not permit head down inclination or uncontrolled hypertension. all subjects included into this single-blind study were prospectively randomized to control (swl alone) or swl with inversion therapy group. swl was performed with storz modulite fx by the 2 attending urologist using real time ultrasound for stone localization. treatment was initiated at 14 kv, and the energy gradually increased between 20 and 24 kv, depending on the maximum level that the patient could tolerate. the numbers of shock waves (sw) used were determined by calyceal stone sizes; 4-10 mm stones (1500 sw), 11-15 mm (2000 sw), and 1620 mm (2500 sw). patients randomized to the study group had swl at 30º head down in trendelenburg position. patient reassessment was performed immediately at weeks 1, 4, 10, and 6 months after swl therapy, with an evaluation using plain film of the kidney, ureter, and bladder and ultrasonography. cases were accepted as sf if there were no radiological and ultrasonographic evidence of stone as confirmed by a blinded radiologist and validated by another blinded radiologist to provide consistency in reports. stone free status was defined as having no visible residual stone. if the patient had significant residual fragments, swl was repeated, with 1000 sw delivered. complications during and after treatment were recorded. categorical variables were compared with chi-square analysis or fisher’s exact test, and continuous variables were compared using t test. results the clinical characteristics of the subjects are summarized in table 1. no significant differences were found between the 2 treatment modalities in terms of gender and age. there were not any significant difference among swl parameters, such as stone size, session number of swl or schock waves. the overall stone free rate (sfr) was 73% (268/368) in patients with swl alone and 81% (300/372) in swl with inclination at the end of 6th month (p = 0.015) (table 2, figure 1). no significant adverse events were noted in both treatment arms. retreatment and complemetary procedure rates and the duration of treatment were also not significantly different between groups. complications were rare and occurred in 8 patients. three subjects had steinstrasse, two had urinary tract infections whereas hematoma was seen in one patient which subsequently resolved with conservative measures. discussion achieving clearance for renal lower calyceal stones after swl is a difficult task. treatment of these stones by swl does not have brillant success. despite the adequate fragmentation the gravity force hold the fragments in the lower calyx having a reverse angle. therefore it has been claimed that the use of inversion therapy, mechanical percussion, and administration of diuretics might enhance the stone free rates in lower calyceal calculi (10). brownlee in 1990 suggested in his report that multiple sessions of inversion therapy could possibly have a beneficial role in the clearance of stone fragments in gravity-dependent calices following swl (11). however, the previous studies in 90’s were retrospective in nature with limited sample sizes, and their data were methodologically flawed. honey reported in 2008 the swl outcomes of lower pole kidney stones at least two weeks after shock wave lithotripsy. in the series, patients were placed in a prone trendelenberg position at 60º to 70º, received furosemide 20 mg iv immediately before therapy, and underwent 10 minutes of flank percussion using a chest physiotherapy device. their results suggest the aid of the method in stone fragments passage (12). when comparing the effects of adjunctive therapy such as inversion, percussion, or hydration, only 3 prospective randomized studies were found. the first study was done by pace et al. in which a regimen of mechanical percussion, inversion, and diuresis was compared with observation in patients with lower calyceal stones 3 months after table 1. clinical characteristics of treatment groups in the study. inclined control p value stone size 12.65 12.71 0.95 age mean 35.1 36.25 0.93 sw session mean 2.36 2.68 0.10 sw number 7546 8982 0.08 gender f/m 68/304 100/268 0.16 figure 1. outcomes in the treatment groups at the end of 12th week. stone free rates in the inclined swl and swl alone groups were 300/372 (81%) and 268/368 (73%) respectively (p = 0.015). table 2. distribution of outcomes according to treatment groups. stone-free no stone-free total inclined 300 (41%) 72 (10%) 372 (50%) control 268 (36%) 100 (14%) 368 (50%) total 568 (77%) 172 (23%) 740 (100%) cakiroglu_stesura seveso 02/04/15 10:21 pagina 39 archivio italiano di urologia e andrologia 2015; 87, 1 b. cakiroglu, o. sinanoglu, t. tas, i. aydin hazar, m. bahadir can balci 40 swl. treatment outcomes were with a higher sfr versus observation (40% vs 3%) (5). chiong et al. conducted a similar study with encouraging results in which they inclined their patients 45º angle with percussion, forced hydration and diuresis following swl sessions. the sfr was 62% in treatment arm whereas success rate was 35% in observed patients (8). in the most recent prospective study of wing seng leong et al. the evidence suggest that swl with simultaneous inversion is a valuable combination in assisting the passage of lower pole renal stones with a sfr of 76%, despite the lack of significance. the number of their participants were 140. stone size was found to affect the results of the overall sfrs after swl of lower calyceal stones. authors found out that sfrs were 79% and 69% for stones < 10 mm and 11 to 20 mm respectively (10). in our study a total number of 740 were prospectively randomized into two groups. we applied swl sessions only with concomitant 30º inclination without using 45º to 60º inversion, percussion and forced diuresis unlike the previous reports. the adoption of these exagerated auxiliary methods seems to be disappointing because they require additional effort by the doctors and patients during and after swl. there are limitiations to our study; first, we did not stratified the sfr rates according to stone sizes, second, lack of data on stone composition or density and skin to stone distance. lastly, it is also worth noting that although several above mentioned studies support the adjunctive methods in lower calyceal swl treatment, some other authors claimed in the past that there is no benefit of these auxiliary procedures. among these, rodrigues et al. reported outcomes of the study group who received adjunctive therapy following shock wave lithotripsy of oral hydration, 60º to 75º inversion, and percussion. stone-free status was achieved in 84% of participants who did not receive adjunctive therapy, in contrast to 64.7% sfr in those undergoing adjunctive therapy. authors concluded that inversion therapy did not ameliorate outcomes of swl for lower calyceal stones (9). in conclusion, the overall sfr at 6 months after swl in 30º inclined position without usage of forced hydration and/or percussion was 81% vs. 73% of the control group in the present study. therefore we recommend that inclination should be used for lower pole calyx renal calculi because it provides an improved clearance with both minimal patient cooperation and no additional effort of the doctor. competing interests the authors declare that they have no competing interests. authors’ contributions 1. study concept and design: bc; 2. acquisition of data: bc, os; 3. drafting of the manuscript: mbcb, tt; 4. cri tical revision of the manuscript for important intellectual content: ih; 5. statistical analysis: os; 6. admi ni strative, technical, and material support: bc, ih, 7. study supervision: os; 8. design of the generator and probe and acquisition of data relating to the functioning of the apparatus: bc,tt. all authors read and approved the final manuscript. references 1. poch m, haleblian ge. minimally invasive stone surgery: percutaneous, ureteroscopic and extracorporeal approaches to renal and ureteral calculi. medicine & health, rhode island. 2009; 92:339-41. 2. lingeman je, siegel yi, steele b, et al. management of lower pole nephrolithiasis: a critical analysis. journal of urology. 1994; 151:663-7. 3.albala dm, assimos dg, clayman rv, et al. lower pole i: a prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results. j urol. 2001; 166:2072-80. 4. albanis s, ather hm, papatsoris ag, et al. inversion, hydration and diuresis during extracorporeal shock wave lithotripsy: does it improve the stone-free rate for lower pole stone clearance? urol int. 2009; 83:211-216. 5. pace kt, tariq n, dyer sj, et al. mechanical percussion, inversion and diuresis for residual lower pole fragments after shock wave lithotripsy: a prospective, single blind, randomized controlled trial. j urol. 2001; 166:2065-2071. 6. kekre ns, kumar s. optimizing the fragmentation and clearance after shock wave lithotripsy. current opinion in urology. 2008; 18:205-9. 7. raman jd, pearle ms. management options for lower pole renal calculi. current opinion in urology. 2008; 18:214-9. 8. chiong e, hwee st, kay lm, et al. randomized controlled study of mechanical percussion, diuresis, and inversion therapy to assist passage of lower pole renal calculi after shock wavelithotripsy. urology. 2005; 651070-4. 9. rodrigues netto n jr, claro jf, cortado pl, lemos gc. adjunct controlled inversion therapy following extracorporeal shock wave lithotripsy for lower pole caliceal stones. journal of urology. 1991; 146:953-4. 10. leong ws, liong ml, liong yv, et al. does simultaneous inversion during extracorporeal shock wave lithotripsy improve stone clearance: a long-term, prospective, single-blind, randomized controlled study.urology. 2014; 83:40-4. 11. brownlee n, foster m, griffith dp, carlton ce jr. controlled inversion therapy: an adjunct to the elimination of gravity-dependent fragments following extracorporeal shock wave lithotripsy. j urol. 1990; 143:1096-8. 12. honey j. treating lower pole renal stones: in defence of shock wave lithotripsy. canadian urological association journal. 2008; 2:625-7. correspondence basri cakiroglu, md (corresponding author) drbasri@gmail.com hisar intercontinental hospital, saray mah. siteyolu cad.no:7 34768 umraniye, istanbul, turkey orhun sinanoglu, md orhundr@hotmail.com maltepe university medical school, department of urology, maltepe, istanbul, turkey tuncay tas, md tastuncay@gmail.com aydin ismet hazar, md mdhazar@hotmail.com mustafa bahadir can balci, md drbalci@yahoo.com taksim training and research hospital, department of urology, gaziosmanpasa, istanbul, turkey cakiroglu_stesura seveso 02/04/15 10:21 pagina 40 stesura seveso 231archivio italiano di urologia e andrologia 2014; 86, 3 case report primary carcinoid tumour of the testis: a case-report letterio d’arrigo 1, angela costa 1, filippo fraggetta 2, antonio cacciola 1, astrid bonaccorsi 1, francesco savoca 1, francesco aragona 1 1 urology and 2 pathology unit, cannizzaro hospital, catania, italy. testicular carcinoid tumours (tct) account for less than 1% of all testicular neoplasms. a 17-year-old male underwent radical orchiectomy for a painful indurated and increased in size right testicle; a mixed echogenic mass, with a central homogeneous area surrounded by a hypoechoic edge with calcifications was found at ultreasound with increased vascularity at color doppler examination. biochemical markers were within normal limits. these symptoms are not specific and the majority of tct are only diagnosed on histopathology. patients should undergo long-term biochemical and radiological follow-up given potential for delayed metastases, in one case 17 years after primary treatment. key words: testicular neoplasms; neuroendocrine tumour; carcinoid. submitted 20 december 2013; accepted 31 march 2014 summary introduction testicular carcinoid tumours (tct) account for less than 1% of all testicular neoplasms (1). tct may be a component of teratoma, or it may occur in pure form, either as a primary growth or as a metastasis from an extratesticular source. herein, we report a case of primary tct presenting as a painful mass without features of carcinoid syndrome. case report is described in supplementary materials posted on www.aiua.it discussion the term “carcinoid” was introduced to distinguish a group of low malignant neoplasms of the small intestine arising from ne cells. overall, 70 cases of tct have been reported in literature, including primary forms, carcinoid differentiation within a mature teratoma and metastases from an extratesticular site. the histogenesis of primary tct is still debated as the presence of ne cells within the testis has not been described. several hypothesis have been proposed. mai et al. (2) no conflict of interest declared. suggest that tct originate from the same precursor cell from which leydig cells derive; in abbosh et al. opinion (3), the tct results from a chromosomal abnormality. a scrotal mass, either painful or indolent, is the most common presenting symptom. a specific ultrasound (us) pattern is not reported: in most cases, an isoechoic mass with a peripheral hypoechoic rim (4) is found, in some cases scanty intralesional calcifications have been described (5). in a literature review reported by strooma and delaere (6) (61 cases plus a personal one) 16% of the patients had symptoms of carcinoid syndrome (diarrhoea, sweating, palpitations, bronchoconstriction, headache, flushing, abdominal pain) that occur when serotonin, produced by the tumour, is released into the systemic circulation (7). serotonin is metabolised to 5-hiaa and excreted through the urine; thus, it is advisable that any patient with vasoactive symptoms and a testicular mass should have a 24 hour urinary dosage of 5-hiaa prior surgery. however, these symptoms are not specific and the majority of tct are only diagnosed on histopathology. when a tct is diagnosed, a metastasis or an extratesticular primary tumour should be excluded, especially if the tct is larger than 4 cm and/or is associated to carcinoid syndrome. as most carcinoid tumours are found in the ileum and all six testicular carcinoid metastases mentioned by strooma and delaere (6) originated from the ileum, barium contrast studies, computed tomography (ct) scan and gastro-intestinal (gi) video-endoscopy can be used to search for primary intestinal tumours. nowadays, i-111 labelled octreotide scintigraphy has replaced ct scan in localizing metastases with a sensitivity of up to 96% (8). 5-hiaa urinary levels must be measured in a 24 hour urine sample, although only 88% of all carcinoid tumours produce 5-hiaa (10). radical orchidectomy is the treatment of choice of tct and is curative for testis-confined primary forms. a retroperitoneal lymphadenectomy is recommended when tct is a component of teratoma. adjuvant chemo/radiotherapy are known to have little effect on these tumours (9). patients should undergo long-term biochemical and radiological follow-up given potential for delayed metasdoi: 10.4081/aiua.2014.3.231 d'arrigo cr_stesura seveso 08/10/14 12:54 pagina 231 archivio italiano di urologia e andrologia 2014; 86, 3 l. d’arrigo, a. costa, f. fraggetta, a. cacciola, a. bonaccorsi, f. savoca, f. aragona 232 tases, in one case 17 years after primary treatment (5). sutherland et al. (11) suggest three monthly 5-hiaa measurements for the first year after diagnosis and annually thereafter although disease progression may occurs in the absence of elevated urinary 5-hiaa levels. serum chromogranin a, secreted by carcinoid tumours, correlates with relapse in gi carcinoids and may be of use in the follow-up of tct (9). most primary tct have good prognosis even if associated with mature teratoma. a cancer-related death is reported only in patients with metastases from or to the testis. references 1. wang w, guo c, berney d, et al. primary carcinoid tumour of thetestis: a clinicopathologic study of 29 cases. am j surg pathol. 2010; 34:519. 2. mai k, park p, yazdi h, carlier m. leydig cell origin of testicular carcinoid tumor: immunoistochemical and electron microscopic evidence. histopathology. 2006; 49:548. 3. abbosh p, zhang s, maclennan g, et al. germ cell origin of testicular carcinoid tumors. clin cancer res. 2008; 14:1393. figures and full list of references are posted in supplementary materials on www.aiua.it correspondence letterio d’arrigo, md ldarrigo@alice.it angela costa, md ang.urolog@gmail.com antonio cacciola, md tonycacciola@tiscali.it astrid bonaccorsi, md astridbonaccorsi@libero.it francesco savoca, md francescosavoca@virgilio.it francesco aragona, md frank.aragona@virgilio.it urology unit cannizzaro hospital catania via messina 829 95127 catania, italy filippo fraggetta, md filippofra@hotmail.com pathology unit cannizzaro hospital catania via messina 829 95127 catania, italy figure 1. the neoplastic cells were arranged in a nesting and trabecular pattern. no evidence of intratubular germ cell neoplasia. tumor cells showed pale eosinophilic cytoplasm with round to oval nuclei and inconspicuous nucleoli; mitoses were not seen. no evidence of vascular invasion. the histological features were in accordance with a pure testicular carcinoid tumour without teratomatous components. d'arrigo cr_stesura seveso 08/10/14 12:54 pagina 232 stesura seveso 169archivio italiano di urologia e andrologia 2015; 87, 2 case report giant renal artery aneurysm: a case report luca cindolo 1, manuela ingrosso 2, piergustavo de francesco 2, pietro castellan 2, francesco berardinelli 1, franco fiore 3, luigi schips 1 1 urology dept, robotic unit, “s. pio da pietrelcina” hospital, asl abruzzo 2, italy; 2 clinica urologica, “ss. annunziata” hospital, asl abruzzo 2, italy; 3 vascular surgery, “ss. annunziata” hospital, asl abruzzo 2, italy. a case of a 12 cm giant renal artery aneurysm (raa) in an 59-year-old woman is reported. the patient was referred to our hospital for flank pain and spot hematuria. ultrasonography (us) revealed some wide lacunar areas in her right kidney and a thin cortex. three-dimensional computed tomography (3d-ct) revealed a giant right renal arteriovenous malformation (avm). angioct scan showed a pervious right renal artery. the cavities of the right kidney were dilated and the parenchyma was markedly reduced. two months later the patient underwent an open resection of the aneurysm and a right nephrectomy. she had an uneventful recovery and a healthy status (last follow-up: 9 month). in this particular case, a safe approach is the transabdominal approach since the aneurysm was very large, friable, and located on the right side. this report confirms the opportunity of a planned nephrectomy once there is adequate renal reserve in the opposite kidney using a midline approach. key words: renal arteriovenous malformation; renal artery aneurysms; kidney; surgical resection; nephrectomy. submitted 14 january 2015; accepted 19 march 2015 summary no conflict of interest declared. three-dimensional computed tomography (3d-ct) revealed a giant right renal arteriovenous malformation (avm) (figure 2). the abdominal angioct scan showed a pervious right renal artery, free from significant calcified and thrombotic parietal lesions. the artery provided for the supply of aneurysmal dilatation (maximum axial diameter of 7.5 and longitudinal extent of about 12 cm), with calcified walls, that the lower third of the renal sinus stretched right up close to the ipsilateral iliac fossa. dilatation appeared in communication with other vascular structures in the right kidney lodge, and confluent in ipsilateral renal vein; opacification was early in the arterial phase and in the inferior vena cava downstream of the confluence veins of the kidney. the cavities of the right kidney were moderately dilated and the parenchymal was markedly reduced (figures 1 and 3). two months later the patient underwent surgery, after careful evaluation together with vascular surgeons, the surgical consensus was in favor of a right nephrectomy and an excision of the aneurysm of the right renal artery, the patient was advised and she agreed. a chest x-ray showed a slight increase in the volume of left-sided heart, echocardiogram revealed neither cardiomegaly. the routine blood tests were normal, with creatinine 1.03 mg/dl and hb 13.6 g/dl. the surgical approach was laparotomy incision xipho-subumbilical, then, via transperitoneal, the left renal vein and the right renal artery were prepared near of the abdominal aorta. after opening the right paracolic gutter, the large aneurysm was displayed doi: 10.4081/aiua.2015.2.169 introduction the renal artery aneurysms (raa) was mentioned for the first time in 1770 by rouppe, who described the death of a sailor due to rupture of a large false aneurysm (1). renal artery aneurysms are often diagnosed by ultrasound examination for the screening of hypertension. many small aneurysms are repairable, in other large aneurysms nephrectomy may be required for the increased wall shear stress and the destruction of renal parenchyma (2). in recent years, coil embolization or stent-graft with the coil embolization was successful for treating raas and was indicated in that case of narrownecked, saccular, extra-parenchymal aneurysms (3). this paper will deal with the diagnosis and treatment of one giant symptomatic renal artery aneurysm. case report a 59-year-old female patient who presented flank pain and spot hematuria was referred to our hospital. the patient had arterial hypertension in drug treatment and subclinical hypothyroidism in autoimmune thyroiditis. bmi was 30.4 and about 30 years ago she was undergone to right salpingectomy. ultrasonography (us) revealed some wide lacunar areas in her right kidney and a thin cortex (figure 1). figure 1. renal ultrasound scan showing some lacunar areas in right kidney and a thin cortex. cindolo_stesura seveso 02/07/15 11:33 pagina 169 archivio italiano di urologia e andrologia 2015; 87, 2 l. cindolo, m. ingrosso, p. de francesco, p. castellan, f. berardinelli, f. fiore, l. schips 170 complications occurred in the postoperative period, without blood transfusions. the patient was discharged on the 5th postoperative day in good physical conditions with: hb 10,6 g/ dl, 31% hct, wbc 7.86 x10^3/ul, plt 206x10^3 /ul, creatinine 0.78mg/dl. histological examination revealed a large aneurysm of the renal artery size of 8x8.2x4.5 cm, with compression of the renal parenchyma, with diffuse glomerulosclerosis, interstitial inflammation, aspect pseudo-thyroid of tubular component and diffuse atrophy (figure 4). conclusions there are a lot of studies about raas, but little exists on treatment plans for graas. it seems that most giant raas are discovered when they are close to 10 cm in diameter and are usually part of the renal parenchyma. arterial reconstruction or arterial embolization are not always an option since these patients may be elderly and have significant comorbidities. this report confirms the opportunity of a planned nephrectomy once there is adequate renal reserve in the opposite kidney using a midline approach. discussion and supplementary references are posted on www.aiua.it references 1. rouppe dl. renalarteryaneurys. novaactaphysico-medica academiae caesareae leopoldino-carolinae naturae curiosorum. 1770; 4:76. 2. hageman jh, smith rf, szilagyi e, elliott jp. aneurysms of the renal artery: problems of prognosis and surgical management. surgery. 1978; 84:563-72. 3. jibiki m, inoue y, kudo t, toyofuku t. surgical procedures for renal artery aneurysms. annals of vascular diseases. 2012; 5:157-160. correspondence luca cindolo, md (corresponding author) lucacindolo@virgilio.it francesco berardinelli, md berardinelli.francesco@gmail.com luigi schips, md luigischips@hotmail.com urology dept, robotic unit, “s. pio da pietrelcina” hospital via san camillo de lellis, 66054 vasto (ch), italy manuela ingrosso, md manuela-ingrosso@hotmail.com piergustavo de francesco, md piergustavodf@hotmail.it pietro castellan, md castellanpietro@gmail.com clinica urologica, “ss. annunziata” hospital via dei vestini, 66100 chieti, italy franco fiore, md f-fiore@outlook.it vascular surgery, “ss. annunziata” hospital via dei vestini, 66100 chieti, italy figure 2. 3d-ct scan showing a giant right renal arteriovenous malformation (a-b: 3d reconstruction a-front view bposterior view; c: cross-sectional image). figure 3. angio-tc and 3d reconstruction confirming the dilatation of right kidney’s cavity and reduction of right renal parenchyma (a: anterior-posterior axis; b: transverse plane; c: 3d reconstruction). below the kidney. the right renal vein (close to vena cava) and right renal artery (near renal hilum) were clamped and tied twice with prolene 5/0. so right nephrectomy and excision of the aneurysm was practiced, after the closure of the ureter. blood loss during surgery was about 150 ml. no figure 4. postoperative view of the surgical specimen showing a large aneurysm of the renal artery size of 8 x 8.2 x 4.5 cm, with compression of the renal parenchyma. cindolo_stesura seveso 02/07/15 11:33 pagina 170 archivio italiano di urologia e andrologia 2016; 88, 4258 original paper effects of obesity surgery (laparoscopic sleeve gastrectomy technique) on lower urinary tract symptoms, depression and quality of life of males: prospective study fatih uruç 1, serkan akan 1, bekir aras 2, çağlar yıldırım 1, aytaç şahin 1, ozgur haki yuksel 1, mehmet timuçin aydın 3, ayhan verit 1 1 department of urology, fatih sultan mehmet research and training hospital, istanbul, turkey; 2 department of urology, dumlupınar university, evliya çelebi research and training hospital, kütahya, turkey; 3 department of general surgery, fatih sultan mehmet research and training hospital, istanbul, turkey. purpose: technically, obesity weakens the pelvic base muscles by causing an increase in the intraabdominal pressure and intravesical pressure due to increasing fat and it triggers the occurrence of lower urinary tract symptoms. however it is believed that weight loss will cause recovery of these symptoms. our purpose in this study is to research about the effects of the weight loss achieved by using especially the laparoscopic sleeve gastrectomy (lsg) technique of bariatric surgery which is being more and more widely used today. materials and methods: out of all patients who had lsg surgery due to obesity earlier in our center during the period between april 2014 and march 2015, 22 applicable male patients were considered after a brief exclusion criteria application. age, height, weight, and body mass index (bmi) data of these patients were recorded before the operation. international prostate symptom score (ipss), international consultation on incontinence questionnaire short from) (iciq-sf), beck depression inventory (beck) and short form 36 (sf-36) were filled for the patients and the data were recorded. also, the weight loss amounts and bmi decreases of the patients after the operation were recorded. results: after the procedure, the decrease in the averages of beck depression inventory, ipss, iciq-sf and the increase in the mental and physical subgroup scores of sf-36 were found statistically coherent. conclusion: the adverse effect of obesity, which is observed more and more often in today's world, on lower urinary tract symptoms and on the quality of life is undeniable. in our study, we think that the bariatric surgery made by using the lsg technique, not only causes serious amount of weight loss, but also reduces urinary dysfunction and enhances the quality of life among males. key words: obesity; lower urinary system; bariatric surgery; sleeve gastrectomy; quality of life. submitted 12 april 2016; accepted 22 may 2016 summary no conflict of interest declared. according to the data of world health organization (who), it is detected that 1.6 billion adults are overweight. and among these individuals, approximately 300 million females are obese (1, 2). while 67% of the population of united states of america (usa) are classified either as obese or overweight, in many european countries, this ratio is around 40-50% (3). according to the data of 2011, over 40 million of children under 5 years old are overweight (1, 2). it is known that there are approximately 500 million obese adults and that this number is on the rise. approximately 2,8 people a year dies as a result of being overweight or obesity(4). obesity prevalence was found to be 22.3% in the obesity prevalence study (turdep) in turkey, in 1997 (5). in the turdep ii study that was conducted in 2010, the obesity rate in turkey was found to have increased to 32%. this striking fast increase is alarming (6). while weight loss can be achieved with non-surgical methods, it was observed that 66% of these patients reached their former weight in a time period as short as 24 months. the compatibility that the patient will have with the diet during the medical treatment application might form an idea about the patient’s compatibility with post-operational treatment. surgical treatment of morbid obesity stands out due to its possibility of causing deaths as a results of additional diseases and becoming epidemic (7). today, bariatric surgery is the most effective treatment modality that causes 15% or more weight loss than the normal procedure (8). taking mortality, morbidity, cost, patient satisfaction and most importantly the expected weight loss rate into consideration, laparoscopic sleeve gastrectomy (lsg) is one of the most preferred surgical procedures today (9, 10). more than 220.000 bariatric surgical procedures are applied in a year in usa (11). technically, obesity weakens the pelvic base muscles by causing increase in the intra-abdominal pressure and intravesical pressure due to fattening increase and triggers the lower urinary tract symptoms (luts). it is believed that weight loss will cause recovery of these symptoms (12-14). our purpose in this study is to research about the effects of the weight loss achieved by using especially the laparoscopic sleeve gastrectomy (lsg) technique of doi: 10.4081/aiua.2016.4.258 introduction obesity is one of the most important health problems in both developing and developed countries today because of the diseases it brings with it. the number of people with obesity has nearly doubled since the year 1980. uruc_stesura seveso 09/01/17 09:48 pagina 258 259archivio italiano di urologia e andrologia 2016; 88, 4 effects of obesity surgery on lower urinary symptoms bariatric surgery which is being more and more widely used today, on the luts and quality of life of males. material and method twenty-two male patients who has lsg surgery due to obesity between april 2014 and march 2015 were taken into study. the patients who met the exclusion criteria below, were excluded from the study. exclusion criteria’s were: (i) the patient being unwilling, (ii) the patient having a known mental or psychiatric disease, (iii) the patient having had any surgical or unsurgical weight loss treatment earlier, (iv) the patient having had any surgical procedures for incontinence or any medical treatment due to luts earlier, (v) the patient being under the age of 18, (vi) the patient having any respiratory system diseases (copd) or any neurological diseases that can be related to urinary symptoms. twenty-two male patients who met the criteria above were taken under study and the data were evaluated in preoperational and post-operational periods. age, height, weight, and body mass index (bmi) data of these patients were recorded pre-operation international prostate symptom score (ipss), international consultation on incontinence questionnaire short from) (iciq-sf), beck depression inventory (beck) and short form 36 (sf-36) were filled for the patients and the data were recorded. also, the weight loss amounts and bmi decreases of the patients post-operation were recorded. ipss: it is a scoring system originally named as american urology association symptom score and it consists of 8 questions. 0-7 points means mildly symptomatic, 8-19 points mean average symptomatic and 20-35 points means severely symptomatic condition. severity and progression on a certain period of time of symptoms are compared. iciq-sf: it enables measuring of the severity of incontinence symptoms and its effects on quality of life. the scoring system that consists of 4 questions, is evaluated between 0-21 points. beck depression inventory: it is a 21 multiple choice question self-evaluating inventory that is applied to children and adults to measure the severity of anxiety. 0-21 points is evaluated as mild anxiety, 22-356 points is evaluated as average anxiety, 36-63 points is evaluated as severe anxiety. sf-36: it is a reliable, valid and very often used standard in evaluating the quality of life. scale consists of 36 subjects and these ensures the measurement of 8 dimensions. these are; vitality (energy), physical function, pain, general health physical, emotional and social role restrictions, mental health. scoring is summed up in 2 topics that are pcs: physical component summary and mcs: mental component summary. surgery technique the patients were operated using lsg technique. operations were conducted by general surgeons. sleeve gastretomy (sg) first started to be applied as the restrictive component of the duodenal switch operation first. this method was taken into practical use as a risk reducing method in the patients who are at high risk and who may not be able to tolerate long term procedures (15). lsg became a more often used, safe and efficient primary bariatric surgical method that is highly popular among the surgeons and the patients (16). after the large curvature is freed from 2-3 cm proximal of pylorus up to the angle of his (incisura cardiaca), stomach resection is practiced. posterior dissection is applied by making angle of his visible so as not to leave a large fundus pouch. bending of the stomach from incisura angularis is prevented by fixating the sleeve tube by stitching the omentum or gastrocolic fat. lsg has become a very often preferred method alone or alongside the other methods in treatment of morbid obesity (17). statistical analysis: the study was planned as a prospective study. while evaluating the findings obtained during the studyi ibm spss statistics 22 (ibm spss, turkey) program was used fort he statistical analyses. the compatibility of the parameters to the normal range was evaluated with shapiro wilks test during the evaluation of the study data. along with the definitive statistical methods (average, standard deviation) while evaluating the study data, student t test was used in comparisons between two groups of parameters that show normal distribution in the comparison of quantitative data, mann whitney u test was used in comparison between two groups of parameters that don’t show normal distribution. pairedsample t test was used in the same group comparison of parameters that show normal distribution and wilcoxon sign test was used in the same group comparison of parameters that don’t show normal distribution. pearson correlation analysis was used in analyzing the relations between parameters that are compatible with normal distribution. coherence was evaluated at p < 0.05 level. results the study was conducted with 22 male cases that had lsg between the dates april 2014 and march 2015. the ages of the cases vary between 24 and 51 years and the average of the ages is 34.59 ± 8.07 years. statistically meaningful decrease is detected in the average post-operative bmi values, body weight, scores of ipss and beck depression inventory in comparison with the post-operative values (for all of them p = 0.001; p < 0.01). statistically meaningful increases are observed in the pcs and mcs’ of the individuals when pre-operative values are compared to the post-operative ones (for all p = 0.001; p < 0.01). statistically meaningful decrease was detected in iciq-sf between pre-operation and post-operation averages (p = 0.002; p < 0.01) (table 1). there is positive correlation at 62.8% level observed between post-operative bmi change ratio and post-operative ipss change ratio when compared with the pre-operative values (p = 0.002; p < 0.01). no statistically meaningful correlation was shown between post-operative bmi change ratio and post-operative beck depression inventory and iciq-sf parameters change ratio when compared with the pre-operative values (for all p > 0.05). there is no meaningful correlation between pre-operative and post-operative bmi change amount and age (p > 0.05) (table 2). discussion according to the data of nhnes (national health and uruc_stesura seveso 09/01/17 09:48 pagina 259 archivio italiano di urologia e andrologia 2016; 88, 4 f. uruç, s. akan, b. aras, ç. yıldırım, a. şahin, o. haki yuksel, m. timuçin aydın, a. verit 260 nutrition examination survey) it is noted that 35.5% of the males above the age of 20 are obese (bmi ≥ 30 kg/m2) and 73.9% of them are either overweight or obese (bmi ≥ 25 kg/m2) . metabolic syndrome (ms) is a disease that has a multifactorial component that causes insulin resistance whereas its mechanisms are not completely known (18). while ms incident is 42% among individuals at 70 years of age and above, it is 6,7% among the individuals of younger ages between 20-29 years (19). epidemiological and clinical data show that obesity, physical activity and nutrition are changeable risk factors for benign prostate hyperplasia (bph) and luts (20). although the pathophysiological mechanisms that cause luts in obesity are not completely known, many hypotheses were claimed. in many studies, it was shown that obese males have larger prostates that can cause obstruction and consequently luts (21). an important correlation was found between metabolic syndrome and yearly prostate volume increase (22). adipose tissue releases the aromatase enzymes that cause androgens turn into estrogens. it is claimed that prostate growth is lead by the hyperplasia in the prostatic tissue associated with the increase of estrogen/testosterone that originates from the testosterone turning into estrogens in the adipose tissue in obese males (23). adipocytes cause cytokine release. some researchers think that, as a consequence of the occurrence of systemic inflammation or oxidative stress in metabolic syndrome, cytokines are released to cause luts (24). in another study, it is argued that in obesity with the increased sympathetic nervous system activation, increased irritative luts are caused by contraction of the prostatic muscle component (25). however in an experimental animal study, it is shown that apoptosis occurs in the neural cells that are exposed to hyperglycemia for a long time causing an increase in luts as a result of autonomic hyperactivity with respect to the parasympathetic system (26). as seen above, many hypotheses were put forward about the relation between obesity and luts and many studies were conducted on this relationship in the recent years. the results of a 10 year study of 5926 patients, conducted in usa, show that severe luts could be prevented at the rate of 20% in males who preserved their normal weight (27). again, mondul et al. indicated that the total and abdominal fattening increase is a serious risk factor to develop or increase luts severity in males and that it is an important target in prevention and treatment of luts (28). in a study of 7318 patients, penson et al. indicated that decreasing physical activity causes an increase in luts severity in males that are in normal weight, without taking race into account (29). again, in a study on the effect of obesity on urine storage symptoms, which was conducted in 2013 with 6000 participants, it was reported that a strong relation exists between obesity and frequency of micturition in males (30). antithetically to the studies above, demir et al. and yee at al. declared that they did not find any relation between luts and abdominal obesity (31). however they detected that weight loss causes recovery in luts (32). luke et al. evaluated luts of the patients using ipss demonstrating that there is improvement in luts after weight loss, although this was not correlated with the degree of the weight loss or the duration of the weight loss (33). pre-operation ipss average was found to be 4.5 ± 2.22 in our study in which the average age is 34.59 ± 8.07; 19 of our total 22 male patients were mildly symptomatic (0-7 points) pre-operation, 3 of them were in the average symptomatic group with 8-19 points. post-operation ipss average was evaluated as 1.91 ± 1.48 and this decrease was found to be statistically significant. when compared with the pre-operation values, a positive correlation at 62.8% level is observed in post-operation bmi change rates and post-operation ipss change rates. in our study, in order to measure the severity and the effects of incontinence symptoms on the quality of life, the patients were evaluated with iciq-sf form pre-operation and post-operation. incontinence was not observed in 14 patients out of 22 patients (63%) in the pre-operation evaluation. in our study, while it was observed that both pre-operation and post-operation incontinence rates are relatively low, the post-operation decrease observed in iciq-sf average was found to be statistically significant. effects of obesity on depression and quality of life for male patients was also evaluated in our study with beck depression inventory and sf-36 form. average score of beck depression inventory was evaluated as low anxiety preoperation with 15.36 ± 2.4 point; it has shown improvement by decreasing in the post-operation period. in the study that was conducted in turkey in 2010, on the effect of the rheumatoid arthritis disease on the patient’s overall table 1. evaluating post-operation data compared to the pre-operation data of the study parameters in males. pre-operation post-operation avg ± sd (median) avg ± sd (median) bmi 49.57 ± 6.21 38.98 ± 5.51 10.001** weight 149.73 ± 21.34 118.23 ± 19.13 10.001** ipss 4.5 ± 2.22 (5) 1.91 ± 1.48 (2) 20.001** iciq-sf 1.82 ± 2.15 (1) 0.32 ± 0.95 (0) 20.002** beck 15.36 ± 2.4 (15.5) 9.55 ± 2.09 (9) 20.001** pcs 34.5 ± 8.13 42.95 ± 4.95 10.001** mcs 40.92 ± 6.48 46.71 ± 6.48 10.001** 1paired samples test; 2wilcoxon sign test; **p < 0.01. table 2. post-operation bmi change in comparison with preoperation and evaluation of the relations between changes in parameters. fif.1 overall quality of life of males. [ipss: !nternational prostate symptom score – iciq-sf: !nternational consultation on incontinence questionnaire short form – beck: beck depression scale – pcs: physical summary scores – mcs: mental summary scores. series 1: pre-gastrectomy – series 2: post-gastrectomy] post-operation changes bmi percentage change in comparison with pre-operation r p age -0.076 0.736 ipss 0.628 0.002** iciq-sf 0.324 0.142 beck 0.232 0.298 1paired samples test; 2wilcoxon sign test; **p < 0.01. uruc_stesura seveso 09/01/17 09:48 pagina 260 261archivio italiano di urologia e andrologia 2016; 88, 4 effects of obesity surgery on lower urinary symptoms quality of life average pcs in the control group was found 51.28 and mcs was found 41.43 (34). however in our study the average post-operation pcs in the obese patients was measured as 34.5 and mcs as 40.92 that were lower than the population average. post-operation pcs and mcs scores significantly increased to 42.9 and 46.7. conclusion the negative effect of gradually increasing obesity on luts and the quality of life is undeniable in today’s world. we think that while bariatric surgery helps weight loss in serious amounts, it also decreases the urinary dysfunction in males and increases their quality of life. references 1. who factsheet n°311. 2. çıtak akbulut g, özmen mm, besler ht. obesity the disease of the era. tubitak science and technical magazine march 2007: 1. 3. world health organization. who global database on body mass index. 4. world health organization. obesity and overweight. available at http://www.who.int/mediacentre/factsheets/fs311/en/ [accessed 28 sept 2012] 5. satman i, yilmaz t, sengul a, et al. population-based study of diabetes and risk characteristics in turkey: results of the turkish diabetes epidemiology study (turdep). diabetes care. 2002; 25:1551-6. 6. satman i, omer b, tutuncu y, et al. twelve year trends in the prevalence and risk factors of diabetes and pre diabetes in turkish adults. eur j epidemiol. 2013; 28:169. 7. sjostrom l, narbro k, sjostrom d, et al. effects of bariatric surgery on mortality in swedish obese subjects. n engl j med. 2007; 357:741. 8. colquit jl, picot j, loveman e, et al. surgery for obesity. cochrane database syst rev. 2009; 2:cd003641. 9. dixon jb, le roux cw, rubino f, zimmet p. bariatric surgery for type 2 diabetes. lancet. 2012; 379:2300. 10. buchwald h, oien dm. metabolic/bariatric surgery worldwide 2011. obes surg. 2013; 23:427. 11. taylor k. bariatric surgery fact sheet. american society for metabolic and bariatric surgery web site. available at http//www.asbs.org/newsite07/media/asmbs_fs_surgery.pdf. [accessed february 23, 2011] 12. bai sw, kang jy, rha kh, et al. relationship of urodynamic parameters and obesity in women with stress urinary incontinence. j reprod med. 2002; 47:559. 13. han mo, lee ny, park hs. abdominal obesity is associated with stress urinary incontinence in korean women. int urogynecol j pelvic floor dysfunct. 2005; 17:35. 14. wasserberg n, haney m, petrone p, et al. morbid obesity adversely impacts pelvic floor function in females seeking attention for weight loss surgery. dis colon rectum. 2007; 50:2096. 15. brethauer sa, hammel jp, schauer pr. systematic review of sleeve gastrectomy as staging and primary bariatric procedure. surg obes relat dis. 2009; 5:469. 16. brethauer sa. sleeve gastrectomy. surg clin n am. 2011; 91:1265. 17. mason ee, ito c. gastric bypass in obesity. surg clin north am. 1967; 47:1345-51. 18. hammarsten j, hogstedt b. hyperinsulinaemia as a risk fact or for developing benign prostatic hyperplasia. eur urol. 2001; 39:151. 19. ford es, giles wh, dietz wh. prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. jama 2002; 287:356. 20. raheem oa, parsons jk. associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms. curr opin urol. 2014; 24:10. 21. muller rl, gerber l, moreira dm, et al. obesity is associated with increased prostate growth and attenuated prostate volume reduction by dutasteride. eur urol. 2013; 63:1115. 22. glynn rj, campion ew, bouchard gr, silbert je. the development of benign prostatic hyperplasia among volunteers in the normative aging study. am j epidemiol. 1985; 121:78. 23. parsons jk, sarma av, mcvary k, wei jt. obesity and benign prostatic hyperplasia: clinical connections, emerging etiological paradigms and future directions. j urol. 2009; 182:27. 24. furukawa s, fujita t, shimabukuro m, et al. increased oxidative stress in obesity and its impact on metabolic syndrome. j clin invest. 2004; 114:1752. 25. giovannucci e, rimm eb, chute cg, et al. obesity and benign prostatic hyperplasia. am j epidemiol. 1994; 140:989. 26. cellek s, rodrigo j, lobos e, et al. selective nitrergic neuron degeneration in diabetes mellitus a nitric oxide-dependent phenomenon. br j pharmacol. 1999; 128:1804. 27. flegal km, carroll md, kit bk, et al. prevalence of obesity and trends in the distribution of body mass index among us adults 19992010. jama. 2012; 307:491. 28. mondul am, giovannucci e, platz ea. a prospective study of obesity, and the incidence and progression of lower urinary tract symptoms. j urol. 2014; 191:715. 29. penson df, munro hm, signorello lb, et al. urologic diseases in america project. obesity, physical activity and lower urinary tract symptoms: results from the southern community cohort study. j urol. 2011; 186:2316. 30. vaughan cp, auvinen a, cartwright r, et al. impact of obesity on urinary storage symptoms: results from the finno study. j urol. 2013; 189:1377. 31. demir o, akgul k, akar z, et al. association between severity of lower urinary tract symptoms, erectile dysfunction and metabolic syndrome. aging male. 2009; 12:29. 32. yee ch, so wy, yip sk, et al. effect of weight reduction on the severity of lower urinary tract symptoms in obese male patients with benign prostatic hyperplasia: a randomized controlled trial. korean j urol. 2015; 56:240-6; discussion 246. 33. luke s, addison b, broughton k, et al. effects of bariatric surgery on untreated lower urinary tract symptoms: a prospective multicentre cohort study. bju int. 2015; 115:466. 34. kırgız c, senel ö, sever o, arslanoglu e. observing the quality of life of the training personnel that are working in physical education and sports departments. kafkas educational research magazine 1(1), april 2014. correspondence fatih uruç, md (corresponding author) urucmd@gmail.com fatih sultan mehmet research and training hospital, department of urology içerenkoy/atasehir, tr34752 istanbul, turkey serkan akan drserkanakan@gmail.com bekir aras bekiraras1@gmail.com çağlar yıldırım c_yildirim_87@hotmail.com aytaç şahin draytacsahin@gmail.com ozgur haki yuksel yuksel:ozgurhaki@gmail.com mehmet timuçin aydın mtimucina@gmail.com ayhan verit veritayhan@yahoo.com uruc_stesura seveso 09/01/17 09:48 pagina 261 31archivio italiano di urologia e andrologia 2017; 89, 1 original paper comparison of transurethral incision of the prostate and silodosin in patients having benign prostatic obstruction in terms of retrograde ejaculation basri cakiroglu 1, aydin ismet hazar 2, orhun sinanoglu 3, ersan arda 1, sinan ekici 1 1 hisar intercontinental hospital, department of urology, istanbul, turkey; 2 gaziosmanpaşa taksim eğitim araştırma hastanesi, department of urology istanbul, turkey; 3 maltepe university, medical school department of urology, istanbul, turkey. background: to compare the functional outcomes and retrograde ejaculation (re) after transurethral incision of the prostate (tuip) or silodosin in bladder outlet obstruction (boo) secondary to a small prostate. methods: prospectively collected data from december 2011 through december 2014 of 192 luts patients having fertility concerns with prostate volume smaller than 40 ml receiving either tuip or silodosin treatment were prospectively reviewed. the treatment outcomes were evaluated and compared. results: tuip was performed in 96 cases and silodosin 8 mg was prescribed in 96 cases. at 12th months after tuip or continuous silodosin treatment, the decrease in mean international prostate symptom score (ipss) and postvoiding residual urine (pvr) and the improvement of mean maximal flow rate (qmax) were significant (p = 0.000). the improvement in ipps and qmax was significantly higher in tuip group compared to silodosin group (p = 0.005, p = 0.000) with a lower rate of retrograde ejaculation (re) in tuip group. (11/96 vs 33/96) (p = 0.000) conclusions: both tuip and silodosin ensures comparable improvement in pvr, ipss and qmax with a lower rate of re on the tuip group in prostates weighing less than 40 grams suggesting that tuip is a better choice in younger patiens seeking preservation of ejaculation with fertility concerns. key words: prostate; retrograde ejaculation; silodosin; transurethral incision prostate. submitted 26 may 2016; accepted 19 july 2016 summary no conflict of interest declared. matic bph; one blocks the α1-adrenoreceptors, the other inhibits the enzyme 5α-reductase. the former category is expected to provide relatively rapid symptom relief starting within 2-6 weeks (3). silodosin, is an adrenergic blocker considered to be highly selective for α1a receptor subtype and confirmed to be highly effective in patients with bph. however, almost 70% of patients report either anejaculation or hypospermia, with a concomitant orgasmic function (of) impairment in 17% of the patients. younger patients claimed higher rates of ejaculatory dysfunction (4). transurethral resection of the prostate (turp) is the gold standard for surgical treatment of bph. like many invasive modalities, this procedure is associated with with significant morbidity such as bleeding requiring blood transfusion (3%), and hyponatremia (tur syndrome, 1%) as well as long-term complications such as stricture (7%), surgical revision (6%), significant urinary tract infection (4%), bleeding incontinence (3%), erectile dysfunction (10%), and ejaculatory dysfunction (65%) (5, 6). furthermore, it may be an over-treatment for small size prostate in younger patients seeking protection of ejaculatory function. in this context, transurethral incision of the prostate (tuip) became a an established treatment for boo secondary to small-size bph (7). tuip has been reported to be an equivalent symptomatic improvement for men with prostate volume < 30 ml, with the advantages of less hemorrhage and less sexual dysfunction such as ed or re than turp (7, 8). in the present study, our objective is to compare the outcomes of tuip and silodosin treatment in men with luts due to bph seeking protection of fertility in terms of antegrade ejaculation. materials and methods a review of prospectively collected data of patients having luts due to bph with ejaculatory concerns receiving silodosin 8 mg or undergoing tuip. inclusion criteria were patients with mild-moderate luts, seeking preservation of fertility, age ≤ 60 years prostate volume ≤ 40 cc and preoperative cystoscopic evaluation. all patients signed an informed consent agreeing to supply their own anonymous doi: 10.4081/aiua.2017.1.31 introduction lower urinary tract symptoms (luts) due to bladder outlet obstruction (boo) are a common problem in aging males. benign prostatic hyperplasia (bph) is the most common cause of luts (1). the treatment of symptomatic bph is to relieve the boo due to enlarged portion of the prostate. this can be ensured with surgery definitively or with medications providing symptomatic relief. however, the invasive treatment modalities are not free of complications, including permanent urinary incontinence, retrograde ejaculation (re) as well as erectile dysfunction (ed) (2). therefore, to avoid invasive methods, two main categories of drugs are used for the treatment of symptocakiroglu_stesura seveso 04/04/17 09:12 pagina 31 archivio italiano di urologia e andrologia 2017; 89, 1 b. cakiroglu, a.i. hazar, o. sinanoglu, e. arda, s. ekici 32 information for the study. patients included in the alpha blocker treatment arm were prescribed to receive daily dosing silodosin 8 mg for a 12-months course. for tuip procedure and silodosin treatment, prostate volume > 40 cc, the presence of middle lobe, a history of prostate surgery or history of concomitant urethral stricture and hypersensitivity to alpha blockers, orthostatic hypertension, other drug interaction were exclusion criteria, respectively. all tuip procedures were performed or supervised by a single surgeon with a continuous flow 26 ch resectoscope and a video camera. the bladder neck was deeply incised at 5 and 7 o’clock positions just distal to each ureteral orifice to create a groove down to the true capsule to both side of the verumontanum. a 3-way 20ch foley catheter was inserted and connected to drainage and minimal saline irrigation. the patient was discharged once the urine was clear and the patient was able to void without a catheter. the follow-up visits were at 1, 6, and 12 months and then annually. baseline and follow-up data were compared both subjectively and objectively in terms of the international prostate symptoms score (ipss), international index of erectile function (iief), post-void residual urine volume (pvr) (ml), peak flow rate (qmax). only baseline and post treatment 12th month data were then collected and analyzed. statistics the spss 16.0 (statistical package for social sciences, chicago, usa) software was used for all statistical evaluations. changes from baseline data for the same group were compared using the paired t-test while between groups comparison was done by the fisher exact test for categorical variables and mann whitney-u test for continuous variables. p value of less than 0.05 was considered statistically significant. results ninety six patients underwent tuip and 96 patients received silodosin 8 mg. the differences in baseline parameters of treatment groups were not statistically significant; mean age, ipss, prostate volume, iief, pvr, qmax and psa were 48.8 ± 7.6 vs 48.3 ± 6.8, 12.9 ± 4.0 vs 11.9 ± 3.9, 30.1 ± 6.2 vs 31.5 ± 4.6, 24.9 ± 3.2 vs 25 ± 3.2, 68.2 ± 29.6 vs 68.0 ± 26.2, 12 ± 3.5 vs 12 ± 2.4 and, 1.3 ± 0.8 vs 1.4 ± 0.7 in tuip and silodosin groups, respectively (table 1). both groups were comparable in subjective and objective voiding parameters within follow up period at 3th, 6th and 9th month. at 12th months after tuip and continuous silodosin 8 mg treatment, the decrease in mean ipss, and pvr and the improvement of mean maximal flow rate (qmax) were significant in both groups (p = 0.000). no significant change occured in iief scores of either groups. the improvement in ipss and qmax was significantly higher in tuip group compared to silodosin group (4.7 ± 2.0 vs 5.7 ± 2.6 and 20.8 ± 23.2 vs 26.5 ± 26.8) (p = 0.005, p = 0.000) (table 2) with a lower rate of re in tuip group (11/96 vs 33/96) (p = 0.000) (table 3). iief scores in tuip and silodosin groups at 12th month were 24.9 ± 3.1 vs 25.3 ± 3.2 (p = 0.389). discussion the management of boo in bph patients is divided into medical and surgical treatment modalities. medical therapy for the common condition of bph consists of alpha blockers and/or 5-alpha-reductase inhibitors, which can both lead to sexual dysfunction and declines in ejaculatory function (9). according to clinical experience, the younger patients are more likely to encounter ejaculatory and orgasmic problems when using alpha blockers, so the physicians should be more careful when prescribing medicines. additionally, medical treatment options including alpha blokers for bph are only for relieving or palliating symptoms of luts, on the other hand the surgery is the definitive method to eliminate boo due to prostatic enlargement. among surgical treatment modalities open prostatectomy and turp are the leading entities. with the presence of gold standard turp, the minimally invasive procedure, tuip, in patients with small prostates has not gained enough popularity. in fact, the risk of blood transfusion and retrograde ejaculation are significantly lower with tuip when compared to turp. the reintervention rate is lower for turp, but this is compensated with decreased morbidity of tuip (10). tuip is comparable to turp in terms of functional outcomes within the first 12 table 1. preoperative parameters of patients in treatment groups. age ipss volume iief pvr qmax psa tuip (#96) 48.8 ± 7.6 12.9 ± 4.0 30.1 ± 6.2 24.9 ± 3.2 68.2 ± 29.6 12 ± 3.5 1.3 ± 0.8 silodosin (#96) 48.3 ± 6.8 11.9 ± 3.9 31.5 ± 4.6 25.0 ± 3.2 68.0 ± 26.2 12 ± 2.4 1.4 ± 0.7 p value 0.66 0.97 0.07 0.74 0.96 0.98 0.44 tuip: transurethral incision of the prostate, ipss: international prostate symptom score, iief: international index of erectile function, pvr: post voiding residue, qmax: maximum flow rate, psa: prostate specific antigen. student t test table 2. postperative parameters of patients in treatment groups. ipss iief pvr qmax tuip (#96) 4.7 ± 2.0 24.9 ± 3.1 20.8 ± 23.24 19.6 ± 3.9 silodosin (#96) 5.7 ± 2.6 25.3 ± 3.2 26.5 ± 26.8 15.0 ± 4.7 p value 0.005 0.389 0.123 0.000 tuip: transurethral incision of the prostate, ipss: international prostate symptom score, iief: international index of erectile function, pvr: post voiding residue, qmax: maximum flow rate. student t test table 3. retrograde ejaculation (re) status according to treatment modality. re (-) re (+) total tuip 85 (88.5%) 11 (11.5%) 96 (100%) silodosin 63 (65.6%) 33 (34.4%) 96 (100%) total 148 (77.1%) 44 (22.9%) 192 (100%) tuip: transurethral incision of the prostate, p = 0.000. chi square test cakiroglu_stesura seveso 04/04/17 09:12 pagina 32 months postoperatively, except qmax that was more significantly improved with turp (11). the operative time and hospital stay is shorter in the tuip procedure (12). in the present study, we compared silodosin with the invasive procedure, tuip. prostate volume < 40 cc was the inclusion criteria in contrast to the majority of previous reports suggesting that prostate volume should be taken < 30 cc in order to obtain successful results. however, there is little evidence on long-term effectiveness and there is no clear cutoff prostate size that achieves long-term favourable outcomes after tuip (13). in our series, the improvement in ipss, qmax and iief was significantly higher in tuip group compared to silodosin group whereas re rate was significantly lower in tuip group compared to silodosin group. to our knowledge, this is the first study comparing re status in terms of alpha bloker treatment and tuip procedure. there are comparative reports only among different surgical methods in this regard. in the present study, re rates in silodosin vs tuip were 34.4% and 11.5%, respectively. a systematic review comparing turp and tuip procedures reported that re rates were 65.4% and 18.2% respectively (14). the major adverse events of silodosin are ejaculatory dysfunction, dizziness, diarrhea or loose stools, skin rash, nasal congestion, abnormal liver function and thrombocytopenia. patients underwnt tuip avoid all these adverse events additionally (15). lastly, in terms of tuip complications in our series, there were not any short term complication such as bleeding and long term complication such as urethral stricture or bladder neck contracture. of interest, reoperation after tuip for the management of luts secondary to bph was needed after 12 months in 1 patient. there were limitations to our study. first, it was prospective in nature, and second, only the 12 month follow up data after initial treatment were compared. lack of urodynamic studies may be considered as another limitation. conclusions young patients with luts due to bph using highly uroselective alpha blokers experience quite often anejaculation, aspermia and reduced orgasm feeling. therefore, tuip remains as an alternative, safe and efficient procedure to treat boo secondary to a small-sized prostate in young bph patients seeking preservation of ejaculatory and orgasmic function with both infertility and sexual dissatisfaction concerns. acknowledgment all the authors below deny any meaningful affiliation or involvement, either direct or indirect, with any organization or entity with a direct financial interest in the subject matter or materials and any financial or material support for the work. references 1. chute cg, panser la, girman cj, et al. the prevalence of prostatism: a population-based survey of urinary symptoms. j urol. 1993; 150:85-9. 2. reznicek sb. common urologic problems in the elderly. prostate cancer, outlet obstruction, and incontinence require special management. postgrad med. 2000; 107:1634. 3. kaplan sa. use of alpha-adrenergic inhibitors in treatment of benign prostatic hyperplasia and implications on sexual function. urology. 2004; 63:428-34. 4. serino a, ventimiglia e, boeri l, et al. effects of silodosin on sexual function realistic picture from the everyday clinical practice.andrology. 2015; 3:1076-1081. 5. reich o, gratzke c, bachmann a, et al. morbidity, mortality and early outcome of transurethral resection of the prostate: a prospective multicenter evaluation of 10,654 patients. j urol. 2008; 180:246-9. 6. cakiroglu b, sinanoglu o, dogan an. safety of greenlight photoselective vaporisation of prostate in lower urinary tract symptoms due to benign prostatic hyperplasia in patients using anticoagulants due to cardiovascular comorbidities. arch ital urol androl. 2015; 87:141-3. 7. lourenco t, shaw m, fraser c, et al. the clinical effectiveness of transurethral incision of the prostate: a systematic review of randomized controlled trials. world j urol. 2010; 28:23-32. 8. cakiroglu b, gözüküçük r, sinanoglu o. efficacy and safety of 120 w greenlight photoselective vaporisation of prostate in patients receiving anticoagulant drugs. j pak med assoc. 2013; 63:1464-7. 9. adam f, stewart and edward d. kim fertility concerns for the aging male urology. 2011; 78:496-499. 10. taylor bl, jaffe wi. electrosurgical transurethral resection of the prostate and transurethral incision of the prostate (monopolar techniques). can j urol. 2015; 22 (suppl 1):24-9. 11. yang q, peters tj, donovan jl, et al. transurethral incision compared with transurethral resection of theprostate for bladder outlet obstruction: a systematic review and meta-analysis of randomized controlled trials. j urol. 2001; 165:1526-32. 12. saporta l, aridogan ia, erlich n, yachia d. objective and subjective comparison of transurethral resection, transurethral incision and balloon dilatation of the prostate. a prospective study. eur urol. 1996; 29:439-45. 13. hueber pa, zorn kc. let's not forget about tuip: a highly underutilized, minimally-invasive and durable technique for men with < g prostates.can urol assoc j. 2015; 9:255-6. 14. reich o, gratzke c, stief cg. techniques and long term results of surgical procedures for bph. eur urol. 2006; 4:970-78 15. yamanishi t, kaga k, fuse m, et al. six-year follow up of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: what are the factors for continuation or withdrawal? international j urol. 2015; 22:1143-48. 33archivio italiano di urologia e andrologia 2017; 89, 1 retrograde ejaculation correspondence cakiroglu basri, md (corresponding author) drbasri@gmail.com arda ersan, md ekici sinan, md hisar intercontinental hospital, department of urology, saray mh.siteyolu cad. no.7 34768 umraniye, istanbul, turkey hazar aydin ismet, md gaziosmanpaşa taksim eğitim araştırma hastanesi, department of urology istanbul, turkey sinanoglu orhun, md maltepe university, medical school department of urology, istanbul, turkey cakiroglu_stesura seveso 04/04/17 09:12 pagina 33 233archivio italiano di urologia e andrologia 2016; 88, 3 case report non sex-related subtotal rupture of the corpus cavernosum without urethral injury: a case report and literature review zeki bayraktar, selami albayrak department of urology, istanbul medipol university, school of medicine, istanbul, turkey. although penile fracture is a rare case, it is a well-described urologic emergency. it results from the rupture of the tunica albuginea of corpora cavernosa by blunt strain that commonly mandates immediate surgical exploration. urethral injury may also accompany penile fracture. an ideal anamnesis and a special physical examination were determinant to achieve a correct diagnosis. it is usually diagnosed based on clinical examination, but ultrasonography can be very helpful in diagnosis. the treatment is based on the presence of associated urethral injury. early surgery is preferable to conservative management, because it is associated with better outcomes and fewer long-term complications. the surgical repair of cavernous body can produce good results, with a favorable prognosis and minimal rate of complications. we present a penile fracture case of 34-year-old with subtotal rupture of the right corpus cavernosum without urethral injury who treated by early surgery and good results. key words: penile fracture; rupture; diagnosis; treatment; surgery. submitted 12 april 2016; accepted 22 may 2016 summary no conflict of interest declared. examination, there was swelling and subcutaneous hematoma in the penis (on the right penis skin). the defect at the fracture site was palpable. no hematoma was in the scrotum and pubis. penis presented left-sided deviation (figure 1). there was no urethral discharge and also no microscopic hematuria was found in the urine analysis. patient did not declare dysuria or any other urination problem. penile ultrasonography showed the presence of haematoma in the proximal shaft of the penis (30 x 21 mm) with a rupture of the tunica albuginea of the right cavernosal corpora (10 mm) and oedema of the subcutaneous tissue. cavernosal bleeding from the albugineal tears was showed at penile color doppler ultrasonography. the patient was a healthy man with no medications or allergies. he was taken to the operating room for emergency surgery. under the general anesthesia, penile subcoronal circumcising incision was made and the penis degloved. hematoma was limited by buck fascia (figure 2). fascia was incised and hematoma was evacuated (figure 3). doi: 10.4081/aiua.2016.3.233 figure 1. penis presenting left-sided deviation. figure 2. hematoma limited by buck fascia. introduction penile fracture is a urological emergency which is caused by the rupture of the tunica albuginea of the corpus cavernosum following a blunt trauma to the erect penis (1). tunical rupture caused by non-physiological bending of the penile shaft can be in one or two corpus cavernosum and it may be accompanied by urethral injury. the incidence of concomitant injury of the urethra is 0-38% in literature (2). we report the surgical repair of a penile fracture including subtotal disruption of corpus cavernosum without urethral injury. in this case, despite there was a subtotal rupture of the right corpus cavernosum, no urethral injury was observed. case report a 34 -year-old man presented with rapid detumescence, acute penile pain, penile swelling and deviation to left side following a cracking sound at penile manipulation 2 hours before in january 2016. the patient was married. but he did not declare sexual intercourse. on physical bayraktar_stesura seveso 21/09/16 09:04 pagina 233 archivio italiano di urologia e andrologia 2016; 88, 3 z. bayraktar, s. albayrak 234 there was subtotal transverse tears on the right tunica albuginea/corpus cavernosum. there were complete rupture on ventral, medial and lateral walls of the right corpus cavernosum. only a part of dorsal wall of the right corpus cavernosum was not ruptured (figure 4). a 18-french urethral catheter was passed into the bladder. defect/rupture of the right corpus cavernosum was repaired by interrupted 3/0 vicryl sutures (figure 5). for leakage control, artifical erection was provided by saline injected into the right corpus cavernosum. there was no leakage. urethral catheter was removed at postoperative first day and the patient was discharged with oral antibiotic treatment. the patient was advised to abstain from sexual intercourse for at least 4 weeks. one month after surgery, the patient was clinically evaluated for the presence of erectile dysfunction and penile deformity. despite of the ban on sexual intercourse, the patient declared sexual intercourse at postoperative twenty-third day. there was no penile deformity in physical examination. only a minimal induration was palpated at the fracture repair line. patient had normal erectile and voiding functions. no problem such as pain and curvature in erection was declared by patient. discussion and supplementary references are posted on www.aiua.it conclusions penile fracture is a rare condition and is generally diagnosed by clinical findings. ultrasonography is a useful technique for confirmation of clinically suspected corpus cavernosum rupture and most often is sufficient for diagnosis (3). some cases may also be treated as a cosmetic, emergency surgical exploration and treatment is the best guarantee of good functional and cosmetic results. early surgery has a high success rate and low complication in penile fracture. references 1. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 2. kamdar c, mooppan um, kim h, et al. penile fracture: preoperative evaluation and surgical technique for optimal patient outcome. bju int. 2008; 102:1640-44. 3. koifman l, barros r, júnior ra, et al. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology. 2010; 76:1488-92. figure 4. rupture almost complete of the dorsal wall of the right corpus cavernosum. figure 5. repair of the defect/rupture of the right corpus cavernosum by interrupted 3/0 vicryl suture. correspondence zeki bayraktar, md (corresponding author) zbayraktar@medipol.edu.tr istanbul medipol university, school of medicine, department of urology, medipol sefaköy hospital tevfikbey mah. maslakçeşme cad.no:30 küçükçekmece, istanbul, turkey selami albayrak, md salbayrak@medipol.edu.tr istanbul medipol university, school of medicine, department of urology, istanbul, turkey figure 3. fascia incision and hematoma evacuation. bayraktar_stesura seveso 21/09/16 09:04 pagina 234 archivio italiano di urologia e andrologia 2017; 89, 134 original paper influence of secondary diagnoses in the development of urinary incontinence after radical prostatectomy bárbara padilla-fernández 1, álvaro julio virseda-rodríguez 2, lauro sebastián valverde-martínez 3, bruno jorge pereira 4, hugo coelho 5, maria tatiana santos-antunes 6, manuel montesino-semper 7, carlos müller-arteaga 8, josé luis álvarez-ossorio-fernández 9, filippo migliorini 10, ana lorenzo-gómez 11, maría begoña garcía-cenador 11, patricia antúnez-plaza 12, juan miguel silva-abuín 13, maría fernanda lorenzo-gómez 2, 11 1 department of urology, university hospital of the canary islands, tenerife, spain; 2 department of urology, university hospital of salamanca, spain; 3 department of urology, health complex of ávila, spain; 4 department of urology, university hospital of pêro da covilhã, covilha, portugal; 5 department of urology, university hospital of coimbra (chuc), portugal; 6 department of maxillofacial surgery, central hospital complex of lisboa, portugal; 7 department of urology, university hospital virgen del camino of pamplona, spain; 8 department of urology, university hospital complex of ourense, spain; 9 department of urology, university hospital puerta del mar of cádiz, spain; 10 department of urology, university hospital integrated trust of verona, italy; 11 department of surgery, university of salamanca, spain; 12 department of pathology, university hospital of salamanca, spain; 13 department of urology, university hospital san pedro of logroño, spain. objective: to study whether there are factors related to secondary diagnoses (sdg) present in patients with prostate cancer that influence the development of urinary incontinence after radical prostatectomy (rp). materials and methods: a retrospective multicenter observational study was performed reviewing the medical records of 430 men who underwent rp due to organ-confined prostate cancer in 9 different hospitals. two study groups were distinguished: group a (ga): patients without urinary incontinence after rp; group b (gb): patients with any degree of post-surgical urinary incontinence. results: average age at surgery was 63.42 years (range 45-73). 258 patients were continent after surgery and 172 patients complaint of any degree of incontinence after rp. a higher percentage of healthy patients was found in group a (continent after surgery) than in group b (p = 0.001). the most common sdg prior to surgery were hypertension, lower urinary tract symptoms, dyslipidemia, diabetes mellitus and erectile dysfunction, but none did show a greater trend towards post-surgical incontinence. conclusions: a better health status prior to surgery is associated to a lower incidence of new-onset urinary incontinence after radical prostatectomy. however, no correlation was found between the most common medical disorders and the development of post-surgical urinary incontinence. key words: radical prostatectomy; second diagnoses; urinary incontinence. submitted 4 june 2016; accepted 19 july 2016 summary no conflict of interest declared. dence of tumour cells in the prostate (1), a 9.5% will have risk of being diagnosed with prostate cancer throughout their life, and 3% of them will have the probability of dying due to this disease (2, 3). histological signs of prostate cancer have been found in 42% of patients who died due to other causes (4, 5). most prostate cancers are organ-confined at diagnosis (6). when the patient's life expectancy is 10 years or greater and his health status is compatible with general anaesthesia, radical prostatectomy achieves the best results in oncological terms (7). radical prostatectomy is a complex major surgery, which requires dissection and removal of all the prostate gland and disruption and modification of a large part of the anatomical structures that makes up the male sphincteric complex. the different muscles, ligaments and neurovascular elements of the sphincteric complex converge in the prostate apex, in an anatomical funnel, whose upper limit is the prostate gland. the development of urinary incontinence (ui) is one of its most feared complications and is attributed to the technical characteristics of the surgery. the factors that may be associated to an increased risk of developing ui after surgery have been studied, i.e, ageing and deliberate wide resection of the cavernous nerves. the aim of this study was to evaluate whether there are factors related to secondary diagnoses (sdg) present in patients that influence the development of ui after radical prostatectomy (rp). materials and methods a retrospective multicenter observational study was performed. medical records of 430 men who underwent rp doi: 10.4081/aiua.2017.1.34 introduction studies performed in autopsies objectify that up to 3040% of men aged 50 or older will show histological evipadilla_stesura seveso 04/04/17 09:14 pagina 34 35archivio italiano di urologia e andrologia 2017; 89, 1 urinary incontinence after radical prostatectomy due to organ-confined prostate cancer were reviewed. patients were treated at the university hospital of salamanca (spain), university hospital pêro da covilhã (covilhã, portugal), university hospital and hospital of coimbra (portugal), university hospital virgen del camino (pamplona, spain), university hospital complex of ourense (spain), university hospital puerta del mar (cádiz, spain) and university hospital integrated trust of verona (italy). the sample selection was obtained from patients who underwent rp due to organ-confined prostate cancer in the above mentioned health care centres. december 2011 was the date used as reference and cases were selected sequentially in succession and retrospectively. open and laparoscopic rp were performed routinely at the centres involved in the study, but robot-assisted rp was performed in only one centre and in all cases by the same surgeon. for our purposes, we collected the information from the patients' medical records of the following variables: – patient-related variables: age, bmi, personal history, sdg, asa score, prostate volume; – disease-related variables: psa at diagnosis, gleason score of the biopsy, percentage of affected cores, presence of hg-pin or atypical small acinar proliferation (asap), ctnm and ptnm, gleason score of the surgical specimen, affectation of surgical margins; – surgery-related variables: centre of intervention, surgical technique (open, laparoscopic or robot-assisted), intervention's duration, age and experience of surgeon, surgical bleeding, post-surgical complications. post-prostatectomy ui was described as any leakage of urine, not present prior to the surgery. patients without any secondary diagnosis were considered healthy. patients receiving adjuvant or salvage radiation therapy were excluded from the study. two study groups were distinguished: group a (ga): patients without urinary incontinence after radical prostatectomy; group b (gb): patients with any degree of urinary incontinence after radical prostatectomy requiring pads. patients from gb were stratified according to the ui severity: mild ≤ 100cc/24 hours; moderate 101-400cc/24 hours and severe > 401cc/24 hours according to pad test. the results were analyzed with descriptive statistics, tdistribution, chi2, fisher's exact test, anova analysis of variance (with scheffe's test for normal samples and kruskal-wallys for other distributions), pearson's and spearman's correlation studies. statistical significance at p < 0.05 was accepted. the study was approved by the research committee of the university hospital of salamanca, spain. all ethical, legal and regulatory requirements for research on human subjects were considered, meeting the ethical principles for medical research of the declaration of helsinki. results average age at the moment of the surgery was 63.42 years (sd 5.67, range 45-73). 258 patients were continent after surgery (group a) and 172 patients complaint of any degree of incontinence after rp (group b). table 1 shows the general characteristics of patients and of the disease in ga and gb. surgical technique the technique most commonly performed was laparoscopic rp with 217 patients, follow by 190 open rp, and 23 robot-assisted rp (these were all performed at the same centre and by the same surgeon). 56.31% of patients after open rp were continent, as well as 61.29% after laparoscopic rp and 91.30% after robot-assisted rp. table 1. general characteristics of the patient and of the tumour in the whole sample and for groups a and b. group a group b p others age 62.87 (sd 6.09) 64.34 (sd 4.57) 0.26 total ga+gb = 63.42 (sd 5.67) bmi 28.56 (sd 3.59) 27.96 (sd 5.26) 0.55 total ga+gb = 28.83 (sd 4.32) asa 2.01 (sd 0.52) 2.00 (sd 0.52) 0.93 psa 8.61 (sd 4.37) 8.78 ( sd 4.14) 0.85 prostate volume 41.37 (sd 12.59) 41.18 (sd18.66) 0.81 measured during prostate biopsy gleason biopsy 6.13 (sd 0.61) 6.52 (sd 0.74) 0.00 tumour burden (% affected cylinders) 15.56 (sd 2.02) 16.40 (sd 2.53) 0.78 c tnm 7.23 (sd 4.02) 6.75 (sd 3.70) 0.11 * p tnm 3.27 (sd 1.69) 3.35 (sd 1.56) 0.74 ** sd: standard deviation of the mean. * clinical or pre-surgical tnm was codified as: 1 t1, 2 t1a, 3 t1b, 4 t1c, 5 ct1c, 6 t2, 7 t2a, 8 t2b, 9 t2c, 10 ct2a, 11 ct2b, 12 ct2c, 13 t3a, 14 t4. ** pathological tnm after the intervention or ptnm was codified as: 1 pt2a, 2 pt2b, 3 pt2c, 4 pt3a, 5 pt3b, 6 pt3c, 7 pt2, 8vpt3. table 2. most common secondary diagnoses (≥ 10%) in the whole sample. sdg in the whole sample type n % (n = 430) htn 182 42.32 luts general 136 31.62 outlet 55 12.79 filling 16 3.72 bph 68 15.81 dyslipidemia general 109 25.34 hypercholesterolemia 35 8.13 diabetes mellitus general 56 13.02 niddm 28 6.51 iddm 6 1.39 htn: arterial hypertension. luts: lower urinary tract symptoms. bph: benign prostatic hyperplasia. niddm: noninsulin-dependent diabetes mellitus. iddm insulin-dependent diabetes mellitus. padilla_stesura seveso 04/04/17 09:14 pagina 35 archivio italiano di urologia e andrologia 2017; 89, 1 b.padilla-fernández, á.j. virseda-rodríguez, l.s. valverde-martínez, et al. 36 secondary diagnoses only 76 (17.67%) out of 430 patients were healthy, without any sdg. the most common sdg were hypertension (htn), lower urinary tract symptoms (luts), dyslipidemia, diabetes mellitus (dm) and erectile dysfunction (ed). their distribution in the whole sample and in groups a and b are shown in tables 2 and 3. a higher percentage of healthy patients was found in group a (continent after surgery) than in group b, difference that was statistically significant. table 4 shows the distribution of other sdg in the whole sample. discussion luts infections, functional and cognitive impairment, neurological disorders and prostatectomy (8) are considered risk factors for ui in older men. in men in the study, considering the age and without prostatectomy, less than 1% would have some degree of urinary incontinence. a prevalence of up to 40.77% was observed in the 6 weeks following the surgery. incontinence is described as any leakage of urine that was not present prior to the surgery. 33.33% had severe urinary incontinence, 27.45% moderate incontinence and 39.22% mild incontinence. this prevalence is higher than that reported in the literature: 0-11% for minimally invasive prostatectomy and 3-20% for open surgery (9). this discordance may be due to the used ui definition: any leakage of urine, no matter how scarce or transitory it is, which was not present before. data were recorded in the first consultation after surgery. a trend to improvement of the results of continence was observed during all the follow-up time, until 48.12 months. at 24 months, only 26.7% of patients suffered from some degree of incontinence. these results were closer than those reported by other authors. second diagnoses and urinary incontinence after radical prostatectomy the prevalence of sdg in the sample does not differ from that observed in the general population. the most common are htn, luts, dyslipidemia and dm (42.32%, 31.62%, 25.34% and 13.02% respectively). luts and dm have been associated to the risk for ui in men, related to radical prostatectomy but also without prostatectomy history (10, 11). dm has been proposed as an independent factor for the development of urinary incontinence. it is usually associated to age over 65 and to the use of insulin as markers of severity (11, 12). in our series is noteworthy that the prevalence of dm in the group of incontinent patients (2.90%) is lower than in the group of continents (13.56%) (p < 0.0001). dm type 2 or noninsulindependent dm was the most common in the sample, and it had a shorter evolution time than dm type 1. these data are important since both the evolution time and the intrinsic insulin deficiency have been proposed as determinants of axonal damage that eventually causes loss of urine in elderly patients (13, 14). 14.22% of patients were diabetic, from which 77.89% had dm type 2 with a similar pattern of distribution in the groups a and b (78.21% in group a and 76.35% in group b). luts prior to the rp has also been reported as a risk factor for developing urinary incontinence (8, 15). neuroanatomical abnormalities in structures related to male sphincter complex would lead to a series of modifications that would predispose to suffer ui after prostatectomy. these abnormalities could be caused either by a trabeculated bladder, used to withstand high filling pressures (with consequent fibromuscular, irreversible damage) in relation to a distal obstructive element (usually bph) or by a primary hypoor hypertonic bladder (much less common). table 3. most common secondary diagnoses in ga and gb. disease group a group b p n % n % none: healthy 61 23.64 15 8.72 0.001 htn 96 37.20 66 38.37 0.8393 dm 35 13.56 5 2.90 0.0001 ed previous to prostatectomy 13 5.04 10 5.81 0.8275 dyslipidemia 56 21.70 44 25.58 0.3541 table 4. other sdg in the whole sample. other sdg type n % in the whole sample (n = 430) urological relative with prostate cancer 6 1.39 bladder cancer 4 0.93 erectile dysfunction 27 6.27 hydrocele 4 0.93 phimosis 6 1.39 neurological cerebrovascular accident 7 1.62 sequels of meningitis or cerebral palsy 5 1.16 pituitary adenoma 3 0.69 osteoarticular herniated disc 26 6.04 ankylosing spondylitis 3 0.69 hip prosthesis 6 1.39 respiratory asthma 12 2.79 copd 7 1.62 osas 14 3.25 cardiac coronary artery disease 12 2.79 valvular heart disease 11 2.56 arrhythmia: af 8 1.86 hepatopathology steatosis 11 2.56 idiopathic 8 1.86 chronic with portal hypertension 5 1.16 gastrointestinal esophagitis 6 1.39 gastritis 15 3.48 peptic ulcer 7 1.62 hiatal hernia 8 1.86 irritable bowel 4 0.93 colon polyps 6 1.39 haemorrhoids 8 1.86 obesity (bmi > 30) 21 4.88 hyperuricemia 28 6.51 chronic renal failure under dialysis 6 1.39 depression 29 6.74 sense organs glaucoma 11 2.56 hearing loss 14 3.25 vertigo 3 0.69 padilla_stesura seveso 04/04/17 09:14 pagina 36 37archivio italiano di urologia e andrologia 2017; 89, 1 urinary incontinence after radical prostatectomy in our series, 31.62% of patients had some degree of luts with an average ipss of 8.23 points (mild). it was measured in the consultation, by protocol and prior to the surgery, as well as the flowmetry. the flowmetry was performed in 88.34% of the patients included in the study and in 92.98% of patients classified as suffering from luts; it showed an average of 9.33 ml/min (obstructive). epidemiological data (men over 60 years), the rate of prostate symptoms and urinary flow results suggest a tendency to suffer obstructive luts. the results after surgery vary in this subgroup of patients. patients with any degree of ui after rp are similar regarding affectation by luts in the groups of mild, moderate and severe incontinence (35.29%, 32.60% and 33.04% respectively) (p = 0.88). therefore, suffering from luts prior to rp would not be related to the presence of iu after rp. a sphincter complex used to filling and emptying pressures higher than normal could be more prepared than a normal sphincter complex to the aggression of the rp, as the first has a tendency to hyperpressure and hypertrophy. broader studies would be necessary to investigate these pathophysiological aspects. regarding the presence of affected margins in the surgical piece, only the results from one centre (level 4 public hospital) could be studied. it contributed to the sample with 153 cases. affected margin was defined as the surgical piece in which tumour cells are less than 2 mm from the stain with indian ink of the edge (16). no difference between ga (24.04%) and gb (25.71%) (p = 0.4344) was observed in this centre regarding the affectation of margins, as it has been previously reported by this research group (17). the absence of sdg or patients with better health condition was associated with not suffering any degree of ui after rp (23.64% in ga versus 8.72% in gb, p < 0.001). this finding is consistent with other published results (9, 12). erectile dysfunction prior to the surgery has been proposed as a risk factor for iu after rp (18). the hypothesis that erectile dysfunction is associated to sensorineural deficits or to a worse overall condition of sphincter complex structures could explain this relationship with ui (19). in our series, there was no difference in the distribution of hypertension and erectile dysfunction between ga and gb (table 4). conclusions age, body mass index, having diabetes mellitus, hypertension or symptoms of lower urinary tract prior to the surgery do not influence the development of urinary incontinence after radical prostatectomy. however, a better health condition expressed as absence of disease is associated to a lower incidence of new-onset urinary incontinence after radical prostatectomy. author's contributions álvarez-ossorio-fernández (patient selection, data extraction); antúnez-plaza (statistical analysis); coehlo (patient selection, data extraction); garcía-cenador (study design, manuscript review); lorenzo-gómez, a (data extraction); lorenzo-gómez, mf (study design, patient selection, manuscript review); migliorini (patient selection, data extraction); montesino-semper (patient selection, data extraction); müller-arteaga (patient selection, data extraction); padillafernández (study design, manuscript writing); pereira (patient selection, data extraction); santos-antunes (data extraction); silva-abuín (patient selection, data extraction); valverde-martínez (data extraction, statistical analysis); virseda-rodríguez (statistical analysis, manuscript writing). references 1. parkin d, pisani p, ferlay j. estimates of worldwide incidence of eighteen mayor cancers in 1985. int j cancer. 1993; 54:594-606. 2. ilic d, o’connor d, green s, wilt t. screening for prostate cancer: a cochrane systematic review. cancer causes control. 2007; 18:279-85. 3. bartsch g, horninger w, klocker h, et al. tyrol prostate cancer screening group. prostate cancer mortality after introduction of prostate specific antigen mass screening in the federal state of tyrol, austria. urology. 2001; 58:417-24. 4. jemal a, siegel r, ward e, et al. cancer statistics, 2008. ca cancer j clin. 2008; 58:71-96. 5. jensen om, estève j, moller h, renard h. cancer in the european community and its members states. eur j cancer. 1990; 26:1167-256. 6. altwein s. screening of prostatic carcinoma: a critical analysis. the problem of screening and early diagnosis. munich, 19-21 march 1992. clin investig. 1992; 70 (9 suppl):1-8. 7. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part i: screening, diagnosis, and treatment of clinically localised disease. actas urol esp. 2011; 35:501-14. 8. lucas mg, bedretdinova d, bosch jlhr, et al. guidelines on urinary incontinence. urology eao, editor. arhein, netherland: uroweb; 2014; p.126 9. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012; 62:405-17. 10. lucas m, bosch j, cruz f, et al. guidelines on urinary incontinence. in: urology eao, editor. european association of urology guidelines: european association of urology. 2012; p. 7. 11. offermans mp, du moulin mf, hamers jp, et al. prevalence of urinary incontinence and associated risk factors in nursing home residents: a systematic review. neurourol urodyn. 2009; 28:288-94. 12. hsu a, conell-price j, stijacic-cenzer i, et al. predictors of urinary incontinence in community-dwelling frail older adults with diabetes mellitus in a cross-sectional study. bmc geriatr. 2014; 14:137. 13. wiedemann a, anding r, kirschner-hermanns r. (characteristics of urinary incontinence in the elderly). der urologe ausg a. 2014; 53:1543-50. 14. marini g, rinaldi jdc, damasceno dc, et al. changes in the extracellular matrix due to diabetes and their impact on urinary continence. rev bras ginecol obstet. 2014; 36:328-33. 15. irwin d, milsom i, hunskaar s, et al. population-based survey padilla_stesura seveso 04/04/17 09:14 pagina 37 archivio italiano di urologia e andrologia 2017; 89, 1 b.padilla-fernández, á.j. virseda-rodríguez, l.s. valverde-martínez, et al. 38 of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006; 50:1306-14. 16. tan ph, cheng l, srigley jr, et al. international society of urological pathology (isup) consensus conference on handling and staging of radical prostatectomy specimens. working group 5: surgical margins. mod pathol. 2011; 24:48-57. 17. virseda-rodríguez aj, valverde-martínez ls, pereira bj, et al. urinary incontinence after radical prostatectomy. in: urología aed, editor. 79 annual meeting of the spanish urological association; tenerife (spain): asociación española de urología; 2014. 18.carlsson s, drevin l, loeb s, et al. population-based study of long-term functional outcomes after prostate cancer treatment. bju int. 2016; 117:e36-45 19. glickman l, godoy g, lepor h. changes in continence and erectile function between 2 and 4 years after radical prostatectomy. j urol. 2009; 181:731-5. correspondence barbara padilla-fernández, md (corresponding author) padillaf83@hotmail.com department of urology, university hospital of the canary islands carretera de ofra, s/n. 38320 san cristóbal de la laguna, tenerife, spain alvaro julio virseda-rodríguez, md department of urology, university hospital of salamanca salamanca, spain lauro sebastian valverde-martínez, md department of urology, health complex of ávila, avila, spain bruno jorge pereira, md department of urology, university hospital of pêro da covilhã covilha, portugal hugo coelho, md department of urology, university hospital of coimbra (chuc) coimbra, portugal maria tatiana santos-antunes, md department of maxillofacial surgery, central hospital complex of lisboa lisboa, portugal manuel montesino-semper, md department of urology, university hospital virgen del camino of pamplona, pamplona, spain carlos müller-arteaga, md department of urology, university hospital complex of ourense ourense, spain jose luis álvarez-ossorio-fernández, md department of urology, university hospital puerta del mar of cádiz cadiz, spain filippo migliorini, md department of urology, university hospital integrated trust of verona verona, italy ana lorenzo-gómez, md department of surgery, university of salamanca, salamanca, spain maria begona garcía-cenador, md department of surgery, university of salamanca, salamanca, spain patricia antúnez-plaza, md department of pathology, university hospital of salamanca salamance, spain juan miguel silva-abuín, md department of urology, university hospital san pedro of logroño, spain maria fernanda lorenzo-gómez, md department of urology and surgery, university hospital of salamanca salamanca, spain padilla_stesura seveso 04/04/17 09:14 pagina 38 stesura seveso 99archivio italiano di urologia e andrologia 2014; 86, 2 original paper urolithiasis in italy: an epidemiological study domenico prezioso 1, ester illiano 1, gaetano piccinocchi 2, claudio cricelli 2, roberto piccinocchi 3, alberto saita 4, carla micheli 5, alberto trinchieri 6 1 department of neuroscience, reproductive sciences and dentistry, university federico ii of naples, naples, italy; 2 simg, italian society of general medicine; 3 university “campus biomedico” of rome, rome, italy; 4 department of urology, “vittorio emanuele hospital”, university of catania, catania, italy; 5 department of urology and andrology, santa maria della misericordia hospital, university of perugia, perugia, italy; 6 department of urology alessandro manzoni hospital of lecco, lecco, italy. objectives: worldwide the urolithiasis is the third most frequent urological disease affecting both males and females. in literature there are not recent italian epidemiological data about stone disease. the objective of this study is the evaluation of current epidemiology of urolithiasis in italy using the health search/csd longitudinal patient database (hs) database. material and methods: an observational, descriptive, retrospective trial was conducted. inclusion criteria were: family physicianassisted italian living population member of hs database within 31 december 2012, both genders, age over 17 years, at least two years of clinical history recorded from the beginning the trial. data were collected by hs database and elaborated by its software millewin®. results: in italy prevalence of urolithiasis in 2012 was 4.14%, it was higher in males than in females (4.53% versus 3.78%) with a positive relation with increasing age. the highest prevalence rate of urolithiasis was reported in the region campania (6.08%). the general incidence was 2.23 *1000, with the highest incidence in the region sicilia (3.15 *1000). incidence was higher in group age 65-74 years (3.18 *1000). conclusions: in italy the incidence and prevalence of urolithiasis is increasing with particular distribution in relation to gender, age and regional position. key words: urolithiasis, prevalence; incidence; epidemiological trial. submitted 26 january 2014; accepted 31 march 2014 summary introduction urolithiasis is a major clinical and economic burden for healthcare systems; infact is a highly prevalent condition with a high recurrence rate that has a large impact on the quality of life of those affected (1). in 1994 in italy the national institute of statistics (istat) database showed the prevalence as 1.7% and the incidence as 0.17 case/1000 patient with 95000 new cases/year. a national study of family physicians of the società italiana di me dicina generale (simg) in 2006 showed that 19% patients with urolithiasis undergo urologic visit, 4.6% hospitalization, 48.8% ultrano conflict of interest declared. sonography (us), 7.2% urography, 2.6% non-contrast enhanced computed tomography (ncct), 3.4% kidneyureter-bladder radiography (kub) (2). international epidemiological data suggest that the incidence and prevalence of stone disease is increasing (3-11) and an increase is recorded mainly in industrialized countries, as well in western countries probably resulting from improvements in clinical-diagnostic procedures and changes in nutritional and environmental factors (12). many population-based studies investigated prevalence and incidence rates of urolithiasis in different countries. nevertheless it is important to emphasize that precise data on the epidemiology of a disease or disorder can only be determined if geographical position, race, age and sex, climate, nutrition and other environmental factors are also taken in consideration. when analysing the literature, we can highlight the scarcity of new italian epidemiological data about stone disease. these epidemiological data are very important in the planning of health services and social-health; in clinical governance and in assessing the quality of services performed and their impact in terms of both clinical benefits as well as financial savings. to achieve these goals is needed to draw the real dimension of problem, especially the epidemiological dimension. in the latter part of the 20th century and in the early of 21th century a growing application of epidemiological methods was observed, with well-structured analysis of prescriptive profile and flow chart. in italy this system was combined with an evolution in the management of health informatics systems from the collection and storage of performance data and the related reimbursement by the regional health system (eg. hospitalizations, outpatient specialist care, pharmaceutical prescriptions). these are business systems, however are used as economic, clinical and epidemiological database also. this study seeks to evaluate current italian epidemiological situation about stone disease using health search/csd longitudinal patient database (hs) database used by simg. material and methods the study was designed as a observational, descriptive, retrospective trial. the objective is the evaluation of total doi: 10.4081/aiua.2014.2.99 archivio italiano di urologia e andrologia 2014; 86, 2 d. prezioso, e. illiano, g. piccinocchi, c. cricelli, r. piccinocchi, a. saita, c. micheli, a. trinchieri 100 prevalence and incidence of urolithiasis in italian population in 2012 divided by region, age and gender. inclusion criteria were: family physicianassisted italian living population members included in hs database within 31 december 2012 of both genders, aged over 17 years, with at least two years of clinical history recorded from the beginning the trial. the physicians participating to the study were 650 and were considered the most reliable among 1000 family physicians using hs. in fact in 1998 1000 italian familyphysicians were involved in a project of electronic medical recording (emr) in order to create a large hs database. in 2009, 650 italian family-physicians out of the total 1000 italian family-physician initially involved were selected according to their geographical distribution (northeast, northwest, central, south, islands). this group of “selected” 650 family physicians is composed by family physicians who ensured the best quality of reporting in epidemiological research. in order to select this group a quality score was calculated for each family physician. the geographical distribution of patients of these family physicians is similar to general italian population census by istat, without significant differences both in geographical location and age distribution. registered informations were: demographic informations and clinical informations such as body mass index (bmi), smoking, pressure blood value, biochemistry data, imaging, hospitalization, drugs etc. each patient was labelled with a nameless code, so all informations of each patient were reported with equivalent code. the nomenclature of was concordant with official journal, drug’s names were concordant with coding of anatomical therapeutic chemical classification system (atc) and diseases were concordant with coding of international classification of diseases 9° edition (icd-9). data were collected by the database health search and elaborated by its software millewin®. results the examined population is 900.994 with a regional allocation showed in table 1. this table shows the numbers (and rates) of family physician-assisted italian living population members included in hs database within 31 total male female region n % n % n % piemonte/aosta 61701 6.85 29756 6.87 31945 6.82 liguria 29791 3.31 14081 3.25 15710 3.36 lombardia 140973 15.65 69138 15.97 71835 15.34 trentino/fvg 46451 5.16 22196 5.13 24255 5.18 veneto 72553 8.05 35135 8.12 37418 7.99 emilia romagna 54403 6.04 25421 5.87 28982 6.19 toscana 46800 5.19 22555 5.21 24245 5.18 umbria 25127 2.79 11996 2.77 13131 2.80 marche 24930 2.77 12249 2.83 12681 2.71 lazio 79945 8.87 37788 8.73 42157 9.00 abruzzo/molise 29723 3.30 14035 3.24 15688 3.35 campania 77616 8.61 37134 8.58 40482 8.65 puglia 65505 7.27 31682 7.32 33823 7.22 basilicata/calabria 41207 4.57 20052 4.63 21155 4.52 sicilia 81595 9.06 38830 8.97 42765 9.13 sardegna 22666 2.52 10765 2.49 11901 2.54 total 900.994 100.00 432816 100.00 468178 100.00 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 1. family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female region n % n % n % piemonte/aosta 2237 3.63 1241 4.17 996 3.12 liguria 1104 3.71 634 4.50 470 2.99 lombardia 4413 3.13 2547 3.68 1866 2.60 trentino/fvg 1216 2.62 699 3.15 517 2.13 veneto 2119 2.92 1222 3.48 897 2.40 emilia romagna 2486 4.57 1436 5.65 1050 3.62 toscana 1756 3.75 1063 4.71 693 2.86 umbria 960 3.82 592 4.94 368 2.80 marche 1334 5.35 770 6.29 564 4.45 lazio 3160 3.95 1635 4.33 1525 3.62 abruzzo/molise 1306 4.39 659 4.70 647 4.12 campania 4718 6.08 2105 5.67 2613 6.46 puglia 3072 4.69 1461 4.61 1611 4.76 basilicata/calabria 2107 5.11 977 4.87 1130 5.34 sicilia 4355 5.34 2135 5.50 2220 5.19 sardegna 966 4.26 446 4.14 520 4.37 total 37316 4.14 19626 4.53 17690 3.78 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 3. prevalence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female age n % n % n % 15-24 92113 10.22 47883 11.06 44230 9.45 25-34 121663 13.50 60975 14.09 60688 12.96 35-44 160896 17.86 79737 18.42 81159 17.34 45-54 163813 18.18 80216 18.53 83597 17.86 55-64 135266 15.01 66156 15.29 69110 14.76 65-74 114032 12.66 54314 12.55 59718 12.76 75-84 80967 8.99 33309 7.70 47658 10.18 ≥ 85 32244 3.58 10226 2.36 22018 4.70 hs: health search/csd longitudinal patient database. n: number. table 2. family physician-assisted italian living population member of database hs within 31 december 2012 by class age and gender. december 2012 divided by italian re gion and gender (432.816 male versus 468.178 female) while table 2 shows the same population divided by class age (64.55% 25-64 years, while 12.57% ≥ 75 years) and gender (66.33% 2564 years males versus 62.92% 25-64 years females). patients members of hs database within 31 december 2012 with urolithiasis were 37.316, 4.14% of total family physician-assisted italian living population members of hs database within 31 december 2012 (table 3). this table shows an higher prevalence in males compared to females (m 4.53% versus f 3.78%) also, while table 4 shows a positive relation with increasing age. the highest prevalence (6.08%) of urolithiasis was observed in campania (table 3), followed by marche 5.35% and sicilia 5.34% whereas the lowest was recorded in trentino/friuli ve ne zia giulia 3.15% (table 3). in almost all the italian regions the prevalence of stone disease is higher in males (table 3), but in some regions such as campania (m 5.67% vs f 6.46%), puglia (m 4.61% vs f 4.76%), basilicata/cala bria (m 4.87% vs f 5.34%), and sar degna (m 4.14% vs f 4.37%) the prevalence is higher in females (table 3). the higher prevalence was observed in 65-74 years class age (table 4), rating 6.71% (m 8.02% and f 5.51%), follo wed by the 75-84 years (6.35%) and 55-64 years (5.92%) age groups (table 4). in ci dence of urolithiasis in family physician-assisted italian living population member of hs database within 31 december 2012 was 2.23 *1000, with the highest rate in sicilia (3.15 *1000) (table 5). in emilia romagna an higher incidence was recorded among males (3.43 *1000), while in sicilia among females (3.49 *1000) (table 5). as well as the prevalence, the incidence was higher in 65-74 years group age (3.18 *1000) (table 6). female are more affected in this group age (3.03 *1000), while male in 55-64 years group age (3.53 *1000) (table 6). discussion when comparing the epidemiological data of this study with those from literature, temporal references should be taken into account in fact population members of hs database were included within 31 december 2012, whereas those in the literature are related to previous periods, and this condition may have influence on the epidemiology of this chronic disease whose prevalence and incidence trends in recent decades have been changing. the lifetime prevalence of kidney stone disease is estimated at 1% to 15%, with the probability of having a stone varying according to age, gender, race, and geographic location. in previous reports the prevalence of kidney stones varied greatly between geographic locations, ranging from 8% to 19% in males and from 3% to 5% in females in western countries (12). it has been apparent for several years that the inci101archivio italiano di urologia e andrologia 2014; 86, 2 urolithiasis in italy: an epidemiological study total male female region n *1000 n *1000 n *1000 piemonte/aosta 106 1.71 61 2.05 45 1.39 liguria 77 2.54 36 2.52 41 2.55 lombardia 296 2.05 163 2.31 133 1.80 trentino/fvg 53 1.10 29 1.27 24 0.95 veneto 105 1.40 57 1.58 48 1.23 emilia romagna 153 2.72 90 3.43 63 2.10 toscana 78 1.44 45 1.73 33 1.17 umbria 45 1.77 32 2.66 13 0.97 marche 51 2.02 33 2.67 18 1.40 lazio 230 2.72 107 2.71 123 2.73 abruzzo/molise 63 1.97 30 2.00 33 1.95 campania 218 2.71 114 2.97 104 2.47 puglia 174 2.53 78 2.36 96 2.70 basilicata/calabria 113 2.66 64 3.10 49 2.24 sicilia 260 3.15 108 2.76 152 3.49 sardegna 61 2.52 30 2.61 31 2.44 total 2090 2.23 1082 2.42 1008 2.06 ffvg: friuli venezia giulia. hs: health search/csd longitudinal patient database. n: number. table 5. incidence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by italian region and gender. total male female age n *1000 n *1000 n *1000 15-24 81 0.95 34 0.77 47 1.15 25-34 184 1.49 89 1.44 95 1.54 35-44 309 1.86 179 2.18 130 1.54 45-54 438 2.56 226 2.70 212 2.42 55-64 447 3.12 246 3.53 201 2.74 65-74 388 3.18 193 3.34 195 3.03 75-84 211 2.40 100 2.75 111 2.15 ≥ 85 32 0.86 15 1.26 17 0.67 hs: health search/csd longitudinal patient database. n: number. table 6. incidence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by age and gender. total male female age n % n % n % 15-24 601 0.65 236 0.49 365 0.83 25-34 2303 1.89 928 1.52 1375 2.27 35-44 4903 3.05 2384 2.99 2519 3.10 45-54 7381 4.51 3941 4.91 3440 4.12 55-64 8012 5.92 4562 6.90 3450 4.99 65-74 7646 6.71 4355 8.02 3291 5.51 75-84 5142 6.35 2633 7.91 2509 5.27 ≥ 85 1328 4.12 587 5.74 741 3.37 hs: health search/csd longitudinal patient database. n: number. table 4. prevalence of urolithiasis in family physician-assisted italian living population member of database hs within 31 december 2012 by age and gender. archivio italiano di urologia e andrologia 2014; 86, 2 d. prezioso, e. illiano, g. piccinocchi, c. cricelli, r. piccinocchi, a. saita, c. micheli, a. trinchieri 102 dence rates of lithiasis vary dramatically, not only from continent to continent, but also between adjacent regions of a country, even if one allows for differences in methodology and criteria selection among epidemiology studies (13, 14) infact epidemiological data on the occurrence of urolithiasis ranges between 2% and 20% worldwide (15, 16) (being most common in south and south eastern regions of united states, as well as in central europe and the me diterranean area, india and northern pakistan, northern australia and china) (17) in our study the prevalence in 2012 in italy is 4.14%, while the incidence is 2.23 *1000, with a geographic distribution showing higher prevalences and incidences in southern regions. this can be easily explained, by the well documented knowledge that the incidence of urinary stones is higher in countries with warm or hot climates, probably due to low urinary output and scant fluid intake (18). seasonal variation in stone disease is likely related to temperature by way of fluid losses through perspiration and perhaps by sunlight –induced increases in vitamin d (19). in a previous study of the simg (2) in 2008, the prevalence of urolithiasis in italy was evaluated at a lower rate of 3.1%. the higher rate demonstrated in the present study confirm in our country the increasing trend reported in the rest of the world. stone disease typically affects adult men more commonly than adult woman (12). howerver scales et al. (20) observed a dramatic increase from 1997 to 2002 of the adjusted rate of discharges for stone disease in females in american population with a change from 1.7:1 to 1.3:1 of the male-tofemale ratio. the increasing incidence of nephrolithiasis in women might be due to lifestyle associated risk factors, such as obesity (20). in italy the rates in 2012 confirm the 2008 data (2) with higher prevalence in males than in females (m 3.4 vs. f 2.8%) but contrasting results were observed in southern regions.. data from the american database national health and nutrition examination survey (nhanes) indicate that stone prevalence increased in all age groups from 1980 to 1994 though, despite more than 15,000 participants at each time point, the increase was statistically significant only for men aged 60-74 (21). in italy hypercalciuria was more frequent in patients aged 20-39 years (50.3%) than in older patients (36%) and hyperuricosuria was lower in the younger patients (5%) than in the older patients (10%) (22). in our study the age group most affected is 65-74 years (6.71%, m 8.02% and f 5.51%), instead of the 55-64 years age group (4.5% m 5.40% and f 3.60%) in 2008 (2), however in both studies a similar trend was observed. conclusions this is the first study that evaluated prevalence and incidence of urolithiasis in italy by age, gender and italian region. these data are important for clinical workforce planning, training, service delivery and research in the field of urolithiasis. references 1. semins mj. medical evaluation and management of urolithiasis. ther adv urol. 2010; 2:3-9. 2. campo s, pasqua a, simonetti m, mazzaglia g. studio sulla nefrolitiasi nel setting delle cure primarie italiane. rivista della società italiana di medicina generale 2011; 2:1-5. 3. pearle m, calhoun e, curhan g. urologic diseases in america project: urolithiasis j urol. 2005; 173:848-57. 4. romero v, akpinar h, assimos d. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010; 12:86-96. 5. stamatelou k, francis m, jones c, et al. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003; 63:1817-23. 6. soucie j, thun m, coates r, et al. demographic and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-9. 7. sánchez-martín f, millan rodríguez f, esquena fernández s, et al. incidence and prevalence of published studies about urolithiasis in spain. a review. actas urol esp. 2007; 31:511-20. 8. amato m, lusini m, nelli f. epidemiology of nephrolithiasis today. urol int. 2004; 72 (suppl. 1):1-5. 9. serio a, fraioli a. epidemiology of nephrolithiasis. nephron. 1999; 81 (suppl. 1):26-30. 10. hesse a, brändle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003; 44:709-13. 11. trinchieri a, coppi f, montanari e, et al. increase in the prevalence of symptomatic upper urinary tract stones during the last ten years. eur urol. 2000; 37:23-5. 12. trinchieri a. epidemiology of urolithiasis: an update clinical cases in mineral and bone metabolism. 2008; 5:101-106. 13. andersen da. histological and geographical differences in the pattern of incidence of urinary stones in relation to possible aetiological factors. renal stone research. edinburgh: churchill livingstone 1969; 22-29. 14. pak cy. kidney stone. lancet. 1998; 351:1797-1801. 15. hesse a, siener r. current aspects of epidemiology and nutrition in urinary stones.world j urol. 1997; 15:167-171. 16. trinchieri a. epidemiology of urolithiasis. arch it urol. 1996; 68:203-250. 17. finlayson b. renal lithiasis in review. urologic clinics of north america 1974; 180-1. 18. lópez m, hoppe b. history, epidemiology and regional diversities of urolithiasis pediatr nephrol. 2010; 25:49-59. 19. sternberg k, greenfield sp, williot p, wan j. pediatric stone disease: an evolving experience. j urol. 2005; 174:1711-1714. 20. scales cd jr, curtis lh, norris rd, et al. changing gender prevalence of stone disease. j urol. 2007; 177:979-82. 21. stamatelou kk, francis me, jones ca, et al. time trends in reported prevalence of kidney stones in the usa:1976-1994. kidney int. 2003; 64:1817-1823. 22. vitale c, tricerri a, manganaro m, et al. clinical and metabolic features of renal calculi in adults in regard to age of onset. minerva urol nefrol. 1999; 51:71-74. correspondence domenico prezioso, md (corresponding author) ester illiano, md department of neuroscience, reproductive sciences and dentistry. university federico ii of naples, naples, italy gaetano piccinocchi, md simg. italian society of general medicine claudio cricelli, md simg. italian society of general medicine roberto piccinocch, md university “campus biomedico” of rome, italy alberto saita, md department of urology. “vittorio emanuele hospital”. university of catania, italy carla micheli, md department of urology and andrology. santa maria della misericordia hospital. university of perugia, perugia, italy alberto trinchieri, md department of urology alessandro manzoni hospital of lecco, lecco, italy 219archivio italiano di urologia e andrologia 2017; 89, 3 original paper investigation of the effect of body mass index (bmi) on semen parameters and male reproductive system hormones mehmet zeynel keskin 1, salih budak 1, evrim emre aksoy 2, cem yücel 1, serkan karamazak 1, yusuf ozlem ilbey 1, zafer kozacıoğlu 1 1 tepecik training and research hospital, izmir, turkey; 2 kırkağaç state hospital, manisa, turkey. aim: to evaluate the effects of body mass index (bmi) ratio on semen parameters and serum reproductive hormones. materials and methods: the data of 454 patients who prsented to male infertility clinics in our hospital between 2014 and 2015 were analyzed retrospectively. weight, height, serum hormone levels and semen analysis results of the patients were obtained. bmi values were calculated by using the weight and height values of the patients and they were classified as group 1 for bmi values ≤ 25 kg/m2, as group 2 for bmi values 25-30 kg/m2 and as group 3 for bmi values ≥ 30 kg/m2. results: the mean values of bmi, semen volume, concentration, total motility, progressive motility, total progressive motile sperm count (tpmsc), normal morphology according to kruger, head abnormality, neck abnormality, tail abnormality, fsh, lh, prolactin, t/e2, total testosterone and estradiol parameters of the patients were considered. patients were divided according to bmi values in group 1 (n = 165), group 2 (n = 222) and group 3 (n = 56). there was no statistically significant difference in terms of all variables between the groups. conclusions: we analyzed the relationship between bmi level and semen parameters and reproductive hormones, demonstrating no relationship between bmi and semen parameters. in our study, bmi does not affect semen parameters although it shows negative correlation with prolactin and testosterone levels. key words: infertility; bmi; semen parameters; reproductive hormones. submitted 18 may 2016; accepted 19 august 2016 summary no conflict of interest declared. number of studies and in some studies this decrease was found as associated to the increase in obesity prevalence (2). but, there is not a consensus in the literature and contradictory results were published. in this study, we analyzed the effect of bmi on semen parameters and the relationship with reproductive hormone levels. materials and methods the data of 454 patients who presented to male infertility clinics in our hospital between 2014 and 2015 were analyzed retrospectively. weight, height, serum hormone levels and semen analysis results of the patients were considered. bmi values were calculated by using the weight and height values of the patients and they were classified as group 1 for bmi values ≤ 25 kg/m2, as group 2 for bmi values 25-30 kg/m2 and as group 3 for bmi values ≥ 30 kg/m2. semen analysis was performed after a 3-5 days of sexual abstinence. semen analysis was performed according to who 2010 criteria (semen volume ≥ 1.5 ml; sperm concentration ≥ 15 × 106/ml; total motility ≥ 40%, progressive motility ≥ 32% and morphology ≥ 4%). after 5-30 minutes of sample collection, the analysis was performed after the sample was liquefied. for the microscopic examination in semen analysis, phase contrast light microscope was used and the examination was performed with 10 x 20 magnification. for sperm concentration, makler counting chamber was used and the sperm count (concentration) was found in million/ml with the sperm count in 10 squares in a 100 square area. motility was evaluated in 3 groups as linear progressive motility, non-progressive motility and immotility. for the morphological examination, semen sample which was dropped on slides, washed with 70% alcohol previously, according to sperm concentration were dried with 45 degrees angle. then, it was stained with diffquick kit and at least 200 sperm were analyzed under immersion oil with 100x objective and the percentage of the sperm having normal morphology was determined. for the hormone levels, blood sample was collected in the morning before 10.00 a.m. hormone analysis was performed with roche hitachi cobase 601 equipment and by using microparticle enzyme immunoassay method. fsh, lh, prolactin, total testosterone and estradiol levels were analyzed. the statistical analysis was performed with ibm statistical package for social sciences (spss) version 22.0 doi: 10.4081/aiua.2017.3.219 introduction being overweight and obesity are among the most significant health problems in our era. world health organization (who) described as overweight a patient with body mass index (bmi) ≥ 25 kg/m2 and as obese a patient with bmi ≥ 30 kg/m. according to who data, 35% of the young patients, who are in their twenties, are overweight and 11% of them are obese (1). it was reported that the overweight and obesity incidence dramatically increased in developed countries in last 30 years (2). infertility is another health problem affecting 15% of the couples in developed countries (3). a significant decrease in the sperm quality was shown by studies conducted in last 25 years (4, 5). the reason of this decrease aroused interest and it became a subject for research. especially, its relation with the obesity was analyzed in a keskin_stesura seveso 28/09/17 10:24 pagina 219 archivio italiano di urologia e andrologia 2017; 89, 3 m. zeynel keskin, s. budak, e. emre aksoy, c. yücel, s. karamazak, y. ozlem ilbey, z. kozacıoğlu 220 programme. a value of p < 0.05 was accepted as statistically significant. results the mean values of bmi, semen volume, concentration, total motility, progressive motility, total progressive motile sperm count (tpmsc), normal morphology according to kruger, head abnormality, neck abnormality, tail abnormality, fsh, lh, prolactin, t/e2, total testosterone and estradiol parameters of the patients are shown in table 1. patients were divided according to bmi values in group 1 (n = 165), group 2 (n = 222) and group 3 (n = 56). there was no statistically significant difference in semen parameters between the groups. bmi ratio do not affect semen parameters but it shows negative correlation with prolactin and total testosterone. discussion the effect of obesity on semen parameters is multifactorial and it was tried to be explained with different pathophysiological mechanisms (6, 7). the fact that testosterone is aromatized to estradiol (e2) in fat tissue (8), the decrease in sex hormone binding globulin (shbg) levels (9), the suppression of luteinizing hormone (lh) secretion with the increase of endorphin levels (10), hyperinsulinemia and hyperlipidemia (11) were found as responsible for this relationship, although there are contradictory results in the literature. in a meta-analysis conducted by macdonald et al., no relationship between semen parameters and bmi was detected (12). moreover, in other similar original studies, this relationship was not found (13, 14). on the contrary, in a meta-analysis conducted by sermondade et al., a negative relationship between bmi and semen parameters was detected (7). there are also original studies reporting similar results (15-17). while a statistically significant negative relationship was detected between bmi and semen volume, concentration and motility in a comprehensive cohort study including 10665 patients conducted by belloc table 1. mean volues of data and p values according to bmi groups. bmi parameter < 25.0 kg/m2 25.0-30.0 kg/m2 > 30.0 kg/m2 p value bmi (kg/m2) minimum 18.78 25.01 30.04 maximum 24.98 29.98 43.55 mean 22.65 27.06 33.09 std. dev. 1.69 1.35 3.44 volume (ml) 0.330 minimum 0 0 0 maximum 11 8 8 mean 2.88 2.69 2.58 std. dev. 1.71 1.67 1.65 concentration (106/ml) 0.576 minimum 0 0 0 maximum 168 170 140 mean 33.28 35.56 33.74 std. dev. 36.91 36.29 35.59 total motility (%) 0.754 minimum 0 0 0 maximum 85 85 90 mean 46.34 49.76 47.63 std. dev. 25.29 22.22 27.26 progressive motility (%) 0.694 minimum 0 0 0 maximum 80 94 80 mean 30.15 31.94 30.66 std. dev. 21.89 21.55 22.91 tpmsc (million) 0.790 minimum 0 0 0 maximum 352.8 361.08 220 mean 40.66 44.40 41.97 std. dev. 59.97 62.83 56.67 normal morphology (kruger) (%) 0.554 minimum 0 0 0 maximum 10 9 7 mean 2.43 2.60 2.26 std. dev. 2.23 2.12 2.00 head abnormality (%) 1.000 minimum 0 0 0 maximum 100 91 86 mean 50.16 51.75 48.20 std. dev. 39.93 38.41 40.82 neck abnormality (%) 0.937 minimum 0 0 0 maximum 14 14 14 mean 5.72 6.15 6 std. dev. 5.12 4.89 5.29 tail abnormality (%) 0.561 minimum 0 0 0 maximum 11 13 14 mean 4.16 4.66 3.80 std. dev. 3.86 3.94 4.02 fsh (miu/ml) 0.299 minimum 1.56 1.57 1.68 maximum 31 44.72 17.15 mean 3.42 2.76 2.18 std. dev. 5.58 2.18 3.74 lh (miu/ml) 0.452 minimum 2 1.63 2.02 maximum 14.63 19.57 16.87 mean 5.61 5.29 6.04 std. dev. 2.74 5.72 3.22 prolactin (ng/ml) 0.018 minimum 3.35 2.98 5.83 maximum 27.85 49.29 27.04 mean 11.44 9.87 10.88 std. dev. 5.51 5.84 4.37 t/e ratio (%) 0.815 minimum 6.98 2.05 8.31 maximum 22.16 39.13 14.87 mean 11.82 15.49 11.59 std. dev. 8.26 9.77 4.63 testosterone (ng/dl) 0.001 minimum 9.1 4.31 147.10 maximum 851.7 856 676.20 mean 488.32 398.20 377.61 std. dev. 175.13 139.71 113.36 estradiol (pg/ml) 0.270 minimum 16.32 7.21 32.76 maximum 44.24 160.30 57.29 mean 29.88 34.93 45.02 std. dev. 9.87 37.12 17.34 keskin_stesura seveso 28/09/17 10:24 pagina 220 et al., no relationship with morphology was detected (18). in another study with 42 patients conducted by leisegang et al., it was reported that bmi level and sperm concentration are negatively correlated and no correlation was detected with motility and morphology (19). in a cohort study, which stewart et al. conducted with 225 fertile male patients, it was reported that bmi and sperm count are negatively correlated (20). in our study, no statistically significant relationship was found between bmi level and semen parameters. in a recent study, on the other hand, the relationship between bmi and semen parameters and reproductive hormone levels was analyzed and a statistically significant negative relationship between bmi and semen volume, shbg and total testosterone (t) level was detected (21). in the study conducted by relwani et al., it was reported that bmi level does not affect semen parameters but it statistically significantly decreases t, shbg and free t level (22). in the literature, there is a general consideration that obesity especially decreases total testosterone and shbg levels but it is partially correlated to free testosterone levels (16, 23). in our study, we observed that when bmi level is high, prolactin and total testosterone levels are significantly lower. conclusions in our study, when we analyzed the relationship between bmi level and semen parameters and reproductive hormones, no relationship was detected between bmi and semen parameters. on the contrary bmi level shows a negative correlation with prolactin and testosterone levels. however, to reveal the relationship between bmi and male infertility, large, randomized and prospective studies are needed. references 1. joint who/fao expert consultation. diet, nutrition and the prevention of chronic diseases. who technical report series 916. world health organization, geneva; 2003. 2. finucane mm, stevens ga, cowan mj, et al. global burden of metabolic risk factors of chronic diseases collaborating group (body mass index). national, regional, and global trends in bodymass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. lancet. 2011; 377:557-567. 3. eisenberg ml, kim s, chen z, et al. the relationship between male bmi and waist circumference on semen quality: data from the life study. hum reprod. 2014; 29:193-200. 4. carlsen e, giwercman a, keiding n, skakkebaek ne. evidence for decreasing quality of semen during past 50 years. br med j. 1992; 305:609-613. 5. swan sh, elkin ep. declining semen quality: can the past inform the present? bioessays 1999; 21:614-621. 6. eisenberg ml, kim s, chen z, et al. the relationship between male bmi and waist circumference on semen quality: data from the life study. hum reprod. 2015; 30:493-4. 7. sermondade n, faure c, fezeu l, et al. bmi in relation to sperm count: an updated systematic review and collaborative meta-analysis. hum reprod update. 2013; 19:221-231. 8. schneider g, kirschner ma, berkowitz r, ertel nh. increased estrogen production in obese men. j clin endocrinol metab. 1979; 48:633-638. 9. stellato rk, feldman ha, hamdy o, et al. testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the massachusetts male aging study. diabetes care. 2000; 23:490-494. 10. blank dm, clark rv, heymsfield sb, et al. endogenous opioids and hypogonadism in human obesity. brain res bull. 1994; 34:571-574. 11. lampiao f, du plessis ss. insulin and leptin enhance human sperm motility, acrosome reaction and nitric oxide production. asian j androl. 2008; 10:799-807. 12. macdonald aa, herbison gp, showell m, farquhar cm. the impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. hum reprod update. 2010; 16:293-311. 13. aggerholm as, thulstrup am, toft g, et al. is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? fertil steril. 2008; 90:619-626. 14. li y, lin h, ma m, et al. semen quality of 1346 healthy men, results from the chongqing area of southwest china. hum reprod. 2009; 24:459-469. 15. jensen tk, andersson am, jørgensen n, et al. body mass index in relation to semen quality and reproductive hormones among 1,558 danish men. fertil steril. 2004; 82:863-870. 16. erdemir f. relationship between obesity and male infertility. j clin anal med. 2013; 4:76-82. 17. hofny er, ali me, abdel-hafez hz, et al. semen parameters and hormonal profile in obese fertile and infertile males. fertil steril. 2010; 94:581-584. 18. belloc s, cohen-bacrie m, amar e, et al. high body mass index has a deleterious effect on semen parameters except morphology: results from a large cohort study. fertil steril. 2014; 102:1268-73. 19. leisegang k, bouic pj, menkveld r, henkel rr. obesity is associated with increased seminal insulin and leptin alongside reduced fertility parameters in a controlled male cohort. reprod biol endocrinol. 2014; 12:34:2-12. 20. stewart tm, liu dy, garrett c, et al. associations between andrological measures, hormones and semen quality in fertile australian men: inverse relationship between obesity and sperm output. hum reprod. 2009; 24:1561-1568. 21. ehala-aleksejev k, punab m. the different surrogate measures of adiposity in relation to semen quality and serum reproductive hormone levels among estonian fertile men. andrology. 2015; 3:225-234. 22. relwani r, berger d, santoro n, et al. jindal semen parameters are unrelated to bmi but vary with ssri use and prior urological surgery. reprod sci. 2011; 18:391-7. 23. allen ne, appleby pn, davey gk, key tj. lifestyle and nutritional determinants of bioavailable androgens and related hormones in british men. cancer causes control. 2002; 13:353-63. 221archivio italiano di urologia e andrologia 2017; 89, 3 investigation of the effect of body mass index (bmi) on semen parameters and male reproductive system hormones correspondence mehmet zeynel keskin, md (corresponding author) zeynel_akd@hotmail.com salih budak, md salihbudak1977@gmail.com cem yücel, md meclecuy@hotmail.com serkan karamazak, md drkaramazak@hotmail.com yusuf ozlem ilbey, md ozlemyusufilbey@hotmail.com zafer kozacıoğlu, md drzafko@hotmail.com tepecik training and research hospital, izmir, turkey evrim emre aksoy, md dreaksoy@yahoo.com kırkağaç state hospital, manisa, turkey keskin_stesura seveso 28/09/17 10:24 pagina 221 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4306 original paper sexuality and erectile function after implantation of an adjustable transobturator male system (atoms) for urinary stress incontinence. a multi-institutional prospective study alexander friedl 1, wilhelm bauer 1, maximilian rom 2, danijel kivaranovic 3, werner lüftenegger 4, clemens brössner 1 1 department of urology, hospital göttlicher heiland, dornbacher straße 20-28, 1170 vienna, austria; 2 department of urology, vienna general hospital, medical university of vienna, vienna, austria; 3 center for medical statistics, informatics, and intelligent systems, medical university of vienna, vienna, austria; 4 department of urology, kaiser franz josef hospital, smz-süd, kundratstraße 3, 1100 vienna, austria. objectives: to investigate erectile function and sexuality before/after implantation of the atoms device including continence outcome, pain perception and co-morbidities. materials and methods: we collected data from 34 patients (2010-2014) who were provided with an atoms implant due to mild or moderate stress urinary incontinence (sui) after radical prostatectomy (rpe), transurethral resection (turp) or radiotherapy. previous failed implants were no contraindication. sexuality was evaluated with the international index of erectile function (iief-5). the visual analog scale (vas) and leeds assessment of neuropathic symptoms and signs (lanss) were used to analyse pain perception. results regarding continence, influence of co-morbidities and drug intake were interpreted. results: iief-5 score increased 6 months after atoms implantation with a mean difference of 2.18 (cl: 1.22, 3.14), p < 0,001). non-sexually active patients had the greatest benefit. however, 50% of patients achieved a mean iief-5 of 10.1 and 38% of patients reported a new onset of sexual activity at follow up (mean iief-5 score of 12.9). this is in accordance with reduced sui and absence of persistent pain syndrome. overall success rate regarding 24h pad-use was 88% (no pad rate 38%). previous failed implants did not influence results but diabetes, obesity and drug intake (beta-blockers, antidepressants) led to poorer outcomes. conclusion: sexuality and erectile function improves significantly 6 months after atoms implantation. we postulate that reduced sui (also during sexual activity) and absence of chronic pain are the improving factors. atoms should be offered to men with mild to moderate sui who are interested in regaining their erectile function and sexual activity. key words: stress urinary incontinence; sexual activity; erectile function. submitted 25 may; accepted 30 september summary no conflict of interest declared. my (rpe). 27% to 38% of patients are incontinent two years after rpe (1). an urodynamic study with 3 tesla mri was able to identify functional and anatomical changes causing post prostatectomy incontinence (ppi). a decrease in urethral length (31-35%), sphincter distorsion (85.7%), lacking build-up of urethral pressure and an increased angle of the neo-bladder neck funnel (28.9°) were recognised and associated with ppi (2). equally preand postoperative psychological stress has a negative effect on the development of ppi (3), especially if patients expect urinary symptoms after prostate treatment the hospital anxiety and depression scale (hads) shows poor values (18). the fear of urinary leakage during sexual intercourse affects 44.4% of patients 3 months after surgery and 36.1% after 2 years (4). an american study (n = 15) demonstrated an improved sexual quality of life (qol) after implantation of an artificial urinary sphincter (aus) or a sling device in ppi patients (5). we thus found out that the erectile function can be positively affected by the reduction of urinary leakage and lack of permanent pain syndrome as well as by the anatomical location and placement of the implant. we have an unproven assumption that the atoms device, with its central cushion directly placed on the bulbospongiosus muscle is probably able to improve erectile function by changing the behaviour of the nearby spongious body of the penis (figure 1). therefore further studies have to prove this hypothesis. incontinence implants vary greatly from non-adjustable/non-anchored systems, nonadjustable/anchored systems or adjustable/non-anchored systems to artificial urinary sphincteric (aus) systems with on-off cuff function. sling systems are preferable to aus systems for mild and moderate sui (6). erosion rates of 3-13% and wound infection rates of 3-11% vary between studies and may lead to explantation (7). the atoms, which is characterized by firm anchoring and adjustability, has the advantage that its position at the distal bulbospongiosus muscle allows it to be applied even prior to and following radiotherapy. doi: 10.4081/aiua.2015.4.306 introduction male stress urinary incontinence (sui) continues to be the most common complication after radical prostatecto307archivio italiano di urologia e andrologia 2015; 87, 4 sexuality and erectile function after atoms-implantation it has been constantly established on the market for about 5 years (8). the overall success rate after 18 months lies at 92%, whereby 63% of patients are continent and 29% report an improvement of sui in terms of a reduced paduse. an average pad-use reduction from 7.1 to 1.3/24h was recognised (9). erosions are rare due to the lack of contact with the urethra and transient perineal/scrotal dysesthesia can be avoided by intraoperative lateralization of the neurovascular bundle including the posterior scrotal nerves. materials and methods patients in this prospective, non-randomized, single center study a total of 34 men with mild (1 to 2 pads per day) to moderate (3 to 5 pads per day) sui were provided with an atoms implant between january 2010 and march 2014 after urodynamic investigation. a valid approval from the ethics committee and written consent from all patients were obtained. 30 of the patients had a previous rpe (76% retropubic rpe (rrpe) 24% endoscopic rpe (erpe)), 4 patients had got a transurethral resection of the prostate (turp) only, and 9 figure 3. sui classification preand postoperatively. sui classification regarding 24h pad-use: 0 = no incontinence, 1-2 = mild incontinence, 3-5 = moderate incontinence, > 5 = severe incontinence. the number of patients with moderate incontinence could be considerably reduced. a no pad-rate of 38% was achieved; hence 13 out of 34 patients did not suffer from incontinence at follow up. figure 1. the atoms implant placed on the bulbospongiosus muscle. the central cushion is placed on the bulbospongiosus muscle and indirectly on the spongious body. the atoms implant is characterized by firm transobturatoric anchoring and easy adjustability by transdermal punction of the inguinal or scrotal port. the position at the distal bulbospongiosus muscle allows further radiotherapy. figure 2. iief-5 score preand postoperatively. every patient is represented by his iief-5 score pre and postoperatively. points above (below) the black line indicate an improvement (decline) of erectile function. for points above the dotted red line, the iief-5 score increased for at least 3 score points after 6 months. a significant improvement appeared only to patients with iief-5 = 0 preoperatively. archivio italiano di urologia e andrologia 2015; 87, 4 a. friedl, w. bauer, m. rom, d. kivaranovic, w. lüftenegger, c. brössner 308 patients had received adjuvant radiotherapy after rpe or turp. in 6 patients the bladder neck had to be opened intraoperatively by sachse urethrotomy to enable the placement of a transurethral indwelling catheter. twenty-seven patients received the recent atoms generation with a scrotal port, seven patients received an inguinal port which requires an additional inguinal incision. preand postoperative assessment the patients were questioned regarding their erectile ability and pain condition the day before surgery and 6 months after surgery via an anonymous questionnaire. the visual analogue scale (vas) (20) with numeric description and leeds assessment of neuropathic symptoms and signs (lanss) (19) were used to evaluate pain. a lanss score of bigger than 12 points describes the existence of neuropathic pain syndrome in the tested skin area. the erectile function was elicited via the international index of erectile function (iief-5) and was categorized correctly by the number of points (< 5 no sexual intercourse, 5 to 7 severe ed, 8 to 11 moderate ed, 12 to 16 moderate to weak ed, 17 to 21 weak ed, 22 to 25 no ed). psa level, 24h pad-use as well as co-morbidities (diabetes mellitus (dm), arterial hypertension, coronary heart disease (chd) and obesity (body mass index > 30) were recorded. the long-term use of antidepressants and beta-blockers was also taken note of. erectogenic aids or sexual stimulating drugs were not taken by patients during the observed period. six patients had anastomotic stricture at time of implantation which were corrected in the same setting. exclusion criteria for implantation were none or severe sui, a recent psa increase, an acute febrile urinary tract infection, detrusor overactivity and pronounced dementia/cognitive disorders. all patients were anesthetically evaluated preoperatively and internal medical risk was assessed. the implantation was carried out under dual antibiotic therapy (amoxicillin 825 mg clavulanic acid 125 mg for 7 days with gentamicin and 240 mg for 3 days) and thrombosis prophylaxis. the transurethral indwelling catheter was removed after one day, wound checks and physical examination were performed daily. the implant cushion was filled intraoperatively with 7-9 ml saline solution, the first readjustment was carried out after 6 weeks in the outpatient setting, when required with 1-2 ml saline. before discharge (3 to 5 days postoperatively) residual urine was measured sonographically and oral pain medication (metamizol or non-steroidal anti-inflammatory drugs) were prescribed if required. outcome variables the primary outcome measure was whether patients sexuality and erectile function (ieff-5) vary before and after atoms implantation. change of 24h pad-use (e.g. overall success, no pad rate) and change of the pain perception (vas + lanss pain scale) was also noted over time. subgroup analysis including operation type (inguinal/scrotal port), co-morbidities, age, time from prostate treatment to atoms implantation, previous implants, as well as complications (infections, explantation) were provided. statistical analysis data were descriptively analysed through mean values and standard deviation for continuous variables, and absolute values and percentages for categorical variables. descriptive analysis was stratified for the operation method (scrotal port/inguinal port). a t-test for paired data was used to test for improvement in erectile function and reduction in pads use before and after implantation. also paired t-tests were calculated for the difference in lanss and vas score. additionally 95% confidence intervals were estimated for all comparisons. pearson’s correlations were calculated for age, iief-5 score, 24h pad-use and time from prostate operation to atoms implantation. p-values of 0.05 or less were considered to be statistically significant. all calculations were performed in r 3.0.2. results a total of 34 men with a mean age of 70.7 years (range 54.9 to 82.9) were registered at the time of atoms implantation. the average age at the time of the rpe, turp or radiotherapy was 64.5 years (range 52.2 to 78.8). the mean time from prostate treatment to atoms implantation was 75.1 months. 24% of patients had a history of previous unsuccessful incontinence implants (proact, invance). the average observation period was 5.7 months. mean preoperative psa was 0.137 ng/ml and 0.163 ng/ml at follow up. during the stated period no patient received androgen deprivation therapy (adt), chemotherapy, or adjuvant radiotherapy. the following comorbidities were recorded according to frequency: dm (12%), arterial hypertension (56%), chd (9%) and obesity (12%). regular antidepressant and beta-blocker intake was noted in 21% and 26% of patients respectively. descriptive data are summarized in table 1. sexuality the average iief-5 score increased from 1.6 (+/-0.7) before atoms implantation to 3.8 (+/-0.8) after 6 months. the mean difference was 2.18 (ci: 1.22, 3.14), p < 0.001). however figure 2 indicates that mostly patients with no sexual intercourse benefited from atoms implantation and many patients achieved a 3 points higher iief-5 score than at baseline, which can be definitely interpreted as not just a theoretically improvement. for patients with moderate or weak ed, the iief5 score has increased marginally or not at all. preoperatively, 88% of patients had rarely tried to be sexual active (iief-5: < 5 points), 12% of patients reported sexual activity with spontaneous erections and the ability to penetrate with a mean iief-5 score of 11.5. of these, 3 patients had moderate to weak ed and 1 patient had severe ed. six months postoperatively, 17 (50%) continued to have not the ability for sexual intercourse (iief-5: < 5 points). their mean iief-5 score was 3.8 and however, higher than preoperatively. seventeen (50%) were sexually active postoperatively with a mean iief-5 score of 10.1. of these, 12 patients had severe ed, 309archivio italiano di urologia e andrologia 2015; 87, 4 sexuality and erectile function after atoms-implantation 2 had moderate ed and 3 had moderate to weak ed. 44% of all patients had an improved iief-5 score (from 2.3 to 7.1) at 6 months. 38% of all patients had new onset of sexual activity postoperatively with an average iief-5 score of 12.9. subgroup analysis showed that diabetics (4 patients) had worse outcomes compared to non-diabetics regarding preand postoperatively iief-5 and 24h pad-use (mean values; preoperatively: 0.0/3.8 vs. 1.9/3.4 and postoperatively: 2.0/2.8 vs. 4.1/1.3). patients with arterial hypertension showed no differences when compared to others without arterial hypertension regarding 24 pad use, iief5, vas and lanss score. patients under continuous antidepressant intake had a lower mean iief-5 score (2.1) at follow up then others. patients with beta-blocker intake had a poor improvement of iief-5 score (+1.0) at follow compared to others. pain perception results of the t-tests showed that none of both pain scores significantly increased after 6 months. the mean differences were 0.32 (ci: -0.76, 1.41), p = 0.5484) and 0.11 (ci: -0.36, 0.59), p = 0.6187) for lanss score and vas score, respectively. nobody got a fully developed perineal neuropathic pain syndrome (lanss > 12) after 6 months but postoperatively wound pain was mostly existing for a few days. compared to others, diabetics had less pain pre(vas: 0.0 vs. 0.5; lanss. 0.0 vs. 1.1.) and postoperatively (vas: 0.0 vs. 0.7; lanss: 0.0 vs. 1.5). pad-use the average 24h pad-use significantly decreased from 3.5 (+/-0.2) preoperatively to 1.5 (+/-0.3). the mean difference was -2.0 (ci: -2.5, -1.5), p < 0.001). thirty patients reduced their daily pad-use after 6 months, resulting in an overall success rate of 88%, 38% were completely dry (no pad rate) and 18% used one pad daily (one pad rate). twelve percent of implantations were unsuccessful, of these four implants were explanted prematurely due to uncontrolled wound infection. for no patient, the daily pad-use increased after 6 months. figure 3 shows the shift of incontinence groups preand postoperatively. obese patients had a poor improvement regarding daily pad-use (3.3 to 2.0) then patients of normal weight. discussion this study is the first to examine potency and erectile function after implantation of atoms, an adjustable implant cushion firmly anchored transobturatorally and indirectly attached to the spongious erectile tissue. the series was an unselected patient group, men who had been treated with rrpe, erpe, radiotherapy or turp and had partly previous implants in history. while other studies observe long term pain syndromes after implantation of transobturatoric devices (17), persistent pain rate was low in our study because implantation was done with full protection of the neurovascular bundle next to the bulbospongiosus muscle. however, wound pain was existing for a few days postoperatively. in general, vas and lanss score differ slightly between preand postoperative situation because of further implants as you can see in table 1 but there is no significant comparison. all the men were suffering from sui which had been urodynamically confirmed and was resistant to conservative therapy. while preoperative selection of patients is significant to treatment outcome (10), we deliberately selected patients with sui of different aetiologies, which also had significant co-factors for the formation of an ed (e.g. dm). the overall success rate of 88% and the no to one padrate of 56% at follow up is in accordance with previous reports and studies (8, 9). male urinary incontinence is not a new problem, but it is still taboo in many countries and is a social and economic problem. an aging society also contributes to the increase of neurogenic bladder dysfunction, thus incontinence therapy has increasingly total inguinal port scrotal port (n = 34) (n = 7) (n = 27) age atoms implantation 70.7 (+/-1.2) 72.3 (+/-2.1) 70.3 (+/-1.4) previous implants 10 (29%) 2 (29%) 8 (30%) turp 4 (12%) 1 (14%) 3 (11%) rrpe 26 (76%) 4 (57%) 22 (81%) erpe 4 (12%) 2 (29%) 2 (7%) radiotherapy 9 (26%) 0 (0%) 9 (33%) chd 3 (9%) 2 (29%) 1 (4%) arterial hypertension 19 (56%) 3 (43%) 16 (59%) dm 4 (12%) 0 (0%) 4 (15%) obesity (bmi > 30) 4 (12%) 0 (0%) 4 (15%) beta-blocker intake 9 (26%) 3 (43%) 6 (22%) antidepressant intake 7 (21%) 0 (0%) 7 (26%) preoperatively psa value (ng/ml) 0.137 (+/-0.1) 0.208 (+/-0.1) 0.119 (+/-0.1) iief-5 score 1.6 (+/-0.7) 0 (+/-0) 2.1 (+/-0.8) 24h pad-use 3.5 (+/-0.2) 3.6 (+/-0.5) 3.4 (+/-0.2) vas pain scale 0.5 (+/-0.2) 0.4 (+/-0.4) 0.5 (+/-0.2) lanss pain scale 1 (+/-0.6) 1.1 (+/-1.1) 1 (+/-0.7) follow up psa value 0.163 (+/-0.1) 0.224 (+/-0.1) 0.147 (+/-0.1) iief-5 score 3.8 (+/-0.8) 2.6 (+/-1.2) 4.1 (+/-0.9) 24h pad-use 1.5 (+/-0.3) 0.7 (+/-0.4) 1.7 (+/-0.3) vas pain scale 0.6 (+/-0.2) 0.1 (+/-0.1) 0.7 (+/-0.3) lanss pain scale 1.3 (+/-0.5) 0.7 (+/-0.7) 1.5 (+/-0.6) time to atoms implant (months) 75.1 (+/-10.1) 57 (+/-14.2) 79.9 (+/-12.1) overall success (pad-use reduction) 30 (88%) 7 (100%) 23 (85%) no pad rate 13 (38%) 4 (57%) 9 (33%) follow up (months) 5.7(+/-0.5) 7.3(+/-1.6) 5.3 (+/-0.5) wound infection 6 (18%) 0 (0%) 6 (22%) explantation 4 (12%) 0 (0%) 4 (15%) table 1. descriptive analysis according to operation method. descriptive analysis was stratified according to operation method (inguinal port/scrotal port). mean values and standard deviation were calculated for continuous variables, and absolute values and percentages for categorical variables. archivio italiano di urologia e andrologia 2015; 87, 4 a. friedl, w. bauer, m. rom, d. kivaranovic, w. lüftenegger, c. brössner 310 moved into the spotlight. the wish for better quality of life, sustaining body image and reintegration into everyday life are common reasons for patients to opt for surgical incontinence interventions. access to incontinence centres with implant surgery depends on area of residence (rural vs. urban), ethnicity and age, according to a large american study (11, 12). only 6% of all patients receive incontinence surgery after rpe (median 20 months). this low rate may reflect the underused situation of potentially beneficial procedures (11). in addition to tumor follow up sexual rehabilitation and incontinence therapy are important components of postrpe care. in 35% of cases sexual dissatisfaction, increase of ppi, depression and loss of ability to work are the cause of poor generic quality of life after implantation of an aus (13). the improvement of erectile function and sui with the same implant could significantly enhance the quality of life and keep the body image undisturbed. a recent study shows that 15% of the men (n = 1729 of 11 726) opt for active surveillance and after 5 years follow up 64% of these continue with this. this data shows that a decrease in the rpe due to the introduction of active surveillance, including age at diagnosis and tumor risk/stage, can be expected. a high number of unreported cases of patients with ppi (> 59%) such as those after turp (> 10%) will always be present (14), and therefore incontinence surgery is still a legitimated therapy option. a large number of studies, some of which with small case numbers, report the successes and failures of incontinence implants. the majority of studies have been on aus surgery. it has been shown that the learning curve for aus surgery is very long and with increasing surgeon experience the re-operative rates slowly decrease (reoperative rate: 24.0% vs. 18.1% after 5 and 100 cases) (15). incontinence surgery with its large variety of available implant is in a constant state of flux and very dynamic. new implants are constantly being designed, improved, copied, but also rejected (16). a small study of 15 evaluable patients after anti-incontinence surgery with aus/male sling surgery (between 2000 and 2007) showed a beneficial effect of anti-incontinence surgery on ppi during sexual activity (100% undergoing aus and > 50% undergoing sling procedure reported marked improvement in sexuality) (5). ppi during sexual activity is seen as a disturbance in 44.4% after 3 months and 36.1% after 24 months. bother from incontinence during sexual activity and from sui were strongly associated at all times. therefore it is expected that with reduction of ppi, an improvement of sexual satisfaction can be achieved (4). this was demonstrated in the current study. there are some limitations to the present study which should be pointed out. first, the number of subjects included may not be sufficient to achieve statistically significance. some patients attended other hospitals for care and adjustment after implantation. there is currently no standard for use of implants in incontinence surgery, thus there is variation between departments and their implant expertise. second, it is not a randomized study and follow up was short (5.7 months). third, the iief-5 score is limted to evaluate erectile function. thus the current situation with family partner in connection with libido and sexual behaviour preand postoperatively could not be elicited. conclusion within the limitation of this study, we conclude that 6 months after atoms implantation sexuality and erectile function, measured with the iief-5, improve significantly. we postulate that reduced sui (also during sexual activity) and absence of chronic pain are the improving factors. atoms should be offered to men with mild to moderate sui who are interested in regaining their erectile function and sexual activity. references 1. touijer k, eastham ja, secin fp, et al. comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conducted in 2003 to 2005. j urol. 2008; 179:1811-1817. 2. cameron ap, suskind am, neer c, et al. functional and anatomical differences between continent and incontinent men post radical prostatectomy on urodynamics and 3t mri: a pilot study. neurourol urodyn. 2015; 34:527-32. 3. seklehner s, hladschik-kermer b, lusuardi l, et al. psychological stress assessment of patients suffering from prostate cancer. scand j urol. 2013; 47:101-107. 4. mitchell sa, jain rk, laze j, lepor h. post-prostatectomy incontinence during sexual activity: a single center prevalence study. j urol. 2011; 186:982-985. 5. jain r, mitchell s, laze j, lepor 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transobturator male sling patients for treatment of postprostatectomy incontinence. urology. 2014; 83:1186-1188. 11. kim ph, pinheiro lc, atoria cl, et al. trends in the use of incontinence procedures after radical prostatectomy: a population based analysis. j urol. 2013; 189:602-608. 12. matsushita k, chughtai bi, maschino ac, et al. international variation in artificial urinary sphincter use. urology. 2012; 80:667672. 13. holm hv, fosså sd, hedlund h, dahl aa. study of generic quality of life in patients operated on for post-prostatectomy incontinence. int j urol. 2013; 20:889-895. 311archivio italiano di urologia e andrologia 2015; 87, 4 sexuality and erectile function after atoms-implantation 14. arai y, kaiho y, takei m, et al. burden of male stress urinary incontinence: a survey among urologists in japan. int j urol. 2009; 16:915-917. 15. sandhu js, maschino ac, vickers aj. the surgical learning curve for artificial urinary sphincter procedures compared to typical surgeon experience. eur urol. 2011; 60:1285-1290. 16. gupta s, peterson ac. stress urinary incontinence in the prostate cancer survivor. curr opin urol. 2014; 24:395-400. 17. bauer rm, hübner w, knopf hj, et al. adjustable transobturatoric sling system in men: diagnosis and therapy recommendations to persistent pain. urologe a. 2014; 53:1175-1180. 18. namiki s, saito s, tochigi t, et al. psychological distress in japanese men with localized prostate cancer. int j urol. 2007; 14:924-9. 19. bennett m. the lanss pain scale: the leeds assessment of neuropathic symptoms and signs. pain. 2001; 92:147-57. 20. breivik h, borchgrevink pc, allen sm, et al. assessment of pain. br j anaesth. 2008; 101:17-24. correspondence alexander friedl, md alexander.friedl@khgh.at wilhelm bauer, md clemens brössner, md department of urology, hospital göttlicher heiland pelvic floor center, teaching hospital of the medical university of vienna dornbacher straße 20-28, 1170 vienna, austria maximilian rom, md department of urology, vienna general hospital, medical university of vienna vienna, austria danijel kivaranovic, md center for medical statistics, informatics, and intelligent systems, medical university of vienna, vienna, austria werner lüftenegger, md department of urology, kaiser franz josef hospital, smz-süd kundratstraße 3, 1100 vienna, austria stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4276 original paper comparison of efficacy of laser lithotripter with ultrasonic lithotripter in mini percutaneous nephrolithotomy fatih akbulut, onur kucuktopcu, emre kandemir, erkan sonmezay, abdulmuttalip simsek, burak ucpinar, faruk ozgor, gokhan gurbuz department of urology, haseki training and research hospital, istanbul, turkey. objective: the aim of the study was to compare the efficacy of the laser lithotripter with the ultrasonic lithotripter in mini percutaneous nephrolithotomy (miniperc). material and methods: from june 2013 to january 2014; medical records of 77 consecutive patients who underwent miniperc operation were retrospectively evaluated. ultrasonic lithotripter was used in 22 patients (group 1), while laser was used in 55 patients. in the laser group, 22 patients were randomly selected who had same characteristics compared to group 1 (group 2). success rate, total operative time, complications according to modified clavien classification, fluoroscopy time, haemoglobin drop, hospital stays and cost analysis were assessed. success rates were evaluated on the second postoperative day and after the first month. results: total operative time (p = 0.635) and fluoroscopy time (p = 0.248) were not significantly different between the two groups. in the laser group, the success rate (81.8%) was notably more than in the ultrasonic lithotripter group (68.2%) but there was no statistically significance (p = 0.296). ten reusable ultrasonic probe were used for 22 patients, due to thinness and sensitiveness of the probe. conversely, one single laser fiber (550 micron) was used for 22 patients. when the cost analysis of lithotripsy was considered, the cost per case was 190 dollar in group 1 and 124 dollar in group 2. (p = 0.154) complication rate, hospital stay and haemoglobin drop were similar in both groups. conclusion: laser lithotripsy seems to be more cost effective than ultrasonic lithotripsy for miniperc but larger number of patients are required to confirm this estimation. key words: laser lithotripsy; ultrasonic lithotripsy; mini percutaneous nephrolithotomy. submitted 30 may 2015; accepted 4 july 2015 summary no conflict of interest declared. tion (2). in the following years, jackman et al. used this technique in adult patients (3). recently published studies underlined that complications like bleeding have declined along with the use of smaller renal access sheaths (4, 5). in a prospective randomized study, the authors suggested that while miniperc and conventional pnl had similar stone clearance rates, complication rate was significantly lower in the miniperc group (6). in the miniperc series, the lithotripter choice is important for stone fragmentation. laser, pneumatic, and ultrasonic lithotripters are available fragmentation methods for pnl. while pneumatic lithotripsy is the most common technique used for kidney or ureteral stones, stone retropulsion and migration rate is clearly higher compared with other devices. ganeasomoni et al. compared laser and pneumatic lithotripsy with miniperc and observed that laser lithotripsy group had a lower stone migration rate (7). the ultrasonic lithotripsy enables simultaneous stone fragmentation and aspiration. low retropulsion rate and absence of the need of stone retrieval are the main advantages of ultrasonic lithotripsy. however, to the best of our knowledge, there is no published study evaluating the efficacy of the ultrasonic lithotripter with miniperc. in this study, we aimed to compare laser lithotripter and ultrasonic lithotripter with miniperc for the treatment of kidney stones. materials and methods from june 2013 to january 2014, medical records of 77 consecutive patients with kidney stones treated with miniperc were retrospectively evaluated. patients were classified according to the lithotripter type used during the procedure. ultrasonic lithotripter was used in 22 patients (group-1). ho:yag laser lithotripter was used in 55 patients and 22 of them (group-2) were matched to the group-1 based on the size, area, and localization of the stone. informed consent was taken from all patients in the study. patient demographics, operative parameters (operation time, fluoroscopy time, and cost), and post-operative parameters (hemoglobin drop, hospitalization time, and success and complications rates) were evaluated. all patients were evaluated with kidney, ureter, and bladder plain radiography (kub), intravenous urography, and/or computed tomography (ct) preoperatively. doi: 10.4081/aiua.2015.4.276 introduction percutaneous nephrolithotomy (pnl) is the primary recommended treatment modality for the kidney stones larger than 2 cm and an optional treatment choice for stones between 1 and 2 cm (1). even though pnl is a safe method with high stone clearance rate, it has serious complications like hemorrhage requiring transfusion and kidney loss. in order to reduce these complications, minipnl (miniperc) was first described in pediatric popula277archivio italiano di urologia e andrologia 2015; 87, 4 efficacy of lithotripters in mini percutaneous nephrolithotomy the patients were assessed with complete blood count, serum biochemistry, coagulation parameters, and urine cultures before the operation. miniperc technique all procedures were performed by the same experienced surgical team (fa and gg). under general anesthesia, a 5 fr ureteral catheter was placed into the ureter in lithotomy position, and the bladder was drained with a 16 fr foley catheter. percutaneous renal access was performed in prone position, under fluoroscopic guidance using an 18 g access needle. a guidewire with hydrophilic tip was inserted into the collecting system through the access needle. tract dilatation was carried out by either amplatz or balloon dilatators up to 18-20 fr. stone fragmentation were performed by using ho:yag laser probe (sphinx 30, lisa laser, usa) or ultrasonic lithotripter (swiss lithoclast, ems, nyon, switzerland) and stone fragments were removed with retrieval graspers through a 17 fr nephroscope (karl storz, tuttlingen, germany). a 550-micron laser probe was used with energy and frequency settings of 1.5 joule and 10 to 20, respectively. the ultrasonic lithotripsy was performed with a 6 fr ultrasonic probe. the flexible nephroscope was used with laser and nitinol basket catheter in situations where the rigid nephroscope couldn’t reach the calyces or stones. operations were terminated when no residual stone fragments could be detected with the help of rigid and/or flexible nephroscope and fluoroscopy. after completion of the operation, a 14-fr nephrostomy tube was inserted in all patients. nephrostomy tubes were removed in post-operative 1st or 2nd days. all patients were initially evaluated with kub in post-operative day one. one month later, patients were reevaluated with kub or ct. ct was performed when non-opaque stones were present or when evaluation of the stone status was insufficient with kub. residual fragments smaller than 3 mm were defined as clinically insignificant residual fragments (cirf) (8). larger stones were defined as residual stones. patients who were completely stone free or who had only cirf were considered to have had a successful surgery. success rates at first day and at first month were given separately. post-operative complications were classified according to the modified clavien classification system cost analysis the total cost per patient was calculated as the sum of hospitalization, surgery, and broken probes costs. when a second intervention or hospitalization was needed, these costs were also added to the sum. costs per patient were compared between the groups. statistical analysis statistical analyses were performed with the computer software statistical package for the social sciences (spss, ibm software) v. 16.0. values were described as numbers, percentages, means, and standard deviations. categorical and continuous variables were compared using chi square and student ttests. p values less than 0.05 were considered as statistically significant. results patients’ data with regard to location, size and number of stones, age, gender, body mass index (bmi) and access location were reported in table 1. total operative time (p = 0.635) and fluoroscopy time (p = 0.248) were not significantly different between two groups. in the laser group, the stone clearance rate (81.8%) was notably higher than in ultrasonic lithotripter group (68.2%) at post-operative 1st day according to kub, although the difference was not statistically significant (p = 0.296). at post-operative first month, none of the patients had spontaneous passage of residual stones. nine of reusable ultrasonic probes were broken, thus 10 reusable ultrasonic probes were used in 22 patients, due to fragility of the probe. conversely, only one reusable laser probe (550 micron) was used in 22 patients. when the cost analysis of lithotripters was considered, the cost/per case was 190 dollar in-group 1 and 124 dollar in-group 2 (p = 0,597). complication rate, hospital stay and hemoglobin drop were similar in both groups (table 2). laser ultrasonic p value number of patients 22 22 gender male 14 15 0.750 female 8 7 mean body mass index (kg/m2) 26.2 ± 3.6 25.1 ± 9.3 0.584 mean age (years) 44.4 ± 12.6 40.6 ± 14.8 0.385 mean stone size (mm) 21.14 ± 8.5 21.55 ± 6.0 0.855 stone localization 0.380 upper pole 0 2 middle calyx 2 1 lower pole 6 4 pelvis 2 5 multiple calyceal 12 10 access site 0.295 upper pole 0 2 middle calyceal 2 3 lower pole 20 17 laser ultrasonic p value hemoglobin drop (mg/dl) 0.93 ± 1 1.15 ± 1,15 0.520 success rate at post operative first day (%) 81.8% 68.2% 0.296 success rate at post operative 81.8% 68.2% 0.296 first month imaging (%) hospitalization time (hours) 74.2 ± 22.1 79.6 ± 38.7 0.569 clavien complications 0,304 2 2 0 3a 5 4 mean operation time (minutes) 113.5 ± 50.5 107 ± 34.9 0.635 mean fluoroscopy time (minutes) 7.7 ± 4.6 6 ± 4.5 0.248 mean cost per case (us dollar) 124 190 0.597 table 1. preoperative patient demographics. table 2. comparison of postoperative parameters between laser lithotripsy and ultrasonic lithotripsy groups archivio italiano di urologia e andrologia 2015; 87, 4 f. akbulut, o. kucuktopcu, e. kandemir, e. sonmezay, a. simsek, b. ucpinar, f. ozgor, g. gurbuz 278 discussion percutaneous nephrolithotomy is a commonly and successfully performed surgical treatment option for large and complex renal stones. however in standard pnl series, there are non-negligible complications like bleeding, which may happen during and/or after the operation. because of these complications, smaller access sheaths and instruments have increasingly been used since 1998 (3). according to these advancements, miniperc surgery is an alternative option to retrograde intrarenal surgery (rirs) for management of small renal stones (9). in the miniperc surgery, laser and pneumatic lithotripters have been used for fragmentation of stones (7). however, there is no study in the literature, which shows the advantages/disadvantages of ultrasonic lithotripters in miniperc surgery. utilization of the suitable lithotripter is important, because migration rates and operation times may vary in different lithotripter types. with holmium: yag laser, achievement of the stone fragmentation is achieved by phototermal effect. we used the laser at lower energy and high frequency setting to disintegrate the stone into smaller fragments and prevent the migration of the stone into different calyces or the ureter. if the energy is increased, the operation time decreases, but the rates of retropulsion of the stones tend to be higher (10) and larger stone fragments are produced (11). the ability of fragmenting all hard types of calculi such as calcium oxalate monohydrate and cystine stones is the most important advantage of the holmium: yag laser (12). despite this, the fragmentation time can be longer in the management of larger renal calculi. the ultrasonic lithotripter has been widely used in standard pnl up to now. in this lithotripter, it is used mechanical energy that is produced by piezo-ceramic elements. the mechanical energy conveys through the probes to the stone with a drilling effect. the ultrasonic probe performs both stone fragmentation and stone particle aspiration simultaneously (13, 14). in the literature, the stone free rates were up to 97% in standard pnl series (15). however, the success rate with miniperc is lower, mainly because a thinner diameter probe has to be used. in this context, in our series with miniperc the stone free rate was 68.2% which was lower compared with the standard pnl series. even though ultrasonic lithotripter has high success rates in the literature, the achievement of fragmentation declines when used for hard stones, such as calcium oxalate monohydrate and cystine stones (16). in the ultrasonic lithotripter, the probe has potential overheating effect because of conversion of vibration energy to heat energy. this undesired effect may lead to tissue injury. in an experimental study, diri et al. showed that ultrasonic probes may cause tissue injury in rat models (17). furthermore, the overheating effect may lead to the breakage of the thin and fragile ultrasonic probe. in our series, we have used 10 reusable ultrasonic probes for 22 patients. for this reason, the costs of the operation were higher in-group 1. conversely, in group 2 we used only one reusable 550 micron laser probe for 22 patients. cost per case was notably lower (190 dollar/case in group 1, 124 dollar/case in-group 2) but the difference was not statistically significant. in larger patient series , the cost analyses could reveal more statistically significant differences. notably, the 550-micron reusable laser probe is guaranteed for reuse up to 100 times. our study has some limitations. the first and the most important limitation was the retrospective design of the study. possibly because of the inadequate power of the study we did not observe significant differences between the groups for stone clearance rates and costs. another limitation was our lack of knowledge regarding the stone compositions, which might have affected the surgical results. conclusions our study showed that both ultrasonic and laser lithotripsy were safe and effective stone fragmentation methods in miniperc. laser lithotripsy seems to be less costly and more effective than ultrasonic lithotripsy during miniperc operations but larger numbers of patient series are required to further investigate these preliminary findings. author contributions concept f.a.; design f.a.; supervision g.g., e.s., a.s.; resource: e.s., e.k, f.o.; materials o.k., e.k., b.u.; data collection &/or processing o.k., e.k., f.o.; analysis&/or interpretation o.k., e.s., a.s.; literature search f.a., f.o, b.u.; writing f.a., b.u., g.g.; critical reviews g.g., a.s. references 1. türk c, knoll t, petrik a, et al. eau guidelines on urolithiazis, 2014 http://www.uroweb.org/guidelines/online-guidelines. 2. helal m, black t, lockhart j, figueroa te. the hickman peelaway sheath: alternative for pediatric percutaneous nephrolithotomy. j endourol. 1997;11:171-2. 3. jackman sv, docimo sg, cadeddu ja, et al. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998;16:371-4. 4. bader mj, gratzke c, seitz m, et al. the "all-seeing needle": initial results of an optical puncture system confirming access in percutaneous nephrolithotomy. eur urol. 2011; 59:1054-9. 5. desai mr, sharma r, mishra s, et al. single-step percutaneous nephrolithotomy (microperc): the initial clinical report. j urol. 2011; 186:140-5. 6. mishra s, sharma r, garg c, et al. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju int. 2011; 108:896-9. 7. ganesamoni r, sabnis rb, mishra s, et al. prospective randomized controlled trial comparing laser lithotripsy with pneumatic lithotripsy in miniperc for renal calculi. j endourol. 2013; 27:1444-9. 8. pareek g, armenakas na, fracchia ja. hounsfield units on computerized tomography predict stone-free rates after extracorporeal shock wave lithotripsy. j urol. 2003; 169:1679-81 . 9. kirac m, bozkurt of, tunc l, et al. comparison of retrograde 279archivio italiano di urologia e andrologia 2015; 87, 4 efficacy of lithotripters in mini percutaneous nephrolithotomy intrarenal surgery and mini-percutaneous nephrolithotomy in management of lower-pole renal stones with a diameter of smaller than 15 mm. urolithiasis. 2013; 41:241-6. 10. finley ds, petersen j, abdelshehid c, et al. effect of holmium:yag laser pulse width on lithotripsy retropulsion in vitro. j endourol. 2005; 19:1041-4. 11. spore ss, teichman jm, corbin ns, et al. holmium: yag lithotripsy: optimal power settings. j endourol. 1999; 13:559-66. 12. teichman jm, vassar gj, bishoff jt and bellman gc. holmium:yag lithotripsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. j urol. 1998; 159:17-23. 13. begun fp. modes of intracorporeal lithotripsy: ultrasound versus electrohydraulic lithotripsy versus laser lithotripsy. semin urol. 1994; 12:39-50. 14. fuchs gj. ultrasonic lithotripsy in the ureter. urol clin north am. 1988; 15:347-59. 15. karakan t, diri a, hascicek am, et al. comparison of ultrasonic and pneumatic intracorporeal lithotripsy techniques during percutaneous nephrolithotomy. scientific world journal. 2013; 2013:604361. 16. krambeck ae, miller nl, humphreys mr, et al. randomized controlled, multicentre clinical trial comparing a dual-probe ultrasonic lithotrite with a single-probe lithotrite for percutaneous nephrolithotomy. bju int. 2011; 107:824-8. 17. diri a, resorlu b, astarci m, et al. tissue effects of intracorporeal lithotripsy techniques during percutaneous nephrolithotomy: comparison of pneumatic and ultrasonic lithotripters on rat bladder. urol res. 2012; 40:409-13. correspondence fatih akbulut, md (corresponding author) drfakbulut@hotmail.com seyitnizam mahallesi yunus emre caddesi merkez park yel evleri a2 blok kat:1 daire:3 zeytinburnu, 34015 istanbul,turkey onur kucuktopcu, md onurktp@hotmail.com emre kandemir, md emrekandemir@gmail.com erkan sonmezay, md drekans@gmail.com abdulmuttalip simsek, md simsek76@yahoo.com burak ucpinar, md drburakucpinar@gmail.com faruk ozgor, md md.farukozgor@yahoo.com gokhan gurbuz, md zafergokhangurbuz@yahoo.com haseki training and research hospital, department of urology, istanbul, turkey stesura seveso archivio italiano di urologia e andrologia 2015; 87, 162 original paper effect of immobilization on urine calcium excretion in orthopedic patients with pelvic fracture treated by skin traction ali derakhshan 1, nima derakhshan 2, hamid namazi 3, fariborz ghaffarpasand 2 1 nephrology urology research center, 2 neuroscience research center and 3 department of orthopedics shiraz university of medical sciences, shiraz, iran. objectives: to determine the effects on urine calcium excretion of immobilization by skin traction in patients with pelvic fracture. methods: in a prospective study, a consecutive series of patients with pelvic fracture treated by skin traction were enrolled. serum (calcium, phosphorous, alkaline phosphatase, sodium, potassium, uric acid, bun, creatinine) and fasting urine calcium, creatinine, sodium, potassium and uric acid were checked within 48 hours of hospitalization and at 7, 14 and 21 days of immobilization and then after 3 months of mobilization. trends in changes of variables were recorded. results: fifty five patients were enrolled in this study; they were 45 (81.8%) males and 10 (18.2%) females with a mean age 19.4 ± 12.7 years. we found that serum levels of calcium (p = 0.004), phosphorous (p = 0.047) and alkaline phosphatase (p = 0.001) increased significantly during the 3 weeks of immobilization. in the same way, urine calcium/urine creatinine ratio increased significantly in the study period (p = 0.004). no symptomatic renal stone formation was observed during the study period. conclusions: immobilization even in short term causes hypercalciuria in orthopedic patients. although it is transient and improves with subsequent mobilization, it is needed to be considered specifically by the team caring for this group of patients. key words: hypercalciuria; short term immobilization; pelvic fracture; skin traction. submitted 2 september 2014; accepted 31 october 2014 summary no conflict of interest declared. immobilized (12, 13). also the effect of immobilization on hypercalciuria and hypercalcemia at intermediate term has been studied (14). there are only few reports (mostly case reports) regarding the hypercalciuria in patients who are immobilized temporarily due to orthopedic fractures (1520). in this study, we have investigated the effect of short term immobilization on urinary calcium excretion and also on serum calcium and parathormone in patients who are immobilized with skin or skeletal traction for a pelvic fracture in orthopedic wards. patients and method study population this was a prospective cross-sectional study being performed during a 1-year period from 2012 to 2013 in chamran and nemazi hospitals, both tertiary orthopedics healthcare centers affiliated with shiraz university of medical sciences. the study protocol was approved by institutional review board (irb) and ethics committee of shiraz university of medical sciences. all the recruited patients provided their informed written consents before inclusion in the study. we consecutively included all the patients younger than 40 years of age with traumatic pelvic fractures who underwent skin traction and were immobilized. the age limit of 40 was selected to lower the risk of interaction of natural process of resorption induced by aging. patients with metabolic bone disease, patients with primary or metastatic bone tumor, patients on steroid, calcium or vitamin d supplements, and patients with abnormal baseline serum or urinary calcium level were excluded from the study. we also excluded those patients who were lost at follow-up during the initial 3 weeks of the study, those with renal insufficiency at any time during the study, those with urinary tract infection and any those taking any medication interfering with urinary calcium excretion. all of the patients were in complete physical health before the accident which led to hospitalization. study protocol all the patients underwent complete physical examination by attending physician and the findings were recorded in a doi: 10.4081/aiua.2015.1.62 introduction hypercalciuria is the most common metabolic cause of renal stone in children and adults (1-4). hypercalciuria is defined as urinary calcium excretion of more than 4 mg/kg in 24 hour urine or a calcium/creatinine ratio of 0.20 mg/mg in a random urine sample (5, 6). in addition to urinary stones, hypercalciuria can cause hematuria, dysuria, frequency, urgency and occasionally enuresis (7-11). long term immobilization causes hypercalciuria and hypercalcemia in patients with meningomyelocele who are derakhshan_stesura seveso 02/04/15 10:24 pagina 62 63archivio italiano di urologia e andrologia 2015; 87, 1 urine calcium excretion after immobilization data gathering form. we arbitrarily defined the short term immobilization as immobilization of less than 3 weeks. the first sampling was done within 48-hour of hospitalization. serum levels of albumin, calcium (ca), phosphorous (p), blood urea nitrogen (bun), creatinine (cr), sodium (na), potassium (k) were measured. we also obtained spot urine sample to measure urine ca, cr, na and k. the samples were tested with the same technique in the two university hospital laboratories. the tests were repeated on days 7, 14 and 21 of hospitalization (immobilization). also, they were repeated 2 to 3 months after mobilization. in addition, parathormone (pth) level was measured on day 21 day of admission and the sera were refrigerated; after collection of all pth samples, it was examined in a special reference endocrine and metabolism laboratory. statistical analysis all the data was analyzed using statistical package for social science (spss inc., chicago, usa) software for window version 16.0. frequency distribution of the variables, means and standard deviations of the values were presented in tables and charts. the mean values were compared in different time intervals using repeated measure and paired t-test. proportions were compared using chi-square test. a 2-sided p-value less than 0.05 was considered statistically significant. results fifty five patients were enrolled in this study; they were 45 (81.8%) males and 10 (18.2%) females with a mean age 19.4 ± 12.7 years. the baseline characteristics are summarized in table 1. we found that serum levels of calcium increased significantly during the 3 weeks of immobilization (p = 0.004). in the same way, the serum level of phosphorous increased significantly during 3 weeks of immobilization (p = 0.047). the serum levels of alkaline phosphatase also increased during the study period (p = 0.001). however there was no significant difference in serum levels of bun, creatinine and albumin after the 3 weeks of skin traction. the values for serum sodium and potassium were within normal limits throughout the study. the urine calcium/urine creatinine ratio increased in the study period significantly (p = 0.004) (figure 1). after mobilization, we had the opportunity to check the urine calcium/urine creatinine ratio in 47 patients who had returned for follow-up visit 2 to 3 months after discharge from the hospital. the ratio after the 3 months was similar to the baseline (0.13 ± 0.04 vs. 0.13 ± 0.06; p = 0.381). table 1. the baseline characteristics and changing trend of laboratory findings in 55 patients with pelvic fracture treated by skin traction. baseline day 7 day 14 day 21 p-value serum ca (mg/dl) 9.2 ± 0.74 9.3 ± 0.65 9.3 ± 0.85 10.1 ± 0.87 0.004 serum p (mg/dl) 4.6 ± 1.2 4.5 ± 0.9 4.8 ± 1.3 5.0 ± 0.71 0.047 urine ca/urine cr 0.13 ± 0.06 0.17 ± 0.11 0.22±0.12 0.29 ± 0.17 0.001 bun (mg/dl) 14.4 ± 4.5 14.1 ± 2.9 13.9 ± 3.6 13.8 ±5.9 0.186 creatinine (mg/dl) 0.81 ± 0.28 0.79 ± 1.7 0.94 ± 0.84 0.93 ± 0.16 0.098 alp (iu) 424.6 ± 316.2 448.6 ± 298.3 561.6 ± 181.6 575.3 ± 227.1 0.001 albumin (g/dl) 4.1 ± 0.32 3.9 ± 0.14 4.0 ± 0.56 4.1 ± 0.32 0.783 alp: alkaline phosphatase; bun: blood urea nitrogen; ca: calcium; p: phosphorous figure 1. calcium/creatinine ratio at baseline and throughout the study. figure 2. urine ca/cr ratio in patients < 20 years and 20-40 years. derakhshan_stesura seveso 02/04/15 10:24 pagina 63 archivio italiano di urologia e andrologia 2015; 87, 1 a. derakhshan, n. derakhshan, h. namazi, f. ghaffarpasand 64 serum pth was checked only once at the end of the 3rd week and it was 17.42 ± 10.04 ng/ml. the study population was then divided into 2 groups; 28 patients were between 2-20 years with a mean age of 8.8 ± 6.6 years and 27 were 21-40 years with the mean age of 30.3 ± 6.7 years (figure 2). the above mentioned parameters were similar to the results in the whole group and no significant inter-group differences were observed. no symptomatic renal stone formation was observed during the study period. discussion hypercaciuria is the most common metabolic cause of renal stone in children and adults (1-4). hypercalciuria may present with different signs and symptoms specifically in children such as hematuria, abdominal pain, frequency, dysuria and occasionally enuresis (7-11). in a well-designed study by zerwekh et al., the biochemical markers of bone turnover and calcium homeostasis were evaluated in normal volunteers subjected to 12 weeks of bed rest. they found a significant rise in biomarkers of the bone turn over, urine, and serum calcium (21). hypercalciuria is a known consequence of long and intermediate term immobilization which leads to decreased bone mineral density. this entity has been studied in patients with stroke and long term immobilization and also in children with intermediate term immobilization with legg-calvé-perthes disease and developmental dysplasia of the hip joint (12-14). in this study, even after one week of immobilization in children with legg-calveperthes disease urine calcium increased 2.3 times as compared to the baseline value but this did not happen in children with developmental dysplasia of the hip who had never been ambulated before immobilization. immobilization and associated hypercalciuria can lead to stone formation which has been reported even within a few days of immobilization in children (17). in this prospective study, the effect of short term immobilization in 55 orthopedic patients with pelvic fracture who were assigned for short term immobilization (skin traction) was studied. even after the first week of immobilization, urine calcium excretion increased from the baseline level and the test was repeated in the 2nd and 3rd weeks of immobilization; we found higher levels of calcium/creatinine ratio but not significantly different from the first week value. this indicates that immobilization induces bone resorption and is associated to hypercalciuria even after a few days. we had the opportunity to check urine calcium/creatinine ratio 2-3 months after mobilization in the majority of our patients (number = 47); it had returned to previous values in the majority of patients, 0.13 ± 0.04 (p = 0.38) with pearson correlation = 0.846. this indicates that the effect of immobilization on urine calcium excretion is transient. serum calcium was also checked simultaneously with urine calcium in the first, second and third week, although it was higher than the baseline level in the third week of immobilization but the p value didn't reach a statistically significant level (p = 0.057). regarding the serum calcium level, we didn't reach the same conclusion as previous studies which were mostly case reports (12, 13, 16, 18, 22, 23). in some of these reports, the period of immobilization was more than that of our study. our results regarding serum parameters were similar to the results of korkes et al. (14) with almost no change in serum parameters in that study. symptomatic stone formation was not seen in any case in our study as in those of korkes f (14) and andrews pi (18). in conclusion, immobilization even in short term causes hypercalciuria in orthopedic patients. although it is transient and improves with subsequent mobilization, it is needed to be considered specifically by the team caring for this group of patients. acknowledgements we would like to thank the vice chancellor for research for his financial support. the authors would also like to thank dr. nasrin shokrpour for editorial assistance and ms rosta for statistical analysis at center for development of clinical research of nemazi hospital. we also thank the cooperation of mrs. oraghi (nemazee hospital cast room nurse) and mr. mozaffari (chamran hospital orthopedic ward nurse) in sample collection. references 1. monk rd, bushinsky da. kidney stones. in: kronenberg hm, melmed s, polonsky ks, larsen pr (eds) williams textbook of endocrinology. wb saunders, philadelphia. 2011; 1350-1367. 2. bushinsky da, coe fl, moe ow. nephrolithiasis. in: brenner bm (ed) the kidney. wb saunders, philadelphia. 2012; 1455-1507. 3. worcester em, coe fl. calcium kidney stones. n engl j med. 2010; 363:954-963. 4. van’t hoff wg. aetiological factors in paediatric urolithiasis. nephron clin pract. 2004; 98:45-48. 5. safarinejad mr. urinary mineral excretion in healthy iranian children. pediatr nephrol. 2003; 18:140-4. 6. alconcher lf, castro c, quintana d, et al. urinary calcium excretion in healthy school children. pediatr nephrol. 1997; 11:186-188. 7. stapleton fb, roy s 3rd, noe hn, jerkins g. hypercalciuria in children with hematuria. n engl j med. 1984; 310:1345-1348. 8. fallahzadeh mk, fallahzadeh mh, mowla a, derakhshan a. hypercalciuria in children with urinary tract symptoms. saudi j kidney dis transpl. 2010; 21:673-677. 9. parekh dj, pope jc 4th, adams mc, brock jw 3rd.the association of an increased urinary calcium-to-creatinine ratio, and asymptomatic gross and microscopic hematuria in children. j urol. 2002; 167:272-274. 10. stapleton fb. idiopathic hypercalciuria: association with isolated hematuria and risk for urolithiasis in children. the southwest pediatric nephrology study group. kidney int. 1990; 37:807-811. 11. raes a, dossche l, hertegonne n, et al. hypercalciuria is related to osmolar excretion in children with nocturnal enuresis. j urol. 2010; 183:297-301. 12. riehl j, brandenburg vm, dietrich cg, block f. immobilization hypercalcemia as a complication of polyneuropathy. nervenarzt. 2000; 71:655-659. derakhshan_stesura seveso 02/04/15 10:24 pagina 64 65archivio italiano di urologia e andrologia 2015; 87, 1 urine calcium excretion after immobilization 13. quan a, adams r, ekmark e, baum m. bone mineral density in children with myelomeningocele: effect of hydrochlorothiazide. pediatr nephrol. 2003; 18:929-933. 14. korkes f, segal ab, heilberg ip, et al. immobilization and hypercalciuria in children. pediatr nephrol. 2006; 21:1157-1160. 15. stewart af, adler m, byers cm, et al. calcium homeostasis in immobilization: an example of resorptive hypercalciuria. n engl j med. 1982; 306:1136-1140. 16. cheng cj, chou ch, lin sh. an unrecognized cause of recurrent hypercalcemia: immobilization. south med j. 2006; 99:371-374. 17. muller ce, bianchetti m, kaiser g. immobilization, a risk factor for urinary tract stones in children. a case report. eur j pediatr surg. 1994; 4:201-204. 18. andrews pi, rosenberg ar. renal consequences of immobilisation in children with fractured femurs. acta paediatr scand. 1990; 79:311-315. 19. scharli af, rumlova e, schubiger g. immobilisation hypercalciuria after limb fractures in children. z kinderchir. 1983; 38:240-242. 20. rosen jf, wolin da, finberg l. immobilization hypercalcemia after single limb fractures in children and adolescents. am j dis child. 1978; 132:560-564. 21. zerwekh je, ruml la, gottschalk f, pak cy. the effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects. j bone miner res. 1998; 13:1594-60. 22. kaul s, sockalosky jj. human synthetic calcitonin therapy for hypercalcemia of immobilization. j pediatr. 1995; 126:825-827. 23. meythaler jm, tuel sm, cross ll. successful treatment of immobilization hypercalcemia using calcitonin and etidronate. arch phys med rehabil. 1993; 74:316-9. correspondence ali derakhshan, md professor of pediatric nephrology nephrology urology research center shiraz university of medical sciences, shiraz, iran nima derakhshan, md (corresponding author) nima_med83@yahoo.com resident of neurosurgery neuroscience research center shiraz university of medical sciences chamran hospital, chamran avenue, shiraz, iran hamid namazi, md associate professor of orthopedic surgery department of orthopedics shiraz university of medical sciences, shiraz, iran fariborz ghaffarpasand, md resident of neurosurgery neuroscience research center shiraz university of medical sciences, shiraz, iran derakhshan_stesura seveso 02/04/15 10:24 pagina 65 stesura seveso 317archivio italiano di urologia e andrologia 2015; 87, 4 original paper ultrasound evaluation of the striated urethral sphincter as a predictive parameter of urinary continence after radical prostatectomy lucio dell’atti department of urology, university hospital “st.anna”, ferrara, italy. objectives: the purpose of this study was to evaluate preoperatively the results of transrectal ultrasound (trus) in the detection of morphological, vascularization status of urethral rhabdosphincter (rs) and evaluate the correlation with urinary continence after radical prostatectomy (rp). methods: 211 patients who underwent rp were prospectively studied using trus scan of the rs thickness. at the end of the examination a study was performed with the use of colour-doppler for the assessment of the rs vascularity pattern. the level of continence was graded on a 5 point scale as: 1 = complete continence, 2 = 1 pad daily, 3 = 2-3 pads daily, 4 = 4 or more pads daily, and 5 = complete incontinence. results: it was possible to visualize the rhabdosphincter and its vascularity in all patients. patients with normal continence (level 1 and 2) showed a sphincter-muscle thickness of 3.5 mm (± 0.4) and a hypoechoic ultrasound pattern. with respect to the other levels 3, 4 and 5 of urinary incontinence rs thickness was 2.8 mm (± 0.5), 2.1 mm (± 0.6), 1.7 (± 0.7) respectively. incontinence after rp (≥ 3 level) was associated with urethral sphincter deficiency in the great majority of patients. statistical significant differences were observed in the vascularity between continent and incontinent men in all measured vascularity variables (p < 0.005). conclusions: this study suggests that rs integrity is a good predictor of urinary continence after rp and this information can be important during the preoperative phase as part of the informed consent. key words: transrectal ultrasound; urinary incontinence; radical prostatectomy; urethral sphincter. submitted 17 june; accepted 30 september summary no conflict of interest declared. rovascular bundle, and puboprostatic ligament preservation) as possible causes of urinary incontinence (2-5). in males, urethral sphincter is a cylindrical structure surrounding the urethra and extending vertically from bladder neck to perineal membrane, consisting of urethral smooth sphincter and urethral striated sphincter (6). histomorphological studies demonstrated a separate external urethral sphincter, also termed rhabdosphincter (rs), in both men and women (7-9). strasser h et al. (10) described this sphincter as an “omega-shaped” structure. the rs plays an important role in actively maintaining continence (11). the integrity and functional preoperative capacity of the urethral rs is a fundamental prerequisite of ui in men after rp. the purpose of this study was to evaluate the results of transrectal ultrasound (trus) in the detection of morphological, vascularization and preoperative functional status of urethral rs. starting from this point of view, we used trus to determine the anatomical changes in urethral sphincter after rp and evaluated the correlation between these changes and postoperative urinary continence. materials and methods between september 2007 and december 2013, 211 consecutive patients who underwent rp (treated by three experienced operators: 76 with laparoscopic technique and 135 with open technique) were prospectively studied using 2-dimensional (2d) trus scan of the rs dimensions and vascularity. patients who had neurogenic bladder, incontinence or urinary retention before prostatectomy were excluded. all procedures were performed in empty bladder, since we believe that even the state of bladder repletion may be an element of discomfort during the exam performance. each patient was treated under local anesthesia with lidocaine spray (10 gr/100 ml), applied two minutes before the procedure (12). trus was performed with the patient in the left lateral decubitus using a general electric logiq 7 machine equipped with a 5-9 mhz multi-frequency convex probe “end-fire”. each trus performed included an assessment of the prostatic diameter, the volume of the whole prostate, the transition zone, capsular and seminal vesicle characteristics, as well as morphological description of potential pathological features. this transducer prodoi: 10.4081/aiua.2015.4.317 introduction radical prostatectomy (rp) is the most common treatment for localised prostate cancer. urinary incontinence (ui) is one of the most disturbing aftereffects of rp (1). postoperative ui has a negative effect on the health-related quality of life after rp (2). in literature some authors analysed the influence of perioperative factors (patient age, body mass index, and prostate volume), anatomic factors (trigonal denervation, puboperinealis musclesparing dissection, and preservation of endopelvic fascia), and technical factors (bladder neck preservation, mucosal eversion, urethral length preservation, neuvides 2d sagittal and axial section of the posterior urethra and urethral sphincter complex. in males, urethral sphincter complex is a cylindrical structure surrounding the urethra and extending vertically from bladder neck to perineal membrane (inferior fascia of urogenital diaphragm), consisting of urethral smooth sphincter (presenting a hyperechogenic echostructure) and urethral rs (presenting a hypoechoic incomplete band around the central core). the striated urethral sphincter was clearly identified by its distinctive “omega-shaped” configuration and its hypoechoic ultrasound (us) pattern (6). the distance between urethra and the clearly demarcated inner contour of the sphincter was measured. the measurement points were aligned to the middle of the omega contour of the sphincter (figure 1). at the end of the examination a study was performed with the use of colour-doppler (cd) mode for the assessment of the urethral and rs vascularity pattern, both in sagittal and axial sections. the examination technique was standardized to an exact protocol that also included the execution of trus to determine anatomical changes in urethra after rp in incontinent patients. all patients were studied with 2d-trus pre and post-operatively by a single experienced surgeon in urologic ultrasound. informed consent for this study design was obtained from each patient. all patients completed a postoperative questionnaire on urinary function and were followed up for 12 months postoperatively. the level of stable continence was graded on a 5 point scale as: 1 = complete continence, 2 = 1 pad daily, 3 = 2-3 pads daily, 4 = 4 or more pads daily, and 5 = complete incontinence. the removal of the catheter and the teaching of pelvic floor exercises have been applied for 9 days after surgery. time to stable continence after surgery was measured in months and the percentages of patients regaining urinary continence at 3, 6 and 12 months after catheter removal were assessed. all patients incontinent at 12 months were subjected to urethroscopy and urodynamic study, excluding the presence of postoperative stenosis or overactive bladder. statistical analysis comparison of quantitative (follow-up time, age, prostate archivio italiano di urologia e andrologia 2015; 87, 4 l. dell’atti 318 figure 1. transrectal ultrasound in axial section of a continent patient with the urethra (u) and rhabdosphincter (rs) presenting a hypoechoic incomplete band around the central core. the thickness of rs measures 3.6 mm. volume, prostatic specific antigen [psa]) and categoric (pathologic stage, gleason) variables between group of continent patients and group of incontinent patients were performed with the use of mann-whitney u and chi-square tests, respectively. the level of statistical significance was set at p < 0.005. results clinical and pathological characteristics of our 211 patients have been summarized in table 1. no significant difference was noted between the groups (a = continent group and b = incontinent group) when comparing age, preoperative psa level, prostate volume, body mass index (bmi), clinical stage and gleason grade. continence was regained in 188 (89.1%) patients (group a), while incontinence (≥ 3 level of questionnaire) was noted in 23 (10.9%) patients at 3, 6 and 12 months following the catheter removal. twenty-three patients remained incontinent with a level ≥ 3, of which: 16 level 3, 4 level 4, and 3 level 5. the median follow-up period for patients incontinent was 12.3 months. 2d trus proved an accurate imaging technique for rs visualization. it was possible to visualize the rhabdosphincter in all patients, and the vascularity of this structure was clearly observed. the omega-shaped muscular loop presents as a hypoechoic structure surrounding the membranous urethra at its ventral and lateral aspects. patients with normal continence (1 and 2 questionnaire levels) showed a sphincter-muscle thickness of 3.5 mm (± 0.4) and a hypoechoic us pattern. patients continent incontinent p-value characteristics group group (≥ 3 level) (n = 188) (n = 23) age at diagnosis (yrs) (mean): 68.5 (56-76) 69.7 (57-74) ns mean preoperative psa (ng/ml): 6.8 (2.1-17) 6.1 (1.2-15) ns mean prostate volume (cc): 48.2 (19-115) 51.6 (21-98) ns body mass index (kgm-2) (%): ns < 18.5-24.9 35 (18.6) 4 (17.4) 25.0-29.9 56 (29.8) 8 (34.8) > 30.0 97 (51.6) 11 (40.3) clinical stage n. (%): ns t1 49 (26.1) 7 (30.5) ≥ t2 139 (73.9) 16 (69.5) pathological gleason score n. (%): ns ≤ 6 103 (54.8) 13 (56.5) 7 69 (36.7) 7 (30.5) ≥ 8 16 (8.5) 3 (13) type of surgery n. (%): ns open 120 (63.8) 15 (65.2) laparoscopic 68 (36.2) 8 (34.8) median follow-up (months) 11.9 (6-12) 12.3 (6-12) ns intraoperative complications n. (%): 7 (3.7) 1 (4.3) ns postoperative complication n. (%): 8 (4.2) 1 (4.3) ns ns: not significant; psa: prostate-specific antigen. table 1. clinical and pathological characteristics of patients. in the other levels of urinary incontinence (3, 4 and 5) rs thickness was 2.8 mm (± 0.5), 2.1 mm (± 0.6), 1.7 (± 0.7) respectively (figure 2). incontinence after rp (≥ 3 level) was associated with urethral sphincter deficiency in the overwhelming majority of patients. furthermore in the continent group an inverse relation was observed between the thickness of rs and the time required to reach the stable continence. in seven patients of level 3, in all patients of level 4 and in three patients with complete incontinence (level 5) the sphincter-muscle was noted as inhomogeneous echogenicity. cd analysis showed reproducible results for both axial and sagittal plane parameters (table 2). statistical significant differences were observed in the vascularity between continent and incontinent men in all measured vascularity variables (figure 3). there was no statistically significant difference in patients of the incontinent group depending on the different surgical approach used (p = 0.246). also regarding intraoperative (excessive bleeding, prolonged operative time, and presence of surgical adhesions) and postoperative complications (presence of hematoma or lymphocele), the two groups did not reach a statistical significance (p = 0.034). overactive bladder was showed in one patient of 4 level. bladder-neck strictures occurred in five patients (2.7%) of group a 6 months after catheter removal and in four patients (2.2%) 12 months after catheter removal. discussion the rs of the adult male is a muscular coat ventral and lateral to the membranous urethra and prostate, the core of which is an omega-shaped loop around the urethra. the sphincter-loop is continuous with muscle bundles which run along the anterior and lateral side of the prostate and extend cranially until they reach the bladder neck (13, 14). a number of studies have discussed a variety of risk factors that influence ui following rp. identification of the reliable risk factors may aid in the prevention of postoperative ui and selection of patients. however, substantial controversy exists regarding the risk factors (1, 5, 10). preoperatively, the patient’s age, urinary function, detrusor status, prostate volume, bladder capacity, and compliance are known. intraoperatively, the surgical technique and degree of preservation of the neurovascular bundles have been 319archivio italiano di urologia e andrologia 2015; 87, 4 ultrasound evaluation of the striated urethral sphincter as a predictive parameter of urinary continence after radical prostatectomy figure 2. transrectal ultrasound in axial section of an incontinent patient (level 5) with rhabdosphincter (rs) presenting an inhomogeneous us pattern. the thickness of rs measures 1.9 mm [arrows]. figure 3. transrectal ultrasound in axial section with the use of colour doppler in an incontinent patient (level 5) with rhabdosphincter (rs) presenting poor vascularization. trus results continent incontinent p-value group group (≥ 3 level) (n = 188) (n = 23) preoperative rs thickness mean ± sd, (mm): 3.5 mm (0.4) 2.3 (0.5) < 0.001 rs ultrasound pattern n. (%): hypoechoic echogenicity 181 (96.2%) 9 (39.1%) < 0.005 inhomogeneous echogenicity 7 (3.8%) 14 (60.9%) < 0.005 rs axial fv mean ±sd, (cm/sec): 0.41 (0.13) 0.19 (0.07) < 0.001 rs axial a mean ±sd: 0.06 (0.05) 0.02 (0.01) < 0.001 rs axial ri mean ±sd: 0.88 (0.14) 0.99 (0.05) < 0.005 rs axial pi mean ±sd: 2.13 (1.19) 3.25 (1.46) 0.01 rs sagittal fv mean ±sd, (cm/sec): 0.39 (0.1) 0.18 (0.09) < 0.001 rs sagittal a mean ±sd: 0.1 (0.05) 0.02 (0.02) < 0.001 rs sagittal ri mean ±sd: 0.78 (0.23) 0.98 (0.04) < 0.001 rs sagittal pi mean ±sd: 1.84 (0.24) 2.89 (1.32) < 0.001 sd: standard deviation; rs: rhabdosphincter; fv: flow velocity; a: area of the vessels; ri: resistence index; pi: pulsatility index. table 2. 2-dimensional and colour doppler transrectal ultrasound (trus) results. archivio italiano di urologia e andrologia 2015; 87, 4 l. dell’atti 320 shown as independent predictors of long term urinary continence (15). in this study, we examined the possible relationship between preoperative anatomic integrity of rs (in terms of thickness and vascularity) and ui after rp. several studies emphasized the significance of maximizing urethral length for favourable urinary control after rp. myers et al. (16) examined the anatomy of the male pelvic floor before undergoing rp and defined the anatomy, sphincter urethral length, levator ani muscles, puboprostatic ligaments and their anatomic relations. they calculated the mean sphincter urethral length as 21 mm (range 15-24 mm) in midline sagittal images and 20 mm (15-24 mm) from coronal images and recommended various operative methods for maintaining the length of urethral stump to achieve in urinary continence after rp. similarly coakley et al. (17) reported the mean sphincter urethral length before they underwent rp. they also reported that when a threshold of 12 mm was selected, 23-26% of patients with a preoperative urethral length of 12 mm or less were at least partially incontinent 1 year after surgery compared with 11% with a length of greater than 12 mm. unlike other authors, strasser et al. (18) examined the rs of male urethra in 77 patients with urinary incontinence after transurethral resection of the prostate or rp. they detected defects and postoperative scarring in the majority of the patients with postoperative urinary stress incontinence. furthermore, the patients presented with thinning in parts of the muscle and atrophy of the rs. certain authors measured rs using urodynamic assessment (8, 19). in other studies rs was examined using endorectal magnetic resonance imaging (9, 20, 21) or intraurethral us (22). however, to the best of our knowledge, no studies are currently available regarding the measurement of rs in terms of thickness and vascularity by preoperative 2d trus. statistical significant differences were observed in the us pattern and vascularity between continent and incontinent patients. however, there was no statistically significant difference between the two groups depending on the different surgical approach used. several limitations need to be acknowledged. a first limitation of our study concerns the race: the participants are white, therefore results might not be extended to other races. the size of the cohort was small, making it difficult to statistically identify variables, such as rs thickness or vascularity, that may have a clinical significant effect on continence. rs and its vascularity measured with endorectal us and assessed with our personal definition cannot still be considered as a standard diagnostic modality. further studies with a larger cohort will be useful to confirm this classification. finally, the median follow-up time of 12 months turned out to be insufficient, so that further studies with a longer follow-up are necessary. this study suggests that rs integrity is a good predictor of urinary continence after rp and this information can be important during the preoperative phase as part of the informed consent. conclusions in conclusion, 2d trus permits direct assessment of the integrity and vascularity of rs by means of a newly defined quantitative parameter. according to our preliminary results, in contrast to the other studies which mentioned the importance of preoperative sphincter urethral length in regaining continence after rp, preoperative thickness and vascularity rs may not be the sole important factor for urinary incontinence after rp. in the future, the studies that include measurements of preoperative measurements of rs in continent and incontinent patients might help to solve the important factors likely to contribute to postoperative continence after rp. references 1. de carlo f, celestino f, verri c, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: surgical, oncological, and functional outcomes: a systematic review. urol int. 2014; 93:373-383. 2. ganzer r, stolzenburg ju, neuhaus j, et al. is the striated urethral sphincter at risk by standard suture ligation of the dorsal vascular complex in radicalprostatectomy? an anatomic study. urology. 2014; 84:1453-1460. 3. majoros a, bach d, keszthelyi a, et al. analysis of risk factors for urinary incontinence after radical prostatectomy. urol int. 2007; 78:202-207. 4. cambio aj, evans cp. minimising postoperative incontinence following radical prostatectomy: considerations and evidence. eur urol. 2006; 50:903-913. 5. rocco f, carmignani l, acquati p, et al. early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. eur urol. 2007; 52:376-383. 6. wang xd, liu s, xiong lx, et al. normal anatomy of urethral sphincter complex in young chinese males on mri. int urol nephrol. 2014; 46:1469-1476. 7. strasser h, klima g, poisel s, et al. anatomy and innervation of the rhabdosphincter of the male urethra. prostate. 1996; 28:24-31. 8. porena m, mearini e, mearini l, et al. voiding dysfunction after radical retropubic prostatectomy: more than external urethral sphincter deficiency. eur urol. 2007; 52:38-45. 9. haga n, ogawa s, yabe m, et al. association between postoperative pelvic anatomic features on magnetic resonance imaging and lower tract urinary symptoms after radical prostatectomy. urology. 2014; 84:642-649. 10. strasser h, frauscher f, helweg g, et al. transurethral ultrasound: evaluation of anatomy and function of the rhabdosphincter of the male urethra. j urol. 1998; 159:100-104. 11. hinata n, murakami g, miyake h, et al. urethral sphincter fatigue after robot-assisted radical prostatectomy: descriptive questionnaire-based study and anatomic basis. urology. 2014; 84:144-148. 12. dell’atti l, daniele c. lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomfort and pain of the procedure: results of a randomized clinical trial. arch ital urol androl. 2010; 82:125-127. 13. steiner ms, morton ra, walsh pc. impact of anatomical radical prostatectomy on urinary continence. j urol. 1991; 145:512514. 14. zvara p, carrier s, kour nw, tanagho ea. the detailed neuroanatomy of the human striated urethral sphincter. br j urol. 1994; 74:182-187. 15. myers rp. male urethral sphincteric anatomy and radical prostatectomy. urol clin north am. 1991; 18:211-227. 16. myers rp, cahill dr, devine rm, king bf. anatomy of radical prostatectomy as defined by magnetic resonance imaging. j urol. 1998; 159:2148-2158. 17. coakley fv, hricak h. radiologic anatomy of the prostate gland: a clinical approach. radiol clin north am. 2000; 38:15-30. 18. strasser h, pinggera gm, gozzi c, et al. three-dimensional transrectal ultrasound of the male urethral rhabdosphincter. world j urol. 2004; 22:335-338. 19. kleinhans b, gerharz e, melekos m, et al. changes of urodynamic findings after radical retropubic prostatectomy. eur urol. 1999; 35:217-221. 20. coakley fv, eberhardt s, kattan mw, et al. urinary continence after radical retropubic prostatectomy: relationship with membranous urethral length on preoperative endorectal magnetic resonance imaging. j urol. 2002; 168:1032-1035. 21. paparel p, akin o, sandhu js, et al. recovery of urinary continence after radical prostatectomy: association with urethral length and urethral fibrosis measured by preoperative and postoperative endorectal magnetic resonance imaging. eur urol. 2009; 55:629-637. 22. frauscher f, helweg g, strasser h, et al. intraurethral ultrasound: diagnostic evaluation of the striated urethral sphincter in incontinent females. eur radiol. 1998; 8:50-53. 321archivio italiano di urologia e andrologia 2015; 87, 4 ultrasound evaluation of the striated urethral sphincter as a predictive parameter of urinary continence after radical prostatectomy correspondence lucio dell’atti, md, phd. (corresponding author) dellatti@hotmail.com department of urology university hospital “st.anna”. 8 a. moro street 44124 cona, ferrara, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 172 original paper is routine ureteral stenting really necessary after retrograde intrarenal surgery? ekrem ozyuvali 1, berkan resorlu 2, ural oguz 3, yildiray yildiz 1, tolga sahin 1, cagri senocak 1, omer faruk bozkurt 1, erman damar 1, murat yildirim 1, ali unsal 4 1 department of urology, kecioren training and research hospital, ankara, turkey; 2 department of urology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey; 3 department of urology, giresun university, faculty of medicine, giresun, turkey; 4 department of urology, gazi university, faculty of medicine, ankara, turkey. objectives: to investigate the situations in which ureteral double-j stent should be used after retrograde intrarenal surgery (rirs). patients and methods: patients with no ureteral double-j stent after rirs constituted group 1, and those with double-j stent after rirs constituted group 2. patients’ age and gender, renal stone characteristics (location and dimension), stone-free status, vas score 8 hours after surgery, post-procedural renal colic attacks, length of hospitalization, requirement for re-hospitalization, time to rehospitalization and secondary procedure requirements were analyzed. results: rirs was performed on 162 renal units. double-j stent was used in 121 (74.6%) of these after rirs, but not in the other 41 (25.4%). at radiological monitoring at the first month postoperatively after rirs, complete stone-free status was determined in 122 (75.3%) renal units, while residual stone was present in 40 (24.6%). no significant differences were observed between the groups in terms of duration of fluoroscopy (p = 0.142), operation (p = 0.108) or hospitalization times (p = 0.798). vas values determined routinely on the evening of surgery were significantly higher in group 1 than in group 2 (p = 0.025). twenty-eight (17.2%) presentations were made to the emergency clinic due to renal colic within 1 month after surgery. double-j catheter was present in 24 (85.7%) of these patients. conclusions: routine double-j stent insertion after rirs is not essential since it increases costs, morbidity and operation time. key words: retrograde intrarenal surgery; ureteral stent; urolithiasis. submitted 26 september 2014; accepted 30 november 2014 summary no conflict of interest declared. holmium laser technology and the entry into use of new generation flexible ureteroscopes and miniature instruments, retrograde intrarenal surgery (rirs) has now become a significant alternative in the treatment of renal stones (1). many renal stones can today be effectively treated using this technique without the need for invasive methods such as pnl or open surgery. rirs is particularly employed as a primary treatment method in stones smaller than 2 cm where swl has been unsuccessful and in patients with skeletal deformities and bleeding diathesis (2). while double-j stent following endourological surgical procedures is not routine, it is frequently employed for the purpose of preventing potential obstruction associated with postoperative ureteral edema or residual stone fragments (3). however, a wide range of complications, including infection, urinary complaints, hematuria, stent migration, encrustation and rupture can be seen in a significant proportion (10-85%) of patients following double-j stent insertion (4). with the development of flexible ureteroscopes and miniaturization of calibration devices there has been a relative decline in the incidence of ureteral trauma, and routine double-j stent has become controversial (3, 4). although there have been various studies concerning the use of double-j stent after rigid urs, there are no data in the literature regarding the situations in which double-j stent should be used post-rirs (5). use of ureteral access sheaths during rirs and the frequent observation of complications such as postoperative renal colic and urosepsis differentiate this technique from rigid operations. this study investigated the situations in which double-j stent should be used post-rirs. patients and methods one hundred fifty-six patients (162 renal units) diagnosed with renal stone, who underwent rirs at our clinic between january 2011 and june 2012 and met the inclusion criteria, were included in the study. seventy-nine patients (50.56%) were men and 77 (49.4%) women, with a mean age of 39.4 years (2-82). seventy-three stones (45%) were located in the right renal unit and 83 (51.2%) doi: 10.4081/aiua.2015.1.72 introduction shock wave lithotripsy (swl), ureteroscopy (urs) and percutaneous nephrolithotomy (pnl) are the most popular, minimally invasive options in the treatment of urinary system stone disease. thanks to recent advances in ozyuvali_stesura seveso 02/04/15 10:26 pagina 72 73archivio italiano di urologia e andrologia 2015; 87, 1 is routine ureteral stenting really necessary after retrograde ıntrarenal surgery? in the left. bilateral renal stones were present in 6 patients (3.7%). stone dimensions and the longest axis for each stone were calculated. mean stone size was 14.6 mm (535 mm) and mean stone number 1.3. patients’ demographic characteristics are shown in table 1. patients with stones smaller than 2 cm (total 35 mm in multiple stones), obese patients, patient with skeletal deformity or bleeding diathesis, patients with renal stones requiring complete removal (repeating infection, pilots, etc.) and subjects with stone in which swl treatment had been ineffective were included. patients with a pre-diagnosis of tumor, with a diagnosis of ureteral stricture, with severe mucosal injury or ureteral perforation arising during surgery and patients with a solitary kidney were excluded. complete blood count, blood biochemistry, coagulation parameters, elisa tests and urine tests and culture analyses were investigated pre-operatively in all patients. patients with growth in culture were given the appropriate antibiotic therapy, and surgery was planned once urine was sterile. all patients scheduled for surgery after diagnosis of renal stone were assessed with preoperative contrast examination (intravenous urography [ivu] or computerized tomography [ct]) if this had not been performed previously and was not contraindicated (allergy, pregnancy, etc.). surgical technique all operations were performed under general anesthesia and with the patient in the dorsal lithotomy position. an 8f feeding tube was inserted into the bladder by the urethral path in order to avoid perioperative bladder filling. a 7.5 f storz flex-x2 was used for flexible urs. a guide wire was first inserted into the ureter under fluoroscopic monitoring, and the ureteral access sheath was then pushed forward as far as the renal pelvis. the guide wires used were coated in polytetrafluorethylene (ptfe) or hydrophilic material, and ranged between 80 and 260 cm in length and 0.035 or 0.038 inch in diameter. the ureteral access sheaths used had an external diameter of 9.5-14 f and were 35-55 cm in length. double open ended 4f, 4.8f, or 6f catheters were used for double-j stent. catheters were inserted into the ureter with the help of a guide wire. patients with no pain or fever were discharged on the 1st day postoperatively. stone clearance was assessed intraoperatively by direct urs and postoperatively by imaging. all patients underwent ultrasonography (us) and radiographic study examination on a routine basis the day after rirs to ensure the absence of hydronephrosis and stone. treatment success was defined as stone-free or clinically insignificant residual fragments (residual fragment < 3 mm). double-j stents were removed from patients in 2-4 weeks postoperatively. before stent removal, patients were monitored radiologically for presence of stone. patients with no ureteral double-j stent after rirs constituted group 1, and those with double-j stent after rirs constituted group 2. patients’ age and gender, renal stone characteristics (location and dimension), stone-free status, vas score 8 h after surgery, post-procedural renal colic attacks, length of hospitalization, requirement for re-hospitalization, time to re-hospitalization and secondary procedure requirements were analyzed. categoric variables were expressed as numbers and percentages and constant variables as means. categoric variables between groups were compared using the chi square test. the mannwhitney u test was used to examine differences between groups after normality testing. data obtained were analyzed on spss 15.0. significance was set at p < 0.05. results rirs was performed on 162 renal units. double-j stent was used in 121 (74.6%) of these post-rirs, but not in the other 41 (25.4%). mean stone dimension was 14.6 mm (535 mm) and mean stone number was 1.3 (1-3). stone was located in the renal pelvis in 98 (60.4%) renal units and in the calyx in 64 (39.6%). mean length of surgery was 37.2 minutes (15-140). mean duration of scope was 39 sec (0140 sec) and mean length of hospitalization was 1.8 days (1-8 days). the results are summarized in table 2. at radiological monitoring at first month postoperatively post-rirs, complete stone-free status was determined in 122 (75.3%) renal units, while residual stone were present in 40 (24.6%). one renal unit with more than one stone achieved stone-free status using pnl on the 5th day. stone-free status was achieved with urs in four patients one month postoperatively and in six patients by repeating rirs. five patients were referred for swl with insertion of a double-j stent. the other cases did not continue with the protocol. mean stone size in the double-j stent group was 15 mm, table 1. patient and stone characteristics. no. of patients (renal unit) 156 (162) mean age (year) 39.4 (2-82) male/female 79/77 stone side (%) left 83 (51%) right 73 (45%) bilateral 6 (3.7%) stone location (%) renal pelvis 98 (60.4%) calyx 64 (39.6%) mean stone size (mm) 14 (5-35) mean stone number 1.3 (1-3) table 2. comparison of groups according to gender, stone location, swl history, success and re-hospitalization rates. group 1 group 2 total p value gender male 24 (58%) 57 (47%) 81 (50%) 0.206 female 17 (42%) 64 (53%) 81 (50%) stone location pelvis 16 (39%) 82 (68%) 98 (60%) 0.002* calyx 25 (60%) 39 (32%) 64 (40%) previous swl yes 25 (60%) 68 (56%) 93 (57%) 0.725 success 78% 74% 75% 0.794 re-hospitalization 4 (9%) 24 (19%) 28 (17%) 0.216 * statistically significant at p < 0.05. ozyuvali_stesura seveso 02/04/15 10:26 pagina 73 archivio italiano di urologia e andrologia 2015; 87, 1 e. ozyuvali, b. resorlu, u. oguz, y. yildiz, t. sahin, c. senocak, o. faruk bozkurt, e. damar, m. yildirim, a. unsal 74 compared to 12 mm in the group without stent (p = 0.019). no significant difference was observed between the groups in terms of stone number (p = 0.098). a significant rate of the stones in both groups were located in the renal pelvis (n = 98, 60.4%). a significantly higher proportion of stones were located in the renal pelvis in group 2 than in group 1 (p = 0.002). in addition, vas values determined routinely on the evening of surgery were significantly higher in group 1 than in group 2 (p = 0.025). no significant difference was observed between the groups in terms of age (p = 0.123) or gender (p = 0.206). no significant differences were determined between the groups in terms of duration of fluoroscopy (p = 0.142), operation (p = 0.108) or hospitalization times (p = 0.798). ureteral perforation was observed as a complication in two patients. these were treated with insertion of a double-j stent. no extravasation or stricture pattern was observed at ivu performed in the 3rd month postoperatively, and stone-free status was subsequently achieved using repeat rirs. urosepsis was observed in one case in group 2. this patient was treated with antibiotic therapy under intensive care conditions. urinary tract infection was observed in 23 cases (14.1%) within the 1st month postoperatively. these were treated on the basis of culture antibiogram results. twenty-eight (17.2%) presentations were made to the emergency clinic due to renal colic within 1 month after surgery. double-j catheter was present in 24 (85.7%) of these patients. no major complication such as avulsion, iatrogenic organ injury, urinoma or hydropneumothorax developed in any renal unit (table 3). discussion stents have been used in the treatment of kidney and ureter stones for more than 30 years (6). development of fine callibration ureteroscopes and improvements in lithotriptor effectiveness have led to a decrease in the use of stents. while stent use is necessary after traumatic procedures, some authors suggest that routine stent insertion is not necessary postprocedurally (7, 8). complication retes in the literature range from 5% to 10%, with a rate of major complications of approximately 1% (9). ureteral avulsion continues to represent a major acute complication. complications are strongly correlated with equipment used and urologist experience (6, 7, 9). in our case, ureteral perforation during ureteral sheath insertion developed in two renal units. the procedure in these patients was concluded with double-j stent insertion. no findings of extravasation or urinoma were detected at postoperative follow-up period. the purpose of stent insertion after ureteroscopic lithotripsy is to prevent ureteral stricture, achieve healing and to facilitate passage of stone fragments in the ureter with passive dilation (10, 11). stent is required after urs in the event of mucosal edema, epithelium injury, mucosal bleeding and ureteral perforation and in patients with solitary kidney. stents can also be inserted for the purpose of preventing potential complications in patients undergoing ureteral lower tip dilation before urs. stent insertion has been shown to reduce temporary lower urinary system pain and symptoms (12). renal colic develops within the first 24 hours in patients not using stent. when injury develops during rirs, 48-72 hours are needed to elapse for edema to develop, and it is therefore incorrect to attribute renal colic attacks in the first 24 hours to edema alone. residual stone fragments, coagulum or ureteral spasm or both are among the possible causes (13). tanrıverdi et al. reported that emergency double-j stent insertion in the early postoperative period (first 24 hours) in 23 patients with uncompleted urs prevented progressive obstruction and potential post-surgical complications (14). however, there are some disadvantages of stents, including urinary tract infection, dysuria, pollakiuria, hematuria and need for repeated cystoscopy for stent migration or stent extraction. some authors are of the opinion that stent insertion increases costs by prolonging length of surgery and due to cystoscopy requirement for stent removal. the stent removal procedure has also been reported to be traumatic (15). byrne et al. reported that stent insertion increased length of surgery by 12 min (16). netto et al. reported a length of surgery of 65 min in a group with stent insertion and 45 min in patients without stenting (17). mean duration of surgery in the 41 renal units without stent insertion in our study was 33.6 min (18-65 min), compared to 38.4 min (15-140) in the 121 renal units with stenting (15140 min). the difference was not significant (p > 0.05) but no cost analysis was performed in our study. some studies evaluating complication rates associated with table 2. patient demographics, stone characteristics and operative findings of groups mean median min max ss p value age (years) group 1 35 37 2 76 16,18 group 2 40 42 2 82 18,03 total 39 40,5 2 82 17,64 0.123 stone size (mm) group 1 13 12 5 30 5,92 group 2 15 15 6 35 5,22 total 14 14 5 35 5,43 0.019* stone number group 1 1,27 1 1 3 0,55 group 2 1,31 1 1 6 0,73 total 1,30 1 1 6 0,69 0.998 operation time (min) group 1 33 32 18 65 11,27 group 2 38 36 15 140 16,73 total 37 35 15 140 15,63 0.108 fluoroscopy (sec) group 1 37 24 0 140 36,27 group 2 39 35 0 132 26,68 total 39 34,5 0 140 29,29 0.142 hospitalization time (days) group 1 1,6 2 1 3 0,61 group 2 1,8 2 1 7 1,02 total 1,8 2 1 7 0,93 0.798 vas level group 1 5,9 6 2 10 1,86 group 2 5,1 5 2 10 1,88 total 5,3 5 2 10 1,90 0.025 * statistically significant at p < 0.05. ozyuvali_stesura seveso 02/04/15 10:26 pagina 74 75archivio italiano di urologia e andrologia 2015; 87, 1 is routine ureteral stenting really necessary after retrograde ıntrarenal surgery? stent use have reported higher levels of complications in the group without stent insertion (15, 18). the fact that double-j stent was inserted in 121 renal units although a 7.5 f flexible ureteroscope was used in our study group conflicts with existing urs data. however, those studies were performed for rigid urs and generally used a pneumatic lithotriptor. the studies performed with rirs/holmium;yag lasers are insufficient. in our study, renal colic attacks were observed in 78 patients (64%) of the group receiving double-j stents post-procedurally and in 24 (58%) of the group not receiving double-j stent with secondary double-j stent insertion required in 16 of these. however, no statistically significant difference was determined regarding this finding (p = 0.239). the incidence of renal colic attacks and number of double-j insertions being greater than those in the literature may be attributed to the use of a ureteral sheath during rirs and probably to ureteral edema. in addition, working under constant positive hydrostatic pressure in order to overcome the inadequacy of flexible urs in providing an optimal image of a narrow channel during rirs can trigger renal colic attacks and infection leading to fornix rupture and pyelolymphatic and pyelo-renal backflow. no significant differences were determined in our study in terms of age, gender, stone number, history of surgical intervention before the procedure, history of swl, length of surgery, length of scope use, renal colic, analgesic requirement and duration of hospitalization, and double-j stent requirement (p > 0.05). the guidelines generally state that ureteral stent insertion is not necessary after urs performed for stone without complications. however, there are reports in the current literature of increasing double-j stent requirement due to increasing incidence of ureteral trauma related to use of the ureteral access sheath (7). conclusion routine double-j stent insertion after rirs is not essential since it increases costs, morbidity and operation time. double-j stent insertion in stones larger than 15 mm located in the renal pelvis is positively and significantly correlated with vas score (p < 0.05). we think that further studies with wider case series and long-term follow-up are needed to better assess this topic. references 1. akıncı m, esen t, tellaloglu s. urinary stone disease in turkey: an update epidemiological study. eur urol. 1991; 20:200-3. 2. resorlu b, unsal a. retrograde intrarenal surgery (rirs) for renal stones. turk urol sem. 2011; 2:64-7. 3. ates f, adayener c, akyol i, et al. üreteroskopik litotripsi sonrası her zaman üreteral stent yerlestirmek gerekir mi? bakırköy tıp dergisi. 2010; 6:142-7. 4. geavlete p, georgescu d, nita g, et al. complications of 2,735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 2006; 20:179-85. 5. resorlu b, unsal a, gulec h, et al. a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the ‘resorlu-unsal stone score’. urology. 2012; 80:512-8. 6. johnson de, cromeens dm, price re. use of the holmium:yag laser in urology. lasers surg med. 1992; 12:353-63. 7. sayer j, johnson de, price re, et al. ureteral lit¬hotripsy with the holmium:yag laser. laser med. 1993; 11:61-5. 8. alan c, koçoglu h, ersay ar. retrograde iıntrarenal surgery: technic, clinical results, tips and tricks,the new journal of urology. 2011; 6:32-41. 9. conlin mj ureteropyeloscopy for calculi in nakada sy, pearle ms. (eds) advanced endourology, humana press inc, totowa new jersey 2006, pp 105-108. 10. atug f, akay f, akkus z, et al. komplike olmayan üreteroskopik litotripsilerden sonra üreteral stent yerlestirilmesi gerekli midir? türk üroloji dergisi. 2006; 32: 225-9. 11. tepeler a, resorlu b, sahin t, et al. categorization of intraoperative ureteroscopy complications using modified satava classification system. world j urol. 2014; 32:131-6. 12. damiano r, oliva a, esposito c, et al. early and late complications of double pigtail ureteral stent. urol int. 2002; 69:136-40. 13. keeley fx jr, timoney ag. routine stenting after ureteroscopy: think again. eur urol. 2007; 52:642-4. 14. tanrıverdi o, yencilek f, koyuncu h, et al. emergent stenting after uncomplicated ureteroscopy. urology. 2011; 77:305-8. 15. borboroglu pg, amling cl, schenkman ns, et al. ureteral stenting after ureteroscopy for distal ureteral calculi: a multi-institutional prospective randomized controlled study assessing pain, outcomes and complications. j urol. 2001; 166:1651-7. 16. byrne rr, auge bk, kourambas j, et al. routine ure-teral stenting is not necessary after ureteroscopy and ureteropyeloscopy: a randomized trial. j endourol. 2002; 16:9-13. 17. netto nr jr, ikonomidis j, zillo c. routine ureteral stenting after ureteroscopy for ureteral lithiasis: is it really necessary? j urol. 2001; 166:1252-4. 18. joshi hb, stainthorpe a, macdonagh rp, et al. indwelling ureteral stents: evaluation of symptoms, quality of life and utility. j urol. 2003; 169:1065-9. correspondence ekrem ozyuvali, md yildiray yildiz, md tolga sahin, md cagri senocak, md omer faruk bozkurt, md erman damar, md murat yildirim, md department of urology, kecioren training and research hospital, ankara, turkey berkan resorlu, md (corresponding author) drberkan79@gmail.com canakkale onsekiz mart universitesi, terzioglu yerleskesi, barbaros mh, 17100, canakkale, turkey ural oguz, md department of urology, giresun university, faculty of medicine, giresun, turkey ali unsal, md department of urology, gazi university, faculty of medicine, ankara, turkey ozyuvali_stesura seveso 02/04/15 10:26 pagina 75 stesura seveso 325archivio italiano di urologia e andrologia 2015; 87, 4 case report robot-assisted excision of seminal vesicle cyst associated with ipsilateral renal agenesis marcello scarcia, francesco paolo maselli, giuseppe cardo, giovanni pagliarulo, giuseppe mario ludovico urology department mininvasive robotic center “f. miulli” hospital, acquaviva della fonti, bari, italy. seminal vesicle cysts (svcs) associated with other genitourologic abnormalities are rare. often associated with ipsilateral renal agenesis in a symptomatic patient. in symptomatic patients open surgical excision is the treatment of choice. the laparoscopic approach is a less invasive option. recently robot-assisted management has gained a primary role for the treatment of this condition. key words: seminal vescicle cyst; robotic surgery; genitourologic abnormalities. submitted 14 april; accepted 30 june summary no conflict of interest declared. materials and methods the clinical presentation may have a wide range of symptoms. such as perineal pain, emptying phase symptoms and intermittent haemospermia, epididymitis; the physical examination may be negative and in some cases the rectal exam reveal a cystic mass in the area of seminal vescicles. transrectal or abdominal ultrasonography, ct scan and mri (figures 1-1a-2-2a) are the diagnostic tools indicated for the diagnosis; seldom vesiculography and semen analysis may be useful in cases with ejaculatory duct obstruction. uroflussometry may show obstruction and endoscopic view can show bulging of the bladder wall with dislocation of the ureteric virtual orifice, in cases with large cysts. robotic technique a standard transperitoneal approach could be carried with six trocars in “w” configuration if a four arms robot is used, but four or five access are also described. moderate trendelemburg position was obtained. the bladder was drained with a foley catheter. the posterior surface of the bladder was approached by transverse peritoneal incision between the bladder and the rectum and a cleavage plane was developed. left vas deferens, seminal vesicle and cyst were identified (figures 3-3a). then the cyst was gently dissected from the bladder wall, resected and the communication with the seminal vesicle closed with 4/0 absorbable suture (figures 4-4a). the peritoneal layers were sutured and no drain was left. no complications were observed. foley catheter was removed on day one. postoperative hospital stay was two days. after one year follow-up total relief of symptoms without complications was shown. ct scan and postoperative flowmetry showed normal findings. doi: 10.4081/aiua.2015.4.325 introduction seminal vesicle cysts (svcs) are rare lesions that can be either congenital or acquired (1). the majority remain asymptomatic. however, those cysts could become symptomatic and usually require surgical management. open surgery (3-4-5) is the gold standard of treatments with good results; surgical experiences are reported since 1914 by zinner (7); however associated with significant morbidity, such as rectal and bladder wall injuries, ureteral injury, and also possible erectile dysfunction due to neurovascular bundle damage. seldom are reported pelvic urinomas. in the last decade the a laparoscopic treatment (4-5-6) allows a less invasive route, with reduced morbidity, and hospitalization. the robotic surgery offers a more feasible treatment due to the more accurate dissection and 3d visualization. moore et al. in july 20072 described the first robotassisted excision of a svc. figures 1, 1a. ct scan. archivio italiano di urologia e andrologia 2015; 87, 4 m. scarcia, f.p. maselli, g. cardo, g. pagliarulo, g.m. ludovico 326 genital seminal vesicle cyst associated with ipsilateral renal agenesis. urol int. 2011; 87:238-40. 4. mcdougall em, afane js, dunn md, et al. laparoscopic management of retrovesical cystic disease: washington university experience and review of the literature. review j endourol. 2001; 15:815-9. 5. han p, dong q, shi m, et al. seminal vesicle cyst and ipsilateral renal agenesis: laparoscopic approach. arch androl. 2007; 53:285-8. 6. cherullo ee, meraney am, bernstein lh, et al. laparoscopic management of congenital seminal vesicle cysts associated with ipsilateral renal agenesis. j urol. 2002; 167:1263-7. 7. zinner, a. ein fall von intravesikaler samenblasenzyste. wein med wochenschr. 1914; 64:605. correspondence marcello scarcia, md scarciam@hotmail.com francesco paolo maselli, md giuseppe cardo, md giovanni pagliarulo, md giuseppe mario ludovico, md urology department mininvasive robotic center "f. miulli" hospital strada prov 127, 70021 acquaviva delle fonti, bari, italy figures 2, 2a. rm. figures 3, 3a. left svc. figures 4, 4a. suture of surgical field. conclusions svcs associated with ipsilateral renal agenesis are rare but they should be considered in men with otherwise inexplicable voiding symptoms, perineal discomfort or other genitourinary complaint of unclear etiology. laparoscopic-robot-assisted procedure provides excellent intraoperative access and visualization with absence of postoperative morbidity. it is likely to become the treatment of choice for this rare developmental anomaly. obviously in centers with a high volume surgery, performed by experienced surgeons. bibliography 1. embryology of the genitourinary system. in: tanagho ea, mcaninch ja (eds). smith’s general urology, 14th edn. appleton & lange, norwalk. 1995; 17-30. 2. moore cd, erhard mj, dahm p. robot-assisted excision of seminal vesicle cyst associated with ipsilateral renal agenesis. j endourol. 2007; 21:776-9. 3. shah k, pal b, rizvi sj, modi p. laparoscopic excision of a conarchivio italiano di urologia e andrologia 2013; 85, 282 introduction percutaneous nephrolithotomy is the gold standard in treating kidney stones larger than 2 cm (1). the technique has been modified and customized by many endourologists since its introduction in 1976 by fernstrom and johanson. many various safe and effective changes in patient positioning for pcnl have been proposed over years, including reverse lithotomy position (2), prone split-leg position (3-4), lateral decubitus (5, 6), supine position (7), and galdakao-modified supine valdivia (gmsv) position (8). in recent years it has been observed a remarkable increase in performing pcnl in supine original paper split-leg percutaneous nephrolithotomy: a safe and versatile technique eugenio di grazia, pasquale la rosa u.o.c. urologia-arnas garibaldi, catania, italy. objectives: percutaneos nephrolithotomy (pcnl) is the gold standard for treatment of urinary stones larger than 2 cm and refractory to eswl. nowadays most debate about surgical technique is related to the positioning of patients. we report our experience on prone pcnl with split-leg variant (sl-pcnl) materials and methods: 30 consecutive patients underwent prone sl-pcnl. preoperative stone size was determined by measuring stones longest diameter on ct scan. in cases with multiple stones, stone size was determined by the sum of each stone diameter on ct scan. patients evaluated consisted of 20 females and 10 males and median age was 55 (20-72). the average bmi was 27 (24-35). 15 patients had multiple stones, 10 pyelocalicial, 10 pelvic larger than 2 cm, 2 in horseshoe kidneys and 3 staghorn stones. results: stone free rate was 87% after first look and 97% after second look. in 2 cases, we used a flexible ureteroscopy 7.5 fr (flex 2 storz) to treat a calculus in ureter or for a contemporary double access (endoscopic combined retrograde intrarenal surgery ecirs). in 28 cases we placed a 20 fr nephrostomy while in two cases procedure was tubeless. in 20 cases we placed a double-j catheter. in 2 cases we performed two tract and in 2 horseshoe kidneys access was close to spine. the average surgical time was about 90 minutes (range 30-120 minutes). hemoglobin drop was about 1.5 mg/dl (range 1-3 .4 mg/dl) and no major complications were reported. conclusions: in our experience pcnl in prone with spread-legs variant is a versatile technique and allows to match the advantages you have with same technique in supine, providing at the same time benefits in cases of anatomical abnormalities, challenging cases, or when multi-tract accesses are required. key words: pcnl; percutaneous nephrolithotomy; urinary stones; prone; supine. submitted 12 october 2012; accepted 31 december 2012 no conflict of interest declared summary decubitus, although others have remained faithful to prone technique because supine decubitus doesn't seem to provide great benefits for morbidity and effectiveness (9), otherwise the prone position provides a larger area for the percutaneous renal access, a wider space for instrument manipulation, and a presumed lower risk of splanchnic injury. recently we adopted a variant to our technique in prone position, by splitting legs allowing surgeons a dual approach through retrograde and anterograde paths whithout changing decubitus. aim of this study is to test safety, advantages and feasibility of this technique. di grazia_stesura seveso 24/06/13 11:03 pagina 82 83archivio italiano di urologia e andrologia 2013; 85, 2 split-leg percutaneous nephrolithotomy: a safe and versatile technique procedure after general anesthesia patient was placed in prone position with legs apart (figures 1-2). with a 15 f flexible cystoscope (stors) under fluoroscopic guidance (c-arm) a 5 f open-end ureteral catheter was positioned until renal pelvis for contrast dye injection during percutaneous access; in 2 cases, we used a flexible ureteroscopy 7.5 fr (flex 2 -storz) to treat a calculus in ureter or for a combined access endoscopic combined intrarenal surgery (ecirs). the percutaneous kidney access is performed by combined echo-radiological approach and tract is dilated with balloon to place a 24 f amplatz sheath (x force-bard). the litotripsy was accomplished by a 24 f rigid nefroscope or 15 f flexible nefroscope (storz) using ultrasound energy sources (storz), ballistic (ems) and laser (dornier). operative time was determined by estimating the time from the application of the ureteric catheter to the placement of the nephrostomy tube. at the end of procedure we usually place a 20 f nephrostomy or ureteral stent according to the degree of bleeding or of stone clearence. results all cases were punctured successfully. stone free rate was 87% after first look and 97% after second look (table 2). at the end of procedure in 28 cases we placed a 20 f nephrostomy while in two case the procedure was tubematerials and methods after a series of about 300 patients undergoing pcnl from 2002 to 2012, we evaluated 30 consecutive cases performed in prone decubitus with split-leg variant (slpcnl). preoperative evaluation included history, clinical examination and basic laboratory investigations. radiological investigations included pelvi-abdominal ultrasonography and computerized tomography (ct) for all patients. preoperative stone size was determined by measuring stones longest diameter on ct scan. in cases with multiple stones, stone size was determined by the sum of each stone diameter on ct scan. patients evaluated consisted of 20 females and 10 males and median age was 55 (20-72). the average bmi was about 27 (2435 bmi). 15 patients had multiple stones, 10 pyelocalicial, 10 pelvic larger than 2 cm, 2 in horseshoe kidneys and 3 staghorn stones (table 1). we practiced an antibiotic prophylaxis the evening before the procedure with a cephalosporin of iii generation in case of sterile urine culture. when culture was positive generally we started a targeted antibiotic therapy a week earlier. site 15 multiple 10 pyelocalicial 5 pyelic 3 staghorn; 2 horseshoe kidney associated ureteral stones 2 cases accesses 28 single accesses 2 double accesses 2 upper calix accesses in horseshoe kidney table 1. stone characteristics. figure 1. figure 2. success rate first look (87%) second look (97%) complications bleeding requiring transfusion in 1 (3,3%) persistent fever over 38,5 c° in 4 (13,3%) prolonged urinary leakege in 2 (6,6%) table 2. success rate and complications. di grazia_stesura seveso 24/06/13 11:03 pagina 83 archivio italiano di urologia e andrologia 2013; 85, 2 e. di grazia, p. la rosa 84 sitating extra nurses. after draping, we start the procedure in prone and upper urinary tract may be contemporary instrumented both in an antegrade and retrograde fashion by two surgeons. the main difference between prone and supine is the impossibility for surgeon using flexible scopes to access upper urinary tract in prone while both semirigid or flexible instruments can be used in the latter. another criticism over prone position rise up when obese patients or patients affected by respiratory diseases are concerned, or in cases where extensive controlateral or omolateral ureteral instrumentation is requested before or contemporary to percutaneous access. croes studies demonstrated no significant differences in complications between prone and supine when such patients are concerned (11). in our opinion further experience on using flexible ureteroscope in split-leg position may overwhelm these presumed obstacles in traditional prone position. if no gross disadvantages are reported between prone and supine, we assert benefits that prone decubitus can account for: easier way of perform mutiple tracts when is necessary, greater freedom of movement of instrumentation. in addition, upper-pole calyx calyceal puncture is quite challenging as upper pole is normally more medial and posterior and concealed deeply in the rib cage, when patient is positioned supine (12). prone position account for an easier access to horseshoe kidney as target calix is normally close to spine, rendering access in supine very challenging. this is a description of technique with no direct comparison with a homogeneous control population treated in others surgical positions, however the advantage we obtained by adopting this variant to the traditional prone position makes us to propose such technique as a useful option for percutaneous renal surgery. conclusions in our experience pcnl in prone with spread-legs variant is a versatile technique that allows to match the advantages you have with same technique in supine, providing at the same time benefits in cases of anatomical abnormalities, challenging cases, or when multi-tract accesses are required. references 1. fernstrom s, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j nephrol urol. 1976; 10:257-9. 2. lehman t, bagley dh. reverse lithotomy, modified prone position for simultaneous nephroscopic and ureteroscopicprocedures in women. urology. 1988; 32:529-31. 3. grasso m, nord r, bagley dh. prone split leg and flank roll positioning antegrade and retrograde: simultaneous access to the upper urinary tract. j endourol. 1993; 7:307. 4. scarpa rm, cossu fm, de lisa, et al. severe recurrent ureteral stricture: the combined use of an anterograde and retrograde approach in the prone split-leg position without x-rays. eur urol. 1997; 31:254-6 5. kerbl k, clayman rv, chandhoke ps, et al. percuta neous less. in 20 cases we placed a double-j catheter. the nephrostomy was retrieved when any bleeding ceased and when no residual fragments were demonstrated at post-surgery radiological assessment. in those cases with residual fragments we performed a second look with flexible nefroscope, small baskets and holmium laser lithotripsy accessing the same matured tract without amplatz sheath. when 20 f nephrostomy is withdraw the tract is large and mature enough to allow access of 15 f flexible nephroscope through the kidney without patient discomfort as performed in an outpatient procedure. in 2 cases we performed two tract to clear stones and in 2 horseshoe kidneys target calix was close to the spine. the average surgical time was about 90 minutes (range 30-120 minutes). the drop in hemoglobin was about 1.5 mg/dl (range 13.4). applying classification of clavien-dindo in 1 case (3.3%) we practiced a transfusion of a blood unit (grade ii). 4 patients (13.3%) had a persistent fever over 38.5° c for more than 2 days (grade ii). in 2 cases (6,6%) was necessary to reposition the stent for persistent urinay leakage (grade ii). no case of visceral perforation or other major complications were reported. discussion the slpcnl is a technique already presented in literature by grasso et al. with aim of facilitating both contemporary antegrade and retrograde approach to upper urinary tract. in their experience grasso et al. reported a 41% of cases where this position was useful for dual instrumentation (3). also scarpa et al. described this approach in solving a ureteral stenosis with combined antegrade and retrograde approach (4). many studies have now demonstrated equivalence of pcnl in supine and prone positions, however proponents of supine believe that it offers advantages over the prone: no repositioning, lack of patient handling, spontaneous gravitational fall of fragments, less time consuming because of not repositioning, greater comfort for surgeon, reduced x-ray exposure, low pyelic pressures, retro and antegrade access simultaneously (8-9-10). nevertheless as seen by our experience slpcnl provides as many benefits as supine. many endourologists performing pcnl in prone position place a ureteral catheter for injecting contrast dye in supine decubitus, then they reposition patient in prone to start their percutanous procedure. a real criticism can be that patient repositioning is timeconsuming and associated with patient discomfort, increases radiological hazard to urologist’s hands, and asks for several nurses to be present for intraoperative changes of decubitus in case of simultaneous retrograde instrumentation of ureter (implying evident risks related to pressure points and possible ocular, spinal, or peripheral nerve injuries). in our experience it should be correct to talk of “positioning” patient in prone position, rather than “repositioning”, as patient is gently rotated from a stretcher to operating bed without spending much time and necesdi grazia_stesura seveso 24/06/13 11:03 pagina 84 85archivio italiano di urologia e andrologia 2013; 85, 2 split-leg percutaneous nephrolithotomy: a safe and versatile technique stone removal with the patient in a flank position. j urol. 1994; 151:686-8. 6. gofrit on, shapiro a, donchin a, et al. lateral decubitusposition for percutaneous nephrolithotripsy in the morbidlyobese or kyphotic patient. j endourol. 2002; 16:383-386. 7. uria in valdivia jg, valle gerhold j, lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol. 1998; 160:1975-8. 8. scoffone cm, cracco cm, cossu m, et al. endoscopic combined intrarenal surgery in galdakao-modified supine valdivia position: a new standard for percutaneous nephrolithotomy? eur urol. 2008; 54:1393-403. 9. valdivia jg, scarpa rm, duvdevani m, et al. croes pcnl study group. supine versus prone position during percutaneous nephrolithotomy: a report from the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011; 25:1619-25. 10. autorino r, giannarini g. prone or supine: is this the question? eur urol. 2008; 54:1216-1218. 11. fuller a, razvi h, denstedt jd, et al. croes pcnl study group. the croes percutaneous nephrolithotomy global study: the influence of body mass index on outcome. j urol. 2012; 188:138-44. 12. de la rosette jj, tsakiris p, ferrandino mn, et al. beyond prone position in percutaneous nephrolithotomy: a comprehensive review. eur urol. 2008; 54:1262-9. correspondence eugenio di grazia, md (corresponding author) via galermo 171/c 95123 catania, italy eugeniodigrazia@hotmail.com la rosa pasquale, md via palermo 636 95100 catania, italy pasq.larosa@alice.it di grazia_stesura seveso 24/06/13 11:03 pagina 85 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 166 original paper use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: results of a prospective randomized pilot study simone brardi 1, gabriele cevenini 2, tiziano verdacchi 3, giuseppe romano 4, roberto ponchietti 5 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of surgery and bioengineering, university of siena, siena, italy; 3 extracorporeal shock wave lithotripsy unit, s. donato hospital, arezzo, italy; 4 urology unit, s. maria della gruccia hospital, montevarchi, italy; 5 postgraduate nephrology school, university of siena, siena, italy. . objectives: to evaluate, by means of a prospective randomized study, the efficacy of cinacalcet in the forms of nephrolithiasis associated with primary hyperparathyroidism in both the hypercalcemic and normocalcemic variant. materials and methods: ten patients suffering from active nephrolithiasis associated with primary hyperparathyroidism (4 hypercalcemics and 6 normocalcemics), equally divided between males and females, were randomly but not blindly addressed to treatment with potassium citrate and allopurinol, or to the same therapeutic regimen in combination with cinacalcet. the dosage of cinacalcet was optimized for each patient in order to obtain a reduction of parathyroid hormone (pth) within normal limits while enabling the maintenance of adequate calcemic values. all study participants were given the same diet based on a reduction in sodium intake, oxalate-rich foods and animal protein with standardized intake of calcium and an increase in hydration. after a follow up period of 10 months , cinacalcet was associated to standard therapy and diet in patients who were not taken it, conversely cinacalcet was withdrawn in the remaining patients who remained on standard therapeutic regimen and diet. follow up was continued for a second period of observation of the same duration of the first. results: at the end of the period of treatment with cinacalcet, for both variants of hyperparathyroidism, a statistically significant reduction in the overall number and in the diameter of renal stones was found. conclusions: this prospective randomized study shows the effectiveness of cinacalcet used in combination with a diet with normalized calcium intake, in reducing the number and size of urinary stones in hypercalemic and normocalcemic forms of primary hyperparathyroidism. key words: nephrolithiasis; normocalcemic primary hyperparathyroidism; cinacalcet; prospective randomized study. submitted 26 september 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction primary hyperparathyroidism is a disease characterized by elevated levels of parathyroid hormone (pth) that in 7080% of cases is caused by isolated parathyroid adenoma and in the remaining from a diffuse hyperplasia of all glands (1). primary hyperparathyroidism is one of the most common endocrine disorders and classically presents with hypercalcemia, nephrolithiasis and reduced bone mass (2). since last decade it has also been described a new clinical form of primary hpt, defined normocalcemic primary hyperparathyroidism, characterized by total and ionized calcium concentrations within the normal limits even in the presence of a constant elevation of the levels of pth and in the absence of alterations that may justify a secondary elevation of pth (3). diagnosis of primary hyperparathyroidism implies absence of secondary causes of elevation of pth such as 25-hydroxyvitamin d deficiency, decreased creatinine clearance, use of drugs such as hydrochlorothiazide and lithium salts, idiopathic hypercalciuria, gastrointestinal disorders associated with malabsorption syndromes (3). nephrolithiasis is present in 15-20% of patients with hypercalcemic primary hyperparathyroidism (4) but also normocalcemic primary hyperparathyroidism is associated with such an high prevalence of nephrolithiasis (18.2% according to amaral et al.) (2). similar incidences were demonstrated for bone fractures (2). most stones found in patients with primary hyperparathyroidism are composed of calcium oxalate and, in case of alkaline urine, of calcium phosphate (5). in this context, hypercalciuria (due to the fact that the increase of filtered calcium related to hypercalcemia compensates and even surpasses distal tubular reabsorption of calcium directly induced by parathyroid hormone) is a predisposing factor for stone formation (6). however it is not clear why some patients with primary hyperparathyroidism, both normocalcemic or hypercalcemic, tend to form stones and others do not. in fact, in studies that aimed at comparing the biochemical profile of patients with hyperparathyroidism with or without associated doi: 10.4081/aiua.2015.1.66 brardi print_stesura seveso 02/04/15 10:25 pagina 66 67archivio italiano di urologia e andrologia 2015; 87, 1 use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: pilot studt nephrolithiasis (7, 8) hypercalciuria was found in only 39% of the patients with hyperparathyroidism and only 29% of those with hypercalciuria had nephrolithiasis (9). on the other hand, the urinary excretion of calcium not necessarily differentiates patients with and without kidney stones because urinary excretion of calcium is only one of at least six factors that can cause urinary supersaturation of calcium salts leading to the formation of kidney stones. for this reason very high levels of urinary calcium excretion are no longer considered an indication for parathyroidectomy (9, 10). regarding the clinical management of the two forms of primary hyperparathyroidism while there are clear indications about the hypercalcemic classical form, where a relapsing form of nephrolithiasis is considered a clear indication to parathyroidectomy (10, 11), for the normocalcemic form there are currently insufficient data to recommend parathyroidectomy or just observation (12). on the other hand, also in some classical form of hypercalcemic hyperparathyroidism, when parathyroidectomy has not a sure indication or is not feasible or is refused by the patient, there is an option for adequate monitoring and prevention measures such as hydration and a dietary regimen with normalized calcium intake similarly to that recommended in the general population or for the use of specific drugs (1). pharmacological therapy consists mainly of bisphosphonates, which inhibit bone resorption and can increase bone density while lowering the blood concentration and urinary excretion of calcium (1) and calcimimetics, such as cinacalcet, which act as activators of the calcium-sensing receptor at level of both the parathyroid and the kidney and are capable of inducing a suppression of parathyroid secretion and thus reducing serum calcium levels, while increasing serum phosphorus (1, 13). cinacalcet can be used to normalize the serum calcium in patients with symptomatic hypercalcemia that they cannot be submitted to parathyroidectomy, particularly if bone density is normal, because this drug is not able to reduce the bone turn-over or to increase bone mineral density (13, 14). however, effects of cinacalcet on calciuria are not well known and in fact in a study of peacock et al. (14) urinary calcium was reduced in treated patients both in the first morning urine and in 24 hour urine, but this difference appeared statistically significant only for first morning urine. it is likely that the basis of such behavior is the complexity of the mechanism of action of cinacalcet that on one hand determines an increase in of calcium excretion but on the other hand reduces the levels of serum calcium and the filtered load of calcium (1). the finding of reduced urinary calcium in the early morning urine in absence of a reduction of calcium excretion in the 24-hour urine may be explained by the fact that the 24-hour urinary calcium reflects a component linked to intestinal absorption of calcium that appears to be increased in patients with hyperparathyroidism forming stones (15). to date, however, there is no data in the literature on what may be the consequence (in terms of change in the number and size of stones) arising from the use of cinacalcet in the forms of nephrolithiasis associated with both hypercalcemic and normocalcemic primary hyperparathyroidism (1, 11) the present pilot study was therefore intended to investigate possible direct effects on renal stone formation with the use of cinacalcet in the forms of nephrolithiasis associated with both hypercalcemic and normocalcemic primary hyperparathyroidism. materials and methods study design to evaluate the therapeutic effects of cinacalcet in patients with active nephrolithiasis associated with primary hyperparathyroidism were enrolled 10 patients equally divided between males (mean age 55.6 ± 8.3 years) and females (mean age 62.4 ± 11 8 years, all postmenopausal except one). four patients, equally divided between males and females, were affected by the hypercalcemic variant of primary hyperparathyroidism and the other six, which are also equally divided between males and females, were instead affected by the normocalcemic variant of hyperparathyroidism (table 1). criteria for inclusion and exclusion patients were considered eligible for the study if they had a documented active form of kidney stone disease (2 or more stones formed during the previous two years) associated to both hypercalcemic or normocalcemic primary hyperparathyroidism characterized by intact pth levels, as determined by the method immunoassay, consistently high (> 79.6 pg/ml). we excluded patients with known causes of secondary elevation of parathyroid hormone such as 25-hydroxyvitamin d deficiency (defined as serum 25-hydroxyvitamin d less than 20 ng/ml) (16), decreased creatinine clearance (defined as the finding of a gfr less than 50 ml/min) (14), use of drugs such as hydrochlorothiazide and lithium salts, gastrointestinal disorders associated to malabsorption of calcium and idiopathic hypercalciuria (defined as the presence of urinary calcium > 300 mg/24 h in men and 250 mg/24 h in women or urinary calcium levels in 24 hour urine greater than 4 mg/kg body weight for both sexes in the absence of known causes of hypercalciuria such as sarcoidosis, rapidly progressive osteoporosis, excessive intake of vitamin d or calcium, immobilization, hyperthyroidism, renal tubular acidosis and the presence of any neoplasm) (17). in this regard, we specify that in the study were also enrolled two patients (one male suffering from the hypercalcemic variant of hyperparathyroidism and a female affected by the normocalcemic variant hyperparathyroidism) with higher values of urinary calcium (> 4 mg/kg body weight). in order to exclude an elevation of pth secondary to hypercalciuria, before starting the study, we treated these patients for three months with a thiazide diuretic such as hydrochlorothiazide at a dose of 12.5 mg bis in die, according to coe et al. (17), and we were able to observe that despite the reduction of urinary calcium within normal limits, there was no decrease of parathyroid hormone that was further increased in association with an increase of serum calcium. on this basis we assumed that in such patients, as well as in at least another case already described in the study of coe et al. (17), hypercalciuria was not the cause of the elevation of pth thet was rather primitive and independent of the levels of calciuria since it remained unchanged in spite of the correction of hypercalciuria. such patients after brardi print_stesura seveso 02/04/15 10:25 pagina 67 archivio italiano di urologia e andrologia 2015; 87, 1 s. brardi, g. cevenini, t. verdacchi, g. romano, r. ponchietti 68 a wash out period without thiazide were then enrolled in the study. finally, the normocalcemic forms were defined by the presence of values of total serum calcium (corrected for albumin) within normal limits with respect to the laboratory reference range used (8.4 to 10.6 mg/dl) and hypercalcemic forms were defined after at least two consecutive determinations consistently high (18). study protocol written informed consent was required to all patients at the time of enrollment. at baseline, all patients maintained their usual meals and were subjected to a screening laboratory including the blood determination of urea nitrogen, creatinine, sodium, potassium, calcium, phosphorus, uric acid, total protein, protein electrophoresis, 25 hydroxy vitamin d and parathyroid hormone while in the 24-hour urine were measured creatinine, citrate, uric acid, calcium, phosphate, oxalate and magnesium, calcium/creatinine ratio and volume. in first morning urine was measured ph and were performed urine culture and brand test to exclude infectious forms or cystinuria. glomerular filtration rate was then calculated with ckd epi formula (19). renal ultrasound was performed to evaluate presence, number and larger diameters of stones and to exclude hydronephrosis. each patient was also subjected to medical examination with determination of weight, height and arterial blood pressure. the same blood and urine tests (except for the test of brand) and ultrasound examination of the urinary tract were repeated at the end of each of the successive periods of observation, when the patients were again subjected to medical examination with recording of weight, blood pressure and data related to compliance with therapy and diet and any adverse reaction to the treatment. since this was a case control study in which patients were controls of themselves, the subjects enrolled were directed to a first observation period of 10 months, during which were assigned to standard treatment with potassium citrate at a dose of 50 meq daily and/or allopurinol at a dose of 300 mg daily, when required by alterations emerged from the metabolic study. this regimen was associated at random but not blindly to cinacalcet administration. the dosage of cinacalcet was optimized for each individual patient to obtain a reduction of pth within normal limits while enabling the maintenance of adequate values of calcemia. at the end of the first observation period, cinacalcet therapy was added, for a second period of observation of the same length as the first, in patients who were not taking it, or withdrawn in patients who were assuming it in the first period. finally, in all patients, at the time of the basal visit was prescribed an equal dietary regimen based on a reduction of sodium intake, foods rich in oxalate and protein of animal origin, with normalized intake of calcium (0, 8-1 g daily) and increase in hydration (> 2 liters daily) by use of mineral waters with moderate calcium content (20). this dietary regimen is ideal for the prevention and the contrast of nephrolithiasis even when it is associated to a form of primary hyperparathyroidism. on the contrary low calcium diet was avoided because it exposes the patient to the risk of osteopenia and has an adverse effect on the risk of stone formation because of the increase of oxalate excretion due to increased intestinal absorption of calcium (1). the parameters used to evaluate the efficacy of therapeutic regimens and dietary regimen during each of the two observation periods were the differential variations of the above mentioned blood and urinary parameters as well as differential changes in the overall number of urinary calculi and the larger diameter of the stones. to accurately quantify the differential changes in the number of stones, spontaneous stone passages were also recorded, as evidence of the formation of new stones , in the absence of the detection of stones at the time of the entry in the study, as well as stone passages without changes in the total number of stones at the final ultrasound examination and also episodes of stone treatment with shock wave lithotripsy and/or surgical removal of stones during the follow-up period. data collection and statistical analysis all determinations were carried out at the laboratory of analysis of the s. donato hospital of arezzo using siemens kit for citraturia, uricosuria and oxaluria based on enzymatic methods and siemens kit for urinary calcium, phosphaturia and magnesuria based on colorimetric methods. determination of intact parathyroid hormone was instead performed by enzyme immunoassay (tosoh aia 900). descriptive statistics (means and standard deviation) for overall patients and group of patients were obtained. statistical comparisons for any significant difference between sexes, observation periods and subgroups with hypercalcemic and normocalcemic variant of hyperparathyroidism were performed. data distributions were normal to the kolmogorov-smirnov test and student t test was used for significant differences between the means of samples. the parametric t test has high power and is therefore able to reveal significant differences also with reduced samples, such as those of the study in question. for multiple paired comparisons the bonferroni correction was applied to at the level of statistical significance equal to 95% (p < 0.05). results all patients completed the two scheduled observation periods, no one was excluded because of intolerance or lack of compliance and during both observation periods no spontaneous expulsion of stones or fragments was recorded nor was necessary to practice any lithotripsy treatment and /or surgical procedure for removal of urinary calculi. effect of cinacalcet and other therapies and dietary recommendations on stone formation at the end of the observation period with cinacalcet a statistically significant reduction in the total number of stones in comparison with the total number at the end of the observation period without cinacalcet (number of stones at the end of the observation period without cinacalcet 3.2 ± 2.5 versus number of stones at the end of the period of observation with cinacalcet 2.3 ± 2.8; p = 0.019) and with the total number at enrollment (number of stones at enrollment: 3 ± 2.5 units vs. number of stones at the end of the observation period with cinacalcet 2.3 ± 2.8 units; p = 0.045) was found, while there was no change between this figure at enrollment and the one recorded at the end of the observation peribrardi print_stesura seveso 02/04/15 10:25 pagina 68 69archivio italiano di urologia e andrologia 2015; 87, 1 use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: pilot studt od without cinacalcet. at the end of the observation period with cinacalcet it was also found a statistically significant reduction of the larger diameter of stone in comparison with the period of observation without cinacalcet (diameter of larger stone at the end of observation period without cinacalcet: 0.78 ± 0.36 cm versus larger diameter of stone at the end of the observation period with cinacalcet: 0.47 ± 0.38 cm; p = 0.000) and at enrollment (larger diameter of stone at enrollment: 0.805 ± 0.21 cm versus larger diameter of stone at the end of the observation period with cinacalcet: 0.47 ± 0.38 cm; p = 0.002), while no there was no change between this figure at enrollment and the one recorded at the end of the observation period without cinacalcet (table 2). effect of cinacalcet and other therapies and dietary recommendations on biochemical parameters at the same time, as expected, a statistically significant reduction in serum calcium and parathyroid hormone was recorded at the end of the observation period with cinacalcet in comparison with both the observation period without cinacalcet (serum calcium at the end of the observation period without cinacalcet 10.2 ± 0.94 mg/dl versus serum calcium at the end of the period observation with cinacalcet: 8.9 ± 0.6 mg/dl; p = 0.000) (pth at the end of the period of observation without cinacalcet: 126.5 ± 73.3 pg/ml versus pth at the end of the period of observation with cinacalcet: 68.9 ± 38.7 pg/ml; p = 0.039) and at enrollment (serum calcium at enrollment: 10 ± 0.8 mg/dl versus serum calcium at the end of the observation period with cinacalcet: 8.9 ± 0.6 mg/dl; p = 0.000) (pth at enrollment: 136.3 ± 72.5 p /ml versus pth at the end of the observation period with cinacalcet: 68.9 ± 38.7 pg/ml; p = 0.016), while there was no variation between data at enrollment and data recorded at the end of the observation period without cinacalcet. a statistically significant increase of serum phosphorus and first morning urinary ph was observed when data at enrollment and data recorded at the end of the observation period with cinacalcet were compared (serum phosphorus at enrollment: 2.9 ± 0.69 mg/dl versus phosphorus at the end of the observation period with cinacalcet: 3.6 ± 0.6 mg/dl; p =0.001), (fasting urine ph at enrollment: 5.3 ± 0.47 versus fasting urine ph at the end of the observation period with cinacalcet: 6.5 ± 0.9; p = 0.039), whereas no change was found in the comparison between data found at the end of the observation period without cinacalcet and data at the end of the observation period with cinacalcet and in the comparison of data at enrollment and data at the end of the period without cinacalcet. finally a statistically significant reduction of uric acid excretion was found comparing data at enrollment and data observed at the end of the observation periods with and without cinacalcet (24-h urinary uric acid at enrollment: 509.1 ± 165.4 mg/24 h versus 24-h urinary uric acid at the end of the observation period without cinacalcet: 347 ± 118 mg/24 h; p = 0.024) (24-h urinary uric acid at enrollment: 509.1 ± 165.4 mg/24 h versus 24-h urinary uric acid at the end of the observation period with cinacalcet: 323 141 ± 6 mg/24 h; p= 0.031) whereas there was no change between the data found at the end of the two observation periods (table 2). comparison of hypercalcemic and normocalcemic hyperparathyroidism as expected, higher mean values of serum calcium (serum calcium at enrollment: 11 ± 0.16 mg/dl for the hypercalcemic variant versus 9.3 ± 0.35 mg/dl for the normocalcemic variant, p = 0.000; serum calcium at the end of the observation period without cinacalcet: 11.2 ± 0.25 mg/dl for the hypercalcemic variant versus 9.5 ± 0.24 mg/dl for the normocalcemic variant, p = 0.000; serum calcium at the end of the observation period with cinacalcet: 9 52 ± 0.35 mg/dl for the hypercalcemic variant versus 8.64 ± 0.50 mg/dl for the normocalcemic variant, p = 0.017) and lower mean values of serum phosphate (serum phosphate at enrollment: 2.23 ± 0, 30 mg/dl for the hypercalcemic variant versus 3.4 ± 0.40 mg/dl for the normocalcemic variant, p = 0.005; serum phosphate at the end of the observation period without cinacalcet 2.4 ± 0.50 mg/dl for the hypercalcemic variant versus 3.6 ± 0.49 mg/dl for the normocalcemic variant, p = 0.010; serum phosphate at the end of the observation period with cinacalcet 3.1 ± 0.20 mg/dl for the hypercalcemic variant versus 3.97 ± 0.59 mg/dl for the normocalcemic variant, p = 0.025) were observed in patients suffering from hypercalcemic variant of hyperparathyroidism than in those affected by the normocalcemic variant both at enrollment and at the end of the observation period with and without cinacalcet. similarly higher mean pth values in patients with the hypercalcemic variant of hyperparathyroidism than in those with the normocalcemic variant were found both at enrollment and at the end of the observation period without cinacalcet (pth at enrollment 191 ± 87.4 pg/ml for the hypercalcemic variant versus 99.9 ± 29.9 pg/ml for the normocalcemic variant, p = 0.042; pth at the end of the observation period without cinacalcet 191.4 ± 80.5 pg/ml for the hypercalcemic variant versus 83.3 ± 13.6 pg/ml for the normocalcemic variant, p = 0.011). conversly, at the end of the observation period with cinacalcet no statistically significant difference between the mean values of pth in the two variants of primary hyperparathyroidism was observed. finally, no statistically significant difference between the two variants of hyperparathyroidism for all other parameters taken into account, including the number and size of the stones, was found (table 3). results of the t test for equality of means between females and males t-test for equality of means between females and males led to the identification of a statistically significant difference only for the larger stone diameter that was greater in female subjects both at enrollment and at the end of the observation period with cinacalcet (larger diameter of stone at enrollment in female subjects: 0.94 ± 0.18 cm versus larger diameter of stone in males: 0.67 ± 0.15 cm; p = 0.027; larger diameter of stone at the end of the observation period with cinacalcet in female subjects: 0.71 ± 0.36 cm versus larger diameter of the stone after of the observation period with cinacalcet in males: 0.24 ± 0.24 cm; p = 0.038). brardi print_stesura seveso 02/04/15 10:25 pagina 69 archivio italiano di urologia e andrologia 2015; 87, 1 s. brardi, g. cevenini, t. verdacchi, g. romano, r. ponchietti 70 adverse reactions of treatment no problem related to adverse reactions or intolerance was reported in any of the two major therapeutic groups. tables posted in supplementary materials on www.aiua.it discussion this study, with the limits of a pilot trial conducted on a limited number of patients, shows, for the first time, the ability of cinacalcet, used in combination with a dietary regimen with a standardized intake of calcium, to reduce in a statistically significant way the total number of renal stones and the larger diameter of stones in patients with nephrolithiasis associated with primary hyperparathyroidism both in the normocalcemic and hypercalcemic variant. our data also shows the ineffectiveness, within the same period of comparison, of the traditional therapeutic and dietary approach. the aforementioned variations in the number and size of renal stones with the use of cinacalcet resulted associated to changes in the endocrine and metabolic parameters, as widely expected, with a statistically significant reduction in serum calcium and parathyroid hormone and a statistically significant increase of serum phosphorus (pth inhibits the tubular reabsorption of phosphorus and thus increases its urinary excretion) (21) and of urinary ph in the first morning urine (high levels of parathyroid hormone result in an initial transient renal acidosis which is offset by an increase in net acid excretion and the release of alkaline bases of bone resorptive origin) (22). as for the comparison between the two variants of hyperparathyroidism (normocalcemic and hypercalcemic), we observed, as expected, statistically significant higher values of serum calcium and statistically significant lower phosphorus values in patients with the hypercalcemic variant. values of parathyroid hormone were significantly higher in patients with the hypercalcemic variant of hyperparathyroidism than in those affected by the normocalcemic variant although this difference disappeared at the end of the observation period cinacalcet. absence of statistically significant difference between the mean values of parathyroid hormone in the two variants of hyperparathyroidism is a finding directly related to the use of cinacalcet at individually tailored dosages to achieve a normal range for pth. precisely, with the use of cinacalcet at an optimized dose for each patient in order to enable the achievement of values of parathyroid hormone in the normal range, as described above, and to mantain adequate values of calcemia, no statistically significant difference between the two forms of hyperparathyroidism in the number and size of stones was observed. therefore, the above reported findings should be explained by cinacalcet administered in association with a diet standardized in calcium intake at a average daily dose of 48.86 ± 30.09 mg titrated in each patient to achieve values of parathormone within the normal range and serum calcium levels as well within the limits of the normal range. obviously doses of cinacalcet were higher (and mostly refracted in two daily doses) in subjects suffering from the hypercalcemic variant of primary hyperparathyroidism (mean daily dose 63.75 ± 39.44 mg in two doses in 75% of cases with the hypercalcemic variant versus 38.92 ± 20.02 in two doses in 50% of cases with the variant normocalcemic variant). as mentioned in the introduction, although a factor which contributes to the formation of stones in primary hyperparathyroidism is hypercalciuria, the urinary excretion of calcium per gram of creatinine do not necessarily differentiate patients who associate or not nephrolithiasis to primary hyperparathyroidism (7-9). furthermore, although a high concentration of serum calcitriol linked to stimulation by pth of renal hydroxylation of 25-hydroxyvitamin d, can contribute both to hypercalciuria and the formation of kidney stones, as shown in a study of 50 patients (23), this finding has to be confirmed because it was not observed in another study carried out in an even greater population (24). there are no differences in serum parathyroid hormone, calcium or calcitriol in patients with hyperparathyroidism with and without associated nephrolithiasis, though hypercalciuria is more often found in the group suffering from kidney stones (9, 25). this evidence is confirmed by the results of this study clearly showing that cinacalcet used in combination with a diet with standardized calcium intake (and not other treatment or dietary recommendations or the combination of both) has induced a reduction in the number and size of stones in association with a correction within normal limits of normality of parathyroid hormone without changes of other metabolic parameters taken into account (except for the increase of ph in the first morning urine). significant changes in urinary calcium induced by cinacalcet were not expected in consideration of the mechanism of action of calcium mimetics that act as allosteric activators of the receptors for calcium by increasing the sensitivity of these to calcium ions (21). at renal tubular level the activation of the calcium-sensitive receptors leads to a reduction in the absorption of calcium and therefore to an increase in urinary calcium that appears counterbalanced however, in most patients, by the simultaneous decrease of the levels of pth and serum calcium induced by the same treatment with calcium mimetics (21). the fractional excretion of calcium depends on the interaction between filtered load and tubular reabsorption and cinacalcet acts on both mechanisms, by reducing the first, through a reduction in serum calcium, and the second with its action in the distal tubular with a final net effect of substantially unchanged (1). this was confirmed, by example, in the study of crockett et al. (26) where it was found that cinacalcet normalized serum calcium and safely lowered pth without increasing the urinary excretion of calcium in the study subjects and so proving the potential benefit of this medical treatment for primary hyperparathyroidism. in the prospective study by peacock et al. it was also reported minimal change in urinary calcium in patients treated with cinacalcet 30-60 mg daily, although there was a statistically significant reduction in fasting urinary calcium (14). only patients carrying the polymorphism arg990gly of the calcium-sensitive receptor, that leads to a permanent increase in the sensitivity of these receptors, respond more strongly to cinacalcet, and could be exposed to an increased risk of nephrolithiasis during treatment with calcium mimetics (21). brardi print_stesura seveso 02/04/15 10:25 pagina 70 71archivio italiano di urologia e andrologia 2015; 87, 1 use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: pilot studt hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. j clin endocrinol metab. 2005; 90:135. 15. clarita v. odvina, khashayar sakhaee, howard j. heller, et al. biochemical characterization of primary hyperparathyroidism with and without kidney stones. urol res. 2007; 35:123-128. 16. ross ac, taylor cl, yaktine al and del valle hb, eds. committee to review dietary reference intakes for vitamin d calcium institute of medicine. 2011 dietary reference intakes for calcium and vitamin d. in: dietary reference intakes. washington, dc 2011, the national academies press. 17. coe fl, canterbury jm, firpo jj, reiss e. evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. j clin invest. 1973; 52:134-42. 18. silverberg sj, bilezikian jp. evaluation and management of primary hyperparathyroidism. j clin endocrinol metab. 1996; 81:2036. 19. levey as, stevens la, schmid ch, zhang yl, castro af 3rd, feldman hi, kusek jw, eggers p, van lente f, greene t, coresh j, ckd-epi (chronic kidney disease epidemiology collaboration). a new equation to estimate glomerular filtration rate. ann intern med. 2009; 150:604. 20. charles yc pak. pharmacotherapy of kidney stones. expert opin. pharmacother. 2008; 9:1509-1518. 21.rothe hm, liangos o, biggar p, et al. cinacalcet treatment of primary hyperparathyroidism. int j endocrinol. 2011; 2011:415719. 22. hulter hn, peterson jc. acid-base homeostasis during chronic pth excess in humans. kidney int. 1985; 28:187. 23. broadus ae, horst rl, lang r, et al. the importance of circulating 1,25-dihydroxyvitamin d in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. n engl j med. 1980; 302:421. 24. silverberg sj, shane e, jacobs tp, et al. nephrolithiasis and bone involvement in primary hyperparathyroidism. am j med. 1990; 89:327. 25. peacock m. primary hyperparathyroidism and the kidney: biochemical and clinical spectrum. j bone miner res. 2002; 17 suppl 2:n87. 26. sajid-crockett s, singer fr, hershman jm. cinacalcet for the treatment of primary hyperparathyroidism.metabolism. 2008; 57:517-21. 27 mollerup cl, vestergaard p, frøkjaer vg, et al. risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. bmj 2002; 325:807. 28. vitale c, marangella m, varvello g, et al. effects of parathyroidectomy on citrate excretion in patients with primary hyperparathyroidism and calcium nephrolithiasis. ital j mineral electrolyte metab. 1992; 6:109-12. conclusions it is not possible to draw other conclusions from our study, in particular for the limited number of subjects enrolled and the limited period of observation, other that in subjects suffering from nephrolithiasis in association with primary hyperparathyroidism (both normocalcemics and hypercalcemics, with exception of the carriers of the polymorphism arg990gly) the normalization of parathyroid hormone induced by cinacalcet, used in combination with a diet with normalized calcium intake, allows to control the "primary cause" of the renal stone complication and thus achieve, as long as you continue therapy, a concrete clinical advantage in terms of reduction in the number and size of stones, similarly to what can be definitely achieved, with greater certainty, by surgical parathyroidectomy that is definitely associated with a significant risk reduction of calcium stones,frequent remission or reduction of relapses (27, 28). references 1. marangella m, vitale c. iperparatiroidismo primitivo e nefrolitiasi: vi è spazio per i calciomimetici? gtn&d 2009;. 1:25-29. 2. amaral lm, queiroz dc, marques tf, et al. normocalcemic versus hypercalcemic primary hyperparathyroidism: more stone than bone? journal of osteoporosis 2012, article id 128352, 4 pages. 3. natalie e. cusano, shonni j. silverberg, and john p. bilezikian. normocalcemic primary hyperparathyroidism. journal of clinical densitometry: assessment of skeletal health. 2013; 16:33e39. 4. silverberg sj, bilezikian jp. evaluation and management of primary hyperparathyroidism. j clin endocrinol metab. 1996; 81:2036. 5. parks j, coe f, favus m. hyperparathyroidism in nephrolithiasis. arch intern med. 1980; 140:1479. 6. gesek fa, friedman pa. on the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. j clin invest. 1992; 90:749. 7. bilezikian jp, brandi ml, rubin m, silverberg sj. primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. j intern med. 2005; 257:6. 8. silverberg sj, shane e, jacobs tp, et al. nephrolithiasis and bone involvement in primary hyperparathyroidism. am j med. 1990; 89:327. 9. ghada el-hajj fuleihan, shonni j silverberg, clifford j rosen, jean e mulder. clinical manifestations of primary hyperparathyroidism. www.uptodate.com. 2014 uptodate 10. bilezikian jp, khan aa, potts jt jr. guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. third international workshop on the management of asymptomatic primary hyperthyroidism. j clin endocrinol metab. 2009; 94:335. 11. shonni j silverberg, ghada el-hajj fuleihan, clifford j rosen, jean e mulder. management of primary hyperparathyroidism. www.uptodate.com. 2014 uptodate. 12. bilezikian jp, khan aa, potts jt jr. 2009 guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. j clin endocrinol metab. 94:335-339. 13. khan a, grey a, shoback d. medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. j clin endocrinol metab. 2009; 94:373. 14. peacock m, bilezikian jp, klassen ps, et al. cinacalcet correspondence simone brardi, md sibrardi@gmail.com hemodialysis unit, s. donato hospital, arezzo, italy gabriele cevenini, md cevenini@unisi.it department of surgery and bioengineering, university of siena, siena, italy tiziano verdacchi, md tiziano.verdacchi@usl8.toscana.it extracorporeal shock wave lithotripsy unit, s. donato hospital, arezzo, italy giuseppe romano, md giuseppe.romano@usl8.toscana.it urology unit, s. maria della gruccia hospital, montevarchi, italy roberto ponchietti, md ponchietti@unisi.it postgraduate nephrology school, university of siena, siena, italy brardi print_stesura seveso 02/04/15 10:25 pagina 71 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 156 original paper change of practice patterns in urology with the introduction of the da vinci surgical system: the greek nhs experience in debt crisis era dimitros deligiannis, ioannis anastasiou, vasileios mygdalis, evangelos fragkiadis. konstantinos stravodimos 1st department of urology, university of athens, medical school “laiko” hospital, athens, greece. objective: to determine the attitudinal change for urologic surgery in greece since the introduction of the da vinci surgical system (dvs). we describe contemporary trends at public hospital level, the initial greek experience, while at the same time greece is in economic crisis and funding is under austerity measures. materials and methods: we retrospectively analyzed annualized case log data on urologic procedures, between 2008 (installation of the dvs) and 2013, from “laiko’’ hospital in athens. we evaluated, using summary statistics, trends and institutional status regarding robot-assisted surgery (ras). we also analyzed the relationship between the introduction of ras and change in total volume of procedures performed. results: 1578 of the urological procedures performed at “laiko’’ hospital were pooled, 1342 (85%) being open and 236 ras (15%). we observed a 6-fold increase in the number of ras performed, from 7% of the total procedural volume (14/212) in 2008 to 30% (96/331) in 2013. for radical prostatectomy, in 2008 2% were robot-assisted and 98% open while in 2013, 46% and 54% respectively. pyeloplasty was performed more often using the robot-assisted method since 2010. ras-dedicated surgeons increased both ras and the total number of procedures they performed. from 86 in 2008 to 145 in 2013, with 57% of them being ras in 2013 as compared to 13 % in 2008. conclusions: robot-assisted surgery has integrated into the armamentarium for urologic surgery in greece at public hospital level. surgical robot acquisition is also associated with increased volume of procedures, especially prostatectomy, despite the ongoing debate over cost-effectiveness, during economic crisis and international monetary fund (ifn) era. key words: urology in greece; da vinci; practice patterns; prostatectomy; robot-assisted surgery. submitted 13 october 2014; accepted 30 november 2014 summary no conflict of interest declared. cardiac, gynecological and general surgeons also using the dvs in practice (1). since the first reports, ras has become a fundamental part of urologic surgery with initial enthusiasm changing to a broad acceptance (22). there is an increasing adoption of ras with robot-assisted radical prostatectomy (rarp) being the most commonly carried out robotic procedure worldwide, with increasing numbers performed each year (1, 5). robot-assisted radical nephrectomy (ran) is showing also an increasing development (2). the robot has also allowed non-experienced surgeons to successfully perform robotassisted pyeloplasty (rpyel) with excellent results (3, 4). other procedures also performed are partial nephrectomy and cystectomy. there is limited knowledge about how the diffusion of robotics has influenced urological individual practice patterns in greece. the first da vinci surgical system (dvs) in a public hospital in greece was installed in july of 2008 at “laiko’’ hospital in athens. there are seven more installed in greece, all based in private hospitals. most procedures currently being carried out are urological with general surgeons also using the system, mostly for bariatric procedures. urologists have been quick to embrace this novel technology and rarp is the most commonly carried out robotic procedure, followed by rpyel, ran and robot-assisted nephro-ureterectomy (rnut). this is extremely interesting taking into account the fact that greece is suffering from economic crisis and funding is under austerity measures proposed by the international monetary fund (imf) (23). using retrospective case log data from “laiko’’ hospital, in this study we seek to determine practice patterns in open and robotic urologic surgery in greece since the installation of the dvs. this study examined contemporary trends in a public hospital in greece and the relationship between robot acquisition and changes in the total procedural volume. materials and methods data for our study we obtained annualized case log data on urologic procedures between 2008, when the dvs was doi: 10.4081/aiua.2015.1.56 introduction there is increasing patient and surgeon interest in minimally-invasive techniques, particularly with the introduction of the da vinci surgical system in 2001. the majority of procedures carried out are urological, with deligiannis_stesura seveso 02/04/15 10:23 pagina 56 57archivio italiano di urologia e andrologia 2015; 87, 1 the da vinci in urology in greece in debt crisis era installed, and 2013, from “laiko’’ hospital in athens, greece. we identified six urologic surgeons who performed the procedures, two of whom were ras-dedicated surgeons with specialized training. the procedures that were pooled and analyzed, open and robot-assisted respectively, are: prostatectomy, nephrectomy, nephroureterectomy and pyeloplasty. patient characteristics were not recorded or analyzed at this instance. methods we used summary statistics to describe current practice patterns, after stratifying the surgical procedures with regard to the following variables: a) the surgeon who performed the procedure (dedicated ras or not); b) open or robot-assisted surgery; c) type of procedure: prostatectomy, nephrectomy, nephro-ureterectomy and pyeloplasty. we analyzed trends in open and ras in each type of procedure. especially in prostatectomy and pyeloplasty, where a large attitudinal change seemed to exist. we also analyzed trends regarding each surgeon separately, especially the two ras-dedicated surgeons. furthermore, we determined the relationship between the introduction of ras and change in the total volume of procedures performed at “laiko’’ hospital. results 1578 of the urological procedures that were performed at “laiko’’ hospital in athens, greece, between 2008 and 2013, of whom 1342 (85%) were open and 236 ras (15%), were pooled and studied. these procedures were prostatectomy, open and ras (rrprarp), nephrectomy, open and ras (orn-ran), nephro ure te recto my, open and ras (onutralnu) and pyeloplasty, open and ras (opyel-rlpp), respectively. we identified six surgeons. sur geons a and b, were rasdedicated surgeons, surgeons c and d performed exclusively open procedures and the other two, surgeons e and f, performed mostly open procedures and rather occasionally ras. surgeons a and b were 50 and 48 years old respectively, having specialized training in laparo scopy and urologic robotics. they performed 199 ras of a total of 236 robot-assisted procedures between 2008 and 2013 (84%). surgeons c and d were 57 and 56 years old respectively, without specialized training and performed exclusively open procedures. surgeons e and f were 59 and 45 years old respectively and performed the remaining 37 ras (16%), having basic training in robotics and having the ras-dedicated surgeons as actors-proctors. a large increase in the number of urological procedures performed with robotassisted approach during the 6-year study period was recorded. in 2008, urologists performed 198 open procedures and 14 ras, which is 7% of the total procedural volume. this percentage gradually increased to 9% in 2009, 11% in 2010, 18% in 2012. in 2013, which was the last year studied, 235 open procedures and 96 ras were performed, with ras being 30 % of the total procedural volume. there was an almost 6-fold increase in ras from 2008 to 2013, but also an increase by 56% in the total procedural volume. however, we observed that there was a clear downward trend in ras in 2010-2011 that is attributed to the beginning of the dept crisis era in greece. in fact, the dvs was not operating for a major period from 2010 to 2011, due to lack of funds for yearly maintenance and supply of disposal instrumentation. even though this adverse conjuncture, there was a large increase in the number of ras performed during the 6year study period. furthermore, we observed that after the introduction of the dvs at “laiko’’ hospital and especially after 2012 when it was in use again, there was a significant increase in the total number of procedures performed by the six high-volume surgeons, from 212 procedures in 2008 to 331 in 2013. figures 1 and 2 show the relationship between open, ras procedures and the total procedural volume from 2008 to 2013. type of procedure when stratifying the procedures by type, we observed a noticeable change both in the annual proportion of prostatectomies and pyeloplasties performed using the robot-assisted method and in the total volume, from 2008 to 2013. figure 1. ras compared to open and total procedural volume from 2008 to 2013. figure 2. ras compared to total procedural volume each year 2008; 7%, 2010: 11%, 2013: 30%. deligiannis_stesura seveso 02/04/15 10:23 pagina 57 archivio italiano di urologia e andrologia 2015; 87, 1 d. deligiannis, i. anastasiou, v. mygdalis, e. fragkiadis. k. stravodimos 58 prostatectomy figure 3 shows the evolution of radical prostatectomy (rp) performed open and robotassisted, from 2008 to 2013. in 2008 urologists in “laiko’’ hospital, performed a total of 94 rp, two of them being ras (2%). in 2013 they performed 124 rp, 57 of them being ras, which is 46% of the total volume of procedures and 67 open, which is 54% of the total procedural volume. we observed a dramatic increase both in the total number of rp during the 6-year study period and in the number of ras. thus in 2013 there was a 27-fold increase in rarp and the number of rarp was almost equal to that of open rp. figure 4 shows, the increase in the total number of rp’s performed at “laiko’’ hospital after the introduction of the dvs and especially after 2012, when it was in broad use again. we recorded that the increase is attributed mostly to the two ras-dedicated surgeons and consequently to the rarps they performed, since the other surgeons and especially those performing exclusively open procedures kept almost steady the number of procedures they performed reaching a plateau. pyeloplasty figure 5 shows the attitudinal change in pyeloplasty from 2008 to 2013 in “laiko’’ hospital with the use of the dvs. in 2008, only two pyeloplasties were performed, both with the robot-assisted method. in 2010, pyeloplasties were done more often with the robot-assisted method rather than open, while in 2013 eight out of nine procedures performed were robot-assisted (89%). ras dedicated surgeons figure 6 shows the procedures performed by the two ras-dedicated surgeons, a and b, from 2008 to 2013. a large increase in the number of ras done was identified. they gradually decreased the number of open procedures and increased the number of ras performed and consequently in 2013, they performed more ras than open procedures. furthermore, the two ras-dedicated surgeons increased the total procedural volume performed by them from 86 procedures in 2008 to 145 in 2013, with 13% of then being ras in 2008 and 57% in 2013. the introduction and use of the dvs resulted in more patient seeking treatment at “laiko’’ hospital in order to undergo ras and consequently as the numbers of ras increased, the total procedural volume increased also. the annual proportion of procedures done by surgeon a increased by almost 70%, with a large increase in the number of ras, during the 6-year study period. the percentage of ras cases he performed increased from 13% in 2008 to 72% in 2013. at the same time there figure 3. the evolution of open and robot-assisted radical prostatectomy. figure 4. radical prostatectomies performed both open and ras by the six surgeons from 2008 to 2013. figure 5. evolution in the numbers of open and ras pyeloplasty. figure 6. procedures done open and ras by the 2 ras dedicated surgeons and the comparison with the total procedural volume. deligiannis_stesura seveso 02/04/15 10:23 pagina 58 59archivio italiano di urologia e andrologia 2015; 87, 1 the da vinci in urology in greece in debt crisis era was a 20-fold increase in the number of rarp, especially after 2012 and an increase in the total volume of radical prostatectomies by 36%, as fi gure 7 shows. surgeon b, increased his ras cases from 12% in 2008 to 39% in 2013. he decreased the number of open rp, increased the number of rarp by 10-fold and the total number of rps by 50%. discussion since the fda clearance for the dvs in prostate surgery was granted in 2001 (7, 11), urology has seen a dramatic clinical expansion and explosion of ras and especially its greatest application with rp. other studies have previously examined practice patterns in minimally invasive surgery in financially-advanced countries: one survey of urologists in the midwest united states in 2003 regarding laparoscopic surgery (2, 17), a study in 2012 in the us about current trends in rarp (9) and a survey in 2014 about urologic laparoscopy in germany, austria and switzerland (18). thus one of the major advantages of the present study is that it gives us the first results of the use of the dvs, in a country in debt crisis with austerity measures and funding being under the imf guidance (23). comparative studies have suggested ras to have proven benefits compared to open procedures (3). most important of them being decreased blood loss, decreased postoperative pain, shorter hospital stay, faster mobilization and faster recovery of the patient and less wound complications. likewise, similar advantages have been demonstrated for rarp in several studies (11-13). furthermore, decreased blood loss, fastest recovery of urinary incontinence and more effective nerve-sparing technique, are the most important advantages of rarp (24-26). no difference in terms of oncologic outcomes has been reported (11, 14). the most important drawbacks of the dvs is the substantial cost, its long setup time and mostly longer operation (2, 3, 16). the robot itself costs about $1,3-$1,5 million, with yearly maintenance fee of $100,000, and a recurring cost of $400 to $1200 per case for disposable instrumentation, depending upon the procedure (16). rarp remains the most commonly performed ras with increasing numbers performed each year. while 1500 rarp were performed in the united states in 2000, that number increased to 8000 in 2004 and 50000 in 2007 (2, 8). in 2010, 67% of rp were done robotically in the u.s. with a substantial increase in the total number of procedures performed (9). the most commonly reported estimates from seer (surveillance, epidemiology and end results)medicare are not current, but show that minimally invasive rp rate increased from 9% in 2003 to 42% in 2006 (9, 19). indeed, most urologists declare rarp to be the gold standard for prostatectomy (2). it has surpassed open rp, despite the lack of prospective evidence showing its oncologic advantages or cost-effectiveness (9, 14). robot-assisted nephrectomy is a more recent development of robotic urologic surgery (2), but the technical advantages over the standard laparoscopic procedure are less evident than those of rp (10). it is interesting that robot-assisted partial nephrectomy (pn) seems to have now supplanted laparoscopic pn as the most common minimally invasive approach for pn (21). greek citizens had the opportunity to have free access to the dvs via public health services after the installation of the system at “laiko’’ hospital in athens, a public hospital, in july 2008. our analysis of case log data from “laiko’’ hospital provides insight into contemporary practice patterns of greek urologists, regarding robot-assisted surgery. the most important study finding is the substantial increase in the number of ras in this 6-year period. as well, an increase in the total volume of procedures done during the study was also observed. we found that ras dedicated urologists who performed ras and especially rarp had a higher annual volume than those who performed only open procedures. based on these finding and those of others (9, 19, 20), it appears that the uptake of robotics has contributed to the centralization of urological procedures (mostly rp) in the hands of higher volume surgeons. indeed, surgeons who performed ras in our study had a higher volume and a greater absolute number of procedures. apart from urologists with specialized training, other surgeons who had basic training in robotics also performed ras depending probably on the affiliation with the academic hospital, the existence of the dvs and the existing surgical skills, having the ras-dedicated surgeons as actors-proctors. significant factors that contributed to the prevalence of ras in urology in “laiko’’ hospital, as mentioned by previous similar studies (18), were: use of trained personnel (nurse, anesthesiologist), structured training programs (in cooperation with karolinska university hospital, stockholm, sweden), dedicated operating room, organized surgery schedule exclusively for ras. the benefits of ras for the patients are proven and undeniable, especially for rarp. there is also increasing interest and desire from the patients to have a robot-assisted surgery after the introduction of the dvs. in order to keep in touch with the figure 7. surgeons’ a practice patterns regarding radical prostatectomy. deligiannis_stesura seveso 02/04/15 10:23 pagina 59 archivio italiano di urologia e andrologia 2015; 87, 1 d. deligiannis, i. anastasiou, v. mygdalis, e. fragkiadis. k. stravodimos 60 novel technology and patients’ selection for minimally invasive techniques, urologists at “laiko’’ hospital switched towards ras in line with developed countries worldwide. as a result and due to the broad use of the dvs in urologic surgery, an increasing number of patients are turning to the greek national health system, seeking treatment mostly for rp. the effort made in “laiko’’ hospital and the results are being highlighted by the fact that over the last years the adverse conjuncture of debt crisis in greece has led to dramatic changes in health care system (23). it has to be mentioned, that the activity of the dvs was suspended for almost 1 year from 2010 to 2011. even though, the study suggests that ras has become a surgical standard in urology in the greek national health system (nhs), especially for procedures such as radical prostatectomy, where the benefits are proven and undeniable (3, 15). due to austerity measures, a very few resources were available for public health in greece. on the other hand, surgeons at “laiko’’ hospital had to be consistent with the university setting and the educational element of the hospital. so, despite cost cuts they transferred funds in order to keep in touch with technology and sustain in use the dvs. a limitation of this study is its retrospective design. moreover it is a purely descriptive study, lacking any clinical or pathological data that would provide valuable clinical information. selection bias could be considered the specific types of procedures pooled and examined, not including the whole armamentarium of urologic surgery. the number of procedures done open and ras are rather small. however, this study highlights the development of ras in a public hospital in a country at dept crisis. therefore it could be a stepping stone for a cost-effectiveness analysis of the dvs in the context of public national health system hospitals. conclusions robotassisted surgery using the dvs has integrated into the minimally invasive armamentarium for urologic surgery in greece at national hospital level, in line with developed countries worldwide. its greatest application is seen in radical prostatectomy and pyeloplasty. there is attitudinal change towards ras, which is combined with an increase in the total volume of procedures performed, which is mostly attributed to the experience gradually gained, the undeniable benefits for the patients and patients’ desire. surgeon characteristics and practice patterns have a clear role in the type of the procedure performed, as ras-dedicated surgeons have dramatically increased both the number of ras and the total procedural volume performed. the significant recession and debt crisis in greece this period highlights the value of this study, showing the increasing use of ras despite the ongoing debate over its usefulness and cost-effectiveness, in a country with strict austerity measures. references 1. murphy dg1, hall r, tong r, et al. robotic technology in surgery: current status in 2008. anz j surg. 2008; 78:1076-1081 2. yuh be, hussain a, chandrasekhar r, et al. comparative analysis of global practice patterns in urologic robot-assisted surgery. j endourol. 2010; 24:1637-1644. 3. thiel dd, winfield hn. robotics in urology: past, present and future. j endourol. 2008; 22:825-30. 4. bentas w, wolfram m, brautigam r, et al. da vinci robot assisted anderson-hynes dismembered pyeloplstay: technique and 1 year follow-up. world j urol. 2003; 21:133. 5. intuitive surgical. intuitive surgical investor report 2007. available from url: http://investor.intuitivesurgical.com/phoenix. zhtml?c=122359&p=irol-irhome (accessed 5 january 2008). 6. davies bl, hibberd rd, copcoat mh, wickham je. a surgeon robot prostatectomy-a laboratory evaluation. j med engtechnol. 1989; 13:273. 7. davies bl, hibberd rd, ng ws, et al. the development of a surgeon robot for prostatectomies. procinst mech eng. 1991; 205:35. 8. wexnersd, bergamashi r, lacy a, et al. the current status of robotic pelvic surgery: results of a multinational inter-disciplinary consensus conference. surg endosc. 2009; 23:438-443. 9. lowrance wt, eastham ja, savage a, et al. contemporary open and robotic radical prostatectomy practice patterns among urologists in the united states. j urol. 2012; 187:2087-2092. 10. poon sa, silberstein jl, chen ly, et al. trend in partial and radical nephrectomy: an analysis of case logs from certifying urologists. journal of urology. 2013; 190:464-469. 11. subhasis g, diptendra ks. current status of robotic surgery. indian j surg. 2012; 74:242-247. 12. ahleringte, woo d, eichel l, et al. robot-assisted versus open radical prostatectomy: a comparison of one surgeon’s outcomes. urology. 2004; 63:819-822. 13. menon m, tewari a, baise b, et al. prospective comparison of radical retropubic prostatectomy and robot-assisted anatomic prostatectomy: the vattikuti urology institute experience. urology. 2002; 60:864-868. 14. ficarra v, novara g, fracalanza s, et al. a prospective, nonrandomized trial comparing robot-assisted laparoscopic and retropubic radical prostatectomy in one european institution, bju int. 2009; 104:534-539. 15. farnham sb, webster tm, herrell sd, smith ja. intraoperative blood loss and transfusion requirements for robotic-assisted radical prostatectomy. urology. 2006; 67:360 16. thaly r, patel vr, shah kk. the robotic revolution: advancing laparoscopy nad urology further into the future. contemp urol. 2006; 18:28. 17. wang ds, winfield hn. survey of urological laparoscopic practice patterns in the midwest. j urol. 2004; 172:2282-2286. 18. imkamp f, herrmann trw, stolzenburg ju, et al. development of urologic laparoscopy in germany, austria, and switzerland: a survey among urologists. world j urol. 2014;doi 10.1007/s00345014-1250-4 19. makarov dv, yu jb, desai ra, et al. the association between diffusion of the surgical robot and radical prostatectomy rates. med care. 2011; 49:333. 20. stitzenberg kb, wong yn, nielsen me, et al. trends in radical prostatectomy: centralization, robotics, and access to urologic cancer care. cancer. 2011; 118:54. deligiannis_stesura seveso 02/04/15 10:23 pagina 60 61archivio italiano di urologia e andrologia 2015; 87, 1 the da vinci in urology in greece in debt crisis era 21. ghani kr, sukumar s, sammon jd, et al. practice patterns and outcomes of open and minimally invasive partial nephrectomy since the introduction of robotic partial nephrectomy: results from the nationwide inpatient sample. j urol. 2014; 191:907-913. 22. guru ka, hussain a, chandrasekhar r, current status of robotassisted surgery in urology: a multi-national survey of 297 urologic surgeons. can j urol. 2009; 16:4736-41. 23. kentikelenis a, karanikolos m, reevers a, greece’s health crisis: from austerity to denialism. the lancet. 2014; 383:748-753. 24. novara g, ficarra v, wilson tg. systematic review and metaanalysis of perioperative outcomes and complications after robotassisted radical prostatectomy eur urol. 2012; 62:431-52. 25. ficarra v, novara g, rosen rc. systematic review and metaanalysis of studies reporting urinary continence recovery after robotassisted radical prostatectomy eur urol. 2012; 62:405-17. 26. ficarra v, novara g, montorsi f. systematic review and metaanalysis of studies reporting potency rates after robot-assisted radical prostatectomy eur urol. 2012; 62:418-30. correspondence dimitros deligiannis, md (corresponding author) d.delijohn@yahoo.gr ioannis anastasiou, md ekati2@otenet.gr vasileios mygdalis, md vasmig@gmail.com evangelos fragkiadis, md frangiadis@yahoo.com konstantinos stravodimos, md kgstravod@yahoo.com 1st department of urology, university of athens, medical school “laiko” hospital, 17 agiou thoma str., 11527 athens (greece) deligiannis_stesura seveso 02/04/15 10:23 pagina 61 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3210 original paper once-a-day tadalafil administration improves the spermogram parameters in fertile patients antonio corvasce 1, 2, giuseppe albino 1, teresa leonetti 2, agnese filomena buonomo 2, ettore cirillo marucco 1 1 unit of urology, “l. bonomo” hospital, asl bat, andria, italy; 2 centre of andrology and reproductive pro.andròs certified iso 9001-2008 certified sia. objectives: we explored the safety of tadalafil once-daily treatment for 12 week and its effects on semen quality in a clinical subpopulation of men with psychogenic erectile dysfunction (ed). patients and methods: twenty-seven men, between 19 and 35 years, unaware of their fertility status, suffering from psychogenic ed were enrolled. the examination of the seminal fluid was performed twice before administration of tadalafil and twice after three months of continuous daily administration of tadalafil 5 mg. the volume of the seminal fluid, the concentration of sperm, the concentration of sperm with type “a+b” motility, the concentration of sperm with type “a” motility, the concentration of normal sperm were taken into consideration. the results before treatment with tadalafil (t0) and after 3 months of treatment (t3m) were compared. results: the administration of once-daily tadalafil 5mg, brings to an average increase of the total number of sperm cells, both total and fast motility (type a) and the percentage of nemasperms, and to an average increase of semen volume of only 0.41 ml. these quantitative and qualitative improvements of the seminal fluid resulted statistically significant as regard motility, nemasperm percentage and seminal fluid volume. no unespected safety findings were observed. conclusions: tadalafil administration improves the quality of sperm cells and seminal fluid: in particular motility, percentage of nemasperms and volume of seminal fluid. we emphasize the safety of the once-daily treatment with tadalafil 5mg and the positive effects on spermatogenesis. key words: pde5 inhibitor; tadalafil; spermiogram. submitted 6 february 2015; accepted 31 march 2015 summary no conflict of interest declared. effects have been amply demonstrated. its daily administration has a dual effect: the curative effect on the organic erectile dysfunction with predominant vascular component, and the reduction of the psychological influence that, on the contrary, the on-demand administration can enhance. sperm motility is a significant parameter for the assessment of the fertilizing capacity of the subject under examination, just like the concentration and morphology of the sperm cells. the camp plays a role for the upregulation of tyrosine phosphorylation, that determines the sperm capacitation and motility. recently, it has been tried to influence the phosphorylation of tyrosine to increase sperm motility of normo or asthenic semen samples using pentoxifylline, which is a pde inhibitor. yunes (5) suggests that the increased motility determined by pentoxifylline is mediated by the tyrosine phosphorylation in the sperm tail. the levels of camp are regulated by two metabolic reactions: synthesis from atp through the adenylyl cyclase and its degradation by its cyclic nucleotide (6). this study has the aim to test the effects of the daily administration of a pde inhibitor like tadalafil 5 mg on semen quality. materials and methods the aim of the study was to evaluate the effects of tadalafil 5 mg/daily administered for 3 consecutive months on semen quality in fertile patients. twentyseven young patients, from 19 to 35 years, were enrolled (average 29.6 years) suffering from psychogenic erectile dysfunction. they were not aware of their fertility status. their consent to perform the semen analysis was obtained. they were fertile according to the evaluation criteria of the who 2010 (7), with a sperm concentration exceeding 15.000.000/ml., a progressive motility (a+b type) ≥ 35%, volume > 1.5 ml, and normal morphology > 4%. inclusion criteria were: general state of good health, none chronic medical therapy in the period of three months before the first semen analysis, absence of morphological or vascular alterations at the doppler ultrasonography, fsh, lh and testosterone levels in the normal range, age not exceeding 35 years. exclusion cridoi: 10.4081/aiua.2015.3.210 introduction tadalafil is a phosphodiesterase 5 (pde5) inhibitor and it is specifically used for treatment of erectile dysfunction (ed). additional beneficial effects have been reported in other fields different from andrology, such as in the treatment of pulmonary hypertension (1), luts (2), raynaud's syndrome (3). on the contrary, no adverse effects on spermatogenesis and on the production of sexual hormones were proven (4). due to its characteristics of duration of action it may be administered daily rather than on-demand. good tolerability and very few side corvasce_stesura seveso 23/09/15 12:34 pagina 210 211archivio italiano di urologia e andrologia 2015; 87, 3 once-a-day tadalafil administration improves the spermogram parameters in fertile patients. teria were: smoking, chronic alcoholism, drug use, history of cryptorchidism, prostatitis and infectious-inflammatory diseases of the genitals, varicocele (also already solved surgically), sexually transmitted diseases, urinary tract infections, leucocyturia, leukocytospermia. the diagnosis of psychogenic erectile dysfunction has been confirmed by the administration of the iief questionnaire, anamnesis, physical examination and dynamic penile ultrasound doppler with10 mcg of pge1. methods of collection and analysis of the semen sample the spermatogenic cycle is completed within about 72 days (8), so we considered sufficient to assess the effects of chronic administration of tadalafil 5 mg for 3 months, thus covering the whole maturation cycle of the single sperm. the examination of the seminal fluid was then performed twice before administration of tadalafil (after two weeks from the first one) and twice after three months of continuous daily administration of 5 mg tadalafil (always at a distance of two weeks), always by the same operator in the same laboratory (the centre of andrology and reproductive pro.andròs certified iso 90012008 and certified sia) in accordance with who guidelines 2010. so ultimately each patient was subjected to four tests of the seminal fluid, before and immediately after the administration of three months of tadalafil 5 mg, once-a-day. the collection of the liquid has been rigorously performed in the centre with a planned withdrawal for 4 days, via masturbation, after cleaning the genitals with liquid soap at physiological ph. the ejaculated fluid was collected directly into sterile containers for urine culture. adverse effects or side effects for all subjects of the study there were no significant variations of the side or unwanted effects of tadalafil compared to those described in the literature. in any case, no one was forced to discontinue administration, demonstrating the good tolerability of 5 mg, once-a-day. results during the administration of tadalafil no unespected safety findings were observed. of each semen analysis, the volume of the seminal fluid (ml), the concentration of sperm (millions of sperm/ml), the concentration of sperm with type “a+b” motility, the concentration of sperm with type “a” motility, the concentration of normal sperm were taken into consideration. the average results of the two spermiograms before treatment with tadalafil (average t0) and the average results of the two spermiograms after 3 months of treatment (average t3m) were calculated. the "t0 average results" were compared with the "t3m average resuls" and the differences were calculated. the mean values of pre-treatment spermiograms (spermiogram i and ii) were compared with the average values of spermiograms at the 10th and 12th week of treatment with tadalafil 5 mg (spermiogram iii and iv). the results were subjected to analysis of variance using "student's test". the differences are statistically significant (table 1) what we observed is even more evident in the diagrams that compare the confidence intervals (ci) and the averages of spermiograms’ parameters before and after therapy (table 2). as showed in the reported diagrams reported, the confidence intervals (ci) tend to overlap, but with the averages shifted upward, as it is shown by the graphs that describe the changes in each subjects (an example is in table 3) discussion tadalafil (cialis®) is used in the treatment of erectile dysfunction as a potent, reversible, competitive inhibitor of phosphodiesterase 5 (pde5), an enzyme that inactivates pre post treatment treatment difference concentration millions/ml 44 48.7 +4.7 n.s. a + b motility % 53.94 57.59 +3.6% p < 0.05 type a % 32.44 35 +2.6% n.s. normal morphology % 48.91 54.74 +5.8 p < 0.05 volume ml 1.97 2.38 +0.41 p < 0.001 table 1. table 2. corvasce_stesura seveso 23/09/15 12:34 pagina 211 archivio italiano di urologia e andrologia 2015; 87, 3 a. corvasce, g. albino, t. leonetti, a.f. buonomo, e.c. marucco 212 cyclic guanosine monophosphate (cgmp) (9, 10). inhibition of pde5 in the corpus cavernosum of the penis increases intracellular cgmp levels, thereby facilitating relaxation of smooth muscle and leading to penile erection (11, 12). clinical trials with tadalafil administered orally on-demand to patients with erectile dysfunction have demonstrated enhanced erectogenic response in both the clinic setting and the at-home setting (13, 14). the recent interest of many authors to demonstrate the causal link between ed and luts has also led to reevaluate the presence of nos not only in the endothelium and smooth muscle cells of the corpora cavernosa, but also in the prostate, in the bladder and in the testicular parenchyma. to show the causal relationship between ed and luts with a biological plausibility one of the most studied theories is “the nitric oxide synthase (nos)/no theory”. this hypothesis attempts to explain the link between ed and luts by the reduced production of nos/no in the pelvis, including the penis, the bladder and the prostate (15). no is a multifunctional molecule originally described as a vasodilator (16). it is synthesized from its precursor l-arginine via nos, which exists in three isoforms; two are constitutively expressed in endothelial (enos) and neuronal (nnos) structures, and produce small amounts of no, whereas inducible nos (inos) is induced by cytokines, infection or other stimuli, and produces large amounts of no (17). it is widely accepted that no is important in the relaxation of corpus cavernosum smooth muscle and vasculature. neurogenic no is considered the main factor responsible for the immediate relaxation of corpus cavernosum, while endothelial no is essential for maintaining relaxation (18). conditions associated with reduced function of nerves and endothelium, e.g. ageing, hypertension, smoking, hypercholesterolaemia and diabetes, can cause circulatory and structural changes in penile tissues, resulting in ed. no is also present in the human prostate and bladder and putatively modulates smooth muscle tone. histochemical staining and immunohistochemistry confirmed dense nitrinergic innervation of glandular epithelium, fibromuscular stroma and blood vessels in the normal human prostate (19). we are interested to the effect of no on fertility. liman et al. (20) studied the cellular localization of the endothelial (enos) and inducible (inos) forms of nitric oxide (no) synthase in the cat testis, using enzyme histochemical and immunohistochemical techniques. stagedependent nuclear and cytoplasmic enos/inos immunoreactivity were found in all germ cells, including spermatogonia, primary spermatocytes (preleptotene, zygotene, and pachytene spermatocytes), and round and elongating spermatids of the seminiferous epithelium. the pachytene spermatocytes exhibited strong positive reactions at all spermatogenic stage. interestingly, in elongated spermatids enos and inos immunostainings was observed only in the cytoplasm but not in the nuclei. enos and inos immunolabeling was observed in the acrosomal vesicle of some round spermatids and in the acrosomal cap of elongating spermatids at stage ii. positive reactions were also observed in the sertoli and leydig cells as well as in other tissues including vascular endothelial and smooth muscle cells and peritubular myoid cells. these results suggest that no may play an important role in chromatin condensation, spermatid shaping, and the final release of sperm from the spermatogenic epithelium. furthermore, no may also be involved in spermiogenesis, steroidogenesis, and apoptotic cell death. it is therefore likely that the no-mediated mechanisms on prostate and testicular parenchyma, increased by tadalafil, is the basis of the improvement of the quality of the sperm. conclusions the comparison between the parameters of spermio grams, obtained before and after administration of tadalafil 5 mg, showed an average increase in the number of sperm, both total and fast motility (type a) and the percentage of nemasperms and an average increase of semen volume of 0.41 ml. these quantitative and qualitative improvements of the seminal fluid are statistically significant, as regard total progressive motility (a+b), normal sperm percentage and seminal fluid volume. the administration of tadalafil has just directed the production of sperm and seminal fluid to the highest values. it is just like the testicles were pushed toward their highest "functional reserve". in addition, we emphasize the safety of the once-daily treatment with tadalafil 5mg and the absence of negative effects on spermatogenesis. it would be interesting to test whether the administration of tadalafil may improve in a statistically significant way the seminal fluid of patients with abnormalities of the baseline spermiogram (at time 0). references 1. affuso f, palmieri ea, et al. tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension. int j cardiol. 2006; 108:429-31 table 3. corvasce_stesura seveso 23/09/15 12:34 pagina 212 213archivio italiano di urologia e andrologia 2015; 87, 3 once-a-day tadalafil administration improves the spermogram parameters in fertile patients. 2. gonzalez rr, kaplan sa. tadalafil for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. expert opin drug metab toxicol. 2006; 2:609-17. 3. baumhaekel m, scheffler p, et al. use of tadalafil in a patient with a secondary raynaud's phenomenon not responding to sildenafil. microvasc res. 2005; 69:178-9. 4. hellstrom wj, overstreet jw, et al. tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. j urol. 2003; 170:887-91. 5. yunes r, fernández p, et al. cyclic nucleotide phosphodiesterase inhibition increases tyrosine phosphorylation and hyper motility in normal and pathological human spermatozoa. biocell. 2005; 29:287-93. 6. bentley jk, beavo ja. regulation and function of cyclic nucleotides. curr opin cell biol. 1992; 4:233-40. 7. world health organization. who laboratory manual for the examination and processing of human semen. 5th edition, cambridge university press, cambridge, 2010. 8. meistrich ml, hess ra. assesment of spermatogenesis through staging of seminiferous tubules. methods mol biol 2013; 927: 299307. 9. francis sh, corbin jd. cyclic gmp: synthesis, metabolism, and function. in advances in pharmacology, ed. murad p. new york: academic press 1994; 115-70. 10. padma-nathan h, mcmurray jg, pullman we, et al. ondemand ic351 (cialis®) enhances erectile function in patients with erectile dysfunction. int j impot res 2001; 13:2-9. 11. thompson wj. cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. pharmacol. ther. 1991; 51:13-3. 12. lue tf. erectile dysfunction. n engl j med. 2000; 342:1802-13. 13. brock gb, mcmahon cg, chen kk, et al. efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. j urol. 2002; 168: 1332-6. 14. carson cc, rajfer j, eardley i, et al. the efficacy and safety of tadalafil: an update. br j urol int. 2004; 93: 1276-81. 15. mcvary kt, mckenna ke. the relationship between erectile dysfunction and lower urinary tract symptoms: epidemiological, clinical, and basic science evidence. curr urol rep. 2004; 5:251-7. 16. palmer rm, ferrige ag, moncada s. nitrite oxide release accounts for the biological activity of endotheliumderived relaxing factor. nature. 1987; 327:524-6. 17. marletta ma. nitrite oxide synthase structure and mechanism. j biol chem. 1993; 268: 12331-4. 18. andersson ke. erectile physiological and pathophysiological pathways involved in erectile dysfunction. j urol. 2003; 170: s6-14. 19. bloch w, klotz t, loch c, et al. distribution of nitric oxide synthase implies a regulation of circulation, smooth muscle tone, and secretory function in the human prostate by nitric oxide. prostate. 1997; 33: 1-8. 20. liman n, alan e, beyaz f, gürbulak k. endothelial and inducible nitric oxide synthase (nos) immunoreactivity and nosassociated nadph-diaphorase histochemistry in the domestic cat (felis catus) testis. theriogenology. 2013; 80:1017-32. correspondence antonio corvasce, md centre of andrology and reproductive pro.andròs unit of urology, “l. bonomo” hospital, asl bat, andria, italy giuseppe albino, phd, md (corresponding author) peppealbino@hotmail.com ettore cirillo marucco, md unit of urology, “l. bonomo” hospital, asl bat, andria, italy teresa leonetti, md agnese filomena buonomo, md centre of andrology and reproductive pro.andròs corvasce_stesura seveso 23/09/15 12:34 pagina 213 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2148 case report a case with primary signet ring cell adenocarcinoma of the prostate and review of the literature orcun celik, salih budak, gokhan ekin, ilker akarken, yusuf ozlem ilbey tepecik educational and research hospital urology department, 35140, izmir, turkey primary signet cell carcinoma of the prostate is a rare histological variant of prostate malignancies. it is commonly originated from the stomach, colon, pancreas, and less commonly in the bladder. prognosis of the classical type is worse than the adenocarcinoma of the prostate. primary signet cell adenocarcinoma is diagnosed by eliminating the adenocarcinomas of other organs such as gastrointestinal tract organs. in this case report, we present a case with primary signet cell adenocarcinoma of the prostate who received docetaxel chemotherapy because of short prostate specific antigen doubling time. key words: signet cell; adenocarcinoma; prostate adenocarcinoma. submitted 28 april 2014; accepted 31 may 2014 summary introduction primary signet cell carcinoma of the prostate is a rare histological variant of the prostate malignancies. it is a subtype of the prostate adenocarcinomas, which releases mucin. it is called signet cell because the mucin released pushes the nucleus to the periphery and makes the cell looks like a signet cell. however, there are also some other types that do not release mucin (1). generally, it is originated from the stomach, colon and pancreas and less commonly from the bladder. it constitutes approximately 3-4% of the all stomach cancers (2). it is rare in the prostate and at a later stage when diagnosed (1). classical type has a worse prognosis when compared to prostatic adenocarcinoma (5). in this manuscript, we present a case with primary signet cell adenocarcinoma of the prostate that was diagnosed at a later stage, gave a poor response to the anti-hormonal treatment and had a short prostate specific antigen (psa) doubling time, therefore received chemotherapy. additionally, we reviewed the current literature in relation with our case. case report a 66-year-old man presented to an outpatient service complaining of difficulty in urination. at rectal examinano conflict of interest declared tion, his prostate was found to be hard in texture. apart from chronic obstructive pulmonary disease (copd) and diabetes mellitus (dm) he had no prior disease history. a transrectal ultrasound-guided 10-quadrant fine needle biopsy of the prostate was performed as his psa level was above 100 ng/dl. we detected the classical type of the prostate adenocarcinoma with gleason score of 4 + 5 in all of the 10 quadrants and planned a whole body bone scintigraphy to grade the carcinoma. there were multiple bone metastases. abdominal computerized tomography showed bilateral hydronephrosis, enlarged para-aortic and para-iliac lymph nodes. therewith, the patient with a urinary catheter was referred to our center, which is a tertiary clinic. his psa level was above 6658 ng/dl and his bone scintigraphy indicated a very dense metastasis in the vertebra. thus, we planned leuprolide acetate monotherapy and palliative radiotherapy to prevent bone fractures. we performed transurethral prostate resection as he had the catheter and detected poorly differentiated signet cell adenocarcinoma with a gleason score of 5 + 5. because of the diagnosis of the signet cell adenocarcinoma, we explored for a primary adenocarcinoma locus but we did not detect any other malignity. following a 3-month hormonotherapy, his psa level was 441 ng/dl. however, it increased again and we planned antiandrogen treatment. following leuprolide acetate and antiandrogen treatment, at the end of the ninth month, his psa level was 84.4 ng/dl and testosterone level was < 20 ng/ml. subsequently, his psa level increased again and three months later was 271 ng/dl. we considered the case as castration resistant and we graded it again. docetaxel on day one of a 3-week cycle with a dose of 75 mg/m2 was administered with a 3-week cycle. after the 12th cycle, his symptoms decreased, although his psa level remained between 200 and 281 ng/dl. he developed urosepsis during the chemotherapy and received antibiotic therapy. however, he died of urosepsis after 22 months. discussion primary signet cell adenocarcinoma of the prostate was described first in 1979. since then, there are only 69 cases reported and mean duration of survival in those reported cases was 28 months (3, 4). mean age of these doi: 10.4081/aiua.2014.2.148 149archivio italiano di urologia e andrologia 2014; 86, 2 a rare pathology type of prostate cancer cases was 68.2 years (1). the tumor can present with voiding problems as in the classical presentation of the prostate cancer. however, it can present with symptoms related to metastasis. our case presented with urination problems. in total, 42% of the cases in the literature are at stage t4 and this indicates the aggressive nature of the signet cell adenocarcinoma of the prostate (1, 2). the name signet cell was given because of the appearance of the cell as large vacuoles push the cell nucleus to the periphery (1). it is generally originated from colon, pancreas and breast. prostate as a primary location of signet cell adenocarcinoma is rare. some similar conditions should be considered and eliminated before diagnosing a primary signet cell adenocarcinoma. such conditions include prostate lymphoma in which the prostate is infiltrated by lymphocytes and has aspects of the muscle cells as after radiotherapy and antihormonal therapy (1, 2). we diagnosed our case after leuprolide acetate treatment. thus, we considered that the condition might be related to antihormonal therapy. however, we eliminated this diagnosis using immunohistochemical staining. negative results of leucocyte common antigen (lca), alpha-smooth muscle actin (asma), cytokeratin-7 and 20 and positive psa results favor the diagnosis (3-6). carcinoembryonic antigen (cea) was positive in 20% of the cases in the literature (10) whereas psa and prostate specific acid phosphatase (psap) were positive in 87% of the cases (10). additionally, in the literature, positive staining with periodic acid-schiff stain (pas) was positive in 60%, with alcian blue 60% and with mucicarmin 50% (11). some authors suggested that signet cells should be present in more than 20% of the tumor tissue (10, 11). in the current case, psa, pas, psap, alcain blue were positive. on the other hand, lca, asma, cea and cytokeratin 7 and 20 were negative. diagnosing the primary signet cell adenocarcinoma of the prostate is difficult because it is problematic to exclude the possibility of the metastases of other organs to the prostate. presence of a tumor in the gastrointestinal tract should be explored with radiologic and endoscopic methods (3). in our case, we screened the gastrointestinal tract with colorectal and gastro esophageal endoscopy and did not find any locus. primary signet cell adenocarcinoma of the prostate is more aggressive with less treatment response and poor prognosis when compared to the classical type of the prostate adenocarcinoma. three-year survival is 55% and 5-year survival is 12%. in previous publications poor response to antihormonal therapy was reported (7, 9). in our case, treatment response to antihormonal therapy was good for a short period of time, but later tumor became castration resistant. roldan et al., had almost full response with oxaliplatin, 5-fu, and leucovorin (folfox) combination which are used for colorectal cancer (8). studies indicate that prognosis is related to the grade of the tumor when diagnosed (8). conclusions primary signet cell carcinoma of the prostate is a rare histological variant of prostate adenocarcinomas. gastrointestinal tract should be screened for other tumor loci and this possibility should be eliminated for diagnosing cases with primary signet cell adenocarcinoma of the prostate. in contrast to the other signet cell carcinomas, treatment of the primary signet cell adenocarcinoma of the prostate is the same with the classical adenocarcinoma. prognosis of this carcinoma is bad as it is a rare and aggressive tumor and diagnosis is generally made at an advanced stage of the disease. references 1. fujita k, sugao h, gotoh t, et al. primary signet ring cell carcinoma of the prostate: report and review of 42 cases. int j urol. 2004; 11:178-81. 2. kwon w, oh th, ahn sh, et al. primary signet ring cell carcinoma of the prostate. can urol assoc j. 2013; 7:768-71. 3. skodras g, wang j, kragel pj. primary prostatic signet-ring cell carcinoma. urology. 1993; 42:338-42. 4. smith c, feddersen rm, dressler l, et al. signet ring cell adenocarcinoma of prostate. urology. 1994; 43:397-400. 5. kuroda n1, yamasaki i, nakayama h, et al. prostatic signet-ring cell carcinoma: case report and literature review. pathol int. 1999; 49:457-61. 6. guerin d, hasan n, keen ce. signet ring cell differentiation in adenocarcinoma of the prostate: study of five cases. histopathology. 1993; 22:367-71. 7. akagashi k, tanda h, kato s, et al. signet-ring cell carcinoma of the prostate effectively treated with maximal androgen blockade. int j urol. 2003; 10:456-8. 8. roldán am, núñez nf, grande e, et al. primary signet ring cell carcinoma of the prostate with bone metastasis with ımpressive response to folfox and cetuximab. clin gen cancer. 2012; 10:199-201. 9. lilleby w, axcrona k, alfsen gc, et al. diagnosis and treatment of primary signet-ring cell carcinoma of the prostate. acta oncol. 2007; 46:1195-7. 10. randolph tl, amin mb, ro jy, et al. histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. mod pathol. 1997; 10:612-29. 11. torbenson m, dhir r, nangia a, et al. prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. mod pathol. 1998; 11:552-9. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com salih budak,, md gokhan ekin, md ilker akarken, md yusuf ozlem ilbey, md associate professor endourology section urology department, tepecik educational and research hospital gaziler cd.no:468, yenisehir 35140, izmir, turkey archivio italiano di urologia e andrologia 2016; 88, 4262 original paper relationship between lower urinary tract symptoms and inguinal hernia aykut buğra sentürk 1, musa ekici 1, ibrahim tayfun sahiner 2, tuncay tas 3, basri cakiroglu 4 1 hitit university corum training and research hospital, urology department, turkey; 2 hitit university corum training and research hospital, general surgery department, turkey; 3 istanbul esenyurt university, private esencan hospital, department of urology, turkey; 4 hisar intercontinental hospital, department of urology, turkey. aim: to determine the relationship between inguinal hernia (and inguinal hernia subtypes) and low urinary tract symptoms (luts) due to benign prostate hyperplasia (bph), that could be more common than we think. method: the study was designed retrospectively and was done in accordance with the principles of the declaration of helsinki, including 100 patients aged > 50 years that were divided into 2 groups: patients with bph (bph group) and patients with bph and inguinal hernia (bph-ih group 2). in addition, the bph-ih group was subdivided according to 2 inguinal hernia subtypes; patients of bph-ih subgroup a had direct inguinal hernia (n = 25) and those of bph-ih subgroup b had indirect inguinal hernia (n = 25). results: there was no statistical relationship and difference in rates between ipss scores in both groups (p = 0.659) and there wasn’t a significant correlation between ipss symptom severity and type of hernia, based on chi square analysis (p = 0.104) conclusion: we were not able to prove our hypothesis that patients with inguinal hernia and bph would have higher ipss scores because of voiding dysfunction. key words: inguinal hernia; lower urinary tract symptoms; benign prostatic hyperplasia. submitted 19 may 2016; accepted 19 august 2016 summary no conflict of interest declared. the prevalence of inguinal hernia increases with age, and inguinal hernias account for 75% of all abdominal hernias. it is difficult to determine the precise prevalence of inguinal hernias within the general community, however, they do occur more commonly in men with a lifetime risk of 27% (2). multiple etiological factors are associated with hernia. chronic cough, chronic obstructive pulmonary disease, constipation, prostatism, pregnancy, ascites, and heavy lifting are known to cause inguinal hernia, via an increase in intra-abdominal pressure. congenital diseases of the connective tissue, collagen synthesis defects, and a family history of hernia are all considered congenital causes. moreover, inguinal hernia is more common in smokers than in nonsmokers. it has been reported that mechanisms underlying the collagen synthesis degradation pathways could cause inguinal hernia. overall, although inguinal hernia is one of the most common surgically treated conditions, it remains to be fully understood, given not only the multiple factors associated with its etiology and recurrence, but also the wide range of treatment alternatives available (2, 3). in urology practice, the coexistence of inguinal hernia and luts due to bph is very common. patients with inguinal hernia reportedly have higher ipsss than those without inguinal hernia (4). the aim of the present study is to determine the relationship between inguinal hernia (and inguinal hernia subtypes) and luts, on account of bph. materials and methods this retrospective study was undertaken in accordance with the principles of the declaration of helsinki, and involved 100 patients aged > 50 years who were divided into two groups—namely, patients with bph ("the bph group"; n = 50) and patients with bph and inguinal hernia ("the bph-ih group"; n = 50). in addition, the bph-ih group was subdivided according the two inguinal hernia subtypes: those in bph-ih subgroup a had a direct inguinal hernia (n = 25), and those in bph–ih subgroup b had an indirect inguinal hernia (n = 25). diagnosis and subtyping of inguinal hernias were performed by a general surgeon. patients with a history of inguinal hernia repair or of prostate surgery, bph medication use, prostate cancer, urinary tract infection, or urethral stricture disease were excluded from this study. doi: 10.4081/aiua.2016.4.262 introduction lower urinary tract symptoms (luts) due to benign prostatic hyperplasia (bph) are very common among elderly men. conditions that occur more frequently with age such as atherosclerosis, obesity, and insulin resistance, can be important underlying etiological factors for benign prostatic enlargement (bpe) that is generally caused by the histopathological condition known as bph. bpe, like bph, is also commonly found among elderly men. bpe is the most common cause of luts in elderly men, occurring in 40% of men aged 50 years and in 90% of those aged 90-99 years (1). in urological practice, symptom scores are used to evaluate luts due to bph. the most commonly used prostate symptom questionnaire is that which generates the international prostate symptom score (ipss), which classifies the severity of symptoms as mild (score: 0-7), moderate (score: 8-19), or severe (score: 20-35). senturk_stesura seveso 09/01/17 09:49 pagina 262 263archivio italiano di urologia e andrologia 2016; 88, 4 inguinal hernia and bph ipss and a questionnaire used to measure the quality of life according to urinary symptoms (qi) were completed by the patients in the outpatient clinic prior to physical examination. total prostate-specific antigen (t-psa), urine analysis, and urine culture tests were performed. ipss was used to assess the severity of the symptoms, and the duration of the symptoms was noted. prostate volume (anteroposterior diameter × transverse diameter × longitudinal diameter × 0.52) was measured by suprapubic sonography using a 3.1-mhz superficial ultrasonic probe, and this was immediately followed by uroflowmetry (mms, holland). statistical analysis statistical analysis was performed using ibm spss statistics for windows v. 22 (ibm corp., armonk, ny). descriptive statistics are presented as mean ± standard deviation (sd) for continuous variables with normal distribution, as median ± sd for continuous variables not normally distributed, and as number (n) and ratio for categorical variables. data normally distributed were analyzed through the use of shapiro-wilk and kolmogorov-smirnov tests. comparisons of two independent continuous variables were performed using the independent samples t-test and mann-whitney u test for normally distributed and not normally distributed data, respectively. the relationship between two categorical variables and two ratios was determined via the chisquare test. the level of statistical significance was set at p < 0.05. results in the total study population, the mean age was 61.45 ± 8.33 years, the mean ipss was 15.24 ± 8.19, the mean peak flow rate was 13.40 ± 5.28 ml/sec, and the mean prostate volume was 44.30 ± 13.96 ml (table 1). the mean age was 61.38 ± 9.19 years in the bph-ih group, versus 61.52 ± 7.47 years in the bph group; the difference was not significant (p = 0.934). the mean flow rate (qmax) was 13.78 ± 4.28 ml/sec (median: 15; range: 6-20) in the bph-ih group, versus 13.04 ± 6.12 ml/sec (median: 12; range: 3-32) in the bph group; again, the difference was not significant (p = 0.175). the mean prostate volume in the bph-ih group was 47.16 ± 13.57 ml (median: 45; range: 15-72), versus 41.39 ± 13.88 ml (median: 40; range: 20-75) in the bph group; this difference was significant (p = 0.036). the mean ipss in the bph-ih group was 14.46 ± 8.64 (median: 13; range: 1-32), versus 16.02 ± 7.72 (median: 15.50; range: 5-30) in the bph group; the difference was not significant (p = 0.348) (table 2). mild, moderate, and severe luts was observed in 10 (20%), 22 (44%), and 18 (36%) of the patients in the bph group, respectively, versus 10 (20%), 26 (52%), and 14 (28%) of those in the bph-ih group. there was no statistical relationship between, or difference in, the rates between the ipsss of the two main groups (p = 0.659) (table 3). mild, moderate, and severe luts were noted in 8 (32%), 9 (36%), and 8 (32%) of the patients in bph-ih subgroup a (direct inguinal hernia) and in 3 (12%), 16 (64%), and 6 (24%) of those in bph-ih subgroup b (indirect inguinal hernia). there was no significant correlation between ipss symptom severity and hernia type, based on chi square analysis (p = 0.104) (table 4). the mean ipss did not differ significantly between bphih subgroup a and subgroup b (p = 0.763) (table 5). table 1. descriptive statistics. n mean ± sd median range age (years) 100 61.45 ± 8.33 60.5 45-87 ipss score 100 15.24 ± 8.19 15 1-32 qmax (ml/sec) 100 13.40 ± 5.28 13 3-32 prostate volume (ml) 100 44.30 ± 13.96 45 15-75 table 3. the frequency and percentage of ipss symptom severity, based on the chi-square test. group mild moderate severe p n n n bph 10 (20%) 22 (44%) 18 (36%) 0.659 bph-ih 10 (20%) 26 (52%) 14 (28%) 0.659 table 2. between-group comparisons. group n mean ± sd median range p age (years) bph-ih 50 61.38 ± 9.19 62.5 50-84 0.934 bph 50 61.52 ± 7.47 60 45-87 ipss score bph-ih 50 14.46 ± 8.64 13 1-32 0.348 bph 50 16.02 ± 7.72 15.50 5-30 qmax (ml/sec) bph-ih 50 13.78 ± 4.28 15 6-20 0.175 bph 50 13.04 ± 6.12 12 3-32 prostate volume (ml) bph-ih 50 47.16 ± 13.57 45 15-72 0.036* bph 50 41.39 ± 13.88 40 20-75 * statistically significant p < 0.05. table 4. the frequency and percent of ipss symptom severity in the hernia subgroups, based on the chi-square test. 0-7 mild 8-19 moderate 20+ severe total p direct hernia 8 (32%) 9 (36%) 8 (32%) 25 (100%) 0.104 indirect hernia 3 (12%) 16 (64%) 6 (24%) 25 (100%) total 11 (22%) 25 (50%) 14 (28%) 50 (100%) table 5. ipss score in bhp-ih subgroup a and subgroup b. group n mean ± sd median p ipss bhp-ih subgroup a 25 14.28 ± 9.64 13 0.763 bhp-ih subgroup b 25 14.64 ± 7.71 13 * statistical significant p < 0.05. senturk_stesura seveso 09/01/17 09:50 pagina 263 archivio italiano di urologia e andrologia 2016; 88, 4 a buğra sentürk, m. ekici, i. tayfun sahiner, t. tas, b. cakiroglu 264 discussion as mentioned, the incidence of bph increases with age, and bph is the most common cause of luts in elderly men. among bph patients with pre-existing comorbidities, quality of life is further impaired. among elderly men, the co-occurrence of inguinal hernia and luts due to bph is very likely, given that the prevalence of both conditions increases with age. luts can have a negative effect on quality of life in bph patients. ipss, prostate volume, detrusor resistance index, intravesical prostatic protrusion, capillary artery resistive index, intraprostatic pressure, post-void residual, uroflowmetry, bladder wall thickness, and pressure flow assessments are commonly used to evaluate patients with luts due to bph (5). in the present study, these methods were used to evaluate patients with bph, and those with and without inguinal hernia were compared. bph and inguinal hernia are both associated with aging. an earlier study reports that patients with inguinal hernia tend to have higher ipsss than patients without it; the difference is thought to be due to an increase in intraabdominal pressure in patients with obstructed voiding dysfunction, which can then lead to susceptibility to inguinal hernia formation (4). in the present study, there is no significant difference in ipsss between the bph and bph-ih groups (p = 0.348) (figure 1), or in those between the bph-ih subgroups a and b (p = 0.104). uroflowmetry is commonly used to evaluate the strength of urinary flow in men with luts. the maximum flow rate is the best indicator among all parameters that can be analyzed via uroflowmetry. it is important in diagnosing bph, estimating the severity of obstruction, and evaluating treatment; however, to date, only a weak correlation has been reported between the maximum flow rate and symptom scores. in the present study, there was no significant difference in uroflowmetry parameters between the bph and bph-ih groups (p = 0.175). ludwig et al. (6) report that 33% of patients scheduled to undergo radical prostatectomy have concomitant inguinal hernia. additionally, another study that investigated the incidence of inguinal hernia following prostate surgery, reports that the incidence rate of inguinal hernia after radical prostatectomy, open prostatectomy, and transurethral resection of the prostate (tur-p) was 23.9%, 18.9%, and 2%, respectively. it is also reported that inguinal hernia develops during the first two years post surgery in 91.9% of patients that have undergone radical retropubic prostatectomy, and in 83.3% of patients that have undergone open prostatectomy (7). sanchez-ortiz et al. (8) report that patients with an ipss > 15 before radical retropubic prostatectomy should be evaluated for additional surgical hernia repair. irrespective of prostate size, patients with preoperative lower urinary tract dysfunction were reported to have a five-fold greater risk of undergoing an inguinal hernia repair procedure during radical prostatectomy. these two conditions are related to aging and commonly coexist. it has been reported that 11-30% of patients with luts who undergo a surgical procedure to repair inguinal hernia will develop urinary retention after surgery and require a urological intervention. general surgeons and urologists should be aware of this coexistence and inform patients about possible outcomes (4). the general consensus is that these two surgeries should be performed simultaneously. bawa et al. (9) report that there is no increase in duration of surgery or postoperative hospitalization among patients who undergo simultaneous inguinal hernia repair and tur prostatectomy. in the present study, there was no significant difference in the prevalence of mild, moderate, or severe luts between the bph and bph–ih groups (p = 0.348). additionally, when patients in the bph–ih group were divided into subgroups a and b (direct and indirect inguinal hernia, respectively), the prevalence of mild, moderate, and severe luts did not differ significantly between the subgroups (p = 0.763). conclusion in the present study, ipss, uroflowmetry, and prostate volume were evaluated in bph patients. our hypothesis was that patients who have high ipsss on account of voiding dysfunction would have a higher ipsss in the presence of an inguinal hernia; our results, however, do not support this hypothesis. this unexpected outcome may have derived from the small study population. further larger-scale studies are needed to more clearly discern whether high ipsss are associated with inguinal hernia. references 1. berry sj, coffey ds, walsh pc, et al. the development of human benign prostatic hyperplasia with age. j urol 1984; 132:474-479. figure 1. boxplot of ipss score in each group. senturk_stesura seveso 09/01/17 09:50 pagina 264 265archivio italiano di urologia e andrologia 2016; 88, 4 inguinal hernia and bph 2. wagner jp, brunicardi fc, amid pk, et al. schwartz’s principles of surgery, tenth edition. new york: mcgraw-hill education. 2015; p 1495. 3. rutkow im. a selective history of groin hernia surgery in the early 19 th century. the anatomic atlases of astley cooper, franz hesselbach, antonio scarpa, and jules-germain cloquet. surg clin north am. 1998; 78:921. 4. reis rb, rodrigues neto aa, reis lo, et al. correlation between the presence of inguinal hernia and the intensity of lower urinary tract symptoms. acta cir bras. 2011; 26(suppl 2):125-128. 5. çakıroglu b, sinanoglu o, hazar ai, et al. infravesical obstruction index in patients with benign prostatic hyperplasia is the best? jarem. 2012; 2:109-112. 6. ludwig ww, sopko na, azoury sc, et al. inguinal hernia repair during extraperitoneal robot-assisted laparoscopic radical prostatectomy. j endourol. 2016; 30:208. 7. sekita n, suzuki h, kamijima s, et al. incidence of inguinal hernia after prostate surgery: open radical retropubic prostatectomy versus open simple prostatectomy versus transurethral resection of the prostate. int j urol. 2009; 16:110-113. 8. sanchez-ortiz rf, andrade-geigel c, lopez-huertas h, et al. preoperative international prostate symptom score predictive of inguinal hernia in patients undergoing robotic prostatectomy. j urol. 2016; 195:1744. 9) bawa as, batra rk, singh r. management of inguinal hernia with benign prostatic hyperplasia: simultaneous inguinal hernioplasty with transurethral resection of prostate. int urol nephrol. 2003; 35:503-506. correspondence aykut buğra sentürk (corresponding author) aykutbugra@gmail.com musa ekici hitit university corum training and research hospital, urology department, turkey ibrahim tayfun sahiner hitit university corum training and research hospital, general surgery department, turkey tuncay tas istanbul esenyurt university, private esencan hospital, department of urology, turkey basri cakiroglu hisar intercontinental hospital, department of urology, turkey senturk_stesura seveso 09/01/17 09:50 pagina 265 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3216 original paper 500 penile prostheses implanted by a surgeon in italy in the last 30 years diego pozza 1, mariangela pozza 1, marco musy 1, carlotta pozza 2 1 studio di andrologia e di chirurgia andrologica, rome, italy; 2 department of experimental medicine, sapienza university of rome, italy. objectives: the aim of our study was to report our experience with patients affected by erectile dysfunction (ed) and undergoing penile prosthetic implantation (ppi) in a single center by a single surgeon. material and methods: we retrospectively evaluated the clinical outcome of 500 patients (mean age: 51.5 years, range: 20-86 years) affected by ed and referred to our private andrological center from january 1984 to december 2013 who underwent penile prosthesis implantation, including the reported level of patient satisfaction. results: 182 silicone, 180 malleable, 18 monocomponent hydraulic and 120 multicomponents hydraulic prostheses were implanted by the same experienced surgeon. all patients were hospitalized for the procedure. all patients were evaluated immediately, 1 month (496 patients) and, for the great majority, every year after implantation. one hundred twenty five patients were lost to follow-up. twenty two patients underwent revision surgery for complications in the postoperative period. the most serious postoperative complications were mechanical problems (45 patients, 9.0%) and infection (15 patients, 3%). forty two (8.4%) prostheses were explanted. overall, 80% (400/500) of patients were able to have sexual intercourse and were fully satisfied with the results. conclusions: in our experience prosthetic surgery should be considered a good solution for men affected by ed and not responsive to other therapeutic solutions. prosthetic surgery can be performed not only in large public hospitals but also in smaller private facilities. key words: impotence; erectile dysfunction; penile disease; penile prosthesis; impotence treatment; impotence surgery; prosthesis complications; prosthesis infections. submitted 5 january 2015; accepted 31 march 2015 summary no conflict of interest declared. in italy, the use of muse and vacuum pumps never spread, and penile prosthesis implantation (ppi) did not develop as in other western countries. our private andrology center has been performing ppi, carried out by the same experienced surgeon (dp) since 1984. after 30 years of surgical activity we wanted to review our experience with 500 patients affected by ed and undergoing ppi. we report the different types of implanted prostheses, any complication (medical complications, hemorrhages, micturition problems, infections, mechanical failures during hospitalization and the postoperative period) and the level of personal and relational acceptance of this ed treatment. materials and methods from january 1984 to december 2013, 35,675 patients (5-86 years old, mean age: 48.8) underwent an andrological visit at our andrology center due to routine uroandrological screening (1097 pts. 3.0%), bladder and prostate diseases (4826 pts., 13.5%), genital malformations (2120 pts., 5.9%), infertility (12.555 pts., 35.2%), urogenital infections (6400 pts., 17.9%), ejaculatory (1645 pts., 4.6%) or erectile problems (8032 pts., 22.5%) (figure 1). one specialist (dp) saw all the pts., collected their medical history, performed the clinical examination and organized the diagnostic protocol, at the end of which an individualized therapeutic measure was suggested. a total of 8032 pts. (22.5%, mean age 48 years, range 1886 years) attended the center for problems concerning the penis and its function. out of them 436 (6%) did not return for successive consultations. in total 7564/8032 patients completed the diagnostic program, all undergoing blood and hormone assays, color duplex ultrasonography and intracavernous pge1 test. furthermore 383 patients underwent the rigiscan nocturnal test and, up to 2008, 212 patients underwent dynamic cavernosometry and cavernosography. other specific investigations were performed in particular cases. in 1984, at the beginning of our experience, only psychological, hormonal and surgical (prostheses) solutions could be offered to patients with ed. in 1987 we started offering self-injections of vasoactive drugs (7, 8). between 1988 and 1998 we performed 86 venous surgical procedures (5, 6). doi: 10.4081/aiua.2015.3.216 introduction over the last century, efforts to treat ed have led to the development and use of psychological treatment (early 1900s), hormonal therapies (1960) (1, 2), prosthetic surgery (1971) (3, 4), arteriovenous surgery (1981) (5, 6), vasoactive intracavernosal self-injection (1982) (7, 8), vacuum pumps (1986) (9), intraurethral pge1-medicated urethral system for erections (muse) (1994) (10) and 5phosphodiesterases inhibitors (5pdhei) (1997) (11). pozza_stesura seveso 30/09/15 09:32 pagina 216 217archivio italiano di urologia e andrologia 2015; 87, 3 500 penile prostheses implanted in italy with the appearance of 5pdeis in 1997 (11), many of our patients were able to benefit from a simple new treatment. the vacuum system (9) and muse (10) were rarely suggested for the treatment of ed in our patients. patients who underwent ppi signed a detailed informed consent form and agreed to pay the related costs (private clinic, surgical and anesthesiologist fees, prosthesis, postoperative follow-up). these medical expenses are not covered by the italian national health service. this aspect undoubtedly influenced the choice of many patients as to whether or not to opt for surgery and if so, what prosthesis to implant; many patients could not afford this option. any aspirin and anticoagulant treatments were stopped 10 days before surgery. in all diabetic patients, blood glucose levels were stabilized before surgery. results of the 7564 pts with ed, 3010 (39.8%) were diagnosed with arterial insufficiency, 1339 (17.7%) with peyronie’s disease, 1135 (15.0%) with venous insufficiency, 1029 (13.6%) with diabetic neurovascular problems, 393 (5.2%) with hormonal dysfunction, 340 (4.5%) with post-surgical neurovascular problems, and 318 (4.2%) with psycho-morphological complaints. implantation of a cavernous prosthesis to restore penetrative ability was suggested to 610 patients. 500 (81%) patients agreed to the procedure. all patients in a stable relationship were asked to inform their partner about their choice. the conclusive diagnosis of these 500 patients was: arterial disease in 192 (38.4%), venous disease in 137 (27.4%), peyronie’s disease in 70 (14.0%), diabetes mellitus in 60 (12.0%) and previous pelvic surgery in 30 (6.0%). 11 (2.2%) patients with no specific organic disease opted for a prosthetic implant after psychotherapy (table 1). surgical procedure until 2002, patients were admitted to the clinic the day before operation (332/500, 66%). in the last 10 years we have preferred, when possible, to hospitalize patients on the day of surgery (168/500, 34%). patients stayed in the clinic for at least 24 hours. hospitalization duration ranged between 1 and 7 days (mean 2.6). in the last 13 years we have generally prescribed oral ciprofloxacin from 3 days before surgery to 7 days post-surgery, gentamicin sulfate 80 mg intravenously from 1 day before surgery to 1 day postsurgery and ceftriaxone 2 g. intravenously just before surgery and 1 g for 7 days post-surgery. patients were recommended to clean their genitals with iodopovidone fluid twice a day for the 3 days leading up to surgery (12). since 2006, we have performed skin shaving as routinely done for other surgical procedures a few hours before surgery. usual iodopovidone cleansing in the operating table. in 76 cases (mainly at the beginning of our experience) we used general anesthesia. currently, most procedures are performed under spinal anesthesia. in 68 cases of implants of semi-rigid malleable rods we used local anesthesia with deep sedation. a urethral catheter was inserted in all patients in the operating room and maintained until the day after surgery. all penises were carefully dressed until the removal of the catheter. urinary retention affected only 13 cases, treated by re-catheterization for 1-2 days. one patient retained the catheter for 10 days. the skin incision was infrapubic in 76, subcoronal in 24, subcoronal and penoscrotal in 12 and penoscrotal in 388 patients. in 122 patients we found a thick cavernous fibrosis and used the carrion-rossello cavernotome (13) to dilate the cavernous body to the desired caliber. in 48 cases of penile curvature, insertion of the rods successfully no. patients (%) disease 500 arterial disease 192 (38.4%) venous disease 137 (27.4%) peyronie’s disease 70 (14%) diabetes 60 (12%) post pelvic surgery 30 (6%) other 11 (2.2%) table 1. conclusive diagnosis of the 500 patients with penile prostheses. figure 2. flow diagram of the study. pozza_stesura seveso 30/09/15 09:32 pagina 217 archivio italiano di urologia e andrologia 2015; 87, 3 d. pozza, m. pozza, m. musy, c. pozza 218 straightened the penis. in a few cases a wilson maneuver (14) was used, with satisfactory results. in 8 patients with a persisting significant curvature after malleable implant, we performed a plaque incision without any suture. in 35 cases (both with malleable and hydraulic implants) we excised the plaque and used various artificial heterologous patches (sis, pelvicol, veritas, hydrix) (15). there were no significant complications associated with patch insertion. in the last 10 years, after implanting a hydraulic system we have used aspirating drainage in the scrotum until 1 day post-surgery (16). all patients underwent a clinical visit 7-15 days after surgery. all patients returned after 30-40 days for a second medical visit. most also returned regularly after 1 year but 86 (17%) were lost to follow-up after 1 year. prosthesis implantation overall, we implanted 182 silicone semi-rigid rods (74 almed implantal, 34 ssda-gis, 30 eurogest, 25 smallcarrion and 19 subrini) and 180 malleable rods (66 mentor acuform-coloplast genesis, 54 ams 600, 25 jonasjacobi, 14 vedise, 14 dacomed omniphase, 6 dacomed duraphase, 1 ams spectra). a total of 138 patients with sufficient income or supported by private medical insurance opted for a hydraulic prosthesis. we implanted 18 hydraulic monocomponent prostheses (10 ams hydroflex, 8 ams dynaflex) and 120 multicomponent prostheses (38 mentor alpha i, 25 ams 700 cx, 20 coloplast titan, 17 mentor mark ii, 14 ams 700 ultrex, 3 ams 700 lgx, 3 ams ambicor) (table 2). complications medical complications we recorded 22 medical complications clearly related to the surgical procedure. in two cases (0.4%) we perforated the septum during cavernous dilation and inserted the two rods in the same cavernous space. after discovering the problem we reinserted the two rods correctly in the cavernous spaces, with good results and no further complications. in one case (0.2%) the tip of the cavernous body was perforated. we detached the glans, applied a patch of veritas, and re-implanted a rod 0.5 cm shorter than the length measured during operation. no subsequent complication was recorded. in another patient (0.2%) we perforated the crus of one cavernous body during dilation with the cavernotomes. we performed a new perineal incision to detect the perforation site, which was sutured after placing an rt extender in the crus of the cavernous body (17). the insertion of the rod was subsequently successful. we did not register any bladder lesion when hydraulic prostheses were implanted. hemorrhage in 2 (0.4%) cases of semi-rigid prostheses (penoscrotal incision) we recorded a scrotal hematoma the day after age prostheses patients yrs, range mean mechanical surgical failures explants complications 500 20-86 51.0 48 (9.6%) 26 (5.2%) 53 (10.6%) soft silicone 182 20-73 39.7 2 (1.2%) 7 (3.8%) 1 (0.6%) almed implantal 74 20-73 36.3 1 3 0 ssda-gis 34 22-62 43.3 1 1 0 eurogest 30 29-65 40.2 0 1 1 small-carrion 25 27-73 46.2 0 2 0 subrini 19 30-38 0 0 0 semirigid malleable 180 28-86 53.7 7 (3.8%) 4 (2.2%) 8 (4.4%) mentor acuform-coloplast genesis 66 28-83 53.2 0 1 1 ams 600 54 28-85 53.5 0 2 0 jonas 25 35-65 45.4 1 0 1 vedise 14 55-67 50.6 0 0 0 omniphase 14 44-72 67.4 3 1 3 duraphase 6 49-86 63 3 0 2 ams-spectra 1 51 51 0 0 1 hydraulic monocomponent 18 43-65 52.2 14 (77.7%) 0 8 (77.7%) ams-hydroflex 10 47-55 50.5 8 0 8 ams-dynaflex 8 43-65 54 6 0 6 multicomponents 120 26-85 58.4 25 (20.8%) 15 (12.5%) 36 (30%) mentor alpha ii 38 27-66 49.6 5 4 9 ams 700 cx 25 43-73 65.3 7 4 11 coloplast titan 20 26-74 45.4 4 3 6 mentor mark ii 17 31-65 54.3 1 0 1 ams700 ultrex 14 41-85 62.8 8 3 9 ams700 lgx 3 66-71 63.3 0 0 0 ams ambicor 3 66-70 68 0 1 0 table 2. 500 penile prostheses implanted in relation with age of patients, mechanical failures, surgical complications and explanted cases with ckf on dialysis. pozza_stesura seveso 30/09/15 09:32 pagina 218 219archivio italiano di urologia e andrologia 2015; 87, 3 500 penile prostheses implanted in italy surgery, which required 2 more days of hospitalization and medical treatment. in the first group of 50 hydraulic prostheses, implanted without any drainage, 11 cases (22%) of scrotal hematomas were recorded the day after surgery, requiring longer observation and in 8 cases needle aspiration and medical treatment. since 2004 we routinely applied scrotal drainage (16) observing only 5 cases (5.6%) of scrotal hematoma due to obstruction of the drain. these hematomas were easily evacuated using the tubing of the draining system, prolonging hospitalization (to 3 and 4 days) in just two cases (2/5). in one of these patients, who underwent ams 700 cx implantation after excision of a fibrous plaque of ipp and veritas patch (3x2 cm) insertion, we recorded an extensive hematoma including the scrotum and penis. this scrotal hematoma begun to appear soon after the deflation of corporal cylinders the day after surgery, even with an empty aspirating drainage. in this case we discovered the hemorrhage after 3-4 hours. we re-inflated the cylinders and after repeated aspiration succeeded in stopping the hemorrhage. this patient developed an infection some weeks later and after 2 months we decided to remove the hydraulic system. micturition only 13 of 500 patients (0.26%) were unable to urinate after removal of the urethral catheter the day after surgery, thus requiring re-catheterization; this was maintained for the next day in 12 cases, while one patient was discharged with the catheter still fitted. it was removed, after medical treatment, 10 days post-surgery. infection fifteen (3%) cases of infections were recorded. overall, in 6 patients (1.2%) we had to explant the prosthesis (19) (table 2). in 4 cases we observed high fever, chills and signs of infections in the immediate period after surgery. in 3 cases, intravenous medical therapy resolved the infection. in one case the infection lasted more than 20 days and we decided to explant the prosthesis. in 2 cases (0.5%) of semi-rigid prosthesis and in 5 cases (3.6%) of hydraulic prosthesis we recorded a prosthesis infection after 3 to 18 months, requiring removal of the prosthesis. two patients (53 and 62 years, who suffered from diabetes and hypertension) implanted respectively with mentor mark ii and ams 700 cx started to develop scrotal swelling with pain and skin perforation due to extrusion of the scrotal pump after 45 days in the first case and 36 days in the second. in both cases we removed the prosthetic system entirely, leading to the disappearance of infectious signs and symptoms. both patients refused a subsequent penile implant (20). one patient (62 years, a smoker and hypertensive) started to develop fever and pain at the base of the penis 15 days post-surgery, and a small discharge of purulent yellowish material began to appear from a small hole in the skin at the base of the penis. the amount of purulent material increased on squeezing the penis and inflating the cavernous cylinders. the fistula was repeatedly cleaned with iodopovidone and physiological solution mixed with gentamicin 3 times a day for 10 days, with resolution of the discharge and ultimate closure of the hole. after 8 years the patient continues to use his prosthesis satisfactorily. another “uncommon” infection arose in a 51-year-old patient after replacement of a mentor alpha i due to tubing leakage near the reservoir. after implantation of a new alpha i, the patient started to develop swelling of the left hemiscrotum, with pain when touching the pump. fever was mild. the patient did not benefit from a complex antibiotic therapy. the presence and persistence of the inflammation and pain referred to the hemiscrotum along with high white blood cells (wbc) counts induced us to remove the hydraulic system after 20 days of complex intravenous therapy, with an immediate drop in fever and wbc counts and resumption of healing. the patient did not wish to remain without a prosthesis. after 7 days without fever we therefore implanted two ams spectra rods in order to keep the cavernous bodies open until it was possible to implant another hydraulic system (ams 700cx), which was fitted in a different hospital 5 months later. mechanical problems apical extrusion of one prosthetic rod occurred in just 8 out of 362 semi-rigid (2.2%) prostheses. in 3 cases we covered the apical rupture and re-implanted a shorter semirigid rod. in 5 cases the patients preferred to retain only one rod, with satisfactory penetrative function (table 2). three patients (0.8 %) with semi-rigid rods complained of the “rotation” of the rods during sexual activity, with some unpleasant discomfort. we sometimes observed irregularity in the length of the two cavernous bodies at the end of operation, in which case we re-opened the cavernous body and extracted the shorter rod in order to insert a longer rear tip extender until obtaining good penile symmetry. in 2 cases (1.4%) we had to re-operate due to incorrect positioning and difficult activation of the pump into the scrotum. scrotal incision and re-positioning of the pump were performed 5 and 25 days after the original operation and were uneventful. the prostheses continue to work after 9 and 11 years. we explanted 3 omniphase (1, 1 and 2 years after implantation) and 2 duraphase (1 and 3 years after implantation) prostheses due to breakage. another patient decided to maintain the broken rods without changing them. we removed 14 (77.7%) of the 18 self-contained hydraulic prostheses (8 hydroflex and 6 dynaflex) due to clearly evident malfunction 4-16 months post-surgery. the other 4 patients with self-contained prostheses were lost to followup; they lived in different cities or in any case far from our private clinic and in the event of any complications, probably consulted a different medical facility. leakage of the tubing with a completely non-functional system occurred in 22 cases (15.9%) from 3 months to 96 months after implantation. seventeen patients were re-operated shortly thereafter (1-3 months), with implantation of a new hydraulic prosthesis. two of 5 patients who had discovered the malfunction after several months opted for fitting of a malleable prosthesis. three patients refused a new implant. pozza_stesura seveso 30/09/15 09:32 pagina 219 archivio italiano di urologia e andrologia 2015; 87, 3 d. pozza, m. pozza, m. musy, c. pozza 220 in 3 cases of ams700 ultrex implantation there was a malfunction due to aneurismatic dilatation of the cavernous cylinders appearing 9, 10 and 16 months after the implant. all 3 cases underwent explantation and subsequent successful hydraulic prosthetic re-implantation. in total we explanted 42/500 (8.4%) prostheses, of which 6/362 (1.6%) malleable, 14/18 (77.7%) hydraulic monocomponent and 22/120 (18.3%) hydraulic multicomponent. repeated prostheses three patients received 3 prostheses in the space of 5 years. all of them were first implanted with a mentor acuform. after 3 years they wanted to switch to a hydraulic multicomponent prosthesis. they received a mentor alpha i (2 cases) and a ams 700 cx (1 case). two patients suffered from subsequent infections and 1 from tubing rupture, causing removal of the hydraulic system in all cases. finally, they were implanted with a semirigid (almed) prosthesis. dissatisfaction, refusal thirty-two patients reported dissatisfaction with the length of the operated penis (22). in 8 cases, the patients’ disappointment was due to perception of the tubing at the base of the penis. three patients reported absolute refusal with the prostheses. in 2 cases (one malleable and one hydraulic) patients required subsequent explant (2 and 4 months post-implant). conclusions in our experience prosthetic implants appear to be a good solution for erectile and penetrative dysfunction. the surgical technique is relatively simple, even if some problems can occur. our data confirm that this kind of surgery can be performed even in a small private clinic. the possibility of having a penile prostheses under the national health system continues to be very difficult in italy. in several public hospitals, even with advanced urological departments, there are no surgeons experienced in penile prosthetic surgery and this solution is not offered to patients with ed. furthermore, many general practitioners do not consider a penile prosthesis as a possible mean of restoring penetrative function. for this reason, they do not normally suggest this solution to any patients consulting them during the early phase of the ed diagnostic process. the financial aspect of the surgical treatment of ed may greatly limit the patient’s choice if no other medical treatments are effective (23). the number of patients submitted to ppi appears in line with other distinguished european urological centers (24, 25). in our experience, younger patients preferred semi-rigid silicone prostheses, considering them simpler to use during sexual intercourse. many of our younger patients reported a subsidiary spontaneous erection of the tissue surrounding the prosthetic rods during the preliminary sexual phase (26). this “accessory” erection is also considered highly positive from an emotional point of view. many patients sometimes used 5pdei to achieve better subsidiary tumescence. the 6 patients aged over 80 years did not experience any complications or problems different to those in younger patients (27). they all confirmed their satisfaction at the 1-year follow-up visit. in 1 case with coloplast titan inflatable prosthesis a turp for bph was easily performed. patient satisfaction with hydraulic prostheses was very high (80%). the most important aspect is related to the fact of having an erection only when sexual intercourse is desired. another reason is the possibility of having sexual intercourse without informing their partner of its presence, which can be easily masked. many of our patients reported that they did not tell their partners about their prosthesis, even though we consider the partner’s cooperation to be very important, especially in the first sexual experiences following the penile implant. almost all our patients reported some relational problems during the first months after ppi. it is extremely important not to have to conceal the presence of the prosthesis and to practice pumping and deflating the cylinders. in our experience a well-trained male can hide his prosthesis from a new partner for a considerable period. more than 80% of partners who had been told about the prosthesis declared their satisfaction with their partner’s choice and no sexual refusal was reported to us. references 1. wesson mb. the value of testosterone to men past middle age. j am geriatr soc. 1964; 12:1149. 2. margolis r, leslie ch. review of studies on a mixture of nux vomica, yohimbine and methyl testosterone in the treatment of impotence. curr ther res clin exp. 1966; 8:280. 3. small mp, carrion hm, gordon ja. small-carrion penile prosthesis: new implant for management of impotence. urology. 1975; 5:479. 4. scott fb, bradley we, timm gw. management of erectile impotence: use of inflatable prostheses. urology. 1973; 2:80. 5. lewis rw. arteriovenous surgeries: do they make any sense? in: lue tf. world book of impotence.london: smith-gordon; 1992; p.199. 6. craig f, donatucci md, lue tf. venous surgery: are we kidding ourselves? in: lue tf world book of impotence. london: smithgordon; 1992; p. 221. 7. virag r. intracavernous injection of papaverine for erectile failure. lancet. 1982; 2:938. 8. ishii n, watanabe h, irisawa c, et al. intracavernous injection of prostaglandin e1 for treatment of erectile impotence. j urol. 1989; 141:323. 9. nadig pw, ware jc, blumoff r. non invasive device to produce and maintain an erection-like state. urology. 1986; 27:12. 10. padma-nathan h, keller t, poppiti r, et al. hemodynamic effects of intraurethral alprostadil: the medicated urethral system for erection(muse). j urol. 1994; 151:469. 11. boolell m, allen mj, ballard sa, et al. sildenafil an orally active type 5 cyclic gmp-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. int j impot res. 1996; 8:47. 12. yeung ll, grewal s, bullock a, et al. a comparison of chlorhexidine-alcohol versus povidone-iodine for eliminating skin flora before pozza_stesura seveso 30/09/15 09:32 pagina 220 221archivio italiano di urologia e andrologia 2015; 87, 3 500 penile prostheses implanted in italy genitourinary prosthetic surgery: a randomized controlled trial. j urol. 2013; 189:136. 13. pozza d, rossello barbarà m, carrion h. l’utilizzazione del cavernotomo di carrion-rossello per l’impianto di protesi intracavernose. acta urol ital. 1993; 2:87. 14. wilson sk, delk jr 2nd. a new treatment for peyronie's disease: modeling the penis over an inflatable penile prosthesis. j urol. 1994; 152:1121. 15. egydio ph, kuehhas fe. distal penile shaft reconstruction and reinforcement: the "double-windsocks" technique. j sex med. 2013; 10:2571. 16. sadeghi-nejad h, ilbeigi p, wilson sk, et al. multi-institutional outcome study on the efficacy of closed-suction drainage of the scrotum in three-piece inflatable penile prosthesis surgery. int j impot res. 2005; 17:535. 17. wilson sk. rear tip extender sling: a quick and easy repair for crural perforation. j sex med. 2007; 4:231. 18. garber bb, bickell m. delayed postoperative hematoma formation after inflatable penile prosthesis implantation. j sex med. 2014; 28:1111. 19. muench pj. infections versus penile implants: the war on bugs. j urol. 2013; 189:1631. 20. talib ra, shamsodini a, salem ea, et al. isolated pump erosion of an inflatable penile prosthesis through the scrotum in a diabetic patient. arch ital urol androl. 2013; 85:53. 21. montague dk. penile prosthesis implantation: size matters. eur urol. 2007; 51:887. 22. caraceni e, utizi l. a questionnaire for the evaluation of quality of life after after penile prosthesis implant: quality of life and sexuality with penile prosthesis (qolspp): to what extent does the implant affect the patient's life? j sex med. 2014; 11:1005. 23. mondaini n, sarti e, giubilei g, et al. penile prosthesis surgery in out-patient setting: effectiveness and costs in the “spending review” era. arch ital urol androl. 2014; 86:161. 24. minervini a, ralph dj, pryor jp. outcome of penile prosthesis implantation for treating erectile dysfunction: experience with 504 procedures. bju int. 2006; 97:129. 25. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503. 26. grasso m, lania c, fortuna f, et al. evaluation of post-operative residual function of corpora cavernosa after softpenile prosthesis implant for peyronie's disease. arch ital urol androl. 2006; 78:49. 27. morey af. re: should being aged over 70 years hinder penile prosthesis implantation? j urol. 2011; 185:1328. correspondence diego pozza, md (corresponding author) diegpo@tin.it mariangela pozza, md mariangelapozza@gmail.com marco musy, md tortas@libero.it studio di andrologia e di chirurgia andrologica via b.gozzoli 82, 00142 roma, italy carlotta pozza, md carlotta.pozza@gmail.com department of experimental medicine, sapienza university of rome, roma, italy pozza_stesura seveso 30/09/15 09:32 pagina 221 introduction bladder cancer is the second most common tumour of the genito-urinary tract. in 2010, approximately 70,000 new cases of bladder cancer with almost 15,000 deaths were estimated in the usa alone (1). when the disease is first diagnosed it is non-muscle-invasive (nmibc) in 75-80% of cases while the remaining cases are muscle-invasive (mibc) (2). over 50% of nmibc recur, while 15-20% advance towards a muscle-invasive form. early diagnosis 73archivio italiano di urologia e andrologia 2013; 85, 2 original paper her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) luca bongiovanni 1, vincenzo arena 2, fabio maria vecchio 2, marco racioppi 1, pierfrancesco bassi 1, francesco pierconti 2 1 department of urology, 2 department of pathology catholic university of the sacred heart, policlinico “agostino gemelli”, rome, italy objectives: to evaluate if the human epidermal growth factor receptor 2 (her-2) expression levels may be used as potential prognostic marker in high grade t1 bladder cancer (t1g3) methods: specimens from transurethral resection of bladder tumour (turbt) of 103 patients with high-grade t1 bladder cancer were collected. this pathologic database was reviewed. four-year follow-up data were matched with pathologic data. eighty-three patients entered the study. her-2 staining was performed. patients were grouped for her-2 status. statistical analysis included kaplan meier survival analysis and log-rank test. results: pathological review of turbt specimens confirmed high-grade t1 transitional cell bladder cancer in all patients. median follow-up was 12 months (mean 23,5; range 3-48). twenty-one patients (25.4%) present strong her-2 expression (3+), 28 (33.7%) moderate expression (2+), 26 (33.7%) weak staining (1+) and 8 (9.6%) negative expression (0). thirtyone patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. forty-one patients had high grade t1 recurrence. patients with her-2 status 0 did not showed progression of disease. patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. median disease-free survival (dfs) for all patients was 12 months (dfs probability (pdfs) = 49.3%; 95% ci, -11.1/+10.1). median dfs in her-2 groups was 8 (pdfs 37.5%; 95% ci,-28.8/+29.9), 24 (pdfs 46.1%; 95% ci,-19.5/+17.5), 20 (pdfs 46.4%; 95% ci,-18.8/+16.9) and 10 months (pdfs 47.6%; 95% ci,-21.9/+19.1) respectively in her-2 status 0,1+,2+,3+. log-rank test is not statistically significant (p = 0,39). conclusions: this study showed that her-2 expression does not represent a prognostic marker of recurrence/progression of disease in high-grade t1 bladder cancer. key words: her-2 expression; prognostic marker; bladder cancer; t1g3. submitted 13 september 2012; accepted 30 december 2012 no conflict of interest declared summary of bladder tumour improves the patient’s prognosis and reduces the number of cases where cystectomy is needed. high-grade t1 lesions of the bladder (t1g3) have a high propensity to recur and progress to muscle invasion and are associated with a significant risk of metastasis and death. long-term progression and death rates as high as 53% and 34%, respectively, have been reported (3). these bladder tumours are heterogeneous in nature and bongiovanni_stesura seveso 24/06/13 11:01 pagina 73 archivio italiano di urologia e andrologia 2013; 85, 2 l. bongiovanni, v. arena, f.m. vecchio, m. racioppi, p. bassi, f. pierconti 74 from 103 subjects (74 males and 29 females; average age 67,8 years, range 41-90) undergoing complete transurethral resection of the bladder tumour (turbt) at department of urology, catholic university of sacred hearth, rome-italy. in january 2010 we have performed a review on this pathologic database. our uropathologist (f.p.) reviewed bladder tumour resection specimens in order to confirm stage/grade of the bladder tumour. the 2002 tnm classification (updated to 2009 tnm classification) was used for pathological staging. the 2004 who/isup classification was used for pathological grading. then, 4-year follow-up data (clinic database) of all patients were matched with pathologic data. inclusion criteria of the study encompassed, namely: presence of highgrade t1 transitional cell bladder cancer (established by pathological examination of complete turbt specimens in whom muscularis propria was present and negative), all patients were first-diagnosed bladder cancer, all patients had complete 4-year follow-up clinical data. exclusion criteria encompassed bacillus-calmetteguèrin(bcg)-treated patients following turbt; incomplete follow-up data. ten patients were excluded because not first-diagnosed, 8 because lost at first follow-up, 2 because incomplete follow-up data. eighty-three patients (67 males and 16 females, average age 69,2 years, range 45-88) of 103 entered the study. thus, her-2 ihc analysis was performed. this study was carried out in accordance with the guidelines set out by the ethics committee and all subjects prior to participation were required to sign an informed consent form. follow-up data the follow-up assessment adopted for these patients includes 3-months cystoscopy and urinary cytology for the first 2 years, then every 6 months for the following 2 years. no second tur was done. approximately after 2 to 4 weeks following turbt, bcg intravesical therapy induction course was performed, followed by bcg maintenance therapy if there was not evidence of disease recurrence/progression. ihc analysis of her-2 four-micron-tissue sections, prepared from a formalinfixed and paraffin-embedded representative of the tumor sample, were used (one to two conventional slides of tumor when available). after deparaffinization, rehydration and antigen retrieval in citrate buffer (10 mmol, ph 6,1), tissue sections were stained for her2 (a0485 policlonal antibody; 1/1500, dako, glostrup, denmark). her2 positivity was assessed using the asco scoring system, evaluating only membranous staining (20). specimen of normal breast tissue were used for negative control and invasive ductal breast carcinoma served as positive controls. the level of her2 protein expression was assessed semiquantitatively by the intensity and percentage of staining and score on a scale of 0 to 3+. score of 0 and 1+ are categorized negative, 2+ as weakly positive, and 3+ as strongly positive. score 0 was defined as negative membrane staining in all neoplastic cells or thus difficult to treat. nevertheless, many of these tumours can be treated successfully with bladder preservation approaches. the dilemma facing the urologist is how best to treat these tumours in a timely manner so that the chances of bladder preservation and cancer control are maximised, while the risks of overtreatment with radical therapy are minimised (4). useful prognostic variables and various biological makers have been proposed to assess the prognosis of bladder cancer, but the efficacy of these variables is still inadequate to accurately predict its heterogeneous behaviour. new reliable molecular indicators are required yet. also, during the past few decades, numerous trials have been conducted to develop new treatment regimens for both nmibc and mibc, because there is an urgent need to identify new agents to prevent bladder cancer recurrence and progression. human epidermal growth factor receptor 2 (her-2) is a transmembrane tyrosine kinase receptor in the epidermal growth factor receptor family and it plays a fundamental role in cell growth, survival and migration. abnormal activation of her-2 has been proposed to lead to oncogenic transformation (5, 6). human epidermal growth factors are involved in oncogenesis through its action on several pathways leading to proliferation, angiogenesis, cell survival and metastatic potential. the role of her-2 has been most studied in breast cancer, in which constitutively active her-2 is overexpressed in 18-22% of cases, correlating with poor prognosis (5, 6). but the prognostic significance of her2 expression status in transitional cell carcinoma (tcc) of the bladder remains uncertain. numerous studies showed that higher her-2 expression levels are associated with poor prognosis (7-10). recently her-2 positivity was identified as an independent predictor of disease recurrence and disease specific survival in patients with tcc of the bladder after radical cystectomy (11). in contrast, other analysis showed only limited or no prognostic value of her-2 expression (12-17). using tissue microarray (tma) data of 184 patients with primary tcc of the bladder, kassouf et al. reported no significant correlation between her-2 expression status and clinical outcomes (16). similarly, another study reported no statistically significant difference in survival rates of 80 consecutive patients with mibc between cases positive and normal her-2 status (12). however, a positive her2 protein expression status could represents a potential prognostic factor in patients affected by tcc of the bladder, particularly in high-grade t1 lesions, and it could be used as a novel target for adjuvant therapy (18, 19). thus, the purpose of our work was to evaluate her-2 immunohistochemical (ihc) expression as prognostic marker of disease recurrence and/or progression in highgrade t1 bladder tumour (t1g3). methods patients selection, inclusion and exclusion criteria. from june 2005 to october 2006, specimens of highgrade t1 transitional cell bladder cancer were collected bongiovanni_stesura seveso 24/06/13 11:01 pagina 74 75archivio italiano di urologia e andrologia 2013; 85, 2 her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) groups) and its matching with follow-up data (no evidence of disease (ned), recurrence (rec) and progression (prog) data). please note that 31 patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. thus, 41 patients had high-grade t1 recurrence, 8 patients of whom with an association of carcinoma in situ of the bladder (cis). eleven patients of 83 showed progression from nmibc to mibc, requiring cystectomy. her-2 status and its relative association with pathological examination of cystectomy specimens is reported in table 2. high-grade t1 lesions with her-2 status 0 did not showed progression of disease. interestingly, all patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. figure 2 and 3 shows the kaplan meier plots of dfs for all patients and dfs between the 4 patient groups of her-2 status. median dfs for all patients was 12 months (dfs probability (pdfs) = 49.3%; 95% ci, -11.1/+10.1). median dfs in her-2 groups was respectively: • her-2 status 0 = 8 months (pdfs 37.5%; 95% ci, -28.8/+29.9); • her-2 status 1+ = 24 months (pdfs 46.1%; 95% ci, -19.5/+17.5); when membrane staining was observed in <10% the tumor cells. score 1+ was defined as faint/ barely perceptible membrane staining in > 10% of the cells and the cells exhibit incomplete membrane staining. score 2+ was defined weak-to-moderate complete membrane staining detected in > 10% of tumor cells. score 3+ was defined a strong complete membrane staining in > 10% of tumor cells (figure 1). a cytoplasmic staining was considered non specific. outcome measures and statistical analysis after her-2 staining, patients were grouped for her-2 status in 4 groups. kaplan-meier survival analysis was performed to obtain survival values as disease-free survival (dfs) for all patients and dfs between 4 patient groups of her-2 status. the difference in survival rates was determined by logrank test. statistical significance (p) was set at 0.05. statistical tests were carried out using medcalc statistical software (medcalc software bvba, mariakerke belgium). results pathological review of bladder tumour specimens confirmed high-grade t1 transitional cell bladder cancer in all patients (average diameter of lesions 2 cm, range 13,5 cm). median follow-up was 12 months (mean 23,5; range 3-48) regarding the expression of her-2 protein, 21 patients (25.4%) present strong expression (her-2 score 3+), 28 (33.7%) moderate expression (her-2 score 2+), 26 (33.7%) weak staining (her-2 score 1+) and 8 (9.6%) negative expression (her-2 score 0). table 1 shows her-2 status of patients (grouped in 4 figure 1. membrane her-2 stain intensity. her-2 status n (%) ned (%) rec (%) prog (%) (0) 8 (9.6) 1 (3.2) 7 (17.2) 0 (0) (1+) 26 (31.3) 11 (35.5) 11 (26.8) 4 (36.4) (2+) 28 (33.7) 12 (38.7) 13 (31.7) 3 (27.2) (3+) 21 (25.4) 7 (22.6) 10 (24.3) 4 (36.4) total 83 (100) 31 (100) 41 (100) 11 (100) (37.4) (49.4) (13.2) table 1. her-2 status of patients (grouped in 4 groups) and its matching with follow-up data (no evidence of disease (ned), recurrence (rec) and progression (prog) data). her-2 status prog (%) pathological examination of cystectomy specimens (0) 0 (0) no cystectomy specimens (1+) 4 (36.4) 3 (pt2a pn0 pmx g3) 1 (pt3a pn1 pmx g3) (2+) 3 (27.2) 2 (pt2b pn0 pmx g3) 1 (pt3a pn1 pmx g3) (3+) 4 (36.4) 2 (pt3a pn1 pmx g3) 1 (pt3a pn2 pmx g3) 1 (pt4a pn2 pmx g3) total 11 (100) table 2. her-2 status and its association with pathological examination of cystectomy specimens. bongiovanni_stesura seveso 24/06/13 11:01 pagina 75 archivio italiano di urologia e andrologia 2013; 85, 2 l. bongiovanni, v. arena, f.m. vecchio, m. racioppi, p. bassi, f. pierconti 76 • her-2 status 2+ = 20 months (pfs 46.4%; 95% ci, -18.8/+16.9); • her-2 status 3+ = 10 months (pdfs 47.6%; 95% ci, -21.9/+19.1). log-rank test was not statistically significant (p = 0,39). discussion at each stage of bladder cancer, clinical management strategies are aimed at preventing disease recurrence/progression and the use of unnecessary and potentially lifealtering procedures. once the disease becomes muscle-invasive, the main goal of treatment is threefold: to maximize long-term survival, to prevent pelvic recurrence or metastases, and to provide a good quality of life (21). general guidelines exist for treatment of high-risk tcc of the bladder (22, 23). however, to predict exactly which patients will progress, and who could, therefore, require more aggressive therapy, needs an individualized approach, although assessment remains more an art than science (24). zhau et al. reported her2 amplification and overexpression in bladder cancer for the first time in 1990 (25). in contrast with its known importance in breast cancer, the significance of her2 expression and/or her-2 gene amplification in bladder cancer is controversial. it was found that her2 is overexpressed with a greater frequency in higher grades (40%) and stages (38%) than in lower grades (0%) and stages (8%)[8] and several studies confirmed that her-2 could have a role as prognostic factor in bladder cancer, correlating its overexpression with poor prognosis for patients (shorter median survival time, reduced complete response to chemoradiation therapy) (8, 10, 13, 26-29). recently bolenz et al. identify her-2 positivity as an independent predictor of disease recurrence and specific survival in patients tcc of the bladder after radical cystectomy (11). in literature other data seem to indicate limited or no prognostic value of her-2 expression (12, 14-17). in a large series of patients with primary tcc of the bladder, no significant correlation between her-2 expression status and clinical outcome it has been reported (15). moreover, no statistically significant difference in the survival rates of 80 consecutive patients with mibc has been observed (14). a recent study showed that, in a large series of transurethral resection and cystectomy (1005 cases), 5,1% of mibc had a her-2 gene amplification with complete concordance (100%) between ihc and fluorescence in situ hybridization (fish) analyses (30). these variations in results are due to the heterogeneity of studies with respect to kits and type of antibodies used for ihc analysis, protocols, stage of the disease studied (nonmuscle-invasive vs muscle-invasive), definition of her-2 positivity and the material studied (fresh/formalin fixed). thus, discordant results reported in the literature highlight a need for standardized laboratory methods. in our work we evaluate her-2 ihc expression as prognostic marker of disease recurrence and/or progression in high-grade t1 bladder tumour (t1g3) high grade t1 lesions with her-2 status 0 did not showed progression of disease. interestingly, all patients with her-2 status 3+, undergoing cystectomy because progression of disease, had a pathological stage > pt2 and a nodal involvement. no statistically significant association between her-2 ihc expression and recurrence/progression of disease it has been found. conclusions this study showed that her-2 expression does not represent a prognostic marker of recurrence/progression of disease in high-grade t1 bladder cancer. the numbers of this cohort are actually quite small and they could affect the significance of statistical analysis. further studies analyzing a large group of disease progression are needed. figure 3. kaplan meier plot of disease-free survival (%) for groups of her-2 status. figure 2. kaplan meier plot of disease-free survival (%). bongiovanni_stesura seveso 24/06/13 11:01 pagina 76 references 1. jemal a, siegel r, xu j, et al. cancer statistics, 2010. ca cancer j clin. 2010; 60:277-300. 2. malkowicz sb, van poppel h, mickisch g, et al. muscle-invasive urothelial carcinoma of the bladder. urology. 2007; 69(1 suppl):3-16. 3. cookson ms, herr hw, zhang zf, et al. the treated natural history of high risk superficial bladder cancer: 15-year outcome. j urol. 1997; 158:62-67. 4. kulkarni gs, hakenberg ow, gschwend je, et al. an updated critical analysis of the treatment strategy for newly diagnosed high-grade t1 (previously t1g3) bladder cancer. eur urol. 2010; 57:60-70. 5. olayioye ma, neve rm, lane ha, et al. the erbb signaling network: receptor heterodimerization in development and cancer. embo j. 2000; 19:3159. 6. yarden y. biology of her2 and its importance in breast cancer. oncology. 2001; 61(suppl.2):1. 7.sato k, moriyama m, mori s, et al. an immunohistologic evaluation of c-erbb-2 gene product in patients with urinary bladder carcinoma. cancer. 1992; 70: 2493 8. kruger s, weitsch g, buttner h, et al. overexpression of c-erbb2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome. int j oncol. 2002; 21:981. 9. lipponen p, eskelinen m, syrjanen s, et al. use of immunohistochemically demonstrated c-erb b-2 oncoprotein expression as a prognostic factor in transitional cell carcinoma of the urinary bladder. eur urol 1991; 20:238. 10. kolla sb, seth a, singh mk, et al. prognostic significance of her2/neu overexpression in patients with muscle invasive urinary bladder cancer treated with radical cystectomy. int urol nephrol. 2008; 40:3219. 11. bolenz c, shariat s, karakiewicz p, et al. human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. bju 2010; 106:1216. 12. mellon jk, lunec j, wright c, et al. c-erbb-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value. j urol. 1996; 155:321. 13. jimenez re, hussain m, bianco fj, et al. her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. clin cancer res. 2001; 7:2440. 14. liedberg f, anderson h, chebil g, et al. tissue microarray based analysis of prognostic markers in invasive bladder cancer: much effort to no avail? urol oncol. 2008; 26:17. 15. chow nh, chan sh, tzai t, et al. expression profiles of erbb family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. clin cancer res. 2001; 7:1957. 16. kassouf w, black pc, tuziak t, et al. distinctive expression pattern of erbb family receptors signifies an aggressive variant of bladder cancer. j urol. 2008; 179:353. 17. lonn u, lonn s, friberg s, et al. prognostic value of amplification of c-erb-b2 in bladder carcinoma. clin cancer res. 1995; 1:1189. 18. bellmunt j, albiol s, suarez c, et al. optimizing therapeutic strategies in advanced bladder cancer: update on chemotherapy and the role of targeted agents. crit rev oncol hematol. 2009; 69:211. 19. shariat sf, karam ja, lerner sp. molecular markers in bladder cancer. curr opin urol. 2008; 18:1. 20. wolff ac, hammond me, schwartz jn, et al. american society of clinical oncology/college of american pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. j clin oncol. 2007; 25:118. 21. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001; 19:666-675. 22.stenzl a, cowan nc, de santis m, et al. treatment of muscleinvasive and metastatic bladder cancer: update of the eau guidelines. eur urol. 2011; 59:1009-1018. 23. hall mc, chang ss, dalbagni g, et al. guideline for the management of non-muscle-invasive bladder cancer (stages ta, t1, and tis): 2007 update. j urol. 2007; 178:2314-2330. 24. chang ss, cookson ms. non-muscle-invasive bladder cancer: the role of radical cystectomy. urology. 2005; 66:917-922. 25. zhau he, zhang x, von eschenbach ac, et al. amplification and expression of the c-erb b2/neu protooncogene in human bladder cancer. mol carcinog. 1990; 3:254-25. 26. gandour edward r, lara pn jr, folkins ak, et al. does her2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? cancer. 2002; 95:1009. 27. wolff ac, hammond me, schwartz jn, et al. american society of clinical oncology/college of american pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. j clin oncol. 2007; 25:118. 28. chakraverti a, winter k, wu cl, et al. expression of the epidermal growth factor receptor and her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the radiation therapy oncology group. int j radiat oncol biol phys. 2005; 62:209. 29. underwood m, bartlett j, reeves j, et al. c-erbb-2 gene amplification: a molecular marker in recurrent bladder tumors? cancer res. 1995; 55:2422. 30. laé m, couturier j, oudard s, et al. assessing her2 gene amplification as a potential target for therapy in invasive urothelial bladder cancerwith a standardized methodology: result in 1005 patients. ann oncol. 2010; 21:815. 77archivio italiano di urologia e andrologia 2013; 85, 2 her-2 immunohistochemical expression as prognostic marker in high-grade t1 bladder cancer (t1g3) correspondence luca bongiovanni, md, phd (corresponding author) lucabongiov@yahoo.it vincenzo arena, md fabio maria vecchio, md marco racioppi, md pierfrancesco bassi, md francesco pierconti, md, phd department of pathology catholic university of the sacred heart, policlinico “agostino gemelli" l.go f. vito 1 00168 rome, italy bongiovanni_stesura seveso 24/06/13 11:01 pagina 77 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2126 review painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management william rourke 1, shahid aziz anwer khan 2, kamran ahmed 1, shikohe masood 3, prokar dasgupta 1, muhammad shamim khan 1 1 mrc centre for transplantation, king’s college london, department of urology, guy’s hospital, london, uk; 2 east surrey hospital, canada ave, redhill, uk; 3 medway maritime hospital, windmill road, gillingham, kent, uk. interstitial cystitis or bladder pain syndrome (bps) is often a chronic debilitating condition characterised by predominantly storage symptoms and associated frequently with pelvic pain that varies with bladder filling. the aetiology is uncertain as the condition occurs in the absence of a urinary tract infection or other obvious pathology. resulting discomfort may vary and ranges from abdominal tenderness to intense bladder spasms. diagnosis and management of this syndrome may be difficult and is often made by its typical cystoscopic features. this review discusses the diagnosis and management of interstitial cystitis according to the current available best evidence and advises a multimodal approach in its management. key words: bladder pain syndrome; interstitial cystitis; chronic pelvic; treatment; management; diagnosis. submitted 26 august 2013; accepted 15 january 2014 summary introduction interstitial cystitis (ic)/painful bladder syndrome (pbs) was defined in 2005 by the international society of bladder pain syndrome (essic) as “the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology”. the definition of ic is the same as pbs, while also including “typical cystoscopic and/or histological features”. the essic collectively term ic and pbs as bladder pain syndrome (bps), however it’s important that the distinction is made as this can affect patient management (1). to further define bps, it’s important to recognise that it is a form of chronic pelvic pain (cpp), and therefore this review investigates not only its role but also other factors relating to cpp (2). cpp is difficult to classify, as it is defined by the symptom of pain and has no obvious associated cause, much the same as bps (2). rackow et al. define cpp as ‘pain that persists for six months requiring medical evaluation and intervention’. they concluded that in young women bps is an aetiological factor for no conflict of interest declared. cpp (3). this highlights the importance of considering both of them together by examining other factors beyond the bladder, as the cause of bps. in their case study, warren et al. found that the strongest risk factor for bps is non-bladder syndromes (4). therefore, studying the pathogenesis of non-bladder syndrome, of which cpp is included, might reveal the pathogenesis of bps (4). prevalence rand interstitial cystitis epidemiology (rice) conducted 146,231 household telephone calls in the united states and found that, according to the high sensitivity definition, 6.53% (95% ci 6.28, 6.79) of women met the symptom criteria of a bps sufferer. based on the high specificity definition, 2.70% (95% ci 2.53, 2.86) women met the criteria of a bps sufferer. the study showed that bps is an under-diagnosed condition and its prevalence may be higher in the population (5). parsons et al. concur with rice’s study in as much that ic/pbs has a substantially underestimated prevalence (6). after surveying 8 studies, carried out between 1975 and 2005, they suggested that the prevalence over the last decade was 197 for every 100,000 women and 41 for every 100,000 men in the united states (6). nickel et al. found the prevalence of interstitial cystitis to be 7.9% in women and 0.4% men when 48 urologists completed an audit on the cases seen in their outpatient practice, showing it’s a condition that affects women more often than men (7). aetiology a lack of consensus on how to classify bps means that its aetiology is still uncertain. a number of theories have been proposed as the mechanisms involved are poorly understood and in order to obtain a clear understanding, it is imperative that the risk factors are fully evaluated. kennedy et al. surveyed 645 women, and noted a positive correlation with smoking, irritable bowel syndrome (ibs) and generalised pain disorder (8). a twins study by tettamanti et al. contradicted this result, concluding that smoking is likely to be the confounding factor. they however found that tea consumption increased the likelihood of experiencing bps (9). nickel et al. noted ibs is doi: 10.4081/aiua.2014.2.126 rourke_stesura seveso 04/07/14 12:04 pagina 126 127archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management more prevalent in sufferers of bps (10). this association is important, the understanding of which may be significant in comprehending the aetiology of bps. one suggestion put forward was that the clinical components of sufferers of bps, ibs or systemic pain syndromes could be the three stages of a single combined syndrome. this proposed syndrome progresses from being organ specific initially, which is the bladder in the case of bps, then progressing regionally and finally eventually leading to systemic pain syndrome (10). this theory is similar to that proposed by butrick et al. who described the bladder as a ‘symptom generator’ for cpp (11). 1a. genetics the importance of genetic factors responsible for bps is mounting and is based on the high prevalence of bps in first degree relatives (12). in a study of 25,000 twins, altman et al. found that there was a genetic component to the aetiology of bps. for the first time, they were able to assess the importance of genetic and environmental influences on the possibility of developing bps in a large population of monozygotic and dizygotic twins (13). 1b. previous surgery ingber et al. found in a survey carried out on women with bps, that here was a statistically higher prevalence of pelvic surgeries. they state that most of the surgeries were carried out before the diagnosis of bps, inferring that the increase in surgeries observed is not due to the bps diagnosis (14). langenberg et al. study shows more bps suffers have had pelvic surgery than the control group. however, the study does conclude that there is a high chance that the reason for the pelvic surgery is a confounding factor. the study provides evidence that cpp in particular may be the reason for many of the surgeries whilst also being the cause of it (15). 1c. infection warren et al. carried out a case-control study and found that 18% to 36% women showed evidence of a urinary tract infection (uti) at the onset of bps (16). warren et al. proposed two hypotheses for the pathogenesis of utis that could cause bps. the first hypothesis is that the acute symptoms are the start of the chronic disease. the other possibility is that uti causes a physiological response that result in bps (16). 1d. glycosaminoglycan layer defects urothelial glycosaminoglycans (gags) line the bladder’s surface and it has been hypothesised that a deficiency in gags reduces protection of the bladder wall, resulting in bps. engelhardt et al. describe the gag layer as the urinetissue barrier and showed the long-term efficacy of treatment with intravesical hyaluronan; this successful treatment is the best indication that the urine-tissue barrier hypothesis is correct (17). maccari et al. conducted a study that shows that this hypothesis cannot be proven by levels of urinary gags, as they are not representative of the amount of urothelial gags. this study is important to oppose the use of urinary gags concentration as a diagnostic tool (18). 1e. neurobiology/no metabolism in a study by aizawa et al. it was found that nitric oxide (no) has a major role in the control of bladder filling by modulating the afferent nerves in rats. no signalling may therefore play a major role in the hypersensitivity of bps (19). kumar et al. found that adenosine triphospahte (atp) is released from the urothelium of bladders with overactive detrusor activity; which has been observed in bps sufferers (20). daly et al. concluded that recent studies showed further evidence of the role of excitatory and inhibitory mediators, from the urothelium, which act on afferent nerves. these afferent nerves have been implicated in the symptoms of urgency and frequency in bps. the review concludes that a better understanding of the afferent system of the bladder will provide a good therapeutic target for bps (21). 1f. mast cells/autoimmunity whilst experimenting on mice, chen et al. showed that bps is associated with the activation of distinct mast cell pools in the bladder. this release was found to be mediated by tumour necrosis factor (tnf). the pain in bps may be attributed to the release of the inflammatory mediators from the mast cells. it has been further hypothesised that an autoimmune response may be responsible for the irritation of the bladder (22, 23). patient evaluation in the aua guidelines by hanno et al, the complications with diagnosis of bps become apparent. the variety of definitions, the complex aetiology and the insufficient number of publications makes its diagnosis complex. therefore, diagnosis is partly based on the exclusion of other diseases. diagnosis is often based on a ‘clinical principle’ which is an informal consensus among urologist that may or may not be based on evidence from within the medical literature (24). when a patient presents with symptoms of cpp, a full history and examination must first be carried out with the elimination of differential diagnoses. in the event of a complicated diagnosis, a cystoscopy and/or urodynamics should be considered (25). when taking a full history, physicians should put emphasis on the symptoms and common risk factors. nipkow et al. describe the symptoms to be urgency, frequency and suprapubic pain (26). hanno et al. reported that the pain sufferers of bps describe is related to bladder filling and occurs suprapubically but in can include pain in the urethra, vulva, vagina and the rectum (24). it is important to recognise that this pain can be described as a feeling of ‘pressure’. the symptoms can be affected by the consumption of specific food and drinks and the presence of these symptoms strongly suggests bps. hanno et al. state that, alongside the patient’s pain history, the general history should include assessment of risk factors such as: previous pelvic operations, urinary tract infections (uti), history of urological diseases, previous pelvic radiation treatment and the presence of autoimmune diseases (24). in a cohort study by butrick et al., significant number of patients presented not with pain but with either stress/urge urinary incontinence or pelvic rourke_stesura seveso 04/07/14 12:04 pagina 127 archivio italiano di urologia e andrologia 2014; 86, 2 w. rourke, s. aziz anwer khan, k. ahmed, s. masood, p. dasgupta, m.shamim khan 128 organ prolapse. therefore, these should also be considered during evaluation (11). a common physical exam of the lower abdomen should followed by assessment of bladder fullness and suprapubic tenderness. in female patients, a vaginal exam should be carried out and the presence of pain involving the vulva, vagina or the surrounding organs should be carefully documented. in men, digital rectal exam is recommended with pain mapping of the scrotal-anal region (24). a urine dipstick should be used to eliminate the differential diagnosis of an infection. if ‘sterile pyuria’ is detected then, a culture for tuberculosis and fastidious organisms should be performed (25). in complicated presentations, it is recommended that urodynamics and cystoscopy should be included. kuo et al. found that the common urodynamic findings in bps sufferers were the presence of early sensory urgency and reduced bladder capacity. their study showed that symptoms of urgency and pain coupled with a small cystometric bladder capacity of less than 350 ml and a positive potassium chloride test is diagnostic of bps with a positive predictive value of 91.2% (27). the essic define ic based on the classic findings of ulcer’s noted on a cystoscopy (28). the classic patch of red urothelium with radiating small blood vessels was first described by hunner in 1914 (29). the presence of these lesions is associated with pain and urinary urgency and removal of these lesions can improve these urinary symptoms. glomerulations can also be identified during cystoscopy of patients affected by bps (30, 31). the cytoscopic features are considered in the context of the essic standardised procedure for cystoscopy involving systematic inspection of the bladder wall and grading of the lesions based on the lesion type (table 1) (28). management the poorly understood aetiology of bps has brought about many different treatment and management options. they include different types of behavioural, dietary, interventional, pharmacologic and surgical therapies. conservative conservative therapy options should be exhausted before providing less reversible surgical therapies. initial therapy for bps should focus on educating the patient and providing them with an understanding of the common exacerbating factors and treatment options. hanno et al. state that behaviour modification can improve symptoms and therefore should be the first avenue of treatment. patients should be told to avoid certain foods and drink; commonly, coffee and citrus products as these are irritants. certain types of exercise, sexual intercourse, stress, tight-fitting clothing and constipation may also be exacerbating factors in some patients. relieving factors should be explained such as local heat or cooling over the bladder region and pelvic floor relaxation techniques (24). oral therapy 2a. pentosan polysulfate oral pentosan polysulfate (pps) is the only oral medication approved by the us food and drug administration (fda) for bps. it has a structure similar to that of the gags in the urinary tract and therefore allows restoration of the urothelial layer, reducing the amount of noxious substance stimulating the sub-mucosal nerves (32, 33). 2b. analgesics pain management is an important part in the management of bps, however it is not sufficient and other avenues of treatment should be explored. in complicated cases, a multidisciplinary team approach to pain management may be required (24). gabapentin, an epileptic drug used in combination with amitriptyline and nsaids has shown considerable promise in reducing the oab symptoms after 4 weeks of treatments. large scale studies are however needed to verify these results (34). 2c. antidepressants amitriptyline is recommend by the american urological association for its mast cell stabilising effect (24). however, evidence to support this is mainly from single site clinical trials and case reports. a multicentre, randomised control trial carried out by foster et al. showed that there was no significant improvement in symptoms of bps sufferers when treated with amitriptyline. however, they conclude that if a daily dose of 50 mg or greater can be achieved, then amitriptyline may be of benefit (35). 2d. h2-receptor antagonist in a pilot study, seshadri et al. found encouraging results with the use of cimetidine in the treatment of bps. using the h2-antagonists (300 mg bd orally); 66% of patients experienced symptom relief while 44% reported a complete and sustained response (36). 2e. antihistamines hydroxyzine, a mast cell stabilizer seems and thus may play a role in mediating the inflammatory processes observed in pbs/ic. however the only reported study reporting hydroxyzine as a treatment for ic is an open label, non-consecutive case series. given the multifactorial aetiology of pbs/ic, patients with bladder mastocytosis seemed to benefit more from the treatment (37). grade lesion type 0 normal mucosa 1 petechiae in at least 2 quadrants 2 large sub-mucosal bleeding 3 diffuse global mucosal bleeding 4 mucosal disruption with or without bleeding/oedema table 1. essic grading based on lesion type identified by cystoscopy (28). rourke_stesura seveso 04/07/14 12:04 pagina 128 129archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management intravascular tanezumab mast cell degranulation is a proposed aetiology for bps. in the study by evans et al. the degranulation of mast cells resulted in the release pro-inflammatory agents, one of which is the neurotrophin ngf. ngf is involved in the generation of pain in tissue injury and inflammation (38). tanezumab is a proposed drug that is administered intravenously and is composed of anti-ngf antibodies and thus it prevents interaction with pain receptors on afferent neurones. the results showed that patients that took tanezumab were 7 times more likely to have a 50% or greater reduction in pain compared to the placebo arm. they also observed a significant reduction in urgency episodes. intravesical therapy 3a. dimethylsulfoxide dimethylsulfoxide is an anti-inflammatory, analgesic and muscle relaxant (39). it was approved to treat bps since 1977 and is the most commonly prescribed intra-vesical therapy. it results in symptom improvement in 50% of patients with bps (33). 3b. heparin heparin acts by replacing the damaged gag layer and therefore restores the urothelial barrier. it is used alone or in combination with pps and can provide immediate symptom relief (33, 39). 3c. liposomes a study carried out by lee et al. concluded that intravesical administration of liposomes once a week for one month resulted in 50% improvement with the effect being maintained for 2 months. it was concluded that liposomes help maintain the urothelial barrier. the study also concluded that the use of intravesical liposomes, injected once a week for 4 weeks could achieve either a similar or better effect compared to oral pentosan polysulfate. they suggested that more frequent treatment may improve clinical outcome. however, they further large-scale studies, with placebo controls, are required to fully evaluate the effect of intravesical liposomes (32). 3d. bacillus calmette-guerin (bcg) bcg works on the basis of an autoimmune aetiology therefore acting via an immunological mechanism (39). peters et al. showed in a long-term follow up of patients treated with bcg that 89% continued to have excellent response when evaluating 24 to 33 months after treatment was initiated (40). 3e hyaluronic acid and chondroitin sulphate intravesical hyaluronic acid (gag) mono therapy or in combination with sodium chondroitin sulphate (synthetic gag) offers effective symptom improvement and long-term efficacy in the treatment of bps (41). nickel et al. demonstrated in their rct that sodium chondroitin offers safe and effective treatment leading to a greater reduction in icsi (interstitial cystitis symptom index) and vas (visual analogue score) when compared with controls. however, it must be made clear that replacement therapy should only be effective in patients with ic/bps and gag abnormalities or deficiencies. the uncertain aetiology of bps/ic therefore requires a multimodal approach and monotherapy with the above agents is therefore not advocated (42). surgical 4a. botulinum toxin pinto et al. used the noxious relieving effects of botulinum toxin as pain relief in bps patients (43). their study investigated the effect of trigonal botulinum toxin injections and established that the treatment was both safe and effective. a pilot study by gottsch et al. showed that periurethral injections of botulinum toxin however did not effectively treat the pain symptoms of bps (44). botox should be considered when other intra-vesical therapies have failed. 4b. hydrodistension as explained by aihara et al., hydro-distension has an unknown mechanism of action but it has been shown in animal studies to damage the sub-mucosal nerve plexus forming the basis of its therapeutic use. they reported that hydro-distension was therapeutically effective in 71% of patients after one month but the affect diminished over time and only 37% of patients reported improvement at 6 months. in conclusion, therapeutic use of hydro-distension has a poor long term efficacy (45). 4c. transuretheral resection – coagulation of hunners lesions hunner first described the lesion that could be resected to relieve symptoms. cystoscopic ablation of ‘hunners lesions’ can result in temporary improvement in symptoms and the procedure could be repeated if symptoms recurred (29, 30). 4d. sacral neuromodulation sacral neuromodulation is a minimally invasive procedure in which the s3 sacral nerve is stimulated by a mild electrical current generated via a pulse generator. several studies have demonstrated it to be effective in the management of refractory pbs with good long-term outcomes. the main reported adverse effects of this treatment apart from the risks of bleeding or infection relate to lead displacement, device malfunction and early replacement which have cost implications (46). 4e. cystoplasty enterocystoplasty is a popular technique when bps is refractory to conservative therapies. the basis for the treatment is to enlarge the bladder and provide symptom relief. trigone sparing techniques allow for reduced complications by avoiding ureteral reflux. it has also been found that ileocecal bowel segments offer better results. ophoven et al. concluded that enterocytoplasty remains a rourke_stesura seveso 04/07/14 12:04 pagina 129 archivio italiano di urologia e andrologia 2014; 86, 2 w. rourke, s. aziz anwer khan, k. ahmed, s. masood, p. dasgupta, m.shamim khan 130 valuable surgical intervention with 15 of the 18 patients reporting excellent therapeutic results (47). 4f. urinary diversion the most common surgical treatment for bps is urinary diversion with the formation of an ileal conduit (25). this is the most invasive option and being irreversible requires strict selection criteria and careful patient evaluation. rossberger et al. found that 94% of patients with hunner-type disease reported complete resolution of their symptoms (48). it was also found that the treatment for those with hunner-type disease is far more unpredictable and this should be factored in when urinary diversion is being contemplated. furthermore, before contemplating irreversible intervention, patients must be made clear that the pain may not disappear even after a urinary diversion. conclusions this review shows the complexity behind the aetiology of bladder pain syndrome. this tangled web of hypothesis creates confusion in the diagnosis and its subsequent m<anagement. the importance of research particularly pertaining to the aetiology of bps has been highlighted. this should provide physicians with a common understanding of the syndrome so that diagnosis is established early and an effective management plan tailored to the patient needs are devised. references 1. van de merwe jp, nordling j, bouchelouche p, et al. diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an essic proposal. eur urol. 2008; 53:60-7 2. fall m, baranowski ap, elneil s, et al. eau guidelines on chronic pelvic pain. eur urol 2010; 57:35-48. 3. rackow bw, novi jm, arya la, pfeifer sm. interstitial cystitis is an etiology of chronic pelvic pain in young women. j pediatr adolesc gynecol 2009; 22:181-5. 4. warren jw, clauw dj, wesselmann u, et al. sexuality and reproductive risk factors for interstitial cystitis/painful bladder syndrome in women. urology. 2011; 77:570-5. 5. berry sh, elliott mn, suttorp m, et al. prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the united states. j urol 2011; 186:540-4. 6. parsons jk, kurth k, sant gr. epidemiologic issues in interstitial cystitis. urology. 2007; 69(4 suppl):5-8. 7. nickel jc, teichman jmh, gregoire m, et al. prevalence, diagnosis, characterization, and treatment of prostatitis, interstitial cystitis, and epididymitis in outpatient urological practice: the canadian pie study. urology. 2005; 66:935-40. 8. kennedy cm, bradley cs, galask rp, nygaard ie. risk factors for painful bladder syndrome in women seeking gynecologic care. int urogynecol j pelvic floor dysfunct 2006; 17:73-8. 9. tettamanti g, nyman-iliadou a, pedersen nl, et al. influence of smoking, coffee, and tea consumption on bladder pain syndrome in female twins. urology. 2011; 77:1313-7. 10. nickel jc, tripp da, pontari m, et al. interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. j urol 2010; 184:1358-63. 11. butrick cw, sanford d, hou q, mahnken jd. chronic pelvic pain syndromes: clinical, urodynamic, and urothelial observations. int urogynecol j pelvic floor dysfunct 2009; 20:1047-53. 12. warren jw, jackson tl, langenberg p, et al. prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. urology 2004; 63:17-21 13. altman d, lundholm c, milsom i, et al. the genetic and environmental contribution to the occurrence of bladder pain syndrome: an empirical approach in a nationwide population sample. eur urol 2011; 59:280-5. 14. ingber ms, peters km, killinger ka, et al. dilemmas in diagnosing pelvic pain: multiple pelvic surgeries common in women with interstitial cystitis. int urogynecol j pelvic floor dysfunct 2008; 19:341-5. 15. langenberg pw, wallach ee, clauw dj, et al. pelvic pain and surgeries in women before interstitial cystitis/painful bladder syndrome. am j obstet gynecol 2010; 202:286.e1-6. 16. warren jw, brown v, jacobs s, et al. urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome. urology 2008; 71:1085-90. 17. engelhardt pf, morakis n, daha lk, et al. long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis. int urogynecol j 2011; 22:401-5. 18. maccari f, buzzega d, galeotti f, volpi n. fine structural characterization of chondroitin sulfate in urine of bladder pain syndrome subjects. int urogynecol j 2011; 22:1581-6. 19. aizawa n, igawa y, nishizawa o, wyndaele j-j. effects of nitric oxide on the primary bladder afferent activities of the rat with and without intravesical acrolein treatment. eur urol 2011; 59:264-71. 20. kumar v, chapple cr, rosario d, et al. in vitro release of adenosine triphosphate from the urothelium of human bladders with detrusor overactivity, both neurogenic and idiopathic. eur urol 2010; 57:1087-92. 21. daly dm, collins vm, chapple cr, grundy d. the afferent system and its role in lower urinary tract dysfunction. curr opin urol 2011; 21:268-74. 22. chen mc, blunt lw, pins mr, klumpp dj. tumor necrosis factor promotes differential trafficking of bladder mast cells in neurogenic cystitis. j urol 2006; 175:754-9. 23. ratliff tl, klutke cg, hofmeister m, et al. role of the immune response in interstitial cystitis. clin immunol immunopathol 1995; 74:209-16. 24. hanno pm, burks da, clemens jq, et al. aua guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. j urol 2011; 185:2162-70. 25. vij m, srikrishna s, cardozo l. interstitial cystitis: diagnosis and management. european j obstetr gynecol reprod biol 2012; 161:1-7. 26. nipkow l, chai tc. interstitial cystitis: modern tools for an accurate diagnosis. curr urol rep 2003; 4:381-4. 27. kuo yc, kuo hc. potential factors that can be used to differentiate between interstitial cystitis/painful bladder syndrome and bladder oversensitivity in women. int j clin pract 2012; 66:146-51. 28. van de merwe jp, nordlingg jr, editors. interstitial cystitis : definitions and confusable diseases 2005. rourke_stesura seveso 04/07/14 12:04 pagina 130 131archivio italiano di urologia e andrologia 2014; 86, 2 painful bladder syndrome/interstitial cystitis: aetiology, evaluation and management 29. hunner gl. a rare type of bladder ulcer in women; report of cases. the boston medical and surgical journal 1915; 172:660-4. 30. payne ra, connor rco, kressin m, guralnick ml. endoscopic ablation of hunner’s lesions in interstitial cystitis patients can urol assoc j. 2009; 3:473-7. 31. tomaszewski je, landis jr, russack v, et al. symptoms in interstitial cystitis: results from the interstitial cystitis database study. 1993; 4295:67-81. ??? 32. lee w-c, chuang y-c, lee w-c, chiang p-h. safety and dose flexibility clinical evaluation of intravesical liposome in patients with interstitial cystitis or painful bladder syndrome. kaohsiung j med sci 2011; 27:437-40. 33. parsons cl. current strategies for managing interstitial cystitis. expert opin pharmacother 2004; 5:287-93. 34. lee jw, han dy, jeong hj. bladder pain syndrome treated with triple therapy with gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug. int neurourol j 2010; 14:256-60. 35. foster he, hanno pm, nickel jc, et al. effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. j urol 2010; 183:1853-8. 36. seshadri p, emerson l, morales a. cimetidine in the treatment of interstitial cystitis. urology 1994; 44:614-6. 37. hanley rs, stoffel jt, zagha rm, et al. multimodal therapy for painful bladder syndrome/interstitial cystitis: pilot study combining behavioral, pharmacologic, and endoscopic therapies. int braz j urol 2009; 35:467-74 38. evans rj, moldwin rm, cossons n, et al. proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. j urol 2011; 185:1716-21. 39. dawson te, jamison j. intravesical treatments for painful bladder syndrome/interstitial cystitis. cochrane database syst rev. 2007; (4):cd006113 2 40. peters km, diokno ac, steinert bw, gonzalez ja. the efficacy of intravesical bacillus calmette-guerin in the treatment of interstitial cystitis: long-term followup. j urol 1998; 159:1483-6 41. engelhardt pf, morakis n, daha lk, et al. long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis. int urogynecol j. 2011; 22:401-5 42. nickel jc, hanno p, kumar k, thomas h. second multicenter, randomized, double-blind, parallel-group evaluation of effectiveness and safety of intravesical sodium chondroitin sulfate compared with inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. urology 2012; 79:1220-4 43. pinto r, lopes t, frias b, et al. trigonal injection of botulinum toxin a in patients with refractory bladder pain syndrome/interstitial cystitis. eur urol 2010; 58:360-5. 44. gottsch hp, miller jl, yang cc, berger re. a pilot study of botulinum toxin for interstitial cystitis/painful bladder syndrome. neurol urodyn 2011; 30:93-6. 45. aihara k, hirayama a, tanaka n, et al. hydrodistension under local anesthesia for patients with suspected painful bladder syndrome/interstitial cystitis: safety, diagnostic potential and therapeutic efficacy. int j urol 2009; 16:947-52. 46. gajewski jb, al-zahrani aa. the long-term efficacy of sacral neuromodulation in the management of intractable cases of bladder pain syndrome: 14 years of experience in one centre. bju int 2011; 107:1258-64 47. van ophoven a, oberpenning f, hertle l. long-term results of trigone-preserving orthotopic substitution enterocystoplasty for interstitial cystitis. j urol 2002; 167:603-7. 48. rössberger j, fall m, jonsson o, peeker r. long-term results of reconstructive surgery in patients with bladder pain syndrome/interstitial cystitis: subtyping is imperative. urology 2007; 70:638-42. correspondence william rourke, md kamran ahmed, phd, mrcs prokar dasgupta, md, frcs (urol), febu muhammad shamim khan, obe, frcs (urol), febu mrc centre for transplantation, king’s college london, department of urology, guy’s hospital, london (uk) se1 9rt shahid aziz anwer khan, frcs (urol) febu (corresponding author) saak_2000@yahoo.co.uk east surrey hospital, canada ave redhill (uk) rh1 5rh shikohe masood, frcs, frcs (urol), febu medway maritime hospital, windmill road gillingham, kent (uk) me7 5ny rourke_stesura seveso 04/07/14 12:04 pagina 131 stesura seveso 179archivio italiano di urologia e andrologia 2015; 87, 2 case report lower pole renal cut injury due to the iliac wing fracture: a rare case report çaglar yildirim, özgür haki yüksel, serkan akan, ahmet ürkmez, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey the most frequent causes of blunt genitourinary injuries are falls from heights, motor vehicle accidents and sports injuries. firearm injuries and penetrating stab wounds are also frequently encountered. skeletal system traumas in the vicinity of the urogenital system can cause urological organ injuries. though rarely, renal traumas can be dependent on the kinetic energy of the trauma and the retroperitoneal movement capacity of the kidneys and cannot be explained with the proximity of the kidney to the skeletal system. in cases with high-energy decelerations, renal pedicle and ureteropelvic junction traumas are more frequently observed. herein, we presented a grade 3 left kidney lower pole injury developed secondary to a2 type pelvic fracture following a high energy deceleration trauma. it should not be forgotten that especially in this type of fractures, injuries of the lower renal pole can occur. key words: lower pole renal trauma; iliac wing fracture. submitted 12 january 2015; accepted 15 march 2015 summary no conflict of interest declared. interpreted as benign injuries. however, potentially lifethreatening critical abdominal injuries with serious vascular or neurological wounds should be also contemplated (4). we presented a patient with multiple traumas secondary to a fall from a height which included an advanced case comminuted fracture of the iliac wing with secondary lower pole injury of the kidney. based on our literature review, ours is the first case report on renal injury secondary to an iliac wing fracture. case report a 33-year-old obese (bmi: 32) female patient was brought into the emergency service after a fall from a height. her first physical examination revealed a moderate-bad health state with a glasgow coma score of 10 (e2m5v3). on inspection diffuse dermabrasion, edema and ecchymosis on left side of her pelvis and an open fracture line on her left ankle were noted. bloody urine was draining from her urethral catheter. abdominal guarding and rebound were not detected during physical examination. on her left side costovertebral angle tenderness was elicited. arterial blood pressure (abp) was: 80/50 mmhg and pulse rate was 110/min bpm. at her admission hemoglobin and hematocrit values were 11 gr/dl and 34%, respectively but they declined rapidly. indeed one hour after her referral hb and hct values were 6.6 gr/dl and 20%, respectively. arterial blood gas ph 7.2 and serum creatinine 1.06 mg/dl values were also measured. computed tomography obtained in the emergency service revealed the presence of multi fragmented displaced fractures of the right and left inferior and superior pubic rami, right acetabulum, right iliac wing and left femur neck. in addition, grade 3 laceration of the lower pole of the left kidney with subcapsular hematoma in the lower pole of the left kidney with its largest diameter of 8 mm were noted (figure 1 and 2). orthopedicians scheduled the patient for surgery, however rapid deterioration of patient’s health state necessitated her treatment to be made in the intensive care unit 2 hours after her admission. despite massive transfusion of blood and an inotropic solution, her hypotensive state did not improve and she was lost because of hypovolemic shock. doi: 10.4081/aiua.2015.2.179 introduction urinary system injuries occur in 10% of the trauma patients. kidney injuries are seen in 1-5% of all trauma patients and 80-90% of them are blunt traumas. in trauma patients, isolated urogenital injuries are very rare (1). they are observed as components of multiple traumas especially as a result of falls from a height and traffic accidents (2). urogenital injury in blunt traumas can occur as a primary impact of the trauma and secondary to injuries of the adjacent organs exposed to trauma. in this context, incidence rates of urogenital trauma in patients with pelvic fractures have been estimated as 3.5 and 5% in the female and male patients, respectively. among them most frequently bladder, urethra and corpus cavernosum injuries have been observed. bladder rupture demonstrates similar distribution (median, 3%) among men and women. urethral injuries are seen at a rate of 1.54% in men, while its incidence is lower in women (≈ 0.15%) (3). iliac wing fractures are not frequently cited in the literature. these fractures generally occur as a result of exposure to direct blow and they maintain their stability at a vertical and rotational plane. since isolated pelvic ring fractures do not disrupt pelvic ring stability, they can be yildirim_stesura seveso 02/07/15 11:41 pagina 179 archivio italiano di urologia e andrologia 2015; 87, 2 ç. yildirim, ö. haki yüksel, s. akan, a. ürkmez, a. verit 180 discussion, and supplementary references are posted on www.aiua.it references 1. mcaninch jw, carroll pr, klosterman pw, et al. renal reconstruction after injury. j urol. 1991; 145:932-937. 2. santucci ra, wessels h, bartsh d, et al. evaluation and management of renal injuries consensus: statement of the renal trauma subcommittee. bju int. 2004; 93:937. 3. biurlin ma, fantus rj, mellet mm, goble sm. genitourinary injuries in pelvic fracture morbidity and mortality using the national trauma data bank. j trauma. 2009; 67:1033-1039 4. abrassart s, stern r, peter r. morbidity associated with isolated iliac wing fractures. j trauma. 2009; 66:200-203. correspondence çaglar yildirim, md özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com serkan akan, md ahmet ürkmez, md ayhan verit, md, prof. dept. of urology, fatih sultan mehmet research & training hospital içerenköy/ataşehir tr34752 istanbul, turkey figure 1. multislice 3d ct images (showed by arrow). figure 2. multislice ct images transverse axis (showed by arrow). conclusion renal traumas are classified under two categories as penetrating and blunt traumas based on their pathogenic mechanisms. blunt renal traumas can happen as a consequence of primary impact of the trauma and also secondary to concurrent bone fractures (rib fracture and vertebra transverse process fractures etc.). in the literature, a direct relationship between pelvic fracture and renal trauma has not been described so far. we presented a case with grade 3 lower pole injury of the kidney with a fatal course which was presumably correlated with iliac wing fracture. we think that in cases with pelvic fractures, not only lower urogenital tract, but also upper urinary system should be meticulously examined. yildirim_stesura seveso 02/07/15 11:41 pagina 180 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4322 notes on surgical technique penile prosthesis implant for erectile dysfunction: a new minimally invasive infrapubic surgical technique gabriele antonini 1, gian maria busetto 1, ettore de berardinis 1, riccardo giovannone 1, patrizio vicini 2, vincenzo gentile 1, paul e. perito 3 1 department of gynecological-obstetrics sciences and urological sciences, sapienza rome university, policlinico umberto i, rome, italy; 2 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 3 perito urology, coral gables hospital miami, florida, usa. erectile dysfunction, the most common male sexual disorder after premature ejaculation, with its important impact on man and partner’s sexuality and quality of life is a persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual performance. non-surgical treatments with controversial results are usually applyed before surgical treatment that has reached high levels of satisfaction. we describe a new surgical technique to implant three-pieces penile prosthesis in patients suffering from erectile dysfunction (ed) not responding to conventional medical therapy or reporting side effects with such a therapy. implantation of an inflatable prosthesis, for treatment of ed, is a safe and efficacious approach with high satisfaction reported by patients and partners. surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease common complications and to obtain a better aesthetic result. key words: erectile dysfunction; penile prosthesis; infrapubic access. submitted 17 march; accepted 30 june summary no conflict of interest declared. requiring repair, explants or replacement are: fluid leak from the device, supersonic transport (sst) deformity, cylinder’s aneurismal dilatation or extrusion (8). infections remain the most common and serious surgical complications with the risk of further penile shortening, urethral injury with erosion and tissue loss (9, 10). patients with comorbidities (diabetes, immunosuppression, spinal cord injury, etc.) are usually at increased risk of infectious complications (11). infectious mechanism is characterized by bacterial implantation on the surface of the device creating a biofilm that avoid the immune system and antibiotics to exert their effect (12). at this time cylinders, pump and tubing of the three-piece ipp are impregnated with antibiotics (rifampicin and minocycline) which have been associated with the reduction in post operative infections (13). surgical technique we report a new surgical technique of penile prosthesis implant in patients suffering from erectile dysfunction not responding to conventional medical therapy or reporting side effects with such a therapy. all subjects underwent primary penile prosthesis implant and all the procedures had been carried out at department of urological sciences of sapienza rome university by a single surgeon. the prostheses were either the ams 700™ cx (ams, minnetonka, mn, usa) or the coloplast titan® otr (coloplast corporation, minneapolis, mn, usa) with controlled expansion cylinders optimize girth (14). the ams prostheses are connected with an ams conceal™ low profile reservoir coated with parylene and are characterized by momentary squeeze pump with one-touch button designed for easy deflation and lock-out valve designed to resist auto-inflation; inhibizone™ antibiotic treatment (minocycline and rifampicin) creates a zone of inhibition effective against the bacteria commonly associated with inflatable prosthesis infections. the coloplast prostheses are connected with coloplast titan® cl reservoir with a four-leaf clover shape and are characterized by lock-out™ safety valve designed to prevent auto-inflation and one touch release (otr) for easy deflation of the device; hydrophilic coating decreases infection risk. the implants were performed by a minimally invasive technique and, after the patient was shaved, the skin doi: 10.4081/aiua.2015.4.322 introduction erectile dysfunction (ed), the most common male sexual disorder after premature ejaculation, with its important impact on man and partner’s sexuality and quality of life is a persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual performance. the incidence ranges between 2-28.9% in the age group from 30-39 to 41.9-83% in the age group from 70-80 (1-3). regarding treatment, to date, first-line approach is performed with the usage of pharmaceuticals such as pde5 inhibitors and second-line with intracavernous injection (ici), vacuum devices or intraurethral alprostadil. medical therapy has a high drop-out rate that is up to 80% (4, 5). surgical treatment, as third-line therapy, can be performed after failure of all other options. penile prosthesis implant, although invasive, has reached high levels of satisfaction and is associated with better sexual function, perception and with patient and partner’s high gratification (6, 7). complications related to mechanical failure of prosthesis, 323archivio italiano di urologia e andrologia 2015; 87, 4 penile prosthesis implant for erectile dysfunction: a new minimally invasive infrapubic surgical technique space for the reservoir (filled with 100 ml of saline solution), posterior to transversalis fascia in cephalad to caudal position (figures 5, 6), is created. after exposure, cylinders are placed using stay sutures for retraction and functional/cosmetic result are checked by rapidly inflating the prosthesis (figure 7). once again, the nasal speculum is utilized, this time, to develop the subdartos pouch into dependant portion of scrotum (figure 8). after performing the hydraulic test (figure 9) we finally close the corporotomies using the stay suture previously placed. we then connect the appropriate tubing and a jackson-pratt drain is placed in dependent portion of pepped for 10 minutes with a poviodone-iodine solution and intravenous cefazolin was administered. the first step is induction of an artificial erection that allows to identify any pathology needing correction, verifies “true” dilation of the corpora supplanting serial dilations and facilitates the identification of the dorsal nerve and lateral placement of stay sutures. an infrapubic 3 cm skin incision followed by 1.5 cm bilateral corporotomy incision is applied (figures 1, 2). using the furlow, the proximal and distal corpora cavernosa are measured and dilated (figures 3, 4). we place color-coded stay sutures in the corpora, lateral to the dorsal nerve. using a 3½ inch nasal speculum a figure 1. figure 2. figure 3. figure 4. figure 5. figure 6. figure 7. figure 8. archivio italiano di urologia e andrologia 2015; 87, 4 g. antonini, g.m. busetto, e. de berardinis, r. giovannone, p. vicini, v. gentile, p.e. perito 324 scrotum (figure 10) and skin incision closed with subcuticular sutures (15). there were no reported intraoperative complications and the median time to complete the implant was 39 min (26-74). following the implant regular follow-up controls were scheduled; the first activation of the prosthesis is applied 8-10 days after the implantation and the patient starts sexual intercourse after 6 weeks. after surgery ten days of cefazolin and a single dose of gentamycin are administered. all treatments applied are part of routine standard care and the surgical technique was conducted in line with european urology and good clinical practice guidelines, with ethical principles laid down in the latest version of the declaration of helsinki. every patient has been informed and signed the consent. in accordance with literature data, patients satisfaction and qol is better after implant of a three-pieces device because inflatable penile prostheses are characterized by improved flaccidity and rigidity and are usually preferred because of the more “natural” erection obtained (16-18). bernal et al. in a meta-analyzed 20 years of literature reached the conclusion that despite the variability of used methods and lack of approved questionnaire, patients are satisfied with the implant and with the subsequent sexual activity (19). moskovic et al. analyzed partners satisfaction concluding that male satisfaction correlate positively with female’s one, while unsatisfied men have a relation with female suffering from sexual activity quality (20). we can conclude that our technique is very fast, safe and the aesthetic result is guaranteed with a small skin incision of only 3 cm. all of these results are part of a system that consists of an experienced surgical staff, a safe, rapid and minimally invasive surgical technique and the usage of the latest technology in prosthesis equipment. references 1. lindau st, schumm lp, laumann eo, et al. a study of sexuality and health among older adults in the united states. n engl j med. 2007; 357:762-74. 2. porst h, sharlip i. history and epidemiology of male sexual dysfunction. in: porst h, buval j, eds. standard practice in sexual medicine. malden, ma: blackwell publishing; 2006; 43-8. 3. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 4. mulhall jp, bella aj, briganti a, et al. erectile function rehabilitation in the radical prostatectomy patient. j sex med. 2010; 7:1687-98. 5. gontero p, fontana f, zitella a, et al. a prospective evaluation of efficacy and compliance with a multistep treatment approach for erectile dysfunction in patients after non-nerve sparing radical prostatectomy. bju int. 2005; 95:359-65. 6. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfaction after ams inflatable penile prosthesis implant. j sex med. 2010; 7:304-9. 7. minervini a, ralph dj, pryor jp. outcome of penile prosthesis implantation for treating erectile dysfunction: experience with 504 procedures. bju int. 2006; 97:129-33. 8. henry gd, wilson sk, delk jr ii, et al. revision washout decreases penile prosthesis infection in revision surgery: a multicenter study. j urol. 2005; 173:89-92. 9. carson cc. diagnosis, treatment and prevention of penile prosthesis infection. int j impot res. 2003; 15(suppl 5):s139-46. 10. montague dk, angermeier kw, lakin mm. penile prosthesis infections. int j impot res. 2001; 13:326-8. 11. carson cc. infections in genitourinary prostheses. urol clin north am. 1988; 16:139-47. 12. wilson sk, costerton jw. biofilm and penile prosthesis infections in the era of coated implants; a review. j sex med. 2012; 9:44-53. 13. wilson sk, zumbe j, henry gd, et al. infection reduction using antibiotic-coated inflatable penile prosthesis. urology. 2007; 70:337-40. 14. montorsi f, rigatti p, carmignani g, et al. ams three-piece inflatable implants for erectile dysfunction: a long-term multi-institutional study in 200 consecutive patients. eur urol. 2000; 37:50-5. 15. perito pe. minimally invasive infrapubic inflatable penile implant. j sex med. 2008; 5:27-30. 16. mulcahy jj, austoni e, barada jh, et al. the penile implant for erectile dysfunction. j sex med. 2004; 1:98-109. 17. montague dk, angermeier kw. penile prosthesis implantation. urol clin north am. 2001; 28:355-61. 18. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-12. 19. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prosthesis. adv urol 2012; 2012:707321. 20. moskovic dj, gittens p, avila d jr, et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2011; 8:1996-2001. correspondence gabriele antonini, md gian maria busetto, md ettore de berardins, md riccardo giovannone, md vincenzo gentile, md department of gynecological-obstetrics sciences and urological sciences, sapienza rome university, policlinico umberto i, rome, italy patrizio vicini, md (corresponding author) patriziovicini@gmail.com department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy paul e. perito, md perito urology, coral gables hospital miami, florida (usa) figure 9. figure 10. stesura seveso 265archivio italiano di urologia e andrologia 2015; 87, 4 original paper the comparative evaluation of apoptosis produced by leuprolide or orchiectomy on rat prostate tissue basri cakiroglu 1, aydin ismet hazar 2, seyit erkan eyyupoglu 3, mustafa bahadir can balci 2, orhun sinanoglu 4, pinar tuzlali 5 1 department of urology, hisar intercontinental hospital, istanbul, turkey; 2 department of urology, taksim training and research hospital, istanbul, turkey; 3 department of urology, amasya training and research hospital, amasya, turkey; 4 department of urology, maltepe university medical school, istanbul, turkey; 5 department of pathology, taksim training and research hospital, istanbul, turkey. introduction: organisms are constantly in a balance meaning that while new cells are produced, some of the older ones die which takes place in 2 ways: necrosis or apoptosis. apoptosis is the programmed cellular death triggered by intrinsic or extrinsic stimuli. in this study we have evaluated the apoptosis of prostate tissue generated by surgical or medical orchiectomy. material and method: in this experimental study, we used 36 adult male rats that were evaluated in 3 groups. the first group (group 1) consisted of 12 rats that had bilateral orchiectomy; the second group (group 2) included 12 rats that were given leuprolide acetate and the third group (group 3) consisted of 12 control rats. immunohistochemical staining of the prostate of all rats was performed and the presence of glandular atrophy and apoptosis were evaluated in the three groups. the statistical differences between the two groups were evaluated by the fisher exact test. results: glandular atrophy was not determined in any rat of the control group, and the apoptotic staining was in the normal limits in all the control rats. in leuprolide group, glandular atrophy was mild in 7 cases, and moderate in 3 rats. in 2 rats of the leuprolide group, atrophy was not demonstrated. in surgical orchiectomy group, glandular atrophy was present in all cases. atrophy was observed as cystic atrophy. statistical analysis with the fisher exact test revealed that glandular atrophy was statistically significantly more common in surgical orchiectomy group compared with leuprolide group (p = 0,012). conclusion: if the aim of treatment in androgen dependent prostatic adenocarcinoma or benign prostate hypertrophy is the construction of a robust apoptosis, bilateral orchiectomy generates a more powerful apoptosis compared with leuprolide. key words: prostate; orchiectomy; leuprolide; apoptosis. submitted 18 june 2015; accepted 15 september 2015 summary no conflict of interest declared. taken away by cellular death in order to preserve this balance. the cellular death has two modalities: apoptosis and necrosis (2, 3). in both of them, cellular death takes place at the end of the regular, consecutive biochemical and morphological events (4). necrosis may be defined as the death of cells before their appropriate time. the period after the exposure of cells to any chemical or physical agent that may damage the cellular plasma membrane is defined as the necrosis. necrosis takes place as a result of acute, non-physiological cellular injury and it is the pathological form of cellular death (5, 6). cellular necrosis is characterized by cellular ballooning, ballooning of organelles, budding of cellular membrane and increase in cellular permeability. commonly karyolysis accompanies necrosis and dna breakages are present in a non-specific way (7). on the other hand, apoptosis is the programmed cellular death triggered by intrinsic and extrinsic stimulants (3, 5, 6, 8). conversely to necrosis, apoptosis develops in normal physiologic conditions and it is a physiological period of the cell. apoptosis starts with the embryological development and continues through the whole life. normal development and hemostasis of multicellular organisms are regulated by apoptosis. if there is no more need for the cells or the cells are damaged, they are eliminated with the apoptosis (9). apoptosis is an important biological period not only during the normal cellular physiology but also in benign and malign disease conditions. understanding the exact cause triggering apoptosis will be the basis of many therapeutic strategies. according to the cellular kinetic studies, neoplastic prostate enlargement depends on the loss of balance between cellular proliferation and apoptosis (10, 11). in benign prostate hypertrophy (bph) normal growth control mechanisms are not in process. probably the reason is the overexpression of bcl-2 which is a potent apoptosis inhibitor originating from prostate glandular cells and basal cells of the old gland during hypertrophic proliferation (12, 13). this hypothesis is at the basis of potential molecular mechanism that protects long-living cells from self-destruction as in the case of prostate epithelial cells (13, 14). bcl-2-mediated, mitodoi: 10.4081/aiua.2015.4.265 introduction prostate is the organ most commonly affected by malign lesions in males and prostate cancer is the second most common cause of death in men in many countries (1). organisms are constantly in a quite equilibrium. while new cells are produced, some of the existing cells are archivio italiano di urologia e andrologia 2015; 87, 4 b. cakiroglu, a. ismet hazar, s. erkan eyyupoglu, m. bahadir can balci, o. sinanoglu, p. tuzlali 266 chondria associated cell survival pathway (intrinsic pathway) is one of the major pathways that are targeted for inducing apoptosis in cancer cells. in addition to this, another major pathway that promotes apoptosis in cancer cells is the death receptor-mediated pathway (extrinsic pathway) (15). in this study we have evaluated the apoptosis of prostate tissue triggered by surgical or medical orchiectomy. for this reason, bilateral orchiectomy was performed in a group of rats and lh-rh analogues were given to the other group; the apoptosis was determined by immunohistochemical staining and compared between the two groups. materials and methods in this experimental study, we used 36 adult male rats (sprague dawley) with an average of 250 gr weight and 10 weeks of age that were divided in 3 groups. the first group (group 1) consisted of 12 rats that had bilateral orchiectomy; the second group (group 2) included 12 rats that were given leuprolide acetate and the third group (group 3) consisted of 12 control rats. in the rats of the first group, after the intraperitoneal anesthesia of 25 mg/kg pentothal, bilateral orchiectomy was performed, through an incision of the scrotum on the raphe, the cord was tightened with 4/0 vicryl, the bleedings were cauterized and the skin was closed with 4/0 rapid vicryl. single dose depot leuprolide acetate was administered to the rats in the second group. the third group was regarded as the control group in which no intervention was performed. after 4 weeks, the rats were sacrificed after the injection of 100 mg/kg pentothal and bladder, prostate, vesicula seminalis and penis were taken en bloc, and put in formaldehyde. histopathology prostate glands were put on pbs and cut longitudinally; then they were fixed with tamponed formalin, embedded on paraffin and slices were obtained. all slices were investigated for the presence of inflammatory infiltration, edema, fibrosis, basal cell degeneration, hyperplasia, endothelial cellular volume density. immunohistochemical staining the material used for the staining was bax:b-9 rat monoclonal igg2b antibody. bax protein eliminates the apoptosis by inhibiting the effects of bcl-2 gene in cells and accelerates apoptotic cellular death bax antibody attaches to the bax protein that has an increased concentration in cases with accelerated apoptosis. at the beginning of the procedure, the tissue slices were cleaned from the paraffin; incubated for 15 minutes in hydrogen peroxide solution and washed 2 times with tbs. a citrate tampon was produced on microwave oven and cooled at room temperature for 20 minutes and the slices were washed with tbs for 4 times. to prevent non-specific background staining, ultra v block (protein blockage) was performed at room temperature for 5 minutes. without washing, only ultra v block on the lam was transferred. bax antibody was dripped to cover the tissue and incubated for 1 hour, then diluted with water at a 1/100 ratio and washed with pbs for 4 times. we waited for twenty minutes after dripping biotinylated goat antipolyvalent solution (link yellow) serum and then we washed with pbs for 4 times and incubated until colored with aec chromogen. preparation of aec was obtained by dripping 1 drop chromogen into 1 ml substrate and washing with distilled water. then, we counter-stained with mayer's hematoxylin and waited for 1 minute at most; finally we washed with distilled water and closed with ultramount. slices were investigated under light microscopy. bax (+) staining demonstrates granular staining in cytoplasm. increase in staining strength was recorded as (+), strong increase was recorded as (++) and normal staining was shown as (n). arithmetical decrease in glandular component, cystic formation, flattening in epithelium are regarded as the signs of atrophy and recorded as mild (+), moderate (++) and severe (+++) atrophy (table 4). the statistical differences of the results between the two groups were evaluated by fisher exact test. results after immunohistochemical staining, all the three groups were evaluated for glandular atrophy and apoptosis in general and the results are summarized in table 1. in 12 rats of control group glandular atrophy was not reported (figure 1) and apoptotic staining was in the normal limits (figure 2). in the leuprolide group, glandular atrophy was mild (+) in 7 cases, and moderate (++) in 3 rats. in 2 rats of the leuprolide group, atrophy was not demonstrated. in surgical orchiectomy group; glandular atrophy was present in all cases. the atrophy was control bilateral orchiectomy leuprolide cases glandular atrophy apoptosis glandular atrophy apoptosis glandular atrophy apoptosis 1 n ++ ++ + + 2 n ++ + ++ ++ 3 n + ++ + + 4 n + + + + 5 n ++ + n 6 n + + + + 7 n + ++ + + 8 n + ++ n 9 n + ++ + + 10 n + ++ + + 11 n + ++ ++ ++ 12 n + ++ ++ ++ table 1. the evaluation of glandular atrophy and apoptosis in prostates of leuprolide, bilateral orchiectomy and control rat groups. atrophy is evaluated as absent (-), mild atrophy (+), moderate atrophy (++), severe atrophy (+++). apoptosis is evaluated as; bax staining normal (n) (atrophy is not present), increase in staining (+), strong increase in staining (++). observed as cystic atrophy. in 9 rats of the orchiectomy group, glandular atrophy was mild (+) and in 3 cases moderate (++) glandular atrophy was present. in this group, apoptotic staining was increased mildly in 4 cases and moderately in 8 cases. glandular atrophy was not present in 2 cases of the leuprolide group (2/12, 16.6%) and in this group statistically significant glandular atrophy was present (fisher exact test < 0.001). the statistical analysis with fisher exact test revealed that glandular atrophy was statistically significantly more common in surgical orchiectomy group compared with leuprolide group (p = 0.012). in the evaluation of apoptosis, in the 12 leuprolide acetate administered rats, normal apoptotic staining was present in 2 rats (2/12, 16,6%), while apoptotic staining was increased in 5 rats (5/12, 41.6%) and apoptotic staining was strongly increased in the other 5 rats (5/12, 41.6%). statistically significant apoptotic staining was also reported in this group (fisher exact test < 0.001). in 12 rats with bilateral orchiectomy, normal apoptotic staining was not reported in any rat, while apoptotic staining was increased in 4 rats (4/12, 33,3%) and apoptotic staining was strongly increased in the other 8 rats (8/12, 66,6%). statistically significant apoptotic staining was also reported in this group (fisher exact test < 0.001). in the orchiectomy group, apoptotic staining was statistically significantly more strong and more distinct compared with the leuprolide group (fisher exact test < 0.001). in atrophic cases apoptosis increases and this increase is in parallel with the density of atrophy. the drug produced 83.3% atrophy (more commonly mild) but severe atrophy was not observed in the drug group. atrophy was as a decrease in glands sometimes together with periductal fibrosis but occasionally it was cystic in structure. discussion in this study, we evaluated the apoptotic changes in prostates of castrated rats and leuprolide administered rats. in atrophic prostates increase in apoptosis and a direct correlation of this increase with the density of atrophy were observed. we demonstrated that in leuprolide administered group, atrophy developed in 83.3% of the cases and the atrophy was mild; on the other hand in orchiectomy group atrophy was 100% and the atrophy was predominantly moderate. in both groups, together with the atrophy, in some cases periductal fibrosis or formation of cystic structures were observed. though many studies were performed, new substances or more rational drug combinations are still required in limiting growth of androgen resistant prostate cancer cells. increasing evidences support the role of protein kinases and anti-apoptotic signal cascades in therapeutic resistance of castration resistant prostate cancer (16, 17). an antiapoptotic signal with hyperactive pi3k pathway was suggested to be the probable cause of resistance to treatment in prostate cancer cells (18). owing to the dependence of bph and prostate cancer to the androgen steroids, these diseases became the model for studies of apoptosis of the prostate. apoptosis, a decrease in cellular proliferation, is one of the main mechanisms causing prostate depletion in androgen deficient conditions. ten days after castration, rat prostate ventral tissue regresses completely and prostate androgen dependent epithelial cells degenerate with a ratio of 80% (19). the normal growth and hemostasis of multicellular organisms are regulated with apoptosis. prostate glandular epithelial cells are separated from basal lamina by interglandular stroma composed of smooth muscle cells and fibroblasts. in adult prostate, glands and ducts are arranged as double layered by luminal and basal epithelial cells. basal cell layer, that is suggested to contain prostatic stem cells giving rise to both basal and luminal epithelial cells, is reproduced in castrated mice after testosterone replacement (20, 22). after castration, depletion in prostate gland results in apoptosis of luminal cells and approximately 80% of epithelial cells die (23). the glandular atrophy is not complete, and rudimentary glandular structures are observed for a long time after castration (24). androgen deprivation due to castration stimulates apoptosis in human prostate tissue. the apoptotic response in human prostate tissue is less than that of the rat ventral prostate. in the first day after castration, the percentage of tunel (+) cells (apoptotic index) increases, reaching to a maximum level at the fourth day after castration and then the apoptotic index progressively decreases (25). the ventral prostate of rat is a good model for in vivo apoptosis; prostate epithelial cells become independent to androgenic steroids when they are cultured (26). in 267archivio italiano di urologia e andrologia 2015; 87, 4 apoptosis on rat prostate figure 1. glandular atrophy. figure 2. apoptotic staining. archivio italiano di urologia e andrologia 2015; 87, 4 b. cakiroglu, a. ismet hazar, s. erkan eyyupoglu, m. bahadir can balci, o. sinanoglu, p. tuzlali 268 sensitive dunning r3327pap rat prostate adenocarcinoma, after castration tumor volume and epithelial stromal cells were reported to be stable, however when 50 microgram estradiol benzoate was added to the castration total tumor volume was reported to be decreased and tumor cells died (27). in bph development, normal adult prostate enlarges unusually. in bph, tissue proliferative/ apoptotic balance is deteriorated in the favor of proliferation in both epithelial and stromal cells. endogenous apoptosis ratios are significantly decreased in bph (28, 29). this decreased apoptotic activity in human bph samples, reflects the activity of antiapoptotic protein bcl-2 in epithelial cells of these tissues (30). in bph, morphological induction of apoptosis as a response to doxazosin in prostatic stromal smooth muscle cells was reported. in pre-treatment biopsies of patients with bph, any apoptotic cells were not observed with terminal transferase end labeling. with 3 months of doxazosin treatment, a dramatic apoptosis induction was observed in those patients in smooth muscle cells with terminal transferase end labeling (31). increase in cell number in bph and prostate carcinoma depends on the decrease in apoptotic cellular death. the administration of alpha adrenergic antagonists decreases the surgical treatment requirements in bph. moreover, they reduce the tonus of bladder neck and these agents change the course of the disease by inducing apoptosis. terazosin causes apoptosis in prostate epithelium in a dose dependent manner (32). in rat ventral prostate, 5-alpha reductase inhibition also results in apoptosis but apoptosis caused by castration is more marked. while 60% cellular decrease is observed on the 9th day with finasteride, castration results in 90% decrease of cells (33). cardillo et al. investigated 26 patients who were hormonally ablated with lh-rh analogues for one month before radical prostatectomy. they compared the apoptosis in pretreatment biopsy and radical prostatectomy materials. they observed that after androgen deprivation apoptosis was present in normal prostatic epithelial cells and prostate cancer cells (34). conclusion if the aim of treatment in androgen dependent prostatic adenocarcinoma or benign prostate hypertrophy is construction of robust apoptosis, bilateral orchiectomy generates more powerful apoptosis compared with leuprolide. in leuprolide administered cases, apoptosis was observed with a ratio of 83.3%. authors’ contributions bc, see and aih and conducted the experiments and participated in acquisition, analysis, and interpretation of data. bc, see and mbcb participated in analysis and interpretation of data, and drafted the manuscript. os helped in analyzing the data and in drafting the manuscript. pt drew the study conception and design, critically participated in revising the manuscript for important intellectual content and has given the final approval of the version to be submitted. all authors read and approved the final manuscript. acknowledgement we thank pathology laboratory, taksim training and research hospital for laboratory facilities, technical assistance and financial aid. references 1. ellison lf, wilkins k. cancer prevalence in the canadian population. health rep. 2009; 20:7-19. 2. ameisen js:the origin of programmed cell death. science 1996; 272:1278. 3. thompson cb. apoptosis in the pathogenesis and treatment of disease. science. 1995; 267:1456. 4. kiess w, gallaher b. hormonal control of programed cell death/apoptosis. eur j. endocrin 1998; 18:482. 5. hetts sw. to die or not to die:an overview of apoptosis and its role in disease. jama 1998; 278:300. 6. majno g, joris i. apoptosis, oncosis and necrosis:an overview of cell 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87, 4 apoptosis on rat prostate correspondence basri cakiroglu, md (corresponding author) drbasri@hotmail.com department of urology hisar intercontinental hospital department of urology saray mah. siteyolu cad. no:7 34768 umraniye, istanbul, turkey aydin ismet hazar, md mustafa bahadir can balci, md department of urology, taksim training and research hospital istanbul, turkey seyit erkan eyyupoglu, md department of urology, amasya training and research hospital istanbul, turkey orhun sinanoglu, md department of urology, maltepe university medical school, istanbul, turkey pinar tuzlali, md department of pathology, taksim training and research hospital, istanbul, turkey stesura seveso archivio italiano di urologia e andrologia 2015; 87, 128 original paper a conservative approach to perineal fournier's gangrene giulio milanese 1, luigi quaresima 1, marco dellabella 2, alessandro scalise 3, giovanni maria di benedetto 3, giovanni muzzonigro 1, daniele minardi 1 1 department of clinic and specialistic sciences, urology, polytechnic university of the marches region, a.o. ospedali riuniti ancona, italy; 2 uoc urologia, inrca-irccs, ancona, italy; 3 department of experimental and clinical medicine, plastic surgery, polytechnic university of the marches region, a.o. ospedali riuniti ancona, italy. fournier’s gangrene (fg) is a disease involving necrosis of perineum and external genitalia; in 95% of cases it is possible to diagnose the fournier’s gangrene just by physical examination. the clinical presentation of fg varies from an initial localized infection to large areas with necrotizing infection. the disease typically affect elderly men (6°-7° decade) with important systemic comorbidities; women are less frequently affected. despite improvements in diagnosis and management, the mortality rate nowadays is between 20% and 43%. the severity and mortality of the disease is dependent upon the general condition of the patient at presentation and upon the rate of spread of the infection. treatment involves a multidisciplinary approach: intensive systematic management, broad-spectrum antibiotic therapy, early surgical debridement (wide abscission of necrotic tissues and surgical drainage of peritoneum, scrotum, penis, and inguinal areas), hyperbaric oxygen therapy; surgery can eventually be repeated if necessary; reconstructive surgery has an important role in the final treatment of the disease. the technical difficulties frequently encountered and the inability to make a complete removal of the necrotizing tissues at the time of surgery in some cases has led to the application of combined techniques, in view of the enhancement effect of specific advanced medications, targeted antibiotic therapy and hyperbaric medicine. we have considered 6 patients affected by fournier’s gangrene treated at our institution; all the patients received treatment with the help of plastic surgeons of the same institution. after debridement, all the patients were treated with advanced specific dressings consisting of plates and strips made of calcium alginate, hydrogels and polyurethane and twodimensional cavity foams. reconstructive surgery was necessary in one case. hyperbaric oxygen therapy (hbo) has been performed in all cases. the multidisciplinary approach, the combined use of hbo therapy and the adoption of advanced specific dressings, have made possible the complete healing of the lesions in a shorter period, avoiding further surgery in 5 out of 6 patients. key words: fournier’s gangrene; hyperbaric oxygen therapy; conservative management. submitted 23 february 2015; accepted 15 march 2015 summary no conflict of interest declared. introduction at the end of xix century fournier described a disease characterized by an acute necrotizing process of cellulits and fasciitis of the penis and scrotum, rapidly evolving at high mortality and originally described as idiopathic gangrene of genitalia (1). nowadays under the name of fournier’s gangrene (fg) we include disease which involve a necrosis of perineum and external genitalia; in 95% of cases it is possible to diagnose the fournier’s gangrene just by clinical presentation and examination. the necrotizing process commonly arises from an anorectal infection, or from an infection of the genitourinary tract or of the genital’s dermis; less frequently it may develop as a consequence of acute leukemia, systematic erythematous lupus, crohn’s disease or hiv infection; fg can also be caused by iatrogenic and non-iatrogenic perineal trauma (2). it is also known that other systemic diseases, that can compromise the immune system, have a key role in the development of the necrotizing process (diabetes mellitus, obesity, chronic alcoholism, cirrhosis, immunosuppressive therapies, etc.). the clinical presentation of fg varies from an initial localized infection to large areas with necrotizing extended infection. the disease typically affect elderly men (6°7° decade) with important systemic comorbidity; women are less frequently affected. despite the improvements in diagnosis and management, the mortality rate is nowadays between 20% and 43% (3-9). the severity and mortality of the disease is dependent upon the general condition of the patient at the presentation and upon the rate of spread of the infection. high hematic values of creatinine, bicarbonate, leukocytes and sodium represent negative independent prognostic factors. the spread of necrosis to the abdominal wall or even worse to the peritoneum means that there is no space for resolution of the situation by surgery only. for this reason the treatment involves a multidisciplinary approach: intensive systematic management, broad-spectrum antibiotic therapy, early surgical debri dement (wide abscission of necrotic tissues and surgical drainage of peritoneum, scrotum, penis, and inguinal areas), hyperbaric oxygen (hbo) therapy; surgery can eventually be repeated if necessary; reconstructive surdoi: 10.4081/aiua.2015.1.28 minardi2_stesura seveso 02/04/15 10:19 pagina 28 29archivio italiano di urologia e andrologia 2015; 87, 1 a conservative approach to perineal fournier's gangrene gery has an important role in the final treatment of the disease (2, 4). surgical reconstructive techniques used for the treatment of fg are represented by simple free skin grafts to more complicated muscle flaps, myocutaneous (like the gracilis muscle) or fasciocutaneous flaps (as the anterolateral of the thigh or the "singapore sling"). these techniques are undoubtedly valid but present some drawbacks; in fact not all patients with fg are fit for surgery. the reconstruction with free skin grafts often brings drawbacks to the patients, mainly dimpling of the testicles and low plasticity of the new skin. the myocutaneous flaps are definitely the best choice but their use is limited in many cases by the complex surgical technique. the technical difficulties frequently encountered and the inability to make in some cases a complete removal of the necrotic tissues at the time of surgery has led to the application of combined techniques; in fact specific advanced medications, targeted antibiotic therapy and hyperbaric medicine have a combined effect that enhances each other. patients and methods we have considered 6 patients affected by fg treated in the period april 2010-october 2012 at the institute of urology of the polytechnic university of marches region, a.o. ospedali riuniti ancona, italy; all the patients received treatment with the help of the medical staff of the institute of plastic surgery of the same institution. we have evaluated the severity of the disease at the presentation using the fournier's gangrene severity index (fgsi) (3), taking into consideration the clinical and instrumental data of all six patients at the moment of hospitalization. depending on the severity of the presentation and the clinical conditions, some patients underwent to emergency surgical debridement and decompression in the operating theatre (4 patients) or as an outpatient procedure (2 patients). as first treatment, all patients received empirical treatment with parenteral broad spectrum antibiotics, and subsequently targeted antibiotic therapy on the basis of the results of colture investigations; in addition, all the patients received several sessions of hyperbaric oxygen therapy (90 min at 2.5 ata) (average number of sessions 10, range 7-12). lesions were then reviewed as bedsores and classified on the basis of npuap (national pressure ulcer advisory panel, http://www.npuap.org/) classification. all patients were treated with specific advanced medications consisting of plates and strips made of calcium alginate, hydrogels and polyurethane and two-dimensional cavity foams. reconstructive surgery was necessary in 50% of cases. results mean patients age was 70.1 years. all patients are alive at a minimum follow-up of two years from the presentation. table 1 summarizes the clinical and medical history of the patients. the patients were subjected to debridement with removal of necrotic tissues and consequent multiple loss of substance in the scrotal area (n = 4), buttock-perineal (n = 3), penile (n = 3), inguinaldeferential (n = 1) and suprapubic-inguinal (n = 1). in one patient at the time of the perineal debridement a wide necrotic lesion of the corpus spongiosum of bulbar urethra was detected. in two patients (2 men) debridement was performed as an outpatient procedure. a urethral catheter was placed in all the patients and also a suprapubic catheter in 4 patients. in all the patients the post-operative medications were performed on an outpatient basis using specialist advanced medications. in the first instance, calcium alginate dressings have been used until the lesion appeared well cleaned and granulating; then, when the healing process was good and there was not extensive loss of substance, hydrogel and polyurethane dressings were used (n = 4). in one case it was necessary the plastic reconstructive surgery using local flaps. case reports case 1 g.l., 71 years old woman. the patient was sent to our observation by the staff of a long-term care hospital where she was admitted two months earlier; she was having a poorly controlled insulin-dependent diabetes for 20 years and hypertension. at examination she had a large necrotic area in the inferior left gluteal, perineal and vulvar area, in communication between them. the lesion involved the skin in its full-thickness, invading the underlying fascia with the exposure of the muscle. the fgsi was 8. in emergency, surgery was made table 1. patients clinical and medical history. pts age sex db ri i hp localization colture procedure 2nd surgery hbo med. g.l. 71 f + 8 + gluteum-perineum-vulva pseud+candidae op theatre no 30 230 l.l. 73 m + 7 scrotum clostridium outpatient no 15 55 s.i. 69 f + 8 + gluteum-perineum-vulva e.coli+morganella op theatre yes 30 240 g.i. 65 m + + 13 + scrotum-penis-inguinal streptoc+clostridium op theatre no 30 120 and suprapubic region, urethra p.p. 75 m + 10 + scrotum-perineum streptoc. beta emol. outpatient no 30 90 n.c. 68 m + + 12 + scrotum-perineum proteus+e.coli op theatre no 30 90 db = diabetes; ri = renal impairment; i = fgsi (fournier's gangrene severity index); hp = hypertension; hbo = hyperbaric oxygen therapy; med = length of medications (days). minardi2_stesura seveso 02/04/15 10:19 pagina 29 archivio italiano di urologia e andrologia 2015; 87, 1 g. milanese, l. quaresima, m. dellabella, a. scalise, g.m. di benedetto, g. muzzonigro, d. minardi 30 with exposure of the necrotic foci and removal of the damaged tissues (figure 1). a swab colture of the wound has been obtained during surgery, and an empirical broad spectrum antibiotic therapy was started. the patient underwent to two cycles of 15 sessions each of hyperbaric therapy (90 min per session at 2.5 atmospheres ata) and to three weekly dressings with calcium alginate, with progressive improvement (figure 2). intravenous ciprofloxacin and fluconazole were started in the 5th post-operative day as soon as the report of the swab showed the presence of pseudomonas aeruginosa and candida albicans. the wound healing to therapy was good, making unnecessary further surgery. the process of wound repair was completed in about 230 days (figure 3). case 2 l.l., 73 years old man. the patient was sent to our clinic by his general practitioner (gp). the patient reported of having for about 2 months two fistulous lesions in the scrotum; at examination they resulted to be of 4 cm and 7 cm respectively (figure 4). the patient had insulin-dependent diabetes, cardiac failure; at presentation he showed leukocytosis and fever (38.5 °c); the total fgsi was 7. the patient was judged unfit for surgery, therefore we proceeded to debridement in an outpatient setting under local anaesthetic. a wound swab has been taken. because of the secretions from the lesions, hydrogel dressing + polyurethane foams were used at alternate days (figure 5); simultaneously, the patient underwent to 15 sessions of hyperbaric oxygen therapy (90 min per session 2.5 ata). the swab showed the presence of microorganisms of the clostridium strains, and appropriate antibiotic therapy was started. wound healing was complete in 55 days without doing further surgery (figure 6). case 3 s.i., 69 years old woman. she was referred from a longterm care hospital, where she has been treated for about 1 year with antibiotic ointment and iodoform gauzes. the lesion involved the entire right gluteal, perineal and vulvar area, widely secreting and smelly. the fgsi score was 8. at referral, the patient was taking insulin, digitalis, antihypertensives and broad-spectrum figure 3. figure 4. figure 5. figure 6. figure 1. figure 2. minardi2_stesura seveso 02/04/15 10:19 pagina 30 31archivio italiano di urologia e andrologia 2015; 87, 1 a conservative approach to perineal fournier's gangrene antibiotics. she underwent to emergency surgery, with opening of the infected regions (figure 7); a wound swab was taken at the time of surgery; medications with calcium alginate were started (figure 8) and also 2 cycles of hyperbaric therapy (90 min per session 2.5 ata). the swab was found to grow e. coli and morganella, and a specific therapy was started. within five months there was improvement; but in consideration of the width of the lesions, it was decided to proceed to further surgery, and two fasciocutaneous flaps from the gluteal region were prepared, to cover the loss of residual substance; in the post-operative period there was a dehisce of a small part of the wound, treated conservatively; the ulcer was completely healed after about eight months. case 4 g.i., 65 year old man, referred from another hospital for pain and necrosis of genitalia, associated with leucorrhea from the urethra; the lesion started about 2 weeks before, and suddenly involved the scrotum, the penis and the inguinal region. the patient had a history of hypertension, treated with beta-blockers and calcium antagonists, renal failure (serum creatinine 2.5) and poorly controlled diabetes. the fgsi was 13. the huge presence of edema associated with a strong gaseous component with crackling of the subcuticular tissue indicated emergency surgery; it consisted of decompression and cleaning of infected foci, with removal of a large amount of scrotal tissue (testicles were not involved in the necrotic process) and multiple decompressive incisions of the penile area, and of the inguinal and suprapubic region in order to prevent the necrotic process to reach the abdominal wall; during surgery we could observe the involvement of the bulbar urethra, which appeared necrotic for 2/3 of its circumference for 3 cm of length. the patient then received daily medications using advanced dressings based of calcium alginate and iodoform gauzes. from the 20th post-operative day the patient started 2 cycles of hyperbaric oxygen therapy (90 min per session 2.5 ata). the swab colture showed the presence of streptococcus coagulase-negative and clostridium, and a specific antibiotic therapy was started. with this conservative treatment, the wound had a quick repair, so reconstructive plastic surgery could be avoided. a complete healing was observed after about 120 days. the retrograde urethrography performed after 100 days from the operation showed the fully restoration of the urethra. case 5 p.p., 75 years old man. the patient was referred from a nearby mental health center because of the presence of two lesions, one in the lower part of the scrotum and another perianal, with an underlying communication, and contaminated by feces. in addition to the psychiatric disease, the patient had a poorly controlled insulindependent diabetes and arterial hypertension; the fgsi was 10. the patient did not consent to surgery, therefore debridement was done as an outpatient procedure, using a scalpel, a volkmann spoon and full washing with betadine solution. hyperbaric oxygen therapy was started early (2 cycles of 15 each, 90 minutes per session to 2.5 ata), associated with daily wound dressings with calcium alginate tape. targeted antibiotic therapy against betahemolytic streptococcus was started. after about 60 days the wound appeared granulating, and the alginate dressings were replaced it with hydrogel and polyurethane foam. the complete healing of the wound was observed in 90 days. case 6 n.c., 68 years old man. xx aa. the patient came overnight to the emergency of our hospital seriously ill and with high temperature (39.2 °c) in the last 3 days. a fistulous lesion starting from perineal area, secreting smelling pus and crackling, was observed. in the medical history, the patient had non-insulin dependent diabetes, mild renal impairment and hypertension treated with calcium antagonists (fgsi 12). during emergency surgery, it was observed that the fistula reached the inguinal orifice and the spermatic cord. the patient started two cycles of 15 sessions each of oti (90 min per session 2.5 ata); daily wound medications with ringer lactate solution and covering with calcium alginate tape were performed. targeted antibiotic therapy was started on the basis of the swab colture, that revealed the presence of proteus and escherichia coli. the quick healing of the lesion avoided further surgery, with complete resolution in about 90 days. discussion the fournier's syndrome is a serious disease for which early treatment is mandatory, aiming to expose the foci of infections and to decompress the abscesses as soon as possible. the cornerstone of treatment of patients affected by the fg is the early and radical surgical removal of the necrotic tissue, as shown by numerous studies (2-9). figure 8. figure 7. minardi2_stesura seveso 02/04/15 10:19 pagina 31 archivio italiano di urologia e andrologia 2015; 87, 1 g. milanese, l. quaresima, m. dellabella, a. scalise, g.m. di benedetto, g. muzzonigro, d. minardi 32 nevertheless, sometimes for different reasons (patient unfit for surgery, refusal to surgery, etc ..) it is not possible to perform surgical treatment and alternative solutions need to be found out. hyperbaric oxygen (hbo) therapy is widely recognized as a valid therapeutic procedure, especially in cases with extended tissue necrosis (2, 10). furthermore, a conservative treatment based on the use of ancillary techniques (special medications) associated to hbo therapy can eliminate the need for repeated surgical debridement, and in selected cases, with low fgsi, it can represent an alternative way to reconstructive surgery. in some cases the width of the necrotic lesions would make delayed, if not extremely difficult, the reconstructive surgery; the use of specific medications has made possible a quicker tissue growth, speeding up the healing time and avoiding reconstructive surgery in some cases. laor et al. (3) developed a severity index for the fg in order to stratify risk groups in this complex patient population. the authors observed that a fgsi greater than 9 is a sensible and specific predictor of mortality for patients with fg, regardless of treatment. in our series, 3 patients had a fgsi < 9 and 3 a fgsi > 9; the use of specific advanced medications, in association with hbo therapy, has enabled rapid healing of large losses of substance and therefore avoided in 5 cases further reconstructive surgery. noteworthy, the re-epithelialization until complete healing of the wide urethral lesion was possible, without the need of reconstructive urethral surgery. in conclusion the multidisciplinary approach, the combined use of hbo therapy and the adoption of advanced specific dressings, have made possible the complete healing of the lesions in a shorter period, avoiding further surgery. references 1. fournier ja. gangrene foudroyante de la verge. semin med. 1883; 3:345. 2. eke n. fournier's gangrene: a review of 1726 cases. br j surg. 2000; 87:718-28. 3. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier’s gangrene. j urol. 1995; 154:89. 4. corcoran at, smaldone mc, gibbons ep, et al. validation of the fournier's gangrene severity index in a large contemporary series. j urol. 2008; 180:944-8. 5. dahm p, roland fh, vaslef sn, et al. outcome analysis in patients with primary necrotizing fasciitis of the male genitalia. urology. 2000; 56:31. 6. korkut m, icoz g, dayangac m, et al. outcome analysis in patients with fournier’s gangrene: report of 45 cases. dis colon rectum. 2003; 46:649. 7. yeniyol co, suelozgen t, arslan m, ayder ar. fournier’s gangrene: experience with 25 patients and use of fournier’s gangrene severity index score. urology. 2004; 64:218. 8. tuncel a, aydin o, tekdogan u, et al. fournier’s gangrene: three years of experience with 20 patients and validity of the fournier’s gangrene severity index score. eur urol. 2006; 50:838. 9. ersay a, yilmaz g, akgun y, celik y. factors affecting mortality of fournier’s gangrene: review of 70 patients. anz j surg. 2007; 77:43. 10. mindrup sr, kealey gp, fallon b. hyperbaric oxygen for the treatment of fournier’s gangrene. j urol. 2005; 173:1975. correspondence daniele minardi, md (corresponding author) d.minardi@univpm.it giulio milanese, md luigi quaresima, md giovanni muzzonigro, md g.muzzonigro@univpm.it clinica urologica, università politecnica delle marche, a.o. ospedali riuniti via conca 71 60126 ancona, italy marco dellabella, md uoc urologia, inrca, irccs, ancona, italy alessandro scalise, md giovanni maria di benedetto, md dipartimento di medicina sperimentale e clinica, chirurgia plastica università politecnica delle marche, a.o. ospedali riuniti, ancona, italy minardi2_stesura seveso 02/04/15 10:19 pagina 32 archivio italiano di urologia e andrologia 2013; 85, 150 introduction henoch-schönlein purpura generally resolves without permanent complications. however, serious gastrointestinal (gi) and renal complications may occur. the involvement of male gentalia presenting as the only initial manifestation of hsp is so unusual that the diagnosis can easily be missed. in the literature, a limited number of cases have been reported in which acute scrotum was the initial presenting symptom in patients affected by hsp (1). herein, we report an interesting case who had hsp and subsequently developed acute scrotum resembling torsion of testis while receiving beta-lactam antibiotic and paracetamol therapy because of acute tonsillitis. case report a 5-year-old boy was referred to our pediatric emergency room by his parents with a complaint of acute swelling and pain of the left testis. the patient had an acute tonsillitis one week ago and then, purpuric skin rash appeared at his lower extremities, hips and, genital region while receiving beta-lactam antibiotic and paracetamol. the parents did case report henoch-schönlein purpura without systemic involvement beginning with acute scrotum and mimicking torsion of testis levent verim 1, filiz cebeci 2, m. remzi erdem 3, adnan somay 4 1 departments of urology and 2 dermatology, haydarpasa numune training hospital, istanbul, turkey; 3 department of urology, bezmialem vakif university, istanbul, turkey; 4 department of pathology, fatih sultan mehmet research and teaching hospital, istanbul, turkey. henoch-schönlein purpura (hsp) is the most common systemic vasculitis in children. typical presentations of hsp are palpable purpura of the small vessels in the hips and lower limbs, abdominal pain, arthritis, and hematuria. scrotal involvement manifested by the presence of scrotal pain and swelling during the course of the disease is rarely seen. hsp without systemic involvement with acute scrotum mimicking testicular torsion is even rare in the medical literature. in most cases, patients with this disease achieve complete recovery. herein, we report an interesting hsp case with skin symptoms but without systemic involvement and then progression to acute scrotum resembling torsion of testis. key words: schönlein purpura; non-systemic involvement; scrotal swelling; torsion of testis. submitted 6 august 2012; accepted 31 december 2012 no conflict of interest declared summary not describe of any insect bite or vaccination during the previous 3 months. acute scrotal swelling developed just before his application to our hospital. urgent urologic consultation was asked for the suspicion of testicular torsion. the patient was anxious and had erythematous-purpuric dermal lesions on the left lower limb, groins and scrotum when we observed him (figure 1). his left testis was lifted upwards in the scrotum and very tender on palpation. lifting the testes didn’t enhance the pain. the child voided without difficulty although edema of prepuce and had no gross hematuria or cloudy urine. there was no microscopic hematuria or pyuria in urinalysis and complete blood count (cbc) and blood chemistry data were within normal limits, but erythrocyte sedimentation rate (esr) was 20 mm/hour (normal value 0-15) and c-reactive protein was 15 mg/dl (normal value 0-59). his stool occult blood test was negative. there was no hepatosplenomegaly (hsm) at the abdominal ultrasonography imaging. bilateral painful and erythematous scrotal swelling with scrotal wall thickening was established at the physical examination. a hypoechoic and heterogeneous c-shaped lesion, verim_stesura seveso 18/04/13 12:06 pagina 50 51archivio italiano di urologia e andrologia 2013; 85, 1 henoch-schönlein purpura without systemic involvement beginning with acute scrotum and mimicking torsion of testis prednisolone was administered to treat the hsp orchiepididymitis. scrotal swelling and purpuric rash subsided at 10th day of the treatment and the child was discharged with a stable condition and was followed up two weeks later. edema of the scrotum was diminished and purpuric rash was completely faded away, left testis was softened and regressed to normal volume and structure. discussion henochschönlein purpura (hsp) is the most common vasculitis in children between 4 and 11 years of age and has an incidence of 14 in 100.000 population and usually occurs with a multi-organ involvement (1). typically skin (with a characteristic rash present in all patients), joints of arms and legs, gastrointestinal tract and kidneys are affected. some males also present exter(7 mm x 24 mm in size) was found between the left testis and the enlarged left epididymis at scrotal ultrasound examination (figure 2). blood flow of testes was within normal sequence at color doppler ultrasonography. we ruled out the torsion of the testis and diagnosed a simple epididymoorchitis. the patient was refered to dermatologist for evaluation of skin lesion. the patient was recognized and hospitalized by dermatologist as hsp without systemic involvement. skin biopsy from the scrotum revealed massive perivascular cell infiltrate composed of neutrophils in the upper and mid-dermis, which was associated with nuclear dust, necrosis of endothelial cells and fibrinoid degeneration (figure 3-4). iga deposition was observed along the small blood vessel walls in the upper dermis by direct immunofluorescence staining (leucocytoclastic vasculitis). wide-spectrum antibiotic and, low dose (1,5 mg/kg/day) figure 1. wiev of the erythamatous-purpuric dermal lesions after orchitis. figure 2. wiev of the left testis in scrotal doppler ultrasound examination. figure 3. skin biopsy from the scrotum revealed massive perivascular cell infiltrate composed of neutrophils in the upper and mid-dermis, which was associated with extravasated erythrocytes. h&ex100. figure 4. massive perivascular cell infiltrate composed of polymorphonuclear neutrophils (pmn) which was associated with extravasated erythrocytes and fibrinoid degeneration (leucocytoclastic vasculitis). h&ex400. verim_stesura seveso 18/04/13 12:07 pagina 51 archivio italiano di urologia e andrologia 2013; 85, 1 l. verim, f. cebeci, m. remzi erdem, a. somay 52 references 1. palumbo e. diagnosis of henoch-schonlein purpura in a child presenting with bilateral acute scrotum. acta biomed. 2009; 80:289-91. 2. henoch eh. about a peculiar form of purpura. am j dis child. 1974; 128:78-9. 3. roberts pf, waller ta, brinker tm, et al. henoch-schönlein purpura: a review article. siuth med j. 2007; 100:821-824. 4. kawasaki y. the pathogenesis and treatment of pediatric henochschönlein purpura nephritis. clin exp nephrol 2011; 15:648-57. 5. allen d, diamond lk, howell da. anaphylactoid purpura in children (schonlein-henoch syndrome): review with a follow-up of the renal complications.ama j dis child. 1960; 99:833-54. 6. anil m, aksu n, kara od, et al. henoch-schonlein purpura in children from western turkey: a retrospective analysis of 430 cases. turk j pediat. 2009; 51:429-36. 7. loh hs, jalan om. testicular torsion in henoch-schonlein syndrome. br med j. 1974; 2:96-7. 8. ha ts, lee js. scrotal involvement in childhood henochschönlein purpura. acta paediatr 2007; 96:552-5. 9. patiala b. role of color doppler in scrotal lesions. indian j radiol imaging. 2009; 19:187-90. 10. saulsbury ft. henoch-schönlein purpura in children. report of 100 patientsand review of the literature. medicine. 1999; 78:395-409. 11. davis je, silverman m. scrotal emergencies. emerg med clin north am. 2011; 29:469-84. nal genitalia involvement and/or acute scrotum, with skin petechiae of buttock, legs and infrequently of the upper torso and extremities. schönlein first described the combination of arthritis and acute purpura in children in 1837, and henoch reported the manifestations of nephritis and abdominal pain in 1874 (2, 3). the etiology of hsp remains still unknown. however increased serum circulating immune complexes and deposition of iga in the wall of capillaries are thought to be a cause of acute autoimmune leucocytoclastic vasculitis. iga deposits can be found in both skin and renal biopsy. hsp is typically characterized by palpable nonthrombocytopenic purpura on initial clinical presentation and most frequently on the hips. articular, renal and gastrointestinal (gi) involvement could be associated. the common gi features are abdominal pain (58%), massive colorectal bleeding or occult blood loss (20%). major complications of abdominal involvement develop in 4.6% (1.3-13.6%), of which intestinal perforation, intussusception, and infarction constitute the major surgical complications. scrotal involvement of hsp usually results in pain, tenderness, swelling or discoloration of scrotum. scrotal pain sometimes mimics testicular torsion to various degrees. scrotal swelling and pain in hsp are 2 to 38 percent and the first case was reported by allen et al in 1960 (4-6). involvement of scrotum sometimes appears as scrotal skin edema and a simple purpuric rash without scrotal and testicular swelling. a correct medical history and a careful examination with imaging studies should be done in the presence of painful scrotal swelling associated with hsp because of mimicking testicular torsion. however testicular involvement of hsp and torsion of testis have been reported together (7). therefore differential diagnosis of acute scrotum is a very important condition in order to avoid urgent surgical exploration of the testis (table 1). acute scrotum may be seen in all age groups but mostly seen in preschool and school age group children. at onset of scrotal pain and scrotal swelling have simple urinalysis, color-flow doppler ultrasonography and radionucleide imaging are appropriate. color-flow doppler ultrasound yielded a sensivity and specificity of 89% and 100% respectively, whereas the testicular radionucleide imaging yielded a specificity of 100% (8-10). the doppler ultrasonography reveals a good blood flow to the testes in acute scrotum with hsp syndrome whereas an ischemia of the testis at doppler ultrasound is demonstrated when torsion occurs. untreated testicular torsion causes ischemic damage and concequently disrupt the spermatogenetic function. therefore torsion of testis is a true surgical emergency within 6 hours. scrotal involvement of hsp mimicking testicular torsion is self-limited benign disease and responsive to corticosteroid and/or antibiotic therapy (11). in conclusion, acut scrotal pain in a male child should always be approached as an emergent condition and testicular torsion should be first kept in mind, but differential diagnosis of acute scrotum is considerably important for avoiding unnecessary surgical operation. erythematous rash and acute painful swelling on the scrotum in addition to purpura of the lower extremities and hips should be warning symptoms of hsp orchiepydidimitis for dermatologists, pediatricians and urologists even if there is no other symptom of systemic involvement. correspondence levent verim, md (corresponding author) urologist, urology department, haydarpasa numune training hospital sırcasaray sokak yenigun ap. 4/3 otagtepe kavacık beykoz 34810 istanbul, turkey leventverim@hotmail.com filiz cebeci, md dermatologist, dermatology department, haydarpasa numune training hospital, istanbul, turkey cebecifiliz@yahoo.com m. remzi erdem, md urology resident, urology department, bezmi alem university school of medicine, istanbul, turkey remzierdem@gmail.com adnan somay, md pathologist, department of pathology, fatih sultan mehmet research and teaching hospital, istanbul, turkey adnansomay@hotmail.com table 1. differential diagnosis of the acute scrotum. 1. torsion torsion of testis torsion of appendix testis/epididymis 2. inflammation epididymitis/orchitis (orchiepydidimitis) cellulitis vasculitis limited to skin/testis (hsp) 3. trauma (hematoma) 4. tumor 5. idiopathic scrotal edema verim_stesura seveso 18/04/13 12:07 pagina 52 stesura seveso 81archivio italiano di urologia e andrologia 2014; 86, 2 original paper evaluation of various active surveillance protocols in prostate cancer kayhan yılmaz 1, tahir karadeniz 2, orkunt özkaptan 3, oğuz yilanoglu 4 1 antalya korkuteli state hospital, turkey; 2 medicana hospital group istanbul, turkey; 3 kastamonu state hospital; 4 hatay dörtyol state hospital, turkey. objective: this study aims to investigate whether pathology results obtained by radical retropubic prostatectomy (rrp) were correlated with active surveillance (as) criteria defined by klotz, soloway and d’amico. materials and methods: in our clinic we evaluated 211 patients with diagnosis of localized prostate cancer who underwent rrp between 2007 and 2012. as criteria defined by soloway (ct ≤ t2, psa ≤ 15 ng/dl, gleason ≤ 6), klotz (ct1c-t2a; if age ≥ 70 psa ≤ 15 ng/dl, if age < 70 psa ≤ 10 ng/dl; if age ≥ 70 gleason ≤ 7(3+4), if age < 70 gleason ≤ 6) and d’amico (ct1c-t2a, psa ≤ 10 ng/dl, gleason ≤ 6) were used in our study. pathological stages and gleason scores were evaluated with coherence to as protocols, mis-staging rates, biochemical recurrence (bc) of the mis-staged patients and death due to prostate cancer data was analyzed using ncss 2007 & pass 2008 statistical software (utah, usa). chi square test and mann-whitney u test were applied for analyzing qualitative data. significance was determined as p < 0.05. results: 137 (64.9%) patients were coherent with soloway as criteria, 118 (55.9%) with klotz as criteria and 108 (51.1%) with d’amico as criteria. histopathological results of the patients grouped according to soloway, klotz and d’amico as protocols showed high stage prostate cancer in 40 (29.2%), 32 (27%) and 27 (24.9%) patients, respectively. high grade prostate cancer rates in soloway, klotz, d’amico groups were 55 (40.2%), 46 (38%) and 39 (36.1%); respectively. misstaging rates of soloway, klotz and d’amico as protocols were determined as 65 (47.4%), 54 (45.5%) and 46 (42.5%), respectively. in the soloway group bc rate was 21.9% in those with high stages. relation between bc and high stage was found to be statistically significant (p < 0.05). conclusion: misstaging rates were relatively high in the three groups and there was no difference between the three groups in bc rates. randomized studies with adequate follow up are needed. key words: active surveillance; prostate cancer; radical prostatectomy. submitted 23 august 2013; accepted 5 october 2013 summary no conflict of interest declared. introduction prostate cancer is a multifaceted disease in which genetic and environmental factors play an important role. studies show that prostate cancer is the most common cancer in man over 50 years age and is shown to be the second most reason for death due to cancer (1-3). currently prostate cancer has various treatment options according to the stage and clinical course of the disease such as radical retropubic prostatectomy (rrp), bra chy therapy, external radiotherapy, hormone therapy and chemotherapy. although there has been an increase in the early diagnosis and treatment rates in prostate cancer, there has been no significant decrease in mortality. this fact gives rise to the thought that clinically insignificant disease is being treated excessively and active follow up of these patients should be preferred instead of radical treatment. active surveillance which was first described by coo et al. (4, 5) aims to postpone radical treatment and prevent redundant early treatment. active surveillance in prostate cancer has become popular in the last decade (6, 7). patients who are adequate for active surveillance are determined with criteria; appropriate prostate specific antigen (psa) level, clinical stage and gleason score in the biopsy (8). however, there is no sufficient randomized data available for supporting these criteria. in our study, we retrospectively investigated patients diagnosed as having localized prostate cancer in which rrp was performed in relation to three different active surveillance criteria as established by klotz, soloway and d’amico. we evaluated whether the pathology results obtained from the rrp specimens were correlated with these three active surveillance criteria. materials and methods we evaluated 211 patients with localized prostate cancer diagnosis in which rrp was performed between 2007 and 2012 in okmeydanı training and research hospital/ istanbul. patients who underwent previous hormono the rapy and/or 5-alfa reductase inhibitor or pelvic radiotherapy were excluded from the study. clinical stages were determined using 2002 tmn classifidoi: 10.4081/aiua.2014.2.81 archivio italiano di urologia e andrologia 2014; 86, 2 k. yılmaz, t.karadeniz, o. özkaptan, o. yilanoglu 82 cation. all the rrp operations were performed by the same urologist and all biopsy and rrp specimens were evaluated by the same pathologist. since positive biopsy core number and tumor percentage were not present in most of the biopsy pathology results, these active surveillance criteria were not included in the study. the active surveillance criteria defined by soloway (ct ≤ t2, psa ≤ 15 ng/dl, biopsy gleason score ≤ 6), klotz (t1c-t2a; if age ≥ 70 psa ≤ 15 ng/dl, if age < 70 psa ≤ 10 ng/dl; if age ≥ 70 biopsy gleason score ≤ 7 (3 + 4), if age < 70 biopsy gleason score ≤ 6) and d’amico (clinical stage t1c-t2a, psa ≤ 10 ng/dl, biopsy gleason score ≤ 6) were used in our study. patients appropriated for the three active surveillance protocols were determined by retrospectively examination of the preoperative psa value, clinical stage and biopsy gleason score (table 1). pathological stages and rrp specimen gleason scores were evaluated with coherence to active surveillance protocols, misstaging rates, biochemical recurrence of the misstaged patients and death due to prostate cancer. the data of the study there analyzed using ncss (number cruncher statistical system) 2007 & pass 2008 statistical software (utah, usa). in addition to descriptive statistical analyses (mean, standard deviation), chi square test was used for analyzing qualitative data and in order to analyze qualitative data in cases of abnormal distribution mann-whitney u test was applied. significance was determined at the level of p < 0.05. results we evaluated 211 patients who underwent rrp according to total psa, clinical stage and biopsy gleason scores as active surveillance criteria. active surveillance criteria defined by d’amico, solo way and klotz were shown in table 1. 137 (64.9%) of the pa tients were coherent with solo way active surveillance criteria (9), 118 (55.9%) with klotz active surveillance criteria (7) and 108 (51.1%) with d’amico active surveillance (10) criteria (table 1). the clinical features found coherent with active surveillance protocols were compared to final pathology results. the pathology results that showed high grade prostate cancer, gleason score sum ≥ 7) (17), extracapsular extension (eci), seminal vesicle (svi) and/or lymph node involvement (lni) were studied and misstaging rates were determined (table 2). the histopathological results of the patients grouped according to soloway active surveillance protocol showed high stage prostate cancer in 40 patients (29.2%). eci, svi, lni was observed in 32 (23.3%), 7 (5.1%) and 1 (0.7%) patient, respectively. high grade prostate cancer was observed in 55 (40.2%) patients. of the 118 patients classified in the klotz active surveillance protocol 32 (27%) had high stage prostate cancer. eci, svi and lni were found in 26 (22%), 5 (4.2%) and 1 (0.8%), respecselection criteria all patients soloway klotz d’amico and coleman clinical stage ≤ t2 t1c-t2a t1c-t2a psa ≤ 15 if age ≥ 70 ≤ 15 ≤ 10 if age < 70 ≤ 10 biopsy gleason score ≤ 6 if age ≥ 70 ≤ 7 (3+4) if age < 70 ≤ 6 ≤ 6 ≤ 6 patients coherent 211 (%100) 137 (%64,9) 118 (%55,9) 108 (%51,1) with the criteria table 1. criteria for active surveillance protocols. eci extracapsular extension. svi seminal vesicle involvement. lni lymph nod involvement. all cases soloway klotz d’amico (n = 211) (n = 137) (n = 118) (n = 108) min-max min-max min-max min-max (mean ± sd) (mean ± sd) (mean ± sd) (mean ± sd) diagnosis age 44-79 44-79 44-79 44-79 (63,10 ± 64) (62,87 ± 7,24) (63,43 ± 64) (62,61 ± 7,19) preoperative psa 1,20-93 1,20-15 1,20-14 10-1,20 (14,12 ± 14,68) (7,19 ± 2,92) (6,59 ± 6,17) (6,15 ± 2,05) n (%) n (%) n (%) n (%) clinical stage t1c 89 (%42,2) 74 (%54) 65 (%55,1) 61 (%56,5) t2a 89 (%42,2) 55 (%40,1) 51 (%43,2) 47 (%43,5) t2b 33 (%15,6) 8 (%5,8) 2 (%1,7) preoperative 2-6 171 (%81) 137 (%100) 117 (%99,2) 108 (%100) gleason score 7 (3+4) 28 (%13,3) 1 (%0,8) 7 (4+3) 5 (%2,4) 8-10 7 (%3,3) eci 76 (%36) 32 (%23,4) 26 (%22) 22 (%20,3) svi 33 (%15,6) 7 (%5,1) 5 (%4,2) 5 (%4,6) lni 9 (%4,3) 1 (%0,7) 1 (%0,8) pathological 2-6 105 (%49,8) 82 (%59,9) 72 (%61) 69 (%63,9) gleason score 7 (3+4) 68 (%32,2) 43 (%31,4) 36 (%30,5) 32 (%29,6) 7 (4+3) 25 (%11,8) 9 (%6,6) 9 (%7,6) 6 (%5,6) 8-10 13 (%6,2) 3 (%2,2) 1 (%0,8) 1 (%0,9) pathological stage pt0 1 (%0,5) 1 (%0,7) 1 (%0,8) 1 (%0,9) pt2a 47 (%-22,3) 36 (%26,3) 35 (%29,7) 33 (%30,6) pt2b 73 (%34,6) 57 (%41,6) 46 (%39) 42 (%38,9) pt2c 13 (%6,2) 12 (%8,8) 10 (%8,5) 10 (%9,3) pt3a 44 (%20,9) 25 (%18,2) 21 (%17,8) 17 (%15,7) pt3b 30 (%14,2) 7 (%5,1) 5 (%4,2) 5 (%4,6) pt4a 3 (%1,4) misstaging (*) number (%) 65 (%47,4) 54 (%45,7) 46 (%42,5) %95 ci 40.4-54.4 38.9-54.1 34.6-50.2 table 2. pathology results and misstaging rates of rrp. tively. high grade prostate cancer was present in 46 (38%) patients. patients classified according to d’amico active surveillance criteria comprised 27 (24.9%) high stage prostate cancer patients. eci, svi rates were 22 (20.3%) and 5 (4.6%); respectively. in this group 39 (36.1%) patient were categorized as high grade cancer. patients diagnosed as organ confined disease on digital rectal examination had local advanced disease in the prostatectomy pathology result with rates of 21.3% in the group classified by soloway criteria, 22.8% in the group according klotz and 23.3% in the group according d’amico. misstaged patients and misstaging rates of soloway, klotz and d’amico active surveillance protocols were determined as 65 (47.4%), 54 (45.7%), 46 (42.5%); respectively (table 2). average follow up periods were 63 months in the soloway group, 63 months in the klotz group and 61 months in the d’amico group. time until recurrence was 9-48 in the three groups. total numbers of patients in which biochemical recurrence was detected were 16 (11.6%) in the soloway group, 13 (11%), in the klotz group, 11 (10.2%) d’amico group and the period until recurrence in each group was 21, 24 and 25 months, respectively. there was no difference in term of biochemical recurrence rates between the three groups (p > 0.05). in the soloway group biochemical recurrence rate was obtained to be 21.9% in those with high stages. the relation between biochemical recurrence and high stage was found to be statistically significant for solowoy group (p < 0.05) (tables 3, 4). no statistically significant difference was shown between biochemical recurrence rates and high stages according to d’amico and klotz criteria (p > 0.05). high gleason grade (≥ 7 in the prostatectomy specimen) had higher biochemical recurrence values, but this analysis did not reach significance (p > 0.05). there was no statistically significant difference between recurrence and death rates according to misstaging status (p > 0.05). in the soloway and klotz groups two deaths due prostate cancer per group and in the d’amico group one death due prostate cancer were reported. deaths due to prostate cancer were only among misstaged patients in the three groups. statistical analysis was not performed because of the low number of exitus patients (table 4). discussion after the description of active surveillance by coo et a.l, it became more popular for clinicians in the last ten years (4, 6, 7). mortality rates of prostate cancer did not decrease despite early diagnosis and treatment of the disease within this period. this fact led clinicians to come to the opinion that clinically insignificant disease is being treated excessively. our study was performed to evaluate the credibility of various criteria groups used for the selection of active surveillance patients in order to estimate pathological stage. misstaging rates of our study for the groups formed according to d’amico, klotz and soloway active surveillance criteria were found to be 42.4%, 45.7% and 47.4%, respectively. with regard to our results d’amico active surveillance protocol had the most firm patient selection criteria with lower misstaging rates compared to the other groups. in a study by marc et al., 2837 patients who underwent rrp were evaluated retrospectively. patients with appropriate clinical features for separate active surveillance protocols had a misstaging rate between 26-35% according to their pathological features (11). nazareno et al. evaluated 4308 patients treated with rrp in five separate active surveillance protocols including d’amico and klotz retrospectively. pathology reports of patients in groups appropri83archivio italiano di urologia e andrologia 2014; 86, 2 evaluation of various active surveillance protocols in prostate cancer chi square test and fisher’s exact was used. soloway klotz d’amico follow up period min-max 13-120 13-118 13-118 (month) mean ± sd 63,93 ± 32,26 63,93 ± 31,68 61,75 ± 31,92 time until recurrence min-max 9-48 9-48 9-48 mean ± sd 21,87 ± 12,19 24,17 ± 12,87 25,10 ± 13,79 n (%) n (%) n (%) recurrence number (%) 16 (7,3%) 13 (11%) 11 (10.2%) %95 ci 13.1-19.1 10,3-18.9 9,4-18,0 death number (%) 10 (7,3%) 8 (6,8%) 7 (6,5%) %95 ci 3.7-10.9 3.0-10.6 2.6-10.4 cause of death prostate cancer 2 (1,4%) 2 (1,6%) 1 (0,9%) other 8 (5,9%) 6 (5,2%) 6 (5,6%) table 3. follow up periods, recurrence and exitus rates distribution in the groups. misstaging present n (%) absent n (%) p soloway group recurrence 10 (%15,4) 6 (%8,3) 0,199 death 6 (%9,2) 4 (%5,6) 0,409 cause of death prostate 2 (%33,3) 0 (%0) other 4 (%66,7) 4 (%100) klotz group recurrence 9 (%16,7) 4 (%6,3) 0,072 death 5 (%9,3) 3 (%4,7) 0,467 cause of death prostate 2 (%40,0) 0 (%0) other 3 (%60,0) 3 (%100) d’amico group recurrence 7 (%15,2) 4 (%6,5) 0,136 death 4 (%8,7) 3 (%4,8) 0,456 cause of death prostate 1 (%25,0) 0 (%0) other 3 (%75,0) 3 (%100) table 4. recurrence and death rates according to misstaging status in the groups. archivio italiano di urologia e andrologia 2014; 86, 2 k. yılmaz, t.karadeniz, o. özkaptan, o. yilanoglu 84 ate for active surveillance were investigated and high stage and/or high gleason scores were detected in the range 39-56%. according to active surveillance criteria recommended by this study group (psa < 4 ng/ml, ct1 and gleason score < 7), the misstaging rate (7.2%) was found to be statistically significantly decreased. however, the patients’ ratio appropriate for active surveillance was found to be decreased to 6.9% (12) and this rate seemed to be low. in fact in our study the rate of patients suitable for soloway, klotz, d’amico active surveillance protocols were 64.9%, 55.9%, 51.2%, respectively. most important reason for misstaging was determined to be low prostate cancer grade in the biopsy results. the misstaging rate in the biopsy grades with regard to prostatectomy specimen grade were 36.1%, 38.9% and 40.1%, respectively. supporting our finding, dall’era et al. established in their study that the most important reason for changing from active surveillance to radical treatment was the increase in the gleason grades in prostate biopsies repeated periodically and this ratio was reported to be 38% (13). in another study performed by carter et al. this ratio was found to be 30% (14). in the light of these findings we believe that if tumor grade is detected more accurately at the beginning, approximately 30% of patients could be treated with active surveillance protocols instead of rrp without losing the chance of cure. several studies have determined that the sensitivity of digital rectal examination is low in the diagnosis and staging of prostate cancer (15-17). in our study patients with organ confined disease on digital rectal examination had local advanced disease in the prostatectomy pathology results with the rates 21.3%, 22.8%, and 23.3% according to soloway, klotz and d’amico active surveillance groups, respectively. in agreement with this results the evaluation of the propriety of patients for active surveillance showed that there was a misstaging rate of 21.3%-23.3% with digital rectal examination and 36.140.1% with gleason grade. in our study digital rectal examination was found to detect whether the disease is limited to the organ better than grade, however misstaging rates were very high. the final point in active surveillance is not pathological stage, but biochemical recurrence, metastasis and cancer related death. while radical prostatectomy can cure the disease without affecting the quality of life when performed by experienced surgeons, it is still debated whether one should risk this chance with active surveillance (18). warlick et al. compared 38 patients who underwent radical prostatectomy following active surveillance with 150 patients with similar characteristics in which radical prostatectomy was performed immediately. this study indicated that postponing prostate cancer surgery didn’t risk the chance of cure, however the evident difference between the patient population in the groups decreases the credibility of the study (19). in contrast, the toronto active surveillance study followed 299 patients and they performed radical prostatectomy in 24 patients which showed progression; in 14 (14%) pt3 and in two (8%) n1 was detected and these rates are high (20). this indicated the risk of losing the chance for curative treatment after active surveillance (21-23). also the prias (prostate cancer research international: active surveillance) study reported undesired pathological results in 29% of the patients in which radical surgery was performed following a period of 1.3 years: pt3-4 disease and /or gleason score ≥ 4+3 (24). john hopkins reported that the 10 year disease free rate of 23% patients in which rrp was performed due to grade progression in the control biopsy was lesser than 75% (25). however, this rate was not statistically significantly different than patients who have similar clinical features and were operated on with radical surgery within three months (25). in our study the average follow up periods were 61-63 months in three groups. biochemical recurrences and rates were 16 (11.6%) in the soloway group, 13 (11%), in the klotz group, and 11 (10.2%) d’amico group and the period until recurrence in each group was 21, 24 and 25 months, respectively. in comparing the three active surveillance groups in our study according to biochemical recurrence, no statistically difference was noted. statistical significance (p < 0.05) between biochemical recurrence and high stage was remarkable in the soloway group. although there was no statistically significant difference in biochemical recurrence rates in high stages according to d’amico and klotz criteria, high values of biochemical recurrence in high stage were observed. when evaluating the relationship between gleason grades in rrp pathologies and biochemical recurrence, patients with high gleason grades had higher biochemical recurrence values, however this analysis was not statistically significant (p > 0.05). in comparing the biochemical recurrence values of misstaged patients and patients who met the criteria in three active surveillance groups, no statistically significant difference (p > 0.05) was found, however biochemical recurrence rates were higher in misstaged patients. about death due to prostate cancer there were two deaths due to prostate cancer in the soloway and klotz group and one death in the d’amico group. this result was remarkable because all these patients were among the misstaged patients. conclusion all these findings show that there are serious problems in the selection of active surveillance patients. also, there is no consensus in the follow up of active surveillance patient. consequently the controversial status of active surveillance may result in various mood disorders in patients, and this psychological aspect should not be underestimated. after evaluating all the study results, it is evident that the data on radical surgery results following active surveillance in low risk prostate cancer patients are insufficient. at least one fourth of the pathological data are consistent with the need of treatment and it is unknown how this rate will change with longer surveillance periods and how this will affect the patient prognosis. thus, there is no current data that postponing active treatment in these patients decreases the chance of cure. since there are not sufficient randomized studies with adequate follow up periods, active surveillance should only be recommended to a well selected patient group and the patient should be informed about the inconsistencies about active surveillance and all the treatment options should be explained, and the decision should be up to the patient. references 1. sakr wa, grignon dj, crissman jd, et al. high grade prostatic intraepithelial neoplasia (hgpin) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. in vivo. 1994; 8:439-443. 2. nelson wg, de marzo am, isaacs wb. mechanisms of the disease: prostate cancer. n engl j med. 2003; 349:366-381. 3. jemal a, murray t, ward e, et al. cancer statistics, 2005; 55:10-30. 4. choo r, de boer g, klotz l, et al. psa doubling time of prostate carcinoma managed with watchful observation alone. int j radiat oncol biol phys. 2001; 50:615-620. 5. choo r, klotz l, danjoux c, et al. feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. j urol. 2002; 167:1664-1669. 6. carter hb, ferrucci l, kettermann a, et al. detection of lifethreatening prostate cancer with prostate-specific antigen velocity during a window of curability. j natl cancer inst. 2006; 98:1521-1527. 7. klotz l. active surveillance for prostate cancer: for whom? j clin oncol. 2005; 23:8165-8169. 8. aus g, abbou cc, bolla m, et al. eau guidelines on prostate cancer. eur urol. 2005; 48:546-551. 9. mark s. soloway, cynthia t. et al. active surveillance; a reasonable management alternative for patients with prostate cancer: the miami experience. b.j.u. internatıonal. 2007; 101:165-169. 10. d'amico av, coleman cn. role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. j clin oncol. 1996; 14:304-315. 11. smaldone mc, cowan je, carroll pr, davies bj. eligibility for active surveillance and pathological outcomes for men undergoing radical prostatectomy in a large, community based cohort. j urol. 2010; 183:138-143. 12. suardi n, capitanio u, chun fk, et al. currently used criteria for active surveillance in men with lowrisk prostate cancer: an analysis of pathologic features. cancer. 2008; 113:2068-2072. 13. dall'era ma., konety br, cowan je, et al. active surveillance for the management of prostate cancer in a contemporary cohort. cancer. 2008; 112:2664-2670. 14. carter hb, walsh pc, landis p, epstein ji. expectant management of nonpalpable prostate cancer with curative intent: preliminary results. j urol. 2002;167:1231-1234. 15. cevik d, dillioglugil o. staging and grading in prostate cancer. in: ozen h, turkeri l (eds), book of urooncology, ankara: ertem press publication, 2007; pp. 610621. 16. obek c, louis p, civantos f, soloway ms. comparison of digital rectal examination and biopsy results with the radical prostatectomy specimen. j. urol. 1999; 161:494-498. 17. huland h, hubner d, henke rp. systematic biopsies and digital rectal examination to identify nerve-sparing side for radical prostatectomy without risk of positive margin in patients with clinical stage t2, n0 prostatic carcinoma. urology. 1994; 44:211-214. 18. klotz l. active surveillance for prostate cancer: trials and tribulations. world j urol. 2008; 5:437-444. 19. warlick c, trock b, landis p, et al. delayed versus immediate surgical intervention and prostate cancer outcome. j natl cancer inst. 2006; 98:355-7. 20. klotz l. active surveillance with selective delayed intervention for favorable risk prostate cancer. urol oncol. 2006; 24:46-50. 21. simmons mn, stephenson aj, klein ea. natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. eur urol. 2007; 51:1175-1184. 22. porter cr, gallina a, kodama k, et al. prostate cancer-specific survival in men treated with hormonal therapy after failure of radical prostatectomy. eur urol. 2007; 52:446-454. 23. freedland sj, humphreys eb, mangold la, et al. risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. jama 2005; 294:433-439. 24. bul m, zhu x, rannikko a, et al. radical prostatectomy for low-risk prostate cancer following initial active surveillance: results from a prospective observational study. eur urol. 2012; 62:195-200. 25. soloway ms, soloway ct, eldefrawy a, et al. careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. eur urol. 2010; 58:831-835. 85archivio italiano di urologia e andrologia 2014; 86, 2 evaluation of various active surveillance protocols in prostate cancer correspondence kayhan yılmaz, md kayhany@gmail.com aşağı pazar mah. hastane cad. no 71 korkuteli antalya, turkey tahir karadeniz, md karadeniz@gmail.com director of medicana hospital group beylikdüzü cad. no:3 beylikdüzü, istanbul, turkey orkunt özkaptan, md orkunt79@gmail.com fellow in heilbronn urology clinic tatlipinar caddesi yunus apt no 11 d3 fatih istanbul, turkey oğuz yilanoglu, md oyilanoglu@yahoo.com yilanoglu, istasyon cd. 31600 dörtyol hatay, turkey stesura seveso archivio italiano di urologia e andrologia 2015; 87, 2158 short communication use of transvaginal ultrasound in females with primary bladder neck obstruction. a preliminary study vikiela galica, elona toska, pietro saldutto, giuseppe paradiso galatioto, carlo vicentini university of l'aquila, urology department of “g. mazzini” hospital, teramo, italy. introduction and aim: the video-urodynamics study is the principal exam to establish a possible primary bladder neck obstruction (pbno) condition. while trans-rectal ultrasonography plays an important role in the evaluation of the low urinary tract symptoms (luts) and the severity of bladder outlet obstruction (boo) in men, the use of the transvaginal ultrasound (tvus) in women with symptoms suggesting boo remains unclear. we tried to check the utility of the tvus in women with pbno condition. material and methods: we selected female patients which presented boo without pelvic organ prolapse (pop). according to the data of the video-urodynamic exam we selected the patients with the suspicion of pbno. a tvus in basal and during micturition was performed before and after surgery. results: tvus showed a closed bladder neck bladder in basal condition and during micturition similarly to the fluoroscopic image during video-urodynamics. the mean distance from bladder neck to the vaginal mucosa resulted 1.3 cm in this patients. conclusions: tvus results worthy in the evaluation of patients with pbno before and after surgery. key words: primary bladder neck obstruction; transvaginal ultrasound; video-urodynamics; bladder outlet obstruction. submitted 22 december 2014; accepted 31 december 2014 summary no conflict of interest declared. damental in establishing a possible pbno condition. ultrasonography (us) plays an important role in evaluation of luts in men and women. while the role of transrectal us in the evaluation of the prostate central zone in men has been used to correlate luts and severity of boo (7), the use of transvaginal ultrasound (tvus) in women with boo remains unclear. so in this paper we tried to check the role of tvus in women complaining luts from pbno. material and methods we evaluate all female patients presented with boo symptoms in the last three years in our ambulatory division. a detailed comprehensive history, a clinical exam and urinalysis were performed. all patients with pelvic organ prolapse were excluded previously from the study. urinary infection was excluded by a sterile culture obtained before video-urodynamics. fifteen patients presented symptoms of boo without pop. uroflowmetry, video-urodynamics and electromyography (emg) were performed and the data were analyzed by an experienced urologist. we found three patients with suspicion of pbno according to criteria described by most authors in literature (8, 9). so patients with maximal flow (qmax) < 12 ml/sec; detrusorial pressure at maximal flow (pdet qmax) > 20 cm h2o, silent emg and no images for urethral stricture at fluoroscopy were selected (figure 1). subsequently the selected patients underwent a tvus with a particular attention of urethra, periurethral tissues and bladder neck in basal condition with a comfortably full bladder and during micturition. we used a logic 5 ge medical systems console with a 6.5 mhz transducer. the exam was conducted with patients lying in a lithotomic position with the probe adhering to the posterior vaginal wall. the urethra and the bladder neck was studied in both sagittal and transversal planes with particular attention to the bladder neck in the sagittal plane. a possible mass compressing urethra and bladder neck was excluded. the thickness from the bladder neck to the vaginal mucosa was measured. in order to exclude definitively an urethral stricture an urethrocystoscopy was performed. patients with pbno were treated with alpha-blockers for 3 months. uroflowmetry and a post-voiding residual urine were performed monthly. collected data showed a therapy failure in all patients and a transurethral bladder neck incision was programmed. tvus during micturition was repeated at 3 months after surgery. doi: 10.4081/aiua.2015.2.158 introduction bladder outlet obstruction (boo) in women without pelvic organ prolapse (pop) remains still a controversial condition. compared with the boo in men, represent an uncommon condition which can be found in 2.7-8% in women complaining low urinary tract symptoms (luts) (1, 2). the cause of boo in women may be anatomical and/or functional (3). whereas the anatomical causes of boo are more common, the functional ones can only be verified during micturition. once excluded neurological disease, diabetes mellitus and other peripheral neuropathies the main non neurogenic functional causes described in literature are voiding dysfunction (vd) and pbno (4, 5). international continence society describes the vd such as an intermittent and/or fluctuating flow rate due to involuntary intermittent contraction of the periurethral striated or levator muscles during voiding in neurologically normal woman (6). pbno is described as the failure of the bladder neck to open during voiding. the diagnosis of pbno is difficult due to non-specific criteria. a video-urodynamics study is considered fun galica2_stesura seveso 02/07/15 11:28 pagina 158 159archivio italiano di urologia e andrologia 2015; 87, 2 use of transvaginal ultrasound in females with primary bladder neck obstruction. a preliminary study results all patients well accepted tvus. the urethra and the periurethral tissue in healthy females and in the patients with pbno appears as a hypo echoic cylindrical structure (figure 2). during micturition in the patients with pbno the images of the bladder neck remained almost the same with little urine flow (figu re 3). the images were evaluated separately from the urologists, gynecologists and a radiologists which excluded a possible mass compressing the urethra. furthermore tvus permitted us to measure the distance from the bladder neck to the vagina which is an important information prior to the surgery figure 5. there was a mean distance of about 1.3 cm from the bladder neck to the vaginal wall. a trans-urethral incision of the bladder neck was performed in all patients. as it shown in figure 5 the surgeon must be careful not to penetrate in the bladder neck to avoid perforation into the vagina. tvus during micturition performed 3 months after surgery showed the opening of the bladder neck. tvus after surgery in the sagittal plane showed the structure of the bladder neck, urethral and periurethral tissues as it is shown in figure 4a and 4b. an hypoechoic image extends around the bladder neck after surgery and it seems like a stem of flower rather than cylindrical (figure 4b). discussion for many years, physicians specialized in urogynecology and female urology have utilized urodynamics and then video-urodynamics to characterize disorders of female pelvic floor. in the last years increasing availability of us and magnetic resonance imaging (mri) has triggered a figure 1. video-urodynamics evaluation of a forty-nine years old woman with primary bladder neck obstruction (pbno). figure 2. normal urethra and periurethral tissue in a sagittal plane. figure 3. bladder neck during micturition in patient with primary bladder neck obstruction (pbno). figure 4a-b. bladder neck and urethra in a patient with primary bladder neck obstructuion (pbno) after surgery. note the stem of flower-like appearance designed in white (fig. 4b). a. b. galica2_stesura seveso 02/07/15 11:28 pagina 159 correspondence vikiela galica, md elona toska, md elonatoska@yahoo.it pietro saldutto, md giuseppe paradiso galatioto, md carlo vicentini, md university of l'aquila, urology department of “g. mazzini” hospital, teramo, italy archivio italiano di urologia e andrologia 2015; 87, 2 v. galica, e. toska, p. saldutto, g. paradiso galatioto, c. vicentini 160 numerous series of studies in diagnostic imaging in urogynecology, although mri utilize remains limited due to costs and access problems. so us are currently used to better characterize different disorders of lower urinary tract. pbno may be difficult to distinguish and symptoms may be confused with vd. video-urodynamics plays an important role on assessing a pbno suspicion representing the first examination to be performed in these women. video-urodynamics with emg evaluation show a closed bladder neck during detrusor contraction with normal sphincter activity. it’s important to distinguish between vd and pbno because of different therapeutic strategies. us have been used widely in the assessment of organic and functional diseases of female urethra and bladder neck (10, 11). in particular authors have described the use of tvus to check urethral disease (10). perineal ultrasound has been largely used to evaluate urethral angle and bladder neck mobility in women with urinary incontinence (11). it is widely accepted that the suprapubic us evaluation of post-void residual urine is the principal non-invasive method in the follow-up of patients complaining luts before and after any treatment. in our experience we performed tvus to provide a further evaluation element in the study of women with pbno. furthermore tvus showed an adequate evaluation of bladder neck distance to vaginal mucosa and urethra position which are worthy of consideration before a surgical approach. in our study there is a limited number of patients in order to depict a model image of bladder neck in pbno, but as we mention above the use of tvus results worthy in the pre and post-surgery evaluation. in the pre-surgery the use of tvus may be helpful to exclude other pathologies. if the conservative treatment fails, transurethral bladder neck incision is the surgical treatment of choice (12-14). tvus permits to know preventively the distance between the bladder neck and the vaginal mucosa (15, 16), in order to prevent injuries. conclusions diagnosis and management of pbno remains still controversial. of course nowadays videourodynamics with emg remains the principal diagnostic imaging method. us plays an important role during the evaluation of the patients. especially tvus permitted to collect several information before surgery such as urethra position, distance from the bladder neck to vaginal mucosa and excluding periurethral masses. after surgery the tvus during micturition was a non-invasive method of evaluation of the bladder neck. references 1. groutz a, blaivas jg, chaikin dc. bladder outlet obstruction in women: definition and characteristics. neurourol urodyn. 2000; 19:213-20. 2. massey ja, abrams ph. obstructed voiding in the female. br j urol. 1988; 61:36-9. 3. goldman hb, zirmmen pe. the treatment of female bladder outlet obstruction. bju int. 2006; 98(suppl.1):17-23. 4. yande s, joshi n. bladder outlet obstruction. j midlife health. 2011; 2:11-7. 5. brucker bm, fong e, shah s, et al. urodynamic differences between dysfunctional voiding and primary bladder neck obstruction in women. urology. 2012; 80:55-60. 6. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. int urogynecol j. 2010; 21:5-26. 7. corica fa, jacobsen sj, king bf, et al. prostatic central zone volume, lower urinary tract symptom severity and peak urinary flow rates in community dwelling men. j urol. 1999; 161:831-4. 8. abrams p, cardozo l, fall m, et al. the standardization of terminology of lower urinary tract function: report from the standardization sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-78. 9. blaivas jg, groutz a. bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. neurourol urodyn. 2000; 19:553-64. 10. fontana d, porpiglia f, morra i, destefanis p. transvaginal ultrasonography in the assessment of organic diseases of female urethra. j ultrasound med. 1999; 18:237-241. 11. pregazzi r, sartore a, bortoli p, et al. perineal ultrasound evaluation of urethral angle and bladder neck mobility in women with stress urinary incontinence. bjog. 2002; 109:821-7. 12. markic d, maricic a, oguic r, et al. transurethral bladder neck incision in women with primary bladder neck obstruction. wiener klin wochenschr. 2014; 126:217-22. 13. xun-bo jin, hua-wei qu, hui liu, et al. modified transurethral incision for primary bladder neck obstruction in women: a method to improve voiding function without urinary incontinence. urology. 2012; 79:310-313. 14. qiang fu yue-min xu. transurethral incision of the bladder neck using ktp in the treatment of bladder neck obstruction in women. urol int. 2009; 82:61-64. 15. turner-warwick r, whiteside cg, worth ph, et al. a urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and transtrigonal posterior prostatectomy. br j urol. 1973; 45:44-59. 16. delaere kp, debruyne fm, moonen wa. bladder neck incision in the female: a hazardous procedure? br j urol. 1983; 55:283-6. figure 5. distance from bladder neck to vaginal mucosa. galica2_stesura seveso 02/07/15 11:28 pagina 160 stesura seveso 161archivio italiano di urologia e andrologia 2015; 87, 2 short communication internal urethrotomy versus plasmakinetic energy for surgical treatment of urethral stricture levent ozcan 1, emre can polat 2, alper otunctemur 3, efe onen 1, oğuz ozden cebeci 1, omur memik 1, bekir voyvoda 1, emre ulukaradag 1, tayyar alp ozkan 1, murat sener 1, emin ozbek 3 1 derince training and research hospital, department of urology, kocaeli, turkey; 2 istanbul medipol university, faculty of medicine, department of urology, istanbul, turkey; 3 okmeydani training and research hospital, department of urology, istanbul, turkey. purpose: we aimed to compare the longterm outcome of surgical treatment of urethral stricture with the internal urethrotomy and plasmakinetic energy. material and methods: 60 patients, who have been operated due to urethral stricture were enrolled in our clinic. none of the patients had a medical history of urethral stricture. the urethral strictures were diagnosed by clinical history, uroflowmetry, ultrasonography and urethrography. the patients were divided two groups. group 1 consisted of 30 patients treated with plasmakinetic urethrotomy and group 2 comprised 30 men treated with cold knife urethrotomy. results: there were no statistically significant differences between two groups in terms of patient age, maximum flow rate (qmax) and quality of life score (qol) value. a statistical difference between the two groups was observed when we compared the 3rd-month uroflowmetry results. group 1 patients had a mean postoperative qmax value of 16,1 ± 2,3 ml/s, whereas group 2 had a mean postoperative qmax value of 15,1 ± 2,2 ml/s (p < 0.05). in the cold knife group, 3 of 11 (27,7%) recurrences appeared within the first 3 months, whereas in the plasmakinetic group zero recurrences appeared within the first 3 months in our study. the urethral stricture recurrence rate up to the 12 month period was statistically significant for group 1 (n = 7, 23%) compared with group 2 (n = 11, 37%) (p < 0.05). conclusion: we believe that plasmakinetic surgery is better method than the cold knife technique for the treatment of urethral stricture. key words: internal urethrotomy; plasmakinetic energy; urethral stricture. submitted 28 january 2015; accepted 19 march 2015 summary no conflict of interest declared. mentation, and sexually transmitted diseases (2). treatment depends on the localization, length, and type of the stricture (3). the most common technique for the management of urethral strictures is endoscopic internal urethrotomy (viu), because it is an easy, minimally invasive technique (4). endoscopic urethrotomy was first described in 1974 by sachse with the use of a cold-knife technique to incise those stricture segments (5). however low success and high recurrence rates of this technique make urologists to research different types of therapeutic alternatives for stricture treatment (6). sources generating bipolar energy by means of radio frequency waves (gyrus plasmakinetic system) are in use for endourological procedures in recent years. in this study we aimed comparing internal urethrotomy with plasmakinetic energy by urinary flow rate (maximum flow rate) (qmax), quality of life score (qol), international prostate symptom scores (ipss) and duration of operation parameters. materials and methods sixty patients, who have been operated due to urethral stricture were enrolled into the study. none of the patients had a medical history of urethral stricture. the urethral strictures were diagnosed by clinical history, uroflowmetry, ultrasonography and urethrography. all of the patients were preoperatively evaluated with physical examination and laboratory tests such as complete blood count, serum biochemical analysis, urine analysis and urine culture. if there was an active urinary infection, cases were treated with the appropriate antibiotics based on the urine culture. the stricture lengths were measured by urethrography and urethroscopy. after clinical and preoperative evaluation, the patients were divided two groups. group 1 consisted of 30 patients treated with plasmakinetic urethrotomy and group 2 comprised 30 men treated with cold knife urethrotomy. pre-operative and post-operative ipss score qmax, qol score, duration of operations of all patients were recorded. operative time was described as the time interval beginning with insertion of optical urethrotome from external urethral meatus, continuing with the treatment of stricdoi: 10.4081/aiua.2015.2.161 introduction urethral stricture is one of the complex issues of urology due to the difficulty of diagnosis, treatment and risk of recurrence. urethral stricture disease is defined as narrowing of the urethral lumen because of fibrosis, which occurs in urethral mucosa and surrounding tissues. the etiology could be congenital or idiopathic (1). there are several causes of idiopathic urethral stricture, for example, trauma, urethral catheterization, urologic instruozcan_stesura seveso 02/07/15 11:29 pagina 161 archivio italiano di urologia e andrologia 2015; 87, 2 l. ozcan, e. can polat, a. otunctemur, e. onen, o. ozden cebeci, o. memik, b. voyvoda, e. ulukaradag, t.alp ozkan, m. sener, e. ozbek 162 ture and ending with the removal of urethrotome or cystoscope from external urethral meatus. patients with strictures longer than 2 cm, with meatal stenosis and those with history of surgical intervention due to any strictures were excluded from the study. all patients were reevaluated at the 3rd, 9th and 12th month postoperatively. uroflowmetry was performed for the evaluation of strictures. during the follow-up period, if the patients had complaints of voiding difficulty and the maximum flow rate (qmax) was < 10 ml/s, urethroscopy and urethrography were planned. if urethral strictures were present at urethroscopy and urethrography, these were accepted as recurrent strictures and the same procedure was performed again. the procedure was accepted as successful when the patient did not complain of any voiding difficulty and the qmax was > 12 ml/s. surgical technique all patients were operated by the same surgeon. all the patients underwent urethrotomy under spinal anesthesia in the lithotomy position. cephazolin sodium, 1 g, i.v., was administered for preoperative antibiotic prophylaxis. we used a 19 f cystoscope and plasma-cut tm instrument for the plasmakinetic group. first, a safety guide wire was applied through the stricture and cutting of the stricture was performed at 12 o’clock under 60 w with 0.9% sodium chloride as irrigation. a 20.5 f urethrotome was used for the cold knife urethrotomy group. as in the other group, a safety guide wire was first passed through the stricture and the urethrotomy was performed at 12 o’clock. for all patients, a 18 f foley catheter was inserted and left in the bladder for 72 h at the end of the procedure. postoperatively, 500 mg cipro floxacin (twice a day) was prescribed for 7 days. statistical analyses independent-samples t test, and fisher’s exact test were used for comparing the groups of patients. p < 0.05 was considered statistically significant. the computer software used was statistical package for social sciences (spss 12.0.1; spss inc., chicago, il, usa). results group 1 (n = 30, mean age: 61.6 ± 6.7 years) were treated with plasmakinetic urethrotomy. group 2 (n = 30, mean age: 60.3 ± 4.6 years) were treated with cold knife urethrotomy. the mean preoperative qmax values for groups 1 and 2 were 7.9 ± 1.2 and 8.1 ± 1.1ml/s, respectively (p > 0.05). there were no statistically significant differences between two groups in terms of patient age, qmax and qol value (table 1). a statistical difference between the two groups was observed when we compared the 3 month uroflowmetry results. group 1 patients had a mean postoperative qmax value of 16.1 ± 2.3 ml/s, whereas group 2 had a mean postoperative qmax value of 15.1±2.2 ml/s (p < 0.05). increases were statistically significant in both groups (table 2). in the cold knife group, 3 of 11 (27.7%) recurrences appeared within the first 3 months, whereas in the plasmakinetic group no recurrences appeared within the first 3 months in our study. the urethral stricture recurrence rate up to the 12 month follow up was statistically significant for group 1 (n = 7, 23%) compared with group 2 (n = 11.37%) (p < 0.05) (figure 1). operative time was shorter in plasmakinetic group (15.6 ± 3.3 minutes) when compared with cold-knife group (19.5 ± 4.2 minutes). it was statistically significant (p < 0.05). discussion several techniques are currently available for minimally invasive treatment of urethral strictures, including coldknife incision, electrocautery, and various types of laser incisions (7). incision with the cold knife does not cause any thermal effect on surrounding tissues but should create mechanical injury that may lead to recurrence in long term. incision with the electrocautery should cause sigparameters plasmakinetic cold-knife p group (n = 30) group (n = 30) age (y) 61.6 ± 6.7 60.3 ± 4.6 0.41 a preoperative qmax value (ml/sec) 7.9 ± 1.2 8.1 ± 1.1 0.65 a preoperative ipss 18.4 ± 2.4 18 ± 2.2 0.54 a preoperative qol 5.3 ± 0.7 5.2 ± 0.6 0.84 a operative time (min) 15.6 ± 3.3 19.5 ± 4.2 0.00 a recurrence/no recurrence, n (%), 3th month 0 (0)/30 (100) 3 (10)/27 (90) 0.23 b recurrence/no recurrence, n (%), 6th month 3 (10)/27 (90) 7 (23)/23 (77) 0.02 b recurrence/no recurrence, n (%), 12th month 7 (23)/23 (77) 11 (37)/19 (63) 0,04 b a: independent samples t test. b: fisher’s exact test. table 1. characteristics in study groups and comparability of groups treated. plasmakinetic pre-op qmax post-op qmax cold-knife group pre-op qmax post-op qmax p group 7.9 ± 1.2 16.1 ± 2.3 8.1 ± 1.1 15.1 ± 2.2 0.00* pre-op ipss post-op ipss pre-op ipss post-op ipss 18.4 ± 2.4 9.7 ± 2.7 18 ± 2.2 7.1 ± 3.1 0.00* pre-op qol post-op qol pre-op qol post-op qol 5.3 ± 0.7 1.9 ± 0.7 5.2 ± 0.6 1.4 ± 0.5 0.00* * independent samples t test. table 2. pre-post operative qmax, ipss and qol scores of patients in both groups. ozcan_stesura seveso 02/07/15 11:29 pagina 162 163archivio italiano di urologia e andrologia 2015; 87, 2 surgical treatment of urethral stricture nificant thermal effect on healthy surrounding tissues resulting in recurrent strictures during follow-up (7). since 1984, lasers have been used in urethrotomies for the treatment of urethral stricture (8). another energy source have been used for urethrotomies is plasmakinetic. plasma creates an electrically conductive cloud when radiofrequency energy contacts tissue (9). an advantage of plasmakinetic is cutting the tissues at a much lower average temperature (as low as 50°) than conventional electrocautery (10). as a result of this, thermal damage of the surrounding tissue is less than 1 mm. the main goal for using the plasmakinetic system is to vaporize the fibrous tissue. atak et al. reported in their study low-power holmium laser urethrotomy was compared with the cold knife technique (7). according to this study, the operative time of the laser group was shorter than that of the cold knife group and the recurrence rates for the laser and cold knife groups were 19 and 46.7%, respectively. the recurrence-free rates of both groups at 3 month were similar. in addition, the recurrencefree rates at 6, 9 and 12 months were significantly higher in the laser group. there are a few studies about treatment of urethral stricture with plasmakinetic in the literature. basok et al. (11) reported the first clinical experience with plasmakinetic and searched the effectiveness and outcomes of urethrotomies in 22 patients; 17 patients (77.3%) were recurrence-free during the mean follow-up period of 14.2 months; on the other hand, 5 (22.7%) developed strictures during the same period. cecen et al. evaluated the efficacy and outcomes of plasmakinetic urethrotomy against cold knife direct vision internal urethrotomy in terms of recurrence rates in their study and they found recurrence-free rate for the plasmakinetic group was 14% during the 9-month follow-up period, which was statistically significant compared with the cold knife group (30%). but they found no statistical difference between the 2 groups in terms of the recurrence rate at the end of the 18th month (6). another study about treatment of urethral stricture with plasmakinetic showed that the recurrent rate was 37.5% in both groups of urethrotomy and plasmakinetic surgery (12). in our study, the recurrence rates was 36.6 % for the cold knife groups during the 9 month follow up period. in the plasmakinetic group, recurrence rates was 23.3% during the 9 month follow up period. the main difference between the bipolar energy and cold knife procedures is that the fibrotic tissue is not only incised but also evaporated with the vaporization. thus, the recurrence of scar tissue can be decreased (13). “time to recurrence” is also an important parameter in urethral stricture disease. in the cold knife group, 3 of 11 (27.7%) recurrences appeared within the first 3 months, whereas in the plasmakinetic group zero recurrences appeared within the first 3 months in our study. our results like similar previous studies which done by laser (7). another important point that this study emphasis is duration of operation. the operative time of the plasmakinetic group was shorter than that of the cold knife group in our study. also our results like similar previous studies which done by laser (7). it is recommended to perform the internal urethrotomy procedure through the two corpora cavernosa at the 12 o'clock position to avoid bleeding. however, an additional incision may be required at the 6 o'clock position if a single incision does not suffice. alternatively, it is recommended to administer incisions at the 10 and 2 o'clock positions (14). in our series, an incision performed at the 12 o'clock position to open the strictures proved to be sufficient for all patients as no patient suffered from corpora cavernosa damage. on the other hand we observed that the tissue removal was rapid and bleeding was minimal with the vaporization and surgical field visually clearer than the cold knife urethrotomy. as a conclusion, plasmakinetic surgery is a safe, an effective and a minimally invasive method for endoscopic treatment of urethral stricture. when compared with cold knife technique, it provides a better recurrence-free rate during the early period. we believe that plasmakinetic surgery is better method than the cold knife technique for the treatment of urethral stricture. nevertheless, the choice of surgical technique depends on surgeon's experience and whether the hospital is equipped enough. references 1. jordan gh, devine pc. management of urethral stricture disease urol clin north am. 1988; 15:277e89. 2. byun js, song jm. ten years experience of post-traumatic com plete urethral stricture treated with endoscopic internal urethrotomy. korean j urol. 1996; 37:1300-7. 3. huh g, jung gw, yoon jh. clinical assessment of visual internal figure 1. recurrencefree rates for 12 months (statistically significant p value) (fisher’s exact test). ozcan_stesura seveso 02/07/15 11:29 pagina 163 archivio italiano di urologia e andrologia 2015; 87, 2 l. ozcan, e. can polat, a. otunctemur, e. onen, o. ozden cebeci, o. memik, b. voyvoda, e. ulukaradag, t.alp ozkan, m. sener, e. ozbek 164 urethrotomy as primary treatment of urethral stricture. korean j urol. 1996; 37:798-803. 4. kim hm, kang di, shim bs, min ks. early experience with hyaluronic acid instillation to assist with visual internal urethrotomy for urethral stricture. korean j urol. 2010; 51:853-857. 5. sachse h. zur behandlung der harnröhrenstriktur: die transurethrale schlitzung unter sicht mit scharfem schnitt. fortschr med 1974; 92:12-15. 6. cecen k, karadag ma, demir a, kocaaslan r plasmakinetic™ versus cold knife internal urethrotomy in terms of recurrence rates: a prospective randomized study. urol int. 2014; doi: 10.159/000363249. 7. atak m, tokgöz h, akduman b, et al. low-power holmium:yag laser urethrotomy for urethral stricture disease: comparison of outcomes with the cold-knife technique. kaohsiung j med sci. 2011; 27:503-507. 8. dutkiewicz sa, wroblewski m. comparison of treatment results between holmium laser endourethrotomy and optical internal urethrotomy for urethral stricture. int urol nephrol. 2012; 44:717-724. 9. loh sa, carlson ga, chang ei, et al. comparative healing of surgical incisions created by peak plasmablade, conventional electrosurgery, and a scalpel. plast reconstr surg. 2009; 124:1849-1859. 10. ruidiaz me, messmer d, atmodjo dy, et al. comparative healing of human cutaneous surgical incisions created by the peak plasmablade, conventional electrosurgery, and a standard scalpel. plast reconstr surg. 2011; 128:104-111. 11. basok ek, basaran a, gurbuz c, et al. can bipolar vaporization be considered an alternative energy source in the endoscopic treatment of urethral strictures and bladder neck contracture? int braz j urol. 2008; 34:577-586. 12. koca o, sertkaya z, gunes m, et al. internal urethrotomy versus plasmakinetic energy for surgical treatment of urethral stricture. (article in turkish) turkish j urol. 2011; 37:30-33. 13. smith d, khoubehi b, patel a. bipolar electrosurgery for benign prostatic hyperplasia: transurethral electrovaporization and resection of the prostate. curr opin urol. 2005; 15:95-100. 14. motsouka k, inoue m, lida s, et al. endoscopic antegrade laser incision in the treatment of urethral stricture. urology. 2002; 60:968e72. correspondence levent ozcan, md drleventozcan@yahoo.com efe onen, md oguz ozden cebeci, md omur memik, md bekir voyvoda, md emre ulukaradag, md tayyar alp ozkan, md murat sener, md derince training and research hospital department of urology derince, kocaeli, turkey emre can polat, md istanbul medipol university, faculty of medicine, department of urology, istanbul, turkey alper otunctemur, md emin ozbek, md okmeydani training and research hospital, department of urology, istanbul, turkey ozcan_stesura seveso 02/07/15 11:29 pagina 164 stesura seveso 147archivio italiano di urologia e andrologia 2015; 87, 2 short communication evaluation of tl-201 spect imaging findings in prostate cancer sinem ozyurt 1, gokhan koca 2, akif diri 3, koray demirel 2, tolga karakan 3, berkan resorlu 3, meliha korkmaz 2, cankon germiyanoglu 3 1 dr. sami ulus training and research hospital, department of nuclear medicine, van, turkey; 2 ankara training and research hospital, department of nuclear medicine, ankara, turkey; 3 ankara training and research hospital, department of urology, ankara, turkey. objectives: to compare with histopathological findings the findings of prostate cancer imaging by spect method using tl-201 as a tumor seeking agent. methods: the study comprised 59 patients (age range 51-79 years, mean age 65.3 ± 6.8 years) who were planned to have transrectal ultrasonography (trus)-guided biopsies due to suspicion of prostate cancer between april 2011 and september 2011. early planar, late planar and spect images were obtained for all patients. scintigraphic evaluation was made in relation to uptake presence and patterns in the visual assessment and to tumor/background (t/bg) ratios for both planar and spect images in the quantitative assessment. histopathological findings were compatible with benign etiology in 36 (61%) patients and malign etiology in 23 (39%) patients. additionally, comparisons were made to evaluate the relationships between uptake patterns,total psa values and gleason scores. results: a statistically significant difference was found between the benign and malignant groups in terms of uptake in planar and spect images and t/bg ratios and psa values. no statistically significant difference was found between uptake patterns of planar and spect images and gleason scores in the malignant group. conclusions: spect images were superior to planar images in the comparative assessment. tl-201 spect imaging can provide an additional contribution to clinical practice in the diagnosis of prostate cancer and it can be used in selected patients. key words: prostate cancer; scintigraphy; thallium chloride (tl-201); spect. submitted 2 september 2015; accepted 3 november 2014 summary no conflict of interest declared. most useful primary option (4). psa value is not specific for prostate cancer (5) and there is no definite cut-off value of psa to detect prostate cancer (6). trus is not recommended as the primary diagnostic modality due to its high cost price and low predictive value (7). however, the histopathological grading of prostate tissues obtained by trus-guided biopsy is the gold standard method for diagnosing prostate cancer. nuclear medicine had an important role in the diagnosis, treatment planning, and in the evaluation of treatment effectiveness in cancer patients. there are many options such as bone scintigraphy, tumor imaging studies with tc-99m methoxy isobutyl isonitrile, thallium chloride (tl-201), gallium 67 (ga-67) citrate etc. and positron emission tomography (pet) with f-18-fluorodeoxyglucose and other specific radiopharmaceuticals that have an important place in oncological imaging (8). the aim of this study was to show routine clinical use and effectiveness of tl-201 single photon emission tomography (spect) in the detection of prostate cancer. materials and methods patient group between april 2011 and september 2011, 59 patients with a mean age of 65.3 ± 6.8 years (range 51-79 years,) who were planned for a trus-guided biopsy according to the results of trus and serum psa levels or who were planned for a trus-guided biopsy, were included in this study. tl-201 planar and spect imaging were performed on the patients prior to the prostate biopsies. informed consent was obtained from all patients prior to scintigraphic imaging. scintigraphic studies twenty minutes after intravenous administration of 2 mci (74 mbq) tl-201, the scintigraphic images were obtained from the pelvic region with a double-headed gamma camera in the supine position. early static imaging was performed for five minutes abduction of the lower limbs was carried out to obtain better anatomic localization. following the early static images, spect imaging was carried out . one hour after the injection, doi: 10.4081/aiua.2015.2.147 introduction prostate cancer is one of the leading causes of cancer related deaths in men. risk factors include age, race, socioeconomic status, family history, genetic factors, obesity and infections (1-3). adenocarcinomas are the most common tumors of the prostate gland with more than 90% being of epithelial origin. diagnostic methods used for the early diagnosis of prostate cancer are digital rectal examination (dre), serum prostate-specific antigen (psa) levels and transrectal ultrasonography (trus)-guided biopsy. in the determination of prostate cancer risk, a combination of serum psa and dre is the ozyurt_stesura seveso 02/07/15 11:25 pagina 147 archivio italiano di urologia e andrologia 2015; 87, 2 s. ozyurt, g. koca, a. diri, k. demirel, t. karakan, b. resorlu, m. korkmaz, c. germiyanoglu 148 scintigraphic examinations were terminated by taking late static images for five minutes. evaluation of scintigraphic images images were evaluated qualitatively and quantitatively with a joint decision of two blinded nuclear medicine specialists with at least 5 years experience in the field. visual scintigraphic assessment was made to assess the presence or absence of tumor uptake in the early and late planar spect images. in addition, the group with tumor uptake was divided into subgroups of mild, moderate and significant levels of uptake according to the radioactivity uptake patterns. for quantitative evaluation, tumor/background (t/bg) ratios were calculated by drawing a similar region of interest (roi). histopathological evaluation the pathological results of the trus-guided needle biopsy were evaluated in a separate session. the patients who were reported as benign etiology, atypical small acinar proliferation (asap), chronic prostatitis and lesion with low malignant potential were classified as the benign group. otherwise the patients who were reported as adenocarcinoma were classified as the malignant group. whether there was uptake or not and the type of uptake patterns were analyzed according to the results of the pathological examination. the relationships between them were evaluated by comparing the psa values and gleason scores of the malignant group and the psa values of the benign group with the presence of uptake and its uptake pattern. gleason scores were grouped as gleason 1 (the most common pattern), gleason 2 (the second most common pattern) and gleason total (total score). the relationships among the gleason scores and early and late planar and spect images were evaluated se parately. the relationship between the uptake patterns and t/bg ratios was examined for both the benign and malignant groups. statistical analysis data analysis was performed using spss software for windows 11.5 package program. student's t-test and mann-whitney u test were respectively used to evaluate the significance of the difference between the groups for averages and median values. categorical variables were evaluated with pearson's chi-square test. the statistical significance of t/bg ratios for the images to distinguish between the malignant and benign groups was assessed by calculating the area under the roc curves. a level of p < 0.05 was considered as a statistical significance for the results. results following the scintigraphic imaging with tl-201 of 59 male patients, the biopsy specimens were evaluated histopathologically. the results were reported as benign lesions in 36 (61%) and malignant lesions in 23 (39%) patients. in the malignant group, all the patients' biopsy results were adenocarcinoma of the prostate gland. in the benign group, the biopsy results were reported as benign pathological features in 27 patients, asap in 5 patients, chronic prostatitis in 3 patients, lesion with low potential for malignancy in only 1 patient. there was no statistically significant difference (p = 0.304) between the benign and malignant groups of the patients respect to the mean ages (benign: 64.6 ± 6.9 years; malignant: 66.4 ± 6.6 years). average psa values were 7.03 ± 3.89 ng/ml (min.-max.; 2.5824.61) in the benign group and 29.5 figure 1. a pathological tl-201 uptake in the prostatic region is not shown on the early (p: prostatic region; b: background) (a), late (b) planar images. it is noteworthy that the increase in activity in the bladder. transverse spect (c) images show a lack of a pathological tl-201 uptake in the prostatic region coronal spect (d) images show a pathological uptake in the prostatic region. ozyurt_stesura seveso 02/07/15 11:25 pagina 148 149archivio italiano di urologia e andrologia 2015; 87, 2 evaluation of tl-201 spect imaging findings in prostate cancer ± 71.57 ng/ml (min.-max.; 3.70-347.23) in the malignant group. psa values showed a statistically significant difference (p < 0.05) between two groups. early and late static planar and spect images were visually grouped according to the presence or absence of tl201 uptake (figure 1). ten of 36 (27.8%) patients with a benign lesion and 16 of 23 (69.6%) patients with malignant lesion had tl-201 uptake in the early planar images and 10 (27.8%) patients with a benign lesion and 17 (73.9%) patients with malignant lesion had tl-201 uptake in the late planar images. there was a statistically significant difference for the presence of early and late tl-201 uptake between the malignant and benign lesion groups (p = 0.002 and p = 0.001, respectively). spect images were evaluated according to the presence of tl-201 up take and tl-201 uptake was observed in 20 (55.6%) patients in the benign group and in 20 patients (87%) in the malignant group. there was a statistically significant difference (p = 0.012) between the malignant and benign groups the incidence of tl-201 uptake was also higher for all images in the malignant group than in the benign group. t/bg ratios were found to be higher in the malignant group than in the benign group for the three types of image. there were statistically significant differences for t/bg ratios among all groups. this difference was more significant for spect images (p < 0.001). the diagnostic performance of t/bg ratios obtained from the early planar, late planar and spect images was demonstrated by roc analysis to discriminate between malignant and benign cases. according to these results, the areas under the curve for t/bg ratios in the early planar, late planar and spect images were respectively determined to be 0.659 ± 0.074, 0.684 ± 0.018 and 0.912 ± 0.041.the differences were statistically significant (p < 0.05). sensitivity, specificity, accuracy, positive and negative predictive values were calculated for the three types of image. the results are shown in table 1. statistically significant differences were determined (p < 0.001) for the diagnostic performance of these imaging types. the correlations between the uptake patterns and t/bg ratios of the early, late planar and spect images were examined. there was a statistically significant difference (p < 0.001) and a direct correlation between them. spect image for this correlation was stronger than the other types of imaging. the presence of tl-201 uptake and uptake patterns of the images in the malignant group of patients were evaluated by a comparison with gleason scores. the most common gleason pattern was considered to be gleason 1. median (minimum ; maximum) values were calculated as 3 (min: 3; max: 4) in gleason 1, 3 (min: 2; max: 5) in gleason 2 and 6 (min: 5; max: 8) in gleason total. no statistically significant difference was found between gleason score groups and the presence of tl201 uptake on the images. likewise, there was no statistically significant correlation between the uptake patterns and gleason score groups (table 2). conclusions in this study, statistically significant differences were obtained in terms of the presence of tl-201 uptake, uptake patterns and t/bg ratios between benign lesions and malignant lesions. when planar images and spect images were compared, the spect images were found to be more valuable than the planar images. therefore tl-201 spect imaging may contribute to the differentiation of benign and malignant lesions in patients suspected for prostate cancer. discussion and full list of references are posted on the website www.aiua.it indicators definitions early t/bg late t/bg spect t/bg auc 0,659 0,684 0,912 95% ci 0,514-0,805 0,548-0,819 0,831-0,993 cut point 1.104 0.997 1.239 sensitivity tp/(tp+fn) 13/23 (56.5%) 23/23 (100.0%) 22/23 (95.7%) specificity tn/(tn+fp) 27/36 (75.0%) 13/36 (36.1%) 28/36 (77.8%) ppv tp/(tp+fp) 13/22 (59.1%) 23/46 (50.0%) 22/30 (73.3)% npv tn/(fn+tn) 27/37 (73.0%) 13/13 (100.0%) 28/29 (96.6%) accuracy (tp+tn)/(n) 40/59 (67.8%) 46/59 (78.0%) 50/59 (84.7%) p value (chi-square test) 0.015 < 0,001 < 0.001 auc: area under curve, ci: confidence interval, tp: true positive, fn: false negative, tn: true negative, fp: false pozitive, ppv: pozitive predicted value, npv: negative predicted value. table 1. diagnostic performance indicators obtained by roc analysis for t/bg ratios. variables patern 0-1 patern 2-3 p-value early gleason 1 3 (3-4) 3 (3-4) 0.376 a gleason 2 3 (2-5) 3 (2-4) 0.720 a gleason total 6 (5-8) 7 (5-8) 0.769 a late gleason 1 3 (3-4) 3 (3-4) 0.506 a gleason 2 3 (2-5) 3 (2-4) 0.636 a gleason total 6 (5-8) 6 (5-8) 0.975 a spect gleason 1 3 (3-4) 3 (3-4) 0.975 a gleason 2 3 (3-4) 3 (2-5) 1.000 a gleason total 6 (6-8) 6 (5-8) 0.925 a a: mann whitney u test. table 2. distribution according to the tl-201 uptake patterns for gleason 1, gleason 2 and gleason total in the early, late and spect images. ozyurt_stesura seveso 02/07/15 11:25 pagina 149 archivio italiano di urologia e andrologia 2015; 87, 2 s. ozyurt, g. koca, a. diri, k. demirel, t. karakan, b. resorlu, m. korkmaz, c. germiyanoglu 150 references 1. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 2. albano jd, ward e, jemal a, et al. cancer mortality in the united states by education level and race. j natl cancer inst. 2007; 99:1384-94. 3. kinsey t, jemal a, liff j, et al. secular trends in mortality from common cancers in the united states by educational attainment, 1993-2001. j natl cancer inst. 2008; 100:1003-12. 4. catalona wj, hudson ma, scardino pt, et al. selection of optimal prostate specific antigen cut offs for early detection of prostate cancer: receiver operating characteristic curves. j urol. 1994; 152:2037-42. 5. gretzer mb, partin aw. prostat cancer tumor markers, in: walsh pc, retik ab, vaughan edj et al. campbell’s urology, 9th edition, saunders, philadelphia 2007, pp.3042-54. 6. carter hb. a psa threshold of 4.0 ng/ml for early detection of prostate cancer: the only rational approach for men 50 years old and older. urology. 2000; 55:796-9 7. flanigan rc, catalona wj, richie jp, et al. accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. j urol. 1994; 152:1506-9. 8. eary jf. nuclear medicine in cancer diagnosis. lancet. 1999; 354:853-7 correspondence sinem ozyurt, md dr. sami ulus training and research hospital, department of nuclear medicine van, turkey gokhan koca, md koray demirel, md meliha korkmaz, md ankara training and research hospital, department of nuclear medicine, ankara, turkey akif diri, md tolga karakan, md berkan resorlu, md (corresponding author) drberkan79@gmail.com cankon germiyanoglu, md ankara training and research hospital, department of urology ayvali mh, 182.cd 175.sk no:14/8, 06010 ankara, turkey ozyurt_stesura seveso 02/07/15 11:25 pagina 150 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4270 original paper the factors predicting biochemical recurrence in patients with radical prostatectomy osman koca 1, sıtkı ün 2, hakan türk 3, ferruh zorlu 3 1 urology department, horasan state hospital, erzurum, turkey; 2 urology department, katip çelebi university, atatürk research and training hospital, i̇zmir, turkey; 3 urology department, tepecik research and training hospital, i̇zmir, turkey. objective: the main objective of this study was to evaluate the factors predicting recurrence in patients who underwent radical prostatectomy (rp) for localized prostate cancer. materials and methods: a total of 275 patients who underwent rp between 2000 and 2012 years in our clinic were evaluated retrospectively and 238 patients who met our criteria were included in the study. the effect of psa values at diagnosis in addition the histopathological variables on the risk of recurrence was evaluated. biochemical recurrence (bcr) is defined as “an increase of > 0.2 ng/ml or more in the serum total psa count”. the statistical analysis of this study was done using spss for windows version 15.0 package program. values below p < 0.05 are accepted as statistically significant. results: the mean follow up, age and psa of patients were 37,2 months, 66,01 ± 6,85 years and 11,12 ng/ml, respectively. bcr rate was 28% (68/238). univariate analysis revealed that psa levels during initial diagnosis (p < 0.0001), gleason score (gs) (p < 0.0001), prostatic capsule involvement (p < 0.005), extracapsular extension (p = 0.0001), seminal vesicle involvement (p < 0.003) and surgical margin positivity (p < 0.014) were significant factors in predicting recurrence, while multivariate analysis showed that psa at initial diagnosis (p = 0.002) and gs (p = 0.003) were independent prognostic factors. psa > 10 ng/ml and gleason score > 7 are considered as the risk factors for bcr. conclusion: our study results showed that psa value during initial diagnosis as well as gleason score were independent factors in predicting bcr following radical prostatectomy. key words: prostate cancer; biochemical recurrence; radical prostatectomy. submitted 7 january 2015; accepted 31 march 2015 summary no conflict of interest declared. expectancy beyond 10 years. the most important advantage of radical prostatectomy is the curing potential without damaging adjacent tissues. it also provides accurate staging because of total removal of the organ. however, a total cure is not achieved in all the patients with rp. biochemical recurrence (bcr) is observed in 35% of the patients after the operation (3). these patients require further treatment. in this sense it is essential to predict recurrence for treatment and follow-up. in this study, our main aim was to evaluate the localized prostate cancer patients treated by rp who developed bcr in order to determine predicting recurrence factors. materials and methods the data of 706 cases diagnosed with prostate cancer in izmir tepecik education and research hospital urology clinic were retrospectively analyzed. due to pre-operative active follow-up, 11 of the 275 patients treated by rp as the first treatment were excluded from the study. twelve of the patients were excluded for postoperative early hormone therapy due to metastasis in lymph nodes. in the remaining 256 patients, 18 more were excluded from the study, due to preoperative and postoperative missing data. finally, 238 patients who underwent rp in our hospital between 2000 and 2012 and who meet these criteria were included in our study group. the age and preoperative prostate specific antigen (psa) values of all the patients, as well as gleason score (gs), perineural involvement (pni), capsule involvement (ci), extracapsular extension (ece), seminal vesicle involvement (svi), surgical margin positivity (smp), which were obtained by pathological examination of rp specimens, in addition to psa values at postoperative follow-up period were recorded. all the patients were post-operatively controlled in 3-month periods during the first year, 6-month periods in the second and third year and annually thereafter. biochemical recurrence was defined as a single psa value measured as more than 0.2 ng/ml, or a postoperative high psa value (4). for all statistical evaluations, spss version 15.0 package software was used. chi-square test was utilized to categorize the parameters within themselves and to evaluate clinical relevance. independent risk factors were found for univariate and multivariate (binary) logistic regression doi: 10.4081/aiua.2015.4.270 introduction prostate cancer is the most common solid tumor encountered in men, with an incidence of 214 cases in 1000 men in europe (1). according to a study conducted in usa, it is the second leading cause of cancer deaths among men. in the same study, the occurrence rate of clinical prostate cancer was 16%, whereas the rate of death due to this disease was 3% (2). radical prostatectomy (rp) is recognized as the golden standard in treatment of patients with localized prostate cancer and a life 271archivio italiano di urologia e andrologia 2015; 87, 4 the factors predicting biochemical recurrence in patients with radical prostatectomy analysis and recurrence. p values below < 0.05 were defined as statistically significant. results average age of the patients was 66,01 ± 6,85 years (4882), mean psa value was 11,12 ± 9,32 ng/ml and average follow-up period was 37.2 months. during the follow-up, bcr was determined in 68 (28%) of the patients. when the pathological data of the rp specimen were reviewed, it was determined that smp was present in 52 (21.8%) of the patients, ci in 89 (37.4%), ece in 60 (25.2%), svi in 23(9.7%) and pni in 84(35.3%). clinical and pathological features of the patients are summarized in table 1. the relationship of bcr with psa groups following rp can be seen in table 2. bcr rates of patients with psa at diagnosis < 10 ng/ml, between 10 and 20 and > 20 were 17.9%, 37.7% and 66.7% respectively. the difference is statistically significant (p = 0,0001). furthermore, when patients were divided in two groups according to psa (as psa < 10 vs psa ≥ 10), psa above 10 was proved to be a very powerful risk factor for bcr both in univariate and multivariate analysis (p < 0,001, please see table 5). the relationship between gleason score distributions and bcr are evaluated in table 3. it can be observed that the probability of bcr increases with gs. during the 37.2 months of follow-up period, the recurrence rate of the patients with gs 6, gs 7, gs 8, gs 9 were 20,9%, 22%, 82,4% and 81,8% respectively. the difference between the groups is statistically significant (p = 0,0001). furthermore, when grouping is implemented according to gleason scores (as gs ≤ 7 vs gs > 7), gs above 7 was proved to be a very powerful risk factor for bcr both in univariate and multivariate analysis (p < 0.001, please see table 5). the effects of other pathological parameters on bcr can be seen on table 4. in the univariate analysis, the relationship of surgical margin positivity (p = 0.014), capsule involvement (p = 0.005), extracapsular extension (p = 0.001) and seminal vesicle involvement (p = 0.003) with biochemical recurrence were found to be statistically significant, whereas perineural involvement (p = 0548) was not found to be related with recurrence. the data of univariate and multivariate analyses of all varitable 1. clinical and pathological properties of the patients with rp. table 2. bcr relation according to psa distributions. [mean ± standard deviation, % (n/total n)] number of patients 238 age 66,01 ± 6,85 years psa 11,12 ± 9,32 ng/ml psa distribution < 10 %60, 9 (145/238) 10 < psa < 20 %29 (69/238) > 20 %10,1 (24/238) gleason score (gs) 7 ± 0,79 gs distribution 6 46.2% (110/238) 7 42% (100/238) 8 7.1% (17/238) 9 4.6% (11/238) pni 35.3% (84/238) svi 9.7% (23/238) ece 25.2% (60/238) ci 37.4% (89/238) smp 21.8% (52/238) bcr 28% (68/238) recurrence + recurrence total p value psa < 10 26 (17.9%) 119 (82.1%) 145 (100%) p = 0,0001 10 ≥ psa < 20 26 (37.7%) 43 (62.3%) 69 (100%) psa ≥ 20 16 (66.7%) 8 (33.3%) 24 (100%) table 3. bcr relation according to gleason score distributions. recurrence + recurrence total p value gs 6 23 (20.9%) 87 (79.1%) 110 (100%) p = 0,0001 gs 7 22 (22%) 78 (78%) 100 (100%) gs 8 14 (82.4%) 3 (17.6%) 17 (100%) gs 9 9 (81.8%) 2 (18.2%) 11 (100%) table 4. the effect of pathological parameters on bcr. parameters recurrence + (%) recurrence (%) p value smp yes 22 (42.3%) 30 (57.7%) 0,014 no 46 (24.7%) 140 (75.3%) ci yes 35 (39.3%) 54 (60.7%) 0,005 no 33 (22.1%) 116 (77.9%) pni yes 26 (31%) 58 (69%) 0,548 no 42 (27.3%) 112 (72.7%) ece yes 30 (50%) 30 (50%) 0,001 no 38 (21.3%) 140 (78.7%) svi yes 13 (56.5%) 10 (43.5%) 0,003 no 55 (25.6%) 160 (74.4%) table 5. univariate and multivariate analyses of all variables in predicting bcr. variables univariate p value multivariate p value analysis analysis gs 2,597 0,0001 _ _ gs groups (gs ≤ 7 vs gs > 7) 16,867 < 0,0001 10,187 < 0,0001 psa 1,090 0,001 _ _ psa groups (psa < 10 vs psa ≥ 10) 3,877 0,0001 2,416 0,01 svi 3,782 0,003 1,738 0,312 ece 3,684 0,001 1,668 0,310 pni 1,195 0,548 _ _ ci 2,278 0,005 1,041 0,930 smp 2,232 0,014 1,081 0,859 archivio italiano di urologia e andrologia 2015; 87, 4 o. koca, s. ün, h. türk, f. zorlu 272 ables are summarized in table 5. when the variables that proved significant in the univariate analysis were again evaluated using multivariate analysis, only gs and psa were found to be related with bcr (p values 0.003 and 0.002, respectively). furthermore, when we group the patients according to psa values as less than 10 ng/ml and more than 10 ng/ml, statistically significant difference (p = 0.01) was determined between bcr groups both in univariate and multivariate analysis. discussion prostate cancer is a disease which requires a long-term treatment and has to be properly followed up. following the initial curative treatment, 16-35% of the patients require a secondary treatment, regardless of the treatment method received before (5-9).radical prostatectomy (rp) is one of the most commonly used treatments for prostate cancer and provides a very good cancer control. in radical prostatectomy, the main aim is totally removing the cancer while it is still confined within the prostate. however due to clinical staging deficiency, it is known that extraprostatic disease occurs in rp specimens in about 30-40% of the patients with localized prostate cancer (10-11). in addition, bcr develops in 35% of the patients within 10 years of the surgery (12-14). thanks to the excellent sensitivity of psa, recurrence of the disease can be detected early. again due to the very same reason, there is a long time interval between bcr and local recurrence or development of distant metastasis. within these time intervals, the patient may require secondary treatments. which patients and/or in which stage should receive these treatments is disputable. for this reason, it has become important to know the factors predicting bcr, even if they are postoperative. several factors are found to be effective on the postoperative result after radical prostatectomy. one of the best known of these factors is the psa value at the time of diagnosis. many authors studying on biochemical recurrence predictors after radical prostatectomy have found that psa value at the time of diagnosis was a very powerful preoperative indicator both in univariate and multivariate analysis (15-19). supporting these findings, it has been also determined in our study that psa was an independent predictor for biochemical recurrence. besides, kupelian et al. in their study in 1996, have determined the rates of biochemical recurrence at 5 years of follow-up, with respect to psa distributions (psa < 10 ng/ml, 10 < psa < 20 ng/ml, psa > 20 ng/ml) were 31,2%, 44% and 74% respectively (20). these rates seem to be higher than the values obtained in our study but this difference might be due to our comparatively shorter follow-up period. radical prostatectomy specimen gs is also an independent and a powerful predictor for biochemical recurrence in both univariate and multivariate analyses in many studies (15-18). this relationship is much more apparent for the patients with gleason score total value 7 or more. this observation is also confirmed in our study as the most powerful variable in multivariate analysis (p < 0.0001). when we have a look over the studies in general from recurrence point of view, there is no statistical difference in values of gleason score total up to 6. in their study in 2002, hull gw. et al. have determined that the biochemical recurrence rates of the patients with gleason score total value of 6, 7 and 8-10 in 5 years of follow-up period were as 26.6%, 40.1% and 52%, respectively (13). besides, in another study conducted in our country with a mean follow-up period of 43 months, recurrence rates for the same gleason groups were found as 12%, 29% and 90%, respectively (21). in our study, these rates were 20.9%, 22% and 82.1%. the reason that these values do not coincide might be due to the differences in definitions of recurrence as well as the differences in number of patients or follow-up periods. following radical prostatectomy, smp occurs at the rate of 6-41% (22). the difference within these rates may be related to surgical experience. these rates decrease as the surgical experience increases (23-24). in our study, this rate was determined as 21.8%. as it is in many branches of oncological surgery, smp occurrence is an undesired situation that surgeons are concerned in radical prostatectomy as well. although this term means that there are still alive cancer cells remaining in the patient’s body, prognostic significance of occurrence of smp is still disputable for prostate cancer. while smp is shown to be related with high rate of bcr in various studies (25-27), such a relationship could not be shown in many others (28-29). on the contrary, stephenson et al. have determined that number of smp (≥ 1) and extended smp were significant in predicting biochemical recurrence in multivariate analysis (30). again, in their study that investigated 932 patients treated by radical prostatectomy, ahyai et al. have reported that biochemical recurrence developed only in 20% of the patients with smp and remarked that implementation of adjuvant treatment to only selected patients would decrease the risk of overtreatment (31). biochemical recurrence risk of smp in average 5 years of follow-up period varies between 20% and 47% (32-33). moreover, in their study conducted in 2011, psutka et al. have concluded that positivity of surgical margins was an independent predictor for recurrence in pt2 patients, while it was insignificant for pt3 patients (34). in our study within the follow-up period this value was found as 42.3%; as for the patients with surgical margin negativity however, biochemical recurrence rate was found to be 24.7%. although this difference appears to be statistically significant (p: 0,014) in univariate analysis, it is observed that smp is not an independent predictor for bcr in multivariate analysis (p: 0,859). the relationship of tumor with prostate capsule is another factor effecting prognosis. in their study in 1993, epstein et al. have reported that capsular involvement and its degree had prognostic significance (35). yet again, in a relevant serial study with 688 patients, wheeler et al. have evaluated the ci degree of cancer prognosis and its level in multivariate analysis. according to this study, while the rate of recurrence of the patients with only ci in 5 years was 13 %, meanwhile the patients with local ece this rate was found as 27% (36). in the same study, the rate of recurrence of the patients with extended ece in 5 years was found as 58% and extended ece was reported as an independent predictor for biochemical recurrence. in another study by theiss et al. however, 273archivio italiano di urologia e andrologia 2015; 87, 4 the factors predicting biochemical recurrence in patients with radical prostatectomy biochemical recurrence rate in a 10 year follow-up period was reported as 21% for patients with no ci while it was 35.3% for patients with ci, and 61.5% for patients with ece (37). the reporters have suggested that ci and ece should be differentiated. in our study bcr was found in the patients with no ci as 22.1%, in patients with ci as 39.3% and in patients with ece as 50%. while ci and ece were significant for recurrence in univariate analysis, it was determined that it was not an independent variable in multivariate analysis for recurrence. clinical relevance of pni in the radical prostatectomy specimen is controversial. d'amico et al. have shown that pni was an independent prognostic factor for biochemical recurrence (38). however the studies showing that pni was not correlated with bcr have the majority (39-41). jeon et al. also have reported that the patients with pni were related with high gleason scores, extracapsular extension, seminal vesicle involvement and surgical margin positivity (42). in their study in 2010, jun taik lee et al. have determined that pni occurrence was related with lymph node involvement, high gleason score, surgical margin positivity, high volume of tumor and advanced stage prostate cancer. nonetheless, they have determined that pni was not an independent factor for bcr in multivariate analysis (43). in our study, in line with the literature, the patients with pni were not related with bcr in univariate analysis. seminal vesicle involvement is a bad prognostic parameter with biochemical rates of no progression varying between 5-60% (44-45). bloom et al. have published that svi was correlated with high bcr following rp and distant metastasis afterwards (46). freedland et al. have shown the occurrence of significantly high psa values, advanced pathological stage, high grade tumors, accompanying extracapsular extension and/or surgical margin positivity for patients with svi. however in the same study, they stated that prognosis was better in elder patients with svi, low gleason score and surgical margin negativity. this study has concluded that svi was not always an indicator of negative prognosis (47). the reason for different series will result in different outcomes might be due to hidden micro metastases and/or frequently occurring concomitant prognostic pathological data (gleason score > 7, smp, ece). another explanation may be due to the differences in definitions/descriptions of svi. while some authors visualize real seminal vesicle as an intraprostatic part, others accept the part outside the capsule as seminal vesicle involvement (48). what for certain is that svi is a significant prognostic factor. debras et al. have determined that prognostic significance of svi was not stable and the limited involvement in proximal section would progress better than the involvement extending up to distal parts (49). in our study, the probability of biochemical recurrence in patients with svi is a rather high rate of 56.5%, in line with the literature. it did not come out as significant for bcr in multivariate analysis although it did in univariate analysis. the reason for that might be, as mentioned above, the difference in svi definition or the high level of concomitant bad prognostic factors. as previously mentioned, one should keep in mind while evaluating these studies that prostate cancer varies quite a lot with racial and geographical differences.. as much as differences in nutritional habits, black race with more aggressively progressing prostate cancer risk might explain this situation. it is clearly observed in a study conducted in turkey that the patients treated by radical prostatectomy were at a more advanced stage (50). as for our study, the fact that it was retrospective, a shorter follow up period compared to the literature and limited number of patients can be mentioned among the weaknesses. besides, more detailed information could have been obtained from pathological data. for example, if the parameters such as the extension of surgical margins and its number, extracapsular extension being focal or extended, depth of seminal vesicle invasion/involvement and its bilateral character, etc. were also included in the variables, more significant/important information could have been obtained. this is another weakness of our study. conclusions in our study, 28% of the patients treated by radical prostatectomy due to localized prostate cancer developed bcr within an average follow-up period of 37.2 months. in the univariate analysis, psa value, rp specimen gleason score, surgical margin positivity, capsule invasion, extracapsular extension and seminal vesicle involvement/invasion were found to be significant for bcr. perineural invasion however did not turn out to be statistically significant. in the multivariate analysis psa and gs came out as independent factors predicting biochemical recurrence in our study. in particular, psa values over 10 ng/ml and gleason scores above 7 considerably increase the probability of recurrence. we can state that it is still controversial which treatment should be given within the time interval between bcr following rp and metastatic disease main variables that would guide us in treatment should be psa and gleason score. even though svi, ece and smp do not turn out to be independent predictors, in studies with larger 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as a predictor of biochemical recurrence in japanese men with clinically localized prostate cancer. hinyokika kiyo. 2005; 51:241-6. 41. merrilees ad, bethwaite pb, russell gl, et al. parameters of perineural invasion in radical prostatectomy specimens lack prognostic significance. mod pathol. 2008; 21:1095-100. 42. jeon hg, bae j, yi js, et al. perineural invasion is a prognostic factor for biochemical failure after radical prostatectomy. int j urol. 2009; 16:682-6 43. jun taik lee, seungsoo lee, chang jin yun. prediction of perineural invasion and its prognostic value in patients with prostate cancer. korean j urol. 2010; 51:745-751. 44. deliveliotis ch, varkarakis j, trakas n, et al. influence of preoperative vesicle biopsy on the decision for radical prostatectomy. int urol nephrol. 1999; 31:83-87. 45. salomon l, anastasiadis ag, johnson cw, et al. seminal vesicle involvement after radical prostatectomy: predicting risk factors for progression. urology. 2003; 62:304-9. 46. bloom kd, richie jp, schultz d, et al. invasion of seminal vesicles by adenocarcinoma of the prostate: psa outcome determined by preoperative and postoperative factors. urology. 2004; 63:333-6. 47. freedland sj, aronson wj, presti jc, et al. predictors of prostate-specific antigen progression among men with seminal vesicle invasion at the time of radical prostatectomy. cancer. 2004; 100:1633-8. 48. epstein ji, carmichael mj, pizov g, walsh pc. influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. j urol. 1993; 150:135141. 49. debras b, guillonneau b, bougaran j, et al. prognostic significance of seminal vesicle invasion on the radical prostatectomy specimen. rationale for seminal vesicle biopsies. eur urol. 1998; 33:271-277. 50. eskiçorapçı sy, türkeri l, karabulut e, et al. validation of two preoperative kattan nomograms predicting recurrence after radical prostatectomy for localized 74 prostate cancer in turkey: a mluticenter study of the urooncollogy society. urology. 2009; 74:1289-95. correspondence osman koca, md horasan state hospital, urology department, erzurum, turkey sıtkı ün, md (corresponding author) sitki@doctor.com katip çelebi university, atatürk research and training hospital, urology department, izmir, turkey hakan türk, md ferruh zorlu, md tepecik research and training hospital, urology department izmir, turkey stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3194 original paper the relationship between serum hormone levels (follicle-stimulating hormone, luteinizing hormone, total testosterone) and semen parameters mehmet zeynel keskin 1, salih budak 1, tuğba zeyrek 2, orçun çelik 1, oguz mertoglu 1, mehmet yoldas 1, yusuf özlem !lbey 1 1 tepecik research and education hospital, clinic of urology, izmir, turkey; 2 tepecik research and education hospital, assisted reproductive techniques department, clinic of embryology, izmir, turkey. objective: the aim of this study was to investigate the effect of serum gonadotropin and total testosterone levels on semen parameters. materials and methods: three hundred and eighty-two patients that applied to a male infertility polyclinic were included in our study. serum gonadotropin and total testosterone levels and semen parameters of the patients were analyzed during the first visit to the clinic. the reference fsh value was 1.5-12.4 miu/ml, that of lh was 1.7-8.6 miu/ml and the reference value for total testosterone was 249-836 ng/dl. results: while there was no statistically significant difference between the patients with low gonadotropin levels and the controls regarding any of the semen parameters (p > 0.05), there was a strong statistically significant difference between the patients with high gonadotropin levels and the controls regarding sperm concentration (p = 0.000), total motility (p = 0.000), progressive motility (p = 0.000), and morphology (p = 0.000). there was a strong statistically significant difference between the patients with low testosterone levels and the controls regarding total motility (p = 0.012) and progressive motility (p = 0.010), and a weak statistically significant difference in morphology (p = 0.042). there was no statistically significant difference in semen volume or sperm concentration (p > 0.05). there was no statistically significant difference in any of the semen parameters between the patients with high testosterone levels and the controls (p > 0.05). conclusions: our findings especially regarding lh and t levels are not in agreement with previous reports. in this regard, there is a need for larger-scale and randomized trials to resolve this discrepancy. key words: gonadotropin; semen; testosterone. submitted 5 january 2015; accepted 31 march 2015 summary no conflict of interest declared. to testicular obstruction (2) or abnormal hormone levels, leading to dysregulated sperm production. follicle-stimulating hormone (fsh), luteinizing hormone (lh), and testosterone (t) are key hormones in fertility health. fsh and lh are types of ‘gonadotropins’ that are synthetized in the adenohypophysis of vertebrates due to the effect of gonadotropin-releasing hormone (gnrh). production of gonadotropins is controlled by t, estradiol (e2), and inhibin b (3, 4). lh binds to receptors on leydig cells, leading to increased release of intratesticular t. fsh binds directly to sertoli cells, leading to secretion of many factors crucial for sperm development. as leydig cells, sertoli cells, and peritubular cells in the seminiferous tubules are important in spermatogenesis (5), the decrease in fsh and lh production results in reduced testicular function, and infertility. fsh and inhibin b are considered markers of spermatogenesis and sertoli cell function (6-10). in previous studies, a negative correlation was found between fsh levels and sperm concentration, while a positive correlation was found between inhibin b levels and sperm concentration (10-12). no relationship between semen parameters and lh and t levels was detected (10). the aim of this study was to investigate the relationship between semen parameters and serum gonadotropin and total t levels. materials and methods three hundred and eighty-two patients from the outpatient clinics of urology for male infertility problems at the ege maternity hospital between august 2014 and december 2014 were included in the study. initially, history was taken and a physical examination carried out. patients who had a characteristic that could affect semen parameters (drug, hypovolemic testis, varicocele, systemic diseases etc.) were excluded from the study. semen analysis and serum hormone levels were evaluated in the remaining patients. blood samples for determination of hormone levels were collected before 10:00 am. hormone analysis was performed with a roche cobas and 601 hitachi device by microparticle enzyme immunoassay. doi: 10.4081/aiua.2015.3.194 introduction the subfertility rate in couples of worldwide is 15% (1). evaluation of spermatogenesis has an important role in diagnosis, and semen analysis is usually the initial test performed. if an abnormality is determined in patients after semen analysis, hormone levels may then be measured to determine the cause of subfertility. subfertility may be due keskon_stesura seveso 30/09/15 09:27 pagina 194 195archivio italiano di urologia e andrologia 2015; 87, 3 the relationship between serum hormone levels (follicle-stimulating hormone, luteinizing hormone, total testosterone) and semen parameters reference values for fsh levels were 1.5 to 12.4 miu/ml, those of lh were 1.7 to 8.6 miu/ml, and reference values of total t were 249 to 836 ng/dl. semen samples were taken on the same day by manual masturbation, following the patient refraining from sex for 3-6 days. samples were evaluated by the same embryologist in the assisted repro du ction treatment center spermiogram labora tory of the hospital. semen samples were assessed according to the who 2010 criteria (13). the relationship between serum fsh, lh, total t levels and semen parameters was investigated using the ibm statistical package for the social sciences (spss) version 22.0 software. a value of p < 0.05 was taken to indicate statistical significance. results upon analysis of semen parameters and hormone levels of the 382 patients included in the study, the mean fsh level was 7.91 miu/ml and the mean lh level was 6.26 miu/ml. the mean t level was 425.21 ng/dl, semen volume was 2.86 ml, sperm concentration was 26.4 × 106/ml, total motility 42%, progressive motility 29%, and morphology was found to be 2% (table 1). patients were divided into three groups according to fsh, lh, and t levels. patients with a fsh level of 0-1.5 miu ml were considered group 1 (low) (n = 9), patients with a fsh level of 1.5-12.4 miu/ml were considered group 2 (normal) (n = 320)), and those with a fsh level > 12.4 miu/ml were considered group 3 (high) (n = 53). patients with a lh level of 0-1.7 miu/ml were considered group 1 (low) (n = 4), patients with a lh level of 1.7-8.6 miu/ml were considered group 2 (normal) (n = 321), and those with a lh level > 8.6 miu/ml were considered group 3 (high) (n = 57). patients with a t level of 0-249 ng/dl were considered group 1 (low) (n = 45), patients with a t level 249-836 ng/dl were considered group 2 (normal) (n = 333), and those with a t level > 836 ng/dl comprised group 3 (high) (n = 4). upon classifying the patients into low, normal, and high hormone level groups, semen parameters were evaluated. mean, standard deviation, and minimum and maximum values of volume, concentration, total motility, progressive motility, and morphology of semen were assessed according to fsh (table 2), lh (table 3), and t (table 4) levels. n minimum maximum mean std. dev. fsh (miu/ml) 382 0.11 46.00 7.91 8.45 lh (miu/ml) 382 0.31 36.10 6.26 3.78 t (ng/dl) 382 1.94 1173.00 425.21 164.47 volume (ml) 382 0.10 8.50 2.86 1.48 total motility (%) 382 0.00 90.00 41.90 26.39 progressive motility (%) 382 0.00 80.00 29.0393 21.79 concentration (million/ml) 382 0.00 190.00 26.40 33.60 morphology (%) 382 0 10 1.79 1.95 fsh group volume concentration total progressive morphology (ml) (million/ml) motility (%) motility (%) (%) low mean 2.35 22.06 35.22 25.22 1.89 std. dev. 1.47 22.58 28.99 24.4 1.83 minimum 0.20 0 0 0 0 maximum 5 67 75 65 4 normal mean 2.89 30.78 46.60 32.34 2.07 std. dev. 1.48 34.72 23.39 20.45 1.97 minimum 0.10 0 0 0 0 maximum 8.50 190 85 75 10 high mean 2.75 0.72 14.62 9.71 0.08 std. dev. 1.48 1.99 26.74 19.25 0.38 minimum 0.30 0 0 0 0 maximum 7 11.50 90 80 2 table 1. mean data of patients. results of hormone levels and sperm characteristics of 382 patients included in the study. minimum, maximum, mean, and standard deviation were determined for follicle-stimulating hormone (fsh), luteinizing hormone (lh), and testosterone (t) levels, and volume, total motility, progressive motility, concentration, and morphology. table 2. values of semen parameters according to fsh level. relationships between fsh levels and semen parameters. there was no statistically significant difference in semen parameters between the normal and low fsh groups (p>0.05), but there was a significant difference in all semen parameters (with the exception of volume, p = 0.272, p > 0.05) between the normal and high fsh groups (p = 0.000, p < 0.05). lh group volume concentration total progressive morphology (ml) (million/ml) motility (%) motility (%) (%) low mean 2.05 4.30 30 15 1 std. dev. 2.10 7.80 26.77 17.79 2 minimum 0 0 0 0 0 maximum 5 16 55 35 4 normal mean 2.88 30.05 44.80 31.22 2.03 std. dev. 1.49 34.81 24.92 21.34 1.98 minimum 0.10 0 0 0 0 maximum 8.50 190 90 80 10 high mean 2.80 7.43 26.40 17.71 0.49 std. dev. 1.40 16.57 29.15 20.93 1.10 minimum 0.30 0 0 0 0 maximum 7 61 75 60 4 table 3. values of semen parameters according to lh level. relationships between lh levels and semen parameters. there was no statistically significant difference in any of the semen parameters between the normal and low lh groups (p > 0.05), but there were significant differences in all semen parameters (with the exception of volume, p = 0.908, p > 0.05) between the normal and high lh groups (p = 0.000, p < 0.05). keskon_stesura seveso 30/09/15 09:27 pagina 195 archivio italiano di urologia e andrologia 2015; 87, 3 m. zeynel keskin, s. budak, t. zeyrek, o. çelik, o. mertoglu, m. yoldas, y. özlem !lbey 196 discussion fsh is synthesized in the anterior lobe of the hypophysis gland and stimulates sertoli cells to release inhibin b. lh is also synthetized in the anterior lobe of the hypophysis gland and increases intratesticular t levels by acting on leydig cells. intratesticular t stimulates the sertoli cells in a paracrine manner and increases spermatogenesis. previous studies have examined the effects of fsh, lh, and t levels on semen parameters. in a study by kumanov et al. in 2006, fsh and lh levels were found to be significantly negatively correlated with semen parameters, while t levels were not correlated (14). the same study stated that inhibin b levels were a stronger indicator of infertility than fsh and lh levels (14). in a study by subhan et al., serum hormone levels were compared between oligospermic and control groups. serum lh and t levels were found to not be statistically different, but serum fsh levels were significantly higher in the oligospermic group compared to the control group (11). in a 2004 study of 1558 young danish soldiers, jensen et al. found significant correlations of fsh, lh and inhibin b with sperm concentration, motility and morphology (15). in another study in 2003, uhler et al. reported significant correlations between fsh and inhibin b with concentration, motility and morphology. however, they found that lh and t levels did not correlate with those semen parameters (10). meeker et al. (2007) reported in their study significant negative correlations of fsh, lh with concentration, motility and morphology; however, t levels were significantly positively correlated only with motility (16). in studies comparing the diagnostic value of inhibin b and fsh for infertility, inhibin b has been found to be superior by most (9, 14, 17), although some favor fsh as a diagnostic marker of infertility (18, 19). halder et al. (2005) found significant correlations of fsh and inhibin b with semen parameters, but not with lh and t. moreover, inhibin b level was not found to assist the diagnosis of infertility (20). in our study, we investigated the statistical difference between normal and abnormal (low and high) hormone groups with semen parameters. we found no significant difference between the normal group and the low fsh/lh groups. however, we found significant differences in concentration, total motility, progressive motility and morphology between the high fsh/lh groups and the controls. there was a strong significant difference between the low and normal t groups with regard to total motility (p = 0.012) and progressive motility (p = 0.010), and a weak statistically significant difference in morphology (p = 0.042). however, we found no significant difference in semen volume and sperm concentration (p > 0.05). there was no significant difference in any of the semen parameters between patients with high versus normal t levels (p > 0.05). in our study, we detected a significant negative correlation between gonadotropin levels and semen parameters (with the exception of volume), a strong significant positive correlation between t levels and motility, a weakly significant correlation between t levels and morphology, and no correlations among semen volume, concentration, and t levels. conclusions many of these results are conflicting. the lh and t levels reported herein are not in agreement with the current literature. in most studies, although there was no association between semen parameters and t levels, our findings show a strong association between motility and t levels. because of the limited research that has been conducted on the relationship between t levels and sperm motility, there is a need for larger, randomized studies. references 1. greep ro. the dual nature of anterior pituitary influence on the testis. anatomical records 1937; 67(suppl.), 22. 2. anderson ra, sharpe rm. regulation of inhibin production in the human male and its clinical applications. int j androl. 2000; 23:136-144. 3. anawalt bd, bebb ra, matsumoto am, et al. serum inhibin b levels reflect sertoli cell function in normal men and men with testicular dysfunction. j clin endocrinol metab. 1996; 81:3341-3345. 4. sharlip id, jarow jp, belker am, et al. best practice policies for male infertility. fertil steril. 2002; 77:873-882. 5. behre hm, yeung ch, holstein af, et al. diagnosis of male infertility and hypogonadism. in andrology 2001, springer berlin heidelberg, pp.89-124. t group volume concentration total progressive morphology (ml) (million/ml) motility (%) motility (%) (%) low mean 2.48 20.85 32.15 21.53 1.20 std. dev. 1.52 31.12 28.22 21.38 1.50 minimum 0.20 0 0 .00 0 maximum 6 130 85 75 6 normal mean 2.90 27.28 43.09 30.00 1.86 std. dev. 1.47 34.03 26 21.74 1.99 minimum 0.10 0 0 0 0 maximum 8.50 190 90 80 10 high mean 3.75 16.02 52.50 33.25 2 std. dev. 1.25 17.00 15.54 17.95 2.30 minimum 2.00 2.40 30.00 8 0 maximum 5.00 40.00 65.00 50 4 table 5. values of semen parameters according to t level. relationships between levels and semen parameters. there was no statistically significant difference in semen volume (p = 0.069, p > 0.05) or concentration (p = 0.063, p > 0.05), but there was a strong statistically significant difference in total motility (p = 0.012, p < 0.05) and progressive motility (p = 0.010, p < 0.05), and a weak statistically significant difference in morphology (p = 0.042, p < 0.05), between the normal and low t groups. there was no statistically significant difference in any semen parameter between the normal and high t groups (p > 0.05). keskon_stesura seveso 30/09/15 09:27 pagina 196 197archivio italiano di urologia e andrologia 2015; 87, 3 the relationship between serum hormone levels (follicle-stimulating hormone, luteinizing hormone, total testosterone) and semen parameters 6. mabeck lm, jensen ms, toft g, et al. fecundability according to male serum inhibin b a prospective study among first pregnancy planners. hum. reprod. 2005; 20:2909-2915. 7. jensen tk, andersson am, hjollund nhi, et al. inhibin b as a serum marker of spermatogenesis: correlation to differences in sperm concentration and follicle-stimulating hormone levels. a study of 349 danish men 1. jcem. 1997; 82:4059-4063. 8. pierik f, burdorf a, de jong f, weber r. inhibin b: a novel marker of spermatogenesis. ann med. 2003; 35:12-20. 9. pierik fh, vreeburg jt, stijnen t,, et al. serum inhibin b as a marker of spermatogenesis. jcem. 1998; 83:3110-3114. 10. uhler ml, zinaman mj, brown cc, clegg ed. relationship between sperm characteristics and hormonal parameters in normal couples. fertil steril. 2003; 79:1535-1542. 11. subhan f, tahir f, ahmad r, khan, z. oligospermia and its relation with hormonal profile. j pak med assoc. 1995; 45:246-247. 12. mahmoud am, comhaire fh, depuydt ce. the clinical and biologic significance of serum inhibins in subfertile men. reprod toxicol. 1998; 12:591-599. 13. world health organization. who laboratory manual for the examination and processing of human semen. 5th edn. who, 2010. 14. kumanov p, nandipati k, tomova a, agarwal a. inhibin b is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. fertil steril. 2006; 86:332-338. 15. jensen tk, andersson am, jørgensen n, et al. body mass index in relation to semen quality and reproductive hormonesamong 1,558 danish men. fertil steril. 2004; 82:863-870. 16. meeker jd, bailey lg, russ hauser. relationships between serum hormone levels and semen quality among men from an infertility clinic. j androl. 2007; 28:397-406. 17. brugo-olmedo s, de vincentiis s, et al. serum inhibin b may be a reliable marker of the presence of testicular spermatozoa in patients with nonobstructive azoospermia. fertil steril. 2001; 76:1124-1129. 18. bohring c, krause w. serum levels of inhibin b in men with different causes of spermatogenic failure. andrologia, 1999; 31:137-141. 19. andersson am, petersen jh, jørgensen n, et al. serum inhibin b and follicle-stimulating hormone levels as tools in the evaluation of infertile men: significance of adequate reference values from proven fertile men. jcem. 2004; 89:2873-2879. 20. halder a, fauzdar a, kumar a. serum inhibin b and folliclestimulating hormone levels as markers in the evaluation of azoospermic men: a comparison. andrologia, 2005; 37:173-179. correspondence mehmet zeynel keskin, md zeynel_akd@hotmail.com salih budak, md orçun çelik, md oguz mertoglu, md mehmet yoldas, md yusuf özlem ilbey, md tepecik research and education hospital, clinic of urology güney mahallesi, 1140/1 sokak, no:1 yenişehirkonak!zmir, turkey tugba zeyrek, md tepecik research and education hospital, assisted reproductive techniques department, clinic of embryology, izmir, turkey keskon_stesura seveso 30/09/15 09:27 pagina 197 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 286 original paper ureteroscopy and holmium laser lithotripsy: is this procedure safe in pregnant women with ureteral stones at different locations? senol adanur 1, tevfik ziypak 1, fevzi bedir 1, turgut yapanoglu 1, hasan riza aydın 2, mehmet yılmaz 3, mehmet aksoy 4, i̇sa ozbey 1 1 department of urology, medical faculty, ataturk university; 2 department of urology, akçaabat haçkalı baba hospital, trabzon; 3 department of obstetrics and gynecology, medical faculty, ataturk university; 4 department of anaesthesiology and reanimation, medical faculty, ataturk university. objectives: the aim of this study was to assess the safety and effectiveness of ureteroscopy and holmium: yttrium-aluminum-garnet lithotripsy for the treatment of ureteral stones with different localizations in symptomatic pregnant women. methods: a retrospective analysis was performed on 19 pregnant patients referred to our center between january 2005 and december 2012 with symptomatic hydronephrosis requiring surgical intervention. 7.5 f and 9.5 f semirigid ureterorenoscopy with holmium laser lithotripsy was used for treatment in all patients. complications were stratified according to modified clavien criteria. results: the mean age of patients was 25.4 (18-41) years, and the mean gestation duration was 24.8 (7-33) weeks. six cases (31.5%) had a history of stone. solitary kidney secondary to previous nephrectomy was observed in 2 patients and 1 patient had a hypoplastic kidney. abdominal ultrasonography was used as the main diagnostic tool. mean stone size was 9.2 mm (6-13). the location of the stones was the lower, middle, and upper ureter in 8 (42.1%), 5 (26.3%) and 6 (31.5%) cases, respectively. all stones were fragmented with holmium laser lithotripsy. of the 19 patients, 11 (57.8%) required doublr j stent insertion peroperatively. intraoperative urological and obstetric complications were not observed. postoperatively two complications were noted. according to clavien criteria a complication was level 1, and the other was level 2. conclusions: for treatment of pregnant women with symptomatic ureteral stones in every location, holmium laser lithotripsy with a semirigid ureteroscopy can be used as judicious treatment. this approach is effective and safe with an acceptable complication rate. key words: urinary calculi; pregnancy; ureteroscopy; laser lithotripsy. submitted 12 november 2014; accepted 5 october 2013 summary no conflict of interest declared. introduction incidence of symptomatic urinary stones has been reported as 1/200-1/2500 (1). renal colic is the most frequent doi: 10.4081/aiua.2014.2.86 non-obstructive cause of hospitalization during pregnancy with 80-90% of urinary stones in pregnant women diagnosed after the first trimester (2, 3). fifty to eighty per cent of pregnant patients with symptomatic stones tend to pass their stones spontaneously when treated conservatively with analgesics and hydration (1, 4). surgical intervention might be required in the presence of persistent obstruction or intractable pain refractory to analgesics which is the case in nearly one third of the patients (5). advances in fibre optic technology lead to the design of new ureteroscopes, which allow atraumatic access into upper urinary tract (6) and holmium: ytriumaluminium-garnet (yag) laser lithotripsy demonstrated to be able to fragment all types of stone with a certain degree of safety (7). these technical advances in laser lithotiptors and endoscopes offer the urologists an opportunity to safely treat urotlithiasis in pregnant women. in this study, we aimed to retrospectively analyze the effectiveness of the holmium: yag laser lithotriptor with semi-rigid ureteroscope in the management of ureteral stones at different locations in pregnant women. materials and methods in this study we retrospectively evaluated 19 pregnant women who presented to our clinics with the initial diagnosis of symptomatic hydronephrosis between january 2005 and december 2012. these patients whose renal colic and progressive hydronephrosis did not resolve despite conservative treatment during follow-up period underwent ureterorenoscopy (urs) for the detection and treatment of their stones. the medical files of these patients were retrospectively evaluated, and their ages, gestation trimesters, admission symptoms, diagnostic methods, degree of hydronephrosis, past history of urolithiasis or urological interventions, sizes and locations of stones and grades of complications based on modified clavien criteria (8) were recorded. diagnosis of ureteral obstruction was made based on actual clinical manifestations of the patients, their abdominal ultrasound (us) 87archivio italiano di urologia e andrologia 2014; 86, 2 ureteroscopy wıth holmıum: yag laser for treatment ureteral stone ın pregnancy findings, and detection of haematuria in urinalysis. obstructive stones were diagnosed in six (31.5%) patients by us. all patients were also evaluated with whole blood count, urea and creatinine measurements, urine and (if required) blood cultures. the patients underwent obstetric consultations in order to rule out obstetric complications and determine their gestational weeks. conservative treatment such as intravenous fluid replacement and analgesics was started on all hospitalised patients. a third generation cephalosporin (ceftriaxone) was given in cases with infection. urs procedures were postponed in patients with active urinary system infection with documented bacterial growth in their urine cultures until their urine cultures became sterile. preoperative anaesthesiologic and obstetric consultations were required before urs procedure. all patients underwent preoperative intravenous antibiotic prophylaxis. urs procedures were performed under general anaesthesia without using halothane and nitric oxide. urs procedures were realised using a 7.5 f (olympus inc., japan) or a 9.5 f (karl storz inc., germany) semi-rigid ureteroscope under direct endoscopic vision without fluoroscopic guidance. ureters were accessed using 0.038 inch guide wires and in 3 patients balloon dilation of the stenotic distal end of the ureter was needed before intraureteral access. the stones were fragmented using holmium-yag laser (auriga, wavelight laser tecnologie ag, germany). a forcep was used for extraction of stone fragments. cases with oedema secondary to an impacted stone, with presence of a concomitant renal stone or with ureteral trauma caused by urs necessitated double j stent application. during the early postoperative period, meticulous obstetric care was offered to all patients to ensure maternal and foetal well-being. results the mean age of the patients and the mean gestational age were 25.4 (18-41) years and 24.8 (7-33) weeks, respectively. patient characteristics are listed in table 1. medical history of the patients revealed the existence of solitary kidney secondary to nephrectomy in 2, hypoplastich kidney in 1, and a past history of stone disease in 6 (31.5%). the symptoms were renal colic in 14 (73.6%) patients, fever in 2 (10.5%) patients and microscopic ema turia/ pyuria was observed in 9 (47.3%) patients. eight (42.1%) patients had right and eleven (57.9%) had left side hydronephrosis. four (21%) patients had positive urine cultures. the mean stone size determined by pre-operative ultrasound in 6 patients was 9. 2mm (6-13 mm). us detected grade i hydronephrosis in 2 (10.5%), grade ii in 10 (52.9%) and grade iii in 7 (36.8%) patients. ureteric stones were found in the distal ureter in 8 (42.1%), middle in 5 (26.3%) and proximal in 6 (31.5%) patients. the stones of all patients were fragmented using holmium: yag laser lithotriptor. stone fragments of 9 patients were extracted using forceps, while those of other 10 patients were left to spontaneous passage. intraureteral doublej stents were implanted in 11 (57.8%) patients because of procedural oedema by impacted stone, concomitant renal stone, and intraureteral trauma during urs. doublej stents of 7 patients were extracted 2-4 weeks after the first procedure. stents of 3 patients with concomitant renal stones smaller than 2 cm were extracted after successful shockwave lithıtripsy (swl) performed during the postnatal period. doublej stent of one patient migrated on the 1st postoperative day. in 3 patients, following the procedure, an open end 5 f external ureteral catheter was inserted as a transitory stent. the stent was removed within 24 hours after the procedure. details of the procedure and outcomes are presented in table 2. no intraoperative urological and obstetric complication was observed. during postoperative controls preterm uterine contractions (n = 1), and urinary tract infection (n = 1) developed. the patient who suffered from preterm uterine contractions was treated with tocolysis, and the other case with appropriate antibiotics. all newborns were healthy and delivered at term. discussion hydronephrosis induced by pregnancy is the most prevalent cause of urinary tract infection and can lead to characteristic value n (%) patient (n) 19 age (years) 25.4 (18-41) gestation (weeks) 24.8 (7-33) laterality right 8 (42.1) left 11 (57.9) history of urolithiasis 6 (31.6) soliter kidney 2 (10.5) hypoplastic kidney 1 (5.2) symptoms renal colic 14 (73.6) fever 2 (10.5) haematuria-microscopic pyuria 9 (47.3) positive urine culture 4 (21) stone diagnosed by ultrasonography 6 (31.6) stone size on ultrasonography (mm) 9.2 (6-13) table 1. patient characteristic. n (%) degree of hydronephrosis grade i 2 (10.5) grade ii 10 (52.9) grade iii 7 (36.8) stone location proximal 6 (31.6) middle 5 (26.3) distal 8 (42.1) ballon dilatation of ureteral orifice 3 (15.8) double-j stent insertion 11 (57.8) type of lithotriptor laser lithotripsy 19 (100) postoperative complication preterm uterin contraction 1 (5.2) urinary tract infection 1 (5.2) table 2. details of procedure and outcome. archivio italiano di urologia e andrologia 2014; 86, 2 s. adanur, t. ziypak, f. bedir, t. yapanoglu, h. rıza aydın, m. yılmaz, m. aksoy, i̇. özbey 88 flank pain imitating renal colic. upper urinary tract dilation is seen in 90% of pregnant women in their third trimesters, and it may persist up to 12 weeks postpartum. dependent on the position of the foetus, it is more prevalent on the right side (9). during pregnancy, urolithiasis and episodes of renal colic can lead to the development of hydronephrosis and urinary stasis ensuing in pyelonephritis and urinary tract infection. these complications can eventually result in obstetric complications as spontaneous rupture, premature birth and the delivery of low birth weight new-borns (10). fifty to eighty per cent of pregnant women suffering from symptomatic urolithiasis can pass their stones thanks to conservative treatment modalities including intravenous hydration and analgesia (1, 4). in some patients more invasive treatment modalities may be required and in 20-30% of pregnant women with urolithiasis surgical treatment may be required (11). conventional treatment of obstructed ureter can be accomplished by placement of a percutaneous nephrostomy (pcn) tube or insertion of an ureteral stent. however, placement of a pcn tube and of a ureteral stent in the early stages of the pregnancy can be associated with some risks as incrustation, patient’s discomfort and urinary tract infection (12-14). because of physiological hydronephrosis developed during pregnancy, ureteral stents can migrate more frequently (15). recent advances in surgical technology have revolutionised the designs of semi-rigid and flexible ureteroscopes leading to increased use of urs in pregnant women. miniaturisation of ureteroscopes, and advances in intracorporeal lithotripsy technology ensure successful intraureteral access and management of stones at any level of the urinary tract without any traumatic complication (16). since collecting system and ureter undergo physiological dilation in pregnancy, ureteroscopic procedures can be achieved without need for dilatation of the ureteral orifice (17-19). however, rana et al. (12) reported that they had performed ureteral dilatations in 5 (26%) of their 19 pregnant women whereas in another study, bozkurt et.al (20) resorted to ureteral dilatation in 5 (15.6%) of their 32 patients. we also accomplished urs procedures with the indication of symptomatic ureteral stone in 3 (15.7%) of 19 patients only after ureteral dilatation. in pregnancy, all types of intracorporeal lithotriptors have been used. although obstetric complications related to different types of lithotriptors have been underestimated in published reports, there are concerns about unknown harmful foetus-related effects of urs procedures induced by electrothermal energy emitted by certain lithotriptors (21). electrohydraulic lithotriptors (ehl) have the narrowest margin of safety because of their extremely high hydraulic pressure imposed on the ureteral wall (16). relatively safe applications of ultrasonic lithotriptors have been demonstrated as consequence of their limited impact on adjacent structures (22). however, the impact of higher frequency vibrations on foetal organs has not been fully yet acknowledged and possible risks related to the hearing ability of the foetus have been advocated by some authors (19). these concerns have led to the development of devices such as holmium laser, pulsed-dye laser or pneumatic lithotriptors that focus their energy on a localised area with minimal energy dispersion. pneumatic lithotriptors can be used only with a semi-rigid ureteroscope because of their rigid probes. on the other hand, pulseddye laser lithotriptor cannot fragment stones with hard composition (23). as a result of continuous technological advances, a compact laser system was developed, which emits highly water-absorbable shock waves at 2140 nm wavelength. holmium: yag laser disperses its energy via a flexible fibre, which facilitates intracorporeal lithotripsy into collecting system. holmium laser lithotriptor can be safely used if activated 0.5-1.0 mm away from the ureteral wall (24). holmium laser lithotriptor is advantageous over other lithotriptors in that it can be used with both semi-rigid and flexible ureteroscopes, and has the capacity to fragment all types of stones with varying compositions (23). other advantages of holmium laser lithotriptors, can be enumerated including their ability to fragment the stones into relatively small particles when compared with other types of lithotriptors. these small stone particles can be easily eliminated from the collecting system without the need for stone basket or grasper for their extraction (25). when compared with ehl or pneumatic lithotriptors, holmium laser lithotriptors create weak shock waves, which decrease the probability of retropulsion of stones and/or stone particles (25, 26). laing et al. (27) reported a review series consisting of 116 pregnant women who underwent ureteroscopy for ureteral stone treatment: holmium laser was used with success in 27 (23%) patients and a pneumatic lithotriptor in 21 (18%) patients. bozkurt et al. (20) had detected ureteral stones in 27 of 32 patients after urs procedures performed for the management of ureteral stones and used holmium laser lithotriptor in 17 patients for the fragmentation of stones. we successfully fragmented all stones localised in various segments of the ureter using holmium laser lithotriptors in 19 patients who had undergone urs procedures because of progressive hydronephrosis, and uncontrolled renal colic. fragmented stone particles in 9 patients were extracted using stone forceps and very small stone fragments in 10 patients were left to spontaneous passage. ureteral stents placed following urs procedures are adequate to drain obstructed ureters despite increased urinary urate, and calcium concentrations in pregnancy leading to higher risk of incrustation (12). bozkurt et al. (20) reported placement of doublej ureteral stent in 19 (59.4%) of 32 pregnant women after urs procedures. rana et al. (12) also reported placement of doublej ureteral stents in 12 of (63%) 19 pregnant patients who were relieved of obstructive ureteral stones using pneumatic lithotriptors under the guidance of ureterorenoscopy. we also inserted doublej ureteral stents in 11 (57.8 %) of 19 patients following urs procedures. stents were placed with the aid of 9.5 f ureteroscopes under direct vision. however, in patients in whom we used 7.5 f ureteroscopes, firstly a guide wire was inserted and advanced through a ureteroscope under direct vision into the kidney, and then the position of the guide wire was confirmed by us. doublej stents of 7 patients were removed within 2-4 weeks after the first procedure with the aid of a cystoscope under local anaesthesia. on the 1st postoperative day after the urs procedure doublej stent migrated in one patient who was monitored for occurrence of renal colic and development 89archivio italiano di urologia e andrologia 2014; 86, 2 ureteroscopy wıth holmıum: yag laser for treatment ureteral stone ın pregnancy of pelvicalyceal dilation by periodic us examinations. since renal colic and pelvicalyceal dilation did not occur, doublej stent was not re-implanted. double-j stents of 3 patients were removed after they became stone-free following swl in the postnatal period due to the presence of concomitant renal stone. no complication related to the implantation of double-j stents occurred. complications related to urs procedure in pregnant women are not frequent. urs complication rates in pregnant and non-pregnant women are not different. in their meta-analysis consisting of 108 pregnant women who had undergone ureteroscopic stone management, michelle et al. classified a total of 9 complications according to modified clavien criteria (8), and reported 2 level 1, 6 level 2, and 1 level 3 complications (28). in our series a total of 2 patients developed complications consisting in preterm uterine contractions (n = 1) which were managed with tocolysis and urinary tract infection (uti) (n = 1) which was treated with appropriate antibiotics. according to clavien classification, these complications were rated level 1 and 2, respectively. conclusion in conservative treatment of pregnant patients with refractory symptomatic stones at any ureteral location which cannot pass spontaneously, semi-rigid-urs can be used safely for diagnostic and therapeutic purposes. holmium: yag laser lithotripter, which is the most effective intracorporeal lithotriptor for all kinds of stones at every location in the urinary tract with semi-rigid urs, can be used successfully and safely in pregnant women with acceptable maternal and foetal complication rates. references 1. gorton e, whitfield hn. renal calculi in pregnancy. br j urol. 1997; 80 (suppl. 1):4-9. 2. rodriguez pn, klein as. management of urolithiasis during pregnancy. surg gynecol obstet. 1988; 166:103-106. 3. swanson sk, heilman rl, eversman wg. urinary tract stones in pregnancy. surg clin north am. 1995; 75:123-42. 4. parulkar bg, hopkins tb, wollin mr, et al. renal colic during pregnancy: a case for conservative treatment. j urol. 1998; 159:365-368. 5. wein aj, kavoussi lr, novick ac, et al. campbell-walsh urology. matlaga br, lingeman je(ed) urinary calculi during pregnancy, 10th edn. elsevier, philadelphia, 2012; pp 1379-1382. 6. conlin mj, marberger m, bagley dh. ureteroscopy. development and instrumentation. urol clin north am. 1997; 24:25-42. 7. sofer m, watterson jd, wollin ta, et al. holmium:yag laser lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2002; 167:31-4. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 9. boridy ic, maklad n, sandler cm. suspected urolithiasis in pregnant women: imaging algorithm and literature review. ajr am j roentgenol. 1996; 167:869-75. 10. negru i, pricop c, costachescu g.. renal colic in pregnancy. rev med chir soc med nat iasi. 2010; 114:439-44. 11. biyani cs, joyce ad. urolithiasis in pregnancy. ii: management. bju int 2002; 89:819-23. 12. rana am, aquil s, khawaja am. semirigid ureteroscopy and pneumatic lithotripsy as definitive management of obstructive ureteral calculi during pregnancy. urology. 2009; 73:964-7. 13. kavoussi lr, albala dm, basler jw, et al. percutaneous management of urolithiasis during pregnancy. j urol. 1992; 148:1069-71. 14. jarrard dj, gerber gs, lyon es. management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. urology. 1993; 42:263-7. 15. kavoussi lr, jackman sv, bishoff jt. re: renal colic during pregnancy: a case for conservative treatment. j urol. 1998; 160:837-8. 16. zheng w, denstedt jd. intracorporeal lithotripsy. update on technology. urol clin north am. 2000; 27:301-13. 17. drago jr, rohner tj jr, chez ra. management of urinary calculi in pregnancy. urology. 1982; 20:578-81. 18. scarpa rm, de lisa a, usai e. diagnosis and treatment of ureteral calculi during pregnancy with rigid ureteroscopes. j urol. 1996; 155:875-7. 19. ulvik nm, bakke a, høisaeter pa. ureteroscopy in pregnancy. j urol. 1995; 154:1660-3. 20. bozkurt y, penbegul n, soylemez h, et al. the efficacy and safety of ureteroscopy for ureteral calculi in pregnancy: our experience in 32 patients. urol res. 2012; 40:531-5. 21. kroovand rl. stones in pregnancy and in children. j urol. 1992; 148:1076-8. 22. howards ss, merrill e, harris s, cohn j. ultrasonic lithotripsy: laboratory evaluation. invest urol. 1974; 11:273-7. 23. watterson jd, girvan ar, beiko dt, et al. ureteroscopy and holmium:yag laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. urology. 2002; 60:383-7. 24. santa-cruz rw, leveillee rj, krongrad a. ex vivo comparison of four lithotripters commonly used in the ureter: what does it take to perforate?. j endourol. 1998; 12:417-422. 25. teichman jm, vassar gj, bishoff jt, et al. holmium:yag lithotripsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. j urol. 1998; 159:17-23. 26. sofer, denstedt, 2000. sofer m, denstedt j. flexible ureteroscopy and lithotripsy with the holmium:yag laser. can j urol. 2000; 7:952956. 27. laing ka, lam tb, mcclinton s, et al. outcomes of ureteroscopy for stone disease in pregnancy: results from a systematic review of the literature. urol int 2012; 89:380-6. 28. semins mj, trock bj, matlaga br. the safety of ureteroscopy during pregnancy: a systematic review and meta-analysis. j urol. 2009; 181:139-43. correspondence senol adanur, md s.adanur61@hotmail.com tevfik ziypak, md fevzi bedir, md turgut yapanoglu, md i̇sa ozbey, md department of urology school of medicine ataturk university 25240 erzurum, turkey hasan riza aydın, md department of urology-kçaabat haçkalı baba hospital, trabzon, turkey mehmet yılmaz, md department of obstetrics and gynecology, medical faculty ataturk university mehmet aksoy, md department of anaesthesiology and reanimation, medical faculty ataturk university, 25240 erzurum, turkey archivio italiano di urologia e andrologia 2016; 88, 3208 original paper metabolic evaluation in patients with infected nephrolithiasis: is it necessary? elisa cicerello, mario mangano, gian davide cova, franco merlo, luigi maccatrozzo unità complessa di urologia, ospedale ca’foncello, treviso, italy. fifty-four patients with infected renal lithiasis underwent complete metabolic evaluation searching for underlying factors contributing to stone formation including urine analysis and culture. metabolic abnormalities were significantly more present in patients with mixed infected stones (struvite+/-apatite and calcium oxalate) than in patients with pure infected stones (struvite+/-carbonate apatite): hypercalciuria in 40%, hyperoxaluria in 34% and hyperuricosuria in 28% (p < 0.05). urinary excretion of citrate was low in both groups without statistically significant difference (238+/-117 mg/24 h vs 214+/-104 mg/24/h, t = 0.72, p = 0.5). the few metabolic abnormalities present in patients with pure infected stones should suggest that urinary tract infection could change the urine chemistry in a lithogenic direction and be only cause of stone formation. key words: pure infected nephrolithiasis; mixed infected nephrolithiasis; metabolic evaluation. submitted 1 june 2016; accepted 31 august 2016 summary no conflict of interest declared. in despite of the terminology, stone rate of regrowth and/or recurrence in patients with infected nephrolithiasis is high and specific measures preventing stone formation are mandatory. in an effort to clarify the problem of infected nephrolithiasis we reviewed our experience with the metabolic evaluation of patients whose stone analyses reveals the presence of struvite and/or carbonate apatite. materials and methods for the aim of this study we considered 54 patients with infected renal lithiasis who underwent procedures for stone removal between january 1995 to december 2008 in the urologic unit of treviso general hospital. based on the composition of stones or small fragments removed, 19 patients had pure struvite +/-apatite and 35 mixed stones (struvite +/-apatite and calcium oxalate). other types of stone materials were excluded. the mean age of patients was 45 years with a range of 18 to 76 years. there were 33 females and 21 males. all patients underwent a thorough history and physical examination; chemical stone analysis (ecoline diasys diagnostic systems, gmh) and complete metabolic evaluation: twenty-four urine sample was analysed for levels of calcium, oxalate, uric acid, citrate, magnesium and phosphate. after at least 12 hours fasting venous blood was analysed for calcium, phosphate, uric acid and creatinine; morning spot urine was collected for urine analysis and culture. kub x-ray and/or kidney ultrasound were performed from one to three months after the urological procedures for stone removal. intravenous urography and/or computed tomography scan were done when we considered to investigate anatomy of the urinary tract. long-term follow-up information was recorded, with emphasis on recurrence of stone formation and urinary infection. chi-square test was performed to compare the percentage of metabolic abnormalities in the two groups. a paired t-test was used to compare the results of 24hour urine data in the different groups. results all patients required surgical intervention for their stone disease. thirty-three patients underwent nephrostolithotomy (pcnl) with or without shock wave lithotripsy doi: 10.4081/aiua.2016.3.208 introduction infected stones accounts for 10-30% of all stones in various series (1, 2). if infected stones are present, it is difficult to eradicate infection because the stone may harbor the organism within its interstices. even if sterilization of urine should be achieved by antibiotic therapy, reinfection could occur from bacteria harbored by residual stones. for this reason aggressive extirpative management is usually recommended. although the gold standard of infected urolithiasis is the complete elimination of the stone, the need for complete metabolic evaluation of such cases has not often considered. some authors have reported that metabolic anomalies, such as hypercalciuria, are present in greater than 50% of patients with infected renal calculi, while other authors have suggested that stone recurrence after complete elimination of infected stone is uncommon and therefore that metabolic evaluation should be not required (3-6). furthermore, there are differences in terminology: infected renal lithiasis may designate staghorn stones which may have a variety of composition, urolithiasis secondary to urea-splitting bacteria (struvite and/or carbonate apatite) or calcium oxalate calculi that have been secondarily infected (3, 5, 6-9). cicerello_stesura seveso 21/09/16 08:57 pagina 208 209archivio italiano di urologia e andrologia 2016; 88, 3 metabolic evaluation in patients with infected nephrolithiasis: is it necessary? (swl) and eleven were primarily treated by swl alone. kub x-ray carried out from one to three months after treatment showed that 39 patients were stone-free and 15 had residual fragments clinically insignificant (less than 5 mm in diameter). all patients with pure infected stone had risk factors for chronic urinary infections (neurogenic bladder, urinary ileal diversion and urinary tract anomalies). patients with mixed stones were likely to have previous urolithiasis or a positive family history of urolithiasis (table 1). positive urine cultures pretreatment were present in 41 patients, in 17 with pure infected stones and in 24 with mixed stones. escherichia coli was present in 67% of patients with mixed infected stones and proteus in 47% with pure infected stones. patients with pure struvite stones have more infecting organisms than patients with mixed stones (table 2). the results of 24-hour urine studies are listed in table 3. the urinary calcium, oxalate and uric acid excretion in mixed stone patients was higher than in those with pure infected stones. hypercalciuria was present in 40% of mixed infected patients (chi-square = 4.19 p < 0.05), hyperoxaluria in 34% (chi-square = 7.37, p < 0.01) and hyperuricosuria in 28% (chi-square = 4.90, p < 0.05). four patients with mixed stones were hypercalciuric and hyperuricosuric. of the patients with pure struvite only 2 were hypercalciuric and one hyperoxaluric. urinary excretion of citrate was low in both groups without statically significant difference (238+/-117 mg/24 h vs 214+/-104 mg 24/h, t = 0.72, p = 0.5). no patient was hypercalcemic or had primary hyperparathiroidism. the mean of follow-up was 42+/-68 months and despite efforts at stone prevention, both urinary infections and stones were recurrent. all patients received antibiotic profilaxis for long time. patients with mixed stones received also specific medical treatment according to metabolic abnormalities (thiazides, potassium citrate or allopurinol) for long time. in the pure struvite group of 19 patients, 12 had recurrent infection and 9 developed new calculi. in the mixed stone group of 35 patients, 18 had recurrent infection, while new calculi occurred in 11 patients. further procedures for stone treatment were required in 5 patients in the pure struvite group and in 6 patients in the mixed group. discussion the formation of struvite and/or carbonate apatite stones depends on ureolysis in the presence of urease-splitting bacteria. ammonia and carbon dioxide are transformed in ammonium and bicarbonate whose subsequent binding with available urinary cations produces magnesium ammonium phosphate (struvite) and carbonate apatite. this way could be the primary cause of stone formation in those patients with pure infected stones (1). however, it has been previously reported that an infection with urease producing bacteria is not present in all patients with struvite+/-apatite stones (10). since a responsible bacteria cannot always be cultured from voided urine an explanation for the discrepancy is that only urine samples and not stones have been cultured (11). another tentative explanation is that the responsible urease-producing bacteria have not been detected. ureoplasma urealyticum and certain urease-producing corynebacteria are missed if only cultures with conventional tecniques are performed (12). also in our study only routine urine analysis and culture on morning spot urine were performed. calculi usually referred to as metabolic stones (that is stones composed of calcium oxalate, calcium phosphate or uric acid) also frequently associated with urinary tract infections, mostly non-urease producing bacteria. the infection then is considered to be secondary to the stone and not involved in the stone formation (10). however, there are several mechanisms by which non urease splitting bacteria could enhance the formation of urinary tract calculi. thus, escherichia coli have been showed to act as nucleus for the deposition of crystals and to change the urine chemistry in a lithogenic direction (13). other uropathogenic mi croor ganisms have also been shown in experimental studies to damage the mucous coat with an increased adhesion of crystals to the uroepitelium as the results. in our study, where urinary infection was present in 69% calcium oxalate uric acid citrate magnesium phosphate mixed stones 302 ± 98 33 ± 12 603 ± 207 238 ± 117 66 ± 91 832 ± 395 struvite ± carbonate epatite 143 ± 87* 17 ± 6.9* 396± 102* 214 ± 104** 78 ± 33** 723 ± 320** * p < 0.001; ** n.s. table 3. urinary parameters (mg/24h) mixed infected stones (35) pure infected stones(19) escherichia coli 16 (67%) 3 (16%) proteus mirabilis 2 (6%) 9 (47%) klebsiella pneumoniae 3 (9%) 2 (11%) enterococci 1 (3%) 2 (11%) mixed (more than one strain) 2 (6%) 1 (5%) table 2. comparison between the results of pretreatment urine cultures in mixed and pure infected stones. pure struvite (n = 19) mixed stones (n = 35) females 11 (58%) 23 (66%) family history of stones 2 (11%) 12 (34%) previous stones 10 (53%) 25 (71%) previous uti 14 (74%) 20 (29%) neurogenic bladder 12 (63%) 0 ileal urinary diversion 2 (11%) 0 urinary tract anomalies 5 (26%) 0 table 1. risk factors according to stone analysis. cicerello_stesura seveso 21/09/16 08:57 pagina 209 archivio italiano di urologia e andrologia 2016; 88, 3 e. cicerello, m. mangano, g.d. cova, f. merlo, l. maccatrozzo 210 terial load significantly, although urine does not become sterile (21). besides contrasting septic risks, antibiotic therapy reduces recurrence or regrowth of stone after urologic procedures. in patients with mixed infected stones also adequate medical treatment is required, as already reported in previously studies (22). further prospective trials are necessary to confirm this observation. conclusions patients with mixed infected nephrolithiasis show different and metabolic characterics compared to patients with pure infected stones. the infected lithiasis in these patients probably comes to top of metabolic abnormalities present in idiopatic stone formers. conversely, complete metabolic evaluation of patients with pure infected lithiasis should be not necessary. hypocitraturia, in this group of patients, could be due the presence of chronic urinary infection. patients with mixed infected stones could be benefit not only from the usual antibiotic therapy, but also from specific therapies for the underlying metabolic abnormalities. references 1. griffith dp, osborne ca. infection (urease) stones. min electrolyte metab. 1987; 13:278-285. 2. bichler kh, eipper e, naber k, et al. urinary infection stones. int j antimicrob agents. 2002; 19:488-498. 3. resnick mi, boyce wh. bilateral staghorn calculi: patient evaluation and management. j urol. 1980; 123:338-341. 4. smith lh. renal lithiasis and infection. in: thomas wc jr (ed): renal calculi: a guide to management. sprinfield, il: charles c thomas, 1976, chapter 12. 5. segura jw, erickson sb, wilson dm, et al. infected renal lithiasis: results of long-term surgical and medical management. in: smith lh, robertson wg, finlayson b (eds): urolithiasis: clinical and basic research. new york: plenum press. 1981; pp. 195-198. 6. silverman de, stamey ta. management of infection stones: the stanford experience medicine. 1983; 62:44-51. 7. griffith dp. struvite stones. kidney int. 1978; 13:372-382. 8. miano r, germani s, vespasiani g. stones and urinary tract infection. urol int (suppl 1) 2007; 32-36. 9. streem sb, lammert c. long term efficacy of combination therapy for struvite staghorn calculi. j urol. 1992; 147:563-566. 10. hugosson j, grenabo l, hedelin h, et al. bacteriology of upper urinary tract stones. j urol. 1990: 143:965-968. 11. mariappan p, smith g, bariol sv, et al. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urol. 2005; 173:1610-1614. 12. hedelin h, brorson j, grenabo l, pettersson s. ureaplasm urealitycum and upper urinary tract stones. brit j urol. 1984; 56:244249. 13. djojodimirdio t, soebadi dm, sotjipto. escherichia coli infection induces mucosal damage and expression of proteins promoting urinary infection. urolithiasis 2013; 41:295-301. of patients with mixed stones, metabolic anomalies (hypercalciuria, hyperoxaluria and hyperuricosuria) could increase the adhesion of crystals to damaged uroepithelium and promote stone formation. more recently, it has been reported that been that escherichia coli may be related to stone formation by the capacity of bacteria to form biofilm (14). biofilm can promote persistence in the urinary tract and on biomaterial of the devices, protecting bacteria from the clearing effect of hydrodynamic forces and the killing activity of the host defence mechanism and antibiotics. furthermore, nanobacteria have been reported to cause stone disease. nanobacteria are micro-organisms that are 10-100 times smaller than normal bacteria. they may released from the stone during the treatment and create nidi for the formation of stones (15). endotoxins are another factor supposed involved in the pathogenesis of urinary infection from renal stone. also these have been released in the systemic circulation during stone treatment, inducing an inflammatory response. the process is apparently amplified in the presence of obstructive uropathy, due to increased permeability of blood and lymphatic vessels of the renal pelvis (16). our data demonstrate that patients with mixed stones (calcium oxalate plus struvite and /or carbonate apatite) have different metabolic characteristic compared to patients with pure struvite. the presence of hypercalciuria, hyperoxaluria and hyperuricosuria are similar to those observed in our group of idiopathic stone formers (17). indeed the presence of mixed infected calcium stones, such us calcium oxalate plus struvite appears to be a marker for underlying metabolic abnormalities and emphasizes the need for complete metabolic evaluation of these patients. pure infected stones are caused by a chronic bacteriuria (such as in patients with a neurogenic bladder, urinary diversion or anomalies of urinary tract), while metabolic anomalies were present only in 3 patients (in 2 hypercalciuria and in 1 hyperoxaluria). the presence of hypocitraturia in both groups could be due to the degradation of urinary citrate by bacterial enzymes from infection (18). consequently, even in the absence of stone material for analysis, renal stones in this subset of patients could be assumed to be pure infected in nature, and metabolic evaluation will likely be unrewarding. efforts should be directed at the complete eradication of the stone material and of any urea-splitting organism identified. high rates of recurrent infection and recurrent stone formation in both pure and mixed infected stones have been observed. the need for retreatment was high and emphasizes the need for careful follow-up of such patients. antibiotic therapy could decrease bacteriuria, but the persistence of stone or residual fragments or sand compromises the possibility of eradication the infection. persisting urinary tract infection could increase the risk of stone recurrence. urease inibitors could be theoretically used in the treatment of infected nephrolithiasis. besides collateral effects and their low effectiveness, they are little used (19, 20). currently long-term antibiotic therapy is advised in patients with infected stones . antibiotic therapy can reduce the baccicerello_stesura seveso 21/09/16 08:57 pagina 210 211archivio italiano di urologia e andrologia 2016; 88, 3 metabolic evaluation in patients with infected nephrolithiasis: is it necessary? 14. holmgren k. urinary calculi and urinary tract infection. a clinical and microbiological study. scand j urol nephrol (suppl. 98.) 1986; 98:1-71. 15. kajender eo, cifticioglu n. nanobacteria: an mechanism for pathogenic intra and extracellular calcification and stone formation, proc nal acad sci usa. 1998; 95:8274-8279. 16. mcaleer i, kaplan gw, bradley js, et al. endotoxin content in the renal calculi. j urol. 2003; 169:1813-1814. 17. cicerello e, merlo f, maccatrozzo l. nephrolithiasis in medulary sponge kidney. arch ital urol androl. 2011; 83:40-42. 18. cicerello e, merlo f, maccatrozzo l. metabolic evaluation of infected nephrolithiasis. eur urol. 2009; 8 (suppl. 3):s205. 19. griffith dp, gleesen mj, lee h, et al. randomized double –bind trial of lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. eur urol. 1991; 20:243-247. 20. iqbal mw, youssef rf, neisius a, et al. contemporary management of struivite stones using combined endourological and medical tratament: predictors of unfavorable clinical outcome. j endourol. 2013; 28:1-7. 21. cicerello e, merlo f, gambaro g, et al. effect of alkaline theraphy on clearance of residual stone fragments after shock wave lithotripsy in sterile and calcium nephrolithiasis patients. j urol. 1994; 15:5-9. 22. sun by, lee yh, jiaan bp, et al. recurrence rate and risk factors for urinary calculi after shock wave lithotripsy. j urol. 1996; 156:903-906. correspondence elisa cicerello, md (corresponding author) elisa.cicerello@tin.it mario mangano, md m.mangano@ulss.tv.it gian davide cova, md gd.cova@ulss.tv.it franco merlo, md f.merlo@ulss.tv.it luigi maccatrozzo, md l.maccatrozzo@tv.it unità complessa di urologia, ospedale ca’foncello piazza ospedale -31100 treviso, italy cicerello_stesura seveso 21/09/16 08:57 pagina 211 stesura seveso 167archivio italiano di urologia e andrologia 2015; 87, 2 case report recurrence of sigmoid colon carcinoma in the retained urethra after cystectomy: a case report and review of the literature yusuke yagihashi, yoshitaka arakaki department of urology, okinawa chubu hospital. urethral recurrence arising from a primary colorectal adenocarcinoma is rare. here, we report a case of urethral recurrence of sigmoid colon cancer, which developed after cysto-prostato-sigmoidectomy for sigmoid colon cancer invading the bladder. the patient underwent urethrectomy successfully and is currently tumor-free. surgeons who follow patients with colorectal cancer invading the bladder should be aware of this case. the early detection of recurrence improves the chances for disease-free survival. key words: fistula; recurrence; residual urethra; sigmoid colon cancer. submitted 5 january 2015; accepted 15 march 2015 summary no conflict of interest declared. nineteen lymph nodes were retrieved, and all were free of tumor. no malignancy was found in the prostate. colonic margins were clear. pathological diagnosis was adenocarcinoma of colonic origin, staged as pt4n0m0 (stage b of dukes classification). post-operatively, the patient underwent 8 courses of chemotherapy with capecitabine. forty-four months later, the patient reported a small amount of bloody discharge from the external urethral meatus. mri showed a lesion from the urethral stump to the bulbar urethra with tumor-like qualities, but no additional metastases (figure 1). urethroscopy revealed a papillary tumor that blocked the bulbar urethra completely. a urethral punch biopsy revealed a well-differentiated adenocarcinoma, which was histologically similar to the previous colon carcinoma. based on the diagnosis of solitary urethral recurrence, a total urethrectomy was performed through the perineum. the postoperative course was uneventful. gross examination of the specimen demonstrated a 55 × 30 mm papillary lesion inside the urethra. the pathologic examination showed well-differentiated adenocarcinoma of the urethra, consistent with the colonic primary tumor (figure 2). indeed, the histologic appearance of the sigmoid colon tumor and the urethral tumor was similar. the adenocarcinoma was confined to the inner aspect of the urethra, and the surgical margins were disease free. the patient still remains recurrence-free 15 months postoperatively. conclusion we report a case of urethral recurrence of sigmoid colon cancer, which developed after cysto-prostato-sigmoidectomy for sigmoid colon cancer invading the bladder. this report is the case of recurrence of a non-urothelial malignant tumor in the residual urethra after cystoprostatectomy. our case highlights that the residual urethra after cystoprostatectomy is a possible site for recurrence of nonurothelial malignancies. surgeons who follow patients with colorectal cancer invading the bladder should be aware of this case. the early detection of recurrence improves the chances for disease-free survival. doi: 10.4081/aiua.2015.2.167 introduction primary urethral carcinoma is uncommon, and metastatic urethral carcinoma is even rarer. here we report a case of urethral recurrence of sigmoid colon cancer, which developed after cysto-prostato-sigmoidectomy for sigmoid colon cancer invading the bladder. a complete review of the english literature on this topic was performed through pubmed search (1-11). case report a 59-year-old man presented with pneumaturia and fecaluria. cystoscopy showed an inflammatory mass on the dome of the bladder and the presence of a fistula. colonoscopy, barium enema, and computed tomography demonstrated a 7-cm-long sigmoid colon tumor that had invaded the bladder. the patient underwent full-body positron emission tomography and pelvic magnetic resonance imaging (mri) to assess for metastases. the results of these studies were negative. on laboratory examination, the carcinoembryonic antigen level was not elevated (0.8 ng/ml [reference, < 5 ng/ml]). based on the diagnosis of sigmoid colon cancer with sigmoid-vesicular fistula, the patient underwent sigmoidectomy using a hartmann’s procedure combined with radical cystoprostatectomy and urinary diversion without urethrectomy. the pathology report showed a well-differentiated adenocarcinoma with invasion into the bladder mucosa. yagihashi_stesura seveso 02/07/15 11:31 pagina 167 archivio italiano di urologia e andrologia 2015; 87, 2 yusuke yagihashi, yoshitaka arakaki 168 discussion is posted on www.aiua.it references 1. selikowitz sm, olsson ca. metastatic urethral obstruction. arch surg. 1973; 107:906-8. 2. okaneya t, inoue y, ogawa a. solitary urethral recurrence of sigmoid colon carcinoma. urol int. 1991; 47:105-7. 3. van thillo el, van poppel h, baert l. urinary retention due to urethral metastases from rectal adenocarcinoma. acta urol belg. 1993; 61:41-2. 4. stragier j, van poppel h, mertens v, et al. adenocarcinoma of the rectum with a solitary metastasis to the urethra in a female. eur j surg oncol. 1994; 20:696-7. 5. kupfer hw, theunissen p, delaere kp. urethral metastasis from a rectal carcinoma. acta urol belg. 1995; 63:31-2. 6. yoshimura k, isogawa y, yoshida h, kawase n, taki y. recurrence of sigmoid colon carcinoma in the residual urethra after cystectomy. int j urol. 1999; 6:479-82. 7. chitale sv, burgess na, sethia kk, et al. management of urethral metastasis from colorectal carcinomas. anz j surg. 2004; 74:925-7. 8. chang yh, chuang ck, ng kf, liao sk. urethral metastasis from a colon carcinoma. urology. 2007; 69:575.e1-3. 9. noorani s, rao ar, callaghan ps. urethral metastasis: an uncommon presentation of a colonic adenocarcinoma. int urol nephrol. 2007; 39:837-9. 10. martín martín s, garcía lagarto e, egea camacho j, fernández del busto e. urethral metastasis from a colon carcinoma 14 months alter cystoprostatectomy and sigmoidectomy. actas urol esp. 2010; 34:291-3. 11. luo hl,tsai kl, lin se, chiang ph. outcome of urinary bladder recurrence after partial cystectomy for en bloc urinary bladder adherent colorectal cancer resection. int j colorectal dis. 2013; 28:631-635. correspondence yusuke yagihashi, md (corresponding author) uroyagiyagi@yahoo.co.jp yoshitaka arakaki, md arakaki_yoshitaka@hosp.pref.okinawa.jp department of urology, okinawa chubu hospital okinawa, japan figure 1. magnetic resonance image showing a well-demarcated mass in the residual urethra. figure 2. microscopic appearance of the tumor showing well-differentiated adenocarcinoma consistent with the colonic primary tumor. yagihashi_stesura seveso 02/07/15 11:31 pagina 168 stesura seveso 385archivio italiano di urologia e andrologia 2014; 86, 4 case report inflammatory abdominal aortic aneurysm presenting as bilateral hydroureteronephrosis: a case report and review of literature andrea benedetto galosi 1, carlo grilli cicilioni 2, giulia sbrollini 1, andrea angelini 2, guevar maselli 1, luciano carbonari 2 1 uoc urologia, ospedale “augusto murri”, fermo, area vasta n° 4, asur marche; 2 uoc chirurgia vascolare, ospedali riuniti, ancona, italy. we report a case of inflammatory abdominal aortic aneurysm (iaaa) producing bilateral hydro-ureteronephrosis. a 74-year-old patient presented to urologist office for bilateral hydronephrosis detected by kidney and bladder ultrasound (us). patient reported lower urinary tract symptoms and inconstant and slight low back pain irradiated to inguinal region dating 3 weeks. renal function, urine analysis and abdominal examination were normal. however the repeated ultrasound in the urologist office revealed abdominal aortic aneurism extended to iliac vessels. the patient was sent directly to vascular surgery unit where contrast computerized tomography (ct) and successful surgical repair were done. final diagnosis was iaaa. the post-operative course was uneventful. renal function was regular and the hydronephrosis reduced spontaneously under monitoring by ct and us. we review diagnosis and management of hydronephrosis that is sometimes linked to iaaa rather than standard aaa. abdominal ultrasound is mandatory in any bilateral hydronephrosis and it could save lives. key words: hydronephrosis; inflammatory abdominal aortic aneurysm; ultrasound; kidney; diagnosis. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. ultrasound in ultrasound clinic, that was prescribed by general physician. patient reported mild and inconstant low back pain irradiated to inguinal region dating 3 weeks associated to lower urinary tract symptoms. then the patients was referred to the urologist to evaluate hydronephrosis and symptoms. he had visceral obesity, hypertension and hyperuricemia. renal function and urine analysis were normal. abdominal examination was negative. the former ultrasound (us) was restricted to urinary tract only. at abdominal us done in the urologist office any stone or solid mass was detected in the kidney or in the bladder, but us showed a thick and hypoechoic wall (diameter 2 cm) located around the aorta and iliac vessels. the us diagnosis was suspected fractured abdominal aortic aneurism extended to iliac vessels (figure 1). the patient was sent directly to emergency department, where it was referred to vascular surgery unit where contrast chest and abdominal computerized tomography (ct) was carried out and subsequent surgery was performed. severe hypertension was the reason for emergency surgery. successful repair with an open approach using a bifurcated dacron graft was made. final diagnosis was iaaa. immunoglobulin g4-related systemic disease was ruled out by pathologist on the surgical specimen of the aortic wall. the post-operative course was uneventful, the renal function was in the normal range and the hydronephrosis was monitored by ct and us. hydronephrosis spontaneously reduced and the patien was followed for after 8 months to detect complete regression or retroperitoneal fibrosis. discussion iaaas represent from 3 to 10% of all abdominal aortic aneurysms and are associated with peri-aortic inflammation (2, 3). the most common clinical features of these aneurysms are represented by symptoms, such as abdominal or back pain, obstructive uropathy (¼ of cases) and by an elevated ves, pcr. however isolated hip pain associated with tender bilateral testicular swellings may be the doi: 10.4081/aiua.2014.4.385 presented at 19th national congress sieun, fermo 2014 introduction abdominal aortic aneurysms are rare causes of ureteric obstruction. however inflammatory abdominal aortic aneurysm (iaaa) may be associated to ureteral obstruction in relation to peri-aortic inflammation in 30-20% of cases (1, 2). we report a case of iaaa producing bilateral hydroureteronephrosis in a patient with normal renal function, urinary symptoms and mild abdominal pain not requiring analgesics. case report a 74-year-old patient presented to the urologist office for bilateral hydronephrosis detected by kidney and bladder galosi_stesura seveso 16/01/15 11:24 pagina 385 archivio italiano di urologia e andrologia 2014; 86, 4 a.b. galosi, c. grilli cicilioni, g. sbrollini, a. angelini, g. maselli, l. carbonari 386 presentation symptoms. entrapment of near-standing organs can develop with compression of the ureter and the duodenum and consequent hydroureteronephrosis and bowel obstruction (4). preoperative diagnosis is possible by abdominal us. ct allows a specific diagnosis by the typical image of soft tissue surrounding the aortic wall enhanced with contrast administration (“enhancing periaortic soft-tissue mantle sign”) and demonstrates ureter entrapment, mural aortic thrombus and wall calcification (5). in patients with acute renal failure or even obstructive anuria the diagnosis can be suspected by non-contrast ct and echo-doppler us and the diagnosis established by contrast ct. pre-operative ureteral stenting is indicated in case of severe renal failure. evolution of peri-ureteral or retroperitoneal fibrosis after surgery is still debated because some studies have reported complete regression of inflammation and others partial regression or persistence of fibrotic process. often surgical treatment is inadequate to control retroperitorenal fibrosis and so the surgeon has to use perioperating pharmacolocical therapy and/or ureteral stenting. despite the similarity of infected and inflammatory aaa, the infected one generally shows a more rapid change in clinical condition, leading to a fatal outcome; in addition, delayed diagnosis and misuse of corticosteroid or immunosuppressing drugs may lead to uncontrolled growth of microorganisms (4, 5). it is mandatory that detection of aortic aneurysm is followed by accurate differential diagnosis among aortic aneurysm, infected and inflammatory aortic aneurysm. differential diagnosis between infected and inflammatory sometimes may not be easy for the following reasons: (1) symptoms, such as abdominal and/or back pain and fever, and blood test abnormalities, such as elevated c-reactive protein and figure 1. abdominal contrast ct (a + b) showing bilateral hydronephrosis, periaortic soft and tick tissue (i) with inflammatory tissue, that appear as hypoechoic at the us (d). echocolor-doppler (c) showing the aorta and the inferior mesenteric artery (arrow) inside the thick inflammatory wall of the aneurism. correspondence andrea b. galosi, md (corresponding author) galosiab@yahoo.it giulia sbrollini, md, resident of urology guevar maselli, md division of urology, dept. of surgery, “augusto murri” general hospital, area vasta 4, az. sanitaria unica regione marche 63900 fermo (fm), italy carlo grilli cicilioni, md grillicicilioni@tiscali.it andrea angelini, md angelini@fastwebnet.it luciano carbonari, md luciano.carbonari@ospedaliriuniti.marche.it uoc chirurgia vascolare, ospedali riuniti, ancona, italy enhanced erythrocyte sedimentation rate, are common in infected aortic aneurysm, but they are not found infrequently also in inflammatory aortic aneurysm; (2) some inflammatory aaa are immunoglobulin g4-related, but not all of them; (3) the prevalence of igg4 positivity in infected/inflammatory aortic aneurysm has not been well investigated (6, 7). furthermore is recommended to rule out igg4-related systemic disease in order to estabilish the usefulness of steroid therapy and proper follow-up. conclusion abdominal ultrasonography is the first step in the diagnostic pathway of hydronephrosis. potentially life-threatening diagnoses including aaa may mimic renal colic or inflammatory-aaa give hydronephrosis (mono or bilateral) and must be ruled out. monolateral or bilateral hydronephrosis can be associated more frequently to iaaa than non-inflammatory aaa. in iaaa, the igg4 systemic disease should be ruled out. references 1. sánchez r, arroyo a, gesto r, et al. obstructive arf caused by an inflammatory abdominal aortic aneurysm. am j kidney dis. 2003; 41:e9. 2. ruiz de la illa s, vega manrique r, lacasa viscasillas i, et al. inflammatory aortic aneurysm and its relationship to urological disease: a case report and a literature review. actas urol esp. 2009; 33:1024-7. 3. carter mr, green br. renal calculi: emergency department diagnosis and treatment. emerg med pract. 2011; 13:1-17 4. rubini p, bonati l, parolari a, spirito r. inflammatory abdominal aortic aneurysms. minerva chir. 2001; 56:287-98. 5. bajardi g, pecoraro f, mirabella d, bellisi mg. inflammatory abdominal aortic aneurysm. ann ital chir. 2009; 80:171-6. 6. kasashima s, zen y. igg4-related inflammatory abdominal aortic aneurysm. curr opin rheumatol. 2011; 23:18-23. 7. mazzucchelli r, racchini s, barbisan f, et al. igg4-related sclerosing disease: an emerging entity frequently misdiagnosed. anal quant cytol histol 2013; 35:189-196. galosi_stesura seveso 16/01/15 11:24 pagina 386 archivio italiano di urologia e andrologia 2013; 85, 120 introduction pharmacological therapy taken by the male partners of subfertile couples could represent a pathogenic factor that may negatively influence seminal parameters. the potential negative effects could impact on spermatogenesis, thus affecting the sperm number and morphology, and also epididymal maturation, which could affect progressive sperm motility. in the literature, there are few studies regarding the relationship between the effects of long-term and shortterm drug therapies and seminal parameters; moreover, such studies usually consider only a single class of drugs (such as statins, antihypertensives, etc.). original paper impact of long-term and short-term therapies on seminal parameters jlenia elia, norina imbrogno, michele delfino, rossella mazzilli, vincenzo spinosa, fernando mazzilli department of clinical and molecular medicine, sant’andrea hospital, unit of andrology, university of rome “sapienza”, rome, italy. aim: the aim of this work was: i) to evaluate the prevalence of male partners of subfertile couples being treated with long/short term therapies for non andrological diseases; ii) to study their seminal profile for the possible effects of their treatments on spermatogenesis and/or epididymal maturation. methods: the study group was made up of 723 subjects, aged between 25 and 47 years. semen analysis was performed according to world health organization (who) guidelines (1999). the superimposed image analysis system (sias), which is based on the computerized superimposition of spermatozoa images, was used to assess sperm motility parameters. results: the prevalence of subjects taking pharmacological treatments was 22.7% (164/723). the prevalence was 3.7% (27/723) for the short-term group and 18.9% (137/723) for the long-term group. the subjects of each group were also subdivided into subgroups according to the treatments being received. regarding the seminal profile, we did not observe a significant difference between the long-term, short-term or the control group. however, regarding the subgroups, we found a significant decrease in sperm number and progressive motility percentage in the subjects receiving treatment with antihypertensive drugs compared with the other subgroups and the control group. conclusions: in the management of infertile couples, the potential negative impact on seminal parameters of any drugs being taken as long-term therapy should be considered. the pathogenic mechanism needs to be clarified. key words: male fertility; semen, long-term therapy; short-term therapy. submitted 3 october 2012; accepted 31 december 2012 no conflict of interest declared summary concerning long-term therapies, one of the first papers on the effects of drug treatment on seminal parameters concerned sulfasalazine, generally used for intestinal illness. toth et al. (1) and cosentino et al. (2) reported a reduction in progressive sperm motility and an increase in atypical forms. subsequently, there were other papers, which concerned antiepileptics, antiretrovirals, alpha-lytics and statins. in particular, chen et al. (3) showed the negative effects “in vitro” on sperm motility of carbamazepine, phenytoin, valproate and phenobarbital. these data were also confirmed in other studies (4-6). in addition, several studies (7-8) elia_stesura seveso 18/04/13 11:00 pagina 20 21archivio italiano di urologia e andrologia 2013; 85, 1 impact of long-term and short-term therapies on seminal parameters controlled incubator at 37°c within 60 min of ejaculation and then analyzed according to world health organi zation (who) guidelines 1999 (16). the superimposed image analysis system (sias) (delta sistemi, rome italy), which is based on computerized image superimposition, was used to asses sperm motility parameters (17, 18). sperm morphology was assessed using the bryanleishman stain technique and examined at a magnification of 1000x, with an olympus cx 31 light microscope, using a micrometric scale. all the subjects had at least 2 standard semen analyses and the mean of the results obtained was established for each seminal parameter; at least 200 spermatozoa were evaluated. the total subjects were then subdivided into two groups, based on the pharmacological therapies being taken: – long-term therapy group (more than 6 months); – short-term therapy group (more than 7 days and less than 15 days). statistical analysis results are expressed as percentages, mean values and standard deviations. the fisher exact test and the student t-test for independent samples were performed to compare the means of the two distributions. a p value < 0.05 was considered significant. results the prevalence of subjects who were taking pharmacological treatments was 22.7% (164/723). in particular, the prevalence was 3.7% (27/723) for the short-term therapy group and 18.9% (137/723) for the long-term therapy group. subsequently, the subjects of each group were further subdivided into subgroups, according to the treatment being taken. the remaining subjects that were not taking any pharmacological therapies (559/723; 77.3%) were employed as a control group. the short-term therapy group the subjects in short-term therapy were subdivided as follows: antibiotics 2.3% (17/723); antinflammatory 1.1% (8/723) and pde5-inhibitors 0.3% (2/723); (table 1). regarding the seminal profile, we did not observe any significant differences between the shortterm group and the control group; the same was true for the subgroups. the long-term therapy group the subjects in long-term therapy group were subdivided into the following subgroups (table 1): a) antipsysuggested an enhancement in semen quality parameters following the cessation of pharmacological therapies. other authors showed a reduction of progressive sperm motility caused by antiretroviral drugs (9), by statin treatment (10) and by tamsulosin (11), that affect also sperm number and atypical forms. regarding short-term therapies, there are very few reports in the literature: schlegel et al. (12) defined antibiotics (nitrofurans, sulfasalazine, minocycline) as “potential hazards to male fertility” owing to potentially dangerous effects on sperm concentration. other studies regard the possible interaction between pde5-inhibitors and semen parameters; however, there are conflicting data about their action. aversa et al. (13) observed that sildenafil did not change seminal parameters; on the other hand, pomara et al. (14) observed an increase of progressive sperm motility in subjects treated with sildenafil (50 mg), while the use of tadalafil (20 mg) produced a decrease in semen quality. finally, jarvi et al. (15) studied the possible effects of daily treatment for 6 weeks with vardenafil and tadalafil; in both cases, no changes were observed on seminal parameters. the aim of this work was: i) to evaluate the prevalence of male partners of subfertile couples being treated with long/short term therapies for non andrological diseases; ii) to study their seminal profile for the possible effects of their treatments on spermatogenesis and/or epididymal maturation. materials and methods subjects the clinical study was conducted according to the hospital ethics’ committee guidelines. the study group was made up of 723 subjects, aged between 25 and 47 years, who were referred to our andrology unit from december 2007 to december 2011 for various andrological examinations. a full medical history was taken afterthat the patients underwent a diagnostic and therapeutic program comprising: clinical and seminal examination and hormonal profile. all subjects with hormonal alterations, treated cryptorchidism, previous testicular trauma, seminal obstructions or genetic alterations were excluded from the study. semen analysis semen samples were collected by masturbation after a sexual abstinence period of 3-5 days. after liquefaction (for 15-30 min at 37°c), the semen samples were stored in a short -term therapy group long-term therapy group control group n. 27/723 (3.7%) n. 137/723 (18.9%) n. 559/723 antibiotics antipde-5 antipsycotic/ antihypertensive antihistamine gastrohormone miscellaneous combined no therapy inflammatory inhibitors antiepileptic protective n. 17 n. 8 n. 2 n. 29 n. 19 n. 18 n. 12 n. 8 n. 17 n. 34 n. 559 (2.4%) (1.1%) (0.3%) (4.0%) (2.6%) (2.5%) (1.7%) (1.1%) (2.3%) (4.7%) (77.3%) table 1. total subjects in pharmacological treatments (shortand long-term therapy groups) and control group. elia_stesura seveso 18/04/13 11:00 pagina 21 archivio italiano di urologia e andrologia 2013; 85, 1 j. elia, n. imbrogno, m. delfino, r. mazzilli, v. spinosa, f. mazzilli 22 on the other hand, regarding the subgroups, we found a significant decrease in sperm number and progressive motility percentage in subjects treated with antihypertensive drugs compared with the other long-term therapy subgroups (p < 0.05) (figure 2). chotic and antiepileptic drugs: 4.0% (29/723 cases); b) antihypertensive drugs: 2.6% (19/723 cases); c) antihistaminic drugs: 2.5% (18/723 cases); d) gastroprotective drugs 1.7% (12/723 cases); e) hormone 1.1% (8/723 cases); f) miscellaneous (antiretroviral, statins, oral antidiabetic drugs or anticoagulants, etc) 2.3% (17/723 cases); g) combined therapy (antihypertensive and gastroprotective drugs; antipsychotic and metabolic drugs; antihypertensive, anticoagulant and statin drugs): 4.7% (34/723 cases). regarding the seminal profile, we did not observe any significant differences between the long-term therapy group and the control group (figure 1). figure 1. semen parameters in long-term therapy group and in control group. boxes indicate 25th and 75th percentiles while the horizontal line within the box indicates the 50th percentile value (median). vertical lines give 10th and 90th percentile limits of the data, while single points indicate extreme values outside this range. figure 2. semen parameters in long-term therapy subgroups and control group. a) control group; b) antipsychotic/antiepileptic; c) antihypertensive; d) antihistamine; e) gastroprotective; f) hormone; g) miscellaneus; h) combined. * p < 0.05 vs control group. boxes indicate 25th and 75th percentiles while the horizontal line within the box indicates the 50th percentile value (median). vertical lines give 10th and 90th percentile limits of the data, while single points indicate extreme values outside this range. elia_stesura seveso 18/04/13 11:00 pagina 22 23archivio italiano di urologia e andrologia 2013; 85, 1 impact of long-term and short-term therapies on seminal parameters discussion in this study we considered the prevalence of male partners of subfertile couples under long-term and shortterm pharmacological treatments for non andrological diseases and the possible effects of such treatment on seminal parameters. regarding the first, the prevalence of pharmacological treatments identified was 22.7%, almost double that of hayashi’s data (19). it is a remarkable prevalence, especially in such a relatively young population. we differentiated in short-term treatment for the possible effects only on epididymal maturation and long-term for possible effects on the process of spermatogenesis and/or epididymal maturation. the prevalence found was 3.7% in the short-term group and mainly involved the use of antibiotics and antinflammatory medication and only minimally the use of pde5 inhibitors. in subjects taking long-term therapy, the prevalence observed was 18.9%; this concerned the use of various classes of drugs, including antipsychotic, antiepileptic, antihypertensive, antihistamine medications and also drugs associations. regarding the seminal profile, we did not observe any significant differences between the shortterm therapy group, or the subgroups, vs the control group. regarding antinflammatory medication, this is not surprising since they are commonly used for the treatment of genital tract inflammation. however, even antibiotics did not appear to have a negative impact on seminal parameters. the number of subjects taking pde5 inhibitors was too small to have a statistical significance. also the long-term group did not show any significant variations compared with the control group. on the other hand, the long-term subgroup treated with antihypertensive drugs (calcium channel blockers, beta blockers, angiotensin converting enzyme inhibitors) showed a significant decrease in sperm number and progressive motility percentage compared with the other long-term therapy subgroups and the control group. the possible pathogenic mechanism may be an alteration in local blood flow, also at the hemato-testicular barrier, which would produce a reduction of the nutrients needed in spermatogenesis, or perhaps direct damage to the epididymis, which would inhibit kinetic sperm properties and then motility. in conclusion, long-term drug therapy is a factor that should always be taken into consideration in the management of infertile couples, owing to the potential negative impact of such treatment on seminal parameters. the pathogenic mechanisms involved need to be clarified. references 1. toth a. reversible toxic effect of salicylazosulfapyridine on semen quality. fertil steril. 1979; 31:538-40. 2. cosentino mj, chey wy, takihara h, cockett at. the effects of sulfasalazine on human male fertility potential and seminal prostaglandins. j urol. 1984; 132:682-6. 3. chen ss, shen mr, chen tj, lai sl. effects of antiepileptic drugs on sperm motility of normal controls and epileptic patients with long-term therapy. epilepsia. 1992; 33:149-53. 4.taneja n, kucheria k, jain s, maheshwari mc. effect of phenytoin on semen. epilepsia. 1994; 35:136-40. 5. roste ls, tauboll e, haugen tb, et al. alterations in semen parameters in men with epilepsy treated with valproate or carbamazepine monotherapy. eur j neurol. 2003; 10:501-6. 6. isojarvi ji, lofgren e, juntunen ks, et al. effect of epilepsy and antiepileptic drugs on male reproductive health. neurology. 2004; 62:247-53. 7. yerby ms, mccoy gb. male infertility: possible association with valproate exposure. epilepsia. 1999; 40:520-1. 8. hayashi t, yoshinaga a, ohno r, et al. asthenozoospermia: possible association with long-term exposure to an anti-epileptic drug of carbamazepine. int j urol. 2005; 12:113-4. 9. van leeuwen e, wit fw, repping s, et al. effects of antiretroviral therapy on semen quality. aids. 2008; 22:637-42. 10. dobs as, schrott h, davidson mh, et al. effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. metabolism. 2000; 49:1234-8. 11. hellstrom wj, sikka sc. effects of alfuzosin and tamsulosin on sperm parameters in healthy men: results of a short-term, randomized, double blind, placebo-controlled, crossover study. j androl. 2009; 30:469-74. 12.schlegel pn, chang ts, marshall ff. antibiotics: potential hazards to male fertility. fertil steril. 1991; 55:235-42. 13. aversa a, mazzilli f, rossi t, et al. effects of sildenafil (viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. hum reprod. 2000; 15:131-4. 14. pomara g, morelli g, canale d, et al. alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men. fertil steril. 2007; 88:860-5. 15. jarvi k, dula e, drehobl m, et al. daily vardenafil for 6 months has no detrimental effects on semen characteristics or reproductive hormones in men with normal baseline levels. j urol. 2008; 179:1060-5. 16. world health organization. laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 4rd ed. new york: cambridge university press. 1999. 17. mazzilli f, rossi t, sabatini l, dondero f. superimposed image analysis system (sias) software: a new approach to sperm motility assessment. fertil steril. 1995; 64:653-6. 18. mazzilli f, rossi t, delfino m, nofroni i. application of the upgraded image superimposition system (sias) to the assessment of sperm kinematics. andrologia. 1999; 31:187-94. 19. hayashi t, miyata a, yamada t. the impact of commonly prescribed drugs on male fertility. hum fertil. 2008; 11:191-6. correspondence jlenia elia, md norina imbrogno, md michele delfino, md rossella mazzilli, md vincenzo spinosa, md sant’andrea hospital, unit of andrology, university of rome “sapienza” via di grottarossa 1035 00189 roma, italy fernando mazzilli, md (corresponding author) professor sant’andrea hospital, unit of andrology university of rome “sapienza”, via di grottarossa 1035 00189 roma, italy fernando.mazzilli@uniroma1.it elia_stesura seveso 18/04/13 11:00 pagina 23 stesura seveso lucio dell’atti department of urology, university hospital “st.anna”, ferrara, italy correspondence lucio dell’atti, md, phd dellatti@hotmail.com department of urology, university hospital “st.anna” 8 a. moro street 44124, ferrara, italy archivio italiano di urologia e andrologia 2016; 88, 2154 no conflict of interest declared. doi: 10.4081/aiua.2016.2.154 reply to the letter: we really need a classification of prostatic abscess? key words: prostatic abscess; needle aspiration; classification. dear author, i appreciate your interest in and comments on the article titled: “a new ultrasound and clinical classification for management of prostatic abscess” (1). in this article i don’t propose a treatment algorithm that identifies patients to be treated or the type of treatment. i simply reported a descriptive review of the ultrasound images derived from the database of our university referral hospital and literature case reports. currently, there are significant gaps in managing of prostatic abscesses (pa), and there is a need for a multidisciplinary approach to patient safety (2). however, a multidisciplinary approach involves drawing appropriately from multiple disciplines to redefine problems, and therefore it requires a common language. the aim of this classification was to improve a common and accurate language between multiple disciplines, often involved in this clinical situation. the “dell’atti classification” does not want to reveal the exact correlation between the type of pa and the type of the treatment. i perfectly known that in absence of symptoms, if a lesion is ultrasonographically identified as a pa, the lesion should not be treated. references 1. dell’atti l. a new ultrasound and clinical classification for management of prostatic abscess. arch ital urol androl. 2015; 87:246-9. 2. oliveira p, andrade ja, porto hc, et al. diagnosis and treatment of prostatic abscess. int braz j urol. 2003; 29:30-4. stesura seveso 123archivio italiano di urologia e andrologia 2014; 86, 2 original paper awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation: 5 years experience giuseppe la pera department of urology, san camillo forlanini hospital, rome, italy. objectives: to assess the cure rate of patients with premature ejaculation who underwent a treatment involving: 1) awareness of the pelvic floor muscles 2) learning the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase 3) pelvic floor rehabilitation (bio feed back, pelvic exercises and electrostimulation). materials and methods: we recruited 78 patients with lifelong premature ejaculation who completed the training. the patients were informed of the role of the pelvic floor. they were taught to carry out the execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase to control the ejaculatory reflex. in order to improve the awareness, the tone and the endurance of the pelvic floor muscles, patients were treated with the rehabilitation of pelvic floor (rpf) consisting mainly in biofeedback, pelvic exercises and in some cases also in electro-stimulation (es). the training was carried out for a period of about 2-6 months with an average of 2-5 visits per cycle. results: 54% of patients who completed the training were cured of premature ejaculation and learned over time to be able to postpone the ejaculation reflex. in a subgroup of 26 patients was also measured the ielt which on the average increased from < 2 minutes to >10 minutes. the best results occurred mainly in patients aged less than 35 where the cure rate was 65%. there were no side effects. conclusions: in this study, approximately half of patients with premature ejaculation were cured after applying the above treatment.this therapy, necessitates a fairly long period of time (2-6 months) and a great commitment on the part of the patient, nevertheless it can be a valid and effective treatment for patients with premature ejaculation. this treatment makes the patient independent in that he is not bound to specific times for taking medication. furthermore there are no side effects and this therapy is particularly effective in young males. key words: premature ejaculation; awareness; timing; pelvic floor muscles; pre-orgasmic sensation. submitted 26 may 2014; accepted 16 june 2014 summary no conflict of interest declared. doi: 10.4081/aiua.2014.2.123 introduction the pelvic floor rehabilitation (pfr) consisting in biofeedback, pelvic exercises (kinesis-therapy) and pelvic floor electrical stimulation in the treatment of lifelong premature ejaculation has been introduced since 1996 (1) and was later confirmed by other authors (2). since then, from 2008, compared to the previously described technique, i introduced some changes in the therapeutic protocol: 1. adopting the new definition of premature ejaculation (pe) of the essm (3); 2. introducing into the protocol the awareness of the pelvic floor muscles (4); 3. teaching patients when to execute and maintain the contraction of the pelvic floor muscles. in order to inhibit the ejaculatory reflex this contraction must occur during the sensation of the pre-orgasmic phase. as regards the changes to the protocol of training, these are based on the observation that patients with premature ejaculation very often are not aware of the role of the pelvic floor muscles (4). therefore some patients may suffer premature ejaculation simply because they do not know what to do or are not able to make a selective effective contraction of the pelvic floor and not because of an early arrival of the stimulus. the purpose of this study was to evaluate the cure rates in an unselected population of patients with lifelong premature ejaculation undergoing rehabilitation treatment of the pelvic floor who have been taught the role of the pelvic floor and the timing of contraction of these muscles. materials and methods recruitment of patients we retrospectively reviewed the charts of 108 patients with lifelong premature ejaculation. out of them 78 patients (72%) completed the protocol training. patients with erectile dysfunction and patients with signs of prostatitis were excluded. the majority of patients excluded from treatment or who did not complete the protocol preferred an immediate drug treatment instead of a treatment that archivio italiano di urologia e andrologia 2014; 86, 2 g. la pera 124 required numerous sessions spread over a period of several months. the average age was 41 +/8 and a median age of 40 (range 18 to 64). definition of a patient with premature ejaculation the definition of a patient with premature ejaculation refers to the definition adopted by the essm 2008 (3); all patients had the ielt (5) in less than one minute and a pedt (6) test > 11. in the hormone screening was found only one patient with hyperthyroidism; in all the other patients, the hormonal values of the thyroid function were always found normal. eight patients had a significantly low testosterone. in all these cases of hormonal alteration, the hormonal treatment implemented to correct hypogonadism or hyperthyroidism did not change the symptoms of premature ejaculation. description of the technique the technique to inhibit the ejaculatory reflex and to teach the patient how to take greater control consists of four steps. the 4 steps are: 1) have the patient become aware of the existence of the pelvic floor muscles; 2) teach the patient the selective contraction of the muscles of the pelvic floor; 3) teach the patient and have him try out the timing of the execution and maintenance of contraction of the muscles of the pelvic floor during the sensation of the pre-orgasmic phase; 4) reinforcement of the pelvic floor muscles. awareness of the role of pelvic floor muscles at the beginning of treatment, all patients were made aware of the role of the pelvic floor through a test described in 2012 (4). in practice, the patient lying down is asked to contract his pelvic floor muscles while performing a digital rectal examination. at the end of this procedure the patient is asked whether he is aware that the contraction of the muscles of the pelvic floor is able to inhibit the ejaculatory reflex. a more accurate description of this technique and the demonstration of its validation was previously published (4) pelvic floor rehabilitation (pfr) to learn how to selectively use the muscles of the pelvic floor, i.e. without activating antagonist muscles such as the abdominal muscles, we used the technique of pfr that involves biofeedback, pelvic exercises and in some cases electro-stimulation. this technique has already been described for fecal and urinary incontinence and in the treatment of premature ejaculation (1). the pfr not only reinforces the tone and strength of contraction of the pelvic floor muscles but at the same time allows the patient to better understand the role of these muscles and acquire the capacity to perform the contraction selectively. a more detailed description of the technique was previously published in 1996 (1). nearing the orgasmic phase and timing of the contraction of the pelvic floor muscles one of the techniques used up to now for the treatment of premature ejaculation has historically been that of “stop and start” proposed by masters and johnson since the 1960’s (7). basically it consists in stopping the stimulation when the excitation reaches the pre-orgasmic phase and and when the ejaculation is about to arrive. the innovation we have brought to our technique is that of adding, during the sensation of the pre-orgasmic phase, the execution and maintenance of contraction of the muscles of the pelvic floor until the sensation of upcoming orgasm has passed. to obtain this result obviously the first step is to be informed of the existence and the role of the pelvic floor muscles. the second moment is to be able to carry out the contraction of the muscles of the pelvic floor in a selective manner and this can be obtained through biofeedback. the third element consists of the selective and coordinated contraction of the pelvic floor muscles to be carried out at the very pre-orgasmic moment before ejaculation becomes irreversible. this technique starts from the assumption that the contraction, performed in a coordinated and timely way, would be able to inhibit the ejaculatory reflex similarly to what happens in the bladder where the contraction of the pelvic floor muscles if done at a certain moment is capable of delaying the urge of urination through inhibition of detrusor contraction (8). in order to teach the patient the “timing” of the contraction and have him figure out at what moment of preorgasmic sensation it is still possible to inhibit the ejaculatory reflex, exercises of masturbation are assigned to do at home. in these focusing exercises the patient begins to masturbate and gets to a stage of pre-orgasmic excitement; through “trial and error” he must learn to be able to recognize in what moment during the sensation of pre-orgasmic excitement it is still possible to inhibit the ejaculatory reflex in stopping masturbation, contracting the muscles of the pelvic floor and maintaining the contraction until the sensation of imminent orgasm ceases. once the patient has achieved inhibition of the ejaculatory reflex and the sensation of imminent orgasm ceases the patient resumes masturbation and in the same session repeats this cycle 3 or 4 times. after 4 or 5 cycles the patient can let himself reach ejaculation. the results of this training and in particular the way the contraction is performed and its effectiveness in postponing the ejaculatory reflex are discussed with the patient once a month; any doubts are cleared up and further improvements made. measurement of results and definition of healing patients were considered cured if able to control their ejaculatory reflex and when they pass from a pdet score above 10 to one equal or less than 8. furthermore in one group of patients was evaluated the ielt (5) both before and at the end the training. results all patients at the end of the training due to awareness tests (4) have become conscious of the role of the pelvic floor in the control of ejaculation; 43 patients or 55% of all those who completed the training were cured of premature ejaculation and learned to be able to postpone the moment of ejaculation. in a subgroup of 26 patients was also measured the ielt which on the average went from < 2 minutes to > 10 minutes. the best results occurred mainly in patients aged less than 35 where the cure rate was 65%. in the course of more than five years, there were no side effects in the whole sample involved. thirty-five patients (45%) after a minimum period of three months did not demonstrate any benefit from the technique proposed here and drug therapy was begun with them. the non-response to treatment was mainly due to the fact that the patient was not able to selectively contract the pelvic floor muscles or could not recognize the moment to make the contraction. among these 35 patients, however, there were 12 in which the patient, even though making a regular and effective contraction of the muscles of the pelvic floor and even recognizing the moment when it was necessary to perform the contraction, had no beneficial effect on the length of ejaculatory latency. probably this subset of patients is that in which premature ejaculation is the consequence of the early arrival of the ejaculatory stimulus. discussion awareness of the role of the pelvic floor muscles, the pfr and learning to recognize the timing of the execution and maintenance of contraction of the pelvic floor muscles are the crucial elements of this technique in order to inhibit and improve control over the ejaculatory reflex. the limit of this method is that it takes a few months for the patient to understand the dynamics of the sequence of events, learn control over the ejaculatory reflex and naturally carry it during sexual intercourse. in many family and clinical situations there is not always a long time available and thus the patient may request something faster such as drug therapy available today. another limitation of this technique is that not all patients are able to perform a selective contraction of the pelvic floor muscles without activating other antagonist muscles or are not able to recognize the sensation that precedes the inevitability of ejaculatory reflex in order to perform the contraction of the muscles of the pelvic floor to block and inhibit ejaculation. in the course of this experience, we observed that although some patients were able to correctly perform the contraction of the muscles of the pelvic floor this technique did not prove effective. this percentage of patients is typically around 15%. these limits are, however, largely offset by the fact that recovery from premature ejaculation with this technique brings the patient around to be “independent”, not influencing his sexual activity by taking a drug and not exposing him to potential side effects or drug interactions. these results confirm moreover the fact that the population of patients with premature ejaculation is a heterogeneous population with different etiological factors. there are not only patients in whom there is an early arrival of the ejaculatory reflex. the positive results of this technique, which does not act on the arrival of the ejaculatory reflex but only on the control, suggest the hypothesis that premature ejaculation, in some cases, may be due to another four causes: – lack of knowledge of the fact that is necessary to contract the pelvic floor muscles; – inability to contract these muscles; – inability to know how to recognize at what moment during the sensation of the pre-orgasmic phase it is still possible to block the ejaculatory reflex; – result of a disease of the muscles of the pelvic floor. these data raise therefore the urgent need not only to reassess the definition of premature ejaculation or at least redefine the concepts that define it but to re-evaluate the criteria for inclusion or exclusion in therapeutic trials on premature ejaculation taking into consideration the variables of awareness and neuromuscular coordination of the pelvic floor, the perception of the arrival of the ejaculatory reflex and diseases of the pelvic floor muscles. conclusions in this study, approximately half of the patients with premature ejaculation were cured after they learned role and use of the muscles of the pelvic floor, having learned the timing of execution and maintenance of contraction of the pelvic floor muscles during the sensation of the pre-orgasmic phase and having undergone pfr. despite the fact that this therapy in order to achieve positive results requires a fairly long period of time (2-6 months) and a greater commitment on the patient’s part, it can be a valid and effective treatment to offer a patient with premature ejaculation. this treatment makes the patient independent in that he is not bound to specific times for taking medication. furthermore there are no side effects and this therapy is particularly effective in young males. references 1. la pera g, nicastro a. a new treatment for premature ejaculation: the rehabilitation of the pelvic floor. j sex marital ther. 1996; 22:22-6. 2. pastore al, palleschi g, leto a, et al. a prospective randomized study to compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong premature ejaculation. int j androl. 2012; 35:528-33. 3. mcmahon cg, althof se, waldinger md, et al. an evidence-based definition of lifelong premature ejaculation: report of the international society for sexual medicine (issm) ad hoc committee for the definition of premature ejaculation. j sex med. 2008; 5:1590-606. 4. la pera g. awareness of the role of the pelvic floor muscles in controlling the ejaculatory reflex: preliminary results. arch ital urol androl. 2012; 84:74-8. 5. waldinger md, hengeveld mw, zwinderman ah, olivier b. an empirical operationalization study of dsm-iv diagnostic criteria for premature ejaculation. int j psychiatry clin pract 1998; 2:287-293. 6. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 7. masters wh, johnson ve. premature ejaculation. in: human sexual inadequacy. boston, mass: little brown & company. 1970; 92-115. 8. burgio kl, et al. behavioral vs drug treatment for urge urinary incontinence in older women. jama 1998; 280:1995-2000. 125archivio italiano di urologia e andrologia 2014; 86, 2 awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation correspondence giuseppe la pera, md (corresponding author) lapera@libero.it dept of urology, san camillo forlanini hospital, rome, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3198 original paper the histology and the proapoptotic control in the ipsilateral and the contralateral testes following unilateral vasectomy aydin ismet hazar 1, basri cakiroglu 2*, ertan sakalli 3, mustafa bahadir can balci 1, erkan eyyupoglu 4, tuncay tas 1, orhun sinanoglu 5, pinar tuzlali 6, nusret can cilesiz 1 1 taksim training and research hospital, department of urology istanbul, turkey; 2 hisar intercontinental hospital, department of urology istanbul, turkey; 3 zonguldak state hospital, department of urology, zonguldak, turkey; 4 amasya training and research hospital, department of urology, amasya, turkey; 5 maltepe university medical school, department of urology, istanbul, turkey; 6 taksim training and research hospital, department of pathology, istanbul, turkey. objective: the aim of this study was to enlighten both the testicular histology and the genetic aspects of the apoptotic process. thus an experimental study was designed with a model of unilateral vasectomy. methods: twenty-two adult male rats were used and 4 main groups were formed. the first (a), the second (b), the third (c), and the fourth group (d) consisted of 4, 4, 4 and 10 rats respectively. rats in group a had sham operation while rats in other groups (b, c, d) underwent left vasectomy operation including binding of ductus deferens with a 3/0 silk and cutting a minimum of 1 cm part while preserving the vascular structure under 9x magnification. rats undergoing unilateral vasectomy were sacrificed at the 1st, 2nd and 8th weeks and their testicular structure and proapoptotic gene proteins were compared with that of the control group undergoing sham operation. results: we found that vasectomy gradually caused destruction and both ipsilateral and contralateral testicles were affected showing initial apoptosis. conclusion: the procedure causes destruction in the testicular structure by causing bilateral intratubular germ cell necrosis, unilateral obstruction, increase in the tubular pressure and processes that are aggravated by some probable autoimmune reactions. key words: testis; spermatogenesis; vasectomy; apoptosis; bcl-2 protein. submitted 18 december 2014; accepted 31 march 2015 summary no conflict of interest declared. gene’s pro regulation, and they have great importance in the modulation of this process (2-4). since it was first detected in b cell lymphoma-2 cells it was named as bcl-2. some proteins of the bcl-2 gene family such as “bcl-2, bcl-xl and bcl-w” support cell growth and play an apoptotic role while others such as “bax, bam, bad, bok, bid and bim” antagonise the effect of others and play an apoptotic role (5). the competition between these two cells and their being a homodimer such as bcl/bcl, bax/bax or a heterodimer such as bax/bcl assign the cell either to die or to live (6, 7). the naming “bax” is formed as bcl-2 associated x protein and is based on the ralationship between these two immunohistochemical (ihc) measurements of the proapoptotic and antiapoptotic proteins are used in determining the apoptosis as well as the detection of the dna fragmantation (8). bax overexpression has been shown with drug-induced apoptosis in human germ cells (9). the same finding was found in animal experiments after vasectomy (10, 11). although vasectomy is a popular male contraception method and its reversals have been widely studied, the effect of vasectomy on testicular histology is still controversial (12, 13). however, even apoptosis in the ejaculate has been studied in diabetes, schizophrenia and in immunopathologies (14) the relationship between the post vasectomial testicular histology and apoptosis and its clinical effects haven’t been studied widely (8, 15-18). in this study adult rat unilateral vasectomy was compared with the control group and the answer to 4 questions were required: 1) the role of vasectomy on testicular damage 2) its genetic effect based on bax in apoptosis in normal spermatogenesis 3) the effects of vasectomy on the contralateral testicle 4) the possible effects of the unilateral vas deferens damage due to inguinal surgery on testicular histopathology. materials and methods in this experimental study, 22 adult male sprague dawley 16 weeks old rats weighing 250 grams were used and studied in 4 main groups. the first group (a) consisted of 4 rats, the second (b) 4, the third (c) 4 and the fourth doi: 10.4081/aiua.2015.3.198 introduction spermatogenesis is a process in which spermatogonial stem cells form mature sperm cells (spermatozoa) by cell differentiation which is characterized by mitotic and meiotic cell divisions. germ cell deaths occur in addition to cell growth and proliferation during normal spermatogenesis which is of critical importance in the formation of the mature sperm cells (1). apoptosis is the process that destructs the cells with a damaged dna after receiving internal or external induction signals. the effectors of this death process are the caspases and the bcl-2 protein family which is responsible for 17 p53 hazar corr_stesura seveso 30/09/15 09:28 pagina 198 199archivio italiano di urologia e andrologia 2015; 87, 3 proapoptotic control in unilateral vasectomy group (d) 10 rats. all the rats had anesthesia with intraperitoneal 25 mg/kg pentothal injection. while rats in group a had sham operation in an aseptic environment, rats in group b, c, d had a left vasectomy operation in which ductus deferens was tied with a 3/0 silk and a minimum of 1 cm part was excised with an inguinal incision preserving the vascular structure. animals were sacrificed with 75 mg/kg pentothal injection and standard orchiectomy was applied and the testicular histopathology was examined at the 1st (b), the 2nd (c) and the 8th (d) week. histopathology the testes were fixed in bouin solution and buried in paraffin and sections were prepared from tissue blocks. all the samples were examined for inflamatory infiltrate, edema, fibrosis, sperm granuloma, intratubular spermatic necrosis. ihc coloring bax b-9 rat monoclonal igg2b antibody which is essential for coloring was used. bax protein eliminates the inhibitory effects of bcl-2 gene and speeds up apoptotic deaths, thus bax antibody binds to the bax protein in the cell in which the apoptotic death is increased. in the beginning of the procedure, tissue sections were incubated in hydrogen peroxidase solution for 15 minutes then washed with phosphate buffer saline (pbs) twice, citrate tamponade was made in microwave and then cooled in room temperature for 20 minutes, afterwards washed with pbs for four times. in order to avoid non specific arka plân coloring, ultra v block application (protein blockage) was made in room temperature for 5 minutes. it was not washed, but bax antibody was used to cover the tissue by dropping the ultra v block onto the microscope slide and incubated for an hour. dilution was made at 1/100. then it was washed with pbs for 4 times. afterwards “biotinylated goat anti polyvalent solution” (link saru) was dropped and after 20 minutes was washed with pbs for 4 times and incubated with aec chromogen until it was colored (aec preparation: 1 drop of chromogen was added to 1 ml of substrate and washed with distilled water). the contrast coloring was made with mayer’s haematoxylin that was kept there for 1 minute maximum before being washed with distiled water and closed with ultramount. preparates were examined with a light microscope and bax (+) coloring was defined as granular type coloring of the cytoplasm. increased intensity of coloring (+), excessive increase in coloring (++) and normal coloring were recorded. randomized 10 tubules diameters were measured in all the samples under the ocular micrometer of the olympus ch30 light microscope. necrosis level of intratubular germ cells were classified according to their cell level. statistical analysis kruskal wallis test was used to compare groups, mannwhitney u test was used for dual comparisons and fisher (exact) test was used to compare the qualitative data. all the results were evaluated in a ci of 95% and p < 0.05 was defined as statistical significance. results after the ihc, all four groups were evaluated for apoptosis and morphology and these results were found: all 4 cases in the control group had spontaneous apoptosis and apoptotic coloring was dominant (+) in the spermatocyte level in 3 cases and in the spermatid level in 1 case. at the 1st week of the unilateral vasectomy bax coloring level increased to (++) while it remained the same (+) in one case. dominant level was the spermatocyte level, the same as the control group. on the contralateral side bax coloring was (+) but in 3 cases bax dominant cell level had increased to spermatids while in one case it remained in the spermatocyte level. at the 2nd (c) and the 8th weeks (d) bax colorings were negative both in the vasectomy operated side and the contralateral side. the difference in the bax positivity in the vasectomy operated testes were statistically significant when compared with the 2nd and the 8th weeks. likewise 1st week’s bax positivity of the contralateral side was statistically significant when compared to that of the 2nd and the 8 weeks (table 1). during the first week, neither the ipsilateral nor the contralateral testicles had any inflammation. at the second week 3 of the ipsilateral testicles had inflamation of the tunica albuginea while there were no such inflammation in the contralateral testis. at the 8th week inflammation was detected in 4 vasectomy operated testes and in 2 contralateral testes. when the inflammation rate of the first control bax bax cell (dominant) case 1 left testis (+) spermatocyte right testis (+) spermatocyte case 2 left testis (+) spermatocyte right testis (+) spermatocyte case 3 left testis (+) spermatocyte right testis (+) spermatocyte case 4 left testis (+) spermatid right testis (+) spermatocyte 1st week case 1 v1 (++) spermatocyte c1 (+) spermatid case 2 v2 (++) spermatocyte c2 (+) spermatocyte case 3 v3 (++) spermatocyte c3 (+) spermatid case 4 v4 (+) spermatocyte c4 (+) spermatid 2nd week case 1 v1 (-) (-) c1 (-) (-) case 2 v2 (-) (-) c2 (-) (-) case 3 v3 (-) (-) c3 (-) (-) case 4 v4 (-) (-) c4 (-) (-) v = vasectomy = left testis, c = contralateral testis = right testis, the staining type: none( -), low (+), moderate (++) table 1. weekly bax staining results. hazar corr_stesura seveso 30/09/15 09:28 pagina 199 archivio italiano di urologia e andrologia 2015; 87, 3 a. ismet hazar, b. cakiroglu, e. sakalli, m. bahadir can balci, e. eyyupoglu, t.tas, o. sinanoglu, p. tuzlali, n. can cilesiz 200 week was compared with the patients 2nd (p < 0.0001) and the 8th week (p < 0.001) statistically significant increase was detected. when the contralateral testicles were evaluated, no such increase according to weeks was detected (p > 0.05). when the ipsilateral and the contralateral testes were compared there were no statistically significant difference at the 1st week (p > 0.05) but at the end of the 2nd and the 8th week, inflammation rate was higher in the vasectomy operated group (p < 0.001) (table 2). peritubular fibrosis was seen in the vasectomy operated group at the first week and 2 cases at the 2nd and 8th week while it wasn’t seen in any in the contralateral group. while there was a significant rise in peritubular fibrosis at 2nd weeks when compared with the 1st week (p < 0.01), there was no significant increase at 8th week when compared to the 2nd (p > 0.05). in the vasectomy group peritubular fibrosis was significantly higher at the 1st, 2nd and 8th week when compared to the contralateral testicles (p < 0.0001). intratubular germ cell necrosis was not detected during the 1st week. at the 2nd week, 4 cases had moderate and 1 case had mild intratubular germ cell necrosis while it was not seen in the contralateral side. dominant level was the spermatocyte level in 2 cases and the spermatid level in 2 cases. at the 8th week 9 out of 10 testes with vasectomy had intratubular germ cell necrosis. intratubular germ cell necrosis was mild in 2 cases, moderate in 5 cases and severe in 2 cases. dominant level was the 1° spermatocyte level in 1 case, the 2° spermatocyte level in 7 cases and the spermatid level in 1 case. when the contralateral testes were examined intratubular germ cell necrosis was found in 9 out of 10 cases. in 6 cases it was moderate and in 3 cases it was mild. dominant level was the spermatid level in 5 cases, the 1° spermatocyte level in 3 cases and 2° spermatocyte level in 1 case (table 2). statistical analyses revealed that germ cell necrosis mainly in the spermatid area was statistically significant at the 2nd week when compared with that of the 8th week (p < 0.0001). there was statistically significant increase in intratubular germ necrosis at the 2nd and the 8th week when compared with the 1st week (p < 0.001). when the contralateral testicles were evaluated internally, increase in germ cell necrosis in spermatids at the 8th week was statistically significant (p < 0.0001). in the preoperative operation no sperm granuloma was seen while it was encountered in one case at the 2nd week and in 3 cases at the 8th week. when compared with the 1st week, the possibilty of granuloma detection rate was higher at the 2nd and the 8th week and this difference was statistically significant (p < 0.0001). no testicular necrosis or atrophy were shown. the morphology of the epididymis was preserved at the 8th week. the diameter of the tubules was 235.3 ± 12.9 μ in the vasectomy operated side and 248 ± 12.9 μ in the contralateral side at the 1st week. in the second week the mean diameter of the tubule in the vasectomy operated testicle was 234.5 ± 3.87 μ and the mean diameter of the contralateral side was 249.3 ± 3.20 μ. at the 8th week this diameter was measured as 230.1 ± 7.66 μ in the ipsilateral side and 250.4 ± 2.5 μ in the contralateral side. when the statistical analyses were made for the mean tubule diameters and weekly change, the difference was not statistically significant at the 1st week (p > 0.05) while it was statistically significant at the 2nd (p < 0.05) and the 8th week (p < 0.001). there was no statistically significant difference when the vasectomy operated testes were compared with each other (p > 0.05) (table 3). 1st week inflammation pt fibrosis intratubular necrosis sperm granuloma v1 (-) (+) (-) (-) c1 (-) (-) (-) (-) v2 (-) (-) (-) (-) c2 (-) (-) (-) (-) v3 (-) (-) (-) (-) c3 (-) (-) (-) (-) v4 (-) (-) (-) (-) c4 (-) (-) (-) (-) 1st week inflammation pt fibrosis intratubular necrosis sperm granuloma degree dominant v1 (-) (-) (++) 2°spermatocyte (-) c1 (-) (-) (-) (-) (-) v2 (+)t.albuginea (+) (++) spermatid (+) c2 (-) (-) (-) (-) (-) v3 (+)t.albuginea (+) (+) 2°spermatocyte (-) c3 (-) (-) (-) (-) (-) v4 (+)t.albuginea (-) (++) spermatid (-) c4 (-) (-) (-) (-) (-) 8th week intratubular necrosis pt fibrosis sperm granuloma inflammation degree dominant case 1 v1 (+) 1°spermatocyte (-) (-) (+) c1 (++) spermatid (-) (-) (-) case 2 v2 (++) 2°spermatocyte (+) (+) (-) k2 (++) sperma (-) (-) (-) case 3 v3 (++) 2°spermatosit (-) (+) (+) c3 (++) spermatid (-) (-) (-) case 4 v4 (+++) 2°spermatocyte (-) (-) (-) c4 (+) spermatid (-) (+) (-) case 5 v5 (++) 2°spermatocyte (-) (-) (-) c5 (++) sperma (-) (-) (-) case 6 v6 (+) 2°spermatocyte (+) (+) (+) c6 (++) sperma (-) (-) (+) case 7 v7 (++) spermatid (-) (-) (-) c7 (++) spermatid (-) (-) (-) case 8 v8 (+++) 2°spermatocyte (-) (-) (-) c8 (+) spermatid (-) (-) (-) case 9 v9 (++) 2°spermatocyte (-) (-) (+) c9 (-) (-) (-) (-) (+) case 10 v10 (-) (-) (-) (-) (-) c10 (+) 2°spermatocyte (-) (-) (-) table 2. weekly histopathology results. hazar corr_stesura seveso 30/09/15 09:28 pagina 200 201archivio italiano di urologia e andrologia 2015; 87, 3 proapoptotic control in unilateral vasectomy discussion the effect of vasectomy on testicular histology is still controversial. testicular stem cells and spermatids which are formed by differentiated stem cells are in close relationship with the seminifer tubules’ luminar cells and sertoli cells of the testicular interstitium. in order to maturize to sperm cells they need the epididymis and its functions as well. the high rate of fertilisation in conductive fertilisation techniques after vasectomy and its reversals suggest that vasectomy does not cause an important disorder in testicular functions. althrough the studies in the literature are controversial, there is more data supporting that there is a worsening of the sperm functions and dilatation in the seminiferous tubules in the early stages and inflammation and peritubular fibrosis with a decrease in germ cell levels in the later stages (19). spermatic cysts behave as shock absorbers and help in preserving the functions and give physiological support (20). lower fertilization rates in patients with short-term vasectomy than in patients with long-term vasectomy support the late stage findings of testicular histology. recent studies have shown that apoptosis is the most important mechanism for spermatogenesis in germ cells. apoptosis has been widely studied in the spermatogonia, the spermatocytes and spermatids and, many apoptotic factors have been described. testicular germ cell apoptosis is a physiological event that occurs throughout life (21). in the end the number of potential spermatozoa decrease by 75%. apoptosis has 2 functions in spermatogenesis. the first is to limit the germ cell population which sertoli cells can support, the second is to be selective in decreasing the abnormal spermatozoa (21). the relationship between the fertility and apoptosis was shown by the increased apoptosis in patients with oligospermia. on the other hand there are few studies regarding the effect of vasectomy on this process and its genetic control. there’s almost no studies on the apoptotic process in normal testicles. its clinical importance is the potential effect on fertility in vas deferens injuries that does not last with orchiectomy. we did not detect any testicular necrosis or atrophy in our experimental study. but there were increase in sperm granuloma formations and significant increase in tubular diameters and decrease in the wall thickness. the increase of the granuloma is more significant at the 8th week. since spermatogenesis continues after vasectomy, there can be leaks from the slimming tubules due to the widening of the epididymis and ductus deferens and this stimulates the granuloma formation. it is possible that the granulomas relieve the inflamatory pressure. it may be related to intraluminar phagocytosis. phagocytosis causes stimulation of the immune system which cause antisperm antibodies formation. on the other hand it is also possible that extravasation may induce autoimmune responses. there are many articles about the autoimmune response to the testicular tissue. t lymphocytic cells and monocytes are responsible from this immunity and phagocytosis. after detecting the antigen, t lymphocytic cells stimulate b lymphocytic cells to produce antibodies. monocyte-monocyte interaction leads the phagocytosis pathway to activate and this formation causes inflammation and fibrosis in testicular germ cells (22). in our study in the later stages at the 8th week in 9 out of 10 cases intratubular germ cell necrosis was present in vasectomy operated side, in addition to inflammation and fibrosis, 2 cases had mild, 5 cases had moderate and 2 cases had severe intratubular germ cell necrosis. dominant stage was the 1° spermatocyte in one case, the 2° spermatocyte in 7 cases and the spermatid in one case. studies that explain the impairment in spermatogenesis after iatrogenic damage to vas deferens are classified as: 1) immunologic response to the testicular tissue 2) reactive oxygen species 3) apoptotic changes in germ cells (23-26). however, it is also suggested that adult vas deferens obstruction does not affect apoptosis (27). abnormal spermatogenesis was shown to occur due to dysfunctional expression of the genes (28-34). in our study we observed that increased apoptosis in the testis undergoing vasectomy this is compatible with previous literature findings (35). thus, with our vasectomy experiment protocol, we tried to find an answer to 2 main questions which include the changes in the ipsilateral histology and apoptosis. bax staining increased in the contralateral testicle during the initial period in our vasectomy model. the affected cell level was more mature in contrast to the ipsilateral testicle. it is known that apoptosis in stem cells affects the physiological regulation. despite the fact, this high apoptosis level in the low-resistant spermatids which are under high exposure to external factors in the contralateral testicle suggest a possible systemic effect after vasectomy (36, 37). this early stage of apoptosis occurs without intratubular and peritubular changes and the granuloma formation may not be dependent on the immunity. we found findings suggesting that this effect supports the late stage inflammation. we believe that bax proteins has a role in this modulation. we did not detect any tubular or peritubular pathologies in the contralateral testis since the increase of pressure does not affect the contralateral one. if these findings with common avascular fibrosis which is seen during the complete mobilization of vas deferens in inguinal surgery was further evaluated, it may enlighten the underlying factors of this situation which causes sterility with a range of 78%. furthermore, the excessive mobilization of the cord and the operation technique are highly important in the inguinal surgery in order to sustain fertility (38). tubule diameters 1st week 2nd week 8th week kw pv1 vasectomy 235.3 ± 12.09 234.5 ± 3.87 230.1 ± 7.66 1.38 > 0.05 contralateral testes 248 ± 3.91 249.3 ± 3.20 250.4 ± 2.5 2.54 > 0.05 mw 2 0 0 p > 0.05 < 0.05 < 0.001 table 3. the testicular tubular diameter change per weeks in the ipsilateral and contralateral testi. hazar corr_stesura seveso 30/09/15 09:28 pagina 201 archivio italiano di urologia e andrologia 2015; 87, 3 a. ismet hazar, b. cakiroglu, e. sakalli, m. bahadir can balci, e. eyyupoglu, t.tas, o. sinanoglu, p. tuzlali, n. can cilesiz 202 conclusions the damage in testicular histology following the obstruction of ductus deferens depends by complex mechanisms rather than a single mechanism. apoptosis is responsible for the initial germinal cell damage. unilateral ductal obstruction causes damage on the testicular structure by causing bilateral germ cell necrosis due to the increase in pressure and processes that are 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mice. mol reprod dev. 2008; 75:40-7. 37. billig h, furuta i, rivier c, et al. apoptosis in testis germ cells: developmental changes in gonadotropin dependence and localization to selective tubule stages.endocrinology. 1995; 136:5-12. 38. matsuda t, muguruma k, horii y, et al. serum antisperm antibodies in men with vas deferens obstruction caused by childhood inguinal herniorhaphy.fertil steril 1993; 59:1095. correspondence aydin ismet hazar, md mustafa bahadir can balci, md tuncay tas, md nusret can cilesiz, md taksim training and research hospital, department of urology, istanbul, turkey basri cakiroglu, md (corresponding autor) drbasri@hotmail.com hisar intercontinental hospital department of urology saray mah. siteyolu cad., no:7 34768 umraniye, istanbul, turkey ertan sakalli, md zonguldak state hospital, department of urology, zonguldak, turkey erkan eyyupoglu, md amasya training and research hospital, department of urology, amasya, turkey orhun sinanoglu, md maltepe university medical school, department of urology, istanbul, turkey pinar tuzlali, md taksim training and research hospital, department of pathology, istanbul, turkey hazar corr_stesura seveso 30/09/15 09:28 pagina 203 279archivio italiano di urologia e andrologia 2016; 88, 4 original paper analysis of myo-inositol effect on spermatozoa motility, in hyper viscous ejaculates and in patients with grades ii and iii varicocele filomena scarselli 1, anna maria lobascio 1, mario terribile 1, valentina casciani 1, pierfrancesco greco 1, giorgio franco 2, maria giulia minasi 1, ermanno greco 1 ¹ centre for reproductive medicine, european hospital, rome, italy; 2 dept. gynaecological-obstetrical and urological sciences, sapienza university, rome, italy. the goal of this study is to evaluate myoinositol effects on spermatozoa motility, in patients’ ejaculates with severe varicocele or hyper viscosity. the study included normal viscosity ejaculate from 30 patients affected by varicocele and hyper viscosity ejaculate from 33 patients without any testicular pathologies. all selected samples showed sperm concentration > 2 million/ml and progressive motility < 32%. in both groups, the pellet obtained after centrifugation in buffered medium, was divided in two aliquots, both incubated for 15 minutes at 37°c: one with myo-inositol and the other one, as control, only in phosphate buffered saline (pbs). afterwards, the sperm progressive motility was assessed using computer assisted sperm analysis (casa system). incubation with myo-inositol improved sperm progressive motility in high viscosity samples compared to control group (38.9% ± 3.0 vs 24.35% ± 2.41, respectively; p ≤ 0.0001). conversely, no statistically significant difference was observed in total sperm progressive motility in varicocele samples compared with control group (22.7% ± 2.07 vs 26.7% ± 3.31, respectively; p = 0.085). the myo-inositol positive effect on spermatozoa motility may depend on the type of sperm damage: heavy structural and biochemical defects which typically affects patients with varicocele are not restored by inositol. on the contrary, myoinositol is able to improve sperm motility in semen samples with high viscosity, since those samples show no substantial structural sperm defects. key words: myo-inositol; asthenozoospermia; varicocele; hyper-viscosity; spermatozoa motility. submitted 14 july 2016; accepted 19 august 2016 summary no conflict of interest declared. seminiferous tubules by the sodium/myo-inositol protein (slc5a3), which is up-expressed in sertoli cells (1, 2). several roles of myo-ins are known: it is involved in mitochondrial membrane potential (mmp) maintenance, in the control of intracellular ca²+ concentration, in the cytoskeleton assembly, in gene expression regulation and it is also an important component of the structural lipids. phosphatidylinositol (pi) is involved in diacylglycerol (dag) and inositol triphosphate (ip3) formation, which are produced from phospholipase c (plc) that hydrolyses phosphatidylinositol 4,5-bisphosphate (pip2) to dag and ip3, two second messengers involved in the cellular signal transduction and in the regulation of intracellular calcium concentration, respectively. ip3 binds to its receptor (ip3r) placed on the intracellular membrane of ca²+ storages and triggers ca²+ release necessary for sperm motility. there is evidence of the ip3rlinked ca²+ storages presence at the base of sperm flagellum, where only two membrane-bound organelles have been detected: mitochondria and the redundant nuclear envelope (rne) (3). the latter arises from excess of nuclear envelope which is discarded during sperm nuclear chromatin condensation. observations indicate that rne has only a storages role and upon induction it releases ca²+ which seems to act directly on the axoneme and, perhaps, indirectly on mitochondrial atp production, both necessary to improve sperm motility. as reported in literature, myo-ins treatment does not affect the mitochondrial function of spermatozoa in normozoospermic patients, whereas it increases significantly the number of spermatozoa with high mmp in oligoasthenoteratospermic (oat) patients (4). observations show that the number of spermatozoa with high mmp levels correlates positively to sperm concentration and sperm progressive motility (5, 6). furthermore spermatozoa with high mmp are directly linked to fertilization rate, in vivo and in vitro (7). however, the effects of myo-ins on phosphatidylserine (ps) externalization, an early marker of apoptosis, on chromatin compactness and on dna fragmentation, in normozoospermic and oat patients, were not known (4, 8). low sperm motility is a primary cause of male infertility, doi: 10.4081/aiua.2016.4.279 introduction inositol (c6h 12o6) is a chemical compound existing in nine different stereoisomers synthesized from glucose-6phosphate. the most widespread form of inositol in nature is myo-inositol (myo-ins), which belongs to the vitamin b group. myo-ins is synthesized by two different enzymes: myo-1-phospate synthase (isyna1) and myomonophospatase-1 (impa1). these enzymes are present in high concentration in seminal plasma and in the testis, particularly in sertoli cells rather than in germinal cells. after its synthesis, myo-ins is co-transported in the fluid of scarselli_stesura seveso 09/01/17 09:54 pagina 279 archivio italiano di urologia e andrologia 2016; 88, 4 f. scarselli, a.m. lobascio, m. terribile, v. casciani, p. greco, g. franco, m.g. minasi, e. greco 280 associated with biochemical defects and/or with delayed or missing semen liquefaction. semen samples coagulation and liquefaction with their physiological characteristics are still not fully understood; however, the negative effects of hyperviscosity on semen parameters, above all motility, are known. as reported in literature, hyperviscosity is due to a “trapping effect” that prevents normal sperm progression through the female genital tract (9, 10-12). there is evidence of a correlation between hyperviscosity (shv) and low levels of fructose in seminal plasma, due to an impaired function of the seminal vesicles (11). some studies show a potential correlation between hyperviscosity and altered levels of ca²+, zinc and acid phosphatase for prostate dysfunction (13, 14). data reported in literature, correlate shv to an excess of reactive oxygen species (ros) (15), infections and/or genital tract’s inflammations (16) and to genetic factors, such as the cystic fibrosis transmembrane conductance regulator (cftr) gene expression. the cystic fibrosis causes defects in active ions transport (cl-), resulting in a lower water content in the intraluminal secretions that may be responsible for reduced semen fluidity and for progressive obstruction and destruction of the vas deferens and epididymis (17). other authors demonstrate that hyper viscosity is not due to a single factor, but rather to several factors, which act in synergy (10). varicocele is a well-known infertile male condition. it is found in 10-20% of male population and it is associated to progressive decline of testicular function. three grades of varicocele are known: grade i, palpable with valsalva maneuver only; grade ii, palpable without valsalva maneuver and grade iii, palpable and visible through the scrotal skin. varicocele is associated to several conditions: altered testicular thermoregulation (18), blood stasis in spermatic veins (19) and elevated levels of abnormal sperm-associated reactive oxygen species (ros) (20). the effects of varicocele consist in a reduced testicular volume, a compromised sperm quality (motility, morphology and concentration) and reduced leydig cells function. some authors suggest a possible relation between varicocele and abnormal retention of sperm cytoplasmic droplets, typical of sub-fertile men (21). the aim of this study was to evaluate the myo-ins effect on spermatozoa motility, in ejaculates of patients with severe varicocele (grade ii and iii) and in ejaculates with hyper viscosity. materials and methods the study was performed from september 2012 to january 2013. semen samples were collected by masturbation after 3-5 days of sexual abstinence. after 30 minutes of liquefaction at 37°c, semen parameters were analysed according to world health organization (who) criteria 2010 (22). the thread length of both ejaculates with hyper viscosity and ejaculates of patients with grades ii and iii varicocele were measured, gently aspirating the semen liquid into a glass disposable pipette and leaving fall down, in gravity, a drop of sample on a slide. when the viscosity is normal, the semen sample leaves the pipette in small discrete drops; if viscosity is abnormal (increased), such as in shv group, the drop will form a thread more than 2 cm long. the thread length was measured on a centimetre scale. ejaculates of 30 patients (mean male age 39.9 years old, sd ± 10.89) with grade ii and iii varicocele (according to sarteschi classification), with sperm concentration > 2 million/ml, normal viscosity and low progressive motility (< 32%, according to who 2010) (22), were included in the study (varicocele group). ejaculates of 33 patients without testicular pathologies (mean male age 39.6 years old, sd ± 1.15), with sperm concentration > 2 million/ml, high viscosity (thread length > 2 cm) and low progressive motility (< 32%, according to who 2010) (22), were analysed (shv group). the enrolled semen samples were centrifuged in mopsbuffered medium (g-mops ™ plus vitrolife, sweden) at 1800 rpm/10 minutes an the pellet was divided in two aliquots: the first one was incubated with 2 mg/ml of myo-ins (andrositol dgn, lo.li. pharma s.r.l., italy), for 15 minutes at 37°c temperature, in mops-buffered medium (g-mops™ plus vitrolife, sweden) and the second one, as control, was incubated at the same conditions. after incubation, sperm progressive motility, using computer assisted sperm analysis (casa system sperm class analyzer automatic diagnostic systemsmicroptic s.r.l. spain), was evaluated. statistical analysis statistical analyses were performed using student t-test and wilcoxon t-test (parametric and non-parametric statistical test, respectively); p value of < 0.05 was considered to be statistically significant. results were expressed as mean ± sd. results no statistically significant differences in total sperm progressive motility (slow and rapid) were observed in ejaculates of patients with grades ii and iii varicocele, after incubation with myo-ins and in control group (22.7% ± 2.07 and 26.7% ± 3.31, respectively; p student = 0.085). on the contrary, incubation with myo-ins improved sperm progressive motility in shv group. our data demonstrate an enhanced sperm motility in semen with hyper viscosity (38.9% ± 3.0), compared to control group (24.35% ± 2.41) (wilcoxon test p ≤ 0.0001; figure 1). the effects of myo-ins treatment observed in ejaculates of patients of varicocele group and in ejaculates of shv group, have been separated in four categories, according to andrositol-lab procedure, which divides the responses to inositol in the following classes, summarized in table 1: 1. high responder (hr): samples with increased sperm progressive motility from ≥ 60% to 100%. 2. middle responder (mr): samples with increased sperm progressive motility from ≥ 30% to < 60%. 3. poor responder (pr): samples with increased sperm progressive motility from ≥ 1% to < 30%. 4. no responder (nr): samples with none increased sperm progressive motility. scarselli_stesura seveso 09/01/17 09:54 pagina 280 discussion the aim of this study was to evaluate the myo-ins effects on sperm motility in samples with shv or varicocele, in which asthenozoospermia is a common features. a positive effect of inositol on sperm progressive motility (slow and rapid) in ejaculates of patients with shv was observed. particularly, sperm progressive motility increased from ≥ 30% to < 60% (mr) and from ≥ 60% to 100% (hr), in shv group. an increase in sperm progressive motility from ≥ 1% to < 30% (pr) or absence of response (nr) to myoins was observed in varicocele group. asthenozoospermia is one of male infertility causes, that involves an array of functional and biochemical sperm defects. asthenozoospermic patients show both low sperm motility and low fertilizing ability due to their poor capability of hyper activation-capacitation linked. a relationship between sperm membrane fluidity and tyrosine phosphorylation is well known. specifically, a deficit in tyrosine phosphorylation in asthenozoospermic patients produces a low sperm membrane fluidity and, therefore, a low sperm motility (23). some authors (24), found an increase in sperm motility after 2 hours of incubation with myo-ins (2 mg/ml), in oat samples. in our study, a positive inositol effect, at the same concentration, is observed on motility in shv samples, after 15 minutes of incubation. incubation attempts at 15 minutes, 30 minutes and 2 hours were done, but the highest inositol effect on semen samples was observed at 15 minutes. the faster inositol effect observed in this study, is probably due to the samples rinsing with mops-buffered medium, before myo-ins treatment. it is possible that in shv samples, the most of mucoid mass in which spermatozoa are tangled is dissolved or taken-away by rinsing. as a consequence, myo-ins may easily tie up sperm and mitochondrial membrane and active ion fluxes (mainly hco³-, na+, k+, and ca²+) which are involved in tyrosine phosphorylation and in sperm capacitation (motility and hyperactivation) (25). however, our hypothesis is in agree with colone et al. (24), who observed, through scansion electron microscopy (sem), that spermatozoa of oat patients appear entirely covered with an amorphous fibrous material, perhaps responsible of semen high viscosity and consequently of a reduced sperm motility. additionally, colone observed, through transmission electron microscopy (tem), altered mitochondrial cristae, placed in sperm intermediate tract of oat samples. nevertheless, after incubation with myo-ins, the authors found that, the surface spermatozoa and mitochondrial cristae of enrolled samples, appeared to be more similar to the controls (absence of amorphous fibrous material on sperm surface and intact mitochondrial cristae). these results show the ability of inositol to dissolve the amorphous fibrous material and to improve spermatozoa motility, perhaps inducing a modification in semen samples ph and then acting on spermatozoa plasma and mitochondrial membranes. even the ejaculates of patients with grade ii and iii varicocele show low sperm motility. nevertheless, in this study, the incubation with myo-ins did not always increase progressive sperm motility as in shv samples. it is possible that pr and nr, observed in varicocele group, are due to a damaged spermatogenesis and/or to irreversibly altered biochemical factors. several studies demonstrate that in varicocele, the secretions of impaired sex accessory glands, such as fructose, might have a negative influence on motility of ejaculated spermatozoa (26). other studies assert that fructose levels in varicocele samples are not significantly different to those of samples without varicocele (27). steroid hormones, such as testosterone, play a fundamental role not only in sexual differentiation and in expression of secondary sexual characteristics but also, in spermatogenesis. wang et al. (28), report that the action of androgens is mediated by androgen receptors (ar), which act as a ligand-inducible transcription factor. ar ligands are: testosterone (t) and dihydrotestosterone (dht), its more active metabolite. ejaculated mammalian spermatozoa express ar in the head and in the mid piece, this 281archivio italiano di urologia e andrologia 2016; 88, 4 analysis of myo-inositol effect on spermatozoa motility, in hyper viscous ejaculates and in patients with grades ii and iii varicocele table 1. effect of myo-inositol on progressive sperm motility in the ejaculates of patients with hyperviscosity or with varicocele (hr = high responder, mr = middle responder, pr = poor responder, nr = no responder). hr mr pr nr (≥ 60 100) % (≥ 30 < 100) % (≥ 1 < 30) % (0) % shv group 19/33 (57.6%) 8/33 (24.2%) 4/33 (12.1%) 2/33 (6.1%) varicocele group 6/30 (20%) 5/30 (16.7%) 8/30 (26.7%) 11/30 (36.7%) figure 1. analysis of image, using casa system, of spermatozoa motility in ejaculates with hyper viscosity not incubated with myo-inositol (control, part a) and in ejaculates with hyper viscosity incubated with myo-inositol (part b). the coloured lines indicate the spermatozoa showing rapid progressivity (red), slow progressivity (green), in-situ motility (blue) and immotile spermatozoa (yellow), respectively. in hyper viscosity samples, the lines red and green are significantly increased after incubation with myo-inositol. scarselli_stesura seveso 09/01/17 09:54 pagina 281 archivio italiano di urologia e andrologia 2016; 88, 4 f. scarselli, a.m. lobascio, m. terribile, v. casciani, p. greco, g. franco, m.g. minasi, e. greco 282 latter corresponding to the mitochondria site. ar play an important role in sperm survival and capacitation, acting on pi3k/akt signaling pathway (29-31). as reported, during capacitation, spermatozoa undergo a final maturation by increasing cholesterol efflux which acts on tyrosine phosphorylation and on sperm membrane fluidity (32). some authors (33), found that the basal cholesterol efflux is reduced in spermatozoa of patients with varicocele compared to spermatozoa of patients without varicocele. this provokes a reduced sperm membrane fluidity and thus a decreased motility, in varicocele samples. these authors also observed that in normal spermatozoa, dht induced g6pdh activity, an enzyme involved in glucose metabolism, through pi3k/akt pathway. this effect is not observed in varicocele samples (33). jackaman et al. (34) and al-daghistani et al. (27) demonstrate that testosterone levels in samples without varicocele are lower than in samples with varicocele. this feature may indicate severe atrophy of seminiferous tubules, sclerosis and leydig cells hyperplasia, causing the humoral immune response and then asa (anti sperm antibodies) production; these latter, as known, are involved in a reduced sperm motility. it is probable that in ejaculates with varicocele, oxidative stress and spermatogenesis dysfunction are the two main causes of an impaired tyrosine phosphorylation and, consequently, an altered membrane fluidity. it is known, for example, that sperm motility and capacitation are related to sperm membrane composition: high levels of polyunsaturated fatty acids makes it oversensitive to the attack of reactive oxygen species which cause both an altered tyrosine phosphorylation and altered signal transduction, resulting in low membrane fluidity and consequently, reduced sperm motility (35, 36). in sustain of that, some authors establish that spermatozoa of patients with varicocele, have an abnormal retention of cytoplasmic droplets due to excessive ros production (21). ros are negatively correlated with sperm motility, through oxidation of membrane fatty acids which alter sperm membrane fluidity (37, 38). excessive ros production, associated to increased testicular temperature, typical condition of varicocele, and to abnormal retention of cytoplasmic droplets, due to an impaired spermatogenesis, causes a reduced/altered sperm functions correlated with dna damages. studies confirm higher levels of damaged and fragmented dna ros related and thus reduced mmp and decreased sperm motility (39), in infertile men with varicocele compared to fertile men without varicocele (40-41). conclusions the lack or absence of myo-inositol effect observed in varicocele group seems principally due to impaired spermatogenesis and to heavy biochemical and structural sperm defects. defects linked to varicocele considerably compromise sperm functionality on which inositol has no or partially positive effect (the benefits of varicocelectomy to improve sperm quality are discussed). on the contrary the increase of sperm motility observed in shv group after incubation with myo-inositol, may be connected to the absence of substantial structural sperm defects. the low spermatozoa motility observed in shv samples is most probably related above all to mucoid mass in which sperm are tangled and of which, the partial or total removal, allows the improving of sperm motility by inositol activity. in conclusion myo-inositol appears to have a positive effect on spermatozoa motility, depending on the type of sperm damage: heavy structural defects, typical of varicocele samples, are not restored by inositol. references 1. robinson r, fritz ib. myoinositol biosynthesis by sertoli cells, and levels of myoinositol biosynthetic enzymes in testis and epididymis. can j biochem. 1979; 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17:276-87. 38. keating j, grundy ce, fivey ps, et al. investigation into the association between the presence of cytoplasmic residues on the human sperm midpiece and defective sperm function. j reprod fertil. 1997; 110:71-7. 39. blumer cg, fariello rm, restelli ae, et al. sperm nuclear dna fragmentation and mitochondrial activity in men with varicocele. fertil steril. 2008; 90:1716-22. 40. saleh ra, agarwal a, sharma rk, et al. evaluation of nuclear dna damage in spermatozoa from infertile men with varicocele. fertil steril. 2003; 80:1431-6. 41. smith r, kaune h, parodi d, et al. increased sperm dna damage in patients with varicocele: relationship with seminal oxidative stress. hum reprod. 2006; 21:986-93. 283archivio italiano di urologia e andrologia 2016; 88, 4 analysis of myo-inositol effect on spermatozoa motility, in hyper viscous ejaculates and in patients with grades ii and iii varicocele correspondence filomena scarselli, msc (corresponding author) filomenascarselli@virgilio.it anna maria lobascio, phd mario terribile, phd valentina casciani, phd pierfrancesco greco maria giulia minasi, msc ermanno greco, md centre for reproductive medicine, european hospital via portuense 700, 00149 rome, italy giorgio franco, md dept. gynaecological-obstetrical and urological sciences, sapienza university, rome, italy scarselli_stesura seveso 09/01/17 09:54 pagina 283 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3190 original paper improvement of seminal quality and sexual function of men with oligoasthenoteratozoospermia syndrome following supplementation with l-arginine and pycnogenol® yoshitomo kobori ¹, keisuke suzuki ¹, toshiyuki iwahata ¹, takeshi shin ¹, yuko sadaoka ¹, ryo sato ¹, kojiro nishio ¹, hiroshi yagi ¹, gaku arai ¹, shigehiro soh ¹, hiroshi okada ¹, jeffry michael strong ², peter rohdewald ³ ¹ department of urology, dokkyo medical university koshigaya hospital, saitama, japan; ² horphag research, cointrin/geneva, switzerland; ³ institute of pharmaceutical chemistry, university of munster, munster, germany. we evaluated the effectiveness of antioxidant co-supplementation therapy using larginine and pycnogenol® in japanese men with oligoasthenozoospermia and mild erectile dysfunction (ed). a total of forty-seven adult males with oligoasthenoteratozoospermia syndrome (oat) were eligible for enrollment. the effectiveness of supplementation with a combination of l-arginine 690 mg and french maritime pine bark extract (pycnogenol®) 60mg for oat and ed was investigated. the sperm concentration was enhanced significantly after treatment 2 and 4 months (11.79 ± 9.86 to 21.22 ± 28.17 and 20.15 ± 23.99 × 106/ml). significant improvements in the international index of erectile function (iief) were observed in the total score of iief (57.69 ± 11.04 to 59.43 ± 12.57) and domain of orgasmic function (9.01 ± 1.92 to 9.34 ± 1.66) after 4 months of treatment. l-arginine acts to increase the production of nitric oxide and pycnogenol® activates the endothelial nitric oxide synthase and it is a potent antioxidant and inhibitor of inducible nitric oxide synthase. this study suggests that the combination of pycnogenol® and l-arginine (edicare®) is helpful for infertile men to ameliorate simultaneously quality of sperms as well as erectile functions. key words: male infertility; spermatogenesis, erectile dysfunction, l-arginine, pycnogenol. submitted 1 may 2015; accepted 30 june 2015 summary conflicts of interest: partly supported by a grant from kobayashi pharmaceutical. mill/ml and 31.9% produced a total sperm number below 40 mill/ml. these numbers are below the limits given in the who manual for examination and processing of human semen (3). so a significant proportion of men will have a lower chance to achieve fertilization because of their sub-optimal semen quality. there is doubtless a need to enhance male fertility for those men diagnosed to have the oligoasthenoteratozoospermia syndrome (oat) (4). clinical studies conducted in europe and usa have confirmed that the proprietary, patented combination of larginine aspartate and pycnogenol® french maritime pine bark extract marketed as prelox® (both trademarks of horphag research ltd.,) can improve mild to moderate erectile dysfunction (ed) and increase quantity and quality of sperms (5). pycnogenol is a specific pine bark extract consisting of a concentrate of polyphenols, mainly procyanidins, and is listed in the united states pharmacopoeia 34 as maritime pine extract (6). pycnogenol demonstrates its action to improve ed by activating endothelial nitric oxide synthase (e-nos), thereby increasing nitric oxide production and promoting vasodilation (7). a synergistic effect in nitric oxide production is achieved when pycnogenol is administered in combination with larginine, the substrate for e-nos (8). it has been reported that the combination of pycnogenol and l-arginine may increase testosterone concentration, which is suggested to be a physiologic response secondary to increased sexual activity (9). a pycnogenol and l-arginine containing supplement formulated for the japanese population (edicare®) for ed has been tested in japanese patients specifically and improved after 8 weeks of ingestion the erectile function significantly (10). in the present pilot study the influence of edicare® on quality of sperms was evaluated. simultaneously, the influence of the preparation on ed on men with confirmed oat was investigated. doi: 10.4081/aiua.2015.3.190 introduction world-wide about 1 in 7 couples have problems in conceiving. male infertility is involved in 30-50% of involuntarily childless couples according to european guidelines on male infertility (1). a specific investigation on male fertility was performed in japan. semen quality of 1559 young japanese men was evaluated in a large multi-center, cross-sectional study (2). within this group of men between 18-24 years, 9% had a lower sperm concentration than 15 kobori_stesura seveso 23/09/15 12:30 pagina 190 191archivio italiano di urologia e andrologia 2015; 87, 3 effectiveness of l-arginine and pycnogenol for oat and ed materials and methods subjects this study was conducted in compliance with the helsinki declaration after obtaining the approval of the ethics committee of dokkyo medical university koshigaya hospital. subjects were selected from 47 outpatients with oat and mild to moderate ed who had given written informed consent. all presented with infertility after at least 2 years of unprotected intercourse. male infertility was diagnosed if one or more standard semen parameters were below cutoff levels (sperm concentration < 20 × 106/ml, sperm motility < 50%, normal morphology < 30%, and/or semen volume based < 2 ml) based on at least two semen analyses performed 3 months apart to eliminate accidental and possible adverse effects of exogenous factors on spermatogenesis. after providing a complete medical and reproductive history exploring all aspects that might be related to fertility, patients underwent physical examination and serum chemical and hematological laboratory tests. testicular volume was measured using a punched orchidometer. serum follicle stimulating hormone, luteinizing hormone, and testosterone levels were measured in all patients (table 1). subjects who did not meet the following 12 exclusion criteria were selected: habitual consumption of medication and/or a food supplement intended for ed improvement; habitual consumption of medication and /or food supplement that contained either l-arginine, aspartic acid or maritime pine bark extract; allergy to the substances investigated in this study; participation in another clinical study at the start of the study; existence of diabetes mellitus, heart disease, renal disease, hepatic disease, moderate or severe hypertension; habitual consumption of any food supplement to improve the circulation; body mass index (bmi) ≥ 35 kgm2; receiving concurrent dental treatment; reported smoking 20 or more cigarettes a day; morning erection achieved most days. those judged by the investigator (on the basis of laboratory test value or other reasons) as inappropriate for participation in this study were also excluded. sperm preparation semen samples were obtained at start of the study and after 2 and 4 months. after at least 2 days of sexual abstinence, ejaculates were obtained by masturbation in sterile plastic containers. after liquefaction at room temperature, semen volume was determined and samples were immediately examined microscopically according to the guidelines of the who (3). motility of spermatozoa was investigated at 37°c and given as average motility rate. each specimen was investigated by two laboratory technicians. erectile function to evaluate the influence of edicare® on erectile function, participants answered to the questions contained in the international index of erectile function (iief) in the extended version with 15 questions (11). the questionnaire of iief, translated into japanese, was provided to the subjects for assessment before the start of the study, at 4 weeks and again at 8 weeks. we examined the total score of iief, iief5, and each domain: erectile function (ef); orgasmic function (of); sexual desire (sd); intercourse satisfaction (is); and overall satisfaction (os). supplement use the commercialized food supplement edicare® (manufactured by kobayashi pharmaceutical co., ltd.) containing 10 mg of pycnogenol, 115 mg of l-arginine and 92 mg of aspartic acid per tablet was used in the present study. the subjects were asked to take six tablets each day and to record their supplement intake in a diary. statistical analysis the student’s t-test was employed for inter-group comparison of the change in iief and each domain scores using the statcel 3 program (oms publishing, 2011, japan). for seminal parameters wilcoxon’s signed rank sum test was used for intra-group comparisons, and differences in mean values were assayed. in each case, the level of statistical significance was set at p < 0.05. results baseline values of the participants are given in table 1. testosterone levels are partly below, lh and fsh are characteristics range mean ± sd age 26-48 36 ± 9 age of wife 22-44 34 ± 8 serum hormones: testosterone (ng/dl) 169-988 464 ± 151 lh (iu/l) 1.1-11.5 4.9 ± 2.8 fsh (iu/l) 1.6-26.8 1.6-26.8 testicular volume (ml): right 8 -26 18 ± 5 left 4-26 16 ± 5 n = 47 lh, luteinizing hormone; fsh, follicle-stimulating hormone. normal reference range lh: 2.2-8.4 mlu/ml; fsh: 1.8-12.0 mlu/ml; testosterone: 225-1040 ng/dl. mean ± sd baseline 2 months 4 months semen volume (ml) 3.02 ± 1.55 2.69 ± 1.38 2.63 ± 1.42 p-value 0.12 0.09 sperm concentration (×106/ml) 11.79 ± 9.86 21.22 ± 28.17 20.15 ± 23.99 p-value * 0.02 * 0.01 sperm motility (%) 32.31 ± 24.47 35.42 ± 23.71 33.81 ± 21.46 p-value 0.15 0.08 wilcoxon signed-ranks test *: p < 0.05. table 1. characteristics of the patients. table 2. sperm variables throughout the study. kobori_stesura seveso 23/09/15 12:30 pagina 191 archivio italiano di urologia e andrologia 2015; 87, 3 y. kobori, k. suzuki, t. iwahata, t. shin, y. sadaoka, r. sato, k. nishio, h. yagi, g. arai, s. soh, h. okada, j.m. strong, p. rohdewald 192 partly high but the mean is in the normal range. supplementation with the combination of l-arginine and french maritime pine bark extract effectively increased the average sperm concentration significantly after 2 and 4 months (table 2). furthermore, there was a slight, but not significant improvement in the motility rate and the number of functioning sperms after supplementation for 4 months. during the initial screening, volunteers showed a mild erectile dysfunction according to iief. erectile function was significantly ameliorated after 4 months according to the answers of the participants in the total score of iief and domain of of (table 3). discussion several approaches have been proposed for the management of infertility and ed caused by oxidative stress. once an individual has been identified as having oxidative stress-related reproduction and sexual dysfunction, treatment should be aimed at identification and amelioration of the underlying cause before considering antioxidant treatment. lifestyle behaviors such as smoking, poor diet, alcohol abuse, pollution and environmental toxins, obesity, and psychological stress have all been linked to oxidative stress. while the effectiveness of eliminating these lifestyle triggers on oxidative stress has not been formally tested, it is likely that making positive lifestyle changes such as changing to a diet high in fruit and vegetables, maintaining normal weight, and reducing smoking or alcohol intake would have at least some beneficial effects on sperm health. several studies have reported that levels of reactive oxygen species within semen can be reduced by augmenting the scavenging capacity of seminal plasma using oral antioxidant supplements (7). the obtained results show the positive effect of the combination of l-arginine and pycnogenol® in edicare® on sperm function and erectile function. the dosage of larginine 690 mg and pycnogenol® 60 mg used in this investigation was considerably lower than the amounts of l-arginine and pycnogenol® given in previous studies of stanislavov and nikolova with 1.43 g l-arginine and 120 mg pycnogenol® (4, 5). a comparison of the results of the present study with the studies with the higher dosage indicate that the lower dosage is less effective. the assumption, that the lower body weight of japanese men compared to bulgarian men will compensate the lower dosage is not fully justified. in principle, the combination of pycnogenol® and l-arginine acts by increasing the production of no from larginine. as has been demonstrated with healthy japanese volunteers that pycnogenol® activates the endothelial nitric oxide synthase (e-nos) (12). an enhanced activity of e-nos plus a high concentration of its substrate l-arginine results in a greater production of no. no is activating guanylate cyclase to produce cgmp. the cgmp-protein kinase g singling pathway leads to an increase of sperm motility (13). another positive effect of pycnogenol® is based on its inhibition of inducible nitric oxide synthase (i-nos) (14). this enzyme is over-expressed in oat and causes oxidative damage of the sperms. as pycnogenol® is a potent antioxidant (7) and inhibitor of i-nos, it is reasonable to assume that the supplementation with edicare® is able to reduce the damage of sperms of the patients with oat syndrome. these effects led the improvement of ed. as no unwanted effects were observed or reported from patients, edicare® may considered as a safe natural product which helps to improve fertility in men with oat syndrome. contributions all authors participated in the experimental design and method, and the collection, analysis and interpretation of the data. references 1. jungwirth a, giwercman a, tournaye h et al. european association of urology guidelines on male infertility: the 2012 update. eur urol. 2012; 62:324-332. 2. iwamoto t, nozawa s, mieno mn, et al. semen quality of 1559 young men form four cities in japan: a cross-sectional populationbased study. bmj open. 2013; 3: e 00222 doi: 1136/bmj open-2012002222. 3. who manual for examination and processing of human semen. 5th ed. who 2010. 4. stanislavov r, nikolova v, rohdewald p. improvement of erectile function with prelox®: a randomized, double-blind, placebo-controlled, cross-over trial. int j impot res. 2008; 20:173-180. 5. stanislavov r, rohdewald p. sperm quality in men is improved by supplementation with a combination of l-arginine, l-citrullin, roburins and pycnogenol®. minerva urol nefrol. 2014; 66:217-23. 6. stanislavov r, nikolova v, rohdewald p. improvement of seminal parameters with prelox®: a randomized, double-blind, placebocontrolled, cross-over trial. phytother res. 2009; 23:297-302. 7. rohdewald p. a review of the french maritime pine bark extract (pycnogenol®), a herbal medication with a diverse pharmacology. int j clin pharmacol ther. 2002; 40:158-168. 8. stanislavov r, nikolova v. treatment of erectile dysfunction mean ± sd baseline after treatment p-values os 7.36 ± 1.55 7.63 ± 1.23 0.12 is 9.02 ± 3.18 9.13 ± 3.94 0.11 sd 6.86 ± 1.46 6.95 ± 1.83 0.69 of 9.01 ± 1.92 9.34 ± 1.66 * 0.03 ef 25.43 ± 5.90 26.36 ± 6.14 0.08 total 57.69 ± 11.04 59.43 ± 12.57 * 0.02 iief5 21.26 ± 4.75 21.47 ± 5.67 0.25 wilcoxon signed-ranks test *: p < 0.05. os: overall satisfaction, is: intercourse satisfaction, sd: sexual desire, of: orgasmic function, ef: erectile function table 3. scores for erectile function – iief. kobori_stesura seveso 23/09/15 12:30 pagina 192 193archivio italiano di urologia e andrologia 2015; 87, 3 effectiveness of l-arginine and pycnogenol for oat and ed with pycnogenol® and l-arginine. j sex marital ther. 2003; 29:207-213. 9. lamm s. prelox® for improvement of erectile quality. eur j endocrinol. 2009; 4:70-74. 10. aoki h, nagao j, ueda t, et al. clinical assessment of a supplement of pycnogneol and l-arginine in japanese patients with mild to moderate erectile dysfunction. phytother res. 2012; 26:204-207. 11. rosen rc, cappelleri jc, gendrano n 3rd. the international index of erectile function (iief): a state of the science review. int j impot res. 2002; 14:226-244. 12. nishioka k, hidaka t, nakamura s, et al. pycnogenol, french maritime pine bark extract, augments endothelium-dependent vasodilation in humans. hypertens res. 2007; 30:775-780. 13. o’bryan mk, zini a, cheng cy, et al. human endothelial nitric oxide synthase expression: correlation with sperm motility. fertil steril. 1998; 70:1143-1147. 14. uhlenhut k, högger p. facilated cellular uptake and suppression of iducible nitric oxide synthase by a metabolite of maritime pine bark extract (pycnogenol®). free radic biol med. 2012: 53:305-313. correspondence yoshitomo kobori, md (corresponding author) ykobori@dokkyomed.ac.jp department of urology, dokkyo medical university koshigaya hospital 2-1-50 minami-koshigaya, koshigaya, saitama 343-8555, japan keisuke suzuki, md toshiyuki iwahata, md takeshi shin, md yuko sadaoka, md ryo sato, md kojiro nishio, md hiroshi yagi, md gaku arai, md shigehiro soh, md hiroshi okada, md department of urology, dokkyo medical university koshigaya hospital, saitama, japan jeffry michael strong horphag research, cointrin/geneva, switzerland peter rohdewald institute of pharmaceutical chemistry, university of munster, munster, germany kobori_stesura seveso 23/09/15 12:30 pagina 193 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 120 original paper smoking, diabetes, blood hypertension: possible etiologic role for peyronie’s disease? analysis in 279 patients with a control group in sicily carlo pavone 1, francesco d’amato 1, nino dispensa 1, federico torretta 2, carlo magno 3 1 section of urology, department of surgical, oncological and stomatological sciences, aoup “p. giaccone”, university of palermo, italy; 2 department of economics and statistics (dseas), university of palermo, italy; 3 unit of urology, department of human pathology, aou “g. martino”, university of messina, italy. objective: to assess the proportion of patients with peyronie’s disease (pd) and the possible association with its potential risk factors in the general population of the central and western sicily in our weekly andrological outpatient clinic. materials and methods: we recruited a sample of 279 consecutive patients consulting our andrological outpatient clinic. two arms were created: the first one composed by pd patients (men with symptoms suggestive for pd), the second one composed by patients with other andrological diseases (control arm). for each patient we evaluated the age, cigarette smoking, diabetes, blood hypertension and erectile function. in the pd arm we administered validated questionnaires to determine the erectile function status by the international index of erectile function 5 (iief-5) and the pain status during erection by the visual analogue scale (vas). a univariate analysis was conducted using r software. results: we enrolled 279 consecutive patients. the number of pd patients was 97 (34,7%). the univariate analysis showed a correlation between pd and cigarette smoking (p = 0.0242), blood hypertension (p < 0.001), erectile dysfunction (p < 0.001). no significant association was observed between diabetes and pd (p = 0.358). the median age of pd arm was 60 years and the median age of the control arm was 63,5 years; therefore the median age of pd arm resulted lower than the median age of the control arm (p = 0,031). conclusions: peyronie’s disease is more common than we might think; furthermore it can be diagnosed among young patients. according to our results, cigarette smoking and blood hypertension may be considered statically significant risk factors for developing pd. on the contrary diabetes seems not to be a risk factor for pd. according to our results pd should be sought also in young patients. further studies are necessary to confirm that removing the indicated risk factors may reduce the incidence of pd. key words: peyronie’s disease; age; diabetes; cigarette smoking; blood hypertension; erectile dysfunction; pain. submitted 18 december 2014; accepted 31 january 2015 summary no conflict of interest declared. introduction peyronie's disease (pd) is an andrological condition of unknown pathogenesis. the interest for such disease derives not only from its sexual, physical and psychological aspects but also from its undefined etiological, epidemiological,physiopathological aspects since it was described for the first time in 1743 by francois girot de la peyronie. these features of the disease have influenced also the treatment, nowadays not curative. the use and the success of oral therapies for erectile dysfunction (ed) in the last years have contributed to uncover the hidden sexual pathologies leading the patient to the specialist. however pd is underdiagnosed and the time between diagnosis and therapy is still excessive (1). pd seems to be a pathology of connective tissue, a disorder of the penile tunica albuginea that determines a scar or a palpable plaque, often in the dorsal surface of the penis that could determine a penile curvature and change of length and diameter of the penis during erection. the condition often associated to pd is the ed, but it is hard to understand if the ed is a consequence of penile fibromatosis or a psychological consequence to the altered body image linked to the penile curvature or to the pain during intercourse. the physiopathological theories for the disease are multiple: trauma during intercourse with an aberrant healing (2), genetic predisposition, autoimmune disorder, over-expression of pro-inflammatory cytokines (3) etc. probably the genesis of this disease is multi-factorial (4). there are no certainties even about therapies: nowadays a medical therapy does not exist with a tested clinical effectiveness. the surgical approach is recommended specially when the disease is stabilized, after 6-12 months from the first appearance of symptoms, when the acute inflammatory process is ended and there are no recent changes in penis deformity. however the surgical approaches are even burdened by limits (e.g. penis size reduction, possible relapse of the curvature, alteration of penile sensitivity and ed). the studies on the prevalence of pd are limited; the epidemiological data from literature are different for types of population studied and according to the different definition of the disease. the prevalence of pd in general population ranges between 0.39% (5) and 7.1% (6), but it goes up to 20.3% in diabetic patients with ed (7). the data on doi: 10.4081/aiua.2015.1.20 pavone2_stesura seveso 02/04/15 10:16 pagina 20 21archivio italiano di urologia e andrologia 2015; 87, 1 smoking, diabetes, blood hypertension: possible etiologic role for peyronie’s disease? possible epidemiological and symptomatic links in patients affected with pd and other comorbidities (diabetes and smoking habits) are multiple and there are no univocal conclusions. for these reasons the aim of our study was to evaluate the possible association of pd with other pathologies and life-styles in a cohort of 279 consecutive patients from central-western sicily who consulted our andrology outpatient clinic. materials and methods from october 2012 to november 2013 we recruited a sample of 279 consecutive male outpatients consulting our andrological outpatient clinic. the main diseases were: benign prostatic enlargement (bpe), erectile dysfunction (ed), varicocele, premature ejaculation (pe), lower urinary tract symptoms (luts), infertility, prostatitis and pd. the patients were divided into two arms: the first arm was composed by pd patients, the second arm was composed by patients with other diseases without signs and symptoms suggestive for pd and it was considered as control arm. inclusion criteria in the first arm were presence of a scar or a palpable plaque under penis surface; penis curvature; pain in erection or during intercourse with penile curvature, pd naive patients or with a previous diagnosis of pd. previous surgical treatment of pd was not considered an exclusion criteria. an accurate clinical history was recorded during the first visit, the presence of comorbidity was evaluated and an accurate physical examination was performed. a database including age, cigarette smoking, diabetes, blood hypertension and erectile function for each patient was created. validate questionnaires to analyze the ed status (iief-5) (8) and pain (vas) (9) were administered to the patients of pd arm. according to iief-5 five classes of ed were indentified: severe (5-7); mild (8-11); low-mild (12-16); low (17-21); normal (22-25). according to vas four classes of pain were identified: severe pain (8-10); mild pain (5-7); low-mild pain (2-4); low/no pain (0-1). all analysis was conducted using r software. to check on a relation among potential risk factors and pd an univariate analysis was performed using wilcoxon signedranks test for age and pearson x2 test for the other qualitative variables (diabetes, blood hypertension, smoking and erectile dysfunction). results a total number of 279 consecutive male patients was enrolled. among them, 59 (21%) patients had diabetes, 158 (57%) had blood hypertension, 178 (64%) were smokers and 128 (46%) had ed (table 1). the pd arm included 97 (34.7%) patients, the control arm included the remaining 182 (65.3%) patients. the median age was 60 (range 25-78 years) in the pd arm, and 63.5 (range 21-81 years) in the control arm (p = 0.031) (table 2). among the initial 279 patients, 128 (46%) had ed and 151 (54%) had no history of ed. among patients with ed, 67 (52%) had also pd, while among patients without ed the diagnosed patients with pd were 30 (20%) (p < 0.001). according to iief-5 the patients in the pd arm presented these scores: 0 patients severe; 7 (7.2%) patients mild; 23 (23.7%) patients low-mild; 37 (38.1%) patients low; 30 (30.9%) patients normal. the patients affected with pd who referred pain during erection were 65 (67%). according to vas the patients were divided in: 0 patients severe; 14 (14.4%) patients mild; 36 (37.1%) patients low-mild; 47 (48.4%) low/no pain (table 3). in our sample 178 (64%) patients were smokers and 101 (36%) were not smokers. among the smokers pd was diagnosed in 71 (40%) patients, while it was diagnosed in 26 (26%) patients among the not smoker ones (p = 0.024). one-hundred fifty-eight (57%) patients had blood hypertension and 121 (43%) referred normal blood prestable 1. basal characteristic of population. number of patients 279 (100%) diabetes yes 59 (21%) no 220 (79%) smoking yes 178 (64%) no 101 (36%) blood hypertension yes 158 (57%) no 121 (43%) erectile dysfunction yes 128 (46%) no 151 (54%) table 3. iief-5 and vas scores in pd population. iief-5 number of patients with percentage disease stratification severe (5-7) 0 mild (8-11) 7 (7,2%) low/mild (12-16) 23 (23,7%) low (17-21) 37 (38,1%) normal (22-25) 30 (30,9%) vas disease stratification severe (8-10) 0 mild (5-7) 14 (14,4%) low/mild (2-4) 36 (37,1%) low/no pain (0-1) 47 (48,4%) vas: visual analogue scale iief-5 = international index of erectile function 5. age median mean sd p-value pd arm 60 59,1 8,3 • 0,031 control arm 63,5 60,2 13,9 pd = peyronie’s disease table 2. summary of statistics demonstrating age influence on the presence or absence of pd. pavone2_stesura seveso 02/04/15 10:16 pagina 21 archivio italiano di urologia e andrologia 2015; 87, 1 c. pavone, f. d’amato, n. dispensa, f. torretta, c. magno 22 sure. among patients with blood hypertension pd was diagnosed in 69 (44%) patients; among patients with normal blood pressure it was diagnosed in 28 (23%) patients (p < 0.001). fifty-nine (21%) patients had diabetes and 220 (79%) were not diabetic. among diabetic patients pd was diagnosed in 24 (41%), while it was diagnosed in 73 (33%) of not diabetic patients (p = 0.358) (table 4). discussion in italy pathologies such as diabetes mellitus and blood hypertension are widely diffused. from a recent study published in 2012 the prevalence of diabetes in a region of italy is shown to rise from 3.0% in 2000 to 4.2% in 2007 (40% more in only 7 years). the incidence shows a rate of 4 cases per 1000 per year (10). in other italian regions higher prevalence values are published (11). the overall prevalence of blood hypertension is about 24.4% in a population of three european macro-areas; among them, a third was under antihypertensive treatment, but a significant rate (56%) was unaware of high levels of blood pressure. the prevalence in the region of abruzzo was 28.87% (12). in italy the current smokers are the 21.7% (22.7% in 2011 and 20.8% in 2012) of general population (13). despite diabetes the trend of the habit of smoking is in a weak but progressive decrease so that, maintaining constant the ratio between those who start to smoke and those who quit, the prevalence at the end of next three decades is going to stabilize at 12.1% for women and 20.3% for men (14). a definite analysis of prevalence of pd is impossible because of different definitions of disease, poor knowledge of disease also in health sector and patients’ reluctance to show this condition. the epidemiologic data are extremely variable and depend mostly on methods of enrolling patients, on geographic differences and on characteristics of population chosen as sample. the prevalence of the disease seems to be directly proportional to ageing (6). in our study a lower median age is shown in the pd arm compared to control group (p = 0.031) (table 2). this data may indicate that in our sample the diagnosis is not related to ageing and therefore the disease should be sought also in young patients. in one of the most quoted studies about this argument, the prevalence of pd in general population of rochester (minnesota, usa) is 0.39%. blood hypertension was the most associated disease in patients with pd, nevertheless no difference in the prevalence of diabetes was highlighted in the ill population in comparison to local general population (5). diabetes, nevertheless, is one of the diseases mostly associated to pd in different studies. in another study (sommer et al, 2002) the prevalence of patients affected with pd in the population of the area of koln (germany) is 3.2%. in this report the percentage of diabetic patients with pd was 18.3% versus 6% of diabetic patients without pd. the 40.8% of patients with pd had also ed. no further correlation between pd and other disorders or life-style (e.g. smoking) was demonstrated (15). in the study by arafa et al. (2007) the prevalence of pd among patients with diabetes and ed is 20.3%. a significant correlation was found between pd and age, obesity and smoking. moreover all the patients with pd presented ed (7). the diabetes might condition the gravity of the disease because it would worsen the micro-circulation of penis and determine a considerable fibrotic process due to disease (16-17). in our survey among the 59 patients with diabetes the pd patients were 24 (41%), while among 220 without diabetes the pd patients were 73 (33%). in spite of a higher percentage of disease in diabetic patients demonstrated in our study, no statically significant difference between pd arm and control arm was shown (p = 0.358). therefore the diabetes would not be associated to the disease and its absolute prevalence among pd patients might be casual or dependent from confounding external factors. the percentage of pd among the 128 patients with ed is 52%, while the percentage of pd patients among the 151 without ed is lower (20%) (p < 0.001); according to the data of literature in our survey a statistically significant association between pd and ed was evident; the analysis of results obtained administering the iief-5 to affected patients demonstrated that most of patients with pd had ed from low to mild gravity; however it was not possible to establish if ed was a consequence of pd and to quantify how the pd affected the erectile function. the only italian multicentric study (la pera et al, 2001) reports a prevalence of pd in general population of 7.1%, with a significant correlation between smoking and diagnosis of pd. no significant correlations with other diseases (cardiovascular, diabetes, alcoholic abuse) were found (6). in our survey among the 178 smokers the patients affected with pd were 71 (40%), while among the 101 not smokers the pd patients were 26 (26%). according to data presented in literature these percentages resulted statistically significant and therefore smoking could be considered an important risk factor for pd and consequentially a lifestyle to evaluate during anamnestic work-up of pd patients (p = 0.024). however the high rate of statistical association between smoke and pd did not explain how smoking habit may influence the pathogenesis of disease and the macroscopic alterations caused. in a study by el sakka (2006) the prevalence of pd in patients with ed is 7.9%, with a table 4. percentages of patients with pd disease in relation to risk factors. pd patients p-value diabetes yes 24 (41%) 0,358 no 73 (33%) smoking yes 71 (40%) 0,0242 no 26 (26%) hypertension yes 69 (44%) < 0,001 no 28 (23%) erectile dysfunction yes 67 (52%) < 0,001 no 30 (20%) pavone2_stesura seveso 02/04/15 10:16 pagina 22 23archivio italiano di urologia e andrologia 2015; 87, 1 smoking, diabetes, blood hypertension: possible etiologic role for peyronie’s disease? significant association between pd and other typical risk factors of ed such as obesity, age, smoking habit, and conditions like diabetes, hypercholesterolemia and psychological disorders (18). in a study by mulhall et al. (2004) the prevalence of patients with pd in a population screened for prostate cancer was 8.9% with coexistence of conditions such as blood hypertension and diabetes in the population with pd (19). in our sample among the 158 patients with blood hypertension 69 (44%) had pd, while among the 121 patients without blood hypertension the patients not affected with pd were 28 (23%); therefore the percentage of pd and blood hypertension patients is nearly twofold of the percentage of pd patients without blood hypertension (p < 0.001). this result, as mulhall’s study reported, could show a very strong association between pd and blood hypertension. blood hypertension could be considered an important risk factor for pd and consequentially a clinical parameter to evaluate during diagnostic work-up of pd patients. blood hypertension and smoking are shown to be differently associated to pd, even though the etiological and pathophysiological factors of this association are unknown. our study was not an epidemiological prevalence study, although the percentage (34.7%) of pd patients in a series of consecutive outpatients during an year was a relevant data; this condition is still probably underestimated, as an autoptic study showed (20). the analysis of vas demonstrated that 67% of patients with pd had pain during erection: this not less important aspect showed how the disease may cause a very frequent painful symptomatology. conclusions pd is more common than we might think. the social and cultural changes in italian population, in primis the progressive use of treatment for ed, probably are going to determinate a higher prevalence of the disease in the future. according to our results smoking habit and blood hypertension are shown to be potential risk factors for pd; despite some studies diabetes would not be shown to be related with the onset of disease. in the literature the prevalence of pd seems to be related to ageing; on the other hand, our results suggest that the age of disease onset could be not so advanced, therefore the presence of the disease should be evaluated also among young patients. erectile dysfunction is frequently associated to the disease and it is often the reason why patients consult a physician as well as for the pain. pain during erection, even though not so important in our sample, is widely diffuse among pd patients and influences their sexual and relational lives. in our opinion this study has two biases, the small number of patients and the lack of information about the diabetic patients (type 1 or type 2, treated or untreated); these biases do not allow to make definitive conclusions about association between pd and its potential risk factors: further studies are necessary to confirm if smoking and blood hypertension have a causal relationship for determining the pd condition. the frequent association showed between these pathologies and abuse conditions should lead the physician to evaluate also the possible sexual dysfunctions not revealed by the patients. in a study of 2011, 11420 american over 18 years men were enrolled in an online interview about pd symptoms, previous diagnosis or treatment for pd. the prevalence of the disease ranges from 0.5% (diagnosis of pd) to 13% (diagnosis, treatment and symptoms of pd), but the most interesting data is that among people who asked for a therapy, 74% did not obtain any treatment from the first physician and 92% did not obtain diagnosis of pd (1). therefore a better understanding of the symptoms and signs of the disease are desirable, especially among general practitioners, to avoid to underestimate a pathology of high impact on the relational psychological life. smoking cessation and blood pressure control could be precautions to reduce the incidence and recurrence of pd in the general population. references 1. dibenedetti db, nguyen d, zografos l, et al. a population-based study of peyronie's disease: prevalence and treatment patterns in the united states. adv urol. 2011. volume 2011, article id 282503, 9 pages doi:10.1155/2011/282503. epub 2011 oct 23. 2. perimenis p, athanasopoulos a, gyftopoulos k, et al. peyronie’s disease: epidemiology and clinical presentation of 134 cases. int urol nephrol. 2001; 32:691-4. 3. pavone c, caruana g, abbadessa d, et al. cytokine gene expression in the tunica albuginea of patients with peyronie's disease. pilot study with a control group. urologia. 2012; 79:189-96. 4. mulhall jp. expanding the paradigm for plaque development in peyronie’s disease. international journal of impotence research. 2003; 15:96-102. 5. lindsay mb, schain dm, grambsch p, et al. the incidence of peyronie’s disease in rochester, minnesota, 1950 through 1984. j urol. 1991; 146:1007-1009. 6. la pera g, pescatori es, calabrese m, et al. peyronie’s disease: prevalence and association with cigarette smoking: a multicenter population-based study in men aged 50-69 years. eur urol. 2001; 40:525-530. 7. arafa m, eid h, el-badry a, et al. the prevalence of peyronie’s disease in diabetic patients with erectile dysfunction. int j impot res. 2007; 19:213-217. 8. rhoden el, telöken c, sogari pr, vargas souto ca. the use of the simplified international index of erectile function (iief-5) as a diagnostic tool to study the prevalence of erectile dysfunction. int j impot res. 2002; 14:245-50. 9. williamson a, hoggart b. pain: a review of three commonly used pain rating scales. j clin nurs. 2005; 14:798-804. 10. monesi l, baviera m, marzona i, et al. prevalence, incidence and mortality of diagnosed diabetes: evidence from an italian population-based study. diabet med. 2012; 29:385-92. 11. ballotari p, chiatamone ranieri s, vicentini m, et al. building a population-based diabetes register: an italian experience. diabetes res clin pract. 2014; 103:79-87. 12. costanzo s, di castelnuovo a, zito f, et al. prevalence, awareness, treatment and control of hypertension in healthy unrelated pavone2_stesura seveso 02/04/15 10:16 pagina 23 archivio italiano di urologia e andrologia 2015; 87, 1 c. pavone, f. d’amato, n. dispensa, f. torretta, c. magno 24 male-female pairs of european regions: the dietary habit profile in european communities with different risk of myocardial infarction-the impact of migration as a model of gene-environment interaction project. j hypertens. 2008; 26:2303-11. 13. gallus s, lugo a, colombo p, et al. smoking prevalence in italy 2011 and 2012, with a focus on hand-rolled cigarettes. prev med. 2013; 56:314-8. 14. carreras g, gorini g, gallus s, et al. predicting the future prevalence of cigarette smoking in italy over the next three decades. eur j public health. 2012; 22:699-704. 15. sommer f, schwarzer u, wassmer g, et al. epidemiology of peyronie’s disease. int j impot res. 2002; 14:379-383. 16. kendirci m, trost l, sikka sc, hellstrom wj. diabetes mellitus is associated with severe peyronie’s disease. bju int. 2007; 99:383-6. 17. tefekli a, kandirali e, erol b, et al. peyronie’s disease: a silent consequence of diabetes mellitus. asian j androl, 2006; 8:75-9. 18. el-sakka ai. prevalence of peyronie’s disease among patients with erectile dysfunction. eur urol. 2006; 49:564-569. 19. mulhall jp, creech sd, boorjian sa, et al. subjective and objective analysis of the prevalence of peyronie’s disease in a population of men presenting for prostate cancer screening. j urol. 2004; 171:2350-2353 20. smith bh. subclinical peyronie’s disease. am j clin path. 1969; 52:385-390. correspondence pavone carlo, md carlo.pavone@unipa.it d’amato francesco, md (corresponding author) resident fdamato85@yahoo.it dispensa nino, md dispensa@libero.it section of urology, department of surgical, oncological and stomatological sciences, aoup “p. giaccone”, university of palermo via del vespro 129 90127 palermo, italy torretta federico, md federico.torretta@unipa.it department of economics and statistics (dseas), university of palermo viale delle scienze, ed. 13 90128 palermo, italy magno carlo, md cmagno@unime.it unit of urology, department of human pathology, aou “g. martino”, university of messina via consolare valeria 1 98125 messina, italy pavone2_stesura seveso 02/04/15 10:16 pagina 24 stesura seveso 387archivio italiano di urologia e andrologia 2014; 86, 4 case report prolonged antibiotic therapy increases risk of infection after transrectal prostate biopsy: a case report after pancreasectomy and review of the literature guevar maselli, giacomo tucci, daniele mazzaferro, asim ettamimi, giulia sbrollini, marco cordari, gaetano donatelli, andrea benedetto galosi division of urology, “augusto murri” general hospital, asur marche, fermo, italy. infection due to prostate biopsy afflicted more than 5% of patients and is the most common reason for hospitalization. a large series from us seer-medicare reported that men undergoing biopsy were 2.26 times more likely to be hospitalized for infectious complications within 30 days compared with randomly selected controls. the factors predicting a higher susceptibility to infection remain largely unknown but some authors have higlighted in the etiopathogenesis the importance of the augmented prevalence of ciprofloxacin resistant variant of bacteria in the rectum flora. we present one case of sepsis after transrectal prostate biopsy in a patient with history of pancreatic surgery. based on our experience patients candidated to prostate biopsy with transrectal technique with history of recent major surgery represent an high risk category for infective complication. also major pancreatic surgery should be consider an high risk category for infection. a transperineal approach and preventive measures (such as rectal swab) should be adopted to reduce biopsy driven infection. key words: prostate; biopsy; infection; sepsis; abdominal surgery. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. antibiotics presented 9 days after 12 core transrectal prostate biopsy. ciprofloxacin 1000 mg extended release was given before biopsy according local guidelines (4), preoperative urine culture was negative. the patient was submitted in the june 2013 to cephalo-pancreatic-duodenectomy and reconstructive surgery due to a carcinoma of vater papilla; surgical recovery was complicated by infection and treated with attention. during hospitalization he was treated with prolonged antibiotics (imi penem-cilastatin). we consider a review of the literature to establish factors associated with higher susceptibility to infection and to highlight possible relationship between pancreatic surgery and risk of infective complications during prostate biopsy. pubmed search was performed using key words: prostate biopsy; urosepsis; pancreatitis and pancreatic surgery, 76 papers were retrieved and 25 were considered as pertinent to our aim. result the infective course showed 2 episodes of recurrence with fever and urine culture positive for e. coli with multidrug resistant. the first hospital admission: after an empiric therapy with ciprofloxacin the patient was treated with i.v. association (ceftriaxone and piperacillintazobactam) for 10 days, then discharged with oral antibiotics. after 15 days, the second hospital admission was due to fever (39°c) and urinary symptoms and the hospital stay was 5 days. transrectal ultrasound was negative for abscess or significant post-void urinary residue. a second cycle of i.v. antibiotic association (ceftriaxone and piperacillin-tazobactam) resolved the fever. further follow-up was uneventful. discussion several reports have recently suggested an increased rate of infective complications following transrectal prostate biopsy in both north america (5) and europe (6). the reasons for this increase and the factors associated with a higher susceptibility to infection remain largely unknown. based on our experience, candidates to transrectal prostate biopsy with anamnesis of recent major doi: 10.4081/aiua.2014.4.387 presented at 19th national congress sieun, fermo 2014 introduction prostate biopsy presents a significant percentage of complication. the infection afflicted more than 5% of patients submitted to prostate biopsy (1) and is the most common reason for hospitalization for prostate biopsy (2, 3). the factors predicting a higher susceptibility to infection remain largely unknown but some authors have highlighted in the etiopathogenesis the importance of augmented prevalence of ciprofloxacin resistant bacterial strains (e. coli) in the rectum flora. we present one case of sepsis after transrectal prostate biopsy in patient with history of pancreatic surgery due to a carcinoma of vater papilla. material and methods a 53 years-old men was admitted in january 2014 by access in emergency ward with fever not responsive to maselli_stesura seveso 16/01/15 11:34 pagina 387 archivio italiano di urologia e andrologia 2014; 86, 4 g. maselli, g. tucci, d. mazzaferro, a. ettamimi, g. sbrollini, m. cordari, g. donatelli, a.b. galosi 388 surgery represent an high risk category for infective complication. so this category should be consider to reducing risk of sepsis by bacteria resistant to the common antibiotics adopted in prophylaxis. a transperineal approach should be chosen for this reason in such cases. in prospective multinational study on infective complications after prostate biopsy florian et al. (7) supports the findings that the presence of fecal fluoroquinolone-resistant bacteria is the most important risk factor. strategies to identify fluoroquinolone-resistant bacteria should be sought so as to decrease infective complications. multivariate analysis did not identify any patient subgroups with a significantly higher risk of infection after prostate biopsy. causative organisms were isolated in 10 cases (37%) with 6 resistant to fluoroquinolones. fluoroquinolone resistance has increased globally, and the presence of fluoroquinoloneresistant organisms on rectal swab culture is a significant predictor of infection after prostate biopsy (8). a rectal swab has been proposed at the visit preceding prostate biopsy and is plated on macconkey agar containing ciprofloxacin (9). patients with ciprofloxacin sensitive bacteria can then receive ciprofloxacin prophylaxis, while culture results can guide an alternative selection for those with resistance. a few non-randomized studies have examined the results of targeted prophylaxis with results in accordance. to date, there are no randomized studies showing that targeted prophylaxis using rectal swabs results reduces infection and cost compared with standard or expanded prophylaxis. in the specific population represented by patient afflicted with acute necrotic pancreatitis result changing the bowel, like alteration of ph, that conduce to a selection in some germs (e.g.: e. coli) to the disadvantage of the usual dominant microorganism (bifidus). this may represent the cause of an increased growth of opportunist pathogenous (10). besides the exposition to prolonged antibiotic prophylaxis or prolonged antibiotic therapy (like is usual in patient submitted to major surgery) is the cause of the selection of species drug resistant (11). it not well understood if the change in enteric-biliar circule resulting by pancreatic surgery could be also a cause of the develop of drug resistence of the enteric flora. therefore in this patient group it may be useful to perform a fecal swab before transrectal prostate biopsy to verify bacterial resistence and consider an adequate antibiotic prophylaxis alternative to fluoroquinolones. history of a previous surgery of the pancreas with consequent exposure to prolonged antibiotic therapy might suggest to use transperineal approach to perform prostate biopsy for reduce dissemination of bacteria present in the rectum. the prolonged antibiotic therapy performed after prosthetic or major surgery changes the enteric flora and select multi-resistant strains (12). literature does not investigate if the enterohepatic bile alteration secondary to pancreatic surgery could further contribute to antibiotic resistance of the bacteria flora. conclusion prolonged antibiotic therapy associate with major pancreatic surgery may increase the risk of infective complications after prostate biopsy. this result is linked to fecal fluoroquinolone-resistant bacteria that increase after prolonged antibiotic therapy. the transperineal approach should be considered in this category of patients. in addition preoperative rectal swab are suggested to identify antibiotic resistance in bacterial strains. references 1. loeb s, carter hb, berndt si, et al. complications after prostate biopsy: data from seer-medicare. j urol. 2011; 186:1830-4. 2. stacy loeb, annelies vellekoop, hashim u. ahmed, et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-892. 3. williamson da, roberts sa, paterson dl, et al. escherichia coli bloodstream infection after transrectal ultrasound-guided prostate biopsy: implications of fluoroquinolone-resistant sequence type 131 as a major causative pathogen. clin infect dis 2012; 54:1406-12. 4. martino p, galosi ab, bitelli m, et al. imaging working groupsocietà italiana urologia and società italiana ecografia urologica andrologica nefrologica. practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. 5. wolf js j, bennett cj, dmochowski rr, et al. urologic surgery antimicrobial prophylaxis best practice policy panel. best practice policy statement on urologic surgery antimicrobial prophylaxis. american urological association web site. www.auanet.org/content/clinicalpracticeguidelines/clinicalguidelines. updated 2012. 6. grabe m, bjerklund-johansen te, botto h, et al. guidelines on urological infections. european association of urology web site. www.uroweb.org/gls/pdf/17_ urological%20infections_lr%20ii. pdf. updated 2012. 7. florian me wagenlehner, edgar van oostrum, et al. infective complications after prostate biopsy: outcome of the global prevalence study of infections in urology (gpiu) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. eur urol. 2013; 63:521-7. 8. williamson da, masters j, freeman j, roberts s. travel-associated extended-spectrum beta-lactamase-producing escherichia coli bloodstream infection following transrectal ultrasound-guided prostate biopsy. bju int. 2012; 109:e21-2. 9. duplessis ca1, bavaro m, simons mp, et al. rectal cultures before transrectal ultrasound-guided prostate biopsy reduce post-prostatic biopsy infection rates. urology. 2012; 79:556-61. 10. wu ct, li zl, xiong dx. relationship between enteric microecologic dysbiosis and bacterial translocation in acute necrotizing pancreatitis. world j gastroentero, 1998; 4:242-245. 11. taylor s1, margolick j, abughosh z, et al. ciprofloxacin resistance in the faecal carriage of patients undergoing transrectal ultrasound guided prostate biopsy. bju int. 2013; 111:946-53. 12. walder m, leandoer l, törnqvist a, forsgren a. long-term ef fects on bacterial sensitivity patterns of preoperative antibiotic pro phylaxis in colorectal surgery. scand j infect dis. suppl. 1988; 53:59-64. correspondence guevar maselli, md, urologist (corresponding author) guevarmaselli@katamail.com giacomo tucci, md tucci.giacomo@virgilio.it daniele mazzaferro, md, urologist mazzaferro.dr@gmail.com asim ettamimi, md ettamimi.asim@tiscali.it giulia sbrollini, md, resident in urology giuliasbrollini@libero.it marco cordari, md, urologist, m.cordari@tin.it gaetano donatelli, md, urologist g.donatelli@als11.marche.it andrea benedetto galosi, md, phd, urologist galosiab@yahoo.it division of urology, “augusto murri” general hospital, asur marche, fermo, italy maselli_stesura seveso 16/01/15 11:34 pagina 388 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3154 introduction prostatic abscess is uncommon and difficult to diagnose because initial clinical presentation may mimic several other diseases of the lower urinary tract. the incidence of prostatic abscess has markedly decreased because of the widespread use of antibiotics and the decreased incidence of gonococcal urethritis. in the forties, mortality ranged from 6% to 30%, and major microorganism involved was neisseria gonorrhea (1). more recent data suggests a mortality rate from 3% to 16% (2), enterobacteriacae being the most common agents. among these, escherichia coli has the highest prevalence, in about 70% of the cases (3). in this paper we report a case of prostatic abscess treated in our department and review the literature as far as the clinical presentation, diagnostic modalities and management is concerned. case report a 52-year-old male presented at the emergency department of our hospital with dysuria, high fever, chills, perineal pain and poor general condition. a few days before he visited a private urologist who diagnosed acute prostatitis with urine culture positive for e. coli. he received ciprofloxacin and although there was an improvement at the beginning, the symptoms recurred. he was a known diabetic patient. on physical examination, his blood pressure, pulse rate case report prostatic abscess: case report and review of the literature orestis porfyris, paraskevas kalomoiris urology department, general hospital of sparta, sparta, greece. we report a case of prostatic abscess in a 52 year old male with a history of diabetes mellitus. the abscess was treated successfully with surgical drainage by transurethral unroofing of the cavity of the abscess. the use of transrectal ultrasound is valuable in the diagnosis, treatment and follow up of the abscess, while drainage is usually necessary for the treatment, which can be done by transrectal, transperineal and transurethral route. key words: abscess; prostate; drainage. submitted 2 april 2013; accepted 31 may 2013 no conflict of interest declared summary and temperature were 130/80mmhg, 95 per minute and 39° c, respectively. at rectal examination, the prostate was tender and enlarged with a fluctuating area between the two lobes. urine and blood cultures were obtained prior to starting antibiotic therapy. transabdominal ultrasonography of the prostate showed a hypoechoic area. transrectal ultrasonography showed two hypoechoic areas, one in the right and one in the left lobe (figure 1). computed tomography scan revealed two hypodense, homogenous areas with size 3 x 3,5 cm, in the same region of the prostate (figure 2). the patient was treated with ciprofloxacin, amikacin and metronidazole intravenously. under ultrasonography guidance the abscess was drained transrectally. about 7 ml of pus were obtained and its culture showed klebsiella pneumoniae. the same agent was found in blood cultures as well. during follow up the same procedure was repeated due to incomplete emptying of the abscess cavities. finally it was decided that the patient should have a transurethral drainage of the abscess. the simultaneous use of transrectal ultrasound confirmed the complete drainage of the abscess. the postoperative recovery of the patient was normal and on the 6th day after the tur the patient was discharged. one month later, the patient was symptom free, the urine culture was negative and the transrectal ultrasound appeared normal (figure 3). doi: 10.4081/aiua.2013.3.154 155archivio italiano di urologia e andrologia 2013; 85, 3 prostatic abscess: case report and review of the literature discussion prostatic abscess is an infrequent condition in the modern antibiotic era with an incidence of 0.5% to 2.5% of diseases accompanying prostatic symptoms (4). it can occur in patients of any age (including neonates) but is mainly found in men in their 5th and 6th decade of life (2). predisposing factors for the development of prostatic abscess are diabetes mellitus, bladder outlet obstruction, indwelling catheter, biopsy of prostate, chronic renal failure, haemodialysis, chronic liver disease and hiv infection (5,6). as far as pathogenesis is concerned, it is the retrograde flow of contaminated urine during micturition into prostatic ducts that promotes the formation of microabscesses that coalesce and form prostatic abscesses (3). it is already mentioned that e. coli and enterobacteriacae are the most prevalent bacteria in prostatic abscess. nevertheless, as the number of immunocompromised patients increase, atypical pathogens may be found, like mycobacteria, fungi, anaerobes and in case of haematogenous spread from distant foci, staphylococcus aureus (7). clinical manifestation of the disease includes dysuria, urgency and frequency in 96% of the cases, fever in 30% to 72% of the cases, perineal pain in 20% of the cases and urinary retention in 1/3 of the cases (1, 2, 4). the most typical sign of prostatic abscess is a fluctuating area in the prostate palpated by digital examination, although this finding is observed in 16% to 88% of the patients (1,2). in case of improper treatment or delayed diagnosis possible complications are the spontaneous rupture of the abscess and fistula formation towards the urethra, bladder, perineum and rectum and also septicemia with mortality rate between 3% and 16% (4). figure 1. transrectal ultrasound showing prostatic abscess with two cavities. figure 3. transrectal ultrasound 1 month after transurethral resection. figure 2. ct scan depicting the prostatic abscess. archivio italiano di urologia e andrologia 2013; 85, 3 o. porfyris, p. kalomoiris 156 the diagnostic study of choice to assist the treatment and follow up of patients with prostatic abscess is transrectal ultrasonography. the most common finding is one or more hypoechogenic lesions, of different sizes, located in the transitional or central zone of the prostate and surrounded by a hyperechogenic halo, that can cause distortion of the anatomy of prostate gland (8). color and power doppler sonography show a high perilesional vascularity. differential diagnosis includes neoplasias, cystic lesions, granulomas and acute prostatitis. ct scan and mri scan usually add few information as far as diagnosis is concerned. they are useful at the estimation of the extent of the abscess in the periprostatic tissues, at the detection of gas in the fluid of abscess and when extensive types of procedures are being planned after patient diagnosis (8). the treatment consists of parenteral broad-spectrum antibiotic administration and abscess drainage. due to the rareness of the disease there are no specific guidelines for the treatment of prostatic abscess. the administration of antibiotic agents by itself is effective in limited cases, such as monofocal abscess less than 1 cm in diameter. usually surgical intervention is required, which can be done under ultrasound guidance by transrectal (9, 10) or transperineal route (11, 12). these procedures are easy to perform under local anaesthesia, have low morbidity and can be repeated in case of failure. the culture of pus that is aspirated is important because pathogens isolated are often different from those found in urine culture. this can result in modification of antibiotic treatment. several authors recommend the insertion of drainage tubes (e.g. nephrostomy tubes) in the abscess cavity for achieving better drainage (10, 12). when the abscess recurs or cannot be completely evacuated, transurethral unroofing is a more appropriate approach, leading to better drainage of the abscess cavity with early recovery of the patient (7, 9). although there is a theoretical danger of haematogenous spread of the pathogen during transurethral resection, the use of preoperative broad-spectrum antibiotics prevents the occurrence of septicemia. finally, in very few cases, open surgical drainage may be indicated mainly in those patients with extraprostatic involvement (7). conclusion prostatic abscess should be suspected in patients presenting with fever and persistent voiding symptoms despite proper antibiotic treatment, in diabetics and those with a disease that causes immunodeficiency. it is important to rapidly establish a definitive diagnosis because mortality rate remains high. surgical drainage is usually required, even with minimal invasive techniques, but the optimal therapeutic modality for each patient should be individualized, aiming to prompt control of symptoms and early recovery. references 1. weinberger m, cytron s, servadio c, et al. prostatic abscess in the antibiotic era. rev infect dis. 1988; 10:239-49. 2. granados ea, caffaratti j, farina l, hocsman h. prostatic abscess drainage: clinical-sonography correlation. urol int. 1992; 48:358-61. 3. meares em, jr. prostatic abscess. j urol. 1996; 129:1281-2. 4. granados ea, riley g, salvador j, vincente j. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-2. 5. olivieira p, andrade ja, porto hc, et al. diagnosis and treatment of prostatic abscess. int braz j urol. 2003; 29:30-34. 6. trauzzi sj, kay cj, kaufman dg, lowe fc. management of prostatic abscess in patients with human immunodeficiency syndrome. urology. 1994; 43:629-33. 7. ludwig m, scroederprintzen i, schiefer hg, weidner w. diagnosis and therapeutic management of 18 patients with prostatic abscess. urology. 1999; 53:340-5. 8. barozzi l, pavlica p, menchi i, et al. prostatic abscess: diagnosis and treatment. ajr. 1998; 170:753-757. 9. collado a, palou j, garcia-penit j, et al. ultrasound-guided needle aspiration in prostatic abscess. urology. 1999; 53:548-52. 10. aravantinos e, kalogeras n, zygoulakis n, et al. ultrasound-guided transrectal placement of a drainage tube as therapeutic management of patients with prostatic abscess. j endourol. 2008; 22:1751-4. 11. bachor r, gottfried hw, hautmann r. minimal invasive therapy of prostatic abscess by transrectal ultrasound-guided perineal drainage. eur urol. 1995; 28:320-4. 12. basiri a, javaherforooshzadeh a. percutaneous drainage for treatment of prostate abscess. urol j. 2010; 7:278-80. correspondence orestis porfyris, md (corresponding author) orestisporfyris@yahoo.gr epia thourias 24009 kalamatan, greece paraskevas kalomoiris, md diy@hospspa.gr vrasidou 156 23100 sparta, greece stesura seveso archivio italiano di urologia e andrologia 2015; 87, 2136 original paper influence of antiplatelet-anticoagulant drugs on the need of blood components transfusion after vesical transurethral resection alvaro julio virseda-rodríguez 1, barbara padilla-fernández 2, mirian lópez-parra 3, maria tatiana santos-antunes 4, lauro sebastian valverde-martínez 1, maria jesus nieto-gonzález 3, jesus fernando san miguel-izquierdo 5, anabel lorenzo-gómez 4, maria begoña garcía-cenador 4, patricia antúnez-plaza 6, maria fernanda lorenzo-gómez 1,4 1 department of urology, university hospital of salamanca; 2 department of urology, university hospital of the canary islands (tenerife); 3 department of haematology, university hospital of salamanca; 4 department of surgery, university of salamanca; 5 clinical and translational medicine of the university of navarra; 6 department of pathology, university hospital of salamanca; university hospital of salamanca. surgery department of the university of salamanca. ibsal (instituto de investigación biomédica de salamanca). aims: the effect of the antithrombotic preventive therapy on haemorrhage keeps uncertain. we investigate the influence of the antiplatelet and anticoagulant drugs (ap/ac drugs) on the transfusion requirement after vesical transurethral resection (vtur). we also describe the epidemiology of the blood components transfusion in our department. materials and methods: retrospective observational study of a series of patients needing blood transfusion at the urology department between june 2010 and june 2013. selection of 100 consecutive patients who were transfused after vtur due to bladder transitional cell carcinoma (btcc) (group a = ga). control group: 100 consecutive patients who underwent vtur due to btcc and were not transfused (group b = gb). transfusion criteria: haemoglobin < 8 g/dl + anaemia symptoms. age, gender, associated ap/ac treatment, secondary diagnoses, toxics, tumour stage and grade were analysed. results: 212 patients required transfusion of a blood component. 169 were men (79%) and 43 women (21%). median age 77.59 years (sd 9.42, range 50-92). secondary diagnoses: diabetes mellitus 64%, high blood pressure 77%, dyslipidemia 52%. 60% of patients were previously treated with ap/ac drugs. average haemoglobin pre-transfusion values: 7.4 g/dl (de ± 0.7). average haemoglobin post-transfusion values: 8.9 g/dl (de ± 0.72). most frequent transfusion indications were bladder cancer (37%), kidney cancer (11%), prostate cancer (8%), benign prostatic hyperplasia (bhp) (8%), other urological diagnoses (36%). intraoperative transfusions indicated by the anaesthesiologist: kidney cancer (33%), bph (28%). patients who underwent vtur due to btcc were older in ga (77.59 years sd 9.42) than in gb (68.98 years sd 11.78) (p = 0.0001). similar gender distribution (15 women in ga and 24 in gb). less patients were asked to keep their treatment with asa 100mg (acetylsalicylicacid) in ga (25.64%) than in gb (50%) (p = 0.0330). more aggressive tumour grade in ga (p = 0.0003) and higher stage in ga (p = 0.0018) regardless of concomitant treatment with ap/ac drugs. conclusions: the pathologies which most needed blood components' transfusions in the urology department were (in order of frequency): bladder cancer, kidney cancer, prostate cancer, prostate adenoma. asa100mg did not influence the transfusummary no conflict of interest declared. introduction the urologic surgery is considered as having a high haemorrhagic risk. the development of several blood components in the last decades has changed the management of multiple pathologies and has increased the survival of millions of patients. haematuria with anaemia which requires blood transfusion is considered a surgical complication in the recording codes of the hospital processes. there are in the market several antiplatelet and anticoagulant drugs (ap/ac) which are frequently part of the regular treatment of many urological patients. other specialists (haema tologists, cardiologists, anaesthesiologists,...) prescribe withdrawal and reintroduction standards when a vesical transurethral resection (vtur) is required. we investigated the factors which could condition the transfusion requirement in patients taking ap/ac drugs. aims of the study were: to describe the number of transfusions performed in a "standard" urology department attending to 333,000 inhabitants and their indication and to investigate the risk factors related with the blood transfusion requirements in patients who underwent vtur due to bladder transitional cell carcinoma (btcc). doi: 10.4081/aiua.2015.2.136 sion's requirements in vtur due to btcc. tumour stage and higher grade have a greater influence in transfusion's requirements than concomitant ap/ac treatment. the heterogeneity of ap/ac protocols does not allow to establish the benefit of stopping those drugs before surgery in terms of avoiding blood transfusions when performing a vtur. key words: transurethral resection; bladder transitional carcinoma; blood transfusion. submitted 23 december 2014; accepted 28 january 2015 virseda _stesura seveso 02/07/15 11:22 pagina 136 137archivio italiano di urologia e andrologia 2015; 87, 2 influence of antiplatelet -anticoagulant drugs on the need of blood components transfusion after vesical transurethral resection materials and methods in order to reach the aims of the study, we have selected two series of patients and carried out two independent retrospective observational studies: • series of patients needing blood transfusion at the urology department between june 2010 and june 2013. • selection of 100 consecutive patients who were transfused after vtur due to bladder transitional cell carcinoma (btcc) (group a = ga) between june 2008 and june 2013. control group: 100 consecutive patients who underwent vtur due to btcc and were not transfused (group b = gb) at the same period. the same transfusion criteria are applied for all patients: haemoglobin < 8 g/dl + anaemia symptoms. age, gender, associated ap/ac treatment, second diagnoses, toxics, tumour stage and grade were analysed. descriptive statistics, student's t-test, fisher's exact test, anova were utilized and p < 0.05 was considered significant. results 212 patients required transfusion of a blood component when admitted at the urology department during the period of the study. 169 were men (79%) and 43 women (21%). median age 77.59 years (sd 9.42, range 50-92). secondary diagnoses: diabetes mellitus 64%, high blood pressure 77%, dyslipidemia 52%. 60% of patients were previously treated with ap/ac drugs. transfusion was indicated with an average haemoglobin pre-transfusion value of 7.4 g/dl (de ± 0.7). the average haemoglobin posttransfusion value was 8.9 g/dl (de ± 0.72). the most frequent transfusion indication was bladder cancer (37%), followed by kidney cancer (11%). prostate cancer and benign prostatic hyperplasia (bph) share the third place (8% each) (figure 1). table 1 shows the distribution of those indications which required blood components' transfusion at the urology department (table 1). most intraoperative transfusions indicated by the anaesthesiologist were due to kidney cancer (33%) and bph (28%) (table 2). n % m % w % bladder cancer 79 37.3 55 68 24 32 kidney cancer 24 11.9 13 54 11 46 prostate cancer 17 8.7 17 100 0 0 bph 17 8.7 17 100 0 0 stones 3 1.1 1 33 2 66 intra abdominal abscess 3 1.1 2 66 1 33 urinary tract cysts 2 0.94 1 50 1 50 haematuria as admission diagnosis at the emergency department 36 16.98 23 63.1 13 36.9 gross haematuria at the emergency department with concomitant ap/ac 27 74.9 14 53.1 13 46.9 with final diagnosis after discharged at the first admission total 19 52.3 13 64.2 6 35.8 bladder cancer 9 25 7 77 2 23 bph 4 11 4 100 kidney cancer 3 8.3 2 66.6 1 33.4 other 3 8.3 2 66.6 1 33.4 without final diagnosis after discharged at the first admission total 17 47.7 9 52 8 48 anticoagulated 13 76.2 7 54 6 46 not-anticoagulated 4 23.8 1 33 3 66 m: men; w: women. table 1. distribution of those indications which required blood components' transfusion at the urology department. n % m % w % total 39 18.2 28 70.8 10 29.2 kidney cancer 13 33.3 7 54.3 6 45.7 bph 11 28.1 11 100 bladder cancer 6 15.3 4 66.6 2 33.4 kidney rupture, cystic pathology 2 stones , kidney trasplantation, others 2 table 2. surgeries with transfusion requirements. ap/ac group a (%) group b (%) signification warfarin 33.33 31.58 0.7215 asa 100 25.64 50 0.0330 asa 300 7.69 7.89 0.6728 enoxaparin 7.69 0 0.0938 pentoxifilin 7.69 0 0.1692 clopidogrel 5.13 10.25 0.4309 bemiparin 5.13 0 0.7152 diosmin+hesperidin deriv 5.13 0 0.6430 trifusal 2.56 0 0.4810 table 2. concomitant ap/ac drugs in patients undergoing vtur. figure 1. main diagnosis in patients who required blood transfusion. virseda _stesura seveso 02/07/15 11:22 pagina 137 archivio italiano di urologia e andrologia 2015; 87, 2 virseda-rodríguez, padilla-fernández, lópez-parra, santos-antunes, valverde-martínez, nieto-gonzález, san miguel-izquierdo, et al. 138 those patients who underwent vtur due to btcc were older in ga (77.59 years sd 9.42) than in gb (68.98 years sd 11.78) (p = 0.0001). similar gender distribution (15 women in ga and 24 in gb). the usual ap/ac treatment of patients admitted for vtur due to btcc was investigated (table 3). acetylsalicylic acid (asa) 100 mg was not removed. table 4 shows the tumour grade and stage of the btcc operated. discussion patients who undergo urological surgery are frequently treated with ap/ac drugs. withdrawal and reintroduction standards are varied and must be adjusted depending on several risk factors and the characteristics of each patient. the effects of the antithrombics prophylaxis remains uncertain (1). in some meta-analysis, main or total haemorrhage is increased with the use of antiplatelet-anticoagulant drugs (ap/ac), but in other studies no increase was found (1). major surgery is associated with an important blood loss which involves a high morbidity and mortality (2). preoperative evaluation is essential for the blood transfusion reduction and requires a detailed medical record, physical examination, previous family or personal haemorrhagic events and a list of ap/ac drugs which may be withdrawn or substituted prior to surgery (3). acetylsalicylic acid (asa) irreversible inactivation of the cyclooxygenase enzyme required for prostaglandin and thromboxane synthesis (4, 5). the elimination half-life depends on the dose ingested, but its action duration does not have a direct relationship with the plasmatic half-life because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide becomes saturated (6). oral administration is rather selective to platelets due to its pre-systemic withdrawal (7, 8). after asa administration, the txa2 production is not recovered until the platelets cohort has been substituted in 7-10 days (7, 8). clinical essays have shown the efficacy of asa in several situations with similar efficacy in a dose range of 501500 mg/day; those doses inhibited nearly completely the thromboxane synthesis in platelets (8). nevertheless, the asa's side-effects have a clear relationship with the dose, recommending a low dose for thrombotic prophylaxis (75 mg per day) (9). with very high doses, asa also has an inhibitory effect on the haemostasis depending on vitamin k, modifying the prothrombin production and developing an hypoprothrombinemia (9). we did not find a higher bleeding risk in patients usually treated with asa 300 mg (p = 0.6728) after a preoperative withdrawal of 6-10 days. when asa 100 mg was taken preoperatively, a higher bleeding proportion was found in gb (p = 0.0330). clopidogrel it is an oral, thienopyridine class antiplatelet agent with a similar structure and mechanism of action to ticlopidine (7). it works by irreversibly inhibiting the p2y12 receptor, an adenosine diphosphate (adp) chemoreceptor on platelet cell membranes (10). it is more effective than asa reducing the number of atherosclerotic events in people on high risk (11). it has a similar tolerability to asa, but clopidogrel seems to develop more severe neutropenia events (7). the drug is rapidly absorbed after oral administration of repeated doses of 75-milligram clopidogrel (min. 8 days), with peak plasma levels (approx. 3 mg/l) of the main circulating metabolite occurring approximately one hour after dosing (12). when clopidogrel administration is stopped, its effect takes 5 more days to disappear (13). its main side-effect is haemorrhage. it is recommended to withdrawn clopidogrel 5 days before major surgery in order to avoid excessive bleeding (11). it has been reported an haemorrhage global incidence for patients treated with clopidogrel and asa of 9.3%, with an incidence of severe cases of 1.4% for clopidogrel and 1.6% for asa (11). for patients taking clopidogrel, the incidence of gastrointestinal bleeding observed was 2%, and a 0.7% required admission. for patients taking asa, the corresponding percentages were 2.7% and 1.1%, respectively (11). the incidence of other bleeding was higher in the clopidogrel group compared with asa (7.3% versus 6.5%). nevertheless, the incidence of severe side-effects was similar in both treatment groups (0.6% versus 0.4%). most frequently reported side-effects with both treatments were: purpura, ecchymosis, hematoma and epistaxis (nosebleed). other less frequent reported sideeffects were: haematuria and red eye (subconjunctival haemorrhage). the incidence of intracranial hemorrhage was of 0.4% in patients receiving clopidogrel and of 0.5% with asa (11). concomitant administration of clopidogrel and naproxen increased the fecal occult blood. nevertheless, more studies are needed to know if the increase of gastrointestinal bleeding is applicable to other nonsteroidal antiinflammatory drugs (nsaids) (14). in our series, the clopidogrel withdrawal standard is given by the anaesthesiologist at the preoperative study, varying between 7 and 12 days prior to surgery. with this withdrawal standard, we did not find a greater proportion of patients in group a with previous treatment with clopidogrel. group a group b signification (-) ap/ac (+) ap/ac (-) ap/ac (+) ap/ac pta 13.72 20.68 35.41 22.22 0.4271 pt1 15.68 13.79 33.33 38.88 0.6109 pt2 45.09 41.37 16.66 13.88 0.0815 pt3 17.64 20.68 4.16 5.55 0.0018 pt4 7.84 3.45 2.08 0.0004 g1 3.92 3.45 18.75 13.88 0.6182 g2 1.96 10.34 35.41 30.55 0.7151 g3 49.02 37.93 27.08 30.55 0.0003 table 4. distribution of the tumour stage and grade in patients with or without ap/ac drugs who underwent vtur due to btcc. virseda _stesura seveso 02/07/15 11:22 pagina 138 139archivio italiano di urologia e andrologia 2015; 87, 2 influence of antiplatelet -anticoagulant drugs on the need of blood components transfusion after vesical transurethral resection acenocoumarol it is an anticoagulant that functions as a vitamin k antagonist. the peak level is reached 1-3 hours after its administration. it has an average half-life of 9 hours. prothrombin time is restored to normal in a few days after withdraw. its plasmatic elimination half-life is 8-11 hours: only an 0.12-0.18% is excreted unchanged in urine. the cumulative excretion of metabolites and unchanged active drug during 8 days reaches a 60% in urine and a 29% in stool (15). due to interindividual changes, no correlation between the acenocoumarol plasma concentration and the prothrombin level can be made (15). elderly patients (> 70 years old) usually have higher plasma concentrations than young patients with the same daily dose (15). bleeding in several sites have been reported (gastrointestinal tract, brain, urogenital system, uterus, liver, gallbladder, eyes) depending on therapy's intensity, patient's age and the base illness, but not on the treatment's duration (16). it has been also reported a 32% of haemorrhages with warfarin and an 11% with acenocoumarol (16). mechanisms related with acenocoumarol's interactions are absorption's disorders, inhibition or induction of the metabolizing enzymatic system and a reduced vitamin k availability. it is necessary to look close after coagulation and to control it often when other drugs are prescribed acenocoumarol or when simultaneous intake is stopped (17). we are advised against giving acenocoumarol with other drugs which modify the hemostasis in order not to increase the bleeding risk (heparin, acetylsalicylic acid and derivatives, phenylbutazone and other pyrazolonic derivatives). when combining acenocoumarol with nsaids, it is recommended to check more often the coagulation (17). in our series, a variation on the withdrawal standard was found, varying between 3 and 7 days prior to surgery. no differences in the transfusion requirements between ga and gb were found. a case of acenocoumarol and asa interaction was recorded, which required the urgent transfusion of ten bags with packed red blood cells in a female patient who underwent a cystocele correction plus remeex system placement for complex urinary incontinence, requiring an endopelvic packing to save the patient's life (18). flavonoids they are an aromatic group of heterocyclic pigments with anti-allergic, anti-inflammatory, antioxidant, anti-microbial (antibacterial, antifungal, and antiviral, anti-cancer, anti-thrombotic and anti-diarrheal activities (19). the treatment with flavonoids is not exempt from pharmacological interactions. in some cases they can inactivate certain isoenzymes of the cytochrome p450 (3a4 and 2c9) or inhibit the hepatic glucuronosyltransferases (20). we usually recommend to stop the intake of any flavonoids 710 days prior to surgery, suggested by the urologist. triflusal it is a platelet aggregation inhibitor of the salicylate family but it is not a derivative of asa, effective in the prevention of cardiovascular events (stroke, acute treatment of cerebral infarction, myocardial infarction) but with less gastrointestinal effects than asa (stomach haemorrhage and peptic ulcer) (21). less than a 1% of haemorrhagic events have been reported (22). additive effects can be observed with ac/ap drugs, nsaids and thrombolytic drugs. high doses of salycilates (> 6 g/day) can also develop an hypoprothrombinemia, and additional bleeding risk factor (23). pentoxifylline it is a semisynthetic dimethylxanthine derivative with haematologic effects (24). its plasmatic concentrations are increased with concomitant ciprofloxacin (the quinolone reduces the hepatic metabolism of the pentoxifylline and increases the erythrocytic metabolism) (25). cimetidine, an inhibitor of the hepatic enzymes, can also increase the pentoxifylline's plasmatic concentrations (25). it has been reported an increase of the prothrombin time when using pentoxifylline and warfarin at the same time (25). it is recommended to monitor prothrombin time, haemoglobin and haematocrit (25). the simultaneous administration of antiplatelet drugs and pentoxifylline has not been studied, so special attention to synergism must be paid (25). in a small number of patients stabilized with theophylline, pentoxifylline's administration increased its plasmatic level with the subsequent toxicity risk. it should be noted that both drugs are xanthine derivatives and no cross-reactions are described (25). as shown in table 3, there are no patients treated with enoxaparin, pentoxifylline, bemiparin, diosmin+hesperidin derivatives or triflusal in gb. although there are no significant differences, it is possible that in other series with larger n the explanation to this difference could be found. more patients with high grade (p = 0.003) and higher t stage (p = 0.0018) tumours were found in ga after a vtur due to btcc, regardless of wether ac/ap drugs were previously taken. conclusions the pathologies which most needed blood components' transfusions in the urology department were (in order of frequency): bladder cancer, kidney cancer, prostate cancer, prostate adenoma, other urological diagnoses. asa 100 mg did not influence the transfusion's requirements in vtur due to btcc. tumour stage and higher grade have a greater influence in transfusion's requirements than concomitant ap/ac treatment. the heterogeneity of ap/ac protocols does not allow to establish the benefit of stopping those drugs before surgery in terms of avoiding blood transfusions when performing a vtur. references 1. lozano-sanchez f. valoración de la eficacia en la prevención de la enfermedad tromboembólica venosa en pacientes médicos y quirúrgicos, in enfermedad tromboembólica venosa, e. rochahernando and r. lecumberri-villamediana, editors. 2012, grupo acción médica: madrid. p. 105-110. 2. karkouti k, et al. the independent association of massive blood loss with mortality in cardiac surgery. transfusion. 2004; 44:1453-62. virseda _stesura seveso 02/07/15 11:22 pagina 139 archivio italiano di urologia e andrologia 2015; 87, 2 virseda-rodríguez, padilla-fernández, lópez-parra, santos-antunes, valverde-martínez, nieto-gonzález, san miguel-izquierdo, et al. 140 3. paramo j, et al., fundamentos básicos para el empleo de hemoderivados y estrategias de ahorro de sangre en cirugía. rev med univ navarra. 2008; 52:9-14. 4. fitzgerald ga, patrono c. the coxibs, selective inhibitors of cyclooxygenase-2. n engl j med. 2001; 345:433-42. 5. flower rj. the development of cox2 inhibitors. nat rev drug discov. 2003; 2:179-91. 6. hawkey cj. cox-2 inhibitors. lancet. 1999; 353:307-14. 7. patrono c, et al. platelet-active drugs: the relationships among dose, effectiveness, and side effects: the seventh accp conference on antithrombotic and thrombolytic therapy. chest 2004; 126(3 suppl):234s-264s. 8. ware ja, heistad dd. seminars in medicine of the beth israel hospital, boston. platelet-endothelium interactions. n engl j med. 1993; 328:628-35. 9. hawkey c gastrointestinal toxicity of non steroids anti-inflammatory drugs, in therapeutic toles of selective cox2 inhibitors, j. vane and r. botting, editors. 2001, william harvey press: londres. p. 355-394. 10. kunapuli sp, daniel jl p2 receptor subtypes in the cardiovascular system. biochem j. 1998; 336 (pt 3):513-23. 11. caprie.steering.committee, a randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (caprie). caprie steering committee. lancet. 1996; 348:1329-39. 12. mills dc, et al. clopidogrel inhibits the binding of adp analogues to the receptor mediating inhibition of platelet adenylate cyclase. arterioscler thromb, 1992; 12:p. 430-6. 13. caplain h, d'honneur g, cariou r. prolonged heparin administration during clopidogrel treatment in healthy subjects. semin thromb hemost. 1999; 25 suppl 2:61-4. 14. kamath s, et al. a prospective randomized trial of aspirin-clopidogrel combination therapy and dose-adjusted warfarin on indices of thrombogenesis and platelet activation in atrial fibrillation. j am coll cardiol. 2002; 40:484-90. 15. barcellona d, et al. warfarin or acenocoumarol: which is better in the management of oral anticoagulants? thromb haemost. 1998; 80:899-902. 16. amian a, et al. comparative study of the stability of oral anticoagulant treatments (warfarin vs acenocoumarol). sangre (barc). 1996; 41:9-11. 17. myers s. interactions between complementary medicines and warfarin. australian prescriber. 2002;25:54-56. 18. padilla-fernández b, et al. complicaciones graves y fracasos de la corrección quirúrgica de la incontinencia urinaria de esfuerzo mediante prótesis remeex. aportación de nuestra serie 45 casos., in xii con greso sinug (sociedad iberoamericana de neurourología y uroginecología). s.i.d.n.y. uroginecología, editor. 2012: cádiz. españa. 19. sax n, lewis r. diccionario de química y de productos químicos. 2 ed ed, ed. hawley. 1993, barcelona:omega. 20. prasain jk, carlson sh, wyss jm. flavonoids and age-related disease:risk, benefits and critical windows. maturitas. 2010;. 66:163-71. 21. matias-guiu j, et al. comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the tacip study: a randomized, double-blind, multicenter trial. stroke. 2003; 34:840-8. 22. sanchez de miguel l, et al. the effect of triflusal on human platelet aggregation and secretion: the role of nitric oxide. rev esp cardiol. 2000; 53:205-11. 23. murdoch d, plosker gl. triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. drugs. 2006; 66:671-92. 24. vinik ai, et al. diabetic neuropathies. diabetes care. 1992; 15:1926-75. 25. goodnan-gilman a. las bases farmacológicas de la terapéutica. 10 ed ed, ed. mcgraw-hill/intramericana de mexico 2003. correspondence maría fernanda lorenzo-gómez (corresponding author) mflorenzogo@yahoo.es c/ esmeralda 6. urb las canteras. villamayor. 37185 salamanca, spain 616422924 alvaro julio virseda-rodríguez, md lauro sebastian valverde-martínez, md department of urology. university hospital of salamanca. barbara padilla-fernández, md department of urology. university hospital of the canary islands, tenerife mirian lópez-parra, md maria jesus nieto gonzález, md department of haematology. university hospital of salamanca maria tatiana santos-antunes, md anabel lorenzo-gómez, md maria begoña garcía-cenador, md department of surgery, university of salamanca jesus fernando san miguel-izquierdo, md clinical and translational medicine of the university of navarra patricia antúnez-plaza, md department of pathology, university hospital of salamanca virseda _stesura seveso 02/07/15 11:22 pagina 140 stesura seveso 49archivio italiano di urologia e andrologia 2015; 87, 1 original paper evaluation of laparoscopic vs robotic partial nephrectomy using the margin, ischemia and complications score system: a retrospective single center analysis stefano ricciardulli 1, 2, qiang ding 1, xu zhang 1, hongzhao li 1, yuzhe tang 1, guoqiang yang 1, xiyou wang 1, xin ma 1, alberto breda 3, antonio celia 2 1 department of urology, chinese pla general hospital, beijing, china; 2 department of urology, san bassiano hospital, bassano del grappa, italy; 3 department of urology, foundacio puigvert universidad autonoma de barcelona, spain. objective: to evaluate differences between laparoscopic partial nephrectomy (lpn) and robot-assisted partial nephrectomy (rapn) using the margin, ischemia and complications (mic) score system and to evaluate factors related with mic success. materials and methods: single centre retrospective study on 258 lpn and 58 rapn performed between january 2012 and january 2014. success was defined when surgical margins was negative, warm ischemia time (wit) was ≤ 20 minutes and no major complications occurred. mann-whitney-u and pearson χ2 correlation were used to compare lpn and rapn. a matched pair comparison was also performed. spearman correlation (rho) was used to evaluate the relationship between clinical, intra and post-operative and pathological patients characteristics with mic score. a binary regression analysis was also performed to evaluate independent factors associated with mic success. results: the mic rate in lpn and rapn was 55% and 65.5% respectively. no differences in clinical, intra and post-operative outcomes between groups were found. clinical tumor size (p-value: < 0.001; or: 0.829; 95% ci: 0.697-0.987), padua score (p-value: < 0.001; or: 0.843; 95% ci: 0.740-0.960), padua risk groups (intermediate; p-value: < 0.001; or: 0.416; 95% ci: 0.2380.792; high: p-value: < 0.001; or: 0.356; 95% ci: 0.1990.636), wit (p-value: < 0.001; or: 0.598; 95% ci: 0.5300.675) were independently associated with mic. egfr (< 60 vs ≥ 60 ml/min per 1.73 m2: p-value: < 0.001; or: 3.356; 95% ci: 1.701-6.621) and fuhrman nuclear grade (p-value: 0.014; or: 1.798; 95% ci:1.129-2.865) were also independently associated with mic. conclusions: mic score system is a simple and useful tool to report and to compare different surgical approach. key words: complications; laparoscopic partial nephrectomy; positive margins; robot-assisted partial nephrectomy; warm ischemia time. submitted 5 september 2014; accepted 31 december 2014 summary no conflict of interest declared. introduction international guidelines on renal cell carcinoma (rcc), states that renal tumors ≤ 7 cm are best managed by nephron sparing surgery (nss) (1, 2). open partial nephrectomy (opn) represents the gold standard for renal tumors ≤ 7 cm, while laparoscopic partial nephrectomy (lpn) and robot-assisted partial nephrectomy (rapn) are the main alternatives. partial nephrectomy (pn) is a more complex procedure and several aspects must to be evaluated (3). in recent years pn become a challenge procedure to have less warm ischemia time (wit), which represent the most important predictor of renal function after pn (4). as reported by some authors (5) the best pn should ideally be without ischemia, but, when required, it should not exceed 20 minutes for warm ischemia and < 35 minutes for cold ischemia. ten years after the first case described by gettman et al. (6), rapn seems to be a promising procedure able to bridge the technical difficulties of lpn (7). rapn has helped to reduce the surgical learning curve needed, and shortened operative and ischaemic times with less blood loss compared with lpn. in 2012 buffi et al. (8), proposed a new score system to evaluate success in pn, the margin, ischemia and complications (mic). according to this newly proposed scoring system, an optimal pn is accomplished when surgical margins (sm) are negative, wit was ≤ 20 minutes and no major complication (9) (clavien-dindo grade 3-4) were observed. the use of this simple system could be of paramount importance to compare and evaluate different approach used to perform pn. aim of this study is to evaluate difference between lpn and rapn, from a single center experience, using the mic score and to evaluate pre, intra and post-operative factors that may potentially influence this scoring system. materials and methods this is a retrospective single centre study approved by the local ethical committee. all patients were counselled about the risks, benefits and alternative treatments for doi: 10.4081/aiua.2015.1.49 ricciardulli_stesura seveso 02/04/15 10:22 pagina 49 archivio italiano di urologia e andrologia 2015; 87, 1 s. ricciardulli, qiang ding, xu zhang, hongzhao li, yuzhe tang, guoqiang yang, xiyou wang, xin ma, a. breda, a. celia 50 the condition; individual informed consent was obtained. all patients that underwent lpn and rapn performed by a single experienced surgeon between january 2012 and march 2014 were included in the analysis. patients with solitary kidney, multifocal tumours, those with radiography evidence of metastases and pn performed with no ischemia time or cold ischemia were not considered suitable for the inclusion. lpn was performed with a retro-peritoneal approach as previously described (10-11) with renal artery clamping. the rapn was performed using da vinci si four-arm robot (intuitive surgical inc, sunnyvale, ca, usa) with standardized trans-peritoneal approach (7, 12-13) with renal artery clamping. from january 2012 to september 2014 all pns were performed laparoscopically, after september robotically. to eliminate bias related to surgeon learning curve the first 30 rapn (7) were eliminated from the database. before surgery, all patients underwent a computed tomography (ct) scan or magnetic resonance imaging (mri) in order to evaluate the clinical stage and the anatomical characteristics of the tumors. based on image of ct scan or mri, a preoperative aspect and dimension used for an anatomical (padua) score (14) was assigned to each patients by two different examiners. tumors were stratified into low-risk (padua score 6-7), intermediate-risk (padua score 8-9), and high-risk (padua score ≥ 10) (14). the wit and the estimated blood loss (ebl) were assessed by an anesthesiologist. postoperative complications, occurred during the first 30 days after surgery, were classified according to the dindo modification of the clavien system (9, 15) and defined as minor (grade 1-2) and major (grade 3-4). surgery duration was defined as the time from trocar placement to trocars removed for lpn and the console time for rapn. renal function was calculated by estimating the glomerular filtration rate (gfr) through the modification of diet in renal disease study (mdrd) formula preoperatively and post-operatively (16) using preoperative and latest postoperative (median 30 days after surgery) serum creatinine (scr). renal function was staged according to the national kidney foundation disease outcome quality initiative classification. postoperative change in scr and egfr was also evaluated. an egfr < 60 ml/min per 1.73 m2 was definited as an undesiderable event. the following information was available for each patient included in the study: age, bmi, asa, charlson comorbidity index (cci), gender, clinical tumor size, padua score and padua anatomical features, wit, surgery duration, ebl, conversion to open, intra and post-operative complications, pre and postoperative scr. pathological tumor size, histological subtypes according with the world health organization classification (17), tumor extension according with the tnm classification (18), nuclear grade according to the fuhrman classification (19) and positive surgical margin rate were also reported. positive surgical margins (psm) were defined as the extension of the tumor over the inked parenchymal surface. according with the mic score system success of procedures was defined when wit was ≤ 20 minutes, negative sm and no major grade of post-operative complications occurred (8). for this group of patients we assigned three points. if only two of these characteristics compared we assigned two points; only one of this characteristics, one point. descriptive statistics was performed. continuous variables were reported as median and interquartile range (iqr); categorical variables were reported as number of cases (no) and percent (%). a matched pair analysis was performed to adjust for preoperative using multivariable logistic regression on this covariates: clinical tumor size (continuous) and padua score (continuous and categorical). the matching was carried out with a 1:1 ratio (58 matched in lpn and 58 in rapn) with respect to surgical approach (lpn vs rapn). non-parametric mann-whitney-u test was used to compare lpn and rapn and matched lpn and rapn with continuous variables, pearson χ2 correlation was used for categorical variables. spearman rank order correlation (rho) was used to evaluate the relationship between clinical, intra and post-operative and pathological patients characteristics with mic score. the relationship was defined as small (rho = 0.10 to 0.29), medium (rho = 0.30 to 0.49) and large (rho = 0.50 to 1). a binary regression analysis was done in order to evaluate the association between clinical, intra and post-operative and pathological characteristics with mic. we used only factors statistically significant in spearman analysis. a two side p-value of < 0.05 was defined as statistically significant. all data were analyzed using spss v. 20 with phyton extension (ibm corp., armonk, ny, usa). results a total of 316 patients were enrolled in this study (258 lpn vs 58 rapn). table 1 described patients’ preoperative characteristics between lpn and rapn. no difference was found between lpn and rapn in demographic patients characteristics. the asa score was higher in rapn (pvalue: 0.041). interestingly, the two groups presented the similar tumor characteristics, median size (3.1 [iqr: 2.13.8] vs 3.1 [iqr: 2.2-3.8]; p-value: 0.634), median padua score (8.5 vs 8.2; p-value: 0.306) and similar clinical stage (p-value: 0.487). according with padua score system, the padua risk groups presented a similar distribution between lpn and rapn (low risk: 33.7% vs 32.8%; intermediate risk: 34.9% vs 39.7%; high risk: 31.4% vs 27.5%; p-value: 0.765). the only difference was founded in tumor face location, with a predominance of tumor located in the posterior face in lpn (63.2% vs 36.2%) and a predominance of tumor located on anterior face in rapn (63.8% vs 36.8%). no difference was found in preoperative scr. 6.2% of patients in lpn (vs 1.7% in rapn) had a egfr level < 60 ml/min per 1.73 m2, but this was not statistically significative (p-value: 0.172). table 2 showed intra, post-operative and pathological patients’ characteristics. in this series we did not find any significant difference (p-value: 0.321) in wit between lpn and rapn (20.8 vs 19.4 minutes). wit was ≤ 20 minutes in 60.1% and ≥ 30 minutes in 12.8% in lpn, while it was 65.5% and 5.2% in rapn. no difference in intra and post-operative complications between lpn and rapn was found. we reported a rate of intraoperative complications of 10.5% in lpn and 6.9% in rapn. no conversion to opn was observed in rapn while 3 ricciardulli_stesura seveso 02/04/15 10:22 pagina 50 51archivio italiano di urologia e andrologia 2015; 87, 1 mic in laparoscopic and robotic partial nephrectomy table 1. pre-operative patients characteristics. lpn = laparoscopic partial nephrectomy; rapn = robot-assisted partial nephrectomy; iqr = interquartile range; bmi = body mass index; asa = american society of anesthesiologist; iqr = interquartile range; padua = preoperative aspects and dimension used for an anatomical; scr = serum creatinine; egfr = estimated glomerular filtration rate. table 2. intra, postoperative and pathological results. lpn = laparoscopic partial nephrectomy; rapn = robot-assisted partial nephrectomy; wit = warm ischemia time; iqr= interquartile range; ebl = estimated blood loss; opn = open partial nephrectomy; scr = serum creatinine; egfr = estimated glomerular filtration rate; psm = positive surgical margin; rcc = renal cell carcinoma; crcc = clear renal cell carcinoma; mic= margin, ischemia and complications. * fuhrman nuclear grading was avaible only in 198/215 rcc instances in lpn group. variable lpn (n = 258) matched (n = 58) rapn (n = 58) p-value (full data set) p-value (matched) median age, years (iqr) 49.3 (41-58) 48.4 (41-56) 51.6 (45-59) 0.174 0.142 gender, no (%) 0.172 0.108 male 169 (65.5) 36 (62.1) 44 (75.9) female 89 (34.5) 22 (37.9) 14 (24.1) median bmi, kg/m2 (iqr) 25.3 (22.4-27.5) 25.4 (20-25) 25.6 (21-25) 0.834 0.842 median asa, no (iqr) 1.8 (2) 1.8 (2) 1.9 (2) 0.041 0.052 median cci, no (iqr) 0.55 (0-1) 0.5 (0-1) 0.5 (0-1) 0.439 0.562 median clinical tumor size, cm (iqr) 3.1 (2.1-3.8) 2.9 (2-3.5) 3.1 (2.2-3.8) 0.634 0.263 clinical stage, no (%) 0.487 0.593 t1a 196 (76) 46 (79.3) 46 (79.3) t1b 56 (21.7) 11 (19) 12 (20.7) t2a 6 (2.3) 1 (1.7) 0 (0) median padua score, no (iqr) 8.5 (7-10) 8.6 (7-10) 8.2 (6-10) 0.306 0.260 padua risk groups, no (%) 0.765 0.892 low (6-7) 87 (33.7) 17 (29.3) 19 (32.8) intermediate (8-9) 90 (34.9) 23 (39.7) 23 (39.7) high (≥ 10) 81 (31.4) 18 (31) 16 (27.5) side, no (%) 0.178 0.135 right 135 (52.3) 28 (48.3) 36 (62.1) left 123 (47.7) 30 (51.7) 22 (37.9) face, no (%) < 0.001 0.003 anterior 95 (36.8) 21 (36.2) 37 (63.8) posterior 163 (63.2) 37 (63.8) 21 (36.2) median preoperative scr, μmol/l (iqr) 75.9 (62-85) 73.4 (63-80) 76.4 (64-86) 0.474 0.243 median preoperative egfr, ml/min per 1.73 m2 (iqr) 98.9 (76-116) 99.4 (78-116) 95.8 (85-108) 0.958 0.651 preoperative egfr < 60, no (%) 16 (6.2) 3 (5.2) 1 (1.7) 0.172 0.309 variable lpn (n = 258) matched (n = 58) rapn (n = 58) p-value (full data set) p-value (matched) intra-operative characteristics median wit, min (iqr) 20.8 (17-25) 20.6 (16-26) 19.4 (16-22) 0.321 0.472 % wit, no (%) 0.201 0.284 ≤ 20 155 (60.1) 35 (60.3) 38 (65.5) 21-29 70 (27.1) 15 (25.9) 17 (29.3) ≥ 30 33 (12.8) 8 (13.8) 3 (5.2) median surgery duration, min (iqr) 112 (90-130) 110 (87-150) 114 (90-120) 0.385 0.372 median ebl, ml (iqr) 68 (30-85) 68 (30-50) 104 (50-110) < 0.001 0.007 intra-operative complications, no (%) 27 (10.5) 5 (8.3) 4 (6.9) 0.409 0.729 conversion to opn, no (%) 3 (1.2) 1 (1.7) 0 (0) 0.409 0.315 post-operative complications post-operative complications, no (%) 0.414 0.778 minor, no (%) 44 (17.1) 14 (24.1) 15 (25.9) major, no (%) 2 (0.8) 0 (0) 1 (1.7) median hospital stay, days (iqr) 7 (7-8) 7 (7-8) 7 (7-8) 0.975 0.892 median post-operative scr, μmol/l (iqr) 85.7 (68-96) 86.1 (67-93) 85.8 (69-97) 0.951 0.827 median post-operative scr increase, μmol/l (iqr) 9.8 (0.5-20) 12 (3.5-25) 9 (0.15-16) 0.411 0.180 median post-operative egfr, ml/min per 1.73 m2 (iqr) 86.4 (67-101) 84.9 (65-99) 86.2 (75-100) 0.695 0.615 median postoperative egfr decrease, ml/min per 1.73 m2 (iqr) 12.4 (0.7-25) 14 (4-28) 9 (0.1-20) 0.207 0.063 % egfr decrease, no(%) 0.098 0.219 ≤ 25% 187 (72.5) 42 (72.4) 49 (84.5) 25.1-49.9% 68 (26.4) 15 (25.9) 9 (15.5) ≥ 50% 3 (1.1) 1 (1.7) 0 (0) post-operative egfr < 60, no (%) 36 (14) 11 (19) 8 (13.8) 0.975 0.452 pathological characteristics median pathological tumor size, cm (iqr) 3.3 (2.3-4.1) 3.1 (2.1-4.1) 3.2 (2.05-4) 0.334 psm, no (%) 13 (5) 5 (8.3) 0 (0) 0.020 0.022 hystological subtypes 0.276 0.156 crcc 196 (76) 41 (70.7) 50 (86.2) chromophobe rcc 8 (3.19 2 (3.4) 0 (0) papillary rcc 11 (4.3) 1 (1.7) 1 (1.7) benign 43 (16.7) 14 (24.1) 7 (12.1) pathological stage 0.113 0.360 t1a 150 (69.9) 36 (80) 41 (80.4) t1b 58 (26.9) 9 (20) 7 (13.7) t2a 5 (2.3) 0 (0) 1 (2) t3a 2 (0.9) 0 (0) 2 (3.9) fuhrman nuclear grade, no (%)* 0.569 0.810 grade 1 42 (1.2) 7 (17.5) 10 (19.6) grade 2 138 (69.7) 29 (72.5) 34 (66.7) grade 3 16 (8.1) 4 (10) 7 (13.7) grade 4 2 (1) 0 (0) 0 (0) mic score, no (%) 0.243 0.117 1 point 2 (0.8) 0 (0) 1 (1.7) 2 points 114 (44.2) 29 (50) 19 (32.8) 3 points 142 (55) 29 (50) 38 (65.5) ricciardulli_stesura seveso 02/04/15 10:22 pagina 51 archivio italiano di urologia e andrologia 2015; 87, 1 s. ricciardulli, qiang ding, xu zhang, hongzhao li, yuzhe tang, guoqiang yang, xiyou wang, xin ma, a. breda, a. celia 52 occurred in the group treated with lpn. table 3 summarize and described intra and post-operative complications. according with our hospital policy, the median hospitalization time was 7 days (iqr: 7-8) both for lpn and rapn. no difference was found in post-operative scr. lpn had a median increase of scr 9.8 μmol/l versus 9.3 μmol/l in rapn (p-value: 0.411). in the group treated with lpn we observed a decrease in postoperative egfr ≤ 25% in 72.5% (vs 84.5%), between 25.1-49.9% in 26.4% (vs 15.5%) and ≥ 50% in 1.1% (vs 0%) of the patients. the only difference between lpn and rapn was found in psm rate, with a 5% and 0% respectively (p-value: 0.020). finally, the success of treatment defined with mic score was higher in rapn (65.5%) than lpn (55%) but it was statically not significant (p-value: 0.243). the matched pair analysis shows the same results in terms of pre, intra and post-operative outcomes between lpn and rapn. table 4 showed the spearman correlation between clinical, intra and post-operative characteristic with mic system. we found that median tumor size (rho: -0.170 p-value: 0.002), median padua score (rho: -0.179; p-value: < 0.001), padua risk groups (rho: -0.191; p-value: < 0.001), renal rim (rho: -0.113; p-value: 0.044), renal sinus (rho: -0.154; p-value: 0.006), urinary collecting system (ucs) (rho: -0.170; p-value: 0.002) and tumor size coded as categorical variable (rho: -0.152; p-value: 0.007) were inversely related with mic score system. complications type treatment n, lpn n, rapn clavien-dindo grade peritoneum injury intraoperative intraoperative repair 9 0 na bleeding intraoperative blood transfusion 6 1 na bleeding intraoperative conversion to opn 3 0 na spleen/liver injury intraoperative intraoperative repair 0 2 na renal vein injury intraoperative intraoperative repair 5 1 na diaphragram injury intraoperative intraoperative repair 4 0 na fever postoperative medical therapy 12 4 1 pain postoperative medical therapy 10 2 1 tachycardia postoperative medical therapy 1 2 1 atrial fibrillation postoperative medical therapy 2 0 1 urine leak postoperative conservative menagement 8 3 1 urine retention postoperative catheritation 3 0 1 hb decrease postoperative blood transfusion 8 4 2 urine leak postoperative jj placement 1 0 3 hb decrease postoperative selective embolitation 1 0 3 kidney abscess postoperative intraoperative drainage 0 1 3 table 3. intra and post-operative complications occurred (full data set). lpn = laparoscopic partial nephrectomy; rpn = robot-assisted partial nephrectomy; opn = open partial nephrectomy; hb = hemoglobin; na = not applicable. table 4. spearman correlation between clinical, intra and post-operative characteristics and mic score system. mic = margin, ischemia and complications; padua = preoperative aspects and dimension used for an anatomical; iqr = interquartile range; ucs = urinary collecting system; psm = positive surgical margins; lpn = laparoscopic partial nephrectomy; rapn = robot-assisted partial nephrectomy; egfr= estimated glomerular filtration rate; crcc = clear renal cell cancer; rcc = renal cell cancer. variable mic rho p-value 1 point 2 points 3 points (n = 3) (n = 133) (n = 180) median age, years (iqr) 65 (57-70.5) 48 (40-57) 50 (42-59) 0.044 0.437 median clinical tumor size, cm (iqr) 4.02 (3.24-4.25) 3.38 (2.4-4.3) 2.93 (2-3.6) -0.170 0.002 median padua score, no (iqr) 8.6 (7-10) 8.9 (8-10) 8.2 (7-10) -0.179 < 0.001 padua risk groups, no (%) -0.191 < 0.001 low 1 (33.3) 29 (21.8) 76 (42.2) intermediate 1 (33.3) 54 (40.6) 58 (2.2) high 1 (33.3) 50 (37.6) 46 (25.6) longitudinal polar location, no (%) -0.089 0.115 superior/inferior 1 (33.3) 79 (59.4) 120 (66.7) middle 2 (66.7) 54 (40.6) 60 (33.3) exophytic rate, no (%) -0.015 0.793 ≥ 50% 3 (100) 63 (47.4) 94 (52.2) < 50% 0 (0) 53 (39.8) 65 (36.1) endophytic 0 (0) 17 (12.8) 21 (11.7) renal rim, no (%) -0.113 0.044 lateral 1 (33.3) 73 (54.9) 117 (65) medial 2 (66.7) 60 (45.1) 63 (35) renal sinus, no (%) -0.154 0.006 not involved 2 (66.7) 87 (65.4) 143 (79.4) involved 1 (33.3) 46 (34.6) 37 (20.6) ucs, no (%) -0.170 0.002 not involved 1 (33.3) 39 (29.3) 84 (46.7) infiltrated/dislocated 2 (66.7) 94 (70.7) 96 (53.3) tumor size -0.152 0.007 ≤ 4 2 (66.7) 91 (68.4) 149 (82.8) 4.1-7 1 (33.3) 39 (29.3) 28 (5.6) ≥ 7 0 (0) 3 (2.3) 3 (1.7) median wit, min (iqr) 27.2 (26-30) 25.5 (22-29) 16.8 (15-20) -0.672 < 0.001 clavien dindo complication, no (%) -0.137 0.015 minor 0 (0) 26 (19.5) 33 (18) major 2 (66.7) 1 (0.8) 0 (0) psm, no (%) 1 (33.3) 12 (9) 0 (0) -0.256 < 0.001 surgical tecnique 0.072 0.204 lpn 2 (66.7) 114 (85.7) 142 (79.9) rapn 1 (33.3) 19 (14.3) 38 (21.1) egfr, no (%) egfr < 60 ml/min per 1.73 m2 1 (33.3) 29 (21.8) 14 (7.8) 0.206 < 0.001 egfr ≥ 60 ml/min per 1.73 m2 2 (66.7) 104 (78.2) 166 (92.2) median fuhrman nuclear grade, (iqr) 2 (2-3) 1.8 (2) 1.8 (2) -0.144 0.023 pathological stage, no (%) -0.111 0.069 t1a 1 (33.3) 76 (67.9) 117 (76) t1b 1 (33.3) 31 (27.7) 33 (21.4) t2a 1 (33.3) 3 (2.7) 2 (1.3) t3a 0 (0) 2 (1.8) 2 (1.3) histologic subtypes, no (%) -0.005 0.932 crcc 2 (66.7) 104 (78.2) 140 (77.8) chromophobe rcc 0 (0) 2 (1.5) 6 (3.3) papillary rcc 1 (33.3) 4 (3) 7 (3.9) benign 0 (0) 23 (17.3) 27 (15) ricciardulli_stesura seveso 02/04/15 10:22 pagina 52 as aspect, the strongest factor related with mic score system was wit (rho: -0.672; p-value: < 0.001). the surgical technique (lpn vs rapn) was not statically related with mic in this report (p-value: 0.204). clavien dindo complications and psm were inversely related with mic score system (rho: -0.137 and -0.256; p-value: 0.015 and < 0.001 respectively). two important aspects we found in this analysis. an egfr level ≥ 60 ml/min per 1.73 m2 (rho: 0.206; p-value: < 0.001) and fuhrman nuclear grade (rho: -0.144; p-value: 0.023) were related with mic. table 5 showed binary logistic regression analysis reporting independent factors related with mic success (wit ≤ 20 minutes, no major complications, no psm). clinical tumor size (p-value: < 0.001; or: 0.829; 95% ci: 0.697-0.987), padua score (p-value: < 0.001; or: 0.843; 95% ci: 0.740-0.960), padua risk groups (low: reference; intermediate; p-value: < 0.001; or: 0.416; 95% ci: 0.2380.792; high: p-value: < 0.001; or: 0.356; 95% ci: 0.1990.636), wit (p-value: < 0.001; or: 0.598; 95% ci: 0.530-0.675) were independently related with mic success. egfr (≥ 60 vs < 60 ml/min per 1.73 m2: p-value: < 0.001; or: 3.356; 95% ci: 1.701-6.621) and fuhrman nuclear grade (p-value: 0.014; or: 1.798; 95% ci:1.1292.865) were also independent factors. discussion the findings of this study shows that mic score system is a simple and useful tool to report and compare different surgical approach. we did not find any difference in clinical, intra and post-operative outcomes between lpn and rapn. clinical tumor size, padua score, padua risk groups and wit were independently associated with mic. several authors (8) recently proposed a score system to evaluate partial nephrectomy based on wit ≤ 20 minutes, negative sm and no major complications. this system is similar to the trifecta outcomes proposed and validated by other groups of authors (20-21). hung et al (21), definited the trifecta outcomes when there was negative sm, minimal renal function decrease and no urological complications. khalifeh et al. (20), definited trifecta outcomes as a wit ≤ 25 minutes, negative sm and no intra and post-operative complications. recently, minervini et al. (22) validated the trifecta outcomes in a matched-pair comparison between opn and lpn in clinical t1a renal mass. the mic system (8) is based on aspects validated by literature. recently a panel of experts proposed that wit should not ideally exceed 20 minutes 4 and every minute counts when the hilum is clamped (23). the clavien-dindo classification is the most validated tool to standardized and report surgical complications. mottrie (8) defined the mic score system simple to use and encouraged new research to assess is efficacy, especially by comparing its use in different surgical approaches (opn, lpn and rapn). porpiglia (24) was the first to assess the learning curve in lpn using this scoring system. he divided his experience in 4 eras and noted an increase of mic along the learning curve. in the current study we reported a mic rate of 55% and 65.5% in lpn and rapn respectively. we evaluated rapn performed in the last year after the learning curve was completed (7) and the approach was standardized. in this report, lpn and rapn groups had similar clinical, intra and post-operative characteristics. in a recent meta-analysis (25) lpn and rapn did not show any difference in operative time, ebl, hospital stay, oncological results and postoperative outcomes, but rapn had a shorter wit than lpn. in the current study the median wit was similar between the two groups (20.8 vs 19.4 minutes) and this results are in line with the literature (7, 12, 25). ficarra et al. (26), in a multicenter study, reported a median wit of 16 for low-risk tumors in rapn and porpiglia et al. (24), showed that wit decreases along the learning curve in lpn with results comparable to opn and rapn. a recent study (13) showed that there was no difference between rapn and lpn in complex tumors (median renal score 8), and this was explained by the authors on the basis of experienced surgeon’s experience in laparoscopic and robotic surgery in high volume centers. the transition from lpn to rapn is simple and can be associated with immediate improvements in perioperative parameters for surgeons with a solid baseline experience with lpn. rapn may reduce the technical difficulties of lpn (7), especially in complex cases, but a laparoscopic skills are important in robotic surgery. the absence of psm reported in our rapn cohort, described the oncological safety of rpn (7). negative sm is the first goal of pn, and a combination of a highly malignant tumor with psm seems to increase the risk of local recurrence (24). another important aspect of this study is the evaluation of mic score. pn is a complex procedure that require several aspects to assess the success. mic represents a good tool to assess the success of pn. tumor’s anatomical characteristics were related with mic success. as reported by porpiglia (24), mic rate was higher in low risk groups. our study efforts this theory. mic score system was inversely related with padua score and clinical tumor size. interestingly we found a correlation between post-operative egfr level ≥ 60 ml/min per 1.73 m2 and furhman nuclear grade. this finding might be explained by the influence of wit on renal function and by the aggressiveness of the tumor assessed by the furhman nuclear grade. this finding needs further evaluations. this is a retrospective single center single surgeon study. this study has several limitations; long-term oncological follow-up was not reported in this series. the lpn group was bigger than rapn group. we report53archivio italiano di urologia e andrologia 2015; 87, 1 mic in laparoscopic and robotic partial nephrectomy variable p-value or 95% ci clinical tumor size 0.035 0.829 0.697-0.987 padua score (continuously coded) < 0.001 0.843 0.740-0.960 padua risk group 6-7 < 0.001 reference 8-9 < 0.001 0.416 0.238-0.729 ≥ 10 < 0.001 0.356 0.199-0.636 wit < 0.001 0.598 0.530-0.675 post operative egfr level egfr < 60 ml/min per 1.73 m2 < 0.001 reference egfr ≥ 60 ml/min per 1.73 m2 < 0.001 3.356 1.701-6.621 fuhrman nuclear grade 0.014 1.798 1.129-2.865 table 5. independent factors related with mic success: multivariable analysis. or = odds ratio; ci = confidence interval; padua = preoperative aspect and dimension used for an anatomical; egfr = estimated glomerular filtration rate ricciardulli_stesura seveso 02/04/15 10:22 pagina 53 archivio italiano di urologia e andrologia 2015; 87, 1 s. ricciardulli, qiang ding, xu zhang, hongzhao li, yuzhe tang, guoqiang yang, xiyou wang, xin ma, a. breda, a. celia 54 ed the rapn performed in the last year after the learning curve was completed (> 30 cases). pn was performed by retroperitoneal approach in laparoscopic group and by transperitoneal approach in robotic groups. in our institute the retroperitoneal approach is the standardize methods for laparoscopic kidney surgery, both for posterior and anterior masses. the matched-pair analysis was performed in order to evaluate if the different number of patients into the two groups can alter our statistical results. other authors (22) used this method to compare different groups. we set the matched-pair analysis on 1:1 ratio in order to obtain two similar groups. the matched pair analysis was based on the tumor characteristics (size and padua score). we found no differences also in the matched pair analysis. the full data set was used in the spearman correlation and logistic regression in order to didn’t have overfitting problems. another important limitation is a short follow-up for evaluating kidney function (median 30 days) assessed only by egfr. mdrd equation has limitations for egfr evaluation. scr is the best predictor of egfr in mdrd equation, but his levels are impacted by bmi, gender, ethnicity, age and hydratation status. conclusion our report showed that the mic score system is simple and useful to report and compare different surgical approach. the use of nephrometry score system, as reported by other authors (26-27), is useful to predict outcomes after partial nephrectomy. the mic score is influenced by several anatomical aspects and the use of nephrometry score is useful to predict mic success. from our experience, we believe that mic system could be a helpful tool to assess pn outcomes and to compare different surgical approach. references 1. ljungberg b, cowan nc, hanbury dc, et. eau guidelines on renal cell carcinoma: the 2010 update. eur urol. 2010; 58:398-406. 2. novick ac, campbell sc, belldegrun a, et al. guideline for management of the clinical stage 1 renal mass. american urological association web site. http://www.auanet.org/content/media/renal mass09.pdf 3. van poppel h, da pozzo l, albrecht w, et al. a prospective randomized eortc intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2007; 51:1606-15. 4. becker f, van poppel h, hakenberg ow, et al. assessing the impact of ischaemia time during partial nephrectomy. eur urol. 2009; 56:625-34. 5. pignot g, bouliere f, patard jj. warm ischaemia: the ultimate enemy for partial nephrectomy? eur urol. 2010; 58:337-9. 6. gettman mt, blute ml, chow gk, neururer r, et al. roboticassisted laparoscopic partial nephrectomy: technique and initial clinical experience with davinci robotic system. urology. 2004; 64:914-8. 7. mottrie a, de naeyer g, schatteman p, et al. impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumours. eur urol. 2010; 58:127-33. 8. buffi n, lista g, larcher a, et al. margin, ischemia, and complications (mic) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery. eur urol. 2012; 62:617-8. 9. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 10. zhang x, li hz, ma x, et al. retroperitoneal laparoscopic nephron-sparing surgery for renal tumors: report of 32 cases. urology. 2005; 65:1080-4. 11. zhang x, fu b, lang b, et al. technique of anatomical retroperitoneoscopic adrenalectomy with report of 800 cases. j urol. 2007; 177:1254-7. 12. benway bm, bhayani sb, rogers cg, et al. robot-assisted partial nephrectomy: an international experience. eur urol. 2010; 57:815-20. 13. long ja, yakoubi r, lee b, et al. robotic versus laparoscopic partial nephrectomy for complex tumors: comparison of perioperative outcomes. eur urol. 2012; 61:1257-62. 14. ficarra v, novara g, secco s, et al. preoperative aspects and dimensions used for an anatomical (padua) classification of renal tumors in patients who are candidates for nephron-sparing surgery. eur urol. 2009; 56:786-93. 15. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. mitropoulos d, et al.; european association of urology guidelines panel. eur urol. 2012; 61:341-9. 16. levey as, bosch jp, lewis jb, et al. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann int med. 1999; 130:461-70. 17. eble jn, sauter g, epstein ji, et al., editors. pathology and genetics of tumors of the urinary system and male genital organs. world health organization classification of tumors. lyon, france: iarc press; 2004. 18. greene fl, gospodarowicz m, wittekend c, et al. american joint committee on cancer (ajcc) staging manual. ed. 7. philadelphia, pa: springer; 2009. 19. fuhrman s, lasky lc, limas l. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol 1982; 6:655-63. 20. khalifeh a, autorino r, hillyer sp, et al. comparative outcomes and assessment of trifecta in 500 robotic and laparoscopic partial nephrectomy cases: a single surgeon experience. j urol. 2013; 189:1236-42. 21. hung aj, cai j, simmons mn, gill is. "trifecta" in partial nephrectomy. j urol. 2013; 189:36-42. 22. minervini a, siena g, antonelli a, et al. open versus laparoscopic partial nephrectomy for clinical t1a renal masses: a matchedpair comparison of 280 patients with trifecta outcomes (record project). wj urol. 2014; 32:257-63. 23. thompson rh, lane br, lohse cm, et al. every minute counts when the renal hilum is clamped during partial nephrectomy. eur urol. 2010; 58:340-5. 24. porpiglia f, bertolo r, amparore d, fiori c. margins, ischaemia ricciardulli_stesura seveso 02/04/15 10:22 pagina 54 and complications rate after laparoscopic partial nephrectomy: impact of learning curve and tumour anatomical characteristics. bju int. 2013; 112:1125-32. 25. aboumarzouk om, stein rj, eyraud r, et al. robotic versus laparoscopic partial nephrectomy: a systematic review and metaanalysis. eur urol. 2012; 62:1023-33. 26. ficarra v, bhayani s, porter j, et al. predictors of warm ischemia time and perioperative complications in a multicenter, international series of robot-assisted partial nephrectomy. eur urol. 2012; 61:395402. 27. sea jc1, bahler cd, mendonsa e, et al. comparison of measured renal tumor size versus r.e.n.a.l. nephrometry score in predicting patient outcomes after robot-assisted laparoscopic partial nephrectomy. j endourol. 2013; 27:1471-6. 55archivio italiano di urologia e andrologia 2015; 87, 1 mic in laparoscopic and robotic partial nephrectomy correspondence stefano ricciardulli, md (corresponsing author) stefano.ricciardulli@gmail.com department of urology, san bassiano hospital via dei lotti 40 bassano del grappa, italy department of urology, chinese pla general hospital no. 28 fuxing road, beijing 100853, china quiang ding, md dingqiangchina@foxmail.com xu zhang phd, md (corresponding author) xzhang@foxmail.com hongzhao li, md urolancet@126.com yuzhe tang, md townyuzhe@gmail.com guoqiang yang, md gqyang@outlook.com xiyou wang, md 510198870@qq.com xin ma, md department of urology, chinese pla general hospital no. 28 fuxing road, beijing 100853, china urologist@foxmail.com alberto breda, md albbred@hotmail.com department of urology, foundacio puigvert universidad autonoma de barcelona barcelona (spain) antonio celia, md antonio.celia@aslbassano.it department of urology, san bassiano hospital bassano del grappa, italy ricciardulli_stesura seveso 02/04/15 10:22 pagina 55 237archivio italiano di urologia e andrologia 2016; 88, 3 case report fournier's gangrene: clinical case and review of the literature remigio pernetti 1, fabiano palmieri 1, elisabetta sagrini 2, marco negri 3, claudio morisi 4, andrea carbone 5, paolo bassi 6, salvatore voce 1 1 uo urology, santa maria delle croci hospital, ravenna, italy; 2 uo internal medecine, santa maria delle croci hospital, ravenna, italy; 3 uo general surgery, santa maria delle croci hospital, ravenna, italy; 4 ambulatory surgery wounds-necrotic ulcers, santa maria delle croci hospital, ravenna, italy; 5 uo plastic surgery, santa maria delle croci hospital, ravenna, italy; 6 uo infectious diseases, santa maria delle croci hospital, ravenna, italy. fournier's gangrene is a life-threatening acute necrotizing fasciitis of perianal,genitourinary and perineal areas. nowadays, is well known that fournier gangrene is almost never an idiopathic disease. in this article we report a case of a 70-year-old patient that initially was not treated properly. the gold standard therapy of the fournier's gangrene remains today a complete, early and extended surgical debridement. key words: fournier's gangrene; necrotizing fasciitis; scrotal gangrene; perianal abscess; surgical debridement; staphylococcus aureus, klebsiella pneumonia; pseudomonas aeruginosa; proteus mirabilis; eenterococci; bacteroides fragilis. submitted 22 january 2016; accepted 22 may 2016 summary no conflict of interest declared. ly gangrenous; gangrenous process spread to the right and left groins and perineum (figure 1), patient was febrile and complained severe perineal pain. blood pressure was 87/50 mmhg, heart rate was 124 beats/min, and respiratory rate was 24 breaths/min with an oxygen saturation of 100% on room air. aggressive intravenous (iv) fluid resuscitation with normal saline was begun and, with a provisional clinical diagnosis of fournier’s gangrene, iv clindamycin, and ampicillin/sulbactam, was administered, and urgent surgical consultation was performed. his initial ed labs were remarkable for a white blood cell count of 12,000/mm and a lactate of 2.2 meq/l. after initial clinical stabilization patient was immediately referred to the surgical theatre. an extensive debridement was carried out with denudation of both testes, proximal penile shaft, and the external aponeurosis in the entire right and left inguinal area extending posteriorly to the perianal area were exposed (figure 2). the testicles were tied together to prevent the twist but both testicles (figure 3) were then removed due to the extensive spread of the disease (figure 4). the patient became afebrile in two days. after 7 days we started again the patient on hyperbaric oxygen. consecutive local treatment consisted of wound irrigation with hydrogen peroxide through multiple catheters with bulky dressings and honey resulting in a clean wound within seven days and healthy granulation within three weeks (figure 5). a split-level thickness graft was taken from the thigh and used to cover the scrotum and perineum (figure 6).the patient was discharged at the end of the third week (figure 7). conclusion the gold standard terapy of the fournier's gangrene remains today a complete, early and extended surgical debridement. introduction complete, discussion and supple men tary references are posted on www.aiua.it doi: 10.4081/aiua.2016.3.237 introduction fournier’s gangrene is a life-threatening acute necrotizing fasciitis of perianal, genitourinary and perineal areas (1-4). we describe the case of a diabetic patient with fournier’s disease presented with severe sepsis and successfully treated with urgent deep debridement and reconstructive surgery. case report a 70-year-old presented to the emergency department of his city with a history of inflamed scrotum and perianal abscess. the medical history was remarkable for diabetes and prostate cancer. he was afebrile and the vital signs were stable. on clinical examination, his scrotum was oedematous and erythematous with well-delineated black necrotic areas. the lactate was within normal limits. the patient was given broad-spectrum antibiotics and iv fluids and urgently referred to urology department. he was taken to the theatre for a simple incision of the scrotum and of the perianal abscess and debridement by the urology consultant. he was then transferred to the emergency department (ed) of our hospital to perform hyperbaric therapy at the specialized centre of ravenna. when he arrived the scrotal skin was all clearpernetti_stesura seveso 21/09/16 09:09 pagina 237 archivio italiano di urologia e andrologia 2016; 88, 3 r. pernetti, f. palmieri, e. sagrini, m. negri, c. morisi, a. carbone, p. bassi, s. voce 238 references 1. eke n. fournier gangrene: a review of 1726 cases. br j surg. 2000; 87:718-728. 2. paty r, smith ad. gangrene and fournier gangrene. urol clin north am. 1992; 19:149-162. 3. yanar h, taviloglu k, ertekin c, et al. fournier gangrene: risk figure 1. gangrenous process spread to the right and left groins and perineum. figure 3. testicles were tied together to prevent twisting. figure 4. both testicles removed due to the extensive spread of the disease. figure 5. healthy granulation within three weeks. figure 6. split-level thickness graft was taken from the thigh and used to cover the scrotum and perineum. figure 7. end of the third week. figure 2. extensive debridement. correspondence remigio pernetti, md r.pernetti@virgilio.it fabiano palmieri, md salvatore voce, md, prof uo urology, santa maria delle croci hospital, ravenna, italy elisabetta sagrini, md uo internal medecine, santa maria delle croci hospital, ravenna, italy marco negri, md uo general surgery, santa maria delle croci hospital, ravenna, italy claudio morisi, md ambulatory surgery wounds-necrotic ulcers, santa maria delle croci hospital, ravenna, italy andrea carbone, md uo plastic surgery, santa maria delle croci hospital, ravenna, italy paolo bassi, md uo infectious diseases, santa maria delle croci hospital, ravenna, italy factors and strategies for management. world j surg. 2006; 30:1750-1754. 4. norton ks, johnson lw, perry t, et al. management of fournier gangrene: an eleven year retrospective analysis of early recognition, diagnosis, and treatment. am surg. 2002; 68:709-13. pernetti_stesura seveso 21/09/16 09:09 pagina 238 introduction adenomatoid tumor is the most common epididymal tumor and accounts for approximately 30% of all paratesticular neoplasms, second only to lipoma (1). adenomatoid tumors occur in men with a wide range of ages, with the majority being diagnosed in patients aged 20-50 years. patients usually present with a painless scrotal mass. the tumors are round, well-circumscribed and can vary in size from a few millimetres up to 5 cm. they are believed to be of mesothelial origin and are universally benign (2). although more frequent in the tail, adenomatoid tumors may occur anywhere in the epididymis and have also been reported in the spermatic cord and tunica albuginea (3). on ultrasound (us) scans, they typically appear isoechoic and homogeneous mass. because of the adenomatoid tumor’s sonographic similary to malignant neoplasms, patients with these tumors usually undergo a surgical treatment. in this case report is analyzed a case of adenomatoid tumor of the epididymis in a young-adult man. case report a 46 years old man referred to our department for painless enlargement in the left hemiscrotum. personal and 41archivio italiano di urologia e andrologia 2013; 85, 1 case report ultrasound diagnosis of unusual extratesticular mass: case report and review of the literature lucio dell’atti urology unit, arcispedale “s. anna”, ferrara, italy. the adenomatoid tumor of the epididymis (eat) is a neoplasm located in the paratesticular region. mesothelial origin has been mentioned and inflammation has played some role in the development of these tumors. physical examination and testicular ultrasound constituted important tools in the diagnosis. some reports have mentioned malignant behavior, but it is very rare. surgical treatment is the procedure of choice. we present the case of a 46-year-old patient with an adenomatoid tumour located in the head of the left epididymis that referred to our department with gradually enlarged intrascrotal mass. key words: ultrasound; extratesticular mass; epididymis; adenomatoid tumor. submitted 27 august 2012; accepted 31 december 2012 no conflict of interest declared summary familiar history were unremarkable, without epididymitis, torsion or trauma. at physical examination colour changes and slight edema of the superior third of the scrotum were found, where it was observed a well defined, nodular, encapsulated tumor of 3 x 3 x 2 cm with firm consistency and related to the left epididymis, with which it formed a mass. no other relevant signs were found. ultrasonography confirmed a solid isoechoic lesion lying on the border between epididymal head and upper pole of the left testis without any disruption of the architecture of the testicular parenchyma (figure 1). the testicular parenchyma immediately adjacent to the mass showed slightly decreased echogenicity compared with the parenchyma elsewhere. preoperative laboratory investigation, including blood count and blood chemisties were within normal limits. plasma levels of !-hcg (!-subunit human chorionic gonadotropin), "-fetoprotein (afp), lactic dehydrogenase (ldh) were within normal ranges. the patient underwent surgical testicular exploration, which verified the existence of a nodular lesion in the upper pole of the left testicle meaduring 3 x 3 x 2 cm, ovoid shaped, firm, limited and adherent to the testicle. subsequently a tumorectomy was performed, with the dell'atti_stesura seveso 18/04/13 12:05 pagina 41 archivio italiano di urologia e andrologia 2013; 85, 1 l. dell’atti 42 the possible histogenesis of adenomatoid tumors has aroused controversy and so far data are still contradictory. however, the most recent investigations favour a mesothelial origin (9) although other pathologists considered it as a reaction to injury or inflammation. however, it is difficult to demonstrate such irritating factors in intrascrotal adenomatoid tumors. conclusion us can be used to quickly and accurately estanilish whether an abnormal lesion is intratesticular or extratesticular. if it is extratesticular and cystic, a specific diagnosis can often be made (hydrocele, epididymal cyst, varicocele) and the patient can be reassured that the mass is benign. because of their sonographic features, the benign characteristics of solid extratesticular masses can be somewhat more problematic to diagnose by gray-scale and color flow doppler sonography. magnetic resonance imaging can be a problem-solving modality in some cases. however extratesticular solid masses of uncertain diagnostic significance require surgical treatment as procedure of choice. references 1. benson cb, doubilet pm, richie jp. sonography of the male genital tract. ajr am j roentgenol. 1989; 153:705-713. 2. benign non-cystic scrotal tumors and pseudotumors. acta radiol. 2012; 53:102-111. 3. kim tj, kim sh, sim js, seong ck, lee dk. ultrasonographic findings of an intratesticular adenomatoid. j ultrasound med. 2000; 19:227-229. intraoperative histopathologic diagnosis of a benign lesion (figure 2). histological appearance of this paratesticular tumor is represented by cuboidal cells, with vacuolated cytoplasm and with gaping spaces. discussion sakaguchi in 1963, described the first benign tumor of the epididymis, meanwhile golden and ash (4) in 1945, first used the eat acronym, to indicate the most common paratesticular neoplasm. in 1976, beccia et al. (5) gathered a total of 314 epididymal tumors, of which 75% were benign and of these 73% resulted to be eat (55% of the total), followed by leiomyomas (11%) and by papillary cystadenomas (9%). angiomas, lipomas, and hamartomas constitute the remaining 7%. gupta et al. (6) refer that primary malignant tumors of the epididymis constitute 25% of the tumors of this zone, although in geographical areas where still exists a high incidence of epididimary tuberculosis this incidence can fall below 1% to constitute 3 groups: sarcomas, epithelial tumors and dysembrionary tumors. although the eat are considered by the majority of authors as benign, malignant forms of this tumor were also described (6-7). a variety of neoplasms derived from mesenchymal elements may arise by the paratesticular tissues: carcinoma of rete testis, malignant mesothelioma, ovarian-type epithelial tumors, epididymidal carcinoma and metastatic carcinoma. most adenomatoid tumors of epididymis are asymptomatic and are found accidentally by the patient or by the physician during physical examination, as a non painful scrotal mass more commonly located at the tail of the epidydimis, which generally remains unchanged in size for years (8). figure 1. longitudinal power-doppler images of the scrotum shows an paratesticular mass, avascular, isoechoic with circumscribed aspect. figure 2. macroscopic findings on the surgical exploration. the testis appears normal. the tumor is connected to the head of the epididymis. dell'atti_stesura seveso 18/04/13 12:05 pagina 42 43archivio italiano di urologia e andrologia 2013; 85, 1 ultrasound diagnosis of unusual extratesticular mass: case report and review of the literature 7. bestard vallejo je, tremps velázquez e, blázquez mañá c, et al. tumor adenomatoide de epidídimo: el tumor más frecuente de las estructuras paratesticulares. actas urol esp. 2008; 32:611-7. 8. fan k, johnson df. adenomatoid tumor of ejaculatory duct. urology. 1985; 25:653-4. 9. delahunt b, eble jn, nacey jn, thomton a. immunohistochemical evidence for mesothelial origin of paratesticular adenomatoid tumour. histopathology. 2001; 38:479. 4. golden a, ash je. adenomatoid tumors of the genital tract. am j path. 1945; 21:63-79. 5. beccia dj, krane rj, olsson ca. clinical management of nontesticular intrascrotal tumors. j urol. 1976; 116:476-479. 6. gupta n, rajwanshi a, srinivasan r, nijhawan r. fine needle aspiration of epididymal nodules in chandigarh, north india: an audit of 228 cases. cytopathology. 2006; 17:195-8. correspondence lucio dell’atti, md u.o. urologia, azienda ospedaliero-universitaria arcispedale “s. anna” via aldo moro 8 44124 cona, ferrara, italy dellatti@hotmail.com dell'atti_stesura seveso 18/04/13 12:05 pagina 43 stesura seveso 93archivio italiano di urologia e andrologia 2015; 87, 1 case report ischemia of the glans penis following circumcision: case report and revision of the literature pietro pepe, francesco pietropaolo, giuseppe candiano, michele pennisi urology unit, cannizzaro hospital, catania, italy. ischemic complications of the glans penis are rare and commonly result from trauma, inadvertent administration of vasoconstrictive solutions, diabetes mellitus, circumcision and vasculitis; we refer about a young man with severe ischemia of the glans penis following circumcision. the patient had undergone circumcision 5 days before in a surgery department under local anesthesia (1% mepivacaine hydrochloride). the patient noticed a brownish color and edema of the glans penis at 24 h after he opened the wound dressing, but arrived to our hospital only 5 days after circumcision because these findings had progressed. physical examination revealed the black color or necrotic appearance of the glans penis, and edema on the dorsal penile skin. the patient underwent antibiotic, antiplatatelet, corticosteroid and iperbaric therapy achieving a complete restitutio ad integrum. key words: ischemia of the glans penis; circumcision complications; glans penis. submitted 1 september 2014; accepted 30 november 2014 summary no conflict of interest declared. sound of the penis was normal. there were no urination problems and all laboratory findings, including whole blood count, blood chemistry, and bleeding-clotting profile were within normal limits. the patient underwent antibiotic (1 tablet of levofloxacin 500 daily for 15 days), antiplatatelet (1 tablet of aspirin 330 mg daily for 1 month), corticosteroid (prednisone 25 mg daily for 10 days) and iperbaric therapy (for 15 days) and achieved a complete restitutio ad integrum (figure 1b). doi: 10.4081/aiua.2015.1.93 introduction ischemic complications of the glans penis are rare and commonly result from trauma, inadvertent administration of vasoconstrictive solutions, diabetes mellitus, circumcision and vasculitis (1-6). we refer about a young man with severe ischemia of the glans penis following circumcision. case report a 20-year-old man was admitted to our hospital with complaints of black color and swelling of the glans penis. the patient had undergone circumcision 5 days before in a surgery department under local anesthesia (1% mepivacaine hydrochloride) and was discharged 12 hours following circumcision. the patient noticed a brownish color and edema of the glans penis at 24 h after he opened the wound dressing, but arrived to the hospital only 5 days after circumcision because these findings had progressed. physical examination revealed the black color or necrotic appearance of the glans penis, and edema on the dorsal penile skin (figure 1a); moreover colordoppler ultrafigure 1. severe ischemia of the glans penis (1a) at clinical admission (5 days after circumcision); normal color and trophism of the glans (1b) after medical treatment (15 days later) a. b. pepe_stesura seveso 02/04/15 10:33 pagina 93 archivio italiano di urologia e andrologia 2015; 87, 1 p. pepe, f. pietropaolo, g. candiano, m. pennisi 94 discussion ischemia of the glans penis is a rare condition; the most frequent causes are circumcision, trauma, penile strangulation, and application of vasoconstrictive agents (1-6). additionally, there are several pathologies which cause glanular ischemia or necrosis in adults, including diabetes mellitus (7), acute arterial occlusion, foreign bodies, fournier’s gangrene, spider bite (8) and topical treatment with 1% gentian violet (9). ischemia of the glans penis following circumcision commonly results from dorsal penile nerve block with local anesthetics (3, 4) and inadequate surgical technique or devices. the main goal of the treatment is to provide sufficient blood flow and oxygen delivery to the ischemic penis. burke et al. (3) described ischemia of the glans penis occurring 40 min after dorsal penile nerve block with 0.75% ropivacaine, and successfully treated with an intravenous infusion of iloprost. broughton et al. (8) reported that hyperbaric oxygen and methylprednisolone treatment was an effective treatment for a patient with glanular skin necrosis due to spider bite. on the other hand, penile necrosis in patients with diabetes mellitus and fournier’s gangrene may need aggressive surgical debridement and partial penectomy following hyperbaric oxygenation. the literature reports cases in which pentossifillina (ptx), an orally active hemorheological agent which is widely used to treat peripheral vascular and cerebrovascular diseases, was used in the treatment of post-circumcisional ischemia of the glans penis (1, 10); it was suggested that the valuable effect of ptx on ischemia-reperfusion injury might be related to the stimulation of prostaglandin production, and inhibition of the phosphodiesterase activity, which led to camp synthesis. aslan et al. (10) encountered a similar clinical picture in a case of ischemia of the glans on the third day after circumcision; moreover, tzeng et al. (11) treated a 33-year-old patient with ptx and hyperbaric oxygen therapy and reported that the ischemia resolved completely. recently, efe et al. (12) reported a case of severe glans ischemia occurred 24 hours after circumcision with local anesthesia (0.1% xylocaine containing ephedrine) in a children 7 years old that was successfully treated with subcutaneous injection of enoxaparin (low-molecularweight heparin) for 5 days. in the presented case, although the precise cause of the severe glanular ischemia was not known, it might have been secondary to the circumferential nerve block or very firm wound dressing for 24 h; anyway, medical therapy (aspirin, prednisone and antibiotic) combined with hyperbaric oxygen treatment allowed to achieve a complete restitutio ad integrum. references 1. karaguzel e, tok ds, kazaz io, et al. postcircumcisional ischemia of the glans penis treated with pentoxifylline. case rep urol. 2013; 2013:278523. 2. wiliams n, kapila l. complications of circumcision. br j surg. 1993; 80:1231-1236. 3. burke d, joypaul v, thomson mf. circumcision supplemented by dorsal penile nerve block with 0.75% ropivacaine: a complication. reg anesth pain med. 2000; 25:424-427. 4. soh cr, ng sba, lim sl. dorsal penile nerve block. paediatr anaesth. 2003; 13:329-333. 5. brecheteau f, grison p, abraham p, et al. successful medical treatment of glans ischemia after voluntary buprenorphine injection. j sex med. 2013; 10:2866-2870. 6. pepe p, panella p, candiano g, et al. partial priapism secondary to idiopathic segmentary thrombosis of corpora cavernosa. arch ital urol androl. 2012; 84:101-103. 7. nomura t, sakamoto f. a case of penile necrosis in a patient with diabetes mellitus. nippon hinyokika gakkai zasshi. 1992; 83:1138-1141. 8. broughton g. management of the brown recluse spider bite to the glans penis. mil med. 1996; 161:627-629. 9. zabala egurrola ja, pertusa peña c, arruza echevarría a, et al. glans penis necrosis secondary to gentian violet treatment. arch esp urol. 1989; 42:800-802. 10. aslan a, karaguzel g, lu mm. severe ischemia of the glans penis following circumcision: a successful treatment via pentoxifylline. int j urol. 2005; 12:705-707. 11. tzeng ys, tang sh, meng e, lin tf, sun gh. ischemic glans penis after circumcision. asian j androl. 2004; 6:161-163. 12. efe e, resim s, bulut bb, et al. successful treatment with enoxaparin of glans ischemia due to local anesthesia after circumcision. pediatrics. 2013; 131:e608-11. correspondence pietro pepe, md piepepe@hotmail.com francesco pietropaolo, md giuseppe candiano, md michele pennisi, md urology unit, cannizzaro hospital via messina 829 catania, italy fax ++ 39 95 7263259 pepe_stesura seveso 02/04/15 10:33 pagina 94 stesura seveso 249archivio italiano di urologia e andrologia 2014; 86, 4 original paper clinical presentation of urolithiasis in older and younger population murat dursun 1, emin ozbek 2, alper otunctemur 3, suleyman sahin 4, suleyman sami cakir 5 1 bahcelievler state hospital, department of urology, istanbul, turkey; 2 katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey; 3 okmeydani training and research hospital, department of urology, istanbul, turkey; 4 bilecik state hospital, department of urology, bilecik, turkey; 5 bayburt state hospital, department of urology, bayburt, turkey. aim of the study: we compared stone size, localization, complaint at the time of applying, comorbidity, treatment and complications between older (60 years of age and older) and younger patients with urolithiasis (59 years of age and younger). materials and methods: we retrospectively reviewed the records of 950 consecutive patients who presented to our clinic and underwent surgery for urolithiasis from january 2007 to march 2012. the patients were divided into two groups: patients ≥ 60 years an patients < 60 years. results: there were 174 men and 61 women in elderly group, 528 men and 187 women in younger group. ureteral stones were found more often in the younger group compared to elderly patients (p < 0.05). conversely, bladder stone was more frequent in the elderly group. in the elderly group comorbidities are more frequent (diabetes mellitus, hypertension, ischemic heart disease, congestive heart disease, osteoarthritis and chronic obstructive lung). patients ≥ 60 years significantly had larger kidney and bladder stones compared the younger, but ureteral stone sizes were not statistically different between the two groups. older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0.05) although postoperative complications (e.g. urinary retention, cardiac dysrythmia, fever, constipation) were not serious and resolved with medical treatment. the average length of stay in hospital was longer in the elderly group, but the difference was not statistically significant. conclusions: elderly patients with urolithiasis usually have larger and more complex stone disease, more comorbidities and atypical presentation. key words: urinary calculi; elderly; comorbidities. submitted 5 february 2014; accepted 30 june 2014 summary no conflict of interest declared. both men and women (3,4). the lifetime recurrence risk is 50% with an estimated time to recurrence < 1 year in 10% of cases, < 5 years in 35 to 50% of cases and < 10 years in 50% or greater (5). stones along the urinary tract can be located in the kidneys, ureters and urinary bladder. while approximately 90% of stones are successfully passed out of the urinary tract, the remaining stones generally have to be surgically removed by ureteroscopy or percutaneous nephro lithotomy or comminuted by non-invasive shock wave lithotripsy (6). stone occurrence is relatively uncommon before age 20 but peaks in incidence in the fourth to sixth decades of life. geriatric stone formers comprise 10%-12% of all stone formers and may have a proclivity to develop stones due to metabolic changes associated with ageing (7, 8). altough it has been shown that geriatric patients with stones tend to have their first episode after age 50, it is not well described how the presentation of stones differs in elderly patients (7). according to the world health organization (who), ageing is defined as living beyond 60 years in a developing country or 65 years in a developed country. the number of ageing people is increasing faster than is any other age group; in 2025, there will be an estimated 1.2 billion individuals over the age of 60, and this number could reach 2 billion by 2050 (9). so, we reported a study of clinical presentation of urolithiasis in elderly compared to younger. we compared the stone size, localization, complaint at the time of applying, comorbidity, treatment and complications between the old (60 years of age and older) and young patients (59 years of age and younger). material and methods we retrospectively reviewed the records of 950 consecutive patients who presented to our clinic and underwent surgery for urolithiasis from january 2007 to march 2012. the diagnosis of urolithiasis was assessed by either ultrasonography, intravenous urography or abdominal ct. we excluded the patients who did not have surgery or eswl and were followed by medical therapy because doi: 10.4081/aiua.2014.4.249 introduction urolithiasis is the third most common urological disease affecting the urinary tract after urinary infection and prostatic pathology (1). the prevalence of urolithiasis varies between 2 and 20% throughout the world (2). the worldwide prevalence of the disease appears to have increased in the last quarter of the twentieth century for dursun_clin_stesura seveso 16/01/15 09:22 pagina 249 archivio italiano di urologia e andrologia 2014; 86, 4 m. dursun, e. ozbek, a. otunctemur, s. sahin, s. sami cakir 250 the follow up of these patients is difficult in our hospital. we also excluded the patients who have hormonal therapy which is associated with urolithiasis. the patients were evaluated by internal medicine specialist and consent was acquired in all the patients. the patients were divided into two groups: patients ≥ 60 years an patients < 60 years. there were 235 patients in the elderly group and 715 patients in the younger group. stone size, localization, complaint at the time of applying, comorbidity, treatment and complications were compared between groups. a retrospective case-control study was used and data were analyzed by univariate statistics. frequency analyses and descriptive statistics, i.e. mean and standard deviation (sd), were performed. the student’s t test was used to compare the groups. results there were 174 men and 61 women in elderly group, 528 men and 187 women in younger group. the mean age of elderly patients was 66.86 ± 0 years and 35 ± 2,82 years in young group. there were 85 (36.2%) patients with renal stones, 76 (32.3%) patients with ureteral stones and 74 (31.5%) patients with bladder stones in the elderly group and 257 (36%), 411 (57.4%) and 47 (6.6%) patients respectively in the younger group. so, ureteral stones were found more often in younger group compared to elderly patients (p < 0,05). also bladder stone was more frequent in the elderly group as shown in figure 1. elderly and young patients were compared for comorbidities and in the elderly group comorbidities are more frequent (table 1). there was a statistically significant difference for diabetes mellitus, hypertension, ischemic heart disease, congestive heart disease, osteoarthritis and chronic obstructive lung disesase prevalence between groups. the presenting complaints were compared as flank pain, hematuria, dysuria, urinary tract infection and no symptoms (figure 2). flank pain seems more often in the younger population and other complaints seems more often in the elderly group, but no statistically siginificant difference was shown. mean stone size was found 28 ± 5.65 mm for the largest stone diameter in ≥ 60 years group and 20 ± 14.14 mm in < 60 years group. elderly patients had larger stones compared the younger (p < 0.05). for localization as kidney, ureter and bladder; mean stone size was measured 34.23 ± 5.65 mm, 14.28 ± 12.72 mm and 25.94 ± 6.36 mm in elderly patients and 21 ± 12.72 mm, 15 ± 7.07 mm and 19 ± 1.41 mm in younger patients respectively (figure 3). patients ≥ 60 years significantly had larger kidney and bladder stones compared the younger, but ureteral stone sizes were not statistically different between groups. comorbidity prevelence in ≥ 60 prevelence in < 60 years group (%) years group (%) diabetes mellitus 32.3 11 hypertension 57.4 29 congestive heart failure 17.4 1 ischemic heart disease 34.1 9 gastroesophageal reflux disease 31.9 17.4 stroke 5.5 1.9 chronic obstructive lung disease 27.6 7.1 osteoarthritis 43.4 7.5 table 1. comparison of some comorbidities between groups. figure 1. comparison of stone location between younger and elderly groups. figure 3. comparison of mean kidney, ureter and bladder stone size between elderly and younger groups. figure 2. comparison for presenting complaints between groups (no significant difference was found for each complaint) (uti= urinary tract infection). dursun_clin_stesura seveso 16/01/15 09:22 pagina 250 patients in both groups were treated by similar treatment methods as percutaneous nephrolithotomy (pcnl), ureteroscopy (urs), extracorporeal shock wave lithotripsy (eswl), cystolithotripsy or open surgery according to stone localization. in younger group, 9 patients (19%) underwent cystholitotomy and 38 (81%) cystolithotripsy for bladder stone. cystholithotomy was seen more frequently in older patients, in fact 24 patients (32%) underwent open surgery for bladder stone in the older group. in the older group 3 patients (3%) underwent open surgery for kidney stones, 26 patients (30%) eswl and 26 patients (65%) pcnl. in the younger group the numbers of patients were respectively 32 (12%), 84 (32%) and 141 (56%). in elderly populations, pcnl was used more frequently for kidney stones, but difference was not statistically significant. in younger group, 21 patients (5%) underwent open surgery, 156 patients (38%) eswl and 234 (57%) urs for ureteral stones. similarly, in the older group 55% of patients underwent urs and 40% of eswl. there was no difference in the rate of intraoperative complications between groups, but older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0,05). postoperative complications (e.g. urinary retention, cardiac dysrythmia, fever, constipation) were not serious and resolved with medical treatment. in our study, all patients underwent surgery or eswl, and 465 patients of the younger group and 179 patients of the older group stayed in hospital for a period. the average length of stay in hospital was longer in the elderly group compared to the younger group (2.3 and 2 day, respectively), but difference was not statistically significant. discussion the geriatric population is the fastest growing segment in many parts of the world. most developed countries have accepted the chronologic age of 65 years as a definition of “elderly” or older person; however, the united nations agreed a cut off of 60 years to refer to the older population. age itself is not an illness, however, the changes in cardiopulmonary reserve of the elderly patients make them less tolerant to certain stressors, such as an increase in demand during the perioperative period, bleeding, or medical complications (10, 11). on the other hand, increasing incidence and considerable recurrence along with severe renal functional consequences make urolithiasis a surgical and a medical problem which needs a prompt diagnosis and appropriate management in elderly populations (12, 13). therefore, careful selection and preparation of the patients are very important in the geriatric population with urolithiasis for decreasing lifethreatening complications. accordingly, in this study we compared comorbidities, stone size, localization, treatment options and complications between elderly and younger populations in order to contribute in treatment choice and patient selection in the elderly population with urolithiasis. like in our study, bladder stones have been found to be frequent in the elderly as reported by some studies (14) but not in others (15). according to daudon et al. (14), 40.0% of the patients they analyzed were men over 80 years. in our study, 6.6% of the stones were from the bladder in the younger group, but elderly men were most affected (31.35%). in contrast to, ureteral stone rate was found higher in the younger group. prostatic hyperplasia, which is considered a frequent cause of bladder outlet obstruction, is frequent in old men and could be a possible explanation for the high frequency of bladder stones in the elderly (14, 16). our findings confirmed that older patients with urolithiasis had more comorbidities than younger as shown in previous studies (17-19). in our study, especially comorbidities related to metabolic syndrom seems to be more frequent in the elderly group. the association between metabolic syndrome and kidney stones has been established by some studies (20-22). furthermore, the risk of a stone former to develop diabetes mellitus is partially supported by two recent investigations (23, 24) and some studies provide evidence of an association between kidney stone formation and cardiovascular disease (25, 26). in fact these comorbidities were more frequent in the elderly group and may be cause of stone formation in these patients. our data suggest that elderly patients had a more atypical presentation of disease as shown in figure 2 and these atypical presentations cause delay in the diagnosis. this may explain why mean kidney stone size was found larger in older group compared to the younger. this finding confirm what previously described by mccarthy et al. (19) although in their study were described only 26 older patients whereas in our study we reported a larger number of 235 older patients. another explanation is the steady decline in renal function that occurs with advanced age, as supersaturation and stone formation have been attributed to renal tubular cell damage (27-29). for the treatment modalities, there were no statistical difference between groups. according to comorbidities, stone size and localization, patients underwent different treatment options. in previous studies, pcnl was demonstrated to be a safe and effective treatment for urinary calculi in both elderly patients and those with comorbid conditions (30, 31) and we did not found statistical difference for different treatment options between older and younger patients. the average length of stay in hospital was longer in the elderly group, probably owing to the occurence of more postoperative complications in older patients. in fact, in our study, older patients had a higher postoperative complication rate than younger patients (16% versus 3%, p < 0.05). urinary retention may be caused by benign prostate hyperplasia (bph) that is more frequent in older patients. other comorbidities like cardiac problems and hypertension are more often in older group, consequently older patients are usually at risk of ischemic cardiac disease and arythmia. infections be cause fever in postoperative period in consideration of the poor immune system of older patients. in conclusion, elderly patients with urolithiasis usually have larger and more complex stone disease, more comorbidities and atypical presentation. because of that physicians have to be careful in the preoperative and 251archivio italiano di urologia e andrologia 2014; 86, 4 relation between age and urolithiasis dursun_clin_stesura seveso 16/01/15 09:22 pagina 251 archivio italiano di urologia e andrologia 2014; 86, 4 m. dursun, e. ozbek, a. otunctemur, s. sahin, s. sami cakir 252 postoperative period for the treatment of urolithiasis in elderly populations. treatment of stones in elderly patients can be delayed and they may admitted to the hospital due to other problems, because they usually have silent stone disease. like in our study, older patients may have larger stones when they admitted to hospital. we must plan carefully the treatment algoritm in older patients with urolithiasis because of the risk of postoperative complications the complaints of older patients may be serious and require prompt intervention. references 1. smith lh. the medical aspects of urolithiasis: an overview. j urol. 1989; 141:707. 2. curhan gc. epidemiology of stone disease. urol clin n am. 2007; 34:287-293. 3. stamatelou kk, francis me, jones ca et al. time trends in reported prevalence of kidney stones in the united states: 1976–1994. kidney int. 2003; 63:1817-1823. 4. hesse a, brandle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2000; 44:709-713. 5. pearle ms, calhoun ea, curhan gc. urolithiasis. in: litwin ms, saigal cs, editors. urologic diseases in america. us department of health and human services, public health service, national institutes of health, national institute of diabetes and digestive and kidney diseases. washington, dc: us government publishing office; 2007. pp. 283-319. nih publication no. 07-5512. 6. lingeman je, matlaga b, evan ap. surgical management of urinary lithiasis. in: walsh pc, retik ab, vaughan ed, wein aj, editors. campbell’s urology, chap 44. philadelphia: saunders. 2006; pp. 1431-1507. 7. gentle dl, stoller ml, bruce jr, leslie sw. geriatric urolithiasis. j urol. 1997; 158:2221-2224. 8. mhiri mn, achiche s, maazoun f, et al. urinary calculi in a geriatric setting. ann urol (paris) 1995; 29:382-388. 9. biggs a, bloom d, burtless g, fujiwara m, hayashi k, kanzler l, et al. a slow burning fuse; a special report on aging populations. the economist. 2009; 27:1-15. 10. tonner ph, kampen j, scholz j. pathophysiological changes in the elderly. best practi res clin anaesthesiol. 2003; 17:163-177. 11. ng cf. the effect of age on outcomes in patients undergoing treatment for renal stones. curr opin urol. 2009; 19:211-214. 12. lancina martín ja, novás castro s, rodríguez-rivera garcía j, et al. age of onset of urolithiasis: relation to clinical, metabolic risk factors. arch esp urol. 2004; 57:119-125. 13. trinchieri a, ostini f, nespoli r, et al. prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999; 162:27-30 14. daudon m. évolution de la composition et de la localisation des calculs chez le sujet âgé. feuillets de biologie. 2003; 25:51-4. 15. neuzillet y, lechevallier e, ballanger p, et al. urinary stones in subjects over the age of sixty. prog urol. 2004; 14:479-84. 16. el-reshaid k, mughal h, kapoor m. epidemiological profile, mineral metabolic pattern and crystallographic analysis of urolithiasis in kuwait. eur j epidemiol. 1997; 13:229-34. 17. pinkawa m, fischedick k, gagel b, et al. impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment. bmc cancer. 2009; 9:296. 18. mao jj, armstrong k, bowman ma, et al. symptom burden among cancer survivors: impact of age and comorbidity. j am board fam med. 2007; 20:434-443. 19. mccarthy j-p, skinner taa, norman rw. urolithiasis in the elderly. the canadian journal of urology. 2011; 18:5717-5720. 20. west b, luke a, durazo-arvizu ra, et al. metabolic syndrome and selfreported history of kidney stones: the national health and nutrition examination survey (nhanes iii) 1988–1994. am j kidney dis 2008; 51: 741-747. 21. rendina d, mossetti g, de filippo g, et al. association between metabolic syndrome and nephrolithiasis in an inpatient population in southern italy: role of gender, hypertension and abdominal obesity. nephrol dial transplant. 2009; 24:900-906. 22. jeong ig, kang t, bang jk, et al. association between metabolic syndrome and the presence of kidney stones in a screened population. am j kidney dis. 2011; 58:383-388 23. ando r, suzuki s, nagaya t, et al. impact of insulin resistance, insulin and adiponectin on kidney stones in the japanese population. int j urol. 2011; 18:131-138. 24. chung sd, chen yk, lin hc. increased risk of diabetes in patients with urinary calculi: a 5-year followup study. j urol. 2011; 186:1888-1893. 25. elmfeldt d, vedin a, wilhelmsson c, et al. morbidity in representative male survivors of myocardial infarction compared to representative population samples. j chronic dis. 1976; 29:221-231. 26. westlund k. urolithiasis and coronary heart disease: a note on association. am j epidemiol. 1973; 97:167-172. 27. kumar s, sigmon d, millet t, et al. a new model of nephrolithiasis involving tubuler dysfunction/injury. j urol. 1991; 146:1384-1389. 28. khan sr, canales bk. genetic basis of renal cellular dysfunction and the formation of kidney stones. urol res 2009; 37:169-180. 29. khan sr. renal tubuler damage/dysfunction: key to the formation of kidney stones. urol res. 2006; 34:86-91. 30. patel sr, haleblian gl, pareek g. percutaneous nephrolithotomy can be safely performed in the high-risk patient. urology. 2010; 75: 51-55. 31. karami h, mazloomfard mm, golshan a, et al. does age effect outcomes of percutaneous nephrolithotomy? j urol. 2010; 7:17-21. correspondence murat dursun, md mrt_drsn@hotmail.com bahcelievler state hospital, department of urology 34180, kocasinan merkez, bahcelievler, istanbul, turkey emin ozbek, md katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey alper otunctemur, md okmeydani training and research hospital, department of urology, istanbul, turkey suleyman sahin, md bilecik state hospital, department of urology, bilecik, turkey suleyman sami cakir, md bayburt state hospital, department of urology, bayburt, turkey dursun_clin_stesura seveso 16/01/15 09:22 pagina 252 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3164 review is there a place for nutritional supplements in the treatment of idiopathic male infertility? davide arcaniolo 1, vincenzo favilla 2, daniele tiscione 3, francesca pisano 4, giorgio bozzini 5, massimiliano creta 1, giorgio gentile 6, filippo menchini fabris 7, nicola pavan 8, italo antonio veneziano 9, tommaso cai 4 on behalf of young commision of italian andrological society (sia) 1 department of urology, university of federico ii, naples, italy; 2 department of urology, university of catania, catania, italy; 3 department of urology, santa chiara hospital, trento, italy; 4 department of urology, university of turin, turin, italy; 5 department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy; 6 department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna; 7 department of urology, university of pisa, pisa, italy; 8 department of urology, university of trieste, trieste, italy; 9 department of urology, ospedale madonna delle grazie, matera, italy. objective: infertility affects 15% of couples in fertile age. male factor is a cause of infertility in almost half of cases, mainly due to oligoasthenoteratozoospermia (oat). the purpose of this study is to review the effects of nutritional supplements as medical treatment for idiopathic male infertility. material and methods: a pub med and medline review of the published studies utilizing nutritional supplements for the treatment of male infertility has been performed. results: clinical trials on vitamin e, vitamin a, vitamin c. arginine, carnitine, n-acetyl-carnitine, glutathione, coenzyme q10, selenium and zinc were reviewed. although there is a wide variability in selected population, dose regimen and final outcomes, nutritional supplements both alone and in combination seems to be able to improve semen parameters (sperm count, sperm motility and morphology) and pregnancy rate in infertile men. conclusions: there are rising evidences from published randomized trials and systematic review suggesting that nutritional supplementation may improve semen parameters and the likelihood of pregnancy in men affected by oat. this improvement, however, is not consistent and there is a wide variation in the treatment regimens used. well designed and adequately powered rcts are needed to better clarify the role of nutritional supplements as treatment for male infertility. key words: phytotherapy; male fertility; oligoasthenotera tozoospermia; n-acetyl-carnitine; vitamin e; semen parameters. submitted 15 july 2014; accepted 31 july 2014 summary no conflict of interest declared. introduction almost 15% of all couples trying to conceive are affected by infertility and seek treatment for this condition (1). in a 50% of childless couples, it is possible to recognize a male-infertility-associated factor (2). male infertility could be consequence of some definable conditions (varicocele, cryptorchidism, hypogonadism, genetic abnormalities), but in 30-40% of infertile male no cause may be determined. such idiopathic infertility is characterized by a decreased number of spermatozoa, decreased sperm motility and abnormal sperm morphology in men with no history of diseases impairing fertility and with normal findings on physical examination and laboratory testing (3). idiopathic oligoasthenoteratozoospermia is supposed to be determined by several causes, including endocrine disorders, genetic abnormalities or reactive oxygen species (4). high ros level and oxidative stress have been implicated in the pathophysiology of male infertility (5) and correlated with sperm dna damage, reduced sperm motility, impaired fertilization and embryo development (6, 7). ros affect sperm function as they damage lipids, amino acids, carbohydrates, protein, and dna of the spermatozoa (8). in human ejaculate there are some endogenous antioxidants, but many studies have shown that seminal antioxidant capacity is suppressed in infertile men with high ros levels compared to men with normal levels of ros (9, 10). many medical therapies have been historically used for male fertility, including herbs, vitamins, and nutritional supplements, and many of them rely on antioxidant properties. according to eau guidelines on male infertility there is little scientific evidence for an empirical approach and medical therapy should be reserved only in case of hypogonadotropic hypogonadism (4). doi: 10.4081/aiua.2014.3.164 arcaniolo_stesura seveso 09/10/14 10:23 pagina 164 165archivio italiano di urologia e andrologia 2014; 86, 3 phytoterapy and idiopathic male infertility treatment the aim of this manuscript is to accurately review the role of nutritional supplements in the treatment of male infertility, evaluating their effect on semen parameters and pregnancy rate. materials and methods the medline database was searched using pubmed with various keywords, including various combinations of search terms. “male infertility”, “nutraceuticals”, “nutritional supplements”, “antioxidants” and “antioxidant therapy” were the most relevant search terms, combined via boolean operators. from the numerous search results, studies were selected on the basis of their quality: studies that were biased, incomplete or otherwise considered untrustworthy were excluded. data were analyzed in order to provide a complete overview of the literature. results vitamin e vitamin e is a fat-soluble vitamin belonging to the tocopherol family. it acts inhibiting free-radical-induced damage to cell membranes, preventing lipid peroxidation and improving the activity of other antioxidants. (11, 12). it has been demonstrated that vitamin e is able to decrease seminal ros in infertile males and there are some epidemiological data that support a direct correlation between improvement of seminal parameters and increased dietary intake of vitamin e. (13-15). vitamin e has been widely used for the treatment of male infertility and many randomized controlled trials have been performed to assess the effect of this compound in infertile men. pre-clinical evidences demonstrated that vitamin e alone or in combination with vitamin c is able to reduce lipid peroxidation, improve dna fragmentation and improve binding of the spermatozoa to the zona pellucida (13, 16, 17). however, often these data “in vitro” do not correlate with clinical evidences. suleiman et al. demonstrated increased sperm motility, with 21% of couples treated with 300 mg of vitamin e achieved pregnancy compared with 0% in the placebo group, but kessopoulou et al. failed to demonstrate an improvement in semen parameters or seminal ros levels compared to placebo. a recent trial assessed the synergic effect of vitamin e, coenzyme q10 and vitamin c in men with oat. authors demonstrated an improvement of sperm count and sperm motility after 3 and 6 months of treatment with a pregnancy rate of 28%. the big limitation of this trial is the lack of a control group. (18). vitamin c vitamin c is a water soluble vitamin that act as a potent antioxidant. it is involved in the synthesis of collagen, proteoglycans, and components of the intercellular matrix (19). few studies have been published using vitamin c alone in the treatment of male infertility. so any possible effect on semen parameters could be the effect of synergistic combinations of vitamin c and other antioxidants like vitamin e, beta carotene, zinc, selenium, etc (15, 20, 21). in vitro studies demonstrated that vitamin c plays a crucial role in preserving sperm from oxidative damage and reducing dna fragmentation (17, 22, 23). dawson et coll. demonstrated the effectiveness of high dose supplementation of vitamin c (1000 mg/die), compared to placebo, in improving sperm quality (count and viability, motility and morphology) in heavy smokers (24). vitamin a vitamin a is a fat-soluble vitamin with a slight antioxidant activity (25). there is a lack of studies investigating the effect of vitamin a alone in male fertility. combined treatment with vitamin a and other nutraceuticals (vitamin e, zinc, selenium, vitamin c) can improve sperm motility up to 30% in infertile man (26) and sperm count after varicocele repair (27). arginine arginine is a semi-essential amino acid which is involved in various human biochemical process as ammonia detoxification, hormone secretion and immune modulation. it is also a precursor of nitric oxide (no) (28) and it is necessary for the synthesis of putrescine, spermidine, and spermine, which are thought to be essential to sperm motility (29). many studies have been carried out to investigate the role of arginine supplementation in male infertility, but to date it is not possible to give evidence-based recommendation on its use. some historical studies have reported that arginine can improve sperm concentration and motility (30-32), while others have failed to demonstrate any improvement in semen parameters or pregnancy rates (33, 34). there is a lack of recent, well-designed studies on arginine supplementation in male infertility, so it is difficult to conclude definitively that arginine supplementation improves male fertility. carnitine carnitines are amines derived from the synthesis of lysine and methionine. carnitines stimulate both fatty acid breakdown and glycolysis in sertoli cells (35) and have an antioxidant effect protecting cells from ros. lcarnitine and l-acetylcarnitine are concentrated in the epididymis, spermatozoa, and seminal plasma (36). carnitines are the most studied nutritional supplements for the treatment of idiopathic male infertility. lenzi et al. demonstrated an increase in all sperm parameters and in pregnancy rate after combined carnitine treatment (2 g/d l-carnitine and 1 g/d l-acetyl-carnitine for 6 months) in 60 men suffering from oat, compared to placebo. the most significant improvement was observed in sperm motility in patients who had lower initial absolute values of motile sperm (37). similarly, balercia et al showed a significant improvement in both sperm motility and morphology in men treated with lcarnitine or l-acetyl-carnitine supplementation, for 24 weeks compared to placebo (38). the role of carnitines in patient with varicocele-associated oat has been investigated by cavallini et al. in a placebo controlled randomized study (39). pregnancy rates increased in patients treated with carnitine alone or in combination with cinnoxicam, over the placebo arm. in addition, improvements in sperm concentration, motility and arcaniolo_stesura seveso 09/10/14 10:23 pagina 165 archivio italiano di urologia e andrologia 2014; 86, 3 d. arcaniolo, v. favilla, d. tiscione, f. pisano, g. bozzini, m. creta, g. gentile, f. menchini fabris, n. pavan, et al. 166 morphology were observed in patients with no varicocele or small or moderate-grade varicoceles treated with carnitine, alone or in combination with cinnoxicam, while no improvement was noted in those with large varicoceles. the combination of carnitine and nonsteroidal anti-inflammatory drugs resulted effective also in improving semen parameters in men with abacterial prostatovesiculoepididymitis and elevated seminal leukocyte concentrations (36). other studies confirmed the positive effect of carnitine therapy on sperm count and motility (40-44). nevertheless sigman et al. in a randomized placebo controlled trial showed no improvements of semen parameters in men treated with carnitines (45). more recently, busetto et al. demonstrated the beneficial effect of an antioxidant complex containing carnitines (l-carnitine, acetyl-l-carnitine, fructose, citric acid, selenium, coenzyme q10, zinc, ascorbic acid, cyanocobalamin, folic acid) in improving sperm progressive motility compared to baseline (46). coenzyme q-10 coenzyme q-10 (coq10) acts as an electron carrier in the mitochondrial respiratory chain (hidaka et al., 2008) and therefore it is involved in mitochondrial bioenergetics, which is important in sperm maturation (47). some studies in the past showed a positive effect of coq10 in improving sperm concentration and motility, although no differences in pregnancy rate were found (48-50). a more recent small trial demonstrated the effectiveness of coq10 in improving semen parameters in men with varicocele (51). two big randomized placebo-controlled trials confirmed that coq10 and its reduced form, ubiquinol, are safe and effective in improving sperm density, sperm motility and sperm morphology in men with unexplained infertility compared to placebo arm. patients treated with coq10 and ubiquinol presented higher catalase and sod, higher inibin b levels and lower fsh if compared to placebo (52, 53). safarinejad et al. found also a partner pregnancy rate of 34% in infertile men with idiopathic oat treated with coq10, but this study lack of a control group (54). a recent metaanalysis concluded that there is no evidence in the literature that coq10 increases either live birth or pregnancy rates, but there is a global improvement in sperm parameters (55). glutathione glutathione plays a significant role in the antioxidant defences of the spermatogenic epithelium, the epididymis, and perhaps in ejaculated spermatozoa. it is produced endogenously in the liver and is one of the most abundant antioxidants found in the body (56) few and dated studies have been published on the role of glutathione in male infertility. these data showed improved sperm motility, sperm concentration and decreased sperm dna fragmentation in infertile men treated with glutathione or a combination of glutathione and other antioxidants (56-58). intramuscular glutathione therapy resulted effective in increasing sperm motility in patients suffering from varicocele (57). glutathione is not well adsorbed in gastrointestinal tract and the parenteral use represents the major limitation for this therapy. n-acetylcysteine nac is an amino acid precursor to glutathione and acts as ros scavenger (59) (zembron-lacny et al., 2009). in vitro data showed a positive effect of nac in improving total sperm motility and reducing ros levels (60). in a randomized placebo-controlled trial, conducted in 120 men with idiopathic infertility, has been demonstrated that nac therapy (600 mg/daily for 3 months) significantly increase seminal volume, sperm motility and viscosity (61). another randomized trial confirmed the beneficial role of nac alone or in combination with selenium in improving all semen parameters if compared to baseline and placebo treatment (62). combination therapy with selenium resulted in a significant improvement of sperm count, motility and morphology, suggesting a synergistic effect. selenium selenium is an essential trace element which is involved in antioxidant reactions (63) and it seems to be necessary for normal testicular development, spermatogenesis, and the process of sperm capacitation (64). as previously described, selenium alone or in combination with other antioxidants can ameliorate sperm count, motility, and morphology (62) and many other studies confirmed the synergic activity of selenium combined with other nutraceuticals like vitamin e (65-67). selenium demonstrated positive effects on male infertility, which appear synergistic when used with other supplements. optimal dosing appears to be between 100 and 210 mg on the basis of the studies above. zinc zinc is a trace mineral essential for normal functioning of the male reproductive system. it plays a role in testicular steroidogenesis, testicular development, spermatozoa oxygen consumption, nuclear chromatin condensation, the acrosome reaction, acrosin activity, sperm chromatin stabilization, and conversion of testosterone to 5a-dihydrotestosterone (68). many biochemical mechanism are zinc-dependent and it acts as cofactor for more than 200 enzyme in the whole body, including those involved in dna transcription and protein synthesis (68). zinc deficiency is related to oligospermia, hypogonadism and compromised immune system function (69). in addition, zinc deficiency is involved in the pathogenesis of oligoasthenospermia in diabetic patients (70). a prospective randomized controlled study was carried out to investigate the effects of zinc sulfate, folic acid and combination of both on sperm quality, protamine content and acrosomal integrity after surgical treatment of varicocele. researchers concluded that co-administration of zinc and folic acid significantly improved sperm parameters and increased varicocelectomy outcomes (71). more recently, raigani et al. investigated in a randomised, double-blind, placebo-controlled clinical trial, the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic men. this study failed to demonstrate that zinc sulphate and folic acid supplementation ameliorate sperm quality in infertile men with severely compromised sperm parameters (72). arcaniolo_stesura seveso 09/10/14 10:23 pagina 166 167archivio italiano di urologia e andrologia 2014; 86, 3 phytoterapy and idiopathic male infertility treatment discussion despite the big amount of studies published on nutraceuticals and male infertility, to date it is not possible to give any recommendation about their use as therapy in infertile male. a significant number of studies lack randomization and placebo-controlled arms and in many cases the pregnancy rate is not the primary endpoint. additionally, many studies have been unable to control or account for dietary intake of potential fertility-affecting food sources. in fact, usually a balanced diet cannot make it necessary the supplementation. another limitation of the proposed studies is the inherent tendency of biological fluctuation in consecutive semen samples from the same individual, the geographical variation in semen quality, the lack of standardization in carrying out the tests used in assessing semen variables and the intra-observer and inter-observer semen assessment bias. nevertheless, based upon the results of the selected studies, it seems that selective supplementation with nutritional supplements could have beneficial consequences on sperm parameters, even if there is a wide range of dosing regimens used across the different trials. unfortunately, the clinical heterogeneity of the included studies meant a meta-analysis of their results could not be performed. a systematic review published by ross et al. in 2010, selected 17 randomized trial to evaluate the effects of oral antioxidants on sperm quality and pregnancy rate in infertile men. their results showed that treatment of infertile men with oral antioxidants reduces seminal oxidative stress and could improve sperm motility, but has a less predictable impact on sperm concentration and morphology. furthermore, oral antioxidant therapy was associated with a significant improvement in spontaneous and assisted conception pregnancy rates in 6 out of the 10 randomized studies included in the analysis (14). the role of antioxidants therapy for the treatment of male infertility has been reviewed extensively by the cochrane collaboration (73). the primary end point of this review was to identify whether supplementation with oral antioxidants would improve outcomes of assisted reproductive techniques when used in male partners of couples undergoing assisted reproduction techniques (art), while secondary endpoint was to assess how antioxidants may influence pregnancy rate, sperm parameters and sperm dna fragmentation. 34 trials were included in the pooled analysis with 2876 couples in total. antioxidants therapy is associated with a statistically significant increase in live birth rate (or 4.85, 95% ci 1.92 to 12.24; p = 0.0008) and in pregnancy rates (or 4.18, 95% ci 2.65 to 6.59; p < 0.00001), if compared with the men in control group. however, authors stated that it is not possible to draw conclusions on the effect of antioxidants on sperm parameters, due to the very poor quality of evidence in the reviewed trials and concluded that antioxidant supplementation might improve live birth and pregnancy rate outcomes for subfertile couples undergoing art in addition, data from this review are not sufficient to draw any conclusions from the head to head comparisons between antioxidants. so, to date, one antioxidant did not appear to have any effect on pregnancy rate per couple or sperm parameters over those of another antioxidant (73). starting from 2013, eau guidelines changed their recommendation according to these findings (4). more recently, clark et al. reviewed 37 rcts on complementary and alternative medicine, including antioxidant and nutritional supplements, for the treatment of male infertility. they concluded that despite some preliminary evidences of the effectiveness of cam interventions among infertile patients, there is a need for further investigation before they can be considered for routine clinical use (74). the same conclusions have been reached by imamovic kumalic et al. they reviewed 32 studies from 2000 to 2013 and found that the majority of these studies confirmed beneficial effect of antioxidants on at least one of the semen parameters, with the most relevant effect on sperm motility, confirming a possible role of nutritional supplements for the treatment of idiopathic oligoasthenoteratozoospermia (75). comhair et al. evaluated the clinical efficacy of different treatment for male infertility by calculating the numbers needed to treat (nnt) in 4143 infertile couples, based on controlled trials. antioxidant therapy resulted in a nnt of 7.8, while varicocele treatment yielded a nnt of 6.3. the nnt of the combination of varicocele treatment with nutraceuticals supplementation was 2.6 and combination of nutraceuticals and ivf had a nnt of 4.0. so authors concluded that there may be a trend for the use of nfs to improve the success rate of varicocele treatment and of ivf (76). nutritional supplements are usually well tolerated and must be considered safe, nevertheless there are some possible dose-related adverse events that must be taken into consideration (table 1). conclusions even if it is not possible to give any firm recommendation about nutritional supplementation for the treatment of idiopathic male infertility, rising evidences from randomized trials and systematic review suggests that oral antioxidant supplementation may improve semen parameters and the likelihood of pregnancy. this improvement, however, is not consistent and there is a wide variation in the treatment regimens used. there is therefore a need to plan further large randomized controlled studies, with clear inclusion/exclusion criteria, to evaluate the effect of standardized doses of specific antioxidants on both spontaneous and assisted conception pregnancy rates, in order to select the population that could benefit from oral antioxidants therapy. references 1. 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imamovic kumalic s, pinter b. review of clinical trials on oligoasthenoteratozoospermia. biomed res int. 2014; 2014:426951. 76. comhaire f, decleer w. comparing the effectiveness of infertility treatments by numbers needed to treat (nnt). andrologia. 2012; 44:401-4. correspondence davide arcaniolo, md massimiliano creta, md max.creta@gmail.com department of urology, university of federico ii, naples, italy vincenzo favilla, md department of urology, university of catania, catania, italy daniele tiscione, md tommaso cai, md ktommy@libero.it department of urology, santa chiara hospital, trento, italy francesca pisano, md department of urology, university of turin, turin, italy giorgio bozzini, md department of urology, istituto di ricovero e cura a carattere scientifico, policlinico san donato, university of milan, milan, italy massimiliano creta, md department of urology, university of federico ii, naples, italy giorgio gentile, md department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy filippo menchini fabris, md department of urology, university of pisa, pisa, italy nicola pavan, md department of urology, university of trieste, trieste, italy italo antonio veneziano, md department of urology, ospedale madonna delle grazie, matera, italy arcaniolo_stesura seveso 09/10/14 10:23 pagina 170 stesura seveso introduction varicocele can affect all parameters of sperm characteristics, including sperm count, sperm motility, and morphology. different techniques have been suggested for varicocele treatment, both surgical and non-surgical. the surgical techniques include the open surgical (inguinal, subinguinal, retroperitoneal approach), laparoscopic and microsurgical varicocelectomies. the non-surgical are 143archivio italiano di urologia e andrologia 2013; 85, 3 original paper varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization on 463 cases giangiacomo ollandini 1, giovanni liguori 1, stanislav ziaran 2, tomá! málek 2, giorgio mazzon 1, bernardino de concilio 1, stefano bucci 1, sara benvenuto 1, emanuele belgrano 1, carlo trombetta 1 1 urologic unit, cattinara hospital, university of trieste, trieste, italy; 2 urology clinic, university hospital in bratislava, comenius university, bratislava, slovakia. objectives: to determine whether there are differences in sperm parameters improvement after different varicocele correction techniques. to determine the role of age in sperm parameters improvement. methods: 2 different european centers collected preand postoperative sperm parameters of patients undergoing varicocele correction. among 463 evaluated patients, 367 were included. patients were divided in procedure-related and age-related groups. ivanissevich inguinal open surgical procedure (os), lymphatic-sparing laparoscopic approach (lsl) and retrograde percutaneous transfemoral sclerotization (rps) were performed. as outcome measurements sperm count (millions/ml, sc) and percentage of mobile sperms were analyzed. univariate and multivariate regression between the defined groups; bivariate regression analysis between age and sperm count and motility. results: number of patients: os 78; lsl 85; rps 204. mean age 30.2 (sd 6.83); postoperative sc increased from 18.2 to 30.1 (ci 95% 27.3-32.9; p < 0,001); motility from 25.6 to 32.56% (30.9-34.2; p < 0.001). os: sc varied from 16.9 to 18.2 (p < 0.001); sperm motility from 29% to 33% (p < 0.001). lsl: sc from 15.5 to 17.2 (p < 0.001); motility from 27 to 31% (p < 0.001). rps: sc from 18.9 to 36.2 (p < 0.001); motility from 24% to 32% (p < 0.001). univariate and multivariate analysis confirmed the significant difference of sc variation in rps, compared to the other groups (p < 0.001). no significance between lsl and os (p = 0.826). no significant differences regarding motility (p = 0.8). conclusions: varicocele correction is confirmed useful in improving sperm parameters; sclerotization technique leads to a better sperm improvement compared to other studied procedures; improvement in seminal parameters is not affected by age of the patients treated. key words: andrology; infertility; sclerotization; spermatozoa; varicocele. submitted 18 july 2013; accepted 31 july 2013 no conflict of interest declared summary represented by the radiological-assisted techniques: embolization or sclerotherapy (1, 2). several studies related the outcome in terms of invasiveness and costs between the different techniques used (3, 4); however a comparison of the efficacy on sperm parameters improvement of open ligation, laparoscopic approach and sclerotization is still missing. doi: 10.4081/aiua.2013.3.143 archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 144 the goal of our study was to compare the clinical outcomes in terms of sperm quality after varicocele correction using the three cited techniques. we also referred to patients’ age in order to analyze whether there are significant differences of postoperative sperm improvement related to age increment. material and methods two different centers collected data of patients undergoing varicocele treatment from 1986 to 2011. patients were complaining both from infertility or testicular pain. all patients underwent a complete history, physical examination in a warm room, hormonal assessment, semen analysis. each center treated the patients with a different technique: open ligation of the spermatic vein according to ivanissevich technique, laparoscopic approach or retrograde sclerotization of the spermatic vein. at least 3 months after surgery, semen analysis and physical examination have been performed: in fact al bakri et al. in 2012 demonstrated that there is no significant improvement in sperm parameters after 3 months from correction (6). on a total of 463 patients, 96 have been excluded according to the following criteria: persistence of varicocele, endocrinological abnormalities, history of undescended testis, bilateral varicocele, and abnormal right testis. mean age of patients was 30.2 yr (sd 6.83); median clinical grade was 2 (iqr 1); mean sperm concentration was 18.0 millions/ml (sd 14.7) and mean sperm motility was 25.6% (sd 17.51). surgical procedures: the operative procedures are widely described in the literature. in ivanissevich open surgery inguinal approach (under general anesthesia) the exposure of the internal spermatic vessels within the inguinal canal takes place through an incision of the external oblique aponeurosis (7). in laparoscopic ligation of spermatic veins (under general anesthesia) the patients underwent varicocelectomy by the lymphatic sparing technique. in this procedure the internal spermatic veins alone were divided. using a microsurgical technique both the artery and the lymphatics were preserved (8). patients underwent retrograde percutaneous sclerotization of their left spermatic vein, using the right transfemoral retrograde percutaneous approach. the femoral vein is entered below the inguinal ligament using the standard seldinger technique. renal phlebography is carried out by injection of contrast medium under valsalva maneuver. after superselective catheterization of the spermatic vein, a guidewire is introduced and act as a guide for a very distal catheterization, through continuous fluoroscopy. superselective angiography shows every possible collateral circle and the possible presence of multiple spermatic veins. sclerotization technique is performed by injecting a 2-4 ml of sodium tetradecyl sulfate 3% mousse. patients are required to perform a valsalva maneuver at least 10 seconds long during the injection. venography is then performed again: should there be bulky veins, the operation is repeated at a higher lumbar level. after this procedure, a control venography is performed to confirm the absence of renospermatic reflow (9, 10). it is known from the literature that up to 20% of patients have anatomical abnormalities of their veins, that could eventually make not possible the retrograde technique. when this happened, we performed anterograde sclerotization according to tauber technique during the same session (11). semen analysis specimens were obtained by masturbation after 3 to 5 days of abstinence. the specimens were valuated within 1 hour from collection for the following parameters: sperm concentration (millions/ml), percentage of sperms with a + b motility (a, speed linear motility; b, slow linear motility; c, motility in situ; d, no motility at all), percentage of morphologically typical sperms. the laboratories evaluated the parameters according to who criteria. statistical analysis statistical analyses were performed with spss 17.0 software package. description of population and parameters have been reported as mean values with standard deviation (sd) for continuous variables, and with median values with interquartile range (iqr) for non-continuous ones. the significances of differences between preoperative and postoperative values within groups have been valued with the paired student t-test, if appropriate, or with the wilcoxon signed rank test. means variations between two groups has been valuated with mannwhitney u test. anova univariate analysis of variance with lsd post-hoc evaluation has been carried out in order to compare mean values of more than two groups. manova multivariate analysis has been then performed between our data. the linear regression coefficients have been calculated in order to test the correlation between age and parameters. probability values < .05 were considered significant. results patients included in the study were a total of 367. among these, 78 underwent open surgical approach; 85 were treated by laparoscopy and 204 by sclerotization technique. persistence and minor complication rates are shown in table 1. no major complications occurred. complications in surgical ligation of spermatic vein were hydrocele, difficult wound healing and hematomas. complications among sclerotization techniques were mostly represented by persistent (more than 3 days) pain at the spermatic chord. due to the injection of sclerosing substance, though, self-recovery pain and an acceptable increase of volume and consistence of the chord was not considered as a complication. sperm concentration increased postoperatively in 73% of global cases; motility from 25.6 to 32.56% (p < 0.001). average postoperative sperm concentration increased to 30.1 millions/ml (sd 29.9; ci 95% 27.332.9; p < 0.001) and motility to 32.56% (sd 17.3; ci 95% 30.9-34.2; p < 0.001). patients have been divided into three groups, according to the procedure performed, and into 4 groups, according to their age. every difference within the groups obtained a significance p-value < 0.001. differences between the groups univariate anova regression analysis and multivariate manova have been performed in order to evaluate the differences between the groups and set their significance (table 2). post hoc evaluation of variances between procedure-related groups have been reported for sperm count. variation of sperm count has been demonstrated to be related to the procedure (figure 1), being significantly higher for patients treated by sclerotization procedure. age decades showed no significant differences in mean values of sperm count and sperm motility improvement (table 2). mean variation of sperm concentration showed also no significant differences between age-related groups (figure 2). the linear regression standardized coefficient between age and sperm motility for preoperative values is -0.09 (p = 0.048) and for postoperative values is -0.10 (p = 0.021). therefore there is no significant difference between the calculated coefficients (figure 3). discussion in our study we found: • as already known from the literature, varicocele correction is confirmed as useful in improving sperm parameters 145archivio italiano di urologia e andrologia 2013; 85, 3 varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization figure 1. mean variation of sperm concentration and motility between the three procedure-related groups. technique n excluded included complications other reasons recurrency (%) total open surgery 77 2 7 (9,1%) 9 68 7% laparoscopic 80 4 1 (1,3%) 5 75 0% sclerotization 366 57 25 (9,3%) 82 284 5% total 523 63 33 96 427 table 1. total number of treated and excluded and rate of overall post-operative complications. age (sd) sperm concentration (95% ci) motility (95% ci) pre post* pre post* procedure open surgery 32,1 (6,85) 16,9 (13,4-20) 18,2 (15,0-21,5) 29 (25,8-32) 33,1 (30,9-35,4) laparoscopy 26 (5,6) 15,5 (13,7-17,1) 17,2 (15,5-18,9) 27 (23,5-29,6) 31,2 (28,7-33,8) sclerotization 25,9 (5,2) 18,9 (17-20,1) 36,2 (32,8-40,7) 24 (21,3-29,9) 32,9 (30,3-35,6) p-value univariate 0,2 < 0,0001 0,25 0,21 multivariate 0.18 < 0,0001 0.18 0.15 age decades group 1 0-20 18,8 (13,7-23,9) 27,3 (25,7-38,8) 30,6 (26,1-35,2) 38,5 (33,9-43,0) group 2 21-30 17,8 (15,7-19,9) 29,5 (25,4-33,6) 26,3 (24,0-28,5) 33,8 (31,5-36,2) group 3 31-40 17,2 (15-19,4) 30,9 (26,2-35,5) 24,1 (21,2-27,0) 30,9 (28,1-33,7) group 4 > 41 22,5 (17,1-27,9) 36,4 (28,2-44,6) 23,2 (16,0-30,3) 30,2 (24,7-35,7) p-value univariate 0,85 0,32 0,08 0,004 multivariate 0.97 0.30 0.13 0.003 table 2. univariate anova and multivariate manova analysis of variance. *p-value < 0,001 for each of the parameters withing the groups. archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 146 • sclerotization technique leads to a better sperm improvement compared to other studied procedures • improvement in seminal parameters is not affected by age of the patients treated. the usefulness of varicocele repair remains a highly debated topic. the 2009 updated cochrane review by evers and collins discussed the indication to varicocele treatment in infertile men, and according to their metaanalysis there was no clear evidence of indication in varicocele correction to improve fertility (12). this review, though, have been debated by a contrary opinion: the authors (ficarra et al.) analyzed the methodology of the study and concluded that it was weak and poorly significant, as they included patients with subclinical varicoceles and normal semen parameters (13). more recently a randomized, controlled trial by abdel-eguid et al. (14) concluded that there is a statistically significant improvement in semen quality after microsurgical correction of varicocele and a higher pregnancy rate, comparing the results with the control arm. therefore the main focus of our study was not to demonstrate the outcome in terms of fertility and pregnancy rate, but to compare the efficacy in sperm improvement between the different used techniques. in 1998 barbalias et al. carried out a randomized clinical trial comparing a total of 88 patients who underwent varicocele correction either by retroperitoneal, inguinal, subinguinal or percutaneous approach. they analyzed pre and postoperative sperm parameters concluding that microsurgical subinguinal technique had a greater performance (15). a newer study in 2010 confirmed that microsurgical approach obtains better results compared to the standard inguinal approach (16). however microsurgical treatment of varicocele needs a greater amount of time and instruments than the other techniques. several studies compared the open surgery technique to sclerotization procedure, with contradictory results (12, 13, 17, 18); though one of the main outcomes of those studies was the pregnancy rate, this parameter seems to be affected by too many confounding factors to be eligible as a main outcome. many other studies, moreover, focused on the costs of the treatments, and the time to recovery: operative costs are shown to be similar for all the studied procedures, but the time to recovery is significantly less for patients treated by sclerotization technique. therefore bechara et al. concluded that the radiologicalassisted procedure has a cost-benefit compared to surgical treatment (19). the rate of technical failure of sclerotization procedure is described to vary from 5% to 20%, due to the anatomical abnormalities, venospasm or technical difficulties (13, 17, 19). in our experience the intervention is converted during the same session to an anterograde sclerotization, according to tauber technique. this possibility permits to obtain a 100% rate of technical success. our data clearly show that the sclerotization technique leads to a better improvement of sperm concentration compared to laparoscopic and ivanissevich techniques. moreover, these appear to obtain a similar outcome both regarding sperm density improvement and sperm motility improvement. the hypothesis regarding the better results of sclerotization techniques are probably related to: • better anatomical view and complete repair of varicocele • complete manteinance of lymphatic vascularization • no arterial injuries. figure 2. variation of sperm concentration is not significantly different among patients from different age decades. figure 3. pre and postoperative percentage of motility among age groups: the negative trend remains constant. sclerotization differs from the surgical approaches because of the venography that is repeated during the whole procedure, in order to guide step by step the intervention. this allows to obtain a clear imaging of the venous vascularization, and to close selectively every single vessel that is implicated in varicocele formation. in fact it is commonly known, that 19% of patients with varicocele have an aberrant anatomical situation (20). this situation cannot be completely discovered by laparoscopic and surgical approach, and will be probably not treated completely, even if post operatively there is no sign of clinically detectable persistence. the pathogenetic factors involving poor sperm quality on varicocele patients, if not completely corrected, could in fact continue their damage of the testis, that have been showed in several studies (21, 22). moreover, the risk of injuries to the testicular arteries is significantly higher in patients undergoing surgical procedures than in patients undergoing sclerotization, due to the procedure itself (23), even if the role of artery injury in sperm parameter’s outcome is not certainly significant (23, 24). finally, the preservation of lymphatic vessels is assured with sclerotization technique, while in patients undergoing surgical procedures the lymphatic damage is most likely avoided (laparoscopy) or most probably occurs (ivanissevich). lymphatic vessels ligation is thought to induce a significant worsening of testicular function, due to testicular edema (8). we may assume these factors cooperate in obtaining a better result in sperm concentration improvement in patients undergoing sclerotization of their varicocele instead of the other procedures. though there is an evidence of correlation between patients’ age and sperm parameters worsening in some studies in the literature (26, 27), according to other recent studies the role of age in sperm quality improvement after varicocele correction is believed to be not significant (9, 25). in our study the only significant trend, at linear regression estimation, is the decrease of sperm motility in relation to patients’ age. this trend is not affected by the intervention, as it remains constant after correction of varicocele, and represents the normal decrement of motility due to patient’s age. conclusions varicocele treatment leads to improvement in seminal parameter examined in 73% of the cases. both surgical and non-surgical approaches are effective, as in each group postoperative values are significantly better than preoperative ones. sclerotization of varicocele showed a better improvement of the postoperative sperm concentration, and is a safe and easy procedure, and should be therefore offered as a routine first line treatment to patients affected by varicocele, where the indication for treatment occurs. finally, even patients more than 40 years old showed a significant improvement of their sperm count and motility, and could be offered the treatment as well. references 1. will ma, swain j, fode m, et al. the great debate: varicocele treatment and impact on fertility. fertil steril. 2011; 95: 841-52. 2. belgrano e, trombetta c, liguori g. scleroembolization techniques in the treatment of varicocele. ann urol. 1999; 33:203-9. 3. al-kandari am, shabaan h, ibrahim hm, et al. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007; 69:417-20. 4. shamsa a, mohammadi l, abolbashari m, et al. comparison of open and laparoscopic varicocelectomies in terms of operative time, sperm parameters, and complications. urol j. 2009; 6:170-5. 5. dubin l, amelar rd. varicocele size and results of varicocelectomy in selected subfertile men with varicocele. fertil steril. 1970; 21:606-9. 6. al bakri a, lo k, grober e, et al. time for improvement in semen parameters after varicocelectomy. j urol. 2012; 187:227-31. 7. ivanissevich o. left varicocele due to reflux; experience with 4,470 operative cases in forty-two years. j int coll surg. 1960; 34:742-55. 8. kocvara r, dvorácek j, sedlácek j, et al. lymphatic sparing laparoscopic varicocelectomy: a microsurgical repair. j urol. 2005; 173:1751-4. 9. liguori g, ollandini g, pomara g, et al. role of renospermatic basal reflow and age on semen quality improvement after sclerotization of varicocele. urology. 2010; 75:1074-8. 10. trombetta c, liguori g, bucci s, et al. percutaneous treatment of varicocele. urol int. 2003; 70:113-8. 11. tauber r, pfeiffer d. surgical atlas varicocele: antegrade scrotal sclerotherapy. bju int. 2006; 98:1333-44. 12. evers jh, collins j, clarke j. surgery or embolisation for varicoceles in subfertile men. cochrane database syst rev. 2009; (1):cd000479. 13. ficarra v, cerruto ma, liguori g, et al. treatment of varicocele in subfertile men: the cochrane review--a contrary opinion. eur urol. 2006; 49:258-63. 14. abdel-meguid ta, al-sayyad a, tayib a, farsi hm. does varicocele repair improve male infertility? an evidence-based perspective from a randomized, controlled trial. eur urol. 2011; 59:455-61. 15. barbalias ga, liatsikos en, nikiforidis g, siablis d. treatment of varicocele for male infertility: a comparative study evaluating currently used approaches. eur urol. 1998; 34:393-8. 16. abdel-maguid af, othman i. microsurgical and nonmagnified subinguinal varicocelectomy for infertile men: a comparative study. fertil steril. 2010; 94:2600-3. 17. nabi g, asterlings s, greene dr, marsh rl. percutaneous embolization of varicoceles: outcomes and correlation of semen improvement with pregnancy. urology. 2004; 63:359-63. 18. shlansky-goldberg rd, vanarsdalen kn, rutter cm, et al.percutaneous varicocele embolization versus surgical ligation for the treatment of infertility: changes in seminal parameters and pregnancy outcomes. j vasc interv radiol. 1997; 8:759-67. 19. bechara cf, weakley sm, kougias p, et al. percutaneous treatment of varicocele with microcoil embolization: comparison of treatment outcome with laparoscopic varicocelectomy. vascular. 2009; 17(suppl 3):s129-36. 20. marsman jw. the aberrantly fed varicocele: frequency, veno147archivio italiano di urologia e andrologia 2013; 85, 3 varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization archivio italiano di urologia e andrologia 2013; 85, 3 g. ollandini, g. liguori, s. ziaran, t. málek, g. mazzon, b. de concilio, s. bucci, s. benvenuto, e. belgrano, c. trombetta 148 graphic appearance, and results of transcatheter embolization. ajr am j roentgenol. 1995; 164:649-57. 21. gat y, zukerman z, chakraborty j, gornish m. varicocele, hypoxia and male infertility. fluid mechanics analysis of the impaired testicular venous drainage system. hum reprod. 2005; 20:2614-9. 22. smith r, kaune h, parodi d, et al. increased sperm dna damage in patients with varicocele: relationship with seminal oxidative stress. hum reprod. 2006; 21:986-93 23. cuda sp, musser je, belnap cm, thibault gp. incidence and clinical significance of arterial injury in varicocele repair. bju int. 2011; 107:1635-7. 24. yamamoto m, tsuji y, ohmura m, et al. comparison of arteryligating and artery-preserving varicocelectomy: effect on post-operative spermatogenesis. andrologia 1995; 27:37-40. 25. ishikawa t, fujisawa m. effect of age and grade on surgery for patients with varicocele. urology 2005; 65:768-72. 26. centola gm, eberly s. seasonal variations and age-related changes in human sperm count, motility, motion parameters, morphology, and white blood cell concentration. fertil steril. 1999; 72:803-8. 27. sobreiro bp, lucon am, pasqualotto ff, et al. semen analysis in fertile patients undergoing vasectomy: reference values and variations according to age, length of sexual abstinence, seasonality, smoking habits and caffeine intake. sao paulo med j. 2005; 123:161-6. correspondence giangiacomo ollandini, md (corresponding author) g.ollandini@gmail.com viale gabriele d’annunzio 63, 34138 trieste (italy) giovanni liguori, md giorgio mazzon, md bernardino de concilio, md stefano bucci, md sara benvenuto, md emanuele belgrano, md carlo trombetta, md urologic unit, cattinara hospital, university of trieste via di fiume 447 34149 trieste, italy stanislav ziaran, md tomá! málek, md urology clinic, university hospital in bratislava, comenius university, bratislava, slovakia stesura seveso archivio italiano di urologia e andrologia 2014; 86, 144 case report rare case of intra-testicular adenomatoid tumour filippo migliorini 1, roberto baldassarre 1, walter artibani 1, guido martignoni 2, matteo brunelli 2 1 urology department, university hospital, ospedale policlinico, azienda ospedaliera integrata, verona, italy; 2 department of pathology and diagnostic, university hospital, ospedale policlinico, azienda ospedaliera integrata, verona, italy. adenomatoid tumors are rare benign neoplasms considered of mesothelial origin. they are usually asymptomatic and slow growing masses. they account for 30% of paratesticular tumors and very rarely involve the testicular parenchyma. only ten such cases have been reported in the literature so far. ideal treatment should be excision of the tumor avoiding orchidectomy. nevertheless, because of the rarity of the lesion and the difficulty of distinguishing it from malignancy, radical orchidectomy is often performed. we describe a case of a 31 years old caucasian man who presented with a moderately symptomatic left testicular mass, normal tumor markers and normal sex hormones levels. the ultrasound showed an hypoechoic intratesticular nodule of 0.8 cm in diameter. the patient underwent intraoperative frozen section of the nodule which could not exclude malignancy with certainty. a radical orchiectomy was therefore performed. subsequent definitive histological and molecular report described an adenomatoid tumor involving the parenchyma of the testis. key words: adenomatoid tumour; testis; pathologic findings; orchifuniculectomy. submitted 7 february 2014; accepted 28 february 2014 summary introduction adenomatoid tumors are relatively uncommon benign tumors of mesothelial origin, usually occurring in the genital tract of both males and females. extragenital localization is rare and has been reported in adrenal glands, heart, mesentery, lymph nodes and pleura. adenomatoid tumors are responsible for 30% of all paratesticular masses and are most commonly found at the head of the epididymis. exceptionally, these tumors involve the testicular parenchyma and only ten cases have been previously reported in the literature (1-2). the ideal treatment should be excision of the nodule with preservation of the testicle. this is not always possible no conflict of interest declared because the morphological features on the frozen section don’t allow a certain exclusion of malignancy. case report and figures are posted in suppementary materials on www.aiua.it. discussion here we report a case of adenomatoid tumor of the testis with intratesticular growth and describe the ultrasound, gross and pathologic characteristics of this entity. to the best of our knowledge, only 10 cases have been previously reported in the literature (3). adenomatoid tumors are rare benign neoplasms occurring in both sexes and very rarely present as intratesticular masses. these tumors originate from the tunica albuginea but might also be found in the tunica vaginalis and rete testis. they present as well-circumscribed unencapsulated tumors with tan white cut surface and might be indistinguishable from seminoma (1-2). microscopically, they show different morphological patterns as tumor cells can form solid cords, nests, glandular-like spaces or tubules. a typical feature of the neoplastic cells is the presence of vacuolated cytoplasm and cytologic atypia with absence of mitosis. the stroma is usually fibrous although a smooth muscle component might be present. even though tumors may focally infiltrate between testicular tubules, such finding should not be considered as evidence of malignancy. a useful hint for the diagnosis of these lesions is the presence of lymphoid aggregates often localized at the periphery of the tumor. interestingly, this characteristic is usually lacking in tumors arising in females. the immunophenotipic profile of adenomatoid tumors shows positivity for pancytokeratins, podoplanin, wt1 and calretinin and can be very useful in the differential diagnosis with neoplasms that may resemble adenomatoid tumors, namely yolk sac tumor (negative for wt1 and calretinin), leydig cell tumor (negative for wt1) and metastatic carcinoma (1-2). also, negativity for vascular markers like cd34 helps in excluding tumors of vascular origin. a difficult differential diagnosis is represented by malignant mesothelioma which is distindoi: 10.4081/aiua.2014.1.44 migliorini cr_stesura seveso 26/03/14 10:41 pagina 44 45archivio italiano di urologia e andrologia 2014; 86, 1 intra-testis adenomatoid tumour guished from adenomatoid tumor for its larger size, invasive growth pattern and involvement of adjacent structures. since adenomatoid tumors have never shown malignant behavior, the aim in treating these masses is to prevent unnecessary orchidectomy thus preserving fertility and testosterone production. in this regard, accurate imaging and preoperative assessing of serum tumor markers like alpha-fetoprotein, ldh and beta-hcg might help in excluding a malignant lesion. intraoperative frozen section can also help in determining benignity of a testicular mass; accordingly, the value of intraoperative biopsy evaluation has become more popular in the last years, allowing organ-sparing procedure for non-malignant lesions. however, in the literature, only in one case of adenomatoid tumor with intratesticular growth was performed a conservative tumorectomy. this proves the extreme difficulty for a pathologist to rule out malignancy on frozen section in the case of an adenomatoid tumor with intratesticular growth. in our case, a diagnosis of benignity on the intraoperative biopsy was not possible and an orchidectomy was carried out. in conclusion, adenomatoid tumor with intratesticular growth is a rare neoplasm that can show different morphological features and therefore represents a diagnostic challenge, especially on frozen section. the pathologist must be aware of this entity when evaluating intraoperative biopsies of testicular masses. it must be stated, however, that ruling out malignancy is often not possible and orchidectomy cannot be avoided most of the times references 1. borislav aa, lauren fx, jonathon eh, et al. adenomatoid tumor of the testis with intratesticular growth: a case report and review of the literature. int j surg pathol. 2011; 19:838-842. 2. pacheco aj, torres jl, de la guardia fv, et al. intraparenchymatous adenomatoid tumor dependent on the rete testis: a case report and review of literature. indian j urology. 2009; 25:126-128. 3. alexiev ba, xu lf, heath je, et al. adenomatoid tumor of the testis with intratesticular growth: a case report and review of the literature. int j surg pathol. 2011; 19:838-842. correspondence filippo migliorini, md (corresponding author) filippo.migliorini@ospedaleuniverona.it roberto baldassarre, md roberto.baldassarre@ospedaleuniverona.it walter artibani, md walter.artibani@univr.it urology department, university hospital, ospedale policlinico, azienda ospedaliera integrata, p.le ludovico scuro 10 37134 verona, italy guido martignoni, md guido.martignoni@univr.it matteo brunelli, md matteo.brunelli@univr.it department of pathology and diagnostic, university hospital, ospedale policlinico, azienda ospedaliera integrata, p.le ludovico scuro 10 37134 verona, italy figure 1. intraoperative biopsy. note the nodule with an intra-testis localization (left side). normal testicular parenchyma inked on the right side (h&e, 4x). migliorini cr_stesura seveso 26/03/14 10:41 pagina 45 245archivio italiano di urologia e andrologia 2016; 88, 3 case report primary pure carcinoid tumour of the testis: a case report and review of the literature hideki takada 1, shoichiro iwatsuki 1, yasunori itoh 1, shinya sato 2, 3, masa hayase 4, takahiro yasui 4 1 department of nephro-urology, nagoya city west medical center, japan; 2 department of experimental pathology and tumor biology, nagoya city university graduate school of medical sciences, japan; 3 department of diagnostic pathology, nagoya city west medical center, japan; 4 department of nephro-urology, nagoya city university graduate school of medical sciences, japan. the authors contributed equally. primary testicular carcinoid tumours (tct) are very rare, and a large tumour size and the presence of carcinoid syndrome predict a malignant course. histologically, it is difficult to differentiate between benign and malignant tcts. we report a case of a primary pure tct with an unusual presentation in a 23year-old man, who had an asymptomatic, enlarged scrotum on the right side for 7 years. on gross examination, the tumour was 9.6 cm in diameter. the ki-67 labelling index was 19.8%. high inguinal orchidectomy was performed, and 30 months after surgery the patient remains asymptomatic. key words: primary pure carcinoid tumour; prognosis; testicular cancer. submitted 11 may 2016; accepted 6 june 2016 summary no conflict of interest declared. tory of testicular trauma, haematuria, undescended testis, systemic symptoms, or weight loss, and there was no family history of testicular cancer. physical examination revealed a hard, non-tender testicular mass in the right testis. the left testis appeared normal. magnetic resonance imaging revealed a multilocular cystic tumour, measuring 8.5 × 7.8 × 9.6 cm in the right testis (figure 1). betahuman chorionic gonadotropin and alpha-fetoprotein lactate dehydrogenase levels were normal. computed tomography scanning of the chest, abdomen, and pelvis revealed no significant para-aortic or iliac lymphadenopathy, no pulmonary abnormality, and no intestinal tumour. these findings favoured the diagnosis of a primary testicular tumour. the patient underwent high inguinal orchidectomy of the right testis. gross examination revealed that the right testis measured 9.0 × 8.5 × 9.6 cm. cut sections of the tumour demonstrated a lobulated cystic lesion with more than one yellowish septum, and regions of haemorrhage and necrosis. doi: 10.4081/aiua.2016.3.245 introduction testicular carcinoid tumours (tcts) are rare neoplasms, accounting for 0.2-1% of all testicular tumours (1, 2). to date, approximately 60 tct cases have been described in the literature (2, 3). tcts can be divided into three subgroups: primary pure tcts, carcinoid tumours associated with teratomas (~20% of cases), and carcinoid metastasis to the testis (~9% of cases) (4). upon detection of a tct, a multimodal approach should be taken to exclude the possibility of a metastasis from another organ. the mean age of patients with tcts at diagnosis is 46 years (range, 10-83 years (4). patients with carcinoid tumours may present with a self-detected testicular mass or testicular ache (as occurs with common testicular tumours) or, more infrequently, carcinoid syndrome with red-hot flushing (face, neck, and upper chest), severe and debilitating diarrhoea, abdominal pain, palpitations, and bronchospasms (5). herein, we report on a young patient with a primary pure tct having a high malignant potential, and discuss the clinicopathological features, diagnosis, treatment, and prognosis in relation to the relevant literature. case report a 23-year-old man had an asymptomatic, enlarged scrotum on the right side for 7 years. he did not have a hisfigure 1. magnetic resonance imaging revealed a multilocular cystic tumour, measuring 8.5 × 7.8 × 9.6 cm in the right testis. takada_stesura seveso 21/09/16 09:15 pagina 245 archivio italiano di urologia e andrologia 2016; 88, 3 hideki takada, shoichiro iwatsuki, yasunori itoh, shinya sato, masa hayase, takahiro yasui 246 the tumour was confined to the testis and epididymis without lymphovascular invasion. histology revealed monomorphic cells arranged in a nested trabecular pattern (figure 2a). the tumour cells were circular or polygonal with round to oval nuclei, a distinct nuclear membrane, granular cytoplasm, and ‘salt and pepper’-like chromatin. an immunohistochemical examination revealed the tumour cells to be strongly immunopositive for synaptophysin, facilitating the diagnosis of a neuroendocrine tumour (net) (figure 2b), but negative for inhibin, haematopoietic progenitor cell antigen, epithelial membrane antigen, and calretinin. the ki-67 labelling index was 19.8% (figure 2c). no teratomatous elements were identified, and a diagnosis of primary pure tct was confirmed. at 30 months after surgery, the patient remains asymptomatic. discussion and supplementary references are posted on www.aiua.it conclusion our case adds to the other reports in the literature of primary tcts having a high malignant potential. our patient should undergo frequent biochemical and radiological examinations and long-term monitoring for recurrence and the development of metastases. references 1. rathert m, ubrig b, atkins dj, roth s. carcinoid tumor of the testis. urologe a. 2011; 50:340-2. 2. alsharif s, al-shraim m, alhadi a, et al. primary neuroendocrine tumor of the testis. urol ann. 2014; 6:173-5. 3. zavala-pompa a, ro jy, el-naggar a, et al. primary carcinoid tumor of testis. immunohistochemical, ultrastructural, and dna flow cytometric study of three cases with a review of the literature. cancer. 1993; 72:1726-32. 4. stroosma ob, delaere kp. carcinoid tumours of the testis. bju int. 2008; 101:1101 5. 5. merino j, zuluaga a, gutierrez-tejero f, et al. pure testicular carcinoid associated with intratubular germ cell neoplasia. j clin pathol. 2005; 58:1331-3. figure 2. a) microscopic appearance of the tumour showing monomorphic cells arranged in a nested trabecular pattern (haematoxylin & eosin-stained, ×40 magnification); b) tumour cells exhibiting strong immunopositivity for synaptophysin (×40 magnification). c) ki-67 positive cells (×40 magnification). correspondence hideki takada, md htakada@cronos.ocn.ne.jp shoichiro iwatsuki, md yasunori itoh, md department of nephro-urology, nagoya city west medical center 1-1-1 hirate-mati kita-ku nagoya aichi-462-8508, nagoya, japan shinya sato, md department of experimental pathology and tumor biology, nagoya city university graduate school of medical sciences department of diagnostic pathology, nagoya city west medical center nagoya, japan masa hayase, md takahiro yasui, md department of nephro-urology, nagoya city university graduate school of medical sciences nagoya, japan takada_stesura seveso 21/09/16 09:15 pagina 246 stesura seveso 151archivio italiano di urologia e andrologia 2015; 87, 2 short communication different presentation types of primary brucella epididimo-orchitis huseyin aydemir 1, gokcen budak 2, salih budak 3, orcun celik 3, okan yalbuzdag 3, !brahim keles 4 1 department of urology, ministry of health sakarya teaching and research hospital, sakarya, turkey; 2 department of infectious disease clinic, tire state hospital, sakarya, turkey; 3 tepecik educational and research hospital, department of urology, izmir, turkey; 4 department of urology, school of medicine, afyon kocatepe university, afyonkarahisar, turkey. brucellosis is a zoonotic disease that involved genitourinary system in 2-20% and most commonly cause single sided epididymo-orchitis. in our country brucella is an endemic disease and causes serious and different diagnosis of acute scrotum and epididymoorchitis. in this paper six cases of epididymo-orchitis cases which were resistant to classical treatment were discussed according to clinical and laboratory findings. we describe different types of presentation of brucella epididymoorchitis with diagnosis and treatment modalities. key words: brucellosis; testis; epididymo-orchitis; acute scrotum; infection. submittec 5 november 2014; accepted 28 january 2015 summary no conflict of interest declared. patient developed joint and muscle pain lately. at physical examination, body temperature was 37.2°c, swelling on right testicle with extensive tenderness was present, epididymis was hard, scrotum was erythematous and local temperature increased. examination of other systems was normal. scrotal color doppler ultrasonography reported findings consistent with right epididymo-orchitis. laboratory findings included leucocytes 8700/mm3, sedimentation rate 27 mm/h, crp 30 mg/l and tube agglutination test positive at 1/160 titers. there was no growth in blood cultures. patient was treated with rifampicin 600 mg/day, doxycycline 200 mg/day and anti-inflammatory treatment for 6 weeks. symptoms were regressed after first week of treatment. there was no recurrence on the follow up. case 2 (septicemia) a 63 year old male patient working with farm animals, presented with fever, night sweating and joint pain for 15 days for the last 2 days he had dysuria, swelling in the right testicle and pain. physical examination showed 37.8°c body temperature, right epididymis very tender and swelling of the testicle, local erythema of the scrotum with temperature increase. physical examination of other systems was normal. laboratory results showed leucocyte count 13500/mm3, sedimentation rate 67 mm/h, crp 70 mg/l, brucella tube agglutination test positive for 1/640 titer. brucella spp. growth was documented in blood cultures. whereas there was no growth in urine culture. patient’s treatment was planned for 6 weeks with rifampicin 600 mg/day, doxycycline 200 mg/day and anti-inflammatory treatment but in the second week of his treatment testicular pain was not regressed and patient continued to have frequent fever (38°c). one g/day streptomycin im was added to treatment for two weeks and treatment was finished up to 6 weeks. after addition of streptomycin on the 3rd day of treatment patient complaints were relieved dramatically. there was no relapse in 18 months follow up. case 3 (acute scrotum, septicemia) a 27 year old male farmer presented with acute left testicular pain, fever, shivering, nausea and vomiting startdoi: 10.4081/aiua.2015.2.151 introduction brucellosis is spread to humans by infected or contaminated animals and less than sufficiently pasteurized milk and milk products (1, 2). brucellosis can infect many organs and present with different clinical symptoms (3). brucellosis infects genitourinary system in 2-20% and most commonly causes single sided epididymo-orchitis (3). brucella epididymoorchitis (beo) generally causes acute clinical symptoms (78%) (3-5). differential diagnosis of the disease with other emergency urological conditions causing acute scrotum (testicular torsion, testicular tumors, etc.) must be conducted precisely to prevent consequences of surgery. this paper is aimed to describe differential diagnosis of epididymo-orchitis cases that are resistant to classical treatment or recurrent considering diagnosis and treatment of brucellosis that still maintains its importance. it also calls attention to different clinical pictures of brucella epididymoorchitis. case reports case 1 (unsuccessful treatment) a 42 years old male patient with right testicular pain, edema and fever started 2 months before was treated withoute success for recurrent orchitis in another center. aydemir _stesura seveso 02/07/15 11:26 pagina 151 archivio italiano di urologia e andrologia 2015; 87, 2 aydemir huseyin, budak gokcen, budak salih, celik orcun, yalbuzdag okan, keles !brahim 152 ed one day before. at physical examination his body temperature was 38.7°c and blood pressure was 90/60 mmhg, he had minimal swelling of left testis, severe tenderness whereas examination of other systems was normal. laboratory findings showed leucocyte count 21000/mm3, sedimentation rate 50 mm/h, crp 77 mg/l. scrotal color doppler ultrasonography revealed finding of left epididymo-orchitis. patient was hospitalized, monitored and treated with 2 g/day ceftriaxone. on the 3rd day of treatment, symptoms and vital findings were not recovered enough, left testicular edema increased dramatically and erythema and edema involved the left side of scrotum. brucella was suspected and coombs test for brucella was positive, tube agglutination test was positive for 1/320 titer. in blood culture brucella spp. growth was observed. patient was treated with rifampicin 600 mg/day, doxicycline 200 mg/day and streptomycin 1 gr/day im. vital findings were normalized after the 2nd day of treatment. testicular findings recessed after 2 weeks. patient’s treatment was completed in 6 weeks (streptomycin at 15th day). patient did not have any recurrence orchitis but due to recurrent arteritis patient was transferred to specialized clinic. case 4 (nonspecific epididmoorchitis) a 50 years old male patient presented with dysuria and right testicular pain for 6 weeks. at physical examination tenderness of right testicular and inguinal canal was present, vital findings and other systems examination was normal. in laboratory findings leucocyte count was 4500/mm3, sedimentation rate was 12 mm/h and crp was 9 mg/l. scrotal color doppler ultrasonography showed findings consistent with right epididymo-orchitis. patient was treated with ciprofloxacin 100 mg/day. at the 4th day of treatment patient presented again with high fever and swelling of right testicle. physical examination revealed swelling of right testicle, erythema and temperature increase at the right side of the scrotum. his body temperature was 38.2°c. patient detailed history revealed that he was treated for brucellosis 6 months prior. brucellosis coombs test was positive and tube agglutination test was positive for 1/160 titer. there was no growth in blood and urine cultures. patient was treated with rifampicin 600 mg/day, doxycycline 200 mg/day and anti-inflammatory drugs for 6 weeks. his symptoms were diminished after the first week of treatment. there was no recurrence in 6 months follow up of the patient. case 5 (bilateral epididymoorchitis) a 22 years old male patient presenting with long lasting bilateral testicular pain. physical examination showed minimal tenderness of both testicles, vital findings and other system examination were normal. laboratory findings showed no specific findings in urinary analysis, leucocyte count 4100/mm3, sedimentation rate 8 mm/h, and crp 6 mg /l. scrotal color doppler ultrasonography revealed bilateral testicular increased blood flow. patient’s family was treated for brucellosis, so brucellosis panel was studied. rose bengal test was positive and tube agglutination test was positive for 1/160 titer. there was no growth in blood or urine culture. patient was treated with rifampicin 600 mg/day, doxycycline 200 mg/day and antiinflammatory drugs for 6 weeks. patient’s symptoms were decreased after the 2nd week of the treatment. there was no recurrence in the 3 month follow up of the patient. case 6 (testicular tumor suspicion) a 30 years old male patient presented to the urology clinic with a left testicular painful mass. physical examination revealed left testicular stiffness at palpation. examination of other system was normal. there was no significant clinical or family history. laboratory findings included leucocyte count 10200/mm3, crp 72 mg/l, αfeto protein (afp) 1.8 (< 13.4), bhcg < 1.2. emergency scrotal ultrasonographyshowed an hypodense 31.8 mm solid mass of left testicle. after a preliminary diagnosis of seminoma, magnetic resonance imaging (rmi) was scheduled that demonstrated unclear demarcation of the mass with heterogeneous pattern that was reported as consistent with epididymo-orchitis (figure 1). brucella tube agglutination test was positive for 1/250 titer. there was no growth in blood culture. patient was treated with rifampicin 600 mg/day and doxycycline 200 mg/day. pain and swelling regressed and scrotal ultrasonography 2 week after treatment showed dramatic regression. ultrasonography conducted 3 months later showed further decrease of mass size and at 1 year follow up ultrasonography findings were normal. there was no recurrence at 2 years follow up. discussion brucellosis is very rare in developed countries. but it is an endemic zoonotic disease in the mediterranean basin and middle east (2). turkey is in the brucellosis endemic region and its incidence is 2-6% (6). in systemic brucellosis, epididymo-orchitis is most commonly seen as unilateral (3, 6, 7). in a study of 12 cases with genitourinary figure 1. left testicular heterogeneous mass, consistent with epididymoorchitis. aydemir _stesura seveso 02/07/15 11:26 pagina 152 153archivio italiano di urologia e andrologia 2015; 87, 2 different presentation types of primary brucella epididimo-orchitis complications due to brucellosis, 10 cases presented with epididymoorchitis (5). in the same study the ten beo patients were compared with 15 non-specific epididymoorchitis (eo) cases and beo was characterized by long-lasting clinical presentation, history of unpasteurized milk consumption, lower urinary system symptoms, normal urinary analysis and frequent leukocytosis (5). some tests are required for the diagnosis of brucellosis, in addition to patient history and physical examination (rose bengal, tube agglutination, coombs test, blood culture). values of tube test higher of 1/160 titer and blood culture positivity are important for diagnosis (8). delayed diagnosis and treatment, can lead to various complications (e.g., testicular abscess, atrophy, necrosis and infertility) (9). it is very difficult to distinguish beo from non-specific eo (10). detailed history from the patient is important for diagnosis in case of eo unresponsive to conventional therapy, that should bring to mind brucella eo. acute epididymo-orchitis is a frequent disease in urology clinic and one of the causes of acute scrotum. differential diagnosis of acute scrotum includes testicular torsion, testicular tumors, appendicular testicular torsion and testicular trauma. diagnosis of torsion and tumor are crucial because they require fast treatment, so futher radiological tests must be considered. in our 6th case, even though ultrasonography diagnosis was consistent with a testicular tumor mri results demonstrated epididymoorchitis. tumor markers in the normal range and tube agglutination test consistent with brucellosis helped the clinical diagnosis. in consideration of the association of tumor and epididymo-orchitis, frequent and close follow up is suggested. world health organization recommends a 45 day course of oral doxycycline 200 mg/day and streptomycin 1 g/day im for brucellosis treatment. an alternative is a 45 day course of oral rifampicin 15 mg/kg/day (600-800 mg) and doxycycline 200 mg/day (11). in cases unresponsive to medical treatment orchiectomy is practiced. afsar et al. reported 2 cases requiring orchiectomy in a 13 cases study with doxycycline and rifampicin treatment (12). in conclusion, brucella epididymo-orchitis must be kept in mind in the differential diagnosis of acute scrotum and epididmo-orchitis in brusella-endemic countries. references 1. mesner o, riesenberg k, biliar n, et al. the many faces of human-to-human transmission of brucellosis: congenital infection and outbreak of nosocomial disease related to an unrecognized clinical case clin infect dis. 2007; 45:135-140. 2. pappas g, papadimitriou p, akritidis n, et al. the new global map of human brucellosis. lancet infect dis. 2006; 6:91-99. 3. young ej. brucella species. in mandell gl, dolin r, bennett je (eds) mandell, douglas, and bennett’s principles and practice of infectious diseases 6th ed., churchill livingstone, philadelphia 2005; pp 2669-2674. 4. doganay m, alp e. brucellosis. in rakel re, bope et (eds). conn’s current therapy, 2006. 5. ibrahim ai, awad r, shetty sd, et al. genitourinary complications of brucellosis. br j urol. 1988; 61:294-298. 6. sözen th. bruselloz. in topcu aw, soyletir g, doganay m (eds) infeksiyon hastalıkları. 2.baskı. istanbul: nobel tıp kitabevleri; 2002, pp 636-642. 7. canda ae, akay o, gürkan l, et al. brucella epididimoorsiti: agrı bölgesinde saptanan 4 olgunun sunumu. türkiye ekopatoloji dergisi. 2006; 12:17-21. 8. mert a, ozaras r, tabak f, et al. the sensitivity and specificity of brucella agglutination tests. diagn microbiol infect dis. 2003; 46:241-243. 9. colmenero jd, munoz-roca nl, bermudez p, et al. clinical findings, diagnostic approach, and outcome of brucella melitensis epididymo-orchitis. diagn microbiol infect dis. 2007; 57:367-372. 10. memish za, venkatesh s. brucellar epididymo-orchitis in saudi arabia: a retrospective study of 26 cases and review of the literature. bju int. 2001; 88:72-76. 11. brucellosis in human and animals. geneva (switzerland): world health organization; 2006. 12. afsar h, baydar i, sırmatel f: epididymoorchitis due to brucellosis, br j urol. 1993; 72:104-105. correspondence aydemir huseyin, md department of urology, ministry of health sakarya teaching and research hospital, sakarya, turkey gokcen budak, md department of infectious disease clinic, tire state hospital sakarya, turkey salih budak, md (corresponding author) salihbudak1977@gmail.com orcun celik, md okan yalbuzdag, md tepecik educational and research hospital, department of urology 35140 izmir, turkey !brahim keles, md department of urology, school of medicine, afyon kocatepe university afyonkarahisar, turkey aydemir _stesura seveso 02/07/15 11:26 pagina 153 stesura seveso 89archivio italiano di urologia e andrologia 2016; 88, 2 original paper can perineural invasion detected in prostate needle biopsy specimens predict surgical margin positivity in d’amico low risk patients? ozgur haki yuksel 1, ahmet urkmez 2, ayhan verit 1 1 department of urology, fatih sultan mehmet research & training hospital, istanbul, turkey; 2 haydarpasa numune research and training hospital, dept. of urology, istanbul, turkey. objectives: in this study, our aim was to estimate the value of perineural invasion (pni) in prostate needle biopsy (pnb) specimens in the prediction of surgical margin positivity (smp) and its prognostic significance (upgrade gleason score) in patients who had undergone radical retropubic prostatectomy (rrp) with low risk prostate cancer according to d’amico risk assessment. materials and methods: we retrospectively analyzed the data of 65 patients who were diagnosed as clinical stage t1c prostate cancer (pc) and underwent rrp between january 2010 and june 2013. pathological specimens of pnb and rrp were separately examined for the parameters of pni, vascular invasion (vi), gleason score (gs) and smp. results: the patients’ mean age was 63.65 ± 4.93 (range 4775) years. pni in pnb specimens were identified in 12 of 65 patients and 11 of 12 patients showed smp on rrp specimens. while 53 of 65 patients had not pni on pnb, only 11 of them demonstrated smp on rrp specimens. smp was 30.64-fold more frequently encountered in pnb specimens obtained from pni-positive patients relative to pni-negative patients. in our study, pni detected in pnb specimens was statistically significantly associated with smp on rrp specimens (p = 0.0001). conclusion: it is well known that higher psa values and gs were independent predictors of smp in clinically localized prostate cancer (clpc). we think that pni in pnb specimens may be a useful prognostic factor for predicting smp in cases with clpc. key words: prostate needle biopsy; prostate adenocarcinoma; perineural invasion; lymphovascular invasion; positive surgical margins. submitted 22 october 2015; accepted 20 january 2016 summary no conflict of interest declared. (rrp) specimens is an important marker in the prediction of locally advanced tumor or those with metastatic potential. besides, tumor stage detected in pnb and rrp specimens is expected to be same. in patients with t1/t2 prostate cancer treated with rrp, biochemical recurrencefree rates were reported as nearly 80 and 60% within 5 and 10 years of follow-up, respectively (1). post-rrp recurrence has been most frequently reported within the first postoperative year, which is possibly associated with clinical understaging of the tumors (2). although a consensus exists proposing surgical margin positivity (smp) as a prognostic marker, which significantly increases the probability of treatment failure, a standard treatment method specified for these patients is lacking. besides it is apparent that clinical progression is not observed in all patients (3). psa levels, gleason scores (gs), pathological stage, prostate volume (in various studies prostate volume less than 40 gr has been considered as a risk factor for prostate cancer), body mass index (bmi), tumor volume occupying more than 10 % of the prostate, capsular and perineural invasion (pni) have been defined as basic risk factors for predicting smp (4). in this study, our aim was to estimate the value of pni in pnb specimens in the prediction of smp and prognostic significance (upgrade gs) in patients who had undergone rrp with low risk pc according to d’amico risk assessment. material and methods we retrospectively analyzed data of 65 patients who were diagnosed as clinical stage t1c pc and underwent rrp between january 2010 and june 2013. all patients underwent 12 quadrant prostate biopsies. patients, who were diagnosed as low risk pc according to the d’amico classification, were included in the study. pathological specimens of pnb and rrp were separately examined for the parameters of pni, vascular invasion (vi), gs and smp. all specimens were prospectively processed according to the stanford protocol (3 mm). statistical analysis for statistical evaluation of study data, ibm spss statistics 22 program was used. compliance with the normal distridoi: 10.4081/aiua.2016.2.89 introduction prostate cancer (pc) is one of the most frequently seen fatal malignancies. detection of the disease at an early stage can ensure complete cure, however uncertainties about actual clinical stage and preoperative prognosis are still prevalent. pc is diagnosed and staged based on histopathological examination of prostate needle biopsy (pnb) specimens or tissue samples obtained from transurethral prostatic resection (tur-p). stage of the tumor contained in the radical retropubic prostatectomy haki-yuksel2_stesura seveso 01/07/16 12:09 pagina 89 archivio italiano di urologia e andrologia 2016; 88, 2 o. haki yuksel, a. urkmez, a. verit 90 bution of parameters was evaluated by shapirowilks test. in the evaluation of study data, descriptive statistical methods (means, standard deviation, median, frequencies, ratio and minimum, maximum) were used. for the comparison of quantitative data and pairwise intergroup comparisons of variables without normal distribution mannwhitney u test was used. in addition to descriptive statistical methods (means, standard deviation, frequency) for the comparison of qualitative data fisher’s exact test, chisquare test and mc nemar test were used. statistical significance was evaluated at p < 0.01, and p < 0.05. results patients’ mean age was 63.65 ± 4.93 (range 47-75) years. patients’ psa values and prostate volumes ranged respectively between 4-10 ng/ml (7.35 ± 1.96) and 18-120 ml (mean: 45,29 ± 18,97 ml). mean preoperative and postoperative gs of the patients were 5.80 ± 0.4 (range: 5-6) and 6.27 ± 0.80 (range: 5-9), respectively (table 1). increase in postoperative gs of the patients was seen in 23 (35.4%) cases. a statistically significant difference did not exist between incidence rates of increased gleason scores and presence of preoperative pni (p > 0.05). increases in gleason scores were detected in 38.5, and 34.6% of the cases with and without preoperative perineural invasion, respectively (table 2). preoperatively pni was detected in 16.9% (n = 11) of 25 (38.5%) cases who postoperatively revealed surgical margin positivity, while the remaining cases demonstrated surgical margin negativity. therefore sensitivity (44.00%), specificity (97.50%), accuracy (91.67%), positive (73.58%) and negative (76.92%) cut-off values of the test were determined as indicated within respective parentheses. smp was 30.64-fold more frequently encountered in pnb specimens obtained from pni-positive patients relative to pni-negative patients [or: 30.643 (95% ci: 3.619-259.473)] (table 3). discussion in a long-term multiple center study, smp following rrp has been demonstrated in 10-38% of the cases (5). our estimate (38.5%) appears to be above upper limit of psm incidence reported in the literature. none of the nomograms predictive of surgical margin have been validated up to now. in a recent study, one of the most important parameters predicting smp have been indicated as angiolymphatic invasion and gs (6). efforts aiming at development of an ideal algorithm encompassing preoperative clinical criteria and biopsy results so as to predict smp are still continuing. although some authors have asserted that the detection of pni in needle biopsy specimens might increase risk of extraprostatic extension, this issue is still debatable. in their systematic review, harnden et al. (7) investigated the importance of the detection of pni in cases with postoperative and postradiotherapeutic recurrences and demonstrated its significant prognostic value, especially in patient subgroups defined based on serum psa levels and gs. they also indicated that patients whose biopsy specimens had evidence of pni were not suitable for watchful waiting and they required early therapeutic intervention. in more than 67 % of the studies where external radiotherapy was applied (excluded brachytherapy) prognostic value of pni has been demonstrated. in the year 2007, passavanti et al. detected 53% pni positivity in rrp specimens of 94 patients, and demonstrated pni positivity in pnb samples of only 45% of these cases. in our study, we observed pni-positivity in 18.5% (n = 12) of biopsies, but 56.9% (n = 37) of radical prostatectomy specimens. passavanti et al. analyzed patients with serum psa levels between 4 and 20 ng/ml in their study and confirmed the correlation between pni and higher gs as was also proved in our study. as min-max mean ± sd age 47-75 63.65 ± 4.93 psa (ng/ml) 4.00-10 7.35 ± 1,96 prostate volume (ml) 18-120 45,29 ± 18,97 preop gleason score 5-6 5.80 ± 0.4 postop gleason score 5-9 6.26 ± 0.80 prostatic involvement (%) 0.30-50.00 13.35 ± 12.40 n % preop pni 12 18.5 postop pni 37 56.9 preop lvi 1 1.5 postop lvi 17 26.2 vsi 5 7.7 surgical margin positivity 25 38.5 pvol: prostate volume; pni: perineural invasion; lvi: lymphovascular invasion vsi: vesiculo-seminal invasion. preop pni yes no n (%) n (%) surgical margin positivity 11 (91.6) 14 (26.4) 0.001** increase in gleason score 5 (41.6) 18 (33.9) 1.000 fisher’s exact test; **p < 0.01. table 1. distribution of characteristic features of the patients. table 2. evaluation of surgical margin positivity and increases in gleason scores relative to the preoperative presence of perineural invasion. surgical margin invasion present absent total n % n % n % preop yes 11 16.9 1 1.5 12 18.5 pni no 14 21.5 39 60.0 53 81.5 total 25 38.5 40 61.5 65 100 table 3. assessments of preoperative pni based on the results of surgical margin invasion. haki-yuksel2_stesura seveso 01/07/16 12:09 pagina 90 a result of their study, passavanti et al. revealed significance of pni-positivity detected in pnb specimens for the treatment plan, while pni positivity found in rrp specimens was indicated to be meaningful for biological behaviour and progression of the tumor (8). however in our study, which took in consideration psa interval between 4-10 ng/ml, a statistical correlation between pni and gs upgrade was not detected. pni in pnb was considered as an important criterion in the decisionmaking of active surveillance in several studies. still, in these studies, pni was associated with higher tumor volume, which did not indicate a poor prognosis (9-11). in an investigation performed by walsh and epstein in 1993, the authors reported that knowledge about the presence and extent of pni in needle biopsy specimens might provide information about capsular penetration and aid in the decision-making process for nerve-sparing surgery (12). in another prognostic study, pni was found to be correlated independently with adverse histopathological characteristics and worse survival outcomes after rrp (13). since higher percentage of cases with extraprostatic tumoral extension associated with pni have been reported in the literature, some authors have advocated routine resection of neurovascular bundle at the pni-positive side so as to achieve an ipsilateral surgical margin negativity. however cannon et al. conducted a multivariate analysis on 425 patients in the year 2005 and reported presence of a weak correlation between pni-positivity and smp contrary to a significant correlation between pni-positivity and organ-confined disease. they indicated that though pni-positivity highly predicts extracapsular extension, bilateral nerve-sparing surgery is not required in these patients (14). in a multivariate analysis of preoperative psa levels, gs, digital rectal examination, tumor volume and pni, pni could predict extraprostatic invasion in nearly 10% of the cases (15). however in another study, any correlation between pni and gs estimated based on histopathological examination of rrp specimens, extraprostatic extension, smp, lvi and upgrading of the tumor was not detected (16). in a study similar to ours, pni was indicated as an effective factor on smp and psa recurrence during 5 years of follow-up in patients who had undergone rrp with the indication of localized prostate cancer (17). this study documents that longterm prostate cancer outcomes are best estimated with a combination of gs, detection of pni and ki-67 expression. given its low cost, rapid assessment and strong predictive power, we believe that combining presence of ki-67 expression, pni and estimated gs based on histopathological examination of biopsy specimens should be considered as a standard by which all new biomarkers must be compared with before introducing them into clinical practice (18). we know the importance of estimated gs of pnb specimens, preoperative psa values and pni in the prediction of postoperative clinical course. though we have observed that higher psa and gs predicted smp at a large extent, we have also seen smp in patients with relatively lower gs and psa values independent of histopathological characteristics of the surgical specimen. uncertainties exist about criteria on which clinicians should base their therapeutic decisions. we think that criteria of pni detected in pnb specimens can explain and predict this phenomenon. similarly, as described above, even though relevant data are debatable, it has been asserted that determinable characteristic of pni may predict smp and even in some studies prognostic value of pni has been specified. we think that questioning the place of pni in the prediction of smp is the most accurate approach in patients categorized in the lower risk group according to d’amico classification, in parallel with this assumption, in our study, we observed that pni detected in histopathological examination of the biopsy specimens could predict smp independent of psa and gs. therefore, we conceive that inclusion of histopathologically detected pni in preoperative nomograms should be debatable. the limitations of our study were that it was retrospective one with limited study group and had not a prognostic predictive design. prospective studies are needed to have data on disease-free survival in patients with pni at biopsy who underwent to prostatectomy, and eventually understand if pni can be a decisive factor in the choice of not radical treatment for the prostate cancer detected at biopsy. references 1. yossepowitch o, bjartell a, eastham ja, et al. positive surgical margins in radical prostatectomy: outlining the problem and its long-term consequences. eur urol. 2009; 55:87-99. 2. eastham ja, scardino pt. radical prostatectomy; in walsh pc (ed). campbell’s urology. philadelphia, elsevier, 2005: 3080-102. 3. sofer m, hamilton-nelson kl, civantos f, et al. positive surgical margins after radical retropubic prostatectomy: the influence of site and number on progression. j urol. 2002; 167:2453-6. 4. ko j, falzarano sm, walker e, et al. prostate cancer patients older than 70 years treated by radical prostatectomy have higher biochemical recurrence rate than their matched younger counterpart. prostate. 2013; 73:897-903. 5. schiavina r, borghesi m, dababneh h, et al. survival, continence and potency (scp) recovery after radical retropubic prostatectomy: a long-term combined evaluation of surgical outcomes. eur j surg oncol. 2014; 40:1716-23. 6. la roca rl, cunha iw, bezerra sm, et al. radical prostatectomy and positive surgical margins: relationship with prostate cancer outcome. int braz j urol. 2014; 40:306-15. 7. harnden p, shelley md. the prognostic significance of perineural invasion in prostatic cancer biopsies: a systematic review. cancer. 2007; 109:13-24. 8. passavanti g, pizzuti v. perineural invasion in prostatic carcinoma treated with radical prostatectomy: the role of tr systematic biopsy. arch ital urol androl. 2007; 79:23-5. 9. trpkov c, yilmaz a, trpkov k. perineural invasion in prostate cancer patients who are potential candidates for active surveillance: validation study. urology. 2014; 84:149-52. 10. cohn ja, dangle pp, wang ce, et al. the prognostic significance of perineural invasion and race in men considering active surveillance. bju int. 2014; 114:75-80. 91archivio italiano di urologia e andrologia 2016; 88, 2 can perineural invasion detected in prostate needle biopsy specimens predict surgical margin positivity in d’amico low risk patients? haki-yuksel2_stesura seveso 01/07/16 12:09 pagina 91 archivio italiano di urologia e andrologia 2016; 88, 2 o. haki yuksel, a. urkmez, a. verit 92 11. gorin ma, chalfin hj, epstein ji, et al. predicting the risk of non-organ-confined prostate cancer when perineural invasion is found on biopsy. urology. 2014; 83:1117-21. 12. bastacky si, walsh pc, epstein ji. relationship between perineural tumor invasion on needle biopsy and radical prostatectomy capsular penetration in clinical stage b adenocarcinoma of the prostate. am j surgpathol. 1993; 17:336-41. 13. delancey jo, wood dp jr, he c, et al. evidence of perineural invasion on prostate biopsy specimen and survival after radical prostatectomy. urology. 2013; 81:354-7. 14. cannon gm jr, pound cr. perineural invasion in prostate cancer biopsies is not associated with higher rates of positive surgical margins. prostate. 2005; 63:336-40. 15. tsuzuki t, hernandez dj, aydin h, et al. prediction of extraprostatic extension in the neurovascular bundle based on prostate needle biopsy pathology, serum prostate specific antigen and digital rectal examination. j urol. 2005; 173:450-3. 16. elharram m, margel d, finelli a, et al. perineural invasion on prostate biopsy does not predict adverse pathological outcome. can j urol. 2012; 19:6567-72. 17. d'amico av, wu y, chen mh, et al. perineural invasion as a predictor of biochemical outcome following radical prostatectomy for select men with clinically localized prostate cancer. j urol. 2001; 165:126-9. 18. tollefson mk, karnes rj, kwon ed, et al. prostate cancer ki-67 (mib-1) expression, perineural invasion, and gleason score as biopsy-based predictors of prostate cancer mortality: the mayo model. mayo clin proc. 2014; 89:308-18. correspondence ozgur haki yuksel, md (corresponding author) ozgurhaki@gmail.com ayhan verit, md, prof. department of urology, fatih sultan mehmet research & training hospital içerenköy/atasehir tr34752 istanbul, turkey ahmet urkmez, md haydarpasa numune research and training hospital, dept. of urology istanbul, turkey haki-yuksel2_stesura seveso 01/07/16 12:09 pagina 92 stesura seveso 371archivio italiano di urologia e andrologia 2014; 86, 4 original paper modifications of echogenicity of the testis during acute torsion may be a predictive factor of organ damage? giuseppe benedetto, filippo nigro, emiliano bratti, andrea tasca department of urology, san bortolo hospital, vicenza, italy in the setting of symptoms of testicular torsion the absence of diastolic flow or color flow on doppler ultrasound has traditionally prompted emergent scrotal exploration. this practice emanates from the difficulty on ultrasound of distinguishing salvageable testes from those that are not salvageable. we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. key words: testicular torsion; echogenicity of testicular torsion. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. flow in the testis wrong. six boys underwent orchiectomy for testicular necrosis and histological examination documented hemorrhagic necrosis of the testis consistent with testicular torsion. the ultrasound pattern of these patients documented in all the presence of a dishomogeneous and heterogeneous echotexture of the testis. in the other eight patients an hypoechoic and isoechoic homogeneous testicular framework was documented, compatible with the integrity of the testis as assessed at scrotal exploration the average time between the onset of symptoms and the scrotal exploration was 9 hours (range 6-18) in patients in whom the testis was preserved, and 15 hours (range 9-21) in patients undergoing then to orchiectomy. there were no intraand postoperative complications in patients undergoing orchiectomy discussion in our series the heterogeneously hypoechoic testicular parenchyma showed an irreversible organ damage that required removal of the organ. doi: 10.4081/aiua.2014.4.371 presented at 19th national congress sieun, fermo 2014 introduction and aims during the acute torsion of the testis, in addition to clinical signs and symptoms, the scrotal doppler ultrasound can be of support in evaluating the absence of testicular flow. we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. material and methods we retrospectively analyzed, the scrotal ultrasound of patients undergoing scrotal exploration for testicular torsion in the last year in our department, evaluating the sonographic features and comparing them to the outcome of the scrotal exploration, and in case of orchiectomy to outcome for histology. was also evaluated the average time between the onset of symptoms and evaluation in the emergency room and the scrotal exploration. results during the past year, 14 children were evaluated at our department for acute torsion of the testis and underwent scrotal exploration. all underwent preoperative scrotal doppler ultrasound that documented the absence of figure. dishomogeneous torsion testis alteration. benedetto_stesura seveso 16/01/15 10:59 pagina 371 archivio italiano di urologia e andrologia 2014; 86, 4 g. benedetto, f. nigro, e. bratti, a. tasca 372 therefore, taking into account echotexture and obvious signs of torsion scrotal exploration cannot be emergent. on the other hand, an homogeneous echotexture heralds testicular viability and the need to scrotal exploration in emergency. conclusion we evaluated the changes of echogenicity in the course of testicular torsion of the testis to identify characteristics predictive of irreversible organ damage. however the smallness of our sample requires confirmation by in-depth studies of larger series. references 1. kaye jd, shapiro ey, levitt sb, et al. parenchymal echo texture predicts testicular salvage after torsion: potential impact on the need for emergent exploration.j urol. 2008; 180(4 suppl):1733-6. 2. nistal m, paniagua r, gonzalez-peramato p, reyes-múgica m. testicular torsion, testicular appendix torsion and other forms of testicular infarction. pediatr dev pathol. 2014. correspondence giuseppe benedetto, md g_benedetto@yahoo.it filippo nigro, md filippo.nigro@ulssvicenza.it emiliano bratti, md emiliano.bratti@ulssvicenza.it andrea tasca, md andrea.tasca@ulssvicenza.it uoc urologia, ospedale san bortolo, via rodolfi, 37 vicenza, italy benedetto_stesura seveso 16/01/15 10:59 pagina 372 195archivio italiano di urologia e andrologia 2016; 88, 3 original paper in the search of novel urine biomarkers for the early diagnosis of prostate cancer. intracellular or secreted proteins as the target group? where and how to search for possible biomarkers useful in the everyday clinical practice amalia katafigioti 1, ioannis katafigiotis 1, stavros sfoungaristos 2, christos alamanis 1, konstantinos stravodimos 1, ioannis anastasiou 1, eleni roumelioti 1, mordechai duvdevani 2, constantinos constantinides 1 1 1st university urology clinic, laiko hospital, athens, greece; 2 hebrew hadassah university medical center, jerusalem, israel. objective: to search which category of proteins can be detected in urine in order to examine subsequently its ability to improve our accuracy for the diagnosis of prostate cancer (pca) as biomarkers in clinical useful fluids like urine and serum. material and method(s): urine samples of 127 patients were obtained after a vigorous transrectal prostatic massage to both lobes. the patients were considered to have a high risk for pca according to their psa (> 4 ng/ml), their digital rectal examination (dre) (positive for suspicious prostatic lesions) or to their abnormal psa kinetics (psa velocity (psav > 0.75 ng/ml). all patients subsequently were subjected to an extended 10-core per prostatic lobe trus-b (total 20 prostatic samples). the proteins that were chosen to be detected in the urine samples with western-blot, as possible biomarkers, were glutathione peroxidase 3 precursor (gpx3), cofilin-1 (cfl1), heat shock protein-90β (hsp 90β), zinc alpha 2-glycoprotein (zag) and secreted protein acidic and rich in cysteine (sparc).these proteins have been detected previously in the prostatic tissue by proteomics proving their discriminative ability between patients with prostate cancer and benign prostatic hyperplasia. result(s): from the five proteins, only the secreted zinc alpha 2-glycoprotein was detected in urine showing a promising ability in the improvement of our diagnostic accuracy for the early diagnosis of prostate cancer. conclusions: from various categories of proteins that have already been detected in the tissue of prostate by proteomics, only secreted protein zinc alpha 2-glycoprotein showed a clear signal in the urine, proving its discriminative potential for the early diagnosis of pca. key words: prostate cancer; biomarker; urine; zinc alpha 2-glycoprotein. submitted 14 february 2016; accepted 8 may 2016 summary no conflict of interest declared. rise of pca incidence over the last 20 years has been attributed also to the psa (2). nevertheless, psa is a test specific for the prostate but not specific for cancer and it can be elevated due to benign prostatic hyperplasia (bph) and prostatitis. while the conventional psa threshold of 4 ng/ml has been used in the previous years as a recommendation for transrectal ultrasound guided biopsy (trus-b), today psa is considered a continuous parameter with higher levels of the test rising the likelihood of pca (3). pca can be present despite low psa values and even aggressive pca with gleason score > 7 can be diagnosed with low serum psa values, precluding the definition of an optimal psa threshold for the early diagnosis of psa and constituting the urgent need of more specific biomarkers for pca (3, 4). in our study we tried to examine prospectively, various proteins in the urine of patients with suspect of pca according to their psa values or their digital rectum examination (dre), who subsequently were subjected to trus-b. five proteins were meticulously chosen. four were previously detected by the use of proteomics in the tissue of patients with (bph) and pca helping to differentiate these two diseases, while the fifth was chosen due to its proven utility as a secreted protein in bladder cancer (5, 6). at the same time we classified the proteins in two major categories intracellular and secreted. our goal was to see which category of proteins can be detected in urine in order to examine subsequently its ability to help us improve our diagnostic accuracy for the pca as biomarker in clinical useful fluids like urine and serum. materials and methods urine samples of 127 patients were obtained after a vigorous transrectal prostatic massage to both lobes and they were immediately stored to -80˚c. the patients were considered to have high risk for pca according to their psa (> 4 ng/ml), their digital rectal examination (dre) (positive for suspicious prostatic lesions) or to their abnormal psa kinetics (psa velocity (psav > 0.75 doi: 10.4081/aiua.2016.3.195 introduction prostate cancer (pca) constitutes the most common cancer and the second cause of cancer specific death in men (1). the widespread use of prostate specific antigen (psa) test has revolutionized pca diagnosis. in fact the katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 195 archivio italiano di urologia e andrologia 2016; 88, 3 a. katafigioti, i. katafigiotis, s. sfoungaristos, c. alamanis, k. stravodimos, i. anastasiou, e. roumelioti, m. duvdevani, c. constantinides 196 ng/ml). all patients subsequently were subjected to an extended 10-core per prostatic lobe trus-b (total 20 prostatic samples). the specimen was analyzed in a blinded fashion by an experienced uropathologist (k.p.) and the results of the histology were collected. exclusion criteria were patients with known pca, psa > 25 ng/ml, patients taking finasteride or dutasteride, patients who had been previously subjected to a trus-b or to an operation for bph and patients with rectal extirpation. patients with psa > 25 ng/ml were excluded due to the fact that as psa rises, the probability of pca also increases and the goal was to examine specific the patients that could cause diagnostic dilemma to the urologist and how urine biomarkers could help to the differential diagnosis and no these that pca diagnosis was higher based to the psa. nevertheless psa > 25 ng/ml was a random choice based on the higher probability of pca. the study was approved by the ethical committee of the athens university medical school and laiko hospital and all the patients signed a written consent after a detailed information. urine samples-proteins-western blot the proteins that was chosen to be detected in the urine samples as possible biomarkers were glutathione peroxidase 3 precursor (gpx3), cofilin-1 (cfl1), heat shock protein-90β (hsp 90β), zinc alpha 2-glycoprotein (zag) and secreted protein acidic and rich in cysteine (sparc). gpx3, cfl1, hsp 90β, zag, were chosen based on their performance in the tissue with the use of quantitative proteomics analysis in a previous study of ours, where all these four proteins showed different levels between bph tissue (obtained from suprapubic prostatectomy or transurethral prostatectomy) and pca tissue (obtained from radical retropubic prostatectomy) 5 (table 1). specifically, gpx3 was up-regulated (2.19 ± 0.57 fold change) in pca compared to bph tissue, cfl1 was also up-regulated (3.29 ± 1.20 fold change) in pca compared to bph tissue, hsp 90β was also up-regulated (3.2 ± 0.61 fold change) in pca compared to bph tissue, while zag was down-regulated (0.43 ± 0.13 fold change) in pca compared to bph5 (table 1). the fifth protein sparc was detected from another study of our team, where this protein was found to be differentially expressed at statistically significant levels in the secretome of a cell line model for aggressive bladder cancer, and due its performance and its secreted nature was also chosen in order to examine its possible utility in pca (6) (table 1). sample preparation urine samples were thawed on ice. trichloroacetic acid (tca) with the carrier sodium lauroyl sarcosinate (nls) precipitation was conducted as followed: 0.1% nls 7.5% tca was added to every sample. samples were vortexed and incubated at -20°c o/n. samples were thawed and centrifuged at 10.000g for 10 min at 4°c. protein pellet was washed with ice cold tetrahydrofuran (thf) and centrifuged at 10.000g for 10 min at 4°c. washing step was repeated one more time. pellet was resuspended in lysis buffer (7m urea, 2m thiourea, 4% chaps, 1% dte, 2% ipg). bath sonication was performed for 30 min and finally samples were centrifuged at 10.000g for 10 min rt; 3.6% protease inhibitors (roche) were added to the supernatant and stored at -20°c until used. western blot analysis total protein (20 μg) of urine samples were separated by 10% sds-page under reducing conditions and electroblotted to hybond-ecl nitrocellulose membrane (amersham biosciences). after blocking with 5% non-fat dried milk in tbst (20 mm tris/ph 7.6, 137 mm nacl, 0.1% tween 20) for 2 h at room temperature, membranes were washed with tbst and incubated overnight at 4 °c with the primary antibodies, as applicable: mouse antihuman sparc (santa cruz; dilution 1:500), mouse antihuman zag (santa cruz; dilution 1:1000), mouse antihuman cofilin (santa cruz; dilution 1:2000), mouse antihuman gpx-3 (santa cruz; dilution 1:1000), goat antihuman hsp90b (santa cruz; dilution 1:3000). membranes were then washed with tbst and incubated with antimouse or antigoat hrp-conjugated secondary antibody (santa cruz; dilution 1:10 000) for 2 h at room temperature. a final wash with tbst was made and target protein was detected by enhanced chemiluminescence (perkin-elmer las, inc.) detection system. films were scanned and images were analyzed using quantity one software (bio rad). results sample baseline characteristics are presented in table 2. proteins nature performance in tissue between bph detection in urine explanation and pca or other utility gpx3 secreted up-regulated detected in few samples extensive unspecific binding (2.19 ± 0.57 fold change) in pca of the antibody cfl1 intracellular up-regulated not detected both in normal intracellular (3.29 ± 1.20 fold change) in pca and prostate cancer samples hsp 90β intracellular up-regulated not detected both in normal albumin masking effects (3.2 ± 0.61 fold change) in pca and prostate cancer samples sparc secreted expressed at statistically significant not detected both in normal intracellular levels in aggressive bladder cancer and prostate cancer samples zag secreted down-regulated significant increase in patients secreted (0.43 ± 0.13 fold change) in pca with positive histology for pca table 1. proteins of the study. katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 196 gpx-3 a representative image of western blot analysis of urine samples with anti-gpx-3 (mw: 23 kda) is depicted in figure 1. glutathione peroxidase 3 is a secreted protein that protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides and organic hydroperoxide, by glutathione (7). this protein has been previously found to be up-regulated (2.19 ± 0.57 fold change) in pca compared to bph tissue specimens by a quantitative proteomics analysis (5) (table 1). gpx-3 was detected in a few samples (79, 80, 84). this was mainly attributed due to the extensive unspecific binding of the antibody as shown in figure 1. many optimization protocols were applied to reduce the effect of unspecific binding (lower amount of starting material loaded on the gel, different antibody dilutions and incubation times, different blocking times, different enhanced chemiluminescence detection systems, different film exposure times) without any improvement on the results obtained. cofilin-1 representative image of western blot analysis of urine samples with anti-cofilin 1 (mw: 19-21 kda) is depicted in figure 2. cofilin-1 is an intracellular protein that regulates actin cytoskeleton dynamics. it plays a role in the regulation of cell morphology and cytoskeletal organization (8). it has been also found to be up-regulated (3.29 ± 1.20 fold change) in pca compared to bph tissue specimens by a quantitative proteomics analysis (5) (table 1.). however, cofilin-1 was not detected in both normal (1, 2, 3, 4) and pca (6, 15, 19, 21) urine samples as shown in figure 2. an explanation for this could be the fact that cofilin-1 is an intracellular protein which reduces the chances to be detected in biological fluids such as urine. sparc western blot analysis of anti-sparc (mw: 43 kda) in urine samples is depicted in figure 3. sparc is a secreted protein that appears to regulate cell growth through interactions with the extracellular matrix and cytokines (6). it binds calcium and copper, several types of collagen, albumin, thrombospondin, pdgf and cell membranes (6). 197archivio italiano di urologia e andrologia 2016; 88, 3 in the search of novel urine prostate cancer biomarkers figure 1. western blot analysis of glutathione peroxidase 3 precursor (gpx3). figure 3. western blot analysis of secreted protein acidic and rich in cysteine (sparc). figure 2. western blot analysis of cofilin-1 (cfl1), table 2. demographics and clinical characteristics. n (%) age (years), mean (sd) 65.7 (8.7) bmi (kg/m2), mean (sd) 27.5 (3.5) smoking no 44 (34.6) ex-smoker 48 (37.8) yes 35 (27.6) family history of cancer no 60 (47.2) yes 67 (52.8) family history of prostate cancer no 102 (80.3) yes 25 (19.7) psa (ng/ml), mean (sd) 9.1 (5.3) psa (ng/ml) < 4 6 (4.7) 4-10 89 (70.1) > 10 32 (25.2) dre negative 68 (54.0) positive 59 (46.0) histology no pca 56 (44.1) high grade pin 29 (22.8) pca 42 (33.1) prostate volume (ml) 45 bmi, body mass index; high grade pin, prostatic intraepithelial neoplasia. katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 197 archivio italiano di urologia e andrologia 2016; 88, 3 a. katafigioti, i. katafigiotis, s. sfoungaristos, c. alamanis, k. stravodimos, i. anastasiou, e. roumelioti, m. duvdevani, c. constantinides 198 this protein was found to be differentially expressed at statistically significant levels in the secretome of a cell line model for aggressive bladder cancer (6). sparc could not be detected in both normal (1, 3, 7, 8) and pca (6, 14, 19) urine samples as shown in figure 3. in most cases a band of 60-70 kda was detected corresponding to the mw of albumin. sparc binds to albumin which is present in urine samples making sparc detection quite difficult due to albumin masking effects. hsp 90β western blot analysis of anti-hsp 90β (mw: 90 kda) in urine samples is depicted in figure 4. hsp 90β is an intracellular protein that acts as a molecular chaperone promoting the maturation, structural maintenance and proper regulation of specific target proteins involved in many functions such as: cell cycle control and signal transduction (9). this protein has been found to be up-regulated (3.2 ± 0.61 fold change) in pca compared to bph tissue specimens by quantitative proteomics analysis (5). hsp 90β was not detected in urine samples mainly because of its intracellular location which does not allow for its detection in body fluids such as urine (figure 4). statistical analysis (table 2 and 3) continuous variables are presented as mean and standard deviation or median and interquartile range (iqr) while qualitative variables are presented as absolute and relative frequencies. the kruskal-wallis test was used for the comparison of the five proteins between different patient groups. all p values reported are two-tailed. statistical signifi cance was set at 0.05 and analyses were conducted using stata statistical software (version 9.0). zag western blot analysis of urine samples with anti-zag (mw: 47 kda) is depicted in figure 5. zag is a secreted protein which stimulates lipolysis in adipocytes and is responsible for the reduction of fat which is associated with some advanced cancers (10, 11). zag was found to be down-regulated (0.43 ± 0.13 fold change) in pca compared to bph tissue specimens by quantitative proteomics analysis (5). contrary to the downregulation of zag in tissues, zag in urine showed a significant increase in patients with positive histology for pca. zag levels were significantly increased as psa was increased (p = 0.005) and in the patients with positive histology for pca (p = 0.004) (table 3). zag due to its performance showing statistical significant differences between the urine of patients with bph and pca it was further analyzed and proved its utility at least in our preliminary results published by our group. figure 4. western blot analysis of heat shock protein-90β (hsp 90β). figure 5. western blot analysis of zinc alpha 2-glycoprotein (zag) n. zag gpx-3 cofilin-1 sparc hsp 90β median iqr p protein that not detected both not detected both not detected both psa detected only in normal in normal in normal 0-4 0 0.0-0.1 0.005 in a few urine and prostate and prostate and prostate 4-10 1.1 0.5-1.9 samples cancer samples cancer samples cancer samples > 10 1.4 0.8-2.9 gleason score 4-6 1.2 1-2.9 0.291 7 1.4 1.3-2.8 8-10 1.9 1.5-3.2 histology negative (bph) 1 0.3-1.8 0.004 high grade pin 0.8 0.4-1.4 adenocarcinoma 1.4 1.2-3.0 table 3. kruskal – wallis test – association of five urine proteins with psa levels, gleason score and histology. katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 198 discussion the advent of proteomics made possible the identification of thousands of proteins among which, a large number of possible novel biomarkers especially for pca (5, 12). psa is the best example of a clinical useful biomarker and is still considered the best biomarker in our disposal for the early diagnosis of pca. however, although it is organ specific, it is not disease specific and high levels of psa > 4 ng/ml are not necessarily attributed to pca, and at the same time pca of high gleason score > 7 can be diagnosed in low psa levels < 4 ng/ml, even lower than < 1 ng/ml, while 75% of patients are submitted to high number of unnecessary trus-b due to their increased levels of psa particularly those in the zone of 4-10 ng/ml (3, 12, 13). on the other hand the combination of the high diversity of the nature of pca, with the increase of the trus-b due to the use of psa, has led to the “overdiagnosis” of pca of low aggressiveness (gleason score </= 6) and subsequently to overtreatment with a serious operation like radical retropubic prostatectomy, for a disease that would possibly not affect their longevity and their quality of life (14). the confound results from the largest studies pclo-erspc concerning psa screening, and the inherent problems of psa, resulted to the conclusion that the best use of psa for pca is that there is no cut-off point of psa with sensitivity and specificity and psa constitutes a continuous parameter, with higher levels indicating greater likelihood of pca (11, 15, 16). as a result novel biomarkers are urgently needed in order to address the problems of psa and taking into consideration that the long latency time of pca and our ability to effectively manage at least the organ confined disease, pca is the ideal candidate for a biomarker-based diagnosis and follow-up as psa has already indeed proved. the problem is where and how to find new biomarkers and how to transit from the theory to the everyday clinical practice with a biomarker both sensitive and specific. proteomics in tissue is perhaps the first step and our suggestion, since it can identify proteins which help differentiate pca from other prostatic diseases (5, 12). we used the results of our previous work in order to examine the possible use of proteins that showed discriminative ability for pca and after a thorough literature research we concluded to four proteins two intracellular (clf1, hsp 90β) and two secreted (gpx3, zag) that according to their biochemical effect could be analyzed in clinical useful fluids like urine. we also analyzed a fifth secreted protein (sparc) that has been proved very useful in bladder cancer (6). gpx3 is a secreted protein important for the protection of the cell from oxidative stress, which has been linked to cancer pathogenesis (7) and even though was found to be up-regulated (2.19 ± 0.57 fold change) in pca compared to bph tissue specimens (table 1) (5), was detected in a few urine samples (79, 80, 84),which was mainly attributed to the extensive unspecific binding of the antibody as shown in figure 1 without the ability to overcome this problem. we then chose and analyzed clf1 both because is an intracellular protein regulating cell morphology and cytoskeletal organization, which theoretically is disrupted in cancerous procession (8) and because it has been found to be up-regulated (3.29 ± 1.20 fold change) in pca compared to bph tissue specimens (table 1) (5), but was not detected in both normal (1, 2, 3, 4) and pca (6, 15, 19, 21) urine samples as shown in figure 2, which could be explained by its intracellular nature. hsp 90β also an intracellular protein which is important for the structural maintenance and the signal transduction of the cell, mechanisms which are disorganized in the cancerous procession (9), was found to be up-regulated (3.2 ± 0.61 fold change) in pca compared to bph tissue specimens (5), but again was not detected in urine samples (figure 4), that could also be explained by its intracellular location. sparc is a secreted protein responsible for the cell growth interacting with extracellular matrix found to be connected with the aggressiveness of bladder cancer (6). we chose to analyze sparc for pca in urine due to its clear effect in our previous study6, but again this protein could not be detected in both normal (1, 3, 7, 8) and pca (6, 14, 19) urine samples as shown in figure 3, due to the masking effects of albumin from the binding with sparc. the last protein was zag a secreted protein which stimulates lipolysis in adipocytes, leading to the development of cachexia and advanced cancer stages (10, 11) which was found to be down-regulated (0.43 ± 0.13 fold change) in pca compared to bph tissue specimens (5). zag in urine showed a very clear signal (figure 5) with significant increase in patients with positive histology for pca11 and its further utility as a possible novel urine biomarker has already been examined from our team (11) (table 3). zag levels were significantly increased as psa was increased (p = 0.005) and in the patients with positive histology for pca (p = 0.004) (table 3). it is clear that proteomics help us both to detect the proteome of a tissue and to quantify the differences between normal and pathogenic cells (5, 12). but tissue is not a clinical useful material for the everyday clinical practice due to the need of invasive methods for the specimen and of course due to the fact that tissue sampling means a final pathologist histology diagnosis based on the cell regardless of a biomarker (12). urine is perhaps the easiest to obtain biological fluid without causing any distress to the patient and already a large number of different markers in the literature have been detected as possible biomarkers for pca such as sarcosine, annexin a3, tmprss2:erg fusion gene and pca3, with the latter being already an established urine biomarker incorporated to official guidelines (11, 17). on the other hand urine is a difficult biological fluid to analyze because of its complex nature with abundant compounds interfering with the electrophoretic migration of other proteins constituting the detection of biomarkers in some cases very difficult (18). nevertheless from the four proteins we chose to detect in urine based on their previous proteomic performance in tissue (gpx-3, clf1, hsp 90β, zag) and the fifth protein that was chosen according to its utility in bladder cancer (sparc) only zag, a secreted protein, showed not only a clear signal (figure 5) but the ability to help in the discrimination of pca (11). it seems that perhaps secreted proteins like zag and of course psa may be easier to detect and analyze in urine. 199archivio italiano di urologia e andrologia 2016; 88, 3 in the search of novel urine prostate cancer biomarkers katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 199 archivio italiano di urologia e andrologia 2016; 88, 3 a. katafigioti, i. katafigiotis, s. sfoungaristos, c. alamanis, k. stravodimos, i. anastasiou, e. roumelioti, m. duvdevani, c. constantinides 200 the detection of a protein in tissue, even the ones that have statistical significant different levels between pca and bph, doesn’t mean that this protein will be automatically detected in a clinical useful fluid like urine. the combination of a protein with discriminative levels in tissue, with pathophysiology route allowing its presence in urine in different levels between normal and cancerous samples and of course a biochemistry compatible with our detection abilities is needed in order to find and establish a clinical useful biomarker in urine. conclusions proteomics in tissue of known histology may be the first step to spot new possible biomarkers. the goal is to detect these proteins to clinical useful fluids like urine and serum for the early diagnosis of pca. a protein that has proved already its efficacy in tissue doesn’t mean automatically that it would be also useful in urine and serum. various factors like the pathophysiology of the proteins and our methodology may contribute to the inability of the detection of a protein to urine. in our case form the five proteins gpx3, cfl1, hsp 90β, zag and sparc, only a secreted protein zag has been detected and proved its efficacy both in tissue and in urine. references 1. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin. 2012; 62:10-29. 2. fitzpatrick jm, schulman c, zlotta ar, schröder fh. prostate cancer: a serious disease suitable for prevention. bju int. 2009; 103:864-70. 3. tosoian j, loeb s. psa and beyond: the past, present, and future of investigative biomarkers for prostate cancer. scientific world journal. 2010; 10:1919-31. 4. thompson im, pauler dk, goodman pj, et al. prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. n engl j med. 2004; 350:2239-46. 5. garbis sd, roumeliotis t, et al. search for potential markers for prostate cancer diagnosis, prognosis and treatment in clinical tissue specimens using amine specific isobaric tagging (itraq) with twodimensional liquid chromatography and tandem mass spectrometry. j proteome res. 2008; 7:3146-58. 6. makridakis m, roubelakis mg, bitsika v, et al. analysis of secreted proteins for the study of bladder cancer cell aggressiveness. j proteome res. 2010; 9:3243-59. 7. el haddad m, jean e, turki a, et al. glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival. j cell sci. 2012; 125:6147-56. 8. schönhofen p, de medeiros lm, chatain cp, et al. cofilin/actin rod formation by dysregulation of cofilin-1 activity as a central initial step in neurodegeneration. mini rev med chem. 2014; 14:393-400. 9. cambiazo v, gonzález m, isamit c, maccioni rb. the beta-isoform of heat shock protein hsp-90 is structurally related with human microtubule-interacting protein mip-90. febs lett. 1999; 457:343-7. 10. byrne jc, downes mr, o'donoghue n, et al. 2d-dige as a strategy to identify serum markers for the progression of prostate cancer. j proteome res. 2009; 8:942-57. 11. katafigiotis i, tyritzis si, stravodimos kg, et al. zinc β2-glycoprotein as a potential novel urine biomarker for the early diagnosis of prostate cancer. bju int. 2012; 110:e688-93. 12. pin e, fredolini c, petricoin ef 3rd. the role of proteomics in prostate cancer research: biomarker discovery and validation. clin biochem. 2013; 46:524-38. 13. dijkstra s, mulders pf, schalken ja. clinical use of novel urine and blood based prostate cancer biomarkers: a review. clin biochem. 2014; 47:889-96. 14. cary kc, cooperberg mr. biomarkers in prostate cancer surveillance and screening: past, present, and future. ther adv urol. 2013; 5:318-29. 15. eckersberger e, finkelstein j, sadri h, et al. screening for prostate cancer: a review of the erspc and plco trials. rev urol. 2009; 11:127-33. 16. andriole gl, grubb rl 3rd, buys ss, et al. plco project team. mortality results from a randomized prostate cancer screening trial. n engl j med. 2009; 360:1310-9. 17. truong m, yang b, jarrard df. toward the detection of prostate cancer in urine: a critical analysis. j urol. 2013; 189:422-9. 18. beretov j, wasinger vc, schwartz p, et al. a standardized and reproducible urine preparation protocol for cancer biomarkers discovery. biomark cancer. 2014; 6:21-7 correspondence amalia katafigioti, md katafigiotis.giannis@gmail.com ioannis katafigiotis, md, mls, phd (corresponding author) katafigiotis@yahoo.com christos alamanis, md alamanis@otenet.gr konstantinos stravodimos, md kgstravod@yahoo.com ioannis anastasiou, md ekati2@otenet.gr eleni roumelioti, md eleniroum81@gmail.com constantinos constantinides, md ckonstan@med.uoa.gr 2st university urology clinic, laiko hospital agiou thoma 17 athens, greece stavros sfoungaristos, md sfoungaristosst@gmail.com mordechai duvdevani, md moti_duv@yahoo.com hebrew hadassah university medical center, jerusalem, israel katafigioti nuova versione_stesura seveso 21/09/16 08:51 pagina 200 stesura seveso 17archivio italiano di urologia e andrologia 2016; 88, 1 original paper the preoperative serum ratio of total prostate specific antigen (psa) to free testosterone (ft), psa/ft index ratio, and prostate cancer. results in 220 patients undergoing radical prostatectomy antonio b. porcaro 1, beatrice caruso 2, alessandro terrin 1, nicolò de luyk 1, giovanni cacciamani 1, paolo corsi 1, davide inverardi 1, davide de marchi 1, roberto baldassarre 1, mariangela cerruto 1, claudio ghimenton 3, matteo brunelli 3, stefano zecchini antoniolli 1, aldo petrozziello 4, walter artibani 1 1 urologic clinic, 2 department of laboratory medicine, 3 department of pathology, 4 department of geriatric medicine university hospital, ospedale policlinico, azienda ospedaliera universitaria integrata, verona, italy. objectives: to evaluate associations of preoperative total prostate specific antigen (psa) to free testosterone (ft), the psa/ft index ratio, with features of pathology prostate cancer (pca) and to investigate its prognostic potential in clustering the pca population. patients and methods: after excluding criteria, the records of 220 patients who underwent radical prostatectomy (rp) were retrospectively reviewed. serum samples of psa, total testosterone (tt) and ft were collected at 8.00 a.m., one month after biopsies and before rp. the psa/ft ratio was computed in the population of patients who were clustered in groups according to ranking intervals of the psa/ft ratio which identified at least 4 clusters which were coded as a, b, c, and d. the independent associations of the psa/ft index ratio were assessed by statistical methods and a two-sided p < 0.05 was considered to indicate statistical significance. results: tt correlated to ft which was a significant predictor of psa in the population of patients who were subsequently clustered, according to increasing interval values of the psa/ft index ratio, in groups that showed a stronger linear association of ft with psa. the psa/ft index ratio significantly associated with pathology features of prostate cancer such as pathology gleason score (pgs), invasion of the seminal vesicles (pt3b), proportion of positive cores (p+) and proportion of cancer involving the volume of the prostate. in the population of patients, tt, psa/ft index ratio and p+ independently associated with pgs ≥ 7 and pt3b; moreover, the odds ratio (or) of the psa/ft index ratio resulted 9.11 which was stronger than tt (or = 1.11) and p+ (or = 8.84). in the pca population, tt, psa/ft index ratio and p+ also independently associated with pt3b pca; interestingly, the or of psa/ft index resulted 54.91 which was stronger than tt (or = 1.31) and p+ (26.43). conclusions: preoperative psa/ft index ratio is an independent strong factor which directly associates with aggressive features of pathology pca; moreover, it might express prognostic potential for clustering the patient population in risk classes. confirmatory studies are required. key words: prostate cancer; prostate specific antigen; total testosterone; free testosterone; pathology gleason score; seminal vesicle invasion. submitted 3 march 2015; accepted 14 july 2015 summary no conflict of interest declared. introduction the biology of the prostate gland is closely related to the endocrine system which includes the hypothalamus, the pituitary, the adrenals and the testes. the interstitial cells of leydig of the testes are responsible for the production of 95% of all circulating androgens in the form of total testosterone (tt). approximately 98% of the circulating androgens are bound to plasma proteins, including a specific beta-globulin, testosterone-binding globulin (tebg). the free testosterone (ft) in the blood is the physiologically important fraction. it has been shown that prostate cancer (pca) is an endocrine tumor which is androgen dependent (1) and associates with increased psa serum levels (2, 3). since the pioneering work of charles huggins (1), androgens have been universally considered as being pivotal in the regulation of normal function and malignant growth of the prostate; moreover, pretreatment tt serum levels have been detected abnormal in the pca population (4-7). actually, according to updated statistics, pca, in the usa as in europe, is, after lung cancer, the second most frequent solid tumor in adult males (8). moreover, it has been estimated a cumulative risk of 3.9% and a mortality rate of 1.2% for pca (9). the stratification of pca patients in clinical class risk (ccr) groups is important for planning treatments of low (l), intermediate (i) and high (h) pca ccr (10). the inclusion of pca patients in ccr classes involves the computation of total prostate specific antigen (psa), biopsy gleason score (bgs) and clinical staging (ct). however, although being an endocrine dependent tumor, pca is generally staged without investigating on hormonal features. as a result, the ccr of pca patients do not include endocrine features which may relate to tumour biology. the primary aim of the study was to evaluate independent associations of preoperative total psa to ft ratio, the psa/ft index ratio, with features of pathology pca. the secondary endpoint of the trial was to investigate the prognostic potential of the psa/ft index ratio for clustering the pca population into risk classes. doi: 10.4081/aiua.2016.1.17 porcaro_stesura seveso 08/04/16 11:26 pagina 17 archivio italiano di urologia e andrologia 2016; 88, 1 a.b. porcaro, b. caruso, a. terrin, n. de luyk, g. cacciamani, p. corsi, d. inverardi, d. de marchi, r. baldassarre, m. cerruto, et al. 18 patients and methods the present study, carried out from 2007 to 2011, was part of a larger trial which aimed at evaluating a potential link between pca and the hypothalamus pituitary testis prostate axis. the investigation included only patients who had not previously received 5α-reductase inhibitors, lh-releasing hormone analogues or testosterone replacement treatment. the trial was retrospective and included patients who underwent standard retropubic prostatectomy (rrp) which was eventually associated with local lymph node dissection (lnd). the diagnosis of pca was performed by the 14-core trans rectal ultrasound scan (trus) guided prostate biopsy technique which also included additional cores of lesions detected by either trus and/or digital rectal examination (dre). the biopsy gleason score (bgs) of positive cores was assessed by an experienced pathologist. the percentage of positive cores (p+) detected by trus was computed after diagnosis of pca. the prostatectomy specimens were fixed in toto overnight (10% neutral buffered formhaldeyde), coated with india ink and then weighted (wi). tissue sections of 4 µm were prepared in standard fashion and stained with hematoxylin and eosin. patients were classified according to primary tumor stage, lymph node and metastatic status, using the tnm categories. patients were then classified according to the d’amico ccr groups (10). tumors invading and extending beyond the capsule were coded as pt3a. invasion of the bladder neck without involvement of the seminal vesicles was also staged as pt3a. seminal vesicle invasion was defined as tumor involving of the muscular wall and was coded as pt3b. surgical margins (sm) were stated as free (n) or involved by cancer (p). tumors were graded according to the gleason grading system and the pathology gleason score (pgs) was computed after summing up the two pathology gleason patterns (pgp), prevalent (pgp-i) and secondary (pgp-ii). also, overall proportion of cancer involving prostate volume was estimated coded as v+. a detailed informed signed consent was obtained by the patients who were preoperatively assessed for simultaneous serum levels of tt, ft and total psa. the samples were collected at least one month after prostate biopsies at 8.00 ante meridian and analyzed at our laboratory. tt (normal range: 9-29 nmol/l) and psa (normal range: 2-4 ug/l) were measured by immunochemiluminescent test performed by advia centaur xp immunoassay system (siemens company). ft (normal range: 31-163 pmol/l) was measured by immunoradiometric test (dsl, usa). the population was clustered by sequencing into intervals the range of the psa/ft index ratio which was obtained by dividing total psa by ft (psa/ft index ratio) in each patient. the psa/ft index ratio ranged between 0.04 to 1.48. according to the interval values of the psa/ft index ratio, patients were clustered in the following 3 patterns: (i) ab (0.04 ≤ psa/ft ≤ 0.18) and cd (0.18 < psa/ft ≤ 1.48); (ii) a (0.04 ≤ psa/ft ≤ 0.13), b (0.13 < psa/ft ≤ 0.18), c (0.18 < psa/ft ≤ 0.27) and d (0.27 < psa/ft ≤ 1.48); (iii) a1 (0.04 ≤ psa/ft ≤ 0.10), a2 (0.10 < psa/ft ≤ 0.13), b (0.13 < psa/ft ≤ 0.18), c (0.18 < psa/ft ≤ 0.27), d1 (0.27 < psa/ft ≤ 0.43) and d2 (0.43 < psa/ft ≤ 1.48). statistical methods it was computed the summary statistics of the patient population of patients who were stratified according to ccr groups in which differences were assessed by the kruskal-wallis test (continuous variables) and by the chi squared test (categorical variables). the association of ft with psa was assessed by simple linear regression analysis in either the population and subpopulations of patients who were clustered according to the psa/ft index ratio. the differences between groups of the population of patients who were clustered according to the psa/ft index ratio were assessed by the chi squared and kruskal-wallis statistic tests. the association of the variables, including also the psa/ft index ratio, with aggressive pca (pgs ≥ 7 or pt3b) was assessed by logistic regression which also included the analysis of multiple independent clinical models predicting aggressive pca biology. a two-sided p < 0.05 was considered to indicate statistical significance. results the analysis included 220 patients whose summary statistics has already been reported elsewhere (11, 12). table 1 shows the comparing statistics of the 220 operated patients who were stratified according to ccr groups (10). as shown, the ccr groups were significantly different for many of the investigated variables. tt and ft did not show any difference among the ccr groups of patients who however had different values of the psa/ft index ratio (p < 0.0001). in the population of patients, tt correlated to ft which significantly associated with psa (supplementary materials fi gu re 1). table 2 shows the results of simple linear regression analysis of ft predicting psa which was always significant in the population, clusters (ab/cd, a/b/c/d) and subclusters (a1/a2 and d1/d2) of patients who were grouped according to the psa/ft index ratio. interestingly, the coefficient of determination (r2) progressively increased along the psa/ft index ratio by which the population was clustered (table 2) (supple men tary materials figures 2-4). as shown in table 3, the psa/ft index not only associated with ccr, high grade (pgs > 7, pgs-i > 3) and high stage (pt3b) pca, but also contributed in assessing more risk clusters inside each group of ccr (l, i, h), pgs (6, 7, > 7) and pt (2, 3a, 3b). in particular, a low psa/ft index ratio associated with less aggressive pca (low ccr, grade and stage pca), while a high psa/ft index ratio progressively associated with more aggressive and extensive disease (high ccr, high grade and high stage disease). the psa/ft index ratio directly and significantly associated with p+ and v+ (biology aggressive pca) (supple mentary materials tables 4a, 4b, 4c). moreover, as expected, the psa/ft index ratio directly associated with total psa and inversely with tt. there was no association of the psa/ft index ratio with age and wgt of the prostate. the psa/ft index ratio was a significant and strong independent predictor which directly associated with pgs ≥ 7 (supplementary materials table 5). interestingly, the psa/ft index ratio was the strongest independent predictive variable porcaro_stesura seveso 08/04/16 11:26 pagina 18 19archivio italiano di urologia e andrologia 2016; 88, 1 the preoperative serum ratio of total prostate specific antigen (psa) to free testosterone (ft), psa/ft index ratio, and prostate cancer which directly associated with pgs ≥ 7; indeed, for every increase of one-unit in the psa/ft index ratio, the risk of pgs ≥ 7 increased 9.11 times (supplementary materials table 6 model b6). tt, psa, p+, v+ and psa/ft associated with pt3b pca in simple models (supplementary materials table 6 section a1-a8). in multivariate models, the psa/ft index ratio was a significant and independent predictor of pt3b pca. interestingly, the psa/ft index ratio was the strongest independent variable when predicting pt3b disease (supplementary materials table 6 model b7); indeed, the association indicated that for every increase in one unit of the psa/ft index ratio, the risk of pt3b increased 54.914 times. discussion in the present study, we have shown that ft significantly associated with psa in the population of patients. since the prediction of ft on psa was linear, we consequently clustered the population of patients according to the psa/ft index ratio which geometrically represents the variation of the gradient of the regression line associating ft with psa (table 2) (supplementary ma terials figures 1-4). the psa/ft index ratio independently associated with biologically aggressive prostate cancer (supplementary materials tables 5-6); moreover, the association was strong since the or was 9.11 when the psa/ft ratio predicted pgs ≥ 7 and 54.91 when it pretable 1. statistics of the patient population stratified according to the d'amico's class risk. legend: ccr, cancer class risk; l, low class risk; i, intermediate class risk; h, high class risk. porcaro_stesura seveso 08/04/16 11:26 pagina 19 archivio italiano di urologia e andrologia 2016; 88, 1 a.b. porcaro, b. caruso, a. terrin, n. de luyk, g. cacciamani, p. corsi, d. inverardi, d. de marchi, r. baldassarre, m. cerruto, et al. 20 table 3. statistics of the categorical variables of the patient population (n = 200) stratified according to the psa/ft index ratio. in different clusters. legend: b, coefficient; sde, standard deviation error; bo, constant; ft, ft predictor; r², coefficient of determination. table 2. simple linear regression models in the population and subpopulation of patients according to the psa/ft index ratio. legend: b, coefficient; sde, standard deviation error; bo, constant; ft, ft predictor; r², coefficient of determination. porcaro_stesura seveso 08/04/16 11:26 pagina 20 21archivio italiano di urologia e andrologia 2016; 88, 1 the preoperative serum ratio of total prostate specific antigen (psa) to free testosterone (ft), psa/ft index ratio, and prostate cancer dicted pt3b. the measure of the association with pca is interesting; indeed, when the psa/ft index ratio predicted pgs ≥ 7, the or indicated that for every increase of one-unit in the psa/ft index ratio, the risk of pgs ≥ 7 increased 9.11 times; moreover, when it independently predicted pt3b, the or indicated that for every increase in one unit of the psa/ft index ratio, the risk of pt3b increased 54.91 times. because of the strong association with either pgs ≥ 7. and pt3b, the psa/ft index ratio was effective for grouping preoperatively the patient population in sub clusters according to rising the values of the of the index variable. interestingly, rising values of the psa/ft ratio directly associated with pca biology expressed by tumor grade and stage. the strong association of the psa/ft index ratio with pca biology might be related to pca physiopathology along the hypothalamic-pituitary-testis prostate axis in which ft, since being the biologically active androgen, stimulates either normal and cancerous cells which both produce psa which not only relates to prostate volume but also to pca. as a result, the psa/ft index ratio is a parameter functionality related to pca biology and this might also explain why, in multivariate logistic models (supplementary materials tables 5-6), the independent prediction of psa/ft was stronger than psa in either pgs ≥ 7 (or: 9.11 versus 1.05) and pt3b (or: 54.91 versus 1.13). as a theory, the psa/ft index ratio is a potential prognostic factor because it associates functionally with biology and natural history of pca (13-16). the present larger study confirms our preliminary investigations which showed that pca biology relates to either psa and ft serum levels; moreover, the psa/ft ratio is as a growing rate parameter which expresses cancer phenotype biology (17-19). indeed, the production of psa in most tumors is initially androgen regulated and undergoes a sharp decline following medical or surgical castration (20). the stratification of pca patients in ccr groups (l, i, h) is important for prognosis and treatment (3). however, l -i ccr groups are not homo genous be cause of the limits related to clinical staging procedures; as a result, high risk pca is missed. indeed, low risk pca may be treated by active surveillance (as) which offers low cancer specific mortality (21); however, about a third of these cases will progress requiring definitive treatment (21-22). the present investigation showed that the psa/ft index ratio was a strong independent predictive factor associated with aggressive pca. interestingly, in either l and i ccr, the psa/ft index ratio identified different clusters (a, b, c, d) and sub clusters (a1, a2, d1, d2). clusters c and d associated with aggressive pca which was missed by clinical staging procedures. in h ccr pca, it was not detected any low risk cluster (a, b) but only high risk ones (c, d). in our opinion, the psa/ft index ratio selects pca patients in prognostic groups because it represents the specific growing rate parameter which is expression of the biology of the tumor (17-19). the measures of tt and ft serum levels in l-ccr of patients who undergo as might express prognostic potential. indeed, it has been shown that, in as patients, the risk of progression associates with low ft serum levels (23). the present study showed that the psa/ft index ratio identified clusters (a, b, c, d) in which the mean values of tt and ft were decreasing significantly (supplementary materials table 4); as a result, lower mean levels of androgens were detected in aggressive pca. the results of our study might have theoretical drawbacks of pca molecular biology. indeed, the psa/ft index ratio associated with pgs > 7 (table 3) of which a high rate was detected in subclusters a1 (17%), c (26.1%) and d2 (34%); moreover, mean psa values were detected lower in subclusters a1 and c, which showed different mean values of ft (higher in the former and lower in the latter), but increasingly higher in d1-d2 which both had lower mean values of ft (sup ple mentary materials table 4). as a consequence, we speculate that high grade tumors in a, b clusters have a phenotype which is less aggressive than that in c-d subgroups. however, the hypothesis need to be verified by studies investigating pca molecular biology. there are limits in our study which was retrospective, included a small number of cases, did not relate molecular biology to the grade of tumours and lacks of confirmatory studies. finally, it does not include follow-up which however is still ongoing and will be the subject of further analysis. however, in our opinion, this is the first study that shows, in pca cases, a functional relationship between psa and ft which is expressed by the psa/ft ratio which directly associates with pca biology. conclusions our study shows that the preoperative psa/ft index ratio is a strong independent factor which directly associates with aggressive pca features; moreover, it might have prognostic potential for clustering the patient population into risk classes. confirmatory studies are required. tables 4-6 and figures 1-4 are posted on www.aiua.it references 1. huggins c and hodges cv. studies on prostate cancer. i: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. cancer res. 1941; 1:293-297. 2. stamey ta, yang n, hay ar, et al. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987; 317:909-916. 3. armbruster da. prostate-specific antigen: biochemistry, ana lytical methods, and clinical application. clin chem. 1993; 39:181-195. 4. miller lr, partin aw, chan dw, et al. influence of radical prostatectomy on serum hormone levels. j urol. 1998; 160:449-53. 5. olsson m, ekstrom l, schulze j, et al. radical prostatectomy: influence on serum and urinary androgen levels. prostate. 2010; 70:200-205. 6. harper me, pierrepoint cg, griffiths k. carcinoma of the prostate: relationship of pretreatment hormone levels to survival. eur j cancer clin oncol. 1984; 20:477-82. 7. chen ss, chen kk, lin at, et al. the correlation between pretreatment serum hormone levels and treatment outcome for patients with prostatic cancer and bony metastasis. bjui. 2002; 89:710-3. porcaro_stesura seveso 08/04/16 11:26 pagina 21 archivio italiano di urologia e andrologia 2016; 88, 1 a.b. porcaro, b. caruso, a. terrin, n. de luyk, g. cacciamani, p. corsi, d. inverardi, d. de marchi, r. baldassarre, m. cerruto, et al. 22 8. siegel r, naishadham d, jemal a. cancer statistic, 2012 ca cancer j clin. 2012; 62:10-29. 9. ferlay j, autier p, boniol m, et al. estimates of the cancer incidence and mortality in europe in 2006. ann oncol. 2007; 18:581-92. 10. d’amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 11. porcaro ab, petrozziello a, ghimenton c, et al. serum total testosterone is a significant preoperative variable independently contributing to separating the prostate cancer population into prostatectomy gleason score groups. urol int. 2013; 91:55-61. 12. porcaro ab, petrozziello a, ghimenton c, et al. associaations of pretreatment serum total testosterone measurements with pathologydetected gleason score cancer. urol int. 2013 dec 11. (epub ahead of print). 13. pound cr, partin aw, eisenberger m, et al. natural history of progression after psa elevation following radical prostatectomy. jama. 1999; 281:1591-1597. 14. hull gw, rabbani f, abbas fa, et al. cancer control with radical prostatectomy alone in 1,000 consecutive patients. j urol. 2002; 167:528-534. 15. freedland sj, humphreys eb, mangold la, et al. risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. jama. 2005; 294:433-439. 16. cuzik j, fisher g, kattan mw, et al. long-term outcome among men with conservatively treated localized prostate cancer. british journal of cancer 2006; 95:1186-1194. 17. porcaro ab, migliorini f, romano m, et al. investigative clinical study on prostate cancer: on the role of the pretreatment total psa to free testosterone ratio in selecting different biology groups of prostate cancer patients. int urol nephrol. 2010; 42:673-681. 18. porcaro ab, monaco c, romano m, et al. investigative clinical study on prostate cancer part ii: on the role of the pretreatment total psa to free testosterone ratio as a marker assessing cancer prognostic groups after radical retro pubic prostatectomy. urol int. 2010; 85:152-8. 19. porcaro ab, petrozziello a, romano m, et al. investigative clinical study on prostate cancer part iii: exploring total and psa free testosterone distributions and linear correlations in groups and subgroups of operated prostate cancer patients according to the psa/ft ratio. urol int. 2010; 85:406-9. 20. sadar md, hussain m and bruchovsky. prostate cancer: molecular biology of early progression to androgen independence. endocrine-related cancer. 1999; 6:487-502. 21. dall’era ma, albertsen pc, bangma c, et al. active surveillance for prostate cancer: a systematic review of the literature. eur urol. 2012; 62:976-83. 22. klotz l, zhang l, lam a, et al. clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. j clin oncol. 2010; 28:126-131. 23. san francisco if, rojas pa, de wolf w, morgentaler a. low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance. bjui 2014; 114:229-235. correspondence antonio benito porcaro, md (corresponding author) drporcaro@yahoo.com azienda ospedaliera universitaria integrata verona, dipartimento ad attività integrata di chirurgia e oncologia pancreas center, divisione clinicizzata di urologia, policlinico gb rossi p.le la scuro, 10 37134 verona, italy beatrice caruso, md department of laboratory medicine ospedale policlinico, azienda ospedaliera universitaria integrata, verona, italy alessandro terrin, md de luyk nicolò, md giovanni cacciamani, md corsi paolo, md inverardi davide, md de marchi davide, md roberto baldassarre, md mariangela cerruto, md stefano zecchini antoniolli, md walter artibani, md professor of urology clinica urologica ospedale policlinico, azienda ospedaliera universitaria integrata, verona, italy claudio ghimenton, md matteo brunelli, md department of pathology ospedale policlinico, azienda ospedaliera universitaria integrata, verona, italy aldo petrozziello, md department of geriatric medicine ospedale policlinico, azienda ospedaliera universitaria integrata, verona, italy porcaro_stesura seveso 08/04/16 11:26 pagina 22 stesura seveso 5archivio italiano di urologia e andrologia 2015; 87, 1 original paper tubular ectasia of the rete testis (tert). differential diagnosis of cystic testicular disorders alois mahlknecht 1, peter mahlknecht 2, mohamad fallaha 1, anton wieser 3 1 department of urology, general hospital meran, italy; 2 department for evidence-based medicine and clinical epidemiology, danube university krems, austria; 3 department of radiology, general hospital meran, italy. the ultrasound scan plays an essential role in the urological-andrological diagnosis. high-resolution transducers (8-15 mhz) make it possible to prove increasingly small changes. the assessment of cystic masses in the testis can also be difficult for experienced doctors. however, a precise diagnosis is crucial for the patient to avoid further invasive diagnostics and therapy. the differential diagnosis of benign intra-testicular cystic lesions include the tubular ectasia of the rete testis (tert), the cystic dysplasia, epidermoid cysts, dermoid cysts, simple testicular cysts and cysts of the tunica albuginea. malign testicular tumours with cystic changes are particularly the mature teratoma, carcinomas of the epididymis and metastasis. the following overview shows different sonographic images and interpretations with a particular focus on tert. key words: tubular ectasia of the rete testis (tert); testicular cysts; tubular ectasia; cystic dysplasia. submitted 15 september 2014; accepted 30 november 2014 summary no conflict of interest declared. tubular ectasia of the rete testis (tert) the tubular ectasia of the rete testis (tert) is defined as an intra-testicular area outgoing from the testicular hilum, which contains numerous tight and anechoic (cystic) lesions (4, 5). the typical sonographic image arises from the enlargement of the numerous canaliculi of the rete testis. pathogenesis of tert the etiology of tert has not been definitely clarified. nistal et al. (6) consider four possible causes: – a mechanical obstruction, – primary congenital deformity, – ischaemic degeneration of the efferent ducts (from the rete testis to the epididymis) and – hormonal mechanisms, particularly an androgen deficiency. the vascular hypothesis is the most widely accepted one. the artery which supplies the caput epididymis is a very thin branch of the testicle’s main artery; therefore, arteriosclerotic changes in old age can lead to circulatory disorders. according to this, tert mainly appears at an advanced age, normally between the age of 54 and 64. because of reduced perfusion there is a degeneration of the metabolically active tissue in the region of the rete testis. physiologically, 90% of the seminal fluid is reabsorbed and only 10% of the quantity of secretion is transmitted into the epididymis through the efferent tubules. as a consequence of the degeneration, the process of reabsorption can’t occur anymore and thus the prime seminal fluid accumulates in the branched canal system of the rete testis. the androgen deficiency, which appears usually from the age of 50, applies to the incidence of tert at an advanced age as well. the androgen deficiency leads to an atrophy of the epididymal duct with following mechanical outflow obstruction of the seminal fluid. an interaction of vascular and endocrinal factors is also conceivable in the development of tert. however, the frequent association of tert with a spermatocele in the region of the epididymis militates for the mechanically caused development of tert. the term doi: 10.4081/aiua.2015.1.5 introduction with the almost routine use of scrotal sonography, cystic masses are increasingly diagnosed; however, the clinical significance is often unclear. in general formations of cysts of the testicle are difficult to evaluate, because intratesticular cavities can also be typically formed by teratomatous germ cell tumours (1). the magnetic resonance imaging (mri) can be used for further clarification; in contrast to the sonography the mri has the advantage that a more exact tissue differentiation obtained through the evaluation of several signal qualities (2). the indication for diagnostic operative exploration is frequently made resulting in the demonstration of cystic lesions. only in recent years it has been shown that most of the cystic cavities in the testicle have a benign character and that under no circumstances surgery is required (3). in the following, the pathogenesis and the sonographic image of tert will be described and the differential diagnosis in comparison with other cystic formations in the testis will be illustrated. mahlknecht_stesura seveso 02/04/15 10:12 pagina 5 archivio italiano di urologia e andrologia 2015; 87, 1 a. mahlknecht, p. mahlknecht, m. fallaha, a. wieser 6 “intra-testicular spermatocele” has therefore been coined by davis (7). some of the cases of tert described in the literature show a history of anamnestic surgery like a hernioplasty or a vasectomy; as well pre-existing conditions, like epididymitis are often present. sonographic aspects of tert (figures 1, 2) with the improvement of the sonographic technique, cystic changes in the testicle are diagnosed as an incidental finding with increasing frequency. first case reports which today correspond to tert were published in 1987 (8), among which the lesions were considered to be a curiosity without systematic classification of the result. cystic masses can be shown with high diagnostic certainty only with high-resolution sound frequency of 7.5-12.0 mhz. the first systematic description of tert as a distinct entity was given in 1992 (3). the benign character of tert has been clearly proved by the evaluation of 31 cases. the term “tert” was proposed by tatar et al. (9) in 1993 and nowadays is generally recognised (10). the sonographic image of tert consists of an area outgoing from the mediastinum testis with numerous tight, anechoic and rounded nodules which show a short-path dorsal acoustic enhancement. the anechoic single lesions are mostly smaller than 3 mm; however, also bigger ones can exist. the mri can be used for further diagnosis; certainly, the costs are higher and it is more time-consuming. nevertheless, the mri has the advantage that the examinations can be carried out with the application of contrast agents (gadolinium), and the organs can therefore be examined in several signal qualities. tert was first examined with mri in 1993 (9). therapy of tert the benign character of tert is well assured. therefore, a specific therapy, and especially surgery, is not required. differential diagnosis 1) the most important differential diagnosis of tert is the cystic teratoma. about 10% of all germ cell tumours contain teratomatous content. but in these cases – in contrast to tert – there is mostly an increase in size of the testicle or a palpable tumour. sonographically, a solid content is almost always provable. the eccentric, peripheral localisation of an intra-testicular cyst militates against tert, which is always located at the mediastinum testis. in those cases, the implementation of mri and a surgical exploration are indicated. 2) the cystic transformation of the rete testis has also sonographic similarities with tert, but it is a congenital deformity. pathogenetically, it concerns a developmental disorder in which the canaliculi of the mesonephros have no connection to the gonad blastema. since the canaliculi of the mesonephros will develop into the efferent ducts, the outflow for the testicular secretion towards the epididymis is missing (11). consequently, it comes to impoundment of the testicular secretion. clinically, a swelling of the testicles results; sonographically, there is an area centrally located in the testicles with numerous anechoic lesions. these lesions are usually visible unilaterally. the cystic transformation of the rete testis is very often associated to ipsilateral renal agenesis or other renal dysplasias. 3) another differential diagnosis of tert is the simple testicular cyst which can be randomly found. sono graphically they appear as round and anechoic, mostly solitary cyst with a size of 0.2-2.0 cm. the pathogenesis is unknown. with a higher resolution an echoic margin, which surrounds the cyst, appears. in this case, it concerns a testicular parenchyma. 4) cysts of the tunica albuginea are mostly solitary and exhibit generally a size of 5-8 mm. the cause is unknown and the result is benign. a posttraumatic or postinfectious genesis, as well as a development from embryonic structures is possible. cysts of the tunica albuginea were first classified as a separate entity by figures 1, 2. typical findings of a tert: anechoic areas differing in size in the region of rete testis which fill the major part of the testis and therefore suppress the remaining parenchyma; 58-year-old patient. 1. 2. mahlknecht_stesura seveso 02/04/15 10:12 pagina 6 7archivio italiano di urologia e andrologia 2015; 87, 1 tubular ectasia of the rete testis (tert). differential diagnosis of cystic testicular disorders frater in 1929 (12). sonographically, they appear localized and anechoic as well. they have a thin margin and are adherent to the tunica albuginea (figure 3). 5) the epidermoid cyst is a benign cystic mass in the testis which consists of a fibrous facing, inside of a keratinised squamous epithelium and at the centre of cell debris. the cysts can reach a size of several centimetres. they were first described by dockerty and priestly in 1942 (13). epidermoid cysts appear in adolescence and in young adulthood, the typical age of testicular tumours. a highly echogenic margin is the sonographic characteristic. it corresponds to the structure of the margin of the cyst consisting of fibrous material with partial calcification. alternating hypoechogenic and hyperechogenic rings (“onion ring” pattern) represent strata of compact keratin and loosely spread desquamated cells. in contrast to tert, weak echo reflexes can occur in the centre of epidermoid cysts; these weak echo reflexes are caused by the viscous cyst content. as a result, the epidermoid cyst sonographically appears as a target. conclusion for practice cystic masses of the testicle can be benign or malignant. concerning the establishment of the further treatment, a differentiation of these two entities is significant for the patient and the physician in charge. therefore, the scrotal ultrasonography is absolutely necessary. if a benign cystic mass of the testis is diagnosed, an organ sparing therapy or a follow-up procedure can be recommended in most cases. references 1. connolly ss, d`arcy ft, gough n, et al carefully selected intratesticular lesions can be safely managed with serial ultrasonography. bju int. 2006; 98: ì1005-1007. 2. nagler-reus m, guhl l, volz c, et al. magnetresonanztomo gra phie des skrotums. erfahrungen an 129 patienten. radiologe 1995; 3:494-503. 3. brown dl, benson cb, doherty fj, et al cystic testicular mass caused by dilated rete testis: sonographic findings in 31 cases. am j roentgenol. 1992; 15:1257-1259. 4. older ra, watson lr. tubular ectasia of the rete testis: a benign condition with a sonographic appearance that may be misinterpreted as malignant. j urol. 1994; 152:477-478. 5. rouviere o, bouvier r, pangaud c, et al. tubular ectasia of the rete testis: a potential pitfall in scrotal imaging. eur radiol. 1999; 9:1862-1868. 6. nistal m, mate a, paniagua r. cystic transformation of the rete testis. am j surg pathol. 1996; 20:1231-1239. 7. davis rs. intratesticular spermatocele. urology. 1998; 51:167-169. 8. gooding ga, leonhardt w, stein r. testicular cysts: us findings. radiology. 1987; 163:537-538. 9. tartar vm, trambert ma, balsara zn, mattrey rf. tubular ectasia of the testicle: sonographic anmr imaging appearance. am j roentgenol. 1993; 160:539-542. 10. pavlica p, ramini r, barozzi l tubular ectasia of the rete testis. the ecographic aspects. radiol med. 1994; 87:493-497. 11. eberli d, gretener h, dommann-scherrer c, et al. cystic displasia of the testis: a very rare paediatric tumor of the testis. urol int. 2002; 69:1-6. 12. frater k. cysts of the tunica albuginea (cysts from the testis). j urol. 1929; 21:135-140. 13. dockerty mb, priestly jt. dermoid cysts of the testis. j urol. 1942; 48:392-400. correspondence mahlknecht alois, md alois.mahlknecht@asbmeran-o.it mohamad fallaha, md general hospital “franz tappeiner” v. rossini 5 39012 merano, italy peter mahlknecht, md department for evidence-based medicine and clinical epidemiology danube university krems, krems, austria anton wieser, md department of radiology, general hospital merano, italy figure 3. large intratesticular cyst. mahlknecht_stesura seveso 02/04/15 10:12 pagina 7 stesura seveso 161archivio italiano di urologia e andrologia 2014; 86, 3 original paper penile prosthesis surgery in out-patient setting: effectiveness and costs in the “spending review” era nicola mondaini 1, enrico sarti 1, gianluca giubilei 2, andrea gavazzi 3, antonio costanzi 1, arben belba 3, tommaso cai 4, riccardo bartoletti 1 1 urology unit, santa maria annunziata hospital (iot), florence, italy; 2 urology unit, leonardo da vinci hospital, empoli, italy; 3 urology unit, cfo oncology center florence, italy; 4 department of urology, santa chiara regional hospital, trento, italy. introduction: penile implant patients are required to remain in the hospital after the operation for monitoring, antibiotic and analgesia administration. cost containment, however, has resulted in the increased use of ambulatory surgery settings for many surgical procedures. few studies have studied the feasibility of performing penile prosthesis insertion in an outpatient setting. the results are controversial and nowadays, in the most of centers that deal with prosthetic surgery, patients are still hospitalized. aim: the aim of our investigation was to compare the feasibility of the performance as well as the complication profiles of penile implant surgery performed in an in-patient and an outpatient setting at a single center by a single surgeon. methods: from january 2009 to june 2014, 50 patients of the same uro-andrological unit underwent penile prosthesis implantation performed by a single surgeon (n.m.). twenty implantations were performed in an ambulatory day surgery setting. main outcome measures: effectiveness and costs of outpatient setting versus the in-patient setting of the penile prosthesis surgery. results: there were some differences between the two groups in the intra-operative parameters, such as, operating time. time lost from work was similar in both groups approximating 14 days. the mean number of analgesic pills ingested by the patients post-operatively was similar in both groups, averaging just under 25 pills per patient. there weren’t post-operative complications in the outpatient group. cost were 17% less in outpatient clinic. conclusions: the outpatient setting for this surgery is safe and effective even in patients with comorbidities or in case of secondary procedures. costs are reduced by 17%. key words: penile prosthesis; out-patient; erectile dysfunction; costs; spending review. submitted 15 july 2014; accepted 31 july 2014 summary no conflict of interest declared. introduction inflatable penile prosthesis often represent the last or the only chance to get back to a normal life for patients with erectile dysfunction, reporting 70-87% satisfaction rates (1). prosthesis can be either malleable or inflatable; the second one are preferred by most of patients but are much more expensive. at the moment, penile implant patients are required to remain in the hospital following the operation for monitoring, antibiotic and analgesia administration. cost containment however, has resulted in the increased use of ambulatory surgery settings for many surgical procedures (2). few studies have studied the feasibility of performing penile prosthesis insertion in an ambulatory setting (table 1) (3-6). the results are controversial and nowadays, in the most of centers that deal with prosthetic surgery, patients are still hospitalized. the aim of our investigation was to compare the feasibility of performance as well as the complication profiles of penile implant surgery performed in an inpatient and an outpatient setting at a single center by a single surgeon. materials and methods from january 2009 to june 2014, 50 patients of the same uro-andrological unit underwent penile prosthesis implantation performed by a single surgeon (n.m.). the first 30 were operated in an inpatient setting; the other 20 implantations were performed in an ambulatory day surgery setting. the day of the operation, all patients had intravenous antibiotics administrated: the inpatient group had teicoplanin 200 mg and imipenem/cilastatin 500 mg x 3, while the out-patient group had amoxicillin/clavulanic acid 1 gr and gentamicin 80 mg x 2. all procedures were performed through a transverse scrotal incision. the twopiece implant used was the ambicor1 device (ams, minneapolis, usa), while the three-piece implant used was the cx 700 device (ams minneapolis, usa). the indications for insertion of a two-piece rather than a three-piece device included a history of radical cystectomy, bilateral inguinal hernia surgery and patient choice. in both groups doi: 10.4081/aiua.2014.3.161 mondaini_stesura seveso 08/10/14 11:42 pagina 161 archivio italiano di urologia e andrologia 2014; 86, 3 n. mondaini, e. sarti, g. giubilei, a. gavazzi, a. costanzi, a. belba, t. cai, r. bartoletti 162 the foley catheter, which was placed intra-operatively, was removed the day after and a large scrotal compression dressing was placed (a scrotal support filled with fluffed gauze dressings) with also a large amount of ice, which was prescribed for the first 24 hours. the patients of the inpatient group where discharged after 1-3 days; while the patients of the outpatient group were discharged 3 hours after operation, on treatment with amoxicillin/clavulanic acid (1 gr po twice daily for 10 days), gentamicin (80 mg im twice daily for 10 days) and oral analgesics (paracetamol/codeine 1 pill every 4-6 hours). the patients treated in ambulatory setting were seen the day after and at 1-4 and 8 weeks post-operatively. at the 4-week follow up visit, the patients were asked to count all analgesic pills taken, as well as the date of their return to work. on this date, they were also counseled regarding the proper utilization of their penile implant. indeed, they were instructed to inflate and deflate the device daily for the next month. costs were calculated using the actual price of antibiotics, hospital stay and penile prosthesis in our country. statistical analysis between the groups was conducted using a student’s ttest (excel, microsoft corp., usa). results there were not any demographic statistical differences in patient age, co-morbidity profile between the two groups of patients (table 2). follow-up was longer in the inpatient group. there were some differences between the two groups in the intra-operative parameters, such as, operating time (table 3). time lost from work was similar in both groups, approximating 14 days. the mean number of analgesic pills ingested by the patients post-operatively was similar in both groups, averaging just under 25 pills per patient (table 3). there weren’t post-operative complications in the outpatient group (table 3). cost were 17% less in outpatient setting (table 4). author year out-patient age prosthesis complications anesthesia two-piece ipp three-piece ipp mondaini n. 2014 n = 20 64,2 (53-74) 10 ams ambicor 10 ams 700 cx 0 spinal hsu gl. 2004 n = 10 67.4 ± 9.9 7 ams ambicor 3 ams 700 cx na crural nerve block 278 mg 0,8% lidocaine sol. and adrenaline mulhall j. 2001 n = 46 64 ± 10 9 ams ambicor 37 mentor alpha-1 2 (4,3%) spinal/general (laringeal mask) + 0,5% plain bupivacaine infiltrated in the scrotal incision garber bb. 1997 n = 95 57 0 94 mentor alpha-1/ams 700 6 (6,3%) general lubensky jd. 1991 n = 74 42-79 0 74 ams 700 (100%) 2 (2,7%) spinal/general table 1. out-patient setting for penile prosthesis implantation in literature. in-patient out-patient (n = 30) (n = 20) age (y) 63,3 (22-78) 64,2 (53-74) follow-up (months) 56,5 (36-77) 12,1 (1-24) two-piece device 5 (16,6%) 10 (50%) three-piece device 25 (83,3%) 10 (50%) secondary procedures 5 (16,6%) 2 (10%) in-patient out-patient (n = 30) (n = 20) intra-operative blood loss (mls) 100 80 or time (min) two-piece device 80 55 three-piece device 120 90 time lost from work (days) 14 13 narcotic use (pills) 25 26 overall complications 2 (6,6%) 0 device infection 1 (3,3%) 0 table 2. patient demographics. in-patient out-patient (1-3) days 1 day hospital stay ! 800 x 3 = 2400 ! 800 intravenous antibiotics (targosid) 41,61 x 3 = 124,83 ! 3,75 (tenacid) ! 23,97 x 9 = 215,73 (gentalyn) ! 2,30 x 2 = 4,60 cost ! 2.740,56 ! 808,35 total cost ! 11.240 ! 9.308,35 * cost are reduced by 17%. table 4. cost difference between in-patient and out-patient settings for three-piece-device. table 3. operative and post-operative data. mondaini_stesura seveso 08/10/14 11:42 pagina 162 discussion when available, outpatient surgery is well tolerated and often preferred by patients and in the past decade various studies were conducted about cost containment and safety of the management in outpatient setting in an increasing number of different surgery procedures (711). nowdays, in italy, the total cost for an implantation of an inflatable prosthesis is about ! 9000-15000, depending on conventions between hospitals and the local administrations. the cost includes pre-operative examinations, imaging, prosthesis, surgeon, anesthesiologist, hospital stay and medications. for this reason, living in a period of spending review involving all the western countries, the cost of this surgery restricted to 500 the total operations made annually in italy. our data demonstrate that in terms of safety and effectiveness the ambulatory setting is absolutely similar to the inpatient setting, reducing days of hospitalization (1-3) and using less expensive antibiotics (table 4). this results in an overall saving of 17%. previous studies (9-13) about the feasibility of implantation of inflatable penile prosthesis in ambulatory settings showed complications rate of 1.86%. to our knowledge only mulhall (9) in 2001 compared performance and complications of inpatient and outpatients groups with penile prosthesis insertion. overall complication rates were 6% for the inpatient group and 4% for the outpatient group, infection rate was 3% for the first group and 2% for the second. our data confirm mulhall study strengthening it, as our outpatient complications and infection rates are 0%. the main study limitation is the small sample size, but emphasizes that surgeon’s experience and a tight followup are essential in order to perform this procedure in an ambulatory setting, discharging the patient a few hours after surgery. it’s also important underline that complications rate are now lower thanks to the evolution of prosthetic materials (12), which today are covered by antibiotic substances and discharging the patient with catheter and prosthesis inflated reduce the risk of postoperative hematoma, which often leads to infection. about the post-operative use of analgesics our data are similar to the literature. conclusion the outpatient setting for this surgery is safe and effective even in patients with comorbidities or in case of secondary procedures. costs are reduced by 17%. acknowledgments we thank the team of anesthesia of the day service iot hospital, florence: antonella orvieto, anna mancini, elena gandini, eleonora gentili, eleni kastamoniti, anna cian ciullo, vanna viviani. references 1. parsons kf, fall m, irani j, llorente c. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. [internet]. european urology. 2013. available from: http://www.uroweb.org/guidelines/online-guidelines/ 2. hollingsworth jm1, saigal cs, lai jc, et al. medicare payments for outpatient urological surgery by location of care. j urol. 2012; 188:2323-7. 3. hsu g-l, hsieh c-h, wen h-s, et al. outpatient penile implantation with the patient under a novel method of crural block. int j androl. 2004; 27:147–51. 4. mulhall jp, bloom k. comparison of in-patient and out-patient penile prosthesis surgery. int j impot res. 2001; 13:251-4. 5. garber bb. outpatient inflatable penile prosthesis insertion. urology. 1997; 49:600-3. 6. lubensky jd. outpatient inflatable penile prosthesis. j urol. 1991; 145:1176-7. 7. krummenauer f, günther k-p, witzlebf w-c. the incremental cost effectiveness of in-patient versus out-patient rehabilitation after total hip arthroplasty results of a pilot investigation. eur j med res. 2008; 13:267-74. 8. pineault r, contandriopoulos ap, valois m, et al. randomized clinical trial of one-day surgery. patient satisfaction, clinical outcomes, and costs. med care. 1985; 23:171-82. 9. morgan m, beech r. variations in lengths of stay and rates of day case surgery: implications for the efficiency of surgical management. j epidemiol community health. 1990; 44:90-105. 10. roos np. what is the potential for moving adult surgery to the ambulatory setting? cmaj. 1988; 138:809-16. 11. weale a r. randomized clinical trial of the effectiveness of emergency day surgery against standard inpatient treatment (br j surg. 2002; 89:423-7). brit j surg 2002; 89:1323. 12. muench pj. infections versus penile implants: the war on bugs. j urol. 2013; 189:1631-7. 163archivio italiano di urologia e andrologia 2014; 86, 3 penile prosthesis surgery in out-patient setting: effectiveness and costs in the “spending review” era correspondence nicola mondaini, md info@nicolamondaini.it enrico sarti, md antonio costanzi, md riccardo bartoletti, md urology unit, santa maria annunziata hospital (iot), florence, italy gianluca giubilei, md urology unit, leonardo da vinci hospital, empoli, italy andrea gavazzi, md arben belba, md urology unit, cfo oncology center florencen, italy tommaso cai, md department of urology, santa chiara regional hospital, trento, italy mondaini_stesura seveso 08/10/14 11:42 pagina 163 stesura seveso 95archivio italiano di urologia e andrologia 2015; 87, 1 case report complete intraperitoneal displacement of a double j stent: a first case filippo maria turri 1, francesca manassero 1, andrea mogorovich 1, maurizio de maria 1, andrea falleni 2, cesare selli 1 1 department of translational research, section of urology, university of pisa, italy; 2 department of emergency medicine, section of diagnostic radiology, aoup, pisa, italy. objectives: ureteral double-j stents are known to migrate proximally and distally within the urinary tract, while perforation and stent displacement are uncommon. possible mechanisms of displacement are either original malpositioning with ureteral perforation or subsequent fistula and erosion of the excretory system, due to infection or long permanence of the device. we present the unique case of complete intraperitoneal stent migration in a 59-year-old caucasian male without evidence of urinary fistula at the moment of diagnosis, so far an unreported complication. materials and methods: eight months after the placement of a double-j stent for lower right ureteral stricture at a district hospital, the patient came at our observation for urosepsis and hydro-uretero-nephrosis. a ct scan demonstrated intraperitoneal migration of the stent outside the urinary tract. cystoscopy failed to visualize the lower extremity of the stent, a percutaneous nephrostomy was placed to drain the urinary system and the stent was removed through a small abdominal incision on the right lower quadrant. results: in our case we presume that during the positioning manoeuvre the guide wire perforated simultaneously the lower ureteral wall and the pelvic peritoneum, and that once the upper end of the stent was coiled, the lower extremity was also attracted intraperitoneally. the lack of pain due to the spinal lesion concurred to this unusual complication. conclusions: we must be aware that ureteral double j stents may be found displaced even inside the peritoneal cavity, and that the use of retrograde pyelography during placement is of paramount importance to exclude misplacement of an apparently normally coiled upper extremity of the stent. key words: ureteral stent; stent displacement; endourology; abdominal imaging; ct scan. submitted 15 october 2014; accepted 31 december 2014 summary no conflict of interest declared. stent displacement, hematuria, obstruction, malpositioning, iatrogenic lesions and forgetfulness of the stent (2). more peculiar complications are knotting (3) or rupture (4) of the stent, ureteral wall erosion and stent migration outside of the urinary tract (5-7). materials and method a 59-year-old man with motor and sensitive deficiency secondary to cervical spine trauma and with a history of previous transurethral resection (tur) for non muscleinvasive bladder cancer, underwent placement of a dj stent for a lower right ureteral stricture at a district hospital in april 2013. eight months later he came to our observation for urosepsis. physical examination was negative. sonography revealed right hydro-uretero-nephrosis with no evidence of lithiasis. abdominal ct scan demonstrated the right ureteral stent displaced outside the urinary tract, intraperitoneally for its whole length (figures 1-3). at cystoscopic examination it was impossible to visualize the stent. a right percutaneous nephrostomy was placed, purulent urine was drained and an antegrade contrast study showed a dilated ureter with blind end at the level of l 5, without extravasation of the contrast medium. doi: 10.4081/aiua.2015.1.95 introduction first described in 1967 by zimskind et al. (1), ureteral double j (dj) stents are widely employed in urology. the most frequent complications are flank pain, irritative voiding symptoms, urinary tract infections, encrustation, figure 1. basal ct scan: right hydronephrosis and upper coil of the stent located inside the peritoneal cavity. turri_stesura seveso 02/04/15 10:34 pagina 95 archivio italiano di urologia e andrologia 2015; 87, 1 f.m. turri, f. manassero, a. mogorovich, m. de maria, a. falleni, c. selli 96 results following urine drainage the patient became afebrile and four days later surgical exploration was performed: the intraperitoneal stent was extracted through a small muscle splitting incision in the right lower quadrant (figure 4). one month after nuclear renography showed a glomerular filtration rate (gfr) of 45 ml/min for the left kidney and of 8 ml/min for the right kidney. given the impaired general conditions of the patient, who had developed a subsequent cerebral hemorrhage, and the severely reduced gfr of the right kidney, it was decided to leave an indwelling nephrostomy to avoid obstruction, without considering ureteral reconstruction. discussion while cranial or caudal migration of ureteral dj stents is a relatively common event, their displacement outside the urinary tract occurs infrequently, and has been described as retroperitoneal and incomplete (5-7); migration has been reported even inside the lumen of the vena cava (8). the possible mechanisms of stent displacement are either original malpositioning following ureteral perforation or subsequent erosion of the excretory system, due to infection or long permanence of the device. although in one case report the upper tip of a dj was displaced inside the peritoneal cavity through a fistula of the upper pole of the kidney with concomitant urinary peritonitis (9), to the best of our knowledge this is the first report of complete intraperitoneal stent migration without evidence of urinary extravasation or fistula at the time of diagnosis. since the intraperitoneal stent appeared clean and patent, we presume that during the positioning manoeuvre the guide wire perforated simultaneously the lower ureteral wall and the pelvic peritoneum, and that once the upper end of the stent was coiled, the lower extremity was also attracted intraperitoneally. the lack of pain due to the spinal lesion probably concurred to this unusual complication and such a late presentation. a small open surgical access on the right lower quadrant was preferred to a laparoscopic approach because we felt that it was faster and less invasive overall. conclusions clinicians must be aware that ureteral dj stents may be found displaced even inside the peritoneal cavity, and that figure 2. 3d volume rendering of ct scan revealing the upper coil of the stent displaced anteriorly to the kidney and the lower coil in the right lower quadrant. figure 4. retrieval of the intraperitoneal stent through a short muscle-splitting incision in the right lower quadrant. figure 3. oblique reconstruction of the uro-ct scan revealing a tortuous and dilated right ureter not containing the ureteral stent. turri_stesura seveso 02/04/15 10:34 pagina 96 the use of retrograde pyelography during stent placement is of paramount importance to exclude misplacement. references 1. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. j urol. 1967; 97:840-4. 2. christopher wolter, roger dmochowski. insertion of double-j stent. in: hashim h, abrams p, dmochowski r (ed), the handbook of office urological procedures. london: springer-verlag, 2008; 142. 3. picozzi s, carmignani l. a knotted ureteral stent: a case report and review of the literature. urol ann. 2010; 2:80-2. 4. witjes ja. breakage of a silicone double pigtail ureteral stent as a long-term complication. j urol. 1993; 150:1898-9. 97archivio italiano di urologia e andrologia 2015; 87, 1 complete intraperitoneal displacement of a double j stent: a first case correspondence filippo maria turri, md fm.turri@gmail.com francesca manassero, md francy_manassero@hotmail.com andrea mogorovich, md mogorovich@hotmail.it maurizio de maria, md m.demaria@ao-pisa.toscana.it cesare selli, md, professor of urology (corresponding author) c.selli@med.unipi.it department of translational research, section of urology university of pisa, via paradisa i-56124 pisa, italy andrea falleni, md a.falleni@ao-pisa.toscana.it department of emergency medicine, section of diagnostic radiology aoup, pisa, italy 5. abraham g, das k, george d. retroperitoneal migration of a double-j stent: an unusual occurrence. j endourol. 2011; 25:297-9. 6. shivde sr, joshi p, jamkhandikar r. extrusion of a double j stent: a rare complication. urology 2008; 71:814-5. 7. ioannis c, ioannis z, evangelos i, et al. retrovesical migration of malpositioned double-j ureteral stent. int urol nephrol. 2003; 35:325-6. 8. falahatkar s, memmati h, gholamjani mk. intracaval migration: an uncommon complication of ureteral double-j stent placement. j endourol. 2012; 26:119-21. 9. ivica s, dragan s. long-term indwelling double-j stents: bulky kidney and urinary bladder calculosis, spontaneous intraperitoneal perforation of the kidney and peritonitis as a result of "forgotten" double-j stent. vojnosanit pregl. 2009; 66:242-4. turri_stesura seveso 02/04/15 10:34 pagina 97 stesura seveso 43archivio italiano di urologia e andrologia 2014; 86, 1 case report penile strangulation: an unusual sexual practice that often presents an urological emergency lucio dell’atti department of urology, arcispedale “s. anna”, ferrara, italy placement of constricting devices around the penis for autoerotic purposes or increasing of sexual performance represents a well-known challenge for urologists. penile incarceration is a urologic emergency with potentially severe clinical consequences. in many cases a rapid intervention and a sudden removal of the foreign body it is enough so that patients need no further intervention. we report three different cases of strangulating objects (metallic ring, metal bearing and plumbing pipe) presented at our emergency department and three different methods of devices extraction practiced. remove these devices can be challenging and often requires resourcefulness and multidisciplinary approach. key words: penile strangulation; ring; penis; ischemia. submitted 11 november 2013; accepted 31 december 2013 summary case report the frequency of self-injuries on penis is currently increasing in certain cultures. the aim of their use may be to enhance the sexual performance, to prolong the erection, to achieve erotic or auto-erotic effects or simply sexual curiosity (1,2). penile incarceration is a rare but serious problem, which can easily lead to strangulation and infarction. therefore it is a urological emergency that needs a quick treatment in order to prevent long-tail claims. failure in removing those devices can lead to significant ischemia and loss of tissue (3). the treatment of penile strangulation is decompression of the constricted penis to facilitate free blood flow and micturition (4). we report three cases of penile strangulation that have been presented at our attention. case report and figures are posted in suppementary materials on www.aiua.it discussion there are sporadic reports of penile strangulation in the medical literature (5). this condition is not common, but it is certainly a urological emergency as prompt removal of the constricting object and the decompression of the penis are required to prevent long-term complications (6). strangulation may occur when various items, made of metal or non-metal no conflict of interest declared material, are pulled over the penis. non-metallic objects can cause much more serious injuries, but they are more easily removed than metal objects. the reason for the higher level of damage in case of non-metallic objects is that they are more elastic and can therefore exert a greater pressure on the penis (2) . among the objects pulled onto the penis there are: metal rings, wedding rings, iron sleeves, nuts, pipes, bearings, bicycle parts, all kinds of bottles, tools and rubber bands. objects pulled onto or wound round the penis can cause mechanical damage. clamping of the penis causes venous stasis or blockage. as result of venous stasis, the penis lymph vessels and arteries may be blocked, with consequence of ischaemia or infarction (5). after several hours, necrosis and gangrene may develop. in some case, such as ours, not only the penis, but also the scrotum is ligated. the most important task is to remove the foreign body, which can involve serious technical difficulties in the case of metal devices. an equipment with various tools is essential for a successful removal of different forms of strangulating object. this is followed by conservative or surgical treatment of the damaged tissue of penis. in these cases a psychological or psycho-sexual evaluation of the patients seems to be suitable, but unfortunately our patients refused any further assessment. references 1. osman m, al kadi h, al hafi r. gangrene of the penis due to strangulation by a metallic ring. scand j urol nephrol. 1996; 30:77-78. 2. perabo fg, steiner g, albers p, muller sc. treatment of pe ni le strangulation caused by costricting devices. urology. 2002; 59:137. 3. ivanovski o, stankov o, kuzmanoski m, et al. penile strangulation: two case reports and review of the literature. j sex med. 2007; 4:17751780. 4. pannek j, martin w. penile entrapment in a plastic bottle. j urol. 2003; 170:2385. 5. noh j, kang tw, heo t, et al. penile strangulation treated with the modified sting method. urology. 2004; 64:591. 6. kimber rm, mellon jk. the role of special cutting equipment and corporeal aspiration in the treatment of penile incarceration with a barbell retaining collar. j urol. 2004; 172:975. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology, arcispedale “s. anna”, via a. moro 8 44124 cona, ferrara, italy doi: 10.4081/aiua.2014.1.43 dell'atti cr_stesura seveso 26/03/14 10:37 pagina 43 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 128 review functional anatomy of pelvic floor salvatore rocca rossetti professor of urology, university of torino, torino, italy. generally, descriptions of the pelvic floor are discordant, since its complex structures and the complexity of pathological disorders of such structures; commonly the descriptions are sectorial, concerning muscles, fascial developments, ligaments and so on. on the contrary to understand completely nature and function of the pelvic floor it is necessary to study it in the most unitary view and in the most global aspect, considering embriology, philogenesy, anthropologic development and its multiple activities others than urological, gynaecological and intestinal ones. recent acquirements succeeded in clarifying many aspects of pelvic floor activity, whose musculature has been investigated through electromyography, sonography, magnetic resonance, histology, histochemistry, molecular research. utilizing recent research concerning not only urinary and gynecologic aspects but also those regarding statics and dynamics of pelvis and its floor, it is now possible to study this important body part as a unit; that means to consider it in the whole body economy to which maintaining upright position, walking and behavior or physical conduct do not share less than urinary, genital, and intestinal functions. it is today possible to consider the pelvic floor as a musclefascial unit with synergic and antagonistic activity of muscular bundles, among them more or less interlaced, with multiple functions and not only the function of pelvic cup closure. key words: pelvic floor; anatomy; function; micturition; continence; defecation; coitus; posture. submitted 17 october; accepted 31 december 2015 summary no conflict of interest declared. function. although urologists, gynecologists and gastroenterologists generally consider the pelvic floor only for the support activity of pelvic organs and for their functions, it is necessary not to neglect its great contribution for the behavior life to appreciate its value in the body economy; on the other hand also the pelvic organs function is part of the behavior life. this one is greatly based on pose and on body movements as well as on some functions to be done at the right time and at the right place; in that the unitarity of pelvic floor functional value is recognizable, because pelvic floor function, gait, and all movements of behavior life are functionally linked. so it is worthwhile to consider some notions that very few have to do with urology “sensu stricto” but that help to understand the true value of the pelvic floor: sherrington (1) underlined “the posture follows movements like a shadow”, that means that posture is the evolutional results in which every living beings must adapt themselves to the environment in which they live, where they can carry out their static and dynamic activity. according to a strictly anthropologic point of view it was affirmed that we became humans in our loins and in our pelvis well before than in our brain (2), because pelvic modifications made possible the constant upright position, superior limbs freeing, exclusively biped gait and human beings delivery. today the personality development and the body structure are believed to proceed simultaneously and then the habitual posture (how to show oneself) express the personal character that one “represents how to stay in the world, to face the reality, that means the visible conclusion of all that allowed us to outlive” (3). today psychological research studies the relations between posture and personality and consider the intelligence (capacity in solving problems) like a body dimension, the mind like hands and implements generally used extension. so for all that there are evidences on the necessity to consider the pelvic floor in the must unitary shape and not only in relation to urinary, gynecologic, and gastrointestinal functions. generality to start, it must be remembered that this part of the trunk, particularly the pelvis or bony basin, has been built in the evolution for organs containment and protection; our axial skeleton, that means vertebral column and pelvic bone represents the fish vertebra-type residue doi: 10.4081/aiua.2016.1.28 introduction generally the descriptions of the pelvic floor are discordant, since its complex structures and the complexity of pathological disorders of such structures; commonly the descriptions are sectorial, concerning muscles, fascial developments, ligaments and so on. on the contrary to understand completely nature and function of the pelvic floor it is necessary to study it in the most unitary view, in the most global aspect, considering embriology, philogenesy, anthropologic development and its multiple activities others than urological, gynaecological and intestinal. the pelvic floor function is mainly involved in postural aptitude, in the upright position, in the gait, in the physical conduct. only considering those aspects all together it is possible to have a clear view of pelvic floor anatomy and presented at urop congress, taormina 28 may 2015 rocca rossetti_stesura seveso 08/04/16 11:27 pagina 28 29archivio italiano di urologia e andrologia 2016; 88, 1 pelvic floor (it is well known that we came from sea), that posteriorly covers the spinal cord and anteriorly the visceral organs like a bony or cartilaginous carapace. such a disposition in human body is identifiable only on chest, but the nature proceeds from simple to complex, living in the complex the simple trace (of what is found in lower in zoological scale animals), the mylohyoid line, the hyoid bone, the sternum xipoid process, the abdominal alba line just depict the traces; moreover sometimes on these structures it is possible to find some ossifications testifying the old carapace trace. obviously the pelvic floor cannot be consider independently from the bony pelvis, whom evolution greatly was owed to the upright position, the biped gait and the skull capability increasing, which allowed the shortening of iliac wings, the increasing of their width and superior and inferior straits width, the pelvis verticalization, the sacrum posterioralization with consequent lumbar lordosis, dorsal kifosis, cervical lordosis and occipital hole anterioralization; and also the lateralization of the hip cavity and the femur axis. the upright position determined the center of gravity elevation at the fifth lumbar vertebra peduncles; from them the force lines coming down from top diverge laterally at each side towards the iliac-sacral joints and discharge the head and trunk weight on the hip joints and on inferior limbs; as many force lines from ground go up towards the pelvis bone lengthways the femur axis; this one, since the pelvis enlargement and the consequent hip joints lateralization, breaks of at level of the femur neck and bends itself internally and posteriorly; so these force lines make a compression action on the pubic rami, necessary for opposing to the lateral expansion forces due to the new skull dimensions and to the changed delivery mechanism (clear results of that compression is visible on malacic pelvis like in rickets or osteoporotic bones: y pelvis deformation, since the push from femurs is stronger that the pubic arch resistance) (4). for our study it is convenient to consider the body standing up, in vertical position (not supine or in lithotomic position), as well as the classic anatomic position for which it is considered the meaning of anterior, posterior, medial, lateral and so on. in the vertical position the anterior-superior iliac spine and pubis are on the same coronal plane, the pelvis opening looks anteriorly and the ischio-pubic branches are parallel to ground as well as the urinary, gynecologic and intestinal hiatus; in that position the abdominal and pelvic visceral pressure falls on pelvic bones and is minimized on the muscular framework. the bony pelvis has a funnel shape with the larger part on the top (plane passing for the iliac crests) and the narrow one below (plane passing for the ischial tuberosities and coccyx apex); iliac wings and fossae are topographically part of the abdomen, lodging abdominal organs surgically attackable; in this way only the part included between superior strait (plane from pubis to sacral promontory through the “innominate” line) and inferior one (plain from ischial tuberosities to coccyx apex) is considered as pelvis; perineum is the pelvic bottom closure. for all those considerations, it happens that abdominal organs have no place to be lodged below, so they move upward together with the peritoneum from which they are covered or received; consequently below the peritoneum a large connectival space: called subperitoneal space is formed. two diaphragms enclose all the pelvic-abdominal organs: superiorly the thoraco-abdominal diaphragm or diaphragm properly called, inferiorly the pelvic diaphragm; both have an intricate structure and embriologic derivation (5-7). the pelvis is partially closed inferiorly from a series of muscles, fasciae, ligaments for the better understanding of which it is necessary to remember their embriologic and philogenetic derivation (8). in concomitance with the first outlines of pelvic organs formation, two separate groups of muscles start to grow: tail muscle or pubo-caudal muscle and cloacal or gegenbauer muscle; from the former the ischio-coccigeus muscle, levator ani muscle and pubo-sacral and sacro-spinal ligaments will descent, from the latter the sphincters. after the genito-urinary septum will separate the rectum posteriorly from the urethra-vagina anteriorly, the gegenbauer's muscle will divide itself in two sphincters, one for the urethra and one for the rectum; successively ischio-cavernous muscle, bulbo-cavernous muscle and superficial and deep transverse muscles are added; the sacro-touberous and sacro-spinous ligaments are a kind of fibrous transformation of caudal muscles. already in fetus period (9) and much more in adult one those muscles or caudal and cloacal groups of muscles are puzzling among them, in sense that they don't show themselves separate, as in some marauders (tiger); the puzzling or mixing of muscles of different derivation, function and innervation (sacral plexus the former, pudendal plexus the latter) is the main reason of the contrasting descriptions of muscles and pelvic ligaments in men. for instance, if we consider the mixing and sometimes the fusion of levator ani fibers with the deep transverse muscle and with the urethral sphincter where this one surrounds partially the prostate we find the reason of difficulty in understanding the true function of each group of pelvic muscles; apparently the upright posture and the bipede gait, compared to quadrupedes, are almost part of the reason of above mentioned muscular mixing. the pelvis bone above cited modifications, due to the new behavioral conditions, have caused the functional unitariety among the musculo-fascial structures of pelvis cavity (small pelvis) in a concordant function of support and activity of pelvic organs (bladder, urethra. womb, vagina, rectum, anus). muscles of such musculo-fascial structures shrivel, relax, synergize, antagonize, stabilize (stabilizer muscle is that one which shrivel isometrically to keep stable the body part towards which the movement goes).according with pelvic organs activity (filling, voiding) or resting; their fibers are for 2/3 of the first type, red fibers at slow contraction and for 1/3 of the second type at quick contraction (10, 15). their activity doesn't work out only for visceral functions, but also for supporting organs, for keeping the correct position and, as we said, for maintaining the posture, the deambulation and correlate problems as respiration (12); so synergism and antagonism happen also with other muscular groups of different part of the body. considering the framework of this part it is easy to rocca rossetti_stesura seveso 08/04/16 11:27 pagina 29 archivio italiano di urologia e andrologia 2016; 88, 1 s. rocca rossetti 30 understand synergism and antagonism among pelvic muscles and those of the abdominal anterior part. the pelvic diaphragm, pubo-coccigeous, ileo-coccigeous, and ischio-coccigeous (levator ani) puts itself like an hammock of pelvic and abdominal elastic containment; the transverse abdominis muscle being the deeper is the most synergic with pubo-coccigeus and ischio-coccigeus; also the gluteus major solidarizes with pelvic musculature to maintain the upright position and posture. the pelvic musculature supplies a fundamental contribution to stability and body movements (many of posterior thigh muscles, particularly abductors, take insertions on ischiatic tuberosity and on sacro-tuberous ligament); the solidarity of pelvi-trochanteric muscles, particularly internal obturator and piriform and rotators of thigh, is also very important; their fasciae assure solidity to the pelvis framework (13). commonly but wrongly the pelvic floor muscles activity is considered in the same manner of majority skeletal muscles activity as moving (one or more) skeletal bones in a coordinated contraction or decontraction of agonists, antagonists, stabilizers; but that is wrong because among the pelvis bones only coccyx is partially movable. it is well known that the muscular contraction is either isotonic or isometric; this is true and evident for monoor poly-joints muscles, whose contraction creates the displacement of a skeletal segment, as forearm flection on the arm, like a lever with fulcrum on elbow; the isometric contraction doesn’t create any displacement thanks to the antagonists action; that nevertheless also functions for skeletal displacement in regulating its degree, amplitude and rapidity. muscles of pelvic diaphragm, except for pubo-rectalis (visceral ones), insert themselves on fixed bony segments, such pubis, ilium, ischium and sacrum; the slightest movements, nutation and contra-nutation, of the latter happen only in the expulsive period of delivery (14, 15); the coccyx, scarcely movable in the same phase is generally kept fix by the major gluteus muscle tone and contraction. the importance of those muscles tonic phase and the characteristics of their contraction have to be considered. the pelvic muscles activity is essential in keeping a constant although variable tonic condition and in contracting in certain circumstances like urination, defecation, coitus. these muscles tone is quite peculiar, consisting in an intermediate stage between tone and contraction and since it is constant, or in any case prolonged, it would be exposed to exhaustion (typical of striated muscle contraction) if a series of sophisticate neurological interactions wouldn't avoid it. the reason why this musculature is different to the others concerning tone lies also in the peculiar shape of bony pelvis and in the obliged position of the organs since the narrowing of the pelvis lower part (3). for descriptive convenience, it is used to consider in the pelvis closure a superior strait, pelvis diaphragm, a medium one, uro-genital diaphragm and an inferior one, perineum; such a distinction is completely artificial and only partially responds to systematic anatomy requirements in muscles, fasciae, vessels and nerves description. that being stated, i think not to do without in respecting the distinction because it is still kept in the uro-gynecological literature. pelvic diaphragm pelvic cup closure, since its funnel conformation, is insured by the musculo-fascial solidarity whose fibrous and muscular structure are steady attached to bony prominences, which were spirally developed starting from the primitive nucleus of cotyl from which ilium, ischium and pubis originated (8). generally it is said that the pelvic cup is occupied by ischio-coccigeus and elevator ani muscles; the latter formed by ilio-coccigeus and pubo-coccigeus bellies; in that matter pubo-, ilioand ischio-coccigeus form the pelvic diaphragm, with their insertions on ilium, ischium an pubis. in recent literature there are not few divergences regarding the description before related, that, strictly anatomically speaking, i think is correct. indeed there are authors who consider. the levator ani the only muscle of pelvic diaphragm (31), that means they include the ischio-coccigeus as part of levator ani. oppositely other authors consider the coccigeus the only muscle of pelvic diaphragm with its pubic, iliac and ischiatic insertions. some but not few authors use to separate bellies for support, ilio-coccigeus, ischio-coccigeus and a little part of pubo-coccigeus, from those for visceral function, puborectalis, which is the bigger part of pubo-coccigeus (in its turn, part of levator ani). incidentally little internal fibers of pubo-rectalis are the only part of levator ani which really lifts anus, since their insertions on anal subcutaneous. evidently those descriptive divergences certainly don't help for the better understanding of the subject; so necessity was felt to apply at international nomenclatures (18). the anatomic nomenclature gives names to muscles on the base of shape (deltoid), of bellies composition (biceps), of insertions (sterno-cleido-mastoideous), or of function characteristics (supinator); so i don’t think it is scandalous in considering the pelvic musculature on the base of its function, at least in distinguishing support from visceral function. if we consider that biggest part of levator ani and ischio-coccigeus attend to organ support and to the pelvic cup closure, while only pubo-rectalis bellies of levator ani reach rectum, urethra and vagina, call the latter viscerals on the base of function could seem logical. since pelvic disorders are prevalent in women there are authors who studying those muscles only for their uro-gynaecological functions, use to call them pubo-urethral, pubo-vaginal, pubo-perineal, puboanal on the base of an excessive functional nomenclature. all that didn't contribute to clarity about (20, 28). calling pelvic muscles according to support or to visceral function, we may consider the pelvic diaphragm made by the levator ani whose bellies, ilio, ischio and pubococcigeus have an exclusively bony insertion and constitute the plate and the pelvic excavation closure, while the internal bellies of pubococcigeus practice a visceral action; those are frequently called pubo-rectalis; since their action is made not only on rectum, but also on urethra and vagina, it is better to call them pubo-visceralis. the former are put between bone and bone and exert tone and isometric contraction; the latter.have an isotonrocca rossetti_stesura seveso 08/04/16 11:27 pagina 30 31archivio italiano di urologia e andrologia 2016; 88, 1 pelvic floor ic contraction and don't insert themselves directly and properly on organs but with their contraction they shorten and make a leave action as fulcrum followed by a movement of the organ or of a part of it. all of them contribute to circumscribe the hole through which prostate, urethra, vagina and rectum pass; these are kept in place thanks to a connectival thickness which makes connection between organ and muscle; some authors call that connective tissue hiatal ligament (30). the support muscular bundles insert themselves directly or through fascial coverings on perineal tendineous center, the perineal body, on which the three perineal fasciae converge together with cloacal and caudal muscles in an anatomically and functionally unitary constitution. the pubo-visceral bundles (part of pubo-coccigeous) have a quite oblique direction and go down to encompass posteriorly the rectum (pubo-rectals properly said) and form something like a hammock at recto-anal level; they also encompass posteriorly urethra and vagina in women, prostate and urethra in men; they adhere to and partially joint themselves with the urethral striped sphincter and make like a ring all around vagina (28). it is fundamental for function understanding to consider the muscular fibers direction and their force lines; in the pelvic diaphragm that direction is grossly sagittal, but their true action must be considered on the base of their insertions or fusions with pelvic fascia, ligaments, tendons and so on. differently to what dissection anatomy shows the pelvic musculature being funnel like up to down, magnetic resonance, that means living anatomy, demonstrates the disposition of their bundles be horizontal, as a plate or flat console and not like the cup walls (pubo-visceral bundles are the exception). this divergence is due to the complete absence of muscles contraction in cadavers while in living beings a firm tone is constantly present, which expires only during micturition and defecation (on the recto-anal hammock tone perseverance still are some divergences in literature). the tri-dimensional study of levator ani (20) shows that the anterior portion, pubo-visceral, is made as we said, by bundles downward obliquely directed; they partially insert themselves on perineal body ( tendineous center of perineum) and in bigger part they make a sling posteriorly to rectum, vagina and urethra; their contraction tighten the uro-genital diaphragm hole pushing rectum, vagina and urethra towards the pubic bone. the posterior part of levator ani, ilio-coccigeus, ischio-coccigeus and some bundles of pubo-coccigeus are put horizontally, in a flat disposition, forming the pelvic organs support; they become oblique, funnel like, in case of direct or neurological lesions with consequent prolapse risk. the muscular and fascial fibers direction explains their action effect, particularly well studied in women (28); the force lines developed in median perineal aponeurosis and in deep transverse of perineum muscle (often hypotrophic or absent in women (23) are directed towards ischio-pubic branches and reinforce the urethra and vagina closure action. since muscles contraction can pull, but not push (15) synergism and antagonism must be respected also for pelvic muscles in their relations with pelvi-trochanteric muscles (obturator and piriform) and with thigh muscles, particularly with adductors (adductor, gracile, pectineous); that is worth especially for monoor bifoot-lever movements (4) and also for the help that those muscles contraction could give during movements for which urinary and fecal continence needs the greatest effort. as already said, the pelvic cup closure is done by a strong musculo-aponeurotic framework, for that the fascial and aponeurotic structures are of an anatomic and functional importance; they in certain sense precede origin and organization of muscles bundles, almost for what is concerning the mesenchimal, sub-mesothelial and vascular derivation (8, 24). to have a quick idea of that it is well worth to consider that the bony pelvis funnel-like shape forces the organs with their peritoneum to go up towards the abdomen since they have no place in the narrow strait below; for that a conspicuous subperitoneal connectival tissue is formed, called endopelvic fascia; this one, guided by zonal vessels already present in that district, became divided in lodges for the organs; thus from hypogasric artery and its prolongation (anteriorly obturator artery, posteriorly lateral sacral artery) hypo gastric sheath is formed which connects pubis and sacrum; in the same time in coronal plane other bands or sheaths are formed; going from forward to backward umbelicoprevescical sheath is strechted between the two unbelical arteries; the vescico-rectal sheath between the two vesciculo-deferential arteries; the denonvilliers sheath between the two median rectals arteries (some authors improperly compare this sheath with the women large ligament; the true equivalent otherwise is the recto-vaginal sheath); in this manner retropubic space, vesico-prostatic lodge, utero-ovaric lodge, rectal lodge and presacral space are delimited (30). the hypogastric fascia thickens, as said, in the pubosacral ligament and extends covering all pelvic cup muscles (particularly internal obturator and levator ani) in the pelvic sheath formation; this one is also called deep perineal sheath or superior to be distinct from the inferior or superficial and from median one; between levator ani and internal obturator the pelvic fascia thickens forming the so called white line or levator ani tendineous arch which joints pubis and ischiatic spine and on which some fibers of elevator insert. each pelvic diaphragm muscle has its perimysium, more or less thin, sticked with pelvic fascia, which wraps up also the levator inferior side in what some authors call. improperly endopelvic fascia; as we said the endopelvic fascia is properly the sheath put between the visceral peritoneum and pelvic fascia that is particularly thick in correspondence of cardinal ligaments and paracolpium. it is well known that pelvic organs, where not covered by peritoneum, have a more or less thin adventitia which is in continuation with bands or zonal ligaments. therefore urethra, prostate, bladder neck, base and side, vagina, womb neck and rectum are sagittally adherent to pubosacral ligament through bands especially well visible at urethral and vaginal level; the connections with pubovisceral muscles (internal part of pubo-coccigeous, also called pubo-rectalis) superimpose on them. these connections are generally connectival in nature, like adventitia and perimysium;.the only exception is the adhesion rocca rossetti_stesura seveso 08/04/16 11:28 pagina 31 archivio italiano di urologia e andrologia 2016; 88, 1 s. rocca rossetti 32 of the internal part of pubo-rectalis muscle whose fibers scatter on prostatic capsule; some authors call that adhesion “prostate levator muscle” (30). the adhesion and connection among organs, fasciae, ligaments and muscles connective tissue is more or less dense, elastic and plentiful in conformity with organs, sex, and zones, what is not without importance for continence and micturition mechanisms; this connective mass represents a true and proper structure (pubo-vesical urethral vaginal) that “joints” these organs to pubis, pelvic fascia and tendineous levator arch; the structure is commonly considered to be part of pubo-urethral ligaments which are the first part of pubo-sacral long ligament. this dense connectival structure seems to play an important role in the vagina and urethra compression against pubis together with the well-known musculo-fascial structures in maintaining the continence threatened by intra-abdominal sudden increased pressure (28). as it is a functionally important synergism between pelvic muscles and those of trunk and limbs it exists a not less important synergism among fasciae, ligaments, and muscular structures of the zone. the fasciae are formed by collagen, elastic tissue and smooth muscles; they also have proprioceptors which are activated by the ligaments stretching, which by reflex induces the muscular contraction useful to abolish ligaments and fascial tension; so it exists a musculo-fascial and ligaments balance that gives the correct grade of tone and contraction of pelvic floor (32). evidently the muscular and aponeurotic organization was obliged to adapt itself to pelvic organs presence and functioning and in the same time to the necessity in ensuring to the pelvis the upright position stabilization and that one of movements on one or both feet. this task is obtained by levator ani with its pubo-visceral bundles and by coccigeus with pubic, iliac and ischiatic derivation bundles; practically all the other bellies of levator ani (indeed, as already said, some authors assimilate ischio-coccigeus muscle to levator ani) (23). uro-genital diaphgram perineum below the pelvic diaphragm, made by levator ani, the urogenital diaphragm lies formed by perineal membrane (or midperineal aponeurosis) which spans the deep perineal muscles (or deep transverse muscles); some authors (16) believe that for the urogenital one the word diaphragm is improper; truly there isn't a real and proper separation ( this indeed is the meaning of diaphragm) but a strengthening which joints the pelvic diaphragm to the underlying perineum; its anterior part lets urogenital conduits pass to which it is in certain manner connected.. the urogenital diaphragm or triangle is formed, as said, by midperineal aponeurosis or carcassonne’s fascia and by deep transverse perineal muscle; the unitariety of pelvic floor is well visible in this strong aponeurosis disposition and structure, strained between the two ischiopubic branches; its apex looks anteriorly toward the pubic symphysis; this triangle, bored by urethra and vagina, fills the space where in the anterior part of perineum the two levators ani don't joint each other and it is put both anteriorly and posteriorly to urethra and vagina; the preurethral part, also called transverse perineal ligament is strongly connected to ischiopubic branches and to obturator fascia; it has very dense structure so much to become so sharp to guillottine the urethra in the ischiopubic fractures dislocations. the retro-urethral part divides itself in two sheets, inferior, well thick and pressure-proof, and superior thin; between them gouthrie or deep perineal muscle lies; this is quite thin in women, even if existent. the two sheets of perineal membrane are in continuation: the inferior one with the inferior perineal fascia covering the superficial transverse perineal muscle; the superior one with denonvilliers fascia or the levator perimysium; from that it seems clear that the urogenital triangle and the whole perineal framework are compact and tightly linked to the overlanding pelvic diaphragm and to the underline ischioand bulbo-cavernous muscles. although generally the pelvic cup closure is described as tree superimposed layers, pelvic diaphragm, urogenital diaphragm and perineum, really, as we said, this division results quite artificial at least for the two presumed inferior layers; indeed it is impossible not to include the urogenital diaphragm in the perineum and not to include in this one descending levator pubo-rectalis bundles, belongings to pelvic diaphragm; in this connection there are authors who consider perineum the musculo-fascial whole which represents the outlet pelvis closure; so it is clear why the international literature rather has to speak generically of pelvic floor, also keeping dictions like pelvic diaphragm, urogenital diaphragm and perineum. with the aim to recall literature names or dictions it is good to remember that the deep perineal transverse muscle part included between the two carcassonne's sheets is also called guthrie muscle; this one is actually the retro-urethral portion of perineal deep muscle; wilson muscle is instead the whole of deep perineal muscle fibers which scatter on superior carcassonne's sheath and adhere at external urethral sphincter; this one is a true circular muff around the urethra just below perineal membrane; on top those fibers disperse themselves round the prostate without joining posteriorly; at this level some muscular fibers joining prostate, levator ani and longitudinal rectal bundle are called recto-urethral or henle muscle (varies structures synonyms were cited with the aim to facilitate for readers the comprehension of those differently called in literature). genitourinary hiatus in women is obviously bigger because of the vagina presence between urethra and rectum, the deep perineal muscle hypotrophy and the presence of pubo-urethral fibers, compressor vaginae, which are the internal part of levator ani, also called pubo-visceralis. the perineum also lodges in addiction to superficial and deep (transverse) perineal muscles, striated urethral and anal sphincters and bulbo and ischio-cavernous muscles in both sexes; the levator ani bundles called properly pubo-visceral because they join urethra, vagina and rectum go down in perineum making a hammock-like sling round the recto-anal junction where part of them melt with the longitudinal bundle of rectum and with striated anal sphincter; the more superficial of those fibers reach the anal subcutaneous and consequentially they are the only ones deserving the name levator ani. as we said the rocca rossetti_stesura seveso 08/04/16 11:28 pagina 32 33archivio italiano di urologia e andrologia 2016; 88, 1 pelvic floor pubo-visceral fibers are often called pubo-rectal. among varies contradictions of this topic there are some concerning the real outline and function of pubo-rectal muscle; there are authors (33) who through dissection and microscopic research deny that this muscle belongs to levator ani to which they only ascribe pubo-coccigeous and ilio-coccigeous bellies; so pubo-rectal muscle would be part of external ani sphincter (sphincteric complex) thanks to the confluence of its fibers with that muscle and with the longitudinal rectal fibers; the two levators of right and left side would cross each other at the anococcygeus raphe on which they don’t put insertion. the pubo-visceral most anterior portion makes an analogous loop around the mid urethra part and vagina, in women creating the so called compressor vaginae muscle. urethra, vagina and rectum are kept in place and in certain sense supported by pubosacral ligaments to which they adhere through connections called from time to time pubo-urethral, pubo-vaginal, pubo-rectal, sacrorectal ligaments. the pubo-sacral ligament is in continuity with the pelvic fascia of which on the other hand represents a thickening of what is the many times mentioned fascial or better musculo-fascial unitariness. this is a synthetic view of the anatomical region and its musculo-aponeurotic structures settlement; to us it isn't to be surprised from the strictly surgical habit in emphasizing fragments of fasciae or ligaments variously called in the aim to show their positive or negative value in the interpretation of pelvic dysfunctions as incontinence or ptosis, and consequent surgical operations suggestion. continence-micturition micturition is the abolishing of continence and the outside expulsion of urine. the muscular mechanisms of this function are well known: inhibition of cervico-urethral contraction, detrusor contraction and if necessary anterior abdominal musculature contraction (to which micturition, defecation, vomiting and delivery is classically tribute). for what is concerning the pelvic floor, sphincteric inhibition a part, the micturition needs pelvic diaphragm musculature decontraction (chiefly pubo-coccygeus muscle); a sequence of sophisticated neurologic, medullar and encephalic mechanisms rules the coordination among orthosympathic inhibition (cervical trigone relaxation), parasympathic action (concentric detrusor contraction) and levator ani tone abolishing; the coordination is essential to obtain the sphincteric and pelvic relaxation just before the bladder contraction (33) and also to respect the fact that those phenomenona are subjected to will and subconsciousness to be carry on where and when is convenient. a series of very interesting and particularly complicate reflexes rules all that (11, 35). other reflexes are ruled by superior neurologic centers concerning pelvic floor tone and contraction in a constant adaptation to sudden body balance variations and its consequent micturition possibility. obviously the function of this reflexes acts through inhibition (quantitatively bigger impulses) and muscular action; the result of this one on starting and maintaining the micturition, for what is concerning the pelvic floor support, is obtained through the total or partial relaxation of its muscles with the consequence not only of the urethra going down but also of its shortening; lenght decrease is useful for the micturition because, according with laplace law length decrease create wall resistance decease (in wall distensible tubes, like vessels or hole organs the filling up deforms the wall, which develops a tension compared to the lengthening); obviously the shortening of the urethra causes the decrease of resistance (33). considering the closure and opening of bladder and urethral neck it is to remember hormonal effect, particularly that of catecholamines: for instance it is known that passing from supine to upright position a sudden increase of catecholamines in blood creates a pelvic floor tone and contraction increase with consequent continence mechanism strengthening; that is pathologically evident in case of long standing hypertone with the impossibility to pass urine (patients who mast pass water lying); .in some spinal cord lesions the denervation of smooth urethral muscles creates a bigger sensitivity to catecholamines (decentralization supersensitivity) with pelvic floor hypertone. in opposite side there are cases, fortunately rare, in which the global pelvic floor flaccidity causes the posterior prolapse of the bladder and big urethral bend on perineal body with micturition impossibility (35). for what is concerning the pelvic floor relaxation during normal micturition it must be considered that the relaxation happens only for the pubo-visceral bundles and not for all those of levator ani; shafik (33) asserts that the increasing tone or really the support levator bundles contraction causes the bladder neck and urethra relaxation; such effect would be reflected on micturition mechanism thanks to the poiseuille's law regarding resistance to flow modifications (also this low was studied for blood vessels relaxation). according to that research the pubo-rectal muscle would be contracturant and at opposite the levator ani relaxant at sphincteric level; practically the pubo-urethralis relaxes freeing the urethra, the levator contracts making traction on urethral walls, obtaining the opening. if i may open a parenthesis in appendix of this little chapter concerning the physics laws in the urinary phenomenona interpretation, i would like to remember here what in the theatre i showed to students and fellows during radical cystectomy; i let to put the removed piece on a rigid place and pushing hardly on the bladder i showed that no drops of urine got out; i utilized that show to remember them that the passive or physic continence can be done only from active muscular force to let urine pass; i also remembered that some urologists (erroneously) call upon pascal's law to demonstrate that, being the closed bladder neck radius equal zero it could be necessary an infinitive force from the bladder to open it; bladder neck and urethra are them opened thanks to a muscular activity for starting and maintaining the micturition (37). in the last few years research appeared in literature regarding urinary continence, meanly with the aim to repair its dysfunctions; the research where particularly concerning spontaneous incontinence, then female incontinence. sonography, magnetic resonance, functional magnetic resonance regarding encephalic areas for movements and rocca rossetti_stesura seveso 08/04/16 11:28 pagina 33 archivio italiano di urologia e andrologia 2016; 88, 1 s. rocca rossetti 34 stress, microscopy, histology, histochemistry, molecular research for receptors, electromyography have greatly increased our knowledge of the topic. for what is concerning the pelvic floor muscle-aponeurotic structure active in continence mechanism, de lancey (38) anatomical and functional systematization is to well known to be here recalled. it seems instead useful to describe some research that doesn't agree completely with that thesis; for instance sasaki and al. (39) through meticulous histologic and histo-chemical research believe that connective-elastic and smooth muscles transition has a particular rule in “fibrous perineal skeleton” constitution. this one contributes to urinary and rectal continence in women through fusion and synergic action of the abundant perineal smooth muscle (urethra, rectum, vagina) with levator striated one; the authors describe at each side of urethra and vagina a smooth muscular mass in a catamaran ship configuration whom seal would be represented by rectal-vaginal fascia; the two lateral masses are made from urethra and rectal smooth sphincters, longitudinal intrinsic rectal fibers and vaginal adventitia; to those the fibers of striated rectal sphincter and levator ani unify and melt. the pubo-vaginal muscle action represents the active continence value of “fibrous skeleton” but concerning the ptosis it is quite independent. an other divergent aspect compared with ashton miller and de lancey theory is that regarding on which part of the urethra the abdominal pressure and the pubo-visceral muscle action exert their power (40); also in past time frequent debates happened regarding enhorming g. theory (42) on pressure percentile fall on the abdominal portion of the urethra compared to that one on the bladder (50% according to some, 75% to others; see discussion in 35, pages 734-35) and regarding the urethral bend on perineal body. recent interesting studies still confirm those discrepances (41) and confirm the existence of cases in which normal continence was present also when all portions of urethra laid below the perineal body (in contrast of enhorming theory). with regard of this subject lazarswski mb (40) speaking about stress incontinence biomechanics shows its theory on the action of so called non-permanent structures on which forces compressing vagina and urethra act in keeping continence: those structures have to be repaired during surgical procedures. the author starts from the wellknown fact that continence is assured by a pressure gradient, cervico-urethral pressure a little greater than bladder pressure; this is due to tone and contraction propriety of smooth and striated urethral musculature, to visceral turgidity consisting in vascular network and to the elastic characteristics of urethral tube; those characteristics are variable from fellow to fellow according with age, hormonal state, previous deliveries, scars or tissue lesions. the sphincteric complex is sufficient to keep continence also for little abdominal pressure increasing; for bigger increasing instead the extra-urethral factors contribution is necessary in maintaining the pressure gradient, that means urethral pressure a little higher than bladder pressure (closure pressure), and continence. those extra-urethral factors of under stress continence , in the author view, are due to compression of the urethra on strong structures not permanently acting, but only when the abdominal pressure (stress) causes the physiologic urethro-vesical sphincteric complex displacement below and anteriorly; this displacement stretches the endopelvic fascia that thanks to the different elasticity and resistance of its parts makes different compressive effects on pelvic organs; the zone just below the proximal urethra is the less elastic and the more resistant; thus on this one the compressive force to keep the continence acts. according with this point of view below the proximal urethra and vagina such an hammock-like connectival mass would be present, made by pubo-genito-urinary ligament and sub-urethral connective tissue; the latter is the pubo-cervical fascia, which joints cervix and vagina to pubis and tendineous arch; also the perineal body (mid perineal fascia) and the tendineous perineal center could be part of sub-urethral support non permanently acting. connections among continence, posture and body functions apparently independent from urinary, genital and intestinal function are very interesting; at this regard barbic (43), studying the relation between cough and continence in a group of normally continent women, trough point isolated monopolar electrodes inside levator ani, proved that this muscle contraction precedes the abdominal muscles activation involved in coughing reflex; so levator ani contraction supports and stabilizes bladder neck and lets effective transmission of abdominal pressure on proximal urethra. deffieux and al. (44, 45), trough electromyographic research, assessed that in continent women the pelvic muscles contraction precedes the abdominal increased pressure due to external intercostal muscles and abdominal muscles contraction during cough. defecation for what is concerning the pelvic floor musculature, defecation happens for partially voluntary and partially reflex action of both smooth and striated sphincters and pubo-rectal muscle relaxation; so the recto-anal angle opens and consequently feces pass down and are ejected, being not any more blocked by sphincteric tone and contraction. about pubo-rectal muscle, as already said, there are authors that consider it not as part of levator ani, but a muscle completely independent from the pubo-coccygeus bundle of levator; thus the pubo-rectalis for its connections with the longitudinal intrinsic bundle of rectum and with the striated sphincter, in the authors' view, would be part of the sphincter complex (33). the conscious and voluntary part of defecation is referred both to the perception of moment and place socially suitable (that seems to be controlled by cingulum gyre.and internal part of prefrontal zones) and to the voluntary valsalva action (abdominal straining) that increasing abdominal pressure gets pelvic floor lowering and stimulates the recto-anal inhibitory reflex; this reflex consists in the inhibition of anal sphincters tone (and contraction) and in the inhibition of ano-rectal compression from pubo-rectal muscle. the reflex is greatly dependent from autonomous nervous system, although influences coming from nitric oxide, vasoactive intestinal peptide (vip) and atp are also present; the defecatory reflex is regulated by parasympathetic system, while internal sphincter tone and rocca rossetti_stesura seveso 08/04/16 11:28 pagina 34 35archivio italiano di urologia e andrologia 2016; 88, 1 pelvic floor the consequent gastroenteric reflex are regulated by orthosympathetic system; the gastroenteric reflex consists in the peristalsis inhibition caused by sphinteric hypertone or contraction; those spinal and superspinal reflexes are caused by the ampulla filling sensation from fecal material pushed down form colic peristalsis (47). in the defecation physiology it is to be remembered that there are other important reflexes such the colic one, which gives the so called rectal detrusor inhibition and those of bladder reflex afferences: the lowering of bladder sensitivity causes the increasing of filling threshold is the explanation of the fact that micturition and defecation do not happen simultaneously (47). coitus in man the pelvic floor musculature takes part to this function by pelvic diaphragm contraction according with variability of movements; bulbo-cavernous muscle contraction (mainly of its internal part, so called houton muscle which like a loop envraps the deep dorsal penile vein) stops the blood emptying contributing to maintain the erection; also ischio-cavernous muscle seems to take part to such a mechanism because its contraction crushes veins but not arteries; (physiologists at this regard seem not to agree). the meanly flat part of the levator ani contributes to a suitable erection through its contraction by which prostate and urethra are lift and the urethral curvature eliminated with consequent urethral and penile straitening. the activity of pubo-rectal bundles that insert on prostate and embrace the seminal vesicles in full coordination with those organs intrinsic contraction helps the ejaculation at least for the emission step. well-timed reflexes rule urethral and anal sphincters contraction in keeping their closure and inhibiting the just possible micturition and defecation desire. the sudden urethral sphincter relaxation during the emissive ejaculation step seems to cause such a seminal liquid aspiration toward prostatic urethra so creating a bolus ready to be ejected thanks to intrinsic urethral musculature and bulbo-cavernous activity. in addittion to all that the entire musculo-fascial pelvic apparatus will be strongly activated. in the many times mentioned antagonisms and synergisms together with varies muscular body groups implicated in coital and respiratory movements (48). pelvic floor musculature in women. acts in maintaining vaginal introitus open thanks to pubococcygeus fibers called pubo-vaginals in coordination with the collagenelastic-muscular connective tissue which joints pubis (pubo-genita-sacral ligament) and fascia pelvica. the vaginal modifications due to levator and to connective tissue that fills the anterior part of pelvic hiatus, so called hiatal ligament, are particularly interesting; those structures, pulling laterally from each side, amplify vaginal cavity creating the so called ballooning, suitable in accepting the ejaculate and following ejection in cervical womb, thanks to the pubo-rectal contraction; this muscles activity synchronizes with the intrinsic vaginal muscles activity in creating vaginal volume adaptation to penile dimension, that seems to help in maintaining a full erection. also in women a lot of sophisticated reflexes rules vaginal, urethral and anal contraction and relaxation (32). vertical position and posture the pelvic floor contribution is very important in keeping upright position and posture; this one means the capacity in keeping stable the body position, still or in motion, in balance with gravity center falling on the support base (between the two feet in upright position). posture is an active, reflex and involuntary phenomenon caused by tone, contraction and relaxation of muscles which set themselves against the gravity force (anti-gravitary or postural muscles); vestibular afferences inform cerebellum which in its turn constantly informs all the body of where could be its gravity center (12). for what is concerning the upright position. the gluteous major big development (compared to other hominids without constant and obliged up right position) is to be considered; synergism and antagonism with lumbar and abdominal muscles (particularly oblique and transverse) are constant also if in different kind of tone and contraction type; the pelvic musculature acquired indeed a specific characteristics regarding tone, automatism and voluntary, or at least conscious, contraction; pelvic diaphragm muscles tone consists, as already said, in an intermediate state between tone and contraction useful for the function of support; peculiar and sophisticated neurological central controls ensure the absence of muscular exhaustion otherwise present in contracted fibers; it must be added the solidarity of fascial structures, whose composition includes a lot of smooth muscular tissue, which jointly with striated musculature ensure the suitable support tension. the contraction, also being conscious, cannot be considered voluntary. at least for the majority of non-visceral bundles fibers; it corresponds to automatism in common with all postural structures answering to a series of intricate stimulations perceived through different kind of .sensible, sensorial, hormonal receptors and to not less complicated reflexes, that rule contraction and relaxation as the occasion may require. pelvic diaphragm muscles and fasciae represent a functional unity and so they contract simultaneously, bilaterally and synergically, in spite of the fact that it is possible that in certain conditions some groups of fibers could be activated separately (49). neuroscience recently showed the sophisicated complexity of neuronal connections regarding the reflex correlations between pelvic floor activity and other functions; special synergisms exist with gluteous major (very active in creating and keeping the upright position and coccyx in flexo-extension) and with respiratory muscles, especially the outer intercostals; for what is concerning deep breath and cough it is demonstrated, as said, that pelvic muscles contraction precedes the cough hit (46). this cortical control of synergism is not yet well understood; recently research with magnetic functional resonance has showed an activation of the pre-central encephalic gyrus medial wall for striated voluntary musculature of pelvic diaphragm during gluteous major contraction; such activation doesn’t happen during other movements, like a finger flexion. special receptors for sensitivity and in women for estrogens in pelvic floor muscles have rocca rossetti_stesura seveso 08/04/16 11:28 pagina 35 archivio italiano di urologia e andrologia 2016; 88, 1 s. rocca rossetti 36 essential functions for the peculiar trophism and for automatism progressively decreasing with aging (51-52). deambulation pelvic musculature activity during deambulation is noticeable; this musculo-aponeurotic framework has a synergic and antagonistic function with that one of trunk and inferior limbs resulting essential in stabilizing the pelvic ring, stressed by continuous postural movements action; strong spurs are curried out during deambulation on pelvic bones which tend to displace them while on contrary they must be kept fix since their mobility is null (51). the foot walking on the ground urges femur, cotyle and iliac bone of the side to get up; in mean time the suspended limb urge pubis and iliac bone of the side to get down in contemporary sacrum tendency to anteriorize or posteriorize according to monopedal load. evidently pelvic musculature, synergically with extrapelvic one and with those of trunk must act opposing to those forces and keeping stable the pelvis (4). the examination of musculo-fascial phenomena in each movement could be too long and any way not pertinent to the aim of this work . it is only convenient to specify that the central neurologic control of the coordination among varies muscular compartments is as ever complex and not completely clarified; it is not to be neglected how the muscular tension of pelvic floor urged from walking movements influences statics and dynamics of pelvic organs, particularly urethra and rectum. conclusions last years achievements succeeded in clarifying many aspects of pelvic floor activity, whose musculature has been investigated through electromyography, sonography, magnetic resonance, histology, histochemistry, and molecular research. utilizing recent research concerning not only urinary and gynecologic aspects but also that one regarding statics and dynamics of pelvis and its floor, it is now possible to study this important body part as a unit; that means to consider it in the whole body economy including maintaining upright position, walking, behavior or physical conduct in adjunct to urinary, genital, and intestinal functions. for more than a century nearly every paper on pelvic floor cited the famous r.j. dickinson sentence “there is no considerable muscle in the body whose from form and function are more difficult to understand than those of the levator ani, and about which such nebulous impressions prevail” (22); it is today possible to keep the sentence as an historical fact; and consider the pelvic floor as a musculofascial unity, functioning as a unit in synergic and antagonistic activity of muscular bundles, among them more or less interlaced, appraised for their multiple functions and not only for the pelvic cup closure. it is then possible to hope that the above named contradictions (19) are going towards their elimination. acknowledgements an italian version of the paper with illustrations is available on www.siud.it. references 1. sherrington c, cited by tobias in reference 2. 2. tobias ph.v. il bipede barcollante: corpo, cervello, evoluzione umana. einaudi, torino, 1992, p. 821. 3. traetta j. gymnastic basic paperback. 1979. 4. passigli s. fisiologia articolare del cingolo pelvico. anatomia, 2008. 5. rocca rossetti s. diaframma. enciclopedia medica s.e.s, sansoni editore, 1950, vol. iv, p. 750. 6. virno v. i sistemi digastrici del diaframma umano, ricerche di morfologia. roma, 1925. 7. virno v. la morphologie du canal aortico-diaphrammatique chez l'homme. comptes rendues de l'association des anatomistes. 1925, p. 384. 8. wallner c. development of the pelvic floor: implications for clinical anatomy, phd thesis. faculty of medicine (amc-uva), 2008. 9. wallner c, van wissen j, maas cp, et al. the contribution of levator ani nerve and the pudendal nerve to the innervation of the levator ani muscles; 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40:429-36. 18. messelink b, benson t, berghmans b, et al. standardization of terminology of pelvic floor muscle function and dysfunction: report from the pelvic floor clinical assessment group of the international continence society neurourol urodyn. 2005; 24:374-80. 19. kearney r, sawhney r, delancey jo. levator ani muscle anatomy evaluated by origin-insertion pairs. obstet gynecol. 2004; 104:168-73. 20. bharucha ae. pelvic floor: anatomy and function. neuro gastroenterol motil. 2006; 18:507-519. 21. fröhlich b, hötzinger h, fritsch h. tomographical anatomy of the pelvis, pelvic floor, and related structures. clin anat. 1997; 10:223-30. 22. dickinson rj. studies of levator ani muscle 1889, cited in dickinson rj. the time-element in saving the perineum. ny med j. 1890; 51:371-4. 23. fritsch h, lienemann a, brenner e, ludwikowski b. linical anatomy of the pelvic floor. adv anat embryol cell biol. 2004; 175:iii-ix, 1-64. rocca rossetti_stesura seveso 08/04/16 11:28 pagina 36 37archivio italiano di urologia e andrologia 2016; 88, 1 pelvic floor 24. frea b. il pavimento pelvico maschile: cingolo osseo, muscoli, connettivo e innervazione. ottavo corso di urologia funzionale, torino, 10-11 ott. 2014. 25. cervigni m. il pavimento pelvico femminile: cingolo osseo, muscoli, connettivo e innervazione. ottavo corso di urologia fun zionale, torino, 10-11 ott. 2014. 26. meschia m. pavimento pelvico e dintorni. ottavo corso di uro logia funzionale, torino, 10-11 ott. 2014. 27. vercelli a. pavimento pelvico e dintorni. ottavo corso di uro logia funzionale, torino, 10-11 ott. 2014. 28. barber md. contemporary views on female pelvic anatomy. cleve clin j med. 2005; 72(suppl 4):s3-11. 29. singh k, jakab m, reid w, et al. three-dimensional magnetic resonance imaging assessment of levator ani morphologic features in different grades of prolapse. am j obstet gynecol. 2003; 188:910-15. 30. crapp aar, cuthbertson am. william waldeyer and the rectosacral fascia. surg gynecol obstet. 1974; 138:252-56. 31. ayoub sf. the anterior fibres of the levator ani muscle in man. j anat. 1979; 128:571-80. 32. robertson dg, fleming d. kinetics of standing broad and vertical jumping can j sport sci. 1987; 12:19-23. 33. shafik a. the role of the levator ani muscle in evacuation, sexual performance and pelvic floor disorders. int urogynecol j pelvic floor dysfunct. 2000; 11:361-76. 34. carbone g, rocca rossetti s. fisiopatologia della vescica neurogena. relazione al xli congresso della società italiana di urologia, fiuggi, 1968. 35. de groat wc, yoshimura n mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. prog brain res. 2006; 152:59-84. 36. rocca rossetti s. la ritenzione urinaria nell'anziano. fisio pa tologia, clinica, terapie. g gerontol. 1978; 34:734-5. 37. rocca rossetti s, falqui v, giordano d, et al. il problema pielectasia pieloplastica interpretato alla luce dell'idrostatica boll. atti soc urol centro merid. isole 1969-70; 5:1868. 38. ashton-miller j, delancey jol. functional anatomy of the female pelvic floor ann. n.y. acad sci. 2007; 1101:266-296. 39. sasaki h, hinata n, kurokawa t, murakami g. supportive tissues of the vagina with special reference to a fibrous skeleton in the perineum: a review. ojog open journal of obstetrics and gynecology. 2014; 4:144-157. 40. lazarevski mb. biomechanics of urinary stress incontinence surgery: theory of the non-permanently acting suburethral supportive structure. int urogynecol j pelvic floor dysfunct. 2000; 11:377-85. 41. carone r. la teoria uretro-centrica. litografia saba s.r.l., roma maggio 2011. 42. enhorning g. simultaneous recording of intravesical and intraurethral pressure. a study on urethral closure in normal and stress incontinent women. acta chir scand suppl. 1961; (suppl 276):1-68. 43. barbic m, kralj b, cor a. compliance of the bladder neck supporting structures: importance of activity pattern of levator ani muscle and content of elastic fibers of endopelvic fascia. neurourol urodyn. 2003; 22:269-76. 44. deffieux x, raibaut p, rene-corail p, et al. external anal sphincter contraction during coug: not a simple spinal reflex. neurourol urodyn. 2006; 25:782-787. 45. deffieux x, hubeaux k, porcher r, et al. external intercostal muscles and external anal sphincter electromyographic activity during coughing. int urogynecol j pelvic floor dysfunct. 2008; 19:521-524. 46. stebbing jf, brading af, mortensen nj. nitric oxide and the rectoanal inhibitory reflex: retrograde neuronal tracing reveals a descending nitrergic rectoanal pathway in a guinea-pig model. br j surg. 1996; 83:493-8. 47. kunze wa.furness jb. the enteric nervous system and regulation of intestinal motility. annu rev physiol. 1999; 61:117-42. 48. floyd k, mcmahon sb, morrison jfb. inhibitory interaction between colonic and vescical afferents in the micturition reflex of the cat. j physiol. 1982; 322:45-52. 49. hodges pw, sapsford r, pengel lhm. postural and respiratory functions of the pelvic floor muscles. neururol urodyn. 2007; 26:362-71. 50. kenton e, bubaker r. relationship between levator ani contraction and motor unit activation in the urethral sphincter. j obstet gynecol. 2002; 187:403-6. 51. bernstein it. the pelvic floor uuascles: muscle thickness in healthy and in urinary incontinent women measured by ultrasonography with reference to the effect of pelvic floor training.estrogen receptor studies. neurourol urodyn. 1997; 16:237-75. 52. dimitriou m. human muscles spindle sensitivity reflects the balance of activity between antagonistic muscles. j neurosc. 2014; 34:13644-55. correspondence salvatore rocca rossetti, md (corresponding author) salvatore.roccarossetti@unito.it professor of urology, university of torino, torino, italy rocca rossetti_stesura seveso 08/04/16 11:28 pagina 37 stesura seveso 41archivio italiano di urologia e andrologia 2015; 87, 1 original paper comparing robotic, laparoscopic and open cystectomy: a systematic review and meta-analysis thomas fonseka 1, kamran ahmed 2, saied froghi 2, shahid a khan 3, prokar dasgupta 2, mohammad shamim khan 2 1 king’s college london school of medicine, london, uk; 2 mrc centre for transplantation, king's college london, king’s health partners, department of urology, guy’s hospital, london, uk; 3 surrey and sussex healthcare nhs hospital, redhill, uk. objective: to conduct a systematic review and meta-analysis comparing outcomes between open radical cystectomy (orc), laparoscopic radical cystectomy (lrc) and robot-assisted radical cystectomy (rarc). rarc is to be compared to lrc and orc and lrc compared to orc. material and methods: a systematic review of the literature was conducted, collating studies comparing rarc, lrc and orc. surgical and oncological outcome data were extracted and a meta-analysis was performed. results: twenty-four studies were selected with total of 2,104 cases analyzed. rarc had a longer operative time (opt) compared to lrc with no statistical difference between length of stay (los) and estimated blood loss (ebl). rarc had a significantly shorter los, reduced ebl, lower complication rate and longer opt compared to orc. there were no significant differences regarding lymph node yield (lny) and positive surgical margins (psm.) lrc had a reduced ebl, shorter los and increased opt compared to orc. there was no significant difference regarding lny. conclusion: rarc is comparable to lrc with better surgical results than orc. lrc has better surgical outcomes than orc. with the unique technological features of the robotic surgical system and increasing trend of intra-corporeal reconstruction it is likely that rarc will become the surgical option of choice. key words: radical cystectomy; robotic assisted radical cystectomy; laparoscopic radical cystectomy; open radical cystectomy; bladder cancer. submitted 22 december 2014; accepted 31 december 2014 summary no conflict of interest declared. my (rarc) has since emerged as a viable alternative. rarc has been reported to be associated with fewer complications compared to lrc (2) and the appeal of the robotic surgical system has led to the adoption of the procedure worldwide. however the production of high-quality evidence that measures the relative merits of orc, lrc and rarc is lacking with surgeons having to rely on systematic review. this article aims to compare surgical and oncological outcomes of orc, lrc and rarc. methods eligibility criteria data were collected on all patients over the age of 60 with muscle-invasive bladder cancer undergoing rarc, lrc or orc. surgical outcomes were; operative time (opt), estimated blood loss (ebl), length of stay (los) and complication rate 90 days post-operatively. oncological outcomes were; lymph node yield (lny) and positive surgical margins (psm). comparisons were made between rarc, lrc and orc and the outcomes of interest measured included both surgical and oncological outcomes. the studies forming the current meta-analysis include comparative studies, either retrospective or prospective, as well as randomized control trials. for a study to be included in our analysis it had to fulfill the following criteria. the study had to: – compare outcome measures of two or all three surgical techniques (orc, lrc and rarc). – use quantitative data for at least one outcome measure. – be a high quality study. if it was one of two studies that were produced by the same institution, it was ensured the data were mutually exclusive. studies were excluded if they: – lacked reporting of the desired outcome measures listed above or presented the data in such a way that it was not possible to carry out an analysis for the study. – reported on only one of the techniques of orc, lrc and rarc. – were written in non-english language. doi: 10.4081/aiua.2015.1.41 introduction open radical cystectomy (orc) is currently regarded as the gold standard surgical treatment for muscle-invasive and non-muscle invasive high-grade recurrent bladder cancer (1). however, the procedure is associated with high morbidity including increased blood loss, prolonged hospital stay and slower recovery. laparoscopic radical cystectomy (lrc) was developed around two decades but robot-assisted radical cystecto fonseka_stesura seveso 02/04/15 10:21 pagina 41 archivio italiano di urologia e andrologia 2015; 87, 1 t. fonseka, k. ahmed, s. froghi, s.a. khan, p. dasgupta, m. shamim khan 42 information sources a systematic review of the literature was conducted using the following databases; pubmed, medline, the cochrane library and embase. the reference lists of reviews were also cross-referenced. the last search was conducted on 11/12/2014. search the following search terms were used: “open cystectomy”, “open radical cystectomy”, “laparoscopic cystectomy”, “laparoscopic assisted cystectomy”, “laparoscopic radical cystectomy”, “laparoscopic assisted radical cystectomy”, “robotic cystectomy”, “robot* assisted cystectomy”, “robotic radical cystectomy”, “robot* assisted radical cystectomy”, “robot* assisted laparoscopic cystectomy”, “robot* assisted laparoscopic radical cystectomy”, “minimally invasive”, “bladder cancer”. the search terms were combined to ensure as many studies as possible that compared orc, lrc and rarc, or any combination were included. study selection studies were selected by two reviewers (t.f and s.f), independently. where the decision was split and agreement could not be made, the study was included so as to include as many studies as possible. data items after selection of the studies, the following data were extracted; primary author of the study, year of publication, country of study, study design, study exclusion criteria (if mentioned), total number of patients undergoing orc, lrc and rarc, study population characteristics (mean age, mean bmi, mean american society of anesthesiologists (asa) grade, charlson’s co-morbidity index, gender, and pathological stage). for each technique (orc, lrc and rarc), the following data were recorded: primary author of the study, year of publication, total number of patients undergoing each urinary diversion type (conduit or neo-bladder), total number of patients requiring blood transfusion, surgical outcomes (as previously listed) and oncological outcomes (as previously listed). complications were assessed using the clavien-dindo grading system (3). risk of bias in individual studies the newcastle-ottawa quality assessment scale (4) was used to assess the quality of the studies. it was tailored to suit the analysis of the studies included in this evaluation. areas analyzed for quality were patient selection, including representativeness of the exposed cohort, comparability of cohorts, and assessment of outcomes. studies which were rated with five or more stars were deemed to be high-quality. the entire analysis was conducted using review manager version 5 (the cochrane collaboration, software update, oxford). summary measures to assess whether there was a statistically significant difference between data of a dichotomous nature, the odds ratio (or) was calculated. the or is a measure of the probability of an event occurring in an rarc patient group compared to either orc or lrc patient groups or lrc compared to orc. when comparing adverse events, where an or value was less than one it implied that rarc was favored. in order for the point estimate of the or to be considered statistically significant at the p < 0.05 level, the 95% ci must not have included the value of one. when handling continuous data the mean weighted difference (mwd) was used instead of the or. a negative mwd value indicated rarc was favored. synthesis of results guidance was sought from the cochrane collaboration as well as information from the quorum guidelines (5) to provide the framework of the statistical analysis. when studies reported of medians, ranges or confidence intervals for continuous variables, statistical algorithms were used to derive the appropriate means and standard deviations. the or for continuous variables could be calculated using the mantle-haenszel chi square method with the ‘random effects’ meta-analytical technique. the ‘random effects’ model is particularly useful when conducting surgical research. this is because it takes into account the almost inevitable natural variation inherent between studies. subsequently a more conservative or is produced. for both or and mwd, corresponding 95% ci’s were calculated. regarding the forest plots produced, a square represents the point estimate of the treatment effect, that is the or or mwd, with a horizontal bar going through the square showing the 95% ci. the summary measure of the pooled studies with 95% ci’s is represented by a diamond. results study selection the initial literature search identified 598 papers, which matched the search criteria. of these, 486 papers were eliminated due to broad incoherency with the aims of this study. of the 112 remaining, a further 83 papers were excluded based on the exclusion criteria as outlined above. on more in depth examination of the 29 remainfigure 1. fonseka_stesura seveso 02/04/15 10:21 pagina 42 43archivio italiano di urologia e andrologia 2015; 87, 1 robotic cystectomy: a meta-analysis ing papers, a subsequent 5 were removed for not meeting the requirements of the inclusion criteria. thus 24 studies were included in the final quantitative and qualitative analysis (figure 1) (6-29). study characteristics characteristics of all 24 studies included in the analysis are summarized in table 1 (6-29). there were three randomized control trials with the remaining 21 made up of retrospective and prospective studies. each study was either 2-arm or 3-arm. for the purposes of the statistics rarc was always regarded as experimental. lrc was also considered experimental except when being compared to rarc, in which case it was used as control. all of the studies included were fairly recent with the oldest published in 2006. the two reviewers who selected the studies were in complete agreement (100%) about data extraction. a total of 2,104 cases were analyzed, with 1,100 (52.3%) undergoing orc, 276 (13.1%) lrc and 728 (34.6%) rarc. approximately 65% of patients were male. with regards to the pathological stage of the tumors, the average percentage of tumors that were non-organ confined (pt34) was similar in both rarc and orc groups. on average 30.1% of patients reported in the rarc studies had nonorgan confined tumors compared with 29.5% in orc group and 14.5% in the lrc group. on average 28% of patients undergoing rarc developed complications 90 days post-operatively. major complications were defined as table 1. study characteristics. matching: 1 age; 2 bmi; 3 asa; 4 charlson; 5 gender; 6 pathological stage; 7 urinary diversion type. study type: rct randomized control trial; r retrospective, p prospective. study study type cases matching mean age, yaers exclusion criteria study quality country orc lrc rarc orc lrc rarc abaza 2012 r 120 nr 35 1,2,6 69.8 nr 67.3 undergoing lesser *** usa node dissection due to a history of radiation, aortoiliac grafting or significant comorbidity abraham 2007 p nr 20 14 1,2,3,5,7 nr 77.6 76.5 nr **** usa gan 2013 p 20 19 20 nr nr nr nr nr **** uk galich 2006 p 24 nr 13 1,2,3,6 63.03 nr 66.2 morbid obesity (generally **** usa body mass index _ 35), prior pelvic radiation, or significant medical comorbidities including pulmonary obstructive airway disease gondo 2012 p 15 nr 11 1,2,4,5,6,7 69.7 nr 68.9 nr **** japan guillotreau 2009 p 30 38 1,2,3,5,6,7 64.9 (12.3) 67.9 (9.0) ******* france ha 2010 r 34 36 1,2,5,6 55.9 (9.8) 67.5 (8.9) ***** korea haber 2008 r 50 50 1,2 67 66 *** usa kader 2013 r 100 nr 103 1,2,3,5,6,7 66 nr 67 nr ***** usa khan 2012 p 52 58 48 1,2,3,5,6,7 65 69.8 66.5 nr **** uk knox 2013 r 84 nr 58 1,2,3,5,6,7 67.07 (1.2) nr 65.9 (1.2) nr **** usa lin 2014 rct 35 35 1,2,3,5,6 63.6 (8.9) 63.2 (9.1) ******* china martin 2010 p 14 nr 19 1,2,3,5,6 68 nr 74 nr **** usa musch 2014 p 42 100 1,2,3,4,5,6,7 69.0 (11.5) 71.4 (9.4) ******* germany nepple 2013 r 29 nr 36 1,2,5,6,7 67 nr 72 contraindication ***** usa to robotic surgery ng 2010 p 104 nr 83 1,2,3,5,6,7 67.2 nr 70.9 nr ***** usa nix 2010 rct 20 nr 21 1,2,3,5,6,7 69.2 nr 67.4 1) not surgical candidates, **** usa 2) not allowing randomization 3) those with preference for specific surgical modality parekh 2013 rct 19 nr 20 1,2,3,5,6 69.5 nr 69.5 1) inability to give informed ***** usa consent, 2) unsafe for robotic approach, 3) clinical t4 bladder cancer, 4) clinical lymph node positive bladder cancer with grossly enlarged pelvic or retroperitoneal lymph nodes, 5) age younger than 30 or older than 90 years and 6) pregnancy. porpiglia 2007 p 22 20 nr 1,2,3,5,6,7 71 63.5 nr nr ***** italy pruthi 2007 r 24 nr 20 1,6,7 68.2 nr 62.3 nr *** usa rhee 2006 p 23 7 1,2,3,5,6 67 (13) 60 (9) ******* usa richards 2010 r 35 nr 35 1,2,3,5,6,7 66 nr 65 nr **** usa styn 2012 p 100 nr 50 1,2,3,4,5,6,7 65.6 nr 66.6 nr ***** usa sung 2012 r 104 nr 35 1,2,3,5,6 65.9 nr 62.2 had undergone radiotherapy **** korea before operation or for whom palliative treatment was the primary aim fonseka_stesura seveso 02/04/15 10:21 pagina 43 archivio italiano di urologia e andrologia 2015; 87, 1 t. fonseka, k. ahmed, s. froghi, s.a. khan, p. dasgupta, m. shamim khan 44 complications above clavien grade 3, including return to operating room (or) within 30 days post-operatively and death within 90 days post-operatively. 8.51% of patients undergoing rarc had major complications with 3 deaths (0.412%) within 90 days post-operatively. in the lrc studies, 72.1% of patients developed complications with 3 deaths (1.087%) within 90 days post-operatively. the overall complication rate in orc was 47.2% with an average of 8.5% of patients having major complication. there were 7 deaths (0.64%) within 90 days post-operatively. the type of urinary diversion created with each technique was broadly classified into either conduit or bladder substitution (neo-bladder). on average 17.4% of rarc patients had a bladder substitution compared to 13.04% in lrc and 12.4% in the orc groups and the remaining had an ileal conduit urinary diversion. synthesis of results rarc versus lrc as shown in figure 2, opt was significantly longer in rarc when compared to lrc (p = 0.02; mean weighted difference (mwd) was 47.61 with 95% confidence interval (ci) of 8.83 to 86.40). there was no statistically significant difference concerning los (p = 0.63; mwd = -1.95, 95% ci = -9.88 to 5.97) (figure 3). there was also no statistical significance observed when comparing ebl (p = 0.17; mwd = -167.52, 95% ci = -408.48 to 73.44) (figure 4). rarc versus orc opt was significantly longer in rarc when compared to orc (p = < 0.00001; mwd = 60.78, 95% ci = 49.64 to 71.92) (figure 5). comparing other parameters of ebl, los and complications the analysis showed that there was significant reduction in ebl (p = < 0.00001; mwd = -638.24, 95% ci = -850.26 to -426.21) (figure 6), los after rarc (p = 0.004; mwd = -1.75, 95% ci = -2.94 to -0.56) (figure 7) and complications in the rarc group (p = < 0.0001; mwd = 0.53, 95% ci = 0.40 to 0.71) (figure 8). there was no statistical difference in lny (p = 0.87; mwd = -0.22, 95% ci = -2.83 to 2.39) (figure 9) or psm (p = 0.42; mwd = 0.80, 95% ci = 0.47 to 1.37) (figure 10). figure 2. figure 3. figure 4. figure 5. fonseka_stesura seveso 02/04/15 10:21 pagina 44 lrc versus orc comparing lrc to orc operative time was significantly longer using lrc (p = 0.002; mwd = 34.93, 95% ci = 12.76 to 57.10) (figure 11). ebl was significantly reduced in the lrc group (p = 0.0009; mwd = -480.96, 95% ci = -765.04 to -196.88) (figure 12). likewise los was signif45archivio italiano di urologia e andrologia 2015; 87, 1 robotic cystectomy: a meta-analysis figure 6. figure 7. figure 8. figure 9. fonseka_stesura seveso 02/04/15 10:21 pagina 45 archivio italiano di urologia e andrologia 2015; 87, 1 t. fonseka, k. ahmed, s. froghi, s.a. khan, p. dasgupta, m. shamim khan 46 icantly shorter in the lrc group (p = 0.001; mwd = -2.54, 95% ci = -4.08 to -0.99) (figure 13). there was no statistical difference in lny (p = 0.99; mwd = 0.01, 95% ci = -1.11 to 1.13) (figure 14). discussion comparing rarc to lrc, the results show that there is no statistical difference in los or ebl but the operating time is significantly longer. more data is needed to see figure 10. figure 11. figure 12. figure 13. figure 14. fonseka_stesura seveso 02/04/15 10:21 pagina 46 whether complication rate is significantly reduced when comparing rarc to lrc. rarc takes longer to do than orc but produces better surgical outcomes with reduced ebl, shorter los and fewer complications. there are equivalent oncological outcomes (lny and psm.) when comparing lrc to orc, lny is equivalent but there is an increase in opt, reduction in ebl and shorter los using the laparoscopic approach. the results therefore are in favor of using lrc in preference to orc. it may be that it is when the robotic technique is used with intracorporeal urinary diversion, as opposed to extracorporeal, that it is superior to lrc. most studies included used extracorporeal urinary diversion. intracorporeal urinary diversion has been demonstrated to be technically feasible with good oncological outcomes (13,30). more data is needed to assess long-term outcomes. the difficulty in obtaining data on complications results from a lack of consistency in reporting complications. in this paper the clavien-dindo system was used and it is broadly accepted as the better current standard for reporting of surgical complications. all future trials assessing the complications in radical cystectomy should use this system to facilitate universal comparison (31). one outcome in which data was lacking was psm. a study using data from the international robotic cystectomy consortium (ircc) (32) found that the rate of psm was similar between rarc and orc, consistent with the results of this meta-analysis. variables associated with increased probability of psm using rarc included older age, higher pathological t stage and lymph node positivity. a similar study by the ircc reviewed the outcomes of extended lymph node dissection, an essential part of radical cystectomy (33). similar lymph node yields were obtained in rarc and orc, which were found to be the case in this study. the study also identified that high volume institutions (≥ 100 cases) had 3.46-times increased probability of carrying out extended lymph node dissection (lnd). it is crucial that survival data is reported in the studies of different surgical techniques to see if technology is having an influence on the survival of these patients. this would only be possible with longer follow up after surgical procedures. kaplan-meier plots to compare survival rates between the three operative techniques would prove valuable in assessing the evidence for rarc. guru et al. (34) have shown that surgical and oncological outcomes constantly improve with each rarc case the surgeon performs. the learning curve for rarc was defined by results from the ircc. using proxy measurements for rarc quality such as opt, ebl, lny and margin positivity it was found that acceptable proficiency in the procedure was attained by the 30th case. the cost of rarc is estimated to be about $20,000 per case and is an important factor to consider when evaluating the use of rarc. lee et al. (35) have found that rarc is less expensive than orc when ileal conduit or continent cutaneous diversion is performed. the main driver of cost was los and though material cost was higher with rarc, in high-volume centres rarc can be more costeffective particularly with ileal conduit urinary diversion. the true benefit of rarc may lie in the improved ergonomics of the robotic system. the more comfortable operating system may cause less fatigue to the surgeon as compared to laparoscopic methods, thereby leading to fewer errors. this was shown by elhage et al. (36) where time taken to perform a suturing task was not only shorter compared to laparoscopic and open, but there were also fewer errors made when compared to the laparoscopic method. the major limitation of this study is the possibility of bias. when evaluating surgical procedures there is always a lack of blinding and natural variation in both the skill of the surgeon pathology of different cases. this is reflected in the significant heterogeneity found in the forest plots of this study. inclusion criteria varied among studies as well as there being different systems of followup with differing outcome definitions. publication bias is also a possibility that was not factored into this study. conclusions the results of this meta-analysis shows that lrc provides better outcomes than orc but that rarc provides similar outcomes to lrc, only with longer opt. more randomised control trials are required to provide conclusive evidence to show whether or not rarc is in fact a better alternative to orc or lrc. these studies must use a unified system for the classification of complications and assess both surgical and oncological outcomes. more data is also needed on the ergonomics, learning curve, cost-effectiveness and patient-perspectives of rarc. acknowledgements p.d. acknowledges financial support from the national institute for health research (nihr) biomedical research centre based at guy’s and st thomas’ nhs foundation trust and king’s college london. the views expressed are those of the author(s) and not necessarily those of the nhs, the nihr or the department of health. p.d. also acknowledges the support of the mrc centre for transplantation, london deanery, london school of surgery and olympus. p.d., s.k. and k.a. acknowledge funding for the simulate project from the urology foundation (tuf) and the baus. ka and pd acknowledge educational funding from the royal college of surgeons of england. references 1. springer c, mohammed n, alba s, et al. laparoscopic radical cystectomy with extracorporeal ileal neobladder for muscle-invasive urothelial carcinoma of the bladder: technique and short-term outcomes. world j urol. 2013; 1-6. 2. khan ms, elhage o, challacombe b, et al. analysis of early complications of robotic-assisted radical cystectomy using a standardized reporting system. urology. 2011; 2:357-362. 3. dindo d, demartines n, clavien p. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 4. wong wc, cheung cs, hart gj. development of a quality assess47archivio italiano di urologia e andrologia 2015; 87, 1 robotic cystectomy: a meta-analysis fonseka_stesura seveso 02/04/15 10:21 pagina 47 archivio italiano di urologia e andrologia 2015; 87, 1 t. fonseka, k. ahmed, s. froghi, s.a. khan, p. dasgupta, m. shamim khan 48 ment tool for systematic reviews of observational studies (qatso) of hiv prevalence in men having sex with men and associated risk behaviours. emerg themes epidemiol. 2008; 5:23. 5. moher d, cook dj, eastwood s, et al. improving the quality of reports of meta-analyses of randomised controlled trials: the quorom statement. the lancet. 1999; 354:1896-1900. 6. abaza r, dangle pp, gong mc, et al. quality of lymphadenectomy is equivalent with robotic and open cystectomy using an extended template. j urol. 2012; 187:1200-1204. 7. abraham jba, young jl, box gn, et al. comparative analysis of laparoscopic and robot-assisted radical cystectomy with ileal conduit urinary diversion. j endourol. 2007; 21:1473-1480. 8. galich a, sterrett s, nazemi t, et al. comparative analysis of early perioperative outcomes following radical cystectomy by either the robotic or open method. jsls, jsls. 2006; 10:145-150. 9. gondo t, yoshioka k, nakagami y, et al. robotic versus open radical cystectomy: prospective comparison of perioperative and pathologic outcomes in japan. jpn j clin oncol. 2012; 42:625-631. 10. kader ak, richards ka, krane ls, et al. robot-assisted laparoscopic vs open radical cystectomy: comparison of complications and perioperative oncological outcomes in 200 patients. bju int. 2013; 112:e290-e294. 11. khan ms, challacombe b, elhage o, et al. a dual-centre, cohort comparison of open, laparoscopic and robotic-assisted radical cystectomy. int j clin pract. 2012; 66:656-662. 12. knox ml, el-galley r, busby je. robotic versus open radical cystectomy: identification of patients who benefit from the robotic approach. j endourol. 2013; 27:40-44. 13. jonsson mn, adding lc, hosseini a, et al. robot-assisted radical cystectomy with intracorporeal urinary diversion in patients with transitional cell carcinoma of the bladder. eur urol. 2011; 60:1066-1073. 14. nepple kg, strope sa, grubb iii rl, et al. early oncologic outcomes of robotic vs. open radical cystectomy for urothelial cancer. urol oncol, 2013; 31:894-898. 15. ng ck, kauffman ec, lee m, et al. a comparison of postoperative complications in open versus robotic cystectomy. eur urol. 2010; 57:274-282. 16. nix j, smith a, kurpad r, et al. prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results. eur urol. 2010; 57:196-201. 17. parekh dj, messer j, fitzgerald j, et al. perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. j urol. 2013; 189:474-479. 18. porpiglia f, renard j, billia m, et al. open versus laparoscopyassisted radical cystectomy: results of a prospective study. j endourol. 2007; 21:325-329. 19. pruthi rs, wallen em. robotic assisted laparoscopic radical cystoprostatectomy: operative and pathological outcomes. j urol. 2007; 178:814-818. 20. richards ka, hemal ak, kader ak, et al. robot assisted laparoscopic pelvic lymphadenectomy at the time of radical cystectomy rivals that of open surgery: single institution report. urology. 2010; 76:1400-1404. 21. styn nr, montgomery js, wood dp, et al. matched comparison of robotic-assisted and open radical cystectomy. urology. 2012; 79:1303-1308. 22. sung hh, ahn j, seo si, et al. a comparison of early complications between open and robot-assisted radical cystectomy. j endourol. 2012; 26:670-675. 23. gan c, ismail f, cheung g, et al. 1033 a pilot prospective single-centre 3-arm randomised controlled trial of open, robotic and laparoscopic (coral) radical cystectomy for bladder cancer. eur urol suppl. 2013; 12:e1033-e1034. 24. ha u, kim si, kim sj, et al. laparoscopic versus open radical cystectomy for the management of bladder cancer: mid-term oncological outcome. int j urol. 2010; 17:55-61. 25. guillotreau j, gamé x, mouzin m, et al. radical cystectomy for bladder cancer: morbidity of laparoscopic versus open surgery. j urol. 2009; 181:554-9. 26. haber g-p, crouzet s, gill is. laparoscopic and robotic assisted radical cystectomy for bladder cancer: a critical analysis. eur urol. 2008; 54:54-64. 27. lin t, fan x, zhang c, et al. a prospective randomised controlled trial of laparoscopic vs open radical cystectomy for bladder cancer: perioperative and oncologic outcomes with 5-year follow-up. br j cancer. 2014; 110:842-9. 28. musch m, janowski m, steves a, et al. comparison of early postoperative morbidity after robot-assisted and open radical cystectomy: results of a prospective observational study. bju international. 2014; 113:458-67. 29. rhee jj, lebeau s, smolkin m, theodorescu d. radical cystectomy with ileal conduit diversion: early prospective evaluation of the impact of robotic assistance. bju international. 2006; 98:1059-63. 30. sala lg, matsunaga gs, corica fa, et al. robot-assisted laparoscopic radical cystoprostatectomy and totally intracorporeal ileal neobladder. j endourol. 2006; 20:233-236. 31. johar rs, hayn mh, stegemann ap, et al. complications after robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. eur urol. 2013; 64:52-57. 32. hellenthal n, hussain a, andrews p, et al. status of surgical margins after robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. j urol 2010; 183:e636-e637. 33. marshall sj, hayn mh, stegemann ap, et al. impact of surgeon and volume on extended lymphadenectomy at the time of robotassisted radical cystectomy: results from the international robotic cystectomy consortium (ircc). bju int. 2013; 111:1075-1080. 34. guru ka, perlmutter ae, butt zm, et al. the learning curve for robot-assisted radical cystectomy. jsls. 2009; 13:509-514. 35. lee r, ng ck, shariat sf, et al. the economics of robotic cystectomy: cost comparison of open versus robotic cystectomy. bju int. 2011; 108:1886-1892. 36. elhage o, challacombe b, shortland a, et al. an assessment of the physical impact of complex surgical tasks on surgeon errors and discomfort: a comparison between robotic-assisted, laparoscopic and open approaches. bju int 2014. doi: 10.1111/bju.12680. correspondence thomas fonseka (bsc) king’s college london school of medicine, london, uk kamran ahmed, mrcs, phd (correspondent author) kamran.ahmed@kcl.ac.uk saied froghi, mbbs prokar dasgupta, msc, md, febu, frcs urol mohammad shamim khan, obe, febu, frcs urol nihr academic clinical lecturer /specialist registrar in urology mrc centre for transplantation, guys hospital st thomas street, london se1 9rt, uk shahid a khan, frcs urol surrey and sussex healthcare nhs hospital, redhill, uk fonseka_stesura seveso 02/04/15 10:21 pagina 48 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3250 case report late-onset secondary nocturnal enuresis in adolescents associated with post-traumatic stress disorder developed after a traffic accident serkan akan, ahmet ürkmez, caglar yildirim, aytac sahin, özgür haki yüksel, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey. secondary nocturnal enuresis is generally seen between 5 and 7 years of age and it is rarely encountered when compared with the primary incontinence. patients with suggested diagnosis of secondary nocturnal enuresis should be examined for neurological and spinal anomalies and diabetes mellitus, diabetes insipidus, renal failure and urinary tract infection should be ruled out in differential diagnosis (1-3). herein, we are presenting case reports of adolescent patients with secondary nocturnal enuresis refractory to medical therapy and developed after in-vehicle and extravehicular accidents. key words: secondary nocturnal enuresis; medical therapy; psychotherapy; adolescent. submitted 8 may 2015; accepted 30 june 2015 summary no conflict of interest declared. findings, urinalysis, urine culture and urinary system ultrasound. during 2 months of follow-up with prescription of keeping a voiding diary, behavioural treatment and fluid restriction, her complaints decreased, but still persisted. then daily oral desmopression (one 120 µg lyophilized tablet a day) therapy was initiated. since her complaints did not fully resolve, she was transferred to the department of pediatric psychiatry and complete cure was achieved with combined treatment. case 2 a 12-year-old girl had an in-vehicle accident nearly 6 months previously. at the time of the accident, a serious wound except for a minor head trauma was not observed in the patient sitting in the back seat and she was evaluated the same day in the emergency service and discharged. she consulted to us with complaints of night-time bedwetting (enuresis nocturna) persisting for 6 months. she expressed that from the day of the accident on she had complaints of sleeping disorders and she had been having nightmares. before the accident she hadn’t had any complaint of incontinence. her physical and neurological examination findings were within normal limits. laboratory parameters, urinalysis, urine culture and urinary system ultrasound findings were unremarkable. the patient was started on daily oral dsesmopressin therapy (one 120 µg lyophilized tablet a day). her complaints regressed at a rate of 50 percent. since complete dryness could not be achieved, she was consulted to pediatric psychiatry department. she underwent psychotherapy in combination with medical therapy for 3 months and her complaints regressed considerably. discussion enuresis nocturna is a quite disturbing common problem for children and their families. the underlying causative factors are functional disorders as bladder dysfunction. however it can be rarely seen in association with anatomical abnormalities and neurogenital disorders and diseases as diabetes insipidus, chronic renal failure and tubulopathies. besides, some cases with nocturnal enuresis have been observed after use of clozapine, risperidone and valproic acid (1). doi: 10.4081/aiua.2015.3.250 introduction enuresis nocturna is defined as involuntary night-time bedwetting during sleep in children over 5 years of age. it is a very disturbing common problem for children and their families. however secondary nocturnal enuresis is generally seen between 5 and 7 years of age and it is quite rare compared with primary nocturnal enuresis. herein, we are presenting case reports of adolescent patients with secondary nocturnal enuresis refractory to medical therapy and developed after in-vehicle and extravehicular accidents. case presentations case 1 a 14-year-old girl had an extravehicular traffic accident. the same day she was examined in the emergency service. since she hadn’t any serious wound(s), she was discharged without prescribing any medical therapy. she presented to us with complaints of nocturnal enuresis recurring nearly every night the patient did not mention any behavioural problem starting after the traffic accident. she hadn’t any complaint of bedwetting before the accident. her physical examination findings were within physiologic limits. any abnormality was not observed in her laboratory akan intero_stesura seveso 23/09/15 12:44 pagina 250 251archivio italiano di urologia e andrologia 2015; 87, 3 late-onset secondary nocturnal enuresis in adolescents associated with post-traumatic stress disorder developed after a traffic accident its psychological etiology has not been known yet. however delayed maturation of cortical or central autonomic mechanisms regulating the functions of voluntary micturition center has been stated in its pathogenesis (2). secondary nocturnal enuresis is generally seen between 5 and 7 years of age and it is rarely encountered when compared with the primary incontinence. patients with suggested diagnosis of secondary nocturnal enuresis should be examined for neurological and spinal anomalies and diabetes mellitus, diabetes insipidus, renal failure and urinary tract infection should be ruled out in differential diagnosis. the largest scale-study in the literature has been conducted by tal eidlitz-markus et al. on 5 patients with secondary nocturnal enuresis. as is reported by us, classifical information about late-onset secondary nocturnal enuresis or secondary nocturnal enuresis in adolescents have not been cited in relevant references. incidence of incontinence is higher in children with behavioural and emotional problems (3). in some studies performed, the authors stated that 20-40% of the children with daytime and 20-30 % of night-time urinary incontinence and 50% of pediatric cases with fecal incontinence met dsm-iv (diagnostic and statistical manual of mental disorders) criteria of psychiatric disorders (4, 5). in these studies, the authors indicated that compliance with psychological treatment favourably contributed to success rates of the treatment of incontinence. from the clinical perspective, the incidence of behavioural disorders has been indicated in 10-15% of children and adolescents. these behavioural disorders include anxiety, fear, depressive mood, hyperactivity, anorexia nervosa and autism. in these patients incidence of incontinence (including all of its subtypes) is higher relative to normal continent population. epidemiological studies have demonstrated that 20-30% of the children with nocturnal enuresis displayed behavioural problems. besides, these rates demonstrate increases in line with age, male gender and lower socioeconomic status (6). subclinical behavioural problems may go undetected. apparently all subtypes of incontinence constitute a risk for lower quality of life and loss of self-esteem (7). however, parents of these children become intolerant to this problem and put their children under a lot of stress (8). literature studies have indicated that children diagnosed as nocturnal enuresis also carry higher (75%) risk of psychological disorders (9). following posttraumatic stress disorders, symptoms of hyperactivity, decrease in attention span, bursts of anger, sleep disorders, distemper and undisciplined behaviours, headache and dizziness can be seen. international children’s continence society (iccs) has released psychological and psychiatric evaluation and treatment guidelines for pediatric patients with dayand night-time urinary or fecal incontinence (10). it should not be forgotten that posttraumatic secondary nocturnal enuresis and incontinence can be seen during adolescent period. in addition to its specific treatment, pediatric psychological and psychiatric assessments in line with evidence-based application parametres and directives should be suggested. the importance of behavioural counselling and healthcare services in the acquisition of correspondence serkan akan, md ahmet ürkmez, md caglar yildirim, md aytac sahin, md özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com ayhan verit, md. prof. fatih sultan mehmet research and training hospital, dept. of urology, içerenköy/ataşehir, tr34752 istanbul, turkey optimal therapeutical outcomes for the children and their families should be taken into consideration. conclusions it should not be forgotten that posttraumatic secondary nocturnal enuresis and incontinence can be seen during adolescent period. in addition to its specific treatment, pediatric psychological and psychiatric assessments in line with evidence-based application parametres and directives should be suggested. the importance of behavioural counselling and healthcare services in the acquisition of optimal therapeutical outcomes for the children and their families should be taken into consideration. references 1. zaïem a, aouinti i, lakhoua g, et al. secondary nocturnal enuresis associated with valproic acid. therapie. 2013; 68:59-60. 2. eidlitz-markus t, shuper a, amir j. secondary enuresis: posttraumatic stress disorder in children after car accidents. isr med assoc j. 2000; 22:135-7. 3. von gontard a and nevéus t: management of disorders of bladder and bowel control in childhood. london: mackeith press 2006. 4. world health organization: multiaxial classification of child and adolescent psychiatric disorders: the icd-10 classification of mental and behavioural disorders in children and adolescents. cambridge: cambridge university press 2008. 5. american psychiatric association: diagnostic and statistical manual of mental disorders, text revision (dsm-iv-tr). washington, dc 2000. 6. baeyens d, roeyers h, vande walle j, et al: behavioural problems and attention-deficit hyperactivity disorder in children with enuresis: a literature review. eur j pediatr. 2005; 164:665. 7. bachmann c, lehr d, janhsen e, et al. health related quality of life of a tertiary referral center population with urinary incontinence using the dcgm-10 questionnaire. j urol. 2009; 182:2000. 8. butler rj, golding j, heron j, et al: nocturnal enuresis: a survey of parental coping strategies at 7 1/2 years. child care health dev. 2005; 31:659. 9. von gontard a, mauer-mucke k, plück j, et al: clinical behavioral problems in dayand nightwetting children. pediatr nephrol. 1999; 13:662. 10. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international children’s continence society. j urol. 2006; 176:314. akan intero_stesura seveso 23/09/15 12:44 pagina 251 archivio italiano di urologia e andrologia 2017; 89, 126 original paper comparison of the clinical parameters of benign prostate hyperplasia in diabetic and non diabetic patients levent ozcan 1, huseyin besiroglu 2, murat dursun 3, emre can polat 2, alper otunctemur 2, emin ozbek 2 1 department of urology, derince training and research hospital, kocaeli, turkey; 2 department of urology, okmeydani training and research hospital, istanbul, turkey; 3 department of urology, bahcelievler state hospital, istanbul, turkey. objective: we evaluated the correlation between benign prostate hyperplasia (bph) measures and diabetes mellitus in men with benign prostate hyperplasia in a prospective study. materials and methods: between 2008-2012, 100 diabetic and 200 non diabetic patients undergoing surgery due to benign prostate hyperplasia were enrolled in the study. the parameters evaluated for each patients included prostate volume, fasting blood glucose, hba1c, total testosterone, total prostatic specific antigen (t-psa), triglicerides, total cholesterol and body mass index (bmi). a questionnaire including international prostate symptom score (ipss) was sdministered and uroflow test measuring the peak urinary flow rate was performed to appreciate the complaints of the patients objectively. results: diabetic patients are more likely to have larger prostate volume. the symptom score evaluated by ipss and post micturition residual volume were also significantly higher in diabetic groups. the other statistically significant different parameter between two groups was total testosterone that diabetic patients tend to have lower levels. diabetic counterparts were established to have higher bmi. no statistically significant differentiation was observed about trigliceryde and total cholesterol levels and uroflow rates. conclusions: our study suggests a positive correlation between high prostate volume and diagnosis of diabetes mellitus in patients with benign prostatic hyperplasia. we also observed a positive correlation between symptom scores and post micturion residual volumes and diagnosis of diabetes mellitus suggesting that the presence of diabetes is related to both static and dynamic components of benign prostate hyperplasia. additionally testosterone levels were lower in diabetic patients. further studies need to confirm these relationship in a larger population. key words: benign prostate hyperplasia; diabetes; international prostate symptom score; prostate volume; prostatic specific antigen (psa); testosterone. submitted 23 may 2016; accepted 3 september 2016 summary no conflict of interest declared. bph is still unclear, but multiple partially overlapping and complementary systems (nerve, endocrine, immune, and vascular) as well as local factors are likely to be involved (2, 4). although the specific pathway remains poorly investigated, it seems that the pathogenetic mechanism is endocrine controlled (4). diabetes mellitus (dm) and bph progression occur in similar ages in men and dm is thought to be an important entity contributing development and progression of bph (5, 7). histologically, bph is a non malignant unregulated hyperplasia of stromal and epithelial prostate cells (8). it seems there is a significant correlation between prostate enlargement and dm. there are many reports suggesting a causal relationship between high insulin levels and the development of bph and an increased sympathetic nerve activity in men with bph has been suggested (9, 10). this process contributes to an increase in the activation of the alfa adrenergic system leading to smooth muscle contraction throughout genitourinary system particularily in the bladder neck and prostate (11, 12). obesity is an another entity whose direct relationship was shown with bph and lower urinary tract symptoms (luts) in many studies probably via secondary hyperinsulinemia or the increased estrogen-to-androgen ratio (13-19). androgens are well known facts contributing to bph/luts although they are not a clearly causative aspect of bph. the relationship between sex hormones on regulation of prostatic growth and bph/luts is quite complex and still not thoroughly understood (20, 21). consequently, androgens, estrogens, stromal-epithelial interactions, growth factors and neurotransmitters may play a role, either singly or in combination, in the etiology of the hyperplastic process. the aim of this study to evaluate the bph componenets in diabetic and non diabetic patients undergoing surgery owing to bph. materials and methods study population from 2008 to 2012 300 patients undergoing surgery owing to bph were included in the study. for patients with suspicious prostate cancer in terms of high prostate specific antigen (psa) and abnormal digital rectal examination (dre), ultrasonography guided transrectal biopsy doi: 10.4081/aiua.2017.1.26 introduction benign prostate hyperplasia (bph) is a prevalent process in aging man with severe and frequent low urinary symptoms reducing the quality of life (1). despite intense research to identify the underlying mechanism of prostatic growth in older man, cause and effect relationship has not been yet established (2, 3). the etiology of ozcan_stesura seveso 04/04/17 09:09 pagina 26 27archivio italiano di urologia e andrologia 2017; 89, 1 benign prostate hyperplasia in diabetic and non diabetic patients was performed before surgery. the indications of turp were provided as following: recurrent urinary retention, recurrent urinary tract infections, recurrent macroscopic hematuria, bladder stones or diverticula, or dilation of the upper urinary tract with or without renal insufficiency. patients were divided in two groups according to the presence of dm. diabetic groups included 100 patients and non diabetic groups included 200 patients. patients found to have prostate cancer after prostate biopsies and patients having previous prostate and urethral surgery were excluded from the study. additionally, patients with bacteriuria or pyuria were excluded likewise. measurements detailed medical history and physical examination was performed for all patients. the weight and height of participants were measured and body mass index (bmi) was calculated as weight in kilograms divided by height in meters squared (kg/m2). blood samples were drawn from fasting patients to determine fasting blood sugar (fbs), hba1c, total-testosterone (tt), triglycerides (tg) and total cholesterol (c). prostate volume (pv) was measured according to the prostate ellipsoid formula, multiplying the largest anteroposterior (height, h), transverse (width, w), and cephalocaudal (length, l) prostate diameters by 0.524 (h×w×l×π/6) by using transrectal ultrasonography (trus). the symptoms of the patients were assesed using international prostate symptom score (ipss). post micturion residual volume (pmr) was measured for all patients by ultrasonography. the patients were divided into two groups including diabetic and non diabetic participants. statistical analysis all statistical analysis was performed by using spss ver. 13.0 (spss inc., chicago, il, usa). we divided the study population into two groups: the diabetic group and the non-diabetic group. we compared the ipss, voiding symptom subscore, storage symptom subscore, quality of life (qol), and prostate related parameters between the two groups. statistical analysis including student’s t-test and pearson’s correlation coefficient was performed. student’s t-test was used to describe the difference in prostate volume and voiding-related symptom score. pearson’s correlation coefficient was used to test the linearity of the relationships between metabolic components and prostate volume. in all comparisons of values, p-values of less than 0.05 were considered to be statistically significant. results the mean age of the patients was 68.2 ± 7.4 years. the mean age for the two groups were 69.2 ± 2 years and 67.8 ± 7.5 years, respectively and there was no statistically difference. baseline characteristics of the patients included in this study are presented in table 1. bmi in diabetic group was significantly higher. fbs and hba1c levels were also found to be statistically differnt (144.2 ± 33.5 and 89.7 ± 11.9 respectively; 7.3 ± 1.3 and 5.6 ± 0.4 respectively). diabetic patients were more likely to report severe luts and the symptom score evaluated with ipss was significantly higher in diabetics group (19.5 ± 1.7 and 18.4 ± 1.5) as post micturional residual volume (104.8 ± 28.8 and 79.8 ± 19.8 respectively). in addition, serum psa level and pv were significantly higher in the patients with diabetes than in the patients without diabetes. tt levels were significantly lower in diabetic patients than in non diabetic (2.8 ± 0.8 and 3.6 ± 0.9 respectively). table 2 shows association between the parameteres of diabetic patients including prostate size, t-psa and tt and the other parameters of all patients. in the analysis a positive link was established between prostate volume and age indicating that older patients are likely to have larger prostate size (p = 0.003). similarly, t-psa levels correlates with the prostate size (p = 0.00001). another parameter that appears to show a significant link with prostate volume was fbs (p = 0.038). a negative correlation was found between tt and t-psa levels (p = 0.006). it was also found that fbs was negatively correlated with tt levels (p = 0.003). it was also established that patients with higher post micturion residual volume are likely to have higher t-psa levels (0.013). the same comparison between the parameters of non diabetic patients and the parameters in all patients were shown in table 3. age and prostate volume significantly correlated, like in diabetic group (p = 0.00001). bmi and both pv and t-psa levels were also found to be correlated (p = 0.002 and p = 0.006 respectively). a negative association was established between tt and tpsa levels (p = 0.018) similarly to the diabetic group. there was also positive correlation between ipss and t-psa levels (p = 0.049). conversely from diabetic groups bmi was found to be correlated with pv and t-psa levels (p = 0.002 and p = 0.006 respectively). table 1. baseline charasteristics of men (n: 300) with and without diabetes. characteristic total patients without dm patient with dm p no of patients 300 200 100 age (y) 68.2 ± 7.4 67.8 ± 7.5 69.2 ± 2 0.11 weight (kg) 77.7 ± 9.1 75.2 ± 8.9 83.4 ± 7.6 0.000* height (cm) 170.9 ± 5.3 171.4 ± 5.3 170.7 ± 5.6 0.32 bmi (kg/m2) 26.2 ± 2.9 25.2 ± 2.7 28.1 ± 2.5 0.000* fbs (ng/ml) 106.5 ± 32.9 89.7 ± 11.9 144.2 ± 33.5 0.000* hba1c % 6.2 ± 1.1 5.6 ± 0.4 7.3 ± 1.3 0.000* tg (mg/dl) 127.4 ± 44.3 124.3 ± 46.2 133.7 ± 39.8 0.08 c (mg/dl) 166.7 ± 36.1 167.5 ± 36.7 165.1 ± 35 0.59 tt (ng/ml) 3.4 ± 0.9 3.6 ± 0.9 2.8 ± 0.8 0.000* psa (ng/dl) 3.3 ± 1.3 3.1 ± 1.4 4.2 ± 1.7 0.000* pv (ml) 64.7 ± 26.4 59 ± 23.6 85.3 ± 42.2 0.000* ipss 18.8 ± 1.7 18.4 ± 1.5 19.5 ± 1.7 0.000* pmr (ml) 87.7 ± 25.6 79.8 ± 19.8 104.8 ± 28.8 0.000 uroflow (qmax) 8.8 ± 1.9 8.8 ± 1.8 8.9 ± 2.1 0.73 bmi: body mass index, fbs: fasting blood glucose, tg: triglycerides, c: cholesterol; tt: total testosterone, psa: prostate specific antigen, pv: prostate volume, ipss: international prostate symptom score, pmr: post micturion residual volume. ozcan_stesura seveso 04/04/17 09:09 pagina 27 archivio italiano di urologia e andrologia 2017; 89, 1 l. ozcan, h. besiroglu, m. dursun, e. can polat, a. otunctemur, e. ozbek 28 discussion in this study clinical parameters of bph in diabetic and non diabetic patients undergoing surgery were compared. since the etiology of bph is still unclear and probably depends on a complex mechanism, there is an enhanching attention of researchers about this topic. the connection of diabetes and bph has been known for years being firstly mentioned by bourke and griffin who suggest an association between diabetes and bph etiology based on the higher prevalance of diabetes mellitus among patients in need of surgery (22). dm seems to play role in pathogenesis of bph via both static and dynamic components. in this study we observed a significant correlation between prostate volume and diabetes. there may be several mechanism attributed to this condition particularly including hyperinsulinemia and insülin growth factor (igf). it has been known for decades that prostatic tissue has igf receptors which exist in both stromal and epithelial cells (23, 24). it has been demonstrated in experimental models that prostate atrophy induced by androgen deprivation as well as with the effect of antiandrogens and of 5 alfa reductase inhibitors is achieved through local growth factors (25, 26). the activity of igf is likely to be managed by the adrogens and in the absence of androgens insuline like growth factor binding protein (igfbp) levels reduces like igf-1 receptors and igf-1 mrna (27). some studies established some evidences that insulin resistance is an important factor for enhancement of prostate gland. the decrease in the level of insulin was supposed to be correlated with the reduction of pv (28, 29). we also observed significant correlation between pv and fbs. won tae kim et al. found positive correlation between pv and fbs in non diabetic benign prostatic hiperplasia patients with normal tt levels (30). this study indicate that other unknown factors affecting prostate growth through other mechanism than testosterone such as obesity or abnormal glucose homeostasis. in another study including 422 men parsons et al reported obesity, elevated fasting glucose and diabetes as risk factors for larger prostate size (31). a study giving similar result by ozden et al was reported demonstrating significantly higher annual rates of increase in the volume of the transizional area in diabetics compared to the patients with low levels of serum glucose (12). the pathogenesis of this connection may result from insulin resistance and high insulin levels in the blood. vikram et al. reported enhancement in the proliferation of prostatic epitels in insulin resistans rat model (32). in another study by the same authors hipoinsulinemia was found to be correlated with decrease in the prostate volume (28). similarly, hammareston and et al. described a relationship between plasma insulin levels and bph showing that patients with higher levels of plasma fasting insulin had a significantly larger prostate volume and higher annual bph growth (13). in another study by sarma et al. investigating the association between dm and bph parameters in community dwelling black and white men it was found that dm was more related to dynamic components of bph (24). on the contrary, we found that dm was related to both static and dynamic components of bph/luts. we observed that prostate volume was higher in diabetic counterparts as well as high ipss and post micturional residual volume. table 2. comparison of prostate size, t-psa and testosterone of the diabetic patients with other parameters. prostate size t-psa testosterone parameters correlation (r) p correlation (r) p correlation (r) p age (y) 0.291* 0.003 0.104 0.303 -0.181 0.072 weight (kg) 0.064 0.524 0.081 0.420 -0.089 0.378 height (cm) 0.000 0.999 0.144 0.154 -0.113 0.264 bmi (kg/m2) 0.087 0.387 -0.024 0.815 0.013 0.895 fbs (ng/ml) 0.183 0.038* 0.184 0.067 -0.293* 0.003 hba1c % 0.027 0.791 0.014 0.886 -0.088 0.383 tg (mg/dl) 0.066 0.513 0.084 0.406 -0.140 0.165 c (mg/dl) 0.142 0.159 0.028 0.786 -0.056 0.577 tt (ng/ml) -0.188 0.061 -0.273* 0.006 1 psa (ng/dl) 0.382* 0.000 1 -0.273* 0.006 pv (ml) 1 0.382* 0.000 -0.188 0.061 ipss 0.133 0.258 0.058 0.623 -0.192 0.101 uroflow (qmax) -0.181 0.122 -0.179 0.127 0.091 0.440 pmr (ml) 0.316 0.005 0.279* 0.013 -0.140 0.222 * statistically significant; – negative correlation. bmi: body mass index, fbs: fasting blood glucose, tg: triglycerides, c: cholesterol; tt: total testosterone, psa: prostate specific antigen, pv: prostate volume, ipss: international prostate symptom score, pmr: post micturion residual volume. table 3. comparison of prostate size, t-psa and testosterone of non diabetic patients with other parameters. prostate size t-psa testosterone parameters correlation (r) p correlation (r) p correlation (r) p age (y) 0.255* 0.000 0.060 0.396 -0.215* 0.002 weight (kg) 0.233* 0.001 0.157* 0.026 0.009 0.902 height (cm) 0.078 0.270 -0.041 0.569 -0.037 0.607 bmi (kg/m2) 0.220* 0.002 0.192* 0.006 0.013 0.851 fbs (ng/ml) 0.045 0.529 0.103 0.145 -0.051 0.473 hba1c% 0.109 0.124 0.039 0.582 -0.004 0.955 tg (mg/dl) 0.077 0.281 0.076 0.287 -0.069 0.330 c (mg/dl) -0.001 0.992 -0.005 0.942 -0.052 0.461 tt (ng/ml) -0.042 0.551 -0.166* 0.018 1 t-psa (ng/dl) 0.273* 0.000 1 -0.166* 0.018 pv (ml) 0.273* 0.000 -0.042 0.551 ipss -0.052 0.510 0.155* 0.049 0,030 0.706 uroflow(qmax) -0.176* 0.026 -0.017 0.832 -0.059 0.459 pmr (ml) -0.054 0.496 0.015 0.853 -0.043 0.585 * statistically significant; – negative correlation. bmi: body mass index, fbs: fasting blood glucose, tg: triglycerides, c: cholesterol; tt: total testosterone, psa: prostate specific antigen, pv: prostate volume, ipss: international prostate symptom score, pmr: post micturion residual volume. ozcan_stesura seveso 04/04/17 09:09 pagina 28 29archivio italiano di urologia e andrologia 2017; 89, 1 benign prostate hyperplasia in diabetic and non diabetic patients we also observed that dm affects the functional components of low urinary tract system. the post micturition residual volume and the symptom score evaluated with ipss were quite higher in diabetic patients suggesting detrusor impairment (33) which is very frequent in diabetic patients. the distinction between luts secondary to dm and luts secondary to bph is difficult to distinguish. altough both irritative and obstructive symptoms are prevalant in diabetic patients the bothersome of irritative symptoms are more common in patients with 39%-61% of them having some degree of frequency and urgency (34, 35). there are many mechanisms proposed to associate the development of low urinary tract symptoms in diabetic patients. firstly, hyperinsulinemia associated with increased sympathetic activity via enhanced glucose metabolism in ventromedial hypothalamic neurons (36) may contribute to an increase in the activation of the alfa adrenergic pathway with contraction of smooth muscle of the urinary tract contributing to the development of luts. this concept was studied ın the rat model by mcvary et al. who observed an association between autonomic neural input to the prostate and the prostatic growth rate whereas the absence of this input resulted in regression of the gland volume (37). in this study, we observed that in diabetic patients the tt levels are lower than non diabetic counterparts. altough bph is known as an androgen dependent disease this finding may indicate that development of disease is not only depend on tt but on many various hormonal and local growth factor interactions. a study by rohrmann et al. (38) including 260 individuals from nhanes iii reported that elevated estrogen levels and molar estradiol/testosterone ratios as well as lower androstanediol glucuronide (a metabolite of dihydroxytestosterone [dht]) levels were associated with greater luts risk. a direct correlation was found by schatzl et al. (39) between elevated estradiol levels and prostatic volume determined by trus. there are number of studies with contradictory findings to indicate that the regulation and impact of sex hormones on prostatic growth and bph is quite complex (40). conclusions we have presented an association between dm and increased prostate volume indicating that dm is an important factor for static component of bph/luts. furthermore we demonstrated association between dynamic components of bph and diabetes. peak urinary flow rate was lower and post micturonal residual volume was higher in diabetic group indicating diabetes is associated with not only static components but also with dynamic components of bph/luts. further evaluations of the association between diabetes and bph with larger populations are warranted. references 1. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984; 132:474-9. 2. lee c, kozlowski jm, grayhack jt. etiology of benign prostatic hyperplasia. urol clin north am. 1995; 22:237-46. 3. donnell rf. benign prostate hyperplasia: a review of the year’s progress from bench to clinic. curr opin urol. 2011; 21:22-6. 4. partin aw, oesterling je, epstein ji, et al. influence of age and endocrine factors on the volume of benign prostatic hyperplasia. j urol. 1991; 145:405-409. 5. hammarsten j, hogstedt b, holthuis n, mellstrom d. components of the metabolic syndrome risk factors for the development of benign prostatic hyperplasia.prostate cancer prostatic dis. 1998; 1:157-162. 6. michel mc, mehlburger l, schumacher h, et al. effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. j urol. 2000; 163:1725-1729. 7. boon ta, van venrooij ge, eckhardt md. effect of diabetes mellitus on lower urinary tract symptoms and dysfunction inpatients with benign prostatic hyperplasia. curr urol rep. 2001; 2:297-301. 8. mongiu ak, mcvary kt. lower urinary tract symptoms, benign prostatic hyperplasia and obesity curr urol rep. 2009; 10:247-53. 9. hammarsten j, damber je, karlsson m, et al. insulin and free oestradiol are independent risk factors for benign prostatic hyperplasia.prostate cancer prostatic dis. 2009; 12:160-5. 10. nandeesha h, koner bc, dorairajan ln, sen sk. hyperinsu linemia and dyslipidemia in non-diabetic benign prostatic hyperplasia. clin chim acta. 2006; 370:89 93. 11. mcvary k. lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. bju int. 2006; 2:23-8. 12. ozden c, ozdal ol, urgancioglu g, et al. the correlation between metabolic syndrome and prostatic growth in patients with benign prostatic hyperplasia. eur urol. 2007; 51:199-203. 13. hammarsten j, högstedt b. hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. eur urol. 2001; 39: 151-8. 14. joseph ma, harlow sd, wei jt, et al. risk factors for lower urinary tract symptoms in a populationbased sample of africanamerican men. am j epidemiol. 2003; 157:906-14. 15. laven ba, orsini n, andersson so, et al. birth weight, abdominal obesity and the risk of lower urinary tract symptoms in a population based study of swedish men. j urol. 2008; 179:1891-5. 16. becker s, dossus l, kaaks r. obesity related hyperinsulinaemia and hyperglycaemia and cancer development. arch physiol biochem 2009; 115:86-96. 17. kogai ma, lutov uv, selyatitskaya vg. hormonal and biochemical parameters of metabolic syndrome in male patients with body weight excess and obesity. bull exp biol med. 2008; 146:806-8. 18.giovannucci e, rimm eb, chute cg, et al. obesity and benign prostatic hyperplasia am j epidemiolo 1994; 140:989-1002. 19. abdollah f, briganti a, suardi n, et al. metabolic syndrome and benign prostatic hyperplasia: evidence of a potential relationship, hypothesized etiology, and prevention korean j urol. 2011; 52:507516. 20. ansari ma, begum d, islam f. serum sex steroids, gonadotrophins and sex hormone-binding globulin in prostatic hyperplasia. ann saudi med. 2008; 28:174-8. 21. roberts ro, jacobson dj, rhodes t, et al. serum sex hormones and measures of benign prostatic hyperplasia. prostate. 2004; 61:124-31. 22. bourke jb, griffin jp. hypertension, diabetes mellitus,and blood groups in benign prostatic hypertrophy br j urol. 1966; 38:18-23. ozcan_stesura seveso 04/04/17 09:09 pagina 29 archivio italiano di urologia e andrologia 2017; 89, 1 l. ozcan, h. besiroglu, m. dursun, e. can polat, a. otunctemur, e. ozbek 30 23. safarinejad mr. prevalence of benign prostatic hyperplasia in a population-based study in iranian men 40 years old or older int urol nephrol. 2008; 40:921-931. 24. sarma av, burke jp, jacobson dj, et al. associations between diabetes and clinical markers of benign prostatic hyperplasia among community-dwelling black and white men. diabetes care. 2008; 31:476-482. 25. peehl dm, cohen p, rosenfeld rg. the insulin-like growth factor system in the prostate world j urol. 1995; 13:306-311. 26. zhang j, hess mw, thurnher m, et al. human prostatic smooth muscle cells in culture: estradiol enhances expression of smooth muscle cell-specific markers prostate. 1997; 30:117-129. 27. gregory cw, kim d, ye p, et al. androgen receptor up-regulates insulin-like growth factor binding protein-5 (igfbp-5) expression in a human prostate cancer xenograft endocrinology. 1999; 140:2372-2381. 28. vikram a, tripathi dn, ramarao p, jena gb. intervention of d-glucose ameliorates the toxicity of streptozotocin in accessory sex organs of rat. toxicol appl pharmacol. 2008; 226:84-93. 29. ikeda k, wada y, foster he jr, et al. experimental diabetesinduced regression of the rat prostate is associated with an increased expression of transforming growth factor-beta. j urol. 2000; 164:180-5. 30. kim wt, yun sj, choi yd, et al. j korean med sci. 2011; 26:1214-8 31. parsons jk, carter hb, partin aw, et al. metabolic factors associated with benign prostatic hyperplasia. j clin endocrinol metab. 2006; 91:2562-8. 32. vikram a, jena gb, ramarao p. increased cell proliferation and contractility of prostate in insulin resistant rats: linking hyperinsulinemia with benign prostate hyperplasia. prostate. 2010; 70:79-89. 33. michel mc, mehlburger l, schumacher h, et al. effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. j urol 2000; 163:1725-1729. 34. kaplan sa, te ae, blaivas jg. urodynamic findings in patients with diabetic cystopathy j urol. 1995; 153:342-344. 35. brown js, wessells h, chancellor mb. urologic complications of diabetes diabetes care. 2005; 28:177-185. 36. landsberg l. diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. q j med. 1986; 61:1081-90. 37. mcvary kt, razzaq a, lee c, et al. growth of the rat prostate gland is facilitated by the autonomic nervous system. biol reprod. 1994; 51:99-107. 38. rohrmann s, nelson wg, rifai n, et al. serum sex steroid hormones and lower urinary tract symptoms in third national health and nutrition examination survey (nhanes iii). urology. 2007; 69:708-13. 39. schatzl g, brossner c, schmid s, et al. endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function, the prostate study group of the austrian society of urology. urology. 2000; 55:397402. 40. gann ph, hennekens ch, longcope c, et al. a prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia. prostate. 1995; 26:40-9. correspondence levent ozcan, md (corresponding author) drleventozcan@yahoo.com derince training and research hospital, department of urology, kocaeli, turkey huseyin besiroglu, md emre can polat, md alper otunctemur, md emin ozbek, md okmeydani training and research hospital, department of urology, istanbul, turkey murat dursun, md bahcelievler state hospital, department of urology, istanbul, turkey ozcan_stesura seveso 04/04/17 09:09 pagina 30 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 2150 case report malignant priapism due to penile metastases: case series and literature review francesco de luca 1, evangelos zacharakis 2, majed shabbir 2, angela maurizi 3, emy manzi 4, antonio zanghì 5, carlo de dominicis 3, david ralph 1 1 st peter's andrology and the insitute of urology, university college london hospital, london, uk; 2 department of urology, guy’s hospital, kings college london, uk; 3 department of gynecologic-obstetric sciences and urological sciences, sapienza university of rome, rome, italy; 4 department of general surgery and organ transplantation sapienza university of rome, rome, italy; 5 general surgery and breast unit, department of surgery university of catania, catania, italy. malignant priapism secondary to penile metastases is a rare condition. this term was originally used by peacock in 1938 to describe a condition of painful induration and erection of the penis due to metastatic infiltration by a neoplasm. in the current literature there are 512 case reports. the primary tumor sites are bladder, prostate and rectum. the treatment has only palliative intent and consists of local tumor excision, penectomy, radiotherapy and chemotherapy. we present one case of malignant priapism originated from prostate cancer, and two from urothelial carcinoma of the bladder. different approaches in diagnosis and therapy were performed. the entire three patient reported a relief of the pain following the treatment, with an improvement of their quality of life, even though it was only temporary as a palliative. malignant priapism is a rare medical emergency. penile/pelvis magnetic resonance imaging (mri) scan and corporal biopsies are considered an effective method of diagnosis of the primary organ site. key words: priapism; tumour; metastases. submitted 19 october 2015; accepted 8 december 2015 summary no conflict of interest declared. with gleason score 9 (4+5). as a result of his prostatectomy and radiation therapy he developed erectile dysfunction which was well responding to alprostradil 20 micrograms. two years postoperatively the patient was admitted to a&e with 8-week history of persistent and painful erection. on clinical examination the penis was tender and some nodules and warts were noted along the penile shaft and glans. the penile and pelvic mri scan showed that both corpora cavernosa had severe fibrosis with thickening of the tunica and urethra throughout. the glans appeared abnormal with a number of exophitic lesions arising from it. numerous bony metastases were also seen within the inferior pubic ramus and pubic symphysis and in the right acetabulum. a recurrent disease was noted at the level of the vescicourethral anastomosis. a computed tomography (ct) total body scan confirmed several small metastatic nodules within the lungs. the bone scan showed osteoblastic metastases in the lumbar spine and pelvis. in order to confirm the diagnosis a glans wedge biopsy and multiple trucut biopsies of both corpora were performed. the final histopathology report showed extensive infiltration by metastatic prostatic adenocarcinoma composed mainly of fused acinar structures (equivalent to gleason 4 pattern) with focal lymphovascular and perineural invasion. after multidisciplinary team meeting discussion, he was offered a penile palliative radiotherapy and a pudendal nerve block to alleviate his pain and hormonal therapy. case 2: a 48 year old patient underwent radical cystoprostatectomy with extended lymph node dissection and formation of an ileal conduit for urothelial bladder carcinoma (pt4a pn0). a month later the patient was readmitted with 7 days history of ischemic priapism, refractory to primary treatment and t shunt. during the t shunt bilateral corporal biopsies were obtained and confirmed the presence of recurrence of primary disease. following the multi disciplinary team meeting outcome the patient was offered a palliative penectomy followed by adjuvant chemotherapy. a palliative radical penectomy with formation of perineal urethrostomy was performed. the final histological report showed extensive infiltration along the entire length of the penis, the feadoi: 10.4081/aiua.2016.2.150 introduction malignant priapism secondary to penile metastases is a rare condition. this term was originally used by peacock in 1938 to describe a condition of painful induration and erection of the penis due to infiltration by metastatic neoplasm. clinical manifestations of penile metastasis are priapism, painful or painless palpable penile nodules, swelling, haematuria and urinary retention. in the current literature there are 512 case reports. the primary tumor sites are usually the bladder, prostate and rectum. the treatment has only palliative intent and consists of hormone therapy, chemotherapy, radiotherapy, local tumor excision and penectomy. presentation of case(s) we reported three cases of malignant priapism. case 1: a 62 year old man with diabetes mellitus type ii and a history of prostate cancer underwent laparoscopic radical prostatectomy, followed by salvage radiotherapy. the histopathology report showed advanced disease 151archivio italiano di urologia e andrologia 2016; 88, 2 malignant priapism due to penile metastases: case series and literature review tures are consistent with high grade urothelial carcinoma, with focal sarcomatoid differentiation. case 3: a 72 year old man, with a history of urothelial cell carcinoma of the bladder and concurrent incidental primary rectal adenocarcinoma in april 2008, underwent laparoscopic anterior resection and radical cystectomy with formation of ileal conduit. the bowel histology showed upper rectal g2pt1 n1 disease fully resectedwith no vascular invasion and the bladder histology showed g3pt4a (prostate) n2 disease with extensive vascular invasion. therefore the patient had adjuvant chemotherapy. a ct scan and positron emission tomography (pet) post chemotherapy underlined a new lesion at right lower lobe of the lung. the biopsy of this lesion showed metastatic urothelial cancer. one year postoperatively the patient was admitted with a 4 day history of pain in his genitalia. the clinical examination revealed a semi-erect firm glans, with palpable tumour nodules. abdomen mri confirmed the presence of extensive pelvic lymph nodes. the clinical progression of priapism, with excruciating pain non responding to conventional medical therapy and conservative treatment, led to the medical decision for a palliative radical penectomy without any previous corporal biopsies, as the diagnosis of metastatic cancer was clear on the mri scan. discussion to date there are 512 published cases of secondary penile metastasis, as a result of the 118 founded in our pubmed review of 64 published case reports of secondary penile metastasis in the last 10 years (from january 2004 to may 2014) searching for “penile metastasis”, “penile metastases”, “malignant priapism”, “secondary malignancy penis”, plus the 394 cases reviewed by yu-hsiang l. et al. in our review 157(30.6%) patients present metastasis of bladder origin, 152(29.6%) from prostate, 72(14%) recto-sigmoid, 34(6.6%) kidney, 20(3.9%) lower gi (excluding rectosigmoid), 15(2.9%) testis, 13(2.5%) lung, 11(2.1%) upper gi tract, 6(1.1%) bone, 5(0.9%) lymphoma, 4(0.7%) leukemia, 4(0.7%) melanoma, 4(0.7%) upper airways, 3(0.5%) hepatobiliary, 2(0.3%) ureter, 1(0.1%) tongue, 1(0.1%) thyroid, 1(0.1%) seminal vesicle, 1(0.1%) glomangiosarcoma and 6(1.1%) from others origin. the most common clinical signs of penile metastases are, priapism (40%), painful or painless penile nodules (27.5%), swelling (15%) pain (7.5%), haematuria (5%) and urinary retention (5%) (1). the most common ways in which the primary cancer can spread to the penis are; the retrograde venous route due to the vast communication between the pelvic organs and dorsal venous system of the penis; via retrograde lymphatic flow and direct invasion from the close organs with advanced cancer. direct arterial spread is another route, but less common. in our specific case the ischaemic priapism was due to the invasion of malignant cells into the cavernous sinuses blocking the venous draining veins, without blocking the arterial flow (2). according to kendi et al., the mri scan plays an important role in the diagnosis and stadiation (3). however the key point in order to confirm the diagnosis and the primary site of neoplasm is the biopsy of the corpora. penile metastasis is an advanced stage related to a poor prognosis; the treatment is just palliative in order to improve the quality of life and reveal the pain. it could be hormone therapy, chemotherapy, radiotherapy or surgery (shunt or penectomy). the shunt surgery has limited success, especially if the duration of the iscahemic priapism is more than 48 hours. mdt(multidisciplinary team meeting) discussion should always be made for the treatment management in each case. the overall survival is 12 months (range 6-18 months) from the time of the diagnosis. primary site number of cases % bladder 157 30.6 prostate 152 29.6 recto-sigmoid 72 14 kidney 34 6.6 lower gi tract (excluding recto-sigmoid) 20 3.9 testis 15 2.9 lung 13 2.5 upper gi tract 11 2.1 bone 6 1.1 lymphoma 5 0.9 leukemia 4 0.7 melanoma 4 0.7 upper airways 4 0.7 hepatobiliary 3 0.5 ureter 2 0.3 thyroid 1 0.1 tongue 1 0.1 seminal vesicle 1 0.1 glomangiosarcoma 1 0.1 other 6 1.1 total 512 table 1. primary site of penile metastases. figure 1. corpora cavernosa infiltrated by tumor. figure 2. extensive permeation of the vascular channels of the corpus spongiosum and corpus cavernosum by tcc of the bladder. figure 3. evidence of intravascular tumour thrombi. archivio italiano di urologia e andrologia 2016; 88, 2 f. de luca, e. zacharakis, m. shabbir, a. maurizi, e. manzi, a. zanghì, c. de dominicis, d. ralph 152 conclusion malignant priapism is a rare event. the most frequent primary sites are bladder, prostate and recto-sigmoid. corporal biopsies are considered an effective method of diagnosis of the primary organ site. references 1. lin yh, kim jj, stein nb, khera m. malignant priapism secondary to metastatic prostate cancer: a case report and review of literature. rev urol. 2011; 13:90-4. 2. kumar n, bhattacharyya t, mandal ak, et al. penile metastasis secondary to bladder cancer: a report of two cases. indian j palliat care. 2014; 20:57-60. 3. kendi t, batislam e, basar mm, et al. magnetic resonance imaging (mri) in penile metastases of extragenitourinary cancers. int urol nephrol. 2006; 38:105-9. correspondence francesco de luca, md (corresponding author) francescodeluca10@gmail.com david ralph, md dralph@andrology.co.uk st peter's andrology and the insitute of urology university college london hospital, london, uk evangelos zacharakis, md evangelos.zacharakis@doctors.org.uk department of urology, guy’s hospital kings college london, uk majed shabbir, md majedshabbir@hotmail.com department of urology, guy’s hospital kings college london, uk angela maurizi, md angmau81@hotmail.com carlo de dominicis, md carlo.dedominicis@uniroma1.it department of gynecologic-obstetric sciences and urological sciences sapienza university of rome, rome, italy emy manzi, md emymanzi@hotmail.it department of general surgery and organ transplantation sapienza university of rome, rome, italy antonio zanghì, md amzanghi@unict.it general surgery and breast unit, department of surgery university of catania, catania, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 114 original paper light-emitting diode exposure enhances sperm motility in men with and without asthenospermia: preliminary results nader salama 1, mohamed el-sawy 2 1 departments of urology and 2 clinical pathology, alexandria faculty of medicine, alexandria, egypt. objective: to evaluate the effect of lightemitting diode (led) on sperm motility in men with and without asthenospermia. material and methods: semen samples from 27 men were assessed and washed. an aliquot was taken from each sample as a control. the remaining amount was exposed to red led for 2, 5 and 10 minutes. sperm motility from the test and control tubes were re-checked at the end of each time interval. in 11 of these 27 samples, the same protocol was repeated without sperm washing. evaluation of sperm creatine kinase (ck) activity, hypoosmotic swelling (hos) test and aniline blue staining (anbs) were undertaken after phototherapy in additional 15 samples. results: progressive sperm motility increased significantly after led treatment at the different time intervals whether in washed (p = 0.000) or non-washed (p = 0.003) samples. the amount of the increase in motility in washed aliquots was significantly more (p = 0.000) than in naive semen. sperm ck activity increased, but was not significant whilst there were no changes regarding hos and anbs. conclusion: red led is a promising safe tool to boost sperm motility in vitro. this may have a great implication on maximizing the possibilities and outcomes of intrauterine insemination trials. key words: sperm; motility; light-emitting diode. submitted 15 november 2014; accepted 31 december 2014 summary no conflict of interest declared. ization can occur. asthenospermia or abnormal motility is, therefore, a common etiology of infertility in the male. it may be presented as an isolated anomaly or in combination with other sperm parameter defects in 19% and 63% of patients, respectively (5). treatment of asthenospermia has in the past involved an in-vivo approach subjecting the patient to either medical treatment (6, 7), varicocelectomy (8) or both. with the recent advent of assisted reproductive techniques (art), enhancement of sperm motility has progressed by other means. the enhancement is done as an in-vitro process (9) using some enrichment media with or without motility-improving agents like platelet activating factor (10). improvement in sperm motility is essential for a good outcome of some of these arts like intrauterine insemination (iui) (11). to have a good ranked motility, the sperm has to have a well-developed and functional tail which is the basic tool for sperm motility. in its proximal part, the tail is marked out by the mitochondrial sheath. mitochondria have the highest amount of chromophores within the cell, particularly the cytochrome of electron transport chain (12). mitochondria are able to absorb the photon energy due to this rich chromophores content (13). the absorbed photon energy can be utilized in the adenosine triphosphate (atp) production necessary for the cellular physiological processes like sperm motility (13). photodynamic treatment is the application of light to stimulate photosensitizers which can be present as cellular components or introduced as exogenous matter. lightemitting diode (led), which is a complex semiconductor, has recently been introduced as a new option in light therapy. it emits non-coherent light with narrow spectrum using the electric current (14). several studies indicated its efficiency in treating numerous medical disorders. examples include wound healing (15), pain soothing (16) and allergic and inflammatory skin disorders (17). this impressing effect of the led was attributed to its photobiomodulating effect. however, no studies so far have investigated the led effect on human sperm. the objective of the current study was, therefore, to study any possible effect of the led on the human sperm motility in men with and without asthenospermia using several time points of light exposure. doi: 10.4081/aiua.2015.1.14 introduction recently, there has been increasing public concern over the likelihood of reduction in human fertility and semen quality (1). extensive epidemiological studies reported a clinically relevant range of current infertility rates between 5-15% (2). male factor infertility represents about 40-50% of etiologies of human infertility (3). semen quality is considered as a good marker of success to achieve pregnancy (4). sperm motility is one important parameter which can define sperm quality. it is an important prerequisite for fertilization. a good sperm motility ensures effective swimming in the female genital tract until reaching the sperm’s final destination which is the ovum where fertilsalama_stesura seveso 02/04/15 10:15 pagina 14 15archivio italiano di urologia e andrologia 2015; 87, 1 led and sperm motility material and methods semen samples twenty-seven consecutive patients gave semen samples, between january and march 2014, during evaluation of their fertility status at the andrology clinic, department of urology, alexandria faculty of medicine. exclusion criteria included men with a history of azoospermia, intake of recreational drugs, use of medications which may adversely affect the testis or any systemic disease as diabetes. each patient collected his semen into a sterile plastic container by masturbation without any lubricants after 3-5 days of sexual abstinence. semen stayed at the incubator (37º c) for 30 minutes to allow liquefaction. a computer-aided sperm analysis (casa) automatic system (sperm class analyser sca gii, barcelona, spain) checked immediately semen parameters based on who criteria, version v (18). the check-up of semen included evaluation of semen volume, sperm count/ml, percentage motility in its different grades (pr: progressive, npr: non-progressive, im: immotile) and percentage normal sperm forms. each patient gave consent to use his semen sample for research purposes. the departmental review board gave approval for the protocol of the study. sperm preparation an aliquot (200 µl) was taken from each semen sample and underwent centrifugation (400 x g, 10 minutes) at room temperature to separate seminal plasma. the supernatant was discarded and the resulting pellet was re-suspended in 1 ml ham’s f-10 culture medium (irvine scientific, santa ana, ca), and the tube contents were thoroughly mixed. the sperm suspension was distributed equally between 2 glass sterile tubes (bd bioscience, usa), one tube represented the control (c1) and the other tube was assigned to receive the light treatment (irradiated tube, number 1 or rt1). in the lastly recruited 11 patients, an extra step was taken. an aliquot of the naïve semen (800 µl) was taken from each sample before the separation of seminal plasma. these aliquots did not undergo the previous sperm preparation. instead, they were distributed equally between 2 tubes, one represented the control (c2) and the other tube received the light treatment (irradiated tubes, number 2 or rt2). this extra step was done to verify the real impact of light exposure on sperm motility as the washing medium, ham’s f-10, in this experiment, is well-known about its antioxidant effect and may indirectly affect sperm motility (19). in addition, we aimed to report the most promising circumstances to get the maximal effect of led on sperm motility. exposure to led and sperm motility analysis all tubes settled in a dark room. the rt1 and rt2 were exposed to a red led source (wavelength 636.6-nm, total output power 1.3 w) which was kept at 5-cm distance. at each time point light exposure (2, 5 and 10 minutes), an aliquot of sperm suspension inside the rt1 and c1 tubes were subjected to the assessment of sperm motility. accordingly, the irradiation energy imposed on the sperm tubes were calculated to be 496 mj/cm2, 1.241 j/cm2 & 2.482 j/cm2 for the 2, 5 and 10 minutes of light exposure. the chosen time points of light exposure were previously used by other researchers (20, 21). in the last 11 samples, the naïve semen tubes (rt2 and c2) were treated in the same way. casa involved checking the tracks of at least 200 motile sperms each tube. supplementary studies a. determination of sperm creatine kinase (ck) activity free energy released from hydrolysis of atp is required for sperm motility. the ck activity is regarded as an indicator of the rate of atp synthesis in sperm (22). we hypothesized that, sperm ck activity would be altered under led treatment. therefore, it would be useful to check the validity of this hypothesis to explain any possible mechanism behind the changes occurring in the sperm motility after the application of the led treatment. this step was expedited through studying the sperm ck levels after 5-minute phototherapy. we selected this time point because our early observations identified that led-enhancing effect on sperm motility was maximal at that time point and any changes in sperm ck would be augmented and detected at ease. semen samples from another 7 consecutive patients were collected at the end of the current study. the samples were treated without washing as previously described. reagents were purchased from sigma aldrich. ck concentrations were assayed as previously described (23). in brief, an aliquot of naïve semen (100 µl) was taken from the tubes (rt 2 and c2) at the time point 5 min of the experimental procedure. the aliquots (100 µl) were washed with cold imidazole buffer (0.03 m imidazole and 0.15 m na cl, ph 7.0) at a volume/volume of 1: 15. the tubes were centrifuged at 500 x g for 10 minutes. the supernatant per each tube was removed. the remaining pellet was resuspended in a 0.1% triton x-100 solution with the help of strong vortexing for 20 seconds. the tube was centrifuged again for 10 minutes at 500 x g. the supernatant was retrieved and checked for ck activity by spectrophotometry using a ck kit. the ck activity was expressed in international units/106 sperms. b. examination of sperm membrane integrity to check for the safety of the sperm-led treatment, the sperm membrane integrity was checked by the hypoosmotic swelling (hos) test (24). the same 7 semen samples described above were used. after the maximum duration of led treatment used in the present study (10 minutes), 100 µl from rt2 was mixed with 1.0 ml of the hypoosmotic buffer (1.35 g of fructose and 0.73 g of sodium citrate.2 h2o in 100 ml of distilled water). the mixture was incubated in a 5% co2 incubator, at 37º c for 2 hours. the control samples (c2) were also included. the sperms were observed under 400 x magnification. two hundred spermatozoa were analyzed in each sample. percentage of sperms having curled tails was calculated. c. evaluation of sperm head chromatin condensation this was done for further confirmation of the safety of our treatment after the maximal duration of light treatment (10 minutes). it was accomplished using aniline blue staining (anbs) method (25). eight new and consecutive semen samples were pooled during august 2014. they were treated without washing with led for salama_stesura seveso 02/04/15 10:15 pagina 15 archivio italiano di urologia e andrologia 2015; 87, 1 nader salama, mohamed el-sawy 16 10 min, as previously described. smears were taken from these samples, air-dried and fixed in 3% glutaraldehyde in phosphate-buffered saline for 30 min. then, they were stained in 5% aqueous aniline blue solution (ph 3.5) for 5 min. the controls were included. if the sperm head does not hold condensed chromatin, it stains blue, but if not it does not pick up the stain. the percentage of stained sperms were calculated by assessing 200 sperms, and 25% was taken as the cutoff point (25). 2.5. statistical analysis the study data were expressed as mean ± s.d. the data were examined using spss statistical software for windows release 16 (spss inc., chicago, usa). the impact of led phototherapy on sperm motility, ck activity, anbs and membrane integrity was studied using the wilcoxon-singed ranked test. the effect of the duration of the led exposure on the sperm motility was studied using one-way anova with tukey post-hoc test. we also arranged the semen samples into 2 groups. the first group included samples with isolated asthenospermia while the second group consisted of those with normal semen parameters. the size of the increase in percentage sperm pr motility was calculated as the difference between initial motility once the samples were received and that percentage at the end of each time point of the study. a comparison between the size of the increase in this motility at the different time points for asthenospermia and normal semen groups was made by the mann-whitney test. the same test was also used to compare between percentage normal sperm forms of the 2 groups. p-value < 0.05 was considered significant. results semen parameters all the initial 27 patients had normal sperm count (42.4 x 106/ml ± 13.98). sperm motility was normal in 9 (33%) but low in 18 (67%) patients. the normal sperm forms in either group had normal percentage (≥ 4%) but significant difference could be seen between both (16.6% ± 2.2 for the normal motility group vs 12.5% ± 2.8 for the asthenospermic group, p = 0.002). effect of led exposure on sperm motility in washed samples the led irradiation induced significant increase in sperm motility at the different (2, 5 and 10 minutes) time points of the study, as demonstrated by the increase in pr sperm category (figure 1). this increase went parallel with a significant decrease in im sperm category (table 1). the pr motility showed a rising trend at the 5-minute time point compared with that of the 2-minute point. however, the difference between both time points was not significant (p = 0.39). then, this rising trend started to decline to be significantly lower at the 10-minute point compared with that of the 5-minute point (p = 0.000). this behavior of the led-associated pr motility was in contrast to the corresponding pattern in absence of led treatment. in the latter case, the pr motility progressively declined with time (figure 1). response to led exposure in relation to the presence/absence of asthenospermia initially, the 2 sample groups (asthensopermic and normal) in the present study had significant differences in between in relation to the pr and im sperm motility (table 2). after light application, enhancement of sperm motility was found in both types. however, the size of this enhancement for pr motility was significantly higher in the normal semen samples than that in the asthenospermic samples at the 2-minute point only (figure 2). non-washed sperm samples these samples showed the same behavior as the washed ones on the led irradiation. there were significant increases in pr motility at the different time points (table 3). the increase in pr motility reached also its peak after the 5table 1. the changes in percentage (mean ± sd) npr and im washed sperms at the different time points (n = 27)*. study time point before led therapy after led therapy p-value* 2 minutes 74.1 ± 9.4 62.2 ± 12.8 0.000 5 minutes 78.1 ± 9.5 56.8 ± 12.01 0.000 10 minutes 81.1 ± 10.99 71.5 ± 12.4 0.000 * wilcoxon-singed ranked test. figure 1. pr motile sperms (washed samples) before and after the led phototherapy at the different time points of the study. *p-value = 0.000 (wilcoxon-singed ranked test) table 2. initial motility (%) in the 2 groups of the study semen samples (n = 27). motility grade asthenospermia group normal semen group p-value* pr 23.4 ± 5.03 40.9 ± 5.7 0.000 npr 21 ± 6.5 22.8 ± 9.4 0.68 im 55.6 ± 9.1 36.3 ± 9.5 0.000 * mann-whitney test. salama_stesura seveso 02/04/15 10:15 pagina 16 17archivio italiano di urologia e andrologia 2015; 87, 1 led and sperm motility minute light exposure, although this rise was not significantly higher than the rise happening after 2 minutes (p = 0.85). then, the pr motility dropped significantly (p = 0.01) after that on arriving at the 10-minute point. these enhancements in pr motility were also associated with a significant drop in im sperms (table 3). the size of the increase in pr motility in non-washed samples were significantly lower than those of the washed samples (table 4). supplementary studies a slight increase in sperm ck activity after 5-minute led treatment was detected as compared to that of the control samples (7.9 ± 4.7 vs 7.4 ± 4.7 unit/106 sperms, p = 0.61). both the sperm membrane integrity and head chromatin condensation remained stable after the treatment for 10 minutes as the hos test did not show notable changes (58.4% ± 13.2 (before) vs 59.2% ± 18.8 (after), p = 0.61), and also the anbs (86.5% ± 6.3 (before) vs 85.8 % ± 6.7 (after), p = 0.5). discussion the present work is an in-vitro study which investigated the effect of red led exposure on the sperm motility in semen samples pooled from men with and without asthenospermia. the retrieved data indicated that exposure to red led induced a significant improvement in sperm motility. to the best of our knowledge, this is the first report presenting an investigational evidence for the enhancing impact of red led on human sperm motility. the current data come in line with the previous workers who also showed enhanced sperm motility after treatment of semen samples with low level laser (9, 20, 21). good motility with the ability of forward progression is an essential element to ensure the sperm successful trip inside the female genital tract and achieve its final objective for fertilization. poor sperm motility or asthenospermia is a common cause of male factor infertility. it is implicated as a possible causative factor in up to 82% of these cases (5). it is diagnosed when there is pr < 32% or total motility < 40% (18). a cell holds several components which contain chromophores. mitochondria may be the most important of these components containing the highest concentration of chromophores inside the cell, particularly the cytochrome of electron transport chain. mitochondria are, therefore, able to absorb the photon energy due to its rich chromophores content (13). photons with wavelength 655-nm are mainly absorbed by cytochrome a/a3 inside the cell (26) with production of atp, which can be used in the physiological processes within the cell. in sperm, the mitochondria activity is closely linked to the sperm motility. this occurs through the mitochondria-generated energy (27, 28). the red led-enhancing effects on sperm motility, in the present study, are suggested to be related to an increase in the level of net energy available for sperm motility. this energy was agitated after absorption of the ledassociated photon energy and its interaction with the chromophores contained within sperm mitochondria. in support of this speculation, the level of the sperm ck activity, in the enrolled semen samples, showed an increase although insignificant after led treatment for only 5 minutes. recent studies considered the activity of sperm ck as an indicator of the rate of atp synthesis in sperm (22). extension of the current work to include more semen samples and treat them with more powerful led for longer duration may change this insignificant ck level; giving a clear clue about the real figure 2. the size of the increase in pr sperm motility (washed samples) after the led application for the different time points in the 2 study groups (asthenospermia & normal). p-value: +0.035, ++0.135, +++0.179 (mann-whitney test was done between each bar in the asthenospermia type & its correspondent bar in the normal type). table 3. the changes in the motility % (mean ± sd) of the different grades during the study at the different time points for non-washed samples (n = 11) *. table 4. the size of the increase in pr motility (%) with and without washing of the sperm samples *. study time point/grade before led therapy after led therapy p-value* 2 minutes/ pr 23.6 ± 8.7 27.7 ± 8.9 0.003 npr 21.2 ± 7.2 21.2 ± 5.8 0.52 im 56.1 ± 9.5 51.1 ± 9.95 0.014 5 minutes/ pr 22.7 ± 10.3 31.3 ± 7.8 0.003 npr 17.4 ± 7 15.7 ± 5.4 0.128 im 59.9 ± 10.4 52.3 ± 7.6 0.008 10 minutes/ pr 19.5 ± 11.3 22.9 ± 10 0.003 npr 19.2 ± 8.7 17 ± 5.9 0.065 im 60.4 ± 10.5 60.1 ± 9.7 0.86 * wilcoxon-singed ranked test. time point non-washed samples washed samples p-value 2 min. 4.1 ± 1.97 12.3 ± 6.6 0.000 5 min. 9.3 ± 2.8 21 ± 8.8 0.000 10 min. 4.4 ± 1.9 11.8 ± 4.8 0.000 * mann-whitney test. salama_stesura seveso 02/04/15 10:15 pagina 17 archivio italiano di urologia e andrologia 2015; 87, 1 nader salama, mohamed el-sawy 18 role of the enzyme during led treatment. the led-augmenting effect on motility can also be attributed to the change in the level of calcium inside the sperm cell after exposure to led (29). calcium is an essential element to trigger sperm motility (30). future research is highly recommended to address the exact mechanism explaining the motility-enhancing red led effect on sperm motility. intrauterine insemination (iui) is considered as the most cost-effective and first-line treatment of moderate cases of male infertility (31). one important prognostic marker to achieve a good result with iui is the availability of processed total motile sperm count of > 10 million (11). the success of iui may be questioned if this motile sperm count is < 10 million. men who does not fulfill such sperm count will not be suitable candidates for iui. the motile sperm count must be considered before deciding to proceed with iui. in the present study, the significant enhancement in sperm motility after the led phototherapy can help improving the iui prerequisites, and unsuitable candidates for the insemination procedure may change to suitable ones. sperm treatment with led can be, therefore, an alternative to medical/surgical treatment of asthenospermia which still have nonencouraging results in several patients after waiting for many months (32, 33). in this study, sperm motility decreased significantly after 10 minutes of the phototherapy. this may attract attention to the power and energy densities of the currently used led. both may not be enough to generate more atp production to sustain the improved motility noticed at 5-minute exposure. the led phototherapy has a definite role in enhancing sperm motility as is shown by the improvement noticed while applying led into naïve semen samples. however, there was a significant difference in the size of the increase in motility grades between samples with processed sperms versus naïve semen. two lines of evidence were present, which may contribute to this difference. first, centrifugation of semen helped discarding seminal plasma. this means: a) no semen viscidity which may hinder sperm motility. b) a significant decline in the level of sperm-associated reactive oxygen species (ros) which have a detrimental effect on sperm motility (34). second, the use of cell culture medium, the ham’s f10 which is a well-known potent antioxidant (19) opposing the sperm-associated ros. in the present study, most sperm samples (67%) had poor motility, but they showed good response to led therapy. this may go in line with the suggestion that the effects of photodynamic therapy like that delivered by low-level laser therapy will be striking if applied to stressed cells (35). the current data, at the same time, revealed that sperm samples with good motility had significantly more motility enhancement than those with low motility. this may be attributed to the presence of significantly more normal sperm forms in semen samples with good motility as compared to those samples with asthenospermia. previous reports indicated that anomalies in mid-piece may be associated with variable degree of mitochondrial dysfunction and low membrane potential which affect sperm motility (36). thanks to the novel work of nasa and outstanding effort of nichia chemical in japan, led has been introduced into our daily life with tremendous applications. led treatment in the current study has several advantages compared to laser. in addition to its cheaper costs, it has a large planar array which can help application to a large area containing many cells at the same time and in a hand-free manner. this is in contrast to laser which is applied in a pointed manner which would limit the treatment to a certain small area with limited number of targeted cells (37). in the present study, we have been using a red led with a wavelength 636.6-nm and total power 1.3 w. the selection of this led with such criteria came by the merest chance as we do not have any access to consultation facilities about led especially from physics and engineering points of view. however, we think that this random selection of this kind of led was suitable as it was well absorbed by the sperm mitochondrial chromophores giving a good photobiological response. it was also a safe procedure as the hos test and anbs did not show any remarkable changes until 10 minute application; indicating a steady sperm membrane integrity and chromatin condensation. as the biological response to phototherapy is wavelength-dependant at equal doses (35), we do not know the potential response of sperm to led therapy with different wavelengths, power and energy densities. therefore, an extension of the current work to include these variables will be the only avenue to provide suitable answers. the current study is a preliminary report. some limitations are, of course, present in it. the sperm motility parameters were not checked. one of these parameters is straightness, which may show how much the sperm motility is effective which in turn can save energy (20). however, both who manual (38) and eshre guidelines devised by the andrology special interest group (39) did not give any recommendation on which of the sperm motility kinematic parameters should be calculated because of its biological importance. in addition, there is no standardized mathematical algorithm to compute these sperm kinematics, which can be used by the different casa machines (38, 39). another limitation was the lack of follow-up checks on motility beyond 10-minute irradiation to establish how long the led-enhancing effect would continue. this may be an important point during the iui procedure. a last limitation was that we checked the sperm atp, hos and head chromatin condensation in a non-integrated way using a relatively small number of patients. this was due to our financial shortage. however, our chromatin condensation and hos results come in accordance with other investigators (9, 20). conclusion the results of this in vitro study may have practical implications for those involved in assisted reproductive techniques. we could reveal for the first time that treating sperm with red led could safely enhance its motility; especially if preceded with sperm processing. results from this pilot study should be corroborated in larger studies with a detailed investigation on the effect of red led treatment on sperm quality and functional characteristics. salama_stesura seveso 02/04/15 10:15 pagina 18 19archivio italiano di urologia e andrologia 2015; 87, 1 led and sperm motility references 1. joffe m. 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correspondence nader salama, md (corresponding author) nadersalama58@yahoo.com department of urology, alexandria faculty of medicine, alexandria, egypt mohamed el-sawy, md elsawymohamed@gmail.com department of clinical pathology, alexandria faculty of medicine, alexandria, egypt salama_stesura seveso 02/04/15 10:15 pagina 19 stesura seveso 185archivio italiano di urologia e andrologia 2015; 87, 3 original paper benign prostatic hyperplasia – an economic assessment of fixed combination therapy based on a literature review roberto messina 1, vincenzo mirone 2 1 national chairman, federanziani senior italia, italy; 2 general secretary of siu – italian urology society. federanziani senior italia and siu – italian society of urology – have decided to work together to draft a document focussing on benign prostatic hyperplasia (bph), and to stress the importance of adherence with pharmacological treatment in this setting, from both a scientific and a patient standpoint. starting from a literature search, the two associations analysed to what extent an increase in treatment adherence amongst these patients influences hospital savings and to what extent therapy persistence levels are affected by monotherapy rather than free drug combinations. these estimates were performed only on patients taking medicinal products belonging to the 5 α-reductase inhibitors (5ari) class that, although not indispensable, are the compounds that bring the greatest benefits, especially in the elderly and for which we know that every additional 30 days of therapy reduced the likelihood of acute urinary retention (aur) and surgery by 14% and 11% respectively *. the results show that the use of fixed combination therapy would involve an increase in persistence due to the lower rate of patients abandoning treatment over time. each 30 day-increment of 5ari therapy, i.e. for an expenditure of 10.6 million euros extra per year for 5ari medication, savings of approximately 24.3 million euros in hospital costs could be achieved. key words: benign prostatic hyperplasia; alpha blockers; 5ari drugs; fixed combination drugs; therapy adherence/ persistence; acute urinary retention (aur); lower urinary tract symptoms (luts). submitted 14 july 2015; accepted 31 july 2015 summary no conflict of interest declared. patient’s therapy persistence.the elderly consume more healthcare services than younger people and consequently require special attention in that they have special needs. these needs are quite simply the result of various factors that can include the physiological changes that take place during life, the possibility of developing several diseases, the fact that the over-65 age class is often neglected in the development of new types of medicinal product and, last but not least, the complicated management, in everyday life, of the use of medicinal products. this latter factor can be caused by polydrug use, which, unless it is appropriately managed is likely to become a potential risk factor for poor adherence with the treatments prescribed. as a solution to the polypharmacy issue, the world health organisation suggests the development and implementation of fixed dose combinations (fdc), which would help reduce the number of pills taken by the individual patients and consequently improve treatment adherence (3). a literature search performed on a sample of 75 further literature reviews revealed how treatment adherence is the most recurrent condition for a better use of medicinal products. the other measures taken to improve adherence also include simplifying the ways in which medicinal products are taken, intended as combining the various active ingredients in the same drug (fdc fixed dose combination) (4, 5). amongst the other cases of non-adherence, the saba strategic advisory board on adherence, like the who and aifa (italian medicines agency), identified the complexity deriving from polytherapy/appropriate therapy as an area of intervention for the simplification of treatments and therapeutic continuity (6). it would therefore appear to be a paradigm recognised by the entire scientific community that a greater number of medicinal products taken is related to poorer treatment adherence (7), especially in elderly patients with cognitive impairment. another study shows that patients taking one tablet a day have an optimum adherence of 80%, a percentage that drops rapidly if subjects need to take more than one drug or need to take the same drug several times a day; if we consider that this value drops to 50% for medicinal products taken 4 times a day, it is easy to postulate that 75% of all patients and 50% of chronic patients are doi: 10.4081/aiua.2015.3.185 introduction treatment non-adherence can have a strong impact on health costs and on the success of the pharmacologic treatment (1). whereas in italy and the rest of europe there are currently no studies on what could be the value in terms of savings obtained by better treatment adherence, in the united states it has been estimated that it may be as much as 100 billion dollars (2). the aim of this paper is to start to overcome this lack of information by proposing, in the urological setting, an economic evaluation of treatment adherence, focussing on benign prostatic hyperplasia (bph) and highlighting the positive impact that fixed combination therapy may have on a messina_stesura seveso 23/09/15 12:28 pagina 185 archivio italiano di urologia e andrologia 2015; 87, 3 r. messina, v. mirone 186 unable to follow the treatment regimen prescribed (2, 8). federanziani senior italia involved agenzia italiana del farmaco (italian medicines agency) (aifa), federazione italiana dei medici di medicina generale (italian federation of general practitioners) and federfarma in drawing up a joint document on the importance of treatment adherence in today’s society: “aderenza alla terapia: leva per la salute e la sostenibilità nel futuro” (treatment adherence: a lever for health and sustainability in the future) (9). this document identifies treatment adherence, especially when appropriate, as the first step towards a global management of patients by the main players in the healthcare supply chain: doctors, pharmacists, patients and institutions. “federanziani is firmly convinced that we need to use all possible strategies to solve the problem of poor treatment adherence” (r. messina, chairman of federanziani senior italia). it is not merely patient associations such as federanziani senior italia that are sensitive to these issues, other associations, such as some pharmacists’ associations, also believe that “patient management is a priority objective of pharmacy: accompanying patients throughout their treatment programme improves treatment adherence by chronic patients. greater adherence with therapy means more health for citizens and a better use of the public and private resources available, thereby avoiding relapses and restricting the number of re-admissions” (annarosa racca, chair of federfarma) or that “for some time now, treatment adherence has been the main front in improving the population’s health conditions and the sustainability of health services. our profession has taken this pathway by implementing field trials studying how pharmacists can assist patients and general practitioners and promoting training on all levels” (andrea mandelli, chairman of fofi federation of italian pharmacists associations). for general practitioners “generating significant growth in treatment adherence” means “increasing the efficacy of community treatment for citizens’ health” [giacomo milillo, national secretary of the fimmg federazione italiana dei medici di medicina generale (italian general practitioners federation)]. as regards treatment adherence, the ministry of health states that the elderly are “scared they will forget to take their medicines” (marcella marletta, director general of the ministry of health’s medical devices and pharmaceutical service). materials and methods this paper evaluates to what extent a one-month increase in persistence in bph can weigh in economic terms. the analysis is conducted on 5 α-reductase inhibitors (5aris) alone as they are the drivers of poor adherence and for the reduction in hospitalisation, in this area of urology. to do so, the authors first attempted to perform a literature review, where it would appear that most articles agreed in highlighting the importance of fixed combinations for adherence to treatment. secondly, an economic evaluation of the cost of bph patients in italy was obtained by multiplying the condition’s prevalence rate for the various age ranges by the absolute number of male inhabitants of italy in 2014 (most recent istat data available). the total number of patients was then multiplied by those seeking treatment (55%) (10) and, of these, those who are effectively treated (78% of those seeking treatment) (11). the number of males not on treatment was estimated by subtraction. table 1 summarises the results of this first investigation. compared to the total number of people being treated, we know from the pharmaceutical market (13) that the drug prescription percentages are 65% for alpha blockers (abs), 20.11% for 5aris and 14.9% for free combinations; therefore, by dividing the absolute number of patients treated per age range with these percentages, we obtain the exact number of subjects taking a given type of medicinal product. in order to understand the economic value related to hospital admissions for bph, we calculated the hospitalisation rate without surgery of those taking 5ari as both monotherapy (23.6 every 1,000 patients) and combination therapy (17.5 every 1,000 patients), and the hospitalisation rate with surgery (23.4 every 1,000 patients for 5ari monotherapy and 17.3 every 1,000 patients for free combinations (14). by estimating an average cost for both surgical drgs of € 3, 126 and non-surgical diagnosis-related groups (drg) of € 1,788 (15), we estimated the hospital cost for patients treated with 5ari as both monoand combination therapy (ct), as being equal to 200.9 million euros (table 2). by weighing the economic value of one-month’s consumption of 5ari in italy, by multiplying this value by the total number of those taking 5aris in italy, it was possible to estimate the total cost of one month therapy with this type of products. the main results of this analysis are provided below. age range prevalence % males in italy prevalence of bph patients seeking treatment patients treated not treated 35-44 0.6% 4,534,581 27,207 14,964 11,672 3,292 45-54 4.5% 4,742,341 213,405 117,373 91,551 25,822 55-64 20.0% 3,699,097 739,819 406,901 317,383 89,518 65-74 42.0% 3,067,166 1,288,210 708,515 552,642 155,873 75-84 51.6% 2,008,867 1,036,575 570,116 444,691 125,426 >=85 50.3% 601,001 302,304 166,267 129,688 36,579 tot 18,653,053 3,607,521 1,984,136 1,547,626 436,510 source: authors’ processing of data provided by thales (10), geodemo (11), spatafora et al. (12). table 1. bph epidemiological situation – italy 2014. messina_stesura seveso 23/09/15 12:28 pagina 186 187archivio italiano di urologia e andrologia 2015; 87, 3 benign prostatic hyperplasia – an economic assessment of fixed combination therapy based on a literature review results literature agrees in stating that the prevalence for bph increases with age, and consequently the number of subjects affected is on the increase due to the ageing of the population (15, 17, 18). however, the number of subjects in whom bph becomes symptomatic, i.e. it actually causes discomfort, is approximately half. environmental components have been excluded from the condition’s aetiology, and it is thought that a role may be played by hereditary factors, given the increased risk amongst the family members of subjects affected by the condition (19). as is the case for all chronic illnesses, bph treatment warrants the best results when taken constantly. the patient does not usually perceive the gradual improvements made possible by therapy as, from a subjective point of view, the disease is only considered resolved once urinary symptoms have improved. this is one of the causes, possibly the most important, of the poor persistence of treatment in bph therapy (19, 20). 66% of patients with bph in italy present comorbidities and consequently are treated with a number of various drugs (21). lower urinary tract symptoms (luts) determine a gradual impairment in quality of life (social relationships, leisure activities and relations with partners); however, less than 50% of men with luts visit their doctor, in general the first consultation of men with their doctor occurs about two years before the manifestations of symptoms, the main reasons for this being: lack of knowledge about prevention (22), embarrassment when talking about symptoms, the idea that these symptoms are “normal” and the fear of surgery (10, 19). this patient reluctance calls for a pro-active approach by the doctor in identifying patients with luts secondary to bph, although doctors often tend to consider bph more a “syndrome” than a chronic invalidating condition (23). the european d-impact study, which also involved italy, showed that approximately 3 out of 4 patients with lower urinary tract symptoms (luts) who go to their general practitioners practice have an enlarged prostate. men presenting with a greatly enlarged prostate are more likely to develop acute urinary retention (aur) and undergo surgery than subjects with a smaller prostate (23). bph also has a very high social and health-related impact: bph is responsible for over 68 thousand hospital admissions per year; 35,000 of which undergo full surgery, whereas more than 32 thousand are merely admitted (24). in italy, bph accounts for over 320 million euros spent for pharmacological treatment and 74,834 days off work (19). the most recent osmed report (for 2014) indicates that the majority of patients (approximately 70%) are treated with alpha blockers that have a prevalently symptomatic action and do not affect the natural history of the underlying condition. approximately one third of patients is treated with 5aris, which by reducing the volume of the prostate, can affect the mechanisms underlying bph and reduce disease progression and related complications. the greater prescription of alpha blockers is presumably due to the fact that the patient hopes to resolve the symptoms as quickly as possible (25). according to current treatment options, approximately one fifth of symptomatic patients who go to their doctor will experience a gradual progression of symptoms and related discomfort with a consequent increased need for admission for surgery or emergency department/day hospital appointments for the introduction of a catheter to resolve situations of aur (19). in order to obtain a maximum benefit from pharmacological therapy, all the most important guidelines recommend, particularly in patients with a greater risk of disease progression, the use of a combination of an alpha blocker and a 5ari (18, 26, 27). to provide further support to the above, we can quote the study analysing the prescription of drugs for bph and the corresponding hospitalisation rates for luts. the results showed that over the years in which the study was conducted (2004-2008) ab and 5ari prescriptions dropped, whereas prescriptions for ct increased by 5.4%. over the same period, both medical and surgical hospitalisation rates, per 1000 patients, related to bph dropped, showing a greater reduction for medical drgs than surgical ones from 4.9% in 2004 to 3.6% in 2008 and 5.5% in 2004 to 5.1% in 2008, respectively. this shows that the use of fixed combinations would appear to be more efficient in age range cost of non-surgical hospitalisation x 1,000 (aur*) cost of surgical hospitalisation x 1,000** tot 5ari ct tot 5ari ct tot 35-44 € 319 € 236 € 555 € 551 € 409 € 960 € 1,514,889 45-54 € 2,500 € 1,852 € 4,353 € 4,325 € 3,205 € 7,530 € 11,882,225 55-64 € 8,667 € 6,422 € 15,089 € 14,994 € 11,109 € 26,103 € 41,192,505 65-74 € 15,092 € 11,182 € 26,274 € 26,108 € 19,344 € 45,452 € 71,726,405 75-84 € 12,144 € 8,998 € 21,142 € 21,008 € 15,565 € 36,574 € 57,715,622 85 and over € 3,542 € 2,624 € 6,166 € 6,127 € 4,539 € 10,666 € 16,831,998 tot € 42,264 € 31,315 € 73,579 € 73,113 € 54,171 € 127,285 € 200,863,644 * aur → icd9cm 788.20 acute urinary retention; icd9cm 599.6 urinary obstruction. ** bph-related surgery → icd9cm 57.0 bladder stone or blood clot drainage; icd9cm 57.91 endoscopic incision of the neck of the bladder; icd9cm 57.94 bladder catheterisation; icd9cm 60.21 transurethral prostate ablation procedure; icd9cm 60.29 transurethral prostate resection procedure; icd9cm 60.3 adenomectomy: icd9cm 60.4 adenomectomy source: author’s processing of data from spatafora (10), thales (11), geodemo (12), ims (13), arno 2013 (15), nonis m. et al. (16]). table 2. cost of admission per type of treatment subdivided by age range. values expressed in euros. messina_stesura seveso 23/09/15 12:28 pagina 187 archivio italiano di urologia e andrologia 2015; 87, 3 r. messina, v. mirone 188 the treatment of bph-related complications (28). in general, bph treatment persistence is approximately 30% per year; this is related, on one hand, as mentioned previously, to patients’ tendency to discontinue treatment and, on the other, to doctors’ general trend of not recommending continuous chronic therapy and not monitoring bph appropriately over time (29). in one recent study on patients with newly diagnosed bph, it was observed that most patients suspended their bph therapy early: about one third of patients discontinued treatment after 3 months, and 64% in one year. there are a number of reasons why patients suspend medication early: some because they felt better, some due to a lack of efficacy on symptoms, others due to the side effects (19). it goes without saying that an early discontinuation of therapy does not make it possible to obtain and maintain all the benefits for which it was prescribed. it is interesting to note that in the 36% of patients who took medication for more than one year, the authors suggested they had a good relationship with their doctor, thanks to which patients were well informed about the risk factors of bph progression (increased prostate volume and high psa levels). this may have meant that patients took their condition more seriously and took the treatment for a longer period. the various treatments available for this condition achieved different adherence levels in the different patients taking them (19). one italian study conducted on a sample of 1.5 million male patients with bph analyses the effects that monotherapy and free combination therapy (concomitant taking of two tablets) have on treatment persistence. the study states that, although the alpha blocker-5ari combination is beneficial in the treatment of bph in terms of both control over symptoms and disease evolution, in real life the persistence of patients treated for bph varies according to the medicinal product taken: in particular, it was seen that patients treated with free combinations abandon therapy more frequently than patients treated with monotherapy. the same study group showed, in a previous study, that the shares of patients who continued taking treatment in the subsequent 12 months were 35%, 18% and 9% respectively for alpha blockers, 5aris and free combination therapy. as mentioned previously, on average 29% of patients continues therapy for at least one year. these percentages dropped in the subsequent 5 years to 15%, 8% and 3% respectively, i.e. 13% overall (30). at equal conditions, there is an increase in adherence in the switch from extemporaneous combination (2 tablets) to monotherapy (1 tablet) in a potential 9%-26% range in the first year and 5%-12% in the fifth year (30). the assumptions that are considered from here on show an improvement in both economic terms and treatment persistent terms that would be gained if fixed combination therapy were introduced instead of treatment with free combinations (3). it is plausible to suppose that the added value of fixed combination therapy is 2-fold: the increase in adherence obtained with the alpha blocker (35%), which acts on symptoms; the overall efficacy of 5aris (18% adherence). 5aris achieve a lower hospitalisation rate but also poorer adherence; alpha blockers have a higher level of adherence because, as said previously, they are symptomatic but also have a higher hospitalisation rate; whereas ct (free combinations) show intermediate hospitalisation rates compared to those for abs and 5aris, but also low adherence levels as they bring together a number of different medicinal products and therefore the patient abandons therapy more quickly (29). in the knowledge that every 30 extra days of 5ari treatments reduce the probability of the onset of acute urinary retention and need for surgery by 14% and 11% respectively, thereby reducing health care costs by 15% (31), by estimating the cost of one month’s treatment with 5ari in italy (13), for both free combination therapy or monotherapy, the savings obtained by using therapy for this condition for 30 extra days were calculated. 30 extra days of treatment with 5aris cost the system 10.6 million euros. it is therefore possible to postulate that with a one-month increase in therapy, in one year it is possible to save approximately € 24.3 million. this sum is calculated using the 14% reduction applied to the cost of non-surgical hospitalisations and the 11% reduction applied to the cost of surgical hospitalisations. conclusions literature shows that combination therapies can improve adherence levels and therefore reduce the medical costs of relapses. however, given the lack of studies on this topic, it is extremely difficult to estimate to what extent these combinations would have a positive impact on any increase in adherence. in this study, the authors merely quantified the savings obtained with 30 days of extra treatment with 5aris in one year, when administered both in combination and as monotherapy. a number of critical aspects of the management of patients with bph were also observed: these undoubtedly included patient empowerment, a correct and updated training to healthcare professionals, intented as both urologists and general practioners practitioners, that can contribute to the development of an appropriate pathway along which to guide patients. the authors performed projections using data from countries whose healthcare systems have different characteristics, as well as different intrinsic characteristics of the populations analysed (habits, lifestyle, diet). the estimates presented in this paper were calculated using the hospital expenditure for patients taking medication, a measurable estimate. however, it is possible to postulate that medical expenditure and the corresponding savings are greater due to the health costs incurred for patients not taking medication, but that in any case have to be hospitalised for complications related to their condition and that cannot therefore be included in the analyses. furthermore, in order to simplify the analyses, the paper only considered the market shares of alpha blockers, 5aris and free combinations; all other types of drugs were intentionally excluded as the lion’s share of the market is occu(3) the fixed dose combination dutasteride-tamsulosina has already been developed and as a consequence it would help to increase adherence to therapy and provide cost savings to the national healthcare system. however this combination is very low used in italy due to the lack of the main condition for its use, that is reimbursement. messina_stesura seveso 23/09/15 12:28 pagina 188 pied by these three product types. the authors hope that the method used in this study can pave the way for the development of further studies with the aim of analysing the positive economic implications related to the correct use of medicinal products, not just in urological settings. references * oelke m, becher k, castro-diaz d, et al. appropriateness of oral drugs for long-term treatment of lower urinary tract symptoms in older persons: results of a systematic literature review and international consensus validation process (luts-forta 2014). age ageing. 2015 jun 23. pii: afv077. 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25 marzo 2015 http://www. cortegiustiziapopolare.it/ 20. koh js, cho kj, kim hs, kim jc. twelve-month medication persistence in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. j clin pract. 2014; 68:197-202. 21. hutchinson a. hutchinson a, farmer r, et al. characteristics of patients presenting with luts bph in six european countries, european urology 2006; 50:555-562. 22. the bph survey: a male perspective. market research undertaken by kantar healthcare, an independent market research company that specialises in medical and pharmaceutical studies; summer 2011; 1,161 men over 50 years of age across france, germany, italy, spain and the united kingdom completed an online survey as part of the national health and wellness survey. data on file. 23. carballido j, fourcade r, pagliarulo a, et al. can benign prostatic hyperplasia be indentified in the primary care setting using only simple tests? results of the diagnosis improvement in primary care trial, int j clin pract. 2011; 65:989-96. 24. ministero della salute rapporto sdo (schede di dimissione ospedaliera) 2013. 25. osservatorio nazionale sull’impiego dei medicinali, l’uso dei farmaci in italia, rapporto nazionale 2013, roma: agenzia italiana del farmaco, 2014. 26. siu società italiana di urologia: decalogo sull’utilizzo dei 5ari nella pratica clinica: nuove evidenze e indicazioni utili, pubblicato il 03/07/2012, http://www.siu.it/news/display/266. 27. füllhasea c, chappleb c, cornuc j-n, et al. systematic review of combination drug therapy for non-neurogenic male lower urinary tract symptoms. eur urol. 2013; 64:228-43.. 28. cindolo, et al. actual medical management of lower urinary tract symptoms related to benign prostatic hyperplasia: temporal trends of prescription and hospitalization rates over 5 years in a large population of italian men. springer science + business media dordrecht 2013. 29. cindolo l, pirozzi l, fanizza c, et al. drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. eur urol. 2014; 20. pii: s0302-2838(14)01180-4. 30. cindolo, et al. patient’s adherence on pharmacological therapy for benign prostatic hyperplasia (bph)-associated lower urinary tract symptoms (luts) is different: is combination therapy better than monotherapy?. 31. eaddy m1, kruep e, lunacsek o, goodwin b. establishing the clinical and economic benefits of adherence to 5-alpha reductase inhibitors in benign prostatic hyperplasia: an assessment of medicare and medicaid patients. expert opin pharmacother. 2012; 13:2593-600. 189archivio italiano di urologia e andrologia 2015; 87, 3 benign prostatic hyperplasia – an economic assessment of fixed combination therapy based on a literature review correspondence roberto messina (corresponding author) segreteria.presidenza@federanziani.it national chairman, federanziani senior italia, italy vincenzo mirone, md, professor mirone@unina.it general secretary of siu – italian urology society, italy messina_stesura seveso 23/09/15 12:28 pagina 189 171archivio italiano di urologia e andrologia 2016; 88, 3 original paper a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts is able to improve sexual quality of life in patient with premature ejaculation salvatore sansalone 1, giorgio ivan russo 2, nicola mondaini 3, francesco cantiello 4, gabriele antonini 5, tommaso cai 6 1 department of experimental medicine and surgery, university tor vergata, rome, italy; 2 department of urology, university of catania, catania, italy; 3 urologic unit, santa maria annunziata hospital, bagno a ripoli, florence, italy; 4 urology unit, magna graecia university of catanzaro, italy; 5 department of urology, "sapienza" rome university, rome, italy; 6 department of urology, santa chiara regional hospital, trento, italy. objective: the management of patient affected by premature ejaculation (pe) is nowadays not highly satisfactory. here, we aimed to evaluate the tolerability and efficacy of a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts in order to improve sexual quality of life in patients with premature ejaculation. materials and methods: all patients attending to 5 urological centers from january 2015 to march 2015, due to premature ejaculation were enrolled in this study. at the enrolment visit, all subjects underwent self-administered iief-5, male sexual health questionnaire-ejaculation disorder (mshqejd), pedt and ielts (calculated as mean from that perceived by partner and that perceived by patient) and underwent urological visit and laboratory examinations. all patients received one tablet per day of a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts for 3 months (group a). after 3 months all patients underwent follow-up visit with the same investigations that have been carried out in the enrolment visit. the results were compared with a cohort of patients enrolled in the same period in another urological center and considered as a control group (group b). all patients in the control group underwent counseling and sexual behavioral treatment without any pharmacological compound. results: at the follow-up analysis, significant changes in terms of ielt in the group a (mean difference: 31.90; p < 0.05) at 3 months and versus group b at the intergroup analysis (mean difference: 30.30; p < 0.05) were reported. in the group a, significant differences from baseline to last follow-up were observed relative to iief-5 (mean difference: 1.04; p < 0.05), pedt (mean difference: -2.57; p < 0.05) and fsh (mean difference: -16.46; p < 0.05). conclusion: in conclusion, patients affected by pe may significantly benefit from oral therapy with a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts in terms of ielt and pedt scores improvement. key words: premature ejaculation; erectile dysfunction; tryptophan; satureja montana; tribulus terrestris; phyllanthus emblica. submitted 9 november 2015; accepted 4 december 2015 summary no conflict of interest declared. introduction over the past 30 years, the premature ejaculation (pe) treatment paradigm, which previously limited to behavioral psychotherapy, has expanded to include drug treatment (1). dapoxetine (priligy, johnson & johnson, new brunswick, nj) is the first and the only product licensed for the treatment of pe in men aged 18-64 years, and it belongs to a class of drugs called selective serotonin reuptake inhibitors (ssris), which are frequently used to treat depression (2-4). across trials, receiving dapoxetine 30 and 60 mg were well tolerated with a low incidence of adverse events (aes) (2). the most common aes were those typically accompanied with ssris agents, and the symptoms were mild (2). furthermore, although treatment with marketed ssris had been associated with sexual dysfunctions and suicide attempts, there were no reports on sexual dysfunctions or suicide events as well as suicide attempts in these 5 rcts (5-6). however, there were limited available data about using dapoxetine for a long time. phytotherapeutics should be an interesting option because of their generally low side effects and high acceptance by the patients. we focused our attention on some compounds that may be useful for the treatment of pe. tryptophan is an interesting phytotherapeutic compound. 5-hydroxytryptophan (5-htp) is the intermediate metabolite of the essential amino acid l-tryptophan in the biosynthesis of serotonin (7-8). the role of serotonin in the ejaculation control is well known and the well demonstrated (9-10). moreover, 5-htp is well absorbed from an oral dose, with about 70% was found in the bloodstream (11). furthermore, 5-ht showed a good pharmacological profile with good efficacy and appeared to be better tolerated than ssris (12). on the other hand, satureja montana (winter savory) is a medicinal plant traditionally used to treat different disorders including male sexual dysfunction (13). recently, zavatti et al. found that satureja montana is able to delay ejaculation latency without exerting any negative effect on the other parameters of sexual behavior and without exerting a sedative effect (13). finally, the role of phyllanthus emblica. chebulagic doi: 10.4081/aiua.2016.3.171 sansalone_stesura seveso 21/09/16 08:39 pagina 171 archivio italiano di urologia e andrologia 2016; 88, 3 s. sansalone, g.i. russo, n. mondaini, f. cantiello, g. antonini, t. cai 172 acid, the major constituent of phyllanthus emblica, is a benzopyran tannin compound with various kinds of medicinal potentials including improvement of male sexual dysfunction (14-15). in fact, chebulagic acid is able to inhibit rho-kinase 2 and may be useful in management of erectile dysfunction (14). here, we aim to evaluate the tolerability and efficacy of a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts (eiacumev®) in order to improve sexual quality of life in patients with premature ejaculation. patients and methods study design all patients attending to 5 urological centers from january 2015 to march 2015, due to premature ejaculation were enrolled in this study. at the enrolment visit, all subjects underwent self-administered iief-5, male sexual health questionnaire-ejaculation disorder (mshq-ejd), pedt and ielts and underwent urological visit and laboratory examinations. the ielt has been calculated as mean from that perceived by partner (ppielt) and that perceived by patient (ielt). all patients underwent preliminary assessment including a detailed medical and sexual history to evaluate the presence of underlined risk factors such as infections or diabetes mellitus. all patients received one tablet per day of a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts for 3 months (group a). after 3 months all patients underwent follow-up visit with the same investigations that have been carried out in the enrolment visit. the results were compared with a cohort of patients enrolled in the same period in another urological center and considered as a control group (group b). all patients in the control group underwent counseling and sexual behavioral treatment without any pharmacological compound. all subjects gave written informed consent before entering the study, which was conducted in accordance with the declaration of helsinki. inclusion and exclusion criteria the primary inclusion criteria were age ≥ 18 years of age and in a stable monogamous relationship for ≥ 6 months were eligible if they met the dsm-iv-tr criteria for pe for ≥ 6 months, indicated at least moderate pe-related distress or interpersonal difficulty, and reported an ielt of ≤ 2 min in ≥ 75% of evaluable events during a 4-wk screening/baseline period. exclusion criteria were as follows: any medical treatment for sexual dysfunction before or during the study, congenital or acquired penile curvature or chordee with hypospadias, age > 75 years, hypogonadism (total testosterone level < 8 nmol or serum testosterone in the range of 8-11 nm and free testosterone < 220 pmol, assessed at least on two occasions). to be able to exclude organic sexual dysfunctions and other underlying illnesses, fasting blood glucose level, urinalysis, complete blood count, sex hormones, and prolactin levels were measured. all measurements were conducted by a single physician unaware of the treatment status. moreover, all patients with erectile dysfunction (a reported iief-15-efd score ≤ 21) were excluded, as suggested by salonia (16). questionnaires and urological examinations sexual health was evaluated using available validated instruments for the study of erectile function (inter national index of erectile function-15 erectile function domain [iief-15-efd]) (17) and ejaculatory status (pedt) (18). in order to exclude all patients with lifelong pe, a careful urological visit with disease history collection has been performed at the arrival at each centre, as suggested by jannini et al. (19). moreover, the male sexual health questionnaire-ejaculation disorder (mshq-ejd) was also used to evaluate the ejaculation function (20). assignment to the groups all patients were assigned to each group on the basis of the attending center. all patients attending to 5 centers (rome 2 centers, catania, florence, catanzaro) were assigned to group a, while all patients attending another center (trento) were assigned to group b (controls). the study design is displayed in figure 1. group a the first group received one tablet orally a day for 3 months and one tablet consisted of 300 mg of satureya figure 1. the figure shows the study design schedule. sansalone_stesura seveso 21/09/16 08:39 pagina 172 montana, tribulus terrestris, phyllanthus emblica, cardamomo, l-tryptophan, ascorbic acid, vitamin pp, vitamin b1, vitamin b6 (eiacumev®, farmaceutica mev, siena, italy). we monitored adverse events on the light of common terminology criteria for adverse events (ctcae) guidelines. safety assessments included treatment-emergent adverse events (teaes), serious aes (saes), and orthostatic vital signs (blood pressure and heart rate). group b all patients in the control group underwent counseling and sexual behavioral treatment without any pharmacological compound. the counseling and sexual behavioral treatment has been carried out in collaboration with a dedicated psychologist, as commonly in our routinely clinical practice. the sexual counseling and psychotherapy has been performed in line with the suggestions of rowland and cooper (21). main outcome measures the primary end point was stopwatch-measured ielt (held by the partner), reported for each intercourse episode. secondary outcomes were the change from baseline to end point of mshq-ejd, iief-5 and pedt. statistical analysis and study population as null hypothesis, we assumed there would be no difference in terms of mean ielt score, between the two groups. a sample size of 60 subjects per treatment group provided 90% power (two-sided α = 0.05), to detect a 30 seconds difference in mean ielt between patients and controls. the maximum sample size was set to 70 subjects per group, allowing for a 15% dropout rate. at baseline, the independent sample 2-tailed t-test was used to compare variables. for categorical parameters, chisquare test was applied. changes from baseline to end of therapy were analyzed using ranked one-way analysis of variance (anova) with a term for treatment group. data were reported as means ± standard deviation (sd). for all statistical comparisons, significance was considered as p < 0.05. all reported p-values are two-sided. all statistical analyses were performed by using spss 11.0 for apple-macintosh (spss, inc., chicago, illinois). results one hundred and seventy patients were enrolled. fortytwo patients were excluded and 128 patients were finally randomized, 63 and 65 subjects in the group a and in the group b completed the study protocol. the flow chart of this study is presented in figure 2. baseline characteristics all anamnestic, clinical, and questionnaires characteristics of all enrolled patient are displayed in table 1. 173archivio italiano di urologia e andrologia 2016; 88, 3 premature ejaculation and phytotherapy approach group a group b no. of patients 63 65 age (yr), mean ± sd 32.03 ± 8.68 35.37 ± 8.81 bmi (kg/m2), mean ± sd 26.36 ± 3.0 25.2 ± 3.5 lh, mean ± sd 87.96 ± 56.92 86.76 ± 55.43 fsh, mean ± sd 57.00 ± 37.29 54.61 ± 35.70 total testosterone, mean 6.89 ± 3.87 7.01 ± 3.02 smoking habit, n (%) 25 (39.68) 26 (36.92) iief-5, mean ± sd 27.31 ± 2.86 27.71 ± 3.77 pedt, mean ± sd 13.82 ± 2.79 14.05 ± 2.54 ielt (sec), mean ± sd 54 ± 17.76 52 ± 18.82 ejq, mean ± sd 14.89 ± 1.07 15.01 ± 1.35 psv, mean ± sd 31.52 ± 6.60 30.02 ± 5.56 edv, mean ± sd 1.5 ± 1.0 1.2 ± 2.0 bmi = body mass index; iief-ef = international index of erectile function-erectile function; iief-is = international index of erectile function-intercourse satisfaction; iiefof = international index of erectile function-orgasmic function; iief-sd = international index of erectile function-sexual desire; iief-os = international index of erectile function-overall satisfaction; mshs-ejd = male sexual health questionnaireejaculation disorder; sqol-m = sexual quality of life instrument for men; psv = peak systolic velocity; edv = end diastolic velocity. table 1. baseline characteristics of patients enrolled. figure 2. the figure shows the study flow chart in accordance to the consort guidelines. sansalone_stesura seveso 21/09/16 08:39 pagina 173 archivio italiano di urologia e andrologia 2016; 88, 3 s. sansalone, g.i. russo, n. mondaini, f. cantiello, g. antonini, t. cai 174 follow-up examination the table 2 lists the mean change differences from baseline to 3 months relative to main outcome measures. when concerning the primary endpoint of this study, we observed significant changes of the iielt in the group a (mean difference: 31.90; p < 0.05) at 3 months and versus group b at the intergroup analysis (mean difference: 30.30; p < 0.05). in the group a, significant differences from baseline to last follow-up were observed relative to iief-5 (mean difference: 1.04; p < 0.05), pedt (mean difference: -2.57; p < 0.05) and fsh (mean difference: -16.46; p < 0.05). significant differences were found at the intergroup analysis when considering previous outcome measures (table 2; figure 3). when considering serum tt and msh-ejd, both groups did not show any difference after 3 months. adverse events all subjects included in the study protocol, tolerated the treatments and none reported adverse events. discussion even if pe is one of the most common sexual dysfunctions among young male patients and in spite of the increasing interest in pe in the field of sexual medicine, a highly satisfactory treatment in terms of efficacy and safety is still needing (22). for these reasons, even if the preferred management of pe is on-demand dapoxetine, many urologists used other treatment options in 35% of the initial treatment cases and 50% of the second-line treatment cases (23). here, we demonstrated that the use of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts is able to improve the patient’s ejaculatory control, with a higher ielt and higher level of quality of life. moreover, we demonstrated a high level of treatment compliance, probably due to the low frequency of adverse events and the efficacy of the treatment in terms of ejaculatory control improvement. the results of our study are probably due to synergic efficacy of satureja montana and tryptophan. it is really difgroup a group b lh, mean ± sd 12.72 ± 60.07 10.50 ± 55.00 fsh, mean ± sd -16.46 ± 37.42 a, b 2.52 ± 5.76 total testosterone, mean 1.55 ± 10.93 1.23 ± 9.81 iief-5, mean ± sd 1.04 ± 1.67 a 0.31 ± 0.87 pedt, mean ± sd -2.57 ± 2.38 a, b -1.03 ± 2.45 ielt (sec), mean ± sd 31.90 ± 45.68 a, b 1.60 ± 9.81 ejq, mean ± sd -0.015 ± 0.65 0.02 ± 0.89 a p < 0.05 vs. baseline; b p < 0.05 vs. group b. table 2. mean changes from baseline to 3 months for primary and secondary outcomes. figure 3. the figure shows the significant differences found at the intergroup analysis (group a) when considering outcome measures. v0: enrolment time; v1: follow-up visit (at 3 months from the treatment starting). iief-ef = international index of erectile function-erectile function; mshs-ejd = male sexual health questionnaireejaculation disorder; pedt = premature ejaculation diagnostic tool; ielts = intravaginal ejaculatory latency time: calculated as mean form partner and patient perceived ielt. sansalone_stesura seveso 21/09/16 08:39 pagina 174 ficult to evaluate the efficacy of each single compound on the pe improvement. several authors demonstrated that serotonin may be associated with physical health as well as mood (24) and, in particular, in healthy people with high trait irritability, tryptophan, relative to placebo, decreased quarrelsome behaviors, increased agreeable behaviors and improved mood (25). nonpharmacologic methods of raising brain serotonin may not only improve mood, social functioning of healthy people, but would also improve sexual quality of life, improving the ejaculatory control. 5-hydroxytryptophan is the immediate precursor to serotonin and, by acting on 5-ht1a cerebral autoreceptors, spinal 5-ht1b and 5-ht2c receptors, has a determining role on ejaculation. on the other hand, zavatti et al. demonstrated that that the acute administration of satureja montana extract is able to significantly increase the ejaculation latency and reduced the number of intromissions before ejaculation, without affecting the percentage of animals achieving ejaculation (100% in all experimental groups) (13). they hypothesized that the efficacy of satureja montana on premature ejaculation is due to its impact on male sexual behavior (13). however, even if the plants belonging to the genus satureja are traditionally known as aphrodisiac remedy, no study was performed to confirm this property (13, 26). however, even if our results are promising, this study shows several limitations to take into account. firstly, the number of enrolled patients. even if the number need to treat is correctly calculated is very important to highlight that the safety of phytotherapy should be evaluated with a long-term follow-up, in order to discover delayed adverse side effects. moreover, the lack of a long-term follow-up in order to evaluate the long-term efficacy of this compound. conclusion in our study, we demonstrated that patients affected by pe may significantly benefit from oral therapy with tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts by improving ielt, pedt and slightly iief-5. acknowledgements we are grateful to professor john denton (department of modern philology, university of florence) for manuscript language revision. references 1. althof se, mcmahon cg, waldinger md, et al. 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practice patterns in the management of premature ejaculation: a nationwide survey. j sex med. 2008; 5:199-205. 24. young sn. how to increase serotonin in the human brain without drugs. j psychiatry neurosci. 2007; 32:394-399. 25. aan het rot m, moskowitz ds, pinard g, et al. social behaviour and mood in everyday life: effects of tryptophan in quarrelsome individuals. j psychiatry neurosci. 2006; 31:253-62. 26. haeri s, minaie b, amin g, et al. effect of satureja khuzestanica essential oil on male rat fertility. fitoterapia 2006; 77:495-499. correspondence salvatore sansalone, md salvatore.sansalone@yahoo.it department of experimental medicine and surgery, university tor vergata, viale oxford, 81 00133 rome, italy giorgio ivan russo, md department of urology, university of catania, catania, italy nicola mondaini, md urologic unit, santa maria annunziata hospital, bagno a ripoli, florence, italy francesco cantiello, md urology unit, magna graecia university of catanzaro, italy gabriele antonini, md department of urology, "sapienza" rome university, rome, italy tommaso cai, md department of urology, santa chiara regional hospital, trento, italy sansalone_stesura seveso 21/09/16 08:39 pagina 176 archivio italiano di urologia e andrologia 2016; 88, 4284 case report verruciform xanthoma of the penis: a rare benign lesion that simulates carcinoma aldo franco de rose 1, mattia tosi 1, guglielmo mantica 1, nataniele piol 2, carlo toncini 2, carlo terrone 1 1 department of urology, irccs san martino, university of genova, italy; 2 department of pathology, irccs san martino hospital, university of genova, italy. verruciform xanthoma is a rare and benign condition predominantly affecting the oral cavity, but also skin and female anogenital mucosa. it can be flat, papular-warty or crateriform-cystic. furthermore it can simulate hpv viral lesion such as condyloma and malignant neoplasia such as verrucous squamous cell carcinoma. an accurate diagnosis is important to avoid overtreatment, considering it is a benign lesion that does not require any radical treatment. we present an extremely rare case of a 64 year-old man with a small, slighty raised, gray reddish-dotted lesion on the left portion of the ventral side of his glans. key words: verruciform xanthoma; penis. submitted 12 april 2016; accepted 14 april 2016 summary no conflict of interest declared. partner. we decided to perform a radical excision of the lesion as outpatients under local anaesthesia. after standard formalin fixation and paraffin embedding of the specimen, 4 μm sections were cut and stained with hematoxylin-eosin. histopathological examination revealed the presence of acanthosis, hyperkeratosis and parakeratosis, associated with neutrophil exocytosis and with inflammatory infiltrates of large foamy histiocytes at the apex of the dermal papillae (figure 1). histiocyties were highlighted by immunohistochemical staining for cd68 + (figure 2) and for ps100 +, thus confirming the diagnosis of vx. negative immunostaininig for p16 ruled out a possible viral aetiology. we clinically evaluated the patient 3 months after radical excision, no recurrence of the lesion was apparent. doi: 10.4081/aiua.2016.4.284 figure 1. this microphotographs show an hyperplastic epithelium with papillary configuration, acanthosis and hyperparakeratosis associated with neutrophil exocytosis. no epithelial atypia is observed. foamy histiocytes can be seen at the apex of the papillae. figure 2. immunostaining for cd68 pg-m1 highlights foamy histiocytes. introduction verruciform xanthoma (vx) is a rare, benign lesion usually affecting oral mucosa, but also skin and sometimes anogenital mucosa, predilecting females (vulva) rather than males (scrotum, foreskin, etc.) (1). histologically, foamy histiocytes aggregates in the subepithelial stroma or in the papillary dermis in association with verrucous epithelial acanthosis and hyperparakeratosis, are the hallmark of this lesion (2). the extra-oral (cutaneous) occurrence of vx is extremely uncommon with less than few dozen cases reported in literature, most of which occurred on anogenital areas such as vulva and scrotum. penis involvement (foreskin or glans) is even more infrequent with very few cases described in the literature so far (3). we present a rare case of vx localized on the glans. case report a 64 year-old caucasian man, with a silent past medical history, was admitted to our institution with a small, slightly raised, grey reddish-dotted lesion on the left portion of the ventral side of his glans, previously unsuccessfully treated with antibiotic creams, antifungal therapy and antiinflammatory corticosteroid for about one month. no other similar cutaneous, genital or oral lesions were detected upon physical examination and no inguinal lymphadenopathy was present. blood test, particularly lipid profile and serological test for sexual transmitted disease were negative both for the patient and his tosi_stesura seveso 09/01/17 11:32 pagina 284 285archivio italiano di urologia e andrologia 2016; 88, 4 verruciform xanthoma of the penis: a rare benign lesion that simulates carcinoma discussion clinically vx is a flat, raised or pebbled-warty lesion, its color being pink, greyish or yellowish depending on the degree of keratinization. it occurs mostly in adult patients in their fifth to sixth decade of life as an usually single, not sore and well-circumscribed lesion of oral mucosa, but it can also occur on anogenital areas (4). histologically vx is most frequently observed in its papular-warty form, but it has been described, although less frequently, in other architectural pattern such as flat and crateriform-cystic (5). histological features of the lesion are the same independent of architectural pattern and localization. epithelium has elongated rete ridges all extending in the underlying stroma to the same level and sometimes with fusion of their bases. acanthosis, hypogranulosis and hyperparakeratosis are common findings in association with neutrophil exocytosis, especially localized between the stratum corneum and the stratum spinosum. no epithelial atypia nor koilocytosis can be found. subepithelial stroma shows a papillomatous pattern with thin papillae between epithelial ridges, the former with foamy histiocytes which are localized particularly at the apices of the papillae. tlymphocytes e plasma cells, the latter usually as a band-like infiltrate under the level of elongated rete ridges, are usually present (6). vx was described for the first time in 1971 by shafer in its oral localization and in 1979 by santa cruz in extraoral site; particularly vx of penis it was firstly described by kraemer et colleagues in 1981 (7). its etiopathogenesis is still nowadays not entirely known; viral causes having been investigated, and in particular a correlation with hpv infection, because of similar clinical and histological similarities between vx and hpv-related lesions such as condylomata (8-9). a second pathogenetic hypothesis concerns the correlation with lipid disorders, but many patients do not show alterations in their clinical and laboratory exams to support this possibility (10). today the most quoted hypothesis is that vx can have a traumatic pathogenesis, namely keratinocytes disruption due to traumatic injury primes the establishment of an inflammatory status which typically attracts t lymphocytes and neutrophils and later macrophages in order to degrade damaged cellular debris thus becoming foamy histiocytes (10). differential diagnosis includes above all viral (hpv) and malignant lesions (11), vx sharing morphological similarities both with condylomata and with verrucous squamous cell carcinoma. a correct diagnosis is fundamental, especially excluding the possibility of cancer, because vx is a benign lesion that does not require any radical treatment and so any over-treatment should be avoided (12). conclusion recognition of genital vx is important to avoid unnecessary investigations or surgical procedures and to reduce patient’s anxiety. to diagnose vx is essential to perform a biopsy for histoplatologic examination. microscopy features allow for a distinction between vx and squamous cell carcinoma, which is included in its differential diagnosis. the treatment of vx typically involves a simple surgical excision. references 1. mohsin sk, lee mw, amin mb, et al. cutaneous verruciform xanthoma: a report of five cases investigating. am j surg pathol. 1998; 22:479-87. 2. cobb cm, holt r, denys fr. ultrastructural features of the verruciform xanthoma. j oral pathol. 1976; 5:42-52. 3. sinnya s, wheller l, carroll m, et al. verruciform xanthoma of the penis: a rare australian case. australas j dermatol. 2015; 56:99-101. 4. xia tl, li gz, na yq, et al. verruciform xanthoma of the penis: report of a case. chin med j. 2004; 117:150-2. 5. philipsen hp, reichart pa, takata t, et al. verruciform xanthoma: biological profile of 282 oral lesions based on literature and survey with nine new casesfrom japan. oral oncol. 2003; 39:325-36. 6. woo s-b. diseases of the oral mucosa. in: mckee ph, claonje e, granter sr. pathology of the skin with clinical correlations. 3rd ed. volume 1. philadelphia: elsevier mosby, 2005; pp 412-413. 7. kraemer bb, schmidt wa, foucar e, et al. verruciform xanthoma of the penis. arch dermatol. 1981; 117:516-518. 8. khaskhely nm, uezato h, kamiyama t, et al. association of human papilloma virus type 6 with verruciform xanthoma. am. j. dermatopathol. 2000; 22:447-52. 9. rohwedder a, murphy m, carlson fa. multiple human papillomavirus dna identified in verruciform xanthoma by nested polymerase chain reaction with degenerate consensus primers. j. cutan. pathol. 2003; 30:344-6. 10. zegarelli dj, zegarelli-schmidt ec, zegarelli ev. verruciform xanthoma: a clinical, light microscopic and electron microscopic study of two cases. oral surg. 1974; 38:725-34. 11. takiwaki h, yokota m, ashan k, et al. squamous cell carcinoma associated with verruciform xanthoma of the penis. am. j. dermatopathol. 1996; 18:551-4. 12. astori g, lavergne d, benton c, et al. human papillomaviruses are commonly found in normal skin of immunocompetent hosts. actas dermosifiliogr 2008; 99:75-6. correspondence aldo franco de rose, md aldofdr@libero.it mattia tosi, md matti.grifone@hotmail.it guglielmo mantica, md carlo terrone, md department of urology, irccs san martino, university of genova, genova, italy nataniele piol, md carlo toncini, md department of pathology, irccs san martino hospital, university of genova, genova, italy tosi_stesura seveso 09/01/17 11:32 pagina 285 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4270 original paper the adverse influence of spina bifida occulta on the medical treatment outcome of primary monosymptomatic nocturnal enuresis basri cakiroglu 1, tuncay tas 2, seyit erkan eyyupoglu 3, aydın !smet hazar 2, mustafa bahadır can balcı 2, yunus nas 4, fazli yilmazer 4, suleyman hilmi aksoy 5 1 hisar intercontinental hospital, department of urology, umraniye, istanbul, turkey; 2 taksim training and research hospital, department of urology, taksim, istanbul, turkey; 3 amasya training and research hospital, department of urology, amasya, turkey; 4 hisar intercontinental hospital, department of pediatry, umraniye, istanbul; 5 hisar intercontinental hospital, department of radiology, umraniye, istanbul, turkey. objective: previous reports have suggested that the incidence of spina bifida occulta (sbo) in patients with primary monosymptomatic nocturnal enuresis (pmne) is higher than the general population. the purpose of this study was to investigate the effect of spina bifida occulta on the medical treatment outcome of pmne. material and methods: between january 2008 and december 2011, a total of 223 children (151 boys and 72 girls, aged 6-16 years; mean age: 10.1 ± 3.04 years) with pmne were reviewed retrospectively. all of the children underwent physical examination, urine analysis, urinary tract ultrasonography and kidney ureter bladder (kub) scout film. all patients were initially treated with a timed voiding program and were given desmopressin acetate when necessary. results: spina bifida occulta was detected in 75 children (33.6%). spina bifida occulta affected l4 in 2 children, l5 in 6 children, l4-l5 in 3 children, s1 in 52 children, s2 in 7 children and s1-s2 in 2 children. treatment was successful in 79% of the children without sbo, and in only 48% of the children with sbo. medical treatment success rates differed significantly between the study groups. conclusion: the presence of spina bifida occulta significantly affects the response to medical treatment in patients with pmne. thus, verifying spina bifida occulta status in pmne can facilitate prognostic predictions about the response to medical treatment. key words: spina bifida occulta; primary monosymptomatic nocturnal enuresis; children; desmopressin. submitted 15 june 2014; accepted 14 july 2014 summary no conflict of interest declared. decreases to 1-2% above 17 years of age. the spontaneous recovery rate in enuretic patients has been estimated to be 15%/year (1). although many factors have been suggested to play a role in the etiology of enuresis including nocturnal polyuria, sleep disturbances, reduced bladder capacity, detrusor instability and urinary tract infections, the exact cause is still unclear (2, 3). in the absence of any additional lower urinary tract symptoms of, including urgency or daytime incontinence enuresis is defined as mono-symptomatic nocturnal enuresis (mne) (4). treatment gains more importance in order to improve self-esteem and life standard of these children. nowadays, a variety of treatment modalities have been used for the treatment of enuresis nocturna including desmopressin, tricyclic antidepressants and behavioral therapy. however, the reason why some enuretic children respond poorly to medical treatment is not clearly elucidated. spina bifida (sb) is a congenital deformity involving failure of normal midline fusion of the neural tube. the exact etiology of sb is still unknown, but there is growing evidence in favor of a multifactorial origin. the term includes both spina bifida occulta (sbo), which involves only a bony (vertebral) arch defect and spina bifida (sb) cystica (aperta), which involves a bony defect and a neural tube (spinal cord) defect (5). in sbo, there’s a small defect or gap in one or more vertebrae. the commonest type is sbo, in which there is a defect in the vertebral arch of l5 or s1, resulting in the failure of posterior arch to fuse in the midline. many authors have published data on the frequency of sbo, with varying results. in fact, it’s been estimated that 12-23% of healthy people have sbo (6, 7). interestingly it has been reported earlier that; among patients with enuresis, the incidence of sbo has been increased up to 37.5% (8). however, the effect of sbo on the response to nocturnal enuresis (ne) treatment is controversial. in this study, we aimed to investigate the association between the presence of sbo and medical treatment outcome in patients with primary monosymptomatic mne. doi: 10.4081/aiua.2014.4.270 introduction enuresis nocturna is a common health problem among children and adolescents. while the prevalence of enuresis at the age of 5 is as high as 15-20%, the prevalence cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 270 271archivio italiano di urologia e andrologia 2014; 86, 4 primary nocturnal enuresis and spina bifida material and methods a total of 223 children, aged 6-16 years, who have been diagnosed with pmne in the urology outpatient clinic of hisar intercontinental hospital between january 2008 and december 2011, were enrolled to the study. the study protocol was approved by the ethical committee, of taksim training and research hospital (ethical code: taksim training and research hospital, etics committee of clinical research no.31/04.12.2013). the diagnosis of mne was in accordance with the international children’s continence society standardization (4). children with a minimum of one wet night per week were included in the study. all patients underwent a detailed clinical evaluation including; medical history, physical examination, urinalysis, urinary tract ultrasonography, and kidney-ureter-bladder scout film. plain radiography of the spine had been performed to all patients before the start of treatment patients with a history of urinary tract infection or neurological disease and dysfunctional elimination syndrome (children who have problems with both bowel and bladder control with chronic constipation, fecal retention, stool withholding and encopresis). written informed consents were obtained from the parents of the patients. on plain x-ray films of the spine, the presence or absence of the fusion of the posterior elements of the lumbar and/or sacral spinous processes were examined to in order to detect sbo. x ray films were evaluated by experienced radiologists and, the initial sbo diagnosis was confirmed with subsequent computed tomography imaging. the children were assigned to one of the 2 treatment groups according to the treatment they receive; either desmopressin monotheraphy or combination therapy including tolteradine with desmopressin patients were homogenously assigned to treatment groups with regard to the presence or absence of sbo. the children and parents had underwent thorough counseling which involved a review of the usual interval between dinner and bedtime (aiming to prolong that period to over 3 hours), a review of the hydration state of each child (aiming to restrain night-time hydration), and a discussion of the treatment plan and its goals. in the single drug therapy group, the initial daily doses were 0.2 mg for desmopressin. in the desmopressin only group dosage had been adjusted by increments of 0.2 mg at 2 weeks in case of insufficient response and the maximal dosage for desmopressin was 0.4 mg at bedtime. the drug was administered orally 30 minutes before bedtime. patients had been asked to record whether they were “wet” or “dry” the next morning. “wet” and “dry” nights were documented daily for 14 days before treatment (baseline) and during the 6-month treatment period. we calculated the baseline enuretic frequency from the data collected prior to medical treatment commencement. we also calculated the frequency of enuresis from the data collected at 1, 3 and 6 months after the initiation of medical treatment. efficacy was measured based on the percentages of 5 patient responses. response was categorized as “excellent” when the frequency of ne decreased to zero or to once monthly, “good” when frequency decreased by more than 90% compared to baseline, “fair” when frequency decreased by more than 70%, “partial” when frequency decreased by 50% or more and “no response” when frequency decreased by less than 50%. the final follow-up visit was performed at 6 months after the start of treatment. complete and good response was considered as successful treatment. statistical analyses all analyses were performed using spss 11.5 (statistical package for social sciences,chicago, usa). data were expressed as mean values ± standard deviation. chisquare analysis was used to examine the significance of response to treatment between the 2 groups. a value of p < 0.05 was considered as statistically significant. results charts of a total of 223 children (151 boys and 72 girls, aged 6-16 years; mean age: 10.1 ± 3.04 years who have been diagnosed with pmne were reviewed retrospectively. spina bifida occulta was detected in 75 children (33.6%). sbo affected l4 in 2 children, l5 in 6 children, l4-l5 in 3 children, and s1 in 52 children, s2 in 7 children and s1-s2 in 2 children (table 2). response to treatment among patients with and without sbo is summarized in table 3. treatment was successful in 79% of the children without sbo, and in only 48% of the children with sbo. the difference between those with and without sbo was statistically significant in terms of the medical treatment success rate (p < 0.001). response to treatment m/f age (years) n % nocturnal enuresis without spina bifida 92/56 9.6 ± 2.9 117 79* group i (n = 148) nocturnal enuresis with spina bifida 59/16 11.1 ± 3.0 36 48 group ii (n = 75) chi-square tests: value = 17,33 significance (p) = 0.0001. table 1. demographical features of the study groups. male female total l4 1 1 2 l5 5 1 6 l4-5 1 2 3 l5-s1 3 3 s1 5 47 52 s2 3 4 7 s1-s2 1 1 2 16 59 75 table 2. incidence and distribution of spina bifida occulta in the study population. cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 271 archivio italiano di urologia e andrologia 2014; 86, 4 b. cakiroglu, t. tas, s. erkan eyyupoglu, a. ismet hazar, m. bahadır can balcı, y. nas, f. yilmazer, s. hilmi aksoy 272 discussion spina bifida occulta (sbo) is a variable syndrome with manifestations such as vertebral cleft, foot deformities, midline skin lesions, spondylolysis, syringomyelia, tethered cord syndrome and genitourinary dysfunction. enuresis may be the only evidence of the disease (9). the data concerning the effect of sbo in treatment response among patients with enuresis nocturna is controversial. in a recent study, similar to our findings, shin et al. studied 160 children with enuresis and reported a higher success rate with desmopressin response rate in the group without sbo compared to the group with sbo (10). in another study conducted by miyazato et al., although there was no difference in the overall response rates between children with and without sbo, patients with l and l/s sbo were less responsive to treatment compared to the patients with s sbo (11). on the other hand kumar et al., reported that outcome of patients with sbo was not different than the patients without sbo. however, they only compared the outcome of patients on behavioral therapy (12). in an earlier study, ritchew et al. compared the treatment success rates among 127 children with diurnal enuresis. among those, 48 patients were having sbo and all 127 patients were initially treated with a timed voiding program and 28 with persistent enuresis were given anticholinergic medications. the mean follow-up for both groups was 3 years and the authors determined that the outcome for enuretic children with sbo was comparable to those with normal spine x-rays (13). in their prospective study, kajbafzadeh et al. evaluated 109 children with less than 50% reduction in wet nights despite different treatments for at least 6 months. they specifically looked for the presence of associated sbo and compared the treatment outcome with the outcomes of 40 healthy children. they determined that sbo was present in 86 (78,9%) patients with persistent primary ne and 10 (25%) normal children and the difference was statistically significant (14). despite the fact that, this was a cross-sectional study and a direct causal relationship could not be made with these findings, this data also supports that there may be a common developmental etiology between unresponsive enuretic patients and sbo. this finding is also imperative to realize the increased rates of medical treatment unresponsiveness among patients with enuresis nocturna. in normal healthy children the incidence of sbo is about 17-23% while sbo incidence reaches 35-60% in enuretic children (15-17). although the exact mechanism linking these two pathologies is not obvious, everyone should be aware of this association since these two conditions, are common in childhood. moreover recent increase in the prevalence of sbo may also result in an increased prevalence of ne because of this association. sbo of the sacrum is the most common type of spinal deformity. spina bifida cystica and occulta present with a wide spectrum of urodynamic abnormalities including upper and lower motor neuron types of bladder and urethral dysfunction (18). it has been suggested that sbo might be associated with incomplete neurogenesis of the sympathetic nerves that control the internal sphincter at the vesicourethral junction. these dysfunctions may be the cause of association of sbo and enuresis nocturna but studies are warranted to determine the exact link between these disorders (10). in another interesting study dealing with this subject, dik et al. studied 241 patients with sb and determined that 13 of them had true ne. these patients were treated with desmopressin (0,4 mg, 1x1) and the drug was successful in 12 patients: only 1 of whom relapsed during the follow-up follow up (19). this study is also important in terms of that; response rate was very high despite the presence of sbo. however since the number of patients was as low as 13, strict conclusions can not be drawn with this data. in our study with 223 subjects with pmne, we have determined that children with sbo have poorer medical treatment response at 6 months than those without this deformity. enuresis nocturna is an important health problem, distressing social lives of all affected children and their families. although many treatment modalities are present; it is still not clear why some children do not respond to medical treatment while some of them recover spontaneously. in that aspect, it may be helpful for the physicians to determine associated conditions that may play a role in predicting medical treatment success rate in enuresis nocturna. conclusion the presence of sbo affects the response to medical treatment among patients with primary mne. if the increasing prevalence of sbo is considered, this phenomenon gains more importance. in the light of these data, we suggest that determination of the existence of sbo may be helpful to predict the response to treatment in pmne. future prospective, randomized studies comparing the efficacy of different treatment modalities with regard to the presence of absence of sbo are warranted in order to assess sbo’s real prognostic value in this setting. references 1. alon u. nocturnal enuresis. pediatr nephrol. 1995; 9:94-103. 2. ozden c, ozdal ol, altinova s, et al. prevalence and associated factors of enuresis in turkish children. int braz j urol. 2007; 33:216-22. 3. pereira rf, silvares ef, braga pf. behavioral alarm treatment for nocturnal enuresis. int braz j urol. 2010; 36:332-8. treatment outcome en patients with sbo en patients without sbo (n = 75) (n = 148) complete response 30 (40,0%) 106 (71,6%) good response 6 (8,0%) 11 (7,4%) partial response 26 (34,7%) 12 (8,1%) no response 13 (17,3%) 19 (12,8%) en: enuresis nocturna, sbo: spina bifida occulta. table 3. treatment outcomes in the study groups. cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 272 273archivio italiano di urologia e andrologia 2014; 86, 4 primary nocturnal enuresis and spina bifida 4. neveus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents; report from the standardization committee of the international children’s continence society. j urol. 176:314-324. 5. de marco p, merello e, mascelli s, et al. current perspectives on the genetic causes of neural tube defects. neurogenetics.. 2006; 7:201-21. 6. eubanks jd, cheruvu vk. prevalence of sacral spina bifida occulta and its relationship to age, sex, race, and the sacral table angle: an anatomic, osteologic study of three thousand one hundred specimens. spine (phila pa 1976). 2009; 34:1539-43. 7. fidas a, macdonald hl, elton ra, et al. prevalence and patterns of spina bifida occulta in 2707 normal adults. clin radiol. 1987; 38:537-42. 8. agarwal hc, mohan d, mukerji dp. eneuresis. an etiological and therapeutic review. indian j med sci. 1967; 21:668-75. 9. zambito a, dall'oca c, polo a, et al. spina bifida occulta. foot deformities, enuresis and vertebral cleft: clinical picture and neurophysiological assessment. eur j phys rehabil med. 2008; 44:437-40 10. shin sh, im yj, lee m-j, et al. spina bifida occulta: not to be overlooked in children with nocturnal enuresis. int j urol. 2013; 20:831-5. 11. miyazato m, sugaya k, nishijima s, et al. location of spina bifida occulta and ultrasonographic bladder abnormalities predict the outcome of treatment for primary nocturnal enuresis in children. int j urol. 2007; 14:33-38. 12. kumar p, aneja s, kumar r, et al. spina bifida occulta in functional enuresis.. indian j pediatr. 2005; 72:223-5. 13. ritchey ml, sinha a, di pietro ma, et al. significance of spina bifida occulta in children with diurnal enuresis. j urol. 1994; 152:815-8. 14. kajbafzadeh a, espandar l, mehdizadeh m, et al. spina bifida occulta in persistent primary nocturnal enuresis. iran j radiol. 2004; 66. 15. kawauchi a, kitamori t, imada n, et al. urological qbnormalities in 1,328 patients with nocturnal enuresis. eur. urol. 1996; 29:231-4. 16. samuel m, boddy sa. is spina bifida occulta associated with lower urinary tract dysfunction in children? j urol. 2004; 171:2664-6. 17. boone d, parsons d, lachmann sm, et al. spina bifida occulta: lesion or anomaly? clin. radiol. 1985; 36:159-61. 18. sakakibara r, hattori t, uchiyama t, et al. uroneurological assessment of spina bifida cystica and occulta. neurourol. urodyn. 2003; 22:328-34. 19. dik p, veenboer pw, and de jong t. desmopressin in the treatment of nocturnal enuresis in patients with spina bifida. cerebrospinal fluid research 2010; 7(suppl 1):s10. correspondence basri cakıroglu, md, urologist (corresponding author) drbasri@gmail.com hisar intercontinental hospital, department of urology saray mah. siteyolu cad.no:7, 34768 umraniye, istanbul, turkey tuncay tas, md, urologist drtastuncay@gmail.com aydın !smet hazar, md, urologist mdhazar@yahoo.com mustafa bahadır can balcı, md, urologist drbalci@yahoo.com taksim training and research hospital, department of urology taksim, istanbul, turkey seyit erkan eyyupoglu, md, urologist seeseesee@hotmail.com amasya training and research hospital, department of urology amasya, turkey yunus nas, md, pediatrist ynas@hisarhospital.com fazli yilmazer, md, pediatrist fyilmazer@hisarhospital.com hisar intercontinental hospital, department of pediatry umraniye,istanbul suleyman hilmi aksoy, md, radiologist saksoy@hisarhospital.com hisar intercontinental hospital, department of radiology umraniye, istanbul, turkey cakiroglu_ad_stesura seveso 15/01/15 13:04 pagina 273 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2156 case report triorchidism: genetic and imaging evaluation in an adult male arben belba 1, valentina riversi 2, francesca mari 3, eleonora cellesi 1, roberto ponchietti 1 1 urological and andrological unit, department of medicine, surgery and neuroscience, siena, italy; 2 imaging department aous of siena, italy; 3 medical genetics unit, department of medical biotechnologies, siena, italy. we report the results of imaging and cytogenetic studies in a case of triorchidism in a 54 years old male without any associated anomaly. a scrotal ultrasonography revealed the presence of two testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. there was no focal abnormal echogenicity suggesting malignancy. scrotal mri confirmed two soft-tissue structures in the left hemiscrotum with normal signal intensity at t1w and t2w images. both testes had a tunica albuginea with low-signal intensity. cytogenetic analysis resulted in normal male karyotype 46xy. array-cgh analysis detected the presence of two interstitial rearrangements: a ~120 kb deletion of chromosome 1 and a ~140 kb deletion of chromosome 16. currently there are little details on the functions of both genes. key words: polyorchidism; ultrasonography; mri; cytogenetic evaluation. submitted 4 january 2014; accepted 31 january 2014 summary introduction polyorchidism is a rare genital anomaly defined by the presence of supernumerary testes usually within the scrotum. to date there have been almost 200 cases reported in the literature (1, 2). the most common presentation of polyorchidism is triorchidism with the supernumerary testis being confined to the left side. the exact mechanism for occurence of polyorchidism is still unknown. several theories have been proposed, including peritoneal folding, segmentation of the primitive gonads, longitudinal or transverse division of the genital ridge. no single theory can explain all types of polyorchidism since some involve testicular tissue only and others involve complete duplication of the testis, epididymis and vas deferens (3, 4). most cases of polyorchidism are found incidentally in association with undescended testis, hydrocele, hernia or torsion. it is also reported as increased risk of testicular malignancy. no conflict of interest declared. case report a 54 years old man presented to our outpatients department with complaints of erectile dysfunction. his past medical history revealed diabetes type 1 since the age of 28 years and 10-year history of a left-sided scrotal swelling associated with some discomfort. he was married and fathered two daughters. abdominal examination was normal with no palpable mass or groin herniae. scrotal examination revealed a normal right testis and scrotal content, but on the left side there were two similar size lumps. laboratory studies, including hormonal and oncological markers, were within normal limits. a scrotal ultrasonography revealed the presence of 2 testes within the left hemiscrotum with complete septation and echotexture and vascular flow pattern similar to the vascular flow of the normal right testis. there was no focal abnormal echogenicity suggesting malignancy (figure 1). scrotal mri confirmed 2 soft-tissue structures in the left hemiscrotum with normal signal intensity at t1w and t2w images. both testes had a tunica albuginea with low-signal intensity (figure 2). chromosomal preparations for the karyotype analysis were obtained according to standard techniques. cytogenetic analysis at a resolution of 400 bands resulted in normal male karyotype 46xy. patient dna was analysed by array-cgh analysis using a commercially available oligonucleotide microarrays containing about 44.000 60-mer probes (human genome cgh microarray 44b kit, agilent technologies, santa clara, california) according to the manufacturer’s instructions. array-cgh analysis detected the presence of two interstitial rearrangements: a ~120 kb deletion of chromosome 1(arr1q31.1(79,356,819-79,476,571)x1) and a ~140 kb deletion of chromosome 16 (arr 16q22.1(70,052,16470,193,889)x1). parents were not available for testing. the microdeletion of chromosome 1 includes the eltd1 (latrophilin and seven transmembrane domain containing1) gene, while the microdeletion of chromosome 16 includes the pdpr (pyruvate dehydrogenase phosphatase regulatory subunit) gene. currently there are little details on the functions of both genes. the protein encoded by eltd1 could be involved in cardiac development. the doi: 10.4081/aiua.2014.2.156 157archivio italiano di urologia e andrologia 2014; 86, 2 triorchidism: genetic and imaging evaluation in an adult male protein encoded by pdpr is a regulatory subunit of human mitochondrial pyruvate dehydrogenase phosphatase. it decreases the sensitivity of pdp1 to magnesium ions, and this inhibition is reversed by the polyamine spermine. both these proteins are expressed also in testis. a diagnosis of triorchidism was made and the patient was placed in sonographic follow up. figures are reported in supplementary materials posted on www.aiua.it discussion polyorchidism is a rare congenital anomaly defined by the presence of more than two histologically proven testes. the commonest variant is triorchidism, the supernumerary testis being commonly reported on the left side which often appears as a painless scrotal mass or may be found as an incidental finding on sonography. ultrasonography is diagnostic, mri plays a confirmatory role and may provide additional information in conditions that may complicate polyorchidism, such as torsion, cryptorchidism and neoplasia (4-6). most patients with polyorchidism have a normal 46xy karyotype and adult patients have normal secondary sexual characteristics. because polyorchidism is rare and poorly described, genetic studies are lacking. chromosomal abnormality such deletion of the long arm of chromosome 21 has been reported in a severe malformed male newborn (7). the current knowledge does not allow to attribute a causative role to the aploinsufficency of two genes in determining the phenotype of our patient. additional array-cgh analysis in patients with supernumerary testis are required to increase data and to define the role of these genes in the pathogenesis of polyorchidism. management of polyorchidism has been the subject of much debate (8). the incidence of testicular malignancy in polyorchidism is between 5.7-7% and was found only in a non-scrotal (abdominal or inguinal) supernumerary testis. with recent improvements in imaging techniques such as ultrasound and mri scans, most cases of polyorchidismc can be diagnosed and followed up accurately without any need for surgical exploration or histological examination. conservative treatment with sonographic follow-up is the choice of treatment in uncomplicated cases (9). references 1. bergholz r, wenke k, polyorchidism: a meta-analysis. j urol. 2009; 182:2422-2427. 2. savas m, yeni e, ciftci h, et al. polyorchidism: a three-case report and review of the literature andrologia 2010; 42:57-61. 3. thum g, polyorchidism: case report and review of literature. j urol. 1991; 145:370-372. 4. singer br, donaldson jg, jackson ds. polyorchidism: functional classification and management strategy. urology. 1992; 39:384-388. 5. chung tj, yao wj. sonographic features of polyorchidism. j clin ultrasound. 2002; 30:106-108. 6. yalçınkaya s, sahin c, sahin af. polyorchidism: sonographic and magnetic resonance imaging findings. can urol assoc j. 2011; 5:84-86. 7. arslanoglu a, tuncel sa, hamarat m. polyorchidism: color doppler ultrasonography and magnetic resonance imaging findings. clin imaging. 2013; 37:189-191. 8. shabtai f, schwartz a, hart j, et al. chromosomal anomaly and malformation syndrome with abdominal polyorchidism. j urol. 1991; 146:833-834. 9. nayak sp, sreejayan mp. management of supernumerary testis in an adult: case report and review. andrologia 2011; 43:149-152. correspondence roberto ponchietti, md (corresponding author) roberto.ponchietti@unisi.it eleonora cellesi, md arben belba, md urological and andrological unit, department of medicine, surgery and neuroscience, university of siena, siena, italy valentina riversi, md imaging department aous of siena, siena, italy francesca mari, md phd medical genetics unit, department of medical biotechnologies, siena, italy figure 1. a. sagittal sonographic image of the left scrotum showing two testicles completely separated. the supernumerary testis is smaller and superior to the more normal-sized and it appears as an oval, isoechoic mass with a homogeneously echogenic pattern identical to that of the other testicle; they share the epididymis and the vas deferens. b. color doppler image showing the same vascular pattern of the normal and accessory testicle. c. both testicles have approximately the same size. stesura seveso archivio italiano di urologia e andrologia 2016; 88, 152 review diagnosis and treatment in primary bladder small cell carcinoma: literature review orcun celik 1, gokhan ekin 1, tumay ipekci 2, salih budak 1, yusuf ozlem ilbey 1 1 tepecik educational and research hospital, urology department, izmir, turkey; 2 baskent university, faculty of medicine, alanya research hospital, antalya, turkey. small cell bladder carcinoma is a rare and frequently fatal disease. it can be distinguished from classical urothelial carcinoma microscopically and immunohistochemically. small cell bladder carcinoma has histologically similar properties with other small cell carcinomas in other organs. it has a worse prognosis when compared to urothelial bladder cancer. multimodal treatments are recommended although there is no widely accepted consensus regarding to the treatment algorithm because of its rarity. in this review, clinical properties and diagnosis of small cell bladder carcinoma, its histopathological and immunohistochemical properties and treatment modalities are examined. key words: neuroendocrine carcinoma; bladder cancer; small cell cancer. submitted 5 january 2015; accepted 15 march 2015 summary no conflict of interest declared. develops from cells of the same origin. there are two different theories regarding to the origin of the cells. according the first theory, amine precursor uptake and decarboxylation (apud) cells take origin from neural crest and migrate to different epithelial areas in the body. apud cells present intracytoplasmic neurosecretory granules and can be positively stained with chromogranin a (cga). according the second theory, clonality studies have shown that net is originated from multipotent root cells that can be converted in different tissue types. thus cancers have similar molecular abnormalities. epidemiology bladder carcinoma (bc) is the fourth most frequent cancer in men and is responsible for 14,000 cancer-related deaths in united states of america annually (2). 90% of bc is urothelial carcinoma and the most frequently types out of urothelial carcinoma are squamous cell carcinoma and adenocarcinoma (2, 3). smcc is a rare form of bc and responsible for < 1% of primary bc (3). smcc is frequently seen in men in seventh or eighth decade (1, 4, 5). its incidence between 1991 and 2005 in united states of america has increased from 0.05 to 0.14 in 100.000 inhabitants (3). in men, it is observed as 3 times more than women and in white race, it is observed as 10 times more than the other-than-white races (3). it is more frequent in advanced age and average incidence age is 71 years (4-6). smoking is considered to be a risk factor and smoking history is present in 50-70% of smcc patients (7). in most of the patients, there are non-specific risk factors such as bladder stone, bladder manipulation and chronic cystitis (4, 5, 7). exposure to second-hand smoking and chemicals is controversial (7). clinical properties and diagnosis smcc bc is similar to bladder urothelial carcinoma in terms of age of onset, gender and symptoms. it presents with local, systemic or paraneoplastic symptoms. the most frequent symptom is painless gross hematuria that is observed in 80-90% (1, 4, 7, 8). dysuria, obstructive voiding symptoms, abdominal pain, pelvic pain and recurrent urinary tract infection are other frequently observed symptoms. sometimes it may also occur with doi: 10.4081/aiua.2016.1.52 introduction neuroendocrine tumors (net) are a heterogeneous group of tumors that developed from neuroendocrine cells. they are separated in sub categories according to the organs from which they originate. net was first described in the bronchopulmonary tract by barnard in 1926 (1). small cell carcinoma (smcc) is developed from the lower respiratory tract and spreads out rapidly and is common in chronic smokers. smcc may develop in extrapulmonary regions and its diagnostic criteria are the same as in pulmonary smcc. uniform small cells with scant cytoplasm, salt-pepper like chromatin and inconspicuous nucleoli are the diagnostic findings. extrapulmonary net can develop from almost every part of the body except central nervous system. primary location can be esophagus, gastrointestinal tract, pancreatobiliary system, larynx, salivary glands, uterus, cervix uteri, vagina, bladder, prostate, breast, lacrimal gland and dermis. in urinary system, net was firstly described by resnick in 1966 as a carcinoid subtype in the kidney whereas 1977, wenk described net with smcc subtype in the prostate. regarding to bladder, cramer has first described net in 1981 with a sub-type of smcc (1). today in the urinary system, net is most frequently observed in the bladder, then prostate, kidneys and ureter respectively (1). net, both pulmonary or extrapulmonary, celik2_stesura seveso 08/04/16 11:29 pagina 52 53archivio italiano di urologia e andrologia 2016; 88, 1 diagnosis and treatment in primary bladder small cell carcinoma: literature review systemic symptoms such as weight loss and fatigue. it can rarely present by a paraneoplastic syndrome although less frequently when compared to pulmonary smcc. paraneoplastic syndrome may cause hypercalcemia, hypophosphatemia, cushing syndrome and sensorial neuropathy (9, 10). smcc and urothelial bc cannot be definitely differentiated via imaging methods. computerized tomography (ct) of urothelial carcinoma shows in 70-80% a focal asymmetric bladder wall thickening occurs and in 20% the muscle invasive carcinoma is demonstrated as a solitary mass (11). at ct, smcc presents as large solitary lesion consisting of necrosis and calcifications at different ratios. frequently, diffuse bladder wall thickening is seen and extension to perivesical fat and surrounding tissues occurs (11). diagnosis is made by cystoscopy and microscopic evaluation of the tissue obtained via transurethral resection of bladder tumor (tur-bt). macroscopically it presents as a polypoid mass from 1,5 to 13 cm large (4, 11, 12). despite most of the tumors are located on the lateral wall of the bladder, they may less often located on the base, trigon, anterior wall and fornix of the bladder (1, 4, 8). lesional cells can be observed in the urine cytology (13). histopathological and immunohistochemical assessment microscopically smcc bc is similar to smcc in other organs and classification is performed according to the world health organization (who) classification system. although tumor occurs as a diffuse growth without pattern, sometimes focal nests and trabecula can be seen (14). nests are formed of small or medium-size cells. cells are formed by round oval overlapping nuclei and regularly distributed salt-and-pepper like chromatin and inconspicuous nucleoli (14). cytoplasm of the cells is scarce and organelles are rare. frequently mitosis, crush artifact and geographical necrosis are seen. azzopardi effect (crush artifact) is the indicator of high proliferation ratio. electron microscopy shows the presence of membrane-limited dense core granules with a diameter of 150-250 mm (9). bladder smcc is in mixed type more frequently when compared to pulmonary. it is 40-70% mixed and most frequently is accompanied to urothelial carcinoma (13, 15). according to their frequency, it may be accompanied also to squamous cell carcinoma, adenocarcinoma and rarely sarcomatoid carcinoma (15). prognosis of mixed tumors, even if smcc is present in a small focal area, is similar to the bad prognosis of pure smcc (8, 16). thus it should be always demonstrated whether there is presence smcc in classical urothelial carcinoma or not. in case of rarely seen diagnostic difficulties, immunohistochemical staining may be applied to verify the diagnosis. thus synaptophysin, cga, neuron specific enolase (nse), cd56 and similar staining can be applied although their sensitivity for bladder smcc is relatively low (15). independent morphologic appearance of bladder smcc should be sufficient according to who diagnosis criteria (13). cga is also known as parathyroid secretory protein 1 and coded by the chga gene. because it is related to the release of amine/peptide, cga is expressed from β cells of pancreas in the cells similar to enterochromaffin and in chromaffin cells although it is not present in steroid hormone producing cells (13). it is the neuroendocrine marker for bladder smcc with the lowest sensitivity and it is stained with a one-third to one-half ratio (15). a 5% positivity is observed in urothelial bladder carcinoma (17). synaptophysin is known as the major synaptic vesicle protein p38 and coded by the syp gene. it is present in all the cells producing amine/peptide and steroid hormone and in all the neurons (13). cd56 is known as the neural cell adhesion molecule and coded by the ncam1 gene. it is present in the membrane of neurons, glia, skeletal muscles and natural killer cells (13). for bladder smcc, the sensitivity of synaptophysin and cd56 is higher than cga. in a study of buza et al., they have found sensitivity of cd56 as 71.4% and suggested that it is the most sensitive marker for the bladder smcc (18). in the same study, sensitivities of synaptophysin and cga are found as 64.3% and 28.6% respectively (18). nse is known as γ-enolase or enolase 2 and coded by the eno2 gene. it shows phosphopyruvate hydratase activity and is present in mature neuron cells. its sensitivity for bladder smcc is about 80% and its specificity is very low (14, 18, 19). thyroid transcription factor 1 (ttf-1) is known as nk2 homeobox 1 and coded by the nkx2-1 gene. it is the transcription factor that is produced in thyroid follicular cells, clara cells and type 2 pneumocytes in the lungs and diencephalon in the brain (13). cheuk et al. have found the sensitivity of ttf-1 for extrapulmonary smcc as 42% (20). jones et al. have observed ttf-1 positivity in the bladder smcc in 50% (21). no relationship between ttf-1 expression and the prognosis of bladder smcc is found (21). thus it is not reliable for the diagnosis of primary smcc and there is no prognosis anticipation. the p53 is coded by the tp53 gene and it is a tumor suppressor protein. various cancers are developed by the mutation of p53 and these generally progress by poor prognosis. a p53 overexpression in bladder smcc is seen between 37 and 80% (13, 14). no relationship between p53 overexpression and the prognosis of bladder smcc is found (14). the p16 is known as cycline-dependent kinase inhibitor 2a and coded by the cdkn2a gene (13). it takes place in the regulation of p16 cell cycle and various cancers develop by the p16-retinoblastoma pathway in its mutations. normal tissues and normal urothelial mucosa has heterogeneous staining pattern with p16 and is positive in 1-10% (22). in the study of buza et al. in which they have taken 10% as the limit value for abnormal p16 staining, they have found p16 positivity as 92.8 in bladder smcc and as 43.7 in high-grade urothelial carcinoma (18). this data shows that the changes in p16retinoblastoma pathway are required for the development of bladder smcc. the p63 is known as the transformation-related protein 63 and coded by the tp63 gene (13). it is a member of p53 family and it features as a transcription factor. the p63 activity is different between the bladder smcc and high-grade urothelial carcinoma. while p63 is found negative in 92.8% of the patients with bladder smcc, it celik2_stesura seveso 08/04/16 11:29 pagina 53 archivio italiano di urologia e andrologia 2016; 88, 1 o. celik, g. ekin, t. ipekci, s. budak, y. ozlem ilbey 54 is found positive in 81.3% of the patients with urothelial carcinoma (18). thus p63 is an immunohistochemical marker that may help to differentiate the bladder smcc and urothelial carcinoma. various cytokeratin stains were also studied in bladder tumors. ck20 expression shows that tumor aggressiveness is low. while buza et al. found the ck7 positivity as 64.3% in the bladder smcc, ck20 was only stained focally in 2 cases (18). in bladder smcc, cam 5.2 is found positive in 60-70%, 34βe12 in 40-45% and epithelial membrane antigen as 75-80% (4, 5, 13-15, 17, 18, 20, 21). uroplakin is a urothelium-specific transmembrane protein and it is a terminal urothelial cytodifferentiation marker. despite it is positive at various ratios in the bladder urothelial carcinoma, jones et al. have found it negative in all 44 patients with smcc (21). there are also studies regarding to the c-kit that is a transmembrane tyrosine kinase receptor and proto-oncogene (cd117) and also human epidermal growth factor receptor 2 (her2/neu) with positivity between 30 and 50% is found (10). positivity of these two markers may be important in terms of treatment and prognosis in the future. in the diagnosis of bladder smcc, the differentiation between poor differentiated urothelial carcinoma, alveolar rhabdomyosarcoma, lymphoma, lung smcc metastasis and spreading of smcc of adjacent organs should be done. immunohistochemical studies help for the differential diagnosis instead of diagnosis. in prostatic smcc, prostate-specific antigen is frequently negative and it does not assist in the differentiation of bladder smcc. in prostatic smcc, p501s and prostate membrane antigen is low (approximately 20%) positive. although the determination of tmprss2-erg gene fusion establishes the diagnosis of prostatic smcc, it does not exclude the prostatic origin (13). alveolar rhabdomyosarcomas may not show the classical alveolar structure and they help positive staining by myogenin, myod1 and desmine that show muscle differentiation (10, 13). non-hodgkin lymphoma is differentiated from bladder smcc because of positive cd45 and negative ck (10). staging and treatment in simple staging used for lung smcc, the disease is divided in “limited” and “extensive” (10). limited disease consists of a single radiotherapy port or operation area. in 2007, international association for the study of lung cancer group has recommended tumor-node-metastasis (tnm) staging for lung smcc because it is well related to the prognosis of the patients (10). according to our own experiences, tnm staging for bladder smcc is better in the suggestion of prognosis. as in the bladder tumors, thorax and abdomen ct are standard approaches for staging. because magnetic resonance imaging shows the distribution of local disease better than ct, moretto et al. recommend it in the patients for whom radical cystectomy is planned (10). due to the risk of lymph nodes, liver and bone metastasis and less often of lung and brain metastasis of the disease, some clinicians also recommend 99mtc-mdp bone scanning and 18f-fdg positron emission tomography (9, 10). ct-urography for demonstration of filling defect in the urinary tract is controversial (10, 11). multimodal approach is suggested in the treatment (9, 10). because it is a rarely-seen disease, there is no treatment scheme (guideline) except that of the canadian association of genitourinary medical oncologists (9, 10), but they refers to the results of a single center retrospective study and their evidence and suggestion levels are low. while surgery, surgery and adjuvant or neoadjuvant chemotherapy and surgery and/or chemotherapy can be applied for the limited disease, only chemotherapy can be applied in extensive diseases. individual surgery options are radical cystectomy and tur-bt. simple tur-bt treatment is an insufficient option for the disease control due to high recurrence ratio and a survival period of 3-6 months (9, 23). however, if the general status of the patient does not permit any other treatment modality, it can be applied in this limited patient group. cheng et al. cannot find 5-year survival difference between the patients with and without individual radial cystectomy (%15 vs. %18, p = 0,65) (4) although choong et al. have shown a 5-year survival in the patients to whom individual radical cystectomy was applied of 63.6% (12). these studies have shown that surgery alone, even if radical cystectomy is applied, does not extend survival in the patients except in selected ones. the combination of surgery and neoadjuvant chemotherapy increases long-term survival ratios. in fact bladder smcc is a systemic disease, even if not initially demonstrated, and its cells respond to platinum-based chemotherapies. the more frequently used chemotherapy protocol is a 3-week cycle including intravenous etoposide 100 mg/m2 dose on 1st-3rd day and intravenous cisplatin 70-100 mg/m2 on the 1st day (24, 25). carboplatin may be changed with cisplatin due to its better toxicity profile. it is argued that the disease is down-staged by preoperative chemotherapy and that chemosensitive micro metastases are treated and accordingly the survival periods could be increased. when siefker-radtke et al. have compared patients treated with radical cystectomy after preoperative chemotherapy to those treated with radical cystectomy alone, they found that the 5-year survival period was 78% and 36% respectively (26). siefker-radtke et al. have determined in another study that pathologic downstaging was present in 78% of the patients via neoadjuvant chemotherapy and median overall survival was 58 months (24). the results of lynch et al. about neoadjuvant chemotherapy are more dramatic. in their study, radical cystectomy after neoadjuvant chemotherapy and radical cystectomy alone and adjuvant chemotherapy after radical cystectomy were compared. in the patients to whom radical cystectomy had been applied after neoadjuvant chemotherapy, median survival was found as 159.5 months and 5year survival was found as 79% (25). the results of the other arms of the study were similar to the literature. in short, neoadjuvant chemotherapy and radical cystectomy in the patients who are suitable for surgery seems to be the gold standard treatment. application of radiotherapy and surgery and/or chemotherapy is a bladder-protective method and can be an alternative to cystectomy. chemoradiotherapy can be celik2_stesura seveso 08/04/16 11:29 pagina 54 55archivio italiano di urologia e andrologia 2016; 88, 1 diagnosis and treatment in primary bladder small cell carcinoma: literature review applied simultaneously or successively. lohrisch et al. reported a 44% 5-year survival in 10 patients after chemoradiotherapy (9). bex et al. obtained a complete response in 88% of 17 patients via chemoradiotherapy after turbt and median overall survival was found as 32.5 months. the 5-year survival was calculated as 36% (27). trimodal approach can be applied as an alternative method in the patients who are not suitable for operation or who do not want radical cystectomy and especially in the patients with low performance status. at the time of diagnosis, prognosis of metastatic smcc is poor and median survival is between 5 and 13 months (8, 16, 27). platin-based chemotherapy regime is the standard treatment (8, 12, 16, 26). as an alternative regime, iphosphamide-doxorubicin can be used and as single agent, also paclitaxel and irinotecan can be used (8, 12, 26). despite it is chemosensitive, overall survival is relatively poor. when the disease relapse is observed after the treatment, the same induction regime can be applied by considering the response to the first treatment and the disease-free interval. otherwise second-line chemotherapy regimes can be used and, as a single agent, topetecan or vinorelbine can be used (28). as a combination, cav (cyclophosphamide, doxorubicin, vincristine) regime can be used (28). response ratios to the second-line regimes are variable. radiotherapy can be used as palliative in the patients who have symptomatic bone metastasis or brain metastasis. although there are some clinicians recommending prophylactic cranial radiotherapy due to the combination of advanced stage disease and brain metastasis, there is no exact data regarding to its efficiency (9). prognosis of the patient is related to his performance status and the spreading of the disease at the time of diagnosis. no relation is found between the age, gender, symptoms of the patient and p53 and prognosis (8, 9, 13). histologically the patients with pure smcc can have poorer prognosis than the patients with mixed smcc (16). conclusion bladder small cell carcinoma is biologically an aggressive tumor and it is in most of cases in the advanced or metastatic stage at the time of diagnosis. diagnosis can be easily made by microscopic examination. immunohistochemical stainings are supportive for diagnosis. its prognosis is poor and multimodal approach is recommended in the treatment. it is important to refer the patients to centers with experience of multimodal treatment. in limited disease, radical cystectomy after platinum-based adjuvant chemotherapy seems to be the best treatment method. in extensive diseases, chemotherapy is the primary treatment. studies explaining the molecular pathogenesis are needed and will be instructive for the diagnosis and treatment of the disease. correspondence orcun celik, md (corresponding autor) orcuncelik82@hotmail.com gokhan ekin, md tumay ipekci, md salih budak, md yusuf ozlem ilbey, md assoc. prof. tepecik educational and research hospital, urology department 35170, izmir, turkey tumay ipekci, md baskent university, faculty of medicine,alanya research hospital 07070, antalya, turkey celik2_stesura seveso 08/04/16 11:29 pagina 55 stesura seveso 93archivio italiano di urologia e andrologia 2016; 88, 2 original paper safety and efficacy of percutaneous nephrolithotomy in the galdakao modified supine valdivia position: a prospective analysis luigi quaresima, alessandro conti, alexia vici, marco tiroli, daniele cantoro, admena rreshketa, emanuele principi, matteo tallè, luca moroni, mahmoud yehia, giovanni muzzonigro department of clinical and specialist sciences, division of urology polytechnic university of the marche region medical school, ancona, italy. introduced as poster at the 14th national iea congress 26-28/02/2015, milan, italy. objective: aim of the present study was to evaluate the safety and efficacy of percutaneous nephrolithotomy (pcnl) in the galdakaomodified supine valdivia (gmsv) position in order to predict operative time, stone-free rate and onset of complications taking into account comorbidity, stone-related parameters and anatomic upper urinary tract abnormalities. material and methods: a prospective evaluation of patients who underwent to pcnl in gmsv position for renal stones > 2 cm, from january 2009 to february 2015 was performed. according to the technique, upper urinary tract abnormalities, stone chemical and morphological characteristics, and patients' history were matched with operative outcome, in terms of stone-free, intervention time and incidence of perioperative complications. results: seventy-two cases were collected; mean operative time was 105 minutes (ds 41): staghorn stones and the presence of comorbidity resulted statistically significant variables. the complication-rate resulted in line with data showed in literature: hyperpyrexia and hemorrhage were the more frequently complications found. the overall stone-free was reached in 48 patients (67%), and it was influenced by patients’ anatomic abnormalities. conclusions: in the treatment of renal stones, pcnl may be a safe and effective choice; nevertheless, patients’ anatomic abnormalities or staghorn-stones may influence the outcomes. thus, a prospective study with a larger population is needed to verify our outcomes. key words: stones; percutaneous nephrolithotomy (pcnl); stone-free rate; staghorn stones; complications. submitted 1 october 2015; accepted 4 december 2015 summary no conflict of interest declared. with patients set in a prone (2) position, in order to obtain a marked ventralization of the peritoneal structures and minimize the risk of accidental bowel perforation. the possibility of a supine position was first reported by valdivia uria et al. (3) in 1998, with the purpose of allowing an easier management of the airways from the anestesiologic side. moreover, this position allows to the surgeon to perform a combined access to the upper urinary tract in an anterograde-retrograde fashion (endoscopic combined intrarenal surgery-ecirs) (4). currently a standardization for this procedure is missing, many centers still adopting the original standard prone position, while the use of gsmv is, in our opinion limited by concerns about the surgical advantages and the increased difficulty for the surgeon to achieve an appropriate access to the inferior calyces compared to the standard technique. aim of our study is to evaluate the advantages of the procedure in terms of efficacy (capacity of obtaining a complete removal of the stone burden stone-free) and reduction of intraand postoperative complications at our department. material and methods we prospectively collected clinical data from patients treated at our institution with pcnl in gsmv position for renal stone disease between january 2011 and february 2015. the following clinical variables at intervention were considered for the purposes of the study: gender, age, comorbidities, urine status and possible antibiotic therapy. according to radiologic findings, also the following characteristics of the urinary tract were recorded: wideness of calyx and renal ampulla and presence of anomalies of kidney vessels or voluminous renal cysts, as shown by the pre-operative abdomen ct. as for characteristics of the lithiasis, stone burden and number and radio-opacity were the main features considered. the post-operative outcomes were evaluated according to the following characteristics: duration of the intervention, complete stone-free, intraor postoperative complications. patients’ follow up, conducted with radidoi: 10.4081/aiua.2016.2.93 introduction percutaneous nephrolithotomy (pcnl) is an effective choice in the treatment of large kidney stones because of excellent outcomes and acceptable low morbidity (1). standard treatment introduced in the 80’s consists in percutaneous puncture of the lower calyx of the kidney, with subsequent progressive dilatation and positioning of an operative channel, a rigid or flexible nephroscope can be passed through, in order to perform the intrarenal lithotripsy. this access was originally obtained archivio italiano di urologia e andrologia 2016; 88, 2 l. quaresima, a. conti, a. vici, m. tiroli, d. cantoro, a. rreshketa, e. principi, m. tallè, l. moroni, m. yehia, g. muzzonigro 94 ological, clinical and labor investigations, was at least 3 months. age was considered as a dichotomic variable (< 65 y vs > 65 y). group comparisons for continuous variables were performed by means of mann-whitney u test; all results were summarized with percentiles. association of categorical variables were estimate with fisher yates’ exact test. statistical significance was fixed at the 5% level for all tests. results a total of 72 patients were treated during the period considered. forty-seven of them were males. mean age at intervention was 54 years. in 41 cases (57%) patients had been referred to the intervention because of complete staghorn calculi; in 28 cases (39%) intervention was performed because of 3 or more single stones. radiopaque lithiasis was observed in 51 cases (71%), while in all other cases partially opaque or radiolucent stones at abdomen -rx were observed. population's pre-operative characteristics are reported in detail in table 1. in the post-operative period, 38 patients presented with complications requiring prolonged hospitalization. in particular, for 12 cases (16%) an early-postoperative anemia, treated with blood transfusion was reported; 5 patients (6,9%) developed renal hematoma and 2 patients complicated utis. a list of recorded complications is reported in table 2. mean duration of the procedure was 105.5 minutes (± 41.3), with a significantly longer operative time in patients with single staghorn stones compared to the group with multiple stones (112 ± 35.6 min vs 46.7 ± 24.9, p = 0.043), as showed in figure 1. presence of comorbidities resulted associated with longer operative times (p = 0.03), but no difference could be found between the different comorbidity types (p > 0.05) (figure 2). finally, no difference was found between the different age groups. in 48 cases (67%) complete removal of the stone burden (stone-free patients) could be achieved, while in 24 cases (33%) multiple small residuals were identified at the first follow-up; in 10 cases (13,8%) difficulties were to be ascribed to the presence of anatomic anomalies. the stone-free rate was therefore higher in patients without anatomical anomalies (94% vs 6%, p = 0.025), as highlighted in figure 3. no significant associations were found between possibility of stone-free and type of stone (staghorn vs multiple lithiasis, p = 0.215). the difference in stone-free rate, according to the presence of staghorn calculi, is reported in figure 4. n. patients % sex m 47 65 f 25 35 age < 65 years 52 72 > 65 years 20 28 characteristic of the stone radiolucent 13 18 partially opaque 8 11 radiopaque 51 71 single stone 41 57 multiple stones 28 39 comorbidity hypertension 25 35 ischemic heart disease 13 18 chronic bronchitis 6 8 diabetes 15 21 chronic renal failure 4 6 complications n. patients % anemia required blood transfusion 12 16.6% fever 10 13.8% renal hematoma 5 6.9% atrial fibrillation required cardioversion 3 4.1% peritoneal/pleuric effusion 4 5.5% persistent haematuria 2 2.7% complicated urinary tract infections 2 2.7% table 1. pre-operative patients features. table 2. post-operative pcnl complications. figure 1. pcnl operative time in relation to the presence/absence of staghorn stones. figure 2. pcnl operative time in relation to the comorbidity. discussion although pcnl is considered the gold standard treatment modality for large renal stones, this procedure is not lacking of side effects. in particular, damage to the large blood vessel and late hemorrhage are rare (less than 1%) but serious and potentially life-threatening complications of pcnl (5). blood transfusion and prolonged hospital stay, or readmission due to the hemorrhage may occur, requiring extra costs on the health care system (6), several authors have analyzed the variables associated to the perioperative hemorrhage: a prospective multicenter observational study leaded by de fata et al. (7), on 397 supine pcnl procedure performed in 15 spanish centers, showed how multiple percutaneous tracts and middle calix puncture have resulted the only statistically significant variables associated with the decrease in hemoglobin levels. positive preoperative urine culture or preexisting uti were reported by several authors as a significant parameter predicting complications (8-10): according to other studies (11, 12) we have not founded this correlation with complications. few studies investigated the correlation between normal or impaired renal function and onset of complications with discordant results: yaycioglu (13) reported no difference, while sairam and falahatkar (14, 15) showed a significantly increased complication rates associated to chronic kidney disease. in our study, only four patients were affected by impaired renal function pre pcnl, and with a postoperative progress in line with other patients. the association between anatomic upper urinary tract abnormalities and complication rates in patients undergone to pcnl was investigated by some authors. in particular, osther (16) and rais-bahrami (17) demonstrated as alteration in position and axis of the kidney, renal morphology, vasculature and mobility of the kidney, morphology of calices, pelvis and upper ureter were statistically associated to a higher number of complications, according to our results. stone-related parameters (size, opacity, number, localization, staghorn and complex/multiple stones) resulted to be connected in our experience to a higher complication rate, in line with de la rosette (18) and akman’s (19) studies. in the study leaded by shin stone’s size and staghorn or complex stone had a significant influence only in minor complications, such as uti or pain (20). some studies (9, 15), one of the most recent was published on february 2015 by falahatkar et al. (15) reported the pcnl complications according to the modified clavien system (mcc), a scale that allows to classify complications basing on life-treating condition, interventions required, and disability. nevertheless the mcc cannot predict, as said by the same authors, the occurrence of a specific complication and cannot reveal its reason. moreover, also due to different surgical managements, the sub classification of the higher clavien grades has low reliability (15). regarding the mean operative time, our experience highlights a longer time than what it is usually presented in literature: comorbidity resulted statistically correlated to the length of the procedure instead of the patient’s age. the overall stone-free rate was reached in 67% of patients, in line with the data reported in litherature: recently noureldin et al compared two different scoring system to predict stone-free status post percutaneous nephrolithotomy, guy’s versus s.t.o.n.e., highlighting how both systems were significantly associated with the estimated blood loss (21). interestingly several articles reported different results about the effect of operative time on complications (9, 11, 15, 18, 20): labate et al. found that prolonged operative time has significantly predicted a higher risk of major complication, such as bleeding requiring blood transfusion or impaired renal function while falahtakar et al. reported no correlation. our study presents some limitations: although we included all cases during the period of the study in order to complete a prospective evaluation, patients’ number have not reached the specimen analyzed in other articles. moreover, the procedure included in our study were per95archivio italiano di urologia e andrologia 2016; 88, 2 safety and efficacy of percutaneous nephrolithotomy in the galdakao modified supine valdivia position: a prospective analysis figure 3. influence of anatomical anomalies in the stone-free rate. figure 4. influence of staghorn stones in the stone-free rate. archivio italiano di urologia e andrologia 2016; 88, 2 l. quaresima, a. conti, a. vici, m. tiroli, d. cantoro, a. rreshketa, e. principi, m. tallè, l. moroni, m. yehia, g. muzzonigro 96 formed by two different operators, even though both surgeons had a long-standing experience in percutaneous nephrolithotomy. therefore, a prospective randomized study with a larger population is needed to confirm our observations. conclusion in conclusion, pcnl in gsmv may be a safe and effective choice to treat large renal stones. nevertheless, patients’ anatomic abnormalities may influence stone-free rate while the presence of comorbidity or a staghorn stone may increase operative time. thus, a prospective study with a larger population is needed to verify our outcomes. references 1 segura jw, patterson de, leroy aj, et al. percutaneous lithotripsy. j urol. 1983; 130:1051-4. 2. alken p, hutschenreiter g, gunter r, et al. percutaneous stone manipulation. j urol. 1981; 125:463-466. 3. valdivia uria jg, valle gerhold j, lopez lopez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol 1998; 160:1975-8. 4. ibarluzea g, scoffone cm, cracco cm, et al. supine valdivia and modified lithotomy position for simultaneous anterograde and retrograde endourological access. bju int. 2007; 100:233-236. 5. basiri a, tabibi a, nouralizadeh a, et al. comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial. urol j. 2014; 11:1932-7. 6. stuard wolf j. urinary lithiasis: percutaneous approaches to the upper urinary tract collecting system. in wein aj, kavoussi lr campbell-walsh urology 10th ed. philadelphia, elsevier; 2012; p.1348-54. 7. ramón de fata f, pérez d, resel-folkersma l, et al. analysis of the factors affecting blood loss in percutaneous nephrolithotomy: a registry of the spanish association of urology in the supine position. actas urol esp. 2013; 37:527-32. 8. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stonefree rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012; 79:1236-41. 9. palmero jl, nuño de la rosa i, miralles j, et al. study of predictive factors for complications after percutaneous nephrolithotomy according to the clavien classification. actas urol esp. 2013; 37:412-8. 10. olbert pj, hegele a, schrader aj, et al. preand perioperative predictors of short-term clinical outcomes in patients undergoing percutaneous nephrolitholapaxy. urol res. 2007; 35:225-30. 11. labate g, modi p, timoney a, et al. the percutaneous nephrolithotomy global study: classification of complications. j endourol. 2011; 25:1275-80. 12. onal b, dogan hs, satar n, et al. factors affecting complication rates of percutaneous nephrolithotomy in children: results of a multi-institutional retrospective analysis by the turkish pediatric urology society. j urol. 2014; 191:777-82. 13. yaycioglu o, egilmez t, gul u, et al. percutaneous nephrolithotomy in patients with normal versus impaired renal function. urol res. 2007; 35:101-105. 14. sairam k, scoffone cm, alken p, et al. percutaneous nephrolithotomy and chronic kidney disease: results from the croes pcnl global study. j urol. 2012; 188:1195-200. 15. falahatkar s, moghaddam kg, kazemnezhad e, et al. factor affecting complications according to the modified clavien classification in complete supine percutaneous nephrolithotomy. can urol assoc j, 2015; 9:e83-92. 16. osther pj, razvi h, liatsikos e, et al. percutaneous nephrolithotomy among patients with renal anomailes: patients characteristics and outcomes; a subgroup analysis of the clinical research office of the endourological society global percutaneous nephrolithotomy study. j endourol. 2011; 25:1627-32. 17. rais-bahrami s, friedlander ji, duty bd, et al. difficulties with access in percutaneous renal surgery. ther adv urol. 2011; 3:59-68. 18. de la rosette jj, zuazu jr, tsakiris p, et al. prognostic factors and percutaneous nephrolithotomy morbidity: a multivariate analysis of a contemporary series using the clavien classification. j urol. 2008; 180:2489-93. 19. akman t, binbay m, akcay m, et al. variables that influence operative time during percutaneous nephrolithotomy: an analysis of 1897 cases. j endourol. 2011; 25:1269-73. 20. shin ts, cho hj, hong sh, et al. complications of percutaneous nephrolithotomy classified by the modified clavien grading system: a single center’s experience over 16 years. korean j urol. 2011; 52:769-75. 21. noureldin ya, elkoushy ma, andonian s. which is better? guy’s versus s.t.o.n.e. nephrolithometry scoring systems in predicting stone-free status post-percutaneous nephrolithotomy. world j urol. 2015; 33:1821-5. correspondence luigi quaresima (corresponding author) luigiquaresima@yahoo.it department of clinical and specialist sciences, division of urology polytechnic university of the marche region medical school via conca 71 60100 ancona, italy alessandro conti alexia vici marco tiroli daniele cantoro admena rreshketa emanuele principi matteo tallè luca moroni mahmoud yehia giovanni muzzonigro stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4340 original paper lidocaine spray administration in transrectal ultrasoundguided prostate biopsy: five years of experience lucio dell’atti department of urology, university hospital “s. anna”, ferrara, italy. objectives: we report in this singlecenter study our results of a five-year experience in the administration of lidocaine spray (ls) during ultrasound-guided prostate biopsy (tpb). material and methods: between august 2008 and july 2013 a total of 1022 consecutive male patients scheduled for tpb with elevate psa (≥ 4 ng/ml) and (or) abnormal digital rectal and (or) suspect trus were considered eligible for the study. each patient was treated under local anaesthesia with ls (10 gr/100 ml), applied two minutes before the procedure. tpb was performed with the patient in the left lateral decubitus using multi-frequency convex probe “end-fire”. two experienced urologists performed a 14-core biopsy, as first intention. after the procedure each patient was given a verbal numeric pain scale (vns). the evaluation was differentiated in two scales vns: vns 1 for the insertion of the probe and the manoeuvres associated, while vns 2 only for the pain during needle’s insertion. results: pain scores were not statistically significant different with regard to the values of psa and prostate gland volume. pain score levels during probe insertion and biopsy were significantly different: the mean pain score according to vns was 3.3 (2-8) in the first questionnaire (vns1) (p < 0.001) and 2.1 (1-7) in the second one (vns2) (p < 0.125). the 8.2% of cases referred severe or unbearable pain (score ≥ 7), 74% of patients referred no pain at all. only 21 patients would not ever repeat the biopsy or would request a different type of anaesthesia, while 82% of them would repeat it in the same way. in only eight patients we have not been able to insert trus probe. conclusions: our pain score data suggest that ls provides efficient patient comfort during tpb reducing pain both during insertion of the probe and the needle. this non-infiltrative anaesthesia is safe, easy to administer, psychologically well accepted by patients and of low cost. key words: prostate biopsy; lidocaine spray; pain; anaesthesia; age. submitted 3 october 2014 ; accepted 31 october 2014 summary no conflict of interest declared. introduction transrectal ultrasound-guided prostate biopsy (tpb) is the most commonly used procedure to detect prostate cancer. during the last decade, the number of needle biopsy cores taken has increased, as have biopsies in younger patients and repeated biopsies (1). currently, there is no universally accepted anaesthetic method for prostate biopsy as evidenced by numerous methods that have been tried and published in the literature. two factors are usually responsible for pain during tpb: anal pain due to ultrasound probe, that causes pressure and stretching of muscle fibres, and insertion pain of the needle through the prostate (2). there are several different approaches that can be used for this purpose, including a rectal lidocaine gel, a periprostatic nerve blocks, sedation and caudal blockage (3-5). the selection of a method includes patient tolerance to pain, existing pathologies (especially anorectal diseases), medical history, biopsy experience, socio-cultural level and age (6). we report in this single-centre study, our results of five years of experience in the use of lidocaine spray (ls) administration tpb. to knowledge, this is the first study analysing ls as local anaesthetic technique for prostate biopsy (7). matherials and methods between august 2008 and july 2013 a total of 1022 consecutive male patients scheduled for tpb with elevate psa (≥ 4 ng/ml) and (or) abnormal digital rectal and (or) suspect trus were considered eligible for the study. patients were excluded if they had a history of previous prostate biopsy, had chronic prostalgia/pelvic pain syndrome, anal surgery, concomitant analgesic medication or any other medical condition that could potentially interfere with pain assessment. patients on anticoagulation/antiplatelet therapy were considered eligible for the study, providing they had followed the instructions of stopping antiplatelet drugs at least 5 days before the biopsy, or stopping anticoagulation drugs and replacing them with low molecular weight heparin at least 5 days before the biopsy. patients were instructed to take antibiotics, usually levofloxacin 500 mg orally, for 5 days starting the evening before the procedure and a small evacudoi: 10.4081/aiua.2014.4.340 presented at 19th national congress sieun, fermo 2014 dell'atti_stesura seveso 15/01/15 12:19 pagina 340 341archivio italiano di urologia e andrologia 2014; 86, 4 lidocaine spray and prostate biopsy ative enema two hours before the procedure. all procedures were performed after emptying of the bladder, since we believe that even the state of bladder repletion may be an element of discomfort during the performance of mapping biopsy. each patient was treated under local anesthesia with ls (10 gr/100 ml), applied two minutes before the procedure (figure 1). tpb was performed with the patient in the left lateral decubitus using an general electric logiq 7 machine equipped with a 5-9 mhz multi-frequency convex probe “end-fire”. each transrectal ultrasound that was performed included an assessment of the prostatic diameter, the volume of the whole prostate, the transition zone, capsular and seminal vesicle characteristics, as well as morphological description of potential pathological features. after imaging of the prostate, sampling was carried out with a 18-gauge tru-cut needle powered by an automatic spring-loaded biopsy disposable gun. two experienced urologists performed a 14-core biopsy, as first intention, including 2 lateral peripheral (1 basal and 1 apical), the 3 conventional parasagittal, and 2 midline peripheral samples (1 basal and 1 apical) on each side. after the procedure each patient was given a verbal numeric pain scale (vns), which was designed with 0 representing absence of pain and 10 the maximum pain they perceived in life. the evaluation was differentiated in two scales vns: vns 1 for the insertion of the probe and the manoeuvres associated, while vns 2 only for insertion pain of the needle through the prostate biopsy. additionally, was determined the relationship between the level of pain, prostate volume, age and psa. after the procedure, all patients underwent follow-up for at least one hour for any complications and were discharged. chi square test was used to assess differences in the response between the two questionnaires and fisher’s test if necessary. p value less than 0.05 was considered statistically significant. results in only eight (0.8%) patients we were not able to insert trus probe: in six of them because of the presence of fibrous anal lesion and in the other two cases the reason was the presence of a severe haemorrhoidal prolapse. the mean age of patients was 68 years (range 48-78), the mean value of the psa ng/ml was 8.2 (range 2.5-17.8), total prostate mean volume was 57 ml (range 36-135). the number of biopsies performed in each patient was 14 (range 6-21). a statistically difference was determined when vns1 and vns2 were evaluated; in fact pain score levels during probe insertion and biopsy were significantly different: the mean pain in the visual numerical scales in patients was 3.3 (2-8) in the first questionnaire (vns1) (p < 0.001), 2.1 (1-7) in the second one (vns2) (p < 0.125) (table 1). the 8.2% of cases (83/1014) referred severe or unbearable pain (score ≥ 7), 749 patients (74%) referred no pain at all. only 21 patients would not ever repeat the same biopsy or would request a different type of anaesthesia, while 831 (82%) of them would repeat it in the same way. the relationship between the level of patient pain, age, psa and prostate volume was analysed. it was determined that pain level decreased, whereas age increased (≥ 65 years old), and this result was statistically significant (p = 0.001). it is also shown that subjects aged ≥ 65 years tolerate the procedure better in the two questionnaires (average pain was respectively vns1: 2.4 and vns2: 1.7) (figure 2). the patients were homogeneous in terms of pain with regard to the values of psa and prostate gland volume and pain scores were not statistically significant. prostate cancer was diagnosed in 35% (357/1014) of patients who had undergone biopsy. pain scores were compared variables n° of patients 1022 age (yrs) 68 (48-78) serum psa (ng/ml) 8.2 (2.5-17.8) prostate volume (ml) 57 (36-135) n° of biopsy 14 (6-21) pain vns 1 3.3 (2-8) pain vns 2 2.1 (1-7) patients not able to insert probe 8 – fibrous anal 6 – severe haemorrhoidal prolapse 2 table 1. patiens’ clinical characteristics and vns results.figure 1. figure 2. comparison of pain score between patients ≥ 65 years old and patients < 65 years old. administration of lidocaine spray before transrectal prostate biopsy. dell'atti_stesura seveso 15/01/15 12:19 pagina 341 archivio italiano di urologia e andrologia 2014; 86, 4 l. dell’atti 342 between the 357 patients with prostate cancer (vns 1: 3.4 and vns2: 1.9) and the 657 patients (65%) without cancer (vns 1: 3.6 and vns2: 2.5). we found out that pain scores were statistically lower in vns 2 of patients with prostate cancer (p < 0.001). a minimal rectal bleeding was observed in 38% of the patients after the biopsy. a short duration of hypotension was detected in ten patients, but the patients recovered from this condition in a short time. complication requiring active treatment occurred in 1.3% (13/1014): 4 acute urinary retention, 6 rectal bleeding and 3 urosepsis. discussion pain during tpb can occur during transrectal probe insertion and when the needle pierces the capsule of the prostate through the rectal wall. lidocaine was synthesized by lofgren and lundqvist in sweden in 1943 and introduced into clinical practice in 1947 (8). lidocaine gel (lg) is the most widely used lubricant agent during tpb, but its efficacy when instilled transrectally is controversial (9, 10). lg has a small effect on anal sphincter tone and low efficacy for the insertion and movements of the probe during the procedure (11). in fact, intrarectal lubricant agents with lg alone had no impact on the general tolerance of tpb compared to placebo. thus, the analgesic efficacy of this method has not been universally confirmed (12, 13). after the introduction of periprostatic nerve block (ppnb) by nash et al. (14), several studies reported the necessity of local anesthesia, because the pain during tpb from insertion and movements of the probe is somatic, as the rectum is innervated by the inferior rectal branches of the pudendal nerve (15). in another study from philip et al. (16), the authors concluded that the introduction of the trus probe was significantly more painful than the biopsy after the application of ppnb anaesthesia and suggested the use of a topical perianal anaesthetic/muscle relaxant, especially in young patients. to our knowledge, this is the first study analysing ls as local anaesthetic technique for prostate biopsy (7). the present study is focused on the comparison of pain scores between patients who underwent tpb receiving ls as the only form of local anaesthesia, due to the fact that in our opinion probe insertion and movements were more painful than needle puncture of the prostate capsule, requiring some form of anaesthesia. ls applied at anal sphincter’s level has a rapid and effective action on muscle fibres causing a reduction of the secretion of cytokines, prostaglandins and leukotrienes associated with pain during tpb (17). the analgesic effect starts two minutes after application. the goal of clinicians should be the reduction of the pain and discomfort associated with tpb. acceptable pain scores were reported in patients who received ls; in fact the 82% of them would repeat it in the same way. in only eight patients we have not been able to insert trus probe for anal diseases and a short duration of hypotension was detected in ten patients, but the patients recovered from this condition in a short time. however, an important result is the fact that subjects aged ≥ 65 years tolerated the procedure better in the two questionnaires. many factors may contribute to reducing pain perception, including the decrease in the number of nociceptors; nociceptive afferents account for the high threshold and tolerance pain, reduction of nociceptive information related to the multiplicity of stimuli and reduced ability to discriminate of older, probably a consequence of a disease process rather than ontogenetic changes or development dependent on age (6, 18). our study had three several limitations: the first concerns the study design and the statistical power related to the lack of a placebo group that influenced the statistical results; the second one was that impossibility in determine the optional dosage of ls for the muscle fibres of anal sphincter anaesthesia. finally, the third limitation is that it represents a singlecentre study that should be extended to other urological departments and experienced by various specialists. conclusions in our experience, tpb is generally well tolerated with ls as the only anaesthesia. our pain score data suggest that ls provides efficient patient comfort during tpb by reducing pain both during insertion probe and needle. this new technique represents an excellent alternative to those currently practiced by most urologists, causing a sharp reduction of anal sphincter tone with better patient compliance and tolerability to the ultrasound probe in the performance of biopsies. this non-infiltrative anaesthesia is safe, easy to administer, psychologically well accepted by patients and low cost. to determine the optimal dose of ls for anal sphincter anaesthesia, further well-designed, placebo-controlled prospective studies involving larger populations will be needed. references 1. loebs s, vellekoop a, ahmed hu. et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-92. 2. lee hy, lee hj, byun ss, lee se, et al. effect of intraprostatic local anesthesia during transrectal ultrasound guided prostate biopsy: comparison of 3 methods in a randomized, double-blind, placebo controlled trial. j urol. 2007; 178:469-472. 3. noh dh, cho mc, park hk, et al. the effects of combination perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block for pain control during transrectal ultrasound guided biopsy of the prostate: a randomized, controlled trial. korean j urol. 2010; 51:463. 4. turgut a, ergun e, kosar u, et al. sedation as an alternative method to lessen patient discomfort due to transrectal ultrasonography-guided prostate biopsy. eur j radiol. 2006; 57:148-153. 5. cesur m, yapanoglu t, erdem af, ozbey i, et al. caudal analgesia for prostate biopsy. acta anaesthesiol scand. 2010; 54:557-561. 6. dell’atti l, borea pa, russo gr. age: “a natural anesthetic” in pain perception during the transrectal ultrasound-guided prostate biopsy procedure. urologia 2011; 78:257-261. 7. dell’atti l, daniele c. lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomdell'atti_stesura seveso 15/01/15 12:19 pagina 342 343archivio italiano di urologia e andrologia 2014; 86, 4 lidocaine spray and prostate biopsy fort and pain of the procedure: results of a randomized clinical trial. arch ital urol androl. 2010; 82:125-127. 8. tammalin le, lofgren n: the action of anesthetics upon interfaces; on the mechanism of anesthesia. acta chem scand. 1947; 1:871-883. 9. hergan l, kashefi c, parson jk. local anesthetic reduces pain associated with transrectal ultrasound –guided prostate biopsy: a meta-analysis. urology. 2007; 69:520-525. 10. cevik i, ozveri h, dillioglugil o, akda a. lack of effect of intrarectal lidocaine for pain control during transrectal prostate biopsy: a randomized prospective study. eur urol. 2002; 42:217-220. 11. saad f, sabbagh r, mccormack m, peloquin f. a prospective randomized trial comparing lidocaine and lubricating gel on pain level in patients undergoing transrectal ultrasound biopsy. can urol. 2002; 9:1592-1594. 12. stirling bn, shockley kf, carothers gg, maatman tj. comparison of local anesthesia techniques during transrectal ultrasound-guided biopsies. urology. 2002; 60:89-92. 13. galosi ab, minardi d, dell’atti l, et al. tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. j endourol. 2005; 19:738-743. 14. nash pa, bruce je, indudhara r, et al. transrectal ultrasound guided prostate nerve blockade eases systematic needle biopsy of the prostate. j urol. 1996; 155:607-609. 15. jones js, ulchaker jc, nelson d, et al. periprostatic local anesthesia eliminates pain of office-based transrectal prostate biopsy. prostate cancer disease. 2003; 6:53-57. 16. philip j, mccabe je, roy sd, et al. site of local anaesthesia in transrectal ultrasonography-guided 12-core prostate biopsy:does it make a difference? bju int. 2004; 93:1218-1220. 17. zisman a, leibovici d, kleinmann j, et al. the impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety, and erectile dysfunction. j urol. 2001; 165:445-454. 18. miller pf, sheps ds, bragdon ee, et al. aging and pain perception in ischemic heart disease. am heart j. 1990; 120:22-30. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology university hospital “s. anna” via a. moro 8 44124 cona, ferrara, italy dell'atti_stesura seveso 15/01/15 12:19 pagina 343 stesura seveso 1archivio italiano di urologia e andrologia 2015; 87, 1 original paper venous leakage treatment revisited: pelvic venoablation using aethoxysclerol under air block technique and valsalva maneuver ralf herwig 1, salvatore sansalone 2 1 vienna international medical clinic, department of urology, austria; 2 medical university tor vergata, department of urology, italy. . objective: we evaluated the effectiveness of pelvic vein embolization with aethoxysclerol in aero-block technique for the treatment of impotence due to venous leakage in men using sildenafil for intercourse. the aim of the procedure was to reduce the use of sildenafil. methods: a total of 96 patients with veno-occlusive dysfunction, severe enough for the need of pde5 inhibitors for vaginal penetration, underwent pelvic venoablation with aethoxysclerol. the mean patient age was 53.5 years. venous leaks were identified by color doppler ultrasound after intracavernous alprostadil injection. under local anesthesia a 20-gauge needle was inserted into the deep dorsal penile vein. the pelvic venogram was obtained through deep dorsal venography. aethoxysclerol 3% as sclerosing agent was injected after air-block under valsalva manoeuver. success was defined as the ability to achieve vaginal insertion without the aid of any drugs, vasoactive injections, penile prosthesis, or vacuum device. additionally, a preand posttherapy iief score and a digital overnight spontaneous erections protocol (osep) with the neva™-system was performed. results: at 3 month follow-up 77 out of 96 patients (80.21%) reported to have erections sufficient for vaginal insertion without the use of any drug or additional device. four (4.17%) patients did not report any improvement. follow up with color doppler ultrasound revealed a new or persistent venous leakage in 8 (8.33%) of the patients. no serious complications occurred. conclusions: our new pelvic venoablation technique using aethoxysclerol in air-block technique was effective, minimally invasive, and cost-effective. all patients were able to perform sexual intercourse without the previously used dosage of pde5 inhibitor. this new method may help in patients with contra-indications against pde5 inhibitors, in patients who cannot afford the frequent usage of expensive oral medication or those who do not fully respond to pde5-inhibitors. key words: venous leak; sclerotherapy; embolization; erectile dysfunction; pelvic venoablation; color doppler ultrasound. submitted 2 august 2014; accepted 30 november 2014 summary no conflict of interest declared. introduction pde5-inhibitors have become the standard therapy in erectile dysfunction (ed) over the past 20 years (1). but, most men with ed are treated with options that are not cause specific (1). in a dose-response premarketing study, improved erections were reported after 24 weeks of treatment by 56% and 77% of men taking respectively 25 or 50 mg of sildenafil compared with 25% of men taking placebo (1). the efficacy of and satisfaction with sildenafil in another study in patients with venous leak were considered good for 50 patients (31.84%), fair for 46 patients (29.29%), and bad for 61 patients (38.85%) (2). in patients failing to respond to medical treatment and denying a penile implant option remain a challenge. many of them, including those suffering ed after radical prostatectomy (rp), complain of difficulties in maintaining normally occurring erections (3). especially younger patients complaining of the inability to maintain enough rigidity to achieve satisfactory intercourse, even after improvement by pde5-inhibitors, are in search of a curative or at least a long term treatment (4). ultrasound has proven to be the major tool in the differentiation of vascular processes in erectile dysfunction (5, 6), particularly in patients not responding to first-line orally active drugs and seeking an explanation as to why these agents failed (6). the improvement of patient’s selection by ultrasound (7) for different forms of therapy lead to a revisitation of venous leak interventions over the last years. the guidelines for varicous veins treatment recommend a proximal compression of the veins to enhance the time the sclerosing agent is affecting the venous wall (8). this important aspect is lacking in the techniques described for sclerotherapy in penile venous leak (9-12). therefore, we developed a technique, that allows to bring all the recommended and proven concepts of venous sclerotherapy into sclerotherapy in case of penile venous leak. this includes the use of polidocanol 3% and injection in air-block technique under valsalva maneuver. this procedure was performed in local anaesthesia. we report our experience with this improved technique. doi: 10.4081/aiua.2015.1.1 herwig_stesura seveso 02/04/15 10:11 pagina 1 archivio italiano di urologia e andrologia 2015; 87, 1 r. herwig, s. sansalone 2 material and methods routine evaluation consisting of medical history, physical examination, complete blood analysis, hormonal analysis, biochemistry studies, iief15-score and color doppler ultrasound after intracavernous injection of 0.02 mg alprostadil was performed in patients presenting with erectile dysfunction. peak systolic velocity less than 25 cm per second was accepted as a criterion for arterial insufficiency. a resistive index (ri) lower than 0.90 in combination with an end-diastolic blood flow (edv) of 5 cm or greater and persistence of flow on valsalva maneuver according to the criterion of fuerst and virag was defined as venous leakage. all patients with confirmed diagnosis were informed about the results, advantages and disadvantages of available treatment options. ninety-six patients diagnosed with venous leakage with a mean age of 53.5 years (range, 30 to 74) elected deep dorsal vein abllation. an overnight spontaneous erection protocol (osep) was obtained with the neva™ -system (urometrics inc, st. paul, mn, usa) preand immediately postoperative and three months after treatment. additionally, the iief15-score was ascertained three months after therapy. after penile block with lidocaine a 1 to 2 cm penile dorsal midline incision was made at the penile base. the superficial dorsal vein was ligated. the deep dorsal vein was identified and isolated for about 2 cm length under the buck´s fascia. the distal end was ligated with 4-0 vicryl™ to prevent backflow into the glans penis and corpus cavernosum. circumflexed veins, which branched off from the isolated portion of the deep dorsal vein at the penile base, were ligated with 4-0 vicryl™, too. the proximal end was catheterized with a 20 gauge steel needle. the venous tract was confirmed by venography (figure 1). an air-block was set by antegrade injection of 1 ml air followed by 4 ml aethoxysclerol 3% for venoablation. the patient was asked to do a valsalva maneuver for about 3060 seconds. the occluded dorsal vein and its occluded collaterals were visualized (figure 2). the penile incision was anatomically closed with absorbable suture material. again an osep was obtained immediately after therapy. patients were reassessed by iief-score and osep at three months follow up. results the mean age at the time of surgery was 53.5 years (range 30 to 74), mean duration of disease was 3.7 years (range 0.5 to 10). the mean duration for the procedure was 23.8 minutes (range 12 to 41) with a mean use of 4 ml aethoxysclerol 3% (table 1). at 3-months post-operative follow-up schedule 77 (80.21%) patients reported to be able to penetrate without the aid of pde5 inhibitors and 15 patients (15.63%) still needed aid with pde5 inhibitors. four (4.17%) patients did not report any improvement. a typical picture before and after successful sclerotherapy is shown in figure 1. this patient presented with a doubled dorsal vein and a massive venous leak with varicous veins in the lower pelvis. these veins disappeared after sclerotherapy in the above described manner. follow up color doppler ultrasound revealed a venous leakage in 8 (8.33%) of the patients. preoperative iief15scores changed significantly from 20.5 (range 12 to 41) to 72.5 (range 70 to 75) at 3-months follow up (p = 0.02) (table 2). furthermore the incidence of overnight spontaneous erections increased from 2.83 preoperatively to 6.5 (p = 0.002) at 3-months follow up. volumetric analysis of the penis showed a significant increase from 119.47% (+/74.66%) preoperatively to 258.44% (+/85.40%, p = 0.006) at 3-months follows up (table 2). after a follow up of 12 months (n = 22) up to now 16 (72.73%) patients still reported to have a strong enough erection for sexual intercourse. four (18.18%) patients used pde5 inhibitors and 2 (9.09%) patients did not report any change to their preoperative state. figure 2. figure 1. herwig_stesura seveso 02/04/15 10:11 pagina 2 3archivio italiano di urologia e andrologia 2015; 87, 1 new technique for treatment of venous leak the procedure itself did not cause any intraoperative complication. postoperative minor hematomas occurred in 12 patients, but resolved without any intervention. discussion pde5-inhibitors have become the first-line standard therapy in erectile dysfunction (1). nevertheless, this therapy is not cause dependent and has a success rate at standard doses of 77% (1). this type of medication is not indicated for patients treated with certain cardiac medicaments or with other known contraindications. pde5-inhibitors have some, not always harmless, side effects who prevent patients from continuous use. furthermore, the medication is not covered by most health insurances and therefore is not affordable for many patients. virag et al. reported, that after 2 years from the completion of the trial only 32% of the patients (17.2% of the initial cohort) were still using sildenafil as a single treatment (2). in those patients who do not respond to sildenafil, a structural alteration in the components of the erectile mechanism can be suspected (1). penile erection is believed to be the result of venous occlusion along with increased arterial inflow and corporeal smooth muscle relaxation. a failure of the closing mechanism of the penile veins is one of the most common causes of vasculogenic erectile dysfunction. in the past procedures as deep dorsal vein ligation have been performed to recover erectile function (10). however data have shown that the success rate of surgical treatments for veno-occlusive disease, especially simple penile vein ligation, is poor. the long-term data show a clear decrease of erectile ability (10). one possible explanation for this fact is the opening-up of thin collateral veins from the corpora cavernosa resulting in a similar veno-occlusive disease state as prior to the surgery at long term follow up. our data on the contrary did not show such a significant worsening of erectile function. a possible explanation for our results may be the use of aethoxysclerol as sclerosing agent. because of the application of the aeroblock techique in valsalva maneouvre the sclerosing agent is maintained at place and can lead to a sufficient sclerosing of the deep dorsal vein network, including small veins. however we did experience a decrease of the success rate from about 80% at 3 months after surgery to 72% 12 months after intervention. such development may be based on the natural ability of neovascularization. therefore it may be that in some cases sclerotherapy may lead to a temporary improvement of erectile function, which will last for a while but will ultimately result in erectile dysfunction again. due to the minimal side effects observed, this minimal invasive method should be offered to most patients suffering from erectile dysfunction due to venous leak with either low/no effect of pde5-inhibitor or to patients, who do not want or can not afford pde5-inhibitor therapy. nevertheless in many cases this sclerosis treatment option has shown very good results, and has brought major relief for the patients in psychological as well as in psychosexual terms (9-11, 13-21). our technique leads to the occlusion of multiple venous channels, such as the prostatic plexus, internal pudendal veins and inferior vesical veins. aethoxysclerol is a sclerosing agent that has been used extensively in varicositas treatment. to our knowledge no study has reported the use of aethoxysclerol for the treatment of venogenic erectile dysfunction. an injection of this agent into a vein leads to a permanent emobolization and consequent closure of the vein. this features have been used for the treatment of varicose veins for many decades (12) (22). although we have not observed any event like this, it exists the possibility of small migrations in the lungs and before the procedure it should be diagnosed the presence of an open foramen oval in between the two auricles. use of the principles of well known procedures (12) in combination with current findings in anatomy (4, 23) may lead to better long-term result in venous leak patients. may be that this could lead to a minimal invasive procedure, that offers more options than penile prosthesis after pde5-inhibitor failure or in patients who cannot use this therapeutic option. our short-term and preliminary intermediate term results are encouraging and should be followed-up in the future. conclusions our new pelvic venoablation technique using aethoxysclerol in air-block technique was effective, minimally invasive, and cost-effective. all patients were able to perform sexual intercourse without the previously used dosage of their pde5 inhibitor. this new method may help in patients with contra-indications against pde5 inhibitors, in patients who can not afford the frequent usage of expensive oral medications or those who do not fully respond to pde5-inhibitors. references 1. hatzimouratidis k, amar e, eardley i, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol. 2010; 57:804-814. 2. virag r indications and early results of sildenafil (viagra) in erectile dysfunction. urology. 1999; 54:1073-1077. 3. nehra a, goldstein i, pabby a, et al. mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. j urol. 1996; 156:1320-9. table 1. mean min max age (years) 53.53 30 74 duration of ed (years) 3.7 1 10 pde 5 inhibitor per intercourse (mg) 75 50 100 operation time (min) 15.8 12 41 table 2. prae op post op significance iief 15 20.5 72.5 0.02 spontaneous erections 2.83 6.5 0.002 volume enhancement 119.47% 258.44% 0.006 herwig_stesura seveso 02/04/15 10:11 pagina 3 archivio italiano di urologia e andrologia 2015; 87, 1 r. herwig, s. sansalone 4 4. virag r, paul jf. new classification of anomalous venous drainage using caverno-computed tomography in men with erectile dysfunction. j sex med. 2011; 8:1439-1444. 5. altinkilic b, hauck ew, weidner w evaluation of penile perfusion by color-coded duplex sonography in the management of erectile dysfunction. world j urol. 2004; 22:361-4. 6. aversa a, sarteschi lm the role of penile color-duplex ultrasound for the evaluation of erectile dysfunction. j sex med. 2007; 4:14371447. 7. virag r, sussman h. exploration of the deep dorsal vein of the penis using pulsed doppler ultrasonography. preliminary study. j mal vasc. 1998; 23:195-198. 8. campbell b. varicose veins and their management. bmj. 2006; 333:287-92. 9. henriet jp value of sclerotherapy in the treatment of certain types of impotence caused by venous leakage. phlébologie. 1987; 40:975. 10. henriet, jp. value of sclerotherapy in the treatment of certain types of impotence caused by venous leakage. phlebologie. 1987; 40:975-980. 11. miwa y, shioyama r, itou y, et al. pelvic venoablation with ethanol for the treatment of erectile dysfunction due to veno-occlusive dysfunction. urology. 2001; 58:76-9. 12. nakata m, takashima s, kaminou t, et al.. embolotherapy for venous impotence: use of ethanol. j vasc interv radiol. 2000; 11:1053-1057. 13. redondo p, cabrera j. microfoam sclerotherapy. semin cutan med surg. 2005; 24:175-83. 14. basche s1, eger c, elsebach k, ulshöfer b. veno-occlusive dysfunction as a cause of erectile impotence: therapy of venous leak with retrograde embolization of the internal pudendal vein. vasa. 2003; 32:47-50. 15. herwig r, margreiter m, kuehhas f. pelvic venoablation for the treatment of erectile dysfunction caused by venous leakage. eur urol suppl. 2012; 11:87 16. kutlu r, soylu a. deep dorsal vein embolization with n-butyl2-cyanoacrylate and lipiodol mixture in venogenic erectile dysfunction: early and late results. radiol oncol. 2009; 43:17-25. 17. muller sc, schild h, fritz t, witzsch u. percutaneous transpenile and retrograde venous occlusion for the treatment of venous leak impotence. eur urol. 1991; 19:101-103. 18. peskircioglu l, tekin i, boyvat f, et al. embolization of the deep dorsal vein for the treatment of erectile impotence due to veno-occlusive dysfunction. j urol. 2000; 163:472-5. 19. popken g, katzenwadel a, wetterauer u. long-term results of dorsal penile vein ligation for symptomatic treatment of erectile dysfunction. andrologia. 1999; 31: 77-82. 20. schild h, müller sc, bürger ra, fritz t. transpenile venous occlusion in the treatment of erectile impotence.rofo. 1989; 151:470-2. 21. vale ja, feneley mr, lees wr, kirby rs. venous leak surgery: long-term follow-up of patients undergoing excision and ligation of the deep dorsal vein of the penis. br j urol. 1995; 76:192-195. 22. zhang b, chen j, xiao h, et al. treatment of penile deep dorsal venous leakage of erectile dysfunction by embedding the deep dorsal vein of the penis: a single center experience with 17 patients. j sex med. 2009; 6:1467-1473. 23. hsu gl, chen hs, hsieh ch, et al. insufficient response to venous stripping surgery: is the penile vein recurrent or residual? j androl. 2006; 27:700-706. 24. paul jf, virag r. does anatomy of the pubic arch interfere with the maintaining of erection? j sex med 2013; 10:777-781. correspondence ralf herwig, md, professor (corresponding author) dr.ralf.herwig@gmail.com vienna international medical clinic kreuzgasse 17-19 1170 vienna (austria) salvatore sansalone, md salvatore.sansalone@yahoo.it viale oxford, 81 00133 rome, italy herwig_stesura seveso 02/04/15 10:11 pagina 4 microsoft word 17valentino.docx no conflict of interest declared. 378 archivio italiano di urologia e andrologia 2014; 86, 4 presented at 19th national congress sieun, fermo 2014 original paper doi: 10.4081/aiua.2014.4.378 incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? massimo valentino 1, michele bertolotto 2, pasquale martino 3, libero barozzi 4, pietro pavlica 5 1 uo di radiologia, ospedale s. antonio, tolmezzo, udine, italy; 2 dipartimento di radiologia, università di trieste, trieste, italy; 3 uo di urologia i universitaria, università di bari, italy; 4 uo di radiologia, ospedale maggiore, bologna, italy; 5 gvm care and research, villalba hospital, bologna, italy. summary the increased use of ultrasound in patients with urological and andrologi significant role in the characterization of focal lesions in liver, pancreas, spleen and kidneys. their use in the cal symptoms has given an higher detection of intra-testic ular nodules. most of these lesions are hypoechoic and their interpretation is often equivocal. recently, new ultrasound techniques have been developed alongside of b-mode and color-doppler ultrasound. although not completely standardized, contrast-enhanced ultrasound (ceus) and tissue elastography (te), added to traditional ultrasonography, can provide useful infor mation about the correct interpretation of incidentally detected non-palpable testicular nodules. the purpose of this review article is to illustrate these new techniques in the patient management. key words: testicular lesions; ultrasound; contrast enhanced ultrasound; elastography. submitted 3 october 2014; accepted 31 october 2014 introduction the increased use of ultrasound (us) in patients with uro logical and andrological symptoms has given an higher detection of intra-testicular nodules. most of these lesions are hypoechoic and their interpretation is often equivocal (1). the incidence of non-palpable testicular lesions depends on their size. non-palpable nodules with a diam eter of 10 mm account for about 0.2-1% of the patients with testicular nodules investigated with us (2-5). most of these nodules are benign, including leydig cell tumor as the main lesion. nevertheless, if us is inconclusive, surgi cal exploration is the treatment of choice due to possible malignant nature of the nodule (6). by overcoming the limitation of b-mode and color doppler ultrasound, new techniques such as contrast enhanced ultrasound (ceus) and tissue elastography (te) were explored for characterizing the testicular nodules in order to select the appropriate treatment. contrast-enhanced ultrasound over the past decade, us contrast agents have gained a testis is not well establish, even if some authors advo cated their utility in trauma, infarction, and tumors. us contrast agents are gas-filled microbubbles of small size (less than 10 µm) able to diffuse in the blood allow ing the visualization of the vascularization of the nod ules. they are administered intravenously at the dose of 4.8 ml (one vial of contrast agent) followed by 10 ml of saline solution by an antecubital vein. after a mean delay of 20 seconds, the contrast agent reaches the testes giv ing its vascular map. the nodules can be depicted as hyper-enhancing, hypo-enhancing or non-enhancing masses in comparison with surrounding tissue. some authors advocated use of ceus in the preoperative assessment of testicular lesions with hypervascularity as an important feature in the diagnosis of malignancy (7). bubbles remain visible for 2-3 minutes after injection, therefore contrast intensity gradually decreases. tissue elastography tissue elastography (te) has been recently introduced for making non-invasive measurements of the mechanical properties of tissue. it is an imaging method of assess ment for the elasticity of biological tissues (8). it repre sents a “new way” of palpation, where a portion of tissue is compressed and the degree to which it displaces is assessed. the most common way to displace the tissue is a manual application of a slight longitudinal compres sion with a conventional probe (so called “strain imag ing”): the different tissues create different responses according to their specific elastic modulus (9). te evalu ates the relative elasticity of different tissues in a selected region of interest by using a fast cross correlation tech nique and a combined autocorrelation method. it creates an elastogram that is superimposed to the b-mode ultra sound image of the tissue and updated in real-time. by convention, the elastograms display a colour-coded map of the relative elasticity. the normal testis in color scale elasticity imaging shows homogenous, soft stiff ness. focal lesions depicted as hard on elastography are suspicious for malignancy. some authors found 87.5% 379 archivio italiano di urologia e andrologia 2014; 86, 4 m. valentino, m. bertolotto , p.martino, l. barozzi, p. pavlica sensitivity, 98.2% specificity, 93.3% ppv, 96.4% npv and 95.8% accuracy in differentiating malignant from benign lesions in 144 nodules/pseudo-nodules using te (8). they concluded that te was a very useful technique in assessing small testicular nodules and all types of pseusonodules and could be helpful in deciding the most appropriate clinical approach, allowing in particular con servative management in selected cases. testicular adrenal rests testicular adrenal rests are benign corticotropin-depend ent lesions that are often asymptomatic and occur fre quently in male patients with congenital adrenal hyperpla sia (cah) but have also been described in patients with cushing’s syndrome and addison’s disease (10). the reported prevalence by sonography however varies between 24% and 94%. histologically, testicular adrenal rests consist of hyperplastic adrenal cortical tissue origi nating from aberrant adrenal tissue that descends with the gonads during embryonic migration (11). on sonog raphy, the testicular adrenal rests mostly appear hypoe choic although they may be heterogeneous or hypere figure 1. adrenal rest. a) b-mode us shows a hypoechoic nodule with calcifications. b) on color doppler the nodule appear hypovascular. c) at ceus the nodule shows to be hyperenhancing in the arterial phase. d) on te the nodule is soft, similar to the surrounding testis. choic. calcifications may be present. the adrenal rests are usually bilateral. an important finding in adrenal rests is that vessels coursing through the lesion are not deviated and this is considered an important feature. ceus shows the nodules to be hyperenhancing in arte rial phase with isoenhancement in the venous and later phase. on te the nodules are usually soft, similar to the surrounding testis (figure 1). segmental testicular infarction segmental testicular infarction is an uncommon clinical situation. etiology is largely considered idiopathic, but cases have been described occurring in patients with hyper-coagulability disorders, vasculitides, or following torsion, trauma, infection (12), and iatrogenic vascular injury (13-15). according with bilagi et al. (1), segmen tal testicular infarction typically presents as a solitary solid wedge shaped or round area in the testis, hypoe choic or with mixed echogenicity, with markedly dimin figure 2. segmental testicular infarction. a) b-mode us shows a hypoechoic nodule with mixed echogenicity. b) on color doppler the vascularity is absent. c) ceus shows a characteristic with a perilesional rim of enhancement. d) on te consistency is slightly soft. incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? 380 archivio italiano di urologia e andrologia 2014; 86, 4 ished or absent vascularity. differential diagnosis with a tumor less vascularised than surrounding testicular parenchyma may be problematic in rounded lesions and when vascularity is not completely absent at color doppler interrogation. ceus improve characterization showing a non-enhancing lesion formed by ischemic parenchymal lobules. it therefore provided additional information that may be useful to differentiate this non surgical lesion from hypovascular tumors also in cases with equivocal features at color doppler interrogation by presence of intralesional color spots. as the nodule is composed of necrotic tissue, on te segmental testicular infarction is usually soft, although in acute cases consis tency may be slightly increased due to edema (figure 2). leydig cell tumor leydig cell tumor is a relatively uncommon condition that is characterized by focal proliferation of the andro gen-synthesizing interstitial cells of leydig (16). histologically, it is characterized by an increased number of testicular leydig cells which displace and compress the seminiferous tubules. leydig cell tumor constitute about 1-3% of all testicular tumors, and it affects males of 22 to 61 years with a mean age of 37 years (17). on b-mode us, leydig cell tumor commonly appears as an hypoechoic nodule within the testicular parenchyma. the vascularity within the nodules is variable but usual figure 3. leydig cell tumor. a) b-mode us shows a hypoechoic nodule. b) at color doppler vascularity is present. c) at ceus the nodule demonstrates early contrast enhancement, more than the normal testis. d) on te leydig cell tumor a hard pattern, probably depending on the number of the cells. ly increased. the nodule usually demonstrates early con trast enhancement at ceus, more than the normal testis. wash-out is often rapid. on te leydig cell tumor can demonstrate a soft or a hard pattern, depending on the number and in the size of the leydig cells, lymphatic or vascular invasion, cytonuclear atypia, number of mitoses, absence of well-defined edge or a capsule (figure 3). seminoma classic seminomas histologically are usually homoge neously solid, lobulated masses that may contain sharply circumscribed areas of necrosis. microscopically, tumor cells are uniform with abundant clear cytoplasm charac teristically arranged in nests outlined by fibrous bands; in 80% of cases, these bands are infiltrated by lympho cytes and plasma cells, possibly due to a host reaction to the tumor (18). the imaging features of seminomas reflect their histologic characteristics and their uniform cellular nature. on us, seminoma is a homogeneously figure 4. seminoma. a) b-mode us shows a hypoechoic rounded lesion. b) at color doppler the lesion appears hypovascular. c) ceus shows a rapid enhancement of the lesion. d) on te the nodule is hard. m. valentino, m. bertolotto , p.martino, l. barozzi, p. pavlica 381 archivio italiano di urologia e andrologia 2014; 86, 4 hypoechoic rounded lesion; it may be lobulated or multinodular appearance. cystic-like spaces are uncom mon. seminoma is usually hypervascular at color doppler interrogation. ceus shows a rapid enhance ment of the lesion with an abnormal depiction of cross ing vessel within the nodule. there is a rapid wash-out but a persistence of the crossing vessels sign. on te the nodule is usually hard, on occasion, with soft intrale sional areas due to necrotic changes (figure 4). nonseminomatous germ cell tumors this is a large group of histologically heterogeneous neo plasms. four basic types can be recognized: embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor. the combination of two or more types of these neoplasms results in mixed gcts. embryonal carcinoma has a more variable appearance than seminoma. it is mainly a solid tumor containing foci of hemorrhage and necrosis. teratoma is predominantly cystic and multiloc ulated. all types of tissues can be seen within the tumor, most commonly fat, cartilage and various types of epithelium. these tumors are further divided into mature and immature teratomas and those with malig nant areas. choriocarcinoma represents the most lethal form of testicular carcinomas. this tumor is often small, usually hemorrhagic, and partially necrotic. yolk sac tumor has a soft consistency and a microcystic appear figure 5. teratoma. a) b-mode us shows a hypoechoic not homogeneous nodule. b) at color doppler vascularity is poor. c) ceus demonstrates some bubbles within the nodule suggesting the malignancy. d) on te the nodule appears clearly hard ance. therefore, nonseminomatous testicular tumors are expected to appear as hypoechoic not homogeneous masses on us, with anechoic areas of necrosis and hyper echoic areas of calcification. increased vascularity may or may not be demonstrated. however, ceus is more able to demonstrate the vascularity of the nodule, sometimes with rare microbubbles within the lesion suggesting the malignancy. on te these nodules appear clearly hard (figure 5). conclusion us is the imaging modality of choice for scrotal patholo gies. opposite to palpable testicular masses, non-palpable incidental testicular nodules are often benign and an accu rate diagnosis is relevant for the appropriate treatment. advanced and innovative us technology allows a better characterization of small testicular nodules. ceus and te are a useful adjunct to traditional b-mode and color doppler examination, clearly identifying vascularization and consistency of the nodule. although no ultrasound appearances may be entirely diagnostic, a combined evaluation of the grey-scale, vas cular, and elastographic features of the nodule may allow a better confidence in the final diagnosis guiding the urologist to the appropriate treatment. references 1. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasms diagnosed by ultrasound. j urol. 2003; 170:1783-6. 2. avci a, erol b, eken c, ozgok y. nine cases of nonpalpable tes ticular mass: an incidental finding in a large scale ultrasonography survey. int j urol. 2008; 15:833-6. 3. connolly ss, d'arcy ft, gough n, et al. carefully selected intrat esticular lesions can be safely managed with serial ultrasonography. bju int. 2006; 98:1005-7. 4. müller t, gozzi c, akkad t, et al. management of incidental impalpable intratesticular masses of < or = 5 mm in diameter. bju int. 2006; 98:1001-4 5. toren pj, roberts m, lecker i, et al. small incidentally discovered testicular masses in infertile men-is active surveillance the new stan dard of care? j urol. 2010; 183:1373-7 6. albers p, albrecht w, algaba f, et al. european association of urology. eau guidelines on testicular cancer: 2011 update. eur urol. 2011; 60:304-19. 7. lock g, schmidt c, helmich f, et al. early experience with con trast-enhanced ultrasound in the diagnosis of testicular masses: a feasibility study. urology. 2011; 77:1049-53. 8. goddi a, sacchi a, magistretti g, et al. real-time tissue elastog raphy for testicular lesion assessment. eur radiol. 2012; 22:721-30. 9. aigner f1, de zordo t, pallwein-prettner l, et al. real-time sonoelastography for the evaluation of testicular lesions. radiology. 2012; 263:584-9. 10. dogra v, nathan j, bhatt s. sonographic appearance of te sticular adrenal rest tissue in congenital adrenal hyperplasia. j ultrasound med. 2004; 23:979-81. 11. stikkelbroeck nm, suliman hm, otten bj, et al. testicular adrenal incidentally detection of non-palpable testicular nodules at scrotal ultrasound: what is new? 382 archivio italiano di urologia e andrologia 2014; 86, 4 rest tumours in postpubertal males with congenital adrenal hyperpla sia: sonographic and mr features. eur radiol. 2003; 13:1597-603. 12. bilagi p, sriprasad s, clarke jl, et al. clinical and ultrasound features of segmental testicular infarction: six-year experience from a single centre. eur radiol. 2007; 17:2810-8. 13. magill p, jacob t, lennon gm. a rare case of segmental testicu lar infarction. urology. 2007; 69:983 e987-8. 14. mincheff t, bannister b, zubel p. focal testicular infarction from laparoscopic inguinal hernia repair. jsls. 2002; 6:211-3. 15. secil m, kocyigit a, aslan g, et al. segmental testicular infarc tion as a complication of varicocelectomy: sonographic findings. j clin ultrasound. 2006; 34:143-5. 16. mati w, lam g, dahl c, et al. leydig cell tumour--a rare tes ticular tumour. int urol nephrol. 2002; 33:103-5. 17. carmignani l1, salvioni r, gadda f, et al. long-term followup and clinical characteristics of testicular leydig cell tumor: experi ence with 24 cases. j urol. 2006; 176:2040-3. 18. ulbright tm germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. mod pathol. 2005;18 suppl 2:s61-79. correspondence massimo valentino, md massimo.valentino@ass3.sanita.fvg.it uo di radiologia, ospedale s. antonio, 33028 tolmezzo, udine, italy michele bertolotto, md dipartimento di radiologia, università di trieste, trieste, italy pasquale martino, md uo di urologia i universitaria, università di bari, italy libero barozzi, md uo di radiologia, ospedale maggiore, bologna, italy pietro pavlica, md gvm care and research, villalba hospital, bologna, italy stesura seveso 165archivio italiano di urologia e andrologia 2015; 87, 2 case report correcting and sharing our complications. misplacement of pigtail catheter, during a robot assisted pyeloplasty. clinical findings, diagnosis, possible causes and endoscopic treatment konstantinos stravodimos 1, ioannis katafigiotis 2, evangelos fragkiadis 3, stavros tyritzis 3, constantinos a. constantinides 4 1st university urology clinic, laiko hospital, greece. objective: robotic assisted pyeloplasty (rap) is rapidly adopted by surgeons around the world. we present a unique complication of the technique, consisting of pigtail misplacement, which was endoscopically resolved. we discuss the clinical findings, differential diagnosis and principles of endoscopic treatment. materials and methods: a 41 years old female patients underwent transperitoneal right side rap with the hynes-anderson technique for ureteropelvic junction obstruction. pigtail was placed intraoperatively in an antegrade fashion. post operative course appeared normal but kidney-ureterer-bladder(kub) x-ray, revealed a misplaced pigtail. patient underwent a semirigid ureterorenoscopy demonstrating that the pigtail was exiting the collecting system in the rear line of suturing between continuous sutures. pigtail was retrieved with a stone retrieval forceps with short upward motions in the renal pelvis under fluoroscopy and then removed from patient, in order to avoid stressing the anastomosis. no leakage was noted in fluoroscopy, a pigtail was correctly placed and patient recovery was uneventful. results: retrograde pyelography was the key to accurate diagnosis and endoscopic treatment, because the exact point of exit and anastomosis integrity were established. retrieval of the pigtail was the most challenging part. lack of proper visualization and mobilization of the rear part of the anastomosis during surgery, combined with lack of tactile feedback, because of robotic instrumentation, were of critical importance in the manifestation of such a mishap. endoscopy facilitated case resolve, but proper handling is required to protect the anastomosis. conclusions: the introduction of novel techniques can carry the burden of novel complications. a surgeon must always keep in mind the complications inherent to the technique and at the same time the limitations of the equipment used, especially the lack of tactile feedback in robotic instrumentation. key words: robotic assisted pyeloplasty; misplaced pig tail; pyeloplasty complication. submitted 1 december 2014; accepted 28 january 2015 summary no conflict of interest declared. ureteropelvic junction obstruction (upjo). the good efficacy of the method, the excellent surgeon control of dissection and suturing, combined with the fast recovery, minimal pain and good aesthetic results may explain the rapid diffusion of the robotic approach (1-3). the introduction of novel techniques can carry the burden of novel complications. a surgeon must always keep in mind the complications inherent to the technique and at the same time the limitations of the equipment used, especially the lack of tactile feedback in robotic instrumentation. case presentation a female patient aged 41 was subjected to robot assisted transperitoneal right dismembered hynes-anderson pyeloplasty, after excision of the stenotic part of the upj. a pigtail was placed in an antegrade fashion over a ptfe guidewire after the completion of the rear part of the anastomosis with a continuous pds suture 4.0. after the pigtail placement the anastomosis was completed, a drain was placed near the upj area through a robotic port. patient recovered normally from general anaesthesia and was transferred to the urology ward. post operative course was uneventful. patient was mobilized in the same evening and received a light supper and fluids. standard use of paracetamol as analgesic was adequate for managing patient post-operative pain. drainage fluid collection was minimal (less than 50 cc) in the first 24 hours. clinical examination was normal with normal abdomen sounds and no signs of peritoneal distress in abdomen palpation. in the first postoperative day a kub x-ray was performed as standard care to confirm the correct placement of the stent (figure 1). the kidney-ureter-bladder (kub) x-ray showed a rather complicating picture in which the upper part-tail of the stent seemed to be in correct position inside the renal pelvis but the lower part was misplaced. an emergency ultrasound following the kub x-ray, confirmed that the upper part of the pigtail was placed inside the renal pelvis while was negative for urinoma. pigtail end was not found inside the bladder. doi: 10.4081/aiua.2015.2.165 introduction robot assisted pyeloplasty (rap) constitutes a less invasive but similar safe and effective method compared to open pyeloplasty for the surgical management of the stravodimos_stesura seveso 02/07/15 11:29 pagina 165 archivio italiano di urologia e andrologia 2015; 87, 2 k. stravodimos, i. katafigiotis, e. fragkiadis, s. tyritzis, c.a. constantinides 166 reached the urinary bladder, the right orifice was easily recognized and catheterized. retrograde pyelography was performed with fluoroscopy, no sign of leakage was noticed, while only the initial upper part of the pigtail was in the renal pelvis. a hydrophilic zip-wire was easily placed as a safety wire and a ptfe wire as guidewire. semirigid ureteroscopy over the guidewire was performed all the way up to the renal pelvis (figure 2.). at the rear part of the anastomosis in between the suturing line, the pigtail was recognized exiting the urinary tract. after correct diagnosis the next step was to remove the misplaced pigtail. in order to remove the pigtail we chose to handle it not from the tip but exactly from the site that was exiting the anastomosis using a stone retrieval forceps. slow short curved moves were used to tract the pigtail backwards and upwards inside the renal pelvis, so as to put minimal tension on the anastomosis under simultaneous optical and fluoroscopy guidance. after complete retrieval of the stent inside the urinary tract the tip of the pigtail was pulled again with the forceps and removed with the ureteroscope. a second look retrograde pyelography revealed minor leakage and a new pigtail was placed under fluoroscopy (figu re 3). patient had no drain output during the next 24 hours, no pain, normal bowel movement and she was discharged the following day. a new intravenous pyelography was performed as a follow-up two months later depicting an intact pyeloureteric anastomosis discussion and supplementary references are posted on www.aiua.it references 1. autorino r, eden c, el-ghoneimi a, et al. robot-assisted and laparoscopic repair of ureteropelvic junction obstruction: a systematic review and meta-analysis. eur urol. 2014; 65:430-52. 2. mendez-torres f, woods m, thomas r. technical modifications for robot-assisted laparoscopic pyeloplasty. j endourol. 2005; 19:393-6. 3. sethi as, regan sm, sundaram cp. robot-assisted laparoscopic pyeloplasty with and without a ureteral stent. j endourol. 2011; 25:239-43. correspondence konstantinos stravodimos, md associate professor kgstravod@yahoo.com ioannis katafigiotis, md (corresponding author) resident katafigiotis@yahoo.com evangelos fragkiadis, md associate scientist-urologist. e.fragkiadis@gmail.com stavros tyritzis, md associate scientist-urologist statyr@freimail.gr constantinos a. constantinides, md professor of urology ckonstan@med.uoa.gr 1st university urology clinic, athens university medical school laiko hospital, 17 agiou thoma str., 11527, athens, greece figure 1. kub x-ray depicting the misplacement of the pig-tail. figure 2. semirigid ureteroscopy and retrieval of the pig tail inside the renal pelvis. figure 3. fluoroscopy depicting minor leakage of the ureteropelvic anastomosis differential diagnosis the differential diagnosis included three case scenarios. initial concern was that the guidewire during the placement either never reached the bladder and as a result the pigtail was not properly placed in the bladder but the whole lower part and the tip of course curled inside the ureter. another possibility was that during the insertion of the pigtail, even though we used the flexible tip inside the urinary tract, a perforation had occurred and as a result the pigtail was exiting the urinary tract through the perforation of the ureter inside the abdomen. the last but the worst case scenario was that the double j was misplaced at the initial placement in the anastomosis, thus meaning that during the insertion the guidewire not only didn’t entered the ureter but was moving freely inside the abdomen cavity with the risk of traumatizing a vital organ-tissue. our primary concerns were to place a new pigtail in a proper position to establish normal urine drainage and to remove the misplaced pigtail without compromising the integrity of the anastomosis and the ureter or risking any abdomen organ injury. we opted for an endoscopic approach for optimum diagnosis and the possibility of final resolution. endoscopy treatment cystoscopy, as expected, revealed that the pigtail had not stravodimos_stesura seveso 02/07/15 11:29 pagina 166 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2158 case report rare type of bladder cancer: malign fibrous histiocytoma orcun celik, hakan turk, salih budak, yusuf ozlem ilbey tepecik educational and research hospital, urology clinic, izmir, turkey malignant fibrous histocytoma (mfh) is the most common soft tissue sarcoma in adults. urinary tract is a very rare location for mfh. involvement of the bladder is more common in males and at the 6th decade of life. a case of mfh of the bladder with poor prognosis is presented. prognostic factors for mfh are tumor grade, amount of invasion, age, tumor size, and histological type. survival rate is very low and 3-year disease specific survival is approximately 40%. key words: malignant fibrous histocytoma; bladder; tumour. submitted 28 april 2014; accepted 31 may 2014 summary introduction malignant fibrous histocytoma (mfh) is a mesenchimal tumor, which was described by o’brien and stout in 1964 (1). mfh is an aggressive tumor with fusiform cells that is the most common soft tissue sarcoma in adults (2). urinary tract, especially bladder is a very rare location for mfh with only 29 previously reported cases. involvement of the bladder is more common in males and at the 6th decade of life. clinical presentation is similar to other bladder tumors. in the bladder this mesenchimal tumor and its variants should be distinguished with immunohistochemical methods from sarcomatoid carcinoma, inflammatory myofibroblastic tumor and leiomyosarcoma (3). mfh spreads fast and is generally metastatic. size, depth and histologic features of the tumor are important factors for metastasis (4). because of its rapid local and distant metastatic character, radical cystectomy, lymph node dissection and adjuvant radiotherapy are the first line treatments (5, 6). despite this treatment, 3-year survival is approximately 40%. this is probably due to its low frequency and lack of consensus on treatment. in the current article, we aim to review the relevant literature in the light of a case. case report a 57-year old man applied to our clinic with hematuria for one month. he had a trauma history that occurred 20 no conflict of interest declared years before and he was using tak. following the initial examination and investigation, we detected a bladder tumor and transurethral resection (tur) was performed. pathological examination showed a muscle-invasive tumour with the characteristics of a malignant fibrous histocytoma. toraco-abdominal tomography, hemogram, and biochemical tests were planned for staging. hydronephrosis in the left kidney and high calcium levels (15 mg/dl) were detected. because of the high calcium levels, we performed a bone scintigraphy and detected suspicious areas in ribs and femur head probably indicating the presence of bone metastasis. all these lesions were confirmed with magnetic resonance imaging (mri). high calcium level could not be lowered with medical treatment. therefore, patient underwent haemodialysis, but calcium levels remained high even after dialysis. after patient and patient’s relatives request, patient was discharged and died one month later. discussion mfh as a common soft tissue sarcoma in adults that constitutes 10-21% of all sarcomas. it is observed more commonly in lower extremities (50%), upper extremities (20%) and retroperitoneal space (15%). it is rare in the urinary tract and if seen, it is located mostly in the kidneys. non-epithelial tumors of the bladder consist of 2% of all bladder tumors and mesenchimal tumors of the bladder consist of 0.23-0.67% of all bladder tumors (7). mfh in the bladder is more common in males (4:1) and at the 6th decade of life and commonly presents with macroscopic hematuria. some experts suggested that it is related to radiotherapy and chemotherapy and it often cooccurs (approximately 13%) with other tumors (leukemia, hodgkin lymphoma, multiple myeloma) (5, 8). mfh in bladder presents as a large-sized tumor, with diameter of approximately 6.4 cm (1-15 cm). in our case, the diameter of tumor was 10 cm and extracted material was 30 cc. at diagnosis, 16% of patients are t2, 72% of patients t3 and 14% t4 (9). disease specific survival is 47.8% at 1 year and 31.9% at 2 years (9). as it is an aggressive and rare type of tumor and there is limited number of studies, treatment is not very successful. there are mainly four morphological types (3): 1) inflammatory type (36%), 2) storiform-fascicular type (40%), 3) pleomorphic type (13%) and 4) myxoid type (9%) (10). at immunohistodoi: 10.4081/aiua.2014.2.158 159archivio italiano di urologia e andrologia 2014; 86, 2 rare type of bladder cancer: malign fibrous histiocytoma chemical evaluation, it is vimentin, alpha-1 antichymo trypsin and factor 13a positive. in our case, the tumor was positive for vimentin and cd68. conclusion mfh in the bladder is a rare tumor and there are approximately 29 cases reported in the literature. it presents with macroscopic hematuria and is more common in men and in the 6th decade of life. the tumor is generally large and locally advanced or metastatic like in our case. survival rate is low and there is no consensus on treatment strategies. histochemical evaluation is needed to distinguish mfh that has four morphological variants from similar tumors. prognostic factors for mfh are tumor grade, amount of invasion, age, tumor size, and histological type. because of its aggressive characteristics, local and distant metastases are likely. therefore, cystectomy and lymph node dissection and further adjuvant radiotherapy to prevent local recurrence and adriamicin chemotherapy for distant metastasis can be used. however, there is no consensus on treatment strategies (11). survival rate is very low and 3-year disease specific survival is approximately 40% (9). further studies are needed in this topic. references 1. kearney mm, oule eh, ivins jc. malignant fibrous histiocytoma. a retrospective study 0f 167 cases. cancer. 1980; 45;167-78 2. weiss sw, enzinger fm. malignant fibrous histiocytoma: an analysis of 200 cases. cancer. 1978; 41:2250. 3. lott s, lopez beltran a, montironi r, et al. soft tissue tumors of the urinary bladder. part ii: malignant neoplasms. human pathology. 2007; 38:963-77. 4. brennan m, singer s, maki rg, et al. sarcomas of the soft tissues and bone 7th ed. philadelphia, lippincott williams & wilkins. 2005; 1581-1631. 5. beltran a, pacelli a, rothenberg hk, et al. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998; 159:1497-503. 6. froehner m, manseck a, haase m, et al. locally recurrent malignant fibrous histiocytoma: a rare and aggressive genitourinary malignancy. urologia internationalis. 1999; 62:164-70. 7. kunze e, theuring f, kruger g. primary mesenchymal tumors of the urinary bladder. a histological and immunohistochemical study of 30 cases. pathol res pract. 1994; 190:311-32. 8. helpap b. nonepithelial neoplasms of the urinary bladder, virchows arch. 2001; 439:497-503. 9. gunia s, may m, koch s, et al. is radical oncosurgery justified for the treatment of primary malignant fibrous histiocytoma of the urinary bladder? report of two cases and analyses of diseasespecific survival rates based on a review of the literature urol int. 2011; 86:261-268. 10. martín lp, vilar dg, sanz mb, et al. malignant fibrous histiocytoma of the bladder. a literature review actas urol esp. 2010; 34:378-85. 11. oesterling je, epstein ji, brendler cb. myxoid malignant fibrous histiocytoma of the bladder. cancer. 1990; 66:1836-1842. correspondence orcun celik, md (corresponding author) orcuncelik82@hotmail.com hakan turk, md salih budak, md yusuf ozlem ilbey, md tepecik educational and research hospital, urology clinic 35140 izmir, turkey microsoft word 04barozzi.docx no conflict of interest declared. 319 archivio italiano di urologia e andrologia 2014; 86, 4 presented at 19th national congress sieun, fermo 2014 review contrast enhanced ultrasound in the assessment of urogenital pathology libero barozzi 1, diana capannelli 2, michele imbriani 1 doi: 10.4081/aiua.2014.4.319 1 department of diagnostic imaging, radiology unit, maggiore hospital, bologna, italy; 2 cardio-thoracic-vascular department, radiology unit, university of bologna, policlinico sant’orsola-malpighi, bologna, italy. . summary contrast enhanced ultrasound (ceus) is an innovative technique that ceus also allows evaluation of renal ischemia, infections and trauma. employs microbubble contrast agents to demonstrate parenchymal perfusion. although initial clinical applica tion was focused on the liver pathology, a wide variety of clinical conditions can be assessed now with ceus. ceus is a well-tolerated technique and is acquiring an increasing role in the assessment of renal pathology because contrast agents are not excreted by the kidney and do not affect the renal function. ceus demonstrated an accuracy similar to contrast enhanced multi-detector computed tomography (ce mdct) in detecting focal lesions, with the advantage of the real-time assessment of microvascular perfusion by using time-intensity curves. the aim of this paper is to review the main indications of ceus in the assessment of renal and urogenital pathology. imaging examples are presented and described. advantages and limitations of ceus with ref erence to conventional us and ce-mdct are discussed. key words: ultrasonography; contrast enhanced ultrasonography; urology. submitted 3 october 2014; accepted 31 october 2014 introduction ceus contrast enhancement ultrasound (ceus) is a new tech nique that employs microbubble contrast agents and complementary harmonic pulse sequences to demon strate parenchymal perfusion. ceus is widely employed in several fields of clinical prac tice the 2011 updated european federation of societies of ultrasound in medicine and biology (efsumb) guidelines and recommendations on the clinical practice of ceus have identified the current indications for the administra tion of us contrast agents for the study of different parts of the body, including the kidneys (1). ceus is useful in the detection and characterization of lesions, by differentiating solid neoplastic masses from pseudotumors or by graduating complex cystic lesions according with the bosniak system (2, 3). ceus allows a real-time multiplanar evaluation of microvasculature, which colour doppler ultrasound can not detect: it is useful to characterize the perfusional pat tern of solid lesions (arterial and late phase). other advantages of ceus include its safety, simplicity, patient tolerance, lack of irradiation (conversely to ce-mdct scans) (4-6). microbubble contrast agents are not excret ed by the kidney and do not affect renal function: they can be safely administrated to patients with renal insuf ficiency. current contraindications are known hypersen sitivity to any of the contrast agent components (even if ultrasound contrast agents have low rate of anaphylactic reactions) and recent acute cardiopulmonary diseases. the main limit of this technique in the urinary tract assessment is that contrast agents are not concentrated in the collecting system and ceus cannot give information about urinary excretory system. ceus also have the same limitations of conventional ultrasound (us): poor sonic window due to bowel gas, ribs or patients with large body habitus (obesity) prevents good quality images. in these cases, ce-mdct can give more information. microbubble contrast agents microbubble contrast agents consists of gas microbubbles (air or perfluorocarbon) stabilized by a biodegradable shell of protein, lipid or polymer. the small size of microbubbles (from 1 to 10 micrometres, as the size of a red blood cell) allows their passage unfiltered through the lungs but prevents entry into the interstitium allowing them to remain entirely intravascular (“pure blood pool” agents) (4-5, 7). under us exposition, microbubbles oscillatory contract and expand themselves with the same resonance frequency of us waves, by amplifying the us signal. after circulating for several minutes, microbubbles dissolves: the gas is exhaled by the lungs whereas the biodegradable shell is metabolised by the liver. technique kidney has a single arterial blood supply, conversely to the liver. after endovascular bolus injection of the con trast agent, microbubbles diffuse to the blood pool. at first, it can be detected an arterial phase with corti comedullary differentiation lasting for 20-40 seconds. 320 archivio italiano di urologia e andrologia 2014; 86, 4 l. barozzi, d. capannelli, m. imbriani during the later phase (45-120 sec), the enhancement is homogeneous and the differentiation between cortex and medulla is lost. the lesion contrast enhancement is eval uated in comparison with the surrounding parenchyma (4). kidneys are highly vascularized and the contrast enhancement is faster than other abdominal organs: this allows the characterization of renal parenchyma but also the evaluation of liver (in the remaining 3 minutes after kidneys) and spleen (that retrains the contrast agent for as long as 7 minutes). kidney renal infections the diagnosis of acute pyelonephritis is based on clinical evaluation and laboratory findings (1). conventional baseline us demonstrates increased size of the kidney and cortical scarring, suggestive of previous episodes of infections. ceus has an important role when the patient is still febrile after 72 hours despite of antibiotic treat ment and a complicated pyelonephritis is suspected. as ce-mdct, ceus can show focal parenchymal areas of pyelonephritis that appear as wedge-shaped areas of reduced enhancement because of the parenchymal oede ma (figure 1). sometimes pyelonephritis can complicate with parenchy mal abscessualization: a focal inhomogeneous non enhancing area with intense peripheral uptake (figure 2). purulent material in pelvicalyceal system can be easily detected as echogenic material with no contrast uptake, since contrast agents are not concentrated in the collect ing system. this finding is useful to differentiate pus from uro-endothelial tumours (5). renal ischaemia kidney has an abundant blood flow but can undergo a variety of vascular injuries. ceus demonstrates high accuracy in detecting kidney parenchymal ischaemia, comparable to ce-mdct. ceus shows a higher sensibility in comparison to colour doppler by detecting smaller blood vessels with slower blood flow. microbubbles reach the microvasculature and amplify the us signal, allowing a direct evaluation of parenchy mal perfusion. renal ischaemia appears as a triangular o wedge-shaped area with no contrast uptake, easily detectable in comparison to the surrounding normal parenchyma (figure 3). ceus may also provide more precise information about tissue vitality: it can differentiate infarcts from areas of diminished perfusion. even if both injuries appear at colour doppler as non-vascularized areas, the key find ing is that only infarcts show complete lack of contrast enhancement after injection. kidney transplant the renal transplant represent the ideal application of ceus because the organ is superficial and well vascular ized. renal transplant can undergo a wide range of possi ble complications in the early post-operative period. the main important is the acute rejection. figure 1. contrast enhancement ct shows an inhomogeneous parenchymal enhancement due to the presence of parenchymal oedema (a). baseline us (b) demonstrates a wedge-shaped ipoechogenic area with poor vascularization on colour doppler evaluation (c). ceus confirms the lack of contrast enhancement in this area (d). figure 2. abscessualization. ceus shows a poor-defined area of lack of contrast with an early and intense peripheral enhancement. a b figure 3. baseline us examination shows an ipoechogenic area involving the upper pole of the right kidney (a). ceus demonstrates a well-defined, triangular-shaped area of enhancement defect, suggestive of renal ischaemia (b). the first-line evaluation is typically performed with spec tral doppler measurements in order to assess abnormal values in resistance index (ri). contrast enhanced ultrasound in the assessment of urogenital pathology 321 archivio italiano di urologia e andrologia 2014; 86, 4 figure 4. normal kidney transplant: regular and homogeneous perfusion (a). acute rejection in kidney transplant: ceus demonstrates a dishomogeneous perfusion (b). figure 6. contrast enhancement ct scan shows a complicated cystic lesion with diffuse/smooth contrast enhancement (a). colour doppler examination demonstrate a heterogeneous mass with ipoechoic and fluid component without significant vascular apply (b). ceus reveals an internal enhancing soft tissue component, suggestive of bosniak iv category (c). spectral doppler assess ment only provide indi rect information about the parenchymal perfu sion, whereas micro bubble contrast agents allow a direct visualiza tion of microcircula tion. ceus findings are also earlier than abnormal ri (8 10). in acute rejection, the parenchymal perfusion is delayed. the time-intensity curves can demonstrate a diffuse delayed and slow contrast enhancement of the renal parenchyma. in a later phase, ceus can also show perfusional defects (figure 4). ceus is also useful in monitoring the anti-rejection therapy, by assessing an improved parenchymal perfusion (11). cystic lesions renal cysts are a common finding, but any cyst that does not show the typical features of a benign cyst is by defi nition “complicated” and requires further assessment. ceus can be useful in differentiating benign cysts from cystic tumours. even if the bosniak classification system was developed on the basis of contrast-enhancement findings of cystic renal masses on ce-mdct (2-3), ceus can provide useful information for the manage ment of these lesions: surgical treatment or observation. ceus is acquiring an increasing role in the assessment of indeterminate cystic lesions (bosniak iif and iii) by detecting the presence and the enhancement of solid components. recent comparative studies (12) between ceus and ct revealed that ceus imaging was superior figure 5. contrast enhancement ct scan shows a complicated cystic lesion with grossly thicked walls (a), well marginated, without significant ce of the walls (b), suggestive of bosniak category iii. baseline us examination shows echoic content (solid/haemorrhagic echo in the liquid content of the cyst) and confirms the ct finding of thicked walls (c). ceus demonstrates a well enhancing mural nodule (arrow) within the lesion, suggestive of bosniak iv category (d). to ct in term of detecting additional septa, thickness of the wall or septa and solid components. microbubble contrast agents circulate in the micro vessels of septa and walls and ceus provides the evaluation of sophisticated internal structures of cystic renal masses with a higher resolution than ct. in particular, the demonstration of solid components is the key factor in differential with the categories iii and iv, that are considered malignant and must be surgically removed (figures 5, 6). solid masses the majority of renal tumours are renal cell carcinomas, whereas oncocytomas and angiomyolipomas represent a small part of renal solid lesions. renal malignancies have a rich blood supply and ceus can show an increased and heterogeneous enhancement (figure 7), fast filling and rapid wash-out (figure 8). however, the kidney itself has abundant blood supply and the lesion may appear isoechoic to the surrounding renal cortex (5, 13). ceus is not currently used for differentiating between benign and malignant solid lesions. even if several stud ies propose new methods for qualitative and quantitative assessment of contrast enhancement, solid malignancies does not show a specific perfusion pattern (5, 14). ceus may provide useful information in case of haem orrhage by detecting an underlined lesion into the haematoma that appear to conventional us evaluation as a large heterogeneous mass. another important role of ceus is to differentiate pseudo tumors (or renal column dysplasia) from solid malignan figure 7. contrast enhancement ct scan shows a heterogeneous solid lesion, with intense peripheric enhancement (a). colour doppler examination shows an increased vascularization, both intralesional and peripherical (b). ceus demonstrates an intense peripherical hyperenhancement, suggestive of renal clear cell carcinoma (c). l. barozzi, d. capannelli, m. imbriani 322 archivio italiano di urologia e andrologia 2014; 86, 4 figure 8. time-intensity curves display two different pattern of solid lesion contrast enhancement. in the first case (a), the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal renal cortex. the red time-intensity curve shows a higher fast filling hyperenhancement with reference to the normal renal parenchyma, suggestive of renal clear cell carcinoma. whereas in the second case (b), the red time-intensity curve show a later and lower enhancement with reference to the normal cortex, suggestive of ipovascularizated solid malignant lesion. figure 10. baseline us examination (a) is inadequate to detect renal laceration because it is isoechoic to the surrounding parenchyma. colour doppler (b) shows a relative homogeneous perfusion. after contrast injection, ceus demonstrates a filling defect due to parenchymal laceration (c, d). a b figure 9. baseline us examination (a) shows an ipoechoic mass, suggestive of a solid occupying lesion. ceus reveal a normal intravascular flow within this region, with homogeneous vascular enhancement without vessels distortion, suggestive of renal column dysplasia (b). cies. renal column hypertrophy is a congenital renal dys plasia that mimic a solid lesion of the cortex. ceus demon strates normal courses of renal vessels without an occupy ing lesion and a dynamic pattern of contrast enhancement identical to the surrounding parenchyma (figure 9). trauma ceus with second-generation contrast agents shows a high sensitivity both in lesion detection and grading, but ceus should be reserved for the assessment of stable, low-energy isolated trauma patients with unilateral pain. these patients have low risk for multi-organ and severe traumatic involvement, are haemodynamically stable and can be conservatively treated and evaluated during the follow-up (15-16). instead, the modality of choice for the first-line evalua tion in emergency room of severe traumatic patients is the conventional fast (focus assessment with sonography in trauma) us. fast-us allows to exclude free abdomi nal, pleural and pericardial fluids, but it has low sensi tivity in detection of parenchymal traumatic lesions, which may be isoechoic and can be missed (17). ce-mdct remains the reference examination in high energy multitrauma because of high spatial resolution, very fast execution and higher sensibility. ce-mdct also allows to exclude active bleeding, multitraumatic involvement of deep organs (pancreatic trauma) and gut perforations. the main indication ceus is in the second line evaluation of patients with low-energy isolated abdominal trauma. ceus demonstrates an accuracy sim ilar to ce-mdct in detecting and grading renal trau matic lesions. parenchymal lacerations and haematomas appear as non-enhancing areas after contrast injection (figure 10). the main limit of ceus in kidney traumat ic lesions is the impossibility to visualize pelvicalyceal and ureter injuries, since contrast agents are not concen trated in the collecting system. in these cases, ce-mdct should be always performed in ceus-positive patients to exclude active bleeding and urinomas. urinary excretory system the main limit of ceus in urinary excretory system is that contrast agents are not concentrated in the collect ing system and only voluminous pelvicalyceal neoplastic masses can be detected. ceus is also acquiring an increasing role in the assess ment of vesicoureteral reflux in children, because of the safety of the technique and the lack of irradiation (con versely to retrograde cystourethrography). after intra bladder administration of microbubble, ceus is able to assess and quantify the grade of vesicoureteral reflux. urethra can also be involved in coital trauma. the intraurethral administration of microbubble constrast agent may improve the visualization of traumatic lesions or the detection of active urine extravasion. prostate trans-rectal ceus has a high sensitivity in showing the cancer induced neovascularization and significantly improves ultrasound imaging for prostate cancer detection and localisation. in 85% of cases, prostate cancer is multi focal and it tends to grow along the capsule of the gland contrast enhanced ultrasound in the assessment of urogenital pathology 323 archivio italiano di urologia e andrologia 2014; 86, 4 figure 11. hipoechoic prostatic lesion on conventional trans-rectal us assessed with ceus. the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal prostatic parenchyma. the red time-intensity curve shows a poor contrast enhancement within the lesion, suggestive of hypovascularized prostatic tumour. with an oblong shape. prostate cancer differs from benign prostate tissue because of the loss of normal glandular architecture, increased cellular density and altered microvasculature. the loss of normal glandular architec ture, characteristic of high-grade prostate cancer, results in fewer reflective interfaces and reduced echotexture on con ventional ultrasound. the classic gray scale ultrasound finding of cancer is a hypoechoic lesion (figure 11). however, prostate cancer may appear echogenic or isoechoic and conventional us examination can miss them (18). in these cases, ceus can help in the detection of malig nant lesions by demonstrating an area with early and increased enhancement, with reference to the surround ing parenchyma. the main differential diagnosis includes chronic prostatitis that can mimic the gray scale appearance of prostate cancer. prostatitis may result in a heterogeneous appearance in the prostate peripheral zone and can present with hypoechoic lesions that are indistinguishable from cancer. ceus evaluation with time-intensity curves may help in the differentiation. ceus also provides useful information to precisely target biopsies: a tailored approach to prostate biopsy based on contrast-enhanced ultrasound represents an innovative approach to detecting significant disease with fewer biopsy cores. scrotum acute scrotal pain is a challenging clinical problem that requires prompt diagnosis to determine appropriate treatment. it can be the result of a variety of causes, including torsion, epididymo-orchitis and tumours. the first-line examination in patients with a painful scro tum is conventional us with colour doppler. according with the 2011 updated efsumb guidelines (1), ceus is acquiring an increasing role in the management of acute scrotal pain, because ceus allow the correlation of macroscopic anomalies with possible perfusion alter ations, providing a working diagnosis that would enable the urologist to pursue appropriate management: surgi cal treatment or observation. in case of epididymitis or epididymo-orchitis, convention al us show a heterogeneous enlarged epididymis or testis with thickening. both colour doppler and ceus demon strate increased vasculatization of the epididymis or testis. sometimes inflammation can complicate with abscessu alization. us tipically shows a sharp heterogeneous area without vascular signal inside the focal lesion on colour doppler. ceus demonstrates focal absence of enhance ment with hyperechoic peripheral rim. ceus aquired an important role in emergency practice also in the detection of testicular torsion. the testis appears on conventional us as a normal sized testicle with decreased flow on colour doppler. ceus can shows the reduction or the complete absence of contrast enhancement of the testis, respectively in case of partial or complete torsion (figure 12) (19). ceus is the imaging investigation of choice in case of scrotal trauma because it is able to depict parenchymal disorders on the basis of vascularity, helping in the dif ferential diagnosis of scrotal lesions and traumatic changes. the key factor is to exclude testicular rupture and, in particular, the interruption of the tunica albug inea, allowing the urologist to decide when remove the injured testis or attempt salvage (15). testicular trauma appears as a hypoechoic interruption of the border of the testis with large surrounding haematoma. the integrity of the tunica albuginea may always be assessed. intratesticular hyperechoic areas are suggestive of haemorragia. in case of testicular rupture, ceus demonstrates a lack of contrast enhancement in the hypoechoic area. ceus can also detect active bleeding. ceus also help in detecting and characterizing testicular lesion of undefined nature at us. testicular neoplasms have a wide range of us presenta tion and the diagnosis is not possible on the basis of con ventional us. tumour can appear as heterogeneous hypoechoic area with poor vascularization on colour doppler. ceus has a higher sensitivity in detecting ves figure 12. acute testicular torsion. conventional us (b) shows a normal sized testicle. ceus demonstrates the complete lack of contrast enhancement within the testis due to the absolute absence of testicular blood flow (a). l. barozzi, d. capannelli, m. imbriani 324 archivio italiano di urologia e andrologia 2014; 86, 4 figure 13. hypoechoic lesion on conventional us is assessed with ceus. the red roi was drawn in a suspicious area whereas the yellow roi was drawn in an area representing the normal testicular parenchyma. the red time-intensity curve shows a higher fast filling hyperenhancement with reference to the normal testicular parenchyma and a rapid wash-out in the later phase, suggestive of testicular tumour. sels within the lesion and can show a slight or strong enhancement within the lesion in the early phase, that become hypoechoic compared to the surrounding parenchyma in the late phase. time-intensity curves demonstrates an increased enhancement in early phase and rapid wash-out (figure 13). penis sometimes penis can be involved in scrotal trauma, typ ically coital trauma. as for the testis, the key finding is the integrity of the tunica albuginea. the intracavernous administration of microbubble constrast agent may improve the visualization of traumatic lesions or the detection of active bleeding. references 1. piscaglia f, nolsøe c, dietrich cf, et al. the efsumb guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (ceus): update 2011 on non-hepatic applications. ultraschall med. 2012; 33:33. 2. bosniak ma. diagnosis and management of patients with compli cated cystic lesions of the kidney. ajr am j roentgenol. 1997; 169:819. 3. bosniak ma.the use of the bosniak classification system for renal cysts and cystic tumors. j urol. 1997; 157:1852. 4. mcarthur c, baxter gm. current and potential renal applications of contrast-enhanced ultrasound. clin radiol. 2012; 67:909. 5. cokkinos dd, antypa eg, skilakaki m, et al. contrast enhanced ultrasound of the kidneys: what is it capable of? biomed res int. 2013; 59:5873 6. jakobsen ja, oyen r, thomsen hs, morcos sk. members of contrast media safety committee of european society of urogenital radiology (esur). safety of ultrasound contrast agents. eur radiol. 2005; 15:941. 7. correas jm, bridal l, lesavre a, et al. ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. eur radiol. 2001; 11:1316. 8. lebkowska u, janica j, lebkowski w, et al. renal parenchyma per fusion spectrum and resistive index (ri) in ultrasound examinations with contrast medium in the early period after kidney transplanta tion.transplant proc. 2009; 41:3024. 9. fischer t, filimonow s, dieckhöfer j, et al. improved diagnosis of early kidney allograft dysfunction by ultrasound with echo enhancer-a new method for the diagnosis of renal perfusion. nephrol dial transplant. 2006; 21:2921. 10. granata a, andrulli s, fiorini f, et al. diagnosis of acute pyelonephritis by contrast-enhanced ultrasonography in kidney trans plant patients.nephrol dial transplant. 2011; 26:715. 11. fischer t, mühler m, kröncke tj, et al. early postoperative ultra sound of kidney transplants: evaluation of contrast medium dynamics using time-intensity curves. rofo. 2004; 176:472. 12. park bk, kim b, kim sh, et al. assessment of cystic renal masses based on bosniak classification: comparison of ct and contrast enhanced us. eur j radiol. 2007; 61:310. 13. ignee a, straub b, schuessler g, dietrich cf. contrast enhanced ultrasound of renal masses. world j radiol. 2010; 2:15. 14. wang xh, wang yj, lei cg. evaluating the perfusion of occupy ing lesions of kidney and bladder with contrast-enhanced ultrasound. clin imaging. 2011; 35:447. 15. valentino m, de luca c, barozzi l, et al. contrast-enhanced us evaluation in patients with blunt abdominal trauma. j ultrasound. 2010; 13:22. 16. cokkinos dd, antypa e, kalogeropoulos i, et al. contrast enhanced ultrasound performed under urgent conditions. indications, review of the technique, clinical examples and limitations. insights imaging. 2013; 4:185. 17. smith za, wood d. emergency focused assessment with sonogra phy in trauma (fast) and haemodynamic stability. emerg med j. 2014; 31:273. 18. mitterberger m, pelzer a, colleselli d, et al. contrast-enhanced ultrasound for diagnosis of prostate cancer and kidney lesions. eur j radiol. 2007; 64:231. 19. valentino m, bertolotto m, derchi l, et al. role of contrast enhanced ultrasound in acute scrotal diseases. eur radiol. 2011; 21:1831. correspondence libero barozzi, md (corresponding author) libero.barozzi@ausl.bologna.it michele imbriani, md michele.imbriani@ausl.bologna.it department of diagnostic imaging, radiology unit, maggiore hospital largo nigrisoli 22 40100 bologna, italy diana capannelli, md diana.capannelli@yahoo.it cardio-thoracic-vascular department, radiology unit, university of bologna, policlinico sant’orsola-malpighi via massarenti 9 40138 bologna, italy stesura seveso archivio italiano di urologia e andrologia 2014; 86, 156 practical recommendations for performing ultrasound scanning in the urological and andrological fields aim: us scanning has been defined as the urologist’s stethoscope. these recommendations have been drawn up with the aim of ensuring minimum standards of excellence for ultrasound imaging in urological and andrological practice. a series of essential recommendations are made, to be followed during ultrasound investigations in kidney, prostate, bladder, scrotal and penile diseases. methods: members of the imaging working group of the italian society of urology (siu) in collaboration with the italian society of ultrasound in urology, andrology and nephrology (sieun) identified expert urologists, andrologists, nephrologists and radiologists. the recommendations are based on review of the literature, previously published recommendations, books and the opinions of the experts. the final document was reviewed by national experts, including members of the italian society of radiology. results: recommendations are listed in 5 chapters, focused on: kidney, bladder, prostate and seminal vesicles, scrotum and testis, penis, including penile echo-doppler. in each chapter clear definitions are made of: indications, technological standards of the devices, the method of performance of the investigation. pasquale martino 1, andrea benedetto galosi 2, marco bitelli 3, paolo consonni 4, fulvio fiorini 5, antonio granata 6, roberta gunelli 7, giovanni liguori 8, silvano palazzo 1, nicola pavan 8, vincenzo scattoni 9, guido virgili 10, and imaging working group società italiana urologia (siu) in collaboration with the società italiana ecografia urologica andrologica nefrologica (sieun) reviewers: libero barozzi 11, michele bertolotto 12, andrea fandella 13, paolo rosi 14, carlo trombetta 8 1 department of emergency and organ transplantation-urology i, university “aldo moro”, bari, italy 2 division of urology, “murri” general hospital, asur marche, fermo, italy 3 department of urology andrology unit, ospedale san sebastiano martire, frascati, roma 4 u.o. urologia casa di cura “s. maria”, castellanza, italy 5 nefrologia soc azienda sanitaria ulss 18 rovigo, rovigo, italy 6 u.o. nefrologia e dialisi asp agrigento, agrigento, italy 7 u.o. urologia ospedale g.b. morgagni-l. pierantoni azienda usl di forlì, forlì, italy 8 department of urology, university of trieste, ospedale di cattinara, trieste, italy 9 department of urology, university vita-salute, scientific institute san raffaele, milan, italy 10 department of urology, university of tor vergata, rome, italy 11 emergency, surgery and transplants department radiology unit, s. orsola-malpighi university hospital, bologna, italy 12 uco di radiologia, dipartimento di scienze mediche, chirurgiche e della salute università degli studi di trieste, ospedale di cattinara, trieste, italy 13 divisione urologica, casa di cura giovanni xxiii, monastier (treviso), italy 14 clinica urologica ed andrologica, university of perugia, perugia, italy. summary review the findings to be reported are described and discussed, and examples of final reports for each organ are included. in the tables, the ultrasound features of the principal male uro-genital diseases are summarized. diagnostic accuracy and second level investigations are considered. conclusions: ultrasound is an integral part of the diagnosis and follow-up of diseases of the urinary system and male genitals in patients of all ages, in both the hospital and outpatient setting. these recommendations are dedicated to enhancing communication and evidence-based medicine in an interand multi-disciplinary approach. the ability to perform and interpret ultrasound imaging correctly has become an integral part of clinical practice in uro-andrology, but intra and inter-observer variability is a well known limitation. these recommendations will help to improve reliability and reproducibility in uro-andrological ultrasound scanning. key words: recommendation; ultrasound scanning; kidney; bladder; prostate; scrotum; penis. history of the papers submitted 24 february 2014; accepted 3 march 2014 no conflict of interest declared doi: 10.4081/aiua.2014.1.56 lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 56 57archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields introduction these recommendations have been drawn up by the “imaging” working group of the società italiana di uro logia (siu) in collaboration with the società italiana di ecografia urologica andrologica nefrologica (sieun). the specialists involved in the work include urologists, andrologists, nephrologists and radiologists. the aim of this work is to support urologists in clinical practice, supplying a series of recommendations to be followed during the phases of ultrasound diagnosis of renal, prostatic, bladder, scrotal and penile diseases. these recommendations are based on a review of the literature, on previous recommendations and on the opinions of the experts (1-3). this document is the first to be devoted to this sector, although the american urological association (aua) and the american institute of ultrasound in medicine (aium) recently (november 2011) published practical guidelines for the performance of ultrasound in the urological field [www.aium.org] (2). the references will serve to make a constructive comparison with other clinical experiences. these recommendations were developed and drawn up with the aim of ensuring minimum standards of excellence for ultrasound imaging in urological practice, based on the assumption that ultrasound plays an essential part in this practice. doctors specializing in urology can gain particular skills and training in the use of ultrasound scanning during their residency years, in post-graduate dedicated courses organized by universities, in training courses organized by urological scientific societies (siu, sia, eau, aua) and dedicated societies (esui, sieun), both nationally and internationally. for the urologist, us scanning is an integral part of the processes of diagnosis and follow-up to manage diseases of the urinary tract and male genitals in patients of all ages, in both a hospital and an outpatient setting. the ability to perform and interpret imaging studies has become an integral part of clinical practice in all nations, also in order to optimize resources and provide patients with efficacious, rapid care. us scanning has been defined as the urologist’s stethoscope. this also applies in the andrological field. urologists must combine skilful use of sophisticated imaging devices with a deep knowledge of the physiological and pathological processes affecting the human body. if the diagnostic test will be performed in another department they must be able to select the best test or series of tests to be made for the specific patient, to optimize the management of the urological patient. these recommendations may be useful to ensure minimum shared or reference standards in the urological and andrological fields also for other medical specialists who perform urological us scanning, such as radiologists, internists, geriatricians, gynecologists or other doctors who study the urinary tract. the aims of the present recommendations are: • to define the purpose of each specific ultrasound investigation (to clarify what each investigation aims to discover). • to define the indications. • to establish the requisite technological standards of the devices. • to outline the method of performance of the investigation. • to establish the expected accuracy of the investigation in question. • to indicate the reporting method. apart from their utility as a theoretical-practical tool for making a correct ultrasound examination of the genito-urinary apparatus, these recommendations we propose have the aim of guiding the urologist in the assessment of the risks and benefits of diagnostic imaging so as to optimize the management of the urological patient [“patient care is optimized when urologists coordinate the use of imaging techniques and dedicated devices in the most advantageous place for their patients” – see (aua, aium develop joint guidelines for urologic ultrasound exams)] (2). below, brief recommendations regarding the equipment, documentation, reporting of the findings, training requirements and patient safety in ultrasound studies, are listed. equipment ultrasound scanning must be performed with devices that can provide images in real-time, thanks to the use of transducers that can optimize the penetration of the ultrasound waves inside the tissues, with excellent resolution obtained by setting appropriate frequency intervals. the advised transducer frequencies are 3.0-5.0 mhz for abdominal scanning, 6.0-9 mhz for transrectal and 7.012.0 mhz for genital scanning, while intraoperative renal or testicular scanning can be done with the transducer set at 6-10 mhz in linear mode. the correct setting of the device must also include the generation of good documentation of the investigations made. documentation each ultrasound investigation must be concluded with the production of appropriate, unequivocally clear images, recorded on a durable support (digital format is preferable) and saved in the patient's clinical files. the operator must check that the images are correctly recorded on the electronic support and readable in terms of contrast and luminosity. the ultrasound images must also be labeled with the patient's personal data and those of the health care facility where the investigation is made (hospital department or outpatients clinic). the date and type of probe are automatically specified by the device. reporting of findings apart from acquiring full documentation of the investigation, complete reporting of the findings must be made, specifying any conditions during the execution phase that could affect the reliability or accuracy of the test (e.g. anatomical causes [bowel gas, malformations], causes depending on the patient [poor compliance, pain during lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 57 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 58 the test], conduction in emergency regime, etc.). the report must include the name and signature of the doctor. ultrasound scanning is performed for specific purposes and the simple production of images, even of good quality, can never replace a description of the clinical picture and the interpretation of the findings by the operator. training requirements adequate training is an essential prerequisite for the correct performance and interpretation of ultrasound investigations. this training must be obtained both by residents at the specialist schools and by those who are already specialists in urology. they should all undergo regular updating of their ultrasound scanning skills, the former during their specialist studies and the latter at regular periodical updating courses. the main scientific societies are active in organizing such updates, and issue certificates of attendance at such training and updating courses. patient safety ultrasound procedures must be performed only for the specific indications of the case, like any other imaging technique. in fact, like all specialists, urologists should comply with the principles of alara (4), reducing to a minimum patients' exposure to acoustic energy (5). in addition, the operator must ensure that the ultrasound probe is clean and protected, to comply with the guidelines of the cdc (centers for disease control and prevention) for the standards of disinfection and sterilization of the devices (6, 7), as well as the technical recommendations specified by the manufacturers of the various devices. regular periodical controls of the devices must be made, with the collaboration of the manufacturers and complying with the safety norms they list. process of assessment of the recommendations an assessment of the true effectiveness of these recommendations in modifying behavior and improving the clinical outcome will be made using control procedures that are currently being defined. updating in the expectation of upcoming technological and/or diagnostic advances, the present recommendations will be integrated by further publications, likely every 3 years. ultrasound scanning of the kidney introduction the kidneys are a pair of organs located at the retroperitoneal level: each kidney is situated along the lateral margin of the psoas muscle, that lines it posteriorly, while it is adjacent to the bowel anteriorly. the right kidney lies about 2-3 cm lower than the left. the kidneys have the function of purging the organism of a great number of substances, and also play a part in many metabolic pathways (protein, lipid and glucides), including the metabolism of hormones and vitamins, as well as control of the blood pressure. healthy kidneys are easily assessed by ultrasound scanning because the parenchymal component is well delineated by the capsule and has a different echostructure from the perirenal fat and the pyelic structures. measurements measurements of the kidney length are made by scanning along the major axis parallel to the adjacent psoas muscle. the oblique plane of this long axis is measured by scanning the superior pole more medially and the inferior plane more laterally/anteriorly. the angle between the long axis and the sagittal plane ranges between 8 and 10 degrees (1). variations in this angle produce the variability between ultrasound measurements of the length and measurements made with conventional radiology or urography (2). with ultrasound scanning it is easy to make reliable, repeatable real-time measurements of the kidney long axis. it is clear that to make a precise measurement of the kidney axis it is necessary to identify the superior and inferior poles: this may be complex in cases of a malrotated, ectopic, ptosic, or scoliotic kidney, etc. measurement of the interpolar renal diameter is more accurate when the patient is placed in supine decubitus, slightly turned toward the contralateral side. oblique posterior longitudinal scanning is performed with the patient holding the homolateral arm above the head and breathing deeply, to shift the kidney under the ribs. measurements in prone position tend to result in an underestimation of the kidney length, but may need to be done if the kidney is poorly visualized in other scans (3). in clinical practice ultrasound measurement of the kidney volume is not performed because it is difficult to do and highly error-prone, even if it can be useful to assess renal anomalies (4). renal volume can be assessed by measuring the 3 orthogonal diameters and applying the following formula: volume v = 0.49 x l x w x ap where l is the length of the major axis (longitudinal scan), w is the length measured at the renal hilum (transverse scan) and ap the anteroposterior diameter again measured at the hilum (transverse scan) (5). the photos on which the measurements were based should be stored in the documentation of the investigation. it may soon be possible to make ultrasound measurements of the renal volume using 3d probes, that allow a greater precision than the common 2d probes (6). in any case, correct measurement of the volume of the kidneys requires good operator skills and knowledge of the renal anatomy, consisting of three different components: 1) the hyperechogenic external capsule; 2) the hypo-isoechogenic parenchyma as compared to the echostructure of the liver and spleen, between the capsule and pelvis, consisting of lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 58 59archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields a. the external echogenic cortex, being the functional portion b. the internal hypoechogenic medulla, corresponding to the medullary pyramids with a triangular structure and the base toward the outside. 3) the kidney sinus, hyperechogenic due to the presence of many interfaces consisting of intrarenal adipose tissue. indications renal ultrasound scanning is indicated in the first approach to patients with renal disease and in the follow-up. the investigations include: • assessment of the kidneys, in normal or ectopic sites; • assessment of the ultrasound morphology; • diagnostic workup in patients with acute or chronic kidney disease; • assessment of any dilation of the excretion pathways and differential diagnosis between obstructive and non obstructive acute renal failure (arf); • identification of space-occupying lesions (cysts and tumors); • searching for stones; • echocolordoppler assessment of the renal vascularization (both with color-powerdoppler and, in selected cases, contrast enhanced ultrasound [ceus]) (11); • assessment of the intrarenal resistance indexes (ri) at the level of the interlobar and/or arcuate arteries in nephropathic, hypertense, diabetic, nephroangiosclerotic patients; • guidance of renal needle biopsy performed in the course of kidney disease or to exclude cancer; • guidance of renal puncture in the course of hydrone phrosis, abnormal cysts inducing symptoms; • assessment of kidney transplant/s (just like the native kidney) and complications. • intraoperative guidance in conservative kidney surgery, percutaneous lithotrypsy, non surgical ablation of expanding lesions; • post-surgical monitoring or endourological treatments. preparation for the investigation although no specific preparation is considered strictly necessary, some suggestions are made with the aim of optimizing the performance of the investigation. it is better if the patient is asked to refrain from drinking fizzy drinks, fermented cheeses, vegetables, fruit and wholemeal foods, pulses. in cases of a “sluggish” bowel the patient should take a laxative the evening before. since renal studies should always include a study of the bladder, this should be replete but not distended. specifications of the minimum requirements for the echograph and probes to study the kidney, a latest generation echograph, if necessary portable, should be used, of average range equipped with color-powerdoppler module and if possible, suitable software for contrast enhancement. multi fre quency convex probes allow study of the native and transplanted kidney, but for facilities that receive kidney transplant patients it is very useful to be able to employ a multifrequency linear probe. a thermal printer is indispensable, as is a magnetic image storing system. a recent generation us device offers pre-settings of the parameters to be assessed for each organ and probe, especially during echocolor-doppler investigations. these settings are defined during the installation but must be checked by the operator, updated or modified according to need and the characteristics of the tools available, as approved by the manufacturer. parameter assessed 1. position of each kidney, including malpositioning: unilateral agenesis, ptosic, malrotated, or dysmorphic kidney, (horseshoe, etc.); 2. kidney size (7): maximum interpolar diameter (normal.: right cm 10.646 ± 1.345, left cm 10.130 ± 1.165) transverse diameter (normal.: right cm 4.920 ± 0.638, left cm 5.303 ± 0.744) parenchymal thickness (normal: 1.5-2.0 cm) [measurement of cortical thickness is not always possible due to poor cortico-medullary differentiation, and suffers from high inter and intraobserver variability, so it is not commonly used] (8, 9); 3. assessment of the kidney outline, that may feature the persistence of fetal lobes in the tract between two consecutive pyramids and/or the presence of grooves (scars after pyelonephritis) at one or more calyces; 4. check for stones (hyperechogenic image measurable by posterior shadow cast); 5. check for distension of the kidney ampulla and calyces (pyelic ectasia, calico-pyelic ectasia or hydronephrosis); 6. check for distension of the ureter (hydrouretero nephrosis); 7. check for space-occupying lesions and differentiate between fluid (cysts) and solid lesions (neoplasia); 8. assess renal vascularization using color and powerdoppler to identify “minus” signs (9); 9. assess renal vascularization by contrast enhancement (ceus), that improves diagnostic confidence in the assessment of deficiency signs (11); 10. assess the intrarenal resistance indexes (ri): vn < 0.70 (10) (optional, depending on the clinical picture). example of report kidney ultrasound kidneys in situ, maximum longitudinal/transverse size within normal limits (right cm____/____; left cm____/____), regular outlines. parenchyma thickness normal (_____mm). regular echogenicity of parenchyma. no direct or indirect signs of kidney stones. regular excretion pathways with no ectasia or calicopyelic dilation (or distinguish ectasic/ pyelic, calico-pyelic dilation, associated or not with ureteral dilation). no space-occupying lesions. adrenal loggia, no expanding lesions. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 59 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 60 renal echo-color-doppler intrarenal resistance indexes (interlobar or arcuate arteries) within normal limits (ri < 0.70) systolic peak velocity (spv) of the renal arteries at the ostium, initial, medial, distal and anterior and posterior segmentary tracts within normal limits. flowmetry normal. pervious renal veins. at powerdoppler, good vascular appearance of parenchyma. minimum imaging documentation to be included: 1. two images per kidney: transverse and longitudinal scans with measurements. 2. orientation of images (liver/spleen on left). 3. arrow on photo, indicating organ analyzed and side 4. accessory images illustrating any anomalies. 5. if the bladder is described in the findings, at least one bladder scan image must be included. ultrasound of the bladder indications • to measure post-voiding residue. • to measure bladder filling volume. • to assess anatomic modifications/complications associated with obstruction (diverticuli, trabeculation/columnar thickening, stones, detrusor thickness). • to assess hypermobility of the bladder neck in women with stress incontinence. • to assess hematuria originating in the lower urinary tract. • to assess lower urinary tract symptoms luts. • to check for suspected ureteral stone migrating intramurally. • to check for congenital malformations (ureterocele, diverticuli, etc.). • post-surgical monitoring (vesical bleeding, position of catheter, etc). • follow-up in non infiltrating cancer. • follow-up of bowel loop orthotopic bladder after cystectomy. tools during standard investigations in the adult a convex 3.5mhz probe (range 3-5.5 mhz) is used (in pediatric patients a higher frequency transducer can be used). to measure bladder volume in post voiding controls, automatic equipment can be used. in dynamic studies (e.g. assessment of cystocele) trans-rectal or trans-vaginal probes can be used. to stage bladder tumors trans-rectal probes can be used. technique use adequate amounts of gel. for optimal imaging of the bladder it should be full but not overdistended, especially in cases of obstruction. the patient should be lying supine (supine or lithotomic or in orthostatic position in cases of use of a trans-rectal probe). the bladder wall and lumen will be assessed during the investigation, with both transverse and sagittal scans (1). systematic search and documentation must be made of: any changes in the echographic appearance of the bladder wall and neck at rest, trabeculature of the detrusor, endophytic neoplasia, diverticuli, stones, the presence of a third prostatic lobe. any focal lesions observed (in particular masses) and other diseases (diverticuli, stones, clots, etc.) must be described, specifying site and size. when indicated, the distal ureters should be assessed to exclude dilation or other anomalies (intramural or juxtavesical stones, ureterocele). echo-doppler study may be useful to assess ureteral jet and make a differential diagnosis of bladder tumors (2). fine regulation of the light is essential to obtain a significantly improved image quality and correctly visualize the anterior wall (superficial as compared to the skin) and posterior wall (deep). use the second tissue harmonic imaging tool to improve the imaging and reduce reverberation artefacts. calculate bladder volume: (ellipsoid formula) v = 0.52 ! r1 ! r2 ! r3. it is recommendend to assess post-voiding urine residue by ultrasound using automatic measurement tools or using the ellipsoid formula based on bladder diameters. in cases of a significant post voiding residue the patient should be asked to make a further attempt to void and then the measurements repeated until a reliable indication of the voiding capacity is obtained. in cases of assessment of the detrusor thickness (not normally more than 3 mm) the study will be conducted with moderate bladder filling (calculated as between 250 and 350 ml, with 250 ml as threshold value), the mean of 3 measurements made on the same image is calculated. to obtain the best results the assessment must be made at the level of the anterior wall/apex and it is better if a high frequency (7.5 mhz) convex or linear probe is employed (1). the ultrasound appearance of the detrusor is as a sandwich structure (hypoechogenic muscular wall between the mucosa and adventitial layers, that are slightly hyperechogenic). the detrusor thickness must always be measured in areas that are orthogonal to the ultrasound focus (3-8). the findings report should include: • the patient’s name and surname; • the name of the service where the investigation was performed and the telephone number (in case further clarification should be required); • the date of the ultrasound examination; • if possible include all pertinent clinical information, including the indications for the investigation; • the type of ultrasound examination performed, and if endocavitary techniques are employed the method must be specified; lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 60 61archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields • specify the orientation of the image, if different from standard (superior part on the right of the screen); • use appropriate anatomical and ultrasound terminology; in cases of variations from normal sizes the measurements must be specified (e.g. increased detrusor thickness, diverticuli, endoluminal masses, etc.); • compare with previous imaging studies if available; suggest types of studies for further investigation, any differential diagnosis hypotheses; • name and signature of the examiner, date; • if the results of the ultrasound are considered by the doctor performing the investigation to be of particular clinical importance and unexpected, such as to require urgent intervention to guarantee proper patient care, ideally the doctor who did the investigation should contact the patient’s doctor directly to check that the findings report has been received; • describe the state of other organs in the abdomen only if qualified to do so; • pay attention to the degree of distension of the bladder, that can negatively affect the visualization of the ureters in the juxtavesical tract, and the seminal vesicles; • use the tissue harmonic imaging tool to reduce reverberation artifacts and obtain better detail; • indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas), underlining any limits of the test and so its diagnostic value. example of final report 1. presence or absence of bladder. 2. orthotopic site and symmetry. 3. shape. 4. degree of bladder distension (essential for reliability of investigation). 5. presence or absence of wall alterations (assessment of lesions > 3 mm). 6. presence or absence of third lobe (in cases where present, volume and/or degree of extension into the bladder: intravesical prostatic protrusion). 7. presence and size of calcifications (diameter > 3 mm), fixed or mobile with patient’s movements in decubitus. 8. characteristics of bladder neck (in man, protrusion of prostate). 9. presence of the ureters and any dilation or abnormal outlet or stones. 10.presence of pelvic masses and ab-extrinseco compression of the bladder. 11.quantification of post voiding residue. note: it is necessary to calculate the bladder filling volume only if needed to measure the detrusor thickness or estimate the bladder weight (reliable for values ! 250 ml) or if needed for clinical reasons. describe any clinical conditions that prevent adequate bladder filling (incontinence, pain due to reduced compliance). images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of the bladder in transverse scan. 2. one image of the bladder in longitudinal scan. 3. one image of the bladder in transverse/longitudinal scan showing the bladder neck. 4. one or more images of any anomaly. 5. in cases of a lesion obstructing the juxtavesical ureter (stone or vegetating lesion) oblique scanning must be done. preparation for investigation and patient position 1. the patient does not need to be fasting. 2. the bladder must be replete with at least 300 cc; to ensure this it is necessary: a. for the patient to drink at least 500 cc of fluids during the three hours before the investigation; b. for the patient to refrain from urinating within two hours before the investigation; c. for the patient to feel the urge to urinate (this latter parameter is extremely subjective and not always reliable). the investigation is normally performed with the patient in supine position. lateral right or left decubitus may rarely be necessary, in cases where a lesion extends into the lumen (neoplastic disease, clots, “intravescical prostatic protrusion”) and its mobility must be checked. in cases requiring oblique scanning, this is done by rotating the probe by about 40° to its longitudinal axis, taking care that the bladder filling is not more than 250-300 cc (otherwise the ureters would appear crushed by the bladder volume itself). us paremeters to evaluate bladder modifications in patients with bladder outlet obstruction progressive changes in the bladder wall are observed in men with lower urinary tract obstruction secondary to benign prostatic enlargement (bpe). the high pressure discharge cause initially an increase in the proportion of smooth muscle (hyperplasia/hypertrophy of the detrusor) to changes in the advanced stages of bladder decompensation (fibrosis), hyperactivity and decreased functional capacity. early identification of bladder changes by noninvasive transabdominal ultrasound can move towards therapeutic choices that can prevent further organ damage in the bladder wall. measurement of the bladder wall thickness (bwt) or detrusor wall thickness (dwt) by us is reliable, at least 3 measurements of the anterior bladder wall taken at a filling volume of ! 250 ml. in particular, the dwt [thickness of the muscle hypoechoic between two layers hyperechoic serosa and mucosa] is considered the best diagnostic tool to measure detrusor hypertrophy using cut-off value > 2.9 mm in men. us derived measurements of bladder weight (estimated bladder weight, ebw) is another noninvasive tool for assessing bladder modifications in patients with bladder outlet obstruction (boo): cut-off value 35 gr. technique for measuring the bwt and lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 61 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 62 ebw relies in conventional us 7.5-4 mhz or using the automatic system of calculation (bvm 6500 3.7 mhz). the variability of measuring intra (4.6 to 5.1%) and interoperator (12.3%) is acceptable. also conventional us detects established signs of bladder damage: diverticulosis, trabecolations in the bladder wall (pseudo-diverticula), calculi and post-void residual urine (> 50 cc). furthermore the intravescical prostate protrusion (ipp), easy measured by transabdominal ultrasound, is strongly correlated to obstruction in men with bpe (cut-off 12 mm). measure, quantify and monitor the cervico-urethral obstruction in men with symptomatic bpe is possible by non-invasively us monitoring the response of the bladder wall. early identification has the advantage of adopting therapeutic measures sufficient to prevent progression of bladder damage measuring dwt, ebw in addition to established us paremeters (3, 5-10). diagnostic accuracy in the diagnosis and follow-up of bladder tumors or hematuria, it should be noted that the standard method is uretero-cystoscopy. ultrasound scanning is an alternative for non invasive low grade tumors and for the initial assessment of hematuria. cystoscopy allows the operator to assess and solve any doubts about the integrity and regularity of the bladder wall raised at ultrasound scanning. bladder lesions smaller than 5 mm may not be identified at ultrasound. not all bladder tumors are observed at ultrasound: slow-growing non vegetative tumors like carcinoma in situ are not diagnosed by imaging. the diagnostic capacity for vegetating/papillary lesions > 5 mm is high, even if in some circumstances differential diagnosis with clots may be difficult despite echocolordoppler. parameter pattern acute cystitis wall thickness and echogenicity. increased hypoechogenicity, increased thickness of bladder wall, between the serosa and mucosa. chronic cystitis no characteristic pattern, assessment of post-micturition residue, search for foreign bodies in bladder. bullous cystitis wall thickness, echogenicity. increased bladder wall thickness, anechogenic areas wall hypoechogenicity. diverticuli presence/absence. formation of anechogenic paravesical areas with the presence of asonic funnelling to bladder (diverticular neck): transrectal scanning can better reveal the diverticular neck. color-doppler can enable dd between tumors and endodiverticular clots, although it is not the ultimate test. in doubtful cases ceus or other radiological or endourological imaging should be done. detrusor hypertrophy thickness detrusor wall (calculated increased (> 3 mm) with irregularities (trabeculatures or even pseudo (5-7, 9) at ! 250 ml of filling, as mean of 3 diverticuli). measurements, hypoechogenic tissue low level evidence, recommendations need to be verified on vast scale, included between two lines of evidence levels based on opinions of experts and case series. hyperechogenic tissue: mucosa parameter to be assessed, advised by experts. for use in clinical studies. and bladder serosa). ureterocele anechogenic formation (cyst) at the level of the ureteral meatus with evidence at color-doppler of ureteral jet. juxtavesical juxtavesical ureter obstructive lesion hyperechogenic image with posterior shadow included in the thickness ureter lesion (stone or vegetating lesion). of the ureteral wall (between hyperechogenic serosa). eco-color-doppler: useful to identify color signals (artifacts) in the shadow area and in dd of vegetating lesions also with eco-power-doppler. evidence or not of urethral jet at color-doppler. stones hyperechogenic images with shadow, mobile depending on decubitus movements. hyperactive bladder bladder weight (uebw-ultrasoundno consensus in literature as to standardized cut-off values to be used (5, 10) estimated bladder weight). in clinical studies. non neoplastic diseases parameter pattern superficial lesions bladder wall structure generally no echostructural alterations of the wall. endophytic tumors appear as hypoechogenic, fixed proliferative lesions, but sometimes they are hyperechogenic due to the presence of superficial calcifications. at color-doppler hypervascularization is observed. infiltrating lesions bladder wall structure interruption/deformation of the wall, that appears thickened, sometimes extension beyond the bladder wall. neoplastic diseases although staging is not currently approved on the basis of the ultrasound findings, we report indications for a possible interpretation. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 62 63archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields addendum: possible use of 3d studies, especially for post surgical assessment (sling). clinical studies to assess the presence of funneling of the neck, hypermobility of the neck-urethra complex, cystocele, ureteral fixity. no standards have yet been established for mobility parameters (among proposals see schaer et al. int urogynecol j pelvic floor dysfunc 1996, pajoncini c. in atlante di ecografia uro nefrologica ed andrologica 1996 ed. cic, merz et al. ultraschall med 2004, tunn r. et al. update recommendations on ultrasonography in urogynecology. int urogynecol j 2005 16, 236-241). trans-perineal introital trans-vaginal trans-rectal instruments convex sector endfire linear biplanar linear biplanar 3.5-5 mhz probe 5 7.5 mhz probe 7.5 mhz probe 7.5 mhz probe patient position lithotomic lithotomic orthostatic lithotomic orthostatic quality of image + + +++ +++ measurement of mobility ++ ++ +++ +++ invasiveness + + ++ +++ artifacts in 3-4 grade cystocele ++ ++ +++ + ultrasound of the pelvic floor (4, 11-24) prostate and seminal vesicles prostatic ultrasound scanning with the suprapubic technique method the prostate must be analyzed on two orthogonal planes: transverse and longitudinal. in this study it is essential to examine: • juxtavesical ureters. • bladder. • prostate. • seminal vesicles (1-6). the prostate diameters to be assessed are: latero-lateral, antero-posterior and cranio caudal. in cases of an obstructive lesion of the juxtavesical ureter (stone or vegetating lesion) oblique scans must be made. images to be included (not all are always indispensable, depending on the clinical picture). 1. one image of the bladder in longitudinal/transverse scan. 2. one image of the prostate in transverse scan showing the bladder. 3. one image of the prostate in longitudinal scan showing the bladder. 4. one image of the right juxtavesical ureter in oblique scan. 5. one image of the left juxtavesical ureter in oblique scan. 6. one or more images of any anomalies. report of the findings 1. date and place of performance of the investigation. 2. patient data (including birth date). 3. mention of clinical history and diagnostic purpose. 4. value of last total psa blood test. 5. comparison with previous tests if available. both the images and findings must be easy to read by other operators and at later dates. the findings must therefore be reported as unambiguously as possible. in cases of any diagnostic doubt, this must be pointed out, indicating possible hypotheses and suggesting any further instrumental investigations that may help to solve any doubts. terminology 1. identification of the medial lobe and its size and relations with the pelvic floor 2. any picture of cervico-ureteral obstruction due to prostatic hypertrophy causing severe detrusor impairment, any presence of bladder stones (table 1). indications 1. to assess the size and volume of the prostate gland before medical, surgical or radiation treatment (in particular, to assess the volume displacement caused by the third lobe and correlations with detrusor hypertrophy, the presence of bladder pseudodiverticuli and diverticuli (1, 6). 2. to assess the patient with lower urinary tract symptoms (1). 3. to assess congenital anomalies. essential parameters to be specified in the final report prostate 1. presence or absence of the prostate. 2. orthotopic or heterotopic site. 3. shape. 4. size. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 63 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 64 5. presence or absence of third lobe (if present, volume and/or size of protrusion into the bladder: intravesical prostatic protrusion). 6. presence and size of any gross calcifications (diameter > 5 mm). 7. presence and size of any gross abscesses/cysts (diameter > 5 mm). 8. presence of the ureters and any dilation or anomalous outlet. 9. quantification of post voiding residue. note: lesions of any nature with a diameter of " 5 mm are not identifiable with suprapubic ultrasound scanning. the suprapubic technique cannot visualize the echostructure of the peripheral zone of the prostate due to technical image resolution limitations. seminal vesicles 1. presence or absence. 2. site. 3. symmetry. bladder an accurate description of the bladder is essential, see previous chapter. preparation for investigation and patient position 1. the patient does not need to be fasting 2. the bladder must be replete with at least 300 cc; to ensure this it is necessary: a. for the patient to drink at least 500 cc of fluids during the three hours before the investigation; b. for the patient to refrain from urinating within two hours before the investigation; c. for the patient to feel the urge to urinate (this latter parameter is extremely subjective and not always reliable). the investigation is normally performed with the patient in supine position. lateral right or left decubitus may rarely be necessary, in cases where a lesion extends into the lumen and its mobility must be checked. example of final report mention of clinical history: _______________________ diagnostic purpose_____________________________ last total psa value: the bladder… yes/no hyperechogenic bladder images depicting stones, nor dilation of the juxtavesical and intramural bilateral ureters. the prostate is shown in orthotopic/heterotopic site and is grossly triangular, size within normal limits (more/less), (ll x ap x cc), having a theoretical calculated volume of about ___ml. presence of third lobe protruding into the bladder by __cm. post voiding residue is about cc. non/mild/fair/marked tenderness or pain on palpation of the hypogastrium at the start/throughout the duration of the investigation. diagnostic accuracy it is important to note that the elective method for the study of the prostate gland includes the use of endocavitary probes (7, 8). in fact, suprapubic ultrasound scanning is not contemplated in the guidelines for the study of the prostate drawn up by the main scientific societies due to its limited diagnostic power (2-5). in particular, it is thought that prostate ultrasound results in an overestimation by more than 30% to 50% of the true prostate volume. according to some authors, moreover, the use of the ellipsoid formula to calculate the prostate gland volume with the aid of suprapubic ultrasound leads to an error of about 20% (9). notes on clinical practice a. attention must be paid to the degree of distension of the bladder, that can affect the visualization of the juxtavesical ureters and seminal vesicles b. use the tissue harmonic imaging tool to reduce reverberation artifacts and obtain better detail c. indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas), underlining any limits of the test and so its diagnostic value. d. remember that if the prostate is larger than normal, its morphology may vary, especially in cases of prostatic hyperplasia. devices and transducers used convex transducer with a frequency of 3.5 mhz, or multifrequency 5-2 mhz probes depending on the patient’s constitution and how deeply the gland is located. transrectal prostatic ultrasound method the investigation is dynamic and apart from longitudinal and transverse scans, with the probe inclined more craniocaudally than for the study of the bladder, oblique scans will also be performed to study the seminal vesicles, that generally lie on the transverse/oblique plane. the prostate must be analyzed on two orthogonal planes: transverse and longitudinal, from the apex to the base of the gland. at the same time, it is essential to study: • the urethra sphincter, cowper’s glands; • the seminal vesicles; • the juxtavesical tract of the ureters; • the deferens ducts; • the bladder (insofar as it is explorable). additionally, any gross alterations of the rectal wall should be pointed out, and referred to the competent specialist colleague. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 64 65archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields the diameters to be assessed is latero-lateral, antero-posterior and cranio-caudal, to calculate the total volume, and also the volume of the transition zone (periureteral hypertrophy). for the seminal vesicles the diameters assessed are: antero-posterior. the apparent size of the latter may be affected by the degree of distension of the bladder, by ejaculation and by forms of obstruction (1-4). images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of the prostate in transverse scan (indicating the diameters of both the entire gland and adenoma). 2. one image of the prostate in longitudinal scan (indicating the diameters of both the entire gland and adenoma). 3. one image of the prostate in transverse scan showing the bladder. 4. one image of the prostate in longitudinal scan showing the bladder. 5. one image of the seminal vesicles in transverse scan. 6. one or more images of any anomalies. 7. any images of the juxtavesical ureter in longitudinal scan. calculate total prostatic volume and transition zone volume it is important to note that all latest generation ultrasound devices automatically calculate the volume of the prostate, bladder and seminal vesicles. if this is not possible, multiply the 3 diameters by 0.52 according to the ellipsoid formula. data on the volume of the entire gland and adenoma are clinically essential for therapeutic and surgical workup purposes (5-11). orientation of the ultrasound images the ultrasound probe always appears at the bottom of the image. in transverse scans: the patient’s right side is conventionally on the left side of the image (as also in ct and mr images). in longitudinal scans: the superior/proximal part/patient’s head is conventionally on the left side (as in abdominal ultrasound imaging), and the distal part on the right side. documenting the findings 1. date and place where the investigation was performed. 2. patient data (including birth date). 3. mention of clinical history and diagnostic query. 4. value of last total psa blood test. 5. outcome of rectal exploration, that should always be done before the investigation. 6. comparison with previous examinations, if available. both the images and findings must be easy to read by other operators and at later dates. the findings must therefore be reported as unambiguously as possible. in cases of any diagnostic doubt, this must be pointed out, indicating possible hypotheses and suggesting any further instrumental investigations that may help to solve any doubts. terminology 1. hypoechogenic pars adenomatosa, as compared to pars peripherica of the prostate (6, 8). 2. identification of medial lobe, and its size and relationships with the bladder floor (5). 3. presence of calcifications (diameter ! 3 mm), that appear hyperechogenic with a posterior shadow (possibly showing signs of previous inflammation). 4. presence of focal hyperechogenic areas with no posterior shadow (diameter ! 3 mm) (possibly showing signs of previous inflammation). 5. presence of abscesses and/or hypo/anechogenic areas (diameter ! 3 mm), that appear prevalently with a fluid anechogenic or dyshomogenenous component, possibly showing inflammation processes in active phase. anechogenic/echogenic areas of inflamed abscesses table 2. 6. in a picture of cervico-ureteral obstruction due to prostatic hypertrophy causing severe detrusor impairment, any presence of bladder stones table 1. 7. dilation/cysts of the ejaculatory ducts. 8. perviousness and funneling of the cervical or anastomotic region in surgical scars. indications 1. to assess the size and volume of the gland for medical/surgical workup, regardless of the type of treatment or underlying disease (1-14). 2. prostatic biopsy guidance. 4. suspected prostatitis and/or prostatic abscess. 5. to examine congenital anomalies. 6. in infertility of the couple (morphological study of the seminal tracts). 7. study of the bladder neck – functional diseases of the bladder neck (sclerosis, iatrogenic stenosis or ndd); – neurological bladder; – outcome of surgery of the cervico-prostatic region (prostatic trans-vesical adenomectomy, endoscopic resection or enucleation of prostatic adenoma, endoscopic incision of bladder neck); – identification and examination of cysts of bladder neck or third prostatic lobe; 8. postoperative controls (post disobstructive surgery or radical prostatectomy). 9. post-treatment controls for prostatic tumors (radiotherapy, hifu, cryotherapy) (8). essential parameters that must be specified in final report for all types of report preliminarily, transrectal exploration must be performed, indicating the presence, size (x 2-3), surface, consistenlineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 65 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 66 cy, margins, presence or absence of a medial groove, any nodules, their characteristics and localization), tenderness or pain on palpation of the gland. prostate 1. presence or absence of the prostate. 2. orthotopic or heterotopic site. 3. symmetry. 4. size/volume of the gland (latero-lateral, antero-posterior and cranio-caudal, to be multiplied by 0.52, according to the ellipsoid formula, if the device does not make an automatic calculation). 5. size/volume of the transition zone/adenoma. 6. presence or absence of third lobe (if present, volume and/or measurements of protrusion into the bladder) (5, 16). 7. presence and size of calcifications (diameter ! 3 mm) table 1. 8. presence and size of abscesses/cysts (diameter ! 3 mm) (17). 9. presence and size of intra-prostatic cysts or bladder neck cysts (diameter ! 3 mm) (17). 10. echostructure of the peripheral portion (18). 11. integrity of prostatic capsule. 12. presence of the ureters and any dilation or anomalous outlet. 13. any pain elicited during the investigation table 2. addendum in particular cases presence of the deferens and any dilation. urethra any lesions evident at ultrasound. morphology and function of the internal urethral sphincter (only in cases of ultrasound performed for functional purposes). seminal vesicles 1. presence or absence. 2. site. 3. symmetry. 4. morphology. 5. any dilation (> 12 mm in antero-posterior site). bladder 1. morphology of walls. 2. morphology of content. 3. presence of vegetation and description. 4. presence of stones. a. prostatic biopsy guidance 1. in cases of suspected tumor areas, describe: – site; – size; – morphology; – ultrasound appearance; – margins; – relations of lesion with the capsule, bladder neck, seminal vesicles in cases of basal nodules with extracapsular extension. if several nodules are present, each must be detailed as described above (19-20). 2. in cases of multiple prostatic biopsy sampling, indicate: – type of patient preparation; – antibiotic prophylaxis administered*; – results of preliminary rectal exploration (and any agreement between increased consistency areas at palpation and suspicious ultrasound images); – type of anesthesia (site, drug and dosage); – number of samples, specifying scheme adopted – course of procedure; – indications for patient care in days after the manoeuvre; – any home antibiotic therapy*. b. assessment of congenital anomalies in particular, apart from studying alterations of the course of the juxtavesical ureters, transrectal prostatic ultrasound is able to demonstrate intraprostatic cysts. cystic lesions appear as round or oval, with distinct margins and an asonic content. the definition of the site is particularly important, namely: 1. vesical. 2. medial posterior: mullerian/prostatic utricle. 3. paramedial/lateral: ductal dilatation/cysts of ejaculatory duct. 4. due to retention (17). c. morphologic study of the seminal tract ejaculatory ducts 1. presence or absence. 2. presence or absence of calcifications and any obstruction caused. 3. any dilation. deferens ducts 1. presence or absence. 2. presence or absence of calcifications or lesions and any obstruction caused. 3. any dilation. seminal vesicles 1. diameters (latero-lateral, antero-posterior and craniocaudal). 2. any dilation. 3. any congestion. 4. anomalies with the deferens. * antibiotic prophylaxis has proven useful for the prevention of complications such as asymptomatic bacteriuria, urinary tract infections, bacteremia and sepsis (1). the fluoroquinolones (such as ciprofloxacin xr 1000 mg), due to a better prostatic penetration, allow maintenance of constant levels of antibiotic in tissue, thus ensuring optimum prophylactic efficacy (2). references 1. zani el, clark oa, rodrigues netto n jr. antibiotic prophylaxis for transrectal prostate biopsy. cochrane database syst rev. 2011; (5):cd006576. 2. grabe m (chairman), bjerklund-johansen te, botto h, et al. guidelines on urological infections. european association of urology 2013. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 66 67archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields d. study of the bladder neck 1. morphology (5). 2. symmetry. 3. any calcifications. 4. any cysts (17). e. study of the prostatic loggia after radical prostatectomy or other treatments presence of areas suggesting disease recurrence in the perianastomotic region: – site; – size; – localization with respect to the anastomotic region and rectal wall; – ultrasound appearance; – margins; – vascularization; – presence/absence of seminal vesicles residues. the ultrasound data must necessarily be correlated with the total psa values and clinical history, because subsequent treatments for postoperative urinary incontinence may modify the echostructure and mimic lesions (macroplastique, collagen, bulkamid). if biopsy samples are taken of the perianastomotic region, all suspicious areas should be sampled; this can be done under ultrasound guidance (15). preparation for the investigation and patient position the patient must undergo at least one enema two hours before the investigation, to avoid artifacts caused by fecal matter in the rectum. fasting is not necessary. the patient must not urinate for at least two hours before the investigation (the bladder must be replete). the investigation is normally performed with the patient in lateral left decubitus. if this is impossible, it can be done in lateral right decubitus or semilithotomic position. example of final report standard transrectal prostatic ultrasound mention of clinical history:________________________ last total psa value:____________________________ preliminary rectal exploration shows the prostate in situ, enlarged (x), with a smooth surface, parenchymatous consistency, distinct margins, flattened medial groove. no tenderness or pain on palpation. the prostate, investigated with a transrectal “end-fire” ultrasound probe with variable frequency, is visible in situ and roughly triangular in shape; the size is x x mm (ll x ap x cc), for a theoretical calculated volume of about cc. a central nodular area of hyperplasia is present, with a dyshomogeneous echostructure, and theoretical calculated volume of about cc. along the cleavage plane of the nodular hyperplasia, and in the periureteral site, calcifications are evident, likely the outcome of previous inflammatory processes. within the nodular hyperplasia area there are gross calcifications as well as some anechogenic images compatible with cysts due to retention/microabscesses. the peripheral gland shows a substantially homogeneous structure, with no signs of disease foci in course. the seminal vesicles are orthotopic and normal in shape. the bladder is in situ, moderately distended. no ultrasound alterations of the posterior bladder wall are apparent, insofar as the area is visible through the transrectal acoustic window. post-voiding urinary residue is … transrectal prostatic ultrasound to study the seminal vesicles the prostate is described as above. no evidence of obstructive lesions of the ejaculatory ducts and deferens ducts bilaterally. the seminal vesicles are orthotopic and normal in shape. the maximum diameters of the right seminal vesicles are x x x mm (cc x ap x ll), for a theoretical calculated volume of about cc. the maximum diameters of the left seminal vesicle are x x x mm (cc x ap x ll), for a theoretical calculated volume of about cc. post-voiding urinary residue is cc. deferens present, symmetrical and not dilated. prostatic ultrasound of the perianastomotic region after prostatectomy the perianastomotic region appears homogeneous/dyshomogeneous, showing areas of .. in size, localized at the level of .., with …margins, vascularized, suspicious for growth processes. diagnostic accuracy the diagnostic accuracy of transrectal prostatic ultrasound varies according to the diagnostic query. in particular, as regards assessing the size of the prostatic adenoma, the diagnostic accuracy of transrectal prostatic ultrasound is extremely high, while the risk of overestimation of the true prostatic volume and weight (later measured in the various studies on the anatomic piece) ranges between 4 and 10% (21-28). as regards the identification of prostatic nodules suspected of growth processes, it should be noted that 60% of them appear hypoechogenic, 30% isoechogenic and 10% hyperechogenic. therefore, the overall diagnostic accuracy of this method alone is about 30% (this is why in most cases prostatic biopsy sampling is done randomly, in the absence of ultrasound areas raising suspicion (19-20). the presence of a hypoechogenic image alone is not the only criterion indicating the need for prostatic biopsy. the criteria for mapping prostatic biopsies are clinical and based on the psa values and trend, on rectal exploration, the presence of risk factors, and also on the prostatic volume and ultrasound findings. granulomatous prostatitis (acute or chronic) can induce hypoechogenic modulations that are indistinguishable from those of neoplasia. finally, as regards the use of transrectal ultrasound to assess the perianastomotic region, the diagnostic accuracy of this investigation is strictly linked to the total lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 67 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 68 psa value. the positive predictive value is about 65%, and the negative predictive value about 20% (15). for all lesions suspected to be cancerous, ultrasound alone can never replace biopsy. notes on clinical practice • use tissue harmonic imaging to reduce reverberation artifacts and obtain better detail. • indicate any difficulties encountered while performing the investigation (patient’s collaboration and constitution, presence of bowel gas, presence of artifacts due to insufficient bowel cleansing), underlining any limits of the test and so its diagnostic value. • if the prostate is larger than normal, its morphology may vary, especially in cases of prostatic hyperplasia. • when performing ultrasound guidance for prostatic biopsy sampling, it is useful to ask the patient to void the bladder after the diagnostic phase • the longitudinal diameter of the seminal vesicles varies according to the size of the gland and also the degree of bladder repletion. • in cases with many gross calcifications along the cleavage plane between the pars adenomatosa and pars peripherica, in the periureteral intra-adenomatous site, the shadow created by the calcifications may make ultrasound exploration of the bladder or pars peripherica difficult. the role of ecocolordoppler color doppler and power doppler are generally used to identify neovascularization foci, possibly expressing abscesses (vascularization absent in the center) or tumors (29-31). new technologies the limited sensitivity and specificity of gray-scales ultrasound in transrectal prostatic ultrasound has led to the adoption of new technologies based on the different vascular pattern identifiable in neoplastic foci, and hence on doppler techniques. the use of 3d ultrasound and histoscanning seems to be able to reduce the overall number of cores necessary, contributing to a better definition of the target, but such investigations should only be considered in clinical studies (20, 32). the use of contrast medium recent studies have not reported any increased sensitivity in the detection rate of prostatic tumors by contrast enhanced ultrasound (ceus), as compared to extensive mapping (33, 34). elastosonography the use of elastosonography increases the detection rate by about 20% as compared to traditional ultrasound, ultimately leading to a reduction in the number of necessary cores. however, operator experience and the degree of pressure exerted on the tissues strongly limit large scale use of this technique (35). 3d ultrasound thanks to the inclusion of the coronal plane, 3d ultrasound provides information helping to assess the seminal vesicles and ejaculatory ducts, as well as offering a better detection rate of prostatic tumors, according to some studies (20). devices and transducers real time endocavitary transducer (transrectal) with a frequency ! 6 mhz (or anyway high). high frequency is used because the prostate is superficial as compared to the probe plane (internal rectal wall): • a linear monoplanar probe: for prostate sections along the longitudinal plane. • a convex-linear or bi-convex biplanar probe: associates transverse and longitudinal scanning, through two orthogonal convex probes. • a variable frequency probe (end-fire): allows transverse, longitudinal and oblique scanning. pathologic mechanism size macroscopic evidence number site (increased intraprostatic ph and increased precipitation of calcium salts) endogenous amyloid bodies macrolithiasis disseminated single periurethral reaction to foreign body in intra-acinar site (max. diameter ! 2 mm) +/posterior shadow exogenous stasis of prostatic secretion microlithiasis thickened multiple lobar intraprostatic reflux (max. diameter " 2 mm) +/ posterior shadow perinodular prostatitis ejaculatory ducts table 1. stones and hyperechogenic prostatic images. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 68 69archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields ultrasound of the scrotum indications 1. to evaluate the acute scrotum: testicular trauma, ischemia, suspected torsion and infectious or inflammatory diseases (4, 7, 16). 2. to assess palpable masses in the inguinal or scrotal site (18, 22). 3. to assess any asymmetry and increased volume of the scrotum (21). 4. to assess a possible scrotal hernia (13). 5. for diagnosis and staging of varicocele. 6. to evaluate male infertility. 7. in follow-up of previous lesions shown at ultrasound (10). 8. to assess cryptorchidism (12). 9. to search for an occult primitive tumor in a patient with germinal tumor metastases. 10. in follow-up of patients with a primitive testicular tumor, lymphoma or leukemia (23). 11. in follow-up after testicular surgery. 12. in diagnostic workup for anomalies observed at other imaging studies like ct, mri or pet. 13.to assess intersexual conditions. essential parameters in the study of the scrotum (20) 1. the scrotal wall. 2. the testicular volume. 3. the testicular echostructure. 4. the epididymis (volume and echostructure). 5. vascularization. 6. the pampiniform plexus. preparation for the investigation and patient position the investigation must be performed in a darkened room, to protect the patient’s privacy, and the room temperature must not be cold because this could elicit the cremasteric reflex, in a more accentuated form in children, that could cause the testicle to rise up. initially, the patient should lie supine with a scrotal support to facilitate exposure. the penis will be positioned superiorly or supero-laterally (5, 8).after examining the content of the scrotal sac in clinostatic position, the investigation should be continued with the patient in orthostatic position, making a careful evaluation of the venous flow of the spermatic cords. b-mode study will already reveal table 2. definition of ultrasound characteristics of different disease pictures. peculiarities shows pars peripherica separated from pars adenomatosa thanks to a cleavage plane and different echogenicity (pars adenomatosa is more hypoechogenic than pars peripherica) there may be nodular oval or rounded areas, with distinct margins, and an isoechogenic appearance to the surrounding parenchyma, expressing prostatic hyperplasia intra-adenomatous areas or focal prostatitis areas in cases of abscess, this will show distinct margins and a highly hypo/anechogenic content. hyperechogenic lesions may be present within the abscess area, showing an irregular morphology demonstrating partial colliquation of such abscesses. in cases of inveterate chronic prostatitis, there may be a dyshomogeneous appearance, with alternating hypo-isoechogenic and hyperechogenic areas differential diagnosis abscess areas, in very hypoechogenic images calcification areas, in very hyperechogenic images tumoral areas (possible only with biopsy) neoplasia, especially in cases of suspected abscess colliquation neoplasia, especially in cases of granulomatous prostatitis observed in subjects with a history of endovesical chemo-immunoprophylaxis with bcg. disease picture prostatic hypertrophy acute prostatitis chronic prostatitis morphology increased size due especially to enlarged pars adenomatosa increased gland size increased size or no change echogenicity showing pars peripherica separated from pars adenomatosa thanks to an evident cleavage plane and different echogenicity (pars adenomatosa is hypoechogenic and dyshomogeneous as compared to pars peripherica) less than normal tendency to be increased, in cases with calcifications as inflammatory outcomes vascularization no variation increased doppler signal, correlated to increased vascularization due to inflammatory processes variable margins free normally free, sometimes blurred in cases of sub capsular abscess and direct involvement of the margins free lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 69 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 70 the presence of varicose veins, but it is convenient to go on immediately to color doppler study to examine the characteristic patterns of varicocele (11). notes on clinical practice and indications for echocolordoppler the first task in scrotal ultrasound is to make a correct calculation of the testicular volume. the formula most commonly used today is the ellipsoid (volume in ml = product of the three diameters (in cm) x 0.52) (3). the testicles must be assessed on two planes: longitudinal and transverse. the transverse plane is focused on the superior medial and inferior testicular portions, and the longitudinal plane on the central portion, as also medial and lateral. once the whole testicle has been measured, the investigation continues with the epididymis (head, body and tail) (6). the testicular measurements and echogenicity should then be compared with those of the contralateral testicle. color doppler can be helpful, especially in cases of acute pain (2). in this case, both longitudinal and transverse scanning is useful, as well as comparison of the two testicles. the doppler parameters must be set to analyze slow flow. should it be impossible to visualize the flow, power doppler can be employed to highlight the images (9). color doppler is essential in the diagnosis and staging of varicocele. devices and transducers the investigation is conducted using a real time scanner, preferably with a linear transducer. the transducer is set to scanning mode at the highest frequency of the device. in the latest ultrasound devices the frequency may range from 8 to 15 mhz or more (1, 19). the transducer length may range between 4 and 8 cm. resolution must be sufficient to discriminate different ultrasound characteristics in any lesions observed. if there is a markedly increased volume of the scrotum, the use of lower frequencies is indicated to make a correct study of the gonads (15); alternatively it is possible to rely on the trapezoid assessment available in more modern ultrasound devices (14). the doppler frequencies must be as high as possible to optimize the resolution and show the blood flow. modern devices offer a frequency range of 5 to 10 mhz (17). example of final report scrotal echocolor doppler toshiba aplio; examination performed with linear probe 11.5 mhz history: previous right orchiectomy for embryonal testicular k. known left varicocele. didymi: left didymis in situ with normal echostructure and volume, markedly hyopotrophic approx 3.5 cc (ellipsoid formula calc. 0.52 x 3 diameters) epididymi: normal echostructure and size; small cyst of head of left epididymis. small scrotolite present. vascularization of didymis-epididymis: within normal limits left pampiniform plexus: severe peritesticular ectasia with vessel diameter exceeding 4mm. colordoppler investigation of pampiniform plexus in orthostatic position. left pampiniform plexus: basal reflux little modified by functional manoeuvers. diagnostic conclusion: left varicocele, grade v according to sarteschi classification. images to be included (not all are always indispensable, depending on the clinical picture) 1. one image of each testicle and epididymis in transverse scan. 2. one image of each testicle and epididymis in longitudinal scan. 3. one image of both testicles and epididymi for direct comparison. 4. one image of the prostate in longitudinal scan showing the bladder. 5. one or more images of the pampiniform plexus at rest and under valsalva. 6. one or more images of any palpable anomalies. important notes in clinical practice cause ultrasound appearance second level investigations non inflammatory heart failure thickened scrotal wall, with alternating idiopathic lymphedema hyperechogenic and hypoechogenic layers lymphatic and venous obstruction (onion-like appearance) epidermoid cysts inflammatory cellulitis thickening of the scrotal wall and presence of hypoechogenic areas, showing increased blood flow fournier gangrene thickening of the scrotal wall with signs ct; mri of inflammation; gas may be visible as numerous hyperechogenic foci table 1. lesions of the scrotal wall. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 70 71archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields ultrasound appearance second level investigations non inflammatory shows bowel wall, presence of peristalsis, hyperechogenic area if omentum present. ct distinguish direct or indirect if inferior epigastric artery shown by doppler. presence of stricture (ss 90%; sp 93%) hydrocele anechogenic fluid collection surrounding the testicular parenchyma hematocele appearance similar to cysts, with septs and loculi pyocele table 2. inguinal or scrotal swelling. ultrasound appearance second level investigations varicocele multiple tortuous vascular structures, hypoechogenic with variable diameters spermiogram exceeding 2 mm. color doppler set for low flow to show a characteristic flow pattern, with phase alterations and retrograde filling during valsalva (ss and sp 100%) grading varicocele accordig to an established classification. the suggested classification is the grading system according to sarteschi classification. tumors lipoma, sarcoma and rhabdomyosarcoma have the same non specific ct, and better mri, to enhance of spermatic cord ultrasound appearance visualization of the tissues table 3. spermatic cord (22). ultrasound appearance orchi-epididymitis epididymis enlarged and hyperechogen or hypoechogenic. a reactive hydrocele may be present, and if there is testicular involvement the didymis will be enlarged, with a dyshomogeneous ultrasound appearance. doppler will show hyperemia and increased blood flow (peak systolic rate > 15 cm/sec) chronic epididymitis epididymis enlarged, increased echogenicity and possibly calcifications epididymis masses spermatocele and epididymis cysts are shown as hypoechogenic lesions that may be as much as 1-2 cm in diameter, with acoustic enhancement in the posterior wall. they may contain protein fluid or spermatozoa with a low echogenicity. adenomatoid tumors can be hypoechogenic, isoechogenic or hyperechogenic table 4. epididymis (18). ultrasound appearance second level investigations testicular torsion absence of intratesticular blood flow (ss 86%, sp 100%) increased testicular volume and reduced echogenicity (4-6 h) after 24 h, dyshomogeneous echostructure due to vessel congestion, hemorrhage and infarction. spiral appearance under the torsion point, that appears as a homogeneous extratesticular oval or rounded mass, with or without blood flow orchitis hyperemia and dyshomogeneous ultrasound appearance. increased or enhanced intratesticular blood flow testicular microlithiasis multiple echogenic foci with no shadow (at least 5 microliths per field) benign lesions cysts of tunica albuginea: may be unilocular or multilocular, with calcifications simple cysts: may be multiple or solitary, generally adjacent to the mediastinum. they appear anechogenic and with no wall. epidermoid cysts: ultrasound appearance of a halo with a central area and increased echogenicity or else as a mass defined by an echogenic circle, or else a classic “onion” appearance. doppler will not show blood flow ectasia of rete testis: visible at us as fluid-filled tubular structures. possible presence of cysts intratesticular varicocele: multiple, anechogenic tortuous tubular structures. bloodflow shows characteristic reflux during valsalva malignant lesions seminomatous tumors: homogeneous hypoechogenic lesions, with uniform tumoral markers smooth margins. very often the tumor occupies much of the parenchyma non seminomatous tumors: may have very variable us appearance: tumoral markers dyshomogeneous echostructure (71%), irregular or with poorly defined margins (45%), echogenic foci (35%) and a cystic component (61%) lymphomas: testicles homogeneously hypoechogenic or with multifocal hypoechogenic lesions of various diameters. the didymis, in diffuse forms, appears hypervascularized (d.d. with orchitis) testicular trauma rupture or interruption of the albuginea, irregular echostructure with poorly mri defined margins. color /power doppler can help to show the vascular pattern of the parenchyma, capsule table 5. testicle (4, 12). lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 71 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 72 ultrasound of the penis introduction penile us is an essential tool in urological clinical practice both as an investigation in itself and integrated with color doppler of the penile vascularization (1). indications indications for penile us: 1. erectile dysfunction. 2. priapism. 3. penile fibrosis and plastic induratio penis. 4. penile or urethral anomalies observed at physical examination. 5. neoplasia of the penis. 6. penile trauma. 7. thrombosis of the dorsal vein. 8. urethral disorders (cysts, diverticuli, stenosis). 9. stones or foreign bodies in urethra or penis. technique of investigation at least two scans must be performed: transverse and longitudinal. the probe is positioned dorsally or centrally to obtain a better visualization of the corpi cavernosi, the intercavernous septum, the tuniche albuginea and buck’s fascia and the urethra (3). the transverse scan must be done in the proximal, medial and distal portions of the penis. the longitudinal scan must be done on the two corpi cavernosi, visualizing the cavernosum artery. in addition, to study the crural portion of the corpi cavernosi, the transducer is placed perineally (4). size, echogenicity (hyper, hypo, iso) and symmetry of the corpi cavernosi must be described and documented with appropriate images. any alterations of the tuniche, either echogenic or structural, must be documented by accurate measurements both on longitudinal and transverse scans. any palpable alteration or penile anomaly must be closely studied directly on the involved zone, documented by appropriate images. assessment of the vascular integrity is done by integrating color doppler (6). to study of the urethra (2, 5), hydrosoluble gel is injected through a catheter positioned at the level of the navicular fossa; longitudinal scans are done to study any alterations of the urethral lumen (7-9) . specific devices penile us is done in real time b-mode scanning, using a linear probe with a frequency of 7.5/10 mhz and more (10). penile echo color doppler penile echocolor doppler (1) is generally performed in the following cases: • erectile dysfunction [after intra cavernous injection (fic) of pge1). • peyronie’s disease. • to assess penile morphology and vascularization after trauma. • in cases of blood collection or infection. methodology assessment pre fic: • the investigation must be performed in calm surroundings avoiding outside interruptions. detailed explanation of the different phases must be given, as • grade 1: prolonged reflux in vessels in the inguinal channel only during valsalva’s manoeuvre, while scrotal varicosity is not evident in the previous grey-scale study. • grade 2: small posterior varicosity that reaches the superior pole of the testis and whose diameter increases after valsalva’s manoeuvre. the cdu evaluation clearly demonstrates the presence of a venous reflux in the supratesticular region only during valsalva’s manoeuvre. • grade 3: is characterised by vessels that appear enlarged to the inferior pole of the testis when the patient is evaluated in a standing position, while no ectasia is detected if the examination is performed in a supine position. cdu demonstrates a clear reflux only under valsalva’s manoeuvre. • grade 4: is diagnosed if vessels appear enlarged, even if the patient is studied in a supine position; dilatation increases in an upright position and during valsalva’s manoeuvre. enhancement of the venous reflux after valsalva’s manoeuvre is the criteria that allows the distinction between this grade from the previous and the next one. hypotrophy of the testis is common at this stage. • grade 5: is characterised by an evident venous ectasia even in an upright position. cdu demonstrates the presence of an important basal venous reflux that does not increase after valsalva’s manoeuvre. table 6. color doppler ultrasound (cdu) grading classification of varicocele. in accordance with sarteschi, varicocele can be divided into five grades according to the characteristics of the reflux and its length, and to changes during valsalva’s manoeuvre (24, 25). lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 72 73archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields well as of the possible complications, obtaining written informed consent. • the basal study must include longitudinal and transverse scans to make an accurate study of the corpora cavernosa, corpus spongiosum, intercavernous septum, the morphology of the cavernous arteries, the gland and the urethra. the cavernous arteries are shown as parallel lines, fine and echogenic, and any anatomical variants, even lacking clinical significance (e.g. duplication of the cavernous artery must be documented) (2). fic: • single intracavernous injection of pge1 in basal cavernous site, at variable doses (2.5 mcg in young, psychogenic men with a high risk of priapism due to correlated disease) and if necessary redosing. remember that a state of anxiety in the patient could delay the effect of the drug. post fic assessment: • spectral doppler must be done at 0,5,10,15,20,25 and 30 minutes after fic at the level of the proximal third of the cavernous arteries and/or in crural site. • measurement of peak systolic velocity (psv), telediastolic velocity (tdv) and resistence index (ri) using an ideal spectral angle of 60°. • manual or visual stimulation is not usually necessary to obtain an adequate erection. • if the flowmetry result is considered adequate, the investigation can be interrupted before the measurements at 25 and 30 minutes. • after flowmetry it is useful to make a morphological study of the penile vascularization by power imaging, to assess the microcirculation, describing whether the helical branches are visible or not, and their angle of incidence on the cavernous artery (normally > 90°) (3). this method is also used to visualize traumatic lesions (4). • the dynamic phase after fic is also useful to study peyronie’s disease plaques, both in b-mode and color power imaging, as well as fibrosis, structural variations and any zones of venous leakage around the plaques. • describe the degree of erectile response in terms of tumescence and rigidity at 20/30 minutes after fic. diagnostic criteria: • b-mode: detailed description of the anatomical symmetry of the corpi cavernosi, fibrous septum, any plaques or calcifications of the intracavernous zone or tuniche, any hypoechogenic lesions. • arterial compartment: any increased diameter post fic, intravascular flow. values of psv > 35 cm/sec are considered normal in the literature, between 25 and 35 cm/sec “borderline”, that should be integrated with the degree of erectile response, values < 25 cm/sec are considered pathologic (5). • venous compartment: with an increased intracavernous pressure and so increased psv there is a decrease in tdv that may become negative with inversion of the diastolic wave, a sign of integrity of the venoocclusive mechanism. a persistence of tdv values > 5-7 cm/sec throughout all the phases of the test indicates a deficit of the venoocclusive mechanism. • it is important always to integrate flowmetry data with the degree of erectile response to fic because a poor rigidity (low dosage of pge1, a state of anxiety) and hence a minor arterial inflow will limit the degree of response of the venous compartment and hence the sensitivity and specificity of the test (6). • in the findings, note the patient’s psychoemotional approach to the test. after the test: • ascertain complete detumescence before the patient leaves, informing him of the possibility of a prolonged erection/priapism and the management of this complication, as well as how to obtain further assistance if necessary. • produce an accurate report with appropriate images both of the flowmetry and the morphology. tools high frequency 7.5 mhz or more linear transducer, us device equipped with color-power spectral doppler; high doppler frequencies are advisable (higher than 10 mhz) because they provide optimal resolution and facilitate the examination of intravasal flow (7). example of final report test performed with linear probe (7.5/10) mhz. test performed in basal conditions and after drug infusion of … mcg. of prostaglandins (pge1); patient gave written informed consent to the procedure. normal conformation of the corpi cavernosi, that appear symmetrical and of the corpus spongiosus of the urethra.; otherwise describe any alterations/irregularities of the tunica and septum, such as hyper-reflection, hyperechogenicity and any images suggesting induratio penis plastica. cavernous arteries present, with a twisted course, pulsating. after fic, increased volume of the corpi cavernosi with dilation and straightening of the cavernous arteries, that appear pulsating/non pulsating. erectile response to fic at ….minutes (poor/fair/good/excellent) for tumescence and rigidity with/without deviation of the penile axis (in cases of deviation describe whether it is dorsal, ventral or lateral, and the degree) grade of eas (erection assessment scale): 1 to 5 (no erectile response/full rigidity) flowmetry study performed in crural site: measurement of the systo-diastolic velocities with spectral doppler analysis at 5,10,15,20,25 and 30 minutes after fic. psv (peak systolic velocity) equal to ….cm/sec on left and …cm/sec on right at …minutes after fic showing normal/reduced arterial inflow. tdv (tele diastolic velocity) …cm/sec with/ without progressive reduction or with/without negativization of the diaslineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 73 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 74 tolic wave at 20/30 minutes after fic, showing integrity/deficit of the veno-occlusive mechanism. ir </=/> 1 phase 3 obtained at …minutes phase 4 obtained/not obtained at ….minutes morphological study performed with color power doppler: cavernous arteries morphologically normal, well distended and straightened. good/fair/poor visualization of the helicine branches by 1°,2°and 3° presenting an angle of incidence </> 90°, demonstrating integrity/deficit of the microcirculation (in cases of ipp) presence/absence of peri-plaque venous leakage at ….. minutes after fic there is/is not progressive penile detumescence. psychoemotional attitude to test: poor/fair/good images to include (not all are indispensable, depending on clinical picture) 1. two basic images. 2. six doppler spectral images with relative flowmetry values. 3. two images showing microcirculation. references introduction 1. documento siumb per le linee guida in ecografia. giornale italiano di ecografia (siumb editore) i.r. al vol. 8-n 4. december 2005: 2. aua, aium practice guideline for the performance of an ultrasound examination in the practice of urology, 2011. www.aium.org 3. linee guida sieog società italiana di ecografia ostetrico gine co logica, edition 2010. 4. bevelacqua jj. practical and effective alara. health phys. 2010; 98 (suppl 2):s39-47. 5. eeg kr, khoury ae, halachmi s, et al. single center experience with application of the alara concept to serial imaging studies after blunt renal trauma in children--is ultrasound enough?. j urol. 2009; 181:1834-40; discussion 1840. 6. rutala wa. disinfection and sterilization in 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the bladder 1. kanu gb. ultrasonography of the urinary bladder, j med ultrasound. 2010; 18:105-114. 2. seung hk. ultrasound of the urinary bladder, revisited j med ultrasound. 2007; 15:77-90. 3. aganovic d, hasanbegovic m, prcic a, et al. which is a better indicator of bladder outlet obstruction in patients with benign prostatic enlargement--intravesical protrusion of prostate or bladder wall thickness? med arh. 2012; 66:324-8. 4. athanasiou s1, khullar v, boos k, et al. imaging the urethral sphincter with three-dimensional ultrasound. obstet gynecol. 1999 aug; 94:295-301. 5. blatt a, chan l. the importance of bladder wall thickness in the assessment of overactive bladder. current bladder dysfunction reports 2009; 4:220-224. 6. franco g, de nunzio c, leonardo c, et al. ultrasound assessment of intravesical prostatic protrusion and detrusor wall thickness--new standards for noninvasive bladder outlet obstruction diagnosis? j urol. 2010; 183:2270-4. 7. galosi ab, mazzaferro d, lacetera 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irritative urinary symptoms? bjog. 2002; 109:145-8. 11. costantini s, esposito f, nadalini c, et al. ultrasound imaging of the female perineum :the effect of vaginal delivery on pelvic floor dynamics. ultrasound obstet gynecol. 2006; 27:183-7. 12. costantini s, nadalini c, esposito f, et al. perineal ultrasound evaluation of the urethrovesical junction angle and urethral mobility in nulliparous women and women following vaginal delivery. int urogynecol j pelvic floor dysfunction. 2005; 16:455-9. 13. granados loarca ea, alcahe vr, de leon lópez h, echeverria reyes j. the usefulness of perineal ultrasound in urinary incontinence in women arch esp urol. 1999; 52:778-82. 14. masata j, martan a, halaska m, otsenásek m. ultrasonography of the funneling of the urethra ceska gynekol. 2000; 65:87-90. 15. martan a, masata j, halaska m, et al. the effect of bladder filling on changes in ultrasonography parameters of the lower urinary tract in women with urinary stress incontinence ceska gynekol. 2000; 65:10-3. 16. minardi d, piloni v, amadi a, et al. correlation between urodynamics and perineal ultrasound in female patients with urinary incontinence. neurol and urodyn. 2007; 26:176-182. 17. peschers um, fanger g, schaer gn, et al. bladder neck mobility in continent nulliparous women. bjog. 2001; 108:320-4. 18. reilly et, freeman rm, waterfield mr, et al. prevention of postpartum stress incontinence in primigravidae with increased bladder neck mobility: a randomised controlled trial of antenatal pelvic floor exercises. br j obstet gynecol. 2002; 109:68-76. 19. schaer gn, koechli or, schuessler b, haller u. perineal ultrasound: determination of reliable examination procedures. ultrasound obstet gynecol. 1996; 7:347-52. 20. siracusano s, bertolotto m, d'aloia g, et al. colour doppler ultrasonography of female urethral vascularization in normal young volunteers: a preliminary report. bju int. 2001; 88:378-81. 21. strasser h, ninkovic m, hess m, et al. anatomic and functional 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153:1549-54. transrectal prostatic ultrasound 1. società italiana di radiologia medica –linee guida della diagnostica per immagini 2009http://www.sirm.org/it/documenti/ cat_view/ 66-linee-guida.html. 2. american college of radiology –ultrasound guidelineshttp://www.acr.org/quality-safety/standards-guidelines/practiceguidelines-bymodality/ultrasound. 3. european association of urology 2012 guidelines http://www. uroweb.org/guidelines/online-guidelines . 4. american association of urology guidelines http://www.auanet. org/content/clinical-practice-guidelines/clinical-guidelines.cfm. 5. stravodimos kg, petrolekas a, kapetanakis t, et al. trus versus transabdominal ultrasound as a predictor of enucleated adenoma weight in patients with bph: a tool for standard preoperative work-up? int urol nephrol. 2009; 41:767-71. 6. ash d, flynn a, battermann j, et al. estro/eau/eortc recommendations on permanent seed implantation for localized prostate cancer. radiother oncol. 2000; 57:315-21. 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urology. 2009; 181:647-657. 18. shinbo h, kurita y. application of ultrasonography and the resistive index for evaluating bladder outlet obstruction in patients with benign prostatic hyperplasia. curr urol rep. 2011; 12:255-60. 19. purohit rs, shinohara k, meng mv, carroll pr. imaging clinically localized prostate cancer. urol clin north am. 2003; 30:279-93. 20. martino p, palazzo s, bufo p, et al. three-dimensional digital ultrasound for early staging of prostatic adenocarcinoma jour. urol. 2000; 164:456. 21. alkan i, turkeri l, biren t, et al. volume determinations by transrectal ultrasonography in patients with benign prostatic hyperplasia: correlation with removed prostate weight. int urol nephrol. 1996; 28:517-523. 22. loeb s, han m, roehl ka, aet al. accuracy of prostate weight estimation by digital rectal examination versus transrectal ultrasonography. j urol. 2005; 173:63-65. 23. lee js, chung bh. transrectal ultrasound versus magnetic resonance imaging in the estimation of 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29. morelli g, pagni r, mariani c, et al. results of vardenafil mediated power doppler ultrasound, contrast enhanced ultrasound and systematic random biopsies to detect prostate cancer. j urol. 2011; 185:2126-31. 30. taverna g1, morandi g, seveso m, et al. 31. colour doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling. bju int. 2011; 108:1723-7. 31. braeckman j, autier p, garbar c, et al. computer-aided ultrasonography (histoscanning): a novel technology for locating and characterizing prostate cancer. bju int. 2008; 101:293-8. 32. piscaglia f, nolsøe c, dietrich cf, et al. the efsumb guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (ceus): update 2011 on non-hepatic applications. ultraschall med. 2012; 33:5-7. 33. jiang j, chen y, zhu y, et al. contrast-enhanced ultrasonography for the detection and characterization of prostate cancer: correlation with microvessel density and gleason score. clin radiol. 2011; 66:732-7.. 34. strazdina a, krumina g, sperga m. the value and limitations of contrast-enhanced ultrasound in detection of prostate cancer. anticancer res. 2011; 31:1421-6. 35. giurgiu cr, manea c, crisan n, et al. real-time sonoelastography in the diagnosis of prostate cancer. med ultrason. 2011; 13:5-9. ultrasound of the scrotum 1. akin ea, khati nj, hill mc. ultrasound of the scrotum. ultrasound q. 2004; 20:181-200. 2. baldisserotto m, de souza jc, pertence ap, dora md. color doppler sonography of normal and torsed testicular appendages in children. ajr am j roentgenol. 2005; 184:1287-1292. 3. basu s, howlett dc. high-resolution ultrasound in the evaluation of the nonacute testis. abdom imaging. 2001; 26:425-432. 4. bhatt s, dogra vs. role of us in testicular and scrotal trauma. radiographics. 2008; 28:1617-29. 5. bertolotto m; trombetta c (eds). scrotal pathology. 1st edition. berlin: springer 2012. 6. casalino dd, kim r. clinical importance of a unilateral striated pattern seen on sonography of the testicle. ajr am j roentgenol. 2002; 178:927-930. 7. dogra vs, bhatt s. acute painful scrotum. radiol clin north am. 2004; 42:349-363. 8. dogra vs, gottlieb rh, oka m, rubens dj. sonography of the scrotum. radiology. 2003; 227:18-36. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 76 77archivio italiano di urologia e andrologia 2014; 86, 1 practical recommendations for performing ultrasound scanning in the urological and andrological fields 9. dogra vs, rubens dj, gottlieb rh, bhatt s. torsion and beyond: new twists in spectral doppler evaluation of the scrotum. j ultrasound med. 2004; 23:1077-1085. 10. dogra vs, gottlieb rh, rubens dj, liao l. benign intratesticular cystic lesions: us features. radiographics. 2001. 11. gorman b, carroll ba. scrotal sonography. in: rumack cm, wilson sr, charboneau jw (eds). diagnostic ultrasound, 3rd ed. chicago, il: cv mosby co. 2005; 849-888. 12. hörmann m, balassy c, philipp mo, pumberger w. imaging of the scrotum in children. eur radiol. 2004; 14:974-983. 13. karmazyn b, steinberg r, kornreich l, et al. clinical and sonographic criteria of acute scrotum in children: a retrospective study of 172 boys. pediatr radiol. 2005; 35:302-310. 14. kim w, rosen ma, langer je, banner mp, et al. us mr imaging correlation in pathologic conditions of the scrotum. radiographics. 2007; 27:1239-53. 15. mirochnik b, bhargava p, dighe mk, kanth n. ultrasound evaluation of scrotal pathology. radiol clin north am. 2012; 50:317-32. 16. pavlica p, barozzi l. imaging of the acute scrotum. eur radiol. 2001; 11:220-8. 17. pearl ms, hill mc. ultrasound of the scrotum. semin ultrasound ct mr. 2007; 28:225-48. 18. philips s, nagar a, dighe m, et al. benign non-cystic scrotal tumors and pseudotumors. acta radiol. 2012 feb 1; 53:102-11. 19. ragheb d, higgins jl jr. ultrasonography of the scrotum: technique, anatomy, and pathologic entities. j ultrasound med. 2002; 21:171-85 20. sudakoff gs, quiroz f, karcaaltincaba m, foley wd. scrotal ultrasonography with emphasis on the extratesticular space: anatomy, embryology, and pathology. ultrasound q. 2002; 18:255-273. 21. woodward pj, sohaey r, o’donoghue mj, green de. from the archives of the afip: tumors and tumorlike lesions of the testis—radiologic-pathologic correlation. radiographics. 2002; 22:189-216. 22. yang dm, kim sh, kim hn, et al. differential diagnosis of focal epididymal lesions with gray scale sonographic, color doppler sonography. 23. galosi ab, lacetera v, muzzonigro g. clinica delle malattie testicolari di interesse ecografico. urologia vol 75, n.4, s12, 2008: pag s59-66. 24. chiou rk, anderson jc, wobig rk, et al. color doppler ultrasound criteria to diagnose varicoceles: correlation of a new scoring system with physical examination. urology. 1997; 50:953-6. 25. liguori g, trombetta c, garaffa g, et al. color doppler ultrasound investigation of varicocele. world j urol. 2004; 22(5):378-81. texts american institute of ultrasound in medicine; american college of radiology; society of radio logists in ultrasound. aium practice guideline for the performance of scrotal ultrasound examinations. j ultrasound med. 2011; 30 (1):151-5. practice guideline for the performance of an ultrasound examination in the practice of urology http://www.auanet.org/content/education-and-meetings/aium-ultrasound-guidelines.cfm ultrasound of the penis 1. bassiouny hs, levine la. penile duplex sonography in the diagnosis of venogenic impotence.j vasc surg. 1991; 13:75-82. 2. bearcroft pw, berman lh. sonography in the evaluation of the male anterior urethra. clin radiol. 1994; 49:621-626. 3. broderick ga, lue tf. the penile blood flow study: evaluation of vasculogenic impotence. in:jonas u, thon w, f stief cg (eds). erectile dysfunction. berlin, germany: springer-verlag; 1991. 4. chou yh, tiu cm, pan hb, et al. high-resolution real-time ultrasound in peyronie’s disease.j ultrasound med. 1987; 6:67-70. 5. choudhary s, singh p, sundar e, kumar s, sahai a. a comparison of sonourethrography and retrograde urethrography in evaluation of anterior urethral strictures. clin radiol. 2004; 59:736-742. 6. kadiou a, tefekli a, erol h, cayan s, kandirali e. color doppler ultrasound assessment of penile vascular system in men with peyronie’s disease. int j impot res. 2000; 12:263-267. 7. kim b, kawashima a, leroy aj. imaging of the male urethra. semin ultrasound ct mr 2007; 28:258-273. 8. king bf, lewis rw, mckusick ma, evaluation of impotence. in: bennett ah (ed). impotence: diagnosis and management of erectile dysfunction. philadelphia, pa: wb saunders co; 1994. 9. morey af, mcaninch jw. sonographic staging of anterior urethral strictures. j urol. 2000; 163:1070-1075. 10. patel u, lees wr. penile sonography. in: solbiati l, rizzatto g (eds). ultrasound of superficial structures. london, england: churchill livingstone; 1995: 229-242. penile echo color doppler 1. halls j, bydawell g, patel u. erectile dysfunction: the role of penile doppler ultrasound in diagnosis. abdom imaging. 2009; 34:712-25. 2. broderick ga. evidence based assessment of erectile dysfunction. int j impot res. 1998; 10 suppl 2:s64-73; discussion s7-9. 3. benson cb, aruny je, vickers ma, jr. correlation of duplex sonography with arteriography in patients with erectile dysfunction. ajr am j roentgenol. 1993; 160:71-3. 4. quam jp, king bf, james em, et al. duplex and color doppler sonographic evaluation of vasculogenic impotence. ajr am j roentgenol. 1989; 153:1141-7. 5. patel u, amin z, friedman e, et al. colour flow and spectral doppler imaging after papaverine-induced penile erection in 220 impotent men: study of temporal patterns and the importance of repeated sampling, velocity asymmetry and vascular anomalies. clin radiol. 1993; 48:18-24. 6. fitzgerald sw, erickson sj, foley wd, et al. color doppler sonography in the evaluation of erectile dysfunction: patterns of temporal response to papaverine. ajr am j roentgenol. 1991; 157:331-6. 7. bertolotto m. (ed) color doppler us of the penis. springer, berlin heidelberg 2008, isbn:978-3-540-36676-8. acknowledgment we would like to thank mary v.c. pragnell, b.a., for language assistance. lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 77 archivio italiano di urologia e andrologia 2014; 86, 1 p. martino, a.b. galosi 78 correspondence coordinators pasquale martino, md (corresponding author) department of emergency and organ transplantation-urology i, university "aldo moro", bari, italy pasqualeluciomartino@libero.it andrea benedetto galosi, md division of urology, “murri” general hospital, asur marche, fermo, italy galosiab@yahoo.it authors marco bitelli, md urologist, rome, italy paolo consonni, md u.o. urologia casa di cura “s. maria”, castellanza (va), italy fulvio fiorini, md nefrologia soc azienda sanitaria ulss 18 rovigo, italy fiorini.fulvio@azisanrovigo.it antonio granata, md u.o. nefrologia e dialisi asp agrigento, agrigento, italy roberta gunelli, md u.o. urologia ospedale g.b. morgagni-l. pierantoni azienda usl di forlì via carlo forlanini, 34 forlì, italy giovanni liguori, md department of urology, university of trieste, ospedale di cattinara, trieste, italy silvano palazzo, md department of emergency and organ transplantation-urology i, university "aldo moro", bari, italy silvano.palazzo@alice.it nicola pavan, md urologist, trieste, italy vincenzo scattoni, md department of urology, university vita-salute, scientific institute san raffaele, milan, italy scattoni.vincenzo@hsr.it guido virgili, md department of urology, university of tor vergata, rome, italy guidovirgili@tiscali.it reviewers libero barozzi, md società italiana radiologia emergency, surgery and transplants department radiology unit s. orsola-malpighi university hospital via albertoni 10, bologna, italy michele bertolotto, md uco di radiologia, dipartimento di scienze mediche, chirurgiche e della salute, università degli studi di trieste, ospedale di cattinara strada di fiume 447, trieste, italy andrea fandella, md divisione urologica, casa di cura giovanni xxiii monastier (treviso), italy afandella@alice.it paolo rosi, md clinica urologica ed andrologica, university of perugia, perugia, italy uropg@unipg.it carlo trombetta, md member of esui-eau department of urology, university of trieste, trieste, italy trombcar@units.it lineeguida engl ok_stesura seveso 26/03/14 10:51 pagina 78 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4314 review pathological issues in biopsy specimens of men with prostate cancer eligible for active surveillance roberta mazzucchelli 1, andrea benedetto galosi 2, antonio lopez-beltran 3, marina scarpelli 1, liang cheng 4, rodolfo montironi 1 1 section of pathological anatomy, polytechnic university of the marche region, school of medicine, united hospitals, ancona, italy; 2 division of urology, “augusto murri” general hospital, asur marche, fermo, italy; 3 department of surgery, cordoba university medical school, cordoba, spain; 4 department of pathology and laboratory medicine, indiana university school of medicine, indianapolis, in, usa. active surveillance (as) is an important management option for men with lowrisk, clinically localized prostate cancer. the clinical parameters for patient selection and definition of progression for as protocols are evolving as data from several large cohorts become mature. vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for as. these findings need to be reproducible and accurately reported by pathologists. repeated biopsy after initial diagnosis of prostate cancer is recommended before inclusion in active surveillance for early detection of significant cancer. key words: prostate cancer; prostate biopsy; active surveillance; tumour extent; immunohistochemistry. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. often with psa kinetics and serial biopsy. any progression of the cancer while patients are monitored appears unlikely to threaten length of life (6). through this report we aim at facilitating dissemination of information on the critical role pathological parameters play in identifying appropriate candidates for as. clinical perspective on as specific inclusion criteria for as vary across institutions (7, 8). patients are selected for as on the basis of their age, psa density (psa/prostate volume), measures of psa kinetics, such as psa velocity, percent of positive biopsy cores, the extent of prostate cancer in any core, and gleason score 3 + 3 = 6 (9). some of these cohorts include patients with intermediate-risk clinical parameters, allowing for inclusion of patients with psa at diagnosis greater than 10 ng/ml or including selected men with gleason 3 + 4 = 7 pca. surveillance schedules for as are variable across institutions. most pca experts agree that surveillance should include a combination of serial psa and rectal examinations as well as repeat prostate biopsy. biopsy grade reclassification has emerged as a more meaningful endpoint for men on as. higher-grade tumors (gleason 7 and higher) clearly confer a higher likelihood of clinical progression. a finding of upgrading cancer on repeat biopsy commonly prompts treatment. this upgrading may represent undersampling at the time of initial diagnostic biopsy where the pre-existing highgrade prostate cancer was missed (10). tables 1 and 2 include, as an example, inclusion criteria, surveillance schedule and the definition of progression of three as protocols. repeated biopsy repeated biopsy after initial diagnosis of prostate cancer is recommended before inclusion in active surveillance, since repeated biopsy improves cancer grading and reduce the risk of undersampling of significant cancer. repeated biopsy should follow criteria of saturation doi: 10.4081/aiua.2014.4.314 presented at 19th national congress sieun, fermo 2014 introduction the overwhelming majority of men diagnosed with prostate cancer (pca) opt for primary curative therapy, such surgery to remove the prostate, i.e., radical prostatectomy, or radiation therapy to eradicate the tumor. however, most pcas are indolent and the number of newly diagnosed cases far outnumbering that of lethal cases (1). the magnitude of this so-called overdiagnosis, where cancers are identified that would never progress or cause harm to the patient if left untreated, ranges from 15% to 84% of new pca cases (2, 3). patients are exposed to the risk of overtreatment. even if overtreatment is avoided, overdiagnosis induces anxiety associated with the new cancer diagnosis, often resulting in further tests and expenses, and confers upon the patient a ‘cancer survivor’ label he carries for the rest of his life (4). male offspring may worry about familial inheritance and increased risk of the disease. given the indolent course of many pca detected by psa screening (5), active surveillance (as) has emerged as an initial management alternative, thus men avoiding the side effects of pca treatment. under most as strategies, patients undergo careful monitoring of the cancer, most mazzucchelli_stesura seveso 15/01/15 11:01 pagina 314 315archivio italiano di urologia e andrologia 2014; 86, 4 pathology in prostate cancer active surveillance biopsy (20 core or more based on prostate volume) (11). anterior gland should be included in the repeated biopsy. magnetic resonance imaging can be performed before re-biopsy since the negative predictive value for significant cancer raise 95%, however the positive predictive value is lower. men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation. the role of the pathologist the essential reporting items for cancer containing prostatic needle biopsies are listed in table 3. tumor extent measurements and the gleason score are the most important pathologic parameters in needle biopsies determining eligibility for as protocols. tumor extent measurements there is no consensus on the best tumor quantification methods, which include: cancer percentage in each core, greatest percentage of cancer, cancer length in each core, greatest length of cancer (glc), total percentage of carcinoma in all cores, total length carcinoma in all cores, fraction of positive cores, total carcinoma surface area and total percentage of carcinoma surface area in all cores. tumor measurements are performed as a visual estimate or using an ocular micrometer or other morphometric measurement such as computerized methods. visual estimation of percentage without morphometric measurements is commonly performed, although many recent studies do not actually describe whether visual estimation or morphometric measurements were used. some use a regular ruler or the side graticule available on most microscopes for estimation of length and percentage. the knowledge of the diameter of the field at each magnification for the microscope used to measure tumor extent can also help maximize accuracy of visual estimation of length. in a recent abstract, mahamud et al. found no overall difference between visual estimation and measurement when determining percent involvement of prostate biopsies assessed only by whole slide images. however, there was a significant difference between the two methods when they considered a subset of cores deemed to have 40-60% involvement by visual estimation. it is unclear whether the accuracy of visual estimation of an image can be compared with that of a tissue core on a glass slide on a microscope. data are conflicting whether morphometric measurements are superior to visual estimation and whether differences in the two methods would affect clinical management. computerized morphometric measurements are considered time-consuming and not practical for most pathologists. measurements of core length given in gross descriptions should not be used as these may not always be accurate. a few studies have assessed the value of the different methods of tumor extent measurement in prostate needle biopsy in predicting pathological stage or prognosis. quintal et al. (12) found that total percentage of carcinoma in all cores and number and percentage of cores with cancer were significantly stronger than other methods inclusion criteria johns hopkins university of toronto prias n° of patients 870 453 2494 clinical stage t1c ≤ t2 psa density ≤ 0.15 ng/ml/cc ≤ 0.20 ng/ml/cc psa ≤ 15 ng/ml ≤ 10 ng/ml no. of +ve cores ≤ 2 ≤ 2 % cancer per core ≤ %50 gleason score ≤ 6 ≤ 7 (3+4) ≤ 6 surveillance schedule institutions psa and dre repeat prostate biopsy definition of progression johns hopkins every 6 months yearly gleason score > 6, or > 2 cores, or > 50% any core university of toronto every 3 months for 2 yrs, 6-12 months after diagnosis, psadt < 3 years then every 6 months then every 3-4 years prias every 3 months for 2 yrs 1, 4, 7 and 10 yrs gs > 6, or ≥ 3 positive cores, and then every 6 months after diagnosis or psadt < 3 yearly table 1. active surveillance inclusion criteria for selected institutions (see text). 1. location of positive cores 2. tumor extent 3. gleason grades and score 4. histologic type 5. other (reported only if present) • extraprostatic extension • perineural invasion • lymphovascular invasion • intraductal carcinoma 6. other atypical acinar foci suspicious for carcinoma table 3. essential reporting elements for cancer bearing prostatic needle biopsies. table 2. surveillance schedule and definition of progression for selected institutions (see text). mazzucchelli_stesura seveso 15/01/15 11:01 pagina 315 archivio italiano di urologia e andrologia 2014; 86, 4 r. mazzucchelli, a.b. galosi, a. lopez-beltran, m. scarpelli, l. cheng, r. montironi 316 such as greatest percentage of cancer or length in a single core in predicting biochemical recurrence. total percentage of carcinoma in all cores had the strongest correlation and when combined with preoperative psa and gleason score improved prediction of pt3 in multivariate analysis. this was also independent for risk of biochemical recurrence. bismar et al. (13) found that although many tumor measurements such as greatest percentage of cancer, total tumor length in millimeters, fraction of positive cores and total percentage of carcinoma were significant in univariate analysis, only the fraction of positive cores was significant in multivariate analysis in predicting pt3 disease or positive margins. in this study all the measures were highly related to one another in a formal correlation analysis. park et al. (14) examined the significance of the number of cores positive for cancer, percentage of positive biopsy cores, total linear cancer length, total percentage of carcinoma and maximum cancer core length and found that, when considering psa and gleason score, none were significant in predicting pt3 disease in multivariate analysis. in a study by brimo et al. (15), it was found that the fraction of positive cores, total percentage of carcinoma and both total and greatest cancer core length were closely associated with pathological stage and biochemical failure. the fraction of positive cores was found to be the factor most closely associated with pt3 disease in radical prostatectomy. correlating needle biopsy cancer measurements with tumor volume in radical prostatectomy, poulos et al. (16) found that the highest percentage of carcinoma in any biopsy site, percentage of adenocarcinoma at the biopsy site with the highest grading, the number of positive biopsy sites and tumor bilaterality were significant with the percentage of biopsy sites positive for disease the most significant predictor of tumor volume. in a study by lewis et al. (17), tumor volume was best predicted by a combination of linear extent of carcinoma and number of positive cores. in a survey sent to 93 genitourinary pathologists the extent of cancer on needle biopsies was quantified by all the respondents with 80% reporting the number of cores involved by cancer. linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). considering the tumor quantification methods actually requested by urologists, in a 2005 study, 95% french and belgian urologists requested the number of positive cores compared with 53% requesting length of cancer. in a study by rubin et al. (18) 30 67% of urologists requested the percent involvement of each core by cancer, 33%, the number of cores with prostate cancer and 29% the length of core involvement. recommendations by the college of american pathologists, association of directors of anatomic and surgical pathology and the world health organization for reporting carcinoma extent have been summarized. given these recommendations, the extent parameters currently in use in as protocols and the evidence from the literature, it is suggested that pathologists should report the absolute number of involved cores out of total number cores and the amount of cancer in the single core with the greatest amount of tumor expressed as the percentage involvement by carcinoma, with or without the linear extent of carcinoma in that core. percentage involvement by carcinoma and or linear extent of carcinoma in each positive core may also be provided. all other measurements are optional. linear extent of carcinoma in each core may also be provided. other measurements are optional. the extent of cancer in prostate needle biopsy cores in patients potentially candidates for as should based on the recording of: 1. number of positive cores/total number of cores. the number of positive cores could possibly affect subsequent therapy in terms of suitability for as, such that it is justified to perform an immunohistochemical work-up of additional atypical foci (either hmwck or p63 or combination of the two with amacr). 2. linear percentage of prostatic tissue involved and/or total linear measurement of carcinoma and total core length. this can be done calculating the percentage of each core involved by cancer, based on the linear length of cancer (mm) divided by the core length, then multiplied by 100. the other method is to provide a percentage estimate of involvement of each of the cores derived by visual estimation. it has been shown that the former is more accurate and reproducible when patients are evaluated for eligibility for an as protocol. problems associated with tumor extent measurements measuring discontinuous foci of cancer when measuring discontinuous foci of cancer on a prostate needle biopsy core, the pathologist has to specify presence of discontinuous foci, linear extent in aggregate of discontinuous foci, percentage involvement of the core, and the core length spanned by discontinuous foci. the following sentence is suggested as a template for the pathology report: “prostate biopsy core (length: 1.2 cm) with two discontinuous foci, measuring 1.5 and 1.2 mm (measuring 2.7 mm in aggregate), respectively, of gleason score 3 + 3 = 6 acinar pca separated by 4 mm of intervening benign tissue. the tumor spans 56% of the core length, involving 22% of the core”. tissue core and tumor fragmentation concerning the number of cores per cassette, the ideal would one core per cassette. two biopsies from the same location could be embedded together. it has been shown that simultaneous inclusion of 3 biopsies in the same cassette can lead to the loss of a mean length of 1.15 cm of assessable tissue which corresponds to the average length of one prostate biopsy. when multiple cores are submitted in a single cassette or jar by the urologist and processed in a single cassette, many pathologists give the overall percentage of cancer for the entire slide as opposed to the percentage for each individual core. at the pathology laboratory of united hospitals, ancona, we attempt to give the percentage of cancer per core for each individual positive core, regardless of how many cores are on a given slide. mazzucchelli_stesura seveso 15/01/15 11:01 pagina 316 317archivio italiano di urologia e andrologia 2014; 86, 4 pathology in prostate cancer active surveillance when reporting biopsies with multiple cores in the same jar, the pathologist has to provide linear measurement (in millimeters) or linear extent (as percentage) of prostatic tissue involved for the most involved core and the overall linear percentage or measurement in millimeters of tissue submitted from the site(s) with cancer. if there are multiple fragmented small cores containing cancer, an accurate assessment of percentage of cancer per core cannot be determined, and only an overall percentage of cancer per fragmented specimen can be noted. in this scenario, one cannot even determine with certainty the number of positive cores. there is evidence in the literature that there is a greater tendency to core fragmentation when > 1 core is submitted in a container. it is our experience that needle biopsies collected onto gauze or paper are more likely to fragment. assessment of number of cores involved by pca is difficult in the presence of core fragmentation. a comment should be made suggesting that the urologist/clinician obtaining the biopsy is in the best position to make determination of number of cores involved based on the original submission of number of cores, and, if necessary, to undertake clinico-pathologic correlation (19). minimum acceptable core length currently there is no definition for adequate or minimum acceptable core length. the percentage of cancer in a short core (e.g. < 5-10 mm) versus that in a sufficiently long core mean entirely different tumor lengths. this has implications for interpretation of percent core involvement in the setting of as. since percent core involvement is based only on total length of prostatic parenchyma, non-prostatic elements should not be included in total core length assessment. gleason score the previous decade has seen considerable change in practice relating to gleason grading of prostatic carcinoma, and in 2005 the international society of urological pathology (isup) undertook a major revision of the gleason grading system. this was designed to reflect current practice and to incorporate recently gained knowledge on the biology of prostate cancer. the isup 2005 modification of the gleason grading system has resulted in changes to the definitions of gleason patterns 3 and 4 tumors. this is of particular importance for those patients in which deferred treatment is contemplated, as grade is central to the criteria utilized for identifying patients suitable for inclusion in as programs. two features define gleason pattern 3 glands: clearly infiltrating glands (in contrast to the overall nodular configuration of glands in gleason patterns 1 and 2) and each gland being a single discrete individual glandular structure that is well formed. the 2005 isup modification of the gleason grading system defined virtually all cribriform glands as gleason pattern 4, although in this classification well circumscribed, small, ovoid to round cribriform glands with regular bridging were included in gleason pattern 3. more recently it has been suggested that as all cribriform glands appear to be associated with a less favorable prognosis; these glands should also be classified as pattern 4. glands with a glomeruloid architecture are also considered as pattern 4. using these criteria, classification as gleason pattern 3 should be confined to tumors consisting of well formed, separate glands with lumina. accurate distinction of gleason pattern 3 from gleason pattern 4 is critical for eligibility for most as protocols. when there is doubt, it is suggested: • defaulting to a lower grade, • following the focus on deeper serial sections, • sharing such borderline cases with a colleague as the presence of a gleason pattern 4 may preclude the patient from as. biopsy gleason grade reclassification has emerged as one of the most meaningful intervention criteria for men on as. situations that should exclude a patient from as the presence of perineural invasion does not represent an exclusion criterion. however, there are rare pathologic situations that should likely exclude a patient from as: • histologic types: prostatic adenocarcinoma with predominant ductal carcinoma histology, sarcomatoid carcinoma, small cell carcinoma • intraductal carcinoma without invasive carcinoma • extraprostatic extension in needle biopsy • lymphovascular invasion in needle biopsy. conclusions given the overdiagnosis and overtreatment of low risk prostate cancer, as should be a ubiquitously adopted and formalized strategy. men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation. there are several issues and key questions that arise from the combined clinico-pathologic experience from formal and informal as treatment management strategies that would be applicable to the management of prostate cancer patients outside of academic centers and clinical trials. these need to be resolved over the next few years to tighten criteria of selection for patients contemplating as and their subsequent management. references 1. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. eur urol. 2014; 65:124-37. 2. carter hb, kettermann a, warlick c, et al. expectant management of prostate cancer with curative intent: an update of the johns hopkins experience. j urol. 2007; 178:2359-64. 3. dall’era ma, konety br, cowan je, et al. active surveillance for the management of prostate cancer in a contemporary cohort. cancer. 2008; 112:2664-70. 4. ercole b, marietti sr, fine j, albertsen pc. outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era. j urol. 2008; 180:1336-9. 5. roemeling s, roobol mj, de vries sh, et al. active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, psa doubling times, and outcome. eur urol. 2007; 51:1244-51. mazzucchelli_stesura seveso 15/01/15 11:01 pagina 317 archivio italiano di urologia e andrologia 2014; 86, 4 r. mazzucchelli, a.b. galosi, a. lopez-beltran, m. scarpelli, l. cheng, r. montironi 318 6. van as nj, norman ar, thomas k, et al. predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance. eur urol. 2008; 54:1297-305. 7. dall’era ma, cooperberg mr, chan jm, et al. active surveillance for early-stage prostate cancer: review of the current literature. cancer. 2008; 112:1650-9. 8. van den bergh rcn, roemeling s, roobol mj, et al. prospective validation of active surveillance in prostate cancer: the prias study. eur urol. 2007; 52:1560-3. 9. klotz l. active surveillance with selective delayed intervention is the way to manage “good-risk” prostate cancer. nat clin pract urol. 2005; 2:136-42. 10. lacetera v, galosi ab, cantoro d, et al. transrectal ultrasound (trus) and trus-biopsy’s accuracy in potential candidates for prias active surveillance protocol but treated with immediate radical prostatectomy. arch ital urol androl. 2012; 84:4:272-275. 11. ploussard g, xylinas e, salomon l, et al. the role of biopsy core number in selecting prostate cancer patients for active surveillance. eur urol. 2009; 56:891-8. 12. quintal mm, meirelles lr, freitas ll, et al. various morphometric measurements of cancer extent on needle prostatic biopsies: which ispredictive of pathologic stage and biochemical recurrence following radicalprostatectomy? int urol nephrol. 2011; 43:697-705. 13. bismar ta, lewis js jr, vollmer rt, humphrey pa. multiple measures of carcinoma extent versus perineural invasion in prostate needle biopsy tissue in prediction of pathologic stage in a screening population. am j surg pathol. 2003; 27:432-40. 14. park hj, ha ys, park sy, et al. incidence of upgrading and upstaging in patients with low-volume gleason score 3+4 prostate cancers at biopsy: finding a new group eligible for active surveillance. urol int. 2013; 90:301-5. 15. brimo f, montironi r, egevad l, et al. contemporary grading for prostate cancer: implications for patient care. eur urol. 2013; 63:892-901. 16. poulos ck, daggy jk, cheng l. prostate needle biopsies: multiple variables arepredictive of final tumor volume in radical prostatectomy specimens. cancer. 2004; 101:527-32. 17. lewis js jr, vollmer rt, humphrey pa. carcinoma extent in prostate needle biopsy tissue in the prediction of whole gland tumor volume in a screening population. am j clin pathol. 2002; 118:442-50. 18. rubin ma, bismar ta, curtis s, montie je. prostate needle biopsy reporting: how are the surgical members of the society of urologic oncology using pathology reports to guide treatment of prostate cancer patients? am j surg pathol. 2004; 28:946-52. 19. galosi ab, muzzonigro g, lacetera v, mazzucchelli r. specimen orientation by marking the distal end: (potential) clinical advantages in prostate biopsy. prostate cancer. 2011; 2011:270403. correspondence roberta mazzucchelli, md r.mazzucchelli@univpm.it marina scarpelli, md m.scarpelli@unvpm.it rodolfo montironi, md (corresponding author) r.montironi@univpm.it pathological anatomy, polytechnic university of the marche region, school of medicine, united hospitals, via conca 71, i−60126 torrette, ancona, italy andrea benedetto galosi, md galosiab@yahoo.it division of urology, “augusto murri” general hospital, asur marche fermo, italy antonio lopez-beltran, md em1lobea@gmail.com department of surgery, cordoba university medical school cordoba, spain liang cheng, md linag_cheng@yahoo.com department of pathology and laboratory medicine, indiana university school of medicine, indianapolis, in, usa mazzucchelli_stesura seveso 15/01/15 11:01 pagina 318 stesura seveso 205archivio italiano di urologia e andrologia 2014; 86, 3 original paper injection devices for bulking agents in uro-gynaecology maria angela cerruto, carolina d’elia, pierpaolo curti urology clinic, a.o.u.i. verona, italy. stress urinary incontinence (sui) affects a large proportion of middle-aged and elderly women. when all conservative means are ineffective, a surgical treatment including retropubic suspension, pubovaginal and tension-free slings, is contemplated. intra-urethral injections with bulking agents have been used as an alternative to the mentioned surgical procedures with alternate results. many urethral bulking agents are available, such as bovine glutaraldehyde cross linked (gax) collagen, polytetrafluoroethylene (teflon), polydimethyl-sillxane elastomer (silicone), carbon coated zirconium beads, hyaluronic acid/dextranomer, and autologous tissues such as fat and cartilage. these substances may be injected in a retrograde or antegrade fashion in the periurethral tissue and whether one route of injection is better than another is not well documented in the literature. we briefly describe the main injection techniques and devices of the most common bulking agents used in the treatment of female sui. key words: stress urinary incontinence; bulking agents; transurethral injections. submitted 3 october 2013; accepted 31 december 2013 summary introduction stress urinary incontinence (sui) affects a large proportion of middle-aged and elderly women, considerably lowering their quality of life and causing major economical costs to the society. when all conservative means are ineffective, a surgical treatment is contemplated, including retropubic suspension, pubovaginal and tension-free slings. tensionfree tapes are considered minimally invasive procedures, yielding a lesser degree of discomfort and a faster return to normal daily activities for the patients, but they still require the use of the operating room, troncular anaesthesia, and an overnight hospital stay in most instances. intra-urethral injections with bulking agents have been used as an alternative to the mentioned surgical procedures with alternate results, also due to the different characteristics of the various agents utilized, the most common shortcomings being lack of biocompatibility, allergenicity and short permanence in the tissue. continuous advances in materials technology have provided the possibility that many urethral bulking agents are available (1), such as bovine glutaraldehyde cross linked (gax) collagen, polytetrafluoroethno conflict of interest declared. ylene (teflon), polydimethyl-sillxane elastomer (silicone), carbon coated zirconium beads, hyaluronic acid/dextranomer, and autologous tissues such as fat and cartilage (2). these substances may be injected in a retrograde (more common) or antegrade fashion in the periurethral tissue around the bladder neck and proximal urethra. whether one route of injection is better than another is not well documented in the literature. schulz et al. compared the transurethral injection route with paraurethral one (3). the authors showed a trend towards better subjective and objective outcomes in favour of transurethral injection without reaching statistical significance. although there is no evidence that transurethral route is better than paraurethral, the argument in favour of the former is supported by the finding of more complications following paraurethral injection (4). we briefly describe the main injection techniques and devices of the most common bulking agents used in the treatment of female sui. transurethral and periurethral injection technique and devices of collagen the precise placement of the injected material is essential to ensure the most desired clinical outcome (5). the injection may be performed through a needle placed directly through the cystoscope or periurethrally with a spinal needle placed percutaneously at the introitus and positioned in the tissue adjacent to the urethra. the collagen implant syringe contains 2.5 ml of sterile bovine gax collagen dispersed in phosphate buffered physiological saline. transurethral injection is performed using a 18 fr cystoscope. the needle is advanced into the urethral wall just below the bladder neck and the implant is injected submucosally until the urethral coaptation is observed at the needle penetration site. injections may be repeated at multiple sites (from 1 up to 5 injections) as needed until closure of the proximal urethral lumen is achieved (6). periurethral injection could minimize possible complications such as bleeding and extrusion of the injected substance (5). it should be easy to handle the spinal needle and cystoscope simultaneously to ensure precise placement of the needle tip in the periurethral tissue in the proximal urethra just below the bladder neck. the patient is placed in the lithotomy position, and after the anaesthetic procedures, a 20or 22-gauge spinal needle, doi: 10.4081/aiua.2014.3.205 cerruto_stesura seveso 08/10/14 12:12 pagina 205 archivio italiano di urologia e andrologia 2014; 86, 3 m.a. cerruto, c. d’elia, p. curti 206 with the obturator in place, is placed at 4 o’clock position with the bevel of the needle directed medially toward the lumen of the urethra (5). the needle is advanced through the urethral muscle into the lamina propria, remaining entirely submucosally. in this plane, the needle should advance with ease. during needle advancement, a 17-18 fr cystoscope employing either a 0or 30-degree lens may be used to ensure optimal needle placement. the needle should be positioned 0.5 cm below the vesical neck within the lamina propria (6). after removing the spinal needle obturator, the substance is injected with one hand while stabilizing the cystoscope with the other one. the collagen is seen accumulating first within the lining of the urethra as a whitish bulging of the urethral mucosa. the material should be injected slowly to allow accommodation within the tissues. when the urethra is 50% or greater occluded, the needle is removed and reinserted on the opposite side in the 8 o’clock position. additional collagen may be injected until the urethral mucosa coapts, creating the desired urethral occlusion. to prevent remodelling of the injected material, care should be taken not to advance the cystoscope proximal to the injected material. should the urinary bladder become over-distended during the injection process, the cystoscope may me removed and a 12fr catheter inserted to drain the bladder (5). transurethral injection technique and devices of silicone microimplants (macroplastique; polydimethylsiloxane) macroplastique is a soft tissue bulking agent and is comprised of soft, flexible, highly-textured irregularly shaped implants of heat vulcanized polydimethylsiloxane (a solid silicone elastomer) suspended in a bio-excretable carrier gel. the carrier gel is a pharmaceutical grade, water-soluble, low molecular weight polyvinylpyrrolidone (pvp or povidone) hydrogel which is absorbed by the reticuloendothelial system and excreted unchanged in the urine. polydimethylsiloxane elastomer and polyvinylpyrrolidone have favorable biocompatibility properties. polydimethylsiloxane is well tolerated by the cellular immune system and is non-genotoxic, non-carcinogenic and non-teratogenic (7). the endoscopic injection procedure can be performed under general, regional or local anaesthesia. during the transurethral procedure, under direct cystoscopic vision, the needle, inserted through the cystoscope operative channel, is placed submucosally into the urethra at the six, ten and two o’clock positions 1.5 to 2.0 cm distal from the bladder neck. the material is slowly injected until a sufficient mucosal bleb is achieved. the procedure is completed if there is a total mucosal apposition together with occlusion of the urethral lumen. the injectable can also be administered periurethrally, under cystoscopic control by inserting a spinal needle percutaneously adjacent to the urethra. after injecting, the cystoscope should not be advanced past injected areas and only small ‘in and out’ catheters (8-12 fr) should be inserted because this may result in compression or extrusion of the bulking agent afterwards. to improve and simplify the transurethral implantation technique and to minimize problems associated with endoscopic procedures, the macroplastique implantation system (mis) was developed for the treatment of female sui. the device seems to allow a constant placement of the implants at predefined depth and angles at the six, ten and two o’clock position of mid-urethra within the same circumferential plane. to identify the site of implantation correctly, the ruler measuring scale on the topside of the device is used. the site of the bladder neck is identified as the position where the water flow from the fluid drainage channel ceases while the tip of the device is slowly withdrawn from the fluid-filled bladder. the standard implantation position is defined by withdrawing the device from the urethra to the appropriate location of the mid-urethra, i.e., 10-15 mm distance from the level of the bladder neck. before withdrawing the needle, it is advisable to wait for at least 30 seconds in order to avoid any material leakage. transurethral injection technique and devices of zirconium oxide beads (durasphere) durasphere injection is performed using pre-packaged syringes containing 1.0 ml durasphere and a 18 g needle delivery device. urethral bulking agent injections are usually performed transurethrally at the level of the bladder neck under direct vision. more than one site may be injected. in 2003 majar et al. described a modified technique for an easier implantation of this agent (8). after routine video monitored cystoscopy the bladder is completely drained. the cystoscope is withdrawn to the distal urethra, so that the mid-urethra, proximal urethra and bladder neck are viewed simultaneously. the needle is introduced through the cystoscopic sheath. with the bevel pointing toward the urethral lumen, the needle is directed at 45 degrees to the lumen and into the urethral wall at the 4 o’clock position (left hand dominant surgeons may find the 8 o’clock position preferable). after the needle tip penetrates the urethral wall and the bevel is no longer seen, the needle is advanced, this time parallel to the urethral lumen, for 1 to 2 cm. at this point 1.5 ml 1% lidocaine solution are injected into the submucosal layer. this step results in partial coaptation of the urethral walls and hydrodissection of the space to which the beads are eventually injected. using this technique the whole circumference of the urethra coapts with no need to change the needle location from its original 4 o’clock position. the bulking agent is then injected with steady and consistent thumb or thenar eminence pressure on the plunger using 1 hand, while holding the cystoscope with the contralateral hand. resistance to injection at this point is managed by gradual withdrawal/advancement of the needle tip and by turning the bevel in a clockwise or counterclockwise direction. insistence on injecting the beads at exactly the same location and bevel orientation would result in further bead impaction and limits the capability of bead delivery. complete needle withdrawal is avoided. this step is repeated as needed with the surgeon steadily holding the delivery system and maintaining the needle at exactly the same location under cystoscopic guidance: the assistant replaces the used syringe with a new, full syringe, so that further material can be injected (usually cerruto_stesura seveso 08/10/14 12:12 pagina 206 207archivio italiano di urologia e andrologia 2014; 86, 3 injection devices for bulking agents correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, f.e.b.u. (corresponding author) karolinedelia@gmail.com pierpaolo curti, md curtipierpaolo@gmail.com urology clinic, a.o.u.i. verona, policlinico g.b. rossi piazzale l.a. scuro 10 37134 verona, italy 2 to 3 syringes are needed) until nearly complete urethral lumen coaptation is achieved. when almost complete coaptation is attained, the syringe is replaced and 1.5 ml normal saline are injected at the same position. this step enables beads remaining in the needle to be deployed at the injection site. the needle tip is then maintained at the same position for another 10 seconds. at the end of the procedure the bladder is emptied using a 12fr straight catheter. carbon bead bulking agent may be injected also periurethrally (9). a rigid 0° cystoscope is introduced into the urethra to allow visualization of the bladder neck. a 1.5-in, bent, 18 g needle is then inserted periurethrally at either 4-o’clock or 8-o’clock position at approximately 0.5 cm distal to the bladder neck.. then the material is injected until either the luminal appearance demonstrates mucosa coaptation or 6 ml of the product has been used. if good circumferential coaptation of the tissue has been achieved by injecting the carbon beads from just one injection site, the needle is not inserted on the other side. transurethral injection technique and devices of nasha/dx copolymer (zuidex) nasha/dx copolymer comprises dextranomer (dx) microspheres (80 to 250 m) in a carrier gel of non-animalstabilized hyaluronic acid (nasha). the gel is a biocompatible, biodegradable material free of animal products, has no immunogenic properties, and has been shown not to migrate to different organs after submucosal injection. a guiding instrument, named the implacer, has been developed to facilitate reproducible and standardized transurethral injection of nasha/dx copolymer, without the need for surgical facilities or cystoscopic guidance (10). zuidex™ gel is a dextranomer/hyaluronic acid (dx/ha) copolymer. dextranomer (dextran 2.3 dihydropropyl 2-hydroxy-1.3 propane-diethylethers) is made by hydrophylic dextran polymer particles (microspheres 80-120 micron), configurated as a network. it acts as a cell carriers, recruiting connective fibers from the surrounding tissues. it is non-alergic, as it has no free dextran molecules. hyaluronic acid is a 1% solution, highly viscous, highly molecular weight polysaccaride. it is non-immugenic as it is not extracted from animals but from bacteria. the zuidex system is composed of: 4 pre-filled syringes, each containining 0.7 ml of zuidex™ gel, and a zuidex implacer. the latter is a plastic device that consists of i) one hand piece, ii) a head with 4 thin channels where the 21 g needles of the 4 syringes are passed, and iii) a specially designed sliding cannula. the cannula covers the needles for the smooth insertion into the urethral lumen and once withdrawn, enables the prick of the urethral submucosa in 4 sites. the procedure may not require the use of the operating room and it is made on an outpatient basis, in the office, under local anaesthesia. nevertheless, general and/or local anaesthesia may be administered, depending on investigator preference. the first step is the urethral length measurement. this is done by means of a foley catheter with the filled balloon gently snuggled against the bladder neck, by marking the catheter surface at the exit from the external meatus. in an office setting, only 5 mg of anaesthetic gel are instilled into the urethra and left in place for 10 minutes. the implacer and the four syringes are assembled. the needles are thereafter covered by the cannula pushed to its bottom position. at this point the distal tip of the cannula is advanced through the meatus as far as the mid-urethra, and is firmly kept in this position throughout the whole procedure. the cannula is slid backward to uncover the needles in the urethral lumen. each needle is withdrawn 1 cm and push forward again to perforate the urethral mucosa and the zuidex gel is injected into the urethral wall. this manoeuvre may be started at 2 o’clock position in a clockwise direction. subsequently, all the syringes and the implacer itself are removed. no transurethral catheter is used after the procedure. the patient is observed until she voids with no significant residual urine. conclusions as bulking materials develop, understanding of the preferred injection technique also is being gained, as well as the best delivery method and injection site. every effort should be done for making these devices safe and easy to manage, more and more. references 1. appell ra, dmochowski rr, herschorn s. urethral injections for female stress incontinence. bju int. 2006; (98 suppl) 1:27-30. 2. smith arb, daneshgari f, dmochowski r, et al. surgery for urinary incontinence in women. in: abrams p, cardozo l, khoury s, wein a: incontinence. 3rd edition 2005; 1297-1370. 3. schulz ja, nager cw, stanton sl, baessler k. bulking agents for stress urinary incontinence: short-term results and complications in a randomized comparison of periurethral and transurethral injections. int urogynecol j pelvic floor dysfunct. 2004; 15:261-5. 4. pickard r, reaper j, wyness l, et al. periurethral injection therapy for urinary incontinence in women. cochrane database of systematic reviews 2003, issue 2. cd003881. 5. winters jc, appell r. periurethral injection of collagen in the treatment of intrinsic sphincter deficiency in the female patient. urol clin north am. 1995; 22:673-678. 6. groutz a, blaivas jg, kesler ss, et al. outcome results of transurethral collagen injection for female stress incontinence: assessment by urinary incontinenc score.j urol. 2000; 164:2006-9. 7. ter meulen ph, berghmans lcm, van kerrebroeck p. systematic review: efficacy of silicone microimplants (macroplastique®) therapy for stress urinary incontinence. eur urol. 2003; 44:573-582. 8. madjar s, covington-nichols c, secrest cl. new periurethral bulking agent for stress urinary incontinence: modified technique and early results. j urol. 2003; 170: 2327-2329. 9. kershen rt, dmochowski rr, appell ra. beyond collagen: injectable therapies for the treatment of female stress urinary incontinence in the new millennium. urol clin north am. 2002; 29:559-574. 10. von kerrebroeck p, ter meulen p, larsson g, et al. efficacy and safety of a novel system (nasha/dx copolymer using the implacer device) for treatment of stress urinary incontinence. urology. 2001; 58:12-15. cerruto_stesura seveso 08/10/14 12:12 pagina 207 stesura seveso introduction the efficacy and the cost-effectiveness analysis of bacille calmette-guérin (bcg) therapy in the management of high-risk superficial bladder cancer (nmibc) or treatment of carcinoma in situ (tis) has been demonstrated (1-3). the goal of bcg therapy is to eradicate the disease and to inhibit tumor recurrence and prevent the progression of cancer (4-6). although used in large number of patients, the immunotherapy mechanism of action of bcg has remained a black box for three decades. a local inflamma157archivio italiano di urologia e andrologia 2013; 85, 4 original paper dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy raffaella rossi 1, miriam lichtner 2, francesco iori 3, angela ermocida 1, claudia mascia 1, fabio mengoni 1, ilaria sauzullo 1, danilo dini 3, claudio m. mastroianni 2, vincenzo vullo 1 1 department of public health and infectious diseases, “sapienza” university, rome, italy; 2 infectious diseases unit “sapienza” university, latina, italy; 3 department of urology, “sapienza” university, rome, italy. objectives: immunotherapy with bcg (bacille calmette-guérin) after transurethral resection of the bladder tumor represents a highly effective primary treatment for intermediate and high-risk superficial bladder cancer. the effectiveness of this therapy has been documented, but its mechanism of action is not clear yet. in the present study, we investigated the changes of dendritic cells (dc) numbers in peripheral blood and urine of patients with superficial bladder cancer undergoing bcg intravescical therapy material and method: we have enumerated plasmacytoid and myeloid dcs in the peripheral blood and in the urine of patients with bladder cancer in order to clarify the role of these cells in the evolution of the disease and the effect of therapy. dcs in blood and urine samples were assessed using the single-platform trucount assay with monoclonal antibodies. the study population included 37 healthy donors and 13 patients with diagnosis of primitive superficial bladder cancer. results: at the time of diagnosis a reduction of blood dcs was found in patients as opposed to healthy donors, while dcs were not found in the urine in the same way as in healthy subjects. six of these patients were followed before and after weekly and monthly instillations of bcg. in the peripheral blood, we observed an immunological recovery of dcs from the third weekly instillation up to the sixth. in the urine of patients, we didn’t find mdcs or pdcs at t0, but we found a statistically significant change from the third instillation up to the sixth. on the contrary, we didn’t find mdcs in urine during monthly instillation. conclusions: dc count could be used in the monitoring of patients undergoing bcg therapy. immunological restoration of mdc numbers in peripheral blood and the efflux in urine could be important for confirming the effectiveness of bcg instillation. key words: dendritic cells; trucount assay; bcg therapy; superficial bladder cancer; urine. submitted 10 may 2013; accepted 31 july 2013 no conflict of interest declared summary tion, characterized by an influx of mononuclear cells into the bladder wall and by the secretion of pro-inflammatory cytokines into the urine, has been described in patients undergoing bcg instillations (7-9). recently, a central role in the prevention bladder tumor recurrence has been suggested for granulocyte-macrophage colony-stimulating factor (gm-csf) and tumor necrosis factor (tnf)-!, which are essential cytokines in the induction of dendritic cell (dc) response (10). in fact, both natural and adapdoi: 10.4081/aiua.2013.4.157 archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 158 tative immunity seem to be involved in the local response to bcg therapy. several studies showed the presence of natural killer (nk) cells, cd4+ and cd8+ t lymphocytes in the bladder wall in patients with superficial transitional cell carcinoma (tcc) undergoing bcg instillations. this presence was correlated with a reduction in superficial bladder cancer recurrence (11). few studies have examined the significance of the presence of dendritic cells (dc) in the urine from patients with bladder cancer. the importance of dcs as immunotherapy against cancer has been widely studied (12-14). in fact, dcs are considered professional antigen presenting cells (apcs) for inducing anticancer immunity, both in vitro and in vivo (15), and they can induce both primary and secondary immune responses. nishiyama et al, propose dc-based cancer immunotherapy as an additional treatment against advanced bladder cancer (16). cheadle et al. demonstrated in vitro that bcg-infected dc are potent activators of t-cells and adaptive immune response (17). two types of immature circulating dcs were found in human blood: myeloid dcs (mdcs) and plasmacytoid dcs (pdcs) that can be identified for their phenotypic markers and different function (18). a recent study tested the hypothesis that dcs may also migrate in the urine of bladder cancer patients. the authors speculate that variability in the percentage of urinary dcs may reflect changes in immunological activity at the tumor site (19). however, they did not enumerate circulating dcs in the periphery. in this study, we used a single-platform flow cytometric trucount assay to count the absolute number of the two subsets of dcs in both peripheral blood and urine samples from patients with bladder cancer before transurethral resection. in addition, in a longitudinal study, the enumeration of mdcs and pdcs count was done at different times of weekly and monthly bcg instillation. materials and methods the study population included 13 patients with diagnosis of primitive bladder cancer, confirmed by transurethral resection bladder (turb) (10 males, 3 females; age range, 55-81 years old). tnm (t: size or direct extent of the primary tumor. n (0-3): degree of spread to regional nodes. m (0/1): presence of metastasis) classification of tumors in studied patients was as follows: tag1 in 1 patient, tag2 in 3 patients, tag3 in 5 patients, t1g3 in 3 patients and t2g3 in 1 patient. six patients (3 with tag2 and 3 with tag3) were repeatly analyzed during weekly and monthly instillations with bcg, according to the lamm’s protocol (20). all patients were admitted to the department of urology of the azienda policlinico umberto i, sapienza university of rome. twentysix healthy donors were included as control group. informed consent was obtained from all subjects before being included in the present study. the study was approved by the institutional review board (department of infectious and tropical diseases, sapienza university of rome). blood and urine were collected in the first mornfigure 1. cytofluorimetric analysis of dc subsets in blood sample using trucount assay. this is one representative example of dc count in a healthy donor and a patient with superficial bladder cancer. in r1 gate we have identified lymphocytes and monocytes (pbmcs), using as parameters the side scatter channel (ssc) and the cd45-percp. beads are on the right of the dot plot (a). gate r2 recognized pbmcs that were lineage-negative (b). gate r4 represents trucount beads events and it was obtained in an ungated dot plot of fl1 vs. fl2 (c). finally, to define mdc and pdc, events from r1 and r2 were analyzed in a contour plot of cd11c or cd-123 vs. hla-dr (d). all cd11chi-hla-dr+ and cd123hi-hla-dr+ were included in this gating strategy. 159archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy figure 2. cytofluorimetric analysis of dc subsets in urine sample using trucount assay. this is one representative example of dc count in healthy donor and patient with superficial bladder cancer. the same strategy of blood sample was used and the figure shows the contour plot of mdcs and pdcs events (gate r3) in the urine. ing before turb. all patients had no change in lymphocytes and monocytes values. to identify dc subsets, we used a new single platform flow cytometric assay, based on trucount tm tubes, which contain a known number of fluorescent beads as inside control. this method has many advantages: first of all, we use whole blood and not conventional ficoll-density separation. the absolute number of pdcs or mdcs (cells/ml blood) was calculated by the following formula: (mdc or pdc events x known trucount beads)/ (beads events x 0.1 ml). in this way, we eliminate the count obtained from haematology blood analyzer data. besides, this count is highly reproducible with intra and inter assay, and fast to execute. for dc enumeration, peripheral blood was conserved in edta (ethylenediaminetetraacetic acid) tubes. whole blood (0.1 ml) was directly labeled in trucount tm tubes, adding monoclonal antibodies (mabs) and isotype control and using lyse/no wash assay. mabs for the labelling were: anti cd45-percp to identify peripheral blood mononuclear cells (pbmcs), anti hla-dr-apc that marks dcs and activated cells, lineage-fitc cocktail (composed of anti-cd3, anticd14, anti-cd16, anti-cd19, anti-cd20, anti-cd56) because dcs do not express this marker, anti-cd11c-pe or anti-cd123-pe specific markers for mdcs or pdcs respectively. finally mouse anti-igg1a-pe and mouse anti-igg2a-pe were used for isotype control. gating strategy is shown in figure 1. all antibodies and trucount tm tubes were purchased from becton dickinson (bd biosciences pharmingen, italy). after mixing, the tubes were incubated for 15 minutes in the dark at room temperature (rt); then 450 µl of facs lysing solution (bd) was added to each tube, after which they were vortexed and incubated for 15 minutes at rt. as for urine, before the staining of dcs, the samples were concentrated 1:100. then, mabs and isotype control were added following the protocol for dcs staining in peripheral blood (figure 2). all samples were analyzed within 1-3 h of staining using a facscalibur flow cytometer and cellquest 1.0, and 100.000 events were acquired (becton dickinson, mountain view ca). all data were collected using identical instrument settings. for statistical analysis sigma stat 2.2 (jandel scientific software, san rafael, ca) was used. values are given as median and ranges. the statistical differences of values were analyzed using the nonparametric mann-whitney u test and spearman coefficients were calculated to measure the association among parameters. results cross-sectional study the enumeration of both mdcs and pdcs was performed in peripheral blood and urine samples from 13 patients before transurethral resection (time 0). mdcs and pdcs were significantly reduced in peripheral blood from patients with superficial bladder cancer in comparison archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 160 with healthy donors. in fact, the median value of mdcs in patients was 8825 cells/ml (range 4187-15317) vs 15300 cells/ml (8901-45917) in healthy donors (p < 0.001). similarly, a decrease in pdc count was found (bladder cancer: 5411 cells/ml, range: 2897-10693; healthy donors: 13553, 3875-52111; p < 0.001) (figure 3). when patients were stratified on the basis of cancer grading, we observed a significant reduction of mdcs (p = 0.004) in low grade groups (g1 and g2) when compared with the higher grade group (g3). no significant differences were found in pdcs count (p = 0.918) between the two groups. when urine samples were assessed by cytofluorimetric analysis, we did not detect the presence of mdcs and pdcs either in patients or healthy donors. longitudinal study after transurethral resection, six patients were followed during weekly and monthly instillations with bcg. during a median follow up of 24 months, all patients were free of recurrences. we counted dcs subpopulations in blood and urine before and after 24 hours of the first (t1-t2), third (t3-t4), fifth (t5-t6) and sixth (t7t8) weekly instillations and before and after 24 hours of the sixth monthly instillation (t9-t10). in the peripheral blood, the patients had a recovery of mdcs respect to figure 3. circulating mdc and pdc count in peripheral blood. two subsets of dcs were measured using trucount assay and asignificant reduction in both mdcs (a) and pdcs (b) was found in the patients. figure 4. circulating mdc and pdc count in peripheral blood post-instillations. mdcs and pdcs were measured using trucount assay. a significant increase was found in mdcs at t8 of weekly instillations compared to t0 (a). no significant differences in pdc count were found (b). lines ---represent the median values of mdcs and pdcs in the healthy donors. or lamina propria and frequently have a good response to therapy. the treatment for superficial tcc is transurethral resection bladder (turb), and 80% survival is achieved, but less than half are cured because of the relapse (50-70%). this resection is followed by intravescical therapy that has been shown to be the treatment of choice for intermediate and high superficial bladder cancer. this therapy was first used in the management of bladder cancer in 1976 by morales et al. and it is an immunotherapy based on instillations with live attenuated tuberculosis vaccine, bacille calmette-guérin (bcg). in the present study, we investigated the changes of dc numbers in peripheral blood and urine of patients with superficial bladder cancer undergoing bcg intravescical therapy (22). we found for the first time a significant decrease of both circulating mdcs and pdcs absolute count in patients with superficial bladder cancer, before transurethral resection, compared to healthy donors. the reduction of dcs in peripheral blood may have functional consequences on dcs activity against the progression of tumor: mdcs play an important role in cancer for their antitumor properties, while pdcs are the natural ifnproducing cells in the immune system. on the other hand, when patients were stratified for tumor grading, data showed that lower cancer grading was associated with the lowest count of mdcs in blood, suggesting that dcs deficit depends on a major recruitment of mdcs at the tumor site, rather than on a peripheral disruption. in a longitudinal study, we have followed six patients after transurethral resection and during weekly and monthly instillations of bcg. we observed a numerical recovery of both circulating dcs in these patients at the end of the weekly treatment. the number of dcs increased from the third instillation, and it may represent a good evidence for the efficacy of bcg immunotherapy in immunological recovery. bcg causes a local inflammation and an influx of mononuclear cells into the bladder wall (8). bcg induces maturation and activation of dcs with interaction with tlrs 2 and 9 and with dectin1 (17,19,24,25,26,27) that are important components of the innate immune response. in our patients, mdcs were found in urine after bcg therapy, particularly at the third instillation that corresponds to blood dcs increase. the mdcs found at the site of immunotherapy in those patients with lower grades may be involved in the protective immune responses elicited by the treatment. many studies underlined the presence of cells, such as nk cells, cd4+ and cd8+, t lymphocytes in the bladder wall, after bcg instillations in patients with superficial tcc. this presence was correlated with a reduction in superficial bladder cancer recurrence (10) but the results were often conflicting (28,29,30). in other studies, pro-inflammatory cytokines (il-1, il-2, il-6, tnf!, ifn-") were found in urine after bcg instillations (7, 9, 10, 31) but their role in weekly instillations is not 161archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy figure 5. mdc count in the urine, post-instillations, using trucount assay. a significant increase was found in mdcs from the third up to the sixth weekly instillations (t4, t6 and t8) compared to t0. no statistically increase was found at sixth monthly instillation (t10) if compared to t0. lines ---represent the median values of mdcs in the healthy donors. t0 (p = 0.04) and at the end of weekly instillations, the values were comparable to healthy donors (p = 0.7). at the sixth monthly instillation, none of the patients showed numerical reduction of mdcs. there was an increase from the third instillation (figure 4a). no significant changes were observed before and after 24 hours of the bcg instillations (data not shown). for the pdcs, we found only a partial increase compared to t0 at the end of weekly instillations without a statistical significance (p = 0.2) (figure 4b). at the sixth monthly instillation, the pdc values decreased to the pre-instillation levels, indicating that peripheral blood pdcs were partially affected by bcg instillation. the analysis of the urine showed that mdcs were detectable in the urine from the third instillation up to the sixth instillations. no changes were found before and after 24 hours of the bcg instillations. in fact, during the first instillation we didn't find mdcs before and after 24 hours. otherwise, at the third instillation, mdc were detected in urine and remained stable until the end of weekly instillation. little or no mdc release was found in urine during monthly instillations (figure 5). analysis using the spearman rank correlation test showed that there was no statistically significant correlation between mdcs in urine and blood (r = 0.240, p = 0.3). discussion transitional cell carcinoma (tcc) is found in more than 90% of patients with bladder cancer, and this type of cancer is either superficial (70%) or muscle-invasive. patients with muscle-invasive or metastatic disease have a poor prognosis and they will die within 2-3 years after diagnosis. superficial tumors are confined to the mucosa archivio italiano di urologia e andrologia 2013; 85, 4 r. rossi, m. lichtner, f. iori, a. ermocida, c. mascia, f. mengoni, i. sauzullo, d. dini, c.m. mastroianni, v. vullo 162 clear. recently, some studies correlated the presence of leukocytes in the urine of patients with bladder cancer undergoing bcg therapy with a reduction of recurrence (10). dcs were found in the urine of bladder cancer patients, and it was speculated that variability in the percentage of urinary dcs may reflect changes in immunological activity at the tumor site (32). it is conceivable that the mdcs we found in the urine of patients under bcg immunotherapy may play a crucial role in the antitumor activity of bcg therapy. they may interact with the nk cells, t cells and other leukocytes and with various cytokines, through a reciprocal cross-talk that activates anti-tumor responses (33, 34). indeed a very recent report showed that bladder tumour mature dendritic cells and macrophages are predictors of response to bcg therapy (34). in the last years there has been a lot of interest in the evaluation of peripheral blood dc subsets, as an improvement in the enumeration methods has been obtained (35). using flow cytometry for dc counts, a reduction of circulating mdcs and pdcs was demonstrated for the first time in hiv infection (36-38). several studies have shown that dcs in blood are decreased by viral, parasitic and bacterial infectious diseases (39, 40). in addition, recent studies have shown variations of dc counts in peripheral blood in some tumor such as breast cancer in advanced stage (41, 42) and in a urological tumor, prostate adenocarcinoma (43, 44). dcs are present in very low percentages in peripheral blood, and for this reason it is difficult to obtain a real and reproducible enumeration of these cells. in our study we have obtained an absolute count of dcs using a single platform tru count assay and a flow cytometric analysis for rare events that gives a standardization of dcs counting in clinical practice (35). all treated patients showed a release of dcs into the urine, with a burst increase at the third instillations. in agreement with previous data, we suggest that bcgmediated antitumor activity may be a localized phenomenon that induces immune responses against cancer, using mdcs antitumor proprieties. the quantification of dcs using a single platform tru count assay may be very important to understand the mechanism of bcg action and perhaps to monitor the treatment efficacy. finally, pdcs seem to have a different role: they decreased in patients with superficial bladder cancer, remained low during bcg treatment and they were never found in urine. from these data we can speculate that deficit of pdcs was a characteristic related to other tumor forms (breast, prostate) (41-44) rather than a consequence of the cancer development. conclusion the results of our study indicate that the number of dcs in blood and urine shows variations during endovescical instillations with bcg in patients after transurethral resection of superficial bladder cancer. mdcs seem to play a crucial role at the tumor site and they were recruited in urine by bcg 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beatty jd, islam s, north me, et al. urine dendritic cells: a noninvasive probe for immune activity in bladder cancer? bju int. 2004; 94:1377. 33. abadie v, badell e, douillard p, et al. neutrophils rapidly migrate via lymphatics after mycobacterium bovis bcg intradermal vaccination and shuttle live bacilli to the draining lymph nodes. 2005; blood. 106:1843. 34. ayari c, larue h, hovington h. bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus calmette-guérin immunotherapy. eur urol. 2009; 55:1386. 35. vuckovic s, gardiner d, field k, et al. monitoring dendritic cells in clinical practice using a new whole blood single-platform tru count tm assay. jim. 2004; 284:73. 36. grassi f, hosmalin a, mcilroy d, et al. autran b. depletion in blood cd11c-positive dendritic cells from hiv-infected patients. aids. 1999; 13:759. 37. pacanowski j, kahi s, baillet m, et al. reduced blood cd 123+(lymphoid) and cd 11 c+ (myeloid) dendritic cell numbers in primary hiv-1 infection. blood. 2001; 98:3016. 38. servet c, zitvogel l, hosmalin a. dendritic cells in innate immune responses against hiv: curr mol med. 2002; 2:739. 39. lichtner m, maranon c, vidalain po, et al. hiv type 1-infected dendritic cells induce apoptosis death in infected and uninfected primary cd4 lymphocytes. aids res hum retroviruses. 2004; 20:175. 40. lichtner m, rossi r, mengoni f, et al. circulating dendritic cells and interferon-! production in patients with tuberculosis: correlation with clinical outcome and treatment response. clin expl imm. 2006; 143:329. 41. manna pp, mohanakumar t. human dendritic cell mediated cytotoxicity against breast carcinoma cells in vitro. j leukoc biol. 2002; 72:312. 42. tschoep k, manning tc, harlin h, et al. disparate functions of immature and mature human myeloid dendritic cells: implications for dendritic cell-based vaccines. j leukoc biol. 2003; 74:69. 43. heiser a, coleman d, dannull j. autologous dendritic cells transfected with prostate-specific antigen rna stimulate ctl responses against metastatic prostate tumors. j clinic invest. 2002; 109:409. 44. sciarra a, lichtner m, autran ga, et al. characterization of circulating blood dendritic cell subsets dc123+ (lymphoid) and dc11c+ (myeloid) in prostate adenocarcinoma patients. prostate. 2007; 67:1. 163archivio italiano di urologia e andrologia 2013; 85, 4 dendritic cells in blood and urine samples from bladder cancer patients undergoing bcg immunotherapy correspondence raffaella rossi, md (corresponding author) raffaella.rossi@hotmail.it angela ermocida, md angela.ermocida@tiscali.it claudia mascia, md claumascia@tiscali.it fabio mengoni, md fabio.mengoni@ uniroma1.it ilaria sauzullo, md ilariasauzullo@libero.it vincenzo vullo, md vincenzo.vullo@uniroma1.it department of public health and infectious diseases, “sapienza” university, piazzale aldo moro 5 00161 rome, italy miriam lichtner, md miriam.lichtner@uniroma1.it claudio mastroianni, md claudio.mastroianni@uniroma1.it infectious diseases unit “sapienza” university, latina, italy francesco iori, md francescoiori@virgilio.it danilo dini, md danilo.dini@libero.it department of urology, “sapienza” university, rome, italy, archivio italiano di urologia e andrologia 2013; 85, 136 introduction peyronie’s disease (pd) is characterized by the development of a fibrotic process involving the tunica albuginea. information on the prevalence is not homogeneous but generally it is assumed that approximately 5% of men aged 50 years or older will experience the disease (1). the penile fibrosis may begin with a variety of penile deformities including curvature, notching, palpable nodule or plaques, hourglass narrowing, penile shortening (with or without curvature), difficulty with coitus and erectile dysfunction. the average age of onset is 53 years, varying between 40 and 60 years of age, but the disease is known to occur in patients as young as 18 years of age (3). mulhall reported that untreated pd resolves in only 12% of men, with 40-48% of men demonstrating worsening of curvature at 12 months, and stable curvature in the remaining men (4). despite a general perception that the condition is benign, pd is progressive and can have significant emotional and psychological consequences in men with this case report peyronie’s disease: a “triple oxygenant therapy” francesco ciociola 1, giovanni maria colpi 2 1 specialista in endocrinologia e malattie del ricambio consulente andrologo u.o.c. urologia 2 andrologia e riproduzione assistita, azienda ospedaliera san paolo polo universitario, milano, italy; 2 specialista in andrologia, urologia ed endocrinologia direttore u.o.c. urologia 2 andrologia e riproduzione assistita, azienda ospedaliera san paolo polo universitario, milano, italy. objectives: to evaluate the effects of upregulators of nitric oxide in one patient with peyronie’s disease, after non significant improvement following intracavernosal verapamil. methods: a 20-years-old caucasian male presented with penile induration in flaccid state, persistent during erection and associated with mild pain at third middle of penis. after treatment with intracavernosal verapamil for 4 months with relief of penile discomfort, followed by counseling on the use of penile extender for at least 6 hours per day, he was prescribed pentoxifylline associated with tadalafil plus levo-arginine, propionil-carnitine and vitamin b3. results: after almost 2 years, the septal thickness was reduced at ultrasound evaluation after this “triple oxygenant therapy”. conclusion: no-inos biology in peyronie patients is the very protagonist in modulating penile fibrosis through up-regulation of no-cgmp pathway that influences penile health by preventing and reversing fibrosis in the tunical albuginea. key words: peyronie's disease; pentoxifylline; penile fibrosis; phosphodiesterase inhibitors; tadalafil; l-arginine. submitted 31 july 2012; accepted 31 december 2012 no conflict of interest declared summary condition. the exact etiology of pd remains unknown and is likely multifactorial (1). pd is the result of a complex interplay between genetic predisposition, trauma and trapped inflammation. the presence of dupuytren’s contractures among some men with pd suggests that a genetic predisposition to scarring and fibrosis may be associated with tunica albuginea fibrosis and scarring. the concept introduced by horton and devine that trauma to the penis leads to pd continues to be accepted two decades after its introduction (5), but as potential contributors to the pathogenesis of plaque, we can also include failure of fibrin degradation, altered collagen deposition in the tunica albuginea with a shift in the type of collagen released from predominant type i to type iii, resulting in extracellular matrix scarring, production of free radicals (peroxynitrite) in cavernosal tissue of men with pd (6). bivalacqua et al. have demonstrated increased levels of inos protein and decreased levels of enos protein in ciociola_stesura seveso 18/04/13 12:04 pagina 36 37archivio italiano di urologia e andrologia 2013; 85, 1 peyronie’s disease: a “triple oxygenant therapy” mg (cialis r, eli lilly italia spa, sesto fiorentino) three time a week plus levo-arginine 2500 mg daily, propionilcarnitine 250 mg daily and vitamin b3 20 mg daily (ezerex r, sigma tau spa, roma). physical examination and blood pressure measurements were planned.at regular intervals. after 1 year, the penile plaque was of 1.9 x 12.4 mm (thickness x length) and resulted hypoechogenic at ultrasound examination (figure 2) and soft at physical evaluation. this clinic evidence confirmed the favourable evolution of the fibrotic disease. moreover, using penile extender for at least 6 hours daily for 1 year, the lenght of stretched penis improved from 11.5 cm at the onset of the disease to the final 14 cm, with changing of penile girth at midshaft from 11.5 cm to 12.5 cm. the evolution was noteworthy and confirmed at almost 2 years after the beginning of treatment with a septal thickness of 1.6 x 7 mm (figure 3) by ultrasound evaluation, but without further changes of penile length and girth. the cavernosal tissue of men with pd 7. the production of inos is stimulated by cytokines (il-1, tnf-!), interferon and nf-kb; at supraphysiological levels, no resulting from inos upregulation in smooth muscle cells and macrophages starts to play a role as an oxidant generator (7). however, the role of inos in wound healing is confusing because under certain circumstances it promotes wound healing while under others it maybe fibrogenic and destructive (8). furthermore, vernet et al have explored the impact of no on fibroblast differentiation in the rat model of pd: chemical inhibition of inos resulted in an increase in myofibroblast number, suggesting that inos may play some role in limiting the myofibroblast population in an effort to reduce tunical scarring and contraction (9). case report a 20-years-old caucasian male reported the evidence of penile induration in flaccid state, persistent during erection and associated with mild pain at third middle of penis. this mass appeared only 2-3 weeks before the consultation, but then it remained stable in size and discomfort. at the beginning, he ruled out any penile curvature or shortening during erection and his sexual activity was normal with regular vaginal intercourses twice a week. the patient denied any traumatic injury or acute pain during intercourse or masturbation before the development of this condition. his general health was excellent; he didn’t report use of alcool, tobacco, illegal drugs or other medications. he ruled out family history of this condition or other fibrotic disease such as scleroderma, dupuytren’s contractures or lederhose’s disease (aponeurotic plantar fibrosis). on physical examination, the patient presented only keloid fibrotic scar for previous abdominal surgery for appendicitis; his hands and feet were free of fibromatosis and contractures, his left testis was normal, but right testis was reported into scrotum at the age of 2 years. the blood examinations were normal but mild hyperuricemia, so we performed diet therapy and follow-up. after 1 month, he started with topical verapamil hydrochloride and iontophoresis applied twice a week over the entire shaft of the penis without any significant improvement of penile plaque or pain. at the end of this period, he noted penile curvature with hourglass deformity and shortening of the penis during erection without erectile dysfunction. then, patient was elegible to intracavernosal infusion with verapamil 5 mg dissolved in phleboclysis 100 cc saline solution for 8 weeks (9) with relief of penile discomfort, followed by counseling on the use of penile extender for at least 6 hours per day (10). his penis retained a hard palpable septal plaque at midshaft by physical examination and a fibrotic defect of 2.3 x 13.6 mm (thickness x length) was revealed by ultrasound evaluation after 10 mcg of pge1) (figure 1). treatment after informed consent, the patient was prescribed pentoxifylline 400 mg (trental r, sanofi-aventis spa, milano) ter in die for 2 years associated with tadalafil 5 figure 1. ultrasound scan image of penis after 10 mcg of pge1: fibrotic defect of 2,3 x 13,6 mm (thickness x lenght) before treatment. figure 2. ultrasound scan image of penis: after 1 year of therapy: the penile plaque resulted of 1,9 x 12,4 mm (thickness x lenght). ciociola_stesura seveso 18/04/13 12:04 pagina 37 archivio italiano di urologia e andrologia 2013; 85, 1 f. ciociola, g.m. colpi 38 nitrotyrosinilation of proteins: so, peroxynitrite acts as an apoptotic but presumably non-fibrotic compound (17). ferrini showed that in human pd plaque, as compared with normal tunica, inos mrna and protein were both induced. from cell culture experiments based on incubation of fibroblast cultures from the human pd plaque and the normal tunica albuginea with inos inhibitor and cgmp and nitric oxide donors, the myofibroblasts resulted differentiated from normal tunica albuginea fibroblasts and increased during plaque formation. myofibroblasts are key cells during wound healing, which, at the completion of this process, are normally eliminated by apoptosis; when they persist, this persistence leads to scar formation (18). infact, vernet et al. have explored the impact of no on fibroblast differentiation in the rat model of pd: chemical inhibition of inos resulted in an increase in myofibroblast number, suggesting that inos may play some role in limiting the myofibroblast population in an effort to reduce tunical scarring and contraction (19). intriguingly, the sustained pharmacological increase of cgmp and/or nitric oxide by long-term continuous administration of drugs such as the pde inhibitors and/or nitric oxide generators should reduce the fibrotic plaque in the tgf-"1 rat model of pd (20). no, as well as its product cyclic-guanosine monophosphate (cgmp), also inhibits collagen synthesis directly as demonstrated in fibroblast cultures from the normal human tunica (21). however, the role of no in inflammation seems to be more complex, also involving beneficial effects exerted through the interference with the proinflammatory function of macrophages and lymphocytes. contradictory effects of cyclic-adenosine monophosphate (camp) on macrophages no release might partly be explained by dual, dose-dependent role of intracellular camp rise in inos induction in these cells, with higher camp concentrations exerting inhibitory effect (22). on the other hands, it has been demonstrated that the enhancement of inos-mediated no synthesis in these cells by camp-increasing pde inhibitors. moreover, cellsensible inos modulation highlights a possible role of cgmp levels in vascular smooth muscle, in which both cgmp and camp regulate inos activation in similar manner (23). the therapeutic effects on the endothelial and cavernosal smooth muscle in the penis after longterm continuous pde-5 inhibitor therapy involves specific molecular mechanism. emerging evidences in this field of study underline non-erectogenic beneficial uses of pde5-inhibitors (24), e.g. by counteracting the penile fibrotic process in a rat model of peyronie’s disease (21). therefore, there is a possibility that some pde inhibition-unrelated features of certain drugs or drug families might contribute to their effect on inos-mediated no synthesis (23); this indeed could be the case with methylxanthines and their derivatives, the antioxidant activity of which might be partly responsible for their blocking of redox-sensitive activation of inos transcription factor nf-kb (25). methylxanthine derivative pentoxifylline is a non specific camp-pde inhibitor used for a wide variety of inflammatory and fibrotic conditions. pentoxifylline downregulates tgf", reduces the production of tnf, inhibits the discussion current papers about the origin of peyronie’s disease emphasize that collagen deposition and fibrosis of the tunica albuginea and adjacent corpus cavernosum are the result of an inflammatory process following vascular trauma. in fact, after infiltration and activation of polymorphonuclear leukocytes and macrophages, the process of wound healing is followed by a stage of fibroplasia (fibrosis) characterized by fibroblast migration and proliferation, and extracellular matrix deposition (11). a large number of growth factors and fibrogenic cytokines, such as platelet derived growth factor (pdgf), fibroblast growth factor (fgf), tgf-", interleukin-1 (il-1), and tumor necrosis factor (tnf-!) mediate migration of fibroblasts and their proliferation. as the repair process progresses, the number of proliferating fibroblasts and endothelial cells decreases and the fibroblasts begin to deposit collagen and other components of extracellular matrix. pdgf, fgf and il-1 stimulate this collagen synthesis, and tgf-" is thought to play an important role in chronic inflammatory fibrosis disorders (12). no isoforms, particularly inos, have been revealed to modulate the onset and the progression of fibroblastic or wound healing process (13). in fact monocytes, macrophages and fibroblasts have been shown to synthesize no through an nf-kb activated inos-dependent mechanism after injury (14). however, there is a conflicting evidence to show that no production via overexpression of inos and consequent peroxynitrite loading could be an important mediator of the resolution/suppression of collagen deposition or a stimulator of collagen synthesis in injured organ (15). like to what has been observed in other tissues, such as heart, liver and kidney, when fibrosis develops after these tissues have been exposed to both long-term and continuous inhibition of total nitric oxide production (16), ferrini (17) proposed that nitric oxide derived from inos activation was able to bind ros, the profibrotic compounds produced by oxidative stress, producing peroxynitrite. this is scavenged by inducing the figure 3. septal penile fibrosis by ultrasound scan image: almost 2 years after beginning therapy, the septal thickness resulted of 1,6 x 7 mm. ciociola_stesura seveso 18/04/13 12:04 pagina 38 39archivio italiano di urologia e andrologia 2013; 85, 1 peyronie’s disease: a “triple oxygenant therapy” action of platelet-activating factor on neutrophils, and suppresses the production of platelet-activating factor. recently, pretreatment with pentoxifylline attenuates both collagen fiber deposition and elastogenesis in tunica albuginea-derived fibroblasts exposed to tgf-"1 (26). clinically, brant (27), after using pentoxifylline 400 mg three times a day for 2 years demonstrated improvement of penile curvature and ultrasonographic disappearance of lesion. furthermore, an antifibrotic regimen consisting of upregulators of no production (pentoxifylline and sildenafil), demonstrated amelioration of the corporal fibrosis associated with recalcitrant priapism (28). in patients with early chronic peyronie’s disease, safarinejad (29) showed that almost a third of men assessed had an improvement in their curvature and about half had their deformity stabilized. carnitine is a naturally occurring metabolic intermediate. propionil-l-carnitine acts as superoxide scavenger and it is protective against peroxidative damage to arterial endothelium membranes. recent data suggest that propionil-lcarnitine and verapamil are effective in terms of plaque size reduction, pain, and penile curvature (30). vitamin b3 or nicotin acid, acts as vasorelaxant effect to improve peripheral arterial circulation and penile response to no. however, vitamin b3 is precursor of nadp (nicotine adenine dinucleotide phosphate), that is a pivotal enzymatic co-factor in redox signaling. to date, the exact pathogenesis of pd is unknown and this case report did not reveal any potential trigger factor. the correct clinical and ultrasound recognition of the active disease may influence the treatment that should be tailore on the individual patient. certainly, the first 6-8 months are the most critical for the therapeutic success which remains unpredictable for both the andrologist and the patient. in our case,it is not possible to exclude a spontaneous healing of the septal fibrosis, but the young age of the patient required a careful reassessment of alternative treatment. the favourable clinical and ultrasound outcome after our protocol can not be explained as stochastic and it challenges to consider this therapeutic option. conclusion this case report demonstrates that no-inos biology is preeminent in peyronie patients by modulating penile fibrosis. it stresses that up-regulation of no-cgmp pathway can influence penile health by preventing and reversing fibrosis in the tunical albuginea. this is the first evidence that long-term therapy with tadalafil plus pentoxifylline and l-arginine with other cofactors may modify either gene expression or protein synthesis/degradation by cyclic nucleotide ehancement. the beneficial “reconstitution” of tunical/cavernosal integrity remains the “gold standard” for peyronie’s disease but the best practice has still to be assessed. early identification, and assessment of patient’s expectations though discussion of non-surgical treatment options aimed to stabilization of the disease are crucial. in our experience, penile length and girth gain by traction device that helps to enforce the pharmacological effects of drugs. the clinical results so far obtained are very encouraging and should stimulate further interest in studying the potential use of pde5 inhibitors in association with other drugs as penile antifibrotic agents. this report promotes a multi-modal approach for non-surgical therapy of peyronie’s disease aimed to sustain the blockage of the tgf-" signaling pathway. acknowledgements all authors contributed to bibliographic research, critical evaluation of the articles included in the manuscript and writing of the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests.this study was not supported by any grant. bibliography 1. smith jf, walsh tj, lue tf. peyronie’s disease: a critical appraisal of current diagnosis and treatment. int j imp res. 2008; 20:445-459. 2. mulhall jp, creech sd, boorjian sa, et al. subjective and objective analysis of the prevalence of peyronie’s disease in a population of men presenting for prostate cancer screening. j urol. 2004; 171:2350-3. 3. bella aj, perelman ma, brant wo, et al. peyronie’s disease. j sex med. 2007; 4:1527-1538; 4. mulhall jp, schiff j, guhring p. an analysis of the natural history of peyronie’s disease. j urol. 2006; 6:2115-8. 5. devine cjj, somers rd,jordan gh, et al. proposal: trauma as the cause of peyronie’s lesion. j urol. 1997; 157:285. 6. sikka sc, helstrom wjg. role of oxidative stress and 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inducible nitric oxide synthase by camp-elevationg phosphodiesterase inhibitors. curr drugs targets inflamm & allergy. 2003; 2:63-79. 24. moustafa t. oral phosphodiesterase type 5 inhibitors: nonerectogenic beneficial use. j sex med. 2008; 5:2502-2518. 25. tomita k, chikumi h, tokuyasu h, et al. functional assay of nf-kappa b translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. naunyn schmiedebergs arch phamacol. 1999; 359:249-255. 26. lin g, shindel aw, banie l, et al. pentoxifylline attenuates transforming growth factor-beta-1 stimulated elastogenesis in human tunica albuginea-derived fibroblasts part 2: interference in a tgf-beta1/smad dependent mechanism and downregulation of aat1. j sex med. 2010; 7:1787-1797. 27. brant wo, dean rc, lue tf. treatment of peyronie’s disease with oral pentoxifylline. nat clin pract urol. 2006; 3:111-115. 28. raifer j, gore jl, kaufman j, et al. case report: avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide. j sex med. 2006; 3:173-176. 29. safarinejad mr, asgari ma, hosseini sy, et al. a double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic peyronie’s disease. bju int. 2010; 106:240-248. 30. safarinejad mr, housseini sy, kolahi aa. comparison of vitamin e and propionyl-l-carnitine, separately or in combination, in patients with early chronic peyronie’s disease: a double-blind, placebo controlled, randomized study. j urol. 2007; 178:1398-1403. correspondence francesco ciociola, md (corresponding author) specialista in endocrinologia e malattie del ricambio consulente andrologo u.o.c. urologia 2 andrologia e riproduzione assistita azienda ospedaliera san paolo polo universitario via antonio di rudinì, 8 20142 milano, italy ciociolafrancesco@libero.it giovanni maria colpi, md specialista in andrologia, urologia ed endocrinologia direttore u.o.c. urologia 2 andrologia e riproduzione assistita azienda ospedaliera san paolo polo universitario via antonio di rudinì, 8 20142 milano, italy gmcolpi@yahoo.com ciociola_stesura seveso 18/04/13 12:04 pagina 40 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3208 review chronic inflammation of the prostate type iv with respect to risk of prostate cancer antonio b. porcaro 1, emanuele rubilotta 1, aldo petrozziello 2, claudio ghimenton 3, filippo migliorini 1, stefano zecchini antoniolli 1, vincenzo lacola 1, carmelo monaco 1, pierpaolo curti 1, stefano cavalleri 1, romeo pianon 1, walter artibani 1 1 urologic clinic, 2 geriatric medicine/endocrinology, 3 pathology, university hospitals, ospedale policlinico and ospedale civile maggiore, azienda ospedaliera universitaria integrata, verona, italy. background: chronic inflammatory infiltrate (cii) might be involved in prostate cancer (pca) and benign hyperplasia (bph); however, its significance is controversial. chronic inflammatory prostatitis type iv is the most common non cancer diagnosis in men undergoing biopsy because of suspected pca. objective: to evaluate potential associations of coexistent cii and pca in biopsy specimens after prostate assessment. design, setting, and participants: between january 2007 and december 2008, 415 consecutive patients who underwent prostate biopsy were retrospectively evaluated. the investigated variables included age (years) and psa (ug/l); moreover, cii+, glandular atrophy (ga+), glandular hyperplasia (gh+), prostate intraepithelial neoplasm (pin+), atypical small acinar cell proliferation (asap+) and pca positive cores (p+) were evaluated as categorical and continuous (proportion of positive cores). outcome measurements and statistical analysis: associations of cii+ and pca risk were assessed by statistical methods. results and limitations: in the patient population, a biopsy core positive for pca was detected in 34.2% of cases and the rate of high grade pca (hgpca: bgs ! 8) resulted 4.82%. cii+ significantly and inversely associated with a positive biopsy core p+ (p < 0.0001; or = 0.26) and hgpca (p = 0.0005; or = 0.05). moreover, the associations indicated that patients with coexistent cii+ on needle biopsy were 74% less likely to have coexistent pca than men without cii+ as well as 95% less likely to have hgpca in the biopsy core than men without coexistent cii+. there were limits in our study which was single centre and included only one dedicated pathologist. conclusions: there was an inverse association of chronic inflammation of the prostate type iv and risk of pca; moreover, hgpca was less likely to be detected in cancers associated with coexistent cii. in prostate microenvironment, prostate chronic inflammation may be protective; however, its role in pca carcinogenesis remains controversial and needs further research. key words: prostate; prostate cancer; prostate-specific antigen; prostate biopsy; chronic inflammation; biopsy gleason score. submitted 23 december 2014; accepted 31 march 2014 summary no conflict of interest declared. introduction chronic inflammation plays an important role in human carcinogenesis (1, 2). development and progression of cancer might be related to reactive oxygen and nitrogen species developing in tissue microenvironment after related damage and regeneration. prostate cancer (pca) carcinogenesis has also been related to chronic inflammation. presence of chronic inflammatory infiltrate (cii) has been detected in pca specimen from prostatectomies, transurethral resection of the prostate (turp) and transrectal ultrasound (trus) biopsies (3, 4). literature investigations suggest that cii might be involved in chronic diseases of the prostate including pca and benign prostatic hyperplasia (bph) (5). the prostatitis syndromes have been classified in four categories by the national institutes of health (nih) (6). the last category, named type iv, has been coded as asymptomatic inflammatory prostatitis which is diagnosed in patients who have no history of genitourinary tract pain complaints, but undergo prostate biopsy for evaluation of possible pca because of elevated serum prostate-specific antigen (psa) level. as a result, chronic prostatitis is the most common non cancer diagnosis, based on histological criteria, in these men. since the significance of cii in prostate specimens with and without cancer is still unclear and controversial, we evaluated the association, if any, of coexistent cii and pca in patients undergoing trus biopsies after prostate assessment. material and methods between january 2007 and december 2008, we retrospectively evaluated 475 men referred to our institute for prostatic biopsy because of increased serum psa and/or abnormal digital rectal exam (dre). psa was measured by immuno-radiometric test (2-4 ug/ml) and abnormal dre findings were as follows: diffusely hard prostate, discrete firm area, irregular contours or prominent lobe asymmetry. patients with dre findings associated with painful prostate were excluded. the 14-core trus guided prostate biopsy technique was routinely performed and additional cores were taken with a lesion on either trus or dre was evident. for each biopsy core, the dedicated pathologist systematically assessed the following issues: doi: 10.4081/aiua.2014.3.208 porcaro abbr_stesura seveso 08/10/14 12:13 pagina 208 209archivio italiano di urologia e andrologia 2014; 86, 3 chronic inflammation of the prostate type iv with respect to risk of prostate cancer (i) pca and its grade according to the gleason score system (biopsy gleason score: bgs); (ii) prostatic intraepithelial neoplasia (pin); (iii) chronic inflammatory infiltrate (cii); (iv) glandular atrophy (ga); (v) atypical small acinar cell proliferation (asap); (vi) glandular hyperplasia (gh). atypical adenomatous hyperplasia (aah), since not systematically assessed, was not included in the present analysis. chronic inflammation criteria included the following findings: (i) inflammatory cell infiltrate within the stroma of the prostate; (ii) inflammatory cell infiltrate composed predominantly of lymphocytes with admixed plasma cells; (iii) peri-glandular distribution of the inflammatory cell infiltrate. criteria excluding a diagnosis of chronic inflammation of the prostate type iv were as follows: (i) sheets of neutrophils around and within the glands; (ii) granulomatous prostatitis. a diagnosis of chronic inflammation of the prostate type iv (6) was carried out after excluding other types of inflammation. statistical analyses the variables were evaluated as both categorical and continuous; moreover, the histological ones were coded as proportion of the number of positive cores and were labelled as cii+, ga+, gh+, pin+, asap+ and p+, respectively. summary statistics of population, subpopulations (with or without pca) and relative groups was computed. student t-tests were used to compare subpopulations and relative groups. in populations and subpopulation of patients, !2 tests were used to evaluate associations of cii+ with age at the first quartile (q1), psa at q1, ga+, gh+, asap+, pin+, p+, bgs ! 8 and dre. moreover, to evaluate the strength of associations, the odds ratio (or) and relative 95% confidence interval (95%ci) were also computed. cii+ independent associations with age, psa, ga+, gh+, asap+, pin+, p+ and dre (1 = abnormal, 0 = normal) were evaluated by multivariate regression analysis in the population and subpopulations of patients. because of the high level of correlation between cii+ and ga+ (correlation coefficient = 0.49, p < 0.0001), the multivariate independent associations of bgs were separately evaluated for cii+ and ga+. all tests were two-sided, with a significance level of 0.05. results after removing cases with incomplete data or excluding criteria, 415 of the 475 cases were able to be evaluated. overall clinical characteristics of population and subpopulations with relative groups are reported in table 1. compared with cases without pca, the pca subpopulation was significantly older at diagnosis (69.23 years vs. 66,56; p < 0.0007); less likely to have larger cii+ (0.06 vs. 0.38, p < 0.0001), ga+ (0.16 vs. 0.50, p < 0.0001) and gh+ (0.01 vs. 0.10, p = 0.0002); but more likely to have higher psa serum levels (29,6 ng/ml vs. 13,69, p = 0.02) and higher pin+ (0.07 vs. 0.03, p = 0.001). in the subpopulation without pca, the group without cii+ was less likely to have larger ga+ (0.44 vs. 0.58, p = 0.001), but more likely to have larger proportion of gh+ (0.14 vs. 0.07; p = 0.06). however, in the pca subpopulation, the cii+ group was significantly older (72.6 years vs. 68.10; p = 0.003), more likely to have larger proportion of ga+ (0.33 vs. 0.11; p = 0.0003), but less likely to have greater psa values (11.2 vs. 36.10 ug/l; p = 0.04) as well larger proportions of p+ (0.25 vs. 0.42; p < 0.0001). the group with bgs " 6, showed lower proportions of p+ than bgs = 7 (0.25 vs. 0.48; p < 0.0001) and bgs ! 8 (0.25 vs. 0.65; p < 0.0001) as well as of asap+ than bgs ! 8 (0.01 vs. 0.00; p = 0.01); interestingly, the bgs " 6 group was more likely to have increased proportions of cii+ than bgs = 7 (0.17 vs. 0.07; p = 0.02) and bgs ! 8 (0.17 vs. 0.005; p < 0.0001); moreover, significantly increased ga+ proportions were detected in the bgs " 6 group than bgs ! 8 (0.22 vs. 0.03; p < 0.0001). the group with bgs ! 8 was more likely to be detected with increased proportions of p+ than the bgs = 7 group (0.65 vs. 0.48; p = 0.04), but less likely to have increased proportions of cii+ (0.005 vs. 0.07; p = 0.008) and ga+ (0.03 vs. 0.14; p = 0.01) than the bgs = 7 group. table 2 and figure 1 show the associations of cii+ with the investigated variables in population and subpopulations of patients. cii+ was detected at a rate of 45.06% in the population, 26.65% in the subpopulation with pca and 44.32% in the subset without pca. age " q1 resulted 61.67 years in population, 64.37 in the pc subpopulation and 60.93 in the subset without pca. cii+ inversely associated with age in the pca subpopulation (p < 0.0001; or = 0.40). total psa serum levels " q1 were 4.99 ng/ml in the population, 4.71 in the pca subpopulation and 5.14 the other subset. cii+ inversely associated with psa " q1 in the population (p = 0.002; or = 0.47) and subpopulation without pca (p = 0.005; or = 0.44). ga+ was detected at a rate of 58.3% in the population, 38.7% in the pca subpopulation and 68.5 in the other subset. cii+ directly associated with ga+ in the population (p < 0.0001; or = 5.14), pca subpopulation (p < 0.0001; or = 5.34) and subset without pca (p < 0.0001; or = 3.77). a biopsy core positive for pca was detected in 34.2% of the population. cii+ inversely associated with a positive biopsy core p+ (p < 0.0001; or = 0.26). in the pca subpopulation, cii+ inversely (p = 0.0004; or = 0.28) associated with a proportion of positive cores larger than the median (p+ > 0.33). the rate of high grade pca (hgpca: bgs ! 8) resulted 4.82% in the population and 14.08% in the pca subpopulation. cii+ inversely associated with hgpca in both population (p = 0.0005; or = 0.05) and subpopulation (p = 0.05; or = 0.13). an abnormal dre was detected in 30.84% of the patient population and inversely associated with cii+ (p = 0,01); however, the association was weak (or = 0.58) and was not confirmed in the two subpopulations. the independent and multivariate associations of cii+ and bgs are reported in table 3. in the population of patients, cii+ associated with ga+ (p < 0.0001), gh+ (p = 0.02) and bgs (p = 0.05); moreover, the association was positively related to ga+ (regression coefficient, b = 0.38), but negatively related to gh (b = -0.16) and bgs (b = -0.01). in the analysis excluding ga+, bgs positively associated with p+ (p < 0.0001; b = 9.85); pin+ (p = 0.0004; b = 2.67) and age (p = 0.02; b = 0.02), but inversely with cii+ (p = 0.003; b = -0.68). in the analysis excluding cii+, bgs directly associated with p+ (p < 0.0001; b = 9.77), pin+ (p = 0.007; b = 2.58) and porcaro abbr_stesura seveso 08/10/14 12:13 pagina 209 archivio italiano di urologia e andrologia 2014; 86, 3 porcaro, rubilotta, petrozziello, ghimenton, migliorini, zecchini antoniolli, lacola, monaco, curti, cavalleri, pianon, artibani 210 age (p = 0.02; b = 0.02), but inversely with ag+ (p< 0.002; b = -0.68). in the pca subpopulation, cii+ directly associated with ga+ (p = 0.001; b = 0.30), but inversely with bgs (p = 0.05; b = -0.03). in the analysis excluding ga+, bgs directly associated with p+ (p < 0.0001; b = 2.007), psa (p = 0.04; b = 0.001), but inversely with cii+ (p = 0.03; b= -0.82). in the analysis excluding cii+, bgs directly associated with p+ (p < 0.0001; b = 2.06) and psa (p = 0.05; b = 0.001); however, there was no association with ga+ (p = 0.31; b = 0.36). in the subpopulation without pca, cii+ directly associated with ga+ (p < 0.0001; b = 0.39), but inversely with gh+ (p = 0.02; b = -0.18). in the analysis excluding ga+, cii+ inversely associated with gh+ (p = 0.01; b = -0.23) and pin+ (p = 0.05; b = -0.56). in the analysis excluding cii+, ga+ inversely associated only with pin+ (p = 0.03; b = -0.63). tables and figure 1 are posted in supplementary materials on www.aiua.it discussion our findings showed that, in a patient population undergoing prostate biopsy, chronic inflammation was independently and inversely associated with pca. cii+ in men with positive biopsy cores was detected less frequently (8.43%) than in those without (25.78%); moreover, the or of pca in men with chronic inflammation was 0.26. these findings suggest that, on biopsy cores, the presence of cii+ decrease the probability of detecting pca by 76%. we stress out that these findings indicate only an inverse independent association of cii+ with pca; moreover, the relation does not necessary mean causation. the result of our investigation concord with previous studies discovering an evident inverse association between chronic inflammation and pca (4, 7-9). as a result, cii+ might protect from the different steps involving genesis of cancer. the relation between chronic inflammation and pca was further investigated by our study which showed that, in the population, cii+ independently and inversely associated with hgpca. as a result, cii+ in biopsy cores with hgpca was found less frequently (0.2%) than men without (4.8%); moreover, the or of hgpca was 0.05. these results suggest that, on biopsy needle cores, the presence of cii+ decreases the probability of hgpca by 95%. similar findings were detected in the pca subpopulation. indeed, cii+ in positive biopsy cores with hgpca was found less frequently (0.7%) than in those without chronic inflammation (14.1%). the or of hgpca in cii+ was 0.13 which means that, in men with needle core biopsies positive for pca, the probability of detecting hgpca was decreased by 87%; moreover, cii+ was more common in needle biopsy cores with low intermediate grade cancers (23.9%) than in those with hgpca (0.70%). these findings agree with the results of zhang et al. who showed that chronic inflammation was more common in radical prostatectomy specimens with low grade tumours than in those with hgpca (10). once again; the protective association of cii+ should not be considered as causation; however, these findings suggest the chronic inflammation might protect from pca progressing from low to high grade disease. our data also showed that, in the pca subpopulation, chronic inflammation was inversely and independently associated with a larger volume of percentage of positive biopsy cores. indeed, a cii+ was detected less frequently (6.3%) in men with p+ > 0.33 than in patients without coexistent cii (41.6%). the or of pca with p+> 0.33 in men with cii+ was 0.28. this finding indicated that, on positive biopsy cores, the coexistence of chronic inflammation reduces the chance of having a proportion of p+ > 0.33 by 72%. once again these findings, although not meaning causation, confirmed that there is inverse association between cii+ and pca (4, 7-10). the subject dealing with pca associated with chronic inflammation has also been approached by other investigators, who, however, failed to detect any association (1113). our investigation is a single centre study including a large number of patients collected consecutively in an appropriate time of interval (24 months); also, biopsy specimens have been evaluated by a dedicated pathologist, who routinely reports the presence or absence of cii+ in each biopsy core. moreover, our investigation, although consistent with other reports (4, 7-10), clearly shows that the coexistence of cii+ in needle biopsy specimens reduces the risk of aggressive prostate cancer. this issue might have important drawbacks when approaching treatment options for pca cancer such as active surveillance. it has been postulated that the exposure to non-steroidal anti-inflammatory drugs (nsaid) reduces the risk of cancer-genesis (14, 15). however, observational studies has shown that the pca risk is increased after nsaid exposure (16, 17). moreover, cancer susceptibility and severity may be associated with functional polymorphisms of inflammatory cytokine genes, and deletion or inhibition of inflammatory cytokines inhibits the development of experimental cancer (18). our study outlines the predictive role of chronic inflammation in pca biology; it also supports the non appropriate role of nsaid exposure in prostate cancer genesis. our results indicated that, in a subpopulation without pca, chronic inflammation inversely associated with psa " q1 (5.14 ug/l) which means that psa serum levels " q1 were detected less frequently (10.3%) in patients with coexistent cii+ in the biopsy specimen than in those without (25.3%). the or of 0.44 indicates that the presence of cii+ in the specimens decreases the probability of detecting psa serum levels " q1 by 56%. these results agree with other investigations showing that chronic inflammation associates with elevated psa serum levels (19-21). moreover, it has recently been reported that baseline prostate inflammation is associated with a reduced risk of pca in men undergoing repeat prostate biopsy (22). as a theory, cii+ associates with increased psa serum levels when there is contact and disruption of the glandular epithelium of the prostate. there are limits in our study which was single centre and including only one dedicated pathologist. ga+ was not porcaro abbr_stesura seveso 08/10/14 12:13 pagina 210 211archivio italiano di urologia e andrologia 2014; 86, 3 chronic inflammation of the prostate type iv with respect to risk of prostate cancer characterized according to the atrophy classification, proposed in 2006 by the working group for histology classification of prostate atrophy lesions which include simple atrophy, simple atrophy with cist formation, post atrophic hyperplasia and partial atrophy (23). the classification of low and high grade pin was also not computed. another limit of the present study may be related to the missed measurement of prostate volume with negative drawbacks on sampling procedures. indeed biopsy procedures might not sample appropriately the large prostates with respect the smaller ones. finally, patients with inflammation may undergo to biopsy procedures more frequently than men without inflammation because of potential higher psa levels. conclusions there is an inverse negative association of chronic inflammation of the prostate type iv and risk of pca. chronic inflammation of the prostate type iv is less frequently detected in prostates with cancer. moreover, hgpca is less likely to be detected in cancers associated with coexistent cii. as a consequence, chronic inflammation of the prostate type iv might have important drawbacks for approaching and managing prostate diseases. moreover, chronic inflammation in prostate microenvironment might be protective; however, the role of chronic inflammation in pca carcinogenesis remains a controversial issue which needs further clinical and basic research. references 1. coussens lm, werb z. inflammation and cancer. nature. 2002; 420:860-67. 2. mantovani a, allavena p, sica a, balkwill f. cancer related inflammation. nature. 2008; 464:436-44. 3. welson wg, de marzo am, isaacs wb. prostate cancer. n engl j med. 2003; 349:366-81. 4. blumenfeld w, tucci s, marayan p. incidental lymphocytic prostatitis. selective involvement with non malignant glands. am j surg pathol. 1992; 16:975-81. 5. de nunzio c, kramer g, marberger m, et al. the controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. eur urol. 2011; 60:106-17. 6. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999; 282:263-67. 7. gerstenbluth re, seftel ad, maclennan gt, et al. distribution of chronic prostatitis in radical prostatectomy specimens with up-regulation of bcl-2 in areas of inflammation. j urol. 2002; 167:2267-70. 8. irani j, goujon jm, ragni et al. high-grade inflammation in prostate as a prognostic factor for biochemical recurrence after radical prostatectomy. pathologist multi center study group. urology. 1999; 54:467-72. 9. karakiewicz pi, benayoun s, begin lr, et al. chronic inflammation is negatively associated with prostate cancer and high-grade prostatic intraepithelial neoplasia on needle biopsy. int j clin pract. 2007; 61:425-430. 10. zhang w, sesterhenn ia, connelly rr, et al. inflammatory infiltrate (prostatitis) in whole mounted radical prostatectomy specimens from black and white patients is not an etiology for radical difference in prostate specific antigen. j urol. 2000; 163:131-36. 11. roberts ro, bergstralh ej, bass se, et al. prostatitis as a risk factor for prostate cancer. epidemiology. 2004; 15:93-99. 12. davidsson s, fiorentino m, andren o, et al. inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer. cancer epidemiol biomarkers prev. 2010; 20:2280-87. 13. engelhardt pf, brustmann h, seklehner s, riedl cr. chronic asymptomatic inflammation of the prostate type iv and carcinoma of the prostate: is there a correlation? scand j urol. 2013; 47:230-5. 14. thun mj, henley sj, patrono c. nonsteroidal anti-inflammatory drugs as anticancers agents: mechanistic, pharmacologic, and clinical issues. j natl cancer inst 2002; 94:252-66. 15. gridley g, mclaughlin jk, ekbom a et al. incidence of cancer among patients with rheumatoid arthritis. j nat. cancer inst. 1993; 85:307-11. 16. langman mj, cheng kk, gilman ea, lancashire rj. effect antiinflammatory drugs on overall risk of common cancer: case-control study in general practice research data base. bmj. 2000; 320:1462-66. 17. neugut ai, rosenberg dj, ahsan h, et al. association between coronary heart disease and cancer of the breast, prostate and colon. cancer epidemiol biomarkers prev. 1998; 7:869-73. 18. balkwill f, mantovani a. inflammation and cancer: back to virchow? the lancet. 2001; 357:539-45. 19. hoekx l, jeuris w, van marck e, wyndaele jj. elevated serum prostate specific antigen (psa) related to asymptomatic prostatic inflammation. acta urol bel. 1998;66:1-2. 20. sindhwani p, wilson cm. prostatis and serum prostate-specific antigen. curr urol rep. 2005; 6:306-12. (21) hochreiter ww. the issue of elevated prostate cancer evaluation in men with elevated prostate-specific antigen and chronic prostatitis. andrologia 2008; 40: 130-33. 12. moreira dm, nickel jc, gerber l, et al. baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy. cancer. 00, 2013. 23. de marzo am, platz ea, epstein ji, et al. a working group classification of focal prostate atrophy lesions. am j surg pathol. 2006; 30:1281-91. correspondence antonio benito porcaro, md drporcaro@yahoo.com filippo migliorini, md stefano zecchini antoniolli, md vincenzo lacola, md carmelo monaco, md pierpaolo curti, md stefano cavalleri, md romeo pianon, md walter artibani, md, professor azienda ospedaliera universitaria integrata verona, dipartimento ad attività integrata di chirurgia ed oncologia, pancreas center, divisione clinicizzata di urologia, policlinico gb rossi p.le la scuro, 10 37134 verona, italy emanuele rubilotta, md aldo petrozziello, md dpt. geriatric medicine/endocrinology, azienda ospedaliera universitaria integrata, ospedale policlinico and ospedale civile maggiore, verona, italy claudio ghimenton, md dpt. pathology, azienda ospedaliera universitaria integrata ospedale policlinico and ospedale civile maggiore, verona, italy porcaro abbr_stesura seveso 08/10/14 12:13 pagina 211 stesura seveso 253archivio italiano di urologia e andrologia 2014; 86, 4 original paper percutaneous nephrolithotomy in patients with a solitary kidney tufan süelözgen, salih budak, orcun celik, okan yalbuzdag, oguz mertoglu, selcuk isoglu, mehmet yoldas, yusuf ozlem ilbey tepecik training and research hospital, urology clinic, izmir, turkey. material and method: the results of percutaneous nephrolithotomy applied to 716 patients in our clinic between january 2008 and january 2014 were retrospectively evaluated. age, gender, urinary calculi size (mm2), urinary calculi localization, eswl history, operation duration (min), fluoroscopy duration (sec), access type, reason of solitary kidney, hemoglobin drawdown (g/dl) and operation success of the patients with a solitary kidney were recorded. the patients having no preoperative and postoperative non contrast abdominal tomography were excluded from the study. results: fifteen of nineteen patients (79%) were men and 4 of them (21%) were women. the average age of the patients was 42.52 ± 16.72 (14-72). ten patients had anatomical solitary kidney and nine patients had physiological solitary kidney. in fact counter kidney was non functional in 9 patients (47%) whereas there was agenesis in 2 (11%) and outcome of nephrectomy in 8 (42%) patients. in our study, presence of residual stone less than 4 mm at 1st month postoperative non contrast abdominal tomography was accepted as a successful result and accordingly our success rate was detected as 84%. mean urinary calculi size was 405 ± 252.9 mm2; urinary calculi localization was pelvic, lower pole, upper-middle pole, middle-lower pole and staghorn in 11 (58%), 4 (21%), 1 (5%), 1 (5%) and 1 (5%) patients, respectively; previous eswl history was 16%; operation duration was 55.47-± 28.1 min and fluoroscopy duration 131.10 ± 87.6 sec; access type was subcostal in 79%, supracostal in 10.5% and multiple in 10.5%; hemoglobin drawdown was 1.75 ± 0.97 mg/dl. conclusions: pnl can be effectively and safely administered for the treatment of solitary kidney. in the treatment of large urinary calculi in patients with a solitary kidney, pnl has some advantages such as short surgery duration, less complication, acceptable hemoglobin drawdown and high success rates. according to our study, pnl operation in patients with a solitary kidney is a good option for carefully and poisedly selected cases. key words: percutaneous nephrolithotomy; solitary kidney; urinary calculi. submitted 21 july 2014; accepted 18 august 2014 summary no conflict of interest declared. introduction urinary tract calculus disease continues to be a major health problem in our country. in a study conducted in 2011, calculus prevalence was determined as 11.1% and it was emphasized that our country has been among endemic countries (1). it was stated that 2.2% of general population was treated due to urinary tract calculus disease and 16% of them had more than one procedure (2). percutaneous nephrolithotomy (pnl) in the trratment of urinary calculi was firstly described by fernström and johansson in 1976 (3). since it was first developed, pnl procedure has been refined by means of improvements of optical system, endo-camera, lithotripsy energy systems, design of the nephroscope and advances in its accessories. as a result of all these improvements, need for open surgery in current urology practice is decreased to 0.7-4% and pnl has replaced it as first choice in the treatment of large urinary calculi (4). in this study, we retrospectively examined the patients with a solitary kidney who underwent pnl operation and we evaluated the results of the treatment. material and methods the results of percutaneous nephrolithotomy applied to 716 patients in our clinic between january 2008 and january 2014 were retrospectively evaluated. nineteen patients with a solitary kidney were included in the study. in our clinic, preoperative complete blood count, biochemical tests, including urea and creatinine levels, and urine culture are carried out for all patients who are planned to be treated with pnl. the patients were informed about operation and informed consent was obtained. one hour before the operation, antibiotic prophylaxis was carried out via parenteral administration of second generation cephalosporin. age, gender, urinary calculi size (mm2), urinary calculi localization, extracorporeal shock wave lithotripsy (eswl) history, operation duration (min), fluoroscopy duration (sec), access type, reason of solitary kidney, hemoglobin drawdown (mg/dl) and operation success of the patients with a solitary kidney were recorded. the patients having no preoperative and postoperative non contrast abdominal tomography were excluded from the study. doi: 10.4081/aiua.2014.4.253 budak_stesura seveso 15/01/15 12:56 pagina 253 archivio italiano di urologia e andrologia 2014; 86, 4 t. süelözgen, s. budak, o. celik, o. yalbuzdag, s. isoglu, s. isoglu, m. yoldas, y.ozlem ilbey 254 in lithotomy position, a 5 f open-end catheter was inserted in the ureter via a 22 f cystoscope under general anesthesia and set to a foley catheter by a silk suture. then, prone position was given to the patient. collecting system was visualized with fluoroscopy by injection of opaque contrast through the ureteral catheter. percutaneous needle access to the urinary tract was obtained by bi-planar planning of the access site. tract was dilated with amplatz dilators over guide wire and a 30 f amplatz sheath was placed. kidney collecting system was entered by a 22 f rigid nephroscope. ultrasonic lithotripter was preferred for litotripsy and pneumatic lithotripter was used when necessary. after evaluation of the last fluoroscopy images, a 14 f malecot nephrostomy catheter was placed and the operation was completed. all patients were followed up with non contrast abdominal tomography one month after operation. results fifteen of nineteen patients (79%) were men and 4 of them (21%) were women. the average age of the patients was 42.52 ± 16.72 (1472). ten patients had anatomical solitary kidney and 9 patients had physiological solitary kidney. in fact counter kidney was non functional in 9 patients (47%) whereas there was agenesia in 2 (11%) and outcome of nephrectomy in 8 (42%) patients. there was no previous history of surgery of the solitary kidney in all the patients. eswl was administered to three patients (16%) but it was not successful. stones location was pelvic, lower pole, upper-middle pole, middle-lower pole and staghorn in 11 (58%), 4 (21%), 1 (5%), 1 (5%) and 1 (5%) patients, respectively. average stone size was 405 ± 252.9 mm2 (100-1050). subcostal lower calyx access was performed in 15 of 19 patients (79%). intercostal upper pole access was carried out in two patients (10.5%) and multiple intercostal and subcostal accesses were required in two patients (10.5%). average operation duration was 55.47 ± 28.1 (21-139) minutes and average duration of fluoroscopy use was 131.10 ± 87.6 (35-351) seconds. average decrease in hemoglobin level of patients was 1.75 ± 0.97 (03-4.4) g/dl in postoperative period, but blood transfusion was not required. three patients developed fever in postoperative period. no further complication developed. at follow-up of the patients, residual stones were detected in 4 patients (21%) at non contrast abdominal tomography one month after operation. three of these (75%) were larger than 4 mm and 1% (25%) was less than 4 mm. presence of residual stones less than 4 mm was considered as a successful result and therefore our success rate was estimated as 84%. no age gender stone-size stone eswl operation skope approach why soliter decrease of operation (mm2) location history time(min) time(sec) time hemoglobine succes 1 43 m 625 pelvis no 67 94 subcostal nonfunctional 1.4 residue (more than 4 mm) 2 53 m 277 upper middle pole no 90 222 multiple access nonfunctional 3.7 stonefree 3 20 m 625 pelvis no 55 141 subcostal nonfunctional 0.9 stonefree 4 66 m 280 pelvis no 28 82 subcostal nonfunctional 0.5 stonefree 5 21 m 256 middle-lower pole no 56 86 subcostal nephrectomy 1.2 stonefree 6 39 f 280 pelvis yes 60 89 subcostal nonfunctional 1,7 stonefree 7 45 m 900 pelvis no 60 354 subcostal nonfunctional 2 stonefree 8 65 m 500 pelvis no 60 138 subcostal nonfunctional 0,7 stonefree 9 38 m 350 pelvis no 60 53 subcostal nonfunctional 1,2 residue (more than 4 mm) 10 19 f 130 lower pole no 64 105 subcostal agenesis 0,3 stonefree 11 33 m 300 pelvis yes 77 96 subcostal nephrectomy 2,8 residue (less than 4 mm) 12 55 m 175 middle pole no 30 139 intercostal nephrectomy 1,9 stonefree 13 43 m 250 pelvis no 65 140 intercostal nonfunctional 1,6 stonefree 14 72 f 1050 staghorn no 139 340 multiple access nephrectomy 4.4 residue (more than 4 mm) 15 41 m 350 lower pole no 25 45 subcostal nephrectomy 1,8 stonefree 16 38 m 297 lower pole no 40 150 subcostal nephrectomy 1,2 stonefree 17 44 m 100 lower pole yes 21 93 subcostal nephrectomy 2 stonefree 18 59 m 600 pelvis no 27 31 subcostal agenesis 1,5 stonefree 19 14 f 300 pelvis no 30 93 subcostal nephrectomy 1,5 stonefree table 1. characteristics and clinical outcome of percutaneous nephrolithotomy in patients with a solitary kidney. budak_stesura seveso 15/01/15 12:56 pagina 254 discussion the main aim of pnl is to clear more calculi with the least morbidity. although pnl is accepted as a minimal invasive treatment method, severe complications such as bleeding requiring transfusion, internal organ injuries, hydrothorax and sepsis can occur. nephrectomy may be necessary due to uncontrollable bleeding. this event in a patient with solitary kidney involve that the patient will become anephric. a multi-center study of complications occurring after pnl was coordinated by the croes (clinical research office of the endourological society). the global pnl study group published it in 2011 reporting that general complication rate of pnl was 25% (1175/5724); 80% of these were minor and 20% major complications and the most common complications were fever and bleeding (5, 6). some studies showed that access to calyceal system can lead to a decrease in hemoglobin levels (2.1-3.3 g/dl.) (7). bleeding after pnl can be prevented by clamping the nephrostomy tube. when bleeding cannot be stopped, selective arterial occlusion may be required (8, 9). staghorn and large calculi, obesity, prolonged operation time and absence of hydronephrosis were reported as the risk factors causing excessive bleeding during pnl (10). in our study, average decrease in hemoglobin levels in postoperative period was 1.75 g/dl. in the treatment of staghorn calculi, more severe bleeding can occur due to need for multiple access (11). in fact the patient with staghorn calculus and multiple accesses was the patient with the most severe bleeding which caused a < 4.4 g/dl decrease in the hemoglobin level. it was stated that 28.7% of the patients with negative preoperative urine culture who had prophylactic antibiotic therapy developed fever after pnl and that urgent bacteriological evaluation was not necessary if hemodynamic stability was balanced in patients with negative preoperative urine culture who had fever higher than 38.5°c and started to receive prophylactic antibiotic therapy (12). in our series, 3 of 19 patients (15%) developed fever after pnl, however none of them had sepsis. pulmonary complications after pnl are usually seen in case of supracostal access. it was stated that pneumothorax and hydrothorax rate after pnl was about 6-12% (6). four patients needed supracostal access in our study, but we did not face with any pulmonary complication. success rate after pnl ranges between 40% and 90% depending on number of stones, location, chemical structure and experience of the surgeon (12). escape of the calculus or of its fragments to an unapproachable calyx and termination of operation due to bleeding or prolonged time can be the reasons for not providing a complete calculus clearance in pnl. residual calculus fragments imply postoperative risks such as pain, urinary infection, calculus enlargement, obstruction and need for secondary surgery to patient. therefore, it is quite important to obtain a stone-free status after pnl and non-contrast abdominal tomography was recommended for evaluation of stone-free situation (13). in our study, our success rate was estimated as 84% at first month postoperative control. modern treatment of upper urinary tract calculi of solitary kidneys includes mini-invasive techniques as eswl, pnl and retrograde intrarenal surgery (rirs). in solitary kidney calculi, the results of eswl treatment are promising and it was stated that eswl was a safe and feasible method with low complications rates in the patients having only one kidney (14). efficiency of eswl was reported as 92% for kidney calculi smaller than 10 mm, 5989% for 10-20 mm calculi and 39-70% for calculi larger than 20 mm (15). rirs is a good option to remove kidney calculus in the patients having one kidney due to its high success and low morbidity rates. however, more than one procedure can be required for the patients having large urinary calculi (16, 17). yet, there are limiting factors such as that rirs is not available everywhere, operation duration is relatively longer, requires experience and is more suitable for 1.5-2 cm calculi. although pnl is today accepted as a safe and minimal invasive treatment method for treatment of urinary calculi, it is recommended that it should be always administered in high case-volume centers and by expert urologists in the patients with solitary kidney because of the risk of causing an anephric condition in case of severe complications (18). in the literature, success rates of pnl and its complications in the patients with a solitary kidney were reported in the range of acceptable levels (19, 20). conclusions pnl can be effectively and safely administered for the treatment of solitary kidney. in the treatment of large urinary calculi in patients with a solitary kidney, pnl has some advantages such as short surgery duration, less complication, acceptable hemoglobin drawdown and high success rates. according to our study, pnl operation in patients with a solitary kidney is a good option for carefully and poisedly selected cases. references 1. muslumanoglu ay, binbay m, yuruk e, et al. updated epidemiologic study of urolithiasis in turkey. i: changing characteristics of urolithiasis. urol res. 2011; 39:309-14. 2. akinci m, esen t, tellaloglu s. urinary stone disease in turkey: an updated epidemiological study. eur urol. 1991; 20:200-3. 3. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976; 10:257-9. 4. matlaga br, assimos dg. changing indications of open stone surgery. urology. 2002; 59:490-4. 5. labate g, modi p, timoney a, et al. on behalf of the croes pcnl study group. the percutaneous nephrolithotomy global study: classification of complications. j endourol. 2011; 25:1275-80. 6. türk c, knoll t, petrik a, et al. guidelines on urolithiasis. european association of urology 2013. 7. kessaris dn, bellman gc, pardalidis np. management of hemorrhage after percutaneous renal surgery. j urol. 1995; 153:604-8. 8. bedir s, bozlar u, tahmaz l, et al. severe uncontrolled delayed bleeding after percutaneous nephrolithotomy. 24th world congress of endourology, august 17-20, cleveland, ohio, usa, 2006. 9. keoghan sr, cetti rj, rogers ae, walmsley bh. blood transfu255archivio italiano di urologia e andrologia 2014; 86, 4 solitary kidney percutaneous nephrolithotomy budak_stesura seveso 15/01/15 12:56 pagina 255 archivio italiano di urologia e andrologia 2014; 86, 4 t. süelözgen, s. budak, o. celik, o. yalbuzdag, s. isoglu, s. isoglu, m. yoldas, y.ozlem ilbey 256 sion, embolisation and nephrectomy after percutaneous nephrolithotomy (pcnl). bju int. 2013; 111:628-32. 10. nouralizadeh a, ziaee sa, hosseini sharifi sh, et al. delayed post percutaneous nephrolitotomy hemorrhage: prevalance, predictive factors and management. scand j urol. 2013; 21. 11. martin x, tajra lc, gelet a, et al. complete staghorn stones: percutaneous approach using one or multiple percutaneous accesses. j endourol. 1999; 13:367-8. 12. cadeddu ja, chen r, bishoff j, et al. clinical significance of fever after percutaneous nephrolitotomy. urology. 1998; 52:48. 13. park j, hong b, park t, park hk. effectiveness of noncontrast ct. in evaluation of residual stones after percutaneous nephrolithotomy. j endourol. 2007; 21:684-7. 14. graff j, diederichs w, schulze h. long term follow-up in 1003 extracorporeal shock wave lithotripsy patients. j urol. 1988; 140:479-83. 15. penn ha, demarco rt, sherman ak, et al. extracorporeal shock wave lithotripsy for renal calculi. j urol. 2009; 182 (4 suppl):1824-7. 16. gıustı g, proietti s, cindolo l, et al. is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney?. world j urol. 2014; 1-6. 17. palmero jl, castello a, miralles j, et al. results of retrograde intrarenal surgery in the treatment of renal stones greater than 2cm. actas urológicas españolas. 2014; 38:257-262. 18. mahboub dmr, shakıbı mh. percutaneous nephrolithotomy in patients with solitary kidney. urology journal. 2009; 5:24-27. 19. akman t, binbay m, tekinarslan e, et al. outcomes of percutaneous nephrolithotomy in patients with solitary kidneys: a singlecenter experience. urology. 2011; 78:272-276. 20. bucuras v, gopalakrishnam g, wolf js, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: nephrolithotomy in 189 patients with solitary kidneys. j endourol. 2012; 26:336-341. correspondence tufan süelözgen, md tsuelozgen@hotmail.com salih budak,md (corresponding author) salihbudak1977@gmail.com orcun celik, md orcuncelik82@hotmail.com okan yalbuzdag, md oguz mertoglu, md selcuk isoglu, md selcukisoglu@hotmail.com mehmet yoldas, md myoldas@hotmail.com yusuf ozlem ilbey, md, associate prof. ozlemyusufilbey@hotmail.com tepecik training and research hospital, urology clinic, izmir, turkey budak_stesura seveso 22/01/15 10:28 pagina 256 stesura seveso 77archivio italiano di urologia e andrologia 2016; 88, 1 doi: 10.4081/aiua.2016.1.77 original paper current approach for urinary system stone disease in pregnant women orcun celik, hakan türk, rahmi gokhan ekin, ozgur cakmak, salih budak, mehmet zeynel keskin, guner yildiz, yusuf ozlem ilbey urology department, tepecik educational and research hospital, i̇zmir, turkey. due to a technical error, dr. salih budak was omitted from the author list of this article. the correct author details and order appear above. archivio italiano di urologia e andrologia doi: 10.4081/aiua.2015.4.280 erratum: erratum_stesura seveso 08/04/16 11:34 pagina 77 archivio italiano di urologia e andrologia 2017; 89, 2114 original paper premature ejaculation: pharmacotherapy vs group psychotherapy alone or in combination carlo pavone, daniela abbadessa, giuseppa gambino, giovanna scaduto, marco vella section of urology, department of surgical, oncological and stomatological sciences, university of palermo, palermo, italy. objectives: premature ejaculation (pe), the commonest sexual dysfunction in males, is generally treated with local anesthetic and ssri (dapoxetine). the aim of our study was investigate group psychotherapy as an alternative treatment for pe and compare the efficacy of pharmacological treatment and psychotherapy, either alone or in combination, in terms of response and improved quality of life (qol). from a male outpatient population screened for pe, those who received a diagnosis of pe were proposed for the study, enrolled and divided into 3 groups (a, b and c). each group was treated with dapoxetine, group psychotherapy alone and dapoxetine and group psychotherapy, respectively. materials and methods: out of 1237 male outpatients, 353 received a diagnosis of premature ejaculation. of them, 279 were enrolled in the study and randomized into 3 groups (a, b and c). only 157 patients were evaluable. before and after treatments all participants completed two questionnaires to evaluate pe status and anxiety and referred their ielt. results: group a: the mean post-treatment premature ejaculation diagnostic tool (pedt) score decreased from 12.95 to 8.26, while the mean intra-vaginal ejaculation latency time (ielt) increased from 50.77 sec to 203 sec. (p < 0.05); group b: reduction in the mean pedt from 13.44 to 5.11 and an increased ielt from 48.33 to 431.11 sec (p < 0.001); group c: the mean post-treatment pedt score decreased from 12.29 to 5.57, while the mean ielt increased from 46.86 to 412.14 sec (p < 0.001). all groups recorded an improvement in anxiety. conclusions: according to our results group psychotherapy is an alternative method of treatment for pe. group psychotherapy plays a significant role in the treatment of pe, determining a better improvement of symptoms than dapoxetine alone even if not statistically significant. key words: premature ejaculation; group psychotherapy; psychotherapy; dapoxetine; sexual therapy. submitted 11 october 2016; accepted 1 march 2017 summary no conflict of interest declared. al consequences (1). it seems to be the most common sexual disorder in males (2) with an incidence of about 2540% of the world’s male population. it's etiology is multifactorial and include biological, psychological, social and situational factors. all psychological and behavioral approaches to the treatment of pe were based on the hypothesis of an emotional origin of the disorder, and on physical rehabilitation through special techniques such as squeeze-pause and start-stop (3), but pharmacotherapy with serotonin selective re-uptake inhibitors (ssris) has changed the management of this disorder and eclipsed the use of psychological treatments (4). nowadays, the literature seems to identify both organic and psychological multifactorial events in the pathogenesis of pe that are involved to varying extents in each patient. a multifactorial pathogenesis calls for a multidisciplinary approach that strives to achieve a global evaluation of the patient. several studies have concluded that combined therapy is more effective than pharmacological therapy alone for men with erectile dysfunction (ed) and pe (5, 6). although psychotherapy has been used and considered as a possible treatment of pe, the use of group psychotherapy that had a huge emphasis during the 1970s and 1980s (7, 8) within psychiatry and psychology nowadays has fallen into disuse in the clinical practice and has been considered not fit for sexual disorder by some authors (9). as far as we know there are no studies comparing group psychotherapy with pharmacotherapy. our prospective and randomized study has the intent to evaluate the feasibility of group psychotherapy in treatment of pe and evaluate the efficacy of two different treatments (pharmacological and psychological), either alone or in combination and as far as we know it's the first study comparing the pharmacotherapy to a grouppsychotherapy. materials and methods between january and december 2012, a sample of male outpatients aged 20 to 68 years was screened for pe. the pe patients were enrolled in the study. inclusion criteria were: lifelong pe measured with intravaginal ejaculatory latency time (ielt) ≤ 2 minutes and premature ejaculation diagnostic tool (pedt) > 9 (see below). exclusion criteria were: presence of psychiatric disordoi: 10.4081/aiua.2017.2.114 introduction according to an updated report from the international society of sexual medicine (issm), premature ejaculation (pe) is defined as a male sexual dysfunction characterized by ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong type) or a clinically significant reduction in latency time often to about 3 minutes or less (acquired type), the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personpavone_stesura seveso 20/06/17 11:16 pagina 114 115archivio italiano di urologia e andrologia 2017; 89, 2 premature ejaculation: combination therapy ders requiring medical treatment, drugs and alcohol abuse, severe chronic disease, neoplastic diseases. this study was performed at the urology department, university of palermo, outpatients clinic. patients, after giving informed consent to participation in the study, were randomly assigned following simple randomization procedures (computerized random numbers) to 3 different treatment groups as follows: group treatment a: dapoxetine group treatment b: group psychotherapy alone. group treatment c: dapoxetine (as in group a) in combination with group psychotherapy. patients of all the 3 groups were also followed up by the urologist for 12 weeks during the study with 4 monthly scheduled visits. ielt was collected as reported by patients at the beginning and at the end of the study. prior to treatment any participant, regardless of treatment group, completed two validated questionnaires, and repeated them at the end of all treatments. differences between scores at baseline and after treatments were evaluated. the pedt was used to assess pe status. this five-item questionnaire was developed according to the dsm-ivtr criteria used to diagnose pe (10), and covers the following five domains: ejaculation control, frequency of pe, ejaculation with minimal sexual stimulation, distress, and interpersonal difficulty. response options for all items are on a five-point likert-type scale ranging from 0 to 4, with higher scores indicating greater sexual impairment. the total score is computed by summing up all item scores. therefore, the primary endpoint of the study was to evaluate differences in pedt scores across groups, before and after treatment. secondary endpoint was ielt defined as the mean duration of intercourse, expressed in seconds. ielt was reported from patients in order to reduce the anxiety induced by the use of a device such as a chronometer: this anxiety could negatively impact on the pe, reducing ielt (11); moreover, as reported by jannini et al. (11) “the presence of a stopwatch, even for short diagnostic purpose, is not frequently accepted”. at ante-portam ejaculation was assigned an ielt of 0 minutes. in order to identify anxiety in the psychological context of the examined subjects, the state-trait anxiety inventory (stai) test, a self-administered questionnaire, was used (12, 13). it consists of two different scales (stai-x1 and stai-x2) of 20 items each, with multiple choice answers (never, sometimes, often, and always). stai-x1 is directed at investigating the state anxiety and provides a transitory estimation of the emotional state, which varies in intensity and fluctuates in time as a function of the stressors impinging on the individual at the time of starting the procedure. stai-x2 is directed at relatively stable individual differences in subjects who become anxious in different circumstances (14) psychometric tests were performed to identify the presence of state anxiety (stai-xl) and trait anxiety (staix2) before and after each treatment, as well as the prepost treatment anxiety fluctuations. the threshold scores for stai questionnaires were chosen according to previously published methods (15) (normal range = 28-44 and 28-48 for the x1 and x2 form, respectively). all groups psychotherapy were conducted by an expert postdoctoral-level psychotherapists trained in groupanalytical approach: group psychotherapy was preceded by 2 individual interviews aimed at discussing and informing upon general aspects of group psychotherapy and its rules. group psychotherapy was delivered in 16 weekly sessions of 2 hours each. time was spent at the end of each session to help participants to integrate cognitively the experience with theory. each group, open and shortterm, was composed of about 10 male patients, and after randomization resulted homogeneous for ielt (≤ 2), pedt (≥ 9) and stai-y (≥ 40). in our study we used the homogeneous group psychotherapy, time-limited, that is characterized by the presence of patients who shared the same symptom, diagnosis or typology of problems (i.e. pe). the earliest experience of this group psychotherapy is due to pratt (16, 17), professor of medicine at boston hospital, who developed a class-based method for treating patients with psychosomatic conditions and emotional dimensions of chronic and recurrent illness, and traced some dynamics which could be activated in this type of group. the presence of patients with similar issues offers participants the opportunity to interact with others in a safe, supportive environment: this fact facilitates the expression of those feelings which are often difficult to express outside of group, and to try out new behaviors and engage with others not only in receiving valuable feedback from other group members, but also in giving it. in fact homogeneity is at the basis of the mirroring process that enables the emergence of commuting, resonance and effective narration functions that, at the same time, generate a special sense of belonging (18). the goals of group psychotherapy was to elaborate the meaning of sexual dysfunction, to permit patients to acquire internal and relational competence useful to achieve a most satisfying quality of life, to increase the ability to analyze and manage new events, start thinking to possible changes and ameliorations after a treatment cycle, reduction of anxiety, increase of compliance to medical treatment. in this study we used dapoxetine 30 mg (dose increasable to 60 mg if ineffective), 1 tablet 1 hour before intercourse with a couple of glasses of water. an alpha level of .05 (two-tailed) was chosen for all statistical tests in this study. we tested for differences between treatment groups on ielt and pedt, stai-x1 and stai-x2 by using analyses of variance, before and at the end of treatment; post-hoc tukey hsd tests were performed to investigate differences across groups at the end of treatment; finally, to determine the effects of the treatments in producing clinical improvement at the end of treatment, paired samples t-tests were performed. statistical analysis was performed using the computer statistical package spss/17.0 (spss, chicago, il, usa). to determine the effects of the treatments in producing clinical reduction of state and trait anxiety at the end of treatment, we performed an intention to treat cochran’s q test of the percentage of patients who had reduced anxiety at stai-x1 and/or stai-x2. for each measure, two categories were created: normal range and pathologpavone_stesura seveso 20/06/17 11:16 pagina 115 archivio italiano di urologia e andrologia 2017; 89, 2 c. pavone, d. abbadessa, g. gambino, g. scaduto, m. vella 116 ical range. patients were deemed to have clinically reduced anxiety if their score was shifted from the pathological range to the normal range; otherwise, those not having reduced anxiety remained in the normal range or in the pathological range. an intention to treat cochran’s q test (itt) was performed on a larger data set comprising subjects who completed the study, as well as subjects who dropped out the study for various causes, so not being analyzed in the post-test phase. in such an analysis the pre-test condition (normal vs pathological) was carried forward to serve as the post-test condition of dropouts. no patient witnessed either an increased in their state or trait anxiety level. effect sizes were finally calculated: cohen’s d was calculated for t tests, cohen’s f for anovas; phi coefficient for the x2 tests, and cramer’s v for the cochran’s q tests. results figure 1 shows a flow chart of the study. out of 1237 male outpatients, 353 received a diagnosis of pe and a total sample of 279 patients who met the entry criteria, agreed to randomization and was analyzed in a pre-treatment phase. patients were randomly divided in 3 groups, each of them was composed of 93 patients. out of 279 enrolled patients, only 157 patients completed the intervention and were analyzed post-treatment; in detail the drop out rate was of 33% in group a, 36% in group b and 61% in group c respectively (drop out reasons are showed in figure 1). there were no significant differences in all demographic and clinical variables between eligible patients carried through the intervention to the end and those who left the study. preliminary comparisons at baseline demonstrated that the three treatment groups did not show significant differences on 15 demographic and clinical variables (age, marital status, employment status, stable love affair, cigarette smoking, diabetes, hypertension, obesity, heart condition, neuropathy, prostatitis, sexually transmitted diseases, depression, anxiety, and erectile dysfunction). the demographic and clinical characteristics of the treatment groups at baseline are shown in table 1. then, it was verified that assumptions for anovas, paired samples t-tests and cochran’s q tests were not violated. table 2 shows the results at baseline and at the end of treatment for all patients for whom results were available on the four main outcome measures (ielt, pedt, stai-x1 and stay-x2). at baseline, no differences in outcome measures were found between the groups (see table 2). all three groups improved during treatment, while at the end of treatment groups b and c improved more significantly than group a, on all the study variables. no significant differences among group b and group c were found at the end of treatment, on any of the study variables (table 2). finally, table 3 shows the number (and percentage) of patients who were in the normal or pathological range of anxiety in each group at baseline and at the end of treatment. in the sample as a whole, patients significantly reduced their level of both state and trait anxiety (staix1 and stai-x2, respectively) from the pathological to the normal range. specifically, both state and trait anxiety significantly decreased in all groups, and most patients improved to the normal range (table 3). discussion pe seems to be the most common sexual disorder in males (2). as described previously pe has a multifactorial etiology and many authors concentrated their attention on the study of a biopsychosocial approach to this disorder (19, 29, 30). psychological and behavioral approaches to the treatment of pe were based on the hypothesis of an emotional origin of the disorder, and on physical rehabilitation through special techniques such as squeeze-pause and start-stop (3). nowadays the literfigure 1. flow diagram of the progress through the phases of the randomized study. pavone_stesura seveso 20/06/17 11:16 pagina 116 117archivio italiano di urologia e andrologia 2017; 89, 2 premature ejaculation: combination therapy ature seems to identify both organic and psychological multifactorial events in the pathogenesis of pe that are involved to varying extents in each patient. with the introduction of ssri in the treatment of pe several studies have concluded that combined therapy is more effective than pharmacological therapy alone for men with ed and pe (5, 6). as discussed before, the use of group psychotherapy that had a huge emphasis during the 1970s and 1980s (7, 8) within psychiatry and psychology, nowadays has fallen into disuse in the clinical practice and has been considered not fit for sexual disorder by some authors (9). those who are affected by pe often appear to be discouraged by the unsatisfying duration of intercourse, as well as by the sense of inadequacy related to their inability to satisfy their partner, it has negative consequences on the quality of life (qol) of patients and their partners. a recent study conducted by limoncin et al. (22) showed that women with a partner affected by pe were more likely than controls to experience significant sexual distress. until 2008 the pharmacological treatment of pe was based on off-label use of ssris; in 2009 the european agency for the evaluation of medicinal products (ema) approved the use of dapoxetine for the specific treatment of pe in patients aged between 18 and 64 years. the efficacy of dapoxetine compared to placebo has been proven in many studies. although its side effects are rarely serious and generally well tolerated (23), patients’ compliance to table 1. demographic and clinical features of treatment groups at baseline. figures are numbers (percentage) of patients unless stated otherwise. patient group a group b group c total sample differences characteristics dapoxetine (n = 93) group therapy (n = 93) combination (n = 93) (n = 279) between groups mean (range) age (years) 45.79 (22-64) 37.00 (28-56) 48.44 (20-68) 45.32 (20-68) f (2, 276) = 2.12, ns marital status married 39 (41.93) 48 (51.61) 36 (38.71) 123 (44.09) χ2 (2) = 3.40, ns marital status single 47 (50.54) 34 (36.56) 48 (51.61) 129 (46.24) χ2 (2) = 5.28, ns marital status divorced 7 (7.53) 11 (11.83) 9 (9.68) 27 (.10) χ2 (2) = .98, ns employment status employee 30 (32.26) 23 (24.73) 37 (39.78) 90 (32.26) χ2 (2) = 4.82, ns employment status director 7 (7.53) 5 (5.38) 4 (4.30) 16 (5.73) χ2 (2) = .93, ns employment status self-employed 11 (11.82) 13 (13.98) 6 (6.45) 30 (10.75) χ2 (2) = 2.91, ns employment status unemployed 45 (48.38) 52 (55.91) 46 (49.46) 133 (51.25) χ2 (2) = 1.23, ns stable love affair 69 (74.19) 77 (82.80) 79 (84.95) 225 (80.65) χ2 (2) = 3.86, ns cigarette smoking 31 (33.33) 27 (29.03) 19 (20.43) 77 (27.60) χ2 (2) = 4.02, ns diabetes 7 (7.53) 3 (3.23) 8 (8.60) 18 (6.45) χ2 (2) = 2.48, ns hypertension 15 (16.13) 17 (18.28) 24 (25.81) 56 (20.07) χ2 (2) = 2.99, ns obesity 3 (3.23) 5 (5.38) 10 (10.75) 18 (6.45) χ2 (2) = 4.63, ns heart condition 6 (6.45) 13 (13.98) 10 (10.75) 29 (10.39) χ2 (2) = 2.85, ns neuropathy 1 (1.08) 2 (2.15) 1 (1.08) 4 (1.43) χ2 (2) = .51, ns prostatitis 3 (3.23) 4 (4.30) 8 (8.60) 15 (5.38) χ2 (2) = 2.96, ns sexually transmitted diseases 0 (0) 0 (0) 0 (0) 0 (0) depression 3 3.23) 6 (6.45) 2 (2.15) 11 (3.94) χ2 (2) = 2.46, ns anxiety 18 (19.35) 26 (27.96) 31 (33.33) 75 (26.88) χ2 (2) = 4.70, ns erectile dysfunction 46 (49.46) 38 (40.86) 41 (44.09) 125 (44.80) χ2 (2) = 1.42, ns table 2. mean scores on two main outcome scales at baseline and at the end of treatment. outcome measures mean scores differences (sd; 95% ci) (n) between groups tukey hsd post-hoc tests patient characteristics group a dapoxetine group b group therapy group c combination ielt: baseline (279) 50.77 (13.52; 48.02 46.86 (10.95; 48.54 48.33 (13.11; 45.67 f (2, 276) = 2.29, ns for all pairwise comparisons: to 53.52) (n = 93) to 53.00) (n = 93) to 50.99) (n = 93) ps > .05 end of treatment (139) 231.86 (39.97; 221.91 412.14 (45.36; 400.57 431.11 (53.96; 413.48 f (2, 154) = 320.50, group a vs group b: p < .001; to 241.81) (n = 62) to 423.71) (n = 59) to 448.74) (n = 36) p < .001 group a vs group c: p < .001; group b vs group c: ns t (61) = -35.67, p < .001 t (58) = -61.86, p < .001 t (56) = -42.56, p < .001 pedt: baseline (279) 12.95 (2.32; 12.48 12.29 (1.97; 11.89 13.44 (6.28; 12.16 f (2, 276) = 1.91, ns for all pairwise comparisons: to 13.42) (n = 93) to 12.69) (n = 93) to 14.72) (n = 93) ps > .05 end of treatment (139) 10.61 (8.59; 8.47 5.57 (10.62; 2.86 5.11 (13.86; .58 f (2, 154) = 7.57, group a vs group b: p < .05; to 12.75) (n = 62) to 8.28) (n = 59) to 9.64) (n = 36) p < .05 group a vs group c: p < .05; group b vs group c: ns t (61) = 2.14, p < .05 t (58) = 4.86, p < .001 t (35) = 3.61, p < .001 pavone_stesura seveso 20/06/17 11:16 pagina 117 archivio italiano di urologia e andrologia 2017; 89, 2 c. pavone, d. abbadessa, g. gambino, g. scaduto, m. vella 118 dapoxetine still remain poor as demonstrated in recent study in which the dropout at one year was of about 90% (24). some authors believe that the first approach with pe must consider topical therapy with anesthetic gel (lidocain, prilocain), which has demonstrated greater efficacy compared to placebo (25). some authors expressed concern that the administration of medical treatments for sexual disorders without attention to psychological factors may not be sufficient (26, 27). according to hunt and mchale (28) men suffering from andrological problems, such as ed and pe, commonly have concomitant psychosocial problems, vary in nature and severity, and that in many cases they may benefit from some form of psychotherapy. group therapy is a form of psychotherapy in small group of individuals with the purpose to assist them in emotional growth and personal problem solving, that encompasses many different kinds of groups with varying theoretical approaches. group psychotherapy characterized by a psychodynamic approach (such as in our study) is able to facilitate active and introspective work among the participants with the aim to reduce invalidating symptoms and to achieve a change in their personality and modality of interaction. moreover, our choice of a short group psychotherapy was born from the evidence of effectiveness in patients affected by moderate anxiety and depression (29); furthermore, short psychotherapy showed lower drop-out rate compared to long term one (30). on the contrary, in our study patients' partners were not included to reduce/minimize patients' inhibition and create an environment free from couple dynamics (feelings like sadness, anxiety, anger, dissatisfaction and sexual disorders often underlie dysfunctional relationships) (31). some teorical limitations of this study were the facts that is not blinded (it is not possible to blind a psychotherapy group), the absence of a placebo group versus dapoxetine (in the presence of a drug with certain indication for the treatment of pe it didn't seems ethical a placebo group). the follow up is not extremely long but congruos with the aims of a prospective randomized study and the superior efficacy of a short therm therapy (30). it should be interesting in future studies to evaluate with a cross-over analysis the correlation between single arms. another potential limitation of the study is the lack of an objective method for the evauation of ielt, as the stop watch techniques, but this is a method unfit in the clinical setting of our patients and in any case the authors give more importance of the subjective evaluation of the time as reported by jannini et al. (11) “the presence of a stopwatch, even for short diagnostic purpose, is not frequently accepted”. poor compliance remains a limit of this disorder as also showed in a recent study of mondaini et al. (24) but it's also depend on the organization problems linked to the psychotherapy. conclusions the pe is a complex sexual disorder with a multifactorial pathogenesis that needs to be taken into account for proper treatment. this is only possible by adopting a multidisciplinary approach, indeed, psychotherapeutic treatment not only contributes to treating the disorder in those cases in which the psychological pathogenesis is more relevant, but also decreases anxiety, reducing relapses and helping patients deal with the disorder. ultimately, an improvement of qol is achieved in those patients. our study highlights the importance in considering a combination of therapies as a correct way to treat pe, either due to a hypothetical psychological etiology, or due to frequent perelated psychological consequences. our results showed that psychotherapy may also improve the efficacy of pharmacotherapy (compliance with medical treatment). moreover, in our experience group psychotherapy seems to be suitable also for patients with this kind of sexual disorder (25). finally, as claimed by hunt and mchale (28) who stated that “for most men the most effective treatment for andrological disorders, depending on the cause of the problem, may be a combination of medical and psychological treatment”, we would like to underline the importance of multidiscirange stai-x1 group a dapoxetine group b group therapy group c combination baseline end of treatment baseline end of treatment baseline end of treatment (n = 93) (n = 62) (n = 93) (n = 59) (n = 93) (n = 36) normal 76 59 68 52 69 33 pathological 17 3 25 7 24 3 baseline end of treatment comparisons χ2 (2) = 5.98, p < .05 χ2 (2) = 4.90, p < .05 χ2 (2) = 4.79, p < .05 differences between groups baseline: χ2 (2) = 2.26, ns end of treatment: χ2 (2) = 1.96, ns stai-x2 group a dapoxetine group b group therapy group c combination baseline end of treatment baseline end of treatment baseline end of treatment (n = 93) (n = 62) (n = 93) (n = 59) (n = 93) (n = 36) normal 25 45 18 38 27 25 pathological 68 17 75 21 66 11 baseline end of treatment comparisons χ2 (2) = 31.37, p < .001 χ2 (2) = 31.49, p < .001 χ2 (2) = 17.62, p < .001 differences between groups baseline: χ2 (2) = 2.56, ns end of treatment: χ2 (2) = .95, ns table 3. number (%) of patients' range at stai-x1 and stai-x2, at baseline and at the end of treatment. pavone_stesura seveso 20/06/17 11:16 pagina 118 119archivio italiano di urologia e andrologia 2017; 89, 2 premature ejaculation: combination therapy plinarity (32, 33): our data showed that group c, treated with the combination of pharmacotherapy and psychotherapy, was the one that improved the most in terms of results, as shown in table 2. according to the results of our study, group psychotherapy appears to be effective in improving ielt, sexual satisfaction and anxiety both alone or in combination with dapoxetine in treatment of pe. considering the multi-pathogenic nature of pe, combined treatment seems to be preferable to a single therapy, whether pharmacological or psychotherapeutic, even though the study does not show any statistically significant difference between treated groups. references 1. althof se, mcmahon cg, waldinger md, et al. an update of the international society of sexual medicine’s guidelines for the diagnosis and treatment of premature ejaculation (pe). j sex med. 2014; 11:1392-422. 2. laumann eo, paik a, rosen rc. the epidemiology of erectile dysfunction: results from the national health and social life survey. int j impot res 1999; 11(suppl 1):s60-4. 3. cooper k, martyn-st james m, kaltenthaler e, et al. behavioral therapies for management of premature ejaculation: a systematic review. sex med. 2015; 3:174-88 4. althof se. psychological approaches to the treatment of rapid ejaculation. jmhg. 2006; 3:180-186 5. abdo ch, afif-abdo j, otani f, machado ac. sexual satisfaction among patients with ed treated with counseling, sildenafil or both. j sex med. 2008; 5:1720-6. 6. althof se, needle rb. psychological and interpersonal dimensions of sexual function and dysfunction in women: an update. arab j of urol. 2013; 11:299-304. 7. perelman ma. the treatment of premature ejaculation by time-limited, group sex therapy, columbia university, 1980. 8. zilbergeld b. group treatment of sexual dysfunction in men without partners; j sex marital ther. 1975; 1:204-214. 9. di maria f, lo verso g. la psicodinamica dei gruppi. raffaello cortina, milano, 1995. 10. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 11. jannini ea, lenzi a. from diagnosis to treatment: the office management of premature ejaculation in: jannini ea, mcmahon cg, waldinger md eds.: premature ejaculation. from etiology to diagnosis and treatment, springer 2013, p.334. 12. sanavio e, bertolotti g, michielin e, et al. cba 2.0-scale primarie. os: florence, italy 1986. 13. spielberger cd, gorsuch r, lushene re. manual for the state trait anxiety inventory. consulting psychologist press; palo alto, calif, us, 1970. 14.aversa a, rocchietti-march m, caprio m, et al. anxiety-induced failure in erectile response to intracorporeal prostaglandin-e1 in nonorganic male impotence: a new diagnostic approach. int j androl. 1996; 5:307-313. 15. rocco a, mori f, baldelli r, et al. effect of chronic bromocriptine treatment on psychological profile of patients with prl-secreting pituitary adenomas. psychoneuroendocrinology. 1993; 18:57-66. 16. pratt jh. principles of class treatment and their application to various chronic diseases. in hospital social service quarterly. 1922; 6:401-411. 17. sabin je. joseph hersey pratt's cost-effective class method and its contemporary application: some problems in biopsychosocial innovation. psychiatry. 1990; 53:169-184 18. marinelli s. funzioni dell'omogeneità nel gruppo. in: corbella s, girelli r, marinelli s. gruppi omogenei. borla, roma, 2004. 19. semans jh. premature ejaculation: a new approach. south med j. 1956; 49:353-358. 20. masters wh, & johnson ve. human sexual inadequacy. boston: little, brown & co. 1970. 21. kaplan hs. the new sex therapy. new york: brunner/mazel. 1974. 22. limoncin e, tomassetti m, gravina gl, et al. premature ejaculation results in female sexual distress: standardization and validation of a new diagnostic tool for sexual distress. j urol. 2013; 189:1830-5. 23. pavone c, scalici gesolfo c, abbadessa d, et al. compliance to therapy with dapoxetine in patients affected by premature ejaculation. urologia. 2013; 80:53-63. 24. mondaini n, fusco f, cai t, et al. dapoxetine treatment in patients with lifelong premature ejaculation: the reasons of a “waterloo”. urology. 2013; 82:620-4. 25. martyn-st james m, cooper k, et al. topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. sex health. 2016; 13:114-23. 26. rosen rc, leiblum sr: treatment of male erectile disorders: current options and dilemmas. sexual and marital ther. 1993; 8:5-8. 27. rosen rc, leiblum sr. treatment of sexual disorders in the 1990s: an integrated approach. j of consulting and clinical psychology. 1995, 63:877-890. 28. hunt n, mchale s. what is the importance of psychosocial issues, counseling and psychotherapy in andrology. in: the american society of andrology: handbook of andrology ii ed., allen press. 2013. 29. budman sh, simeone pg, reilly r, demby a. progress in shortterm and time-limited group psychotherapy: evidence and implications. in a. fuhrinam e gm. burlingame (eds), handbook of group psycotherapy. an empirical and clinical synthesis. new york: wiley. 1994. 30. sledge wh, moras k, hartley d, levine m. effect of time-limited psychotherapy on patients drop-out rates. american journal of psychiatry. 1990; 147:1341-1347. 31. graziottin a, althof s. what does mean to the man, the woman and the couple? j. sex med. 2011; 8(suppl. 4):304-309. 32. rowland d, cooper s. practical tips for sexual counseling and psychotherapy in premature ejaculation, j sex med. 2011; 8(suppl 4):342-52. 33. perelman ma. a new combination treatment for premature ejaculation: a sex therapist's perspective. j sex med. 2006; 3:1004-12. correspondence carlo pavone, md (corresponding author) carlo.pavone@unipa.it daniela abbadessa, md danielaabbadessa@hotmail.com giuseppa gambino, md gambino.giusi@alice.it giovanna scaduto, md giovanna.scaduto@libero.it marco vella, md marco.vella@libero.it via del vespro 129, 90100, palermo, italy pavone_stesura seveso 20/06/17 11:16 pagina 119 archivio italiano di urologia e andrologia 2013; 85, 144 introduction abdominoscrotal hydrocele (ash) is a rare entity with unclear etiology. it extends into the abdominal cavity through the inguinal canal (1, 2). mostly observed in pediatric patients, ash is scarcely described in adult population with only a few cases associated with one sided hydronephrosis reported in the literature (3, 4). we present a case of ash with bilateral hydronephrosis. case presentation a 49-year-old male was admitted to our clinic with progressively increasing left scrotal swelling along a period of one year. during initial physical examination lower abdominal mass on the left and hydrocele of the left testis were observed (figure 1). hydrocele had simultaneous fluctuation with the lower abdominal swelling. in spite of clinical diagnosis based on physical findings and ultrasound imaging an urethral foley catheter was inserted to rule out the presence of urinary retention and associated hydronephrosis demonstrating an empty bladder. bilateral hydronephrosis occurred as a result of the compression of the bladder and the left ureter by the sac (figure 2, 3). surgery was scheduled by inguinal approach in order to perform an high ligation of the processus vaginalis with complete excision of the abdominal component of the case report abdominoscrotal hydrocele with bilateral hydronephrosis in an adult: case report bircan mutlu, yusuf ozlem ilbey, alper bitkin, ali i̇hsan taşçı bakırköy dr. sadi konuk training and research hospital, istanbul, turkey. abdominoscrotal hydrocele is a rare entity with unclear etiology which may be diagnosed with general examination and ultrasound imaging. during examination it may misinterpreted as acute urinary retention of the bladder (globe-like) especially if associated with hydronephrosis. it should be treated surgically. here we present a case of left abdominoscrotal hydrocele with accompanying left grade 2 and right grade 1 hydronephrosis. key words: hydrocele; hydronephrosis; ultrasound. submitted 10 january 2013; accepted 28 february 2013 no conflict of interest declared summary lesion. during the abdominal dissection of the sac we injured the peritoneum and it was repaired. we also mobilised the scrotal part of the sac in order to excise the figure 1. mutlu_stesura seveso 18/04/13 12:05 pagina 44 45archivio italiano di urologia e andrologia 2013; 85, 1 abdominoscrotal hydrocele with bilateral hydronephrosis in an adult: case report leg edema in pediatric patients (6, 7). in our case at initial diagnosis we have observed bilateral hydronephrosis. ash should be considered for the differential diagnosis of bilateral hydronephrosis. mostly, it is one sided but in the literature bilateral ash is also reported (8). paratesticular malignant mesothelioma associated with ash has also been reported in a 14-year-old boy (9). ultrasound, magnetic resonance imaging (mri) and computed tomography (ct) may be used for the diagnosis. during surgical treatment of ash, dilated inguinal ring due to large sac shoud be repaired and mesh method should be used to avoid secondary herniation. although open surgery is generally a preferred option, as we did, bouhadiba et al. reported laparoscopic excision of ash (10). figure 2. a: computed tomography images demonstrating right grade one and left grade two hydronephrosis. b: abdominal part of abdominoscrotal hydrocele. a. b. figure 3. a: compression of abdominoscrotal hydrocele on left side of the bladder. b: bladder h: hydrocele. b: inguinal and scrotal part of abdominoscrotal hydrocele. b: bladder h: hydrocele t: testicle. tunica vaginalis of the testis and suture the edges of the remaining tunica vaginalis posterior to the testis. mesh (lichtenstein) method was used for inguinal hernia repair. testis and cord were normal. the postoperative period was uneventful. discussion the etiology of ash is not clear but there is general consensus on the need of surgical treatment. according to a pubmed search there is only one case which authors successfully managed by conservative approach (5). ash is not a real benign condition, because it may be complicated with acute appendicitis, and it may lead to ureterohydronephrosis, testicular dismorphism and even a. b. mutlu_stesura seveso 18/04/13 12:05 pagina 45 archivio italiano di urologia e andrologia 2013; 85, 1 b. mutlu, y. ozlem ilbey, a. bitkin, a. i̇hsan taşçı 46 6. halilbasic a, hotic n, skokic f, et al. both-sided large abdominoscrotal hydrocele associated with testicles atrophy. med arh. 2011; 65:182-4. 7. faure a, bouali o, chaumoitre k, et al. abdominoscrotal hydrocele with leg edema in a 4-month-old boy. prog urol. 2009; 19:639-42. 8. arslan as, incesu l, yalin t, et al. bilateral abdominoscrotal hydrocele. abdom imaging. 1996; 21:177-178. 9. velasco al, ophoven j, priest jr, brennom ws. paratesticular malignant mesothelioma associated with abdominoscrotal hydrocele. j pediatr surg. 1988; 23:1065-7. 10. bouhadiba n, godbole p, marven s. laparoscopic excision of abdominoscrotal hydrocele. j laparoendosc adv surg tech a. 2007; 17:701-3. references 1. celayir ac, akyüz u, ciftlik h, et al. a critical observation about the pathogenesis of abdominoscrotal hydrocele. j pediatr surg. 2001; 36:1082-4. 2. kaplan m, atakan ih, aktoz t, inci o. giant unilateral abdominoscrotal hydrocele in an adult: case report.int urol nephrol. 2006; 38:667-70. 3. avolio l, chiari g, caputo ma, bragheri r. abdominoscrotal hydrocele in childhood: is it really a rare entity? urology. 2000; 56:1047-9. 4, singh d, aga p, goel a. giant unilateral hydrocele "en-bisac" with right hydronephrosis in an adult: a rare entity. indian j urol. 2011; 27:142-3. 5. upadhyay v, abubacker m, teele r. abdominoscrotal hydrocele-is there a place for conservative management? eur j pediatr surg. 2006; 16:282-4. correspondence bircan mutlu, md (corresponding author) tevfik saglam cad. no:11 zuhuratbaba, istanbul, turkey mutlubircan@yahoo.com yusuf ozlem ilbey, md ozlemyusufilbey@hotmail.com alper bitkin, md alperbitkin@gmail.com ali i̇hsan taşçı, md aliihsantasci@hotmail.com bakırköy dr.sadi konuk training and research hospital, istanbul, turkey mutlu_stesura seveso 18/04/13 12:05 pagina 46 241archivio italiano di urologia e andrologia 2016; 88, 3 case report ultrasonographic study of subcutaneous penile granuloma secondary to silicone injection lucio dell’atti department of urology, university hospital “st.anna”, ferrara, italy. penile augmentation has been reported in the literature by injecting various materials. this study reports our experience in management of penile augmentation complications associated with selfpenile injection of silicone liquid. after a careful ultrasound study, the penile skin was excised through a circumferential sub-coronal incision and dissected with the silicon mass. histology was well-compatible with silicone granulomas. the patient was discharged after 24 hours. ultrasonography has permitted preoperatively to determine if the plane between the indurated inflammatory tissue and the buck’s fascia was preserved for the complete surgical excision of affected tissue. key words: penile augmentation; complications; silicon; granuloma. submitted 14 march 2016; accepted 8 may 2016 summary no conflict of interest declared. were not involved. the patient requested surgical removal of the mass. the procedure was performed under spinal anaesthesia in the supine position. the patient was catheterized for avoiding injury to the urethra. the surgical access was through a circumferential sub-coronal dorsal incision and penile skin was dissected with the silicon mass. following excision of the mass, the corpora cavernosa were inspected for integrity. penile skin was re-draped over the shaft and the incision was closed in one layer. the catheter was removed after 12 hours and the patient was discharged after 24 hours. histology of the resected skin and solid tissue showed focal epidermal ulceration with dispersed areas of homogeneous basophilic material surrounded by mononuclear chronic inflammation cells, fibrosis, and micro-vesicular alteration. pathologic examination was well-compatible with silicone granulomas. discussion the literature presents scarce information on augmentation of the shaft by fillers, most in the form of case reports. injection of fillers was in the hand of physicians, lay people, or even by the individual’s own hand (3). the most common method employed in recent years for penile girth extension has been lipofilling but with disappointing results mainly because of lack an exact plane for fat injection (4). silicone liquid injection also has been used commonly for cosmetic purposes in recent years with a wide range of indications, like correction of scars, cutaneous and subcutaneous atrophies. silicone increases tissue bulk ideally by stimulating new collagen and fibrosis. in the case of the penis, increasing fibrosis with time could impair penile function by circumferentially compressing penile circulation (3). the first case reports of complications caused by silicone injection for penis augmentation appeared in the 1960s (5). although silicone has been used for penile girth augmentation, as described plaza et al. (5), it is not recommended because of many complications: swelling, penile deformities, migration and granulomatous reactions. the granulomatous reaction can further cause lymph obstruction, edema, and deformity of the penis. other patients may present with severe infection causing multiple abscesses. there are have been few studies describing the ultrasound features of penile granulomatous reaction. us is doi: 10.4081/aiua.2016.3.241 introduction a new field of male genital cosmetic surgery has developed in the past decade. the majority of men who request augmentation of their penis usually have a normally sized and functioning penis (1). however, some men want an enhancement of their penis and, therefore, use alternative filler materials injected under the skin of the genitals to increase girth, such as paraffin oil, metallic mercury, collagen, hyaluronic acid, mineral oils, and silicone (2-5). we reported a case of subcutaneous granuloma of the penis secondary to self-penile injection with silicone liquid for augmentation purposes. case report a 34-years-old caucasian male patient presented to our urology department with dysuria and painful swelling of the penis two months after self-penile injection with silicone for augmentation. at physical examination a tender and highly swollen penis with ulcerated tissue, especially on the ventral surface, and a considerable phimosis was seen. an ultrasonography (us) of the penis was done in the flaccid state using a 9-12 mhz linear array transducer. longitudinal and transverse view of penile shaft showed diffuse thickening of the subcutaneous tissue surround the buck’s fascia with increased echogenicity (figure 1). the corpora cavernosa and glans penis dell'atti_stesura seveso 21/09/16 09:12 pagina 241 archivio italiano di urologia e andrologia 2016; 88, 3 l. dell’atti 242 ideal in evaluating superficial structures like the penis in view of its high spatial resolution. in our case, us has permitted to determine if the plane between the indurated inflammatory tissue and the buck’s fascia was preserved for the complete surgical excision of affected tissue. it is important for the surgeons to know if there is a clear space between the foreign body material and the buck’s fascia because the complete excision of the foreign body is not possible if the buck’s fascia is involved. in conclusion, according to the majority authors of the literature the definitive treatment for this malpractice is the complete radical excision to remove the foreign body. however, successful treatment of granuloma with oral corticosteroids has also been reported by some studies (6). the figures of surgical treatment are posted in supplementary materials on www.aiua.it figure 1. longitudinal (a) and transverse (b) ultrasound b-mode view of penile shaft show diffuse thickening of the subcutaneous tissue surround the buck’s fascia with increased echogenicity (white stars); corpora cavernosa (cc) and glans penis (g) were not involved. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology, university hospital “st.anna”. 8 a. moro street 44124 cona, ferrara, italy references 1. sukop a, heracek j, mestak o, et al. penis augmentation by application of silicone material: complications and surgical treatment. acta chir plast. 2013; 55:31-3. 2. shaeer o, shaeer k. delayed complications of gel injection for penile girth augmentation. j sex med. 2009; 6:2072-8. 3. silberstein j, downs t, goldstein i. penile injection with silicone: case report and review of the literature. j sex med. 2008; 5:2231-7. 4. inn fx, imran fh, ali mf, et al. penile augmentation with resultant foreign material granuloma and sequalae. malays j med sci. 2012; 19:81-3. 5. plaza t, lautenschlager s. penis swelling due to foreign body reaction after injection of silicone. j dtsch dermatol ges. 2010; 8:689-91. 6. lawrentschuk n, angus d, bolton dm. sclerosing lipogranuloma of the genitalia treated with corticosteroids. int urol nephrol. 2006; 38:97-9. dell'atti_stesura seveso 21/09/16 09:12 pagina 242 stesura seveso 325archivio italiano di urologia e andrologia 2014; 86, 4 original paper predictive value of resistive index in graft survival after kidney transplant saverio forte, pasquale martino, silvano palazzo, matteo matera, floriana giangrande, francesco paolo selvaggi, pasquale ditonno, michele battaglia urology, andrology and kidney transplantation unit, department of emergency and organ transplantation, university of bari, bari, italy. introduction: the intrarenal resistance index (ri) is a calculated parameter for the assessment of the status of the graft during the follow-up ultrasound of the transplanted kidney. currently it is still unclear the predictive value of ri, also in function of the time. materials and methods: we retrospectively investigated the correlation between the ri and the graft survival (gs) and the overall survival (os) after transplantation. we evaluated 268 patients transplanted between 2003 and 2011, the mean followup was 73 months (12-136). the ri was evaluated at 8 days, 6 months, 1 year and 3 years. the roc analysis was used to calculate the predictive value of ri and the kaplan mayer curves was used to evaluated the os and ps. results: the roc analysis, correlated to the gs, identified a value of ri equal to 0.75 as a cut-off. all patients was stratified according to the ri at 8 days (ri ≤ 0,75: 212 vs ri > 0.75: 56), at 6 months (ri ≤ 0.75: 237 vs ri > 0.75: 31), at 1 year (ri ≤ 0.75: 229 vs ri > 0.75: 39) and at 3 years (ri ≤ 0.75: 224 vs ri > 0.75: 44). the ri showed statistically significant differences between the two groups in favor of those who had an ri ≤ 0.75 only at 8 days and at 6 moths (p = 0.0078 and p = 0.02 to 8 days to 6 months) on the gs. on the contrary, we observed that the ri estimated at 1 year and 3 years has not correlated with the gs. the same ri cut-off was correlate with ps after transplantation. we observed that there are no correlations between the ri and os. conclusions: the ri proved to be a good prognostic factor on survival organ when it was evaluated in the first months of follow-up after transplantation. this parameter does not appear, however, correlate with os of the transplanted subject. key words: kidney transplant; doppler sonography; resistive index; graft survival; patient survival. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. is routinely used to evaluate renal allografts (3, 4). the ri is derived from the pulsatile flow-velocity waveform. the ri pourcelot is a semiquantitative parameter, it is calculated on the curve speed/time as the ratio (sd)/s, where s is the peak systolic velocity and d the peak diastolic velocity (5). previous cross-sectional study linked an increased intrarenal resistive index after kidney transplantation with an increased risk of graft loss or recipient death (6). the role of ri on the graft survival (gs) and overall survival (os) is still controversial, the ri appears to be related to the gs and os; but his real role in the follow-up the patient is still not clear. according to some recent studies the ri, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft (7-8). the purpose of this study was to analyze the impact of ri value on graft survival in relationship to the time of the doppler. material and methods we retrospectively investigated the correlation between the ri and the gs and the os after transplantation. we evaluated 268 patients transplanted between 2003 and 2011, the mean follow-up was 73 months (12-136). the ri was evaluated at 8 days, 6 months, 1 year and 3 years. the roc analysis was used to calculate the predictive value of ri and the kaplan mayer curves was used to evaluated the os and ps. the ri were measured by duplex ultrasound, the doppler spectra were obtained from the segmental arteries at three different location and the values were obtained from the mean of the three different location. the ri were measured at 8 days, 6 months, 1 year and 3 years after kidney transplantation. the donor variables collected from the database were: age, body mass index (bmi), serum creatinine levels, clearance at the time of death and biopsy by the remuzzi-karpinsky score. recipient variables were: age, bmi, time on dialysis, cold ischemia time, delayed renal function incidence, hospitalization, incidence of acute graft rejection, gs and os. the roc analysis, correlated to the gs, was used to doi: 10.4081/aiua.2014.4.325 presented at 19th national congress sieun, fermo 2014 introduction kidney transplantation (ktx) is the optimal method of treatment in patients with end-stage kidney disease since the 1960s, and it has good outcomes in terms of morbidity, mortality and quality of life (1, 2). in many renaltransplantation centers, measurement of the intrarenal resistive index (ri) by means of doppler ultrasonography archivio italiano di urologia e andrologia 2014; 86, 4 s. forte, p. martino, s. palazzo, m. matera, f. giangrande, f.p. selvaggi, p. ditonno, m. battaglia 326 identify the ri cut-off, the gs and os were calculated by kaplan mayer analyses. the lang-rank test was used to compare survival curves; p < 0,05 was considered statistically significant. statistical analyses were performed by medcalc software. results in our transplant center, 268 kidney transplant from cadaveric donors were performed. mean follow-up time of 73 months (ci 12-136). table 1 shows the main characteristics of donor and recipients according to ri groups. the roc analyze was used to identify the ri cut-off. we correlated the value of ri at 8 days, 6 months, 1 year and 3 years after kidney transplantation correlated to the gs. the area under the curve (auc = 0,647) was better when the ri was calculated at 8 days. the cut-off identified was 0,75 with better relationship between sensitivity and specificity (sensitivity: 49%, specificity: 82%, p = 0,0014) (figure 1). this value was used as cut-off; thus all patients was stratified according to the ri at 8 days (ri ≤ 0,75: 212 vs ri > 0.75: 56), at 6 months (ri ≤ 0,75: 237 groups ri at 8 days groups ri at 6 months donors ri ≤ 0,75 ri > 0.75 p ri ≤ 0,75 ri > 0.75 p means age 44,7 ± 17,1 (13-77) 49,8 ± 15 (17-72) ns 44,9 ± 16,9 (13-77) 55,7 ± 13,4 (25-75) 0,001 karpinsky score 1,38 ± 1,47 (0-6) 2,1 ± 1,5 (0-5) 0,009 1,62 ± 1,58 (0-6) 2,15 ± 1,3 (0-4) ns mean cold ischemia 14,8 ± 5,2 (7-32) 15,8 ± 4,1 (8-24) ns 15,1 ± 4,9 (7-31) 19,1 ± 6,1 (12-32) 0,004 recipients mean age (years) 43,5 ± 10,6 (14-65) 49,5 ± 9,1 (25-62) < 0,001 44,8 ± 10,2 (14-64) 53,2 ± 7,5 (36-65) < 0,001 mean bmi (kg/m2) 23,7 ± 4,5 (17,3-37) 22,53 ± 3,9 (16,1-31,6) ns 23,4 ± 4,2 (17,3-37,2) 22,9 ± 4,5 (16,1-35) ns mean time of dyalisis 67,4 ± 54,8 (3-264) 101,5 ± 68,9 (3,4-339,6) < 0,001 72,2 ± 55,9 (3-267) 82,8 ± 70,7 (11-339) ns scr (mg/dl) at moment of ri 1,77 ± 0,70 (0,7 4,0) 2,5 ± 1,17 (0,9-5,7) < 0,001 1,60 ± 0,50 (0,8-3,5) 1,78 ± 0,52 (0,9-3) ns table 1. diagnostic findings of cases series. figure 1. the roc analyze identified as cut-off 0,75 with better relationship between the sensitivity and specificity (auc = 0,647). figure 2. the kaplan-mayer estimates graft survival correlated to ri at 8 days (p = 0.0078). figure 3. the kaplan-mayer estimates graft survival correlated to ri at 6 months (p = 0.02). 6. radermacher j, mengel m, ellis s, et al. the renal arterial resistance index and renal allograft survival. n eng j med. 2003; 349:115-124. 7. impedovo sv, martino p, palazzo s, et al. value of the resistive index in patient and graft survival after kidney transplant. arch ital urol androl. 2012; 84:279-282. 8. naesens m, heylen l, lerut e, et al. intrarenal resistive index after renal transplantation. 2013; 369:1797-1806. 9. kahraman s, genctoy g, cil b, et al. prediction of renal allograft function with early doppler ultrasonography. transplant proc. 2004; 36:1348-1351. 10. krumme b, grotz w, kirste g, et al. determinants of intrarenal doppler indices in stable renal allograft. j am soc nephrol. 1997; 8:813. 11. wang sm, lai mk, chueh sc, chen j. the utility of resistance index of distal interlobular areteries evaluating renal graft function. transplant proc. 2004; 36:2184-2185. 12. vallejos a, alperovich g, moreso f, et al. resistive index and chronic allograft nephropathy evaluated in protocol biopsies as predictors of graft outcome. nephrol dial transplant. 2005; 20:2511-2516. 13. saracino a, santarsia g, latorraca a, gaudiano v. early assessment of renal resistance index after transplant can help predict longterm renal function. nephrol dial transplant. 2006; 21:2916-2920. 14. kolonko a, chudek j, zejda je, wiecek a. impact of early kidney resistance index on kidney graft and patient survival during a 5-years follow-up. 2012; 27:1225-1231. 327archivio italiano di urologia e andrologia 2014; 86, 4 predictive value of resistive index in graft survival after kidney transplant vs ri > 0.75: 31), at 1 year (ri ≤ 0,75: 229 vs ri > 0.75: 39) and at 3 years (ri ≤ 0,75: 224 vs ri > 0.75: 44). kaplan-maier estimates of cumulative gs we significantly worse in patients who had an ri > 0.75, in correlation to the ri calculated at 8 days (figure 2) and 6 moths (figure 3) (p = 0.0078 and p = 0.02 to 8 days and to 6 months). when the population was stratified in correlation to ri calculation at 1 years and at 3 years, its values is not correlated to the gs. when we evaluated the os in relationship to the ri, we did not find any relationship. discussion after kidney transplantation, several complications may occur. for many years, research has been focused on non-invasive diagnostic techniques, that would be reliably predict the outcome of transplantation and graft function. doppler ultrasonography is a useful tool for early evaluation of the kidney vasculature and function (9). according to previous studies, clinical parameters associated with increased ri were older donor and recipient age and vascular compliance (10-13). kolonko et al. concluded that the high ri values measured in the very early post-transplant period predict worse kidney graft function and increased risk of allcause graft loss, and he said the ri is not completely independent from the adverse influence of delayed graft function (dgf) on the premature graft loss (14). other author concluded the same (7). naesens et al. confirmed that the ri, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft (8). we estimated that the ri has an importance when it is calculated in the early months after the transplantation. we identified a value of 0,75 as cut-off. the importance of ri is within 6 months, but it is correlated only with the gs but not with the os. conclusions the ri proved to be a good prognostic factor on survival organ when it was evaluated in the early months of followup after transplantation. this parameter does not appear, however, correlate with os of the transplanted subject. references 1. vollmer wm, wahl pw, blagg cr. survival with dialysis and transplantation in patients with end-stage renal disease. n eng j med. 1983; 308:1953-1958. 2. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999; 341:1725-1730, 3. danavotich gm, ed. handbook of kidney transplantation. 5th ed. philadelphia: lippincott wiliams & wilkins, 2000. 4. nankievell bj, kuypers dr. diagnosis and prevention of chronic kidney allograft loss. lancet. 2013; 378:1428-1437. 5. pourcelot l. velocimetrie ultrasonare doppler. seminare inserm. paris, france. edition inserm. 1974; 213-240. correspondence saverio forte, md saverio.forte@gmail.com pasquale martino, md martino@urologia.uniba.it silvano palazzo, md silvano.palazzo@alice.it matteo matera, md materamatteo@libero.it floriana giangrande, md giangrandefloriana@libero.it francesco paolo selvaggi, md selvaggi@urologia.uniba.it pasquale ditonno, md ditonno@urologia.uniba.it michele battaglia, md battaglia@urologia.uniba.it policlinico di bari, divisione urologia universitaria i piazza g. cesare 11 70124 bari, italy stesura seveso archivio italiano di urologia e andrologia 2016; 88, 174 no conflict of interest declared. doi: 10.4081/aiua.2016.1.74 reply to: clarification to provide further understanding of the conduct and design of tropic: a phase 3 trial of cabazitaxel versus mitoxantrone in patients with metastatic castration-resistant prostate cancer dear editors, thank you for bringing to our attention the letter from johann de bono, liji shen and oliver sartor concerning our article entitled “efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. a systematic review and meta-analysis” published in the archivio italiano di urologia e andrologia. we wish to thank johann de bono, liji shen and oliver sartor for their interest in our work and we are grateful to the editors for giving us the opportunity to respond to their comments and remarks. perletti and co-authors’ response (row 1): according to cochrane standards, risk of bias is “unclear” when the available information is insufficient to allow evaluation of the risk. the fact that dynamic allocation was instigated in few occasions in the tropic trial makes the risk of selection bias difficult to evaluate. in this respect, a tradeoff between balance and predictability is a constitutive component of dynamic allocation strategies. perletti and co-authors’ response (row 2): when the study protocol is not available together with the study article (protocols were provided as online supplementary material of the affirm and cou-aa-301 reports), or elsewhere in the internet, the evaluation of the risk of bias becomes more difficult and the level of uncertainty naturally increases. the risk of misinterpretation also increases when a journal sets a strict word count limit for the text of a trial report of considerable importance, and important information is presented in a very synthetic form. perletti and co-authors’ response (row 3): although quality of life data were not collected, pain was an important component of the composite pfs endpoint of tropic. pain is the typical endpoint that may be substantially biased when patients are unblinded to their treatment allocation. perletti and co-authors’ response (row 5): unclear risk of bias does not represent a negative evaluation of the quality of the evidence. simply, the assessors are waiving any evaluation of the risk of bias when full assessment is hampered by lack of information, ambiguity, or any other factor making it difficult to assign the score “low” or “high” to a specific item in the rob tool. according to the opinion of the rob evaluators, “the last date a patient is known to be alive” was not a detailed, unambiguous description of a censoring criterion. if death (with death mostly occurring a certain time after tumor, pain, or psa progression) were considered as progression time point, the risk of bias would have been rated as high. again, detailed information featured in an “open access” study protocol minimizes the margins of uncertainty in the evaluation of a manuscript. perletti and co-authors’ response (row 7): as specified above, an unclear risk of bias is not a negative evaluation of the quality of the evidence. the 25%/25% baseline prevalence of visceral disease is shown in table 1. the bahl et al. 2013 paper (ann oncol. 2013 sep; 24(9):2402-8) reports that for the updated > 2y os analysis baseline visceral disease was present in 15% and 19.4% patients in the cabazitaxel and mitoxantrone arms, respectively. the figures are too small to allow evaluation of the reasons for such (likely accidental) out-selection of patients with baseline visceral disease in the cabazitaxel arm. perletti and co-authors’ response (remark 1): we regret this omission. indeed, the time-to tumor progression is aligned with the rpfs definition, and the hazard ratio and confidence interval for this endpoint (0.61; 95% ci:0.49 to 0.76; p < 0.0001) could have been added to the plot in figure 3. no further assessment was however possible, as pooled analysis of rpfs was only performed for studies including anti-androgen agents versus placebo. perletti and co-authors’ response (remark 2, item 1): a comparison was not made nor attempted in that sentence, which was simply summarizing, at the beginning of the discussion section, the available evidence in terms of overall survival. to make clear that comparisons between such absolute differences are not feasible, we stated at the very beginning of the discussion: “different baseline characteristics between studies (e.g., the prevalence of highly-prognostic visceral metastases or severe pain at enrollment) likely explain the inter-study variability of overall survival, especially as assessed in the control arms of each trial”. perletti and co-authors’ response (remark 2, item 2): that sentence had survival as subject. mitoxantrone has indeed antitumor activity, but no effect on survival. in the introduction section of their report, de bono and co-authors state that though mitoxantrone could be administered for its effects on the quality of life, at the time (year 2010) no intervention showed to increase survival in the post-docetaxel setting (de bono et al., lancet 2010; 376:1147-52). perletti letter ok_stesura seveso 08/04/16 11:34 pagina 74 75archivio italiano di urologia e andrologia 2016; 88, 1 reply to the letter to the editors references 1. de bono js, oudard s, ozguroglu m, et al. prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. lancet. 2010; 376:1147-54. 2. bahl a, oudard s, tombal b, et al. impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the tropic trial. ann oncol. 2013; 24:2402-8. 3. therasse p, arbuck sg, eisenhauer ea, et al. new guidelines to evaluate the response to treatment in solid tumors. european organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of canada. j natl cancer inst. 2000; 92:205-16. gianpaolo perletti department of biotechnology and life sciences, section of medical and surgical sciences, università degli studi dell’insubria, busto a., varese, italy department of basic medical sciences, ghent university, ghent, belgium correspondence gianpaolo perletti, phd gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences università degli studi dell’insubria via a. da giussano, 10 21052 busto arsizio, italy perletti letter ok_stesura seveso 08/04/16 11:34 pagina 75 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4328 original paper quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia giuseppe albino 1, ciro michele niro 2, cristina muscarella 3 1 department of urology asl bat, andria, italy; 2 siicp (società italiana interdisciplinare per le cure primarie) course coordinator of specific training in general medicine of puglia region, foggia, italy; 3 course of specific training in general practice, doctors order of foggia, italy. introduction: less than 40% of men with luts consult their doctor. patients consider the luts as physiological and are resigned to endure them. it is necessary to foster awareness of the micturition disorders, to monitor their development and to assess the effectiveness of therapies. at present the only validated test is the ipss-q8, but in italy it is used by only 4% of general practitioners (gps). because the ipss is complex and not easy to handle, we need a more simple test but nevertheless efficient. the italian society of urology (siu) and the italian society for interdisciplinary primary care (siicp) presented the "quick prostate test" (qpt) in november 2012. we aimed to evaluate the efficiency of qpt versus the ipssq8 and its suitability in primary care. materials and methods: the qpt is composed of 3 questions to be answered "yes" or "no." the answer "yes" just to one question makes "positive" the test. we enrolled 64 men, ≥ 50 years old, suffering from bph, extracted from the database of five gps. the patients were randomized into two arms: to the arm 1 only qpt was administered, to verify efficiency of the test; to the arm 2 both the qpt that the ipss-q8 were administered. results: into the arm 1, the 96.4% has tested positive for qpt. into the arm 2, the 89% of patients with one or two positive responses to the qpt showed a moderate ipssq8 score; the 75% of the patients with three positive responses to the qpt had a serious ipss-q8 score. the gps (80%) have expressed the highest level of satisfaction for the qpt for the "time of administration" and for the "simplicity" of the test. conclusions: the experience with the qpt has shown that the test is efficient and suitable in the primary care setting. we want to encourage the gps to use the qpt for the monitoring of patients with lower urinary tract symptoms (luts) and to contribute to the validation of the test. key words: benign prostatic hyperplasia; lower urinary tract symptoms; international prostate symptom score. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction the benign prostatic hyperplasia (bph) is a chronic disease characterized by prostate alterations resulting in the lower urinary tract symptoms (luts), related to the phases of filling, emptying of the bladder and to the postvoiding period, that interfere with quality of life of male subjects (1). in clinical practice, only 30-40% of patients with overt bph starts a diagnostic and therapeutic program, for a moderate-severe symptomatology, and about half of these for the appearance of more or less serious complications (infections, urinary retention). the 60% of men with bph, for the slow onset of symptoms, lives together with them, thus favoring the deterioration of the bladder. they will contact their physicians when the detrusor alterations will be irreversible. as these aren’t disorders that endanger life, bph and luts are likely to be underestimated, regarded as disorders inexorably associated with aging. in fact they represent a real socio-economic problem because have an impact both on the quality of life of patients and on the health system that supports the costs of these disorders, characterized by their high prevalence and progression over time (1-3). the progression of bph is not identifiable only by an increase in the gland volume but also by a worsening of the uroflowmetry, of the clinical symptomatology and, consequently, of the quality of life (4, 5). the symptoms related to bph can be divided into three groups (1): • symptoms of bladder emptying phase: starting hesitancy, intermittency, weak urinary stream, use of abdominal pressure, spraying or bifid urinary stream, terminal drip; • symptoms of bladder filling phase: urgency, frequent urination, nocturia, urge incontinence, altered bladder sensation; • symptoms of post micturition phase: feeling of failure to empty the bladder, post-voiding dribbling. the perception of his urinary disorders is fundamentally subjective. for their assessment, we need simple, easily repeatable and validated tools (reliable and reproducible), in order to quantify the severity of luts, their doi: 10.4081/aiua.2014.4.328 presented at 19th national congress sieun, fermo 2014 albino2_stesura seveso 15/01/15 12:05 pagina 328 329archivio italiano di urologia e andrologia 2014; 86, 4 quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia finally, the ipss includes an eighth question, which quantifies the quality of life in relation to own urinary condition at the time and must not be added to the scores of the previous seven questions. quick prostate test (qpt) the qpt test consists of 3 questions that the patient must answer "yes" or "not". it is a quick and simple test that can help to optimize the management of the health status of the patient with bph, facilitating doctor-patient dialogue in the first visit and on subsequent visits for follow-up. it allows you to monitor the well-being of patients with bph with or without ongoing treatments. it consists of three questions related to luts, but it is not associated with a rating/score. the composition of the test takes into account the following aspects: it evaluates the most prevalent and troublesome symptoms; the severity of symptoms is proportional to the discomfort; the severity of the symptoms and discomfort is proportional to the risk of progression. two questions investigate irritative or "filling" symptoms, one question investigates the obstructive or "emptying" symptoms, for a total of only three questions (table 1). the affirmative answer to one of the three questions indicates that the test is positive. study design the study lasted five months, from 1 may 2012 to 30 september 2012. in the first phase of recruitment we have obtained the lists of patients to be included in the study by extrapolating data from gps softwares and using the following search criteria (keywords): the diagnosis of bph or drugs used in the medical treatment of bph: α-blockers (alfuzosin, doxazosin, terazosin, tamsulosin, silodosin), or 5-α-reductase inhibitors (5ari) (dutasteride, finasteride). the inclusion criteria were: ≥ 50 years old men; bph diagnosed; therapy with α-blockers for at least a month and with inhibitors of 5-alpha reductase (5ari) for at least three months or in combined therapy. some of the extracted patients were invited to a phone interview for medical history and for each of them has been agreed on a date. other patients were subjected to the test in an "opportunistic" way: on the occasion of their visit to the general practitioner, that occurred for other reasons. patients were randomized into two arms: “the arm 1” has been subjected to administration of the interview only variation over time (also in relation to the various treatments) and the impact on quality of life. in this regard, the experts of the consensus conference on guidelines for the management of bph recommended "an increasing involvement of the general practitioner in the follow up of the patient in treatment for luts/bph, so that clinical monitoring of these patients is more consistent and effective" (1). the most used rating scale of the symptoms is the ipss (international prostate symptom score). the ipss is recommended as a tool to measure the symptoms, to be used for the initial assessment of their severity in men with luts. to perform the test you have to answer 7 questions, each corresponding to a score from 0 to 5. the score obtained by the sum of all seven questions allows you to categorize urinary disorders in 'absent', 'mild', 'moderate', 'severe'. the ipss finally provides an eighth question, which quantifies the quality of life (qol = q8) in relation to own urinary condition at the time and must not be added to the previous seven questions. despite "the symptom scores" in general, and the ipss-q8 in particular, are recommended they are rarely used in italy: only 3.5% of general practitioners uses the ipssq8 and in addition, because of the poor handling of the test only 15% of urologists uses it (2). given the complexity, the poor handling of the ipss questionnaire and the closer times of work in the primary care setting, the general practitioner needs for a "symptom questionnaire" to be easier administered than ipss, but at the same time efficient, both to put the suspected diagnosis and for the subsequent follow-up of patients with bph and during medical therapy. for this reason, in november 2012, jointly by the siu (italian society of urology) and by the siicp (italian society for interdisciplinary primary care) the "quick prostate test" (qpt) was presented as a quick and easy tool to put the suspicion of luts and to assess the development of the bph and the effectiveness of the therapies, appropriate to the setting and the time of the "basic medicine". waiting for cohort studies on large series are completed, since there is no data in the literature, we wanted to evaluate the efficiency of the qpt versus the ipss-q8, in the patient with luts/bph and during pharmacological treatment and its suitability in primary care. materials and methods ipss-q8 the international prostate symptom score (ipss) is recommended as a tool for measurement of the symptoms to be used for baseline assessment of their severity on men with luts (6, 7). the ipss also incorporates a question that assesses the overall impact of luts on the quality of life (qol = q8). to perform the test you have to answer 7 questions each corresponding to a score from 0 to 5. the sum of the scores of the seven questions allows you to classify urinary disorders in: • absent or mild urinary disorders if the sum is between 0 and 7 • moderate urinary disorders if the sum is between 8 and 19 • severe urinary disorders if the sum is between 20 and 35. table 1. quick prostate test: yes to one question indicates positive test. quick prostate test 1. in the last month, did you get up at least twice from bed by night to urinate (from when you go to sleep in the evening until you wake up in the morning? 2. in the last month, had you difficulties several times to delay the urination? 3. in the last month, had you ever the feeling of not to be able to completely empty your bladder? albino2_stesura seveso 15/01/15 12:05 pagina 329 archivio italiano di urologia e andrologia 2014; 86, 4 g. albino, c.m. niro, c. muscarella 330 with qpt, to verify efficiency of the test in relation to the ongoing therapy (α-blockers, 5ari, α-blockers + 5ari); “the arm 2” has been subjected to interview with administration of both the qpt and the ipss-q8 to evaluate efficiency of qpt compared to the validated test (ipss-q8). a total of 64 patients were interviewed. at 28 patients (arm 1) it was administered the qpt (quick prostate test) and at 25 patients (arm 2) they were administered both the qpt and the ipss-q8. age, pharmacological treatments, associated diseases and treatment for bph were recorded for each enrolled patient. at the end of the study, the general practitioners who participated in the data collection were invited to express their level of satisfaction after using the qpt taking into account two parameters: "time used for administration of the qpt" and "simplicity of the questions". a linear scale was made to assess the acceptance of the qpt by physician: it quantifies the level of satisfaction of each general practitioner (figure 1). the satisfaction level is represented on a line that brings numeric values from 0 to 5 in ascending order (useful to display the wedge drawn on the line that represents numeric values in increasing order). the zero indicates dissatisfaction while 5 indicates the maximum satisfaction and approval. results for administration of the test it was necessary a time varying from 5 to 20 minutes, with the variability associated with the type of questionnaire (time for qpt < time for ipss-q8). the choice to not participate to the study was made for the following reasons: patients no longer in therapy, which in most cases has been voluntarily suspended without inform their doctor; patients who had undergone prostate surgery (not reported in the software of general practitioners), and therefore not eligible in our study; lack of real willingness on the part of some physicians "for time problem"; patients who did not come to the appointment set. sixty-four patients were interviewed: 9 patients had discontinued therapy, and therefore the qpt had not been administered to them (group of patients excluded); 2 patients, despite having already undergone turp, were excluded from the study, but were also submitted to the qpt for follow-up after the surgery. the mean age of patients was 69 years. the prevalence of the most important comorbidities calculated on the total sample (64 patients) are: 62.5% hypertension; 21.87% diabetes mellitus; 12.5% dyslipidemia; 6.25% chronic obstructive pulmonary disease; 4.68% gastro-esophageal reflux; 4.68% arthrosis. the effectiveness and/or appropriateness of ongoing therapy has been evaluated on the 28 patients of qpt group. twenty-five patients in medical therapy for bph were submitted to both qpt and ipss (qpt-ipss group) with the aim to evaluate the efficacy of the ongoing therapy and to get results able to demonstrate the efficiency of the qpt, performing a comparison with its validated predecessor (ipss). results obtained in the “qpt-ipss group” (arm 2) are summarized in table 2. qpt 0 = all “negative to qpt” patients had a mild ipss score (< 8); qpt 1 = the majority of the patients with only one positive response to the qpt obtained a moderate ipss score (8-19); qpt 2 = the majority of the patients with two positive responses to the qpt obtained a moderate ipss score (815); qpt 3 = the majority of the patients with three positive responses to the qpt obtained a severe ipss score (> 19). the two patients who had undergone turp were both positive to qpt test, index of disease progression, and were sent to the attention of their general practitioners. four out of five gps expressed a level of satisfaction equal to 5 (highest level of satisfaction), and one expressed a level of satisfaction equal to 4. discussion the qpt has helped to assess the effectiveness and/or appropriateness of ongoing medical therapy for patients with bph. the use of qpt allows to analyze in a short time the prostatic symptoms in their main aspects. the arm 2 (patients underwent both qpt and ipss) revealed a close correlation between the positivity to the qpt and the increasing of the ipss score. from the comparison of the two tests it results that the majority of patients who got one or two affirmative answers to qpt had a medium ipss score, therefore between 8 and 19. a significant correlation has also emerged among patients who have given three affirmative answers to the qpt, in fact they have shown an ipps score between 20 and 35, expression of severe urinary disorders. these surprising data form the basis for the validation of the qpt and for the applicability as a more simple substitute for the ipss, test figure 1. level of satisfaction of the general practitioner displaying the qpt. dear colleague, on the basis of your level of satisfaction in the completion of the qpt-bph test, please cross a number from zero (lower level of satisfaction) to five (highest level of satisfaction), considering the parameters “time” and “simplicity” of application. qpt0 qpt1 qpt2 qpt3 ipss slight (1-7) xxx x x ipss moderate (8-19) xxxxxxxxxx xxxxxx x ipss severe (20-35) xxx table 2. level of satisfaction of the general practitioner displaying the qpt. albino2_stesura seveso 15/01/15 12:05 pagina 330 331archivio italiano di urologia e andrologia 2014; 86, 4 quick prostate test (qpt): motion for a tool for the active contribution of the general pratictioner to the diagnosis and follow up of benign prostatic hyperplasia that has not reached the so expected widespread diffusion due to the complexity of the eight questions and answers that compose it. from the data obtained by comparing the two tests you can think of the qpt as a suitable replacement for the ipss, perfect for the work of the general practitioner which is subject to the "time" factor. in fact it is evident as the time required for the administration of the two tests is very much in favor of qpt, simple test and easy to handle, which analyzes with only three questions the urinary problems associated with benign prostatic hyperplasia (2). furthermore, given its simplicity, the qpt could be conceived as a test of self-administration unlike the ipss, more specialised test, which requires the aid of a qualified personnel. data in the literature show that the ipss is used only by 3.5% of general practitioners and 15% of urologists. therefore the low level of use even among specialists demonstrates its poor practicality in terms of ease of administration and of time needed for administration. the study has also allowed us to make an assessment of the "satisfaction" of the 5 general practitioners who participated in the enrollment of patients, based on "time required" and "simplicity of the questions" of the qpt. eighty percent of the gps expressed a level of satisfaction equal to 5 (the highest level of satisfaction), and the remaining 20% expressed a satisfaction level of 4. these data show the suitability of the qpt, relatively to the time spent on administration and to the simplicity of the three questions that comprise it, in the general practice setting. the qpt can be an "opportunistic" test, that can evaluate the progress of the urinary disease during a normal office visit for reasons of other nature, and to assess from the outset the need for diagnostic procedures and/or of any adjustment in course of therapy. the general practitioner needs a tool that is fast in administration and efficient for the evaluation of patients with bph. by our study, although conducted on a small sample of patients (64), it was found that the quick prostate test could effectively replace the ipss for the monitoring of the patient with bph in the setting of general practice. in fact the experts of the consensus conference on guidelines for the management of bph recommend "an increasing involvement of the general practitioner in the follow up of the patient in treatment for luts/bph, so that the clinical surveillance of these patients is more constant and effective" (1). conclusions based on the data we collected in our experience with the qpt, despite the small number of patients enrolled in the study, we verified the possible efficiency of the test and the sure suitability for the setting of primary care, taking into account the simplicity and rapid time of administration. while we await trials on a much larger number of patients and therefore statistically validating, we want to encourage general practitioners to use the qpt in the setting of general practice to monitor the patient with luts, with the opportunity to contribute with the number of their patients in the validation of the test. references 1. spatafora s, casarico a, fandella a, et al. evidence-based guidelines for the treatment of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in italy: updated summary from auro.it. ther adv urol. 2012; 4:279-301 2. spatafora s, conti g, perachino m, et al. for the auro.it bph guidelines committee evidence-based guidelines for the management of lower urinary tract symptoms related to uncomplicated benign prostatic hyperplasia in italy: updated summary. curr med res opin. 2007; 23:1715-32. 3. van exel n, koopmanschap m, mcdonnell j, et al. for the triumph pan-european expert panel. medical consumption and costs during a one-year follow-up of patients with luts suggestive of bph in six european countries: report of the triumph study. eur urol. 2006; 49:92-102. 4. sciarra a, cistini c, gentilucci a, et al. ipertrofia prostatica benigna: una patologia in progressione. ipotesi per una terapia preventiva, urologia. 2006; 73:257-64. 5. emberton m, cornel e, bassi p, et al. benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. int j clin pract. 2008; 62:1076-86. 6. barry mj, fowler fj jr, o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549-57. 7. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trial. eur urol. 1997; 31:129-40. correspondence giuseppe albino, md, phd peppealbino@hotmail.com department of urology asl bat, andria, italy cristina muscarella, md, general practitioner cri.musca@libero.it medical doctor, foggia, italy ciro michele niro, md, general practitioner and urologist ciro.niro@alice.it siicp (società italiana interdisciplinare per le cure primarie) course coordinator of specific training in general medicine of puglia region, foggia, italy albino2_stesura seveso 15/01/15 12:05 pagina 331 stesura seveso 257archivio italiano di urologia e andrologia 2014; 86, 4 original paper urolithiasis in renal transplantation: diagnosis and management elisa cicerello, franco merlo, mario mangano, giandavide cova, luigi maccatrozzo unità complessa di urologia, ospedale ca’ foncello, treviso, italy obiectives: to report our experience of diagnosis and multimodal management of urolithiasis in renal transplantation. patients and methods: from january 1995 to december 2012, 953 patients underwent renal transplantation in the kidney transplant unit of treviso general hospital. ten (10%) of them developed urinary calculi and were referred at our institution. their mode of presentation, investigation and treatment were recorded. results: seven had renal and 3 ureteral calculi. urolithiasis was incidentally discovered on routine ultrasound in 6 patients, 1 presented with oliguria, 1 with anuria and acute renal failure and in 2 urolithiasis was found at removal of the ureteral stent. nephrostomy tube was placed in 5 patients. hypercalcemia with hyperparathyroidism (hpt) was present in 5 patients and hyperuricemia in 3. two patients were primary treated by shock wave lithotripsy (swl) and one of them was stone-free after two sessions. two patients, one with multiple pielocaliceal calculi and the other with staghorn calculus in the lower calyx, were treated with percutaneous nephrolitothotomy (pcnl). three patients were treated by ureteroscopy (urs) and in one of them two treatments were carried out. one patient had calculus impacted in the uretero-vesical anastomosis and surgical ureterolithotomy with re-do ureterocystoneostomy was performed after failure of urs. two patients with calculi discovered at removal of the ureteral stent were treated by urs. conclusions: the incidence of urolithiasis in renal transplantation is uncommon. in the most of patients the condition occurs without pain. metabolic anomalies and medical treatment after renal transplantation may cause stone formation. advancements in endourology and interventional radiology have influenced the management of urolithiasis that can be actually treated with a minimal incidence of risk for the renal allograft. key words: urolithiasis management, renal transplantation. submitted 15 march 2014; accepted 30 june 2014 summary no conflict of interest declared. in the most of cases stone formation appears to form “de novo” after renal transplantation, although some studies suggest that the calculi are more often transplanted with the graft to the recipient (1, 5, 6). theremore, metabolic anomalies causing stone formation could be present in allograft rather than native kidneys (7). urolithiasis is often asymptomatic and the clinicians are not able to diagnose urinary calculi in renal transplant at an earlier stage. neverthless, the prompt diagnosis and the subsequently stone removal is necessary to prevent adverse effects on a solitary kidney whose renal function is often borderline. today the development of endourological tecniques for calculi management and interventional radiology for the emergency management of acute obstruction have minimized the potential risk for renal graft. however, such minimally invasive procedures could be performed only in centers that are well equipped and have expertise to offer the appropriate treatment. we evaluated our experience of renal transplant patients with urolithiasis, regarding the risk factors associated with the condition and the management by endourological and open procedures. patients and methods from january 1995 to december 2012, 953 patiens underwent renal transplantation in the kidney transplant unit of treviso general hospital. the transplant were performed in the right or left iliac fossa with vascular anastomosis to the iliac artery and vein. ureteral implantation (ureterocistoneostomy) was performed using the extravesical tecnique of lich-gregoir, with routine use of ureteral catheter that was removed 4-6 weeks later by flexible cystoscopy. immunosoppression varied with the transplantation era. ten (10%) of them developed urinary calculi and referred to our institution. for the diagnosis of urolithiasis one or more of the following investigations were required: ultrasonography (us), plain abdominal x-ray, intravenous urography (ivp), nephrostography and computed tomography (ct). chemistry profile including serum analysis for urea, creatinine, calcium, phosphate, urate, sodium, potassium, phosphate, alkaline phosphatase and parathyroid hormon and urine analysis (routine and culture) were performed. management of doi: 10.4081/aiua.2014.4.257 introduction urolithiasis in renal transplantation is uncommon, with reported prevalence rates between 0.2% and 6.3% (1-4). cicerello_stesura seveso 15/01/15 12:58 pagina 257 archivio italiano di urologia e andrologia 2014; 86, 4 e. cicerello, f. merlo, m. mangano, g. cova, l. maccatrozzo 258 these calculi involved shock wave lithotripsy (swl), ureteroscopy (urs), percutaneous nephrolithotomy (pcnl) and ureterolithotomy with re-do ureterocistoneostomy. results six patients were females and 4 males. ages ranged from 31 to 59 years (mean 43 years). seven had renal and 3 ureteral calculi. the overall diameter range was 0.7-3 cm (mean 1.2 cm). urolithiasis was incidentally discovered on routine ultrasound in 6 patients with calculi located in the calices. one patient with multiple pielocaliceal calculi presented with oliguria and 1 with calculus impacted in the vesico-ureteral anastomosis with anuria and acute renal failure. in 2 patients urolithiasis was found at removal of the ureteral stent. nephrostomy tube was quickly placed in the following cases: calculi causing oliguria, anuria or hydronephrosis and in 2 patients with calculi discovered removing ureteral stent. hypercalcemia with hyperparathiroidism was present in 5 patients and hyperuricemia in 3. four patients had urinary tract infections (utis), in 3 infecting organism was e. coli and in 1 proteus mirabilis (table 1). two patients were primary treated by swl (lithostar plus siemens) in prone position and one of them with calculus in the upper calyx was stone free after two sessions, while in the other with calculus in the lower calyx urs was performed after failure of swl. two patients, one with multiple calculi and the other with staghorn in the lower calyx, were treated with pcnl. three patients were treated with ureteroscopy and in one of them two treatments were carried out. one patient had calculus impacted in the uretero-vesical anastomosis and ureterolithotomy with re-do ureterocistoneostomy was performed after the failure of urs (table 2). discussion urolithiasis in patients with kidney transplantation is often asymptomatic. a possible explanation for this observation is denervation of the transplanted graft (1, 2, 5, 8). in some cases, concomitant increase of serum creatinine should be considered with caution to avoid a misdiagnosis of episode of acute rejection (9). in our experience urolithiasis was incidentally discovered on routine ultrasound in one-half of them. the presence of uncomplicated calculus is not a contraindication to urological procedures. in fact, as it has previously been reported, calculus in the kidney transplantation, such as in patients with solitary kidney, must be removed in every case because it may cause urinary infection or pass in the ureter causing anuria with acute renal failure (10). previous studies have shown that swl is the treatment of choice for unobstructive calculi with diameter less than 1.5 cm (11). however, there are potential difficulties in locating transplant calculi because of the overlying bony pelvis which may limit visualization of stones on fluoroscopy as well mitigate the propagation of shock waves energy. prone position with ultrasound targeting may counter these disadvantages (12). an additional disadvantage of swl is the need for multiple sessions. challacombe et al. have reported stone free rate in 13 patients with kidney transplantation and urolithiasis who underwent swl, but in 8 of them multiple procedures were required. in our study two patients with asymptomatic calculi were primarily treated by swl and pts ex age clinics metabolic anomalies utis 1 f 31 oliguria hpt no 2 f 41 anuria hpt yes 3 m 45 renal us hyperuricemia yes 4 m 47 renal us no no 5 f 48 hydronephrosis hyperuricemia no 6 m 51 renal us no no 7 f 59 renal us hpt no 8 f 34 failure to remove dj hpt yes 9 f 42 failure to remove dj hpt yes 10 m 35 renal us hyperuricemia no table 1. characteristic of patients with renal transplantation and urolithiasis. diameter location nephrostomy swl urs pcn ureterolithotomy (cm) with re-do ureterocystoneostomy 1 3 pielocaliceal yes yes 2 1.3 ureteral-vesical anastomosis yes failure yes 3 0.8 lower calix no failure yes 4 0.7 upper calix no yes 5 1.2 upj yes yes 6 1.1 upper calix no yes 7 1.0 middle calix no yes 8 1.4 distal ureter yes yes 9 1.5 distal ureter yes yes 10 1.2 lower calix no yes table 2. characteristic of calculi and urologic treatments. cicerello_stesura seveso 15/01/15 12:58 pagina 258 only one of them was stone-free. in both cases not more than 2 treatments were performed and urs was carried out in 1 patient after failure of swl. actually urs is the treatment of choice emerging as for small renal and ureteral calculi within kidneys transplantation (13). access to these kidneys may be difficult because of their position in the pelvis and the location of the neo-ureteric orifice. using both retrograde and anterograde approaches, stone-free rate of the calculi in kidney transplantion could be obtained with minor complications. we used both approaches in those patients with nephrostomy tube placed because urinary tract obstruction and after failure to remove ureteral stent, while in the other cases only a retrograde approach was performed. however, as endoscopes have become increasingly miniaturized and deflectable, ureteral dilation has become unnecessary and all urinary collecting system can be accessed in a straightforward manner. in our experience semirigid retrograde urs was performed over a decade ago and the access to the ureter was facilitated with angled catheters and hydrophilic wires and ureteral orifice was balloon dilated with a high-pressure balloon dilator. nowday, urs has carried out by flexible ureteroscopy. this method and disintegration of calculi with holmium laser is an effective method for the treatment of urolithiasis in kidney transplantion and the access to the neoureteric orifice and to the pelvis may be achieved by introducing the ureteroscope over a guide wire. instruments with “active” secondary deflection are particularly useful in reaching calculi in transplanted kidney. in our experience, according to hymas et al., we could suggest that urs is a viable treatment modality as well. for renal calculi with diameter greater then 1.5 cm, pcnl has been effective to remove all stone fragments in one procedure. the superficial position of transplanted kidney makes straightforward percutaneous procedure so that may be justified by maximal stone clearance and carried out in special centers because of the greater risk in patients with solitary kidney (14). in fact, due to the proximity of the bowels to the renal graft, the risk of perforation is high. furthemore, there have been reports of allograft renal artery injury and arteriovenous fistulae after trans abdominal access. theremore, tract dilatation can become difficult to perform because of the presence of a fibrous sheath and limited mobility of the kidney during rigid nephroscopy (15). in our experience percutaneous nephrolithotomy was only carried out in two patients, one with staghorn calculus located in the lower calyx and the other with multiple pielocaliceal calculi. previous reports have reported that calculi occurring in transplanted kidney are composed of calcium oxalate and calcium phosphate (5, 7). infected stone consisting of struvite or mixed form of struvite and calcium phosphate are also relatively common (4, 16). lithogenic factors include hyperparathyroidsm, hypercalciuria, hypocitraturia, hyperuricosuria, chronic urinary tract infection (utis), urinary stasis, incrusted double j stent and nidus such as nonabsorbable suture (7). hyperparathyroidism has been reported the most important factor in calculus formation in kidney transplantion (16, 17). medical treatments, such as cinecalcet hydrochloride, have been shown to be efficacious in treating hyperparathyroidism by soppression of the action of parathyroid hormone. however, if the hyperparathiroidism persist after 1 or 2 years, a parathyroidectomy must be carried out (2). furthemore, immunosoppressive agents may have a contributory role in the cause of calculi in transplant. ciclosporin, a calcineurin inhibitor used more commonly in the past, is associated with hypeuricemia (18). however, this has not been necessarily associated to an an increase in uric acid calculi risk (16, 19). ciclosporin has been superseded by tacrolimus, another calcineurin inhibitor which has not been shown to affect uric acid levels (20). stapenhorst et al. have reported that calcineurin inhibitor, treatment can lead to hypocitraturia, whereas hyperoxaluria can be primarily the result of a removal of significant body oxalate stores deposited during the dialysis (21). these authors have suggested to treat these patients with alkaline citrate to increase their urinary citrate excretion and urinary solubility index decreasing the risk for calculi formation. in our experience hyperparathiroidism was present in 5 patients and hyperuricemia in 3, but complete metabolic assessment was not carried out in all patients. however, it has been reported that low urinary excretion of citrate could also due to chronic urinary infections (22), that can be present in patients with renal transplantation (incrusted ureteric stents, retention of suture materials, immunosopression agents). consequently, if urinary infection is present, antibiotic prophilaxis could be associated to specific therapies for underlying metabolic anomalies present in patients with renal transplantation and urolithiasis. conclusions the incidence of urolithiasis in renal transplantation is low. in our experience hyperparathyroidism is the most frequent cause of stone formation. urs for its safety and effectiveness could be the treatment of choice of urolithiasis in renal transplantation. open surgery could be carried out after failure of endourological procedures in selected cases. references 1.shoskes da, hanbury d, cranston d, morris pj. urological complications in 1,000 consecutive renal transplantation recipients. j urol. 1995; 153:18-21. 2. benoit g, blanchet p, eschwege p, et al. occurrence and treatment of kidney graft lithiasis in a series of 1500 patients. clin transplant. 1996; 10:176-180. 3. crook tj, keoghane sr. renal transplant lithiasis: rare but timeconsuming. bju int. 2005; 95:931-933. 4. khositseth s, gillingham kj, cook me, chavers bm. urolithiasis after kidney transplantation in pediatric recipients: a single center report. transplantation. 2004; 78:1319-1323. 5. klinger hc, kramer g, lodde m, marberger m. urolithiasis in allograft kidneys. urology. 2002; 59:344-348. 6. lu hf, shekarriz b, stoller ml. donor gifted allograft urolithiasis: early percutaneous management. urology. 2002; 59:25-27. 259archivio italiano di urologia e andrologia 2014; 86, 4 urolithiasis in renal transplantation: diagnosis and management cicerello_stesura seveso 15/01/15 12:58 pagina 259 archivio italiano di urologia e andrologia 2014; 86, 4 e. cicerello, f. merlo, m. mangano, g. cova, l. maccatrozzo 260 7 harper jm, samuell ct, halllson pc, et al. risk factors for calculus formation in patients with renal transplants. br j urol. 1994; 74:147-150. 8. lancina-martin ja, garcia-buitron jm, diaz-bermudez j. urinary lithiasis in transplanted kidney. arch esp urol. 1997; 50:141-150. 9. rhee bk, breatan pn jr, stooler ml. urolithiasis in renal and combined pancreas renal/transplant recipients. j urol. 1999; 161:14581462. 10. cicerello e, merlo f, maccatrozzo l. management of residual fragments after swl. arch ital urol. 2008, 80:34-38. 11. montanari e, zanetti g. management of urolithiasis in renal transplantation. arch ital urol. 2009; 81:175-181. 12. challacome b, dasgupta p, tiptaft r, et al. multimodal management of urolithiasis in renal transplantation. bju int. 2005; 96:385-389. 13. hymas e, marien t, bruhn a, et al. ureteroscopy for transplant lithiasis. j endourol. 2012; 26:819-822. 14. krambeck ae, leroy aj, patterson de, gettman mt: percutaneous nephrolithotomy success in the transplant kidney. j urol. 2008; 180:2545-2549. 15. francesca f, felipetto m, mosca f, et al. percutaneous nephrolithotomy of transpanted kidney. j endourol. 2002; 16:225-227. 16. kim h, cheigh js, ham jw. urinary stones foolowing renal transplantation. korean j intern med. 2011; 16:118-122. 17. stravodimos kg, adamis s, tyritzis s, et al. renal transplant lithiasis: analysis of our series and review of literature. j endourol. 2012; 26:38-44. 18. noordzij tc, leunissen km,van hooff jp. renal handling of urate and the incidence of gouty arthritis during cyclosporine and diuretic use. transplantation 1991; 52:64-67. 19. numakura k, satoh s, tsuchiya n, et al. hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. transplantation. 2012; 94:145-171. 20. malheiro j, almeida m, fonseca i, et al. hyperuricemia in adult renal allograft recipients: prevalence and predictors. transplant proc. 2012; 44:2369-72. 21.stapenhorst l, sassen r, beck b, et al. hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. pediatr nephrol 2005; 20:652-656. 22.cicerello e, merlo f, fandella a, maccatrozzo l. metabolic evaluation of infected urolithiasis. eur urol. suppl 2009; 8:2005. correspondence elisa cicerello, md elisa.cicerello@tin.it franco merlo, md f.merlo@ulss.tv.it mario mangano, md m.mangano@ulss.tv.it giandavide cova, md gd.cova@ulss.tv.it luigi maccatrozzo, md l.maccatrozzo@ulss.tv.it unità complessa di urologia, ospedale cà foncello piazza ospedale 31100 treviso, italy cicerello_stesura seveso 15/01/15 12:58 pagina 260 stesura seveso 383archivio italiano di urologia e andrologia 2014; 86, 4 case report enterovesical fistula and acute pyelonephritis in renal transplantation. role of ultrasound antonio de pascalis, alessandro d’amelio nephrology and dialysis unit, v fazzi hospital, lecce, italy. the enterovesical fistula is a communication between the urinary tract and the colon and is a rare complication of various inflammatory and cancer diseases. the most frequent cause is represented by diverticulitis of the sigmoid colon and less frequently from crohn's disease, tumors of the colon and bladder, trauma, radiation therapy and appendicitis. in this report we describe the occurrence of an enterovesical fistula in a patient with renal allograft from a cadaveric donor, which onsetted with signs of acute pyelonephritis and pneumaturia due to diverticulitis of the sigmoid colon, clinically silent. the ultrasound in the diagnosis of enterovesical fistula, yet with a minor role compared to computed tomography (ct), is fundamental being always the first level examination. key words: fistula; bladder; pyelonephritis. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. the presence of a fistula between the sigmoid colon and the left side wall of the bladder, associated with numerous diverticula of the colon (figure 2). after starting antibiotic therapy with ciprofloxacin and teicoplanin we assisted to a dramatic improvement of the clinical picture. subsequentely patient underwent surgical sigmoidectomy and bladder repair. discussion enterovesical fistulas account for over 80% of fistulas between digestive and urinary tract and, the most frequent between the bladder and sigmoid colon. diverticulitis of the colon is the most frequent cause of fistula with the bladder, followed by crohn's disease and colon cancers (1). in the case reported the patient had complicated diverticulitis of the colon, with a very few symptoms (the patient reported only alternating diarrhea and constipation) evidently because of steroid therapy. however, the clinical picture dominating the majority of patients with enterovesical fistula, as reported in the literature and as moreover observed in our case, are the urinary symptoms (fever, dysuria, or even pneumaturia and fecaluria) (2). the occurrence of pneumaturia is a highly specific sign of a communication between the intestine and bladder, reported in 60-85% of cases described in the literature (3). in the literature there are few reports about the ultrasound scan for pneumaturia and then about the diagnosis of enterovescical fistula by ultrasound examination. the typical signs described are: the presence of the socalled echogenic beak, i.e. an area of hyperechoic beak, between the bladder and adjacent bowel, without solution of continuity; the passage of air and echogenic material in the urine, after the abdominal compression; the presence of irregular hyperechoic foci with shadow cone back (4). the most sensitive and specific test is, of course, ct which allows you to directly highlight the presence of the fistula, the cause that generated it and its associated complications (5). less sensitive and specific and therefore not indicated, is the intravenous urography. cystoscopy is obviously highly sensitive and specific and is often performed as an examination of the level before the ct in suspected enteric fistula with bladder. doi: 10.4081/aiua.2014.4.383 presented at 19th national congress sieun, fermo 2014 case report a 64 years old male, with a kidney transplantation from cadaveric donor for about 5 years and treated with prednisone, tacrolimus and mycophenolate, presented to the emergency room with signs and symptoms suggestive of urinary sepsis (fever, hypotension, dysuria, pain in the right iliac fossa, where the graft was allocated). laboratory tests showed: mild worsening of renal function (creatinine 2.4 mg/dl), neutrophilic leukocytosis (gb 14.440/ml with 91% neutrophils), elevated inflammatory markers (esr 120, crp 153 mg/dl, procalcitonin 5 mg/l), urine examination revealed leukocyturia, hematuria, bacteriuria. the patient reported that he had noticed at home the issue of foamy urine. an ultrasound of the kidney and urinary tract showed a transplanted kidney of globular shape with multiple hypoechoic areas suggestive for hydroureteronephrosis grade ii, presence of intrapyelic hyperechogenic material and a diffusely thickened bladder (figure 1); color doppler evaluation showed an increased intraparenchymal doppler ri (0.84). we therefore decided to perform a computed tomography (ct) scan which confirmed the signs of acute pyelonephritis of the graft, showing also the presence of hydro-air level and archivio italiano di urologia e andrologia 2014; 86, 4 a. de pascalis, a. d’amelio 384 in conclusion, we reported a case, one of the few in the literature, of enterovesical fistula secondary to diverticulitis of the colon in a kidney transplanted patient. concomitant immunosuppressive therapy and steroids in particular, has probably masked the clinical picture until the onset of acute graft pyelonephritis. the ultrasound in the diagnosis of enterovesical fistula, yet with a minor role compared to ct, is fundamental being always the first level examination because of its non-invasiveness, repeatability and low cost, and it can provide guidelines that address the diagnosis. bibliography 1. krco mj, jacobs sc, malangoni ma, lawson rk. colovescical fistulas. urology. 1984; 23:340-342. 2. vesallane´s j, llado carbonell c, valverde sintas j, bielsa gali o. fistulas vesico-sigmoideas. arch espurol. 1991; 44:1133-1138. 3. kirsh gm, hampel n, shuck jm, resnick mi. diagnosis and management of vesicoenteric fistulas. surg gynecol obstet. 1991; 173:91-97. 4. long ma, boultbee je. case report: the transabdominal ultrasound appearances of a colovesical fistula. br j radiol. 1993; 66:465-467. 5. jarrett tw, vaughan ed. accuracy of computerized tomography in the diagnosis of colovesical fistula secondary to diverticular disease. j urol. 1995; 153:44-46. figure 1. us. hyperechoic material in pelvis with acoustic shadowing and thickened ureteral wall. figure 2. ct. air-urine level in the bladder. correspondence antonio de pascalis, md (corresponding author) depascalis.a@libero.it alessandro d’amelio, md nephrology and dialysis unit, v fazzi hospital piazza muratore 1 73100 lecce, italy stesura seveso 241archivio italiano di urologia e andrologia 2014; 86, 4 original paper robotic simple prostatectomy: a consideration for large prostate adenomas joshua b. nething 1, daniel j. ricchiuti 2, rhys irvine 1, david drevna 1 1 northeastern ohio medical university department of urology, akron, ohio; 2 st. elizabeth health center, division of urology, youngstown, ohio. background: the management of benign prostatic hyperplasia (bph) has changed considerably over the last several decades. first line treatment of bph and lower urinary tract symptoms (luts) with medical therapy has created a population of men with much larger prostate glands, many of whom require surgical intervention. patients with prostate glands greater than 80 to 100 grams may be better managed surgically with a retropubic prostatectomy. we explore our experience with robotic assisted simple prostatectomy and review the relevant literature. database: the database reviewed includes our experience with seven patients undergoing robotic simple prostatectomy, and a comprehensive review of the previously published series of this procedure. in addition, the literature pertaining to a pure laparoscopic approach to simple prostatectomy is reviewed. conclusion: robotic experience and training has become a standard in resident training programs; while classic transurethral resection is being performed less for large prostate glands. the robotic approach to simple prostatectomy provides an excellent option for surgical treatment of very large prostate glands, providing patients acceptable results in terms of operative time, estimated blood loss, hospital stay and duration of foley catheter. key words: robotics; prostatectomy; prostatic hyperplasia; laparoscopy; transurethral resection of prostate; adenoma. submitted 5 may 2014; accepted 31 may 2014 summary no conflict of interest declared. have gradually decreased from 229.2 to 268.3 per 100,000 men in 1980 through 1991 to 131.3 per 100,000 in 1994. in 2005 turp represented 39% of bph procedures compared with 81% in 1999 (4). as a result, graduating urologists leaving residency training have performed fewer electrosurgical turps and the complication rate requiring a second procedure has increased (5). this lack of experience is exaggerated in very large glands as the potential for complications is expected to be higher. while urologists who trained in the “golden age” of turp are often confident approaching the largest adenomas transurethrally, less experience has led to reluctance to do so by younger urologists. with the rapid increase in popularity of robotic surgical techniques, recent graduates are often more familiar with this minimally invasive technique to surgery. we present seven patients who underwent robotic assisted laparoscopic simple prostatectomy and a review of the contemporary literature on this subject. patients and methods our experience consists of seven patients, all of which had failed multimodal medical treatment, with persistent bothersome luts leading to subsequent surgical intervention. each patient underwent a successful robotic assisted laparoscopic simple prostatectomy without open conversion. the data that was collected through the course of our research is presented in table 1. post-operative pathologic diagnosis on all specimens was prostatic hyperplasia. the foley catheter was removed on the above-mentioned days (table 1) after a cystogram was negative for leak. with an average follow-up time of 10 months, all patients were doing well with no noted longterm complications. no patients required further catheterization and all report overall improvement in their luts. a detailed report of the operative technique is described elsewhere in the literature (6). briefly the key operative steps in this approach include dropping the bladder from the anterior abdominal fascia to enter the space of retzius, then entering the bladder using a transverse incision 1 cm proximal to the bladder neck. a circumferential incision is made through the bladder mucosa and a plane is developed between prostate and capsule with combination of doi: 10.4081/aiua.2014.4.241 introduction in the united states, more than $4 billion is spent annually on the medical management (1) of benign prostatic hyperplasia (bph) and more than $2 billion on the surgical management (2). electrosurgical transurethral resection of the prostate (turp) is the “gold-standard” for surgical treatment of bph, growing in popularity since it was first described in 1911 by hugh young (3). the introduction of medications, the development for various lasers, the bipolar button and other novel technologies have all further decreased the number of turps being performed (4). the number of turps being performed nething_stesura seveso 15/01/15 12:52 pagina 241 archivio italiano di urologia e andrologia 2014; 86, 4 j.b. nething, d.j. ricchiuti, r. irvine, d. drevna 242 blunt dissection and electrocautery. the prostate is than removed piecemeal at times and larger portions are morselated or removed using a reusable tissue retrieval bag. the mucosa of the bladder neck is tacked to the prostatic fossa using 2-0 vicryl, and the bladder closed in 2 layers ensuring it is watertight. discussion the 2003 aua guidelines recognize transurethral resection of prostate (turp) as the benchmark for therapy of bph as it permits a high success rate in symptom scores, urinary flow, post void residual and low retreatment rate on long term follow up (7). this is a statement that the revised 2010 guidelines avoid making, further highlighting the decreased favorability of turp. multiple complications can be observed with turp, including perioperative bleeding requiring blood transfusions, transurethral resection syndrome, prolonged catheterization, long hospital stay, urinary incontinence and retrograde ejaculation (4). these drawbacks obviate the need for alternative treatment modalities, particularly with larger adenoma size, where the technical challenge and complication rate are magnified. for patients with very large glands, typically defined as greater than 80 to 100 ml, management options often include open simple prostatectomy (8). open prostatectomy accounts for 14-32% of the total invasive procedures for bph in europe, and as many as 68% in some developing countries (9). traditional approaches for this procedure have been through an open incision, using a retropubic, suprapubic or perineal approach. simple prostatectomy may be more effective than turp at relieving obstruction of urinary flow, however it is usually associated with a larger blood loss, increased pain and longer hospital stay (8). in an effort to reduce these sequelae, laparoscopic and robotic approaches to this procedure have been explored. the initial reported case of laparoscopic simple prostatectomy was in 2002 by mariano et al. (10). the procedure was preformed in 225 minutes with an ebl of 800 ml and the patient was discharge home in four days. mariano recently published his six year data, reviewing 60 patients, and demonstrated shorter hospital stay (3.46 days ± 0.89), lower intraoperative blood loss (330.98 ml ± 149.52) and more rapid removal of urinary catheter (4.6 days ± 1.2) (11). similar results have been published by several other authors, validating laparoscopic simple prostatectomy. zhou et al. (12) used an extraperitoneal approach to laparoscopic adenomectomy. in their series of 45 patients, average surgical time was 105.4 ± 26.5 minutes, ebl was 360.1 ± 165.4 ml, and average adenoma resected was 78.2 ± 16.3 grams. patients required a catheter for an average of 4.6 days and hospital stays of 4.6 days. yun et al. (13) published series of 11 patients undergoing laparoscopic retropubic simple prostatectomy and found an average or time of 191.9 minutes, mean ebl of 390.9 ml, and resected adenoma weight of 72.4 grams. the foley catheter remained indwelling for 5.6 days and postoperative hospitalization was 6.5 days. baumert et al. (14) compared their data 30 consecutive laparoscopic simple prostatectomies to 30 open prostatectomies. the results showed laparoscopic simple prostatectomy is associated with lower blood loss (367 ml vs. 643 ml), a shorter postoperative catheterization (4 days vs 6.8 days) and shorter hospital stay at the expense of a longer operative time (115 mins vs 54 mins). since this time, the approach has been studied by several other authors (15-18) and been shown to provide patients with a feasible alternative with acceptable symptom relief, and importantly reduced ebl. despite these series showing favorable outcomes (table 1), this technique is still not widely utilized due to its complexity. robotic surgery provides a more favorable learning curve (19) and provides surgeons with a speed and dexterity advantage over even expert laparoscopists (20). series avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size (mins) (days) (days) (grams) (grams) patient 1 188 min 100 ml 7 days 2 days 187.04 g. 111 g. patient 2 175 min 1200 ml 7 days 2 days 94.39 g. 125 g. patient 3 135 min 300 ml 9 days 2 days 70 g. 71 g. patient 4 225 min 200 ml 7 days 2 days 144 g. 56 g. patient 5 213 min 400 ml 7 days 2 days 169 g. 86 g. patient 6 245 min 50 ml 12 days 7 days 200 g. 123 g. patient 7 242 min 1400 ml 9 days 1 days 150 g. 102 g. averages 204.7 min 521.4 ml 8.28 days 2.57 days 144.9 g. 96.3 g. table 1. data of patients. series # pts. avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size path (mins) (days) (days) (grams) (grams) van velthoven, 2004 18 145 192 3 5.9 95.1 47.6 mariano, 2005 60 138.48 330.98 4.6 3.46 144.5 131 sotelo, 2005 17 156 516 6.3 2 93 72 baumert, 2006 30 115 367 4 5.1 121.8 77.2 zhou, 2008 45 105.4 360.1 4.6 6.3 85.4 78.2 yun, 2010 11 191.9 390.9 5.6 6.5 109.3 72.4 castillo, 2011 59 123 415 4.2 3.5 108.5 95.2 table 2. published series for laparoscopic simple prostatectomy. nething_stesura seveso 15/01/15 12:52 pagina 242 sotelo et al. (2008) (7) was the first to report their series of seven patients with robotic simple prostatectomy. he reported an ebl of 298 ml, average operative time of 205 minutes, average hospital stay of 1.4 days and foley duration of 7 days. when comparing their findings to their previously reported series on laparoscopic simple prostatectomy, they concluded that robotics approach allows for greater precision and visualization with similar cost analysis (laparoscopic $10,465 vs. $12,093 for robotics). several recent publications on robotic simple prostatectomy showed similar results. yuh et al. (21), in 2008, reported on a case series of three simple prostatectomies with average or time of 211 minutes, ebl of 558 ml and mean hospital stay of 1.3 days. next, john et al. (22) reported their experience using an extraperitoneal approach. the series consisted of 13 patients with average or time of 210 minutes, ebl of 500 ml, adenoma weight of 82 grams, foley duration of 6 days and hospital stay of 6 days. in 2010, uffort (23) series of 15 patients provided further evidence substantiating robotic simple prostatectomy as a valid treatment option. average operative time was 128.8 minutes, ebl was 139 ml, average hospital time was 2.5 days and foley duration was 4.6 days. finally, coelho et al. (24) further contribute to the published data in their series of six consecutive patients. the authors suggest a slightly modified procedure. following resection of the adenoma, instead of performing the usual “trigonization” of the bladder neck, they proposed three modified steps as follows: placation of the posterior capsule, a modified van velthoven continuous visco-urethral anastomosis and suturing of the anterior prostatic capsule to the anterior bladder wall. detailed description of the procedure and illustrations can be referenced in the original publication. the authors reported a mean or time of 90 minutes, ebl 208 ml, hospital stay of 1 day and foley duration was 4.8 days. the authors suggest that technical modification offers the potential advantage of decreased blood loss, no need for postoperative continuous bladder irrigation, and shorter length of hospital stay. a complete review of the written literature, included our experience of robotic simple prostatectomy is summarized in table 3. conclusion the 2010 aua clinical guidelines cite longer catheter duration, greater ebl and longer hospital stay with the open prostatectomy, but continue to list this as a more effective treatment than turp at relieving blockage of urine flow in men with very large glands (greater than 80 to 100 ml). as opposed to the theory that laparoscopic and robotic approaches are investigational, we believe that the advantage of a robotic approach is relevant and clearly defined by our experience and the referenced landmark papers discussed here. robotic surgery offers an obvious advantage to traditional laparoscopy in regards to visual enhancement, and wristed movements allowing for increased dexterity. the robotic approach allows for a shorter learning curve to a complex case. this article should highlight the excellent patient outcomes achievable with laparoscopic simple prostatectomy, and one that is feasible with most contemporary urologists comfort and skill for robotic surgical assistance. references 1. holtgrewe hl, ackermann r, bay-nielsen h, et al. report from the committee on the economics of bph. in: cockett atk et al., eds. third international consultation on benign prostatic hyperplasia (bph). jersey: scientific communication international. 1996; 51-70. 2. mcconnell jd, barry mj, bruskewitz rc, et al. benign prostatic hyperplasia: diagnosis and treatment. clinical practice guidelines no. 8. ahcpr publication no. 940582. rockville, maryland: agency for health care policy and research. public health service, us dept of health and human services, 1994. 3. ellis h. the early days of prostatectomy for benign prostatic hypertrophy. j perioper pract. 2011; 10:359. 4. rocco b, albo g, ferrreira r, et al. recent advances in the surgical treatment of benign prostatic hyperplasia. ther adv urol. 2011; 3:263-272. 5. sandhu j, jaffe w, chung d, et al. decreasing electrosurgical transurethral resection of the prostate surgical volume during graduate medical education training is associated with increased surgical adverse events. j urol. 2010; 183:1515-1519. 6. sotelo r, clavijo r, carmona o, et al. robotic simple prostatectomy. j urol. 2008; 179:513-515. 7. american urologic association. guidelines for management of bph, 2003. available at: http://www.auanet.org/content/clinicalpractice-guidelines/clinical-guidelines/archived-guidelines/chapt_ 1_appendix.pdf. accessed february 24, 2012. 8. american urologic association. management of bph (revised, 2010). available at: http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm. accessed february 24, 2012. 9. vela navarette r, gonzales enquita c, garcia cardoso, et al. the impact of medical therapy on surgery for benign prostatic hyperplasia: a study comparing changes in a decade. bju int. 2005; 96:1045-1048. 243archivio italiano di urologia e andrologia 2014; 86, 4 robotic simple prostatectomy: a consideration for large prostate adenomas series # pts. avg. or ebl foley hospital adenoma adenoma time (ml) duration stay size trus size path (mins) (days) (days) (grams) (grams) sotelo, 2008 7 205 298 7 1.4 77.66 50.48 yuh, 2008 3 211 558 na 1.3 323 301 john, 2009 13 210 500 6 6 100 82 uffort, 2010 15 129 139 4.6 2.5 70.85 46.4 coelho, 2011 6 90 208 4.8 1 157 145 this series 5 187.2 440 7.4 1.8 132.89 89.8 table 3. published series of robotic simple prostatectomy. nething_stesura seveso 15/01/15 12:52 pagina 243 archivio italiano di urologia e andrologia 2014; 86, 4 j.b. nething, d.j. ricchiuti, r. irvine, d. drevna 244 10. mariano mb, graziottin tm, tefilli mv. laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. j urol. 2002; 167:2528-2529. 11. mariano mb, tefilli mv, graziottin tm, et al. laparoscopic prostatectomy for benign prostic hyperplasiaa six year experience. eur urol. 2006; 49:127-132. 12. zhou ly, xiao j, chen h, et al. extraperitoneal laparoscopic adenomectomy for benign prostatic hyperplasia. worl j urol. 2009; 27:385-387. 13. yun hk, kwon jb, cho sr, et al. early experience with laparoscopic retropubic sumple prostatectomy in patients with voluminous benign prostatic hyperplasia (bph). korean j urol. 2010; 51:323-329. 14. baumert h, ballaro a, dugardin f, et al. laparoscopic versus open simple prostatectomy. j urol. 2006; 175:1691-1694. 15. sotelo r, spaliviero m, garcia sequi a, et al. laparoscopic reteropubic simple prostatectomy. j urol. 2005; 173:757-760. 16. castillo oa, bolufer e, lopezfontana g, et al. laparoscopic simple prostatectomy (adenomectomy): experience in 59 consecutive patients. actas urol esp. 2011; 35:433-437. 17. van velthoven r, peltier a, laguna mp, et al. laparoscopic extraperitoneal adenomectomy (millin): pilot study on feasibility. eur urol. 2004; 45:103-109. 18. desai m, aron m, canes d, et al. single port transvesical simple prostatectomy: initial clinical report. urology. 2008; 72:960-965. 19. yohonnes p, rotariu p, pinto et al. comparison of robotic versus laparoscopic skills: is there a difference in the learning curve? urology. 2002; 60:39-45. 20. sarle r, tewari a, shrivastava a, et al. surgical robotics and laparoscopic training drills. j endourol. 2004; 18:63-67. 21. yuh b, laungani r, et al. robotic assisted millins retropubic prostatectomy: case series. can j urol. 2008; 15:4101-4105. 22. john h, bucher c, engel n, et al. preperitoneal robotic prostate adenomectomy. urology. 2009; 73:811-815. 23.uffort e, jensen j. robotic assisted laparoscopic simple prostatectomy: an alternative minimally invasive approach for prostate adenoma. j robotic surg. 2010; 4:7-10. 24.coelho r, chauhan s, sivaraman a, et al. modified technique of robotic assisted simple prostatectomy: advantages of a vesico-urethral anastomosis. bju int. 2012; 109:426-433. correspondence joshua b. nething, md jnething@gmail.com rhys irvine, md (corresponding author) rwirvine@gmail.com dave drevna ddrevna@neomed.edu northeastern ohio medical university department of urology 215 west bowery street, suite 3500, akron, ohio 44308 daniel j. ricchiuti, md dricchiuti@yahoo.com st elizabeth health center, division of urology 1044 belmont avenue, youngstown, ohio 44501 nething_stesura seveso 15/01/15 12:52 pagina 244 archivio italiano di urologia e andrologia 2017; 89, 2160 case report acute urinary retention after venlafaxine use şaban oğuz demirdöğen 1, esen yıldırım demirdöğen 2, şenol adanur 1 1 urology department atatürk university, turkey; 2 department of child and adolescent psychiatry atatürk university, turkey. we describe a case of lower urinary system symptoms (lusss) and acute urinary retention that developed after treatment with a low dose of venlafaxine. a 48-year-old male patient was admitted to our clinic because of difficulty urinating, an intermittent stream, and trickling at the end of urination, together with urinary retention that had started about 45 days ago. the patient had been taking venlafaxine for the previous 6 months. the drug had been prescribed by the psychiatry department for a diagnosis of major depression, and the dose had been increased from 75 mg/day to 150 mg/day 1.5 months earlier. the patients’ symptoms were thought to be related to venlafaxine, and the symptoms disappeared completely after venlafaxine was replaced with agomelatine. we concluded that the lusss and urinary retention were due to the venlafaxine treatment. key words: acute urinary retention; lower urinary tract symptoms; venlafaxine. submitted 17 december 2016; accepted 11 january 2017 summary no conflict of interest declared. and had started after the venlafaxine dosage had been increased from 37.5 mg twice daily (75 mg/day) to 75 mg twice daily (150 mg/day) 1.5 months earlier. the patient had no history of significant disease or abdominal or urologic surgery, and his family history revealed nothing of significance. a physical examination revealed a vesical globe. kidney-ureter-bladder film was normal. no pathology was observed in the abdomen or urinary system on ultrasonography, and no pathology was found on cranial and lumbar magnetic resonance images. a transurethral (tu) catheter was placed, as the patient had a vesical globe. a urine culture was sterile. the results of urodynamic tests were normal. no urogenital system pathology was found that could explain the patient’s condition, and a psychiatry consultation was therefore requested to evaluate whether the problem was associated with the venlafaxine treatment. the psychiatry department suggested that the patients’ symptoms were related to venlafaxine. thus, the dose of venlafaxine (150 mg/day) was decreased gradually and discontinued after five days. the patient was prescribed a daily dose (25 mg) of agomelatin, which is a melatoninergic receptor agonist antidepressant. the tu was removed one day after the dose of venlafaxine was decreased to 37.5 mg twice a day, and urination was monitored. the tu was inserted again when the patient developed a vesical globe. the tu catheter was removed three days after venlafaxine was discontinued. during uroflowmetry, the patient was unable to urinate freely (qmax 3 ml/s), but no significant postvoiding residual urine (pvr) was seen in the bladder. uroflowmetry was repeated the next day. the qmax was 8.1 ml/s, with no significant pvr. the patient was discharged and advised to continue taking his current medical treatment. at outpatient follow-up 10 days later, the symptoms had disappeared completely, the qmax was 19.3 ml/s, and the pvr was 10 cc on uroflowmetry. discussion venlafaxine belongs to the serotonin-noradrenalin reuptake inhibitor group and exerts its effects by blocking serotonin, noradrenalin and, at high doses, dopamine uptake bidirectionally. it is used to treat major depression and anxiety. it is administered orally and is a safe drug that can usually be tolerated (2). the effects of vendoi: 10.4081/aiua.2017.2.160 introduction lower urinary system symptoms (lusss) consist of symptom subtypes related to urinary storage and drainage. lusss are an important health problem due to their negative effects on quality of life. acute urinary retention develops due to an inability to urinate and results in a full and tense bladder, together with suprapubic pain and tenderness. the most common cause of lusss is benign prostate hyperplasia. acute urinary retention can develop due to genitourinary system tumors, vesical or urethral stones, urethral strictures, and medications, in addition to acute prostatitis and neurological diseases (1). several case reports have described venlafaxine-related acute urinary retention when the drug was used in combination and in high doses.we describe a case of lusss and acute urinary retention that developed following the use of low-dose venlafaxine monotherapy. case report a 48-year-old male patient with a diagnosis of major depression presented to our clinic with lusss, which included difficulty urinating, an intermittent stream, and trickling at the end of urination, together with an inability to urinate. the symptoms had lasted for about 20 h demridogen_stesura seveso 20/06/17 10:04 pagina 160 161archivio italiano di urologia e andrologia 2017; 89, 2 urinary retention and venlafaxine lafaxine are similar to those of tricyclic antidepressants, which also affect serotonin and noradrenalin receptors, but it has relatively few side effects due to its lack of affinity to other receptors. the most common side effects are nausea, somnolence, dry mouth, dizziness, irritability, constipation, asthenia, anxiety, anorexia, blurred vision, abnormal ejaculation or orgasm, and impotence. however, these effects are usually mild and rarely require treatment cessation. in addition to the above-mentioned side effects, hypertension was reported to be a common problem among patients taking venlafaxine (3). due to its tolerability and few side effects mentioned above, venlafaxine is considered a good option for patients with major depression. lusss and acute urinary retention can occur following the use of opiates, antihistamines, alpha adrenergic agonists, ganglion blockers, phenothiazines, and monoamino oxidase (mao) inhibitors. these findings are attributed to the contraction of the urethral sphincter muscle as a result of anticholinergic stimulation (4). previous studies also showed that lusss and acute urinary retention developed following treatment with antidepressant and antipsychotic drugs. the development of lusss was reported after the use of duloxetine, a selective serotonin noradrenalin reuptake inhibitor (5) and milnasipram, another antidepressant (6). urinary side effects, such as urinary incontinence, related to venlafaxine have previously been reported in the literature (7, 8), and several cases of lusss and acute urinary retention following the use of venlafaxine were reported. however, these side effects only occurred when venlafaxine was used in combination with another drug or when venlafaxine was administered at high doses (375 mg once daily) when used as monotherapy (9, 10). our case is important, as it is the first report of the development of lusss and acute urinary retention when venlafaxine was used as monotherapy and at a low dose. lusss and acute urinary retention are thought to be due to adrenergic stimulation, which occurs as a result of venlafaxine inhibiting noradrenaline reuptake. these side effects can be severe and can interfere with the continuation of treatment, as in the present case. despite these side effects, in a limited patient series, venlafaxine was reported to increase the quality of life of patients with neurological disorders by reducing their daily urination frequency and increasing their bladder capacity (11). in the present case, agomelatine, which is used to treat depression and sleep disorders, was thought to be a safer option than venlafaxine due to its lack of interaction with the relevant receptors and the patient’s clinical condition, and no urinary tract side effects were observed. conclusion venlafaxine is a safe and effective antidepressant for the treatment of major depression and anxiety disorders. however, it may not be suitable for patients with accompanying prostate disease or micturition disorders. prior to prescribing venlafaxine, it should be considered that venlafaxine monotherapy can cause lusss and urinary retention. references 1. irwin de, et al., population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006; 50:1306-14. 2. stahl sm. stahl's essential psychopharmacology: neuroscientific basis and practical applications. 2013: cambridge university press. 3. rudolph rl, derivan at. the safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database. j clin psychopharmacol. 1996; 16(3 suppl 2): p. 54s-59s. 4. cardozo l. voiding difficulties and retention. urogynecology, 1st ed., 1997, new york, ny: churchill livingstone, 305-320. 5. thor kb, katofiasc ma. effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. j pharmacol exp ther. 1995; 274:1014-24. 6. akpınar a. milnasipran tedavisine bağlı ani gelişen prostatizm: bir olgu sunumu. türk psikiyatri dergisi. 2009; 20:403. 7. polimeni g, salvo f, cutroneo p, et al. venlafaxine-induced urinary incontinence resolved after switching to sertraline. clin neuropharmacol. 2005; 28:247-8. 8. selvaraj v, gunasekar p, kumar s, alsakaf i. urinary incontinence due to overactive detrusor muscle: a rare side effect of venlafaxine. case rep urol. 2015; 690931. 9. alexander j, mckenny b, chaudhary j. venlafaxine associated urinary symptoms. aust n z j psychiatry. 2010; 44:1145. 10. benazzi f. urinary retention with venlafaxine-haloperidol combination. pharmacopsychiatry. 1997; 30:27. 11. inghilleri m, conte a, frasca v, et al. venlafaxine and bladder function. clin neuropharmacol. 2005; 28:270-3. correspondence şaban oğuz demirdöğen, md oguzdemirdogen@hotmail.com şenol adanur, md s.adanur61@hotmail.com atatürk university urology department, turkey esen yıldırım demirdöğen, md esenyildirim08@hotmail.com atatürk university department of child and adolescent psychiatry, turkey demridogen_stesura seveso 26/06/17 09:01 pagina 161 stesura seveso 47archivio italiano di urologia e andrologia 2016; 88, 1 review primary adenocarcinoma of the seminal vesicles. a review of the literature ioannis katafigiotis 1, stavros sfoungaristos 2, mordechai duvdevani 2, panagiotis mitsos 1, eleni roumelioti 1, konstantinos stravodimos 1, ioannis anastasiou 1, constantinos a. constantinides 1 1 1st university urology clinic laiko hospital, athens, greece; 2 hebrew hadassah university medical center, jerusalem, israel. primary adenocarcinoma of the seminal vesicles (sv) are extremely rare and approximately only 60 cases have been reported in the literature. due to the lack of specific symptoms the patients often present in an advanced stage of their disease. the only clinical examination that can indicate the presence of a neoplasm in the svs is the digital rectal examination (dre). serum prostatic specific antigen (psa) and prostate specific acid phosphatase (pap) are usually normal in patients with primary adenocarcinoma of the sv and only ca-125 can be proved a useful blood biomarker contributing to the diagnosis and the follow up of the sv adenocarcinoma. computed tomography (ct) and magnetic resonance imaging (mri) and fdg-pet/ct have been used for the diagnosis and the staging of the sv adenocarcinoma. various combinations of radical surgery, radiotherapy androgen deprivation therapy and chemotherapy have been proposed for the management of the disease but the prognosis is poor and the mean survival is two years after the diagnosis. key words: primary adenocarcinoma of the seminal vesicles; seminal vesicle cancer; primary neoplasm of the seminal vesicle. submitted 27 october 2015; accepted 5 december 2015 summary no conflict of interest declared. able. also papers that were referring to primary cancer of the seminal vesicle but to histology types other than adenocarcinoma were excluded from the main text but were used to the formation of table i in the classification of the histology types. an additional search was made with “primary seminal vesicle carcinoma” being the key words; 185 papers was the result and only 2 were chosen. the majority of the papers excluded were either the same papers as in the first search either irrelevant to the subject. after the final selection 23 papers were chosen on which the review was based. one additional reference (reference 3) was not present in the pubmed search but was traced from another paper and was used only for the historical aspect of the subject since it was the first paper published referring to the subject. discussion 1. epidemiology primary carcinomas of the svs are extremely rare and the first case presented in the literature was by lyons in 1925 (1, 3). although primary adenocarcinomas of the svs are rare it isn’t very easy to record with precision the exact number of the cases recorded in the literature. following the papers published year by year in the literature, in 2000 only 48 cases were recorded (4), in 2006 49 cases (5), 50-51 cases in 2011 (6, 7), and 5 more since then rising the total number of cases to 55-56 (1, 8-11).the mean patient age at diagnosis is 62 years old (range: 13-90 years) (9). 2. histology types primary adenocarcinoma is the most common neoplasm of the svs. other histology types of the primary neoplasms of the svs that have been recorded in the literature are sarcomas, squamous cell carcinoma, yolk salk tumor, neuroendocrine carcinoma, paraganglioma, epithelial stromal tumors, lymphoma (burkitt, b-cell), extragastrointestinal stromal tumor (egist), myxoid solitary fibrous tumor, and seminoma peripheral primitive neuroectodermal tumor (ppnet) (table 1). benign tumors of the svs are even rarer (5) and the reported histology types in the literature are cystic dysplasia, fibroepithelial tumor, leiomyoma, cystadenoma and schwannoma (table i). doi: 10.4081/aiua.2016.1.47 introduction primary adenocarcinoma of the seminal vesicles (sv) are extremely rare and approximately only 60 cases have been reported in the literature (1). due to the lack of specific symptoms the diagnosis and differentiation of a sv adenocarcinoma from neoplasms of the anatomic vicinity like the prostate, bladder and rectum that infiltrate secondarily the svs is usually difficult (2). we present a comprehensive review of the literature. material and methods-aearch atrategy two different pubmed-based search strategies were followed in order to acquire the necessary data for a complete review. the first search was “primary adenocarcinoma of the seminal vesicles” and 87 papers was the original result. from these 87 papers 21 papers-references were chosen and constituted the main base of the review; 66 papers were excluded either because they were irrelevant to the subject, either because no abstract was availkatafigiotis_stesura seveso 08/04/16 11:29 pagina 47 archivio italiano di urologia e andrologia 2016; 88, 1 i. katafigiotis, s. sfoungaristos, m. duvdevani, p. mitsos, eleni roumelioti, k. stravodimos, i. anastasiou, c.a. constantinides 48 3. diagnosis from 1956 already dalgaard and giertson described the following criteria for the diagnosis of a primary adeonocarcinoma of a svs: the tumor should be a macroand microscopically verified carcinoma, localized exclusively or mainly to the seminal vesicle; there must be no other primary carcinoma in the body; and the tumor should preferably be a papillary adenocarcinoma that resembles the architecture of the non-neoplastic seminal vesicle (4, 12). nevertheless these criteria are referring mainly to the final specimen of the surgical resection4 and the presurgical diagnosis is a difficult task and the differential diagnosis from the primary adenocarcinomas of the prostate, bladder and colon that infiltrate the svs is even more difficult (6, 9, 11). a) symptoms due to the lack of specific symptoms the patients often present in an advanced stage of their disease (13). all the data in the literature refer to non-specific symptoms from the genitourinary and the gastrointestinal tract (1, 5). the main symptoms from the genitourinary system can be dysuria, frequency, hematuria, hematospermia and bladder outlet obstruction (1, 5, 9). from the gastrointestinal tract the main symptoms can be constipation and intestinal bleeding (8, 11). other symptoms that have been reported are painful sensation in the pelvis and perineum and general symptoms like appetite loss (1, 8). b) clinical examination-digital rectal examination (dre) the only clinical examination that can indicate the presence of a neoplasm in the svs is the dre. although there is no unanimous description of the findings of a dre in sv neoplasm the majority of the cases in the literature refer to a large irregular mass above the prostate (13). usually the mass is non tender and immobile with a hard elastic composition (5, 9, 8, 13). even though an abnormal dre constitutes an integral part of the diagnosis, up to 30% of patients have no abnormal findings during dre (9). c) blood biomarkers -table 2 serum prostatic specific antigen (psa) and prostate specific acid phosphatase (pap) are usually normal in patients with primary adenocarcinoma of the svs (1, 9, 6, 13). also in our case the patient had a normal psa of 1.5 ng/ml. apart from the psa also ca-19.9 has been reported to be normal in patients with primary adenocarcinoma of the svs (1, 9). special consideration must be taken for the other two biomarkers cea and ca-125. normal serum cea can be interpreted as absence of invasion of a colon carcinoma (9). although usually cea is normal in primary adenocarcinoma of the svs, increased serum cea levels are seen in rare cases (1, 9, 13). ca-125 is a useful biomarker in sv adenocarcinoma since there are reports of tumors producing ca-125 elevating the levels of the marker in serum (9, 14). ca-125 is a useful biomarker not only for the diagnosis but also for the follow-up of the patient since it can be decreased even to normal value after the treatment or rise again up to 6 months before the occurrence of clinical metastases (8, 14). finally there is a reference of an elevated ca15-3 in a patient with primary sv adenocarcinoma (9). d) imaging-biopsy computed tomography (ct) and magnetic resonance imaging (mri) have been widely used for the depiction of a sv neoplasm (1, 9, 13). various descriptions of a sv mass during a ct have been reported in the literature from a solid mass originating from the svs mildly enhancing to a lesion with an hypodense central area presenting peripheral contrast enhancement (1, 8, 13). mri imaging can depict a high signal-intensity fluid in the sv (t1-weighted), a papillary mass (t2-weighted), or primary neoplasms histology type references of the svs malignant 1. squamous cell wang j, et al. 2013 tabata k, et al. 2001 2. yolk salk dong yao, et al. 2012 3. neuroendocrine kreiner b, et al. 2010 4. paraganglioma alvarengai ca, et al. 2012 5. epithelial stromal tumor hoshi a, et al. 2006 6. extragastrointestinal stromal tumor song w, et al, 2012 7. myxoid solitary fibrous tumor wei yc, et al. 2006 8. seminoma adachi y, et al. 1991 9. lymphoma burkitt ouyang j, et al. 2009 b cell jiang zhu, et al. 2011 10. sarcomas -leiomyosarcoma -angiosarcoma -extraskeletal osteosarcoma -cauvin c,et al. 2011 -chang k, et al. 2014 -choi jd, et al. 2011 11. peripheral primitive neuroectodermal tumor (ppnet) lawrentschuk n, et al. 2008 benign 1. cystic dysplasia domínguez dm, et al. 1999 2. fibroepithelial tumor zanetti gr, et al. 2003 3. leiomyoma gentile at, et al. 1994 4. cystadenoma lee cb, et al. 2006 5. schwannoma arun g, et al. 2014 psa normal ca-19.9 normal ca-125 usually elevated but could be normal ca 15-3 normal rarely elevated table 1. histology types. table 2. profile of blood biomarkers in primary adenocarcinoma of the seminal vesicles. katafigiotis_stesura seveso 08/04/16 11:29 pagina 48 49archivio italiano di urologia e andrologia 2016; 88, 1 primary adenocarcinoma of the seminal vesicles. a review of the literature even a malignant cystic-necrotic lesion with irregular solid components (9, 13). nevertheless mri can also depict the anatomy and the extent of the sv neoplasm contributing to the preoperative evaluation of the case (7, 15). fdg-pet/ct has also been used for the diagnosis the staging and the assessment of the treatment response (1, 8). fdg-pet/ct usually confirms radiopharmaceutical uptake in the primary sv lesion (1, 8). transrectal ultrasonography has been recommended as the first imaging method because can contribute both to the depiction of the mass and a simultaneous biopsy that will set the diagnosis (1, 9). a solid mass or a cystic lesion with the inclusion of a solid mass is the usual depiction at transrectal ultrasonography (13, 16). cystoscopy is usual negative and has been reported to be normal up to 20% of patients and it isn’t the standard method used for the depiction and the diagnosis of a sv (1, 9). colonoscopy has been proposed for the exclusion of a primary rectal tumor (8, 17). e) immunohistochemical analysis and differential diagnosis (table 3) immumohistochemical analysis can play a vital role both for the diagnosis and the differentiation of a sv adenocarcinoma from prostate, bladder and the colorectal carcinomas (1, 4, 6, 9). all the data in the literature report an absence of staining both for prostate specific antigen (psa) and prostate-specific acid phosphatase (pap) of the sv adenocarcinoma contributing in the differentiation from a prostatic adenocarcinoma (1, 4). ca-125 a large, highly glycosylated glycoprotein, though is used as a marker of mullerian differentiation, can even show a paradoxical immunoreactivity to a well-differentiated papillary sv adenocarcinoma that is of a wolffian duct origin (4, 6). ca-125 can help in the differentiation of a sv adenocarcinoma from prostatic, bladder and rectal tumors, since these carcinomas are usually negative (4). ca-125 immunoreactivity alone may be not sufficient for the diagnosis of a sv adenocarcinoma, since other tumors that can express ca-125, although less frequently, like breast, pancreatic, lung, colon carcinomas, primary serous carcinoma of the peritoneum, clear cell adenocarcinoma of the bladder and metastases especially from a pancreatic-biliary carcinoma and clear cell adenocarcinoma of the bladder must be ruled out (4, 6). at the same time there are cases in the literature of sv adenocarcinomas especially with a poor differentiation that are ca-125 negative (1, 4). simultaneously, poorly differentiated prostatic adenocarcinomas can be negative to psa and pap although only in 1% to 2% of cases, constituting the use of additional markers necessary (4). the profile of cytokeratins 7 and 20 can help further in the differential diagnosis of a sv adenocarcinoma since ck7 is usually positive and ck20 negative (1, 4, 6). the combination of psa, pap, ca-125, ck7, and ck20 markers can help in the discrimination of a sv adenocarcinoma from a bladder, prostatic and colon adenocarcinoma, since the psanegative, pap-negative, ck20-negative and ck7 and ca125 positive profile of a sv adenocarcinoma is unique (4). also the negative immunoreactivity of the cdx-2 of a sv adenocarcinoma can contribute to the discrimination form a colon cancer (1, 6). cea should be negative in a primary sv adenocarcinoma but there are many cases of cea positive or focally positive sv adenocarcinomas reported in the literature (1, 4, 9, 17). 4. metastases primary adenocarcinoma of the svs can invade both the adjacent organs and give distant metastases. invasion to the rectum leads to rectal bleeding (8, 11). due to the anatomic vicinity. primary adenocarcinoma can invade both the prostate and the bladder (18, 19). lymph node metastases to the pelvis, to the infrarenal para-aortic nodes, to the cervical chain and the mediastinal lymph nodes have been reported (6, 9, 10). apart from the lymph nodes, metastases to the lungs and the liver are common (2, 6, 8, 9, 11). skeletal metastases with severe pain have also been reported to one case in the literature (20). there is also a rare case of an isolated penile metastasis from seminal vesicle adenocarcinoma (2). finally a case of a disseminated carcinoma with metastases to lymph nodes, pleura, pericardium, liver, heart, and lung revealed to an autopsy of a patient died from a primary adenocarcinoma of the seminal vesicles (6). 5. treatment although local excision of the mass-svs has been proposed the majority of the data in the literature propose a radical surgery as a part of a multimodal approach combined with hormone therapy, radiation therapy and chemotherapy. local excision, whenever possible due to the adhesions with the surrounding tissues, has been proposed as a conservative surgical approach again as a part of a multimodal approach (9, 20). in one case the local excision couldn’t achieve a complete removal of the tumor leaving residual mass to the bladder and the rectum9. radical surgery and the extent of the necessary limits are not well defined and various operations have been performed in order to achieve a complete resection of the tumor (10, 11, 21, 22). radical prostatectomy, radical cystoprostatectomy, partial cystectomy and total pelvic exenteration with ileal conduit for urinary diversion and a sigmoid colostomy, combined with pelvic lymphadenectomy are the various radical operations suggested in the literature (1, 0, 11, 13, 21). the best chance of extended survival seems to be the combination of a radical surgery with clear margins combined with adjuvant hormone therapy, or radiotherapy or both (10, 21-23). hormone therapy has been proposed as an adjunct therapy to surgery or to radiotherapy both for the local control of the tumor and the management of the metastases (2, 8, 20, 22, 23). in the hormone manipulation and the achievement of androgen deprivation, estrogens and bilateral orchiectopsa negative pap negative ca-125 positive ck 7 positive ck20 negative table 3. profile of immunohistochemical markers in primary adenocarcinoma of the seminal vesicles. katafigiotis_stesura seveso 08/04/16 11:29 pagina 49 archivio italiano di urologia e andrologia 2016; 88, 1 i. katafigiotis, s. sfoungaristos, m. duvdevani, p. mitsos, eleni roumelioti, k. stravodimos, i. anastasiou, c.a. constantinides 50 my and have also been used (2, 20, 24). radiotherapy to the whole pelvis combined with antiandrogen blockade without surgery has been proposed as a sole therapy but the patient developed liver metastases 19 months later receiving two cycles of docetaxel and cisplatin chemotherapy and finally dying of his disease 22 months after the diagnosis (8). radiotherapy has also been proposed also for the management of local lymph node metastases, with pelvic irradiation combined with chemotherapy and for the management of residual mass after the operation (1, 9, 10). as an adjuvant therapy for the management of residual mass a total dose of 50 gy in 2 gy fractions has been proposed (9). hormone therapy or chemotherapy or the combination of both modalities have been used for the management of distal metastases (1, 2, 8, 9, 20). various combinations of chemotherapy regimens have been used, like docetaxel and cisplatin (2 cycles) for the management of liver metastases, cisplatin and 5-fu (6 cycles) for pulmonary lesions, and taxol with caroplatinum (6 cycles) for a left transverse perineal muscle lesion (1, 8, 9). in one case with skeletal metastases an one year estrogen therapy resulted the disappearance of the metastases and the survival of the patient for at least for two years (20). finally the combination of six cycles of 5-fluorouracil, leucovorin, and oxaliplatin chemotherapy with bilateral orchiectomy to a patient with an isolated metastasis to penis, resulted the clinical improvement of the patient and the regression of penile swelling and seminal vesicle mass, but the patient developed later lung metastases and died (2). 6. prognosis prognosis of a primary vesicle adenocarcinoma of the svs is general considered poor due to delayed diagnosis and approximately the 95% of the patients die in less than three years (9, 11, 22, 23). although there is a case of a patient dying three months postoperatively and two cases of a prolonged survival of 3 years and 4 months in one case and 5 years in the other, the majority of the cases in the literature refer to an approximately 2 years survival after the diagnosis (8, 10, 11, 13, 18, 20). 7. follow-up the main goal of the follow up of the patient with a primary vesicle adenocarcinoma is the detection of metastases. a combination of clinical examination, serum tumor markers, ct (chest and abdomen) mri and [18f]fdg-pet/ct has been proposed for the follow up (1, 8, 9, 22). ca-125 can be used for the detection of the recurrence and the clinical course of the disease (8, 15, 22). ca-125 elevation in some cases precede up to 6 months before the emergence of the metastases (8). suspicious lesions to the surgical bed to patients with possible residual mass or positive surgical margins can be detected with the use of mri (9). ct scan of the chest and the abdomen combined with clinical examination and serum markers every 3 months for the first year and every 6 months thereafter have been proposed as a follow up scheme (1). [18f]fdg-pet/ct can help in the clarification of suspicious lesions depicted in the ct (1, 9). lesions to soft tissues depicted to [18f]fdg-pet/ct can be further clarified with the use of an mri1. finally ultrasound guided cytology has been used during the follow up for the confirmation of a metastasis (1). 8. risk factors and bilateral primary sv adenocarcinomas although may not be easy to locate the sv from the cancer originates, due to the volume of the mass, there are cases that clearly declare the bilateral origin of the primary vesicle adenocarcinoma (10, 18). the bilateral primary sv adenocarcinoma is considered even more rare (18). considering the risk factors or predisposition for the occurrence of a primary sv adenocarcinoma the presence of a renal agenesis or dysgenesis has been reported to be a possible aggravating factor (10, 13). the renal agenesis or dysgenesis seems to contribute either to a ipsilateral or a bilateral sv adenocarcinoma (10, 13). the proposed pathway for the development of a sv adenocarcinoma is the chronic stimulation of the ectopic ureter’s secretion (13) references 1. sollini m, silvotti m, casali m, et al. the role of imaging in the diagnosis of recurrence of primary seminal vesicle adenocarcinoma. world j mens health. 2014; 32:61-5. 2. thyavihally yb, tongaonkar hb, gupta s, gujral s. primary seminal vesicle adenocarcinoma presenting as isolated metastasis to penis responding to chemotherapy and hormonal therapy. urology. 2007; 69:778.e1-3. 3. lyons o primary carcinoma of the left seminal vesicle. j urol. 1925; 13:477. 4. ormsby ah, haskell r, jones d, goldblum jr. primary seminal vesicle carcinoma: an immunohistochemical analysis of four cases. mod pathol. 2000; 13:46-51 5. hoshi a, nakamura e, higashi s, et al. epithelial stromal tumor of the seminal vesicle. intern j urol. 2006; 13:640-642 6. stenzel p, wettach g, leroy x. primary seminal vesicle carcinoma. intern j surg path. 19(3)401-404. 7. angulo jc, romero i, cabrera p, et al. vesiculectomy with laparoscopic partial prostatectomy in the treatment of primary adenocarcinoma of the seminal vesicle with carcinomatous transformation of the ejaculatory duct. actas urol esp. 2011; 35:304-9. 8. mizuno n, fujikawa n, hayashi n, et al. a case of primary seminal vesicle cancer detected by fdg-pet/ct. nihon hinyokika gakkai zasshi. 2012; 103:704-7. 9. eken a, izol v, aridogan ia, et al. an unusual cause of hematospermia: primary adenocarcinoma of the seminal vesicle. can urol assoc j. 2012;6:e259-e262. 10. campobasso d, fornia s, ferretti s, et al. primary bilateral seminal vesicle carcinoma: description of a case and literature review. int j surg pathol. 2012; 20:633-5. 11. kinjo t, nonomura d, yamamoto y, et al. primary adenocarcinoma of the seminal vesicle difficult to differentiate from rectal carcinoma : a case report. hinyokika kiyo. 2013; 59:597-601. 12. dalgaard jb, giertson jc. primary carcinoma of the seminal vesicle: case and survey. acta pathol microbiol scand. 1956; 39:255-67. katafigiotis_stesura seveso 08/04/16 11:29 pagina 50 51archivio italiano di urologia e andrologia 2016; 88, 1 primary adenocarcinoma of the seminal vesicles. a review of the literature 13. lee bh, seo jw, han yh, et al. primary mucinous adenocarcinoma of a seminal vesicle cyst associated with ectopic ureter and ipsilateral renal agenesis: a case report. korean j radiol. 2007; 8:258-61. 14. ohmori t, okada k, tabei r, et al. ca125-producing adenocarcinoma of the seminal vesicle. pathol int. 1994; 44:333-7. 15. navallas m, vargas ha, akin o, et al. primary seminal vesicle adenocarcinoma. clin imaging. 2011; 35:480-2. 16. al-saeed o, sheikh m, kehinde eo, makar r. seminal vesicle masses detected incidentally during transrectal sonographic examination of the prostate. j clin ultrasound. 2003; 31:201-6. 17. m. tarján, i. ottlecz, t. tot. primary adenocarcinoma of the seminal vesicle. indian j urol. 2009; 25:143-145. 18. ormsby ah, haskell r, ruthven se, mylne ge. bilateral primary seminal vesicle carcinoma. pathology. 1996; 28:196-200. 19. tanaka t, takeuchi t, oguchi k, et al. primary adenocarcinoma of the seminal vesicle. hum pathol. 1987; 18:200-2. 20. kindblom lg, pettersson g. primary carcinoma of the seminal vesicle. case report. acta pathol microbiol scand a. 1976; 84:301-5. 21. möhring c, bach p, kosciesza s, goepel m. a primary adenocarcinoma of the seminal vesicles. case report of a rare malignancy. urologe a. 2008; 47:616-9. 22. thiel r, effert p. primary adenocarcinoma of the seminal vesicles. j urol. 2002; 168:1891-6. 23. benson rc jr, clark wr, farrow gm. carcinoma of the seminal vesicle. j urol. 1984; 132:483-5. 24. rodriguezkees os. clinical improvement following estrogenic therapy in a case of primary adenocarcinoma of the seminal vesicle. j urol. 1964; 91:665-70. correspondence ioannis katafigiotis, md, mls, phd, resident in urology (corresponding author) katafigiotis@yahoo.com panagiotis mitsos, md resident in urology mitsospanagiotis@yahoo.com eleni roumelioti, finance and statistics eleniroum81@gmail.com konstantinos stravodimos, md, phd, febu associate professor in urology kgstravod@yahoo.com ioannis anastasiou, md, phd, febu assistant professor in urology ekati2@otenet.gr constantinos a. constantinides, md, phd, febu professor in urology ckonstan@med.uoa.gr 1st university urology clinic laiko hospital agiou thoma 17 11527 athens, greece stavros sfoungaristos, md, phd sfoungaristosst@gmail.com mordechai duvdevani, md, associate professor in urology moti_duv@yahoo.com hebrew hadassah university medical center jerusalem, israel katafigiotis_stesura seveso 08/04/16 11:29 pagina 51 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4274 original paper the effects of electromagnetic waves emitted by the cell phones on the testicular tissue muhammet ihsan karaman 1, ali murat gökçe 1, orhan koca 1, bilal karaman 1, metin ishak öztürk 1, necati yurdakul 2, feriha ercan 2 1 haydarpasa numune training and research hospital, department of urology, istanbul, turkey; 2 marmara university school of medicine, department of histology and embryology, istanbul, turkey. objectives: various risks have emerged in parallel to the rapidly increasing use of cell phones. herein we studied the effects of cell phone emitted electromagnetic waves (emw) on rat testes. material and methods: twenty one adult male albino rats were grouped into 3 groups each consisting of 7 rats. the first group was exposed to emw on talk mode for 8 hours per day for 20 days and then their testes were extracted. the testes of the second group were extracted after 20 days of whole day emw exposure. the third group was the control group. for the statistical analysis mannwhitney u analysis was performed. results: at light microscopic examination of the testicular tissue, the existence of a high number of immature cells in the lumen of the seminiferous tubule in addition to the normal seminiferous tubules, besides irregular tubules with a reduction in the spermatogenic cell lines and tubules without lumen were observed in groups 1 and 2. histopathological alterations were scored as 0 = none, 1 = low, 2 = medium, 3 = serious. the average scores of the three groups were found to be 4.25 ± 1.5 for the group 1, 4.33 ± 3.9 for the group 2 and 0.37 ± 1.1 for the group 3 respectively. as a result of the statistical evaluation, group 1 and group 2 had significantly higher scores than the control group (p = 0.001). conclusion: infertility is one of the current problems of today due to a rapid increase in its incidence and cost. the negative effects of the emws on the testis should be taken into account and the necessary measures should be taken for prevention. key words: cell phone; electromagnetic waves; testes. submitted 18 july 2014; accepted 18 august 2014 summary no conflict of interest declared. many laboratory studies and epidemiological surveys have reported the correlation between the electromagnetic field exposure and severe health-related problems. immunity, nervous system, neuro-endocrine system, cardiovascular system and blood parameters are affected from the electromagnetic fields (1-3). the male partner is pathologic in nearly 50% of the infertile couples (4). first and foremost reason for this is the reduction in the quality and quantity of the ejaculated sperm. there are many factors that affect the sperm quality and quantity such as drugs, radiation, viral causes, genetic diseases. as the sufficient exposure time period has not passed for conduction of community based studies regarding the cell phones and base stations, there are certain epidemiological challenges in determining the exposure of human communities objectively. it is known that the use of cell phones is more common in young and middleaged people who carry them in their pockets, close to the scrotal area. according to the information obtained from recent studies, we developed a rat model to investigate the effects of the cell phone emitted electromagnetic waves (emws) on the testes which are the most important organs of the reproduction system. materials and methods after ethics committee approval, in order to study the effects of the emws emitted by the cell phones on the testes of the rats, 21 adult male wistar albino rats were divided into 3 groups. every group of 7 rats was kept in standardized cages with the dimension of 40 x 60 cm, indoor lighting illuminated for 12 hours and left in dark for 12 hours, kept at temperature of 22 ± 2°c and humidity ratio of 50 ± 10%, and with free pellet feed and easy access to water. cell phones were suspended 1 cm above the cover of the cage of group 1 and 2. philips genie 900® (singapore) cell phones having the highest specific absorption rate (sar) value in the market (1.52 w/kg) were used. every day the cell phones were plugged in the charger for 24 hours and they remained on talk mode for 8 hours and standby mode for 16 hours. doi: 10.4081/aiua.2014.4.274 introduction the risks of the electromagnetic fields on human health are increasing due to more intense use of new technologies in the daily life. particularly, the increasing use of cell phones in recent years and concordant widespread of the base stations had impact in threatening human health. kamran_eff_stesura seveso 15/01/15 13:05 pagina 274 275archivio italiano di urologia e andrologia 2014; 86, 4 effects of cell phone on testes group 1 rats were exposed to the cell phone emws emitted from talk mode for 8 hours and standby mode for 16 hours every day for 20 days and then their testes were extracted. group 2 rats were exposed to the emw emitted by talk mode for 8 hours and standby mode for 16 hours every day for 20 days followed by exposition to standby mode in the laboratory environment for 20 days and then their testes were extracted. the rats in the third group (control group) were not exposed and were fed in the standard laboratory environment for 20 days and then their testes were extracted. for the extraction of the testes of the rats, intraperitoneal ketamine hydrochloride 45 mg\kg was injected for anaesthesia. then, their testes were extracted. the testicular material after extraction was divided in two parts for light and electron microscopic examination. light microscopic preparation testes samples taken for the light microscopic examinations were fixed in 10% formaldehyde, then they were incubated through rising alcohol solution and rinsed with toluene. the cross-sections with a thickness of approximately 5 µm were stained with hematoxylin and eosin (h&e) and examined with olympus bx51 photomicroscope for general morphological evaluation. three different criteria were taken into consideration. intercellular connections, normal, loose cellular organization and eosinophilic cytoplasm, cellular damages such as pyknotic nucleus; abnormal formation of germ cells and sertoli cells and disruption in the intercellular connections; very low number of germ cells and sertoli cells with disrupted sertoli cells alone or disrupted intercellular connections. five identical areas of each cross-section were evaluated at x 100 magnification for histopathological scoring. histopathological alterations were scored as 0 = none, 1 = low, 2 = medium, 3 = serious. the scoring was made individually for each criterion and the total scores of the three criteria were used for comparison purpose. transmission electron microscopic preparation for the examination with transmission electron microscopy tissues were fixed in 2.5% phosphate buffered glutaraldehide solution (0.1 m, ph 7.4) and were incubated in 1% phosphate buffered osmium tetroxide solution, then were polymerized in drying oven at 600c in epon 812 after dehydration with alcohol solutions at serial increasing concentrations. the thin cross-sections with approximately 60 nm were examined with the jeol 1200 tem (tokyo, japan) scanning electron microscope after contrasted via the uranyl acetate and lead cirate. statistical analysis for the statistical analysis spss statistical program was used, and mann-whitney u analysis method was performed. p < 0.05 (p value lower than 0.05) was considered as statistically significant. results the light microscopic examination of the testicular tissue, revealed seminiferous tubules with spermatogenic cell series having a normal morphology in the control group (group 3) (figure 1a). at electron microscopic examination, the seminiferous tubules with spermatogenic series had a normal morphology (figure 1b). at the light microscopic examination of the testes of the group of rats that were examined after additional 20 days following the initial exposure to emws for 20 days (group 2), besides normal seminiferous tubules, tubules with a reduced spermatogenic cell lines and those lacking lumen were observed. immature spermatogenic cells were present in the seminiferous tubule lumens (figure 1c). electron microscopic examination revealed enlarged spaces between detected sertoli cells and cells of spermatogenic series but there were several spermatid at the spermiogenesis process (figure 1d). at the light microscopic examinations of the group of rats exposed to emws for 20 days (group 1), there was a high number of immature cells in the lumen of the seminiferous tubule and in addition to the normal appearing tubules also irregular tubules with reduced spermatogenic cell lines and tubules without lumen were observed (figure 1e). at electron microscopic examination, enlarged spaces between the sertoli cells and the spermatogenic cells as well as increased spermatid were observed (figure 1f). the average scores of each of the three groups were found to be 4.25 ± 1.5 for the group 1, 4.33 ± 3.9 for the group 2 and 0.37±1.1 for the group 3 respectively (table 1). as a result of the statistical assessment made between the groups no significant difference was observed between the groups 1 and 2 (p > 0.05), but average scores of both group 1 and 2 were significantly higher (p = 0.001) than the control group. discussion with the progress in technology, human life became easier but every new technological product brings certain disadvantages threatening human health. many products as hair dryer, microwave oven, television and computers, that make life easier, have negative impact on human health due to emws they emit. one of recent and widely used emw emitting device is the cell phone. the radiofrequency waves emitted by the cell phones are thought to cause many hazardous effects at cellular and molecular levels. recent studies revealed that the radiofrequency waves emitted, especially from the third generation cell phones, might have effects on living organisms, immunological system, nervous sysaverage ± sd median range group 1 4.25 ± 1.5 4.5 3 group 2 4.33 ± 3.9 4.5 9 group 3 0.37 ± 1.1 0 3 p* p < 0.05 *group 1 and group 2 p > 0.05; group 1 and group 3 p = 0.001; group 2 and group 3 p = 0.001. table 1. comparison between the mean scores of three groups. kamran_eff_stesura seveso 15/01/15 13:05 pagina 275 archivio italiano di urologia e andrologia 2014; 86, 4 muhammet ihsan karaman, ali murat gökçe, orhan koca, bilal karaman, metin ishak öztürk, necati yurdakul, feriha ercan 276 tem, haematological function, cardiac functions, urinary system, growth and development as well as genetic structure (5). the emws emitted from the base stations and cell phones have damaging effects on tissues with two mechanisms. the thermal effects occur when electromagnetic energy absorbed by the body is converted into heat and the body temperature increases. this effect is balanced by the blood circulation. the non-thermal effects are manifested by changes in the brain functions, sleep and attention disorders, and headache (6). emws might also cause carcinogenesis (7). heat sensitivity of the testicular tissue was investigated in many studies (8). in the studies concerning the effects of emws on the testicular tissue, it was reported that high level of emw exposition might increase the temperature of the testicular tissue causing serious pathologies such as degeneration, oedema, haemorrhage and reduction in spermatogenesis (8).the testicular damage we detected in this study might be due to such temperature increase. dasdag et al. reported that the rectal temperature of the radiated mice were observed to be higher than the rectal temperature of the other mice (9). akdag et al. also observed histopathological changes of mice testes following 9450 mhz microwave radiation and thus concluded that long-term chronic microwave application might affect the epididymal sperm quantity, sperm morphology, weight of testes and epididymis, testicular and epididymal morphology of the mice and that the findings observed in the study increased depending on the duration of microwave application (10). contrary to these studies, dasdag et al. showed that the diameters of the emw-treated rat seminiferous tubules were affected although sperm morphology and seminiferous tubules were not affected (9). the explanation of this result might be the insufficient period of daily exposure in such studies. furthermore, as the cell phones used in our study had the highest sar value (1.52) among all that available in the market, we conclude that microscopic findings of our cases might be due to this reason. agarwal et al reported that the sperm mobility and surfigure 1. control group: normal morphology of seminiferous tubules (a), sertoli cells and spermatogenic cells with normal ultrastructure (b). group 2: normal morphology of seminiferous tubules (arrow head), irregular tubules with a reduction in the spermatogenic cell lines and tubules without lumen (arrow), interstitial zone (*) (c), spaces between the sertoli cells and spermatogenic cells (arrow), spermatid extending towards the lumen (arrow head) (d). group 1: normal morphology of seminiferous tubules (arrow head), irregular tubules with a reduction in the spermatogenic cell lines and tubules without lumen (ok), interstitial zone (*) (e), spaces between the sertoli cells and spermatogenic cells (arrow), spermatid extending towards the lumen (arrow head) (f). a, c, e; haematoxylin-eosin stain, original magnification: x 100, small pictures: x 200, b, d, f: electron micrograph, original magnification: x 5000. kamran_eff_stesura seveso 15/01/15 13:05 pagina 276 277archivio italiano di urologia e andrologia 2014; 86, 4 effects of cell phone on testes vivability of the samples exposed to emw decreased noticeably, ros levels increased and the score number of the ros-tac level decreased (11). the existence of tubules without lumen and an increase in the number of immature sperms were observed. likewise, it was observed at electron microscopy that there are enlarged spaces between the sertoli cells and the spermatogenic cells. considering that the cell phones are positioned close to the testes during daily life, such findings might have an effect on infertility. statistically insignificant result of the light microscopic findings among the groups 1 and 2 point out that the effect of the emws on testis is irreversible. however, many spermatids in the spermiogenesis process were also detected in group 2 at the electron microscopic examination which gives the idea that such effects can be reversed in the longer time period. considering the possible teratogenic and carcinogenic effects of emws due to their negative effects on chromosomes and dna structure, unconscious use of cell phones by children and pregnant women might cause dangerous clinical outcomes in the long term. in order to take the necessary precautions, public information programs should be promoted. in our study some possible biases are improper size of the cell phones used with respect to the size of rats, and the lack of direct analysis of the effects on sperm motilities and fertility. conclusion in conclusion, it should be kept in mind that cell phones might create a risk on human reproductive health taking into account of their widespread use and the location on the body where they are carried. emws emitted by cell phones cause histopathological changes of testicular tissue. considering the long term effects of such changes, they could play an important role in the pathogenesis of important clinical diseases. particularly special attention should be given to the damages that can be caused by the use of cell phones among risk groups (adults, children and pregnant women). therefore, cell phones should be carried distant from the sensitive parts of the body such as testes. unnecessary use of cell phones should be also prevented in order to minimize the deleterious effects. references 1 eliyahu i, luria r, hareuveny r, et al. effects of radiofrequency radiation emitted by cellular telephones on the cognitive functions of humans. bioelectromagnetics. 2006; 27:119-26. 2. hardell l, mild kh, carlberg m, hallquist a. cellular and cordless telephone use and the association with brain tumors in different age groups. arch environ health. 2004; 59:132-7. 3. koyu a, cesur g, ozguner f, et al. effects of 900 mhz electromagnetic field on tsh and thyroid hormones in rats. toxicol lett. 2005; 157:257-62. 4. dohle gr, colpi gm, hargreave tb, et al. eau guidelines on male infertility. eur urol. 2005; 48:703-11. 5. hardell l, sage c. biological effects from electromagnetic field exposure and public exposure standards. biomed pharmacother. 2008; 62:104-9. 6. nakamura h, matsuzaki i, hatta k, et al. nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats. reprod toxicol. 2003; 17:321-6. 7. yakymenko i, sidorik e. risks of carcinogenesis from electromagnetic radiation of mobile telephony devices. exp oncol. 2010; 32:5460. 8. setchell bp. the parkes lecture. heat and the testis. j reprod fertil. 1998; 114:179-94. 9. dasdag s, ketani ma, akdag z, et al. whole-body microwave exposure emitted by cell phones and testicular function of rats. urol res. 1999; 27:219-23. 10. akdag mz, çelik. ms, ketani a, et al. effect of chronic lowintesity microwave radiation on sperm count, sperm morphology, and testicular and epididymal tissue of rats. electro-and magnetobiology. 1999; 18:133-141. 11. agarwal a, desai nr, makker k, et al. effects of radiofrequency electromagnetic waves (rf-emw) from cell phones on human ejaculated semen: an in vitro pilot study. fertil steril. 2009; 92:1318-25. correspondence muhammet ihsan karaman, md ali murat gökçe, md orhan koca, md (corresponding author) drorhankoca@hotmail.com bilal karaman, md metin ishak öztürk, md haydarpasa numune training and research hospital, department of urology, tıbbiye cad. no:2 üsküdar zip:34718 istanbul, turkey necati yurdakul, md feriha ercam, md marmara university school of medicine, department of histology and embryology, istanbul, turkey kamran_eff_stesura seveso 15/01/15 13:05 pagina 277 243archivio italiano di urologia e andrologia 2016; 88, 3 case report adenomatous hyperplasia of the rete testis: a rare intrascrotal lesion managed with limited testicular excision francesco catanzariti 1, lucilla servi 2, andrea fabiani 2, alessandra filosa 3, gabriele mammana 2 1 surgery department, section of urology, asur marche area vasta 4, a. murri hospital, fermo, italy; ² surgery department, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; ³ section of pathological anatomy, department of clinical pathology, asur marche area vasta 3, macerata hospital, macerata, italy. introduction: testicular cancer is one of the most frequent in young men and its incidence is increasing in recent years because of incidental finding during routine ultrasound exams. adenomatous hyperplasia of the rete testis is one of the benign and rare pathological types incidentally detected and very few cases are described in the literature. case report: a 40 years old man come to our attention for a balanoposthitis without testicular pain. during andrological examination we performed palpation of the testes and we noticed a palpable nodule of hard consistency in the left testicle. we then performed an ultrasound exam of the testis which highlighted the presence of an intra-didymus neoformation with diameters of 1.2 x 1.6 cm and with the presence of cysts inside. we also performed blood tests to check tumor markers alpha fetoprotein, beta hcg and ldh which resulted inside the normal range. we then conducted a chest and abdomen ct scan that showed no pathological elements. therefore, as we suspected that this tumor was benign, we performed an enucleation of the neoplasm. the definitive histological examination revealed the presence of dilated ducts lined with epithelial cubic-columnar cells with clear cytoplasm rich in glycogen and the pathologist so concluded that the tumor could be classified as adenomatous hyperplasia of the rete testis. at three months of follow up, the patient doesn’t have any recurrent lesion to either testicles. discussion: adenomatous hyperplasia of the rete testis is a very rare intrascrotal lesion. this histological type is the most frequent between benign lesion of the ovary, but few works in literature reported this histological type in the male gonad and, in most of these works, authors described these lesion at epididymis. conclusion: we believe that a conservative approach must be considered mandatory in case of testicular lesions 1.5 cm in diameter. a radical approach might have alterate fertility of the patient and also have caused psychological trauma more than an enucleation. however a longer follow up is needed to understand if this was the right decision for the oncological point of view. key words: adenomatous hyperplasia of the rete testis; testicular neoplasm enucleation; benign lesion of the testis. submitted 26 march 2016; accepted 5 august 2016 summary no conflict of interest declared. at a young age and in a phase of life fully sexually active. adenomatous hyperplasia of the rete testis is one of the benign and rare pathological types incidentally detected and very few cases are described in the literature. case report a 40 years old man came to our attention for a balanoposthitis without testicular pain. during andrological examination we performed palpation of the testes and we noticed a palpable nodule of hard consistency in the left testicle. we then performed an ultrasound exam (figure 1) of the testis which highlighted the presence of an intra-didymus neoformation with diameters of 1.2 x 1.6 cm and presence of cysts inside. we then performed blood tests to check tumor markers alpha fetoprotein, beta hcg and ldh which resulted inside the normal range, respectively: 5.39 ng/ml, 0 miu/ml and 151 u/l. we also conducted a chest and abdomen computed tomography (ct) scan that showed no pathological elements. we performed an enucleation of the neoplasm: after incision of skin, dartos and vaginal stratum and identification of the lesion we cut albuginea layer and we easdoi: 10.4081/aiua.2016.3.243 introduction testicular cancer is one of the most frequent tumours in young men and its incidence is increasing in recent years because of incidental finding during routine ultrasound exams (1). even if the germ cell tumors are the majority of testicular neoplasms, there are some benign lesions those would require less aggressive treatment considering how the loss of a testicle may adversely affect those patients for the psychological point of view, moreover if we consider that these men come to a diagnosis of cancer figure 1. ultrasoud exam of the left testis which show an intra-didymus neoformation with diameters of 12 x 16 mm and with the presence of cysts inside. catanzariti2_stesura seveso 21/09/16 09:13 pagina 243 archivio italiano di urologia e andrologia 2016; 88, 3 f. catanzariti, l. servi, a. fabiani, a. filosa, g. mammana 244 ily removed the nodule, with low blood loss. albuginea was then repaired with 3-0 absorbable suture. no clamp at spermatic cord was used. the definitive histological examination revealed the presence of dilated ducts lined with epithelial cubic-columnar cells with clear cytoplasm rich in glycogen (figure 2). these cells were ck8 negative, ck18 positive, low weight ck positive, wt1 negative and calretinine negative. the pathologist so concluded that the tumor could be classified as adenomatous hyperplasia of the rete testis. at three months of follow up, the patient doesn’t have any recurrent lesion to either testicles. discussion adenomatous hyperplasia of the rete testis is a very rare intrascrotal lesion. this histological type is the most frequent between benign lesion of the ovary, but few works in literature reported this histological type in the male gonad and, in most of these works, authors described these lesion at epididymis. the histogenesis of these ovarian-type epithelial tumours of the testis and paratestis remains unknown, but some authors (2) explained that this lesion could be a müllerian metaplasia within the testicular parenchyma due to inclusions of the mesothelium during the embryonic period. one of the first studies about this rare tumor is by kosmehl (3) in 1989. he described a 50 years old man with a unilocular cystic intratesticular tumour. he defined that lesion as the male analogue of the respective ovarian growth. after this, very few other studies have been published. the most important manuscripts in the last 5 years were those by by elliot (4) in 2010 and by olla in 2013 (5). elliot and his colleagues described a 55-year-old man with painless right testicular swelling of 16 years duration that at ultrasound appeared as a hypovascular mass measuring 6.5 cm in diameter, containing an area of curvilinear calcification. microscopically, the lesion had mucinous epithelium resembling endocervical type cells with focal intestinal type epithelium, qualifying the tumour as a mucinous neoplasm of low malignant potential or “borderline” type. two years ago a paper by olla described a 58-year-old male patient with an occasional finding of two separate intratesticular nodules on the left testicle. at microscopic examination these lesions were classified as papillary serous cystadenoma with focal cytologic atypia for the presence of cysts with an epithelial lining almost entirely of ciliated columnar type with the presence of sporadic evidence of cytological atypia and no mitoses. in our case report pathologist described the lesion similar to these examples we cited, but the surgical approach we used was different from the others described in the literature. therefore, as we suspected by ultrasound that this tumor was benign, we decided to perform an enucleation instead of an orchiectomy, also because of the young age of our patient. a radical approach might have affected its fertility and also have caused psychological trauma more than an enucleation. as previously reported, we believe that a conservative approach must be considered mandatory in case of testicular lesions 1,5 cm in diameter. the close collaboration with a dedicated uro-pathologist, also during frozen section examination, may be determinant (6, 7). however a longer follow up is needed to understand if this was the right decision for the oncological point of view. acknowledgements the authors would like to thank pathologists of macerata hospital for their cooperation and for providing us histological images of the lesion. references 1. huyghe e, matsuda t, thonneau p. increasing incidence of testicular cancer worldwide: a review. j urol. 2003; 170:5-11. 2. walker an, mills se, jones pf, et al. borderline serous cystadenoma of the tunica vaginalis testis. surg pathol. 1988; 1:431-6. 3. kosmehl h, langbein l, kiss f. papillary serous cystadenoma of the testis. int urol nephrol. 1989; 21:169-74. 4. elliott je, klein jr, drachenberg de. primary testicular mucinous neoplasms: case report and literature review. can urol assoc j. 2010; 4:e112-115. 5. olla l, di naro n, puliga g, tolu ga. intraparenchymal serous papillary cystadenoma of the testis: a case report. pathologica. 2013; 105:15-7. 6. fabiani a, filosa a, fioretti f, et al. diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules. a single institution experience. arch ital urol androl. 2014; 86:373-7. 7. fabiani a, filosa a, pieramici t, mammana g. testicular nodules suspected for malignancy: pathologist make the difference in decision making for organ sparing surgery? anal quant cytopathol histpathol. 2015; 37:147-52. figure 2. definitive histological examination: dilated ducts lined with epithelial cubic-columnar cells with clear cytoplasm rich in glycogen. a) hematoxylin and eosin. b) calretinine. c) cam 5.2. d) wt1. diagnosis: adenomatous hyperplasia of the rete testis. correspondence francesco catanzariti, md (corresponding author) fracatanzariti@libero.it surgery dpt, section of urology, asur marche area vasta 4, a.murri hospital, fermo, italy lucilla servi, md andrea fabiani, md gabriele mammana, md surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy alessandra filosa, md section of pathological anatomy, department of clinical pathology, asur marche area vasta 3, macerata, italy catanzariti2_stesura seveso 21/09/16 09:13 pagina 244 stesura seveso 311archivio italiano di urologia e andrologia 2014; 86, 4 review repeated biopsy in the detection of prostate cancer: when and how many cores vincenzo scattoni, andrea russo, ettore di trapani, umberto capitanio, giovanni la croce, francesco montorsi department of urology, university vita-salute, scientific institute san raffaele, milan, italy purpose: we performed an analysis of the literature about the optimal prostate biopsy (pbx) scheme in the repeated setting methods: we performed a clinical and critical literature review by searching medline database from january 2005 up to january 2014. electronic searches were limited to the english language. the keywords were: prostate cancer, prostate biopsy, transrectal ultrasound, transperineal prostate biopsy. results: the recommended approach in repeated setting is still the extended scheme (epbx) (12 cores). an approach with more than 12 cores according to the clinical characteristics of the patients may optimize cancer detection. saturation pbx (> 20 cores) clearly improves cancer detection if clinical suspicion persists after previous negative biopsy. nevertheless international guidelines do not strongly recommended spbx in all situations of repeated setting. epbx or spbx may be, in the future, substituted by multiparametric mri-targeted biopsies. conclusions: since the scenario in which a pbx is changing, the issue about the number and location of the cores in pbx is still a matter of debate in repeated setting. at present, epbx are still the gold standard even if spbx seems to be necessary in many cases. however, random pbx does not represent the approach of the future, but rather imaging targeted biopsy. key words: prostate cancer; prostate biopsy; transrectal ultrasound; ttransperineal prostate biopsy. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. tocol in each patient, or whether to modify the protocol for different clinical situations. moreover, it is still controversial whether the detection rate may increase with additional biopsies or whether it is necessary to modify the locations where the cores are taken (1, 3). methods we performed a clinical and critical review of electronic databases by searching medline, web of knowledge and the cochrane library from january 2005 up to january 2014 to identify all relevant studies. electronic searches were limited to the english language, and the keywords prostate cancer, prostate biopsy, transrectal ultrasound, transperineal prostate biopsy were used. two independent authors performed all aspects of the search strategy, screening the titles and abstracts of all articles and then reviewing the full-text articles in detail. prostate biopsy strategy in the repeat setting candidates to repeat pbx include patients with a prior negative pbx but with a persistent suspicion of pca on the basis of repeated psa values and/or dre findings (and other markers such us %fpsa, complexed psa, psad, psa velocity and urinary pca3 score), previous peculiar hystological diagnosis (such as atypical small acinar proliferation of prostate asap or high-grade prostatic intraepithelial neoplasia hgpin), candidates to active surveillance or to focal therapy. how and how many cores should be taken in these different scenarios is still unclear and schemes may significantly change in the different patients. based on the findings that even initial extended pbx (epbx) miss almost a third of cancers, a spbx has been adopted to improve pca dr in patients with suspicious clinical findings following previous negative standard pbx. there is now good evidence in the literature that spbx are superior than epbx in this setting. zaytoun et al. reported their experience at cleveland clinic where they compared epbx with spbx in a clearly defined, heterogeneous population of patients undergoing repeat biopsy after a single prior biopsy that failed to diagnose pca (2). they showed that office-based spbx significantly increases dr in repeat biopsy compared to epbx. spbx detected almost onethird more cancers. for patients with benign initial biopdoi: 10.4081/aiua.2014.4.311 presented at 19th national congress sieun, fermo 2014 introduction management of patients with negative biopsy often presents a dilemma. urologists know well that a negative biopsy does not mean the absence of cancer, and a second biopsy is one of the options. the saturation prostate biopsy (spbx) was initially introduced to improve prostate cancer (pca) detection rates (dr) in the repeat setting because initial 10to 12-core biopsy schemes may miss almost a third of cancers (1). nevertheless, the most efficient scheme with the optimal number and location of cores has not been defined yet (1). it is not clear when and how to perform a second biopsy, whether it is necessary to perform the same sampling proscattoni_stesura seveso 15/01/15 10:46 pagina 311 archivio italiano di urologia e andrologia 2014; 86, 4 v. scattoni, a. russo, e. di trapani, u. capitanio, g. la croce, f. montorsi 312 sy, spbx demonstrated significantly greater pca detection. for previous asap and/or hgpin, a trend for higher pca dr was demonstrated in the saturation group but did not reach statistical significance. similarly, scattoni et al. recently tried to identify the optimal combination of sampling sites (number and location) to detect pca in patients previously submitted to an initial negative prostatic biopsy (3). they prospectively performed a transrectal ultrasound (trus)-guided systematic 24-core pbx in 340 consecutive patients after a first negative biopsy (at least 12 cores). subsequently, they set the cancer-positive rate of the 24-core pbx at 100% and calculated pca dr for 255 possible combinations of sampling sites. they reported that the more cores taken, the higher the cancer dr. they showed a continuum of improvement of the cancer dr when increasing the number of cores, even if the cancer dr of the 24 cores was significantly higher than only the mean dr rates of 14-core schemes. moreover, at a given number of cores, the dr rates varied significantly according to the different combination of sites considered. all of these studies demonstrate that spbx provides a higher cancer dr than the extended approach in the repeat setting and that the higher the number of cores, the higher the number of cancers detected. nevertheless the regular use of spbx in clinical practice is not approved (4-5). the national comprehensive cancer network (nccn) suggests performing a second extended protocol after an initial negative extended scheme and suggests considering spbx only in patients with a high risk of cancer after multiple negative biopsies. the 2013 european association of urology (eau) guidelines on pca do not indicate the template that should be used. consequently, the ideal strategy for a second pbx procedure has yet to be fully elucidated. recently, interest has increased in defining more efficient biopsy schemes for pca detection with the minimum number of cores. different variables, both clinical and not clinical, may have an impact on the cancer dr. apart from the clinical characteristics of the patients, some procedural characteristics may have an even greater impact on the cancer dr. intuitively, adding more biopsies to prostatic areas not sampled by common extended schemes should increase the dr. it should be noted, however, that increasing the number of biopsy cores is not the solution to the problem and that the relationship between the number of biopsy cores and the resulting cancer dr does not correlate linearly. as a matter of fact, the curve of saturation tends to plateau, and the increase of cores taken in the template is not equivalent to the increase of cancer detected. kawakami et al. analyzed the pca detection rate by using a three-dimensional (3d) 26-core systematic super-epbx protocol (6). in these analyses, subset biopsy schemes were determined by recursive partitioning to achieve a maximum cancer detection rate at a given number of biopsy cores through a single transrectal approach, a single transperineal approach, or a 3d combination of transrectal and transperineal approaches. they were able to extract a 3d 14-core biopsy protocol that could detect 95% of cancers with the fewest number of cores. nevertheless, their approach has the disadvantage of requiring general anesthesia to perform the double approach (transrectal and transperineal). moreover, they have not specified the most advantageous biopsy protocol according to the clinical characteristics of the patients. all of these data demonstrate that cancer detection is influenced not only by the number of cores but also by the exact location of the cores. the report by delongchamps et al. is a reminder that the urologist needs to do a better job of biopsying the prostate (7). a fairly extensive 36-core biopsy performed in 48 autopsied prostates (median volume: 35 ml) missed 5 of 12 (42%) cancers found on whole-mount pathologic analysis. in fact, the 36-core biopsy offered no benefit over an 18-core protocol in terms of pca detection (7). adopting a scheme that is able to maximize the dr with the fewest number of cores represents a possible new modality of performing pbx. this approach is clinically preferable to adopting a saturation scheme that is unable to increase the cancer dr with the same proportion of increasing numbers of cores. scattoni et al. recently demonstrated that both the number and the location of biopsy cores taken affect cancer dr in a repeated biopsy setting (3). they also showed that the “optimal” repeat biopsy scheme varies according to the clinical characteristics of the patients. analysis revealed that for patients with previous asap diagnosis, the most advantageous scheme was a combination of a 14-core biopsy (without tz biopsies). for patients with no previous asap diagnosis and percentage of free prostate-specific antigen (%fpsa) of 10% or less, the most advantageous scheme was a 14-core biopsy (including four tz biopsies). the most advantageous sampling scheme for patients with no previous asap and %fpsa greater than 10% was a combination of a 20-core biopsy (including 4 tz biopsies). moreover, the number of repeated biopsy is controversial, also because the dr is inversely related to the subsequent procedure. djavan et al. reported in 2001 an original work on the risk of pca on repeat biopsies performed 6 weeks after an initial negative set. these investigators found that cancer detection rates on biopsies 1, 2, 3 and 4 were 22%, 10%, 5% and 4%, respectively, and that 58%, 60.9%, 86.3% and 100% of patients who had rp had organ confined disease on biopsies 1, 2, 3 and 4. the investigators concluded that biopsy 2 in all cases of a negative finding on biopsy 1 seems justified (8). similarly, campos-fernandes et al. in a cohort with extended biopsies found that 18%, 17%, and 14% of patients had pca in second, third, and fourth biopsies, respectively. pca detected at these sets of biopsies was significant in 85% of cases (9). detection of clinically insignificant pca (according to epstein’s criteria) is an inevitable risk of repeat biopsy, and its association with the number of biopsy cores is an issue of considerable debate. moreover, spbx has been evaluated as a staging tool to improve the characterization of low-volume and well-differentiated pca, but whether spbx improves prediction of tumor insignificance remains open to debate. it should be also noted that, in general, cancer missed on initial prostate biopsy is likely to be smaller or more insignificant than those cancers identified on first attempt. in this context, the real issue with pca detection is not overdiagnosis, since only diagnosis or misdiagnosis exist, but rather potential overtreatment. detection and treatment of pca should always be considered independent processes, and concern about overdetecscattoni_stesura seveso 15/01/15 10:46 pagina 312 tion must be weighed against the risk of missing clinically significant cancers. finally, in patients with a diagnosis of pca candidate to active surveillance spbx is preferable even if not mandatory, while in cases of focal therapy spbx may not be sufficient and considered a surrogate to transperineal grid template biopsy. however, the optimal number and location of prostate biopsies in patients in active surveillance with a low grade and low volume pca and patients who are candidate to focal therapy has not been established. several benefits appear to be associated with an image guided approach to prostate biopsy. in summary, fewer men are biopsied overall, a greater proportion of men with clinically significant prostate cancer are biopsied, and fewer men are attributed a diagnosis of clinically insignificant. even if the randomized epbx and spbx remain the gold standard, many patients demand advances beyond the ‘‘old-fashioned’’ randomized biopsy, which is not considered the “future”. nowadays, multiparametric mri (mpmri) has demonstrated to have a high degree of accuracy for the detection of clinically significant prostate cancer and can be used to define a target area before prostate biopsy. in the last five years, the role of image-guided targeted biopsy has grown. the likelihood of detecting cancer in such a visible lesion is definitely higher than with a randomized biopsy if the detection rate per core is considered. mpmri-targeted biopsies have demonstrated superiority over systematic randomized biopsies for the detection of clinically significant disease and representation of disease burden, while deploying fewer cores. there is evidence that the gleason score obtained in a targeted biopsy reflects the true gleason score better than the gleason score obtained by a randomized pbx (10). hambrock et al. have demonstrated that mri-guided biopsies significantly improve pretreatment risk stratification by obtaining cores that are representative of the true gleason grade (11). in a recent review about mpmri-targeted biopsies, men with a clinical suspicion of prostate cancer, a biopsy of the prostate that used mri to inform the sampling was associated with a detection rate of clinically significant prostate cancer of 42%. this approach might permit a reduction in the number of men who need to undergo biopsy if they are deemed to have a normal mri. the efficiency of the targeted sampling appeared superior to the standard approach (70% vs 40%). since the randomized pbx was associated with a diagnosis of insignificant prostate cancer in 10% of men biopsied, this cancer diagnosis might have been avoided if men had undergone targeted biopsy alone (11). the authors also concluded that adopting mpmri-targeted biopsies rather than randomized pbx, fewer men are biopsied overall, a greater proportion of men with clinically significant prostate cancer are biopsied, and fewer men are attributed a diagnosis of clinically insignificant prostate cancer. on the contrary, other authors have shown that in cases combining targeted and randomized biopsies during one pbx session, a substantial number of cancers were detected in only the randomized cores (12). relying on the targeted biopsy alone would have led to a significant rate of underdetection in these studies. there is no doubt that epbx might better characterize pca volume and cancer extent than just a targeted biopsy: the positive cores give us information on not only the cancer extent but also the number of negative cores. targeted biopsies seem to reflect the true gleason score, yet they might underestimate the extent of the cancer. probably the combination of both targeted and extended biopsies will show the most appropriate information about the correct cancer characteristics. conclusions the issue about the number and location of the cores is still a matter of debate in repeat setting also because the scenarios in which pbx is required are changing. at present, spbx seems to be necessary in most of the cases. however, random prostate pbx do not represent the future while imaging target biopsy are becoming more popular. references 1. scattoni v, zlotta s, montironi r, et al. extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. eur urol. 2007; 52:1309-1322. 2. zaytoun om, moussa as, gao t, et al. office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. j urol. 2011; 186:850-4. 3. scattoni v, raber m, capitanio u, et al. the optimal rebiopsy prostatic scheme depends on patient clinical characteristics: results of a recursive partitioning analysis based on a 24-core systematic scheme. eur urol. 2011; 60:834-41. 4. scattoni v, maccagnano c, capitanio u, et al. random biopsy: when, how many and where to take the cores? world j urol. 2014; 32:859-69. 5. ukimura o, coleman ja, de la taille a, et al. contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. eur urol. 2013; 63:214-30. 6. kawakami s, okuno t, yonese j, et al. optimal sampling sites for repeat prostate biopsy: a recursive portioning analysis of threedimensional 26-core systematic biopsy. eur urol. 2007; 51:675-83. 7. delongchamps nb, de la roza g, jones r, et al. saturation biopsies on autopsied prostates for detecting and characterizing prostate cancer. bju int. 2009; 103:49-54. 8. djavan b, ravery v, zlotta a, et al. prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? j urol. 2001; 166:1679-83. 9. campos-fernandes jl, bastien l, nicolaiew n, et al. prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. eur urol. 2009; 55:600-6. 10. moore cm, robertson nl, arsanious n, et al. image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. eur urol. 2013; 63:125-40. 11. hambrock t, hoeks c, hulsbergen-van de kaa c, et al. prospective assessment of prostate cancer aggressiveness using 3-t diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. eur urol. 2012; 61:177-84. 12. kuru th, roethke mc, seidenader j, et al. critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. j urol. 2013 ; 190:1380-6. 313archivio italiano di urologia e andrologia 2014; 86, 4 the optimal number of cores in the detection of prostate cancer after an initial negative biopsy correspondence vincenzo scattoni, md (corresponding author) scattoni.vincenzo@hsr.it andrea russo, md ettore di trapani, md umberto capitanio, md giovanni la croce, md francesco montorsi, md department of urology, university vita-salute, scientific institute h san raffaele. via olgettina 60 20132 milan, italy scattoni_stesura seveso 15/01/15 10:46 pagina 313 archivio italiano di urologia e andrologia 2013; 85, 292 introduction radical prostatectomy (rp) is the most common treatment option for prostate cancer, with more than 80 000 rps annually in the usa (1). urinary incontinence (ui) is a common and costly complication in men after rp, often adversely affecting their quality of life (qol) (2). despite improvements in surgical techniques and a better understanding of pelvic anatomy, the reported stress urinary incontinence (sui) rates are between 5% and 48% (3). conservative treatment of the urinary leakage represents the first line management of ui after rp, but the value of the various conservative approaches to treat postprostatectomy ui after rp remains uncertain (4). the last cochrane systematic review on this topic found that there was conflicting information about the benefit of pelvic floor muscle training for either prevention or review continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review maria angela cerruto, carolina d'elia, walter artibani department of surgery urology clinic, university of verona, italy. objectives: to analyze continence and complications rates after male slings as first line surgical treatment, in order to improve patient counseling for the management of sui postprostatectomy. method: a medline search using specified search terms was done on january 23, 2012. this research rendered 160 records. results: no controlled trial was available for analysis. the majority of papers dealing with outcome and complications came from a few centres. at a median follow-up of 15 months the pooled cure rates for all kinds of slings was 77.4; in the advance group the pooled cure rates was 72.5%; in the invance group it was 74.2% while in the remeex group it was 84.3%. conclusions: only a few number observational studies addressed review selection criteria. the pooled overall cure rates is high but there are no data concerning reliable preand postoperative prognostic factors affecting treatment failure and complications rates, thus it is not possible to have suitable criteria for a better patient selection. the statistically pooled results obtained should be interpreted with caution because of several limitations due to several study selection limitations: observational study design, few number of analysed studies, heterogeneity, lack of outcome definition and standardisation, between-study variability, high risk of bias. key words: sling; male incontinence; radical prostatectomy; continence; complications. submitted 17 july 2012; accepted 31 december 2012 no conflict of interest declared summary treatment of urine leakage after prostate surgery. more research of better quality is needed to assess conservative managements (4). when conservative treatments are unsuccessful after a reasonable period of time (e.g. 8-12 weeks), invasive therapies should be considered (5). according to the last international consultation on incontinence recommendations, for sui due to sphincter incompetence the recommended option is the artificial urinary sphincter (aus) (grade b); other options, such as a male sling, may be considered (grade c) (5). these low grades of recommendation can be explained by the fact that, although there are several options for surgical treatment of ui after prostatectomy, surprisingly only one randomised clinical trial was identified in the literature, comparing aus implantation and injectable treatcerruto_cont_stesura seveso 24/06/13 11:06 pagina 92 93archivio italiano di urologia e andrologia 2013; 85, 2 continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review length of follow-up, time period of surgery, type of prostatectomy), sling types, outcomes (overall cure rates, complications rates). a single reviewer (mac) assessed risk of bias at the study level. the downs-black quality assessment tool (9) was used for nonrandomized studies; a score ! 17 of 31 was considered higher quality. few studies presented their original data in a format amenable to meta-analysis. articles that presented data as a median and range were converted to means according to hozo et al. (10). a single weight-adjusted mean or proportion for each variable or outcome was computed for each of the nonrandomized studies. to derive pooled estimates of proportions for the outcomes explored, random effects models were used. pooling was conducted using comprehensive meta analysis version 2.2.046 (englewood, nj). given that this review assessed measures of prevalence, publication bias was not evaluated. results and discussion from screening 160 records, 49 full-text articles were retrieved with only 5 articles included in the systematic review (figure 1). the 5 included articles involved 356 participants living in 8 countries with a median followup after sling implant of 15 months (interquartile range, 12-21) and sling surgeries conducted between 2002 and 2009. patients’ mean age at time of surgery was 68.06 (standard deviation, 1.37) years. study characteristics and quality are summarized in table 1 (11-15). ment with macroplastique (6). for other surgical procedures such as male slings, pro-act system, other bulking agents and stem-cell therapy, only non-randomised studies were identified (7), making impossible to answer questions about treatment comparison in terms of efficacy, safety, complications and long term results. despite the lack of information, when patients seek effective and durable treatment to achieve a continence status, it is necessary to adequately make aware them of continence rates and all possible complication of any proposed treatment as first line surgical option. the aim of this review was to analyze continence and complications rates after male slings as first line surgical treatment, in order to improve patient counseling for the management of sui postprostatectomy. methods the preferred reporting items for systematic reviews and meta-analyses (prisma) checklist was used to help guide this report (8). we conducted a pubmed database search through january 2012 for relevant prospective cohort studies and case series that met the following inclusion criteria: english language; adults with sui postprostatectomy who underwent male slings as first surgical option for continence recovery; studies carried out on ! 20 patients with a mean follow-up of ! 1 year;because the majority of papers dealing with outcome and complications came from a few centres, only the most recent publication(s) from each centre were included to avoid the same patients being presented several times. multiple free-text searches were performed including the following terms: suburethral slings, suburethral sling, transobturator tape, transobturator tapes, transobturator suburethral tape, trans-obturator tape, male sling, male slings, argus sling, advance sling, invance sling, remeex sling, urinary incontinence, urinary stress incontinence, post prostatectomy, post-prostatectomy, prostatectomy, prosta tectomies, suprapubic prostatectomies, suprapubic prosta tectomy, retropubic prostatectomies, retropubic prosta tectomy. in addition, other significant studies cited in the reference lists of the selected papers were considered. both authors independently reviewed all records by title and abstract followed by full-text articles for those meeting the screening criteria. both authors independently abstracted data on study details (authors, year of publication, journal, location, study design), patient characteristics (age, figure 1. preferred reporting items for systematic reviews and meta-analyses (prisma) flow diagram. source publication journal nation patient time period rp rate patient sling type mean risk year number of surger (%) mean age follow-up of bias grise p, et al. (11) 2011 urology france 103 2007-2009 94.8 69.4 i-stop toms 12 high cornu jn, et al. (12) 2011 bju int france 136 2007-2009 92 67.4 advance 21 high cornel eb, et al. (13) 2010 j urol the netherlands 35 2007-2008 80 68.5 advance 12 high gallagher bl, et al. (14) 2007 urology usa 31 2002-2005 94 66 invance 15 high sousa-escandon a, et al. (15) 2007 eur urol spain, italy, 51 2002-2005 84.3 69 remeex 32 high greece, germany, portugal table 1. characteristics of included observational studies. 160 records identified by medline search 49 records for full text screen 5 records included in the analysis 111 removed by title abstract/screen 6 removed by full text screen cerruto_cont_stesura seveso 24/06/13 11:06 pagina 93 archivio italiano di urologia e andrologia 2013; 85, 2 m.a. cerruto, c. d'elia, w. artibani 94 ment in continence, necessitating long-term clean intermittent catheterization. the average time to removal of the sling because of infection was 99 days (range 35 to 163). all these patients presented with pain and superficial infections. in the remeex case series (15) the mesh was removed in 1 case owing to urethral erosion and the varitensor in 2 cases owing to infection. there were five (9.8%) uneventful intraoperative bladder perforations at the postoperative period, and there were three mild perineal haematomas (5.9%). most patients felt perineal discomfort or pain, which was easily treated with oral medications. conclusion the male slings approved for use currently include a variety of types: bone anchored slings, adjustable slings, and transobturator slings. this review tried to systematically assessed the outcomes of male slings used as the first line treatment, after conservative therapy failure, for the treatment of post-prostatectomy sui. only a few number of the observational studies published in the literature addressed review selection criteria. the pooled overall cure rates is high but there are no data concerning reliable preand postoperative prognostic factors affecting treatment failure and complications rates, thus it is not possible to have suitable criteria for a better patient selection. the statistically pooled results obtained should be interpreted with caution because of several limitations due to several study selection limitations: observational study design, few number of analysed studies, heterogeneity, lack of outcome definition and standardisation, between-study variability, high risk of bias. in order to better select patients for male slings in the management of post-prostatectomy sui as first line treatment, it is mandatory to carried out both well designed randomized clinical trials and longitudinal cohort studies, using standardised protocols and outcome measures. references 1. united states agency for healthcare research and quality. healthcare cost and utilization project (usa). available at: http://hcupnet.ahrq.gov/. accessed january 2012. 2. haab f, beley s, cornu jn, et al. urinary and sexual disorders following localised prostate cancer management. bull cancer. 2010; 97:1537-49. 3. schröde a, abrams p, andersson ke, et al. guidelines on urinary incontinence. in arnheim ag, editor. eau guidelines. arnheim, the netherlands: european association of urology. 2010; p.11-28. 4. campbell se, glazener cm, hunter kf, et al. conservative management for postprostatectomy urinary incontinence. cochrane database syst rev. 2012; 1:cd001843. 5. abrams p, andersson ke, birder l, et al. fourth international consultation on incontinence recommendations of the international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. neurourol urodyn. 2010; 29:213-240. 6. imamoglu ma, tuygun c, bakirtas h, et al. the comparison of artificial urinary sphincter implantation and endourethral macroplasthe types of slings considered were: the 4-arm i-stop toms transobturator male sling (cl medical) (11) (that is an adapted version of the 2-arm toms bulbar sling) (16); the advance sling (12, 13) (a retrourethral transobturator sling working by relocating the lax and descended supporting structures of the posterior urethra and sphincter region after prostate surgery into the former preprostatectomy position (17); the invance sling (american medical system) (14) (a nonadjustable sling system characterised by a silicon-coated polyester sling positioned under the bulbar urethra via a perineal incision to obtain a compression (18); the remeex system (15) (a readjustable sling positioned under the bulbar urethra (19). figure 2 pooled the continence rates achieved after the analysed sling procedures. at a median follow-up of 15 months the pooled cure rates for all kinds of slings was 77.4% (95% ci 66.0-85.8); in the advance group the pooled cure rates was 72.5 (95% ci 65.0-68.8); in the invance group it was 74.2% (95% ci 56.3-86.5) while in the remeex group it was 84.3% (95% ci 71.6-92). these statistically pooled results should be interpreted with caution because of several limitations due to several study selection limitations: study design, number of analysed studies, betweenstudy variability, high risk of bias. concerning overall complications rate it was impossible to obtain this information. grise et al. did not report complications, such as bladder perforation, intraoperative bleeding (> 200 ml), or nerve, bowel, or vascular injury, occurred during the implant of the i-stop toms male sling, except for wounding of the corpus cavernosum in 4% of patients (11). the authors reported a successful catheter removal 48 hours after surgery in 98.9% of patients. moreover, 97.3%-100% were free of urinary tract infection at the different follow-up visits, and 96.5%-100.0% of the patients had not experienced urinary tract infection in the month before the visits. immediately after the advance implant, cornu et al. (12) reported only two cases of dysuria, one case of perineal haematoma and two cases of perineal paresthesia. during follow-up 10% of 10% of patients had perineal pain and 14% of patients had mild dysuria, but none require surgical management. in the other case series (13) complications developed in 2 patients, including sling infection and postoperative urinary retention in 1 each. in the invance group (14) 4 patients (13%) underwent sling removal; two removals were because of infection (both of these patients had undergone previous radiotherapy), one because of pain, and one because of the lack of improvefigure 2. pooled analysis of reported overall cure rates. grise p, et al. (11), 2011 cornu jn, et al. (12), 2011 cornel eb, et al. (13), 2010 gallagher bl, et al. (14), 2007 sousa-escandon a, et al. (15), 2007 cerruto_cont_stesura seveso 24/06/13 11:06 pagina 94 95archivio italiano di urologia e andrologia 2013; 85, 2 continence and complications rates after male slings as primary surgery for post-prostatectomy incontinence: a systematic review tique injection for the treatment of postprostatectomy incontinence. eur urol. 2005; 47:209-13. 7. silva la, andriolo rb, atallah an, da silva em. surgery for stress urinary incontinence due to presumed sphincter deficiency after prostate surgery. cochrane database syst rev. 2011; (4):cd008306. 8. moher d, liberati a, tetzlaf j, et al. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. bmj. 2009; 339:332-336. 9. downs sh, black n. the feasibility of creating checklist for assessment of the methodological quality both randomized and non-randomized studies of health care interventions. j epidemiol community health. 1998; 52:377-384. 10. hozo sp, djubegovic b, hozo i. estimating the mean and variance from median, range and the size of the sample. bmc med res methodol. 2005; 5:13. 11. grise p, vautherin r, njinou-ngninkeu b, et al. i-stop toms transobturator male sling, a minimally invasive treatment for post-prostatectomy incontinence: continence improvement and tolerability. urology. 2012; 79:458-63. 12. cornu jn, sèbe p, ciofu c, et al. mid-term evaluation of the transobturator male sling for post-prostatectomy incontinence: focus on prognostic factors. bju int. 2011; 108:236-40. 13. cornel eb, elzevier hw, putter h. can advance transobturator sling suspension cure male urinary postoperative stress incontinence? j urol. 2010; 183:1459-63. 14. gallagher bl, dwyer nt, gaynor-krupnick dm, et al. objective and quality-of-life outcomes with bone-anchored male bulbourethral sling. urology. 2007; 69:1090-4. 15. sousa-escandón a, cabrera j, mantovani f, et al. adjustable suburethral sling (male remeex system) in the treatment of male stress urinary incontinence: a multicentric european study. eur urol. 2007; 52:1473-9. 16. grise p, geraud m, lienhart j, et al. transobturator male sling toms for the treatment of stress post-prostatectomy incontinence, initial experience and results with one year’s experience. int braz j urol. 2009; 35:706-713. 17. rehder p, gozzi c. transobturator sling suspension for male urinary incontinence including post-radical prostatectomy. eur urol. 2007; 52:860-7. 18. fassi-fehri h, bader l, cherass a, et al. efficacy of the invancetm male sling in men with stress urinary incontinence. eur urol. 2007; 51:498-503. 19. sousa-escandon a, cabrera j, mantovani f, et al. externally readjustable sling for treatment of male stress urinary incontinence: points of technique and preliminary results. j endourol. 2004; 18:113-8. correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it urology clinic, department of surgery university of verona & aoui, p.le l scuro 10 37134 verona, italy cerruto_cont_stesura seveso 24/06/13 11:06 pagina 95 archivio italiano di urologia e andrologia 2016; 88, 4266 original paper different patterns of pelvic ureteral endometriosis. what is the best treatment? results of a retrospective analysis salvatore butticè 1, antonio simone laganà 2, giuseppe mucciardi 1, francesco marson 3, tzevat tefik 4, christopher netsch 5, salvatore giovanni vitale 2, emre sener 6, rosa pappalardo 1, carlo magno 1 1 department of human phatology, section of urology, university of messina, messina, italy; 2 unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina, italy; 3 department of urology, university of studies of torino, torino, italy: 4 department of urology, istanbul university, istanbul faculty of medicine, istanbul, turkey: 5 department of urology, asklepios hospital barmbek, hamburg, germany: 6 department of urology, school of medicine, marmara university, istanbul, turkey. objective. endometriosis is an estrogendependent disease. the incidence of urinary tract endometriosis (ue) increased during the last few years and, nowadays, it ranges from 0.3 to 12% of all women affected by the disease. the ureter is the second most common site affected. the ureteral endometriosis is classified in extrinsic and intrinsic. the aim of this study is to individuate the best treatments for each subset of ureteral endometriosis. materials and methods. 32 patients diagnosed with surgically treated ue were retrospectively reviewed. the patients were divided into 3 subsets (intrinsic ue, extrinsic ue with and without obstruction). the patients with intrinsic ue (n = 10) were treated with laser endoureterotomy. the patients with extrinsic ue (n = 22) were divided in two subsets with (n = 16) and without (n = 6) hydronephrosis. all the patients underwent ureteral stenting, and resection and reimplantation was performed in the first group, and when the mass was > 2.5 cm (n = 3) boari flap was performed. laparoscopic ureterolysis (shaving) was performed in the second group. results. in the extrinsic subset of ue, we obtained an high therapeutic success (84%). conversely, in the intrinsic subset there was a recurrence rate of the disease in 6/10 of the patients (60%). conclusions. ureterolysis seems to be a good treatment in extrinsic ue without obstruction. resection and reimplantation allows excellent results in the extrinsic ue with obstruction. in the intrinsic subset, the endoureterotomy approach is inadequate. key words: ureteral endometriosis; laparoscopic ureterolysis; laser endoureterotomy; ureteral reimplantation; laparoscopy. submitted 3 april 2016; accepted 22 may 2016 summary no conflict of interest declared. the disease most often affects the ovaries (up to 88% of all cases), sacrouterine ligaments, fallopian tubes, rectum, cervico-vaginal zone, and urinary tract. the incidence of urinary tract endometriosis (ute) increased during the last few years and, nowadays, it ranges from 0.3 to 12% of all women affected by the disease (7). the ureter is the second most common site affected by ute, after bladder, showing an increasing incidence in the contemporary literature because of the improvement in diagnostic tools as well as a greater awareness and skill among clinicians in recognizing this disease. in most cases ureteral involvement is completely unnoticed (8, 9). there are two major types of ureteral endometriosis (ue): intrinsic and extrinsic, occurring respectively with a 1:4 ratio (10-12). the distinction of the extrinsic or intrinsic nature of ureteral involvement may be considered as arbitrary. the depth of invasion in the extrinsic form has to be confirmed by the final histological examination; thus, differentiation cannot be reliably made, either preoperatively or during surgery. in extrinsic pattern, the endometrial tissue invades only the ureteral adventitia or surrounding connective tissue and, consequently, it causes ureteral obstruction (13-15). this is the most common form of ue and represents 80% of cases (16). in intrinsic disease (which occurs in only 20% of cases), ectopic endometrial tissue directly infiltrates the muscle layer of the ureteral wall within the muscularis propria, lamina propria or ureteral lumen; nevertheless, the two types of ue may coexist. the preoperative diagnosis and choice of an appropriate surgical approach are both essential for the treatment of patients with ureteral endometriosis. regarding surgical treatment for ureteral endometriosis, currently the gold standard is represented by lapa roscopy (17), although others (18) suggest the use of robotic surgery in order to improve surgical accuracy and minimize complications. considering this evidence, the purpose of our study was to identify the best surgical treatments for different types of ue. doi: 10.4081/aiua.2016.4.266 introduction endometriosis is an estrogen-dependent disease (1) characterized by the ectopic presence and growth of functional endometrial tissue, glands and stroma, outside the uterine cavity (2, 3). approximately 10% of women in reproductive age are estimated to be affected by this disease (4, 5). its symptoms and signs include acute or chronic pelvic pain, abnormal bleeding, infertility (6). butticà_stesura seveso 09/01/17 09:51 pagina 266 267archivio italiano di urologia e andrologia 2016; 88, 4 the management of ureteral endometriosis materials and methods as standard protocol of the university hospitals in which the study was carried out, each patient was informed at the admission and signed an informed consent allowing data collection for research purposes. the study design is in accordance with the helsinki declaration, conforms the committee on publication ethics (cope) guidelines and was approved by the institutional review board (irb) of the university hospitals in which it was performed. all the design, analysis, interpretation of data, drafting and revisions followed the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies (19), available through the equator (enhancing the quality and transparency of health research) network. below the surgical approaches that were used to treat different types of ue are described. we enrolled only the patients with histologically confirmed endometriosis. management of the intrinsic ureteral endometriosis accumulating evidence suggests that indications for endoureterotomy include an intrinsic ureteral lesion and/or lesions smaller than 3 cm with the lesion being located under the level of the iliac vessels (14, 20). in our case series, we used a 0.035 inch guidewire to introduce the ureteroscope through the ureteral orifice. the storz rigid ureteroscope was applied in all cases. moreover, we performed cup biopsy of the ureteral mass, and a 6.0 f stent was left in each patient. one week later, after the histological confirmation of ureteral endometriosis, patients underwent an endoureterotomy with laser (120w 2-μm continuous-wave tm:yag laser, revolix 2). a retrograde cutting pattern was performed, by slowly advancing the ureteroscope proximally. the incision began at roughly 0.5 cm below the mass margin and extended over the obstruction for another 0.5 cm. the ureteroscope could be used to assist the procedure by mild lateral parting of the cutting edges. in case of bleeding, we cauterized the lesion by defocused laser beam and the incision was deepened until the periureteral fat was seen. a 6 f stent was left indwelling for 4 weeks with urethral catheterization of 2 days. management of the extrinsic ureteral endometriosis the enrolled cases of extrinsic ue were divided in in two subsets: with or without obstructive pattern. all patients of the two subsets underwent pre-surgical preparation, began 24 hours prior to surgery with oral intake of selgesse 1000 (promefarm, milan, italy), plus mylicon tablets (warner lambert, milan, italy). ureteral stenting (6 f) was performed before the procedure. all patients underwent laparoscopic approach with standard technique including the use of 10-mm operative laparoscope and three 5-mm ancillary trocars, at 12-mm hg intra-abdominal pressure. the first surgical step was the same for each subset, consisting in the exposure of the peritoneum and careful blunt dissection of the ureter. in cases without obstructive pattern, the dissection started where the ureter was clearly visible and without adhesions, and progressed in the direction of the uterosacral ligaments until insertion into the bladder. at the end of the dissection, the ureter was completely mobilized and visible from the pelvic brim to its insertion into the bladder. endometriosis lesions on the ureter, both those circularly encasing it and those involving just part of its circumference, were carefully removed. in cases with obstructive pattern, after ureteral mobilization, we performed resection and reimplantation (lichgregoire technique); moreover, in 3 of the 16 patients, because of the extension of the mass (> 2.5 cm), we had to perform also a boari flap to obtain a tension-free anastomosis. at follow-up, we performed ultrasound after one week, urography, ultrasound, blood (included ca125) and urine tests after one, six months and one year recurrence of the disease was defined by ultrasound, urography and serum level of ca125. results we performed a retrospective analysis of our data, collected from march 2000 to august 2014. we enrolled 32 patients, 10 with intrinsic and 22 with extrinsic ue. in the extrinsic subset, we enrolled 16 patients with and 6 patients without obstructive pattern. the clinic characteristics and the symptoms associated of the patients are shown in the tables 1 and 2. all the operations were performed by two surgeons with great experience in endourology, open and laparoscopic surgery. in the table 1. patients characteristics. extrinsic ue extrinsic ue intrinsic ue obstructive without obstruction (n = 10) (n = 16) (n = 6) age (mean ± sd) 42.18 ± 11.25 42.83 ± 10.10 47.6 ± 10.75 bmi (mean ± sd) 23.68 ± 4.81 20.83 ± 3.92 23.6 ± 4.85 site of involvment left (n,%) 10 (62.5) 4 (66.6) 5 (50) right (n,%) 5 (31.2) 2 (33.3) 5 (50) bilateral (n,%) 1 (6.2) 0 0 comorbidities hypertension (n,%) 4 (25) 1 (16.6) 3 (30) diabetes (n,%) 1 (6.2) 0 2 (20) metabolic syndrome (n,%) 2 (12.5) 0 1 (10) hypercholesterolemia (n,%) 0 1 (16.6) 0 pcos (n,%) 3 (18.7) 2 (33.3) 0 table 2. symptoms in patients with ureteral endometriosis. extrinsic ue extrinsic ue intrinsic ue obstructive without obstruction (n = 10) (n = 16) (n = 6) dysmenorrhea (n,%) 7 (43.7) 1 (16.6) 3 (30) dyspareunia(n,%) 4 (25) 0 2(20) chronic pelvic pain (n,%) 2 (12.5) 1 (16.6) 1 (10) hematuria (n,%) 7 (43.7) 3 (50) 5 (50) recurrent uti (n,%) 3 (18.7) 2 (33.3) 3 (30) infertility (n,%) 6 (37.5) 2 (33.3) 0 luts (n,%) 2 (12.5) 1 (16.6) 4 (40) no symptoms (n,%) 1 (6.2) 2 (33.3) 0 butticà_stesura seveso 09/01/17 09:51 pagina 267 archivio italiano di urologia e andrologia 2016; 88, 4 s. butticè, a.s. laganà, g. mucciardi, f. marson, t. tefik, c. netsch, s.g. vitale, e. sener, r. pappalardo, c. magno 268 extrinsic subset of ue, we obtained a good urological therapeutic success (84%). conversely, in the intrinsic subset there was a recurrence of the disease, in 6 patients (60%) grade 1 hydronephrosis persisted with one of the patients having haematuria. in the extrinsic ue, 10 patients underwent to open surgery and 12 to laparoscopic surgery. no major complications occurred, although two patients treated with open surgery had surgical wound infection and another one needed blood transfusion. kaplan-meier survival curve shows (figure 1) the difference between two groups; comparison of recurrence curves was made by using log-rank test, which was statistically significant (p = 0.0007). discussion the goal of treatment for ue is to relieve obstruction and preserve as much renal function as possible. in most cases, management needs multi-disciplinary approach (21). medical therapy is indicated only for early-stage disease, but not for advanced disease due to high recurrence and the limited effect on scar tissue. according to zanetta et al. (23), medical treatment after total abdominal hysterectomy with bilateral salpingo-oophorectomy can decrease the recurrence from 27% to 3%. of course, this combined treatment is not advisable when the patient is young and it is mandatory to preserve its fertility. furthermore, there is no consensus on which medical treatment is the best to manage ue, currently danazol, gnrh agonist (leuprolide, goserelin), medroxyprogesterone, oestrogen-progestin combination and progestin alone being used (23, 24). in particular, danazol and gnrh are most commonly used in case of iii-iv stages, with the aim of antagonizing the effect of gonadotropin, entailing the eventual effect of inhibition of ovarian function. even if several authors reported use of these two hormonal treatments, clearly evidence about long-term outcome is still missing (25). considering these assumptions, to date surgery still maintains a key role in the management of ue. the aim of surgery is to remove or relieve obstruction, especially in cases of advanced stage of disease, and to resolve the haematuria. in iii-iv stages, in fact, there is a predominance of profibrotic response (5) and the derived fibrotic perilesional tissue, typically, does not respond to hormonal therapy (26-28). despite numerous papers previously published in the literature, to date there is no definitive answer about the best surgical procedure to manage ue. it is widely accepted that two surgical approaches are mainly used: resection of the ureteral segment and ureterolysis (which frees the ureter from extrinsic compression through a laparoscopic “shaving” technique). most surgeons are familiar with both techniques, though the reasons that guide their choice remain unclear, particularly as recommendations on the surgical management of ute tend to reflect experience or personal convictions based on scarce evidence. thus, some authors (29) recommend radical resection to reduce the risk of recurrences as much as possible, while others (30) reserve ureterectomy only for limited cases and believe conservative surgery to be the management of choice in relieving ureteral obstruction and removing endometriosis mass, even in patients with moderate or severe pyelic dilatation. the “carcinologic” approach is adopted by surgeons who strongly believe that the radical removal of all endometriotic foci is the most effective way to prevent the risk of recurrences, much as radical surgery does in cancer. thus, ureteral resection should be performed to avoid leaving intrinsic implants. conversely, other authors proposed an approach to ute that focuses more on the woman's needs and the resolution of symptoms, than on prior lesion excision. this approach becomes possible where medical treatment is associated with surgery and long-term administered. in our experience regarding extrinsic subset, we performed a radical approach in cases with obstructive pattern and a conservative one in cases without obstructive pattern: this seems to be effective and consent to minimize side effects maximizing the results. regarding intrinsic subset (always obstructive), we performed an endoscopic approach (endoureterotomy) with laser: this has been proven to be effective only in 40% of cases, making it a controversial option. conclusion despite our study is limited by the little number of patients and the small period of follow-up, we can suggest that in the extrinsic ue subset without obstructive pattern, ureterolysis is an appropriate treatment. in the extrinsic ue with obstructive subset, the resection and reimplantation allows excellent results. in the intrinsic subset, the endoureterotomy approach reported high rates of failure, showing to be effective only in 40% of patients. this finding suggests the general idea that, in case of intrinsic ue, endoscopic treatment can be proposed by advising the patients that the rate of success is only 40%; even if our figure 1. graphic recurrence probability/time (months). butticà_stesura seveso 09/01/17 09:51 pagina 268 269archivio italiano di urologia e andrologia 2016; 88, 4 the management of ureteral endometriosis number of treated patients is relatively small, our kaplanmeier curves clearly shows that recurrence generally appears within one year after surgery: this suggest to plan an early follow-up, in order to detect recurrences as early as possible. a second possibility could be to treat intrinsic ue by resection and reimplantation from the beginning; this is also a viable possibility, considering low rates of success by endourological approach. further evaluations with a more consistent number of patients and with longer follow-up are still needed before solid conclusions can be drawn. references 1. giudice lc, kao lc. endometriosis. lancet. 2004; 364:1789-99. 2. laganà as, sturlese e, retto g, et al. interplay between misplaced müllerian-derived stem cells and peritoneal immune dysregulation in the pathogenesis of endometriosis. obstet gynecol int. 2013; 2013:527041. 3. bulun se. endometriosis. n engl j med. 2009; 360:268-279. 4. sofo v, götte m, laganà as, et al. correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. arch gynecol obstet. 2015; 292:973-86. 5. marana r, lecca a, biscione, et al. endometriosis: the gynecologist's opinion. urologia. 2012; 79:160-166. 6. triolo o, laganà as, sturlese e. chronic pelvic pain in endometriosis: an overview. j clin med res. 2013; 5:153-63. 7. maccagnano c, pellucchi f, rocchini l, et al. ureteral endometriosis: proposal for a diagnostic and therapeutic algorithm with a review of the literature. urol int. 2013; 91:1-9. 8. nezhat c, nezhat f, nezhat ch, et al. ds: urinary tract endo metriosis treated by laparoscopy. fertil steril 1996; 66:920-924. 9. butticè s, laganà as, barresi v, et al. lumbar ureteral stenosis due to endometriosis: our experience and review of the literature. case rep urol. 2013; 2013:812475. 10. mounsey al, wilgus a, slawson dc. diagnosis and management of endometriosis. am fam physician 2006; 74:594-600. 11. mahutte ng, arici a. medical management of endometriosisassociated pain. obstet gynecol clin north am. 2003; 30:133-150. 12. takagi h, matsunami k, ichigo s, et al. novel medical management of primary bladder endometriosis with dienogest: a case report. clin exp obstet gynecol. 2011; 38:184-185. 13. comiter cv. endometriosis of the urinary tract. urol clin north am 2002;29:625-635 14) yohannes p: ureteral endometriosis. j urol. 2003; 170:20-25. 15. seracchioli r, mabrouk m, montanari g, et al. conservative laparoscopic management of urinary tract endometriosis (ute): surgical outcome and long-term follow-up. fertil steril. 2010; 94:856-861. 16. takamura m, koga k, osuga y, et al. post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. hum reprod. 2009; 24:3042-3048. 17. antonelli a. urinary tract endometriosis. urologia. 2012; 79:167-70. 18. nezhat c, modest am, et al. the role of the robot in treating urinary tract endometriosis. curr opin obstet gynecol. 2013; 25:308-11. 19. von elm e, altman dg, egger m, et al. the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. lancet. 2007; 370:1453-1457. 20. marcelli f, collinet p, vinatier d, et al. ureteric and bladder involvement of deep pelvic endometriosis. value of multidisciplinary surgical management. prog urol. 2006; 16:588-593. 21. langebrekke a, qvigstad e. ureteral endometriosis and loss of renal function: mechanisms and interpretations. acta obstet gynecol scand. 2011; 90:1164-6. 22takeuchi s, minoura h, toyoda n, et al. intrinsic ureteric involvement by endometriosis: a case report. j obstet gynaecol res. 1997; 23:273. 23. zanetta g, webb m, segura jw. ureteral endometriosis diagnosed at ureteroscopy. obstet gynecol. 1998; 91:857. 24. pittaway de, daniell jf, maxson ws, et al. recurrence of ureteral obstruction caused by endometriosis after danazol therapy. am j obstet gynecol. 1982; 143:720. 25. matsuura k, kawasaki n, oka m, et al. treatment with danazol of ureteral obstruction caused by endometriosis. acta obstet gynecol scand. 1985; 64:339. 26. feng cc, ding q, zhang yf, et al. pigment epithelium-derived factor expression is down-regulated in bladder tumors and correlates with vascular endothelial growth factor and matrix metalloproteinase-9. int urol nephrol. 2011; 43:383-90. 27el kahder k, guille f, patard jj, et al. ureteral reimplantation on psoas bladder: long-term results. acta urol belg. 1998; 66:15. 28. kupajski m, tkocz m, ziaja d. modern management of stone disease in patients with a solitary kidney. videosurgery miniinv. 2012; 7:1-7. 29. chapron c, chiodo i, leconte m, et al. severe ureteral endometriosis: the intrinsic type is not so rare after complete surgical exeresis of deep endometriotic lesions. fertil steril. 2010; 93:21152120. 30. donnez j, nisolle m, squifflet j. ureteral endometriosis: a complication of rectovaginal endometriotic (adenomyotic) nodules. fertil steril. 2002; 77:32-37. correspondence salvatore butticè, md (corresponding author) salvobu@gmail.com giuseppe mucciardi, md rosa pappalardo, md carlo magno, md department of human phatology, section of urology, university of messina via consolare valeria 1, 98125 messina, italy antonio simone laganà, md salvatore giovanni vitale, md unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina, italy francesco marson, md department of urology, university of studies of torino, torino, italy tzevat tefik, md istanbul university, istanbul faculty of medicine, department of urology, istanbul, turkey christopher netsch, md department of urology, asklepios hospital barmbek, hamburg, germany emre sener, md department of urology, school of medicine, marmara university, istanbul, turkey butticà_stesura seveso 09/01/17 09:51 pagina 269 85archivio italiano di urologia e andrologia 2017; 89, 1 case report ultrasound findings of ruptured peyronie’s plaque: case report and review of the literature lucio dell’atti 1, andrea benedetto galosi 2 1 department of urology, university hospital “st.anna”, ferrara, italy; 2 department of urology, marche polytechnic university, ancona, italy. we present here a rare case of rupture of tunica albuginea and corpus cavernosum, in the site of a peyronie’s plaque, which happened in a 61year-old man during a vacuum cleaner masturbation. ultrasound study showed an irregular hyperechoic defect at the cavernosal rupture site in correspondence of the peyronie’s plaque. the hematoma was evacuated, partially plaque excised, and the tear repaired. ultrasonography is an ideal technique for evaluating patients with penile trauma and can be routinely used in an emergency. it is a non-invasive method that gives faster results than cavernosography and magnetic resonance imaging. key words: peyronie’s disease; penile trauma; plaque; ultrasound; masturbation. submitted 11 december 2016; accepted 11 january 2017 summary no conflict of interest declared. high-frequency (7-12.0 mhz) linear transducer. the exact location of the tear has been demonstrated as an interruption of the thin echogenic line of the tunica albuginea and showed an association of hematoma outside dorsal side of the corpora cavernosa (figure 1). color-doppler ultrasound revealed some vascularity at the periphery of the lesion, however the corpus spongiosum was intact, and vascular structures appeared to have a normal flow. after the informed consent process, the patient was subjected to surgery. the hematoma was evacuated, partially plaque excised, and the tear repaired with prolene 3/0. in the setting of a dorsal curvature, a short full-thickness vertical incision was made on the ventral shaft tunic opposite the area of maximum curvature, which was then closed transversely to shorten the ventral aspect and correct the curvature. an artificial erection created with intracavernosal injection of normal saline showed an intact repair with no leakages and angulations. the wound was closed with 3/0 vicryl. duration of hospital stay was 2 days after surgery. after 10 weeks, the patient was able to be sexually active as before. follow-up with patient occurred every 3 months for 15 months, and did not show any significant angulations of penis. doi: 10.4081/aiua.2017.1.85 figure 1. b-mode longitudinal ultrasound image shows extra-cavernosal hematoma and the site of ruptured tunica albuginea in correspondence of a dorsolateral peyronie’s plaque. introduction we present here a rare case of rupture of tunica albuginea and corpus cavernosum, in the site of a peyronie’s plaque, that happened in a 61-year-old man during a vigorous masturbation. in addition we have reviewed the literature for similar reports and, to our best knowledge, there is the first case reported. case report a 61-year-old male patient was admitted to our department of urology due to the swollen penis with hematoma and penile pain following a sexual act of masturbation with a vacuum cleaner in march 2015. approximately 14 months before, due to peyronie’s disease (pd) in the active stage, he had been advised by the urologist to undergo intralesional verapamil 5 mg one injection/week for a period of 12 weeks and oral medication with vitamin e 400 mg once a day for a period of 18 weeks. his medical history was unblemished, aside from a routine appendectomy when he was 8 year-old and an essential hypertension arose from about 5 years. at the time of our first observation (approximately two hours after the trauma), ultrasound study showed an irregular hyperechoic defect at the cavernosal rupture site in correspondence of a dorsolateral peyronie’s plaque during its stable phase. ultrasound study of the penis was performed using a general electric logiq 7 machine equipped with a dell'atti_stesura seveso 04/04/17 09:33 pagina 85 archivio italiano di urologia e andrologia 2017; 89, 1 l. dell’atti, a.b. galosi 86 discussion penile trauma (pt) is a rare urological emergency (1). usually, it happens in the setting of an erect penis during vigorous sex, masturbation, falls, forceful manipulation, and direct trauma (2). in literature, pt is widely thought to be an important etiology for pd (3-5). pd is defined as a chronic benign fibrotic alteration of the penis of unknown etiology, characterized by the development of plaques or nodules. occasionally, the patient may be asymptomatic, and the lesion will only be detected by physical examination. in some cases, erectile dysfunction may occur as a result of pain, veno-occlusive dysfunction, or deformity of the penis (4). pd is thought to arise from microvascular trauma during sexual acts leading to inflammation, an aberrant deposition of fibrin, and consequently plaque formation (5). 1980 hinman proposed that pt could induce mechanical stresses that would lead to plaque formation (6). devine et al. (7) showed that pd results from acute or repetitive trauma to the penis with microvascular injury. various factors including genetic predisposition and tissue ischemia have a role in the pathogenesis of the pd (3). penson et al. (8) observed site specific hemodynamic changes in patients with various degrees of penile trauma and showed that pd may be due to trauma-induced hemodynamic pathology. to our knowledge, however, the association of the pd as a risk factor for occurrence of a pt has never been directly examined let alone proven and there is the first case reported in literature. probably, in this case study a strong trauma leading to the rupture of the peyronie’s plaque produce a minor resistance in this site due to the accumulation of fibrin and inflammatory cells into the injured area. we hypothesize that an instantaneous and vigorous trauma to the partial erection of penis during a masturbatory act may be cause of the increased mechanical stress associated with the buckling that occurs in patients affected by pd. jarow and lowe (4) demonstrated that the frequency of pt of any kind was significantly greater in both the pd (40%) and impotence (37%) patients than in the controls (11%). however, the reduced incidence of engaging in sexual relations with a partial erection among the pd patients shows that partial impotence is not a predisposing factor for pt (2). ultrasonography (us) is an ideal technique for evaluating patients with pt and can be routinely used in an emergency. it permits an evaluation of normal and pathologic anatomic structures (generally smaller than 2 mm), and a full evaluation of penile vascularity with sensitivity of color-doppler to low flow (3). in us, tunica albuginea is easily pictured as a hyperechoic linear line. it can show the integrity of the tunica albuginea, the extent and location of a tunical tear or to quantify the fibrotic involvement caused by the pd. it is very accurate in determining the precise location of the lesions in the penis, as well as the length, width, and thickness of the plaques or to see any hematoma on either side of the tunica (5). moreover, an ultrasound study is a non-invasive method that gives results faster than cavernosography and magnetic resonance imaging (mri). however, pd is best viewed in t2-weighted images of mri (2). in mri, peyronie’s plaques are observed as irregularlythickened, low signal intensity areas of tunica albuginea (2). it can be an excellent tissue contrast in evaluation of pt, but it is expensive and not widely available everywhere in emergency. us is operator-dependent and an edematous swelling of the penis within the tear can deteriorate the image contrast, hiding the defect (8). in our opinion, independently of the presence of a peyronie’s plaque in the rupture site, an immediate surgical treatment is associated with a reduced risk of fibrosis, permanent penile curvature, shorter duration of hospital stay, and decreased return time to normal erectile function. references 1. acikgoz a, gokce e, asci r, et al. relationship between penile fracture and peyronie's disease: a prospective study. int j impot res. 2011; 23:165-72. 2. koifman l, barros r, júnior ra, et al. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology. 2010; 76:1488-92. 3. joice ga, burnett al. nonsurgical interventions for peyronie's disease: update as of 2016. world j mens health. 2016; 34:65-72. 4. jarow jp, lowe fc. penile trauma: an etiologic factor in peyronie's disease and erectile dysfunction. j urol. 1997; 158:1388-90. 5. levine la, burnett al. standard operating procedures for peyronie's disease. j sex med. 2013; 10:230-44. 6. hinman f jr. etiologic factors in peyronie's disease. urol int. 1980; 35:407-413. 7. devine cj jr, somers kd, jordan sg, et al. proposal: trauma as the cause of the peyronie's lesion. j urol 1997; 157:285-90. 8. penson df, seftel ad, krane rj, et al. (1992) the hemodynamic pathophysiology of impotence following blunt trauma to the erect penis. j urol. 1992; 148:1171-80. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology, university hospital “st.anna” 8 a. moro street 44124 cona, ferrara, italy andrea benedetto galosi, md department of urology, marche polytechnic university ancona, italy dell'atti_stesura seveso 04/04/17 09:33 pagina 86 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3138 introduction penile prosthesis (pp) is reserved for man who cannot use or fail to respond to first and second line treatments of erectile dysfunction (ed). although majority of patients were satisfied with pp, satisfaction rates sometimes drop to 80 percent (1, 2). in a european study, the satisfaction rate decreased to 75 percent for specific pp types (3). according to the latter study, patients’ dissatisfaction was especially related to the rigidity of pp. comparison of the hardness of erections before and after implantation revealed that hardness varied with the diforiginal paper axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation abdulla al ansari, raidh a. talib, onder canguven, ahmad shamsodini urology department, hamad general hospital, doha, qatar introduction: penile prosthesis implantation is one of the treatment choices that is kept for patients who were not satisfied with other treatments. although penile prosthesis satisfaction rates are higher, there are some dissatisfied patients. the patients’ reasons are mostly shortness and softness of implanted prosthesis. it was previously demonstrated that penile axial rigidity of more than 500 grams is enough for successful vaginal intromission. to our knowledge, there is no study comparing axial rigidity of penile prosthesis and satisfaction. objectives: the aim of this study was to examine whether axial rigidity of penile prosthesis had impact on patient and partner satisfaction. materials and methods: we enrolled one hundred patients who were implanted penile prosthesis before to evaluate their penile axial rigidity. we used rigidometry (by using the digital inflection rigidometer) to assess the minimal axial pressure to bend the implanted penis. results: we demonstrated that mean axial pressure to bend the implanted penis was 984.8 ± 268.7 grams. overall satisfaction score with the penile prosthesis implant was 4.55 and 4.49 (out of 5) in patients and partners, respectively. in total, seven men were unsatisfied with their implant and reported a mean satisfaction score of 0.6 ± 0.48 (out of 5). all prostheses types showed good and more than 500 grams axial rigidity. the patients with ambicor type, which were buckled at about 710.5 grams, showed worse satisfaction rates in comparison to other prostheses in two patients. digital inflection rigidometer results of other penile prosthesis types in unsatisfied patient were 842.0, 872.0, 887.0 and 920 g. in cx700, titan, genesis and titan otr, respectively. conclusion: we demonstrated that dissatisfaction rate was highest in ambicor prosthesis implanted patients. additionally, patients with 3-piece penile prosthesis were more satisfied than 2-piece or malleable ones, interestingly, although some cases had lower axial rigidity results. key words: axial buckling test; erectile dysfunction; penile rigidity, satisfaction. submitted 10 july 2013; accepted 31 july 2013 no conflict of interest declared summary ferent prosthesis types; patients reported that erections were harder than before in its’ natural form (3). in order to evaluate newly introduced pp, the researchers also investigated patients’ satisfaction rates (4, 5). in most of the studies, patients were requested to fill questionnaires by phone or mail, researchers did not evaluate the patients by objective measurement techniques in addition to questionnaires (3, 6, 7). the aim of this study was to assess axial rigidity of six types of pp (ambicor, cx700, genesis, spectra, titan and doi: 10.4081/aiua.2013.3.138 139archivio italiano di urologia e andrologia 2013; 85, 3 axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation titan otr) in 100 consecutive patients with ed. se con dary objective included assessment of patients’ and partners’ satisfaction with these pps. to our knowledge this is the first report of objective and subjective pp performance by measuring their axial rigidity. material and methods a chart review was performed on patients that underwent pp implant surgery from january 2008 through january 2013. all surgeries were performed by the same team. all prostheses were placed through penoscrotal incision and cylinder sizes used were primarily 15-21 cm. enrollment and data collection were conducted at a follow-up visit at least 3 months and up to 5 years after implantation. at the follow-up visit, medical history and demographic data were collected, along with operative data and rigidity measurements. additionally, a 10-question questionnaire from the literature (8) was used to assess satisfaction with various domains related to the pp (table 1). the questions were designed with a likert grading scale scored 1 through 5 (1-very unsatisfied, 2moderately unsatisfied, 3-satisfied, 4-moderately satisfied, 5-very satisfied). scores ! 3 to the question were classified as satisfied. answers for partner’s satisfaction were attained from participants. moreover, total score was calculated by addition of 7 questions’ results (7-35). the primary efficacy endpoint for the clinical evaluation of penile rigidity by the investigators was a positive penile buckling test using the digital inflection rigidometer (dir). rigidometry was carried out to evaluate the minimal axial pressure to bend the implanted penis, using the dir (h501, electromedicina, baleares, spain). with the patient in a supine position, the plastic cap was applied to the tip of the penis in a downward direction by the investigator. a force of nearly 1.0 kg was slowly achieved on the weight scale by steadily increasing the downward force. the shaft of the penis was observed for buckling resulting from the load. three consecutive readings of the actual axial (buckling) rigidity were averaged. procedure rigidity measurements were performed by same study investigator and technician with the dir using the following procedure. 1. after ensuring the inflatable pp was completely deflated, the subject was asked to inflate his pp to a point where he thought it would be sufficient for sexual intercourse. (this phase was omitted in malleable pp implanted patients). 2. the investigator held the dir in their primary hand and pushed the dir pressure pad on the head of the penis. 3. the pressure pad was held for at least 5 seconds with a moderate pressure (500-1500 gram) or until penis buckled. the output from the dir was recorded. 4. if penis buckled, the output from the dir as the buckling force was recorded. 5. the investigator inflated pump when penis buckled with low pressures to see if inflation could be performed sufficiently. statistical analysis statistical package spss version 16.0 (chicago, il, usa). for continuous variables, statistics included means, standard deviations, and 95% confidence intervals for the means when normal distribution assumptions are not violated. comparison of the dir and the satisfaction rate between the various pps was performed using the pearson chi-square test. further patient data were obtained retrospectively from medical records. a p-value of " 0.05 was considered significant. the study was carried out with the approval of the review board of medical research center and all patients provided informed, written consent. results a total of hundred patients was enrolled in this study to assess the axial penile rigidity of implanted pp. mean age of the study participants was 61.4 ± 9.8 years and the questions for patients responses* 1. how would you rate the ease of use of your pp? 1-5 2. how would you rate the rigidity of your pp for intercourse? 1-5 3. how satisfied are you with the length of your pp? 1-5 4. how satisfied are you with the width of your pp? 1-5 5. how satisfied are you with the orgasms you achieve with your pp? 1-5 6. how satisfied do you think your sexual partner is with your pp? 1-5 7. what is your overall satisfaction with your pp? 1-5 8. in retrospect, would you undergo this procedure again? yes no 9. would you recommend this procedure to other patients? yes no 10. how many times do you use your pp for sexual activity each month? as numbers per month; e.g. 4/month frequency table 1. the questionnaire administered to patients and their sexual partners (8). *1-5 (1-very unsatisfied, 2-moderately unsatisfied, 3-satisfied, 4-moderately satisfied, 5-very satisfied). pp: penile prosthesis archivio italiano di urologia e andrologia 2013; 85, 3 a. al ansari, r. a. talib, o. canguven, a. shamsodini 140 common causes of ed were diabetes mellitus (74), atherosclerotic disease (18), and radical surgery (8). only 8 patients had peyronie’s disease. mean follow-up was 7 months (range: 3-60). the results of each question were given in table 2. types of the implants and unsatisfaction rates were described in table 3. mean male and female satisfaction with the pp implant was 4.55 and 4.49 (out of 5), respectively. interestingly, nearly one third (28/100) of patients admitted that their wives do not know that they had pp. overall, seven men were unsatisfied with their pp implant and reported a mean satisfaction score of 0.6 ± 0.48 (out of 5). pp types of unsatisfied patients and the rates according to the same type implantation were ambicor (3/15), cx700 (1/42), genesis (1/9), titan (1/13), titan otr (1/15) (table 3). average dir of all types of pp was 984.8 ± 268.7 g. in three patients, investigator inflated pump when penis buckled with low pressures and found that the inflation was not sufficiently obtained by the patients. the mean age of these patients were 74 ± 1.33 years. we found dir results of pp in unsatisfied patient as 710.5, 842.0, 872.0, 887.0 and 920 g. in ambicor, cx700, titan, genesis and titan otr, respectively. especially, dir results of 3 ambicor pp that were implanted 5 years ago were significantly lower than the other satisfied patients’ average dir. in general, main reasons of dissatisfaction were hardness and shortness of penis. for retrospective question (#8), 89 patients responded that they would undergo this procedure again. for recommendation question (#9), 91 patients responded that they would recommend this procedure to other patients. the average of pp usage for sexual activity was 9.18 ± 5.31 per month. pearson’s correlation analysis suggested a direct correlation between answers for questions #2 and #7 (p < 0.01; r = 0.723). there was a significant correlation between average dir and overall satisfaction (p < 0.05; r = 0.232). interestingly, there was no statistically significant relation between total score and penile length and width (table 4). discussion the pp implantation is one of the modality of treatment with high success rate for ed. although axial rigidity objectively defines the capability of the pp to resist buckle during vaginal intromission, there is no study specifically assessing axial rigidity of implanted pp. this study extends current knowledge in the satisfaction of pp by further examining the axial rigidity of the different types of pps. in this study, we demonstrated that five different pp types other than ambicor pp had good axial rigidity that is needed for a successful intercourse. we showed that 95% male participants were satisfied with pp implantation. the history of surgical implantation for ed was first recorded in 1930s by bogoras, who used a tailored section of rib cartilage to create the os penis of animals and produce rigidity in a reconstructed penis (9). today pps can broadly be divided into malleable and inflatable ones. since pp implants are associated with a high level of patient satisfaction, researchers always investigate and compare firstly introduced pp with the previous types from different points of satisfaction (3, 4, 6). axial and radial rigidity of penis share a common dependency upon intracavernosal pressure. however, axial rigidity, not radial penile mean ± std. deviation age (year) 61.42 9.77 1st q score (1-5) 4.82 0.54 2nd q score (1-5) 4.55 1.15 3rd q score (1-5) 4.41 1.39 4th q score (1-5) 4.58 1.11 5th q score (1-5) 4.67 1.03 6th q score (1-5) 4.49 1.18 7th q score (1-5) 4.55 1.09 total score of 7 questions (7-35) 32.10 6.10 average dir (g) 984.78 268.74 minimum dir (g) 647.53 278.69 maximum dir (g) 1275.12 337.83 sexual intercourse frequency/month 9.18 5.31 table 2. the scores of each question and results of mean digital inflection rigidometer (dir). types of prostheses n n/n (%) mean dir (implanted) (unsatisfied) cx700 ((3-piece, ams) 42 1/42 (2.4%) 985 ambicor (2-piece, ams) 15 3/15 (20%) 870 titan (3-piece, coloplast) 13 1/13 (7.7%) 1068 titan otr (3-piece, coloplast) 15 1/15 (6.6%) 953 genesis (coloplast) 9 1/9 (11.1%) 857 spectra (ams) 6 837 total 100 7/100 (7%) 984.8* table 3. mean digital inflection rigidometer (dir) and dissatisfaction percentages of six type of penile prosthesis. * there was no statistically difference between mean digital inflection rigidometer of all types (984.8 grams) and each type of penile prosthesis (p > 0.05). (ams: american medical system; otr: one touch release). average digital inflection rigidometer penile length penile width total score p = 0.022* p = 0.252 p = 0.146 table 4. correlation between the total score of 7 questions (32.1 ± 6.1) with digital inflection rigidometer, penile length and penile width, provided by pearson correlation analysis. *p-value of ! 0.05 was considered significant. m al le a i nf la ta bl e 141archivio italiano di urologia e andrologia 2013; 85, 3 axial penile rigidity influences patient and partner satisfaction after penile prosthesis implantation deformation, is the physical parameter which best defines the capability of the erect penis to resist buckle during vaginal intromission, and pelvic thrusting following penetration (10). the penile buckling force classically measures axial rigidity. axial rigidity assessment was introduced during the early 1980s at some stage in sleep laboratory research and remains a simple and inexpensive diagnostic tool (11). later, during the evaluation of efficacy of interventions for ed, researchers used and recommended axial rigidity parameter in their studies (10, 12-14). karacan et al. demonstrated that force on a rod less than 500 gram (g.) were unable to achieve intromission in any female subject (11). based on karacan's study, it has been assumed that 500 g. axial force is the minimum pressure necessary for vaginal penetration. in our study, mean average dir for all types of prosthesis was about 985 g. that is sufficient for intromission. on the other hand, although our unsatisfied patients’ dir results were above 500 g. they were less than the average. according to our results, axial rigidity, which is nearly 1000 g. by dir, is necessary for pp implanted patients’ satisfaction. in our study, we found that dissatisfaction rate was highest in ambicor pp implanted patients. significantly, dir results were almost 30% less in unsatisfied ambicor implanted patients than the average dir. ambicor is a 2piece inflatable pp which was introduced in 1994 and underwent reinforcement of the pump tubing connection to decrease fluid leak failure in 1998 (5). unfortunately, one of our ambicor unsatisfied patient also revealed spontaneous deflation during intercourse, which occurred 5 years after the implantation. in a multicentre study, examining 3 different pp, ambicor was found as the less hard than the other two pp (3). in literature, the ratio of mechanical failure is found in between 0.7% to 15% with the ambicor pp (3, 5). previosuly, less hardness of ambicor was connected to the limited volume of fluid transferred out of the cylinders in the ambicor (5). although pp is the last option in treatment of ed, almost all the patients and their partners were satisfied after pp implantation (3, 4, 6). as has been found in the previous study, pp has the second highest satisfaction rate after oral medications among other treatment modalities e.g. intracavernosal injections and vacuum device (15). in order to describe satisfaction and partner sexual function after pp implantation, moskovic et al. designed a survey to assess various aspects of patient and partner satisfaction related to their pp (8). according to their study results, partner satisfaction scores were higher, respectively, in men with higher pp satisfaction than those with lower pp (8). studies, which are examining satisfaction of patients and partners at the same time, offer us both objective and subjective satisfaction rates. the more impressive functional results of studies investigating both patients and partners are that the results are mostly in close proximity to each other (4, 8). it was demonstrated that both patients and their female partners report high levels of satisfaction several years after inflatable pp implantation (6). we found very high satisfaction rates for both patients and partners. this result is consistent with literature about this subject (3, 4, 6). in a european study, natali et al. reported a satisfaction in 97% of patient who underwent pp implantation and in 91% of their partners (3). the results of the present study showed that majority (89%) of our study participants responded that they would undergo pp procedure again. we believe that this high rate positive answer for the latter has important clinical implication from point of satisfaction. an important observation of our study was that three of our study patients could not inflate the pp until the requested rigidity. this was mostly due to the fact that they evaluate the degree of rigidity obtained was enough good for penetration. there is no available data in the literature on the number of squeezes necessary to get enough hardness of erection, because of variability of volumes needed in relation to the patient’s penis size. although the number of patients who could not inflate pp properly was minor in this study, we propose that this point should be kept in mind in differential diagnosis of patients’ complain for reduced hardness of pp, especially in elder people. on the other hand, 3-piece inflatable pps (ams cx700 and titan otr) demonstrated good results in terms of rigidity measured by dir. additionally, these 3-piece inflatable pps also did not show any mechanical failure in long-term follow up of in our study participants. a recent study conducted by bernal and henry who reviewed last 20 years’ articles that included more than 30 patients showed that patients with ed who underwent 3-piece pp placement reported the highest satisfaction rates (16). the present study was designed with the purpose of assessing axial rigidity in association with patients and partners satisfaction. to our knowledge, this is the first study evaluating pp by axial rigidity. however, the present study might have some limitations. a limitation of this study is that we could not apply our satisfaction questions directly to the partners. this was mainly because of culture difference in our region that our study patients did not want us to speak with their wives on this subject. it should be pointed out that the patient-reported partner satisfaction might have been overestimated because of this reason. however, regarding partner satisfaction, we surprisingly discovered that nearly one-third our patients’ partner do not have any knowledge about their spouses’ prosthesis. a further limitation is the difference in the numbers of different pp types evauated. since we implant 3-piece inflatable pp more than the others, there was a big discrepancy in numbers, which could not be avoided. conclusion using dir, we demonstrated that five different pp types have good axial rigidity for successful intercourse with high patient and partner satisfaction. dir results of 2piece ambicor pp were significantly lower than the other pp especially in dissatisfied patients. patient and partner satisfaction rates were roughly similar to those reported in the literature. we believe that reporting specific data for different implant types with axial rigidity for patient and partner satisfaction is significant for the future researches. archivio italiano di urologia e andrologia 2013; 85, 3 a. al ansari, r. a. talib, o. canguven, a. shamsodini 142 acknowledgements a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of dr. abdulbari benar for his assistance with the statistics used in this study and also our technician mr. ahmed sandly for his help while using rigidometer. references 1. porena m, mearini l, mearini e, et al. penile prosthesis implantation and couple's satisfaction. urol int 1999; 63:185-7. 2. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-33. 3. natali a, olianas r, fisch m. penile implantation in europe: successes and complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-12. 4. jensen jb, madsen ss, larsen eh, et al. patient and partner satisfaction with the mentor alpha-1 inflatable penile prosthesis. scand j urol nephrol. 2005; 39:66-8. 5. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007; 177:262-6. 6. bettocchi c, palumbo f, spilotros m, et al. patient and partner satisfaction after ams inflatable penile prosthesis implant. j sex med. 2010; 7:304-9. 7. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfaction outcomes of the ams 700cx inflatable penile prosthesis: results of a long-term multicenter study. ams 700cx study group. j urol. 2000; 164:376-80. 8. moskovic dj, gittens p, avila d jr., et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2011; 8:1996-2001. 9. kaneko s, mizunaga m, yachiku s, et al. clinical applicability of a new tactile sensor for evaluating rigidity of the penis: a comparative study with rigiscan. int j urol. 1996; 3:379-82. 10. udelson d, park k, sadeghi-nejad h, et al. axial penile buckling forces vs rigiscan radial rigidity as a function of intracavernosal pressure: why rigiscan does not predict functional erections in individual patients. int j impot res. 1999; 11:327-37; discusion 37-9. 11. karacan i, moore ca, sahmay s. measurement of pressure necessary for vaginal penetration. sleep res. 1985; 14:269-72. 12. henry gd, jennermann c, eid jf. evaluation of satisfaction and axial rigidity with titan xl cylinders. adv urol. 2012; 1-6. 13. sidi aa, lange ph. recent advances in the diagnosis and management of impotence. urol clin north am. 1986; 13:489-500. 14. goldstein i, auerbach s, padma-nathan h, et al. axial penile rigidity as primary efficacy outcome during multi-institutional inoffice dose titration clinical trials with alprostadil alfadex in patients with erectile dysfunction. alprostadil alfadex study group. int j impot res 2000; 12:205-11. 15. hassan a, el-hadidy m, el-deeck bs, mostafa t. couple satisfaction to different therapeutic modalities for organic erectile dysfunction. j sex med. 2008; 5:2381-91. 16. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. adv urol. 2012; 1-5. correspondence abdulla al ansari, md associate professor raidh a. talib, md urology department onder canguven, md (corresponding author) associate professor ocanguven@yahoo.com ahmad shamsodini, md urology department urology department, hamad general hospital hamad medical corporation 3050, doha, qatar stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4332 original paper biopsy follow-up in patients with isolated atypical small acinar proliferation (asap) in prostate biopsy luca leone 1, vito lacetera 1, rodolfo montironi 2, ubaldo cantoro 1, alessandro conti 1, giulia sbrollini 1, luigi quaresima 1, luciana mariani 1, giovanni muzzonigro 1, andrea benedetto galosi 3 1 institute of urology, 2 institute of pathology, azienda ospedaliera-universitaria, polytechnic university of marche region, ospedali riuniti ancona, italy; 3 division of urology, “augusto murri” general hospital, asur marche, fermo, italy. the incidence of prostate cancer (pca) was evaluated in 155 patients with isolated atypical small acinar proliferation (asap) found on initial prostate biopsy, after a medium-term follow-up (40 months) with at least one re-biopsy. clinical and histological data were analysed. cancer was detected in 81 of 155 (52.3%). the cancer detection rate was 71.6%, 91.3%, 97.5%, 100% at the 1st re-biopsy, 2nd, 3rd, and 4th rebiopsy respectively. at the uniand multivariate analyses, prostate volume (≤ 30 cc), transition zone volume (≤ 10 cc), small core length at the initial biopsy (≤ 10 mm) and few number of cores at initial biopsy (≤ 8) are predictive of cancer. furthermore, tumour characteristics on the whole surgical specimens was assessed in 30 men: 13 of 30 (43 %) had clinically relevant cancer (volume > 0.5 ml or/and gleason score ≥ 7, or pt3). most of relevant cancers were detected in the distal apex, anterior gland and midline. these anatomical sites could be under-sampled at the initial biopsy using the transrectal approach. our data suggest that follow-up biopsy is recommended in all cases of isolated asap detected after biopsy using endfire transrectal probe. the re-biopsy strategy should increase the number of cores (or a saturation biopsy), focusing on area of asap in the initial biopsy, but also including the under-sampled areas (anterior gland, distal apex and midline) to detect clinically relevant cancers. key words: atypical small acinar proliferation; prostate neoplasms; biopsy; diagnosis; radical prostatectomy. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. cases associated with pin or cancer were excluded. asap isolated is found in about the 5% of prostate biopsy in men with long life expectancy (> 20 years) (1-3). thus isolated asap in biopsy is an important clinical dilemma for patients and for physicians in order to identify concurrent relevant cancer. we evaluate retrospectively our experience at medium-term follow-up. principal aim of our study was to evaluate the prostate cancer after 40 months of follow-up with at least 1 re-biopsy. secondary aims was to describe tumour characteristics and anatomical location analysing whole surgical specimens in men who underwent surgery for cancer at repeated biopsy. material and methods from april 1998 to february 2014, we evaluated 4862 biopsies performed in our hospitals using transrectal echo-guided mapping. we retrospectively selected 190 patients with isolated asap on biopsy. only men who had all clinical data available including at least 1 followup re-biopsy were included in the series. a database including histological (site, side, number and length of cores) and clinical findings (age, total and free psa, digital rectal examination and trans-rectal ultrasound findings, prostatic volume) was analysed and matched with follow-up data. selection criteria were: isolated asap, available clinical data, central review of all slides, at least 6 months follow-up with at least one repeated biopsy. indications to re-biopsy and follow-up strategies were discussed on individual basis according to patient and urologist preference depending on patient age, life expectancy, serum psa values, imaging (transrectal ultrasound or magnetic resonance) and digital rectal exploration findings. the technique of transrectal biopsy was previously described and included the use of end-fire ultrasound probe and sandwich technique to pre-embedding the biopsy fragment between 2 sponges (4). no more than two cores per cassette were collected in order to avoid tissue loss during micro-section. follow-up time was considered from the initial biopsy with asap to the last follow-up visit or date of cancer diagnosis. surgery was proposed in patients with cancer on re-biopsy and candidate to surgery according to doi: 10.4081/aiua.2014.4.332 presented at 19th national congress sieun, fermo 2014 introduction the atypical small acinar proliferation (asap) is a pathological definition and is not a disease (1). asap is a very small area composed by few glans with atypical epithelium suspect, but non-diagnostic, for cancer and therefore it is not considered a disease such a pre-neoplastic lesion as high grade prostatic intraepithelial neoplasia (pin) or cancer (2). asap can be isolated or associated to concomitant high grade pin or associated to adenocarcinoma (figure 1). we evaluated the isolated asap only, and leone_stesura seveso 15/01/15 12:10 pagina 332 333archivio italiano di urologia e andrologia 2014; 86, 4 follow-up of isolated asap of the prostate european guidelines. whole prostatectomy specimens were analysed by a step section protocol and cancer volume was calculated. central review of all slides (including initial and follow-up biopsies) and surgical specimens was made by a single expert uro-pathologist (5). before diagnosis of isolated asap, 28 of 155 patients (18%) had previous negative biopsy. all data were analysed using univariate and multivariate analyses to detect clinical factors associate with cancer or not. confidence interval was calculated at 95% and standard deviation (±) value was reported. results isolated asap was identified in 3.9% of patients (190/4862). 155 of 190 asap were selected and analysed, 40 patients were excluded because lost at follow-up or declined re-biopsy. the mean follow-up was 40.2 months (min 6, max 143). baseline characteristics of the 155 patients with isolated asap, at the original biopsy, were the following: median number of cores at the initial biopsy was 14.5 cores (range 6 to 24); median age was 65.1 years (± 7.2, c.i. 52-77); median psa was 6.9 ng/ml (± 4.8, c.i. 2-16.3); mean prostate volume was 47 ± 23 cc. cancer was detected overall in 81/155 (52,3%). 114 patients had the 1st re-biopsy, 29 had the 2nd re-biopsy, 7 had the 3rd re-biopsy, 3 the 4th, 1 had the 5th and 1 had the 6th re-biopsy. specific cancer detection rate in each follow-up re-biopsy set was: 71.6% (58/81) at the 1st rebiopsy, 19.7% (16/81) at 2nd, but declined to 6.1% (5/81) at the 3rd re-biopsy, and 2.4% (2/81) at 4th rebiopsy. no cancer was found at the 5th and 6th re-biopsy (0/81) (table 1). therefore the cancer detection rate was 71.6%, 91.3%, 97.5%, 100% at the 1st re-biopsy, 2nd, 3rd, and 4th rebiopsy after asap diagnosis. the median number of cores was 15.6 (min 6, max 59 cores, ± 6.7) at the 1st rebiopsy and 13.7 (min 8 max 24 cores, ± 4) at the 2nd re-biopsy. the number of cores was decided according to the volume of the prostate gland. only few variables had a significantly positive association with prostate cancer in univariate and multivariate analyses: total prostate volume (≤ 30 cc) and transitional zone volume (≤ 10 cc), psa velocity, small core length at the initial biopsy (≤ 10 mm) and few number of cores at initial biopsy (≤ 8) are predictive of cancer in follow-up. pathological analysis of the whole prostate was available in 30 of 81 patients who underwent retropubic or robotic radical prostatectomy. pathology report after radical surgery detected 17 insignificant cancer (liberal definition: t2, gleason score 3 + 3 = 6, volume < 0.5 ml) and 13 relevant cancer (volume > 0.5 ml, presence of gleason pattern 4 or/and stage ≥ t3a). relevant disease was detected in 43% (13/30) cases. extra-capsular disease or seminal vesicles invasion (pt3 a-b) was found in 8 cases, positive margin (pr1) was found in 3 cases, association of both findings was detected in 1 case. significant disease was observed also in 5 patients who had a low volume of cancer (< 0.5 ml) in the anterior gland (subcapsular and fibromuscolar anterior stroma), distal apex, midline area in the peripheral gland (sub-urethral) (figures 2, 3). discussion in our experience the cancer detection rate is 52.3% while in literature the average incidence is 40.7% (1760%) (6-10): our series also includes a long follow-up (40 months) and repeated biopsy (range 1 to 6). we found most cancer (71.6%) within the first re-biopsy, as reported in literature (7-9). usually we found large tumours frequently located in the anterior zone of large prostate. in our experience, if clinical findings are positive (nodules at the palpation or/and ultrasound), histological inflammation is not present, the initial biopsy is poor in quality (< 9 cores, mean core length < 14 mm), the cancer in follow-up biopsy raise to 70% (figure 1: left side). there are few series about the cancer pathology based on prostatectomy after initial finding of asap (10-11). based on previous experiences, cancer can be clinically relevant or not relevant: the first case is a massive tumour n° re-biopsy n° pts months from initial biopsy cap incidence cap detection 1st 114 9.6 (1-53) 58/81 (71.6%) 71.6% 2nd 29 25.4 (6-80) 16/81 (19.7%) 91.3% 3rd 7 33.2 (16-45) 5/81 (6.1%) 97.4% 4th 3 47 (33-67) 2/81 (2.4%) 100% 5th 1 67 0/81 (0%) 6th 1 80 0/81 (0%) total 155 40.6 81/155 (52.3%) table 1. specific cancer detection rate at re-biopsy. figure 1. pt2 cancer is under-sampled by transrectal biopsy: in the right side a low grade and small volume cancer is missed and tangentially sampled (2 arrows); in the left side, a large volume cancer is near-missed (arrow). leone_stesura seveso 15/01/15 12:10 pagina 333 archivio italiano di urologia e andrologia 2014; 86, 4 l. leone, v. lacetera, r. montironi, u. cantoro, a. conti, g. sbrollini, l. quaresima, l. mariani, g. muzzonigro, a.b. galosi 334 tangentially sampled because localized near the biopsy track (55%), the second one is a microfocus (< 0.5 cc gs 3 + 3) (45%). cancer biopsy under-sampling is a convincing option in relation to uncommon location or small volume of cancer or both (figure 1) (11-13). the under-sampling of small volume cancer can be divided in two categories: low risk (well differentiated, gleason score 3 + 3, t2) or insignificant, and high risk (gleason score > 6 or t3) or significant cancer. in our experience high risk and small volume cancer was present in 5 cases. therefore not all small volume cancers are insignificant cancer. this observation is important for diagnostic imaging (ultrasound or magnetic resonance), where threshold volume for detection is 0.5 cc. furthermore, the anatomical location of tumour foci could be not usual as generally believed: anterior gland (subcapsular and fibromuscolar anterior stroma), distal apex, midline area (sub-urethral) of the peripheral zone may harbour cancer. unusual anatomical location associated with low cancer volume may explain because biopsy under-sampling occurs. in fact biopsy shows only a small foci of asap on initial biopsy. therefore a different strategy in the repeated biopsy should include the anterior area (figure 2) and midline zone. this strategy, that we adopted resulted in diagnosis and treatment of relevant cancer even of small volume cancers, as we observed in five cases. our detection of asap (3.9% of prostatic biopsies) is similar to literature data (5%) (6-8), defining good quality control of our experience. also inflammation could mimic asap or cancer leading to misinterpretation of few atypical glands. we support this hypothesis if clinical findings and imaging are negative, inflammation is prominent in biopsy specimen, the initial biopsy is of good quality (> 12 cores, mean core length ≥ 14 mm); in this group, the cancer rate is low (25%) in follow-up biopsy (data not shown). conclusions in patients with isolated asap, the overall cancer detection rate is 52.3% after 40 months of follow-up and at least 1 repeated biopsy. most cancer (97.6%) are detected with the 3rd repeated biopsy. cancer detected after initial asap is still curable, however 8 of 30 (26.6%) cases submitted to surgery had adverse pathological features and 13/30 (43%) are clinically relevant. five relevant tumours had low volume associated with particular anatomical location (anterior, subcapsular o suburethral). the re-biopsy strategy should increase the number of cores, or a saturation biopsy, focusing on the area of asap in the initial biopsy, but also including the anterior gland, distal apex and midline that could not be sampled initially. references 1. montironi r, scattoni v, mazzucchelli r, et al. atypical foci souspicious but not diagnostic of malignancy in prostate needle biopsies (also referred to as “atypical small acinar proliferation suspicious for but not diagnostic of malignancy”). eur urol. 2006; 50:666-674. 2. epstein ji, herawi m. prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. j urol. 2006; 175:820-834. 3. epstein ji, yang xj. “finding of atypical glands suspicious for cancer”, in: epstein ji, yang xj: prostate biopsy interpretation. chicago, il: lippincott williams & wilkins. 2002; 177-184. 4. galosi ab, lacetera v, leone l, et al. biopsy follow-up in patients with isolated atypical small acinar proliferation (asap) on prostate needle biopsy. anticancer research. 2011; 31: 1938-1939. 5. galosi ab, lacetera v, cantoro d, et al. carcinomi prostatici di piccolo volume (< 0,5 ml): caratterisctiche e implicazioni cliniche. urologia 2009; 76:236-241. 6. schlesinger c, bostwick dg, iczkowski ka. high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. am j surg pathol. 2005; 29:1201-1207. 7. postma r, roobol m, schroder fh, et al. lesions predictive for prostate cancer in a screened population: first and second screening round findingd. prostate. 2004; 260-266. 8. chan ty, epstein ji. follow-up of atypical prostate needle biopsies suspicious for cancer. urology. 1999; 53:531-535. figure 2. a: axial image of the distal apex, using end-fire transrectal probe. arrow show biopsy track. b: ecopower-doppler. c: biopsy in the anterior stroma of the transition zone (arrow) figure 3. hypoechoic area in the anterior gland, observed with end-fire probe (arrow), a: eco-power-doppler. leone_stesura seveso 15/01/15 12:10 pagina 334 335archivio italiano di urologia e andrologia 2014; 86, 4 follow-up of isolated asap of the prostate 9. iczkowski ka, chen hm, yang xj, et al. prostate cancer diagnosed after initial biopsy with atypical small acinar proliferation suspicious for malignancy is similar to cancer found on initial biopsy. urology. 2002;60:851. 10. kopp rp, parsons jk, shiau j, et al. prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy. prostate cancer prostatic diseases. 2011; 14:149-154. 11. chen yb, pierorazio pm, epstein ji. initial atypical diagnosis with carcinoma on subsequent prostate needle biopsy: findings at radical prostatectomy. j urol. 2010; 184:1953-1957. 12. galosi ab, montironi r, mazzucchelli r, muzzonigro g. clinical pathology of prostate cancer: focus on diagnosis, predictive and prognostic factors and quality indicators. arch ital urol androl. 2007; 79:45-51. 13. galosi ab. asap nella biopsia prostatica: gestione nella pratica clinica. urotime. 2011; 34:11-12. correspondence luca leone, md, resident in urology lucaleone85@virgilio.it vito lacetera, md, febu, urologist vlacetera@gmail.com ubaldo cantoro, md, resident in urology ubaldocantoro@tiscali.it alessandro conti, md, urologist alessandroconti@hotmail.com giulia sbrollini, md, resident in urology giuliasbrollini@libero.it luigi quaresima, resident in urology luigiquaresima@yahoo.it luciana mariani, md, urologist lucianamariani@virgilio.it giovanni muzzonigro, md, director, professor of urology g.muzzonigro@univpm.it institute of urology, azienda ospedaliera-universitaria, polytechnic university of marche region, ospedali riuniti ancona, italy rodolfo montironi, md, frcp, professor of pathology r.montironi@univpm.it institite of pathology, azienda ospedaliera-universitaria, polytechnic university of marche region, ospedali riuniti ancona, italy andrea benedetto galosi, md, phd, urologist (corresponding author) galosiab@yahoo.it division of urology, dept. of surgery, “augusto murri” general hospital, area vasta 4, az. sanitaria unica regione marche 63900 fermo (fm), italy leone_stesura seveso 15/01/15 12:10 pagina 335 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4288 original paper evaluation of the pathologic results of prostate biopsies in terms of age, gleason score and psa level: our experience and review of the literature selcuk sarıkaya 1, mustafa resorlu 2, ural oguz 3, mustafa yordam 1, omer faruk bozkurt 1, ali unsal 1 1 keçioren training and research hospital, departmant of urology, ankara, turkey; 2 canakkale onsekiz mart university, faculty of medicine, departmant of radiology, canakkale, turkey; 3 giresun university, faculty of medicine, departmant of urology, giresun, turkey. objective: to evaluate the pathologic and clinic results of our large series of transrectal prostate biopsies in relation to gleason score, age and psa level. materials and methods: we reviewed the pathologic results of transrectal prostate biopsies performed because of high psa levels and abnormal digital rectal examination findings between january 2008 and february 2012. results: the pathologic result of 835 prostate biopsies was benign in 82.2% and malign in 17.8%. furthermore in 3.7% high grade pin (prostatic intraepitelial neoplasia) or asap (atypical small acinar proliferation) was shown. in the interval of total psa values between 4 and 10 ng/dl, that is thw so-called grey zone, cancer detection rate was 12.4%. there was a significant relationship between cancer detection and cancer stage at all high levels of psa also in the grey zone. the most common gleason score observed was 3 + 3 wirh a rate of 7.4% whereas the second most commonly observed scare was 3 + 4 with a rate of 2.5%. in the patients with abnormal digital rectal examination findings but normal psa levels according to age the cancer detection rate was 8.7%, in patients with only high psa levels the rate was 41.2% and in the patients with both high psa levels and abnormal digital rectal examination findings. the rate was 49.3%. conclusion: our study underlines the relationship between age, psa level and pathologic stage of prostate cancer and also the importance of digital rectal examination. key words: prostate biopsy; gleason score; prostate specific antigen. submitted 20 september 2014; accepted 30 november 2014 summary no conflict of interest declared. diagnosis of prostate cancer is important as it gives direction to the treatment improving long-term survival (4). serum psa level is the most commonly examination used to screen prostate cancer (5). prostate biopsy, is the main method for the diagnosis of prostate cancer and higher psa levels and abnormal digital rectal examination findings are the indications of prostate biopsy (4, 6). in the united states of america it is reported that over 1 million prostate biopsies are performed annually (3). pain, infection and hemorrage are some of the complications of transrectal ultrasonography guided prostate biopsy (6). gleason score of prostate cancer is used for determining treatment and follow-up modalities (7, 8). in this study, we reviewed the pathologic results of prostate biopsies and their relationships with gleason score, age and psa level. materials and methods the results of prostate biopsy performed between january 2008 and february 2012 were reviewed retrospectively. the indications to prostate biopsy were higher psa levels according to age and abnormal digital rectal examination findings. in our clinic, transrectal ultrasonography guided prostate biopsies were performed for the patients under the age of 50 whewn psa level was over 2.5 ng/dl, for the patients with age between 50 and 60 when psa was over 3.5 ng/dl and for the patients over the age of 60 when psa level was over 4 ng/dl. biopsies were also performed for the patients with abnormal digital rectal examination findings regardless of psa level. after digital rectal examination, biopsies were performed in the left lateral decubitus position. four ml lidocaine (2%) or prilocaine (2%) were used for local anesthesia. diposable or re-usable guides and 18-gauge biopsy needles were used for the biopsies. biopsies were performed taking 12 cores (6 for right lobe, 6 for left lobe). detailed consent forms were obtained from the patients who were given detailed information before the biopsy procedure. after the procedure the patients were directed to the uro-oncology polyclinic with the results of biopsies and treatment modalities were decided according to the results. doi: 10.4081/aiua.2014.4.288 introduction prostate cancer, is the most common cancer observed in men and when deaths due to cancer are considered, prostate cancer ranks second after the lung cancer (1, 2). in 2008, 340.000 patients were diagnosed with prostate cancer and over 70.000 deaths were reported due to prostate cancer in european union countries (3). early sarikaya_stesura seveso 22/01/15 10:01 pagina 288 289archivio italiano di urologia e andrologia 2014; 86, 4 evaluation of the pathologic results of prostate biopsies in terms of age, gleason score and psa level: our experience and review of the literature results the results of 835 prostate biopsies showed 656 benign findings (78.5%), 4 gleason 2+3 adenocarcinomas (adenoca) (0.5%), 1 gleason 3+2 adenoca (0.1%), 61 gleason 3+3 adenoca (7.4%), 21 gleason 3+4 adenoca (2.5%), 14 gleason 4+3 adenoca (1.7%), 16 gleason 4+4 adenoca (1.9%), 1 gleason 5+3 adenoca (0.1%), 20 gleason 4+5 adenoca (2.5%), 6 gleason 5+4 adenoca (0.7%) and 4 gleason 5+5 adenoca (0.4%). finally high grade pin or asap were reported in 31 patients (3.7%) (table 1). prostate cancer detection rate was 17.8% in our prostate biopsy series. there was a significant relationship between higher psa levels and cancer detection and cancer stage in the interval of total psa values between 4 and 10 ng/dl, that is the so-called grey zone, cancer detection rate was 12.4%. when the pathologic results were revie wed by the range of serum psa levels, in patients with benign prostatic hyperplasia (bph) psa level was < 4 ng/dl in 9.3%, 4-10 ng/ml in 66.8% and > 10 ng/dl in 23.9% of the patients whereas in patients with adenocarcinoma psa level was < 4 ng/dl in 4%, 4-10 ng/dl in 49.3% and > 10 ng/dl. in 52%. when pathologic data of the patients with adenocarcinoma were examined, gleason score was higher than 7 in 33% of the patients with psa level < 4 ng/dl, in 13.8% of the patients with psa level 4-10 ng/dl and in 46.7% of the patients with psa level > 10 ng/dl (table 2). when the digital rectal examination findings (dre) were reviewed, in 71% of the patients with bph dre findings were normal and in 29% were abnormal, whereas in 41.9% of the patients with adenocarcinoma digital rectal examination findings were normal and in 58.1% abnormal (p < 0.005). adenocarcinoma detection rate was 8.7% in the patients with normal psa levels but abnormal dre findings, 41.2% in the patients with normal dre findings but higher psa levels and 49.3% in the patients with both higher psa levels and abnormal dre findings. furthermore, cancer was diagnosed in 7.5% of the patients under the age of 50, 14.4% of the patients between the age of 50 and 60, 27% of the patients over the age of 70. gleason score was higher than 7 in 2.5% of the patients under the age of 50, in 3.7% of the patients with age between 50 and 70, in 10.3% of the patients over the age of 70 (p < 0.05) (table 3). discussion transrectal ultrasonography guided prostate biopsy is the main method used for diagnosing prostate cancer.9 the pathological results of 82.2% of prostate biopsies were reported as benign and in 66.8% of the cases with benign pathological results, psa levels before biopsy procedure were between 4 and 10 ng/dl. on the other hand, according to the literature reviewing the two indications to prostate biopsy, digital rectal examination is considered a subjective parameter (10). there are several studies about pathologic results of prostate biopsies performed because of high psa level and abnormal dre findings. according to the results of ojewola et al. the total average cancer detection rate was 44% and more specifically in presence of high psa level with normal dre finding the rate was 30%, in presence of normal psa level and abnormal dre finding the rate was 17% and in presence of both high psa level and abnormal dre finding the rate was 62% (11). in the study of shim et al. (12) the patients were divided in two groups: 721 patients with normal dre findings and 192 patients with abnormal dre findings. prostate cancer detection rate was higher in the group with abnormal dre findings but the result was not significant in the patients that had psa levels between 2.5 and 3.9 ng/dl and also in the patients with age between 45 and 59 (12). in another study of thompson et al, including 2950 patients, cancer detection rate was 6.6% for the patients with psa level < 0.5 ng/dl, 10.1% for the patients with psa level between 0.6 and 1 ng/dl, 17% for patients with psa level between 1.1 and 2.0 ng/dl, 23.9% for patients with psa level between 2.1 and 3.0 ng/dl and 26.9% for patients with psa level between 3.1 and 4 ng/dl. the result of this study is important as it shows that prostate cancer would be detected also at lower psa levels (13). another study by catalona et al. (14) about biopsies performed only for abnormal digital rectal findings demonstrated a cancer detection rate of 0%. this rate was 6% for the study by brawer et al. (15) and 17% for another pathologic number abnormal high psa abnormal result of patients dre level according dre (+) findings to age high psa levels 2+3 adenoca 4 3 3 2 3+2 adenoca 1 1 1 1 3+3 adenoca 61 30 54 24 3+4 adenoca 21 10 19 8 4+3 adenoca 14 8 14 8 4+4 adenoca 16 11 15 10 5+3 adenoca 1 1 1 1 4+5 adenoca 20 14 17 11 5+4 adenoca 6 6 6 6 5+5 adenoca 4 2 4 2 total 148 86 (%58.1) 134 (%90.5) 73 (%49.3) table 2. the distibution of the patients according to pathologic results and relationship between pathologic results, dre findings and psa levels. pathologic result number percentage benign 656 %78.5 2+3 adenoca 4 %0,5 3+2 adenoca 1 %0,1 3+3 adenoca 61 %7,4 3+4 adenoca 21 %2,5 4+3 adenoca 14 %1,7 4+4 adenoca 16 %1,9 5+3 adenoca 1 %0,1 4+5 adenoca 20 %2,5 5+4 adenoca 6 %0,7 5+5 adenoca 4 %0,4 asap/high pin 31 %3.7 total 835 %100 table 1. the distribution of pathologic results and gleason scores of the prostate biopsies. age 40-50 50-60 60-70 70 ↑ psa 0-4 ng/dl 5 19 23 10 4-10 ng/dl 26 112 161 130 > 10 ng/dl 9 26 113 101 total 40 157 397 241 table 3. the age distribution of psa levels. sarikaya_stesura seveso 22/01/15 10:01 pagina 289 archivio italiano di urologia e andrologia 2014; 86, 4 s. sarıkaya, m. resorlu, u. oguz, m. yordam, o. faruk bozkurt, a. unsal 290 study by mettlin et al. (16) the cancer detection rate of the biopsies performed only for high psa levels was 16% in the study by catalona et al. (14) and 19% for the study by brawer et al. (15) the review of the pathologic results of the biopsies performed for the presence of both high psa levels and abnormal dre findings showed a cancer detection rate of 33% in the study by catalona et al. (14), 16% in the study by brawer et al. (15), and 38% in the study by mettlin et al. (16). in our study, prostate cancer detection rate was 8.7% for the patients with normal psa level but abnormal dre finding, 41.2% for the patients with high psa level and normal dre and 49.3% for the patients with both high psa level and abnormal dre finding. when we look at the results of our study; the rate for the patients with only abnormal dre finding is consistent with the literature, but the rates for the patients with only high psa level or with both two indications, are higher than the rates of literature. the rate in presence of two indications was higher than in presence of only one of the indications. this results shows the importance of dre altough it is a subjective parameter. pain, hemorrhage and infection are some of the complications of prostate biopsy as it is an invasive procedure and the rate of temporary bacteriemia is 70% and the rate of bacteriuria is 53% (6, 17, 18). according to our previous observations,there was a significant relationship between presence of prostate cancer and risk of bleeding complication after prostate biopsies (19). furthermore the bleeding complication was observed at higher rates for the patients with higher gleason scores (19). serum psa level and digital rectal examination are important parameters for the diagnosis and the choice of the method of treatment of prostate cancer. the cancer detection rates are higher when are present both high psa levels according to age and abnormal digital rectal examination findings. other results of our study that are consistent with the literature, are the increase of psa levels with age and the increase of gleason score with age. there are several limitations about our study and the most important is that the free/total psa ratio was not evaluated for the patiens with the psa level between 4 and 10 ng/dl. in fact free psa values for some patients were not found and accordingly this parameter was excluded from the analysis. another important limitation was that the analysis was not extended to psa levels in the follow-up and to re-biopsy requirements for the patients with normal pathologic results. despite all these, we think that the results of this study are relevant as they show the relationship between age, psa level and pathologic stage and also the importance of digital rectal examination. references 1. alptekin a, ozgok iy, kilciler m, et al. our results of transrectal ultrasonography guided prostate biopsies. turkish journal of urology. 1998; 24:140-144. 2. jemal a, siegel r, ward e, et al. cancer statistics. cancer j clin. 2008; 58:71-96. 3. carignan a, roussy jf, lapointe v, et al. increasing risk of infectious complications after transrectal ultrasound-guided prostate biopsies: time to reassess antimicrobial prophylaxis?. eur urol. 2012; 62:453-459. 4. tuygun c, demirel f, imamoglu a, et al. comparison of two different prediction systems for calculating the prostate cancer risk before prostate biyopsy. international haematology-oncology journal. 2009; 2:75-81. 5. ozden e, inal t, kupeli s, et al. the diagnostic value of transrectal ultrasonography for detecting the prostate cancer of the patients that have psa level of < 4 ng/ml. turkish journal of urology. 2004; 30:155-159. 6. erturhan s, seckiner i, yagci f, et al. antibiotic prophlaxis for transrectal ultrasonography guided prostate biopsy: the comparison of two different antibiotics. turkish journal of urology. 2007; 33:487-490. 7. bostwick dg. grading prostate cancer. am j clin pathol. 1994; 102:38-56. 8. gleason df. classification of prostatic carcinoma. cancer chemoter rep. 1966; 50:125-8. 9. akyol i, ates f, adayener c, et al. the effects of age, prostate volume and number of cores on pain score for transrectal ultrasonography guided protate biopsy. turkish journal of urology. 2008; 34:22-26. 10. kurtulus f, fazlioglu a, evirgen m, et al. the accuracy of digital rectal examination, prostate spesific antigen, transrectal ultrasonography, psa density, free/total psa ratio for the diagnose of prostate cancer. turkish journal of urology. 2004; 30:40-44. 11. ojewola rw, tijani kh, jeje ea, et al. an evaluation of usefulness of prostate spesific antigen and digital rectal examination in the diagnosis of prostate cancer in an unscreened population:experience in an nigerian teaching hospital. west afr j med. 2013; 32:8-13. 12. shim hb, lee se, park hk, ku jh. digital rectal examination as a prostate cancer-screening method in a country with a low incidence of prostate cancer. prostate cancer and prostatic diseases. 2007; 10:250-255. 13. thompson im, pauler dk, goodman pj, et al. prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0 ng per milliliter. n engl j med. 2004; 350:2239-46. 14. catalona w, smith d, ratcliff t, et al. measurement of prostate specific antigen in serum as a screening test for prostate cancer. n engl j med. 1991; 324:1156-1161. 15. brawer mk, aramburu eag, chen gl, et al. the inability of psa index to enhance the predictive value of psa in the diagnosis of prostatic carcinoma. j urol. 1993; 150:369-373. 16. mettlin c, lee f, drago j, et al. the american cancer society national prostate cancer detection project finding on the detection of early prostate cancer in 2425 men. cancer. 1991; 67:2949-2958. 17. ruebush tk, mcconville jh, calia fm. a double-blind study of trimetoprim-sulfamethoxazole prophylaxis in patients having transrectal needle biopsy of the prostate. j urol. 1979; 122:492-494. 18. melekos md. eficacy of prophylactic antimicrobial regimens in preventing infectious complications after transrectal biopsy of the prostate. int urol nephrol. 1990; 22:257-262. 19. oguz u, resorlu b, bayindir m, unsal a. does existance of prostate cancer increase the risk of bleeding as a complication of transrectal ultrasonography guided prostate needle biopsies? turkish clinics j urology. 2012; 3:41-5. correspondence selcuk sarıkaya, md mustafa yordam, md omer faruk bozkurt, md ali unsal, md keçioren training and research hospital, departmant of urology, ankara, turkey mustafa resorlu,md mustafaresorlu77@gmail.com canakkale onsekiz mart university, faculty of medicine, departmant of radiology, terzioglu yerleskesi, barbaros mh, 17100, canakkale ural oguz, md giresun university, faculty of medicine, departmant of urology, giresun, turkey sarikaya_stesura seveso 15/01/15 13:20 pagina 290 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 2144 short communication our percutaneous nephrolitotomy experience in patients with horseshoe kidney tufan suelozgen, cemal selcuk isoglu, hakan turk, mehmet yoldas, ozlem yusuf ilbey, ferruh zorlu tepecik training and research hospital, urology clinic, izmir, turkey. objectives: horseshoe kidney is the most common renal congenital fusion anomaly. kidney stone formation is more common in horseshoe kidneys and some of them requires surgical procedure. so we want to evaluate the results of pnl in patients with horseshoe kidney anomaly. matherial and method: between january 2009january 2014 pnl operation was performed in 6 patients with horseshoe kidney anomaly in our clinic. success of surgery and postoperative/peroperative complications were evalutaed retrospectively. results: no severe complications occured in any patient caused by surgery. three patients became stonefree. one patient had less than 4 mm. residual stone, two patients had more than 4 mm. residual stone. conclusion: pnl is safe surgical method and it can be performed successfully in patients with horseshoe kidney anomaly. key words: horseshoe kidney; stone formation; percutaneous nephrolithotomy. submitted 2 september 2014; accepted 3 november 2014 summary no conflict of interest declared. patients had symptoms becasue of stone. detailed anamnesis was taken and physical diagnosis is performed for each patient. after that biochemical tests including complete blood count, urea, creatinine and urine culture are made. all the patients were evaluated with non-contrast abdomen tomography. imaging methods requires contrast drugs weren't used. all patients were informed about the operation and informed conset is taken . in opreation morning, second generation cephalosporin antibiotic prophlaxis was performed 1 hour before surgery. under general anesthesia, 5 fr. open end uretheral catheter was placed with 22 fr. cystoscope in lithotomy position. and it was fixed to the urinary cathater with silk. prone position was given to the patient. contrast material was given from the uretheral catheter and collector system was visualised with fluoroscopy. after planning the access place, biplanar percutanous access was placed with access needle. tract was dilated with amplatz dilator over guide wire. 30 fr. amplatz sheet was placed. renal collecting system was entered with 22 fr. rigid nephroscope. ultrasonic lithotriptor was used to break the stones. five of 6 patients were have one access. two access including upper pole intercostal entry and subcostal middle pole entry were performed to one of the patients. finally, after evaluation of the fluoroscopic images, 14 fr. mallecot nephrostomy catheter was placed and the operation was terminated. results all 6 patients were male. average age was 44,82 (32-63). four patients (66.6%) had left, 2 patients (33.3%) had right kidney stone. three patients (50%) had pelvis and lower pole stone, 2 patients (33.3%) had pelvis stone, 1 patient had pelvis-lower pole and middle pole stone. none of the patients had neither operation nor eswl history. average stone size was 1007 mm2 (375-1480), average operation time was 117.1 min. (44-250 min.), average fluoroscopy time was 209 seconds (45-450). intercostal upper pole access between 11th and 12th ribs was made in 5 patients. for the patient who had upper middle and lower pole stones; upper pole access was made between 11 and 12th ribs and subcostal access was made to the middle calix under the 12.th rib (table 1). doi: 10.4081/aiua.2015.2.144 introduction horseshoe kidney is the most common renal congenital fusion anomaly with a incidence of 1/400. in 95% of cases fusion is in the lower pole of kidney. it is 2 times more common in males (1, 2). most of the patients are asymptomatic. symptoms come out because of kidney stone formation, infection caused by kidney stone and obstruction. kidney stone formation is more common in horseshoe kidneys and some of them requires surgical procedure (3-5). eswl treatment can be used in stones up to 2 cm in horseshoe kidneys. in literature there are studies that shows success rates between 50%-75% (5-7). but percutanous nephrolitotomy (pnl) should be the first treatment choise for stones more than 2 cm. in this study, results of pnl in horseshoe kidney patients in our clinic are given. matherials and method between january 2009january 2014 pnl operation was performed in 6 horseshoe kidney patients. all of the suelozgen_stesura seveso 02/07/15 12:19 pagina 144 145archivio italiano di urologia e andrologia 2015; 87, 2 our percutaneous nephrolitotomy experience in patients with horseshoe kidney in 4 patients (66.6%) there was decrease in hematocrit, average decrese was 5% (4-7) .but there was no need for blood transfusion. none of the patients had fever and lung complications after surgery. three patients (50%) were stonefree in the control non contrast abdominal tomography which performed 1 month after the surgery. one patient had less than 4 mm. (16.6%) residual stone, 2 patients had averagely 6.5 mm residual stone (6-7) (table 1). becasue of the stones were in the lower pole and didn't casue sypmtoms, additional operation wasn't considered for these 2 patients. they were being followed-up. patients were followed with direct x-ray at intervals of 6 months. average follow-up time was 25.3 months (6-54). during the follow up period, there was no increase in the stone size of the patients. discussion percutanous approach for horseshoe kidney stones was firstly reported by fletcher et al. in 1973 (8). yohannes and smith pointed that eswl treatment should be chosen for the stones less than 2 cm in horseshoe kidney, percutanous approach should be chosen when eswl fails or for bigger stones (9). with the practicing of percutaneous surgery, complications of open surgery is decreased. the most common complications that can be seen during or after pcnl procedure are fever, bleeding, urine leakage, complications caused by residual stones (10). in our study there was no high fever postoperatively. as is known, because of the vessels of the horseshoe kidney enters the hilum from anteromedial and calyxes rotates to posterior, the vascular injury risk during access is not higher than normal kidney (11, 12). in our patient group decrease of hematocrit was seen in 4 patients (66.6%) but there was no need for blood transfusion. for the kidneys with normal anatomy upper pole access is generally perfomed from over the 12th rib so intrathoracical complications are more common. horseshoe kidneys are placed more inferior and far from pleura so access for upper pole becomes more secure. pneumothorax risk for upper pole access in horseshoe kidneys were found to be 6% in a study (3). although all the accesses were made over the 12th rib there was no intrathoracic complication in our study. in various studies, the success rate after pcnl in horshoe kidneys were reported as 72%-85% and residual stones under 4 mm. were included to the group considered as succesful (13-15). when we consider the residual stones under 4 mm as successful, our success rate becomes 66,6% and this result is consistent with the literature. before the surgery the stone burden of 2 patients, who had residual stone more than 4 mm, was higher than the others. we think that this situation can be one of the reasons of the significant residual stone. conclusion pnl is safe surgical method and it can be performed successfully in patients with horseshoe kidney anomaly. studies with more patients are needed for to make certain conclusions. references 1. salas m, gelet a, martin x, et al. horseshoe kidney: the impact of percutaneous surgery. eur urol .1992; 21:134-7. 2. jones dj, wickham je, kellett mj. percutaneous nephrolithotomy for calculi in horseshoe kidneys. j urol. 1991; 145:481-3. 3. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horseshoe kidneys. j urol. 2003; 170:48-51. 4. evans wp, resnick mi. horseshoe kidney and urolithiasis. j urol. 1981; 125:620-1. 5. pitts wr jr, muecke ec. horseshoe kidneys: a 40-year experience. j urol. 1975; 113:743-6. 6. clayman rv. effectiveness of extracorporeal shockwave lithotripsy in the management of stone-bearing horseshoe kidneys. j urol. 1998; 160:1949. 7. gallucci m, vincenzoni a, schettini m, et al. extracorporeal shock wave lithotripsy in ureteral and kidney malformations. urol int. 2001; 66:61-5. patient 1 patient 2 patient 3 patient 4 patient 5 patient 6 age 32 38 45 47 54 63 gender m m m m m m stone size (mm2) 975 375 1115 1480 900 1200 stone location left kidney pelvis left kidney pelvis right kidney pelvis left kidney pelvis, left kidney pelvis right kidney pelvis and lower calyx and lower calyx lower and middle calyx and lower calyx access place intercostal intercostal intercostal intercostal intercostal intercostal upper calyx upper calyx upper calyx upper calyx, subcostal, upper calyx middle calyx operation time (min.) 60 48 90 250 80 175 fluoroscopy time (sec.) 50 45 90 450 80 153 residual stone size < 4 mm no no 6 mm no 7 mm table 1. parameters before and after surgery. suelozgen_stesura seveso 02/07/15 12:19 pagina 145 archivio italiano di urologia e andrologia 2015; 87, 2 t. suelozgen, c. selcuk isoglu, h. turk, m. yoldas, o. yusuf ilbey, f. zorlu 146 8. fletcher ew, kettlewell mg. antegrade pyelography in a horseshoe kidney. am j roentgenol radium ther nucl med. 1973; 119:720-2. 9. yohannes p, smith ad. the endourological management of complications associated with horseshoe kidney. j urol. 2002; 168:5-8. 10.türk c, knoll t, petrik a, et al. guidelines on urolithiasis. european association of urology, 2013. 11. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones: review of 1,000 cases. j urol. 1985; 134:1077-81. 12. janetschek g, kunzel kh. percutaneous nephrolithotomy in horseshoe kidneys. applied anatomy and clinical experience. br j urol. 1988; 62:117-22. 13. lampel a, hohenfellner m, schultz-lampel d, et al. urolithiasis in horseshoe kidneys: therapeutic management. urology. 1996; 47:182-6. 14. al-otaibi k, hosking dh. percutaneous stone removal in horseshoe kidneys. j urol. 1999; 162:674-7. 15. lingeman je, saw kc: percutaneous operative procedure in horseshoe kidneys. j urol. 1999; 161:371. correspondence tufan suelozgen, md tsuelozgen@hotmail.com cemal selcuk isoglu, md hakan turk, md mehmet yoldas, md ozlem yusuf ilbey, md ferruh zorlu, md tepecik training and research hospital, urology clinic izmir, turkey suelozgen_stesura seveso 02/07/15 12:19 pagina 146 archivio italiano di urologia e andrologia 2013; 85, 134 introduction molecular mechanisms responsible from varicocele induced testicular dysfunction and male infertility have not been completely unknown. recent years have witnessed a huge amount of scientific works devoted to the mechanism of varicocele associated male infertility and rapid progress in research on its cellular and molecular mechanisms, including apoptosis and oxidative stress of germ cells. here we evaluated internal spermatic vein and brachal vein ischemia modified albumin (ima) level in 40 adult male patients with varicocele. materials and methods after ethical comittee approval a total of 40 normal gonadotropic patients, aged between 23 and 37 years, attending a male infertility clinic because of prolonged (more than 1 years) subfertility were included in the study. all patients were evaluated by physical examination and scrotal color doppler ultrasonography. all had unilateral grade ii or iii primary varicocele but no testicular atrophy was diagnosed. on the right side, scrotal doppler ultrasonography and physical examination were normal in all cases. those with abnormal hormone analysis, testicular atrophy, genito-urinary tract infection, azoospermia were excluded. the mean sperm concentration was 9.9 ± 2.3 x 106 spermatozoa/ml, while the mean percentage of motile spermatozoa after 1 h was 38.1 ± 1.6%. the mean percentage of morphologically normal spermatozoa was 29.3 + 0.8%. original paper lack of significant difference between internal spermatic vein and brachial vein ischemia modified albumin levels in patients with varicocele yuksel aliyazicioglu 1, emin ozbek 2, levent ozcan 3, s. sami cakir 2, murat dursun 2 1 department of biochemistry school of medicine, karadeniz technical university, trabzon, turkey; 2 okmeydani research and education hospital, department of urology, istanbul, turkey; 3 sinop state hospital, department of urology, sinop-turkey. varicocele is the most common and surgically correctible cause of male infertility in men attending to infertility clinics. infertility affects 15% of all couples and male factor is the primary or contributing cause in 40% to 60% of cases. varicocele has been shown to cause male infertility in about 15% of infertile couples. molecular mechanisms responsible from varicocele induced testicular dysfunction and male infertility have not been completely unknown. recent years have witnessed a huge amount of scientific works devoted to the mechanism of varicocele associated male infertility and rapid progress in research on its cellular and molecular mechanisms, including apoptosis and oxidative stress of germ cells. here we evaluated internal spermatic vein and brachal vein ischemia modified albumin (ima) level in 40 adult male patients with varicocele. ima level was analyzed using albumin cobalt-binding test. spermatic vein and brachial vein ima levels were 0.381 ± 0.135 absu (absorbance units) and 0.385 ± 0.131 absu, respectively. there was no statistically significant difference between the two areas. ima levels in the internal spermatic vein of patients with varicocele should not be used as a marker of hypoxia. key words: infertility; ischemia modified albumin; oxidative stress; varicocele. submitted 30 october 2012; accepted 28 february 2013 no conflict of interest declared summary ozbek_lack_stesura seveso 18/04/13 12:03 pagina 34 35archivio italiano di urologia e andrologia 2013; 85, 1 lack of significant difference between internal spermatic vein and brachial vein ischemia modified albumin levels in patients with varicocele stroke and myocardial infarction and testicular torsion are associated with increased serum ima concentrations (5). taking into account the evident ischemia-related oxidative stress in varicocele we compared in spermatic and brachial veins of patients with varicocele the ima level as sensitive marker of ischemia and oxidative stress. despite the increased oxidative stress and ischemia related to varicocele, ima concentrations in spermatic veins were not significantly higher than brachial veins. this finding is difficult to explain, although it may be possibly explained by the presence of only relatively small ischemic areas and by the short transit time of ischemic blood within the dilated internal spermatic veins. as a result of our study we have to conclude that ima levels in the internal spermatic veins of varicocele patients should not be used as a marker of hypoxia. references 1. sun y, wang l, xu c, et al. ypoxia-induced apoptosis in the bilateral testes of rats with left-sided varicocele: a new way to think about the varicocele. j androl. 2010; 31:299-305. 2. ozbek e, turkoz y, gokdeniz r, et al. increased nitric oxide production in the spermatic vein of patients with varicocele. eur urol. 2000; 37:172-5. 3. chen ss, huang wj, chang ls, wei yh. 8-hydroxy-2’deoxyguanosine in leukocyte dna of spermatic vein as a biomarker of oxidative stress in patients with varicocele. j urol. 2004; 172:1418-21. 4. kutlu o, mentese a, turkmen s, et al. investigation of the possibility of using ischemia-modified albumin in testicular torsion: an experimental. fertil steril. 2011; 95:1333-7. 5. mastella ak, moresco rn, da silva db, et al. evaluation of ischemia-modified albumin in myocardial infarction and prostatic diseases. biomed pharmacother. 2009; 63:762-6. 6. bar-or d, lau e, winkler jv. a novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. j emerg med. 2000; 19:311-315. whole blood samples (1.5 ml) were drawn using a 25gauge-needle during surgery for varicocele from a brachial vein and from the internal spermatic vein. the dilated spermatic vein was punctured immediately after exposing the spermatic cord and before any further manipulation. after obtaining blood samples in plain tubes contained separation gels, the samples was allowed to clot for 30 minutes and centrifuged before separating the serum. the samples were then immediately frozen and stored at -80°c for assays ima. ima level was analyzed using albumin cobalt-binding test (6). results spermatic vein and brachial vein ima concentrations were 0.381 ± 0.135 absu (absorbance units) and 0.385 ± 0.131 absu, respectively. there was no statistically different at comparison with mann whitney u test (p > 0.05). discussion in a study (1) using expression of the alpha subunit of hypoxia-inducible factor 1 (hif-1 alpha) as a marker of hypoxia, it was reported that left-sided experimental varicocele in the rat causes bilateral testicular hypoxia and germ cell apoptosis. role of nitric oxide (no) and reactive oxygene species in varicocele induced male infertility have also been extensively reported (2, 3). ischemia modified albumin (ima) is produced when hypoxic heart tissue induces modification of circulating albumin (4). therefore ima is proposed as a biomarker of ischemia and oxidative stress. modifications that alter the binding capacity of albumin for cobalt may arise during ischemia as a result of acidosis, reduced oxygen tension and generation of free radicals. several clinical conditions such as pulmonary embolism, mesenteric ischemia, peripheral arterial occlusion, deep venous thrombosis, correspondence yuksel aliyazicioglu, md department of biochemistry school of medicine-karadeniz technical university, trabzon, turkey emin ozbek, md (correspoinding author) department of urology okmeydani research and education hospital darul aceze caddesi, 34384, sisli, istanbul, turkey ozbekemin@hotmail.com levent ozcam, md department of urology sinop state hospital sinop, turkey s. sami cakir, md murat dursun, md department of urology okmeydani research and education hospital istanbul, turkey ozbek_lack_stesura seveso 18/04/13 12:03 pagina 35 157archivio italiano di urologia e andrologia 2016; 88, 3 review fournier’s gangrene. a clinical review ariana singh, kamran ahmed, abdullatif aydin, muhammad shamim khan, prokar dasgupta mrc centre for transplantation, king’s college london; department of urology, guy’s and st. thomas’ nhs foundation trust king’s health partners, london, united kingdom. introduction and hypothesis: fournier’s gangrene is a rare, necrotising fasciitis of the external genitalia, perineal or perianal regions. the disease has a higher incidence in males and risk factors for development include diabetes, hiv, alcoholism and other immune-compromised states. the aggressive disease process is associated with a high mortality rate of 20-30%. in addition, the increasing age and prevalence of diabetes in the population, begs the need for increased clinical awareness of fournier’s gangrene with emphasis on early diagnosis and management. this review aims to highlight the relevant research surrounding fournier’s gangrene, in particular the various prognostic indicators and management strategies. methods: a search was conducted on the medline database for all applicable research; clinical reviews, retrospective studies and case reports. in addition to which a search of the european association of urology, the british association for urological surgeons and the british medical journal was conducted for the most recent recommendations. results: immediate broad-spectrum antibiotic therapy and urgent surgical debridement are the core managerial principles of fournier’s gangrene. the use of adjunctive therapies such as hyperbaric oxygen and vacuum assisted closure are supported in some aspects of the literature and disputed in others. the lack of randomized controlled studies limits the use of these potential additional therapies to patients unresponsive to conventional management. the value of unprocessed honey as a topical antimicrobial agent has been highlighted in the literature for small lesions in uncomplicated patients. conclusion: fournier’s gangrene is a urological emergency with a high mortality rate despite advances in the medical and surgical fields. the aggressive nature of the infection advocates the need for early recognition allowing immediate surgical intervention. the opposing results of available research as well as the lack of high quality evidence surrounding emergent therapies prevents their routine use in the management of fournier’s gangrene. the absence of a specific care pathway may hinder efficient management of fournier’s gangrene, thus based on current guidelines a management pathway is suggested. key words: fournier’s gangrene; necrotizing fasciitis; fournier’s gangrene severity index (fgsi); surgical debridement. submitted 20 march 2015; accepted 28 march 2015 summary no conflict of interest declared. talia. however, the parisian venereologist, jean alfred fournier is more commonly associated with the eponymous condition. in his 1883 manuscript, he described a fulminant gangrene of idiopathic nature and abrupt onset, of the scrotum and penis, in a series of 5 young males (1). since then our understanding of the aetiology and pathophysiology of this condition has grown to reveal a more indolent nature and identifiable cause in the majority of cases. contrary to the earlier descriptions, the disease is not restricted to young males, but has been reported to occur in women and children, although at a lower incidence. basic management of fournier’s gangrene employs a multi-disciplinary team approach and the three fundamental principles of urgent haemodynamic stabilization and crucial surgical debridement with or without plastic reconstruction, under the cover of antibiotic therapy. definition fournier’s gangrene is a type i necrotizing fasciitis of the perineal, perianal or genital areas. over the years, fournier’s gangrene has been referred to by several names, such as “streptococcus gangrene”, “synergistic necrotizing cellulitis” and “peri-urethral phlegmon”, all of which describe a soft tissue disease that is infective, destructive and fatal (2). epidemiology fournier’s gangrene is a relatively uncommon condition, representing a mere 0.02% of hospital admissions according to a recent epidemiological study, although its incidence is increasing with the ageing population and higher prevalence of diabetes. sorensen et al. highlighted an overall incidence rate of 1.6 cases per 100,000 males/year and showed a peak in incidence past the age of 50 at 3.3 cases per 100,000 males/year (3). a retrospective case review of 1726 cases, revealed a mean of 97 cases per year during the period of 1989-1998 (4). aetiology j.a. fournier described the condition as an idiopathic process, however, fournier’s gangrene is rarely truly idiopathic and with diligent observation and investigation an underlying cause can be identified in the majority of cases. the necrotizing fasciitis frequently stems from an infection doi: 10.4081/aiua.2016.3.157 introduction in 1764 baurienne described an idiopathic, fatal, necrotizing process with resultant gangrene of the male genikamran_stesura seveso 21/09/16 13:35 pagina 157 archivio italiano di urologia e andrologia 2016; 88, 3 a. singh, k. ahmed, a. aydin, m.s. khan, p. dasgupta 158 of the ano-rectum (30-50%), uro-genitalia (20-40%) or genital skin (20%) (4). trauma to these regions, whether intentional or accidental has been reported in the literature as a possible source of infection. fournier’s gangrene has been shown to be strongly associated with diabetes, chronic alcoholism, human immunodeficiency virus (hiv), lympho-proliferative diseases, chronic steroid abuse and cytotoxic drugs (5). the underlying principle of all these conditions being compromised host immunity creating a favourable environment to establish infection. malnutrition and lower socio-economic status have also been shown to be associated with the development of fournier’s gangrene. these two factors potentially associated with poor perineal hygiene and lower immunity accounting for their association with the development of fournier’s gangrene (5). predisposing factors diabetes the insistent nature of fournier’s gangrene poses a threat to the immuno-competent host so that patients suffering from systemic disorders such as diabetes mellitus are at an additional risk. sustained hyperglycaemia has detrimental effects on host immunity via its adverse effect on cellular adherence, chemotaxis and phagocyte activity (6). diabetes has been indicated as a predisposing factor in 32% to 66% of cases of fournier’s gangrene (6). an evaluation of cases of fournier’s gangrene in diabetics has shown that this co-morbid condition has an impact on the clinical course of the soft-tissue infection. primarily, the patient profile tends to be of a younger age and wound cultures reveal different bacterial colonies. candida albicans has been identified in the cultures of diabetic patients (7). rarely, fournier’s gangrene has been reported as the initial manifestation of diabetes in a previously undiagnosed diabetic (8, 9). the degree of diabetic control has been shown to correlate directly with the extent of the disease and therefore the patient prognosis. hence, uncontrolled diabetics will have a poorer prognosis requiring more aggressive wound care and extensive debridement. human immunodeficiency virus human immunodeficiency virus (hiv) is a retrovirus that infects and destroys the host’s immune system by invading cd4+ cells, which are at the very core of the immune response. it is therefore not surprising these patients are more susceptible to opportunistic infections. accordingly, it is logical to propose that these patients are more prone to developing fournier’s gangrene than a hiv negative group. hiv has been reported as a comorbidity in 4% of patients with fournier’s gangrene (10). various studies have documented a significant rise in the prevalence of cases of fournier’s gangrene since the advent of the hiv epidemic (11). a handful of cases have reported fournier’s gangrene as the initial presentation of the hiv infection (11, 12). notably, although the presence of comorbid hiv may predispose to fournier’s gangrene, it does not seem to adversely affect the natural course of the disease or patient prognosis. the fundamental principles of early recognition and timely initiation of treatment have been highlighted in the literature repeatedly as the ideals to a successful outcome. the identical principles apply to the prognosis of patients infected with hiv. pathophysiology the presence of a localized infection adjacent to the portal of entry, table 1, allows the entry of normally commensal bacteria, such as staphylococcus spp., and escherichia coli, into the perineum. essentially the infectious organisms trigger an inflammatory response resulting in an obliterative endarteritis of the surrounding vasculature. subsequent thrombosis of the nutrient vessels and a resultant reduction in blood flow to this region leads to tissue ischaemia. the reduced oxygen tension of the tissues promotes further anaerobic bacteria proliferation and fascial necrosis and digestion. causative microorganisms it was previously suggested that the necrotizing fasciitis could be attributed to infection by streptococcal species alone however; later clinical investigations have highlighted the polymicrobial nature of this infection (13). wound cultures from patients with fournier’s gangrene show an average of 4 different microorganisms per case (14). streptococcus, staphylococcus and escherichia are commonly identified species. spread advanced fournier’s gangrene can extend through the fasuro-genital ano-rectal cutaneous traumatic men (26, 50-58) urethral strictures, calculi, peri-anal, peri-rectal, ulceration due to scrotal inguinal hernia repair (52), prostatic massage ischio-rectal abscesses, pressure (51), hidradenitis prostatic biopsy, vasectomy (53), anal fissures, diverticulitis, suppurative, poor perineal diathermy for genital warts, appendicitis, colonic hygiene e.g. paraplegics anal perforation (foreign body), malignancy (50), rectal cancer penile prosthesis (54), genital piercings (55), penile injection (56), steroid enemas (57), urethral instrumentation women (58) septic abortions, vulval hpv lesions (58) hysterectomy. episiotomy abscess, bartholin’s abscess children (59) circumcision, strangulated post-varicella rash (59) urethral instrumentation congenital inguinal hernia table 1. reported cases in men, women and children of various portals of entry leading to fournier’s gangrene. kamran_stesura seveso 21/09/16 13:35 pagina 158 cial planes ascending as high as the torso and descending to the thigh. the location of the portal of entry and anatomy of the fascial planes determines the extent of the infection (15). the deep layer of superficial perineal fascia, colles’ fascia, is continuous with scarpa’s fascia of the anterior abdominal wall and buck and dartos’ fascia of the penis and scrotum. therefore, infection can spread via these routes. colles’ fascia is attached to the perineal body and urogenital diaphragm posteriorly and the pubic rami laterally (15). thus limiting the progression of infection in these directions. testicular involvement is rare and this has been attributed to their nonperineal blood supply. clinical assessment patient presentation the most common symptoms of fournier’s gangrene include scrotal pain, swelling and erythema (16). systemic features such as fever, rigor and tachycardia are often present. although originally described to be of sudden onset, experience has shown the condition 159archivio italiano di urologia e andrologia 2016; 88, 3 fournier’s gangrene. a clinical review figure 1. the imbalance between host defenses and the virulence of microorganisms in fournier’s gangrene (12, 14). figure 2. potential care pathway for fournier’s gangrene. 1 pain may be out of proportion to clinical findings early in disease process; 2 early on skin changes are a poor reflection of the infectious process. kamran_stesura seveso 21/09/16 13:35 pagina 159 archivio italiano di urologia e andrologia 2016; 88, 3 a. singh, k. ahmed, a. aydin, m.s. khan, p. dasgupta 160 more frequently has an indolent onset. the symptoms of pruritus, pain and general discomfort tend to worsen over 3-5 days before hospital admission. in up to 40% of cases, the onset of the disease is more insidious resulting in delayed diagnosis and management (17). examination may reveal purulent discharge, crepitus, and patches of necrotic tissue with surrounding oedema. cutaneous manifestations tend to appear later in the disease process as these patches progress to florid gangrene (17). a thorough history, revealing diabetes, chronic alcohol abuse, steroid abuse, hiv, malignancy, lympho-proliferative disease as well as recent catherisation, instrumentation and perineal trauma, should all increase the index of suspicion for a soft-tissue necrotizing infection. investigations although the diagnosis of fournier’s gangrene is only certain after surgical exploration, laboratory studies and radiological evaluation are invaluable tools in risk assessment and in cases of diagnostic uncertainty. risk stratification laboratory risk indicator for necrotising fasciitis (lrinec) & fournier’s gangrene severity index (fgsi) necrotising fasciitis is a complicated disease with a complex patient presentation, making early recognition a difficult task. the lrinec has been highlighted in the literature as a system capable of differentiating necrotizing fasciitis from other soft tissue infections enabling early intervention (18). more specific to fournier’s gangrene, the (fgsi) is a numerical scoring system, put forward by laor et al. in 1995, to determine patient outcome and risk of mortality (19). the fgsi score is based on 9 physiological variables, table 3, taken on admission including, temperature, heart rate, respiratory rate, these parameters similar to those of the lrinec, represent the state of equilibrium and any deviation has been highlighted in the literature as the key factor predictive of outcome. these researchers determined that a score of greater than 9 was a sensitive indicator of mortality, with a 75% probability of death (19). renal function lin et al. proposed a simplified fgsi with a focus on 3 parameters; serum potassium, serum creatinine and haematocrit (20). their study showed a non-inferior predictive value for patient outcome utilizing this 3 score index in their patient series. it is acknowledged that abnormalities in these variables are commonly found in renal failure. a mortality rate of 83.3% in patients with renal pathology, in this study, implores the concept of early risk assessment and aggressive management to improve survival in this group of patients (20). a number of studies of patients with fournier’s gangrene have highlighted that renal function is an important prognostic indicator and that dysfunction is associated with a higher mortality. dysfunction of the key elements of the immune system such as neutrophils, monocytes and alterations to the elements of the inflammatory cascade, accumulate to increase the severity of sepsis and risk of death in these patients (20). an appreciation of these risks to patients with renal pathology, allowing early recognition and aggressive management such as dialysis, may improve the patient’s chance of survival. imaging if a soft-tissue necrotizing infection is suspected urgent surgical exploration is required nevertheless, there is a place for imaging in the investigation and management of these patients. plain radiographs, ultrasonography, computed tomography (ct) and magnetic resonance imaging (mri) may demonstrate air in the soft tissue planes as well as help determine the extent of the disease. the use of imaging modalities must not delay surgical intervention. conventional radiography radiography may reveal subcutaneous emphysema extending from the perineum and external genitalia to the inguinal regions, thigh and anterior abdominal wall (12). the presence of subcutaneous air is not pathognomic but should increase the index of suspicion of a soft-tissue necrotizing infection. 90% of patients with fournier’s gangrene have been reported to have subcutaneous emphysema (12). radiography may also reveal significant swelling of the scrotal tissue. ultrasonography (us) us investigation may reveal subcutaneous emphysema, seen as echogenic areas demonstrating reverberation artifact with ‘dirty’ shadowing, in the scrotal or perineal regions (22). another ultrasound finding in fournier’s gangrene may be a thickened, oedematous scrotal wall. complete blood count • leucocytosis; wbc count > 15.4 x 109 l • haemoglobin < 11 g/dl • haematocrit < 20/> 60% biochemistry panel • serum na < 135 mmol/l • glucose level >10 mmol/l • serum creatinine > 141 μmol/l • serum k < 2.5/> 7 mmol/l • bicarbonate < 15/> 52 mmol/l • reduced serum mg raised inflammatory markers • crp > 150 mg/l raised serum lactate urea > 18 mg/dl dic panel • sepsis induced coagulopathy arterial blood gas • acidosis (possibly due to hypo/hyperglycaemia or septic disturbance) * lrinec -laboratory risk indicator for necrotising fasciitis. wbc count, haemoglobin, crp, serum na, glucose, creatinine. fgsi table 2. common investigation findings and prognostic factors in fournier’s gangrene (14, 18). kamran_stesura seveso 21/09/16 13:35 pagina 160 in cases of diagnostic doubt, quick and efficient radiological evaluation allows for timely treatment. morrison et al. emphasized that the diagnosis of fournier’s gangrene can be made with bedside ultrasound, at a very high sensitivity (23). us is also useful in differentiating a soft-tissue necrotizing infection from other scrotal pathology. in this context, us is superior to radiography. computed tomography (ct) soft-tissue thickening, inflammation and subcutaneous emphysema are the ct features found in fournier’s gangrene. the main role of ct in soft-tissue necrotizing infections however is in identifying the infectious origin and in delineating the extent of the disease (22). the extent of fascial destruction on ct has been shown to correlate with the total affected tissue at surgery (22). magnetic resonance imaging (mri) only a few cases in the literature describe the use of mri in fournier’s gangrene even though it yields greater soft tissue detail than the other imaging modalities. the reason for this may be its limited availability in many hospitals as well as a longer scan time, reducing its practical usefulness. however, a number of cases have detailed the use of mri in the diagnosis of fournier’s gangrene showing subcutaneous emphysema, scrotal wall thickening and fluid accumulation (24, 25). mri enables a wider field of view, allowing the spread of the infection to be assessed and is suggested to be advantageous in advanced lesions (25). differential diagnosis the differential diagnosis of fournier’s gangrene may include scrotal, perineal, intra-abdominal or systemic disorders (table 3). management the cornerstones of management in this life-threatening condition are urgent patient resuscitation, broad-spectrum antibiotic therapy and surgical debridement. the goal of treatment is to reduce systemic toxicity, halt progression of the infection and eliminate the causative microorganisms. antibiotic coverage a parenteral broad-spectrum antibiotic regime is required, table 4, on presentation in the management of fournier’s gangrene. subsequent culture and sensitivity results may modify the choice of antibiotics. currently there are no recommendations for optimal antibiotic therapy in fournier’s gangrene and patient management depends on local hospital guidelines. surgical debridement the early and radical removal of necrotic and devitalized tissue is the crucial step in halting progression of the infection. the necessity for rapid surgical debridement is appreciated, with even a few hours delay increasing the risk of death (26). in a retrospective analysis of 72 patients with fournier’s gangrene, kabay et al. highlighted that a time delay in surgical debridement was associated with significant mortality (27). removal of the deep fascia and underlying muscle is not usually necessary and these structures are rarely involved in the disease process. nonetheless, it is important to highlight that the magnitude of the infection cannot be judged by the degree of cutaneous necrosis and surgical exploration is imperative (12). the initial debridement, with adequate resection of the non-viable tissues, is considered the most important factor for survival (26). extensive debridement, including a slim window of healthy adjacent tissue, has been advocated in the literature. close observation of the wound and repeated debridement are necessary measures to control the infection. a mean of 3.5 debridement operations per patient has been suggested to be necessary for adequate infection control (28). plastic reconstruction the rapid and aggressive pathological process underlying fournier’s gangrene can result in large scrotal, perineal and abdominal defects. the choice of surgical reconstruction is based on the characteristics of the defect, that is, the size, location and depth as well as the availability of local tissue (29). the use of local skin flaps, split-thickness skin grafts, fasciocutaneous perforator flaps and myocutaneous flaps have all been described in the literature. the ideal reconstructive technique would occur as a single procedure, yield optimal function, a natural appearance of the wound and minimal post-operative and donor site complications. primary closure of the wound is the closest to this ideal, providing the best functional and cosmetic results, but is only useful in small to medium sized lesions. 161archivio italiano di urologia e andrologia 2016; 88, 3 fournier’s gangrene. a clinical review vancomycin/linezolid • mrsa positive clindomycin • streptococcal spp fluoroquinolone • broad spectrum both gram negative spp and gran positive spp cephalosporin • gram positive spp metronidazole • anaerobic bacteria * antibiotic regime accounting for gram positive, gram negative and anaerobic bacteria table 4. european association of urology (eau) suggested initial antibiotic options* (49). scrotal cellulitis inguino-scrotal strangulated hernia testicular torsion/abscess/haematoma gonococcal balantis acute epididymitis vasculitis polyarteritis nodosum table 3. differential diagnosis of fournier’s gangrene. kamran_stesura seveso 21/09/16 13:35 pagina 161 archivio italiano di urologia e andrologia 2016; 88, 3 a. singh, k. ahmed, a. aydin, m.s. khan, p. dasgupta 162 scrotal advancement flap the scrotum is involved in the majority of cases and scrotal advancement flaps are suitable in small-medium size lesions. a recent review of 43 reconstructive cases revealed the need for scrotal reconstruction in 93% of the cases (29). scrotal advancement flaps apply the surgical principle of “replace like with like” providing coverage from local scrotal tissue. advancement flaps have been used to repair scrotal deficits up to 96 cm2 (30). the larger the skin defect, the longer advancement distance required and therefore the more stress on the tissue and greater risk of reconstructive complications. the higher tension in the flap may compromise the blood supply leading to wound edge necrosis and flap failure, yet it has been shown that as little as one third of healthy scrotal skin can be expanded to provide complete scrotal coverage, possibly due to the expandable and resilient nature of scrotal tissue (29). this reconstructive technique, where suitable, provides excellent clinical and aesthetic results. in more complicated cases, involving perineal and/or abdominal wall defects after debridement, local scrotal flaps may be insufficient to provide wound coverage. split thickness skin grafts (stsg) maguina et al. described four cases of scrotal reconstruction by meshed split thickness skin grafts (stsg) (31). these cases illustrated both the efficiency and effectiveness of stsg by the reduction in recovery time and excellent functional and aesthetic results. various studies have highlighted the similarities in colour, shape and thickness of the neo-scrotum to normal scrotal tissue (32, 33). post-operative complications of scrotal skin grafting including bleeding, shearing and infection have been reported. some studies reported cases of graft contracture and undesirable cosmetic results. chen et al. applied stsg to nine patients with good clinical and cosmetic results. these authors recommend this method in scrotal defects with abdominal wall involvement (30). skin grafts in the perineal region have been reported unsatisfactory due to continuous wound contamination. fasciocutaneous/perforator flap various fasciocutaneous flaps have been used for scrotal and perineal reconstruction. these tissue flaps provide a large surface area of wound coverage and are used in cases where skin graft coverage is insufficient (34). the literature also reports superior functional and cosmetic outcomes compared to reconstruction with split thickness skin grafts, possibly due to the reduced incidence of skin contracture (34). superomedial thigh, pudendal, inguinal and anterolateral thigh fasciocutaneous flaps have been described in the reconstruction of the scrotum and perineum. these flaps have the advantage of having a reliable blood supply, minimal donor site morbidity and preservation of the underlying muscle (35). the tissue flaps can be harvested as sensate flaps, with preservation of the nerve supply, to allow sensation to the scrotal and perineal skin. myocutaneous/muscle flap in cases of radical debridement and deep pocket formation, a muscle flap is the recommended reconstructive method of choice, to eliminate the empty space. a gracilis muscle flap has been used to provide wound coverage for large, deep perineal defects. the close proximity of the muscle to the perineal region and its highly vascularized tissue providing a greater resistance to wound contamination, make the technique ideal for this region (35). a number of cases have reported successful functional and aesthetic outcomes after gracilis myocutaneous flap reconstruction of the scrotum and perineum (36, 37). notably, the anterolateral thigh flap can be harvested as a myocutaneous flap, with fibres of the vastus lateralis muscle within its core. this allows coverage of the deep wound, with an adjustable muscle mass, without compromising the integrity of the quadriceps femoris muscle (37). fibrin tissue sealant fibrin sealant has been reported in a number of cases as a useful adjunct in the management of complicated wounds of the perineum and external genitalia. it has been suggested that the fibrin adhesive strengthens the wound site, supports closure and provides a route for the slow release of growth factors and antibiotics (38). in regards to reconstruction of defects in fournier’s gangrene, fibrin sealant has been shown to promote effective closure of thigh fasciocutaneous flaps and other large flaps, with decreased infection and resultant clinically stable wounds without further complications (39). surgical adjuncts fecal & urinary diversion in certain cases of perineal involvement, faecal contamination may be prevented by colostomy formation. cases of anal sphincter insufficiency, fecal incontinence and continuous contamination of the wound affecting healing necessitate fecal diversion (40). diversion colostomy is a surgical operation and therefore carries additional risks to the patient. stoma site infection, stoma ischaemia and evisceration have been reported. korkut et al. emphasized a significantly higher mortality, 38%, in patients that required colostomy compared to the mortality, 7%, of those that did not require colostomy (41). the flexi-seal fecal management system is a form of fecal diversion that may serve as an alternative to colostomy. the catheter maneuvers faecal material away from the wound, preventing contamination and promoting healing. a recent study highlighted the use of bowel catheter over that of colostomy revealing a reduction in hospital stay and expenses (42). however, the use of the catheter was limited to those patients without anal sphincter and rectum involvement. clear contraindications to the use of this device include rectal neoplasms, penetrating rectal injuries and fistulas (42). urinary diversion may be necessary in cases of urethral inflammation or penile involvement (43). urethral catherisation may suffice but in more severe cases, cystostomy is indicated. vacuum assisted closure vacuum assisted closure (vac) is a method employed to accelerate the healing of surgical wounds and complikamran_stesura seveso 21/09/16 13:35 pagina 162 cated wounds that fail primary healing. the open wound is exposed to negative pressure, which is thought to reduce oedema of the tissues, increase blood flow and thereby promote healing and debridement. there is some evidence that suggests vac is advantageous over conventional wound treatment in certain patients. assenza et al. found that vac reduced hospitalization, patient morbidity and allowed early reconstructive surgery (44). emerging therapies honey recently the antimicrobial properties of unprocessed honey and its ability to stimulate epithelial cell growth have been recognized in the management of fournier’s gangrene. a low ph of 3.6, a high osmotic pressure and enzymatic activity, are the properties, which allow honey to digest necrotic tissue and bacteria. tahmaz et al. compared the classic triad of management of fournier’s gangrene to that of topical unprocessed honey and triple antibiotic therapy, without debridement, in 33 male patients (45). these researchers showed better clinical and cosmetic outcomes in the group of patients treated with unprocessed honey and antibiotic therapy. notably, this group of patients was younger, healthier and had less severe lesions. a recent review of 25 trials analyzing the use of topical unprocessed honey and its impact on wound healing concluded that honey dressings, do not impact healing and in some cases may delay the healing process (46). hyperbaric oxygen therapy hypoxia due to arterial vessel thrombosis results in tissue ischaemia, necrosis and creates a favourable environment for anaerobic bacteria. therefore, the creation of an environment with optimal oxygen uptake by tissues, is a sensible adjunct to surgical debridement and triple antibiotic therapy. hyperbaric oxygen therapy is thought to hasten tissue healing by optimizing the immune system’s activity through fibroblast proliferation, maximizing neutrophil function, reducing oedema and increasing intracellular transport of antibiotics (47). indeed the use of hyperbaric oxygen has yielded promising clinical and cosmetic results. however, the most recent review examining 42 patients with fournier’s gangrene highlighted a higher morbidity and mortality with hbo. although it was acknowledged to possibly be due to patient selection bias. hbo therapy is indicated in those patients unresponsive to conventional treatment, in clostridial or severe anaerobic infection or deep tissue involvement (48). conclusions fournier’s gangrene remains a surgical emergency and urgent, complete debridement is at the foundation of patient survival (49). the management of fournier’s gangrene focuses on patient monitoring for sepsis, broad-spectrum antibiotics and surgical removal of unviable tissue. the lack of high quality evidence in surgical adjuncts and emergent therapies prevents their routine use in patient management. survival rates greater than 70% have been reported in those patients groups receiving early diagnosis, complete debridement and appropriate, concurrent antibiotic therapy. references 1. fournier ja, jean-alfred fournier 1832-1914. gangrene foudroyante de la verge (overwhelming gangrene). sem med 1883. dis colon rectum. 1988; 31:984-8. 2. mallikarjuna mn, vijayakumar a, patil vs, shivswamy bs. fournier's gangrene: current practices. isrn surg. 2012; p. 942437. 3. sorensen md, et al. fournier's gangrene: population based epidemiology and outcomes. j urol. 2009; 181: p. 2120-6. 4. eke n. fournier's gangrene: a review of 1726 cases. br j surg. 2000; 87:718-28. 5. pastore al, palleschi g, ripoli a, et al. a multistep approach to manage fournier’s gangrene in a patient with unknown type ii diabetes: surgery, hyperbaric oxygen, and vacuum assisted closure therapy: a case report. j med case rep. 2013; 7:1. 6. nisbet aa, thompson im. impact of diabetes mellitus on the presentation and outcomes of fournier's gangrene. urology. 2002; 60:775-9. 7. perkins ta, bienick jm, sumfest jm. solitary candida albicans causing fournier’s gangrene and review of fungal etiologies. rev urol. 2014; 16:95-98. 8. sehmi s, osaghae s. type ii diabetes mellitus: new presentation manifesting as fournier’s gangrene. jrsm 2011; 2:651. 9. cheng tj, tang yb, lin bj. fournier’s gangrene as the initial presentation of diabetes mellitus. j formos med assoc. 1996; 95:184-6. 10. elem b, ranjan p impact of immunodeficiency virus (hiv) on fournier's gangrene: observations in zambia. ann r coll surg engl. 1995; 77:283-6. 11. chazan b, chen y, raz r, et al. hiv as the initial presentation of fournier’s gangrene. int j infect dis. 2007; 11:184-5. 12. smith gl, bunker cb, dinneen md. fournier's gangrene. br j urol. 1998; 81:347-55. 13. meleney fl hemolytic streptococcus gangrene. arch surg. 1924; 9:317-364. 14. ulug m, gedik e, girgin s, et al. the evaluation of microbiology and fournier's gangrene severity index in 27 patients. int j infect dis. 2009; 13:e424-30. 15. ndubuisi e, raphael je. fournier’s gangrene. http://cdn.intechopen.com/pdfs-wm/18914.pdf. accessed dec.2014. 16. tahmaz l, erdemir f, kibar y, et al. fournier's gangrene: report of thirty-three cases and a reviewof the literature. int j urol. 2006; 13:960-7. 17. fournier's gangrene. in: grabe m, bjerklund-johansen te, botto h, et al. guidelines on urological infections. arnhem, the netherlands: european association of urology (eau); 2011; p. 76-8. 18. wong ch, khin lw, heng ks, et al. the lrinec (laboratory risk indicator for necrotizing fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. crit care med. 2004; 32:1535-41. 19. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier's gangrene. j urol. 1995; 154:89-92. 20. lin ty, ou ch, tzai ts, et al. validation and simplification of fournier's gangrene severity index. int j urol. 2014; 21:696-701. 163archivio italiano di urologia e andrologia 2016; 88, 3 fournier’s gangrene. a clinical review kamran_stesura seveso 21/09/16 13:35 pagina 163 archivio italiano di urologia e andrologia 2016; 88, 3 a. singh, k. ahmed, a. aydin, m.s. khan, p. dasgupta 164 21. benjelloun bb, souiki t, yakla n, et al. fournier’s gangrene our experience with 50 patients and analysis of factos affecting mortality. wjes. 2013, 8:13. 22. gupta n, zinn km, bansal i, weinstein r. fournier's gangrene: ultrasound or computed tomography? med ultrason. 2014; 16:38990. 23. morrison d, blaivas m, lyon m. emergency diagnosis of fournier's gangrene with bedside ultrasound. am j emerg med. 2005; 23:544-7. 24. kickuth r, adams s, kirchner j, et al. magnetic resonance imaging in the diagnosis of fournier's gangrene. eur radiol. 2001; 11:787-90. 25. levenson rb, singh ka, novelline r. fournier’s gangrene: role of imaging. radiographics. 2008; 28:519-28. 26. thwaini a, khan a, malik a, et al. fournier's gangrene and its emergency management. postgrad med j. 2006; 82:516-9. 27. kabay s, yucel m, yaylak f, et al. the clinical features of fournier's gangrene and the predictivity of the fournier's gangrene severity index on the outcomes. int urol nephrol 2008; 40:997-1004. 28. chowla sn, gallop c, mydio jh. an analysis of repeated surgical debridement. eur urol. 2003; 43:572-75. 29. ferreira pc, et al. fournier's gangrene: a review of 43 reconstructive cases. plast reconstr surg. 2007; 119:175-84. 30. chen sy, fu jp, chen tm, chen sg. reconstruction of scrotal and perineal defects in fournier's gangrene. j plast reconstr aesthet surg, 2011; 64:528-34. 31. maguina p, palmieri tl, greenhalgh dg. split thickness skin grafting for recreation of the scrotum following fournier's gangrene. burns. 2003; 29:857-62. 32. black pc, friedrich jb, engrav lh, wessells h. meshed unexpanded split-thickness skin grafting for reconstruction of penile skin loss. j urol. 2004; 172:976-9. 33. nikhare sn, kura mm. split thickness grafting: a novel approach in the treatment of fournier’s gangrene. indian j dermatol venereol leprol. 2006; 72:159-160. 34. sinna r, et al. perforator flaps: a new option in perineal reconstruction. j plast reconstr aesthet surg, 2010; 63:e766-74. 35. lee sh, rah dk, lee wj. penoscrotal reconstruction with gracilis muscle flap and internal pudendal artery perforator flap transposition. urology. 2012; 79:1390-4. 36. ioannovich j, kepenekidis a, stamatopoulos k, matar n. use of gracilis musculocutaneous flap in tissue loss caused by fournier's gangrene. ann chir plast esthet. 1998; 43:58-63. 37. tremp m, meyer zu schwabedissen m, schaefer dj, et al. the combined pedicled anterolateral thigh and vastus lateralis flap as filler for complex perineal defects. ann plast surg. 2014. 38. erba p, summa pg, wettstein r, et al. fibrin sealant for fasciocutaneous flaps. j reconstr microsurg. 2010; 26:213-7. 39. evans la, morey fa. current applications of fibrin sealent in urologic surgery. int braz j urol. 32:131-41. 40. akcan a, et al., necessity of preventive colostomy for fournier's gangrene of the anorectal region. ulus travma acil cerrahi derg. 2009; 15:342-6. 41. korkut m, et al. outcome analysis in patients with fournier's gangrene: report of 45 cases. dis colon rectum. 2003; 46:649-52. 42. estrada o, martinez i, del bas m, et al. rectal diversion without colostomy in fournier's gangrene. tech coloproctol. 2009; 13:157-159. 43. villanueva-sáenz e, martínez hernández-magro p, valdés ovalle m, et al. experience in management of fournier’s management. tech coloproctol. 2002; 6:5-13. 44. assenza m, cozza v, sacco e, et al. vac (vacuum assisted closure) treatment in fournier's gangrene: personal experience and literature review. clin ter. 2011; 162:e1-5. 45. tahmaz l, et al. fournier's gangrene: report of thirty-three cases and a review of the literature. int j urol. 2006; 13:960-7. 46. sufya n, matar n, kaddura r, zorgani a. evaluation of bactericidal activity of hannon honey on slowly growing bacteria in the chemostat drug healthc patient saf. 2014; 6:139-44. 47. janane a, hajji f, ismail to, et al. hyperbaric oxygen therapy adjunctive to surgical debridement in management of fournier's gangrene: usefulness of a severity index score in predicting disease gravity and patient survival. actas urol esp. 2011; 35:332-8. 48. grabe m, bjerklund-johansen te, botto h, et al. guidelines on urological infections. 2011; eau; p 76-77. http://www.uroweb.org/ gls/pdf/15_urological_infections.pdf 49. burch dm, barreiro tj, vanek vw. fournier's gangrene: be alert for this medical emergency. jaapa. 2007; 20:44-7. 50. chan cc, williams m. fournier gangrene as a manifestation of undiagnosed metastatic perforated colorectal cancer. int surg. 2013; 98:43-8. 51. backhaus m, et al. pressure sores significantly increase the risk of developing a fournier's gangrene in patients with spinal cord injury. spinal cord. 2011; 49:1143-6. 52. dinc t, et al. fournier's gangrene as a postoperative complication of inguinal hernia repair. case rep surg. 2014; p. 408217. 53. lema vm. fournier's gangrene complicating vasectomy. east afr med j. 2003; 80:492-6. 54. walther pj, et al. fournier's gangrene: a complication of penile prosthetic implantation in a renal transplant patient. j urol. 1987; 137:299-300. 55. ekelius l, et al. fournier's gangrene after genital piercing. scand j infect dis. 2004; 36:610-2. 56. khan f, et al. fournier's gangrene associated with intradermal injection of cocaine. j sex med. 2013; 10:1184-6. 57. nabha ks, badwan k, kerfoot bp. fournier's gangrene as a complication of steroid enema use for treatment of radiation proctitis. urology. 2004; 64:587-8. 58. tsinti m, et al. fournier's gangrene associated with local cutaneous hpv lesions in a previously healthy girl. case rep pediatr. 2013: p. 704532. 59. jefferies m, saw nk, jones p. fournier's gangrene in a five year old boy beware of the child post varicella infection. ann r coll surg engl. 2010; 92:w62-3. correspondence ariana singh bsc (hons) kamran ahmed mbbs, mrcs, phd (corresponding author) kamran.ahmed@kcl.ac.uk abdullatif aydin bsc (hons), mbbs muhammad shamim khan frcs (urol), febu, obe prokar dasgupta msc, md, frcs (urol), febu king's college london guy's hospital, london (uk) kamran_stesura seveso 21/09/16 13:35 pagina 164 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2152 case report delayed-onset ureteral lesions due to thermal energy: an emerging condition cesare selli, filippo maria turri, cristina gabellieri, francesca manassero, maurizio de maria, andrea mogorovich department of urology, university of pisa, italy. objectives: to describe the risks of ureteral damage occurring during urological and gynecological procedures utilizing energybased surgical devices (esd) during both laparoscopic and open procedures. materials and methods: during the last 20 months we observed five cases of iatrogenic ureteral lesions caused by esd which required open surgery. there were 3 lesions of the lower ureter occurring during gynecological laparoscopic or robotic procedures, and 2 lesions of the upper ureter occurring during open enucleation of low-stage renal cell carcinomas. results: in the laparoscopic gynecological lesions the cause was attributable to monopolar cutting and bipolar coagulation: they presented with urine extravasation after 20, 15 and 15 days respectively and required ureteral reimplantation in 2 out of 3 cases. in the upper ureteral lesions the causes were bipolar coagulation and ligasure impact tm used for perirenal fat dissection: they presented after 2 and 4 months respectively and required uretero-ureterostomy and inferior nephropexy in one case and nephrectomy in the other. in 3 out of 5 cases there was an unsuccessful attempt at placing an ureteral double j stent, and in the 2 cases where it was placed it did not prevent the formation of subsequent stricture in one. conclusions: the widespread diffusion of esd has the potential drawback of inadvertent thermal energy transmission to the ureter. delayed presentation of ureteral lesions and difficulties in ureteral stent placement were the common features of the cases observed. inadvertent ureteral damage by different thermal energy sources is an emerging condition, requiring awareness, prompt recognition and adequate treatment with the reconstructive urology principles. key words: ureteral injury; energy-based surgical devices; reconstructive urology. submitted 24 october 2013; accepted 31 january 2014 summary no conflict of interest declared. presented as an oral communication at the 24th sun congress in modena, november 2012. trolled bipolar) and ultrasonic (1-3). the ureter, due to its relatively small caliber and continuous flow of urine is particularly susceptible to inadvertent damage with thermal energy: monopolar energy is the most destructive one and laparoscopic lesions tend to be more extensive than those occurring in open surgery (4-5). case report we report herein our experience with the management of inadvertent ureteral lesions due to esd occurring during both open and laparoscopic gynecological and urological procedures. cases report are described in supplementary materials posted on www.aiua.it discussion in a review of laparoscopic ureteral injury in pelvic surgery, ostrenski et al. (6) in 2003 reported a delayed clinical occurrence in 70% of cases, with thermal injury accounting for only 1.4%. however with the present spread of minimally invasive gynecologic surgery and the use of esd also in open procedures, this percentage is presumably higher. in laparoscopic gynecological procedures the ureter is likely to be injured in three locations: at the infundibolopelvic ligament, deep to the ovarian fossa and at the ureteral canal (6). in the three cases that came at our attention the site of thermal damage was likely to be of the third type. a constant care of the ureteral location should characterize all female pelvic dissections, and this applies particularly to robotic surgery, where the tri-dimensional vision and the possibility of a very fine dissection, possibly minimizing the amount of thermal energy, are intrinsic advantages of the technology. thermal injury of the upper ureter has been reported following percutaneous radiofrequency treatment of small renal tumors (7) or as a consequence of laparoscopic partial nephrectomy using a microwave tissue coagulator (8), while to the best of our knowledge there is no description of ureteral damage caused by esd for dissection of the perirenal fat during open conservative surgery for kidney tumors. doi: 10.4081/aiua.2014.2.152 aim energy-based surgical devices (esd) are increasingly used both in laparoscopic and open procedures in many surgical branches the most frequently used systems are electrosurgical (monopolar, bipolar, impedance-con153archivio italiano di urologia e andrologia 2014; 86, 2 thermal ureteral lesions in our experience, as well as in that of others, ureteral lesions secondary to esd present a delayed clinical appearance, in common with other iatrogenic damages (9-11). this can be explained by the fact that thermal injury damages vascular supply beyond the area of actual contact, leading to delayed necrosis or scarring of the ureteral wall (11). the real extent of tissue damage is greater than that appearing with imaging techniques, and adequate ureteral mobilization is necessary for tensionfree surgical repair. in the present experience upper ureteral lesions became clinically evident later than lower ureteral lesions associated with gynecological procedures, which all became apparent between two and three post-operative weeks with the appearance of either vaginal discharge or with acute abdomen due to uroperitoneum. an endourological approach should be obviously attempted first, but in our experience in 3 out of 5 cases the placement of a double j stent was unsuccessful and in one out of 2 case when it was placed it did not prevent the formation of subsequent stricture. we believe that, in case of failure of conservative management, an open surgical approach provides the best chances for and adequate ureteral mobilization, necessary for tension-free surgical repair, but robot-assisted ureteral reconstructive procedures are showing promising results (12). figures are reported in supplementary materials posted on www.aiua.it references 1. song c, tang b, campbell pa, et al. thermal spread and heat absorbance differences between open and laparoscopic surgeries during energized dissections by electrosurgical instruments. surg endosc. 2009; 23:2480-2487. 2. alkatout i, schollmeyert t, haldawar n, et al. principles and safety measures of electrosurgery in laparoscopy. j soc lap surg. 2012; 16:130-139. 3. kennedy js, stranahan pl, taylor kd, chandler jg: high burststrength feedback-controlled bipolar vessel sealing. surg endosc. 1998; 12:876-878. 4. phillips ck, hruby gw, durak e, et al. tissue response to surgical energy devices. urology. 2008; 71:744-748. 5. tulikangas pk, smith t, falcone t, et al. gross and histologic characteristics of laparoscopic injuries with four different energy sources. fertil steril. 2001; 75:806-810. 6. ostrzenski a, radolinski b, ostrzenska km. a review of laparoscopic ureteral injury in pelvic surgery. obstet gynecol surv. 2003; 58:794-799. 7. doody o, given mf, harper m, et al. rendezvous technique following thermal ureteric injury after radiofrequency ablation in a solitary kidney. j vasc interv radiol. 2008; 19:1112-1114. 8. harabayashi t, shinohara n, kakizaki h, et al. ureteral stricture developing after partial nephrectomy with a microwave tissue coagulator: case report. j endourol. 2003; 17:919-921. 9. manoucheri e, cohen sl, sandberg em, et al. ureteral injury in laparoscopic gynecologic surgery. rev obstet gynecol. 2012; 5:106-111. 10. gao js, leng jh, liu zf, et al. ureteral injury during gynecological laparoscopic surgeries: report of twelve cases. chin med sci j. 2007; 22:13-16. 11. oh br, kwon dd, park ks, et al. late presentation of ureteral injury after laparoscopic surgery. obstet gynecol. 2000; 95:337-339. 12. kozinn si, canes d, sorcini a, et al. robotic versus open distal ureteral reconstruction and reimplantation for benign stricture disease. j endourol. 2012; 26:147-151. correspondence cesare selli, md (corresponding author) c.selli@med.unipi.it filippo maria turri, md fm.turri@gmail.com cristina gabellieri, md gabelliericristina@interfree.it francesca manassero, md francy.manassero@hotmail.com maurizio de maria, md m.demaria@ao-pisa.toscana.it andrea mogorovich, md mogorovich@hotmail.it urologia universitaria via paradisa 2 50124 pisa, italy figure 1. case 1. uro-ct scan demonstrating uroperitoneum and a jet of contrast medium originating from the right pelvic ureter. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4344 original paper diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management: a short report from a single urologic center andrea fabiani 1, alessandra filosa 2, valentina maurelli 1, fabrizio fioretti 1, lucilla servi 1, mara piergallina 1, giovanni ciccotti 1, matteo talle’ 1, gabriele mammana 1 1 surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; 2 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy. objectives: prostatic abscess (pa) is an infrequent condition in the modern antibiotic era. the everyday use of transrectal ultrasound (trus) during diagnostic work-up and the widespread recurrence to prostatic biopsies may lead to an increase of pa diagnosis. in this short report we analyze the patients characteristics and the management of seven recent cases of pa diagnosed in our institution. materials and methods: the records of 7 patients admitted to our center for luts associated to septic fever or acute urinary retention, was prospectively collected. suspect of pa was done on digital rectal examination (dre) and confirmed by trus performed after urinary system ultrasound (uus) evaluation. patients were admitted to hospital only in case of septic signs. a sovrapubic (spc) or urethral catheter (uc) was placed depending on symptoms. a trus-guided aspiration of pa was performed with patient in lithotomic position, using a 18 gauge two-part needle, side/end fire needle access. patient was discharged with antibiotic therapy and followed up until complete resolution of the pa and symptoms. results: mean age was 62 years (range 24-82). two patients were diabetics and one was affected by the immunodeficiency acquired syndrome (hiv). in one case, pa was detected after a persistent fever post trus guided prostate biopsy. average prostate volume was 69 ml (range 19-118 ml). dre was able to diagnose pa only in 2 cases (29%), uus evaluation in 1 case (14%). all cases were confirmed by trus as hypo-anechoic areas with or without internal echoes in all patients. mean pa dimension was 3.64 cm (range 1.5-8). spc was placed in 3 cases (43%), uc in 3 patients (43%). only 1 patient refused catheterization. side fire needle aspiration was performed in all cases and in combination with end fire access in case of particular location of abscess cavities. second look was needed in 2 cases (29%). antibiotics were administered in all cases. the aspirated pus showed a positive culture for escherichia coli (43%), klebsiella pneumoniae (29%), pseudomonas aeruginosa (14%) and enterococcus faecalis (14%). pa resolution time mean was 9 days (range 3-24). conclusions: trus evaluation in case of persistent luts associated with fever or acute urinary retention is determinant in the diagnosis of pa. office or institutional management with trus needle aspiration is a good option in these cases. key words: prostatic abscess; trus; end fire probe; side fire access luts; uroseptic fever. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction prostatic abscess (pa) is an infrequent condition in the modern antibiotic era. nevertheless, the wide use of antibiotics in patients with lower urinary tract symptoms (luts) could be responsible of the growing pa incidence in the last years (1). the diagnosis may be difficult because at onset of the symptoms pa may mimic several other diseases of the lower urinary tract. simple interpretation of the clinical symptoms and digital rectal examination (dre) could be not able to make a diagnosis. the routine use of transrectal ultrasound (trus) evaluation in each case of luts associated to fever or predisposing factors for the development of pa may aid the clinician in the daily practice (2). in this short report we present data about seven patients diagnosed with prostatic abscess, discussing clinical findings, diagnostic criticisms and treatment results obtained by trus guided needle aspiration. material and methods we prospectively collected the clinical and instrumental data of a short series of 7 patients admitted from emergency department to our section of urology in macerata hospital for luts associated to septic fever and/or acute urinary retention in a 12 months period. at the urologic evaluation, the patients underwent to dre and systematically to trus after an urinary system ultrasound (uus) study. in case of confirmed suspect of pa, a sovrapubic (spc) or urethral catheter (uc) was placed depending on symptoms. a trus-guided needle aspiration of pa was performed with patient in lithotomic position, using a 18 gauge two-part needle, with a probe b-k type 8818 (bk medical, denmark), side/end fire needle access, without local anesthesia. all procedures were performed in an ambulatory setting. patients were admitted to hospital only in case of septic signs. the patients were discharged with antibiotic therapy and followed up with trus until complete resolution of the pa and symptoms. results diagnostic and management data are presented in tables 1 and 2. the figures show particular aspects of pa diagdoi: 10.4081/aiua.2014.4.344 presented at 19th national congress sieun, fermo 2014 345archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management nosis and treatment in same patients. mean age was 62 years (range 24-82). two patients were diabetics and one was affected by the immunodeficiency acquired syndrome (hiv). in one case, pa was detected after a persistent fever post trus guided prostate biopsy (24 biopsy cores). average prostate volume was 69 ml (range 19118 ml). dre was able to diagnose pa only in 2 cases (29%), uus evaluation in 1 case (14%). pa was confirmed by trus (both bi-plane and end-fire probe) as a hypo-anechoic areas with or without internal echoes in all patients. pa was located in transitional zone in 4 cases, peripheral zone was involved in 1 case. combined localization was observed in 2 cases. pa dimension mean was 3.68 cm (range 1.5-8). spc was placed in 3 case (43%), uc in 3 patients (43%). only 1 patient refused catheterization. side fire needle aspiration was performed in all cases. combination with end fire needle access was performed in four cases (57%) due to the localization of abscess cavities. second look was needed in 2 cases (29%). intravenous parenteral antibiotics (imipenem plus teycoplanine) was administered only in case of hospitalization (43%). in cases managed at home, a combination of 3-rd generation cephalosporine and aminoglycoside was administered. the aspirated pus showed a positive culture in all patients (escherichia coli n = 3, klebsiella pneumoniae n = 2, pseudomonas n = 1 and enterococcus faecalis n = 1). mean pa resolution time was 9 days (range 3-24). no patients died for this condition. discussion pa is a potential life threatening condition that, when not adequately treated, may progress to sepsis and death. thus, an accurate diagnostic and an efficient treatment are both required. in available scientific literature data about pa consisted in cases reports and there is no standardization of the diagnostic and therapeutic routine. in review articles, we found several reports discussing clinical presentation, diagnostic work up and therapeutic approach to pa. the summary of these individual experiences permitted to delineate some lines of action (3-4). first of all, we think that pa incidence will be increasing in the next years. in the modern antibiotic era incidence is estimated between 0.5% to 2.5% of diseases accompanying prostatic symptoms. we should expect a shift of the epidemiological profile of pa due to a widespread routine use of broad-spectrum antibiotics to patients with luts, without the investigation required (1), and to an increase in population longevity that lead to a further need to manage chronic illness, such as diabetes mellitus or chronic renal failure, promoting the infectious risk. also others diseases altering the immune system could be responsible, e.g. immunodeficiency patient age co-morbidities clinical presentation dre diagnostic + uus diagnostic * abscess location pathogen 1 61 bph fever post trus biopsies + tz k. pneumoniae (24 cores)* 2 70 bph luts and fever pz pseudomonas 3 68 dmnid fever * tz pz k. pneumoniae 4 24 infertility aur and fever after tz e.coli recurrent hematospermia 5 82 bph fever* tz e.coli 6 60 dmnid fever and aur tz enterococcus faecalis 7 69 hiv fever* + tz pz e. coli * hospitalization. bph: benign prostatic hyperplasia. dmnid: non insulin dependent diabetes mellitus. hiv: immunodeficiency acquired syndrome. aur: acute urinary retention. trus: transrectal ultrasound. dre: digital rectal examination. uus: urinary system ultrasound. tz: transitional zone. pz: peripheral zone. table 1. diagnostic findings of cases series. patient age prostate volume (ml)/ soprapubic catheter urethral catheter side fire (sf)/ second look time resolution abscess diameter (cm) positioned * positioned ° side fire + end fire needle aspiration + (days) (sfef) accesss 1 61 75 ml/3,9 cm * sf 7 2 70 71 ml/3,1 cm sf 5 3 68 69 ml/4,9 cm * sfef + 9 4 24 19 ml/2,1 cm ° sf 9 5 82 118 ml/8 cm ° sfef 6 6 60 68 ml/1,5 cm ° sfef 3 7 69 61 ml/2,3 * sfef + 24 sf: side fire access. sfef: combined accessside fire and end fire. table 2. technical management of cases. archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, v. maurelli, f. fioretti, l. servi, m. piergallina, g. ciccotti, m. talle’, g. mammana 346 acquired syndrome (5). then, if we recognize that the abscess is a result of the retrograde flow of contaminated urine during micturition into prostatic ducts that promotes the formation of microabscesses that coalesce and form prostatic abscesses (6-7), the rate of this disease is certainly more important than what reported in the scientific literature. differential diagnosis between acute bacterial prostatitis and pa is difficult if based only on clinical symptoms and digital rectal examination (dre) (2) or lower abdominal ultrasound evaluation. the routine use of trus evaluation in each case of luts associated to fever or predisposing factors for the development of pa may aid the clinician in the daily practice (3). at dre prostatic abscess could be appreciate as a painful fluctuating area (4). in our short report this findings was observed in 2 cases. similarly, prostate lower abdominal ultrasound evaluation was able to pose the pa suspect only in 1 case in which the exam revealed an hypoechoic irregular area within prostate parenchyma suggesting the diagnosis confirmed by trus (figures 1a, 1b). in the other cases, abdominal ultrasound was unremarkable. in our experience trus showed to be an excellent tool in making the diagnosis. the most common finding is the presence of one or more hypo-anechoic areas, of several sizes, containing thick liquid and located in the transition zone and/or in central zone of the prostate, permeated by hyperechogenic areas and anatomical gland distortion. in our series these findings were variably observed in 100% of the cases. although other conditions could have a similar trus appearance, as neoplastic process, cystic lesions and granulomas (8-10), the trus appearance of pa is quite characteristic and can be differentiated on the basis of determined criteria (11). as reported in the literature, trus should also be considered the diagnostic study of choice to assist the treatment and follow-up of patients with prostatic abscess (12). figures 2a-2b show the results of trus guided needle aspiration at follow up of one patient. as observed in our cases, clinicians need to suspect pa in case of fever with luts especially in patients presenting with fever and persistent luts despite antibiotics use, for diabetics or immune-deficient men with protracted symptoms, for those with luts and fever progressing to urinary retention and after the performance of prostatic biopsy. in all scientific reports, diabetes mellitus and hiv infection are invariably referred as risk factors for the development of pa. in our series, a peculiarity was represented by case 4 (figure 3) that was a young patient (24 years old) who developed aur due to infectious enlargement of a midline cyst and was symptomatic for recurrent hematospermia, as revealed by clinical history taken at the moment of emergency evaluation. these results highlight the importance to investigate with trus younger patients with genito-urinary symptoms (13). in reference to prostate biopsy as risk factor of pa, it should be underlined that data from european randomized study of screening for prostate cancer (rotterdam section) (erspc) revealed growing evidence of increasing hospitalizations for serious infectious complications within 2 week of prostate biopsy (14). specifically, the authors found a 10% increase in the frequency of hospital admissions and most of these were for infectious complications figure 1a. bladder ultrasound: 68 years old, presented at our attention for persistent fever and prostatic abscess (*). figure 1b. transrectal ultrasound (end-fire probe) view of the figure 1a confirm a multisided prostatic abscess (*). figure 2a-b. trus evaluation (endfire probe) at follow up of patient in figures 1a-b, axial (a) and longitudinal (b). 347archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management probably related to rising antimicrobial resistance. it is well known that men with prostatic enlargement and diabetes or major co-morbidities had an increased risk of febrile complications after prostate biopsy (15). these results highlight the importance of judicious patient selection for psa screening because these men may be less likely to benefit from early prostate cancer detection and also have a greater risk of complications from the diagnostic work-up. however, we considered that in case of patient number 1 of our series, neither prostate volume (57 ml) neither co-morbidities predicted pa onset, due to a multi resistant klebsiella pneumoniae. in our local experience with trus guided biopsies, on 1382 procedures performed in the last 6 years, we found only thissingle case of pa (0.07%) and 10 cases of hospitalizations for septic fever (0.72%) with 1 admission to intensive care unit. no deaths from this complication was observed (unpublished data). we can confirm that the frequency of hospital admission for septic fever after prostate biopsy is low (< 1%) (15). the problem is represented by the high level of antimicrobial resistance. we must take into consideration the use of a combination of 3-rd generation cephalosporine and aminoglycoside or imipenem and teicoplanine as better antibiotic therapy than traditional fluorquinolones. trus-guided needle aspiration is the method of choice for treatment of pa (16). the treatment options included also surgical intervention such as transurethral prostate incision (tuip), transurethral de-roofing (turp) or transperineal tube placement. turp is a more invasive approach and it is associated with several risks such as hemorrhage, retrograde ejaculation and sepsis. an alternative to simple aspiration could be the continuous drainage with a tube placed under trus guidance either by transperineal or transrectal route. however, this approach is fraught with a serious risk of developing a prostate-rectal fistula formation and prolonged hospitalization (17-18). tiwari et al. (19) reported 24 patients treated with transurethral de-roofing in 17 cases, transperineal needle aspiration trus guided in 3 cases. the remnants patients was managed conservatively. invasive treatment was applied in case of dimension of cavities abscess > 1 cm or multi-loculated. vias et al. (3) published one of the largest series of pa managed with trus-guided needle aspiration. of 48 patients, they report a 100% of diagnostic accuracy by trus and a success treatment rate of 85.42%, avoiding the risk of potential disadvantages of tur. the diameter “cut off” of cavities considered eligible for aspiration was 2 cm. in our short report, we confirm the high diagnostic accuracy (100%) of trus with a similar success rate. applying the dimensional cut-off proposed by vias, only two patient needed a second look aspiration due to the persistence of cavities within the prostate. no tur de-roofing was performed. in all cases, our trus follow up revealed a complete resolution of pa. technically, our trus guided needle aspiration consisted in the use of a biplane probe (6-12mhz, type 8818, bk medical, denmark) with a side fire needle access in all patients (figure 4). when pa was multifocal (four patients), especially in two cases in which cavities was located in the anterior zone of the prostate, we resorted to an end fire access (figure 5) in view of the potential increased capacity of this configuration, showed during prostate biopsies, to sample this anatomical area of the gland (20). we approached all cases with catheterization. suprapubic catheter was placed in three case. in one case, patient refused catheterization both urethral and suprapubic. also in this case the evolution of treatment was positive without need of ancillary procedures. figure 3. a midline prostatic utricle cyst after trus guided needle aspiration in young men with acute urinary retention. wall cyst presents small calcification. the surrounding right seminal duct is shown in figure 5. figure 4. trus guided aspiration with a biplane probe, side fire needle access. archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, v. maurelli, f. fioretti, l. servi, m. piergallina, g. ciccotti, m. talle’, g. mammana 348 conclusions the diagnosis of prostatic abscess should be warranted for patients presenting with fever and persistent luts despite antibiotics use, for diabetics or immune-deficient patients with protracted symptoms and for those with luts and fever progressing to urinary retention and after the performance of prostatic biopsy. trus evaluation is determinant and mandatory for the diagnosis.. in our experience, office or institutional management with trus needle aspiration is a good option in all cases. references 1. granados ea, riley g, salvador j, vicente j. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-2 2. oliveira p, andrade ja, porto hc, et al diagnosis and treatment of prostatic abscess int braz j urol. 2003; 29:30-4. 3. vias bj, ganpule sa, ganpule ap, et al. transrectal ultrasoundguided aspiration in the management of prostatic abscess: a singlecenter experience indian j radiol imaging. 2013; 23:253-257. 4. granados ea, caffaratti j, farina l, hocsman h: prostatic abscess drainage: clinical-sonography correlation. urol int. 1992; 48:358-61. 5. trauzzi sj, kay cj, kaufman dg, lowe fc. management of prostatic abscess in patients with human immunodeficience syndrome. urology. 1994; 43:629-33. 6. meares em, jr. prostatic abscess. j urol. 1996; 129:1281-2. 7. porfyris o, kalomoiris p. prostatic abscess: case report and review of the literature arch ital urol androl. 2013; 85,3:154-6. 8. galosi ab, parri g, lacetera v. et al. management of large prostatic abscess associated with urethral stenosis and penile cancer recurrence. arch ital urol androl. 2010; 82:181-5. 9. galosi ab, montironi r, fabiani a, et al. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation j urol. 2009; 181:647-657. 10. hamper um, epstein ji, sheth s, et al. cystic lesions of the prostate gland: a sonographic-pathologic correlation. j ultrasound med. 1990; 9:395-402. 11. barozzi l, pavlica p., menchi i., et al. prostatic abscess: diagnosis and treatment. ajr am j roentgenol 1998;170:753-7 12. lee f jr, lee f, solomon mh, et al. sonographic demonstration of prostatic abscess. j ultrasound med. 1986; 5:101-2. 13. akhter w., khan f., chinegwundoh f. should every patient with hematospermia be investigated? a critical review cent european j urol. 2013; 66:79-82. 14. loeb s, van den heuvel s, zhu x, et al. infectious complications and hospital admissions after prostate biopsy in a european randomized trial eur urol 2012; 6 1:1110-14. 15. loeb s, carter hb, berndt si, et al. complications after prostate biopsy: data from seer-medicare. j urol. 2011; 186:1830-4. 16. lim jw, ko yt, lee dh, et al. treatment of prostatic abscess: value of transrectal ultrasonographycally guided needle aspiration. j utrasound med. 2000; 19:609-17. 17. aravantinos e, kalogeras n, zygoulakis n, et al. ultrasound – guided trasrectal placement of drainage tune as therapeutic management of patients with prostatic abscess. journal of endourology. 2008; 22:1751-4. 18. arrabal-polo ma, jimenez-pacheco a, arrabal-martin m. percutaneous drainage of prostatic abscess: case report and literature review. urol int. 2012; 88:118-20. 19. tiwari p, pal kd, tripathi a. et al. prostatic abscess: diagnosis and management in the modern antibiotic era. saudi j kidney dis transpl. 2011; 22:298-301. 20. galosi ab, tiroli m, cantoro d, et al. biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. arch ital urol androl. 2010; 82:248-52. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it valentina maurelli, md valentinamaurelli@hotmail.it fabrizio fioretti, md, phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it mara piergallina, md mara.piergallina@tiscali.it giovanni ciccotti, md giovanni.ciccotti@sanita.marche.it matteo talle’, md matteo.talle@gmail.com gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, head of section of urology asur marche area vasta 3, macerata hospital, macerata, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy figure 5. longitudinal view of patient in figure 3: trus guided aspiration with an endfire probe, endfire needle access. archivio italiano di urologia e andrologia 2016; 88, 2136 review the role of cucurbita pepo in the management of patients affected by lower urinary tract symptoms due to benign prostatic hyperplasia: a narrative review rocco damiano 1, tommaso cai 2, paolo fornara 3, corrado antonio franzese 4, rosario leonardi 5, vincenzo mirone 6 1 department of urology, university of catanzaro, catanzaro, italy; 2 department of urology, santa chiara regional hospital, trento, italy; 3 department of urology, martin-luther-university, halle saale, germany; 4 urology, asl na3 sud, naples, italy; 5 urology, gecas institute, catania, italy; 6 department of urology, university of naples, federico ii, naples, italy. objective: phytotherapeutic compounds are largely used in the treatment of lower urinary tract symptoms (luts) related to benign prostatic hyperplasia (bph) due to low side-effect profiles and costs, high level of acceptance by patients and a low rate of dropout. here, we aimed to analyze all available evidence on the role of cucurbita pepo in the treatment of luts-bph. material and methods: in may 2016 a systematic search was carried out thorough national library of medicine pubmed, scopus database and the isi web of knowledge official website in order to identify all published studies on cucurbita pepo and bph. the following search strings were used: “cucurbita pepo” or “pumpkin seed” and “prostate”; “cucurbita pepo” and “antiandrogen” or “antiproliferative” or “anti-inflammatory” or “antioxidant activities”; “cucurbita pepo” or “pumpkin seed” and “luts” and “symptoms improvement” or “quality of life”. we consider for the present analysis only studies related to luts-bph. results: among all 670 screened, 16 were related to lutsbph and finally analyzed. among all, ten of them were performed in “in vitro setting” showing anti-inflammatory and antiandrogen effect, and a reduction in prostate growth and detrusor activity, while six were clinical studies. in all studies an improvement in international prostatic symptoms score (ipss) and uroflowmetry parameters has been reported. in 4 studies, an improvement in quality of life has been reported. conclusion: on the basis of our narrative review, the use of cucurbita pepo in the management of patients affected by luts-bph seems to be useful for improving symptoms and quality of life. however, future clinical trials are requested to confirm these promising results. key words: bph; cucurbita pepo; luts; prostate disease; pumpkin seed. submitted 27 may 2016; accepted 5 june 2016 contributions: rd, tc, caf, rl data collecting; rd, tc analyzing and manuscript writing; vm, caf, rl and pf supervision. summary conflict of interests: the authors declare no potential conflict of interests. funding: chefaro pharma supported the publication of this narrative review. introduction benign prostatic hyperplasia (bph) affects most men after the age of 50 years and is considered the most common urologic disease among elderly men (1). bph is a chronic disease with early initiation and slow progression, due to an overgrowth of the epithelial and stromal cells from the transition zone and the periurethral area (2). it is essentially a histological diagnosis, which can be clinically manifested as benign prostatic enlargement (bpe) in almost half of the cases. bph starts as a simple micro nodular hyperplasia and evolves into a macroscopic nodular enlargement that gradually results in benign prostatic obstruction (bpo). the increase in prostatic size may eventually compress the urethral canal leading to bpo characterized by progressive development of lower urinary tract symptoms (luts) as urinary hesitancy and frequency, dysuria, sexual dysfunction, increased risk of urinary infection and at least urinary retention. aging, dietary factors, presence of androgens, growth factors, oxidative stress and chronic prostatic inflammation are necessary for the development and progression of bph, but the pathogenesis is still largely unresolved and there is no consensus as to which is the primary one (3). in the management of bph, is necessary to reduce cell growth by blockage of testosterone conversion in dht, and reduce the sustaining of the chronic prostatic inflammation. patient acceptability of treatment is key to decreasing the human and economic burden of this condition. maintaining sexual function is a crucial topic nowadays. alpha blockers, 5-alphareductase inhibitors (i-5ar) and phosphodiesterase 5 inhibitors (i-pde5), as monotherapy or in combination, have been used in bph treatment (4). notwithstanding these drugs have a positive effect on the patient with bph, side effects (including sexual ones) progressively favor patient withdrawal from therapy and progressively enhance interest in drugs of plant origin with less adverse effects (5). phytotherapy dates back thousands of years, and currently represent almost 50% of all medicine predoi: 10.4081/aiua.2016.2.136 damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 136 137archivio italiano di urologia e andrologia 2016; 88, 2 cucurbita pepo in bph scribed for bph in italy. nowaday, due to low side-effect profiles and costs, high level of acceptance by patients and low rate of drop-out, the use of phytotherapy is progressively increasing. here, we focused our attention on cucurbita pepo. cucurbita is a well-known traditional herbal medicinal product used from centuries worldwide and its medicinal use was described in many manuscripts and textbooks. the cucurbita genus comprises many species widespread in europe, asia and america. cucurbita pepo in the form of ethanolic pumpkin seed soft extract has been used for more than thirty years in the european community, mainly as a remedy for various difficulties associated with an enlarged prostate gland and micturition problems related to overactive bladder (6, 7). the active compounds in cucurbita pepo l. seeds are δ5-, δ7and δ8-sterols: δ7-sterols, which are largely predominant in cucurbita pepo, are considered to be the key active constituents of pumpkin seed in the treatment of benign prostatic hyperplasia. much smaller amounts of δ5and δ8-sterols are also present in cucurbita pepo (7-11). high content of carotenoids, polyunsaturated fatty acids and liposoluble vitamins have also a role in its activity (12). therefore, in the present narrative review, we summarize all evidence available on the role of cucurbita pepo in the management of patients affected by luts due to bph. materials and methods search strategy and evidence acquisition we searched electronic databases including pubmed, the scopus database and the isi web of knowledge for published studies that analyzed the role of cucurbita pepo in the management of patients affected by luts due to bph up to may 31, 2016. the following medical subject headings terms and free text were used: “cucurbita pepo” or “pumpkin seed” and “prostate”; “cucurbita pepo” and “antiandrogen” or “antiproliferative” or “anti-inflammatory” or “antioxidant activities”; “cucurbita pepo” or “pumpkin seed” and “luts” and “symptoms improvement” or “quality of life”. there was no restriction on population or publication year. additionally, we conducted a manual search using the bibliographies of all the identified studies, reviews, and editorials to identify references that we may have missed during our primary search. finally, the search included original articles, review articles and editorials and these were reviewed in order to select relevant articles. when necessary, we contacted the authors to obtain any relevant information we found to be missing from published papers. the figure 1 shows the study selection process diagram. selection criteria inclusion criteria: (1) all studies related to luts-bph; (2) all pre-clinical and clinical trials. exclusion criteria: (1) the language of the studies was not english or german; (2) if multiple publications for the same data from the same study group occurred, only the most informative and recent article was recruited into final analysis; (3) letters to editor, review articles, commentaries, clinical guidelines, or case reports and case series. results six-hundred and seventy studies were selected up to may 31, 2016. after the first-step analysis, 16 studies were included in this narrative review. ten studies were considered in the pre-clinical setting and 6 in the clinical setting. pre-clinical setting antioxidant activity. four commercially available pumpkin seeds (cucurbita pepo, cucurbita moschata, cucurbita maxima and cucurbita mixta) extracts were screened for their antioxidant activity and their inhibitory activity against lipid peroxidation (13). the results showed that radical scavenging activity depends on their total phenolic content. in particular, pumpkin seed water extracts inhibited lipid peroxidation at 1.5 mg/ml, while the acetone extracts inhibit 50% of lipoxygenase activity at the range from 0.16 to 0.80 mg/ml. antiandrogen activity. in an in vitro study in human prostate fibroblasts, the isolated pumpkin δ7-sterols showed antiandrogenic activity dose-dependently blocking the binding of dihydrotestosterone (dht). the cultures were incubated with 120 ng labeled dht for 24 hours and the binding rate was calculated as a difference from the concentration remaining in the supernatant. the binding rate in the control was 63%. in the cultures pre-treated with 120 ng or 240 ng pumpkin sterols (each in a double set-up) the binding rate was 51.7% and 43.3% or 37.5% and 38.3% respectively (14). furthermore, schmidlin and kreuter (15) described influence of the cucurbitae pepo extract on activity of aromatase and 5-α-reductase type ii in the homogenates of human and rat placenta. by using 10 mg/ml-concentration extract, about 50% reduction of aromatase activity and 90% of 5-α-reductase type ii inhibition were achieved. subsequently, in the “in vivo” prostate hypertrophy model the pumpkin extract (100mg/kg) reduced prostate weight of 31% vs 76% of the subcutaneous finasteride injection (1 mg/kg). figure 1. selection process of studies. damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 137 archivio italiano di urologia e andrologia 2016; 88, 2 r. damiano, t. cai, p. fornara, c.a. franzese, r. leonardi, v. mirone 138 anti inflammatory activity. three different extracts of pumpkin seeds showed immunological activity suppressing dose dependently mitogen-induced neopterin production and tryptophan degradation induced by cytokine interferon-γ (ifn-γ) (16). in particular, pumpkin seeds of cucurbita pepo (citrullinina greb. var. styriaca greb) from biological culture were finely grounded (10 g of the powder was added to 100 ml of medium roswell park memorial institute (rpmi 1640). then the peripheral blood mononuclear cells (pmbc) were isolated from the whole blood from healthy human donors and stimulated with phytohaemagglutinin and concanavalin-a. tryptophan and neopterin concentrations, two biochemical pathways stimulated by cytokine interferon-γ, were measured in the supernatants in order to assess the anti-inflammatory activity of the pumpkin seeds extracts. finally, a dose dependant suppression of mitogen-induced neopterin production and tryptophan degradation was recorded compared to control pmbcs. likewise, fahim et al. (17) used an experimental murine model of arthritis to test anti-inflammatory activity of pumpkin seed oil administered in intramuscular injection. for comparison, other two groups of rats respectively received indomethacin – a classic anti-inflammatory agent – and no further treatment. blood samples were collected to measure: blood glutation (gsh), plasma total proteins, albumin serum sulfhydryl group (sh-gps), ceruloplasmin (cp) and lysosomal marker – n-acetyl-β-d-glucosaminidase (nag). after completing the experiment, liver samples were used for determination of glucose-6-phosphate dehydrogenase (g6p dh) activity and protein content of liver homogenates was established. adjuvant inoculation resulted in decrease of serum sh-gps, with an increase of serum cp reduction of blood glutathione and total proteins and albumins levels. liver g6p dh activity was markedly increased. the treatment with pumpkin seed oil resulted in normalization of altered parameters, notably in chronic phase, except serum nag influence. pumpkin oil administration inhibited paw oedema during the chronic phase in about 44% as compared to the control untreated group. it reduced also liver g6p dh activity to almost 50% of the arthritic groups’ level. no increase in the antiinflammatory effects of indomethacin combined with pumpkin seed oil was observed. bladder contractility. the effects of non-specified water soluble extract of pumpkin seeds and soybean germ extract on in-bladder pressure (cystometrogram) and urination frequency of male rats were tested (18). pumpkin seed water-soluble extract (250 mg/kg) compared to control solvent (1% dimethyl sulfoxide diluted in sterile physiological saline) and soybean germ extract significantly increased bladder volume, decreased urination frequency and increased urination delay index. according to the authors, the observed effects of the relaxation of the bladder and decrease of in-bladder pressure are related to the increased productions of no via the arginine/no pathway. arginine is present in the pumpkin seed extract in two fold the concentrations of other amino acids. it was suggested that arginine/no metabolism, independently of adrenaline and acetylcholine, is involved in relaxation of urination muscle at a stage of full bladder (19). prostate gland growth. abdel-rahman et al. (20) performed a comparative study to examine the effect of pumpkin seeds diet implementation on prostate growth. the authors used an experimental model where benign prostatic hyperplasia (bph) in ventral prostate was induced by orally administering citral (c10h16o) into stomach of male rats. citral was administered to all rats except negative control group. the rats were subsequently grouped according to their diet – normal or different level of pumpkin seeds – and sacrificed. briefly, citral significantly increased prostate weight (p < 0.05), while pumpkin seeds given orally dose-dependently inhibited citral induced hyperplasia of the prostate, especially at high concentration seed dose (10%, p < 0.02). in a testosterone-induced bph murine model gossell-williams et al. found that administration of testosterone significantly increased prostate size ratio (weight of prostate/b.w. of the rat) (p < 0.05) although this increase was significantly inhibited by treatment with pumpkin seed oil at 4.0 mg/100 g b.w. gossell-williams (21). likewise, tsai et al. (22) tested pumpkin seed oil efficacy for 14 days, in experiments performed in rats on the model of prostatic growth induced by subcutaneous daily injection of testosterone (1.25 mg/kg/day) together with prazosin (30 μg/kg/day) (t-p). pumpkin seed oil (pso) (2.5 ml/kg/day) extracted from pumpkin seeds was administered concomitantly together with t-p. as compared with t-p alone group, the t-p group treated with pso had significant lower weight ratio for ventral prostate (p = 0.01) and lower protein levels within ventral lobe and dorsolateral lobe (p = 0.03 and p = 0.003, respectively). table 1 summarizes all evidence available in the pre-clinical setting. clinical setting hamvas et al. (23) reported an overall improvement of urinary symptoms after 10 months of medication with cucurbita pepo. the daily dosage was 3 x 2 capsules in the first month and 3 x 1 capsule for the rest of the time. changes despite pre-treatment conditions in uroflow test and patients symptoms perception were the used outcomes. control visits were scheduled after 4-7-10 months of medication. at the end of follow up, an improvement in uroflowmetry parameters was recorded (respectively: qmax 15.4 vs 18 ml/sec, qave 9.5 us 12.5 ml/sec, post voiding residual 90 vs 50 ml). furthermore, a reduction of nocturia, urinary frequency and relief of urinary pain were reported. finally, about 90% of patients felt a “very good” or “good” improvement of their urinary symptoms after therapy. in a multicentre setting, bach et al. (24) performed a randomized double-blind, placebo-controlled study enrolling 476 men (mean age 63 yrs) suffering from mild or moderate bph symptoms and at early stages (i or ii) of clinical bph as defined by alken (25). the study was carried out in accordance with recommendations of the international consultation on benign prostatic hyperplasia (26). the duration of treatment was 12 months and the main efficacy criterion was the international prostate symptom score (ipss). after a 1 month run-in-period under placebo, patients were randomized to daily treatment for 12 months with either 2 x 500 mg of the soft extract (15-25:1, ethanol 92%, damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 138 139archivio italiano di urologia e andrologia 2016; 88, 2 cucurbita pepo in bph m/m) from pumpkin seeds (n = 233) or placebo (n = 243). five post-randomization visits were scheduled after 1, 3, 6, 9 and 12 months. an improvement of at least 5 points in the ipss at study end was defined as a therapy response. even though the 'placebo effect' was considerable, this therapy response was reported by significantly more patients in the cucurbita group than in the placebo group (65% vs. 54%, p = 0.021). also, an improvement of at least 3 points in the ipss was reported by more patients in the cucurbita group (82.5%) than in the placebo group (67.9%, itt population). the mean reduction in ipss of 6.7 points (from 17.6 to 10.9) in the pumpkin seed group was significantly greater than the mean reduction of 5.5 points (from 17.7 to 12.2) after placebo treatment (p = 0.014). no significant changes were evident in either group in uroflowmetry parameters, residual urine, quality of life, prostate volume or serum prostate specific antigen levels. likewise, friederich (27) performed an observational study including 2245 patients with mild or moderate bph symptoms and administering 500 mg or 1.000 mg of pumpkin seed soft extract daily for 12 weeks. during therapy ipss scores improved by 41% (7.7 points, from 18.6 to 10.9) and quality of life index scores by 46% (from 3.4 to 1.8). the average frequency of micturition decreased from 6.7 to 5.1 during the day and from 2.3 to 1 during the night. improvement of dysuric disorders, such as painful urination, micturition burning, feeling of pressure and tension was reported by 52 % of the patients. diary recorded micturition frequency during the day and during the night was reduced within just 4 weeks to mean values of 5.8 (day) and 2.1 (night), with further improvement after 8 weeks to 5.2 and 1.5, reaching 4.8 during the day and 1.1 during the night after 12 weeks of treatment. at subgroup analyses, the most pronounced improvement was observed for the micturition frequency during the night, whereas patients with acute disorders benefited most. in these patients nocturia was reduced by 60% (from 2.35 to 0.94), and in patients with chronic complaints by 48% (from 2.75 to 1.43). in a retrospective survey involving urologists in private practice the treatment progression of 185 patients (aged between 44 and 85 years) receiving pumpkin seed soft extract was recorded and evaluated (28). among those, 173 patients received pumpkin seed soft extract as therapy to treat luts due to bph. most patients (63%) took 1 capsule per day, 27% took 2 capsules, and 9% of the patients were treated with more than 2 capsules. the recorded observation periods for individual patients ranged between one week and several years. however, for the majority (81%) data on the course of treatment were recorded within the first 3 months. urge symptoms and micturition frequency were reduced in most patients. the proportion of patients having reported more than one micturition during the night at start of treatment was reduced from 90% to 30%. residual urine was found to be reduced in 80% of the patients. hong et al. (29) carried out a randomized, double-blind, placebo-controlled trial over 12 months, enrolling 47 patients with bph with mean age of 53.3 years and international prostate symptom score over 8. the study design contemplated four comparative study arms: sweet potato starch (group table 1. summary of experimental studies supporting a role of pumpkin seeds in the treatment of bph-luts. bph-luts author, yearetiology role part of plant model main study finding xanthopoulou 2009 winkler 2005 fahim et al. 1995 schilcher 1990 schmidlin and kreuter 2003 hata 2005 abdel-rahman 2006 gossell-williams 2006 tsai 2006 seed extract seed extract seed oil pumpkin δ7-sterols seed extract seed extract seed seed oil seed biochemical for lipid peroxidation biochemical: blood stimulated mononuclear cells from healthy men arthritis rats model biochemical: human prostate fibroblasts culture biochemical: homogenates of human and rat placenta urodynamic test in rats bph induced with citral in rats bph induced with testosterone in rats testosterone plus prazosin induced prostate growth in rats inhibited lipid peroxidation inflammatory induced pathways (ifn-γ mediated) were reduced oxidative parameters commonly altered during arthritis were modulate; furthermore a reduction of rats’paw oedema was achieved dihydrotestosterone binding aromatase and 5-α-reductase type ii activity reduction; reduction of prostate weight increase bladder volume decrease frequency high concentration seed dose inhibites prostate growth inhibition of testosterone induced prostatic hyperplasia prostate weight was decreased pr os ta te g ro w th an dr og en in fla m m at or y bl ad de r co nt ra ct ilit y damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 139 archivio italiano di urologia e andrologia 2016; 88, 2 r. damiano, t. cai, p. fornara, c.a. franzese, r. leonardi, v. mirone 140 a, placebo, 320 mg/day), pumpkin seed oil (group b, 320 mg/day), saw palmetto oil (group c, 320 mg/day) or pumpkin seed oil plus saw palmetto oil (group d, each 320 mg/day). international prostate symptom score, quality of life, serum prostate specific antigen, prostate volume and maximal urinary flow rate were measured. so far, in groups b, c and d, the international prostate symptom score were reduced after 3 months (respectively from 20.7 ± 2.3, 18.3 ± 2.0, 19.0 ± 2.6 to 8.7 ± 1.5, 9.1 ± 1.4, 4.7 ± 17). quality of life score was improved after 6 months in group d (pumpkin seed oil plus saw palmetto oil) from 3.8 ± 0.4 to 2.5 ± 0.4 and was maintained stable afterwards while those of groups b (pumpkin seed oil) and c were improved after 3 months, compared to the baseline value respectively from 4.2 ± 0.4 to 3.0 ± 0.4 and from 3.6 ± 0.3 to 3.0 ± 0.4). finally, no difference was found in prostate volume in all treatment groups. maximal urinary flow rate were gradually improved in groups b (pumpkin seed oil) and c, with statistical significance after 6 months in group b and after 12 months in group c. more recently, vahlensieck et al. (30) investigated the efficacy of pumpkin seed in men with luts suggestive of bph performing a placebo controlled three-armed randomized trial. overall 1431 patients (aged 50-80 years) were randomly assigned to either pumpkin seed (5 g b.i.d.), capsules with pumpkin seed extract (500 mg b.i.d.) or placebo. the primary outcome was a decrease in ipss of > 5 points from baseline after 12 months. secondary outcome measure included ipss – related quality of life, ipss single items and diary recorded nocturia. after 12 months, the response rate differed significantly between pumpkin seed and placebo (58% vs 47%). overall, 12 months of treatment with pumpkin seed led to a clinically relevant reduction in ipss from (15.9 ± 1.8 and 15.8 ± 1.9, to 11.4 ± 5.5 and 10.2 ± 5.1) compared with placebo (from 16.1 ± 1.9 to 11.7 ± 5.4). adverse effects to note, no adverse effects were registered from above open clinical studies of pumpkin seeds. only mild gastrointestinal complaints (diarrhoea, nausea, vomiting) in table 2. clinical studies on pumpkin seeds in men affected of bph-luts. figure 2. international prostatic symptoms score analyzed in clinical studies. author, year study design patients comparator treatment outcomes measured number length hamvas 1991 60 pre-treatment 10 mo uroflow features improvement: qmax 15.4 vs 18 ml/s; qave 9.5 vs 12.5 ml/s; decrease in nocturia time, relief of dysuria and painful discharge about 90% referred a mild or very good improvement in symptoms gravity bach 2000 randomized 476 placebo 12 mo significative increase in response rate (itt population): controlled trial 67.5% vs 56.2% decrease in ipss 17.6 ± 3.7 vs 10.9 ± 4.5 mean ipss after treatment/change to baseline (itt): 10.9 ± 4.5 change: -6.7 (-38%) vs 12.2 ± 5.1 change: -5.5 (-31%) friederich 2000 multicentric 2245 pre-treatment 12 weeks ipss decreased from 18.6 to 10.9 (by 1.4%) and qol score improved from 3.4 to 1.8 (by 46.1%) 96% reported no undesired side effects burbach 2002 retrospective 185 pre-treatment 3 mo decrease in storage symptoms, nocturia (and pvr) hong 2009 randomized placebo47 placebo (four arms) 12 mo overall: controlled trial decrease ipss: 20.7 ± 2.3 vs 8.7 ± 1.5 improvement of qol score: 3.4 ± 0.4 vs 2.5 ± 04 vahlensieck 2015 randomized 1431 placebo 12 mo decrease in ipss (itt): -5.4 ± 5.1, -4.2 ± 5.4 vs -4.0 ± 5.6 controlled trial (three arms: ipss response rate increased by 6% pumpkin seed, improve in qol 36% and 33,4% vs 29,2% pumpkin seed extract and placebo) damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 140 141archivio italiano di urologia e andrologia 2016; 88, 2 cucurbita pepo in bph no more than 4% of the patients was reported in in friederich study whereby it seems that upon administration within the therapeutic dose range, there is no risk of serious side effects on all three rcts. no sexual side effects were reported during the use of cucurbita pepo compounds. table 2 shows all clinical studies performed in the management of luts-bph. moreover, figure 2, figure 3 and figure 4 show impact of the cucurbita pepo on ipss, uroflowemetry parameters and patients qol, respectively. discussion main findings several studies performed in the pre-clinical and clinical setting showed that the use of cucurbita pepo in the management of patients affected by luts-bph seems to be useful for improving symptoms and quality of life. several aspects should be taken into account; in particular, some limitations of the evidence available need to be considered. analysis of the evidences in the context of the current knowledge more recent knowledge about the physiological regulation of bladder function makes it plausible that ubiquitous substances may also contribute to the overall effect of pumpkin seeds, in particular for maintaining normal bladder function and preventing functional disorders. fatty oil of pumpkin seeds is characterized by a high content of linoleic acid, accounting for 35-68% of the total fatty acids (31, 32) administration of this essential precursor of prostaglandin metabolism (formation of pge2 and pg2α) might cause an increase in prostaglandin synthesis. prostaglandins are formed by the detrusor muscle and increase its tone (33) resulting in an improved bladder function. the average tocopherol content of soft-shelled pumpkin seeds is 0.5 mg/g, whereas – in contrast to most other plant oils – γ-tocopherol is present in fiveto ten-fold higher concentrations than the α-isomer (34, 35). according to more recent studies, γ-tocopherol is thought to be significantly involved in the preventive role of vitamin e and also to have a beneficial effect in chronic inflammation (36-40). medicinal pumpkin seeds are rich in amino acids such as the no precursors arginine, glutamine and aspartic acid as well as γ-aminobutyric acids. these are involved in the regulation of bladder function as direct or indirect central neurotransmitters (41-43). observational studies (27), retrospective surveys (28) and randomized controlled trials (24, 29, 30) provide further evidence on beneficial effects of cucurbita pepo for patients with luts related to benign prostatic hyperplasia, as reduction of urge and micturition frequency was observed. the published literature shows that the benefits of pumpkin seeds treatment depend on the tonic influence on the bladder, sphincter relaxation and alleviation of micturition symptoms. it was therefore suggested that pumpkin seeds could be used in patients without significant obstruction of the prostate and low risk for disease progression (44). provided that the patient undergoes regular urological control visits, medical treatment with seeds of cucurbita pepo can be recommended for patients with micturition symptoms related to bph in early disease stages, including those with symptoms of overactive bladder. limits the few available studies were often outdated and enrolled a small number of patients, and only three rcts were of good quality. other limits are difficulties in data extraction on changes in patients classification (alken versus ipss). nevertheless all studies analyzed showed improvement in micturition parameters related to luts/bph. conclusion in the context of the present narrative review, cucurbita pepo seems to show significant efficacy in improving urinary symptoms with mild adverse effects however few clinical studies support the use of that drug. moreover, figure 3. quality of life assessment. figure 4. qmax assessment in clinical studies. damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 141 archivio italiano di urologia e andrologia 2016; 88, 2 r. damiano, t. cai, p. fornara, c.a. franzese, r. leonardi, v. mirone 142 all clinical studies are based on the evidence raising from experimental studies in pre-clinical setting that showed an interesting action of pumpkin seed elements on some bph etiological mechanism. large randomized study are needed to confirm these interesting result and recommend the use of pumpkin seed in the management of patients affected by luts due to bph. references 1. mcvary kt, roehrborn cg, avins al, et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol. 2011; 185:1793-1803. 2. roehrborn cg. chapter 91 benign prostatic hyperplasia: etiology, pathophysiology, epidemiology, and natural history. in: kavoussi lr, novick ac, partin aw, peters ca editor(s). campbell-walsh urology. 10th edition. vol. 3, philadelphia: elsevier saunders, 2011b. 3. vignozzi l, gacci m, maggi m. lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome. nat rev urol. 2016; 13:108-19. 4. management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo) in european association of urology guidelines, available on https://uroweb.org/guidelines/ 5. cai t, morgia g, carrieri g, et al. an improvement in sexual function is related to better quality of life, regardless of 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abd-el-fattah aa, agha am, gad mz. effect of pumpkin-seed oil on the level of free radical scavengers induced during adjuvant-arthritis in rats. pharmacol res. 1995; 31:73-79. 18. hata, tanahashi s, wakida y, et al. effects of pumpkin seed extract on urinary bladder fun ction in anesthetized rats. med sci pharm sci. 2005; 54:1-10. 19. andersson ke, wein aj. pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. pharmacol rev. 2004; 56:581-63. 20. abdel-rahman mk. effect of pumpkin seed (cucurbita pepo l) diets on benign prostatic hyperplasia (bph): chemical and morphometyric evaluation in rats. world j chem. 2006; 1:33-40. 21. gossell-williams m, lyttle k, clarke t, gardner m, simon o. supplementation with pumpkin seed oil improves plasma lipid profile and cardiovascular outcomes of female non-ovariectomized and ovariectomized sprague-dawley rats. phytother-res 2008; 22:873-877. 22. tsai y-s, tong y-c, cheng j-t, lee c-ho. pumpkin seed 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47:909-915. 34. murkovic m, hillebrand a, winkler j, pfannhäuser w. damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 142 143archivio italiano di urologia e andrologia 2016; 88, 2 cucurbita pepo in bph variavility of vitamin e content in pumpkin seeds (cucurbita pepo l.) z. lebensm. unters. forsch, 1996a; 202:275-278. 35. rucker rb, suttie jw, mccormick db, machlin lj. handbook of vitamins 3rd ed. new york: marcel dekker inc. 2001; pp 183-4. 36. freeman vl, meydani m, yong s, et al. prostatic levels of tocopherols, carotenoids, and retinol in relation to plasma levels and selfreported usual dietary intake. am j epidemiol. 2000; 151:109-18. 37. giovanucci e. gamma-tocopherol: a new player in prostate cancer prevention? j natl cancer inst. 2000; 92:1966-7. 38. helzlsouer kj, huang hy, alberg aj, et al. association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. j natl cancer inst. 2000; 92:2018-23. 39. hensley k, benaksas ej, bolli r, et al. new perspectives on vitamin e: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. free radic biol med. 2004; 36:1-15. 40. jiang q, ames bn. gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicoanoids and inflammation damage in rats. faseb j. 2003; 17:816-22. 41. de groat. anatomy of the central neural pathways controlling the lower urinary tract. eur urol. 1998; 34 (suppl 1): 2-5. 42. korting ge, smith sd, wheeler ma, et al. a randomized double-blind trial of oral l-arginine for treatment of interstitial cystitis.j urol. 1999; 161:558-65. 43. persson k, igawa y, mattiasson a, anderson ke. inhibition of the arginine/nitric oxide pathwy causes bladder hyperactitivy in the rat. acta physiol scand. 1991; 144:107-8. 44. madersbacher s, ponholzer a, berger i, marszałek m. medical management of bph: role of plant extracts. eau ebu update series. 2007; 5:197-205. correspondence rocco damiano, md damiano@unicz.it department of urology, magna graecia university of catanzaro viale europa germaneto 88100 catanzaro, italy tommaso cai, md department of urology, santa chiara regional hospital trento, italy paolo fornara, md department of urology, martin-luther-university halle saale, germany corrado antonio franzese, md urology, asl na3 sud, naples, italy rosario leonardi, md urology, gecas institute, catania, italy vincenzo mirone, md department of urology, university of naples, federico ii naples, italy damiano tabelle nostre!_stesura seveso 01/07/16 11:10 pagina 143 archivio italiano di urologia e andrologia 2013; 85, 286 introduction benign prostatic hyperplasia (bph) is a highly prevalent medical condition worldwide. the prevalence of lower urinary tract symptoms (luts) associated with bph among older and middle-aged men is significant and is original paper comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique. 3 year follow-up roberto giulianelli, luca albanesi, francesco attisani, barbara cristina gentile, giorgio vincenti, francesco pisanti, teuta shestani, luca mavilla, david granata, manlio schettini division of urology nuova villa claudia clinic, rome, italy. objective: transurethral resection of the prostate (turp) is the current optimal therapy for the relief of bladder outflow obstruction, with subjective and objective success rate of 85 to 90%. aim of this study was to evaluate efficacy and safety of plasmakinetic energy (gyrus electro surgical system), which produces vaporization of tissue immersed in isotonic saline against standard monopolar transurethral resection of the prostate. methods: from january 2002 to april 2002, 160 consecutive patients, who had low urinary tract symptoms (luts) of benign prostatic hyperplasia (bph) were enrolled in this study. patients were randomised to undergo bipolar turp (80 patients) or monopolar turp (80 patients). preoperative work-up was assessed by administering ipss, iief-5 and qol questionnaires. all patients were submitted to uroflowmetry, transrectal ultrasound (trus), post-voidal residual urine measurement and psa determination. in the two groups, ipss, iief-5 and qol, uroflowmetry, trus, post-voidal residual urine measurement, psa determination and number of reoperations were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months follow up, and then every year. furthermore, in both groups operative time, resected tissue weight and perioperative complications were analysed. total postoperative catheter time, total post-operative hospital stay, haemoglobin loss were also recorded in the two groups. results: comparative data on ipss symptom score, iief-5, qol, psa, peak urinary flow rate and post-void residual urine volume were similar in the two groups but showed a significant improvement respect to baseline values. the postoperative haemoglobin levels, postoperative catheterization time, hospital stay and 3-year overall surgical re-treatment-free rate were significantly better in the bipolar group. conclusions: bipolar turp has a comparable outcome to standard monopolar turp at short and medium term regard to subjective and objective outcome measurements. its impact on bladder outlet function is also similar to that of monopolar turp. improvement in ipss, qol index, iief-5, qmax and post-void residual urine volume were comparable in both group denoting similar efficacy of the techniques. key words: bipolar turp; monopolar turp; outcome; gyrus device. submitted 21 february 2013; accepted 30 april 2013 no conflict of interest declared summary growing alongside the increasing age of western populations. it has been calculated that approximately 30% of the male population in europe and the united states have a chance of undergoing to standard transurethral giulianelli ok_stesura seveso 24/06/13 11:05 pagina 86 87archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique resection of the prostate (turp) during their lifetimes (1). transurethral resection of the prostate (turp) is the current optimal therapy for the relief of bladder outflow obstruction, with subjective and objective success rate of 85 to 90% (2). besides these excellent success rate, bleeding, transurethral resection syndrome, urinary tract infection, retrograde ejaculation and incontinence are the complications associated with the procedure (3). these complications have been estimated to develop in approximately 15% of the patients (4) and they may sometimes be of clinical relevance (5). contemporary turp uses a monopolar electrocautery system in which the current passes through the patient’s body: from the active electrode, placed on the resectoscope, towards the return plate, normally placed on the patient’s leg. this has several disadvantages such as heating of deeper tissue, nervous or muscle stimulation and possible malfunction of cardiac pace-maker (6). resectoscopes using bipolar electrocautery offer an alternative with active and return electrode placed on the same axis on the resectoscope using high current locally but with limited negative effects at distance. another risk of standard monopolar turp is the absorption of hypoosmolar irrigation fluid causing the tur syndrome. as bipolar resectoscopes use isotonic saline solution for irrigation, the risk of tur syndrome is eliminated. the first bipolar device for endourological procedures was the gyrus device using the bipolar electrocautery to electrovaporize the prostate (7). aim of this study was to evaluate efficacy and safety of plasmakinetic energy (gyrus electro surgical system), which produces vaporisation of tissue immersed in isotonic saline versus standard monopolar transurethral resection of the prostate. materials and methods from january 2002 to april 2002, 160 consecutive patients, with a mean age of 63.34 ± 7.1 years, who had luts of bph were enrolled in this study. out of them, 80 patients with a mean age of 62.5 ± 6.9 years were randomised to undergo bipolar turp (gyrus group) and 80 with a mean age of 64.18 ± 7.2 years to monopolar turp (traditional group). all surgical procedures were performed by the same surgeon who was fully trained in bipolar and monopolar turp. preoperative work-up included administration of ipss, iief-5 and qol questionnaires. all patients were submitted to uroflowmetry, transurethral ultrasound (trus), post-voidal residual urine measurement and psa determination. the patients provides informed written consent and were randomized to the traditional or gyrus group with a schedule balanced in blocks of 4. all patients were operated on within 4 weeks of randomization. exclusion criteria were patients with documented or suspected prostate cancer, bladder calculus, neurogenic bladder, previous prostate surgery, renal impairment, associated hydronephrosis and urethral stricture. the instruments (12° storz 24.5 f resectoscope) and the operative technique were the same of monopolar and bipolar turp. in the traditional group the monopolar turp was performed by a gyrus acmi generator, with a standard tungsten wire loop using a cutting current of 80 w and coagulating current of 160 w. in this group standard turp was carried-out using irrigation with a mannitol-sorbitol solution. in the bipolar group, turp was carried out using a gyrus plasmakinetic generator and saline irrigation that allowed electric current to complete the circuit without passing through the patient. the gyrus plasmakinetic system is a bipolar coaxial system with the active and return electrodes located in the same axis, separated by a ceramic insulator. we performed bipolar turp with a cutting current of 120 w and coagulating current of 80 w. at the end of the operation a 20 fr. dufour catheter was inserted and the bladder was continuously irrigated depending on the amount of postoperative bleeding. all tissue retrieved from each patient was investigated histologically. all patients were operated in peridural anesthesia. perioperative and postoperative outcomes were evaluated. in both groups operative time, resected tissue weight and perioperative complications were analysed. total postoperative catheter time, total post-operative hospital stay, haemoglobin loss were also recorded in the two groups. in both groups, ipss, iief-5 and qol scores, uroflowmetry and trus measurements of post-voidal residual urine, psa determinations and number of reoperations were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months. the results were analysed with the use of descriptive statistic and with paired t test and chi-square test to compare the continuous variables and categorical data. significant differences were considered at p < 0.05. baseline characteristics, perioperative data and postoperative interim analyses of ipss symptom scores, peak urinary flow rates and residual volumes in the two groups were compared using the 2-sided mann-whitney test. perioperative and postoperative adverse events were compared with the 2tailed chi-square test (exact fisher’s test). results of 160 men 80 each were randomised to monopolar and bipolar turp. the patient population and their preoperative characteristics are shown in table 1. there was no statistically significant difference in any parameter between the two groups. the perioperative data are shown in table 2 and the postoperative data are shown in table 3. the resection time and the weight of resected prostate tissue were not significantly different in the two groups. histological examination of the retrieved tissue revealed bph and varying degrees of prostatitis. incidental carcinoma of the prostate was found in 7 (4.37%) patients (6 pt1a and 1 pt1b): 5 in the monopolar group and 2 in the bipolar group respectively. table 3 shows comparative data of ipss, iief-5 and qol, psa, peak urinary flow rates and post-void residual urine volumes in the two groups at 1, 3, 6, 12, 24, 30 and 36 months. compared to baseline there was an highly significant improvement for each parameter at all intervals in each group (p < 0.0001). on the contrary there was no signifgiulianelli ok_stesura seveso 24/06/13 11:05 pagina 87 archivio italiano di urologia e andrologia 2013; 85, 2 r. giulianelli, l. albanesi, f. attisani, b.c. gentile, g. vincenti, f. pisanti, t. shestani, l. mavilla, d. granata, m. schettini 88 pvr decreased to 97 ml. (sd ± 57.6, p < 0.05). at 3, 6 and 12 months, mean pvr was 81 ml (sd ± 17.6, p < 0,05), 22.5 (sd ± 15.6, p < 0,001) and 10 ml (sd ± 10, p < 0.001), respectively. the ipss in the bipolar group fell from 22.3 (sd ± 3.2) to 12.8 (sd ± 1.2) at 1 month, 5.3 (sd ± 1.4) at 3 months and 5.0 (sd ± 1.2) at 6 months respectively. there was also a significant modification of the qol score (baseline 3.3), which was 2.3 (p < 0.01) at 1 month, 1.1 (p < 0.001) at 6 months, and 0.9 (p < 0.001) at 12 months (figure 2). those results were stable in the following months. the mean preoperative haemoglobin fell from 14.88 mg/dl (sd ± 0.71) and 14.52 mg/dl (sd ± 0.71) in the monopolar and bipolar group to postoperative values of 10.4 (sd ± 1.2) and 13.6 (sd ± 0.6) respectively. the postoperative haemoglobin levels were lower in monopolar than bipolar group, and in the monopolar group 3 patients required transfusions. postoperative bladder irrigation was always stopped on the first postoperative day. median postoperative catheterization time and hospital stay time were 1 and 2 days in the bipolar group an 2 and 3 days in the monopolar group. nine patients in monopolar group and none in bipolar group were unable to void after initial removal of the catheter; they need to have the catheter reinserted and were discharged 2 days later. four patients in monopolar group and one in bipolar group developed clot retention within 3 weeks from surgery and in the monopolar group other two patients developed haematuria within 1 week from turp, all required readmission for cystoscopy and continuous bladder irrigation. in the monopolar group there were two cases of clinically evident tur syndrome and none in bipolar group. two patients in the monopolar group and fifteen in the bipolar group had postoperative irritative symptoms, which required occasional anticholinergic therapy. urinary tract infections developed in two patients in monopolar group and were treated with appropriate antibiotics. one year after turp 154 patients (75 in the monopolar and 79 in the bipolar group) were assessed for urinary continence and number of retreaments. none patient icant difference between the 2 groups for peak flow rate, improvement in ipps, iief-5 and qol score, psa modification and post-void residual urine volume at all postoperative follow-up evaluations. correlations between baseline and change from baseline showed that in each group improvement was more pronounced in patients with more severe preoperative symptoms and micturition impairment. in the bipolar group the qmax increased from 8.9 ml/sec (sd ± 2.9) preoperatively to 19.7 ml/sec (sd ± 5) after 1 month (p < 0.01). at 3, 6 and 12 months, qmax increased to 24.3 ml/sec (sd ± 3.2, p < 0.01), 25.2 ml/sec (sd ± 1.2, p < 0.001) and 26.7 (sd ± 2.2, p < 0.001), respectively (figure 1). in the same group, post-void residual urine volume (pvr) fell down substantially from the preoperative levels. the baseline value was 243 (sd ± 241.6); after removal of the catheter, the mean preoperative data bipolar turp monopolar turp age (years) 62.5 ± 6.9 64.18 ± 7.2 psa (ng/ml) 2.2 ± 0.5 2.8 ± 1.0 prostate volume (ml) 47.8 ± 14.6 50 ± 9.8 ipss 22.3 ± 3.2 23.4 ± 1.8 qol 3.3 ± 2.1 3.0 ± 2.5 qmax (ml/sec) 8.9 ± 2.9 6.5 ± 4.8 pvr 243 ± 241.6 187 ± 195 iief-5 16 ± 3.6 17 ± 2.5 hb 14.88 ± 0.71 14.52 ± 0.71 table 1. perioperative data bipolar turp monopolar turp resection time (min) 58 ± 14.6 59 ± 18 resected prostate tissue (gr) 30.6 ± 8.6 29.5 ± 7.8 hb (gr/dl) 13.6 ± 0.6 10.4 ± 1.2 time to catheterization (h) 24 ± 12 48 ± 48 hospital stay (h) 48 ± 6 72 ± 48 table 2. postoperative data bipolar turp monopolar turp follow-up (months) 1 3 6 12 18 24 30 36 1 3 6 12 18 24 30 36 ipss 12.8 5.3 5.0 4.5 4.2 3.0 3.0 2.0 8.8 7.8 7.0 5.3 5.0 4.8 4.8 4.0 qol 2.3 1.7 1.1 0.9 0.6 0.5 0.5 0.5 1.8 1.7 1.7 1.5 1.3 1.0 1.0 1.0 qmax 19.7 24.3 25.2 26.7 25.2 23.2 22.8 23.0 21.0 23.7 23.0 23.5 24.0 23.4 20.0 20.0 pvr 97 81 22.5 10 10 0 0 0 75 45 15 10 10 0 0 0 psa 0.55 0.90 0.95 0.90 0.9 0.9 0.60 0.90 1.00 1.00 1.15 1.50 iief-5 21 23 23 24 24 24 24 24 20 21 22 22 24 24 24 24 table 3. giulianelli ok_stesura seveso 24/06/13 11:05 pagina 88 89archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique until it was gradually replaced by transurethral resection of the prostate (turp). although turp is still regarded as the gold standard in patient with bph, it is associated with significant morbidity rates. neal et al. (8) reported a 10% morbidity rate in patients submitted to turp to remove obstruction. in our experience, the tissue ablation with the bipolar device was found to have similar clinical outcome compared to the standard procedure using a monopolar device, but with a significantly reduced bleeding rate. furthermore coagulation areas are found to be smaller when the bipolar resectoscope is used, due to the locally limited energy field between the electrodes of the resectoscope in which high power levels are achieved. this high energy field effectively coagulates bleeding vessels at the surface of the resected tissue. deeper tissue layers are less affected indicating that no energy is wasted to them and distant negative effects, such as deep tissue heating, nervous or muscle stimulation and interfering with cardiac pace-maker, are reduced. the rate of tissue ablation of bipolar resection was comparable to that achieved by a standard resection loop. in the current study we report the durable effect of bipolar turp. in our study the improvement in micturition and symptom scores were immediate and ipss, peak urinary flow rates and post-void residual urine volume returned to normal within 1 month postoperatively in each group. in the first postoperative month ipss, qol and qmax were better in the monopolar group than in the bipolar, but in all subsequent postoperative follow-up examinations were comparable in the 2 groups. at 3 years postoperatively, in the bipolar group, qmax increased significantly and post-void residual urine volume and psa declined. at 3 year follow up, improvement was significantly maintained for ipss, iief-5 and qol in both monopolar and bipolar group in comparison to baseline parameters (figure 3-5), but without statistically significant difference between 2 groups. many advantages of bipolar turp compared with monopolar are related to the haemostatic properties of the first device. intraoperative blood loss and postoperative bleeding were significantly decreased in bipolar group. no patients treated with bipolar turp required blood transfusion in contrast to three in the monopolar group. few investigations have been done on the histopathological changes and the depth of coagulation after bipolar and monopolar turp. huang et al. (9) compared the coagulation depth and specimen changes of figure 1. 3 year qmax improvement in monopolar and bipolar group. compared to baseline there was an highly significant improvement at all intervals in each group (p < 0.0001). figure 2. kaplan-meier curves, 3 year overall surgical re-treatment-free rate. preop 1 3 6 12 18 24 30 36 mo mo mo mo mo mo mo mo 0 2 4 6 8 10 12 36 mo mo mo mo mo mo mo had incontinence, whereas in total 12 patients (7.79%), 10 (6.49 %) and 2 (1.29%) in the monopolar and in the bipolar group respectively, required to be treated endoscopicallty for bladder neck contracture after 6 to 11 months postoperatively. after 24 and 36 months no more patients were submitted to retreatment. according to kaplan-meier plot, the 3-year overall surgical re-treatment-free rate was 92.5% (figure 2). discussion benign prostatic hyperplasia (bph) is a chronic agerelated condition, affecting approximately 50% of men older than 50 years, 75% of men older than 70 years and 90% of men older than 80 years (7). for many years open prostatectomy had been the primary treatment option in patients with benign prostatic hyperplasia giulianelli ok_stesura seveso 24/06/13 11:05 pagina 89 archivio italiano di urologia e andrologia 2013; 85, 2 r. giulianelli, l. albanesi, f. attisani, b.c. gentile, g. vincenti, f. pisanti, t. shestani, l. mavilla, d. granata, m. schettini 90 the prostate after bipolar and monopolar transurethral resection of the prostate in a canine model. the results of this study showed that the pathologic changes in the prostate after bipolar and monopolar turp are similar, but coagulation areas of bipolar turp are deeper and become thinner early after the operation than those the monopolar turp. botto et al. (10) found no significant intraoperative bleeding in 42 treated patients and eaton et al. (11) found that no patient required blood transfusion and no patients showed electrolyte disturbances intraoperatively. as a consequence of decreased bleeding in bipolar group, postoperative bladder irrigation, catheter time and hospital stay were significantly shorter than after monopolar turp. borboroglu et al. (12) recently reported a 0.4% transfusion rate, an average hospital stay of 1.1 days and an average catheter time of 1.4 days after turp. passavanti et al. (13) observed in 20 patients submitted to plasmakinetic resection the possibility to quickly stop continuous irrigation and to early remove the catheter. initially, in our experience with bipolar resection operative time was longer compared to standard turp, which could be due to the learning curve period. in both groups postvoidal residual urine (pvr) significantly decreased after treatment. pvr has traditionally been considered as an important parameter in the evaluation of patients with clinically evident bph. several guidelines on the management of bph consider pvr as a recommended (14) or optional (15) test in the clinical evaluation of patient with bph. another advantage of bipolar versus monopolar electrocautery lays in the use of 0.9% sodium chloride solution for irrigation. therefore the risk of tur syndrome, resulting from the absorption of large amounts of irrigation fluid during prolonged procedures, is theoretically reduced (16). dunsmuir et al. (17) report about a randomized prospective study comparing bipolar electro vaporization of the prostate with the gyrus device to the conventional turp. after one year follow-up symptom scores, qol, flow rates and post-voidal residual volumes were similar. they reported that re-catheterization was higher (30% vs 5%) in the bipolar vaporization group although the rate of postoperative clot evacuation was higher in the conventional turp group. in the bipolar group the 3-year surgical figure 5. a 3 years iief-5 improvement in monopolar and bipolar group. figure 4. a 3 years qol improvement in monopolar and bipolar group. compared to baseline there was highly significant improvement in each parameter at all intervals in each group (p < 0,0001), while there was no significant difference between the 2 groups in qol rates at any time. figure 3. 3 year ipss improvement in monopolar and bipolar group. compared to baseline there was an highly significant improvement at all intervals in each group (p < 0.0001), while there was no significant difference between the 2 groups in ipss score at any time. preop 3 12 24 36 mo mo mo mo preop 3 12 24 36 mo mo mo mo preop 3 12 24 36 mo mo mo mo giulianelli ok_stesura seveso 24/06/13 11:05 pagina 90 91archivio italiano di urologia e andrologia 2013; 85, 2 comparative randomized study on the efficaciousness of endoscopic bipolar prostate resection versus monopolar resection technique correspondence roberto giulianelli, md roberto.giulianelli@virgilio.it luca albanesi, md lucalbanesi@hotmail.com stefano brunori, md barbara cristina gentile, md giorgio vincenti, md stefano nardoni, md francesco pisanti, md teuta shestani, md luca mavilla, md francesco attisani, md gabriella mirabile, md manlio schettini, md division of urology villa tiberia clinic, rome, italy re-treatment-free rate was lower than in the monopolar (2 vs 10 patients). varkarakis e al (18) reported on long-term morbidity in 577 patients with a minimum follow-up of 10 years. the total re-intervention rate was 6%, including 2.4% who required reoperation for bladder neck contracture, 1.9% for recurrent bph obstruction, and 1.7% for urethral stricture. the annual rate of reoperation after minimal turp is 2.5% and the reoperation rate at 8 year follow-up is 23% after minimal resection and 7% after turp (11). conclusion the main advantages of bipolar turp is the use of saline as irrigation fluid, that eliminates the risk of trans urethral resection syndrome (tur syndrome) and the return current, reducing the risk of burns and the stimulation of nerves. in addition, the improved coupling of cut and coagulation may lead to less blood loss. bipolar turp has a comparable outcome to standard monopolar turp at short and medium term in term of subjective and objective outcome measures. its impact on bladder outlet function is also similar to that of monopolar turp. improvement in ipss, qol index, iief-5, qmax and post-void residual urine volume were comparable in both group denoting similar efficacy of the devices. furthermore, intraoperative blood loss, postoperative bleeding, time to catheterization, hospital-stay and the 3-year surgical re-treatment-free rate were significantly decreased with the use of the bipolar tool. references 1. keoghane sr, lawrence kc, gray am, et al. a double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up. bju int. 2000; 85:74-8. 2. down jb, cochett atk, peters pc et al. transurethral prostatectomy: practice aspects of the dominant operations in american urology. j urol. 1989; 141:248 3. mebust wk, holtgrewe hl, cochett atk, et al. transurethral prostatectomy: immediate and post-operative complications. a cooperative study of 13 institutions evaluating 3,885 patients. j urol. 1989; 141:243. 4. hahn rg, nilsson a, farahmand by, et al. blood haemoglobin and the long term incidence of acute myocardal infarction after transurethral resection of the prostate. eur urol. 1997; 31:199. 5. uchida t, ohori m, soh s, et al. factors influencing morbidity in patients undergoing transurethral resection of the prostate. urology. 1999; 53:98. 6. kellow nh. pacemaker failure during transurethral resection of the prostate. anaestesia. 1993; 48:136-8. 7. cabelin ma, te ae, kaplan sa. benign prostatic hyperplasia: challenges for the new millennium. curr opin urol. 2000; 10:301. 8. neal de. the national prostatectomy audit. br j urol. 1997; 79:69. 9. huang x, wang x-h, qu l-j, et al. bipolar versus monopolar transurethral resection of the prostate: pathologic study in canines. urology. 2007; 70:180-184. 10. botto h, lebret t, barre p, et al. electrovaporization of the prostate with the gyrus device. j endourol. 2001; 15:313-6. 11. eaton ac, francis rn. the provision of transurethral prostatectomy on a day-case basis using bipolar plasma kinetic technology. bju. 2002; 89:453-7. 12. borboroglu pg, krane cj, ward jf, et al. immediate and postoperative complications of transurethral prostatectomy in the 1990’s. j urol. 1999; 162:1307. 13. passavanti g, pizzuti v, bragaglia a, et al. the use of bipolar plasmakinetic resectoscope in endoscopic resection of the prostate: our experience. urologia. 2007; 74:160-163. 14. abrams p, griffiths d, hofner k, et al. the urodynamic assessment of lower urinary tract symptoms. in chatelain c, denis l, foo kt, et al. (eds.). benign prostatic hyperplasia. proceedings of the 5th international consultation on benign prostatic hyperplasia. paris, june 25-28, 2000. paris: health pubblication, ltd, 2001; 227-281. 15. aua, practice giudelines committee: aua guideline on management of benign prostatic hyperplasia (2003). chapter 1: diagnosis and treatment recommendations. j urol. 2003; 170:530. 16. aagaard j, jonler m, fuglsig s, et al. total transurethral resection versus minimal transurethral resection of the prostate-a 10years follow-up study of urinary symptoms, uroflowmetry and residual volume. br j urol. 2006; 50:563-8. 17. dunsmuir wd, mcfarlane jp, tan a, et al. gyrus bipolar electrovaporization vs transurethral resection of the prostate: a randomised prospective single-bind trial with a 1 year. follow up. prostate cancer prostatic dis. 2003; 6:182-6 18. varkarakis j, bartsch g, horninger w. long term morbidity and mortality of transurethral prostatectomy: a 10-year follow-up. prostate. 2004; 58:248-51. giulianelli ok_stesura seveso 24/06/13 11:05 pagina 91 81archivio italiano di urologia e andrologia 2017; 89, 1 case report nonabsorbable polymer clip as a cause of chronic perineal pain after radical prostatectomy: description of a case treated by transperineal approach massimiliano creta 1, sergio di meo 1, roberto buonopane 1, bernardo rocco 2, vittorio imperatore 1 1 unità operativa di urologia, buon consiglio fatebenefratelli hospital, napoli, italy; 2 uoc di urologia, fondazione irccs ca’ granda ospedale maggiore policlinico, milano, italy. the occurrence of persistent perineal pain caused by surgical clips has rarely been described after radical prostatectomy (rp). we describe the case of a patient complaining of chronic perineal pain occurred soon after robotic rp, refractory to conventional medical therapy and exacerbated by the sitting position. pain was related to a nonabsorbable polymer clip used to secure lateral pedicles. a transpeerineal approach was used to perform an hydrodissection of the rectovesical space at the level of the surgical clip combined with local injection of mepivacaine and betametasone. the patient experienced a clinically significant reduction of pain that remained stable at three months’ follow-up. key words: pain; prostatic neoplasms; prostatectomy. submitted 3 september 2016; accepted 26 november 2016 summary no conflict of interest declared. the early post-operative course of rp and it worsened in the sitting position. maximum pain intensity was 8 on a visual analogue scale (vas) 0 to 10. the patient denied any lower urinary tract symptom, macroscopic hematuria and fewer. physical examination of the abdomen and the perineum was unremarkable. digital rectal examination excluded local prostate cancer recurrence. however, a nonabsorbable polymer clip could be appreciated along the left neurovascular bundle, far from the urethrovesical anastomosis and finger pressure applied on it was able to elicit and intensify the pain described by the patient. patient post-operative prostate specific antigen was undetectable. findings from laboratory assessments and abdominal ultrasound were unremarkable. we hypothesized that pain could be secondary to a nerve entrapment syndrome caused by the surgical clip at the level of the left pelvic neurovascular bundle. the patient was hospitalized and we decided to manage it based on evidences from scientific literature in the orthopedic field (3). accordingly, we used a transperineal approach to perform an hydrodissection of the rectovesical space at the level of the surgical clip combined with local injection of mepivacaine and betametasone. in detail, the procedure was performed under spinal anesthesia with the patient in the lithotomy position. a18 gauge biopsy needle was used for saline (10 ml) injection in order to obtain hydrodissection of the entrapped neurovascular bundle followed by local injection of 10 ml of mepivacaine 20 mg/ml combined with 2 ml of betametasone 4 mg/2 ml. the procedure was performed under digital and transrectal ultrasound guidance in order to localize the site of injection (figure 1). the procedure was uneventful and the patient was discharged home on post-operative day 1. on post-operative day 1 pain intensity reported by the patient was 2 on a vas 0-10 and on post operative day 5 pain intensity was 4. at 3 months follow up pain intensity remained stable (vas score:4) and the patient declared to be satisfied. finger pressure on the site of the clip during digital rectal examination was unable to intensify pain intensity. doi: 10.4081/aiua.2017.1.81 introduction postoperative pelvic pain is expected after radical prostatectomy (rp) (1). however, pain lasting more than 6 months is uncommon (1). differential diagnosis is vast and includes chronic pelvic pain syndrome, urolithiasis, retained foreign body, pelvic joint dysfunction, surgical clip migration and erosion at the level of the urethrovesical anastomosis (1, 2). there is no previous report of perineal pain caused by normally anchored surgical clips. herein, we present a case of persistent intense post-rp perineal pain caused by a nonabsorbable polymer clips normally anchored along a neurovascular bundle far from the urethrovesical anastomosis and successfully treated with transperineal local hydrodissection and injection of anesthetic and corticosteroids. case report a 66-years old man was referred to our urology unit complaining of chronic perineal pain unresponsive to conventional medical therapy with nonsteroidal antiinflammatory drugs and gabapentin. his past surgical history was relevant for robotic rp performed 10 months before for a gleason 3+4 prostate cancer while his past medical history was unremarkable. onset of pain was in creta_stesura seveso 04/04/17 09:31 pagina 81 archivio italiano di urologia e andrologia 2017; 89, 1 m. creta, s. di meo, r. buonopane, b. rocco, v. imperatore 82 discussion surgical clips are commonly used during laparoscopic and robotic rp in order to secure lateral pedicles by avoiding thermal injury to the neurovascular bundle (1-2). complications related to the use of these clips have been reported and are mainly related to their migration and erosion into the urinary tract (1-2). moreover, biologically inert foreign bodies are known to represent a substrate that can be colonized by biofilms (3). as consequence, authors suggest to minimize the use of clips on tissue immediately adjacent to the anastomosis, and to make every effort to retrieve loose clips after the procedure (1-2). patients most commonly present with urinary retention, obstructive lower urinary tract symptoms, hematuria, pyuria, dysuria, urgency, painful micturition (1). surgical clips may be a source of pain. however, the occurrence of perineal pain related to surgical clips has rarely been described after rp (1). palou j et al. reported the case of a patient with severe perineal pain occurred soon after rp that prevented him from sitting normally (2). pain was secondary to a metal clip protruding into the urethra through the urethrovesical anastomosis (2). to our knowledge, we described for the first time the occurrence of severe and persistent post-rp perineal pain caused by a nonabsorbable polymer clip used to secure lateral pedicles and the technique of transperineal management of this complication. hydrodissection and corticosteroid injection are described in the orthopedic field as a valid option in case of pain related to nerve entrapment (4). hydrodissection dilate the injection space and can free the entrapped structures such as nerves. given the rising number laparoscopic and robotic rp together with the growing use of nonabsorbable polymer clip in this field, the number of clip related complications, including that described in the present case report, is expected to increase. in our experience, this procedure is simple to perform, safe, and can be repeated in necessary. conclusions the present case demonstrates that severe perineal pain may occur as a complication of nonabsorbable polymer clips at the level of neurovascular bundles after rp. the combination of local hydrodissection and injection of anesthetics and steroids through a transperineal approach may represent a valid strategy for patients unresponsive to medical therapy. references 1. yi js, kwak c, kim hh, ku jh. surgical clip-related complications after radical prostatectomy. korean j urol. 2010; 51:683-7. 2. palou j, alberola jm, villavicencio h, vicente j. it's like a pain in th... perineum: a surgical clip protruding into the urethra through the urethrovesical anastomosis after radical prostatectomy. scand j urol nephrol. 1997; 31:493-5. 3. cennamo p, montuori n, trojsi g, et al. biofilms in churches built in grottoes. sci total environ. 2016; 543(pt a):727-38. 4. soneji n, peng pw. ultrasound-guided pain interventions a review of techniques for peripheral nerves. korean j pain. 2013; 26:111-24. figure 1. sonographic anatomy for the injection technique described. b: bladder, n: bladder neck, c: surgical clip, h: hydrodissection space. correspondence massimiliano creta, md max.creta@gmail.com sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it vittorio imperatore, md (corresponding author) v.imperatore@alice.it unità operativa di urologia, buon consiglio fatebenefratelli hospital via a. manzoni, 220, 80123, napoli, italy bernardo rocco, md bernardo.rocco@gmail.com u.o.c. di urologia, fondazione irccs ca’ granda ospedale maggiore policlinico via commenda, 15, 20122 milano (italy creta_stesura seveso 04/04/17 09:31 pagina 82 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4336 original paper accuracy of 3 tesla pelvic phased-array multiparametric mri in diagnosing prostate cancer at repeat biopsy pietro pepe 1, antonio garufi 2, giandomenico priolo 2, giuseppe dibenedetto 1, michele salemi 4, michele pennisi 1, filippo fraggetta 3, francesco aragona 1, michele barbera 5 1 urology unit, 2 imaging department and 3 pathology unit, cannizzaro hospital, catania, italy; 4 section of endocrinology, andrology and internal medicine, department of medical and pediatric sciences, university of catania, italy; 5 urology unit, sciacca, italy. introduction. multiparametric pelvic magnetic resonance imaging (mpmri) accuracy in prostate cancer (pca) diagnosis was evaluated. materials and methods. from june 2011 to december 2013, 168 patients (median 65 years) with negative digital rectal examination underwent repeat transperineal saturation biopsy (spbx; median 28 cores) for persistently high or increasing psa values, psa >10 ng/ml or psa values between 4.1-10 o r 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively. all patients underwent mpmri using a 3.0 tesla scanner equipped with surface 16 channels phased-array coil and lesions suspicious for pca were submitted to additional targeted biopsies. results. a t1c pca was found in 66 (39%) cases; spbx and mpmri-suspicious targeted biopsy diagnosed 60 (91%) and 52 (78.8%) cancers missing 6 (all of the anterior zone) and 14 cancers (12 and 2 of the lateral margins and anterior zone), respectively; in detail, mpmri missed 12 (18.1%) pca charaterized by microfocal (1 positive core with greatest percentage of cancer and gleason score equal to 5% and 6, respectively) disease at risk for insignificant cancer. the diameter of the suspicious mpmri lesion was directly correlated to the diagnosis of pca with poor gleason score (p < 0.05); detection rate of cancer for each suspicious mpmri core was 35.3%. diagnostic accuracy, sensitivity, specificity, positive and negative predictive value of mpmri in diagnosing pca was 75.7%, 82.5%, 71.8%, 78.9%, 87.9%, respectively. conclusion. multiparametric pmri improved spbx accuracy in diagnosing significant anterior pca; the diameter of mpmri suspicious lesion resulted significantly predictive of aggressive cancers. key words: prostate cancer; multiparametric mri; prostate targeted biopsy; pelvic phased-array mri.. submitted 12 january 2014; accepted 31 october 2014 summary no conflict of interest declared. biopsy, still today, constitutes about 30% of the entire procedure with an estimated diagnosis of cancer equal to 20-40%. therefore, the ideal biopsy scheme should perform targeted biopsies to diagnose only significant pca, reducing the number of unnecessary procedures and false negative rate. in this light, multiparametric magnetic resonance imaging (mmri) using pelvic phased-array coil (mpmri) or endorectal coil (memri) has been proposed as a more accurate alternative in comparison with transrectal ultrasound (trus) to increase the detection rate for pca, especially in case of repeat biopsy (3-16). the accuracy of mpmri in diagnosing pca in men submitted to repeat biopsy was prospectively evaluated. materials and methods from june 2011 to december 2013, 168 patients, all of caucasian origin and between the ages of 49 and 75 years (median 65 years), with negative digital rectal examination underwent spbx (median 28, range: 6-35 cores) for persistent suspicion of pca. the 168 patients enrolled in a prospective, monocentric and multi-departmental study were selected from a case-finding protocol for pca detection (17) and had one single previous negative extended transperineal biopsy (18 cores) performed at least six months before (range: 6-20 months); the indications for repeat spbx were: persistently high or increasing psa value, psa > 10 ng/ml or psa values between 4.1-10 or 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively. all patients, provided a written informed consent, underwent mpmri 3-10 days before undergoing the spbx. all examinations were performed using a 3.0 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in supine position; multiplanar turbo spin-echo t2-weighted (t2w), axial diffusion weighted imaging (dwi), axial dynamic contrast enhanced (dce) and spectroscopy were performed for each patient (figure 1). the criteria (14) for a positive lesion on t2w (figure 1) were the presence of a circumscribed, low signal intensity lesion (hypointense); a posidoi: 10.4081/aiua.2014.4.336 introduction although extended (12-18 cores) and saturation biopsy (spbx; > 20 cores) have been suggested (1, 2) to improve detection rate for prostate cancer (pca), repeat prostate presented at 19th national congress sieun, fermo 2014awarded as sieun best urological communication pepe_stesura seveso 15/01/15 12:14 pagina 336 337archivio italiano di urologia e andrologia 2014; 86, 4 accuracy of 3 tesla pelvic phased-array multiparametric mri in diagnosing prostate cancer at repeat biopsy tive lesion on dce (figure 1) was characterized by the presence of foci showing early and intense enhancement and rapid washout after power injection (3.0 ml/s) of gadobutrol 0.1 ml/kg (gadovist®; bayer schering pharma, germany) followed by a 15 ml saline flush. a positive lesion on spectroscopy (figure 1) was any area where the choline to citrato ratio was 3 or more standard deviations above the mean healthy value. two radiologists (af, gp) blinded to pre-imaging clinical parameters evaluated the mri data separately and independently. spbx was performed transperineally using a tru-cut 18 gauge needle (bard; covington, ga usa) and a ge logiq 500 pro ecograph (general electric; milwaukee, wi usa) supplied with a biplanar transrectal probe (5-6.5 mhz) under sedation and antibiotic prophylaxis (18). to ensure that histopatological findings matched with mri images the assessment of radiological images and spbx scheme were performed dividing the prostate into 14 regions: apex, middle zone and base of posterior zone for each lobe beginning parasagittally to reach the outer edges of the gland (six regions for each lobe), anterior and transitional zone (15). in the presence of mpmri lesions suspicious for cancer, 3-4 (median: median 3.5 cores) targeted trus guidedbiopsies in addition to standard spbx were performed. a probability (p) level of less than 0.05 was considered statistically significant. results all patients had negative trus; median psa was 10.4 ng/ml (range: 3.7-45 ng/ml): 69 (41%) had psa > 10 ng/ml, 92 (54.8%) between 4-10 ng/ml and 7 (4.2%) between 2.6-4 ng/ml, respectively. multi pa rametric pmri was positive in 94 (56%) out of 168 patients (table 1); in the patients submitted to mpmrisuspicious targeted biopsy, 329 cores were performed; in 84 (89.3%) out of 94 the lesions were included in the spbx scheme, on the contrary, in 10 (10.7%) cases, the suspicious areas were localized in the anterior zone (figure 1a, 1b) near the bladder neck. none had significant complications from spbx that needed hospital admission; moreover, the mpmri procedure was well tolerated and successfully performed in all cases. a t1c pca was found in 66 (39%) out of 168 patients and normal parenchyma in the remaining 102 (61%). clinical parameters, biopsy quantitative histology, gleason score (gs) and mpmri findings in the presence of pca and normal parenchyma are listed in table 1. spbx scheme and mpmri-suspicious targeted biopsy diagnosed 60 (91%) and 52 (78.8%) out of 66 pca, respectively; in detail, spbx and mpmri missed 6 (all of the anterior zone) and 14 cancers (12 and 2 of the lateral margins and anterior zone) equal to 9% and 21.2% of the cases, respectively. in the presence and absence of pca the nodular suspicious mpmri lesions (figure 1) had a median diameter equal to 12 mm (range = 5-32 mm) vs 6 mm (range = 5-13 mm), respectively; a cut-off of 10 mm resulted predictive of cancer in 22 out 27 patients (81.5% of the cases) with a false positive rate of 9.6%. in detail, mpmri missed 12 (18.1%) pca charaterized by microfocal biopsy disease (1 positive core with a greatest percentage of cancer and gleason score equal to 5% and 6, respectively) (19) at risk for insignificant pca (cancer volume < 0.5 ml and gs < 6) (20). median nodular diameter on mpmri was correlated to gs (gs 6 = 9 mm; gs 7 = 16 mm; gs 8 = 20 mm) showing a significantly difference between gs 6 vs gs 8 (p < 0.05). the detection rate of cancer for each core performing spbx vs mpmri targeted biopsy was 9.5% vs figure 1. 3 tesla pelvic phased-array multiparametric mri patterns in patients with prostate cancer. a. b. c. d. e. f. • t2-weighted (a) and dce (b) mri of an anterior nodular area. • t2-weighted (c) and dce (d) mri of a peripheral nodular area (1 cm). • large (e) peripheral t2-weighted hypointense area with positive spectroscopy (f) that exceeded the surrounding tissue. pepe_stesura seveso 15/01/15 12:14 pagina 337 archivio italiano di urologia e andrologia 2014; 86, 4 p. pepe, a. garufi, g. priolo, g. dibenedetto, m. salemi, m. pennisi, f. fraggetta, f. aragona, m. barbera 338 35.3%, respectively (p < 0.05). diagnostic accuracy, sensitivity, specificity, positive and negative predictive value of multiparametric mpmri in diagnosing was 75.7%, 82.5%, 71.8%, 78.9%, 87.9%, respectively. discussion although trus imaging was enriched in recent years by the introduction of three-dimensional, computerized images and contrast media, which allow better characterization of intraparenchymal microvasculature (21), ultrasound accuracy is poor in performing targeted-biopsy (22, 23); therefore, spbx still today remains the gold standard (2, 18) in case of repeat prostate biopsy. on the other hand, transrectal prostate biopsy, recently, has been associated with an increased risk of complications secondary to urinary tract infection and sepsis (1% of the cases), with the necessity for hospital admission in 2% of the cases (24); conversely, transperineal prostate biopsy demonstrated a better accuracy in comparison with transrectal approach in the diagnosis of anterior zone pca (15, 25), resetting the risk of sepsis (26, 27). in the last years, mmri has gained growing importance in pca diagnosis and staging using mpmri or memri (316); recently, 3 tesla mri has been suggested in the reevaluation of patients enrolled in active surveillance protocols (9), and is highly representative of the true gs (12, 14, 15) and predictive of significant pca (11, 12, 15). the estimated sensitivity and specificity for pca detection by mri varies between 57% and 100% vs 44% and 96%, respectively (3); therefore, there is increasing interest in using mri, especially in men with prior negative prostate biopsy and persistent suspicion of pca. multiparametric pmri and emri have been introduced in clinical practice to detect suspicious areas which could be submitted to real-time mri-guidance targeted-biopsy or translated into real-time mri/trus imaging fusion to perform targeted biopsy (4, 7, 11, 16). pinto et al. (4) showed a greater detection rate of cancer for each core using mri imaging/ultrasound fusion-guided biopsy in comparison with standard 12-core transrectal biopsy (20.6% vs 11.7%, respectively). franiel et al. (5) and hambrock et al. (6) in patients with previous negative biopsy submitted to mri-guided biopsy demonstrated a detection rate for pca of 39% and 59%, respectively; kuru et al. (7), recently, evaluated the prostate imaging reporting and data system (pirads) in mpmri based on single-core histology suggesting that pirads can be used as a decision-support system for targeting of suspicious lesions. although emri had the best sensitivity and specificity in diagnosing and staging pca, recently 3 tesla pmri demonstrated good accuracy in detecting areas suspicious for pca and increasing diagnosis of cancer localized in the anterior zone of the gland (5, 15, 25). the use of mpmri provides, in daily practice, more advantages in comparison with memri; in fact, its use is widespread in many general hospitals, it is easy to perform and it does not generate discomfort to the patient. in addition, whole-body mri has been suggested as a one-step procedure for staging men with high-grade pca (28). in our series, mpmri detected 52 out 66 pca; in detail, mpmri in comparison with spbx diagnosed 4 significant cancer of the anterior zone missing 12 cancers characterized by microfocal biopsy histological disease (18) at risk for insignificant pca (22). in addition, a correlation between mpmri suspicious lesion diameter vs pca diagnosis and tumour grade was found. some limitations and considerations of the present study deserve mention. firstly, we do not know the true diagnostic accuracy of mpmri in pca diagnosis because the detection rate for cancer was compared with spbx results. secondly, we do not know if the false-positive rate (23.8% of the cases) of mpmri was secondary to false-negative spbx results or was biased because an mri imaging/ultrasound fusion-guided biopsy, theoretically more accurate, was not performed. in conclusion, in case of repeat biopoverall pca gs 6 gs 7 gs 8 normal parenchyma no of patients: 168 66 (39%) 44 18 4 102 (61%) median psa ng/ml (range: 3.7-45) 10.6 12 10 16 10.3 positive mpmri 52 (78.8%) 30 (68.2%) 18 (100%) 4 (100%) 40 (39.2%) positive t2w (hypointense area) 52 (78.8%) 23 (52.2%) 18 (100%) 4 (100%) 40 (39.2%) positive dwi 51 (77.3%) 25 (56.8%) 18 (100%) 4 (100%) 37 (36.2%) positive dce 52 (78.8%) 25 (56.8%) 18 (100%) 4 (100%) 36 (35.3%) positive spectroscopy 29 (43.4%) 2 (12.5%) 14 (77.8%) 4 (100%) 36 (35.3%) negative mpmri 14 (21.2%) 14 (31.8%) 0 0 62 (60.8%) gpc 40% (2-100%) 15% (1-60%) 85% (50-100%) 100% no. (%) of positive cores: spbx 7.5 (26.7%) 2.8 (9.7%) 12 (42.8%) 16 (57.1% mpmri-suspicious biopsy 2.5 (62.6%) 1.3 (32.5%) 3 (75%) 3.2 (80%) median diameter (mm) of mpmri suspicious area 12 (5-25) 9 (5-16) 16 (9-32) 20 (18-25) 6 (5-13) < 10 mm 30 23 7 0 35 > 10 mm 22 7 11 4 5 psa: prostate specific antigen; pca: prostate cancer; gleason score: gs; gpc: greatest percentage of cancer; spbx: saturation prostate biopsy; t2w: t2-weighted; dwi: diffusion-weighted imaging; dce: dynamic contrast-enhanced. table 1. patients’ characteristics. pepe_stesura seveso 15/01/15 12:14 pagina 338 339archivio italiano di urologia e andrologia 2014; 86, 4 accuracy of 3 tesla pelvic phased-array multiparametric mri in diagnosing prostate cancer at repeat biopsy sy, mpmri targeted biopsy improves diagnosis of anterior zone pca missing cancers at risk for clinically insignificant disease; moreover, suspicious mpmri lesions > 10 mm are highly predictive of aggressive pca. references 1. pepe p, aragona f: prostate needle biopsy: 12 vs. 18 cores. is it necessary? urol int. 2005; 74:19-22. 2. chun fk, epstein ji, ficarra v, et al. optimizing performance and interpretation of prostate biopsy: a critical analysis of the literature. eur urol 2010; 58:851-864. 3. lawrentschuck n, fleshner n. the role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies elevated prostatic-specific antigen levels. bju int. 2009; 103:730-733. 4. pinto pa, chung ph, rastinehad ar, et al. magnetic resonance imaging/ultrasound fusion guided prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric magnetic resonance imaging. j urol. 2011; 186:1281-1285. 5. franiel t, stephan c, erbersdobler a, et al. areas suspicious for prostate cancer: mr-guided biopsy in patients with at least on us-guided biopsy with a negative finding. multiparametric mr imaging for detection and biopsy planning. radiology. 2011; 259:162-172. 6. hambrock t, somford dm, hoeks c, et al. magnetic resonance imaging-guided prostate biopsy in men with repeat negative biopsies and increased prostate-specific antigen. j urol. 2010; 185:520-527. 7. kuru th, roethke mc, rieker p, et al. histology core-specific evaluation of the european society of urogenital radiology (esur) standardised scoring system of multiparametric magnetic resonance imaging (mpmri) of the prostate. bju int. 2013; 112:1080-1087. 8. rosenkrantz ab, mussi mendrinos s, babb js, taneja ss: prostate cancer foci detected on multiparametric resonance imaging are distinct from those not detected. j urol. 2012; 187:2032-2038. 9. quentin m, biondin d, klasen j, et al. evaluation of a structured report of functional prostate magnetic resonance imaging in patients with suspicion for prostate cancer or under active surveillance. urol int. 2012; 89:25-29. 10. hambrock t, hoeks c, hulsbergen-van de kaa c, et al. prospective assessment of prostate cancer aggressiveness using 3-t diffusion-weighted magnetic resonance image-guided biopsies versus systematic 10-core transrectal ultrasound prostate biopsy. eur urol. 2012; 61:177-184. 11. turkbey b, shah vp, pang y, et al. is apparent diffusion coefficient associated with clinical risk scores for prostate cancers that are visible on 3-t mri images? radiology. 2011; 488-493. 12. turkbey b, pinto pa, mani h, et al. prostate cancer: value of multiparametric mri imaging at 3 t for detection-histopathologic correlation. radiology. 2010; 255:89-94. 13. arsov c, quentin m, rabenalt r, et al. repeat transrectal ultrasound biopsies with additional targeted cores according to results of functional prostate mri detects high-risk prostate cancer in patients with previous negative biopsy and increased psa a pilot study. anticancer res. 2012; 32:1087-1092. 14. turkbey b and choyke pl. multiparametric mri and prostate cancer diagnosis and risk stratification. curr opin urol. 2012; 22:310-315. 15. pepe p, garufi a, priolo g, et al. prostate cancer detection at repeat biopsy biopsy: can pelvic phased-array multiparametric mri replace saturation biopsy? anticancer res. 2013; 33:1195-1199. 16. sonn ga, natarajan s, margolis dj, et al. targeted biopsy in the detection of prostate cancer using an office based magnetic resonance ultrasound fusion device. j urol. 2013; 189:86-92. 17. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14,453 patients. prostate cancer prostatic dis. 2010; 13:316-319.. 18. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 19. pepe p, candiano g, fraggetta f, et al. is a single focus of low grade prostate cancer, diagnosed on saturation biopsy, predictive of clinically insignificant cancer? urol int. 2010; 84:440-444. 20. epstein j, walsh p, carmichael m. pathological and clinical findings to predict tumor extent of non palpable (stage t1c) prostate cancer. jama. 1994; 271:368-374. 21. mitterberger m, horninger w, pelzer a, et al. a prospective randomized trial comparing contrast-enhanced targeted versus systematic ultrasound guided biopsies: impact on prostate cancer detection. prostate. 2007; 67:1537-1542. 22. pepe p, panella p, patanè d, aragona f. does the adjunct of echographic contrast medium levovist improve the detection rate of prostate cancer? prostate cancer prostatic dis. 2003; 6:159-162. 23. pepe p, candiano g, pennisi m, aragona f. can sonovue targeted biopsy replace extended or saturation biopsy in prostate cancer diagnosis? our experience at primary and repeat biopsy. arch it urol androl. 2010; 82:155-159. 24. pinkhasov gi, lin yk, palmerola r, et al. complications following prostate needle biopsy requiring hospital admission or emergency department visits experience from 1000 consecutive cases. bju int. 2012; 110:369-374. 25. komai y, numao n, yoshida s, et al. high diagnostic ability of multiparametric magnetic resonance imaging to detect anterior prostate cancer missed by transrectal 12-core biopsy. j urol. 2013; 190:867-873. 26. pepe p, aragona f: morbidity following transperineal prostate biopsy in 3,000 patients submitted to 12 vs 18 vs more than 24 needle cores. urology. 2013; 81:1142-1146. 27. pepe p, aragona f. prostate biopsy: results and advantages of the transperineal approach-twenty-year experience of a single center. world j urol. 2013 jun 7. [epub ahead of print]. 28. lecouvet fe, mouedden je, collette l. can whole-body magnetic resonance imaging with diffusion-weighted imaging replace 99m tc bone scanning and computed tomography for single-step detection of metastases in patients with high risk prostate cancer? eur urol. 2012; 62:68-75. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com giuseppe dibenedetto, md michele pennisi, md francesco aragona, md urology unit, cannizzaro hospital, via messina 829, catania, italy antonio garufi, md giandomenico priolo, md imaging department, cannizzaro hospital, via messina 829, catania, italy michele salemi, md section of endocrinology, andrology and internal medicine, department of medical and pediatric sciences, university of catania, catania, italy filippo fraggetta, md pathology unit, cannizzaro hospital, via messina 829, catania, italy michele barbera, md urology unit, sciacca, italy pepe_stesura seveso 15/01/15 12:14 pagina 339 stesura seveso 83archivio italiano di urologia e andrologia 2015; 87, 1 short communication urolithiasis is associated with low serum testosterone levels in men alper otunctemur 1, emin ozbek 1, suleyman sami cakir 2, murat dursun 3, emre can polat 4, levent ozcan 5, huseyin besiroglu 1 1 okmeydani training and research hospital, department of urology, istanbul, turkey; 2 bayburt state hospital, department of urology, bayburt, turkey; 3 bahcelievler state hospital, department of urology, istanbul, turkey; 4 istanbul medipol university, faculty of medicine, department of urology, istanbul, turkey; 5 derince training and research hospital, department of urology, kocaeli, turkey. objective: to evaluate the relationship among urolithiasis, metabolic syndrome (mets) and serum testosterone (t) level in men. material and methods: 513 men older than 18 years were enrolled in this study: 313 of the subjects had a history of stones (group 1) and 200 had no history of stones (controls, group 2). early morning t levels were recorded and anthropometric measurements were invastigated to evaluate mets. analyses were completed using chi-square tests. result: serum t level was lower in stone forming patients than coltrol subjects and 161 (%51.4) men in group 1 and 92 (%46) men in group 2 were diagnosed with metabolic syndrome. t level was found lower limit (< 285 ng/dl) in the mets and urolithiasis group (p 0.002, or 2.71). conclusions: we found low testosterone levels in the patients with stone disease and prevalance of the mets in men with urolithiasis was higher than in men without stone disease. our findings show that levels of testosterone had no effect on stone formation, but the factors that cause stone formation can have an effect on the level of testosterone. key words: urolithiasis; metabolic syndrome; testosterone. submitted 29 september 2014; accepted 30 november 2014 summary no conflict of interest declared. noted. the national cholesterol education program adult treatment panel iii (atp iii) definition is the one most used today because it incorporates the key concepts of mets; it relies on commonly used laboratory studies available to most physicians, and is less restrictive than the other classifications (3). mets has been linked to a number of urologic diseases including nephrolithiasis, benign prostatic hyperplasia and lower urinary tract symptoms, erectile dysfunction, male infertility, female incontinence, and prostate cancer (1). the prevalence of urolithiasis ranges from 2 to 20% throughout the world based on the geographic and socioeconomic characteristics of the different populations. the worldwide prevalence of the disease appears to have increased in the last quarter of the twentieth century for both men and women. the identification of common, modifiable risk factors for kidney stones may result in new approaches to the treatment and prevention of urolithiasis (4). much like mets and obesity, the prevalence of nephro lithiasis in the united states and other countries is increasing. there is evidence that these parallel changes might be linked (5). studies have shown that mets and its components (obesity/increased waist circumference, htn, etc.) are associated with increased rates of nephrolithiasis (6-8). although the exact pathophysiologic mechanisms underlying the association between metabolic syndrome and nephrolithiasis are unclear, hovewer, metabolic syndrome has been associated with changes in urinary constituents, including lower urinary ph, decreased citrate excretion, and increased uric acid and calcium excretion, leading to increased risks of uric acid and calcium stone formation (9-12). there is growing evidence that testosterone in men plays a major role not only in aspects of sexual health, but also in muscle and bone mass maintenance, erythropoiesis, and even glucose and lipid metabolism. low testosterone levels are significantly associated with prevalence of mets (13, 14). it is well established that urolithiasis occurs with greater frequency in males. the relative frequency has been noted to be three times that of women in multiple studies, and the rate of formation of idiopathic calcium doi: 10.4081/aiua.2015.1.83 introduction metabolic syndrome (mets) is an important public health problem worldwide, and its prevalence is increasing (1). mets, the simultaneous occurrence of hyperglycemia, hyperlipidemia, hypertension, and visceral obesity, is a chronic disease associated with high mortality. in addition, this condition substantially increases the risk of developing cardiovascular diseases and type 2 diabetes (2). throughout the years, numerous definitions of mets have been proposed by various organizations. each of the definitions shares many similarities, including the presence of criteria relating to obesity, hyperglycemia, dyslipidemia, and hypertension (htn). however, several differences among the classifications are otunctemur_stesura seveso 02/04/15 10:28 pagina 83 archivio italiano di urologia e andrologia 2015; 87, 1 a. otunctemur, e. ozbek, s. sami cakir, m. dursun, e. can polat, l. ozcan, h. besiroglu 84 stones has been reported to be four to five times higher in men than in women (15-19). this sexual disparity seems to be influenced by age. interestingly, stone formation in the prepubescent population is similar between males and females (20). the greatest difference in idiopathic calcium oxalate stone formation is seen in the third and fourth decade of life (21). in the sixth decade of life, stone incidence, as well as testosterone levels, begin to decline in men (22-24). each of these observations supports a role for sex hormones in lithogenesis. we aimed to invastigated relationship among serum testosterone levels, metabolic syndrome and urinary stone disease in this study. materials and methods between january 2008 and february 2012, we prospectively invastigated biochemical parameters and anthropometric measurements (height, weight, and waist circumference) of 313 men as the study group (group 1) who visited our urology clinic for urinary tract stone and of 200 randomly selected men who had no history of stone as controls (group 2). patients who had experienced spontaneous stone passage, had a surgery for urolithiasis (percutaneous nephrolithotomy, ureterorenoscopy) or whose stones were radiologically (ultrasonography, computed tomography or intravenous urography) visible at the time of clinical symptoms, were enrolled the study. patients were excluded from the study if they had primary hyperparathyroidism, chronic diarrheal syndromes, intestinal malabsorption, complete distal renal tubular acidosis, primary hyperoxaluria, recurrent or active urinary tract infection, history of kidney transplantation, ongoing 5-alpha reductase inhibitor therapy, liver disease, primary gout, any debilitating chronic illness, or a calculated creatinine clearance of ≤ 50 ml/minute. weight, waist circumference, and blood pressure were measured after an overnight fast, and a blood sample was drawn. plasma fasting glucose, serum total cholesterol, high-density lipoprotein (hdl) cholesterol, serum testosterone (t) levels and triglycerides were measured using enzymatic methods with an autoanalyzer. metabolic syndrome was defined according to the criteria established in 2005 by the ncep/atp iii. for the criteria for metabolic syndrome, abdominal obesity was defined as waist circumference > 102 cm in men and > 88 cm in women, according to the ncep/atp iii obesity criteria. metabolic syndrome was diagnosed in those who satisfied at least 3 of the following 5 criteria: waist circumference > 102 cm in men, triglyceride concentration > 150 mg/dl or undergoing treatment for hypertriglyceri demia, hdl cholesterol concentration < 40 mg/dl in men or undergoing treatment for low hdl-c level, blood pressure > 130/85 mm hg or undergoing treatment for hypertension, and fasting plasma glucose level > 100 mg/dl or undergoing treatment for hyperglycemia (3). serum testosterone levels were also evaluated and blood samples were taken between 08.00 and 10.00 in the fasting state. analyses were completed using chisquare tests. odds ratios (or) were calculated. statistical determinations were within the 95% confidence interval (ci). all p values were two-tailed, and p < 0.05 was considered statistically significant. the data were analyzed with an spsstm (spss version 13.0, chicago, il) statistical software package. results baseline demographic characteristics of the 513 participants are listed in table 1. in the study population, 313 were patients with urolithiasis aged 24-67 years and 200 were patients without urolithiasis aged 31-64 years. serum t levels were detected in the lower limit (< 285 ng/dl) on 112 (35.7%) of the patients with stone disease and 32 (16%) men with no stone disease. we have shown that lower t levels in men was associated with increased risk of urolithiasis (p 0.000, or 2.93) (table 2). 161 (51.4%) men in group 1 and 92 (46%) men in group 2 were diagnosed with metabolic syndrome. in the mets group, t level was found at lower limit (< 285 ng/dl) more frequently in the ürolithiasis group (p 0.002, or 2.71). also in the group without mets, t level was found at lower limit more frequently in the ürolithiasis group (p 0.001, or 3.1). the prevalence of lower t levels in men with table 1. demographic characteristics of the participants. stone (+) stone (-) n 313 200 age 44.3 ± 12.3 42.7 ± 13.3 mets (+) 161 (51.4%) 46 (23%) mets (-) 152 (48.6%) 154 (77%) t < 285 ng/dl 112 (35.7%) 32 (16%) t > 285 ng/dl 201 (64.3%) 168 (84%) mets (+) and t < 285 ng/dl 64 (20.4%) 9 (4.5%) mets (+) and t > 285 ng/dl 97 (30.9%) 37 (18.5%) mets (-) and t < 285 ng/dl 48 (15.3%) 23 (11.5%) mets (-) and t > 285 ng/dl 104 (33.2%) 131 (65.5%) table 3. relation of urinary stone disease with metabolic syndrome and serum testosterone level. stl stone (+) stone (-) p odds ratio ci for mets (-) n = 152 n = 154 t < 285 ng/dl 48 (31.6%) 23 (14.9%) 0.001 3.1 1.61-5.98 t ≥ 285 ng/dl 104 (68.4%) 131 (85.1%) for mets (+) n = 161 n = 46 t < 285 ng/dl 64 (39,8%) 9 (19.6%) 0.002 2.71 1.48-4.96 t ≥ 285 ng/dl 97 (60.2%) 37 (80.4%) stl: serum testosterone levels; mets: metabolic syndrome; ci: confidence interval. table 2. the association between serum testosterone levels and urinary stone disease. stl group 1 group 2 p odds ci (stone +) (stone ) ratio overall t < 285 ng/dl 112 (35.7%) 32 (16%) 0.000 2.93 1.88-4.56 t ≥ 285 ng/dl 201 (64.3%) 168 (84%) stl: serum testosterone levels; ci: confidence interval. otunctemur_stesura seveso 02/04/15 10:28 pagina 84 85archivio italiano di urologia e andrologia 2015; 87, 1 urolithiasis and testosterone metabolic syndrome was higher than in men with nonmets. the prevalance of the mets in men with stone disease was higher than in men without stone disease (table 3) (figure 1). discussion in our study, metabolic syndrome was associated with a significantly increased risk of urolithiasis and low testosterone level. a recent cross-sectional study from italy demonstrated that individuals with mets are twice as likely to have ultrasonographic evidence of nephrolithiasis. west and associates similarly showed that the odds of self-reported stone disease are approximately twice as likely in individuals with mets than those without (25). there are a number of possible reasons for the association between mets and nephrolithiasis. it has been demonstrated that features of mets are associated with decreased urine ph. one study noted that increasing insuline resistance (ir) (measured by comparing glucose disposal rates via euglycemic clamp with 24-hour urine studies) is associated with more acidic urine (26). several investigators have determined that urine ph decreases with increasing bmi (27-30). they also found that the components of mets significantly associated with urinary ph are bmi, serum glucose, and serum hdl (26). low urine ph is a well-described feature of uric acid urolithiasis, so it is not surprising that people with features of mets tend to preferentially have uric acid stones or risk factors for their development. a higher prevalence of type 2 diabetes (t2dm), glucose intolerance, and hypertriglyceridemia in pure uric acid stone formers has been reported (31). similar to other studies, significant association was shown between the metabolic syndrome and urinary stone in our study. at the same time, the metabolic syndrome is closely related to low testosterone levels. there is growing evidence that testosterone in men plays a major role not only in aspects of sexual health, but also in muscle and bone mass maintenance, erythropoiesis, and even glucose and lipid metabolism (32). low testosterone levels are significantly associated with prevalence of mets (33, 34). men with prostate cancer (pca) who undergo long-term androgen deprivation therapy (adt) also have significantly higher rates of mets than those who do not (35). numerous studies have demonstrated that mets features such as htn, obesity, hyperinsulinemia, t2dm, hyperglycemia, hypertriglyceridemia, as well as low hdl are associated with diminished serum testosterone levels (36-38). all these clinical sydromes or diseases are also associated with increased urinary stone prevalence. our findings support the association of low t level and urolithiasis. however, there are many studies that showing the relationship between high testosterone level and formation of urinary stone in the literature. in a study by watson et al, a higher total serum testosterone level was found in stone-forming men than in non-stone forming controls (39). in literature there is no clinical study except this one regarding the relation between urolithiasis and serum t levels. but, in this study patient and control number are extremely lower. they have used total 55 patients. of the 55 patients, 25 had no history of urolithiasis and 30 had a history of urolithiasis. in other words, totally 30 lithogenic patients have been evaluated to show the association of urolithiasis and serum t concentrations. naghii et al. reported the role of androgenic sex steroids in a case study (40). it is not possible to explain this association with case studies. further metabolic evaluations are needed to confirm this suggestion. we have more patients to demonstrate urolithiasis and serum t association. our results also clearly show that serum t levels are lower in stone forming metabolic patients than non-stone forming patients with metabolic syndrome. our findings also show the coexistence of low serum t levels and urolithiasis. our previous and other works show the dicreased bone mineral density in stone formers (41, 42). taking also into account that t has a significant role in bone mineralisation, our work supports the association of low serum t and urolithiasis. experimental studies in rats have demonstrated that testosterone promotes stone formation and that estrogen inhibits stone formation, although the mechanisms remain unclear (43). in contrast to these findings, we found low t levels in the patients with stone disease and higher prevalence of mets in men with urolithiasis than in men without stone disease. components of the metabolic syndrome such as obesity and htn which have been shown in association with urolithiasis, can also be associated with low level of testosterone. in our opinion, levels of testosterone had no effect on stone formation, but the factors that cause stone formation affect level of testosterone. as a conclusion, urolithiasis is associated with low serum t levels, especially in patients with metabolic syndrome. stone forming male patients should be evaluated for t deficiency and hypogonadism. references 1. gorbachinsky, i, akpinar h, assimos dg. metabolic syndrome and urologic diseases. rev urol. 2010; 12:e157-80. 2. eckel rh, treating dyslipidemia of the metabolic syndrome: where's the evidence? nat clin pract endocrinol metab. 2007; 3:437. 3. huang pl, a comprehensive definition for metabolic syndrome. dis model mech. 2009; 2:p. 231-7. 4. binbay m1, yuruk e, akman tet al. updated epidemiologic study of urolithiasis in turkey ii: role of metabolic syndrome components on urolithiasis. urol res. 2012; 40:247-52. figure 1. relation of urinary stone disease with metabolic syndrome and serum testosterone level. otunctemur_stesura seveso 02/04/15 10:28 pagina 85 archivio italiano di urologia e andrologia 2015; 87, 1 a. otunctemur, e. ozbek, s. sami cakir, m. dursun, e. can polat, l. ozcan, h. besiroglu 86 5. stamatelou kk, et al. time trends in reported prevalence of kidney stones in the united states: 1976-1994. kidney int. 2003; 63:1817-23. 6. taylor en, stampfer mj, curhan gc. obesity, weight gain, and the risk of kidney stones. jama. 2005; 293:455-62. 7. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005; 68:1230-5. 8. curhan gc, et al. body size and risk of kidney stones. j am soc nephrol. 1998; 9:1645-52. 9. jeong ig, et al. the association of metabolic syndrome and its components with serum prostate-specific antigen levels in a koreanscreened population. cancer epidemiol biomarkers prev. 2010; 19:371-80. 10. sakhaee k, maalouf nm. metabolic syndrome and uric acid nephrolithiasis. semin nephrol. 2008; 28:174-80. 11. sakhaee k. recent advances in the pathophysiology of nephrolithiasis. kidney int. 2009; 75:585-95. 12. iba a. insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome. bju int. 2010; 106:1550-4. 13. yassin aa, saad f, gooren lj. metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone. andrologia. 2008; 40:259-264. 14. kupelian v, hayes fj, link cl, et al. inverse association of testosterone and the metabolicsyndrome in men is consistent across race and ethnic groups. j clin endocrinol metab. 2008; 93:3403-3410. 15. robertson wg, peacock m, heyburn pj, hanes fa. epidemiological risk factors in calcium stone disease. scand j urol nephrol 1980; 53:15-30. 16. soucie jm, thun mj, coates rj, et al. demographic and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-899. 17. fetter tr, zimskind pd, graham rh, brodie de. statistical analysis of patients with ureteral calculi. jama 1963; 186:21-23. 18. westbury ej. some observations on the quantitative analysis of over 1000 urinary calculi. br j urol. 1974; 46:215-227. 19. lee yh, huang wc, tsai jy, et al. epidemiological studies on the prevalence of upper urinary calculi in taiwan. urol int. 2002; 68:172177. 20. kohri k, kodama m, ishikawa y, et al. relationship betweenmetabolic acidosis and calcium phosphate urinary stone formation in women. int urol nephrol. 1991; 23:307-316. 21. marshall v, white rh, de saintonage mc, et al. the natural history of renal and ureteral calculi. br j urol. 1975; 47:117-124. 22. johnson cm, wilson dm, o’fallon wm, et al. renal stone epidemiology: a 25-year study in rochester, minnesota. kidney int. 1979; 16:624-31. 23. soucie jm, thun mj, coates rj, et al. demographic and geographic variability of kidney stones in the united states. kidney int. 1994; 46:893-899. 24. kaufman jm, vermeulen a. the decline of androgen levels in elderly men and its clinical and therapeutic implications. endocr rev. 2005; 26:833-876. 25. west b, et al. metabolic syndrome and self-reported history of kidney stones: the national health and nutrition examination survey (nhanes iii) 1988-1994. am j kidney dis. 2008. 51:741-7. 26. maalouf nm, et al. low urine ph: a novel feature of the metabolic syndrome. clin j am soc nephrol. 2007; 883-8. 27. li wm, et al. association of body mass index and urine ph in patients with urolithiasis. urol res. 2009; 37:193-6. 28. siener r, et al. the role of overweight and obesity in calcium oxalate stone formation. obes res. 2004; 12:106-13. 29. taylor en, curhan gc. body size and 24-hour urine composition. am j kidney dis. 2006; 48:905-15. 30. ekeruo wo et al. metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. j urol 2004; 172: 159-63. 31. sakhaee k, et al. pathophysiologic basis for normouricosuric uric acid nephrolithiasis. kidney int. 2002; 62:971-9. 32. yassin aa, saad f, gooren lj. metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone. andrologia. 2008; 40:259-64. 33. kupelian v. et al. inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. j clin endocrinol metab. 2008; 93:3403-10. 34. goncharov np, et al. three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. aging male. 2008; 11:118-22. 35. braga-basaria m, et al. metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. j clin oncol. 2006; 24:3979-83. 36. khaw kt, barrett-connor e. blood pressure and endogenous testosterone in men: an inverse relationship. j hypertens. 1988; 6:329-32. 37. svartberg j, et al. association of endogenous testosterone with blood pressure and left ventricular mass in men. the tromso study. eur j endocrinol. 2004; 150:65-71. 38. phillips gb, jing t, heymsfield sb. relationships in men of sex hormones, insulin, adiposity, and risk factors for myocardial infarction. metabolism. 2003; 52:784-90. 39. watson jm, shrewsberry ab, taghechian s, et al. serum testosterone may be associated with calcium oxalate urolithogenesis. j endourol. 2010; 24:1183-7. 40. naghii mr, hedayati m. determinant role of gonadal sex hormones in the pathogenesis of urolithiasis in a male subject a document for male predominancy (case study). endocr regul. 2010; 44:143-6. 41. tugcu v, ozbek e, aras b, et al. bone mineral density measurement in patients with recurrent normocalciuric calcium stone disease. urol res. 2007; 35:29-34. 42. arrabal-polo ma, arrabal-martin m, de haro-munoz t, et al. mineral density and bone remodelling markers in patients with calcium lithiasis. bju int. 2011; 108:1903-8. 43. lee yh, huang wc, chiang h, et al. determinant role of testosterone in the pathogenesis of urolithiasis in rats. j urol. 1992; 147:1134-1138. correspondence alper otunctemur, md (corresponding author) alperotunctemur@yahoo.com emin ozbek, md huseyin besiroglu, md okmeydani training and research hospital, department of urology 34384 sisli, istanbul, turkey suleyman sami cakir, md bayburt state hospital, department of urology, bayburt, turkey murat dursun, md bahcelievler state hospital, department of urology, istanbul, turkey emre can polat, md istanbul medipol university, faculty of medicine, department of urology, istanbul, turkey levent ozcan, md derince training and research hospital, department of urology, kocaeli, turkey otunctemur_stesura seveso 02/04/15 10:28 pagina 86 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3258 case report distal corpus cavernosum fibrosis and erectile dysfunction secondary to non-ischaemic priapism evangelos zacharakis 1, 2, david j ralph 2, miles walkden 3, asif muneer 2 ¹ department of urology, guy’s hospital, kings college london; 2 department of urology, university college london hospitals; 3 department of radiology, university college london hospitals, uk. non-ischaemic priapism is a rare type of priapism and is associated with penile or perineal trauma. the absence of ischaemia should theoretically prevent smooth muscle necrosis and corporal fibrosis which occurs in ischaemic priapism. the aim of this study was to first report a patient series with non-ischaemic priapism that developed distal corpus cavernosum fibrosis and erectile dysfunction. over a 5 year period, a cohort of 6 patients diagnosed with non-ischaemic priapism presented to a single centre. the diagnosis was based on a clinical history, penile examination with confirmation using a combination of cavernosal blood gas analysis, colour duplex ultrasonography of the penis and angiography. patients were followed up in clinic at regular intervals with clinical examination and repeat imaging. following a median follow up of 4 weeks (range 2-12) the patients reported either the development of erectile dysfunction with distal penile flaccidity. five patients required the use of pde-5 inhibitors to achieve full tumescence. the remaining patient eventually underwent insertion of a penile prosthesis due to the failure of pharmacotherapies. based on these findings we suggest that superselective embolisation of non-ischaemic priapism cases occasionally should be performed after a shorter period of conservative treatment. key words: non-ischaemic; perineal trauma; superselective embolization. submitted 4 march 2015; accepted 30 april 2015 summary no conflict of interest declared. comes in a unique cohort of patients diagnosed with non-ischaemic priapism who have paradoxically developed fibrosis within the distal corpus cavernosum following conservative treatment. case presentation a subgroup of 6 patients selected from a priapism database diagnosed with non-ischaemic priapism required treatment for erectile dysfunction using either pharmacotherapy or a penile prosthesis. the initial diagnosis of non-ischaemic priapism was based on the clinical history and examination and penile duplex ultrasonography. where there was diagnostic doubt, intracavernosal po2 and ph levels were also measured in 5 patients. once the diagnosis was confirmed, patients were followed up regularly in clinic and underwent serial penile duplex studies with penile mri being performed in 4 patients due to the development of early distal penile flaccidity. non-resolution of the priapism at a median 4.5 weeks (range 2-12 weeks) resulted in all patients requiring angiography and superselective embolisation. selective internal pudendal angiography used local anaesthesia and a retrograde femoral artery puncture. a 5-french sheath was inserted under fluoroscopic control and selectively run through the internal pudendal artery. the arteriogram demonstrated a significant leak (blush), confirming the laceration of the cavernosal artery and the formation of the arterial-lacunar fistula. the therapeutic embolization was performed with a superselective catheterisation of the cavernosal artery using a microcatheter (2.7fr) distally to the site of the fistula followed by gelfoam® embolisation. immediately following the embolisation a repeat angiogram was performed to confirm the absence of an arterial leakage. following successful embolisation patients were followed up in clinic. in 2 patients repeat embolisation was required due to persistent high flow priapism within 2 weeks following the initial procedure. in the remaining 4 patients embolisation resulted in resolution of the priapism immediately after the procedure. following the resolution of the priapism, this cohort of patients developed either erectile dysfunction (n=1) or suboptimal erections due to distal penile flaccidity (n=5) according to the iief 5 questionnaire (table 1). these patients were initially treated using doi: 10.4081/aiua.2015.3.258 introduction priapism is a urological emergency and requires a prompt diagnosis and intervention. non-ischaemic (high flow) priapism is rare and occurs as a result of unregulated arterial inflow into the corpus cavernosum, commonly after direct perineal or penile trauma (1-3). unlike ischaemic priapism, where there is stasis of ischaemic blood within the corpus cavernosum, in nonischaemic priapism the corpus cavernosum remains perfused with oxygenated blood and therefore patients are commonly managed conservatively until spontaneous resolution occurs (1-3). if there is a failure of resolution with conservative measures then superselective embolisation is performed. the time interval to allow a conservative approach is not defined and therefore patients can be left for several months without intervention until the fistula spontaneously closes. this study presents the outzacharakis_stesura seveso 23/09/15 12:47 pagina 258 259archivio italiano di urologia e andrologia 2015; 87, 3 distal corpus cavernosum fibrosis and erectile dysfunction secondary to non-ischaemic priapism pde-5 inhibitors (n=5) followed by intracavernosal alprostadil (n=1). a total of 6 patients were identified from a subgroup analysis of the data. the mean age at diagnosis was 39.2 years (range 20-56). the duration of the priapism and the aetiology for each case are listed in table 1. the majority of the patients presented with a prolonged erection following penile or perineal trauma (n=5) which was not associated with pain and therefore clinically in keeping with the absence of an ischaemic environment. penile duplex ultrasonography was used to confirm high systolic velocities in the corpus cavernosum (range 50-75 ml/sec). all of the patients had a fistula demonstrated on ultrasonography and probe compression of the fistula resulted in temporary resolution in one patient. in 4 patients presenting with distal flaccidity a penile mri scan was performed to assess the corporal smooth muscle for fibrosis and demonstrate the fistula (figure 1). the time point at which superselective embolisation was performed for each patient is shown in table 1 together with the post procedure erectile function according the iief-5 score. two patients undergoing superselective embolisation required a second attempt before the fistula was closed and the priapism resolved (figure 2). five patients responded to pde-5 inhibitors which resolved the distal flaccidity and erectile dysfunction. one patient who developed erectile dysfunction failed oral pharmacotherapies and intracavernosal injections and after 6 months underwent insertion of a penile prosthesis. discussion and supplementary references are posted in supplementary materials on www.aiua.it conclusions we suggest close clinical follow up of patients presenting with non-ischaemic priapism combined with reimaging using penile doppler and penile mri. features suggesting distal smooth muscle fibrosis either on imaging or the development of distal flaccidity should lead to earlier superselective embolisation to prevent long term erectile dysfunction. references 1. bastuba md, saenz de tejada i, dinlenc cz, et al. arterial priapism: diagnosis, treatment and long-term follow up. j urol. 1994; 151:1231-7. 2. witt ma, goldstein i, saenz dt, i, greenfield a, krane rj. traumatic laceration of intracavernosal arteries: the pathophysiology of nonischemic, high flow, arterial priapism. j urol. 1990; 143:129-132. 3. montague dk, jarow j, broderick ga, et al. american urological association guideline on the management of priapism. j urol. 2003; 170:1318. patient age (yrs) aetiology duration of priapism material used iief -5 score treatment up to the first embolization (weeks) for embolisation (6 months post priapism) 1 20 perineal injury 2 gel foam 20 pde 5 inhibitors 2 41 perineal injury 4 gel foam 3 penile prosthesis 3 56 idiopathic 4 gel foam 19 pde 5 inhibitors 4 30 penile fracture 3 gel foam 21 pde 5 inhibitors 5 39 perineal injury 5 gel foam 18 pde 5 inhibitors 6 52 perineal injury 12 gel foam 23 intracavernosal alprostadil injections figure 1. t1 post contrast mri shows patchy reduced enhancement of both distal corpora compatible with fibrosis. figure 2. selective angiogram of the left internal pudendal artery showing a large fistula arising from a branch of the main cavernosal artery. post embolisation internal pudendal angiogram showing successful occlusion of the fistula using microcoils. note the main cavernosal artery is still patent. table 1. patient’s clinical details. correspondence evangelos zacharakis, md department of urology, guy’s hospital, kings college, london, uk david j ralph, md (corresponding author) dralph@andrology.co.uk department of urology, university college london hospitals the institute of urology, 145 harley st london, w1g 6bj, uk miles walkden, md department of radiology, university college london hospitals, london, uk asif muneer, md department of urology, university college london hospitals, london, uk zacharakis_stesura seveso 23/09/15 12:47 pagina 259 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3246 original paper a new ultrasound and clinical classification for management of prostatic abscess lucio dell’atti department of urology, university hospital “st. anna”, ferrara, italy objectives: in literature, most of the published data regarding prostatic abscess (pa) are case reports, whereas there is no standardization of the diagnostic and therapeutic routines. the purpose of this study is a new classification of ultrasound imaging of pa with clinical features correlation. material and methods: we retrospectively analysed the ultrasound database archives and performed a medline® research of the peer reviewed literature on diagnosis and case reports of pa using the terms “prostate and abscess”. results: pa can be classified into five types: type i pa is present focally in a prostate lobe (≤ 10 mm). type ii pa is present in a prostate lobe (> 10 mm) and/or partially overcrosses the border of the midline prostatic glandular. type iii pa is present in both glandular lobes form of multifocal areas (≤ 10 mm). type iv pa is present in both glandular lobes form of multifocal areas (> 10 mm). type v pa involving intra or extraprostatic structures (bladder, urethra, seminal vesicles and prostatic capsule). the different ultrasound imaging and diagnostic criteria are listed for each type and subtype. conclusions: the sonographic pattern of pa is usually characteristic and easily differentiated from other glandular lesions. the purpose of the study was to associate the use of trus to a clinical standardized classification in order to facilitate pa diagnosis and localization directing the clinician treatment to the correct management and adequate therapeutic treatment. key words: prostatic abscess; transrectal ultrasound; classification. submitted 27 february 2015; accepted 30 april 2015 summary no conflict of interest declared. imaging (mri) (5). however, trus is the most widely employed imaging modality for pa and the best technique executable in a short time, with low radiant exposure, and low costs at detecting smaller abscess (6). to date, in the literature there is no specific classification based on imaging, and clinical aspects of different types of prostatic abscess. in this study we present a review of pa ultrasound imaging and propose a new classification of pa related to clinical features of the patients. materials and methods we retrospectively analysed the ultrasound database at our department of urology, which contains the stored images of 4000 cases from august 2007 to december 2014. only 1300 of these images (33%) are trus to study prostate diseases. all cases were evaluated by an expert urologist (ld). each patient was treated under local anesthesia with lidocaine spray (10 gr/100 ml), applied two minutes before the trus (7). the procedure was performed with the patient in the left lateral decubitus using a general electric logiq 7 equipped with a 5-9 mhz multi-frequency convex probe “end-fire”. each trus examination included an assessment of the prostatic diameter, the measurement of the whole prostate volume, and the evaluation of the transition zone, capsular and seminal vesicle characteristics, as well as the morphological description of potential pathological features. on 1 january, 2015 a medline® search of the peer reviewed literature on diagnosis and case reports of pa was done using the terms “prostate and abscess” . a total of 47 papers were evaluated. we propose a classification of prostatic abscess into 5 distinct types according to the literature and validated by our experience. results type i prostatic abscess is present focally in a prostate lobe (≤ 10 mm). if the prostatic abscess interests focally (≤ 10 mm) one prostate lobe (type i), frequently is present also in the transition zone and in the central zone of the prostate (2,4). we can divide it into three subtypes (ia, ib and ic) on the basis of ultrasonography (us) pattern and the type of clinical symptoms. in the subtype ia, pa presents a discrete low echoic or anechoic area with irregular contour. this contour shows along the outermost periphery doi: 10.4081/aiua.2015.3.246 introduction prostatic abscess (pa) in an unusual condition with an incidence of about 0.5% of all prostatic disorders (1). this prostatic disease is thought to arise most commonly as a consequence of inadequately treated acute bacterial prostatitis. other causes include bladder outlet obstruction such as: benign prostatic hypertrophy, indwelling urethral catheters and lower urinary tract invasive procedures as prostate biopsy (2, 3). immunosuppressed states and diabetes mellitus predispose to the formation of pa (4). the signs and symptoms of pa are non-specific and include urinary retention, dysuria, a palpably enlarged and tender prostate gland, and fever. several studies employed in pa diagnosis include transrectal ultrasound (trus), computed tomography (ct) scanning, or magnetic resonance dell'atti_stesura seveso 30/09/15 09:43 pagina 246 247archivio italiano di urologia e andrologia 2015; 87, 3 a classification for prostatic abscess a diffuse enlargement with a homogeneous low level of echogenicity due to oedema and inflammatory cell infiltration. this subtype of pa is incidentally diagnosed during a routine ultrasound for diagnostic purposes or follow-up for different urologic problems (urinary retention, urinary tract infection, chronic indwelling catheter, prostate biopsy). these subtypes must be differentiated from the prostatic retention cyst, which is frequently (0.5-7.9%) observed in the gland as an isolated lesion surrounded by normal tissue. ultrasound features are an anechoic content (less than 8 mm diameter) with thin and smooth walls or threadlike septa (8). in the subtype ib, pa presents a non-homogeneous content with well-defined edges and/or irregular contour (with possible thickened aspect for homogeneous low level echogenicity or hyperechoic structure). this nonhomogeneous content like fluid material within prostatic abscess shows a movement by changing the position of the patient. in the antibiotic era, gram-negative bacilli (mainly e. coli) cause about 60 to 80% of cases. other significant pathogens include pseudomonas species, staphylococcus species, and occasionally obligate anaerobic bacteria (9). in the subtype ic, pa can appear with the characteristics of both types ia and ib, but is diagnosed to detect a potential pa following the appearance of nonspecific symptoms such as hematuria, hemospermia, lower urinary tract symptoms (luts), urinary retention and fever. this subtype is the most frequent because of its clinical presentation during the fifth or sixth decade of life and constitutes approximately 0.51% of patients hospitalized for prostatic disorders (10). often type i is considered to be a sequel of an acute o chronic prostatitis that has either not been treated or that has been treated inappropriately (11). type ii prostatic abscess is present in a prostate lobe (> 10 mm) and/or partially overcrosses the midline prostatic glandular border. if the prostatic abscess interests one prostate lobe (> 10 mm) focally or overcrosses the midline prostatic glandular border (type ii), it can be frequently located in the transition zone, as well as in the peripheral zone of the gland (5, 12). we can divide it into three subtypes (iia, iib and iic) on the basis of us pattern and the type of clinical symptoms. the subtypes iia and iib have the same ultrasound pattern of subtypes ia and ib, although dimensions are ≥ 10 mm and/or extended in the contralateral part of the prostate gland (figure 1a, b). these pa subtypes are diagnosed incidentally during a routine ultrasound. in the subtype iic, pa can appear with the characteristics of both subtypes iia and iib, but it is diagnosed to detect a potential pa following the appearance of nonspecific symptoms such as hematuria, hemospermia, luts, urinary retention, dysuria, a palpably enlarged and tender prostate gland, fever, and sepsis. subtypes ic and iic are more often haemorrhages rather than infectious prostate biopsy's complication. hemorragic post-biopsy pa are rare with an incidence of 1.3% (12). it is not possible to differentiate by trus the sonographic distinctive features of the two conditions, although often the patient's medical history or a multiparametric mri are helpful. type iii prostatic abscess is present in both glandular lobes form of multifocal areas (≤ 10 mm). if pa interests both glandular lobes by two or more multifocal areas each of size ≤ 10 mm (type iii), we can divide it into two subtypes (iiia, iiib) on the basis of ultrasound pattern and of clinical symptoms (figure 2). in the subtype iiia, pa presents a hypoechoic or anechoic or non-homogeneous content with irregular rim (possible thickened aspect or hyperechoic echostructure). this subtype of pa is diagnosed incidentally during a routine ultrasound. in type iiib, pa can appear with the us patterns of subtype iiia, but this subtype is diagnosed to detect a potential pa following the appearance of symptoms (hematuria, hemospermia, luts, urinary retention) or in the case of painful and palpably tender prostate gland. this subtype is the most frequent cause of clinical presentation of granulomatous prostatitis. the exact aetiology of granulomatous prostatitis remains unclear and in many cases it may be idiopathic (13), although it can be also caused by several specific (as mycobacterium tuberculosis) (14) and non-specific infectious agents. it can also be secondary to prostatic surgery such as transurethral resection (15). however, the areas of abnormally low hypoechoic or non-homogeneous structure occurring in granulomatous prostatitis have no characteristic ultrasonography pattern to differentiate them from cancer and histological confirmation is necessary to obtain a definitive diagnosis (16). figure 1a. trus shows in transverse scan a prostatic abscess (12 mm) that interests one prostate lobe in the peripheral zone of the gland. it presents a discrete low echoic area with irregular contour (type iia). figure 1b. trus shows in longitudinal scan two prostatic abscesses (> 10 mm) in the transitional and peripheral zone of the gland (type iv). dell'atti_stesura seveso 30/09/15 09:43 pagina 247 archivio italiano di urologia e andrologia 2015; 87, 3 lucio dell’atti 248 type iv prostatic abscess is present in both glandular lobes form of multifocal areas (> 10 mm). if pa interests both glandular lobes by two or more multifocal areas each of size > 10 mm (type iv). this type can be divided in the iv a and iv b according to the appearance of the clinical symptoms. the most common trus finding in all patients was the detection of a hypoechoic area with non-homogeneous structure. in some patients irregular contour and hyperechoic areas were additionally described (17). in literature and in our experience the pa type iv is related to a massive caseous necrosis induced in patients that had received intravesical instillations of bacillus calmette-guerin (bcg) for superficial bladder tumor (18-20). type v prostatic abscess involving intra or extraprostatic structures (bladder, urethra, seminal vesicles and prostatic capsule). if the prostatic abscess, regardless of its size, presents compressive phenomena involving intra or extraprostatic structures as bladder, urethra, seminal vesicles and/or prostatic capsule (type v), it always causes clinical symptoms due to extrinsic compression (6) of the structures listed as: hemospermia, hematuria, purulent urethral secretions, urinary retention, dysuria, incomplete bladder emptying or urinary urgency, and sometimes fever. although fluctuation to the rectum should make one suspect abscess, this is not a constant finding, as in the case of para-urethral or bladder localization (figure 3). treatment of pa implied parental broad-spectrum antibiotic administration and/or abscess drainage. this may be performed, depending on its localization by transrectal or transperineal ultrasound, by perineal route, transurethral incision or resection of the prostate, or open perineal drainage (2). discussion pa is uncommon and difficult to diagnose because initial clinical presentation may mimic several other diseases of the lower urinary tract. its incidence has markedly decreased for the widespread use of antibiotics (9). pa should be suspected in patients presenting with fever and persistent luts that do not respond to antibiotics. predisposing factors for the development of pa are diabetes mellitus, bladder outlet obstruction, indwelling catheter, prostate biopsy, chronic renal failure, chronic liver disease and hiv infection (2, 21). the diagnosis and localization of pa have been facilitated with the advent of trus (22). transabdominal ultrasonography is usually not sufficient to make a diagnosis because it does not delineate the anatomical details of pa, owing to its peripheral glandular location or to the physical constitution of the patient. trus can exactly define the localization, number and size of pa and help in the management and follow-up. however, according to some authors trus is not feasible in all patients as it is highly painful in presence of pa, and mri or ct scan are more suitable to define the disease (23). in our experience the use of local anesthesia with lidocaine spray, allowed to perform trus in all patients in a comfortable way, except in a few conditions that might be a contraindication such as in patients with severe haemorrhoids or anal fistulas or submitted abdominoperineal resection (7). the most common finding of pa is a hypoechoic or anechoic lesion with more or less defined edges and a peripheral hyperechoic halo. a remarkable finding is the alteration of prostate ultrasound anatomy. however, a differential diagnosis must be made for a similar ultrasound appearance of tumors, cystic lesions, and focal acute prostatitis (8). prostatic imaging with ct and mri is important in the differential diagnosis of pa. some studies shown that the more cost-effective ct and mri hold no advantage over trus unless the abscess has penetrated the confines of the prostate (type v) or there are further abscess foci suspected (24, 25). therefore, a histological confirmation is necessary to obtain a definitive diagnosis in doubtful cases. trus is the most widely used technique in the guide for percutaneous aspiration or pa biopsy and in evaluation of response to treatment (1, 2, 4, 9). in this study the classification of pa into five distinct types proposed is based on ultrasonography pattern and clinical evidence of the disease as reported in numerous studies. however, most published data regarding pa are case reports, and there is no standardization of the diagnostic and therapeutic routines. in review articles, the summary of several individual experiences permits to delineate some lines of action for pa. figure 2. trus shows in transverse scan multiple prostatic abscesses (≤ 10 mm) involving both lobes (type iii).). figure 3. trus shows in transverse (a) and longitudinal (b) scan prostatic abscesses (type v) interesting more multifocal areas with inhomogeneous content and irregular rim bulging the capsule and urethra (white arrows). dell'atti_stesura seveso 30/09/15 09:43 pagina 248 249archivio italiano di urologia e andrologia 2015; 87, 3 a classification for prostatic abscess in the literature, few authors as lim et al. (25) or gorus et al. (26) tried to classify the pathology based on the ultrasound images acquired with trus but with the purpose to standardize a treatment of percutaneous aspiration rather than a clinical and ultrasonographic classification of the disease. barozzi et al. (27) described the sonographic features of their patients related to bacterial etiology after abscess drainage of the gland, but not making a standardized imaging classification. limitations of this classification could perhaps be identified in the lack of comparison with pathological features after biopsy. additional studies with more detailed exposure measurement are warranted to evaluate questions about ultrasound imaging, pathology features, etiology and the best management for the treatment and therapy duration. conclusions in last years prostatic imaging modalities (trus, ct and mri) gained a wide acceptance in diagnosis of pa. of these imaging modalities trus is widely used in diagnosis of pa for the low cost and low radiation exposure (28). the sonographic pattern of pa is usually characteristic and easily differentiated from other glandular lesions. the purpose of the study was to associate the use of trus to a clinical classification standardized to facilitate the diagnosis and localization of pa in order to direct the clinician to the correct management and adequate therapeutic treatment. other studies will be required to verify its validity and clinical utility and to implement it. references 1. granados ea, riley g, salvador j, vincente j. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-82. 2. oliveira p, andrade ja, porto hc, filho je, vinhaes af. diagnosis and treatment of prostatic abscess. int braz j urol. 2003; 29:30-34. 3. langer je, cornud f. inflammatory disorders of the prostate and the distal genital tract. radiol clin north am. 2006; 44:665-677. 4. varkarakis j, sebe p, pinggera gm, bartsch g, strasser h. threedimensional ultrasound guidance for percutaneous drainage of prostatic abscesses. urology. 2004; 63:1017-1020. 5. afaq a, koh dm, padhani a, et al. clinical utility of diffusionweighted magnetic resonance imaging in prostate cancer. bju int. 2011; 108:1716-1722. 6. bayne ce, davis wa, rothstein cp, engel jd. seminal vesicle abscess following prostate biopsy requiring transgluteal percutaneous drainage. can j urol. 2013; 20:6811-6814. 7. dell’atti l. lidocaine spray administration transrectal ultrasound guided prostate biopsy: five years of experience. arch ital urol. 2014; 86:340-343. 8. galosi ab, montironi r, fabiani a, et al. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation. j urol. 2009; 181:647-657. 9. jang k, lee dh, lee sh, chung bh. treatment of prostatic abscess: case collection and comparison of treatment methods. korean j urol. 2012; 53:860-864. 10. collins sm, correa h, ortenberg j. prostatic abscess in the newborn: an unrecognized source of urosepsis. urology. 2001; 57:554. 11. collado a, palou j, garcía-penit j, et al. ultrasound-guided needle aspiration in prostatic abscess. urology. 1999; 53:548-552. 12. herranz amo f, verdú tartajo f, díez cordero jm, et al. hemorrhagic prostatic cyst following ultrasound guided biopsy. a case report. arch esp urol. 1999; 52:379-80. 13. naik ks, carey bm. the transrectal ultrasound and mri appearances of granulomatous prostatitis and its differentiation from carcinoma. clin radiol. 1999; 54:173-175. 14. gorse gj, belshe rb. male genital tuberculosis: a review of the literature with instructive case reports. rev infect dis. 1985; 7:511-524. 15. carrero lópez vm, rodríguez antolín a, caballero j, et al. granulomatous prostatitis. an infrequent diagnosis. review of our series. actas urol esp. 1994; 18:77-84. 16. liu s, miller pd, holmes sa, et al. eosinophilic prostatitis and prostatic specific antigen. br j urol. 1992; 69:61-63. 17. bour l, schull a, delongchamps nb, et al. multiparametric mri features of granulomatous prostatitis and tubercular prostate abscess. diagn interv imaging. 2013; 94:84-90. 18. aust tr, massey ja. tubercular prostatic abscess as a complication of intravesical bacillus calmette-guérin immunotherapy. int j urol. 2005; 12:920-921. 19. caulier p, yombi jc, dufaux m, et al. prostate abscess following intravesical bcg therapy. acta clin belg. 2009; 64:436-437. 20. matlaga br, veys ja, thacker cc, assimos dg. prostate abscess following intravesical bacillus calmette-guerin treatment. j urol. 2002; 167:251. 21. trauzzi sj, kay cj, kaufman dg, lowe fc. management of prostatic abscess in patients with human immunodeficiency syndrome. urology. 1994; 43:629-633. 22. cytron s, weinberger m, pitlik sd, servadio c. value of transrectal ultrasonography for diagnosis and treatment of prostatic abscess. urology 1988; 32:454-458 23. ludwig m, schroeder-printzen i, schiefer hg, weidner w. diagnosis and therapeutic management of 18 patients with prostatic abscess. urology 1999; 53:340-345. 24. somuncu i, saglam m, yagci s, et al. multiloculated prostate abscess: treatment with transrectal ultrasound guided transrectal needle aspiration and lavage with the saline and antibiotic. clin imaging. 2003; 27:251-255. 25. lim jw, ko yt, lee dh, et al. treatment of prostatic abscess: value of transrectal ultrasonographically guided needle aspiration. j ultrasound med. 2000; 19:609-617. 26. gögüs c, ozden e, karaboga r, yagci c. the value of transrectal ultrasound guided needle aspiration in treatment of prostatic abscess. eur j radiol. 2004; 52:94-98. 27. barozzi l, pavlica p, menchi i, de matteis m, canepari m. prostatic abscess: diagnosis and treatment. ajr am j roentgenol. 1998; 170:753-757. 28. dell'atti l. prostatic abscess after transrectal ultrasound-guided prostate biopsy. case report. g chir. 2013; 34:260-262. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology, university hospital “st.anna”. 8 a. moro street, 44124 cona ferrara, italy dell'atti_stesura seveso 30/09/15 09:43 pagina 249 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3130 introduction prostate cancer (pca) is the most frequent tumor diagnosed in elder men with about 1 million biopsies for year performed in the united states (1). in the last decade a greater rate of prostate biopsy side effects has been reported and serious complications incidence requiring hospital admission ranges from 1.2% (2) to 2.5% (1) secondary, in the most of the cases, to urinary tract infection (uti), fever or sepsis (in case of transrectal biopsy). among minor complications erectile dysfunction (ed) has been reported in a little percentage of patients and it has been ascribed to anxiety (3), local anesthesia and/or number of needle cores (4, 5) inducing a clinical impact on patient well-being and quality of life (6). in our study ed incidence following repeat transperineal saturation prostate biopsy (spbx) was prospectively evaluated. materials and methods from january 2011 to june 2012 295 patients of ages between 56 and 71 years (median 63 years) underwent original paper erectile function after repeat saturation prostate biopsy: our experience in 100 patients pietro pepe, francesco pietropaolo, giuseppe dibenedetto, francesco aragona urology unit, cannizzaro hospital, catania, italy. introduction: erectile dysfunction (ed) incidence following repeat saturation prostate biopsy (spbx) was evaluated. materials and methods: from january 2011 to june 2012 295 patients underwent repeat transperineal spbx (median 28 cores) under sedation. the indications for biopsy were: abnormal dre, psa > 10 ng/ml or included between 4.1-10 with free/total psa < 25%. all patients were prospectively evaluated with the 5-item version of the international index of erectile function (iief-5) at baseline and 1, 3 and 6 months from spbx. results: 100/200 men with benign histology and normal sexual activity completed the study; median iief-5 score before and after spbx was equal to 18.3 (baseline) vs 17.8 (1 month later) vs 18 (3 months later) vs 18.1 (6 months later) (p > 0.05); in detail, 1 month from biopsy 5 (5%) men referred a mild ed that disappeared at 3 and 6 months evaluation. conclusions: repeat transperineal spbx under sedation did not significantly worsened erectile function; the minimal risk of temporary post-biopsy ed could be previously discussed (not emphasised) with potent patients. key words: erectile dysfunction; saturation prostate biopsy; sexuality; prostate biopsy. submitted 27 february 2013; accepted 30 april 2013 no conflict of interest declared summary repeat spbx (median 28 cores; range: 26-31) for persistent suspicious of pca. the indications for biopsy were (7): abnormal digital rectal examination (dre), persistent elevated or increasing psa values, psa > 10 ng/ml, psa values between 4.1-10 with free/total psa < 25%. prostate biopsy was performed transperineally (8) using a tru-cut 18 gauge needle (bard; covington, ga), a ge logiq 500 pro ecograph (general electric; milwaukee, wi) supplied with a biplanar transrectal probe (5-6.5 mhz). the spbx included at least 12 cores in the posterior zone of each lobe (apex, middle zone and base of the gland) beginning parasagittally to reach the outer edges of the gland (lateral margins) plus 2-3 cores in the transition and anterior zone. the procedure was performed under sedation and antibiotic prophylaxis, respectively. among clinical complications incidence of ed was evaluated only in men with benign histology (normal parenchyma), on the contrary patients with cancer, asap or hgpin were not included to eliminate anxiety from the hypothetical cause of ed. all patients were prospectively evaluated doi: 10.4081/aiua.2013.3.130 131archivio italiano di urologia e andrologia 2013; 85, 3 erectile function after repeat saturation prostate biopsy: our experience in 100 patients with the 5-item version of the international index of erectile function (iief-5) (9) before and 1, 3 and 6 months from spbx. none of the patients used 5-phosphodiesterase inhibitors or prostaglandins to improve sexual activity. for statistical analysis the t student’ test was used; a p value < 0.05 was considered statistically significant. results histological specimen showed a pca in 90/295 (30.5%) cases, an hgpin in 4 (1.3%), an asap 1 (0.4%) and a normal parenchyma in 200 (67.8%), respectively; 100/200 (50%) men with a referred normal sexual activity characterized by a median baseline iief-5 score equal to 18.3 (range: 16-25) completed the study. clinical (comorbidities, drug therapy) and laboratory data collected before spbx are reported in table 1. among clinical complications none of the patients needed hospital admission and 10 (10%) underwent emergency clinic visit within 2 day (median; range: 1-3 days) from spbx in 7 cases (7%) for acute urinary retention, in 2 (2%) for gross hematuria and in 1 (1%) for urinary tract infection; moreover, hemospermia was the most frequent side effect recorded in 36 (36%) and 9 (9%) patients 3 and 6 months from the procedure, respectively. a significantly difference between ieef-5 score at baseline (18.3) and 1 (17.8), 3 (18) and 6 (18.1) months from spbx was not found (p > 0.05) (table 2); in detail, after 1 month 5 (5%) patients with a pre-biopsy normal sexual activity (iief > 22) referred a mild de that disappeared at 3 and 6 months evaluation (table 2). discussion a minimal risk of temporary ed following prostate biopsy has been correlated with the increasing number of needle cores, use of periprostatic nerve block, disease involving neurovascular bundles, anxiety and diagnosis of pca. although tuncel et al. (10) reported a male sexual dysfunction combined with negative effect on female sexual function exceeding six months from biopsy, most of the papers (5,10) agree that prostate biopsies could have a significantly impact on short-term (30 days) erectile function that disappears at medium-term (3-6 months). glaser et al (3) in a systematic review reported that prostate biopsy was associated with short-term exacerbation of urinary symptoms score, anxiety and ed without a distinct relationship to the periprostatic nerve block or the number of cores biopsied. zisman et al. (4) attributed to anxiety a ed rate in anticipation of biopsy in 7% of the cases evaluated; akbal et al. (5) in 88 patients cancer-free after spbx showed a risk of ed after 1 and 6 months clinical findings no (%) of patients median age (years) 61 (range: 56-71) psa 4.1-10 ng/ml 68 psa > 10 ng/ml 32 abnormal dre luts 67 qmax 11 (8-19) ipss (median) 11 (4-29) comorbidities: 18 diabetes mellitus 3 hypertension 10 gastritis 18 other 3 drug therapy (overall): 86 oral hypoglycemic 2 antihypertensive 10 antiplatelet agents 10 diuretic 3 proton pomp inhibitor 19 alfa-blockers 62 other 6 ieff-5 baseline 1 month 3 month 6 month p value (score: 5-25) pts (%) pts (%) pts (%) pts (%) absence of ed 45 (45%) 40 (40%) 43 (43%) 44 (44%) > 0.05* (22-25) (p = 0.477) (p = 0.777) (p = 0.888) mild ed 39 (39%) 40 (40%) 42 (42%) 40 (40%) > 0.05* (17-21) (p = 0.886) (p = 0.688) (p = 0.886) mild-moderate ed 16 (16%) 20 (20%) 15 (15%) 16 (16%) > 0.05* (12-16) (p = 0.464) (p = 0846) (p = 1) moderate ed (8-11) severe ed (5-7) table 1. clinical findings in 100 patients who underwent repeat saturation prostate biopsy. table 2. iief-5 (international index erectile function) in 100 patient before (baseline) and after (1, 3 and 6 months) repeat transperineal saturation prostate biopsy. dre: digital rectal examination; luts: lower urinary tract symptoms; ipss: international prostate symptoms score. ed: erectile dysfunction; *p value did not showed a statistically significant difference when baseline iief-5 was compared with postbiopsy iief-5 (1, 3 and 6 months from the procedure). archivio italiano di urologia e andrologia 2013; 85, 3 p. pepe, f. pietropaolo, g. dibenedetto, f. aragona 132 equal to 11.6% and 0%, respectively. although in the last years number of repeat biopsies and/or needle cores (spbx) has been supposed to temporary induce ed the literature data are conflicting. in fact, fujita et al. (11) in 231 patients enrolled in active surveillance (as) protocol for pca found a correlation between number of repeat biopsy (3 or more) and erectile function; on the contrary, hilton et al. (12) in 427 men on as showed that sexual activity was not associated with biopsy exposure. recently, klein et al. (13) in 198 patients submitted to 10 (155 cases) and 20 (53 cases) needle cores demonstrated that erectile function was transiently affected by prostate biopsy regardless of periprostatic nerve block and the number of cores. in our series, to our knowledge the first that evaluated patients submitted to repeat transperineal spbx under sedation, ed incidence did not significantly increased 1, 3 and 6 months from biopsy; only 5/100 (5%) men with a pre-biopsy normal sexual activity (ieef-5 > 22) referred at first month evaluation a mild ed (ieef-5 score between 17 and 21) that disappeared 3-6 months later. regarding our results some considerations should be done. firstly, the true sexual activity of the couple administering a sexual questionnaire to the partners was not investigated. secondly, we don’t know if the transperineal biopsy approach and/or the absence of local anesthesia had a clinical impact on our results. finally, in the absence a of control group we don’t know if the onset of de one month from spbx (5% of the cases) was really given by prostate biopsy. in conclusion, repeat transperineal spbx under sedation did not significantly worsened erectile function; the minimal risk of temporary post-biopsy ed could be previously discussed (not emphasised) with potent patients. references 1. pinkhasov gi, lin yk, palmerola r, et al complications following prostate needle biopsy requiring or emergency department visitsexperience from 1000 consecutive cases. bju int. 2012; 110:369-374. 2. pepe p, aragona f. morbidity following transperineal prostate biopsy in 3,000 patients submitted to 12 vs 18 vs more than 24 needle cores. urology. 2013; 81:1142-1146. 3. glaser ap, novakic k, helfand bt. the impact of prostate biopsy on urinary symptoms, erectile function, and anxiety. curr urol rep. 2012; 13:447-454. 4. zisman a, leibovici d, keinmann j, siegel yi, lindner a. the impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety and erectile dysfunction. j urol. 2001; 165:445-454. 5. akbal c, turker p, tavukcu hh, et al. erectile function in prostate cancer-free patients who underwent prostate saturation biopsy. eur urol. 2008; 53:540-544. 6. palumbo f, bettocchi c, spilotros m, et al. a prospective study on patient’s erectile function following transrectal ultrasound guided prostate biopsy. arch ital urol androl. 2010; 82:265-268. 7. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14453 patients. prostate cancer prostatic dis. 2010; 13:316-319. 8. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 9. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999; 11:319-326. 10. tuncel a, kirilmaz u, nalcacioglu v, et al. the impact of transrectal prostate needle biopsy on sexuality in men and their female partners. urology. 2008; 71:1128-1131. 11. fujita k, landis p, mcneil bk, pavlovich cp. serial prostate biopsies are associated with an increased risk of erectile dysfunction in men with prostate cancer on active surveillance. j urol. 2009; 182:2664-2669. 12. hilton jf, blaschko sd, whitson jm, et al. the impact of serial prostate biopsies on sexual function in men on active surveillance for prostate cancer. j urol. 2012; 188:1252-1258. 13. klein t, palisaar rj, holz a, et al. the impact of prostate biopsy and periprostatic nerve block on erectile and voiding function: a prospective study. j urol. 2010; 184:1447-1452. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com francesco pietropaolo, md giuseppe dibenedetto, md francesco aragona, md urology unit cannizzaro hospital, via messina 829 catania, italy introduction prostate cancer (pca) is one of the most common cancers in men, with about 700,000 patients diagnosed worldwide each year (1). this figure is closely related to the development of early pca detection programmes, which are based on an increased public awareness about this type of cancer, prostate-specific antigen screening efforts, and the improvement of systematic transrectal ultrasound (trus)-guided prostate biopsy (pbx) techniques. pbx has evolved from the digitally guided pbx technique, described by astraldi (2) in 1937, to the standard sextant 69archivio italiano di urologia e andrologia 2013; 85, 2 original paper the effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy alper otunctemur 1, murat dursun 1, huseyin besiroglu 1, emre can polat 2, suleyman sami cakir 1, emin ozbek 1, tahir karadeniz 1 1 okmeydani training and research hospital, department of urology, istanbul, turkey; 2 balikligol state hospital, department of urology, sanliurfa, turkey. aim: transrectal ultrasound (trus) guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. many different protocoles are applied to reduce the pain during the process. in this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respectively in addition to perianal intrarectal lidocaine gel on the pain control in prostate biopsy by trus. methods: 473 patients who underwent prostate biopsy guided trus between 2008-2012 were included in the study. 10-point linear visual analog pain scale(vas) was used to evaluate the pain during biopsy. the patients were divided into two groups according to anesthesia procedure. in group 1, there were 159 patients who had perianal-intrarectal lidocaine gel, in group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. the pain about probe manipulation was aseesed by vas-1 and during the biopsy needle entries was evaluated by vas-2. results were compared with mann-whitney u and pearson chi-square test. results: mean vas-2 scores in group 1 and group 2 were 4.54 ± 1.02 and 2.06 ± 0.79 respectively. the pain score was determined significantly lower in the group 2 (p = 0.001). in both groups there was no significant difference in vas-1 scores, patient’s age, prostate volume, complication rate and psa level. conclusion: the combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel. key words: transrectal prostete biopsy; visual analog scale; lidocaine; periprostatic nerve blockade. submitted 7 february 2013; accepted 28 february 2013 no conflict of interest declared summary method, described by hodge et al. (3) in 1989. transrectal ultrasound guided prostete biopsy (trus-bx) is accepted as a standard procedure in the diagnosis of prostate cancer. having established that the prostate spesific antigen (psa) could be a useful marker for detection of prostatic cancer there has been a significant increase in the number of biopsies (4). however most of patients undergoing trus-bx have discomfort and % 20 of these patients experienced severe pain about the procedure (3, 5). altough trus-bx is a standard common procedure there otunctemur_stesura seveso 24/06/13 11:00 pagina 69 archivio italiano di urologia e andrologia 2013; 85, 2 a. otunctemur, m. dursun, h. besiroglu, e. can polat, s. sami cakir, e. ozbek, t. karadeniz 70 500 mg of ciprofloxacin starting two days before and at least five days after the procedure. bowel preparation was made with two fleet enema, one of them at previous night and the other one two hours before the procedure. after giving detailed information and obtaining consent form, the patients were taken to the table on the lateral decubit position. trus was performed using a 6.5-mhz transrectal probe. the prostate volume was calculated using both sagittal and transverse plans. ten point linear visual analog scale (vas) was used to determine the degree of the pain during transrectal ultrasound guided prostate biopsy. the pain arising from the probe input and manipulation (vas-1) and the pain caused by the needle while taking biopsies from prostate (vas-2) were assesed. all patients were observed for two hours for any complications such as rectal bleeding, hematuria, voiding difficulty and fever. differences in the age, psa levels, prostate volume, vas scores were compared between two different anestethic practice groups. the comparisons about age, prostate volume and pain scores between two groups were applied using mann-whitney u test. complication rates were examined with the pearson chi-square test. results the mean ages were not statisticially different between two groups: 65.2 ± 8.3 for group 1, 66.1 ± 7.7 for group 2. mean psa levels, prostate volumes and complication rates were similar and there was no statistically differences between the groups (table 1). a critical status did not develop with respect to complications. the mean psa levels were similar in group 1 (15.5 ± 23.1) and in group 2 (11.9 ± 13.6 ng/ml). the only statistically significant difference was determined in vas-2 score between two groups. mean pain score caused by the needle while taking biopsies from prostate (vas-2) was lower in group 2 than in group 1. mean vas-2 scores were 4.54 ± 1.02 in group 1 and 2.06 ± 0.79 in group 2, respectively. there was no meaningful difference between the two groups of vas-1 score which shows the pain about probe manipulation (table 2). is no certain protocol or guideline for the preparation of the patient and need for analgesia and the technique used for administration (3, 5). there are many different approaches to reduce the pain and enhance the patients adaptation to the procedure. there is no concensus about which method to use but the patient’s consciousness, prior history about anorectal diseases, pain threshold of the patient, biopsy experience, socio-cultural level are important factors for the decision. the use of periprostatic nerve blockade (ppnb) had been introduced as early as 1996 (6) for minimizing prostatic biopsy pain with lignocaine local anaesthesia. many studies evaluated and conclusively proved the benefit of ppnb (7-9). in this study, we evaulated the pain control in patients who have trus-bx for detection prostate cancer, using ppnb for anaesthesia. we compared the efficacy of periprostatic nerve blockage with intrarectal gel instillation and just perianal intrarectal gel instillation during trus-guided prostate biopsy. materials and methods 473 men who underwent ultrasound guided prostate biopsy from 2009 to 2012, were enrolled in this study. increased prostate speific antigen (psa), abnormal digital rectal examination findings and serum psa levels higher than 2.5 ng/ml were the inclusion criterias. the patients were divided into two groups: in group 1 (159 patients) biopsies were performed after administering perianal intrarectal lidocain gel and in group 2 (314 patients) periprostatic nerve blockade was performed in addition to perianal intrarectal lidocain gel. injections were delivered at the angle between the seminal vesicle and prostate on each side using 5 cc of 2% lidocain. exclusion criterias are as follows: bleeding diathesis and/or use of anticoagulant; anorectal diseases such as hemorrhoids, anal fissures, anal surgery; acute prostatitis; pelvic pain syndrome; history of lidocaine allergies; inability to rate a visual analog scale (vas). all patients receieved standard antibiotic prophylaxis with group 1 group 2 p value number of patients 159 314 age (years) 65.2 ± 8.3 66.1 ± 7.7 0.405 psa (ng/ml) 15.5 ± 23.1 11.9 ± 13.6 0.331 prostate volume (ml) 60.3 ± 24 65.3 ± 26.5 0.07 complication rate (n, %) 64, 40.3 72, 48.3 0.1969 table 1. data of the patients in group 1 and group 2. group 1 group 2 p value pain score (vas1) 2.19 ± 0.9 2.18 ± 0.9 0.904 pain score (vas2) 4.54 ± 1.02 2.06 ± 0.79 0.001 table 2. the statistical data of vas scores in the two groups. otunctemur_stesura seveso 24/06/13 11:00 pagina 70 71archivio italiano di urologia e andrologia 2013; 85, 2 the effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy 4. wang mc, papsidero ld, kuriyama m. prostate antigen: a new potential marker for prostatic cancer. prostate. 1981; 2:89-96. 5. clements r, aideyan ou, griffiths gj, peeling wb. side effects and patient acceptability of transrectal biopsy of the prostate. clin radiol. 1993; 47:125-6. 6. nash pa, bruce je, indudhara r, shinohara k. transrectal ultrasound guided prostatic nevre blockade eases systemic needle biopsy of the prostate. j urol. 1996; 155:607-9. 7. soloway ms, obek c. periprostatic local anaesthesia before ultrasound guided prostate biopsy. j urol 2000; 163:172-3. 8. alavi as, soloway ms, vaidya a, et al. local anaesthesia for ultrasound guided prostate biopsy: a prospective trial comparing 2 methods. j urol. 2001; 166:1343-5. 9. pareek g, armenaskas na, fracchia ja. periprostatic nerve blockade for transrectal ultrasound guided biopsy of the prostate: a randomized, double-blind, placebo controlled study. j urol. 2001; 166:894-7. 10. irani j, fournier f, bon d, et al. patient tolerance of transrectal ultrasound-guided biopsy of the prostate. br j urol. 1997; 79:608-10. 11. crundwell mc, cooke pw, wallace dm. patients’ tolerance of transrectal ultrasound-guided prostatic biopsy: an audit of 104 cases. bju int. 1999; 83:792-5. 12. krishna ns, kumar pm, morrison l. patients’ tolerance of transrectal ultrasound-guided prostatic biopsy: an audit of 104 cases. bju int. 1999; 84:890. 13. jones js, ulchaker jc, nelson d, et al. periprostatic local anesthesia eliminates pain of office-based transrectal prostate biopsy. prostate cancer prostatic dis. 2003; 6:53-5. 14. skriapas k, konstandinidis c, samarinas m, et al. pain level and anal discomfort during transrectal ultrasound for guided prostate biopsy. does intrarectal administration of local anesthetic before periprostatic anesthesia makes any difference? minerva urol nefrol. 2009; 61:137-42. 15. lynn nn, collins gn, brown sc, o’reilly ph. periprostatic nerve block gives better analgesia for prostatic biopsy. bju int. 2002; 90:424-6. 16. leung sy, wong bb, cheung mc, et al. intrarectal administration of lidocaine gel versus plain lubricant gel for pain control during transrectal ultrasound-guided extensive 10-core prostate biopsy in hong kong chinese population: prospective double-blind randomised controlled trial. hong kong med j. 2006; 12:103-7. 17. shrimali p, bhandari y, kharbanda s, et al. transrectal ultrasound-guided prostatic biopsy: midazolam, the ideal analgesic. urol int. 2009; 83:333-6. 18. kim s, et al. effect of oral administration of acetaminophen and topical application of emla on pain during transrectal ultrasound-guided prostate biopsy. korean j urol. 2011; 52:452-6. 19. saad f, yoon bi, kim sj, et al. a prospective randomized trial comparing lidocaine and lubricating gel on pain level in patients undergoing transrectal ultrasound prostate biopsy. can j urol. 2002; 9:1592-4. 20. ozok hu, sagnak l, ates ma, et al. the efficiency of a sedative or analgesic supplement to periprostatic nerve blockage for pain control during transrectal ultrasound-guided prostate biopsy a prospective, randomized, controlled, double blind study. arch med sci. 2010; 6:787-92. 21. izol v, soyupak b, seydaoglu g, et al. three different techniques for administering analgesia during transrectal ultrasound-guided prostate biopsy: a comparative study. int braz j urol. 2012; 38:122-8. discussion ultrasound guided prostate biopsy is a standard method used to detect prostate cancer. pain during trus-bx is an important problem that is associated with the patient tolerance about procedure (5, 10-12). pain mainly depends on two factors: anal discomfort due to the probe insertion and manipulation of the probe and the insertion of the needle through prostate capsule. periprostatic nerve blockage was firstly defined by nash et al. in 1996 and it is a good choice to reduce the pain (6). in this study it was suggested to inject at the junction of the base of the prostate and seminal vesicles. these findings were similarly confirmed by pareek et al. (9). there are many studies demonstrating that periprostatic nerve blockade is better than plasebo (13-21). recently new methods are being tested in various studies. in a study with 430 patients, acetaminophen and emla cream with intravenous injection of tramadol were found safe, easy, and effective methods of controlling pain during the procedure (18). in some studies midazolam was considered to be a suitable anesthetic during prostate biopsy (17, 20, 21). the application of perianal intrarectal gel and cream provides a good pain relief caused by probe manipulation (14, 23, 24). in the other hand, there are some studies showing that lidocaine gel did not diminish the sensation of pain (16, 25, 26). lidocaine suppositories are found an easyto-use and cheap method of local analgesia, with acceptable results (27). in a study published in 2011 by skriapas et al., the use of topical lidocaine gel and glyceryl trinitrate ointment (gtn) as an adjunct to periprostatic anesthesia to reduce anal pain and discomfort due to probe insertion was found very effective and safe (28). in the other study lidocaine spray was found to provide significantly better pain control than cream and anaesthetic gel (29). furthermore there are some studies comparing different anesthetic substances for pain relief. in a study by olmez et al., tramadol and lornoxicam were used for pain reduction and tramadol was found to be more effective (30). hirsh et al. had similar findings about tramadol in their study (31). in our study, pain scores related to probe manipulation was similar between two groups but there was a very significant difference between the pain score caused by the needle used to take biopsy cores. it was shown that periprostatic nerve blockade is a very good choice for pain control and compliance of the patient to the procedure although it is not effective for anorectal discomfort caused by the probe. we recommend the use of perianal intrarectal lidocain gel and periprostatic nerve blockade combination in trus-guided prostate biopsises. this combination is effective, cheap, safe and easy to perform. references 1. parkin dm, bray f, ferlay j, pisani p. global cancer statistics, 2002. ca cancer j clin. 2005; 55:74-108. 2. astraldi a. diagnosis of cancer of the prostate: biopsy by rectal route. urol cutaneous rev. 1937; 41:421-422. 3. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-4. otunctemur_stesura seveso 24/06/13 11:00 pagina 71 archivio italiano di urologia e andrologia 2013; 85, 2 a. otunctemur, m. dursun, h. besiroglu, e. can polat, s. sami cakir, e. ozbek, t. karadeniz 72 22. song jh, doo sw, yang wj, et al. value and safety of midazolam anesthesia during transrectal ultrasound-guided prostate biopsy. korean j urol. 2011; 52:216-20. 23. alvarez-mugica m, gonzález alvarez rc, jalón monzón a, et al. tolerability and complications of ultrasound guided prostate biopsies with intrarectal lidocaine gel. arch esp urol. 2007; 60:237-44. 24. siddiqui ej, ali s, koneru s. the rectal administration of lignocaine gel and periprostatic lignocaine infiltration during transrectal ultrasound-guided prostate biopsy provides effective analgesia. ann r coll surg engl 2006; 88:218-21. 25. diaz perez ga, meza montoya l, morante deza c, et al. pain during transrectal ultrasound guided needle biopsy of the prostate: comparison of the use or not of lidocaine gel. actas urol esp. 2009; 33:134-7. 26. argüelles salido e, congregado ruiz cb, conde sánchez jm, et al. ultrasound guided transrectal prostatic biopsy and pain. prospective randomized study comparing lubricant gel, lidocaine gel, and anesthetic blockage of the neurovascular bundles with 1% lidocaine. arch esp urol. 2008; 61:579-90. 27. goluza e, hudolin t, kastelan z, et al. lidocaine suppository for transrectal ultrasound-guided biopsy of the prostate: a prospective, double-blind, randomized study. urol int. 2011; 86:315-9. 28. skriapas k, konstantinidis c, samarinas m, et al. comparison between lidocaine and glyceryl trinitrate ointment for perianalintrarectal local anesthesia before transrectal ultrasonographyguided prostate biopsy: a placebo-controlled trial. urology. 2011; 77:905-8. 29. dell'atti l, daniele c. lidocaine spray administration during transrectal ultrasound guided prostate biopsy modified the discomfort and pain of the procedure: results of a randomized clinical trial. arch ital urol androl. 2010; 82:125-7. 30. olmez g, kaya s, aflay u, sahin h. comparison of lornoxicam versus tramadol analgesia for transrectal prostate biopsy: a randomized prospective study. int urol nephrol. 2008; 40:341-4. 31. hirsh i, kaploun a, faris g, et al. tramadol improves patients’ tolerance of transrectal ultrasound-guided prostate biopsy. urology. 2007; 69:491-4. correspondence alper otunctemur, md murat dursun, md (corresponding author) mrt_drsn@hotmail.com huseyin besiroglu, md suleyman sami cakir, md emin ozbek, md tahir karadeniz, md okmeydani training and research hospital, department of urology 34384, darulaceze cad. no: 25 sisli, istanbul, turkey emre can polat, md balikligol state hospital, department of urology, sanliurfa, turkey otunctemur_stesura seveso 24/06/13 11:00 pagina 72 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4180 introduction urolithiasis represents a process of unwanted calcification and the recurrence is the rule (1). the underlying mechanisms of stone formation are not clearly known. in addition, there are no markers able to distinguish between patients who will have stone recurrence from those who will not. therefore, it is clinically important to identify potential factor(s) that may help clinicians in making decision. original paper serum fetuin-a and recurrent urolithiasis in young adults domenico prezioso 1, alberto saita 2, mario motta 2, massimo porena 3, carla micheli 3, ester illiano 1, dario bruzzese 4, vincenzo bisesti 5, paolo ferrari 6, tullio lotti 7, domenico russo 5 1 department of gynecology, obstetric and urology, university federico ii, naples, italy; 2 department of urology, “ospedale vittorio emanuele”, university of catania, catania, italy; 3 department of urology and andrology, ospedale santa maria della misericordia, university of perugia, perugia, italy; 4 department of preventive medical sciences, university federico ii, naples, italy; 5 department of nephrology, university federico ii, naples italy; 6 department of urology, ospedale hesperia, modena, italy; 7 university federico ii, naples, italy. objective: recurrence of urolithiasis is frequent. there are no reliable markers able to indicate recurrent stone former patients. fetuin-a inhibits hydroxyapatite crystals formation and expansion. this study aims at evaluating whether serum fetuin-a may predict recurrent urolithiasis in young adults. materials and methods: this is a multicentre study. young adults patients with recurrent urolithiasis attending 3 urology clinics were enrolled from july 2011 to december 2012. inclusion criteria were: age 18-40 years, presence of more than one kidney stone. exclusion criteria were: diabetes mellitus, metabolic disorders, obesity, hypertension, cardiovascular disease, infection diseases. controls were participants without history of urolithiasis and currently undetected stones. routine biochemistry, serum concentration of oxalate, fetuin-a, and parathyroid hormone (pth) were assessed; 24/h urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, and protein was measured. kidney ultrasonography and plain x-ray examination was performed. results: the total cohort was represented by 120 young adults participants (90 patients, and 30 controls). clinical characteristics were not different between patients and controls. no significant differences were found in serum concentrations as well as in 24/h urinary excretion of recorded variables. no significant difference was found in serum concentration of fetuin-a (median 35.1 ± 18.62 sd vs 35.12 ± 14.12, µg/ml; p = 0,908). conclusions: the data of present study do not substantiate the hypothesis that serum fetuin-a may be a reliable predictor of recurrent urolithiasis in young adults. key words: calcification; inhibition; extra osseous calcification; fetuin-a; recurrent urolithiasis. submitted 14 april 2013; accepted 30 april 2013 no conflict of interest declared summary along with the multiple traditional pathogenic factors involved in stone formation (1-3), great relevance has been recently given to inhibitors of ectopic calcification (4, 5). inhibitors raise the concentrations of calcium and oxalate required for spontaneous formation of new crystals and decrease crystal growth, aggregation, and binding to renal cells. fetuin-a plays a crucial role in the extra osseous calcifidoi: 10.4081/aiua.2013.4.180 prezioso_stesura seveso 18/12/13 10:42 pagina 180 181archivio italiano di urologia e andrologia 2013; 85, 4 serum fetuin-a and recurrent urolithiasis in young adults cation process by inhibiting the formation and expansion of hydroxyapatite crystals (6-8). unfortunately there is scarce information on fetuin-a in patients with recurrent urolithiasis. one sole study evaluated urine fetuin concentration in patients with urolithiasis (9). since urinary excretion of fetuin-a may result inaccurate as ascertained in several renal injury models (10, 11), in the present study serum fetuin-a was assessed in patients with recurrent multiple urolithiasis and compared with that of normal subjects. so far there is no data on this issue. materials and methods this is a multicentre study performed in outpatients attending 3 urology clinics from july 2011 to december 2012. the study protocol was approved by the institutional review board of catania. procedures were carried out according to the declaration of helsinki. before enrollment all patients signed informed consent. inclusion criteria were: age 18-40 years, recurrent urolithiasis, current presence of kidney stones. exclusion criteria were: diabetes mellitus, metabolic disorders, congenital or acquired dyslipidemia, obesity, hypertension, cardiovascular disease, infection diseases. serum concentration of glucose, creatinine, sodium, potassium, uric acid, calcium, phosphorus, magnesium, total cholesterol, triglycerides, oxalate, fetuin-a, and parathyroid hormone (pth) was assayed. urinary excretion of creatinine, uric acid, calcium, sodium, phosphorus, potassium, magnesium, glucose, oxalate, amylase, protein was assessed on 24-hour collections. kidney ultrasonography and plain x-ray examination was performed. serum fetuin-a was measured by human fetuin-a elisa (biovendor laboratory medicine). the intraand interassay variations were evaluated by measuring three different samples in 33 replicates (intra-assay coefficient of variation < 5,2%, inter-assay coefficient of variation < 3,8%, limit of detection 0.35mg/l). the body mass index (bmi) of patients and controls was calculated. mann-whitney test (abnormal data distribution), nonpaired t-test (normal data distribution), chi square, and fisher exact test were used to compare data of subjects with and without urolithiasis; p < 0.05 was considered as significant. results we enrolled 90 young adults patients (30 patients in each centre; 58 men, 32 women) with documented recurrent formation of urinary stones, and 30 individuals (10 in each centre; 14 men, 16 women) without urolithiasis. clinical characteristics and laboratory variables of patients with and without urolithiasis are reported in tables 1, 2 and 3. both groups were homogeneous for age, and bmi. there were no significant differences in serum concentration except for serum calcium and phosphorus; both ions controls patients p mean ± sd median (range) mean ± sd median (range) age 28.47 ± 5.75 27.5 [19-40] 31.21 ± 7.18 32 [18-42] 0.068 bmi 23.47 ± 3.06 24 [18-31] 23.03 ± 2.73 23 [18-30] 0.413 table 1. clinical characteristics of controls and patients with urolithiasis. controls patients variables mean ± sd mean ± sd p fetuin-a (µg/ml) 35.1 ± 18.6 (35.1 ± 18.6 µg/ml ) 35.1 ± 14.1 (35.1 ± 14.1µg/ml) 0.908 oxalate (µmol/l) 97 ± 22 (8.7 ± 1.9 mg/l) 124 ± 73 (11.1 ± 6.6 mg/l) 0.612 pth (ng/l) 46 ± 20 (46 ± 20 pg/ml) 47 ± 18 (47 ± 18 pg/ml) 0.701 sodium (mmol/l) 144 ± 3.4 (144 ± 3.4 meq/l) 142 ± 2.2 (142 ± 2.2 meq/l) 0.177 potassium (mmol/l) 4.6 ± 0.9 (4.6 ± 0.9 meq/l) 4.7 ± 0.4 (4.7 ± 0.4 meq/l) 0.028 calcium (mmol/l) 2.3 ± 0.10 (9.22 ± 0.42 mg/dl) 2.4 ± 0.10 (9.56 ± 0.42 mg/dl) 0.041 phosphorus (mmol/l) 1.29 ± 0.20 (4.0 ± 0.62 mg/dl) 1.15 ± 0.29 (3.57 ± 0.89 mg/dl 0.028 total cholesterol (mmol/l) 4.65 ± 0.75 (181 ± 29 mg/dl) 4.78 ± 1.16 (187 ± 45 mg/dl) 0.331 triglycerides (mmol/l) 0.85 ± 0.21 (75 ± 19 mg/dl) 1.06 ± 0.55 (94 ± 49) 0.396 table 2. baseline serum concentration of variables measured in controls and patients with urolithiasis. bmi: body mass index. pth: parathyroid hormone. prezioso_stesura seveso 18/12/13 10:42 pagina 181 archivio italiano di urologia e andrologia 2013; 85, 4 d. prezioso, a. saita, m. motta, m. porena, c. micheli, e. illiano, d. bruzzese, v. bisesti, p. ferrari, t. lotti, d. russo 182 were significantly different between patients with and without urolithiasis (serum calcium: mean 9.22 mg/dl ± 0.42 sd vs 9.56 mg/dl ± 0.42 sd; p 0.041; serum phosphorus: mean 4.0 mg/dl ± 0.62 sd vs 3.57 mg/dl ± 0.89 sd; p 0.028). there were no significant differences in 24/h urinary excretion of measured variables. serum concentration of fetuin was similar in patients and controls (mean 35.1 ± 18.62 sd vs 35.12 ± 14.12 µg/ml; p = 0.908). discussion in this study a potential association was investigated between serum concentration of fetuin-a and recurrent urolithiasis in young adults. formation of stones within the urinary tract is a complex process driven by multiple factors. although normal urine is frequently supersaturated with respect to calcium and oxalate, most individuals do not form stones. typically, any crystals formed are rapidly passed before achieving a size sufficient for retention. increased quantities of calcium and/or oxalate are excreted by many stone former. therefore, increased supersaturation alone does not account for urinary stone; as a consequence, other factors may influence their formation and growth. therefore, it is clinically relevant to identify new potential factor(s) that may help clinicians in making decision. fetuin-a inhibits the precipitation of hydroxyapatite from supersaturated solutions of calcium and phosphate by forming fetuin-mineral complex, a high molecular mass complex (6-8, 12). this inhibitory action is at least in part facilitated by the transient formation of soluble, colloidal spheres, so-called calciprotein particles, containing fetuina, calcium, and phosphate. the action of fetuin-a is most prominent in organs involved in the secretion or transport of mineral-rich fluids or in the generation of local ph changes such as the kidney. fetuin-a deficient rats have calcification in the pelvis but not in the medulla or the cortex compared to wild type; in this experimental model, calcification was primarily a consequence of the lack of fetuin-a and not of renal damage. interestingly, animals had calcium and phosphate concentrations within the normal range; this finding rules out hypocalcaemia or hyperphosphatemia as a cause of the ectopic calcification. therefore, the underlying mechanism may involve a direct interaction of fetuin-a with the mineral phase and the prevention of large crystal formation. owing to the crucial role of fetuin-a in the process leading to extra osseous calcification, it was stimulating to evaluate its potential role in patients with recurrent urolithiasis. ascertaining a role of serum fetuin a in recurrent urolithiasis should be of clinical interest considering that the recurrence of urolithiasis is the rule in all formingstone patients and that there are no laboratory markers able to distinguish between patients who will have stone recurrence from those who will not. there is at present scarce information on urine fetuin-a in patients with recurrent urolithiasis. in one sole study, urine fetuin concentration was found lower in 38 patients with urolithiasis who were compared to 22 controls (9). the lower urine fetuin-a levels were not due to other conventional promoters and inhibitors of urine crystallization. on the basis of these data, measurement of urinary fetuina was suggested as more reliable risk predictor than the traditional markers of recurrent urolithiasis (9). this interesting suggestion, however, should be viewed with caution taking in account the data attained by proteonomics that have shown that urinary excretion of fetuin-a is altered in several renal injury models (11). urinary exosomal fetuin-a is elevated in patients with acute kidney injury in intensive care unit (11). recently, urinary exosomal fetuin-a levels was found significantly increased after cisplatin-induced tubule damage (11). thus, urinary fetuin-a excretion may be strongly affected in presence of structural renal injury. the data of the present study do not confirm the hypothesized relationships between serum fetuin-a concentration and recurrent urolithiasis. in fact, there was no significant difference in serum fetuin-a concentration between patients and controls. similarly, there were no significant differences in traditional variables. these data confirm that there are no markers able to distinguish between patients who will have stone recurrence from controls patients phosphate (mmol/24 h) 368 ± 68 (1141± 211 mg) 334 ± 108 (1037 ± 335 mg) 0.451 uric acid (μmol/24 h 39792 ± 10290 (669 ± 173 mg) 38365 ± 14454 (644.97 ± 242.67 mg) 0.634 calcium (mmol/24 h) 37.4 ± 9.2 (150 ± 37 mg) 59.6 ± 34.9 (239 ± 140 mg) 0.095 amylase (u/24 h) 236 ± 171.42 247.77 ± 100.5 0.158 sodium (mmol/24 h) 164.14 ± 36.06 179.33 ± 61.58 0.315 potassium (mmol/24 h) 73.67 ± 22.36 57.29 ± 21.6 0.058 chlorine (mmol/24 h) 182.7 ± 46.6 186 ± 69.97 0.747 proteinuria (mg/24 h) 142± 42 188 ± 134 0.508 magnesium (mmol/24 h) 58 ± 25.1 (141 ± 61 mg) 44.4 ± 17.8 (108 ± 43 mg) 0.148 glycosuria (mmol/24 h) 4.8 ± 1.5 (87 ± 27 mg) 4.7 ± 1.9 (85 ± 35 mg) 0.771 table 3. 24/h urinary excretion of variables measured in controls and patients with urolithiasis. prezioso_stesura seveso 18/12/13 10:42 pagina 182 183archivio italiano di urologia e andrologia 2013; 85, 4 serum fetuin-a and recurrent urolithiasis in young adults those who will not. in addition, neither serum concentration nor urinary excretion of fetuin-a may be regarded as reliable predictors of recurrent urolithiasis. hopefully, studies performed with proteonomics may find true predictor(s) of recurrent urolithiasis. conclusions the data of present study do not substantiate the hypothesis that serum fetuin-a may be a reliable predictor of recurrent urolithiasis in young adults. references 1. coe fl, favus mj, asplin jr. nephrolithiasis. in brenner bm, ed. the kidney. 7th ed, philadelphia:saunders. 2004; 1819-1866. 2. de yoreo jj, qiu sr, hoyer jr. molecular modulation of calcium oxalate crystallization. am j physiol renal physiol. 2006; 291: f1123-f1132, 3. asplin jr, parks jh, coe fl. dependence of upper limit of metastability on supersaturation in nephrolithiasis. kidney int. 1997; 52:1602-1608, 4. schinke t, amendt c, trindl a, et al. the serum protein alpha2hs glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. a possible role in mineralization and calcium homeostasis. j biol chem. 1996; 271:20789-20796. 5. schafer c, heiss a, schwarz a, et al. the serum protein alpha 2heremans-schmid glycoprotein⁄fetuin-a is a systemically acting inhibitor of ectopic calcification. j clin invest. 2003; 112:357-366, 6. heiss a, duchesne a, denecke b, et al. structural basis of calcification inhibition by alpha 2-hs glycoprotein⁄fetuin-a. formation of colloidal calciprotein particles. j biol chem. 2003; 278:1333313341. 7. westenfeld r, schafer c, kruger t, et al. fetuin-a protects against atherosclerotic calcification in ckd. j am soc nephrol 2009; 20:1264-74. 8. schlieper g, westenfeld r, brandenburg v, ketteler m. inhibitors of calcification in blood and urine. semin dial. 2007; 20:113-21. 9. stejskal d, karpisek m, vrtal r. et al. urine fetuin-a values in relation to the presence of urolithiasis bju international. 2008; 101:1151-1154. 10. heiss a, pipich v, jahnen-dechent w, schwahn d. fetuin-a is a mineral carrier protein: small angle neutron scattering provides new insight on fetuin-a controlled calcification inhibition. biophys j. 2010; 99:3986-95. 11. zhou h, pisitkun t, aponte a, et al. exosomal fetuin-a identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. kidney int. 2006; 70:1847-1857. 12.price pa, lim je. the inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex j biol chem. 2003; 278:22144-22152. correspondence ester illiano, md (corresponding author) ester.illiano@inwind.it domenico prezioso, md dprezioso@libero.it department of gynecology, obstetric and urology, university federico ii, naples, italy alberto saita, md alsaurol@hotmail.com mario motta, md mmotta@unict.it; mmotta@mbox.unict.it department of urology “ospedale vittorio emanuele”, university of catania, catania, italy massimo porena, md uropg@rdn.it carla micheli, md carla.micheli@libero.it department of urology and andrology, ospedale santa maria della misericordia, university of perugia, perugia, italy dario bruzzese, md dbruzzes@unina.it department of preventive medical sciences, university federico ii, naples, italy vincenzo bisesti, md vincenzo.bisesti@libero.it domenico russo, md domenicorusso51@hotmail.com department of nephrology, university federico ii, naples, italy paolo ferrari, md pferrari@hesperia.it department of urology, ospedale hesperia, modena, italy tullio lotti, md pferrari@hesperia.it university federico ii, naples, italy prezioso_stesura seveso 18/12/13 10:42 pagina 183 stesura seveso 237archivio italiano di urologia e andrologia 2014; 86, 3 case report efficacy of pentoxifylline in peyronie’s disease: clinical case of a young man lucio dell’atti, gianni ughi urology unit, arcispedale “s. anna”, university of ferrara, italy. peyronie’s disease (pd) is a localized connective tissue disorder of the tunica albuginea of the penis and its surrounding tissue which results in a painful erection, penile curvature and erectile dysfunction. the great number and variety of purposed treatments for pd is in proportion to the difficulty of its management.in fact no medical treatment is currently available to cure patients with pd. pentoxifylline (ptx) is a non specific phosphodiesterase inhibitor with anti-inflammatory properties that has been used to treat claudication. ptx has also been used to decrease inflammation and fibrosis in kidney transplants, open heart surgery, dermatological conditions and after radiation injury. with respect to penile diseases, clinical studies have suggested that ptx decreases calcification in new-onset pd. these traits make ptx an interesting potential option for pd therapy. key words: peyronie’s disease; pentoxifylline; ultrasound; phosphodiesterase inhibitor. submitted 5 september 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction peyronie’s disease (pd) is a relatively common disorder in men (3-9%) and a frequent cause of sexual distress (1). pd (or induratio penis plastica) is characterized by the formation of a fibrous plaque within the tunica albuginea of the penile corpora cavernosa. most patients present with concerns about a penile lump, curvature, painful erections or erectile dysfunction. a short list of differential diagnoses, such as congenital chordee, dorsal vein thrombosis, infiltrative cancer or a sexually transmitted disease need to be excluded. oral pharmacotherapy should be considered as a treatment option for acute and earlier chronic phases. many oral medicines, including vitamin e, potassium para-aminobenzoate, tamoxifen, colchicines, propionyl-lcarnitine, have been used, but there is no satisfactory oral medical treatment available (2). pentoxifylline (ptx) has anti-inflammatory and antifibrogenic properties, with inhibitory effects on the basic mechanisms of fibrogenesis, cell proliferation and extracellular matrix synthesis (3). these mechanisms of actions might reverse the fibrotic process in pd. doi: 10.4081/aiua.2014.3.237 case report a 35 years old caucasian male had for about 5 years difficulties in penetration during sexual act due to a lack of rigidity and tumescence in the terminal part of the penis. however the patient during erection did not report the presence of curving of the penis. this disorder was not associated with erectile dysfunction, ejaculatory dysfunction or low libido. there is no personal or family history of fibrotic disorders. he does not smoke and has an occasional alcoholic beverage, moreover his general health was excellent and he doesn’t make use of medicines or drugs. physical examination revealed nothing abnormal in his testicles, epididymis or scrotum. however, a large fibrotic lesion was palpable in correspondence of the dorsal portion of the penis approximately below the root to the glans. laboratory evaluation was normal including complete blood count, routine biochemistry analyses, kidney and liver function tests, sex hormones, prolactin and serum lipid measurement. penile b-mode sonography revealed a calcified peyronie plaque that involved about 1cm in length below the glans the entire tunica albuginea of both corpora cavernosa. this plaque created a deep notch on the medial profile that in addition to affect both the corpora cavernosa on one side penetrated ventrally causing dislocation and compression of the cavernous arteries, while on the other side back penetrated leading to removal of albuginea from buck’s fascia (figure 1). to evaluate the penile vasculature, an intracavernosal injection with 20 µg of prostaglandin e1 was administered and color and duplex doppler sonography were performed during tumescence. the study revealed a peak systolic flow velocity (psv) of 60 cm/s (figure 2), an end-diastolic flow velocity (edv) of 4 cm/s with resistivity index (ri) 0,93 in the cavernosal arteries below the plaque, while in the cavernosal arteries above the plaque psv was 20 cm/s (figure 3), edv 5 cm/s and ri 0.73. the patient was given sildenafil citrate at 50 and 100 mg orally for addressing erectile dysfunction without any benefit in terms of tumescence of the terminal part of the penis. the patient was prescribed ptx 400 mg three times a day for 6 months. upon re-evaluation 6 months dell'atti cr_stesura seveso 09/10/14 10:32 pagina 237 archivio italiano di urologia e andrologia 2014; 86, 3 l. dell’atti, g. ughi 238 later, the patient reported improvement of tumescence of the glans with the possibility to have penetration during sexual intercourse in association of occasional use of 5phosphodiesterase inhibitors. pentoxifylline use was continued, and, upon reassessment one years later, improved erectile function was reported without the use of erectogenic agents. conclusion the management of patients with pd would be improved by the development of a treatment strategy that can reverse the abnormal fibrotic reaction of the tunica albuginea. although the case reported certainly presents as an atypical form of pd, it was improved by ptx administration that increased tissue perfusion and psv and showed anti-inflammatory and antifibrogenic properties, with inhibitory effects on the basic mechanisms of fibrogenesis, e.g. cell proliferation and extracellular matrix synthesis. we believe that more studies are required to determine the optimal doses and treatment duration. references 1. schwarzer u, sommer f, klotz t, et al. the prevalence of peyronie’s disease: results of a large survey. bju int. 2001; 88:727-30. 2. abern mr, larsen s, levine l. combination of penile traction, intralesional verapamil and oral therapies for peyronie’s disease, j sex med. 2012; 9:288-295. 3. windmeier c, gressner am. pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. gen pharmacol. 1997; 29:181-96. discussion and full list of references are posted in supplementary materials on www.aiua.it correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com gianni ughi md gianniughi@ospfe.it urology unit, arcispedale “s. anna” via a. moro 8 44124 cona, ferrara, italy figure 1. penile b-mode sonography revealed a calcified peyronie plaque. figure 2. penile color-doppler sonography revealed a psv of 60 cm/s in the cavernosal arteries below the plaque. figure 3. penile color-doppler sonography revealed a psv of 20 cm/s in the cavernosal arteries above the plaque. dell'atti cr_stesura seveso 09/10/14 10:32 pagina 238 stesura seveso 9archivio italiano di urologia e andrologia 2014; 86, 1 original paper evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction. a new parameter in the diagnosis of vascular erectile dysfunction. our experience on 59 cases domenico prezioso, fabrizio iacono, umberto russo, giuseppe romeo, antonio ruffo, nicola russo, ester illiano department of urology, university federico ii of naples, italy. objective: a precise characterization of erectile dysfunction (ed) of vascular origin has not yet been achieved, although cavernous peak systolic velocity (psv) is generally considered a major parameter. nevertheless the penile dynamic color doppler is invasive and linked to several complications. the intima-media thicknesses (imt) of cavernosal artery would add to the predictive value of vasculogenic ed risk and outcomes. we also hypothesized the existence of a correlation between imt cavernosal artery and imt carotid arteries. this study seeks to evaluate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal doppler ultrasound findings for discriminating patients with vasculogenic ed. material and methods: a total of 59 subjects (32 vasculogenic ed patients group a and 27 no vasculogenic ed patients group b) were evaluated in our andrological center from september 2012 to june 2013 and enrolled in the study. all subjects underwent medical history, erectile function domain of the international index of erectile function, physical examination, routine and sex hormone blood tests, and high resolution dynamic color doppler ultrasound evaluation of carotid and penile districts and valutation of imt in both districts. results: the values of cavernosal artery imt in group a were higher than in group b (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm). even the values of carotid artery imt in vasculogenic ed group were higher than in no vasculogenic ed group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). the cavernosal imt showed a moderate (r = 0.61) positive linear correlation (p < 0.001) with the carotid artery imt. conclusions: an increased cavernous imt might predict ed of vascular origin with more accuracy than psv and could be a sensitive predictor also for systemic atherosclerosis at an earlier phase. key words: intima media thickness; vascular erectile dysfunction; endothelial dysfunction. submitted 19 august 2013; accepted 5 october 2013 summary no conflict of interest declared. introduction erectile dysfunction (ed) is a pervasive disorder that afflicts as many as 30 million men in the united states (1), with an estimated 100 million men affected worldwide (2, 3).the risk of ed is related to many factors, including age, smoking, diabetes, heart disease, depression, and hypertension (4, 5). vascular disease is by far the most common cause of ed (6) formerly dismissed as a psychological condition, ed has now assumed center stage as a readily treatable disorder and a powerful risk-marker for cardiovascular disease (cvd) (6, 7). infact because cvd and ed share etiologies as well as pathophysiology (endothelial dysfunction) and because of evidence that degree of ed correlates with severity of cvd, it has been postulated that ed is a sentinel symptom in patients with occult cvd (8). endothelial dysfunction is intimately linked to atherogenesis and increased cvd risk (9). dysfunction arises following alteration in the release of several vasoactive factors, mainly nitric oxide (no), from endothelial cells (9, 10). endothelial dysfunction due to an abnormality in the release and/or action of no is characterized by vasoconstriction, coagulation, increased leucocyte adhesion and stimulation of smooth muscle (sm) cell growth, and is, therefore, central to atherogenesis (9). several traditional cardiovascular risk factors, such as aging, smoking, hypertension, dyslipidemia and diabetes, and some less traditional risk factors, including inflammation, hypoxia, oxidative stress and homocysteinemia, are related to endothelial dysfunction (11, 12). therefore given that endothelial dysfunction predates atherosclerosis development, this possibility is consistent with the so-called ‘artery size’ hypothesis (13). this theory posits that atherogenesis is likely to present earlier with clinical symptoms in arteries of a smaller diameter, such as in the penis, than in larger sized arteries, such as in the coronary circulation (14). in as much as the vascular disease is the most common cause of ed, after an intracavernosal injection of a vasodilatory agent, color doppler sonography is performed to evaluate cavernosal arteries and dorsal vessels, and to demonstrate both arterial insufficiency (primary diagnostic criteria for arterial doi: 10.4081/aiua.2014.1.9 prezioso_stesura seveso 26/03/14 10:11 pagina 9 archivio italiano di urologia e andrologia 2014; 86, 1 d. prezioso, f. iacono, u. russo, g. romeo, a. ruffo, n. russo, e. illiano 10 insufficiency include a peak systolic velocity (psv) of less than 25 cm/sec and waveform dampening) (15) and venous incompetence (most investigators used to diagnose venous leakage when arterial end-diastolic velocity is greater than 5 cm/sec) (15). that makes it a valuable tool in the diagnostic evaluation of ed (15). color doppler ultrasonography is a valuable, informative and minimally invasive tool in the diagnosis of ed (16). color doppler imaging offers several advantages over duplex imaging, including rapid localization of the cavernosal artery and accurate angle correction; depiction of cavernosal artery and dorsal vein flow progression; and demonstration of venous flow and arterial variants (15). however, due to the common pathogenesis that characterizes ed and cvd, the classical color doppler could be complemented with a new method in use in the study of atherosclerosis of the carotid arteries, the intima-media thickness (imt). carotid-wall imt infact is a surrogate measure of atherosclerosis (17) associated with cardiovascular risk factors (18) and with cardiovascular outcomes (19-22). it is the distance from the lumen-intima interface to the media-adventitia interface of the artery wall, as measured on noninvasively acquired ultrasonographic images of the carotid arteries (20). the imt is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases, like disease of cavernosal artery). we hypothesized that the imt of cavernosal artery would add to the predictive value of vasculogenic ed risk and outcomes. we also hypothesized the existence of a correlation between imt cavernosal artery and imt carotid arteries. this study seeks to evaluate these hypotheses with our experience, investigating the predictive accuracy of carotid and cavernosal doppler ultrasound (cdu) findings for discriminating patients with vasculogenic ed. material and methods the study design consisted of a observational trial conduced from september 2012 to june 2013. the study was conducted according to the helsinki declaration. written informed consent was obtained from all patients. we enrolled 59 patients, mean age was 55,3 ± 3,7 years. inclusion criteria were: over 51,6 years of age, male patients with stable marital relations and affected by ed. exclusion criteria were: international index of erectile function (iief) score ! 26, alcoholism, smoking, hypertension, cvd, neurogenic syndrome (multiple sclerosis, multiple atrophy, parkinson’s disease, tumors, stroke, disk disease, spinal cord disorders, polyneuropathy, uraemia), peyronie’s disease, penile fracture, congenital curvature of penis, micropenis, hypospadias, epispadias, hyperprolattinemia, hyperand hypothyroidism, cushing’s disease, drug assumption (pde5 inhibitors, intracavernous administration of vasoactive drugs, antihypertensives, antidepressants, antipsychotics, antiandrogens, antihistamines, heroin, cocaine and methadone), radiotherapy (pelvis or retroperitoneum) and lower pelvic surgery (oncological pelvic surgery, lower urinary and genital tract surgery). we enrolled 59 patients presenting at the andrology department of our clinic. at visit patients were evaluated by means of a detailed medical and sexual history. a general (including assessment of body mass index bmi and blood pressure) and urological objective examination was carried out to identify the presence of any diseases that could interfere with erectile function such as peyronie's disease, cancer of the penis, hypospadias, epispadias, signs and symptoms suggestive of hypogonadism (small testes, alterations in secondary sexual characteristics, decreased libido), neurological disorders. in all patients in whom an autonomic neuropathy was suspected, especially in patients with diabetes, it was assessed by the evocation of the bulbo-cavernous reflex. each patient finally performed a rectal examination to search for a possible benign prostatic hypertrophy (bph) to be associated with the presence of lower urinary yract symptoms (luts). in each patient lipid and metabolic levels (triglycerides, total cholesterol, hdl cholesterol, fasting blood glucose), hormone levels (testosterone (t), dihydrotestosterone (dht), luteinizing hormone (lh), follicle-stimulating hormone (fsh), estradiol, prolactin), clinical examination were evaluated. we asked all patients to complete the international index of erectile function (iief) questionnaire: the iief domain was calculated and ed grading was so determined: absence of ed (ef score 26 to 30), mild ed (ef score 17 to 25), moderate ed (ef score 11 to16) and severe ed (ef score < 10) (23). all patients were evaluated with gray scale ultrasound and color doppler ultrasound just before injection and 1, 5, 15, 20 minutes after injection and the images were recorded. a 7.5 mhz linear transducer with a mechanical standoff wedge to produce a favorable insonating angle throughout the entire field of view was used for the doppler ultrasound examinations. the degree of erection was classified into flask erection, tumescence, full erection, rigid erection and detumescence phases by an urologist. spectrum pattern, peak systolic velocity (psv), end diastolic velocity (edv) values and compliance were measured with conventional penile doppler ultrasound 5 minutes after pharmacological stimulation for each subject. according to the reference levels given in the recommendations of the european association of urology (eau) guidelines, a positive test is a rigid erectile response (unable to bend the penis) that appears within 10 min after the intracavernous injection and lasts for 30 min, and a peak systolic blood flow higher than 30 cm/s and a resistance index higher than 0.8 are generally considered normal in a duplex ultrasound of penile arteries (24). patients were divided in 2 groups: vasculogenic ed (group a) and no vasculogenic ed (group b) according to color doppler image findings. the group a was composed of 32 patients, while the group b was composed of 27 patients. imt values of common carotid artery and of cavernosal artery were calculated in all patients. intimamedia interface lines were manually traced as continuous lines by a certified reader, and imt values were calculated (25). the mean imt of the common carotid artery was measured over a segment of the common carotid artery that was 1 cm long, located approximately 0.5 cm below the carotid-artery bulb, and considered not to contain any plaque (i.e., not to have any perceivable protrusion of the prezioso_stesura seveso 26/03/14 10:11 pagina 10 artery wall into the lumen) (26). in each individual patient, the measurement was made bilaterally while for the statistical study was considered the media of the two values obtained. imt of cavernosal artery was measured in the proximal artery, choosing the straight portion that offered the best visualization. also in this case the measurement was bilateral and the average of the values obtained was used for the study. the measurement was made by the same skilled operator for each patient, using a scanner philips iu22 xmatrix ultrasound system and a probe l12-5 50 mm broadband linear array transducer with a frequency range from 12 to 5 mhz. the results of both groups were compared by student t test (p < 0.05). results at initial evalutation in the group a the iief total score was 10.8 ± 3.2, moderate ed, while in the second group the iief total score was 17.4 ± 4.1, mild ed, (p < 0.001). this result was expected and is obviously in agreement with the belief that hemodynamic alterations of the penile vasculature are the factors that can mostly impair erectile function.in the group a the diastolic blood pressure was 92.3 ± 5.1 mmhg versus 86,9 ± 6,1 in group b, while the systolic blood pressure was 143.2 ± 7.5 mmhg and 134,4 ± 9,2 respectively (p < 0.001). furthermore in the group a glucose (p = 0.021) and triglycerides (p = 0.013) levels were higher than those in group b, while cholesterol levels were lower.(p = 0.016). infact the glucose levels in group a were 114,7 ± 20,3 mg/dl versus 103,4 ± 21,2 mg/dl in group b. triglycerides levels were 175,3 ± 30,6 mg/dl in vasculogenic ed group , and 160,2 ± 17,0 mg/dl in no vasculogenic group. different trend showed the cholesterol levels infact they were higher in group b (43,9 ± 10,2 mg/dl – group a – vs 49,3 ± 8,4 mg/dl – group b). there were not statistically significant differences between the groups in bmi values (28.1 ± 3.1 vs 26.5 ± 4.5). table 1 shows the characteristics of the two groups. these findings supported the association of ed with cvd, atherosclerosis and cardiovascular risk. table 2 shows the findigs of carotid and cavernosal artery imt. the values of cavernosal artery imt in group a were higher than in group b (0,28 ± 0,06 mm vs 0,17 ± 0,07 mm).this suggested that hemodynamic functional alterations evaluated in penile color doppler image were correlated with morphological alterations of cavernosal artery evaluated by ultrasound. even the values of carotid artery imt in vasculogenic ed group were higher than in no vasculogenic ed group (0,74 ± 0,14 mm vs 0,59 ± 0,11 mm). this result is in complete agreement with the association between carotid atherosclerosis and polydistrectual atherosclerosis like cavernosal atherosclerosis. lastly we wanted to analyze the possibility of a correlation between the values of cavernous imt and carotid imt in our study population. as graphically represented in figure 1, the cavernosal imt showed a moderate (r = 0.61) positive linear correlation (p < 0.001) with the carotid artery imt. the explanation of these results was that the same risk factors and pathogenesis of vascular injury caused simultaneously endothelial damage in different distrects. 11archivio italiano di urologia e andrologia 2014; 86, 1 evaluation of penile cavernosal artery intima-media thickness in patients with erectile dysfunction vasculogenic ed no vasculogenic ed p (n = 32) (n = 27) age mean (sd) 53,2 ± 8,2 49,6 ± 7,6 ns iief-5 mean (sd) 10,8 ± 3,2 17,4 ± 4,1 p < 0,001 bmi mean (sd) 28,1 ± 3,1 26,5 ± 4,5 ns systolic blood pressure (mmhg) mean (sd) 143,2 ± 7,5 134,4 ± 9,2 p < 0,001 diastolic blood pressure (mmhg) mean (sd) 92,3 ± 5,1 86,9 ± 6,1 p < 0,001 glycemia (mg/dl) mean (sd) 114,7 ± 20,3 103,4 ± 21,2 p = 0,021 total cholesterol (mg/dl) mean (sd) 193,3 ± 42,0 176,0 ± 24,8 ns cholesterol hdl (mg/dl) mean (sd) 43,9 ± 10,2 49,3 ± 8,4 p = 0,016 triglycerides (mg/dl) mean (sd) 175,3 ± 30,6 160,2 ± 17,0 p = 0,013 bmi: body mass index; ed: erectile dysfunction; hdl: high-density lipoprotein; iief-5: international index of erectile function. table 1. characteristics of patients: vasculogenic ed (group a) and no vasculogenic ed (group b). vasculogenic ed no vasculogenic ed p (n = 32) (n = 27) imt cavernosal artery mean (sd) 0,28 ± 0,06 0,17 ± 0,07 p < 0,001 imt carotid artery mean (sd) 0,74 ± 0,14 0,59 ± 0,11 p < 0,001 bed: erectile dysfunction; imt: intima–media thickness.. table 2. intima-media thickness (imt) values of common carotid artery and of cavernosal artery. prezioso_stesura seveso 26/03/14 10:11 pagina 11 archivio italiano di urologia e andrologia 2014; 86, 1 d. prezioso, f. iacono, u. russo, g. romeo, a. ruffo, n. russo, e. illiano 12 discussion the association between ed and cvd has previously been recognized (27). patients with cvd frequently describe preexisting ed (28).these patients must be clearly distinguished from those who have neither cvd nor cardiovascular risk factors and have a defect in the generating no-3-5-cyclic guanosine monophosphate peripheral vascular system in sm that is independent of other systemic vascular diseases (29). it has been suggested, but never demonstrated, that early treatment of coronary heart disease risk factors may reduce the later risk of ed (30). furthermore, it has been hypothesized that ed is a harbinger of cvd (31, 32). in a study of men with diabetes with vs without ed, ed was the most efficient predictor of coronary artery disease (33). a largescale study of 25 650 men found a 75% increased risk of peripheral vascular disease in men with preexisting ed (34). ian m. thompson demonstrated the substantial association between incident as well as prevalent ed and subsequent cvd, including angina, myocardial infarction, stroke, and transient ischemic attack (35). several epidemiological studies in selected patient populations have clearly shown that the major cardiovascular risk factors – aging, smoking, diabetes, hyperlipidemia and hypertension – have raised prevalence in individuals with ed (36, 37). the prevalence of ed is also directly related to the number of cardiovascular risk factors present, being highest in individuals with more than three. patients with coronary artery disease have a high frequency of ed (38, 39) which correlates with the number of stenotic and calcified arteries and predates symptomatic disease (40). notably, a patient with vasculogenic ed is likely to have one coronary artery with a 50% stenosis (38, 39). cardiometabolic risk in abdominally obese subjects is now well-defined as the metabolic syndrome (41). ed prevalence increases with the number of components of the metabolic syndrome, being as high as 40% in individuals with four components, and is especially prevalent in those with diabetes (42). in individuals with the metabolic syndrome, ed has a linear relationship with evidence of endothelial dysfunction (43). a plausible theoretical link between erectile and endothelial dysfunction posits that cardiovascular risk factors could induce ed by impairing no release from endothelial cells following neuronal activation and initiation of a penile erection. a residual, important question, however, is whether ed reflects endothelial dysfunction independent of traditional cardiovascular risk factors (43). carotid-artery imt, measured noninvasively with the use of carotid-artery ultrasonography, is an independent predictor of new cardiovascular events in persons without a history of cvd (43). a review of eight epidemiologic studies showed that the imt of the common carotid artery by itself (in all eight studies) or combined with the imt of the internal carotid artery and presented as a score (in one of the eight studies) had independent predictive power with respect to cardiovascular events (44) .the presence of plaque (defined as an internal-carotid artery imt ! 1.9 mm) has been shown to be associated with increased event rates (45). gokkaya investigated the predictive accuracy of carotid and cdu findings for discriminating patients with vasculogenic erectile dysfunction (edv). of total 50 patients, 29 (58%) were included in vasculogenic ed group and 21 (42%) in non-vasculogenic ed group according to p-cdu findings. there was a significant difference between groups for cavernosal imt (p = 0.012) but not for carotid imt (p = 0.601). when patients were reclassified according to carotid imt values (imt of the first group < 0.9 mm and the second > = 0.9 mm), carotid psv and edv values were different (p = 0.033 and 0.018, respectively). cavernosal psv and edv displayed no difference (p = 0.816 and 0.123) while cavernosal imt and percent change of cavernosal caliper were significantly different (p = 0.014 and 0.018) (46). caretta performed a high magnification ultrasonographic study in order to compare functional and morphological parameters of the cavernous artery to psv and their relation with penile and systemic atherosclerosis (47). a total of 109 subjects (84 ed patients and 25 controls) were evaluated. cavernous parameters were significantly different between ed and controls. multivariate model showed that imt was the only predicting parameter for ed of vascular origin. cavernous imt showed a strong direct correlation with carotid and femoral imt. ed patients with two or more cardiovascular risk factors had a significantly higher cavernous imt (47). ucar investigated the relationship between penile color doppler sonography (cds) findings and sonographic endothelial parameters in patients with ed, including imt of common carotid arteries (cca) and flow-mediated dilatation (fmd) of brachial artery (48). fifty-six ed patients were included in the study. imt values were higher in arterial/combined insufficiency group when compared to cavernous veno-occlusive disease but the difference was not statistically significant. the combined use of imt and fmd established the diagnosis of vasculogenic ed with 100% sensitivity and 59.2% specificity. the positive predictive value was 72%, negative predictive value 100% and accuracy 80%. the combined use of brachial artery fmd and carotid arteries imt measurements may be suggested as an alternative method to evaluate vasculogenic ed (48). vlachopoulos evaluated figure 1. correlation between carotid artery imt and cavernosal artery imt. imt: intima–media thickness. prezioso_stesura seveso 26/03/14 10:11 pagina 12 arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic ed and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment (49). hypertensive patients with ed had higher common carotid imt (0.95 ±.19 vs. 0.83 ± 0.18 mm, p = 0.003) and carotid-femoral pulse-wave velocity (8.89 ± 1.38 vs. 8.11 ± 1.10 m/s, p = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 ± 1.64 vs. 4.07 ± 1.68%, p = 0.003). in hypertensive men, the presence but not the severity of vasculogenic ed is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation (49). conclusion the increase of imt is an expression of morphological and structural alterations of the vessel wall due to atherosclerotic phenomena. both the carotid and cavernous imt proved significantly higher in patients suffering from ed vasculogenic, in association with the classical risk factors for cvd. in particular, the evaluation of imt cavernous arteries could be done, together with the color-doppler evaluation of psv, by edv, a new sonographic parameter useful in identifying those cases of vasculogenic ed in a more precise way than what can not be done with the alone assessment of psv. the penile color doppler with intracavernous injection of vasoactive substances is a diagnostic method for a long time widely used in the evaluation of patients with ed. however, it is invasive and linked to several complications such as bruising, hematoma and penile priapism, not to mention that this method is considered embarrassing by most of the patients. in addition, the anxiety that comes from intracavernous injection can induce an abnormal response in the patient who may have adrenergic inhibitory effect, in fact decreasing the sensitivity of this test. further studies should be aimed at understanding if the assessment of cavernous imt is a reliable screening test for those subjects with multiple cardiovascular risk factors at risk of vasculogenic ed, or even if it can completely replace the more invasive and less tolerated colordoppler investigation with intracavernous injection in the instrumental assessment of erectile function. references 1. lewis rw. epidemiology of erectile dysfunction. urol clin north am. 2001; 28:209-216. 2. nih consensus development panel on impotence. impotence. jama. 1993; 270:83-90. 3. zusman rm, morales a, 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artery intimamedia thickness (imt) with risk factors and prevalent cardiovascular disease: comparison of mean common carotid artery imt with maximum internal carotid artery imt. j ultrasound med. 2010; 29:1759-68. 26. polak jf, o’leary dh, kronmal ra, et al. sonographic evaluation of carotid artery atherosclerosis in the elderly: relationship of disease severity to stroke and transient ischemic attack. radiology. 1993; 188:363-70. 27. bai q, xu qq, jiang h, et al. prevalence and risk factors of erectile dysfunction in 3 cities of china: a community-based study. asian j androl. 2004; 6:343-348. 28. montorsi f, briganti a, salonia a, et al. erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and -angiographically documented coronary artery disease. eur urol. 2003; 44:360-364. 29. debusk r. sexual activity in patients with angina.jama. 2003; 290:3129-3133. 30. fung mm, bettencourt r, barrett-connor e. heart 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erectile dysfunction and coronary risk factors: prospective results from the massachusetts male aging study. prev med. 2000; 30:328-338. 38. greenstein a, et al. does severity of ischemic coronary disease correlate with erectile function?int j impot res. 1997; 9:123-126. 39. kloner ra, et al. erectile dysfunction in the cardiac patient: how common and should we treat? j urol 2003; 170 (suppl):s46-s50. 40. solomon h, et al. relation of erectile dysfunction to angiographic coronary artery disease. am j cardiol. 2003; 91:230-231. 41. grundy sm, et al. american heart association; national heart, lung, and blood institute diagnosis and management of the metabolic syndrome: an american heart association/national heart, lung, and blood institute scientific statement.circulation. 2005; 112:2735-2752. 42. esposito k, et al. high proportions of erectile dysfunction in men with the metabolic syndrome. diabetes care. 2005; 28:1201-1203. 43. giugliano f, et al. erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men j endocrinol invest. 2004; 27:665-669. 44. lorenz mw, markus hs, bots ml, et al. prediction of clinical cardiovascular events with carotid intimamedia thickness: a systematic review and meta-analysis. circulation. 2007; 115:459-67. 45. rundek t, arif h, boden-albala b, et al. carotid plaque, a subclinical precursor of vascular events: the northern manhattan study. neurology. 2008; 70:1200-7. 46. gokkaya cs, aktas bk, et al. is there a concordance between carotid and penile cavernosal artery intima-media thickness in patients with erectile dysfunction? international journal of impotence research 2012; 24:44-48. 47. caretta n, palego p, at al. cavernous artery intima-media thickness: a new parameter in the diagnosis of vascular erectile dysfunction. j sex med. 2009; 6:1117-26. 48. ucar g, et al. the combined use of brachial artery flow-mediated dilatation and carotid artery intima-media thicknessmeasurements may be a method to determine vasculogenic erectile dysfunction. int j impot res. 2007; 19:577-83. 49. vlachopoulos c, aznaouridis, et al. arterial function and intima-media thickness in hypertensive patients with erectile dysfunction. j hypertens. 2008; 26:1829-36. correspondence domenico prezioso, md dprezioso@libero.it fabrizio iacono, md fiacon@tin.it umberto russo, md umberto.russo@libero.it giuseppe romeo, md giuseppe.romeo85@gmail.com antonio ruffo, md antonio.ruffo7@gmail.com nicola ruffo, md stoiconk@hotmail.com ester illiano, md (corresponding author) ester.illiano@inwind.it department of urology university federico ii of naples via pansini 5 80131 naples, italy prezioso_stesura seveso 26/03/14 10:11 pagina 14 stesura seveso introduction penile prosthesis implantation is the solution of choice in patients who have failed or present contraindication to the use of all conservative treatment for erectile dysfunction 133archivio italiano di urologia e andrologia 2013; 85, 3 original paper long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis antonio vitarelli 1, lucia divenuto 1, francesca fortunato 2, antonio falco 3, vincenzo pagliarulo 1, gabriele antonini 4, vincenzo gentile 4, alessandro sciarra 4, stefano salciccia 4, salvatore sansalone 5, maria rosaria di placido 4, giulio garaffa 6, arcangelo pagliarulo 1 1 “urologia ii universitaria”, department of emergency and transplant, section of urology and andrology, university hospital “azienda ospedaliera policlinico”, bari, italy; 2 department of medical sciences and occupational medicine, section of hygiene, university of foggia, italy; 3 epidemiologic observatory of puglia, italy; 4 department of urology, university “la sapeinza”, rome, italy; 5 department of urology, “tor vergata” university, rome, italy; 6 st. peter’s andrology and the urology centre, broomfield hospital, chelmsford, uk. objective: penile prosthesis implantation is the solution of choice in patients who have failed or present contraindication to the use of all conservative treatment for erectile dysfunction (ed). overall, satisfaction rates are high, with more than 80% of patients and partners fully satisfied with cosmetic and functional result of surgery. chronic postoperative pain, penile shortening, soft or hyposensitive glans, pencil like penis syndrome and difficulty to cycle the device represent the most common causes of patient’s dissatisfaction. satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits) the aim of our study was to analyze the long-term mechanical reliability of the ams 700cx/cxm inflatable penile prosthesis and the patient’s satisfaction rate using iief and edits questionaire as standard reference. materials and methods: a retrospective case notes review of all patients who have undergone implantation of a three pieces inflatable penile prosthesis ams 700 cx and cxr between october 1997 and december 2010. overall, 80 patients have undergone implantation of 3 pieces inflatable penile prosthesis ams 700 cx inhibizone. patients have been administered the iief-5 and edits questionnaires in combination with a non validated 9 domain questionnaire that assesses penile rigidity, sensation, orgasmic function, frequency of intercourse, impact of surgery on the quality of life, satisfaction rate. results: overall 10 years survival estimate according to the kaplan meier method of ams 700 cx touch pump and ams 700 cx momentary squeeze pump are respectively 77.6% and 82.5%. the median postoperative iief5 and edits score were respectively 21.46 and 73.11, which show a high level of satisfaction. 59 patients (90.8%) were able to cycle the device and were engaging in penetrative sexual intercourse. conclusions: penile prosthesis implantation yields excellent results in terms of cosmetic and functional outcome and therefore has a significant impact on patients’ satisfaction, sex life and overall quality of life. overall, long term reliability has been significantly improved and complication rates are low in the hands of experienced surgeons. key words: penile prosthesis; erctile disfunction; impotence; questionnaires. submitted 28 may 2013; accepted 25 june 2013 no conflict of interest declared summary (ed). overall, 25-30% of patients with ed will fail to respond to phosphodiesterase type 5 inhibitors (pde5i) and will therefore be offered intracavernosal injection (ici) doi: 10.4081/aiua.2013.3.133 archivio italiano di urologia e andrologia 2013; 85, 3 vitarelli, divenuto, fortunato, falco, pagliarulo, antonini, gentile, sciarra, salciccia, sansalone, di placido, garaffa, pagliarulo 134 of prostaglandin e (pge). since ici is associated with a high rate of drop out, around 10-15% of patients with ed will be candidate for penile prosthesis implantation (1). although prosthetic surgery in virgin corpora is associated with higher satisfaction rates in patients and partners than pde5i, intra and postoperative complications are not uncommon and therefore the procedure should be carried out only by a large volume surgeon. inflatable device have been initially introduced by scott in 1973 (2) and now are available in a two and three pieces version. in general, inflatable penile prosthesis are associated with higher satisfaction rates among patients and partners than their semirigid counterpart as they allow girth expansion, thus preventing the risk of “pencil penis” syndrome, and can be deflated mimicking the flaccid penile state. the most widely used three pieces inflatable penile prostheses are produced by american medical systems (ams, minnetonka, minnesota usa) and coloplast (coloplast corporation, humlebaek, denmark). since their initial introduction in 1973, three pieces inflatable penile prosthesis have undergone significant improvement in order to increase their long-term mechanical reliability and reduce the risk of infections. a major breakthrough has been the introduction by ams of the ams 700 cx model, which was characterized by controlled expansion cylinders. this has led to a reduction of mechanical failure from 62% to 15% at 5 years due to the reduced risk of aneurysmal dilatation of the cylinders (3). at present ams is on the market with two varieties of three pieces inflatable penile prosthesis: the ams 700cx, and the ams 700cxr, which presents narrow base cylinders and is designed for implantation in severely fibrotic corpora, where dilatation is difficult. the coloplast counterparts are respectively the titan and the titan narrow base. another breakthrough has been the introduction by ams of controlled girth and length expansion cylinders, this prosthesis, initially introduced on the market under the name of ultrex, was associated with a high rate of erosion and mechanical failure and therefore has been improved and it is now available under the name of lgx (length and girth expansion) which allows a length expansion up to 4 cm and is associated with a 5 year survival of 94% in carefully selected patients (4). also the pump has been redesigned, to render cycling easier and to reduce the incidence of mechanical failure. in particular, the introduction of the lock out valve has reduced the incidence of spontaneous autoinflation of the device and the momentary squeeze pump (ms) has allowed an easier deflation of the device (5-8). another breakthrough in the ams implants has been the use of the parilene coating of the cylinders, which renders the implant more resistant to friction and therefore reduces the risk of wearing, and the impregnation of the rods with inhibizone, a combination of rifampicin and minocyclin, which has significantly reduced the risk of infection from 1,61% a 0,68% and from 2,41% a 1,36% respectively in virgin and revision implants (7-10). indication for penile prosthesis implantation is refractory erectile dysfunction, which fails to respond to medical treatment. also patients who have medical contraindications to the use of pde5i, ici and vacuum device are candidates for penile prosthesis implantation. the choice between an inflatable penile prosthesis depends on the patient’s choice, funding, previous abdominal and genital surgery, body habitus and hand dexterity (1). in general, poor hand dexterity and multiple abdominal surgeries are relative contraindications to the implantation of an inflatable penile prosthesis. larger penises and physically active patients are instead better served with a three pieces inflatable device. adequate preoperative counseling is paramount, as excessively high patients expectations will lead to lower postoperative satisfaction rates. in particular, patients must be warned that stretched penile length is a good indicator of the postoperative penile length and that the procedure is irreversible. although the reliability of the device has been significantly improved, mechanical failure rates at 5 years still vary between 10 and 20%. if the failure occurs in the early months, it not necessary to remove the entire device and the identification and exchange of the faulty component usually suffices. if the mechanical failure occurs after 2 years instead, it is advisable to exchange the entire device. mechanical failure can occur in all components of the prosthesis, from the tubings, to the connectors, the pump, the reservoir and the cylinders. penile prosthesis infection still represents the most fearful complication, occurs in 1% to 3% of patients and is more common in case of diabetes, compromised immunitary system, neurological condition, revision surgery and fibrosis. in case of infection the entire device has to be removed and patients can be offered immediate (mulcahy procedure) or delayed reimplantation. erosion, necrosis, purulent discharge and systemic infection are contraindications for immediate reimplantation. erosion of the device is uncommon and occurs in 3% to 6% of cases and it usually occurs at the navicular fussa or at the corona. overall, satisfaction rates are high, with more than 80% of patients and partners fully satisfied with cosmetic and functional result of surgery. chronic postoperative pain, penile shortening, soft or hyposensitive glans, pencil like penis syndrome and difficulty to cycle the device represent the most common causes of patient’s dissatisfaction (11). satisfaction rates are better assessed with the use of validated questionnaires such as the international index of erectile function (iief) and the erectile dysfunction inventory of treatment satisfaction (edits) (12-13). the aim of our study was to analyze the long-term mechanical reliability of the ams 700cx/cxm inflatable penile prosthesis and the patient’s satisfaction rate using iief and edits questionaire as standard reference. materials and methods a retrospective case notes review of all patients who have undergone implantation of a three pieces inflatable penile prosthesis ams 700 cx and cxr between october 1997 and december 2010. this study was conducted after approval of the protocol from our department institutional committee and informed consent was obtained from all patients. overall, 80 patients have undergone implantation of 3 pieces inflatable penile prosthesis ams 700 cx inhibizone; a tactile pump has been used in 42 patients and momentary sqeeze® pump in the remainder. the median age at the time of implantation was 56 years (range 40-77). the aetiology of ed was radical pelvic surgery in 32 patients (43.2%), vasculogenic in 25 (33.8%), peyronie’s disease in 12 (16.2%), spinal cord injury in 4 (5.4%) and fibrosis post low flow priapism in 1 (1.4%). diabetes mellitus was present in 24 patients (20%) and 6 had already undergone explantation of an infected penile prosthesis and presented with severe corporeal fibrosis. implantation of the device has been carried out through a penoscrotal approach in 50 patients (62.5%) and through an infrapubic one in the remainder. implantation has been difficult in 7 patients due to severe corporeal fibrosis and a second subcoronal incision has been necessary in 4 cases to allow adequate distal dilatation. patients have been administered the iief-5 and edits questionnaires in combination with a non validated 9 domain questionnaire that assesses penile rigidity, sensation, orgasmic function, frequency of intercourse, impact of surgery on the quality of life, satisfaction rate. patients were invited to give a score between 1 and 4 for each of the questions (1: excellent; 2: good; 3: moderate; 4: poor) as reported in table 1. postoperative penile length has also been recorded. statistical analysis statistical data analysis was done with the statistical software medcalc software demo for windows, version 9.3. the kaplan-meier method was used to analyze the survival of the ams 700cx/cxm inflatable penile prostheses also a student’s t-test was performed and a p value of < 0.05 was considered to indicate a significant difference. results after a median follow up of 68.7 months (range 6164), infection of the device has occurred in 2 patients (2.5%) and has required the removal of the device followed by delayed reimplantation at 6 months. mechanical failure of the device has occurred in 10 patients (12.5%) and was due to pump failure, cylinder rupture and fluid leak from the reservoir in respectively 5, 3 and 2 patients. all patients have been managed with complete exchange of the device. erosion through the corona/glans occurred in 3 patients, through the scrotal skin in 1 and through the urethra in 1, as shown in figure 1 and 2. all the components of the implants have been removed in all patients. overall, 65 patients have completed all the questionnaires. both iief-5 and edits questionnaire have shown a mean improvement of the sexual function and of quality of life. the median postoperative iief5 and edits score were respectively 21,46 and 73,11, which show a high level of satisfaction. 59 patients (90,8%) were able to cycle the device and were engaging in penetrative sexual intercourse. with regards to the impact of surgery on the quality of life, 58 patients (89,2%) were fully satisfied with the outcome of surgery, and 57 (57%) were globally satisfied. 55 patients (84,6%) would undergo surgery again and 57 would advise a friend to undergo the same treatment. although patients who reported good sensitivity during intercourse scored higher at the edits (74,6 ± 19,2; ci95%: 69,4-79,7) and the iief-5 (21,7 ± 5,2; ci95%: 20,2-23,2) questionnaires than patients who had poor sensation [edits (63,8 ± 16,3; ci95%: 51,4-76,4); iief5 (19,6 ± 4,3; ci95%: 16,2-22,9)], the difference was not statistically significant (p > 0.05). patients who reported an adequate rigidity during intercourse scored significantly higher at the edits (76,8 ± 15,8; ci95%: 72,5-81,2) and iief-5 (22,2 ± 4,7; ci95%: 20,9-23,5) questionnaires than patients with moderate rigidity [edits (54,7 ± 23,4; ci95%: 38,9-70,5); iief-5 (17,7 ± 7,0; ic95%: 12,9-22,5)]. the difference reached statistical significance. also patients who reported an excellent/good orgasm scored higher at the edits (76,5 ± 15,7; ci95%: 72,280,7) and iief-5 (22,5 ± 3,6; ci95%: 21,5-23,5) questionnaires than patients who had a moderate/poor orgasm [edits (54,5 ± 25,6; ci95%: 36,2-72,8); iief-5 (15,8 ± 9,3; ci95%: 9,1-22,5)] and the difference reached statistical significance the median length of the cylinders in patients who reported an improvement in the quality of sexual life was superior (19 ± 1,9; ci 95% 18,5-19,5) than the one of 135archivio italiano di urologia e andrologia 2013; 85, 3 long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis 1. are you using the device? 1 2 3 4 2. is the device easy to cycle? 1 2 3 4 3. did you notice an improvement in your sexual life? 1 2 3 4 4. are you satisfied? 1 2 3 4 5. would you advise a friend to undergo the same procedure? 1 2 3 4 6. would you undergo the same procedure? 1 2 3 4 7. do you have sensation during intercourse? 1 2 3 4 8. do you obtain adequate rigidity? 1 2 3 4 9. do you achieve an orgasm? 1 2 3 4 table 1. the domains of the non validated questionnaire. figure 1. erosion of one cylinder through the urethra. figure 2. erosion through the glans penis. archivio italiano di urologia e andrologia 2013; 85, 3 vitarelli, divenuto, fortunato, falco, pagliarulo, antonini, gentile, sciarra, salciccia, sansalone, di placido, garaffa, pagliarulo 136 patients who did not report an improvement in sexual life (17,3 ± 1,9; ci 95% 15,5-19,0). this difference was statistically significant (p = 0,0284). also the cylinders were statistically longer (19 ± 1,9; ic 95% 18,5-19,5) in patients who would advise a friend to undergo surgery than in patients who would not advise to undergo the procedure (17,2 ± 1,7; ic 95% 15,8-18,7) (p = 0,0151) and in patients who were globally satisfied (19 ± 1,9; ci 95% 18,5-19,5) than in patients who were dissatisfied (17 ± 1,7; ic 95% 15,4-18,6) (p = 0,0087). there is a progressive but not statistically significant increase in the iief-5 and edits score with increasing length of the cylinders. when considering the type of prosthesis implanted, the median edits and iief-5 score of patients with an ams 700cx ms [edits (74,9 ± 15,1; ci 95% 69,3-80,6); iief-5 (21,5 ± 5,0; ci 95% 19,6-23,4)] was higher than the one of patients who have undergone implantation of a ams 700cx tactile pump [edits (71,5 ± 22,0; ci 95% 63,9-70,1); iief-5 (21,3 ± 5,7; ci 95% 19,4-23,3)], but the difference did not reach statistical significance. edits and iief-5 scores were lower in patients who presented comorbidities [edits (72,4 ± 20,0; ci95%: 67,177,7); iief-5 (21,1 ± 5,7; ci 95% 19,6-22,7)] than in patients with no comorbidities [edits (78,1 ± 9,1; ci 95%: 70,5-85,8); iief-5 (23,4 ± 0,9; ci 95%: 22,6-24,1)], but the difference did not reach statistical significance. overall, patients who have experienced complications scored lower both at the edits and iief-5 questionnaires [edits (54,9 ± 30,1; ci 95%: 34,7-75,2); iief-5 (14,4 ± 10,1; ic 95%: 8,6-22,2)] than patients who had no complications [edits (75,3 ± 16,9; ic 95%: 70,879,7); iief-5 (22,3 ± 3,9; ic 95%: 21,2-23,3)]. the difference reached statistical significance. overall 10 years survival estimate according to the kaplan meier method of ams 700 cx touch pump and ams 700 cx momentary squeeze pump are respectively 77,6% (ic 95%: 58,0-88,8) and 82,5% (ic 95%: 63,092,2), as reported in table 2 and 3. discussion penile prosthesis implantation represents the only solution for patients with refractory erectile dysfunction. overall, mechanical reliability and overall patients’ satisfaction of 3 pieces inflatable penile prosthesis has progressively increased since the first description of a hydraulic device by scott et al. more than 30 years ago (2). in particular, 5 years survival can be as high as 92.1% with patients’ satisfaction rates of 85.6% and a prevalence of mechanical failure of 9.1% (1416). the main limitation of all these studies is that patients’ satisfaction was assessed subjectively by the surgeon and not with a validated questionnaire. mulhall et al. in 2003 has been the first to use validated questionnaires such as iieftable 2. kaplan meier overall survival estimate (%). years overall survival [95% conf. int.] following estimate (%) 0 100 . . 1 97,2 89,4 99,3 2 97,2 89,4 99,3 3 97,2 89,4 99,3 4 91,9 79,0 97,0 5 86,4 71,3 93,8 6 86,4 71,3 93,8 7 82,5 65,3 91,6 8 82,5 65,3 91,6 9 77,6 58,0 88,8 10 77,6 58,0 88,8 table 3. kaplan meier overall survival estimate (%) according to the type of implant. type years overall survival [95% of implant following estimate (%) conf. int.] ams 700 cx 1 100 tactile pump 3 100 5 88,8 72,8 95,6 10 79,7 59,2 90,7 ams 700 cx 1 94,3 79,0 98,5 momentary 3 94,3 79,0 98,5 squeeze pump 5 10 5 and edits to assess patients’ satisfaction 6 months postoperatively (10). the present series using validated questionnaires confirms a statistically significant correlation between mechanical complications, degree of rigidity and quality of the orgasm with patient’s satisfaction. interestingly, the quality of sensation did not affect iief-5 and edits scores in a statistically significant way. overall 87.7% of the patients in the present series were satisfied with the cosmetic and functional result of surgery, and these results are similar to the one previously reported in the literature (17, 18). also median prosthesis survival rate in the present series was 97.2% at 1 year, 91.9% at 4 years and 77.6% at 10 years, substantially similar to the data reported by dhar et al. (19). the strength of our results has been to have used a validated questionnaires to assess the functional results, compared with other previously similar experiences. some limits of our study must be underlined: first, this is a retrospective analysis and not a prospective and randomized study. second, the follow-up was not so longer (68.7 months) to better evaluate the satisfaction of patients in a long time from surgery, however it is similar to previous experience in this field. conclusions penile prosthesis implantation yields excellent results in terms of cosmetic and functional outcome and therefore has a significant impact on patients’ satisfaction, sex life and overall quality of life. overall, long term reliability has been significantly improved and complication rates are low in the hands of experienced surgeons. references 1. montague dk. penile prosthesis implantation in the era of medical treatment for erectile dysfunction. urol clin north am. 2011; 38:217-25. 2. scott fb, bradley we, timm gw. management of erectile impotence: use of implantable inflatable prosthesis. urology. 1973; 2:80. 3. nickas me, kessler r, kabalin jm. long term experience with controlled expansion cylinders in the ams 700 cx inflatable penile prosthesis and comparison with earlier version of the scott inflatable penile prosthesis. urology. 1994; 44:400. 4. milbank aj montague dk, angermeier kw, et al. mechanical failure of the american medical system ultrex inflatable penile prosthesis: before and after 1993 structural modification. j urol. 2002; 167:2502-6. 5. daitch ja, angermeier kw, lakin mm, et al. long term mechanical reliability of ams 700 series inflatable penile prostheses: comparison of cx/cxm and ultrex cylinders. j urol. 1997; 158:1400. 6. wilson sk, cleves ma, delk jr 2nd. comparison of mechanical reliability of original and enhanced mentor alpha i penile prosthesis. j urol. 1999; 162:715-8. 7. delk j, knoll ld, mc murray j, et al. early experience with the american medical system new tactile pump: results of a multicentre study. j sex med. 2005:266-71. 8. knoll ld, henry g, culkin d, et al. physician and patient satisfaction with the new ams700 momentary sqeeze inflatable penile prosthesis. j sex med. 2009; 6:1773-8. 9. carson cc efficacy of antibiotic impregnation of inflatable penile prosthesis in decreasing infection in original implants. j urol. 2004; 171:1611-1614. 10. carson ci. initial success with the ams 700 series inflatable penile prosthesis with inhibizione antibiotic surface treatment: a retrospective review of revision cases incidence and comparative results versus non-treated devices. j urol. 2004; 171:236. 11. mc laren rh, barret dm. patient and partner satisfaction with the ams 700 penile prosthesis. j urol. 1992; 147:62. 12. mulhall jp, ahmed a, branch j, parker m. serial assessment of efficacy and satisfaction profiles following penile prosthesis surgery. j urol. 2003; 169:1429-1433. 13. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-9. 14. carson cc penile prosthesis implantation in the treatment of peyronie desease” int j imp res. 1998; 10:125. 15. choi deuk y, jin choi y, hwan kim j, ki choi h. mechanical reability of the ams 700 cmx inflatable penile prosthesis for the treatment of male erectile dysfunction. j urol. 2001; 165:822-4. 16. carson cc, mulcahy jj, govier fe. efficacy, safety and patient satisfaction outcome of the ams 700 cx inflatable penile prosthesis: result of a long term multicenter study. ams 700 cx study group. j urol. 2000; 164:376-80. 17. bhojwani ag, jain s, kockelbergh rc, terry tr. sexual satisfaction after penile prosthesis insertion for the treatment of erectile dysfunction. sex dysfunction. 1998; i:133-136. 18. goldstein i, jain l, kockelbergh rc, terry tr. safety and efficacy outcome of mentor alpha1 inflatable penile prosthesis implantation for impotence treatment. j urol 1997; 157:833-9. 19. dhar nb, angermeier kw, montague dk. long-term mechanical reliability of ams 700cx ™/cxm inflatable penile prosthesis. j urol. 2006; 176:2599-2601. 137archivio italiano di urologia e andrologia 2013; 85, 3 long term patient satisfaction and quality of life with ams700cx inflatable penile prosthesis correspondence antonio vitarelli, md antoniovitarelli@hotmail.com lucia divenuto, md ldivenuto@urologia.uniba.it vincenzo pagliarulo, md vpagliarulo@urologia.uniba.it arcangelo pagliarulo, md apagliarulo@urologia.uniba.it urologia ii universitaria, department of emergency and transplant, section of urology and andrology, university hospital, azienda ospedaliera policlinico, bari, italy francesca fortunato, md f.fortunato@unifg.it department of medical sciences and occupational medicine, section of hygiene, university of foggia, foggia, italy antonio falco, md a.falco@unifg.it epidemiologic observatory of puglia, foggia italy stefano salciccia, md (corresponding author) stefi_sal77@tiscali.it gabriele antonini, md gabrieleantoninimd@gmail.com vincenzo gentile, md vincenzo.gentile@uniroma1.it alessandro sciarra, md sciarrajr@hotmail.com maria rosaria di placido, md m.diplacido@uniroma1.it department of urology, university “la sapienza”, viale del policlinico 155 00161 roma, italy salvatore sansalone, md salvatore.sansalone@yahoo.it department of urology, tor vergata, university, rome, italy giulio garaffa, md giuliogaraffa@gmail.com st. peter’s andrology and the urology centre, broomfield hospital chelmsford (uk) archivio italiano di urologia e andrologia 2016; 88, 4270 original paper are erectile functions affected by ab0 blood group? erdal benli 1, abdullah çırakoğlu 1, ercan öğreden 2, selamettin demir 3, yasemin kaya 4, mustafa i̇bas 5, ali ayyıldız 6, ahmet yüce 1 1 department of urology, ordu university, faculty of medicine, ordu, turkey; 2 department of urology, giresun university, faculty of medicine, giresun, turkey; 3 clinic of urology, istanbul hospital, van, turkey; 4 department of internal medicine, ordu university, faculty of medicine, ordu, turkey; 5 intern, necmettin erbakan university, faculty of medicine, konya, turkey; 6 clinic of urology, ankara training research hospital, ankara, turkey. aim: the aim of this study was to investigate whether there is a relationship between erectile dysfunction (ed), thought to be a vascular disease, and ab0 blood group. material and method: the study included 350 people abiding by the study criteria who applied to our clinic from april 2012-april 2015. the patients were divided into two groups including those with ed (group 1) and those without (group 2). age, blood group, iief-5 score and presence of additional diseases were recorded. erectile functions were analyzed according to blood group. results: there was no difference between the mean age of 111 patients with ed and that of 239 patients without ed included in the study (p = 0.284). there was no difference between patients in the two groups in terms of smoking, alcohol use, hypertension and diabetes (p > 0.05). among patients in the ed group, the mean iief-5 score according to blood group was 19.8 ± 5.04 in the 0 blood group, 16.5 ± 5.2 in the a blood group, 17.2 ± 5.3 in the b blood group and 13.3 ± 3.02 in the ab blood group. the iief-5 scores of individuals in the 0 blood group were significantly high compared to individuals in other blood groups (p = 0.004). logistic regression analysis found that compared to the 0 blood group, the erectile dysfunction risk was 3.9 times greater for the a blood group, 3.5 times greater for the b blood group and 4.7 times greater for the ab blood group (p = 0.001) (table 3). conclusion: the risk of erectile dysfunction was significantly increased for individuals in the a, b and ab blood groups compared to individuals in the 0 blood group. key words: ab0 blood group; erectile dysfunction; vascular disease. submitted 6 may 2016; accepted 31 may 2016 summary no conflict of interest declared. factors such as aging, hypertension, diabetes, smoking, central obesity and dyslipidemia increasing the risk of atherosclerotic coronary artery disease (cad) are also important risk factors for ed. for both cad and ed, early indicators of the common vascular disease of atherosclerosis may occur in erectile tissue (2, 3). the relationship between ab0 blood groups and some diseases was first reported by alexzender for the first time in 1921 (4). later studies have reported a close relationship between vascular diseases like coronary artery disease and thrombosis, and also a variety of cancers such as pancreatic and bladder cancer (5, 6). according with the demonstrated correlation with many vascular diseases, the correlation between ab0 blood groups and another vascular disorder such as ed has not been investigated. in this study we aimed to investigate whether there was a correlation between ab0 blood groups and erectile dysfunction. materials and methods the data belonging to 972 patients applying to our clinic from april 2012 to april 2015 were retrospectively investigated. the study included 350 patients with age, blood group, ieff-5 score and presence of additional diseases recorded. permission was obtained from the local ethics committee of ordu university (decision no. 2015/1). the exclusion criteria for the study included congestive heart failure, hyperprolactinemia, hypogonadism, renal function disorders, peripheral or autonomic neuropathy, psychiatric problems and treatment for sexual function disorders. patients were divided into two groups; those requiring treatment due to lack of or to unsustained erections (ed group) and those with problem-free sexual relations (control group). the erectile functions of patients were determined using the international index of erectile function-5 (iief-5). each question on this from is scored from 1 to 5. if the patient could not fill out the form, help was given by the same person. the total iief-5 score is calculated by adding the scores (from 1-5) given to 5 questions. according to total points sexual function was defined as normal (22-25), mild (17-21), moderate (12-16) and severe dysfunction (1-11). doi: 10.4081/aiua.2016.4.270 introduction erectile dysfunction (ed) is defined as either continuous or repeated lack of erection, or lack of sustained erection, necessary for satisfying sexual relations (1). the penis includes a very rich and specialized vascular system. the complete endothelium furnishing this vascular system plays an important role in erectile tissue function. disruption of the complete endothelial may cause development of atherosclerotic vein diseases, in addition to affecting erectile functions. studies have shown that risk benli_stesura seveso 09/01/17 09:52 pagina 270 271archivio italiano di urologia e andrologia 2016; 88, 4 ab0 blood types and erectile dysfunction results the mean age of all patients included in the study was 62.34 ± 8.51 (41-84) years. the mean age of the 111 patients in the ed group was 63.05 ± 8.5 (41-84) years, while the mean age of patients in the control group without ed complaints was 62 ± 8.5 (43-84) years. there was no difference between the groups in terms of age (p = 0.284). apart from cardiac disease, there was no difference between patients in the ed group and those in the non-ed group in terms of demographic characteristics (table 1). the distribution of individuals with erectile dysfunction in terms of blood groups is shown in table 2. the mean iief-5 score of patients in the ed group according to blood group was found as 19.8 ± 5.04 for 0 blood group, 16.5 ± 5.2 for a blood group, 17.2 ± 5.3 for b blood group and 13.3 ± 3.02 for ab blood group. the mean iief-5 score for individuals with the 0 blood group was identified to be significantly high compared to other blood groups (p = 0.004). the presence of ed was found in 15.7% of patients with 0 blood group, in 41.6% of patients with a blood group, in 39.3% of patients with b blood group and in 46.7% of patients with ab blood group (p < 0.001). logistic regression analysis showed that compared to the 0 blood group the risk of erectile dysfunction was 3.9 times increased for a blood group, 3.5 times increased for b blood group and 4.7 times increased for ab blood group (p = 0.001) (table 3). statistical analysis descriptive statistics for continuous variables are given as mean, standard deviation, minimum and maximum values, while for categorical variables these are given as number and percentage. to determine whether there was a difference in ed presence for continuous variables, the student t test was performed. to determine the correlation between categorical variables, the chi-square test was used. additionally to determine the possible risk factors affecting erectile dysfunction, multiple logistic regression analysis was performed. for calculations the level of statistical significance was taken as 5% and calculations used the spss (ver. 13) statistical package program. discussion the results of our study found a relationship between ed and ab0 blood groups and ed was identified to have increased incidence in a, b and ab blood groups compared to 0 blood group. the clearly increased ed risk in the ab blood group may be related to the synergic effect caused by the presence of a and b antigens together. the increased risk identified in the study using multivariate analysis shows the ed risk is independent of promoting factors such as alcohol, smoking and hypertension. the penis, with a very rich vein network, is one of the richest organs in terms of endothelium per unit area (7). healthy endothelium releases material with antifibrinolytic and anticoagulant properties, as well as strong vasodilatator materials like no. disruption of the completeness of the endothelium disrupts these functions and synthesis of vasoconstrictor materials like thromboxane a2, endotelin, and angiotensin 2 increases. additionally loss of the permeability and antithrombocyte properties of endothelium is proposed to trigger the atherosclerotic process (8). as a result, studies related to atherosclerotic vascular diseases have frequently used measurements of endothelial functions. diseases that form a risk for vascular disease, like hypertension, hypercholesterolemia, diabetes and obesity, affect the endothelin in the vein walls, by affecting homeostasis function (9). as a result the process beginning with endothelial disruption is reported to show itself in a variety of diseases such as angina, stroke and cad where tissue perfusion is disrupted (9, 10). the degree of endothelial dysfunction is related to the severity of these diseases experienced by the patient (11). endothelial dysfunction is shown to be an effective factor in the development of ed (12). this effect is thought to be due to effects on the vein elasticity of erectile tissue and on the release of endothelial factors like no released by endothelium (13, 14). a study by davignon et al. proposed table 1. demographic characteristics of participants in the research. characteristics ed n (%) p-value (present/absent) present absent alcohol present 9 (33.7) 18 (66.7) 0.832 absent 101 (31.6) 219 (68.4) smoking present 38 (33) 77 (67) 0.728 absent 73 (31.2) 161 (68.8) diabetes present 26 (37.7) 43 (62.3) 0.289 absent 84 (31) 187 (69) hypertension present 37 (33.3) 74 (66.7) 0.711 absent 73 (31.1) 162 (68.9) cardiac disease present 29 (43.9) 37 (56.1) 0.27 absent 82 (73.9) 202 (84.5) table 2. distribution of blood groups in ed. blood group erectile dysfunction n (%) present absent 0 blood group 21 (18.9%) 113 (47.3) a blood group 52 (46.8) 73 (30.5) b blood group 24 (21.6) 37 (15.5) ab blood group 14 (12.6) 16 (6.7) table 3. results of logistic regression analysis. odds ratio (or) 95.0% c.i. p-value lower upper age 1.009 .979 1.040 0.556 a blood group 3.949 2.143 7.279 0.001 b blood group 3.504 1.712 7.173 0.001 ab blood group 4.742 1.960 11.473 0.001 or: odds ratio; ci: confidence interval. for blood group 0 is the reference category. benli_stesura seveso 09/01/17 09:52 pagina 271 archivio italiano di urologia e andrologia 2016; 88, 4 e. benli, a. çırakoğlu, e. öğreden, s. demir, y. kaya, m. i̇bas, a. ayyıldız, a. yüce 272 that one of the earliest indicators of atherosclerosis is changes in no activity (15). thus, ed is thought to occur as a part of the systemic vascular disease of atherosclerosis (16). many studies on this topic have shown a close relationship between ed and vascular diseases. in fact, some studies have proposed ed is the first symptom of systemic vascular disease. montorsi et al. in a study reported that problems related to ed began 3 years before the occurrence of coronary artery disease, while ponholzer et al. reported such problems began 10 years before stroke (17, 18). while explaining the reasons for this, the researchers used the artery diameter hypothesis. according to this hypothesis, as the size of penile arteries (1-2 mm) is small compared to coronary arteries (3-4 mm), the same level of atherosclerotic/endothelial damage causes greater reduction in perfusion in erectile tissue compared to coronary or other veins (19). as a result ed may occur in erectile tissue as the first indicator of systemic atherosclerosis (20, 21). researchers have proposed that erectile tissue may be a sensitive indicator of systemic atherosclerotic diseases (7). the reason for the relationship between ab0 blood groups and ed identified in our study may be related to endothelial dysfunction and related atherosclerosis occurring in erectile tissue. many studies supporting this hypothesis have shown a relationship between atherosclerotic vascular diseases and ab0 blood groups (1). atherosclerotic vascular diseases like myocardial infarct, peripheral vascular diseases, intermittent claudication, and venous thromboembolism are reported to be encountered more frequently in the non-0 blood groups compared to the 0 blood group (22, 23). a study by carpenggiani et al. investigated the blood groups of 4901 patients undergoing coronary angiography due to atherosclerotic cad and reported that atherosclerotic coronary disease was most frequently observed in non-0 blood groups (24). this conclusion may explain our results. probably blood groups cause atherosclerotic results or endothelial dysfunction leading to development of ed. the reason for the relationship between ab0 blood groups and atherosclerotic vascular diseases is not fully known. the genetic nature of the ab0 blood groups may affect this. there are many hypotheses to explain this situation. one of these is the atp-binding cassette 2 (abca2) gene known to be important for cholesterol balance and carried in the 9q34 locus of chromosome 9 together with ab0 blood groups (25, 26). the study by carpeggiani et al. identified a significant relationship between non-0 blood group and hypercholesterolemia and family history (24). in human and animal models, hypercholesterolemia is shown to disrupt smooth muscle relaxation linked to endothelium, enzyme activity of endothelial nitric oxide synthesis (enos) and penile angiogenesis resulting in ed (16, 27). another hypothesis is related to adhesion molecules such as sicam-1 (high soluble intercellular adhesion molecule-1), spselectin (soluble p-selectin) and se-selectin (soluble eselectin) which affect ab0 blood groups and are thought to cause endothelial disruption (28). another opinion gaining great interest is related to blood groups affecting von willebrand factor (vwf) and factor 8 levels causing development of atherosclerosis (29). these factors, known as adhesion molecules, are reported to be effective on thrombocyte leukocyte interaction, adhesion of thrombocytes to veins, migration of leukocytes into veins and development of atheroma plaque; in short on the development of atherosclerosis (30, 31). studies have identified higher vwf and f8 levels in individuals with a and b blood groups compared to 0 blood group (32, 33). the study by sarode et al. reported that a and b blood groups were effective on adhesive activity of vwf (34). again a study by ray et al. on acute coronary syndrome and a study by convay et al. on thromboemboli and stroke diseases reported a close relationship between ab0 blood group and vwf (35, 36). in short there are many studies in the literature showing the close relationship between ab0 blood groups and atherosclerotic vascular diseases (37). in fact a study by kaya et al. reported that ab0 blood groups may be related to the complications of atherosclerosis, in addition to the development of atherosclerosis (38). in our study, a, b and ab blood groups were found to be related to the risk of a person experiencing erectile dysfunction. as mentioned in many studies above, due to the relationship shown between vascular diseases and ab0 blood groups, the relationship with ed thought to be a vascular disease is not surprising. we consider that this effect progresses through endothelial dysfunction and atherosclerotic processes. we consider that endothelial damage affects synthesis of a variety of materials like no known to play an important role in erections, disrupts the effect of endothelium on vascular tonus, narrows the venous lumens due to atherosclerosis and finally affects blood flow to erectile tissue. there are some limitations to this study. these include its retrospective nature, reflecting results from a single center and that laboratory results from patients including lipid profile, serum f8 and vwf level were not examined. conclusion this study found a close relationship between a, b and ab blood groups and ed. we believe this correlation is due to effect of the complicated process resulting in endothelial dysfunction, similar to the correlation previously reported for blood groups and atherosclerotic events. in spite of 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2000; 109:857-64. 35. ray kk, francis s, crossman dc. measurement of plasma von willebrand factor in acute coronary syndromes and the influence of abo blood group status. j thromb haemost. 2004; 2:2053-4. 36. conway ds, pearce la, chin bs, et al. plasma von willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 1321 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors. circulation. 2002; 106:1962-7. 37. tarján z, tonelli m, duba j, et al. correlation between abo and rh blood groups, serum cholesterol and ischemic heart disease in patients undergoing coronarography. orv hetil. 1995; 136:767-9. 38. kaya a, tanboga ih, kurt m, et al. relation of abo blood groups to coronary lesion complexity in patients with stable coronary artery disease. anadolu kardiyol derg. 2014; 14:55-60. correspondence erdal benli, md (corresponding author) drerdalbenli@gmail.com abdullah çırakoğlu, md dr_cirakoglu@yahoo.com ahmet yüce, md ahmetyuce7@gmail.com department of urology, ordu university, faculty of medicine, ordu, turkey ercan öğreden, md 9isik061@mynet.com department of urology, giresun university, faculty of medicine, giresun, turkey selamettin demir, md drselami1978@hotmail.com clinic of urology, istanbul hospital, van, turkey mustafa i̇bas, md ibasmustafa91@hotmail.com intern, necmettin erbakan university, faculty of medicine, konya, turkey ali ayyıldız, md urology52@gmail.com clinic of urology, ankara training research hospital, ankara, turkey benli_stesura seveso 09/01/17 09:52 pagina 273 stesura seveso 101archivio italiano di urologia e andrologia 2016; 88, 2 original paper metabolic assessment of recurrent and first renal calcium oxalate stone formers basri çakıroğlu 1, erkan eyyupoğlu 2, aydin ismet hazar 3, bekir sami uyanik 4, barış nuhoğlu 3 1 department of urology, hisar intercontinental hospital, umraniye, istanbul, turkey; 2 department of urology, amasya sabuncuoğlu serefeddin training and research hospital, amasya, turkey; 3 department of urology, taksim training and research hospital, gaziosmanpasa, turkey; 4 department of clinical biochemistry, hisar intercontinental hospital, umraniye, istanbul, turkey. objectives: this study aimed to demonstrate the dominant role of metabolic disorders in the formation of calcium oxalate stones in patients with recurrent urolithiasis, as well as in patients experiencing their first episode of urolithiasis. patients and methods: the records of the patients who attended our kidney stone outpatient clinics between 2008 and 2012 were reviewed, and the data of 318 calcium oxalate stone patients who had undergone a metabolic assessment were retrospectively analysed. the patients were divided in two groups. the first group included the patients who presented with their first episode of urolithiasis (group 1, n = 170), and the second group included patients with recurrent urolithiasis (group 2, n = 148); intergroup comparisons of metabolic disorders were performed. results: a significant difference was found between the two groups in mean urine calcium levels (group 1, 0.25; group 2, 0.31; p = 0.001); the mean serum calcium level was found to be significantly higher although at less extent in group 2 (group 1, 9.4; group 2, 9.6); p = 0.04). significant differences were also found in mean urine citrate (group 1, 481.9; group 2, 397.2, p < 0.0001) and oxalate levels (group 1, 22.1; group 2, 28.5; p < 0.0001) . conclusions: this study revealed a metabolic tendency to hypercalciuria in calcium oxalate stone patients, predominantly in those with recurrent calcium oxalate urolithiasis. urinary oxalate excretion was found to be higher in recurrent urolithiasis in comparison to the first episode of calcium oxalate urolithiasis and urinary citrate excretion lower in recurrent urolithiasis. key words: kidney stone; calcium oxalate; first episode; recurrent. submitted 18 june 2015; accepted 4 december 2015 summary no conflict of interest declared. occur within the first five years after the first episode of urolithiasis (1). calcium oxalate stones (caox) are the most common type of urinary stones (60% pure calcium oxalate stones and 20% mixed stones) (2, 3). we decided to analyse the metabolic states of our patients with caox urolithiasis since our sample size was adequate to have a significant evaluation. urine volumes and urine components both give an indication about the health of the kidneys and constitute a collective indicator of complex body functions, all interacting with each other. therefore, we tried to achieve an understanding about the metabolism of the patients who presented with a first episode of urolithiasis and with recurrent caox urolithiasis by interpreting their 24-hour urine analyses (2, 3-5). materials and methods study population the admissions/follow-up records of 3,500 patients who attended two different kidney stone outpatient clinics of two different departments of urology between 2008 and 2012 were reviewed in order to achieve an adequate sample size to investigate any differences between the patients who presented with the first episode of urolithiasis and patients with recurrent urolithiasis, regarding metabolic abnormalities underlying idiopathic caox stones. a total of 2,653 cases at the first episode and 847 cases of recurrent urolithiasis were identified. stone analyses were performed using a fourier transform computed infrared (ft-ir) spectrometer. caox stones (including monohydrate and dehydrate calcium oxalate, pure or mixed wirh apatite) were detected in 176 patients who experienced their first episode of urolithiasis and in 210 patients with recurrent urolithiasis. anamnesis, past medical history, previous surgery, and medication use that had been recorded in the patient files were reviewed in terms of exclusion criteria. exclusion criteria included age younger than 18 years; missing height and weight data; use of thiazide, triamterene, or loop diuretics; use of potassium or potassium citrate; use of other antihypertensive agents; diabetes, hyperlipidemia, coronary heart disease, stroke, or doi: 10.4081/aiua.2016.2.101 introduction today, about 10% of the male population and 5% of the female population suffer from kidney stone disease, which is more prevalent between 30 to 40 years of age. the recurrence rate in patients who recover from a firs kidney stone episode, either spontaneously or through intervention, was found to be about 4% to 5% per year; based on this percentage, the cumulative rate of recurrence will be 75% within 20 years. most recurrences archivio italiano di urologia e andrologia 2016; 88, 2 b. çakıroğlu, e. eyyupoğlu, a. ismet hazar, b. sami uyanik, b. nuhoğlu 102 the use of chronic disease medications such as anticoagulants and vasodilators; having a solitary kidney; corticosteroid use; being on treatment for osteoporosis; known parathyroid disease or known disorders of aminoacid or carbonhydrate metabolism; use of gout medications; a history of gastrointestinal surgery; thyroid disorders and oncologic diseases; being on dialysis; urinary tract obstructions and abnormalities (ureteropelvic stenosis, horseshoe kidney, etc.). finally, the data for a total of 318 patients who met the inclusion criteria were analysed: 170 first-episode patients were included in group 1 and 148 patients with recurrent disease were included in group 2. for metabolic assessment blood and urine samples were randomly collected during asymptomatic periods, in order to obtain results that might reflect the common dietary habits of the patients; the samples of the patients who underwent surgery or shock wave lithotripsy (swl) were obtained one and a half month after the procedure. standard methods were used to collect 24-h urine samples in plastic containers that did not react with urine, and the samples were stored at 2-8° c. volume, ph, and density of the urine, as well as the creatinine, uric acid, calcium, sodium, potassium, phosphate, oxalate, citrate and magnesium concentrations were determined. in addition, these two groups were compared to each other in terms of the blood urea, creatinine, uric acid, calcium, sodium, potassium, phosphate, magnesium, parathormone, and vitamin d3 levels, if available. furthermore, the urine citrate/creatinine (cit/crea), calcium/citrate (ca/cit), phosphorus/creatinine (p/crea), calcium/creatinine, and oxalate/creatinine ratios were assessed and the two groups were compared to each other regarding these ratios. statistical analysis not every parameter could be studied for each individual patient, due to the retrospective design of the study. however, the data that reflected the mean value for each group were compared to each other. descriptive data were tabulated and box plot graphs and bivariate linear regression models were used. spss 12.0 (spss inc. chicago, il, usa) statistical software package was used to analyse the data, which were tested by an independent t-test to determine the significance of the differences between the mean values of the groups; the levene test was used to assess the equality of the variances. a p < 0.05 value was considered statistically significant. in addition, the data were pooled and pearson’s correlation test was used to test whether there was a correlation between the urinary metabolites of the patients with idiopathic caox urolithiasis and the ratios of these metabolites to each other. results a significant difference was found between the two groups in age (group 1, 32.5 years; group 2, 36.8 years; p = 0.004).however, the female/male ratios were similar in the two groups (group 1, 1.92; group 2, 2.16; p > 0.05). mean body mass index was found to be higher in group 2 (24.2 years/26.1 years; p > 0.05). urine volumes were similar (group 1, 1795; group 2, 1777; p > 0.05). a significant difference was found between the two groups in urine calcium levels (group 1, 0.26; group 2 2, 0.32; p = 0.001), while the serum calcium level was found to be significantly higher in group 2 (group 2, 9.4; group 2, 9.6; p = 0.04), although this difference was less significant than the difference in the urine. significant differences were also found in urine citrate (group 1, 481.8; group 2, 397.1; p < 0.0001) and oxalate (group 1, 22.1; group 2, 28.5; p < 0.0001) levels. no statistically significant differences were found between the two groups in serum parathormone (group 1, 43.3; group 2, 48.2; p > 0.5) and vitamin d3 (group 1, 23.5; group 2, 23.9; p > 0.5) levels. no significant difference was found between the two groups in the urine ph (group 1, 6.9; group 2, 5.7; p > 0.5), urine sodium (group 1, 165.7; group 2, 166.1; p > 0.5), and urine magnesium (group 1, 0.8; group 2, 0.4; p > 0.5) levels. however, there was a significant difference between the two groups in urine potassium levels (group 1, 41.5; group 2, 46.9; p < 0.05). the 24-hour urinary excretion of calcium was higher than normal in patients with recurrent urolithiasis (310 mg), and 24-hour figure 1. box plots of 24 hr urinary oxalate excretion in firsttime and recurrent urolithiasis. urine volume was lower than 2 litres in both groups. no cases of hyperoxaluria and hypocitraturia were detected. in addition, a statistically significant difference was found between the two groups in the urinary cit/crea ratio (p < 0.05), and the difference between the two groups in ca/cit ratio was strongly significant (p < 0.001). the differences between the two groups in urinary p/crea (p < 0.05), ca/crea (p < 0.05), and ox/crea ratios (p < 0.05) were also statistically significant (table 1) (figures 1-4). 103archivio italiano di urologia e andrologia 2016; 88, 2 metabolic assessment of recurrent and first renal calcium oxalate stone formers figure 2. box plots of 24 hr urinary calcium excretion and calcium/citrate ratio in first-time and recurrent urolithiasis. figure 3. box plots of 24 hr urinary potassium and creatinine excretion in first-time and recurrent urolithiasis. figure 4. correlations between 24 hr urinary oxalate and calcium excretion in the cases with urolithiasis. archivio italiano di urologia e andrologia 2016; 88, 2 b. çakıroğlu, e. eyyupoğlu, a. ismet hazar, b. sami uyanik, b. nuhoğlu 104 discussion we could not find a comprehensive review on the metabolic assessment of the patients presenting with the first episode of idiopathic cacox urolithiasis in spite of the presence of a number of studies of 24-hour urine and spot urine regarding nephrolithiasis (6-13). therefore, our study probably address a relevant question. although the retrospective design of the study may be considered a limitation, meticulous attention given to the inclusion-exclusion processes and lack of interventions that may occur in an ongoing study prove the reliability of this study. demographics data of our patients show an age difference between the recurrent group and first-episode group that may be considered as related to the characteristics of the groups; sex distribution was comparable between the groups although bmi was higher in group 2. in relation to metabolic assessment, we focused on mean 24 hour urine volumes that were less than 2 litters in both groups and mean urinary calcium of recurrent stone formers that was higher than 300 mg (hypercalciuria). fluid intake is closely related to supersaturation and acidic ph (14) and the importance of fluid intake in the prevention of recurrences has been demonstrated in randomized prospective studies (15). in a previous comprehensive study of patients with recurrent urolithiasis, the metabolic abnormalities associated with recurrent urolithiasis were found to be (listed in a decreasing order) hypercalciuria, low urinary volume, hypocitraturia, hyperoxaluria, and hyperuricosuria, and their incidences were found to be 65%, 62%, 41%, 38%, and 24%, respectively (15). urine volume was not mentioned in another study of the metabolic abnormalities in patients experiencing their first episode of urolithiasis and in patients with recurrent urolithiasis. in this study the observed metabolic abnormalities were hypocitraturia, hypercalciuria, hyperoxaluria, and hyperuricosuria (listed in a decreasing order) with reported incidences of 45%, 39%-43%, 32%-33%, and 29%-23%, respectively (16). in the first-episode group and in the recurrent group, the mean daily amounts of citrate and oxalate excreted in urine were found to be 481 ± 188 mg versus 397 ± 146 mg and 22 ± 9 mg versus 28 ± 12 mg. the mean values of these parameters did not suggest the presence of hyperoxaluria and hypocitraturia since the mean daily amount of oxalate excreted in the urine was less than 40 mg and the mean daily amount of citrate excreted in the urine was more than 300 mg. hyperoxaluria may occur via three ways: increased oxalate production (primary hyperoxaluria), increased hepatic turnover and increased oxalate absorption. a mild metabolic hyperoxaluria may be observed in 37% of the patients with idiopathic caox urolithiasis. hyperoxaluria has been explained by pyridoxine deficiency. when dietary oxalate restriction failed to treat hyperoxaluria, oral supplementary calcium may be given to reduce intestinal oxalate absorption and pyridoxine may also be used empirically for this purpose. mean serum calcium level was found as 9.44 ± 0.89 mg/dl in group 1 (n = 167) and 9.63 ± 0.71 mg/dl (reference range: 8.5-10.5 mg/dl) in group 2. these values were within normal limits and the p value of the difference between two groups was found to be less than 0.05. changes in urine acidity are as important as urine volume in the formation and recurrence of urinary stones (17, 18) but no statistically significant difference was found between the two groups in urine ph (urine ph 6.9 and 5.7, respectively) (p > 0.05). the levels of urinary magnesium, which lower the urinary free oxalate amount by forming complexes with oxalate, were found to be 165 ± 52 meq/day in group 1 (42) and 166 ± 46meq/day in group 2 (30) and no significant difference was found between the mean values detected in the first-episode and in the recurrent group (p > 0.05). daily urinary magnesium reference range was 50-150 mg/day in our study. however, the difference in magnesium variances indicated that low magnesium was more important in the recurrent group. hyperuricosuria is another important issue. urinary levels of uric acid higher than 750 mg in non-acid-preserved 24-hour urine are considered as a risk factor. in our study hyperuricosuria was found in 7% of the samfirst-time recurrent p mean ± sd mean ± sd value age (years) 32,5 ± 12,9 36,8 ± 13.6 **0.004 volume, urine (ml/d) 1795 ± 567 1777 ± 570 0.802 ph, urine 6.0 ± 0.7 5.8 ± 0.8 0.359 calcium, serum (mg/dl) 9.4 ± 0.9 9.6 ± 0.7 *0.040 uric acide, serum(mg/dl) 5.5 ± 1.3 5.8 ± 1.4 0.143 creatinine, serum (mg/dl) 0.75 ± 0.21 0.78 ± 0.23 0.228 parathormone, serum(pg/ml) 43.3 ± 18.5 48.2 ± 33.6 0.135 vitamin d3(25-oh), serum(ng/ml) 23.5 ± 10.9 23.9 ± 14.0 0.780 creatinine, urine (g/d) 0.75 ± 0.21 0.78 ± 0.23 0.720 calcium, urine (g/d) 0.26 ± 0.13 0.32 ± 0.15 **0.001 phosphorus, urine (g/dl) 1.05 ± 0.57 0.89 ± 0.40 *0.012 potassium, urine (meq/d) 41.5 ± 8.9 46.9 ± 10.9 *0.037 sodium, urine (meq/d) 165.7 ± 52.6 166.2 ± 46.2 0.973 magnesium, urine(g/d) 0.70 ± 0.46 0.51 ± 0.37 0.204 cystin, urine (mg/d) 481.8 ± 188.7 397.1 ± 146.3 0.807 citrate, urine (mg/d) 481.8 ± 188.7 397.1 ± 146.3 ***0.000 oxalate, urine (mg/d) 22.1 ± 9.9 28.5 ± 12.4 ***0.000 calcium/creatinine(g/g crea) 0.16 ± 0.9 0.28 ± 0.23 *0.049 calcium/citrate (g/g citrate) 0.65 ± 0.46 1.02 ± 0.74 ***0.000 phosphorus /creatinine (g/g crea) 0.82 ± 0.31 0.64 ± 0.19 *0.010 citrate/creatinine (mg/g crea) 501.6 ± 181.4 337.7 ± 191.4 **0.006 oxalate/creatinine (mg/g crea) 19.7 ± 5.8 23.8 ± 5.9 *0.023 table 1. laboratory data in first-time and recurrent urolithiasis. student’s t test: significance (p): * < 0.05, ** < 0.01, ***< 0.001 ns: not significant ples that we tested for uric acid, and this result was not consistent with the data in the medical literature. therefore, the mean urinary uric acid levels, which were found as 480 mg mg in group 1 and 550 in group 2, were not included in the discussion. mean levels of uricemia in our patients were also in the normal range (group 1, 5.51 ± 1.37, n = 122 and group 2, 5.78 ± 1.43, n = 114), and similar (p = 0.14) in the two groups. however, we still want to put emphasis on the studies suggesting that hyperuricosuria might be a major risk factor for recurrent stone formation when associated with a low urinary ph (9, 18). recent studies have also demonstrated that the metabolic syndrome characterized by obesity, hyperlipidemia, hypertension and diabetes might be associated with a higher incidence and increased severity of kidney stone disease (19). conclusion mean values, standard deviations, and variances were used to compare the metabolic values of the patients experiencing their first episode of calcium oxalate urolithiasis and patients with recurrent urolithiasis, and to analyse these data on the basis of the reference ranges accepted in the literature. from this perspective, while the serum values were quite similar, the major difference in the urinary metabolites was in calciuria that was higher in patients with recurrent urolithiasis. although there was a difference between the groups in the amount of oxalate excreted in urine, the mean values in both groups were found to be lower than 40 mg per day. these data are relevant for preventive treatment and indicate that pharmacotherapy is not required in patients who present with the first episode of urolithiasis. in consideration of the increasing incidence of stone disease and the importance of prophylactic treatment, we believe that the reference values and the values that indicate a metabolic risk should be partially revaluated. references 1. maloney me, springhart wp, ekeruo wo, et al. ethnic background has minimal impact on the etiology of nephrolithiasis. j urol. 2005; 173:2001-2004. 2. cakiroglu b, dogan an, tas t, et al. a case of recurrent renal aluminum hydroxide stone. case rep urol. 2014; 2014:212314. 3. wilson dm. clinical and laboratory approaches for evaluation of nephrolithiasis. j urol. 1989; 141:770-774. 4. worcester em, coe fl. clinical practice. calcium kidney stones. n engl j med. 2010; 363:954-963. 5. pak cyc. sould patients with single stone ocurrence undergo diagnostic evaluation. j urol. 1962; 127:855. 6. tefekli a, esen t, ziylan o, et al. metabolic risk factors in pediatric and adult calcium oxalate urinary stone formers: is there any difference? urol int. 2003; 70:273-7. 7. parvin m, shakhssalim n, basiri a, et al. the most important metabolic risk factors in recurrent urinary stone formers urol j. 2011; 8:99-106. 8. moreira dm, friedlander ji, hartman c, et al. using 24-hour urinalysis to predict stone type. j urol. 2013; 190:2106-11. 9. sakhaee k, capolongo g, maalouf nm, et al. metabolic syndrome and the risk of calcium stones. nephrol dial transplant. 2012; 27:3201-9. 10. taylor en, curhan gc. determinants of 24-hour urinary oxalate excretion. clin j am soc nephrol. 2008; 3:1453-60. 11. cameron ma, sakhaee k. uric acid nephrolithiasis. urol clin north am. 2007; 34:335-46. 12. negri al, spivacow r, del valle e, et al. clinical and biochemical profile of patients with "pure" uric acid nephrolithiasis compared with "pure" calcium oxalate stone formers. urol res. 2007; 35:247-51. 13. fink ha, wilt tj, eidman ke, et al. medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an american college of physicians clinical guideline. ann intern med. 2013; 158:535-43. 14. yagisawa t, chandhoke ps, fan j. comparison of comprehensive and limited metabolic evaluations in the treatment of patients with recurrent calcium urolithiasis. j urol. 1999; 161:1449-52. 15. borghi l, meschi t, amato f, et al. urinary volume, water and recurrences of idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. j urol. 1996; 155:839-843. 16. eisner bh, sheth s, dretler sp, et al. abnormalities of 24-hour urine composition in first-time and recurrent stone-formers. urology. 2012; 80:776-9. 17. curhan gc, willett wc, speizer fe, stampfer mj. twentyfour-hour urine chemistries and the risk of kidney stones among women and men. kidney int. 2001; 59:2290-8. 18. dent ce, senior b. studies on the treatment of cystinuria. br j urol. 1955; 27:317-32. 19. cho st, jung si, myung sc, kim th. correlation of metabolic syndrome with urinary stone composition. int j urol. 2013; 20:208-13. this article of ethical approval istanbul gaziosmanpaşa taksim training and research hospital local ethical committe no; 30.03.2015.e.p.k.k no.18 105archivio italiano di urologia e andrologia 2016; 88, 2 metabolic assessment of recurrent and first renal calcium oxalate stone formers correspondence basri çakıroğlu, md (corresponding author) drbasri@gmail.com department of urology, hisar intercontinental hospital saray mah.siteyolu cad. no.7 34768 umraniye, istanbul, turkey erkan eyyupoğlu, md department of urology, amasyasabuncuoğluserefeddin training and research hospital, amasya, turkey aydin ismet hazar, md barış nuhoğlu, md department of urology, taksim training and research hospital, gaziosmanpasa, turkey bekir sami uyanik, md department of clinical biochemistry, hisar intercontinental hospital umraniye, istanbul, turkey stesura seveso archivio italiano di urologia e andrologia 2015; 87, 18 original paper sexual dysfunctions after transurethral resection of the prostate (turp): evidence from a retrospective study on 264 patients carlo pavone, daniela abbadessa, giovanna scaduto, giovanni caruana, cristina scalici gesolfo, dario fontana, luigi vaccarella section of urology, department of surgical, oncological and stomatological sciences, university of palermo, italy. objectives: benign prostatic hyperplasia (bph) and sexual dysfunctions are diseases with a high prevalence in aged men. several studies have found a link between bph and luts resulting from deterioration in sexual function in men aged 50 years and older for whom turp is considered the gold standard. the impact of turp on sexual functions still remain uncertain, nor is it clear what pathophysiological mechanism underlying the emergence of new episodes of erectile dysfunction (ed) following turp in patients with normal sexual function before surgery, while retrograde ejaculation and ejaculate volume reduction represent a clear side effect; derived from bph treatment. the aim of this study was to retrospectively evaluate the effects of transurethral resection of the prostate (turp) on sexual function in patients operated in the period 2008-2012 at the department of urology of the university hospital p. giaccone, and at villa sofia-cervello hospitalpalermo. secondary objective was to reconnect the sample data to interventional practice and international standards. materials and methods: the retrospective longitudinal study was conducted on 264 of the 287 recruitable patients, aged between 50 and 85 years, suffering from bph who underwent to turp in the period 2008-2012. telephone interviews were conducted and the international index of erectile function (iief) was administered to assess sexual function. patients enrolled were asked to respond to the test by referring at first to their sexual status in the period before surgery and subsequently to the state of their sexual function after treatment so as to obtain, for each patient, a preand post-turp questionnaire in order to get comparisons that corresponding to reality and to avoid overestimation of the dysfunctional phenomenon. results: in the pre-turp, the 94.32% of the sample reported being sexually active, with good erectile function in 41.3% of cases, ed mild/moderate in 51.5% and complete ed in 1, 5% of cases; good libido in 62.9% of cases, lack of libido in 31.4% of cases and absent in 5.7% of cases (the latter data corresponded to patients not sexually active); to be sexually satisfied in 29.5% of cases, slightly dissatisfied in 11, 7% of cases, moderately in 35.3% of cases, dissatisfied and very dissatisfied in 23.5% of cases (of which 17.8% sexually active and 5.7% non-active).in the post-turp 89.4% of the sample summary no conflict of interest declared. introduction benign prostatic hyperplasia (bph) and sexual dysfunctions are disorders that occur with high prevalence in aged men. several studies have found a link between low urinary tract symptoms (luts) due to bph and deterioration of sexual function in men over the age of 50 (1) and for which transurethral resection of the prostate (turp) is considered the gold standard treatdoi: 10.4081/aiua.2015.1.8 reported being sexually active, with good erectile function in 39.1% of cases, de mild/moderate in 46.9% and complete de in 4% of cases; good libido in 53.8% of cases, lack of libido in 33.7% of cases and absent in 13.5% of cases (including 1.9% of sexually active and 10.6% of non-active); to be sexually satisfied in 29.5% of cases, slightly dissatisfied in 9.5% of cases, moderately in 35.3% of cases, dissatisfied and very dissatisfied in 17.8% of cases (of which 14.8% sexually active and 10.6% inactive). retrograde ejaculation was referred in 47.8% of those sexually active after turp (42.8% if we consider the whole sample). conclusions: turp had no negative impact on erectile function in contrast to ejaculatory function. of the109 patients with good erectile function in pre-turp, 5.8% reported a worsening of erectile function after turp. among the 136 patients with ed moderate/mild pre-turp 3.7% reported a worsening in the post-turp, 16.2% reported an improvement, while 9.5% stopped any sexual activity. in 3.7% of the cases a complete ed was reported after turp, while a decline of libido and sexual satisfaction was detected in all patients with worsening of sexual function. retrograde ejaculation was observed in 48% of those sexually active after turp. particular attention has to be paid to the psychological aspects, bothbefore surgery and in the postoperative period, which may become an important factor in the decline of sexual activity. key words: benign prostatic hyperplasia (bph); erectile dysfunction (ed); transurethral resection of the prostate (turp), international index of erectile function (iief); low urinary tract symptoms (luts). submitted 30 july 2014; accepted 30 august 2014 pavone_stesura seveso 02/04/15 10:14 pagina 8 9archivio italiano di urologia e andrologia 2015; 87, 1 sexual dysfunctions after transurethral resection of the prostate (turp): evidence from a retrospective study on 264 patients ment despite the new minimally invasive surgical options (2, 3). however, the impact of turp on sexual function still remain uncertain and contradictory, with a number of patients who actually refers new episodes of ed following endoscopic resection (4). nor is it clear what pathophysiological mechanism is underlying the emergence of new episodes of ed after turp in patients with normal sexual function before surgery. recent studies have shown that the treatment of luts by turp lead to an overall improvement of sexual function in patients suffering from ed and ejaculatory discomfort existing before surgery, and that this proportion of patients is still higher than that of those who have any kind of sexual disorders as a result of turp (5, 6). similar considerations also apply to other aspects of sexual function, such as libido, ejaculatory orgasm and comfort, with the exception of retrograde ejaculation and ejaculate volume reduction which represent a clear side effect derived from bph treatment. several comparative studies that have linked sexual outcomes after turp with those obtained with the use of new minimally invasive techniques have also shown similar results except for retrograde ejaculation (7). however, to date none of these new techiniques in respect to turp in the treatment of bph (8). therefore primary objective of this study was to understand if the sexual dysfunction’s area, especially erectile dysfunction, should be considered severable from the long-term complications of endoscopic resection surgery as the more recent literature would seem to indicate. secondary objective was to connect our data to surgery good practice and international standards. materials and methods at the departmentof urology of the university hospita “p. giaccone” and the “villa sofia-cervello” hospital of palermo, according to the inclusion criteria listed in table1, was conducted a longitudinal retrospective study on a group of 287 recruitable patients who underwent to turp after diagnosis of bph from january 2008 to december 2012 (table 1). the patient list was obtained by consulting university hospital’s electronic archives and by verification of villa sofia-cervello hospital’s records. all patients were contacted by telephone and, after explaining the purpose of the study, they were interviewed after obtaining consent to participate in total anonymity about the sensitive data. telephone interviews were conducted and the international index of erectile function (iief) was administered to assess sexual function. patients enrolled were asked to respond to the test by referring at first to their sexual status in the period before surgery and subsequently to the state of their sexual function after treatment so as to obtain, for each patient, a preand a post-turp questionnaire in order to get information about outcomes corresponding to reality and avoid over estimation of dysfunctional phenomenon. speculation about libido, its eventual decay and overall satisfaction derived from sexual intercourse may also allow to have a complete picture of the psychological component of sexual health and to hypothesize the impact on the recovery of sexual function after surgery. results of the 287 patients recruitable, 23 were lost for various reasons (refusal to join the study, health status deteriorated, inability to understand the questions and/or not compliance to the test, patients not found by phone). therefore, the sample was composed of 264 patients aged between 50 and 85 years. to overcome the bias “age” related to the time frame of the study (5 years), the average age of the sample was calculated to t0 (before-turp) = 67.9 years and t1 (after-turp) = 71.3 years. of the 264 patients enrolled, 249 (94.32%) reported having been sexually active in the pre-turp and at iief 109 (41.3%) reported adequate erectile function; 136 (51.5%) reported episodes of mild or moderate ed; while only 4 cases (1.5%) reported complete erectile dysfunction (figure 1). also before-turp, libido (figure 2) was reported as good in 166 patients (62.9%), while it was poor in 83 patients (31.4%) in combination with mild to moderate ed. the 15 patients (5.7%) not sexually active claimed that they had no sexual desire, and we have no other data about the status of their sexual function. regarding the satisfaction derived from sexual activity preturp (figure 3), among the sexually active patients: 78 (29.5%) were satisfied; 31 (11.7%) were slight dissatisfied; 93 (35.3%) were moderately dissatisfied; the remaining 47 (17.8%) showed a severe degree of dissatisfaction. the sexually active patients in the post prostatic resection period were 236 (89.4%) and at iief: 103 (43.6%) reported a satisfactory erection capacity; 124 (52.5%) a moderate or mild ed; while the presence of complete erectile dysfunction was found in 9 individuals (3.8%) (figure 4). following turp, 89 patients (37.7%) among those sexually active had low libido; in 28 patients (10.6%) who had not had sexual intercourse after surgery, libido was absent. furthermore, while in 4 patients suffering from severe ed before surgery was not found a decreased libido, in 5 new cases of ed following turp was present a total decay of sexual desire (figure 5). after turp, 89 patients (37,7%) among sexually active ones had low libido; no libido was present in 28 patients (10,6%) who had not had sexual intercourses after operation. moreover while no decrement of libido was detected in 4 patients with complete ed before surgery, in 5 new cases of ed after turp a complete decrement of sexual desire was found (figure 5). after operation 78 patients (29,5%) kept on being satisfied; 25 patients (9,5%) were a little unsatisfied; 94 (35,6%) mildly unsatisfied; 39 sexually active patients (14,8%) were highly unsatisfied, as well as 13 patients table 1. inclusion criteria. – aged between 50 and 85 years – suffering from bph and luts symptoms – undergoing turp in the period january 2008 december 2012 – compliance to the interview and iief pavone_stesura seveso 02/04/15 10:14 pagina 9 archivio italiano di urologia e andrologia 2015; 87, 1 c. pavone, d. abbadessa, g. scaduto, g. caruana, c. scalici gesolfo, d. fontana, l. vaccarella 10 figure 1. erectile function before-turp. figure 2. sexual desire before-turp. figure 3. sexual satisfaction before-turp. figure 4. erectile function after-turp figure 5. sexual desire after-turp. pavone_stesura seveso 02/04/15 10:14 pagina 10 11archivio italiano di urologia e andrologia 2015; 87, 1 sexual dysfunctions after transurethral resection of the prostate (turp): evidence from a retrospective study on 264 patients who stopped sexual activity after operation and became not sexually active. absence of ejaculation or an important dicrease of ejaculated volume, before surgery, were seen after turp in 113 patients (47.8% considering the sexually active patients; 42.8% considering the whole sample). discussion the survey about the sexual dysfuncions before and after surgery for bph allowed to obtain post-surgical outcomes scientifically verified. it is noteworthy (figures 1 and 4) that 103 of 109 patients with good sexual function before turp maintained the same state of functionality after operation, in contrast to 6 patients who referred a low or mild decrement. however, considering the average age of the sample, there is the doubt that this decrement may be related to increasing age, as the epidemiological data suggest. comparing our data pre and post-turp (figure 7) we may infer there are no significant variations in erectile function. in addition we found that in 22 (16.2%) of 136 patients with low/mild ed pre-turp little improvements of the frequency of dysfunctional episodes were detected. even the percentage of patients with mild/low ed reporting a noteworthy pejorative change of the sexual condition in the questionnaire about the post-operative period is restrained: only 13 (9.5%) of 136 initial patients stopped any sexual activity after operation. in these patients, considering the retrospective study, there is no way to evaluate the possible onset of functional worsening but we may suppose the onset of (psychological vicious circle) major psychological agitation related to operation. a further factor making us to think there might be a possible psychological cause for the decrement of sexual function in patients with luts in bph, and eventually also in the same patients after surgical therapy, was the finding of a contemporary decrement of libido. in 83 (61%) of 136 patients who already had a mild/low ed before surgery, a poor sexual desire was detected in association with a low satisfaction from sexual intercourse. several authors have explained this situation (9), finding out a condition of psychophysical discomfort due to symptoms of bph, that could act on the patient's feeling of a disease state. such feeling, that often lasts more than the moment of surgery and, therefore, the subsequent overcoming of symptoms, would affect the sexual desire significantly, inducing setbacks on frequency and quality of patient's sexual activity. moreover, a further decrement of libido has been always detected in 24 patients who referred a worsening of their sexual function after operation, in terms of higher incidence of ed and interruption of sexual activity (figure 8). in similar studies (10) analogous data have been related to a psychological effect due to operation itself that may interfere with consciousness of own sexual capacity (11). figure 6. sexual satisfaction after-turp. figure 7. changes in sexual function after-turp. pavone_stesura seveso 02/04/15 10:14 pagina 11 archivio italiano di urologia e andrologia 2015; 87, 1 c. pavone, d. abbadessa, g. scaduto, g. caruana, c. scalici gesolfo, d. fontana, l. vaccarella 12 the satisfaction derived from sexual intercourse, highly connected to the capacity of completing the sexual intercourse successfully, indeed, decreases with the increase of frequency of ed episodes, and it expires in patients who have a complete ed or no sexual activity. considering other specific aspects of sexual functionality, the patients did not report any problems in the orgasm or in a possible painful or late ejaculation when they had a complete sexual intercourse. on the contrary, as we expected, the failed ejaculation or a considerable decrement of ejaculation volume, not present in the preoperative period, were detected in 47.8% of sexually active patients after turp (the 42.8% of sample). these conditions are caused by the operation of prostatic resection that wreaks a lesion of closure mechanism of bladder neck during ejaculation with consequent retrograde ejaculation. it is important to underline that the absence of a normal ejaculation might be felt as a deficiency of patient's sexual capacity what does not allow him to complete normally a sexual intercourse. therefore this functional consequence of turp would deserve higher attention during the preoperative counselling (12). it must be emphasized that the data referred to cases of patients with complete ed pre-turp (1.6% of total preturp sexually active patients, 1.5% of sample) are compatible with indexes of incidence of the phenomenon in the general population (figure 9) (13, 14). at the same time, the increase of number of completely dysfunctional patients after turp (3.4% of sexually active patients after turp), among patients who had ed already before therapy, may not be indicative of a possible damage caused by the surgery. in fact, this condition should be related with patients' age, as a consequence of the ageing or other newly occurring diseases during the period of observation, in some cases as long as 5 years. several authors have reported some peri-operative complications after turp, such as drilling of prostatic capsule or a not well known effect of thermal lesion on the surrounding nervous structures, may represent important risk factors for the progress of ed in the short or long term (15). through our survey it was not possible to determine if such complication has presented. however, not detecting significant data about a higher presence of de novo ed episodes after turp is somehow re-assuring, considering the frequency of these peri-operative complications in the surgical reality. finally, the data about a low im proving of erectile function in a restricted group of patients of our sample, condition detected in other similar studies (5), do not allow to confirm an effective benefit to sexual health in its various aspects due to the operation of figure 9. effect of varying degrees of ed in the general population (adapted by writers from data by feldman ha et al., 1994 and lyngdorf p. et al., 2004). figure 8. association between decreased libido and impaired sexual function. pavone_stesura seveso 02/04/15 10:14 pagina 12 13archivio italiano di urologia e andrologia 2015; 87, 1 sexual dysfunctions after transurethral resection of the prostate (turp): evidence from a retrospective study on 264 patients prostatic resection. moreover, in our sample the frequency of sexual dysfunction significantly from the incidence of dysfunctional situation in the general population with same age. in addition it must be said there is an over-evaluation of the sexual deficit considered consequent to turp, because we were not able to search the presence of contemporary diseases and risk factors that notoriously may influence adversely the sexual activity. however, turp is demonstrated to influence adversely none of sexual health aspects, except for ejaculatory function. since in case of ed a variable level of decrement of libido was always detected, we might consider the psychological aspect may have a certain importance in dysfunctional patients, even when it is not the “primum movens”. conclusions the identified concordance between the latest literature about this thorny topic and our results, although with the limits of a retrospective study, allows us to deduce a common consciousness of the effects of turp on sexual function is going to be gleaned. from the analysis of our data no direct correlation between ed and the most used surgical therapy for bph is found out. always considering the effects on ejaculation, that by now notoriously affect a large proportion of patients, the turp is in any case the gold standard in the treatment of symptomatic prostatic adenoma. it derives that the specialist can indicate turp with science and consciousness as a preferential option of treatment for patients who ask for this kind of therapeutic approach, wishing anyway a recovery of their sexual life. it is apparent that the specialist must pay particular attention to the psychological implications, both in the preoperative and in the postoperative time, that may start a vicious circle and become cause, in some cases primary cause, of the decay with consequent avoidance of sexual activity in this kind of patients. according to actual researches, the patient can be reassured and correctly taught about the real possibilities of recovery and/or improvement of his own sexual function. in addition it would be desirable requiring assessments to evaluate the patient's sexual history before the prostatic resection that might help doctor (and patient himself) to understand what results will be present in the post-operative period. that means a specialist's higher consciousness who, relating with the patient at the time of the choice of the best therapeutic option, will be able to choose turp, confident to guarantee with good probability a correct recovery of sexual functionality in the post-operative time in the post-operative time, clearly just in case it was previously satisfying previously and the requirements and conditions were adequate. references 1. rosen r1, altwein j, boyle p, et al. lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (msam-7). eur urol. 2003; 44:637-49. 2. reich o, gratzke c, stief c. techniques and long-term results of surgical procedures for bph. eur urol. 2006; 49:970-8 (discussion 978). 3. donovan jl, peters tj, neal de, et al. a randomized trial comparing transurethral resection of the prostate, laser therapy and conservative management in men with symptoms associated with benign prostatic enlargement: the clasp study. j urol. 2000; 164:65-70. 4. tscholl r, largo m, poppinghaus e, et al. incidence of erectile impotence secondary to transurethral resection of benign prostatic hyperplasia, assessed by preoperative and postoperative snap gauge tests. j urol. 1995; 153:1491-3. 5. van moorselaar rja, hartung r, emberton m, et al. alfuzosin 10 mg once daily improves sexual function in men with lower urinary tract symptoms and concomitant sexual dysfunction. bju int. 2005; 95:603-8. 6. de rose af, carmignani g, corbu c, et al. observational multicentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. urol int. 2002; 68:95-8. 7. mishriki sf,. grimsley sjs, lam t, et al. turp and sex: patient and partner prospective 12 years follow-up study. bju international. 2012; 109:745-750. 8. brookes st, donovan jl, peters tj, et al. sexual dysfunction in men after treatment for lower urinary tract symptoms: evidence from randomized controlled trial . bmj. 2002; 324:1059-64. 9. muntener m, aellig s, kuettel r, et al. sexual function after transurethral resection of the prostate (turp): results of an independent prospective multicentre assessment of outcome. eur urol. 2007; 52:510-516. 10. ibrahim al, el-malik em, ismail g, et al. risk factors associated with sexual dysfunction after transurethral resection of the prostate. ann saudi med. 2002; 22:8-12. 11. spengler a. psychosexual disorders following genital operations in urology. wien med wochenschr. 1988; 138:81-5. 12. soderdahl dw, knight rw, hansberry kl: erectile dysfunction following transurethral resection of the prostate. j urol. 1996; 156:1354-6. 13. feldman ha, goldstein i, hatzichristou dg, et al. construction of a surrogate variable for impotence in the massachusetts male aging study. j clin epidemiol. 1994; 47:457-467. 14. lyngdorf p, hemmingsen l. epidemiology of erectile dysfunction and its risk factors: a practice-based study in denmark. int j of impot res. 2004; 16:105-111. 15. poulakis v, ferakis n, witzsch u, et al. erectile dysfunction after transurethral prostatectomy for lower urinary tract symptoms: results from a center with over 500 patients. asian j androl. 2006; 8:69-74. correspondence carlo pavone, md, professor (corresponding author) carlo.pavone@unipa.it daniela abbadessa, md giovanna scaduto, md giovanni caruana, md cristina scalici gesolfo, md dario fontana, md, professor dariofontana1987@yahoo.it luigi vaccarella, md section of urology, department of surgical, oncological and stomatological sciences, university of palermo, palermo, italy pavone_stesura seveso 02/04/15 10:14 pagina 13 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 190 case report an unusual case of intrarenal coiled and ruptured guidewire francesca manassero 1, simona ortori 2, cristina gabellieri 1, michela gabelloni 2, cesare selli 1 1 section of urology and 2 section of radiology, department of translational research, university of pisa, italy. objective. to the best of our knowledge there are only 3 reports of fractured guidewires inside the pelvicalyceal system, successfully removed with endourology techniques, and this is the first one presenting a tightly coiled intraparenchymal section. material and methods: a 59-year-old woman was hospitalized for surgical treatment of a right kidney of reduced size. past history revealed pyelolithotomy for a staghorn stone 14 months earlier at another institution with subsequent ureteral obstruction, one failed attempt at ureteral double-j catheter insertion and one failed attempt at percutaneous nephrostomy placement 5 months postoperatively. another nephrostomy was placed, but left indwelling briefly. ct scan demonstrated a small-size kidney with residual stone fragments and presence of a “device” in the lower pole. the tapered distal extremity of an hydrophilic guidewire, with a tightly coiled central section wedged in the renal tissue was found inside the nephrectomy specimen. results: while the radiologist who read the ct scan hypothesized that the “device” was a fragment of double-j ureteral stent or nephrostomy catheter, it consisted of the hydrophilic extremity of a guidewire, broken during a previous attempt at nephostomy placement. perirenal fibrosis and inappropriate angle between the needle and the lower calyx are the likely causes of guidewire coiling during its advancement and subsequent rupture during withdrawal. conclusions. urologists must be aware that, although percutaneous nephrostomy has a very high technical success rate, unusual complications like guidewire fracture may occur, and that modern imaging techniques can provide an accurate picture of this condition. key words: nephrostomy; percutaneous; radiology; interventional; computed tomography spiral; nephrectomy. submitted 12 october 2014; accepted 31 december 2014 summary no conflict of interest declared. endoscopic placement of an ureteral double j stent (1). the reported technical success rate ranges between 98 and 100% in a review dealing with both emergency and routine pcn catheter placement (2). the risk of technical failure is slightly higher in obese patients and in absence of collecting system dilatation, where a success rate of 92 to 96% has been reported (3, 4). the more relevant acute major complications of this endourological procedure consist in sepsis, hemorrhage, vascular injury, bowel and pleural perforation (5). there is surprisingly very little data in the literature concerning long-term complications, mostly related to the presence of intrarenal foreign bodies as a consequence of technical or device failures during the performance of the procedure. case report a 53-year-old woman was admitted for treatment of a right kidney of reduced size. previous history revealed right pyelolithotomy for staghorn stone fourteen months earlier at a district hospital, with postoperative high temperature and early spontaneous dislodgement of the nephrostomy tube. the ureteral double j stent left at surgery was removed after 30 days. two months later the patient presented flank pain and fever and underwent at the same hospital an unsuccessful attempt at endoscopic double j stent placement. sonography revealed moderate dilation of the pelvicalyceal cavities, and 5 months after surgery at the same institution there was one failed attempt of percutaneous nephrostomy placement, followed by a successful one 7 days later. no detailed reports of both procedures were available in the patient medical records. however the pcn catheter was maintained for a few days and then removed. at hospitalization in our institution sequential renal scan with 99 dtpa tecnetium revealed a 19.6% function on the right side and 80.4% on the left. ct scan showed a kidney of reduced size with residual stone fragments and an intrarenal “device” protruding inside the renal cavities at the level of the lower pole, which was judged to be the fractured end of double j stent or nephrostomy catheter by the radiologist who read the scan (figures 1, 2). an open nephrectomy was performed using an anterolateral extraperitoneal approach, and extensive adhesions were found intraoperatively, particularly on the posterior doi: 10.4081/aiua.2015.1.90 introduction percutaneous nephrostomy (pcn) using a fine needle and a guidewire, originally described by gunther et al. is more than thirty years later the more widespread and accepted way to decompress the renal cavities when ureteral obstruction or anatomic conditions preclude the manassero_stesura seveso 02/04/15 10:32 pagina 90 91archivio italiano di urologia e andrologia 2015; 87, 1 an unusual case of intrarenal coiled and ruptured guidewire planes. opening the operative specimen with an incision on the lateral kidney surface, it appeared that the “device” consisted in the tapered distal extremity of an hydrophilic guidewire broken during one of the previous attempts at percutaneous nephrostomy placement (figure 3): the tightly coiled central section was wedged inside the renal tissue. postoperative course was uneventful and the patient was discharged on the sixth postoperative day. discussion to the best of our knowledge, this is the first report of a tightly coiled guidewire inside the renal tissue and the pyelocalyceal system. in a series of 21 retained renal foreign bodies there was only one inner core of a guidewire, successfully removed with a percutaneous approach, and the vast majority (15 out of 21) were ureteral stents. the fracture of a lunderquist guidewire inside the pelvicalyceal system at the junction of the stiff portion with its flexible tip has also been described, and removed percutaneously as well as a fractured and retained cutting acucise wire with stone formation (6-8). a possible cause of guidewire fragmentation during percutaneous renal procedures can also be the inadvertent damage produced by holmium laser (9). since no detailed reports of the two pcn catheter procedures were available in the patient medical records, we can hypothesize that during the first attempt, due to the presence of intense perirenal fibrosis, documented also at surgery, following needle puncture of the lower calyx, further advancement of the guide wire was difficult, due also to an inappropriate angle between the needle and the calyx. when withdrawal was attempted, it resulted in tight coiling of the guidewire and subsequent breakage at the junction between the stiff metallic section and the hydrophilic one. from the imaging point of view the ct scan, particularly the volume rendering, accurately depicted the unusual occurrence of a tightly coiled portion of the guidewire lodged in the thinned renal parenchyma, but the exact nature of the “device” as a guidewire was not preventively determined. however this did not make any difference for the patient, since the kidney needed surgical removal and an endourological retrieval procedure was out of question. conclusions in endourological procedures as in open surgery, a careful assessment of all equipment at the end of the procedure is required, either successful or not, especially of guidewires and laser fibers, used during all the passages to assess for damage and the risk of retained fragments in the urinary tract. a superficial check can result in the foreign body acting as a nidus for infection or stone formation or mimic a renal neoplasm (10-12). the diagnosis and the extraction of retained renal foreign bodies can be challenging for the endourologist. although a retrograde endoscopic approach should be tried first for foreign bodies related to previous endourological procedures, a percutaneous renal access must be considered to treat large stone burden often found on or with these retained objects: we believe in a rational approach where the treatment should be tailored to each patient (13). figure 1. axial ct scan of the right kidney revealing a radiopaque curved structure inside the dilated lower calyx with a wider extremity lodged inside the thinned renal parenchyma. figure 3. appearance of the guidewire distal extremity removed from the nephrectomy specimen, with a densely coiled midportion which was originally located inside the renal tissue of the lower pole. figure 2. volume rendering image of the kidneys, revealing on the right side residual stones and the intrarenal “device”. manassero_stesura seveso 02/04/15 10:32 pagina 91 archivio italiano di urologia e andrologia 2015; 87, 1 f. manassero, s. ortori, c. gabellieri, m. gabelloni, c. selli 92 references 1. gunter r, alken p, altwein je. percutaneous nephropyelostomy using a fine-needle puncture set. radiology. 1979; 132:228-30. 2. millward sf. percutaneous nephrostomy: a practical approach. j vasc interv radiol. 2000; 11:955-64. 3. patel u, hussain ff. percutaneous nephrostomy of non dilated renal collecting system with fluoroscopic guidance: technique and results. radiology. 2004; 233:226-33. 4. maher mm, fotheringham t, lee mj. percutaneous nephrostomy. semin intervent radiol. 2000; 17:329-39. 5. ramchandani p, cardella jf, grassi cj, et al. quality improvement guidelines for percutaneous nephrostomy. j vasc interv radiol. 2001; 12:1247-51. 6. eisenberg mn, lee kl, stoller m. endoscopic management of retained renal foreign bodies. urology. 2009; 73:1189-94. 7. bezirdjian dr, tisnado j, cho sr. percutaneous retrieval of a broken lunderquist guidewire from the pelvicalyceal system. south med j. 1989; 82:1269-71. 8. johnson je, conlin m. calculus formation on a retained acucise wire. urology. 2001; 57:168. 9. biyani cs, powell cs. guidewire fragmentation during holmium:yag laser endopyelotomy. tech urol 1998; 4:51-53. 10. ahn j, trost dw, topham sl et al. retained nephrostomy thread providing a nidus for atypical renal calcification. br j radiol. 1997; 70:309-10. 11. singh v, srinivastava a, kapoor r, et al. can the complicated forgotten indwelling ureteric stents be lethal? int urol nephrol. 2005; 37:541-46. 12. dogra pn, tandon s, ansari ms, et al. suture foreign body granuloma masquerading as renal neoplasm. int nephrol. 2005; 37:27-29. 13. bultitude mf, tiptaft rc, glass jm, et al. management of encrusted ureteral stents impacted in upper tract. urology. 2003; 62:622-26. correspondence francesca manassero, md phd (corresponding author) francy_manassero@hotmail.com cristina gabellieri, md gabelliericristina@interfree.it cesare selli, md c.selli@med.unipi.it department of translational research, section of urology section of urology, university of pisa via paradisa i 56124 pisa, italy simona ortori, md s.ortori@libero.it michela gabelloni, md michelagabelloni@libero.it department of translational research, section of radiology university of pisa, pisa, italy manassero_stesura seveso 02/04/15 10:32 pagina 92 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4278 original paper neoadjuvant chemotherapy versus cystectomy in management of stages ii, and iii urinary bladder cancer mohammed a. osman 1, ayman m. gabr 2, mohammad s. elkady 3 1 general organization for teaching hospitals institutes, egypt; 2 national institute of urology & nephrology, egypt; 3 ain shams university, egypt. purpose: this phase iii trial was de signed to compare the survival benefit, surgical respectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy (arm a), with those treated by radical cystectomy (arm b) in the management of stage ii, iii urinary bladder cancer. patients and methods: for inclusion, patients should have pathologically proven urothelial carcinoma in urinary bladder, clinical stages from t2n0m0 to t4an0m0, patient age less than 65 years, and performance state ≤ 2. additionally, patients should have adequate hematological, renal, and liver functions. arm a patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy, while arm b patients underwent radical cystectomy directly. results: thirty patients had been enrolled in each arm between september 2009 and april 2014 in 3 educational institutes in egypt. the 3 year os (overall survival) for arm a, and b were 60% and 50% respectively. the median os for arm a was 36+ months and that for arm b was 32.5 months. the 3 year progression-free survival (pfs) for arm a, and b were 57% and 43% respectively. the median pfs for arm a was 36+ months and for arm b was 28 months. a subgroup analysis was performed to correlate between 3 year os and predetermined prognostic factors including age, tumor size, pathological stage, and the response to neoadjuvant chemotherapy. the later was performed only in arm a. both treatment arms were tolerated well with mild toxicities profiles. conclusion: neoadjuvant chemotherapy achieved better survival, surgical respectability, with nearly equivalent toxicities when compared with radical cystectomy. key words: neoadjuvant; cisplatin; cystectomy; survival; 3yos; arm a. submitted 14 july 2014; accepted 30 september 2014 summary no conflict of interest declared. incidence of transitional cell carcinoma (tcc) has been increasing while squamous cell carcinoma (scc) has been decreasing. active exposure to tobacco smoke has a strong relationship to tcc. previous studies have reported a 2.6 fold risk of developing bladder cancer in smokers compared to nonsmokers (1). stage ii bladder cancer refers to stages pt2an0m0, where the tumor invades superficial muscularis propria, and pt2bn0m0, where it invades deep muscularis propria. stage iii refers to pt3n0m0, where the tumor invades perivesical tissue, and pt4an0m0, where it invades prostatic stroma, uterus, vagina (2). according to the recent nccn guidelines, the standard management of stages ii, and iii bladder cancer included radical cystectomy, with strong consideration of neoadjuvant chemotherapy (3). a trial conducted by the medical research council and the european organization for research and treatment of cancer randomly assigned 976 patients with locally advanced (t3 or t4a) or high grade muscle-invasive (t2) bladder cancer to undergo either definitive treatment immediately or definitive treatment (surgery or radiotherapy) preceded by three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate. at a median follow-up of 8.0 years, os was significantly greater in the arm randomly assigned to receive neoadjuvant chemotherapy. the authors concluded that, the survival benefit from neoadjuvant chemotherapy conferred a 6% absolute increase in the likelihood of being alive at 3 years (56% vs. 50%), 5 years (49% vs. 43%), and 10 years (36% vs. 30%) (p 0.037) (4). a meta-analysis of ten randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that cisplatin-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in 5% improvement in 5-year survival from 45% to 50% (p 0.016) (5). a subsequent meta-analysis of eight trials used multiagent, cisplatin-based chemotherapy, showed neoadjuvant chemotherapy was associated with a 6.5% absolute benefit in 5-year os (50% vs. 56.5%) (p 0.006) (6). study objective was to compare the survival benefit, surdoi: 10.4081/aiua.2014.4.278 background bladder cancer is the ninth most common cancer throughout the world and is considerably more common in developing countries. recently, it was shown that, osman_stesura seveso 15/01/15 13:09 pagina 278 279archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer gical resectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy with those underwent radical cystectomy in the management of stage t2n0, t3n0, and t4an0 urinary bladder cancer. the primary end point was survival benefit. patients and methods patients were eligible to be enrolled in the study if they had pathologically proven urothelial carcinoma in urinary bladder. patients should have clinical stages from t2n0m0 to t4an0m0 (as defined by ct scan) (7). patient age had to be less than 65 years and performance state had to be ≤ 2. patients should have adequate hematological, renal, and liver functions. written informed consent was taken from patients before enrolment. female patients in the childbearing period must had a negative pregnancy test (serum β-hcg) and both male and female patients must employ effective contraceptive measures prior to start of until four weeks after the last dose of chemotherapy. additionally, patients must had no concurrent malignancy. patients were allocated to either arms; arm a consisted of 3 cycles of neoadjuvant chemotherapy in the form of cisplatin and gemcitabine followed by radical cystectomy, arm b consisted of radical cystectomy. settings the study was conducted at the oncology unit, ain shams university hospitals, ismailia oncology teaching hospital, and national institute of nephrology and urology. the last 2 hospitals are run under the general organization for teaching hospitals institutes, egypt. study design the study design was shown in table 1. the neoadjuvant chemotherapy administration protocol for arm 1 was as follows: 1. cisplatin: pre-chemotherapy, normal saline 0.9% 1 litre over 30-60 minutes, followed by cisplatin iv in normal saline 0.9% 500 ml over 1 hour. postchemotherapy, normal saline 0.9%1 litre, with kcl (potassium chloride) 20meq, mgso4 (magnesium sulphate) 1 gm, and mannitol 30 gm over 1 hour. 2. gemcitabine iv in normal saline 0.9% 250 ml over 30 minutes. cycles of chemotherapy were administered after checking cbc, renal function tests, gfr, liver function tests, bilirubin, before day 1, and 8 of each cycle, with subsequent dose modification based on the following table 2 (7). evaluation baseline ct thoracic-abdominal-pelvic (tap) was performed before treatment protocol at the time of diagnosis. after the end of chemotherapy, patients underwent ct ap to evaluate chemotherapy response (table 3). two weeks after cycle 3 of chemotherapy, patients underwent radical cystectomy, pelvic lymphadenectomy, and urinary diversion, with transurethral resection (tur) prior to the surgery to know the disease extent. after surgery, pathological evaluation was performed to evaluate the chemotherapy response in arm a, and to confirm pathological staging in arm b. follow-up after the end of the treatment protocol, patients were followed according to the nccn guideline for follow-up after bladder cancer treatment; by regular clinic visits every 3 months for the first 2 years, then every 6 months for the following 3 years, then annually thereafter. in each visit, patients were evaluated by history taking, physical examination, laboratory investigations in the form of cbc, liver, renal functions every 3months for the first 2 years then as clinically indicated. ct tap were done every 6 months in the first 2 years, then as clinically indicated (3). toxicity toxic effects were graded according to the national cancer institute common toxicity criteria, version 2.0 (8). early chemotherapy toxicities were defined as toxicities that occurred during treatment till 8-10 weeks post chemotherapy. surgical early morbidities were defined 1. hematology for day 1 of each cycle: neutrophils (10³/ml) platelets (10³/ml) dose ≥ 1 and > 100 100% both 0.5 to 0.99 or 75 to 100 75% of gemcitabine only < 0.5 or < 75 delay both drugs for gemcitabine only day 8: ≥ 1 and > 100 100% 0.5 to 0.99 or 75 to 100 75% < 0.5 or < 75 omit 2. renal function test (gfr) (ml/min) gfr cisplatin dose gemcitabine dose ≥ 60 100% 100% 45 to 59 35 mg/m2 d1+2 100% (same pre-hydration as 70 mg/m2 dose) < 45 delay delay table 1. treatment protocol of the current trial. table 2. dose modification based on hematological, and renal function results. treatment protocol arm 1 arm 2 neoadjuvant chemotherapy; cisplatin (70 mg/m2 day 1), gemcitabine (1250 mg/m2 day 1,8) q 3 weeks for radical cystectomy 3 cycles radical cystectomy osman_stesura seveso 15/01/15 13:09 pagina 279 archivio italiano di urologia e andrologia 2014; 86, 4 m.a osman, a.m. gabr, m.s. elkady 280 as complications that occurred from day 1 postoperative till full recovery from the surgery usually 6-8 weeks postoperative. late toxicities referred to those occurred > 10 weeks after finish of treatment protocol. statistical analysis all calculations were carried out using prism 6 software for windows. all analyses were carried by intention to treat. mean and median values were used for the description of continuous data. for comparison between the 2 group characteristics, t test, and p value were used. overall survival (os) and progression-free survival (pfs) for each arm were analyzed by the kaplan-meier method. further, they were compared using the log rank and wilcoxon tests. os was measured from the time of randomization till death from bladder cancer or the last follow-up visit. pfs was measured from the time of randomization till relapse, or the last follow-up visit. log rank approach and hazard ratio were used to examine the effects of pre-specified prognostic factors including age, tumor size, pathological staging, and pathological response to neoadjuvant chemotherapy on the 3 year os. p value was significant at ≤ 0.05. results between september 2009 and april 2014, 60 patients were enrolled in the current study. 30 patients were assigned to each treatment arm. all patients fulfilled eligibility criteria for enrolment in the current study. the mean age was 50.6 years (range 30-65 years). 56 patients were males, and 4 were females (93.3%, 6.7% respectively). the median performance status was 1 (range 0-2). the mean tumor size was 3.75 cm (range 1.8-5.5 cm). 12 patients had stage t2n0, 38 had stage t3n0, and 10 had stage t4an0. (20%, 63.3%, 16.7% respectively) (table 4). treatment protocol for arm a: all arm a patients received neoadjuvant chemotherapy, and a total of 89 cycles were performed. mean chemotherapy cycles were 3 (range 2-3). to evaluate treatment response, ct ap was checked at mean time of 2.2 weeks after cycle 3 (range 1-3 weeks). neoadjuvant chemotherapy response among the 30 patients enrolled, cr was achieved in 6 patients (20%), pr was observed in 16 patients (53.3%), and sd was in 6 patients (20%). the remaining 2 patients had dp (6.7%). surgery radical cystectomy, pelvic lymphadenectomy, and urinary diversion were performed in 58 out of the 60 patients. for arm a patients, 28 underwent cystectomy, the remaining 2 refused surgery and lost follow-up. of them, 19 had neobladder, 7 ileal conduit, and 2 underwent cutaneous urinary diversion. surgery was done at a mean of 2 weeks after cycle 3 chemotherapy (range 1021 days). the mean admission time for surgery was 8.3 days (range 7-14 days). the average blood loss was 900 ml (range 500-2000 ml). pathological evaluation after cystectomy was done in all the 28 patients. r0 was achieved in all except 2 patients who had r1 disease. pcr (pathological complete remission) (pt0) was achieved in 10 patients (35%), ppr (pathological partial remission) in 12 patients (43%) (8 pt1, and 4 patients pt2). the remaining 6 had sd (stable disease) (22%) (2 pt2, 3 pt3, and 1 pt4). the mean number of dissected pelvic lymph nodes was 15 (range 7-20): 4 patients had positive lymph node biopsies. for arm b, all the 30 patients underwent cystectomy. of them, 18 underwent neobladder, 6 ileal conduit, 5 cutaarm a arm b characteristics number % number % p value age 35-40 40-50 50-60 60-65 mean age 48.9 --52.3 --0.04 sex male female performance status 0 1 2 performance status (mean, median) 0.7, 1 --0.9, 1 --0.1 tumor size 12 cm 2.1-4 cm > 4 cm mean tumor size 3.7 --3.8 --0.1 histopathological grade 1 2 3 grade mean, median 2.5, 3 --2.6, 3 --0.1 tumor stage pt2n0 pt3n0 pt4an0 tumor stage median t3 t3 0.07 table 3. response definitions. table 4. patients and diseases characteristics of each treatment. complete response (cr) complete disappearance of the tumor partial response (pr) 50% or more reduction in the size of the tumor disease progression (dp) 25% or more increase in the size of the tumor stable disease (sd) all other situations 1 20 7 2 3.3% 67% 23% 6.7% 0 14 10 6 0% 47% 33% 20% 0.1 0.1 0.1 0.03 4 17 9 13.3% 56.7% 30% 3 15 12 10% 50% 40% ------3 7 20 10% 23.3% 66.7% 2 6 22 6.7% 20% 73.3% ------6 18 6 20% 60% 20% 8 18 4 26.7% 60% 13.3% ------28 2 93% 7% 29 1 96.7% 3.3% ----11 17 2 36.3% 56.7% 7% 9 16 5 30% 53.3% 16.7% ------osman_stesura seveso 22/01/15 10:20 pagina 280 281archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer neous reservoir, and 1 had cutaneous urinary diversion. surgery was done at mean of 3 weeks after diagnosis (range 17-30 days). the mean admission time for surgery was 7 days (range 6-10 days). the average blood loss was 850 ml (range 4502000 ml). pathological evaluation was done in all the 30 patients. r0 was achieved in 26 patients. the remaining 4 had r1 disease. pathological staging was pt2, pt3, and pt4a in 7, 18, and 5 patients respectively. the mean number of dissected pelvic lymph nodes was 13 and 6 patients had positive lymph node biopsies. adjuvant chemotherapy was given to 4 patients from arm a for positive lymph node in the form of cisplatin and gemcitabine for 3 cycles. additionally, 13 patients from arm b received adjuvant chemotherapy (6 positive lymph nodes, 2 r1, and 5 pt4a) in the form of either cisplatin and gemcitabine, or carboplatin and gemcitabine. (6, and 7 patients respectively), for a mean of 4 cycles (range 3-6). survival data the 3 year os for arm a, and arm b were 60%, 50% respectively (figure 1) . the median os for arm a was 36+ months and that for arm b was 32.5 months. the 3 year pfs for arm a and b were 57% and 43% respectively (figure 2). the median pfs for arm a was 36+ months and that for arm b was 28 months. during the 36 months follow-up period, 11 patients died from arm a (9 bladder cancer relapses, 1 cardiovascular cause, and 1 unknown cause). for arm b, 15 patients died (12 bladder cancer relapses, 2 pulmonary embolism, and 1 unknown cause). during the 36 months follow-up period, 12 patients from arm a relapsed, (9 locoregional, and 3 metastatic), and 17 relapsed from arm b (11 locoregional and 6 metastatic). for subgroup analysis, the 3 year os for arm a patients who were < 60 y.o was 64%, and for those > 60 years was 50%. the 3 year os for arm b patients who were < 60 y.o was 54%, and for those > 60 years was 17%. (p value 0.02, chi square 5.5). the 3 year os for arm a t2 patients was 83%, and for t3-t4a patients was 54.5%. the 3 year os for arm b t2 patients was 75%, and those with t3-t4a was 41% (p value 0.01, chi square 5.7). the 3 year os for arm a patients who have tumors < 4 cm was 70%, and for those > 4 cm was 37.5%. the 3 year os for arm b patients who figure 1. the 3 year os for the study groups p value = 0.05, chi square = 3.66. figure 3. the kaplan-meier survival curve for arm a patients grouped by their pathological response to neoadjuvant chemotherapy. p value = 0.3. figure 2. the 3 year pfs for the study groups p value = 0.02, chi square = 4.88. arm a (%) arm b (%) p value hazard ratio 1. age < 60 years old 64 54 0.02 1.8 > 60 years old 50 17 0.2 1.1 2. pathological stage pt2 83 75 0.05 1.6 pt3-t4a 54.5 41 0.08 1.55 3. tumor size < 4 cm 70 61 0.1 2.0 > 4 cm 37.5 33 0.09 1.2 table 5. the 3 year os for each treatment arm categorized by the prognostic factors. osman_stesura seveso 22/01/15 09:58 pagina 281 archivio italiano di urologia e andrologia 2014; 86, 4 m.a osman, a.m. gabr, m.s. elkady 282 have tumors < 4cm was 61%, and for those > 4 cm was 33% (p value 0.1, chi square 2.2). for the 3 year follow-up for arm a patient, all those who achieved pcr were still alive (100%). of them, only 1 patient relapsed (10%) after 26 months of treatment. for those who achieved ppr, 8 patients were still alive (67%), and 3 died from cancer recurrence. further, 1 patient recurred, and was still alive. for those who achieved sd pathologically, all of them died. (p value 0.0001, chi square 23.3) (figure 3). toxicity profile chemotherapy side effects: for arm a, among the 89 chemotherapy cycles given, dose reduction was done in 10% of cycles for leuconeutropenia. treatment delay was in 10% of cycles. the mean delay time was 1 week (range 1-2 weeks). cisplatin was replaced by carboplatin in the last 2 cycles for 1 patient for persistent low gfr. treatment was stopped in the last cycle in 1 patient for persistent urinary tract infection (uti), and poor general condition. no deaths occurred related to treatment in each group (table 6-7). table 6 summarize grade 3-4 side effects, and their percentage for arm a group. table 7 showed the early surgical complications in both arms and their percentage. all patients who developed early surgical complications recovered smoothly. late toxicities during the 36 months follow-up period, 1 patient from arm a died by congestive cardiac failure at 30 months. further, 1 patient developed impaired renal function from repeated uti and he still alive and did not require dialysis, yet. for arm b patients, 2 patients died from pulmonary embolism (18, 27 months). discussion the role of neoadjuvant chemotherapy in urinary bladder cancer was strongly encouraged in stages pt2-t4a bladder cancer, based on 3 important trials, including that of griffiths et al., 2011, vale et al., 2003, and winquist et al., 2004 (4-6). however, there are still controversies about its impact on survival. griffiths et al., 2011 (4), reported that, neoadjuvant chemotherapy (mvac) slightly improved survival by 6% over 5 years. however, this slight improvement in survival can be attributed to their use of mvac regimen, which was associated with significant toxicity profile (9). the aim of neoadjuvant chemotherapy is to achieve tumor downstaging, improved respectability, and better survival (10, 11). neoadjuvant chemotherapy is considered better than adjuvant chemotherapy in relation to its tolerability, and patients usually receive adequate cycles of neoadjuvant chemotherapy with effective doses. it is still unclear which neoadjuvant chemotherapy regimen offers the best results. in patients with advanced or metastatic tcc the combination of gemcitabine and cisplatin achieved comparable survival results with mvac, and was associated with less toxicity (10). for the current study, although, there was no clear epidemiological trials that reported definite disease characters among the egyptians, our patient cohort, and distribution were nearly equivalent to that of fedewa et al., 2009 (1), which showed the incidence of bladder cancer in the nile delta region of egypt. further, our patients were properly randomized with no significant differences in patient characters between the 2 arms. there were non-statistically significant differences between the 2 groups in relation to age, tumor size, and performance state in favor of arm a. however, the difference in age was statistically significant for the group of patients > 60 years. this was explained by the fact that the investigators tried to avoid giving chemotherapy in older ages to avoid its long term complications , as well as to avoid delay in the definitive surgery especially with larger tumor sizes in this group. in the current trial, the primary end point was survival for neoadjuvant chemotherapy as compared with the standard treatment that is cystectomy. we believed that survival benefit had to be the main concern for trials like ours that treated cancers with curative intent. however, the follow-up period was not long enough to show clear survival benefit over a long period of time. the researchers of the current trial used to define survival in side effect arm a grade 4 (%) grade 3 (%) leuconeutropenia 12.2 2.2 anemia 2.2 --thrombocytopenia 17.8 --febrile neutropneia 2.2 --nausea, vomiting 4.4 ---mucositis 5.5 --others (uti) 7% ---table 6. grade 3-4 side effects, and their percentage for arm a group. side effect arm a grade 4 (%) grade 3 (%) leuconeutropenia 12.2 2.2 anemia 2.2 --thrombocytopenia 17.8 --febrile neutropneia 2.2 --nausea, vomiting 4.4 ---mucositis 5.5 --others (uti) 7% ---table 7. the early surgical complications in both arms and their percentage. osman_stesura seveso 15/01/15 13:09 pagina 282 283archivio italiano di urologia e andrologia 2014; 86, 4 nact versus cystectomy in bladder cancer relation to several subgroup analysis for better evaluation, and to define which subgroup would benefit most from treatment protocol. further, the researchers planed to make an updated report for the survival benefit, and toxicity profile after 5 years, and hopefully after 10 years follow-up periods. for the diversion procedures, although orthotopic diversion was the standard in our institutes, the authors tried to avoid the metabolic complications of orthotopic diversion especially after neoadjuvant cisplatin containing regimen. the current study clearly showed survival benefit for neoadjuvant cisplatin and gemcitabine combination over radical cystectomy. further, the survival was better for each subgroup for arm a over arm b. the current study showed better surgical resectability for arm a patients, when compared with arm b patients. arm a patients had higher r0 number over arm b (100% vs 86% respectively). further, neoadjuvant chemotherapy achieved tumor downstaging in 78% of patients. for toxicity profile, neoadjuvant chemotherapy was tolerated well, and was associated with mild grade 3-4 toxicities. surgery after chemotherapy was associated with very comparable side effects with that of arm b. bleeding complication were relatively higher among the group who received neoadjuvant chemotherapy. for the delayed side effects, the incidence of them was nearly equivalent between the 2 treatment groups. further, reports with relatively longer follow-up durations are needed before confirming that point. conclusion neoadjuvant chemotherapy before cystectomy achieved better survival results, surgical respectability, and nearly equivalent toxicities when compared with radical cystectomy in the management of stage ii, and iii urothelial bladder cancer. references 1. fedewa sa, soliman as, ismail k, et al. incidence analyses of bladder cancer in the nile delta region of egypt. cancer epidemiol. 2009; 33:176-181. 2. edge sb, byrd dr, compton cc, et al. eds.: ajcc cancer staging manual. 7th ed. urinary bladder. new york, ny: springer, 2010, pp 497-505. 3. nccn clinical practice guidelines in oncology, bladder cancer, version 1, 2014, http://www.nccn.org/professionals/physician_gls/ f_guidelines. asp#bladder. 4. griffiths g, hall r, sylvester r, et al. international phase iii trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the ba06 30894 trial. j clin oncol. 2011; 29:2171-2177. 5. vale c, advanced bladder cancer meta-analysis collaboration mrc clinical trials unit: neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. lancet. 2003; 361:1927-1934. 6. winquist e, kirchner ts, segal r, et al. neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. j urol. 2004; 171:561-569. 7. bcca protocol summary for palliative therapy for urothelial carcinoma using cisplatin and gemcitabine. http://www.bccancer. b c . c a / n r / r d o n l y r e s / a 2 4 5 1 2 0 5 5 c 1 3 4 3 3 c a a d e 2e0dc1519d71/67037 /guavpg_protocol_1nov2013. pdf, 2013. 8. common toxicity criteria (ctc) version 2.0, http://www.eortc. be/services/doc/ctc/ctcv20 4-30-992.pdfpublished april 30, 1999. 9. calabrò f, sternberg cn. localized and locally advanced bladder cancer. curr treat options oncol. 2002; 3:413-28. 10. von der maase h, sengelov l, roberts jt, et al. long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin plus cisplatin in patients with bladder cancer. j clin oncol. 2005; 23:4602-4605. 11. herr hw, dotan z, donat sm, bajorin df. defining optimal therapy for muscle invasive bladder cancer. j urol. 2007; 177:437-443. correspondence mohammed a osman, md (corresponding author) mmoneam@hotmail.com oncology consultant, general organization for teaching hospitals institutes egypt ayman m gabr, md keshta64@gmail.com urology consultant, national institute of urology & nephrology, egypt mohammad s elkady, md mselkady@hotmail.com ass. professor oncology, ain shams university, egypt osman_stesura seveso 15/01/15 13:09 pagina 283 introduction the lymphatic drainage of the testis follows the vessels around the spermatic vein until the retroperitoneal nodes between the lower thoracic and lumbar vertebrae. for this reason testicular cancer spreading usually involves the lymph nodes in the retroperitoneum as primary landing site. however, atypical lymphatic sites may be involved and a 2% incidence of inguinal metastases in testicular cancer has been reported (1-4). this atypical spreading has been related to history of previous surgery in the inguinal region or scrotum. a modified lymphatic drainage can be created by surgical violation during orchidopexy, relief of hydrocele or varicocelectomy (5-10). in 47archivio italiano di urologia e andrologia 2012; 84, 4 case report inguinal polypropylene plug: a cause of unusual testicular tumor pelvic metastasis marco grasso 1, salvatore blanco 1, angelica anna chiara grasso 2, luca nespoli 3 1 department of urology, azienda ospedaliera san gerardo, università degli studi di milano-bicocca, monza, italy; 2 department of urology, fondazione irccs ca’ granda ospedale maggiore policlinico, università degli studi di milano, milano, italy; 3 department of general surgery, azienda ospedaliera san gerardo, università degli studi di milano-bicocca, monza, italy. we report the case of a patient who had undergone polypropylene plug placement 3 years before and referred to our institution with testicular tumor. ct scan demonstrated an enlargement of pelvic lymph nodes on the tumor side while retroperitoneal nodes were normal. orchifunicolectomy was performed and histopathological examination showed a mixed germ cell tumor involving the tunica vaginalis, rete testis, epididymis and spermatic cord. after surgery the patient was addressed to adjuvant chemotherapy according to peb scheme. clinical re-staging showed a decrease of the pelvic bulk disease whereas retroperitoneal nodes were still normal and tumor markers were negative. left external, internal and common iliac lymphadenectomy as well as left modified template nervesparing retroperitoneal lymph node dissection was performed. intraoperatively the node bulk was firmly adherent to the external iliac artery and extended until the common iliac bifurcation. in the deeper part of this enlarged and firm lymphatic chain the polypropylene plug placed at the time of hernioplasty was found. behind the plug all retroperitoneal nodes appeared normal and resulted negative on histopathologic examination. the patient had an unusual metastatization, probably due to the plug. key words: testicular tumor; polypropylene plug; metastasis. submitted 2 november 2012; accepted 31 december 2012 no conflict of interest declared summary these cases direct lymphatic drainage to the inguinal nodes can be developed. we report a case of unusual lymphatic spreading of testicular cancer after previous hernioplasty in which a polypropylene plug was deeply placed into internal inguinal ring according to the the lichtenstein tensionfree mesh onlay repair (11). case report a 26 years old man was examined on march 2001 for left testicular mass which appeared as clinically malignant. he grasso_stesura seveso 18/04/13 12:06 pagina 47 archivio italiano di urologia e andrologia 2012; 84, 4 m. grasso, s. blanco, a.a.c. grasso, l. nespoli 48 lene plug placed at the time of hernioplasty was found (figure 3). behind the plug all retroperitoneal nodes appeared normal and resulted negative on histopathologic examination. external iliac and otturatory lymph nodes however showed large tissue necrosis and focal mature teratoma. after 3 years the patient underwent left inguinal lymphadenectomy for lymphnodes enlargement. hystopathologic examination showed no recurrent cancer. at the last follow-up the patient was healthy and free of disease, father of a child spontaneously conceived two years ago. discussion inguinal hernioplasty represents one of the most frequently performed surgical operations. the recent introduction of prosthetic mesh made bassini operation obsolete, with more space gained by the newly developed “tension -free” and “sutureless” surgical technique (12, 13) the study proposed by gandolfo showed the tissutal reaction consequent to the plug. at ultrasonography the mesh presented as a small hyperechoic layer. in some patients a seroma was present above the mesh. the seroma disappeared spontaneously between 30 and 90 days postoperatively and was probably related to the size of the hernia and the number of plugs (14). various studies analyzed the factors associated with postoperative complications and hernia recurrence (15). in about 2% of cases testicular cancer lymphatic metastatization is atypical and includes inguinal lymph nodes (1-4). this unusual lymphatic spreading may happen for a significant variation of an otherwise normal anatomical pattern. it has been clearly reported in literature that in almost all cases of atypical lymphatic metastatization patients had previously undergone scrotal or inguinal surgery (orchidopexy, relief of hydrocele, trans-scrotal biopsy or varicocelectomy) (5-10). however, lymphnode metastases in the inguinal region can be found in patients with no previous surgery, mostly in patients with germ cell tumours, and these are probably due to infiltration from metastases of the spermatic cord (9, 16). in our case of atypical node metastatization, the lymphathad undergone lichtenstein tension-free mesh onlay repair by a “plug” technique three years before. alpha-fetoprotein (normal range 0-15 iu) and beta-hcg (normal range 0-5 iu) were both raised to 9.9 iu and 15 iu, respectively. ct scan showed bulk disease of pelvic lymph nodes on the left side while retroperitoneal nodes were normal (figure 1). orchifunicolectomy was performed and histopathological examination showed a mixed germ cell tumor involving the tunica vaginalis, rete testis, epididymis and spermatic cord. after surgery the tumor markers were still raised. the patient was addressed to adjuvant chemotherapy according to peb scheme. clinical re-staging showed a decrease of pelvic bulk disease, retroperitoneal nodes still normal and negative tumor markers. left external, internal and common iliac lymphadenectomy as well as left modified template nerve-sparing retroperitoneal lymph node dissection was performed (figure 2). intraoperatively the node bulk was firmly adherent to external iliac artery and extended until the common iliac bifurcation. in the deeper part of this enlarged and firm lymphatic chain the polypropyfigure 1. ct scan showing bulk disease of pelvic lymph nodes on the left side. figure 2. retroperitoneal lymph node dissection. figure 3. polypropylene plug found in the deeper part of the enlarged and firm lymphatic chain. grasso_stesura seveso 18/04/13 12:06 pagina 48 49archivio italiano di urologia e andrologia 2012; 84, 4 inguinal polypropylene plug: a cause of unusual testicular tumor pelvic metastasis node metastases following a torek orchiopexy. urology. 1983; 21:300-1. 6. herr hw, silber i, martin dc. management of inguinal lymph nodes in patients with testicular tumors following orchiopexy, inguinal or scrotal operations. j urol. 1973; 110: 223-45. 7. klein fa, whitmore wf jr, sogani pc, et al. inguinal lymph node metastases from germ cell testicular tumors. j urol. 1984; 131:497-500. 8. nishimoto k, ono h, hirayama m, et al. inguinal lymph node metastasis from contralateral testicular origin. urology. 1993; 41:275-7. 9. stein m, steiner m, suprun h, robinson e. inguinal lymph node metastases from testicular tumor. j urol. 1985; 134:144-5. 10. wheeler js jr, babayan rk, hong wk, krane rj. inguinal node metastases from testicular tumors in patients with prior orchiopexy. j urol. 1983; 129:1245-7. 11. lichtenstein il, shore jm. simplified repair of femoral and recurrent inguinal hernias by a "plug" technic. am j surg. 1974; 128:439-44. 12. leardi s, navarra l, pietroletti r, et al.the use of prosthetic meshes in the surgical treatment of inguinal hernia: the costs and profits for the local health screening unit. minerva chir. 1998; 53:581-5. 13. nathan jd, pappas tn. inguinal hernia: an old condition with new solutions.ann surg. 2003; 238(6 suppl):s148-57. 14. gandolfo l, donati m, privitera a, et al. ultrasound tissue modifications after polypropylene prosthesis apposition in inguinal hernia. chir ital. 2007; 59:835-41. 15. richard d. matthews et al. factors associated with postoperative complications and hernia recurrence for patients undergoing inguinal hernia repair: a report from the va cooperative hernia study group. am j surg. 2007; 194:611-617. 16. daugaard g, karas v, sommer p. inguinal metastases from testicular cancer. bju int. 2006; 97:724-726. ic spreading was very unusual since it only involved nodes in the pelvic area. this can be explained by the alteration of normal lymphatic drainage pattern in the spermatic cord during inguinal hernioplasty as well as during tissue healing in the post-operative period. the polypropylene plug deeply placed in the internal inguinal ring might have played a role in the alteration of the normal lymphatic circulation in the spermatic cord. the blockage of normal lymphatic up-flow probably caused a chronic extravasation and created new lymphatic communications with the pelvic nodes. as a consequence, the bulk pushed the plug deeper, up to the common iliac bifurcation. the absence of involved nodes above confirms the lymphatic barrier effect caused by the plug. another point of discussion is the left inguinal node enlargement that occurred three years later. as above mentioned, the inguinal node involvement in cases of previously scrotal or inguinal surgery or in cases of locally advanced disease is well known. for this reason the patient underwent inguinal lymphectomy, without evidence of disease. the treatment of these rare cases is matter of debate. on one hand mianne does not consider ipsilateral node dissection necessary, owing to the efficacy of primary or secondary chemotherapy in non seminomatous testicular tumors, while for testicular seminoma, he suggests additional inguinoscrotal radiotherapy (2). on the other hand van ahlen considers as therapy of choice the adjiuvant chemotherapy and salvage lymphadenectomy in case of residual tumor, including peri-iliac lymphadenectomy (3). conclusion in the case reported we stress that a polypropylene plug located near iliac vessels could induce an important tissutal reaction and alter the lymphatic flow, with the consequent metastatic involvement of pelvic nodes preserving the common iliac and paraortic nodes. in this case the massive local diffusion of the disease could allow a simple diagnosis, but nowadays in many cases the lymph nodes involvement is only microscopic, therefore not clinically evaluable. on the other hand the use of propylene plug for hernioplasty is very frequent. we think that is mandatory to consider the opportunity of extending surgical or radiant approach to iliac and obturator region in patients suffering from testicular germ cell cancer if they had previously underwent hernioplasty with polypropylene plug. references 1. stein m, steiner m, suprun h, robinson e. inguinal lymph node metastases from testicular tumor. j urol. 1985; 134:144-53. 2. mianne dm, barnaud p, altobelli a, et al. inguinal lymphatic metastasis of cancer of the testis: staging and therapeutic approach. ann urol. 1991; 25:199-202. 3. van ahlen h, von stauffenberg, porst h, vahlensieck w. inguinal metastasis of stage i testicular tumors. urologe a. 1988; 27:275-8. 4. daugaard g, karas v, sommer p. inguinal metastases from testicular cancer. bju int. 2006; 97:724-6. 5. crawford ed, cain dr, black wc, borden ta. inguinal lymph correspondence marco grasso, md grasso.m@virgilio.it salvatore blanco, md sblanco_74@yahoo.it luca nespoli, md l.nespoli@hsgerardo.org azienda ospedaliera san gerardo, via pergolesi 33 20900 monza, italy angelica anna chiara grasso, md (corresponding author) fondazione irccs ca’ granda ospedale maggiore policlinico via della commenda 15 20100 milano, italy angelica_grasso@yahoo.it grasso_stesura seveso 18/04/13 12:06 pagina 49 stesura seveso 1archivio italiano di urologia e andrologia 2014; 86, 1 original paper antioxidant cosupplementation therapy with vitamin c, vitamin e, and coenzyme q10 in patients with oligoasthenozoospermia yoshitomo kobori, shigeyuki ota, ryo sato, hiroshi yagi, shigehiro soh, gaku arai, hiroshi okada department of urology, dokkyo medical university, koshigaya hospital, japan. objective: overproduction of reactive oxygen species results in oxidative stress, a deleterious process that damages cell structure as well as lipids, proteins, and dna. oxidative stress plays a major role in various human diseases, such as oligoasthenozoospermia syndrome. materials and methods: we evaluated the effectiveness of antioxidant co-supplementation therapy using vitamin c, vitamin e, and coenzyme q10 in men with oligoasthenozoospermia. overall, 169 infertile men with oligoasthenozoospermia received antioxidant therapy with 80 mg/day vitamin c, 40 mg/day vitamin e, and 120 mg/day coenzyme q10. we evaluated spermiogram parameters at baseline and at 3 and 6 months of follow-up. results: significant improvements were evident in sperm concentration and motility following coenzyme q10 therapy. treatment resulted in 48 (28.4%) partner pregnancies, of which 16 (9.5%) were spontaneous. significant improvements in sperm cell concentration and sperm motility were observed after 3 and 6 months of treatment. conclusions: vitamin c, vitamin e, and coenzyme q10 supplementation resulted in a significant improvement in certain semen parameters. however, further studies are needed to empirically determine the effect of supplementation on pregnancy rate. key words: vitamin c; vitamin e; coenzyme q10; male infertility. submitted 27 august 2013; accepted 5 october 2013 summary introduction there is much evidence to show that oxidant radicals and reactive oxygen species play a harmful role in human reproduction and male infertility (1). testicular oxidative stress is important in a number of conditions known to be detrimental to male infertility. these include a broad spectrum of diseases and conditions due to lifestyle factors such as smoking, alcohol, and obesity (2), environmental hazards such as pestino conflict of interest declared. cides, plasticizers, and heavy metals (3), systemic infections (4), chronic diseases and inflammation such as diabetes, chronic renal failure, and varicocele (5), and a number of iatrogenic or idiopathic causes (6). a previous open, controlled pilot study of a cohort of infertile men with idiopathic asthenozoospermia showed that exogenous administration of coenzyme q10 (coq10) increases the level of both coq10 and ubiquinol (qh2) in semen and is effective in improving sperm kinetics (7). in addition, administration of vitamins e and c significantly reduced hydroxyguanine levels in spermatozoa and led to an increased sperm count (8). we previously found that a relatively low intake of coq10 (30-60 mg/day) improved semen parameters (unpublished data). these data encouraged us to assess the possible effectiveness of this therapeutic approach by conducting a 6month trial of cosupplementation antioxidant therapy (vitamin c, vitamin e, and coq10) in a cohort of infertile men with idiopathic oligoasthenozoospermia. change in semen parameters and achievement of pregnancy were evaluated after 6 months of treatment. materials and methods patients a total of 169 consecutive patients (mean age 36, range 25-58 years) with idiopathic oligoasthenoteratozoospermia were enrolled in the study. all presented with infertility after at least 2 years of unprotected intercourse. male infertility was diagnosed if one or more standard semen parameters were below the cutoff levels according to the criteria of the world health organization, 1999 (sperm concentration < 20 ! 106/ml, sperm motility < 50%, normal morphology < 30%, and/or semen volume < 2 ml) based on at least two semen analyses performed 3 months apart to eliminate accidental and possible adverse effects of exogenous factors on spermatogenesis. after providing a complete medical and reproductive history exploring all aspects that might be related to fertility, patients underwent physical examination and doi: 10.4081/aiua.2014.1.1 kobori_stesura seveso 26/03/14 10:10 pagina 1 archivio italiano di urologia e andrologia 2014; 86, 1 y. kobori, s. ota, r. sato, h. yagi, s. soh, g. arai, h. okada 2 serum chemical and hematological laboratory tests. testicular volume was measured using an orchidometer. serum follicle stimulating hormone, luteinizing hormone, and testosterone levels were measured in all patients. patients with infection, liver dysfunction, renal dysfunction, or a metabolic disease (e.g., diabetes mellitus) were excluded, as were patients with malignant neoplasm and those with spouses with diseases or conditions that may affect conception. study design all patients underwent antioxidant therapy with 120 mg coq10, 80 mg vitamin c, and 40 mg vitamin e daily (two tablets of so support; partners, yokohama, japan). semen parameters were evaluated before and at 3 and 6 months of treatment with co-supplementation. pregnancy outcome and use of assisted reproduction technology was evaluated after 3 and 6 months of treatment. ethics all patients provided informed consent. the study design was approved by the institutional review board. statistical analysis statistical analysis was performed using spss 17.0 (spss inc., chicago, il). data are expressed as mean ± sd values. differences between groups were estimated using the paired t-test. p < 0.05 was considered statistically significant for hypothesis testing. results baseline patient characteristics are shown in table 1. the mean duration of infertility was 2.3 years. table 2 shows mean (± sd) semen parameters before and at 3 and 6 months of treatment. the t-test performed on single variables for the homogeneity at baseline showed that there were no significant differences regarding atypical sperm cells and semen volume. on the contrary, significant improvements in sperm cell concentration and sperm motility were observed after 3 and 6 months of treatment. a total of 48 (28.4%) pregnancies were achieved, including 16 (9.5%) spontaneous pregnancies as follows: seven after 3 months, eight after 6 months, and one after 9 months of treatment. overall, 32 pregnancies were achieved using assisted reproductive technology. six couples used artificial insemination by husband (aih), eight couples used conventional in vitro fertilization (ivf) and 18 couples used intracytoplasmic sperm injection (icsi). oral administration of coq10, vitamin c, and vitamin e was generally well tolerated, and no adverse effects or laboratory abnormalities were observed. discussion several approaches have been proposed for the management of infertility caused by oxidative stress. once an individual has been identified as having oxidative stressrelated infertility, treatment should be aimed at identification and amelioration of the underlying cause before considering antioxidant treatment. lifestyle behaviors such as smoking, poor diet, alcohol abuse, pollution and environmental toxins, obesity, and psychological stress have all been linked to oxidative stress. while the effectiveness of eliminating these lifestyle triggers on oxidative stress has not been formally tested, it is likely that characteristic range mean ± sd age (yrs) 25-58 36 ± 9 age of wife (yrs) 22-44 34 ± 8 serum hormones testosterone (ng/dl) 169-988 406 ± 88 lh (iu/l) 1.1-11.5 3.5 ± 2.4 fsh (iu/l) 1.6–26.8 5.0 ± 4.1 testicular volume (ml) right 8-26 18 ± 5 left 4-26 16 ± 5 fsh: follicle stimulating hormone; lh: luteinizing hormone table 1. baseline patient demographics, serum hormone levels, and semen parameters. baseline 3 months 6 months sperm variable mean ± sd mean sd mean sd sperm concentration (n x 106/ml) 26.3 ± 36.0 37.5 54.0 49.0 ± 59.0 p value 0.03 < 0.001 sperm motility (%) 25.2 ± 18.1 39.1 ± 20.3 41.3 ± 22.1 p value < 0.001 < 0.001 atypical sperm cells (%) 25.4 ± 10.0 22.6 ± 10.3 23.4 ± 12.0 p value 0.43 0.44 semen volume (ml) 3.1 ± 1.9 3.1 ± 2.2 4.3 ± 2.9 p value 0.78 0.08 table 2. descriptive statistics of sperm variables throughout the study. kobori_stesura seveso 26/03/14 10:10 pagina 2 making positive lifestyle changes such as changing to a diet high in fruit and vegetables, maintaining normal weight, and reducing smoking or alcohol intake would have at least some beneficial effects on sperm health. several studies have reported that levels of reactive oxygen species within semen can be reduced by augmenting the scavenging capacity of seminal plasma using oral antioxidant supplements. vitamin e is a major chain-breaking antioxidant in sperm membranes and this effect appears to be dose dependent. vitamin e scavenges the three major types of free reactive species, namely superoxide, hydrogen peroxide, and hydroxyl radicals. in a randomized, doubleblind, placebo-controlled trial (9), in vitro functional tests of human spermatozoa improved after 3 months of vitamin e (600 mg/day) therapy. while some studies suggest a potential role for vitamin e in the management of male infertility, another randomized trial failed to confirm these findings (10). vitamin c is another important chain-breaking antioxidant and is present at a higher concentration in seminal fluid than in plasma as well as being present in low but detectable amounts in sperm cells (11). vitamin c neutralizes hydroxyl, superoxide, and hydrogen peroxide reactive species and prevents sperm agglutination, while preventing lipid peroxidation, recycling vitamin e, and protecting against dna damage induced by hydrogen peroxide radicals (12). it has been suggested that oral administration of vitamin c with vitamin e significantly reduces hydroxyguanine levels in spermatozoa and also leads to an increased sperm count (8). coq10 is a component of the mitochondrial respiratory chain and plays a crucial role in energy metabolism and as a liposoluble chain-breaking antioxidant for cell membranes and lipoproteins (13). recently, the role of coq10 as a gene inducer has also been investigated (14). coq10 biosynthesis is markedly active in the testis (15), and high levels of its reduced form, qh2, are present in sperm (16), suggesting a protective antioxidant role. levels of coq10 and qh2 in seminal plasma and sperm cells of infertile men with idiopathic and varicocele-associated asthenospermia were reduced significantly (17). on the basis of this finding, coq10 likely contributes to the total antioxidant buffer capacity of semen, and a decrease in levels is deleterious in terms of dealing with oxidative stress. the mode of action of coq10 in male infertility is not clear but may be useful for vitalizing cells by providing greater energy to mitochondria, thereby improving motility and preventing oxidative damage through its actions as a free radical scavenger. coq10 recycles vitamin e and prevents its pro-oxidant activity (18). qh2 also acts as an antioxidant by preventing lipid peroxidation, whereas coq10 inhibits hydrogen peroxide formation in the seminal fluid and seminal plasma of infertile men (19). in a randomized, double-blind, placebo-controlled trial, the exogenous administration of coq10 increased the level of both coq10 and qh2 in semen and was effective in improving sperm kinetics in patients with idiopathic asthenozoospermia (17). when a molecule of vitamin e neutralizes a free radical it loses its antioxidant ability which is subsequently restored by the actions of other antioxidants such as vitamin c and coq10 (20). the synergy provided by combination supplementation may improve the qualitative and quantitative parameters of the seminogram in patients with oligoasthenoteratozoospermia. conclusion co-administration of vitamin c, vitamin e, and coq10 may play a positive role in the treatment of oligoasthenozoospermia, possibly mediated by the mitochondrial respiratory chain and by its antioxidant effects. however, further studies are needed to draw firm conclusions; the effect of such supplementation on pregnancy rate is currently being investigated in a randomized, double-blind, placebo-controlled trial. references 1. alvarez jg, storey b. spontaneous lipid preoxidation in rabbit epididymal spermatozoa: its effect on sperm motility. biol reprod. 1982; 27:1102-8. 2. singer g, granger dn. inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. microcirculation. 2007; 14:375-87. 3. aitken rj, koopman p, lewis sem. seeds of concern. nature 2004; 432:48-52. 4. reddy mm, mahipal sv, subhashini j, et al. bacterial lipopolysaccharide-induced oxidative stress in the impairment of steroidogenesis in rats. reprod toxicol. 2006; 22:493-500. 5. fretz pc, sandlow ji. varicocele: current concepts in pathophysiology, diagnosis, and treatment. urol clin north am. 2002; 29:921-38. 6. arnon j, meirow d, lewis-roness h, ornoy a. genetic and teratogenic effects of cancer treatments on gametes and embryos. hum reprod update. 2001; 7:394-403. 7. balercia g, arnoldi g, fazioli f, et al. coenzyme q10 levels in idiopathic and varicocele-associated asthenozoospermia. andro lo gia. 2002; 34:107-11. 8. kodama h, yamaguchi r, fukuda j, et al. increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. fertil steril. 1997; 68:519-24. 9. kessopoilou e, powers hj, sharma kk, et al. a double blind randomized placebo cross over controlled trial using the antioxidant vitamine e to treat reactive oxygen species associated male infertility. fertil steril. 1995; 64:825-31. 10. rolf c, cooper tg, yeung ch, nieschlag e. antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin c and vitamine e: a randomized, placebo-controlled, double-blind study. hum reprod. 1999; 14:1028-33. 11. saeid g, ismail l. antioxidant therapy in human endocrine disorders. med sci monit. 2010; 16:9-24. 12. buettner gr. the pecking orded of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. arch biochem biophys. 1993; 300:535-43. 13. ernster l, forsmark-andree p. ubiquinol: an endogenous antioxidant in aerobic organisms. clin invest. 1993; 71:60-5. 3archivio italiano di urologia e andrologia 2014; 86, 1 antioxidant cosupplementation therapy with vitamin c, vitamin e, and coenzyme q10 in patients with oligoasthenozoospermia kobori_stesura seveso 26/03/14 10:10 pagina 3 archivio italiano di urologia e andrologia 2014; 86, 1 y. kobori, s. ota, r. sato, h. yagi, s. soh, g. arai, h. okada 4 14. groneberg d, kindermann b, althammer m, et al. coenzyme q10 affects expression of genes involved in cell signaling, metabolism and transport in human caco-2 cells. int j biochem cell biol. 2005; 37:1208-18. 15. kalen a, applekvist el, chojnaki t, dallner g. nonaprenyl-4hydroxibenzoate transferase, an enzyme involved in ubiquinone biosynthesis in endoplasmic reticulum-golgi system. j bio chem. 1990; 25:1158-64. 16. mancini a, de marinis l, littarru gp, balercia, g. an update of coenzume q10 implications in male infertility: biochemical and therapeutic aspects. biofactors. 2005; 25: 165-74. 17. balercia g, buldreghini e, vigini a, et al. coenzyme q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo-controlled, double blind randomized trial. fertil steril. 2009; 91:1785-92. 18. thomas sr, neuzil j, stocker r. cosupplementation with coenzyme q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of ldl to transition mental-dependent oxidation initiation. arterioscler thromb vasc biol. 1996; 17:687-96. 19. alleva r, scararmucci a, mantero f, bompadre s, leoni l et al. the protective role of ubiquinol-10 against formation of lipid hydroperoxides in human seminal fluid. mol aspects med. 1997; 18:s221-8. 20. huang hy, caballero b, chang s, et al. multivitamin/mineral supplements and prevention of chronic diseases. evid rep technol assess (full rep) 2006; 139:1-117. correspondence yoshitomo kobori, md (corresponding author) ykobori@dokkyomed.ac.jp shigeyuki ota, md ryo sato, md hiroshi yagi, md shigehiro soh, md gaku arai, md hiroshi okada, md department of urology, dokkyo medical university, koshigaya hospital 2-1-50, minamikoshigaya, koshigaya (japan) 343-8555 kobori_stesura seveso 26/03/14 10:10 pagina 4 stesura seveso 373archivio italiano di urologia e andrologia 2014; 86, 4 original paper diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules. a single institution experience andrea fabiani 1, alessandra filosa 2, fabrizio fioretti 1, lucilla servi 1, mara piergallina 1, giovanni ciccotti 1, valentina maurelli 1, matteo talle’ 1, gabriele mammana 1 1 surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; 2 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy. introduction and objectives: the widespread use of scrotal ultrasound (sus) has led to a marked increase in the number of incidentally detected testicular lesions. a small incidental nodule (stn) has defined as a non palpable (< 10 mm), asymptomatic solid lesion with normal levels of oncological testicular markers. nowadays the lack of agreement on the topic causes managing problems to andrologists. we present our experience consisting in 8 cases of stn discovered by sus performed for different clinical indications. matherial and methods: we retrieved from our ultrasonographic files the clinical information about 717 patients evaluated for andrological problems. patients with stn underwent to a complete clinical history and physical examination as well as oncological testicular markers measurement and ormonal assessment and then received a diagnostic ultrasound guided excisional biopsy (deb). surgical approach was performed through an inguinal incision. using the coordinates previously obtained from preoperative sus, stn was localized by intraoperative sus. the lesion was enucleated and sent to the pathology department for frozen section examination (fse). biopsies of affected testis (tb) were also performed. post-excision ultrasound has been used to confirm the complete removal of the nodule. whether pathological findings were benign, testis sparing surgery (tss) was performed. immediate radical orchidectomy (iro) was performed if fse and tb findings suggested a malignant lesion. results: stns were discovered in 8 patients (1,1%). very small lesions (< 5 mm) were detected in 50% of cases. we performed four iro and four deb with consequent tss. in one case we performed a delayed radical orchidectomy (dro). at fse pathologist reported 3 leydig cell tumor and 3 seminoma and an inflammatory regressive lesion in one case. fse on tb reported intratesticular neoplasia (tin) in three cases. in one case nodule wasn’t sent to fse. we observed a concordance between fse and definitive pathologic report in six cases (75%). conclusions: the management of stn is still a challenge for the surgical andrologist. a correct diagnosis has a crucial role in making the best treatment and patients outcome. ultrasound guided excisional biopsy and the close collaboration with a dedicated pathologist are very useful in reducing errors.. key words: scrotal ultrasound; small testicular nodules; seminoma; leydig cell tumor; intratesticular neoplasia. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction the widespread use of scrotal ultrasound (sus) has led to a marked increase in the number of incidentally detected small testicular nodules (stns). stn is defined as a non palpable, asymptomatic solid lesion with normal levels of oncological testicular markers (1). stns still represent an important diagnostic and therapeutic challenge for the surgical andrologist. it is difficult to decide the strategy to use with these lesions since there are no defined prognostic parameters. many series in the literature revealed that the majority of non palpable intratesticular masses are malignant (2) while others suggested the benign nature of most of them (3). nowadays the reported conclusions are difficult to compare due to a selection bias of the population studied. however, evidence deriving from well-conducted retrospective outcome studies with considerable follow-up suggests that the organ-sparing approach (tss) stands for a viable treatment modality for testicular tumors of different histology and biology, both in the pediatric and adult population (4) we herein present 8 cases of small (< 10 mm) incidental intratesticular nodules discovered by sus performed for different clinical indications. material and methods we retrieved from our ultrasonographic data base files the clinical information of 717 patients referred for an andrological evaluation at macerata hospital, surgical department, urology unit during a 43 months period. stns were discovered in 8 patients (1,1%). these patients underwent a diagnostic ultrasound guided excisional testicular biopsy (deb) associated to a random testicular biopsies (tb). each patient included in our study firstly underwent a complete clinical history and physical examination as well as oncological testicular markers measurement and ormonal assessment. scrotal ultrasonography and doppler examination were performed with a 7.5 mhz b-mode linear array transducer with color doppler capability (bk medical, denmark). after assessing testicular diameter and volume, focal intratesticular echostructural anomalies were described (site, dimensions and echotexture). all our patients, informed about doi: 10.4081/aiua.2014.4.373 presented at 19th national congress sieun, fermo 2014 fabiani 2_stesura seveso 16/01/15 11:05 pagina 373 archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, f. fioretti, l. servi, m. piergallina, g. ciccotti, v. maurelli, m. talle’, g. mammana 374 the chance of ruling out a malignant tumor, preferred surgery despite active surveillance. surgical approach was performed through an inguinal incision with clamping of the spermatic funiculus. the gonad was exteriorized from the same access after sectioning the gubernaculum. using the coordinates previously obtained from preoperative ultrasonographic study, the lesion was localized by intraoperative ultrasound (7,5 mhz b-mode linear array transducer, bk medical, denmark) and a small caliber needle was placed adjacent to the lesion. the tunica albuginea overlying the lesion was then transversally incised and the nodule visualized by gently displacing the surrounding testicular parenchyma. the lesion was then enucleated, leaving a rim of normal appearing testicular parenchyma and sent to the pathologist department for frozen section examination. intratesticular biopsies was randomly performed in number of 4 specimen including perinodular testicular parenchyma and polar zone not involved by primary lesion. biopsies was performed with the scissors through small incisions of the albuginea. post-excision ultrasound has been used to confirm the complete removal of the nodules and the absence of intratesticular hematoma. if pathological findings were benign, the testis and wound were irrigated with sterile water, the vascular clamp on the spermatic cord was removed, and after achieving complete hemostasis, the tunica albuginea was closed with running 4-0 or 5-0 absorbable suture. if pathological findings of deb and in tb suggested a malignant lesion, immediate radical orchidectomy (iro) was performed. results during a 43 months period, 717 scrotal ultrasound examinations were performed for a variety of indications as varicocele, echo-color-doppler for fertility study, andrological screening, scrotal pain or discomfort or general clinical screening. small (< 10 mm) incidental testicular nodules were discovered in 8 patients (1,1%). very small lesions (< 5 mm) were detected in 50% of cases. clinical, ultrasound and pathological data are shown in table 1. figure 1a and 1 b show the ultrasonographic features of the small incidental testicular nodule in two different patients. figure 2 shows the result after lesion removal at follow up control. patient age nodule nodule ultrasonographic fse result fse result final pathology type note diameter location indication on testicular on nodule biopsy-nodule of (mm) and biopsy surgery testicular side 1 18 5 /left 2 36 4/left 3 42 6/right 4 23 6,5 /left 5 27 6/ right 6 40 8 /left 7 38 2,5/right 8 30 2,7/right tin intratesticular neoplasia. ro radical orchidectomy. tss testicular sparing surgery. iro immediate radical orchidectomy. ct computed tomography. fse frozen section examination table 1. clinical and pathological findings of 8 patients with non palpable testicular nodules less than 10 mm diagnosed by several andrological ultrasound evaluation. figure 1a. hypoechoic mesotesticular lesion of right testicle in a 38 years old azoospermic man. final histological report revealed a leydig cell tumor. lower pole upper pole lower pole mesotesticular lower pole mesotesticular mesotesticular lower pole recent trauma seminal infection scrotal discomfort bilateral gynecomastia unilateral gynacomastia severe oligoastenospermia azoospermia follow-up of cryptorchydism normal tissue tin tin normal tissue normal tissue normal tissue normal tissue tin inflammatory and haemorragic infiltrate seminoma seminoma leydig cell tumor leydig cell tumor seminoma leydig cell tumor intratesticular neoplasia (tin)hemorrhagic infiltrate tin-seminoma tin-seminoma normal tissue leydig cell tumor normal tissue leydig cell tumor normal tissue leydig cell tumor normal tissue leydig cell tumor tinseminoma tss iro iro tss tss iro tss iro patient underwent ro for seminoma 6 months later pre surgical ct findings of retroperitoneal lymphadenopathy non obstructive azoospermia; bilateral small testicular volume no nodule sent to fse fabiani 2_stesura seveso 16/01/15 11:05 pagina 374 nodule to send to the pathologist for fse. we had observed a concordance between intraoperative frozen section examination and definitive pathologic report in six cases (6/8). no complication was observed in each patient. discussion the recent marked increase in the number of incidentally detected and small testicular nodules is to be attributable to the widespread use of scrotal ultrasound. the management options of these type of lesion represent a problematic challenge for the uro-andrologist and include radical orchidectomy, immediate (iro) or delayed (dro), diagnostic excisional biopsy (deb) or active surveillance. although high resolution ultrasound can reliably detect solid intratesticular masses, benign lesions cannot be conclusively distinguished from malignant ones (5-6) the widely accepted surgical maxim that “a solid intratesticular mass, even if non palpable, must be considered malignant until proven otherwise”, must be partially revisited. the old dogma that equaled diagnosis of any testicular mass to immediate radical orchidectomy has been confuted by the clinical experience accumulated in the last decade.several series are now available reporting an unremarkable follow up when, because of non palpable testicular nodules, patients received either tss or ro (4) an aggressive approach to a non palpable testicular lesion is reasonable in case of the presence of other risk factors of testicular tumor (7). it must be minimized the risk of performing a radical orchidectomy and the related patient overtreatment in the case of a benign nodule. on the other hand, in the case of a malignant nodule, the diagnostic excisional biopsy could lead to an alteration of the predictable pattern of lymphatic spread or determine a positive margin, without neglecting the possibility of unrecognizing lesions or tin in the remaining testis. the last option management may be the active surveillance. general consensus for this approach exists only in the presence of a recent inflammation (7). the risk of an active surveillance is that the disease could progress to a higher stage in the case of a malignant lesion (8). in the management of small testicular nodules, it could be avoided these risks with use of the clinical and instrumental information obtained during the diagnostic work-up. however the known prognostic factors are still inaccurate (7). in patients with small testicular lesions a prevalence of benign tumors has to be expected, compared to patients with palpable testicular lesions which are malignant in over 90% of cases (9). in a series of 27 patients with ultrasound detected testicular lesions carmignani et al. (1) reported an overall 51.8% prevalence of benign disease at definitive histology, with 80% of non-palpable lesions being benign. similarly, sheynkin et al. (10) reported a 75% prevalence of benign lesions among eight non-palpable testicular masses. it is noteworthy that up to 100% of non-palpable testicular lesions are benign leydig cell tumor. it has also been shown that smaller lesions (< 2 cm) are more likely to be benign (7). in our series of 8 small testicular nodules, we found 37.5% of benign tumors. at the definitive pathological 375archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules figure 1b. hypoechoic lesion of lower pole in right testicle in a 30 years old normospermic man. the ultrasonographic evaluation was performed for follow up of cryptorchidism. figure 2a-b. follow up of patient in figure 1a. no residual or innovative lesions was found. we have performed four (4/8) immediate radical orchidectomy (iro) and four (4/8) excisional biopsy with consequent testis sparing procedure (tss). in one case (1/8) we have performed a delayed radical orchidectomy (dro). at intraoperative fse, both leydig cell tumor and seminoma have been diagnosed in three cases and flogosis with hemorrhagic infiltration in one case. in this last one case, six months after tss we have performed a ro due to the discovery during the follow up of a new nodular lesion revealed as seminoma. at fse of testicular biopsies, pathologist diagnosed in three cases an intratesticular neoplasia (tin). in one case we were not able to identify the fabiani 2_stesura seveso 16/01/15 11:05 pagina 375 archivio italiano di urologia e andrologia 2014; 86, 4 a. fabiani, a. filosa, f. fioretti, l. servi, m. piergallina, g. ciccotti, v. maurelli, m. talle’, g. mammana 376 report, seminoma was diagnosed in 3 cases and a definitive diagnosis of tin has been made in 1 case. in case of lesions less than 5 mm (4/8), we founded a seminoma in two case (50%) and a benign leydig cell tumor in one case (25%). muller et al. (11) reported a series of 20 men diagnosed with a tumor mean diameter of 3.5 mm with four patients (20%) who underwent an iro because the lesions were found to be malignant. in all case, the resected specimen revealed a multifocal tin. according to this previous report, our limited experience did not confirm that the benign lesions are smallest than malignant ones. moreover, in our small series, clinical information or imaging data was not always useful for predicting the benign or the malignant nature of testicular lesion. two patients with gynecomastia had a definite diagnosis of leydig cell tumor. on the other hand, although the presence of retroperitoneal lymphadenopathy was considered an indication to immediate radical orchidectomy, in our patient it has not been associated with a malingnant neoplasia. moreover inflammatory and hemorrhagic infiltrate in a clinical setting of recent trauma lead us to a sparing surgical approach, but definitive pathological examination revealed intratesticular neoplasia (tin) and patient underwent radical orchidectomy 6 months later for a new testicular mass (seminoma) detected after ultrasound follow-up. therefore, at the best of our knowledge, in small nodular lesions of the testes the intra-operative ultrasound excisional biopsy is mandatory. the first description of the operative technique of ultrasound guided testicular nodule excision was made by stoll et al. (12) and progressively developed until 2002, when hopps and goldstein codified the procedure introducing the use of a magnificent system, with the aim of improving the identification and complete excision of small non palpable lesions (13). rolle et al. (14) described their experience on a series of 14 hypoechoic testicular lesions that underwent surgical exploration with the aid of the operating microscope. with a mean size of the nodules of 5.7 ± 4.6 mm, they reported the identification and the complete excision of lesions in all patients. the intraoperative frozen section examination (fse) showed a benign lesion in 12 cases and intratesticular neoplasia (tin) in two who underwent ro. the definitive histological analysis always confirmed the frozen section examination report. after a mean clinical and ultrasound follow-up of 15 months, they not reported complications. valotto et al. (15) described a total of 25 patients with negative testicular cancer markers who underwent an inguinal surgical exploration for a testicular non palpable suspected lesion of a mean diameter of 16.1 mm (range 4-89 mm) without use of magnificent systems. they identified and successfully removed all lesions. fse revealed benign lesion in 21 cases (84%) but this findings was confirmed in 18/21 (84%). dro was performed with a diagnosis of seminoma in two cases. and the pathological report was negative in one case. when fse revealed a malignant lesion (4 cases), the definitive pathological report on radical orchidectomy specimen confirmed this findings in 75%. after a median follow up of 18 months they not reported relapse. also in our series we used only intraoperative ultrasonography with needle lesion localization. we have not enough experience about lesion less than 5 mm in diameter (4 cases of 8) for considering microsurgery useless in such cases. in any case a microsurgical approach to small testicular lesions can provide the opportunity to identify all lesion and remove it with appropriate margins in case of a solitary testis or bilateral malignancies (16). ultrasound excisional biopsy has been very difficult for us in case of very small nodules. in particular, in one patient, we were not able to identify the lesion (diameter 2.7 mm) despitr the use of intra operatory ultrasound. immediate radical orchidectomy was decided considering the diagnosis of tin on testicular biopsies. definitive histopathologic evaluation reported a small seminoma. the use of a magnificent system could have helped the dissection improving the identification, the complete nodule excision and the accuracy of the diagnosis, especially during the intraoperative biopsy for frozen section examination. intraoperative fse could provide a diagnosis of nature with absolute certainty. fse has demonstrated to be a highly reliable method to characterize testicular masses. subik et al. reported in 36 (83.7%) of 43 cases with benign frozen section assessments, the capability to successfully avoid a radical orchidectomy (17). therefore there is general consensus that fse is useful for permitting testicular preservation, especially in men with small, non palpable, incidentally found masses as well as other benign lesions where a clinical diagnosis of malignancy is in doubt (17). in our series we observed a concordance between fse and definitive pathologic report in six cases (75%). misdiagnoses were made in absence of the dedicated pathologist. in addition to the need for magnification tools, we recognize, especially in cases of very small lesion, that diagnostic accuracy in fse may be influenced by the expertise of the attending dedicated pathologist, which cannot be translated to every community hospital. conclusions small (< 10 mm) testicular nodules are nowadays commonly observed due to the widespread use of scrotal ultrasound evaluation. the management of this topic is still a challenge for the surgical andrologist and the pathologist. treatment options include radical orchidectomy, diagnostic excisional biopsy and active surveillance. in our single centre experience, ultrasound guided excisional biopsy with frozen section examination is the preferred option for initial management. intra-operative ultrasound excisional biopsy is mandatory but very difficult in many cases, especially without use of magnificent systems, when lesion is very small (< 5 mm). misdiagnosis is possible and close collaboration with a dedicated uropathologist is needed. fabiani 2_stesura seveso 16/01/15 11:05 pagina 376 references 1. carmignani l, gadda f, gazzano g, et al. high incidence of benign testicular neoplasm diagnosed by ultrasound, j urol. 2003; 170:1783-6. 2. comiter cv, benson cj, capelouto cc, et al. non palpable intratesticular masses detected sonographically. j urol. 1995; 154:1367-1369. 3. horstman wg, haluszka mm, et al. management of testicular masses incidentally discovered by ultrasound. j urol, 1994, 151:1263-1265. 4. giannarini g, mogorovich a, bardelli i, et al. testis-sparing surgery for benign and malignant tumors: a critical analysis of the literature. indian j urol. 2008; 24:467-474. 5. grasso m, blanco s, raber m, nespoli l. elasto-sonography of the testis: preliminary experience. arch ital urol androl. 2010; 82:160-3. 6. goddi a, sacchi a, magistretti g, et al. real-time tissue elastography for testicular lesion assessment. eur radiol. 2012; 22:721-730. 7. carmignani l, morabito a, gadda f, et al. prognostic parameters in adult impalpable ultrasonographic lesions of the testicle. j urol. 2005, 174:1035-8. 8. powell tm, tarter th, management of nonpalpable incidental testicular masses. j urol. 2006; 176:96-99. 9. leroy x, rigot jm, aubert s, et al. value of frozen section examination for the management of non palpable incidental testicular tumors. eur urol. 2003; 44:458-60. 10. sheynkin yr, sukkarieh t, lypke m, et al. management of non palpable testicular tumors. urology. 2004; 63:1163-7. 11. muller t, gozzi c, akkad t, et al. management of incidental impalpabile intratesticular masses of < 5 mm in diameter. bju international. 2006; 98:1001-4. 12. stoll s, goldfinger m, rothberg r, et al. incidental detection of. impalpable testicular neoplasm by sonography. ajr am j roentgenol. 1986; 146:349-350. 13. hopps vc, goldstein m. ultrasound guided needle localization and microsurgical exploration for incidental nonpalpable testicular tumors. j urol. 2002; 168:1084-87. 14. rolle l, timpano m, tamagnone a, et al. microsurgical approach for testis sparing surgery in hypoechoic non palpable testis lesions. gimser.. 2006; 13:91-96. 15. valotto c, zattoni f, guttilla a, et al. ultrasound detected nonpalpable testicular lesions: what do you do? j urol. 2012; 187(supplement 4): e304-5, c743. 16. lawrentschuk n, zuniga a, grabowski ac, et al. partial orchiectomy for presumed malignancy in patients with a solitary testis due to a prior germ cell tumor: a large north american experience. j urol. 2011; 185:508-513. 17. subik mk, gordetsky j, yao jl, et al. frozen section assessment in testicular and paratesticular lesions suspicious for malignancy: its role in preventing unnecessary orchiectomy. hum pathol. 2012; 43:1514-9. 377archivio italiano di urologia e andrologia 2014; 86, 4 diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md, phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it mara piergallina, md mara.piergallina@tiscali.it giovanni ciccotti, md giovanni.ciccotti@sanita.marche.it valentina maurelli, md valentinamaurelli@hotmail.it matteo talle’, md matteo.talle@gmail.com gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, head of section of urology asur marche area vasta 3, macerata hospital, macerata, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy fabiani 2_stesura seveso 16/01/15 11:05 pagina 377 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2144 case report giant isolated renal cyst hydatid: from diagnosis to treatment senol adanur, erdem koç, tevfik ziypak, turgut yapanoglu, ozkan polat department of urology, medical faculty, ataturk university, erzurum, turkey hydatid cyst disease is a parasitic infestation caused by echinococcus granulosus. renal involvement is rarely seen as 2-4% of all cases. rarely renal involvement is isolated whereas commonly it accompanies involvement of other organs. we aimed to present a 30-year-old male patient with renal involvement reaching a giant size and undiagnosed in another center. key words: hydatid disease; renal; nephrectomy. submitted 24 march 2014; accepted 31 may 2014 summary introduction hydatid cyst disease is a parasitic infestation caused by echinococcus granulosus (1). echinococcus granulosus may involve any part of the body but the urinary tract involvement is extremely rare (2-4%) (2). cyst hydatid disease cannot be diagnosed preoperatively in one out of three patients despite existing serological tests and imaging modalities (3). we aimed to present an isolated hydatid cyst renal involvement that reached giant size and was undiagnosed in another center who referred to our clinic. case a 31-year-old male patient was admitted to our clinic with the complaint of left flank pain radiating to the back during last 2 months. patient's past medical history included endoscopic right ureteral stone treatment with right ureteral double-j (dj) stent placement in another center one month before. microscopic hematuria and leukocyturia were present at urine analysis of the patient. creatinine level was 1.2 mg/dl in biochemical blood tests. eosinophil ratio was 10.1% (normal range: 0.9-6) respectively at blood count. a 89 x 144 mm sized septate multicystic mass lesion in the left kiney and grade i hydronephrosis in the right kidney was demonstrated at urinary tract ultrasonography (us). contrast enhanced computed abdominal tomography (ct) also displayed a 118 x 165 mm sized hypodense multicystic mass lesion arising from mid-lower pole at the level of the renal pelvis level extending to the anterior and right lateral no conflict of interest declared side and containing septa belonging to daughter vesicles (figure 1a-b). the ct scan was negative for cystic lesions in liver, lung and spleen. preoperative indirect hemagglutination test was positive. total nephrectomy was planned and preoperatively albendazole at the daily dose of 400 mg twice daily dose was administered one month before the surgical procedure (figure 1c-d). no postoperative complication was registered. discussion hydatid disease is a parasitic infestation caused by the larval form of echinococcosis granulosus. the disease is most common in sheep-raising countries including doi: 10.4081/aiua.2014.2.144 figure 1. a. ct view of giant cystic lesion containing septa belongs to the daughter vesicles in the left kidney. b. 3d volume rendering techniques imaging view of the left renal hydatid cyst. c. macroscopic appearance of nephrectomy material. d. macroscopic appearance of daughter vesicles. 145archivio italiano di urologia e andrologia 2014; 86, 2 giant isolated renal cyst hydatid turkey. all parts of the human body are exposed to the disease although liver and lungs are the most common locations. isolated renal involvement constitutes 2-3% of all cases (4). hydatid cysts rarely affect the renal function. diagnostic approach includes ultrasonography, kub radiography or more often by abdomen ct displaying the calcified thick-walled spherical cyst filled with liquid (5). serological tests are helpful in diagnosis but they have only 60-90% sensitivity. our case was admitted to our clinic due to the increase in the complaint of left flank pain radiating to the back that was related to the undiagnosed left renal hydatid cyst but the history of endoscopic intervention for right ureteral stone one month before. blood count showed eosinophilia. contrast enhanced computed abdominal tomography imaging was compatible with giant multicystic isolated renal hydatid cysts with septation by daughter vesicles inside. serological tests were also positive. preoperative praziquantel and albendazole treatment for 7 to 10 days is recommended to prevent and minimize cultivation of daughter vesicles if the accidental contamination of operation field occurs (6). we also administered albendazole at the dose of 400 mg twice daily for one month before total nephrectomy in order to minimize the effect of accidental contamination of the operation field in the case of rupture of the giant hydatid cyst by pressure of the surrounding tissue. surgery is the main treatment modality of renal hydatid cyst disease. the type of surgical procedure should be decided according to the cyst size, localization, relationship with adjacent tissues and degree of renal parenchymal mass destruction. simple nephrectomy, partial nephrectomy, endocystectomy plus link closure, pedunculated omentoplasty may be performed. perioperative albendazole treatment should be given for a reasonable period of time to prevent disease recurrence and anaphylaxis (7). in the present case total nephrectomy was performed but we were anable to remove the cyst en bloc due to its giant size. nephrectomy was completed after reduction of cyst size by draining daughter vesicles to prevent contamination of the abdomen. post-operatively medical treatment with albendazole was continued for one month. renal hydatidosis has the tendency to slow growing to reach giant size and may cause renal function loss by the compression of the renal parenchyma of the affected renal unit. although extremely rare, the diagnosis of renal hydatid cyst should be kept in mind in the differential diagnosis especially in endemic areas. references 1. schantz pm, chai j, craig ps. epidemiology and control of hydatid disease. in: thompson rca, lymberg aj, editors. echinococcus and hydatid disease. wallingford: cab international, 1995; 233. 2. gogus c, safak m, baltaci s, turkolmez k. isolated renal hydatidosis: experience with 20 cases. j urol. 2003; 169:186-189. 3. angulo jc, sanches-chapado m, diego a, et al. renal echinococcosis: clinical study of 34 cases. j urol. 1997; 157:787-794. 4. gögüs o, bedük y, topukçu z. renal hydatid disease br j urol. 1991; 68:466-469. 5. horchani a, nouira y, chtourou m, et al. retrovesical hydatid disease: a clinical study of 27 cases eur urol. 2001; 40:655-60. 6. the medical letter, 2010. the medical letter: drugs for parasitic infections. med lett treat guide 2010; 8:1-13. 7. unsal a1, cimentepe e, dilmen g, et al. an unusual cause of renal colic: hydatiduria . int j urol. 2001; 8:319-21. correspondence senol adanur, md s.adanur61@hotmail.com erdem koç, md tevfik ziypak, md turgut yapanoglu, md ozkan polat, md department of urology, medical faculty, ataturk university 25240 erzurum, turkey 97archivio italiano di urologia e andrologia 2016; 88, 2 original paper the management of total avulsion of the ureter from both ends: our experience and literature review cuneyd sevinc 1, muhsin balaban 1, orkunt ozkaptan 1, ugur yucetas 2, tahir karadeniz 1 1 medicana international istanbul hospital, urology clinic, istanbul, turkey; 2 istanbul training and research hospital, urology clinic, istanbul, turkey. objective: to evaluate the treatment modalities of total ureteral avulsion and to clarify the risk factors of this serious complication. methods: this study retrospectively analyzed the data of 3 patients with complete ureteral avulsion during ureteroscopy. of the three patients, two had distal ureteral complete avulsion, and one total ureteral avulsion on both ends. ureteroneocystostomy (unc) was immediately performed after distal ureteral avulsion cases. ileal ureter substition was performed on the same session after the total ureteral avulsion in both ends. two of the patients were under chronic use of corticosteroid treatment due to diagnosis of idiopathic trombocytopenic purpura and myastenia gravis and all patients had unsuccesful shockwave litotripsy (swl) treatment history with at least 1 month period before surgery. results: the patient who had ileal ureter substitution was followed at 3-month intervals by ultrasonography and renal function tests and she was uneventful after a 2 year follow-up period. the patients treated with unc were followed up at 3 month interval by ultrasonography and renal function tests. they had normal renal function 1 year after the operation conclusion: complete ureteral avulsion is a rare but severe complication. treatment modality can vary and ileal ureter can be applied succesfully in the total ureter avulsion in both ends when bladder capacity is not enough for a boari flap. failed swl and/or corticosteroid treatment history of patients seems to increase the risk of the ureteral avulsion. key words: avulsion; lithotripsy; ureterorenoscopy. submitted 5 september 2015; accepted 6 june 2016 summary no conflict of interest declared. quency of complications varies between 0.5% and 10% in the literature (1-3). ureteral avulsion is the most serious complication and occurs in 0-0.5% patients (4). treating ureteral avulsion is a challenge. patient comorbidities, the condition of the kidney, severity of the ureteral damage, and experience of the surgeon can affect the choice of treatment. in this study, we aimed to discuss our experience and possible leading factors of this serious complication in the light of the current literature. materials and methods we retrospectively analyzed three ureteral avulsion cases and treatment modalities at two referral hospitals between january 2008 and october 2014. all patients underwent rigid ureteroscopic procedures for removing ureteral stones, and ureteral avulsion occurred during the retrograde examination of the ureter. of the three patients (1 man, 2 women; age: 28-65 years, one right, two left), the avulsed ureter was repaired during the same session of the ureterorenoscopic surgery. the ureter stones were located in the distal ureter in two patients and in the proximal ureter in one patient. all patients had unsuccessful swl treatment and at least a 2 week interval before further investigation and treatment were applied. two patients who have been diagnosed with idiopathic thrombocytopenic purpura and myastenia gravis received chronic corticosteroid treatment. the patients were evaluated with abdominal x-ray, ultrasonography, intravenous urography (ivp), and/or computerized tomography, and the ureterorenoscopy (urs) operation was planned. patients were asked not to use antithrombotic or antiaggregant agents at least 1 week before the procedure. urinalysis and urine culture were examined, and in the case of infection, antibiotic therapy was started according to the culture antibiogram. the urs operation was performed with a 9.5 f wolf semirigid ureteroscope with the insertion of a safety guide-wire in the ureter in the lithotomy position. fluoroscopy was used in all cases, and balloon dilatation was needed in one case for a narrow ureteral orifice. the guide-wire was not inserted proximal to the stones due to the edematous ureter distal to the calculi in all cases and folded distal on the fluoroscopic view. doi: 10.4081/aiua.2016.2.97 introduction urolithiasis plays an important role in urinary disease. the treatment for ureteral calculi has evolved within the last decade, due to technological advances. a high success rate depends on advanced instruments, the introduction of the new energy sources and devices, better optical quality, and experience. ureteroscopy is a common endourological technique in urology. if standard recommendations are followed, the method is safe. however, it may sometimes result in complications such as ureteral false passage, ureteral perforation, bleeding, intussusceptions, and avulsion of the ureter; postoperative complications include infection, fever, urinoma, and strictures. the fresevinc_stesura seveso 01/07/16 11:02 pagina 97 archivio italiano di urologia e andrologia 2016; 88, 2 c. sevinc, m. balaban, o. ozkaptan, u. yucetas, t. karadeniz 98 distal ureteral avulsion occurred during the attempt to reach the distal ureteral stone in one case (diagnosis was made after suspicion of ureteral injury with retrograde ureterography) or when the urs was pulled back with force after the stone was caught with forceps in the other case. approximately 3 cm of the avulsed ureter exited from the ureteral orifice coating the stone and forceps. the other avulsed case repair procedures were performed with an open surgical approach during the same urs session. the bladder was mobilized by freeing its peritoneal attachments. the damaged ureter was identified as it crossed the iliac vessels, mobilized, and divided just above the avulsed segment. the ipsilateral bladder dome was fixed to the psoas muscle, and ureteroneocystostomy (unc) was performed. a double-j stent was used in both cases. total ureteral avulsion in both ends occurred when the ureteroscope was withdrawn after an unsuccessful attempt to remove a proximal ureteral stone and when was planned to switch to a treatment with a flexible urs. the full-length ureteral wall including the proximal, middle, and distal segments were seen covering the scope after the withdrawal of urs (figure 1). ileal ureter interposition was performed during the same session of the urs procedure after informed consent was received from the patient’s family. the patient’s bladder capacity was insufficient for boari flap ureteroplasty and psoas hitch; thus, ileal interposition was used to reconstruct a figure 1. avulsed ureter from both ends after releasing it from urs. case 1 2 3 age (year) 65 38 28 sex f f m ureteral stone diameter (mm) 10 12 13 side right left left operation unc+psoas ileal ureter unc+psoas hitch substition hitch intervation time same session same session same session comorbidities myastenia idiopathic gravis trombocytopenic purpure steroid usage yes yes no swl treatment before urs yes yes yes follow up (month) 60 18 12 table 1. patients and operation characteristics. unc: ureteroneocystostomy; swl: shockwave lithotripsy urs: ureterorenoscopy; f: female; m: male figure 2. a: ct of the abdomen. b: ct urography view of the ileal ureter and normal ureter. new ureter. the intestinal substitute was derived from the terminal ileum measuring 15 cm in length with preservation of the blood supply. the anastomosis was made between the cephalic end of the ileal tube and the pelvis of the kidney using interrupted 4/0 absorbable sutures with a 6 f double-j stent application. the nephrostomy tube was also inserted in the same side. the distal end of the ileal tube was then anastomosed to the bladder with the nonrefluxing procedure. the characteristics of the study patients are given in table 1. results the postoperative period was uneventful. ureteral j stent was removed 6 weeks after surgery in all cases.. followup was performed with renal functional tests and urinary ultrasonography at 3-month periods. radiological investigation with computed tomography urography was done at the third month. both renal parenchymas were normal, and there was no hydronephrosis (figure 2). ct: computed tomography. sevinc_stesura seveso 01/07/16 11:02 pagina 98 the patients were followed up for 30 months (12-60 months), and during that period, no hydronephrosis or gross hematuria was seen. the ileal ureter substitution case had two episodes of urinary infection and tolerable pain after the surgery until the 3rd month but after then the follow-up was uneventful. discussion ureteroscopic examination or treatment procedures may lead to various complications; such as stone residuals, mucosa injury, perforation, bleeding, and edema (5). postoperative complications such as infection, fever, urinoma, and stricture can also be seen. ureteral avulsion is a rare but serious complication; fortunately, its incidence is only 0.06% to 0.45% (6). although ureteral avulsion is rare, this catastrophic complication should be taken into consideration while performing an ureteroscopy, and an urologist should be familiar with management options in different avulsion scenarios. the paucity of literature on this complication and its management strategies may lead to urologists in trouble when they plan a repair procedure due to this unexpected rare serious complication. moreover, comorbidities, the age of the patient, the condition of the ipsilateral and contralateral kidney, location and severity of the ureteral damage, patient expectations, and surgeon experience can affect the choice of the treatment. risk factors for ureteral avulsion include symptomatic stones persisting > 3 months, stones > 5 mm, proximal ureteral distention, stones tightly encapsulated by granulation tissues, and a strong sense of tightness when the ureteroscope is moved. the muscle in the proximal ureteral tissue is weaker, and therefore, the use of a stone basket to remove the impacted stone in the upper third of the ureter increases the risk of avulsion (7). we usually do not use a basket catheter to remove stones or stone fragments. alternatively, grasping forceps are used to remove stone fragments larger than 3 mm, and sometimes, the ureteroscope is withdrawn to cause fragmented stones to disperse (8). a rigid ureteroscope is also a risk factor for ureteral avulsion as presented in the literature (9, 10) and in the three patients in our series. common features of our patients were symptomatic stone at least 3 months with three swl sessions before being admitted to our institution for further evaluation and treatment. all stones were larger than 10 mm. swl treatment may induce inflammation and increase the fragility of the ureter at the location of the stone. goktas et al. showed that urine inflammatory cytokines increased after swl treatment (11). thus, unsuccessful swl treatment seems to increase the risk of avulsion. two patients were on chronic corticosteroid treatment due to a diagnosis of idiopathic thrombocytic purpura and myastenia gravis. steroid treatment causes muscle atrophy in rat models (12). chronic use of the corticosteroid treatment may lead to atrophy of the muscle in the ureter wall, and this condition might facilitate the avulsion. minimal pressure was applied on that patient’s ureteroscopy before the stone was reached, and avulsion of the ureterovesical junction (uvj) and the ureteropelvic junction (upj) occurred when the urs was withdrawn to change it with a flexible urs to reach the stone (figure 1). moreover, the ureteral region around the stone proximal to the avulsed ureter was seen as inflamed, thinned, and necrosed during the open reconstructive surgery. ureteral avulsion is difficult to manage. for proximal ureteral avulsion, end-to-end anastomosis can be a good choice. boari flap and psoas hitch are recommended for the middle third of ureteral avulsion. for distal ureteral injuries, ureteral re-implantation is recommended (13). if avulsion is diagnosed during the postoperative period, a percutaneous nephrostomy can be placed, and a definitive treatment can be performed when the patient is stable (7). nephrectomy is also reported as an option for extensive injuries of the ureter in the literature (14). for extensive injuries like one case in our series, there are limited options such as ileal interposition or renal autotransplantation. appendix interposition has also been reported as a treatment option for extensive injuries in some literature (15, 16). there is a paucity of literature on the surgery approach of the total ureteral avulsion from both ends. ordon et al. reported three cases that named it as “the scabbard avulsion”. a nephrostomy tube was placed postoperatively, and finally, all patients underwent a nephrectomy (14). ge et al. (17) presented four cases of ureteral avulsion, and two occurred on both ends of the ureter. the authors reported that one patient was treated with autotransplantation and the other underwent pyeloureterostomy plus greater omentum investment outside. the kidney of the patient who underwent autotransplantation was normal in the follow-up while the other patient underwent nephrectomy after 25 months of follow-up. thai et al. (18) reported six ureteral avulsion cases in their series. five had avulsion on the upj and the uvj. the authors preferred nephrectomy for one patient, boari flap for two patients, ileal interposition for one patient, and ureteral re-implantation for one patient. unsal et al. (19) reported four ureteral avulsion cases in their series, and they performed two boari flap and two ureteral re-implantation procedures. one of the ureteral re-implantation cases was normal during the follow-up period while the other case developed hydronephrosis. we had three cases of ureteral avulsion and managed them with ureteroneocystomy with a psoas hitch or ileal ureter substitution (table 2). in this study, we presented three ureter avulsion cases with possible risk factors that facilitate this serious complication and management strategies. for distal ureteral avulsion, we performed the unc with psoas hitch. we did not prefer the boari flap because after we mobilized the bladder and fixed the dome to the psoas muscle, we obtained enough distance for the unc procedure. we applied anti-reflux surgery techniques for both distal ureteral avulsion cases. for total ureteral avulsion in both ends, we prefer ileal ureter substitution due to our experience of orthotopic ileal bladder diversion for invasive bladder cancer. despite the common belief that this surgery is a complex procedure and has potential complications such as anastomotic stenosis, ileus, and urinary obstruction. the postoperative period was uneventful except for one 99archivio italiano di urologia e andrologia 2016; 88, 2 the management of total avulsion of the ureter from both ends: our experience and literature review sevinc_stesura seveso 01/07/16 11:02 pagina 99 archivio italiano di urologia e andrologia 2016; 88, 2 c. sevinc, m. balaban, o. ozkaptan, u. yucetas, t. karadeniz 100 attack of urinary infection. for this case, autotransplantation or ureteral re-implantation is an alternative approach, but due to the paucity of literature on ureteral re-implantation, this approach was not preferred. in addition, since we have ileal bladder experience, we did not prefer kidney autotransplantation. conclusions ureteral avulsion is a rare but very serious complication of the urs procedure. unc is an option for distal ureteral complete avulsion cases and ileal ureteral substitution is should be kept in mind for total avulsion of the ureter in both ends. in the case of swl and/or corticosteroid treatment history of patients with urs, the risk of ureteral avulsion seems to increase, and more care should be taken during the procedure. references 1. al-awadi k, kehinde eo, al-hunayan a, et al. iatrogenic ureteric injuries: incidence, aetiological factors and the effect of early management on subsequent outcome. int urol nephrol. 2005; 37:235-241. 2. butler mr, power re, thornhill ja, et al. an audit of 2273 ureteroscopies—a focus on intra-operative complications to justify proactive management of ureteric calculi. surgeon. 2004; 2:42-46. 3. fuganti pe, pires s, branco r, et al. predictive factors for intraoperative complications in semirigid ureteroscopy: analysis of 1235 ballistic ureterolithotripsies.urology. 2008; 72:770-774. 4. d’addessi a, bassi p. ureterorenoscopy: avoiding and managing the complications. urol int. 2011; 87:251-259. 5. abdelrahim af, abdelmaguid a, abuzeid h, et al. rigid urete roscopy for ureteral stones: factors associated with intraoperative adverse events. j endourol. 2008; 22:277-280. 6. ben slama mr, zaafrani r, ben mouelli s, et al. urete roca licostomy: last resort in the treatment of certain forms of ureteropelvic junction stenosis. report of 5 cases. prog urol. 2005; 15:646-649. 7. de la rosette jj, skrekas t, segura jw. handling and prevention of complications in stone basketing. eur urol. 2006; 50:991-998. 8. canguven o, boz m, bulbul m, et al. withdraw of the ureteroscope causes fragmented ureter stones to disperse. int braz j urol. 2013; 39:756-7. 9. martin x, ndoye a, konan pg, et al. apropos of 4 cases of avulsion of the ureter. prog urol. 1998; 8:358-362. 10. alapont jm, broseta e, oliver f, et al. ureteral avulsion as a complication of ureteroscopy. int braz j urol. 2003; 29:18:22. 11. goktas c, coskun a, bicik z, et al. evaluating eswl-induced renal injury based on urinary tnf-alpha, il-1alpha, and il-6 levels. urol res. 2012; 40:569-73. 12. ma k, mallidis c, bhasin s, et al. glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. am j physiol endocrinol metab. 2003; 285:363-71. 13. gupta v, sadasukhi tc, sharma kk, et al. complete ureteral avulsion. scientificworld journal. 2005; 28:125-127. 14. ordon m, schuler td, honey rj. ureteral avulsion during contemporary ureteroscopic stone management: ''the scabbard avulsion''. j endourol. 2011; 25:1259-1262. 15. dagash h, sen s, chacko j, et al. the appendix as ureteral substitute: a report of 10 cases. j pediatr urol. 2008; 4:14-19. 16. juma s, nickel jc. appendix interposition of the ureter. j urol. 1990; 144:130-131. 17. ge c, li q, wang l, et al. management of complete ureteral avulsion and literature review. a report on four cases. j endourol. 2011; 25:323-326. 18. taie k, jasemi m, khazaeli d, et al. prevelance and management of complications of ureteroscopy: a seven-year experience with introduction of a new maneuver to prevent ureteral avulsion. urol j. 2012; 9:356-360. 19. unsal a, oguz u, tuncel a, et al. how to manage total avulsion of the ureter from both ends: our experience and literature review. int urol nephrol. 2013; 45:1553-60. correspondence cuneyd sevinc, md cuneydsevinc@yahoo.com muhsin balaban, md (corresponding author) muhsinbalaban1980@yahoo.com orkunt ozkaptan, md tahir karadeniz, md medicana international istanbul hospital, urology clinic, yeni mah., pegagaz sok. soyak evreka:a5-44, soganlik, kartal 34880 istanbul, turkey ugur yucetas, md dryucetas@yahoo.com istanbul training and research hospital, urology clinic, istanbul, turkey literature case number reason treatment kidney in follow-up ordon et al. (14) 3 ureteroscope 3 nephrectomy ge et al. (17) 2 na 1 autotransplatation normal 1 pyeloureterostomy plus greater underwent nephrectomy omentum investment outside taie et al. (18) 5 ureteroscope 1 ureteral re-implant underwent nephrectomy 2 boari flap both normal 1 ileal interposition normal 1 nephrectomy unsal et al. (19) 4 ureteroscope 2 ureteral re-implant 1 normal, 1 hydronephrosis 2 boari flap both normal our series 3 ureteroscope 2 ureteral re-implant both normal 1 ileal interposition normal table 2. series of ureteral avulsion form both ends in the literature and in our own series. na: not applicable. sevinc_stesura seveso 01/07/16 11:02 pagina 100 stesura seveso 239archivio italiano di urologia e andrologia 2014; 86, 3 case report first case of 18f-facbc pet/ct-guided salvage radiotherapy for local relapse after radical prostatectomy with negative 11c-choline pet/ct and multiparametric mri: new imaging techniques may improve patient selection eugenio brunocilla 1, riccardo schiavina 1, cristina nanni 2, marco borghesi 1, matteo cevenini 1, enrico molinaroli 1, valerio vagnoni 1, paolo castellucci 2, francesco ceci 2, stefano fanti 2, caterina gaudiano 3, rita golfieri 3, giuseppe martorana 1 1 department of urology, university of bologna, s. orsola-malpighi hospital, bologna, italy; 2 department of nuclear medicine, university of bologna, s. orsola-malpighi hospital, bologna, italy; 3 department of radiology, s. orsola-malpighi hospital, bologna, italy. we present the first case of salvage radiotherapy based on the results of 18f-facbc pet/ct performed for a psa relapse after radical prostatectomy. the patients underwent 11ccholine pet/ct and multiparametric mri that were negative while 18f-facbc pet/ct visualized a suspected local relapse confirmed by transrectal ultrasound-guided biopsy. no distant relapse was detected. thus the patient was submitted to salvage radiotherapy in the prostatic fossa. after 20 months of follow-up, the psa was undetectable and 18f-facbc pet/ct was negative. salvage radiotherapy after surgery, provided that it is administered at the earliest evidence of the biochemical relapse, may improve cancer control and favourably influence the course of disease as well as the adjuvant approach. new imaging techniques may increase the efficacy of the salvage radiotherapy thus helping in the selection of the patients. preliminary clinical reports showed an improvement in the detection rate of 20-40% of 18f-facbc in comparison with 11c-choline for the detection of disease relapse after radical prostatecomy, rendering the 18f-facbc the potential radiotracer of the future for prostate cancer. key words: prostate cancer; pet/ct; 11c-choline; 18ffacbc; salvage radiotherapy; biochemical relapse; local relapse. submitted 12 september 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction about 30% of all patients undergoing radical prostatectomy (rp) or radiation therapy for prostate cancer (pca) will develop local or distant recurrences within 10 years from initial therapy, and a third of patients will receive secondline treatment within five years (1, 2). generally the biochemical relapse precedes the disease relapse by many doi: 10.4081/aiua.2014.3.239 years and disease relapse with undetectable psa is exceptionally rare (3). conventional imaging techniques are not adequate in localizing the site of recurrence in the early phase of the psa relapse. nowadays, positron emission tomography/computerized tomography (pet/ct) with 11carbonium or 18-fluoro-choline may identify the site of recurrence earlier, with better accuracy than conventional imaging and in a single step (4). however, choline pet/ct has showed limited accuracy in the detection of local recurrence in patients with low level of psa. multiparametric magnetic resonance showed encouraging results to detect local recurrence in patients with low psa and with small disease relapse (5). in recent years the investigational synthetic l-leucine analogue (anti1amino-3-18f-fluorocyclobutane-1-carboxylic acid, in brief 18f-facbc) has been proposed as a possible alternative radiopharmaceutical to detect pca relapse (6). from a clinical point of view the performance of 18ffacbc for the evaluation of pca relapse showed first very promising results (7). in the setting of the salvage treatments for disease relapse of pca, many observational studies of salvage radiotherapy (rt) have shown complete responses in a substantial proportion of patients in the early phase of the psa relapse with comparable results as adjuvant radiotherapy (6). we present the first case to our knowledge of salvage radiotherapy based on the results of 18f-facbc pet/ct performed for a psa relapse after radical prostatectomy. case report 57 years-old men was scheduled for radical treatment for clinical t2 prostate cancer with biopsy gleason score of 4+3 and preoperative psa of 12.0 ng/ml. preoperative evaluation with bone scan and 11c-choline pet/ct showed the absence of distant or lymphatic metastases. the patients underwent radical prostatectomy plus extended pelvic lymph-node dissection including interbrunocilla cr_stesura seveso 08/10/14 12:22 pagina 239 archivio italiano di urologia e andrologia 2014; 86, 3 brunocilla, schiavina, nanni, borghesi, cevenini, molinaroli, vagnoni, castellucci, ceci, fanti, gaudiano, golfieri, martorana 240 nal, external, obturator lymph-nodes and common lymph-nodes up to the cross of the ureters. the final histology after surgery showed a pt3a pca with gleason score = 4 + 4 and no lymph-node metastases (lnms) out 21 lymph-nodes retrieved. after 24 months from surgery, psa increased up to 1.1 ng/ml (psa doubling time of 10 months). bone scan was negative. he underwent endorectal multiparametric mri, 18f-facbc pet/ct and 11ccholine pet/ct within one week in the setting of a comparative study protocol approved by the ethical committee of our hospital (9). 11c-choline pet/ct and mri were negative (figures 1, 2) while 18f-facbc showed a positive uptake within prostatic fossa (figure 3). transectal ultrasound-guided biopsy confirmed the presence of prostate cancer relapse (gleason score = 4 + 4) and intensity modulated radiotherapy (64.8 gy) plus androgen deprivation therapy for 6 months were administrated. after 20 months after radiotherapy psa was undetectable with no androgen deprivation therapy. no treatment complications were recorded. figures are posted in supplementary materials on www.aiua.it discussion choline-pet/ct is nowadays the most important imaging technique in the assessment of pca relapse and can detect the site of disease recurrence even with very low psa level. the most important limitation is the limited spatial resolution of pet/ct scanner with little detection rate for small local relapse. furthermore, when cholinepet/ct identifies a suspected lesion, almost twice as many metastases are present and the detection rate of choline-pet/ct is still suboptimal (4). one important reason for this low sensitivity is the slow proliferation of pca cells reflecting a slow membrane metabolism and resulting in a small amount of choline uptake. for this reason, some metastatic deposit even greater than 10 mm may be completely negative at pet/ct scan. multiparametric mri has demonstrated higher global accuracy than choline-pet/ct for local relapse detection but small lesion can be missed (5). the functional activity of the new radiotracer 18ffacbc for pet/ct is related to two different amino acid transporters (asc and lat1) which appears to be upregulated in prostate cancer progression to metastatic disease (6, 7). preliminary clinical reports with 18f-facbc showed an improvement in the detection rate of 20-40% in comparison with 11c-choline, rendering the 18f-facbc the potential radiotracer of the future (7). although data from randomized trials are lacking, substantial evidence from retrospective, observational studies shows that salvage rt is effective at controlling local recurrence and reduces the risk of distant metastasis and disease specific mortality (1, 8). new diagnostic tools such as 18ffacbc pet/ct may improve the potential of this approach by increasing the assessment and the selection of the patients. the ability of 18f-facbc pet/ct of visualizing the site of recurrence in the early phase of prostate cancer relapse may improve the tailoring of the treatment planning and may enhance the response to salvage treatments. the present clinical report and fist clinical studies encourage going on in the research of new imaging techniques in the detection of prostate cancer recurrence. references 1. stephenson aj, bolla m, briganti a, et al. postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. eur urol. 2012; 61:443-51. 2. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 3. pepe p, fraggetta f, tornabene f, et al solitary lung metastasis after radical prostatectomy in presence of undetectable psa. arch ital urol androl. 2012;84:208-10. 4. farsad m, schiavina r, franceschelli a, et al. positron-emission tomography in imaging and staging prostate cancer. cancer biomarker. 2008; 4:277-84. 5. panebianco v, sciarra a, lisi d, et al. prostate cancer: 1hmrsdcemr at 3t versus [(18)f]choline pet/ct in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (rrp). eur j radiol. 2012; 81:700-8. 6. schuster dm, savir-baruch d, nieh p, et al. detection of recurrent prostate carcinoma with anti-3-18f-fluorocyclobutane-1carboxylic acid pet/ct and 111in-capromab pendetide spect/ct. radiology 2011; 259:852-861. 7. nanni c, schiavina r, boschi s, et al. comparison of 18f-facbc and 11c-choline pet/ct in patients with radically treated prostate cancer and biochemical relapse: preliminary results. eur j nucl med mol imaging 2013, apr 17. 8. tramacere f, gianicolo ea, pignatelli a, portaluri m. analysis of survival in radical and postoperative radiotherapy for prostate cancer. arch ital urol androl 2011; 83:188-94. correspondence eugenio brunocilla, md riccardo schiavina, md (corresponding author) rschiavina@yahoo.it marco borghesi, md matteo cevenini, md enrico molinaroli, md valerio vagnoni, md giuseppe martorana, md department of urology of university of bologna, s. orsola-malpighi hospital, via palagi 9, 40134, bologna, italy cristina nanni, md paolo castellucci, md francesco ceci, md stefano fanti, md department of nuclear medicine of university of bologna, s. orsola-malpighi hospital, bologna, italy caterina gaudiano, md rita golfieri, md department of radiology, s. orsola-malpighi hospital, bologna, italy brunocilla cr_stesura seveso 08/10/14 12:22 pagina 240 stesura seveso 261archivio italiano di urologia e andrologia 2014; 86, 4 original paper the importance of internet usage for urologic patients cahit sahin 1, murat tuncer 1, ozgur yazici 1, alper kafkasli 1, utku can 1, bilal eryildirim 1, orhan koca 2, kemal sarica 1 1 dr. lutfi kirdar training and research hospital, urology clinic, istanbul, turkey; 2 hydarpasa numune training and research hospital, urology clinic, istanbul, turkey. objectives: to evaluate internet usage frequency, rate of searched diseases and impact of internet derived data on future patientphysician relationship in patients applying to an urology department. methods: a well prepared questionnaire has been given to 1000 referring cases, out of which 589 accepted to participate on a volunteer basis to a face to face interview. patients were divided into subgroups with respect to age, gender and as well as their educational and economical status. regarding internet, questions inquired the use of internet, the point of view about it, opinions about healthcare system and most commonly urological diseases searched in internet. results: of 589 patients participating, 38.2% reported access to the internet; in relation to subgroup analysis of data, there was a statistically significant relationship between the use of internet and age (p < 0.001), gender (p = 0.048), educational status (p < 0.001) and economical status of (p = 0.002) the cases evaluated. diseasespecific information was most frequently sought: 18.2% searched for urolithiasis, 14.2% for non-cancer related kidney diseases, and 14.2% for urologic cancers. conclusions: younger patients with higher educational status tended to use internet and the majority of these cases share all these information with their physicians during their visit. these findings indicate that all physicians should consider this fact seriously and make their future plans in the light of internet based activities which provides numerous advantages. key words: internet; urologic patient; urological diseases. submitted 2 february 2014; accepted 31 march 2014 summary no conflict of interest declared. use it for medical purposes (3). a questionnaire study of andreassen et al. about 7934 people in 7 different european countries reported that frequency of internet usage and rate of searching for medical knowledge were 61% (81-42) and 71% (79-54), respectively (4). internet usage allows the patients to have the chance of following the disease course effectively by providing rapid, suitable, easy, real information about their diseases (5). related with this subject, particularly, the patients with uro-oncological diseases search internet in a more effective manner to obtain information concerning the etiology, treatment and follow up of the disease after first diagnosis of the pathology (6). they also tend to read some guideline information from internet before referring to a physician. parallel to these developments, traditional patient-physician relationship, which gives a passive position to the patient, has evolved in a situation where the patient came into a central position (7). the aim of this study was to evaluate the internet usage frequency and the rate of searched diseases along with the impact of internet derived data on future patientphysician relationship in patients applying to an urology policlinic of a training and research hospital in a developing country. material and methods our present prospective study aimed to evaluate the use of internet in detail among the patients referring with urological complaints to our outpatient department between june 2013 and july 2013. a well prepared questionnaire was given to 1000 referring cases, out of which 589 accepted to participate on a volunteer basis to a face to face interview. the questionnaire had two parts consisting of questions concerning the demographic characteristics of the cases and other questions assessing the use of internet in a detailed basis (tables 1, 2). patients were divided into subgroups with respect to age, gender and as well as their educational and economical status. regarding internet questions aimed to inquiry the use of internet, point of view and opinions of patients about the healthcare system and most commonly searched urological diseases from the internet (table 2). doi: 10.4081/aiua.2014.4.261 introduction internet is a perfect tool which enables easy access to existing information in all parts of lives and to share it with whole world in a very practical manner (1). in addition to its extremely common usage in all parts of life, medical aspect of its usage also show an increasing popularity (2). in a recent study, it was shown that 74% of adult people in usa use internet and out of them 90% were found to archivio italiano di urologia e andrologia 2014; 86, 4 c. sahin, m. tuncer, o. yazici, a. kafkasli, u. can, b. eryildirim, o. koca, k. sarica 262 patients being able to use internet (almost every day or at least once in a week) have been accepted as true users. patients between 18 and 90 years participating into the questionnaire study in a voluntarily basis have been included into the study program; patients with mental retardation, severe psychiatric disorders and illiterate ones were excluded from the study program. the study program has been approved by the ethics committee of the institution and a informed consent has been obtained from all cases included into the program. statistical analysis was performed with ncss (number cruncher statistical system) 2007&pass (power analysis and sample size) 2008 statistical software (utah, usa). in addition to descriptive statistics (frequency, ratio), chi-square and fisher-freeman-halton test were used for the examination of qualitative data. statistical significance was defined at p < 0.05. results among 1000 consecutive cases referring to our outpatient department, 600 accepted to participate into our study program. however, only a total of 589 completed the inquiry form, of which 390 were male (66.2%) and 199 (33.8%) were female (m/f: 1.96). evaluation of the percentage of internet use on an age based manner revealed that while 19. 4 % was < 30 years; 298 cases (50.6 %) were among 30-60 years and the remaining 177 cases (30.1%) were over 60 years. with respect to their educational status again, intenet use among cases with primary, intermediate and high school degrees were 441 (74.9%), 53 (9%) and 95 (16.1%), respectively. lastly, evaluation of the cases based on their economical status showed that the percentage of internet use was 35.7 % (210 cases) in cases with lower income, 63.3% (373 cases) in intermediate and 1% (6 cases) in cases with high income. overall analysis of our data among subgroups demonstrated that there was a statistically significant relationship between the use of internet and age (p < 0.001), gender (p = 0.048), educational status (p < 0.001) and economical status (p = 0.002) of the cases evaluated (table 1). of all the cases partecipating into the study program, 225 (38,2%) acknowledged routine use of internet; of these users 165 (73.3%) were able to get the necessary healtcare information from the internet (table 2). additionally among the internet users 169 cases (75.1%) had an e mail account in order to institute a mutual cooperation. the overall attitude of the cases with respect to internet use and search for medical information is summarized in table 2. concerning the area of interest for medical problems, our data clearly demontotal sample nternet users internet users (n = 589) (+) (n = 225) (-) (n = 364) n % n % n % age (year) < 30 114 19.4 87 76.3 27 23.7 a0.001** 30-60 298 50.6 122 40.9 176 59.1 > 60 177 30.0 16 9.0 161 91.0 gender male 390 66.2 160 41.0 230 59.0 a0.048* female 199 33.8 65 32.7 134 67.3 educational status primary school 441 74.9 115 26.1 326 73.6 a0.001** intermediate school 53 9.0 33 62.3 20 37.7 high school 95 16.1 77 81.1 18 18.9 economical status < 1000 tl 210 35.7 71 33.8 139 66.2 b0.002** 1000-4000 tl 373 63.3 148 39.7 225 60.3 > 4000 tl 6 1.0 6 100.0 0 0.0 a pearson chi-square test; b fisher-freeman-halton test; *p < 0.05; **p < 0.01 table 1. demographic characteristics of the patients n % do you use internet? no 364 61.8 yes 225 38.2 do you have email address? 169 75.1 do you check the internet related with your problem prior to the examination? 165 73.3 do you share the healtcare information obtained from the internet with your physician? 89 39.7 do you find the healthcare information derived from the internet as useful? 173 77.2 do you rely on the healthcare information derived from the internet? 119 53.1 table 2. multiaspect evaluation of the information derived from the interner by the patients strated that while 41 cases (18.2%) searched for urinary system stone disease, 32 (14.2%) cases searched for noncancer related kidney diseases, 32 (14.2%) for urologic cancer, 22 (9.7%) for sexual disorders, 21 (9.3%) for infertility, 17 (7.6%) for lower urinary tract symptoms (luts), 9 (4%) for overactive bladder (oab) and 12 (5.3%) for other medical subjects. the remaining 39 cases (17.3% ) however quoted that they did not search any subject related with health care from the internet (table 3). discussion the rapid, easy and practical aspects of internet search has made it a very useful tool to look for as well as obtain the required healthcare information on various medical problems. the efficiency of internet in global circulation of the information is being accepted as the second revolutionary innovation following the invention of printing systems in 1447 by johannes gutenberg (1). the internet has been first proposed to supply the military needs of usa army during nuclear armament after 1960’s (advanced research projects agency of the united states department of defense to produce acomputer communications network arpanet) following its introduction this system gained an enormous importance which brought it in an irresistable position as a highly important part of the daily life (8). at our present time this amazing revolution is further going on with the use of mobile phones which enable us for an extremely easy and practical search of all necessary information with an evident accelaration (9). determining the percentage of internet use and its utility in developing countries is highly important. taking this fact into account, we aimed to evaluate the attitude of the urology patients in turkish society concerning the use of internet facility in their daily life. similarly to other studies dealing with the relationship between demographic variables and internet use (10, 11), the evaluation of our data also showed a positive correlation between educational (p < 0.001) and economical status (p = 0.002) of the cases and percentage of internet use. furthermore, there was a negative correlation between the age of the cases and the percentage of internet use (p < 0.001), and a positive correlation in favor of male gender (p = 0.048). similarly, in their original study, kendra et al. were able to show a positive correlation between internet use and educational as well as economical status of the evaluated population (10). they also demonstrated that younger generation used the internet in a more common and practical manner than adults (12). in relation to this subject pew internet and american life project studies again well demonstrated that the use of internet increased steadily in older ages with values of 2% in 1996, 15% in 2002 and 22% in 2004 (13, 11). in the same study they recorded a higher internet use rate (68%) among subjects with higher educational degree (university) when compared with relatively lower educational levels (high school graduated) (52%) (11). although no direct relationship between socioeconomic status and internet use could be shown, education opportunity and being able to buy a computer system indicate an indirect positive relationship between these two important parameters. studies point out that the use of internet is enormously inceased during the last 2 decades. in relation with this subject, internet world states 2012 data revealed that the whole worldwide number of users is 2.405.518.376 (14) and 200 million in usa (15). with respect to these values, in our country turkish statistics institution has announced that the percentage internet users among 1674 class age was 47.4% whereas the percentage of regular users seemed to drop to 37.8% (16). in addition to the common use of the internet in every part of daily life, its use is apparently increasing worldwide also in healthcare sector (17). currently internet has proven itself to have an extraordinary potential in offering the necessary healthcare information to both normal healthy people as well as to patients suffering from different pathologies (18). in accordance with this fact again it has been reported that the use of internet in order to obtain the necessary pathology-related information is again evidently increasing among the urology patients (19). studies indicate that as much as one third of internet user patients share the obtained information with their physicians (4). as a result of the all these achievements, the paradigm between patient and physician seems to change in a considerable manner (7). last but not least, it is very well known that the specific aims of using the internet in healthcare system is to obtain information (content), share the obtained information (community) and send this information to others (communication, e-mail) (7). furthermore the use of internet in this sector may give the advantages of communication between patients and physicians as well as getting the necessary support from family, friends and related environment (20). of course, another additional advantage will be to get appoinment from the hospitals as well as physician’ offices in a quick and practical manner. in their study dealing with emergency department cases pourmand et al. noted that 92.6% of the cases used the intenet and of these users 94.5% had a personal email address (21). michele et al. reported that among all internet users, 55% used their personal e-mail addresses to cooperate with medical institutions providing medical 263archivio italiano di urologia e andrologia 2014; 86, 4 use of internet in the urological outpatient n % urinary system stone disease 41 18.2 non-cancer related kidney diseases 32 14.2 urologic cancers 32 14.2 sexual disorders 22 9.7 i̇nfertility 21 9.3 luts 17 7.6 other subjects 12 5.3 oab 9 4.0 remaining (not-searching for any spesfic topic) 39 17.3 table 3. urologic problems searched in the internet by the patients referred to our department (n = 225). archivio italiano di urologia e andrologia 2014; 86, 4 c. sahin, m. tuncer, o. yazici, a. kafkasli, u. can, b. eryildirim, o. koca, k. sarica 264 support (22). pew internet and american life project 2009 study reported the use of personal e-mail address among the internet users to be 91% (23). in our current study, 75.1% of our cases reported to have a personal e-mail address. the use of e-mail in healthcare sector will make the communication between medical support providers and patients more practical and quicker. additionally, patient follow-up, scheduling the appoinments and planning other medical procedures will be more practical in a highly effective manner (24). concerning this issue, schwartz et al. reported that while 7.6 % of the internet user patients shared this information with their physicians in a permanent manner, 52,6% shared it occasionally (10). however taylor et al. reported that 53% of internet user patients shared these data with their physicians (25). similarly to reported literature, according to our data 39.7% of the participants of our study shared the internet derived information with their physicians in a permanent manner which in turn again indicated the highly important role of internet use for a proper and cooperative communication between the patients and physicians. regarding the use of internet in order to get information about present health related problems, it has been shown that the patients may look for either specific or general topics on this aspect. with respect to this issue, in their study, nicholas et al. found that out of 1322 internet users 97% searched for specific topics related with their problems (26), while this rate has been reported to be 79% by kendra et al. (10). our data showed that among the participants referring to an urology department, 82.7 % searched for urology related topics (table 3). further evaluation of the topics searched demonstrated that 18.2 % of our cases searched for urolithiasis, 14% searched for urologic cancers and 14% for general kidney diseases. in another study, concerning the inquiries in patients from 7 countries in europe, andreassen et al. reported that 52% of the cases searched for specific topics in internet [4]; pew internet and american life project 2013 study revealed that 55% of the users searched for specific diseases or medical conditions (27). the relatively lower rate of search for some specific medical topics demonstrated in our study could be related to the fact that patients suffering from sexual as well as andrologic problems could refrain from using internet for this aim. one further aspect of internet use is the benefit for the patients to discuss about internet-obtained data during the interview with their physician. there are studies in the literature dealing with consideration and satisfaction of the patients with respect to the internet derived data (11, 28). in our current study 77.2% of the cases expressed the usefulness of the data obtained from internet. ybarra et al. were able to show that 73.3% of their cases were satisfied with the data obtained and 78% of the cases stated that the internet derived data eased their daily life conditions (22). baker et al. reported that 67% of relatively older users noticed that internet data let them to realize their healthcare problems in a more understandable manner (28). last but not least in the european union eurobarometer inquiry study, 41.5% of the participants found the internet derived data were highly useful to deal with their healthcare problems (29). another aspect of internet use is the reliance of users on the data obtained with respect to their adequacy and safety: a concern that has been subjected to numerous studies in the literature (30). in relation with this subject, 53.1% of the cases in our study found the internet obtained medical data reliable and useful; traver et al. reported the rate of treliability in urology and nephrology web sites as 41% and 51% respectively (31). on the other hand however, in their original study, smith et al. found the internet derived data for medical problems as reliable in 21%, adequate in 77% and useless in 2% of the cases evaluated (6). depending on our as well as on similar published data in the literatüre, we may say that patients seemed to be careful and selective in using internet to derive information for their medical problems. the limited number of subjects evaluated and the lack of data concerning a detailed evaluation of the web sites used as well as their individual reliability from patient’ perspective are possible limitations of our study. however, we believe that despite all these certain limitations, in consideration of the highly limited data regarding the use of internet among urology patients in our country as well as in developing countries, our findings could be accepted as valuable enough to give further information about the use of internet in healthcare system. we again believe that further studies with larger number of participants and focusing on specific parameters are certainly needed. conclusion in the light of our data as well as of the published literature findings, it seems that younger patients with higher educational status tend to use internet to derive information about their health problems in a more common and efficient manner. the majority of these cases share all these information with their physicians during their visit. we believe that use of internet data in a proper manner will provide reliable information with respect to the diagnosis and management of the health problems which will contribute to patient-physician relationship in a more positive manner. all physicians should consider this fact seriously and make their future plans in the light of internet based activities which provides numerous advantages. references 1. ullrich pf jr, vaccaro ar. patient education on the internet: opportunities and pitfalls. spine (phila pa 1976). 2002; 27:e185-8. 2. vance k, howe w, dellavalle rp. social internet sites as a source of public health information. dermatol clin. 2009; 27:133-6. 3. rainee l. internet, broadband, and cell phone statistics. washington dc, usa: pew internet and american life project. 2010. 4. andreassen hk, bujnowska-fedak mm, chronaki ce, et al. european citizens' use of e-health services: a study of seven countries. bmc public health. 2007; 7:53. 5. goldsmith j. how will the internet change our health system? health aff (millwood). 2000; 19:148-56. 6. smith rp, devine p, jones h, et al. internet use by patients with prostate cancer undergoing radiotherapy. urology. 2003; 62:273-7. 7. mc mullan m. patients using the internet to obtain health information: how this affects the patient-health professional relationship. patient educ couns. 2006; 63:24-8. 8. doyle dj, ruskin kj, engel tp. the internet and medicine: past, present, and future. yale j biol med. 1996; 69:429-37. 9. smith a. mobile access. washington dc, usa: pew internet and american life project. 2010. 10. schwartz kl, roe t, northrup j, et al. family medicine patients' use of the internet for health information: a metronet study. j am board fam med. 2006; 19:39-45. 11. fox s. older americans and the internet. washington dc, usa: pew internet and american life project. 2004. 12. fast am, deibert cm, boyer c, et al. partial nephrectomy online: a preliminary evaluation of the quality of health information on the internet. bju int. 2012; 110:e765-9. 13. pautler se, tan jk, dugas gr, et al. use of the internet for selfeducation by patients with prostate cancer. urology. 2001; 57:230-3. 14. internet world stats.internet users in the worl. 2012; available at:http://www.internetworldstats.com/stats.htm. accessed december 2013. 15. sadasivam rs, kinney rl, lemon sc, et al. internet health information seeking is a team sport: analysis of the pew internet survey. int j med inform. 2013; 82:193-200. 16. t.c. basbakanlık türkiye istatistik kurumu haber bülteni. hanehalkı bilisim teknolojileri kullanım arastırması (turkey prime ministry turkish statistical institute news bulletin. household informatics technology usage investigation). 2012; available at:http://www.tuik.gov.tr. accessed december 2013. 17. eng tr, maxfield a, patrick k, et al. access to health information and support: a public highway or a private road? jama. 1998; 280:1371-5. 18. weaver jb 3rd, mays d, lindner g, et al. profiling characteristics of internet medical information users. j am med inform assoc. 2009; 16:714-22. 19. hellawell go, turner kj, le monnier kj, brewster sf. urology and the internet: an evaluation of internet use by urology patients and of information available on urological topics. bju int. 2000; 86:191-4. 20. mechanic d. how should hamsters run? some observations about sufficient patient time in primary care. bmj. 2001; 323:266-8. 21. pourmand a, sikka n. online health information impacts patients' decisions to seek emergency department care. west j emerg med. 2011; 12:174-7. 22. ybarra ml, suman m. help seeking behavior and the internet: a national survey. int j med inform. 2006; 75:29-41. 23. jones s, fox s. generations online in 2009. new york, ny, usa: pew internet and american life project. 2009. 24. anderson jg, rainey mr, eysenbach g. the impact of cyberhealthcare on the physician-patient relationship. j med syst. 2003; 27:67-84. 25. taylor h. cyberchondriacs. in: on the rise? . new york, ny, usa: harris interactive. 2010. 26. nicholas d, huntington p, gunter b, et al. the british and their use of the web for health information and advice: a survey. aslib proc. 2003; 55:261-76. 27. fox s. health online. new york, ny, usa: pew internet and american life project. 2013. 28. baker l, wagner th, singer s, bundorf mk. use of the internet and e-mail for health care information: results from a national survey. jama. 2003; 289:2400-6. 29. european commission survey of online health information. 2003; available at http://europa.eu.int/comm/public_opinion /archives/eb/eb59/eb59_rapport_final_en.pdf; accessed december 2013. 30. ziebland s, chapple a, dumelow c, evans j, prinjha s, rozmovits l.how the internet affects patients' experience of cancer: a qualitative study. bmj. 2004; 6;328:564 31. traver ma, passman cm, leroy t, et al. is the internet a reliable source for dietary recommendations for stone formers? j endourol. 2009; 23:715-7. 265archivio italiano di urologia e andrologia 2014; 86, 4 use of internet in the urological outpatient correspondence cahit sahin, md (corresponding author) cahitsahin129@gmail.com murat tuncer, md ozgur yazici, md alper kafkasli, md utku can, md bilal eryildirim, md kemal sarica, md dr. lutfi kirdar training and research hospital, urology clinic gömeç sok. sabancı -2 sitesi a1 kat 4 daire 24 acıbadem/kadıköy istanbul, turkey orhan koca, md hydarpasa numune training and research hospital, urology clinic istanbul, turkey stesura seveso 353archivio italiano di urologia e andrologia 2014; 86, 4 original paper improvement of lower urinary tract symptoms and sexual activity after open simple prostatectomy: prospective analysis of 50 cases lorenzo montesi, luigi quaresima, marco tiroli, vito lacetera, ubaldo cantoro, giulia sbrollini, giovanni muzzonigro, massimo polito institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy. objectives: to evaluate the improvement of lower urinary tract symptoms (luts) and erectile function (ef) evaluated before and after open simple prostatectomy, focusing on which patients this procedure allows better outcomes in term of sexual activity. material and methods: 50 men with large size benign prostatic hyperplasia (bhp) greater than 80 gr were prospectively evaluated before and 6 months after open simple prostatectomy (freyer procedure) between october 2012 to september 2013. patients had a pre-operative transrectal ultrasound (trus) for volume evaluation and filled pre and post operative questionnaires for international prostate symptom score (ipss) and international index of erectile function (iief-5) score. results: mean patients age was 71 years (d.s. 3,5), mean prostate volume results 103 ml (d.s. 23,7); regarding luts and ef, mean improvement of ipss score was 15,3 (d.s. 4) and mean increase of iief-5 score was 3,4 (d.s.3). this study highlights a correlation between patients’ age and increase of iief-5 score; no correlation with prostate size was found. conclusion: according to the eau guidelines 2014, large size bph (over 80-100 ml) with luts refractory to medical management continue to have open prostatectomy as the treatment of choice. in our experience we found not only an reduction of luts after the procedure but also an improvement of erectile function; this improvement was related with patient’s age. key words: prostate; benign prostatic hyperplasia (bph); open simple prostatectomy; erectile dysfunction; lower urinary tract symptoms (luts). submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. the gland has been related with the level of dihydrotestosterone (dht), although in the last years it has progressively gained credibility the hypothesis of a possible involvement of environmental factors in the pathogenesis of bph. inflammation seems to play a significant role, and this evidence was frequently reported in the literature. recently zlotta et al. (1) evaluated the association between acute and chronic inflammation and prostatic hypertrophy; from their study on cadavers was evident the association between chronic flogosis and volume of the prostate gland, with a probability to observe bph 6.8 times greater in those with chronic inflammation than in those whitoutt. the growth of the prostate is responsible of lower urinary tract symptoms (luts) such as urinary frequency, nocturia, hesitancy, feeling of incomplete voiding, terminal dropping that involve a substantial reduction in quality of life (qol) for the patient (2, 3). associated with these symptoms has evolved over time the idea that inflammatory bph may affect the reduction of sexual potency in the old man, especially if associated with other contributing factors such as diabetes, hypertension or vascular disease. by now it is well established the beneficial role of surgery, either endoscopic or open, in the improvement of urinary symptoms. recently, garcia et al. (4) compared the open simple prostatectomy (osp) with laparoscopic extraperitoneal adenomectomy showing how obtain great results with this technique especially in terms of intraoperative bleeding and days of hospitalization. the technique is a feasible alternative to the intervention of osp which is still today the gold standard procedure. more uncertain remain instead the apparent benefit on the recovery of erectile function. in 1997 goriunov et al. (5) assessed erectile function in 818 patients undergoing to surgery for bph. it appeared that the osp deteriorated the erectile function (ef) of sexually active patients, but also that, in a low percentage of cases (5%), sexual function was recovered in patients previously not sexually active. over time, new researches have shown the association between prostatic hypertrophy and reduction of ef: with the improvement of surgical techniques, the recovery of sexual function becomes a goal to be pursued both clinically and surgically. doi: 10.4081/aiua.2014.4.353 presented at 19th national congress sieun, fermo 2014 introduction benign prostatic hyperplasia (bph) affects the male population indiscriminalety and its incidence is increasing in relation to the raise of the population’s average age. it affects approximately 5-10% of men under 40 years and up to 80% of men between 70-80 years. the growth of quaresima 2_stesura seveso 15/01/15 12:50 pagina 353 archivio italiano di urologia e andrologia 2014; 86, 4 l.montesi, l. quaresima, m. tiroli, v. lacetera, u. cantoro, g. sbrollini, g. muzzonigro, m. polito 354 aim of our study was to evaluate the improvement of luts and ef valued before and after osp, focusing in particular to show in which patients this procedure allows better outcomes in term of sexual activity. materials and methods the study was conducted prospectively. were included in the study patients who underwent osp between september 2012 and february 2014. all the patients were subjected before surgery to uroflowmetry and filling of the validated questionnaires international index of erectile function (iief5) and international prostate syntoms score (ipss). the same were repeated 6 months after the surgery, in presence of negative urine cultures and without use of phosphodiesterase-5 (pde-5) inhibitors drugs. the surgical procedures were performed by three different surgeons with more than 10 years of experience. exclusion criteria were drop outs at follow-up, presence of significant comorbidities and use of 5alpha reductase inhibitor (5-ari) and/or 5-pde drugs in the 6 months before enrollment, data were analyzed with the statistical program spss. a value of p < 0.05 was considered statistically significant (figure 1). results fifty patients who underwent osp between september 2012 and february 2014 were included in the study; the average age of the patients was 71 years (sd 6.5), mean prostate volume was 103 ml (sd 33.7 ) with a maximum volume of 200 ml and a minimum of 40 ml. six patients showed preoperatively at least one episode of acute retention of urine and 4 of them came to surgery with catheter placed for chronic retention. forty-one patients were treated at least once with alpha-blockers, while 22 of them have been submitted at least once to therapy with 5-ari but not in the months before completing the questionnaire. the average improvement in ipss was 15.3 (ds 8) with a maximum value of 32 and a minimum value of 0 (figure 2). the average improvement of iief5 was 3.4 (ds 5) with maximum improvement of 19 and minimum improvement of 0 mean improvement in subgroup of patients less than 70 years resulted 4.6 (ds 5,3). no difference between patients with different prostate size was observed. six patients had positive urine cultures at subsequent checks for which it was set an appropriate antibiotic therapy; one patient had wound infection. no episode of acute retention occurred in our study in the six months follow-up after surgery and in none of the patients it was necessary to reset the alpha-blocking therapy (figure 3). discussion our study proved to be concurring with the current european guidelines for the treatment of prostatic hypertrophy. in fact, in agreement with the eau guidelines 2014, bph with high volume (greater than 80 ml) had as first line treatment the open simple prostatectomy procedure (6-8). new techniques have been compared with osp: raimbault et al. (9) have compared the results obtained with photo-selective vaporization of the prostate to those obtained by osp in high volume prostates (> 80 ml): it resulted a lower cost compared to the benefit obtained and an inferior percentage of reoperations in the one year follow-up. kim et al. (10) have recently tested the effect of the holmium laser enucleation of the prostate demonstrating a good improvement of the sexual function of patients, especially when associated with an improvement of irritative luts. to sum up, a huge number of studies in international literature have compared surgical results of different techniques, some of them analyzed the ef, but few studies tried to find prognostic factors to predict which category of patients has the best outcome in term of improvement of ef after ops; in our experience the only patients characteristic that predict ef outcome was patients age. figure 2. ipss scores pre and 6 months after osp procedure. figure 3. iief-5 scores pre and 6 months after osp procedure figure 1. distribution of patients’ prostate sizes. quaresima 2_stesura seveso 15/01/15 12:50 pagina 354 conclusions the results obtained show how osp procedure provides excellent results as regards the obstructive voiding symptoms. encouraging results were also obtained with regard to the recovery of sexual potency, in particular correlated to the patient's age; additional studies with a bigger sample size are strongly recommended to confirm this theory. references 1. zlotta ar, egawa s, pushkar d, et al. prevalence of inflammation and benign prostatic hyperplasia on autopsy in asian and caucasian men. eur urol. 2014; 66:619-22. 2. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function:report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-78. 3. chapple cr, wein aj, abrams p, et al. lower urinary tract symptoms revisited: a broader clinical perspective. eur urol. 2008; 54:563-9. 4. garcía-segui a, gascón-mir m. comparative study between laparoscopic extraperitoneal and open adenomectomy. actas urol esp. 2012; 36:110-6. 5. goriunov vg, davidov mi. sexual readaptation after the surgical treatment of benign prostatic hyperplasia. urol nefrol (mosk). 1997; (5):20-4 6. tubaro a, carter s, hind a, et al. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001; 166:172-6. 7. mearini e, marzi m, mearini l, et al. open prostatectomy in benign prostatic hyperplasia: 10-yearexperience in italy. eur urol 1998; 34:480-5. 8. serretta v, morgia g, fondacaro l, et al. open prostatectomy for benign prostatic enlargement in southern europe in the late 1990s: a contemporary series of 1800 interventions. urology. 2002; 60:623-7. 9. raimbault m, watt s, bourgoin h, et al. comparative analysis of photoselective vaporization of the prostate with the greenlight laser and open prostatectomy for high volume prostate hypertrophy. prog urol. 2014; 24:470-6. 10. kim sh, yang hk, lee he, paick js, oh sj. holep does not affect the overall sexual function of bph patients: a prospective study. asian j androl. 2014. 355archivio italiano di urologia e andrologia 2014; 86, 4 improvement of lower urinary tract symptoms and sexual activity after open simple prostatectomy: prospective analysis of 50 cases correspondence lorenzo montesi, md lorenzomontesi@yahoo.it luigi quaresima, md (corresponding author) luigiquaresima@yahoo.it marco tiroli, md marcotiroli@libero.it vito lacetera, md vlacetera@gmail.com ubaldo cantoro, md ubymaior@libero.it giulia sbrollini, md giuliasbrollini@libero.it giovanni muzzonigro, md g.muzzonigro@univpm.it massimo polito, md max_polito@virgilio.it institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy quaresima 2_stesura seveso 15/01/15 12:50 pagina 355 stesura seveso 15archivio italiano di urologia e andrologia 2014; 86, 1 original paper urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption ali abdel raheem, hassan el-tatawy, ahmed eissa, abdel hamid elbahnasy, mohamed elbendary urology department, tanta university hospital, egypt. objectives: penile fracture with concomitant complete urethral disruption is an uncommon urologic disorder. data about the treatment and outcome measurements of this condition are scarce in the literature. the aim of the present study is to evaluate the long term urinary and sexual functions of patients with penile fracture associated with complete urethral injury after immediate surgical reconstruction. patients and methods: twelve patients met our inclusion criteria and were included in this retrospective case series study; however, one was lost during follow-up. patient's medical records were reviewed and all patients were interviewed for clinical evaluation. urinary function was assessed by history, uroflometry and retrograde urethrography, while, sexual function was assessed by questionnaire (sexual health inventory for men) and penile doppler for patients with erectile dysfunction. results: patients’ mean age was 32.3 ± 7.5 years (range 21-43) and the mean follow-up period was 72.6 ± 45.4 months (range 14-187). vigorous sexual intercourse was the main cause in 91% of our patients. no serious long term complications was found. only 1 patient (9%) suffered from anterior urethral stricture, 1 patient (9%) complained of weak erection, 3 patients (27%) had a palpable fibrosis and 2 patients (18%) reported a slight penile curvature during erection. ninety one percent of all our patients maintained their normal urinary and sexual functions. conclusion: on the long term follow-up, most of the patients maintained their normal erectile and voiding functions with no harmful long-term complications. we advocate immediate surgical intervention and reconstruction of both corpora cavernous and urethra as a first line treatment for those patients.. key words: urinary function; sexual function; penile fracture; surgical treatment. submitted 31 july 2013; accepted 5 october 2013 summary introduction penile fracture is a rare emergent urologic condition, which is characterized by disruption of the tunica albuginea of one corpus cavernosum or both (1). till the year 2001, only 1331 cases had been reported in the literature (2). it seems that its incidence is higher in middle-east countries than in usa and western countries (3, 4). penile fracture may be associated with urethral injury in up to 38% of cases (5). many causes of penile fracture have been reported, including sexual intercourse, sudden forced flexion, masturbation, and direct blunt trauma or rolling over in bed onto an erect penis (6). with fully erected penis, the tunica albuginea which is one of the strongest fascia in the human body – can withstand pressures up to 1500 mmhg – stretches and becomes as thin as 0.25-0.5 mm thick, while in the flaccid state it is 2.4 mm (7, 8). so the erected penis is much more vulnerable to rupture after trauma than the flaccid penis. fracture penis is a clinical diagnosis, typically the patient describes hearing a popping or snapping sound followed by sudden detumescence and pain. clinically penile swelling, hematoma, ecchymosis and penile deformity are present (figure 1) (2). no conflict of interest declared figure 1. the classic clinical picture for penile fracture (swelling, hematoma and penile deformity). doi: 10.4081/aiua.2014.1.15 raheem_stesura seveso 26/03/14 10:12 pagina 15 archivio italiano di urologia e andrologia 2014; 86, 1 a. abdel raheem, h. el-tatawy, a. eissa, a. hamid elbahnasy, m. elbendary 16 suspicion of urethral injury is increased with presence of blood at the external meatus or hematuria (3), therefore, retrograde urethrography is prefered by many authors to confirm urethral injury diagnosis (9, 10). regarding the role of imaging studies in the diagnosis of penile fracture still there is controversy. some studies showed the usefulness of ultrasound, cavernosography and mri (11, 12) with superiority of mri in identification of corporal injury (13). however, a recent study showed that mri is not able to reveal detailed information about extent of corporal and urethral injury over surgical exploration (14). for treatment of penile fracture immediate surgical exploration and repair has the advantages of short hospital stay, better patient satisfaction, and improved outcomes with lower incidence of erectile dysfunction (6, 15, 16). the aim of this retrospective study is to report our experience and to assess the long-term urinary and sexual functions for patients with penile fracture and complete urethral injury who were treated with immediate surgical reconstruction. material and methods this retrospective study was approved by our ethical committee review board. the medical records and database at our institute were reviewed to identify all patients with penile fracture who were treated surgically from 1985 till 2012. overall 246 patients were detected of whom 34 patients had associated urethral injury (22 partial and 12 complete). we included only patients with complete urethral disruption. we reviewed the history, presentations, investigations, operative and postoperative data of these patients. surgical technique: prophylactic antibiotic was used before surgery. under spinal anesthesia all patients underwent an immediate surgical exploration through a subcoronal circumcising incision with degloving of the penis (figure 2a). once the site of the tunical tear was identified and the hematoma was evacuated we closed the tear with 3/0 absorbable (polydioxanone or polyglycolic acid) either continues or interrupted sutures (figure 2b-2c). an artificial erection test through intracorporal saline injection was done to detect any leakage from the tunical tear or curvature at the repaired site. the urethra was repaired over 18 french silicon catheter. the urethral edges were dissected at both sides, trimmed, spatulated and closed with interrupted absorbable sutures using (3/0 or 4/0 polydioxanone) after ensuring tension-free end-to-end anastomosis (figure 2d-2e). suprapubic catheter insertion or not was determined by the surgeon preference. postoperative care: patients received oral antibiotics for 1 week, analgesics on demand and diazepam 5 mg nightly in an attempt to prevent nocturnal erections. all patients were instructed to abstain from sexual activity for at least 8 weeks. the urethral catheter was left in place for at least 3 weeks and then removed. if a suprapubic catheter was inserted it was closed for at least 3 days after urethral catheter removal to ensure adequate and normal voiding before its removal. follow-up: we contacted patients through the telephone and an interview was done with each patient at the followup in our outpatient clinic. all patients were examined with particular concern for local penile examination to detect penile curvature and/or fibrotic nodules. patients' sexual function was evaluated subjectively through the sexual health inventory for men (shim), a questionnaire of 5 questions which is a short version of the long international index of erectile function (iief-15) questionnaire (17). color doppler ultrasonography was performed for patients with erectile dysfunction. the urinary function was evaluated objectively with uroflowmetry. retrograde urethrography was done for all patients early after catheter removal to ensure urethral healing and during follow-up if voiding symptoms present. figure 2. surgical technique description: a) degloved penis with large hematoma at the fracture site. b) after hematoma evacuation both corpora was injured with complete urethral separation. c) after closure of the tunical tear with continuous 3/0 pds suture. d) the urethral edges were dissected at both sides, trimmed and spatulated with stay sutures. e) the urethral edges were closed with interrupted absorbable sutures after ensuring tension free end-to-end anastomosis. raheem_stesura seveso 26/03/14 10:12 pagina 16 results twelve patients who met our inclusion criteria were included in this retrospective series. all patients were married and their mean age was 32.3 years (range: 21-43) and mean follow-up period was 72.6 months (table 1). all patients (100%) presented with penile swelling, hematoma and urethral bleeding on examination, while, 3 patients (25%) and 4 patients (33%) were presented with acute urinary retention (aur) and voiding difficulties, respectively. the mean time elapsed between the occurrence of the trauma and the patients' arrival was 5.5 hours (range: 1-15) (table 1). the most common cause of penile fracture was vigorous sexual intercourse in 11 patients (91%) while one patient reported a history of forced penile pending (table 1). a routine urethrography was done in all patients and showed extravasation of dye with loss of urethral patency at the anterior penile urethra. the site of the tear was at penile mid-shaft in all patients and the urethra disruption level was opposite to and at the same tear level (figure 3). suprapubic catheter was inserted in 5 patients. the mean operative time was 60.3 minutes, the duration of catheterization ranged from 21 to 29 days, and the mean hospital stay was 2.1 days (table 1). one patient was lost during follow-up due to unknown causes and was excluded from our study. during patients' assessment a palpable fibrosis and slight penile curvature during erection were found in 27% and 18% of patients respectively. ten out of 11 patients reported good voiding function with mean qmax 20.9 ± 4.2, no significant post voifing residual (pvr) urine and normal urethrography. only one patient complained of voiding difficulites and his urethrography showed a ring stricture at the anterior urethra which was treated successfully by regular urethral dilatation (figure 4). regarding the sexual function, all patients maintained normal sexual activity with complete recovery of their erectile function as shown in their shim with mean value 22.2 ± 3, except one patient who suffered from weak erection and was treated successfully with oral sildenafil® 100 mg on demand. 17archivio italiano di urologia e andrologia 2014; 86, 1 urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption clinical presentation: – penile swelling all patients (100%) – hematoma all patients (100%) – urethral bleeding all patients (100%) – sever pain all patients (100%) – acute urinary retention 3 patients (25%) – voiding difficulties 4 patients (33%) predisposing factors: – vigorous sexual intercourse 11 patients (91%) – forced penile pending 1 patient (9%) perioperative data: mean ± sd (range) – age (years) 32.3 ± 7.5 (21-43) – time of presentation (hours) 5.5 ± 3.9 (1-15) – operative time (minutes) 60.3 ± 6.5 (45-68) – hospital stay (days) 2.1 ± 0.7 (1-3) – duration of catheterization (days) 22.5 ± 2.5 (21-29) – follow-up period (months) 72.6 ± 45.4 (14-178) long term complications: – stricture urethra 1 patient (9%) – erectile dysfunction 1 patient (9%) – palpable fibrosis 3 patients (27%) – penile curvature during erection 2 patients (18%) uroflometry: mean ± sd (range) – qmax (ml/s) 20.9 ± 4.2 (14-28) – voided volume (ml) 29.9 ± 18.5 (0-70) – pvr urine (ml) 264.7 ± 66.5 (160-370) sexual health inventory questionnaire mean ± sd (range) 22.2 ± 3 (14-25) table 1. patients' characteristics, perioperative and follow-up data. figure 3. showing the usual site of the tear at mid-shaft of the penis in and the urethra disruption level was opposite to and at the same tear level with retraction of urethral edges. figure 4. a retrograde urethrogram showing a ring stricture at the anterior urethra. raheem_stesura seveso 26/03/14 10:12 pagina 17 archivio italiano di urologia e andrologia 2014; 86, 1 a. abdel raheem, h. el-tatawy, a. eissa, a. hamid elbahnasy, m. elbendary 18 discussion this retrospective study is the biggest series reported in the literature for long term functional outcomes of 11 patients with penile fracture associated with complete urethral disruption. to our knowledge, only few case reports and some case series with small number of patients reported this rare condition (18-21). in the present study the incidence of urethral injury in patients with penile fracture was 13.8% (34/246), and this finding was in accordance with koifman et al. who showed an incidence 12.5% for associated urethral injury (22). the result of our study refers to both hematuria and blood at the external meatus as a hallmark findings for concomitant urethral injury diagnosis, since all of our patients (100%) showed both findings on examination, the same findings were reported by derouiche et al. who observed that 10 out of 10 patients (100%) who presented with bloody urethral discharge had associated urethral injury (3). other clinical presentations such as penile swelling, hematoma, pain and penile deformity are common findings in all patients with penile fracture, but not specific for diagnosis of urethral injury. although 58% of our patients had voiding difficulties and aur, however, these findings may present in the absence of urethral injury, due to the presence of penile deformity, large hematoma and severe edema causing urethral obstruction (23). it seems to us that the association of complete urethral injury and penile fracture need more forcible trauma to occur and this was evident in our study, since, the main underlying etiology in 11/12 patients was due to vigorous sexual intercourse. el-assmy et al. reported that vigorous coital trauma was the commonest cause (50%) of penile fracture associated with urethral injury (19). and this may also explain that all our patients had a bilateral corporal rupture owing to the severity of the trauma. in our series all patients underwent retrograde urethrography as it is a routine investigation in our department for patients with penile fracture if a high clinical suspicion of associated urethral injury is present. the sensitivity of retrograde urethrography in the diagnosis of associated urethral injury was 100%. in contrast, mydlo, found that the sensitivity of this test is only 50% with a possibility of a false negative results (1). conservative treatment for penile fracture treatment consisted mainly of cold compresses, pressure dressings, antibiotics and anti-inflammatory drugs (24-26). nowadays, many studies supported the superiority of surgical treatment over conservative treatment (27, 28). moreover, excellent long-term results and lower complication rates have been reported with immediate surgical repair (1, 6, 29). the mean follow-up for our patients was 72.6 months; of them 91% showed no voiding difficulties. several studies and case reports aroused the important role of immediate surgical repair on restoring back the normal urinary function even with complete urethral disruption (6, 19, 20) and their findings was in match with our results. ninety one percent maintained normal erectile function and sexual activity of our patients, whereas other studies reported similar result in 83% and 93% respectively (19, 30). of the long-term complications a palpable fibrosis was found in 27% of patients and slight penile curvature on erection in 18%, but this did not affect their sexual activity. a palpable penile fibrosis is a common long-term complication with an incidence ranging from 41% up to 93 % (30, 4). a limitation of the present study is being a retrospective case series: in addition to, the surgical technique was not uniform regarding suprapubic catheter insertion and suturing of the tunica albuginea. however, being a retrospective study with a small number of patients may be explained by the rarity of this condition and the difficulty to be evaluated prospectively in regard to optimal initial treatment. also it seems that the difference in some surgical steps did not affect the outcome of surgery during follow-up. in summary, penile fracture concomitant with complete urethral rupture, although being uncommon, however, is still a urological emergency which if not managed correctly may carry the risk of many long-term complications such as erectile dysfunction, penile curvature, fibrosis and urethral stricture. to our knowledge penile fracture is diagnosed clinically, in addition, the presence of urethral bloody discharge represents an alarm for an associated urethral injury and a retrograde urethrography is recommended. the risk of concomitant complete urethral injury is increased with increase of the severity of the trauma, and most cases are due to vigorous sexual intercourse. complete urethral disruption often present at the same level of the tunical tear and usually the tear involve both corpora. after final diagnosis we recommend immediate surgical repair of both ruptured corpora and urethra as it carries a lower risk of complication and better long-term functional outcomes for both urinary and sexual functions. conclusion penile fracture associated with complete urethral injury is a very rare, yet, an emergent urological condition. vigorous sexual intercourse was found to be the most common cause of concomitant complete urethral disruption. blood at the external urethral meatus and hematuria represents a hallmark for urethral injury. immediate surgical treatment reduces the serious long-term complications and improves the functional outcomes. references 1. mydlo jh. surgeon experience with penile fracture. j urol. 2001; 166:526-8. 2. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 3. derouiche a, belhaj k, hentati h, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111-4. 4. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 353 patients from kermanshah, iran. j sex med. 2009; 6:1141-50. 5. fergany af, angermeier kw, montague dk. review of cleveland clinic experience with penile fracture. urology. 1999; 54:352-5. 6.ibrahiem ei, el-tholoth hs, mohsen t, et al. penile fracture: longraheem_stesura seveso 26/03/14 10:12 pagina 18 term outcome of immediate surgical intervention. urology. 2010; 75:108-11. 7. bitsch m, kromann-andersen b, schou j, sjontoft e. the elasticity and the tensile strength of tunica albuginea of the corpora cavernosa. j urol. 1990; 143:642-645. 8. de rose af, giglio m, carmignani g. traumatic rupture of the corpora cavernosa: new physiopathologic acquisitions. urology. 2001; 57:319-22. 9. cross m, arnold t, peters p. fracture of the penis with associated laceration of the urethra. j urol. 1977; 117: 725. 10. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164:364-6. 11. mydlo jh, hayyeri m, macc rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology 1998; 51:616-9. 12. rahmouni a, hoznek a, duron a, et al. magnetic resonance in penile rupture: aid to diagnosis. j urol 1995; 153:1927-8. 13. fedel m, venz s, anderssen r, et al. the value of magnetic resonance imaging in the diagnosis of suspected penile fracture with atypical clinical findings. j urol. 1996; 155:1924-1927. 14. hatzichristodoulou g, gschwend j, herkommer k, niko z. accuracy of magnetic resonance imaging for diagnosis of penile fracture – comparative analysis with intraoperative finding. j urol. 2013; 189, 4s. 15. nicolaisen gs, melamud a, williams rd, mcaninch jw. rupture of the corpus cavernosum: surgical management. j urol. 1983; 130:917-9. 16. asgari ma, hosseini sy, safarinejad mr, et al. penile fractures: evaluation, therapeutic approaches and long-term results. j urol. 1996; 155:148-9. 17. rosen rc, cappelleri jc. the sexual health inventory for men (shim): a 5-year review of research and clinical experience. int j impot res 2005; 17:307-19. 18. el-assmy a, el-tholoth hs, mohsen t, ibrahiem ei. long-term outcome of surgical treatment of penile fracture complicated by urethral rupture. j sex med. 2010; 7:3784-3788. 19. tanello m, bettini e, griggi s, et al. a rare case of penile fracture with complete urethral rupture during sexual intercourse. arch ital urol androl. 2005; 77:153-4. 20. soylu a, yilmaz u, davarci m, baydinc c. bilateral disruption of corpus cavernosum with complete urethral rupture. int j urol. 2004; 11:811-2. 21. tsang t, demby am. penile fracture with urethral injury. j urol. 1992; 147:466-8. 22. koifman l, cavalcanti ag, manes ch, et al. penile fracture experience in 56 cases. int braz j urol. 2003; 29:35-9. 23. davies dm, mitchell i. fracture of the penis. br j urol. 1978; 50:426. 24. creecy aa, beazlie fsjr. fracture of the penis: traumatic rupture of corpora cavernosa. j urol. 1957; 78:620. 25. farah rn, stiles r jr, cerny jc. surgical treatment of deformity and coital difficulty in healed traumatic rupture of the corpus cavernosa. j urol. 1978; 120:118-20. 26. mydlo jh, gershbein aband macchia rj. non-operative treatment in patients with presumed penile fracture. j urol. 2001; 165:424-425. 27. muentener m, suter s, hauri d, sulser t. long term experience with surgical and conservative treatment of penile fracture. j urol. 2004; 172:576-579. 28. yapanoglu t, aksoy y, adanur s, et al. seventeen years’ experience of penile fracture: conservative vs. surgical treatment. j sex med. 2009; 6:2058-63. 29. mansi mk, emran m, el-mahrouky a, el-mateet ms. experience with penile fractures in egypt: long-term results of immediate surgical repair. j trauma 1993; 35:67-70. 30. ateyah a, mostafa t, nasser ta, et al. penile fracture: sur gical repair and late effects on erectile function. j sex med. 2008; 5:1496-502. 19archivio italiano di urologia e andrologia 2014; 86, 1 urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption correspondence ali abdel raheem, md hassan el-tatawy, md ahmed eissa, md abdel hamid elbahnasy, md mohamed elbendary, md (corresponding author) professor of urology mbendary@hotmail.com urology department tanta university hospital, egypt raheem_stesura seveso 26/03/14 10:12 pagina 19 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4184 introduction lower urinary tract symptoms due to benign prostatic hyperplasia (bph/luts) and benign prostatic enlargement are very common diseases in men older than 40 years (1). male sexual dysfunction are, also, very common original paper an improvement in sexual function is related to better quality of life, regardless of urinary function improvement: results from the idiprost® gold study tommaso cai 1, giuseppe morgia 2, giuseppe carrieri 3, carlo terrone 4, ciro imbimbo 5, paolo verze 5, vincenzo mirone 5, idiprost® gold study group * 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology and department of hygiene and public health, university of catania, catania, italy; 3 department of urology and renal transplantation, university of foggia, foggia, italy; 4 division of urology, aso maggiore della carità university hospital, university of eastern piedmont, novara, italy; 5 department of urology, university federico ii of naples, italy. objective. the relationship between lower urinary tract symptoms (luts) and erectile dysfunction (ed) has recently received increased attention. the aim of this study was to evaluate the efficacy of the alfa-5® association of serenoa repens, pinus massoniana bark extract (pmbe) and crocus sativus (idiprost® gold) in improvement of patient’s quality of life, when compared with serenoa repens alone. materials and methods. all patients with clinical and instrumental diagnosis of luts due to benign prostatic hyperplasia (bph) and ed, attending 5 italians urological institutions from may to december 2012 were enrolled in this prospective, multicentre, phase 3 study. participants were assigned to receive oral capsules of idiprost® gold (one capsule q24 h) or serenoa repens 320 mg (one capsule q24h) for 3 months. clinical and instrumental analyses were carried out at the enrolment and at the end of therapy. ipss, iief-5 and sf-36 questionnaires have been used. the main outcome measure was the improvement of quality of life at the end of the whole study period. results. 129 (mean age 45-71 ± 4.36) men were randomly allocated to idiprost® gold (n = 83) or serenoa repens (n = 46). the baseline questionnaire mean scores were 17.1 ± 6.4, 14.9 ± 3.7, 96.3 ± 1.2 for ipss, iief-5 and sf-36, respectively. at the follow-up examination, statistically significant differences have been reported in terms of ipss (11.9 vs 13.8; p < 0.001), iief-5 and sf-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; p < 0.003; p < 0.001). moreover, statistically significant differences were then reported between the two visits, in terms of ipss, iief-5 and sf-36 scores (p < 0.003; p < 0.001; p < 0.001), only in the idiprost® gold group. conclusions. in conclusions, we found that idiprost® gold significantly improve the quality of life of patients affected by luts due to bph and ed, specifically in terms of sexual function, highlighting that a better sexual quality of life is correlated with an higher overall quality of life regardless of the urinary function. key words: bph; luts; erectile dysfunction; serenoa repens; crocus sativus; quality of life. submitted 27 july 2013; accepted 5 october 2013 no conflict of interest declared summary in this population; in the european male ageing study of 3,369 community-dwelling men aged 40-79 years, moderate or severe erectile dysfunction (ed) was reported by 6% of men in their forties, rising to 64% of men aged over doi: 10.4081/aiua.2013.4.184 cai_stesura seveso 18/12/13 10:43 pagina 184 185archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life 70 years (2). moreover, in the multinational survey of the ageing male (msam-7) the overall prevalence of luts was 90%, while the overall prevalence of ed was 49%, highlighting that rate of ed was significantly dependent on age and correlated highly with the severity of luts (3). both bph⁄ luts and sexual dysfunction have a substantial negative impact on a man’s quality of life and are considered a serious socio-economic problem (4). the current therapies for bph/luts are associated with bothering sexual side effects, however, differing in rate and characteristics between different classes of medications, different medications within the same classes, and different combinations of drugs (5). for these reasons, pde5-is are introduced in the italian pharmacopeia as an effective and treatment for luts associated with ed. even if pde5-is are effective either alone or in combination with !-blockers in men with bph/luts, some adverse events, such as headache, dyspepsia, and back pain, are commonly reported (5). furthermore, future studies are needed to evaluate the long-term safety and efficacy outcomes and the overall cost-effectiveness analysis of this treatment (5). on the basis of the evidences, the use of phytotherapy in treating lower urinary tract symptoms and benign prostatic hyperplasia has been popular in europe for many years with promising results. in the last years, the attention has been focused on the both luts/bph and ed treatment, due to the patient’s request to improve his sexual and urinary quality of life. recently, the alfa-5® association of serenoa repens, pinus massoniana bark extract (pmbe) and crocus sativus, named idiprost® gold, has been produced in order to improve the micturition parameters and sexual function in patients affected by luts/bph and ed. the effects on micturition parameters are due to the effects of serenoa repens, as well known, and the effect on sexual function has due to pmbe and crocus sativus. we aimed to evaluate the efficacy of the alfa-5® association serenoa repens, pmbe and crocus sativus (idiprost® gold) in improvement of patient’s quality of life, when compared with serenoa repens alone. materials and methods study design all patients with clinical and instrumental diagnosis of luts due to bph and ed, attending 5 italians urological institutions from may to december 2012 were enrolled in this prospective, multicentre, phase 3 study. all patients underwent clinical and instrumental examinations and ipss, iief-5 and sf-36 questionnaires. after enrolment, all patients were assigned to receive oral capsules of idiprost® gold (one capsule q24h) or serenoa repens 320 mg (one capsule q24h) for 3 months. the main outcome measure was the improvement of quality of life at the end of the whole study period, evaluated by questionnaires results. inclusion and exclusion criteria patients were eligible for inclusion if they had to meet all of the following criteria: age of 50 years or older; to be sexually active; maximal urinary flow rate (cmax) of less than 15 ml/s; post-residual voided volume less than 100 cc; an international prostate symptom score (ipss) of 8 or greater and an ipss-quality of life (qol) score of 2 or greater; prostate specific antigen (psa) less than 4 ng/ml, or higher if negative prostate biopsy; an international index of erectile function (iief-5) score less than 21; to be untreated for luts/bph; testosterone level more than 3 ng/dl. we excluded all patients affected by major concomitant diseases such as diabetes, liver, and/or renal failure; had known anatomical abnormalities or malignancy of the urinary tract, bladder, or upper tract stones, diverticula, foreign bodies, prostatitis, active urinary tract infection, chronic retention or had polycystic kidney disease. moreover, we excluded all patients with urethral stenosis interfering with the evaluation of voiding function; patients with a history of transurethral resections of the prostate (turp), laser therapy, or thermotherapy. similarly, all patients who tested positive for sexually transmitted diseases such as chlamydia trachomatis, ureaplasma urealyticum or neisseria gonorrhoeae were excluded. moreover, all patients with allergy to one or more compounds of idiprost® gold were also excluded. all patients treated with pde5-is were excluded too. study and treatment schedule on arrival at each centre, all eligible individuals signed written informed consent and underwent a baseline questionnaire, urological examination with anamnestic interview and uroflowmetry (cmax) with evaluation of post voided residual volume (pvr), in accordance with the procedure described in eau guidelines (6). psa value has been previously evaluated. all patients who met the inclusion criteria were assigned to groups according to a 1:1 randomization (figure 1). group a: idiprost® gold (one capsule q24h). group b: serenoa repens 320 mg (one capsule q24h). all patients underwent treatment for 3 months. all patients were contacted by telephone on day 30 of the therapy to ensure correct timing and dose treatment. each subject was scheduled for follow-up examination at 3 months from starting therapy, with a urological visit, uroflowmetry with evaluation of pvr and questionnaires to be filled in. no placebo arm was included. the possible biases caused by the lack of placebo arm were considered in the results analysis. the main outcome measure was the improvement of quality of life at the end of the whole study period, in terms of changes in ipss, ipss-qol, cmax, pvr, sf-36 and the iief-5 from baseline to the evaluation point, that is, 3 months. clinical failure was defined as the persistence of symptoms after the treatment, or the suspension of therapy for significant reported adverse effects. in addition, spontaneously reported adverse events, or those noted by the investigator, were recorded during the whole study period. the study was conducted in line with good clinical practice guidelines, with the ethical principles laid down in the latest version of the declaration of helsinki. questionnaires and urological examinations the validated italian versions of the international prostatic symptom score (ipss) (7), international index of erectile function (iief-5) (8) and sf-36 (9) were administered to each patient. cai_stesura seveso 18/12/13 10:43 pagina 185 archivio italiano di urologia e andrologia 2013; 85, 4 t. cai, g. morgia, g. carrieri, c. terrone, c. imbimbo, p. verze, v. mirone, idiprost® gold study group 186 the questionnaire was offered to the patient on arrival at each centre. all questionnaires were also used in determining clinical therapy efficacy. composition and characterisation of the extracts used all patients assigned to group a were orally administered idiprost® gold once daily. idiprost® gold each capsule (950 mg) contains the alfa-5® association consists of serenoa repens 320 mg, crocus sativus 100 mg, pinus massoniana 120 mg. all compound analyses were carried out according to fiamegoset et al. (10). all patients assigned to group b were orally administered serenoa repens 320 mg. statistical analysis in order to analyse the homogeneity of the two groups, the baseline characteristics were compared using the t test and wilcoxon-mann-whitney test for continuous variables and by the chi-square test for categorical variables. the sample size was calculated prospectively under the following conditions: difference between the groups = 10%, alpha error level = 0.05 two-sided, statistical power = 80% and anticipated effect size (cohen’s d = 0.5). the calculation yielded 2 ! 64 individuals per group. analysis of variance (anova) was used for comparing means. bonferroni adjustment test was also used at the second stage of the analysis of variance. the effect size between the means (cohen's d) was also calculated. the differences between the groups regarding semen parameters were obtained using chi-square or fisher’s exact tests. statistical significance was achieved when p was < 0.05. all reported p-values were two-sided. statistical analyses were performed using spss 11.0 for apple-macintosh (spss, inc., chicago, illinois). results from a total population of 146 patients with luts/bph and ed, 132 patients were eventually enrolled and randomised. out of the 14 patients excluded from the study, 10 had refused to be enrolled and 4 were lost at the follow-up. finally, 132 were allocated (figure 2). anamnestic and clinical data at enrolment are described in table 1. no statistically significant differences between the groups were found. from 132 enrolled patients, 85 were allocated to idiprost® gold and 46 to serenoa repens 320 mg. compliance to treatment schedule and adverse effects in group a 83 patients (97.6%) were analysed after 2 were lost at follow up. in group b 46 patients (97.8%) were analysed after 1 was lost at follow up (figure 2). accordingly, compliance to this study protocol was satisfactory. the idiprost® gold formulation was well tolerated in all patients analysed and there were no significant drug-related side effects. in group a, 1 out of 83 patients (1.2%) had mild adverse effects that did not require treatment suspension. also in group b, 1 out of 46 patients (2.1%) reported mild adverse effects. clinical and laboratory results at follow up at the follow-up examination (3 months after treatment), statistically significant differences have been reported between the two groups in terms of ipss (11.9 vs 13.8; df = 127; t = 10.3; p < 0.001), iief-5 and sf-36 mean scores (19.3 vs 16.1; 99.7 vs 96.3; df = 127; t = 17.4; p < 0.003; df = 127; t = 18.4; p < 0.001). moreover, statistically significant differences were then reported between the two visits, in terms of iief-5 and sf-36 scores (p < 0.001; p < 0.001), in the idiprost® gold group. very few aes have been reported in the both groups without any significant difference. figure 1. the figure shows the study design. cai_stesura seveso 18/12/13 10:43 pagina 186 187archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life the table 2 shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. discussion luts due to bph and sexual dysfunction are very common in men and the association between luts/bph and ed is very intriguing. moreover, some epidemiological studies demonstrated that the association between luts/bph and sexual dysfunction in ageing men is independent of the effects of age, other comorbidities and lifestyle factors (11). on the other hand, there is an increasing needed for drugs able to improve the patient’s quality of life without adverse side effects. in the present study we evaluate the efficacy of idiprost® gold in improvement of patient’s quality of life. we found some important findings: 1) the efficacy of idiprost® gold in improve urinary and sexual function in patients affected by luts/bph and ed, when compared with serenoa repens alone; 2) the improvement in sexual quality of life is linked with an higher overall quality of life regardless of the urinary function; 3) very few adverse side effects have been found in the idiprost® gold group. the efficacy of idiprost® gold in the management of urinary and sexual function is due to the association between serenoa repens, pmbe and crocus sativus. even if the efficacy of serenoa repens appears to be a useful option for improving lower urinary tract symptoms (12), the association with pmbe and crocus sativus is able to improve the efficacy of serenoa repens due to: a) antioxidant effect, free radical scavenging activities and vasoprotective effect due to oligomeric proanthocyanidin complexes (opc) of pinus massoniana bark extract (pmbe) (13-14), b) increasing of nitric oxide activity by antioxidant effect of pmbe, c) apoptosis inducing properties of pmbe (15), d) promotion of the diffusion of oxygen in tissues due to crocus sativus effect (16) and e) the aphrodisiac properties of crocus sativus (17). recently, hosseinzadeh et al. demonstrated in an animal model study the aphrodisiac activity of crocus sativus aqueous extract and its constituent crocin (18). moreover, they demonstrated that crocetin, a constituent of saffron, significantly restored the endo thelium-de pen dent relaxation of the thoracic aorta in hypercholesterolemic rabbit, which might be explained by its action to increase the vessel enos activity, leading to elevation of no production (18). figure 2. the figure shows the study flow-chart. cai_stesura seveso 18/12/13 10:43 pagina 187 archivio italiano di urologia e andrologia 2013; 85, 4 t. cai, g. morgia, g. carrieri, c. terrone, c. imbimbo, p. verze, v. mirone, idiprost® gold study group 188 the same authors highlighted that as crocin (the crocetin digentiobiosyl-ester) converts to crocetin, it is possible that this component acts in a way similar to pde-5 inhibitors such as sildenafil (18). furthermore, crocus sativus seems to have affinity to bind benzodiazepine receptors (19) and exhibited antidepressant activity that it might inhibit the reuptake of serotonin (20). moreover, shamsa et al. in a clinical trial found that after the ten days of taking saffron there was a statistically significant improvement in tip rigidity and tip tumescence as well as base rigidity and base tumescence, highlighting that crocus sativus showed a positive effect on sexual function with increased number and duration of erectile events seen in patients with ed even only after taking it for ten days (21). these are the pharmacological basis justifying the effectiveness of idiprost® gold. another aspect to discuss is the fact that we have found that an improvement in sexual quality of life is linked with a higher overall quality of life regardless of the urinary function. it could be due to the fact that the impact of sexual dysfunction on pa tients’ quality of life is higher than luts, as demonstrated by several authors (3, 22.) finally, the present study shows few limitations to take into account; firstly, the lacks of placebo arm. however, we planned this study without a placebo arm due to the fact that we think that is not ethical to not treat patients with luts/bph and ed. moreover, the short follow-up period that not allows to evaluate the possible adverse side effect at long time. idiprost®gold mean (sd or %) serenoa repens 320 mg mean (sd or %) patients (n°) 83 46 background information • age 58.9 (± 3.56) 59.1 (± 3.68) • marital status married 53 (63.8) 30 (65.3) unmarried 20 (24.0) 11 (23.9) divorced 10 (12.2) 5 (10.8) • educational qualification primary school 30 (36.2%) 18 (39.1%) high school 29 (35.0%) 15 (32.7%) university 24 (28.8%) 13 (28.2%) • smooking yes 28 (33.8) 16 (34.7) no 55 (66.2) 30 (65.3) • comorbidity charlson index 1.9 (± 0.8) 2.0 (± 0.9) • bmi (body mass index) 26.9 (± 1.3) 27.1 (± 1.1) baseline clinical data • psa total (ng/ml) 2.02 (± 1.45) 2.08 (± 1.59) • pvr (ml) 29.9 (± 28.8) 32.8 (± 29.9) • uroflowmetry data qmax (ml/sec) 11.7 (± 2.2) 11.9 (± 2.1) • prostate volume (ml) 43.9 (± 21.1) 41.4 (± 17.2) • ipss 17.1 (± 5.9) 16.9 (± 5.8) • iief-5 14.9 (± 3.5) 15.1 (± 3.7) • sf-36 96.4 (± 1.1) 96.9 (± 1.2) table 1. clinical, instrumental and laboratory patient’s data. idiprost®gold serenoa repens 320 mg mean (sd) mean (sd) ipss v1 17.1 (± 5.9) 16.9 (± 5.8) v2 11.9 (± 1.1) 13.8 (± 1.3) iief-5 v1 14.9 (± 3.5) 15.1 (± 3.7) v2 19.3 (± 1.0) 16.1 (±1.2) sf-36 v1 96.4 (± 1.1) 96.9 (± 1.2) v2 99.7 (± 1.2) 96.3 (± 2.3) table 2. questionnaires results at the enrolment and at the follow-up visit. the table shows the anamnestic, clinical and instrumental data from all patients at the enrolment time. n° = number; sd or % = standard deviation or percentage; pvr = post-residual voided volume; ipss = international prostate symptom score; iief-5 = international index of erectile function; sf-36 = short form-36. the table shows all questionnaires results between the two groups at the enrolment and at the follow-up visit. v1 = visit 1 (time 0); v2 = visit 2 (after 3 months). sd = standard deviation; ipss= international prostate symptom score; iief-5 = international index of erectile function; sf-36 = short form-36 cai_stesura seveso 18/12/13 10:43 pagina 188 189archivio italiano di urologia e andrologia 2013; 85, 4 sexual function improvement and quality of life conclusion in conclusions, we found that idiprost® gold significantly improve the quality of life of patients affected by luts due to bph and ed, specifically in terms of sexual function, highlighting that a better sexual quality of life is correlated with an higher overall quality of life regardless of the urinary function. references 1. girman cj, jacobsen sj, guess ha, et al. natural history of prostatism: relationship among symptoms, prostate volume and peak urinary flow rate. j urol. 1995; 153:1510-5. 2. corona g, lee dm, forti g, et al. age-related changes in general and sexual health in middle aged and older men: results from the european male ageing study (emas). j sex med. 2010; 7:1362-80. 3. rosen r, altwein j, boyle p, et al. lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (msam-7). eur urol. 2003; 44:637-49. 4. robertson c, link cl, onel e, et al. the impact of lower urinary tract symptoms and comorbidities on quality of life: the bach and urepik studies. bju int. 2007; 99:347-54. 5. gacci m, corona g, salvi m, et al. a systematic review and metaanalysis on the use of phosphodiesterase 5 inhibitors alone or in combination with !-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. eur urol. 2012; 61:994-1003. 6. madersbacher s, alivizatos g, nordling j, et al. eau 2004 guidelines on assessment, therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (bph guidelines). eur urol. 2004; 46:547-54. 7. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol 1997; 31:129-40. 8. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-30. 9. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin epidemiol. 1998; 51:1025-36. 10. fiamegos yc, nanos cg, vervoort j, stalikas cd. analytical procedure for the in-vial derivatization-extraction of phenolic acids and flavonoids in methanolic and aqueous plant extracts followed by gas chromatography with mass-selective detection. j chromatogr. a 2004; 1041:11-8. 11. mirone v, sessa a, giuliano f, et al. current benign prostatic hyperplasia treatment: impact on sexual function and management of related sexual adverse events. int j clin pract. 2011; 65:1005-13. 12. wilt tj, ishani a, rutks i, macdonald r. phytotherapy for benign prostatic hyperplasia. public health nutr. 2000; 3:459-72. 13. cui yy, xie h, qi kb, et al. effects of pinus massoniana bark extract on cell proliferation and apoptosis of human hepatoma bel7402 cells. world j gastroenterol. 2005; 11:5277-82. 14. neuwirt h, arias mc, puhr m, et al. oligomeric proanthocyanidin complexes (opc) exert anti-proliferative and pro-apoptotic effects on prostate cancer cells. prostate. 2008; 68:1647-54. 15. ma h, liu b, feng d, et al. pinus massoniana bark extract selectively induces apoptosis in human hepatoma cells, possibly through caspase-dependent pathways. int j mol med. 2010; 25:751-9. 16. rìos jl, recio mc, giner rm, manez s. an update review of saffron and its active constituents. phytother res. 1996; 10:189-193. 17. madan cl, kapur bm, gupta us. saffron. econ bot. 1966; 20:377. 18. hosseinzadeh h, ziaee t, sadeghi a. the effect of saffron, crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats. phytomedicine. 2008; 15:491-5. 19. hosseinzadeh h, sadeghnia hr. protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of gabaergic and opioids systems. phytomedicine. 2007; 14:256-262. 20. hosseinzadeh h, karimi gh, niapoor m, antidepressant effects of crocus sativus stigma extracts and its constituents, crocin and safranal, in mice. acta hortic. 2004; 650:435-445. 21. shamsa a, hosseinzadeh h, molaei m, et al. evaluation of crocus sativus l. (saffron) on male erectile dysfunction: a pilot study. phytomedicine. 2009; 16:690-3. 22. lowe fc. treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function. bju int. 2005; 95 (suppl 4):12-8. *appendix idiprost® gold study group. università degli studi di napoli “federico ii” prof. vincenzo mirone: marco franco, roberto la rocca. università degli studi di catania prof. giuseppe morgia: costanza salamone, claudia calì. università degli studi di foggia prof. giuseppe carrieri: giuseppe di fino, mario de siati. università degli studi del piemonte orientale prof. carlo terrone: angela maurizi. università degli studi di milano prof. francesco rocco: franco gadda. correspondence tommaso cai, md (corresponding author) department of urology, santa chiara regional hospital, trento, italy. largo medaglie d'oro, 9 ktommy@libero.it giuseppe morgia, md department of urology and department of hygiene and public health university of catania, catania, italy giuseppe carrieri, md department of urology and renal transplantation university of foggia, foggia, italy carlo terrone, md division of urology, aso maggiore della carità university hospital university of eastern piedmont, novara, italy ciro imbimbo, md paolo verze, md vincenzo mirone, md department of urology university federico ii, napoli, italy cai_stesura seveso 18/12/13 10:43 pagina 189 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 3228 original paper bleeding during laparoscopic partial nephrectomy: can a hemostatic matrix help to improve hemostasis? faruk ozgor, abdulmuttalip simsek, ozgu aydogdu, onur kucuktopcu, omer sarilar, ahmet yalcin berberoglu, mehmet fatih akbulut, murat binbay department of urology, haseki teaching and research hospital, istanbul, turkey. objectives: to evaluate the possible role of an hemostatic matrix on hemostasis, perioperative outcomes and complications in patients who underwent laparoscopic partial nephrectomy (lpn). materials and methods: patients charts were analyzed retrospectively and their demographic characteristics, operative parameters and follow-up results were recorded. patients were divided into two groups, according to those who used an hemostatic matrix as group 1 (n = 41) and those who did not used as group 2 (n = 44). demographic characteristics of patients, tumor features, operation time, clamping of the renal vessels, ischemia time, suturing of the collecting system, perioperative hemorrhage and complications were evaluated. histopathological results, surgical margin status, creatinine level and recurrence at the 3rd month of follow up were analyzed. statistical analyses were performed with spss 17.0 and significance was set at p value of < 0.05. results: the mean renal nephrometry score was 5.9 ± 2.0 and the mean tumor size was 35 ± 12 mm. all patients had a single tumor and 44 of them had a tumor in the right kidney. the renal artery was clamped in 79 cases and the mean ischemia time was 20.1 ± 7 minutes. the mean tumor size and the mean renal nephrometry score was statistically higher in group 1 (p: 0.016 and p < 0.001, respectively). pelvicaliceal repair was more common in group 1 due to deeper extension of tumors in this group (p: 0.038). in group 1, less hemorrhage and blood transfusion requirement, with shorter ischemia and operation time was detected. conclusion: the outcomes of the recent study showed that adjunctive use of an hemostatic matrix improves hemostasis and decreases hemorrhagic complications during lpn. further prospective studies are required to assess the potential role of an hemostatic matrix in lpn. key words: hemostatic matrix; partial nephrectomy; renal cell cancer. submitted 6 december 2015; accepted 31 march 2016 summary no conflict of interest declared. tial complications including urinary leakage and bleeding requiring transfusion (4). since lpn was firstly reported, several techniques for tumor excision and hemostasis have been investigated to achieve a bloodless operative field for precise tumor excision is an acceptable ischemia time and with the least possible deterioration of renal function (5). however, use of the suture techniques is time consuming and may cause additional tissue damage (6). some renal hemostatic agents have been previously described for use during lpn, to improve hemostasis and decrease complication rates. however, there is no consensus on the routine use of hemostatic agents during lpn. in a recent study, we aimed to investigate the possible role of an hemostatic matrix floseal (©floseal baxter healthcare corporation) on hemostasis, perioperative outcomes and complications in patients who underwent laparoscopic partial nephrectomy (lpn). material and methods in our clinic, laparoscopic partial nephrectomy (lpn) for renal tumours was performed in 85 patients by a single surgeon between may 2009 and february 2014. in patients with organ confined renal tumours with up to 7 cm in size, without lymph node and venous involvement, lpn was performed. informed consent was obtained from all the patients. patients’ charts were analyzed retrospectively and their demographic characteristics, operative parameters and follow-up results were recorded. patients were divided into two groups, according to those who used floseal as group 1 (n = 41) and those who did not used as group 2 (n = 44). a transperitoneal technique in the extended flank position with three trocars was preferred in all the patients. if necessary, additional trocar was inserted for liver or spleen retraction and re-postioning of the kidney. after incision of the todt line, dissection continued medially to expose the renal artery and vein. endoscopic bulldog clamps were used to interrupt blood flow, and peripheral small lesions were resected without hilar clamping. partial nephrectomy was performed with monopolar scissors. major transected intrarenal were stiched up with eight sutures, while renal parenchymal hemorrhage was kept. prepackaged hemostatic agent with a combination of 1.5 doi: 10.4081/aiua.2016.3.228 introduction previous studies demonstrated that nephron-sparing surgery has similar oncologic outcomes in selected patients when compared to radical nephrectomy (1, 2). laparoscopic partial nephrectomy (lpn) is a minimally invasive nephron sparing technique with favorable renal function outcomes, shorter hospital stay and decreased postoperative analgesic use (3). however, lpn is a technical challenging procedure and associated with poten229archivio italiano di urologia e andrologia 2016; 88, 3 bleeding during laparoscopic partial nephrectomy: can a hemostatic matrix help to improve hemostasis? ml of bovine gelatin matrix and 5000 us of bovinederived thrombin. this syringe was applied with an application device introduced into the abdomen through a laparoscopic port. the renal artery was then unclamped to terminate warm ischemia. demographic characteristics of the patients and tumor features were compared between the two groups. intraoperative parameters including operation time, clamping of the renal vessels, ischemia time, suturing of the collecting system, perioperative hemorrhage and complications were also evaluated. hemorragic complication was defined as bleeding leading to convert open surgery or radical nephrectomy and intraoperative or postoperative bleeding requiring transfusion. histopathological results, surgical margin status, creatinine level and recurrence at the 3rd month of follow up were also analyzed. statistical analysis statistical analyses were performed with spss 17.0 (new york, usa). results were described as numbers, means, standard deviations and percentages. comparisons were performed by the chi square test, student t test and mann whitney u test. significance was set at p value of < 0.05. results the mean age and the mean bmi of all patients were 58.8+/-10.9 years old and 24.7+/-3.0 kg/m2. all patients had a single tumour and 44 of them had a tumour in the right kidney. eight patients had an asa score of three, while hypertension and diabetes mellitus were the most common comorbidities. the mean renal nephrometry score was 5.9 ± 2.0 and the mean tumor size was 35 ± 12 mm. demographic data are listed in table 1. floseal was used in 41 patients and wedge resection was n° percentage (%) gender male 50 58.8% female 35 41.2% mean follow up time (months) 52.2+/-27.7 mean bmi (kg/m2) 24.7+/-3.0 asa score 1 52 61.2% 2 25 29.4% 3 8 9.4% comorbidities none 50 hypertension 24 diabetes mellitus 19 coronary arterial disease 6 chronic obstructive pulmonary disease 5 smoking yes 53 62.4% no 32 37.6% radiological tumor location lower pole 42 49.4% middle pole 31 36.5% upper pole 12 14.1% complaint follow up 34 40% lower urinary tract symptoms 1 1.2% weakness 1 1.2% hematuria 9 10.6% weight loss 2 2.4% abdominal pain 2 2.4% flank pain 36 42.4% mean r.e.n.a.l. score 5.9+/-2.0 mean tumor size (millimeters) 35+/-12 n° percentage (%) mean preoperative hemoglobin (g/dl) 13.0+/-1.3 mean preoperative creatinine (mg/dl) 1.09+/-0.35 mean postoperative day one hemoglobin (g/dl) 12.0+/-1.5 mean postoperative creatinine at 3rd month (mg/dl) 1.07+/-0.3 side left 41 48.2% right 44 51.8% tumor extraction technique wedge resection 79 92.9% enucleation 6 7.1% hemostatic agent usage yes 41 48.2% no 44 51.8% suturing of the collecting system yes 28 32.9% no 57 67.1% turning to open surgery yes 4 4.7% no 81 95.3% blood transfusion need yes 11 12.9% no 74 87.1% mean perioperative hemorrhage (ml) 153.6+/-50.2 mean operation time (minutes) 136.7+/-55.3 perioperative complications hemorrhage 5 5.9% clavien complications 0 70 82.4% 1 10 11.8% 2 2 2.4% 3 3 3.6% mean ischemia time (minutes) 20.1+/-7 mean hospitalization time (days) 3.5+/-1.6 histology angiomyolipoma 13 15.3% complicated cyst 1 1.2% oncocytoma 3 3.5% renal cell cancer 68 80% grade of rcc 1 42 2 21 3 6 pathological stage t1a 65 76% t1b 18 21.2% t2 2 2.4% surgical margin negative 83 positive 2 recurrance at 3rd month follow up yes 0 no 85 table 1. preoperative demographic data of patients. table 2. perioperative and post operative data of patients. archivio italiano di urologia e andrologia 2016; 88, 3 f. ozgor, a. simsek, o. aydogdu, o. kucuktopcu, o. sarilar, a. yalcin berberoglu, m. fatih akbulut, m. binbay 230 the most common technique for partial nephrectomy. the renal artery was clamped in 79 cases and the mean ischemia time was 20.1 ± 7 minutes. the mean perioperative hemorrhage was 153.6+/-50.2 ml and blood transfusion was required in 11 patients. suturing of the collecting system was performed in 28 patients. the most common histopathology was renal cell carcinoma and angiomyolipoma. patients’ preoperative data and pathological results are detailed in table 2. the mean tumor size and the mean renal nephrometry score was statistically higher in group 1 (p = 0.016 and p < 0.001, respectively). pelvicaliceal repair was more common in group 1 due to deeper extension of tumors in this group (p: 0.038). in group 1, use of floseal provided better bleeding control with less hemorrhage and blood transfusion requirement. because of the less stiches requirement in group 1, the mean ischemia time and the time operation were 18.2 and 115.6 minutes, respectively and these parameters were shorter in group 1 when compared with group 2 (p = 0.038). none of the laparoscopic procedures in group 1 was converted to open surgery whereas in group 2, four patients were converted to open surgery due to uncontrolled bleeding in two, decision for radical nephrectomy in one and technique difficulty in one. comparison between the two groups is summarized in table 3. discussion although previous studies have shown that lpn is a feasible and effective minimally invasive technique in the surgical treatment of selected patients with renal tumors, its potential risk of bleeding requiring transfusion is well known (7, 8). bleeding should be minimized to avoid hypovolemia, anemia, hemodynamic deterioration and exposure to the risk of transfusion (9). it is also important to achieve optimal visualization of the surgical site to enabling an acceptable ischemia time and oncologic outcome (10). control of bleeding in lpn, is an active area of investigation since uncontrolled hemorrhage negatively affects the mortality and morbidity rates, as well as the convalescence period. traditional surgical methods including suture, energy based coagulation systems, ligature and hemostatic clips can be used to handle bleeding (12, 13). available hemostatic agents include absorbable hemostats such as gelatin, collagen and oxidized regenerated cellulose and active hemostats such as thrombin and fibrin sealants (16). fibrin sealants were reported as easy to use but not effective in dealing with major vascular injury. therefore, a combination of different hemostasis methods has been investigated (17). in a previous study the authors compared seven hemostatic agents in an animal partial nephrectomy model (17). the authors concluded that hemostatic agents were hemostatic agent usage yes no p value number 41 44 mean age (years) 56.8 60.7 0.101 mean follow up time (months) 39+/-17.2 64.4+/-24.5 < 0.001 mean bmi (kg/m2) 25.2 24.3 0.169 asa score 0.365 tumor size (mm) 38.2 32 0.016 mean r.e.n.a.l. score 6.8 5.1 < 0.001 mean hemoglobin drop (g/dl) 1.01 1.07 0.842 mean creatinine level change (mg/dl) 0.04 0.02 0.143 mean perioperative hemorrhage (ml) 132.9 172.9 < 0.001 mean operation time (minutes) 115.6 156.4 < 0.001 mean ischemia time (minutes) 18.2 21.9 0.013 mean hospitalization time (days) 3.4 3.6 0.555 comorbities none 27 23 0.399 hypertension 9 13 diabetes mellitus 8 10 coronary arterial disease 0 5 chronic obstructive pulmonary disease 2 3 complaint 0.151 follow up 19 15 lower urinary tract symptoms 0 1 weakness 1 0 hematuria 1 8 abdominal pain 1 1 flank pain 17 19 smoking yes 23 30 0.251 no 18 14 radiological tumor location lower pole 18 24 middle pole 17 14 upper pole 6 6 tumor extraction technique 0.108 wedge resection 40 39 enucleation 1 5 turning to open surgery 0.048 yes 0 4 no 41 40 blood transfusion need 0.005 yes 1 10 no 40 34 clamping of the renal vessels 0.112 yes 36 43 no 5 1 perioperative complication 0.084 hemorrhage 0 5 clavien complications 0.422 0 35 35 1 4 6 2 1 1 3 1 2 histology 0.264 angiomyolipoma 7 6 complicated cyst 0 1 oncocytoma 0 3 renal cell cancer 34 34 grade of rcc 0.044 1 16 26 2 15 6 3 3 3 pathological stage 0.298 t1a 29 36 t1b 10 8 t2 2 0 surgical margin 0.960 negative 40 43 positive 1 1 table 3. comparison of patients according to perioperative hemostatic agent usage. 231archivio italiano di urologia e andrologia 2016; 88, 3 bleeding during laparoscopic partial nephrectomy: can a hemostatic matrix help to improve hemostasis? effective for small vascular injuries. however, sutured bolsters were required for large partial nephrectomies. hutchinson et al. (11) evaluated the effectiveness of fibrin pad consisting of human thrombin and fibrinogen delivered to the targeted site by an absorbable synthetic matrix in an animal model. the authors have demonstrated that fibrin pad was as effective as conventional methods for the primary management of severe bleeding without the need for hilar control with a shorter operative time. dalpiaz et al. (19) reviewed the use of hemostatic agents in 15 animal model studies and 11 clinical trials concluding that fibrin sealants were effective in both animal and clinical studies. richter et al. and bak et al. (20, 21) investigated the use of floseal in lpn in two different studies. in both studies no renal suturing was used, none of the patients underwent pelvicaliceal repair and none of the patients required blood transfusions. gill et al. (6) evaluated the use of floseal during lpn. the authors found that the adjunctive use of floseal substantially enhanced parenchymal hemostasis and decreased the procedural and hemorrhagic complications. lpn with the use of floseal is a feasible and safe method for the treatment of small renal tumour. floseal facilitates the conversion of fibrinogen to fibrin and creates an insoluble fibrin clot acting as a hemostatic sealant. floseal includes gelatin granules, which swell in case of hemorrhage and mechanically control the bleeding by creating a composite hemostatic plug. floseal can be injected through a single laparoscopic port with a short application time and does not require a completely dry surgical field to be effective. disadvantages of floseal include cost, possible allergic reactions and potential transmission of prion diseases (22). in the present study, floseal was used as single hemostatic agent in all the patients. none of the patients experienced adverse effect associated with floseal. suturing was used for renal collecting system repair, in case of major transected intrarenal vessels and severe parenchymal hemorrhage. intraoperatively, hemostasis was sufficient in all the patients. mean tumor size and mean warm ischemia time were 35+/-12 mm and 20.1+/-7 minutes, respectively. these were comparable with previous studies (4, 5, 17). previous studies described an association between the depth of tumor invasion and rate of hemorrhage. ramani et al. (22) investigated complications associated with lpn and showed that 53% of 19 patients requiring transfusion due to hemorrhage had deep tumors. in this study, the floseal group tended toward significantly fewer hemorrhagic complications although the depth of tumor invasion was higher. our findings showed that floseal provides better bleeding control with less hemorrhage and blood transfusion requirements, with significantly shorter operation and warm ischemia time. although our findings support previous trials advocating that floseal is a safe and effective hemostatic agent, we think that it should be used as an adjunctive method in conjunction with suturing techniques, for major bleedings from large vessels or renal parenchyma. although the current study is one of the rare studies investigating the use of floseal as a hemostatic agent in lpn, it has some limitations including its retrospective design and relatively small number of patients. in conclusion, floseal is a safe,reliable and effective hemostatic agent, which can be used during lpn to avoid hemorrhagic complications. floseal may potentially enhance the technique of lpn and help the surgeon to perform the procedure more comfortably. further prospective, randomized and controlled studies are required to evaluate the potential role of floseal in lpn. references 1. belldegrun a, tsui kh, dekernion jb, smith rb. efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node-metastasis staging system. j clin oncol. 1999; 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45:692705. 8. mabjeesh nj, avidor y, matzkin h. emerging nephron sparing treatments for kidney tumors: a continuum of modalities from energy ablation to laparoscopic partial nephrectomy. j urol. 2004; 171:553-60. 9. winfield hn, donovan jf, godet as, clayman rv. laparoscopic partial nephrectomy: initial case report for benign disease. j endourol. 1993; 7:521-6. 10. andonian s, janetschek g, lee br. laparoscopic partial nephrectomy: an update on contemporary issues. urol clin north am. 2008; 35:385-96. 11. hutchinson rw, werrlein s, johns db, et al. an in vivo comparison of hemostatic gelatin matrix products in a porcine spleen biopsy-punch model. surg technol int. 2015; 27:53-7. 12. shander a. financial and clinical outcomes associated with surgical bleeding complications. surgery. 2007; 142(4 suppl):s20-5. 13. boucher ba, hannon tj. blood management: a primer for clinicians.pharmacotherapy. 2007; 27:1394-411. 14. pruthi rs, chun j, richman m. the use of a fibrin tissue sealant during laparoscopic partial nephrectomy. bju int. 2004; 93:813-7. 15. klingler ch, remzi m, marberger m, janetschek g. haemostasis in laparoscopy. eur urol. 2006; 50:948-56; discussion 956-7. archivio italiano di urologia e andrologia 2016; 88, 3 f. ozgor, a. simsek, o. aydogdu, o. kucuktopcu, o. sarilar, a. yalcin berberoglu, m. fatih akbulut, m. binbay 232 16. palm md, altman js. topical hemostatic agents: a review. dermatol surg. 2008; 34:431-45. 17. häcker a, albadour a, jauker w, et al. nephron-sparing surgery for renal tumours: acceleration and facilitation of the laparoscopic technique. eur urol. 2007; 51:358-65. 18. johnston wk 3rd, kelel km, hollenbeck bk, et al. acute integrity of closure for partial nephrectomy: comparison of 7 agents in a hypertensive porcine model. j urol. 2006; 175:2307-11. 19. dalpiaz o, neururer r, bartsch g, peschel r. haemostatic sealants in nephron-sparing surgery: what surgeons need to know. bju int. 2008; 102:1502-8. 20. richter f, schnorr d, deger s, et al. improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (floseal). urology. 2003; 61:73-7. 21. bak jb, singh a, shekarriz b. use of gelatin matrix thrombin tissue sealant as an effective hemostatic agent during laparoscopic partial nephrectomy. j urol. 2004; 171:780-2 22. ramani ap, desai mm, steinberg ap, et al. complications of laparoscopic partial nephrectomy in 200 cases. j urol. 2005; 173:42-7. correspondence faruk ozgor, md md.farukozgor@yahoo.com abdulmuttalip simsek, md simsek76@yahoo.com ozgu aydogdu, md onur kucuktopcu, md omer sarilar, md ahmet yalcin berberoglu, md mehmet fatih ahbulut, md murat binbay, md department of urology, haseki teaching and research hospital millet cad. no: 11, 34096, fatih, istanbul, turkey stesura seveso introduction semen analysis is a crucial and irreplaceable tool for evaluating male infertility and precise thresholds are needed. since 1951, the scientific community recognized this concept and mcload et al. (1, 2) indicated the cut-off values for sperm counts (> 20 x 106 /ml, total sperm count > 100 x 106) for the first time, to distinguish fertility from subfertility. however the clinicians noted several times that some men with a sperm count below these ranges were able to conceive and this creat125archivio italiano di urologia e andrologia 2013; 85, 3 original paper comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis – interpretation of 529 consecutive samples francesco catanzariti, ubaldo cantoro, vito lacetera, giovanni muzzonigro, massimo polito polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, ancona, italy. objective: to quantify how many men with normal semen according to who (who world health organization) 1999 criteria, should be considered with abnormal semen according to 2010 criteria and vice versa; to study which parameter of volume, concentration, motility and morphology is the most responsible of this change. materials and methods: we studied, using who 1999 parameters, 529 consecutive semen samples from 427 men, collected in our department from january 2008 to december 2009, then we re-evaluated those results using who 2010 parameters; we also studied each parameter to understand how changed the classification from normal (defined normal by all parameters) to abnormal (defined abnormal by at least one parameter) using the two who criteria. results: 3 men (0.56%) were azoospermic. among the remaining 526 samples, 199 (37.83%) were considered normal and 246 (46.76%) abnormal both according to who 1999 and who 2010 criteria; we found that none of the samples classified normal according to the previous criteria was classified abnormal according the more recent criteria, while 82 (15.58%) evaluated as abnormal according 1999 criteria changed to normal according 2010 criteria. the concordance between 1999 and 2010 evaluation was 84.44%. conclusions: in this study we noted that the changes from who 1999 to who 2010 criteria did not modify the interpretation of semen quality, because comparing the two classifications we demonstrated that there is a substantial agreement, considering the three parameters (count, motility and morphology) all together, and also considering each single parameter. anyhow, almost 16% of the patients considered infertile according to the old criteria, should be evaluated normal by the new classification and they should not need any treatment for infertility. key words: who 2010 parameters; infertility; semen analysis. submitted 5 june 2013; accepted 30 june 2013 no conflict of interest declared summary ed an uncertainty in the clinical practice. in 1980 the world health organization (who) tried to clarify these doubts, by publishing the first (3) of 5 editions of guidelines for semen analysis. the weak point of that edition was that its criteria had never been prospectively validated by any study, because all the works present in the literature of the following years used either a case-control design, comparing fertile and subfertile couples, or a cohort design among the first pregnancy planners (4, 5). doi: 10.4081/aiua.2013.3.125 archivio italiano di urologia e andrologia 2013; 85, 3 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 126 the ultimate edition published in 2010 (6) used the concepts of “percentile” and “confidence intervals”, for the first time, allowing the clinicians to evaluate the individual semen analysis values in the context of measurement error and indicated reference values for semen parameters based on data from fertile men above the 5th percentile. furthermore, the results were generated in multiple laboratories using standardized procedures and based on real world data. however the last who guidelines for semen analysis radically changed the interpretation of semen analysis of the previous who 1999 (7) guidelines especially regarding the parameters of number (from 20 x 10^6/ml to 15 x 10^6/ml) and morphology (from 30% to 4%). this change mean that some of the patients, who were considered abnormal for the quality of their semen according to the old classification, would be considered normal, as a result of the new classification. our study tried to quantify this change and to understand the percentage of concordance between the two classifications in the assessment of a sample, considering all three parameters at the same time (sperm count, motility and morphology) and analyzing each parameter individually to understand which of them is most responsible for the shift from normospermia to dyspermia. materials and methods we studied 529 consecutive semen samples from 427 men collected in our department from january 2008 to december 2009. semen analysis was performed 2 or more times in 74 patients during this period. this group was composed of healthy men and men affected by different diseases (infertility, infections, varicocele, and other pathologies), semen analysis was performed after at least 3 days of sexual abstinence. semen samples were collected at the hospital by masturbation directly into a 120 ml sterile jar. semen samples were analyzed within 1 hour of ejaculation. after liquefaction, semen volume was measured in a graded syringe with 0.1-ml accuracy. sperm concentration was counted and motility assessed in a makler counting chamber at a magnification of x 200. all semen parameters were classified first, according to the 1999 who criteria, then retrospectively using who 2010 parameters; we also studied each parameter to understand how the results changed from normal (defined as all parameters normal) to abnormal (defined with at least one parameter abnormal) using the two criteria. results the mean age of participants was 30.26 (18-60). sperm characteristics are summarized in table 1. between the 529 samples, we detected 3 (0.56%) cases of azoospermia. in analysing the specimens using the old criteria (figure 1) we found 199 (37.62%) cases of normospermia, 140 (26.47%) cases of asthenozoospermia and 83 (15.69%) cases of oligoasthenozoospermia, while using who 2010 criteria (figure 2) we found slightly different rates of prevalence: 283 (53.50%) cases of normospermia, 105 (19.85%) cases of asthenozoospermia and 85 (16.07%) cases of oligoasthenozoospermia. when we considered only the number (figures 3, 4) we observed that 355 (67.49%) patients had a normal number according to both who 1999 and who 2010 criteria, 138 (26.24 %) patients were considered to have oligozoospermia by both classifications and 33 (6.27%) patients were considered to have a normal number according to who 2010 criteria and to have oligomean 5th-95th percentile age (y) 30.26 18-45 mediana 5th-95th percentile volume (ml) 3 1-6 concentration (10^6/ml) 40 0.28-163.60 total motility (%) 46 10-80 normal morphology (%) 52 20-73 table 1. characteristics of age and semen quality of the patients (n: 529 men). figure 1. number of patients in each category (who 1999). figure 2. number of patients in each category (who 2010) zoospermia according to the who 1999 classification. we found that some patients who had an abnormal number according to old criteria were not considered abnormal according the new one. therefore the concordance between the two classifications for number was 93.73%. considering only the parameter of motility (figures 5, 6) we found that 248 (47.15%) cases had normal motility both according to who 1999 and who 2010 criteria, 192 (36.50%) patients were considered to have asthenozoospermia according to both classifications and 86 (16.35%) patients were considered to have a low motility according to who 1999 parameters and to have a normal motility according to the new parameters. we found that some patients who had an abnormal motility by the old criteria were not considered abnormal according to the new one. the concordance according to the two criteria about motility was 83.65%. studying only morphology (figures 7, 8) we observed that 469 (89.16%) cases presented normal morphology according to both classifications, 2 (0.38%) cases had teratozoospermia according to both who 1999 and who 2010 classification and 55 (10.46%) patients were considered to have abnormal morphology according to the old classification and to have normal morphology according to the new one. we found that patients who had an abnormal morphology by the old criteria were not considered abnormal according to the new one. therefore the concordance between the two classifications of morphology was 89.54%. considering the three parameters together (figures 9, 10) 199 (37.83%) patients were considered normal according 127archivio italiano di urologia e andrologia 2013; 85, 3 comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis figure 3. concordance between who 1999 and who 2010 about number. figure 4. concordance between who 1999 and who 2010 about number. legend nnnn: percentage of men with normal number according to both who 1999 criteria and who 2010 criteria. nno: percentage of men with normal number according to who 1999 criteria and oligozoospermia according to who 2010 criteria. onn: percentage of men with oligozoospermia according to who 1999 criteria and normal number according to who 2010 criteria. oo: percentage of men with oligozoospermia according to both who 1999 criteria and who 2010 criteria. figure 5. concordance between who 1999 and who 2010 about total motility. figure 6. concordance between who 1999 and who 2010 about total motility legend nmnn: percentage of men with normal motility according to both who 1999 criteria and who 2010 criteria. nma: percentage of men with normal motility according to who 1999 criteria and asthenozoospermia according to who 2010 criteria. anm: percentage of men with asthenozoospermia according to who 1999 criteria and normal motility according to who 2010 criteria. aa: percentage of men with asthenozoospermia according to both who 1999 criteria and who 2010 criteria. archivio italiano di urologia e andrologia 2013; 85, 3 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 128 to both who 1999 and who 2010 classification, 246 (46.77%) cases were considered abnormal according to both classifications and 82 (15.59%) cases were evaluated abnormal according to the 1999 parameters and normal according to those of 2010. we found that patients who had all three parameters abnormal by the old criteria were not considered abnormal according to the new one, so that the concordance between 1999 and 2010 interpretation was 84.44%. discussion in literature there are few studies that analyze the changes in the interpretation of semen analysis from who 1999 to who 2010 criteria. murray et al. (8) recently did a multi-institutional retrospective study involving 387 infertile men, with the aim to understand how many semen samples of patients who were classified as infertile by timeline and previous semen analysis criteria would change classifications to be in the normal fertile range based on the 2010 who lower reference limits. they observed that overall, 43 (11.1%) patients who had one or more abnormal parameters in the original analysis would be converted to having all parameters within normal parameters and the most important changes in the interpretation of the data were in motility and morphology. these results are similar to our (11.1% vs 15.59%) another recent study by zou et al. (9) indirectly analyzed this change of interpretation. in his work zou examined figure 7. concordance between who 1999 and who 2010 about morphology. figure 8. concordance between who 1999 and who 2010 about morphology. legend nmnm: percentage of men with normozoospermia according to both who 1999 criteria and who 2010 criteria. nmt: percentage of men with normozoospermia according towho 1999 criteria and teratozoospermia according to who 2010 criteria. tnm: percentage of men with teratozoospermia according to who 1999 criteria and normozoospermia according to who 2010 criteria. tt: percentage of men with teratozoospermia according to both who 1999 criteria and who 2010 criteria. figure 9. total concordance between who 1999 and who 2010. figure 10. total concordance between who 1999 and who 2010. legend ff: percentage of men considered fertile according to both who 1999 criteria and who 2010 criteria. fi: percentage of men considered fertile according to who 1999 criteria and infertile according to who 2010 criteria. if: percentage of men considered infertile according to who 1999 criteria and fertile according to who 2010 criteria. ii: percentage of men considered infertile according to both who 1999 criteria and who 2010 criteria. the determinants of semen quality in a large sample of military personnel from different geographical areas of the people's republic of china. among 1194 patients he found that 88.3% had at least one semen parameter below the normal values according to world health organization (who) recommendations (1999), and 62.5% according to who recommendations (2010). therefore, this study also demonstrated that the new classification created a little shift in the patients from infertile to fertile. metha et al. (10) instead, evaluated the improvement in semen parameters and serum testosterone (t) in their study, following varicocelectomy in those men considered abnormal according to the 1999 who criteria yet normal by the new 2010 criteria. they analysed 152 patients in total, that met the inclusion criteria (sperm concentration 15-20 million/ml, motility 40-50%, or morphology 4-14%): 111 patients (73%) underwent bilateral varicocelectomy, while 41 (27%) underwent a left side varicocelectomy. overall, sperm concentration and serum testosterone (t) improved following surgery. among men who met the inclusion criteria for sperm concentration, only sperm concentration was significantly increased (17.8 vs. 38.0 million/ml, p = 0.03). they concluded that microsurgical varicocelectomy in the subset of men considered to have normal semen parameters according to the 2010 who reference ranges, but abnormal according to the 1999 reference ranges lead to a significant improvement in serum t, sperm concentration, and, in some cases, sperm motility. metha and his colleagues underlined that even among patients considered normal for the new classification but abnormal for the old one, microsurgical varicocelectomy should be performed because of its improvement of fertility potential as well as t levels. our study evaluated if there were any changes in the evaluation of the semen quality according to who 1999 criteria and who 2010 criteria in order to understand if there are cases, which can change from abnormal to normal, and vice versa using the two classifications. we concluded that, considering each parameter by itself and all three parameters together, the concordance is very high. concordance was high according to the number parameter (93.73%) that was slightly changed, from 20 x 10^6/ml (who 1999) to 15 x 10^6/ml (who 2010), but also according to morphology parameter (89.54%) that was radically changed from 30% (who 1999) to 4% (who 2010). another interesting observation from our results is that there are not cases considered normal by the old classification that change to abnormal by the new one, while there are patients that resulted abnormal by the old criteria and normal according to new who 2010 parameters. this change is more consistent for motility (16.35%) than morphology (10.46%), as we expected. this implies that none of the patients that were previously considered normal changed to abnormal, according to the new classification, but some patients, about 15%, changed from abnormal to normal by the new classification. so thanks to the new criteria, the rate of patients that do not need any treatment for infertility is now reduced because they are no more considered infertile. acknowledgements the authors would like to thank all of the patients for their contribution to this study and all the urologists of the department of urology of the polytechnic university of marche in ancona, who contributed to this study, with their data collection and sharing. references 1. macleod j, gold rz. the male factor in fertility and infertility. ii. sperm counts in 1000 men of known fertility and in 1000 cases of infertile marriage. j urol. 1951; 66:436. 2. macleod j, gold rz. the male factor in fertility and infertility. vi. semen quality and other factors in relation to ease of conception. fertilsteril. 1953; 4:10. 3. world health organization.who laboratory manual for the examination of human semen and semen-cervical mucus interaction. singapore: press concern, 1980. 4. bonde jp, ernst e, jensen tk, et al. relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. lancet. 1998; 352:1172-7. 5. zinaman mj, brown cc, selevan sg, clegg ed. semen quality and human fertility: a prospective study with healthycouples. j androl. 2000; 21:145-53. 6. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. human reprod update. 2010; 16:231-45. 7. world health organization. who laboratory manual for the examination of human semen and sperm-cervical mucus interaction, 4th edn. cambridge: cambridge university press, 1999, 128 p. 8. murray ks, james a, mcgeady jb, et al. the effect of the new 2010 world health organization criteria for semen analyses on male infertility. fertilsteril. 2012; 98:1428-31. 9. zou z, hu h, song m, et al. semen quality analysis of military personnel from six geographical areas of the people's republic of china. fertilsteril. 2011; 95:2018-23. 10. mehta a, najari b, rosoff js, goldstein m. impact of the revised who semen analysis reference limits on selection criteria for microsurgical varicocelectomy. j urol. 2012; 187:4s. 129archivio italiano di urologia e andrologia 2013; 85, 3 comparison between who (world health organization) 2010 and who 1999 parameters for semen analysis correspondence francesco catanzariti, md (corresponding author) resident in urology fracatanzariti@libero.it ubaldo cantoro, md resident in urology ubaldocantoro@tiscali.it vito lacetera, md urologist vlacetera@gmail.com giovanni muzzonigro, md professor of urology, chief department of urology g.muzzonigro@univpm.it massimo polito, md urologist, chief department of uro-andrology max_polito@virgilio.it polytechnic university of marche, faculty of medicine department of odontostomatologic and specialized clinical sciences urology clinic, department of general and specialized surgery university hospital of ancona via conca 71 i-60020 ancona, italy stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4210 introduction wunderlich’s syndrome is a clinical condition defined as a spontaneous renal bleeding of non traumatic origin, contained within the gerota’s fascia. in 1700, bonet was the first one who described this condition, while c.r.a. wunderlich was the first to make a clinical de scription in 1856 (1). coenen used the term wunderlich’s syndrome for the first time in 1910 (2). various authors find as underlying causes: nephritis, tu mours, vascular diseases, cysts rupture (3-7). classically it presents with acute flank pain, tender palpable mass and clinical hemodynamic deterioration. these symptoms are defined as the lenk’s classic triad (8). we present three cases of spontaneous renal bleeding. case 1 a 72 years old man presented to the emergency department with severe generalized abdominal pain. he described a 3-hour history of acutely worsening abdominal and left lumbar pain and vomiting. neither urinary symptoms nor history of trauma. he had a previous medical history positive for hypertension, dyslipidaemia and hyperuricemia. clinically he had hypertension (160/100 case report wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated andrea guttilla, alessandro crestani, francesco cattaneo, fabio zattoni, claudio valotto, massimo iafrate, fabrizio dal moro, filiberto zattoni urology clinic, department of surgical, oncological and gastroenterological sciences, university of padua, italy. wunderlich’s syndrome is a clinical condition defined as a spontaneous renal bleeding of non traumatic origin, contained within the gerota’s fascia. wunderlich’s syndrome is rare. spontaneous bleeding of kidney tumors, either benign or malignant, represents the more common causes. classically it presents with acute flank pain, tender palpable mass and clinical hemodynamic deterioration. these symptoms are defined as the lenk’s classic triad. we present three cases of spontaneous renal bleeding. key words: kidney; spontaneous bleeding; angiography; kidney tumours. submitted 21 december 2012; accepted 31 march 2013 no conflict of interest declared summary mmhg), tachycardia, a voluminous lumbar tumefaction and haematoma (figure 1). haemoglobin was 7.1 g/dl. a computed to mography (ct) was performed, showing a figure 1. case 1: voluminous lumbar tumefaction and haematoma. doi: 10.4081/aiua.2013.4.210 211archivio italiano di urologia e andrologia 2013; 85, 4 wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated large (16 cm) left perinephric haema toma with an active bleeding in the sub capsular and perirenal space. normal controlateral kidney (figure 2). the patient’s haemoglobin levels continued to decrease, and he was transfused with 4 units of blood. the patient underwent emergency em bolization (figu re 3) of a 3-cm avascular area in the left kidney at the middle third (possible sub capsular lesion) with an active bleeding from a thin arterial capsular branch of the lower renal pole. then, he was admitted to the in tensive care unit (icu) for close observation and strict bed-rest. his haemoglobin level stabilized, and he was treated conservatively. he was discharged from the urology department after 30 days. ct scans before leaving the hospital and the one made after 90 days showed significant reduction of the perirenal haema toma (figures 4, 5). one year after the patient is fine. the haematoma is completely disappeared (figures 6, 7). he still has problems of blood pressure that he is controlling with different drugs. case 2 a 75 years old woman presented to the emergency department with severe left lumbar pain. neither urinary symptoms nor history of trauma. she had a previous medical history positive for ischemic heart disease, atrial fibrillation in therapy with anticoagulants, hypertension, cronic kidney failure with an atrophic right kidney. clinically he had hypotension (110/70 mmhg), tachycardia, haemoglobin 7 g/dl, serum creatinine 300 mmol/l. the patient’s haemoglobin levels continued to decrease, and she was transfused with 5 units of blood. the patient underwent a ct scan that showed an important lumbar haematoma (figure 8). the patient underwent emergency renal arteriography that described: stenosis of the left renal artery, with no parenchymal vascularisation. the left artery was embolized with kidney exclusion. then, she was admitted to the icu for close observation and strict bed-rest. the haemoglobin levels during the staying in the icu figure 2. case 1: computed tomography (ct) showing a large (16 cm) left perinephric haematoma with an active bleeding in the sub capsular and perirenal space. figure 3. case 1: emergency embolization of a 3-cm avascular area in the left kidney at the middle third (possible sub capsular lesion) with an active bleeding from a thin arterial capsular branch of the lower renal pole. figures 4-5. case 1: ct scans at dismissal and after 90 days showed significant reduction of the perirenal haematoma. archivio italiano di urologia e andrologia 2013; 85, 4 a. guttilla, a. crestani, f. cattaneo, f. zattoni, c. valotto, m. iafrate, f. dal moro, f. zattoni 212 started to rise up. she was discharged from the urology department after 12 days with haemoglobin value of 10.3 mg/dl. the patient was lost at follow-up. case 3 a 57 years old man presented to the emergency department with acute right lumbar pain. neither urinary symptoms nor history of trauma. he had a previous medical history positive for hypertension. clinically he had normal blood pressure (140/80 mmhg). haemoglobin was 12.1 g/dl. a ct was performed, showing a large (10 cm) right perinephric haematoma with no evidence of active bleeding and a 6 cm sub capsular mass. normal contralateral kidney. we decided to treat him conservately and to treat the mass surgically after the acute problem was resolved. he was discharged from the urology department after 12 days. ct scan before leaving the hospital showed significant reduction of the perirenal haematoma and confirmed the presence of a solid area. one month after, the patient underwent open right partial nephrectomy. the pathological report showed a type 2 papillary rc, fuhrman grade 3, pt1anx. discussion wunderlich’s syndrome is a rare syndrome, with about 300 cases described in the literature. the most common causes of these spontaneous haemorrhages are represented by neoplasm (61%) (9). as benign lesion, angiomyolipoma (31.5%) is the most common, while renal cell carcinoma is the most common malignant one (10, 11). some authors have also described some other different causes as vasculitis, arteriovenous fistulas, rupture of renal artery aneurism rupture and nephritis (12). the imaging studies, for patient with suspicious of a spontaneous renal bleeding, are ct scan or angiography (9, 10). ct scan can give the opportunity to know the entity of the haematoma and the presence of an active bleeding. selective angiography with embolization is often useful in the acute phase of the haemorrhage in order to control bleeding, contribute to diagnosis and reduce the need for surgery. the management is dictated by the clinical condition of the patient and by the underlying aetiology. sometimes subjects with unstable haemodynamic condition can require an emergency nephrectomy especially if the cause of the bleeding is clear (i.e. renal cancer). in other cases, as the one described above, a conservative treatment to preserve renal function can be the best choice. also in kidney bleeding following a trauma, many authors recommend a conservative treatment if major complications, as other abdominal injuries, are not present (13, 14). eventually, if the imaging done during the follow-up shows a clear diagnosis a nephrectomy must be perfigures 6-7. case 1: ct scan after 1 year showing that haematomais completely disappeared. figure 8. case 2: ct scan showing an important lumbar haematoma. 213archivio italiano di urologia e andrologia 2013; 85, 4 wunderlich’s syndrome: three cases of acute spontaneous renal bleeding, conservately treated formed. the follow-up, after patient discharge, should be done with ct scans to monitor the haematoma reduction and with measurements of blood pressure to exclude page syndrome (15, 16). conclusion wunderlich’s syndrome is rare. spontaneous bleeding of kidney tumours, either benign or malignant, represents the more common cause. ct scan and angiography are the preferred diagnostic tools. the treatment must be tailored for single cases. conservative treatment with a periodic follow-up is often a feasible approach. references 1. wunderlich cra. handbuch der pathologie und therapie. 2nd ed. stuttgart, ebner & seubert, 1856. 2. bilesio ae, campodonico a, molina r. síndrome périrrenal espontaneo (síndrome de wunderlich). rev urol. 1962; 2:17. 3. hao lw, lin cm, tsai sh. spontaneous hemorrhagic angiomyolipoma present with massive hematuria leading to urgent nephrectomy. am j emerg med. 2008; 26:249 e3-5. 4. pummer k, lammer j, wandschneider g, primus g. renal cell carcinoma presenting as spontaneous retroperitoneal haemorrhage. int urol nephrol. 1990; 22:307-11. 5. mcdougal ws, kursh ed, persky l. spontaneous rupture of kidney with perirenal hematoma. j urol. 1975; 114:181-184. 6. cinman ac, farrer j, kaufman jj. spontaneous perinephric hemorrhage in 65-year old man. j urol. 1985; 133:829-832. 7. belville js, morgentaler a, loughlin kr, tumeh ss. spontaneous perinephric and subcapsular renal hemorrhage: evaluation with ct, us, and angiography. radiology. 1989; 172:733-738. 8. flageat j, vicens jl, cosnard g, foster d, metges pj. hématome périrrénal reévelateur d'une périartérite nouse. j radiol. 1986; 67:419-422. 9. zhang jq, fielding jr, zou kh. etiology of spontaneous perirenal hemorrhage: a meta-analysis. j urol. 2002; 167:1593-6. 10. sebastia mc, perez-molina mo, alvarez-castells a, et al. ct evaluation of underlying cause in spontaneous subcapsular and perirenal hemorrhage. eur radiol. 1997; 7:686-90. 11. oon sf, murphy m, connolly ss. wunderlich syndrome as the first manifestation of renal cell carcinoma. j urol 2010; 7:129-32. 12. albi g, del campo l, tagarro d. wünderlich's syndrome: causes, diagnosis and radiological management. clin radiol. 2002; 57:840-5. 13. moudouni sm, patard jj, manunta a, et al. a conservative approach to major blunt renal lacerations with urinary extravasation and devitalized renal segments. bju int. 2001; 87:290-4. 14. husmann da, gilling pj, perry mo, et al. major renal laceration with a devitalized fragment following blunt abdominal trauma: a comparison between nonoperative (expectant) versus surgical management. j urol. 1993; 150:1774-7. 15. wein aj, kavoussi lr campbell-walsh urology 9th edition, saunders/elsevier, 2007, p.170. 16. monstrey sj, beerthuizen gl, vanderwerken c, et al. renal trauma and hypertension. j trauma. 1989; 29:65-6. correspondence andrea guttilla, md (corresponding author) andrea.guttilla@gmail.com alessandro crestani, md alessandro.crest@gmail.com francesco cattaneo, md i.francescocattaneo@gmail.com fabio zattoni, md fabiozattoni@gmail.com claudio valotto, md claudio.valotto@sanita.padova.it massimo iafrate, md massimo.iafrate@unipd.it fabrizio dal moro, md fabrizio.dalmor@gmail.com filiberto zattoni, md filiberto.zattoni@unipd.it urology clinic, department of surgical, oncological and gastroenterological sciences, university of padua, via giustiniani, 2 35100 padua, italy archivio italiano di urologia e andrologia 2016; 88, 286 original paper is a second look necessary in multiple and/or large ta tumors? sıtkı ün 1, hakan türk 2, mustafa karabıçak 2, rauf taner divrik 3, ferruh zorlu 2 1 katip çelebi university atatürk research and training hospital, department of urology, izmir, turkey; 2 tepecik research and training hospital, department of urology, turkey; 3 şifa university medicine faculty, department of urology, turkey. introduction: most of the bladder cancers are tumors without muscle invasion at the time of diagnosis. transurethral resection is the standard treatment in bladder tumors without muscle invasion. proper review of transurethral resection is important for correct risk classification. in this study, our main objective was to show that a “second look” in patients with multiple and/or > 3 cm tumors regardless of t stage during the early term can be helpful in detection of possible residues and determining risk classification. materials and methods: 156 patients with primary, multiple and/or > 3 cm tumors were included in the study. patients were divided into 3 groups as group 1 (ta), group 2 (t1 without second tur) and group 3 (t1 with second tur). macroscopic tumor occurrence rates were compared in their 3rd month control cystoscopy. results: macroscopic tumor detection rates in patients’ 3rd month control cystoscopy were 21 (46.7%) in group 1, 18 (30%) in group 2 and 4 (7.8%) in group 3. when compared with group 3 patients, group 1 and group 2 had higher statistically significant macroscopic tumor detection rates (p = 0.001) conclusion: a second look in patients with multiple and/or > 3 cm tumors during early term will enable the surgeons to detect possible tumors and do a better job in risk classification. key words: bladder cancer; multiple; large; second look. submitted 4 october 2015; accepted 4 december 2015 summary no conflict of interest declared. materials and methods data of 1406 bladder cancer patients who were diagnosed in our clinic between 2000 and 2014 was retrospectively reviewed; 156 patients with primary, multiple and/or > 3 cm tumors were included in the study. patients with secondary tumors, without complete resection, without muscularis propria tissue in pathology samples and microscopic tumors detected in second tur were excluded. patients were divided into 3 groups as group 1 (ta), group 2 (t1 without second tur) and group 3 (t1 with second tur). patients in group 2 consist of t1 patients before second tur diagnosis. groups were compared in demographic and clinical parameters. macroscopic tumor occurrence rates were compared in their 3rd month control cystoscopy. our main aim was to review the hypothesis “according to tnm staging, patients with ta (multiple and/or large) tumors warrant a second-look”. in order to retrospectively review this hypothesis, we tried to show the relationship between patients with t1 stage tumors who went under second tur and patients who did not receive further surgery. considering that the residual tumor existence can also be seen in patients with ta-stage tumors, we chose this methodology. except intracavitary therapy, no additional local adjuvant therapies were used in that patient group. since the main focus of the study is to prove that a second look is necessary following tur surgery, other patients who received additional local adjuvant therapies were excluded from the study. all patients received a 6-week standard intracavitary therapy protocol. the assessments were made on the 3rd month of treatment using cystoscopy findings. statistical analysis was made using computer software. chi-square test was used in categorical variables and student-t test was used in continuous variables. values under p < 0.05 were considered statistically significant. results out of 156 patients, 45 patients were put into group 1, 60 into group 2 and 51 into group 3. patients were reviewed in terms of sex, age, pathological grade and adjuvant intracavitary treatments (table 1). group 1 doi: 10.4081/aiua.2016.2.86 introduction about 80% of bladder cancers are seen without muscle invasion at the time of diagnosis. the “golden standard” in treatment of bladder tumors without muscle invasion is transurethral resection (tur) (1). proper review of transurethral resection is important for correct diagnosis and treatment as well as risk classification (2). in this study, our main objective was to show that a “second look” in patients with multiple and/or > 3 cm tumors regardless of t stage during the early term can be helpful in detection of possible residues and determining risk classification. sitki_stesura seveso 01/07/16 10:59 pagina 86 87archivio italiano di urologia e andrologia 2016; 88, 2 second look in ta tumors patients had lower statistically significant high-grade tumor rates compared to other groups. there were no statistically significant differences between the groups when other parameters were reviewed. since all patients included in the study required intracavitary therapy, all patients received this treatment. no statistically significant differences were seen between the groups in terms of intracavitary therapy during statistical analysis. macroscopic tumor detection rates at 3rd month control cystoscopy were 21 (46.7%) in group 1, 18 (30%) in group 2 and 4 (7.8%) in group 3. nineteen patients in group 3 were diagnosed with macroscopic tumors during their second tur. when compared with group 3 patients, group 1 and group 2 had higher statistically significant macroscopic tumor detection rates (p = 0.001) (table 2a). when macroscopic tumor detection during re-tur rates in group 3 patients were compared to control cystoscopy results of the other 2 groups, there was a correlation (table 2b). discussion tur is accepted as the basic surgical procedure in diagnosis and treatment of bladder cancers without muscle invasion. however, many studies suggest a second tur after the initial tur for resection of residual tumors (3, 4). tumors detected during initial control cystoscopy on 3rd month of surgery in multiple and/or > 3 cm tumors were known to be mainly residual tumors (5). a residual tumor from a previously incomplete tur detected in first control cystoscopy on 3rd month will be labeled as early recurrence which will change the patient’s risk classification. residual tumors are important in the treatment of multiple and/or tumors larger than 3 cm. literature reports residual tumor rates as 3378% (6). divrik et al. prospective and randomized study reports this rate as 33.8% in t1 patients. in grimm et al. prospective study, the authors suggested a second tur to patients that received the initial tur in their clinic and reported a residual tumor detection rate of 33.7% (8). similarly in our study, 19 (37.2%) out of 51 t1 stage patients who underwent re-tur were diagnosed with residual tumors. herr et al. performed a secondary tur in 150 patients who underwent the initial tur in different clinics and reported 70.4% residual tumor rate (2). the initial tur quality of those patients is unknown as well as the presence of muscle tissue in pathological samples and if the tumor was completely finished or not. in the other 2 studies mentioned above and our study, the initial tur was done in their respective clinics, complete removal of tumor was reported by the surgeon and muscle tissue was found in pathological samples. even after a proper and complete tur, 1 out of 3 patients is diagnosed with residual tumors. this rate is deemed as significant. a significant drop in recurrence and progression rates in high-risk ta/t1 patients was reported with secondary tur (7-9). yet in most of the studies, second tur is only recommended to t1 patients (10-12) there are also studies that recommend second tur in high grade ta patients (13, 14). in a study done by lazica et al., highrisk ta patients who underwent a second tur were reviewed and 41.4% of those patients were diagnosed with residual tumors (14). in this study, there was a significantly higher rate of tumors in multifocal tumor cases diagnosed in second tur. there was a similar increase in tumor detection rates in patients with tumors > 3 cm, but this was not deemed as statistically significant (14). residual tumor presence following tur is connected with the stage, degree, size and number of the initial tumor (7). multiple tumors increase recurrence risk (1518). in addition, tumor size is also found to be in connection with recurrence risk (16, 19). these results were compatible with the meta-analysis reports done by eortc (20). in our study, 19 (37.3%) patients were diagnosed with macroscopic tumors during re-tur and only 4 (7.8%) patients were diagnosed with macroscopic tumors during 3rd month control cystoscopy. it was seen that most of the macroscopic tumors detected during re-tur were residual tumors which were missed during initial tur. 21 (46.7%) patients in group 1 and 18 (30%) patients in group 2 were diagnosed with macroscopic tumors in their 3rd month control cystoscopy. those rates were consistent with macroscopic tumors diagnosed during re-tur rates seen in group 3 patients. we think that a second look done in 4-6 weeks after the initial tur in group 1 patients will decrease those rates similar to group 1 group 2 group 3 p n y z w age (mean ± sd) 66.7 ± 10.9 64.1 ± 12.2 68.0 ± 9.1 0.158 sex male 40 (88.8%) 57 (95%) 48 (94.1%) 0.444 female 5 (11.2%) 3 (5%) 3 (5.9%) grade low 34 (75.5%) 41 (68.3%) 28 (54.9%) 0.009 high 11 (14.5%) 19 (31.7%) 23 (45.1%) adjuvant therapy ic chemotherapy 40 (88.9%) 50 (83.4%) 40 (78.5%) 0.390 ic immunotherapy 5 (11.1%) 10 (16.6%) 11 (21.5%) table 1. comparison of groups in terms of age, sex, grade and adjuvant therapy. macroscopic tumor group 1 group 2 group 3 p yes 21 (46.7%) 18 (30%) 4 (7.8%) 0.001 no 24 (53.3%) 42 (70%) 47 (92.7%) table 2a. group comparison of macroscopic tumor presence detected on 3rd month control cystoscopy. macroscopic tumor group 1 group 2 group 3 p yes 21 (46.7%) 18 (30%) 19 (37.3%) 0.216 no 24 (53.3%) 42 (70%) 32 (62.7%) table 2b. comparison of macroscopic tumors detected on second tur in group 3 patients with group 1 and group 2. sitki_stesura seveso 01/07/16 10:59 pagina 87 archivio italiano di urologia e andrologia 2016; 88, 2 s. ün, h. türk, m. karabıçak, r. taner divrik, f. zorlu 88 group 3 patients. as a result, risk classification and treatment strategies of the patients will be more realistic. the main limitation in our study was the small number of patients. more widespread and prospective studies are necessary on this subject. references 1. babjuk m, oosterlinck w, sylvester r, et al. european association of urology (eau). eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder. eur urol. 2008; 54:303-14. 2. mariappan p, zachou a, grigor km; edinburgh uro-oncology group. detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience eur urol. 2010; 57:843-9. 3. herr hw. the value of a second transurethral resection in evaluating patients with bladder tumors. j urol. 1999; 162:74-6. 4. brauers a, buettner r, jakse g. second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? j urol. 2001; 165:808-10. 5. schulze m, stotz n, rassweiler j. retrospective analysis of transurethral resection, second-look resection, and long-term chemo-metaphylaxis for superficial bladder cancer: indications and efficacy of a differentiated approach. j endourol. 2007; 21:1533-41. 6. miladi m, peyromaure m, zerbib m, et al. the value of a second transurethral resection in evaluating patients with bladder tumours. eur urol. 2003; 43:241-5. 7. divrik rt, sahin af, yildirim u, et al. impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pt1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. eur urol. 2010; 58:185-90. 8. grimm mo, steinhoff c, simon x, et al. effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. j urol. 2003; 170:433-7. 9. babjuk m. transurethral resection of nonmuscle-invasive bladder cancer. eur urol suppl. 2009; 8:542-8. 10. dalbagni g, herr hw, reuter ve. impact of a second transurethral resection on the staging of t1 bladder cancer. urology. 2002; 60:822-4. 11. kulkarni gs, hakenberg ow, gschwend je, et al. an updated critical analysis of the treatment strategy for newly diagnosed high-grade t1 (previously t1g3) bladder cancer. eur urol. 2010; 57:60-70. 12. yucel m, hatipoglu nk, atakanli c, et al. is repeat transurethral resection effective and necessary in patients with t1 bladder carcinoma? urol int. 2010; 85:276-80. 13. herr hw. tumor progression and survival of patients with high grade, noninvasive papillary (tag3) bladder tumors: 15-year outcome. j urol. 2000; 163:60-61. 14. lazica da, roth s, brandt as, et al. second transurethral resection after ta high-grade bladder tumor: a 4.5-year period at a single university center. urol int. 2014; 92:131-5. 15. parmar mk, freedman ls, hargreave tb, tolley da. prognostic factors for recurrence and followup policies in the treatment of superficial bladder cancer: report from the british medical research council subgroup on superficial bladder cancer (urological cancer working party). j urol. 1989; 142:284-8. 16. millán-rodríguez f, chéchile-toniolo g, salvador-bayarri j, et al. multivariate analysis of the prognostic factors of primary superficial bladder cancer. j urol. 2000; 163:73-8. 17. shinka t, hirano a, uekado y, ohkawa t. clinical study of prognostic factors of superficial bladder cancer treated with intravesical bacillus calmette-guerin.br j urol. 1990; 66:35-9. 18. kiemeney la, witjes ja, heijbroek rp, et al. dysplasia in normallooking urothelium increases the risk of tumour progression in primary superficial bladder cancer. eur j cancer. 1994; 30a:1621-5. 19. kurth kh, denis l, bouffioux c, et al. factors affecting recurrence and progression in superficial bladder tumours. eur j cancer. 1995; 31a:1840-6. 20. oosterlinck w, kurth kh, schröder f, et al. a prospective european organization for research and treatment of cancer genitourinary group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage ta, t1 papillary carcinoma of the bladder. j urol. 1993; 149:749-52. correspondence sıtkı ün, md (corresponding author) sitki@doctor.com katip çelebi university atatürk research and training hospital, department of urology basın sitesi, izmir, turkey hakan türk, md mustafa karabıçak, md ferruh zorlu, md tepecik research and training hospital, department of urology rauf taner divrik, md şifa university medicine faculty, department of urology sitki_stesura seveso 01/07/16 10:59 pagina 88 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3238 original paper clinical significance of prostatic-urethral angulation on the treatment outcome of patients with symptomatic benign prostatic hyperplasia treated with tamsulosin hydrochloride hassan el-tatawy 1, tarek gameel 1, mohammed abo el-enen 1, ayman hagras 1, ayman mousa 1, abdel hamid el-bahnasy 1, ali abdel raheem 1, khaled abu-dewan 2 1 urology department, tanta university hospital, egypt. 2 radiology department, tanta university hospital, egypt. objectives: to evaluate the impact of the prostatic-urethral angulation (pua) on the treatment efficacy of selective alpha-1a receptor blocker in male patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (luts/bph). materials and methods: a total of 80 patients with luts/bph and with mean age 53.3 ± 6.3 (range 47-70) were included in our prospective comparative study. the patients were classified into 2 groups as a consecutive cases 40 in each one depending on the pua either ≤ 35˚ (group a) or > 35˚ (group b). pua and different prostatic parameters were measured using transrectal ultrasound. prostate-specific antigen (psa), the international prostate symptom score and quality of life score (ipss/qol score), maximum flow rate (qmax), and postvoid residual (pvr) volume were compared between the groups. the clinical significance of pua was evaluated after 8 weeks of medical treatment with tamsulosin hydrochloride 0.4 mg daily. results: baseline evaluation (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, psa, ipss/qol score, qmax and pvr volume (p-value > 0.05). comparison of parameters after 8 weeks showed that tamsulosin hydrochloride improved the total ipss and all subscores (p < 0.001), qol (p = 0.001), qmax (p = 0.002), and pvr (p = 0.04) in group a (table 1). conclusion: tamsulosin hydrochloride appears to be less effective in improving ipss/qol score, qmax and pvr in patients with lager pua. the pua might be a predictor for the treatment efficacy of α-blockers and more studies are warranted in the future before the final conclusion. key words: prostatic-urethral angulation, benign prostatic hyperplasia and tamsulosin hydrochloride. submitted 20 february 2015; accepted 30 april 2015 summary no conflict of interest declared. up till now the exact pathophysiology of bph is still poorly understood and different theories have emerged and changed over the past years. some studies reported that the prostate volume does not correlate with the clinical luts and/or the degree of bladder outlet obstruction (boo) (2, 3), and other studies discussed several anatomical factors that may explain the clinical effect of bph such as intravesical prostatic protrusion (ipp), transition zone volume (tzv), transition zone index (tzi) and presumed circle area ratio (4-9). recently, cho et al. introduced the term prostatic-urethral angulation (pua) as a new measurement that could be a causal factor for bph (10), and in their subsequent preliminary clinical study using the fluid dynamic model, they reported that the urinary flow rate decreased by more than 27% as the pua increased from 35° to 90° (11). patients with pua ≥ 35° had larger prostate volume and higher boo index, in comparison with those who had pua < 35° (12). further studies showed that the pua is significantly associated with maximum flow rate (qmax) and voiding symptom scores in men with luts (13-14). in terms of medical therapy for bph several drugs are widely distributed in the market and selective α1-blocker is the recommended treatment (15). tamsulosin hydrochloride is a highly selective α1a-blocker that is currently used and proved to be effective and safe in treatment of symptomatic bph alone or in combination with other drugs (16). the effect of pua on the treatment outcome of tamsulosin hydrochloride on men with luts was first evaluated and pua was inversely correlated with changes in qmax and symptoms score after treatment (17). the aim of the present study is to evaluate the clinical outcome of medical treatment (by selective α1a-blocker) on male patients presented with luts/bph and its correlation to the degree of pua. patients and methods this prospective comparative study was conducted at our outpatient clinic of the urology department in the doi: 10.4081/aiua.2015.3.238 introduction benign prostatic hyperplasia (bph) is one of the most common health problems affecting the aging males. it affects more than 200 million males globally (1). lower urinary tract symptoms (luts) secondary to bph (luts/bph) are bothersome symptoms which have a negative impact on men's quality of life (qol). ali raheem_stesura seveso 30/09/15 09:38 pagina 238 239archivio italiano di urologia e andrologia 2015; 87, 3 impact of prostatic-urethral angulation on treatment of bph period between october 2012 and october 2014. the study was approved from our ethical committee and an informed consent was taken from all patients before the start of the study. we included male patients aged ≥ 40 years and < 70 years who presented with luts/bph for at least 6 months and who did not receive any medical treatment for bph before. we excluded patients with suspicious hypersensitivity to alpha blockers, a disease causing luts such as (urinary calculi, urethral stricture, urinary tract infection, primary renal disease, neurogenic bladder, prostatitis), associated co-morbidities such as uncontrolled diabetes mellitus, a history of bladder or prostate carcinoma, previous lower urinary tract surgery, renal impairment, serum psa ≥ 4 ng/ml and a post-void residual (pvr) urine volume > 150 ml. all patients were evaluated through detailed history, full physical examination including digital rectal examination and neurological examination. the international prostate symptom score and quality of life score (ipss/qol score) were estimated for each patient and ipss score was subdivided according to storage symptoms subscore and voiding symptoms subscore. laboratory investigations included urine analysis, fasting blood glucose level, serum creatinine and serum prostate-specific antigen (psa). all patients underwent transrectal ultrasound by the same radiologist to assess the degree of pua and total prostate volume (tpv). we used gevoluson e8 ultrasound machine (8 mhz, general electric company, usa), the patient was placed in right sided raised position and anal dilatation was done before insertion of the rectal probe. we acquired b-mode picture to locate the longitudinal section for the prostate and choose the generic angle and caliber lists (from the keyboard of the apparatus). a line was drawn passing longitudinally through the proximal part of prostatic urethra and another line passing longitudinally through the distal part of prostatic urethra. the angle between the two lines represents the pua (figure 1). the tpv was determined by measuring the length, height, and width of the whole prostate in both transverse and axial sections using the formula (length × width × height × 0.52). uroflowmetry was performed for all patients (at least 2 voids with minimum voided volume = 150 ml), pvr urine was measured using bladder scan after micturition using the formula (length × width × height × 0.7). patients were classified into two groups as consecutive cases according to the pua: group a (patients with pua ≤ 35º) and group b (patient with pua > 35º). the pua cutoff value in previous studies was 35˚; at this angle a significant difference in clinical symptoms and urodynamics parameters in patients and healthy men were found. subsequently, we classified our patients into 2 categories (pua ≤ 35º and pua > 35º) based on these studies (11-12). all patients received medical treatment in the form of tamsulosin hydrochloride 0.4 mg once daily for 8 weeks. the clinical significance of pua was evaluated subjectively by measuring the ipss/qol score and objectively by measuring uroflowmetry parameters (qmax and pvr volume). statistical analysis was performed using spss®17. data are shown as the mean ± sd unless otherwise specified. the student t and paired sample t tests were used for comparison between groups and in the same group, respectively. statistical significance was considered at p < 0.05. results eighty patients were included in our study, 40 in each group. two patients were excluded as they were lost during follow-up (1 patient in each group). patients mean age was 53.3 ± 6.3 (range 47-70). mean ipss score, qol score; qmax, pvr and tpv for all patients were 16.8 ± 2.5, 3.43 ± 0.9, 9.9 ± 1.5, 62.4 ± 12.2 and 57.3 ± 11.9 respectively. baseline evaluation data (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, psa, ipss/qol score, uroflometry and ipp (p-value > 0.05). on the contrary, patients in group a had a smaller prostate than those in group b with mean tpv 49.54 ± 9.03 and tzv 11.6 ± 1.4 (p-value = 0.001 and 0.001, respectively) (table 1). figure 1. ultrasound image used in measurement for pua in two patients of both groups (lt. photo: pua = 32.3º, rt. photo: pua = 44.4º). ali raheem_stesura seveso 30/09/15 09:38 pagina 239 archivio italiano di urologia e andrologia 2015; 87, 3 hassan el-tatawy, tarek gameel, mohammed abo el-enen, ayman hagras, ayman mousa, abdel hamid el-bahnasy, ali abdel raheem, khaled abu-dewan 240 after 8 weeks of follow-up of medication with tamsulosin hydrochloride there was a significant improvement in ipss/qol score, qmax and pvr urine in group a (pvalue = 0.001, 0.001, 0.002 and 0.04 respectively). on the other hand, there was no significant improvement in the above mentioned parameters in group b (table 2). on comparison between both groups there was a statistically significant improvement in group a in ipss/qol score, qmax and pvr volume compared to group b (pvalue = 0.001, 0.03, 0.01, 0.05 and 0.002, respectively) (table 2). there were no moderate or severe side effects in either group lead to discontinuation of medical treatment. in our study, the most common adverse event was dizziness in 7.6 % of patients (3 in each group), while the abnormal ejaculation rates were 5.1% in group a and 7.7% in group b. discussion several anatomical factors of the prostate other that its volume were studied in the past years to assess its impact on the clinical symptoms progression such as ipp, tzi, tzv and presumed circle area ratio (2-9). )another recent anatomical factor was introduced by cho et al. and it might play a role in the pathogenesis of pbh is the pua. the prostatic urethra is a bent tube and by applying the concept of fluid dynamics to the micturition process in the prostatic urethra, they hypothesized that some energy loss could occur during this process and hence decreasing the velocity of urine. in addition, they suggested that this energy loss increased proportionally as the pua increased and qmax decreased by more than 27% as the pua increased from 35° to 90° (10-11). the present study is the first prospective comparative study that addresses the importance of the pua as a predictor of the clinical status and treatment outcome in patients with luts/bph who received selective α1ablockers. as we know α-blockers help to treat bph by relaxation of the smooth-muscle tissue in the bladder neck and the prostate, which facilitate urinary outflow from the bladder more easily. we chose tamsulosin hydrochloride in our study because it is a highly selective α1a-blocker, safe and has long-term treatment efficacy (15, 16, 18). in the present study, baseline age, psa, ipp, uroflowmetry, ipss/qol score did not differ significantly between the two groups. however, tpv and tzv did differ significantly between the groups at baseline (p < 0.05). tpv and tzv were higher in patients with pua > 35º compared to those with lower pua and these findings were in accordance to ku et al. who showed that patients with pua > 35 have higher prostate volume than those with pua ≤ 35 (12). our study showed no significant difference in qmax values in the two groups of patients (p-value = 0.45) (table 1). in contrast to our findings, the urinary flow rate was found inversely associated with the pua (11), and a larger pua was associated with a lower urinary flow rate (14). on the other hand, no significant difference in qmax values between patients with pua more or less 35˚ was reported (12). the reason for this difference between our study and others may be the selection of our patients. in fact we excluded all patients with insignificant symptoms related to their enlarged prostate. consequently, the pre-treatment symptoms and related objective signs are expected to be matching. in contrary, cho et al. (11) did not choose their patients on such group a group b p-value mean ± sd mean ± sd pua˚ ≤ 35º > 35º --patients number 40 40 --age (yr) 55.41 ± 9.03 58.23 ± 6.37 0.78 psa (ng/ml) 2.4 ± 1.13 2.4 ± 1.39 0.83 prostatic measurements: tpv (cm3) 49.54 ± 9.03 62.32 ± 11.99 0.001 ipp (mm) 3.5 ± 1.1 3.7 ± 0.8 0.19 tzv (cm3) 11.6 ± 1.4 19.5 ± 1.3 0.001 uroflometry data: qmax (ml/s) 9.75 ± 1.34 10.37 ± 1.43 0.45 pvr (ml) 69.66 ± 10.49 66.12±11.76 0.09 voided volume (ml) 185.9 ± 11.5 198.72±17.51 0.43 overall ipss score: 17.95 ± 3.61 15.54 ± 3.53 0.68 voiding symptoms 7.84 ± 2.2 6.88 ± 1.72 0.06 storage symptoms 8.48 ± 2.33 7.35 ± 1.64 0.13 bother score (qol) 3.1 ± 1.79 3.37 ± 0.96 0.09 group a group b mean ± sd mean ± sd subjective/objective baseline after treatment p-value baseline after treatment p-value post-treatment parameters p-value total ipss score: 17.95 ± 3.61 11.85 ± 2.43 0.000 15.54 ± 3.53 14.34 ± 3.71 0.9 0.001 voiding symptoms 7.84 ± 2.2 5.93 ± 2.12 0.001 6.88 ± 1.72 6.10 ± 1.43 0.27 0.03 storage symptoms 8.48 ± 2.33 5.95 ± 1.89 0.001 7.35 ± 1.64 5.53 ± 1.79 0.03 0.01 qol score 3.17 ± 1.79 1.97 ± 1.82 0.0011 3.37 ± 0.96 3.12 ± 1.20 0.42 0.006 uroflometry: qmax (ml/s) 9.75 ± 1.34 12.95 ± 1.72 0.002 10.37 ± 1.43 11.10 ± 1.56 0.06 0.05 pvr (ml) 69.66 ± 10.49 58.98 ± 12.64 0.04 66.12 ± 11.76 61.12 ± 12.63 0.32 0.002 table 1. patients characteristics (pretreatment data) in both groups. table 2. intragroup and intergroup comparisons of subjective (ipss score) and objective (uroflometry) parameters after 2 months of treatment with tamsulosin hydrochloride. ali raheem_stesura seveso 30/09/15 09:39 pagina 240 241archivio italiano di urologia e andrologia 2015; 87, 3 impact of prostatic-urethral angulation on treatment of bph basis, that is symptomatic patients who require treatment. in their study the patients were healthy men with no evidence of boo (patients age 50 to 59 years with prostate volume 30 ml and qmax 15 ml/s). moreover, the large number of patients in these studies may help to make clear explanations. after 2 months of medical treatment, a significant improvement in qmax and pvr urine was found in group a (p-value = 0.000 and 0.04), while no improvement was present in group b (p-value = 0.9 and 0.32) (table 2). more recently, it was found that the improvement in qmax values from baseline after 3 months of tamsulosin therapy was poor in patients with higher pua, and this is evident in our study (17). it is well known to us that the ipss/qol score is an essential subjective tool for assessing symptoms severity and disease-specific qol when determining treatment strategies and evaluating treatment outcome in men with luts/bph (19). we utilized the ipss/qol score in the subjective evaluation of medical treatment outcome in our patients. at baseline evaluation (pre-treatment), no difference in the ipss/qol score was found between both groups (p-value = 0.68 and 0.09 respectively) (table 1). these findings are similar and agree with previous reports (12-13). at 2 months of follow-up our study showed a statistically significant improvement in the ipss/qol scores in group a compared to group b (p-value = 0.0005 and < 0.000 respectively) (table 2). this can be explained by the presence of significant mechanical factors for obstruction among patients in group b (pua > 35). in presence of this factor it would be expected no response to alpha blocker drugs that usually affect the dynamic part of the obstruction. our findings were similar to those of hou et al. who investigated the association of the pua and the severity of luts on the aging male. they also evaluated the pua effect on tamsulosin hydrochloride therapy: after 3 months of medical treatment they found that the pua had an extremely strong correlation with ipss score and was inversely correlated with changes in the ipss score after tamsulosin treatment (17). to our knowledge, the prostatic urethra passes through the prostate from its base to its apex and this lead to formation of an anterior angle of 35° proximal to the veru montanum, this angle divides the urethra into proximal and distal regions (20). in men with nodular hyperplasia the angle tends to be > 35°, however, it could be also increased in men without nodular hyperplasia, as found during cystoscopic examination; an increased pua, results in a higher bladder neck without lateral or median lobe enlargement which is suggested as a clinically significant causal factor of male luts (10-11). looking at measurement of the prostatic parameters in our patients, the tpv and tzv were higher in patients with pua > 35˚ and the ipp was similar with no significant difference between both groups. in fact several studies reported that the prostate volume does not correlate with the clinical luts and/or the degree of boo (2, 3); in addition the mean ipp of our patients was small 3.6 ± 1.1 mm, while keqin et al. used an ipp cutoff value of 10 mm for better classification of boo in patients and correlation with clinical symptoms (21). therefore, it is clearly evident that the pua is an important prostatic measurement and it might be a predictor of treatment efficacy of α-blockers in men with luts/bph. medical treatment use for treating symptomatic bph patients may result in a delay in the surgical intervention decision. consequently, patients usually become older, may become unfit for surgery, and may have advanced disease; this may result in unfavorable outcomes and more postoperative morbidities and complications. also, delay in surgical treatment results in more serious and complicated resection (22-23). for this reasons, a predictive factor to those patients who will fail medical treatment in the future can guide us to spend less money as well as to avoid possible complications for such patients that can treated earlier by definitive surgery rather than remaim on medications for some time before going to surgery. the result of our study revealed that patients with higher pua > 35˚ showed a poor response to 0.4 mg tamsulosin hydrochloride in both subjective and objective parameters than those with pua ≤ 35˚. in another recent study, authors reported that patients with pua < 48.3°, did not require transurethral resection of the prostate (turp) within 1 year of medical treatment. while, 19 patients of those with pua > 48.3° finally received turp within 1 year due to lower tamsulosin hydrochloride efficacy (17). there are some limitations in our study as the small number of patients each group, the short term follow-up and the selection bias for patients during classification in groups based on previous cutoff values of pua in other studies. looking at the objective as well as the subjective data at the present study, we are suggesting that the pua may have an important role in the symptomatology of the patients with luts/bph. also, based on the present data of little response to medical treatment among those patients with higher pua > 35, we suggest that patients with higher pua should be offered another line of treatment and )informed explaining the expected results. conclusions in conclusion, this preliminary study suggests that the pua appears to be one of the anatomical factors which has an impact on medical treatment of male patients with luts/bph and it might be a predictor for the treatment efficacy of α-blockers. more studies are warranted in the future before drawing the final conclusion. these studies should include larger numbers of patients with longer follow-up periods and should be focused on the pua and especially on the method of its measurement and the relationship to the symptoms as well as its effect on every available methods of treatment (medical, minimally invasive, or invasive). references 1. verhamme km, dieleman jp, bleumink gs, et al. incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care – the triumph project. eur urol. 2002; 42:323-328. 2. bushman w. etiology, epidemiology, and natural history. urol clin north am. 2009; 36:403-415. ali raheem_stesura seveso 30/09/15 09:39 pagina 241 archivio italiano di urologia e andrologia 2015; 87, 3 hassan el-tatawy, tarek gameel, mohammed abo el-enen, ayman hagras, ayman mousa, abdel hamid el-bahnasy, ali abdel raheem, khaled abu-dewan 242 3. sciarra a, d'eramo g, casale p, et al.relationship among symptom score, prostate volume, and urinary flow rates in 543 patients with and without benign prostatic hyperplasia. prostate 1998; 34:121-128. 4. kaplan sa, te ae, pressler lb, et al. transition zone index as a method of assessing benign prostatic hyperplasia: correlation with symptoms, urine flow and detrusor pressure. j urol. 1995; 154:1764-9. 5. lepor h, nieder a, feser j, et al. total prostate and transition zone volumes, and transition zone index are poorly correlated with objective measures of clinical benign prostatic hyperplasia. j urol. 1997; 158:85-8. 6. chia sj, heng ct, chan sp, et al. correlation of intravesical prostatic protrusion with bladder outlet obstruction. bju int. 2003; 91:371-4. 7. keqin z, zhishun x, jing z, et al. clinical significance of intravesical prostatic protrusion in patients with benign prostatic enlargement. urology 2007; 70:1096-1099. 8. kojima m, ochiai a, naya y, et al. correlation of presumed circle area ratio with infravesical obstruction in men with lower urinary tract symptoms. urology 1997; 50:548-555. 9. doo ck and uh. hs. anatomic configuration of prostate obtained by noninvasive ultrasonography can predict clinical voiding parameters for determining boo in men with luts. urology. 2009; 73:232-236. 10. cho ks, kim j, choi yd, et al. the overlooked cause of benign prostatic hyperplasia: prostatic urethral angulation. med hypotheses. 2008; 70:532-535. 11. cho ks, kim jh, kim dj, et al. relationship between prostatic urethral angle and urinary flow rate: its implication in benign prostatic hyperplasia pathogenesis. urology. 2008; 71:858-862. 12. ku jh, ko dw, cho jy, et al. correlation between prostatic urethral angle and bladder outlet obstruction index in patients with lower urinary tract symptoms. urology. 2010; 75:1467-1471. 13. park yj, bae kh, jin bs, et al. is increased prostatic urethral angle related to lower urinary tract symptoms in males with benign prostatic hyperplasia/lower urinary tract symptoms? korean j urol. 2012; 53:410-413. 14. bang wj, kim hw, leec jy, et al. prostatic urethral angulation associated with urinary flow rate and urinary symptom scores in men with lower urinary tract symptoms. urology. 2012; 80:1333-1337. 15. gravas s, bachmann a, descazeaud a, et al. guidelines on the treatment of non-neurogenic male luts including benign prostatic obstruction. european association of urology, 2014. 16. roehrborn cg, barkin j, tubaro a, et al. influence of baseline variables on changes in international prostate symptom score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the combat study. bju int. 2014; 113:623-35. 17. hou1 c, chen l, lin y, et al. prostatic urethral angle might be a predictor of treatment efficacy of α-blockers in men with lower urinary tract symptoms. drug design, development and therapy. 2014:8 937-943. 18. narayan p, lepor h. long-term, open-label, phase iii multicenter study of tamsulosin in benign prostatic hyperplasia. urology. 2001; 57:466-470. 19. yoshida m, sugiyama y, masunaga k, et al. effect of tamsulosin hydrochloride on lower urinary tract symptoms and quality of life in patients with benign prostatic hyperplasia. evaluation using bother score. drugs today. 2007; 43:1-7. 20. mcneal je. the prostate and prostatic urethra: a morphologic synthesis. j urol. 1972; 107:1008-1016. 21. keqin z, zhishun x, jing z, et al. clinical significance of intravesical prostatic protrusion in patients with benign prostatic enlargement. urology. 2007; 70:1096-1099. 22. borth cs, beiko dt, nickel jc. impact of medical therapy on transurethral resection of the prostate: a decade of change. urology. 2001; 57:1082-5. 23. jepsen jv, bruskewitz rc. recent developments in the surgical management of benign prostatic hyperplasia.. urology 1998; 51:23-31. correspondence ali abdel raheem, md (corresponding author) aliraheem82@yahoo.com hassan el-tatawy hassantat@yahoo.com tarek gameel t_gameel@yahoo.com mohammed abo el-enen m.aboelenen@yahoo.com ayman hagras aymanhagras@yahoo.com ayman mousa hn.hn2020@yahoo.com abdel hamid el-bahnasy mrabdo65@yahoo.com urology department, tanta university hospital, egypt khaled abu-dewan radiology department, tanta university hospital, egypt ali raheem_stesura seveso 30/09/15 09:39 pagina 242 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3188 original paper a study on the effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia ali zarei 1, saeed changizi ashtiyani 2, gholam hassan vaezi 3 1 young researchers club, abadeh branch, islamic azad university, abadeh, iran; 2 department of physiology, arak university of medical sciences, arak, iran; 3 department of biology, islamic azad university, damghan branch, semnan, iran. background: although endocrine disorders are not a common cause of infertility, in some cases, testing thyroid function, and hypothalamus pituitary gonadal axis can determine the cause of infertility. we aimed to investigate the effect of the aerial parts of alhagi camelorum extract on prolactin, cortisol and pituitary gonadal axis activities in rats with hypercholesterolemia. materials and methods: in this study, 35 male wistar rats in 5 groups (n = 7) were assigned as: control group with normal diet, the sham group with fat diet and three experimental groups of hypercholesterolaemic animals which received alhagi camelorum extract at a minimum dose of 100 mg/kg, average dose of 200 ml/kg and maximum dose of 300 mg/kg over a period of 21 days. at the end of the period, blood samples were collected from all groups and blood factors were then measured and analyzed. results: in the sham group compared to the control, cholesterol levels increased and fsh levels decreased, whereas cholesterol levels reduced in the experimental groups. alhagi camelorum extract also reduced testosterone level and increased prolactin and gonadotropins. conclusion: alhagi camelorum extract at low and average doses reduced cortisol, testosterone and cholesterol and increased gonadotropins. so it can cause reproductive disorders in male rats. the extract at maximum dose can increase cortisol and prolactin. as these two hormones work together to produce milk, this plant can help to boost breastfeeding. key words: alhagi camelorum; prolactin; testosterone; cholesterol; gonadotropin. submitted 8 april 2014; accepted 30 january 2014 summary no conflict of interest declared. state in which no pregnancy occurs after a year of sex activity without using birth control methods. when discussing infertility, people generally believe that most problems are related to women. in fact, nearly 30% of infertility problems are related to men and 20% are common problems between women and men. so, 50% of men are involved in problems related to infertility. however, this rate is different in different countries and in different studies. obesity is associated with various hormonal changes that can be responsible for changes in sperm motility and abnormal sexual function. evidence suggests that in obese men, more androgen changes into estrogen in fat tissue and serum testosterone level decreases. however, by increasing the negative feedback of estrogen on pituitary gland, gonadotropin levels decrease. pulse obesity also affects gnrh-fsh-lh which may affect sex hormones secretion and sperm maturation by disrupting leydig and sertoli cells (1, 2). endocrine disorders are not among the common causes of infertility; however, in some cases, the cause of infertility can be determined by testing thyroid, gonadotropins, prolactin and testosterone. the level of fsh rises with germinal cell aplasia and the level of testosterone in men with hypogonadotropic hypogonadism decreases (1). leydig cells are the main source of testosterone and have receptors for prolactin which at normal levels increases testosterone secretion. these studies suggest a synergy between prolactin, lh and testosterone. however, high levels of prolactin reduces testosterone and leads to frigidity (1, 2). prolactin is regulated by dopamine and some other factors such as trh. dopamine is a neurotransmitter that has an inhibitory effect on the hypothalamic-pituitary-gonadal axis (2). trh, secreted from the hypothalamus gland, stimulates prolactin secretion. cholesterol is the precursor of steroid hormones and cholesterol changes into pregnenolone by p450 in mitochondria (1, 3, 4). on the other hand, increased level of blood cholesterol is associated with coronary artery disease, fat liver and infertility. excessive fat causes the male hormone of testosterone to be converted to estrogen which reduces the production of sex cells. doi: 10.4081/aiua.2014.3.188 introduction today, with advances in science and technology, it is recognized that infertility is not just a problem for women. male factors are also involved. infertility is defined as a zarei_stesura seveso 09/10/14 10:38 pagina 188 189archivio italiano di urologia e andrologia 2014; 86, 3 effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia cholesterol levels can be lowered by diet or drugs (1, 4). many plants and compounds can be effective in reducing cholesterol. alhagi camelorum is one of the plants in traditional medicine which is used to treat metabolic, gastrointestinal and liver diseases, rheumatic disorder, migraines and warts. laboratory studies indicate that alhagi camelorum extract reduces body temperature and heart rate. the extract also inhibits the action of acetylcholine to relax the muscles and is helpful in opening the urinary tract and disposal of kidney stones (5). this plant, commonly called camel thorn (figure 1), with the scientific name of alhagi maurorum belongs to the plant family of leguminosae (papilionaceous). the family has about 550 genera and more than 13000 species (6). other chemical researches on this plant indicate that it contains sterols and fatty acids (7, 8), flavonoids (9, 10), coumarins (8), alkaloids (6, 8), and vitamins. about 12 types of flavonoids have been isolated from this plant (1). studies have shown that flavonoids have antiandrogenic and antifertility effects on the reproductive system of dogs (12, 13). studies on the bioactive compounds which have the potential to inhibit or stop cancer cells can pave the way to discover more effective drugs (14). nowadays, people are increasingly using fruits and vegetables due to their protective effects against illnesses like cancer, cardiovascular and liver diseases (15, 16). this is due to the antioxidant compounds present in plants, including vitamins b and c, carotenoids, lycopene and flavonoids, which prevent the damages caused by free radicals (17, 19). as infertility and lipid disorders are increasing and most of the anti-fat drugs and contraceptives available in the pharmaceutical market of iran and the world have multiple side effects, and also thanks to the increasing tendency towards herbal remedies because of their fewer side effects, any study on medicinal plants is of great value (4). with this in mind, the present study aimed to investigate the effects of the extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal axis activities in rats with hypercholesterolemia. methods this is an experimental study .all animals were taken from razi institute in fars province and were kept in standard conditions of temperature and light.this study is based on observing all moral codes of working with laboratory animals established by the ministry of health and medical training (iran). before the research, all the animal were weighed to be within a certain weight range. initially, 35 male wistar rats with the average weight of 5 ± 170 g were randomly divided into 5 groups (n = 7) as follows: controls the animals in this group did not receive any drug or solvent during the experiment and their diet was normal. sham group consisted of hypercholesterolemic rats which received 0.2 ml of solvent (normal saline) for 21 days as gavage; (2% cholesterol was added to their food to make them hypercholesterolemic); experimental group 1, hypercholesterolaemic rats which received a minimum dose of 100 mg/kg of alhagi camelorum extract for 21 days as gavage; experimental group 2: hypercholesterolemic rats that were gavaged for 21 days with an average dose of 200 mg/kg of the extract; and experimental group 3 were hypercholesterolemic rats receiving maximum dose of 300 mg/kg of the extract for the same period as gavage feeding. preparation method for high cholesterol food to obtain a 2% high-cholesterol diet, 20 grams of merck pure cholesterol powder (fluke chemika) was solved in 5 ml of olive oil and the solution was well mixed with a kilogram of rat diet. to avoid deterioration of the food it was kept in the refrigerator for only two days (20, 21). extraction alhagi camelorum plants were collected from the suburb of abadeh (fars province/iran) and were identified and confirmed by the pnu (payame noor university) department of botany (herbarium code was 002/040/073). to prepare the alhagi camelorum alcoholic extract, after providing the aerial parts and removing impurities, 800 grams of the collected plant samples were crushed and mixed with ethyl alcohol 98% by the ratio of 1 to 5. the content obtained was kept in a package for 48 hours in vitro and it was carefully filtered by passing it through different small and big filters. then it was placed in a water bath to concentrate. finally, different concentrations of the obtained extract (about 15 g per 100 g of crushed plant) was prepared by adding different amounts of normal saline. during the experimental period all experimental groups were fed with high fat diet. during the test period (21 days) the animals were daily injected at 9 am. after completing this course and in order to measure plasma biochemical factors of the animals, they were mildly anesthetized with ether and their blood was collected and then centrifuged at 3000 rpm. the serum was separated and transferred to the laboratory for measurement of factors. to measure cholesterol, prolactin, testosterone, cortisol, and gonadotropin ria (ria), pars azmoon kits and ria 1000 machine (made in usa) were used. for statistical analysis the mean obtained (mean ± sem), one way figure 1. the aerial parts of camel thorn (alhagi camelorum). zarei_stesura seveso 09/10/14 10:38 pagina 189 archivio italiano di urologia e andrologia 2014; 86, 3 a. zarei, s. changizi ashtiyani, g. hassan vaezi 190 anova test and tukey and duncan tests were used. all statistical analyses were done using spss software version 17 (p < 0.05). results as shown in table 1 the amount of cholesterol in the sham group increased significantly compared to the control group and in the group receiving the minimum dose of the extract the cholesterol level significantly decreased compared to the sham group (p = 0.02). the differences between experimental groups are not significant. in the case of fsh, mean value in the sham group shows a significant decrease than in the control group. and the group receiving an average dose of alhagi camelorum extract shows a significant increase compared to the sham group and the groups receiving the minimum and maximum doses of the extract (p = 0.001). lh level in the sham group did not show significant changes than in the control group. however, in groups with minimum and average doses there is a significant increase compared to both the sham group and the group receiving the highest dose of the extract (p = 0.01). in the case of testosterone in the sham group no significant change was seen if weighed against the control group, however, the amount of it in groups receiving minimum and average doses a significant decrease was seen compared to the sham group (p = 0.02). none of the changes in experimental groups were significant. prolactin level increased in the sham group compared to the control group, but these changes were not significant. its level in the group receiving the maximum dose showed a significant increase as compared to the sham group and the groups which received minimum or average doses of the extract (p = 0.007). however, no significant difference was observed between the average and minimum groups. cortisol levels in the sham group did not show any significant changes as compared to the control group, but in the groups receiving minimum and average doses of the extract it was significantly lower than in the sham group. cortisol levels in the group receiving the highest dose of the extract compared to sham group as well as the group receiving the least and average doses of the extract showed a significant increase (p = 0.000). discussion test results showed that by increasing the amount of cholesterol in the sham group, fsh levels decreased. the administration of the extract to hypercholesterolaemic rats increased gonadotropin and prolactin levels and decreased the level of testosterone. the level of cortisol in the group receiving the highest dose of the extract reduced, but it decreased in groups with the minimum and average doses. nowadays, with the prevalence of obesity, it has become an important issue that how fertility in men is affected by obesity and fat. in this study, the relationship between increased cholesterol level and functions of pituitarygonadal axis in the sham group was measured. it is important because if obesity is the cause of male infertility, it can be treated. obesity affects fertility in men by various mechanisms, among which we can refer to changes in gonadotropin secretion from the pituitary gland, changes in sex hormone-binding globulins, decreased libido, sperm dna damage ,and so on. another important effect of obesity on fertility is the reduced testicular activity. in adipose tissue ten percent of testosterone which is male hormone turns into estradiol which is a female hormone. increased estradiol makes the breasts grow larger in men and obese men typically have larger breasts (24-22). however, studies in this field are controversial. for example, pauli et al. (25) and relvany et al. (26) showed that weight gain does not affect the fertility of the semen quality parameters while wagner et al. (2010) and paasch et al. (2010) stated that increased bmi has a negative impact on sperm quality and fertility indices (27-28), which is consistent with the results of the present study as it was seen that in the control group by increasing cholesterol, the level of fsh decreased. on the effect of the extract on pituitary gonadal axis activities it can be said that on one hand, the extract reduced cholesterol, testosterone and on the other, it in creased prolactin and gona do tro pin levels. one of the most important ways to adjust lh and fsh groups control sham ac ac ac (100 mg/kg) (200 mg/kg) (300 mg/kg) parameters cholesterol 69.8 ± 2.9 86.57 ± 1.9 66.33 ± 3.3 70.83 ± 7.24 76.16 ± 5.2 * ! lh 1.07 ± 0.2 0.71 ± 0.03 1.40 ± 0.3 1.54 ± 0.2 0.85 ± 0.03 " ! # ! fsh 2.8 ± 0.4 1.03 ± 0.07 1.64 ± 0.45 3.34 ± 0.5 1.60 ± 0.2 * $ ! # testosterone 6.9 ± 2.7 5.94 ± 1.8 1.65 ± 0.3 0.55 ± 0.1 2.67 ± 0.6 ! ! prolactin 3.45 ± 0.25 5.16 ± 0.55 6.49 ± 0.7 6.28 ± 1.4 9.84 ± 1.8 " # ! cortisol 20.2 ± 0.8 20.77 ± 4.8 10.27 ± 0.2 10.33 ± 1.40 27.15 ± 2.4 ! ! " # ! * marks a significant change compared with the control group, ! represents a significant change compared with the sham group. " represents a significant change between the minimum and maximum doses of alhagi camelorum extract. % indicates significant change between average and maximum doses of alhagi camelorum extract. ! represents a significant change in minimum and average doses of alhagi camelorum extract. table 1. effects of different doses of the extract of the aerial parts of alhagi camelorum (ac) on cholesterol, cortisol, testosterone, prolactin and gonadotropin. zarei_stesura seveso 09/10/14 10:38 pagina 190 191archivio italiano di urologia e andrologia 2014; 86, 3 effects of the hydroalcholic extract of the aerial parts of alhagi camelorum on prolactin and pituitary-gonadal activity in rats with hypercholesterolemia gonadotropin levels is through negative feedback effect of testosterone. that is when the level of this hormone increases, gonadotropin levels decrease and vice versa (29). in this study it seems reasonable that by increasing testosterone gonadotropins decreased. leydig cells are the main source of testosterone. leydig cells have receptors for prolactin that at normal levels increases testosterone. this suggests a collaboration between prl and lh and testosterone. however, high levels of prolactin, reduce testosterone (1). the results of this study showed that the alhagi camelorum extract reduced cholesterol and testosterone, but it increased gonadotropins and prolactin. lhrh hormone can be another possibility for the reduction of testosterone level. this hormone increases lh and fsh hormones and at the same time inhibits testicular testosterone synthesis and secretion by reducing lh receptors (30, 31). therefore, in this study, despite the increase in fsh and lh, lower testosterone seems to be reasonable and the results of this study is consistent with previous studies on effect of blue plate extract (centella asiatica) on spermatogenesis, as studies show the chemical compounds in both plants are similar (32). testosterone is one of the hormones needed for spermatogenesis. lower level of this hormone could possibly reduce the number of spermatogonial and spermatocytes cells. these cells produce growth factors such as activin and in the presence of calcium ions, cause karyokinesis, cytokinesis and sperm differentiation (33-34). studies on alhagi camelorum plant indicates that on one hand this herb may inhibit calcium channels and on the other active components of the plant including flavonoids have contraceptives and anti-androgenic effects on reproductive system (12, 13). alkaloids are key ingredients in this plant. alkaloids by reducing androgens lead to atrophy of epithelial cells and subsequently prohibits androgenic effects on tissues and thus cancer is treated (4, 35). alkaloids also easily cross the cell membrane and thus they destroy the cytoskeleton, help a variety of free radicals to release and ultimately cause detrimental changes in cellular structure which in turn causes higher activity of white blood cells (anti-inflammatory), while some studies suggest that they have also antioxidant effects (35, 36-38) in addition, alkaloids inhibit cholesterol synthesis (39). similar studies on berberis indicates that the alkaloid compounds in this plant such as berberine and berbamine can be effective in the prevention of coronary artery diseases and could possibly reduce total cholesterol levels . blocking calcium channel is the major effect of berbamine. berberine increases the production of a receptor in the liver that binds with cholesterol and facilitates its disposal (20, 21). since cholesterol is the precursor of steroid hormones, the extract probably lowers testosterone by reducing cholesterol. bashtiny et al. in a study on feeding animals with alhagi camelorum showed that it increased their milk production. this is consistent with our findings as increased prolactin level is one of the most important factors for increasing milk (40). injecting prolactin and hydrocortisone acetate lactogenic hormone in a variety of lactating mammals induces the synthesis and accumulation of beta-carotene in the mammary glands of rats. research shows that glucocorticoids can be effective only when they are accompanied by prolactin. studies also showed that milk secretion is the result of several hormones, and herbal extracts directly stimulate endogenous prolactin secretion. as a result, it works effectively on mammary glands. for example, pectin compounds in plants are capable of stimulating the secretion of prolactin, growth hormone, lh and endorphins from rat pituitary. most active fractions of the plant that cause prolactin secretion are made of polysaccharides because they have higher amounts of pectin. in addition, there are other compounds involved including prolactin, cortisol and growth hormones (41). conclusion based on the findings in this study, alhagi camelorum extract at the average and minimum doses decreases cortisol, cholesterol, testosterone and increases gonadotropins. so it can cause reproductive disorders in male rats. the extract in the maximum dose can increase cortisol and prolactin. since these two hormones work together in milk production, this plant can act as a milk booster. acknowledgement the authors wish to thank the deputy of research of eghlid payame noor university for their kind help and support. references 1. fritz ma, speroff l. clinical gynecologic endocrinology and infertility. 8th ed. philadelphia: lippincott williams &wilkins. 2010; 157-180. 2. hajishafiha m, garehagaji r, salemi s, et al. survey of association among bmi with semen factors and sex hormones in men. medical journal of mashad university of medical sciences. 2012; 55:102-109 [in persian]. 3. murray r, bender d, botham km, editors. harpers illustrated biochemistry. 29th ed. new york: mcgraw hill. 2012; 415-456. 4. zarei a, changizi-ashtiyani s, rezaei a, et al. the effect of chelidonium majus extract on the lipid profile and activity of pituitary-gonadal axis in hypercholesterolemic rats. zahedan j res med sci 2014; 16:18-22. 5. marashdah ms, farraj ai. pharmacological activity of 2% aqueous acetic acid extract of alhagi maurorum roots. journal of saudi chemical society. 2010; 14:247-250. 6. awaad amani as. maitland dj,. soliman ga. antiulcerogenic activity of alhagi maurorum pharmaceutical biology, 2006; 44:292-296. 7. samejo mq. memon s, bhanger mi, khan km. chemical composition of essential of essential oils from alhagi maurorum. chemistry of natural compounds. 2012; 48:898-900. 8. behari m, gupt sc the isolation and biogenesis of24-alkylsterols in alhagi pseudoalhagi. acta cienc indica chem. 1980; 6:207–208. 9. al-yahya ma, mossa js, al-badr aa, et al. phytochemical and biological studies on saudi medicinal plants part 12. a study on saudi plants of family leguminosae. int j crud drug res. 1987; 25:65-71. zarei_stesura seveso 09/10/14 10:38 pagina 191 archivio italiano di urologia e andrologia 2014; 86, 3 a. zarei, s. changizi ashtiyani, g. hassan vaezi 192 10. singh vp, bineeta y, pandey vb. flavanone glycosides from alhagi pseudalhagi. phytochemistry 1999; 51:587-590. 11. shaker e, mahmoud h, mnaa s. anti-inflammatory and antiulcer activity of the extract from alhagi maurorum (camelthorn). food chem toxicol. 2010; 48:2785-90. 12. bhargava sk. anti-fertility effects of the flavonoids of vitex negundo l. seeds in dogs. plant med. 198; 20:188-197. 13. bhargava sk. antiandrogenic effects of the flavonoid – rich fraction of vitex negundo seeds: a histological and biochemical study in dogs. j ethnopharmacol. 1989; 27:327-39. 14. vuong qv, hirun s, phillips pa, et al. fruit-derived phenolic compounds and pancreatic cancer: perspectives from australian native fruits. j ethnopharmacol. 2014; 152:227-242. 15. pérez-carreón ji1, cruz-jiménez g, licea-vega ja, et al. genotoxic and anti-genotoxic properties of calendula officinalis extracts in rat liver cell cultures treated with diethylnitrosamine. toxicol in vitro. 2002; 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comparative study of hypolipidemic activities of the extracts of melissa officinalis and berberis vulgaris in rats. journal of medicinal plants. 2013; 12:38-47. 22. haghighi s, yaghmaei p, hashemi f, et al. the association between serum chemerin concentration and polycystic ovarian syndrome tehran university medical journal. 2012; 70:320-324. [in persian]. 23. sarvari a, naderi mm, heidari m, et al. effect of environmental risk factors on human fertility. medical journal of reproduction & infertility. 2011; 11: 211-226 [in persian]. 24. chobine h, sedighe gilani ma, hassanzadeh gh, et al. assessment of socio-demographic characteristics of infertile men who referred to shariati hospital, tehran, iran. ijogi. 2013; 16:6-12. 25. pauli em, legro rs, demers lm, et al. diminished paternity and gonadal function with increasing obesity in men, fertil steril. 2008; 90:346-51. 26. relwani r, berger d, santoro n, et al. semen parameters are unrelated to bmi but vary with ssri use and prior urological surgery. reprod sci. 2011; 18:391-7. 27. wegner c, clifford al, jilbert pm, et al. abnormally high body mass index and tobacco use are associated with poor sperm quality as revealed by reduced sperm binding to hyaluronan-coated slides. fertil steril. 2010; 93:332-4. 28. paasch u, grunewald s, kratzsch j, glander h. obesity and age affect male fertility potential. fertil steril. 2010; 94:2898-901. 29. hall je. guyton and hall textbook of medical physiology. 12th ed. philadelphia: wb. saunders, 2010; 881-976. 30. modaresi m, messripour m, toghyani m, rajaii ra. effect of hydroalcoholic extract of cinnamon zeylanicum (bark) on mice pituitary-testis axis. gorgan univ med sci j. 2010; 12:15-19. 31. melmed s, polonsky ks. williams textbook of endocrinology. 12th ed. philadelphia: wb. saunders; 2012; 581-778. 32. heidari m, jamshedi ah, akhondzadeh sh, et al. evaluating the effects of centella asiatica on spermatogenesis in rats. medical journal of reproduction & infertility. 2006; 7:367-374. 33. ahmadi a, nasiri nejad, f, parivar k. effect of aqueous extract of the aerial part of the ruta graveolens on the spermatogenesis of immature balb/c mice. rjms. 2007; 14:13-20. 34. grootegoed ja, siep m, baarends wm. molecular and cellular mechanisms in spermatogenesis. baillieres pract res clin endocrinol metab. 2000; 14:331-43. 35. rahimi-movaghar a, khastoo g, fekri m, akhondzadeh s. treatment of addiction by medicinal herbs sellers in tehran. hakim res j. 2008; 11:11-19. 36. qiu l, zhao f, liu h, et al. two new megastigmane glycosides, physanosides a and b, from physalis alkekengi l. var. franchetii, and their effect on no release in macrophages. chem biodivers. 2008; 5:758-63. 37. zarei a, shariati m, shekar-forosh s, et al. the effect of physalis alkekengi extract on the physiologic function of organ tissues] persian. arak univ. j 2012; 15:94-104 [in persian]. 38. chand n, durrani fr, qureshi ms, durrani z. role of berberis lycium in reducing serum cholesterol in broilers. asian-aust j anim sci. 2007; 20:563-568. 39. zarei a, changizi ashtiyani s, rasekh f, mohammadi a. the effect of physalis alkekengi extracts on lipids concentrations in rats. arak university of medical journal. 2011; 14:36-42 [in persian]. 40. bashtini j, fazaeli h, mirhadi a, malekkhahi m. effect of feeding alhaji browse to lactating ewes on milk yield and performance of lambs. animal science researches. 2013; 23:39-48. 41. sepehri h. la synthese de beta casein par lacide pectique obtenu des extraits des plantes lactogenes. journal of science, university of tehran. 1991; 20:61-72. correspondence ali zarei, phd young researchers club, abadeh branch, islamic azad university, abadeh, iran saeed changizi ashtiyani, phd (correspondig author) dr.ashtiyani@arakmu.ac.ir department of physiology, arak university of medical sciences, arak, iran gholam hassan vaezi, phd department of biology, islamic azad university, damghan branch, semnan, iran zarei_stesura seveso 09/10/14 10:38 pagina 192 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4284 original paper transrectal versus transperineal 14-core prostate biopsy in detection of prostate cancer: a comparative evaluation at the same institution maria angela cerruto 1, fabio vianello 2, carolina d’elia 1, walter artibani 1, giovanni novella 1 1 department of surgery, urology clinic, aoui verona, italy; 2 urology clinic, university of padua, italy. background: the ideal bioptic strategy for cap detection is still to be completely defined. the aim of our study is to compare transperineal (tp) and transrectal (tr) approaches, in a 14-core initial prostate biopsy for cap detection. material and methods: a prospective controlled study was conducted enrolling 108 consecutive patients with a psa level greater than 4 ng/ml and/or an abnormal dre. tr versus tp 14-core initial prostatic biopsies were performed on 54 and 54 patients, respectively, with a randomisation ratio of 1:1. results: the cancer detection rates were 46.29 (25 out of 54 patients), and 44.44% (24 out of 54 patients), respectively, using the tr or the tp approach (p = 0.846). the overall cancer core rate was significantly higher when the tp approach was used: 21.43% (162 out of 756 cores) and 16.79% (127 out of 756 cores), with the tp and the tr approach, respectively (p = 0.022). the cores were significantly longer performing tp approach: at the site “1” (14.92 versus 12.97 mm, p = 0.02); at “5” (15.53 versus 13.69 mm, p = 0.037); at “7” (15.06 versus 12.86 mm, p = 0.001); at “9” (14.92 versus 13.38 mm, p = 0.038); at “11” (16.32 versus 12.31 mm, p = 0.0001); at “12” (15.14 versus 12.19 mm, p = 0.0001); at “13” (17.49 versus 13.98 mm, p = 0.0001); at “14” (16.77 versus 13.36 mm, p = 0.0001). as to the biopsy related pain, the mean pain level perceived by patients during the tr approach was 1.56 ± 1.73 versus 1.42 ± 1.37 registered during tp approach (p = 0.591). conclusions: no significant differences were found in cancer detection rate, cancer core rate between tp and tr approaches for prostatic biopsy. even in terms of complication rate or pain level, it cannot be concluded that one procedure is superior to the other one. apparently, strictly following our protocol, tp approach seems to offer a better sampling at the level of the apex and the tz, however without adding any significant advantage in terms of overall cancer detection rate. key words: prostatic neoplasm; transrectal biopsy; transperineal biopsy; diagnosis; cancer detection rate; prostatespecific antigen. submitted 12 february 2014; accepted 30 june 2014 summary no conflict of interest declared. introduction the widespread use of serum prostate specific antigen (psa) measurement as an opportunistic screening tool to detect early prostate cancer (cap) led to optimise an effective biopsy technique. unfortunately, the ideal bioptic strategy for cap detection is still to be completely defined. at the present, there is still a lack of standardisation regarding both transperineal (tp) and transrectal (tr) approaches. in 2003, emiliozzi et al. carried out a prospective study aiming of comparing the efficacy of tp and tr six-core prostatic biopsy. they performed both biopsy approaches, on the same patients, stating that tp biopsy resulted superior to tr one to detect cap (p = 0.012) (1). in 2007, firstly, kawakami et al. demonstrated that an extended tp biopsy was as effective as its tr counterpart in detecting the presence and the characteristics of the cap, as far as sampling sites were selected to maximize the cancer detection rate (2). more recently, hara et al. carried out a prospective randomized study comparing tp with tr 12-core biopsy, in 246 patients with psa levels ranging from 4.0 to 20.0 ng/ml (3). with patients in lithotomy position, all procedures were performed using spinal anaesthesia (0.5% bupivacaine) or a caudal block (1% lidocaine) according to tp and tr approaches, respectively. the authors did not find any significant difference in cancer detection rate, cancer core rate or complications between the two approaches: they concluded that the preferred approach, as the initial prostate biopsy, might be the tr one as it did not require spinal anaesthesia or other burdensome related processes (3). nevertheless, the same study group even reported that, with a psa in the so-called “grey zone”, significantly more cores were positive when the tp approach was applied, especially for cores coming from the transition zone (4). conclusions were that urologist’s preference could be sufficient for choosing the ideal approach, except for a possible small advantage for tp biopsy when psa is in the “grey zone”. just to compare tp and tr approaches, in a 14-core initial prostate biopsy for cap detection, we have performed a prospective controlled study and these results are herein presented. doi: 10.4081/aiua.2014.4.284 cerruto_stesura seveso 15/01/15 13:18 pagina 284 285archivio italiano di urologia e andrologia 2014; 86, 4 transrectal versus transperineal prostate biopsy: a comparative evaluation material and methods a prospective controlled study was conducted enrolling 108 consecutive patients at our urological center with a psa level greater than 4 ng/ml and/or an abnormal digital rectal examination (dre). tr versus tp 14-core initial prostatic biopsies were performed on 54 and 54 patients, respectively, with a randomisation ratio of 1:1. the inclusion criteria foresaw no previous prostate biopsy, no history of cap and no clinical evidence of acute or chronic prostatitis. all patients were adequately informed on the execution modalities of the bioptic procedure and on its potential complications. they were asked to provide a written consent. each patient underwent a clinical evaluation that included dre and transrectal ultrasound (trus). prostate volume (pv) was measured by means of trus and was calculated as the height per the width per the length per 0.52. table 1 lists patients’ characteristics: no significant differences were found in background factors between the two groups. all patients were instructed to discontinue an eventual anticoagulant therapy for at least 7 days before and after the prostate biopsy. all patients were given an enema the same morning of the procedure and an antibiotic coverage was provided in all cases using an oral fluoroquinolone (prulifloxacin, 600 mg, once a day) for 3 days, starting from the day before the biopsy. for both approaches, the patients were placed in lithotomy position, and all biopsies were carried out only by two skilled urologists included as the co-authors of this paper: gn for the tp approach, and fv for the tr one. all the tp biopsies were performed using a single median tp access 1.5 cm above the anal sphincter, as previously described (5). in all cases, local anaesthesia was provided releasing 2 ml of 1% mepivacaine at the level of the prostate apex. a 18-gauge coaxial needle (truguide bard, 13 cm long) was inserted up to the prostate apex through the anesthetised perineal path under trus guidance. on the removal of the blunt tip stylet, the guiding cannula of the coaxial needle was used as a tp metallic path for repeated atraumatic passages of the biopsy needle. with the tp approach, firstly, a traditional sextant biopsy was performed; then, additional lateral sextant peripheral cores were added and, lastly, two cores were taken from the anterior transitional zone (tz) (6). for systematic tr biopsy, a bilateral periprostatic nerve block was obtained using a 1% lidocaine solution, transrectally injected under ultrasound guidance at the prostate apex and the seminal vesicle-prostatic angles. eight cores were added to the standard tr protocol described by hodge et al (7): six, far laterally in the peripheral zone (pz), and two in the middle tz. tp and tr approaches were both performed under trus guidance (siemens sonoline omnia diagnostic ultrasound system with a 7.75-mhz linear probe was used). with both approaches, an 18-gauge tru-cut needle with a cutting length of 23 mm was applied to obtain specimens. overall 14-core trus guided prostate biopsies have been obtained: 12 specimens from pz and two from tz for each approach. cores of the standard sextant were conventionally labelled from 1 to 6. likewise, additional peripheral cores from the lateral part of prostatic apex, were numbered as “7” and “8”. additional lateral peripheral cores, from the mid prostate, were numbered as “9” and “10”. other cores, from the anterior horn, were numbered as “11” and “12”. finally, biopsies taken from the tz were labelled as “13” and “14”. in all cases, pain level during the bioptic procedure , was evaluated by means of a visual analogue scale/numeric analogue scale in which 0 corresponded to “no pain” and 10 to “the worst, imaginable pain” (5, 6). all patients were clinically evaluated 30 days after the biopsy to record eventual complications related to procedures (5). we determined the cap detection rate, the cancer core rate (ratio of the number of cancer-positive cores to the total number of biopsy specimens) and any complications occurred in order to define efficacy and tolerability of the tp biopsy compared with the tr one. for statistical analysis, chi-square and the mannwhitney u tests were used and a p < 0.05 was considered significant. results patients’ characteristics are listed in table 1. the cancer detection rates were 46.29 (25 out of 54 patients), and 44.44% (24 out of 54 patients), respectively, using the tr or the tp approach (p = 0.846). among patients with psa levels of less than 10.0 ng/ml, the detection rate was 42.22 characteristics tp approach tr approach p value patients (n) 54 54 ns mean age (year) (sd) 66.50 ± 8.87 67.30 ± 8.05 0.627 mean psa (ng/ml) (sd) 15.95 ± 41.04 12.36 ± 39.65 0.646 bmi (kg/cm2) (sd) 27.16 ± 3.18 27.00 ± 3.12 0.794 mean prostate volume 56.29 ± 31.33 61.49 ± 33.39 0.408 (cm3) (sd) abnormal dre 11/54 (20.37) 10/54 (18.52%) 0.810 sd = standard deviation; ns = not significant. table 1. patients’ characteristics. variables tp approach (%) tr approach (%) p value overall 24/54 (44.44) 25/54 (46.29) 0.846 (ns) psa (ng(ml) 0.303 (ns) ≤ 10 15/39 (38.46) 19/45 (42.22) > 10.1 9/15 (60.00) 6/9 (66.67) prostate volume (cm3) 0.283 (ns) < 30 8/9 (88.89) 8/10 (80) 30-50 11/20 (55.00) 7/13 (53.85) > 50 5/25 (20.00) 10/30 (33.33) ns = not significant. table 2. comparison of cancer detection rate according to psa level and prostate volume (determined by trus), between tp and tr approach. cerruto_stesura seveso 15/01/15 13:18 pagina 285 archivio italiano di urologia e andrologia 2014; 86, 4 m.a. cerruto, f. vianello, c. d’elia, w. artibani, gi. novella 286 (19 out of 45) and 38.46% (15 out of 39) when the tr or the tp approach was applied, respectively (p = 0.728). stratifying patients for either psa level or pv, no significant differences were found in the two groups (table 2). the overall cancer core rate was significantly higher when the tp approach was used: 21.43% (162 out of 756 cores) and 16.79% (127 out of 756 cores), with the tp and the tr approach, respectively (p = 0.022). the cancer core rate, in pz cores, was 17.59% (114 out of 648 cores) in case of tr approach, and 21.43% (140 out of 648 cores) going transperineally (p = 0.068). in tz, the corresponding rate was 12.04 (13 out of 108 cores) versus 20.37% (22 out of 108 cores), respectively (p = 0.097) (table 3). the cores were significantly longer performing tp approach, as it follows: at the site “1” (14.92 versus 12.97 mm, p = 0.02); at “5” (15.53 versus 13.69 mm, p = 0.037); at “7” (15.06 versus 12.86 mm, p = 0.001); at “9” (14.92 versus 13.38 mm, p = 0.038); at “11” (16.32 versus 12.31 mm, p = 0.0001); at “12” (15.14 versus 12.19 mm, p = 0.0001); at “13” (17.49 versus 13.98 mm, p = 0.0001); at “14” (16.77 versus 13.36 mm, p = 0.0001). overall, no significant differences were found in terms of post-biopsy complications between the two groups (table 4). as to the biopsy related pain, the mean pain level perceived by patients during the tr approach was 1.56 ± 1.73 versus 1.42 ± 1.37 registered during tp approach (p = 0.591). discussion to our knowledge, the present study is the first prospective controlled evaluation that compares systematic 14-core biopsy using tr and tp approaches, both under local anaesthesia. in 2003, emiliozzi et al. reported a comparison between the two approaches, using the same patients, under local anaesthesia. the aim of that study was to compare the efficacy of tp versus tr six-core prostate biopsies, performing six tp plus six tr biopsies in a group of 107 patients with psa greater than 4 ng/ml. the authors highlighted the superiority of the tp approach with a cancer detection rate of 40% (43 out of 107) using the combination of both approaches; of 38% (41 of 107) with the tp approach alone, and 32% (34 of 107) when the tr approach had been applied alone (1). more recently, hara et al prospectively compared tp and tr approaches and they did not show any significant differences in overall cancer detection rate (3). as to the suggested superiority of the tp approach in detecting tz cancer, shannon et al. reported that the tp approach was more successful in detecting tz cancer because the correct diagnosis rate was greater when the tp approach was used in comparison with the tr approach (89 versus 68%)(8). furthermore, furuno et al., performing a tp ultrasound-guided template biopsy in men with psa levels ranging between 4 and 10 ng/ml, reported that the cancer core rate of the biopsies from the anterior part of the prostate was significantly greater than that from the posterior region (9). they suggested that tr sextant biopsy might be inadequate for detecting cancer localized in the anterior region. on the contrary, hara et al. did not find any differences in cancer core rates whatever zones or approaches were (3). in authors’ opinion, the increased number of biopsy specimens to 12 might reduce the differences in cancer detection rates between the two approaches. in our study, cancer core rates in pz, tz, apex and mid prostate were always higher when tp approach was used, but without reaching any statistical significance. more recently, takenada, hara et al. found that, in patients with psa in the “grey zone” (ranging between 4.1 and 10.0 ng/ml), significantly more cores were positive when tp approach was applied, especially regarding to tz cores (4). they concluded that urologists’ preferences should be sufficient for choosing the best approach, except for possible small advantages for tp biopsy when psa is in the “grey zone”. the results of our study might even support this trend towards a possible advantage of tp biopsy in better sampling both tz and prostate apex. some of our group had previously reported that tp approach would allow a greater sampling of the prostate apex compared with midgland and prostate base (p < 0.001) (10). to possibly characteristics tp approach tr approach p value overall (%) 7/54 (12.96) 7/54 (12.96) ns rectal bleeding (%) 0 (0) 4 (57.16) 0.04 urinary retention (%) 0 (0) 1 (14.28) 0.315 (ns) urethral bleeding (%) 5 (71.43) 0 (0) 0.022 vasovagal event (%) 2 (28.57) 1 (14.28) 0.56 (ns) fever > 38.5°c (%) 0 (0) 1 (14.28) 0.315 (ns) not significant. table 4. complication rates. approach total pz tz apex mid prostate base tp biopsy cores (n) 756 648 108 216 216 216 162 140 22 49 48 46 21.43% 21.60% 20.37% 22.68% 22.22% 21.30% tr biopsy cores (n) 756 648 108 216 216 216 cancer cores (n) 127 114 13 38 40 44 cancer core rate (%) 16.7% 17.59% 12.04% 17.59% 18.52% 20.47% p value 0.022 0.068 0.097 0.186 0.340 0.814 (ns) (ns) (ns) (ns) (ns) ns = not significant. table 3. comparison of cancer-positive core rate by anatomic location between transperineal and transrectal approaches cerruto_stesura seveso 15/01/15 13:18 pagina 286 287archivio italiano di urologia e andrologia 2014; 86, 4 transrectal versus transperineal prostate biopsy: a comparative evaluation confirm this statement, in the present series, the cores resulted significantly longer with the tp rather than with the tr approach, mainly at the apex and in the tz. however, the real advantage of these data is still uncertain as these findings are supported by no significant differences in terms of cancer detection rate reached when the two approaches are used. as to the adverse events, no differences were found in the overall incidence of complications as a result occurring with the two approaches, except for the urethral bleeding in tp group, and the rectal bleeding in tr group. as to some technical difficulties, many authors stated the tr approach is a by far easier procedure and patients’ discomfort may be prevented, using only local anaesthesia. moreover, the tp approach may be not familiar to the majority of the urologists and many patients may complain of some pain when only local anaesthesia is used. however, in our hands, both approaches showed a similar, small, and acceptable discomfort. in our opinion, both methods should be or become equally familiar to urologists. conclusions our results confirmed no significant differences were found in cancer detection rate, cancer core rate between tp and tr approaches for prostatic biopsy. even in terms of complication rate or pain level, it cannot be concluded that one procedure is superior to the other one. apparently, strictly following our protocol, tp approach seems to offer a better sampling at the level of the apex and the tz, however without adding any significant advantage in terms of overall cancer detection rate. references 1. emiliozzi p, corsetti a, tassi b, et al. best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. urology. 2003; 61:961-6. 2. kawakami s, yamamoto s, numao n, et al. direct comparison between transrectal and transperineal extended prostate biopsy for detection of cancer. int j urol. 2007; 14:719-24. 3. hara r, jo y, fuji t, et al: optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. urology. 2008; 71:191-5. 4. takenaka a, hara r, ishimura t, et al. a prospective randomized comparison of diagnostic efficacy between transperineal and transrectal12-core prostate biopsy. prostate cancer prostatic dis. 2008; 11:134-8. 5. novella g, ficarra v, galfano a, et al. pain assessment after original transperineal prostate biopsy using a coaxial needle. urology. 2003; 62:689-92. 6. ficarra v, novella g, novara g et al. the potential impact of prostate volume in the planning of optimal number of cores in the systematic transperineal prostate biopsy. eur urol. 2005; 48:932-7. 7. hodge kk, mcneal je, terris mk, et al: random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-5. 8. shannon ba, mcneal je, cohen rj. transitional zone carcinoma of the prostate gland: a common indolent tumor type that occasionally manifests aggressive behaviour. pathology. 2003; 35:467-71. 9. furuno t, demura t, kaneta t, et al. difference of cancer core distribution between first and repeat biopsy in patients diagnosed by extensive transperineal ultrasound guided template prostate biopsy. prostate. 2004; 58:76-81. 10. ficarra v, martignoni g, novella g, et al. needle core length is a quality indicator of systematic transperineal prostate biopsy. eur urol. 2006; 50:266-71. correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it giovanni novella, md giovanni.novella@ospedaleuniverona.ir urology clinic, aoui verona piazzale l. scuro 10 37134 verona, italy fabio vianello, md fabio.vianello@unipd.it urology clinic, university of padua, padova, italy cerruto_stesura seveso 15/01/15 13:18 pagina 287 stesura seveso 41archivio italiano di urologia e andrologia 2014; 86, 1 case report first case of bilateral, synchronous anaplastic variant of spermatocytic seminoma treated with radical orchifunicolectomy as single approach: case report and review of the literature giorgio gentile 1, francesca giunchi 2, riccardo schiavina 1, alessandro franceschelli 3, marco borghesi 1, ziv zukerman 1, matteo cevenini 1, valerio vagnoni 1, daniele romagnoli 1, fulvio colombo 3, giuseppe martorana 1, eugenio brunocilla 1 1 department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy; 2 department of pathology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy; 3 andrology unit, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, bologna, italy. spermatocytic seminoma (ss) is less common than the classic variant, as its incidence ranges between 1.3% and 2.3% of all seminomas. generally ss is diagnosed in men older than 50 years. the anaplastic variant of spermatocytic seminoma is characterized by an earlier onset when compared to ss, but a benign behavior in spite of its histological patterns similar to classic seminoma. we reported the first case of bilateral, largest and synchronous anaplastic spermatocytic seminoma, in a patient treated with radical orchifunicolectomy alone and with long-term follow-up. the currently available data show that anaplastic ss reveals a clinically benign behavior, and no distant metastases have been reported so far. a close surveillance after surgery could be considered a valid option in the management of this rare testicular neoplasm. key words: testicular cancer; spermatocytic seminoma; anaplastic variant; bilateral disease; radical orchifunicolectomy submitted 5 november 2013; accepted 31 december 2013 summary aim of the paper in this paper we report the seventh case of anaplastic spermatocytic seminoma (ss) (1-14), the first with bilateral and synchronous presentation and unusual clinical features. discussion spermatocytic seminoma (ss) is a rare germ cell tumor, characterized by a benign behavior with slow growth, and is generally localized in the testis; this tumor has a good long term prognosis, and is always controlled by one of the simplest intervention in urology, such as radical orchiectomy with nearly absent risks of complications contrarily to many other urological interventions (15, 16); in literature over 200 cases of ss have been described with only three cases of clearly established metastasis for the no conflict of interest declared conventional type of this tumor (8). it is universally accepted that the sarcomatous differentiation of ss is associated with an aggressive behavior, the presence of metastasis and a poor prognosis (12, 13, 17, 18), despite aggressive surgical and adjuvant treatments (19). on the other hand the anaplastic variant of ss is still poorly known, as in literature only six cases of monolateral tumor have been described so far (6, 9, 14); this is the first case of bilateral, synchronous anaplastic ss described till today. still remain ambiguities about its biological behavior and about the most appropriate diagnostic and therapeutic protocol. however, the present tumor is the largest one described (20 cm) with the longest period of observation (60 months before the surgical intervention plus 36 months of follow-up), which confirm the low risk of metastatic pattern. the main clinical and pathological features of the seven cases (six available in literature and our case) are reported in supplementary materials (table 1). the mean age at the moment of the diagnosis was 45.8 years. this finding confirms the data reported by other authors regarding the early onset of anaplastic variant compared to the classical spermatocytic seminoma (6). furthermore our patient underwent medical examination 5 years after the initial clinical presentation of the disease, which strengthens the hypothesis of an earlier manifestation of the disease. the testicular mass was always asymptomatic and characterized by a slow growth and absence of metastasis; in particular in our case the delay of the diagnosis allowed the tumor to grow disproportionately, reaching an enormous size (20 cm diameter in the left mass) occupying the entire testis, but the growth was limited to the parenchyma without invasion of the tunica albuginea with no lymph node or distant metastases. in all cases there was no intratubular germ cell neoplasia unclassified (igcnu) associated. serum markers !-fp, "-hgb were negative in all cases. the markers commonly used for the diagnosis of classic seminoma (cs) were always negative but only in two cases has been observed the positivity for c-kit (cd117), which has also been reported to be positive in ss in some cases (20, 21); our case was the first with a focal positivity for plap and this is the first identification doi: 10.4081/aiua.2014.1.41 borghesi cr printed_stesura seveso 26/03/14 10:23 pagina 41 archivio italiano di urologia e andrologia 2014; 86, 1 gentile, giunchi, schiavina, franceschelli, borghesi. zukerman, cevenini, vagnoni, romagnoli, colombo, martoranaa, brunocilla 42 of this marker in an anaplastic variant of ss, even if isolated positivity for plap in classic ss has been reported (2022). all the patients underwent radical orchiectomy (ro), while the management after surgery was different but in any case there was the onset of metastasis or recurrence: in 3 cases ro was followed by radiotherapy applied to pelvic and retroperitoneal lymph nodes, in 2 cases the treatment was consolidated with 2 cycles of chemotherapy (carboplatin or cisplatin, etoposide and bleomycin), in two cases ro was followed by surveillance with clinical examination and imaging. histological findings in anaplastic ss, such as areas with extensive necrosis, solid growth pattern, multiple mitotic figures, vascular and tunical invasion, and anaplastic features in lymph node metastasis in primary ss have been described by albores-saavedra et al. (6). according to these findings, the anaplastic variant of ss would seem to have a more aggressive behavior compared to the classical form, even if all the cases described in literature showed a benign behavior and a good prognosis comparable to that of typical ss. in the absence of a specific radiotracer such as for other urological malignancies (23) the pet18f-fdg plus contrast enhanced whole body ct seems the most appropriate follow-up behaviour. references 1. masson p. etude sur le seminome. rev can biol. 1946; 5:361-87. 2. mostofi f, sesterhenn i. tumours of the testis and paratesticular tissue. in: world health organization classification of tumours: pathology and genetics-tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon: international agency for research on cancer (iarc) press 2004; chapt 4, pp 217-278. 3. looijenga lh, stoop h, hersmus r, et al. genomic and expression profiling of human spermatocytic seminomas: pathogenetic implications international. int j androl. 2007; 30:328-35; discussion 335-6. epub 2007 jun 15. 4. bomeisl pe, maclennan gt. spermatocytic seminoma. int j androl. 2007; 177:734. 5. stephenson aj, gilligan td. neoplasms of the testis. in: walsh pc, retik ab, vaughan jr ed, wein aj, editors. campbell’s urology. 10th ed. philadelphia (pa): saunders. 2012; p. 840. 6. albores-saavedra j, huffman h, alvarado-cabrero i, et al. anaplastic variant of spermatocytic seminoma. hum pathol. 1996; 27:650-655. 7. brunocilla e, pultrone cv, schiavina r, et al. testicular sclerosing sertoli cell tumor: an additional case and review of the literature. anticancer res. 2012; 32:5127-30. 8. malizia m, brunocilla e, bertaccini a, et al. liposarcoma of the spermatic-cord: description of two clinical cases and review of the literature. arch ital urol androl. 2005; 77:115-7. 9. dundr p, pesl m, et al. anaplastic variant of spermatocytic seminoma. pathol res pract. 2007; 203:621-4. 10. chung pw, bayley aj, sweet j, et al. spermatocytic seminoma: a review. eur urol. 2004; 45:495. 11. burke ap, mostofi fk. spermatocytic seminoma: a clinicopathologic study of 79 cases. j urol pathol. 1993; 1:21-32. 12. narang v, gupta k, gupta a, et al. rhabdomyosarcomatous differentiation in a spermatocytic seminoma with review of literature. indian j urol. 2012; 28:430-433. 13. menon s, karpate a, desai d. spermatocytic seminoma with rhabdomyosarcomatous differentiation: a case report with a review of the literature. j cancer res ther. 2009; 5:213-5. 14. lombardi m, valli m, brisigotti m, et alhttp://www.ncbi.nlm. nih.gov/pubmed?term=rosaij%5bauthor%5d&cauthor=true&cauthor_uid=21087978. spermatocytic seminoma: review of the literature and description of a new case of the anaplastic variant. nt j surg pathol. 2011; 19:5-10. 15. schiavina r, borghesi m, guidi m, et al. perioperative complications and mortality after radical cystectomy when using a standardized reporting methodology. clin genitourin cancer. 2013; 11:189-97. 16. brunocilla e, pultrone c, pernetti r, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. int j urol. 2012; 19:783-5. 17. chelly i, mekni a, gargouri mm, et al. spermatocytic seminoma with rhabdomyosarcomatous contingent. prog urol. 2006; 16:218-20. 18. true ld, otis cn, delprado w, et al. spermatocytic seminoma of testis with sarcomatous transformation. a report of five cases. am j surg pathol. 1988; 12:75-82. 19. robinson a, bainbridge t, kollmannsberger c. a spermatocytic seminoma with rhabdomyosarcoma transformation and extensive metastases. am j clin oncol. 2007; 30:440-1. 20. cummings ow, ulbright tm, eble jn, et al. spermatocytic semonima: an immunohistochemical study, hum pathol. 1994; 25:54-59. 21. kraggerud sm, berner a, bryne m, et al. spermatocytic seminoma as compared to classical seminoma: an immunohistochemical and dna flow cytometric study, apmis 1999; 107:297-302. 22. dekker i, rozeboom t, delemarre j, et al. placental-like alkaline phosphatase and dna flow cytometry in spermatocytic seminoma, cancer 1992; 69:993-996. 23. nanni c, schiavina r, boschi s, et al. comparison of 18ffacbc and 11c-choline pet/ct in patients with radically treated prostate cancer and biochemical relapse: preliminary results. eur j nucl med mol imaging. 2013; 40(suppl 1):s11-7. case report, table and figures are posted in supplementary materials on www.aiua.it correspondence giorgio gentile, md dr.giorgio.gentile@gmail.com riccardo schiavina, md, assistant professor rschiavina@yahoo.it marco borghesi, md mark.borghesi@gmail.com (corresponding author) ziv zukerman, md ziv.zukerman@gmail.com matteo cevenini, md matteoceve@gmail.com valerio vagnoni, md vagno07@libero.it daniele romagnoli, md danieleromagnoli@hotmail.it giuseppe martorana, md, professor giuseppe.martorana@unibo.it eugenio brunocilla, md, associate professor eugenio.brunocilla@unibo.it department of urology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy francesca giunchi, md francesca.giunchi@aosp.bo.it department of pathology, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy alessandro franceschelli, md, phd alessandro.franceschelli@aosp.bo.it fulvio colombo, md fulvio.colombo@aosp.bo.it andrology unit, azienda ospedaliero-universitaria policlinico s.orsola-malpighi, palagi 9 street, 40138 bologna, italy borghesi cr printed_stesura seveso 26/03/14 10:23 pagina 42 stesura seveso 291archivio italiano di urologia e andrologia 2015; 87, 4 original paper incidence of bacterial colonisation after indwelling of double-j ureteral stent hasan riza aydin 1, lokman irkilata 2, mustafa aydin 2, selim gorgun 3, hüseyin cihan demirel 2, senol adanur 4, mevlüt keleş 2, aynur atilla 5, mustafa kemal atilla 5 1 department of urology, recep tayyip erdoǧan university, rize, turkey; 2 department of urology, samsun training and research hospital, samsun, turkey; 3 department of microbiology, samsun training and research hospital, samsun, turkey; 4 department of urology, ataturk university, erzurum, turkey; 5 department of infectious diseases, samsun training and research hospital, samsun, turkey. objective: to determine the bacterial colonisation after double-j stent use and the risk factors for bacteriuria linked to the stent. materials and methods: a total of 102 patients (61 men and 41 women, mean age 47.5 ± 14.16) were examined. the stents were removed under aseptic conditions, and a urine culture was obtained before the removal of the stents. after the stents were removed, the upper, central and lower sections were separated, and washing water was sent through the stent. results: bacterial colonisation was found in 29.4% (30 of 102) of the stents. the most frequently observed microorganisms were determined as staphylococcus, coagulase negative (8 of 30) and e. coli (5 of 30). the washing fluid used to clean the interior of the catheter produced pathogens in 8 patients (7.8%), and these pathogens were observed to be the same microorganisms that colonised the outside of the stent. there was no statistical difference between the patients with colonisation and those without in terms of age, gender, duration of stenting and reason for stent insertion. conclusions: though stent colonisation does not always entail symptomatic urinary tract infections, as shown in our study, the pathogens in the urine culture are the same as those colonising the stent, confirming the reality that colonisation is the main factor in these events. additionally, according to our study, significant colonisation may be found in the first 3 weeks, contrary to the literature, causing us to consider that urinary tract infections may develop even in the early period. key words: bacterial adhesion; risk factors; ureteral catheterization; urinary tract infection. submitted 22 july 2015; accepted 13 october 2015 summary no conflict of interest declared. of double-j stents, early intolerance and a variety of late complications are present (4). eighty percent of nosocomial urinary tract infections are linked to urological instrumentation, especially the use of the double-j stent (5). the increase in the use of the stent is related to stent-linked infections, and bacterial stent colonisation plays an important role in infections linked to the stent (6, 7). in this study, we aimed to determine the bacterial colonisation after double-j stent use and the risk factors for bacteriuria linked to the stent. materials and methods the study prospectively included 102 patients with double-j stentsused from july through december 2014 for a variety of reasons. the patients gave written consent to participate. double-j stents are generally produced from polyurethane. patients using antibiotics for any reason, patients with immunosuppression and those with bacteria in urine cultures were excluded from the study. all patients were given a single dose of antibiotic (iv 1 g cephalozin) before the procedure. the stents were removed under aseptic conditions, and a urine culture was obtained before the stents were removed. after the stents were removed, the upper, central and lower sections were separated, and washing water was sent through the stent. the suspension to wash the inner surface was normal saline jetted through a 10 ml 21-gauge needle syringe into the inner portion of the stent segment. all samples were inoculated on eosin methylene blue agar and blood agar. positive cultures were defined as the growth of > 105 colony-forming units (cfu)/ml of a single pathogen. ibm spss for windows, version 21.0 (chicago, usa) was used for statistical analysis. data were calculated as mean ± standard deviation. the chisquare, pearson chi-square and fisher’s exact tests were used, and p < 0.05 was accepted as significant. results a total of 102 double-j stents from 102 patients were taken for assessment. the mean age of patients was 47.5 doi: 10.4081/aiua.2015.4.291 introduction in urology practice, the use of the double-j stent had significantly influenced endourologic developments and techniques. the double-j stent is used in a very broad area, including treatments for ureter and kidney stones, hydronephrosis linked to pregnancy or oncological diseases, cleaning fragments after shock wave lithotripsy and treatment of urinary leaks (1-3). in spite of increasing experience linked to the frequent use archivio italiano di urologia e andrologia 2015; 87, 4 h. riza aydin, l. irkilata, m. aydin, s. gorgun, h. cihan demirel, s. adanur, m. keleş, a. atilla, m. kemal atilla 292 ± 14.16 years, with 61 male (59.8%) and 41 female (40.2%) patients. the mean duration of stent insertion was 33.91 ± 22.42 days. the indications for stent insertion were urinary system stone disease in 86 patients (84.4%), ureteral stenosis in 7 patients (6.9%), malignancy in 6 patients (5.9%), hydronephrosis linked to pregnancy in 2 patients (2%) and upj stenosis in 1 patient (1%). bacterial colonisation of the stent was observed in a total of 30 patients (29.4%). the most frequently observed microorganisms were determined as staphylococcus, coagulase negative and e. coli (table 1). in patients with proliferation, the same pathogen was found to colonise all 3 catheter fragments. the washing fluid used to clean the interior of the catheter produced pathogens in 8 patients (7.8%), and these pathogens were observed to be the same microorganisms that colonised the outside of the stent. the urine culture sampling on the same day as the stent was removed found proliferation in 4 (13.3%) of the 30 patients with colonisation. these pathogens were the same as those colonising the stent, with one patient having mrsa staph aureus and the other 3 having e. coli. twenty-six patients (86.7%) had a sterile urine culture. colonisation was found in 19 (31.1%) of the 61 male patients and in 11 (26.8%) of the 41 female patients. there was no statistical difference between the patients with colonisation and those without in terms of age, gender, duration of stent and reason for stent insertion (table 2). discussion the use of double-j stents has become an essential routine in urology practice. while the first studies reported minimal complications linked to stents, the increased frequency of the use of stents has revealed that, in addition to early complications like suprapubic pain, hematuria, the frequent need to urinate and burning during urination, more serious late complications like stent migration, stent fragmentation, encrustation, vesicoureteral reflux, acute pyelonephritis, bacteriemia and chronic renal failure may develop (8-10). bacterial colonisation on the stent plays the main role in infections linked to the stent, though as these infections may follow a subclinical progression, they may result in sepsis leading to death (11). a biofilm layer formed by protein, electrolytes and an unknown variety of molecules causing bacterial adhesion and deposition on the stent is responsible for the first stage of these events (12). the literature presents a variety of rates related to bacterial stent colonisation. riedl et al. reported rates of 100% in permanent stents and 69% for temporary stents (13). similarly, in another study, this rate was given as 68% (14). when other studies are examined, paick et al. published 44%, akay et al. reported 31% proximal and 34% distal, and özgür et al. reported bacteria colonisation of 10% (15-17). in our study, the rate was the samefor each piece of the stent (proximal, central and distal) at 29.4%. the differences between these rates may be linked to the type of stent, duration of insertion and use of antibiotics. when the bacteriuria rates are examined in these studies, they vary from 21-45% with the general view that, just as every stent colonisation will not cause bacteriuria, every negative urine culture does not mean that there is no stent colonisation. in our study, in the 30 patients with stent colonisation, the fact that only 4 (13.3%) had bacteriuria supports this opinion. additionally, as the pathogen found in urine samples from these 4 patients was the same pathogen that colonised their stents, the reality that the main cause of urinary tract infection is stent colonisation should not be forgotten. a variety of risk factors for bacteria colonisation have been researched. kehinde et al. mentioned that the risk increased 2 times for women (18). similarly, atay et al. microorganism n % sterile 72 70.6 staphylococcus, coagulase negative 8 7.8 e. coli 5 4.9 candida 4 3.9 group b streptococcus 3 2.9 staphylococcus epidermidis 2 1.96 diphtheroid 2 1.96 staph aureus (mrsa) 2 1.96 enterobacter 2 1.96 enterococcus 1 0.98 acinetobacter baumoni 1 0.98 colonisation groups present absent total p gender male 19 42 61 0.639 female 11 30 41 total 30 72 102 age 20-29 7 12 19 0.367 30-39 7 11 18 40 and ↑ 16 49 65 total 30 72 102 stent duration 1-21 9 22 31 0.974 22-42 15 37 52 43 and ↑ 6 13 19 total 30 72 102 reason for insertion stone 26 60 86 0.773 other 4 12 16 total 30 72 102 table 1. pathogens colonizing the stent. table 2. comparison of patients with and without colonisation in terms of age, gender, stent duration and reason for insertion. found higher rates of colonisation in women (16). in our study,colonisation was found in 31.1% of men and 26.8% of women, with the difference not significant. when the duration of stent use is assessed, farsi et al. stated that, as the stent duration increased, the colonisation rates increased (before 1 month 58.6%, after 3 months 75.1%) (14). similarly, kehinde et al. stated that, as the duration lengthened, the risk of bacteriuria and colonisation increased (1st month 4.2%, 3rd month 34%) (18). özgür et al. grouped patients according to stent duration as less than 4 weeks, 4-6 weeks and more than 6 weeks and found a significantly increased risk of colonisation after 6 weeks (17). paick emphasised that colonisation began after 2 weeks and that antibiotic use for stents that would be removed before this duration was unnecessary (15). in our study, we divided patients according to stent durations as 1-21 days, 22-42 days and more than 43 days. though the colonisation rates were higher for those with stents inserted for 43 days or more, the difference was not statistically significant similar to akay’s study. however, when it is considered that the stents will remain in the majority of patients for around 4 weeks, the longer duration will likely increase the risk of colonisation. in our study, 9 patients had hypertension, and 2 patients were pregnant. as immunosuppressive and diabetic patients were excluded from the study, we did not assess the effect of comorbidities on colonisation. however, as previous studies have shown, because situations such as chronic renal failure (crf), diabetes mellitus (dm) and pregnancy weaken the immune system, it is possible to mention an increased colonisation risk in these patients (16, 18). rates of urinary system infections may increase due to situations linked to age such as bladder outlet obstruction, hormonal changes and changes in bladder connective tissue (19). in our study, when the patients were divided according to age groups like 20-29, 30-39 and 40 years and above, there was no significant difference determined in terms of colonisation. additionally, when colonisation rates are examined according to reason for stent insertion, comparing urinary system stone disease and other reasons, it was found there was no effect from reason for insertion on colonisation. conclusions double-j stents are a frequently used, essential tool of urological instrumentation and are one of the leading choices for temporary urinary diversion. additionally, it should not be forgotten that there is a range of early and late complications due to stents. one of the most important of these complications is urinary system infection. though stent colonisation does not always entail symptomatic urinary tract infections, as shown in our study, the pathogens in the urine culture are the same as those colonising the stent, confirming the reality that colonisation is the main factor in these events. moreover, according to our study, significant colonisation may be found in the first three weeks, contrary to the literature, causing us to consider that urinary tract infections may develop even in the early period. as a result, the indications for stent insertion should be carefully considered, the duration of the stenting period should be especially optimised, appropriate antibiotic prophylaxis should be organised, and the treatment of patients with risky comorbidities should be well-planned. in our study, though there was no effect of stent duration, age, gender and reason for insertion on colonisation, lengthened stent durations may especially increase the risk of bacterial colonisation and bacteriuria, and it should be remembered that those with diseases like chronic renal failure (crf) and diabetes mellitus (dm) may be at risk. financial support we took support from samsun training and research hospital’s training and research foundation for microbiological evaluation in this study. we want thank to naci murat who performed the statistical analyzes of our study. references 1. lang ek, lanasa ja, garrett j, stripling j, palomar j. the management of urinary fistulas and strictures with percutaneous ureteral stent catheters. j urol. 1979; 122:736. 2. laverson pl, hankins gd, quirk jg. ureteral obstruction during pregnancy. j urol. 1984; 131:327. 3. ball aj, gingell jc, carter ss, smith pj. the indwelling ureteric splint: the bristol experience. br j urol. 1983; 55:622. 4. saltzman b. ureteral stents: indications, variations, and complications. urol clin north am. 1988; 15:481. 5. paz a, amiel ge, pick n, et al. febrile complications following insertion of 100 double-j ureteral stents. j endourol. 2005; 19:147. 6. reid g, sobel jd. bacterial adherence in the pathogenesis of urinary tract infection: a review. rev infect dis. 1987; 9:470. 7. costerton jw, cheng kj, geesey gg, et al. bacterial biofilm in nature and disease. ann rev microbiol. 1987; 41:435. 8. stamm we. guidelines for prevention of catheter associated urinary tract infections. ann intern med. 1975; 82:386. 9. warren jw, muncie hl jr., hall-craggs m. acute pyelonephritis associated with bacteriuria during long-term catheterization: a prospective clinicopathological study. j infect dis. 1988; 158:1341. 10. vallejo herrador j, burgos revilla fj, alvarez alba j et al. double j ureteral catheter. clinical complications. arch esp urol. 1988; 51:361. 11. warren jw, damron d, tenney h, et al. fever, bacteremia, and death as complications of bacteriuria in women with long-term urethral catheters. j infect dis. 1987; 155:1151. 12. habash m, ried g. microbial biofilms: their development and significance for medical device-related infections. j clin pharmacol. 1999; 39:887. 13. riedl cr, plas e, hubner wa, et al. bacterial colonisation of ureteral stents. eur urol. 1999; 36:53. 14. farsi hm, mosli ha, al-zemaity mf, et al. bacteriuria and colonisation of double-pigtail ureteral stents: long-term experience with 237 patients. j endourol. 1995; 9:469. 293archivio italiano di urologia e andrologia 2015; 87, 4 ureteral stent and bacterial colonisation archivio italiano di urologia e andrologia 2015; 87, 4 h. riza aydin, i. irkilata, m. aydin, s. gorgun, h. cihan demirel, s. adanur, m. keleş, a. atilla, m. kemal atilla 294 15. paick sh, park hk, oh sj, kim hh. characteristics of bacterial colonisation and urinary tract infection after indwelling of double-j ureteral stent. urology. 2003; 62:214. 16. akay af, aflay u, gedik a, et al. risk factors for lower urinary tract infection and bacterial stent colonisation in patients with a double j ureteral stent. int urol nephrol. 2007; 39:95. 17. ozgur bc, ekıcı m, nedım yuceturk c, bayrak o. bacterial colonisation of double j stents and bacteriuria frequency. kaoh j med sci. 2013; 29:658. 18. kehinde eo, rotimi vo, al-awadi ka, et al. factors predisposing to urinary tract infection after j ureteral stent insertion. j urol. 2002; 167:1334. 19. beyer i, mergam a, benoit f, et al. management of urinary tract infections in the elderly. z gerontol geriatr. 2001; 34:153. correspondence hasan riza aydin, md hrizaaydin@gmail.com recep tayyip erdoğan university, department of urology, rize, turkey lokman irkilata, md (corresponding author) irkilatamd@gmail.com samsun training and research hospital, department of urology kadıköy mahallesi, altın barıs bulvarı no:199, ilkadım/samsun, turkey mustafa aydin, md mustafaydin28@gmail.com selim gorgun, md compass71@mynet.com hüseyin cihan demirel, md drhcdemirel@gmail.com mevlüt keleş, md drmevlutkeles@gmail.com mustafa kemal atilla, md ass. prof mkatilla@hotmail.com samsun training and research hospital, department of urology, samsun, turkey senol adanur, md s.adanur61@hotmail.com ataturk university, department of urology, erzurum, turkey aynur atilla, md aynur.atilla@gmail.com samsun training and research hospital, department of infectious diseases, samsun, turkey stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2150 case report mixed primary prostatic carcinoma with acinar, neuroendocrine and ductal components alfredo e. romero-rojas 1, julio a. diaz-perez 1, 2, 3, abhinay reddy 2 1 national institute of cancer, bogotá, colombia; 2 university of california san diego, la jolla, ca, usa; 3 university of santander, bucaramanga, colombia. mixed tumors in the prostate gland have been described; they are primarily originate in the gland or are the product of metastatic compromise. mixed primary epithelial carcinomas of the prostate are very rare; here we report the case of a 72-years-old man with histopathologic findings of a primary prostate mixed carcinoma, showing characteristics of acinar, ductal and neuroendocrine adenocarcinoma. we also discuss the clinical, diagnostic, and therapeutic aspects of these uncommon mixed neoplasms. key words: prostatic carcinoma; neuroendocrine carcinoma; ductal carcinoma; acinar adenocarcinoma; mixed tumor. submitted 15 march 2014; accepted 31 may 2014 summary case report here we report the case of a 72-year-old man with histopathologic findings of primary prostate mixed carcinoma, showing characteristics of acinar, ductal and neuroendocrine adenocarcinoma. we also discuss the clinical, diagnostic, and therapeutic aspects of these uncommon mixed tumors. case report and figures are posted in suppementary materials on www.aiua.it discussion mixed prostatic carcinomas are rare; they demonstrate a combination of malignant epithelial or sarcomatoid components (1, 4). the epithelial variant of these carcinomas is often a high-grade acine adenocarcinoma mixed with squamous, urothelial, neuroendocrine, ductal, mucinous (colloid), signet ring, oncocytic, basal cell, and lymphoepithelioma-like components (4). the origin and utility of identification of these mixed carcinomas has been highly controversial; they have been thought by some authors to be derived from a single cell of origin, and are the product of one or multiple types of differentiation or no conflict of interest declared metaplastic changes, rather than representing a combination of separate epithelial neoplasms. however the hypothesis of neoplasm collision has been formulated, in which these neoplasms develop independently in the prostate (14, 15) formed by heterologous elements with lack of morphological and immunophenotipical connection. in our case we found a similar immunophenotypical pattern that is in accordance with the first hypothesis that is also supported by previous studies with analysis of loss-of-heterozygosity (14-16). also multiple authors and classifications refer to these mixed tumors as descriptive variants with no known prognostic significance other than that of acinar adenocarcinoma (2, 7, 9), but it is currently known that these tumors are aggressive neoplasms with an associated poor prognosis (7), and an actual risk of death of 20% within one year of diagnosis. clinically, most patients are older (range 50-89) and present with urinary tract obstruction and symptoms of frequency, urgency, and nocturia (4), similar to our case. other secondary symptoms including bilateral flank pain, microscopic hematuria, and renal insufficiency are also reported (7). serum pap and psa can be normal or elevated (4, 7, 12). in about half of the cases, the initial biopsy diagnosis is an acinar (conventional) adenocarcinoma, followed by hormonal and/or radiation therapy, with a subsequent diagnosis of the mixed component in the histopathologic analysis of the surgical specimen (13). the histopathological analysis conducted with hematoxilin and eosin and is the key to allow for a correct diagnosis and evade diagnostic pitfalls in these tumors. microscopically, the morphology is highly variable and is challenging for the pathologist; metastatic tumors from other sites need to be considered in the differential diagnosis (16, 17). the most common primary sites of tumors to be considered and excluded in the differential diagnosis include carcinomas from the bladder and colon (17). clinical exams by cystoscopy, colonoscopy, chest and abdominal tomography, and others are helpful (16, 17), also a careful immunophenotypical examination, with psa, prostein (p501s), amacr, pap and ck7 positivity, and b-catenin, and cdx2 negativity are beneficial (13, 15, 18, 19). other markers such as thrombodoi: 10.4081/aiua.2014.2.150 151archivio italiano di urologia e andrologia 2014; 86, 2 mixed primary prostatic carcinoma with acinar, neuroendocrine and ductal components modulin, uroplakin and villin that have been used in identifying tumors of urothelial and colonic origin have suboptimal sensitivities (15). immunohistochemistry is also relevant in proving different types of elements, which may be unapparent on hematoxylin and eosin (h&e)-stained sections, like neuroendocrine areas (13). the present case is unique, since a combination of primary acinar, neuroendocrine and ductal adenocarcinoma has not been previously reported in the literature, although is mentioned as a possibility in the rosai textbook (20). in our case the proliferation index assessed by the ki 67 antigen was high in all the components, in accordance with some previous reports (21), and in disagreement with other reports (8), suggesting that the labeling index is variable, and also suggesting that in combined mixed tumors, the choice of the treatment should dictated by the tumor type and stage (1, 14). due to the limited experience, there are no standard treatment recommendations for the management of mixed tumors of the prostate. operable carcinomas are frequently treated with surgery (8). surgeries with curative intent include radical retro-pubic prostatectomy, radical cysto-prostatectomy, supra-pubic prostatectomy, and pelvic exenteration (8, 10). non-surgical therapy (androgen ablation treatment and chemotherapy) seems to be ineffective, and androgen deprivation therapy might provide palliative relief; however, 55.5% of patients are unresponsive to conventional chemotherapy (8). in conclusion, we presented a case of mixed epithelial prostatic malignant tumor, and we discussed clinically relevant aspects for the correct diagnosis and management of these neoplasms, and posit that a careful immuno-phenotypical evaluation is needed to generate a correct diagnosis. references 1. adlakha h, bostwick dg. paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation: report of 30 cases. hum pathol. 1994; 25:135-9. 2. mazzucchelli r, lopez-beltran a, cheng l, et al. rare and unusual histological variants of prostatic carcinoma: clinical significance. bju int. 2008; 102:1369-74. 3. ergen a, balbay md, irwin m, torno r. collision metastasis of bladder and prostate carcinoma to a single pelvic lymph node. int urol nephrol. 1995; 27:743-5. 4. parwani av, kronz jd, genega em, et al. prostate carcinoma with squamous differentiation: an analysis of 33 cases. am j surg pathol. 2004; 28:651-7. 5. hansel de, epstein ji. sarcomatoid carcinoma of the prostate: a study of 42 cases. am j surg pathol. 2006; 30:1316-21. 6. oliai br, kahane h, epstein ji. a clinicopathologic analysis of urothelial carcinomas diagnosed on prostate needle biopsy. am j surg pathol. 2001; 25:794-801. 7. rogers cg, parwani a, tekes a, et al. carcinosarcoma of the prostate with urothelial and squamous components. j urol. 2005; 173:439-40. 8. parada d, peña kb, riu f. sarcomatoid carcinoma of the prostate: ductal adenocarcinoma and stromal sarcoma-like appearance: a rare association. case rep urol. 2011; 2011:702494. 9. epstein ji, algaba f, yang xj, et al. tumours of the prostate. in eble jn, sauter g, epstein ji, sesterhenn ia eds, tumours of the urinary system and male genital organs, chapter 3. lyon: iarc press, 2004:160-208. 10. curtis mw, evans aj, srigley jr. mucin-producing urothelialtype adenocarcinoma of prostate: report of two cases of a rare and diagnostically challenging entity. mod pathol. 2005; 18:585-90. 11. osunkoya ao, epstein ji. primary mucin-producing urothelialtype adenocarcinoma of prostate: report of 15 cases. am j surg pathol. 2007; 31:1323-9. 12. rahmanou f, koo j, marinbakh ay, et al. squamous cell carcinoma at the prostatectomy site: squamous differentiation of recurrent prostate carcinoma. urology. 1999; 54:744. 13. tamas ef, epstein ji. prognostic significance of paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate. am j surg pathol. 2006; 30:980-5. 14. egilmez t, bal n, guvel s, et al. adenosquamous carcinoma of the prostate. int j urol. 2005; 12:319-21. 15. chuang ay, demarzo am, veltri rw, et al. immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. am j surg pathol. 2007; 31:1246-55. 16. gohji k, nomi m, kizaki t, et al. “collision phenomenon” of prostate and bladder cancers in lymph node metastases. int j urol. 1997; 4:222-4. 17. ergen a, balbay md, irwin m, torno r. collision metastasis of bladder and prostate carcinoma to a single pelvic lymph node. int urol nephrol. 1995; 27:743-5. 18. wang w, epstein ji. small cell carcinoma of the prostate. a morphologic and immunohistochemical study of 95 cases. am j surg pathol. 2008; 32:65-71. 19. cohen rj, wheeler tm, bonkhoff h, rubin ma. a proposal on the identification, histologic reporting, and implications of intraductal prostatic carcinoma. arch pathol lab med. 2007; 131:1103-9. 20. rosai j. male reproductive system –prostate and seminal vesicles, chapter 18. in: rosai j. rosai and ackerman's surgical pathology. mosby; 10 edition 2011. 21. pacchioni d, casetta g, piovano m, et al. prostatic duct carcinoma with combined prostatic duct adenocarcinoma and urothelial carcinoma features: report of a case. int j surg pathol. 2004; 12:293-7. correspondence alfredo e. romero-rojas, md (corresponding author) national institute of cancer, bogotá, colombia julio a. diaz-perez, md, ms jdiazperez@ucsd.edu stein clinical research building 245, university of california san diego, 9500 gilman drive, la jolla, ca 92093-0637 abhinay reddy, bs, ms university of santander, bucaramanga, colombia stesura seveso 111archivio italiano di urologia e andrologia 2016; 88, 2 original paper the relationship of enuresis nocturna and adenoid hypertrophy muhsin balaban 1, alper aktas 2, cuneyd sevinc 1, ugur yucetas 3 1 medicana international istanbul hospital, urology clinic, istanbul, turkey; 2 kartal training and research hospital, urology clinic, istanbul, turkey; 3 istanbul training and research hospital, urology clinic, istanbul, turkey. objectives: this study was organized to assess the relationship of enuresis nocturna (en) and upper airway obstruction (uao) in children. material and methods: this study was multi-centrically and prospectively designed including 79 children who presented to a urology clinic with symptoms of en between january 2013 and february 2014. sixty-four age-matched children with no history of urological complaints were randomly recruited from children admitted to a pediatric clinic as a control group. all children and parents were asked to fill out a dysfunctional elimination syndrome (des) questionnaire and children were examined by an ear, nose and throat (ent) specialist to evaluate the uao. descriptive statistics, chisquare and mann-whitney-u tests were used to compare variables. results: the mean ages of the 79 children (48 male, 31 female) in the study group and the 64 children (41 male, 23 female) in the control group were 10.14+/-3.38 and 9.17+/2.85, respectively. family history of the study showed that 19% of the children’s mothers, 10% of the children’s fathers and 37% of the children’s siblings had experienced en. there was a significant difference between the study and the control groups in terms of urge to urinate, bladder emptying, bowel symptoms and psychological stress. there was also a significant difference between rates of tonsillar hypertrophy and nasopharynx obstruction in the en group (p = 0.009). conclusion: in this study we found that half of the children with en had tonsillar hypertrophy, which was significantly higher than in the control group. further studies are needed to clarify the exact relationship between uao and en. key words: adenoids; enuresis; tonsillar hypertrophy. submitted 5 november 2015; accepted 5 december 2015 summary no conflict of interest declared. tions related to the physiopathology of en. it is caused by a hereditary delay in maturation of the somatic mechanisms such as reduction of nocturnal urine production, relaxation of the bladder during sleep hours and a normal arousal to a full bladder that prevents the child from bedwetting (2). evidence suggests a possible association with sleep-disordered breathing. several studies have reported a close relationship between obstructive sleep apnea (osa) and en (3). the most common cause of osa in children is adenotonsillar hypertrophy, and therefore treatment of adenotonsillar hypertrophy is the treatment of choice for osa (4). children with upper airway obstruction have increased negative intrathoracic pressure as a result of increased inspiratory effort during sleep. the continual swing in intrathoracic pressure causes cardiac distension that can lead to release of atrial natriuretic peptide, triggering enuresis (5). in the present study, we aimed to identify the prevalence of adenotonsillar hypertrophy and upper airway obstruction (uao) in children with and without en as well as investigate the risk factors associated with en in children. material and methods this study was multi-centrically and prospectively designed including 79 non-obese children older than 5 years who presented to a urology clinic with symptoms of en between january 2013 and february 2014. en was considered to be present when it occurred in the frequent grade (3-6 times per month) or the almost always grade (> 3 times per week) (6). en was defined in accordance with the international children’s continence society’s standardized terminology (7). parents were asked whether their children currently suffer from enuresis and whether they have ever had a dry period of at least six months in order to distinguish primary from secondary enuresis. only primary en patients were enrolled in the study. sixty-four age-matched children with no history of urological complaints were randomly recruited from children admitted to a pediatric clinic as the control group. all en patients underwent a detailed urological evaluadoi: 10.4081/aiua.2016.2.111 introduction enuresis nocturna (en) is a common childhood condition, present in approximately 5-7 million children in the united states. the prevalence of en decreases with age, but the severity increases (1). it is reported in about 15-20% of 5 year olds, 5-7% of 10 year old, and 1-2% of 15 year old subjects, reaching a plateau of approximately 0.5-1% in adulthood. en occurs when a child is unable to suppress nocturnal bladder contraction. there have been several explanaarchivio italiano di urologia e andrologia 2016; 88, 2 m. balaban, a. aktas, c. sevinc, u. yucetas 112 tion and a thorough clinical and neurological examination to rule out an organic etiology. exclusion criteria were the presence of cerebral palsy, neuromuscular diseases or any underlying systemic diseases or acute infectious processes. additional medical history was taken, including duration of illnesses and current therapies. all children and parents were asked to fill out a 35item questionnaire related to symptoms of dysfunctional elimination syndrome (des) such as diurnal/nocturnal enuresis, voiding habits, urgency, frequency, squatting and bowel movements. the questionnaire consisted of two parts: the first part included 21 multiplechoice questions for the child while the second part consisted of 14 questions asked to the parents. eight questions included in the first part were also directed to the parents to test whether the children could correctly express their complaints. this confirmed the children’s accuracy in answering the questions and ability to understand the problem. the second part had six additional questions for the parents about the frequency of urinary tract infection, school performance and stressful events. parents and children were requested to fill out the form completely. ear, nose and throat (ent) examination were done by an ent surgeon to assess obvious hypertrophied adenoids and tonsils clinically. descriptive statistics, chi-square and mann-whitney-u tests were used to compare variables. results the mean ages of the 79 children (48 male, 31 female) in the study group and the 64 children (41 male, 23 female) in the control group were 10.14+/-3.38 and 9.17+/-2.85, respectively. forty-one males in the study group and 33 males in the control group were circumcised. thirty-three of the 79 children in the study group and 22 of the 64 children in the control group were at pubertal ages. family history of the study group showed that 19% of the children’s mothers, 10% of the children’s fathers and 37% of children’s siblings had experienced en. according to first 9 questions about urgency symptoms in the des questionnaire, the study group’s score was 5.65+/-3.50 and the control group’s score was 1.31+/-2.15 (p < 0.0001). the scores of bowel symptoms (des questions 10-15) were 2.11+/-1.37 for the study group and 1.61+/1.52 for the control group (p < 0.006). the scores of psychological stress (des questions 30-31) were 3.02+/-0.88 in the study group and 2.30+/-0.87 in the control group (p < 0.0001). the total scores of the des questionnaire were 33.24+ 7-11.97 in the study group and 13.02+/-8.83 in the control group (p < 0.0001) (table 1). there was also a significant difference between tonsillar hypertrophy and nasopharynx obstruction in the en group (p = 0.009) (table 2). of the 79 en patients, 46 (58.2%) had monosymptomatic enuresis (me) whereas 33 of 79 (41.8%) had nonmonosymptomatic enuresis (nme). discussion en is the involuntary loss of urine during the night in the absence of organic disease. it is a very common pediatric issue and the number of children who may suffer from this condition is estimated at 3.8% to 25%. in contrast to the relatively high percentage seen among children, only 1% to 2% of adults suffer from this disorder. this difference is a result of the increasing number of children who spontaneously achieve nighttime bladder control. current data suggest an annual healing rate of 15% (8). en can present as monosymptomatic enuresis (me) or nonmonosymptomatic enuresis (nme); this classification should be done before any kind of therapy protocol is initiated due to different treatment approach. the most important criterion of me is the absence of bladder dysfunction, whereas nme is defined by the concomitance of bladder dysfunction such as urge incontinence or dysfunctional voiding. true me is found in less than onehalf of all cases of enuretic children (9). in our study, we enuresis (n = 79) control (n = 64) p mean age (years) 10.14 ± 3.38 9.17 ± 2.85 0.106* gender 48 m/31 f 41 m/23 f 0.685** prepicium 41 circumsised/7 intact 33 circumsised/8 intact 0.536** puberty 33 pubertal/46 prepubertal 22 pubertal/42 prepubertal 0.366** us 5.65 ± 3.50 1.31 ± 2.15 < 0.0001* bs 2.11 ± 1.37 1.61 ± 1.52 0.006* os 1.87 ± 1.49 1.34 ± 1.17 0.041* p 4.11 ± 2.42 0.59 ± 1.17 < 0.0001* ps 3.02 ± 0.88 2.30 ± 0.87 < 0.0001* is 0.17 ± 0.47 0 hf 2.41 ± 2.22 0 total 33.24 ± 11.97 13.02 ± 8.83 < 0.0001* apb 6.74 ± 3.25 2.20 ± 3.01 < 0.0001* ts 39.98 ± 14.80 15.22 ± 11.75 < 0.0001* obstruction (+) obstruction (-) p enuresis (n = 79) 37 42 (47%) (53%) 0.0009 control (n = 64) 13 51 (20%) (80%) table 1. demographic characteristics of groups and comparison of them according to aquestionnaire for dysfunctional elimination syndrome. table 2. compare of groups according to tonsillar hypertrophy and upper airway obstruction. *mann whitney test; **x2 us: urgency symptoms (first 9 questions); bs: bowel symptoms (10.-15. questions) os: obstructive symptoms (16.-21. questions); p: for parents to answer (22.-29. questions) ps: psychological stress (30.-31. questions); is: infection symptoms (32.-33. questions) hf: hereditary factors (34.-35. questions); total: first 35 questions score apb: appendix b (15 questions); ts: total score (total score of all questions) applied a des questionnaire to all study and control group members to evaluate en and its related symptoms. in this questionnaire, urgency symptoms, bowel symptoms, obstructive symptoms, psychological stress, infection symptoms and hereditary factor were evaluated. we found that 33 (41.8%) cases of enuretic children had me whereas 46 (58.2%) cases had nme. the genitourinary tract and the gastrointestinal system are interdependent, sharing the same embryological origin, pelvic region and sacral innervations. although children with voiding disturbances often present with bowel dysfunction, until recently this coexistence was considered coincidental. however, it is now accepted that dysfunction of emptying of both systems, in the absence of anatomical abnormality or neurological disease, are interrelated (10). children with des commonly complain of urinary incontinence, nme, recurrent urinary tract infections, extreme urgency to void and exceptional urinary frequency. the prevalence of des in children free of urinary tract infection as been estimated to be 21% (11). the exact etiology of nocturnal enuresis is multifactorial; however, me has a significant correlation with hereditary factors, arousal problems, overnight polyuria and overactive detrusor activity. in our study, en patients had significant family histories of enuresis, mostly in their siblings. osa in children is characterized by prolonged partial upper airway obstruction and/or intermittent complete obstruction that disrupt normal ventilation during sleep and sleep patterns (12). goldbart et al. suggested an osa sufferer repeatedly slips from deep sleep to light sleep, and when this happens, the bladder sphincter relaxes, releasing urine (13). adults with osa have been shown to have elevated atrial natriuretic peptide (anp), decreased antidiuretic hormone (adh) (14) and no normal decrease in nocturnal urinary output (15). osa causes oxygen desaturation, which influences the normal secretion of adh, leading to the change in nocturnal urine volume. normally the nocturnal secretion of adh slows nighttime urine production and prevents nocturia; inappropriate secretion of adh results in an inability to concentrate the urine, leading to excess urine secretion and bedwetting (16). there is a positive correlation between plasma anp levels and the degree of change in intrathoracic pressure. this correlation may result from elevated preload and atrial volume caused by a more negative intrathoracic pressure, thus stimulating anp production in osa patients. foxman et al. demonstrated a higher occurrence of en among children with osa than reported in otherwise healthy pediatric patients (17). according to weissbach et al., uao in children is greatly associated with nocturnal enuresis (4). in contrast to previous studies, aydin et al. did not find any association between adenoid hypertrophy and nocturnal enuresis (18). the most common cause of osa in children is adenotonsillar hypertrophy and uao. waleed et al. showed a relief of en by removing the uao which was the cause of osa and also a reduction in the total and night urine volume and improvement in nocturnal oxygen desaturation (19). firoozi et al. showed the complete resolution of en in 31-76% of osa patients within months after tonsillectomy and/or adenoidectomy (t&a) (20). in this study, half of the en children had uao and tonsillar hypertrophy; this rate is significantly higher than that of the control group. conclusion children with en have deep sleep and high arousal levels due to hypoxia caused by upper airway obstruction. this study showed that children with en have more adenoid hypertrophy and uao compared with the control group. children with en should be referred to ent surgeons for possible uao and tonsillar hypertrophy evaluation. prospective controlled studies are needed to further clarify these issues and the possible effect of t&a treatment on the en. references 1. yeung ck, sreedhar b, sihoe jd, et al. differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study. bju int. 2006; 97:1069-73. 2. hjalmas k. nocturnal enuresis: basic fact and new horizons. eur urol 1993; 33 suppl 3:53-57. 3. brooks lj, topol hi. enuresis in children with sleep apnea. j pediatr. 2003; 142:515-8. 4. weissbach a, leiberman a, tarasiuk a, et al. adenotonsilectomy improves enuresis in children with obstructive sleep apnea ayndrome. int j pediatr otorhinolaryngol. 2006; 70:1351-6. 5. ritting s, knudsen ub, norgaard jp,, et al. diurnal variation of plasma atrial natriuretic peptide in normals and patients with enuresis nocturna. scand j clin lab invest. 1991; 51:209-17. 6. hjalmas k, arnold t, bower w. nocturnal enuresis an international evidence based management strategy. j urol. 2004; 171:2545-61. 7. neveus t, von gontard a, hoebeke p,, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international children’s continence society. j urol. 2006; 176:314-24 8. robson wl. clinical practice. evaluation and management of enuresis. n engl j med. 2009; 360:1429-1436. 9. neveus t, eggert p, evans j, et al. evaluation of and treatment for monosymptomatic enuresis: a standardization document from the international children’s continence society. j urol. 2010; 183:441-447. 10. feng wc and churchill bm. dysfunctional elimination syndrome in children without obvious spinal cord disease. pediatr clin north am. 2001; 48:1489-504. 11. shaikh n, hoberman a, wise b, et al. dysfunctional elimination syndrome: is it related to urinary tract infection or vesicoureteric reflux. diagnosed early in life? pediatrics. 2003; 112:1134-7. 12. rosen cl. obstructive sleep apnea syndrome (osas) in children: diagnostic challanges. sleep. 1996; 19:274-277. 13. goldbart da, levitas a, greenberg-dotan s, et al. b-type natriuretic peptide and cardiovascular function in young children with apnea. chest. 2010; 138:528-535. 113archivio italiano di urologia e andrologia 2016; 88, 2 enuresis nocturna and adenoid hypertrophy archivio italiano di urologia e andrologia 2016; 88, 2 m. balaban, a. aktas, c. sevinc, u. yucetas 114 14. krieger j, follenius m, sforza e, et al. effects of treatment with nasal continues positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnea. clin sci. 1991; 80:443-449. 15. ichioka m, hirata y, inase n, et al. changes of circulating atrial natriuretic peptide and antidiuretic hormone in obstructive sleep apnea syndrome. respiration 1992; 59:164-168. 16. kaditis ag, finder j, alexopoulos ei, et al. sleep-disordered breathing in 3680 greek children. pediatr pulmonol. 2004; 37:499-509. 17. foxman b, valdez rb, brook rh. childhood enuresis: prevelance, perceived impact, and prescribed treatments. pediatrics. 1986; 77:482-487. 18. aydin s, sanli a, celebi o, et al. prevelance of adenoid hypertrophy and nocturnal enuresis in primary school children in istanbul, turkey. int jof pediatr otorhinolaryngol. 2008; 72:665-668. 19. waleed fe, samia fa, samar m. impact of sleep-disordered breathing and its treatment on children with primary nocturnal enuresis swiss med wkly. 2011; jul 1;141:w13216. 20. firoozi f, batniji r, aslan ar, et al. resolution of diurnal incontinence and nocturnal enuresis after adenotonsillectomy in children. j urol. 2006; 175:1885-8. correspondence muhsin balaban, md (corresponding author) muhsinbalaban1980@yahoo.com cuneyd sevinc, md cuneydsevinc@yahoo.com medicana international istanbul hospital, urology clinic, yeni mah., pegagaz sok. soyak evreka:a5-44, soganlik, kartal 34880 istanbul, turkey alper aktas, md dralperaktas@hotmail.com kartal training and research hospital, urology clinic, istanbul, turkey ugur yucetas, md dryucetas@yahoo.com istanbul training and research hospital, urology clinic, istanbul, turkey introduction angiomyolipoma is a nodule composed of variable amounts of mature adipose tissue, smooth muscle, and thick-walled blood vessels derived from perivascular epithelioid cells usually arising in the renal cortex. its prevalence in the general population has been reported to be 0,3-3% overall in the female patients (1). in the multifocal form, it is usually associated to tuberous sclerosis (2). the average lesion size is from 2 mm to 20 cm maximum diameter. in most cases the angiomyolipoma is asymptomatic and is diagnosed incidentally with ultrasound, ct and mri done for other reasons. renal angiomyolipoma at times can be aggressive and may show extension into renal vein and inferior vena cava (3). we describe a paradigmatic case of a giant kidney angiomyolipoma, not associated with tuberous sclerosis, invading the pelvis and the renal vein. case report the lesion have been incidentally discovered in a 78 years old woman by ultrasound scan done for other reasons. total body ct scan and mri have been done showing large node (18 mm) in the mediastinus, a 8 cm large lesion of the upper pole of the left kidney with prevalence of fat tissue and solid areas invading the renal vein for 4 cm, some large nodes (1 cm) in the retroperitoneum and gallbladder stones (figure 1, 2). past medical history included breast reduction; hyatal hernia surgery; hypothiroidism; pulmu107archivio italiano di urologia e andrologia 2013; 85, 2 case report renal angiomyolipoma with renal vein invasion francesca di cristofano, federico petrucci, guglielmo zeccolini, genesio leo, calogero cicero, dario del biondo, antonio celia department of urology, san bassiano hospital, bassano del grappa (vi), italy. renal angiomyolipoma is a uncommon benign tumor, considered an hamartoma. the lesion, usually benign, can be single or multiple and well-circumscribed. in letterature only few cases of infiltrating angiomyolipomas have been described. the aim of the paper is to describe a paradigmatic case of a giant kidney angiomyolipoma, not associated with tuberous sclerosis, invading the pelvis and the renal vein. the lesion have been discovered incidentally during abdominal ultrasound for other pathology. owing to the extent of the lesion and the appreciable risk of bleeding, we opted for surgical treatment. key words: angiomyolipoma; kidney; renal vein invasion; radical nephrectomy. submitted 20 november 2012; accepted 31 december 2012 no conflict of interest declared summary nary infection during the last months. blood tests: hb 15 g/dl-1 leukocyte 8 x 103 µl-1, urea 44 mg/d-1, creatinine 0.9 mg/dl-1. the extension of the lesion, the risk of bleeding and the risk of renal carcinoma were carefully evaluated in order to decide the surgical treatment. the patient underwent laparoscopic left adrenal sparing radical nephrectomy. definitive histology: renal angiomyolipoma invading the renal vein with negative ilar nodes and normal left renal parenchima (figure 3, 4). no post-operative complications. the patient was discharged in the fifth postoperative day. at the first control, one month after the operation, the patient was asymptomatic, the abdominal ultrasound scan was normal and the blood tests were normal. figure 1. axial ct section showing extension of the lesion into the renal vein. di cristofano_stesura seveso 24/06/13 11:12 pagina 107 archivio italiano di urologia e andrologia 2013; 85, 2 f. di cristofano, f. petrucci, g. zeccolini, g. leo, c. cicero, d. del biondo, a. celia 108 plex cases (7). lesion larger than 4 cm may bleed, may cause flank pain and may be palpable (8). when the lesion is growing, when it is symptomatic or when the differential diagnosis is doubtful, surgical treatment is necessary: enucleoresection, embolization or radical nephrectomy (9). conclusions in most cases angiomyolipoma is asymptomatic and it is an incidental finding during ultrasound scan or ct scan done for other reasons. it may involve regional nodes, renal vein or inferior vena cava, that can suggest an aggressive evolution (10); anyway, these lesions are not considered metastasis. in case of benign lesion the treatment has to be conservative. radical surgery is requested in those rare cases where the angiomyolipoma is really large or involves the renal vein. references 1. wagner bj, wong-you-cheong jj, davis cj. adult renal hamartomas. radographics. 1997; 17:155-69. 2. benanni s, dahami z, dakir m, et al. bilateral renal angiomyolipoma associated with tuberous sclerosis: report of a case. ann urol. 2000; 34:278-282. 3. bakshi ss, vishal k, kalia v, gill js. aggressive renal angiomyolipoma extending into the renal vein and inferior vena cava an uncommon entity. br j radiol. 2011; 84:e166-e168. 4. inomoto c, umemura s, sasaki y, et al. renal cell carcinoma arising in a long pre-existing angiomyolipoma. pathol int. 2007; 57:162-6. 5. inci o, kaplan m, yalcin o, et al. renal angiomyolipoma with malignant transformation, simultaneous occurrence with malignity and other complex clinical situations. int urol nephrol. 2006; 38:417-26. 6. salerno s, lo casto a, sorrentino f, et al. bleeding renal angiomyolipomas. ct findings. radiol med. 2004; 107:229-33. 7. pozzi mucelli r, locatelli m. diagnostica per immagini dell’angiomiolipoma renale: quadri tipici e atipici. radiol med. 2002; 103:474-87. 8. steiner ms, goldman sm, fishman ek, marshall ff. the natural history of renal angiomyolipoma. j urol. 1993; 150:1782-1786. 9. yiu wc, chu sm, collins rj, et al. aggressive renal angiomyolipoma: radiological and pathological correlation. jhk coll radiol. 2002; 5:240-2. 10. wilson ss, clark pe, stein jp. angiomyoplipoma with vena caval extension. urology. 2002; 60:695-6. discussion renal angiomyolipoma is usually a benign lesion, it can be rarely associated to renal adenocarcinoma (4, 5) and to tuberous sclerosis. the histology shows mature adipose tissue, smooth muscle, and thick-walled blood vessels. the sporadic angiomyolipoma is monolateral and more frequent in the females. when associated to tuberous sclerosis, angiomyolipomas are multiple, bilateral and larger. the clinical interest in angiomyolipoma is in its rapid growth, the difficulty in distinguishing it from malignant lesions, the difficulty of establishing the diagnosis and correct treatment. the diagnosis is usually made by ultrasound scan that find a hyperecogenic omogeneus lesion in the renal cortex. the large lesions may have disomogeneus areas that make the diagnosis difficult; tc scan is usually mandatory in the large lesions: the diagnosis is based on the identification of fat inside the lesion (6). mri is useful only in some comcorrespondence francesca di cristofano, md (corresponding author) vico san lorenzo 6 terni, italy fdicristofano@gmail.com federico petrucci, md guglielmo zeccolini, md genesio leo, md calogero cicero, md dario del biondo, md antonio celia, md department of urology san bassiano hospital bassano del grappa (vi), italy figure 2. t2 weighted mri mass shows hyperintense signal with extension into renal vein. figure 3. renal angiomyolipoma: blood vessels with thickened walls mature adipose tissue and smooth muscle cells mixed. eex20 figure 4. renal angiomyolipoma: renal vein invasion. eex5 di cristofano_stesura seveso 24/06/13 11:12 pagina 108 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2138 case report treatment of penile strangulation by the rotating saw and 4-needle aspiration method: two case reports raidh a. talib, onder canguven, abdulla al ansari, ahmad shamsodini hamad general hospital, urology department, doha, qatar. introduction: the aim of this article was to describe our experience in using rotating saw and also combination of the instrument with 4-needle aspiration. methods: a comprehensive review of the literature was performed using pubmed. “penile strangulation, -constriction, -incarceration, -entrapment” were used as search terms, and a manual bibliographic review of cross referenced items was performed. results: search results yielded nearly 70 cases of penile strangulation caused by a variety of objects. various instruments have been described in the literature for their safe removal, each with its own pros and cons. conclusions: penile strangulation should be accepted as a self-induced priapism and managed as an emergency in order to preserve erectile function and to prevent penile necrosis. surgical creativity and patience are necessary in order to have a successful outcome. key words: emergency treatment; incarceration; penis; strangulation. submitted 10 march 2014; accepted 30 april 2014 summary introduction penile strangulation, which is a compartment syndrome, requires urgent treatment in order to nourish corpora cavernosa as well as corpus spongiosum. although the appearance of this disturbance in the medical literature dates back to as early as the mid 1700s, it is on the odd occasion and has been described nearly 70 times in the english literature. constricting rings are the most common cause of penile strangulation. they can be metallic or non-metallic and are mostly used for sexual purposes. unless treated promptly, the rings can result in permanent and severe damage, including penile amputation. here, we report on two cases of penile strangulation due to metallic constricting rings that presented to our emergency department with different clinical presentations and were treated surgically. no conflict of interest declared case 1 a 52-year-old man presented to the emergency department with a strangulated penis of eight-hour history. physical examination showed a metallic ring, 2.5 cm wide and 1.5 cm thick, in the proximal part of the penis, with gross swelling and congestion distal to the ring. the patient had difficulty in voiding and urinary retention. transurethral catheter placement was unsuccessful. by history, he was married and had erectile dysfunction due to venous leakage. after placing a ring, he was unable to remove it from his engorged penile shaft after autostimulation. in the emergency room, removal of the ring was initially attempted using lubricants and aspiration of corporal blood from lateral sides under local anesthesia (penile block with 1% lidocaine), but was unsuccessful due to the tight ring and engorged penis. a handheld rotating saw equipped with a metallic blade was utilized for removal. a metal spatula was placed under the metal ring and the ring was continuously irrigated with cold water during the procedure. following removal of the ring, penile detumescense was achieved in 5 minutes and the patient was able to void. the next day, he had no penile edema and no complication and he was discharged with an oral anti-inflammatory drug, antibiotic, and anti-tetanus injection. two weeks later, the patient returned to the outpatient clinic and stated that he had no difficulty in urination or erections. case 2 a 22-year-old single man presented to the emergency department with a grossly swollen penis. he used a heavy-duty ball-bearing ring for masturbation six hours before. the ring was stuck at the coronal sulcus, causing edema of the penile shaft and glans penis. a handheld rotating saw equipped with a metallic blade was utilized for removal of the ball bearing. however, only the outer layers (1 upper and 2 side layers) of the ball bearing could be cut and removed. attempts to cut the inner layer failed due to its thickness (about 1-cm) and balls on it. as it appeared difficult to cut and remove the ring by available instruments without injuring the doi: 10.4081/aiua.2014.2.138 139archivio italiano di urologia e andrologia 2014; 86, 2 treatment of penile strangulation glans penis, we discontinued cutting with a saw. then, penile aspiration was performed under local anesthesia (penile block with 1% lidocaine) by using four needles (18-gauge), which were introduced from the glans. two needles were placed in distal corpus cavernosa and the other two were placed in the glans penis in an attempt to decrease the girth of the penile shaft and glans immediately (figure 1). in order to relieve skin edema, multiple needle pricks on the skin were performed. because of the high pressure inside the skin, black-colored blood gushed out from the sites of needle insertion. simultaneously, antibacterial liquid soap was applied under the ring to facilitate lubrication. the ring was successfully removed without clear necrosis or iatrogenic damage to the penis. however, the penile edema resolved in 24 hours. one month later, the patient had no difficulty in urination or erections. discussion penile strangulation is a rare clinical entity that is mostly caused by the patient himself for sexual purposes. although either metal or non-metal rings are used for pleasure, the most commonly reported objects causing strangulation are metal rings. silberstein et al. developed a grading system with a modification of two broad categories as lowand high-grade penile injuries (1). highgrade injuries are defined as injuries that are likely to require surgical intervention (1). the patients presented here had low-grade injuries and no surgical intervention was performed after removal of the rings. the treatment of penile strangulation is decompression of the constricted penis to facilitate free blood flow and micturition. non-metallic rings can usually be removed simply by cutting the constricting object. interestingly, highgrade penile injuries are more frequently caused by nonmetallic constricting objects (1). although metallic constricting rings placed around the penis present a challenge to urologists, various instruments may be used whenever available, such as a string, modified string, hammer (2), gigli saw, rotating saw (1), and electric grinder. sometimes, combination (3) or alteration of treatment modalities might be needed as in our second case. penile aspiration technique in penile strangulation was first described by chang et al. who used two 21-gauge butterfly needles. in our case, for the first time to our knowledge, we performed penile aspiration by using four needles in order to achieve rapid detumescence. while protecting the patients’ organ, the surgical team should be aware of potential work injuries for both the patient and staff. horstmann et al. reported an eye problem in one of the medical staff (3). other than risk for blood or fluid spillage, heavy-duty technical equipments scatter metal sparks; therefore, wearing eye-protective glasses should not be neglected. conclusion penile strangulation may result from self-induced priapism and should be treated as an emergency urologic case. if the surgical team fails to remove a constricting ring, alternative treatment modalities should be considered. supplementary figures, extended discussion and full list of references are posted in supplementary materials on www.aiua.it references 1. silberstein j, grabowski j, lakin c, goldstein i. case reports: penile constriction devices: case report, review of the literature, and recommendations for extrication. j sex med. 2008; 5:1747-57. 2. bhat al, kumar a, mathur sc, gangwal kc. penile strangulation. br j urol. 1991; 68:618-21. 3. horstmann m, mattsson b, padevit c, et al. successful removal of a 3.6-cm long metal band used as a penile constriction ring. j sex med. 2010; 7:3798-801. correspondence raidh a. talib, md onder canguven, md, assoc. prof. (corresponding author) ocanguven@yahoo.com abdulla al ansari, md ahmad shamsodini, md hamad general hospital, urology department 3050 doha, qatar figure 1. two needles placed in the distal corpus cavernosa and the other two in glans penis in an attempt to decrease the girth of the penile shaft and glans. stesura seveso archivio italiano di urologia e andrologia 2016; 88, 172 letter to editors about: clarification to provide further understanding of the conduct and design of tropic: a phase 3 trial of cabazitaxel versus mitoxantrone in patients with metastatic castration-resistant prostate cancer no conflict of interest declared. doi: 10.4081/aiua.2016.1.72 dear editors, we read with interest the article “efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. a systematic review and meta-analysis” by perletti et al. in your journal (arch ital urol androl. 2015; 87:121-9), which describes the results of a systematic literature review assessing second-line agents used in the treatment of metastatic castration-resistant prostate cancer (mcrpc) progressing after docetaxel-based regimens. the authors analyzed ten articles reporting the results of five phase 3, randomized, controlled trials that enrolled patients with mcrpc progressing during or after first-line docetaxel treatment. this included the phase 3 tropic trial of cabazitaxel versus mitoxantrone (1), which provided the basis for the regulatory approval of cabazitaxel in this setting. the authors conducted a risk of bias analysis for each trial included in their review and concluded that the tropic trial had a high risk of selection and performance/detection bias. however, in table 2, the authors made several assumptions about the methodology of the tropic trial, which we feel warrant clarification. perletti article assumption (row 1): risk of bias for the random sequence generation used in the tropic study was unclear. the dynamic allocation system was not a random sampling strategy in a strict sense and patients were not allocated randomly because allocation was determined on the basis of prognostic factors chosen as inclusion criteria. author correction: random sequence generation for the tropic study was undertaken using stratified randomization by means of an interactive voice response system (ivrs). stratification used two baseline factors (disease measurability and performance status) (1). a dynamic allocation was rarely instigated and was imposed only if there was an extreme assignment imbalance in a center. perletti article assumption (row 2): risk of bias for concealment of treatment allocation in tropic was high. patients and treating physicians were not masked to treatment allocation. author correction: although individual patients at individual sites were not blinded, a centralized ivrs was used in tropic, therefore patients and treating physicians were not aware of global enrollment information or the treatment allocation at other sites. perletti article assumption (row 3): risk of bias for the blinding of patients and personnel in tropic was high. the study had an open-label design. although survival, biochemical findings and radiographic evidence could not have been influenced by the open-label setting, other endpoints (e.g., pain, quality of life) could have been prone to performance bias. author correction: we agree that efficacy endpoints (overall survival [os], prostate-specific antigen [psa] levels, radiographic response/progression) were not impacted by the open-label study design or subject to bias. we note that quality of life data were not collected. perletti article assumption (row 5): risk of bias for any incomplete outcome data in the tropic trial was unclear because no detailed information about censoring rules was provided. author correction: this statement is puzzling. the primary endpoint of the tropic study was os. the primary publication of tropic data states that os data were censored at the last date the patient was known to be alive or at the analysis cut-off date, whichever was earliest (1). almost all patients died before the end of the study or were censored at the study cut-off date. os data were missing in very few patients. perletti article assumption (row 7): risk of bias for other factors, such as baseline imbalances, was unclear for tropic. in a long-term survival analysis, it was shown that 18% and 9% of patients in the cabazitaxel and mitoxantrone treatment arms, respectively, were alive at 24 months (2). at baseline, the presence of visceral metastases, which can be prognostic for os, was higher in the mitoxantrone arm (20%) compared with the cabazitaxel arm (15%). author correction: data for baseline visceral metastases in tropic are reported incorrectly by perletti et al. among patients receiving cabazitaxel (n = 378) and mitoxantrone (n = 377), 25% of patients in each treatment arm had baseline visceral metastases (n = 94 in each arm) (1), thus no imbalance exists. after 24 months, almost twice as many patients were alive in the cabazitaxel arm (n = 60, 15.9 %) compared with the mitoxantrone arm (n = 31, 8.2%), demonstrating a long-term os benefit for cabazitaxel versus mitoxantrone (2). in addition, a multivariate analysis supports the os benefit of cabazitaxel (2). (remark 1) perletti et al. also assessed the effects of the interventions in the selected trials on os and radiographic progression-free de bono letter_stesura seveso 08/04/16 11:33 pagina 72 73archivio italiano di urologia e andrologia 2016; 88, 1 letter to editors survival (rpfs), which was defined as the time between the date of randomization and the first date of radiographic progression. perletti et al. stated that rpfs data were not available for the tropic study. in fact a composite pfs endpoint was reported for the tropic trial, defined as the time between randomization and progression measured by psa progression, tumor/radiological progression, pain/symptomatic progression, or death (1). median time to tumor progression was also reported using recist criteria (1, 3). thus, the definition of time to tumor progression used in the tropic study is aligned with the definition of rpfs used by perletti et al., and these tropic data could have been included in their assessment. (remark 2) finally, in their conclusions, perletti et al. note that compared with control cohorts in the different studies, survival advantages were 4.8 months for enzalutamide, 4.6 months for abiraterone and 2.4 months for cabazitaxel. we would like to point out that absolute differences in median os between such different clinical trials should not be compared; furthermore it must be made clear that the control arms in these trials are quite different. the control arms of the enzalutamide and abiraterone clinical trials received placebo, whereas in the cabazitaxel trial the control arm received the cytotoxic agent, mitoxantrone, which has antitumor activity in some patients. (remark 3) overall, we commend perletti et al. for their attempts to provide a detailed interpretation and comparison of key trials in the rapidly evolving field of mcrpc treatment. we hope that our clarifications about the design and conduct of the tropic study will enable its important findings to be better understood. references 1. de bono js, oudard s, ozguroglu m, et al. prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. lancet. 2010; 376:1147-54. 2. bahl a, oudard s, tombal b, et al. impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the tropic trial. ann oncol. 2013; 24:2402-8. 3. therasse p, arbuck sg, eisenhauer ea, et al. new guidelines to evaluate the response to treatment in solid tumors. european organization for research and treatment of cancer, national cancer institute of the united states, national cancer institute of canada. j natl cancer inst. 2000; 92:205-16. acknowledgements the tropic study was sponsored by sanofi. editorial support in the preparation of this letter was provided by danielle lindley of meditech media funded by sanofi. the authors, individuallyand collectively, are responsible for all content and editorial decisions and received no payment from sanofi related to the development of this letter. johann de bono 1, liji shen 2, oliver sartor 3 1 royal marsden nhs foundation trust and the institute of cancer research, sutton, uk; 2 sanofi, bridgewater, nj, usa; 3 tulane university medical school, new orleans, la, usa. correspondence johann sebastian de bono, mbchb msc phd frcp fmedsci (corresponding author) johann.de-bono@icr.ac.uk royal marsden and the institute of cancer research, london, downs road, sutton, surrey sm2 5pt, uk liji shen liji.shen@sanofi.com sanofi, bridgewater, nj, usa oliver sartor osartor@tulane.edu tulane university medical school, new orleans, la, usa de bono letter_stesura seveso 08/04/16 11:33 pagina 73 stesura seveso 235archivio italiano di urologia e andrologia 2014; 86, 3 case report renal epithelioid angiomyolipoma mimicking urothelial carcinoma of the upper urinary tract senol adanur 1, ercüment keskin 2, tevfik ziypak 1, erdem koc 1, elif demirci 3, turgut yapanoglu 1, i̇sa ozbey 1, ozkan polat 1 1 department of urology, medica faculty, ataturk university, erzurum, turkey; 2 department of urology, regional training and research hospital, erzurum, turkey; 3 department of pathology, medica faculty, ataturk university, erzurum, turkey. epithelioid angiomyolipoma is a rare mesenchymal tumor arising mainly in the kidney that can potentially behave aggressively. epithelioid angiomyolipoma can often resemble sarcomatoid renal cell carcinoma, high grade renal carcinoma or sarcoma. its similarity to renal cell carcinoma has been emphasized in most of the cases reported in literature. with the purpose of contributing to the awareness of this similarity, a 32-year-old female patient with renal epitelioid angiomyolipoma in the left kidney which radiologically mimicked urothelial cell carcinoma of the upper urinary tract is presented. key words: renal; epithelioid angiomyolipoma; treatment. submitted 12 november 2013; accepted 30 june 2014 summary no conflict of interest declared. introduction angiomyolipomas (aml) are benign tumours of the kidney and are composed of blood vessels, smooth muscle cells and mature fat cells. they comprise 2-6.4% of all renal tumors. angiomyolipomas are among the most common benign lesions of the kidney (1, 2). these tumors may be formed either as a part of the tuberous sclerosis complex (tsc) or as an isolated renal lesion (3). in 50% of patients with tsc, amls tend to be multifocal and bilateral involvment may occur (3). angiomyolipomas are most frequently seen in the kidneys and less commonly found in extra-renal sites such as the retroperitoneum and liver (4). epithelioid angiomyolipoma (eaml) is a variant of aml. although it is histologically a benign tumor, it may show clinically aggressive behavior and may mimick renal cell carcinoma in imaging studies. most reports in literature regarding eaml are related to its radiologic and histologic similarity to renal cell carcinoma. presented in this paper is a case of eaml radiologically mimicking urothelial cell carcinoma of the upper urinary tract. case report a 32-year-old female patient who referred with the complaint of left flank pain for a nine month period was hospitalized in our clinic. the physical examination findings were normal. urine test displayed the presence of many erythrocytes and blood chemistry was normal. at urinary doi: 10.4081/aiua.2014.3.235 system ultrasonography, a solid mass lesion of 76 x 49 mm in size was observed at the mid pole of the left kidney. the right kidney was found to be normal. the upper-lower abdominal phase contrast-enhanced computed tomography (ct) and abdominal dynamic magnetic resonance (mr) images that the patient had prior to coming to our hospital were studied. the abdominal dynamic mr imaging showed a mass lesion 8 x 4 x 6.5 cm in size localized at the mid pole of the renal pelvis which extended towards the exterior and contained hemorrhagic foci. in the postcontrast sections, the lesion showed hemorrhagic foci of minimal heterogenous contrast which decreased in number as the lesion extended towards the renal parenchyma (figure 1). the urine cytology was benign. with diagnostic flexible ureteroscopy, a tumoral lesion filling the left renal pelvis and calyces was observed. urethelial carcinoma was suspected and radical nephro-ureterectomy was performed with removal of the cuff from the bladder. at histopathological examination, tumoral structure including thick-walled vascular structures, wide necrotic and hemorrhagic areas are observed adjacent to the kidney tissue. the tumoral structure consisted of round-oval nucleoled spindle-shaped cells, some multinucleated, some ganglion-like ap pe a rance, showing pa lisading areas and a few mitotic figures. tumoral cells were immunohistoche mically hmb45 po sitive, focally cd68 positive, vimentin positive and nonreactive with s-100, sma, msa, ema, panck, desmin, cd34, cd10, nse, melan-1, factor xiiia, c-kit. the tumor was histo pathologically reported as an epithelioid angiomyolipoma (figure 2a-b). seventeen months postoperatively, abdominal mr imaging confirmed that there was no local recurrence or far metastasis in the patient. figure 1. abdominal mri appearance of the left kidney mass lesion. adanur cr_stesura seveso 08/10/14 12:21 pagina 235 archivio italiano di urologia e andrologia 2014; 86, 3 s. adanur, e. keskin, t. ziypak, e. koc, e. demirci, t. yapanoglu, i̇. ozbey, o. polat 236 dıscussıon angiomyolipoma is a mesenchymal tumor composed of dysmorphic blood vessels, fat tissue, and smooth muscle tissue in varying proportions. only 1% of renal angiomyolipomas show only epithelioid morphology (5). epithelioid angiomyolipoma is a rare mesenchymal tumor recognized in recent years and first reported by mai et al. (6) in 1996. for many years, the tumor was misclassified as an aml. in 2004, the international agency for research on cancer (iarc) of the world health organization classified eaml as an entity different from typical or classical aml and described it as a mesenchymal tumor with malignant potential. the tumor is primarily composed of epithelioid cells, whereas in some cases, it may show similarity to typical aml (7). although the growth pattern of eaml may be similar to that of aml, eaml may also display an invasive growth pattern where the tumor tissue shows hemorrhage, necrosis, and degeneration. it sometimes causes lymph metastasis. however, true cystic lesions and peripheral vascular and renal sinus invasion are rarely seen (8). the epithelioid morphology combined with cytologic atypia may render diagnosis difficult and lead to inaccurate diagnoses such as metastatic melanoma or renal cell carcinoma. immunohistochemistry plays the key role in differential diagnosis (5). the tumor cells of eaml stain negative for the s-100 protein and epithelial markers and stain positive for variable expressions of smooth muscle markers (smooth muscle actin, muscle specific actin) and melanocytic markers (hmb-45 and/or melana) (9). in our case, the immunohistochemical staining was positive for hmb-45, cd-68, and vimentin and negative for desmin and cytokeratin. it is difficult to differentiate malignant eaml from other solid renal tumors such as oncocytoma, renal cell carcinoma and sarcomatous lesions with only imaging studies. ct or mr imaging is frequently used to detect the fat foci which are characteristic of the tumor. however, the diagnosis of eaml is difficult because abnormal blood vessels and mature fat cells are also present in typical aml, but not apparent in eaml. the specific image characteristics of eaml have not been described in literature until recently (10). most eaml reports in literature are related to its radiologic and histologic similarity to renal cell carcinoma. in our case, due to the suspicion of urothelial carcinoma on the abdominal mr images, diagnostic flexible ureteroscopy was performed as a first step. in ureteroscopy, a tumor completely filling the renal pelvis and calyces was observed. according to the prediagnosis of urethelial carcinoma of the upper urinary tract, the cuff was removed from the bladder and nephro-ureterectomy was performed. the reported histopathological diagnosis of the tumor was eaml. the patient was not given any adjuvant therapy. at post-operative 17 months, abdominal mr images of the patient confirmed that there was no local recurrence or any far metastasis. in conclusion, eaml is a rare tumor that can mimic malignant or benign tumors and has unpredictable behaviour. it should be kept in mind that this potentially malignant tumor may radiologically and histologically be confused with renal cell carcinoma and sarcomatous lesions and that it may radiologically mimic urethelial carcinoma of the upper urinary tract. references 1. gamé x, soulié m, moussouni s, et al. renal angiomyolipoma associated with rapid enlargement [correction of enlargement] and inferior vena cava tumor thrombus. j urol. 2003; 170:918-19. 2. tallarigo c, baldassarre r, bianchi g, et al. diagnostic and therapeutic problems in multicentric renal angiomyolipoma. j urol. 1992; 148:1880-4. 3. neumann hp, schwarzkopf g, henske ep. renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex. semin pediatr neurol. 1998; 5:269-75. 4. prasad sr, sahani dv, mino-kenudson m, et al. neoplasms of the perivascular epithelioid cells involving the abdomen and the pelvis: crosssectional imaging findings. j comput assist tomogr. 2007; 31:688-96. 5. aydin h, magi-galluzzi c, lane br, et al. renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. am j surg pathol. 2009; 33:289-97. 6. mai kt, perkins dg, collins jp. epithelioid cell variant of renal angiomyolipoma. histopathology. 1996; 28:277-80. 7. faraji h, nguyen bn, mai kt. renal epithelioid angiomyolipoma: a study of six cases and a meta-analytic study. development of criteria for screening the entity with prognostic significance histopathology. 2009; 55:525-34. 8. cui l, zhang jg, hu xy, et al. ct imaging and histopathological features of renal epithelioid angiomyolipomas. clin radiol. 2012; 67:77-82. 9. bing z, maclennan gt. renal epithelioid angiomyolipoma. j urol. 2009; 182:2468-69. 10. huang kh, huang cy, chung sd, et al. malignant epithelioid angiomyolipoma of the kidney. j formos med assoc. 2007; 106 (2 suppl):51-4. correspondence senol adanur, md (corresponding author) s.adanur61@hotmail.com department of urology school of medicine ataturk university 25240 erzurum, turkey ercüment keskin, md tevfik ziypak, md erdem koç, md turgut yapanoglu, md isa özbey, md ozkan polat, md department of urology, regional training and research hospital erzurum, turkey elif demirci, md department of pathology, medica faculty, ataturk university erzurum, turkey figure 2. a. (hex400) atypical cells with prominent nucleoli, exhibiting multinucleated or ganglion-like appearance. b. (hex100) tumoral formation including palisades areas (thin arrow) and thick-walled vascular structures (thick arrow). adanur cr_stesura seveso 08/10/14 12:21 pagina 236 189archivio italiano di urologia e andrologia 2016; 88, 3 original paper explorative surgery for acute scrotal pain: the importance of patient age, side affected, time to surgery and surgeon andrea fabiani 1, massimo calabrese 2, alessandra filosa 3, fabrizio fioretti 1, valentina maurelli 1, michele scandola 4, stefano noventa 5, flavia tombolini 6, francesco catanzariti 1, lucilla servi 1, gabriele mammana 1 1 surgery departement, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; 2 operative unit of urology ss. filippo e nicola hospital, avezzano (aq), italy; 3 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy; 4 departement of human sciences, university of verona irccs santa lucia foundation, rome, departement of psychology, university of rome "sapienza", rome, italy; 5 center for assessment, university of verona, verona, italy; 6 urologic clinic, polytechnic university of marche region, italy. introduction and objective: testicular torsion must be diagnosed quickly and accurately. the delay of the diagnosis and the subsequent delay of surgery may lead to loss testicular viability and orchidectomy. aim of our retrospective evaluation was to define which element should be considered as major support to the clinician in distinguishing spermatic cord torsion from the other diseases mimicking this clinical emergency requiring surgical exploration. material and methods: we retrospectively reviewed all clinical and instrumental data of emergency scrotal exploration performed for acute scrotal pain at two different urological department in a 10 year period. results of surgical exploration represented the four diagnostic categories in which patients were divided for statistical evaluation. we evaluated the relationship between diagnosis performed by testicular surgical exploration and the all clinical data available including surgeon involved in the procedures. results: a total of 220 explorative scrotal surgery were considered. we divided the cases in 4 categories according to the diagnostic results of each surgical procedure. of all, spermatic cord torsion was diagnosed in 45% (99/220). the total testis salvage rate was of 78.8%. the patients with a diagnosis of spermatic cord torsion were older than patients with appendix torsion (15 vs 11 years in mean). when the affected side was the left, the probability to have a diagnosis of spermatic cord torsion was higher than the right side [χ2 (2, n = 218) = 11.77, p < 0.01]. time elapsing between onset of symptoms and testicular salvagewas significantly lower even than in case of appendix torsion/necrosis (p < .0001), and of others pathologies diagnosed (p = .0383). conclusion: in case of spermatic cord torsion, in addition to the clinical data, patient age and left side affected may represent an independent diagnostic predicting factor. the time elapsing between onset of symptoms and explorative surgery remain the only still prognostic factor for testicular viability. key words: spermatic cord torsion; testicular necrosis; testicular appendages; scrotal surgery; doppler ultrasound. submitted 1 november 2015; accepted 4 december 2015 summary no conflict of interest declared. introduction acute scrotum is an emergency situation that require a prompt evaluation by physician because of the possibility of loss of the testis in case of misdiagnosed or advanced spermatic cord torsion (1). without loss of time it is most important, for the often young patients, the immediate etiologic diagnosis of the acute painful swelling of the scrotum. from a clinical point of view, pain is not the only symptom. it is often accompanied with local signs like skin reddening and general symptoms. the diagnoses to be taken into account are several and includes also the torsion of the appendages of testis, inflammatory diseases, like acute epididymoorchitis, incarcerated inguinal hernia or testicular tumors (2). the spermatic cord torsion requires immediate surgical intervention (3) because the complete testicular ischemia, due to the interruption of blood flow after spermatic cord rotation in longitudinal axis, causes the irreversible loss of organ viability. therefore, testicular salvage is obtained by efficient and accurately diagnostic tools. in clinical routine the medical history, the clinical evaluation and the ultrasound scrotal scan are the three main diagnostic instrument. physical examination is often not sufficient to form a diagnosis especially in case of infants patients (4). ultrasound scan with colordoppler evaluation is not routinely used by the same radiologists (5). when the investigations are not confident, the surgical exploration begins as both a diagnostic and a therapeutic tool, following the old maxim: “if in doubt check it out”. the aim of our retrospective evaluation was to define which type of diagnosis was performed after surgical exploration conducted for an acute scrotal pain in two different urologic centers. we compared diagnosis obtained with several clinical factors and instrumental findings in order to define which element should be considered as a major support to the clinician in distinguishing spermatic cord torsion from the other diseases mimicking this clinical emergency requiring surgical exploration. doi: 10.4081/aiua.2016.3.189 fabiani2_stesura seveso 21/09/16 08:49 pagina 189 archivio italiano di urologia e andrologia 2016; 88, 3 a. fabiani, m. calabrese, a. filosa, f. fioretti, v. maurelli, m. scandola, s. noventa, f. tombolini, f. catanzariti, l. servi, g. mammana 190 material and methods we retrospectively reviewed all clinical and instrumental data of emergency scrotal explorations performed for acute scrotal pain at two different urological department (macerata civic hospital and avezzano hospital) in a 10 year period. over the time period 0f the study, for the surgical procedures 14 surgeons with a different expertise degree were involved. all patients were evaluated at emergency department and then by a consultant urologist. the same consultant performed the scrotal exploration. data were obtained from operating theaters notes and patients charts. they included demographic data like patient age, race, affected side, physical findings, pain duration, results of preoperative ecocolordoppler ultrasound when performed. the results of surgical exploration represented the four diagnostic categories in which patients were divided for statistical evaluation. we considered the two main causes of acute scrotal pain that can lead to a surgical scrotal exploration, alias spermatic cord torsion (categories 1 and 2) and torsion of the appendix testis (category 3) and we included the others findings in category 4. category 1 consisted in patients affected by spermatic cord torsion who underwent a radical orchidectomy for testicular necrosis; category 2 included patients who underwent a funicular de-rotation with subdartos orchidopexy because of the conserved vitality of the testis; category 3 was represented by cases of acute scrotum determined by a torsion/necrosis of testicular appendages. we evaluated the relationship between diagnosis performed by testicular surgical exploration and the all clinical data available. statistical analyses and evaluations were performed by two authors (ms and sn) using χ2 test and multiple comparisons between pairs of proportions, corrected according to bonferroni. results in our 10-year period of retrospective study, we considered eligible a total of 220 explorative scrotal procedures, 118 performed at macerata civic hospital (center a), 102 performed at avezzano hospital (center b). we divided the cases in 4 categories according to the diagnostic results of surgical explorations. demographic data and intra-operative findings are presented in table 1. mean patients’ age was 14.46 years (range 2-40; standard deviation 0.47). no differences were revealed between the two centers. in center a and b, the mean age was 13.74 (range 4-37; standard deviation 0.56) and 15.29 (range 2-40; standard deviation 0.79) years respectively. of a total of 220 scrotal explorative surgeries, 99 (45%) were performed for a spermatic cord torsion (categories 1 and 2). in 21 cases (21.21%) there was a need to perform a radical orchidectomy because of the loss of testicle viability. in the remnants 78 cases, the procedures consisted in the funicular de-rotation with sub-dartoic orchidopexy. thus, the total testis salvage rate was of 78.8% (84% and 73.46% for center a and center b respectively). scrotal explorative surgery not confirmed the suspect of spermatic cord torsion in 121 cases revealing the torsion/necrosis of the appendix testis (category 3) in 101 patients and others pathologies (category 4) in the remnants 20 cases (15 in center b). the patients with a diagnosis of spermatic cord torsion were older than patients with appendix torsion, without differences between the two centers. mean age was 15 years in case of categories 1 and 2. in contrast, the patients in category 3 were 11 years old in mean (figure 1). when the affected side was the left, the probability to have a diagnosis of spermatic cord torsion was higher than in case of right side involvement [χ2 (2, n=218) = 11.77, p < 0.01] (table 2). we noted that appendix testicular torsion/necrosis was diagnosed with significant high frequency in center a vs center b [(χ2 (2, n=220) = 11.74, p < 0.01, v = .231]. cases in category 4 were most in center b. in particular, patients age caucasian affected affected affected spermatic spermatic cord appendix testis echocolor (number) (mean) race (n) side right side left side bilateral cord torsion torsion with torsion/necrosis doppler ultrasound in years (n) (n) (n) with ro (n) derotation (n) (n) performed (n) center a 118 13.74 116 57 59 2 8 42 63 28 center b 102 15.29 98 46 56 13 36 38 102 total 220 14.46 214 103 115 2 21 78 101 130 table 1. demographic data and intraoperative findings of patient in center a and center b included in this study. figure 1. plot age and diagnosis. appendix torsion occur in patients younger than others. cod. 1 spermatic cord torsion cod. 2 appendix torsion/necrosis cod. 3 others pathologies cod.diag.proc ag e fabiani2_stesura seveso 21/09/16 08:49 pagina 190 multiple comparisons between pairs of proportions, corrected according to bonferroni, identified as significant the difference between the center a and b for the diagnosis represented in category 3 and 4 (p = 0.028) (table 3). the average time in hours elapsed between onset of symptoms and explorative surgery is reported in table 4 and figure 2, aggregated and stratified by center. as shown in figure 2, we noted a significant difference between spermatic cord torsion with testicular loss and all other diagnoses (all multiple contrasts, bonferroni corrected p < 0.0001). testicular salvage had an average time significantly lower even than the appendix torsion/necrosis (p < 0.0001), and others pathologies at diagnosis (p = 0.0383). however, it wasn’t no difference between appendix torsion/necrosis and the other pathologies diagnosed at the moment of explorative surgery. as reported in table 5, we analyzed the correlation between surgeons involved in explorative procedures and final diagnosis. in center b distribution of type of explorative surgery diagnoses was uniform. the chi-square test not revealed in fact association between operators and diagnosis [χ2 (12, n = 102) = 11.97, p = .45, p = .20]. at the contrary, in center a, the association between diagnosis and operator was present [χ2 (24, n = 118) = 88,803, p < .0001, p = .50]. in particular, some operators, as the number 7, number 8 and number 10, appeared to be more focused on a type of diagnosis than others. mind for the operator 10 it was de-rotations who saved the testicle. in case of operators 7 and 8, we noted a prevalence of diagnosis of testicular appendeces torsion/necrosis. discussion testicular torsion must be diagnosed quickly and accurately. the delay of the diagno191archivio italiano di urologia e andrologia 2016; 88, 3 explorative surgery for acute scrotal pain: the importance of patient age, side affected, time to surgery and surgeon table 2. laterality of testis involved stratified by diagnostic categories. right side left side category 1 category 2 category 3 category 4 right side left side category 1 3 18 category 2 37 41 category 3 55 45 category 4 8 11 total 103 115 table 3. frequency of diagnosis performed at each center after scrotal explorative procedures. table 4. average time elapsing between onset of acute scrotal pain and surgery in each center of study. center a center b figure 2. time (in hours) between onset of symptoms and explorative surgery stratified for diagnostic categories. cod. 1 spermatic cord torsion with testicular loss cod. 2 spermatic cord torsion with testicular salvage cod. 3 appendix torsion/necrosis cod. 4 others pathologies cod.diag.proc or e. si nt .e xp category 1-2 category 3 category 4 center a center b category 1-2 50 49 category 3 63 38 category 4 5 15 average time (hours) standard error range aggregate data 5.55 0.41 1-72 center b 5.75 0.41 1-24 center a 5.39 0.69 1-72 fabiani2_stesura seveso 21/09/16 08:49 pagina 191 archivio italiano di urologia e andrologia 2016; 88, 3 a. fabiani, m. calabrese, a. filosa, f. fioretti, v. maurelli, m. scandola, s. noventa, f. tombolini, f. catanzariti, l. servi, g. mammana 192 sis and the subsequent delay of surgery may lead to the loss of testicular viability and orchidectomy (1). at the same time, in case of acute scrotal pain, especially in case of very young patients, the urologist tends to follow the old maxim “if in doubt check it out”. this approach may due to the risk of loss of a vital organ with medico-legal consequences. whereas, overdiagnosis often subjects the patients to unnecessary surgery. acute scrotal pain may due to spermatic cord torsion in 16-42% of cases (6-7). our analyses regarded the explorative scrotal surgeries performed in case of acute scrotal pain with the diagnostic suspicious of spermatic cord torsion. we don’t have evaluated all acute scrotal pain episodes presented at the two emergencies departments. thus, we are enables to define which were the effective proportions of etiologies of acute scrotal pain episodes in the population studied. of 220 scrotal surgical explorations performed, we diagnosed spermatic cord torsion in 45%, 78 with testicular de-rotation and subsequent orchidopexis, 21 cases with radical orchidectomy due to the loss of testicular viability. a 55% of patients were operated although their disease could be treated conservatively. thus, we can calculate the testicular salvage rate of our practice. the total testis salvage rate was of 78.8%, 84% for scrotal explorative procedures performed at center a and 73.46% for center b. these results were higher than values reported in literature. mushtaq et al. (8) reported a testis salvage rate of 70% and another study (9) reported this value as 62-85%. finally moslemi and kamalimotlagh (10) calculated a value of 57.5%. we can explain the differences between these studies considering which are the different policies of approach to the acute scrotal pain. in case of disinformation about the importance of the prompt evaluation of acute scrotal pain or when there is a lack of access to the diagnostic procedures, as the scrotal ultrasound evaluation, may occur that explorative surgery was performed too late to avoid irreversible testicular ischemia and the consequent orchidectomy. in center a of our population study, there was a lack of application of scrotal ecocolordoppler ultrasound study, both by consultant urologists and radiologists. the consultant urologist recurred frequently to explorative surgery not as therapeutic procedure but as diagnostic tool. thus, the diagnoses of appendix torsion/necrosis were more frequent than in center b in which ecocolordoppler ultrasound was systematically performed. the elapsing time between onset of symptoms and explorative surgery was another critical point (11). the need of an early treatment of spermatic torsion to avoid testicular infarction is well recognized (8-12). spermatic cord torsion reduces blood supply to the testis, which subsequently leads to hemorrhage, infarction, and necrosis. many studies have shown that testicular infarction begins within the first 2 hours of spermatic cord torsion onset, irreversible damage occurs after 6 hours, complete infarction develops after 24 hours (13). statistical analysis indicates that aggressive treatment performed within 6 hours of spermatic cord torsion onset has a 93% testicular salvage rate. in contrast, only 10% of cases are resolved after 24 hours (14). in our retrospective evaluation we confirmed a significant difference between the times elapsing between onset of symptoms and spermatic cord torsion with testicular loss and all other diagnoses. testicular salvage had an average time of 3.11 hours, significantly lower than the cases of testicular viability loss, characterized by an average elapsing time of 17.19 hours. no cases of testicular salvage after 10 hours were registered in our population study with one case of testicular loss with a time to observation of only 6 hours. in evaluation table 5. surgeon stratified for center and final diagnosis. surgeon spermatic spermatic appendix others center b cord torsion cord torsion necrosis/ diagnosis (identification with radical with de rotation torsion number) orchidectomy and orchidopexy (sct ro) (sct op) 1 5 14 18 9 2 0 2 3 2 3 8 17 13 3 4 0 3 3 0 14 0 0 1 1 surgeon spermatic spermatic appendix others center a cord torsion cord torsion necrosis/ diagnosis (identification with radical with de rotation torsion number) orchidectomy and orchidopexy 5 0 1 1 2 6 1 11 9 0 7 1 8 31 0 8 0 1 10 1 9 0 2 0 0 10 0 15 3 0 11 4 3 7 1 12 2 0 1 1 13 0 1 1 0 fabiani2_stesura seveso 21/09/16 08:49 pagina 192 of acute scrotal pain, patient age may be determinant. the age distribution of testicular torsion is bimodal, with one peak in the neonatal period and the second peak around puberty (15). in our study, we had no cases of newborn patients. mean age was of 14.46 years, with a range between 2 and 40 years. in the only patient 2 years old, a spermatic cord torsion was diagnosed, confirming that testicular viability in neonatal torsion is universally poor. in fact, one literature review of 18 case series with 284 patients found a salvage rate of about 9% (16). in our experience, the patient age in case of appendix testicular torsion was significantly lower than the cases of spermatic cord torsion (11 vs 15 years respectively). as recently reported by hegele et al., the patients with spermatic cord torsion had a mean age of 15.5 years, significantly older than patients suffered from appendix necrosis/torsion or epydidimo-orchitis (17). in scientific literature there is no concordance about the value of the testicular side affected as independent risk factor for testicular torsion. in 2012, in a series of 47 patients who underwent a surgical exploration for acute scrotal pain, yu et al. (18) reported that the left side manifestation was significantly different between testicular torsion and epididymo-orchitis. we confirm this association revealing that when the affected side was the left, the probability to have a diagnosis of spermatic cord torsion was higher than in case of the right side involvement, in which a most common finding was the testicular appendix necrosis. may this association be related to an anatomical etiology? studies on the anatomic aspects of the tunica vaginalis and the association with epididymal anatomy and its anomalies in patients with testicular torsion are scarce (19-20). we know that testicular torsion occurs due to anatomic anomalies of tunica vaginalis or epididymis that allow excessive testicular mobility inside the scrotum. due to this excessive mobility, testis can present medial rotation that ranges from 360º to 720º in its own axis, which can cause interruption of the organ’s vascularization (21). favorito et al. (22), in a series of 50 testes studied during explorative surgery for acute scrotal pain, reported a normal anatomy of tunica vaginalis or epididymis at the side contralateral to the torsion in only 2 cases (4%). anatomic anomalies, classified previously by the same authors (23), were founded bilaterally in the vast majority of cases. these findings stress the need for bilateral orchiopexy in cases of testicular torsion and allows us to exclude the existence of a particular anatomical cause that justifies the higher incidence of testicular torsion in the left side, bringing back the association to a mere statistical randomness. unlike evaluated in others case series published in the literature, we analyzed the correlation between surgeons involved in explorative procedures and the type of the final diagnosis. the results obtained raise some questions. we reported in center a an association between diagnosis and operators, in particular regarding three surgeons that appeared to be more focused on a particular diagnosis than others. in case of the strong association with a testicular de-rotation, an explication may be related to surgeon experience. some experienced surgeons are able to clinically recognize a testicular torsion without any instrumental support (as in the case of the surgeon 10 in center a). however, we must consider the possibility of an untruthful diagnosis, made in order to minimize the overtreatment represented by the explorative surgery in cases without no spermatic cord torsion. likewise, in cases of more evidence of appendix necrosis/torsion, the data could be correlated with the lack of employment of the doppler ultrasound or with the consultant urologist experience. the scrotal exploration was used as a diagnostic tool rather than as a therapeutic tool in order to avoid testicular loss and medico-legal consequences. in these cases, the old maxime “if in doubt check it out” became the gold standard in decision making about acute scrotal pain. conclusions acute scrotum is an emergency condition that requires a prompt evaluation by physician because of the possibility of loss of the testicle. in case of spermatic cord torsion, in addition to the clinical data, patient age and left side affected may represent an independent diagnostic predicting factor. the time elapsing between onset of symptoms and explorative surgery still remain the only prognostic factor for testicular viability. the use of diagnostic instrumental tools, as the echo-color doppler ultrasound, may aid to avoiding unnecessary explorative surgery. references 1. gatti jm, murphy jp. current management of the acute scrotum, seminars in pediatric surgery, vol. 16, no. 1, 2007; pp. 58-63. 2. wampler sm, llanes m. common scrotal and testicular problems. prim care. 2010; 37:613-26. 3. boettcher m, bergholz r, krebs tf, et al. clinical predictors of testicular torsion in children. urology. 2012; 79:670-4. 4. makela e, lahdes-vasama t, rajakorpi h, et al. a 19-year review of paediatric patients with acute scrotum. scandinavian journal of surgery. 2007; 96:62-66. 5. dell’atti l, fabiani a, marconi a, et al. reliability of echo-colordoppler in the differential diagnosis of the “acute scrotum”. our experience. arch ital urol androl. 2005; 77:66-8. 6. lewis ag, bukowski tp, jarvis pd, et al. evaluation of acute scrotum in the emergency department. j pediatr surg. 1995; 30:277-82. 7. watkin na, reiger na, moisey cu. is the conservative management of the acute scrotum justified on clinical grounds? br j urol. 1996; 78:623-7. 8. mushtaq i, fung m, glasson mj. retrospective review of pediatric patients with acute scrotum. anz j surg. 2003; 73:55-58. 9. anderson jb, williamson rc. testicular torsion in bristol: a 25year review. br j surg. 1988;75:988-992. 10moslemi km., kamalimotlagh s. evaluation of acute scrotum in our consecutive operated cases: a one-center study. international journal of general medicine. 2014; 7:75-78. 11. ringdahl e, teague l. testicular torsion. am fam physician. 2006; 74:1739-43. 12. khaleghnejad-tabari a, mirshermirani a, rouzrokh m, et al. early exploration in the management of acute scrotum in children. iran j pediatr. 2010; 20:466-70. 193archivio italiano di urologia e andrologia 2016; 88, 3 explorative surgery for acute scrotal pain: the importance of patient age, side affected, time to surgery and surgeon fabiani2_stesura seveso 21/09/16 08:49 pagina 193 archivio italiano di urologia e andrologia 2016; 88, 3 a. fabiani, m. calabrese, a. filosa, f. fioretti, v. maurelli, m. scandola, s. noventa, f. tombolini, f. catanzariti, l. servi, g. mammana 194 13. cattolica ev, karol jb, rankin kn, et al. high testicular salvage rate in torsion of the spermatic cord. j urol. 1982; 128:66-8. 14. waldert m, klatte t, schmidbauer j, et al. color doppler sonography reliably identifies testicular torsion in boys. urology. 2010; 75:1170-4. 15 callewaert pr, van kerrebroeck p. new insights into perinatal testicular torsion. eur j pediatr. 2010; 169:705-712. 16. nandi b, murphy fl. neonatal testicular torsion: a systematic literature review. pediatr surg int. 2011; 27:1037-1040. 17 hegele a, wappelhorst d, varga z, et al. predictors of spermatic cord torsion—clinical presentation and intraoperative findings open journal of urology. 2011; 1:81-85. 18. yu kj, wang tm, chen hw, et al. the dilemma in the diagnosis of acute scrotum: clinical clues for differentiating between testicular torsion and epididymo-orchitis. chang gung med j. 2012; 35:38-45. 19. parker rm, robison jr. anatomy and diagnosis of torsion of the testicle. j urol. 1971; 106:243-7. 20. caesar re, kaplan gw. incidence of the bell-clapper deformity in an autopsy series. urology. 1994; 44:114-6. 21. ben-chaim j, leibovitch i, ramon j, et al. etiology of acute scrotum at surgical exploration in children, adolescents and adults. eur urol. 1992; 21:45-7. 22. favorito al, cavalcante ag, costa ws. anatomic aspects of epididymis and tunica vaginalis in patients with testicular torsion int braz j urol. 2004; 30:420-424. 23. favorito la, sampaio fj. anatomical relationships between testis and epididymis during the fetal period in humans (10-36 weeks postconception). eur urol. 1998; 33:121-3. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md phd fa.fioretti@libero.it valentina maurelli, md valentinamaurelli@hotmail.it francesco catanzariti md frenzis83@gmail.com lucilla servi, md lucilla.servi@sanita.marche.it gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, macerata, italy massimo calabrese, md calmas@alice.it operative unit of urology ss. filippo e nicola hospital, avezzano (aq), italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy michele scandola, phd michele.scandola@univr.it departement of human sciences, university of verona irccs santa lucia foundation, rome, departement of psychology, university of rome "sapienza", rome, italy stefano noventa, phd stefano.noventa@univr.it center for assessment, university of verona, verona, italy flavia tombolini md, urology resident flavia.tombolini@gmail.com urologic clinic, polytechnic university of marche region, italy fabiani2_stesura seveso 21/09/16 08:49 pagina 194 archivio italiano di urologia e andrologia 2016; 88, 2106 original paper the effects of stress incontinence surgery on sexual function and life quality of women murat tuncer, fatih tarhan, alper kafkasli, kadir demir, ugur yucetas, gokhan faydaci, bilal eryildirim, kemal sarica dr. lutfi kirdar kartal training and research hospital, istanbul,turkey. objective: to evaluate transobturator tape (tot) and burch colposuspension procedure’s effects on sexual functions and life quality. materials and methods: a total of 81 patients who underwent tot (n = 49) or burch (n = 32) with stress incontinence were included in this prospective study. preoperatively and at postoperative 6 month follow up pad and stress tests, physical examinations, female sexual function index (fsfi), international consultation on incontinence questionnaire short form (iciq-sf), urinary distress inventory (udi-6), incontinence impact questionnaire (iiq-7) questionnaires were performed. patient global impression of improvement (pgi-i) questionnare was added postoperatively. results: according to stress test, success rate was found to be 69% and 45%, in the tot and burch groups respectively. pad test decreased in both groups (p < 0.05). pgi-i scores was higher in the tot group when compared to burch group (p = 0.031). iciq-sf scores were improved in both tot (p < 0.0001) and burch groups (p < 0.012). iudi-6 and iiq-7 scores improved only in tot group. total fsfi scores did not change in both groups but only in tot group sexual desire improved. total fsfi scores did not change in patients that were successful and unsuccessful according to the stress test in both tot and burch groups (p < 0.05). conclusions: tot and burch procedures have no effect on the sexual functions. however tot improved life quality of patients. key words: stress urinary incontinence; transobturator tape (tot); burch colposuspension; sexual dysfunction; quality of life. submitted 1 november 2015; accepted 16 january 2016 summary no conflict of interest declared. based on the type (2). sexual dysfunction of women is described as sexual desire, sexual arousal, orgasm and/or sexual pain disorders that cause personal stress (3). sexual dysfunction is seen around 25-71% among women of different age groups (4-6). the dramatic negative effect of urinary incontinence on the sexual life of women was proven in performed studies. so that, this condition may lead women even to abandon sexual activity completely with a high incidence (7, 8). mid-urethral sling procedures, are the most commonly used procedures in the surgical treatment of stress urinary incontinence in women, and they are actually preferred over traditional procedures such as burch colposuspension (9, 10). the initial studies performed to assess the effects of surgical procedures for sui on the sexual function of women were retrospective studies in which small patient groups were evaluated and validated questionnaires were not used. thereafter, many studies were performed in which validated questionnaires were used during preoperative and postoperative periods and sexually active women were included. in these studies, sexual functions were reported as improved, unchanged or worsened after sui surgery (11-14). the aim of this study is to evaluate the effects of transobturator tape (tot) and burch colposuspension procedures performed for urodynamic stress urinary incontinence on the quality of life and sexual functions of women. materials and methods the patients were recruited from our outpatient clinic in a nonrandomized fashion between october 2011 and january 2014. patients who had a diagnosis of sui following urodynamic examination and candidates to be treated surgically were included into this prospective study program. study protocol was approved by dr. lutfi kirdar kartal training and research hospital’s etic committee. all the steps of the study were planned and applied carefully according to helsinki declaration. patients who underwent a previous pelvic organ prolapse or incontinence surgery, who were previously diagnosed with a sexual dysfunction, had hormone replacement therapy and use of drugs that may affect sexual function doi: 10.4081/aiua.2016.2.106 introduction urinary incontinence was described by international continence society (ics) as any involuntary leakage of urine (1). stress urinary incontinence (sui) and sexual dysfunction are problems with a high prevalance that negatively affect the quality of life. the prevalance of urinary incontinence was found to be 29% in a recent study and incontinence prevalance was indicated as 50% for stress urinary incontinence, 28% for urgency urinary incontinence and 22% for mixed urinary incontinence tuncer_stesura seveso 01/07/16 11:04 pagina 106 107archivio italiano di urologia e andrologia 2016; 88, 2 the effects of stress incontinence surgery on sexual function and life quality of women such as antidepressants, antipsychotics, beta-blockers and who did not have a regular sexual life were all excluded from the study program. from october 2011 to december 2012 all the patients underwent burch colposuspension. then from january 2013 to january 2014 tot was performed in all the patients as a new procedure in our clinic. thus, out of a total of 81 patients that were included in our study, 49 patients overall underwent tot procedure (group 1) and 32 underwent the burch colposuspension (group 2). during the preoperative assessment, age, bmi, number of births and medical history of the patients were recorded. a detailed physical examination including 1-hour pad-test and stress test, q-type test and pelvic organ prolapse assessments based on pelvic organ prolapse quantification (pop-q) system (15) was performed. all patients underwent filling cystometry and pressure flow study in accordance with the good urodynamics practice of international continence society (ics) (16) and they all filled the validated version of international consultation on incontinence questionnaire short form (iciq-sf), urinary distress inventory (udi-6), incon tinence impact questionnaire (iiq-7) and female sexual function index (fsfi) preoperatively (17-19). they were re-evaluated at 6 months postoperatively by iciq-sf, udi-6, iiq-7, fsfi questionnaires, stress test and pad-test. vaginal examination was performed in order to assess the complications. in addition to these, patient global impression of improvement (pgi-i) questionare was used to assess the efficiency of the surgical procedure subjectively (20). fsfi score > 22.7 was accepted as normal (4). data were shown as mean ± standard error. prizm 5.0 (graphpad software, san diego, ca) program was used during analysis and the data were assessed by paired t, mann whitney-u, wilcoxon test and mcnemar tests. p < 0.05 was accepted as statistically significant. results the mean age of all evaluated patients was determined to be 49.76 ± 0.97 (32-68) years. there was no statistically significant difference between two groups in terms of demographic results such as age, number of births and bmi (body mass index). demographic characteristics of the cases according to the groups were shown in table 1. according to the stress test, success rate was found higher in tot group compared to burch group (69% vs 45%) (p = 0.417). in preoperative and postoperative pad tests of the patients, a significant decrease was detected in tot group (p < 0.0001) as well as burch group (p = 0.0003). postoperative pgi-i scores that evaluate subjective success was found better in tot group when compared to burch group (1.75 ± 0.20 and 0.79 ± 0.39, respectively (p = 0.031). iciq-sf scores were significantly decreased postoperatively in both tot group (p < 0.0001) and burch group (p = 0.012). the mean pad tests and iciq-sf scores of the patients were given in table 2. improvement in udi-6 ve iiq-7 scores during postoperative period was only seen in tot group. there was a deterioration in udi-6 ve iiq-7 scores in burch group which was not statisticallly significant. the mean udi-6 tot burch colposuspension (n: 49) (n: 32) p age (years) 48.86 ± 1.14 (32-65) 51.84 ± 1.77 0.132 parity (n) 3.16 ± 0.21 (0-7) 3.86 ± 0.44 (1-6) 0.145 bmi (kg/m2) 31.30 ± 0.92 (20-45.9) 30.69 ± 0.99 0.748 tot: transobturator tape; bmi: body mass index. tot burch colposuspension (n: 49) (n: 32) preoperative postoperative p preoperative postoperative p iciq-sf 16.44 ± 0.60 8.51 ± 1.09 < 0.0001* 15.53 ± 1.26 11.32 ± 1.41 0.012** pad test 21.91 ± 3.31 5.60 ± 1.47 < 0.0001* 50.89 ± 22.69 14.00 ± 4.22 0.0003** iciq-sf: international consultation on incontinence questionnaire short form pgi-i: patient global impression of improvement * paired t test, ** wilcoxon test, ***mann-whitney test. table 1. demographic characteristics of the patients according to the groups. table 2. the mean values of preoperative and postoperative pad tests, iciq-sf of the patients. tot burch colposuspension (n: 49) (n: 32) preoperative postoperative p preoperative postoperative p udi-6 9.28 ± 0.49 5.74 ± 0.61 < 0.0001* 7.05 ± 1.49 7.68 ± 0.95 0.755** iiq-7 10.92 ± 1.01 5.19 ± 0.80 < 0.0001* 6.95 ± 1.80 8.00 ± 1.44 0.725** udi-6: urinary distress inventory iiq-7: incontinence impact questionnaire * paired t test, ** wilcoxon test. table 3. preoperative and postoperative udi-6 and iiq-7 scores of the patients according to groups. tuncer_stesura seveso 01/07/16 11:04 pagina 107 archivio italiano di urologia e andrologia 2016; 88, 2 m. tuncer, f. tarhan, a. kafkasli, k. demir, u. yucetas, g. faydaci, b. eryildirim, k. sarica 108 ve iiq-7 scores related to the quality of life were given in table 3. in tot group, no change was observed in total fsfi scores and the other sub-domains except an increase in the sexual desire (p = 003) in the postoperative period. in burch group, there was no significant postoperative change in total fsfi scores and all sub-domains (p > 0.05). the preoperative and postoperative total and subdomain scores of fsfi of the patients were given in table 4. the patients were evaluated according to stress test as improved and nonimproved sui and as a result no difference was detected in postoperatve total fsfi scores between them both in tot and burch groups (p = 0.622 and p = 0.625, respectively). the changes in total fsfi scores of the patients according to the stress test were given in table 5. in tot and burch groups respectively in preoperative period 26.5% (13/49) and 31.2% (10/32) and in postoperative period 18.3% (9/49) and 28.1% (9/32) of the patients had sexual dysfunction. there was no significant change in number of patients with sexual dusfunction before and after the operation for both tot and burch groups (p = 0.683 and p = 0.617, respectively). when surgically successful patients of both groups were evaluated together, again the rate of sexual dysfunction did not have a significant change (p = 0.724). complications developed at a rate of 8.1% (4/49) in tot group and 4.5% (1/32) in burch group. these were mesh erosion in 1 patient, de novo urgency in 2 patients and temporary urinary retention in 1 patient in tot group. in burch group overall complication was de novo urgency only in 1 patient. discussion the main purpose of the medical and surgical treatments performed for the urinary incontinence is to provide an improvement in the quality of life by recovering incontinence and it is thought that an improvement will also be obtained in the sexual functions as a result of this. in our study, tot was found more superior over burch operation in providing sui. although there are some studies supporting the results of our study in the literature (21, 22), a study showed that burch colposuspension surgery is more successful than tot operation (23). on the other hand another meta-analysis found no difference between early and late period success rates between these two methods (24). in a study comparing tvt and burch colposuspension, no difference was found in terms of long-term efficiency and quality of life (25). it is difficult to make a comment since there are few comparative studies regarding quality of life. however, it was reported that among the patients who underwent tot operation a significant improvement was seen in quality of life (26) and udi-6 and iiq7 scores were significantly improved postoperatively (27). in our present study that compared tot and burch surgical techniques, quality of life improved after tot surgery however but there was no improvement in burch group. the results of the limited number of comparative studies that assess the effect of stress incontinence surgeries on sexual functions are conflicting. in a prospective study by cayan et al. comparing the effects of burch colposuspension and vaginal sling procedures on the sexual functions of women, more reduction was detected in fsfi tot burch colposuspension (n: 49) (n: 32) preoperative postoperative p preoperative postoperative p desire 3.11 ± 0.17 3.65 ± 0.11 0.003* 3.08 ± 0.21 3.08 ± 0.24 0.945** arousal 3.49 ± 0.17 3.70 ± 0.13 0.224* 3.11 ± 0.27 3.04 ± 0.28 0.898** lubrication 5.30 ± 0.21 5.57 ± 0.14 0.268* 4.73 ± 0.42 4.56 ± 0.47 0.791** orgasm 4.54 ± 0.18 4.61 ± 0.15 0.612* 4.00 ± 0.36 3.95 ± 0.36 1.000** satisfaction 4.11 ± 0.19 4.00 ± 0.18 0.660* 3.73 ± 0.33 3.53 ± 0.32 0.301** pain 4.51 ± 0.21 4.80 ± 0.25 0.365* 4.85 ± 0.36 4.66 ± 0.49 0.922** total fsfi 25.06 ± 0.83 26.37 ± 0.78 0.158* 23.36 ± 1.53 24.33 ± 1.31 0.583** fsfi: female sexual function index. * paired t test, ** wilcoxon test. table 4. mean total fsfi and sub-area scores for mid-urethral sling and burch colposuspension groups. fsfi tot burch colposuspension (n: 49) (n: 32) preoperative postoperative p preoperative postoperative p stress test (-) 24.53 ± 1.16 26.52 ± 0.96 0.178 23.78 ± 3.84 22.04 ± 2.50 1.000 stress test (+) 25.89 ± 1.13 26.15 ± 1.36 0.842 26.23 ± 3.36 24.33 ± 2.43 0.688 * wilcoxon test. table 5. mean fsfi scores of the patients in both groups according to stress test. tuncer_stesura seveso 01/07/16 11:04 pagina 108 109archivio italiano di urologia e andrologia 2016; 88, 2 the effects of stress incontinence surgery on sexual function and life quality of women scores in burch colposuspension group compared to vaginal sling group (21). in a multicentric and prospective study by filacamo et al. evaluating the effects of mid-urethral sling operations (transobturator procedure and retropubic procedure) on the sexual functions of women and including the patients with urodynamic stress urinary incontinence and sexually inactive patients, a significant increase was observed in total fsfi and sub-area scores of all patients. it was found that the number of sexually active patients improved during the postoperative period and it was suggested that there was no difference between both surgical procedures (28). also, in the study by demirkesen et al. comparing tvt and burch colposuspension operations, it was observed that there was a greater but nonsignificant negative influence on sexual functions in tvt group (29). in our study both types of stress incontinence surgery did not show a positive or negative effect on sexual functions. however, only in tot group, a significant increase was observed in sexual desire following surgery. the reason may probably be related to the improvement in the coital incontinence in this group in which surgical success is high. considering all the mechanisms, it is thought that one of the factors that improves sexuality is probably the treatment of coital incontinence with mid-urethral sling (30), which was not evaluated in our study. according to our knowledge in the previous studies, no analysis on sexual function was carried out in relation to the success of the surgical procedure. we compared fsfi scores of the patients according to the success of the surgical procedure using stress test in order to better understand the effect of the surgical procedure on sexual functions as distinct from the others. when we compare the sexual functions between surgically successful and unsuccesful groups, we found that both had no significant change in pre and postoperative fsfi scores in tot and burch groups. furthermore, no improvement occurred in sexual function following surgery among the ones with preoperative sexual dysfunction. regarding the limitations of our study; non randomzation of the patients could be accepted as a potential limitation but still the patient groups were identical. another limitation was that the patients were not evaluated in terms of coital incontinence. we believe that further prospective and randomized controlled studies including larger series of cases are certainly needed in order to evaluate the effects of sui procedures according to surgical success on sexual function and quality of life. conclusions according to our results, we can say that in tot and burch colposuspension procedures the sexual function of women was not affected by the type of surgical procedure and the success of the operation. however the surgical tecnique affected the quality of life in patients which was improved by tot procedure when compared with burch operation. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation subcommitteeof the international continence society. neurourol urodyn. 2002; 21:167-78. 2. altaweel w, alharbi m. urinary incontinence: prevalence, risk factors, and impact on health related quality of life in saudi women. neurourol urodyn. 2012; 31:642-5. 3. basson r, berman j, burnett a, et al. report of the international consensus development on female sexual dysfunction: definitions and classifications. j urol. 2000; 163:888-93. 4. çayan s, akbay e, bozlu m, et al. the prevalence of female sexual dysfunction and potential risk factors that may impaire sexual function in turkish women. urol int. 2004; 72:52-57. 5. laumann eo, nicolosi a, glasser db, et al. gssab investigators’ group. sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the global study of sexual attitudes and behaviours. int j impot res. 2005; 17:39-57. 6. ponholzer a, roehlich m, racz u, et al. female sexual dysfunction in a healthy austrian cohort: prevalence and risk factors. eur urol. 2005; 47:366-375. 7. morgan dm, dunn rl, stoffel jt, et al. are persistent or recurrent symptoms of urinary incontinence after surgery associated with adverse effects on sexual activity or function? int urogynecol j pelvic floor dysfunct. 2008; 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5:387-93. 14. murphy m, van raalte h, mercurio e, et al. incontinence-related quality of life and sexual function following the tension-free vaginal tape versus the “inside-out” tension-free vaginal tape obturator. int urogynecol j pelvic floor dysfunct. 2008; 19:481-7. 15. bump rc, mattiasson a, bo k, et al. the standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. am j obstet gynecol. 1996; 175:10. 16. schäfer w, abrams p, liao l, et al. international continence society. good urodynamic practices: uroflowmetry, filling cystometry, and pressure-flow studies. neurourol urodyn. 2002; 21:261-74. 17. çetinel b, özkan b, can g. the validation study of iciq-sf turkish version. turkish journal urology. 2004; 30:332-338. 18. cam c, sakalli m, ay p, et al. validation of the short forms of tuncer_stesura seveso 01/07/16 11:04 pagina 109 archivio italiano di urologia e andrologia 2016; 88, 2 m. tuncer, f. tarhan, a. kafkasli, k. demir, u. yucetas, g. faydaci, b. eryildirim, k. sarica 110 the incontinence impact questionnaire (iiq-7) and the urogenital distress inventory (udi-6) in a turkish population. neurourology and urodynamics. 2007; 26:129-133. 19. oksuz e, malhan s. prevalence and risk factors for female sexual dysfunction in turkish women. j urol. 2006; 175:654-8. 20. yalcin i, bump rc. validation of two global impression questionnaires for incontinence. am j obstet gynecol 2003; 189:98-101. 21. çayan f, dilek s, akbay e, çayan s. sexual function after surgery for stress urinary incontinence: vaginal sling versus burch colposuspension. arch gynecol obstet. 2008; 277:31-36. 22. bandarian m, ghanbari z, asgari a. comparison of transobturator tape (tot) vs burch method in treatment of stress urinary incontinence. j obstet gynaecol. 2011; 31:518-20. 23. drahoradova p, martan a, svabik k, et al. longitudinal trends with improvement in quality of life after tvt, tvt o and burch colposuspension procedures. med sci monit. 2011; 17:cr67-72. 24. lapitan mc, cody jd. open retropubic colposuspension for urinary incontinence in women. cochrane database syst rev. 2012; 13:6. 25. ward kl, hilton p. uk and ireland tvt trial group. tensionfree vaginal tape versus colposuspension for primary urodynamic stress incontinence: 5-year follow up. bjog. 2008; 115:226-33. 26. shaker hs, ban hm, hegazy as, mansour mf. functional and quality of life outcome of transobturator tape for treatment of female stress urinary. int urogynecol j. 2011; 22:99-103. 27. liang cc, tseng lh, lo ts, et al. sexual function following outside-in transobturator midurethral sling procedures: a prospective study. int urogynecol j. 2012; 23:1693-8. 28. filocamo mt, serati m, frumenzio e, et al. the impact of midurethral slings for the treatment of urodynamic stress incontinence on female sexual function: a multicenter prospective study. j sex med. 2011; 8:2002-8. 29. demirkesen o, onal b, tunc b, alici b, cetinele b. does vaginal anti-incontinence surgery affect sexual satisfaction? a comparison of tvt and burch-colposuspension. int braz j urol. 2008; 34:214219. 30. serati m, salvatore s, uccella s, et al. female urinary incontinence during intercourse: a review on an understudied problem for women’s sexuality. j sex med. 2009; 6:40-8. correspondence murat tuncer, md (correponding author) murattuncer77@hotmail.com fatih tarhan, md tarhanf@yahoo.com alper kafkasli, md alpkafkasli@hotmail.com kadir demir, md kadirde@gmail.com ugur yucetas, md dryucetas@yahoo.com gokhan faydaci, md faydacig@yahoo.com bilal eryildirim, md bilaleryildirim@yahoo.com kemal sarica, md saricakemal@gmail.com dr. lutfi kirdar kartal training and research hospital, istanbul, turkey tuncer_stesura seveso 01/07/16 11:04 pagina 110 stesura seveso introduction renal cell carcinoma (rcc) has a very well known angiotropism, with up to 10% of tumors presenting neoplastic tumoral thrombosis (1). surgical treatment of this pathology is one of the most challenging procedures in urology, requiring optimal surgical skills and collaboration of many other specialists, like radiologist, heart-surgeon, general surgeon and oncologist (2-4). nowadays, most of urologic treatments can be offered in mini-invasive way (5), but the challenges of this procedure are still to be faced by open surgery (6). the aim of this paper is to review the 10 year experience of our institution in the sur175archivio italiano di urologia e andrologia 2013; 85, 4 original paper renal cell carcinoma with venous neoplastic thrombosis: a ten years review giacomo maria pirola, giovanni saredi, giuseppe damiano, alberto mario marconi urology unit, ospedale di circolo e fondazione macchi, varese, italy. purpose: to review the 10-year experience of our urological unit in the surgical management of renal cell carcinoma (rcc) with neoplastic tumor thrombosis focusing on postoperative survival. materials and methods: we underwent a retrospective analysis of the patients treated for this pathology during the last decade 2002-2012, stratifying them by tumor thrombus level and histological subtype. kaplan-meyer curves were used to assess survival. results: overall, 67 patients underwent surgery for rcc with neoplastic tumoral thrombosis in the period under review. 60 were clear cell rcc, 4 were urothelial papillary tumors of the renal pelvis and 3 were rare histotypes, as a nefroblastoma, a spinocellular tumor of the renal pelvis and an unclassifiable renal carcinoma. thrombus level was i in 40 cases, ii in 17, iii in 2 and iv in 8 patients. we report the main postoperative complications and our survival data, with mean follow up of 36 months. tumor stage is the most important variable in predicting survival. patients with n0m0 disease had 70% survival at 36 months, instead of 20% for those with primitive metastatic tumor. conclusion: our survival results fit with the main reports in literature and our surgical management was completely in keeping with international guidelines. we did not observe relevany post-operative complications, except of hemorrhagic ones that occurred in 6 patients (9% of total) and were always successfully managed. eighteen patients (26.87% of total) underwent caval filter positioning, without evidence of complications during its positioning or removal. life expectancy was particularly low for the cases of rcc without clear cell histotype (7 cases in our series, 10.4% of total) that always was less than one year from surgery. key words: renal cell carcinoma; neoplastic tumor thrombus; neves e zincke criteria; surgery; survival curves. submitted 11 february 2013; accepted 15 july 2013 no conflict of interest declared summary gical management of renal cell carcinoma with neoplastic tumor thrombus focusing on postoperative survival. materials and methods in the period between 2002 and 2012, we observed 67 cases of kidney tumor with neoplastic thrombosi. we stratified patients according clinical presentation, pathological staging and therapeutic approach applied and compared with tumor thrombus level using the chi-square test. kaplan-meyer method was used to estimate cancer-specific survival. doi: 10.4081/aiua.2013.4.175 pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 175 archivio italiano di urologia e andrologia 2013; 85, 4 g.m. pirola, g. saredi, g. damiano, a.m. marconi 176 we registered the main clinical perioperative variables to evaluate possible different outcomes related to thrombus extension, according to neves and zincke classification (7). in collaboration with the oncology division of our institution, we extracted survival data of patients that attended our hospital for follow up, unfortunately only about 50% of the total surgical series. results at the time of diagnosis, mean patients age was 71.5 years (range 3-91) with a median of 72 years, 39 patients (58.2%) were males and 28 (41.8%) were females. the tumor interested the right kidney in 39 cases (58.2%) and left in 28 (41.8%). the mean diameter of the neoplastic primitive mass was 9.4 cm, diameter ranged from a minimum of 3 cm to complete involvement of the whole organ with masses of up to 20 cm. there were 40 (59.7%) cases of level i thrombus, 17 (25.37%) with level ii, 2 (2.98%) with level iii and 8 (11.94%) with supra-diaphragmatic and intra-cardiac tumor thrombus (level iv). neoplastic thrombosis level was assessed according to neves and zincke criteria (7) (figure 1, table 1). at the time of diagnosis, most of our patients presented with definite symptoms, like local flank pain, hematuria and growth of systemic inflammatory parameters (creactive protein crp, erytrocite sedimentation rate esr and leucocytes). otherwise, 25% was totally asymptomatic, according to most of renal carcinomas behavior. ecog performance status was 0 in 43% of the patients, 1 in 45% and 2 in 12% of them, and surgical indication was always integrated with an accurate anesthesiologycal evaluation. mean hospitalization was 16.8 days (range 7-52 days), mostly due to surgical treatment and to peri-operative surgical or medical complications. all patients underwent clinical staging with ultra-sound (us), computed tomography (ct) and renal dynamic scintigraphy. a caval filter was placed in only 18 cases (26.87%) to prevent pulmonary embolism during surgery, because there is not a clear indication for this procedure and the risk of thrombus detachment during caval mobilization is very low. patients that positioned caval filter underwent computed tomography angiography (cta), which documented tumoral thrombosis and its extension into inferior vena cava (ivc). cavography was performed before and after filter implantation (8). the procedure had 100% feasibility. a right internal jugular vein puncture was performed after local anesthesia, and tumour thrombus level was determined by ivc phlebography. after the filter delivery sheath was placed in the suprarenal ivc, the filter was deployed according to the manufacturer’s guidelines. there was no evidence of perior post-procedural complications. all suprarenal ivc filters were removed from 30 to 60 days after surgery, except in three cases, where the filter was too near to neoplastic thrombus and it was necessary to remove it intraoperatively. surgical aim was always the debulking of the whole tumoral mass with the associated neoplastic thrombus (9).this was not possible only in one case, where the infiltration of caval wall was extended and we had to stop the procedure. the other two cases with caval wall thrombus level i ii iii iv operative time 158 175 215 289 (min.) (90-275) (135-275) (195-250) (240-390) blood supplement 0,8 1,6 2 4,6 (u rbc) (0-4) (0-6) (1-3) (3-8) hospitalization 14,4 19,3 20,5 22,6 (days) (7-30) (8-35) (20-21) (15-52) caval filter applied 5 9 2 2 (12,5%) (52,9%) (100%) (25%) peri-operative complications 13 7 1 3 table 1. surgical data and hospitalization data in our series of patients (varese, 2012). figure 1. percentage of neoplastic thrombosis level in our series of patients (varese, 2012). figure 2. surgical access stratified by level of neoplastic thrombosis (varese, 2012). pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 176 infiltration were treated with partial caval resection and apposition of a protesic biological patch. of the 67 patients considered in our series, 20 (30%) had preoperatively a metastatic illness, most of them interesting lung (30%, 6), adrenal glands (25%, 5), liver (20%, 4) and others brain, bone and pancreas (figure 2). level iv thrombosis (8 cases in our series, 12% of total), was always managed with cardiopulmonary bypass (cpb) and hypothermic circulatory arrest to achieve control on atrial region, in collaboration with a heart surgeon (10). we did not have neither perioperative deaths nor reinterventions, and the list of early complications is presented in the following chart (table 2). at pathological evaluation, 60 cases were renal clear cell carcinomas (90% of total), 4 were urothelial papillary neoplasms of renal pelvis (6.67% of total), one was a nefroblastoma (1,5% of total), one a squamous cell carcinoma of the renal pelvis and one an unclassifiable renal tumor. in the 60 clear cell rcc, 27 (45%) were t3a with thrombus limited to the first 2 cm of vena cava or within the renal vein, 21 (35%) were t3b, extended into the ivc, 7 (12%) were t3c, extended over the diaphragm, and 5 (8%) were t4 extended beyond gerota fascia, with a thrombus that involved renal vein in three cases, vena cava in one and supra-diaphragmatic region in another one. we did not perform extended lymphadenectomy, according to european association of urology (eau) guidelines, removing only big size or palpable nodes in six cases (9% of total). fuhrman grade was g2 in 37 cases (61.6%) and g3 in 23 (38.4%) (table 3). the 35 patients in our follow-up are divided in 24 with level i tumor thrombus, 6 with level ii, 2 with level iii and 3 with level iv neoplastic thrombosis. we present our survival data. among those 35 patients, 23 (65.7%) developed metastasis or local neoplastic recurrence, in 21 cases very soon, during the first year after surgery. the metastatic site was mainly pulmonary or hepatic (tables 4, 5). 177archivio italiano di urologia e andrologia 2013; 85, 4 renal cell carcinoma with venous neoplastic thrombosis: a ten years review postoperative complication patients number/% hemorrhage/hematoma 6/9 partial trombectomy 4/6 cvc infection 3/5 anesthesiologycal 2/3 lipothymia 2/3 hypertensive crisis 2/3 pnx 2/3 caval filter replacement 2/3 pulmonary emboli 2/3 arithmyas (fa-fv) 2/3 intestinal anastomosis leakage 2/3 allergic reactions 1/1,5 pneumonitis 1/1,5 paralytic ileus 1/1,5 table 2. post-surgical complications observed in our patients within the first month (varese, 2012). primitive tumor extension number of patients n0m0 n+m0 n0m+ n+m+ p patients with follow-up data t3a 27 21 2 3 1 15 t3b 21 15 6 < 0,01 15 t3c 7 3 1 3 3 t4 5 1 2 2 2 tot. 60 40 3 14 3 35 table 3. post-surgical complications observed in our patients within the first month (varese, 2012). thrombus level number of patients mean survival (months) median survival (months) survival range (months) deaths i 24 24,54 22 5-60 6 (25%) ii 6 25,1 21 14-44 2 (33,3%) iii 2 42 42 36-48 0 iv 3 23,66 24 12-35 2 (66,6%) table 4. patients stratification by tumoral thrombosis level and survival data (varese, 2012). pathologist stadiation number of patients mean survival (months) median survival (months) survival range (months) deaths n0m0 25 28,44 27 5-60 4 (16%) n+m0 1 12 12 12 1 (100%) n0m+ 8 19,75 15 5-35 4 (50%) n+m+ 1 6 6 6 1 (100%) table 5. patients stratification by tumor extension and survival data (varese, 2012. pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 177 archivio italiano di urologia e andrologia 2013; 85, 4 g.m. pirola, g. saredi, g. damiano, a.m. marconi 178 as we can see, tumor thrombus level is not so relevant in predicting survival and life expectancy is more stratified if patients are divided by pathologist stadiation (11). the four cases of urothelial neoplasms of renal pelvis were 3 with level i tumoral thrombosis and 1 with level ii; all of them had aggressive histological subtype, g3 fuhrman’s grade. they underwent uretero-nephrectomy with cystoscopy to exclude bladder invasion and associated trombectomy. all these cases had metastatic invasion, mainly in adrenals, lung and local lymph nodes. their mean survival was 14.25 months (range 11-18) and they had adjuvant chemotherapy with paclitaxel. they unusually represent about 6% of our series, because only few cases of transitional cell carcinoma with neoplastic tumoral thrombosis are presented in literature (12, 13). it is evident that these tumors have a high malignancy, with poor life expectancy for the patient. the three cases with rare histological type (nephroblastoma, spinocellular tumor of the renal pelvis and unclassifiable neoplasm) were all aggressive tumors, with level i tumor thrombus, and their survival was less than one year. despite poor prognosis, surgery was made for palliation, and patients achieved symptoms relief, mainly from hematuria that troubled most of them. discussion for the 60 cases of clear cell rcc the most significant prognostic factors are local tumor extension and fuhrman’s grading. on the contrary thrombus extension is more important for surgical planning than for predicting survival. these inferences are clearly valuable in the kaplanmeyer comparison of survival curves of the group without and with metastatic disease at pathological evaluation (figure 3). according to most of literature, radical surgery is the best option to adopt. cytoreductive aim is also useful for patients with metastatic disease, to achieve better answer to adjuvant immunotherapy on residual neoplastic foci after debulking. surgery is even important to give palliation to neoplastic symptoms, like local flank pain or hematuria, that occur with progressive neoplastic enlargement. survival at 36 months is clearly better for patients without metastatic disease (about 70%), but surgery offers a better life expectance also for advanced tumors (20% survival at 36 months). conclusions this work confirmed that rcc with neoplastic thrombosis is still a relevant health problem, with up to 10% of occurrence out of all patients with renal tumor. surgical treatment is clearly the first option for this pathology, and neoplastic thrombosis does not decline patients survival as an independent prognostic factor, but has to be evaluated together with tumor extension and performance status of the patient. the only difference is related to the surgical technique, more complex if tumoral thrombosis is spread to the whole ivc or even to right atrium, with the need of cpb. caval filter implantation is feasible and can be used to make safer the surgical procedure if thrombosis rises up into sub-diaphragmatic ivc with no complications in our series during its positioning or removal. in spite of all, surgery is effective both in oncological or palliative aim, and mainly safe with the absence of early post-operative deaths or re-operations. our experience in this field is in keeping with international guidelines, both in term of surgical approach and oncological follow-up. a different conclusion has to be made for the seven cases of uncommon renal tumor histotypes (four urothelial tumors of renal pelvis, one nefroblastoma, one spinocellular tumor of the renal pelvis and one unclassifiable renal carcinoma, accounting for 10.4% of our series), where the presence of neoplastic thrombosis was always linked to poor survival (about one year). figure 3. kaplan-meyer survival curves; group 1 (continue line) are n0m0 patients, group 2 (dotted line) are patients with metastatic disease (varese, 2012). time is expressed in months pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 178 references 1. boorjian sa, sengupta s, blute ml renal cell carcinoma: vena caval involvement bju int. 2007; 99:1239-1244. 2. ljungberg b, stenling r, osterdahl b, et al. vein invasion in renal cell carcinoma: impact on metastatic behavior and survival. j urol. 1995; 154:1681-1684. 3. zisman a, wieder ja, pantuck aj, et al. renal cell carcinoma with tumor thrombus extension: biology role of nephrectomy and response to immunotherapy. j urol. 2003; 169:909-916. 4. castelli p, caronno r, piffaretti g, et al. surgical treatment of malignant involvement of the inferior vena cava. int semin surg oncol. 2006; 16:3-19. 5. wotkowicz c, libertino ja, sorcini a, mourtzinos a. management of renal cell carcinoma with vena cava and atrial thrombus: minimal access vs median sternotomy with circulatory arrest. bju int. 2006; 98:289-97. 6. blute ml, leibovich bc, lohse cm, et al. the mayo clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumor thrombus. bju int. 2004; 94:33-41. 7. neves rj, zincke h. surgical treatment of renal cancer with vena cava extension. br j urol. 1987; 59:390 8. carrafiello g, mangini m, fontana f, et al. suprarenal inferior vena cava filter implantation. radiol med. 2012; 117:1190-8. 9. flanigan rc, mickisch g, sylvester r, et al. citoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. j urol. 2004; 171:1071-6. 10. belgrano e, trombetta c, siracusano s, et al. surgical treatment of renal cell carcinoma (rcc) with vena cava tumor thrombus. eur urol suppl. 2006; 5:610-618. 11. skinner dg, pritchett tr, lieskovsky g, et al. vena caval involvement by renal cell carcinoma. surgical resection provides meaningful long-term survival. ann surg. 1989; 210:387-92. 12. prando a, prando p, prando d. urothelial cancer of the renal pelvicaliceal system: unusual imaging manifestations. radiographics. 2010; 30:1553-66. 13. miyazato m, yonou h, sugaya k, koyama y, et al. transitional cell carcinoma of the renal pelvis forming tumor thrombus in the vena cava. int j urol. 2001; 8:575-7. 179archivio italiano di urologia e andrologia 2013; 85, 4 renal cell carcinoma with venous neoplastic thrombosis: a ten years review correspondence giacomo maria pirola, md (corresponding author) gmo.pirola@gmail.com giovanni saredi, md giovannisaredi@yahoo.it giuseppe damiano, md mediciurologia@ospedalivarese.net alberto mario marconi, md albertomario.marconi@ospedale.varese.it division of urology, ospedale di circolo e fondazione macchi, viale borri 57, 21100 varese, italy pirola okkkkkk_stesura seveso 18/12/13 10:35 pagina 179 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4170 introduction it is well-known the importance of urethral sphincter in the preservation of the continence control and it is also known that the “success” of radical prostatectomy for prostate cancer should be defined on the evaluation of five elements including continence that are parts of the so called “pentafecta” (1). in the classic “open” retropubic radical prostatectomy (rrp), bladder dissection from the prostate and bladder neck involves the incision of the bladder neck along its entire circumference and requires the reconstruction according to the so-called “tennis racket” technique or by original paper modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” with optical magnification in the preservation of the bladder neck, and estimation of the urinary continence alberto roggia 1, emilio pozzi 1, guglielmo mantica 1, maurizio salvadore 2, dimitrios choussos 3, carmelo di franco 3, carlo maria bianchi 3 1 division of urology hospital sant’antonio abate gallarate (va); 2 division of anatomopathology hospital sant’antonio abate gallarate (va); 3 graduate school of urology university of pavia. objective: to reassess the double continence technique for open retropubic radical prostatectomy, proposed by malizia and employed by pagano et al., with the “tension free continuum-urethral anastomosis” (t.f.c.u.a.) personal modification and the use of image magnification optical systems and appropriate and delicate surgical tools. materials and methods: a total of 173 radical retropubic prostatectomies, performed by the same surgeon, were evaluated in terms of early and late continence. results: the presence of residual prostate cancer cells within the muscle layer was always excluded by the histopathological examination that also demonstrated that the muscle layer was well represented; satisfactory outcomes were obtained in terms of both early urinary continence (60%) and urinary continence at 6-12 month follow-up (92.4% for the whole series and 97.2% for the last series of patients). conclusions: the “tension free” anastomosis obtained by the suspension of the anterior bladder wall to the the pubis along the median line allowed to achieve satisfactory outcomes in terms of urinary continence, even if these data obviously need to be confirmed by other series and comparative trials. key words: prostate cancer; modified radical prostatectomy; urinary continence; double continence technique; tension free anastomosis. submitted 27 december 2012; accepted 30 june 2013 no conflict of interest declared summary multiple sutures along converging lines, in order to obtain a neo-urinary bladder neck with a caliber proportionate to the diameter of the membranous urethra. the urology school of padova (2) employed the “double continence technique”, proposed by malizia in 1989 (3), by carrying out a meticulous dissection of the bladderprostate furrow along its entire circumference during retrograde prostatovesciculectomy. in this way the prostate block is excised by the bladder, leaving as much as possible untouched the mucosa of the bladder neck and of the urethra, defined as “epithelial continuum”. doi: 10.4081/aiua.2013.4.170 roggia_stesura seveso 18/12/13 10:34 pagina 170 171archivio italiano di urologia e andrologia 2013; 85, 4 modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” materials e methods from 1st june 2009 to 30th june 2012, 195 open retropubic radical prostatectomies were performed at the department of urology of the gallarate hospital: out of them 173 prostatectomies performed by a single surgeon (a.r.) were taken into account for this survey in order to obtain a more homogeneous series. retropubic antegrade prostatovesciculectomy was performed after opening of the endopelvic fascia, section of the pubo-prostatic ligaments and double ligature of the dorsal venous plexus. in particular, the surgical technique was aimed to the careful preservation of the bladder-prostatic epithelial continuum (figures 1, 2) by means of image magnification by a 9 x autofocus frontal microscope or 6 x telescopic lenses, by use of delicate surgical tools such as metzenbaun-fino scissors and micro pliers for the dissection and at the same time by avoiding use of both mono and bipolar electrosurgical tools (since january 2012 malis forceps, jones i.m.a. forceps, micro forceps, jones i.m.a. scissors, micro spring scissors were also used in order to reach greater accuracy in the meticulous dissection at the bladder-prostate furrow level). two stitches , that also incorporated the striated muscle of the urethra, were placed in order to fix firmly the membranous urethra to the elevator muscle of the anus; the rabdosphincter was recovered according to the technique used by rocco (4); the anastomosis between the distal section of the continuum and the membranous urethra was obtained by single stitches after the subversion of the mucous membrane of the continuum. occasionally an incisional biopsy was obtained in correspondence of the bladder-prostate continuum. during the procedure biopsies were marked by sutures of different colours in order to allow the pathologist to obtain sections perpendicular to the mucous surface. histological samples were stained with hematoxylin-eosin (figure 3) and in some cases with anti-actin and anti-desmin antibodies for the research of muscular antigens (figure 4). we revisited the technique described by malizia and pagano by adding an original modification in order to stabilize the anterior bladder wall to the pubis along the median line: a twisted absorbable suture stitch was placed between the anterior bladder wall and the pubic periosteum at a distance of 20 mm from the anastomosis. this original modification (“t.f.c.u.a. = tension free continuum-urethral anastomosis”) aimed to relieve the tension along the anastomotic stitches between the continuum and the membranous urethra. urinary continence was evaluated in 171 patients (98.8%), divided into two groups a and b. continence was considered achieved by the use of no pads or the use of one security liner in 24 hours. in the first group (a) (135 cases), composed by patients subjected to rrp from 1 june 2009 to 31 december 2011, continence was evaluated at 12 months. in the second group (b) (36 cases), composed by patients subjected to rrp from january 2012 to june 2012, continence was evaluated after 6-12 months but also earlier after 7 days from catheter removal. two patients were lost at follow up for urinary continence. results at 6-12 month follow up, out of a total of 171 patients, 158 patients were considered continent (92.4%), while the remaining 13 patients were considered incontinent (7.6%). continence was higher in patients with organconfined tumors pt1-pt2, taking into account that patients with pt3-4 stages were also submitted to adjuvant therapies (radiotherapy +/hormone therapy). figure 1. isolation of the bladder-prostate epithelial continuum. figure 2. muscular structure of the bladder neck after a complete circular section along the circumference of the continuum. roggia_stesura seveso 18/12/13 10:34 pagina 171 archivio italiano di urologia e andrologia 2013; 85, 4 a. roggia, e. pozzi, g. mantica, m. salvadore, d. choussos, c. di franco, c.m. bianchi 172 in the 135 patients of group a, continence was present in 123 (91.1%); in group b, which included 36 patients subjected to rrp in the first semester 2012, continence at 6 -12 month was obtained in 35 (97.2%) while early continence after 7 days from catheter removal was observed in 21 patients (60%) (table 1). histological sections, obtained by the incisional biopsies that were taken at the bladder-prostate continuum, were always negative for neoplastic infiltration; in the sections it was possible to identify the mucosa and, below it, corion and muscle layer (figures 3, 4). discussion the meticulous dissection of the bladder-prostate furrow, using appropriate systems of image magnification (5) such as 6 x telescopic lenses or 9 x autofocus frontal microscope, and delicate surgical tools, and avoiding mono-bipolar electrosurgical tools, allows to isolate carefully and to maintain the continuity of the bladder-urethral mucosa along the entire circumference of the bladder-prostate furrow. in this personal series, the histopathological evaluation never showed the presence of residual prostate glands or cells in this specific anatomic area, while it was clearly shown the presence of the muscle layer. it is known that the preservation of the urinary bladder neck reduces the incidence of anastomotic strictures (6) and achieves a greater incidence of early continence (65% vs 25%) at 4 months from the operation (7). the anastomosis between the more distal section of the continuity of the bladder-urethral mucosa and the membranous urethra is possible without reducing the lumen of the bladder neck, as the bladder neck presents a caliber proportionate to that of the urethral stump. retropubic radical prostatectomy is associated to postoperative bladder descent (8) that could be a contributing factor to the onset of urinary stress incontinence, due to a compression of the bladder-urethral anastomosis by the bladder and the abdominal organs. in order to improve urinary continence, tan et al. (9-10) proposed, after a series of 1383 robotic-assisted laparoscopic prostatectomies, a technical modification entitled a.r.t. (total anatomic restoration technique) which provides an antero-lateral “suspension” of the bladder with some suture stitches between the bladder itself and the pubic tendinous arch: in this way, during the urination, the contractile action of the detrusor would be distributed along several stitches, avoiding increases of pressure on the anastomosis and on the muscular urethral structures (rabdosphincter). the approximating stitch between the anterior wall of the bladder and the pubic periosteum, that we propose (t.f.c.u.a.) in conjunction to the double continence technique used by malizia, has the same assumption, that is to reduce the tension along the stitches of the anastomosis, but also to reduce compression on the bladder-urethral anastomosis due to the intra-abdominal pressures and the contraction of the detrusor. in literature, rates of continence, after open retropubic surgery and robotic and laparoscopic prostatectomy, range from 38.6% to 98.5% at 3, 6, 12 and 18 months of follow-up (table 2) in relation to the definition of continence used, the modality of evaluation of the functional outcome (validated questionnaires) and the population studied (multicenter versus single center survey). hu et al. (11) in a 18-month follow up of a large series of 8.837 radical prostatectomies, including 6899 open radical prostatectomy (rrp) and 1938 minimally invasive radifigure 3. section of an incisional biopsy of the bladder-prostate continuum: in the upper left the mucous surface (hematoxylin-eosin, x40). figure 4. histological section of a incisional biopsy of the continuum: in evidence the muscular tunica (anti-desmin, x40). number of patients n. 171 n. 105 pt 1-2 n. 66 pt 3-4 continence n. 158 (92,4%) n. 98 (93,3%) n. 60 (90,9%) group a n. 123 (91,1%) group b n. 35 (97,2%) early continence 60,0% table 1. personal results. roggia_stesura seveso 18/12/13 10:34 pagina 172 173archivio italiano di urologia e andrologia 2013; 85, 4 modified radical retropubic prostatectomy: personal technical variation “tension free continuum-urethral anastomosis (t.f.c.u.a)” cal prostatectomy (mirp), showed a greater incontinence rate in the minimally invasive group compared to the open surgery one: 15.9% incontinence rate in the mirp against 12.2% in the rrp, with a p value 0.02. in our experience, continence rate at 6-12-month was 92.4%, with a further increase in the last series of patients (group b) in term of both early (60%) and 6-12 month continence rate (97.2%), and can be explained by a greater accuracy in the anatomic dissection by the use of appropriate tools and the greater experience of the surgeon. conclusions it is known that optical magnification is considered one of the greater advantage of laparoscopy and that the level of accuracy of the dissection obtained by the robotic assisted procedure can make the preservation of the urinary sphincter more manageable (31). however also the open retropubic radical prostatectomy with use of optical image magnification systems and delicate tools in order to obtain the meticulous preservation of the bladder-prostate epithelial continuum and so the preservation of the muscular sphincterial structure of the bladder neck in conjunction with a tension free anastomosis (“t.f.c.u.a.”) allows to achieve satisfactory outcomes in terms of both early urinary continence (60%) and urinary continence at 6-12 month follow-up (92.4% for the whole series and 97.2% for the last series of patients). however these data obviously need to be confirmed by other series and comparative trials. references 1. patel vr, sivaraman a, coelho rf, et al. pentafecta: a new concept for reporting outcomes of robot-assisted laparoscopic radical prostatectomy. eur urol. 2011; 59:702-707. 2. pagano f, artibani w, zattoni f. prostatectomia radicale per via retropubica: tecnica chirurgica. atlante fotografico. edizioni meb, 1993. 3. malizia a. modified radical retropubic prostatectomy: double continence technique. aua, abstract 585, 316a, 1989. 4. rocco f, gregori a, stener s, et al. posterior reconstruction of the rhabdosfincter allows a rapid recovery of continence after transperitoneal videolaparoscopic radical prostatectomy. eur urol. 2007; 51:996-1003. 5. varkarakis j, wirtenberger w, pinggera gm, et al. evaluation of urinary extravasation and results after continence-preserving radical retropubic prostatectomy (rrp). bju. 2008, 94:991-95. 6. shelfo sw, obek c, soloway ms. update on bladder neck preservation during radical retropubic prostatectomy: impact on pathologic outcome, anastomotic strictures, and continence. urology. 1998; 51:73-78. 7. freire mp, et al. anatomic bladder neck preservation during robotic-assisted laparoscopic radical prostatectomy: description of technique and outcomes. eur urol. 2009; 56:972-980. 8. dev hs, sooriakumaran p, srivastava a, tewari ak. optimizing radical prostatectomy for the early recovery of urinary continence. nat rev urol. 2012; 9:189-95. 9. tan gy, jhaveri jk, tewari ak. anatomic restoration technique (art): a biomechanics-based approach for early continence recovery after minimally invasive radical prostatectomy. urology. 2009; 74:492-96. tecnica autore anno n° pz 3 6 12 > 18 open rrp stanford (12) 2000 1295 38.6% 60.5% 58% kundu (13) 2004 3477 93% lepor (14) 2004 500 70.1% 87.2% 92.1% 98.5% marien (15) 2008 1110 97% touijer (16) 2008 222 95% rocco (17) 2009 120 70% 93% 97% krambeck (18) 2009 564 93.7% hu (11) 2009 6899 87,80% lrp anestesiadis (19) 2003 230 59.2% 89% lein (20) 2006 952 76% eden (21) 2009 1000 94.9% touijer (16) 2008 193 48% 62% krambeck (18) 2009 286 91.8% stolzemburg (22) 2009 2400 71.7% 94.7% mariano (23) 2009 780 87.9% ralp ahlering (24) 2004 202 77% menon (25) 2006 1142 90% 95% patel (26) 2006 500 89% 95% zorn (27) 2007 300 47% 68% 90% borin (28) 2007 400 89% 97% krambeck (15) 2009 286 91.8% tewari (29) 2009 777 90% 97% rocco (17) 2009 120 70% 93% 97% murphy (30 2009 395 91.4% mirp hu (11) 2009 1938 84,10% table 2. evaluation of the continence. roggia_stesura seveso 18/12/13 10:34 pagina 173 archivio italiano di urologia e andrologia 2013; 85, 4 a. roggia, e. pozzi, g. mantica, m. salvadore, d. choussos, c. di franco, c.m. bianchi 174 10. tan gy, srivastana a, grover s, et al. optimizing vescico-urethral anastomosis healing after robot-assisted laparoscopic radical prostatectomy: lessons learned from three techniques in 1900 patients. j endourol. 2010; 12:1975-1983. 11. hu jc, gu x, lipsitz sr, et al. comparative effectiveness of minimally invasive vs open radical prostatectomy. jama. 2009; 302:1557-1564. 12. stanford jl, feng z, hamilton as, et al. urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the prostate cancer outcomes study. jama. 2000; 283:354-60. 13. kundu sd, roehl ka, eggener se, et al. potency, continence and complications in 3477 consecutive radical retropubic prostatectomies. j urol. 2004; 172:2227-31. 14. lepor h, kaci l. the impact of open radical retropubic prostatectomy on continence and lower urinary tract symptoms: a prospective assessment using validated self-administered outcome instruments. j urol. 2004; 171:1216-9. 15. marien tp, lepor h. does a nerve-sparing technique or potency affect continence after open radical retropubic prostatectomy? bju int. 2008; 102:1581-84. 16. touijer k, eastham ja, secin fp, et al. comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conduced in 2003 to 2005. j urol. 2008; 179:1811-7. 17. rocco b, matei dv, melegari s, et al. robotic vs open prostatectomy: a systematic review and cumulative analysis of comparative studies,. eur urol. 2009; 104: 991-5. 18. krambeck ae, di marco ds, rangel lj, et al. radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robot-assisted techniques. bju int. 2009; 103:448-53. 19. anestesiadis ag, salomon l, katz r, et al. radical retropubic versus laparoscopic prostatectomy: a prospective comparison of functional outcome. urology. 2003; 62:292-7. 20. lein m, stibane i, mansour r, et al. complications, urinary continence, and oncologic out come of 1000 laparoscopic transperitoneal radical prostatectomies-experience at the charité hospital berlin, campus mitte. eur urol. 2006; 50:1278-82. 21. eden cg, neill mg, louie-johnsun mw. the first 1000 cases of laparoscopic radical prostatectomy in the uk: evidence of multiple “learning curves”. bju int. 2009; 103:1224-30. 22. stolzemberg ju, kallidonis p, minh d, et al. endoscopic extraperitoneal radical prostatectomy: evolution of the technique and experience with 2400 cases. j endourol. 2009; 23:1467-72. 23. mariano mb, tefilli mv, fonseca gn,goldraich ih. laparoscopic radical prostatectomy: 10 years experience. int braz j urol. 2009; 35:565-72. 24. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003; 170:1738-41. 25. menon m, shrivastava a, kaul s, et al. vattikuti institute prostatectomy: contemporary technique and analysis of results. eur urol. 2007; 51:648-58. 26. patel vr, thaly r, shah k. robotic radical prostatectomy: outcomes of 500 cases. bju int. 2007; 70:173-7. 27. zorn kc, gofrit on, orvieto ma, et al. robotic-assisted laparoscopic prostatectomy: functional and pathologic outcomes with interfascial nerve preservation. eur urol. 2007; 51:755-62. 28. borin jf, skarecky dw, narula n, alhering te. impact of urethral stump length on continence and positive surgical margins in robot-assisted laparoscopic prostatectomy. urology. 2007; 70:173-7. 29. tewari a, jhaveri j, rao s, et al. total reconstruction of the vesico-urethral junction. bju int. 2008; 101:871-877. 30. murphy dg, kerger m, crowe h, et al. operative details and oncological and functional outcome of robotic-assisted laparoscopic radical prostatectomy: 400 cases with a minimum of 12 months follow-up. eur urol. 2009; 55:1358-66. 31. ficarra v, novara g, mottrie a, artibani w. robotic and laparoscopic prostatectomy: a critical review of existing data. aua update series. 2010, 29 (lesson 30). correspondence alberto roggia, md profroggia@libero.it director of the division of urology emilio pozzi, md (corresponding author) pozzi.emilio@libero.it division of urology guglielmo mantica, md guglielmo.mantica@gmail.com division of urology maurizio salvadore, md maurizio.salvadore@ao.gallarate.it director of the division of anatomopathology hospital sant’antonio abate via pastori 4 21013 gallarate (va), italy dimitrios choussos, md segreteria.chirgen2@smatteo.pv.it graduate school of urology carmelo di franco, md segreteria.chirgen2@smatteo.pv.it graduate school of urology carlo maria bianchi, md segreteria.chirgen2@smatteo.pv.it director of the graduate school of urology university of pavia viale golgi 19 pavia, italy roggia_stesura seveso 18/12/13 10:34 pagina 174 stesura seveso 175archivio italiano di urologia e andrologia 2014; 86, 3 original paper diagnosis and treatment of participants of support groups for hypersexual disorder els tierens, johan vansintejan, jan vandevoorde, dirk devroey department of family medicine, vrije universiteit brussel, belgium. background: the aim of this study is to examine the extent to which members of support groups for hypersexual disorder meet the proposed criteria for hypersexual disorder of kafka, how the diagnosis of hypersexual disorders is made and what treatments are currently given. methods: in this non-interventional research survey, members of support groups for hypersexual disorder received a questionnaire in which the criteria for hypersexual disorder according to kafka were included as well as the way the disease was diagnosed and treated. results: the questionnaire was presented to 32 people but only 10 completed questionnaires were returned. five of the ten respondents met the criteria of kafka. for the other five respondents a hypersexual disorder was not confirmed but neither excluded. only for three respondents the diagnosis was made by a professional healthcare worker. the treatment included – besides the support group in nine cases – also individual psychotherapy. two respondents took a selective serotonin re-uptake inhibitor (ssri), as recommended in the literature. conclusions: the members of support groups for sex addiction were difficult to motivate for their participation. the way hypersexual disorders were diagnosed was far from optimal. only two participants received the recommended medication. key words: sexual disorders, addiction, treatment. submitted 4 november 2013; accepted 15 january 2014 summary introduction definition hypersexual disorder, better known as “sex addiction” is a clinical phenomenon that has received only little attention from researchers up to now. hypersexual disorder was first introduced in the diagnostic and statistical manual of mental disorders (dsm)-iii. the dsm-iii-r specified that hypersexual disorder was different from paraphilia. in the dsm-iv hypersexual disorder was removed because there was a great lack of empirical research and consensus on definition, aetiology and pathogenesis (1). in the dsm-iv hypersexual disorder was placed under “sexual disorder not otherwise specified”. it was specified as “distress about a no conflict of interest declared. pattern of repeated sexual relationships involving a succession of lovers who are experienced by the individual only as things to be used” (2). the proposal to include the condition as “sex addiction” to the dsm-v was rejected for similar reasons. there is still disagreement whether such a condition really exist as a separate entity. it may be a manifestation of another psychiatric disorder (3). kafka suggested in 2010 to include hypersexual disorder as a new psychiatric disorder in the dsm-v (1). the name does not impose any causal link or does not suggest any particular pathogenesis. the criteria (figure 1) a. over a period of at least 6 months, recurrent and intense sexual fantasies, sexual urges, or sexual behaviors in association with 3 or more of the following 5 criteria: a1. time consumed by sexual fantasies, urges or behaviors repetitively interferes with other important (non-sexual) goals, activities and obligations. a2. repetitively engaging in sexual fantasies, urges or behaviors in response to dysphoric mood states (e.g., anxiety, depression, boredom, irritability). a3. repetitively engaging in sexual fantasies, urges or behaviors in response to stressful life events. a4. repetitive but unsuccessful efforts to control or significantly reduce these sexual fantasies, urges or behaviors. a5. repetitively engaging in sexual behaviors while disregarding the risk for physical or emotional harm to self or others. b. there is clinically significant personal distress or impairment in social, occupational or other important areas of functioning associated with the frequency and intensity of these sexual fantasies, urges or behaviors. c. these sexual fantasies, urges or behaviors are not due to the direct physiological effect of an exogenous substance (e.g., a drug of abuse or a medication). specify if: – masturbation – pornography – sexual behavior with consenting adults – cybersex – telephone sex – strip clubs – other:_____________________________ figure 1. proposed criteria for hypersexual disorder (2) used in our study. doi: 10.4081/aiua.2014.3.175 tierens_stesura seveso 09/10/14 10:37 pagina 175 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 176 were drawn up based on a thorough literature review: there must be a disorder of sexual desire and a problem of loss of control over impulses that leads to negative consequences. none of the proposed theories such as disinhibiting of behavior, impulsivity, compulsivity or addiction were proven, but they overlapped. these criteria are not yet tested on a population (1). currently, the american psychiatric association investigates whether or not hypersexual disorder should be included in dsm-v (4). several studies among people with hypersexual disorder showed that 35 to 73% practiced excessive masturbation, 49 to 51% frequently searched pornography, in 13 to 70% consenting adults are involved and 24% practiced phone sex (1, 5-7). kafka also added strip clubs and cybersex to the specifications. however, this cannot be supported by the literature (1). differential diagnosis hypersexuality can also fit in many other psychiatric disorders (3). the most common disorders in the differential diagnosis are paraphilias, sexual disorders not otherwise specified, impulse control disorder not otherwise specified, bipolar affective disorder (type i or ii), posttraumatic stress disorder and adjustment disorder (disturbance of conduct). rather infrequent disorders are substance-induced anxiety disorder (obsessive-compulsive symptoms), substance-induced mood disorder (manic features), delusional disorder (erotomania), obsessive-compulsive disorder, gender identify disorder and finally delirium, dementia, or other cognitive disorders. comorbidity hypersexual disorder can result in many other problems such as sexually transmitted diseases, unwanted pregnancy, relationshipand marital problems and domestic violence. it may also have legal consequences (8). hypersexual disorder is associated with other psychiatric disorders and risky behaviors such as smoking, excessive drinking, illegal drug use and gambling (5, 9). professionals specialised in addiction often look for sexually compulsive behavior after identifying a substance dependence. sex addiction is often associated with substance dependence and is a frequent cause of relapse. this would occur in 39 to 45% of sex addicts. mainly cocaine, alcohol and metamphetamines are concerned. only 17 to 34% of the surveyed population had no other addiction. different addictions can occur simultaneously, reinforce and alternate each other as well (3, 10). within a homosexual population, 45% of those who scored high on sexual compulsivity frequently used alcohol during sex, in contrast to the non-compulsive group in which this was 39%. for drugs this was 37% and 28% respectively (11). epidemiology there are no reliable epidemiological data on hypersexual disorder available. the lack of consensus on a definition and on an empirically validated instrument hampers further research and collection of epidemiological data. for that reason, no large-scale studies have taken place. (3, 5) it is estimated that 3 to 6% of the general population has a hypersexual disorder. it seems to be more common in men than in women; the male-female ratio is estimated at three to five (8). there is an issue of over-and underestimation. an overestimation could be caused by the current social climate and the perception of sexuality. the popularisation of the concept of hypersexual disorder could also play a role. an underestimation is due to shame, secrecy and depression that people refrain to seek professional help (8). the number of sex addicts that looked for help in flanders has increased exponentially in the recent years. in 2010, 14,396 people participated in a study on human sexuality. of the 6,458 men in the study, 107 (1.7%) ever searched help for sexual compulsivity. of the 7,938 included women 69 (0.9%) searched help. the help-seeking men watch more pornography than women. the women seeking help had more psychological symptoms such as depression and anxiety. the study population is not representative because the participants were recruited in the united states and canada through internet sites that provide sexual advice (12). in new zealand, 940 people at the age of 32 were questioned on excessive sexual behavior and risky sexual behavior. in total 3.8% men and 1.7% women reported excessive sexual behavior that interfered with their lives in the past year. they rarely sought help for their sexual behavior. if so, they consulted a psychiatrist, a psychologist, a lawyer or a priest (13). in a swedish study with 2,450 people aged between 18 and 60 years, 12% men and 7% women had “high hypersexuality”. this study enquired about masturbation, use of pornography, number of sexual partners, adultery, multiple sexual relationships at the same time and group sex (9). in 1993, a study recruited people with compulsive sexual behavior through newspapers. in total 36 participants (28 men and 8 women) with sexual preoccupation or excessive sexual behavior and subjective suffering were included. their medical history showed in 39% of the cases depression, phobia in 42% and in 64% substance addiction. the average age of onset of the hypersexual disorder was 18 years and participants suffered on average since nine years. three quarters linked this behaviour to the use of alcohol or drugs (14). treatment persons with hypersexual disorder more often visit a doctor for sexual advice (9). carnes already emphasised the importance of the first line in the detection and counselling of people with an addictive sexual dysfunction (10). if the sexual compulsive behavior is secondary to an addiction or another psychiatric condition, then the latter should be treated first (3). in addition to education, a combination of individual psychotherapy and group therapy is indicated. an early start with the 12-step program based on alcoholics anonymous is highly recommended. several support groups, where peers meet, follow this pattern. these sessions take place without a therapist (3, 5, 10). the effect of the 12-step program has not yet been demonstrated but 23% would complete the first nine tierens_stesura seveso 09/10/14 10:37 pagina 176 steps in 18 months and among them relapse is rare. in the beginning, for 30 to 90 days, total abstinence is recommended. this period may be associated with acute depression, insomnia, irritability, difficulty concentrating, and nausea. the symptoms would only emerge in the first 3 weeks and improve during the two months thereafter. later participants comply with this total abstinence or turn it over to a partial abstinence. this means a total denial of compulsive, destructive sexual behavior. the abstinence means not only a change of behavior but also the avoidance of fantasies (3). in a second phase individual psychotherapy is initiated: cognitive-behavioral and psychodynamic therapy are recommended (3, 5, 10). the effect of this therapy is not yet proven, because it is very difficult to organise a randomised controlled trial because of the complexity of the interaction between the caregiver and the patient (15). the intervention of sexologists would be most effective at a later stage, in the second year and later (3). also couple or family therapy can be added. there are no empirical studies that demonstrate the effect of couple therapy, but partners of addicts are demanding more support from therapists (16). reasons to choose for an inpatient treatment are: suicidal tendencies, little social support, failure of outpatient treatment, multiple addictions and serious consequences (legal, financial, marriage-bound or public exposure). outpatient treatment may be successful when patients are supported by their family. one of the best predictors of success is the will of the patient to succeed (10). although the etiology is unknown, researchers focus on the neurophysiology of sexual arousal that depends on neurological, hormonal and genetic factors. but in humans, culture and context play also a major role (9, 10). patients with pronounced symptoms are advised to start with psychotherapy and medication at the same time because a combination of both gives better results. a therapy with ssris is preferred although tricyclic antidepressants are also prescribed (15). for the more severe cases, particularly offenders, a combination of an ssri with an anti-androgen (cyproterone acetate or medroxyprogesterone acetate) is preferred but lhrh agonists and estrogens are also used (17). evidence about the drug treatment is not available. the study populations are often too small or non-representative population are examined (3, 15, 17). benzodiazepines are not recommended, as these can disinhibit patients (5). for these kind of disorders there is always a risk of relapse. in the first year there is a great agitation but the following six months include the greatest risk. only after 18 months an improvement in quality of life occurs and in the fourth and fifth year relationships can improve. a final recovery is, in principle, never reached (3). aim of the study the aim of this study is to examine the extent to which members of support groups for sex addiction meet the proposed criteria for hypersexual disorder of kafka. secondly, the authors try also to have a better insight on how the diagnosis of hypersexual disorders is made and what treatments are currently provided. methods participating support groups sexaholics anonymous (sa), sexual compulsives anonymous (sca) and sex and love addicts anonymous (slaa), the three support groups active in belgium were invited to participate in the study. only sa and sca decided to participate. the slaa preferred not to contribute to the research because during the meeting they just want to concentrate on the treatment. sa was founded in 1979 in the united states. in 2011, sa had 1611 groups in 42 countries. in belgium there are currently four sa groups. in the course of the four years in which they have operated, there are a few thousand people who attended at least once and about one hundred who attended regularly the meetings. most of the people (95%) attend only once. in december 2011, there were five regular members in each of the four groups. the meetings are chaired by the members themselves, in no sa-meeting professional counsellors are present. sca reported that in their support groups 15 to 20 members worked on their recovery. there is no register of members, so they cannot provide exact figures. procedure non-interventional research was organised in march 2012. the questionnaire was anonymously proposed to members of the participating support groups for sex addiction. the questionnaire consisted of a paper and electronic form and was distributed by the contact person of each support group. the questionnaire was available in dutch as well as in french. after the collection and the analyses of data, the contact persons of the support groups were interviewed in order to clarify and comment the results. ethical approval the protocol for this study was approved by the ethical committee of the university hospital of the vrije universiteit brussel. the participants were informed about the purpose and course of the study, possible risks, confidentiality and the right to information, on the front page of the questionnaire. informed consent was obtained in an alternative manner. by participating in the study and by completing the questionnaire the subject confirmed that he/she was aware of the purpose and course of the study and possible risks. this was the only way to guarantee absolute anonymity. questionnaire the questionnaire consisted of three parts. in a first part, some socio-demographic data were collected. the criteria for hypersexual disorder were collected in the second part. the last section included questions related to diagnosis, treatment and satisfaction with treatment. the socio-demographic variables in the questionnaire were: sex, age, highest degree, ethnicity, sexual orientation and relationship status. to assess whether the members of the support groups actually meet the criteria of kafka a newly developed ques177archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder tierens_stesura seveso 09/10/14 10:37 pagina 177 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 178 tionnaire that reflects these criteria as strong as possible was administrated. there were already several questionnaires used for disease screening and diagnosis. however, these questionnaires were not studied in detail and none of them specifically sets the criteria of kafka (18, 19). they were therefore not eligible for our study. in the third part, participants were asked which health professional made the diagnosis, which professionals did the treatment follow-up, what was the treatment and what the medication was the patient received. it was also checked whether a physician – if any – was involved. finally, the participants were asked for how long they already suffered from hypersexual disorder, for how long the disease was already diagnosed and whether they were satisfied with the treatment so far. statistical analyses all used statistics are descriptive. ibm spss 20 was used for the analyses. results demographics the contact person of sa presented the questionnaire to 25 members and 7 completed questionnaires were returned. the contact person of sca presented the questionnaire to 7 members and 3 completed questionnaires were returned. the response rate was 31%. all participants were male. their ages ranged between 33 and 62 years and averaged 48.2 years. they were all caucasians except two. one participant was partly south american and partly caucasian. the other participant did not answer this question. most of the participants obtained a degree of non-university higher education. all participants of the study were heterosexual except one who was homosexual. seven participants had a partner, the other three had no relationship. diagnosis five out of 10 participants met the three criteria of kafka. all respondents met the first criterion and nine met also the second criterion (table 1). five participants were addicted to substances. the sexual activity of all respondents took place on the field of masturbation and pornography. six respondents had regular sex with consenting adults, four respondents took part in cybersex, one in phone sex and three participants regularly visited strip clubs. four respondents reported other inappropriate behavior like voyeurism in public places, cinemas, nudist beaches and swingers clubs. the diagnosis was made by a professional healthcare worker in three cases, which was in each of these cases a psychologist. one of these three psychologists was an expert in hypersexual disorder by experience. three respondents made the diagnosis themselves, twice the diagnosis was made by the support group and twice the partner made the diagnosis. on average the respondents suffered for 31 years of hypersexual disorder. the age at which it started varied between 4 and 24 years, with an average of 17.5 years, but the diagnosis was on average made at the age of 37 years. treatment eight participants had a family physician. all family physicians (except one) were aware of the diagnosis. four of these eight family physician were involved in the treatment. six participants were treated by a psychologist, four by a sexologist and five by a psychiatrist. one participant indicated that “the literature” was responsible for his treatment. no one sought help from a support group only. the treatment included ambulatory individual psychotherapy in nine participants, two followed relational therapy, one followed an online treatment and one was hospitalised. none of them attended ambulatory family therapy or another group therapy. homeopathy and hypnotherapy were also recorded once each. seven of the ten participants took medication such as aripiprazole, sertraline, escitalopram and benperidol. two participants took complementary or alternative medicine: st. john's wort and homeopathy. a a1 a2 a3 a4 a5 b c participant 1 1 1 1 1 1 1 1 0 participant 2 1 1 1 1 1 1 1 0 participant 3 1 1 1 1 1 1 1 1 participant 4 1 1 1 1 1 1 1 1 participant 5 1 0 1 1 1 1 1 1 participant 6 1 1 1 1 1 1 1 0 participant 7 1 1 1 1 1 0 1 1 participant 8 1 1 1 0 1 1 0 0 participant 9 1 1 1 1 1 1 1 0 participant 10 1 1 1 1 1 1 1 1 (1 = participant meets criterion, 0 = participant does not meet criterion). table 1. results per participant of the kafka 2010 criteria for hypersexual disorder. tierens_stesura seveso 09/10/14 10:37 pagina 178 satisfaction with treatment satisfaction with treatment ranged from neutral to very satisfied. in this study, participants had also the possibility to comment. most comments were positive: the healthcare workers did not judge or condemn. the participants experienced a lot of understanding, help and support. the 12-step program was evaluated as very supportive. one person claimed to have reached a final stabilisation with the 12-step program. one of the reasons is that the support group is much more accessible in case of an emergency. homeopathy and hypnotherapy were perceived as positive. the importance of complementarity was emphasised. some indicated that psychiatrists behaved too formally, they experienced a lack of involvement and participants found a 20-minute consultation too short. some were not satisfied with the treatment in hospitals, others found the results obtained with a sexologist and psychologist insufficient. shame, taboo and sensationalism were perceived as negative elements concerning the treatment. some complained about the high cost of several years of treatment. discussion the low response rate is not surprisingly because the target group was probably cautious and restrained. the discontinuity of anonymity and the fear of stigmatisation is not to be underestimated. the selfishness that accompanies addiction and perhaps also hypersexual disorder, may also play a role. the contact persons indicated that mainly the long-time members participated in the research. in order to achieve a larger study group, more time is needed to build a trusted relationship with the participants by proxy of the contact persons. demographics all participants were male. from the epidemiological studies we know that the majority is male with a ratio between one in three, to one in five (8). the average age of the study group was 48 years. in a similar study, the participants all belonged to the age group between 20 and 29 years (14). this difference in average age seems rather a selection bias problem of that specific study than a significant difference with our study. our participants were recruited in support groups whereas the latter study recruited by advertisements. however, the contact persons indicated that the population attaining the support groups is getting older and that young members are less interested to attend a meeting every week. they prefer quick result. one participant refused to answer the question on ethnicity. immigrants are rare in the support groups. for immigrants hypersexual disorder is a lot harder to endure than for natives because of cultural aspects (14). religion was not questioned in our study. questions about religion are probably delicate for the participants. nevertheless these questions are interesting because religion would play an important role in the perception of hypersexual disorder and in the treatment. a religious person would be faster to accept helplessness and therefore attend faster aid (13). one of the steps of the program is a search for spirituality. in non-religious people this is a taboo but for religious people this is an additional reason to join. according to one study, about 50% of people with hypersexual disorder are homosexual or bisexual (13). in our study all participants (except one) were heterosexual. this reflects better the sexual orientation in the general population. it seems to be speculation to suggest that hypersexual disorder is more common among homosexuals or bisexuals. a fortiori, there is almost no epidemiological evidence about the prevalence of hypersexual disorder among groups with a different sexual orientation. on average, the participants had a degree of non-university higher education. this degree is somewhat higher than in the general population. however, this educational level might be biased by the fact that participants were recruited in support groups. it is known that well-educated patients are more likely to attend support groups. this was at least confirmed for cancer patients (20). seven participants had no partner. this is probably related to difficulties in sexual relationships and the pressure on intimacy. criteria for hypersexual disorder only five of the 10 participants met the criteria of kafka. for the others, the diagnosis was possible but not confirmed by the questionnaire. it is not sure that all participants should attend the support groups because the diagnosis of hypersexual disorder was not confirmed for all of them. before attending a support group the diagnosis of an underlying psychiatric or neurologic disorder should be excluded. otherwise precious time can be lost in a support group. the five participants not meeting the kafka criteria suffered from hypersexual disorder, mainly related to substance addiction. this is in line with the expected comorbidity. substance addiction would occur in 39 to 45% of the hypersexual disorder population. for these participants, one cannot exclude that the substance dependence is the primary disorder. the question is whether this criterion is necessary. dependence of substances and behaviors may have the same aetiology and pathogenesis, making a strict differential diagnosis unnecessary to be able to provide a proper treatment. the distribution of sexual activity in our study reflects relatively well the results from the literature. in the literature review masturbation (35 to 73%) and pornography (49 to 51%) were the leading activities, followed by sex with consenting adults (13 to 70%) (1, 5-7). masturbation and pornography were reported by all participants in our study. six participants had contacts with consenting adults. having cybersex, prostitution and visiting strip clubs were not reported in previous studies. respectively four and three participants of our study mentioned this. probably it is useful to add these common sexual activities in further research. only one participant reported phone sex. this low proportion corresponds with other studies were for example 1 in 36 participants reported phone sex (14). the other reported behaviors are not included in previous research. 179archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder tierens_stesura seveso 09/10/14 10:37 pagina 179 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 180 diagnosis only in three participants the diagnosis was made by a professional healthcare worker, which is regrettable. for the three cases this was a psychologist other healthcare professionals were not listed. in all other cases, the diagnoses were made by themselves, their partner or the support group. previous studies show that patients mainly seek help from psychiatrists, psychologists, lawyers or religious people (15). from the literature we know that the average age of onset of hypersexual disorder is 18 years (16). in our study, the average onset age is also 17.5 years and ranged between 4 and 24.5 years. it is remarkable that some participants show the first signs of the disorder at a very young age. a similar young age of onset was also described in patients with (other) obsessive-compulsive disorder (21). but most remarkable is that the diagnosis was on average only made 20 years after the onset of the problem. many have undergone a long ordeal before they received any help. more attention for the detection and diagnosis of such problems and the possible underlying psychiatric or neurological disorder is desirable in primary healthcare (22). treatment the strong involvement of the family physicians is striking. eight family physicians were informed about the diagnosis and in half of the cases they were involved in the treatment. sexologists can offer help mainly from the second year of treatment. four participants of our study were all already treated by a sexologist and often also by a psychologist. five participants were consulting a psychiatrist and received medication. all participants received – on top of the support group – also another treatment. nine participants received individual psychotherapy. this combination is the recommended treatment. none of the participants with a partner followed no relationship therapy. this is optionally recommended from the second year of treatment but the effectiveness is not documented. two other participants followed relationship therapy with a former partner. an online therapy is not discussed in the literature. only two of the ten patients received an ssri as it is recommended. ssri are the first choice drugs for hypersexual disorder (15, 17). other patients received atypical psychotics, neuroleptics and homeopathic preparations which are not recommended. however, there is almost no evidence for the treatment of hypersexual disorder. before the diagnosis of hypersexual disorder is made, any other underlying psychiatric and neurological disorder should be excluded. therefore, a consultation with a physician before the start of a treatment in a support group or with a psychologist or a sexologist is recommended. the participants were positive about their treatment. this finding is probably not representative, since most of the participants attended the support groups for a long time. they are more likely to continue the treatment and therefore are more satisfied. they indicated that the support groups had a considerable added value in their treatment. participants were generally satisfied about the psychologists, psychiatrists and sexologists. however, some participants were dissatisfied about them. weaknesses and future research the statistical significance of this research is very limited, due to the small number of participants. however, this research may contribute to the awareness of health care workers for hypersexual disorders. they should receive a training to firstly detect such patients and secondly to refer them for treatment. but primary health care workers also have the very import task to inform and follow-up these patients. the number of participants was limited for this research. the short inclusion period on the one hand and the inability to directly recruit subjects on the other hand probably played a major role. the number of questions in the survey was deliberately limited to facilitate parti cipation. the anonymity of the participants was absolutely guaranteed, according to their explicit desire. tendentious questions were avoided to prevent negative reactions and feelings. information about the presence of other psychiatric disorders and risky behavior would have been useful. more detailed questions on the third criterion of kafka were preferable. this would have allowed us to detect hypersexual behavior secondary on substance abuse. meanwhile, the american psychiatric association (apa) investigated whether or not hypersexual disorder should be included in the dsm-v. in april 2012, the kafka criteria were adapted again and finally included in chapter iii (= appendix) of the new dsm-v. criteria included in this chapter require more research and evidence. we cannot estimate how many of our participants would be diagnosed with the adapted criteria because question a was adapted and more detailed information on the third criterion, including manic episodes and general medical conditions are needed. further research to illuminate the cause, the diagnosis and the treatment of hypersexual disorder is needed. for future research, a qualitative methodology such as focus group research should be considered. conclusions it seems very difficult to motivate the members of anonymous support groups to participate in research. in our study, five out of the 10 participants met the criteria of kafka for hypersexual disorder. for the others the diagnosis was possible but not confirmed by the questionnaire. the method of diagnosis is far from optimal. this is certainly due to a lack of well-defined criteria for the diagnosis and validated diagnostic instruments. primary care workers should be sensitised to consider the diagnosis much faster. today, on average, it takes 20 years before a diagnosis is made. especially concerning the pharmacological treatment, there seems to exist a lot of uncertainty. at the moment, a combination of medication, support groups and individual psychotherapy is the recommended treatment. tierens_stesura seveso 09/10/14 10:37 pagina 180 181archivio italiano di urologia e andrologia 2014; 86, 3 diagnosis and treatment of participants of support groups for hypersexual disorder 1a. gender: ! man ! woman 1b. age: ________ in years 1c. ethnicity: ! caucasian ! negroid ! asian ! hispano american ! other: ____________________________ 1d. highest qualification attained: ! primary education or no diploma ! secondary education ! higher non-university education ! university 1e. sexual orientation: ! heterosexual ! homosexual or lesbian ! bisexual 1f. relationship status: ! in a relationship ! single 2.a0. i had for ________________ years_______________ months lots of sex, sexual fantasies and/or a great need for sex (approximate) 2.a1. the time i spent on sex, sexual fantasies and/or a great need for sex repeatedly brought other important (non sexual) goals, activities and commitments into question yes/no 2.a2. i repeatedly had lots of sex, sexual fantasies and/or a great need for sex in response to sadness, anxiety, depression, boredom or irritability yes/no 2.a3. i repeatedly had lots of sex, sexual fantasies and/or a great need for sex in response to stressful events yes/no 2.a4. i have repeatedly tried to control or reduce the amount of sex, sexual fantasies and/or a great need for sex, but failed yes/no 2.a5. i have repeatedly had sex while there was a risk that this would lead to physical or emotional harm for myself or others yes/no 2.b. my social life, hobbies or other important areas suffered from the frequency and intensity of sex, sexual fantasies and/or the need for sex yes/no 2.c. i was addicted to substances such as drugs, alcohol or medication in the period in which i had much sex, sexual fantasies and/or a great need for sex yes/no 2.s. my sexual activity took place primarily on the following areas: (multiple answers possible) ! masturbation ! pornography ! sex with consenting adults ! cybersex ! phone sex ! strip clubs ! other: ____________________________ 3a. my diagnosis was first made by: ! family physician ! psychologist ! sexologist ! psychiatrist ! other: ____________________________ ! in addition to the support group i have consulted no other care providers 3b. the diagnosis was made ______________________ years ___________________ months ago (approximately). 4c. i have a family physician yes/no 4c1. if so, my family physician is aware of my diagnosis yes/no 4d. i am/was treated by the following healthcare professional(s): (multiple answers possible) ! family physician ! psychologist ! sexologist ! psychiatrist ! other: ____________________________ ! in addition to the support group, i was treated by no one else 4e. my treatment consists/consisted, in addition to the support group, of: ! ambulatory individual psychotherapy ! ambulatory relational therapy ! ambulatory family therapy ! ambulatory group therapy other than the support group ! hospitalisation in a (psychiatric) hospital ! hospitalisation in a specialised institute ! online treatment ! other: ____________________________ 4f. my treatment includes medication yes/no 4f1. if so, which? _________________________ 4g. are you satisfied with the treatment you receive? ! not at all satisfied ! rather not satisfied ! not satisfied, not dissatisfied ! rather satisfied ! completely satisfied 4g1. why? ______________________________________________________ ______________________________________________________ ______________________________________________________ ______________________________________________________ questionnaire (translated from the dutch version). the questionnaire consists mainly of multiple choice and yes/no questions. you can always indicate an answer. if multiple answers are possible this is indicated. if none of the answers apply to you, please indicate the most appropriate answer. may i ask you to fill in the questionnaire completely. tierens_stesura seveso 09/10/14 10:37 pagina 181 archivio italiano di urologia e andrologia 2014; 86, 3 e. tierens, j. vansintejan, j. vandevoorde, d. devroey 182 12. winters j, christoff k, gorzalka b. dysregulated sexuality and high sexual desire: distinct constructs? arch sex behav. 2010; 39:1029-1043. 13. skegg k, nada-raja s, dickson n, paul c. percieved “out of control” sexual behavior in a cohort of young adults from the dunedin multidisciplinary health and development study. arch sex behav. 2010; 39:968-978. 14. black d, kehrberg l, flumerfelt d, schlosser s. characteristics of 36 subjects reporting compulsive sexual behavior. am j psychiatry 1997; 154:243-249. 15. guay d. drug treatment of paraphilic and nonparaphilic sexual disorders. clin ther. 2009; 31:1-31. 16. bird m. sexual addiction and marriage and family therapy: facilitating individual and relationship healing through couple therapy. j marital fam ther. 2006; 32:297-311. 17. bradford j. the neurobiology, neuropharmacology, and pharmacological treatment of the paraphilias and compulsive sexual behavior. can j psychiatry 2001; 46:26-34. 18. reid r, garos s, carpenter b. reliability, validity and psychometric development of the hypersexual behavior inventory in an outpatient sample of men. sexual addiction & compulsivity. 2011; 18:30-51. 19. miner m, coleman e, center b, ross m, rosser b. the compulsive sexual behavior inventory: psychometric properties. arch sex behav. 2007; 36:579-587. 20. bauman l, gervey r, siegel k. factors associated with cancer patients’ participation in support groups. j psychosoc oncol. 1992; 10:1-20. 21. lochner c, hemmings sm, kinnear cj, et al. cluster analysis of obsessive-compulsive spectrum disorders in patients with obsessivecompulsive disorder: clinical and genetic correlates. compr psychiatry. 2005; 46:14-19. 22. kaplan ms, krueger rb. diagnosis, assessment, and treatment of hypersexuality. j sex res. 2010; 47:181-198. acknowledgement the authors are grateful to david proot for the english editing and the participants of the support groups for the great cooperation and the fascinating conversations about their world. references 1. kafka m. hypersexual disorder: a proposed diagnosis for dsmv. arch sex behav. 2010; 39:377-400. 2. american psychiatric association. diagnostic and statistical manual of mental disorders, fourth edition. 1994: 538-621. 3. schneider j, irons r. assessment and treatment of addictive sexual disorders: relevance for chemical dependency relapse. subst use misuse. 2001; 36:1795-1820. 4. http://www.dsm5.org/proposedrevision/pages/proposedrevision. aspx?rid=415# 2012, march 2. dsm-v development. american psychiatric association. 5. mick t, hollander e. impulsive-compulsive sexual behavior. cns spectr. 2006; 11:944-955. 6. reid r, carpenter b. exploring relationships of psychopathology in hypersexual patients using the mmpi-2. j sex marital ther. 2009; 35:294-310. 7. dodge b, reece m, cole s, sandfort t. sexual compulsivity among heterosexual college students. j sex res. 2004; 41:343-350. 8. coleman e. is your patient suffering from compulsive sexual behavior? psychiatr ann. 1992; 22:320-325. 9. langström n, hanson k. high rates of sexual behavior in the general population: correlates and predictors. arch sex behav 2006; 35:37-52. 10. carnes p, schneider j. recognition and management of addictive sexual disorders: guide for the primary care clinician. lippincotts prim care pract. 2000; 4:302-318. 11. kelly b, bimbi d, nanin j, izienicki h, parsons j. sexual compulsivity and sexual behaviors among gay and bisexual men and lesbian and bisexual women. j sex res. 2009; 46:301-308. correspondence els tierens, md johan vansintejan, md jan vandevoorde, phd, md vrije universiteit brussel (vub), dept of family medicine laarbeeklaan 103, b-1090 brussels, belgium dirk devroey, phd, md (corresponding author) dirk.devroey@vub.ac.be vrije universiteit brussel (vub), head of the dept of family medicine laarbeeklaan 103, b-1090 brussels, belgium tierens_stesura seveso 09/10/14 10:37 pagina 182 stesura seveso introduction the international continence society defines urinary incontinence as the involuntary loss of urine per urethra that can be objectively demonstrated and that causes social or hygienic problems (1, 2) and affects the psychological, social and sexual life of the patient (3). in spain the prevalence of urinary incontinence in persons older than 60 years was 40% in 2003. others reported a 35.1% prevalence of incontinence in persons older than 64 years of age, namely 23% in women older than 18 149archivio italiano di urologia e andrologia 2013; 85, 3 original paper results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized bárbara padilla-fernández 1, maria begoña garcía-cenador 2, ana gómez-garcía 3, josé antonio mirón-canelo 4, ángel gil-vicente 1, juan miguel silva-abuín 1, maría fernanda lorenzo-gómez 1 1 department of urology. university hospital of salamanca; 2 department of surgery, university of salamanca; 3 family and community medicine. university hospital of salamanca; 4 department of preventive medicine and public health, university of salamanca. objectives: to analyze the short and long term results of tapes of different materials used to treat stress urinary incontinence (sui). a secondary objective was to evaluate the ability to adjust the tape after implantation. materials and methods: retrospective chart review of 355 patients with sui operated between march 2003 and october 2011. eight different types of transobturator tapes were used: gynecare tvt-o®, monarc®, safyre®, contasure kim®, i-stop®, dynamesh®, aris® bandellete and swing-band®. results and complications were recorded. results: the mean age at operation was 61 years. correction of sui was achieved in 87.88% of cases. the best results were obtained with contasure kim® (98.26 % continence). the tape was well tolerated and was elastic enough to be able to be adjusted 48-72 hours after implantation without deformation. slings with macropores and over lock stiches on the superior and inferior borders presented the lower rates of postoperative urinary retention, pain, perior postoperative bleeding and urinary tract infections. conclusions: transobturator tension free tapes require a short operation time and have a low complication rate. the possibility of adjustment in the early postoperative period increases the success rate and reduces complications. knotless meshes with macropores and over lock stiches appear to be better balanced, are quite resistant to stretching and deformation when readjusted after implantation and present a low infection rate. key words: urinary tract; polypropylene; suburethral transobturator tape; physical characteristics. submitted 24 june 2013; accepted 30 june 2013 no conflict of interest declared summary years of age, 20% in women of working age and 14% among women between 40 and 64 years of age (4, 5). the surgical treatment of stress urinary incontinence (sui) in females has changed over time. delancey pointed out the importance of the suburethral sector in any successful surgical strategy for sui (6). in 2001, delorme reported the transobturator approach (tot) which consists of placing a mesh through the obturator foramen behind the mid-urethra (7). doi: 10.4081/aiua.2013.3.149 archivio italiano di urologia e andrologia 2013; 85, 3 b. padilla-fernández, m. begoña garcía-cenador, a. gómez-garcía, j.a. mirón-canelo, á. gil-vicente, j.m. silva-abuín, m.f. lorenzo-gómez 150 there is a multitude of products available for the correction of sui. previous studies have focused on the durability and resistance of the materials but few have addressed clinical results in the short and long term for the various types of tapes available. the goals of our study were to analyze the results obtained with different meshes of various types of materials. materials and methods we conducted a retrospective, multicentric study in a cohort of 363 patients with sui who underwent tot implantation between march 2003 and october 2011 at the university hospital of salamanca and the hospital santísima trinidad of salamanca. a standard study protocol which consisted of anamnesis, general and uro-gynecological physical examination, the iciq-sf incontinence questionnaire (6) and the king’s health or sf36 quality of life tests (7, 8). routine laboratory tests, urine culture and renal and bladder ultrasonography were performed as well. cystography, urodynamic studies, urine cytology and cystoscopy were performed when indicated according to standard practice. surgical procedure: all procedures were performed in a short stay unit with 1 night of hospitalization under spinal anesthesia and under antibiotic coverage. the patient was placed in the dorsal lithotomy position with hyperabducted thighs. a 16 ch balloon catheter with 20 ml in the balloon was inserted in the bladder. extensive hydrodissection between the anterior vaginal wall and the urethra was done. the specially designed fine atraumatic needles were introduced from outside in (figure 1). the tape was attached to the needle and the tape was passed from inside out (figure 2). a vaginal pack was left in place for 12-24 hours. forty-eight to 72 hours later, a revision was performed to evaluate the adjustment of the tape. postoperative controls were performed at one month and one year with anamnesis, and repeat iciq/sf and kings health or sf-36 questionnaires. we compared the results according to the 8 different types of tape utilized. • gynecare tvt-o® (ethicon): polypropylene mesh with macro pores. low density woven mesh (60% porosity). • monarc® (ams): polypropylene mesh with 1 mm diameter macro pores. low density woven mesh (46% porosity). it has acceptable elasticity. • safyre® (promedon) (6): monofilament polypropylene mesh with selfretaining columns of polydimethylsiloxane-polymer . • contasure kim® (neomedic international): knotless monofilament polypropylene tape with over lock stitches in the superior and inferior borders as well as in the middle of the tape. • i-stop® (cl medical): polypropylene mesh with macro pores with spiral borders to maintain rigidity, allow fibrosis and minimize the risk of erosion and migration. • dynamesh® (feg textiltechnik): mesh made of monofilament polyvinylidene fluoride with smooth atraumatic edges. • aris® bandelette (coloplast): woven monofilament polypropylene mesh with macropores. • swing-band® (tht bioscience): light or ultra-light monofilament polypropylene tapes with pores 0.7 to 1.5 cm with low elasticity. we recorded effectiveness and complications taking into account not only continence but overall wellbeing of the patients. complications included lesions to other organs, hemorrhage, hematoma formation, urinary retention, and the development of new urinary incontinence. the data were recorded in an excel® worksheet and imported to ncss® for statistical analysis. fisher exact test, wilcoxon non-parametric test for 2 samples, friedman non-parametric test for more than 2 samples, student’s t-test and pearson chi-square test were used. figure 1. introduction of the fine atraumatic needle from outside-in. figure 2. suburethral tape passed through both obturator foramina. results we implanted tot on 355 women with sui. the median age was 61.16 years (range 41-81 years). incontinence was corrected in 87.88 % of the patients, the rest remained incontinent. the past medical and surgical histories and concomitant treatments were not different among the 8 groups. monarc® tape was used in 42 patients, safyre® in 44, gynecare® in 47, kim system® in 173, i-stop® in 20, dinamesh® in 11, aris® in 4 and swing-band® in 4 (figure 3). contasure kim® presented the best success rate. 98.26% of the women were continent after the operation and tolerated the procedure well. the tape was elastic enough to allow adjustment without deformation (table 1). the success rate with monarch® tapes was overall good (90.47%); however, this tape was inadequate when adjustments were needed because it became elongated and deformed when applying tension. in 4 of the 44 patients who underwent implantation of safyre® tape the retention column became detached from the mesh resulting in incontinence. there was local discomfort and the patients required local anesthesia for the adjustment. the success rate for gynecare® tapes was 82.45%. the tape could be adjusted without deformation. six of 47 women had acute urinary retention which, when corrected, led to permanent urinary incontinence. i-stop®, dynamesh®, aris® and swing-band® tapes had success rates less than 80%, were not malleable and could not be adjusted after implantation. as a group they were less well tolerated and presented a greater rate of urinary retention. tapes with overlock stiches on the superior and inferior edges caused lower rates of postoperative urinary retention (p = 0.0013), patients had less pain (p = 0.0023), intra or post-operative bleeding (p = 0.00013) and urinary tract infections (p = 0.0045). these tapes also allowed postoperative adjustment. tapes made of material with macropores and without knots appear to be better balanced, are highly resistant to deformation allowing a correct and effective postoperative adjustment. 151archivio italiano di urologia e andrologia 2013; 85, 3 results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized figure 3. suburethral tapes used. tape success failure comments n = 319 n = 44 n % n % •monarc® 38 90.47 4 9.53 well tolerated. cannot be adjusted because it deforms and elongates. •safyre® 30 68.18 14 31.82 more local discomfort. 4 failures from dissociation of the silicon columns •gynecare® 47 82.45 10 17.55 6 urinary retentions. 4 urinary incontinences. •kim system® 170 98.26 3 1.74 no urinary retention. 3 urinary incontinences. elasticity sufficient to allow adjustment without deformation. well tolerated. •i-stop® 14 70 6 30 4 urinary retention. 2 urinary incontinences. •dynamesh-sis direct: 8 72.72 3 27.27 inelastic. cannot be adjusted. well tolerated. polyvinylidene fluoride (pvdf)® 1 urinary retention. •coloplast bandelette aris® 3 75 1 25 dense, inelastic. cannot be adjusted. •tht swing-band® 3 75 1 25 suburethral with less material to anchor to the fascia. table 1. success rate, complications and tolerability associated to the type of mesh used. archivio italiano di urologia e andrologia 2013; 85, 3 b. padilla-fernández, m. begoña garcía-cenador, a. gómez-garcía, j.a. mirón-canelo, á. gil-vicente, j.m. silva-abuín, m.f. lorenzo-gómez 152 discussion the use of biomaterials in urology is extensive ranging from suture and ligature materials to the use of ureteral and urethral catheters to drain fluids. within this spectrum are the meshes used to correct sui which act as permanent prostheses implanted at the level of the midurethra. the meshes used for this purpose must be biocompatible fulfilling the following conditions (7): • should not induce an inflammatory reaction since both an exaggerated inflammatory reaction and the presence of dead spaces between the mesh and surrounding tissues increase the risk of seroma formation. this is the case when the mesh is slowly or not incorporated into the surrounding tissues such as is the case with meshes with micropores or of high density. (8, 9). • should not induce an allergic reaction since this will lead to rejection and extrusion of the prosthesis (10). • should not induce tumor formation. experimental studies in rats have shown that type 1 meshes induce the development of a surrounding fibrous capsule which becomes integrated from top to bottom through the pores and small spaces between the monofilaments thus producing a firm anchoring to the surrounding tissues (11). this peripheral capsule allows future identification and removal of the tape when necessary. the integration of the capsule on the center decreases mechanical irritation and the chances of extrusion. this encapsulation also facilitates a better blood supply which might lead to less chances of infection (11). meshes with small pores and without structural homogeneity generate a greater local inflammatory reaction and less collagen synthesis. these meshes induce a foreign body reaction rather than fibrosis with the above mentioned consequences (12, 13). moalli et al. (14) studied 5 commonly used meshes in the usa for the correction of siu by the tvt method. the meshes were subjected to traction and elongation to test their resistance and hardness. this study showed that gynecare® and monarc® were easily deformed with low loads which would be clinically manifested by elongation and deformation with minimal tensions. the elongation caused by cyclic loads (such as coughing) might be irreversible. on the other hand, these features lessen the probability of erosion or migration and might reduce the risk of urinary retention (14). the same authors remark that the gynecare® mesh has an initial region of low hardness which allows the mesh to elongate easily in response to small tensions. this is followed by a transition zone and an area that is very hard. they stated that the mesh increases more than 10% of the usual length in response to a series of cyclical loads (14). nevertheless, neymeyer et al. (15) reported that the gynecare® tape presents better tolerance to tension and less elongation, that is better integrated despite loads or tension. mascarenhas studied in depth the mechanical features of the tapes used to treat sui and the mechanical properties of the pelvic floor during delivery and in genital prolapse (16). her intention was to improve the biomechanical analysis of the pelvic floor tissues and improve understanding of the etiology of pelvic floor dysfunction that leads to the development of meshes and prosthesis. this requires interdisciplinary collaboration including engineers and clinicians (16). studies have found significant differences between aris® and gynecare® in regards to hardness tested both by tension and compression (17). others have analyzed the thermal and structural differences of meshes that could in theory influence the development of urethral and vaginal erosions and extrusion. using calorimetric scanning, infrared spectroscopy and analyzing the geometry and lineal and relative densities it was concluded that there is a direct correlation between the diameter of the fibers, the linear density, the degree of crystallinity, the resistance to flexion and the mechanical properties of the tapes (18). the ability of tapes to be adjusted postoperatively appears to be related to the resistance and elasticity which are determined by the porosity, density, type of material used to manufacture the tapes as well as the manner in which the filaments are knitted and the interaction with the host. overlock stiches at the edges of the mesh confers resistance without decreasing elasticity and malleability. in such tapes elongation in response to tension is less both under physiologic conditions and during adjustments. one must be reminded of the fundamental role of careful patient selection, the investigation of risk factors and the selection of a tape with which the surgeon feels comfortable to achieve a successful correction of sui (19, 20). the weakness of our study lies in its retrospective nature and the scant number of patients in some groups. conclusions surgical correction of sui with transobturator tape (tot) is the procedure of choice because of a shorter surgical time and a lower complications rate compared with retropubic tension free tapes (tvt). with this technique, the possibility of adjustment in the early postoperative period increases the chances of cure and reduces complications. macropore meshes without knots and over lock stitches seem to be better balanced, are resistant to elongation and deformation when subjected to the necessary tension for postoperative adjustment. they also present a low rate of infection. references 1. abrahams p, blaivas j, stanton s. the standarization of terminology of lower urinary tract function. scan j urol nephrol 1988; 114-5. 2. international-continence-society. standardization of terminology of lower urinary tract function. urol. 1977; 9:237. 3. serrano r. el 90% de las iu de esfuerzo se evitan con medidas preventivas. madrid: recoletos.es; 2003 [cited 2003 21-10-2003]; http://www.diariomedico.com/edicion/noticia/0,2458,404697,00.html] 4. médico-interactivo-diario-electrónico-de-la-sanidad. más de 800.000 españoles sufren incontinencia urinaria. madrid: meditex, s.l; 2003 [cited 2003]; nº 892, del 10 de enero de 2003 5. norton p, macdonald l, sedgwick p, stanton s. distress and delay associated with urinary incontinence, frequency, and urgency in women. br med j. 1988; 297:1187-9. 6. palma p, riccetto c, herrmann v, et al. transobturator safyre sling is as effective as the transvaginal procedure. int urogynecol j. 2005; 16:487-91. 7. galmés belmonte i, díaz gómez e. ¿son iguales todos los sistemas empleados para corregir la incontinencia urinaria mediante mallas libres de tensión? actas urológicas españolas. 2004; 28:487-96. 8. cervigni m, natale f. the use of synthetics in the treatment of pelvic organ prolapse. curr opin urol. 2001; 11:429-35. 9. falconer c, soderberg m, blomgren b, ulmsten u. influence of different sling materials on connective tissue metabolism in stress urinary incontinent women. int urogynecol j pelvic floor dysfunct. 2001; 12(suppl 2):s19-s23. 10. debodinance p, delporte p, engrand j, boulogne m. development of better tolerated prosthetic materials: applications in gynecological surgery. j gynecol obstet biol reprod. 2002; 31:527-40. 11. slack m, sandhu j, staskin d, grant r. in vivo comparison of suburethral sling materials. int urogynecol j. 2006; 17:106-10. 12. white r. the effect of porosity and biomaterial on the healing and long-term mechanical properties of vascular prostheses. trans am soc artif intern organs. 1988; 34:95-100. 13. white r, hirose f, sproat r, et al. histopathologic observations after short-term implantation of two porous elastomers in dogs. biomaterials. 1981; 2:171-6. 14. moalli pa, papas n, menefee s, et al. tensile properties of five common used mid-urethral slings relative to the tvttm. int urogynecol j. 2008; 19:655-63. 15. neymeyer jn, abdul-wahab waw, spethmann js, et al. material laboratory testing of suburethral mesh slings: a comparison of their static and dynamic properties. eur urol suppl. 2008; 7:316. 16. da silva-filho a, martins p, parente m, et al. translation of biomechanics research to urogynecology. arch gynecol obstet. 2010; 282:149-55. 17. afonso j, martins p, girao m, et al. mechanical properties of polypropylene mesh used in pelvic floor repair. int urogynecol j pelvic floor dysfunct. 2008; 19:375-80 18. afonso j, jorge r, martins p, et al. structural and thermal properties of polypropylene mesh used in treatment of stress urinary incontinence. acta bioeng biomech. 2009; 11:3. 19. lorenzo gómez mf, gómez garcía a, padilla fernández b, et al. factores de riesgo de fracaso de la corrección de la incontinencia urinaria de esfuerzo mediante cinta suburetral transobturatriz. actas urol esp. 2011; 35:454-8. 20. díez-calzadilla na, march-villalba ja, ferrandis c, et al. factores de riesgo en el fracaso de la reparación quirúrgica del prolapso de suelo pelviano. actas urol esp. 2011; 35:448-53. 153archivio italiano di urologia e andrologia 2013; 85, 3 results of the surgical correction of urinary stress incontinence according to the type of transobturator tape utilized correspondence bárbara padilla-fernández, phd, md (corresponding author) padillaf83@hotmail.com juan miguel silva-abuín, phd, md elviso@usal.es ángel gil-vicente, md mflorenzogo@yahoo.es maría fernanda lorenzo-gómez, phd, md mflorenzogo@yahoo.es department of urology, university hospital of salamanca paseo de san vicente, 58-182 37007 salamanca, spain maría begoña garcía-cenador, phd, biol mbgc@usal.es department of surgery, university of salamanca 37007 salamanca, spain ana gómez-garcía, phd, md agogarci@hotmail.com family and community medicine, university hospital of salamanca 37007 salamanca, spain josé antonio mirón-canelo, phd, md miroxx@usal.es department of preventive medicine and public health university of salamanca campus miguel de unamuno faculty of medicine c/ alfonso x el sabio, s/n 37007 salamanca, spain stesura seveso 181archivio italiano di urologia e andrologia 2015; 87, 2 letter to editors about: rare case of intra-testicular adenomatoid tumour dear editors, we read with interest the article by migliorini et al. (1). the authors reported a case of adenomatoid tumor of the testis with intratesticular growth describing the ultrasound, gross and pathologic characteristics of this entity. they reported only ten cases previously described in scientific literature. from this publication, at the time of writing, pub med research conducted employing a key word “adenomatoid tumor testis” revealed two more cases (2) managed with limited testicular excision. we think that this pathological and clinical entity will come increasingly frequent thanks to greater awareness of the problem by clinicians and pathologists because of continuous signals. in december 2013 we managed a similar clinical condition in a 60 years old caucasian patient presented at emergency department (er) complaining a recurrent right testicular pain poorly responsive to simple analgesics. ultrasound evaluation conducted by ra diologist at er was unremarkable. we performed a scrotal ultrasound assessment again because of presence of a strongly painful small no dular mass on palpation of the right scrotum. the ultrasound revealed a nodular image with well-defined homogeneous limits, homogeneous hyperechoic echostructure and poorly capturing color signal. lesion diameter was 8,8 mm (fi gu res 1a-1b). we prescribed a second level analgesic therapy (tramadol 100 mg) and the measurement of testicular tumor markers. a week later, the patient came to our attention again for a persisting of pain, poorly responsive to therapy prescribed. tumor markers was negative. in agreement with the patient, we decided to perform a right testicular inguinal exploration. the surgery was performed under spinal anesthesia. the operation confirmed the presence of a solid capsulated nodular lesion of right testicular lower pole. we proceeded with enucleation of the nodule that was sent to the pathologic department for frozen section examination (fse). the pathologist, taking into consideration the clinical information and the ultrasonographic appearance, suggested the benign nature of the lesion. resection margins was free. the size of the lump and the absence of border infiltration addressed towards a testis sparing surgery (tss). surgical defect was sutured and the testicle was placed back into the scrotum. definitive histological examination deposed for adenomatoid testis tumor. the painful symptoms declined. the patient was discharged in the second post operative day and three week later we performed an ultrasound control (figure 2). with respect to the case reported by migliorini et al., there are several differences. first of all, patient's age was in our case higher than age reported in most of the recent report. in literature, the patients with an adenomatoid scrotal lesion ranged between 18 and 79 years (3). the sonographic appearance was hyperechoic and homogeneous, as previously experienced by one of the writers (af) (4) and so as described in the literature. although they may also be hypoechoic (5). last, the surgical management in our case consisted in a tss. we would argue as well as in the specific case reported by migliorini et al., it could be possible a conservative management, regardless of the ability of the pathologist to provide a diagnosis of malignancy in fse, considering that the nodule dimensions was less than 1 cm and that the deferred surgical radical treatment did not compromise the oncological control of the disease (6). we think that the information provided to the pathologist about the sonographic appearance of the lesion, clinical presentation and the negativity of cancer markers are almost certainly aimed at the benignity of the diagnosis. the case described by migliorini et al. and our experience must warn the urologists involved in the andrological field regarding the possibility of coming across this type of diagnosis. it required close clinical collaboration with the pathologist so as to minimize the invasiveness of surgical therapy to avoid a surgical overtreatment. doi: 10.4081/aiua.2015.2.181 figure 1a-b. nodular image of the right testis with well-defined homogeneous limits, homogeneous hyperechoic echostructure and poorly capturing color signal. lesion diameter was 8.8 mm. a. b. figure 2. ultrasound control after three weeks from testicular sparing surgery. no conflict of interest declared. fabianiletter_stesura seveso 02/07/15 11:42 pagina 181 archivio italiano di urologia e andrologia 2015; 87, 2 a. fabiani, v. maurelli, a. filosa, f. fioretti, g. mammana 182 references 1. migliorini f, baldassarre r, artibani w, et al rare case of intra-testicular adenomatoid tumour. arch ital urol androl. 2014; 86:44-5. 2. chen d, yu z, ni l, et al adenomatoid tumors of the testis: a report of two cases and review of the literature. oncol lett. 2014; 7:1718-20. 3. chiong e, tan kb, siew e, et al. uncommon benign intrascrotal tumours. ann acad med singapore 2004; 33:305-10. 4. polito m, giannubilo w, galosi ab, et al. adenomatoid tumour of epididymis mimicking a testis tumour: two case reports italian journal of sexual and reproductive. medicine. 2007; 14:147-15. 5. kolgesiz ai, kantarci f, kadioglu a, et al. adenomatoid tumor of the tunica vaginalis testis: a special maneuver in diagnosis by ultrasonography. j ultrasound med. 2003; 22:303-5. 6. passman c, urban d, klemm k, et al testicular lesions other than germ cell tumours: feasibility of testis-sparing surgery. bju int. 2009; 103:488-91. andrea fabiani 1, valentina maurelli 1, alessandra filosa 2, fabrizio fioretti 1, gabriele mammana 1 1 surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy 2 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy correspondence andrea fabiani, md andreadoc1@libero.it valentina maurelli, md valentinamaurelli@hotmail.it fabrizio fioretti, md phd fa.fioretti@libero.it gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3 macerata hospital, macerata, italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology area vasta 3, asur marche, macerata hospital, macerata, italy fabianiletter_stesura seveso 02/07/15 11:42 pagina 182 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4286 original paper a new approach in ureteral access sheath locating in retrograde intrarenal surgery (rirs) by endovisional technique mehmet giray sönmez, cengiz kara department of urology, medical park ankara hospital, ankara, turkey. objective: to compare the results of patients who underwent retrograde intrarenal surgery (rirs) using endovisional technique for ureteral sheat locating with control group in which endovisional technique was not applied. material and methods: of the 41 patients who underwent rirs treatment for kidney stone, between march 2014august 2015, 19 patients treated with endovisional technique formed the study group and remaining 22 patients formed the control group. patients were evaluated for age and gender, baseline and post procedural creatinine level, duration of operation, fluoroscopy and hospitalization time, size and localization of the stone, presence of multiple stones, previous shock wave lithotripsy (swl) procedure, double j catheter requirement, complication rate, residual stone rate and absence of stone ratio. results: there was no statistically significant difference between age, gender, location of the stone, previous swl procedure, presence of multiple stones, baseline and postprocedural creatinine level, absence of stone ratio, double j catheter requirement and hospitalization duration between the groups. the duration of operation and fluoroscopy of the patients were significantly shorter than the control group (p = 0.036 and p < 0.001, respectively). the complication rates of the endovisional technique group was significantly lower than that of the control group (p = 0.032). conclusion: endovisional technique is considered to be an appropriate and useful technique in order to locate the sheath safely in patients who has difficulty in ureteral access sheath locating and to decrease the duration of operation and fluoroscopy. key words: kidney stone; laser lithotripsy; retrograde intrarenal surgery (rirs); flexible ureterorenoscopy; endovisional technique. submitted 2 december; accepted 15 december summary no conflict of interest declared. a new era started after the use for the first time of rigid ureterorenoscopy and ultrasonic lithotripter for kidney pelvic stone by huffman et al. in 1983 and usage of this surgery increased progressively (1). after development of new generation flexible ureterorenoscopes (f-urs) and active and safe lithotripters, retrograde intrarenal surgery became an important alternative to surgical stone treatment. the aim of kidney stone treatment is to provide the least morbidity and achieve no stone state. for this reason, according to european association of urology guidelines, rirs and swl were suggested as the first choice in the treatment of kidney stones smaller than 2 cm. rirs is used as the primary treatment in kidney stones in which swl treatment was unsuccessful and in patients who have stones under 2 cm or muscle-skeletal deformities or bleeding diathesis or who are obese (2, 3). routine use of ureteral access sheath during rirs is still under discussion. advantages of using ureteral access sheath are making ureteroscope access easier, decreasing kidney inner pressure and increasing the excretion of stone fragments and the visual quality during operation (4, 5). there are studies with different views which state that ureteral access sheath increases the stone free rate and conversely that use of access sheath doesn't affect stone clearance (6, 7). the disadvantage of using ureteral access sheath is potential ureteral injury related to the dimensions (8). yet the routine usage is recommended in literature as it decreases operation time and costs and is associated with very low morbidity when used during rirs. in our clinic, rirs operations are made by using ureteral access sheath. sometimes even in young patients, the sheath cannot pass the prostate and the bladder neck causing prostatic urethra and bladder neck injuries and serious urethrorrhagia. again during the operation, long term erections which may take place in male patients make the operation more difficult. these experiences made us to search for a different technique for placement ureteral access sheath. our aim in this article was to describe the surgical technique we used (endovisional technique) and our findings in patients we applied this technique. doi: 10.4081/aiua.2015.4.286 introduction as the result of developments in urinary stone disease treatment, kidney stones which could only be treated by open surgery before can be treated with minimal invasive methods such as percutaneous nephrolithototomy (pnl), retrograde intrarenal surgery (rirs), shock wave lithotripsy (swl) and laparoscopic stone surgery. 287archivio italiano di urologia e andrologia 2015; 87, 4 retrograde intrarenal surgery (rirs) and endovisional technique material and methods of the 41 patients who underwent rirs treatment for kidney stone, between march 2014-august 2015, 19 patients were treated with the endovisional technique forming the study group and the remaining 22 patients formed the control group. patients were evaluated for age and gender, baseline and post procedural creatinine level, duration of operation, fluoroscopy and hospitalization, size and localization of the stone, presence of multiple stones, previous swl procedure, double j catheter requirement, complication rate, residual stone rate and stone free rate. semirigid ureterorenoscopy was always performed before rirs in order to evaluate possible ureter pathologies in all patients. ureteral access sheath was placed in the control group under fluoroscopic control whereas ureteral access sheath was placed in yhe other patients with the endovisional technique. lithotripsy with holmium laser was used to fragment the stones. patient evaluation in the postoperative first month was made with ultrasonography (usg) and direct urinary system x-graphy (dusg). absence of residual stone fragments over 4 mm was considered as a success. our complications were classified in accordance with the modified clavien system. age, creatinine level before and after the operation, size of the stone, duration of operation, fluoroscopy and hospitalization were statistically compared between groups with mann-whitney u and gender, stone localization, presence of multiple stones, previous swl procedure, residual stone occurence rate, complication rate, double j catheter requirement and stone free rate with pearson chi-square. a p < 0.05 value was accepted as statistically significant. statistical evaluation of data was made using spss 15 for windows. surgical technique general anesthesia was preferred in all patients, because the patient can feel pain and variable breathing movements cannot be prevented under regional anesthesia and undesired traumas may develop if the patient is less relaxed the operation was made in dorsal lithotomy position as standard. ureter was dilated up to the proximal tract by entering with 8 f semi-rigid ureterorenoscope before rirs. after that, an hydrophilic guide wire was placed with the help of semi-rigid ureteroscope under fluoroscopy. as ureteral access sheath, a 10/12 f 45 cm sheath was generally preferred. the end of the sheath was cut about 3 cm with straight borders without any burrs and ridges using a scalpel in consideration of the length of the ureteroscope (43 cm) so that it would be 1 cm outside the sheath. after that, the sheath was positioned on the 8 f semi-rigid scope and located by endoscopic guidance (figure 1). fluoroscopic imaging was used to evaluate the ureter from outside during its placement (figure 2). after that a 7.5 f flexible ureterorenoscope was passed inside the sheath (karl storz flex x2, germany) and the kidney was reached. the stones were broken by holmium laser lithotripter and big fragments were extracted with a nitinol basket. a month later, patients were evaluated for stones by dusg and usg. fragments under 4 mm were considered unimportant. results there was no statistically significant difference between age, gender, location of the stone, previous swl procedure, presence of multiple stones, baseline and postprocedural creatinine level, absence of stone ratio, double j catheter requirement and hospitalization duration between the groups. duration of operation was 82.6 ± 9.8 (49.2-125.6) minute (min) in the endovisional technique group and 106.8 ± 11.4 ( 57.8-162.4) min. in the control group. duration of fluoroscopy was 20.1 ± 6.7 (8.7-32.4) second (sec) in the endovisional technique group and 42.3 ± 9.2 (16.7-65.6) sec. in the control group. duration of operation and fluoroscopy was significantly shorter in the endovisional group compared to the control group. (p = 0.036, p < 0.001, respectively). major complication did not develop in any of the patients. clavien grade 1-2 complications developed in 5 patients in endovisional technique group (26.3%) and in 9 patients in the control group (40.9%). complication rate demonstrated was significantly reduced in the study group compared to the control group (p = 0.032). a double-j catheter was located in order to prevent mucosal edema and make easier the passage of small stone fragments (31.5% in the study group and 31.8% in the control group). no difference figure 1. image of the ureteral access sheath placed on the ureteroscope. figure 2. placement of the ureteral access sheath by endovisional technique. archivio italiano di urologia e andrologia 2015; 87, 4 mehmet giray sönmez, cengiz kara 288 was observed between the groups in the need for double-j catheter (p = 0,591). a significant postoperative creatinine increase was not observed in each of the two groups. all patients were evaluated with ultrasonography and direct urinary system graphy (dusg) in the 1st month control. stones of 4 mm or smaller were considered as clinically insignificant. stone free rate was assessed in 84.2% in the study group and 81.8% in the control group. (p = 0.392). data of procedures and patients are summarized in table 1. discussion routine use of ureteral access sheath during f-urs is still under discussion. use of the ureteral access sheath has many advantages such as making ureteroscope access easier, decreasing kidney inner pressure and increasing the excretion of stone fragments and the visual quality during the operation (4, 5). ureteral access sheath atraumatically dilates the distal ureter and make recurrent ureter entrances and exits easier (9). takayasu and aso used teflon tube along the ureter in 1974 for the first time (10). newman et al. introduced the first ureteral access sheath providing the initial basis of ureteral access sheaths used today through progressive refinements (11, 12). on the other hand it was claimed that ureteral access sheath use prevented the breaking and damaging of ureteroscope and prolonged its life (9, 13). the disadvantage of using ureteral access sheath is potential ureteral injury related to the dimensions. traxer et al. stated in their prospective study that ureteral access sheaths may cause injuries of the ureteral wall (8). if ureteral access sheath placement is not made under direct vision, presence of pathologies such as a stone or a tumor in distal and mid ureter may be overlooked. it is reported that ureteral access sheath usage may cause preoperative and postoperative complications such as ureter perforation, mucosal damage, urine extravasation and ureteral narrowing (14-16). ureteral integrity damages occurred during the placement of ureteral access sheath consist of 50% of iatrogenic injuries (8). using of ureteral sheath in our clinic, we observed that the sheath sometimes couldn't pass the prostatic urethra and the bladder neck even in young patients and that it could cause injuries in prostatic ureter and bladder neck. in some patients we observed that even under general anesthesia, long term penile erections took place due to the irritation and trauma. this condition makes placement of the sheath over the guide much difficult. for this reason we searched for a different technique for safe placement of the ureteral access sheath. ureteral access sheath is located in ureter over the guide as a routine (17). too much force could be applied in this technique and this may cause damage and the formation of fake paths in the ureter and even ureter perforation. the complication rates of the endovisional technique group was significantly lower than that of the control group (p = 0,032). when the ureteral access sheath is located under direct view, pathologies present inside the ureter can be evaluated and passed easily and the sheath can be advanced in narrow passages at level of the prostatic urethra and ureteral orifices. furthermore the pressure applied to the ureter can be adjusted. consequently the operation and fluoroscopy time are shortened and the ureteral access sheath is located more safely and quickly. average operation time was measured as 82.6 minutes in endovisional technique group and fluoroscopy time as 20.1 sec. the endovisional technique group n = 19 control group n = 22 p value age 46.2 ± 8,1 (22-71) 43,4 ± 8,7 (20-67) p = 0,386 sex 8w/11m (42,1/%57,8%) 10w/12m (45,4/%54,5%) p = 0,318/p = 0,421 stone size (mm) 10,3 ± 1,7 (7,2-15,4) 10,8 ± 1,9 (6,9-14,7) p = 0,173 right-left 11/8 (57,8-42,1%) 11/11 (50/50%) p = 0,09/p = 0,07 lower calyx 11 (57,8%) 13 (59,1%) p = 0,218 renal pelvis 5 (26,3%) 6 (27,2%) p = 0,329 medium calyx 3 (15,7%) 3 (13,6%) p = 0,167 multiple stones 5 (26,3%) 4 (18,1) p = 0,146 previous swl procedure 7 (36,8%) 8 (36,3%) p = 0,514 preoperative average creatinine (mg/dl) 0,63 ± 0,07 0,81 ± 0,06 p = 0,09 postoperative average creatinine (mg/dl) 0,86 ± 0,08 0,94 ± 0,07 p = 0,131 duration of operation (min) 82,6 ± 9,8 (49,2-125,6) 106,8 ± 11,4 ( 57,8-162,4) p = 0,036 duration of fluoroscopy (sec) 20,1 ± 6,7 (8,7-32,4) 42,3 ± 9,2 (16,7-65,6) p < 0,001 grade 1, 2 complication according to modified clavien system 5 (26,3%) 9 (40,9%) p = 0,032 grade 3, 4, 5 complication according to modified clavien system 0 0 duration of hospitalization (hours) 21,4 (13,3-49,2) 25,2 (16,8-52,4) p = 0,413 double j catheter requirement 6 (31,5%) 7 (31,8%) p = 0,591 stone free rate 16 (84,2% ) 18 (81,8%) p = 0,392 table 1. surgery related and postoperative findings n = 41 (19/22). 289archivio italiano di urologia e andrologia 2015; 87, 4 retrograde intrarenal surgery (rirs) and endovisional technique duration of fluoroscopy and operation were significantly shorter compared to the control group (p < 0.001, p = 0.036 respectively). in two different recent studies about the use of ureteral access sheath, the fluoroscopy time was measured as 39 and 52.72 sec (18, 19). this figures demonstrates that the endovisional technique significantly shortens fluoroscopy time. stone free rate in all studies published recently range 79%-100% (6, 20-22). this rate is similar to that observed in our study too (84.2%), although no significant difference was observed in comparison to the control group (p = 0.392). wu et al. suggested that at the end of the operation, a double-j catheter should be put in all patients after ureteral access sheath application (23). in absence of trauma and when no residual stone was present, it was reported that stent was not needed and that no complication was observed (24, 25). rapoport et al. suggested stent application in their study of 161 patients (26). ozyuvalı et al. stated that the stent application increased the operation time and morbidity (18). in order to make the reduce mucosal edema and facilitate small stone fragment passage, we located a double-j catheter in six patients (31.5%) who had endovisional technique operation and in 7 patients in the control group (31.8%). when compared with literature and the control group, there was no increase in our double-j catheter location rate after endovisional technique (p = 0.591). we preferred general anesthesia in all our patients in order to provide better patient relaxation and to prevent variable breathing movements. unwanted preoperative complications such as ureter perforation (0.6%), mucosal damage (2-20%) and urine extravasation may happen in rirs. uretral narrowing may be observed in a 0.5% ratio preoperatively (8, 22, 27, 28). serious mucosal damage or ureter injury or bleeding affecting visual quality were not observed in any of the patients in which this technique was used. postoperative urine extravasation and ureteral narrowing was never detected. in this study it was also observed that ureteral edema and mucosal damage was less frequent and that bladder neck and urethral injuries, edema and urethral mucosal damage were less frequent in patients whose sheaths were placed with this technique. major complications were not observed in both groups according to the modified clavien system. minor complication rate was 26.3% in the endovision group according to the modified clavien system and 40.9% in the control group (p = 0.032). the results of our study suggests that “endovisional technique” for placement of ureter access sheath in rirs safe, shortens operation and fluoroscopy duration and decreases major ureteral injuries. studies of larger series should be carried out to support our findings. conclusion “endovisional technique” is considered to be an appropriate and useful technique in order to place the sheath safely in patients who has difficulty in ureteral access sheath placement and to decrease the duration of operation and fluoroscopy. references 1. huffman jl, bagley dh, lyon es. extending cystoscopic techniques into the ureter and renal pelvis. experience with ureteroscopy and pyeloscopy. jama. 1983; 250:2002-5. 2. turk c, knoll t, petrik a, et al. european association of urology. guidelines on urolithiasis. 2012; 1-102. 3. papatsoris a, sarica k. flexible ureterorenoscopic management of upper tract pathologies. urol res. 2012; 40:639-646. 4. stern jm, yiee j, park s. safety and efficacy of ureteral access sheaths. j endourol. 2007; 21:119-23. 5. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33-6. 6. l’esperance jo, ekeruo wo, scales cd jr, et al. effect of ureteral access sheath on stonefree rates in patients undergoing ureteroscopic management of renal calculi. urol. 2005; 66:252-5. 7. kourambas j, byrne rr, preminger gm. does a ureteral access sheath facilitate ureteroscopy? j urol. 2001; 165:789-93. 8. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-4. 9. pietrow pk, auge bk, delvechio fc, et al. techniques to maximize flexible ureteroscope longevity. urol. 2002; 60:784-8. 10. takayasu h, aso y. recent development for pyeloureteroscopy: guide tube method for its insertion into the ureter. j urol. 1974; 112:176-8. 11. newman rc, hunter pt, hawkins if, finlayson b. the ureteral access system: a rewiev of the immediate results in 43 cases. j urol. 1987; 137:380-3. 12. newman rc, hunter pt, hawkins if, finlayson b. a general ureteral dilatorsheathing system. urol. 1985; 25:287-8. 13. mona m, dretler sp, landman j, et al. maximizing ureteroscope deflection. “play it straight’’ urology. 2002; 60:902-5. 14. vanlangendonck r, landman j. ureteral access strategies: proaccess sheath. urol clin north am. 2004; 31:71-81. 15. abrahams hm, stoller ml. the argument against the routine use of ureteral access sheaths. urol clin north am. 2004; 31:83-7. 16. lallas cd, auge bk, raj gv, et al. laser doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement. j endourol. 2002; 16:583-90 17. monga m, bhayani s, landman j, et al. ureteral access for upper urinary tract disease: the access sheath. j endourol. 2001; 15:831-4. 18. ozyuvali e, resorlu b, oguz u, et al. is routine ureteral stenting really necessary after retrograde intrarenal surgery? arch ital urol androl. 2015: 31;87:72-5. 19. hatipoglu nk, bodakci mn, penbegul n, et al. our experiences on retrograde intrarenal surgery. dicle med j. 2014; 41:95-98. 20. breda a, ogunyemi o, leppert jt, schulam pg. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol. 2009; 55:1190-6. 21. sofer m, watterson jd, wollin ta, et al. holmium:yag laser archivio italiano di urologia e andrologia 2015; 87, 4 mehmet giray sönmez, cengiz kara 290 lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2002; 167:31-34. 22. bozkurt ih, yonguç t, yarımoglu s. retrograde intrarenal surgery outcomes without using an access sheat. med j of izmir hosp. 2015; 19:15-20. 23. wu nz, auge bk, preminger gm. simplified ureteral stent placement wıth the assistance of a ureteral access sheath. j urol. 2001; 166:206-8. 24. hollenbeck bk, schuster tg, faerber gj, wolf js. routine placement of ureteral stents is unnecessary after ureteroscopy for urinary calculi. urol. 2001; 57:639-43. 25. chen yt, chen j, wong wy, et al. is ureteral stenting necessary after uncomplicated ureteroscopic lithotripsy? a prospective, randomized controlled trial. j urol. 2002; 167:1977-80. 26. rapoport d, perks ae, teichman jm. ureteral access sheath use and stenting in ureteroscopy: effect on unplanned emergency room visits and cost. j endourol. 2007; 21:993-7. 27. watterson jd, girvan ar, cook aj, et al. safety and efficacy of holmium: yag laser lithotripsy in patients with bleeding diatheses. j urol. 2002; 168:442-445. 28. harmon wj, sershon pd, blute ml, et al. ureteroscopy: current practice and long-term complications. j urol. 1997; 157:28-32. correspondence mehmet giray sönmez, md (corresponding author) drgiraysonmez@gmail.com medical park ankara hospital, department of urology kent koop quarter 1868. street batıkent ankara, turkey cengiz kara, md, associate professor medical park ankara hospital, department of urology ankara, turkey 255archivio italiano di urologia e andrologia 2016; 88, 4 original paper laparoscopic heminephrectomy for benign and malignant diseases of the horseshoe kidney altug tuncel 1, anil erkan 1, mustafa sofikerim 2, murat arslan 3, yakup kordan 4, yigit akin 5, yilmaz aslan 1 1 third department of urology, ministry of health, ankara numune research and training hospital, ankara, turkey; 2 department of urology, acibadem hospital, kayseri, turkey; 3 department of urology, izmir university school of medicine, izmir, turkey; 4 department of urology, uludag university school of medicine, bursa, turkey; 5 department of urology, harran university school of medicine, sanliurfa, turkey. objectives: in the current study, we present our pure laparoscopic heminephrectomy experience in 13 patients with horseshoe kidney (hk). material and methods: a total of 13 patients with hk underwent pure laparoscopic heminephrectomy (transperitoneal= 7, retroperitoneal = 6) due to benign and malign renal conditions (non-functional hydronephrotic and/or infected kidney = 12, kidney mass = 1). results: the mean age of the patients was 45.8 years. the mean operating time was 140 minutes, and estimated blood loss was 131 ml. the mean hospital stay was 2.3 days. division of istmus was performed with stapler in 5 patients, ultrasonic scalpel in 3, 15 mm hem-o-lok clip in 3, 10 mm ligasure vessel seal system in one and endoscopic suture by 0 polyglactin in one patient without bleeding. twelve patients underwent pure laparoscopic heminephrectomy due to nonfunctional hydronephrotic and or infected kidney. one patient underwent transperitoneal laparoscopic right heminephrectomy due to kidney mass. according to modifies clavien classification, grade i complication (wound infection) occurred in one patient (7.7%) who underwent heminephrectomy due to non-functional kidney. conclusions: laparoscopic heminephrectomy seems to be technically feasible and safe for benign and malignant diseases in patients with hk. key words: heminephrectomy; horseshoe kidney; laparoscopy. submitted 24 february 2016; accepted 6 march 2016 summary no conflict of interest declared. in the current study, we aimed to present our pure laparoscopic heminephrectomy experience in 13 patients with hk. material and methods between december 2011 and march 2014, a total of 13 patients with hk (3 female, 10 male) underwent pure laparoscopic heminephrectomy (transperitoneal = 7, retroperitoneal = 6) due to benign and malignant renal conditions (nonfunctional hydronephrotic and/or infected kidney = 12, kidney mass = 1) at 5 different medical centers. the data were retrospectively collected with using patients’ medical records. diagnostic radiological examinations such as computerized abdominal tomography or magnetic resonance imaging were performed before the surgeries. non-functional kidney was confirmed by 99tcmag3 renal scintigraphy in the patients. the surgical approach (transperitoneal or retroperitoneal) was selected upon the surgeon’s surgical experience. after written informed consent was obtained from all the patients, all patients underwent pure laparoscopic heminephrectomy (right = 5, left = 8) via transperitoneal or retroperitoneal approach as previously described (2-4). under general anaesthesia, the patient was placed 45 degree lateral position. after co2 insufflation, standard transperitoneal laparoscopic procedures with a 3-trocar technique for left side and 4-trocar technique for right side was performed. in retroperitoneal approach, 3 or 4-trocar were placed. in all the operations, the ureter is identified medial to the psoas muscle and dissected cephalad to identify the renal isthmus. then the isthmus is dissected and divided with using 45 or 60 mm endo-gia® stapler (covidien healthcare, ma, us), harmonic® scalpel (ethicon, uk), 15 mm hem-o-lok® (weck-teleflex, us) clip, 10 mm ligasure® (covidien healtcare, ma, us) vessel sealing system, or endoscopic suturization with using 0 polyglactin suture. at the end of the procedures, a jackson-pratt drain was placed in all the patients. surgical procedures were performed by 5 different skilled laparoscopic surgeons. doi: 10.4081/aiua.2016.4.255 introduction horseshoe kidney (hk) is one of the most common congenital kidney fusion anomalies. its incidence in the population is estimated at 1 in 400. it could be associated with other urologic problems such as kidney stone, vesicoureteral reflux and ureteropelvic junction obstruction. the anomaly presents specific challenges for laparoscopic surgery owing to its position, vascular anomalies, and the presence of an isthmus of kidney parenchyma connecting the two sides (1). in the international literature, few publications have reported the laparoscopic surgery for benign and malignant conditions associated with hk. tuncel_stesura seveso 09/01/17 09:47 pagina 255 archivio italiano di urologia e andrologia 2016; 88, 4 a. tuncel, a. erkan, m. sofikerim, m. arslan, y. kordan, y. akin, y. aslan 256 results the mean age of the patients was 45.8 ± 4.6 (range; 28 to 77) years. seven patients presented initially with a history of moderate to severe degree intermittent flank pain, 2 patients presented with febrile urinary tract infection, 1 patient had abdominal pain, 1 patient had gross hematuria. the remaining of them did not describe any complaint. the mean operating time was 140 ± 1.8 (100-180) minutes, and estimated blood loss was 131 ± 12.6 (30-320) ml. the mean hospital stay was 2.3 ± 1.4 (1-5) days. division of isthmus was performed with 45 or 60 mm endo-gia® stapler (covidien healthcare, ma, us) in 5, harmonic® scalpel (ethicon, uk) in 3, 15 mm hem-o-lok® (weck-teleflex, us) clip in 3, 10 mm ligasure® (covidien healtcare, ma, us) vessel sealing system in 1 and endoscopic suturization by 0 polyglactin suture in 1 patients. twelve patients underwent pure laparoscopic heminephrectomy due to nonfunctional hydronephrotic and or infected kidney (right = 5, left = 7). the etiologic factors were urolithiasis (n = 7) and ureteropelvic junction obstruction (n = 5), respectively. histopathological examination of the specimens revealed xanthogranulomatous pyelonephritis in 1, chronic pyelonephritis in 7 and chronic inflammation in 4 patients. one patient (a 58-year old man) was referred to us for evaluation of gross hematuria. computerized tomography demonstrated a right renal mass (40 x 21 x 18 mm in diameter) with hypodense and calcified areas. the patient underwent transperitoneal laparoscopic right heminephrectomy. histopathological examination of the surgical specimen showed a grade 1, pt1a, clear cell carcinoma and negative surgical margin. according to modifies clavien classification, grade i complication (wound infection) occurred in one patient (7.7%) who underwent heminephrectomy due to nonfunctional kidney. the infection was successfully treated by parenteral third generation cephalosporin treatment. discussion hks represent the most common type of renal fusion anomaly. in this anomaly, two separate kidneys lie vertically on either side of the midline and are connected at their respective lower poles by a parenchymatous or fibrous isthmus that crosses the midplane of the body. the isthmus generally consists of parenchymatous tissue with its own blood supply (5). the isthmus mostly lies anterior to the aorta and vena cava but very rarely may pass between the inferior vena cava and the aorta or even behind both major vessels (6). generally, 33% of all patients with hk are asymptomatic, and the anomaly gets noticed incidentally on radiologic examination. the most common associated findings in hk are ureteropelvic junction obstruction which occurs in 35% of the patients. kidney stones develop in 20% to 60% of patients and may be related with obstruction and recurrent urinary tract infections. renal cell carcinoma, the most common, accounts for 45% of all tumors in patients with hk (6). in our cases, urolithiasis (54%) was the most common etiologic factor whereas the others were ureteropelvic junction obstruction (38.5%) and renal cell carcinoma (7.5%), respectively. laparoscopic approaching to hk is an evolving method, with technical challenges arising from the aberrant location and vasculature of these kidneys. depending on the surgeon’s experience, different approaches such as transperitoenal, retroperitoneal and hand-assisted are used (3, 4, 6-27). yohannes and associates suggested that while the retroperitoneal approach may provide better exposure of the renal hilum in benign diseases, inadvertent entry into the peritoneum may be difficult to avoid given the intimate relation between the anterior aspects of the kidneys and the posterior peritoneum (11). sausville and coworkers claimed that transperitoneal approach is successful and reasonable with minimal morbidity in a hk affected by xanthogranulomatous pyelonephritis (24). transperitoneal approach has been advocated for laparoscopic radical heminephrectomy and partial nephrectomy for malignant diseases in patients with hk (14, 15, 18-21, 27). conversely, lee et al. suggested retroperitoneal approach for laparoscopic partial nephrectomy in a hk for posterior and posterolateral lesions (26). in the current study, 7 (nonfunctional hydronephrotic and/or infected kidney = 6, kidney mass = 1) and 6 (nonfunctional kidney and/or infected kidney = 6) patients underwent transperitoneal and retroperitoneal laparoscopic heminephrectomy, respectively. khan et al. reviewed all the cases of laparoscopic heminephrectomy for hk done until 2010 [6]. a transperitoneal approach was used in the majority of cases (59%). hand-assisted and retroperitoneal approaches were used in 22.5% and 18.5% of cases, respectively. in our cases, we preferred either transperitoneal (n = 7) or retroperitoneal (n = 6) approach for the patients with regard to surgeon’s decision. diagnostic radiographic imaging is important in the preoperative planning of heminephrectomy for hks. in the international literature, computerized abdominal tomography and magnetic resonance imaging were used for better delineation of the anatomy (6, 28). some authors suggested that routine preoperative arteriography is essential to identify all vessels, especially in patients with renal cancer (3, 6). the arterial supply of the hk was investigated by janetschek et al. in 6 postmortem cases (29). they showed accessory arteries originating from the great vessels entering the hilum and aberrant vessels entering directly into the poles of the kidneys and the isthmus. these authors claimed that this vascular pattern of the hk can guide the surgeon during laparoscopic nephrectomy. in the current study, we did not perform arteriography in our patients to avoid unnecessary radiation exposure and possible renal failure risk due to dye loading. we believe that careful dissection of aberrant vessels, isthmus and renal hilum allows to the surgeon to identify all anatomical structures. methods for dividing the renal isthmus have been handled included staplers, bipolar coagulation, microwave coagulation ultrasonic scalpel, cold shears followed by argon beam fulguration, and parenchymal suture (6, 11). in the international literature, stapler is the most common device used (6). success with heminephrectomy in hks depends on achieving vascular control. at this stage, it is critical to see for a direct blood supply to the isthmus. whatever technique is used, it is important not to enter the renal collecting system of the controlateral kidtuncel_stesura seveso 09/01/17 09:47 pagina 256 ney and to get adequate hemostasis. in the present study, division of isthmus was performed with stapler in 5 patients, ultrasonic scalpel in 3, hem-o-lok® clip in 3, vessel sealing system in 1 and endoscopic suture with 0 polyglactin in one patient without bleeding. in our series, no major complications were encountered during division of isthmus. conclusions in conclusion, we believe that laparoscopic heminephrectomy in hk seems to be technically feasible, safe and reliable for benign and malignant diseases in a hk. references 1. grainger r, murphy d, lane v. horseshoe kidney: a review of the presentation, associated congenital anomalies and complications. ir med j. 1998; 76:315. 2. mushtag i. laparoscopic nephrectomy and heminephrectomy. in: godbole pp (ed), pediatric endourology techniques. amsterdam: springer, 2007; p.13. 3. donovan jf, cooper cs, lund go, winfield hn. laparoscopic nephrectomy of a horseshoe kidney. j endourol. 1997; 11:181. 4. saggar vr, singh k, sarangi r. retroperitoneoscopic heminephrectomy of a horseshoe kidney for calculus disease. surg laparosc endosc percutan tech. 2004; 14:172. 5. stuart bb. anomalies of the upper urinary tract. in: walsh pc, retik ab (eds), campbell’s urology. 8th ed. philadelphia: saunders. 2002; p.1885. 6. khan a, myatt a, palit v, biyani cs. laparoscopic heminephrectomy of a horseshoe kidney. jsls. 2011; 15:415. 7. riedl cr, huebner wa, schramek p, pflueger h. laparoscopic hemi-nephrectomy in a horseshoe kidney. br j urol. 1995; 76:140. 8. ao t, uchida t, egawa s, et al. laparoscopically assisted heminephrectomy of a horseshoe kidney: a case report. j urol. 1996; 155:1382. 9. hayakawa k, baba s, aoyagi t, et al. laparoscopic heminephrectomy of a horseshoe kidney using microwave coagulator. j urol. 1999; 161:1559. 10. lapointe sp, houle am, barrieras d. retroperitoneoscopic left nephrectomy in a horseshoe kidney with the use of the harmonic scalpel. can j urol. 2002; 9:1651. 11. yohannes p, dinlenc c, liatsikos e, et al. laparoscopic heminephrectomy for benign disease of the horseshoe kidney. jsls. 2002; 6:381. 12. leclair md, camby c, capito c, et al. retroperitoneoscopic nephroureterectomy of a horseshoe kidney in a child. surg endosc. 2003; 17:1156. 13. kitamura h, tanaka t, miyamoto d, et al. retroperitoneoscopic nephrectomy of a horseshoe kidney with renal-cell carcinoma. j endourol. 2003; 17:907. 14. molina wr, gill is. laparoscopic partial nephrectomy in a horseshoe kidney. j endourol. 2003; 17:905. 15. bhayani sb, andriole gl. pure laparoscopic radical heminephrectomy and partial isthmusectomy for renal cell carcinoma in a horseshoe kidney: case report and technical considerations. urology. 2005; 66:880. 16. patankar s, dobhada s, bhansali m. case report: laparoscopic heminephrectomy in a horseshoe kidney using bipolar energy. j endourol. 2006; 20:639. 17. modi p, patel s, dodia s, goel r. case report: retroperitoneoscopic nephrectomy in pyonephrotic nonfunctioning moiety of horseshoe kidney. j endourol. 2006; 20:330. 18. hammontree ln, passman cm. case report: bilateral handassisted laparoscopic nephrectomy in a patient with polycystic horseshoe kidney. j endourol. 2006; 20:397. 19. tobias-machado m, massulo-aguiar mf, forseto ph, jr., et al. laparoscopic left radical nephrectomy and hand-assisted isthmectomy of a horseshoe kidney with renal cell carcinoma. urol int. 2006; 77:94. 20. araki m, link ba, galati v, wong c. case report: hand-assisted laparoscopic radical heminephrectomy for renal-cell carcinoma in a horseshoe kidney. j endourol. 2007; 21:1485. 21. tsivian a, shtricker a, benjamin s, sidi aa. laparoscopic partial nephrectomy for tumor excision in a horseshoe kidney: eur urol. 2007; 51:1433. 22. kojima y, hayashi y, yasui t, et al. laparoscopic nephrectomy for a girl with giant hydronephrosis of a horseshoe kidney. int j urol. 2007; 14:647. 23. nouri-mahdavi k, izadpanahi mh. laparoscopic heminephrectomy in horseshoe kidney using bipolar energy: report of three cases. j endourol. 2008; 22:667. 24. sausville j, chason j, phelan m. laparoscopic heminephrectomy in a horseshoe kidney affected by xanthogranulomatous pyelonephritis. jsls. 2009; 13:462. 25. zumsteg j, roberts ww, wolf js. laparoscopic heminephrectomy for benign renal anomalies. j endourol. 2010; 24:41. 26. lee ys, yu hs, kim mu, et al. retroperitoneoscopic partial nephrectomy in a horseshoe kidney. korean j urol. 2011; 52:795. 27. reboucas rb, monteiro rc, souza tn, et al. pure laparoscopic radical heminephrectomy for a large renal-cell carcinoma in a horseshoe kidney. int braz j urol. 2013; 39:604. 28. mostavafi m, prasad p, saltzman b. magnetic resonance urography and angiography in the evaluation of a horseshoe kidney with ureteropelvic junction obstruction. urology. 1998; 51:484. 29. janetschek g, kunzel k. percutaneous nephrolithotomy in horseshoe kidneys. br j urol. 1988; 62:117. 257archivio italiano di urologia e andrologia 2016; 88, 4 laparoscopy in horseshoe kidney correspondence altug tuncel, md tuncelaltug@yahoo.com anil erkan, md yilmaz aslan, md ministry of health, ankara numune research and training hospital third department of urology 06120, sihhiye, ankara, turkey mustafa sofikerim, md acibadem hospital, department of urology, kayseri, turkey murat arslan, md izmir university school of medicine, department of urology, izmir, turkey yakup kordan, md uludag university school of medicine, department of urology, bursa, turkey yigit akin, md harran university school of medicine, department of urology, sanliurfa, turkey tuncel_stesura seveso 09/01/17 09:47 pagina 257 stesura seveso 349archivio italiano di urologia e andrologia 2014; 86, 4 original paper prostatic fiducial markers implantation by transrectal ultrasound for adaptive image guided radiotherapy in localized cancer: 7-years experience vito lacetera 1, massimo cardinali 2, giovanna mantello 2, francesco fenu 2, giulia sbrollini 1, flavia tombolini 1, alessandro conti 1, stefania maggi 3, giovanni muzzonigro 1, andrea benedetto galosi 4 1 clinica urologica, 2 sod radioterapia, 3 sod fisica sanitaria azienda ospedaliero-universitaria ospedali riuniti, università politecnica delle marche, ancona; 4 uoc di urologia, ospedale “augusto murri”, asur marche, fermo, italy. objective: we present our 7-years’ experience with fiducial gold markers inserted before image-guided radiotherapy (igrt) focusing on our echo-guided technique reporting early and late complications. material and methods: 78 prostate cancer (pca) patients who underwent fiducial markers placement for adaptive igrt (period 2007-2014) were selected. mean patient age was 75 years (range 60-81), mean psa 7.8 ng/ml (range 3.1-10), clinical stage < t3, mean gleason score 6.4 (range 6-7). we recorded early and late complications. maximum distance between the clinical target volume (ctv) and planning target volume (ptv) was assessed for each direction and the mean ptv reduction was estimated. results: we describe in details our echo-guided technique of intraprostatic gold fiducial markers insertion prior to adaptative igrt. we report rare early toxicity (5-7% grade 1-2), a mean ptv reduction of 37% and a very low late toxicity (only 3.4% bladder g3 and 8% rectal g2 side effects). conclusion: our technique of fiducial gold markers implantation for adaptative igrt is safe and well-tolerated and it resulted helpful to reduce ctv-ptv margin in all cases; the effects on clinical practice seem significant in terms of late toxicity but further investigations are needed with longer follow-up. key words: prostate cancer; fiducial markers; image guided radiotherapy; transrectal ultrasound; cbct: cone beam computer tomography; us: ultrasound; trus: transrectal ultrasound. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. increased accuracy, safety, and efficacy (1). the prostate gland can be displaced by more than 1 cm on day-to-day radiotherapy session resulting in geographical miss of the target and unintentional irradiation of surrounding critical structures (2). for this reason, a standard margin of 1 cm (ctv-ptv margin) is added to clinical target volume (ctv) to define the planning target volume (ptv) (3). aims of our study are to describe technique and our results of ultrasound-guided implantation of fiducial gold markers in the prostate for adaptive igrt in lowintermediate risk cancer. furthermore we report the measurement of ctv to define the ptv margins. materials and methods seventy-eight consecutive patients who underwent fiducial markers placement using transrectal ultrasound guided technique for adaptive igrt between january 2007 and march 2014 were analyzed. all cases were low-intermediate risk prostate cancer according to d’amico risk classification: mean psa was 7.8 ng/ml (range 3.1-10); clinical stage t1c-t2b based on clinical staging and rectal coil magnetic resonance 1.5 tesla; biopsy gleason score 6.4 (range 6-7). exclusion criteria were: high risk prostate cancer according to d’amico risk classification or ct3. we recorded early complications of the procedure instructing patients to contact the radiation oncologists if there were any problems during the week after implantation. the planning ct (ctsim) was acquired 7 days after implantation when markers stability was achieved. in the first 54 patients the ctv was delineated as the prostate only and a standard margin (10 mm) was added to define the ptv. a daily markers match between cbct and ctsim was performed during the whole treatment, in order to correct inter-fraction prostate motion. for each patient, the first five cbcts were then used to create a patient personalized ptv obtained as a merged volume including the 5 days ctv position (3). with the aim to calculate the gain of using gold markers, the maximum distance between the ctv and the ptv, for each direction, was assessed for each patient. the median value of the measured distances, among the whole population, per each direction, was doi: 10.4081/aiua.2014.4.349 presented at 19th national congress sieun, fermo 2014 introduction over the past few decades, advances have been made in image-guided radiotherapy (igrt) to increase the radiation dose to the prostate, while limiting toxicities to adjacent organs such as the bladder and rectum: placement of fiducial markers is an important option in igrt treatment planning to deliver higher total doses with lacetera_stesura seveso 15/01/15 12:44 pagina 349 archivio italiano di urologia e andrologia 2014; 86, 4 v. lacetera, m. cardinali, g. mantello, f. fenu, g. sbrollini, f. tombolini, a. conti, s. maggi, g. muzzonigro, a.b. galosi 350 indeed used to define an anisotropic margin and to compare it with the standard ones. all the patients were submitted an active follow-up. the late toxicity was recorded and classified according to the lent soma score. ultrasound technique fiducial markers were inserted on ultrasound guidance with transrectal approach by the 2 referring urologist (abg, vl) using a logic-q p5 machine (ge healthcare, little chalfont, united kingdom) equipped with end-fire probe (6-8 mhz) and disposable kit also used for biopsy. all patients signed an information consent describing the risks of the procedure and the rationale for undergoing fiducial marker implantation. they self-administered an enema the morning of the procedure and were placed on antibiotics prophylaxis (fluorquinolones) from the day before to 4 days after procedure. patients were instructed to stop anticoagulant and antiplatelet medications 7 days before the implant if appropriate. any patient, who had severe infection after prostate biopsy, was excluded from this evaluation and treated with transperineal approach. patients with multiple and bilateral calcifications of the gland were excluded from the study and treated with igrt since fiducial markers were considered not necessary to image the prostate with ct scan. the equipment needed and the technique are similar to that typically used during a trus-guided prostate biopsy: with the patient in left lateral decubitus position we instilled a topical anesthesia (2% lidocaine-prilocain gel) and a 5 ml povidone-iodium enema in the rectum 5 minutes before insertion of the probe. then a local nerve block was made by injecting lidocaine 1% (using 21guage needle 25 cm long) at the angle between the seminal vesicle and prostate on either side immediate prior to insertion of the fiducials. three fiducial markers (0.9 mm x 3 mm) were placed in the prostate (lateral mid left gland, right apex and base) under ultrasound guidance. the needle was gently advanced for 1.5 centimeter into prostatic tissue and then retracted releasing the marker. each marker was released in the right position according to anatomy of the gland and radiation oncologist’s preference with a triangulation scheme (avoiding the gold markers overlapping on the 3 orthogonal planes). the correct gold markers position was verified by fluoroscopy in the first 50 cases (figure 1). results all procedure were performed successfully under local anesthesia without any severe complication. mean time was 20 minutes. any marker displacement in the urethra, rectum or infection was recorded. the optimal triangulation scheme (avoiding the gold markers overlapping on the 3 orthogonal planes) was obtained in 95% of cases. in 5% of cases the spatial distribution on 3 different planes was difficult in very small prostate (volume < 22 cc) or in prostate with small later-lateral diameter (< 4 cm on axial plane). to avoid markers displacement, we keep away from large cyst (> 1 cm) or close to the urethra lumen in patients who underwent previous surgery. hyperechoic tissue areas mixed with parenchymal calcifications were avoided in order to improve ultrasound control and visibility. the end-fire probe equipped with biopsy track option viable on the monitor allows correct placement in all cases minimizing operator variability. gold markers in most of case, but sometimes carbonium were used. material does not change the technique. patients with obstructive lower urinary tract symptoms before the procedure were treated with medical therapy. both therapies alpha-blockers and 5-alfa reductase inhibitors were allowed during and after igrt treatment. in particular, we added dutasteride or finasteride to treat urinary obstruction and clinical benign prostate enlargement if any antiandrogen or androgen block was used to cancer control. early complications: no cases of severe early complications are reported (bleeding, infections, abscess or markers migration). the commonest new symptom following the procedure was urinary frequency affecting 10% of patients. hematuria, minor rectal bleeding, dysuria and haematospermia affected 5-10% of patients, all cases were self-limiting and of grade 1-2. mean pain score was 2 (range 1-5) during the procedure (according vas scale range from 0 to 10) (table 1). igrt implication and late side effects: the ptv resulted thinner than standard ones for all the patients with a mean reduction of each diameter of 1 mm cranial, 1 mm caudal, and 3.5 mm anterior, 3 mm posterior, 2 mm left and 2.5 mm right. these characteristics result an overall reduction of the ptv of 37% (range 23-59%) (figure 2). the late toxicity was reported for 57/78 patients with at least 12 months follow up: at a median follow-up of 34 months (range 12-84) we recorded 8/57 (14%) grade 1, 5/57 (8%) grade figure 1. a: patient position, b:trus guided fiducial marker’s insertion (right base), c: gold markers needles, d: fluoroscopic control of fiducial markers positions. lacetera_stesura seveso 15/01/15 12:44 pagina 350 2 of late rectal toxicity; 8/57 (14%) grade 1, 1/57 (1.7%) grade 2, 2/57 (3.4%) grade 3 of late bladder toxicity according to lent soma score (table 2). discussion differences in bladder and rectal filling as well as respiratory movements are known barriers to delivering increased radiation doses to the prostate using igrt: fiducial markers provide a tool for reliable and accurate position verification before igrt is delivered, allowing higher dose delivery to the target, while minimizing toxicities to surrounding normal tissue as reported in literature. with gold markers, for daily localization of the prostate, the margins around the gland can be reduced: several feasibility studies have shown the reliability of fiducial markers for prostate position verification during radiotherapy (1-3). so fiducial markers are being increasingly used by radiation oncologists to meet the dual objectives of delivering a higher dose to the pca while sparing normal tissues so urologists are increasingly required to assist them during the trus-guided implantation: we believe that urologists should therefore be familiar with and skilled at the procedure. fiducial marker placement has been described using various techniques, including a transpe rineal route with endorectal us guidance, transrectally with an endorectal probe and transrectally through an endoscope; the number of fiducial markers placed ranges from three to five in most studies, with no evidence suggesting a superior number or configuration (4-6). in our experience we used three gold markers placed under trus guidance with a triangulation scheme that means trying to avoid the markers overlapping on the 3 orthogonal planes according to the radiation oncologists’ preference: the 3 gold markers are usually released in the lateral mid left gland, right apex and base with some exceptions due to particular prostatic anatomy or gland’s volume. based on our experience, the transrectal biplane probe is not useful to obtain the correct spatial distribution, since probe movement is limited in the rectum due to lenght and needle track visibility is limited compared with endfire probe. with our end-fire trus guided technique described in this article we reported a very high technical success rate (all cases) and low early complications (0% g3 and 2% g2) similar to other experiences reported in literature: deipolyi et al. (7) reported 98% success rate of their technique using 3 fiducial markers in 111 consecutive localized pca patients with only 0,9% g3 early complication; linden et al. (4) reported 100% success rate of their technique using 1-3 fiducial markers in 98 consecutive localized pca patients with no severe early toxicity. moman et al. (8) reported the main experience in this field: 914 pca patients, 3 fiducial markers inserted with a trus guided technique, 2/914 cases of severe early toxicity and 5/914 cases of markers migration; kably et al. (9) reported 75 consecutive localized pca patients with 351archivio italiano di urologia e andrologia 2014; 86, 4 fiducial markers implantation: us technique igrt with fiducial markers ptv reduction bladder toxicity rectum toxicity g1 g2 g3 g1 g2 g3 current study 37% (23-59) 14% 1.7% 3.4% 14% 8% 0% table 2. ptv reduction and late toxicity. study no. pts size gold marker no. markers technique technical markers early complication (%) (mm) success migration g1 g2 g3 g4 deipolyi (7) 111 nr 3 transrectal 98% nr 0 0 0.9 0.9 moman (8) 914 5 x 1 3 transrectal nr 0.18% nr nr 2.0 0 transperineal linden (4) 98 5 x 1.1 3 transrectal 100% 0% 0 0 0 0 kably (9) 75 3 x 1.2 4 transrectal 99% 0.3% 6.6 2.6 0 1.3 current study 78 3 x 0.9 3 transrectal 100% 0% 5.5 2.1 0 0 nr: not reported. table 1. our results compared to other studies in literature. figure 2. a: standard ctv-ptv margin of 10 mm (red line). b: ctv-ptv (blue line) margin reduction with gold fiducial markers inserted. lacetera_stesura seveso 15/01/15 12:44 pagina 351 archivio italiano di urologia e andrologia 2014; 86, 4 v. lacetera, m. cardinali, g. mantello, f. fenu, g. sbrollini, f. tombolini, a. conti, s. maggi, g. muzzonigro, a.b. galosi 352 99% of success rate and only 1.3% severe early complication with 0.3% markers migration. other experiences are reported in literature by gill et al. (10), igdem et al. (11) and langenhuijsen et al. (12) with similar results. there are few data quantifying the degree of spared healthy tissue with igrt even in radiation oncology literature. langenhuijsen et al. (13) reported a ctv-ptv margin reduction of 3 mm circumferentially, because of the use of gold markers, led to a mean ptv reduction of 27%; in our experience the mean reduction of each diameter of ptv was 1 mm cranial, 1 mm caudal, 3.5 mm anterior, 3 mm posterior, 2 mm left and 2.5 mm right resulting a mean overall ptv reduction of 37%. as expected, we reported a very low rate of late toxicity (3.4% bladder g3 and 8% rectal g2 side effects). comparing the toxicity profiles between different studies is difficult, because the radiation techniques, doses, and treatment margins are different. limitations of the study include the relatively small patient population, it is not a prospective randomized study comparing igrt with and without gold fiducial markers implantation, the follow-up is too short (mean 12 months) to clarify the favorable impact of fiducial on igrt’s late toxicity profile. conclusions we report our technique of trus-guided fiducial gold markers implantation with its early and late complications in a group of pca patients: it’s a safe and well-tolerated procedure and it results helpful to reduce ctvptv margin in all cases. as expected the late toxicity to surrounding normal tissues (bladder, rectum) resulted very low so the effects on clinical practice seem significant for both radiation oncologists and urologists who are involved in high-precision igrt. references 1. dehnad h, nederveen aj, van der heide ua, et al. clinical feasibility study for the use of implanted gold seeds in the prostate as reliable positioning markers during megavoltage irradiation. radiother oncol. 2003; 67:295-302. 2. shirato h, harada t, harabayashi t, et al. feasibility of insertion/implantation of 2.0-mm-diameter gold internal fiducial markers for precise setup and real-time tumor tracking in radiotherapy. int j radiat oncol biol phys. 2003; 56:240-7. 3. cardinali m, galosi ab, fenu f, et al. adaptative radiotherapy with gold markers to reduce radiotherapy-relateed toxitcy in low risk prostate cancer patients. anticancer research. 2011; 31:1889-90. 4. linden ra, weiner pr, gomella lg, et al. technique of outpatient placement of intraprostatic fiducial markers before external beam radiotherapy. urology. 2009; 73:881-6. 5. shinohara k, roach m 3rd. technique for implantation of fiducial markers in the prostate. urology 2008; 71:196-200. 6. henry am, wilkinson c, wylie jp, et al. transperineal implantation of radio-opaque treatment verification markers into the prostate: an assessment of procedure related morbidity, patient acceptability and accuracy. radiother oncol. 2004; 73:57-59. 7. deipolyi ar, mueller p, efstathiou j, et al. transrectal ultrasound-guided prostate fiducial marker placementfor prostate localization during external beam radiotherapy: a safe and reliable procedure. j vasc interv radiol. 2013; 24:s98-s99. 8. moman mr, van der heide ua, kotte an, et al. long-term experience with transrectal and transperineal implantations of fiducial gold markers in the prostate for position verification in external beam radiotherapy; feasibility, toxicity and quality of life. radiother oncol. 2010; 96:38-42. 9. kably i, bordegaray m, shah k, et al. single-center experience in prostate fiducial marker placement: technique and midterm follow-up. j vasc interv radiol 2014; 25:1125-1132. 10. gill s, li j, thomas j, et al. patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy. br j radiol. 2012; 85:1011-7. 11. igdem s, akpinar h, alço g, et al. implantation of fiducial markers for image guidance in prostate radiotherapy: patientreportedtoxicity. br j radiol. 2009; 82:941-5. 12. langenhuijsen jf, van lin en, kiemeney la, et al. ultrasoundguided transrectal implantation of gold markers for prostate localization during external beam radiotherapy: complication rate and risk factors. int j radiat oncol biol phys. 2007; 69:671-6. 13. langenhuijsen jf, smeenk rj, louwe rj, et al. reduction of treatment volume and radiation doses to surrounding tissues withcntraprostatic gold markers in prostate cancer radiotherapy. clin genitourin cancer. 2011; 9:109-113. correspondence vito lacetera, md (corresponding author) vlacetera@gmail.com giulia sbrollini, md, resident of urology giuliasbrollini@libero.it flavia tombolini, md, resident of urology flavia.tombolini@virgilio.it alessandro conti, md, urologist alessandro.conti@hotmail.com giovanni muzzonigro, md, urologist g.muzzonigro@univpm.it clinica urologica, azienda ospedaliero-universitaria ospedali riuniti via conca 71 61100 torrette di ancona, italy massimo cardinali md, radiotherapist massimo.cardinali@ospedaliriuniti.marche.it giovanna mantello, md,radiotherapist giovanna.mantello@ospedaliriuniti.marche.it francesco fenu, md, radiotherapist francesco.fenu@ospedaliriuniti.marche.it sod radioterapia azienda ospedaliero-universitaria ospedali riuniti, università politecnica delle marche, ancona, italy stefania maggi, medical physic stefania.maggi@ospedaliriuniti.marche.it sod fisica sanitaria, azienda ospedaliero-universitaria ospedali riuniti, università politecnica delle marche, ancona, italy andrea galosi, md, urologist galosiab@yahoo.it uoc di urologia, ospedale “augusto murri”, asur marche, fermo, italy lacetera_stesura seveso 15/01/15 12:44 pagina 352 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4356 original paper the impact of repeated prostate biopsies on sexual function and urinary symptoms in patients with diagnosis of atypical small acinar proliferation (asap): can ecodoppler reduce side effects? luigi quaresima, vito lacetera, luca leone, lorenzo montesi, ubaldo cantoro, massimo polito, giovanni muzzonigro institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy. objectives: to establish whether repeated trans-rectal ultrasound-guided prostate needle biopsies (pnbx) performed in men with diagnosis of small acinar atypical proliferation (asap) predispose these subjects to erectile dysfunction (ed) and to evaluate if ecocolordoppler (ecd) can help to reduce this side effect. materials and methods: we performed a retrospective study regarding 190 men with diagnosis of asap detected between january 2001 and december 2011, who underwent to repeated prostate needle biopsies (pnbx). these patients were investigated about erectile function (ef) and lower urinary tract symptoms (luts) using international index of erectile function (iief-5) and international prostate symptom score (ipss) questionnaires before the first pnbx and 3 months after each other one. in particular, among the 89 men without ed before first pnbx, we compared iief-5 score between 64 patients who underwent to standard pnbx and 25 patients submitted to a pnbx done with in addition ecd ultrasound imaging. results: mean patient age was 65 years (sd 7.7); mean follow-up was 3.2 years (sd 1.8) and the mean number of re-biopsies completed was 2 (sd 1.5). among the 143 men considered, only 89 resulted with a normal ef (iief-5 score > 21): in this group incidence of ed (iief-5 score < 21) among patients who underwent to standard pnbx was 4/64 (6.25%) while in patients submitted to a pnbx with ecd was 1/25 (4%). a greater decrease of ef was observed in patients undergone to 3 or more biopsies; no relationship between ipss score and re-pnbx was identified. conclusion: repeated pnbx done in patients with diagnosis of asap appear to get worse ef; number of biopsies seems to increase the risk of ed. use of ecd in transrectal ultrasound-guided pnbx may have a role to avoid neurovascular bundles (nvbs) and preserve ef; anyway further studies are highly recommended to validate this hypothesis. key words: prostate biopsy; erectile dysfunction; small acinar atypical proliferation (asap). submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction trans-rectal ultrasound-guided prostate needle biopsy (pnbx) is the diagnostic practice of choice for prostate cancer (pca) detection; it is considered a safe and routinely procedure, with a low risk of major complications requiring hospital admission (1), as fever and sepsis. minor complications, such as rectal bleeding, acute urinary retention, hematospermia and hematuria are relatively frequent but usually self-limiting (2, 3). besides this well-documented side-effects, an increasing number of articles is showing a possible role of pnbx to cause erectile dysfunction (ed) (4-6). some studies described this effect as temporary (7-9), and attributed to anxiety (9) rather than a real organic injury (6). moreover, this studies often investigated erectile function (ef) in patients on active surveillance, that is to say with a diagnosis of prostate cancer, a potential negative psychological confounder that may influence their ef (10). another cohort of men who underwent to seriate pnbx is that of patients with diagnosis of atypical small acinar proliferation (asap), a kind of precancerous lesion considered to be an element in the progression of changes in cell morphology between healthy tissue of the prostate and pca (11). furthermore, due to the opinion that at least some cases of asap diagnosis in biopsy specimens are actually undiagnosed cancers (12), the indication to second biopsy in such patients has been commonly accepted (11, 13). to the best of our knowledge, no study has investigated the impact on ef of seriate pnbx done in patients with diagnosis of asap; in the current article, we analyzed this aspect and evaluated if ecocolordoppler can help to prevent this side effect (figure 1). materials and methods this retrospective study includes 190 men with a diagnosis of asap detected between january 2001 and december 2011 and undergone to repeated pnbx. baseline ef was evaluated before the first biopsy using doi: 10.4081/aiua.2014.4.356 presented at 19th national congress sieun, fermo 2014awarded as best poster sieun article quaresima 1_stesura seveso 16/01/15 10:10 pagina 356 357archivio italiano di urologia e andrologia 2014; 86, 4 worse erectile function in patients with diagnosis of asap undergone to repeated biopsies international index of erectile function (iief-5) questionnaire; by the obtained score the patients were stratified in 5 groups (figure 2). according to the literature, patients belonging to group 1 (defined by an iief-5 score > 21), were considered having a normal ef. in order to complete the study of the patients it was also investigated the preexistence of lower urinary tract symptoms (luts) by using international prostate symptom score (ipss). regarding the procedure, after quinolone chemoprophylaxis and local anesthesia, it was managed a 12-16 core transrectal biopsy using a tru cut cook 18g needle under transrectal uiltrasound (trus) control. in particular, in the group 1 of 89 patients (figure 2) not affected by ed (defined by an iief-5 score < 22) before the first pnbx, 64 patients underwent to standard transrectal biopsies; whereas in a subgroup of 25 power doppler evaluation was added to the standard ultrasonography imaging to better identify neurovascular bundles (nvbs) and avoid them with the needle. a comparison of iief-5 and ipss score submitted before and 3 months after pnbx was performed to analyze differences between baseline and follow-up iief-5 scores, and eventually the relation with the number of pnbx done. t student’s test was used; a p value < 0.05 was considered statistically significant. results patients who were analyzed in this study resulted to have a mean age of 65 years (sd 7.7); their mean follow-up was 3,2 years (sd 1.8) and the mean number of re-biopsies was 2 (sd 1.5). among the 143 men who concluded the follow up, only 89 resulted with a normal ef (corresponding to an iief-5 score > 21): in this group incidence of ed (iief-5 score < 21) among patients who underwent to standard pnbx was 4/64 (6.25%) while in patients submitted to a pnbx with ecd was 1/25 (4%). univariate analysis was performed to compare the variation in iief-5 score (considered as the difference between the baseline iief and the iief-5 at the last follow up) in men without previous ed who underwent to repeated pnbx: the p value for this difference was < 0.001, showing a significant correlation between repeated pnbx and ef as illustrated in figure 3. moreover, the variation of the iief-5 score in patients who underwent 0 to 2 re-pnbx resulted significantly lower than in men who underwent more than 2 re-pnbx (p < 0.05), demonstrating a relationship with the number of pnbx done. on the other hand, no significant worsening of ipss score was identified after re-pnbx, with only temporary irritative urinary symptoms reported by some patients. discussion so far is not clearly defined by the international literature whether serial pnbx predispose to a permanent ed over time: nevertheless only few studies, as the one leaded by hilton et al., showed a total absence of correlation between this side effect and the procedure (14). in the majority of the examined studies, the investigators demonstrated a short-term (30 days) impact on ef, assofigure 2. patients stratified in 5 groups by baseline iief-5. figure 3. change of iief-5 score in patients without previous ed (group i, p < 0.001). pa ti en ts pa ti en ts figure 1. neurovascular bundles detected by ecd imaging. quaresima 1_stesura seveso 16/01/15 10:10 pagina 357 archivio italiano di urologia e andrologia 2014; 86, 4 l. quaresima, v. lacetera, l. leone, l. montesi, u. cantoro, m. polito, g. muzzonigro 358 ciated to psychological factors as anxiety and diagnosis of pca (8, 10) rather than to use of periprostatic nerve block and flogosis linked to the procedure. some authors considered pnbx follow-up at 1 and 6 months: akbal et al showed a worsened ef 1 month after pnbx that returns at baseline level at 6 months (3): in this study the authors analyzed specifically only pca-free patients, avoiding bias due to the cancer detection. tuncel et al. described an high number of patients (up to 41%) without ed that developed a deterioration of ef one month after pnbx: 6 months later 15% still had ed, demonstrating a significant correlation between pnbx and ed (4). recently, another article of tuncel showed that the association between pnbx and de might have an organic basis, demonstrating with power doppler ultrasonography an inflammation of the prostate parenchyma and of the surrounding neurovascular bundle in patients suffering from ed after pnbx (6). this last article, may give a possible explication of the utility, described in our study, to add power doppler to the standard ultrasonography imaging, to better identify neurovascular bundles (nvbs), and avoid them with the needle. this care towards the bundles has become nowadays more and more important in consideration to the increase of the number of cores taken in each pnbx such as the practice of submit patients to repeated pnbx. conclusions men with diagnosis of asap who uunderwent to repeated pnbx are at risk of worsening ef; this risk appears to grow with the increase of biopsy number. furthermore, this study proposes the use of ecd in transrectal ultrasoundguided pnbx with the purpose to avoid neurovascular bundles (nvbs) and preserve ef; nevertheless additional studies are highly suggested to validate this hypothesis. acknowledgments we thank prof. stefano bompadre for the guidance supplied. references 1. pinkhasov gi, lin yk, palmerola r, et al. complications following prostate needle biopsy requiring or emergency department visits-experience from 1000 consecutive cases. bju int. 2012; 110:369-374. 2. djavan b, waldert m, zlotta a, et al. safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective european prostate cancer detection study. j urol. 2001; 166:856. 3. akbal c, turker p, tavukcu hh, et al. erectile function in prostate cancer-free patients who underwent prostate saturation biopsy. eur urol. 2008; 53:540. 4. tuncel a, kirilmaz u, nalcacioglu v, et al. the impact of transrectal prostate needle biopsy on sexuality in men and their female partners. urology. 2008; 71:1128-31. 5. fujita k, landis p, mcneil bk, et al. serial prostate biopsies are associated with an increase risk of erectile dysfunction in men with prostate cancer on active surveillance. j urol. 2009; 182:2664-9. 6. tuncel a, toprak u, balci m, et al. impact of transrectal prostate needle biopsy on erectile function: results of power doppler ultrasonography of the prostate. kaohsiung j of med sciences. 2014; 30:194-199. 7. chrisofos m, papatsoris ag, dellis a, et al. can prostate biopsies affect erectile function? andrologia. 2006; 38:79-83. 8. pepe p, pietropaolo f, dibenedetto g, et al. erectile function after repeat saturation prostate biopsy: our experience in 100 patients. arch ital urol androl. 2013; 85:130-132. 9. glazer ap, novakic k, helfand bt. the impact of prostate biopsy on urinary symptoms, erectile function, and anxiety. curr urol rep. 2012; 13:447-454. 10. helfand bt, glaser ap, rimar k, et al. prostate cancer diagnosis is associated with an increased risk of erectile dysfunction after prostate biopsy. bju int. 2013; 111:38-43. 11. adamczyk p, wolski z, butkiewicz r, et al. significance of atypical small acinar proliferation and extensive high-grade prostatic intraepithelial neoplasm in clinical practice. cent european j urol. 2014; 67:136-141. 12. mazzucchelli r, colanzi p, pomante r, et al. prostate tissue and serum markers. adv clin path. 2000; 4:111-20. 13. iczkowski ka, maclennan gt, bostwick dg. atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies: clinical significance in 33 cases. am j surg pathol. 1997; 21:1489-1495. 14. hilton jf, blaschko sd, whitson jm, et al. the impact of serial prostate biopsies on sexual function in men on active surveillance for prostate cancer. j urol. 2012; 188:1252-1258. correspondence luigi quaresima, md (corresponding author) luigiquaresima@yahoo.it vito lacetera, md vlacetera@gmail.com luca leone, md lucaleone@yahoo.it lorenzo montesi, md lorenzomontesi@yahoo.it ubaldo cantoro, md ubymaior@libero.it massimo polito, md max_polito@virgilio.it giovanni muzzonigro, md g.muzzonigro@univpm.it institute of urology, aou united hospitals, polytecnic university of marche region, ancona, italy quaresima 1_stesura seveso 16/01/15 10:10 pagina 358 183archivio italiano di urologia e andrologia 2016; 88, 3 original paper penile vascular diagnostic categorization using penile duplex doppler ultrasound: differences in vascular hemodynamics parameters by differences in anatomic sampling location fabio pezzoni 1, fabrizio ildefonso scroppo 2 1 vascular surgeon, university of milano, italy-member of sia, italy; 2 department of urology and andrology, uoc urology ospedale di circolo, varese, italy. objectives. in 2013 the international society for sexual medicine(issm) published the guidelines regarding the standard operating procedure (sop) for penile duplex doppler ultrasound (pddu). although issm-sop have given important strides in reducing interobserver variability in pddu by procedural protocol and parameters these guidelines do not address the anatomic location along the penis at which hemodynamic measurements have to be done. in our opinion a “double sampling” may be interesting to detect the arteriogenic or venogenic nature of the erectile dysfunction (ed). in particular sampling measurements at the “crus” (at the level of the peno-scrotal junction) may be significative for detection of veno-occlusive dysfunction (vod),whereas an evaluation at “mid penis” (1/2 distance between peno-scrotal junction and coronal sulcus), may be useful to diagnose an arterial insufficiency (ai). material and methods. we evalued 90 men, mean age 56.3, affected with ed of medium degree, responder to pde5-i that urdergone to pddu and also responder after pharmacologic intracavernosal injection (pii)of prostaglandin e1 20 mcg, with rigid erection and normal maintenance. we moreover evalued 90 men in youthful age (mean 35.2), in absence of vascular risk factors, no responder to pde5-i that undergone to pddu by pii at high dosage (bimix: prostaglandin e1 20 mcg, papaverine 20 mg). results. in the first pool the sampling at “mid penis” resulted significative for arterial insuffciency (ai) in 81% (73), in presence of normal or borderline end diastolic velocity (edv). sampling at the “crus” resulted negative for vod in 90% (81). in the second pool, 66.6% (60) resulted responder with rigid erection and normal maintenance in presence of normal hemodynamic parameters: peak systolic velocity (psv) and end diastolic velocity (edv) both at the “crus” and at “mid penis” sampling. 33.4% (30) responded with a semirigid erection and manifested a constant deficit of maintenance; at the “crus”and at “mid penis” the hemodynamic arterial parameters resulted normal. at the “crus” the edv resulted significantly augmented (vod index) in 96.6% (29); at “mid penis” augmented edv was founded in 50% (15). conclusions. these observational data would be able to confirm the utility of a routinary “double sampling” procedure, at the “crus” and at “md penis”, during pddu in order to better distinguish between vod or ai or in any case to be useful to stimulate a future more precise standardization in execution of pddu examination. key words: duplex doppler ultrasonography; erectile dysfunction; penile venous leakage; arteriogenic impotence. submitted 14 january 2016; accepted 21 february 2016 summary no conflict of interest declared. introduction erectile dysfunction (ed), together with premature ejaculation, is the most common male sexual disorder. vascular ed comprehends cavernosal artery insufficiency and dysfunction of penile veno-occlusive system. these two mechanisms frequently cohabit in a single patient, representing two different steps of the same disease. it is demonstrated that around 70% of all ed is related to pathological penile vasculature either through reduced inflow or augmented outflow (1). the recent american urological association (aua) guidelines on ed counsel, in selected patients, a second level vascular diagnostic evaluation (2, 3). the classic test consists in penile duplex doppler ultrasound (pddu) after pharmacologic intracavernosal injection (pii) inducing erection, to discriminate arterial insufficiency (ai) and venoocclusive dysfunction (vod) from other causes of ed. in 2013 the international society for sexual medicine (issm) published the guideline regarding the standard operating procedure (sop) for pddu (4). although issm (sop) have given important strides in reducing interobserver variability in pddu by precise procedural protocols and parameters, these guidelines do not address the anatomic location along the penis at which hemodynamic measurements have to be done, during the execution of the examination. pddu is aimed at the functional and anatomical study of the cavernosal arterial inflow. when vascular evaluation is indicated pddu offers the least invasive and accurate data to assess the penile arterial inflow. the parameters to estabilish the integrity of the arterial flux are: peak systolic flow velocity (psv), cavernous arterial diameters, acceleration time. pddu also can values the cavernous veno-occlusive mechanism in the post-injection phase, considering the end-dyastolic velocity (edv) and the resistance index (ri); persisting diastolic blood flow and/or low ri: suspect of vod. a recent study by pagano has pointed out the importance of the differences in vascular hemodynamics parameters by differences in anatomic sampling location of ultrasound probe placement for cavernosal arteries during dynamic pddu (5). in our opinion a “double sampling” may be interesting to detect the arteriogenic or venogenic doi: 10.4081/aiua.2016.3.183 pezzoni_stesura seveso 21/09/16 08:44 pagina 183 archivio italiano di urologia e andrologia 2016; 88, 3 f. pezzoni, f.i. scroppo 184 nature of the vasculogenic ed (6, 7). in particular sampling measurements “at the crus” (at the level of the penoscrotal junction) may be significatives for detection of vod, whereas an evaluation at “mid penis” (1/2 distance between penoscrotal junction and coronal solcus), may be useful to diagnose an arteriogenic insufficiency (figure 1). material and methods we evalued a total of 90 men, mean age 56.3, affected with persistent ed of medium degree (iief score between 10 and 15), in absence of peyronie’s disease, responder to pde5-inhibitors that undergone to pddu and also responder after pii with rigid erection and normal maintenance (8). according to the international consultation on sexual dysfunction, ed is defined as “persistent” when there is inhability to attain and mantain an erection sufficient to permit satisfactory sexual performance and the symptoms have to persist for a minimum duration of six months. they took pde5-inhibitors (vardenafil or tadalafil) at personalized dosage after an evaluation “case for case” based on: clinical factors, age, frequency of sexual intercourse, life style. pddu assessments were done using a 12 mhz linear array transducer, after pii of prostaglandin e1 20 mcg. parameters that have been considered for a vascular diagnosis were psv, edv, acceleration time and ri. psv was considered normal for mean values > 30 cm/sec.; edv for values < 5 cm./sec., acceleration time for values < 1 sec. to reach psv, and rihad to be > 0.80, according to issm (sop) (4). we moreover evalued 90 men in youthful age, mean 35. 2, in absence of vascular risk factors, no responder to pde5-inhibitors (vardenafil e/o tadalafil) in satisfactory way, also at maximum dosage. they undergone to dynamic pddu by pii at high dosage of “bimix”: prostaglandin e1 20 mcg. + papaverine 20 mg. the same pddu vascular parameters were also analyzed in this group. in all the cases the examinations were performed by a “double sampling” measurements positioning the probe “at the crus” (at the level of the penoscrotal junction) and at “mid penis” (1/2 distance between penoscrotal junction and coronal solcus) with the aim to postulate the arteriogenic or venogenic nature of the vasculogenic ed. results the sampling, in the first group of men at “mid penis” resulted significative for presence of ai in 81% (73): the mean value of psv was 25.3 cm/sec. (figure 2). edv resulted normal or borderline in all the patients (mean 2.1 cm/sec.), acceleration time resulted significative for presence of angiosclerosis in all the men (mean 1.5 sec.), ri had a mean normal value of 0.92 (9) (figure 3). sampling at the “crus” resulted negative for dvo in 90% (81): mean edv resulted 2.5 cm/sec. an edv value > 5 cm/sec. is considered by issm-(sop) a significative dvo presence index (9) (table 1). in the second group of men 66.6% (60) resulted responder with rigid erection and normal maintenance in presence of normal hemodynamic parameters: psv, edv, ri both at the “crus” and at “mid penis” sampling (10). 33.4% (30) responded with a semirigid erection and sampling “mid penis” sampling at the “crus” positive for ai: 81% (73) negative for vod: 90% (81) edv: normal/borderline 100% (90) table 1. first pool of patients (90). figure 2. arteriogenic insufficiency. figure 3. angiosclerosis. figure 1. crus and mid penis. manifested a constant deficit of maintenance; at the “crus” and at “mid penis” the hemodynamic arterial parameters resulted normal (figures 4, 5). at the “crus” edv resulted significantly augmented (dvo index) in 96.6% (29) with a mean value of 7.8 cm/sec.; ri also had a dvo significative mean value of 0.71. at “mid penis” augmented edv was founded in 50% (15) (11) (figure 6) (table 2). pezzoni_stesura seveso 21/09/16 08:44 pagina 184 discussion and conclusions vod is not classified in a precise nosologycal condition, but like a multifactorial ethiology syndrome and the the “venous-leakage” constitues a complex fenomenon interesting structural abnormalities in corpora cavernosa and/or in the tunica albuginea. however these oservational data would be able to confirm the utility of a routinary “double sampling” procedure (at the “crus” and at “mid penis”) during pddu in order to better distinguish between venogenic or arteriogenic vasculogenic disorders or in any case to be useful to stimulate a future more precise standardization in execution of pddu examination. references 1. goldstein i. male sexual circuitry, working group for the study of central mechanisms in erectile dysfunction. sci am. 2000; 2803:70-5. 2. american urological a. (aua guideline. management of erectile dysfunction). arch esp urol. 2011; 64:4. 3. board of directors, american urological association aua. policy statement:diagnostic evaluation of erectile dysfunction, may 2012 (revised). https://www. auanet. org/education/policy-statements/evaluations-of-erectile-dysfunction. cfm (accessed april 1, 2015). 4. sikka sc, hellstrom wj, brock g, morales am. standardization of vascular assessment of erectile dysfunction: standardoperating procedures for duplex ultrasound. j sex med. 2013; 10:120-9. 5. pagano j, stahal pj. variation in penile hemodynamics by anatomic location of cavernosal artery imaging in penile duplex doppler ultrasound. j sex med. 2015; 12:1911-1919. 6. furlow wl, knoll ld. arteriogenic impotence. diagnoses and management. problems in urology 1991; 5:577-93. 7. virag r, zwang g, dermange h. vasculogenic impotence: a review of 92 cases with 54 surgical operations. vasc surg. 1981; 15:9. 8. rosen rc, riley a, wagner g, et al. the international index of erectile dysfunction (iief): a multidimensional scale of assessment of erectile dysfunction. urology 1997; 49:822-30. 9. kim sh, paick js, lee se, et al. doppler sonography of deep cavernosal artery of the penis: variation of peak systolic velocity according to sampling location. j ultrasound med. 1994; 13:591-4. 10. baumhakel m, schlimmer n, kratz m, et al. cardiovascular risk, drugs and erectile function:a systematic analysis. int j clin pract. 2011; 65:289-98. 11. kropman rf, schipper j, van oostayen ja, et al. the value of increased end diastolic velocity during penile duplx sonography in relation to pathological venous leakage in erectle dysfunction. j urol. 1992; 148:314-7. 185archivio italiano di urologia e andrologia 2016; 88, 3 penile vascular diagnostic categorization using penile duplex doppler ultrasound: differences in vascular hemodynamics parameters by... sampling at the “crus” sampling “mid penis” positive for vod: 96.6% (29) negative for ai: 100% (90) negative for ai 100% (90) table 2. second pool of patients (90). figure 4. normal cavernous artery. figure 5. normal arterial parameters. figure 6. edv augmented (dvo). correspondence fabio pezzoni (corresponding author) tel. ++39.333.40.36.098 fabiopezzoni1@alice.it vascular surgeon, university of milano v. g. pezzotti, 36 milano scroppo fabrizio i., md member of sia fabrizio.scroppo@ospedale.varese.it department of urology and andrology,uoc urology ospedale di circolo, viale l. borri, 57 varese, italy pezzoni_stesura seveso 21/09/16 08:44 pagina 185 97archivio italiano di urologia e andrologia 2017; 89, 2 original paper cryotherapy for low risk prostate cancer, oncological and functional medium term outcomes: a three center prospective study valerian ciprian lucan 1*, franco lugnani 2*, salvatore butticè 3*, emre sener 4, christopher netsch 5, michele talso 6, francesco cantiello 7, rosa pappalardo 3, carlo magno 3 1 clinical institute of urology and renal transplants, cluj-napoca, romania; 2 unit of urology, kirurski sanatorij ljubljana, slovenia; 3 department of human pathology section of urology, university of messina, italy; 4 department of urology, school of medicine, marmara university, istanbul, turkey; 5 department of urology, asklepios hospital barmbek, hamburg, germany; 6 department of urology, fondazione irccs ca' granda ospedale maggiore policlinico, università degli studi di milano, italy. 7 department of urology, magna graecia university, catanzaro, italy. * the authors contributed equally to the manuscript. objectives: analyze the oncologic and functional outcomes in patients affected by low risk prostate cancer underwent prostate cryotherapy. materiasl and methods: it’s a prospective tricentric study of 434 patients treated with prostate cryoablation for low risk prostate cancer. by low risk we refer to the d'amico’s risk classification. two cycles of freezing/thawing are run for each patient following the technique described by onik. results: for the 434 patients, the median age was 66 years with a standard deviation of ± 6.68, the average psa was 6.17 ng/d/l, the median 5.55 with a standard deviation of ± 2.13, the mean prostate volume was 35.59 cc, the median 34.00 cc, with a standard deviation of ± 7.89. biochemical failure occurred in 67 patients (15.4%). pre-operative erectile function in men was distributed as follows: severe in 95 patients (19.2%), moderate in 95 (19.2%), medium-moderate in 180 (36.4%), mild in 92 (18.6%), with no dysfunction in 32 (6.5%) patients. post-operative erectile function, measured 1 month after cryotherapy, was distributed as follows: severe in 321 (65%) patients, moderate in 69 (14%), medium-moderate in 79 (16%), mild in 23 (4.7%), and no dysfunction in only 2 patients (0.4%). post-operative erectile function after 3 months was distributed as follows: severe in 233 (47.2%) patients, moderate in 66 (13.4%), medium-moderate in 122 (24.7%), mild in 65 (13.2%), and no dysfunction in 8 patients (1.6%). urinary incontinence was present in 21 patients (4.8%) after 3 months while it dropped to 13 patients (2.9%) after 6 months. conclusions: cryotherapy in the treatment of prostate cancer remains a viable alternative. the availability of new cryoprobes and the use of new diagnostic means such as fusion magnetic resonance will make this more precise and more effective method. key words: prostate cryotherapy; minimally invasive treatment; focal therapy; low risk prostate cancer. submitted 2 january 2017; accepted 18 february 2017 summary no conflict of interest declared. currently there are many different options for treatments of prostate cancer, particularly for the low risk variety from d'amico’s risk classification (2). according to the latest eau guidelines there are different types of standard treatments for low risk prostate cancer. in recent years, with the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies have been proposed: watchful waiting and active surveillance (3). surgical treatment of pca consists of the radical prostatectomy (rp). in low risk patients the gold standard of care is the nerve sparing technique. the goal of surgery is to eradicate the disease by preserving continence and sexual potency when possible (4). pelvic lymph node dissection (lnd) is not required for low-risk tumors because the risk of positive lymph nodes does not exceed 5%, according to briganti’s nomograms (5). radiotherapy for prostate cancer is an important and safe alternative to surgery and is the only form of curative treatment (6-7). for the treatment of clinically localized prostate cancer new therapeutic approaches have emerged as alternative therapeutic options: defined focal therapies that include two methods, the hifu (high-intensity focused ultrasound) and cryotherapy (csap) (8-9). the use of cryosurgery has been enhanced thanks to the introduction of a modern percutaneous approach using trans-rectal ultrasound probe introduced by onik et al. in 1993 (8). in 2008 the aua’s best practice statement on cryosurgery affirmed that cryosurgery is an option for patients with an organ confined disease (10). the aim of this study is to investigate the oncological and functional outcomes in patients affected by low-risk prostate cancer. materials and methods our is a prospective tricentric study of 434 patients treated with prostate cryoablation for low risk prostate cancer. by low risk we refer to the d'amico risk classifidoi: 10.4081/aiua.2017.2.97 introduction in the era of the psa screening the detected rate of prostate cancer has dramatically increased (1). lucan_stesura seveso 20/06/17 09:31 pagina 97 archivio italiano di urologia e andrologia 2017; 89, 2 v. ciprian lucan, f. lugnani, s. butticè, e. sener, c. netsch, m. talso, f. cantiello, r. pappalardo, c. magno 98 cation of clinical stage (< t2a, psa levels < 10.0 ng/ml, and a gleason score ≤ 6). all patients were operated on using the same surgical technique, performed by the same surgeon in 80% of cases. the surgery was performed under general anesthesia. patient preparation includes cleansing with enema and broad spectrum antibiotic prophylaxis. the patient is in the dorsal lithotomy position, in this way facilitating the exposure of the perineum and the movements of the rectal probe (probe longitudinal biplane to 7.5 hz). in all cases the coaxial system stryker cryo/44 was used with cryoprobes of 2.4 mm in diameter, from six to eight in number depending on prostate volume. cryoablation involves 2 cycles, one freezing and one cooling; respectively exploiting cycles of pressurized gas, argon (300 bar of pressure and -180°c) for the freezing cycle and helium for the heating cycle (200 bar of pressure with 180°c temperature exchange to 40°c in 30 seconds). the temperature is monitored inside and outside of the prostate. thermal sensors, are positioned in the apex, external sphincter, and neurovascolar bundle to the right and to the left of the gland. hydrodistention of the rectal area prostate was performed by injecting saline solution mixed with broad-spectrum antibiotic in the denonvilliers' fascia (onik maneuver band). control cystoscopy is performed in order to ensure integrity of the urethra, which is protected by means of an fda-approved continuous flow system with a pump pressure of 4.5 bar, which puts blue methylene physiological solution into circulation at 41°c and keeps adjacent tissues at a temperature of 38°c (11-14). at each cryoablation two complete cycles of freezing/ thawing are run. depending on prostate volume or on prostates with a larger longitudinal diameter of 35 mm, a third cycle with a distal displacement of 10 millimeters of cryoprobes was necessary, in a maneuver referred to as "pull back". the patients were discharged within 24 hours, with a catheter in place for two weeks and were given antiinflammatory drugs for the pain (8). biochemical recurrence was determined according to the phoenix defined by astro criteria as a rising psa, above the nadir of more than 2 ng/ml (15). follow-up was carried out in hospital laboratories by monitoring psa level every month for the first three months and then once every six months for a total of 54 months. statistical analysis statistical analysis was performed with stata 14 software by statacorp, descriptive variables were analyzed using mean, median, standard deviation, and a 95% confidence interval (95% ci). the survival curves were described using the kaplan-meier method. after making the appropriate test for normality (shapiro-wilk test) to validate if the assumptions underlying the model were statistically satisfied. we applied the model of analysis of variance in our sample. results for the 434 patients, the median age was 66 years with a standard deviation of ± 6.68, the average psa was 6.17 ng/dl, the median 5.55 with a standard deviation of ± 2.13, the mean prostate volume was 35.59 cc, the median 34.00 cc, with a standard deviation of ± 7.89. biopsies performed on patients for pre-intervention of disease diagnosis were conducted trans-rectally in 421 patients (97%), and trans-perineally in 13 patients (3%). biochemical failure occurred in 67 patients (15.4%) (figures 1-2). the survival curve it’s shown in the kaplan-meier graph (figure 3). the average hospital stay was for 1.89 days, with a median of 1 and a standard deviation of ± 1.48. figures 1-2. box plot psa/time. lucan_stesura seveso 20/06/17 09:31 pagina 98 pre-operative erectile function in men (figure 4) was distributed as follows: severe in 95 patients (19.2%), moderate in 95 (19.2%), medium-moderate in 180 (36.4%), mild in 92 (18.6%), with no dysfunction in 32 (6.5%) patients. post-operative erectile function, measured 1 month after cryotherapy (figure 4), was distributed as follows: severe in 321 (65%) patients, moderate in 69 (14%), mediummoderate in 79 (16%), mild in 23 (4.7%), and no dysfunction in only 2 patients (0.4%). post-operative erectile function (figure 4) after 3 months was distributed as follows: severe in 233 (47.2%) patients, moderate in 66 (13.4%), medium-moderate in 122 (24.7%), mild in 65 (13.2%), and no dysfunction in 8 patients (1.6%). in 87% of cases (377 patients) two freeze and thaw cycles were applied while three cycles were applied in the remaining 13% of patients (57 patients) due to the size and/or morphology of the prostate. number 4 needles were used in 68 patients (15.6%), number 6 needles in 290 patients (67.4%), and number 8 needles were used in 73 patients (17%). urinary incontinence was present in 21 patients (4.8%) after 3 months while it dropped to 13 patients (2.9%) after 6 months. concerning complications: • perineal hematoma in 207 (47.6%), • luts in 149 patients (34.3%), • scrotal hematoma in 119 patients (27.4%), • urinary tract infection in 44 patients (10%), • perineal pain in 38 patients (8.7%), • scrotal edema in 33 patients (7.6%), • persistent hematuria was present in 22 patients (5%), • urinary fistula in 16 patients (3.6%), • urethral stricture in 14 patients (3.2%), • hydronephrosis in only 1 patient (0.2%). discussion cryotherapy for the treatment of prostate cancer is a technique that was originally introduced in 1960, but was soon abandoned because of excessive morbidity (11-13). the use of this therapeutic approach has increased with its reintroduction by onik et al. in 1993 thanks to the introduction of a modern percutaneous approach with the aid of a trans-rectal ultrasound probe (8). the treatment itself has undergone an evolution over decades of application in clinical practice; the development of interventional radiology has improved cryogenic technology and provided a better understanding of cryobiology (16-17). the action mechanism of cryotherapy is complex. it exerts its effect by: the induction of protein denaturation, dehydration, rupture of the cell membrane due to expansion of ice crystals, the transfer of water from the intracellular side to extracellular spaces, vascular stasis, the induction of apoptosis, increasing the concentration of toxic substances at the intracellular level and finally osmotic shock (8, 11-14). traditionally, supporters of cryotherapy as primary treatment for prostate cancer have sustained that the procedure offers advantages over conventional treatments, allowing a non-invasive treatment of cancer in patients who are very elderly or are suffering from multi-comorbidity and would otherwise not be eligible candidates for traditional surgery; in recent years refinement of the procedure has also allowed an increase in effectiveness and safety. our data on survival free from biochemical recurrence after a follow-up of 54 months proves that this procedure produces efficacy rates that are highly competitive with all other conventional forms of therapy recommended by european and international guidelines; above all with three-dimensional radiation therapy, conformational radiotherapy or brachytherapy. our findings strongly indicate a need to expand the role of cryoablation in clinical practice of prostate cancer treatment. head to head comparison with different modalities of treatment for prostate cancer is affected by several factors such as: • the retrospective nature of the study, • the monocentric nature of most studies, • the often non-uniform or standardized selection of patients, • the use of various dosing procedures and different techniques conducted by different laboratories, • variations, according to different classification criteria, in the definition of biochemical failure. 99archivio italiano di urologia e andrologia 2017; 89, 2 cryotherapy for pca: medium term outcomes figure 3. kaplan-meier curve. figure 4. diagram iief-5 pre operative; post operative; after 3 months. lucan_stesura seveso 20/06/17 09:31 pagina 99 archivio italiano di urologia e andrologia 2017; 89, 2 v. ciprian lucan, f. lugnani, s. butticè, e. sener, c. netsch, m. talso, f. cantiello, r. pappalardo, c. magno 100 as a result, there is no definitive oncological comparative data. however, in a recent comparative study between cryoablation and radiation therapy conducted on 244 patients no significant differences between the two groups (76%) were found (15). in another trial a psa nadir of less than 0.4 ng/ml in 81% of patients was shown without biochemical progression for 12 months of study. in another single-center study with 590 patients and a mean follow-up of 7 years, the percentage of patients free of biochemical recurrence was approximately 61% (16). however, not all data in the literature support the idea that cryotherapy and radiotherapy are equivalent, especially in high-risk patients. uae guidelines, compared with aua guidelines, show a substantial difference in classifying candidate patients for cryotherapy; in fact, in europe, the “model” patient remains the low risk patient, whereas in the united states the procedure has been extended to cases of higher risk, as long as the disease is organ-confined. another aspect to consider is the comparison with invasive treatments such as radical prostatectomy. gould et al. have shown a lower incidence of biochemical recurrence in patients who underwent cryotherapy compared to radical prostatectomy. this study presents several biases and was conducted on a small number of patients (18). active surveillance is one of the treatment options for patients at low risk of prostate cancer. klotz et al. have analyzed patients ranging from t1c and t2a, psa < 10 ng/ml, gleason score < 6, or psa < 15 ng/ml for patients older than 70 years with gleason < 7 (3 + 4) (19-20). with an average follow-up of 6.8 years, survival at 10 years was 97.2%. for the 62% of patients who were still in active surveillance, 30% underwent radical prostatectomy; 10% preferred to switch to active treatment due to a psa doubling time < 3 years or an advancing gleason score. the collective survival varies from 70% to 100%. biochemical failure has occurred in 13% of patients undergoing active surveillance (21). more recently a number of radical prostatectomies for low and intermediate risk patients demonstrated a percentage of psa free survival from 60% to 65% and a cancer specific survival between 94% and 97% with a follow-up of 53 to 153 months. for high risk patients biochemical failure was 44% and 53% after 5 and 10 years respectively (22). in 2010 donnelly et al. published a randomized article that compared patients with localized prostate cancer treated with erbt versus cryotherapy. they demonstrated no significant difference between the two techniques after 36 months in 244 patients with a mean follow-up of 100 months. the was some progression of the disease at 36 months in 23.9% of patients undergoing cryotherapy and 23.7% in patients receiving radiotherapy. no difference was observed in the specific servival of the disease. in another article, donnelly et al. have also compared radical surgery, erbt and brachytherapy with the data of cryotherapy in mediumand high-risk patients. the interval free of biochemical recurrence for medium risk patients was 37-97% for the radical prostatectomy, 2660% for the erbt and 66-82% for the brachytherapy. in high-risk patients the interval free of biochemical recurrence decreases to 16-61% in low-risk, 19-25% in the erbt, and 40-65% in brachytherapy (23). with this data the authors concluded that cryotherapy seems superior to ebrt for moderate and high risk patients, and the data seemed comparable for mediumhigh risk patients undergoing brachytherapy and radical prostatectomy (15). in our series biochemical recurrence occurred in 15.4%, with an incidence lower than many previously published trials. in 2008, cohen et al. reported 370 patients with a mean follow-up of 147 months and an interval free ofbiochemical recurrence in 80%, 74% and 46% respectively, for low, intermediate and high risk patients (24). in our study we assessed erectile function, giving the patient the iief-5 test, we then evaluated the differences between the various categories. from the graphs you can see how classes with greater “movement” of patients towards worse erectile function in absolute terms are the patients with average to moderate dysfunction and slight during the pre-operative assessment phase, passing to the postoperative, respectively from 180 to 79 and 92 to 32, while patients with severe dysfunction increased from 95 to 321 or from 19.2% to 65%. radiation therapy appears to have a lesser impact on erectile function (25). the percentage of maintained erectile function after various interventions was 0.76 after brachytherapy, 0.60 after brachytherapy + external beam irradiation, 0.55 after external irradiation only, 0.34 after nerve-sparing radical prostatectomy and 0.25 after standard radical prostatectomy. selecting studies with a 2 year disease follow-up (excluding brachytherapy), the percentage was 0.60, 0.52, 0.25 and 0.25 respectively (26). in terms of quality of life, there are several studies that compare cryotherapy as a treatment for a locally advanced tumor. patients treated with cryotherapy and brachytherapy reported a higher score of urinary disorders when compared with radical prostatectomy (27). since it was adopted, robotic prostatectomy has not shown significant benefits in functional outcome compared with the open approach. ball et al. compared 719 patients treated with open, laparoscopic and a robotic approach, as well as brachytherapy and cryotherapy (28). men treated with brachytherapy and cryotherapy were older and had more co-morbidities. the analysis demonstrated that cryotherapy has a negative impact on erectile function with respect to brachytherapy, and that this effect is reduced to 3 and 6 months, while the irritative and obstructive symptoms were higher in brachytherapy. in patients undergoing cryotherapy, worse sexual outcomes were 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systematic review of the literature. eur urol. 2012; 62:976-83. 22. yossepowitch o, eggener se, bianco fj jr, et al. radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. j urol. 2007; 178:493-9. 23. donnelly bj, saliken jc, brasher pma, et al. a randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. cancer. 2010; 116:323-30. 24. cohen jk, miller rj jr, ahmed s, et al. ten-year biochemical disease control for patients with prostatecancer treated with cryosurgery as primary therapy. urology. 2008; 71:515-8. 25. fowler fj, barry mj, lu-yao g, et al. outcomes of externalbeam radiation therapy for prostate cancer: a study of medicare beneficiaries in three surveillance,epidemiology, and end results areas. j clin oncol. 1996; 14: 2258-65. 26. robinson w, moritz s, fung t. meta-analysis of rates of erectile function after treatment of localized prostatecarcinoma. int j radiat oncol biol phys. 2002; 54:1063-8. 27. malcolm jb, fabrizio md, barone bb, et al. quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer. international braz j urol. 2011; 37:118. 28. ball j, gambill b, fabrizio md, et al. prospective longitudinal comparative study of early health-related quality of life outcomes in patients undergoing surgical treatment for localized prostate cancer: a short-term evaluation of fiveapproaches from a single institution. journal of endourology. 2006; 20:723-731. 101archivio italiano di urologia e andrologia 2017; 89, 2 cryotherapy for pca: medium term outcomes correspondence valerian ciprian lucan, md lucan_valerian@yahoo.com clinical institute of urology and renal transplants, cluj-napoca, romania franco lugnani, md franco.lugnani@gmail.com unit of urology, kirurski sanatorij ljubljana, slovenia salvatore butticè, md (corresponding author) salvobu@gmail.com rosa pappalardo, md gattoparto@hotmail.it carlo magno, md cmagno@unime.it department of human pathology section of urology, university of messina via consolare valeria 1, 98125, messina, italy emre sener, md dr.emresener@gmail.com department of urology, school of medicine, marmara university, istanbul, turkey christopher netsch, md department of urology, asklepios hospital barmbek, hamburg, germany c.netsch@asklepios.com michele talso, md michele.talso@gmail.com department of urology, fondazione irccs ca' granda ospedale maggiore policlinico, università degli studi di milano, milan, italy francesco cantiello, md cantiello@unicz.it department of urology, magna graecia university, catanzaro, italy lucan_stesura seveso 20/06/17 09:31 pagina 101 stesura seveso 233archivio italiano di urologia e andrologia 2014; 86, 3 case report endometriosis localized to urinary bladder wall mimicking urinary bladder carcinoma mine genç 1, berhan genç 2, serap karaarslan 3, aynur solak 2, musa saraçoğlu 4 1 şifa university school of medicine, department of obstetric and gynecology, izmir, turkey; 2 şifa university school of medicine, department of radiology, izmir, turkey; 3 şifa university school of medicine, department of pathology, izmir, turkey; 4 şifa university school of medicine, department of urology, izmir, turkey. although endometriosis is a common disease in women of reproductive age, urinary system endometriosis is an exceedingly rare disease that may cause important clinical problems. in this paper we discussed a 42-year-old woman who had urinary bladder endometriosis misdiagnosed as urinary bladder tumor in imaging modalities. the diagnosis of endometriosis was made by histopathological examination of the operative material after partial resection of the urinary bladder. urinary bladder endometriosis causes nonspecific signs and symptoms in many patients. in female patients presenting with unexplained urinary symptoms the differential diagnosis should include urinary bladder endometriosis that may mimic urinary bladder cancer and lead to difficulties in making definitive preoperative diagnosis. key words: endometriosis; urinary bladder; urinary tract endometriosis. submitted 22 december 2013; accepted 31 march 2014 summary introduction endometriosis is the presence of functional endometrial tissue in ectopic foci outside the uterine cavity. approximately 10% of women of reproductive age suffer from endometriosis (1). urinary tract endometriosis (ute) is observed in 1-2% of women with endometriosis. among women with ute, about 80% have urinary bladder involvement (2). we presented herein a patient presenting to our clinic with pelvic pain and dysuria who was diagnosed with an endometriosis focus on the roof of the urinary bladder, which was initially misdiagnosed as primary urinary bladder cancer. case report a 42-year-old woman, who had two previous deliveries with caesarean section, presented with pelvic pain and dysuria worsening in the last 6 months. she had no hematuria. her menstrual cycles were regular; however, she stated that the pelvic pain and dysuria worsened during menstrual period. the gynecological examination was no conflict of interest declared. not remarkable. transabdominal ultrasonographic examination revealed an irregular contoured, solid, hypoechoic lesion of 4 x 1.5 cm on the roof of the urinary bladder. magnetic resonance imaging showed a mass lesion with homogenous contrast uptake that appeared hypointense in t1w and hyper-intense in t2w (figure 1). mri images suggested a malignant diagnosis. flexible cystoscopy was performed and a biopsy sample was taken from the lesion. biopsy result was reported as nonspecific urinary bladder tissue. the tumoral mass was then removed with laparotomy and partial cystectomy. examination of the excised tumoral tissue showed macroscopic hemorrhagic foci on the urinary bladder wall. microscopic examination revealed some areas consistent with cystitis glandularis and, in addition, other areas consistent with endometrial glands and stroma inside the muscular layer (figure 2). discussion endometriosis is the presence of functional endometrial tissue in ectopic foci outside the uterine cavity. urinary tract endometriosis (ute) is observed in 1-2% of women with endometriosis. among women with ute, about 80% have urinary bladder involvement (2). this is followed by, in descending order of frequency, ureters, kidney, and urethra. endometrial lesions may assume the appearance of a polypoid mass similar to that of urinary bladder carcinoma when they grow towards the mucosa alongside the muscle layers. urinary bladder endometriosis is termed as “primary” or “secondary” depending on its type of onset: the primary urinary bladder endometriosis occurs when the endometrial tissue is congenitally located within the urinary bladder wall. the secondary urinary bladder endometriosis, on the other hand, is a iatrogenic lesion occurring in patients delivering a baby with caesarean section or undergoing a pelvic operation such as hysterectomy. up to 50% of patients with urinary bladder endo metriosis have a previous history of a pelvic operation. symptoms of urinary bladder endometriosis may vary depending on the localization and the site of the lesion. the symptoms may include recurrent cystitis, pelvic pain, dysuria, tenesmus, and burning sensation. hematuria is present in 20-35% of cases. menouria (hematuria with doi: 10.4081/aiua.2014.3.233 genc cr_stesura seveso 08/10/14 12:20 pagina 233 archivio italiano di urologia e andrologia 2014; 86, 3 m. genç, b. genç, s. karaarslan, a. solak, m. saraçoglu 234 menstruation) is not as common as the acute urethral syndrome, and it is seen in only 20-25% of cases when the mucosa is affected. negative urinary cultures in symptomatic individuals at premenopausal period may suggest urinary bladder endometriosis. ultrasonography (usg) is the first step in the diagnosis of urinary bladder endometriosis. usg may provide information with respect to lesion size and localization as well as the degree of infiltration of mucosa and detrusor muscle. magnetic resonance imaging (mri) is an excellent modality for demonstrating urinary bladder endometriosis (3). the role of cystoscopy is limited in diagnosing urinary bladder endometriosis since the lesion of urinary bladder endometriosis is usually located on the serosal surface or in the submucosal layer of the urinary bladder. cystoscopic findings may be normal despite a positive transvaginal ultreasonography (tv usg). endoscopic biopsy is of pivotal importance for differentiating the lesions from carcinomas, varices, papillomas, angiomas, and also detrusor mesenchymal tumors. however, cystoscopic biopsies except for transurethral resection (tur) procedures are not always diagnostic. also in our case, the lesion went unnoticed in cystoscopy as it was localized to submucosal and intramuscular regions. the differential diagnosis of urinary bladder endometriosis include epithelial tumors of urinary bladder, hemangiomas, myomas of anterior uterine wall, detrusor muscle leiomyomas, fibromas, glandular cystitis, nephrogenic adenoma, and diverticulitis. treatment of disease varies by certain factors including age, fertility preferences, disease extension, severity of lower urinary system symptoms, presence of other pelvic lesions, and degree of menstrual dysfunction. the therapy may be in the form of medical therapy (hormonal agents), surgery, or a combination of the two. in young women willing to maintain their fertility gonadotropin releasing hormone (gnrh) agonists and antagonists, progestins, danazol, and combined oral contraceptives are used. surgical therapy consists of transurethral surgery (tur) and partial cystectomy (laparotomic or laparoscopic). in conclusion, the urinary system is the second most commonly involved site by extrapelvic endometriosis. it constitutes 1-2% of all endometriosis cases. fifty percent of patients with urinary bladder endometriosis have a previous history of a pelvic operation (including caesarean section). the diagnosis may be done by ultrasonography (usg), mri, or cystoscopy. the therapy may be in the form of medical therapy (hormonal agents), surgery, or a combination of the two. the diagnosis of endometriosis should definitely be remembered in patients in whom usg detects a mass at the urinary bladder wall but cystoscopy fails to show any lesion. references 1. olive dl, schwartz lb. endometriosis. n engl j med. 1993; 328:1759-69. 2. shook te, nyberg lm. endometriosis of the urinary tract. urology 1988; 31:1-6. 3. beaty sd, silva ac, de petris g. bladder endometriosis:multrasound and mri findings. radiology case reports. 2006; 1:92-95. figure 1. a. b. figure 2. a. b. c. d. sagittal t1-weighted images: the pre-contrast image (a) demonstrates a mass grown within the muscle layer that shows no luminal projection at the posterior part of the urinary bladder roof (arrows). post-contrast image (b) demonstrates that the mass has a diffuse homogenous contrast uptake (arrows). (a) at the upper part of the image there are areas with features of cystitis glandularis at the urinary bladder’s urothelial epithelium (red arrow) and areas of endometriosis (green arrow) composed of foci of endometrial glands and stroma within muscularis propria at the submucosal layer (h&e x 10); (b) foci of endometriosis within the muscularis propria of the urinary bladder (h&e x 10); (c) a closer view of the areas of endometriosis (h&e x 40); and (d) estrogen receptor (er) positivity in the foci of endometriosis (er x 20). correspondence mine genç, md (corresponding author) doktorminegenc@gmail.com sifa university school of medicine, department of obstetric and gynecology fevzipasa boulevard, n: 172/2 basmane 35240 izmir, turkey berhan genç, md aynur solak, md sifa university school of medicine, department of radiology izmir, turkey serap karaarslan, md sifa university school of medicine, department of pathology izmir, turkey musa saraçoglu, md sifa university school of medicine, department of urology izmir, turkey genc cr_stesura seveso 08/10/14 12:20 pagina 234 stesura seveso 193archivio italiano di urologia e andrologia 2014; 86, 3 original paper the impact of sexual activity on serum hormone levels after penile prosthesis implantation onder canguven, raidh a. talib, ahmed shamsodini, abdulla al ansari hamad general hospital, urology department, doha, qatar. objectives: penile prosthesis implantation is the final treatment option for patients who have erectile dysfunction. most of the patients use their penile prosthesis successfully and frequently for penile-vaginal intercourse. previous literature showed that decrease in sexual activity resulted in decreased serum testosterone levels and vice versa. the aim of this study was to examine the impact of sexual activity on serum sex hormone levels after penile prosthesis usage. material and methods: in this study, we examined sixtyseven patients for their sex hormone changes who had penile prosthesis surgery 2.7 ± 1.5 years ago. results: patients were using their penile prosthesis for sexual activity with a mean of 9.9 ± 5.7 times per month. dehydroepiandrosterone sulfate was significantly higher compared to pre-surgery results (5.3 ± 2.6 vs 4.5 ± 2.9; p = 0.031). mean serum total testosterone levels of patients before and after penile prosthesis usage were clinically significant 15.78 ± 4.8 nmol/l and 16.5 ± 6.1 nmol/l, respectively. mean serum luteinizing hormone levels of patients before and after penile prosthesis usage were 3.98 ± 2.16 iu/l and 5.47 ± 4.76 iu/l, respectively. no statistical significance difference was observed in the mean total and free testosterone, estradiol and luteinizing hormone levels between preand post-surgery. conclusion: this study results demonstrated that sexual activity changed sex hormone levels positively among those men who were implanted penile prosthesis because of erectile dysfunction. key words: androgens; erectile dysfunction; hypogonadism; prosthesis; testosterone. submitted 9 april 2014; accepted 30 june 2014 summary no conflict of interest declared. healthy men (1, 2). testosterone, which has androgenic and anabolic effects on human body, decline gradually with aging in males. major benefits of testosterone on sexual function, mood, and strength are well known from the ancient times. currently, evidence supports the concept that normal testosterone levels reduce cardiovascular disease risk, decrease fat, decrease total cholesterol, increase muscular body mass, and display good glycemic control (3). moreover, epidemiological studies imply that many important disease states and related comorbidities are linked to low testosterone levels (4). although there are mixed results from animal studies (5), male testosterone concentrations before and after sexual activity were shown as increased in human studies (6, 7). insertion of a penile prosthesis (pp) for men who cannot use or fail to respond to first and second line treatments is the final treatment option for ed. actually pp provides a satisfactory, definitive solution for ed. in different patient satisfaction studies it was shown that, of the pp implanted men more than 90% stated they were still using the pp for sexual intercourse with an average frequency of coitus of 5 times monthly (8-10). a recent study conducted by escasa et al. supported previous studies and confirmed that sexual activity increases testosterone level which was more prominent in participants who had sexual intercourse (7). the aim of this study is to examine the influence of sexual activity on serum sex hormone levels after pp practice. materials and methods after institutional review board approved the study, a retrospective chart analysis was performed on patients that underwent pp implantation surgery from january 2009 through january 2013. all participants provided written informed consent. enrollment and data collection were conducted at follow-up visits at least 6 months and up to 4 years after implantation. the 67 patients with pp implantation reported in this study were ambulatory patients seen at our andrology clinic who met all of the following criteria. the principal eligibility criteria included patients who were requested hormonal profile examined in this study (total and free testosterone, estradiol, dehydroepiandrosterone sulfate (dheas) and lh) in the last month before the surgery doi: 10.4081/aiua.2014.3.193 introduction erectile dysfunction (ed) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. many of patients with ed have not had a normal erection in many months or years. previous studies demonstrated that sexual inactivity results in reversible reduction of luteinizing hormone (lh) and serum testosterone levels in ed patients compared to canguven_stesura seveso 08/10/14 12:09 pagina 193 archivio italiano di urologia e andrologia 2014; 86, 3 o. canguven, r.a. talib, a. shamsodini, a. al ansari 194 they had. another important inclusion criteria for the participation was regular sexual intercourse with his wife after pp implantation surgery. prostate cancer, creatinine > 2 mg/dl, myocardial infarction or stroke within 6 months, or congestive heart failure, and use of androgens, antiandrogens comprised major exclusion criteria. medications that influence hormone levels, such as high-dose opiates, glucocorticoids, antiepileptics or any kind of herbal drugs also excluded participation. fasting blood samples were obtained between 7-9 am in the morning. testosterone, lh, dheas and estradiol levels were measured by standard ria kits. we also asked global satisfaction question (gsq) “did the implant permit you to experience satisfactory sexual relations?” and a frequency question “how many times do you use your pp for sexual activity each month?” to all participants at the time of their participations. statistical analysis qualitative and quantitative data values were expressed as frequency (percentage) and mean ± sd. quantitative variables means between pre and post surgery groups were compared using paired t-test. pearson correlation coefficient was used to examine and assess the linear relationship between the two quantitative variables. pictorial presentations of the key results were made using appropriate statistical graphs. a two-sided p value < 0.05 was considered to be statistically significant. all statistical analyses were done using statistical packages spss 19.0 (spss inc. chicago, il). results sixty-seven male subjects who had active sexual life with aid of pp were enrolled in the study. mean age of patients was 59.9 ± 10.9 (range: 30-82) years. the mean duration of ed problem was 2.7 ± 1.5 years. with the gsq, sixtyseven patients who responded as ‘yes’ were included to our study group. with the frequency question, we aimed to learn frequency of the penile intercourse: 64 patients (95.5%) responded to use it frequently, while three (4.5%) declared they use it rarely because of partner related problems. the average of pp usage for sexual activity was 9.9 ± 5.7 (range: 2-28) times per month. the mean time from surgery was 22.6 months (range: 6 months-48 months). paired t-test revealed that post-surgery mean dheas was significantly higher compared pre-surgery results (5.3 ± 2.6 vs 4.5 ± 2.9 μmol/l; p = 0.031) (figure 1). no statistical significance difference was observed in the mean total and free testosterone, estradiol and lh between preand post-surgery results. mean values following post-surgery was found to be observationally higher compared to pre-surgery group for total testosterone (16.5 ± 6.1 vs 15.8 ± 4.8 nmol/l; p = 0.195), free testosterone (86.7 ± 15.9 vs 79.7 ± 20.4 pmol/l p = 0.258), estradiol (11.67 ± 4.69 vs 10.58 ± 3.79 pmol/dl; p = 0.191), and lh (5.1 ± 4.5 vs 4.2 ± 2.2 iu/l); p = 0.158), however these differences were statistically insignificant (p > 0.05). further, pearson’s correlation analysis revealed that variable monthly intercourse were inversely or negatively related to estradiol, lh and age (correlation coefficient r <-0.3) again this correlation coefficient values were not statistically significant (p > 0.05). discussion we tested whether pp usage after a long period of time having no penile-vaginal intercourse and sexual activity in ed patients’ impact on sex hormone levels. we showed that pp usage caused a significant increase in dheas levels after pp usage. we also demonstrated that mean total and free testosterone, estradiol, lh levels were clinically increased after pp usage, however the results were statistically insignificant. our results carry important clinical implications. in particular, the findings suggest that pp implantation presents not only a change in sex life of a man but also change in hormone levels in a positive direction. these increases, especially, becomes more important when we take longitudinal studies into account. because, longitudinal studies in male aging researches have demonstrated that serum testosterone levels decline with age (11). more than forty years ago, a motivating observational study published in journal nature and provided some clues about the effects of sexual activity on testosterone (12). a lone man on an island noted that his beard appeared to grow more around the time of trips to the mainland. as beard growth could be accepted as an indirect sign for testosterone levels, he hypothesized that the sexual interest and activity increased his testosterone, which in turn increased his beard growth (12). in forthcoming years, researchers found that androgens and estrogens were significantly higher following masturbation, but interestingly not after “sham masturbation” (13). in different studies, it was also proven that sexually explicit movies increase men’s testosterone compared with sexually neutral films (6, 14). the development and easy use of salivary testosterone measurement has greatly simplified the inclusion of endocrine variables in biobehavioral research (7, 15). in one of these studies, it was demonstrated that testosterone increased in heterosexual figure 1. serum values of total testosterone, luteinizing hormone (lh), estradiol and dehydroepiandrosterone sulphate (dheas) levels. values are expressed as means of 67 patients before and after usage of penile prosthesis. * p < 0.05 canguven_stesura seveso 08/10/14 12:09 pagina 194 men even exposed to brief conversations with women (15). moreover, show off behaviors was associated with the increase in degree of testosterone. assorted research results have indicated that testosterone increases can occur in a short period, often within 15 min, in response to relevant stimuli, such as sexual activities or competitions (7, 16). in a sex club, researchers found that increase in men’s testosterone level were more pronounced among those participating in sexual activity rather than observing (7). additionally, men's testosterone changes were unrelated to their age (7). according to previous studies, it is obvious that any sexual activity influences testosterone levels in a positive direction more or less (7, 13, 16). in a previous study, jannini et al found dramatic increase in serum total and free testosterone levels three months after various ed therapies including two pp implanted patients (1). contrary to the latter study, although testosterone levels increased in our study, it was not significant. this could be due to the fact that the experimental setting in our study used evaluated testosterone levels not acutely or some weeks after treatment, but after years. the small population size (two pp implanted patients) in jannini et al study might be another explanation for the dramatic increase in testosterone level (1). another study also demonstrated that married men have reduced morbidity and mortality compared with single men (17). on the other hand, gray et al investigated a population of men and found that married men have parallel testosterone levels as single men, but that polygamously married men had higher testosterone than all other men (18). a variety of species have repeatedly been shown to respond to different female stimuli by triggering an increase in luteinizing hormone which was followed by a rise in plasma testosterone levels (19). it is well known and proven that normal testosterone level is vital for general health (3, 20). testosterone has been shown to produce positive effects on endothelial function, glucose metabolism, body composition and mood. although the significance of testosterone is well known, the extent to which testosterone deficiency is involved in the pathogenesis of these conditions is unknown. additionally, which type of testosterone formula could be useful in treatment of hypogonadism is an area of great interest and being searched. at the present time, it is recommended that androgen replacement should be taken in the form of natural testosterone. the significance of hormone alterations related to sexual activity is not known and has not been studied directly. however, it is obvious that acute increase of testosterone should present some benefits to body during sexual intercourse or after it. most studies investigated the effects of hormones on behavior, because hormones have powerful effects on the different body systems throughout life (21). on contrary, our behaviors also affect our hormones that were verified in different studies (2, 7). the “challenge hypothesis” suggests that social interactions affect testosterone levels in males, and testosterone should be high when challenges for sources or the likelihood of challenges are present (22). if we accept the “challenge hypothesis” as true, there should be more in details of testosterone increase. non-genomic actions of steroid hormones are those in which gene transcription is not directly implicated and involves second messenger participation and are rapid in action (within seconds to minutes) (23). scientific information regarding the testosterone is not limited to its’ genomic effect, it has also non-genomic effect (23, 24). animal experiments and clinical studies showed rapid non-genomic relaxant effects of androgens on the smooth musculature of coronary arteries and the aorta (25, 26). a possible protective effect of testosterone during sexual activity might be against skeletal muscle fatigue that was suggested earlier while investigating neuromuscular activity and hormonal profile in athletes (24). it is intriguing to speculate about the possible mechanisms linking testosterone and sexual activity. additionally, according to epidemiological studies there is a positive correlation between testosterone levels and mood (27). therefore there may be different and important issues involved in the testosterone-sexual activity relation. increase in testosterone and so on mood might be translated into increased confidence and behavior in difficult circumstances e.g. sexual activities. we propose, based on results of prior non-genomic testosterone research, that acute elevations in testosterone concentration may be able to reduce or compensate the effects of fatigue during sexual activities in addition to prepare the body for a successful intercourse. however, other possible explanations of increase in testosterone levels among men during sexual activity are warranted. in this study, we demonstrated significant increase in dheas levels after pp usage. actually, dhea has very low androgenic potency, but serves as the major direct or indirect precursor for most sex-steroids. dhea is secreted by the adrenal gland and production is at least partly controlled by adrenocorticotropic hormone. the bulk of dhea is secreted as a 3-sulfoconjugate i.e. dheas. in gonads and several other tissues, most notably skin, steroid sulfatases can convert dheas back to dhea, which can then be metabolized to stronger androgens and to estrogens. significant increase in dheas levels after pp usage may be due to utilize it as precursor of t in addition to testicular production. in our study, the testosterone increase was being driven from the higher levels. as has been demonstrated in the previous studies (1, 2, 6), the current study showed that sexual activity influence serum testosterone levels by increase in lh secretion in males. in a recent review article, researchers looked for potential health benefits of various sexual activities and focused on the effects of different sexual activities (28). among different sexual activities, penile-vaginal intercourse was shown associated with better psychological and physiological health indices (28). from a practical standpoint, our findings imply that penile-vaginal intercourse augmented by pp improved our patients’ testosterone level that is crucial for general health. despite its practical value, our study has limitations. firstly, it consists of lack of prospective study design. secondly, the difference in the time interval between surgery and blood taken for controlling testosterone levels were not same. thirdly, sample size was relatively small. this was mainly due to reluctance of our pp patients to participate in this study that was done years after the surgery. since they did not have any problem and satisfied 195archivio italiano di urologia e andrologia 2014; 86, 3 impact of sexual activity on hormone levels canguven_stesura seveso 08/10/14 12:09 pagina 195 archivio italiano di urologia e andrologia 2014; 86, 3 o. canguven, r.a. talib, a. shamsodini, a. al ansari 196 with their pp, they did not want to participate and give blood samples. according to literature, androgen levels have circadian rhythm and exhibit daily and seasonal fluctuations in addition to age-related decline (21). unfortunately, we did not classify our study patients’ testosterone levels according to their season when blood samples given. however, all blood samples after pp usage were taken in the same month from all participants. conclusions studies, especially in the last decades, demonstrated that sex hormones are closely related with health risks and promotes health. our study investigated possible correlations of the sex hormone levels and sexual intercourse in patients with pp. in conclusion, the present study suggests that penile-vaginal intercourse by pp usage appears to be increasing sex hormone levels relative to baseline levels that were before the pp implantation. however, further prospective controlled studies with large sample size are needed to determine why and how pp usage leads to change in sex hormone levels and how long this alteration continues. ethical standards written informed consent was obtained from patients who participated in this study. acknowledgements a grant from the hamad medical corporation primarily supported this research. we would also like to acknowledge the careful work of dr. prem chandra for his assistance with 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bergstrom j. low serum testosterone and mortality in older men. j clin endocrinol metab. 2008; 93:68-75. 21. anders s, watson n. social neuroendocrinology: effects of social contexts and behaviors on sex steroids in humans. human nature. 2006; 17:212-37. 22. wingfield jc, hegner re, dufty jr. am, ball gf. the 'challenge hypothesis': theoretical implications for patterns of testosterone secretion, mating systems and breeding strategies. the american naturalist. 1990; 136:829-46. 23. waldkirch e, uckert s, schultheiss d, et al. non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue. bju international. 2008; 101:71-5; discussion 5. 24. bosco c, colli r, bonomi r, et al. monitoring strength training: neuromuscular and hormonal profile. med sci sports exerc. 2000; 32:202-8. 25. yue p, chatterjee k, beale c, et al. testosterone relaxes rabbit coronary arteries and aorta. circulation. 1995; 91:1154-60. 26. deenadayalu vp, white re, stallone jn, et al. testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. am j physiol heart circ physiol. 2001; 281:h1720-7. 27. barrett-connor e, von muhlen dg, kritz-silverstein d. bioavailable testosterone and depressed mood in older men: the rancho bernardo study. j clin endocrinol metab. 1999; 84:573-7. 28. brody s. the relative health benefits of different sexual activities. j sex med. 2010; 7:1336-61. correspondence onder canguven, md ocanguven@yahoo.com raidh a. talib, md ahmed shamsodini, md abdulla al ansari, md hamad general hospital urology department 3050, doha, qatar canguven_stesura seveso 08/10/14 12:09 pagina 196 stesura seveso 243archivio italiano di urologia e andrologia 2015; 87, 3 original paper urinary incontinence: clinical observation on 30 patients undergoing treatment with f.r.e.m.s (frequency rhythmic electrical modulation system) massimo massari 1, patrizia desideri 2, paolo menchinelli 3, lucia cerrito 4, luciano de giovanni 3 1 general surgery unit 1, complesso integrato columbus, catholic university of the sacred heart, rome, italy; 2 specialist genesy srl; 3 urologic surgery unit, complesso integrato columbus, catholic university of the sacred heart, rome, italy; 4 department of internal medicine, policlinico a. gemelli, catholic university of the sacred heart, rome, italy. aim of the study: urge incontinence is considered to be a dysfunctional pathology of social interest due to the psychological and relational implications of such disability, the elevated number of affected patients and the consequent treatment costs. we propose an innovative non-pharmacological and non-invasive care methodology: frequency rhythmic electrical modulation system (f.r.e.m.s.) therapy (ft), based on the administration of electric fields of monophasic pulsed, negative, asymmetric current, generated by a neurostimulator with the characteristics of low variable frequency, high voltage and very low impulse duration. material and methods: 30 patients were studied with urodynamic evaluation and radiological diagnostic techniques, and underwent 2 cycles of 15 days therapy, with a 12 months follow-up. results: in 93% of cases, we obtained a positive result, with either disappearance or improvement of symptoms. conclusion: although the authors believe that clinical results deserve further neurohistological and immunohistochemical studies, in order to define the anathomophysiological and biochemical changes induced by ft, they propose it as a possible alternative to traditional pharmacological therapy and electrical stimulation. key words: urge incontinence; f.r.e.m.s.; lorenz therapy; neuromodulation; electrostimulation. submitted 17 march 2015; accepted 30 april 2015 summary no conflict of interest declared. symptomatological concept. currently, it seems reasonable to define urinary urge incontinence as the involuntary urine loss accompanied or immediately preceded by urgency; inversely, urinary stress incontinence can be described as involuntary urine loss during exertion or exercise, sneezing or coughing. mixed incontinence is characterized by losses associated to urinary urgency and effort. symptomatology in women is much more frequent (43.2% of patients affected by urinary incontinence) while in men it can be considered an occasional event with an average frequency of one episode per month (21.9% of patients with urinary incontinence). the overall prevalence in a population by the fourth decade of life onwards is estimated between 12 and 22%, with about 3 million people with ob in italy. despite being a dysfunctional disease, the set of symptoms and the repercussions on everyday relational life of affected patients, make it a disease of social interest due to its entity, incidence and costs (1). normal micturition reflex depends on a proper balance between excitatory and inhibitory descending pathways and on an afferent control coming from bladder, urethra and pelvic floor (2). functions related to detrusor contraction, release of bladder sphincter, contraction and relaxation of the pelvic floor muscles, are determined by the interaction of autonomic nervous system (ans) and the central nervous system (cns) through the spino-ponto-spinal neuronal circuit, where acetylcholine of the parasympathetic postganglionic muscarinic receptors plays an essential role in transmitting the electrical signal coming from detrusor relaxation (3, 4, 5). the muscle hyperexcitability, caused by the partial denervation of the detrusor, the increase of peripheral afferent nerve fibers or their reduced inhibition at different levels of micturition neural circuitry, cause the vesicourethral-pelvic functional imbalance, at the basis of ob symptoms. f.r.e.m.s.therapy (ft) is based on the delivery of electric fields at fixed and variable frequency, administered with doi: 10.4081/aiua.2015.3.243 introduction the term “urge incontinence” includes a symptom complex characterized by pollakiuria, urgency and urge incontinence. in 1971 bates gave the first definition as “bladder instability” or “detrusor instability”, which became in 1988, at international continence society, “detrusor hyperactivity”, divided in “detrusor instability” and “detrusor hyperreflexia”, depending on whether or not the neurological pathology is clinically manifested. successively, paul abrams and alan wein created the term “overactive bladder” (ob) exclusively on a clinicalmassari_stesura seveso 30/09/15 09:42 pagina 243 archivio italiano di urologia e andrologia 2015; 87, 3 m. massari, p. desideri, p. menchinelli, l. cerrito, l. de giovanni 244 a non-invasive transcutaneous technique. the electric fields of ft are generated by a monophasic pulsed negative asymmetrical current (lorenz therapy®), created in the laboratory, administered in patterns of electrical signals, capable of producing depolarizing action potentials on semipermeable membranes of neuronal and muscular cells. in particular, in vitro and in vivo studies (by monticelli and barrella) (6, 7) showed that the action of an electric field with variable frequency, is capable of creating a depolarizing action potential, in highly differentiated nerve cells and muscle cells, based on the recruitment of the highest density of voltage-gated ion channels (ca, k, na, mg) and neurotransmitter-dependent channels, present in semipermeable cellular membranes. the peculiar characteristic of continuous modulation of the pulse frequency allows the sequence of pulses patterns, used by ft, to activate and modulate peripheral muscle reinnervation phenomena and adjust the electrical signals generated or transmitted by neuronal cells. materials and methods in the period from january 2013 to december 2013, we selected thirty patients, 11 males and 19 females, aged between 24 and 76 years old, who came to our attention at the laboratory of urodynamics of integrated complex columbus (urological surgery), excluding the peacemaker bearers, patients with episodes of epilepsy, patients with a neoplasia that has been diagnosed, suspected or in course of chemotherapy. in 15 cases referred symptoms consisted only in urge incontinence, while in the remaining 15 cases there was a mix of stress and urge incontinence. in the 15 cases of simple urge incontinence, symptoms included recurrent cystitis from at least 1 year (3 cases), referred ineffectiveness of therapy with tolterodine and oxybutynin (6 cases) at standard dosages. in 2 cases, the symptoms developed after prostatectomy for a prostatic adenomyoma; in 3 cases it was secondary to surgical correction of cystocele and transvaginal hysterectomy. in the 15 cases with a mix of urge and stress incontinence, symptoms were also associated with recurrent cystitis (6 cases) and suprapubic pain even at average bladder distension (3 cases); in 2 cases symptomatology occurred after prostatectomy for benign prostatic pathology (3 cases), in one case it had a postpartum onset with inability to stop the micturition; ineffectiveness of pharmacological therapy in 2 cases (tolterodine, oxybutynin, administered at standard doses). in 21 cases, not associated to recurrent cystitis, x-ray cystography and pre ft urodynamic examination (slow filling cystomanometry with control of abdominal pressure) were performed. cystography showed normal findings in 2 cases (10%), in 4 cases (20%) bladder floor was moderately under the level of the pubic symphysis, bladder prolapse in 5 cases (23%), cystocele in 3 cases (14%), smoothing of vesicourethral angle in 7 cases (33%). the cystomanometric evaluation, before ft, documented in 11 cases (52%) the reduction in bladder capacity and compliance associated with sphincter hypotonia (6 of 11) and urinary escape (4 of 11); in 6 cases (29%) the detrusor instability with early urinary escape; in 4 cases (19%), the detrusor instability associated with sphincter hypotonia (1 of 4) and increase of proprioceptive sensitivity (3 of 4). the electric fields of ft, generated by the neurostimulator ets 501 (lorenz biotech, medolla, italy) were administered daily, for 15 sessions lasting 30 minutes each, by affixing the skin of pre-gelled electrodes with two methods in each session: a) in bilateral paravertebral lumbosacral region for 10 minutes with a fixed frequency of 110 hz and automatic increase of 33% every 3 minutes, pulse duration 20 μsec and variable voltage 70-250 volts managed by the patient with sub-threshold remote control (+/1 volt); for further 10 minutes with a frequency of 420 hz, pulse duration 10 μsec and variable voltage 70-250 volts managed by the patient; b) in suprapubic region, anode-cathode distance 4-6 cm, for a period of 10 minutes with variable frequency 1-100 hz and variable duration 10-40 μsec (parameters managed by a software), and variable voltage up to 250 volts managed by the patient. results in none of treated patients we recorded side effects.all patients underwent a first cycle of ft. three patients, who did not get any benefit after the first cycle of ft, refused to submit to a second cycle. the remaining 27 patients found partial benefit from the first cycle and required to undergo a second round of 15 daily sessions; the cycle of therapy was administered after an interval of two weeks. at the end of this second cycle it was asked to the patients to express subjective satisfaction with the results, on a scale of four levels: very satisfied, satisfied, moderately satisfied, unsatisfied. we recorded in 93% of cases, 25 patients, a satisfaction for the results obtained (19 satisfied, 6 very satisfied); in particular: in 14 cases (56%) we obtained a disappearance of urge incontinence and of recurrent cystitis episodes (7 cases), in 7 cases (28%) clear improvement of urge incontinence and disappearance of burning micturition and urinary leakage; in 4 cases (16%) improvement of urge incontinence but persistent, even if modest, suprapubic pain (2 cases) and recurrence of cystitis (2 cases).two patients (7%), in which urge incontinence and stress incontinence were both present, affirmed they were moderately satisfied not having achieved greater improvement, compared with that obtained after the first cycle. all 27 patients were monthly supervised in the clinical follow-up, for 12 months. after 6-8 months from the end of the second cycle of ft we recorded recurrence of urge incontinence in 3 cases out of 14 and worsening in 1 out of 4 cases where it was previously improved; recurrent cystitis with a single episode during follow up in 2 cases out of 9. the four patients with relapse or worsening of urge incontinence, asked to undergo a further cycle of ft, obtaining clinical benefit again. massari_stesura seveso 30/09/15 09:42 pagina 244 discussion and conclusions the data derived from clinical observation and follow-up suggest the following brief reflections and conclusions. in patients with a severe condition of functional urological disability or non-responding to traditionally used pharmacological therapies (8, 9), we used a simple, noninvasive method, that is repeatable, without proven side effects, which does not require complementary pharmacological therapies and that allowed us to get results with very low rates of application compared to the traditionally used electrostimulation therapies. we achieved a high level of satisfaction with the results obtained and a low rate of relapse after a quite long healthy period, with clear improvement of psychological and relational conditions in the daily lives of patients. the pathophysiological causes underlying the onset of overactive bladder are related: to the partial denervation or altered generation and conduction of electrical signals from the detrusor neural network, that records the distension of the muscle; to the excess of electrical signals that cover the ascending neuronal pathways of the sympathetic chain and lumbar dorsal root ganglia; the inability of the cns in the pontine area, deputed to function regulation of micturition, to correctly perceive the ascending electrical signals, to adjust the inhibition and the consequent loss of control on micturition, through the use of the descending paragangliar pathways of the sacral plexus. we hypothesize that ft is able, due to the frequency modulation and the peculiar morphological characteristics of the pulse, to stimulate the phenomena of reinnervation in neuronal detrusor plexus and possibly modulate the production and activation of synaptic acetylcholine, through the depolarizing activity on nerve cells, using neurotransmitter-dependent and voltage-gated ion channels, present in the semi-permeable membranes of neuronal cells. we also assumed that ft can play a key role in the partial or complete regression of recurrent cystitis (as documented in the sample of patients that were object of this study): in fact, it has been shown to be able to modulate the synthesis and release of inflammatory cytokines (although only in experimental data). we, therefore, planned a neurohistologic and immunohistochemical evaluation protocol in order to demonstrate the anathomo-pathological changes that ft might be able to stimulate and modulate. bibliography 1. creaseygh, dahlberg je. economic consequences of an implanted neuroprosthesis for bladder and bowel management. arch phys med rehabil. 2001; 82:1520-5. 2. buback d. the use of neuromodulation for treatment of urinary incontinence. aornj 2001; 73:176-8,181-7,189-90. 3. chartier-kastler ej, ruud bosch jl, perrigot m, et al. long-term results of sacral nerve stimulation (s3) for the treatment of neurogenic refractoryurge incontinence related to detrusor hyperreflexia. j urol 2000; 164: 1476-80. 4. janknegt ra, hassouna mm, siegel sw, et al. long-term effectiveness of sacral nerve stimulation for refractory urge incontinence. eur urol. 2001; 39:101-6. 5. walsh ik, thompson t, loughridge wg, et al. non-invasive antidromic neurostimulation: a simple effective method for improving bladder storage. neurourol urodyn. 2001; 20:73-84. 6. barrella m. principi biofisici, meccanismo d’azione e rilievi elettrofisiologici delle correnti impiegate nella neuromodulazione. esperienze su un metodo innovativo di stimolazione transcutanea a modulazione di frequenza e durata di impulsi. applicazioni sul microcircolo. atti congr int “il diabete e le malattie neurologiche invalidanti” orvieto, maggio 2004. 7. monticelli g. neuroni come oscillatori. molte cellule nervose esibiscono attività elettrica periodica. quale è la genesi di tale attività ritmica? è’ possibile indurre particolari segnali periodici mediante interventi esterni? ricerca scientifica ed educazione permanente”, università dgli studi di milano 1979; 6:12-17. 8. bosch rjl e groen j. sacral nerve neuromodulation in the treatment of refractorymotor urge incontinence. curr opin urol. 2001; 11:399-403. 9. scheepens wa, weil eh, van koeveringe ga, et al. buttock placement of the implantable pulse generator: a new implantation technique for sacral neuromodulation-a multicenter study. eur urol. 2001; 40:434-8. 245archivio italiano di urologia e andrologia 2015; 87, 3 urinary incontinence: clinical observation on 30 patients undergoing treatment with f.r.e.m.s correspondence massari massimo, md massimo.massari@virgilio.it menchinelli paolo, md p.menchinelli@libero.it de giovanni luciano, md (corresponding author) lucdegiovanni@libero.it via g. moscati, 31-33, 00168 roma, italy desideri patrizia, md patrizia.desideri@virgilio.it via achille papa, 7/1, 00195 roma, italy lucia cerrito, md lucia.cerrito@hotmail.it largo a. gemelli, 8, 00168 roma, italy massari_stesura seveso 30/09/15 09:42 pagina 245 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2140 case report a case report of urethral prolapse in a 38 year old female with 46xy karyotype helena watson, ewa stasiowska university hospital lewisham, london, uk. a 38-year old female presented with the acute onset of a vulval mass associated with pain and vaginal bleeding. she is female phenotype but has 46xy karyotype and complete androgen insensitivity syndrome (cais). at 15 years old she had a laparotomy and bilateral orchidectomy. following admission, an examination under anaesthesia and cystoscopy was performed. a diagnosis of strangulated complete urethral prolapse was made. the lesion was excised with diathermy and the meatal skin was reanastomosed to the urethra. at follow-up, the urethra was well healed. the patient now attends menopause clinic for oestrogen-replacement therapy. we hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. it provides further incentive for compliance with hormonereplacement therapy for patients with cais following gonadectomy, or other women with premature menopause. key words: complete urethral prolapse; complete androgen insensitivity syndrome; oestrogen deficiency. submitted 22 april 2014; accepted 31 may 2014 summary case report a 38-year old female was referred to a district general hospital in south london. she presented with the acute onset of a vulval mass over a few days, associated with pain and vaginal bleeding. she had dysuria and urinary frequency, but no voiding problems. she is female phenotype but has 46xy karyotype and complete androgen insensitivity syndrome (cais). her family history includes an aunt and cousin who had cais. at 15 years old she had a laparotomy and bilateral orchidectomy. she was commenced on hormone-replacement therapy following her surgery but had been non-compliant for a few years before presentation. following admission, an examination under anaesthesia and cystoscopy was performed. an erythematous, cyanotic, doughnut-shaped mass was protruding from the anterior vaginal wall containing distal urethral mucosa. the bladder and proximal urethra appeared normal. no conflict of interest declared she had a normal length vagina with a well-supported vaginal vault. a diagnosis of strangulated complete urethral prolapse was made. the lesion was excised with diathermy, the meatal skin was re-anastomosed to the urethra and a vaginal pack and in-dwelling catheter were inserted. the pack was removed the next day and the patient discharged to return in one week for review and a trial without catheter. at follow-up, the urethra was well healed. the patient now attends menopause clinic for oestrogen-replacement therapy. discussion we present this case because of its rarity among women in this age group and because of its connection to the individual’s genetic status and her oestrogen deficiency. urehral prolapse is defined as the complete eversion of the terminal urethra through the external urethral meatus. it is an uncommon condition usually seen in prepubertal girls and postmenopausal women. approximately 80% of cases are in the paediatric population where the incidence is 1:3000 (1). there is no reference in the literature to cases amongst women in their 30s, nor in the androgen insensitivity syndrome population. the urethra is composed of inner longitudinal and outer circular-oblique smooth muscle layers. it is a disruption in the natural cleavage plane between these two layers, which results in eversion of the urethral mucosa through the meatus. thus, although the precise cause of urethral prolapse is unknown, likely causes are congenital or acquired defects of the urethra, in particular where there is a weakened attachment between the two muscle layers. congenital defects include abnormally wide or patulous urethra, neuromuscular disorders or abnormal elastic tissue. acquired causes include trauma from childbirth, and rarely periurethral bulking agents (1). a further acquired risk factor is oestrogen deficiency: the mucosa and submucosal vascular plexus are both responsive to oestrogen, when they become atrophied the mucosal seal may be lost, predisposing to stress incontinence and urethral prolapse. oestrogen deficiency certainly seems to have played a role in our case, in light of the patient’s cais. in cais there are no visible signs of androgen action and the subjects are born with normal female external genitalia. the diagdoi: 10.4081/aiua.2014.2.140 141archivio italiano di urologia e andrologia 2014; 86, 2 a case report of urethral prolapse in a 38 year old female with 46xy karyotype nostic criteria also include male (46xy) karyotype, presence of testes, normal testosterone production, absence of mullerian duct remnants and spontaneous feminisation at puberty with no virilisation (1). in cais it is the usual practice to perform a gonadectomy due to an increased risk of testicular malignancies in these patients. in nakhal et al. retrospective evaluation of retained testes in adolescents with cais, pre-malignant foci were found in three out of 25 patients (1). after gonadectomy, oestrogen-only hormone replacement therapy is commenced to prevent menopausal symptoms and osteoporosis. the correlation of non-compliance with oestrogen therapy and presentation of urethral prolapse, suggests that oestrogen deficiency was a contributory cause. another possibility is that given 5α-dihydrotestosterone’s role in embryological development of the urogenital sinus, our patient has some subtle anatomical variation that contributed to urethral prolapse. the phenotypic variations in partial androgen insensitivity syndrome range from hypospadias in male genitalia to female genitalia with a blind-ending vaginal pouch. however there are no urological abdormalities described in the literature for cais, and if an anatomical variation in the urethra was significant, we might have expected it to cause paediatric urethral prolapse. the clinical presentation of urethral prolapse depends on the age group. in the paediatric population it is typically asymptomatic, but occasionally urinary frequency, dysuria or pain are present. postmenopausal women are usually symptomatic with vaginal bleeding, dysuria, urinary frequency and/or haematuria. on examination, urethral prolapse appears as an erythematous doughnutshaped mass protruding form the anterior vaginal wall. it may be infected, ulcerated or necrotic depending on the degree of ischaemia. confirmation that the central opening of this mass is the urethral meatus, either by observation of micturition, catheterisation or cystoscopy, is diagnostic of urethral prolapse. occasionally the diagnosis may only be confirmed on histology after excision of the mass. regarding management of urethral prolapse there are no randomised controlled trials comparing medical with surgical treatment and the majority of the experience reported in the literature is in the paediatric population. traditionally urethral prolapse was treated surgically with excision or cautery. more recently medical treatments have become more popular. rudin et al. experience with 58 cases, treated 20 medically, of which 5 had recurrence, 2 ultimately requiring surgery. in our case, the urethral mucosa was strangulated and ischaemic on presentation, necessitating surgical excision. however, if she had presented earlier topical oestrogens may well have been suitable, particularly in light of her hypo-oestrogenic state. we hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. it provides further incentive for compliance with hormone-replacement therapy for patients with cais following gonadectomy, or other women with premature menopause. consent the patient’s consent was acquired for publication, under the understanding that her name, initials or hospital number, would not be published and all attempts made to ensure anonymity. the patient understood that material may be published in print and/or online, but that material would not be used for advertising or out of context. the signed consent form is retained by the corresponding author. references 1. agzarian ae & agzarian ay. urethral prolapse, report of a case, proceedings of ucla healthcare 2010; vol. 14. 2. harris rl, cundiff gw, coates kw, et al. urethral prolapse after collagen injection, ajog. 1998; 178:p614-615. 3. jaaskelainen j, hughes ia. androgen insensitivity sundromes, in balen ah (ed.) paediatric and adolescent gyanecology: a multidisciplinary approach, cambridge university press, cambridge 2004, pp 253-263. 4. nakhal rs, hall-craggs m, freeman a, et al. evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome, radiology. 2013; 268:153-60. 5. rudin je, geldt vg, evgeny b. a prolapse of urethral mucosa in white female children: experience with 58 cases, j ped surg. 1997; 32:423-525. correspondence dr helena watson, mb bchir mrcog (corresponding author) helenawatson85@gmail.com miss ewa stasiowska, md phd mrcog university hospital lewisham, lewisham high street, se13 6lh, london, uk 83archivio italiano di urologia e andrologia 2017; 89, 1 case report b-lymphocytic infiltration of the prostate to a patient with chronic lymphocytic leukemia. a case report ioannis anastasiou, spyridon skoufias, ioannis katafigiotis, ioannis skarmoutsos, constantinos a. constantinides 1 1st university urology clinic, laiko hospital, athens, greece. involvement of the prostate gland, as an early extra-nodal manifestation of a hematologic disease, or as a secondary infiltration is rare. even rarer is the acute urinary retention due to infiltration by lymphocytes and simultaneously enlarged prostate. we present a case of a 61 years old male patient with a history of chronic lymphocytic leukemia, who was under oncological follow-up with no active treatment and had typical lower urinary tract symptoms due to benign prostatic hyperplasia and was receiving 5-alpha reductase inhibitor. after an acute urinary retention episode which was managed with a suprapubic catheter due to urethral catheter insertion failure, the patient was submitted to a transurethral prostatectomy. histological examination revealed lymphocytic infiltration of the prostatic parenchyma by mostly small b cells. b-lymphocytic infiltration of the prostate gland, causes symptoms similar to benign prostatic hyperplasia. acute urinary retention due to b-lymphocytic infiltration of the prostate is rare and the diagnosis is always histological and an oncological re-evaluation is necessary. the prognosis of these patients is related to the generalized disease rather than to the prostatic involvement. key words: b-lymphocytic infiltration; prostate; chronic lymphocytic leukemia. submitted 12 december 2016; accepted 11 january 2017 summary no conflict of interest declared. diagnosed seven years ago, without receiving any treatment underwent transurethral resection of prostate adenoma. the patient had lower urinary tract symptoms during the last months due to benign prostate hyperplasia and was receiving treatment with dutasteride (5-a reductase inhibitor). his ipss score was 21 and he also had an abnormal uroflow with a maximum flow of 8 ml/sec. his serum prostate-specific antigen was 1.4 ng/ml. ultrasonography showed an intravesical prostate protrusion. after six months of treatment with dutasteride the patient suffered from an acute urinary retention, which was treated with suprapubic catheter placement, due to transurethral catheterization failure. preoperatively his blood count was pathological with 37.000/mm3 wbc. he underwent transurethral prostate resection and the postoperative course was uneventful. he was dismissed after a three-day hospitalization with 35 ml of post voiding residual. histological examination showed that some of the prostate chips were infiltrated by lymphocyte cells (figure 1). that cell population was composed by mainly small cells without proliferation centers. the presence of a few larger cell types was also noticed. immunohistochemistry showed that this lymphocyte population was positive in staining for cd20, cd5, cd23 and negative for cyclind1 and cd3 (figure 1). b-lymphocytic infiltration of the prostate was consistent with patients’ history of chronic lymphocytic leukemia. patient was then referred for oncology reevaluation and followed a therapeutic protocol with filgrastim, epo and rituximab. doi: 10.4081/aiua.2017.1.83 introduction hematological diseases such as lymphomas and chronic lymphocytic leukemia rarely include the prostate gland as an extranodal manifestation and even rarer is their first appearance to be in the lower urinary tract. we present a 61 years old patient with a history of chronic lymphocytic leukemia who underwent transurethral resection of prostate adenoma (tur-p) due to an acute urinary retention. histological examination showed low b-lymphocytic infiltration of the prostate parenchyma of mainly small lymphocytes. case report a 61 years old patient with a history of chronic lymphocytic leukemia, figure 1. positive staining for cd5, cd20 and cd23 respectively. anastasiou_stesura seveso 04/04/17 09:32 pagina 83 archivio italiano di urologia e andrologia 2017; 89, 1 i. anastasiou, s. skoufias, i. katafigiotis, i. skarmoutsos, c.a. constantinides 84 discussion extra-nodal localization of hematological diseases, such as chronic lymphocytic leukemia and lymphomas rarely regards the genitourinary tract and especially prostate gland (1). in the majority of cases leukemic infiltration of the prostate is asymptomatic and serum prostate-specific antigen level is usually normal. acute urinary retention is also rare, whilst in most of the cases prostate gland is not enlarged, and digital rectal examination mostly reveals a rubbery, firm, gland (2). transabdominal and transrectal ultrasound examination may reveal some hypoechoic zones but these are not specific signs. clinical diagnosis is difficult to made before surgery in patients without any history of malignancy. however in patients with a known history of hematological disease, luts might be indicative of prostate infiltration despite the fact, that prostate gland is not a common non-hematopoietic site of neoplastic cells spreading (3). tur-p is usually performed to diagnose and release clinical symptoms due to lower urinary tract obstruction (1). chronic lymphocytic leukemia, as a disease of the elderly often coexists with bph and symptoms usually don’t subside with medical therapy such as α-blockers and 5α reductase inhibitors. final diagnosis is set by histopathology examination and immunohistochemistry. the prognosis of these patients is related to the generalized disease rather than to the prostatic involvement. oncological refer is necessary and most of the times, patients follow therapy protocols after the confirmation of leukemia secondary involvement. conclusions although it is rare, genitourinary tract can be an extranodal site of chronic lymphocytic leukemia. therefore the differential diagnosis should always include the infiltration of the prostate gland by lymphocyte cells. awareness is needed in the elderly men with hematological disease despite the fact that there are no specific lower urinary tract symptoms to indicate prostate infiltration. the diagnosis is always histological and an oncological reevaluation is necessary. references 1. chu pg, huang q, weiss lm. incidental and concurrent malignant lymphomas discovered at the time of prostatectomy and prostate biopsy: a study of 29 cases. am j surg pathol. 2005; 29:693-699. 2. kassar o, gouiaa n, mdhaffar m, et al. primary manifestation of small lymphocytic lymphoma in the prostate: a case report. tunis med. 2015; 93:249-58. 3. d’arena g, guariglia r, villani o, et al. an urologic face of chronic lymphocytic leukemia: sequential prostatic and penis localization mediterr j hematol infect dis. 2013; 5:e2013008. correspondence ioannis anastasiou, md ekati2@otenet.gr spyridon skoufias, md spyskouf@hotmail.com ioannis katafigiotis, md, mls, phd, febu (corresponding author) katafigiotis.giannis@gmail.com ioannis skarmoutsos, md iskarm@gmail.com constantinos a. constantinides, md ckonstan@med.uoa.gr 1st university urology clinic, laiko hospital ag.thoma 17, athens 11527 greece anastasiou_stesura seveso 04/04/17 09:32 pagina 84 stesura seveso 45archivio italiano di urologia e andrologia 2017; 89, 1 original paper prospective study to compare antibiosis versus the association of n-acetylcysteine, d-mannose and morinda citrifolia fruit extract in preventing urinary tract infections in patients submitted to urodynamic investigation giovanni palleschi 1, antonio carbone 1, pier paolo zanello 2, rita mele 3, antonino leto 1, andrea fuschi 1, yazan al salhi 1, gennaro velotti 1, samer al rawashdah 4, gianluca coppola 1, angela maurizi 1, serena maruccia 5, antonio l. pastore 1 1 unit of urology, department of sciences and medico surgical biotechnologies, sapienza, university of rome, latina, italy, uroresearch association; 2 researcher in microbiology and virology, deakos consultant, 3 department of surgical sciences, sapienza university of rome, rome, italy; 4 urology unit, special surgery department, faculty of medicine, mutah university, karak, jordan; 5 unit of urology, irccs policlinico san donato milanese, milano, italy. background: the abuse of antimicrobical drugs has increased the resistance of microorganisms to treatments, thus to make urinary tract infections (utis) more difficult to eradicate. among natural substances used to prevent uti, literature has provided preliminary data of the beneficial effects of d-mannose, n-acetylcysteine, and morinda citrifolia fruit extract, due to their complementary mechanism of action which contributes respectively to limit bacteria adhesion to the urothelium, to destroy bacterial pathogenic biofilm, and to the anti-inflammatory and analgesic activity. the purpose of this study was to compare the administration of an association of d-mannose, n-acetylcysteine (nac) and morinda citrifolia extract versus antibiotic therapy in the prophylaxis of utis potentially associated with urological mini-invasive diagnostics procedures, in clinical model of the urodynamic investigation. methods: 80 patients eligible for urodynamic examination, 42 men and 38 women, have been prospectively enrolled in the study and randomised in two groups (a and b) of 40 individuals. patients of group a followed antibiotic therapy with prulifloxacine, by mouth 400 mg/day for 5 days, while patients of the group b followed the association of mannose and nac therapy, two vials/day for 7 days. ten days after the urodynamic study, the patients were submitted to urine examination and urine culture. results: the follow up assessment didn't show statistical significant difference between the two groups regarding the incidence of uti. conclusions: the association of mannose and nac therapy resulted similar to the antibiotic therapy in preventing utis in patients submitted to urodynamic examination. this result leads to consider the possible use of these nutraceutical agents as a good alternative in the prophylaxis of the uti afterwards urological procedures in urodynamics. key words: urinary tract infection (uti); d-mannose n-acetylcysteine (nac); urodynamic; biofilm. submitted 24 july 2016; accepted 24 december 2016 summary competing interests zanello pierpaolo: consultant: deakos. the other coauthors have no financial or non-financial competing interests to declare. introduction urinary tract infections (utis) are defined as the presence and the proliferation of bacteria which are pathogens in one or more parts of the urinary tract with subsequent invasion of tissue and the onset of symptoms. utis represent a great problem for the public health systems, because they are responsible for high morbility and are also one of the main causes of antibiotic prescriptions associated to an increased resistance to them (1). in europe utis represent the second cause of bacterial infection, after the respiratory, and are the most frequent form of nosocomial infections, associated mostly to the bladder catheterism (2, 3). furthermore, the high volume of antibiotics used to face utis determines high costs for the sanitary systems and their abuse has significantly contributed to the development of resistance mechanisms of the germs to these drugs (4). females are usually more exposed to this pathologic condition due to anatomical factors. however, after the age of 50, the risk of uti increases also for men because of obstructive problems due to the benign prostatic hypertrophy (table 1). some other factors may contribute to increase the risk of developing uti, and they should not be underestimated, such as intrauterine contraceptives (spiral), pregnancy (because it causes urinary stasis), menopausal status, anatomical and endocrine disrupters, constipation, wrong behavioural habits, various types of urinary catheterisms (ureteral stent, nephrostomy, intermittent or indwelling bladder catheterization). the annual epidemiological report of the european centre for disease prevention and control (ecdc) published in april 2015, reported that pathogenic agent which is responsible of most utis (about 70%) is escherichia coli, a bacteria of faecal origin which belongs to the gram-negative (5). e. coli is an emerging problem also regarding community acquired uti either in pediatric population either in the adult and elderly subjects (4). particularly, subjects with severe chronic urinary dysfuncdoi: 10.4081/aiua.2017.1.45 pastore_stesura seveso 05/04/17 16:11 pagina 45 archivio italiano di urologia e andrologia 2017; 89, 1 g. palleschi, a. carbone, p.p. zanello, et al. 46 tions secondary to neuropathies and people recovered in intensive care units are exposed to utis (6, 7). for these reasons, a better understanding of mechanisms which induce the germs’ resistance to antibiotics is needed, such as improvement of the strategies to prevent infections and their recurrences, with the aim to limit use of antibiosis in the clinical practice. in the urinary tract, the interaction between pathogen bacteria and the epithelium is mediated by various factors located on the bacteria cell or secreted by the same. in fact, adhesion of bacteria is a complex process, depending on the presence of certain fimbrial/pili structures that allow a specific interaction of the microbe with certain host cell receptors (8). these structures are represented by proteins, called adhesins, that allow the specific and selective bacterial adhesion. specifically, two different types of pili are distinguished: 1) mannose sensitive, pili or fimbria type i; 2) mannose resistant, pili or fimbria type ii. the type i are the main responsible factor for the colonization and invasion of the lower urinary tract due to the adhesion at urothelium cells level (8). however, another feature of the pathogen bacteria is the ability to produce, under favourable conditions, a large quantity of a particular capsular material: the biofilm (9, 10). pathogenic biofilms represent the still neglected etiology of recurrences. biofilms are polimicrobial structured communities, composed by 15% of bacteria and/or fungi and 85% of a self-produced mucopolysaccharides polymeric matrix. on biological surface, biofilms can be intraor extracellular, in the bladder or on mucous surface respectively, but they can also adhere to an inert structure, such as catether or other medical device. pathogens live in a quiescent state in the deep layers of biofilm as “persister cells”, phenotypically resistant to antibiotics and host defences and ready to re-attack the host. biofilm has an important role in utis pathogenesis, especially when intracellular, established inside bladder cells, because it doesn’t allow to pharmacological treatments and to the autoimmune system to reach bacteria efficiently. furthermore, biofilm have a complex and ingenious architecture that mimics a primitive circulatory system, with particular structures called "water channels" and "pore", allow both the distribution of nutrient, signalling molecule, for the removal of toxic substances too (10). it also allows the transition of genes, thanks to the physical proximity of bacterial cells, contributing to resistant infections and drugsresistance (11). particularly considering the risk to induce drugs resistance by germs, the possible side effects, such as intestinal dysbiosis, the use of antibiotics should be very careful. aim of this research is to find an alternative natural approach instead of antibiotics prophylaxis to prevent utis, such as in mini-invasive diagnostic urodynamics procedures. in fact, a large use of antibiotics is applied to prevent infections, especially in men, potentially related to various diagnostic invasive urological examinations. considering the pathophysiologic mechanisms that mostly contribute to the bacteria adhesion, to prevent the attachment and pathologic growth of bacteria and to promote the degradation of biofilm, must be considered as one of the main strategies to reduce the risk of utis. an alternative to the antibiotic prophylaxis, in the prevention of utis which can arise after urological procedures, could be the use of natural substances, especially when the microbial load is still low. one of these substances is d-mannose, an inert monosaccharide which is physiologically present in the human body (12-14). after assumption, d-mannose is sparely metabolized, and mostly removed through the urine. the mechanism of action is represented by the inhibition of bacterial adhesion to the urothelium, interfering with fimbrial adhesins type i mannose sensitive. d-mannose plays an important role also in other functions such as the ability to regenerate glycosaminoglycans (gags) of bladder and mucosal surface, after injury, and to detach bacteria already linked at the urothelium (12-14). its beneficial effects in reducing uti and complementary and integrative therapy for lower urinary tract inflammatory diseases have been shown by various studies (15-17). however, d-mannose is ineffective against the pathogens inside biofilm thus to induce the need of further action to better prevent the persistence and recurrence of uti, and the bacterial resistance. some evidence has already been provided about the ability of n-acetylcysteine on reducing bacterial biofilm either in vitro and in vivo studies (18, 19). these investigations showed a clinical benefit due to an high ability to distable 1. risk factors and prevalence of utis according to the age and sex. women men age prevalence (%) risk factors prevalence (%) risk factors < 1 1 functional or anatomic alterations of the urinary tract; 1 functional or anatomic alterations of the urinary tract; incomplete immune system incomplete immune system 1-5 4-5 vesicoureteral reflux; congenital alterations 0.5 congenital alterations 6-15 4-5 vesiureteral reflux 0.5 no 16-35 20 sexual relations; diaphragm/spiral and spermicide; 0.5 sexual relations pregnancy 36-65 35 estrogens deficit (post-menopausal); 20 vesicoureteral reflux; gynaecological surgery; neurological disorders; benign prostatic hyperplasia; stenosis; vesicoureteral reflux; vaginal prolapse; neurological disorders; surgery; instrumentations; dismetabolic disease; lithiasis instrumentations; dismetabolic disease; lithiasis > 65 30 idem + incontinence, bladder catheterism; 35 idem + incontinence, bladder catheterism; antimicrobical therapy antimicrobical therapy pastore_stesura seveso 05/04/17 16:11 pagina 46 solve the ripe biofilm matrix. therefore, it has already been reported that n-acetylcysteine could be useful in the treatment of uti, also caused by e. coli, due to its inhibitory effect on both bacterial growth and biofilm formation (20). in recent years, the growing interest in phytotherapic remedies has focused a particular interest also to morinda citrifolia fruit, a native plant of south east asia, polynesia and hawaii. the demonstrated range of therapeutic effects of morinda citrifolia fruit is attributable to the richness of its chemical components: xeronine, proxeronine, scopoletin, octoanoic acid, potassium, vitamin c, terpenoids, alkaloids, anthraquinones, linoleic acid, alizarin, amino acids, acubine, l-asperuloside, caprylic acid, ursolic acid, rutin, carotene, vitamin a (21). the dry fruit extract is commonly used in various nutritional supplements products for its antibacterial, anti-inflammatory, analgesic and immunomodulatory activity, suggesting a great role also in recurrent utis prevention. for all the overmentioned considerations, it appeared of interest to design a study to evaluate the efficacy of a combination of d-mannose, n-acetylcysteine and morinda citrifolia extract on utis after urodynamic procedures. aim of this clinical study was to compare assumption of a phytoterapic product composed by d-mannose, n-acetylcysteine and morinda citrifolia extract (registered as ausilium nac® by deakos s.r.l. corso nazionale, 169 la spezia), versus the antibiotic prophylaxis with fluorochinolones, in preventing utis potentially related to mini-invasive urological diagnostic procedures. to achieve this goal, the urodynamic examination represented the experimental clinical model. materials and methods the clinical study has been conducted at the university of rome, la sapienza, unit of urology, icot hospital, latina. from february to september 2015, 80 patients have been subjected to the urodynamic examination. patients have been chosen random in a cohort study including 42 men and 38 women. at the preliminary urologic consultation, all patients were submitted to history, physical examination including digital rectal examination in men and vaginal exploration in women. the day for the urodynamic investigation was planned and all the subjects were invited to present urine examination and urine culture 7 days before the test. patients with pathological findings at urine examination (presence of nitrites and pathological number of leukocytes in the urine sediment) and/or with positive urine culture suggestive for uti (defined by > 105 colony-forming units/ml) were invited to assume antibiotics basing on antibiogram and were excluded from this protocol. all the other patients with negative urine examination and negative urine culture were considered and accepted to be screened for the study, after they have signed an informed consent. inclusion criteria were considered: legal age (18 years in italy) and ability to understand and sign the informed consent. exclusion criteria were represented by: history of recent hematuria (within 3 months), presence of indwelling catheter or nephrostomy or suprapubic catheter or ureteral stent, recent urological, gynaecological or pelvic surgery (within 3 months), neoplastic disease, evidence or suspicious of fistula, diagnosis of interstitial cystitis, pathological findings at physical examination (e.g., digital rectal exploration suspicious for prostate cancer or suggestive for prostatitis). all patients satisfying inclusion criteria were then enrolled. therefore, the 80 patients considered for the protocol came from a preliminary population of 134 individuals attending our outpatient office. following those criteria, a randomized procedure was used for the random allocation of the enrolled patients into two groups of 40 in equal proportions to ensure a uniform allocation ratio (1:1). a specific protocol has been developed for each group: group a: traditional treatment with antibiotics prulifloxacine by mouth, 400 mg/day, for 5 days starting from the day before the procedure. prulifloxacine is the antibiotic suggested by the service for the prevention and treatment of the infective diseases of the hospital; thus it represents the recommended antibiotic for urological practice in our institution. group b: oral administration of two vials/day of ausilium nac® for 7 days starting from the day of the examination. each vial contain d-mannose 500 mg, n-acetylcysteine 100 mg and morinda citrifolia fruit extract 300 mg, an anti-inflammatory, immunostimulant and analgesic phytoteraphic remedy. after 10 days from urodynamic test, a second laboratory assessment based on urine examination and urine culture was performed in all patients. results were observed and submitted to statistical analysis, which was performed using the s-pss 20.0 software. at beginning, a careful analysis was conduct to evaluated the statistical homogeneity among the two groups (either plurifloxacine, or ausilium nac®) according to the demographic data and comorbidities. then, patients were compared according to their group allocation and analysis of variance was used to find the significance of study parameters among the groups of patients. fisher’s exact test, mann-whitney, and 95% confidence intervals were used as appropriate. two-tailed p value of less than 0.05 was considered as statistically significant. the local ethical committee, as prescribed by law, was informed of this observational investigation before starting the protocol. schematic overview of experimental design is represented in figure 1. results the results obtained from the anamnestic assessments between the two groups did not show significant difference in relation to the age, sex, body mass index, menopausal status, co-morbidities and pharmacotherapy (p value > 0.05). the population enrolled in the study was stratified according to the age, benign prostatic hyperplasia (bph), menopausal status, different birthing modalities, hypertension/heart diseases, diabetes, dysthyroidism, gynaecological and urological surgery or other pathologies, called “other” (such as osteoporosis, dyslipidaemia, depressive illness, etc.) as indicated in table 2. during the treatment, 5 patients spontaneously 47archivio italiano di urologia e andrologia 2017; 89, 1 prospective study to compare antibiosis versus the association of n-acetylcysteine, d-mannose and morinda citrifolia fruit extract in... pastore_stesura seveso 05/04/17 16:11 pagina 47 archivio italiano di urologia e andrologia 2017; 89, 1 g. palleschi, a. carbone, p.p. zanello, et al. 48 abandoned the study due to scarce interest in continuing the protocol: 2 of them (both men) belonged to the group a and 3 (1 man and 2 women) belonged to the group b. patients who left the study have been excluded from the final evaluation. at the end of the study, 75 patients have been evaluated: 38 belonging to the group a and 37 belonging to the group b. they have been divided in other sub-groups according to sex: therefore, 21/38 patients (55%) of group a and 18/37 patients (49%) of group b were men, while 17/38 patients (45%) of group a and 19/37 patients (51%) of group b were women. none patient reported side effects in both treatment groups. schematic overview of experimental design and results obtained are represented in figure 1. obtained data denotes the same utis incidence in the two observed groups: 3/38 (7.89%) of the group a and 2/37 (5.4%) of the group b developed utis (p value = 0.671) (table 3). considering the laboratory examinations performed at the follow-up visit, the results didn't show significant differences between the group a and b in terms of incidence of utis. all the patients with utis were symptomatic; they were prulifloxacine ausilium nac men women tot men women tot patients n = 21 n = 17 n = 38 n = 18 n = 19 n = 37 average age (± 95%) 65 (± 1.62) 56 (± 1.39) 65.4 (± 1.03) 64 (± 1.45) 54.42 (± 1.88) 65.4 (± 1.09) diabets 3 1 4 4 1 5 menopausal status / 12 12 / 11 11 b.p.h.* 15 / 15 12 / 12 hypertension/heart disease 2 2 4 1 2 3 dysthyroidism 1 1 2 / 1 1 natural childbirth / 3 3 / 4 4 urological surgery 2 / 2 2 / 2 uro-gynaecological surgery / 3 3 / 5 5 other / 4 4 / 2 2 * benign prostatic hyperplasia. figure 1. schematic overview of experimental design and results obtained in the study. table 3. percentage of utis occurred and germ isolated in the patients from group a, group b and sub-groups according to the sex. table 2. clinical and demographic characteristics of the two experimental groups performed. patients group a group b analyzed prulifloxacine d-mannose and n-acetylcysteine sex men women tot men women tot n° patients 75 21 17 38 18 19 37 % utis 9.5% 5,8% 7.89% 5.5% 5.2% 5.4% germ isolated escherichia coli 100% escherichia coli 100% pastore_stesura seveso 05/04/17 16:11 pagina 48 treated with antibiotics basing on antibiogram, followed by further laboratory check after 15 days to ensure that uti was cured. the group a and b have been divided in other two subgroups in relation to the sex. only 2/21 (9.5%) male patients and 1/17 (5.8%) female patients of the group a and 1/18 (5.5%) male patients and 1/19 (5.2%) female patients of the group b developed uti after urodynamic procedures (p value = 0.946). the results of this further division did not show particular predispositions to utis depending on the sex, antibiotics or nutraceuticals in urodynamic. discussion the results of this study show that there was no significant difference regarding the incidence of utis between patients undergone treatment with fluorochinolones and those who assumed ausilium nac®. the phytotherapic product combines d-mannose, able to reduce bacterial adhesion, n-acetylcysteine, a mucolitic molecule useful to destroy bacterial biofilms and morinda citrifolia extract, with anti-inflammatory, immune stimulating and analgesic properties, in utis after urodynamics procedures. therefore, assumption of ausilium nac®, two vials/day for one week provided the same protective effect in preventing utis respect to the prophylaxis with fluorochinolone prulifloxacine. the two compared cohorts were substantially similar regarding comorbidities and clinical features, therefore this result has been not conditioned by clinical and demographical differences between the populations and it has to be specifically related to the action of treatments used. in case of invasive diagnostic urological procedure, which potentially carry the risk to induce utis, a very careful protocol is essential, such as sterility of instruments or correct prophylaxis post-intervention. as an additional strategy to reduce the risk of utis, instead of using antibiotics it should be preferable to use natural substances, basing on the evidence that these agents could provide the same protection especially when microbial load is still very low. in vitro studies and preliminary clinical experiences demonstrated that d-mannose and n-acetylcysteine can provide a favourable effect in preventing utis (12, 1520). the present study shows that d-mannose, n-acetylcysteine in association with morinda citrifolia fruit extract in the formulation of ausilium nac®, like plurifloxacine, may provide a favourable effect in preventing uti in case of mini-invasive diagnostic procedures which require bladder catheterism. an important advantage of nutraceutical agents is that a natural mechanism to prevent infections can avoid an unnecessary use of antibiotics, limiting the risk to develop germ resistance. furthermore, even if it did not happen in our study, usually antibiotics are more responsible for dysbiosis and side effects if compared with natural substances. as a further consideration, patients accepted with pleasure to assume a nutraceutical agents rather than antibiotic prophylaxis to prevent utis. the results obtained suggest to better explore, on larger case series, the advantage of this particular association of nutraceuticals, whose action mechanisms are of particularly suitable interest in utis prevention. the synergy between d-mannose, n-acetylcysteine, and morinda citrifolia fruit extract, has suggested a great role in recurrent utis prevention (15-21). a larger experience is needed, also in different type of populations, to amplify the outcomes shown in the present study. in fact, the limit of this study is represented by the single centre experience and the relatively limited number of subjects enrolled. however, the stratification of patients and the prospective design can partially balance these limits. another criticism could be represented by the absence of a “non-treatment” group, but this was not allowed by the local ethical committee. as a further consideration, it has to be underlined that, as various type of infections, also the risk of uti may be strongly reduced by some other natural and non invasive prevention strategies. behavioural aspects, reduction of comorbidities and attention to precipitating factors, are the most important. as a favourable consequence, a better management of antibiotics could limit the development of germ resistance which is becoming a serious health problem, particularly in hospitalized patients (8). in fact, in the last years, many authors reported the increased of uti secondary to germs resistant to conventional antibiotic treatment (21). it is a common experience in real life management to face uti sustained by germs which show multiple resistance, and one of the main factors that has led to multiple resistance is the indiscriminate use of antibiotics. those circumstances require difficult strategies of treatment. sometimes it is necessary the help of experts in contagious disease, a large dose of medicines and also hospitalization. furthermore, in the last years considering the large availability of efficacious antibiotics, clinicians have made an excessive use and at the same time the research for new molecules has been decreased; therefore new classes of drugs suitable for the treatment of infections caused by multidrug-resistant germs are not currently available. for these reasons antibiosis prophylaxis must be restricted and replaced with alternative treatment whenever possible. conclusions this study proved that ausilium nac® is as efficient as the plurifloxacin in order to prevent utis potentially associated with urodynamic examination. this result should induce to consider that the assumption of nutraceutical substances without antibiotic effect can reduce the risk of utis, for less invasive urological procedures. the limited use of antibiotics in selected cases will contribute to reduce the development of antibacterial agents resistance. further studies are requested to support the encouraging results of this experience, focusing the attention on a more careful use of antibiotics for utis prevention related to diagnostic procedures. authors' contributions all authors have contributed equally to the drafting of the manuscript. all authors read and approved the final version of the manuscript. 49archivio italiano di urologia e andrologia 2017; 89, 1 prospective study to compare antibiosis versus the association of n-acetylcysteine, d-mannose and morinda citrifolia fruit extract in... pastore_stesura seveso 05/04/17 16:11 pagina 49 archivio italiano di urologia e andrologia 2017; 89, 1 g. palleschi, a. carbone, p.p. zanello, et al. 50 references 1. lüthje p, brauner a. novel strategies in the prevention and treatment of urinary tract infections. pathogens 2016; 5:e13. 2. xia j, gao j, tang w. nosocomial infection and its molecular mechanisms of antibiotic resistance. biosci trends. 2016; 10:14-21. 3. andré m, ahlqvist-rastad j, beermann b. nedre urinvägsinfektion (uvi) hos kvinnor lower urinary tract infection (uti) in women treatment recommendation. the med. prod agency, sweden 2007; 18. 4. cheng mf, chen wl, huang if, et al. urinary tract infection in infants caused by extended-spectrum beta-lactamase-producing escherichia coli: comparison between urban and rural hospitals. pediatric nephrol. 2016; 31:1305-12. 5. iacovelli v, gaziev g, topazio l, et al. nosocomial urinary tract infections: a review. urol. 2014; 81:222-7. 6. duszynska w, rosenthal vd, szczesny a, et al. urinary 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113:9-10. 17. porru d, parmigiani a, tinelli c, et al. oral d-mannose in recurrent urinary tract infections in women: a pilot study. j clin urol. 2014; 20:1-6. 18. palaniswamy u1, lakkam sr1, arya s1, aravelli s1. effectiveness of n-acetylcysteine, 2% chlorhexidine, and their combination as intracanal medicaments on enterococcus faecalis biofilm. j conserv dent. 2016; 19:17-20. 19. dinicola s, de grazia s, carlomagno g, pintucci jp. n-acetylcysteine as powerful molecule to destroy bacterial biofilms. a systematic review. eur rev med pharmacol sci. 2014; 18:2942-8. 20. naves p, del prado g, huelves l, et al. effects of human serum albumin, ibuprofen and n-acetyl-l-cysteine against biofilm formation by pathogenic escherichia coli strains. j hosp infect. 2010; 76:165-70. 21. abou assi r, darwis y, abdulbaqi im, et al. morinda citrifolia (noni): a comprehensive review on its industrial uses, pharmacological activities, and clinical trialsarab j chem. 2015, in press. correspondence giovanni palleschi, md antonio carbone, md antonino leto, md andrea fuschi, md yazan al salhi, md gennaro velotti, md gianluca coppola, md angela maurizi, md antonio l. pastore, md (corresponding author) antopast@hotmail.com unit of urology, department of sciences and medico surgical biotechnologies, sapienza, university of rome, latina corso della repubblica 79 04100 latina, italy pier paolo zanello, md researcher in microbiology and virology, deakos consultant rita mele, md department of surgical sciences, sapienza university of rome, rome, italy samer al rawashdah, md urology unit, special surgery department, faculty of medicine, mutah university, karak, jordan serena maruccia, md unit of urology, irccs policlinico san donato milanese, milano, italy pastore_stesura seveso 05/04/17 16:11 pagina 50 stesura seveso introduction the aim of this study is to evaluate the effectiveness of tamsulosin in patients affected by low urinary tract symptoms (luts) and erectile dysfunction (ed), and also to compare this monotherapy with one combined with sildenafil, belonging to phosphodiesterase type 5 (pde-5) inhibitors drug class, which are the recommended first-line treatment for ed. type iii chronic prostatitis or chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is characterized by 109archivio italiano di urologia e andrologia 2013; 85, 3 original paper comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type iii chronic prostatitis ubaldo cantoro, francesco catanzariti, vito lacetera, luigi quaresima, giovanni muzzonigro, massimo polito institute of urology, polytechnic university of marche, azienda o.u. ospedali riuniti, ancona, italy. aim: we evaluated the effectiveness of tamsulosin monotherapy versus tamsulosin plus sildenafil combination therapy on erectile dysfunction (ed) in young patients with type iii chronic prostatitis and ed by using symptom score scales. materials and methods: 44 male patients were divided into 2 groups: the first group (20 patients) was treated with tamsulosin 0,4 mg monotherapy and the second one (24 patients) was treated with tamsulosin 0,4 mg plus sildenafil 50 mg combination therapy. “international prostate symptom score” (ipss), “national institute of health chronic prostatitis symptom index” (nih-cpsi) and “international index of erectile function” (iief-5) were investigated in each group of patients, and scores calculated during the first medical examination. both groups were treated with tamsulosin once daily for 60 days, while sildenafil 50 mg was given on demand (at least 2 times per week) for 60 days. during the second medical examination ipss, nih-cpsi and iief-5 scores were analyzed once more. afterwards, the alterations of scores among medical examinations in each group and between both groups were statistically compared. results: the age average of the 44 cases included was 32.04 ± 3.15 years. both groups present a statistically significant decrease, between the first and the second medical examination, in ipss, nih-cpsi scores and statistically significant increase in iief-5 score. in addition, there is no statistically significant difference, in all scores, between mono and combination therapy. conclusions: tamsulosin monotherapy, as well as a combination therapy (tamsulosin plus sildenafil) has an improving effect on symptoms and on ed in patients with type iii prostatitis. in the near future alpha-blockers monotherapy could be used in the treatment of chronic prostatitis and ed cases instead of phosphodiesterase type 5 (pde-5) inhibitors combination therapy. key words: chronic prostatitis; erectile dysfunction; tamsulosin; sildenafil. submitted 8 april 2013; accepted 30 april 2013 no conflict of interest declared summary abdominal, pelvic, genital pain, obstructive or irritative luts and by the absence of urinary tract infection (1). many studies showed its association with painful premature ejaculation and with erectile dysfunction. cp/cpps occurs frequently in young patients and is one of the organic causes of erectile dysfunction (ed) in this age range. therefore, a common pathogenic mechanism for these two diseases is likely to exist (2). adult-old patients luts affected have two times higher doi: 10.4081/aiua.2013.3.109 archivio italiano di urologia e andrologia 2013; 85, 3 u. cantoro, f. catanzariti, v. lacetera, l. quaresima, m. giovanni, m. polito 110 risk to develop ed, since the prevalence of luts is of 72.2% in males affected also by ed and of 37.7% in males with no ed (3). literature data show that ed associates with the severity of luts but, although studies pointed out a correlation between cp/cpps and ed, they do not provide with any explication of pathogenic mechanisms (4). many pathogenic mechanism were investigated to find an explanation to ed in young patients affected by cp/cpps. any connection with hypogonadism neither other endocrine disorders were found, except for a study which, unlike controls, found higher levels of testosterone in patients with cp/cpps (5). another study found an association with hypogonadism, due to the fact that patients took opioids for long periods because of luts severity (6). vascular diseases and arterial insufficiency are well known causes of ed, even though they are uncommon in young patients (7). anyway, one study pointed out alterations in the peripheral arterial tone in patients with cp/cpps (8), due to a endothelial vascular dysfunction mediated by nitric oxide (9). moreover, the arterial flow can be compromised from the outside by spastic contractions of pelvic floor (10). it is known muscle relaxant therapies can have positive effects on ed (11). occlusive vessel disease is a condition which frequently occurs in old patients, also in presence of penile fibrosis. therefore, also this pathogenic mechanism is uncommon in young patients. although ed psychogenic cause was not adequately investigated in patients with cp/cpps, a relation may exist since often patients affected by painful syndromes also suffer from stress, anxiety and maladaptive responses to stressful events (“catastrophizing”) (12). materials and methods our study analyzed a number of 44 patients who were examined at our clinic because affected by type iii chronic prostatitis associated with erectile dysfunction since at least 6 months. all patients were sexually active. we excluded from the study all patients affected by infections of the urinary system, neoplasia, congenital disorders, previous surgeries, urolithiasis and hyperactive bladder. none of the included patients used pde-5 in the past. none of the examined patients presented side effects due to the use of alpha-blockers and pde-5. patients were examined through anamnesis, which is a clinical exam with neurological evaluation of the pelvic floor and rectal examination, uroflowmetry, suprapubic ultrasound evaluation of post-void residual, trans-rectal prostate ultrasound, total psa, microscopic and cultural exams of urine and semen and urethral secretion after prostate massage. the 44 patients were divided into 2 groups: the first group (20 patients) was treated with monotherapy, tamsulosin 0.4 mg, the second one (24 patients) was treated with a combination therapy, tamsulosin 0.4 mg plus sildenafil 50 mg. patients assignment to one group or the other was random. the average age of patients included in the study is 32.04 ± 3.15 years. none of patients was affected by bph; prostate volume range was between 15 and 25 ml. both uroflowmetry parameters and post-void residuals were not pathological. during the first medical examination, all patients were subjected to “international prostate symptom score” (ipss), “national institute of health chronic prostatitis symptom index” (nih-cpsi) and “international index of erectile function” (iief-5). both groups were treated with tamsulosin for 60 days; sildenafil 50 mg was taken when needed before a sexual intercourse (at least 2 times per week) and for 60 days by the second group. during the second medical examination, 60 days later, all patients were subjected again to ipss, nih-cpsi and iief-5. we considered mild patients’ symptoms with ipss score between 0-7 and nih-cpsi between 0-14; moderate respectively between 8-19 and 15-29 and severe between 20-35 and > 30. we considered mild patients’ erectile dysfunction with iief-5 score between 17-21, mildmoderate between 12-16, moderate between 8-11 and severe between 5-7. we statistically evaluated a potential difference in iief-5 scores according to the symptomatic severity of ipss and nih-cpsi and in the last two questionnaires scores according to iief-5 severity. therefore, we statistically evaluated the differences of questionnaires scores means between the two medical examinations in each group and between the two groups. for the statistic analysis we used graphpad prism 5 program. in addition to the descriptive statistic modes (mean, standard deviation), oneway anova, kruskalwallis, mann-whitney and student t test were used for a statistic evaluation. the results were analyzed with a significance level of p < 0.05. results table 1 shows the mean of questionnaires analyzed and the mean of patients’ figures. according to ipss questionnaire, 4 patients presented mild symptoms, 26 moderates and 14 severe; according to nih-cpsi questionnaire 6 patients presented mild symptoms, 29 moderates, 9 severe; according to iief-5 questionnaire 8 patients suffered from mild erectile dysfunction, 17 mild-moderate, 13 moderate, 6 severe. we confronted iief-5 score means of patients with mild, moderate and severe symptoms according to ipss and we did not notice any statistically difference: anova (p = 0,87) and kruskal-wallis (p = 0.92) (table 2). moreover, there is no statistically difference between ipss mean sd range age (year) 32.04 3.15 23-35 pv (ml) 17.20 2.56 15-25 qmax (ml/s) 21.24 3.45 17.8-28.3 pmr (ml) 27.18 8.78 0-42 ipss 13.52 1.49 8-24 ipss-qol 3.87 0.27 0-5 iief-5 12.41 0.66 5.21 nih-cpsi 17.51 1.92 5-28 table 1. general characteristics and mean symptom scores of the cases. score means of patients with mild, mild-moderate, moderate, severe erectile dysfunction: anova (p = 0,43) and kruskal-wallis (p = 0,61) (table 3). we did not notice any statistically difference even through the comparison of iief-5 scores according to nih-cpsi mild, moderate and severe symptoms: anova (p = 0,12), kruskal-wallis (p = 0,25) (table 4); any difference also in nih-cpsi scores according to iief-5: anova (p = 0,18), kruskal-wllis (p = 0,26) (table 5). we noticed, inside each therapy group, a statistically relevant decrease, between the first medical examination and 60 days later, in ipss, ipss-qol and nih-cpsi score. we also pointed out a statistically relevant increase in iief-5 score (table 6 -7). we did not notice, in 60 days, a statistically relevant difference, between the two therapy groups, in all questionnaires score, iief-5 included (table 8). discussion chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a syndrome characterized by pain (abdominal, pelvic, genital), obstructive and irritative luts in absence of infection (1), causing quality of life (qol) decrease (13). although it is known that type iii chronic prostate associates with erectile dysfunction, it is still less clear the etiophatogenesis implied in these two nosological entities. great part of clinical studies examine old patients with luts and ed, but also with concomitant bph and obstruction of urine flow. still few are studies which investigate the presence of ed in younger patients affected by type iii chronic prostatitis in absence of bph and obstruction. the most supported theory explaining the common pathogenic mechanism of luts and concomitant ed, independently from bph, points out there is a hyperactivity of autonomic nervous system and endothelial alterations due to the effects on nitric oxide – cyclic 111archivio italiano di urologia e andrologia 2013; 85, 3 comparison of tamsulosin vs tamsulosin/sildenafil effectiveness in the treatment of erectile dysfunction in patients affected by type iii chronic prostatitis visit 1 visit 2 p ipss 13.26 ± 0.92 8.23 ± 0.72 < 0.001 iief-5 12.54 ± 0.59 17.83 ± 1.46 < 0.001 nih-cpsi 17.87 ± 1.14 10.54 ± 1.35 < 0.001 ipss-qol 3.95 ± 0.22 2.02 ± 0.56 < 0.001 table 6. alterations in ipss, iief-5, nih-cpsi, ipss-qol between visit 1 and visit 2 in group 1 treated with tamsulosin 0,4 mg. visit 1 visit 2 p ipss 13.75 ± 1.84 8.07 ± 0.91 < 0.001 iief-5 12.31 ± 0.78 18.75 ± 1.24 < 0.001 nih-cpsi 17.47 ± 2.09 9.74 ± 1.98 < 0.001 ipss-qol 3.65 ± 0.41 1.82 ± 0.25 < 0.001 table 7. alterations in ipss, iief-5, nih-cpsi, ipss-qol between visit 1 and visit 2 in group 2 treated with tamsulosin 0,4 mg plus sildenafil 50 mg. group 1 group 2 p ipss 8.23 ± 0.72 8.07 ± 0.91 0.751 iief-5 17.83 ± 1.46 18.75 ± 1.24 0.835 nih-cpsi 10.54 ± 1.35 9.74 ± 1.98 0.486 ipss-qol 2.02 ± 0.56 1.82 ± 0.25 0.574 table 8. alterations in ipss, iief-5, nih-cpsi, ipss-qol between group 1 and group 2 after 60 days. mean iief-5 score all cases 12.41 ± 0.66 ipss mild 13.28 ± 0.89 anova p = 0.87 moderate 12.85 ± 0.39 kruskal-wallis p = 0.92 severe 12.13 ± 1.98 table 2. the effect of ipss level on mean iief-5 score. mean iief-5 score all cases 12.41 ± 0.66 nih-cpsi mild 14.28 ± 0.27 anova p = 0.12 moderate 12.05 ± 0.39 kruskal-wallis p = 0.25 severe 15.13 ± 1.16 table 4. the effect of nih-cpsi level on mean iief-5 score. mean ipss score all cases 13.52 ± 1.49 iief-5 mild 13.25 ± 1.17 anova p = 0.43 mild-moderate 14.48 ± 0.96 kruskal-wallis p = 0.61 moderate 14.81 ± 0.91 severe 12.84 ± 1.57 table 3. the effect of iief-5 level on mean ipss score. nih-cpsi score all cases 17.51 ± 1.92 iief-5 mild 22.92 ± 0.87 anova p = 0.18 mild-moderate 19.08 ± 0.56 kruskal-wallis p = 0.26 moderate 17.83 ± 0.74 severe 21.98 ± 1.19 table 5. the effect of iief-5 level on mean nih-cpsi score. archivio italiano di urologia e andrologia 2013; 85, 3 u. cantoro, f. catanzariti, v. lacetera, l. quaresima, m. giovanni, m. polito 112 monophosphate guanosine e alterations in rho-kinase pathway (14). some studies already evaluated the effectiveness of alpha-blockers in treating erectile dysfunction associated with luts (15-16), but it was not compared with pde5 inhibitors and, as stated above, the patients examined were old people with concomitant bph. in our study, after 60 days of therapy, each group showed statistically relevant improvements in questionnaires scores: ipss, ipss-qol, iief-5, nih-cpsi. in other words, tamsulosin, as well as the combination therapy of tamsulosin and sildenafil, improved both luts and ed. sixty days after the therapy, we did not stress out any statistically relevant difference in questionnaires scores between the two groups, despite a pde-5 inhibitors treatment in the second group. moreover, there is no correlation between luts severity (classified according to ipss and nih-cpsi), ed rate and vice versa. these results suggest tamsulosin may improve ed and chronic prostatitis symptoms, reducing the spasm of prostate smooth muscle, the associated inflammation and improving prostate and penis blood flow. anyway, our study has several limitations; it does not have a placebo control arm and it is circumscribed. we are also persuaded other studies are needed for evaluating monotherapy and combination therapy for a longer period than 60 days. moreover, patients’ randomization does not guarantee a complete randomness: patients’ assignment to one study group or the other was made through their alternated insertion in one of the two groups. conclusions luts severity in young patients suffering from type iii chronic prostatitis does not correlate with the severity of ed and vice versa. tamsulosin therapy for the treatment of young patients with type iii chronic prostatitis together with erectile dysfunction has the same effectiveness of the most expensive combination therapy (tamsulosin and sildenafil). we are persuaded in the future the cheaper therapy with alpha-blocker will be used in cp/cpps and ed affected patients. references 1. schaeffer aj, datta ns, fowler jej, et al. overview summary statement. diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (cp/cpps). urology. 2002; 60:1-4. 2. costabile ra, steers wd. how can we best characterize the relationship between erectile dysfunction and benign prostatic hyperplasia? j sex med. 226; 3:676-681. 3. carson cc. combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both? bju int. 2006; 97:39-43. 4. shiri r, ha¨kkinen jt, hakama m, et al. effect of lower urinary tract symptoms on the incidence of erectile dysfunction. j urol. 2005; 174:205-209. 5. dimitrakov j, joffe hv, soldin sj, et al. adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome. urology. 2008; 71:261-6. 6. daniell hw. hypogonadism in men consuming sustained-action oral opioids. j pain. 2002; 3:377-84. 7. gonen m, kalkan m, cenker a, et al. prevalence of premature ejaculation in turkish men with chronic pelvic pain syndrome. j androl. 2005; 26:601-3. 8. shoskes da, prots d, karns j, et al. greater endothelial dysfunction and arterial stiffness in men with chronic prostatitis/chronic pelvic pain syndrome-a possible link to cardiovascular disease. j urol. 2011; 186:907-10. 9. rubinshtein r, kuvin jt, soffler m, et al. assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. eur heart j. 2010; 31:1142-8. 10. shoskes da, berger r, elmi a, et al. muscle tenderness in men with chronic prostatitis/chronic pelvic pain syndrome: the chronic prostatitis cohort study. j urol. 2008; 179:556-60. 11. anderson ru, wise d, sawyer t, et al. sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome: improvement after trigger point release and paradoxical relaxation training. j urol. 2006; 176:1534-8. 12. nickel jc, tripp da, chuai s, et al. psychosocial variables affect the quality of life of men diagnosed with chronic prostatitis/chronic pelvic pain syndrome. bju int. 2008; 101:59-64. 13. mcnaughton collins m, pontari ma, o’leary mp, et al. quality of life is impaired in men with chronic prostatitis: the chronic prostatitis collaborative research network. j gen intern med. 2001; 16:656-62. 14. rosen rc, wei jt, althof se, et al. association of sexual dysfunction with lower urinary tract symptoms of bph and bph medical therapies: results from the bph registry. urology. 2009; 73:562-566. 15. kirby rs, andersen m, gratzke p, et al. a combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. bju int. 2001; 87:192-200. 16. de rose af, carmignani g, corbu c, et al. observational multicentric trial performed with doxazosin: evaluation of sexual effects on patients with diagnosed benign prostatic hyperplasia. urol int. 2002; 68:95-98. correspondence ubaldo cantoro, md (corresponding author) resident in urology ubaldocantoro@tiscali.it francesco catanzariti, md resident in urology fracatanzariti@libero.it vito lacetera, md urologist, resident in urology vlacetera@gmail.com luigi quaresima, md resident in urology luigiquaresima@yahoo.it giovanni muzzonigro md professor of urology and chief institute of urology, resident in urology g.muzzonigro@univpm.it massimo polito, md urologist, resident in urology max_polito@virgilio.it institute of urology, a.o. ospedali riuniti via conca 71 i-60020 ancona, italy stesura seveso archivio italiano di urologia e andrologia 2016; 88, 156 short communication do cigarette and alcohol affect semen analysis? mehmet zeynel keskin 1, salih budak 1, saim gubari 2, kalender durmaz 3, mehmet yoldas 1, orcun celik 1, evrim emre aksoy 4, yusuf ozlem ilbey 1 1 urologic clinic, tepecik training and research hospital, urology clinic, izmir, turkey; 2 assisted reproductive techniques department, tepecik training and research hospital, izmir, turkey; 3 urologic clinic yenişehir state hospital, turkey; 4 urologic clinic kırkagac state hospital, turkey. objectives: there are a number of studies about the effect of cigarette and alcohol on semen parameters in the literature. there is not a consensus on the relationship between use of cigarette and alchol and semen parameters in those studies. the number of studies in which cigarette and alcohol use are evaluated together is limited. this study was aimed to analyze the effect of cigarette and/or alcohol use on semen parameters. methods: in this prospective study, 762 patients who applied to an hospital urology polyclinic between january 2015 and march 2015 due to infertility, were questioned for alcohol and cigarette use in anamnesis. the remaining 356 patients were included in our study. then, semen analysis of the patients was performed. the patients were divided into five groups according to cigarette use, into five groups according to alcohol use and into four groups according to cigarette and/or alcohol use. significant differences were analyzed between the groups in terms of semen volume, semen concentration, total motility, forward motility and morphological (normality, head anomaly, neck anomaly, tail anomaly) values. results: according to cigarette use, only in group 4 (who use more than 20 package-years cigarette) semen volume was significantly lower than the control group (mann-whitney u, p = 0.009). there was no significant difference in any of the other parameters and groups compared with the control group (mann-whitney u, p > 0,05) conclusion:according to our study, using more than 20 package-years cigarette decreases semen volume. the reason of this result might be the fact that the threshold value, from which the effect of cigarette and alcohol use on the semen parameters has to be determined. key words: alcohol, infertility, semen analysis, cigarette. submitted 15 october 2015; accepted 4 december 2015 summary no conflict of interest declared. although the effects on especially liver and cardiovascular system are known, its effects on semen parameters is controversial (6-9). methods in this prospective study, 762 patients, who applied to our hospital urology polyclinic between january 2015 and march 2015 due to infertility, were questioned for alcohol and cigarette use. at least two semen analyses were requested from patients at their first application to the polyclinic as a routine analysis after medical history collection. the patients who were detected with a factor which might affect semen parameters (systemic disease, drug use, inguinal or testicular surgery history, varicocele, undescended testis, hypoplasic testis at physical examination, abnormality in serum gonadotropin, androgen and prolactin levels, and pathology in genetic analysis) were excluded from the study. the remaining 356 patients were included in the study. the patients who had 1 package-year and over cigarette use and the patients who did not ever smoke cigarette were included into the study, the patients who use less than 1 package-year level were excluded from the study. the patients whose alcohol use rate was over 1 units/3 months and the ones who do not drink alcohol were included in the study, the ones who had use rate less than 1 units/3 months were excluded from the study. in our study, all semen analyses were performed after 3-6 days of sexual abstinence. spermiograms were analyzed by the same embryologist in the spermiogram laboratory in our in vitro fertilization center. semen analysis were evaluated according to who 2010 criteria (semen volume ≥ 1,5 ml; sperm concentration ≥ 15 × 106/ml; total motility ≥ 40%, forward motility ≥ 32% and morphology ≥ 4%) (10). the ethical committee approval of the study was obtained by the local ethical committee of our hospital and registered at number 29/12/2014-21/14 together with the form for informed consent form taken from patients included in the study. statistical analysis the statistical relationship was analyzed by using ibm statistical package for social sciences (spss, new york, usa) version 22.0 software programme: p < 0,05 values were accepted as statistically significant. doi: 10.4081/aiua.2016.1.56 introduction cigarette is a significant health problem, which is a common habit that results in early deaths (1, 2). according to data of turkish anti-smoking association, cigarette use rate is 40% in our country (51% in males, 25% in females) (3). the evidences which show that a number of toxic compounds might disrupt sperm quality, and thus male fertility, in both animals and human are increasing in the last 20 years (4). according to data of world health organization (who), 1.8 million people die in a year due to alcohol use (5). keskin ok_stesura seveso 05/04/16 15:54 pagina 56 57archivio italiano di urologia e andrologia 2016; 88, 1 do cigarette and alcohol affect semen analysis? results when the semen parameter mean values of 356 patients who were included into the study were analyzed, the mean semen volume was determined as 2.96 ml, sperm concentration 36.34 x 106/ml, total motility 47%, forward motility 33%, anomaly of the morphology of the head 2.47%, anomaly of neck 43.82%, anomaly of the tail 3.69% (table 1). the patients were divided in 5 groups according to cigarette use. the patients who do not use cigarette were determined as group 0 (control) (n = 172), the patients who use cigarette less than 5 package-years were determined as group 1 (n = 39), the patients who use cigarette 5-10 packageyears were determined as group 2 (n = 52), the patients who use cigarette 10-20 package-years were determined as group 3 (n = 79) and the patients who use more than 20 package-years were determined as group 4 (n = 14). the control group was statistically compared with the others respectively. only in group 4 (who use more than 20 packageyears cigarette), semen volume was significantly lower than the control group (mannwhitney u, p = 0.009). there was no significant difference in any of the other parameters of the other groups compared with the control group (mann-whitney u, p > 0.05) (table 2). the patients were divided in to 5 groups according to alcohol use. the patients who do not use alcohol were determined as group 0 (control) (n = 256), the patients who use alcohol 1 unit/3 months were determined as group 1 (n = 62), the patients who use alcohol 1 unit/month were determined as group 2 (n = 16), who patients who use alcohol 1 unit/week were determined as group 3 (n = 3) and the patients who use alcohol 1 unit/day were determined as group 4 (n = 19). there was no significant difference in any of the parameters and groups compared with the control group (mann-whitney u, p > 0,05) (table 3). the patients were divided in 4 groups according to cigarette and/or alcohol use. the patients who do not use cigarette and alcohol were determined as group 0 (control) (n = 139), the patients who use only cigarette were as group 1 (n = 117), the patients who use only alcohol were as group 2 (n = 33) and the patients who use both cigarette and alcohol were as group 3 (n = 67). there was no statistically significant difference between group 0 and groups 1, 2 and 3 respectively, in terms of semen parameters according to the statistical analysis of semen parameters (mannwhitney u, p > 0.05) (table 4). discussion there are a number of studies about the effect of alcohol on semen parameters in the literature, but there is no consensus on the relationship between the semen parameters in those studies (11-14). a full recovery was reported in minimum maximum mean std dev. age (year) 20 50 33.04 5.43 volume (ml) 0.30 11.00 2.96 1.53 concentration (x106/ml) 0,00 170,00 36.34 36.92 total motility (%) 0.00 90.00 46.54 24.72 progressive motility (%) 0.00 80.00 32.61 21.24 normal morphology (%) 0.00 10.00 2.47 2.25 head anomaly (%) 0.00 100 43.82 40.13 neck anomaly (%) 0.00 18 5.18 5.10 tail anomaly (%) 0.00 14 3.69 3.86 table 2. mean values of semen parameters and p values according to the cigarette use groups. min. max. mean std. dev. p value group 0 volume (ml) 0,30 11 3,14 1,66 (n = 172) concentration (x106/ml) 0,00 170 38,08 37,81 total motility (%) 0,00 90 46,10 24,99 progressive motility (%) 0,00 80 32,94 21,67 normal morphology (%) 0,00 10 2,40 2,20 head anomaly (%) 0,00 89 42,50 39,99 neck anomaly (%) 0,00 18 5,43 5,44 tail anomaly (%) 0,00 14 3,80 4,13 group 1 volume (ml) 0,50 8 3,05 1,59 0,658 (n = 39) concentration (x106/ml) 0,00 168 42,18 42,10 0,683 total motility (%) 0,00 85 48,84 25,58 0,531 progressive motility (%) 0,00 75 34,87 21,35 0,909 normal morphology (%) 0,00 9 2,97 2,61 0,230 head anomaly (%) 0,00 100 49,20 42,02 0,511 neck anomaly (%) 0,00 12 4,86 4,91 0,705 tail anomaly (%) 0,00 8 3,26 3,39 0,674 group 2 volume (ml) 0,50 7 2,92 1,32 0,752 (n = 52) concentration (x106/ml) 0,00 110 30,84 33,10 0,353 total motility (%) 0,00 80 47,65 23,40 0,852 progressive motility (%) 0,00 65 30,48 20,47 0,447 normal morphology (%) 0,00 7 2,40 2,27 0,997 head anomaly (%) 0,00 91 36,30 41,27 0,729 neck anomaly (%) 0,00 12 3,85 4,64 0,258 tail anomaly (%) 0,00 11 2,90 3,59 0,389 group 3 volume (ml) 0,30 7 2,70 1,35 0,068 (n = 79) concentration (x106/ml) 0,00 120 32,21 35,05 0,326 total motility (%) 0,00 80 45,21 24,84 0,766 progressive motility (%) 0,00 70 31,37 20,73 0,548 normal morphology (%) 0,00 8 2,22 2,02 0,663 head anomaly (%) 0,00 91 43,71 40,79 0,630 neck anomaly (%) 0,00 13 4,82 4,72 0,549 tail anomaly (%) 0,00 11 3,74 3,79 0,986 group 4 volume (ml) 1,1 3,4 2,08 0,79 0,009 (n = 14) concentration (x106/ml) 0,00 112 42,32 34,03 0,484 total motility (%) 0,00 80 48,92 25,88 0,561 progressive motility (%) 0,00 65 37,14 22,93 0,416 normal morphology (%) 0,00 10 3,50 2,68 0,109 head anomaly (%) 0,00 82 67,71 30,01 0,173 neck anomaly (%) 0,00 13 9 4,20 0,76 tail anomaly (%) 0,00 11 5,57 3,40 0,217 table 1. mean values of datas (n = 356). keskin ok_stesura seveso 05/04/16 15:54 pagina 57 archivio italiano di urologia e andrologia 2016; 88, 1 m. zeynel keskin, s. budak, s. gubari, k. durmaz, m. yoldas, o. celik, e. emre aksoy, y. ozlem ilbey 58 sperm parameters in only 3 months after giving up the alcohol in a 44-year old patient who was an alcohol addict in a case study conducted in 2010 (15). we have not detected any statistically significant relationship between the alcohol use and semen parameters in our study. li et al. determined that cigarette affects all the sperm parameters negatively in their meta-analysis but effects on semen volume and density display geographical difference (16). sergeri et al. reported that cigarette does not affect semen parameters in their study (17). when the groups who use cigarette and who do not use cigarette were compared in our study, we have found a statistically significant difference between the control group and group 4 (who use more than 20 package-years cigarette) in relation to semen volume, but there was no significant difference in any of the parameters and groups compared with the control group. although the number of studies in which cigarette and alcohol use were evaluated together, effect of use of both were not shown on the semen parameters (18, 19). in our study, the patients who do not use cigarette and alcohol were compared to patients who use both of them or only one of them respectively and no statistically significant difference was detected in any of semen parameters among the groups. in conclusion, a statistical significance was not determined between the ones who do not use neither cigarette nor alcohol and the ones who use cigarette and/or alcohol in terms of semen parameters (semen volume, sperm concentration, total motility, forward motility, morphology). according to our study, using more than 20 packageyears cigarette decreases semen volume. the reason of this result might be the threshold value, from which the effect of cigarette and alcohol use on the semen parameters become to be evident. although no relationship was determined in our study, except the one between semen volume and chronic smoking, in consideration of the publications about the negative relationship of cigarette and alcohol on the reproductive organs and fertility, young individuals in the reproductive age should be careful about cigarette and alcohol use. references 1. tawadrous ga, aziz aa, mostafa t. effect of smoking status on seminal parameters and apoptotic markers in infertile men. j urol. 2011; 186:1986-90. 2. mostafa t. cigarette smoking and male infertility. j advanced res. 2010; 1:179. 3. cinar o, dilbaz s, terzioglu f, et al. does cigarette smoking really have detrimental effects on outcomes of ivf? eur j obstet gynecol reprod biol. 2014;1 74:106-110. 4. sepaniak s, forges t, gerard h, et al. the influence of cigarette smoking on human sperm quality and dna fragmentation. toxicology. 2006; 223:54-60. 5. world health organization. alcohol: facts and figures. 2009; available from: <http://www.who.int/ substance_abuse/facts/ alcohol/en/index.html> (accessed 20.10.09). 6. dawson da, li tk, grant bf. a prospective study of risk drinking: at risk for what? drug alcohol depend. 2008; 95:62-72. 7. gaur ds, talekar ms, pathak vp. alcohol intake and cigarette smoking: impact of two major lifestyle factors on male fertility. indian j pathol microbiol. 2010; 53:35-40. 8. hansen ml, thulstrup am, bonde jp, et al. does last week’s alcohol intake affect semen quality or reproductive hormones? a crosssectional study among healthy young danish men. reprod toxicol. 2012; 34:457-62. 9. povey ac, clyma ja, mcnamee r, et al. modifiable and nonmin. max. mean std. dev. p value group 0 volume (ml) 0,30 11,00 2,94 1,51 (n = 256) concentration (x106/ml) 0,00 170 37,51 38,68 total motility (%) 0,00 90,00 46,26 25,21 progressive motility (%) 0,00 80,00 32,79 21,72 normal morphology (%) 0,00 10,00 2,49 2,32 head anomaly (%) 0,00 100 43,04 40,34 neck anomaly (%) 0,00 18 4,94 5,00 tail anomaly (%) 0,00 14,00 3,60 3,87 group 1 volume (ml) 0,30 8,00 2,96 1,56 0,865 (n = 62) concentration (x106/ml) 0,00 110 30,77 31,68 0,400 total motility (%) 0,00 85,00 48,14 22,56 0,834 progressive motility (%) 0,00 75,00 32,01 19,57 0,748 normal morphology (%) 0,00 7,0 2,40 2,16 0,900 head anomaly (%) 0,00 91,00 46,58 40,35 0,812 neck anomaly (%) 0,00 14,00 5,91 5,53 0,352 tail anomaly (%) 0,00 11,00 3,83 3,80 0,769 group 2 volume (ml) 1,00 7,50 3,26 1,73 0,427 (n = 16) concentration (x106/ml) 0,00 110,00 33,15 30,12 0,971 total motility (%) 0,00 85,00 48,43 23,57 0,949 progressive motility (%) 0,00 70,00 32,37 21,04 0,890 normal morphology (%) 0,00 6,00 2,43 2,15 0,988 head anomaly (%) 0,00 86,00 53,50 41,56 0,568 neck anomaly (%) 0,00 12,00 6,66 5,35 0,346 tail anomaly (%) 0,00 7,00 4,00 3,46 0,727 group 3 volume (ml) 2,00 3,50 2,83 0,76 0,867 (n = 3) concentration (x106/ml) 0,00 70,00 27,33 37,43 0,622 total motility (%) 0,00 75,00 40,00 37,74 0,797 progressive motility (%) 0,00 50,00 26,66 25,16 0,618 normal morphology (%) 0,00 3,00 1,33 1,52 0,431 head anomaly (%) 0,00 0,00 0,00 0,331 neck anomaly (%) 0,00 0,00 0,00 0,337 tail anomaly (%) 0,00 0,00 0,00 0,337 group 4 volume (ml) 1,10 8,50 3,02 1,73 0,948 (n = 19) concentration (x106/ml) 0,00 100 38,72 34,72 0,758 total motility (%) 0,00 80,00 44,57 26,01 0,788 progressive motility (%) 0,00 65,00 33,26 21,72 0,862 normal morphology (%) 0,00 5,00 2,63 1,83 0,579 head anomaly (%) 0,00 82,00 44,57 41,75 0,799 neck anomaly (%) 0,00 13,00 6,00 5,74 0,507 tail anomaly (%) 0,00 11,00 4,85 4,91 0,440 table 3. mean values of semen parameters and p values according to the alcohol use groups. keskin ok_stesura seveso 05/04/16 15:54 pagina 58 59archivio italiano di urologia e andrologia 2016; 88, 1 do cigarette and alcohol affect semen analysis? modifiable risk factors for poor semen quality: a case-referent study. hum reprod. 2012; 27:2799-806. 10. world health organization. who laboratory manual for the examination and processing of human semen. 5th edn. who, 2010. 11. jensen tk, gottschau m, madsen jo, et al. habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young danish men. bmj open 2014; 4:e005462. 12. jensen tk, swan s, jørgensen n, et al. alcohol and male reproductive health; a cross-sectional study of 8,344 healthy men from europe and usa. hum reprod 2014; 29:1801-9. 13. li y, lin h, ma m, et al. semen quality of 1346 healthy men, results from the chongqing area of southwest china. hum reprod. 2009; 24:459-69. 14. karmon ae, toth tl, afeiche m, et al. alcohol and caffeine intake in relation to semen parameters among fertility patients. fertil steril. 2013; 100:supplement:p12. 15. sermondade n, elloumi h, berthaut i, et al. progressive alcohol-induced sperm alterations leading to spermatogenic arrest, which was reversed after alcohol withdrawal. reprod biomed online. 2010; 20:324-7. 16. li y, lin h, li y, cao j. association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses. fertil steril. 2011; 95:116-23. 17. sergerie m, ouhilal s, bissonnette f, et al. lack of association between smoking and dna fragmentation in the spermatozoa of normal men. hum reprod 2000; 15:1314-21. 18. martini ac, molina ri, estofan d, et al. effects of alcohol and cigarette consumption on human seminal quality. fertil steril. 2004; 82:374-7. 19. gül t, yılmaz g, bayram s, et al. the effect of occupational groups and use of alcohol and smoking in thrace on semen parameters. turkish medical student journal. 2014; 1:8-12. correspondence mehmet zeynel keskin, md zeynel_akd@hotmail.com salih budak, md salihbudak1977@gmail.com mehmet yoldas, md yoldas_2297@hotmail.com orcun celik, md orcuncelik82@hotmail.com.tr yusuf ozlem ilbey, md ozlemyusufilbey@hotmail.com urologic clinic, tepecik training and research hospital, izmir, turkey saim gubari, md saimgubari@yahoo.com assisted reproductive techniques department, tepecik training and research hospital, izmir, turkey kalender durmaz, md kaldurmaz@hotmail.com urologic clinic yenisehir state hospital, turkey evrim emre aksoy, md dreaksoy@yahoo.com urologic clinic kırkagac state hospital, turkey min. max. mean std. dev. p value group 0 volume (ml) 0,30 11,00 3,10 1,67 (n = 139) concentration (x106/ml) 0,00 170,00 38,64 38,90 total motility (%) 0,00 90,00 44,81 25,11 progressive motility (%) 0,00 80,00 31,83 21,99 normal morphology (%) 0,00 10,00 2,41 2,24 head anomaly (%) 0,00 89,00 41,72 40,14 neck anomaly (%) 0,00 18,00 5,18 5,31 tail anomaly (%) 0,00 14,00 3,83 4,25 group 1 volume (ml) 0,30 7,00 2,74 1,27 0,170 (n = 117) concentration (x106/ml) 0,00 168,00 36,84 38,57 0,740 total motility (%) 0,00 85,00 47,99 25,33 0,228 progressive motility (%) 0,00 75,00 33,94 21,43 0,549 normal morphology (%) 0,00 10,00 2,58 2,41 0,615 head anomaly (%) 0,00 100,00 44,69 40,95 0,536 neck anomaly (%) 0,00 12,00 4,65 4,62 0,619 tail anomaly (%) 0,00 10,00 3,32 3,36 0,628 group 2 volume (ml) 1,00 8,50 3,31 1,65 0,303 (n = 33) concentration (x106/ml) 0,00 110,00 35,76 33,32 0,856 total motility (%) 0,00 85,00 51,57 24,06 0,127 progressive motility (%) 0,00 70,00 37,63 19,89 0,186 normal morphology (%) 0,00 7,00 2,36 2,08 0,990 head anomaly (%) 0,00 86,00 47,30 40,83 0,855 neck anomaly (%) 0,00 14,00 7,00 6,27 0,249 tail anomaly (%) 0,00 8,00 3,60 3,47 0,951 group 3 volume (ml) 0,30 8,00 2,87 1,54 0,376 (n = 67) concentration (x106/ml) 0,00 110,00 30.98 31.21 0,404 total motility (%) 0,00 85,00 45,14 23,14 0,854 progressive motility (%) 0,00 75,00 29,44 19,74 0,429 normal morphology (%) 0,00 7,00 2,44 2,08 0,779 head anomaly (%) 0,00 91,00 45,64 40,37 0,655 neck anomaly (%) 0,00 13,00 5,50 5,13 0,702 tail anomaly (%) 0,00 11,00 4,07 4,08 0,769 table 4. mean values of semen parameters and p values according to the cigarette and/or alcohol use groups. keskin ok_stesura seveso 05/04/16 15:54 pagina 59 stesura seveso 115archivio italiano di urologia e andrologia 2016; 88, 2 original paper buccal mucosa is a promising graft in peyronie’s disease surgery. our experience and a brief literature review on autologous grafting materials andrea fabiani 1, lucilla servi 1, fabrizio fioretti 1, valentina maurelli 1, flavia tombolini 2, alessandra filosa 3, alessandro zucchi 4, gianni paulis 5, gabriele mammana 1 1 urologic unit, surgical dpt, asur marche area vasta 3, macerata civic hospital, italy; 2 urologic clinic, politechnic university of marche region, ancona, italy; 3 pathologic unit asur marche area vasta 3, macerata civic hospital, italy; 4 urologic and andrologic clinic university of perugia, italy; 5 regina apostolorum hospital, andrologic center, albano laziale, roma, italy. aim: peyronie’s disease (pd) is an under reported acquired benign condition that, at the moment, is not curable with medical therapy. surgery represent the gold standard of treatment. surgical approaches are several and they consist in “plication techniques” or plaque incision/excision with grafting of resulting albuginea defect. among grafting procedures, albuginea defect substitution with autologous materials demonstrated over the years not inferior results respect to heterologous grafts. buccal mucosa graft (bmg) is not usually emphasized in many review articles and clinical series are yet limited. methods: we present our experience with seventeen plaque incision procedures and bmg in surgical correction of complex penile curvatures due to pd performed in a period of 30 months. our analyses was focused on buccal mucosa graft characteristics as major determinant of the surgical success. we also conducted a brief literature review on autologous grafting materials used in reconstructive penile surgery for pd. results: our cosmetics and functional results consists in a 100% of functional penile straightening with no relapses and 5,8% of de novo erectile dysfunction. mean age was 56.4 years, mean follow-up of 22.5 (6-36) months. no complications graft related were observed. operative time was 115.3 minutes in mean. over 94% of patients referred they were “really much better” and “much better” satisfied based on pgi-i questionnaire administrated at the last follow-up visit. conclusion: bmg is revealing as an optimal choice for reconstructive surgery in pd. anatomical characteristics consisting in the great elasticity, the quick integration time and the easy harvesting technique lead to high cosmetics and functional success rate, without omitting economical and invasiveness aspects. key words: buccal mucosa; graft; peyronie disease; autologous materials; surgery. submitted 23 october 2015; accepted 16 january 2016 summary no conflict of interest declared. introduction peyronie’s disease (pd) is an acquired benign condition that presents with a palpable induration and curvature or indentation of the erect penis (1). the average age of men affected by this disease is approximately 50-55 years and prevalence varies between 3,2% and 13 % (2). however, the disease is under reported as a consequence of embarassement felt by affected men (3). more cases are being identified with the advent of pde5 inhibitors (pde5-i) requests for erectile dysfunction treatment (1). moreover, there is an increasing number of cases diagnosed in the younger population (< 40 years) due to the modification of demographic and social contexts determining a better understanding and information on pd (4). at the present, there is no cure for pd. the medical best approach seems to be “multimodal therapy” that is able to achieve greater results than any single drug alone tested in scientific literature (5-6). surgery represent yet the gold standard of treatment. surgical approaches are several, consisting in “plication techniques” or plaque incision/excision with grafting of determined albuginea defect. indications for surgery are well established and the goal is to reliably and rapidly restore a coital function with a satisfactory and comfortable erection for both patient and partner (7). in our surgical practice, we had focused the attention on grafting techniques with buccal mucosa. as in case of medical therapy, because of data variability obtained from the wide range of autologous and heterologous grafts, we are inable to define which is the real “gold standard” for albuginea substitution. from literature, it is possible to note that biocompatible materials do not provide better outcomes in terms of satisfaction or postoperative erectile dysfunction (ed) than autologous grafts (8-9). moreover, many studies did not include complete information about the outcome of surgery such as satisfaction rate or globally post operative ed. when published, the outcomes are comparable, especially between pericardial graft (10-11) and buccal doi: 10.4081/aiua.2016.2.115 archivio italiano di urologia e andrologia 2016; 88, 2 a. fabiani, l. servi , f. fioretti, v. maurelli, f. tombolini, a. filosa, a. zucchi, g. paulis, g. mammana 116 mucosa graft series (12-13). in the present paper we explain how the characteristics of an ideal graft were achieved with this surgical procedure and outcomes data obtained from our series of 17 patients who underwent a complex corporoplasty using a buccal mucosa graft, compared with literature results. we had also conducted a literature review on autologous graft materials focusing on the buccal mucosa patch characteristics respect the main autologous graft employed in reconstructive penile surgery for pd. material and methods we have evaluated the clinical, pathological, intraoperative and post surgical data of a series of 17 consecutive cases treated with a plaque incision/partial excision and buccal mucosa grafting in the correction of severe secondary penile curvatures due to a stabilized pd and not responders to other medical treatment or previous surgical procedures. in a period of 30 months, in our urologic center we performed 17 plaque incision and grafting procedures after a training of 3 cases (not included in this report) carried out under the supervision of the author (az) skilled in the technique. all surgical procedures were performed by the same equipe (af, ls, ff) and each member was employed alternatively in buccal mucosa harvesting time or in penile corporoplasty and grafting. the pre-operative work-up included a clinical examination, a detailed clinical history, the iief (iief-5) questionnaire and penile ultrasound scans in tumescence and pge1-induced erection (10 mcg) to determine plaque dimensions, curvature, erection hardness score (ehs) (14) and vascular penile status. ultrasonographic plaque patterns was defined according on bekos classification (15). the grafts needed were harvested as described by eppley et al. (16). the corporoplasty procedures were done essentially the same way as for all others grafting techniques (17). circumcisions were made by a “sleeve technique” or a “forceps-guided method”. dorsal neurovascular bundle was ever elevated in a centripetal manner. in case of ventral curvature, urethra was carefully isolated from corpora cavernosa. the relaxing incision was made as a double y or h shaped at the point of maximum curvature. the margins of the incision are carefully prepared on all sides, preserving the underlying erectile tissue. after “defatting”, buccal mucosa patch was apposite to cover the albuginea defect with the submucosa surface in contact with the cavernous tissue in order to obtain a quick blood supply and sutured with a 3/0 adsorbable sutures in each of four sides of the graft. artificial erection was repeated in order to evaluate the curvature and deformity correction, defining the need of complementary tunica albuginea plications. buck’s fascia was closed with interrupted adsorbable suture or urethra was fixed to corpora cavernosa with tension free stitches. a drainage was placed between the buck’s fascia and the dartos in order to facilitate secretion discharge. circumcisional incision was closed and a “mummy wrap” with a non sticky dressing was performed around the base to the circumcision site (18). penis was located in a ventralized position. patients were discharged at third post operative day after catheter, drainage and dressing removal. the time of spontaneous erection resumption was recorded for each patient. to improve blood supply to the graft a low-dose pde5-i was prescribed for all patients for a period of two months, starting immediately after discharge. check-ups were scheduled every 3 months. after 6 and 12 months patients underwent to a penile echocolordoppler ultrasound dynamic scan (ehs determination) and compiled the iief-5 and the pgi-i (patient’s global impressions of improvement questionnaires), a 1-item questionnaire designed to assess the patient's impression of changes in his own condition (19). finally partner satisfaction was assessed (very satisfied, satisfied, fairly satisfied, dissatisfied) at each control. after 1 year, check-ups were scheduled at 12 month intervals. literature review on autologous graft materials employed in reconstructive penile surgery for pd was conducted using key words “graft”, “corporoplasty”, “buccal mucosa”, “autologous materials”. results during a 30 months period, seventeen patients underwent complex corporoplasty with buccal mucosa graft. pre-operative data, operative times, complications, and post operative findings are summarized in table 1 and table 2. the mean age was 56.4 years (range 45-71) and the mean follow-up was 22.5 months (range 6 36). all patients had sexual activity with valid erections with or without pde5-i assumption. pde5-i use was declared in medical history by 10 patients before surgery (58,8%). after curvature correction, pde5-i frequency use was confirmed and introduced in one more patient because of de novo erectile dysfunction. in all the cases the procedure was indicated because of great difficult during sexual intercourse caused by penile curvature. all patients previously received a peri-plaque medical treatment with verapamil (70.5%) or pentoxiphilline (29.5%). an immediate post operative complication developed in one patient at the cheek (donor site). resolution was obtained by an haemostatic suture performed 3 hours after the ending of corporoplasty. penile haematoma with spontaneous resolution was observed in one case. at last follow-up no relapses were recorded. one patient refers a worsening of erectile function (iief score 15) nevertless the ehs assessed was the same than in preoperative evaluation. all other patients had complete spontaneous erections 4-5 days after surgery without use of any device. mean operative time was 115.3 minutes (range 80-165). mean plaque volume was 151.45 ml. about pgi-i questionnaire, at last follow-up, over 94% of patients referred they were “really much better” and “much better” (table 3) and 76,5% of partners were satisfied (64,7% “very satisfied”). only one partner reported no change in sexual satisfaction after surgical curvature correction. discussion reconstructive surgery represents the gold standard of therapy in pd in cases of failure of conservative approach in restoring penetrative and coital capacity. when pd is a stabilized disease, the three basic surgical approaches are represented by excisional or incisional corporoplasty (i. e. nesbit or yachia procedures), plication techniques and plaque surgery procedures with or without graft materials employement (7). at the moment, no one surgical technique demonstrates superiority. is it clear that when penis have a severe curvature (> 60°) or deformity or it is affected by marked shortening or narrowing, plaque incision/partial excision and the graft of the resulting albuginea defect is the preferred surgical approach (20). complete excision of the plaque should never be offered to patients, as it would then require a larger graft and therefore it is associated with an unacceptably high rate of post operative erectile dysfunction (21). various graft materials have been used by many investigators. they may be synthetic inert substances, allografts or xenografts, or tissues harvested from the patient (autologous materials) at the time of surgery with a presumed additional morbidity and an highest operative time. the ideal graft should be easy to harvest, be taken reliably, heal without contracture, resistant to infection and preserving erectile capacity (22). despite a large amount of data obtained from numerous studies, ideal graft material has yet to be established. the most common syntethic inert substances used are goretex and dacron while the most common autologous materials used are saphenous vein, dermis, buccal mucosa, rectus fascia and fascia lata. bovine and cadaveric pericardium, porcine small intestine submucosa and cadaveric fascia lata represent the allo/xenograft more frequently employed (23). each grafting material has its own advantages and drawbacks in 117archivio italiano di urologia e andrologia 2016; 88, 2 buccal mucosa is a promising graft in peyronie’s disease surgery pts age medical site of degree of iiief-5 ehs* operative duration bekos plaque complications history/ curvature curvature score time (minutes) of disease plaque type dimensions treatment for pd (months) (mm)** 1 48 dorsal 60 24 4 140 16 a 18 x 15 x 3.5 haemorrage at (491.4 ml) the donor site 2 54 dupuytren disease dorsal 75 22 4 145 19 a 12 x 4 x 2 (49.92 ml) 3 71 dorsal 50 18 2 140 18 c 12 x 6 x 3 de novo (112.32 ml) erectile dysfunction 4 48 pde5i use/ dorsal 60 20 3 150 14 b 8 x 5 x 2 radical prostatectomy (41.6 ml) 5 62 pde5i use/ ventral 45 23 4 165 12 a 10 x 5 x 3 traumatic event (78 ml) 6 52 dorsal 50 23 4 120 17 c 14 x 6 x 3 (131 ml) 7 55 pde5i use/ dorsal 50 22 4 95 13 c 9 x 4 x 3 diabetes mellitus (56.16 ml) 8 50 dorsal 60 22 4 100 14 c 16 x 6 x 3 penile shaft (149.76 ml) haematoma 9 68 pde5i use/ dorsal 45 24 4 80 18 b 20 x 5 x 2 diabetes mellitus (104 ml) 10 58 previous plication dorsal 45 24 4 80 12 b 6 x4 x 2 glandular procedure/pde5i use (24.96 ml) erection pain 11 52 pde5i use dorsal-hg 75 24 4 125 13 c 18 x 7 x 2 (131 ml) 12 63 phymosis/preputial dorsal-lateral 85 18 2 135 16 c 25 x 10 x 3 lichen sclerosus/ (390 ml) pde5i use 13 53 hiv disease dorsal-hgd 90 24 4 145 17 c 25 x 9 x 3 (351 ml) 14 57 pde5i use dorsal 45 22 4 90 12 a 10 x 5 x 2 (52 ml) 15 68 pde5i use/ dorsal 45 21 3 85 24 a 11 x 4 x 2 radical prostatectomy (45.76 ml) 16 55 pde5i use dorsal 60 23 3 85 48 b 6 x 4 x 2 (24. 96 ml) 17 45 dorsal 90 24 3 80 10 c 23 x 10 x 3 (358.8 ml) mean 56.4 -----------------57.4 115.3 17.2 -------151.45 ml table 1. pre-operative patient’s characteristics and surgical informations. * erection hardness score. ** plaque dimensions were recorded during pre operative ultrasound evaluation and calculated considering the ellipsoid volume formula (volume is reported in ml). hgd: hourglass deformity. archivio italiano di urologia e andrologia 2016; 88, 2 a. fabiani, l. servi , f. fioretti, v. maurelli, f. tombolini, a. filosa, a. zucchi, g. paulis, g. mammana 118 terms of availability, antigenicity and cost effectiveness. buccal mucosa is used for reconstructing oral and maxillofacial defects, repairing the conjuctival mucosa of the eye, oral pharyngeal reconstructive surgery and reconstructing vaginal defects (24-25-26-27). in 2005, buccal mucosa was introduced as free autograft in the surgical treatment of pd (28) and then, during the years, evaluated in several others series (12-13-29). results were very interesting since from data reported by shioshvili and collegues (28). after the surgical treatment, with a mean follow-up of more than 3 years, they observed the complete straightening of the penis in 92.3% of 26 patients treated with a residual curvature (< 10°) in two cases (7.7%), the shortening of penis in four patients (15.4%) and in two patients a partial reduction of erectile power (7.7%). they concluded that their plaque excision and graft with buccal mucosa technique, showing high properties of adaptation and revascularization, good anatomical and functional clinical results, and demonstrating a stable elasticity without shrinkage, is simple and can be recommended for wide use in clinics for surgical treatment of pd. similarly, liu et al. (29) performed the surgical replacement of the plaque by free autograft of buccal mucosa on 27 patients with peyronie's disease, ranging in age from pts time of iief-5 iief-5 patient patient patient global partners ehs spontaneous pre operative post operative satisfaction satisfaction satisfaction follow-up satisfaction score at last erections score score at last (pgi-i score) (pgi-i score) (pgi-i score) (months) at last follow-up follow-up resumption (days) follow-up at 3 months at 6 months at 24 months 1 4 24 24 1 1 1 36 1 4 2 3 22 22 1 1 1 36 1 4 3 2 18 15 4 3 4 29 4 3 4 3 20 24 1 1 2 29 2 4 5 4 23 24 2 2 2 29 2 4 6 4 23 24 2 2 2 25 3 4 7 7 22 24 3 3 1 25 1 4 8 5 22 23 2 2 1 25 1 4 9 5 24 24 2 2 22 3 4 10 3 24 24 2 2 18 1 4 11 2 24 24 1 1 18 1 4 12 2 18 24 1 1 18 3 3 13 3 24 24 2 2 18 1 4 14 3 22 24 1 1 12 1 4 15 4 21 24 1 1 12 1 4 16 4 23 24 1 1 7 1 4 17 1 24 24 1 1 6 1 3 table 2. post operative erectile function and couple satisfaction. authors (reference) graft patients mean follow-up (mo) straighteningof penis (%) postop erectile dysfunction (%) shortening of penis (%) patient satisfaction (%) porena m. et al. (31) sv 12 na 83% 0 0 na kadioglu a. et al. (36) sv 22 >60 72.8 13.6 na 81.8 kalsi j. et al. (37) sv 113 12 86 15 25 96 montorsi f. et al. (38) sv 50 >60 72 22 100 60 el sakka ai. et al. (39) sv 112 18 96 12 17 92 akman t. et al. (40) sv 56 37.1 73 8 na na adeniyi aa. et al. (41) sv 51 16 82 8 35 92 akkus e. et al. (42) sv 50 32 80 6 40 88 de stefani s. et al. (43) sv 8 13 87.5 0 0 100 yourkanin jp. et al. (44) sv 22 13.4 66.6 46 0 na shioshvili tj et al. (28) bm 26 38.4 93.6 7.7 15.4 na liu b. et al. (29) bm 24 684 87.5 12.5 12.5 100 cormio l. et al. (12) bm 15 12.1 100 0 0 93.3 zucchi a. et al. (13) bm 28 43 96.5 3,5 0 85 present series bm 17 22.5 100 5,9 0 94 gvasalia b. et al. (45) bm 33 42 100 18 15 85 table 3. results of buccal mucosa (bm) grafting vs saphenous vein (sv) graft as reported in recent scientific literature. 24 to 72 years (mean 53), varying in disease course between 1 and 13 years, with a penile curvature angle of 30°-80° in erection. satisfactory results were achieved in all the cases, with no such complications as hematoma, infection, oral numbness, and tightness of the mouth. of the 24 cases evaluated, with a follow-up ranging from 6 months to 7 years, complete straightening of the penis was achieved in 21, slight residual curvature (< 15 degrees) was noted in 3 (12,5%), a little shortening of the penis (< 1 cm) in 2 (8,3%), and erectile pain in 3 cases (12,5%). the authors underlined in they conclusions the stable elasticity and no shrinkage of buccal mucosa graft. modifying the procedure from a plaque excision with substitution to an incision with insertion of a buccal mucosa patch, cormio and co-workers (12) reported in 15 patients, operated without complications (56.3 years of mean age and 72° of mean penile curvature degree), a 100% of penile straightening, 1.8-cm mean increase in length of affected side, no curvature recurrence or de novo erectile dysfunction, 1.6 mean increase in iief-5 score, and patient and partner satisfaction of 93.3% and 100%, respectively. these results were recently confirmed by zucchi et al. (13) in 32 patients treated with this procedure between 2006 and 2013. in their evaluable 28 cases, they reported no complications and a curvature relapse, after 1 year, in 3.5%. iief scores improved significantly after 1 year confirming stability in 50% of cases after 2 years. patients satisfaction was 85% on pgi-i questionnaire. they concluded that corporoplasty with buccal mucosa represent a good treatment choice for most forms of pd. gvasalia et al. (45) confirmed the previous good results. in a population study of 33 patients with a 43 months of mean follow-up, they reported a satisfaction rate of 85%. complete penis straightening was achieved in 73%, with a residual curvature (< 20°) in 27%. and post operative erectile dysfunction was observed in 18% with a good response to pde 5 inhibitors. authors underline that erectile dysfunction was common in elderly patients. also in our present work we are able to confirm these favorable results even if our series includes a non selected population. in fact, surgical procedures were performed in patients who required surgical correction of a curvature causing a great difficult during sexual intercourse or psychological impairment. patients are variably aging, with a medical general history characterized from different comorbidities as diabetes mellitus, cardiovascular disease, hiv or previous pelvic surgical procedure for prostate cancer. one patient underwent a previous failed plication procedure. pre-operative use of pde5 inhibitors was referred by 10 patients (58.8%). thus, considering that recognized risk factor of post operative erectile dysfunction are pre operative sexual function, patients age and operative technique (larger and ventral graft) (21), the probability of de novo erectile dysfunction was high in several patients of our study. in contrast, results obtained were very comfortable. rate of functional penis straightening was 100%. de novo erectile dysfunction was registered only in one case (5.9%) in which ehs recorded at follow-up was the same than pre operatively anyway. satisfaction for both patient and partner was achieved. globally, in terms of overall success rate, bmg series reported results between 87.5% and 100% (table 3). patient satisfaction rate ranged from 85-100% when investigated (12-13) and no decrease is observed over the years. the rate of “de novo” erectile dysfunction ranged between 0% to 18%. no patch bulging are yet reported. only a case of “seroma” was cited but not reported (13). loss of glans sensitivity or recurrent erection penile pain were common symptoms reported by the patients, especially in the first three or six months from the intervention. as observed in our experience, they are related to surgical procedure “per se” (eg. plaque location near to glans or attached to dorsal neurovascular bundle, requiring difficult dissection) and not directly to the patch. these symptoms are safely managed with the common analgesic/anti-inflammatory drugs. at the least, the need of a multiple harvesting from cheek is very rare and the elasticity of buccal mucosa permits to avoid any patch oversizing respect to plaque dimensions (13). prior of these evidences, the venous graft was advocated as the more physiologic than others autologous tissue (30-31). the advantages presented to support this use were several (32-35). as reported in table 3, overall success rates for straightening of the penis with the use of saphenous vein grafting ranged between 66.6% and 96% (36-45). despite promising theoretical properties, saphenous vein grafting clinical results are not so satisfactory. in fact, penile shortening occurs in 17-100% of cases and de novo erectile dysfunction in up to 46% of cases. in addition, the patient satisfaction rate in the short term ranged from 88% to 100% but it tends to decrease to 60-86% in the few series with a follow-up longer than 5 years (38). the major drawback of venous graft was the need for a second incision to harvest the vein, then the bulging of the graft, indentations or hourglass deformities, sensory loss and persistent pain (36). compared with the others graft material, characteristics of buccal mucosa are more favorable, also considering the functional and cosmetic results as reported in our experience and in literature (table 4 and related references in supplementary materials posted in www.aiua.it). similarly to venous graft, the buccal mucosa is a living tissue with an elevated binding capacity and revascularization which is immediately supplied with blood from the cavernous tissue. as vital tissue, buccal mucosa tends to heal rapidly, immediately integrating with the surrounding albuginea tissue. this translates into a more rapid resumption of spontaneous erections (mean of 3.5 days in our experience) and sexual activity and into a reduced risk of curvature relapse and ed after surgery (13). the thickness of the buccal mucosa is nearly the same of the tunica albuginea favoring easy adaptation to all sides of albuginea’s incision ensuring a perfect seal. these characteristics reduce the risk of curvature relapse and erectile dysfunction after surgery. another advantage of the bmg is its low cost (47). biocompatible materials are expensive and the rehabilitation to prevent scarring related retraction (48) implies the adjunctive cost of buying or hiring a vacuum device. despite these evidences, bmg is not usually emphasized in many review articles and clinical series are yet limited. many authors not understand the anatomic logic for use of buccal mucosa as a tunica albuginea substitutes (49) but it must take into account that, as noted by cormio et al. (12), clinical experience with bmg was 119archivio italiano di urologia e andrologia 2016; 88, 2 buccal mucosa is a promising graft in peyronie’s disease surgery archivio italiano di urologia e andrologia 2016; 88, 2 a. fabiani, l. servi , f. fioretti, v. maurelli, f. tombolini, a. filosa, a. zucchi, g. paulis, g. mammana 120 begun after having examined the ‘‘ideal’’ substitute of penile tunica albuginea in experimental animal models (50). in this experience, buccal mucosa obtained the best results in terms of elasticity, coefficient of lengthening, and morphological structure. plaque excision and bmg was then applied in humans obtaining the reported very interesting cosmetic and functional results. in particular, as previously mentioned, we would like underlines the great elasticity of bmg that permits to harvest a patch with no need of oversizing respect plaque dimensions and the integration time allows a rapid resumption of spontaneous erections. moreover, the absence of accessory wounds and severe complications at the side of patch harvest, lead us to consider bmg as a preferable option for pd surgery. in addition, operative time are no longer than these registered in others penile grafting procedures. we had observed a mean operative time of 115 minutes that we consider very acceptable for a complex surgical procedure that allows to restore a functional penile shaft for sexual intercourse. if in clinical setting also the surgeons expectations, so the reproducibility of surgical technique and the availability of the graft may be considered important, the first outcomes to be achieved in reconstructive surgery for pd are the patient perspectives in terms of patient’s and partner satisfaction that, over the time, bmg seems able to assure. conclusion buccal mucosa graft is revealing as an optimal choice for reconstructive surgery in pd, determining a high satisfaction rate over the time for both the patients and the partner. anatomical characteristics consisting in the great elasticity, the quick integration time and the easy and reproducible harvesting technique lead to high cosmetic and functional success rate, without omitting economical and invasiveness aspects. considering the not satisfactory results observed at the long term in cases of venous grafting procedures, we need an higher follow-up period and an higher number of cases treated with a bmg to define buccal mucosa a first choice in the surgical management of pd. references 1. jalkut m, gonzalez-cadavid n, rajfer j. peyronie's disease: a review. rev urol. 2003; 5:142-8. 2. dibenedetti db, nguyen d, zografos l, et al. a population-based study of peyronie’s disease: prevalence and treatment patterns in the united states. adv urol. 2011:1-9. 3. greenfield jm, levine la. peyronie's disease: etiology, epidemiology and medical treatment. urol clin north am. 2005; 32:469-78. 4. paulis g, cavallini g, barletta d, et al. clinical and epidemiological characteristics of young patients with peyronie’s disease: a retrospective study. res rep urol. 2015; 7:107-111. 5. abern mr, larsen s, levine la. combination of penile traction, intralesional verapamil, and oral therapies for peyronie's disease. j sex med. 2012; 9:288-295. 6. paulis g, farina fp, cavallini g, et al. pentoxifylline associated with other antioxidants (multimodal therapy) on patients with peyronie's disease. results of a controlled study. andrology open access. 2014; 3:123. 7. ralph d, gonzalez-cadavid n, mirone v, et al. the management of peyronie’s disease: evidence based 2010 guidelines. j sex med. 2010; 7:2359-2374. 8. levine la, larsen sm. surgery for peyronie’s disease. asian j androl. 2013; 15:27-34. 9. levine la, burnett al. standard operating procedures for peyronie’s disease. j sex med. 2013; 10:230-244. 10. egydio ph, lucon am, arap s. treatment of peyronie’s disease by incomplete circumferential incision of the tunica albuginea and plaque with bovine pericardium graft. urology. 2002; 59:570-574. 11. chun jl, mcgregor a, krishnan r, carson cc. a comparison of dermal and cadaveric pericardial grafts in the modified hortondevine procedure for peyronie’s disease. j urol. 2001; 166:185-188. 12. cormio l, zucchi a, lorusso f, et al. surgical treatment of peyronie’s disease by plaque incision and grafting with buccal mucosa. eur urol 2009; 55:1469-1475. 13. zucchi a, silvani m, pastore al, et al. corporoplasty using buccal mucosa graft in peyronie disease: is it a first choice? urology. 2015; 85:679-83. 14. mulhall jp, goldstein i, bushmakin ag, et al. validation of the erection hardness score. j sex med. 2007; 4:1626-1634. 15. bekos a, arvaniti m, hatzimouratidis k, et al. the natural history of peyronie’s disease: an ultrasonography-based study. 2008; 53:644–651. 16. eppley bl, keating m, rink r. a buccal mucosal harvesting technique for urethral reconstruction. j urol. 1997; 157:1268. 17. garaffa g, kuehhas ef, de luca f, et al. long-term results of reconstructive surgery for peyronie's disease. sex med rev. 2015; 3:113-121. 18. henry dg, mahle p, caso j, et al surgical techniques in penoscrotal implantation of an inflatable penile prosthesis: a guide to increasing patient satisfaction and surgeon ease. sex med rev. 2015; 3:36-47. 19. viktrup l, hayes rp, wang p, shen w. construct validation of patient global impression of severity (pgi-s) and improvement (pgi-i) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia bmc urology. 2012; 12:30. 20. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie's disease and erectile dysfunction: functional and satisfaction outcomes. j sex med. 2005; 2:132-8. 21. flores s, choi jm, alex b, et al. erectile dysfunction after plaque incision and grafting: short term incidence and predictors. j sex med. 2011; 8:2031-37. 22. carson cc, chun jl. peyronie’s disease: surgical management: autologous materials. int j impot res. 2002; 14:329-35. 23. kadioglu a, sanli o, akman t, et al. graft materials in peyronie’s disease surgery: a comprehensive review j sex med. 2007; 4:581-95. 24. donoff rb. biological basis for vestibuloplasty procedures. j oral surg. 1976; 34:890. 25. leone cr jr. conjunctivodacryocystorhinostomy with buccal mucosal graft. arch ophthalmol. 1995; 113:113. 26. yarington ct jr. reconstruction of the base of the tongue and lateral pharyngeal wall. laryngoscope. 1980; 90:202. 27. lin wc, chang cyy, shen yy, tsai hd. use of autologous buccal mucosa for vaginoplasty: a study of eight cases. hum reprod. 2003; 18:604. 28. shioshvili tj, kakonashivili ap. the surgical treatment of peyronie’s disease: replacement of plaque by free autograftof buccal mucosa. eur urol. 2005; 48:129-35. 29. liu b, zhu xw, zhong dc, et al. replacement of plaque by buccal mucosa in the treatment of peyronie’s disease: a report of 27 cases zhonghua nan ke xue. 2009; 15:45-7. 30. viet qt, dennis hk, timothy fl, et al. review of the surgical approachesfor peyronie’s disease: corporeal plication and plaque incision with grafting. adv urol. 2008; 2008:263450. 31. porena m, mearini l, mearini e, et al. peyronie's disease: corporoplasty using saphenous vein patch graft. urol int. 2002; 68:91-4. 32. chang ja, gholami ss, lue tf. surgical management: saphenous vein grafts. int j impot res. 2002; 14:375-8. 33. nowicki m, buczkowski p, miskowiak b, et al. immunocytochemical study on endothelial integrity of saphenous vein grafts harvested by minimally invasive surgery with the use of vascular mayo stripers. a randomized controlled trial. eur j vasc endovasc surg. 2004; 27:244-50. 34. tsui lc, souza ds, filbey d, et al. localization of nitric oxide synthase in saphenous vein grafts harvested with a novel ‘‘no-touch’’ technique: potential role of nitric oxide contribution to improved early graft patency rates. j vasc surg. 2002; 35:356-62. 35. brannigan re, kim ed, oyasu r, et al. comparison of tunica albuginea substitutes for the treatment of peyronie’s disease. j urol. 1998; 159:1064-8. 36. kadioglu a, sanli o, akman t, et al. surgical treatment of peyronie’s disease: a single center experience with 145 patients. eur urol. 2008; 53:432-40. 37. kalsi j, minhas s, christopher n, et al. the results of plaque incision and venous grafting (lue procedure) to correct the penile deformity of peyronie’s disease. bju int. 2005; 95:1029-33. 38. montorsi f, salonia a, briganti a, et al. five year follow-up of plaque incision and vein grafting for peyronie’s disease. j urol. 2004; 171:331. 39. el-sakka ai, rashwan hm, lue tf. venous patch graft for peyronie’s disease. part ii: outcome analysis. j urol. 1998; 160:2050-3. 40. akman t, sanli o, gurkan l, et al. medial dissection of the neuro vascular bundle in peyronie’s patients with dorsal curvature: demonstration of a technique and analysis of outcome. in abstracts of 8th congress of the european society for sexual medicine 2006; p. 1, a:v-01-001. 41. adeniyi aa, goorney sr, pryor jp, et al. the lue procedure: an analysis of the outcome in peyronie’s disease. bju int. 2002; 89:404-8. 42. akkus e, ozkara h, alici b, et al. incision and venous patch graft in the surgical treatment of penile curvature in peyronie’s disease. eur urol. 2001; 40:531-6. 43. de stefani s, savoca g, ciampalini s, et al. saphenous vein harvesting by ‘stripping’ technique and ‘w’-shaped patch covering after plaque incision in treatment of peyronie’s disease. int j impot res. 2000; 12:299-301. 44. yurkanin jp, dean r, wessells h. effect of incision and saphenous vein grafting for peyronie’s disease on penile length and sexual satisfaction. j urol. 2001; 166:1769-72. 45. gvasalia b, kochetov a, abramov r, et al. buccal mucosa in the surgical treatment of peyronie's disease. j sex med. 2014; 11(suppl 1):33. 46. costantini e, zucchi a. reconstructive surgery in peyronie’s disease: what’s new? world j clin urol. 2015; 4:1-4. 47. rolle l, tamagnone a, bollito e, et al. could plaque excision surgery with sis graft induce a new fibrotic reaction in la peyronie's disease patients? arch ital urol androl. 2007; 79:167-9. 48. levine la. editorial comment on: surgical treatment of peyronie's disease by plaque incision and grafting with buccal mucosa. eur urol. 2009; 55:1475-6. 49. kakonashivili ap, shioshvili tj. substitution of tunica albuginea penis by different autotransplant: an experimental study. georgian med news. 2003; 10:38-42. 121archivio italiano di urologia e andrologia 2016; 88, 2 buccal mucosa is a promising graft in peyronie’s disease surgery correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it lucilla servi, md lucilla.servi@sanita.marche.it fabrizio fioretti, md phd fa.fioretti@libero.it valentina maurelli, md valentinamaurelli@hotmail.it surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, italy flavia tombolini md, urology resident flavia.tombolini@gmail.com urologic clinic, polytechnic university of marche region, italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy alessandro zucchi, md, associate professor zucchi.urologia@gmail.com urology and andrology department, university of perugia, s. andrea delle fratte, perugia, italy gianni paulis, md paulisg@libero.it regina apostolorum hospital, andrologic center, albano laziale (rome), italy gabriele mammana, md gabriele.mammana@sanita.marche.it head of surgery dpt, chief of section of urology, asur marche area vasta 3 macerata hospital, macerata, italy stesura seveso archivio italiano di urologia e andrologia 2015; 87, 3260 case report sex-related penile fracture with complete urethral rupture: a case report and review of the literature marco garofalo 1, lorenzo bianchi 1, giorgio gentile 1, marco borghesi 1, valerio vagnoni 1, hussam dababneh 1, riccardo schiavina 1, alessandro franceschelli 2, daniele romagnoli 1, fulvio colombo 2, beniamino corcioni 3, rita golfieri 3, eugenio brunocilla 1 1 department of urology, university of bologna, s.orsola-malpighi hospital, bologna, italy 2 andrology unit, sant’orsola-malpighi hospital, bologna, italy; 3 department of radiology, university of bologna, s.orsola-malpighi hospital, bologna, italy. objective: to present the management of a patient with partial disruption of both cavernosal bodies and complete urethral rupture and to propose a non-systematic review of literature about complete urethral rupture. material and method case report: a 46 years old man presented to our emergency department after a blunt injury of the penis during sexual intercourse. on physical examination there was subcutaneous hematoma extending over the proximal penile shaft with a dorsal-left sided deviation of the penis and urethral bleeding. ultrasound investigation showed an hematoma in the ventral shaft of the penis with a discontinuity of the tunica albuginea of the right cavernosal corporum. the patient underwent immediate emergency surgery consisted on evacuation of the hematoma, reparation the partial defect of both two cavernosal bodies and end to end suture of the urethra that resulted completely disrupted. results: the urethral catheter was removed at the 12-th postoperative day without voiding symptoms after a retrograde urethrography. 6 months postoperatively the patients was evaluated with uroflowmetry demonstrating a max flow rate of 22 ml/s and optimal functional outcomes evaluated with validated questionnaires. 8 months after surgery the patients was evaluated by dynamic magnetic resonance (mri) of the penis showing only a little curvature on the left side of the penile shaft. conclusion: penile fracture is an extremely uncommon urologic injury with approximately 1331 reported cases in the literature till the years 2001. to best of our knowledge from 2001 up today, 1839 more cases have been reported, only in 159 of them anterior urethral rupture was associated and in only 22 cases a complete urethral rupture was described. in our opinion, in order to prevent long term complications, in case of clinical suspicion of penile fracture, especially if it is associated to urethral disruption, emergency surgery should be the first choice of treatment. key words: penile fracture, complete urethral rupture, surgical repair. submitted 9 february 2015; accepted 31 july 2015 summary no conflict of interest declared. patient with partial disruption of both cavernosal bodies due to sexual intercourse trauma with complete urethral rupture and its surgical reconstruction; we also propose a non-systematic review of literature about penile fracture and anterior urethral rupture. case report a 46 years old caucasian man presented in march 2014 to our emergency department 1 hour after blunt injury of the penis during sexual intercourse. the patient reported a cracking sound and severe penile pain followed by immediate detumescence after a blunt trauma against his partner's perineum during sexual intercourse. he didn't notice blood at the urethral meatus but he was not able to void. on physical examination there was swelling and subcutaneous hematoma extending over the proximal penile shaft, the scrotum and the pubis with a dorsal-left sided deviation of the penis. the typical "rolling sign" was present in the left side of penis' shaft (4 cm from the base of the penis). the scrotum was swollen and painful on physical examination and the testicles were palpable with difficulty due to the oedema. abdominal examinations showed bloating of the lower abdomen: due to inability to void, a 14 ch foley catheter was easily insert with emission of clear urine. the patient was firstly managed with conservative therapy: ice pack on the penis, fluid infusion and antibiotic prophylaxis. penile ultrasound (us) showed the presence of hematoma in the ventral shaft of the penis with a rupture of the tunica albuginea of the right cavernosal corpora and oedema of the subcutaneous tissue. one hour later finding of blood at the urethral meatus suggested an urethral injury and the blood exams revealed anemia. we informed the patients about the potential postoperative complications such as necrosis, stricture, penile deformity or shortening and the potential complication not to operate; after having his consent he underwent immediate emergency surgery. under spinal anesthesia, after a penile degloving a partial rupture of both cavernosal bodies was identified. after the evacuation of the hematoma in the ventral shaft of the penis, a complete urethral disruption and partial bilateral cavernosal boddoi: 10.4081/aiua.2015.3.260 introduction penile fracture is an uncommon urologic injury, with approximately 1331 reported cases in the literature till the year 2001 (1-3). we present the management of a garofalo_stesura seveso 23/09/15 12:48 pagina 260 261archivio italiano di urologia e andrologia 2015; 87, 3 penile fracture with complete urethral rupture ies injury was found (figure 1). a 18 ch urethral catheter was inserted. defect of both two cavernosal bodies were repaired by 4-0 prolene stiches and a end-to-end anastomosis of the urethra was performed with tensionfree 5-0 vicryl double running sutures (figure 2). a broad spectrum antibiotic (cefuroxime 2 g) was given during hospital stay. the patient was dismissed 2 days after surgical intervention with 18 ch foley catheter. the urethral catheter was removed at the 12-th postoperative day after a retrograde urethrography that documented a regular urethral profile without signs of stricture neither fistula (figure 3). four months later the patient referred normal erectile and voiding functions; on physical examination a little scar was palpable on the left side of penis shaft and a slight penile curvature on left side during erection without difficulties during sexual intercourse. at 6 months follow up the patients was evaluated with uroflowmetry demonstrating a max flow rate of 22 ml/s; validated questionnaires demonstrated optimal functional outcomes (ipss =3, qol = 0 and iief-5 = 23). ipss: international prostate symptoms score qol: quality of life iief-5: international index of erectile function. eight months later the patients underwent a magnetic resonance imaging (mri) of the penis, performed after the injection of 10 mcg of prostaglandin-e1 in the corpora cavenosa, showing a little curvature on the left side of the penile shaft with thickening of the tunica albuginea (figures 4, 5). at 12 months follow up penile color doppler ultrasonography confirmed the presence of a thin scar on the middle third of left cavernosal body, with a minimal curvature. ipss, qol and iief-5 were repeated with confirmation of the functional outcomes. discussion discussion and supplementary tables and references are posted in supplementary materials on www.aiua.it conclusions penile fracture is an uncommon urological emergency, probably it is an under reported or hidden and it remains a clinical problem for delayed diagnosis or treatment and mismanagement; very rarely it is associated with complete urethral rupture. we present the 23rd case of penile fracture with total urethral disruption reported in englishwritten literature. in our opinion, in order to prevent long term complications, in case of clinical suspicion of penile fracture, especially if it is associated to urethral disruption, emergency surgery should be the first choice of treatment. references 1. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 2. martinez portillo fj, seif c, spahn m, et al. penile fractures: controversy of surgical vs. conservative treatment. aktuel urol. 2003; 34:33-6. 3. mydlo jh, hayyeri m, macchia rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology 998; 51:616-619. figure 1. intraoperative photo demonstrating bilateral partial rupture of the corpora cavernosa and complete rupture of corpum spongiosum. figure 4. postoperative coronal mri (8 months postoperativelly) showing a minimal curvature on the left side of the penile. figure 5. postoperative sagital mri (8 months post-operativelly) showing a thickening of the tunica albuginea of the left cavernosal body. figure 2. intraoperative photo demonstrating end-to-end anastomosis in one layer of the urethra and suture of both corpora cavernosa, figure 3. postoperative retrograde urethrogram (12 days postoperatively) demonstrating absence of urethral stricture. correspondence marco garofalo, md marco.garofalo@unibo.it lorenzo bianchi, md lorenzo.bianchi3@gmail.com giorgio gentile, md (corresponding author) dr.giorgio.gentile@gmail.com valerio vagnoni, md vagno07@libero.it marco borghesi, md mark.borghesi1@gmail.com riccardo schiavina, md rschiavina@yahoo.it daniele romagnoli md danieleromagnoli@hotmail.it eugenio brunocilla md eugenio.brunocilla@unibo.it department of urology, university of bologna, s.orsola-malpighi hospital alessandro franceschelli, md alessandro.franceschelli@aosp.bo.it fulvio colombo, md fulvio.colombo@aosp.bo.it andrology unit, sant’orsola-malpighi hospital beniamino corcioni, md beniamino.corcioni@aosp.bo.it rita golfieri, md italyrita.golfieri@aosp.bo.it department of radiology, university of bologna, s.orsola-malpighi hospital, bologna, italy, via p. palagi, 9 40138 bologna, italy garofalo_stesura seveso 23/09/15 12:48 pagina 261 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3202 original paper empiric antibiotics therapy for mildly elevated prostate specific antigen: helpful to avoid unnecessary biopsies? andrea fandella 1, sara benvenuto 1, elisa guidoni 1, marco giampaoli 2, alessandro bertaccini 2 1 urology, casa di cura giovanni xxiii monastier, treviso, italy; 2 clinica urologica, alma mater studiorum, università di bologna, italy. purpose: the management of mildly elevated (4.0-10.0 ng/ml) prostate specific antigen (psa) is uncertain. immediate prostate biopsy, antibiotic treatment, or monitoring psa level for 1-3 months is still in controversy. materials and methods: we retrospectively analysed the effect of empiric antibiotics on an increased psa in a mono-institutional study. we analysed the data of 100 patients with a psa of 4-10 ng/ml and normal digital rectal examination undergoing their first prostate biopsy. patients were divided in two different cohorts. one cohort was submitted to antibiotic therapy (levoxacin 500 mg daily for 20 days) and both cohort had a re-dosing of psa before the prostate biopsy. results: average age of the whole group of patients was 66.48 ± 8.32 years and their average initial psa level was 6.67 ± 1.57 ng/ml. in the treated group (n = 49) 29 patients had a decreasing psa value from mean baseline psa value of 6.6 ± 1.54 ng/ml to the re-dosed mean psa level of 5.4 ± 1,61 ng/ml (p = 0.7); 20 patients didn’t experience a decrease psa value, with a mean psa level of 6.9 ± 1.68 ng/ml. in the control group (n = 51), 30 patients had a decrease of psa level from mean baseline psa level of 6.5 ± 1,59 ng/ml to a re-dosed psa level of 5.5 ± 1.57 ng/ml; 21 patients didn’t experience a decrease of psa value, with a mean psa level of 6.7 ± 1.71 ng/ml. multivariate analysis of age, psa changes, antibiotics therapy and biopsy results (presence or absence of cancer) revealed no significant difference between the two cohorts. sepsis after biopsy occurred in 3 patient in the antibiotics group (6%) and in one of the control group (2%). conclusions: the study, even with some limitations, does not seem to show an advantage due to the administration of antibacterial therapy to reduce psa values before prostate biopsy and subsequently to reduce unnecessary prostate biopsies. key words: psa; antibiotics; biopsy; prostate cancer; fluorquinolone. submitted 21 august 2014; accepted 30 august 2014 summary no conflict of interest declared. introduction prostate specific antigen (psa) is a serum protein secreted by prostate tissue both in benign and malignant conditions. elevated values of serum psa are not pathognomonic for prostate cancer but they can be found in various clinical conditions, including inflammation and infection (1). in men with an increasing psa without clinical evidence of infection, a common clinical approach is to empirically prescribe antibiotics and subsequently re-dose the psa. until today, several researchers have examined the impact of empiric antibiotics therapy in patients with an increased psa, in order to find a balanced costs/effective therapy to avoid unnecessary prostate biopsies and to decrease patient discomfort and morbidity from biopsies (2, 3). the common rational is to treat a subclinical prostate infection, having as result a lower serum psa. this might lead to lower the rate of unnecessary prostate biopsies, since unproven sub clinical prostatitis are responsible for the majority of false positive psa elevations (4-6). however, most of the studies available in the literature are limited because they lack a control arm, so it is unclear if the observed psa changes were secondary to natural variations or to the effect of the antibacterial therapies (7). the potential disadvantages of an empiric antibiotic approach include unnecessary expenses, side effects and possible adverse reactions related to the drug intake and an increase in multidrug resistant organisms (8). our goal was to investigate if an antibiotic therapy in patients eligible for prostate biopsies might be effective in order to avoid unnecessary biopsies so reducing false positive psa elevation. materials and methods we conducted a retrospective mono-institutional study (casa di cura giovanni xxiii monastier, treviso, italy). we analysed the data of two different cohort of patients, all submitted to their first prostate biopsy set in the last 3 years in our institution. the first cohort (n = 49) included patients treated with an antibiotic therapy (levofloxacin 500 mg daily) for at least 20 days and then doi: 10.4081/aiua.2014.3.202 fandella_stesura seveso 08/10/14 12:12 pagina 202 203archivio italiano di urologia e andrologia 2014; 86, 3 empiric antibiotics therapy for mildly elevated prostate specific antigen: helpful to avoid unnecessary biopsies? submitted to psa re-dosing prior to the prostate biopsy. otherwise, the second cohort (n = 51) included patients with no antibiotic therapy but with psa re-dosing before prostate biopsy. both cohort presented psa levels between 4.0-10 ng/ml, no prior diagnosis of prostate cancer or pre-neoplastic lesions (hgpin/asap), a negative digital rectal examination (dre) and no clinical or laboratory signs of urinary infections (negative urine sediment and negative urine culture). the analysed data included patient’s age and history. cases with reported events that could have falsely elevated the psa result (e.g. urinary tract infection, urinary retention, urinary catheterization…) were excluded from the study. all the specimens were analysed in our laboratory (using beckam coulter access ii immunoassay system psa). analysis of data [age, psa changes, antibiotic therapy, biopsy result (presence of cancer)] was carried out using spss statistical analysis software (ibm spss statistics 21). data of the second cohort (n = 51) was used as control group. kolmogorov-smirnov test (cut off at p < 0.01) was performed. continuous variables were described using mean ± standard deviation. categorical variables were described using frequency distributions (frequency %). psa values prior to and following antibiotic therapy were compared using the student’s-t-test for independent samples and a multivariate logistic regression analysis was performed. all tests were two-sided and considered significant at p < 0.05. all the patients underwent to a 12-core prostate biopsy according to our standard biopsy procedure (presti procedure) (9). results average age of the whole group of patients (first and second cohort) was 66.48 ± 8.32 years and average initial psa level was 6.67 ± 1.57 ng/ml with no significant difference between first and second cohort. in the treated cohort (n = 49) 29 patients showed a decrease of psa values from mean baseline psa of 6.6 ± 1,54 ng/ml to a mean re-dosed psa of 5.4 ± 1,61 ng/ml (p = 0.7), while 20 patients did not experience a lowering of psa value, with a mean psa level of 6.9 ± 1.68 ng/ml. in the sub-group with decreasing psa levels (n = 29, 59% of first cohort) 6 patients turned out to have prostate cancer (21%), 5 chronic inflammation (17%) and 18 benign prostatic hyperplasia (bph) (62%). in the sub-group with no decrease of psa levels (n = 20, 41% of first cohort) 4 patients demonstrated to have prostate cancer (20%), 8 chronic inflammation (40%) and 8 bph (40%). in the control group (n = 51), 30 patients showed a decrease of psa values from a mean baseline psa of 6.5 ± 1,59 ng/ml to a mean redosed psa of 5.5 ± 1,57 ng/ml, while 21 patients did not experience a lowering of psa value, with a mean psa level of 6.7 ± 1.71 ng/ml. in the sub-group with decreasing psa level (n = 30, 59% of second cohort) 7 patients turned out to have prostate cancer (23%), 5 chronic inflammation (17%) and 18 bph (60%). in the sub-group with no decrease of psa levels (n = 21, 41% of second cohort) 6 patients demonstrated to have prostate cancer (29%), 3 chronic inflammation (14%) and 12 bph (57%). the difference in psa changes between the two cohort was not statistically significant (p = 0.3 ). furthermore there weren’t any statistically significant differences between the two sub-groups in each cohort for cancer detection (p > 0.5) multivariate analysis of age, psa changes, antibiotics therapy and biopsy results (presence or absence of cancer) revealed no significant difference between the two cohorts (p value > 0.05 in all categories). table 1 shows the distribution of diagnoses and performance of biopsies for each subgroup. prostate cancer detection rates were not significantly associated with the changes in psa (either decreasing or increasing). sepsis after biopsy occurred in 3 patient in the antibiotics group ( 6%) and in 1 of control group (2%). discussion in chronic prostatitis, it has been shown that total psa and free psa are all significantly higher in patients with infection. a course of fluoroquinolone therapy in patients with chronic bacterial prostatitis resulted in a median psa decrease from 8.3 to 5.3 ng/ml (10). on the other hand, habermacher et al. (11) demonstrated that most cases of asymptomatic prostatitis are not caused by bacteria, thus eliminating the rationale for antibacterial therapy. in the study of kaygisiz et al. (5), antibiotics were administered to 48 patients who underwent to prostate biopsies. the psa levels decreased below 4 ng/ml in 18 (37%) of them and the biopsies of these men were negative for malignancies. in the subgroup of other 30 men prostate cancer was found in 10.8%. the authors suggested a long course of antibiotic treatment (at least 3 weeks), regardless of inflammation findings, when psa levels are mildly high (i.e. 4-10 ng/ml), in order to decide whether or not to carry out the biopsy on the basis of the subsequent re-dosed psa results. bozeman et al. reported that when serum psa had been normalized with treatment there was no longer an indication for transrectal ultrasound-guided biopsy in almost cohort 1 cohort 2 49 pts 51 pts antibiotics no antibiotics significant decrease of psa (> 10%) + 29 20 + 30 -21 prostate cancer 6 4 7 6 chronic inflammation 5 8 5 3 bph only 18 8 18 12 + affirmative/negative bph = prostate benign hyperplasia psa = prostate specific antigen pts = patients table 1. fandella_stesura seveso 08/10/14 12:12 pagina 203 archivio italiano di urologia e andrologia 2014; 86, 3 a. fandella, s. benvenuto, e. guidoni, m. giampaoli, a. bertaccini 204 half of their 95 patients diagnosed with elevated psa and chronic inflammation, suggesting that chronic prostatitis is an important cause of elevated psa and that, when identified, treatment can decrease the percent of negative biopsies (12). a recent editorial by scardino criticized the unjustified use of antibiotics in a group of patients similar to ours. he emphasized the various inherent disadvantages associated with this approach, such as costs, toxicity, and the promotion of resistant bacterial species development that would have exposed the biopsied patient to more resistant and aggressive sepsis (8). significant fluctuations in psa should raise the suspicion of inflammation or infection as an aetiology, however in these patients it remains controversial; empiric antibiotics therapy prior to a prostate biopsy in order to “normalize” the psa value remains a non evidence-based practice. those who underwent a course of fluoroquinolone antibiotics treatment should not have a prostate biopsy within one month from completing the therapy to allow the colonic flora to re-establish itself to a normal state. akduman et al. demonstrated that patients who received 3 weeks of fluoroquinolones before biopsy had a significantly greater incidence of post-biopsy sepsis (5.4% vs 1.7%) and all sepsis episodes were attributable to quinolone resistant bacteria (13). other studies have similarly shown that previous therapy with quinolones predisposes to rectal flora resistance (14). the results of this study seems to show no advantages due to an empiric antibiotic therapy (full dose floroquinolone for 20 days, in this specific case) to reduce psa values and avoid unnecessary biopsy in patients with psa levels between 4-10 ng/ml and no signs or symptoms of infections. a psa decrease after antibiotic therapy does not rule out prostate cancer and at the same time a lack of decrease does not exclude it. thus antibiotics therapy does not seem to eliminate unnecessary prostate biopsy. our trial does have some limitations: patients number and retrospective design. we had few cases with histological evidence for chronic prostatitis in our study. this might explain why administration of antibacterial therapy was not helpful in our series. we also studied only a single class of antibiotic for 20 days, which we believed to be the most commonly used in current clinical practice. it is possible that a different class or length of therapy might alter the above findings. it is possible that a larger prospective trial might identify a clinical benefit for empiric antibiotic treatments. conclusions it is of crucial importance to use properly and responsibly antibiotics. in patients with an increased psa, antibiotics are appropriate if there is any clinical suspicion or evidence of urinary infection. any rise of psa should be an indication to repeat psa testing. at the same time we advocate the use of antibiotic therapies only if a bacterial cause has been identified. empiric use doesn’t seem to be of clinical benefit in absence of a clinical or laboratory evidence of infection and it might paradoxically be harmful. repeating a new psa test before scheduling a biopsy remains the only acceptable approach. references 1. ornstein dk, smith ds, rao gs, et al. biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers. j urol. 1997; 157:2179-82. 2. lorente ja, arango o, bielsa o, et al. effect of antibiotic treatment on serum psa and percent free psa levels in patients with biochemical criteria for prostate biopsy and previous lower urinary tract infections. int j biol markers. 2002; 17:84-9. 3. ozen h, aygün c, ergen a, et al. combined use of prostate-specific antigen derivatives decreases the number of unnecessary biopsies to detect prostate cancer. am j clin oncol. 2001; 24:610-3. 4. kaygisiz o, ugurlu o, kosan m, et al. effects of antibacterial therapy on psa change in the presence and absence of prostatic inflammation in patients with psa levels between 4 and 10 ng/ml. prostate cancer prostatic dis. 2006; 9:235-8. 5. baltaci s, suer e, haliloglu ah, et al. effectiveness of antibiotics given to asymptomatic men for an increased prostate specific antigen. j urol. 2009; 181:128. 6. serretta v, catanese a, daricello g, et al. psa reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients. prostate cancer prostatic dis. 2008; 11:1485. 7. erol h, beder n, caliskan t, et al. can the effect of antibiotherapy and anti-inflammatory therapy on serum psa levels discriminate between benign and malign prostatic pathologies? urol int. 2006; 76:20-6. 8. scardino pt. the responsible use of antibiotics for an elevated psa level. nat clin pract urol. 2007; 4:1. 9. presti jc jr; prostate biopsy strategies. nat clin pract urol. 2007; 4:505-11. 10. schatteman ph, hoekx l, wyndaele jj, et al. inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum psa and psa density. eur urol. 2000; 37:404-12. 11. habermacher gm, chason jt, schaeffer aj. prostatitis/chronic pelvic pain syndrome. ann rev med. 2006; 57:195-206. 12. bozeman cb, carver bs, eastham ja, venable dd. treatment of chronic prostatitis lowers serum prostate specific antigen. j urol. 2002; 167:1723-6. 13. akduman b, akduman d, tokgoz h, et al. long-term fluoroquinolone use before the prostate biopsy may increase the risk of sepsis caused by resistant microorganisms. urology 2011; 78:250. 14. owens rc jr., ambrose pg. antimicrobial safety: focus on fluoroquinolones. clin infect dis. 2005 (suppl.); 41:s144. correspondence andrea fandella, md afandella@libero.it sara benvenuto, md elisa guidoni, md casa di cura giovanni xxiii monastier, treviso, italy marco giampaoli, md giampaoli.marco85@gmail.com alessandro bertaccini, md (corresponding author) alessandro.bertaccini@gmail.com clinica urologica, alma mater studiorum, università di bologna ospedale sant’orsola-malpighi, bologna, italy fandella_stesura seveso 08/10/14 12:12 pagina 204 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4306 original paper evaluation of the diagnostic and predictive power of pca3 in the prostate cancer. a different best cut-off in each different scenario. preliminary results giuseppe albino 1, ettore capoluongo 2, sandro rocchetti 2, sara palumbo 2, cecilia zuppi 2, ettore cirillo-marucco 1 1 operative unit of urology, asl bat, andria, italy; 2 laboratory of clinical molecular biology, institute of clinical biochemistry, catholic university of sacred heart, roma, italy. introduction: aim of this study is to evaluate the diagnostic performance of pca3 in patients with indication to perform a new biopsy, according to the histological doubt such as high grade prostatic intraepithelial neoplasia (hgpin) or atypical small gland proliferation (asap) or the clinical suspicion. materials and methods: one hundred men were enrolled. we used the pca3 progensa™ procedure. after the pca3 test a repeated prostate biopsy was proposed. the histological findings were correlated to the pca3 scores. we calculated the positive predictive value (ppv), the sensibility, the specificity, the youden's index, the roc curves, the area under the curve (auc) for each cut-off value of pca3 score. results: these results are preliminary, because at present only 50 of the 100 enlisted men were subjected to rebiopsy. we calculated the best cut-off pca3 score 20 at the first diagnosis; for patients with hgpin or asap at first biopsy the best sensitivity cut-off is 45; the best cutoff is 45 when you already have a diagnosis of hgpin, and 35 for asap. if we normalize the pca3 score to the prostate volume, the best cut-off would be 20, with 100% sensitivity with a prostate volume of 65 ml. all results are statistically significant. the real problem, also present in literature, is the constant presence of not diagnosed prostate cancers, for any cut-off value. conclusions: our preliminary results suggest that, to get the best diagnostic performance, it would be wrong to maintain a single cut-off, but it should be chosen according to the scenario of the patients subgroup. it is to explore the possibility to search for the pca3 in the serum to bridge the gap of the aggressive pca missed by the urinary test. key words: prostate cancer gene 3 (pca3) score; repeated biopsies; best cut-off; high grade prostatic intraepithelial neoplasia (hgpin); atypical small gland proliferation (asap); prostate cancer. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction prostate cancer (pca) is one of the most common malignancies in the western world (1). currently, the early detection of pca is mainly based on the digital rectal examination and the increase in psa levels, which lead to prostate biopsy. due to the low positive predictive value (ppv) of psa, that is 18.8% and 20.2% based on the cutoff between 2.5 and 10 ng/ml (2), about 75% of men with psa and suspect digital rectal examination (dre) will be negative at the first prostate biopsy. even the repeated biopsy will be negative in about 80% of patients and positive in 20% (3-5). so when you decide to run a subsequent biopsy, not only the economic aspect has to be taken into account, but also anxiety, discomfort, pain and sometimes severe complications related to diagnostic maneuvers. therefore, there is the need to identify additional tests that may increase the detection rate of repeated biopsies and reduce the number of unnecessary biopsies. in this regard, the prostate cancer gene 3 (pca3) has shown promising results. because of the pca3 gene is overexpressed in 94.6% of prostate cancers (6) at least 34 times more (x34) compared to non-cancerous prostate tissue (7) and the diagnostic performance of psa is poor as test for pca, numerous studies have been performed to evaluate the pca3 score as a first line in the diagnosis of pca. the pca3 test with a score cut-off of 35 results more accurate of the psa, both with cut-off of 4 ng/ml and 3 ng/ml (auc 0.635 vs 0.550 and 0.581) (2). in addition, lowering the cut-off of the pca3 score to 20, the accuracy of the test further improves (auc 0.678) (8). the diagnostic accuracy of the ratio between total psa/free psa with 25% as cut-off is competitive (auc 0.718) to the first diagnosis (9). therefore for the first prostate biopsy there is no real advantage of pca3 on psa. in repeated biopsy, diagnostic accuracy of psa is reduced, while that of the pca3 remains constant (10). aim of this study is to evaluate the performance of pca3 in patients with indication to perform a repeated biopsy, according to the histological doubt such as high grade prostatic intraepithelial neoplasia (hgpin) or atypical small gland proliferation (asap) or the clinical suspicion. doi: 10.4081/aiua.2014.4.306 presented at 19th national congress sieun, fermo 2014 albino_stesura seveso 15/01/15 10:39 pagina 306 307archivio italiano di urologia e andrologia 2014; 86, 4 evaluation of the diagnostic and predictive power of pca3 in the prostate cancer. a different best cut-off in each different scenario. preliminary results patients according to the presence of hgpin or asap: 1) subgroup of patients who showed hgpin or pca (figure 1b), 2) subgroup of patients who showed hgpin in the biopsy performed before or after the pca3 test (figure 1c); 3) subgroup of patients with asap at biopsy performed before the pca3 test (figure 1d). all 50 patients who underwent re-biopsy after running the pca3 test were reassessed after we have "normalized" the pca3 score based on prostate volume that was measmaterials and methods in order to verify the performance of pca3 in patients with indication to perform a new biopsy, on the basis of the histological doubt (hgpin, asap) or of clinical suspicion, 100 men were enrolled between september 2011 and june 2013 (21 months) who have already undergone a prostate biopsy the results of which showed the presence of hgpin or asap, or who have already undergone at least 2 prostate biopsies with negative results for pca, but with high-risk clinical features (suspect dre, elevated psa, unfavorable psa ratio). the characteristics of patients were: 51 patients with hgpin at the 1st biopsy; 13 with asap at the 1st biopsy; 36 with clinical suspicion after > 2 negative biopsies, mean age 65.8 years (range 48-82), mean psa 7.86 ng/dl (range 0.75-33.18) (table 1). after pca3 test, a new prostate biopsy has been proposed to the patients. the histological findings of the new biopsies were correlated to the obtained pca3 score. statistical analysis we calculated the positive predictive value (ppv), the sensitivity, the specificity, the youden's index, the roc curves, the area under the curve (auc) and statistical reliability (p) for each cut-off value taken in consideration, between 20 and 100. the analysis of the roc curve by calculating the area under the curve (auc) measured the diagnostic accuracy of the test. the youden's index was used to identify the best cut-off (11). for the interpretation of the values of the area under the roc curve (auc), you can refer to the classification proposed by swets (12). sampling and laboratory procedures the procedure used is that registered with the brand progensa™. results these results are preliminary, because at present only 50 of the 100 enlisted men were subjected to re-biopsy. the data for these 50 patients are summarized in the table 1. vpp, sensitivity, specificity and youden's index for each cut-off value of the pca3 score were calculated. the roc curve of the group of examined patients was obtained (figure 1a). the same evaluations were performed for subgroups of table 1. patient characteristics. ident nr: identification number of the patient's enrollment: iniz: patient initials; bx before: number of biopsies performed before the enrollment; pre histol: histological diagnosis of previous biopsies; ratio: psa%f/t; vol (ml): prostate volume in ml; pca3: detected pca3 score; after bx outcome: outcome of the biopsy after the pca3 test; after histol: histological diagnosis of the biopsy. albino_stesura seveso 15/01/15 10:39 pagina 307 archivio italiano di urologia e andrologia 2014; 86, 4 g. albino, e. capoluongo, s. rocchetti, s. palumbo, c. zuppi, e. cirillo-marucco 308 figure 1. a. all patients. b. subgroup of patients who showed hgpin or pca. c. subgroup of patients who showed hgpin in the biopsy performed before or after the pca3 test. d. subgroup of patients with asap at biopsy performed before the pca3 test. e. pca3 score based on the volume of prostate gland to a volume of 35 ml. f. pca3 score based on the volume of prostate gland to a volume of 65 ml. ured when we collected the urine sample for pca3, by abdominal ultrasonography (us) of prostate. we started from the following considerations: a prostate of a man over 40, normally has an average volume of about 35 ml; on average, the pca3 score is considered normal with a cut-off of 35; because the pca3 score is given by the formula pca3 mrna/psa mrna x1000, it follows that, in case of pca with a nodule of small volume that partially occupies only one lobe of the prostate, for the same volume of the neoplasm, the score will be inversely proportional to the volume of the prostate, because for the same pca3 mrna (same volume of pca = same pca3 mrna), when greater is the volume of the gland, then greater is also the amount of psa mrna present in the urine after the dre. figure 1e shows data evaluation after we "normalized" the pca3 score based on the volume of the prostate gland to a volume of 35 ml. figure 1f shows data evaluation after we "normalized" the pca3 score based on the volume of the prostate gland to a volume of 65 ml. the mean age was 65.8 years and the mean prostate volume 64.7 ml, the normalization of the pca3 score was performed to an average volume of 65 ml. results are summarized in table 2. a. b. c. d. e. f. albino_stesura seveso 15/01/15 10:39 pagina 308 309archivio italiano di urologia e andrologia 2014; 86, 4 evaluation of the diagnostic and predictive power of pca3 in the prostate cancer. a different best cut-off in each different scenario. preliminary results discussion the pca3 score with cut-off of 35 is the one that offers the best balance between sensibility (58%) and specificity (72%) (13) in the diagnosis of pca at the first biopsy. it shows a positive predictive value ranging between 24% and 54% with a loss of 32% of pca by diagnosis, 4% of which with gleason score (gs) > 7 (2, 13, 14). for this reason, in order to reduce the number of missed pca at the first diagnosis, several authors have proposed the cut-off of 20 (2, 15). with the cut-off of 20, roobol et al. have verified a reduction of pca missed at diagnosis compared to the cut-off of 35 (12.7% vs 32.9%), none of which was gs > 7. in the reduce trial the pca3 has exceeded the psa for pca-specific diagnostic ability on subjects treated with dutasteride. the median pca3 score in the arm of dutasteride treated patients did not differ from the median of the control arm treated with placebo, both after 2 and after 4 years of treatment (16). therefore, dustasteride treatment does not affect pca3 results. as regards biopsies subsequent to the first it was verified that the diagnostic accuracy of the pca3 remains constant regardless of the number of biopsies after the first run on the same patient. haese et al. (10) showed that the auc of pca3 in subsequent biopsies remains constant (between 0.651 and 0.667) with a cut-off of 35. pca3 is higher in patients with hgpin only compared to those without hgpin: mean score of 47.9 (ci 36.159.8) compared to 31.8 (ci 24.0-39.7) respectively. these data agree with our experience. a "gray area" of pca3 in predicting the outcome of the biopsies after the first one. both in the group of all patients and in subgroups with hgpin is indicated a cut-off of 45 to achieve the best sensibility of the test and a balanced cut-off of 65, just to emphasize the confidence intervals indicated by haese when the hgpin is present. this is because in our experience more than 50% of patients undergoing the second (or subsequent) biopsy had a diagnosis of hgpin in the precedent biopsies. the fact that patients with hgpin show a higher mean pca3 score is found also by other authors (17). in fact, there are already present many genetic changes in the cells of pin lesions. the most frequent concern the increased expression of chromosomes 7p, 7q, 8q and inactivation of chromosomes 8p, 10q, 13q, 16q and 18q; the inactivation of suppressor genes including the pten and the overexpression of c-myc and bcl-2 oncogenes, which play an important role in the initiation and progression of pca (18). bussemakers et al. (6) were the first who identified and characterized the dd3 (pca3) gene comparing pca tissues containing areas with non-malignant prostate tissue. since the identification was performed by immunohistochemistry on tissue samples of prostate removed for pca it is possible that "non-malignant" areas also contained hgpin that, as already said, is present in 82% of prostates with pca. it is therefore likely, that the results of de kok et al., which showed that the pca3 was overexpressed x 34 times in malignant tissue and x 6 times in non-malignant tissue, are likely to correlated to the presence of hgpin in the "non-malignant" tissue of a prostate affected by cap (7). the above reasons justified the fact that the best cut-off, identified by youden's index, in a subpopulation of patients who are already at their second or subsequent biopsy, can be placed between 45 and 65, just for the presence of hgpin in more than half of the cases. a different matter concerns the subgroup of patients who underwent re-biopsy for the presence of asap. the term asap was originally used by iczkowski et al. (19) it refers to minutes tumoral foci: small lesions that disappear in other histological sections, or when cytologic categorical criteria to establish a diagnosis of carcinoma are absent. it may represent an only marginally sampled tumor or one of several benign lesions that mimic malignancy. in practice, it is a "non-diagnosis”. in our experience, the best cut-off of the pca3 test performed only on patients with isolated asap (without pin) at the first biopsy has confirmed the score of 35. probably because a missed-diagnosis to the first biopsy, restarts the diagnostic path from "time zero". the scientific literature has now largely confirmed that the pca3 score is not affected by stage and aggressiveness of the disease, but it is certainly correlated to the volume of the disease (15). because the formula for the pca3 score is pca3 mrna/psa mrna x1000, to say that the pca3 score is influenced by the volume of the tumor is a partial affirmation, because it affects only the numerator of the formula. logically, one senses that the pca3 score should be correlated in direct proportion to the volume of the tumor (pca3 mrna in the numerator) and inversely proportional to the volume of prostate without tumor (psa mrna in the denominator). for this reason it was also carried out an assessment of the diagnostic appropriateness of the test after the normalizing of the score according to the prostate volume of each patient. in a first case the result was normalized to prostate of 35 ml in average; in a second case has been carried out the normalization of population under consideration best sensibility best cut-off auc missed missed cut-off (youden’s index) pca gs > 7 all patients 45 65 0.645 p < 0.0001 4/13 2/4 subgroup hgpin + pca 45 65 0.604 p < 0.001 4/13 2/4 subgroup hgpin before or after pca3 45 65 0.616 p < 0.001 1/6 0/1 soubgroup asap 35 35 0.567 p < 0.01 2/10 1/2 pca3 score normalized to 35 ml of prostate vol 20 50 0.656 p < 0.0001 5/13 2/5 pca3 score normalized to 65 ml of prostate vol 20 100 0.584 p < 0.001 5/13 2/5 sensibility: 100% table 2. summary of results. albino_stesura seveso 15/01/15 10:39 pagina 309 archivio italiano di urologia e andrologia 2014; 86, 4 g. albino, e. capoluongo, s. rocchetti, s. palumbo, c. zuppi, e. cirillo-marucco 310 the scores computed on a prostate of 65 ml in average (given that the mean age of the subjects was 65.8 years, and the prostate at that age was of 65 ml in average). normalizing the score for volume of 35 ml the gray area moves toward the cut-off of 20, as before the first biopsy, and we also get the best result with auc 0.657. normalizing the score for prostate volume of 65 ml, with the cut-off of 20 it will reach the sensibility of 100%, whereas the best compromise between sensitivity and specificity is obtained with the cut-off of 100. the real problem of the diagnostic tests in the decision path to decide on the opportunity to perform a prostate biopsy is the number of pca that may escape diagnosis according to the used cut-off (the problem exists both for the psa that for the pca3, that for all other experimental tests). the literature reports the rate of pca escaped the diagnosis using pca3 test: of 12.7% with a cut-off of 20 and 32.9% with a cut-off of 35 at the first biopsy; while it is 14.3% with both cut-off of 20 that with cut-off of 35 in biopsies subsequent to the first one (2). the 36.4% of pca escaped the diagnosis of biopsies following the first one consists of pca with gs > 7. even in our series there are potentially missed pca: between 17% and 38%. we verified the best results in the subgroup composed exclusively of hgpin in which there is a risk of 17% to not diagnose a pca, but none of pca escaped at diagnosis would have had a gs > 7. the reason why it is possible that more aggressive tumors may escape the diagnosis of pca3 test resides entirely in the sampling procedure of the diagnostic test. the collected sample has a chance to contain only the cancer cells that are shed in the urine during the dre. for this to happen it is necessary that the glands, even when they are affected by cancer, continue to be open to the side of the urethra. it is possible, therefore, that the glands with malignancy are no longer open towards the urethra and that the tumor cells, while still producing pca3 mrna, are no longer discharged into the urinary stream making the test falsely negative. conclusions the pca3 test is a useful diagnostic tool able to guide the decision-making in the early diagnosis of prostate cancer. to get the best diagnostic performance should be considered different cut-off based on biopsy session, prostate volume, histology of initial biopsy. our results, although preliminary because taken from the 50% of enrolled men, support that different pca3 cut-off should be used: 20 at the first diagnosis, 35 in isolated asap, 45 in isolated hgpin. a special focus deserves the opportunity to normalize the score to prostate volume. references 1. siegel r, de santis c, virgo k, et al. cancer treatment and survivorship statistics, 2012. ca cancer j clin. 2012; 62:220-41. 2. roobol mj, schröder fh, van leeuwen p, et al. performance of the prostate cancer antigen 3 (pca3) gene and prostate-specific antigen in prescreened men: exploring the value of pca3 for a first-line diagnostic test. eur urol. 2010; 58:475-81. 3. seitz c, palermo s, djavan b. prostate biopsy. minerva urol nefrol. 2003; 55:205-18. 4. raja j, ramachandran n, munneke g, patel u. current status of transrectal ultrasound-guided prostate biopsy in the diagnosis of prostate cancer. clin radiol 2006; 61:142-153. 5. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent update 2013. eur urol. 2014; 65:124-37. 6. bussemakers mj, van bokhoven a, verhaegh gw, et al. dd3: a new prostate-specific gene, highly overexpressed in prostate cancer. cancer res. 1999; 59:5975-9. 7. de kok jb, verhaegh gw, roelofs rw, et al. dd3 (pca3), a very sensitive and specific marker to detect prostate tumors. cancer res. 2002; 62:2695-8. 8. pepe p, fraggetta f, galia a, et al. pca3 score and prostate cancer diagnosis at repeated saturation biopsy. which cut-off: 20 or 35? int braz j urol. 2012; 38:489-95 9. morote j, trilla e, esquena s, et al. the percentage of free prostatic-specific antigen is also useful in men with normal digital rectal examination and serum prostatic-specific antigen between 10.1 and 20 ng/ml. eur urol. 2002; 42:333-7. 10. haese a, de la taille a, van poppel h, et al. clinical utility of the pca3 urine assay in european men scheduled for repeat biopsy. eur urol. 2008; 54:1081-8. 11. d'arrigo g, provenzano f, torino c, et al. diagnostic tests and roc curves analysis. g ital nefrol. 2011; 28:642-7. 12. swets ja. measuring the accuracy of diagnostic systems. science. 1988; 240:1285-93. 13. auprich m, bjartell a, chun fk, et al. contemporary role of prostate cancer antigen 3 in the management of prostate cancer. eur urol. 2011; 60:1045-54. 14. marks ls, fradet y, deras il, et al. pca3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. urology. 2007; 69:532-5. 15. capoluongo e, zambon cf, basso d, et al. pca3 score of 20 could improve prostate cancer detection: results obtained on 734 italian individuals. clin chim acta. 2014; 429:46-50 16. aubin sm, reid j, sarno mj, et al. prostate cancer gene 3 score predicts prostate biopsy outcome in men receiving dutasteride for prevention of prostate cancer: results from the reduce trial. urology. 2011; 78:380-5. 17. galasso f, giannella r, bruni p, et al. pca3: a new tool to diagnose prostate cancer (pca) and a guidance in biopsy decisions. preliminary report of the urop study. arch ital urol androl. 2010; 82:5-9. 18. joniau s, goeman l, pennings j, et al. prostatic intraepithelial neoplasia (pin): importance and clinical management. eur urol. 2005; 48:379-85. 19. iczkowski ka, maclennan gt, bostwick dg. atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies: clinical significance in 33 cases. am j surg pathol. 1997; 21:1489-95. correspondence giuseppe albino, md, phd peppealbino@hotmail.com ettore cirillo-marucco, md operative unit of urology asl bat, andria, italy ettore capoluongo, md sandro rocchetti, md sara palumbo, md cecilia zuppi, md laboratory of clinical molecular biology, institute of clinical biochemistry, catholic university of sacred heart, roma, italy albino_stesura seveso 15/01/15 10:39 pagina 310 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 148 case report surgical repair of the iatrogenic falsepassage in the treatment of trauma-induced posterior urethral injuries faruk doğan 1, ali feyzullah şahin 1, tevfik sarıkaya 2, alper dırık 1 1 department of urology, şifa university medicine school, i̇zmir, turkey 2 department of urology, sivas public hospital, sivas, turkey pelvic fracture associated urethral injury (pfaui) is a rare and challenging sequel of blunt pelvic trauma. treatment of iatrogenic false urethral passage (fup) remains as a challenge for urologists. in this case report we reviewed the iatrogenic fup caused by wrong procedures performed in the treatment of a patient with pfaui and the treatment of posterior urethral stricture with transperineal bulbo-prostatic anatomic urethroplasty in the management of fup. a 37-year-old male patient with pfaui had undergone a laparotomy procedure for pelvic bone fracture, complete urethral rupture, and bladder perforation 8 years ago. after stricture formation, patient had undergone procedures that caused fup. following operations, he had a low urinary flow rate, and incontinence and urgency even with small amounts of urine. fup was diagnosed by voiding cystourethrography and retrograde urethrography. fup was fixed with open urethroplasty with the guidance of flexible antegrade urethtoscopy. false passage should always be taken into account in the differential diagnosis of patients with persistent symptoms that underwent pfaui therapy. in addition, we believe that in the evaluation of patients with pfaui suspected for having a false passage, bladder neck and urethra should be assessed by combining routine voiding cystourethrography and retrograde urethrography with preoperative flexible cystoscopy via suprapubic route. key words: false urethral passage; flexible cystoscoby; pelvic fracture; urethral injury. submitted 30 july 2013; accepted 31 december 2013 summary trauma may cause a life-long morbidity unless properly treated. while treatment approach in partial urethral rupture includes watchful waiting after performing a simple cystostomy, complete urethral rupture can be repaired with 3 methods: 1) realignment of the separated urethral ends over a catheter (urethral realignment), 2) primary anastomosis of separated urethral ends, and 3) immediate suprapubic cystostomy and delayed repair of the resulting stricture on an elective basis (3). emergency treatment of pfaui has not been standardized in developing countries. on majority of cases wrong procedures cause iatrogenic injuries in addition to trauma itself (4). sometimes, careless and/or repeated urethral dilatations also lead to false urethral passage (fup) formation, which results in infections and incontinence. treatment of iatrogenic fup remains as a challenge for urologists (5). furthermore, there is a paucity of data about the urethroplasty procedure performed for urethral stricture formed by fup. in this case report we reviewed the iatrogenic fup caused by wrong procedures performed in the treatment of a patient with pfaui and the treatment of posterior urethral stricture with transperinealbulbo-prostatic anatomic urethroplasty in the management of fup. case report and figures are posted in suppementary materials on www.aiua.it. discussion false passage is an abnormal passage between urinary bladder and urethra, which is observed in association with posterior urethral stricture and is caused by a iatrogenic injury resulting from careless and wrong treatment procedures after trauma. if unnoticed, this false passage between urethra and bladder causes very frequent complaints; furthermore, repeated endoscopic procedures (internal urethrotomy), catheterization, or urethral dilatation become necessary. following dilatation, hesitancy, incontinence, and urgency persist. furthermore, false passage scar tissue around traumatized tissue causes prolonged and chronic infections and hence leads to stricture formation (6). no conflict of interest declared introduction pelvic fracture associated urethral injury (pfaui) is a rare and challenging sequel of blunt pelvic trauma. in 425% of male patients with pelvic bone fractures, simultaneous posterior urethral injury is observed (1). injury to posterior urethra may be a simple contusion, or it may appear as partial or complete rupture (2). urethral doi: 10.4081/aiua.2014.1.48 sahin cr_stesura seveso 26/03/14 10:47 pagina 48 49archivio italiano di urologia e andrologia 2014; 86, 1 surgical repair of the iatrogenic falsepassage in the treatment of trauma-induced posterior urethral injuries methods used for diagnosis of posterior urethral strictures before reconstruction should clearly delineate stricture length and site, determine the anatomy of posterior urethra and bladder neck, and show false passages and fistulas if any. conventional methods include simultaneous ccug and dynamic retrograde urethrography. it is necessary to make a pre-treatment assessment via combined radiological and endoscopic methods especially in obliterated cases where prostatic and proximal urethra cannot be visualized. false passage is diagnosed with urethrography. combined voiding cystourethrography and retrograde urethrography can clearly show the site and path of the passage (7). cystourethroscopy plays a limited role in diagnosis since normal anatomical structures cannot be localized. this was also the case in our patient because his false passage could not be identified despite multiple endoscopic procedures at other medical facilities. a false passage should be taken into consideration for diagnosis in case normal anatomical markers like veru montanum, bladder trigone, and external sphincter could not be seen during cystourethroscopy. a flexible cystoscope advanced through a suprapubic route is highly useful for the diagnosis of false passage. while normal bladder neck is a funnel-shaped, soft, elastic, and of smooth structure, a false passage is a pale mucosal formation associated with a vertical circular dense scar and a coarse granulation that is located close to bladder neck (6). in conclusion, recurrent urethral strictures develop due to inappropriate and insufficient initial therapies in patients with pfaui with complete urethral separation; as a result, various endoscopic procedures and urethral dilatations become necessary. even after these therapies, hesitancy, incontinence, and urgency are observed. false passage should always be taken into account in the differential diagnosis of patients with persistent symptoms that underwent pfaui therapy. in addition, we believe that in the evaluation of patients with pfaui suspected for having a false passage, bladder neck and urethra should be assessed by combining routine voiding cystourethrography and retrograde urethrography with preoperative flexible cystoscopy via suprapubic route. the guidance of a flexible cystoscope via suprapubic route during the operation is quite helpful. it also guides procedures of curettage and dissection to determine the true anatomical structures and to identify the normal urethral tract, particularly in cases where prostatic urethra is blocked. references 1. koraitim mm, marzouk me, atta ma, et al. risk of urethral injury in pelvic fractures. br j urol. 1996; 77: 876-80. 2. lupu an, forrer jh, smith rb, kaufman j. urethral gap in complete disruption of membraneus urethra. urology. 1987; 29:378-82. 3. webstre gd, mathes gl, selli c. prostatomembranous urethral injuries: a review of the literature and a rational approach to their management. i. urol. 1983; 130:898. 4. barbagli g. history and evolution of transpubic urethroplasty: a lesson for young urologists in training. eur urol. 2007; 52:1290-2. 5. barbagli g, palminteri e, lazzeri m, guazzoni g. one-stage circumferential buccal mucosa graft urethroplasty for bulbous stricture repair. urology. 2003; 61:452-5. 6. qiang fu, jiong zhang, ying-long sa, san-bao jin, yue-minxu. transperineal bulbo-prostatic anastomosis for posterior urethral stricture associated with false passage: a single-centre experience. bju int. 2011; 108:1352-4. 7. secrest cl. staged urethroplasty: indications and techniques. urol clin north am. 2002; 29:467-75. correspondence faruk doğan, md (corresponding author) farukdogan58@gmail.com alper dırık, md a_dirik@yahoo.com specialist in urology department of urology, şifa university medicine school, izmir, turkey ali feyzullah şahin, md, febu ali.sahin@sifa.edu.tr asistant professor in urology department of urology, şifa university medicine school sanayi cad. no:7 bornova, izmir, turkey tevfik sarıkaya, md drts98@mynet.com specialist in urology department of urology, sivas public hospital, sivas, turkey figure. preoperative vcug and rug shows the location of a false passage and urethral stricture. the black arrow shows normal bladder neck and prostatic urethra, the blue arrow shows the urethral stricture and the beginning of the intraprostatic false passage, while the white arrow shows the false passage located close to bladder neck. sahin cr_stesura seveso 26/03/14 10:47 pagina 49 177archivio italiano di urologia e andrologia 2016; 88, 3 original paper serenoa repens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients tommaso cai 1, daniele tiscione 1, luca gallelli 2, paolo verze 3, alessandro palmieri 3, vincenzo mirone 3, riccardo bartoletti 4, gianni malossini 1 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of health science, school of medicine, university of catanzaro, catanzaro, italy; 3 department of urology, university of naples, federico ii, naples, italy; 4 department of urology, university of pisa, pisa, italy. objective: to date, the management of patients with chronic bacterial prostatitis (cbp) is not satisfactory, especially in terms of symptoms relief. here, we evaluated the efficacy and the safety of a combination of serenoa repens, selenium and lycopene extract + bromelain and methylsulfonylmethane extract associated with levofloxacin in patients with cbp. materials and methods: all patients with clinical and instrumental diagnosis of cbp, admitted to a single urological institution from march to june 2015 were enrolled in this phase iii study. all enrolled patients were randomized into two groups: group a received levofloxacin 500 mg o.d. for 14 days associated with lycopene and methylsulfonylmethane; group b received levofloxacin (500 mg o.d. for 14 days) only. clinical and microbiological analyses were carried out at the time of admission (t0) and during the followups at 1 month (t1) and 6 months (t2) from the end of the treatment. nih chronic prostatitis symptom index (cpsi), international prostatic symptom score (ipss) and quality of well-being (qol) questionnaires were used. the main outcome measures were the rate of microbiological cure and the improvement in questionnaire results from baseline at the end of the follow-ups period. results: forty patients were enrolled in group a and 39 in group b. during the follow-up (t1), we recorded a significant changes in terms of nih-cpsi and ipss in group a (mean difference: 17.6 ± 2.65; 12.2 ± 2.33; p < 0.01; p < 0.05, respectively) and versus group b at the intergroup analysis (mean difference: -9 ± 1.82; -8.33 ± 1.71; p < 0.05; p < 0.05, respectively). no differences were reported in terms of microbiological findings between the two groups. at the second follow-up visit (t2), questionnaire results demonstrated statistically significant differences between groups (p < 0.001). one patient in group a (2.5%) and 7 patients (17.9%) in group b showed a symptomatic and microbiological recurrence (p = 0.02). conclusions: the combination of serenoa repens, selenium, lycopene + bromelain and methylsulfonylmethane extracts improved the clinical efficacy of levofloxacin in patients affected by cbp without the development of side effects. key words: chronic bacterial prostatitis; levofloxacin; serenoa repens; bromelain. submitted 15 january 2016; accepted 6 march 2016 summary no conflict of interest declared. introduction even if the prevalence of chronic bacterial prostatitis (cbp), category ii according to the national institutes of health (nih) classification of chronic prostatitis-chronic pelvic pain syndrome, ranges in europe between 7 and 14% of all cases with prostatitis (1-2), the impact on patient’s quality of life is high (3-4). although a long-term antibiotic treatment with fluorquinolones represents the gold standard therapy for cbp (5), short-term recurrences and drug-related adverse events are frequently reported (6-7). in this sense, the use of phytotherapy to both alleviate symptoms related to cbp and decrease the rate of symptomatic recurrence is nowadays increasing. it seems related toseveral reasons, e.g. low side-effect and costs (8), high level of adherence (9) and a low rate of efficacy of standard treatments with subsequent patient disappointment and drop-out (10). several phytotherapeutic compounds have recently been investigated to treat or prevent bacterial prostatitis, such as serenoa repens, urtica dioica, or other compounds such as curcumin (11-13). here, we focused our attention on serenoa repens, selenium, lycopene, bromelain and methylsulfonylmethane extracts. the role of serenoa repens, selenium and lycopene is well discussed in the current literature, with convinced results about their efficacy in the treatment of patients with prostatitis (11, 14-15). recently, marzano et al. showed the efficacy of a compound with bromelain in improving urinary symptoms related to benign prostatic hyperplasia (16). the efficacy of bromelain on prostatic symptoms is probably due to its anti-inflammatory effect by increasing the production of anti-inflammatory prostaglandins such as tnf-alfa or interleukin (il)-6 (17). methylsulfonylmethane, also known as dimethylsulfone and methylsulfone, shows several positive effects on a variety conditions, such as osteoarthritis and allergic rhinitis (18). it is well known that il-6 production is rapidly increased in acute inflammatory responses associated with infection, trauma, and other stresses (17). however, high-levels of il-6 could induce an inflammatory state. karlsen et al. demonstrated that methylsulfonylmethane inhibits il-6 doi: 10.4081/aiua.2016.3.177 cai_stesura seveso 21/09/16 08:42 pagina 177 archivio italiano di urologia e andrologia 2016; 88, 3 t. cai, d. tiscione, l. gallelli, p. verze, a. palmieri, v. mirone, r. bartoletti, g. malossini 178 production in macrophage cells, and reduces plasma levels of il-6 in animal model (17). on the basis of these evidences, the use of an association between antibiotic and anti-inflammatory compounds could represents a good option for the treatment of cbp patients. therefore, in the present study we evaluated the efficacy and the safety of a combination of serenoa repens, selenium, lycopene (prostadep plus®) and bromelain, methylsulfonylmethane (zachelase®) associated with levofloxacin, to improve quality of life in patients with cbp. patients and methods study design we performed a randomized, prospective, open-label, and parallel groups study in a single urological institution between march and june 2015. the study was conducted according to the ethical principles of the declaration of helsinki and the protocol was approved by an independent ethics committee. before the beginning of the study, all participants signed the written informed consent. no placebo run-in period was considered necessary for the treatment of patients with urinary culture positivity. experimental protocol all consecutive patients presented us for symptoms related to cbp and post-prostate massage urine culture positive for uropathogens were enrolled in this study. at the time of admission (t0), the patients underwent selfadministered baseline questionnaire [nih-chronic prostatitis symptom index (nih-cpsi) and international prostatic symptom score (ipss)], urological examination with history interview and meares-stamey test performed by the same urologist (tc) in agreement with the european association of urology (eau) guidelines (5). all patients underwent two follow-ups at 1 month (t1) and 6 months (t2) from the end of therapy. during each followup all patients underwent nih-cpsi, ipss questionnaires and urological examination. the meares-stamey test was carried-out only in patients with symptomatic recurrence. in agreement with our previous papers, the patients that were positive to meares-stamey test for uropathogens were treated with other antibiotics depending on the organism and its susceptibility profile (3, 11). inclusion and exclusion criteria the primary inclusion criteria were age between 18 and 45 years and the following conditions: the presence of symptoms related to cbp for at least 3 months (5) and a positive meares-stamey 4-glass test with first voided urine, midstream urine, prostatic secretion and a vb3 urine culture, which had to be ≥ 103 colony forming units (cfu)/ml of uropathogens (5, 20). patients with demonstrated or suspected allergy to fluoroquinolones or other compounds contained in the treatments were excluded. moreover, patients treated in the last 4 weekswith antibiotics were also excluded. patients with positive tests for atypical or sexually transmitted diseases, such as chlamydia trachomatis, ureaplasma urealiticum, or neisseria gonorrhoeae were excluded. in order to obtain an homogenous group to analyze the following bacteria were considered as uro pathogens, in accordance with trinchieri: enteric gramnegative rods; enterococci, staphylococcus saprophyticus; and group b streptococci (20). questionnaires and urological examinations the validated italian versions of the nih chronic prostatitis symptom index (nih-cpsi) (21) and the international prostatic symptom score (ipss) (22) were administered to each patient. the questionnaire was selfadministered when the patient arrived at the centre. figure 1. the figure shows the study schedule. ipss: international prostatic symptom score; nih-cpsi: nih chronic prostatitis symptom index; qol: quality of well-being. v1: visit 1, at the enrolment; v2: visit 2 at the first follow-up; v3: visit 3 at the second follow-up. cai_stesura seveso 21/09/16 08:42 pagina 178 moreover, patient quality of life was measured by using an italian version of the quality of well-being, a validated, multiattribute health scale (23). this scale was selected because it has been successfully applied to acute illnesses, whereas other quality of life scales, including the short form-36 (sf-36) health survey, are more suitable in chronic cases. higher scores on the qol scale reflect a higher quality of life (24). in accordance with the study by nickel et al., prostatitis-like symptoms were considered significant at a pain score of ≥ 4. the nih-cpsi was also used in determining clinical therapy efficacy (25). microbiological considerations in line with our previous study, the biological samples collected during the urological examination and during the meares-stamey test were immediately taken to the laboratory, under refrigerated conditions, and analyzed for cultures (11). microbiological culture was carried out in accordance with the methods described by motrich (26) and mazzoli (27). assignment to the groups patients with cbp and without regard for age, or medical history were randomly allocated to receive either one tablet of levofloxacin (500 mg o.d. orally) for 14 days in association with a tablet of prostadep plus® in the morning and a sachet of zachelase® in the evening (group a); or one tablet of levofloxacin (500 mg o.d. orally) for 14 days alone (group b). the randomization was performed in agreement with our previous studies (28-30). briefly we used a computer program to generate a sequence of treatment allocations by block randomization using a random number generator. investigators were blinded to the block size to avoid selection bias. the study design is displayed in figure 1. we used a treatment course of 14 days to reduce the development of adverse effects related to a long course of treatment (19). the adverse events were evaluated in agreement with the common terminology criteria for adverse events (ctcae) guidelines. safety assessments included treatment-emergent adverse events (teaes) and serious aes (saes). composition and characterization of the extracts used prostadep plus® each tablet contains sabamax® [serenoa repens 600 (537 mg), selenium l-methionine 55 mcg and lycopene (solanum lycopersicum l.) 4 mg]. zachelase® each sachet contains bromelain (500 mg; 1.250 units), methylsulfonylmethane 900 mg and ascorbid acid 500 mg. end points the first end-point was the rate of microbiological cure and the improvement in questionnaire results recorded during the follow-up (t2-t0; t1-t0). we considered that a treatment have a clinical efficacy when a patient is asymptomatic for at least 2 weeks after the end of the treatment. clinical failure was defined as the persistence of clinical symptoms after treatment or the suspension of therapy for significant reported adverse effects. in addition, spontaneously reported adverse events or those noted by the investigator were recorded during the whole study period. 179archivio italiano di urologia e andrologia 2016; 88, 3 quinolones, serenoa repens, bromelain, and methylsulfonylmethane in prostatitis figure 2. the figure shows the study flow-chart in line with the consort guidelines. cai_stesura seveso 21/09/16 08:42 pagina 179 archivio italiano di urologia e andrologia 2016; 88, 3 t. cai, d. tiscione, l. gallelli, p. verze, a. palmieri, v. mirone, r. bartoletti, g. malossini 180 discussion even if cbp has an important impact on patient’s quality of life, a highly satisfactory treatment in terms of efficacy and safety still needs. cbp continues to pose a treatment challenge for all urologists and for these reasons, a lot of non-standardized treatment schedule, sometimes in offtable 1. clinical, instrumental and laboratory patient’s data at the enrolment time. group a group b mean (sd* or %) mean (sd* or %) patients (n°) 39 40 age 34.1 ± 4.58 35.0 ± 5.67 marital status married 15 (38.4) 16 (40.0) unmarried 24 (61.6) 24 (60.0) educational qualification primary school high school 29 (74.3) 28 (70.0) university 10 (25.7) 12 (30.0) smooking yes 27 (69.2) 30 (75.0) no 12 (30.8) 10 (25.0) sexually active (past month) 39 (100) 40 (100) sexual behaviour 1 partner 38 (97.5) 38 (95.0) > 1 partners 1 (2.5) 2 (5.0) contraceptive use condom 29 (74.3) 32 (80.0) coitus interruptus 10 (25.7) 8 (20.0) start of cp# history (months) 21.3 ± 6.21 20.8 ± 7.01 symptoms score at baseline (mean) (range) nih-cpsi§ 19.94 ± 2.1 19.75 ± 3.9 ipss† 17.35 ± 3.4 18.65 ± 3.1 qol‡ 0.55 ± 0.15 0.56 ± 0.18 clinical presentation dysuria 21 (53.9) 21 (52.5) urgency 2 (5.1) 3 (7.5) dysuria + frequency 4 (10.2) 5 (12.5) burning 12 (30.8) 11 (27.5) microbiological results e. coli 22 (56.4) 24 (60.0) enterococcus facealis 11 (28.2) 4 (20.0) other uropathogens 6 (15.4) 8 (20.0) the table shows all anamnestic, clinical and questionnaires data at enrolment. sd*: standard deviation; cp#: chronic prostatitis; nih-cpsi§: nih chronic prostatitis symptom index; ipss†: international prostatic symptom score; qol‡: quality of well-being. table 2. questionnaire results at the first follow-up visit. group a group b difference from baseline difference from baseline (sd* or %) (sd* or %) efficacy outcomes nih-cpsi° 17.6 ± 2.65 8.4 ± 3.1 treatment difference -9 ± 1.82 ipss# 12.2 ± 2.33 5.2 ± 2.52 treatment difference -8.33 ± 1.71 qol§ 0.31 ± 0.10 0.14 ± 0.15 treatment difference 0.17 ± 0.03 the table shows the mean change differences from baseline to 6 months relative to main outcome measures. nih-cpsi§: nih chronic prostatitis symptom index; ipss†: international prostatic symptom score; qol‡: quality of well-being. statistical analysis the required sample size for the present study was calculated under the following conditions: difference between the groups, 2 ± 1 score points in the nih-cpsi pain domain; α error level, 0.05 two-sided; statistical power, 80%; and anticipated effect size, cohen’s d = 0.5. the calculation yielded 2 × 39 individuals per group. at baseline, the independent sample 2-tailed t-test was used to compare variables. for categorical parameters, chi-square test was applied. changes from baseline to end of therapy were analyzed using ranked one-way analysis of variance (anova) with a term for treatment group. all data are expressed as mean ± standard deviation (sd). the threshold of statistical significance was set at p < 0.05. all reported p-values are two-sided. all statistical analyses were performed by using spss 21.0 (ibm corporation, armonk, ny, usa), while g*power (institut für experimentelle psychologie, heinrich heine universität, dusseldorf, germany) was used for power calculation. results patients during the study period, 83 patients were enrolled and randomized in two groups: 40 in the group a and 43 in the group b. one patient in group a and 3 in group b were lost during the follow-up. finally, 39 patients in group a and 40 patients in group b completed the study protocol (mean age 34.8 ± 5.11 years). the flow chart of this study is presented in figure 2. baseline characteristics history, clinical and questionnaires data at the time of admission are reported in table 1. we did not record any difference in terms of symptoms or bacterial strains prevalence between the two groups. follow-up examination during the first follow-up (t1), we recorded a significant difference in terms of nih-cpsi and ipss in the group a (mean difference: 17.6 ± 2.65; 12.2 ± 2.33; p < 0.01; p < 0.05, respectively) and versus group b at the intergroup analysis (mean difference: -9 ± 1.82; -8.33 ± 1.71; p < 0.05; p < 0.05, respectively) (table 2). no differences were reported in terms of microbiological cure between the two groups. during the second follow-up (t2), questionnaire results demonstrated statistically significant differences between groups (all p < 0.001). one patient in group a (2.5%) and 7 in group b (17.9%) showed a microbiologically demonstrated symptomatic recurrence (p = 0.02). significant differences were found at the intergroup analysis when we consider the outcome measures and the qol (figure 3). adverse events all subjects correctly took the treatments showing a 100% of adherence to the treatment a 100% of compliance to the experimental protocol. two patients, 1 (2.5%) in group a and 1 in group b (2.6%) developed mild adverse effects (nausea) that did not require drug discontinuation or other treatments. cai_stesura seveso 21/09/16 08:42 pagina 180 label way, were offered to the patients. here, we demonstrated that the use of combination of serenoa repens, selenium, lycopene (prostadep plus®) and bromelain, methylsulfonylmethane (zachelase®) extracts is able to improve the clinical efficacy of levofloxacin in patients affected by cbp, by improving their level of quality of life. moreover, we demonstrated a high level of treatment compliancethat may be related with the low frequency of adverse events and with the improvement of qol. the improvement in qol should be due to the anti-inflammatory effect of bromealin and methylsulfonylmethane extracts (16-17). several authors have demonstrated the anti-inflammtory effects of these compounds, especially in patients with severe symptoms. it is probably due to the effect of methylsulfonylmethane in il-6 reduction, as demonstrated in other pathological conditions (17-18). the effect of serenoa repens of prostate tissue can contribute to improve the patient’s qol and relief the pain. several authors demonstrated that serenoa repens shows a potent anti-inflammatory properties in the whole prostate tissue (31) and is able to inhibit mcp-1/ccl2 and vcam-1 expression by human prostate and vascular cells in an inflammatory environment, modulating the inflammatory response (32). however, our results are probably due to synergic efficacy of all compounds, in fact it has been well documented that quinolones have antibiotic as well as immunemodulatory effects and are able to decrease the production of pro-inflammatory cytokines (15). in this concern it is not easy to evaluate the efficacy of each single compound on the qol improvement in cbp patients. finally, we believe that the phytotherapy could be an interesting multimodal approach to cbp patients due to the fact that several extracts are able to inhibit many inflammatory pathways in volved in the complex pathogenesis of the disease. however, even if our results are encouraging, this study shows some limitations, particularly the shot time of observation. in fact, it is very important to highlight that the safety of phytotherapy should be evaluated with a long-term follow-up, in order to discover delayed adverse side effects. the use of a short-term anti biotic treatment period (14 days) should not be considered a limitation of the study because we had choice this time in agreement with the paper of bjerklund johansen et al., that documented the minimum duration of antibiotic treatment should be 2-4 weeks (33). conclusion in our study, we demonstrated that combination of serenoa repens, selenium, lycopene (prostadep plus®) and bromelain, methylsulfonylmethane (zachelase®) extracts is able to improve the clinical efficacy of levofloxacin in patients affected by chronic bacterial prostatitis, without the development of adverse drug reactions. acknowledgements we are grateful to professor john denton (department of modern philology, university of florence) for manuscript language revision. contributions tc, dt, data collecting and analyzing; tc, lg, pv manuscript writing; gm, rb, ap, vm supervision. references 1. bartoletti r, cai t, mondaini n, et al. prevalence, incidence estimation, risk factors and characterization of chronic prostatitis/chronic pelvic pain syndrome in urological hospital outpatients in italy: results of a multi center case-control observational study. j urol. 2007; 178:2411-2415. 2. cai t, mazzoli s, meacci f, et al. epidemiological features and resistance pattern in uropathogens isolated from chronic bacterial prostatitis. j microbiol. 2011; 49:448-54. 3. bartoletti r, cai t, nesi g, et al. the impact of biofilm-producing bacteria on chronic bacterial prostatitis treatment: results from a longitudinal cohort study. world j urol. 2014; 32:737-42. 4. magri v, perletti g, bartoletti r, et al. critical issues in chronic prostatitis. arch ital urol androl. 2010; 82:75-82. 181archivio italiano di urologia e andrologia 2016; 88, 3 quinolones, serenoa repens, bromelain, and methylsulfonylmethane in prostatitis figure 3. the figure shows the differences in terms of questionnaires results (§ nih-cpsi; * ipss) between the two groups. v2: visit at the second follow-up (6 months). cai_stesura seveso 21/09/16 08:42 pagina 181 archivio italiano di urologia e andrologia 2016; 88, 3 t. cai, d. tiscione, l. gallelli, p. verze, a. palmieri, v. mirone, r. bartoletti, g. malossini 182 5. european association of urology guidelines on urological infections. 2014. http://uroweb.org/wp-content/uploads/19-urologicalinfections_lr2.pdf 6. lee ys, han ch, kang sh, et al. synergistic effect between catechin and ciprofloxacin on chronic bacterial prostatitis rat model. int j urol. 2005; 12:383-9. 7. naber kg. antimicrobial treatment of bacterial prostatitis. eur urol. 2003; 43:23-26. 8. wilt t, mac donald r, ishani a, et al. cernilton for benign prostatic hyperplasia. cochrane database syst rev 2000. cd001042. 9. cai t, wagenlehner fm, luciani lg, et al. pollen extract in association with vitamins provides early pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome. exp ther med 2014; 8:1032-1038. 10. shoskes da. phytotherapy in chronic prostatitis. urology. 2002; 60:35-7. 11. cai t, mazzoli s, bechi a, et al. serenoa repens associated with urtica dioica (prostamev) and curcumin and quercitin (flogmev) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study. int j antimicrob agents. 2009; 33:549-53. 12. shoskes da. use of the bioflavonoid quercetin in patients with longstanding chronic prostatitis. j am neutraceutical assoc. 1999; 2:18. 13. gupta sc, patchva s, aggarwal bb. therapeutic roles of curcumin: lessons learned from clinical trials. aaps j 2013; 15:195-218. 14. kim hw, ha us, woo jc, et al. preventive effect of selenium on chronic bacterial prostatitis. j infect chemother. 2012; 18:30-4. 15. han ch, yang ch, sohn dw, et al. synergistic effect between lycopene and ciprofloxacin on a chronic bacterial prostatitis rat model. int j antimicrob agents 2008; 31 suppl 1:s102-7. 16. marzano r, dinelli n, ales v, bertozzi ma. effectiveness on urinary symptoms and erectile function of prostamev plus® vs only extract serenoa repens. arch ital urol androl. 2015; 87:25-7. 17. karlsen m, hovden ao, vogelsang p, et al. bromelain treatment leads to maturation of monocyte-derived dendritic cells but cannot replace pge2 in a cocktail of il-1β, il-6, tnf-α and pge2. scand j immunol. 2011; 74:135-43. 18. barrager e, schauss ag. methylsulfonylmethane as a treatment for seasonal allergic rhinitis: additional data on pollen counts and symptom questionnaire. j altern complement med. 2003; 9:15-6. 19. mehlhorn aj, brown da. safety concerns with fluoroquinolones. ann pharmacother. 2007; 41:1859-66. 20. trinchieri a. role of levofloxacin in the treatment of urinary tract infections. arch ital urol androl. 2001; 73:105-13. 21. giubilei g, mondaini n, crisci a, raugei a, et al. the italian version of the national institutes of health chronic prostatitis symptom index. eur urol. 2005; 47:805-11. 22. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol. 1997; 31:129-40. 23. kaplan rm, bush jw, berry cc. health status: types of validity and the index of wellbeing. health serv res. 1976; 11:478-507. 24. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin epidemiol. 1998; 51:1025-36. 25. nickel jc, downey j, hunter d, clark j. prevalence of prostatitis-like symptoms population based study using the national institutes of health chronic prostates symptoms index. j urol. 2001; 165:843-5. 26. motrich rd, cuffini c, mackern oberti jp, et al. chlamydia trachomatis occurrence and its impact on sperm quality in chronic prostatitis patients. j infect. 2006; 53:175-83. 27. mazzoli s. conventional bacteriology in prostatitis patients: microbiological bias, problems and epidemiology on 1686 microbial isolates. arch ital urol androl. 2007; 79:71-5. 28. gallelli l, colosimo m, tolotta ga, falcone d, luberto l, curto ls, rende p, mazzei f, marigliano nm, de sarro g, cucchiara s.prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis living in nursing homes.eur j clin pharmacol. 2010;66:137-44. 29. serra r, gallelli l, buffone g, molinari v, stillitano dm, palmieri c, de franciscis s. doxycycline speeds up healing of chronic venous ulcers.int wound j. 2015;12:179-84. 30. de franciscis s, gallelli l, battaglia l, et al. cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease. int wound j. 2015; 12:250-3. 31. bernichtein s, pigat n, camparo p, et al. anti-inflammatory properties of lipidosterolic extract of serenoa repens (permixon®) in a mouse model of prostate hyperplasia. prostate. 2015; 75:706-22. 32. latil a, libon c, templier m, et al. hexanic lipidosterolic extract of serenoa repens inhibits the expression of two key inflammatory mediators, mcp-1/ccl2 and vcam-1, in vitro. bju int 2012; 110:e301-7. 33. bjerklund johansen te, grüneberg rn, guibert j, et al. the role of antibiotics in the treatment of chronic prostatitis: a consensus statement. eur urol. 1998; 34:457-66. correspondence tommaso cai, md (corresponding author) ktommy@libero.it daniele tiscione, md gianni malossini, md department of urology, santa chiara regional hospital largo medaglie d'oro, 9, trento, italy luca gallelli, md department of health science, school of medicine, university of catanzaro, catanzaro, italy paolo verze, md alessandro palmieri, md vincenzo mirone, md department of urology, university of naples, federico ii, naples, italy riccardo bartoletti, md department of urology, university of pisa, pisa, italy cai_stesura seveso 21/09/16 08:42 pagina 182 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 176 original paper relevance of prostate cancer in patients with synchronous invasive bladder urothelial carcinoma: a monocentric retrospective analysis lucio dell’atti department of urology, university hospital “s. anna”, ferrara, italy. objectives: we retrospectively reviewed data of patients with incidental prostate cancer (pca) who underwent radical cystoprostatectomy (rcp) for invasive bladder cancer and we analyzed their features with regard to incidence, pathologic characteristics, clinical significance, and implications for management. material and methods: clinical data and pathological features of 64 patients who underwent standard rcp for bladder cancer were included in this study. besides the urothelial carcinoma of the urinary bladder, the location and tumor volume of the pca, prostate apex involvement, gleason score, pathological staging and surgical margins were evaluated. clinically significant pca was defined as a tumor with a gleason 4 or 5 pattern, stage ≥ pt3, lymph node involvement, positive surgical margin or multifocality of three or more lesions. postoperative follow-up was scheduled every 3 months in the first year, every 6 months in the second and third year, annually thereafter. results: 11 out of 64 patients (17.2%) who underwent rcp had incidentally diagnosed pca. 3 cases (27.3%) were diagnosed as significant pca, while 8 cases (72.7%) were clinically insignificant. the positive surgical margin of pca was detected in 1 patient with significant disease. the prostate apex involvement was present in 1 patient of the significant pca group. median follow-up period was 47.8 ± 29.2 (range 4-79). during the follow-up, biochemical recurrence occurred in 1 patient (9%). concernig the cancer specific survival there was no statistical significance (p = 0.326) between the clinically significant and clinical insignificant cancer group. conclusions: in line with published studies, incidental pca does not impact on the prognosis of bladder cancer of patients undergoing rcp. key words: bladder cancer;; urothelial carcinoma; prostate cancer; cystoprostatectomy; incidental. submitted 23 october 2014; accepted 31 december 2014 summary no conflict of interest declared. majority of cystectomy patients are in 6th-7th decade and therefore it is not surprising that in some patients prostate carcinoma (pca) is detected incidentally on histological examination of the excised specimen (2). following its initial description, this operation has undergone progressive refinement with the current application of nerve-sparing techniques, extended pelvic lymphadenectomy, and orthotopic bladder substitution (3, 4). however, this procedure is invariably associated with high incidence of sexual complications. alternative techniques have recently been suggested for younger patients, in whom the prostate apex, prostate capsule or even the whole the prostate is preserved, with the aim of improving urinary continence and erectile function (5). these techniques to preserve sexuality raised some concerns because of two essential risks: local invasion of the prostate by the urothelial cancer and a possible association with incidental pca (6). in this study we retrospectively reviewed data of patients with incidental pca who underwent rcp for invasive bladder cancer and our aim was to analyze their features with regard to incidence, pathologic characteristics, clinical significance, and implications for management. materials and methods the clinical data and pathological features of 64 patients who underwent standard rcp for bladder cancer at our institution from january 2006 to may 2013 were retrospectively reviewed. bladder cancer was histologically diagnosed by transurethral resection. the indication for rcp included muscle invasive bladder cancer, carcinoma in situ of the bladder refractory to intravesical bacillus calmette-guèrin therapy and recurrent multifocal highgrade superficial bladder cancer uncontrollable by repeat transurethral resection. standard pelvic lymphadenectomy including the obturator and iliac nodes was performed for all patients. the preoperative assessment included digital rectal examination (dre), prostate-specific antigen (psa), chest radiographies and computed thomography (ct) urography and/or magnetic resonance imaging were used for clinical staging. patients with an abnormal result of dre or psa suspicious of pca and finally confirmed by prostate biopsy before the surdoi: 10.4081/aiua.2015.1.76 introduction radical cystoprostatectomy (rcp) remains the golden standard for muscle invasive bladder cancer or recurrent superficial urothelial carcinoma at high risk (1). the dell'atti_stesura seveso 02/04/15 10:26 pagina 76 77archivio italiano di urologia e andrologia 2015; 87, 1 incidental prostate cancer in radical cystectomy gery were already excluded from the study. all the pathological examination was performed in the same institution. cystoprostatectomy specimens were immersed intact in formalin solution. the prostate and seminal vesicles were removed en bloc from the bladder, and the entire circumference of each resected prostate gland was inked. complete transverse sections were taken from apex to base at 4 mm intervals. all pathological examinations were performed according to the 2002 tnm classification system. besides the urothelial carcinoma of the urinary bladder, the location and tumor volume of the pca, prostate apex involvement, gleason score, pathological staging and surgical margins were evaluated. clinically significant pca was defined as a tumor with a gleason 4 or 5 pattern, stage ≥ pt3, lymph node involvement, positive surgical margin or multifocality of three or more lesions. postoperative follow-up was scheduled at 3-month intervals after the surgery, then every 3 months the first year, every 6 months the second and third year, annually thereafter. serum psa, creatinine and blood chemistry to assess the renal function, urinalysis, abdominal ultrasonography, and chest x-ray constitute the essentials of a follow up visit. in case of node-positive disease, ct scans and bone scintigraphies were performed at regular intervals. a biochemical recurrence was defined as a second confirmatory level of serum psa of > 0.2 ng/ml. statistical analysis chi-square analysis (or fisher’s exact test for nonparametric variables) was used to analyze categoric variables and t test (or mann-whitney test for nonparametric variables) to analyze continuous variables. patient age, tumor volume, and psa level were treated as continuous variables, whereas gleason scores, margin status, stage, multiplicity, and apical tumor involvement were treated as categoric variables. a p < 0.05 was considered to indicate statistical significance. results in our study, primary tumors were transitional cell carcinoma (tcc) of the bladder in 62 patients (96.9%), sarcoma and adenocarcinoma of the bladder in the remaining two patients (3.1%), respectively. carcinoma in situ and non invasive high-grade urothelial papillary carcinoma were seen in 6 (9.7%) and 2 (3.3%) patients, respectively. in 20 (32.3%), 18 (29%) and 13 (20.9%) patients, urothelial carcinoma had invaded the subepithelial connective tissue, muscolaris propria, and perivescical tissue, respectively. stage pt4 (direct extension to the prostate) was seen in 5 patients (7.8%). 11 out of 64 patients (17.2%) who underwent rcp had incidentally diagnosed pca. the mean age was 73.3 ± 7.2 years and 74.9 ± 6.9 years for patients with incidental pca and without incidental cancer, respectively (p = 0.255). a preoperative median psa in 11 cases with incidental pca was 2.79 ± 1.94 ng/ml and in 53 patients without incidental cancer was 2.19 ± 1.88 ng/ml, which showed no significant difference (p = 0.144). median tumor volume was 0.09 cm3 (range 0.01 to 17.62 cm3), and a tumor volume of more than 0.5 cm3 was identified in 7 patients (7/11, 66.6%). two patients were found to have apex involvement of pca. the detailed characteristics of patients who underwent rcp were summarized in table 1. 3 cases (3/11, 27.3%) were diagnosed as significant pca, while 8 cases (8/11, 72.7%) were clinically insignificant. the positive surgical margin of pca was detected in 1 patient with significant disease. the prostate apex involvement was present in 1 patient of significant pca group. there was no statistical difference in pathological staging and the pelvic lymph node involvement of the bladder cancer between the two groups. high-grade prostatic intraepithelial carcinoma (hgpin) was identified in 2 men (2/11, 18.2%) with incidental pca and in 3 men (3/53, 5.7%) who underwent rcp without incidental pca (p = 0.243). table 2 summarizes the pathologic characteristics of the two groups of incidental pca. follow-up data were available for all 64 patients who underwent rcp. median follow-up period was 47.8 ± 29.2 months (range 4-79). all 11 patients with incidental pca had undetectable serum psa levels 3 months after rcp. during the follow-up, biochemical recurrence occurred in 1 patient (9%) that was treated with androgen deprivation therapy. for adjuvant therapy, the 17 patients with bladder tcc received platinum-based combination chemotherapy. of the 62 who underwent rcp with bladder tcc, 8 patients (8/62, 12.9%) experienced pelvic recurrence or distant metastasis from a bladder tumor, 1 patient in clinically insignificant pca group (1/3, 33.4%) and 3 patients in clinically significant group (3/8, 37,5%). there was no pca-related death in table 1. characteristics of patients who underwent cystoprostatectomy. patients characteristics patients with patients without p value (n = 64) incidental pca (n = 11) incidental pca (n = 53) age (yrs), mean ± sd 73.3 ± 7.2 74.9 ± 6.9 ns primary tumor, (n) ns bladder tcc 10 52 sarcoma bladder 1 0 adenocarcinoma bladder 0 1 pathological stage of bladder cancer (tcc): ns carcinoma in situ 1 5 pt1 3 17 pt2 3 15 pt3 2 11 pt4 1 4 previous intravesical chemotherapy/bcg 8 39 ns psa level ng/ml, (range) 2.79 ± 1.94 2.19 ± 1.88 ns hgpin (n) 2 3 ns follow-up, (months) 46.9 ± 28.5 48.7 ± 27.9 ns ns = not significant; pca = prostate cancer; sd =standard deviation; tcc = transitional cell carcinoma; bcg = bacille calmete-guèrin. dell'atti_stesura seveso 02/04/15 10:26 pagina 77 archivio italiano di urologia e andrologia 2015; 87, 1 lucio dell’atti 78 both groups during the follow-up. concerning the cancer specific survival there was no statistical significance (p = 0.326) between the clinically significant and clinical insignificant cancer group. discussion it is not infrequent that patient with muscle-invasive bladder cancer would also concomitantly have incidental pca in rcp specimens (7). it was shown that both prostate and bladder cancers have similar genetic origins, and some suppressor genes play a significant role in both malignancies. in addition, prostatic stem cell expression has been shown in bladder carcinomas, thereby demonstrating the common genetic origin of those malignancies (8, 9). in 1993, stamey et al. discovered unsuspected prostate cancer in 40% of an unselected group of cystoprostatectomy specimens (10). according to epidemiologic data only 8% of prostate cancers are clinically apparent cancers and that these must be the largest tumors, these investigators took 8% of the largest tumors identified in their series (sized 0.5-6.1) and concluded that any tumor over 0.5 cc must be clinically significant. the question is whether screening of these patients for pca is necessary, because patients who are candidates for rcp with serum psa determination and dre have a risk of overdiagnosis for pca (11) and because the diagnosis of pca in a patient with muscle-invasive bladder cancer will probably not cause the death of a given patient, also as demonstrated by our study (p = 0.326). androulakakis et al. suggested that simultaneous finding of pca and bladder cancer did not affect the prognosis of either disease. the patient’s prognosis appears to be related to the characteristics of each tumor, separately (12). more recently it was reported no worse survival in patients with both cancers compared with those with bladder cancer alone (13). however, some authors emphasize the importance of diagnosis of pca in patients with muscle invasive bladder cancer for a correct approach to surgical alternatives in order to preserve sexuality and urinary continence in young adult patients (14, 15). considering the important role of prostate apex for urinary continence and the erectile function, the apexsparing approach and/or the prostate capsule-preserving for improve urinary continence is suggested by several authors and has become a treatment of choice for muscle invasive bladder cancer (16). davila et al. found that erectile function could be significantly preserved by prostate apex-sparing cystectomy (17). vallavicien et al. advocated cystectomy preceded by transurethral resection of prostatic tissue with preservation of the prostatic capsule (15). muto et al. combined cystectomy with adenoma enucleation according to millin (18). in the present study of men having rcp, 17,2% of patients were diagnosed with incidental pca; of those 27,3% were classified clinically significant and 1 patient (1/11, 9%) was found to have prostate apex involvement by prostate adenocarcinoma. our study cohort was a homogenous group, a representative sample of italian population. incidental pca detected in similar international studies ranges between 14 and 60%. international differences in the incidence of pca in cystoprostatectomy specimens could represent a racial variation in cap prevalence (18). in our study, in line with published studies (19-21), incidental pca does not impact on the prognosis of bladder cancer patients undergoing rcp. conclusions however, is important to identify patients with high-risk pca prospectively, so that they can be offered adjuvant treatment with view to longer-term risk reduction. preoperative prostate assessment in those going for rcp may influence not only the decision but also technique used. prostatic apical sparing for better continence or prostate capsule preserving for erectile function in neobladder formation should be considered only in carefully selected patients. therefore, the real impact of prostate-sparing radical cystectomy on functional outcomes requires further investigation. references 1. ozgür bc, köseoglu e, arık ai, et al. synchronous bladder and prostate cancers in the specimens of radical cystoprostatectomy: a multicenter retrospective analysis. kaohsiung j med sci. 2014; 30:371-375. 2. revelo mp, cookson ms, chang ss, et al. incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. j urol. 2008; 179:s27-32. patients with patients without p value significant pca (n = 3) insignificant pca (n = 8) age (yrs), mean ± sd 73.3 ± 7.2 74.9 ± 6.9 ns primary tumor, (n) ns bladder tcc 10 52 sarcoma bladder 1 0 adenocarcinoma bladder 0 1 pathological stage of bladder cancer (tcc): ns carcinoma in situ 1 5 pt1 3 17 pt2 3 15 pt3 2 11 pt4 1 4 previous intravesical chemotherapy/bcg 8 39 ns psa level ng/ml, (range) 2.79 ± 1.94 2.19 ± 1.88 ns hgpin (n) 2 3 ns follow-up, (months) 46.9 ± 28.5 48.7 ± 27.9 ns ns = not significant; pca = prostate cancer; sd =standard deviation; tcc = transitional cell carcinoma; bcg = bacille calmete-guèrin. table 2. clinical data and pathological features of significant and insignificant incidental prostate cancer. dell'atti_stesura seveso 02/04/15 10:26 pagina 78 79archivio italiano di urologia e andrologia 2015; 87, 1 incidental prostate cancer in radical cystectomy 3. novara g, ficarra v, minja a, et al. functional results following vescica ileale padovana (vip) neobladder: midterm follow-up analysis with validated questionnaires. eur urol. 2010; 57:1045-1051. 4. winkler mh, livni n, mannion em, et al. characteristics of incidental prostatic adenocarcinoma in contemporary radical cystoprostatectomy specimens. bju int. 2007; 99:554-558. 5. autorino r, di lorenzo g, damiano r, et al. pathology of the prostate in radical cystectomy specimens: a critical 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168:2413-2417. 16. abdelhady m, abusamra a, pautler se, et al. clinically significant prostate cancer found incidentally in radical cystoprostatectomy specimens. bju int. 2007; 99:326-329. 17. davila hh, weber t, burday d, et al. total or partial prostate sparing cystectomy for invasive bladder cancer: long-term implications on erectile function. bju int. 2007; 100:1026-1029. 18. muto g, bardari f, d’urso l, giona c. seminal sparing cystectomy and ileocapsuloplasty: long-term follow-up . j urol. 2004; 172:76-80. 19. haas gp, delongchamps n, brawley ow, et al. the worldwide epidemiology of prostate cancer: perspectives from autopsy studies. can j urol. 2008; 15:3866-3871. 20. kefer jc, voelzke bb, flanigan rc, et al. risk assessment for occult malignancy in the prostate before radical cystectomy. urology. 2005; 66:1251-1255. 21. koraitim mm, atta m, foda mk. impact of the prostatic apex on continence and urinary flow in patients with intestinal neobbladders. br j urol. 1996; 78:534-536. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology university hospital “s. anna” 8 a. moro street 44124 cona, ferrara, italy dell'atti_stesura seveso 02/04/15 10:26 pagina 79 stesura seveso 5archivio italiano di urologia e andrologia 2014; 86, 1 original paper is there any effect of insulin resistance on male reproductive system? ayhan verit 1, fatma ferda verit 2, halil oncel 3, halil ciftci 4 1 fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey; 2 suleymaniye maternity, research & training hospital, dept. of obstetrics & gynaecology, infertility research & treatment centre, istanbul, turkey; 3 sanliurfa research & training hospital, dept. of urology, sanliurfa, turkey; 4 harran university, school of medicine, dept. of urology, sanliurfa, turkey. objectives: to investigate the possible effect of insulin resistance (ir) on male reproductive system via evaluation of semen analysis, male sex hormones and serum lipid profiles, and testicular volumes. methods: after the exclusions, a total of 80 male patients were enrolled in this prospective study. body mass index (bmi), testicular volume, semen samples, serum hormone/lipid profiles, high sensitive c-reactive protein (hscrp) were obtained from all the subjects. results: the patients were divided into two groups as study and control according to the presence of ir. there were no statistical differences in terms of age, marriage period, testicular volume, serum levels of hormone and lipid profiles and bmi between the groups. there were no relationship between homeostasis model assessment of insulin resistance (homa-ir) and semen volume (r = -0.10, p = 0.37), total sperm count (r = -0.09, p = 0.39), motility (r = -0.15, p = 0.16) and morphology (r = -0.14, p = 0.19). however, homa-ir was closely associated with hscrp levels (r = 0.94, p < 0.0001). conclusions: despite of the documented strong inverse relationships between diabetes mellitus (dm) and male/female fertility, and also between ir and female infertility via ovarian functions as in polycystic ovary syndrome, to our knowledge, there is no report about any influence of ir on male fertility. dm and metabolic syndrome (mets) have negative influence on fertility. thus, ir may be accused of causing detrimental effect on male infertility due to hyperinsulinemic state and being one of the components for mets. interestingly, due to our preliminary results, we do not found any inverse correlation between ir and male reproductive functions. key words: insulin resistance; male reproductive system; male fertility; sex hormones; sperm. submitted 22 september 2013; accepted 5 october 2013 summary introduction the impaired glucose metabolism as in diabetes mellitus (dm) is widely accepted as a negative effecting factor on human fertility in either gender (1, 2). however this no conflict of interest declared. detrimental effect of dm on male infertility has long been regarded as a controversial topic due to the fact that the literature knowledge mostly depended on the conventional semen analysis which is not a well predictor of male fertility (3, 4). nevertheless, it was reported that dm can inversely effect male fertility via sperm functions at molecular level especially on its nuclear and mitochondrial dna and also its repairing systems (3). moreover, dm is responsible for a kind of histological damage of the epididymis that resulted in a negative impact on sperm transit and also promotes inflammatory process in sexual male accessory glands (5). according the relatively new issue of the endless story of glucose metabolism, insulin resistance (ir), is defined as elevated serum insulin levels due to the end of organ resistance at molecular level with reduced glucose uptake (6). ir and hyperinsulinemia play a major role in the pathogenesis of type 2 diabetes (dm2). ir is claimed of inverse effect on female health such as infertility via ovarian functions as in polycystic ovary syndrome (pcos), increased risk pregnancy and elevated lifetime risk of developing type 2 diabetes (7). ir should be taken into account in the definition of metabolic syndrome (mets) which represents a group of abnormalities, including overweight, dyslipidemia, hypertension, endothelial dysfunction, systemic inflammation and impaired glucose metabolism that reflects our modern's world sedentary lifestyle accompanying with over nutrition and thus became one of the major public health challenges worldwide (8, 9). to our interest, the harm of mets on male infertility is mostly attributed to the various problems related with overweight such as high scrotal temperature, variations of serum testosterone levels or dyslipidemia other than ir component of mets (9). despite of the documented well known aforementioned strong inverse relationships between dm and male/female fertility, and also ir and female fertility, to our knowledge, there is no report about any influence of ir on male fertility. thus, in this preliminary study we investigate the possible effect of ir on male reproductive system via evaluation of semen analysis, male sex hormones and serum lipid profiles, and testicular volumes. doi: 10.4081/aiua.2014.1.5 verit_stesura seveso 26/03/14 09:53 pagina 5 archivio italiano di urologia e andrologia 2014; 86, 1 a. verit, f. ferda verit, h. oncel, h. ciftci 6 materials and methods a total of 80 male patients who attended outpatient infertility clinic of urology department of our university hospital between january 2009 and june 2012 were enrolled in this prospective study. this study was approved by university’s institutional review board and all the participants signed the informed consent before the onset of study. a detailed medical history and body mass index (bmi) were obtained from all participants. the patients over 40 years, with known erectile dysfunction, chronic/hereditary disease (including prostatitis, hypertension, dyslipidemia needing medical care), malignancy, and smokers, alcohol drinkers, drug abusers, azoospermics and patients who had varicocele were excluded. systemic and genital examination was performed for all subjects. testicular volume was measured by ultrasound and calculated as the formula of 0.71 x length x width x thickness. the patients were divided into two groups as study and control according to the presence of ir or not respectively. the blood samples were undertaken at 9:00 and 11:00 a.m. after an overnight fast (at least 12 hours) and centrifuged within 2 h after withdrawal and assessed on the same day. ir was determined by the homeostasis model assessment of insulin resistance (homa-ir) via the formula: fasting bloo sugar (mg/dl) × fasting insulin (μiu/ml)/405. a homa value above 4 was accepted for indication of ir. insulin was determined by electrochemiluminescent immunoassay (siemens immu lite 2000, los angeles, usa). gonado tro pins, testosterone and high sensitive c-reactive protein (hscrp) levels were also obtained for all subjects. two semen samples were evaluated in two weeks intervals. semen samples collected by masturbation in a clean specimen container after a sexual abstinence for 2 5 days were allowed to liquefy at 37º c and evaluated immediately according to who recommendations including ejaculate volume, ph, time to liquefaction, sperm concentration, motility and morphology. sperm concentration was expressed as 106 per millilitre of semen, whereas motility and morphology were expressed as percentage. statistical analysis baseline characteristics of the groups were presented as the mean ± sd. variables with a skewed distribution were log transformed for all analyses. demographic, laboratory and semen parameters between the study and control groups were assessed by student’s t test. correlations between homa-ir, semen parameters and hscrp, were assessed by pearson correlation analysis. p < 0.05 was considered as statistically significant. results the results of 80 male subjects were evaluated. of those, 40 were diagnosed with ir due to homa-ir and considered as study group and remaining 40 formed the control group. the data collection was stopped when each group reached to 40. median age of the patients with or without ir were 31.2 ± 5.0 (range 18-40) and 29.6 ± 5.0 (range 18-39) respectively. there were no statistical differences in terms of age, marriage period, testicular volume and bmi between the groups (table 1). semen and serologic characteristics (hormone and lipid profiles, glucose/insulin, hscrp levels and homa-ir) of the groups were also summarized in table 2. subjects with ir subjects without ir p (n = 40) (n = 40) age (year) 31.2 ± 5.0 29.6 ± 5.0 0.15 bmi (kg/m2) 25.6 ± 3.3 25.0 ± 3.3 0.44 testicular volume (cm3) 20.2 ± 3.2 20.9 ± 3.1 0.33 bmi: body mass index; ir: insulin resistance. subjects with ir subjects without ir p (n = 40) (n = 40) fsh (miu/ml) 5.8 ± 2.7 6.4 ± 2.7 0.36 lh (miu/ml) 7.8 ± 2.7 6.9 ± 2.7 0.14 total testosterone(ng/dl) 403.4 ± 66.2 427.9 ± 67.4 0.10 shbg (nmol/l) 23.9 ± 4.4 25.4 ± 4.4 0.13 tg (mg/dl) 158.2 ± 21.1 116.7 ± 20.3 < 0.0001 tc (mg/dl) 191.2 ± 28.8 166.3 ± 28.0 < 0.0001 hdl (mg/dl) 38.2 ± 4.0 44.2 ± 4.2 < 0.0001 ldl (mg/dl) 124.4 ± 20.0 105.9 ± 19.8 < 0.0001 fasting glucose (mg/dl) 111.3 ± 9.7 89.4 ± 9.5 < 0.0001 fasting insulin (µiu/ml) 22.5 ± 4.4 6.5 ± 4.3 < 0.0001 homa-ir 6.1 ± 1.2 1.4 ± 0.9 < 0.0001 hscrp (mg/l) 3.1 ± 1.1 0.9 ± 0.4 < 0.0001 semen parameters volume (ml) 2.6 ± 1.2 2.8 ± 1.3 0.50 total sperm count (sperm! 106/ml) 62.4 ± 39.1 72.1 ± 39.5 0.27 motility (%) 56.1 ± 15.6 60.8 ± 15.5 0.18 morphology (%) 42.7 ± 9.4 45.7 ±9.4 0.16 shbg: sex hormone binding globulin; tg: triglyceride; tc: total cholesterol; hdl: high density lipoprotein; ldl: low density lipoprotein; homa-ir: homeostasis model assessment of insulin resistance; hscrp: high sensitive; c-reactive protein; ir: insulin resistance. table 1. age, body mass index (bmi) and testicular volume of patients who presented to infertility center with/without insulin resistance. table 2. laboratory and semen characteristics of patients who presented to infertility center with/without insulin resistance. verit_stesura seveso 26/03/14 09:53 pagina 6 there were no relationship between homa-ir and semen volume (r = -0.10, p = 0.37), total sperm count (r = -0.09, p = 0.39), motility (r = -0.15, p = 0 .16) and morphology (r = -0.14, p = 0.19). however, homa-ir was closely associated with hscrp levels (r = 0.94, p < 0.0001). discussion although ir with related hyperinsulinemia classically is defined as a decreased sensitivity to the metabolic actions of insulin such as insulin-mediated glucose disposal, it should be considered that insulin itself also has vascular actions under healthy conditions and this issue is a focus of investigation (10). ir, solely itself, was accused of taking part somehow in the etiology of some urologic disease such as urolithiasis and erectile dysfunction, by similar mechanism as in dm via impairing endothelial functions depending on experimental studies (9-12). the suspicion of this detrimental clinical association extends to benign prostate hyperplasia/lower urinary tract symptoms (bph/luts), female incontinence, male infertility and hypogonadism, and even to prostate cancer, besides the risk for some common cancer such as breast, colorectal, liver, and pancreas, if ir is evaluated together with the topic of mets (8, 13). furthermore, in the light of current literature, there are strong evidences about that dm has negative effect on male reproductive functions in various ways as endocrine control of spermatogenesis, spermatogenesis itself or impairing penile erection and ejaculation (1, 3). ali et al. reported sperm dysfunction through sperm motility defect in patients with noninsulin depended dm even in conventional spermiograms (14) (the evaluation just with conventional spermiograms may also be the limitation of the present study) but some other authors did not found any motility defect in dm without complications (15). nevertheless, despite of the ongoing discussion about the mechanism, it is a fact that subfertility was reported in more than half of the diabetic patients (5). however, the independent negative influence of ir on human fertility was confirmed only for female infertility especially in the case of pcos a condition that is characterized by hyperandrogenism, chronic oligoor anovulation and polycystic ovaries. ir accompanies this clinical status with a high rate (50-70%) and is thought to have a central pathogenic role in pcos (16, 17). this relation between ir and ovarian dysfunction induced us to study the possible correlation between ir and male testicular functions through the evaluation of male sex hormones, testicular volumes and spermiograms. ir leads compensatory hyperinsulinemia that is considered to be a promoter of the hyperandrogenism and chronic oligoor anovulation in female with pcos (16). in our study, gonadotropins and testosterone levels were the same as in subjects with ir or not. however, depending on the experimental and clinical studies, it is a clinical fact that dm decrease serum testosterone and increase gonadotropins (3). as opposite to our results, in a preliminary study of small groups of normal, ir and dm subjects (n = 9, 9 and 3 respectively), pitteloud et al. noted that increase of ir leads to a decrease in leydig cell testosterone according to their insulin sensitivity on glucose tolerance tests (18). in the present study there was no significant difference between mean testicular volumes (around 20 cc for both study and control group) that can also be considered as one of the predictors of fertility. bahk et al. concluded that the testicular volume cut off value for fertility is 18 cc (19) and testicular atrophy is a well known clinical situation in dm (20). the proinflammatory cytokine tumor necrosis factor-a (tnf!), that is a known mediator of ir, is elevated either in obese or nonobese pcos patients. this unstable glucose metabolism leading to oxidative stress and proinflammatory status was claimed as the cause of hyperandrogenism and infertility (16). according to the present results, this explanation seemed not adaptable for subfertiles male with ir because gonadotropins and testosterone, and spermiograms were the similar in both groups, although hscrp, as a low-grade chronic inflammatory marker, seemed significantly higher in our subjects with ir. hscrp is found to be elevated in pcos patients with or without metabolic syndrome (21) and, in addition, ir is a factor that elevates hscrp (22). thus, we think that the reason of this elevation should be attributed to the ir rather than male infertility. moreover, insulin, insulin like growth factor 1 (igf-1) and growth hormone (gh) are supposed to be part of the complex coordination function of nutrient balance and metabolic stress. hyperinsulinemia elevates serum concentrations of free igf-1 that can provide important trophic (anti-apoptotic) effects, leading to changes in cellular metabolism (23). either oophorectomy or orchiectomy resulted in elevated igf-1 levels and this suggests that igf-1 may have some role in the infertility process (24-26). nevertheless, further studies especially at sperm molecular level are needed to accurately confirm our preliminary results about the relation between ir and male reproductive system. we think that our results were also independent from the effect of obesity, because bmi values of our study and control groups were similar (considered as slightly overweight for both). according to the limited number of studies, interestingly, it was supposed a loose inverse relation between male subfertility and obesity and that it occurred mostly via sperm quality and especially to the decreasing normal motility of spermatozoa (8). furthermore, dyslipidemia, as another component of mets which was not present in our subjects, was accused of causing negative effect on sperm/testicular functions in both animal and human studies (27-29). however our results are far away from demonstrating the inverse relationship between mets and male fertility with mets components other than ir. conclusions there is no doubt in the literature that dm and mets have a “bad fame” on human fertility. in connection to this statement, ir automatically may be accused of causing detrimental effect on male fertility as a component of mets due to hyperinsulinemic state and impaired glucose uptake as in dm2. thus in this study, we aimed to document the possible isolate effect of ir on male reproductive system via sperm functions, serum hormone and lipid profiles 7archivio italiano di urologia e andrologia 2014; 86, 1 insulin resistance and male reproductive system verit_stesura seveso 26/03/14 09:53 pagina 7 archivio italiano di urologia e andrologia 2014; 86, 1 a. verit, f. ferda verit, h. oncel, h. ciftci 8 and testicular volumes. interestingly, according to our preliminary results, we do not find any inverse correlation between ir and male reproductive system. however, to reach a conclusion on this topic, further studies at molecular level and/or long term clinical studies of male fertility based on birth rates are needed. references 1. agbaje im, rogers da, mcvicar cm, et al. insulin dependent diabetes mellitus: implications for male reproductive function. hum reprod. 2007; 22:1871. 2. codner e, merino pm, tena-sempere m. female reproduction and type 1 diabetes: from mechanisms to clinical findings. hum reprod update. 2012; 18:568. 3. o'neill j, czerwiec a, agbaje i, et al. differences in mouse models of diabetes mellitus in studies of male reproduction. int j androl. 2010; 33:709. 4. jequier am. is quality assurance in semen analysis still really necessary? a clinician's viewpoint. hum reprod. 2005; 20:2039. 5. la vignera s, di mauro m, condorelli r, et al. diabetes worsens spermatic oxidative "stress" associated with the inflammation of male accessory sex glands. clin ter. 2009; 160:363. 6. trussell jc, legro rs. erectile dysfunction: does insulin resistance play a part? fertil steril. 2007; 88:771. 7. pauli jm, raja-khan n, wu x, legro rs. current perspectives of insulin resistance and polycystic ovary syndrome. diabet med. 2011; 28:1445. 8. kasturi ss, tannir j, brannigan re. the metabolic syndrome and male infertility. j androl. 2008; 29:251. 9. gorbachinsky i, akpinar h, assimos dg. metabolic syndrome and urologic diseases. rev urol. 2010; 12:e157. 10. kim ja, montagnani m, koh kk, quon mj. reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. circulation. 2006; 113:1888. 11. steinberg ho, chaker h, leaming r, et al. obesity/insulin resistance is associated with endothelial dysfunction. implications for the syndrome of insulin resistance. j clin invest. 1996; 97:2601. 12. sánchez a, contreras c, martínez mp, et al. role of neural no synthase (nnos) uncoupling in the dysfunctional nitrergic vasorelaxation of penile arteries from insulin-resistant obese zucker rats. plos one. 2012; 7:e36027. 13. arcidiacono b, iiritano s, nocera a, et al. insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. exp diabetes res. 2012; 2012:789174. 14. ali st, shaikh rn, siddiqi na, siddiqi pq. semen analysis in insulindependent/non-insulin-dependent diabetic men with/without neuropathy. arch androl. 1993; 30:47. 15. niven mj, hitman ga, badenoch df. a study of spermatozoal motility in type 1 diabetes mellitus. diabet med. 1995; 12:921. 16. gonzález f. inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. steroids. 2012; 77:300. 17. pauli jm, raja-khan n, wu x, legro rs. current perspectives of insulin resistance and polycystic ovary syndrome. diabet med. 2011; 28:1445. 18. pitteloud n, hardin m, dwyer aa, et al. increasing insulin resistance is associated with a decrease in leydig cell testosterone secretion in men. j clin endocrinol metab. 2005; 90:2636. 19. bahk jy, jung jh, jin lm, min sk. cut-off value of testes volume in young adults and correlation among testes volume, body mass index, hormonal level, and seminal profiles. urology. 2010; 75:1318. 20. wright jr jr, yates aj, sharma hm, et al. testicular atrophy in the spontaneously diabetic bb wistar rat. am j pathol. 1982; 108:72. 21. verit ff. high sensitive serum c-reactive protein and its relationship with other cardiovascular risk factors in normoinsulinemic polycystic ovary patients without metabolic syndrome. arch gynecol obstet. 2010; 281:1009. 22. llauradó g, gallart l, tirado r, et al. insulin resistance, lowgrade inflammation and type 1 diabetes mellitus. acta diabetol. 2012; 49:33. 23. clemmons dr. metabolic actions of insulin-like growth factor-i in normal physiology and diabetes. endocrinol metab clin north am. 2012; 41:425. 24. fogle rh, chang l, patel sk, et al. increased insulin-like growth factor-1 after oophorectomy in postmenopausal women. fertil steril. 2008; 90:1236. 25. sánchez-luengo s, fernández pj, romeu a. insulin growth factors may be implicated in human sperm capacitation. fertil steril. 2005; 83:1064. 26. gao f, yang m, luo cl, wu xh. local insulin-like growth factor-i of ventral prostate was upregulated during long-term castration and may function through the autocrine system. prostate cancer prostatic dis. 2011; 14:136. 27. yamamoto y, shimamoto k, sofikitis n, miyagawa i. effects of hypercholesterol aemia on leydig and sertoli cell secretory function and the overall sperm fertilizing capacity in the rabbit. hum reprod. 1999; 14:1516. 28. saez lancellotti te, boarelli pv, monclus ma, et al. hyper cholesterolemia impaired sperm functionality in rabbits. plos one. 2010; 18;5:e13457. 29. ramírez-torres ma, carrera a, zambrana m. high incidence of hyperestrogenemia and dyslipidemia in a group of infertile men. ginecol obstet mex. 2000; 68:224. correspondence ayhan verit, md (corresponding author) veritayhan@yahoo.com dept. of urology fatih sultan mehmet research and training hospital icerenkoy/atasehir tr34752 istanbul, turkey fatma ferda verit, md associate professor dept. of obstetrics & gynaecology, infertility research & treatment centre suleymaniye maternity, research & training hospital istanbul, turkey halil oncel, md dept. of urology ,sanliurfa research & training hospital sanliurfa, turkey halil ciftci, md associate professor dept. of urology harran university, school of medicine sanliurfa, turkey this study has been presented (poster no: 32) in american society of andrology (asa) xxiind 2013 testis workshop, april 10-13, in san antonio, texas, usa. verit_stesura seveso 26/03/14 09:53 pagina 8 archivio italiano di urologia e andrologia 2013; 85, 128 introduction the peyronie's disease (pd) is an idiopathic disorder of connective tissue of the penis, that involves the tunica albuginea of the corpora cavernosa and the adjacent areolar space. a fibrous plaque replaces the elastic fibers that normally constitute the tunica albuginea, limiting its extensibility, and causing pain during erection, erectile dysfunction and difficulty of penetration, as a result of the deviation of the penis. although it was once considered a relatively infrequent disease, some studies show that the prevalence of ipp is original paper animal experimental model of peyronie’s disease: a pilot study maria angela cerruto 1, carolina d’elia 1, 2, alberto molinari 1, francesca maria cavicchioli 1, antonio d’amico 1, walter artibani 1 1 urology clinic, a.o.u.i. verona, verona, italy; 2 urology clinic, santa chiara hospital, trento, italy. objective: the peyronie's disease (pd) is an idiopathic disorder of connective tissue of the penis, that involves the tunica albuginea of the corpora cavernosa and the adjacent areolar space. it is a growing clinical evidence to support the therapeutic potential of mesenchymal stem cells and histological findings has assumed a possible application of lipofilling technique in patients with pd. the objective of this experimental study is the creation of a murine experimental model of pd, evaluating with mri the penis of the rats (feasibility study), in order to plane the application of lipofilling technique in an animal model. methods: four male wistar rats were anesthetized, fixed in prone position and subjected to mri. the animals underwent, subsequently, an injection of thrombin in the tunica albuginea and mri images were acquired at 7 and 21 days after injection with incision of the dartos. results: the mri acquisitions, both in coronal and axial projection, showed an adequate visibility of the anatomical structures. at 7 days after thrombin injection with the dartos incision it was evident an oedematous portion, visible as a hyperintense area, located at the injection area. at 21 days after injection, oedema was partially resolved: the injection part of the hyperintense area remains unchanged, while the remaining area appears to be part of a re-absorption and re-organization process. conclusions: since none of the various treatment modalities currently available for the management of pd is able to bring healing, the researchers’ attention is increasingly directed towards innovative treatment programs, such as the use of stem cells of mesenchymal origin. at the present time, the research in pd is hampered by the lack of universally accepted animal model and this is likely attributed to the limited insight into pd mechanisms and the difficulties faced by current animal models to truly represent the complexity. key words: peyronie’s disease; murine animal model. submitted 14 january 2013; accepted 31 january 2013 no conflict of interest declared summary comparable to that of diabetes or of urolithiasis (1, 2). a recent epidemiological study reported a prevalence of 3.2% (3), highlighting the potential psychosocial impact of this disease. the peyronie's disease affects predominantly adulthood (approximately 60% of cases between 40 and 60 years) and is still present at young age (10-20% at the age of 40) and advanced age (15-20% over 60 years of age) (4). further studies have tried to identify risk factors associated with pd: smoking, hypertension, hyperlipidemia cerruto_stesura seveso 18/04/13 11:02 pagina 28 29archivio italiano di urologia e andrologia 2013; 85, 1 animal experimental model of peyronie’s disease: a pilot study ischaemia, hyperpermeability, fibrosis and increased ischemia itself. this vicious circle can be broken using the proangiogenetic capacity of mesenchymal stem cells. it is a growing clinical evidence to support the therapeutic potential of mesenchymal stem cells for the revascularization of ischemic tissues and the recovery of their function. in a recent italian study rigotti et al. (20) have tested the effectiveness of purified lipoaspirates on 20 patients operated on for breast cancer with severe side effects and irreversible functional damage from postoperative radiotherapy. 60 to 80 cc of adipose tissue were collected from the medial region of the knee, from the abdominal region or trochanteric: subsequently, the lipoaspirates was centrifuged at 2700 rpm for 15 minutes, in order to remove most of the deposits of triglycerides and to cause injury of membrane in adipocytes, in order to allow the rapid clearance once injected. in this way, the study authors have created a sort of concentration of adult stem cells, which, maintained their three-dimensional microenvironment, appear to be more effective in the neoangiogenetic process (21). in the same paper the ultrastructure of the tissue damaged by radiotherapy has been studied before injection of lipoaspirates and after 1, 2, 6 and 12 months. prior to injection, the tissue showed fibrotic patterns similar to those of scleroderma: duplication in the basement membrane of the capillaries, spaces between the endothelial cells, adipocytes containing lysosomes or clusters of mitochondria, accumulation of collagen. the after-treatment ultrastructural analysis showed signs of neoangiogenetic, neoadipogenetic and antifibrotic activity, due to the activity of adult stem cells contained in lipoaspirates (22-24). at a clinical level, this activity corresponds to a dramatic improvement of symptoms, disappearance of necrosis and wound healing. based on these innovative clinical and histological findings has assumed a possible application of lipofilling technique in patients with pd. it was therefore drawn up an experimental protocol consists of two basic steps: 1. creating an animal model of pd on the basis of experiments already conducted (16, 25) verifying with mri (magnetic resonance imaging) stages of development of the disease; 2. the application of lipofilling technique in an animal model. the objective of this experimental study is the creation of a murine experimental model of ipp (16), evaluated with mri (feasibility study). materials and methods four male wistar rats weighting between 420 and 450 g. were fed with standard rodent diet (rieper spa, italy) and maintained under conditions of controlled temperature and light, respecting the principles of the "nih guide for the care and use of laboratory animals" and the directives of the european community. have all been taken into account, but basically considered to be associated with erectile dysfunction more than strictly to pd. microscopically, the tunica albuginea is largely composed by fibrillar collagen type i, woven with elastin fibers, in order to form organized structures (5). even the plaques of pd are mostly constituted from collagen type i and iii (6), but the elastin component, which gives to the tunica albuginea elongation properties up to 150%, is altered: the decrease elastin, as well the alterations in the arrangement of the tunic layers, are characteristics of pd, that can lead to deviations in penile erection and erectile dysfunction (7). more recent papers have identified a strong association of pd with both dupuytren's disease and the hla b-27 (8). other studies have taken into account immunological factors, showing that patients with pd in 75.8% of cases presented an abnormal immunological test, 48.5% had alte rations in cell-mediated immunity and the 37.9% presented increase in markers for autoimmune diseases (9) but it seems that this predisposition, rather than systemic, is localized to the tunica albuginea. another study has documented evidence of high anti-elastin antibodies in the serum of patients with ipp, hypothesizing, the same way, an autoimmune etiology (10). the role of free radicals in the pathogenesis of plaque seems to be important; bivalacqua et al. (11) have shown, on the basis of other studies (12-14), that the production of nitric oxyd (no) can inhibit the deposition of collagen in the murine model of pd. the most widely accepted theory considers the penile trauma as main causative factor in the pathogenesis of pd: an acute traumatic event or a repetitive microtrauma (e.g. during sexual activity) can result in delamination of the tunica albuginea and microvascular damage (8, 15). fibrin was found to be potentially involved in the development of the fibrotic plaque in a murine model of pd (16). in the same study, and in another more recent (17), was also reported the presence of increased levels of pai-1, an important inhibitor of fibrinolysis and collagenolysis: its increased activation appears to play a key role in the development of penile plaque. the pd has been associated with many other conditions in urologic procedures such as radical retropubic prostatectomy, cystoscopy and introduction of indwelling urethral catheters, genital or peritoneal trauma, urethritis, lipomas (18). even atherosclerosis has been mentioned as a target area on the study of pd, due to the similarities about the pathophysiology (19), regarding the common mechanism of cell hyperproliferation, that leads to the formation of a plaque. since none of the various treatment modalities currently available for the management of pd is able to bring hea ling to the patients who are affected, the researchers' attention is increasingly directed towards innovative treatment programs based on a better understanding of the pathophysiological disease. moreover, the overexpression of cytokines and autoimmune and genetic factors have been cited as cofactors (8). the resulting inflammatory process would be responsible for the onset of a vicious circle of vascular injury, cerruto_stesura seveso 18/04/13 11:02 pagina 29 archivio italiano di urologia e andrologia 2013; 85, 1 m.a. cerruto, c. d’elia, a. molinari, f.m. cavicchioli, a. d’amico, w. artibani 30 before being subjected to mri, the rats were anesthetized in an induction chamber by inhalation of a mixture 70/30% of nitrous oxide and oxygen containing 5% isoflurane. during the execution of the examination, anesthesia was maintained via buccal mask with the same mixture of nitrous oxide and oxygen with isoflurane 3%. image acquisition was performed using a scanner biospec (bruker, karlsruhe, germany) equipped with a horizontal magnet operating at 4.7 tesla with opening of 33 cm (oxford ltd, oxford, uk) (figure 1). the rats were fixed in a prone position on a birdcage type coil diameter of 7.2 cm (figure 2). in order to verify the correct positioning of the animal with respect to the coil, t1-weighted coronal projection acquisitions were performed, while, in order to obtain pre-and post-injection anatomical details, acquisitions t2-weighted images in axial view were performed. the coronal images were acquired with a relaxation time (tr) of 486 ms, echo time (te) of 11 ms, with the use of 2 medium for 20 slices, each of thickness 1 mm. the field of view (fov) was 6 x 6 cm and the matrix choice of 256 x 256, corresponding to a spatial resolution of 0234 mm2/pixel. axial images were acquired with a relaxation time (tr) of 5000 ms, echo time (te) of 67 ms, with the use of 2 medium for 25 slices, each of thickness 1 mm. the field of view (fov) was 6 cm x 3 matrix and the choice of 512 x 256, corresponding to a spatial resolution of 0.117 mm2/pixel. the animals underwent, subsequently, an injection of 60 ml of thrombin in the tunica albuginea, using a 1 ml syringe with 30 g needle. in the first measure, the thrombin was injected without opening the dartos (figure 3): thereafter, considering the substantial ineffectiveness of the first surgery, an incision was performed along the dartos of about 2 mm along the penile axis, in order to have a more secure access to the subdartoic spaces, and the thrombin was injected with the same method (figure 4). mri images were acquired in the same manner as described above at 7 and 21 days after injection with incision of the dartos. figure 1. figure 2. figure 3. figure 4. results the acquisitions, both in projection coronal both in axial, have demonstrated adequate visibility of anatomical structures. figure 5 shows a t1-weighted image, a coronal projection of the penis, while figure 6, t2-weighted axial view, shows the results produced by the thrombin injection, offering a good view of the albuginea and its relationship with the superficial and deeper structures. at 7 days after thrombin injection with incision of the dartos it was evident a edematous portion (figure 7) located at the injection area. oedema, visible as a hyperintense area, appeared to affect the section previously seen as a hypointense rim surrounding the corpora cavernosa of the penis, leaving them intact and with a signal intensity comparable to that seen in the image acquired before the injection. at 21 days after injection, edema was partially resolved (figure 8): in the injection part of the hyperintense area remains unchanged, while the remaining area appears to be part of a reabsorption and reorganization process. cerruto_stesura seveso 18/04/13 11:02 pagina 30 31archivio italiano di urologia e andrologia 2013; 85, 1 animal experimental model of peyronie’s disease: a pilot study discussion the low success rate obtained by standard therapies has fueled our interest in the development of new treatment options, such as the use of stem cells of mesenchymal origin. in literature has recently emerged a growing increase of the clinical evidence to support the therapeutic potential of mesenchymal stem cells for the revascularization of ischemic tissues and the recovery of their function (20). significant clinical results were obtained from autologous endothelial and hematopoietic stem cells from the bone marrow in ischemic lesions at the level of the limbs, myocardium and of the retina in vitro and in animal models, thereby elucidating the mechanisms of stem cell – mediated neo-angiogenesis. the use of stem cells could be useful for the management figure 5. figure 6. figure 7. figure 8. of fibrotic connective tissue diseases such as pd, breaking a vicious circle of self-perpetuating inflammatory condition with post-traumatic vascular injury, subsequent ischemia, hyperpermeability, increased fibrosis and ischemia itself. since there is no data in the literature concerning the role of stem cells in management of pd, we planned to develop a murine model of stable ipp, monitored with imaging (mri), and then try to corroborate the hypothesis that mesenchymal stem cells can have a positive influence on the natural history of this disease. in order to create a murin model of pd we injected 60 μl of thrombin at the level of the tunica albuginea obtaining after 3 weeks after injection the persistence of the inflammatory reaction at the site of inoculation, identificerruto_stesura seveso 18/04/13 11:02 pagina 31 archivio italiano di urologia e andrologia 2013; 85, 1 m.a. cerruto, c. d’elia, a. molinari, f.m. cavicchioli, a. d’amico, w. artibani 32 able to control mri, without secure evidence of fibrosis. moreover, a review of the literature on human mri of the penis was carried out, in order to assess the feasibility of the application of this method in animals: although ultrasound is the primary mode of imaging penis, the mri may use a higher spatial resolution and improved contrast soft tissue. mri is to be considered as an opportunity for progress in penile imaging and is able to solve clinical questions for which the ultrasound is not conclusive. in addition to pd, other diseases can be investigated by this method, such as primitive or secondary penile neoplasms, periurethral abscess, venous thrombosis, fractures; can also be rated the positioning of penile prostheses after surgery. the review of the literature has concerned in particular the possibility to discriminate with the mri the tunica albuginea compared to the remaining structures in humans, so as to apply sequences of acquisition and anatomical similarities also in rats. the t2-weighted images provide more detailed anatomical details: in particular, the tunica albuginea is visible as a hypointense area that surrounds the corpora cavernosa and which also includes buck's fascia. in a work of pretorius et al. (26) also the pd was studied by magnetic resonance imaging: there was evidence of a thickening of the tunica albuginea, visible in both t2weighted both in those t1weighted images. davila et al. (16) have recently proposed an animal model of ipp injecting at the level of the tunica albuginea of rat 30 μ l of fibrin and thrombin, inducing edema after one week after inoculation and fibrosis after three weeks. the use of these components would trigger the final steps of the coagulation cascade and reproduces experimentally what happens after a trauma at the level of the tunica albuginea. the profibrotic effect is most likely due to the fibrin and thrombin deposition in a fibroblasts rich and hypovascularized tissue. the study of davila et al. also showed that, compared to previous methods that used injection of tgf-!1 (27), the fibrin induced plaque develops more quickly (three weeks instead of six weeks). the tgf-!1, in fact, has an anti-inflammatory action in reducing macrophage activation and inhibition of cytotoxic t cells (28, 29): this may explain the study of el-sakka et al. (27) the non-formation of plaque in three weeks and the discovery of the same six weeks, the latter a result of the action of tgf!1 profibrotic same. in our study, after this period there has been found the persistence of the inflammatory condition (edema), probably due to the lower speed of action of thrombin compared to fibrin alone. it is important to observe, that the literature data are only based on histological founds, not also on imaging, as in our study. while the exact mechanism of peyronie's disease (pd) remains an enigma, the pathophysiology of pd is considered to be multifactorial, with interactions of genetic predisposition, trauma, tissue inflammation and aberrant wound healing. the most frequently reported models of pd can be classified as tgf !1, fibrin and surgical trauma-induced models. in vitro studies using peyronie's fibroblast culture media have also provided further insights into cellular mechanism of pd. at the present time, the research in pd is hampered by the lack of universally accepted animal model and this is likely attributed to the limited insight into pd mechanisms and the difficulties faced by current animal models to truly represent the complexity and complete spectrum of human disease. references 1. smith cj, mcmahon c, shabsigh r. peyronie’ disease: the epidemiology, aetiology and clinical evaluation of deformity. bju int. 2005; 95:729-732. 2. sommer f, schwarzer u, wassmer g. et al. epidemiology of peyronie's disease. int j impot res. 2002; 14:379-383. 3. schwarzer u, sommer f, klotz t, et al. the prevalence of peyronie's disease: results of a large survey. bju int. 2001; 88:727-730. 4. pryor jp, ralph dj. clinical presentation of peyronie's disease. int j impot res. 2002; 14:414-417. 5. gentile v, modesti a, la pera g, et al. ultrastructural and immu noistochemical characterization of the tunica albuginea in peyronie' disease and veno-occlusive function. j androl. 1996; 17:96-103. 6. somers kd, sismour en, wright gl jr, et al. isolation and characterization of collagen in peyronie's disease. j urol. 1989; 141:629-631. 7. akkus e, carrier s, baba k, et al. structural alterations in the tunica albuginea of the penis: impact of peyronie's disease, ageing and impotence. br j urol. 1997; 79:47-53. 8. mulhall jp. expanding the paradigm for plaque development in peyronie's disease. int j impot res. 2003; 15 (suppl. 5): s93-102. 9. schiavino d, sasso f, nucera e, et al. immunologic findings in peyronie's disease: a controlled study. urology. 1997; 50:764-768. 10. stewart s, malto m, sandberg l, colburn kk. increased serum levels of anti-elastin antibodies in patients with peyronie's disease. j urol. 1994; 152:105-106. 11. bivalacqua tj, champion hc, hellstrom wjg. implications of nitric oxide synthase isoforms in the pathophisiology of peyronie's disease. int j impot res. 2002; 14:345-352. 12. ferrini m, et al. inducible nitric oxide synthase (inos) and hemoxygenase (ho-1) in the peyronie's plaque. j urol. 2001; 154(suppl.):832a. 13. bivalacqua tj, champion hc, leungwattanakij s, et al. evaluation of nitric oxide synthase and arginase in the induction of peyronie's-like condition in the rat. j androl. 2001; 22:497-506. 14. khan ma, thompson cs, mumtaz fh, et al. the effect of nitric oxide and peroxynitrite on rabbit cavernosal smooth muscle relaxation. world j urol. 2001; 19:220-224. 15. devine cj jr, somers kd, jordan sg, sclossberg sm. proposal: trauma as the cause of the peyronie's lesion. j urol. 1997; 157:285290. 16. davila hh, ferrini mg, rajfer j, gonzalez-cadavid nf. fibrin as an inducer of fibrosis in the tunica albuginea of the rat: a new animal model of peyronie's disease. bju int. 2003; 91:830-838. 17. davila hh, magee tr, zuniga fi, et al. peyronie's disease associated with increase in plasminogen activator inhibitor in fibrotic plaque. urology. 2005; 65:645-648. 18. gholami ss, gonzalez-cadavid nf, lin cs, et al. peyronie's disease: a review. j urol. 2003; 169:1234-1241. 19. mulhall jp, anderson ms, lubrano t, shankey tv. peyronie's cerruto_stesura seveso 18/04/13 11:02 pagina 32 33archivio italiano di urologia e andrologia 2013; 85, 1 animal experimental model of peyronie’s disease: a pilot study disease cell culture models: phenotypic, genotypic and functional analyses. int j impot res. 2002; 14: 397-405. 20. rigotti g, marchi a, galiè m, et al. clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. plast reconstr surg. 2007; 119:1409-1422; discussion 1423-1424. 21. scherberich a, beretz a. culture of vascular cells in tridimensional (3-d) collagen: a methodological review. therapie. 2000; 55:35. 22. rehman j, traktuev d, li j, et al. secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. circulation. 2004; 109:1292. 23. rafii s, lyden d. therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. nat med. 2003; 9:702. 24. peroni d, scambi i, pasini a, et al. stem molecular signature of adipose-derived stromal cells. exp cell res. 2007; 10:1-13. 25. ferrini mg, kovanecz i, nolazco g, et al. effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of peyronie's disease. bju int 2006; 97:625-633. 26. pretorius es, siegelman es, ramchandani p, banner mp. mr imaging of the penis. radiographics. 2001; 21:s283-299. 27. el-sakka ai, hassoba hm, chui rm, et al. an animal model for peyronie’s-like condition associated with an increase of transforming growth factor beta mrna and protein expression. j urol. 1997; 158:2284-2290. 28. tsunawaki s, sporn m, ding a, nathan c. deactivation of macrophages by transforming growth factor-beta. nature. 1988; 334:260-262. 29. ranges ge, figari is, espevik t, palladino ma jr. inhibition of cytotoxic t cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. j exp med. 1987; 166:991-998. correspondence maria angela cerruto, md, febu mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com alberto molinari, md yefet83@yahoo.it francesca maria cavicchioli, md francesca.cavicchioli@gmail.com antonio d’amico, md antonio.damico@ospedaleuniverona.it prof. walter artibani, md walter.artibani@univr.it urology clinic, a.o.u.i. verona p.zza l.a. scuro 10 37134 verona, italy cerruto_stesura seveso 18/04/13 11:02 pagina 33 65archivio italiano di urologia e andrologia 2013; 85, 2 introduction the low specificity of psa test in diagnosing prostate cancer (pca), especially for serum psa values < 10 ng/ml is due to spontaneous fluctuation (1), ejaculation, bph and acute or subclinical chronic prostatitis (cp). psa levels have been correlated with the extent and degree of inflammation (2, 3) and a short trial of antibiotics for a likely subclinical cp has some theoretical advantages in decreasing psa levels (34.6-56% of the cases) (4, 5) thus minimizing the number of biopsies for falsely elevated psa (20-30% of the cases) (6, 7). the difference between pre and post-treatment psa levels appears significant only in benign conditions (bph and prostatitis cases) while in histologically proven original paper does prolonged anti-inflammatory therapy reduce number of unnecessary repeat saturation prostate biopsy? giuseppe candiano, pietro pepe, francesco pietropaolo, francesco aragona urology unit cannizzaro hospital, catania, italy. introduction. the effect of a prolonged oral anti-inflammatory therapy on psa values in patients with persistent abnormal psa values after negative prostate biopsy (pbx) was evaluated. material and methods. from september 2011 to september 2012, 70 patients (median age 62 years), with persistent abnormal psa values after negative extended pbx, were given an herbal extract with anti-inflammatory activity for 3 months (lenidase®; 1 tablet daily constituted of baicalina, bromelina and escina). all patients were submitted to prostate biopsy for: abnormal dre; psa > 10 ng/ml, psa values between 4.1-10 or 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively. three months after the end of anti-inflammatory therapy all patients were revaluated; indication for repeat saturation biopsy (spbx) and detection rate for pca were compared with those previously recorded in our department using the same inclusions criteria for biopsy. results. oral administration of lenidase® was well tolerated and no side effects were observed; psa values decreased in 54 (77.8%) out 70 patients with a median psa reduction of 20.5% (from 8.8 to 7 ng/ml) and remained unchanged in 16 patients (22.2%); the repeat spbx rate resulted significantly lower (22.8% vs 35.5%; p < 0.05) showing a superimposable detection rate for pca (3 cases) in comparison with our previous data (18.7% vs 22%). conclusions. in our preliminary data a prolonged oral anti-inflammatory therapy reduced psa levels in patients with negative pbx and persistent suspicious for pca decreasing the indication to perform repeat spbx (about 30% of the cases). key words: prostate cancer; repeat saturation biopsy; prostatitis; psa; anti-inflammatory therapy. submitted 24 september 2012; accepted 31 december 2012 no conflict of interest declared summary cancer the difference seems unremarkable (8). at the same time, the administration of nonsteroidal antiinflammatory drugs (nsaids) or aspirin, blocking the cyclooxygenase (cox) activity (a strong mediator of inflammation), could have a potential role in decreasing psa values. however, the relationship between oral nsaids consumption, psa levels and pca risk is unknown (9). in this prospective study we evaluated, in patients with negative extended prostate biopsy and persistent abnormal psa values, the effect of a prolonged oral antiinflammatory therapy on psa values in order to reduce the number of unnecessary repeat biopsies. candiano_stesura seveso 24/06/13 10:59 pagina 65 archivio italiano di urologia e andrologia 2013; 85, 2 g. candiano, p. pepe, f. pietropaolo, f. aragona 66 ously recorded in our department using the same inclusions criteria for biopsy. finally, a p value < 0.05 was considered statistically significant. results oral administration of lenidase® was well tolerated and no side effects were observed. among 70 patients enrolled, psa values decreased after anti-inflammatory therapy in 54 (77.8%) with a median psa reduction of 20.5% (from 8.8 to 7 ng/ml) and remained unchanged in the remaining 16 patients (22.2%). clinical parameters and serum exams before and after lenidase® administration are listed in table 1. all 16 patients whose psa did not decrease after therapy underwent repeat spbx (6 had a psa included between 4-10 ng/ml and 10 greater than 10 ng/ml) and in 3 of them a cancer was found (all these men had one previous negative biopsy and a psa > 10 ng/ml). the incidence of repeat biopsy in the patients submitted to anti-inflammatory therapy resulted significantly lower in comparison with our previous data (22.8% vs 35.5%) (p < 0.05), respectively; on the contrary, the detection rate for pca was superimposable (18.7% vs 22%) at repeat spbx. ipss and qmax values were superimposable before and after anti-inflammatory therapy (p > 0.05) (table 1). discussion repeat prostate biopsy constitutes about 30% of all the procedures with an estimated detection rate for pca equal, in our experience, to 20% and 6% at second and third spbx (10), respectively; today, the main goal of any early diagnosis protocol should be to reduce the number of unnecessary spbx due to false positive psa levels. the intra-individual (physiological) variation of psa in men with benign prostate biopsy is equal to 9.5% (12); moreover, many common medications have an effect on serum psa levels: nsaids, thiazide diuretics and statins reduce psa levels from 6% to 26% and the combination of statins with thiazide diuretics could decrease psa levmaterial and methods from september 2011 to september 2012, 70 patients (median age 62 years; range: 49-72 years), with previous negative extended prostate biopsy and persistent abnormal psa values, were given an herbal extract with antiinflammatory activity (lenidase®, 1 tablet daily) for 3 months. all patients, 2 months before assuming the herbal extract, underwent prostate biopsy for: abnormal digital rectal examination (dre); psa > 10 ng/ml, psa values between 4.1-10 or 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively according to our early diagnosis protocol (10). the biopsy was performed by transperineal approach using a 18 g tru-cut needle guided by a 5-6.5 mhz biplanar transrectal probe (ge logiq 500 pro). in case of primary biopsy or repeat saturation biopsy (spbx) a median of 18 (range 16-21) and 28 cores (range 26-35) were taken, respectively. the biopsy protocol included a median of 9-12 cores in the posterior zone of each lobe (apex, med and base) plus 2-4 cores on the transition zone in case of spbx (11). the procedure was performed under sedation and antibiotic prophylaxis. all patients had negative dre and no-one was symptomatic for acute prostatitis. patients with previous hgpin or asap were not included; moreover, all patients signed an informed consent form. clinical parameters of the patients enrolled in the protocol are listed in table 1; 37 (52.8%), 18 (25.7%) and 15 (22.5%) men previously underwent one, two and three negative biopsies, respectively. fifty-eight (64.5%) patients assumed alpha-blockers; none were currently treated with nsaids, aspirin, thiazide diuretic, statins, and 5-alfa-reductase inhibitors. at the end of the 3months course of therapy and after additional 3 months of wash-out, all patients were revaluated with dre, total psa, psa f/t and routine blood test for liver and kidney function. international prostate symptoms score (ipss) and qmax before and after anti-inflammatory therapy were recorded. the patients with persistent suspicious for pca underwent spbx. the repeat spbx rate after anti-inflammatory therapy and detection rate for pca were compared with those previ70 patients baseline after therapy % of reduction p value median psa (ng/ml) 8.8 (range: 4.6-28) 7 (range: 2.9-23) 20.5 < 0.05 decreased psa levels 54 77.2 < 0.05 psa > 10 14 10 28.5 < 0.05 psa 4-10 54 40 26.0 < 0.05 psa < 4 0 20 28.5 < 0.05 ipss (range) 13 (4-26) 12 (5-24) > 0.05 low (0-7) 36 38 > 0.05 intermediate (8-19) 25 23 > 0.05 severe (20-37) 9 9 > 0.05 qmax 11 ml/sec 12 ml/sec > 0.05 urine test negative negative blood test normal normal table 1. clinical parameters at baseline and 6 months after anti-inflammatory therapy. candiano_stesura seveso 24/06/13 10:59 pagina 66 67archivio italiano di urologia e andrologia 2013; 85, 2 does prolonged anti-inflammatory therapy reduce number of unnecessary repeat saturation prostate biopsy? anti-inflammatory therapy reduced psa levels in selected patients (negative prostate biopsy and persistent elevated psa values) decreasing the indication to perform repeat spbx (about 30% of the cases). references 1. nixon rg, lilly jd, liedtke rj, batjer jd. variation of free and total psa levels: the effect on the percent free/total prostate antigen. arch pathol lab med. 1997; 121:385-91. 2. yaman o, gogus c, tulunay o, et al. increased psa in subclinical prostatitis: the role of aggressiveness and extension of inflammation. urol int. 2003; 71:160-164. 3. kandirali e, boran c, serin e. association of extent and aggressiveness of inflammation with serum psa levels and psa density in asymptomatic patients. urology. 2007; 70:743-747. 2. hochreiter ww. the issue of prostate cancer evaluation in men with elevated psa and chronic prostatitis. andrologia. 2008; 40:130-133. 3. stopiglia rm, ferreira u, silva mm, et al. psa decrease and prostate cancer diagnosis: antibiotic versus placebo. prospective randomized clinical trial. j urol. 2010; 183:940-944. 4. magri v, trinchieri a, montanari e, et al. reduction of psa values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection. arch it urol androl. 2007; 79:84-92. 5. serretta v, catanese a, daricello g, et al. psa reduction (after antibiotics) permits to avoid or postpone prostate biopsy in selected patients. prostate cancer prostatic diseases. 2008; 11:148-152. 6. schaeffer aj, wu sc, tennenberg am, kahn jb. treatment of chronic bacterial prostatitis with levofloxacin and ciprofloxacin lowers serum psa. j urol. 2005; 174:161-164. 7. terrone c, poggio m, bollito e, et al. asymptomatic prostatitis: a frequent cause of raising psa. rec prog med. 2005; 96:365-369. 8. erol h, beder n, caliskan t, et al. can the effect of antibiotic therapy and anti-inflammatory therapy on serum psa levels discriminate between benign and malign prostatic pathologies? urol int. 2006; 76:20-26. 9. murad as, down l, davey smith g, et al. associations of aspirin, nonsteroidal-antiflammatory drug and paracetamol use with psadetected prostate cancer: findings from a large, population-based, casecontrol study (the protect study). int j cancer. 2011; 128:1442-48. 10. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14,453 patients. prostate cancer prostatic diseases. 2010; 13:316-319. 11. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 12. boddy jl, dev s, pike dj, malone pr. intra-individual variation of serum psa levels in men with benign prostate biopsies. bju int. 2004; 93:735-38. 13. nieder c, norum j, geinitz h. impact of common medications on serum total psa levels and risk group assignment in patients with prostate cancer. anticancer research. 2011; 31:1735-39. 14. steven l. chang, lauren c. harshman, and joseph c. presti jr: impact of common medications on serum total psa levels: analysis of the national health and nutrition examination survey j clin oncol. 2010; 28:3951-3957. 15. nieder c, norum j, geinitz h. impact of common medications els of 36% after 5 years of combined therapy (13-15). prostatitis is responsible for falsely elevated psa levels, but it remains unclear in which patients we can avoid repeat biopsy without underestimating the risk of cancer (16). singer et al. (17) in 1319 men aged > 40 years observed that psa levels were 24% lower among acetaminophen users compared with non drug takers. several systematic reviews have examined the relationship between nsaid/aspirin consumption and the risk of developing pca. mahmud et al. (18) in a meta-analysis found that aspirin use provided a 10% risk reduction for pca and a 30% risk reduction for advanced disease. harris et al. (19) and jacobs et al. (20) reported that daily nsaid use (including aspirin) was associated with a 39% and 20% risk reduction for pca, respectively. engelhardt and rjedl (21) reported in 20 patients, assuming a daily dose (60 mg) of an isoflavone extract for 1 year, a psa reduction of 33% combined with a significant increase in hepatic transaminases. all these studies agree that the reduction in psa levels due to anti-inflammatory therapy may reduce the number of men referred for prostate biopsy decreasing the number of men diagnosed with pca. however, a clear correlation between nsaids, serum psa and risk of missing a pca diagnosis is still unknown (16). in our study, we used as anti-inflammatory agent a mixture of herbal extract (lenidase®) which has a demonstrated antiedematous and anti-inflammatory activity. each tablet contains: baicalina (190 mg), a flavonoid from scutellaria baicalensis that inhibits 5-lipoxygenase (5-lox) and cox activities and leukotriene synthesis (22-24); bromelina (50 mg), extract from ananas comosus, that is an enzymatic anti-inflammatory agent and escina (30 mg), extract from aesculus hyppocastanum, that has an antiedemigenous effect and enhances corticosteroid receptors activity. a median psa reduction of about 20% was observed in 54/70 (77.2%) patients assuming lenidase®. in details, 15 (28.5%) men reached a psa value < 4 ng/ml and the repeat spbx rate resulted significantly lower in comparison with our previous data (22.8% vs 35.5%; p < 0.05) showing a superimposable detection rate for cancer (18.7% vs 22%). therefore, the significantly reduction of psa levels in comparison with physiological psa fluctuations (12) and the absence of reliable criteria to select patients at risk for pca seems to suggest a prolonged trial of anti-inflammatory therapy before taking any decision in patients with negative prostate biopsy and persistently elevated psa levels. our results deserve some considerations. firstly, the absence of a placebo control group; for our purpose, we used as a surrogate our previously recorded cases. secondly, it is unknown if psa reduction is uniquely secondary to the anti-inflammatory activity or is in some way influenced by anti-proliferative effects of baicalina (25); thirdly, pca incidence is available only in patients whose psa levels remained unchanged after anti-inflammatory trial (the risk of missing pca diagnosis in men with decreased psa is actually unknown). finally, a greater number of patients and a longer follow up are necessary to confirm our results. in conclusion, in our preliminary data a prolonged oral candiano_stesura seveso 24/06/13 10:59 pagina 67 archivio italiano di urologia e andrologia 2013; 85, 2 g. candiano, p. pepe, f. pietropaolo, f. aragona 68 on serum total psa levels and risk group assignment in patients with prostate cancer. anticancer res. 2011; 31:1735-39. 16. platz ea, rohrmann s, pearson jd, et al. nonsteroidal antiinflammatory drugs and risk of prostate cancer in the baltimore longitudinal study of aging. cancer epidemiol biomarkers prev. 2005; 14:390-396. 17. singer ea, palapattu gs, van wijngaarden e. psa levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen: results from the 2001-2002 national health and nutrition examination survey. cancer. 2008; 113:2053-7. 18. mahmud s, franco e, aprikian a. prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and metaanalysis. br j cancer. 2004; 90:93-99. 19. harris re, beebe-donk j, doss h, burr doss d. aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of nonselective cox-2 blockade. oncol rep. 2005; 13:559-583. 20. jacobs ej, thun mj, bain eb, et al. a large cohort study of longterm daily use of adult-strength aspirin and cancer incidence. j natl cancer inst. 2007; 99:608-615. 21. engelhardt pf, rjedl cr. effects of one-year treatment with isoflavone extract from red clover on prostate, liver function, sexual function, and quality of life in men with elevated psa levels and negative prostate biopsy findings. urology. 2008; 71:185-90. 22. burnett bp, jia q, zhao y, levy rm. a medical extract of scutellaria baicalensis and acacia catechu acts as dual inhibitor of ciclooxygenase to reduce inflammation. journal of medical food. 2007; 442-451. 23. lixuan z, jingcheng d, wengin y, et al. baicalin attenuates inflammation by inhibiting nf-kappab activation in cigarette smoke induced inflammatory models. pulm pharmacol ther. 2010; 23:411-19. 24. li c, lin g, zuo z. pharmacological effects and pharmacokinetics properties of radix scutellariae and its bioactive flavones. biopharm drug dispos. 2011; 32:427-45. 25. marks ls, dipaola rs, nelson p, et al. herbal formulation for prostate cancer. urology. 2002; 60:369-75. correspondence giuseppe candiano, md pietro pepe, md (corresponding author) piepepe@hotmail.com francesco pietropaolo, md francesco aragona, md urology unit cannizzaro hospital, via messina 829 catania, italy candiano_stesura seveso 24/06/13 10:59 pagina 68 archivio italiano di urologia e andrologia 2017; 89, 142 original paper urethroplasty with dorsal buccal mucosa graft. is it still the method of choice in long term urethral stenosis? carlo pavone, dario fontana, ninfa giacalone, nino dispensa, marco vella, alchiede simonato uoc urologia, dipartimento di discipline chirurgiche, oncologiche e stomatologiche, università degli studi di palermo, italy. the aim of our work was to evaluate the long-term changes in symptoms (median 42 months) and to analyze data for any negative predictive factors for the application of the procedure, in patients who underwent to urethroplasty with dorsal buccal mucosa graft. during the period from 2010 to 2015 27 patients were examined. than they underwent urethroplasty using dorsal buccal mucosa graft (graft of 4 x 2.5 cm). the evaluation of symptoms has been addressed through the application of the ipss quality of life questionnaire (international prostatic symptoms score) and the evaluation of urinary flow has been carried out by a comparative analysis between the preand post-operative uroflowmetry. as our study has shown, data obtained by the screening tests in the post-operative follow-up indicate that there is an increase in the maximum flow of urine until 1 month after surgery. the results in the long-term follow-up are different because they show a partial reduction of the maximum flow although it is maintained around an average value of 23 ml/s being still higher than the maximum flow in the pre-operative period. according to our results it follows that there is a low failure rate of the procedure after a median of 42 months. only in patients with urethral stenosis longer than 2 cm, a lower long term success is achieved. from what we could observe, this length of the stenosis seems to be the only negative predictive factor for long-term maintenance of a good quality of life in patients undergoing the procedure. the results obtained from our study confirm literature data according to which, the gold standard for 2-cm long bulbar urethral stricture whose lumen is well preserved with circumferential spongiofibrosis limited to 1-2 mm is the dorsal graft urethroplasty with buccal mucosa that in our study showed success rates higher of 80% after a median follow up of 42 months and a percentage of relapse-free patients of 82.1% ( median 3.5 years). key words: urethroplasty; urethral stenosis; urology; andrology. submitted 22 june 2016; accepted 7 september 2016 summary no conflict of interest declared. and a later stage characterized by sclerosis and fibrosis. the different anatomical structure of the urethra (anterior and posterior urethra) also explains the different causes of urethral stenosis between the two segments. today, the most common forms of stenosis are those involving bulbar urethra. in this tract, idiopathic stenosis tends to occur both in adolescents and in young adults, whereas iatrogenic stenosis could occur at any age due to catheterization, mainly in bulbar urethra junction and penis, or due to transurethral resection of the prostate (turp) at the proximal part of bulbar urethra. the pathogenesis has not yet been fully elucidated, histopathological studies of urethral stenosis have shown how the main change at the base of this process is the metaplasia of urethral epithelial which is the transition from a pseudostratified columnar epithelium to a stratified squamous epithelium (2). this change leads to an increased epithelial fragility especially during the distension caused by urination and so causes an extravasation of urine. this will lead to subepithelial fibrosis (3, 4). the formation and fusion of microscopic foci of fibrosis will lead in the following years the formation of macroscopic plaques, which will form a ring restricting totally the urethral lumen. the latest studies carried out the molecular level indicate that in the urethra there is a disproportionate deposition of type 1 collagen compared to type 3 collagen, which instead predominates in other fibrotic processes (5). this characteristic is more pronounced in the urethral stenosis due to traumatic than in non-traumatic stenosis (6), in which there is often a surprisingly high content of smooth muscle (4). it also appears that this spongiofibrosis process may be induced by the neuronal nitric oxide synthasel or by the over-expression of a growth factor of the connective tissue, identified as the cause of other fibrotic diseases (7). the urethral stenosis left untreated is a highly pathogenic substrate, as a result of chronic and recurrent infections or the establishment of high pressures during emptying the bladder, with the complications that may first concern the lower urinary tract and then the upper one. at lower urinary level, the organ more affected is definitely the bladder in which it could be observed a wall thickening, with formation of trabeculae and following sacculation of the bladder as well as to an incomplete emptying of the organ and to a possible occurrence of lithiasis. at upper urinary level a doi: 10.4081/aiua.2017.1.42 introduction the urethral stenosis is a scar of sub-epithelial tissue of the corpus spongiosum which narrows the urethral lumen. the incidence is approximately 1 case in 10,000 in men aged between 25 and 65 years, and 1 case in 1000 in men over 65 years of age. the process leading to urethral stenosis provides for an initial phase in which prevails the inflammatory or hemorrhagic component pavone_stesura seveso 04/04/17 09:17 pagina 42 43archivio italiano di urologia e andrologia 2017; 89, 1 urethroplasty with dorsal buccal mucosa hydroureteronephrosis process might occur developing renal failure (8). diagnostics plays a key role in the staging of urethral stricture disease, and in the planning of the most efficient therapeutic strategy. the clinical and radiological examinations used in the stenosis study are: urine culture, uroflometry, retrograde urethrogram, voiding cystourethrography, ultrasonography and urethroscopy. there is a large number of possible options for surgical treatment proposed over the time. the choices in the treatment of anterior urethral stenosis, depending on the place and the length of the stenosis, as well as by history of any previous surgeries, are: urethral dilation, endoscopic urethrotomy according to sachse or by the use of the laser, and the various techniques of reconstructive urethroplasty. materials and methods from 2010 to 2015, 27 patients underwent urethroplasty surgery using dorsal buccal mucosa graft (graft of 4 x 2.5 cm). after transurethral injection of methylene blue, the procedure involves a longitudinal skin incision on the perineal floor with blunt cutaneous dissection and section of colles fascia that allows the identification of bulbospongiosus muscles and their bilateral dissection. the corpus spongiosum of the urethra is so exposed making possible the isolation of the bulbar urethra and its subsequent lateralization. the dorsal urethral surface is rotated of 180°. this maneuver allows to incise the stenotic segment longitudinally throughout its length. the withdrawal of the buccal mucosa could be performed both before and/or after the perineal incision, and the taken patch is positioned and sutured at the level of the corpora cavernosa. the aim of our work was to evaluate longterm changes in symptoms (average 42 months) and to analyze data for any negative predictive factor for the success of the procedure in patients undergoing urethroplasty with dorsal buccal mucosa graft. the age of the analyzed sample was 43.2 years (range 2477). among the target population 3 patients (8%) have multiple stenosis, 1 patient (2%) an anterior penile stenosis, 4 patients (9.8%) membranous stenosis, and the remaining 19 patients (80.2%) a bulbar stenosis. the evaluation of symptoms was addressed by the application of the ipss quality of life questionnaire (international prostatic symptoms score), to highlight significant variation between pre-operative and postoperative period whereas for the evaluation of the urinary flow a comparative analysis was carried out between the preand post-operative uroflowmetry values with particular attention to the maximum flow rate (qmax) that showed a significant improvement, as it is explained below. results the obtained results from our work confirm literature data according to which, the gold standard for 2-cm long bulbar urethral stenosis in which lumen is well preserved and the circumferential spongiofibrosis is limited to 1-2 mm, is the dorsal graft urethroplasty with buccal mucosa, that showed in our study a high success rate of 80 % after a median follow up of 42 months and a percentage of relapse-free patients of 82.1% (median 3.5 years). as mentioned above, in our series replies to the ipss questionnaire related to quality-of-life before surgery showed an average score of 5.86, whereas in the post-operative period the average score was 3.4 during the 5-year follow-up period (figure 1). we particularly paid attention to values of maximum flow, which allowed us to see an improvement from an average of 7.4 ml/s (range 5-11 ml/s ) to reach a mean value of 23 ml/s (range 5-42 ml/s ) one month after surgery and of 21.16 ml/s in the fifth year following the procedure (figure 2). the ultrasound of corpus spongiosum did not demonstrate a significant change between the preand postoperative period. figure 1. ipss score related to the value of qmax during the preoperative period, 1 month after surgery and at long term (median of 3.5 years). figure 2. maximum pre-operative flow rate (qmax), one month after surgery, and long-term (median of 3.5 years). pavone_stesura seveso 04/04/17 09:17 pagina 43 archivio italiano di urologia e andrologia 2017; 89, 1 c. pavone, d. fontana, n. giacalone, n. dispensa, m. vella, a. simonato 44 conclusions taking into consideration the many and efficient treatment methods for urethral stenosis and the results obtained, we could state that at long-term follow-up of patients with urethral stenosis, the most successful technique is the urethroplasty with buccal mucosa graft. as our study has shown, the results of the examinations in the follow-up after surgery indicate that, as described above, there is an increase in the maximum flow of urine until one month after surgery. in the long-term follow-up we observed a partial reduction of the maximum flow, although the maximum flow was maintained at an average value of 23 ml/s, which was still higher than the maximum flow in the pre-operative period. according to our results, a low failure rate of the procedure was shown after an average of 42 months. only patients with urethral stenosis longer than 2 cm were slightly less successful. from what we could observe, only the length of the stenosis seemed to be the only negative predictive factor for long-term maintenance of good quality of life in patients undergoing this procedure. references 1. mundy ar. the treatment of sphincterstrictures. br j urol. 1989; 64:626-628. 2. chambers rm, baitera b. the anatomy of the uretra stricture. br j urol. 1977; 49:545-551. 3. meria p, anidjar m, brouland jp, et al. an experimental model of bulbar uretra stricture in rabbits using endoscopic rediofrequency coagulation. urology. 1999; 53:1054-1057. 4. singh m, blandy jp. the pathology of uretra stricture. j urol. 1976; 115:673-676. 5. baskin ls, constantinescu sc, howard ps, et al. biochemical characterization and quantification of the collagenous components of urethral stricture tissue. j urol. 1993; 150:642-647. 6. cavalcanti ag, costa ws, baskin ls, et al. a morphometric analysis of bulbar uretra strictures. bju int. 2007; 100:397-402. 7. zhang p, shi m, wei q, et al. increased expression of connective tissue grow factor in patients with uretra stricture. tohoku j exp med, 2008; 215:199-206. 8. romero perez p, mira llinaries a. complications of the lower urinary tract secondary to uretra stenosis. actas urol esp. 1996; 20:786-793. correspondence carlo pavone, md dario fontana, md dariofontana1987@yahoo.it ninfa giacalone, md nino dispensa, md marco vella, md alchiede simonato, md uoc urologia, aoup p. giaccone via del vespro 127 90100 palermo, italy pavone_stesura seveso 04/04/17 09:17 pagina 44 239archivio italiano di urologia e andrologia 2016; 88, 3 case report a rubber tube in the bladder as a complication of autoerotic stimulation of the urethra konstantinos stamatiou, hippocrates moschouris tzaneio hospital, pireas, greece. self-insertion of foreign bodies in the urethra is most commonly associated with sexual or erotic arousal of adolescents with mental health disorders. rarely it may practiced by healthy adults for masturbation. migration of foreign bodies used for the abovementioned purpose from the urethra to adjacent organs is a relatively uncommon urologic problem that may cause serious complications which arose tardive. presentation includes a variety of acute or chronic symptoms that depend of the underlying complications. the method of extraction depends on the shape, size and nature of the object and should be tailored according to the condition of the patient. in the present article we present a case of a rubber tube inserted to the urethra for erotic arousal purposes which migrated to the bladder during masturbation. key words: foreign bodies; urinary tract; fetishism. submitted 29 february 2016; accepted 25 april 2016 summary no conflict of interest declared. of a rubber tube inserted to the urethra for erotic arousal purposes which was migrated to the bladder during masturbation and its successful management. case report a 65-year-old man presented in the emergency department reporting a rubber tube placement in the urethra for sexual pleasure, for more than 36 hours. he reported no dysuria or pain after insertion. physical examination showed no evidence of foreign body in the urethra. laboratory findings revealed microscopic hematuria and mild pyuria in routine urine analysis, but the results of the complete blood count and electrolyte profile were normal. x-ray of the pelvis showed a coiled-up radio-opaque shadow in the bladder (figure 1). cystoscopy confirmed the presence of a red coloured plastic tube in the bladder lumen (figure 2). with the use of a crocodile type endoscopic grasper, rearrangement of the tube in order to facilitate its removal due to inconvenient positioning of the tube inside the bladder was successfully done under local anaesthesia and the tube was finally removed. length of tube was 23 cm (figure 3). no urethral and/or bladder trauma occurred. the complete extraction of the object was confirmed by both endoscopy and radiology at the end of the extraction procedure. postoperative period was uneventful. doi: 10.4081/aiua.2016.3.239 introduction insertion of foreign bodies in the urinary tract is a relatively common condition and is due to different aetiologies. it is usually iatrogenic in the upper urinary tract, however in the bladder and urethra it may equally be iatrogenic or due to self-insertion, and rarely due to migration from adjacent organs (1). self-insertion of foreign bodies in the urethra is an unusual condition and the reasons for it are difficult to comprehend. it is most commonly associated with sexual or erotic arousal of adolescents with psychiatric disorders. other reasons for urethral manipulation include, drug intoxication, mental confusion, sexual curiosity, sexual arousal and/or a desire to get relief from urinary symptoms. foreign bodies used for the above mentioned purpose may include flexible or rigid and fragile or strong materials such as needles, bullets and pens, as well as candles, gauzes, etc. migration from the urethra to adjacent organs is a relatively uncommon urologic problem. the foreign body can remain there for a long time with no or minimal discomfort. in most cases, however, the foreign body causes severe pain, hematuria, and urinary tract infection which rise tardive (2). treatment approach should also minimize urethral and/or bladder trauma and must ensure the complete extraction of the object. the last must be confirmed by radiology or endoscopy at the end of the extraction procedure. here, we report an interesting case figure 1. x-ray of the pelvis shows a coiled-up radio-opaque shadow in the bladder. stamatiou_stesura seveso 21/09/16 09:10 pagina 239 archivio italiano di urologia e andrologia 2016; 88, 3 k. stamatiou, h. moschouris 240 discussion healthy adult individuals rarely practice insertion of foreign bodies in the urethra. this practice in a sexual context concerns men with urethral manipulation fetishes which are commonly referred with the terms urethral sounding and urethral play. both can involve the introduction of either soft or rigid items into the meatus of the penis and farther in the urethra and the prostate. rigid objects such as sounds are usually only inserted about halfway into the glans and can usually be easily retrieved. in contrast, soft objects such as tubes and catheters may be introduced deeper. some items may even be allowed to curl several times or expand within the bladder. this action in the male may be directly or indirectly associated with stimulation of the prostate gland which produce erotic satisfaction (3). urethral manipulation may occur both actively or passively associated with fetishism or masochism respectively. persons who get sexually aroused from the self-insertion of objects into their urethra for autoerotic stimulation purposes falls to the first category and consist the majority of the cases. the second category concerns insertion of foreign bodies in the urethra via medical procedures requested by the person. although this behaviour shares features with masochism since very few of those who engage in such practices report pain, the association does not seem justified based on the clinical evidence reported (4). in our case, despite careful and discrete history taking it wasn’t possible to determine whether the rubber tube was inserted to the urethra by the patient or his sexual companion. according to the literature, a multitude of objects have been found in the urinary bladder. among others, tubes made of rubber are the most commonly used (5). in contrast to our case, most of the reported cases of foreign body insertion to the urinary tract are characterized by severe symptoms such as pain, hematuria, and urinary tract infection (6). in all cases however, careful history taking, physical examination and imaging evaluation are necessary in order to determine the size and location of the foreign body. this is of outmost importance for the selection of the appropriate method to remove the foreign bodies completely with the minimal damage to the bladder and urethra. similarly to our case, endoscopic management is reported to be successful however in a few cases open procedures such as suprapubic cystostomy, external urethrotomy or meatotomy are required (7). our patient refused psychiatric evaluation however it seems that motivation and associated psychosocial issues requires investigation since they are both important in order to prevent future episodes. ethical approval written informed consent was obtained from the patient for publication of this case report and its accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal on request. references 1. rieder j, brusky j, tran v, et al. review of intentionally selfinflicted, accidental and iatrogenic foreign objects in the genitourinary tract. urol int. 2010; 84:471-475. 2. van ophoven a, dekernion jb. clinical management of foreign bodies of the genitourinary tract. j urol. 2000; 164:274-87. 3. http://en.wikipedia.org/wiki/urethral_sounding. accessed on 05/03/2015 4. https://drmarkgriffiths.wordpress.com/tag/urethral-foreign-bodies/. accessed on 05/03/2015 5. cho ds, kim sj, choi jb. foreign bodies in urethra and bladder by implements used during sex behavior. korean j urol. 2003; 44:1131-1134. 6. moon sj, kim dh, chung jh. unusual foreign bodies in the urinary bladder and urethra due to autoerotism. int neurourol j. 2010; 14:186-189. 7. mitterberger m, peschel r, frauscher f, pinggera gm. allen key completely in male urethra: a case report. cases j. 2009; 2:7408. figure 3. the length of the red coloured rubber tube is 23 cm. correspondence konstantinos stamatiou, md stamatiouk@gmail.com tzaneio hospital 2 salepoula str. 18536 piraeus, greece hippocrates moschouris, md tzaneio hospital, pireas, greece figure 2. cystoscopy image of a red coloured rubber tube in the bladder lumen. stamatiou_stesura seveso 21/09/16 09:10 pagina 240 stesura seveso 25archivio italiano di urologia e andrologia 2015; 87, 1 original paper effectiveness on urinary symptoms and erectile function of prostamev plus® vs only extract serenoa repens raffaele marzano, nicola dinelli, valeria ales, maria antonella bertozzi andrology unit, santa chiara hospital, pisa, italy. prostatic inflammation is widespread in the male population. two groups of 50 patients each with symptoms of prostatic inflammation and ecocolordoppler indicative of prostatitis were identified. both groups were further subdivided into two subgroups (respectively a1, a2, b1, and b2). group a1 underwent therapy with oral levofloxacin 500 mg daily for 10 days plus co-treatment with oral serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®) daily for two months; group a2 with oral levofloxacin 500 mg daily for 10 days plus oral serenoa repens extract 320 mg/day for two months; group b1 specific antibiotic treatment for 10 days (included levofloxacin if sensitive) plus co-treatment with oral serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®) daily for two months; group b2 with specific antibiotic treatment for 10 days plus serenoa repens 320 mg/day for two months. the groups treated with prostamev plus® in comparison to the groups treated with serenoa repens extract (saw palmetto) achieved better improvements of both ipss score, urinary flow and sexual life. key words: prostatitis; urinary flow; erectile function. submitted 18 december 2014; accepted 31 january 2015 summary no conflict of interest declared. repens alone in reducing the symptoms of prostatitis in patients with inflammatory prostatitis (bacterial and nonbacterial) detected at ecocolor doppler. it was also evaluated the impact of this combination therapy on quality of life of individuals and their erectile function. materials and methods we identified two groups of 50 patients each, matched for age and symptoms of inflammation of the prostate and with ecocolor doppler of the prostate indicative of prostatitis. inclusion criteria were: age between 40 and 65 years, digital rectal examination (dre) negative for prostate cancer, ecocolor doppler indicative for prostatitis at enrollment, ipss > or = 15, prostatic volume < 60 ml, rpm < 50 ml, reported normal libido and testosterone levels between 1.75 and 7.80 ng/ml. exclusion criteria: ongoing therapy with alpha-lytic, finasteride, dutasteride or tadalafil; presence of kidney or bladder stones, neurogenic bladder, bladder diverticulum, urethral stricture, bladder or prostate cancer, recent abdominal surgery, psychiatric therapy. group a consisted of patients (mean age 58.2) with urethral swab or seminal culture negative for common germs, mycoplasma and chlamydia; group b (mean age 57.9) included patients with microbiology positive for e. coli and enteorcoccus faecalis. both groups were further divided into two subgroups (respectively a1-a2 and b1-b2) which were subjected to different treatments. thus we obtained four sub-groups of 25 subjects each. the treatments administered are shown in table 1. during the study, 6 patients were excluded from follow up due to the need to take other drugs or for other personal reasons. all patients were assessed at enrollment and after two months with uroflowmetry, evaluation of post-voiding volume (pvv), ipss (international prostatic symptoms score), nih-cpsi (national institute of healthchronic symptom index) and iief-5 (international index of erectile function-5). the efficacy of treatment within each subgroup was assessed by t test for paired data (within each group, comparing data before and after treatment). the comparison between the different groups was performed using chi-square test. doi: 10.4081/aiua.2015.1.25 introduction prostatic inflammation is very common and it is a frequent presentation to our outpatient urological and andrology clinic. however, patients, despite the evidence of inflammation at color doppler examination of the prostate, often show negative results of seminal culture or urethral swabs. for this reason the presence of positive laboratory findings cannot be considered essential for the diagnosis of prostatitis. serenoa repens (sr) is a remedy for prostatitis which is recognized in the literature showing effectiveness in both patients with prostatic hyperplasia (bph) and in those with prostatic volume in the normal range. several products on the market associate serenoa repens to other substances with antiinflammatory action. the aim of the study is to evaluate the effectiveness of cotreatment with serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®) in comparison to serenoa marzano_stesura seveso 02/04/15 10:17 pagina 25 archivio italiano di urologia e andrologia 2015; 87, 1 r. marzano, n. dinelli, v. ales, m.a. bertozzi 26 results uroflowmetry (qmax): patients in group a1 showed an improvement of the average value of qmax from 23 ml/sec to 29 ml/sec (+ 26%), while in the group a2 average value of qmax rose from 22 ml/sec to 26 ml/sec (+ 18%). patients in group b1 showed an improvement of the average value of qmax from 19 ml/sec to 24 ml/sec (+ 28%), while in the group b2 qmax increased from 21 ml/sec to 25 ml/sec (+ 20%). therefore the groups a1 and b1 showed an higher overall improvement than the groups a2 and b2 (both groups showed significant increases in flow after 2 months of therapy). post voiding volume (pvv) not statistically significant improvements were observed (p > 0.1). ipss all groups showed a reduction of mean ipss score after treatment, although of limited clinical significance. nih-cpsi results of nih-cpsi scores are listed in table 2. iief-5 finally, patients of groups a1, b1 and b2 showed an improvement of sexual life according to the iief-5 questionnaire by an average of about 10% in comparison to 4% of the group a2. discussion the groups treated with serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®), with or without antibiotic therapy, showed an improvement in all parameters compared to the groups treated with saw palmetto, with or without associated antibiotic therapy. this effect could be explained by the effectiveness of the combination of serenoa repens, bromeline and nettle. bromeline has mainly an anti-inflammatory effect and is particularly effective in localized inflammation especially in the presence of edema. the use of bromeline is safer than other anti-inflammatory drugs due to the difference in the mechanism of action. in fact, conventional non steroidal anti-inflammatory drugs (nsaids) inhibit cyclooxygenase, so blocking the synthesis of prosta glandins. on the contrary, bromeline “hijacks” this synthesis, increasing the production of prostaglandins with anti-inflammatory activity to the detriment of those with pro-inflammatory activity thereby preventing the gastrointestinal damage typical of nsaids. this difference in the mechanism of action explains the synergy that it may have with nsaids, thus obtaining an enhancement of their anti-inflammatory effects. furthermore it is known its synergism with antibiotic and anticancer therapies. nettle (urtica dioica) confirmed a synergistic action with antibiotics in prostatitis (10-12). conclusions both groups of patients treated with the combination of serenoa repens, bromeline and nettle in association with antibiotic therapy showed an improvement in all the table 1. treatment administered. group a1 = levofloxacin 500 mg daily for 10 days + serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®) daily for two months. group a2 = levofloxacin 500 mg daily for 10 days + serenoa repens (320 mg)/day for two months. group b1 = specific antibiotic treatment for 10 days (including levofloxacin if sensitive) + co-treatment with serenoa repens (320 mg) plus bromeline plus nettle (prostamev plus®) daily for two months. group b2 = specific antibiotic treatment for 10 days + serenoa repens (320 mg)/day for two months. figure 1. results of uroflowmetry. figure 2. data about sexual life. pain micturition quality of life (t0/2 months) (t0/2 months) (t0/2 months) a1 8.1/5.2 7.5/5.4 10.2/6.3 a2 8.2/5.5 7.1/5.3 9.7/7 b1 8.7/4.5 8.2/4.7 8.9/5.5 b2 8.5/5.7 7.1/5.8 8.5/6.1 table 2. results of nih-cpsi (n° of cases = 96). marzano_stesura seveso 02/04/15 10:17 pagina 26 27archivio italiano di urologia e andrologia 2015; 87, 1 effectiveness on urinary symptoms and erectile function of prostamev plus® vs only extract serenoa repens parameters considered in this study after 2 months of therapy. the advantage of using a co-treatment that associates nettle and bromeline to saw palmetto is evident both in the improvement of flowmetry values and in the scores of iief-5 and nih-cpsi questionnaires (groups a1 and b1 vs a2 and b2). there were no reported side effects in addition to those provided for the simple antibiotic therapy. the groups treated with the combination of serenoa repens, bromeline and nettle obtained substantial improvements from the point of view of sexual life. references 1. giulianelli r, et al. multicentre study on the efficacy and tolerability of an extract of serenoa repens in patients with chronic benign prostate conditions associated with inflammation. arch ital urol androl. 2012; 84:94-98. 2. lowe fc, et al. phytotherapy in treatment of benign prostatic hyperplasia: a critical review. urology. 1996; 48:12-20. 3. bent s, et al. saw palmetto for benign prostatic hyperplasia.n engl j med. 2006; 354:557-66. 4. barnes, et al. saw palmetto, serenoa repens. also known as serenoa serrulata, sabal serrulata and the dwarf palm. j prim healt care. 2009; 1:323. 5. debruyne f1, boyle p, calais da silva f, et al. evaluation of the clinical benefit of permixon and tamsulosin in severe bph patientspermal study subset analysis. eur urol. 2004; 45:773-9. 6. carraro jc, et al. comparison of phitotherapy (permixon) with finasteride in the treatment of benign prostatic hyperplasia: a randomized international study of 1098 patients. prostate. 1996; 29:231-40. 7. debruyne, et al. comparison of phitotherapy (permixon) with an alpha-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. eur urol. 2002; 41:497-506. 8. gerber gs. the role of a lipido-sterolic extract of serenoa repens in the mamagement of lower urinary tract symtoms associated with benign prostatic hyperplasia. bju int. 2004; 94:338-44. 9. schaeffer aj. chronic prostatitis collaborative research network. overview summary statement. diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (cp/cpps). urology 2002; 60:1-4. 10. pavone c, abbadessa d, tarantino ml, et al. associating serenoa repens, urtica dioica and pinus pinaster. safety and efficacy in the treatment of lower urinary tract symptoms. prospective study on 320 patients. ]. urologia. 2010; 77:43-51. 11. giannarini g, autorino r. re: serenoa repens associated with urtica dioica (prostamev) and curcumin and quercitin (flogmev) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study. int j antimicrob agents. 2009; 34:283-4. 12. cai t, mazzoli s, bechi a, et al. serenoa repens associated with urtica dioica (prostamev) and curcumin and quercitin (flogmev) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study. int j antimicrob agents. 2009; 33:549-53. correspondence raffaele marzano, md nicola dinelli, md (corresponding author) n.dinelli@ao-pisa.toscana.it valeia ales, md maria antonella bertozzi, md, director andrology unit, santa chiara hospital, pisa, italy marzano_stesura seveso 02/04/15 10:17 pagina 27 53archivio italiano di urologia e andrologia 2013; 85, 1 introduction erectile dysfunction (ed) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. surgical treatments are still reserved for men who cannot use or fail to respond to first and second line treatments. the insertion of a penile prosthesis (pp) provides an acceptable, definitive solution for ed. although rare, pp is still subject to complications in the form of infection, erosion or mechanical failure. isolated pump erosion without proven infection is an extra challenging problem for the surgeon. herein, we describe our experience with malleable pp substitution to address isolated pump erosion. case report a 60-year-old patient with ed secondary to adult onset of diabetes mellitus underwent implantation of an inflatable pp (american medical systems 700 controlled expansion) via a scrotal approach nearly one year ago. he was on insulin daily treatment and his preoperative glycosylated hemoglobin was 8.4%. preoperative prophylaxis was achieved by vancomycin (500 mg) and gentamicin (80 mg) injections. strict sterile protocol, reduced operative time and minimization of hospital stay case report isolated pump erosion of an inflatable penile prosthesis through the scrotum in a diabetic patient raidh a. talib, ahmad shamsodini, emad a. salem, onder canguven, abdulla al ansari urology department hamad general hospital, doha, qatar. isolated pump erosion is a rare complication in patients with inflatable penile prosthesis. we describe a case of a diabetic patient who underwent inflatable penile prosthesis implantation with subsequent isolated pump erosion. repeated attempts of conservative repair of the erosion failed. finally, the inflatable penile prosthesis was replaced with a malleable one to avoid new pump erosion. in case of isolated pump erosion, replacement of the inflatable penile prosthesis with a malleable one looks to be a good alternative salvage treatment for the patient. key words: penile prosthesis; pump erosion; diabetes. submitted 26 september 2012; accepted 31 december 2012 no conflict of interest declared summary were achieved. early postoperative days passed uneventful. wound healing was a bit delayed without any sign of infection. on postoperative day 15, after implantation, the patient started to complain from scrotal skin abrasion around the tip of pp pump with erythema, just far from the incision site. on examination, the pump was adherent to the skin with slight red discoloration over the pump site which then became dark in color (figure 1). by that time, no signs of infection appeared at any other site of the pp components, no penile pain over the cylinders, and no mechanical problems with inflation or deflation of the pp were noticed. the leukocyte count was also normal. dark red area over to pump site started to form incrustation, which has fallen later on leaving an ulcer (figure 2). swabs were taken in two different times from around the pump and sent for culture that later revealed negative results. on postoperative day 30, after implantation, patient was admitted to hospital for relocation of pump, because the described ulcer widened and impending perforation was noticed. under general anesthesia, complete excision of the ulcerated area was performed. the pump was placed to a new created space behind the testes. the wound was closed in layers and the pump was kept away talib_stesura seveso 18/04/13 12:07 pagina 53 archivio italiano di urologia e andrologia 2013; 85, 1 r.a. talib, a. shamsodini, e.a. salem, o. canguven, a. al ansari 54 and separated by several layers from the skin. on postoperative day 20, after the relocation of pump, the erosion reurred. under local anesthesia, the new small ulcer was managed and closed in layers. on postoperative day 30, after the relocation of pump, the same sequence occurred for the third time ending in pump protrusion through the scrotal skin (figure 3). the patient was admitted for a salvage therapy eighty days after the pp implantation. finally, the inflatable pp was replaced by a malleable one (coloplast genesis) to avoid further complications. patient was empirically covered with vancomycin and gentamicin at time of admission and at time of surgery and underwent a thorough washout procedure as described by mulcahy (1). the scrotal erosion site was loosely approximated with chromic sutures and was left to heal. penrose drain was left just overnight. patient was sent home on outpatient antibiotics (ciprofloxacin 500 mg orally twice/day for two weeks and ceftriaxone 1 g intramuscular twice/day for seven days). a 9-month follow-up revealed no further problems. discussion our patient who had inflatable pp implantation developed isolated pump erosion on the scrotal skin. all endeavors to repair the pump erosion have failed with occurrence of the same problem. total replacement of the inflatable pp with a malleable one showed to be a good choice to overcome isolated pump erosion. nearly 40 years ago, small et al. described paired sponge filled semirigid silicone pp for ed which could not be treated by means of medical therapies (2). today’s pp can broadly be divided into inflatable and non-inflatable devices. predictably, pps are employed less often than medical therapies, but when utilized, satisfaction is almost always excellent. unfortunately, the most worrisome postoperative complication is infection and erosion of pp (1, 3). isolated pump erosion through scrotal skin, to the best of our knowledge, has been discussed in few articles (4-6). sawczuk and wechsler were the first who reported isolated erosion of the pump of an inflatable pp through the scrotum in a diabetic patient (6). the same group was also the pioneers of insertion of malleable pp at the same sitting (6). lately, kohler et al. reported results of six patients with isolated scrotal pump erosion or infection in patients with inflatable pp (4). the latter group also suggested the malleable pp substitution technique provides an excellent option for management of isolated scrotal pump erosion or infection. there are several described options for pump erosion, which include isolated removal and re-implantation of the scrotal pump, removal of the entire device with delayed re-implantation or immediate re-implantation. although isolated removal and re-implantation of the scrotal pump is rarely described, in the largest published series, four out of four cases failed (7). previous literatures clearly show that when tissue necrosis is occurring, the best option is to remove the prosthesis to relieve any pressure in the wound especially in diabetic patients. the pressure might be contributing to diminished blood supfigure 1. figure 2. figure 3. talib_stesura seveso 18/04/13 12:07 pagina 54 55archivio italiano di urologia e andrologia 2013; 85, 1 isolated pump erosion of an inflatable penile prosthesis through the scrotum in a diabetic patient references 1. mulcahy jj. treatment alternatives for the infected penile implant. int j impot res. 2003; 15(suppl 5):s147-9. 2. small mp. small-carrion penile prosthesis: a report on 160 cases and review of the literature. j urol. 1978; 119:365-8. 3. wilson sk, zumbe j, henry gd, et al. infection reduction using antibiotic-coated inflatable penile prosthesis. urology. 2007; 70:337-40. 4. kohler ts, modder jk, dupree jm, et al. malleable implant substitution for the management of penile prosthesis pump erosion: a pilot study. j sex med. 2009; 6:1474-8. 5. fitch wp, 3rd, roddy t. erosion of inflatable penile prosthesis reservoir into bladder. j urol. 1986; 136:1080. 6. sawczuk i, wechsler m. erosion of the pump mechanism of an inflatable penile prosthesis through the scrotum in a diabetic patient. j natl med assoc. 1985; 77:577-8. 7. wilson sk, delk jr, 2nd. inflatable penile implant infection: predisposing factors and treatment suggestions. j urol. 1995; 153:659-61. ply to the necrotic area. since the immediate implantation of malleable pp eliminates the risk of consequent scarred corpora cavernosa secondary to removal of inflatable pp, it was successfully performed in other studies (4). however, it should also be noted that the malleable pp substitution is not a recommended technique if there is evidence of infection or erosion of the penile components of the prosthesis (4). although studies conducted for pp surgeries showed lower device complication rates, complications of pp included infection, hematomas, erosions, and malpositioning of the components. fortunately, isolated pump erosion was described in a small number of cases. however, diabetic patients, in particular, should be warned of the possibility of developing pump erosion through the scrotal skin. in case of isolated scrotal pump erosion, the malleable pp implantation provides a good option for management of this bothersome issue. correspondence raidh a. talib, md ahmad shamsodini, md emad a. salem, md abdulla al ansari, md urology department hamad general hospital, 3050 doha, qatar onder canguven, md (corresponding author) associate professor urology department hamad general hospital, 3050 doha, qatar ocanguven@yahoo.com talib_stesura seveso 18/04/13 12:07 pagina 55 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 138 review herbal medicines for urinary stone treatment. a systematic review elena monti 1, alberto trinchieri 2, vittorio magri 3, anne cleves 4, gianpaolo perletti 5, 6 1 department of biotechnology and life sciences, università degli studi dell'insubria, busto a., italy; 2 urology unit, a. manzoni hospital, lecco, italy; 3 urology secondary care clinic, asst-nord, milano, italy; 4 cancer research wales library, cardiff university velindre hospital, cardiff, uk; 5 department of basic medical sciences, faculty of medicine and medical sciences, ghent university, ghent, belgium. 6 department of biotechnology and life sciences, section of medical and surgical sciences, università degli studi dell'insubria, busto a., italy. objective: to analyze the clinical evidence on the efficacy of phytotherapy in the treatment of calculi in the urinary tract. methods: to be eligible, full-length articles should include the results of randomized controlled trials enrolling patients affected by urolithiasis, reporting any comparison between an experimental herbal agent versus placebo or any active comparator, aimed at preventing the formation or facilitating the dissolution of calculi in any portion of the urinary tract. fifteen databases were searched for relevant references. the primary outcomes investigated were (i) the reduction of stone size and/or number and (ii) the urinary excretion rates of calcium, urate, or oxalate. the secondary outcome of the review was the adverse effects (ae) of treatment. risk of bias (rob) and quality of the evidence were assessed according to cochrane and grade guidelines. we performed a randomeffect meta-analysis. results: 541 articles were retrieved and 16 studies were finally confirmed as eligible. multiple cochrane rob tool items were rated as having high risk of bias in each analyzed trial report. pooled analysis of continuous data could be performed for three different comparisons: (i) phytotherapy versus citrate as single agent (ii) phytotherapy versus placebo, (iii) preparation of didymocarpus pedicellata (dp) -combined with other herbal agentsversus placebo. results showed that citrate is superior to phytotherapy in significantly decreasing both the size of urinary stones (mean difference: phytotherapy, 0.42 mm higher; 95% ci: 0.23 to 0.6; z = 4.42, p < 0.0001; i2 = 30%) and the urinary excretion rate of urate (mean difference: 42.32 mg/24h higher, 95% ci: 19.44 to 65.19; z = 3.63, p = 0.0003; i2 = 96%), assessed after 3 months on-therapy. no significant differences in the excretion rates of urinary calcium or oxalate were found. the dp preparation was superior to placebo in inducing total clearance (risk ratio: 6.19, 95% ci: 2.60 to 14.74; z = 4.12, p < 0.0001; i2 = 0%) and size reduction (mean difference: dp preparation, 4.93 mm lower; 95% ci: -9.18 to -0.67; z = 2.27, p = 0.02; i2 = 99%) of renal and ureteral stones after 3 months of therapy. no significant differences in the inter-arm variation of excretion rates of urinary calcium or urate were found as result of the pooled phytotherapy-placebo comparison. herbal remedies were in general devoid of side effects and in few cases citrate appeared to induce gi disturbances in a higher fraction of patients. most reports did not provide inferential data concerning ae, and meta-analysis was not feasible. conclusions: citrate is more effective than phytotherapy in decreasing the size of existing calculi in the urinary tract and summary no conflict of interest declared. introduction the overall incidence of stone disease in the urinary tract appears to be increasing worldwide, though such increasing trend is sometimes debated (1). the lifetime prevalence of urolithiasis has been estimated to be 13% among men and 7% among women in western countries, though figures are not always univocal (2). a 2010 study in asymptomatic subjects assessed a prevalence of lithiasis of the urinary tract in 7.8% of all cases, occurring more frequently in males (9.7% vs 6.3% in females) (3). in italy the prevalence of urolithiasis is 4.14%, with men (4.53%) slightly outnumbering women (3.78%), and shows a positive correlation with increasing age (4). urolithiasis is characterized by frequent recurrence, especially in the presence of untreated metabolic disorders, recurrent urinary tract infections, anatomical abnormalities or insufficient hydration. the composition of urinary calculi depends on the specific nucleation process triggered by calculogenic seedcrystals in supersaturated urines. stone nucleation is often ph-dependent and may occur in the presence of metabolic abnormalities like hypercalciuria, hyperoxaluria and hyperuricosuria. calcium-containing stones, like calcium oxalate monohydrate/dihydrate and calcium phosphate (brushite, apatite) calculi, are the most common, occurring approximately in 80% of cases (5). magnesium ammonium phosphate calculi (struvite) occur in 10-15% of cases, followed by uric acid (3-10%) and cystine/xantine stones (0.5-1%), though these figdoi: 10.4081/aiua.2016.1.38 in decreasing the urinary excretion rate of uric acid. a preparation containing didymocarpus pedicellata combined with other herbal agents induces stone size reduction and clearance significantly better than placebo. mayor limitations in the applicability of these results are the low quality of the evidence and the multiple sources of bias assessed in the studies included in the present review. key words: urolithiasis; nephrolithiasis; urinary or kidney stones; urinary or kidney calculi; phytotherapy; herbal remedies; plant extracts; clinical trials. submitted 22 january 2016; accepted 15 february 2016 perletti_stesura seveso 08/04/16 11:28 pagina 38 39archivio italiano di urologia e andrologia 2016; 88, 1 herbal medicines for urolithiasis ures are markedly affected by geographic location, age, gender, ethnicity and even meteorological factors (6). in symptomatic cases, the type of intervention depends mainly on the size and location of the calculi. procedures like extracorporeal shock wave lithotripsy (eswl), or more invasive interventions like ureteroscopy or percutaneous nephrolithotomy are performed, depending on the size and composition of the stone, and the general condition of the patient (7, 8). in asymptomatic subjects with small-sized stones, watchful waiting is a frequently recommended strategy (9). surveillance is often associated with administration of agents aimed at preventing the formation of new calculi, or at facilitating the reduction of existing ones. moreover, as recurrence is a major clinical issue in postsurgery patients, secondary prevention strategies are often based on increased fluid intake and diuresis, aimed at preventing supersaturation of stone components. the armamentarium for existing stone reduction or new stone prevention appears to be quite limited. the european association of urology 2015 urolithiasis guidelines recommend chemolysis of uric acid stones with alkalinizing agents like citrate or bicarbonate as the only treatment with documented efficacy (grade a recommendation) (9). citrate raises urinary ph and can also decrease urinary calcium excretion and bind calcium in a soluble complex, which reduces calcium salt supersaturation. furthermore, citrate inhibits crystal formation, growth and aggregation. a number of herbal extracts and remedies have been tested in vitro or in preclinical in vivo models to assess their activity as chemolytic agents, or as agents preventing new stone formation. a number of clinical studies have also been performed to investigate the efficacy of various herbal remedies in the primary/secondary management of urolithiasis. however, extensive adoption of herbal remedies for urolithiasis is at present hampered by uncertain results of studies not always adequately powered. our work was aimed at systematically reviewing the existing literature in this field and, where possible, to perform meta-analysis of data. materials and methods this review was prepared following the prisma checklist wherever possible (10), within the word count limit established by the present journal. no funding was received to support the present research or the preparation of this report. eligibility criteria studies, participants, interventions we included randomized controlled trials (rct), with an open-label or single/double-blinded design, enrolling patients of both sexes, affected by active urinary stone disease (stones of any size, or post-lithotripsy stone fragments present in the urinary tract). we included only full-text articles written in english, reporting comparisons between any experimental herbal agent (or a supplement or preparation containing, among other components, a herbal extract/derivative), combined or not with other medicines, and placebo or any active comparator (herbal or non-herbal), aimed at preventing (primary or secondary prevention) the formation or facilitating the dissolution of calculi in any portion of the urinary tract (nephrolithiasis, ureterolithiasis or cystolithiasis). we excluded from this systematic review (i) observational studies, case-control studies, non-controlled studies, dose-finding studies, studies exclusively aimed at assessing drug toxicity (e.g., phase i studies), studies on healthy volunteers; (ii) studies investigating phytotherapy agents not directly preventing or inducing the dissolution of urinary calculi (antibacterials, disinfectants, analgesics, spasmolytics, etc.), or agents facilitating the expulsion of calculi during a renal colic (e.g.: endpoint: expulsion time), or agents “protecting” the kidney parenchyma or ureters from lesions induced by calculi or surgical devices (stents), or agents prepared with fossilized plants or organisms as single therapy; (iii) studies on “aromatherapy”, homeopathy, or similar “alternative medicine” procedures, or interventions performed by non-medical healers; (iv) studies not using official taxonomic or galenic terms -but rather local or unofficial jargonfor describing herbal agents. outcomes the primary outcomes considered for this review were (i) the reduction of stone size and/or number (number of residual or ejected calculi, or fragments of calculi, or stone-free rates or analogous endpoints), and (ii) the urinary excretion rates of calcium, urate, or oxalate. the secondary outcome of the review was the adverse effects (ae) of treatments. search strategy and study selection published study reports and supplementary material were identified by searching 15 relevant databases and trial registry platforms, including medline, premedline, embase, cochrane library, web of science and cinahl. no date or language restrictions were applied and all searches were assessed as up to date on december 14th, 2015. an additional pubmed search for e-publications ahead of print was also performed. search strategies and results are available as on-line supplementary material to the present review. quality assessment the risk of bias (rob) of included studies was assessed by two independent reviewers using the cochrane collaboration tool (11), and was graded as high, low, or unclear. the quality of the evidence resulting from analysis of pooled data was evaluated according to the grade framework (12), and reported in a summary of findings (sof) table (table 1). data collection and statistical analysis data extraction was performed by three independent reviewers, using identical extraction tables. to analyze dichotomous data (e.g., number of stone-free patients at specific study time points) we extracted the number of per-protocol or intent-to-treat patients and calculated risk ratios (rr). to perform pooled analyses of continuous data (e.g., average stone size), mean differences were calculated. analyses included the calculation of 95% perletti_stesura seveso 08/04/16 11:28 pagina 39 archivio italiano di urologia e andrologia 2016; 88, 1 e. monti, a. trinchieri, v. magri, a. cleves, g. perletti 40 confidence intervals (ci), and z statistics. we analyzed only available information (available case analysis), without adopting bias-prone imputation strategies for missing data. for analysis of pooled data we used a randomeffects model. heterogeneity was assessed by calculating the i² value. given the small number of studies we did not employ formal methods to explore heterogeneity, to analyze sensitivity or to assess for publication bias. data analysis was performed using the revman 5.3 software. results search and study selection a total of 541 references were retrieved from the database searches, after de-duplication. details are featured in the supplementary material on-line. three independent reviewers selected 25 articles, which were considered of interest to the present review on the basis of title and abstract content. nine articles were excluded after fulltext screening and 16 study reports were finally included in the present review (13-28). among these reports, three lacked efficacy data of interest for the present review (15, 16, 21), and were only evaluated with respect to the risk of bias and adverse effects of treatment. on-line table 1 summarizes the design of the included studies, the number of randomized patients, the experimental interventions, patient dropouts and other study details. risk of bias in included studies figure 1 summarizes the rob evaluations for the included studies. on-line table 2 presents the complete risk of bias assessment for the present review. six trial reports disclosed the randomization strategy. in five cases the rob was low, as adequate randomization techniques were adopted (15, 16, 20, 24, 26). one study adopted block randomization, allowing foreknowledge of the allocation in a fraction of patients (high rob; 21). ten trial reports did not disclose the randomization strategy (unclear rob; 13, 14, 17-19, 22, 23, 25, 27, 28). allocation concealment was deemed as appropriate in three cases (low rob; 15, 16, 27), whereas in two cases the rob was rated as high (21, 24). the rob was unclear in the remaining studies, as concealment strategies were not provided or not easy to interpret. nine trials adopted an open-label design, having high risk of performance bias (13, 14, 17, 18, 22-25, 28). in two studies, 30% and 10% of patients could unmask the allocation by recognizing the peculiar taste of the experimental agent (high rob, 15, 16). six studies were double-blinded, and showed a low risk of performance bias (19-21, 26-28). in six studies assessing physicians were blinded to treatment allocation (low risk of detection bias, 15, 16, 19, 20, 22, 24). five more studies were rated as having high risk of attrition bias. in three cases, no explanation was given concerning incomplete efficacy data (15, 16, 22). in the upadhyay et al. study, no information is given about data from 8 patients that were randomized, but apparently did not complete treatment (28). in the shekar kumaran study no details were given as to whether any censoring was applied to the data pertaining to four patients who discontinued treatment in the placebo group (26). high risk of selective reporting bias was assessed in fourteen studies (14-21, 23-28). among these studies, eleven lacked statistical analysis and inference of key efficacy endpoints, including key comparisons between treatment arms (14-16, 19, 21, 23-28). all sixteen studies were characterized by a high rob linked to the study design, or to baseline imbalances in the clinical presentation of patients, or to the lack of adequate sample size and study power analyses. the detailed rationale for these evaluations is listed in the rob table (on-line table 2) featured in the on-line supplementary data for the present review. the number of pooled studies was too little to allow the evaluation of publication bias and small-study-size effects by visual inspection of funnel plots. effects of interventions a total of 928 patients were randomized to experimental (n = 466) or control interventions (placebo/active drug; n = 415). disclosed dropouts were 46, (one patient missing). in one study, four patients in the placebo cohort withdrew from the trial during treatment, but it appears figure 1. risk of bias summary for the present review. green circles (+) represent low risk of bias; red circles (-) represent high risk of bias; blank spaces indicate unclear risk of bias. perletti_stesura seveso 08/04/16 11:28 pagina 40 41archivio italiano di urologia e andrologia 2016; 88, 1 herbal medicines for urolithiasis that data from these dropped-out patients were included in data analysis, though the trial report does not mention an intent-to-treat design (26). in another study, 72 patients were randomized, but data from 32 patients per-cohort (64 in total) are presented; no information is given about the remaining 8 subjects (28). in the following paragraphs significant differences in outcome measures of interest for this review will be summarized. study reports not allowing full evaluation of results due to incomplete efficacy data, or claiming interarm “significant difference” without showing statistical inference results (e.g. significance probability, or 95% ci), are not included in this section and are rated as having a high risk of reporting bias. changes in stone size ten studies included changes in stone size as primary or correlate endpoint (13, 19, 20, 22-28). the published reports of six of these studies didn’t disclose intergroup statistical inference (19, 23, 24, 26-28). in one study comparing crataeva magna plus musa paradisiaca vs. placebo, patients were divided in two groups, according to the stone size (group a, 5 to 10 mm; group b, > 10 mm) (20). in group a, a 33.04% reduction in size was documented in the active arm, versus a 5.13% increase in the placebo arm (p = 0.017). in the largestone group b, no significant inter-arm differences in size reduction were found. a study comparing orthosiphon grandiflorus infusions with citrate evaluated the rate of stone size reduction per year (rosrpy) at different time-points (2, 5, 7, 10, 13, 18 months). no significant differences were found between treatment arms at any study time-point (22). in a study comparing agropyrum repens extract plus potassium citrate, allopurinol, amiloride-hydrochlorothiazide and pyridoxine versus the same combination without the herbal extract, a significantly greater reduction of stone size in the former arm was claimed (-3.6 ± 0.9 mm vs 0.0 ± 0.8 mm; only 95% ci provided) (13). in a study by singh et al., it was shown that celosia argentea, a putative litholytic agent, can reduce stone size to a greater extent than citrate, after 6 months of therapy (-2.57 mm versus -1.82 mm, respectively; p < 0.05) (25). changes in stone number eight studies included changes in stone number as primary or correlate endpoint (13, 14, 18, 19, 24, 26-28). however, six studies didn’t provide inference data describing intergroup statistical significance (14, 19, 24, 26-28). in a study by brardi et al., comparing therapy with agropyrum repens extract plus potassium citrate, allopurinol, amiloride-hydrochlorothiazide and pyridoxine versus the same combination without including the herbal agent, a significantly higher reduction in the total number of stones was claimed in favor of the former treatment arm (-1.0 ± 0.2 vs 0.0 ± 0.2 stones; 95% confidence intervals available; probability not disclosed) (13). in one open-label study comparing phyllantus niruri with no treatment in post-lithotripsy patients, 90.6% of patients treated with the plant extract were free of lower caliceal stones (without residual fragments), compared to 70% of control patients (18). the difference was statistically significant (p = 0.03). treatment did not perform significantly better than no-treatment in patients affected by upperor middle-caliceal calculi. urinary excretion of calcium, urate, oxalate calcium. six studies included changes in urinary calcium excretion rates as primary or correlate endpoint (13, 17, 19, 23-25). four study reports didn’t disclose inference data about intergroup statistical significance (19, 23-25). in the brardi et al. study, no inter-arm differences in urinary calcium excretion rates were claimed (agropyrum repens, -52.8 mg/24h; controls, +23.1 mg/24h; only 95% ci provided) (13). a study by lin et al. compared administration of “wuling-san” (herbal components are listed in on-line table 1) with placebo (17). after 1-month treatment, the 24hour urine calcium increased by 44.6% in the herbal formula arm, and by 62.7% in the placebo arm. the percentage of change in urinary calcium between the two groups was not significantly different (p = 0.62). urate. six studies included changes in urinary urate excretion rates as primary or correlate endpoint (13, 17, 19, 23-25), but four study reports didn’t disclose inference data describing intergroup comparisons (19, 23-25). in the brardi et al. study no inter-arm differences in urinary urate excretion rates were claimed (agropyrum repens, -164.7 mg/24h; cit -38 mg/24h) (13). in the lin et al. study (“wu-ling-san” versus placebo), the 24-hour urine uric acid increased by 27.6% in the herbal formula group and by 9.5% in the placebo group. the inter-group difference was not significant (p = 0.22) (17). oxalate. five studies included changes in urinary oxalate concentrations as primary or correlate endpoint (13, 19, 23-25). four study reports out of five didn’t disclose intergroup inference data (19, 23-25). in the brardi et al. study, no inter-arm differences in urinary oxalate excretion rates were claimed (agropyrum repens, -1.5 mg/24h; cit +0.4 mg/24h) (13). phytotherapy versus citrate (pooled analysis) we merged three studies, including in total 151 participants (75 in the phytotherapy arm, 76 in the control arm)(23,24,25). all studies compared citrate as single agent with phytotherapy [dolichus biflorus (23), saxifraga ligulata, crataeva nurvala and other components (24), celosia argentea (25)]. data obtained after 3 months of therapy were available for all three studies. pooled analysis resulted in a significantly higher decrease in mean stone size in the citrate group, compared to the phytotherapy group (mean inter-arm difference: 0.42 mm, 95% ci: 0.23 to 0.60; z = 4.42, p < 0.0001) (figure 2, panel a). heterogeneity of this comparison was minor (i2 = 30%). the quality of the evidence, according to the grade guidelines (12), was rated as “low” (table 1). compared to herbal agents, citrate was significantly more effective in decreasing urinary excretion of urate after 3 months of therapy (mean inter-arm difference: 42.32 mg/24h, 95% ci: 19.44 to 65.19; z = 3.63, p = 0.0003) (figure 2). pooled analysis showed no significant differences in the excretion rates of urinary calcium perletti_stesura seveso 08/04/16 11:28 pagina 41 archivio italiano di urologia e andrologia 2016; 88, 1 e. monti, a. trinchieri, v. magri, a. cleves, g. perletti 42 or oxalate at the same time point (figure 2, panel b). all comparisons of excretion rates of urinary risk factors for stone formation were characterized by considerable heterogeneity (calcium, i2 = 98%; urate, i2 = 96%; oxalate, i2 = 90%, figure 2), and the quality of the evidence, according to the grade guidelines, was rated as “very low” in all cases (table 1). in summary, meta-analysis suggests that, compared to the herbal remedies listed above, citrate can be more effective in decreasing both the size of urinary tract stones and the urinary excretion rate of urate. it is known that the most important risk factor for urate stone formation is persistently acidic urine, and that alkalization of urine with potassium citrate or bicarbonate is active in decreasing urinary saturation with respect to uric acid. this is an effective strategy for dissolution of existing stones and for prevention of recurrence (29-31). citrate is also known to decrease urinary excretion of calcium, but not of oxalate (32). in this respect, visual inspection of forest plots (figure 2, panel b) suggests the absence of a frank effect of citrate or herbal medicines on urinary oxalate excretion, but points to heterogeneity generated by the singh 2011 study (24) as the factor preventing pooled analysis from confirming significant superiority of citrate in decreasing urinary levels of calcium (sensitivity test without singh 2011: mean difference = 23.88 mg/24h, 95% ci: 17.29 to 30.46; z = 7.10, p < 0.00001; i2 = 12%). in this respect, it is helpful to remark that the singh 2010 (23) and singh 2012 (25) studies were performed by the same research group, and that the first author of singh 2011 (24) is a coincidental namesake. due to the very small number of pooled studies, sensitivity test results must be interpreted with a high degree of caution. phytotherapy versus placebo (pooled analysis) two studies compared a herbal agent [wu-ling-san formula, whose components are listed in on-line table 1 (17); phillantus niruri (19)] with placebo. the only comparable and poolable endpoints were the variations of figure 2. pooled analysis of changes in average stone size (panel a), and urinary calcium, urate and oxalate excretion rates (panel b) extracted from three randomized trials (23-25) comparing the effect of phytotherapy preparations with citrate after 3 months on-therapy. the number of randomized subjects, mean differences, the 95% confidence intervals, the z value for the overall effect, the significance of the pooled comparisons and heterogeneity data (chi2, i2), are presented. data to the right or left of the vertical line of forest plots represent a greater reduction in average stone size, or urinary excretion rates of stone components, in patients treated with citrate or phytotherapy, respectively. diamonds represent pooled overall effect sizes for each outcome, which extend to the limits of the 95% confidence intervals of mean differences. perletti_stesura seveso 08/04/16 11:28 pagina 42 43archivio italiano di urologia e andrologia 2016; 88, 1 herbal medicines for urolithiasis calcium and urate urinary excretion rates. analysis revealed no significant differences between treatment arms in either endpoint comparison (figure 3). heterogeneity was “considerable” for the calcium endpoint (94%), and “substantial” for the urate endpoint (51%), according to the cochrane handbook heterogeneity interpretation guide (33). the quality of the evidence was rated as “very low” for this comparison. two studies performed by the pralhad patki research group compared the effect of a herbal preparation containing didymocarpus pedicellata (dp) combined with other herbal agents (a complete list of components is provided in on-line table 1) with placebo (26, 27). pooled analysis showed that the dp preparation was superior than placebo in inducing size reduction (mean difference: dp preparation, 4.93 mm lower; 95% ci: -9.18 to -0.67; z = 2.27, p = 0.02, figure 4) and total clearance (risk ratio: 6.19, 95% ci: 2.60 to 14.74; z = 4.12, p < 0.0001, figure 5) of renal and ureteral stones after 3 months of therapy. heterogeneity was “considerable” for the stone size endpoint (99%) and null for the stone clearance endpoint (0%). the quality of the evidence was rated as “moderate” for this comparison. adverse effects of treatments three study reports lacked a section listing adverse effects (ae) of treatment (19, 23, 25). eight studies reported no ae or side effect, nor any complaint from treated patients (13-18, 27, 28). the patankar et al. study report mentions “nausea, giddiness, epigastric pain” assessed in “comparable” fractions of patients in both treatment arms (crataeva magna plus musa paradisiaca vs. placebo; data not disclosed) (20). the premgamone 2001 et al. study (22), comparing the effect of orthosiphon grandiflorus infusions with citrate, reports fatigue and loss of appetite in 26% patients belonging to the citrate arm, and no complaints in the arm treated with the herbal agent (no statistics available). in the singh 2011 study, citrate induced upper gi disturbances in 4 subjects (13.3%), whereas no ae were figure 3. pooled analysis of mean changes in the excretion rates of urinary calcium and urate extracted from two randomized trials (17, 19) comparing the effect of phytotherapy preparations with placebo. the number of randomized subjects, mean differences, the 95% confidence intervals, the z value for the overall effect, the significance of the pooled comparison and heterogeneity data (chi2, i2), are presented. data to the right or left of the vertical line of forest plots represent a greater reduction in urinary excretion rates of calcium or urate in patients treated with placebo or phytotherapy, respectively. diamonds represent pooled overall effect sizes for each outcome, which extend to the limits of the 95% confidence intervals of mean differences. figure 4. pooled analysis of changes in average stone size extracted from two randomized trials (26, 27) comparing the effect of a preparation containing didymocarpus pedicellata (dp) combined with other herbal agents (“cystone”; a list of components is featured in on-line table 1) with placebo after 3 months on-therapy. the number of randomized subjects, mean differences, the 95% confidence intervals, the z value for the overall effect, the significance of the pooled comparisons and heterogeneity data (chi2, i2), are presented. data to the left or right of the vertical line of forest plots represent a greater reduction in average stone size in patients treated with the dp preparation or placebo, respectively. diamonds represent pooled overall effect sizes for each outcome, which extend to the limits of the 95% confidence intervals of mean differences. perletti_stesura seveso 08/04/16 11:28 pagina 43 archivio italiano di urologia e andrologia 2016; 88, 1 e. monti, a. trinchieri, v. magri, a. cleves, g. perletti 44 recorded in the patient cohort treated with a saxifraga ligulata plus crataeva nurvala extract (full list of components available in on-line table 1) (24). in the premgamone 2009 study, comparing the effect of orthosiphon grandiflorus (og) extract versus placebo, a significant difference in the number of patients reporting adverse effects was found after 14 days on-therapy (treatment arm: 2.8% patients with ae; placebo arm: 17.5% patients with ae; p = 0.03) (21). adverse effects were myofascial pain (og, n = 1; placebo, n = 4), fatigue (og, n = 0; placebo, n = 2), back pain (og, n = 1; placebo, n = 2), gastrointestinal symptoms (og, n = 0; placebo, n = 3), “other” ae (og, n = 0); placebo, n = 3) (subgroup statistics not available). in the shekar kumaran and patki trial, vomiting, gastric irritation, and dyspepsia were recorded in three different patients belonging to the group treated with the dp preparation. the authors report “solitary incidence of gastric irritation” in the placebo group, without disclosing additional details (26). conclusions studies on the effect of herbal products on the formation and growth of urinary stones are numerous but generally of low quality. meta-analytical evidence of moderate quality has shown that a herbal formulation containing didymocarpus pedicellata (dp) combined with other herbal agents was superior to placebo in inducing size reduction and total clearance of renal and ureteral stones, whereas pooled analysis of three studies with low quality of evidence resulted that citrate treatment was able to decrease the mean stone size of stones at an higher extent compared to phytotherapy. a limitation of most studies was the absence of information on the composition of the stones. furthermore, imaging is more often based on ultrasound that does not allow to distinguish between radiopaque and radiolucent stones. the lack of information on stone composition makes it difficult to fully evaluate the effects of treatment on stone dissolution. indeed, while uric acid stones can be easily dissolved by administration of alkali salts raising the urinary ph to less acid values of the physiological range, the dissolution of calcium stones is more difficult. calcium phosphate stones can be dissolved by irrigation of kidney cavities with solutions with a high concentration of citrate or other inhibitors activity of the crystallization of calcium salts, as the solution of suby or hemiacidrin (renacidin). the concentrations of citrates used in these solutions are, however, higher than those that can be achieved after oral administration of citrate. in fact the solutions of suby are obtained by dissolving more than 30 grams of citric acid monohydrate in a liter of aqueous solvent with ph around 4. moreover these solutions are not capable of dissolving calcium oxalate stones which require the addition of calcium chelants, such as edta, that can cause local and systemic toxicity (34). for this reason, dissolution of calcium stones by oral treatment is debatable, although some studies have demonstrated the efficacy of citrate therapy in facilitating the clearance and in preventing the regrowth of residual fragments after lithotripsy (35-39). the published comparisons of excretion rates of urinary risk factors for stone formation are characterized by considerable heterogeneity and very low quality of evidence. no significant variations of calcium and urate urinary excretion rates between treatment with herbal agents and placebo was observed. pooled analysis demonstrated that citrate was significantly more effective in decreasing urinary excretion of urate compared to herbal agents although no significant differences of the two treatments in the excretion rates of urinary calcium or oxalate were observed. however, the measurement of uric acid in the urine is influenced by the urinary ph; hence, the higher levels of uric acid measured in the urine after treatment with citrates could be an analytic effect due to higher urinary ph levels. the effect of herbal products could be unrelated to modifications of the metabolism of urinary risk factors. in fact, herbal products may contain macromolecules with direct inhibitory effects on crystallization or enzymes able to digest the organic matrix of the stone. a limitation of herbal medicine is our inability to recognize what is the figure 5. pooled analysis of mean changes in stone clearance extracted from two randomized trials (26, 27) comparing the effect of a preparation containing didymocarpus pedicellata (dp) combined with other herbal agents (“cystone”; a list of components is featured in on-line table 1) with placebo after 3 months on-therapy. the number of randomized subjects, risk ratios for stone clearance, the 95% confidence intervals for risk ratios, the z value for the overall effect, the significance of the pooled comparison and heterogeneity data (chi2, i2), are presented. data to the right or left of the vertical line of forest plots represent a higher risk for stone clearance in patients treated with the dp preparation or placebo, respectively. diamonds represent the pooled overall effect sizes for each outcome, which extend to the limits of the 95% confidence intervals of risk ratios. perletti_stesura seveso 08/04/16 11:28 pagina 44 45archivio italiano di urologia e andrologia 2016; 88, 1 herbal medicines for urolithiasis active component among the several molecules present in every plant. each substance could have effects on the metabolism with consequent modification of the excretion of the urinary risk factors but also an antioxidant action with protective effect on the renal parenchyma or a direct effect on the crystalline structure of the stone. finally, additional factor of uncertainty are the seasonal geographical variability, as well as the methods for cultivating, extracting and analyzing the bioactive components of these plants. herbal medicine is an attractive alternative to the use of synthetic drugs that are often viewed with suspicion by patients due to the risk of side effects. the regulatory rules for production of these preparations rigid than for synthetic products and their marketing is less complicated and less expensive. however, the results of this metaanalysis make available to healthcare providers a limited amount of evidence about the possible use of herbal products to dissolve or eliminate urinary stones. on the other hand, these products did not show any effect on the metabolism of the major urinary risk factors. potential users of these products should be informed about the lack of conclusive evidence on the effectiveness of herbal products for stone treatment and policy makers should seek additional information before introducing reimbursement policies for these products. the results of the meta-analysis do not allow robust conclusions on the role of herbal medicine in the treatment of urinary stones because only a limited number of herbal products were considered. additional, adequately powered and designed randomized controlled trials are warranted to strengthen the available evidence and to evaluate the effect of other herbal products. tables and search strategy are posted as supple men tary material on www.aiua.it references 1. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010; 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18:427-8. perletti_stesura seveso 08/04/16 11:28 pagina 45 archivio italiano di urologia e andrologia 2016; 88, 1 e. monti, a. trinchieri, v. magri, a. cleves, g. perletti 46 correspondence elena monti, dr sci elena.monti@uninsubria.it department of biotechnology and life sciences, università degli studi dell'insubria, busto arsizio, italy alberto trinchieri, md a.trinchieri@ospedale.lecco.it urology unit, a. manzoni hospital, lecco, italy vittorio magri, md vittorio.magri@virgilio.it urology secondary care clinic, asst-nord, milano, italy anne cleves lynchae1@cardiff.ac.uk cancer research wales library, cardiff university velindre hospital, cardiff, uk gianpaolo perletti, dr. sci, m clin pharmacol (corresponding author) gianpaolo.perletti@uninsubria.it dept. of biotechnology and life sciences, università degli studi dell’insubria via a. da giussano, 10 21052 busto arsizio, italy 26. shekar kumaran mg, patki ps. evaluation of an ayurvedic formulation (cystone), in urolithiasis: a double blind, placebo-controlled study. eur j integr med. 2011; 3:23-28. 27. mohanty nk, nayak rl, patki ps. safety and efficacy of an ayurvedic formulation cystone in management of ureteric calculi: a prospective randomized placebo controlled study. am j pharmacol toxicol. 2010; 5:58-64. 28. upadhyay v, malekar s, deshpande s, ahmad s, shamsuddin. safety and efficacy of unex capsules in management of ureteric calculi: a prospective, randomised placebo-controlled study. int j green pharm. 2011; 5:346-9. 29. shekarriz b, stoller ml. uric acid nephrolithiasis: current concepts and controversies. j urol. 2002; 168:1307-14. 30. pak cy, sakhaee k, fuller c. successful management of uric acid nephrolithiasis with potassium citrate. kidney int. 1986; 30:422-8. 31. cicerello e, merlo f, maccatrozzo l. urinary alkalization for the treatment of uric acid nephrolithiasis. arch ital urol androl. 2010; 82:145-8. 32. song y, hernandez n, shoag j, et al. potassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis. urolithiasis. 2015 nov 18. [epub ahead of print] pubmed pmid: 26582172 33. higgins jpt, green s. cochrane handbook for systematic reviews of interventions. chichester, england: john wiley & sons ltd; 2009. 34. oosterlinck w, verbeeck r. chemolysis of calcium containing calculi. a review. acta urol belg. 1994; 62:31-7. 35. fine jk, pak cyc, preminger gm. effect of medical management and residual fragments on recurrent stone formation following shock wave lithotripsy. j urol. 1995; 153: 27-33. 36. cicerello e, merlo f, gambaro g, et al. effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis. j urol. 1994; 151:5-9. 37. soygur t, akbay a, kupely s. effect of potassium citrate therapy on stone recurrence and residual fragments after shock wave lithotripsy in lower calyceal calcium oxalatae urolithiasis: a randomized controlled trial j endourol. 2002; 16:149-152. 38. sarica k, erturhan s, yurtenseven c, et al. effect of potassium citrate therapy on stone recurrence and regrowth after shock wave lithotripsy in children j endourol. 2006; 20:875-879. 39. lojanapiwat bm, tanthanuch mc, pripathanont c, et al. alkaline citrate reduces stone recurrence and regrowth after shock wave lithotripsy and percutaneous nephrolithotomy. int braz j urol. 2011; 37:611-616. perletti_stesura seveso 08/04/16 11:28 pagina 46 stesura seveso 141archivio italiano di urologia e andrologia 2015; 87, 2 original paper safety of greenlight photoselective vaporisation of prostate in lower urinary tract symptoms due to benign prostatic hyperplasia in patients using anticoagulants due to cardiovascular comorbidities basri cakiroglu 1, orhun sinanoglu 2, akif nuri dogan 3 1 hisar intercontinental hospital, department of urology, umraniye, istanbul, turkey; 2 maltepe university department of urology maltepe, istanbul, turkey; 3 hisar intercontinental hospital, department of internal medicine, umraniye, istanbul, turkey. lasers have been used in the management of benign prostatic hyperplasia for the last two decades. to be comparable, they should reduce or avoid the immediate and long-term complications of transurethral resection of the prostate (turp) or open prostatectomy (op), especially bleeding and need for blood transfusion. although holmium laser treatment of the prostate was compared frequently in terms of cardiovascular safety with turp or op, photoselective vaporisation of the prostate (pvp) was not largely evaluated. in this article we analyzed the current literature to see if there is convincing data to support the observation of some authors that use of pvp is associated with increased safety in patients on anticoagulants with cardiovascular comorbidities. with this purpose a medline search between january 2004 to march 2013 was performed using evidence obtained from randomised trials, well-designed controlled studies without randomisation, individual cohort studies, individual case control studies and case reports results: in the last 10 years, several case-control and cohort studies have demonstrated the efficacy of pvp as well as its safety in patients with cardiovascular comorbidities using anticoagulants. the results confirmed the overall lower perioperative and postoperative morbidity of pvp, whereas the efficacy was comparable to turp in the short term, despite a higher reoperation rate. conclusion: although it is still developing, pvp with ktp or lbo seems to be a promising alternative to both turp and op in terms of cardiovascular safety and in patients using anticoagulants. key words: anticoagulant therapy; benign prostate hyperplasia; cardiovascular comorbidities; photoselective prostate vaporization. submitted 6 february 2015; accepted 15 march 2015 summary no conflict of interest declared. adverse events due to bleeding may occur (1). cardio vascular as well as cerebrovascular diseases increase with age and these patients require antithrombotic treatments, therefore alternative techniques have been developed for patients with blood coagulation disorders secondary to anticoagulants or antiplatelet intake. currently, holmium laser enucleation of the prostate (holep) and photoselective vaporization of the prostate (pvr) (with potassium titanyl phosphate [ktp]) are the most studied technical modalities suggesting that they may be valid alternatives to both open prostatectomy (op) and transurethral resection of the prostate (turp) (2). pvp by green laser is an ablative technique with simultaneous hemostasis (3). this technique enables rapid and effective vaporization of the obstructing prostate adenoma, with adequate cavitation and minimal morbidity. ktp laser emits visible green light and has 532 nm wavelenght which is absorbed by hemoglobin, but not by water. it vaporizes the tissue without loss of energy in liquid setting with consequent vaporisation. although patients with normal hemostatic parameters with normal international normalized ratio (inr) do not have bleeding complications, the usage of this procedure in patients with anticoagulant therapy remains an important issue. the leading concerns for turp have been intra-operative bleeding and the need for blood transfusion. the risk is higher in patients on anticoagulants and antiplatelet agents. the great majority of publications evaluating prostate surgery in conjunction with anticoagulants evaluated men who take either on aspirin, clopidogrel and coumadin (4). in the present review, we have attempted to analyze the current literature to see if there is convincing data to support the observation of some authors that use of pvp is associated with lower cardiovascular events and increased safety in patients on anticoagulants. a medline search over the last 10 years january 2004 to march 2014 was performed using evidence obtained from randomised trials, well-designed controlled studies without randomisation, individual cohort studies, individual case control studies and case reports. doi: 10.4081/aiua.2015.2.141 introduction transurethral resection of the prostate (turp) is the gold standard of surgical treatment of bph however, several complications such as incontinence, uretral stricture, impotence, tur syndrome as well as cardiovascular cakiroglu_stesura seveso 02/07/15 11:23 pagina 141 archivio italiano di urologia e andrologia 2015; 87, 2 b. cakiroglu, o. sinanoglu, a. nuri dogan 142 technical aspect the green light photoselective vaporisation of the prostate (pvp) is generated bypassing a neodymium:yttrium aluminium garnet (nd:yag) laser with 1064-nm laser light through a frequency-doubling crystal, reducing the wavelength by half to 532 nm. the older 80-w laser device uses the ktp (potassium titanyl phosphate) crystal, and the latest appliance uses the lbo (lithium borate) crystal with a 120-w power setting. the high absorption of the laser, predominantly by hemoglobin rather than by water, offers enhanced hemostatic properties; therefore, vaporisation is achieved by concentrating heat in a small volume within a very short period of time. the use of saline as irrigating solution avoids the risk of tur syndrome. these findings are of particular interest when using pvp for large prostates, as an alternative to op or turp. the inconvenience of pvp is the lack of specimen for pathologic assessment (5). the superiority of pvp for patients on anticoagulant drugs with cardiovascular comorbidity turp is considered a gold standard in management of bph. for larger prostates open prostatectomy (op) remains the best option. the search of alternatives for both modalities continues considering their disadvantages. one of the most important adverse events for turp and op has been intra-operative bleeding and the necessity for blood transfusion (6). this risk is higher in patients on anticoagulants and antiplatelet agents. additionally intravasation of hypotonic fluid and risk of tur syndrome is high in large prostates causing tur syndrome due to hyponatremia hypoosmolar cellular swelling with hypervolemia which is a burden for patients with high cardiovascular risks. one of the major advantages of pvp is its bloodless nature. in a series, pvp was performed successfully in 66 patients with high cardiac risk, presented with an american society of anesthesiology score of 3 or more (7). within these 66 patients 29 patients were on oral anticoagulant therapy or had a severe bleeding disorder. no intra-operative or postoperative major complication occurred and no blood transfusion was required. furthermore, 77% patients did not require irrigation post-operatively. mean catheterization time was 1.8 ± 1.4 days. two patients required reoperation due to urinary retention. many other studies suggest pvp as a treatment option in patients with benign prostate hyperplasia who are at high risk for clinically significant bleeding [8, 9]. sandhu and colleagues reported the results of the 80-w ktp laser in 24 men receiving various forms of anticoagulation (8). of the 24 men, 8 were taking warfarin, 2 clopidogrel, and 14 aspirin. these patients displayed an increased prevalence of cardiovascular disease: 8 (33%) had a history of myocardial infarction, 7 (29%) of cerebrovascular disease and 7 (29%) of peripheral vascular disease. after laser prostatectomy, no patient developed clinically significant hematuria postoperatively. there were no episodes of clot retention. no transfusions were required. overall, all patients underwent pvp safely without any adverse thromboembolic or bleeding events. one patient had transient postoperative urinary retention requiring catheterization, two patients developed retrograde ejaculation, and two patients had urinary tract infections postoperatively (8). the safety of pvp series in high-risk anticoagulated patients was further studied in a larger series of 83 patients by malloy and colleagues (9). eighty-one of the patients had a defect in coagulation parameters at the time of surgery. immediate postoperative electrolytes and hemoglobin showed no significant changes, with minimal intraoperative blood loss. no transfusions were required, and there were not any thromboembolic events. five patients experienced clot retention in the immediate postoperative period. overall, studies with pvp have shown that it is safe for patients with coagulopathies, platelet disorders, and those considered to be high cardiovascular or cardiopulmonary surgical risks. other studies suggest that pvp combines both ablation and coagulation creating the opportunity for nearly bloodless surgery (10). for this convenience, the method could be used for treatment of larger prostates. it also provides safe and effective treatment in patients with high cardiovascular or pulmonary risks receiving anti-coagulant therapy and in patients with acute urinary retention (4, 11). the results of 80-w ktp laser pvp has also been reported in a large series with 500 patients: no tur syndrome occurred, and only two patients required blood transfusions. despite oral anticoagulation in 45% of the patients, no severe intraoperative complications occurred. the results are presented as a success compared to turp in patients with comorbidities. however the studies before 2008 were performed with pvp using 80-w-ktp with the low rate of vaporization; thus, in patients with a large prostate volume, long operative times were needed (12). a new ktp laser, the 120-w greenlight hps, was introduced to overcome this flaw. the new system emits the same green wavelength with a power of 120 w, resulting in higher vaporization speed. the pvp with 120-w hps provides the possibility of faster tissue vaporization while keeping the hemostatic advantages of its predecessor. the international green light user group reported treatment results of pvp with 120-w hps in 305 patients. they concluded that that the hps can be used effectively and safely in patients receiving anticoagulant and patients with urinary retention or those with a larger prostate (4). in a recent study the outcomes of pvp in 45 patients taking oral anticoagulant therapy and in which withdrawal would have posed a considerable risk of thromboembolic events were reported. furthermore, the study included one patient who had chronic myelogenous leukemia, which is a also severe bleeding disorder. pvp was performed safely in these patients on full anticoagulation, and no thromboembolic or bleeding events occurred (13). in a latest study, 63 patients under anticoagulant treatment undergoing 120-w greenlight hps prostatectomy had considerable symptomatic improvement without bleeding or thromboembolic event (14). in conclusion, ktp and lbo lasers seems to have low risk of bleeding complications in this patient population. other commonly used laser technologies, such as the 2013 nm thulium [revolix (lisa laser, pleasanton, california, usa)] and the 980 nm lasers [evolve (biolitec, inc, east longmeadow, massachusetts, usa)], have not been thoroughly studied in patients receiving to anticocakiroglu_stesura seveso 02/07/15 11:23 pagina 142 143archivio italiano di urologia e andrologia 2015; 87, 2 safety of greenlight photoselective vaporisation of prostate in lower urinary tract symptoms due to benign prostatic hyperplasia... agulation. the two series evaluating holep (holmium laser enuclation of prostate) in patients on anticoagulation in which warfarin and aspirin was continued during surgery reported a higher 8% abortion rate of the procedure and a 10% transfusion rate (15). conclusion patients undergoing prostate surgery are generally older with more comorbidities and frequently receive antithrombotic therapy for cardiovascular diseases. physicians do not stop these medications through prostate surgery to avoid the risk of cardiovascular and cerebrovascular complications. from the limited retrospective, noncomparative studies available, pvp appear to provide superior hemostasis. future investigation with prospective, randomized studies of patients on commonly used oral anticoagulant therapies comparing various lasers with ablative technical modalities is necessary to make definitive conclusions on the most effective technique with the fewest complications. references 1.madersbacher s, alivizatos g, nordling j, et al. eau 2004 guidelines on assessment, therapy and follow-up of men with lowerurinary tract symptoms suggestive of benign prostatic obstruction (bph guidelines). eur urol. 2004; 46:547-554. 2. reich o, gratzke c, stief cg. techniques and long-term results of surgical procedures for bph. eur urol. 2006; 49:970-8. 3. malek rs, nahen k. photoselective vaporisation of the prostate: ktp laser therapy of obstructive benign prostatic hyperplasia. aua update ser. 2004; 23:153-9. 4. woo h, reich o, bachmann a, et al. outcome of greenlight hps 120-w laser therapy in specific patient populations: those in retention, on anticoagulants, and with large prostates (> 80 ml) eur urol supp. 2008; 7:378-83. 5. kuntz rm. current role of lasers in the treatment of benign prostatic hyperplasia (bph). eur urol. 2006; 49: 961-9. 6. fitzpatrick jm. minimally invasive and endoscopic management of benign prostatic hyperplasia. in: wein aj, kavoussi lr, partin aw, novick ac, peters ca, editors. campbell walsh urology. 10th ed. philadelphia: elsevier saunders; 2012. pp. 2655-94. 7. reich o, bachmann a, siebels m, et al. high power (80 w) potassium-titanyl-phosphate laser vaporization of the prostate in 66 high risk patients. j urol. 2005; 173:158-60. 8. sandhu js, ng ck, gonzalez rr, kaplan sa, te ae. photoselective laser vaporization prostatectomy in men receiving anticoagulants. j endourol. 2005; 19:1196-8. 9. yuan j, wang h, wu g, et al. high-power (80 w) potassium titanyl phosphate laser prostatectomy in 128 high-risk patients. postgrad med j. 2008; 84:46-9. 10. rajbabu k, chandrasekara sk, barber nj, et al. photoselective vaporization of the prostate with the potassium titanyl-phosphate laser in men with prostates of >100 ml. bju int. 2007; 100:593-8. 11. yuan j, wang h, wu g, et al. high-power (80 w) potassium titanyl phosphate laser prostatectomy in 128 high-risk patients. postgrad med j. 2008; 84:46-9. 12. ruszat r, seitz m, wyler sf, et al. greenlight laser vaporization ofthe prostate: single-center experience and long-term results after 500 procedures. eur urol. 2008; 54:893-901. 13. wei tao, boxin xue, yachen zang, et al. the application of 120w high-performance system green light laser vaporization of the prostate in high-risk patientslasers med sci. 2013; 28:1151-1157. 14. cakiroglu b, gözüküçük r, sinanoglu o. efficacy and safety of 120 w greenlight photoselective vaporisation of prostate in patients receiving anticoagulant drugs.j pak med assoc. 2013; 63:1464-7. 15. wei tao, boxin xue, yachen zang, et al. the application of 120w high-performance system greenlight laser vaporization of the prostate in high-risk patients lasers med sci. 2013; 28:1151-1157. correspondence basri cakiroglu, md (corresponding author) drbasri@yahoo.com department of urology hisar intercontinental hospital saray mah. site yolu caddesi no:7 umraniye, istanbul, turkey orhun sinaniglu, md department of urology maltepe university department of urology maltepe, istanbul, turkey akif nuri dogan, md department of internal medicine hisar intercontinental hospital umraniye, istanbul , turkey cakiroglu_stesura seveso 02/07/15 11:23 pagina 143 17archivio italiano di urologia e andrologia 2017; 89, 1 original paper the efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: a randomized clinical trial bruno giammusso 1, rosaria di mauro 2, renato bernardini 2 1 policlinico morgagni, catania, italy; 2 biometec, section of pharmacology, university of catania school of medicine, catania, italy. background: chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a complex condition, characterized by uncertain etiology and by limited response to therapy. the definition of cp/cpps includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria, as detected by standard microbiological methods, or another identifiable cause such as malignancy. the efficacy of various medical therapies, has been evaluated in clinical studies, but evidence is lacking or conflicting. we compared serenoa repens in monotherapy versus palmitoylethanolamide (pea) in combination with alpha-lipoic acid (ala) and evaluated the efficacy of these treatments in patients with cp/cpps. methods: we conducted a randomized, single-blind trial. 44 patients diagnosed with cp/cpps (mean age 41.32 ± 1.686 years) were randomly assigned to treatment with palmitoylethanolamide 300 mg plus alpha-lipoic acid 300 mg (peanase®), or serenoa repens at 320 mg. three questionnaires (nih-cpsi, ipss and iief5) were administered at baseline and after 12 weeks of treatment in each group. results: 12 week treatment with peanase significantly improved the ipss score compared to the same period of treatment with serenoa repens, and significantly reduced nih-cpsi score. similar results were observed in the different nih-cpsi subscores break down. however, the same treatment did not result in significant improvement of the iief5 score. both treatments did not produce undesired effects. conclusions: the present results document the efficacy of an association of palmitoylethanolamide (pea) and alpha-lipoic acid (ala) administered for 12 weeks for treating patients with cp/cpps, compared with serenoa repens monotherapy. key words: chronic pelvic pain syndrome; chronic prostatitis; palmitoylethanolamide; serenoa repens; lipoic acid. submitted 14 may 2016; accepted 17 july 2016 summary no conflict of interest declared. ological methods, or another identifiable cause such as malignancy. cp/cpps is a highly prevalent condition affecting males of a wide age range, and can significantly impair the quality of life (qol) and the social functioning of patients. lifetime cp/cpps prevalence is 2% to 10%. many etiologies and mechanisms for cp/cpps pathogenesis have been proposed, including infection, detrusorsphincter dysfunction, immunological dysfunction, interstitial cystitis, and neuropathic pain. cp/cpps is characterized by a wide spectrum of symptoms, including chronic or persistent pain in the pelvic region, irritative and obstructive voiding symptoms, ejaculatory pain, sexual dysfunction, depression and psycho-social maladjustment amongst others. the cp/cpp mechanisms involve ongoing acute pain mechanisms (such as those associated with inflammation or infection) and chronic pain mechanisms (such as central sensitization or visceral hyperalgesia) (1). the efficacy of various medical therapies, such as antibiotics, alpha-adrenergic blockers, anti-inflammatory agents, hormonal therapies, and phytotherapies, has been evaluated in clinical studies of cpps. however, evidence is lacking or conflicting. phytotherapeutics are a noteworthy option due to their generally minimal side-effects; however, few have been subjected to scientific scrutiny and prospective controlled clinical trials. it has been hypothesized that the etiological determinants of cp/cpps are likely to trigger tissue and cellular responses that include inflammation and the upregulation of cytokine expression and release. inflammatory injury may damage tissue components such as nerves and blood vessels, in turn causing pain that may produce contraction of pelvic smooth and skeletal muscles, finally leading to lower urinary tract symptoms, ejaculatory pain and pain in other regions, including the lower back and abdomen. prolonged pain may lead to neurogenic inflammation and peripheral and central sensitization. patients and methods cp/cpps is treated by means of different protocols. we compared serenoa repens in monotherapy versus palmitoylethanolamide (pea) in combination with doi: 10.4081/aiua.2017.1.17 introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a complex condition, characterized by uncertain etiology and by limited response to therapy. the definition of cp/cpps includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria, as detected by standard microbigiammusso_stesura seveso 04/04/17 09:06 pagina 17 archivio italiano di urologia e andrologia 2017; 89, 1 b. giammusso, r. di mauro, r. bernardini 18 alpha-lipoic acid (ala) and evaluated the efficacy of these treatments in patients with cp/cpps. we conducted a randomized, single-blind trial of a community population recruited from june 2014 to january 2015. trial design men aged between 22 and 61 years, attending our outpatient urology clinic were invited to participate in the study. inclusion criteria were: complaints of chronic pelvic pain for at least six months; ipss score higher than 13 at visit 1; pain domain of nih-cpsi higher than 1 at visit 1; total psa lower than 4 ng/ml. patients were included in this study if they exhibited at a first visit signs and symptoms of category iii cp/cpps, according to national institutes of health (nih) criteria (niddk chronic prostatitis workshop, 1995). subjects younger than 22 and older than 61 years, affected by major comorbidities, with known anatomical abnormalities of the urinary tract or with evidence of other urological diseases, and with residual urine volume > 50 ml resulting from bladder outlet obstruction were excluded. males with a reported allergy to the drugs administered during the trial, who had recently (< 4 weeks) undergone oral or parenteral treatment or who were currently using prophylactic antibiotic drugs and/or finasteride were also excluded. all patients positive to tests for chlamydia trachomatis (ct), ureaplasma urealyticum, neisseria gonorrhoeae, herpes viruses (hsv 1/2) and human papillomavirus (hpv) were also excluded. the severity of the chronic prostatitis symptoms was scored by means of an italian validated version of the nih chronic prostatitis symptom index (nih-cpsi), addressing pain and voiding symptoms, and the impact of the disease on patients' quality of life (qol). the international index of erectile function (iief) questionnaire was adopted to assess the erectile function of patients. mild to severe erectile dysfunction (ed) was defined as the sum of the scores for iief questions 1-5 and 15, which in total were inferior to 26. the ipss is a validated, seven-item questionnaire evaluating luts occurring during the preceding month, with lower scores indicating less severe luts. forty-four patients diagnosed with cpps were randomly assigned to treatment with palmitoylethanolamide 300 mg plus alpha-lipoic acid 300 mg (peanase®), two capsules every 24h (group a), or serenoa repens at 320 mg, one capsule every 24h (group b). nih-cpsi, iief, and ipss questionnaires were completed by each patient prior to and 12 weeks after the treatment. mean values of total scores before and following the treatment were compared. at time-point v2 (visit two), after complete clinical and microbiological assessments, patients received a full course of pharmacological therapy. microbiological eradication of pathogens was assessed before enrolment. at time-point v3 (visit three), performed 12 weeks after the start of therapy, symptoms were assessed again with questionnaires. data are presented as means ± standard error. changes from baseline within each group were assessed through one-way analysis of variance (one-way anova), followed by a bonferroni test (bonferroni's multiple comparison test). statistical significance was assessed at a p value < 0.05. the full analysis set included patients who received 84 doses of the study drugs. it was estimated that 22 patients per treatment group were required to demonstrate efficacy in terms of symptoms score changes from baseline. the safety analysis consisted of all randomised subjects who took one dose or more of study medication. results in this study 44 patients were enrolled and randomised into two groups (mean age 41.32 ± 1.686 years). among them, 22 received peanase® (palmitoylethanolamide plus alpha-lipoic acid), group a, and 22 received serenoa repens, group b. the treatment arms were comparable for all variables at the enrollment and randomisation visits. three questionnaires (nih-cpsi, ipss and iief5 scores) were administered at baseline and after 12 weeks of treatment in each group. data indicate that 12 week treatment with peanase significantly improved the ipss score compared to the same period of treatment with serenoa repens (figure 1). however, the same treatment did not result in significant improvement of the second score analysed, the iief5 (figire 2). finally, the 12-week treatment with peanase was able to significantly reduce nih-cpsi score. similar results were observed in the different nih-cpsi subscores break down. on the other hand, statistical of data from patients treated with serenoa repens did not result in significant differences between treated and untreated patients (figure 3). both treatments were well tolerated in all the patients examined, and no significant drug-related side effects were noticed. figure 1. comparative effects of 12-week treatments with either the combination á-lipoic acid-palmitoylethanolamide or the extract from s. repens on the ipss score for evaluation of urinary symptoms in patients with chronic prostatitis. vertical bars are means ± se; *p < 0.05 vs. s. repens (one way analysis of variance, followed by the bonferroni’s multiple comparison test). giammusso_stesura seveso 04/04/17 09:06 pagina 18 discussion the most recent nih classification of prostatitis adopted in 1995 includes several clinical entities, such as acute and chronic bacterial infections, cpps, and asymptomatic inflammation of the prostate. the most common type of prostatitis is category iii, also known as cp/cpps. the current nih definition of cp/cpps includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria, as detected by standard microbiological methods, or another identifiable cause such as malignancy. the efficacy of various medical therapies, such as antibiotics, alpha-adrenergic blockers, anti-inflammatory agents, hormonal therapies, and phytotherapies, has been evaluated clinically and is however a matter of debate. in this short study we demonstrate that the combination of alpha-lipoic acid with palmitoylethanolamide improves significantly parameters related to prostate function in course of inflammatory processes. alpha-lipoic acid (ala), or 1,2-dithiolane-3-pentanoic acid, is a natural-occurring co-factor for vital metabolic multienzyme complexes, including pyruvate dehydrogenase and glycine decarboxylase. ala is absorbed from the diet, and it is readily converted to its reduced form, dihydrolipoic acid, in mammalian cells. ala acts as a redox regulator of thiolcointaining proteins and is effective in the treatment of several pathologic conditions including diabetes, neurodegeneration, radiation injury, and malignancy (2). growing evidence shows that orally supplied ala may not be used as a metabolic cofactor, but instead elicits a unique set of biochemical activities with potential pharmacotherapeutic value against a host of pathophysiologic insults. ala has been described as a potent biological antioxidant, and has been implicated as a modulator of various inflammatory signalling pathways (3-4). this impressive array of cellular and molecular functions has gained considerable interest among the public and the research community for the use of ala both as a nutritive supplement and as a pharmacotherapy. the chemical reactivity of ala is mainly conferred by its dithiolane ring. the oxidized (ala) and reduced (dhla) forms create a potent redox couple that has a standard reduction potential of -0.32 v. this makes dhla one of the most potent naturally occurring antioxidants (5). in fact, there is evidence that both ala and dhla are capable of scavenging a variety of reactive oxygen species. in addition to being direct reactive oxygen species scavengers, both ala and dhla chelate redox-active metals in vitro and in vivo. the oxidized and reduced forms bind a number of metal ions, but with different properties depending on the metal chelated. these results imply, but do not yet prove, that ala supplementation may modulate the labile pool of redox active transition metals, without causing metal depletion. there is growing evidence that ala may act indirectly to maintain cellular antioxidant status by either inducing the uptake or enhancing the synthesis of endogenous low molecular weight antioxidants or antioxidant enzymes. for instance, reports show that ala increases intracellular ascorbate levels. in concert with improving ascorbate status, la markedly increases intracellular glutathione (gsh), an abundant natural thiol antioxidant and co-substrate for detoxification enzymes, in a variety of cell types and tissues (6-7). several clinical trials have been conducted to measure the efficacy of racemic ala in decreasing symptoms of diabetic polyneuropathies; these are the “alpha-lipoic acid 19archivio italiano di urologia e andrologia 2017; 89, 1 palmitoylethanolamide-alphalipoic acid in cp/cpp figure 2. comparative effects of 12-week treatments with either the combination á-lipoic acid-palmitoylethanolamide or the extract from s. repens on the iief5 score for evaluation of erectile function in patients with chronic prostatitis. vertical bars are means ± se; significance was set for a *p < 0.05 (one way analysis of variance, followed by the bonferroni’s multiple comparison test). figure 3. comparative effects of 12-week treatments with either the combination á-lipoic acid-palmitoylethanolamide or the extract from s. repens on the nih-cpsi score for evaluation of pain, urinary discomfort and relative quality of life in patients with chronic prostatitis. vertical bars are means ± se; *p < 0.05 vs. time zero of the combination (one way analysis of variance, followed by the bonferroni’s multiple comparison test). giammusso_stesura seveso 04/04/17 09:06 pagina 19 archivio italiano di urologia e andrologia 2017; 89, 1 b. giammusso, r. di mauro, r. bernardini 20 in diabetic neuropathy” (aladin) trials and the “symptoms of diabetic polyneuropathy” (sydney) trials. ala was given orally, intravenously, or i.v. with oral follow-up. however, some additional studies have found that oral ala is very effective. for example, the oral pilot (orpil) study showed a reduction in diabetic polyneuropathic symptoms after three weeks with 600 mg ala t.i.d. (8) while the first sydney trial used i.v. la (9), the sydney ii study used oral la at 600, 1200, or 1800 mg q.d. for 5 weeks (10); consequently, both studies showed significant improvements in neuropathic endpoints. ala has also been studied for its antioxidant properties in cytokine-induced inflammation; it is also widely known as an inhibitor of nf-kappab (11). results show that ala lowers expression of vascular cell adhesion molecule-1 (vcam-1) and endothelial adhesion of human monocytes, and inhibits nf-kappab-dependent expression of metalloproteinase-9 in vitro (12-13). similarly, ala (25100 ìg/ml = 122-486 ìm) prevents the upregulation of intercellular adhesion molecule-1 (icam-1) and vascular cell adhesion molecule-1 (vcam-1) in spinal cords and in tnf-alpha stimulated cultured brain endothelial cells (14). to date, the anti-inflammatory properties of ala have rarely been investigated in humans. the island trial showed a 15% significant decrease in serum interleukin-6 levels following 4 weeks of supplementation with ala (300 mg/day) (15). although some important aspects of ala’s mechanism of action in vivo are yet to be uncovered, it is apparent that oral ala supplements are clinically effective in mitigating chronic inflammatory conditions, as well as improving or maintaining antioxidant/detoxification defenses that otherwise decline with age. among molecules able to modify the course of chronic pain in adults, palmitoylethanolamide (pea) seems to deserve interest. pea is an endogenous nacylethanolamine produced on demand to promote the resolution of neuroinflammation and pain (16). pea administration seems able to control reactivity of tissue peripheral mast cells located in close proximity to nerve terminals and within the endoneural microenvironment, thereby normalizing the sensitivity and function of primary somatosensory peripheral neurons (17). furthermore, pea act on spinal/supraspinal nonneuronal cells (microglia, resident or infiltrating mast cells, astrocytes) to counteract neuroinflammation and normalize the activity of secondand third-order somatosensory neurons (18, 19). clinical studies demonstrate the efficacy of pea in reducing chronic and neuropathic pain associated with various pathological conditions. a remarkable pharmacological feature of pea is that its addition to ongoing standard therapies for chronic or neuropathic pain in patients with unsatisfactory management of pain relief allows a significant reduction of non-steroidal antiinflammatory drug use (20). in the present study, a significant reduction of the total nih-cpsi score was achieved in the group of patients subjected to combination therapy (ala plus pea) for a period of 12 weeks. notably, this improvement in nihcpsi score was not seen in the group of patients treated with serenoa repens. the same observation comes from the evaluation of iief score in both arms. patient treated with ala plus pea showed a significant improvement in erectile function, not seen in the arm treated with serenoa repens. this study clearly has limitations. the small number of subjects may not be representative of the general population with cp/cpps. the absence of a placebo arm may be considered a limitation in terms of efficacy evaluation of administered treatments, anyway our aim was a direct comparison between a new therapeutic option for cp/cpps and a traditional treatment strategy, rather than an absolute measurement of efficacy. furthermore, a significant psychological component is well described in patients with cp/cpps symptoms, and a comparable placebo effect can be assumed in all patients taking drugs to treat this kind of symptoms. more extensive studies to assess these parameters will enhance our understanding of the mechanism of action of ala plus pea in patients with cp/cpps. in conclusion, given the aforementioned limitations, the present results document the efficacy of an association of palmitoylethanolamide (pea) and alpha-lipoic acid (ala) administered for 12 weeks for treating patients with cp/cpps, compared with serenoa repens monotherapy. the treatment did not produce undesired effects. however, additional long term and thorough clinical studies are needed to better explain the mechanisms of its neuroprotective effects and to further investigate the efficacy of its supplementation. references 1. magri v, marras e, restelli a, et al. multimodal therapy for category iii chronic prostatitis/chronic pelvic pain syndrome in upoints phenotyped patients. exper ther med. 2015; 9:658-666. 2. sunghyup c, kweonsik m, ikjoon c, et al. effects of alpha-lipoic acid on the antioxidant system in prostate cancer cells. korean j urol. 2009; 50:72-80. 3. shay kp, moreau, rf, hagen tm, et al. alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. biochim biophys acta. 2009; 1790:1149-1160. 4. smith ar, shenvi sv, widlansky m, et al. lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. curr med chem. 2004; 11:113546. 5. scott bc, aruoma oi, evans pj, et al. lipoic and dihydrolipoic acids as antioxidants. a critical evaluation. free radic res. 1994; 20:119-33. 6. bast a, haenen gr. interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation. biochim biophys acta. 1988; 963:558-61. 7. busse e, zimmer g, schopohl b, et al. influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. arzneimittelforschung. 1992; 42:829-31. 8. ruhnau kj, meissner hp, finn jr, et al. effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. diabet med. 1999; 16:1040-3. 9. ametov as, barinov a, dyck pj, et al. the sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the sydney trial. diabetes care. 2003; 26:770-6. giammusso_stesura seveso 04/04/17 09:06 pagina 20 10. ziegler d, ametov a, barinov a, et al. oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the sydney 2 trial. diabetes care. 2006; 29:2365-70. 11. packer l, witt eh, tritschler hj. alpha-lipoic acid as a biological antioxidant. free radic biol med. 1995; 19:227-50. 12. kunt t, forst t, wilhelm a, et al. alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. clin sci (lond). 1999; 96:75-82. 13. kim hs, kim hj, park kg, et al. alpha-lipoic acid inhibits matrix metalloproteinase-9 expression by inhibiting nf-kappab transcriptional activity. exp mol med. 2007; 39:106-13. 14. chaudhary p, marracci gh, bourdette dn. lipoic acid inhibits expression of icam-1 and vcam-1 by cns endothelial cells and t cell migration into the spinal cord in experimental autoimmune encephalomyelitis. j neuroimmunol. 2006; 175:87-96. 15. sola s, mir mq, cheema fa, et al. irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the irbesartan and lipoic acid in endothelial dysfunction (island) study. circulation. 2005; 111:343-8. 16. paladini a, fusco m, coaccioli s, et al. chronic pain in the elderly: the case for new therapeutic strategies. pain physician. 2015; 18:e863-e876 17. bettoni i, comelli f, colombo a, et al. non-neural cell modulation relieves neuropathic pain: efficacy of the endogenous lipid palmitoylethanolamide. cns neurol disord drug targets. 2013; 12:34-44. 18. luongo l, guida f, boccella s, et al. palmitoylethanolamide reduces formalininduced neuropathic-like behaviour through spinal glial/microglial phenotypical changes in mice. cns neurol disord drug targets. 2013; 12:45-54. 19. cantarella g, scollo m, lempereur l, et al. endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells. biochem pharmacol. 2011; 82:380-388. 20. domínguez cm, martín a, ferrer fg, et al. n-palmitoylethanolamide in the treatment of neuropathic pain associated with lumbosciatica. pain manage. 2012; 2:119-124. 21archivio italiano di urologia e andrologia 2017; 89, 1 palmitoylethanolamide-alphalipoic acid in cp/cpp correspondence bruno giammusso, md (corresponding author) bgiammusso@hotmail.it policlinico morgagni, via vivante, 3 95123 catania, italy rosaria di mauro rosariadimauro@tiscali biometec, section of pharmacology, university of catania school of medicine, catania, italy renato bernardini renato.bernardini@gmail.com biometec, section of pharmacology, university of catania school of medicine, catania, italy giammusso_stesura seveso 04/04/17 09:06 pagina 21 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 180 original paper effect of microorganisms on etiology of hematospermia musa saracoglu 1, hakan ozturk 1, arzu duran 2, sabri atalay 3 departments of 1 urology and 2 microbiology, school of medicine, sifa university, izmir, turkey; 3 department of infectious diseases and clinical microbiology, tepecik education and research hospital, izmir, turkey. background: hematospermia is the presence of blood in the ejaculate. its etiology is congenital, inflammatory, infectious, obstructive, tumoral, vascular, traumatic, iatrogenic or related to systemic disease. it is a quite irritating and life-quality-disturbing condition for men. it is significant to demonstrate infectious-based hematospermia due to the fact that its treatment is easier than for other reasons. methods: 30 patients, having spontaneous hematospermia, were taken to our study. the serum total psa levels of the patients were examined and microbiological examinations such as direct inspection for ejaculate, routine bacteriological and mycetes culture, gram staining, trichrome staining and mycoplasma hominis/ureaplasma urealyticum culture (mycofast evolution 3, elitech, france) were performed. results: bacteria was isolated in 11 (36%) of 30 patients with hematospermia. s.aureus occurred in five patients (45.5%), u.urealyticum in three patients (27.2%) and e.coli and k.pneumoniae in one each (9.1%). u.urealyticum and s.aureus occurred together in one patient. no statistical difference of scores of national institute of health-chronic prostatitis symptoms index (cpsi) and serum total psa levels between the patients with and without infection was observed. conclusions: hematospermia mostly affects micturition functions of young men and it can be due to infection in one-third of the cases. key words: hematospermia; ejaculate; psa. submitted 24 october 2014; accepted 30 november 2014 summary no conflict of interest declared. prostate biopsy or transurethral instrumentation were excluded from the study being considered as iatrogenic hematospermia. all the patients were scored according to national institute of health-chronic prostatitis symptoms index and were inspected. the levels of serum total psa (elecsys® total psa, roche/hitachi, usa) were measured and microbiological evaluations of ejaculates were made. microbiological evaluations were made according to the prostatitis panel created in our hospital. this panel is directed to evaluation of presence in the ejaculate of bacteria, fungus, parasite and leucocytes and includes direct microscopy and microscopy made after gram and trichrome staining. it includes aerobe bacteria, mycetes, mycoplasma hominis and ureaplasma urealyticum (mycofast evolution 3, elitech, france) cultures. ejaculate samples used for microbiological evaluations were taken by masturbation after cleaning of glans penis and without using lubricant. samples were seeded in sheep blood agar, emb agar and sabouraud dextrose agar (sda) and incubated for 48 hours in an ambient of 350c10% co2; 100 μl of ejaculate was taken for mycoplasma hominis and ureaplasma urealyticum evaluation by mycofast evolution method. student t test was performed in order to determine difference of total psa levels and national institute of health-chronic prostatitis symptoms index scores among sub-groups. results thirty patients were considered in the study. five of them were single and the others were married. the ages of the patients ranged from 17 to 61 and the average was 37.21; 70% of the patients was under the age of 40 and 9 (30%) of them were over 40. data of national institute of health-chronic prostatitis symptoms index scores were reported in table 1 in relation to microbiological findings. bacteria were demonstrated in 11 (36%) of 30 patients having hematospermia. no statistical difference of national institute of health-chronic prostatitis symptoms index scores was observed between patients with and without demonstration of infection. at urological examination, bph findings were observed in 4 patients. all these patients were over 40 years of age. there was no finding suspect of malignity in patients. serum total psa values varied between 0.26 ng/ml and 2.65 ng/ml and the average was 0.92 ng/ml. serum total doi: 10.4081/aiua.2015.1.80 introduction hematospermia is presence of blood in the ejaculate. it is known that is etiology can be congenital, inflammatory, infectious, obstructive, tumoral, vascular, traumatic, iatrogenic and systemic disease related (1). however, its cause cannot be determined in some cases that are considered as idiopathic hematospermia (2). in this study we aimed to investigate the rate of infectious etiology in the patients with hematospermia observed in a 3-year period. patients and methods cases with spontaneous hematospermia were considered in the study. patients with hematospermia subsequent to saracoglu_stesura seveso 02/04/15 10:27 pagina 80 81archivio italiano di urologia e andrologia 2015; 87, 1 effect of microorganisms on etiology of hematospermia value averages of the patients with and without bacteria growth were reported in table 1. there was no significant difference in the statistical comparisons of two groups. bacteria growth was obtained in 11 (36.7%) of 30 patients according to microbiological evaluations. two bacteria were isolated in one patient. out of 11 patients with bacteria isolates, staphylococcus aureus was present in 5 patients (45.5%), (three of them were mrsa and two of them were mssa), ureaplasma urealyticum in 3 patients (27.2%), escherichia coli and klebsiella pneumoniae in one patient each (9.1%) and association of ureaplasma urealyticum and staphylococcus aureus (mssa) in another patient (9.1%). table 2 shows findings obtained when the patients were separated in two groups under and over 40 years of age. serum total psa values of the patients over 40 age were significantly higher. contrary to the expectations, micturition score of national institute of health-chronic prostatitis symptoms index was significantly higher in the patients under 40 age. discussion hematospermia is a symptom known for thousands of years, being present in the written sources of the hippocrates period (3). although it is generally considered as the result of benign conditions, in a study hematospermia was observed in 14% of the prostate cancer patients (4). prostate biopsy, used in the diagnosis of prostate cancer, has become the iatrogenic reason of hematospermia, which occurred more frequently in the last years (5). it is not possible to estimate the period of hematospermia on these patients (6). in order to foresee malign conditions age of the patient, coexistence of hematuria and type of hematospermia, persistent or recurrent, can be taken into consideration. the possibility of malign disease occurrence is higher in the individuals over 40 (7, 8). hematuria can accompany with bladder, kidney and urethra malignancy as well as prostate malignancy. compelete evaluation is required for the patients having hematuria (9). in our study, as expected, serum total psa values of the patients over 40 years was higher. on the contrary it was not expected that micturition score of the patients under 40 was higher. this can be explained by an exaggerated perception of pain in the younger patients. anxiety, caused by hematospermia, is more apparent in young patients, therefore, it can cause an exaggerated perception for the symptoms. one of the most frequent reasons of hematospermia is infection. hematospermia can be observed especially in presence of infectious diseases of prostate (10). infection-based hematospermia tends to recover in a short time and is non-recurrent. in a study on 170 patients having hematospermia, chronic prostatitis rate was determined as 14% (11). in other study, on 67 patients evaluated, chronic prostatitis was diagnosed in 28% (12). in our study, infectious factors were demonstrated in 36% of the patients. the reason of this higher rate respect to the literature is the potential of our analysis panel to demonstrate a wide spectrum of microorganisms. especially, the use of tests for evaluation of myco plasma hominis and ureaplasma urealyticum explains this situation. it is not possible to define characteristics of patients with bacterial isolation because there was no significant difference in clinic symptoms of the patients with or without infection. so, microbiological evaluation of the patients having hematospermia is important in order to determine the underlying pathological condtion. in conclusion, infectious causes have a significant place in the patients having hematospermia. while evaluating the patients having hematospermia, non-invasive and low-cost microbiological evaluations within the first evaluation are significant in order to understand the underlying reason and to apply a more effective treatment. references 1. kumar p, kapoor s, nargund v. haematospermia a systematic review. ann r coll surg engl. 2006; 88:339-42. 2. magoha ga, magoha ob. aetiology, diagnosis and management of haemospermia: a review. east afr med j. 2007; 84:589-94. 3. mulhall jp, albertson pc. haemospermia: diagnosis and management. urology. 1995; 46:463-7. 4. han m, brannigan re, antenor j-av, et al. association of hemospermia with prostate cancer. j urol. 2004; 172:2189-92. 5. manoharan m, ayyathurai r, nieder am, soloway ms. hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. prostate. cancer prostatic dis. 2007; 10:283-7. 6. abdelkhalek ma, abdelshafy m, elhelaly ha, el nasr mk. table 1. national institute of health-chronic prostatitis symptoms index scores and serum total psa values according to bacteria reproduction on patient samples. all bacteria no bacteria p patients reproduction reproducion pain score 4.80 5.82 4.21 0.407 micturition score 2.07 2.09 2.05 0.189 effect-quality score 4.50 5.18 4.11 0.951 total score 11.27 12.55 10.53 0.783 total psa 0.92 0.96 0.89 0.680 table 2. national institute of health-chronic prostatitis symptoms index scores and serum total psa values of patients by class ages. all patients > 40 years < 40 years p pain score 4.80 4.00 5.14 0.608 micturition score 2.07 0.89 2.57 0.011 effect-quality score 4.50 3.67 4.86 0.630 total score 11.27 7.89 12.71 0.070 total psa 0.92 1.35 0.74 0.027 saracoglu_stesura seveso 02/04/15 10:27 pagina 81 archivio italiano di urologia e andrologia 2015; 87, 1 m. saracoglu, h. ozturk, a. duran, s. atalay 82 hemospermia after transrectal ultrasound (trus)-guided pro static biopsy: a prospective study. j egypt soc parasitol. 2012; 42:63-70. 7. leocádio de, stein bs. hematospermia: etiological and management considerations. review. int urol nephrol. 2009; 41:77-83. 8. ahmad i, krishna ns. hemospermia. j urol. 2007; 177:1613-8. 9. polito m, giannubilo w, d'anzeo g, muzzonigro g. hema tospermia: diagnosis and treatment. arch ital urol androl. 2006; 78:82-5. correspondence musa saracoglu, md asst prof musasaracoglu@yahoo.com hakan oztürk, md. asst.prof. (corresponding author) drhakanozturk@yahoo.com.tr basmane hospital of sifa university fevzipasa boulevard no: 172/2, 35240, basmane-konak-izmir, turkey arzu duran, md asst prof arzu.duran@sifa.edu.tr bornova hospital of sifa university sanayi street no: 7, 35100, bornova-izmir, turkey sabri atalay, md drsatalay@yahoo.com tepecik education and research hospital department of infectious diseases and clinical microbiology gaziler street no:468 35120 yenisehir, konak, izmir, turkey 10. klevecka v, jatulis a, kraniauskas v, et al. hemospermia; medicina (kaunas) 2005; 41:359-64. 11. jinza s, noguchi k, hosaka m. retrospective study of 107 patients with hematospermia. hinyokika kiyo. 1997; 43:103-7. 12. kochakarn w, leenanupunth c, ratana-olarn k, viseshsindh v. hemospermia: review of the management with 5 years follow-up. j med assoc thai. 2001; 84:1518-21. saracoglu_stesura seveso 02/04/15 10:27 pagina 82 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 170 case report painful ultrasound detected lesion in the proximal part of the corpus cavernosum: a case of so called “partial priapism”? andrea fabiani 1, flavia tombolini 2, fabrizio fioretti 1, lucilla servi 1, gabriele mammana 3 1 urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche, italy; 2 urologic clinic, polytechnic university of marche region, ancona, italy; 3 chief of urology unit and head of surgery department, macerata civic hospital, area vasta 3 asur marche, italy. partial priapism is a rare disorder generally described in literature as related to an idiopathic etiology leading to the thrombosis of the corpus cavernosum. despite his rarity, this condition has been described in the last years with an increased frequency. it is characterized by thrombosis of the proximal segment of one corpus cavernosum with perineal pain as the more frequent clinical manifestation. few cases were associated with perineal trauma. instrumental appearance suggests for an hematoma in the interstitium of the proximal part of corpus cavernosum. therapy is still controversial. we report a case of a 52-years old man referred to our section of urology suffering from a perineal pain occurred without trauma, sexual arousal or sexual intercourse, during the working office time. laboratory revealed a slightly elevated white blood cells count. the full blood count, protein c reactive, electrolytes, international normalized ratio, activated partial thromboplastin time and urinalysis were within normal range. tunica albuginea was normal. the partial thrombosis of the right corpus cavernosum was hypothesized. treatment was conservative with non steroidal anti-inflammatory drug. only the clinical presentation of symptoms and perineal ultrasound scan performed with color sonography leaded to the diagnosis. eleven days later, at the clinical and ultrasonographic follow-up visit, the patient was asymptomatic with a total clinical and instrumental disappearance of signs of the corpus cavernosum involvement previously described. considering the rarity of the condition, we performed a literature review key words: partial priapism; segmental priapism; penile ultrasound; corpus cavernosum. submitted 13 october 2015; accepted 4 december 2015 summary no conflict of interest declared. also perform a review of similar cases reported in the scientific literature with particular interest on diagnostic and therapeutic management. case report a 52-years old man referred to our section of urology suffering from an acute perineal pain occurred during the working office time, without trauma, sexual arousal or sexual intercourse. onset of symptoms was in the lasting 2 hours from clinical evaluation. medical and pharmacological patient history was unremarkable. no chronic illnesses, no fever, no dysuria, trauma or urethral discharge was referred. on physical examination the pendulous part of the penis was normal without rigidity or inflammation’s signs. distal corpora cavernosa and glans were flaccid. the proximal right corpus cavernosum was tender and painful. perineal color doppler ultrasound scan revealed three anechoic spheroid lesions without the presence of blood flow inside. maximum diameter was 9,78 mm, 7,41 mm and 9,85 mm. the lesions were located around the presumable course of right cavernosal artery (not identified in flaccid state) (figure 1). laboratory revealed a slightly elevated white blood cells count. the full blood count, protein c reactive (pcr), electrolytes, international normalized ratio (inr), activated partial thromboplastin time (aptt) were within normal range. tunica albuginea was normal. the partial thrombosis or interstitial haematoma of the right corpus cavernosum were suggested. the patient was not hospitalized and treated conservatively with analgesic therapy (paracetamol 1000 mg) and non steroidal anti-inflammatory drug (nimesulide 100 mg bd). eleven days later, at the clinical and ultrasonographic follow-up visit, patient was asymptomatic with a total clinical and instrumental disappearance of signs of corpus cavernosum involvement. ultrasound revealed only the residual presence of an hyperechoic lesion without posterior shadow, 4.22 mm in length (figure 2) in the proximal part of the right corpus cavernosum. erectile function was referred normal and no painful. the subsequent hematologic and internistic evaluations revealed no abnormalities. doi: 10.4081/aiua.2016.1.70 introduction partial priapism is a rare condition generally described in literature as related to the thrombosis of the corpus cavernosum. most cases are of an idiopathic nature and very few were associated with perineal trauma. the perineal pain is the more frequent clinical manifestation (1). however, the ultrasound findings may suggest that this condition is expression of an interstitial hematoma of corpus cavernosum as also revealed by images recorded during the follow up of our case reported herein. we fabiani_stesura seveso 08/04/16 11:53 pagina 70 71archivio italiano di urologia e andrologia 2016; 88, 1 painful ultrasound detected lesion in the proximal part of the corpus cavernosum: a case of so called “partial priapism”?. conclusions partial priapism is an unusual clinical condition. in case of perineal acute pain, ultrasonographic evaluation is mandatory. ultrasound appearance may suggest that this condition is expression of an interstitial hematoma of corpus cavernosum as also revealed by the findings founded during the follow up of our case in which the anechoic lesions become progressively hypo echoic until the complete disappearance and substitution by an hyper-echoic lesion without posterior shadow. urologist must know the possibility of the existence of this disorder and that even a conservative management may lead to a full functional and anatomical recovery of corpus cavernosum. interventional approach should be reserved in case of no response of symptoms to medical treatment. references 1. kropman rf, schipper j. hematoma or “partial priapism” in the proximal part of the corpus cavernosum. j sex med. 2014; 11:2618-22. 2. hillis rs, weems wl. priapism: an unusual presentation. j urol. 1976; 116:124-125. 3. del villar m, hernandez c, de bonis w, et al. segmental priapism: a case report. j sex med. 2014; 11 (suppl 5):243. discussion, tables and supplementary references are posted on www.aiua.it figure 1. ultrasound imaging of three anechoic sferoid lesions without the presence of blood flow inside located around the presumable course of right cavernosal artery (not identified) of the proximal part of right corpus cavernosum. figure 2. ultrasound evaluation at follow-up revealed only the residual presence of an hyperechoic lesion without posterior shadow. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, macerata, italy flavia tombolini, md, urology resident flavia.tombolini@gmail.com urologic clinic, polytechnic university of marche region, ancona, italy gabriele mammana, md gabriele.mammana@sanita.marche.it head surgery dpt, chief of section of urology asur marche area vasta 3, macerata hospital, italy fabiani_stesura seveso 08/04/16 11:53 pagina 71 stesura seveso 23archivio italiano di urologia e andrologia 2016; 88, 1 original paper the degree of satisfaction of women undergoing surgical repair of prolapse, compared with clinical and urodynamic findings carlo vecchioli-scaldazza 1, carolina morosetti 2, vincenzo ferrara 1 1 divisions of urology, 2 clinical pathology, asur, area vasta n° 2, jesi, italy. obiective: to assess the degree of satisfaction of women undergoing surgical repair of prolapse, compared with the clinical and urodynamic findings. materials and methods: 72 women hospitalized for pelvic organ prolapse (pop) were enrolled in this prospective study. patients underwent clinical evaluation and urodynamic study before and 4 months after pop repair. women were assessed for urinary symptoms by micturition diary and patient perception of intensity of urgency scale. women were also questioned about defecation and sexual life. pop repair was performed in all cases without the use of a mesh. subjective evaluation was performed by patient global impression of improvement questionnaire. results: 56 women were evaluable. improvements were found in all micturition symptoms and in particular in voiding symptoms. feeling of vaginal bulging disappeared in all patients. a slight improvement was found in constipation; 62% of patients had a normal sexual life but 27% refrained from sexual activity. judgement of patients was between “much improved” and “very much improved”. conclusions: disappearance of the feeling of vaginal bulging was by far the best result. improvements were found in most of the symptoms particularly in voiding symptoms and urodynamic findings. key words: genital prolapse; pelvic organ prolapse surgery; voiding dysfunction; urodynamics; sexual function. submitted 9 october 2015; accepted 15 january 2016 summary no conflict of interest declared. tions; obstructed defecation with the need to strain or reduce the bulge digitally to defecate; sexual disorders, perineal pain and vaginal bulging (4-7) may be described by the patients. however a lot of the studies evaluated only some specific aspects of the question such as the presence of overactive bladder symptoms (oab) and/or detrusor overactivity before and after pop repair (8-13), the impact of prolapse surgery on sexual function (14) or anorectal disorders (4). in this study we considered women with pop to assess changes in symptoms and urodynamic findings before and after prolapse repair, comparing them with the degree of satisfaction of patients. materials and methods from january 2014 to september 2014, 72 women (mean age 64 years; range 48-82) hospitalized for pop were enrolled in this prospective study. all patients underwent a detailed clinical evaluation including a complete history and physical examination. patients with neurological disease, pelvic tumors, previously treated with pelvic surgery and particularly with hysterectomy, pop repair, urinary incontinence surgery and radiation therapy, were excluded. pop was evaluated and graded according to pelvic organ prolapse quantification (pop-q) with the patients in the lithotomy position and maximum straining effort. all patient underwent urodynamic investigation; the study was performed without the prolapse reduction because such reduction can relieve urologic symptoms, which can have an influence on the evaluation of the lower urinary tract function. the study included spontaneous uroflowmetry with post void residual measurement, water cystometry (filling rate 30 ml/min; catheter used: 6 fr double lumen; patients’ position: sitting) with pressure/flow study. parameters evaluated were maximum flow rate (qmax), post-void residual urine (pvr), cystometric capacity (cc), detrusor pressure at maximum flow (pdetqmax) and detrusor overactivity (do). patients were assessed for urinary symptoms. urinary storage symptoms (daytime frequency, nocturia and urinary incontinence) were evaluated by 3-day micturition diary; voiding symptoms and post micturition symptoms (hesitancy, straining, terminal doi: 10.4081/aiua.2016.1.23 introduction pelvic organ prolapse (pop) is an abnormal loss of support of one or more of the pelvic organs leading to prolapse into or outside the vagina (1). it is a condition affecting up to 30% of women (2) and is the most common indication for hysterectomy in women older than 55 years (3). pop may be totally asymptomatic or it may affect the quality of life of women causing physical, psychological and sexual limitations. (2). women with pop often present a complexity of symptoms in relation to the pop stage and the structures involved (urethra, bladder, uterus, bowels and rectum): urinary symptoms such as incontinence or poor stream, hesitancy, straining to void, incomplete emptying, recurrent urinary tract infecvecchioli_stesura seveso 08/04/16 11:27 pagina 23 archivio italiano di urologia e andrologia 2016; 88, 1 c. vecchioli-scaldazza, c. morosetti, v. ferrara 24 dribble and feeling of incomplete bladder emptying) were evaluated by individual perception. urgency was assessed by patient perception of intensity of urgency scale (ppius) represented by a 5-point scale from 0 (no urgency) to 4 (urge incontinence). women were also questioned about the impact of pop on their sexual life and defecation. all patients underwent pop repair without the use of a mesh and a standard fascial anterior repair was performed when anterior compartment was involved; the repair was often carried out in conjunction with transvaginal hysterectomy. none of these patients underwent simultaneously surgery for urinary incontinence. all procedures were performed by the same surgeon. post operative assessment was undertaken at 4 months. patients repeat urodynamic study, 3-day micturition diary and clinical evaluation. afterwards, the subjective evaluation of symptoms and the degree of satisfaction of patients after pop repair were assessed with patient global impression of improvement questionnaire (pgi-i): this is a 7-point scale from “very much improved” (score 1), to “very much worse” (score 7). the research was approved by the institutional review board and the local ethics committee and all patients signed informed consent before starting the study. statistical analysis was performed using the medcalc software package (version14.12.0). data were expressed as means ± sd. comparisons were carried out using the wilcoxon test for paired samples and chi square test. a p value < 0.05 was considered significant. results of the 72 women initially enrolled, 56 (mean age 63 years, range 48-79) agreed to repeat urodynamic study and clinical evaluation and were evaluable for the study. the vaginal compartment involved and the stage of pop are described in table 1: a great number of women with pop stage iii°-iv° and a greater involvement of the anterior and central vaginal compartment were observed. the surgical procedures undertaken are described in table 2. vaginal hysterectomy with anterior repair was the most performed surgical treatment. patients’ characteristics with symptoms and sexual activity expressed in percentages before and after surgery with patients’ evaluation of clinical results are summarized in table 3. improvements were present in urinary symptoms particularly in voiding symptoms but increased daytime frequency, nocturia, urgency and urinary incontinence persisted respectively in 32, 43, 36 and 41 percent of patients after surgery. a slight improvement was found in constipation but the best clinical result was found in feeling of vaginal bulging, which disappeared after surgery in all patients. improvements were found in sexual activity with 62% of women describing a normal sexual life after pop repair but 27% of patients refrained completely from sexual activity because of discomfort or pain and for fear of damaging pop repair. the degree of satisfaction of patients after surgical pop repair was 1.7 of pgii scale that is a judgment between “much improved” and “very much improved”, confirming the efficacy of this treatment in improving the quality of life of patients. table 4 presents a statistical analysis of urinary sympcompartment involvement stage (sec. pop-q) n° i° ii° iii°iv° anterior 56 0 4 52 central 52 0 0 52 posterior 4 0 0 4 before surgery after surgery n° of patients (%) n° of patients (%) patients n° 56 age 63 (48-79) bmi 25.4 (18.5-33.3) pgi-i 1.7 symptoms increased daytime frequency 36 (64) 18 (32) nocturia 33 (59) 24 (43) urgency 33 (59) 20 (36) urinary incontinence 27 (48) 23 (41) hesitancy 47 (84) 9 (16) straining 29 (52) 3 (5) terminal dribble 36 (64) 9 (16) feeling of incomplete bladder emptying 44 (78) 9 (16) constipation 17 (30) 15 (27) gas or solid stool incontinences 0 (0) 0 (0) vaginal bulge 52 (93) 0 (0) sexual activity normal sexual activity 10 (18) 35 (62) sexual activity affected by prolapse 35 (62) 0 (0) no sexual activity because of prolapse 5 (9) 0 (0) no sexual activity because of surgery 15 (27) no sexual activity for other reasons (widows, sisters) 6 (11) 6 (11) table 1. compartment involvement and stage of prolapse sec. pop-q. type of procedure n° vaginal hysterectomy + anterior repair only 48 vaginal hysterectomy + anterior and posterior repair 4 anterior repair 4 table 2. procedure undertaken. table 3. patient characteristics, evaluation of clinical results, symptoms and sexual activity before and after surgery. before surgery after surgery p urinary symptoms daytime frequency 9.8 ± 2.48 8.36 ± 1.77 < 0.0001 nocturia 1.13 ± 1.3 0.59 ± 0.75 0.0229 urgency 1.34 ± 1.21 0.64 ± 0.81 0.0002 urinary incontinence 1.18 ± 1.43 0.54 ± 0.94 0.1092 hesitancy 47 9 < 0.0001 * straining 29 3 < 0.0001 * terminal dribble 36 9 < 0.0001 * feeling of incomplete emptying 44 9 < 0.0001 * statistical analysis performed with wilcoxon test for paired samples except (*) performed with chi square test. table 4. urinary symptoms evaluated with statistical analysis. vecchioli_stesura seveso 08/04/16 11:27 pagina 24 25archivio italiano di urologia e andrologia 2016; 88, 1 prolapse repair and degree of satisfaction of women toms. all parameters evaluated except urinary incontinence, showed statistically significant improvements. urodynamic parameters analyzed are reported in table 5. a significant increase in qmax with a reduction of pvr were found at uroflowmetry. cc did not show a significant change in cystometry but a reduction in the values of pdetqmax was found in pressure/flow study. the number of patients with do decreased without a statistical significance. discussion we evaluated the degree of satisfaction of the women using pgi-i questionnaire because it included an overall assessment of the outcome of the surgical therapy. we also evaluated, before and after pop repair, variations in individual symptoms using both statistical investigation and variations in percentages. this method enabled us to observe how the statistically significant reduction of a symptom was often associated with the persistence of the same symptom in a sizeable percentage of patients. improvement in the urinary symptoms particularly in voiding and post micturition symptoms was found after pop repair. however, while micturition symptoms decreased, the number of symptomatic patients was still sizeable: 32% out of 64 (daytime frequency) and 43% out of 59 (nocturia). urgency evaluated by ppius significantly improved, but 36% out of 59 of patients were still symptomatic. oab symptoms usually improve after pop surgical repair or replacement of pessaries (11, 8, 15), but they can remain after treatment due to other causes as ischemic changes produced by aging (16); furthermore, about 20% of women develop oab after surgery (9). there is no agreement about a relationship between prolapsed compartment, stage and symptoms. some authors believe that the involvement of the anterior compartment is the main cause of oab symptoms (17, 15): the distension of stretch receptors of the urothelium due to the descent of the trigone into the anterior vaginal wall and the denervation of autonomic nerve supply to the detrusor muscle caused by the urethral obstruction are considered the main causes (12, 15, 18, 19-21). in this study the significant improvement shown by voiding and post micturition symptoms were due to the improvement of obstruction caused by pop repair. the increase of qmax, the reduction of pvr and the reduction of pdetqmax at urodynamic study confirm these results. several studies have shown that obstruction is frequently observed in women with severe prolapse (22-24) and pop repair produces improvement in both obstruction and urodynamic findings (8, 16, 22-25). however, no significant change in urodynamic findings after surgery were recorded by stanton sl et al. (27) and rosenzweig et al. (28). ling et al. (29), in their research, pointed out that 70% of patients with severe pop and elevated pvr with voiding difficulty symptoms had urodynamic evidence of obstruction only in one third of cases. unsatisfactory results after pop repair can be found in patients with impaired detrusor contractility, such as in three cases we observed. decreased detrusor contractility may depend on aging of patients as well as the persistence of the obstruction as occurs in men with prostatic hypertrophy. do decreased after surgery but not significantly in this study in line with the results of other authors (13). as for oab, following pop repair, do can improve or persist when the causes are different from prolapse or even arise de novo, due to the surgery. feeling of vaginal bulging was found in 93% of patients before surgery and four months after pop repair it disappeared in all women: this is the best surgical outcome. vaginal bulging is related to the pop stage and 52 out of 56 evaluable women showed a stage iii-iv. disappearance of vaginal bulging was particularly emphasized by patients during clinical evaluation performed 4 months after surgery. a significant correlation between pop stage and vaginal bulging was described by marijke et al. (17) and vaginal bulging was considered the main aspect related to prolapse by pakbaz et al. (30). constipation was the principal negative factor of defecation, whereas no cases of gas or solid stool incontinences was observed. this finding is probably related to the only 4 patients with involvement of the posterior compartment present. a relation between posterior compartment prolapse and bowel disorders including incontinence of flatus, were described by marijke et al. (17) and jelovsek et al. (4). after pop repair only 2 out of 17 women were asymptomatic but constipation is a symptom also found in patients with involvement of different vaginal compartments; furthermore, it is unlikely that prolapse is a significant contributor to constipation (4). normal sexual activity improved after pop repair with 62% of women reporting a normal sexual life compared to 18% observed before surgery. this data is in agreement with findings of other authors (31, 32). an interference of pop with sexual activity was reported by pakbaz et al. (30) in more than 30% of women. we performed pop repair without the use of mesh. the use of mesh is neither associated with a worsening in sexual function nor with an increase in the novo dyspareunia compared with traditional colporraphy (14). the occurrence of dyspareunia after mesh is described in a percentage ranging between 5% and 28%. (33). however 27% of patients in our experience refrained completely from sexual activity because of discomfort or pain as well as of the fear of damaging pop repair. many studies have been carried out on pop and we now have access to a lot of data. various aspects of pop have been analysed for a better understanding especially of the cause of symptoms, their relationship with the degree of prolapse, the prolapsed compartment and the effect that surgery can have on symptoms. the complexity of symptoms and the dynambefore surgery after surgery p urodynamic parameters qmax (ml/s) 12.29 ± 5.79 13.88 ± 4.80 0.0071 pvr (ml) 64.94 ± 59.39 42.65 ± 33.35 0.0405 cc (ml) 435.69 ± 178.84 420.88 ± 166.83 0.0635 do (n° of patients) 11 6 0.1879 * pdetqmax (cmh2o) 36.71 ± 20.18 30.65 ± 10.30 0.0029 do expressed in number of patients. statistical analysis performed with wilcoxon test for paired samples except (*) performed with chi square test. table 5. urodynamic findings before and after surgery. vecchioli_stesura seveso 08/04/16 11:27 pagina 25 archivio italiano di urologia e andrologia 2016; 88, 1 c. vecchioli-scaldazza, c. morosetti, v. ferrara 26 ics of the vaginal compartments after surgery make it difficult to evaluate the effects of surgery (34, 35). furthermore, a simple anatomical correction of prolapse may not be able to improve the symptoms (36). there are still many different opinions about prolapse and data are often contradictory. to a large extent this could be attributed to the great variability of patients. in our study, however, nearly all the patients presented iii°-iv° grade prolapse of anterior and central compartment. however, hysterectomy performed in almost all cases of pop repair may be a potential source of bias and the few cases with involvement of the posterior compartment can explain the few defecation symptoms reported by patients. furthermore, the older age of women enrolled could itself be a cause of symptoms. conclusions improvements in different percentages were found in most of the symptoms considered but the disappearance in all patients of the feeling of vaginal bulging represents the best surgical outcome. significant improvements were also found in voiding symptoms and urodynamic findings. references 1. milsom i, altman d, lapitan mc, et al. epidemiology of urinary (ui) and fecal (fi) incontinence and pelvic organ prolapse (pop). in: abrams p, cardozo l, khoury s, wein a, editors. chapter 1 in epidemiology in incontinence 4th international consultationon incontinence, 4th edition, paris, july 5-8 2008. health publication ltd; 2009. 2. samuelsson ec, arne victor ft, tibblin g, svardsudd kf. signs of genital prolapse in a swedush population of women 20 to 59 years of age and possible related factors. am j. obstet gynecol. 1999; 180:299-305. 3. wilkox ls, koonin lm, pokras r, et al. hysterectomyin the united states 1988-1990. obstet gynecol. 1994; 83:549-555. 4. jelovsek je, barber md, paraiso mfr, walters md. functional bowel and anorectal disorders in patients with pelvic organ prolapse and incontinence. am j obstet gynecol 2005; 193:2105-2111. 5. mouritsen l. classification and evaluation of prolapse. best pract res clin obstet gynaecol. 2005; 19:895-911. 6. rogers gr, villarreal a, kammerer-doak d, qualls c. sexual function in women with and without urinary incontinence and/or pelvic organ prolapse. int urogynecol j pelvic dysfunction. 2001; 12:361-365. 7. albers ll, borders n. minimizing genital tract trauma and related pain following spontaneous vaginal birth. j midwifery womens health. 2007; 52:246-253. 8. basu m, duckett jra. effect of prolapse repair on voiding and relationship to overactive bladder and detrusor overactivity. int urogynecol j. 2009; 20:499-504. 9. dietz-itza i, alpitarte i, becerro a, sarasqueta c. incidence of overactive bladder after vaginal hysterectomy and associated repairs for pelvic organ prolapse. gynecol obstet invest. 2009; 68:65-70. 10. zheng yong yuan, hong shen. pelvic organ prolapse quantification in women referred with overactive bladder. int urogynecol j. 2010; 21:1365-1369. 11. digesu a, salvatore s, chaliha c, et al. do overactive bladder symptoms improve after repair of anterior vaginal wall prolapse? int urogynecol j. 2007; 18:1439-1443. 12. patil a, duckett j. effect of prolapse repair on voiding and bladder overactivity. curr opin obstet gynecol. 2010; 22:399-403. 13. de boer ta, salvatore s, cardozo l, et al. pelvic organ prolapse and overactive bladder. neurourol urodyn. 2010; 29:30-39. 14. dietz v, maher c. pelvic organ prolapse and sexual function. 2013; 24:1853-1857. 15. serati m, salvatore s, siesto g, et al: urinary symptoms and urodynamic findings in women with pelvic organ prolapse: is there a correlation? results of an artificial neural network analysis.europ urol. 2011; 60:253-260. 16. fletcher sg, haverkorn rm, yan j, et al. demographic and urodynamic factors associated with persistent oab after anterior compartment prolapse repair. neurourol urodyn. 2010; 29:1414-1418. 17. slieker-ten hove mc, pool-goudzvaard al, eijkemans mjc, et al: the prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population. int urogynecol j pelvic floor dysfunct. 2009; 20:10371045. 18. gosling ja, gilpin sa, dixon js, gilpin gj. decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. j urol. 1986; 136:501-504. 19. harrison sc, hunnam gr, farman p, et al. bladder instability and denervation in patient with bladder outflow obstruction. br j urol. 1987; 60:519-522. 20. harrison sc, ferguson dr, doyle pt. effect of bladder outflow obstruction on the innervation of the rabbit urinary bladder. br j urol. 1990; 66:372-379. 21. sibley gn: the physiological response of the detrusor muscle to experimental bladder outflow obstruction in the pig. br j urol. 1987; 60:332-336. 22. romanzi lj, chaikin dc, blaivas jg: the effect of genital prolapse on voiding. j urol 1999;161:581-586. 23. groutz a, blaivas jg, chaikin dc. bladder outlet obstruction in women: definition and characteristics. neurourol urodyn. 2000; 19:213-220. 24. nguyen jk, bhatia nn. resolution of motor urge incontinence after surgical repair of pelvic organ prolapse. j urol. 2001; 166:2263-2266. 25. robinson d, staskin d, laterza rm, koelbl h. defining female voiding dysfunction:ici-rs 2011. neurourol urodyn. 2012; 31:313316. 26. romanzi lj, chaikin dc, rosenthal jr, et al. the effects of a pessary on parameters of micturition in women with severe genital prolapse. j urol. 1998; 159:216-21 27. stanton s, hilton p, norton c, cardozo l. clinical and urodynamic effects of anterior colporraphy and vaginal hysterectomy for prolapse with and without incontinence. br j urol. 1982; 89:459-463. 28. rosenzweig ba, soffici ar, thomas s, bhatia nn. urodynamic evaluation of voiding in women with cystocele. j reprod med. 1992; 37:162-166. 29. ling c, chang y, lin y, chang s. significance of bladder trabeculation in postmenopausal women with severe pelvic organ prolapse: clinical and urodynamic assessments. menopause. 2013; 20:813:817. vecchioli_stesura seveso 08/04/16 11:27 pagina 26 27archivio italiano di urologia e andrologia 2016; 88, 1 prolapse repair and degree of satisfaction of women 30. pakbaz m, rolfsman e, mogren i, lofgren m. vaginal prolapseperceptions and healthcare-seeking behaviour among women prior to gynaecological surgery. acta obstet gynecol. 2011; 90:11151120. 31. ghielmetti t, kuhn p, dreher ef, kuhn a. gynaecological operations: do they improve sexual life? eur j obstet gynecol reprod biol. 2006; 129:104-110. 32. komesu ym, rogers rg, kammerer-doak dn, et al. posterior repair and sexual function. am j obstet gynecol. 2007; 197:101e1101e6. 33. milani r, salvatore s, soligo m, et al. functional and anatomical outcome of anterior and posterior vaginal prolapse repair with prolene mesh. bjog. 2005; 112:107-111. 34. hullfish kl, bovbjerg ve, gibson j, steers wd. patient-centered goals for pelvic floor dysfunction surgery: what is success, and is it achieved? am j obstet gynecol. 2001; 187:88-92. 35. crafoord k, sydsjo a, johansson t, et al. factors associated with symptoms of pelvic floor dysfunction six years after primary operation of genital prolapse. acta obstet gynecol. 2008; 87:910-915. 36. basu m, duckett j. the association of changes in opening detrusor pressure with the resolution of overactive bladder symptoms after repair of pelvic organ prolapse. neurourol urodyn. 2011; 30:595-598. correspondence carlo vecchioli-scaldazza, md (corresponding author) cascave@alice.it division of urology, asur, area vasta n°2, jesi, italy corso cavour 66, 62100 macerata, italy carolina morosetti,md c.morose@libero.it clinical pathology, asur, area vasta n°2, jesi, italy vincenzo ferrara, md vincenzoferrara4@gmail.com division of urology, asur, area vasta n°2, jesi, italy vecchioli_stesura seveso 08/04/16 11:27 pagina 27 stesura seveso 207archivio italiano di urologia e andrologia 2013; 85, 4 introduction neoplastic invasion of the inferior vena cava occurs in 515% of the patients with renal cancer (1). in these cases, curative resection might be possible with reasonablelong-term survival. various surgical techniques have been described for these tumors (2, 3). because of the complexity of achieving vascular control, surgical treatment in deep hypothermic circulatory arrest using cardiopulmonary bypass has been established as an interdisciplinary concept (3-6). we report the case of a patient affected by severe double coronary artery disease and voluminous renal cell carcinoma with extended intravascular growth into the inferior vena cava. case report in a 75-year-old man (180 cm, 75 kg) a computed tomography (ct) scan demonstrated a malignant tumor (85x64x88 mm) of the right kidney with continuous growth of a tumor cone into the subdiaphragmal vena cava (figure 1). case report simultaneous management of renal carcinoma with caval vein thrombosis and double coronary artery disease marco grasso 1, salvatore blanco 1, francesco formica 2, giovanni paolini 2, angelica anna chiara grasso 3 1 urology department, san gerardo hospital, university of milano-bicocca; 2 cardiac surgery clinic department of surgical science and translational interdisciplinary medicine university of milano-bicocca; 3 urology department, fondazione irccs ca’ granda ospedale maggiore policlinico, university of milan, italy. introduction: recent advances in surgical and anesthesiology techniques allow simultaneous thoracic and abdominal operations to be performed for severe heart disease and benignant or malignant abdominal diseases. case report: the simultaneous surgical management in a 75-year-old patient suffering from severe double coronary artery disease and a renal cell carcinoma with extended intravascular growth into the inferior vena cava is reported. conclusion: the postoperative course was uneventful. simultaneous surgery proved to be beneficial and safe, showing optimal results in our patient. key words: kidney tumor; coronary heart disease; caval thrombus; hypothermic circulatory arrest. submitted 3 july 2013; accepted 31 july 2013 no conflict of interest declared summary figure 1. right kidney mass with continuous growth into the subdiaphragmal vena cava. doi: 10.4081/aiua.2013.4.207 archivio italiano di urologia e andrologia 2013; 85, 4 m. grasso, s. blanco, f. formica, g. paolini, angelica a.c. grasso 208 the reported symptoms were microhematuria, cough and evening fever. the ecg demonstrated signs of a small previous lateral infarction. coronary angiography and ventriculography revealed a severe double-vessel coronary artery disease and a concentric remodeling hypertrophy of the left ventricular with normal ejection fraction (0.63). the operation was conducted with an interdisciplinary approach by urologists and cardiothoracic surgeons. in the first step of the operation, urologists performed the radical right nephrectomy through a median laparotomy. in the second step a median sternotomy was performed. the left internal mammary artery (lima) and a segment of saphenous vein were harvested. systemic heparinization was established by administering 300 iu/kg with an activated clotting time target > 480 seconds. cardiopulmonary bypass (cpb) was initiated by ascending aorta cannulation with a 22 f arterial cannula and by a right atrial appendage cannulation with a 52 f venous cannula. cpb was started and the patient’s body was cooled up to 20°c of esophageal temperature. during body cooling, coronary artery bypass grafts were performed on beating heart. vein graft was distally anastomosed on the obtuse marginal branch with a running 7-0 monofilament polypropylene suture. the proximal site of the vein graft was anastomosed on the ascending aorta by the heartstring device (maquet, hirrlingen, germany) with a running 6-0 monofilament polypropylene suture without clamping the ascending aorta. finally, the lima was distally anastomosed on the left anterior descending artery with a running 8-0 monofilament polypropylene suture. the heart initiated to fibrillate at 27°c degree and the left ventricle was vented trough a 18 f catheter inserted into the left ventricle through the right upper pulmonary vein. hypothermic circulatory arrest (hca) was established when the body reached a 20°c of esophageal temperature and it was maintained while tumor-thrombus was being removed from the abdominal inferior vena cava (ivc). abdominal ivc was open through a 5 cm longitudinal incision. complete tumor-thrombus resection was performed under direct vision by advancing a foley catheter and by forceps. direct vision, several index finger maneuvers and the use of intraoperative transesophageal echocardiography confirmed the complete tumor resection. the opening of right atrium was not necessary. cavotomy was closed with a running 4-0 monofilament polypropylene suture without narrowing the lumen. cpb was restarted after 32 minutes of hca and the body was progressively heated until 36°c of esophageal temperature. then the cpb was rapidly weaned off and heparin was antagonized with sulphate protamine. after closure of the thorax and the abdomen the patient was transferred to the post-operative intensive care unit. perioperatively the patient received 6 units of red blood cells, 3 units of fresh frozen plasma and 1 unit of platelets. extubation was achieved 12 hours postoperatively. anticoagulation using only intravenous heparin was applied for 7 days. the patient was transferred to the normal ward on the second post-operative day. the postoperative course in the ward was uneventful and the patient was transferred to the rehabilitation clinic on the 30th postoperative day. discussion the number of patients who have both critical coronary artery disease (cad) and surgically resectable cancer concomitantly has been raising as the proportion of elderly in the general population increases, therefore new figure 2. cavotomy. figure 3. intraoperative endoesophageal ultrasound, showing the caval thrombus. 209archivio italiano di urologia e andrologia 2013; 85, 4 simultaneous management of renal carcinoma with caval vein thrombosis and double coronary artery disease routes have been attempted to deal with concomitant life-threatening pathologies (7). tumors invading the juxtahepatic caval vein require an interdisciplinary therapeutic approach and hypothermic circulatory arrest. recent advances in surgical and anesthesiology techniques allow simultaneous thoracic and abdominal operations. despite the aggressiveness and biological invasiveness of the tumor and the intervention performed in deep hypothermia and circulatory arrest, the results are encouraging (8). westaby documented the increased operative risk for non-cardiac procedures performed on individuals with major coronary artery disease (9), but postponing the tumor resection might increase the risk of exposure to the immunosuppressive effects of cardio-pulmonary bypass, which can have a harmful effect on tumor growth and spreading (10-11). furthermore the doubling of costs which can be avoided has to be considered. conclusion to our knowledge only few similar cases were reported in literature,franke reports a case in which the bypass was performed during cardioplegia in the heating phase (12), whereas in our patient the bypass was performed on the beating heart during the cooling phase. in high surgical experience centers, a multidisciplinary approach can ensure a safe and optimal treatment. references 1. langenburg se, blackbourne lh, sperling jw, et al. management of renal tumors involving the inferior vena cava. j vast surg. 1994; 20:385-8. 2. welz a, schmeller n, schmitz c, et al. resection of hypernephromas with vena caval or right atrial tumor extension using extracorporeal circulation and deep hypothermic circulatory arrest: a multidisciplinary approach. eur j cardio-thorac surg. 1997; 12:127-132. 3. baumgartner f, milliken j, scudamore c, et al. extracorporeal methods of vascular control for difficult ivc procedures. am surg. 1996; 62:246-248. 4. glazer aa, novick ac. long-term followup after surgical treatment for renal cell carcinoma extending into the right atrium. j urol. 1996; 155:448-450. 5. laas j, schmid c, allhoff e, borst hg. tumor-related obstruction of the inferior vena cava extending into the right heart – a plea for surgery in deep hypothermic circulatory arrest. eur j cardio-thorac surg. 1991; 5:653-656. 6. wickey gs, martin de, larach dr, et al. combined carotid endarterectomy, coronary revascularization, and hypernephroma excision with hypothermic circulatory arrest. anesth analg. 1988; 67:473-476. 7. takahashi t, nakano s, shimazaki y, et al. concomitant coronary bypass grafting and curative surgery for cancer. surg today. 1995, 25:131-135. 8. navia jl, brozzi na, nowicki er, et al. simplified perfusion strategy for removing retroperitoneal tumors with extensive cavoatrial involvement. j thorac cardiovasc surg. 2012; 143:1014-21. 9. westaby s. complement and the damaging effects of cardiopulmonary bypass. thorax. 1983; 38:321-325. 10. hill ge, whitten cw, landers df. the influence of cardiopulmonary bypass on cytokines and cell-cell communication. j cardiothorac vasc anesth. 1997; 11:367-375. 11. darwazah ak, osman m, sharabati b. use of off-pump coronary artery bypass surgery among patients with malignant disease. j card surg. 2010; 25:1-4. 12. franke uf, wahlers t, wittwer t, schubert j. renal carcinoma with caval vein infiltration and triple coronary disease: one-stage surgical management. eur j cardiothorac surg. 2001; 20:877-9. correspondence marco grasso, md (corresponding author) urology department grasso.m@virgilio.it salvatore blanco, md urology department sblanco_74@yahoo.it francesco formica, md cardiac surgery clinic department of surgical science and translational interdisciplinary medicine f.formica@hsgerardo.org giovanni paolini, md cardiac surgery clinic department of surgical science and translational interdisciplinary medicine g.paolini@hsgerardo.org azienda ospedaliera san gerardo via pergolesi 33 20900 monza, italy angelica anna chiara grasso, md urology department angelicagrasso84@gmail.com fondazione irccs ca’ granda ospedale maggiore policlinico, via della commenda 15, 20100 milano, italy stesura seveso 33archivio italiano di urologia e andrologia 2014; 86, 1 original paper in-vitro effects of pde5 inhibitor and statin treatment on the contractile responses of experimental mets rabbit's cavernous smooth muscle yasin erden 1, esat korgalı 1, gokce dundar 1, semih ayan 1, gökhan gokce 1, sahin yildirim 2, emin yener gultekin 1 1 cumhuriyet university school of medicine department of urology, turkey; 2 cumhuriyet university school of medicine department of pharmachology, turkey. objective: hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and decreased nitric oxide bioactivity in cavernosal tissue. the role of nitric oxide on erectile function is well known. statins have lipid lowering properties and can modulate endothelial nitric oxide bioavailability. sildenafil, enhances smooth muscle relaxation in corpus cavernosum. we invastigated in-vitro effects of sildenafil and rosuvastatin on nonadrenergic, non-cholinergic and nitric oxide mediated cavernosal smooth musle relaxation in metabolic syndrome rabbits, since alterations in this pathway are recognised in diabetic and hypercholesterolemic erectile dysfunction. methods: ten male rabbits were fed a standart diet as control group, fourty male rabbits were fed a hypercholesterolemic diet for 12 weeks. hypercholesterolemic group were divided for without treatment, rosuvastatin treatment, sildenafil teratment, and rosuvastatin + sildenafil treatment (n = 10 per groups). results: serum levels of cholesterol and glucose were significantly higher in the experimental group than in the control group (p < 0.05). after theraphy no differences were found among the groups in relaxation responses to sodium nitroprusside. the relaxation responses to carbachol and efs were significantly reduced in metabolic syndrome group to control group (p < 0.05), but there were no differences between the other groups and control group. there was a significantly lower in-vitro relaxation response in the metabolic syndrome rabbits than in controls and the others (p < 0.05). conclusion: both agents improve in-vitro relaxation responses of erectile tissue from metabolic syndrome rabbits to endothelial non-adrenergic, non-cholinergic and nitric oxide. this finding supports to the results of other clinical studies with these drugs. key words: erectile dysfunction; metabolic syndrome; sildenafil; rosuvastatin. submitted 6 september 2013; accepted 31 december 2013 summary introduction metabolic syndrome (mets) is characterized by insulin resistance (impaired glucose tolerance, hyperinsulinemia and type 2 diabetes), visceral fat accumulation, dyslipidemia (low levels of high-density lipoprotein cholesterol and hypertriglyceridemia) and hypertension and increased risk of metabolic and cardiovascular diseases and erectile dysfunction (1). subjects with mets have a higher prevalence of sexual dysfunction, and in particular erectile dysfunction (ed) (2, 3). in subjects with sexual dysfunction, the prevale nce of mets is age dependent and at midlife could affect almost the half of the population (4). moreover, ed has been recognized as a precursor of forthcoming cv diseases due to same factors impairing both penile and systemic vascular blood flow (5, 6). hyperglycemia, oxidative stress, and impaired lipid profiles conduce to vascular complications, including peripheral nerve perfusion deficits, which play an important role in the etiology of diabetic neuropathy. epidemiological studies have detected that dyslipidemia is an independent risk factor for diabetic neuropathy and ed among diabetic and mets patients (7-9). nowadays selective pde5 inhibitors are used as first line therapy in the treatment of ed and are highly effective and safely. the efficacy of sildenafil was approved in vivo and in vitro, in both animal and human studies (10, 11). the efficacy of pde5 inhibitors in diabetes mellitus, hyperlipidemia or dyslipidemia and hypertension extensively studied and demonstrated beneficial effect with several studies (12). statins are the mainstay of the management of dyslipidemia (13). rosuvastatin is a statin, of which potency has been proved remarkably proved in reducing lowdensity lipoprotein cholesterol levels. on the other hand, rosuvastatin has extra-lipid effects and these effects are on endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, homeostasis, cardiac muscle, and components of the nervous system (14). the effect of lipid-lowering therapies on erectile function have been studied in men with ed, along with some studies including pde5 inhibitors (15-18). these studies sugno conflict of interest declared doi: 10.4081/aiua.2014.1.33 erden_stesura seveso 26/03/14 10:19 pagina 33 archivio italiano di urologia e andrologia 2014; 86, 1 y. erden, e. korgalı, g. dundar, s. ayan, g. gokce, s. yildirim, e. yener gultekin 34 gested that as statins improve erectile function and also may ameliorate endothelial function as well, through its lipid-lowering, anti-inflammatory and antioxidant impacts (19). the use of animal models is important in the researches of ed with dyslipidemia. a non-genomic model of mets was developed by exposing rabbits to a high-fat diet (hfd) and dislipidemia has been shown to cause reduced erectile function in rabbits in in vitro studies, it has yet to be confirmed in a conscious in vivo model (20). in this experimental study, we aimed to investigate the effects of sildenafil, rosuvastatin and combination of both drug therapy in normal and mets rabbits, as the phosphodiesterase-5 (pde-5) inhibitor sildenafil is widely used for treating erectile dysfunction (ed) and as hmgcoa (3-hydroxy-3methylglutaryl coenzyme a) reductase inhibitor rosuvastatin is one of the most common drugs used in hyperlipidemic patients. materials and methods animals adult male new zealand white rabbits (saki yenilli experimental animal production laboratory ankara, turkey), weighing about 3 kg, were individually caged under standard conditions in a temperature and humidity controlled room on a 12-hr light/dark cycle. water and food were unrestricted during the study period. all experimental procedures were approved by animal experimental study local ethics committee of our medical school and were conducted in accordance with nih guidelines for the care and use of laboratory animals. creating metabolic syndrome model after 1 week of standard rabbit diet, animals were randomly divided into control (n = 10), mets (group a) (n = 10) and treatment groups (b, c, d) (n = 10 each group). the control group was maintained to be fed with a standard diet (control) while mets and the treatment groups received hfd, modified form of a previously described protocol, constituted by 0.5% cholesterol and 20% butter providing 65% of total energy need from lipids (hfd rabbit) for 12 weeks (20). at the end of 12th week, therapy group was divided three groups. all of therapy groups and mets group were fed high fat diet and one group received rosuvastatin (crestor; astrazeneca) 20 mg/kg/day (group b) as an oral gavage, the other group received sildenafil (viagra; pfizer) 5 mg/kg/day (group c) as an oral gavage, and the remaining group received combination of rosuvastatin 20mg/kg/day and sildenafil 5 mg/kg/day (group d) during 6 weeks. rabbits weights were recorded at the beginning of study, at 12th week and at the end of the study. blood samples for glucose, total cholesterol, triglycerides, ldl, hdl analyses were obtained from the animals via marginal ear vein at week 0 (baseline), at week 12 and at the end of the study in all groups. plasma cholesterol, triglycerides, and glucose levels were measured by using an automated system (advia 1800 24004 siemens chemistry system; siemens science medical solution diagnostic, ny, usa). in vitro functional studies all rabbits were anesthetized with isoflurane and euthanized. the entire penis was then removed, separated corpus spongiosum and urethra. each corpus cavernosa was dissected into four strips of 5 x 15 mm. isolated cavernous strips were suspended in 10 ml organ baths containing krebs-hco3 solution with the following composition. (mm): 118 nacl, 4.7 kcl, 2.5 cacl2, 1.2 mgso4, 1.2 kh2po4, 25 nahco3, and 11 glucose, ph 7.4, at 37°c and bubbled with a gas mixture of 95% o2 and 5% co2. the cavernous strips were equilibrated for approximately 60 min during which the buffer solution was refreshed every 15 min. pretension of 2 gr was applied to all strips, isometric contractions were measured with a force transducer (grass ft 03 force displacement italy), and normalized based on strip cross-sectional area. following the equilibration, the tissues were challenged with 124 mm potassium chloride (kcl) for 6 min and contracted all strips; washed again with fresh buffer. after more cavernous strips left to settle for the implementation of the agonist and antagonist substances, neurally evoked contractions were induced using electrical field stimulation (efs) via platinum wire electrodes. isolated cavernous strips obtained from control, mets and mets + therapy groups were treated with 124 mm kcl and responses received by kcl graphed; checked the contractility of strips before and after performing the contractile studies (3x 10-6 tox 10-4 m). the strips were pre-contracted with 1x 10-5 m fenilephrine. after the contraction reached a plateau the strips were subjected to electrical field stimulation (efs) using ring platinum electrodes. cavernous strips was evoked with efs 50 v, 0.8 msn; 2, 4, 8, 16, 32, 64 hz frequencies during 10 sec after the equilibration and responses were recorded. before applying the efs atropine 6x 10-5 m and guanetidin 5x 10-5 m was added the organ bath. chemicals carbachol, kcl, atropine, guanetidin, lname, snp, larginine were obtained from sigma-aldrich. statistical analysis arithmetic averages and the standard deviations of serum values were calculated. friedman and wilcoxon tests were used to assess the changes in values. this experiment results were tested by student-t test for the differences between two groups. the significance of differences between groups were evaluated with scheffe's f test. spss 14.0 (spss, chicago, il, usa) was used for the statistical analysis and p < 0.05 was considered statistically significant. results effects of hfd to metabolic parameters in rabbits at the end of the first twelve weeks, there was a significant increase in plasma levels of glucose, total cholesterol, triglycerides, ldl and body weight (p < 0.05) and plasma hdl level was decreased significantly in the hfd group. control rabbits that were fed with a standard chow for 12 weeks did not show any significant difference in all these erden_stesura seveso 26/03/14 10:19 pagina 34 variables. at the end of the treatment phase which is the second phase of the study, plasma levels of glucose, total cholesterol, triglycerides, ldl, hdl in group b and d were comparable with in the initial levels of the study and with the levels in control group. significant changes in plasma levels of glucose, total cholesterol, triglycerides, ldl, hdl observed in the first twelve weeks were observed to continue in group a and c (table 1). in-vitro contraction and relaxation responses there was no difference in contractile response to kcl (124mm) between corporal strips from the all of mets groups and control group. but there was a significant increase in contractile response to fenilefrin in corporal strips mets as compared to control group and other mets groups which received any of the therapeutic intervention (figure 1). relaxation of corpus cavernosum smooth muscle in response to carbachol was significantly decreased in strips from the mets group compared to controls and mets + therapy groups (figure 2). when the strips incubated with 3 x 10-5 m l-name, the relaxation response to carbachol was inhibated and basal tonus was increased. 35archivio italiano di urologia e andrologia 2014; 86, 1 in-vitro effects of pde5 inhibitor and statin treatment on the contractile responses of experimental mets rabbit's cavernous smooth muscle group initial first twelve weeks last six weeks (mg/dl ± sd) (mg/dl ± sd) (mg/dl ± sd) glucose a 129.54 ± 2,30 *162.42 ± 8,67 *178.39 ± 10,85 b 128,40 ± 5,41 *161,80 ± 17,43 170,40 ± 18,64 c 127.60 ± 2,30 *159.80 ± 8,67 *184.60 ± 10,33 d 128.20 ± 5,50 *166.80 ± 22,22 181.00 ± 26,10 total cholesterol a 46.66 ± 2,64 *85.58 ± 3,17 *104.62 ± 2,98 b 54,60 ± 5,68 *103,00 ± 11,34 106,00 ± 11,31 c 49.80 ± 1,64 *88.80 ± 2,17 *103.80 ± 2,77 d 49.60 ± 5,77 *97.00 ± 11,09 93.00 ± 6,24 triglyceride a 46.20 ± 5,96 *94.00 ± 10,95 *116.20 ± 5,68 b 43,80 ± 73 *114,00 ± 17,71 113,20 ± 20,09 c 47.40 ± 5,77 *96.00 ± 9,35 *113.00 ± 5,00 d 47.00 ± 7,00 *105.60 ± 16,08 110.80 ± 14,32 ldl a 12.76 ± 1,14 *23.28 ± 3,87 *32,54 ± 4,92 b 12,20 ± 2,39 *20,00 ± 5,29 22,20 ± 6,10 c 12.60 ± 1,14 *22.20 ± 3,63 *28.60 ± 4,22 d 11.40 ± 1,52 *25.40 ± 3,58 26.00 ± 3,81 hdl a 20,51 ± 4,96 *12,47 ± 3,85 *10.65 ± 2,69 b 21,60 ± 4,83 *11,00 ± 2,92 10,40 ± 3,29 c 21.00 ± 4,36 *11.60 ± 2,07 *10.20 ± 2,17 d 19.80 ± 5,63 *12.00 ± 1,22 12.60 ± 1,67 body weight a 3254,55 ± 82,36 *3396,65 ± 122,32 *3566,85 ± 107,67 b 3220.80 ± 129,22 *3373.40 ± 114,80 3418.40 ± 250,58 c 3183.80 ± 73,96 *3357.80 ± 114,28 *3492.80 ± 104,84 d 3147.40 ± 98,60 *3414.20 ± 143,55 3492.20 ± 155,72 table 1. analysis of serum and body weight change according to the groups. figure 1. concentration-response curve for phenylephrine. figure 2. relaxation responses for carbachol. * p < 0,05 erden_stesura seveso 26/03/14 10:19 pagina 35 archivio italiano di urologia e andrologia 2014; 86, 1 y. erden, e. korgalı, g. dundar, s. ayan, g. gokce, s. yildirim, e. yener gultekin 36 there was not significant difference in relaxation responses to sodium nitroprusside in all groups compared control group (figure 3). efs following phenylephrine precontraction in the presence of 1 x 10-5 m/l atropine and 4x10-5 m/l guanethidine produced frequency-dependent nanc relaxation. relaxtion responses to efs was decreased when strips incubated with 3 x 10-5 m l-name and relaxation response to efs return with 4x10-5 m l-arginin. this findig supported the previous detection. relaxation of corpus cavernosum smooth muscle in response to efs was significantly less in strips from the mets group than controls and all mets + theraphy groups at all frequencies. there was no significant difference between theraphy groups each other and control group (figure 4). discussion in this study, we aimed to investigate in vitro effects of systemic treatments of rosuvastatin, sildenafil and combination of these two agents on contractile responses of cavernous tissue in experimental metabolic syndrome model. the corporal tissue strips of mets rabbits were observed to have significantly decreased in vitro erectile responses than that of the control group whereas in mets groups received a treatment either with a pde5 inhibitor or with a statin, in vitro erectile responses were comparable to each other and to control goup. epidemiological studies have demonstrated that elevated serum cholesterol and diminished high-density lipoprotein (hdl) cholesterol levels are associated with an increased risk of erectile dysfunction (ed). whether restoring a dyslipidemic profile will result in a reduced risk of developing ed has not been established. similarly, it is not known if such an intervention will improve symptoms in patients with established ed. the situation is even more complex by the likelihood that one of the rarer side effects of statins is ed (21). penile erection is the result of relaxation of smooth muscles in the cavernous sinusoids and associated blood vessels (23). smooth muscle relaxation is mediated primarily by nitric oxide (no), which one of the most potent endogenous smooth muscle relaxants. no is synthesized by neuronal no synthase (nnos) in the autonomic postganglionic parasympathetic nerves (nitrergic nerves) 2, 3 and by endothelial nos in the endothelium lining the blood vessels and cavernous sinusoids (23, 24). the negative effects of hyperlipidemia on erectile function are revealed by clinical and experimental studies. azadzoi et al. (25) showed in cavernous tissues of rabbits that atherosclerosis due to hyperlipidemia decreases the activity of nos, upregulates the production of thromboxane and prostaglandin, and accordingly this negatively affects smooth muscle relaxation occurring in response to electrical stimulation which forms the basis of erection. kim et al. (26) also found that the negative effects of hyperlipidemia on cavernous smooth muscle relaxation are related to the contractile effect of oxidized low-density lipoprotein, release of superoxide radicals and elevated levels of nos inhibitors. in our study, in accordance with the findings of these studies, we found that relaxation responses in untreated hypercholesterolemia were significantly reduced. similarly, firoozi et al. reported in their study that relaxation responses were significantly decreased in the hypercholesterolemic group. in their study, when sildenafil and vardenafil were added in vitro to hypercholesterolemic group relaxation response to efs significantly increased however failed to reach the level of response of the control group (20). in our study, apart from the situation indicated above, in all groups where mets model was formed and systemic therapy was added, we found that when atropine and guanetidin added to the therapy, the relaxation response to efs was significantly increased compared to untreated mets group. moreover, these responses were similar compared to responses of the control group. snp-induced relaxation responses were similar in all groups and this suggested that the problem existed until the no release process. this finding indicates that systemic rosuvastatin, sildenafil and combination therapy prevent the development of endothelial dysfunction and ed in hypercholesterolemic group. the beneficial effects of daily use of pde5 inhibitors on erectile function have been shown in many experimental and clinical studies. it is shown that chronic pde5 inhibition improves endothelial function, protects vascular smooth muscle and reduces fibrotic changes in diabetic patients with cardiovascular disease (27, 28). chen et al. (29) reported antioxidative effect of the chronic use of tadalafil prevented the development of diabetic ed with diabetic rats. a study investigating the effect of chronic use of sidenafil figure 3. relaxation responses for sodium nitroprusside. figure 4. relaxation responses for efs. erden_stesura seveso 26/03/14 10:19 pagina 36 in a different ed model formed with cavernous nerve injury in rats showed that sildenafil, independent from endogenous inos, prevents histological changes that occur because of cavernous nerve damage (30). in our study, we have demonstrated that the daily use of sildenafil in hypercholesterolemic rabbits of our mets model significantly improved cavernosal tissue relaxation responses. statins are the most commonly used group of drugs in the treatment of dyslipidemia. recently it has been reported that beside lipid-lowering effects, the beneficial effects of these drugs on vascular system process through modulating enos, inos, nnos enzymes, causing relaxation of smooth muscle cells, affecting the anti-inflammatory and antioxidant mechanisms (14). nangle et al. (31) investigated the effect of use of rosuvastatin on nitric oxide-dependent function in aorta and corpus cavernosum of diabetic mice and reported that rosuvastatin, independent from its extra-lipid effects, restores the defective no-mediated nerve and vascular function in diabetic mice. moreover, dependent on its cholesterol biosynthesis pathway inhibition and anti inflammatory effects, rosuvastatin restores relaxation response which is reduced due to diabetes. maximum no-dependent nonadrenergic, noncholinergic nervemediated relaxations of cavernosum were reduced 2533% by diabetes. rosuvastatin treatment prevented 75% and reversed 71% of this diabetic deficit. morelli et al. (32) reported that atorvastatin did not act on glycemia, plasma lipid levels or the hypogonadal condition in experimental diabetic rat models. in diabetic rabbits, atorvastatin improved the erectile response to electrical stimulation of the cavernous nerve and normalized the sildenafil effect on erectile function which is strongly decreased in diabetic patients. in accordance with literature, results of our study demonstrated that rosuvastatin therapy that was administered to rabbits of mets model provided significantly increased relaxation responses of cavernosal strips. in the literature, although there are experimental studies available concerning various vascular pathologies in which effects of use of systemic statins in combination with pde5 inhibitors were evaluated (33, 34). our study is the first in vitro study investigating the effect of use of systemic rosuvastatin in combination with sildenafil on cavernosal tissue in mets model. we observed that the treatment with either sildenafil or rosuvastatin significantly improves cavernosal smooth muscle relaxation responses in created mets model rabbits as compared to the untreated mets group. however, the combination of these two drugs does not yield an additional advantage in terms of cavernosal tissue contraction responses. the lack of an additive restoring effect of combined treatment might be attributed to no dependent effect which was alraedy provided by either of two drugs. references 1. després jp, lemieux i. abdominal obesity and metabolic syndrome. nature 2006; 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52:2396-402. 32. morelli a, chavalmane ak, filippi, et al. atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced rhoa/rhokinase signaling hyperactivation. j sex med. 2009; 6:91-106. 33. zhang wh, liu cp, zhang yj, et al. additive effect of tadalafil and simvastatin on monocrotaline-induced pulmonary hypertension rats. scand cardiovasc j. 2012; 46:374-80. 34. wang qm, wei y, zheng y, et al. efficacy of combined atorvastatin and sildenafil in promoting recovery after ischemic stroke in mice. am j phys med rehabil. 2013; 92:143-50. correspondence yasin erden, md esat korgalı, md (corresponding author) estkorgali@hotmail.com, estkorgali@gmail.com gokce dundar, md semih ayan, md gökhan gokce, md emin yener gultekin, md cumhuriyet university school of medicine department of urology kampus, merkez sivas (turkey) 58140 sahin yildirim, md cumhuriyet university school of medicine department of pharmachology erden_stesura seveso 26/03/14 10:19 pagina 38 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 290 original paper comparison of the urethrovesical anastomoses with polyglecaprone (monocryl®) and bidirectional barbed (v-loc 180®) running sutures in laparoscopic radical prostatectomy murat arslan 1, altug tuncel 2, yilmaz aslan 2, zafer kozacioglu 3, bulent gunlusoy 3, ali atan 2 1 izmir university school of medicine, department of urology, izmir-turkey; 2 ministry of health, ankara numune research and training hospital, third department of urology, ankara-turkey; 3 ministry of health, bozyaka research and training hospital, department of urology, izmir-turkey. . objective: we compared polyglecaprone (monocryl®) and bidirectional barbed (v-loc® 180) running sutures during urethrovesial anastomosis (uva) in laparoscopic radical prostatectomy (lrp). materials and methods: a total of 92 consecutive patients underwent extraperitoneal lrp for prostate cancer. in the first 47 patients, the running uva was performed using 3-0 monofilament polyglecaprone (monocryl®) suture (group 1). in the subsequent 45 patients, the running uva was performed with the 3-0 barbed suture (v-loc® 180) (group 2). rhabdosphincter reconstruction was performed in all the patients. results: the mean prostatectomy time was 196 and 179 minutes in group 1 and 2, respectively (p < 0.001). moreover, the mean uva time was 40 and 24 minutes in group 1 and 2, respectively (p < 0.001). also, catheterization time, lenght of hospital stay and the number of the patients with urine leakage were significantly lower in group 2 than the other (p < 0.001). no patients in v-loc® 180 suture group and 5 patients in monocryl® suture group experienced postoperative drain leakage in the present study. overall pad usage at 6th month was higher in group 1 than the other group. in group 1 and 2, 78.7% and 93.3% of the patients reported 0 to 1 pads daily, whereas 21.3% and 6.7% reported ≥ 2 pads daily (p = 0.002). conclusions: we therefore consider that use of barbed suture running uva during lrp is associated with a significantly shorter operative time maintaining a proper suturing tension compared with standard suture and it is not associated with a higher incidence of adverse events with no postoperative complications. key words: radical prostatectomy; laparoscopy; barbed suture; anastomosis. submitted 5 december 2014; accepted 31 january 2014 summary no conflict of interest declared. introduction the first laparoscopic radical prostatectomy (lrp) series were published by schuessler and co-workers in 1997 (1). after that, lrp was developed to paralel the success achieved with the open approach, while offering the advantages of minimally invasive surgery (2). intracorporeal suturing is considered to the most challenging and difficult procedure in laparoscopic surgery. the urethrovesical anastomosis (uva) is definitely one of the critical and time consuming step of the lrp and requires an experienced surgeon with advanced laparoscopic skills (3, 4). moreover, suturing and knot tying can be often be challenging in the confines of true pelvis, which requires cautious handling of the suture and tissues.5 to facilitate the uva technique, several techniques with using monofilament sutures have been advised in the international literature (5-7). greenberg and associates demonstrated that monofilament suture has the potential of localized tissue necrosis, reduced fibroblast proliferation, and excessive tissue overlap, all of these factors can reduce the strength of the healed wound (8). to deal with this problem, a barbed suture (v-loc®, covidien healthcare, ma, usa) has been introduced into the surgical practice. the undirectional barbs maintain running suture line tension and purportedly obviate the need for knot tying. in the international literature, this suture has been extensively used during uva in robot-assisted radical prostatectomy (rarp) (916). to our knowledge, there is no publication about barbed suture usage during uva in lrp. in the current study, we compared the efficacy and safety of polyglecaprone (monocryl®, ethicon, nj, usa) and bidirectional barbed (v-loc 180®, covidien healthcare, ma, usa) running sutures during uva in extraperitoneal lrp. material and methods the institutional review board approval was taken for data collection in our radical prostatectomy patients. a doi: 10.4081/aiua.2014.2.90 91archivio italiano di urologia e andrologia 2014; 86, 2 barbed suture in laparoscopy total of 92 consecutive patients underwent extraperitoneal lrp for prostate cancer between august 2010 to september 2012. inclusion criteria included clinically organ confined or locally advanced prostate cancer (clinical ≤ t3a). in the first 47 patients, the uva was performed using 30 standard monofilament polyglecaprone (monocryl®, ethicon, nj, usa) suture (group 1). for the uva, a bidirectional suture with 2 needles was prepared from two 15 cm sutures knotted on the distal ends and used to perform running anastomosis. in the subsequent 45 patients, the uva was performed with the 3-0 barbed suture (v-loc®180, covidien healthcare, ma, usa) (group 2). for the uva, a bidirectional barbed suture with 2 needles was prepared from two 15 cm sutures. after than 3-0 barbed sutures by passing the needle of each suture though the looped end effecter the other and the running anastomosis was performed. the uva was performed in each group by using conventional van velthoven (running) method which has been previously described (6). in group 2, standart van velthoven technique was performed without knot tying at the end of anastomosis. at the end of the anastomosis, we passed a foley urethral catheter into the bladder, and we filled the bladder with 150 ml of sterile saline solution while under direct visualization. just before completion the operation, we routinely placed a jackson-pratt drain to the perianastomotic region. the rhabdosphincter re-construction is performed in all the patients as described previously with using either monocryl® or v-lock®180 barbed suture (17). all the operations were performed by one of us (m.a.). the surgeon had performed 40 lrp until beginning of the current study. the primary outcome measured was the uva time; starting once the anchoring suture was placed and finished when two running sutures were tied together in group 1 and without knot tying in the other group. secondary outcome measured included urinary leak defined as either perioperative saline leakage or postoperative increased drain output confirmed by an elevated drain fluid creatinine level. contrast extravasation on postoperative 10th day was characterized as delayed healing; postoperative day of catheter removal was defined as lenght of urethral catheterization time. postoperative urinary incontinence was assessed at 6th month follow-up visit by patient recorded total daily pad using. statistical analysis statistical analysis was performed with using statistical packet for social sciences for windows (chicago, il, usa) version 13.0 software. descriptive statistics of the groups were calculated. the outcomes were expressed as the mean ± standard deviation. the numerical data with normal distribution were compared with independent sample t test, and the data without normal distribution were compared among groups with the mann-whitney u test. in addition, chi-square and fisher exact tests were used to compare categorical variables. a p value less than 0.05 was significant. results baseline patients characteristics which did not different the each group are summarized in table 1. during the operation, the mean prostatectomy time was 196 and 179 minutes in group 1 and 2, respectively (p < 0.001). moreover, the mean uva time was 40 and 24 minutes in parameters group 1 group 2 p value (n = 47) (n = 45) age (yr) 63.1 ± 6.3 65.2 ± 5.7 0.740 (46-75) (49-76) preoperative psa (ng/ml) 9.0 ± 5.9 11.0 ± 11.5 0.439 (1.3-28.6) (3.5-68) bmi (kg/m2) 27.0 ± 5 26.9 ± 4.5 0.385 (17.0-37.6) (18.3-39.7) biopsy gleason score (n) 6 31 39 0.204 7 16 5 ≥ 8 1 previous abdominal surgery (n) 15 16 0.966 prostate volume (ml) 39.6 ± 14.0 40.4 ± 20.2 0.440 (18-76) (14-108) table 1. effetti clinici e impatto economico della dutasteride e finasteride su uomini italiani con luts. table 2. intraoperative and postoperative parameters of the patients. data presented as median ± standard deviation with minimum and maximum values in parenthesis. parameters group 1 group 2 p value (n = 47) (n = 45) prostatectomy time (min) 196.1 ± 24.2 179.7 ± 20.5 < 0.001 (160-276) (132-220) uva completion time (min) 40 ± 7.1 24.0 ± 5.5 < 0.001 (24-58) (16-45) estimated blood loss (ml) 424.6 ± 172.7 415.1 ± 223,1 0.851 (160-810) (120-900) postoperative leakage 5 0.001 in cystogram (n) catheterization time (d) 14.0 ± 1.7 9.0 ± 1.9 < 0.001 (12-21) (7-13) lenght of hospital stay (d) 4.2 ± 1.5 2.1 ± 0.4 < 0.001 (2-10) (2-4) surgical gleason score (n) 6 21 26 0.987 7 17 18 ≥ 8 9 1 6th month urinary continence rate 0-1 pads daily 37(78.7%) 42 (93.3%) 0.002 ≥ 2 pads daily 10 (21.3%) 3 (6.7%) archivio italiano di urologia e andrologia 2014; 86, 2 m. arslan, a. tuncel, y. aslan, z. kozacioglu, b. gunlusoy, a atan 92 group 1 and 2, respectively (p < 0.001). also, catheterization time, lenght of hospital stay and the number of the patients with urine leakage were significantly lower in group 2 than the other (p < 0.001). all other perioperative parameters were statistically equivalent between the groups, including estimated blood loss and gleason scores (table 2). we did not experience difficulty with the urethral catheter exchange end of the uva in each group. five patients in group 1 and no patient in group 2 experienced the postoperative drain leakage in the present study. the urine leakage was confirmed with using postoperative cystogram. the dranaige was treated with prolonged foley urethral catheterization. three of the patients in group 1 had experienced urinary retention due to bladder neck contracture at a mean follow-up of 4.1 months. all bladder neck contractures were treated using with cold knife incision. overall pad usage at 6th month was higher in group 1 than the other group. in group 1 and 2, 78.7% and 93.3% of the patients reported 0 to 1 pads daily, with 21.3% and 6.7% reported ≥ 2 pads daily (p = 0.002) (table 2). discussion although rarp has tremendously changed the art of performing prostatectomy, lrp still have being routinely performed for localized prostate cancer in many centers that do not have a robot. laparoscopic intracorporeal suturing is one of the most challenging and time-consuming taks for surgeons (8). in lrp and rarp, the initial results indicated on the technical difficulty on uva leading to prolonged operation time. the uva technique was firstly performed with using vicryl® suture on a small 5/8-circle needle in interrupted fashion that was associated with difficulty of multiple knots (18). the difficulties as mentioned above lead to development of continuous uva techniques that dramatically reduced the number of intracorporeal knots (6). uva with monocryl® requires follow-through by assistant when continuous anastomosis is performed. an assistant in training may find it difficult to follow-through, leading to loose throws as well as pure-stringing, instrument clashes, and suture entangling around instrument (16). intracorporeal suturing with the use of standart suture materials having smooth configuration and placement of knots to secure them is a standard practice. though widely used these suture’s may become loose or entangled, necessitating constant traction by an assistant or repeated tightening of suture by the operating surgeon (5). this may potentially lead to instrument collision, tissue tearing, and purse stringing resulting in prolongation of suturing. to overcome these problems, barbed suture has been introduced into the clinical practice. these selfanchoring knotless sutures incorporate tiny barbs spaced evenly in a helical array on the suture. they require little technical skill to deploy making suturing expeditious, requiring less time than standard suturing (19). firstly, weld and associates evaluated the role of barbed suture in urinary tract reconstruction in a porchine model (20). according to in vitro analysis, the authors stated that barbed suture secures tissue approximation at load equivalent to tissue approximation with standard sutures. later, technical feasibility of uva using barbed suture was reported by moran et al. in a microfiber synthetic material experimental model; they found barbed suture better than standard monocryl® in terms of faster deployment and higher security score (21). in the international literature, barbed suture is mainly evaluated in uva during rarp cases. in a study by tewari et al, barbed suture (n = 50) and polyglactine suture (n = 50) were used in uva during rarp (10). they reported that uva time significantly shorter in barbed suture group. also, they did not observe clinically significant urine leak or retention in barbed suture group. in a prospective series by kaul et al., 51 patients underwent uva during rarp with using barbed suture (11). they reported 27% reduction in uva time. also there were no urine leakage at 1 week and no bladder neck stricture. in another recent study, 64 patients underwent uva during rarp with either barbed suture (n = 31) or monofilament polyglecaprone (n = 33) suture (12). the authors demonstrated that uva 26% decreased with no increase in the adverse events, no instances of urinary retention. in a study, a total of 84 patients were divided into two groups underwent rarp, undergoing rhabdosphicter reconstruction and uva using with the v-loc® standard monoflament suture (13). the authors reported that barbed suture associated with a significantly shorter time for uva compared the standard monofilament suture and is not associated with a higher incidence of clinical urinary leak. at a 9-month follow-up no patients in either group has a clinical bladder neck stricture. moreover, they found similar urinary continence rates between the groups at 6 weeks (52% and 48%, respectively) and at 6 months (88% and 84%, respectively). the authors concluded that although urinary continence rates in both groups will continue to improve at longer follow-up, it is reasonable to assume the use of barbed suture for the rhabdosphincter reconstruction and the uva does not affect urinary incontinence. zorn et al. recently published their prospective series in which 30 v-loc®180 barbed uva cases during rarp (14). in their analysis, the mean anastomosis time was 14.6 min with using two knotless, interlocked 6inches 3-0 v-loc®180 sutures. they did not report urinary leak, urinary retention and urinary incontinence after catheter removal in their patients. hence the authors concluded that using the interlocked v-loc®180 suture during rarp for uva appears to be safe and efficient. in a study by hemal and co-workers, 50 patients underwent rarp and uva was performed with using either barbed suture (n = 25) or polyglecaprone suture (n = 25) (16). the authors concluded that barbed suture significantly decreases anastomosis time, hospitalization duration. none of the patient had presented with urine leaks, urinary retention or anastomosis stricture at follow-up of 6 months. in a study by manganiello et al., a total of 70 patients underwent rarp for prostate cancer (15). in this study, first 35 patients, the uva was performed using a two separate monofilament sutures. in the subsequent 35 patients, the uva was performed using two running unidirectional barbed suture. the authors reported that comparing the groups, average 93archivio italiano di urologia e andrologia 2014; 86, 2 barbed suture in laparoscopy time to complete the anastomosis was similar (27.4 vs. 26.4 minutes, p = 0.73) as was the rate of urinary extravasation on cystogram (5.7% vs. 8.6%, p = 0.65). there were no symptomatic bladder neck contractures noted at 5 months of follow-up. the authors also reported that at 5th months, rates of urine leak also were comparable. conversely; in a randomized clinical trial, the authors compared uva using either barbed polyglyconate (n = 45) or polyglactine 910 (n = 36) sutures in rarp (9). although baseline characteristics and overall operative times were similar, barbed sutures were associated with shorter mean anastomosis times (9.7 min vs. 9.8 min, p = 0.019). however, they reported more frequent extravasation (20% vs. 2.8%, p = 0.019), longer catheterization time (11.1 d vs. 8.2 d, p = 0.048) and greater suture costs per case (51.5 usd vs. 8.44 usd, p < 0.001) in barbed suture group. the authors concluded that compared to traditional sutures, barbed suture is more costly and requires technical modification to avoid overtightening, delayed healing, and longer catheterization time. to our knowledge barbed suture has not been evaluated in uva and total operation time in lrp. our results showed that barbed suture led to reduced prostatectomy time, uva time, catheterization duration and lenght of hospital stay in patients underwent lrp. furthermore, we did not detect postoperative urine leakage from drain and cystogram in barbed suture group. manganiello and associates previously claimed that barbed suture obviates the need for an assistant to follow the suture to continually reapply tension to previous throws (15). according to their opinion once the bladder neck and urethral tissue are re-approximated, the tissue stays in place and does not migrate unless there is significant counter tension. we believe that this mechanism may facilitate uva step of the lrp. in the international literature, urine leaks have been reported to be as high as 6.8% at different centers (22). urine leaks may result in clinical problems such as bladder neck contraction, infection, bladder neck contracture and urinary incontinence (23). as we mentioned above, some studies reported that urinary incontinence rate were similar between the standard polyglactine and barbed sutures in rarp (13, 14). in our study, overall pad usage for urinary incontinence at 6th month follow-up was significantly higher in group 1. according to our results, 5 patients in group 1 experienced the postoperative drain leakage in the present study. the urinary incontinence was seen all of those patients. we believe that urine leakage and bladder neck contracture may fascilitate to develop urinary incontinence. conclusions we therefore consider that by using v-loc®180 barbed suture running uva during lrp is associated with a significantly shorter time with maintaining a proper suturing tension compared with standard suture is not associated with a higher incidence of adverse events with no instances of urine leakage, bladder neck contraction, urinary retention and urinary incontinence. in the light of our results, v-loc®180 barbed suture seems to significantly facilitate the surgeon’s duty in uva during lrp. references 1. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy:initial short-term experience. urology. 1997; 50:854. 2. stolzenburg j-u, do m, ranenalt r, et al. endoscopic extraperitoneal radical prostatectomy:initial experience after 70 procedures. j urol. 2003; 169:2066. 3. branco aw, kondo w, henrique a, et al. laparoscopic running urethrovesical anastomosis with posterior fixation. urology. 2007; 70:799. 4. chung sd, tai hc, lai mk, et al. novel inaninate training model for urethrovesical anastomosis in laparoscopic radical prostatectomy. asian j surg. 2010; 33:188. 5. shah hn, nayyar r, rajamahanty s, hemal ak. prospective evaluation of unidirectional barbed suture for various indications in surgeon-controlled robotic reconstructive urologic surgery:wake forest university experience. int urol nephrol. 2012; 44:775. 6. van velthoven rf, ahlering te, peltier a, et al. technique for laparoscopic running urethrovesical anastomosis:the single knot method. urology. 2003; 61:699. 7. shichiri y, kanno t, oida t, kanamaru h. facilitating the technique of laparoscopic running urethrovesical anastomosis using lapra-ty absorbable suture clips. int j urol. 2006; 13:192. 8. greenberg ja. the use of barbed sutures in obstetrics and gynecology. rev obstet gynecol. 2010; 3:82. 9. williams sb, alemozaffar m, lei y, et al. randomized controlled trial of barbed polyglyconate versus polyglactin suture for robotassisted laparoscopic prostatectomy anastomosis:tecnique and outcomes. eur urol. 2010; 58:875. 10. tewari ak, srivastava a, sooriakumaran p, et al. use of novel absorbable barbed plastic surgical suture enables a “self-cinching” technique of vesicourethral anastomosis during robot-assisted prostatectomy and improves anastomotic times. j endourol. 2010; 24:1645. 11. kaul s, sammon j, bhandari a, et al. a novel method of urethrovesical anastomosis during robot-assisted radical prostatectomy using a unidirectional barbed wound closure device:feasibililty study and early outcomes in 51 patients. j endourol. 2010; 24:1789. 12. sammon j, kim t-k, trinh q-d, et al. anastomosis during robot-assisted radical prostatectomy:randomized controlled trial comparing barbed and standard monofilament suture. urology. 2011; 78:572. 13. polland ar, graversen ja, mues ac, badani kk. polyglyconate undirectional barbed suture for posterior reconstruction ans anastomosis during robot-assited prostatectomy:effect on procedure time, efficacy, and minimum 6-month follow-up. j endourol. 2011; 25:1493. 14. zorn kc, widmer h, lattouf j-b, et al. novel method of knotless vesicourethral anastomosis during robot-asisted radical prostatectomy:feasibility study and early outcomes in 30 patients using the interlocked barbed undirectional v-loc180 suture. can urol assoc. 2011; j 5:188. 15. manganiello m, kenney p, canes d, et al. undirectional barbed suture versus standard monofilament for urethrovesical anastomosis archivio italiano di urologia e andrologia 2014; 86, 2 m. arslan, a. tuncel, y. aslan, z. kozacioglu, b. gunlusoy, a atan 94 during robotic assisted laparoscopic radical prostatectomy. int braz j urol. 2012; 38:89. 16. hemal ak, agarwal mm, babbar p. impact of newer undirectional and bidirectional barbed suture on vesicourethral anastomosis during robot-assisted radical prostatectomy and its comparison with polyglecaprone-25 suture:an initial experience. int urol nephrol. 2012; 44:125. 17. rocco f, gadda f, acquati p, et al. personal research: reconstruction of the urethral striated sphincter. (ita) arch ital urol androl. 2001; 73:127. 18. guillonneau b, cathelineau x, doublet jd, et al. laparoscopic radical prostatectomy:assessment after 550 procedures. crit rev onc hemat. 2002; 43:123. 19. hruby g, weld kj, marruffo f, et al. comparison of novel tissue apposing device and standard anastomotic technique for vesicourethral anastomoses. urology. 2007; 70:190. 20. weld kj, ames cd, hruby g, et al. evaluation of a novel knotless selfanchoring suture material for urinary tract reconstruction. urology. 2006; 67:1133. 21. moran me, marsch c, perotti m. bidirectional-barbed sutured knotless running anastomosis v classic van velthoven suturing in a model system. j endourol. 2007; 21:1175. 22. hu j, nelson r, wilson t. perioperative complicationsof laparoscopic and robotic assisted laparoscopic radical prostatectomy. j urol. 2006; 175:541. 23. kostakopoulos a, argiropoulos v, protogerou v, et al. vesicourethral anastomotic strictures after radical retropubic prostatectomy: the experience of a single institution. urol int. 2004; 72:17. correspondence murat arslan, md izmir university school of medicine, department of urology, izmir-turkey altug tuncel, md (corresponding author) tuncelaltug@yahoo.com yilmaz aslan, md ali atan, md ministry of health, ankara numune research and training hospital, third department of urology 06120, sihhiye ankara, turkey zafer kozacioglu, md bulent gunlusoy, md ministry of health, bozyaka research and training hospital, department of urology, izmir-turkey stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4200 introduction lower urinary tract symptoms (luts) are common in aging men with a prevalence ranges from 10.3 to 25.1% depending on the severity threshold (1). benign prostatic hyperplasia (bph) and benign prostatic enlargement original paper clinical effects and economical impact of dutasteride and finasteride therapy in italian men with luts luca cindolo 1, francesco berardinelli 1, caterina fanizza 2, marilena romero 2, luisella pirozzi 2, fabiola raffaella tamburro 1, fabrizio pellegrini 1, fabio neri 1, andrea pitrelli 3, luigi schips 1 1 s. pio da pietrelcina hospital, dept. of urology, vasto, italy; 2 department of clinical pharmacology and epidemiology, consorzio mario negri sud, santa maria imbaro, italy; 3 access to medicine, glaxosmithkline spa, verona, italy. objectives: to investigate differences in the risk of benign prostatic hyperplasia (bph)related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer (pca) diagnosis between patients under dutasteride or finasteride treatment. material and methods: a retrospective cohort study was conducted using data from record-linkage of administrative databases. men aged ≥ 40 years old who had received a prescription for at least 10 boxes/year (index years: 2004-06) were included. the association of the outcomes was assessed using a multiple cox proportional hazard model. propensity scorematched analysis and a 5-to-1, greedy 1:1 matching algorithm were performed. the budget impact analysis of dutasteride vs finasteride in bph-treated patient was performed. results: from an initial cohort of about 1.5 million of italian men, 19620 were selected. the overall hospitalization for bph-non surgical reasons, for bph-related surgery and for new detection of pca incidence rates (irs) were 8.20 (95% ci, 7.62-8.23), 18.0 (95% ci, 17.12-18.93) and 8.62 (95% ci, 8.03-9.26) per 1000 person-years, respectively. the multivariate analysis after the propensity score-matching showed that dutasteride was associated with an independent reduced likelihood of hospitalization for bph-related surgery (hr 0.82; 95% ci 0.73-0.93; p = 0.0025) and of newly detected pca (hr: 0.76,95% ci, 0.65-0.85; p = 0.0116). the ir for bph-non surgical reasons was 8.07 (95% ci, 7.10-9.17) and 9.25 (95% ci, 8.19-10.44) per 1000 person-years, respectively. the ir for bph-related surgery was 18.28 (95% ci, 17.17-20.32) and 21.28 (95% ci, 19.24-23.06) per 1000 person-years among patients under dutasteride compared with those under finasteride, respectively. for new-onset pca, the ir was 8.01 (95% ci, 7.07-9.08) and 9.38 (95% ci, 8.32-10.58) per 1000 person-years the pharmacoeconomical evaluation showed that the net budget impact of the use of dutasteride vs. finasteride in 1000 bph-treated patient for 1 year induces a saving of 3933 €. conclusions: the clinical effects of dutasteride and finasteride are slightly different. the likelihood of hospitalization for bph-related surgery and of newly detected pca seems to be in favor of dutasteride. the budget impact analyses showed a slightly benefit for dutasteride. comparative prospective studies are necessary to confirm these results. key words: benign prostatic hyperplasia (bph); dutasteride; finasteride; epidemiology; medical record-linkage. submitted 14 april 2013; accepted 5 october 2013 summary (bpe) have been recognized as the major contributing factors to the development of luts. the first-line pharmacological therapy for moderate-to-severe non-neurogenic male luts includes alpha-adrenoreceptor antagodoi: 10.4081/aiua.2013.4.200 201archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? nists (abs) and 5alpha-reductase inhibitors (5aris) alone or in combination (2). abs induce a rapid symptom relief, while the 5aris modify the bph natural history by delaying the disease progression (3-6). finasteride and dutasteride are the two 5aris: finasteride inhibits the 5-alpha-reductase isoenzyme type 2, whereas dutasteride inhibits both isoenzyme 1 and 2. the clinical value of the greater serum dihydrotestosterone suppression achieved by dutasteride (7) remains unclear (2). nowadays due to the limited literature (811) the question of “what is the best 5ari" remains unanswered. another point of uncertainty is about the economic impact of the use of dutasteride instead of finasteride. in an attempt to clarify these aspects, we previously performed an observational study on an unselected population that showed a reduction in bph-related hospitalization risk in dutasteridecompared to finasteride-treated patients (12). in that paper (12) we also dealt with the hard issue of the detection of prostate cancer (pca) under 5aris treatments (13-16) showing a positive trend in favor of dutasteride. herein, we report the new results of extended analysis investigating the clinical and economic differences between dutasteride and finasteride treatment in an italian male population ≥ 40 years with luts. material and methods a retrospective study was conducted based on information from three databases: italian population registry, pharmaceutical prescription data, and hospital discharge record including information on about 1.500.000 male aged ≥ 40 years from 22 local health units from northern and southern italy for 6 consecutive years (january 1st 2004 and december 31st 2009). data sources the italian population registry provide demographic information (date of birth, sex and date of death if this occurred) on each subject. the pharmaceutical prescription database records all prescriptions reimbursed by the nhs (drugs coded according to the international anatomical therapeutic chemical system atc) (17). the hospital records include detailed information on primary diagnosis and up to five coexisting diagnoses, performed procedures, and admission/discharge dates. the diagnoses were classified according to the international classification of diseases-ninth revision, clinical modification (icd9-cm) (18). a record linkage of these three databases was carried out and pharmacological and clinical history for each patients was obtained. the reliability of this strategy to produce an epidemiological survey has been previously validated and reported (19-21). all security and protection measures for patient’s data was performed according to national laws on privacy protection. patients and drugs the cohort consisted of men aged ≥ 40 years, who received prescription for at least 10 boxes/year of finasteride or dutasteride between 1 january 2004 and 31 december 2006 (index years). the first prescription of one of these drugs during the index years was considered as index date (day 0). the exclusion criteria were either abs monotherapy and/or short-term 5-ari therapy (< 10 boxes/year). for all patients, the databases were searched during the 12-months period preceding the index date to verify the absence of bph-complications and pca. specifically, patients with an urethral stricture (icd9cm: 598, 589.0, 598.00, 598.01, 598.1, 598.2, 598.8, 598.9) and/or with pca diagnoses (icd9-cm: 185, 198.82, 233.4, 236.5, 239.5, v10.46) and/or at least a prescription of lhrh analogues and/or antiandrogens, were not considered eligible. patients using abs (alfuzosin, tamsulosin, terazosin) were included in the study. patients with acute or chronic urinary retention secondary to bph and treated at the emergency department without hospital admission were not considered. moreover, to assess the comorbidities, the charlson comorbidity index (cci) with the dartmouth-manitoba modification was used (22). clinical outcomes follow-up for each identified patient is extended from the index date to five years or until the occurrence of the following major events: 1) hospitalization for bph-non surgical reasons); 2) hospitalization for bph-related surgery; 3) new diagnosis of pca. bph-related hospitalization was considered when the hospital records included primary diagnosis and/or procedures related to bph. the presence of the icd9-cm 600.xx (prostate hyperplasia) and 222.2 (benign prostate tumor) codes as primary diagnosis without surgical procedures was considered hospitalization for “bph-non surgical reasons”. the presence of icd9-cm 57.0, 57.91, 57.92, 60.21, 60.29, 60.3, 60.4 codes (open or transurethral resection/ablation of prostate or bladder neck), as primary or secondary surgical procedures with any primary diagnoses, was considered hospitalization for “bph-related surgery”. the new diagnosis of pca was identified through hospitalization (icd9-cm:185, 198.82, 233.4, 236.5, 239.5, v10.46) and/or pca medical therapy (gonadotripins releasing hormones agonists l02ae01, l02ae02, l02ae03, l02ae04; and/or antiandrogens: l02bb01, l02bb02, l02bb03). analysis of health resources utilization the budget impact analysis of dutasteride vs. finasteride in bph-treated patient according to the italian nhs perspective has been performed starting form an hypothetical cohort of 1000 bph-treated men under finasteride for one year, here and after “current scenario”; in our analysis this hypothetic cohort has been fully switched to dutasteride, here and after “alternative scenario”. the incidence rates for 1000 person-years by outcomes after propensity score matching were used as source for the budget impact analysis model. drug consumption has been calculated assuming an annual 80% compliance to both treatment (300 days of therapy); in both scenarios patients undergoing to bph-related surgery withdrawn from treatment (assuming they don’t need further treatment for bph). the health resources utilization in both scenarios has been calculated starting from the inciarchivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 202 dence rates (both surgical and non surgical reasons) for 1000 persons/years after propensity score matching. hospital records have been used to estimate the average hospitalization costs according to nhs perspective. the impact on nhs annual budget related to variation of pca detection rate observed with dutasteride vs. finasteride was not analyzed. statistical analysis for the whole sample, patients’ characteristics were reported as frequency (percentage) and mean±standard deviation. differences between patients’ treatment subgroups were assessed using standardized difference. for major outcomes, crude incidence rates (irs) per 1000 men-year were calculated as the number of events divided by the number of person-years of follow-up. furthermore, to check consistency of our results, a propensity score (ps)-matched analysis was performed (24-25). a logistic model -including the same covariates used in the multivariate cox model, plus quadratic terms and a set of two-term interactions between the same covariateswas performed to predict the probability to be assigned to study drugs. ps logistic model was selected in a stepwise fashion and pair-wise comparisons were performed. a 5-to-1, greedy 1:1 matching algorithm (26) was used to identify a unique matched control for treated patient according to their ps. adequacy of covariate balance in the matched sample was assessed via standardized difference between the two groups, considering differences less than 10% as good balance (27). the association of hospitalization for bph, bph-related surgery, pca was assessed using a multiple cox proportional hazard model. all multivariate analyses were adjusted for the following variables: age, charlson comorbidity score, previous hospitalization for bph, previous bph-related surgery, pre-existing severity factors, previous pharmacological treatment with abs. results are expressed as hazard ratios (hrs) and 95% confidence intervals (cis). p-values < 0.05 were considered significant. all analyses were performed using sas statistical package release 9.2 (sas institute, cary, nc, usa). results patients characteristics from 1.417.969 men aged ≥ 40 years, 19620 were chronically exposed to 5aris; 13195 received finasteride and 6425 dutasteride. no significant differences were observed between these two groups with exception of previous abs therapy (table 1). clinical outcomes during follow-up during 5 years, 841 patients were hospitalized for bphnon surgical reasons, 2006 for bph-related surgery and 749 were newly diagnosed with pca. the overall hospitalization ir for bph-non surgical reasons and for bph-related surgery were 8.20 (95% ci, 7.62-8.23) and 18.0 (95% ci, 17.12-18.93) per 1000 person-years, respectively. the matched analysis identified 6362 men under dutasteride that were matched with a similar cohort under finasteride, without significant differences between groups (table 2). among patients under dutasteride compared with those under finasteride the ir for bph-non surgical reasons was 8.07 (95% ci, 7.10-9.17) and 9.25 (95% ci, 8.19-10.44) per 1000 person-years, respectively. moreover, the ir for bph-related surgery was 18.28 (95% ci, 17.17-20.32) and 21.28 (95% ci, 19.24-23.06) per 1000 person-years variable finasteride (13195 pz) dutasteride (6425 pz) standardized n (%) n (%) difference (%) mean age (mean ± sd) 72.25 (9.14) 71.62 (8.46 -7.1538 age 40-55 509 (3.86) 178 (2.80) -5.9106 56-65 4917 (37.26) 2647 (41.61) 8.8940 66-75 5254 (39.82) 2589 (40.69) 1.7876 76-85 2515 (19.06) 948 (14.90) -11.0948 charlson score 0 10945 (82.95) 5312 (83.50) 1.4657 1-2 1397 (10.59) 686 (10.78) 0.6326 >=3 853 (6.46) 364 (5.72) -3.1069 previous hospitalization for bph (non surgical reasons) 924 (7.00) 533 (8.38) 5.1632 previous hospitalization for bph-related surgery 39 (0.30) 32 (0.50) 3.2896 previous bph complications (severity factors) 583 (4.42) 272 (4.28) -0.7011 previous alphablockers therapy 5519 (41.83) 3893 (61.19) 39.4960 table 1. patients' characteristics according to drug used (finasteride or dutasteride). * standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. 203archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? among patients under dutasteride compared with those under finasteride, respectively. for new-onset pca, the ir was 8.01 (95% ci, 7.07-9.08) and 9.38 (95% ci, 8.3210.58) per 1000 person-years (table 3). the multivariate analysis after the propensity score matching cox model showed that dutasteride was associated with an independent reduced likelihood of hospitalization for bph-related surgery (hr 0.82; 95% ci 0.73-0.93; p = 0.0025) and of newly detected pca (hr: 0.76, 95% ci, 0.65-0.85; p = 0.0116) (table 4). annual budget impact analysis in the “current scenario” an hypothetical cohort of 1000 bph-treated patient for 1 year with finasteride generates a total annual impact on nhs budget of 1.017.444 €: 13,4% of this cost is related to finasteride cost (136.145 €), 66,4% is related to hospitalizations due to bph-related surgery (675.423 €) and 20,2% is related to hospitalizations for bph-non surgical reasons (205.872 €). in the “alternative scenario” is generated a total annual variable finasteride (6362 pz) dutasteride (6362 pz) standardized n (%) n (%) difference (%) mean age (mean ± sd) 71.68 (8.42) 71.62 (8.46) 0.71092 age 40-55 175 (2.75) 178 (2.80) 0.28712 56-65 2641 (41.51) 2647 (41.61) 0.19137 66-75 2589 (40.69) 2589 (40.69) 0.00000 76-85 957 (15.04) 948 (14.90) -0.39649 charlson score 0 5294 (83.21) 5312 (83.50) 0.75957 1-2 695 (10.92) 686 (10.78) -0.45479 >=3 373 (5.86) 364 (5.72) -0.6056 previous hospitalization for bph (non surgical reasons) 528 (8.30) 533 (8.38) 0.28427 previous hospitalization for bph-related surgery 19 (0.30) 32 (0.50) 3.23449 previous bph complications (severity factors) 292 (4.59) 272 (4.28) -1.52745 previous alphablockers therapy 3890 (61.14) 3893 (61.19) 0.09675 table 2. patients' characteristics according to drug used (finasteride or dutasteride) after propensity score matching. * standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. outcome finasteride dutasteride incidence rate 95% ci incidence rate 95% ci hospitalization for bph (non surgical reasons) 9.25 8.19-10.44 8.07 7.10-9.17 hospitalization for bph-related surgery 21.28 19.24-23.06 18.28 17.17-20.32 newly detected prostate cancer 9.38 8.32-10.58 8.01 7.07-9.08 table 3. incidence rate for 1000 person-years by outcome considered in finasteride and dutasteride groups after propensity score matching. outcome hr 95% ci p value hospitalization for bph (non surgical reasons) 0.87 0.73-1.05 0.1377 hospitalization for bph-related surgery 0.82 0.73-0.93 0.0025 newly detected prostate cancer 0.76 0.65-0.85 0.0116 table 4. results of propensity score matching cox model: dutasteride vs. finasteride. archivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 204 impact on nhs budget of 10.103.507 €: 25% of this cost is related to dutasteride cost (253.693 €), 57,2% is related to hospitalizations for bph-related surgery (580.204 €) and 17,7% is related to hospitalizations for bph-non surgical reasons (179.610 €) (figure 1). the full switch from finasteride to dutasteride in an hypothetical cohort of 1000 bph-treated patients for one year generates a net saving of 3.933 € to the nhs annual budget. discussion dutasteride and finasteride are the two currently available 5aris, and are widely recommended in patients with moderate-to-severe bph-related luts (2, 4-6). large-scale clinical trials have demonstrated that dihydrotestosterone (dht) suppression with 5aris is effective in the treatment of bph and might have a role in the prevention of pca (4, 5, 13, 14). previous studies confirmed that dutasteride consistently induces a near-maximal suppression of both serum and intraprostatic dht in men with bph and those with pca (7). even if the two available 5-aris are considered to be virtually equivalent regarding the clinical outcomes (13, 14), unfortunately, a direct comparison of the two drugs evaluating the long term effects is still lacking. the epics study, the only randomized clinical trial comparing dutasteride vs. finasteride, did not show significant differences between the drugs in terms of clinical efficacy. however, as pointed out by the authors, given the long-term, progressive nature of bph, the one-year duration of epics may limit the potential to observe major differences between dutasteride and finasteride treatment (11). in lack of relevant, prospective comparative studies, the purpose of this record-linkage study was to analyze the clinical effect of dutasteride and finasteride on bph-related hospitalizations and on pca diagnosis and the economical impact on nhs budget in an italian cohort. after the propensity score matching cox model, the multivariate analysis showed that dutasteride was associated with a statistically significant lower likelihood of hospitalization for bph-related surgery (table 4). these findings are in line with our previous study (12) and the reports from issa (10) and fenter (28. the results of the pharmacoeconomic analysis support health decision maker in the choice of whether or not to implement the treatment of bph patient with dutasteride instead of less costly finasteride. in two papers fenter and naslund (28-29) made a real world economic evaluation of dutasteride vs. finasteride for the treatment of bph patient analyzing restrictively medical and pharmacy claims in two large us administrative databases. these studies were based on american medicare-aged population and showed that dutasteride-therapy resulted in less medical costs than finasteride, suggesting that the higher price of dutasteride may be offset by decreased medical resource consumption. in our analysis we also estimated the cost consequence for the italian nhs of the use of dutasteride instead of finasteride in a hypothetical cohort of 1000 bph-treated patient for one year starting from the clinical differences in major outcomes (hospitalization for surgical and non surgical reason). as a results of our analysis, even in a different nhs framework, the net budget impact of the use of dutasteride instead of finasteride is slightly in favor of dutasteride with a total annual saving of 3.933 €. this overall cost saving for men taking dutasteride could create a overall cost advantage for dutasteride despite its higher price. there is also significant additional value to patients who have a lower risk of bph progression and than prostate surgery under dutasteride, although the figure 1. dutasteride vs finasteride: comparison of nhs costs for one year treatment of 1000 bph patient. finasteride € 1.200.000 € 1.000.000 € 800.000 € 600.000 € 400.000 € 200.000 € dutasteride hospitalization for bph-related surgery hospitalization for bph drug cost€ 205.872 € 675.423 € 136.145 € 179.610 € 580.204 € 253.693 205archivio italiano di urologia e andrologia 2013; 85, 4 5aris comparison. who is the best? monetary value of these benefits is difficult to measure and quantify. as far as the new diagnosis of pca is concerned, we found a pca incidence lower in dutasteridevs. finasteride-treated patients. although our previous study showed only a positive trend in dutasteride group without a statistical significance, however, in the current study, the wider cohort allowed to reach a statistically significant difference in reduction of pca diagnosis (hr: 0.76, 95% ci, 0.65-0.85; p = 0.0116) (table 4). all these evidence suggest that the clinical benefit of the dual 5a-reductase-isoenzymes inhibition might be slightly better. the two molecules are effective in bph; nevertheless, due to its peculiar pharmacokynetic and pharmacodynamic characteristics (longer half-life and dual inhibition of 5a-reductase-isoenzymes), dutasteride seems to be more active. although our results suggest that there are differences between the two 5aris in terms of clinical and economic outcomes, interpretation of the results is limited by the retrospective, non-randomized nature of the study. moreover, no information about symptomatic burden of the disease, urodynamic parameters, baseline psa values, number and kind of core biopsies and gleason score were available in our database. this is a main limitation of the study that hinders any inference about specific outcomes. however, the administrative database are widely used with all the inherent limitations and are considered a valuable source of clinical information (19-21). moreover, the pharmacoeconomic analysis contains further limitations. firstly, in clinical practice physician preferences based on clinical characteristics can impact treatment selection which mathematical model can not account for. secondly, our results are specific to italy and are driven by local practice and healthcare costs and prices. conclusions in conclusion, our results suggest slight differences in clinical and economic outcomes between dutasterideand finasteride-treated patients. further clinical trials are warranted in order to confirm these results and to evaluate the long term effectiveness of these drugs. acknowledgments this study was financially supported by an unconditional grant from glaxosmithkline. references 1. füllhase c, chapple c, cornu jn, et al. systematic review of combination drug therapy for non-neurogenic male lower urinary tract symptoms. eur urol. 2013; 64:228. 2. oelke m, bachmann a, descazeaud a, et al. eau guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2013; 64:118. 3. boyle p, roehrborn c, harkaway r, et al. 5-alpha reductase inhibition provides superior benefits to alpha blockade by preventing aur and bph-related surgery. eur urol. 2004; 45:620. 4. mcconnell jd, roehrborn cg, bautista o, et al. medical therapy of prostatic symptoms (mtops) research group. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n engl j med 2003; 349:2387. 5. roehrborn cg, siami p, barkin j, et al. the effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the combat study. eur urol. 2010; 57:123. 6. robert g, descazeaud a, de la taille a. lower urinary tract symptoms suggestive of benign prostatic hyperplasia: who are the high-risk patients and what are the best treatment options? curr opin urol. 2011; 21:42. 7. clark rv, hermann dj, cunningham gr, et al. marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. j clin endocrinol metab 2004; 89:2179. 8. naslund m, black l, eaddy m, batiste lr. differences in alpha blocker usage among enlarged prostate patients receiving combination therapy with 5 aris. am j manag care. 12007; 3:s17. 9. naslund m, regan ts, ong c, hogue sl. 5-alpha reductase inhibitors in men with an enlarged prostate: an evaluation of outcomes and therapeutic alternatives. am j manag care. 2008; 14:s148. 10. issa mm, runken mc, grogg al, shah mb. a large retrospective analysis of acute urinary retention and prostate-related surgery in bph patients treated with 5-alpha reductase inhibitors: dutasteride versus finasteride. am j manag care. 2007; 13:s10. 11. nickel jc, gilling p, tammela tl, et al. comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: enlarged prostate international comparator study (epics). bju int. 2011; 108:388. 12. cindolo l, fanizza c, romero m, et al. the effects of dutasteride and finasteride on bph-related hospitalization, surgery and prostate cancer diagnosis: a record-linkage analysis. world j urol. 2013; 31:665. 13. thompson im, goodman pj, tangen cm, et al. the influence of finasteride on the development of prostate cancer. n engl j med. 2003; 349:215. 14 andriole gl, bostwick dg, brawley ow, et al. effect of dutasteride on the risk of prostate cancer. n engl j med. 2010; 362:1192. 15. theoret mr, ning ym, zhang jj, et al. the risks and benefits of 5α-reductase inhibitors for prostate-cancer prevention. n engl j med. 2011; 365:97. 16. cohen sa, parsons jk. combination pharmacological therapies for the management of benign prostatic hyperplasia. drugs aging. 2012; 29:275. 17. who collaborating centre for drug statistics methodology. atc index with ddds. oslo, norway: who; 2003 18. us centers for disease control and prevention. international classification of diseases, ninth revision, clinical modification (icd-9-cm). http://www.cdc.gov/nchs/icd/icd9cm.htm. accessibility verified 14 august 2013. 19. monte s, macchia a, pellegrini f, et al. antithrombotic treatment is strongly underused despite reducing overall mortality among high-risk elderly patients hospitalized with atrial fibrillation. eur heart j 2006; 27:2217. 20. macchia a, monte s, romero m, et al. the prognostic influence of chronic obstructive pulmonary disease in patients hospitalized for chronic heart failure. eur j heart fail. 2007; 9:942. archivio italiano di urologia e andrologia 2013; 85, 4 l. cindolo, f. berardinelli, c. fanizza, m. romero , l. pirozzi, f.r. tamburro, f. pellegrini, f. neri, a. pitrelli, l.schips 206 21. macchia a, monte s, pellegrini f, et al. depression worsens outcomes in elderly patients with heart failure: an analysis of 48,117 patients in a community setting. eur j heart fail. 2008; 10:714. 22. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40:373. 23. romano ps, roos ll, jollis jg. adapting a clinical comorbidity index for use with icd-9-cm administrative data: differing perspectives. j clin epidemiol. 1993; 46:1075. 24. d’agostino rb jr. propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. stat med. 1998; 17:2265. 25. yanovitzky i, zanutto e, hornik r. estimating causal effects of public health education campaigns using propensity score methodology. eval program plann. 2005; 28:209. 26. parsons ls. reducing bias in a propensity score matched pair sample using greedy matching techniques. in: proceedings of the twenty-sixth annual sas users group international conference. 2004, sas institute, cary, nc 27. austin pc, grootendorst p, anderson gm. a comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a monte carlo study. stat med. 2007; 26:734. 28. fenter tc, runken mc, black l, eaddy m. finasteride versus dutasteride: a real-world economic evaluation. am j manag care. 2007; 13:s23. 29. naslund m, eaddy mt, kruep ej, hogue sl. cost comparison of finasteride and dutasteride for enlarged prostate in a managed care setting among medicare-aged men. am j manag care. 2008; 14:s167. correspondence luca cindolo, md, febu (corresponding author) lucacindolo@virgilio.it francesco.berardinelli, md berardinelli.francesco@gmail.com fabiola raffaella tamburro, md fabiola.tamburro@libero.it fabrizio.pellegrini, md fabriziopellegrini85@hotmail.it fabio neri, md info@fabioneri.eu luigi schips, md luigischips@hotmail.com s. pio da pietrelcina hospital, dept. of urology, vasto, italy caterina fanizza, md fanizza@negrisud.it marilena romero, md romero@negrisud.it luisella.pirozzi, md pirozzi@negrisud.it department of clinical pharmacology and epidemiology-consorzio mario negri sud, santa maria imbaro, italy andrea pitrelli, md andrea.n.pitrelli@gsk.com access to medicine, glaxosmithkline spa, verona, italy stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4164 introduction prostate cancer (pca) represents the second major cause of cancer death in men (1). radical prostatectomy (rp) and radiotherapy (rt) are well-established primary therapeutic options for management of localized pca, although cancer recurrence still remains a significant concern for patients. in fact, about 27-53% of patients original paper potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform giuseppe albino 1, 2, francesca vendittelli 1, carmela paolillo 1, cecilia zuppi 1, ettore capoluongo 1 1 laboratory of molecular diagnostics, institute of biochemistry and clinical biochemistry, catholic university, rome, italy; 2 unit of urology, ospedale di andria, asl bat, italy. objective: prostate cancer (pca) represents one of the most important medical problems for males, being the second major cause of cancer death. routinely, pca patients are followed up with both periodic evaluation of serum psa levels and imaging. recently, alternative laboratory methods were proposed for pca patients’ monitoring, with contrasting results. aim of the present study was to evaluate the usefulness of a new commercially ce-ivd kit for detection of prostate circulating tumour cells. our intention was to verify the adnagene platform usefulness to identify patients with disease progression, whatever treatment ongoing, in order to modify the therapeutic process even before treatment failure is evident with imaging methods. materials and methods: twenty-one patients were enrolled and subdivided into three groups: n = 10 high risk tumor pca patients; n = 6 low risk pca patients; n = 5 sbjects without any signs of pca. adnatest prostate cancer kit was used for enrichment and molecular characterization of prostate circulating tumour cells. results: healthy subjects (with bph) and patients without metastases resulted as negative, while 3 out of 10 high risk pca patients were positive at least for one molecular marker like psa, while only two showed positivity for psma mrna. our results indicate that the test specificity is 100% and the sensitivity is 100%; of course the sample is too small to give it statistical validity. in detail we verified that only the “not responder” patients resulted positive for adnatest. conclusions: the present preliminary report provides evidence that isolation and detection of circulating tumour cells (ctcs) is feasible and it may be useful in the follow-up of patients with advanced prostate cancer. if the results of this preliminary study would be confirmed by a large prospective cohort study, it could be demonstrated that this test is a rapid diagnostic method, based on the analysis of a blood sample and useful to the clinician to decide when to change therapy for patients resistant to castration or able to confirm that, at that time, the therapy is effective. key words: prostate cancer; circulating prostate tumor cells; adnatest. submitted 12 july 2013; accepted 31 july 2013 no conflict of interest declared summary undergoing rt or rp will develop local or at distance metastases within 10 years from initial treatment and 1635% of pca patients will receive second-line treatment within 5 years of initial therapy (2, 3). routinely, pca patients are followed up with periodic evaluation of serum prostate-specific antigen (psa) levels and imaging doi: 10.4081/aiua.2013.4.164 165archivio italiano di urologia e andrologia 2013; 85, 4 potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform (tc, rmn, bone scintigraphy, 18-f choline pet) (4), although undetectable serum psa does not necessarily indicate the absence of any potential metastatic risk. in this way, the release of tumor cells into bloodstream could represent a peculiar sign of cancer aggressiveness both before and after therapy (5, 6): therefore, circulating tumour cells (ctcs) detection could provide precious informations to the clinician regarding disease status. in this context, due to the lack of additional markers able to early detect pca relapse, use of reliable test for prostate ctcs detection could provide novel opportunities for alternative therapeutic approaches (7, 8). recent studies employed rt-pcr methods for detection of prostate-specific mrnas in whole blood without any pre-selection of ctcs (9, 10). prostate-specific mrnas are considered as surrogate markers of ctc presence, although with conflicting results (11, 12). however, recent studies on individuals with prostate cancer at advanced stages, performed using the cellsearch platform (13-15), found that high ctc counts correlated with poor prognosis (13-18). ctc detection rates are really variable among studies, ranging from 54% to 62%, mainly depending on the characteristics of the patients studied (19-20). some methods for ctc characterization in pca patients are in developing or under clinical laboratory evaluation (20, 21). a recent ce-ivd method, namely adnatest prostate cancer select plus adnatest prostate cancer detect (adnagen ag, langenhagen, germany), has been commercialized for laboratory ctcs detection through multiple amplification for pca-associated transcripts (reviewed as possible useful markers for monitoring of pca patients) (22-24). in the present work, we evaluated adnagene method for discriminating pca patients at risk for metastasis from those with remission or stable disease, in order to establish if this method may be predictive or not of disease recurrence, with any ongoing therapy. we describe preliminary data that might suggest the use of this method for management of pca patients and support the clinical utility of the assay here described. materials and methods patients selection and blood sampling (more details reported in supplemental files) we selected 21 patients who were subdivided into three groups (table 1), according to d’amico (25) classification: n = 10 pca patients belonging to group i (conventionally defined as prognostic grouping stage iv), because of the high risk tumor class (gleason score (gs) = 8-10 or tnm > t2b n0 m0 or psa > 20); n = 6 pca patients included into group ii (conventionally defined as prognostic grouping stage i), who were defined as at low risk tumor class (gs = 2-6 and tnm = t1-t2a and psa < 10); n = 5 patients with benign prostate hypertrophy, without any clinical and biochemical signs of pca, used as negative controls (defined as group iii; (psa < 2 and negative digital rectal exploration or trus). group iii cases were well known patients, with psa < 2 for at least 5 years, taken from the database of our “stone center”. group ii and group iii were assayed as negative control groups. pca patients belonging to intermediate risk class (gs = 7 and tnm = 2b-t2c) were excluded. the intermediate-risk patients were excluded due to their intermediate characteristics, concerning the risk of progression and recurrence of the disease. the design of the study aims to verify, without any doubt, that patients with localized disease or without prostatic cancer may never have circulating tumor cells detectable by this method (group ii and group iii). for logical reasoning, the only patients who might have ctcs are those belonging at high risk group (group i). in the design of the “case-control” study, the group to be studied is the “group i”. groups ii and iii are control groups. we felt it was a waste of resources the introduction of a further control group consisted of intermediate risk patients. overall pca patients (groups i and ii) were treated with single or combined therapy: radical prostatectomy, external beam radiotherapy, total androgen blockade; two patients of group i started chemotherapy, because of their castration resistance. in order to reduce the biases due to the selection during the enrolment, we choose consecutively only patients who received a diagnosis of pca within previous 36 ± 4 months, while the period of observation was 12 month from first blood sample collection for testing adnatest prostate cancer kit. in fact, for each patient enrolled we collected both 7 ml of whole blood using specific preservative tubes for ctcs capture (adnagen, langenhagen, germany) and 3.5 ml of vacutainer tubes for psa measurement at diagnosis (psa time = 0). additional psa assays were done during the follow up period study (2 per year). therapeutic information and clinical characteristics of patients were collected by a trained urologist (table i). all subjects enrolled in this preliminary investigation gave their informed consent. all procedures were made following the helsinki criteria for research studies. adnatest prostate cancer select/detect blood (5 ml) samples were taken using adnacollect blood collection tubes (adnagen, langenhagen, germany) and immediately processed not later than 24 hours after blood withdrawal, since it has been reported the possible lack of stability of cancer cell transcripts (26). the immunomagnetic enrichment of ctcs was performed by using adnatest prostate cancer select and total mrna/bead mixture was retro-transcribed by sensiscript reverse transcriptase (qiagen, valencia, ca, usa) according to the manufacturer’s instructions. analysis of tumor-associated mrnas, a multiplex pcr was carried out using adnatest prostate cancer detect according to the manufacturer’s instructions. the primer mixture consisted of amplified three tumour markers (psma, psa, egfr) and one housekeeping gene (actin). evaluations of cdna run were carried out using experion 1k analysis dna chip (bio-rad hercules, ca) and 4 % agarose gel. results for the correct interpretation of adnagene test results, actin amplicons must be present in all patient’s runs (internal pcr control): actin signal represents, in fact, the positive control for cell separation, reverse transcriparchivio italiano di urologia e andrologia 2013; 85, 4 g. albino, f. vendittelli, c. paolillo, c. zuppi, e. capoluongo 166 tion and multiplex pcr. adnatest was considered positive for ctc presence if a pcr fragment of at least one tumor-associated transcript was clearly detectable and visible (peak concentration ! 10 ng/µl was fixed as the cut-off). peaks outside the above described criteria were defined as inconclusive. all assays run on our samples passed the quality control criteria. results are briefly summarized in table 1. as expected, all healthy individuals, control group iii bph patients, as well as those belonging to group ii (who presented with disease properly controlled by therapy) resulted as negative for adnatest. contrastingly, among patients belonging to group i (staging class iv), adnatest identified as positive only those who were no more responsive to firstor second-line therapy, while as negative those responsive to firstor second-line chemotherapy, although being escaped by hormone therapy. three out of ten pca group i patients resulted as positive for at least one tumor-associated marker like psa, while only two showed positivity also for psma mrna. it is important to underline that the group i patient (listed as number 2 in table 1), who was negative for adnatest during the first-line of chemotherapy, became positive for psa marker five months later (as shown in the comparison between figures 1a and1b). surprisingly, egfr mrna resulted always negative in our patients: in order to establish if the negative results were dependent on limits of adna-kit, we spiked mrna extracted from prostate cancer slices positive at immunehistochemical analysis, and we found a perfect amplification of egfr target (data not shown). our results indicate that specificity of test is 100% and sensitivity was 100% (table 2). in detail, individuals with bph (group iii) and those defined as “stage i” (group ii) resulted as negative, while all patients belonging to group i (defined as stage iv) and responsive to therapy did not show any positivity for adnatest markers, while all “not responder” patients resulted positive for adnatest. the number of patients is too small to apply the tests of analysis of variance. furthermore, figure 1a is representative of a group of patients’ amplicons analyzed with experion instrumentation. clinical characteristics and main results of adnatest are synthetically reported below for each patient. details of clinical features of 15 pca patients studied patient n. 1: showed a psa relapse perhaps only for the infiltration of the bladder neck, but the bone and lymph node metastases were not metabolically active at scintigraphy examination: this test did not indicate the need of radiotherapy on the primitive mass; patient n. 2: was resistant to hormonal treatment. he initially responded to the first level chemotherapy, but subsequently his clinical conditions worsened. the adnatest prognostic patients psa t0 grouping (stage) gs tnm therapy current psa adna markers group ia 1 332 iv 5+5 n+m+ enantone + casodex 1,68 neg 2 12 iv 5+4 n+m+ eligard + casodex + rt + cht 0,98 neg/psa* 3 136 iv 4+4 t4 n+ m0 casodex 50 + rt 0,49 neg 4 15 iv 3+5 n+ gonapeptyl + casodex rt 52 psa/psma 5 5,73 iv 4+4 pt4 rt 0,01 neg 6 7,05 iv 5+3 pt3b m+ eligard + rt 15 psa 7 128 iv 4+5 n+ m+ eligard + casodex + taxotere 68,5 psa/psma 12 9.8 iv 4+4 m+ casodex + enantone + zometa 9,29 neg 13 12 iv 4+4 t4 rt casodex suspension 0,206 neg 14 8.9 iv 3+5 pt3b n+ rrp r1 (margins +) 0,03 neg group iib 8 6,95 i 3+3 n0 m0 rrp 0,04 neg 9 9,24 i 3+2 n0 m0 eligard 0,04 neg 10 5,64 i 3+3 n0 m0 decapeptyl + casodex + rt 0,00 neg 11 9,83 i 3+3 n0 m0 rt 4,01 neg 15 4.32 i 3+3 n0 m0 rrp 4,32 neg 21 7.13 i 3+3 n0 m0 casodex 0,04 neg group iii 16 bph 0,174 neg 17 bph 1,52 neg 18 bph 0,267 neg 19 bph 0,94 neg 20 bph 1,94 neg table 1. therapeutic informations and pathological characteristics of pca and control patients, following the tnm classification (uicc, 2009). tnm = cancer staging system; gs = gleason score (all gs are “biopsy gs” because they were not submitted to rrp; only pts 8-14-15 have “rp-gs”); adna markers: psa, psma, egfr; bph = benign prostate hypertrophy. all 15 healthy normal controls resulted as negative for the three adna markers. a) group i patients belong to stage iv of pca disease, as reported in tnm classification of malignant tumors. uicc international union against cancer. 7th edn, 2009 (ref. 39). b) as reported in the text, group ii patients includes low-risk progression pca individuals, as indicated in the reference (25). *patient n. 2 was firstly negative at the adnagene test, but five month later (following the disease progression) resulted as positive. 167archivio italiano di urologia e andrologia 2013; 85, 4 potential usefulness of ctc detection in follow up of prostate cancer patients. a preliminary report obtained by using adnagene platform has confirmed the disease status; under strict radiological follow up, at distance metastases became evident three months later the molecular test resulted positive. patient n. 3: the test confirmed the efficacy of enlarged radiotherapy; patient n. 4: after lymphadenectomy, positive obturator lymph nodes were found at the extemporary frozen histological section: therefore radical prostatectomy was not performed but enlarged radiotherapy and total androgen blockade were administered. since patient has become refractory to total androgen blockade, an “anti-androgen withdrawal” was started; patient n. 5: adnatest confirmed the efficacy of adjuvant postoperative rt; patient n. 6: he is currently under chemotherapy treatment because of the resistance also to second-line hormonal therapy patient n. 7: he is no longer responsive to chemotherapy since he showing constant disease progression; patient n. 12: despite a psa increase was registered, disease progression is not yet evident. since adnatest negative, a strict monitoring of psa and ctcs overtime has been planned. patient n. 13: adnatest confirmed the good compliance associated to anti-androgen therapy suspension after radiotherapy; patient n. 14: adnatest supported the efficacy of adjuvant radiotherapy after surgery; patient n. 16: (group ii). adnatest, performed before surgery, confirmed the preoperative staging (definitive histological examination: pt2b r0 n0). we underline that patients who responded to the therapies listed in table 2 were always negative for adna markers, while the non-responder resulted as positive for both serum psa increases and prostate ctc markers. discussion several reports showed that circulating tumor cell counts correlate with prognosis in patients with advanced breast, prostate and colorectal cancers, treated by conventional and/or hormonal therapy, suggesting the use of ctcs in the clinical management of cancer patients (18, 27, 28). furthermore, for prognostic and predictive purposes, ctcs detection, when coupled to molecular characterisation of specific cell transcripts or biomarkers, could provide important clinical information in terms of monitoring of efficacy or resistance to targeted therapy: in this way, ctcs represent an accurate laboratory clinical tool for predicting patient’s outcome also in prostate cancer and providing significant advantages in the view of personalised medicine (29). over the past few years, different approaches for enrichment of ctcs in blood have been developed (5, 30-33), associated or not to molecular approaches and/or to immunological characterization, respectively (34-35). the present preliminary study was aimed to assess the usefulness of adnatest prostate cancer for detection of ctcs in two groups of pca patients (with low and high risk) as compared to non pca individuals, in order to establish if the molecular result given by this assay could be helpful for the clinical and drug management of pca patients. this test is, in fact, able to detect some prostate or cancer-specific markers such as psa, psma and egfr (23, 24). in our study we found that adnatest: a) identified patients with disease progression or with biochemical relapse; b) confirmed the clinical staging of patient n.1, who showed biologically aggressive disease (gs 10) and biochemical tumor progression in spite of total androgen blockade or combined androgen blockade; c) likewise, in patient n. 2, molecular test agreed firstly with the efficacy of chemotherapy, due to the blood negativity for adnatest during the first line of cht, while only five months later adnatest resulted as positive, anticipating the results of radiological examination (the latter indicating at distance metastases only after three months from the evidence of a positive test for ctcs); d) adnatest was an useful predictive indicator for patient n.12, who was no more responsive to chemical castration so that anti-androgen therapy was currently discontinued. patients enrolled in the present study are now under stringent follow-up, since they group i patients psa t0 gs tnm therapy current psa adna markers responders 1 332 5+5 n+m+ enantone + casodex 1,68 neg 2* 12 5+4 n+m+ eligard + casodex + rt + cht 0,98 neg 3 136 4+4 t4 n+ m0 casodex 50 + rt 0,49 neg 5 5,73 4+4 pt4 rt 0,01 neg 12 9.8 4+4 m+ casodex + enantone + zometa 9,29 neg 13 12 4+4 t3a rt casodex suspension 0,206 neg 14 8.9 3+5 pt3b n+ rrp r1 (margins +) 0,03 neg not responders 4 15 3+5 n+ gonapeptyl + casodex rt 52 psa/psma 6 7,05 5+3 pt3b m+ eligard + rt 15 psa 7 128 4+5 n+ m+ eligard + casodex + taxotere 68,5 psa/psma responder patient became not-responder 2* 12 5+4 n+m+ eligard + casodex + rt + cht 6,81 pos* table 2. patient stratification based on response to single or combined therapies. archivio italiano di urologia e andrologia 2013; 85, 4 g. albino, f. vendittelli, c. paolillo, c. zuppi, e. capoluongo 168 are followed by psa assays overtime (every four months), and ct scan every six months, in order to plan other ctc tests for monitoring of disease progression. regarding the molecular typing performed after enrichment, the use of multiplex adnagen pcr may improve the detection of at least one marker potentially associated to circulating prostate tumor cells and possibly associated to poor prognosis. although mrna-psa is not unanimously considered as a better independent prognostic factor as compared to serum psa detection (36), a limit of this test is that tumor-associated proteins, like psa, are also expressed in normal cells. nevertheless, in our test, when the suggested cut-off of 10 ng/ml was used, no false-positive results, particularly in bph patients, were found. furthermore, several studies suggested the use of psma, alone or combined to psa-mrna, to increase assay specificity in pca patients (36), psma being over-expressed in advanced or in castration resistant pca (37) and preferentially expressed in anaplastic cells, hormone-refractory cells and bone metastases (38). conclusions in our opinion, molecular analysis of ctcs through psma mrna detection could provide important information for clinicians in terms of prediction of disease recurrence, before imaging findings. this finding demonstrates the potential role of ctcs in the follow up of the prostatic cancer; it can be obtained in a routine practice setting, by a simple blood sampling. we underline that although the present study did not compare the efficiency of adnatest with that of other platforms (in particular the cellsearch system), we can assume that our test may be considered as reliable: in fact, in this regard, andreopoulou e et al have recently reported the concordance between these two methods (40). finally, our results should be confirmed on larger cohorts of patients also considering that this type of test should be performed in laboratories with high expertise personnel in strict relationships with clinical departments. references 1. heidenreich a, bolla m, joniau s, et al. guidelines on prostate cancer eur urol. 2011; 59:61-71 and 59:572-83. 2. taplin me, bubley gj, shuster td, et al. mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. n engl j med. 1995; 332:1393-8. 3. chi kn, bjartell a, dearnaley d, et al. castration-resistant prostate cancer: from new pathophysiology to new treatment targets. eur urol. 2009, 56:594-605. 4. kruck s, gakis g, stenzl a. circulating and disseminated tumor cells in the management of advanced prostate cancer. adv urol. 2012;135281. epub 2011 aug 21. 5. paterlini-brechot p, benali nl. circulating tumor cells (ctc) detection: clinical impact and future directions. cancer lett. 2007; 253:180-204. 6. pantel k, brakenhoff rh, brandt b. detection, clinical relevance and specific biological properties of disseminating tumour cells. nat rev cancer. 2008; 8:329-40. 7. allard wj, matera j, miller mc, et al. tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with non-malignant diseases. clin cancer res. 2004; 10:6897-904. 8. jost m, day jr, slaughter r, et al. molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood. mol cancer. 2010; 2:174. figure 1a-b. amplification results obtained on a group of pca patients. adnatest results on some of patient samples analyzed with the experion instrument (biorad). dna size standards (ladder) and the pcr positive control are shown in the first and in the last lanes. the positive control generates fragments of following sizes: psma: 449 bp, psa: 357 bp, egfr: 163 bp, actin: 111 bp. patients 4 and 7, are positive for psa and psma targets. patient 6 is positive only for psa mrna. the remaining lanes are negative for any tumour associated-markers and show only the actin band as internal control. adnatest result of patient n. 2 on 4% agarose gel after five months from first-line of cht administered. ladder 1 2 3 4 6 7 10 11 + 2 ladder + 1a 1b 1500 850 700 500 400 300 200 150 100 50 15 169archivio italiano di urologia e andrologia 2013; 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65:4-14. 32. wiedswang g, borgen e, schirmer c, et al. comparison of the clinical significance of occult tumor cells in blood and bone marrow in breast cancer. int j cancer. 2006; 118:2013-19. 33. wong ns, kahn hj, zhang l, et al. prognostic significance of circulating tumour cells enumerated after filtration enrichment in early and metastatic breast cancer patients. breast cancer res treat. 2006; 99:63-9. 34. stathopoulou a, vlachonikolis i, mavroudis d, et al. molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. j clin oncol. 2002; 20:3404-12. 35. benoy ih, elst h, van der auwera i, et al. real-time rt–pcr correlates with immunocytochemistry for the detection of disseminated epithelial cells in bone marrow aspirates of patients with breast cancer. br j cancer. 2004; 91:1813-20. 36. doyen j, alix-panabièresd c, hofmanb p, et al. circulating tumor cells in prostate cancer: a potential surrogate marker of survival. crit rev oncol hematol. 2012; 81:241-56. 37. perner s, hofer kr, shah rb, et al. prostate-specific membrane antigen expression as a predictor of prostate cancer progression. hum pathol. 2007; 38:696-701. 38. israeli rs, powell ct, corr jg, et al. expression of the prostatespecific membrane antigen. cancer res. 1994; 54:1807-11. 39. sobin lh, gospodariwicz m, wittekind c. tnm classification of malignant tumors. uicc international union against cancer. 7th edn. wiley-blackwell. 2009; pp. 243-248. 40. andreopoulou e, yang ly, rangel km, et al. comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: adnagen adnatest breastcancer select/detect™ versus veridex cellsearch™ system. int j cancer. 2012; 130:1590-7. correspondence giuseppe albino, md (corresponding author) urology unit ospedale di andria asl bat ospedale “l. bonomo”, andria, italy peppealbino@hotmail.com francesca vendittelli, md carmela paolillo, md cecilia zuppi, md ettore capoluongo, md laboratory of molecular diagnostics, institute of biochemistry and clinical biochemistry, catholic university, largo a. gemelli 8 00168 rome, italy archivio italiano di urologia e andrologia 2016; 88, 4274 original paper the use of autologous platelet rich plasma gel in bulbar and penile buccal mucosa urethroplasty: preliminary report of our first series marcello scarcia, francesco paolo maselli, giuseppe cardo, giuseppe mario ludovico urology department “f. miulli”, general hospital acquaviva delle fonti, bari, italy. objective: the buccal mucosa (bm) urethroplasty (up) is one of the preferred treatments for long or compli-cated urethral strictures. we propose the use of autologous platelet rich plasma gel (aprpg) in order to enhance to vascularization of bm graft and reduce the fibrous spongy. we report the outcome of our ten cases of bulbar and penile up and the safety of this technique. materials and metods: ten patients underwent to bm up with use of aprp gel. median age was 46. stricture etiology was idiopathic, failed hypospadias and flogistic. average stricture length was 3.7 cm. all patient were preoperatively evaluated with uroflowmetry , retrograde urethrography, cystoscopy and questionnaire. the harvesting of the aprp was performed in blood bank from peripheral venous sample. catheter was usually removed after 3 weeks and urethrography was performed after 6 weeks. results: all patients reported no problem on the donor site. at time of follow-up (median 20 month, 12-34) all patients refer no problem and a good uroflowmetry. no re-strictures at the anastomotic sites were demonstrated in any of the patients. conclusion: however in our experience the follow-up is limited and no definitive conclusion or comparison can be made with the original bm up. the use of aprp gel seems feasible and safe. in our opinion it is important to continue investigating this procedure for its advantages in case of complex urethral strictures complicated by fibrous spongy, above all in penile urethral strictures post hypospadia repair. key words: buccal mucosa graft; bulbar urethroplasty; penile urethroplasty; autologous platelet rich plasma gel; urethral strictures. submitted 18 october 2016; accepted 26 november 2016 summary no conflict of interest declared. strictures longer than 6 cm involving both penile and bulbar urethra or associated with local adverse conditions, multistage urethroplasty or mesh graft urethroplasty is mandatory. buccal mucosal (bm) onlay graft urethroplasty (up) is one of the most widely used methods for the repair of the strictures in the bulbar urethra and provides excellent results (8, 12, 16). stricture recurrences can, however, occur despite using an adequate surgical technique and substitution material may deteriorate over time (16, 17). stricture recurrences after bulbar substitution onlay urethroplasty show two different features, namely, extensive fibrous tissue involving the entire grafted area or a short fibrous ring stricture at the distal or proximal anastomotic sites where the apices of the graft are sutured to the apices of the urethral plate (20). we suggest here the use of autologous platelet rich plasma gel (aprpg) in a new technique of bm up to reduce the failures in the treatment of penile urethral strictures after hypospadias repair. methods between january 2013 and october 2014, ten patients with a mean age of 40 years (range, 30-63 years) underwent urethroplasty using buccal mucosal graft and aprpg. six patients had bulbar strictures and four patient had penile strictures. stricture etiology was in 4 cases idiopathic, 2 failed hypospadias and 4 phlogistic. five patients had undergone previous urethrotomy or failed bulbar urethroplasty, two patients had undergone hypospadias repair. the average stricture length was 3.7 cm (range, 3-5 cm) (table 1). two patients with bulbar strictures were managed using a dorsal (asopa’s technique) and ventral (mcaninch’s technique) grafts augmentation, like palminteri’s technique. the bm grafts were applied over the albuginea of the corpora cavernosa using as support aprpg (figure 3) and ventrally with interposition of aprpg between the graft and spongiosa. four patient with bulbar strictures were managed with asopa’s technique and use aprpg as previously described. two patient with penile strictures after hypospadias repair were managed with two-stage urethroplasty (bracka’s technique), and two others with onestage urethroplasty (asopa’s technique) (table 1). doi: 10.4081/aiua.2016.4.274 introduction numerous surgical techniques have been described to repair bulbar urethral strictures according to stricture length, including end-to-end anastomosis, augmented roof strip anastomotic urethroplasty, onlay repair using flap, or graft and multistaged procedures (1). strictures longer than 3 cm are generally managed using tissue (skin or buccal mucosa) transfer procedures accomplished in a variety of ways including dorsal or ventral onlay graft urethroplasty (8, 12). finally, in patients with scarcia_stesura seveso 09/01/17 09:53 pagina 274 275archivio italiano di urologia e andrologia 2016; 88, 4 the use of autologous platelet rich plasma gel in bulbar and penile buccal mucosa urethroplasty: preliminary report of our first series in penile urethroplasty the bm graft were applied using as support aprpg. preoperative evaluation each patient’s clinical history and chart were reviewed. preoperative tests included urine culture, residual urine measurement, retrograde and voiding cystourethrography, urethroscopy and questionnaire (iief, ipss). the etiology of the stricture and its location and length (table 1) were carefully examined to better define the characteristics needed in the buccal mucosal graft. preparation of aprpg in our institution, blood is drawn in the blood bank. to draw blood, a venous infusion catheter is placed in the patient’s antecubital vein. blood is collected in blood bags (campoflex gel 8002125 fresenius emocare) containing an anticoagulant to prevent the blood from clotting. predonation blood volumes (150 to > 500 ml of whole blood) can be obtained, resulting in a prp volume ranging from 15 to > 50 ml. tabletop centrifuges have been used to manufacture smaller volumes of prp from lesser amounts of whole blood (50-150 ml). the choice for system is mainly dependent on the type of surgical procedure, and thus the anticipated amount of prp to be produced. for the picked decomposition unit, centrifugation at 1740 g at 22°c for 6 minutes was used. at the end of centrifugation the aprp werte distributed in 4 mini bags (each mini bag can contain 35 ml of aprp). the aprp product can be used in liquid form or activated with calcium gluconate to produce the aprpg. the aprp can be frozen at -80°c, and will be valid for six months. it will be thawed at the time of the clinical use. the thawing should take place at room temperature under sterile hood. to activate the aprp the contents of the mini bags was aspirated and transferred to a sterile petri capsule. calcium gluconate was added as activator (0.5 ml for 5 ml of aprp). after mixing and waiting for about 15 minutes, aprpg ready for clinical use was formed (figure 1). mechanisms of action tissue repair and surgical wound healing are well orchestrated, and a complex series of events involving cell-cell and cell-matrix interactions in which platelet growth factors serve as messengers to regulate various regenerative processes. initially, tissue repair begins with activation of the coagulation cascade, platelet clot formation, platelet aggregation, and degranulation. during this degranulation period, the platelets release a pool of biologically active proteins (pdgfs) and other substances into the extracellular milieu. in this environment, the biologically active proteins might bind to specific platelet growth factor receptors present in surgical tissues. released growth factors interact and bind with the platelet tyrosine kinase receptor (tkr), which is present in the cell membranes of tissue cells (ligand-receptor interaction) (21). therefore, the actual binding site is on the outer surface of the cell membrane, and thus not directly on the cell nucleus. the tkr is a membrane spanning protein that extends into the cytoplasm of cells. after the platelet growth factor interacts with the external part of the tkr, activation of inactive messenger proteins occurs in the cytoplasm. thereafter, the messenger proteins become activated and bind to the tkr cytoplasmic tail. activated proteins are generated via an active signaling cascade in the cell nucleus where the genes responsible for control of cell division are triggered. thus, transcription of messenger rna is induced, producing a biological response that starts cascades, which in turn provoke tissue repair and tissue regeneration. platelet growth factors in aprp a variety of platelet growth factors are located in the alpha granules of platelets present in the prp. platelet derived growth factor was one of the first growth factors to be identified in platelets. subsequently, additional platelet growth factors have been identified, including transforming growth factor (tgf) and ß, fibroblast growth figure 1. autologous platelet rich plasma gel in sterile petri capsule. figure 2. autologous platelet rich plasma gel shaped with a scalpel. figure 3. autologous platelet rich plasma gel on dorsal plate, during bulbar urethroplasty. table 1. characteristic of urethral stricture and type of urethroplasty. site and length of stricture type urethroplasty bulbar 3 cm asopa bulbar 3 cm asopa bulbar 3 cm asopa bulbar 3,5 cm asopa bulbar 4 cm asopa mcaninch bulbar 3,5 cm asopa mcaninch penile 3 cm one stage asopa penile 4,5 cm one stage asopa penile 5 cm two stage bracka penile 5 cm two stage bracka scarcia_stesura seveso 09/01/17 09:53 pagina 275 archivio italiano di urologia e andrologia 2016; 88, 4 m. scarcia, f.p. maselli, g. cardo, g.m. ludovico 276 factor (fgf), insulin-like growth factor (igf), epidermal growth factor (egf), vascular endothelial growth factor (vgef), and connective tissue growth factor (ctgf) (24). the platelet growth factors have their own specific function and biological activity. the concept of harvesting and concentrating autologous platelets with subsequent transfer and fixation to the wound site within the medium of an autologous soft tissue graft allows access to higher concentrations of multiple growth factors placed directly into the wound site (27). infection prevention in addition to the platelet gel (pg) delivery of growth factors, limited data are available that deal with the role of leucocytes present in the platelet leucocytes gel (plg) to act as an antimicrobial component. it is also rich in concentrated leukocytes, in particular neutrophilic granulocytes, monocytes, and lymphocytes (29). neutrophilic granulocytes and monocytes contain numerous granules full of myeloperoxidase, which catalyzes the oxidation of chloride to generate hypochlorous acid and other reactive oxygen derivates that act as potent bactericidal oxidants toxic to micro-organisms and fungi (31). furthermore, tang et al. (33) have maintained the idea that platelets are also involved in microbicidal activity, suggesting that platelets take part in the platelet host defense mechanism by releasing a variety of platelet microbicidal proteins. wound healing during the initial days of wound healing, an inflammatory process is initiated by migration of neutrophils, and subsequently macrophages, to the wound site. in turn, activated macrophages release multiple growth factors, including platelet-derived growth factor, tgf, interleukin-1, and fgf (35). angiogenesis and fibroplasia start shortly after day 3, followed by collagen synthesis on days 3-5. this process leads to an early increase in woundbreaking strength, which is the most important woundhealing parameter of surgical wounds, followed by epithelialization and the ultimate remodeling process leading to a tissue scar (36). in pg the multiple platelet growth factors and other biological and adhesive proteins work together synergistically and promote mitogenesis of mesenchymal stem cells and growth factors at the surgical wound site, and therefore have the potential to accelerate and boost tissue healing (38). sticking the graft using aprpg the aprpg arrived in the operating room in a sterile petri dish (figure 1), is shaped with a scalpel (figure 2) according to the urethral plate to be rebuilt. depending on the intervention to be performed is placed on the tunica albuginea of the corpora cavernosa and then overlaps the buccal mucosa graft and both are sutured to the urethral mucosa. to the ventral extension, the buccal mucosa is sutured at the urethral mucosa before, and subsequently applies the aprpg and it is covered by the spongy urethra. postoperative care the patient consumes a clear liquid diet and ice cream before advancing to a soft, then regular diet. the patient is discharged from the hospital 3 day after surgery. all patients receive postoperative broad-spectrum antibiotics and are maintained on oral antibiotics until the catheter is removed. three weeks after surgery the foley catheter is removed. postoperative complications a possible early minor complication is urethrorrhagia due to nocturnal erections. possible later minor complications are temporary numbness, dysesthesia to the perineum, and scrotal swelling. results clinical outcome was considered a success or a failure at the time that any postoperative procedure was needed, including dilation. no intraoperative or postoperative complications were observed. transurethral catheter was usually removed after 3 weeks and urethrography was performed after 6 weeks. the uroflowmetry was performed every 3 month and urethrography every 6 month and annually thereafter. average follow-up was 20 months (range, 12-34 months). no re-strictures at the anastomotic sites were demonstrated in any of the patients. no episode of urinary retention was reported. discussion the careful examination of the many different actors assembled in a platelet concentrate allows to expect that these products will offer better healing properties than the fibrin glues still used in many surgical applications. and indeed, like fibrin glues many years ago, these technologies were recently tested in many clinical applications, such as oral and maxillofacial surgery (39), earnose-throat surgery (41), plastic surgery (42), orthopedics and trauma surgery (46), sports medicine (49), general surgery (51), gynecologic (52) and cardiovascular surgery (53) and even ophtalmology (54). historically, these technologies were first widely distributed in oral and maxillofacial surgery, and the dental literature is very wide on this topic. in bone surgery, the classical approach is to mix a bone graft with the platelet gel, and this is one of the first tested applications in maxillofacial surgery. the fibrin matrix is expected to serve as a biological binder between the various bone blocks and to improve the development of the vascularization within the graft, while the growth factors are supposed to accelerate cell proliferation and migration (particularly endothelial cells for angiogenesis). used as a surgical adjuvant, the platelet concentrates are in fact taking the function of an improved blood clot: indeed in bone surgery, bleeding of the surgical site is always expected, because blood regenerative properties are strongly required for the good integration of a bone graft without necrosis sequestrum (this is an old but validated clinical principle). the use of platelet concentrate is somehow a way to mimic and amplify a natural phenomenon: blood coagulation for tissue regeneration. in soft tissue surgery, the classical approach is to cover the surgical site with a wide layer of fibrin gel (55). the platelet gel serves as a biological binder at the interface scarcia_stesura seveso 09/01/17 09:53 pagina 276 277archivio italiano di urologia e andrologia 2016; 88, 4 the use of autologous platelet rich plasma gel in bulbar and penile buccal mucosa urethroplasty: preliminary report of our first series between the skin and the deep tissues (like a fibrin glue), and is also supposed to accelerate soft tissue healing, through angiogenesis stimulation and proliferation of the skin connective tissues. the main function of the platelet concentrate is therefore to protect the surgical site by stimulating the wound closure and avoiding local necrosis of the skin. as surgical adjuvants, all the platelet concentrates follow similar concepts of clinical use: mixed with a bone graft or used as protective glue layer for soft tissues. the general philosophy of these preparations is to stimulate healing and reduce the risk of failure (particularly the necrosis of a bone graft or a cutaneous flap), but these products are sometimes also expected to improve the intrinsic quality of the treated tissues: stronger bone graft remodelling and gingival tissue maturation, invisible cutaneous scar, etc. these surgical adjuvants may be useful in all the sites where biological binder and a stimulation of angiogenesis are required. it is interesting to see that for this kind of applications, fibrin and growth factors are both as important. finally, the antimicrobial properties of these preparations are also very important characteristics that offer many collateral applications, such as local disinfection or contamination control of wounds (60). these products could also act as regulators of the immune reactions, directly with their leukocyte content and growth factors (61), but also indirectly through the angiogenic properties of the fibrin matrix (early vascularization helps to drain edema and inflammation). the concept of in situ regenerative medicine is to inject cells or pharmaceutical preparations with the objective to induce locally the regeneration of a tissue. it is a pharmaceutical concept, where platelet concentrates are no more a surgical adjuvant to the treatment: they become the treatment. this kind of application is an important trend in the field of platelet concentrates, because these preparations contain high concentrations of autologous cells and proteins (particularly growth factors) that could promote a local cell stimulation. the first application based on this concept is to inject unactivated liquid platelet suspensions in various tissues in order to stimulate locally the cells and tissue regeneration. this non-surgical approach is particularly relevant with tendons or aged skin (49). the second application is to use these products as solid biomaterials sustaining the release of regenerative molecules on a wounded site. prp gels technologies allow to produce a significant volume of this fibrin-based biomaterial rich in many healing factors, particularly platelet growth factors. the literature of current pharmaceutical biotechnology, several experts try to highlight the beneficial impact of these therapies in different clinical fields. in the gynecology literature, shackelford et al., conducted a double-blind, randomized, placebo-controlled trial using topical recombinant human platelet derived growth factors gel (pdgf gel) after abdominal wound separation (64). they used the recombinant growth factor to treat the wound and studied the effects on wound healing. the patients in the placebo group closed 54 +/26 days post-operatively, whereas the wounds of patients in the treatment group closed in 35 +/15 days (p = 0.05). the preliminary study suggests that the topical application of 0.01% recombinant human pdgf gel accelerates healing of separated surgical wound significantly, as determined by kaplan-meier analysis. . pg including multiple growth factors, have been used to treat chronic wounds since 1985 (65). since this period, a variety of studies have been published on the application of prp gels in wound care management. a prospective, randomized, controlled, blinded, multicenter clinical study was conducted by driver and associates to evaluate the efficacy and safety of autologous prp gel for the treatment of non-healing diabetic foot ulcers (67). the primary study objective was the proportion of patients with a healed wound. the proportion of completely healed wounds was significantly higher in the prp gel group when compared to the control group (81.3% and 42.1% in the prp gel and control treatment groups, respectively). furthermore, no treatment related adverse effects were noted, indicating safe prp gel preparation and application. from the literature it is clear that aprp and pg have a wide and safe application within a variety of operative procedures as a tissue regenerative agent. its application has extended to patients that are prone to higher surgical complications. however in our experience the follow-up is limited and no definitive conclusion or comparison can be made with the original bm up. the use of aprp gel seems feasible and safe. the short-term results on this our limited series of patients were satisfactory. further comparative studies are necessary to confirm that the use aprp gel is really beneficial. moreover, additional studies are necessary to evaluate whether its use reduces the re-stricture rate. conclusion longer follow-up on a larger series of patients is necessary to confirm our satisfactory preliminary reports using aprp gel. in our opinion it is important to continue investigating this procedure for its advantages in case of complex urethral stenosis complicated by fibrous spongy, above all in penile urethral stenosis post hypospadia repair. we propose the name of this technique maselli-scarcia’s. references 1. barbagli g, palminteri e, lazzeri m, guazzoni g. anterior urethral strictures. bju int. 2003; 92:497-505. 2. andrich de, leach cj, mundy ar. the barbagli procedure gives the best results for patch urethroplasty of the bulbar urethra. bju int. 2001; 88:385-9. 3. kane cj, tarman gj, summerton dj, et al. multi-institutional experience with buccal mucosa onlay urethroplasty for bulbar urethral reconstruction. j urol. 2002; 167:1314-7. 4. elliot sp, metro mj, mcaninch jw. long-term followup of the ventrally placed buccal mucosa onlay graft in bulbar urethral reconstruction. j urol. 2003; 169:1754-7. scarcia_stesura seveso 09/01/17 09:53 pagina 277 archivio italiano di urologia e andrologia 2016; 88, 4 m. scarcia, f.p. maselli, g. cardo, g.m. ludovico 278 5. andrich de, dunglison n, greenwell tj, mundy ar. the longterm results of urethroplasty. j urol2003; 170:90-2. 6. barbagli g, et al. anastomotic fibrous rings as cause of stricture recurrence after bulbar onlay graft urethroplasty: an open issue. j urol. 2006; 175:104, abstract 314. 7. everts pam, overdevest ep, jakimowicz j, et al. the use of autologous platelet-leukocyte gels to enhance the healing process in surgery, a review. surg endosc. 2007; 21:2063-2068. 8. antoniades hn, williams lt. human platelet-derived growth factor: structure and functions. fed proc. 1983; 81:2396-2400. 9. pierce g, mustoe t, altrock b. role of platelet-derived growth factor in wound healing. j cell biochem. 1991; 45:319-326. 10. cieslik-bielecka a, gazdzik ts, bielecki tm, cieslik t. why the platelet-rich gel has antimicrobial activity? oral surg. oral med. oral pathol. oral radiol. endod., 2007; 103:303-305. 11. junqueira lc, carneiro, j. basic histology. mcgraw-hill: new york, 2003, pp. 97-101. 12. tang yq, yeaman mr. selsted me. antimicrobial peptides from human platelets. infect. immun. 2002; 70:6524-6533. 13. mcgrath mh. peptide growth factors and wound healing. clin plast surg. 1990; 17:421-432. 14. cromack dt, pierce gf, mustoe ta. tgf and pdgf medicated tissue repair: identifing mechanisms of action using impaired and normal models of wound healing. clinical and experimental approaches to dermal and epidermal repair: normal and chronic wounds. wiley liss: new york, 1991,; pp. 359-373. 15. brown rl, breeden mp, greenhalg dg. pdgf and tgf-alpha act synergistically to improve wound healing in the genetically diabetic mouse. j surg res. 1994; 56:562-570. 16. whitman dh, berry rl, green dm. platelet gel: an autologous alternative to fibrin glue with applications in oral and maxillofacial surgery. j. oral maxillofac surg. 1997; 55:1294-1299. 17. braccini f, tardivet l, dohan ehrenfest dm. the relevance of choukroun's platelet-rich fibrin (prf). during middle ear surgery: preliminary results. rev. laryngol otol rhinol. (bord.), 2009; 130:175-180. 18. man d, plosker h, winland-brown je. the use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery. plast reconstr surg. 2001; 107:229-237; discussion 238-229. 19. everts pa, devilee rj, brown mahoney c, et al. platelet gel and fibrin sealant reduce allogeneic blood transfusions in total knee arthroplasty. acta anaesthesiol scand. 2006; 50:593-599. 20. mishra a, woodall j. jr., vieira a. treatment of tendon and muscle using platelet rich plasma. clin sports med. 2009; 28:113-125. 21. everts pa, overdevest ep, jakimowicz jj, et al. the use of autologous platelet-leukocyte gels to enhance the healing process in surgery, are view. surg endosc. 2007; 21:2063-2068. 22. fanning j, murrain l, flora r, et al. phase i/ii prospective trial of autologous platelet tissue graft in gynecologic surgery. j minim invasive gynecol. 2007; 14:633-637. 23. khalafi rs, bradford dw, wilson mg. topical application of autologous blood products during surgical closure following a coronary artery bypass graft. eur j cardiothorac surg. 2008; 34:360-364. 24. alio jl, abad m, artola a, et al. use of autologous platelet-rich plasma in the treatment of dormant corneal ulcers. ophthalmology. 2007; 114:1286-1293. 25. man d, plosker h, winland-brown je. the use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery. plast reconstr surg. 2001; 107:229-237. 26. cieslik-bielecka a, bielecki t, gazdzik, et al. autologous platelets and leukocytes can improve healing of infected high-energy soft tissue injury. transfus apher sci. 2009; 41:9-12. 27. woodall j jr., tucci m, mishra a, benghuzzi h. cellular effects of platelet rich plasma: a study on hl-60 macrophage-like cells. biomed sci instrum. 2007; 43:266-271. 28. shackelford dp, fackler e, hoffman mk, atkinson s. use of topical recombinant human platelet-derived growth factor bb in abdominal wound separation. am. j. obstet. gynecol. 2002; 186:701-704. 29. knighton dr, ciresi k, fiegel vd, et al. simulation of repair in chronic, nonhealing, cutaneous ulcers using platelet-derived wound healing formula. surg gyn obstet. 1990; 170:56-58. 30. driver vr, hanft j, fylling cp, beriou jm. a prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. ostomy wound manag. 2006; 52:68-87. correspondence marcello scarcia, md (corrisponding author) scarciam@hotmail.com francesco paolo maselli, md ciccio702001@gmail.com giuseppe cardo md, md giuseppecardo@hotmail.com giuseppe mario ludovico, md giuseppeludovico@hotmail.com urology department of general hospital “f. miulli” s.p. santeramo km 4.100 70021 acquaviva delle fonti, bari, italy scarcia_stesura seveso 09/01/17 09:53 pagina 278 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2154 case report a rare complication of eswl: focal metastatic multiple organ abscesses in a horseshoe kidney ugur kuyumcuoglu 1, bilal eryildirim 2, murat tuncer 2, gokhan faydaci 2, tevfik aktoz 1, hakan akdere 1, kemal sarıca 2 1 trakya university, faculty of medicine, urology clinic, edirne,turkey; 2 lutfi kirdar training and research hospital urology clinic, istanbul, turkey. extracorporeal shock wave lithotripsy (eswl) is an effective treatment modality in the minimal invasive management of urinary system stone disease. although the majority of the complications occuring after eswl are minor ( most common ones are gross haematuria, pain, perinephritic hematoma); bacteriuria may also occur in some cases which sometimes can lead to sepsis and even metastatic abscess formation in a very rare part of the cases treated. in this rare situation infection agent spreads quickly via hematogenous route and causes abscess formation in different parts of the body. majority of such cases usually have an underlying systemic disease like diabetes mellitus (dm), malignancy, hiv or steroid use which lead to disruption of immune system functions. abscess formation following eswl is extremely rare and usually limited with some case reports published in the literature. herein, we present a diabetic case with formation of multiple abscess foci in kidney, as well as in lungs and liver following eswl. the patient was first admitted to our emergency department with high fever and respiratory distress and misdiagnosed as metastatic tumor foci based on radiologic findings. to the best of our knowledge, our case is the first one in the literature in whom simultanous abscess formation in multiple organ systems has been documented following an otherwise uneventful eswl. key words: eswl (extracorporeal shockwave lithotripsy); abscess; complications. submitted 11 september 2013; accepted 31 january 2014 summary introduction as a minimal invasive management alternative eswl is an effective, safe and practicle treatment in the treatment of urinary system stones (1). however, accumulated experience so far has clearly shown that despite its safe nature; some certain complications ( majority of which are minor) may occur following this procedure . in addition to the traumatizing effects of high energy shock waves (hesw) on renal parenchyma: these complications may also originate no conflict of interest declared. from residual stone fragments and infection after the procedure. the trauma induced by hesw during eswl may allow spread of the bacteria in urine to the bloodstream resulting in infectious complications like bacteriuria, bacteraemia, urinary tract infection, urosepsis, perinephric abscess formation and even death in rare cases (2). related with this subject, bacteriemia may occur in 4% of patients treated with eswl which constitutes the main underlying risk for the formation of distant organ metastatic abscesses. last but not least, these infectious complications can cause urosepsis in a rarely encountered manner (3). herein we present a diabetic case admitted to our emergency department with high fever and respiratory distress findings. he was first hospitalized with the diagnosis of acute pneumonia and hyperglycemia attack by chest diseases department. computerized tomography (ct) of thorax and abdomen revealed multiple metastatic masses in lungs, liver and also in parenchyma of horseshoe kidney with an unknown origin. case report we present a diabetic case admitted to our emergency department with high fever and respiratory distress findings. he was first hospitalized with the diagnosis of acute pneumonia and hyperglycemia attack by chest diseases department. computerized tomography (ct) of thorax (figure 1) and abdomen revealed multiple metastatic masses in lungs, liver and also in parenchyma of horseshoe kidney with an unknown origin. case report description and figures are in supple mentary materials posted on www.aiua.it discussion following its clinical introduction in 1982, eswl became the preferred treatment modality in the management of urinary calculi with its successful results (4). accumulated experience in this field of urology did prove the efficacy and safety of this approach based on its minimally invasive nature. however despite its highly successful and safe results, studies did clearly show that this some certain side doi: 10.4081/aiua.2014.2.154 figure 1. 155archivio italiano di urologia e andrologia 2014; 86, 2 metastatic multiple organ abscesses after eswl effects can occur following this procedure. related with this subject the reported complications namely gross haematuria, pain, perinephritic hematoma are generally minor problems which could be treated in a conservative manner in the majority of the cases (5). however, studies again demonstrated that some certain infectious complications such as bacteriuria can also be anticipated after management and it can sometimes lead to sepsis (6). gram (-) bacteria are the most common agent found after eswl which could sometimes lead to metastatic abscess formation (5). related with this subject again metastatic abscess is defined as hematogenous spreading of an infective agent which causes abscess formation in the different parts of the body. concerning the etiopathogenesis of metastatic abscess formation, patients usually suffer from an underlying systemic disease like diabetes mellitus (dm), malignancy, hiv or steroid use which leads to disruption of immune system functions. the release of bacteria from fragmented stones or infected urine due to tissue injury can also sometimes be responsible for abscess formation. when a focal intraparenchymal abscess occurs, depending on the body defense mechanisms, associated co-morbidities along with the type and efficacy of the treatment, enlargement and rupture of this focal infection may result in spread of infection into the perinephritic area causing perinephritic abscess formation. although parenchymal and/or perinephritic abscess formation following eswl has been reported with limited case reports in the literature (7); metastatic abscess formation in other areas of the body following this procedure is an extremely rare complication. while brain abscess formation following eswl was reported by zannoud et al. (3); unal et al reported a giant abscess formation after eswl which was attached to the abdominal wall enlarging towards the thorax (7). in our present case, in addition to the multiple abscess foci in the treated kidney, additional metastatic abscess foci have also been detected in other organs including lungs and liver which probably originated from the hematogenous spread of the infection following eswl. another interesting aspect of our case is that radiologists misdiagnosed the simultaneous hypodense noduler lesions as metastatic tumors of unknown origin involving lungs, liver, and horseshoekidney. to the best of our knowledge, there is no report in the literature demonstrating the simultaneous abscess formation in multiple organs following eswl. li et al. presumed that the predisposing factors for sepsis and abscess formation following eswl are the presence of stones larger than 2 cm, struvite stones, nephrostomy or stents and lastly obstruction in urinary system (5). diabetes mellitıus could be a predisposing risk factor for abscess formation in our case besides, we assume that the patient has not been well evaluated with respect to the presence and degree of urinary system infection before eswl procedure. in that case the procedure might have resulted in bacteriemia originating from an untreated infection before eswl. last but not least, the formation of abscess in right perirenal area following an eswl procedure for the left kidney stone is also an interesting consideration. this can be attributed again with the horseshoe kidney malformation in our case which may predispose the kidney for such a complication. references 1. labanaris ap, kühn r, schott ge, zugor v. perirenal hematomas induced by extracorporeal shock wave lithotripsy (eswl). therapeutic management. scientific world journal. 2007; 17:1563-66. 2. skolarikos a, alivizatos g, de la rosette j. extracorporeal shock wave lithotripsy 25 years later: complications and their prevention. eur urol. 2006; 50:981-90. 3. zannoud m, ghadouane m, kasmaoui eh, et al. metastatic cerebral abscess from klebsiella pneumoniae after extracorporal shock wave lithotripsy for kidney stone (a case report). ann urol. 2003; 37:81-84. 4. chaussy c, schmiedt e. shock wave treatment for stones in the upper urinary tract. urol clin north am. 1983; 10:743-50. 5. li l, shenn z, wang h, eyt al. investigation of infection risk and the value of urine endotoxin during extracorporeal shock wave lithotripsy. chin med j. 2001: 114:510-13. 6. michaels ek, fowler je jr, mariano m. bacteriuria following extracorporeal shock wave lithotripsy of infection stones. j urol. 1988; 140:254-56. 7. unal b, kara s, bilgili y, et al. giant abdominal wall abscess dissecting into thorax as a complication of eswl. urology. 2005; 65:389. correspondence ugur kuyumcuoglu, md, professor kuyumcuugur@yahoo.com bilal eryildirim, md, associate professor bilaleryildirim@yahoo.com murat tuncer, md (corresponding author) murattuncer77@hotmail.com gokhan faydaci, md faydacig@yahoo.com tevfik aktoz, md, associate professor taktoz01@yahoo.com hakan akdere, assistant professor hakdere@yahoo.com kemal sarıca, md, professor saricakemal@gmail.com altunizade mah. atif bey sok.gokdeniz sitesi e blok d:20 kosuyolu, istanbul, turkey a. anterior-posterior chest radiography showing multiple nodular lesions in lungs. b. computerized tomography (thorax) showing multiple nodular lesions in lungs. stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3224 case report treatment of tuberculous ureteritis. what is the appropriate time for invasive treatment? a case report and review of literature özgür haki yüksel, ahmet ürkmez, ayhan verit fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey. we report a case of isolated distal ureter tuberculosis who presented with irritative voiding symptoms treated with sole medical therapy and discuss the clinical, imaging, diagnostic and therapeutical features. in case of irritative voiding symptoms and radiological presentation of ureteral pathologies, genitourinary tuberculosis should be considered in the differential diagnosis. we believe that medical therapy should be the main option before the invasive procedures. key words: ureter tuberculosis; medical therapy; invasive treatment. submitted 14 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction nearly one third of the world’s population is estimated to be infected with mycobacterium tuberculosis. genitourinary tuberculosis is not very common but it is considered as a severe form of extra pulmonary tuberculosis. extra pulmonary tuberculosis accounts for approximately 20% of cases of active tuberculosis. only 20 to 30% of the patients with genitourinary tuberculosis have a history of lung infection (1). urogenital tuberculosis is characterized by clinical polymorphism. however, the isolated ureteric form is very rare (2). we report a case of isolated distal ureter tuberculosis who presented with irritative voiding symptoms treated with sole medical therapy and discuss the clinical, imaging, diagnostic and therapeutical features. case report our case was a 55-year-old woman without significant medical history. the patient consulted us for urinary frequency and microscopic hematuria for the past eight months. the physical examination revealed an exhausted patient. the patient presented with weight loss as 10 kg in eight months. laboratory investigations showed appropriate kidney function with a creatinine of 0.97 mg/dl, an inflammatory syndrome with an erythrocyte sedimentation rate of 54 mm/hour and c-reactive protein of doi: 10.4081/aiua.2014.3.224 2.69 mg/l, whereas the remaining laboratory investigations were unremarkable. the patient then underwent a renal and pelvic ultrasound which showed left hydro nephrosis and hydroureter. this examination was completed by a magnetic resonance urography that revealed a left ureterohydronephrosis in the left distal ureter secondary to focal wall thickening (figure 1). furthermore, considering the irritative voiding symptoms, we suggested a koch’s bacillus assessment of the patient’s urine which resulted strongly positive. the treatment consisted of antituberculous antibiotics. after 6 months of treatment was observed a decline of hydroureteronephrosis (fıgure 2). mycobacterial culture came to be negative. discussion the incidence of tuberculosis is estimated as 26 per 100.000 in turkey. according to the who 2006, extrapulmonary tuberculosis rate is 15-25%. in 2005, surveillance of ministry of health in turkey resulted in 20535 cases suffering from tuberculosis, out of them 91.3% were new cases, 73% and 27% were pulmonary and extrapulmonary tuberculosis, respectively. extrapulmonary tuberculosis cases were genitourinary locations in 4.5%, gastroıntestinal and peritoneal locations in 4.5%; intrathoracic lymphadenitis in 5.5%, extrathoracic lymphadenitis in 26% and pleuric locations in 37%. more rarely bone and central nervous system were affected. risk factors for extrapulmonary tuberculosis are hiv infection, tumour necrosis factor-! antagonists (e.g. infliximab), corticosteroids, malignancy, female gender. being female gender is the unique risk factor for our patient. urogenital tubercolosis comprises renal disease, ureteric disease and genital infection. the diagnosis of renal disease is easily missed, as back or flank pain, dysuria or general symptoms occur in only 30% of patients. renal tubercolosis is usually unilateral and rarely causes renal failure; the exception is tuberculous interstitial nephritis, which may affect both kidneys. renal abscesses may destroy the entire renal parenchyma. pelvo-calyceal involvement may result in thickening of the collecting system; more distally, ureteric fibrosis and stricture formation may cause hydronephrosis, whereas tubercolosis yukselcr_stesura seveso 08/10/14 12:17 pagina 224 225archivio italiano di urologia e andrologia 2014; 86, 3 treatment of tuberculous ureteritis. what is the appropriate time for invasive treatment? a case report and review of literature of the bladder wall may lead to fibrosis. renal biopsy may show granulomatous interstitial nephritis, often with multifocal caseous necrosis. cystoscopy with biopsies of bladder, ureteric or prostate tissue may also be helpful. the ct/mrg urography and intravenous urography with micturition examinations are designed to make an extended assessment of the urogenital tuberculosis lesions. imaging or the renal tract may show a characteristically ‘beaded’ ureter (ureteritis cystica) (3). this is probably due to an extending fibro-inflammatory process with thickening of the ureteral wall that could be confused with a ureteral tumor in evaluation of imaging (4). urogenital tuberculosis is characterized by varied clinical symptoms (5). ureteral localization was always described as secondary to renal disease because it represents the extension of mucosal lesions from the kidney (6). the case reported here did not reveal any visible renal impairment by imaging exploration except hydrourete ronephrosis. endoscopy must always be performed with the patient under general anesthesia with a muscle relaxant to reduce the risk of hemorrhage. the phase of bladder filling should be performed under direct vision. bladder biopsy is contraindicated in the presence of acute tuberculous cystitis (7). indications for ureteroscopy are rare but renal tuberculosis should be included in the differential diagnosis of lateralizing hematuria, especially in the absence of an obvious cause for the bleeding. in this case direct culture of urine from the renal pelvis may have more sensitivity than culture of voided urine (8). the confirmation of the diagnosis is based on assessing microscopically the presence koch’s bacilli in the urine by direct testing for alcohol-acid-resistant bacillus. the koch’s bacillus culture requires a long time for obtaining the final results as long as eight weeks. the identification of koch’s bacillus using polymerase chain reaction is faster and takes 24 to 48 hours, but with a sensitivity reduced to 48.5% (9). according to the who, the antituberculous drug treatment is based on an initial 2 months intensive phase of treatment with three or four drugs (rıfampicın, isoniazid, pyrazinamide, etambutol or streptomycin) to destroy almost all tuberculous bacilli. this is followed by a 4 months manteinance phase with only two drug mostly rıfampicin and ısoniazid (10). the most common site for tuberculous stricture is the ureterovesical junction. uretheral strictures may develop in more than 50% of patients with renal involvement (11). strictures of the lower end of the ureter, which can either be managed medically or surgically, occur in approximately 9% of patients. if obstruction at the lower end of the ureter is present at the start of chemotherapy careful observation is required. these strictures may result from edema and they respond to chemotherapy. the patient should receive chemotherapy and should be monitored by intravenous urograms at weekly intervals. corticosteroids can be added to chemotherapy if there is deterioration or no improvement after 3 weeks. if there is still deterioration or no improvement after a 6 week period, surgical reimplantation should be carried out if an initial attempt of dilatation has failed. double j ureteral catheter drainage may be used during this period for assessing the efficacy of medical therapy. early ureteral stenting or pcn (percutaneous nephrostomy) in patients with tuberculous ureteral strictures may increase the opportunity for later reconstructive surgery and decrease the likelihood of renal loss (12). in all other situations, patients should have at least 4 weeks of extensive chemotherapy before surgery (7). the overall incidence of surgical management of genitourinary tuberculosis in the past 20 years was reported to be about 0.5% of all urological surgical procedures (13). although chemotherapy is the mainstay of treatment, ablative surgery as a first-line management may be unavoidable for sepsis or abscesses (14). medical treatment is the first-line therapy in genitourinary tuberculosis. both radical and reconstructive surgery should be carried out in the first 2 months of intensive chemotherapy (15). the duration of medical therapy has been figure 2. magnetic resonanse urography: at the lower end of the left ureter was observed a significant decrease in contrast enhancement (marked by the arrow). figure 1. magnetic resonanse urography: the left distal ureter secondary to focal wall thickening (marked by the arrow). yukselcr_stesura seveso 08/10/14 12:17 pagina 225 archivio italiano di urologia e andrologia 2014; 86, 3 ö. haki yüksel, a. ürkmez, a. verit 226 reduced to 6 months in uncomplicated cases. only in complicated cases (recurrences of tuberculosis, immunosuppression and hiv/aids) a 9 to 12 month therapy is necessary (6). in conclusion, in the presence of irritative voiding symptoms and radiological imaging showing a pathological ureter, genitourinary tuberculosis should be considered in the differential diagnosis. we believe that medical therapy should be the main option before the invasive procedures. references 1. world health organization (who) (2010) global tuberculosis control 2010: epidemiology, strategy, financing. who/htm/tb 2010. 7. 2. matos mj, bacelar mt, pinto p, ramos i. genitourinary tuberculosis. euro j radiol. 2005; 55:181. 3. figueiredo aa, lucon am, arvellos an, et al. a better understanding of urogenital tuberculosis pathophysiology based on radiological findings. eur j radiol. 2010; 76:246. 4. dhar nb, angermeier kw. idiopathic ureteral strictures without evidence of malignancy. urology. 2004; 64:377. 5. el khader k, lrhorfi mh, el fassi j, et al. tuberculose urogénitale expérience de 10 ans. prog urol. 2001; 11:62. 6. cek m, lenk s, naber kg, et al. members of the urinary tract infection (uti) working group of the european association of urology (eau) guidelines office. eau guidelines for the management of genitourinary tuberculosis. euro urol. 2005; 48:353. 7. warren d, johnson jr, johnson cw, franklin c. lowe: genitourinary tuberculosiscampbell’s urology. 8th ed. saunders; 2002. 8. chan sw, shalhav al, clayman rv. renal tuberculosis presenting as lateralizing hematuria diagnosis by ureteronephroscopy and selective upper tract urine culture. endourol. 1998; 12:363. 9. bouchikhi aa, amiroune d, tazi mf, et al. pseudotumoral tuberculous ureteritis: a case report. j med case rep. 2013; 15:45. 10. world health organization (who) anti-tuberculosis drug resistance in the world. report no. 4. who/htm/tb/2008.394. 11. allen fj, dekock ml. genito-urinary tuberculosis–experience with 52 urology in patients. s afr med j. 1993; 83:903. 12. shin ky, park hj, lee jj, et al. role of early endourologic management of tuberculous ureteral strictures. j endourol. 2002; 16:755. 13. rizzo m, ponchietti r, di loro f, et al. twenty-years experience on genitourinary tuberculosis. arch ital urol androl. 2004; 76:83. 14. carl p, stark l. indications for surgical management of genitourinary tuberculosis. world j surg. 1997; 21:505. 15. gow jg. tuberculosis: genitourinary tuberculosis. br j hosp med. 1979; 22:556. correspondence özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com ahmet ürkmez, md ayhan verit, md, prof fatih sultan mehmet research and training hospital, dept. of urology, icerenkoy/atasehir tr3 4752 istanbul, turkey yukselcr_stesura seveso 08/10/14 12:17 pagina 226 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 120 original paper testicular microlithiasis and dyspermia: is there any correlation? francesco catanzariti, ubaldo cantoro, vito lacetera, giovanni muzzonigro, massimo polito polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, ancona, italy. background: testicular microlithiasis (mt) is an uncommon sonographic finding (prevalence in the literature: 0.7 to 6%). several studies have highlighted its possible correlation with an increased risk of testicular cancer, but few studies have investigated its possible link with dyspermia. objectives: the aim of our study was to investigate in our series the number of patients with microlithiasis, diagnosed by ultrasound, and compare the quality of their sperm with that of patients in a control group with normal testicular ultrasound exam. materials and methods: we performed 277 consecutive testicular ultrasound examinations from january 2012 to july 2012. among all these, we selected 86 patients that showed no pathological elements at echography and 11 patients affected by mt, to one or both testicles. each patient was also submitted to a short-term semen analysis using the who2010 parameters for sperm evaluation. results: among 11 patients with mt, 7 (63.63%) were dyspermic and 4 (36.36%) were normospermic. among the 86 patients with normal testicular ultrasound 51 (59.3%) were dyspermic, 4 (4.65%) were azoospermic, while the remaining 31 (36.05%) were normospermic. comparing the results of the two groups we obtained an odds ratio of 0.99 (95% ci: 0.27 to 3.64, p: 0.98). conclusions: this study, although preliminary, with a low number of partecipants, shows that sperm quality is not affected by the presence of testicular microlithiasis, because the results of spermiograms are almost comparable between the two groups. key words: testicular microlithiasis; infertility; testicular ultrasound. submitted 1 september 2013; accepted 31 december 2013 summary introduction testicular microlithiasis (mt) is a quite rare ultrasound evidence, with a low prevalence, from 0.7 to 6%, as described in literature (1-3), although with the evolution of ultrasound machines, which allow the identification no conflict of interest declared. of structures of diameter less than one millimeter, the prevalence of mt has been increasing. the mt is characterized by the presence of hyperechoic spots of diameter between 1 and 3 mm, which don’t have posterior shadow cone, within testicular parenchima. microlithiasis can be classified as “classic” or “limited” depending on the presence of more or less than 5 hyperechoic spots per ultrasound section (figure 1). several studies in literature have shown a correlation between mt and some pathological conditions, such as testicular cancer, cryptorchidism, varicocele, testicular torsion, epididymitis, orchitis, klinefelter's syndrome, male pseudohermaphroditism, neurofibromatosis and hiv infection (4). some papers studied the association between microlithiasis and testicular cancer (4) and showed that the mt can predispose to the development of a carcinoma in situ (cis) or a germ cell tumors (tgct) of the testis. other authors have also noted that there could be a correlation between mt and intratubular germ cell neoplasia of unclassified type (itgcnu) (5) and that testicular microlithiasis might be part of a complex disease, the testicular dysgenesis syndrome (tds), comprising in addition to the testicular microlithiasis also other features such as infertility, testicular atrophy, cryptorchidism, tgct and other abnormalities of sexual development (6). in literature there are other studies, less numerous and with conflicting results, which analyze the association between infertility and testicular microlithiasis. some studies support the theory that there would be a higher prevalence of testicular microlithiasis among infertile patients (7), compared to fertile men. this evidence should be more frequent in the classical forms than in limited mt and the pathogenetic mechanism underlying this correlation has been described by some authors as the result of reduced inflow of arterial blood caused by microlithiasis (8). other authors instead believe that not statistically significant correlation exists between mt and infertility (9) and exclude that there is a greater number of antisperm antibodies in patients with testicular microlithiasis (10), which could be the cause of infertility in men affected by mt. doi: 10.4081/aiua.2014.1.20 catanzariti_stesura seveso 26/03/14 10:14 pagina 20 21archivio italiano di urologia e andrologia 2014; 86, 1 testicular microlithiasis and dyspermia: is there any correlation? objectives the aim of our work was to study the incidence of microlithiasis in our series, but above all to analyze how this ultrasound evidence can affect sperm quality of patients with this testicular desease, compared to patients normal at testicular ultrasound. materials and methods from january 2012 to july 2012, we performed 277 consecutive testicular ultrasound at our urology clinic. the testicular ultrasound examinations were performed by three different operators, all with good experience in the field of ultrasound, with the same new generation of machine, using a 7.5 mhz linear probe. during the examination particular attention has been placed on detection of hyperechoic areas compatible with testicular mt, distinguishing the limited forms (less than 5 hyperechoic areas for ultrasound section of diameter between 1 and 3 mm without shadow rear) from the classical ones (at least 5 hyperechoic areas for ultrasound section of diameter between 1 and 3 mm without shadow cone rear). among all the examinations, we selected those patients with testicular ultrasound without no alterations of didymus and epididymis (control group) and those with the presence of classical mt at ultrasound (study group). patients with limited mt were eliminated from the study. each patient of both groups was then subjected to a semen analysis that was performed in a short time (within 30 days) from the ultrasonographic examination. the semen analysis was conducted after at least 3 days of sexual abstinence. the semen samples were collected in the hospital asking patients to deposit its seed directly in sterile 120 ml containers. the samples were analyzed within 1 hour from ejaculation. after liquefaction, semen volume was measured by a syringe with an accuracy of 0.1 ml. the sperm concentration and motility was then evaluated by optical microscope through makler chamber with a magnification of x 200. we used who 2010 parameters for the sperm evaluation. results among the 277 testicular ultrasound examinations, we selected 11 (3.97%) patients with classical mt and 86 (31.05%) patients with normal testis at ultrasound investigation (figure 2), while we eliminated from the study the remaining 180 patients who resulted affected by other testicular diseases (varicocele, cysts, inflammation, etc.) at echography. spermiograms among patients with classical mt showed 7 cases (63.63%) of dyspermia, defined as the presence of at least one of the three parameters (concentration, motility and forms) under reference values according to the who 2010 classification. the remaining 4 patients (36.36%) of the study group instead resulted with normal semen analysis. among the patients belonging to the control group we found dyspermia in 51 (59.3%), azoospermia in 4 (4.65%) and normospermia in 31 (36.05%) cases (figure 3). figure 1. a. classic microlithiasis. figure 2. results in 277 consecutive testicular ultrasounds. figure 3. results of spermiograms in patients affected by mt and normal at echography. b. limited microlithiasis. 70 60 50 40 30 20 10 0 mt 36.36 36.05 59.3 4.65 63.63 0 normal % normospermia dyspermia azoospermia classic microlithiasis normal other catanzariti_stesura seveso 26/03/14 10:14 pagina 21 archivio italiano di urologia e andrologia 2014; 86, 1 f. catanzariti, u. cantoro, v. lacetera, g. muzzonigro, m. polito 22 by comparing the results of the two groups and calculating the odds ratio, we discovered a value of 0.99 (95% ci: 0.27 to 3.64, p: 0.98), so that the percentage distribution of dyspermia in the two groups resulted substantially comparable between the two groups and thus the testicular microlithiasis does not seem to determine the presence of dyspermia. conclusions our study showed that the testicular microlithiasis is an ultrasound fairly rare evidence, indeed, the prevalence in our series has remained around 4%, similar to that described in the literature. moreover, we have shown that the testicular microlithiasis not lead to changes in sperm quality, therefore results of spermiograms of patients with normal testes at ultrasound study were similar to those of the mt group. however, our study has several limitations: testicular ultrasound exams as well as semen analysis were performed by different operators so that results may have been affected by the interoperator variability. another important limitation is the low number of patients in the study group, justified by the fact that mt is an unusual disease so that it is difficult to perform a study with a high number of patients. further evaluation with a larger study population and greater standardization for both ultrasound of the testis and sperm evaluation would be necessary to demonstrate our thesis and to reach statistically significant conclusions about the correlation between mt and dyspermia, although our work is one of the few in the literature who analyzed this connection. references 1. yee ws, kim ys, kim sj, et al. testicular microlithiasis: prevalence and clinical significance in a population referred for scrotal ultrasonography. korean j urol. 2011; 52:172-7. 2. dutra ra, perez-bóscollo ac, melo ec, cruvinel jc clinical importance and prevalence of testicular microlithiasis in pediatric patients. acta cir bras. 2011; 26:387-90. 3. peterson ac, bauman jm, light de, et al. the prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. j urol 2001; 166:2061-2064. 4. van casteren nj, looijenga lh, dohle gr. testicular microlitiasis and carcinoma in situoverview and proposed clinical guideline. int j androl. 2009; 32:279-287. 5. tan ib, ang kk, ching bc, et al. testicular microlithiasis predicts concurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassified type in adults: a meta-analysis and systematic review. cancer. 2010; 116:4520-32. 6. tan mh, eng c. testicular microlithiasis: recent advances in understanding and management. medscape. nat rev urol. 2011; 8:153-63. 7. wang py, shen my. testicular microlithiasis: ultrasonic diagnosis and correlation with male infertility. zhonghua nan ke xue. 2009; 15:158-60. 8. deng ch, liu gh, lü jy, et al. testicular microlithiasis influences seminal profile and testicular blood flow in infertile men. zhonghua nan ke xue. 2008; 14:606-9. 9. yee ws, kim ys, kim sj, et al. testicular microlithiasis: prevalence and clinical significance in a population referred for scrotal ultrasonography. korean j urol. 2011; 52:172-7. 10. jiang h, zhu wj. testicular microlithiasis is not a risk factor for the production of antisperm antibody in infertile males. andrologia. 2013; 45:305-9. correspondence francesco catanzariti, md (corresponding author) fracatanzariti@libero.it resident in urology ubaldo cantoro, md ubaldocantoro@tiscali.it resident in urology vito lacetera, md vlacetera@gmail.com urologist giovanni muzzonigro, md g.muzzonigro@univpm.it professor of urology, chief department of urology massimo polito, md max_polito@virgilio.it urologist, chief department of uro-andrology polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, via conca 71 i-60020 ancona, italy catanzariti_stesura seveso 26/03/14 10:14 pagina 22 stesura seveso 23archivio italiano di urologia e andrologia 2014; 86, 1 original paper treatment of urethral strictures in balanitis xerotica obliterans (bxo) using circular buccal mucosal meatoplasy: experience of 15 cases abdulmuttalip simsek 1, sinasi yavuz onol 2, omer kurt 3 1 bakırkoy dr. sadi konuk training and research hospital, department of urology istanbul, turkey; 2 bezmi alem vakıf university, department of urology, istanbul, turkey; 3 bayrampasa state hospital, department of urology, istanbul, turkey. objectives: balanitis xerotica obliterans (bxo) related strictures involving the external urethral meatus. we reviewed our result with the use of circular mucosal graft in the reconstruction of strictures. methods: between march 1997 and january 2012, 15 patients underwent circular buccal mucosal urethroplasy for bxo related anterior urethral strictures. urethral catheter was removed within 2 weeks. follow-up included patient symptoms assessment, cosmetic outcome and uroflowmetry. results: median follow-up was 20.5 months (range 4 to 96). mean postoperative peak urinary flow rate obtained 1 month after catheter removal was 22.4 ml per second. all patients had a normal meatus and none had recurrent stricture, chordee or erectile dysfunction. a functional and cosmetic outcome was achieved in 100% of the patients. conclusions: circular mucosal graft technique for treatment of meatal strictures is an efficient method for the restoration of a functional and cosmetic penis. key words: buccal mucosa; bxo; urethral stricture; meatoplasty. submitted 16 september 2013; accepted 5 october 2013 summary introduction the term balanitis xerotica obliterans (bxo) was first described by stuhmer in 1928, for the chronic, progressive scleroatrophic inflammatory process of unknow etiology affecting the glans penis, prepuce and urethral meatus. the lesions occur as plaques or papules on the glans penis and result in urethral meatal stenosis (1). bxo has been managed both medically and surgically. medical treatment can provide useful palliation but is generally regarded to be limited. the surgical options are more definitive, and include circumcision, dilatation or surgically correction of meatal stenosis and some urethroplasty techniques (2, 3). a large veriety of free extragenital graft tissues have been used for urethroplasty no conflict of interest declared. such as bladder mucosa, buccal mucosa, vein and appendix (4). humby was the first to describe the use of buccal mucosa for the urethral substitution (5). the glandular urethra is unique in that it is most undistensible and the narrowest portion of the urethra. when strictured, this portion becomes extremely narrow. we describe our reconstructive technique for bxo using circular buccal mucosal graft urethroplasty. materials and methods between 1997 and 2012, 15 patients with a mean age of 39.3 years (range 36 to 49) with meatal stenosis underwent circular buccal mucosal substitution urethroplasty in our department. all patients were subjected to preoperative urine culture, uroflowmetry and retrograde urethrogram to document the severity and length of the stricture. stricture etiology was balanitis xerotica obliterans in all patients. all had previously undergone a number of dilatations, the average number of prior formal surgical prosedures was 1.4 (including meatotomy and urethral dilatation). most cases had symptoms of hesitancy, intermittent urine stream, decreased caliber of urine stream, incomplete bladder emptying, nocturia, pain with voiding or even urinary retention. inclusion criteria included bxo and strictures length < 2 cm. exclusion criteria were unhealthy oral cavity, urinary tract infection, strictures length > 2 cm and loss of follow-up. in this study mean duration of disease was 13.3 ± 4.9 months. uroflowmetry demonstrated urinary peak flows ranging from 2.5 ml/s and 14 ml/s (mean 4.18 ml/s). preoperatively, 15 patients underwent suprapubic cystostomy and 3 patients presented with urethrocutaneous fistulae. the catheter was removed 2 weeks after the meatoplasty. the patients were advised self meatal calibration with a 16 f foley catheter two times in a week for 1 month. at each visit of follow up, patient symptoms assessment, cosmetic outcome and uroflowmetry was done. at 6month follow up calibration of distal penile urethra with 16 f foley catheter was also done to evaluate urethral lumen. doi: 10.4081/aiua.2014.1.23 simsek_stesura seveso 26/03/14 10:16 pagina 23 archivio italiano di urologia e andrologia 2014; 86, 1 a. simsek, s. yavuz onol, o. kurt 24 operative technique all cases were performed by the same surgeon (syo). the patient was placed in a standard supine position on the operating table. all surgeries were performed under general anesthesia and a circular submeatal incision was made (figure 1). bad stricture tissue was mobilized until the proximal extent extending about 1 cm into the healthy segment. incision of the stricture was performed, the length of the strictured urethra was measured and the incision was extended at least 0.5 cm into the healthy urethral tissue. a buccal mucosa graft was harvested from one or both cheeks and lower lip using a standard technique. for meatal reconstruction the circular buccal mucosa graft was sutured to the dorsally cut margins of the meatus using a 4-5-zero monofilament suture (figure 2). the patients were discharged from the hospital on first or second postoperative day. results after catheter removal 3 patients did not come to control. therefore, these patients were excluded from this study. stricture length was less than 2.0 cm in all cases (range 0.5 to 1.6). mean operation duration was 45 minutes. patients were followed for a median of 20.5 months (range 4 to 96). durable functional and cosmetic outcome was obtained in all cases. we did not use any of cosmetic outcomes scale. however, not only patients opinion but also surgeons point of view is important for evaluation of cosmetic outcomes. we noticed no significant complications with this technique. mean postoperative peak urinary flow rate obtained 1 month after catheter removal was 22.4 ml per second (range 16 to 38). there were no recurrent strictures or obstructive voiding symptoms during follow up (table 1). discussion glandular strictures are difficult to treat and are sometimes associated with recurrence. the glans becomes inelastic and shows significant scarring, especially in patients of bxo. strictures involving the distal urethra and fossa navicularis are particularly challenging because successful reconstruction requires the creation of a functional urethral conduit as well as maintaining a cosmetically appealing glans penis. treatment of distal urethral strictures developed in the last decades from dilatation, internal urethrotomy to definitive reconstruction techniques such as penile fasciocutaneous flap urethroplasty and buccal mucosa graft urethroplasty (6, 7). urethral meatal stenosis can be treated by ventral meatotomy or dorsal v-meatoplasty. meatotomy in bxo is often followed by restenosis. surgical correction of the meatus, however does not improve the common loss of sensitivity in the glans penis. zungri et al., reported that a complete resection of the glans mucosa and meatoplasty produced complete resolution of the disease in their cases (8). penile skin flap urethroplasty has been used for 1-stage reconstruction of bxo strictures with encouraging short term results (9-11). however the long term outcomes of this technique have been uniformly disappointing (12, 13) venn and mundy reported an almost 100% recurrence rate for 1-stage urethroplasy with genital skin flap (12). in their series all patients with penile characteristics mean range age (y) 39.3 36-49 stricture length (cm) 1.4 0.5-1.6 graft length (cm) 1.8 0.8-2.4 operative time (min) 45 28-94 preoperative peak flow rate (ml/sn) 4.18 2.5-14 postoperative peak flow rate (ml/s) (at 1 mo) 22.4 16-38 follow up (mo) 24.6 4-96 (meadian, 20.5) figure 1. the strictured meatus was circular incised and bad stricture tissue was mobilized until healthy segment appeared. figure 2. the circular buccal mucosa graft was sutured to the dorsally margins of the meatus using a 4-5-zero monofilament on the benique dilator. table 1. patient characteristics (n = 15). simsek_stesura seveso 26/03/14 10:16 pagina 24 skin reconstruction had failure within 2 years with evidence of bxo. ramon et al. reported that using ventral transverse penile skin island flap an overall success rate of 83% with a mean long-term follow-up of 10.2 years (14). we have previously investigated the use of transverse island fasciocutaneous penile flap for reconstruction of strictures of the fossa navicularis and meatus with positive functional and cosmetic outcome in 96% after a mean follow up of 30.2 months (range 4 to 96) (15). deepak dubey et al. reported buccal mucosal urethroplasy for bxo related urethral strictures. they investigated 1-stage dorsal onlay and 2-stage buccal mucosal urethroplasty for strictures. patients with a severely scarred urethral plate,focally dense segments or active infection underwent 2-stage urethroplasty (16). our results demonstrate that circular buccal mucosal meatoplasty provides satisfactory results in selected cases of bxo related anterior urethral strictures. circular buccal mucosal graft can be successfully used for reconstructive distal urethral segment including the meatus. to our knowladge prior to this study there have been no reports in the literature describing circular buccal mucosal graft reconstruction urethral strictures for bxo. goel et al. presented their experience with 10 patients with glandular or meatal strictures treated with double buccal mucosal graft technique. they reported a functional and cosmetic outcome in 100% of patients presenting with anterior urethral stricture (range length 4-6.5 cm) after a mean follow-up of 13.5 months (17). palminteri et al. described the use of buccal mucosa graft both on the dorsal and ventral aspects in cases of severe bulbar urethral strictures with good results (18). the main long term donor site complications included intraoperative hemorrahage, postoperative infection, pain, swelling, damage to the parotid duct, limitations of oral opening and loss or altered sensation of the cheek and lower lip (19). therefore some reconstructive surgeons advocate a 2stage approach involving excision of the diseased urethra and buccal mucosal grafting, followed by stage 2 urethroplasty after 4 to 6 months (12, 13). patients with anterior urethral stricture need lip mucosa and cheek mucosa for urethroplasty and therefore have more morbidity in the form of scar contracture and lip deviation or retraction and long lasting paresthesia and numbness of the lower lip. however in our practice, only 1 patient had a lip retraction and there was no another complication. to our knowledge, this is the largest series of buccal mucosal graft urethroplasties used for repairing anterior urethral strictures. the overall success rate in our series was 100%, which included the repair of meatus in the process of bxo. the results of our study have shown that the circular mucosal graft can be suitable as the transverse ısland fasciocutaneous penile flap for the reconstruction of anterior urethral strictures. circular buccal mucosal graft urethroplasy is easy harvesting and with minimal donor site complications. references 1. stuhmer, a. balanitis xerotica obliterans (post operationem) und ihre beziehungen zur “kraurosis glandis et praeputii penis£. archiv fur dermatologie und syphilis. 1928; 156:613-623. 2. wright je. the treatment of childhood phimosis with topical steroid. australian nz j surg. 1994; 64:327-8. 3. fischer go. lichen sclerosus in childhood. australasian j dermatol. 1995; 36:166-7. 4. dessanti a, rigamonti w, merulla v, et al. autologous buccal mucosa graft for hypospadias repair: an initial report. j urol. 1992; 147:1081-1084. 5. humby g. a one-stage operation for hypospadias. br j surg. 1941; 29:84-92. 6. jordan gh. reconstruction of the fossa navicularis. j urol. 1987; 138:102-4. 7. armenakas na, morey af, mcaninch jw. reconstruction of resistant strictures of the fossa navicularis and meatus. j urol. 1998; 160:359-63. 8. zungri e, chéchile g, algaba f, mallo n. balanitis xerotica obliterans: surgical treatment. eur urol. 1988; 14:160-162. 9. armenakas na, morey af, mcaninch jw. reconstruction of resistant strictures of the fossa navicularis and meatus. j urol. 1998; 160:359. 10. wessels h, morey af, mcaninch jw. single-stage reconstruction of complex anterior urethral strictures: combined tissue transfer techniques. j urol. 1997; 157:1271. 11. morey af, tran lk, zinman lm. q-flapreconstruction of panurethral strictures. bju int. 2000; 86:1039. 12. venn sn, mundy ar. urethroplasty for balanitis xerotica obliterans. bju int. 1998; 81:735. 13. depasquale i, park aj, bracka a. the treatment of balanitis xerotica obliterans. bju int. 2000; 86:459. 14. virasoro r, eltahawy ea, jordan gh. long-term follow-up for reconstruction of strictures of the fossa navicularis with a single technique. bju int. 2007; 100:1143-5. 15. onol sy, onol ff, onur s, et al. reconstruction of strictures of the fossa navicularis and meatus with transverse island fasciocutaneous penile flap. j urol. 2008; 179:143. 16. dubey d, sehgal a, srivastava a, et al. buccal mucosal urethroplasty for balanitis xerotica obliterans related urethral strictures: the outcome of 1 and 2-stage techniques. j urol. 2005; 173:463-6. 17. goel a, dalela d, sankhwar sn. meatoplasty using double buccal mucosal graft technique. int urol nephrol. 2009; 41:885-7. 18. palminteri e, manzoni g, berdondini e, et. al. combined dorsal plus ventral double buccal mucosa graft in bulbar urethral reconstruction. eur urol. 2008; 53:81-90. 19. bhargava s, chapple cr. buccal mucosal urethroplasty: is it the new gold standard? br j urol. 2004; 93:1191-1193. 25archivio italiano di urologia e andrologia 2014; 86, 1 bxo meatoplasy correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com department of urology bakırkoy dr. sadi konuk training and research hospital tevfik saglam cad. no: 11 34000 zuhuratbaba, istanbul, turkey sinasi yavuz onol, md department of urology bezmi alem vakıf university, istanbul, turkey omer kurt, md department of urology bayrampasa state hospital, istanbul, turkey simsek_stesura seveso 26/03/14 10:16 pagina 25 155archivio italiano di urologia e andrologia 2018; 90, 3 original paper the new avicenna roboflex: how does the irrigation system work? results from an in vitro experiment salvatore butticè 1, 2, 6, bahadir sahin 3, tarik emre sener 3, 6, laurian dragos 4, 6, silvia proietti 5, 6, steeve doizi 1, 6, olivier traxer 1, 6 1 pierre & marie curie university, tenon university hospital, paris, france; 2 department of urology, san giovanni di dio hospital, agrigento, italy; 3 department of urology, school of medicine, marmara university, istanbul, turkey; 4 department of urology, emergency county hospital, pius branzeu, timisoara, romania; 5 ville turro division, department of urology, irccs, ospedale san raffaele, milan, italy; 6 members of petra urogroup, progress in endourology, technology and research association. introduction: since 2012 elmed has been working on a robot specifically designed for flexible ureteroscopy. after the first version of avicenna roboflex, a second version was developed in 2015, with significant changes especially in the irrigation system. we consider mandatory for the endourologist that works with the avicenna roboflex be aware of the functioning of the irrigation system. materials and methods: we connected a container to the pump’s irrigation system and measured the quantity of saline per second delivered by each speed setting, with/without the flush in five different modalities: pump on its own, pump with ureteroscope, with two laser fibers, with 1.9 fr basket, and with a terumo guidewire. results: the highest mean flow-rates were observed in the 200micrometer laser fiber, after the pump on its own. median flowrates for all speed settings were significantly higher for the pump on its own than for the urs in both flushed and nonflushed modes (p = 0.045, p = 0.039 respectively). there was no statistically significant difference in median flow-rates between the guide wire and basket in all of the speed settings (p = 0.932 and p = 0.977). for both laser fibers there was no statistically significant difference between the median flow rate on both nonflush and flush modes. (p = 0.590 & p = 0.590). there was a linear correlation between the speed setting and the increase measured with the flush-option for pump only measurements (r = 0.602, p = 0.038). there was no statistically significant difference between laser fibers and the pump on its own on the increase of flow rate with flush mode. (p = 0.443 for the 272micrometer fiber and p = 0.219 for the 200-micrometer fiber). conclusion: the irrigation system of the new avicenna roboflex is optimized compared to the previous version. however other more complex studies concerning the live flow/pressure relationship are needed before firm conclusions can be made. key words: renal stone; ureteroscopy; avicenna roboflex; irrigation system; flexible ureteroscopy; intrarenal flow; urolithiasis. submitted 24 march 2018; accepted 29 april 2018 summary no conflict of interest declared. the rapidly growing popularity of flexible ureteroscopy (furs) has also been sustained by the major companies on the market, which have increased efforts to develop flexible ureteroscopes. indeed no other endourological device has received more attention or undergone more dynamic changes than these delicate endoscopes (2). thus, adaptation of furs to robotic surgery has been inevitable with all the advancements in technology. in fact, elmed (ankara, turkey) has been working on a robot specifically designed for furs since 2012 (3). after the first version of avicenna roboflex in 2012, a second version was developed in 2015, with changes to the console, improved ergonomics and with significant changes in the irrigation system. today the mechanics and electronics of roboflex has been experienced and published but the precise flow produced by the pump in each of the different speed settings remains somewhat unexplored (4). in fact, the first version provided 25 different speed options for the irrigation system, whereas the second one provides 12 speeds, with a dramatic change in the dynamics of intra-renal flow (5). for this reasons we consider it mandatory that the endourologists who work with the new avicenna roboflex be aware of the pump flow rate for each speed setting. the irrigation system as mentioned above, the irrigation system is controlled by a 12-speed mechanical pump and can be attached to a regular rod for gravitational irrigation. the entire device is powered electronically and has two small rotors in the front part to which an infusion tube is connected; which is compatible with others on the market or with the included piece (figure 1) the system is connected to a console with four buttons: one to start and stop, one to increase and another to decrease the flow, and the flush (figure 2) the “flush” allows a rapid increase in flow for about one second, and is different from other mechanical systems that permit a saline adjustment; the flush can be operated approximately every 2 seconds after it has been activated; a refractory time that varies from 1.5 to 2 seconds by switching from low to high speed. doi: 10.4081/aiua.2018.3.155 introduction urolithiasis is one of the major issues in healthcare, with an incidence of around 10%, while the use of flexible ureteroscopes has increased exponentially as one of the best treatment options for renal stones (1). butticè_stesura seveso 03/10/18 09:36 pagina 155 archivio italiano di urologia e andrologia 2018; 90, 3 s. butticè, b. sahin, t. emre sener, l. dragos, s. proietti, s. doizi, o. traxer 156 materials and methods this is an in vitro study in accordance with the helsinki declaration, conforms to the committee on publication ethics (cope) guidelines, and was approved by the institutional review board (irb) of the university hospitals in which the study was carried out. the design, analysis, interpretation of data, drafting, and revisions of the study followed the strengthening the reporting of observational studies in epidemiology (strobe) statement as well as the guidelines for reporting observational studies, available through the enhancing the quality and transparency of health research (equator) network (6). for the study, we connected a container to the pump’s irrigation system and measured the quantity of saline solution per second delivered by each speed setting, both with and without the flush (for 30 seconds for every measurement) in five different modalities: the pump on its own, the pump with ureteroscope (olympus urf-p5), with two laser fibers (200 and 270 μm by rocamed), with a 1.9 fr basket (dakota by boston scientific), and with a 0.018 inch terumo guidewire attached. the pump was fixed to a rod that is used for regular urological irrigation, at a height of 1.60 meters. as infusion tube, we used a t-flow by rocamed which permits the addition of a manual stream via an integrated pump but the pump was not used in this case. every measurement was performed 5 times and the mean values were taken for each modality and speed setting (figure 3). statistical analysis statistical analyses were performed using the original spss software, version 22.0 (ibm corp, ny, usa), with significance set at p < 0.05. baseline variables were described using means and standard deviations, or medians and minimum, maximum values as appropriate. mann-whitney u tests were used to evaluate the difference between quantitative measurements that have non-parametric distribution. linear correlation between numeric variables that have a non-parametric distribution were evaluated with spearman rank coefficient. sensitivities, specificities, and predictive values with 95% confidence intervals were calculated. results the measured mean flow-rate values for different modalities (sets of instruments) with and without flush-mode are given in table 1. the measured values indicate that the highest mean flow-rates were observed in the 200micrometer laser fiber, after the pump on its own. the flow-rates for the 200-micrometer laser fiber were lower in the first four speed-settings than the flow-rates of the ureteroscope (urs). however, after the fourth speedsetting, faster flow rates were measured with the 200micrometer laser fiber. the same pattern applied to the 272-micrometer laser fiber except that faster flow-rates table 1. mean flow rates. without flush with flush free pump 52 54.9 urs 33.9 34.8 guidewire 7.8 8.1 basket 7.1 7.7 272 mm laser fiber 38 39.7 200 mm laser fiber 41.2 42.8 figure 1. the pump of the irrigation system of the new avicenna roboflex. figure 2. the console of avicenna roboflex, it is possible to note on the bottom right, the part that controls the entire irrigation system electronically. figure 3. setting of the experiment at tenon hospital. butticè_stesura seveso 03/10/18 09:36 pagina 156 were achieved after the fifth setting instead of the fourth. median flow-rates for all speed settings were significantly higher for the pump on its own than for the urs in both flushed and non-flushed modes (p = 0.045, p = 0.039 respectively). there was a 33.97% drop in flowrate for the non-flush mode of the urs compared to the non-flush mode of the pump on its own. there was no statistically significant difference in median flow-rates between the guide wire and basket in all of the speed settings, although the median flow-rate with the guide wire was slightly higher in both non-flush and flush modes (p = 0.932 and p = 0.977). the mean decrease during non-flush mode with the guide wire was 87.2% and 81% compared to the pump on its own and the urs respectively. for the basket these drop rates were 88% and 82.1%. instead, the median rates of increase during flush mode were 0.20 (0.101.20) and 0.30 (0.10-4.00) ml/min for the guide wire and the basket respectively. there was no statistically significant difference between the mean increase in flowrates for flush mode between the basket and the guide wire options (p = 0.378). for both laser fibers there was no statistically significant difference between mean flowrates in all of the speed settings, although the mean flow rate for the 200-micrometer fiber was markedly higher (p = 0.590 & p = 0.590). the mean decreases in nonflush mode were 32.9% and 27.2% compared to the pump on its own for the 272-micrometer and the 200micrometer laser fibers respectively. the decrease in rate compared to the pump on its own was inversely related to the speed setting for both laser fiber groups (table 2). there was a linear correlation between the speed setting and the increase measured with the flush-option for pump only measurements (r = 0.602, p = 0.038). the same correlation was also observed for the 272micrometer laser fiber (p = 0.664, p = 0.024) but not for the other disposables (figure 4). with the use of the guide wire, basket, or urs, the median rates of increase for the flush mode were respectively 0.20 (0.10-1.20), 0.30 (0.10-4.00), 0.90 (0.4-1.30) ml/min. these values were significantly lower than the pump on its own which was 1.70 ml/min (0.80-11.90) (p < 0.001 for all three). for both laser fibers, rates of increase for flush mode were respectively 1.50 (0.403.80) and 1.35 (0.60-3.70) ml/min. there was no statistically significant difference between laser fibers and the pump on its own (p = 0.443 for the 272-micrometer fiber and p = 0.219 for the 200-micrometer fiber). discussion the irrigation system is a fundamental component used during furs because it improves visualization, maintains patency of the urinary tract. besides, pressurized irrigation is necessary to maintain sufficient distension of the lumen when accessory instruments (baskets, laser fibers, etc.) are passed through a small working channel (2). in a recent study it had been shown that with the use of 273-micrometer laser fiber flow volume decreases 53.7%. although different sets of laser fibers are used in our study it has been showed that this new irrigation system causes minimal or no loss on flow rate with laser fibers depending on the speed setting preferred by the surgeon (7). the mechanical irrigation systems that are currently on the market provide a continuous flow that can be integrated manually. this is the first pump on the market that allows for robotic adjustment of the flow whilst increasing it according to the needs of the endourologist. when comparing the new irrigation system to the older one, it can immediately be seen that the new pump has a more constant flow when switching to a higher speed. though the “old pump” had more than 25 speed settings, it had a difference in flow rate of 8-10 ml/min at intermediate speed settings, which could potentially develop dangerously high intrarenal pressures. for these reasons, in our previous work we advised caution using the pump 157archivio italiano di urologia e andrologia 2018; 90, 3 avicenna roboflex: how is the irrigation? table 2. correlation between increase with flush mode and increase in speed setting. r p free pump 0.602 0.038 urs 0.339 0.282 guidewire 0.562 0.057 basket 0.504 0.095 272 mm laser fiber 0.644 0.024 200 mm laser fiber 0.329 0.208 r: spearman correlation coefficient. figure 4. decrease of flow rate for 272 mm laser fiber and 200 mm laser fiber compared to free pump (r = 0.979, p = < 0.001 & r = 0.951, p = < 0.001). butticè_stesura seveso 03/10/18 09:36 pagina 157 archivio italiano di urologia e andrologia 2018; 90, 3 s. butticè, b. sahin, t. emre sener, l. dragos, s. proietti, s. doizi, o. traxer 158 at intermediate speed settings (5). although this study does not assess intrarenal pressures, a profile of a safe range of kidney pressure should be developed. the only measurement of pressure using the avicenna roboflex was that done by rassweiler j et al. at wce 2015 who used an intra-pelvic sensor and reached a maximum pressure of 40 cm h2o (8). however, this pump has an important limitation; during typical furs the endourologist or assistant who injects saline by manual pump has a pressure feedback, and is able to sense when intrarenal pressure rises. this depends on subjective feeling and is not scientifically comparable to real intrarenal pressure, but since most centers still do not have a measurement system of renal pressure, the “tactile” sense remains the only means available to the urologist. however, even with feedback on hand, when the operator needs an additional stream and does not have an automated system, they cannot know the quantity of fluid or how fast they are injecting it, into the renal cavity. this situation may result in dangerously unrecognized high intrarenal pressures. this concept is well explained in recent work by jung et al., who analyzed the intrarenal pressures of 20 patients undergoing furs, using an 8 ml/min irrigation system and a 20 ml syringe as an additional irrigation system, they showed how intrarenal pressures, on average, reached 35 (± 10) mmhg and how spikes higher than 288 mmhg were not unusual using the syringe (9). our study also demonstrates how pump flow logically decreases with the use of higher caliber instruments that occupy the working channel of the ureteroscope. the results are in concordance with our previous study evaluating the intrarenal pressure changes on a bench model with different instruments inside the ureteroscope (10). however, the fact that there are no significant differences in flow between the pump on its own and the two fibers helps us understand how the system remains efficient particularly in the fragmentation phase and how, as a result, the flush should be reduced for clearer vision. as there are no significant differences between the two fibers, the choice could switch to greater fiber size and greater power to break up the tougher stones. another advantage of using an automated irrigation system is connected to radiological exposure. in fact, during a standard furs the operating urologist and the assistant that manages the manual watering system are both exposed to ionizing radiation. with an automated irrigation system instead, the operator is further away from the collimator seated in the console, and during the fragmentation phase when additional flow is often required, the assistant is not necessary since the additional flow is managed directly by the operator through the console. conclusions the irrigation system of the new avicenna roboflex is optimized compared to the previous version, the flows developed with the ureteroscope and its various accessories appear to ensure adequate irrigation and a relatively acceptable pressure volume. however other more complex studies concerning the live flow/pressure relationship are needed before firm conclusions can be made. disclosure butticè s, sahin b, sener te, proietti s, dragos l, doizi s: nothing to disclose. traxer o: consultant for coloplast, rocamed, olympus, lumenis, boston scientific, biohealth, ems. references 1. rukin nj, siddiqui za, chedgy ec, somani bk. trends in upper tract stone disease in england: evidence from the hospital episodes statistics database. urol int. 2017; 98:391-396. 2. somani bk, al-qahtani sm, de medina sdg, traxer o. outcomes of flexible ureterorenoscopy and laser fragmentation for renal stones: comparison between digital and conventional ureteroscope. urology. 2013; 82:1017-9. 3. saglam r, muslumanoglu ay, tokatli z, et al. a new robot for flexible ureteroscopy: development and early clinical results (ideal stage 1-2b). eur urol. 2014; 66:1092-100. 4. rassweiler j, rassweiler mc, klein j. new technology in ureteroscopy and percutaneous nephrolithotomy. cur opin urol. 2016; 26:95-106. 5. buttice s, proietti s, dragos l, traxer o. are you familiar with the flow of the roboflex avicenna pump? allow me to explain. j endourol. 2017; 31:418-419. 6. von elm e, altman dg, egger m, et al. the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. int j surg. 2014; 12:1495-9. 7. bach t, geavlete b, herrmann t, gross a. working tools in flexible ureterorenoscopy—influence on flow and deflection: what does matter? j endourol. 2008; 22:1639-44. 8. seo h, shin s, jung n, et al. scientific program of 34th world congress of endourology & swl program book and abstracts.j endourol. 2016; 30(s2):p1-a464. 9. jung h, osther pj. intraluminal pressure profiles during flexible ureterorenoscopy. springerplus. 2015; 4:373 10. sener te, cloutier j, villa l, et al. can we provide low intrarenal pressures with good irrigation flow by decreasing the size of ureteral access sheaths? j endourol. 2016; 30:49-55. correspondence salvatore butticè, md salvobu@gmail.com department of urology, san giovanni di dio hospital contrada consolida, 92100, agrigento, italy bahadir sahin, md drbahadirsahin@gmail.com tarik emre sener, md dr.emresener@gmail.com department of urology, school of medicine, marmara university, istanbul, turkey laurian dragos, md lauriandragos@yahoo.com department of urology, emergency county hospital, pius branzeu, timisoara, romania silvia proietti, md proiettisil@gmail.com ville turro division, department of urology, irccs, ospedale san raffaele, milan, italy steeve doizi, md steeve.doizi@gmail.com olivier traxer, md olivier.traxer@tnn.aphp.fr pierre & marie curie university, tenon university hospital, paris, france petra urogroup progress in endourology, technology and research association, http://www.petraurogroup.org/ butticè_stesura seveso 03/10/18 09:36 pagina 158 stesura seveso 295archivio italiano di urologia e andrologia 2015; 87, 4 original paper the effectiveness of local steroid injection after internal urethrotomy to avoid recurrence mehmet erol yıldırım 1, mehmet kaynar 2, ekrem ozyuvali 1, huseyin badem 3, muzaffer cakmak 4, bahadir kosem 5, ersin cimentepe1 1 department of urology, turgut özal university school of medicine, ankara, turkey; 2 department of urology, selçuk university school of medicine, konya, turkey; 3 department of urology, yüksek i̇htisas education and research hospital, ankara, turkey; 4 department of internal medicine, turgut özal university school of medicine, ankara, turkey; 5 department of anesthesiology, turgut özal university school of medicine, ankara, turkey. objective: local steroid injection to the stricture region after internal urethrotomy (iu) is a promising technique to avoid the recurrence, although the effectiveness and safety of this technique is still controversial. we aimed to determine the efficacy and safety of local steroids as applied with the iu procedure. material-method: a total of 83 patients data with urethral stricture in men were examined retrospectively. patients classified in two groups who had steroid injection with internal urethrotomy or not. metil prednisolone 40 mg was injected with transurethral injection needle in the stricture region at the 5, 7 and 12 o’clock sites at the same session with internal urethrotomy. procedure was considered successful if patient did not report any voiding difficulty and maximum flow rate > 15 ml/second for a voided volume of at least 150 ml after removal of the catheter. patient’s age, time to recurrence, previous recurrences were evaluated. results: the mean age was 56.4 (18-83) years. of those patients 33/83 had recurrent stenosis. nineteen out of these 33 recurrent stenosis patients were treated with local steroid injection and 14/33 had no injection. only two patients of the steroid treated group had recurrence. despite that 12 patients had recurrence in the steroid non-treated group. also the primary stenosis patients showed no recurrence at the steroid+ iu group. conclusions: the use of local steroids with iu seems to decrease the high stricture recurrence rate following iu. when local steroids were administered with complementary intention, the disease control outcomes are encouraging. further robust comparative effectiveness studies are now required. key words: urethral stricture; internal urethrotomy; steroid; recurrence. submitted 27 may 2015; accepted 11 september 2015 summary no conflict of interest declared. tions and external trauma take the lead. the actual incidence of urethral strictures developed after the transurethral resection of prostate is 2-10%, as well as radical (8.4%) and simple (1.9%) prostatectomies (2-4). there are many treatment modalities as dilatation, endoscopic urethrotomy, stent placement and urethroplasty. internal urethrotomy (iu) and dilatation are widely used for urethral strictures less than 2 cm with a success rate of 70% but also have a high rate of stricture recurrence (5-7). although open urethroplasty is a highly successful and durable treatment method, surgeons don’t perform it so often due to its invasiveness, longer catheterization requirement and need of experienced surgery skills (8). the recurrence of stricture occurs as a result of scar that forms into the urethral epithelium and decreases the caliber of urethra (9). there are many investigations about use of drugs such as steroids, mitomycin c, hyaluronidsase to avoid this scar or keloid formation (10-12). we aimed to investigate the combination of steroid injection with iu in order to avoid the recurrence of strictures and cure the patient with minimally invasive treatment. materials and methods we present the data of patients from april 2009 to march 2014 in this retrospective study. the protocol was approved by the scientific and ethical committee of the university (2014/3255). informed and signed consent was taken from all patients after explaining the nature of the study and the consequences of the procedure to be done in detail in their own language. two surgeons performed internal urethrotomy with the same technique. patients were divided into two groups by surgeons’ preference to use steroid injection or not. forty-one patients have been treated with iu adding steroid injection and 42 patients have been treated with only iu without steroid injections. patients had option to opt out of the study at any time without compromising their right of treatment. a total of 83 male patients with diagnosed urethral strictures requiring optical internal urethrotomy were included in this study. patients presenting for the first time for treatment doi: 10.4081/aiua.2015.4.295 introduction urethral stricture is a well-known disease that has been known for centuries as far as ancient greeks, egyptians and hindus (1). difficulty on managing urethral strictures is its tendency to recur. first leading cause of urethral strictures was infection but, even with development of mankind and technologies, iatrogenic instrumentaarchivio italiano di urologia e andrologia 2015; 87, 4 m. erol yıldırım, m. kaynar, e. ozyuvali, h. badem, m. cakmak, b. kosem, e. cimentepe 296 were referred to as primary, whereas those who had undergone some procedure for the treatment of stricture prior to reporting to us were referred as recurrent. in group a (iu only group); the patients underwent internal urethrotomy with cold knife. in group b (iu+ steroid group) metil prednisolone was injected to the stricture site after the internal urethrotomy with cold knife. steroid was injected intralesional at the 5, 7 and 12 o’clock sites of urethrotomy using 22 g william’s bladder injection needle (cook medical, bloomington, usa). forty mg metil prednisolone were injected for strictures less than 1 cm whereas the dosage increased to 40 mg for each cm of stricture. the patients who had recurrence after steroid injection underwent a second iu+ steroid injection session. all of the recurrences were due to the transurethral resection of prostate. inclusion criteria were; presence of obstructive symptoms, peak flow rate on uroflowmetry less than 15 ml/s and short segment strictures (stricture length < 2 cm) as evident on radiological studies, i.e. retrograde urethrography (rgu) and micturating cystourethrography (mcu). exclusion criteria used were complete obliteration of urethral lumen on urethroscopy, balanitis xerotica obliterans, age less than 18 years, multiple strictures, active urinary tract infection. all patients were assessed by a history and a full physical examination, complete blood count, urine analysis, urine culture and sensitivity test, renal function tests, uroflowmetry and retrograde urethrography with micturating cystourethrography if needed. urethroscopy was done with 20 f sheath and 0° telescope. the site and length of the stricture along with the ability of telescope to pass through the stricture was noted on urethroscopy. the procedure was performed under spinal anesthesia at lithotomy position. antibiotic (ciprofloxacin, 500 mg) was given just before and 12 h after procedure and continued for next 7 days twice a day. normal saline was used for irrigation during the procedure. post-operative catheterization has been made by a 20 f urinary catheter. post-operative catheterization time was 7 days. any symptoms pertaining to recurrence were noted as reduced stream of urine (< 10 ml/second), retention of urine (> 50 ml), and burning micturition. procedure was considered successful if patient did not report any voiding difficulty with maximum flow rate > 15 ml/second for a voided volume of at least 150 ml. patients were followed up for at least 18 months. data were analyzed using spss software (the statistical package for the social sciences, version 14.0, spss inc., chicago, illinois, usa). normally distributed variables were described using means with standard deviations. chi-square and student t test were used to compare two groups. non-normal distributed data were analyzed using mann-whitney u test. a p value less than 0.05 was considered statistically significant. results the mean age at the presentation was 56.4 (18-83) years. seventeen patients in the steroid group out of 41 needed 80 mg metil prednisolone due to the length of the stricture. only 2 patients had recurrence in the 80 mg metil prednisolone treated group, whom also had a history of recurrence. so the success rate of the steroid injection was 95%. and the recurrence rate of iu only treated group was 28 % (table 1). thirty-three out of 83 patients had a history of recurrent stenosis. nineteen of these 33 patients were treated with local steroid injection and 14/ 33 had no injection. two patients in the steroid treated group had recurrence at third and eighth month. on the contrary 12 patients had recurrence in the steroid non-treated group. recurrence occurred at the first month in 9 patients and in the remaining patients at the second month of follow-up. thus, for patients with history of recurrence, success rate was 89% for the first injection and 100% for the second injection. in recurrence groups success rates of steroid injection was significantly higher than the iu only treated patients (89% versus 14.2% respectively, p = 0.021). time to recurrence was significantly lower in the iu than the steroid group (1.2 ± 0.4 months, 6 ± 2.5 months, respectively, p = 0.03). discussion the main problem of urologists in relation to urethral stricture is not the disease itself but its nature of recurrence. open urethroplasty has better results especially if performed at the early stage, but it requires a certain expertise and a long period of catheterization (13). optical internal urethrotomy is another standard treatment of urethral strictures with varying success rates although not as good as open urethroplasty (14). in a survey conducted by the american urology association, 86% of the urologists performed iu for urethral strictures probably because of unfamiliarity and lack of expertise in open urethroplasty (15). in a study with 224 patients,the recurrence rate was reported as 68% after the first iu, 96% after the second iu and 100% after the third procedure (16). recurrent ius also decrease the success rates of the urethroplasty (17). so that investigators are searching for minimally invasive and curative treatment modalities for a long time. the main pathogenesis of stricture is the fibrosis formation caused by excessive collagen synthesis and changes in the extracellular matrix of the urethral lumen due to the endoscopic instrumentations, trauma and infections (18). spongiofibrosis occurs in varying degrees and narrows the urethral luminal caliber. so that there are some only iu iu+steroid injection p group (n: 42) group (n: 41) age (years) 61.5 ± 16.2 51.2 ± 18.5 0.397* follow up (month) 30.1 ± 17.3 32 ± 19 0.634* hemoglobine (g/dl) 14.1 ± 1.95 14.2 ± 1.5 0.838* neutrophile 7500 ± 2701 7617 ± 2567 0.840* history of recurrence 14/42 19/41 0.681** number of recurrences 0.681** * student t test performed. ** chi square test performed. p < 0.05 considered the statistically significance. table 1. patients demoghraphic and laboratory data. ideas of treating the fibrosis with antifibrotic agents such as halofugione, mitomycin c, bitoxin a, somatostatin analogues, captopril and steroids (11, 19-23). there have been a few prospective randomized clinical trials in recent literature on comparative study of steroid injection after iu over conventional cold knife for internal urethrotomy. in a study, recurrence rate after iu was reported as varying 50% to 75% in a 2 years follow up period (24). we reported a 28% rate of recurrence in the iu only treated group. our success rates may be due to our iu technique. common practice among urologists is one cut at 12 o’ clock to incise the stricture (86.3%) (8). but a deep cut at this site may cause erectile dysfunction, extravasation and incontinence (25, 26). so we prefer to cut the 5, 7 and 12 o’ clock sites to avoid above complications and to decrease the tension of the stricture. korhonnen et al injected 80 mg triamcinolone to 17 of 21 patients after iu only to the 12 o’clock position and removed the catheter the day after the surgery. although the iu only group had a 71% recurrence rates, steroid injected group had 61% recurrence rates (27). in another study, tabassi et al. performed internal urethrotomy and triamcinolone injection in 34/70 patients with stricture. they noted a recurrence rate of 35.2% in the steroid injected and 41.6% in iu only group. although there were no statistically significant difference between the two groups (p: 0.584), time to recurrence significantly decreased in the triamcinolone treated group (p < 0.05) (28). in our study we observed that steroid injection prolonged the recurrence time significantly from 1, 2 to 6 months (p < 0.03). in addition to that, we removed the catheter at the seventh day after the surgery. kumar et al. also reported a 95.8% success rate in patient treated with holmium laser and 80 mg of triamcinolone (29). we have found a recurrence rate of 5% in the steroid group rather than 28% in iu only treated group. also in the patients with recurrent stenosis, the success rates were better than the iu only treated group (89% versus 14.2% respectively, p = 0.021). several adjuvant therapies including injection of docetaxel, captopril, mitomycin c, hyaluronidase have been also proposed to avoid the recurrence after the iu (10, 11, 18, 23). chung et al. studied the effectiveness of hyaluronidase injection to the stricture site and found a recurrence rate of 9.4% and 22.9% respectively in the injection and in the control group (12). a recurrence rate of 2% versus 50% was reported in patients treated with mitomycin c injection or not, in a small study consisting of 40 patients (11). in a rabbit model, it has been shown that docetaxel significantly inhibited the urethral stricture formation (18). no complications were noted due to the steroid injections. despite the benefits of these materials, steroids comes a step forward so as to its cost effectiveness, lower side effects and also widespread usage in general medicine. conclusion the clinical decision of stricture-recurrence-prevention techniques should be carefully tailored to every individual patient. steroid injection to the stricture site to avoid fibrosis is a safe and effective adjuvant therapy for short segment strictures after internal urethrotomy. metil prednisolone injection during internal urethrotomy may decrease the recurrence rate significantly. as the course of urethral stricture recurrence is rather long spreading over many years, further comparative studies with longer follow-ups are required to accurately evaluate the effect of steroid injection. references 1. webster gd, koefoot rb, sihelnik sa. urethroplasty management in 100 cases of urethral sticture: a rationale for procedure selection. j urol. 1985; 134:892-898. 2. rassweiler j, teber d, kuntz r, hofmann r. complications of transurethral resection of the prostate (turp) incidence, management, and prevention. eur urol. 2006; 50:969-80. 3. elliott sp, meng mv, elkin ep, et al. incidence of urethral stricture after primary treatment for prostate cancer:data from capsure. j urol. 2007; 178:529-34. 4. varkarakis i, kyriakakis z, delis a, et al. long-term results of open transvesical prostatectomy from a contemporary series of patients. urology. 2004; 64:306-10. 5. naude am, heyns cf. what is the place of internal urethrotomy in the treatment of urethral stricture disease? nat clin pract urol. 2005; 2:538-45. 6. albers p, fitchner j, bruhl p, muller sc. long term results of internal urethrotomy j urol. 1996; 156:1611-1614. 7. chilton cp, shah pj, fowler cg, et al. the impact of optical urethrotomy on the management of urethral stricutres. br j urol. 1983; 55:705-710. 8. ferguson gg, bullock tl, anderson re, et al. minimally invasive methods for bulbar urethral strictures: a survey of members of the american urological association. urology. 2011; 78:701-6. 9. latini jm. minimally invasive treatment of urethral strictures in men. current bladder dysfunction reports. 2008; 3:111-6. 10. kumar s, garg n, singh sk, mandal ak. efficacy of optical internal urethrotomy and intralesional injection of vatsala-santosh pgi tri-inject (triamcinolone, mitomycin c, and hyaluronidase) in the treatment of anterior urethral stricture. adv urol. 2014; 2014:192710. 11. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007; 51:1089-92. 12. chung jh, kang dh, choi hy, et al. the effects of hyaluronic acid and carboxymethylcellulose in preventing recurrence of urethral stricture after endoscopic internal urethrotomy: a multicenter, randomized controlled, single-blinded study. j endourol. 2013; 27:756-62. 13. langston j, robson c, rice k, et al. synchronous urethral stricture reconstruction via 1-stage ascending approach: rationale and results. j urol. 2009; 181: 2161-2165. 14. jain sk, kaza rc, singh bk. evaluation of holmium laser versus cold knife in optical internal urethrotomy for the management of short segment urethral stricture. urol ann. 2014; 6:328-33. 15. hradec e, jarolim l, petrik r. optical internal urethrotomy for strictures of the male urethra: effect of local steroid injection. eur urol. 1981; 7:165-168. 16. pansodoro v, emiliozzi p. internal urethrotomy in the management of anterior urethral strictures: long term follow-up. j urol. 1996; 156:73-75. 297archivio italiano di urologia e andrologia 2015; 87, 4 local steroid injection after internal urethrotomy archivio italiano di urologia e andrologia 2015; 87, 4 m. erol yıldırım, m. kaynar, e. ozyuvali, h. badem, m. cakmak, b. kosem, e. cimentepe 298 17. roehrborn cg, mcconnell jd. analysis of factors contributing to success or failure of 1-stage urethroplasty for urethral stricture disease. j urol. 1994; 151:869-874. 18. fu d, chong t, li h, et al. docetaxel inhibits urethral stricture formation, an initial study in rabbit model. plos one. 2014; 9:e112097. 19. nagler a, gofrit o, ohana m, et al. the effect of halofuginone, an inhibitor of collagen type i synthesis, on urethral stricture formation: in vivo and in vitro study in a rat model. j urol. 2000; 164:1776-1780. 20. khera m, boone tb, smith cp. botulinum toxin type a: a novel approach to the treatment of recurrent urethral strictures. j urol. 2004; 172:574-575. 21. andersen h, duch b, gregersen h, et al. the effect of the somatostatin analogue lanreotide on the prevention of urethral strictures in a rabbit model. urol res. 2003; 31:25-31. 22. sciarra a, salciccia s, albanesi l. use of cyclooxygenase-2 inhibitor for prevention of urethral strictures secondary to transurethral resection of the prostate. urol res. 2005; 66:1218-1222. 23. shirazi m, khezri a, samani sm, et al. effect of intraurethral captopril gel on the recurrence of urethral stricture after direct vision internal urethrotomy: phase ii clinical trial. int j urol. 2007; 14:203-8. 24. holm-nielsen a, schultz a, moller-pedersen v. direct vision internal urethrotomy: a critical review of 365 operations. br j urol. 1984; 365:308-12. 25. santucci r, eisenberg l. urethrotomy has a much lower success rate than previously reported. j urol. 2010; 183:1859-1962. 26. albers p, fichtner j, brühl p, müller sc. long-term results of internal urethrotomy. j urol. 1996; 156:1611-1614. 27. korhonen p, talja m, ruutu m, alfthan o. intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. int urol nephrol. 1990; 22:263-9. 28. tabassi kt, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j. 2011; 8:132-6. 29. kumar s, kapoor a, ganesamoni r, et al. efficacy of holmium laser urethrotomy in combination with intralesional triamcinolone in the treatment of anterior urethral stricture. korean j urol. 2012; 53:614-8. correspondence mehmet erol yıldırım, md (corresponding author) doctorerol@yahoo.com ekrem ozyuvali, md ersin cimentepe, md department of urology, turgut özal university school of medicine 06510, yenimahalle ankara, turkey mehmet kaynar, md department of urology, selçuk university school of medicine, konya, turkey huseyin badem, md department of urology, yüksek i̇htisas education and research hospital ankara, turkey muzaffer cakmak, md department of internal medicine,turgut özal university school of medicine ankara, turkey bahadir kosem, md department of anesthesiology, turgut özal university school of medicine ankara, turkey stesura seveso archivio italiano di urologia e andrologia 2014; 86, 126 original paper present and future association between obesity and hypogonadism in italian male valentina boddi 1, valeria barbaro 2, paul mc nieven 3, mario maggi 1, carlo maria rotella 2 1 sexual medicine and andrology unit, department of clinical physiopathology university of florence, florence, italy; 2 department of biochemical experimental and clinical science, section of endocrinology and obesity agency, careggi university hospital; 3 strategyst consulting inc. objective: obesity prevalence is increasing worldwide and it is nowadays considered a real public health problem. obesity is associated with co-morbidities like cardiovascular diseases (cvd) and type 2 diabetes mellitus (t2dm), furthermore visceral obesity can be related to low testosterone (t) plasma levels. the link between obesity and hypogonadism (hg) is complex and not completely clarified. current guidelines suggest that screening for hg should be done in subjects with obesity and t2dm. the aim of this evaluation is to assess the estimated actual and future prevalence of obesity and related co-morbidities, in particular hg, in the italian general population. materials and methods: the strategyst consulting inc. recently completed an epidemiology forecast model for several countries, looking at hg and cv/metabolic disease, based on national health and nutrition examination survey (nhanes) data collected between 1999-2010. data from nhanes survey were used to evaluate the italian estimated prevalence of obesity and hg. results: results show that obesity estimated prevalence will increase in 2030 also in italy. in addition, also the prevalence of obese cvd and t2dm subjects will increase too. even italian hg prevalence is estimated to increase in the next two decades, irrespective of t threshold considered (< 8, 10 and 12 nmol/l). in obese cvd subjects the relative risk (rr) of developing hg (t < 8 nmol/l) is four times greater than in not-cvd obese subjects (rr = 4.1, 3.1 and 1.9 accordingly to the aforementioned t thresholds for defining hg). accordingly, the estimated percentage of hypogonadal obese cvd and t2dm subjects will rise in 2030. conclusions: the strategyst epidemiology forecast model has allowed to assess the current and future prevalence of obesity and its relative co-morbidities like hg in italy. data emerged from this evaluation suggest that obesity and hg prevalence will increase in italian population and confirm the complex link between adipose tissue and male t levels. key words: visceral obesity; hypogonadism; future prevalence; epidemiological forecast model. submitted 19 december 2013; accepted 28 february 2014 summary introduction obesity is an excessive accumulation of body fat mass relative to lean body mass, usually due to unbalanced diet and sedentary lifestyle (1). according to the world health organization (who) the diagnosis of obesity is often based on body mass index (bmi), calculated as weight in kilograms divided by height in meters squared (kg/m2). individuals with bmi higher than 30 kg/m2 are considered obese. obesity is categorized in grade 1, if bmi is of 30 to less than 35; grade 2, if bmi of 35 to less than 40 and grade 3, if bmi is of 40 kg/m2 or greater (2). obesity is the greatest public health problem in the world: several studies reported an association between obesity and increasing risk of developing cvd, cancer and common chronic disease, such as t2dm and hypertension, all diseases that can lead to a reduced quality of life and premature death (3). moreover, visceral obesity has been associated with alteration in sex steroid hormone concentrations like hg, especially in adult males (4-7). the organization for economic co-operation and development (oecd) projections suggest that more than 2 in 3 people will be overweight or obese in some of the oecd countries by 2020 (http://www.oecd.org/els/healthsystems/obesityandtheeconomicsofpreventionfitnotfat.htm). indeed, we are facing with a real global epidemic that is spreading in many countries and it can cause, in the absence of immediate action, very serious health problems in the coming years (1). the strategyst consulting inc. recently completed an epidemiology forecast model for several countries, looking at hg and cv/metabolic disease, based on nhanes data collected between 1999-2010. data from nhanes were used to show the degree of overlap between disease states and then to modify the raw prevalence values in nhanes in order to match the local prevalence in the particular countries, such as italy. the aim of this evaluation is to assess the current and future prevalence of obesity and its relative comorbidities, mostly hg, in italy. material and methods nhanes is a cross-sectional study designed to assess the health and nutritional status of adults and children in the no conflict of interest declared. note that barbaro v and boddi v equally contributed to the paper. doi: 10.4081/aiua.2014.1.26 boddi new_stesura seveso 26/03/14 10:17 pagina 26 27archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy united states. in this survey every subject underwent an interview and an extensive physical examination. in some cases a morning blood sample was collected for biochemical and hormonal analyses, such as t in male (9). informations on age and race/ethnicity were self-reported. during physical examination, height and weight, as well as waist and hip circumferences were measured and bmi was calculated as weight in kilograms divided by the square of height in meters. participants were defined as having diabetes if they answered “yes” to the question, “have you ever been told by a doctor or other health professional you had diabetes or sugar diabetes?” and as having cvd if they answered yes to the question, “have you ever been told by a doctor you had heart attack, an angina pectoris or a coronary heart disease?” (9). detailed information regarding the collection of data in nhanes is available elsewhere (nhanes iii data files, documentation, and codebooks. available online from http://www.cdc.gov/nchs/ nhanes/about_nhanes.htm). the strategyst consulting inc recently completed an epidemiology forecast model for several countries, looking at hypogonadism and cardiovascular/metabolic disease, based on national health and nutrition examination survey (nhanes) data collected between 1999-2010. data from nhanes were analyzed for understanding the general cv/metabolic patient population, as well as the distribution of t levels within the pool, knowing that this differs by age and bmi, and possibly also by cv status. from this data the percentages of relative risk of developing cvd and t2dm were calculated in the u.s. population and then applied for other countries, including italy, on the basis of who data. who had previously performed several forecasting evaluation on cv and metabolic health across the world. this allowed strategyst consulting inc. to make projections for each country of the cv and metabolic diseases from 2013 to 2030. t levels are pretty consistent across the globe, with variations between countries being due to varying demographic profiles and levels of obesity and cv risk factors. for this reason, only nhanes testosterone data were used, as they were the only source that allowed to create hg populations with respect to all the risk factors (and their mutual comorbidities), and embody the very complex set of odds ratios that describe these populations. hence, data from nhanes were used to show the degree of overlap between disease states, then to modify the raw prevalence values in nhanes to match the local prevalence in the particular country analyzed. results and discussion prevalence and trends of obesity in italian adults in the last thirty years, the worldwide prevalence of obesity has almost doubled, not with homogeneously distribution (11). united states is one of the countries that experienced the largest absolute increase in the number of overweight and obese people between 1980 and 2008 (11). about 35% of u.s adults were obese in 2011-2012, with a higher percentage of middle-aged obese adults aged 40-59 than younger adults aged 20-39 or older adults aged 60 figure 1. panel a. male obesity prevalence from 2013 to 2030 in italy. panel b-c. percentage of obesity as a function of age bands in italy, actually (panel b) and in 2030 (panel c). o be si ty p re va le nc e (% ) o be si ty p re va le nc e (% ) obese obese 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 18-29 30-39 40-59 60-64 65* 2013 9.3% 13.6% 15.7% 17.9% 12.5% 11.3% 16.4% 22.6% 21.7% 15.0% 18-29 30-39 40-59 60-64 65+ 2030 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% age bands age bands a. b. c. boddi new_stesura seveso 26/03/14 10:17 pagina 27 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 28 and over (12). according to data released in 2008 by the oecd, in italy about 1 person in 10 was obese (http://www.oecd.org/els/health-systems/obesityandtheeconomicsofpreventionfitnotfat-italykeyfacts.htm). figure 1 shows the trend of obesity (bmi ! 30 kg/m2) prevalence in italy from 2013 to 2030, in the adult male population (18-over 65 years old). at present, according to strategyst estimated data, 13.8% of italian men is obese. this prevalence is similar to that referred by passi (progressi delle aziende sanitarie per la salute in italia), a monitoring system of italian population (http://www.epicentro.iss.it/problemi/obesita/epid.asp). obesity prevalence will increase in the coming years and, on the basis of our estimated data, it will reach 16.8% in 2030 (figure 1, panel a). nowadays, among italian adult obese subjects, there is a higher percentage of patients aged 60-64 (17.9%) than aged 40-59 (15.7%) or aged 65 and over (12.5%) (figu re 1, panel b). in the next future, the percentage of obesity is estimated to rise in each age group, but mostly in middle aged adults, reaching 22.6% among 40-59 years old men and 21.7% among 60-64 years old men, similarly to us male population (figure 1, panel c). prevalence and trends of cvd and t2dm in italian adults the interheart study group identified the abdominal (visceral) obesity as one of the nine major risk factors for myocardial infarction (including smoking, lipids, hypertension, t2dm, diet, physical activity, alcohol consumption, and psychosocial factors), accounting for more than 90% of the worldwide risk (15). these risk factors were shared by men and women, almost in every geographic region and every racial/ethnic group. it is well known that visceral obesity, versus subcutaneous fat, is characterized by a hypersecretion of pro-atherogenic, pro-inflammatory and pro-diabetic adipo-cytokines, and by an enhanced free fatty acid turnover and toxicity (16), an increased basal sympathetic tone, a hypercoagulable state and a chronic low-grade systemic inflammation (17). this causes the development of insulin resistance (ir) and the increased risk of cvd as ischemic heart diseases (angina and myocardial infarction, mi) and congestive heart failure (chf). in addition, visceral obesity can be considered a “conditional” risk for developing t2dm, dyslipidaemia and hypertension, all independent cv risk factors (17). figure 2, panel a shows that the prevalence of t2dm, angina, history of mi and chf is expected to grow highly in the coming a. b. figure 2. panel a. male prevalence of different co-morbidities from 2013 to 2030 in italy [history of myocardial infarction (mi), angina, congestive heart failure (chf) and type 2 diabetes mellitus (t2dm)]. panel b. male prevalence of different co-morbidities as a function of different age bands in italy (history of mi, angina, chf and t2dm). pr ev al en ce o f di ffe re nt c om or bi di ti es ( % ) pr ev al en ce o f di ffe re nt c om or bi di ti es ( % ) age deciles 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ hx of mi angina chf t2dm hx of mi angina chf t2dm 20% 15% 10% 5% 0% 25% 20% 15% 10% 5% 0% boddi new_stesura seveso 26/03/14 10:17 pagina 28 29archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy years. at the moment, the estimated italian proportion of men with a history of mi is 4.8%, of angina 5.4%, of chf 2.7% and of t2dm 9.8% reaching 7.4%, 8.2%, 4.2% and 14.4%, respectively, in 2030. hence, the prevalence of cv and metabolic diseases will be almost doubled within 17 years in italy. concerning the prevalence of angina, history of mi, chf and t2dm as a function of age, it rapidly increases for all these diseases with aging, especially after 40 years old. in particular, for t2dm reaches a prevalence of 21% in 70 years old men (figure 2, panel b). in 2013, among the estimated obese sample, 26% has co-morbidities like t2dm and cvd (12% and 14%, respectively), whereas 74% has not (figure 3, panel a). normal weight subjects have lower rates of cvd (13%) and t2dm (10%), respectively (data not shown). this is consistent with a higher prevalence of cv and metabolic diseases in obese subjects. it is estimated that the prevalence of “unhealthy” obese (with cvd and t2dm) will rise reaching 32% in 2030 (16% t2dm and 16% cvd) whereas “healthy” obese (without cv and metabolic morbidity) will decrease to 68% (figure 3, panel b). overall these data show that prevalence of obesity in italy will increase, in particular the percentage of obese male subjects with co-morbidities. prevalence and trends of hypogonadism in italian adults normal aging is characterized by a slight decline of t levels (18). considering changes in t levels by age, there is not a consensus for definition of hg (19). for example, the american association of clinical endocrinologists (20) and the endocrine society (21) proposed different t cutoffs for diagnosing hg, i.e. 7 nmol/l (200 ng/dl) and 10.4 nmol/l (300 ng/dl) respectively. according to a consensus among different scientific andrology societies (18, 19, 22) men with t levels below 8 nmol/l (231 ng/dl) should receive t replacement therapy, whereas those with t levels above 12 nmol/l (346 ng/dl) should not be treated. moreover, it was introduced the concept of the so-called “late-onset hypogonadism” (loh): a clinical and biochemical condition of the advancing age, characterized by peculiar symptoms and by low levels of serum t, i.e. total t below 12 nmol/l. (2123). recently, wu et al. (24) proposed a t cut off 11 nmol/l (230 ng/dl) and free t levels of less than 220 pmol/l (< 64 pg/ml) for diagnosing loh, in the presence of at least three sexual symptoms (low libido and reduced spontaneous and sex-related erections). therefore, the estimated number of hypogonadal men is different, depending on the t cut off used and on age (18). in italy, by strategyst model evaluation, the present estimated prevalence of hg is 7, 12.5 and 22% considering t < 8, 10 e 12 nmol/l, respectively. it is expected that, in 2030, this prevalence will rise reaching 8.1, 14.7 and 24.2%, respectively (figure 4, panel a). in observational studies involving male general population, the prevalence of hg is increasing as a function of age, although at a different rate, as observed in us (2527) and european male population (24). accordingly, analyzing strategyst italian forecast, hg prevalence increases by age irrespective of t threshold considered, with the highest rate in older subjects (> 65 years old) reaching 7, 12.5, 22%, for t levels < 8, 10, 12 nmol/l, respectively (figure 4, panel b). obesity and hypogonadism several studies have demonstrated an inverse relationship figure 3. panel a-b. estimated distribution of obese male sample in 2013 and 2030; panel a and panel b, respectively. panel c-d. estimated distribution of hypogonadal obese male sample in 2013 and 2030; panel c and panel d, respectively. a-b. c-d. obese+cvd obese+t2dm obese obese+cvd obese+t2dm obese obese+cvd obese+t2dm obeseobese+cvd obese+t2dm obese 2013 2030 2013 2030 boddi new_stesura seveso 26/03/14 10:18 pagina 29 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 30 between bmi and waist circumference, indicators of visceral obesity, and t levels over all age groups (28-30). an increase in bmi from normal weight to obese range may be equivalent to a 15 years fall in t levels (23). in the massachusetts male aging study (mmas) authors demonstrated that a healthy lifestyle, a normal body weight and the absence of chronic disease were more important determinants of androgen levels than ageing (25-26). the link between obesity and hg is complex and not completely understood. visceral obesity can probably be considered an important cause of hg, but at the same time, hg could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle (31-35). figure 5, panel a shows that the estimated percentage of obese males in italy is higher in hg sample than in general population. there are some considerable evidences on the role of t in regulating body composition. it seems that t concurs in increasing and maintaining muscle mass and reducing fat mass (36). this suggests a possible role of t deficiency in the etiology of obesity so that hg might be considered an additional component of metabolic syndrome (mets) in males (37). in fact, in men undergoing androgen ablation therapy for advanced prostate cancer it was observed a significant increase in total body fat mass and reduction in lean body mass (38). criteria for mets were present in more than 50% of these men, predisposing them to higher cv risk (39). the relationship between reduced t levels and cvd still represents a matter of speculation. cross-sectional epidemiological studies clearly show a significant association between hg and cvd (40-41). in a recent meta-analysis araujo et al. demonstrated that hg was associated with an increased risk of all causes and cvd mortality (42). figure 5, panel b shows the estimated italian prevalence of hg (as different t threshold considered: 8, 10, 12 nmol/l) in obese subjects with or without previous cvd. in obese cvd subjects the relative risk (rr) of developing hg (t < 8 nmol/l) is four times greater than in not-cvd obese subjects (rr = 4.1, 3.1 and 1.9 accordingly to t cut off of 8, 10 e 12 nmol/l). this is a cross-sectional analyses, therefore we cannot establish a relationship of causality, however this suggests that the presence of previous cvd predispose obese subjects to develop hg and this risk is higher for lower t plasma levels. a large body of evidence supports the association between low t, t2dm and mets (31-35). according to data shown in figure 5b, in italy the estimated percentage of hypogonadal obese male subjects with t2dm and cvd is 19 and 16%, respectively (figure 3, panel c), higher than in subjects with only obesity (figure 3, panel a). figure 4. panel a. estimated italian hyponadism (hg) prevalence from 2013 to 2030, considering different testosterone (t) cut off. panel b. prevalence of hyponadism (hg) as a function of age bands, considering different testosterone cut off, in italy. a. b. pr ev al en ce o f h g ( % ) pr ev al en ce o f h g ( % ) age bands 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 18-29 30-39 40-49 60-64 > 65 below 12 nmlol/l below 10 nmol/l below 8 nmol/l % below 8 % below 10 % below 12 30% 28% 26% 24% 22% 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 25% 20% 15% 10% 5% 0% boddi new_stesura seveso 26/03/14 10:18 pagina 30 31archivio italiano di urologia e andrologia 2014; 86, 1 obesity and hypogonadism in italy hence, the presence of hg confers a higher probability of developing cvd and t2dm. furthermore, the estimated percentage of obese hypogonadal subjects with cvd and t2dm will rise in 2030, reaching 26 and 20% respectively (figure 3, panel d). this is consistent with previously shown data. current guidelines suggest that screening for hg should be done in subjects with obesity, t2dm and mets (18, 19, 21). conclusion obesity prevalence is increasing worldwide and this phenomenon involves italy too. at this moment, 13.8% men are obese and they will became 16.8% in 2030. the increase of prevalence will be greater in middle aged adult male. in coming years also the prevalence of t2dm, angina, chf and history of mi will rise. italian obese subjects have a higher rate of t2dm and cvd and this rate is estimated to rise. obesity is also related to hg. the estimated prevalence of hg in italy differs according to different cut offs proposed by scientific society, from 2 to 22% and will increase until 8-24% in 2030. concerning the data shown in this evaluation, the estimated prevalence of hg increases as a function of age and hypogonadal subjects are more often obese than general population. conversely, obese subjects have a higher risk of developing hg, in particular if they have suffered from cvd. finally, obese-hypogonadal males have a higher rate of t2dm and cvd than eugonadal obese male. the strategyst epidemiology forecast model allowed to assess the current and future prevalence of obesity and its relative comorbidities like hg in italy. a limitation of the present report should be recognized: prevalence estimations for italy are based on epidemiological values of us male population which could be different from the italian one. however, data emerged from this evaluation suggests that obesity and hg prevalence will increase in the italian population and confirm the complex link between adipose tissue and male t levels. references 1. caterson id, gill tp. obesity epidemiology and possible prevention. best pract res clin endocrinol. 2002; 16:595-610. 2. world health organization physical status: the use and interpretation of anthropometry. technical report series 1995, no. 854. in: geneva: who, 1995. 3. prospective studies collaboration. body-mass index and causespecific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. lancet. 2009; 373:1083-1096. 4. haffner sm, valdez ra, stern mp, katz ms. obesity, body fat distribution and sex hormones in men. int j obes relat metab disord. 1993; 17:643-9. 5. corona g, rastrelli g, forti g & maggi m. update in testosterone therapy for men. j sex med. 2011; 8:639-654. 6. corona g, rastrelli g, vignozzi l & maggi m. emerging medication for the treatment of male hypogonadism. expert opin emerg drugs. 2012; 17:239-59. 7. corona g, rastrelli g, vignozzi l, mannucci e & maggi m. how to recognize late-onset hypogonadism in men with sexual dysfunction. asian j androl. 2012; 14:251-259. 8. http://www.oecd.org/els/health-systems/49716427.pdf 9. selvin e, feinleib m, zhang l, et al. androgens and diabetes in men: results from the third national health and nutrition examination survey (nhanes iii). diabetes care. 2007; 30:234-8. 10. http://www.cdc.gov/nchs/nhanes/about_nhanes.htm 11. pérez rodrigo c. current mapping of obesity. nutr hosp. 2013; 28 (suppl 5):21-31. 12. cynthia l ogden, margaret d carroll, brian k kit, et al. prevalence of obesity among adults: united states, 2011-2012 nchs data brief no. 131 october 2013. 13. http://www.oecd.org/els/health-systems/obesityandtheeconomicsofpreventionfitnotfat-italykeyfacts.htm 14. http://www.epicentro.iss.it/problemi/obesita/epid.asp. 15. yusuf s, hawken s, ounpuu s, et al. interheart study investigators. effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the interheart study): case-control study. lancet. 2004; 364:937-52. figure 5. panel a. percentage of obese and nonobese italian men in hypogonadal sample (hg sample) and general population. panel b. hypogonadism (hg) prevalence in obese and cardiovascular disease (cvd) and obese subjects in italy according to different testosterone thresholds. a. all sample hg sample obese non-obese 8 nmol/l 10 nmol/l 12 nmol/lb. pr ev al en ce o f h g ( % ) obese + cvd obese 100% 80% 60% 40% 20% 0% 80,00 70,00 60,00 50,00 40,00 30,00 20,00 10,00 0,00 boddi new_stesura seveso 26/03/14 10:18 pagina 31 archivio italiano di urologia e andrologia 2014; 86, 1 v. boddi, v. barbaro, p. mc nieven, m. maggi, c.m. rotella 32 16. hajer gr, van haeften tw, visseren fl. adipose tissue dysfunction in obesity, diabetes, and vascular diseases. eur heart j. 2008; 29:2959-71. 17. krauss rm, winston m, fletcher bj, grundy sm. obesity: impact on cardiovascular disease. circulation. 1998; 98:1472-76. 18. buvat j, maggi m, guay a, torres lo. testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. j sex med. 2013; 10:245-84. 19. wang c, nieschlag e, swerdloff r, et al. investigation, treatment and monitoring of late-onset hypogonadism in males: isa, issam, eau, eaa and asa recommendations. eur j endocrinol. 2008; 159:507-514. 20. petak sm, nankin hr, spark rf, et al. american association of clinical endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update. endocr pract. 2002; 8:440-56. 21. bhasin s, cunningham gr, hayes fj, et al. task force, endocrine society. testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. j clin endocrinol metab. 2010; 95:2536-2559. 22. nieschlag e, swerdloff r, behre hm, et al. investigation, treatment and monitoring of late-onset hypogonadism in males: isa, issam, and eau recommendations. int j androl. 2005; 28:125-7. 23. wu fc, tajar a, pye sr, et al. hypothalamic–pituitary–testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the european male aging study. j clin endocrinol metabol. 2008; 93:2737-2745. 24. wu fc, tajar a, beynon jm, et al. emas group. identification of late-onset hypogonadism in middle-aged and elderly men. n engl j med. 2010; 363:123-35. 25. mohr ba, guay at, o'donnell ab, mckinlay jb. normal, bound and nonbound testosterone levels in normally ageing men: results from the massachusetts male ageing study. clin endocrinol (oxf). 2005; 62:64-73. 26. yeap bb, almeida op, hyde z, et al. 2008. healthier lifestyle predicts higher circulating testosterone in older men. the health in men study. clin. endocrinol. (oxf.) 2009; 70:455-63. 27. rohrmann s, platz ea, selvin e, et al. the prevalence of low sex steroid hormone concentrations in men in the third national health and nutrition examination survey (nhanes iii). clin endocrinol. (oxf). 2011; 75:232-9. 28. traish am, feeley rj, and guay a. mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. febs j 2009; 276:5755-67. 29. traish am, saad f, guay a. the dark side of testosterone deficiency: ii. type 2 diabetes and insulin resistance. j androl. 2009; 30:23-32. 30. corona g, mannucci e, ricca v, et al. the age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. int j androl. 2009; 32:720-8. 31. corona g, rastrelli g, morelli a, et al. hypogonadism and metabolic syndrome. j endocrinol invest. 2011; 34:557-567. 32. corona g, monami m, rastrelli g, et al. type 2 diabetes mellitus and testosterone: a meta-analysis study. int j androl. 2011; 34:528-540. 33. corona g, monami m, rastrelli g, et al. testosterone and metabolic syndrome: a meta-analysis study. j sex med. 2011; 8:272-283. 34. corona g, mannucci e, forti g, maggi m. following the common association between testosterone deficiency and diabetes mellitus, can testosterone be regarded as a new therapy for diabetes? int j androl. 2009; 32:431-441. 35. saad f, aversa a, isidori am, et al. onset of effects of testosterone treatment and time span until maximum effects are achieved. eur j endocrinol. 2011; 165:675-685. 36. emmelot-vonk mh, verhaar hj, nakhai pour hr, et al. effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. jama. 2008; 299:39-52. 37. corona g, mannucci e, forti g, maggi m. hypogonadism, ed, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. int j androl. 2009; 32:587-98. 38. chen z, maricic m, nguyen p, et al. low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. cancer. 2002; 95:2136-2144. 39. braga-basaria m, dobs as, muller dc, et al. metabolic syndrome in men with prostate cancer undergoing long-term androgendeprivation therapy. j clin oncol. 2006; 24:3979-3983. 40. ruige jb, mahmoud am, de bacquer d, kaufman jm. en do ge nous testosterone and cardiovascular disease in healthy men: a metaanalysis. heart. 2011; 97:870-5. 41. corona g, monami m, boddi v, et al. low testosterone is associated with an increased risk of mace lethality in subjects with erectile dysfunction. j sex med. 2010; 7:1557-64. 42. araujo ab, dixon jm, suarez ea, et al. clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. j clin endocrinol metab. 2011; 96:3007-19. correspondence valentina boddi, md vboddi@gmail.com mario maggi, md m.maggi@dfc.unifi.it sexual medicine and andrology unit, department of clinical physiopathology university of florence viale pieraccini 6 50139 florence, italy paul mc nieven, md pm@strategyst-consulting.com strategyst consulting inc. carlo maria rotella, md (corresponding author) c.rotella@dfc.unifi.it valeria barbaro, md valeb2282@gmail.com department of biochemical experimental and clinical science section of endocrinology and obesity agency careggi university hospital, florence, italy boddi new_stesura seveso 26/03/14 10:18 pagina 32 archivio italiano di urologia e andrologia 2017; 89, 4272 original paper can re-cturbt be useful in pt1hg disease as a risk indicator of recurrence and progression? a single centre experience roberto giulianelli 1, barbara cristina gentile 1, gabriella mirabile 1, luca albanesi 1, paola tariciotti 1, giorgio rizzo 1, maurizio buscarini 2, mauro vermiglio 3 1 cura, nuova villa claudia clinic, rome, italy; 2 campus biomedico, rome, italy; 3 villa gioia clinic, sora (fr), italy. introduction: understaging after initial transurethral resection is common in patients with high-risk non muscle infiltrating bladder cancer (nmibc) and can delay accurate diagnosis and definitive treatment. the rate of upstaging from t1 to t2 disease after repeated transurethral resection ranges from 0 to 28%, although the rate of upstaging may be even higher up to 49% when muscularis propria is absent in the first specimen. a restaging classic transurethral resection of bladder tumour (re-cturbt) is the better predictor of early stage progression. according to some reports, the rate of positivity for tumor in re-cturbt performed within eight weeks after initial cturbt was as high as 18-77%, and in about 40% of the patients a change in tumor stage was reported. we aimed to investigate, in high risk group, the presence of residual tumor following white light classical transurethral resection of bladder tumor (wlre-cturbt) and the different recurrence and progression rate between patients with persistent or negative (pt0) oncological disease after wlre-cturbt. materials and methods: a cohort of 285 patients presenting with primitive bladder cancer underwent to wlcturbt from january 2011 to december 2015; out of them 92 (32.28%) were t1hg. in according to eau guidelines 2011, after 4-6 weeks all hg bladder cancer patients underwent a wl recturbt . all patients were submitted to a subsequent followup including cystoscopy every 3 months with multiple biopsies, randomly and in the previous zone of resection; urinary citology on 3 specimens and kidney/bladder ultrasound every 6 months. the average follow-up was 48 months. results: following wlre-cturbt we observed a persistent disease in 18 (15.2%) patients: 14 (77.7%) with a hg-nmibc and 4 (22.2%) with a high grade (hg) muscle invasive bladder cancer (pt2hg). after follow up of all 92 patients according to the guidelines eau, we observed recurrence in 36/92 (39.1%) and progression in 14/92 (15.2%). of 14 nmibc with persistent disease, 10 patients (71.4%) showed recurrence: 4 patients (40%) were pt1hg with concomitant carcinoma in situ (cis), 3 patients (30%) multifocal ptahg, 2 (20%) patients cis and one patient (10%) a muscle invasive neoplasm (pt2hg). instead of the group of 48 patients pt0 following wl recturbt, we observed recurrence in 26 patients (54.1%) and in two patients (4.1%) progressions, who presented after 3 months in association with cis. the remaining 22 patients (45.9%) with initial pt1hg are still progression free. multivariate analysis showed that the most important variable of early progression were persistent neoplasm and histopathological findings at wlre-cturbt (p = 0.01), followed by the summary no conflict of interest declared. introduction bladder cancer is a common genito-urinary malignancy, with transitional cell carcinoma comprising nearly 90% of all primary bladder tumours. at the first diagnosis 70% to 80% of urothelial tumours are confined to the epithelium, the remainder is characterized by muscle invasion. a significant number of patients with high risk non-muscle invasive bladder tumours (hg-nmibt) treated with white light classic transurethral resection of bladder tumours (wlcturbt) and intravesical bcg will progress to invasive disease (1-3). progression to muscle invasion (pt2) mandates immediate radical cystectomy (4). wlcturbt is the standard initial therapy for nmibt, but the high percentage of recurrence after surgery is still an unresolved problem (5). high grade pt1 bladder neoplasm (pt1hg) really represents a therapeutic challenge due to the high risk of progression (about 15-30%) to muscle-invasive disease, usually within 5 years (6). however, no consensus exists regarding the treatment of patients with recurrent bladder tumours that invade the lamina propria (pt1) (7-9). recent studies suggested that the first cturbt may be incomplete in a significant number of cases (10). understaging at the time of the initial transurethral resection is common for patients with high-risk nmibc and can delay accurate diagnosis and definitive treatment. it is therefore recommended for patients with high-risk disease and in those with large or multiple tumors or when the initial transurethral resection is incomplete, to repeat wlre-cturbt within 2-6 doi: 10.4081/aiua.2017.4.272 result of the first cystoscopy (p = 0.002) and presence of cis (p = 0.02). discussion: following wlre-cturbt in hg-nmibc patients we identified in 15% of cases a persistent disease with a 4.3% of mibc. in the high risk persistent bladder neoplasms group we observed recurrent and progression rate higher than in t0 bladder tumours group (∆ = + 17.3% and ∆ = + 62.5%, p < 0.05). key words: pt1hg; wlre-cturbt; bcg schedule; pcishg recurrence and progression rate. submitted 14 november 2016; accepted 11 january 2017 giulianelli_stesura seveso 03/01/18 11:58 pagina 272 273archivio italiano di urologia e andrologia 2017; 89, 4 can re-cturbt be useful in pt1hg disease as a risk indicator of recurrence and progression? a single centre experience weeks in order to guide appropriate management (11). we aimed to investigate, in high risk group, the presence of residual tumor following wlcturbt and the different recurrence and progression rate between patients with persistent or negative (pt0) oncological disease after wlre-cturbt. materials and methods in our department from january 2011 to june 2015, 285 consecutive patients with a first diagnosis of clinical bladder tumor underwent wlcturbt. histopathological findings showed 95 high grade (hg) bladder tumours invading the lamina propria (pt1) but only 92 (32.28%) cases were eligible for our study. patients mean age was 68 years (range 42 to 78 yrs, sd 10.4); 22 patients were women; mean follow-up 28 months (range 16-5 months). focality and dimensions are reported table 1. we performed wlcturbt with complete resection of all visible lesions and tumor bed and margins were taken separately. all resections were performed in our institution by the same experienced surgeon, r.g. our exclusion criteria included patients that underwent an incomplete resection or cases whose specimens were without muscle tissue in order to evaluate tumour invasion. we excluded three patients: two because of the lack of muscle tissue in the specimen and one because of the incomplete resection. a wlre-cturbt, according to eau guidelines (11), was routinely performed within 4 to 6 weeks following the first resection if the histopathological findings revealed t1 tumour. the surgeon performed the procedure with the same technique of the initial wlcturbt: complete resection of all suspect residual tumour, separate resection of the underlying bladder wall with an adequate amount of detrusor muscle, wide resection of the margins to exclude the presence of carcinoma in situ (cis) and associated biopsies with a loop resection (‘selected biopsies’) of the abnormal areas of urothelium. if there was not residual tumour or if it was superficial, intravesical immunotherapy conforming to lamm’s schedule was planned (12). in according to eau guidelines (11), urine cytology and follow-up cystoscopy were performed every 3-month for the first year, biannually for the second year and annually thereafter. ultrasonography of the urinary upper tract was performed every six months. however, if muscle invasive residual tumour or cis were detected, subsequent treatment strategy was radical cystoprostatectomy. recurrence free survival, progression free survival and overall survival curves were calculated by the kaplanmeier method (13) and compared by the log rank test (14). statistical analysis was performed using the pearson chi-square test (15). tumors were classified according to the tnm system of the uicc (16) and grading according to who classification. patients were fully informed and consented the procedure. results of the 95 enrolled patients, 92 were considered evaluable for the actual analysis. after wlre-cturbt performed within 4 to 6 weeks following the first resection, we observed 18 (19.5%) patients with recurrence: 4 (4.34%) with muscle invasive bladder cancer (mibc) and 14 (15.2%) with nmibc (table 2). regarding focality, dimension and concomitant cis, all patients with invasive neoplasms were multifocal (p < 0.01), > 3 cm (p < 0.01) or with concomitant cis (p < 0.001) to the first wlcturbt. all mibc patients underwent radical cystoprostatectomy with staging lymphadenectomy and the histopathological evaluation revealed one patient with no evidence of tcc in the cystectomy specimen (pt0) and three patients with muscle invasion (pt2b) but no evidence of positive lymphnodes (pn0). we carried out the follow up of all 92 patients according to the eau guidelines, and we found out recurrence in 36/92 (39.1%) and progression in 14/92 (15.2%). all the 14 patients (15.2%) with nmibc underwent intravesical immunotherapy conforming to lamm’s schedule (12) and 10 (71.4%) of them showed recurrences respectively after 4, 6, 7, 10 and 12 months (see table 3). of these 10 patients, 4 patients (40%) showed recurrences pt1hg with concomitant cis, 3 patients (30.0%) multifocal ptahg, two (20.0%) cis and one (10.0%) a muscle invasive neoplasm (pt2hg). all these patients with high grade persistent disease following bcg-schedule were regarded as "patients progressing" and after pelvis-abdomen ct and scintigraphy, radical cystoprostatectomy with staging lymphadenectomy was suggested. the histopathological evaluation revealed two patients (2.17%) with no evidence of tcc in the cystectomy specimen (pt0), six patients (6.52%) with muscle invasive tumor pt2a and two (2.17%) pt2b, with no evidence of positive lynphnodes (pn0). all of the patients are actually living and disease-free but one (1.08) with muscle invasive tumor (pt2an0) who died for another cause without evidence of disease progression. in the group of patients with table 1. t1hg patients: focality and dimensions. focality pts dimensions pts unifocal 14 < 1 cm 12 multifocal 78 > 1 < 3 cm 54 > 3 cm 26 92 92 table 2. t1hg patients returb: recurrence and progression. re-turb pts pt1 pt2 progression recurrences 18 14 4 % 19.50% 15.10% 4.40% table 3. tahg patients follow-up: bcg, recurrence and progression. bcg rec 4 mo 6 mo 7 mo 10 mo 12 mo 14 pt1hg/cis ptahg cis pt2hg pt1hg/cis pts 10 3 3 2 1 1 15.20% 10.87% 3.27% 3.27% 2.17% 1.08% 1.08% giulianelli_stesura seveso 03/01/18 11:58 pagina 273 archivio italiano di urologia e andrologia 2017; 89, 4 r. giulianelli, b.c. gentile, g. mirabile, l. albanesi, p. tariciotti, g. rizzo, m. buscarini, m. vermiglio 274 persistent disease following wlrecturbt we observed a overall mibc rate of 66.6% (12 pts). instead of the group of 48 patients who were t0 following wlre-cturbt and had intravesical immunotherapy (bcg) conforming to lamm’s schedule (12), we observed recurrence in 26 pts (54.1%) and in only two patients (4.1%) progression, who presented after 3 months, associated with cis. the remaining 22 patients (45.9%) with initial t1hg are still progression free. figures 1 and 2 show kaplan-meier overall recurrencefree and progression-free curves, respectively. discussion wlcturbt is the main-stay approach in the diagnosis and treatment of bladder cancer. on the basis of the eortc risk tables and prognostic factors for t1hg bladder tumours, the probability of recurrence at 1 and 5 year, respectively, is 24-61% and 46-78%, and the probability of progression, respectively, is 1-17% and 6-45% (3). if patients are diagnosed with high-grade t1, a recturbt is strongly recommended regardless of the presence of muscle in specimens because of the possibility of understating due to incomplete resection (17, 18). it provides more accurate pathological staging information, since persistent tumor in second cturbt specimens can be detected in 33%-55% of patients (19, 20). in our experience we observed persistent bladder lesions after wlre-cturbt in 19.5% of patients. in addition, a wlre-cturbt promotes cancer control. in a randomized controlled study, re-cturbt decreased the recurrence rate compared to a single cturbt (21) . in our expeience, in the persistent group, recurrences and progressions were more elevated than in t0 group. persistent disease after wlre-cturbt is a poor prognostic indicator of recurrence and progression. dutta et al. (22) demonstrated that, if a wlrecturbt is performed, the risk of upstaging is near 30%, but the risk of residual tumour is still significant. we already reported our experience concerning the need of wlrecturbt in patients with primary pt1 tcc of the bladder. residual tumour rate was 19.5% in 18 patients who underwent wlre-cturbt following primary diagnosis of t1 disease and overall recurrence was 39.1%. residual neoplasms were detected only in multifocal tumor, concomitant cis and > 3 cm at first pt1hg bladder tumours. our opinion is that the main and most important rule is a complete resection of the nmibc. this procedure is not only mandatory for an adequate staging but also useful to the completion of wlcturbt for most of the non muscle invasion tumours. an inadequate and incomplete resection increases recurrence rate as brausi et al. (10) already showed: in fact the curative effect of an excellent resection is especially showed in superficial disease. grimm et al. (23) investigated the role of wlre-cturbt in an heterogeneous group of patients with superficial bladder cancer. they found that the estimated risk of recurrence after 1, 2 and 3 years was 18%, 29% and 32% respectively and recurrence was observed in 38% pts treated with re-turbt. divrik et al. (24) found the recurrence rate was 13.6%, 22.3% and 31.2% in the first, the second and the third year respectively and that overall recurrence was 25.6%. klan et al. (25) reported a residual tumour rate of 50% in patients with pt1 hg tumours; herr (26) reported a rate of 74% residual tumours in 58 patients with pt1 hg bladder cancer, while mersdorf et al. (27) detected residual tumours in 58% (26 of 45 patients) pt1hg bladder cancer. wlre-cturbt certainly detected a significant percentage of residual tumours and, among them, cis and muscle invasive disease rates were reported with a range of 6% to 24% in different studies (28, 29). kitamura and kakehi (30) suggested that optimal management strategies should be based on pathological findfigure 1. kaplan-meier overall recurrence survival analysis. figure 2. kaplan-meier overall progression survival analysis. giulianelli_stesura seveso 03/01/18 11:58 pagina 274 275archivio italiano di urologia e andrologia 2017; 89, 4 can re-cturbt be useful in pt1hg disease as a risk indicator of recurrence and progression? a single centre experience conclusions wlre-cturbt is a useful tool because in a percentage of the patients this additional surgery results in an improvement of treatment strategy. true recurrence rate can be better evaluated by this approach because residual tumors may be erroneously defined as recurrence. our data showed that it is necessary to perform a wlrecturbt in patients with newly diagnosed, high grade (hg), stage pt1 bladder cancer for a ‘real’ staging and a complete resection (15% persistent disease). in our experience, following wlre-cturbt in hgnmibc risk group patients we dentified a 15% persistent disease with a 4.3% of mibc. in the patients with persistent bladder neoplasms we observed a overall recurrence and progression rate more elevated than in t0 bladder tumours group (∆ = + 17.3% and ∆ = + 62.5%). references 1. andius p, holmang s. bacillus calmette-guerin therapy in stage ta-t1 bladder cancer: prognostic factors for time to recurrence and progression. bju int. 2004; 93:980 2. herr hw, klein ea, rogatko a. local bcg failures in superficial bladder cancer. a multivariate analysis of risk factors influencing survival. eur urol. 1991; 19:97 3. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta-t1 bladder cancer using eortc risk table: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006; 49:466. 4. segal r, yafi fa, brimo f, et al. prognostic factors and outcome in patients with t1 high-grade bladder cancer: can we identify patients for early cystectomy? bju int. 2012; 109:1026-30. 5. kim hs, ku jh, kim sj, et al. prognostic factors for recurrence and progression in korean non-muscle-invasive bladder cancer patients: a retrospective, multi-institutional study. yonsei med j. 2016; 57:855-64. 6. nepple kg, o’donnell ma. the optimal management of t1 highgrade bladder cancer. can urol assoc j. 2009; 3(6 suppl 4):s188s192. 7. brake m, loertzer h, horsch r, keller h. recurrence and progression of stage t1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus calmetteguerin. j urol. 2000; 163:40. 8. bianco fj jr, justa d, grignon dj, et al. management of clinical t1 bladder transitional cell carcinoma by radical cystectomy. urol oncol. 2004; 22;290. 9. smaldone mc, jacobs bl, smaldone am, hrebinko rl. longterm results of selective partial cystectomy for invasive urothelial bladder carcinoma. urology. 2008; 72:613-6. 10. brausi m, collette l, kurth k, et al. variability in the recurrence rate at first follow-up cystoscopy after tur in stage ta-t1 transitional cell carcinoma of the bladder: a combined analysis of seven eortc studies. eur urol. 2002; 41:543. 11. babjuk m, oosterlinck w, sylvester r, european association of urology (eau), et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. eur urol. 2011; 59:997-1008. 12. lamm dl, blumenstein ba, crissman jd, et al. maintenance bacillus calmette-guérin immunotherapy for recurrent ta, t1 and carcinoma in situ transitional cell carcinoma of the bladder: a ranings from second cturbt specimens in patients with t1 disease. they recommended that patients with t0 upon wlre-cturbt should be considered for bcg therapy or watchful waiting. a randomized controlled study is ongoing comparing watchful waiting to bcg therapy in high-grade t1 disease with t0 on wlre-cturbt. bcg instillation into bladder is the gold standard for conservative treatment for high-grade t1 disease. the therapeutic effect of bcg in high-grade t1 has already been established by several meta-analysis studies (31, 32). however, we have to keep in mind that patients die upon progression to mibc, not upon recurrence, and that the effectiveness of bcg at preventing progression was not as great as its effectiveness at preventing recurrence. further, residual tumor in the wlre-cturbt specimen is associated with poor prognosis. in our experience, we observed progressions in 14/92 patients (15.2%): 12 from the group with persistent disease group and two in t0 patients. in the persistent disease group, we identified four patients with muscle inasive disease at wlrecturbt and 8 more patients during the follow-up. according to eau guidelines (11), all patients were submitted to radical cystectomy and staging lymphadenectomy. all patients who had a muscle-invasive disease, confined within the muscle layer, without extra-parietal extension or lymphadenopathy, are today living (ned). early cystectomy was mandatory to have good results. cystectomy has definite advantages for high-grade t1 disease. in the largest study so far, the clinical outcomes of 167 patients with high-grade t1 were reviewed after cystectomy (33). surprisingly, almost 30% experienced disease recurrence, and 18.5% died from bladder cancer. half of the cases had disease upstaging, and 27.5% had extravesical disease. a greater than 3-month delay between cystectomy and last wlcturbt showed a trend toward upstaging, which means that delaying cystectomy for bcg therapy may worsen prognosis. herr et coll showed that of 92 patients with residual t1 cancer in wlre-cturbt, 75 (82%) progressed to muscle invasion within 5 years compared to 49 of 260 (19%) who had no or non-t1 tumor detected on restaging cturbt (34). a similar study reported that early cystectomy seems to prolong cancer-specific survival compared to deferred cystectomy in high-risk high-grade t1 patients (35). considering the high risk of progression and cancer death of high-grade t1 disease, cystectomy would be the best answer for treatment. however, there are disadvantages. first, cystectomy may be overtreatment for highgrade t1 disease. since at least 50% of high-grade t1 patients are not upstaged upon cystectomy (36). second, cystectomy deteriorates the quality of life. finally, cystectomy is a highly complicated surgery in the urological field, and almost 30%-50% of patients experience perioperative or long-term complications (37). in our experience, the most important predictive prognostic factor – in patients with pt1hg tumours – is the presence of concomitant cis. sylvester et al. observed in pt1hg patients without cis a probability of progression around 10% at 1 year and 29% at 5 years. in pt1hg patients with cis, the corresponding features are 29% and 74%, respectively (3). giulianelli_stesura seveso 03/01/18 11:58 pagina 275 archivio italiano di urologia e andrologia 2017; 89, 4 r. giulianelli, b.c. gentile, g. mirabile, l. albanesi, p. tariciotti, g. rizzo, m. buscarini, m. vermiglio 276 domized southwest oncology group study. j urol. 2000; 163:11241129. 13. kaplan el, meier p. nonparametric estimation from incomplete observations. j amer statist assn. 1958; 53:457-481. 14. harrington d. linear rank tests in survival analysis, in encyclopedia of biostatistics, wiley interscience, 2005. 15. pearson k. on the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. the london, edinburgh, and dublin philosophical magazine and journal of science series 5 1900; 50:157-175. 16. cheng l, montironi r, davidson dd, lopez-beltran a. staging and reporting of urothelial carcinoma of the urinary bladder. modern pathology. 2009; 22:s70-s95; 17. ramírez-backhaus m, dominguez-escrig j, collado a, et al. restaging transurethral resection of bladder tumor for high-risk stage ta and t1 bladder cancer. curr urol rep. 2012; 13:109-114. 18. shim js, choi h, noh ti, et al. the clinical significance of a second transurethral resection for t1 high-grade bladder cancer: results of a prospective study. korean j urol. 2015; 56:429-434. 19. jahnson s, wiklund f, duchek m, et al. results of second-look resection after primary resection of t1 tumour of the urinary bladder. scand j urol nephrol. 2005; 39:206-210. 20. vasdev n, dominguez-escrig j, paez e, et al. the impact of early re-resection in patients with pt1 high-grade non-muscle invasive bladder cancer. ecancermedicalscience 2012; 6:269. 21. kim w, song c, park s, et al. value of immediate second resection of the tumor bed to improve the effectiveness of transurethral resection of bladder tumor. j endourol. 2012; 26:1059-1064. 22. dutta sc, smith jr ja, shappell sb, et al. clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. j urol. 2004; 166:539. 23. grimm mo, steinhoff c, simon x, et al. effect of routine repeat transurethral resection for superficial bladder cancer a long-term observational study. j urol 2003; 170:433. 24. divrik rt, yldirim u, zorlu f, ozen h. the effect of repeat transurethral resection on recurrence and progression rates in patients with t1 tumours of the bladder who received intravesical mytomicin: a prospective, randomised clinical trial. j urol. 2006; 175:1644. 25. klan r, loy v, huland h. residual tumour discovered in routine second transurethral resection in patients with stage t1 transitional cell carcinoma of the bladder. j urol. 1991; 148:316. 26. herr hw. the value of a second transurethral resection in evaluating patients with bladder tumours. j urol. 1999; 162:74. 27. mesdorf a, brauers a, wolff jm, et al. 2nd tur for superficial bladder cancer, a must? j urol. 1998; suppl., 159:143, abstract 542. 28. schips l, augustin h, zigeuner re, et al. is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? urology. 2002; 60:822. 29. ojea calvo a, nunuz lopez a, alonso rodrigo a, et al. value of a second transurethral resection in the assesment and treatment of patients with bladder tumour. actas urol esp. 2001; 25:182. 30. kitamura h, kakehi y. treatment and management of highgrade t1 bladder cancer: what should we do after second tur? jpn j clin oncol. 2015; 45:315-322.. 31. shelley md, wilt tj, court j, et al. intravesical bacillus calmette-guérin is superior to mitomycin c in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. bju int. 2004; 93:485-490. 32. böhle a, bock pr. intravesical bacille calmette-guérin versus mitomycin c in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. urology. 2004; 63:682686. 33. gupta a, lotan y, bastian pj, et al. outcomes of patients with clinical t1 grade 3 urothelial cell bladder carcinoma treated with radical cystectomy. urology 2008; 71:302-307. 34. herr hw, donat sm, dalbagni g. can restaging transurethral resection of t1 bladder cancer select patients for immediate cystectomy? j urol. 2007; 177:75-79. 35. denzinger s, fritsche hm, otto w, et al. early versus deferred cystectomy for initial high-risk pt1g3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? eur urol. 2008; 53:146-152. 36. lambert eh, pierorazio pm, olsson ca, et al. the increasing use of intravesical therapies for stage t1 bladder cancer coincides with decreasing survival after cystectomy. bju int. 2007; 100:33-36. 37. hautmann re, abol-enein h, davidsson t, et al. icud-eau international consultation on bladder cancer 2012: urinary diversion. eur urol. 2013; 63:67-80. correspondence roberto giulianelli, md giulianelli0764@gmail.com barbara cristina gentile, md gabriella mirabile, md luca albanesi, md paola tariciotti, md paola.tariciotti@libero.it giorgio rizzo, md cura, nuova villa claudia clinic, rome, italy maurizio buscarini, md campus biomedico, rome, italy mauro vermiglio, md villa gioia clinic, sora (fr), italy giulianelli_stesura seveso 03/01/18 11:58 pagina 276 stesura seveso 297archivio italiano di urologia e andrologia 2018; 90, 4 case report undiagnosed paraganglioma; a challenge during laparoscopic retroperitoneal resection alexander heinze 1, 3, periklis nikomanis 2, ferdinand petzold 2, jens jochen rassweiler 1, ali serdar goezen 1 1 slk kliniken heilbronn, department of urology, university of heidelberg, germany; 2 slk kliniken heilbronn, department of anaesthesiology, university of heidelberg germany; 3 school of medicine, universidad nacional autónoma de méxico, méxico city. objective: report our experience of the management of a patient with undiagnosed retroperitoneal paraganglioma and the intraoperative complications that the theatre team faced. case report: we present a case of a 36-year-old patient who during oncological follow-up for a previous diagnosis of parotid acinar cell carcinoma was incidentally identified as having an interaortocaval tumour. following routine preoperative assessment the patient was arranged to undergo a laparoscopic retroperitoneal tumour resection. after minimal tumour manipulation the patient developed cardiac rhythm abnormalities and became hypertensive. the tumour was successfully removed laparoscopically after a cautious interaortocaval dissection. abruptly, prior to extraction of the tumour containing endobag, the patient developed cardiac arrest. following 35 minutes of life support measures there was a return of spontaneous circulation. the endobag was laparoscopically removed from the abdominal cavity 24 hours later using the initial operative port sites. the patient´s progression was satisfactory and he could be discharged six days postoperatively. conclusions: asymptomatic undiagnosed paragangliomas represent a real challenge during laparoscopic operations. haemodynamic changes and life-threatening events can arise acutely intraoperatively, where an immediate and coordinated response of the whole theatre team may be required to avoid fatal outcomes. key words: paraganglioma; laparoscopic approach; intraoperative complications. aubmitted 25 march 2018; accepted 7 may 2018 summary no conflict of interest declared. urology and anesthesia teams when the correct diagnosis is not suspected preoperatively. clinical case we present the case of a 36-year-old man who attended our urological service. the patient received a diagnosis of parotid acinar cell carcinoma nine months prior, and during oncological follow-up was incidentally identified through the use of computed tomography (ct) imaging which revealed a 4.8 cm lesion with heterogeneous softtissue density in an interaortocaval localization without any sign of vascular infiltration, hence his referral to our urology service. the patient was asymptomatic with a background history of hypothyroidism, gastrooesophageal reflux disease, parotidectomy and neck dissection. physical examination and vital sign parameters were unremarkable and routine laboratory blood tests were within normal ranges. the patient was arranged to undergo laparoscopic retroperitoneal tumor resection following preoperative assessment. after positioning the patient in supine position, we favored a transperitoneal 4-trocars approach, and establishment of a pneumoperitoneum up to 14 mm/hg of pressure. the access to the retroperitoneum was achieved by incision the white line of toldt and by displacing medially the ascendant colon. the interaortocaval localized tumor was then visualized and a careful dissection of the surrounding big vessels and tissue was undertaken. the dissection was carried out with a minimal blood loss. after a minimal tumor manipulation the patient developed cardiac rhythm abnormalities – possibly atrioventricular block – and rapidly became hypertensive with a systolic blood pressure of 250 mmhg and a tachycardia of 160 bpm. the patient was initially administered b-blockers and an attempt to deepen the anesthesia using opiates was undertaken, unfortunately with poor response. the patient subsequently developed respiratory failure with hypoxia and clinically was found to have pulmonary edema. meanwhile surgery was accomplished successfully and the resected specimen was placed into an endobag. abruptly prior to extraction of the endobag through the paraumblical optic trocar incision the patient developed cardiac arrest, indicating pulseless doi: 10.4081/aiua.2018.4.297 introduction paragangliomas are defined as neuroendocrine tumors (net) which may or may not produce catecholamines. these tumors emerged out of chromaffin cells from the neural crest. these type of tumors are distributed along the sympathetic and parasympathetic chains. the most common location is retroperitoneal accounting for up to 77% often pictured as a mass around the corpora paraaortica (1). surgical resection represents the only available curative treatment for these tumors. the laparoscopic approach has proved to be a safe and effective technique for retroperitoneal tumor resection in experienced hands (2, 3). but serious challenges and complications can arise during these operations both for archivio italiano di urologia e andrologia 2018; 90, 4 a. heinze, p. nikomanis, f. petzold, j. jochen rassweiler, a. serdar goezen 298 electrical activity on electrocardiography. therefore, resuscitation maneuvers’ were employed immediately following standardized life support protocols. the port incisions were closed rapidly while operating team begun manual chest compressions – initially by hand and subsequently aided with the mechanical chest compression device ‘“lucas’™ (physio control inc. redmond wa)”. following 35 minutes of resuscitation measures there was a return of spontaneous circulation (rosc) with sinus rhythm, and the patient was transferred to the operative intensive care unit (opi) where respiratory and cardiovascular support was offered through ventilation and catecholamine perfusions. cardiac rhythm and function was assessed with electrocardiography and echocardiography, which initially showed findings consistent with post-resuscitation reduced left ventricular function. follow-up echocardiography indicated a possible early stage hypertensive cardiomyopathy. coronary angiography excluded any coronary artery disease. chest ct of the patient’s identified mild pulmonary edema and postresuscitation atelectasis. a control ct of the patient’s abdomen showed the endobag containing the resected tumor and no other acute pathology. further laparoscopic intervention using the same port places was carried out 24 hours after the initial surgery in order to remove of the endobag with resected tumor. the endobag has been visualized easily in the abdominal cavity and could be removed after minimal manipulation safely through the paraumblical optic trocar incision, tumor pathology and histology results reported a 4.5 cm x 4.5 cm x 2 cm tissue of yellow brownish color surrounded by a thin capsule. inmunohistology was performed being positive for chromogranin a and synaptophysin and negative for pancytoqueratine, protein s-100 and melanina a. this findings were compatible with characteristics of paraganglioma tumors. the patient remained on the opi for a further 72 hours. during this period, the patient showed clinical stabilization and improvement with no lasting neurological or end-organ damage evident. therefore, the patient was transferred to the urological ward from which he was formally discharged six days post-operatively. further followup will be carried out by urology department and further genetic analysis will be performed by genetic department. conclusions asymptomatic undiagnosed paragangliomas represents a real perioperative challenge. ideally, patients with suspected diagnoses of paraganglioma or pheochromocytoma should receive adequate preoperative management for optimal surgical conditions. laparoscopic approach should be considered in experienced hands due to its well known advantages. nevertheless risk of acute hemodynamic changes and life-threatening events can arise in these subgroups of patients; for this reason the entire operating team should be prepared in order to avoid fatal outcomes. references 1. purnell s, sidana a, maruf m, et al. genitourinary paraganglioma: demographic, pathologic, and clinical characteristics in the surveillance, epidemiology, and end results database (2000-2012). urol oncol. 2017; 35:457.e9-457.e14. 2. abe t, sazawa a, harabayashi t, et al. laparoscopic resection of paraaortic/paracaval neurogenic tumors: surgical outcomes and technical tips. surg endosc. 2016; 30:4640-4645. 3. ping w, hong zhou m, jie q, et al. laparoscopic resection of retroperitoneal paragangliomas: a comparison with conventional open surgical procedures. j endourol. 2016; 30:69-74. correspondence alexander heinze, md periklis nikomanis, md ferdinand petzold, md jens jochen rassweiler, md ali serdar goezen, md febu (corresponding author) ali.goezen@slk-kliniken.de slk-kliniken heilbronn, department of urology am gesundbrunnen 20-26, d-74078 heilbronn, germany stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2112 original paper managing female urinary incontinence: a regional prospective analysis of cost-utility ratios (curs) and effectiveness elisabetta costantini 1, massimo lazzeri 1, vittorio bini 2, alessandro zucchi 1, emanuele scarponi 1, massimo porena 1 1 department of medical-surgical specialties and public health, urology and andrology section, university of perugia, perugia, italy; 2 department of internal medicine, university of perugia, perugia, italy. introduction: to evaluate the cost-utility of incontinence treatments, particularly anticholinergic therapy, by examining costs and quality-adjusted life years. materials and methods: a prospective cohort study of women who were consecutively referred by general practitioners (gps) to the urology department because of urinary incontinence. the primary outcome was evaluation of the cost-utility of incontinence treatments (surgery, medical therapy and physiotherapy) for stress and/or urgency incontinence by examining costs and quality-adjusted life years. results: 137 consecutive female patients (mean age 60.6 ± 11.6; range 36-81) were enrolled and stratified according to pathologies: sui and uui. group a: sui grade ii-iii: 43 patients who underwent mid-urethral sling (mus); group b: sui grade i-ii 57 patients who underwent pelvic floor muscle exercise and group c: uui: 37 patients who underwent antimuscarinic treatment with 5 mg solifenacin daily. the cost utility ratio (cur) was estimated as saving more than !1200 per qaly for surgery and physiotherapy and as costing under ! 100 per qaly for drug therapy. conclusions: this study shows that appropriate diagnosis and treatment of a patient with incontinence lowers national health service costs and improves the benefits of treatment and quality of life. key words: female urinary incontinence; cost-utility analysis; anti-muscarinic therapy; mid urethral slings; physiotherapy, qaly. submitted 30 september 2014; accepted 31 december 2014 summary introduction female urinary incontinence (ui) affects between 10% and 60% of women worldwide (1-2). as a major health problem it has a marked social impact, with significant worsening of quality of life (qol) and high costs for national health system (nhs), which vary with the country (3). incontinence imposes very different expenses on payers, providers and patients which can lead to complex no conflict of interest declared. arrangements for where patients get care and what services are covered by health insurance, thus ultimately determining outcomes for patients (4). as the average life-span of western populations is rapidly lengthening, the prevalence of incontinence will continue to rise and the demand for incontinence services will increase (5). since costs are assuming a greater role in health-care decision-making, the aim of the present study was to evaluate the cost-utility of three incontinence treatments by examining costs and quality-adjusted life years. since the type of therapy varies with the nature of incontinence, our objective in this prospective cohort study was not to compare different strategies of incontinence therapy but to determine whether each therapy is cost-useful. this type of assessment is of particular interest in italy as the italian nhs does not fund anticholinergic drugs. material and methods study design a prospective descriptive observational study with no inter-group comparisons was designed and approved as a “research project” by the “umbria region” (annex) to test an innovative organizational model of ui treatment in an attempt to reduce costs and increase patient satisfaction. the approval to conduct the study (number 718) was obtained by regional research scientific committee with the protocol number 0096568, classification xvii.4. before starting the study general practitioners (gps) in the no 2 local health board in perugia (italy) were asked how many patients used nhs-supplied pads. approximately 8% used them, but only about 2% were suitable for recruitment to the present study as the others were very elderly or had other major pathologies such as double incontinence or were bedridden. the study was conducted on women who were consecutively referred by gps to the urology and andrology division (university of perugia) because of ui. patients were affected by stress urinary incontinence (sui), urge urinary incontinence (uui), mixed urinary incontinence doi: 10.4081/aiua.2014.2.112 113archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness (mui). in patients with mixed incontinence, the dominant symptom of either stress or urge incontinence was treated. patients were divided into three groups according to the type and severity of incontinence, in accordance with international continence society (ics) criteria and the ingelman sunderberg classification (6) and were treated with surgery, drugs or physiotherapy. only patients who gave written informed consent to participating in this observational study were included in each group. all information was obtained using validated questionnaires: the iiq 7 and udi6 questionnaires for outcome evaluation and life expectancy eq-5d (see quality of life below) for quality of life evaluation at baseline and at the 3 month follow-up. pad use preand post-treatment was also included in the analysis the primary outcome was evaluation of the cost-utility of 3 incontinence treatments by examining costs and quality-adjusted life years without an inter-group statistical comparison. our aim was to assess the cost-utility of each strategy and its impact on the italian national health service bearing in mind that each treatment was not funded in the same way. cost utility analysis (cua) cost is typically measured in currency, and should reflect the present value of total future expenditures that would be incurred by making a certain decision. utilities are typically measured in quality adjusted life years (qalys). a qaly accounts for the morbidity of a health state, based on the assumption that a year of life with morbidity is not equal to a year of life without morbidity. the value of a year with morbidity, the “utility weight”, can be determined through validated survey instruments. to calculate the cost-utility ratios for incontinence therapy we calculated quality of life and costs. cost-utility ratios are normalized values that reveal how much money (cost) must be paid for a single extra qaly (utility). when deciding between two management options, one should consider the cost of the gain of qalys. this ratio, the cost-utility ratio, is calculated as (cost1 – cost2)/(qaly1-qaly2). if one of the interventions costs less and yields more qalys, that decision is “cost-saving” and “prevails over” the other option. confidence intervals for the cost per qaly ratio were estimated using the non-parametric bias-corrected percentile bootstrap method (7). because of the limited degree of modeling in this cost utility analysis, we carried out sensitivity analyses only on the use of different utility measures: eq-5d index and eq-5d visual analogue scale (vas). quality of life health-related qol was assessed by patients before therapy and 3 months after treatment by means of the life expectancy eq-5d questionnaire, a non-disease-specific self-report instrument for measuring health-related qol. it consists of the eq-5d self-classifier and the eq-5d visual analogue scale ranging from 0 to 100 (8). patients classify their own health status in five dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. answers are given on a three point scale: 1 = no problems, 2 = moderate problems, and 3 = severe problems. theoretically, 243 health statuses could be generated by this classification. each health status can be given a value from -0.59 to 1.0 by means of the time-trade method developed for uk population (9). as incontinence does not impact on life expectancy, qaly was calculated for each patient by subtracting her age at the start of the study from the age-specific life-expectancy values relative to the general female population in the umbria region in 2010 (source istat, national institute of statistics) and then adjusted for eq-5d scores. no further or additional adjustment was done. two types of qaly was obtained as one is calculated on the basis of the descriptive self-classifier and the other on the vas scores. costs according to our regional legislation urodynamic tests are performed only in patients who are candidates for surgery and all the other tests and procedures are performed under an accurate spending review in order to contain costs as much as possible. direct costs, based on prices from the italian diagnosis related groups (drg), were calculated for: 1. diagnosis out-patient appointments and laboratory tests urodynamic testing (only in the surgery group) 2. treatment and/or prevention drug therapy (recommended pharmaceutical company prices) hospital stays in the ward and in the day hospital surgical intervention physiotherapy 3. the following costs could not be quantified in our study treatment for incontinence-related skin infections treatment for urinary tract infections these costs were derived from the arlandis-guzman study published on biomed central ltd. in 2011 (10). all costs are presented as mean costs evaluated in 2011. as the italian national health service does not cover the costs of anticholinergic therapy the astellas company kindly provided the 3 months supply to avoid patients stopping therapy because of the cost of the drugs. we expected to find that no single treatment was worse than any other (the null hypothesis) or that all treatments, though not to the same measure, reduced pad use and incontinence-related complications, thus lowering costs and providing a gain in qaly. statistical analysis preand postincontinence treatment data from the three intervention groups were analyzed using the wilcoxon non-parametric tests for paired discrete data. since the type of therapy varies with the nature of incontinence, our objective in this prospective cohort study was not to compare incontinence treatments but to determine whether each was cost-useful. all analyses were performed using ibm spss release 20.0.0, 2011, with significance level set at p ! 0.05. results from january 2010 to december 2011 gps identified 190 patients as suitable for recruitment to this study. archivio italiano di urologia e andrologia 2014; 86, 2 e. costantini, m. lazzeri, v. bini, a. zucchi, e. scarponi, m. porena 114 after a complete urogynaecological examination the senior urologist divided the patients into three groups according to the type and severity of incontinence. pelvic floor exercises were recommended for patients with mild sui, mid-urethral sling surgery for patients with moderate-severe sui, and anticholinergic therapy for patients with uui or mui with urgency as predominant symptom. figure 1 illustrates the enrolment process and the patients who were included in the study. thirty of the 190 patients were excluded: 10 because poor health status prevented routine check-ups or patients were unable to understand or respond to the questionnaires: 10 because of diabetes, oncological or neurological diseases; 5 in the anticholinergic drug therapy group because of contraindications and 5 because of associated low urinary tract symptoms (luts). of the remaining 160 patients, 50 were assigned to the surgery group, 67 to the physiotherapy group and 43 to the drug group. ultimately only 137/160 female patients (mean age 60.6 ± 11.6; range 36-81) gave written informed consent and were enrolled according to the ui type and severity. group a: sui grade ii-iii: 43 patients (mean age 61 ± 12; range 38-80 years) underwent mid-urethral sling (mus); 7/50 refused surgery. group b: sui grade i-ii 57 patients (mean age 66 ± 10; range 49-79 years) undertook a pelvic floor muscle exercise programme; 10/67 refused to participate and perform the exercises regularly for at least 3 months. group c: uui: 37 patients (mean age 58 ± 11; range 36-77 years) who underwent antimuscarinic treatment with solifenacin 5 mg; 6/43 refused drug therapy (3 because of constipation risk, and 3 because of undeclared personal reasons). no patients were lost during the 3 month follow-up, the principal reasons for not having any drop-outs were the relatively short follow-up and free supply of medication in the drug group. in the surgery and physiotherapy groups additional check-ups at 6 and 12 months confirmed the 3-month results. table 1 shows the estimated costs for each group. table 2 shows questionnaire scores and pad use before and after each treatment. scores improved significantly after treatment in all 3 groups. improvements were confirmed by the cost utility ratio (cur) assessment according to both sections of the eq-5d questionnaire (table 3). the cost was then modified to include pad use (table 4) and the cost of treating skin and urinary tract infections before and after treatment (table 5). estimated costs (!) surgery drug physiotherapy out-patient appointmentsa 33.06 33.06 33.06 urodynamic testing 56.81 uroflussimetry 11.62 11.62 11.62 drug therapyb 61.90 surgical interventionc 4324.00 physiotherapyd 204.58 pade 0.31 0.31 0.31 a: 2 appointments; b: recommended pharmaceutical company prices for 1 months of therapy; c: included hospital stay; d: 24 sessions; e: included waste disposal. table 1. estimated costs applied for each group. table 1. flow chart of patients’ distribution across the three different categories 115archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness surgery and physiotherapy were associated with strong savings for each qaly and drug treatment was linked to a very low cost per qaly. according to both the eq-5d index and the eq-5d vas, the cost utility ratio was estimated at a saving of more than "1200 per qaly for surgery and physiotherapy. drug therapy cost under "100 per qaly. since there are no italian threshold values per qaly,we referred our findings to what the uk nice proposed. according to nice, costs are commonly classified as acceptable up to "30000 per qaly, as possibly acceptable between "30000"45000 per qaly and rejected over "45000 (11). discussion we found that in an italian regional setting appropriate diagnosis and treatment of incontinence may lower national health service costs and improve the benefits of treatment and quality of life. all interventions for incontinence showed a cost per qaly far below the acceptable cut-off according to nice (10). over the past 25 years, health and medical services have become a major part of our economy. applying economics to medical practice does not necessarily mean that less can or should be spent. instead, the underlying belief is that resources should be allocated to treatments that maximize social welfare (4). cost-benefit analyses inform decision makers about how to allocate resources to maximize societal well-being within a limited budget there are different typologies or frameworks for categorizing costs in health care e.g. direct, indirect and intangible costs. direct costs for incontinence include diagnosis, treatment, routine care, (including cost of absorbent type of intervention iiq score iiq score udi score udi score eq-5d eq-5d eq-5d vas eq-5d vas pads pads pre* post* pre* post index pre* index post pre* post* pre* post surgery n 43 43 43 43 43 43 43 43 43 43 median 37 0 20 0 0.59 1 25 90 6 0 minimum 4 0 3 0 -0.17 0.74 10 70 1 0 maximum 65 6 51 4 0.59 1 45 100 15 1 mean 35.37 1.00 22.47 0.28 0.45 0.95 26.42 88.67 6.35 0.05 std. deviation 15.99 1.91 10.05 0.91 0.25 0.08 11.00 5.61 3.04 0.21 drug n 37 37 37 37 37 37 37 37 37 37 median 31 0 21 0 0.59 1 21 90 3 0 minimum 9 0 3 0 0 0.76 11 80 1 0 maximum 48 6 51 3 0.59 1 45 90 7 2 mean 31.38 1.15 24.46 0.62 0.43 0.93 23.08 88.77 3.31 0.38 std. deviation 12.83 2.23 13.15 1.19 0.28 0.11 11.04 2.86 1.60 0.65 physiotherapy n 57 57 57 57 57 57 57 57 57 57 median 28 0 19 0 0.59 1 22 90 2 0 minimum 8 0 3 0 -0.005 0.79 10 70 0 0 maximum 48 6 51 4 0.59 1 45 100 10 2 mean 27.02 0.65 20.96 0.14 0.40 0.96 24.86 88.44 2.54 0.46 std. deviation 10.79 1.56 10.18 0.61 0.21 0.09 10.79 5.07 1.83 0.68 * p < 0.0001 pre vs post in overall type of intervention groupsof therapy; c: included hospital stay; d: 24 sessions; e: included waste disposal. table 2. questionnaire scores and the pad use before and after each type of therapy. cost-utility ratio surgery drug physiotherapy eq-5d index 702 (582; 851) 1453 (1026; 2438) 35 (30; 42) eq-5d vas 560 (486; 651) 1149 (875; 1674) 28 (25; 32) table 3. cost-utility ratios (cur) with 95%ci expressed in euros as the cost of each qaly, according to both sections of the eq-5d questionnaire and treatment. cost-utility ratio surgery drug physiotherapy eq-5d index -735 (-609; -890) 995 (703; 1701) -610 (-529; -732) eq-5d vas -586 (-509; -681) 787 (599; 1147) -494 (-444; -563) table 4. change of the cur (!) when pad use is factored in cost-utility ratio surgery drug physiotherapy eq-5d index -1677 (-1390; -2031) 87 (62; 149) -1519 (-1317; -1822) eq-5d vas -1337 (-1161; -1553) 69 (52; 100) -1229 (-1104; -1402) table 5. cur including the cost of treating skin and urinary tract infections before and after treatment (estimated from published reports) (9). archivio italiano di urologia e andrologia 2014; 86, 2 e. costantini, m. lazzeri, v. bini, a. zucchi, e. scarponi, m. porena 116 pads which, is one of the largest items), incontinencerelated consequences such as fractures from falls, nursing home admissions and uti (12). however the causal link between iu and its consequences is less clear. indirect costs are the value of lost productivity or lost employment due to morbidity (lost productivity and fewer hours of productive work). intangible costs are the monetary value of pain and suffering. the present study included only direct costs because they are easier to assess. costs of incontinence-related consequences were derived from a spanish study in 2011 (10). costs can also be categorized by type or by perspective (i.e who bears the cost: provider, society, patient etc.). cost/utility, cost benefit and cost effectiveness analysis use the perspective category. in a cost of illness analysis (coi) analysis no attempt is made to measure the “value” of treatment while cost-utility and cost -benefit analysis address this particular issue. cost effectiveness analysis (cea) refers to the broad class of calculations where the effectiveness measure is a general health outcome. in studies on incontinence cea focused on strategies for nursing home management (13-14), compared surgical techniques for stress incontinence (15-16), assessed pharmacological therapy of urgency incontinence and overactive bladder (17). two studies using the perspective of the health care system (16, 18) provided evidence that trans-vaginal tape (tvt) is better than colposuspension although it remains unclear if the results would have been different if lifetime costs and benefits had been assessed and if a societal perspective had been included. there are many limitations to cea and there has been widespread convergence on the use of qalys as the preferred health outcome in cost-effectiveness analysis. since the cua is the gold standard in medicine (4) it was used in the present study. it refers to cea using qalys as the outcome measure: qalys denote the relationship between the value of a given health state and the length of time a person lives in that health state. the value of a given health state is measured in “utilities” which represent preferences for a given health state. the present study demonstrated that mid-urethral slings provided considerable savings ranging from 1337 to 1677 " per qaly, in patients with moderate-severe stress urinary incontinence as did physiotherapy in patients with mild stress urinary incontinence, which saved from 1229 to 1519 ". these data confirm that appropriate diagnosis and treatment of incontinence lower national health service costs and clearly improve the benefits of treatment and quality of life. a small but growing area of research has found that urinary incontinence and overactive bladder are associated with important and costly consequences (3) that can have a large impact on costs, morbidity, quality of life and mortality. arlandis-guzman s et al. compared the economic value of overactive bladder (oab) treatment with fesoterodine and extended release tolterodine and solifenacin from the social perspective (9). their results were not comparable with ours because our study did not compare treatments as our aim was to evaluate the cost-utility of each treatment by examining costs and quality-adjusted life years. however, even though our drug treated group was small in number, the present study demonstrated that anti-cholinergic therapy with solifenacin was linked to a much lower cur than 30,000" which the nice adopted as the cost-useful threshold per qaly gained (11). although the cost per qaly appears highly reasonable (less than 100 "), reasons other than cost have to be taken into account before recommending this regimen to patients. furthermore intermittent treatment may be suitable for some cases but needs in depth investigation to assess costs. finally, variations in the cost of drugs from country to country becomes a pressing problem when the national health service does not fund the medication. the major strength of the present study is that clinical research data derived mainly from gp referrals to the national health service urology unit in perugia general hospital. the entire cohort constitutes a representative sample from national health service records in a small region with no private medicine, meaning that all patients could be traced. even though it might be objected that our evaluation is restricted to one italian region and that costs as calculated in this paper would be completely different for each item (pads, surgery) in another healthcare system, we are of the view that umbria provides a good example of a national health service model, which could be translated to other areas. although gp referrals should have ensured matched groups, groups were not in fact matched as allocation to a treatment option depended upon the type and severity of incontinence. surgery, for example, was reserved for the worst cases. in the patients who underwent surgery we had no surgical complications and were unable to assess the costs of possible re-treatments due to the relatively short follow-up (1 year). however, data on midurethral sling outcomes confirm durability (19, 20) and low complication rates (21). other limitations of the present study are lack of a “usual care” arm in which either effectiveness or costs are modeled for comparison, the absence of perspective/ model, secondary effects, and inability to quantify the prevalence, and costs of treating, skin and urinary tract infections in our patients. in fact we had to resort to published reports for these figures. we were also unable to quantify the number, and treatment costs of episodes of depression. therefore these three groups differed in incontinence severity and life expectancy. the costs of other pathologies and incontinence-related personal hygiene are unknown but probably similar in all three groups, though conceivably higher in patients who underwent surgery as they were affected by the most severe incontinence. despite these differences drug therapy emerged as costing more than surgery and physiotherapy. future investigations will have to attempt to create more homogeneous groups on age and life expectancy grounds. for ethical reasons severity of incontinence can never be uniformly distributed across groups. finally, in a certain percentage of patients incontinence is so severe that no treatment has any chance of success. the natural history of ui is not well understood but if it worsens over time, then rather than waiting until it becomes severe before starting therapy. early stage e.g. mild to moderate iu diagnosis and treatment would reduce national health service costs. 117archivio italiano di urologia e andrologia 2014; 86, 2 female urinary incontinence: cost utility ratios and effectiveness conclusions this study shows that appropriate diagnosis and treatment of a patient with incontinence lowers national health service costs and clearly improves the benefits of treatment and quality of life. references 1. hunskaar s, burgio k, diokno a, et al. epidemiology and natural history of urinary incontinence in women. urology. 2003; 62:suppl 1:s16-23. 2. thom d. variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics and study type. j am geriatr soc. 1998; 46:473-80 . 3. foxman b. epidemiology of urinary tract infections: incidence, morbidity, and economic costs. dis mon. 2003; 49:53-70. 4. the-wei hu, th wagner, g hawthorne, et al. economics of incontinence in incontinence abrams p, cardozo l, kohury s and wein a (eds),health publication ltd, plymouth (uk) 2002; 14:965. 5. gold m, siegel je, russell l, weinestein mc. (eds). cost-effectiveness in health and medicine. oxford university press, oxford. 1996. 6. ingelman sunderberg a, ulmsten u. surgical treatment of female urinary stress incontinence. contrib gynecol obstet. 1983; 10:51-69. 7. campbell mk, torgenson dj. bootstrapping: estimation confidence intervals for cost-effectiveness ratios. q j med. 1999; 92:177-82. 8. euroqolgroup: euroqol-a new facility for the measurement of health related quality of life. health policy. 1990; 16:199-208. 9. dolan p. modeling valutations for euroqol health states. med care. 1997; 35:1095-108. 10. arlandis-guzman, et al. cost-effectiveness analysis of antimuscarinics in the treatment of patients with overactive bladder in spain: a decision-tre model. bmc urology. 2011; 11:9. 11. national institute for health and clinical excellence (2012). guide to the methods of technology appraisal. http://www.nice.org.uk/media/ cb1/43/guidetomethodsoftechnologyappraisal2012 12. darkow t, fontes cl, williamson te. costs associated with the management of overactive bladder and related comorbidities. pharmacotherapy. 2005; 25:511-9. 13. schnelle jf, keeler e, simmons d, ouslander, et al. a cost and value analysis of two interventions with incontinence nursing home residents. j am geriatr soc. 1995; 43:1112-7. 14. hu tw, kaltreider dl, igou lc, rohner tj. cost effectiveness of training incontinent elderly in nursing homes: a randomized clinical trial. health serv res. 1990; 25:455-77. 15. ramsey sd, wagner th, bavendam tg. estimating costs of treating stress urinary incontinence in elderly women according to the ahcpr clinical practice guidelines. am j man care. 1996; 2:147-54. 16. manca a, sculpher mj, ward k, hilton p. a cost-utility analysis of tension-free vaginal tape versus colposuspension for primary urodynamic stress incontinence. bjog. 2003; 110:255-62. 17. o’brien bj, goeree r, bernard l, , et al. cost-effectiveness of tolterodine for patients with urge incontinence who discontinue initial therapy with oxybutinin: a canadian perspective. clin ther. 2001; 23:2038-49. 18. quievy a, couturier f, prudohn c, et al. economic comparison of 2 surgical techniques for the treatment of stress urinary incontinence in women: burch’s technique versus the tvt technique. prog urol. 11: 347-53. 19. albo me, litman hj, richter e, et al. for the urinary incontinence treatment network. treatment success of retropubic and transobturator mid urethral slings at 24 months. j urol. 2012; 188:2281-7. 20. porena m, costantini e, frea b, et al. tension-free vaginal tape versus transobturator tape as surgery for stress urinary incontinence: results of a multicentre randomised trial. eur urol. 2007; 52:1481-1490. 21. novara g, artibani w, barber md, et al. updated systematic review and meta-analysis of the comparative data on colposuspensions, pubovaginal slings, and midurethral tapes in the surgical treatment of female stress urinary incontinence. eur urol. 2010; 58:218-38. correspondence elisabetta costantini, md massimo lazzeri, md alessandro zucchi, md (corresponding author) azucchi@unipg.it emanuele scarponi, md massimo porena, md department of medical-surgical specialties and public health urology and andrology section, ospedale s. maria della misericordia loc. s. andrea delle fratte 06100 perugia, italy vittorio bini, md department of internal medicine, university of perugia, perugia, italy introduction the pelvic floor is a complex multifunctional structure made of both muscular and tendineus components. in fact, in addition to providing support to the pelvic organs, the pelvic floor muscles active the peripheral mechanisms of urinary and fecal continence and the evacuation facilitators (1). so, pelvic floor has an important role in the control of bowel and bladder functions. besides this, recently it is emerging the importance of pelvic floor muscles (pfm) on male and female sexual function. in the male, in particular, have been highlighted the ways in which contractions/relaxation of pfm are involved in the mechanisms of erection (2) and ejaculation (3). on this basis, it was postulated that some changes in erectile and ejaculatory function may be secondary to anatomical and functional perineal muscles alterations. finally, and most recently, it has been shown that some algic phenomena evoking symptoms due to an inflammatory prostato-vesicular process, can be supported by functional alteration of the pfm (4). the symptoms of dysfunction of pelvic floor muscles 1archivio italiano di urologia e andrologia 2013; 85, 1 review pelvic floor and sexual male dysfunction antonella pischedda 1, ferdinando fusco 2, andrea curreli 1, giovanni grimaldi 2, furio pirozzi farina 1 1 azienda ospedaliera universitaria di sassari, italy; 2 azienda ospedaliera universitaria federico ii di napoli, italy. the pelvic floor is a complex multifunctional structure that corresponds to the genito-urinary-anal area and consists of muscle and connective tissue. it supports the urinary, fecal, sexual and reproductive functions and pelvic statics. the symptoms caused by pelvic floor dysfunction often affect the quality of life of those who are afflicted, worsening significantly more aspects of daily life. in fact, in addition to providing support to the pelvic organs, the deep floor muscles support urinary continence and intestinal emptying whereas the superficial floor muscles are involved in the mechanism of erection and ejaculation. so, conditions of muscle hypotonia or hypertonicity may affect the efficiency of the pelvic floor, altering both the functionality of the deep and superficial floor muscles. in this evolution of knowledge it is possible imagine how the rehabilitation techniques of pelvic floor muscles, if altered and able to support a voiding or evacuative or sexual dysfunction, may have a role in improving the health and the quality of life. key words: pelvic floor; physical therapy; sexual dysfunction; pelvic floor dysfunction. submitted 18 march 2013; accepted 30 march 2013 no conflict of interest declared summary were divided into 5 groups by ics (table 1). in this evolution of knowledge it is possible to imagine how the rehabilitation techniques of pfm, if altered and able to support a voiding or evacuative or sexual dysfunction, may have a role in improving the health and the quality of life (6). nevertheless, it would seem that the approach to pelvic floor disease related dysfunction is still performed only from a restricted medical group and stenting to become well established in urologists’ routine clinical practice. this article will get closer to the uro-andrologist intriguing possibilities offered by a better understanding of the correlation between pelvic floor dysfunction and male sexual dysfunction. anatomy and physiology of the pelvic muscles of male the differences between male and female urogenital anatomy, also mark some anatomical and functional difpirozzi ok_stesura seveso 18/04/13 10:56 pagina 1 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 2 ferences of the muscle-tendon complex that forms the pelvic floor. that said, in both sexes the pelvic floor muscles are equal and symmetrical and form the pelvic diaphragm that covers the pelvic cavity from the front portion to the rear. the diaphragm supports the bladder and the rectum and is on two levels: the deep and superficial one (1) (figures 1-2). the deep muscles of the plan can be represented in two layers: the outer layer, represented by pubo-coccygeal muscle, ileum-coccygeal and ischium-coccygeal, the inner layer is represented by the pubo-rectalis muscle. the muscles pubo-coccygeal (pc), pubo-rectalis and ischio-coccygeal form a functional unit known as the levator ani muscle (lam). the pelvic diaphragm is completed, posteriorly, by ilio-coccygeal and ischio-coccygeal muscles. the superficial floor musculature is made up of the bulbo-cavernous, ischio-cavernous, external sphincter and superficial transverse perineal muscle (figure 3). this muscle floor plays an important role in erectile function, ejaculation and in the anal sphincter mechanism. the activity of the pc muscle expresses the overall functionality of the lam which is a good measure of definition of the pelvic floor muscles activity as a functional whole. for this reason, through the pc functional study, it is possible implement a reliable diagnostic and therapeutic approach to disorders of the pfm. the pfm is constituted, for approximately two thirds, by table 1. symptoms of pelvic floor muscles dysfunction. 1.1. low urinary tract syntoms • urinary incontinence • frequency/urgency • poor or intermittent stream initiated or supported by muscular effort • hesitancy • terminal dribbling • incomplete voiding 1.2. bowel syntoms • obstructed defecation • constipation • fecal incontinence • rectal/anal prolapse 1.3. vaginal syntoms • pelvic organ prolapse 1.4. sexual function • in women: dyspareunia • in the male: erectile dysfunction and ejaculatory disorders • both: orgasmic dysfunction 1.5. pain • pelvic pain • cronic pelvic pain syndrome (cpps) figure 1. pelvic diaphragm of male inferior view. pirozzi ok_stesura seveso 18/04/13 10:56 pagina 2 3archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction figure 2. pelvic diaphragm of male – inferior view – viscera removed. figure 3 perineum and external genitalia of male – deep dissection. pirozzi ok_stesura seveso 18/04/13 10:56 pagina 3 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 4 slow twitch fibers (type 1) and for about one third of fast-twitch fibers (type 2) (7). slow twitch fibers are stably in a tonic contraction and this muscle tone allows the pfm to support the pelvic organs (7). the sphincteric muscles, including the periurethral, consists of fibers of type 1 and 2 since it must fulfill a dual function: increasing the urethral endurance during the period of raised intra-abdominal pressure (fiber type 1) and the voluntary control of sphincters (fiber type 2) (8). schemes of use of the pelvic floor muscles pfm usage patterns are acquired in childhood and scheduled in cerebral mechanism. afferent stimuli generated by the voiding and sexual apparatus determine a central processing aimed the most appropriate response model of the pfm (10). in this way, in the course of its growth, people gradually learn to “hold” urination, feces and intestinal gas, but also to modulate the relaxation and contraction of the pelvic muscles to handle in the best way the ejaculation. these capabilities are in part related to adequate corticalization of the pfm and, overall, to the efficiency of muscle tone. so, conditions of muscle hypotonia or hypertonicity may affect the efficiency of the pelvic floor, altering both the functionality of the deep and superficial floor muscles. while the alterations of the deep floor muscles may determine effects on urinary continence and intestinal emptying, the alterations of the superficial floor muscles may affect the quality of the erection and ejaculation . in fact it is only under conditions of optimal tonicity that these muscles perform compressive action necessary to avoid the outflow of blood from the crura (m.ischio-cavernous) (1) and the periurethral glans along the spongiosa (m. bulbo-cavernous). with regard to erectile function, grace dorey (2000) conducted a review of the literature showed that the efficiency of the pfm is higher in powerful men than those affected by erectile dysfunction (ed) (11). the hypertonicity of the pelvic floor muscles in cases in which the pfm is chronically incorrectly used, for example when the subject takes the habit of delaying urination or defecation voluntarily by contracting the pelvic musculature, you can establish special patterns chronic pelvic floor summarized under the term “hypertonic” (1). other dysfunctional patterns are those resulting from unsuitable activation in voiding phase of perineal muscles. in these cases, the muscle groups most frequently involved are the abdominal muscles, the diaphragm, the adductors and gluteal muscles (12). when this happens, frequently are established perineal muscular synergies that can be of either agonist or antagonist kind (13). in the agonists synergies, in conjunction with the levator ani contraction, it determines the activation of the adductor muscles and buttocks; in antagonistic synergies, levator ani simultaneously activates the abdominal muscles and the diaphragm (13). the causes of dyssynergia can be congenital or acquired (10). as a congenital cause, has been suggested a poor perineal region corticalization (10). among the acquired causes, first of all, behavioral causes. then, reduced pelvic floor muscles efficiency and the psychological cause (10). in case of activation of the abdominal press, it is established a hypertonic reflection of the pfm that expresses a condition of antagonist muscolar synergism (4). over the time, incongruous patterns of emptying and a state of chronic contraction of the pfm will also involve the anorectal system and ischiocavernous and bulbo-cavernous muscles (4). in more severe cases, the antagonist synergy may increase up to become a dyssynergia. this happens when patient, rather than activate the levator ani muscle, only contracts the abdominal muscles, taking a particular pattern called “inversion of perineal control” (12). in addition, since superficial floor muscles form a functional whole with deep floor ones, the hypertonicity of the pfm and the dyssynergia may come to represent a correlation factor between functional urological alterations and some types of sexual dysfunction (1). in this way it can be caused, or aggravate, premature ejaculation. as regards erectile function, ischio-cavernosa muscle hypertonicity, however it is to determine, may support a reduction of volume expansion capacity of the roots of the corpora cavernosa with consequent reduction of the maximum rigidity. the hypotonia of the muscles of the pelvic floor the condition of hypotonia of the pfm is less frequent in men than in women, in which pregnancy and vaginal delivery (especially in multiparous), obesity, aging and, more discussed, menopausal characteristic hormonal changes (14) are also risk factors of dysfunction (15). although the condition of the pfm hypotonia may have a neurogenic, (1) malformative (16) and iatrogenic postsurgical cause (1). in the male tissue aging-associated changes are the most common cause of muscular hypotonia. this assertion is supported by the finding that the efficiency of the pfm decreases with aging and aging self correlates with an increase of ed (11). this is because with aging, the number of muscle fibers reduces and collagen undergoes both qualitative and quantitative changes, involving muscle bulboand ischio-cavernous hypotonia, and consequently changes in the cavernous veno-occlusive mechanism and post-void dribbling. (17) in support of this, strasser et al. (1997), in a study on human rabdomiosphincter, found a positive correlation between age progression and quantitative decrease of striated muscle fibers so that, in this muscle, fibers are represented as follows: 79% in childhood and 35% at 85 years (18). finally, although in the literature there is still not accordance, it would appear that both the pfm hypotonus and the hypertonicity can support a premature ejaculation, in these cases secondary to reduced efficiency of perineal contraction/decontraction mechanisms having a role in the control of the ejaculatory reflex (1). the clinical evaluation of pelvic floor the pfm correct functionality is linked to its normal morphological development and the integrity of its neuro-vascular component. subject to these assumptions, muscle assessment must define the tone, strength, endurance and fatigue of the pfm. after verifying the pirozzi ok_stesura seveso 18/04/13 10:56 pagina 4 absence of dysfunctional pattern of activation of the pfm, these assessments can be performed manually, introducing a flexed finger hooked in the anal canal or by kinesiological electromyography (emg). with these methods it is possible to detect the fasic strength and various tonic expressions of the strength of the pubo-coccygeal muscle (pc test). emg offers the advantage of measuring the actual muscle activity in microvolts, although the high cost of the equipment makes the technique not common (1). it should be noted, however, that the instrument by which is performed the kynesiological emg is advantageously used also as electromyographic biofeedback, in order to implement a physical therapy aimed at helping patients to optimize their muscles activity (20). the digital rectal evaluation is used to assess the symmetry and balance of muscles that can be explored with this method, differentiating muscle able to close (puborectalis and external anal sphincter) and muscles able to lift (pubococcygeus and ilealcoccygeus) (1). in the male, intra-anal palpation is therefore considered an appropriate sensitive method to assess the strength and tone of the pelvic floor muscles (1). physical therapy of sexual dysfunction secondary to the pelvic floor muscle dysfunction physical therapy of sexual dysfunction secondary to pelvic floor alteration, still lacks of unique and validated benchmark. however, physiotherapeutic treatment will have to be modulated, qualitatively and quantitatively, as a function of the objectives that were set in agreement with the patient and the results obtained progressively. academically, physical therapy is divided in two stages: the educational and rehabilitative in the strict sense. the educational stage is a preparation for the rehabilitation phase. it must provide, in a clear and simple information about the anatomy and physiology of the pelvic floor. the rehabilitation phase has the aim of improving the dysfunctional phenomenology reported by the patient. it is structured according to a treatment plan tailored to suit the type of detected pelvic dysfunction. the main objectives of physical therapy are raise awareness and proprioception of the muscles; discrimination and improve muscle relaxation; normalize muscle tone (25). to pursue these objectives, physiotherapy may use tools such as the electromyographic biofeedback, functional electrical stimulation and pelvic-perineal physiotherapy (25). of all the physiotherapy treatments, biofeedback is only reported in controlled studies (25). electromyographic biofeedback the electromyographic biofeedback is an equipment capable of providing information on the activity of a muscle district, so the patient can re-act and change it (12). takes place via a rectal emg probe associated with surface electrodes. using digital electronic interface connected to a computer, a video with a simplified graphic expresses, real time, electromyographic activity detected (12). in this way the patient highlights, and is able to influence muscular activity escaped from his cortical control mechanisms, or knowingly to put to work the muscle under examination in order to improve the phase and/or the endurance, implementing a kind of “competition” with the machine (12). functional electrical stimulation (fes) the electrical stimulation can be applied directly to the muscle or indirectly, through the stimulation of the n.pudendal fibers (12). usually is performed using indirect stimulation that through the n.peripheral depolarisation generates a nerve impulse that causes muscle contraction (12). administered therapeutically, these contractions help to increase muscle strength using the same mechanisms of exercise therapy. these result in two effects: the facilitation of voluntary movement of the treated muscle group and the improvement of neuromotor control (12). for these reasons, we talk about functional electrical stimulation (fes) for rehabilitation (12). contraindications to the sef are: the perineal complete denervation, the vu reflux, the cardiac pacemaker and urinary infections (12). it is used a biphasic current, 10 to 50hz. ! 50ma x 0.2msec. pelvic-perineal physiotherapy (pelvic floor muscle training or pfmt) the pfmt is the first therapeutic approach to be implemented in the home, after the patient has performed an adequate training learning (26). a good treatment schedule is applyng 1 hour treatment starting from 2 times per week and up to 4 months, then customizing the sessions in function of the results obtained progressively (27). pelvic floor rehabilitation therapy in male sexual dysfunction erectile dysfunction the pelvic floor muscle is involved in the increased intra-cavernous pressure. in fact, as reported above, the activity of the ischiocavernosus muscle facilitates erection while the contraction of the bulbocavernosus muscle slows the venous drainage from the corpora cavernosa, exerting pressure on the deep dorsal vein of the penis (1). this implies that, in case of hypotonia of the pfm can be established erectile dysfunction with venoocclusive mechanism. this can benefit significantly from the physical rehabilitation therapy of the pelvic floor, which aims to increase strength and muscle tone and improve the fatiguability (17, 28). by contrast, in the case of hypertonia of the superficial pelvic floor, and in particular of the cavernosa muscles, the possible reduction of the maximum stiffness that may occur due to a reduction of the expansion volume capacity of the corpora cavernosa roots, can benefit from appropriate therapy with electromyographic biofeedback associated with functional electrical stimulation (1). premature ejaculation clinical trials were conducted in which the ep was treated with different rehabilitation therapy of the pelvic floor (3, 29). pear & g, nicastro a (1996) published that 61% of their patients with pe, reported greater ability to control 5archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction pirozzi ok_stesura seveso 18/04/13 10:56 pagina 5 archivio italiano di urologia e andrologia 2013; 85, 1 a. pischedda, f. fusco, a. curreli, g. grimaldi, f. pirozzi farina 6 the ejaculatory reflex after 15-20 sessions of rehabilitation therapy of the pelvic floor (29). the rehabilitation protocol adopted by these authors included the pelvic-perineal physiotherapy, electrical stimulation and intra-anal electromyographic biofeedback with anal probe (29). actual mechanism that would improve the control over the ejaculatory reflex is not clearly evident. a better management of the pelvic floor may increases awareness of this poorly corticalized area, thus improving its sense of control. according to authoritative authors, during sexual activity, pleasure felt is amplified in both partners, from genital answers provided by the levator contraction (30). in particular, in women, the contractions would be supported by a production of myotonic m. pubo-coccygeal contraction that discharge during orgasm (31). the proposed mechanism for which the active control of the musculature of the pelvic floor may delay its beginning, can be related to the inhibition of the reflex ejaculation by means of an intentional relaxation of the muscles bulbocavernosus and ischiocavernosus during arousal (1). this is a clever technique that can be learned well by using biofeedback. sexual problems post-surgery another potential of pelvic floor rehabilitation therapy, is the treatment of some cases of erectile dysfunction (ed) and/or urinary incontinence (ui) that may occur, sometimes as a complication of surgery for radical prostatectomy. voiding and sexual iatrogenic post-surgical dysfunction, may also occur in other types of pelvic-perineal surgery in both men and women. the exact incidence of sexual dysfunction resulting from surgical pelvic-perineal procedures is not exactly known. there are, in fact, few randomized controlled trials comparing different surgical techniques in voiding function of relapses and, above all, the sexual ones (32). it is true that the ui and ed secondary to prostatectomy and pelvic-perineal surgery, can benefit from rehabilitation therapy of the pelvic floor muscles and, in particular, the use of electromyographic biofeedbeck (33, 34). these results would seem to provide additional capabilities to physical therapy rehabilitation. this provided that it is left over a sufficient amount of muscle tissue on which to operate with such therapeutic methods. chronic pelvic pain the male chronic pelvic pain syndrome (cpps) is frequently associated with sexual dysfunction. these, when present, can be expressed in various manifestation: de, ep, painful erection or, finally, painful orgasm. in a study conducted on 66 patients with turkish cpps, ep had 51 (77.3%), and 10 (15.2%) had ep associated with ed (35). chronic prostatitis-chronic pelvic pain syndrome (cpcpps), has traditionally been associated with infectious causes or inflammation of the accessory glands, especially the prostate. in many cases, however, is difficult to document the inflammation pathogenesis. many causes can simulate cp-cpps symptoms such as musculoskeletal pain, dysfunction of the pelvic floor muscles, myofascial syndrome or functional somatic syndromes (36). a study of dc hetrick (2006) comparing the pelvic floor muscles electromyography of patients with chronic pelvic pain with those of normal subjects, reported that men with pelvic pain show a tapered unstable pelvic muscles than those of normal controls (37). the same study concluded that the electromyography of the pelvic floor muscles, can be a valuable screening tool to identify patients with cp-cpps who may benefit from a treatment aimed at correcting the dysfunction of the pelvic floor muscles, if this was present (37) as evidence of this, it was verified that the treatment of pelvic floor muscles with electromyographic biofeedback is an effective therapeutic method when applied to men with cp-cpps (38, 39). conclusions sexual dysfunction is usually given by more than one factor, and certain components, biological, psychosocial and relational may contribute to dysfunction in men and women. among the many factors involved in sexual dysfunction, pelvic floor seems to have an important role. in conclusion, the treatment of male chronic pelvic pain should also considers physiotherapy techniques that include physical therapy, therapeutic exercises, electrical stimulation and bfb. in this review of the literature on the effectiveness of each technique in the treatment of sexual dysfunction in men and women is revealed that treating pelvic dysfunction may improve sexual health and quality of life. further randomized controlled trials are needed to validate the success of physical therapy. references 1. rosenbaum ty. pelvic floor involvement in male and female sexual dysfunction and the role of pelvic floor rehabilitation in treatment: a literature review. j sex med. 2007; 4:4-13. 2. dorey g, speakman m, feneley r, et al. randomised controlled trial of pelvic floor muscle exercises and manometric biofeedback for erectile dysfunction. british br j gen pract. 2004; 54:819-25. 3. piediferro g, colpi em, castiglioni f, scroppo fi. premature ejaculation. 3. therapy. arch ital urol androl. 2004; 76:192-8. 4. zermann dh, ishigooka m, doggweiler r, schmidt ra. chronic prostatitis: a myofascial pain syndrome infect urol. 1999; 12:84-92. 5. messelink b, benson t, berghmans b, et al. standardization of terminology of pelvic floor muscle function and dysfunction. report from the pelvic floor clinical assessment group of the international continence society. neurourol urodyn. 2005; 24:37480. 6. g. dorey. conservative treatment of male urinary incontinence ad erectile dysfunction. whurr publishers ed. london and philadelphia. 2001; 11-20. 7. gosling ja, dixon js, critchley hod, thompson sa. a comparative study of the human external sphincter and periurethral levator ani muscle. british journal of urology. 1981; 53:35-41. 8. delancey l. functional anatomy of the pelvic floor and urinary continence mechanism. in b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice (3nd edn). springer-verlag. london, 2000; 9-23. 9. wespes e, nogueira mc, herbaut ag, et al. role of the bulbocavernous muscles on the mechanism of human erection. european urology 1990; 18:45-48. pirozzi ok_stesura seveso 18/04/13 10:56 pagina 6 10. zermann dh, ishigooka m, wunderlich h, et al. a study of pelvic floor function preand postradical prostatectomy using clinical neurourological investigations, urodynamics and electromyography. eur urol. 2000; 37:72-8. 11. dorey g. conservative treatment of erectile dysfunction. 3: literature review. br j nurs. 2000; 9:859-63. 12. di benedetto p. valutazione neuro-fisiatrica perineale. in: di benedetto p (ed). riabilitazione uro-ginecologica (2nd edn). torino, minerva medica. 2004; 99-103. 13. di benedetto p. il bilancio muscolare perineale. in: di benedetto p (ed.). riabilitazione uro-ginecologica. torino, minerva medica. 1995; 63-70. 14. sayer t, smith t. pelvic floor biopsy in: b. schüssler, j. laycock, pa. norton, sl. stanton (eds.) pelvic floor re-education (3nd edn). springer-verlag. london, 2000; 98-101. 15. gilpin sa, gosling ja, smith arb, warrell dw. the pathogenesis of genitourinary prolapse and stress incontinence of urine. a histological and histochemical study. br j obstet gynaecol. 1989; 96:15-23. 16. debus-thiede g. magnetic resonance imaging (mri) of pelvic floor. in b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice. (3nd edn). london, springer-verlag. 2000; 78-82. 17. van kampen m, de weerdt w, claes h, et al. treatment of erectile dysfunction by perineal exercise, electromyographic biofeedback, and electrical stimulation. phys ther. 2003; 83:536-43. 18. strasser h, steinlechner m, bartsch g. morphometric analysis of the rhabdosphincter of the male urethra. j urol. 1997; 157(suppl 4):177-180. 19. wang c, swerdloff rs, iranmanesh a, et al. transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. j clin endocrinol metab. 2000; 85:2839-2853. 20. o'donnel pd, doyle r. biofeedback therapy technique for treatment of urinary incontinence. urology. 1991; 37:432-436. 21. laycock j. clinical evaluation of the pelvic floor. in b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice (3nd edn). springer-verlag. london, 2000; 42-48. 22. wilmore j, costill d. physiology of sport and exercise. (2nd edn). human kinetics, champaign; illinois, 1999. 23. mansoor a, jacquetin b, ohana m. evaluation des facteurs de l’incontinence urinaire féminine et indications thérapeutiques. ann. urol. 1993; 27:292-305. 24. vodusek d. electrophysiology. in: b. schüssler, j. laycock, p norton and s. stanton (eds). pelvic floor re-education. principles and practice (3nd edn). springer-verlag. london, 2000: 83-97. 25. rosenbaum ty. physiotherapy treatment of sexual pain disorders. j sex marital ther. 2005; 31:329-340. 26. p. abrams, s. khouri, a. wein. incontinence. 1st international consultation on incontinence. paris:health publication limited, 1999. 27. cornel eb, van haarst ep, schaarsberg rw, geels j. the effect of biofeedback physical therapy in men with chronic pelvic pain syndrome type iii. eur urol. 2005; 47:607-611. 28. claes h, baert l. pelvic floor exercise versus surgery in the treatment of impotence. br j urol.1993; 71:52-7. 29. la pera g, nicastro a. a new treatment for premature ejaculation: the rehabilitation of the pelvic floor. j sex marital ther. 1996; 22:22-6. 30. shafik a. the role of the levator ani muscle in evacuation, sexual performance, and pelvic floor disorders. int urogynecol j pelvic floor dysfunct. 2000; 11:361-76. 31. komisaruk br, whipple b. physiological and percentual correlates of orgasm produced by genital or non-genital stimulation. in: p. kothari (ed) the proceedings of the first international conference on orgasm. parthenon press, england, 1991. 32. achtari c, dwyer p. sexual function and pelvic floor disorders. best prac res clin obstet gynaecol. 2005; 19:993-1008. 33. lewis rw, fugl-meyer ks, bosch r, et al. epidemiology/risk factors of sexual dysfunction. j sex med. 2004; 1:35-39. 34. lue tf, giuliano f, montorsi f, et al. summary of the recommendations on sexual dysfunctions in men. j sex med. 2004; 1:6-23. 35. gonen m, kalkan m, cenker a, ozkardes h. prevalence of premature ejaculation in turkish men with chronic pelvic pain syndrome. j androl. 2005; 26:601-3. 36. potts jm. chronic pelvic pain syndrome: a non prostatocentric perspective. world j urol. 2003; 21:54-6. epub 2003. review. 37. hetrick dc, glazer h, liu yw, et al. pelvic floor electromyography in men with chronic pelvic pain syndrome: a case control study. neurourol urodyn. 2006; 25:46-9. 38. cornel eb, van haarst ep, schaarsberg rw, geels j. the effect of biofeedback physical therapy in men with chronic pelvic pain syndrome type iii. eur urol. 2005; 47:607-11. 39. yezq, cai d, du lan rzgh, et al. biofeedback therapy for chronic pelvic pain syndrome. asian j androl. 2003; 5:155-8. 7archivio italiano di urologia e andrologia 2013; 85, 1 pelvic floor and sexual male dysfunction correspondence ferdinando fusco, md (corresponding author) azienda ospedaliera universitaria federico ii di napoli ferdinando-fusco@libero.it antonella pischedda, md andrea curreli, md furio pirozzi farina, md pirozzi@uniss.it azienda ospedaliera universitaria viale s. pietro 43 07100 sassari, italy giovanni grimaldi, md azienda ospedaliera universitaria federico ii napoli, italy pirozzi ok_stesura seveso 18/04/13 10:56 pagina 7 stesura seveso 121archivio italiano di urologia e andrologia 2015; 87, 2 original paper efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. a systematic review and meta-analysis gianpaolo perletti 1,2, elena monti 1, emanuela marras 1, anne cleves 3, vittorio magri 4, alberto trinchieri 5, paul s. rennie 6 1 biomedical research division, dept. of theoretical and applied sciences, università degli studi dell'insubria, busto arsizio, italy 2 department of basic medical sciences, ghent university, ghent, belgium; 3 cancer research wales library, cardiff university velindre hospital, cardiff, uk; 4 urology secondary care clinic, istituti clinici di perfezionamento, milano, italy; 5 urology unit, a. manzoni hospital, lecco, italy; 6 vancouver prostate centre, university of british columbia, vancouver, canada. objective: we performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mcrpc) that has progressed after docetaxel. pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel). materials and methods: we included phase iii randomized controlled trials that enrolled patients with mcrpc progressing during or after first-line docetaxel treatment. trials were identified by electronic database searching. the primary outcome of the review was overall survival. secondary outcomes were radiographic progression-free survival (rpfs) and severe adverse effects (grade 3 or higher). results: ten articles met the inclusion criteria for the review. these articles reported the results of five clinical trials, enrolling in total 5047 patients. the experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. compared to control cohorts (active drug-treated or placebotreated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% ci 0.53 to 0.75, p < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% ci 0.58 to 0.75, p < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% ci 0.59 to 0.83, p < 0.0001). pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% ci 0.67 to 0.87, p < 0.0001; hazard ratio for radiographic progression: 0.7, 95% ci 0.63 to 0.77, p < 0.00001). androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% ci 2.08 to 15.90; p = 0.0008; risk-ratio for hypertension: 2.29, 95% ci 1.02 to 5.17; p = 0.05). conclusions: in docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or summary no conflict of interest declared. introduction metastatic prostate cancer results from any combination of lymphatic, blood, or local spread, leading to various sorts of clinical presentations. the most common sites of metastasis are bone, lymph nodes and/or other visceral locations (1) at this stage of the disease, the first-line treatment is surgical or pharmacological androgen deprivation, to achieve castrate testosterone levels of 50 ng/dl or lower (2). inevitably, the disease undergoes transition to castration-resistant prostate cancer (crpc) (2). in men with metastatic crpc (mcrpc), docetaxel 75 mg/m2 every 3 weeks, combined with low-dose corticosteroids, is the standard intervention (3, 4). however, in all patients the disease rapidly progresses to a docetaxelrefractory status, characterized by a time to progression of 3 months or less (5). recently, new agents have been tested as second-line options in the post-docetaxel setting, in the frame of randomized phase iii studies. the present systematic review aimed to analyze the published evidence on post-docetaxel therapy for patients affected by mcrpc, in order to evaluate the efficacy and safety of novel treatments, compared with active drugs or placebo. meta-analysis was also performed to evaluate doi: 10.4081/aiua.2015.2.121 to best of care at the time of study (mitoxantrone-prednisone). agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rpfs, compared to placebo. further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others). key words: castration-resistant prostate cancer; hormone therapy; chemotherapy. submitted 15 march 2015; accepted 31 march 2015 perletti_stesura seveso 02/07/15 11:19 pagina 121 archivio italiano di urologia e andrologia 2015; 87, 2 g. perletti, e. monti, e. marras, a. cleves, v. magri, a. trinchieri, p.s rennie 122 the effect of agents targeting the androgen axis on survival, and to assess the adverse effects of treatment. materials and methods this review was prepared following the prisma checklist (5). mecir criteria (http://editorial-unit.cochrane. org/mecir) were implemented whenever possible, within the word count limits established by the journal. eligibility criteria we included phase iii randomized controlled trials (rct) that enrolled patients with mcrpc progressing during or after first-line docetaxel treatment. we included comparisons of an experimental systemic intervention with placebo or an active treatment, combined or not with a corticosteroid. we excluded from the present review (i) studies including post-hoc evaluations of rcts, (ii) studies based on bone-targeting interventions aimed at palliating pain or preventing skeletal complications (e.g., radioisotopes, bisphosphonates, external beam radiation), (iii) studies including patients treated with protocols based on non taxane first-line agents, and (iv) studies investigating docetaxel-based therapies in the post-docetaxel setting (e.g., intermittent or combination therapies). outcomes the primary outcome was overall survival, calculated from the date of randomization to death. secondary outcomes were radiographic progression-free survival (rpfs), calculated between the date of randomization and the first date of radiographic progression, and adverse effects of grade 3 or higher. search strategy and study selection published study reports and supplementary material were identified by searching pubmed, medline, embase, the cochrane library, web of science, biosis, lilacs, other databases and trial registry platforms. search strategies are available as on-line supplementary data to the present review. database searches covered the period between january 2004 (the year docetaxel was first approved as first-line therapy for crpc) and january 2015. quality assessment the risk of bias (rob) of included studies was assessed by three reviewers using the cochrane collaboration’s tool (7). rob was graded as high, low, or unclear. significant bias can be generated depending on how data are managed to estimate time-to-event endpoints like rpfs, where the exact time of progression is not known in most cases. in some studies, the date of death is imputed as the progression event. in others, rpfs is censored at the date of the last visit at which the patient is assessed to be progression-free. studies adopting the latter approach were considered to be at low rob (8), whereas for trials adopting other imputation strategies (i.e., date of first visit post-progression or death used to estimate progression) the risk of attrition bias was rated as high. studies including patients who discontinued anti-androgen therapy ontrial were considered at high rob (study design bias), due to the confounding effect of androgen withdrawal responses. the quality of the evidence resulting from pooled data analysis was evaluated using the grade framework, and reported in a summary of findings table (table 3) (9). data collection and statistical analysis data extraction was performed by three reviewers. for time-to-event data, hazard ratios (hr) were extracted from study reports. to analyze grade ≥ 3 adverse effects at specific study time points, the number of intent-totreat patients was extracted, and risk ratios (rr) were calculated. analyses included the calculation of 95% confidence intervals (ci). we analyzed only available information (available case analysis), without employing bias-prone data imputation strategies for missing data. for analysis of pooled data we used a fixed-effects model. heterogeneity was assessed by calculating the i² value. given the small number of studies (two per metaanalysis) we did not employ formal methods to explore heterogeneity or to assess for publication bias. data analysis was performed using the revman 5.3 software. results results of the search and study inclusion a flow-chart of the search and screening process is shown in figure 1. a total of 6518 publications were identified using our search strategy. from 36 potentially relevant articles selected by two independent reviewers on the figure 1. study selection process for the present review. we retrieved total 6518 records from the following sources: medline (1483 records retrieved); embase (1892 records retrieved); pubmed (314 records retrieved); the cochrane library (234 records retrieved); web of science (1313 records retrieved); biosis (905 records retrieved); lilacs (15 records retrieved); who international clinical trials registry search portal (362 records retrieved). perletti_stesura seveso 02/07/15 11:19 pagina 122 123archivio italiano di urologia e andrologia 2015; 87, 2 second-line agents for castration-resistant prostate cancer basis of title and abstract content, 10 articles met the inclusion criteria for the present review. these articles report the results of five clinical trials: affirm (enzalutamide versus placebo) (10), ca184-043 (ipilimumab versus placebo) (11), cou-aa-301 (abiraterone acetate/ predni sone versus placebo/prednisone) (12-15), tak-700 (orteronel/prednisone versus placebo/ prednisone) (16), tropic (cabazitaxel/prednisone versus mitoxantrone/prednisone) (17-19). table 1 summarizes the characteristics of the included studies, the experimental interventions and key baseline patient characteristics. risk of bias in included studies table 2 and figure 2 summarize the rob evaluations for the included studies. high rob was assessed in few cases. the tropic trial was an open-label study, having high risk of selection and performance/detection bias. the affirm trial was considered as presenting high risk of attrition bias, since a marked imbalance was found between censored pfs data in the placebo (62%) and the enzalutamide (38%) arms. in the ca184-043 and couaa-301 studies, a high number of censored survival data suggests high risk of attrition bias. in the ca184-043 trial, table 1. characteristics of included studies and baseline participant data. ecog = eastern cooperative oncology group performance status; bpi = brief pain inventory score; nd = not determined. figure 2. risk of bias summary. green circles represent low risk of bias; red circles represent high risk of bias; yellow circles represent unknown risk of bias. perletti_stesura seveso 02/07/15 11:19 pagina 123 archivio italiano di urologia e andrologia 2015; 87, 2 g. perletti, e. monti, e. marras, a. cleves, v. magri, a. trinchieri, p.s rennie 124 palliative radiotherapy was allowed for any bone lesion onstudy, and a variable number of lesions was irradiated in each patient to stimulate an immune response, using doses equivalent to external beam palliative radiotherapy. thus, different numbers of patients in each treatment arm may have received different doses of radiation, and the risk of bias due to inter-arm unbalanced radiation treatment may be high. effects of interventions the ten articles included in the present review reported the data of five clinical trials. a total of 5047 patients table 2. risk of bias (rob) of the included studies. perletti_stesura seveso 02/07/15 11:19 pagina 124 were randomized to experimental (n = 3108) or control interventions (placebo/active drug; n = 1939). overall and progression-free survival data are presented. due to limited space, severe (grade ≥ 3) adverse effect data are presented as on-line supplementary material. enzalutamide versus placebo (affirm study) at interim analysis (520 death events), median overall survival was found to be prolonged in the enzalutamide arm, compared to placebo (18.4 vs. 13.6 months, respectively). the hazard ratio for death was 0.63 (95% ci 0.53 to 0.75, p < 0.00001, figure 3) (10). radiographic progression-free survival was significantly prolonged in the enzalutamide arm, compared to placebo (11 vs. 5.6 months, hr: 0.40, 95% ci 0.35 to 0.46; p < 0.0001, figure 3). ipilimumab versus placebo (ca184-043 study) the median overall survival in the ipilimumab arm was 11.2 months, compared to 10.0 months in the placebo arm, resulting in a hazard ratio for death of 0.85 (95% ci 0.72 to 1.0; p = 0.053 [p = 0.06 in our analysis], figure 3 (11). a composite pfs endpoint was adopted for the present study, and rpfs data were not available. abiraterone acetate versus placebo (cou-aa-301 study) administration of abiraterone acetate plus prednisone resulted in significantly prolonged overall survival compared to placebo plus prednisone. the median overall survival in the abiraterone arm was 14.8 months, compared to 10.9 months in the placebo arm, resulting in a significant hazard ratio of 0.65 (95% ci 0.54 to 0.78; p < 0.00001, figure 3) (12-15). radiographic progression-free survival was significantly prolonged in the abiraterone arm, compared to placebo (5.6 vs. 3.6 months; hr for rpfs or death: 0.66, 95% ci 0.58 to 0.75; p < 0.00001, figure 3). orteronel versus placebo (tak-700 study) the median overall survival in the orteronel arm was 17.0 months, compared to 15.2 months in the placebo arm, resulting in a hazard ratio of 0.89 (95% ci 0.74 to 1.06; p = 0.19, figure 3). the study was unblinded after crossing a futility boundary for overall survival (16). radiographic progression-free survival was significantly prolonged in the orteronel arm, compared to placebo (8.3 vs. 5.7 months; hr: 0.76, 95% ci 0.65 to 0.88; p = 0.0004, figure 3). 125archivio italiano di urologia e andrologia 2015; 87, 2 second-line agents for castration-resistant prostate cancer table 3. summary of findings table for the pooled analysis of cou-aa-30112 and tak-70016 studies. ci: confidence interval; hr: hazard ratio; rr: risk ratio; nd: not determined. 1 downgraded for considerable heterogeneity (-1). 2 downgraded for high risk of attrition bias (-1) and moderate heterogeneity (-1). the corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% ci). grade working group grades of evidence. high quality: further research is very unlikely to change our confidence in the estimate of effect. moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. very low quality: we are very uncertain about the estimate. perletti_stesura seveso 02/07/15 11:19 pagina 125 archivio italiano di urologia e andrologia 2015; 87, 2 g. perletti, e. monti, e. marras, a. cleves, v. magri, a. trinchieri, p.s rennie 126 cabazitaxel versus mitoxantrone (tropic study) treatment with cabazitaxel plus prednisone resulted in significantly prolonged overall survival compared to mitoxantrone plus prednisone. the median overall survival in the cabazitaxel arm was 15.1 months, compared to 12.7 months in the mitoxantrone arm (hr: 0.70, 95% ci 0.59 to 0.83, p < 0.0001, figure 3) (17). a composite pfs endpoint was adopted for the present study. radiographic progression-free survival data were not available. intervention active on the androgen axis versus placebo (pooled analysis) we merged two studies (cou-aa-301 and tak-700) (12, 16) including in total 2294 participants (1531 in the active intervention arm, 763 in the placebo arm) treated with the androgen synthesis inhibitors (asi) abiraterone and orteronel, showing equivalent mechanisms of action (selective inhibition 17α-hydroxylase and 17,20-lyase activities of cyp17a1). both studies used placebo plus prednisone as a comparator. analysis of overall survival figure 3. summary of overall survival and radiographic progression-free survival of the included studies. since disease progression was a composite endpoint in the ca184-043 and tropic studies, radiographic progression-free survival data were not available. the number of randomized subjects, hazard ratios for death or progression, the 95% confidence intervals for hazard ratios, the z value and the significance of the single comparisons are presented. perletti_stesura seveso 02/07/15 11:19 pagina 126 resulted in a significantly lower hazard ratio for death of asi compared to placebo (hr: 0.76, 95% ci 0.67 to 0.87; p < 0.0001, figure 4). the quality of the evidence was moderate (table 3). considerable heterogeneity emerged from this analysis (i2 = 82%, chi2 = 5.54, p = 0.02). pooled analysis resulted in a significantly decreased hazard ratio for radiographic progression of the active interventions versus placebo (hr: 0.7, 95% ci 0.63 to 0.77; p < 0.00001, figure 4). the quality of the evidence was low (table 3). moderate heterogeneity was detected for this pooled comparison (i2 = 48%, chi2 = 1.93, p = 0.17). the number of pooled studies was not sufficient for an investigation of the causes of heterogeneity. it is conceivable that the different methods used for censoring missing data between studies may have contributed to the generation of heterogeneity. asi induced significant increases in adverse effects linked to elevated mineralocorticoid secretion. the risk-ratio for hypokalemia was significantly enhanced in the asi arm versus placebo (rr: 5.75, 95% ci 2.08 to 15.90; p = 0.0008). the risk ratio for hypertension, not significantly higher in each separate study, was also significantly increased in our analysis (rr: 2.29, 95% ci 1.02 to 5.17; p = 0.05). pain in the extremities was less frequently detected in the asi arm, compared to placebo (rr 0.55, 95% ci 0.34 to 0.89; p = 0.02). pooled comparisons of aes did not show heterogeneity (i2 = 0% in all cases). a complete list of grade ≥ 3 adverse effects is presented as supplementary material. discussion until recently, docetaxel, administered at the standard dose of 75 mg/m2 every three weeks, was the only therapeutic option with proven life-prolonging efficacy for the management of mcrpc. in the last few years new agents have been approved worldwide for second-line treatment of patients affected by docetaxel-refractory mcrpc. the present review analyzed clinical data extracted from rcts focusing on treatment of mcrpc patients in the post-docetaxel setting. five studies were considered, representing a total population of 5047 patients. different baseline characteristics between studies (e.g., the prevalence of highly-prognostic visceral metastases or severe pain at enrollment) likely explain the inter-study variability of overall survival, especially as assessed in the control arms of each trial (table 1). in three studies, treatment with the experimental interventions could significantly prolong the median overall survival of patients. compared to control cohorts, the survival advantages were 4.8 months for the androgen receptor antagonist enzalutamide, 4.6 months for the androgen synthesis inhibitor abiraterone and 2.4 months for the cytotoxic taxane cabazitaxel (10, 12, 17). radiographic progression-free survival data were available for the enzalutamide vs. placebo comparison (rpfs advantage: 5.4 months) (10), for the abiraterone vs. placebo comparison (rpfs advantage: 2 months) (12), and for the orteronel vs. placebo comparison (rpfs advantage: 2.6 months) (16). in all cases hazard ratios were statistically significant, demonstrating the efficacy of these agents in delaying progression of the disease. all patients enrolled in the included studies had prostate cancer progressing after androgen-deprivation therapy. three studies involved drugs acting on the androgen axis: abiraterone acetate, orteronel and enzalutamide. pooled analysis of studies involving abiraterone acetate plus prednisone and orteronel plus prednisone confirmed that androgen synthesis inhibitors can significantly increase both overall survival and rpfs, compared to placebo-prednisone (figure 4). meta-analysis of overall survival contained data from a study (tak-700) that was prematurely unblinded, due to demonstrated futility, and results must be considered conservatively. nevertheless, the significant survival benefit resulting 127archivio italiano di urologia e andrologia 2015; 87, 2 second-line agents for castration-resistant prostate cancer figure 4. pooled analysis of overall survival and radiographic progression-free survival of the cou-aa-301 and tak-700 studies, comparing the effect of inhibitors of the 17α-hydroxylase and 17,20-lyase activities of the enzyme cyp17a1, involved in the biosynthesis of testosterone, combined with prednisone, and placebo-prednisone. the number of randomized subjects, hazard ratios for death or progression, the 95% confidence intervals for hazard ratios, the z value for the overall effect, the significance of the pooled comparison and heterogeneity data (chi2, i2), are presented. data to left of the black line of forest plots represent greater reduction of the hazard ratios for death or progression in patients treated with androgen synthesis inhibitors. diamonds represent pooled overall effect sizes for each outcome, which extend to the limits of the 95% confidence intervals of hazard ratios. perletti_stesura seveso 02/07/15 11:19 pagina 127 archivio italiano di urologia e andrologia 2015; 87, 2 g. perletti, e. monti, e. marras, a. cleves, v. magri, a. trinchieri, p.s rennie 128 from this analysis substantiates the evidence that mcrpc is not refractory to interventions aimed at further suppressing the androgen axis in patients subjected to surgical or pharmacological castration, and shows that in these patients the androgen receptor-mediated signaling may remain functional and may actively modulate disease progression. in addition, meta-analysis of the cou-aa-301 and tak700 studies evidenced the appearance of severe adverse effects that can be attributed to mineralocorticoid excess, like hypertension and hypokalemia. all experimental agents showed diverse severe adverse effects, which were lethal in some cases. notably, cabazitaxel plus prednisone induced neutropenia of grade ≥ 3 in 82% of cases, and grade ≥ 3 febrile neutropenia, lethal in 5% of cases. this prompted the fda to recommend prophylactic neutrophil growth factor support in susceptible patients (20). rare adverse effects worthy of further consideration were also observed in some of the included studies. for example, during the phase i-ii investigation of enzalutamide, 2% of patients treated with doses ≥ 360 mg/day had seizures (21). although in the affirm study the riskratio for seizure was not significant (10), five (or seven, according to the fda medical review of the study) enzalutamide-treated patients had seizures, whereas in the placebo arm no seizure events were reported. seven patients treated with orteronel were diagnosed with pancreatitis and increased pancreatic enzyme levels. hence, pancreas toxicity deserves further investigation and particular clinical attention. in conclusion, several new agents have shown to be effective in prolonging survival in men with metastatic castration-resistant prostate cancer in the post-docetaxel setting. it may be hypothesized that survival may be further prolonged by combining these agents or by administering them sequentially. randomized studies are warranted to demonstrate this hypothesis, but also to exclude reciprocal detrimental effects of these agents (22-26). acknowledgments we acknowledge the contributions of dr. philipp dahm and dr. molly neuberger, of the cochrane collaboration. references 1. bubendorf l, schopfer a, wagner u, et al. metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. hum pathol. 2000; 31:578. 2-droz jp, flechon a, terret c. prostate cancer: management of advanced disease. ann oncol. 2002; 13 suppl4: 89. 3. mottet n, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part ii: treatment of advanced, relapsing, and castrationresistant prostate cancer. eur urol. 2011; 59:572. 4. tannock if, de wit r, berry wr, et al. docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. new engl j med. 2004; 351:1502. 5. mathew p, dipaola r. taxane refractory prostate cancer. j urol. 2007; 178:s36. 6. moher d, liberati a, tetzlaff j, et al. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. ann intern med. 2009; 151:264. 7.higgins jp, altman dg, gøtzsche pc, et al. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011; 343:d5928. 8. niimi m, yamamoto s, fukuda h, et al. the influence of handling censored data on estimating progression-free survival in cancer clinical trials (jcog9913-a). japan j clin oncol. 2002; 32:19. 9. guyatt gh, oxman ad, kunz r, et al. what is "quality of evidence" and why is it important to clinicians? bmj 2008; 336:995. 10. scher hi, fizazi k, saad f, et al. increased survival with enzalutamide in prostate cancer after chemotherapy. new engl j med. 2012; 367:1187. 11. kwon ed, drake cg, scher hi, et al. ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (ca184-043): a multicentre, randomised, double-blind, phase 3 trial. lancet oncol. 2014; 15:700. 12. de bono js, logothetis cj, molina a, et al. abiraterone and increased survival in metastatic prostate cancer. new engl j med. 2011; 364:1995. 13. fizazi k, scher hi, molina a, et al. abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the cou-aa-301 randomised, double-blind, placebo-controlled phase 3 study. lancet oncol. 2012; 13:983. 14. logothetis cj, basch e, molina a, et al. effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the cou-aa-301 randomised trial. lancet oncol. 2012; 13:1210. 15. sternberg cn, molina a, north s, et al. effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. ann oncol. 2013; 24:1017. 16. fizazi k, jones r, oudard s, et al. phase iii, randomized, double-blind, multicenter trial comparing orteronel (tak-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: elm-pc 5. j clin oncol. 2015; pii: jco.2014.56.5119 [epub ahead of print]. 17. de bono js, oudard s, ozguroglu m, et al. prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. lancet 2010; 376:1147. 18. oudard s. tropic: phase iii trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer. fut oncol. 2011; 7:497. 19. bahl a, oudard s, tombal b, et al. impact of cabazitaxel on 2year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the tropic trial. ann oncol. 2013; 24:2402. 20. cookson ms, roth bj, dahm p, et al. castration-resistant prostate cancer: aua guideline. j urol. 2013; 190:429. 21. scher hi, beer tm, higano cs, et al. antitumour activity of mdv3100 in castration-resistant prostate cancer: a phase 1-2 study. lancet 2010; 375:1437. 22. sartor o, pal sk. abiraterone and its place in the treatment of metastatic crpc. nature rev clin oncol. 2013; 10:6. perletti_stesura seveso 02/07/15 11:19 pagina 128 23. aggarwal r, halabi s, kelly wk, et al. the effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (calgb 90401). cancer 2013; 119:3636. 24. noonan kl, north s, bitting rl, et al. clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. ann oncol. 2013; 24:1802. 25. loriot y, bianchini d, ileana e, et al. antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (mdv3100). ann oncol. 2013; 24:1807. 26. bianchini d, lorente d, rodriguez-vida a, et al. antitumour activity of enzalutamide (mdv3100) in patients with metastatic castration-resistant prostate cancer (crpc) pre-treated with docetaxel and abiraterone. eur j cancer 2014; 50:78. 129archivio italiano di urologia e andrologia 2015; 87, 2 second-line agents for castration-resistant prostate cancer correspondence gianpaolo perletti, phd, m clin pharmacol (corresponding author) gianpaolo.perletti@uninsubria.it elena monti, phd emanuela marras, phd biomedical research division, dept. of theoretical and applied sciences università degli studi dell’insubria via a. da giussano, 10 21052 busto arsizio, italy anne cleves, msc cancer research wales library, cardiff university velindre hospital cardiff, uk vittorio magri, md urology secondary care clinic, istituti clinici di perfezionamento milano, italy alberto trinchieri, md urology unit, a. manzoni hospital, lecco, italy paul s rennie, phd, fcahs vancouver prostate centre, university of british columbia vancouver, canada perletti_stesura seveso 02/07/15 11:19 pagina 129 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 2130 original paper what is the correct staging and treatment strategy for locally advanced prostate cancer extending to the bladder? özgür haki yüksel, ayhan verit, ahmet ürkmez fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey in locally advanced prostate cancer with bladder invasion, frequently encountered problems such as bleeding, urinary retention, hydronephrosis, and pain create distress for the patients. therefore patients’ quality of life is disrupted and duration of hospitalization is prolonged. relevant literature about accurate staging and treatment of locally advanced prostate cancer with bladder invasion was investigated. locally advanced prostate cancer can present as a large-volume aggressive tumor extending beyond boundaries of prostate gland, and involving neighboring structures which can be involved as recurrence(s) following initial local therapy. survival times of these patients can range between 5 and 8 years. their common characteristics are adverse and severe local symptoms unfavorably affecting quality of life control of local symptoms and their effective palliation are independent clinical targets influencing survival outcomes of these patients. the treatment outcomes of locally advanced prostate cancer into the bladder are currently debatable. although in the current tnm classification, it is defined in t4a, we think that this may be categorized as a subgroup of t3 and thus encourage surgeons for the indication of radical surgeries (radical prostatectomy, radical cystoprostatectomy) in selected patient populations after discussing issues concerning consequences of the treatment alternatives, and expectations with the patients. cystoprostatectomy followed by immediate androgen deprivation therapy may be a feasible option for selected patients with previously untreated prostate cancer involving the bladder neck because of excellent local control and long term survival. key words: bladder neck invasion; cystoprostatectomy; locally advanced prostate cancer; radical prostatectomy; staging. submitted 3 november 2014; accepted 31 december 2014 summary no conflict of interest declared. its incidence ranges between 5-15% (2). approximately 5-15% of the pc cases are located in clinical stage of t4. in current tnm staging, bladder neck invasion (bni) has been categorized as stage t4 disease (table 1). management of localized pc and metastatic disease has been summarized in algorithms, although optimal treatment of clinical stage t3-t4n0m0 pc is intensively debated. one of the main reasons of these debates is related to inaccurate local clinical staging over t2 or under staging of positive lymph node (ln) (3). according to european association of urology (eau) guidelines, watchful-waiting, radiotherapy (rt), radical retropubic prostatectomy (rrp), androgen deprivation therapy (adt) and various combinations of these treatment modalities based on general clinical condition of the patient and local invasion of the tumor can be used (table 2). according to the current scientific data, multimodality therapy was recommended for the majority of patients. treatment of locally advanced disease aims at two fundamental goals; the first goal is complete elimination of the disease and the second one is achievement of local control. in terms of biological behavior of pc, low, medium and high risk groups are defined. for high-risk disease, 'clinical t3', 'locally advanced', 'bad differentiated' terms are used and however these are not sufficient to identify the disease (4). definition of high-risk pc is associated with different criteria according to different sources as summarized in table 3. d'amico risk classification grouping is the most widely used. accordingly, prostate-specific antigen (psa) ≥ 20 ng/ml or gleason score (gs) 8-10 or clinical stage ≥ ct2 are considered as high-risk criteria of prostate cancer (5). american urological association (aua) has also used this risk stratification since 2007 (6). traditionally, urologists prefer rt and adt rather than rrp for the treatment of high risk pc. population-based surveillance, epidemiology and end results (seer) cancer data examination results showed us that in clinical t3 disease the rate of patients who underwent rrp, decreases from 18.1 to 9.1% and rt rates increase of 20% (7). in patients under the age of 70 who were diagnosed with high-risk prostate cancer, 25% of them could not receive an effective local treatment (2). according to the cancer of the prostate strategic urological research endeavor (capsure) data, most of the newly diagnosed patients with highrisk localized pc canalize to the adt as if the unique doi: 10.4081/aiua.2015.2.130 introduction locally advanced prostate cancer (lapc) has been clinically described as a cancer extending beyond prostate capsule, with invasion of pericapsullar tissue, apical region of the bladder, bladder neck or seminal vesicles without lymph node involvement or distant metastases. in clinical staging, they are categorized as t3-t4 n0 m0 prostate cancer (pc) and constitute 10-20% of the cases with newly diagnosed cases of pc (1). while in previous reports, nearly 40% of the cases with newly diagnosed pc were categorized in clinical stage t3 (ct3), currently yuksel 2_stesura seveso 02/07/15 11:22 pagina 130 131archivio italiano di urologia e andrologia 2015; 87, 2 correct staging for locally advanced prostate cancer table 1. 2009 tnm staging system of the pc. t: primary tumor tis: no evidence of primary tumor t1a: tumor detected in less than 5% of the total tur [transurethral prostate resection] material, normal dre findings, total gleason score < 7 pts t1b: tumor detected in more than 5% of the total tur material, normal dre, gleason score > 7 pts t1c: tumor diagnosed based on the results of the fine needle biopsies performed because of increased psa levels in a group of patients with normal dre estimates t2a: tumor involving only half or less than 50% of one lobe of the prostate t2b: tumor involving more than one half of one lobe t2c: tumor involving both lobes t3a: uni or bilateral extra-capsular invasion t3b: seminal vesicular involvement t4a: involvement of bladder neck, external sphincter or rectum t4b: tumor invading pelvic wall n: regional lymph nodes n0: no evidence of invasion n1: a single metastatic lymph node measuring 2 cm in diameter n2: a single metastatic lymph node measuring 2-5 cm or multiple metastatic lymph nodes each measuring < 5 cm in diameter n3: a metastatic lymph node larger than 5 cm in diameter m: distant metastases m0: no evidence of metastasis m1a: metastasis to non-regional lymph nodes m1b: bone metastasis m1c: distant rgan metastasis table 3. definitions of high-risk prostate cancer mode of treatment indications and general information degree of evidence watchful waiting asymptomatic, well and moderately differentiated tumors and patients with low life expectancy and a life expectancy ≤ 10 years 3 radical prostatectomy selected ct3a, gleason ≤ 8, psa ≤ 20 ng ml and life expectancy ≥ 10 years 3 selected ct3b-t4, n0 or someone t and n1: multimodality practicable treatment 3 t3a: unilateral nerve-sparing surgery 4 rp+adj ht [bicalutamide 150 mg1x1] useful in increasing progression-free survival nht+rp: ineffective overall survival or disease-free survival radiotherapy t3nomo in the early postoperative period in patients with adjuvant rt [positive surgical margins, especially in the] progression-free survival helpful 1 t2-t3nomo, in patients with persistent elevated psa recurrence of elevated psa and psa 0.5 ng ml before rt can be given in recovery 3 t3-t4nomo ve who performance status-2 for patients; concomitant and adjuvant hormone therapy [3 yr] is beneficial to overall survival 1 t2c-t3 no-x, gleason 2-6 in patients neo-adjuvant and concurrent with short term adt overall survival was helpful 1b high-risk n1mo and without severe comorbidities in patients pelvic external beam rt and concurrent long-term adjuvant hormone therapy, overall survival, biochemical control is useful, due to disease and the development of metastases associated with failure delays 2b hormonotherapy symptomatic, t3-t4, psa > 25-50 ng ml, psa doubling time < 1 year for patients 1 patients suitable for rt are not suitable for hormonal monotherapy nonsteroidal antiandrogen monotherapy is an alternative to castration 2a table 2. 2013 eau guidelines in the light of the treatment of locally advanced pc, some of the alternatives. source definition d’amico et al. (3), aua (4) psa ≥ 20 ng/ml or gs 8-10 or clinical stage ≥ t2c eau (5) psa ≥ 20 ng/ml or biopsy g 8-10 or clinical stage ≥ t3a rtog (6) psa 20-100 ng/ml, biopsy gs 8-10 and any clinical stage or clinical stage ≥ t2c or psa < 100 ng/ml and gs8-10 nccn (7) psa > 20 ng/ml or gs 8-10 or clinical stage ≥ t3 or t2b/c, gs = 7, psa > 10 any two of the parameters eastham et al. (8) kattan nomograms in the 5-year progression probability ≤ 50% d’amico et al. (9) preoperative psa velocity > year 2 ng/ml aua: american urologic association; psa: prostate spesific antigen; gs: gleason score; eau: european urologic association; rtog: radiation therapy oncology group; nccn: national comprehensive cancer network yuksel 2_stesura seveso 02/07/15 11:22 pagina 131 archivio italiano di urologia e andrologia 2015; 87, 2 özgür haki yüksel, ayhan verit, ahmet ürkmez 132 valid treatment option (8). although in the current tnm classification it is defined in clinical stage of t4a, we think that lapc invading the bladder may be categorized as a subgroup of ct3 in order to encourage surgeons to the indication of radical surgeries (rrp, cystoprostatectomy) in selected patient populations and after discussing with the patients issues, concerning consequences of the treatment alternatives and expectations. altogether, we think that clinicians should not strictly obey the classical staging systems in every cases, especially when lapc invaded the bladder. discussion in lapc, rt and adt are considered as standard treatment modalities, however in selected cases, rrp is recommended as a primary treatment alternative. an advantage of rrp which should not be overlooked is that rrp can demonstrate true histopathological stage of the primary cancer and evaluate potential ln invasion. by this modality, patients with disease recurrence and progression risks can be determined. in fact, patients with organ-confined disease (pt2) can be spared from morbidities of adjuvant treatment modalities. extracapsular invasion is found in 88-91% of the cases with clinical manifestations of lapc, while surgical margin positivity (psm) and seminal vesicle involvement (svi) have been reported in 22-53% and 23-29% of the cases, respectively (9). whether bni conveys a high risk for biochemical progression following rrp is a debatable issue. in tnm staging system, bni is not defined in detail with respect to its microscopic and macroscopic characteristics. independent prognostic value of microscopic bni in pc is not clear. in a study encompassing 1845 patients, conically resected bladder neck specimens were evaluated and true bni was defined as pc focus within thick smooth muscle bundles without intermixed benign prostatic tissue. while false bni was described as pc cells intermixed with benign prostatic tissue. bni was evaluated and analyzed within the context of preoperative serum psa levels, extra prostatic invasion, svi, psm, ln involvement, previous rrp (if any), gs and tumor volume in 90 of 1845 patients diagnosed with bni. sixtythree cases of 90 (4.9% of 1845) patients with microscopic bni were classified as true bni and 27 cases were categorized as false bni. in patients with bni, time to biochemical failure was similar in patients with negative and positive surgical margins (kaplan-meier curves). even though bni is related to other pathologic features, as demonstrated in previous studies, it is not an independent marker of psa recurrence. in the light of previous and currently available data, the authors had expressed their expert opinions about tnm staging system and indicated that staging system should be reviewed with respect to bni and these group of patients should be included in the clinical stage of t3a with favorable prognosis (10). dash et al. performed a univariate analysis on their 1123 cases with localized pc and estimated relative probabilities for psa recurrence risks as 1.52, 3.05 and 8.59 for patients with bni, extraprostatic tissue invasion and svi, respectively (11). in a study conducted by ruano et al. in a series of 290 consecutive patients, 55 cases who presented with bni and a subgroup of 18 cases also showing psm according to microscopic criteria of yossepowitch were compared to patients with extraprostatic extension or seminal vesicle invasion showing no statistically significant intergroup difference as assessed by cox proportional hazard model. in conclusion, patients with microscopic bni after rrp had higher preoperative psa values and gs, higher psm, advanced pathologic stage and larger sized tumors when compared to those with extraprostatic involvement but showed similar biochemically detected recurrence-free rates. furthermore, their outcomes were more favorable in comparison to the patients with seminal vesicle involvement and the authors indicated the need for inclusion of these tumors in clinical stage t3a (12). problems encountered in radical surgery performed for lapc with bni include higher rates of svi and ln positivity when compared to the patients with localized disease. however some studies have demonstrated absence of any biochemically detected disease progression within 10 years after rrp in 25% of the patients with svi and without metastatic ln (13). as a reason for this outcome, discrepancies in the definition of svi have been indicated (14). secin et al. evaluated 387 preoperatively treatment naive patients with svi who had undergone rrp and published their 15-year follow-up outcomes (15). in this study, 10 and 15 year disease-free survival rates of 296 (76%) patients with svi but no ln involvement were reported as 89 and 81%, respectively. however their biochemical recurrence rates were indicated as 64 and 68%, respectively. in the same study, 10-year biochemical disease-free and disease-specific survival rates for 92 patients with svi and ln involvement were reported respectively as 10 and 74%. nevertheless, at the end of 10 years, 66% of the patients were still surviving (7). masterson et al. analyzed 24 patients with ln positivity and svi and reported 5-year biochemical disease-free survival rate as 25.9% and they estimated mean time interval up to the psa progression as 6 months (16). boorjian indicated that in cases with only one ln involvement, the risk of disease-specific mortality had increased 4-fold which was two times higher in patients with multiple ln involvement (17). in a higher-stage lapc, as supported by the outcomes of some literature studies, extended ln dissection can be recommended instead of standard pelvic ln dissection. in standard pelvic ln dissection, lymphadenectomy is confined within obturator fossa, whereas in the extended approach, whose importance has been currently emphasized in many publications, in addition to the boundaries of the standard procedure, the target of lymphadenectomy is extended to include external iliac vein, internal iliac vessels, and femoral canal. in a study conducted by heidenreich et al., the authors reported that ln positivity had been 12% in patients who had undergone standard pelvic ln dissection, but it had raised up to 26% in the extended procedure. for high-risk patients as those with bni, extended pelvic ln dissection has been recommended, because, especially in the presence of low-volume, micrometastatic ln involvement, relatively yuksel 2_stesura seveso 02/07/15 11:22 pagina 132 133archivio italiano di urologia e andrologia 2015; 87, 2 correct staging for locally advanced prostate cancer longer disease-free survival can be achieved (18). morbidity of rrp in high-risk pc is similar to that in low-risk patients (4). for these reasons, nowadays rrp in high-risk patients began to be proposed and implemented more frequently. berglund et al. reported that in patients of high-risk groups who underwent rrp; recovery time, duration of catheterization and continence turnaround time were similar with patients of low risk group (19). in rrp patients with clinical t3, perioperative mortality rates were similar with clinical t2 patients (20). in major centers rrp results of the 5-year and 10year biochemical recurrence free rates were 30-70% and 15-60%, respectively (21-22). in another study, clinical t1c-t3b pc patients who underwent rrp or rt were retrospectively compared. at 8-year follow-up results when poor-risk patients treated with rrp were compared to those treated with rt showed that metastatic progression rate of rt group was 9.5% more than to rrp group (4). one of the most important advantage in rrp is the ability to accurate pathological staging. approximately 15-25% of the clinical stage t3 tumors reported as highgraded (23). consequently rrp may provide more information in determining the need for additional treatment. in addition, ln dissection that was performed during rrp helps us to detect micrometastases which cannot be detected by imaging methods. otherwise; removal of the seminal vesicles increases the effectiveness of adjuvant treatment (23). in high-risk patients, considering age, general health status and 10 year life expectation, rrp should be recommended as primary treatment. ten-year biochemical recurrence-free survival rate was 68% in 35% of 175 rrp patients who were reported as organconfined disease according to d'amico risk classification and at the end of follow-up, metastasis-free survival rate and cancer-specific survival rate were 84% and 92%, respectively (24). in a retrospective multicenter study, 3828 patients with high risk of pc who underwent rrp were evaluated between years of 1987 and 2010. ten-year cancer-specific and non-cancer-cause mortality rates were 5.9% and 14.3%, respectively (25). in a multicenter european study, were evaluated 1366 patients who were diagnosed as high-risk pc (26). in 37% of overall patients, organ-confined disease has been identified. this rate in presence of only one of the preoperative risk factor was 45%, but in presence of three risk factors (gs, psa, clinical stage) organ-confined disease detection rate dropped to 9%. fowler et al. reported that the 5-year survival rate of patients with lapc who were treated with hormone therapy alone was 92% with a mean follow-up of 78 months (27). bolla et al. compared the results of combined adt and rt with those of rt alone in lapc and reported that overall survival at 5 years was 79% in the combination group and 62% in the rt alone group (28). however, patients with pc bni were generally highgrade (gs 9-10). in the majority of patients short time to progression and lower urinary tract symptoms were observed. we know the high incidence of complications that occurr when salvage surgery performed after rt (29-30). patients with clinical stage t4 pc are rarely encountered and in only few centers surgical treatment are applied for these patients. evaluation of this group of patients provides little information about treatment outcomes. johnstone et al. followed up 1093 clinical stage t4 pc patients at diagnosis and divided them into 5 categories: rrp, only rt, only adt, rt and adt combination, and untreated group. the authors reported that rrp applied for clinical stage t4 pc patients had provided better survival rates when compared with patients who received mono-rt or mono-adt. survival rates achieved with surgery were found to be comparable with those obtained with rt and adt combination therapy (31). furthermore, the study indicated the survival of rrp over combined rt with adt for clinical t4 pc with lymph node metastases (32). when performing cystoprostatectomy (cp) for pc involving the bladder neck, the possibility of overtreatment should be considered. among clinical t4, compared to patients with pc involving the rectum or pelvic floor muscles, those with bni may be better candidates for cp to achieve local cancer control and improvement of quality of life (qol). manifestations of bi consist of hematuria, urinary urgency, pelvic pain, and bladder outlet obstruction. besides, bladder outlet or ureteral obstruction can lead to renal failure. many patients might be dependent on lifelong requirement for nephrostomy tubes, ureteral, and urethral stents, and more than one invasive procedure might be needed for routine tube replacements or revision operations. complications of long-term tube drainage of the urinary tract comprise obstruction, bladder spasms, bleeding, infection, and stone formation. local symptoms related to bi determine quality of life and reveals the clinical condition. among adjuvant procedures applied for the management of locally advanced and symptomatic pc patients, systemic treatments as adt and chemotherapy, local therapies including cryotherapy or surgery (tur), and local palliative approaches (nephrostomy, and ureteral stent implantation) can be enumerated. the beneficial effect of androgen therapy is restricted with the development of androgen insensitivity. still, in 89% of the patients under systemic chemotherapy, local symptoms were maintained (1). cryotherapy has been tried after failure of rt, but could not prevent lower urinary tract symptoms (33). on the other hand relieve of outlet obstruction by transurethral resection (tur) is short-lasting and repeated transurethral procedures might be required (34). previous reports on patients who had undergone salvage surgery including cp have demonstrated that they have rarely provided cure. however, in these reports palliative role of cp on patients with local symptoms was not investigated. leibovici et al. performed palliative cp on a total of 38 t4 pc patients who developed recurrence following primary disease (n = 17), and rt (n = 21). the authors compared local symptoms, and the need for surgical intervention for the relief of obstruction before the operation, and at postoperative 3 month follow up during a mean follow-up period of 23 months (35) showing that the role of palliative cp was not statistically significant. in several institutions, cp was performed in pc patients with bni showing severe luts for the purpose of relieving those symptoms. kumazawa et al. published outyuksel 2_stesura seveso 02/07/15 11:22 pagina 133 archivio italiano di urologia e andrologia 2015; 87, 2 özgür haki yüksel, ayhan verit, ahmet ürkmez 134 comes of cps they performed on 17 stage t4 patients between the years 1989 and 2005. all the patients in this study, including patients who developed local recurrence, had no local symptoms or no need for catheters for urinary tract obstruction until death. although no study has compared qol after conservative treatment and surgical intervention in pc patients with bni, results indicate that cp may be a treatment option in these patients. postoperatively, all patients received additional surgical or medical castration therapy during the mean postoperative period of 89 months. the authors determined 5-year disease-free biochemical survival rate as 62 percent. they demonstrated that palliative cp can be performed even for lymph node positive patients (36). in the light of these data, we need further researches in order to achieve a more accurate assessment and alternative treatments for lapc patients. references 1. boccon-gibod l, bertaccini a, bono av, et al. management of locally advanced prostate cancer: a european consensus. int j clin pract. 2003; 57:187-94. 2. gallina a, chun fk, suardi n, et al. comparison of stage migration patterns between europe and the usa: an analysis of 11350 men treated with radical prostatectomy for prostate cancer. bju int 2008; 101:1513-1518. 3. hakenberg o, frohner m, wirth m. treatment of locally advanced prostate cancer the case for radical prostatectomy. urol int. 2006; 77:193-199. 4. eastham ja, evans cp, zietman a. what is the optimal management of high risk, clinically localized prostate cancer? urol oncol. 2010; 28:557-567. 5. d’amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama 1998; 280:969-74. 6. denberg td, glodé lm, steiner jf, et al. trends and predictors of aggressive therapy for clinical locally advanced prostate carcinoma. bju int. 2006; 98:335-40. 7. meng mv, elkin ep, latini dm, et al. treatment of patients with high risk localized prostate cancer. results from cancer of the prostate strategic urological research endeavor (capsure). j urol. 2005; 173:1557-61. 8. boorjian sa, thompson rh, siddiqui s, et al. long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. j urol. 2007; 178:864-870. 9. zhou m, reuther am, levin hs, et al. microscopic bladder neck invasıon by prostate carcinoma in radical prostatectomy specimens is not a significant independent prognostic factor. mod pathol. 2009; 22:385-392 10. dash a, sanda mg, yu m, et al. prostate cancer involving the bladder neck: recurrence-free survival and implications for ajcc staging modification. american joint committee on cancer. urology 2002; 60:276-280. 11. ruano t, meirelles l, freitas ll, et al. the significance of microscopic bni in radical prostatectomies: pt4 disease? int urol nephrol. 2009; 41:71-76. 12. johnson cw, anastasiadis ag, mckiernan jm, et al. prognostic indicators for long term outcome following radical retropubic prostatectomy for prostate cancer involving the seminal vesicles. urol oncol. 2004; 22:107-111. 13. epstein ji, partin aw, potter sr, et al. adenocarcinoma of the prostate invading the seminal vesicle: prognostic stratification based on pathologic parameters. urology. 2000; 56:283-288. 14. secin fp, bianco jr fj, vickers aj, et al. cancer-specific survival and predictors of prostate-specific antigen recurrence and survival in patients with seminal vesicle invasion after radical prostatectomy. cancer. 2006; 106:2369-2375. 15. masterson ta, pettus ja, middleton rg, stephenson ra. isolated seminal vesicle invasion imparts beter outcomes after radical retropubic prostatectomy for clinically localized prostate cancer: prognostic stratification of pt3b disease by nodal and magrin status. urology 2005; 66:152-155. 16. boorjian sa, thompson rh, siddiqui s, et al. long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. j urol. 2007; 178:864-870. 17. heidenreich a, varga z, von knobloch r. extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. j urol. 2002; 167:1681-1686. 18. berglund rk, jones js, ulchaker jc, et al. radical prostatectomy as primary treatment modality for locally advanced prostate cancer. a prospective analysis. urology. 2006; 67:1253-6. 19. ward jf, slezak jm, blute ml, et al. radical prostatectomy for clinically advanced (ct3) prostate cancer since the advent of prostate specific antigen testing: 15 year outcome. bju int. 2005; 95:751-6. 20. roehl ka, han m, ramos cg, et al. cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. j urol. 2004; 172:910-4. 21. han m, partin aw, pound cr, et al. long-term biochemical disease-free and cancerspecific survival following anatomic radical retropubic prostatectomy. the 15-year johns hopkins experience. urol clin north am. 2001; 28:555-65. 22. bianco fj jr, scardino pt, eastham ja. radical prostatectomy: long-term cancer control and recovery of sexual and urinary function (“trifecta”). urology 2005; 66:83-94. 23. kozacıoglu z, günlüsoy b. current treatment approaches in locally advanced prostate cancer: urologist approach. j urooncol turkey. 2012; 2:124-8. 24. loeb s, schaeffer em, trock bj, et al. what are the outcomes of radical prostatectomy for high-risk prostate cancer? urology. 2010; 76:710-4. 25. briganti a, spahn m, joniau s, et al. impact of age and comorbidities on long-term survival of patients with high-risk prostate cancer treated with radical prostatectomy: a multiinstitutional competing-risks analysis. eur urol. 2013; 63:693-701. 26. briganti a, joniau s, gontero p, et al. identifying the best candidate for radical prostatectomy among patients with highrisk prostate cancer. eur urol. 2012; 61:584-592. 27. fowler je, bigler sa, duncun wl. hormone therapy for locally advanced prostate cancer. j urol. 2002; 168:546-549. 28. bolla m, gonzalez d, warde p, et al. improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. n engl j med. 1997; 337:295-300. yuksel 2_stesura seveso 02/07/15 11:22 pagina 134 135archivio italiano di urologia e andrologia 2015; 87, 2 correct staging for locally advanced prostate cancer 29. shekarriz b, upadhyay j, pontes je. salvage radical prostatectomy. urol clin north am. 2001; 28:545-553. 30. gheiler el, tefilli mv, tiguert r, et al. predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer. urology. 1998; 51:789-795. 31. johnstone pa, ward kc, goodman m, et al. radical prostatectomy for clinical t4 prostate cancer. cancer. 2006; 106:2603-2609. 32. bolla m1, van poppel h, tombal b, et al. european organisation for research and treatment of cancer, radiation oncology and genito-urinary groups postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (eortc trial 22911). lancet. 2012;380:2018-27. 33. anastasiadis ag, sachdev r, salomon l, get al. comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer. j cancer res clin oncol. 2003; 129:676. 34. crain ds, amling cl, kane cj. palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. j urol. 2004; 171:668. 35. leibovici d, kamat am, petteway ca, et al. cystoprostatectomy for effective pallation of symptomatıc bladder invasion by prostate cancer j urol. 2005; 174:6. 36. kumazawa t, tsuchiya n, saito m, et al. cystoprostatectomy as a treatment of prostate cancer involving the bladder neck. urol int. 83:141-5. correspondence özgür haki yüksel, md (corresponding author) ozgurhaki@gmail.com ayhan verit, md. prof, ahmet ürkmez, md dept. of urology, fatih sultan mehmet research & training hospital içerenköy/ataşehir tr34752 istanbul, turkey yuksel 2_stesura seveso 02/07/15 11:22 pagina 135 stesura seveso 103archivio italiano di urologia e andrologia 2014; 86, 2 original paper medical expulsive therapy for distal ureteric stones: tamsulosin versus silodosin vittorio imperatore 1, ferdinando fusco 2, massimiliano creta 1, sergio di meo 1, roberto buonopane 1, nicola longo 2, ciro imbimbo 2, vincenzo mirone 2 1 department of urology, buon consiglio fatebenefratelli hospital, naples, italy; 2 department of urology, policlinico federico ii of naples, naples, italy. objectives: to compare the efficacy and safety of tamsulosin and silodosin in the context of medical expulsive therapy (met) of distal ureteric stones. patients and methods: observational data were collected retrospectively from patients who received silodosin (n = 50) or tamsulosin (n = 50) as met from january 2012 to january 2013. inclusion criteria were: patients aged ≥ 18 years with a single, unilateral, symptomatic, radiopaque ureteric stone of 10 mm or smaller in the largest dimension located between the lower border of the sacroiliac joint and the vesico-ureteric junction. stone expulsion rate, stone expulsion time, number of pain episodes, need for analgesics use, incidence of side effects were compared. results: stone-expulsion rate in the silodosin and in the tamsulosin groups were 88% and 82%, respectively (p not significant). mean expulsion times were 6.7 and 6.5 days in the silodosin and tamsulosin group, respectively (p not significant). mean number of pain episodes were 1.6 and 1.7 in the silodosin and tamsulosin group, respectively (p not significant). the mean number of analgesic requirement was 0.84 and 0.9 for the silodosin and tamsulosin group, respectively (p not significant). overall, incidence of side effects was similar in both groups. patients taking silodosin experienced an higher incidence of retrograde ejaculation but a lower incidence of side effects related to peripheral vasodilation when compared to patients taking tamsulosin. subgroup analysis demonstrated significantly lower mean expulsion times and pain episodes in patients with stones ≤ 5 mm in both groups. conclusions: tamsulosin and silodosin are equally effective as met for distal ureteric stones sized 10 mm or smaller. met with silodosin is associatd with a lower incidence of side effects related to peripheral vasodilation but an higher incidence of retrograde ejaculation when compared to tamsulosin. key words: silodosin; tamsulosin; medical expulsive therapy; stones. submitted 26 august 2013; accepted 15 january 2014 summary no conflict of interest declared. introduction ureteric stones account for 20% of urinary tract stones and about 70% of them are found in the lower third of the ureter at presentation (1). to date, minimally invasive therapies, such as extracorporeal shock wave lithotripsy and ureterolithotripsy, represent efficacious treatment modalities in almost all cases. nevertheless, these procedures imply high costs and are not risk-free (2). a watchful waiting approach has been reported to be associated with spontaneous stone expulsion in up to 50% of cases but some complications may occur such as urinary tract infections, hydronephrosis and colic events (2). in recent years, the use of the expectant approach for distal ureteric stones has been extended thanks to the use of adjuvant medical expulsive therapy (met), that is able to reduce symptoms and facilitate stone expulsion. in 1970, malin et al. demonstrated the presence of alpha and beta adrenergic receptors (ar) in the human ureter (3). alpha1 are the most abundant ar subtypes at the level of ureteric smooth muscle cells (4). itoh et al. demonstrated that three types of alpha1 ar are expressed in the human ureter (alpha1a, alpha1b and alpha1d) (5-7). antagonists of these receptors have been proved to decrease ureteric basal tone, peristaltic activity, and contractions thus decreasing intraureteric pressure and increasing urine transport (5). three metaanalyses have confirmed a positive effect of alpha-blocker therapy on the stone expulsion rates (8-11). alphablockade has been proved to improve the likelihood of spontaneous stone passage, and to decrease both the time to stone passage and analgesic requirements (12). according to european association of urology guidelines, alpha-blockers or nifedipine are recommended for met (grade of recommendation a) (13). patients who elect for met should have well controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve (13). the alpha1a/d selective alpha-blocker tamsulosin has been demonstrated to be a safe and effective drug that enhances spontaneous passage of distal ureteral stones sized 10 mm or smaller (8). recent studies have demonstrated that the alpha1a subtype plays the major role in mediating phenylephrine-induced contraction in doi: 10.4081/aiua.2014.2.103 archivio italiano di urologia e andrologia 2014; 86, 2 v. imperatore, f. fusco, m. creta, s. di meo, r. buonopane, n. longo, c. imbimbo, v. mirone 104 the human isolated ureter (7). kobayashi et al. found that the selective alpha1a adrenergic receptor antagonist, silodosin, was more effective than the selective alpha1d adrenergic receptor antagonist, bmy-7378, for noradrenaline-induced contraction in the human ureter (14). silodosin is effective as met for ureteric stones (16). according to tsuzaka et al., silodosin was clinically superior for stone expulsion when compared to the selective α1d ar antagonist naftopidil (16). to date, however there are no clinical studied that compare silodosin to tamsulosin as met for lower ureteric stones. we aimed to compare the efficacy of tamsulosin and silodosin as met for symptomatic, uncomplicated distal ureteric stones. materials and methods observational data were collected retrospectively from patients who received silodosin or tamsulosin as met from january 2012 to january 2013. inclusion criteria were: patients aged ≥ 18 years with a single, unilateral, symptomatic, radiopaque ureteric stone of 10 mm or smaller in the largest dimension located between the lower border of the sacroiliac joint and the vesicoureteric junction as assessed on intravenous urography. exclusion criteria were: renal insufficiency, urinary tract infections, high-grade hydronephrosis, previous therapies for the stone, solitary kidney, history of ureteral surgery or previous endoscopic procedures, concomitant calcium-antagonists or corticosteroids medications, ureteric strictures, cardiovascular diseases, incomplete data. the following data were recorded and compared: patients demographics, stone size and side, type of met, stone expulsion rate, stone expulsion time, number of pain episodes, need for analgesics use, incidence of side effects. patients who experienced stone expulsion before first medication, or who were lost to follow-up were excluded from the analysis. statistical analysis of mean values was carried out with the student t test and the chi square test. subgroup analysis was performed according to stone size ≤ or > 5 mm. results overall, data from a total of 100 patients which met inclusion and exclusion criteria were recorded. of them, 50 patients (50%) received a prescription of a daily single dose of tamsulosin 0.4 mg for 28 days and 50 (50%) a prescription of a daily single dose of silodosin 8 mg for 28 days. all patients were advised to drink a minimum of 2 l of water daily and to use symptomatic therapy with injection of 75 mg diclofenac on demand. all patients were advised to filter their urine to detect spontaneous stone passage and to stop taking the medications when the stone was expulsed. patients were followed up weekly with x-ray of the kidney, ureter, and bladder region and with ultrasonography. absence of stone expulsion after day 28 was considered failed therapy. discontinuation of met and intervention within 28 days from the start of the met due to uncontrollable pain, adverse events, urinary tract infections, acute renal failure, or the patient’s desire for stone removal were also considered failed therapy. baseline patients characteristics in both study arms are reported in table 1. the two groups were comparable in terms of mean age, mean stone size, stone side. moreover, the number of patients with smaller stones (≤ 5 mm) and larger (> 5 mm) stones were also comparable in both groups. spontaneous stone expulsion within 28 days was observed in 41 patients in the tamsulosin arm (82%) and in 44 patients in the the silodosin arm (88%) without statistically significant differences (table 2). hospitalization and ureteroscopy were required in 3 patients belonging to the tamsulosin arm and in 2 patients belonging to the silodosin arm. six patients in the tamsulosin arm and 3 in the silodosin arm experienced unsuccessful expulsion after 4 weeks of treatment and required ureteroscopy. not statistically significant differences emerged in terms of mean expulsion tamsulosin silodosin p value expulsion rate n (%) 41 (82) 44 (88) n.s. expulsion time days mean (range) 6.5 (3-9) 6.7 (3-9) n.s. pain episodes mean (range) 1.7 (0-4) 1.6 (0-4) n.s. need for analgesics 0.9 (0-3) 0.84 (0-3) n.s. side effects (n %) retrograde ejaculation 1 (2) 8 (16) < 0.05 side effects related to peripheral vasodilation dizziness 4 (8) 1(2) n.s. nasal congestion 3 (6) 1 (2) n.s. postural hypotension 3 (6) 1 (2) n.s. headache 3 (6) 1(2) n.s. total 13 (26) 4 (8) < 0.05 total side effects 14 12 n.s. n.s.: not statistically significant difference. table 2. overall results. tamsulosin silodosin p value mean age, year (range) 53.5 (33-77) 50.1 (30-77) n.s. ureteric stone side left n (%) 27 (54) 21 (42) n.s. right n (%) 23 (46) 29 (58) n.s. gender n (%) male 50 (100) 50 (100) n.s. mean stone size, mm (range) 6.7 (3-10) 6.5 (3-10) n.s. size n (%) ≤ 5 mm 22 (%) 24 (48) n.s. > 5 mm 28 (%) 26 (52) n.s. n.s.: not statistically significant difference. table 1. baseline patients’ characteristics in both treatment groups. time, mean number of pain episodes and need for analgesics (table 2). overall, the incidence of side effects was similar in both groups. they were mild and did not require cessation of therapy in any patient. the incidence of retrograde ejaculation was significantly higher in the silodosin arm while the incidence of side effects related to peripheral vasodilation (dizziness, postural hypotension, headache, nasal congestion) were significantly higher in the tamsulosin arm (table 2). results from subgroup analysis according to stone size are reported in table 3. the mean expulsion times and the mean number of pain episodes were significantly lower in patients with smaller stones, in both treatment arms. discussion advances in endourology have diverted the management of ureteric stones by open surgery to minimal invasive methods like extracorporeal shock wave lithotripsy and ureterorenoscopy. nevertheless, these techniques are not risk-free. met has recently emerged as an alternative strategy for the initial management of selected patients with distal ureteric stones (17). the stimulation of the alpha1 ar in the ureter increases the force of ureteric contraction and the frequency of ureteric peristalsis. blockade of alpha1 ar inhibits basal tone, reduces peristaltic amplitude and frequency, and decreases intraluminal pressure while increasing the rate of fluid transport and the chances of stone expulsion. alpha1a and alpha1d are the ar subtypes that are more densely expressed in the distal ureter (18). tamsulosin has been widely studied in the context of met for patients with distal ureteric stones smaller than 10 mm. it has been proved that tamsulosin increases stone expulsion rates, decreases pain, reduces mean time to stone expulsion and decreases analgesic usage when compared to placebo (1,5, 19-21). however, a possible class effect has been supported by trials demonstrating increased stone expulsion rates using tamsulosin, doxazosin, terazosin , alfuzosin, and naftopidil (5, 13). itoh performed the first prospective randomized study evaluating the use of silodosin in the management of ureteric stones ≤ 10 mm (15). tsuzaka compared the efficacy of the selective alpha1d ar antagonist naftopidil and the selective alpha1a ar antagonist silodosin in the management of symptomatic ≤ 10 mm ureteral stones (16). to our knowledge, we compared for the first time tamsulosin and silodosin in the context of met for distal ureteric stones. spontaneous stone expulsion rates without met in patients with distal ureteric stones ≤ 10 mm have been reported to vary between 35.2% to 61% with mean expulsion times ranging from 9.87 to 24.5 days (1, 5, 1921). tamsulosin enhances stone expulsion rates and mean expulsion times in this subset of patients with reported values ranging from 79.31% to 89.5% and from 6.31 to 12.3 days, respectively (1, 5, 19-21). stone expulsion rate in patients with distal ureteric stones treated with silodosin has been reported to be 72.7% with mean expulsion time of 9.29 days (15). tsuzaka et al. reported a stone expulsion rate significantly higher in patients treated with silodosin than naftopidil (84% vs 61%, respectively) without significant differences in terms of stone expulsion time or rate of interventions (16). results from the present study demonstrate stone expulsion rates and stone expulsion times in patients treated with tamsulosin that are within the published ranges. patients treated with silodosin exhibit stone expulsion rates and mean expulsion times that are comparable to those reported in the tamsulosin arm. however, stone expulsion rates and times with silodosin in the present study are better than that reported by other authors (15). stone size has been identified as an important predictive factor for ureteral stone expulsion. the probability for distal ureteric stones to pass spontaneously is as high as 71-98% for stones ≤ 5 mm and only 25-51% for stones > 5 mm. studies on met with sub analysis according to stone size demonstrated higher expulsion rates for stones ≤ 5 mm with respect to larger stones (1, 19). stone expulsion rate of 89.5% and 70% in patients treated with tamsulosin with stone size ≤ 5 mm and > 5 mm, respectively, have been reported (1). results from the present study demonstrated higher expulsion rates in patients with stones ≤ 5 mm and this was true for both patients treated with tamsulosin and silodosin. however the difference was not statistically significant. most trials on met for lower ureteric stones with tamsulosin demonstrated significant lower mean number of pain episodes with respect to placebo (1, 5, 19-21). this difference may be attributable to the accelerated stone expulsion with a consecutive shorter time at risk for painful events. however, a true analgesic effect of tamsulosin has been also reported. results from the present study in terms of mean number of pain episodes and need for analgesics are within the published ranges for tamsulosin and similar data have also emerged for silodosin. safety issues and adverse events spectra differ considerably between the available alpha-blockers. adverse side effects commonly reported with different alpha1 ar 105archivio italiano di urologia e andrologia 2014; 86, 2 medical expulsive therapy tamsulosin silodosin ≤ 5 mm > 5 mm p ≤ 5 mm > 5 mm p expulsion rate n (%) 20 (90.90) 21 (75) n.s. 23 (95.83) 21 (80.76) n.s. expulsion time days mean (range) 5.4 (3-8) 7.7 (6-9) < 0.05 5.7 (3-8) 7.9 (6-9) < 0.05 pain episodes mean (range) 1.1 (0-3) 2.1 (0-4) < 0.05 1.1 (0-4) 2.0 (0-4) < 0.05 need for analgesics 0.8 (0-3) 0.9 (0-3) n.s. 0.6 (0-2) 1.0 (0-3) n.s. n.s.: not statistically significant. table 3. results of subgroup analysis according to stone size. archivio italiano di urologia e andrologia 2014; 86, 2 v. imperatore, f. fusco, m. creta, s. di meo, r. buonopane, n. longo, c. imbimbo, v. mirone 106 blockers include dizziness, headache, asthenia, postural hypotension, syncope, rhinitis, sexual dysfunction (22, 23). alpha1 ar subtypes are implicated in blood vessel contraction. the main alpha1 subtype in the large vasculature is the alpha1b ar. the blockage of this receptor is mainly responsible for side effects related to peripheral vasodilation, such as postural hypotension, dizziness, and headache (24-26). the alpha1d subtype is predominant and functional in human epicardial coronary arteries, and its inhibition might mediate coronary vasodilation (26). studies indicate differences among the various alpha1 blockers in terms of cardiovascular side effects (22). studies of pharmacy databases in europe suggest that the administration of alpha1 ar blockers increases the incidence of hip fractures (chosen as a surrogate for clinically important orthostatic hypotension) (25). further analysis with regard to the precise alpha1 ar antagonists prescribed suggests that avoidance of alpha1b ar blockade may result in fewer overall hip fractures (25). interestingly, alpha1 ar expression increases with aging, with the ratio of alpha1b: alpha1a increasing (25). alpha1 ar inhibitors with higher selectivity for the alpha1a subtype have been developed in order to reduce the cardiovascular side effects, while maintaining efficacy on urinary tract (26). tamsulosin preferentially blocks alpha1a and alpha1d ar, with a 10-fold greater affinity than for alpha1b ar. in contrast, silodosin is highly selective for alpha1a ar, with a 162fold greater affinity than alpha1b ar and about a 50-fold greater affinity than for alpha1d ar. the weak cardiovascular effects of silodosin have been demonstrated in many in vivo models (26). studies conducted recently have suggested that silodosin as a consequence of its high subtype selectivity is less likely than tamsulosin to have significant cardiovascular side effects either when used alone or in combination with other agents, which may affect blood pressure (24). an important characteristic of silodosin is the lack of clinically relevant or statistically significant changes in blood pressure or heart rate versus placebo (24). however, a minor but statistically significant difference versus placebo was observed with tamsulosin (24). in a study by yu hg et al., tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure relative to the negligible change of silodosin (27). the incidence of orthostatic hypotension with silodosin has been reported to be < 3% (28). in a study by marks et al., the proportions of patients with treatment emergent orthostatic hypotension were similar for silodosin (2.6%) and placebo (1.5%) (29). results from the present study demonstrate higher incidence of retrograde ejaculation in patients treated with silodosin but lower incidence of side effects related to peripheral vasodilation when compared to tamsulosin. the incidence of side effects is similar to that reported by other authors (23). the lower incidence of side effects related to peripheral vasodilation associated with silodosin use make it more suitable for older patients (24). by contrary, according to literature data, retrograde ejaculation does not appear to be particularly bothersome and only a small percentage of patients reporting this adverse effect enrolled in clinical studies discontinued treatments because of it (23). furthermore, this effect is fully and promptly reversible within a few days after discontinuation of treatment (23). by contrary, cardiovascular side effects may have a greater clinical relevance especially in older patients. the main limit of the present study is the retrospective design. further studies are needed to elucidate the efficacy of silodosin as met for distal ureteric stones. conclusions in conclusions, tamsulosin and silodosin are safe and effective treatments that enhance spontaneous passage of distal ureteric stones sized 10 mm or smaller. they appear to have similar profiles in terms of expulsion rates and times, mean number of pain episodes and need for analgesics. or study demonstrate a lower incidence of side effects related to peripheral vasodilation and an higher incidence of retrograde ejaculation with silodosin thus making this drug mainly suitable for older patients. acknowledgement of financial support there are no financial support. references 1. ahmed af, al-sayed ay. tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones:prospective, randomized, comparative study. korean j urol. 2010; 51:193-7. 2. dellabella m, milanese g, muzzonigro g. randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medicalexpulsive therapy for distal ureteral calculi. j urol. 2005; 174:167-72. 3. malin jm jr, deane rf, boyarsky s. characterisation of adrenergic receptors in human ureter.br j urol. 1970; 42:171-4. 4. küpeli b, irkilata l, gürocak s, et al. does tamsulosin enhance lower ureteral stone clearance with or without shock wavelithotripsy? urology. 2004; 64:1111-5. 5. yilmaz e, batislam e, basar mm, et al. the comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010-2. 6. itoh y, kojima y, yasui t, et al. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol. 2007; 14:749-53. 7. sasaki s, tomiyama y, kobayashi s, et al. characterization of α1-adrenoceptor subtypes mediating contraction in human isolated ureters. urology. 2011; 77:762.e13-7. 8. de sio m, autorino r, di lorenzo g, et al. medical expulsive treatment of distal-ureteral stones using tamsulosin: a single-center experience. j endourol. 2006; 20:12-6. 9. singh a, alter hj, littlepage a. a systematic review of medical therapy to facilitate passage of ureteral calculi. ann emerg med 2007; 50:552-63. 10. parsons jk, hergan la, sakamoto k, lakin c. efficacy of alpha-blockers for the treatment of ureteral stones. j urol. 2007; 177:983-7 11. hollingsworth jm, rogers ma, kaufman sr, et al, hollenbeck medical therapy to facilitate urinary stone passage: a meta-analysis. .lancet. 2006; 368:1171-9. 12. watts hf, tekwani kl, chan cw, et al. the effect of alphablockade in emergency department patients with ureterolithiasis. j emerg med. 2010; 38:368-73. 13. türk c, knoll t, petrik a, et al. guidelines on urolithiasis european association of urology updated march 2011. 14. kobayashi s, tomiyama y, hoyano y, et al. gene expressions and mechanical functions of α1-adrenoceptor subtypes in mouseureter. world j urol. 2009; 27:775-80. 15. itoh y, okada a, yasui t, et al. efficacy of selective α1a adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. int j urol. 2011; 18:672-4. 16. tsuzaka y, matsushima h, kaneko t, et al. naftopidil vs silodosin in medical expulsive therapy for ureteral stones: a randomized controlled study in japanese male patients. int j urol. 2011; 18:792-5. 17. tzortzis v, mamoulakis c, rioja j, et al. medical expulsive therapy for distal ureteral stones. drugs. 2009; 69:677-92. 18. griwan ms, singh sk, paul h, et al. the efficacy of tamsulosin in lower ureteral calculi. urol ann. 2010; 2:63-6. 19. al-ansari a, al-naimi a, alobaidy a, et al. efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients. urology. 2010; 75:4-7. 20. abdel-meguid ta, tayib a, al-sayyad a. tamsulosin to treat uncomplicated distal ureteral calculi: a double blind randomized placebo-controlled trial. can j urol. 2010; 17:5178-83. 21. agrawal m, gupta m, gupta a, et al. prospective randomized trial comparing efficacy of alfuzosin and tamsulosin inmanagement of lower ureteral stones. urology. 2009; 73:706-9. 22. chapple cr. a comparison of varying alpha-blockers and other pharmacotherapy options for lower urinary tract symptoms. rev urol. 2005; 7 suppl 4:s22-30. 23. montorsi f. profile of silodosin eur urol suppl. 2010; 491-495 24. chapple cr, montorsi f, tammela tl, et al. silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, doubleblind, placeboandactive-controlled clinical trial performed in europe. eur urol. 2011; 59:342-52. 25. yoshida m, kudoh j, homma y, et al. safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia. clin interv aging. 2011; 6:161-72. 26. rossi m, roumeguère t. silodosin in the treatment of benign prostatic hyperplasia. drug des devel ther. 2010; 27; 4:291-7. 27. yu hj, lin at, yang ss, et al. non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (luts) associated with benign prostatic hyperplasia (bph). bju int. 2011; 108:1843-8. 28. schilit s, benzeroual ke. silodosin: a selective alpha1a-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. clin ther. 2009; 31:2489-502. 29. marks ls, gittelman mc, hill la, et al. rapid efficacy of the highly selective alpha1a-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. j urol. 2009; 181:2634-40 107archivio italiano di urologia e andrologia 2014; 86, 2 medical expulsive therapy correspondence vittorio imperatore, md v.imperatore@alice.it massimilano creta, md (corresponding author) max.creta@gmail.com sergio di meo, md sedime72@yahoo.it roberto buonopane, md roberto.buonopane@libero.it department of urology, buon consiglio fatebenefratelli hospital via a. manzoni, 220 80123 naples, italy ferdinando fusco, md ferdinando-fusco@libero.it nicola longo, md nicolalongo20@yahoo.it ciro imbimbo, md ciro.imbimbo@unina.it vincenzo mirone, md vmirone@unina.it department of urology, policlinico federico ii of naples via s. pansini, 5 80131 naples, italy 293archivio italiano di urologia e andrologia 2018; 90, 4 case report advanced chondrosarcoma of the pelvis: a rare case of urinary obstruction valerio olivieri 1, valentina fortunati 1, scipio annoscia 1, massimo massarelli 1, luca bellei 1, massimo ollino 1, emy manzi 2, angela maurizi 3, francesco de luca 3 1 urology department, ivrea hospital asl to4, ivrea, turin, italy; 2 department of general surgery, santa scolastica hospital manzi, cassino (fr), italy; 3 department of gynaecological and urological sciences, sapienza university of rome, rome, italy. chondrosarcoma is the second most common malignant tumor of the bone with an incidence of 1 in 200.000 per year. axial skeleton is frequently involved showing poorer oncological outcomes than appendicular one: human pelvis is a site predilection (1). it is rarely associated to urinary obstruction but according to its localization, it can be frequently linked to compression of pelvic organs as bladder, prostate or bowel. we describe the case of a 52 years old caucasian male with history of advanced pelvic chondrosarcoma and severe hydronephrosis due to total bladder dislocation. key words: urology; urinary obstruction; hydronephrosis; bladder dislocation; pelvic chondrosarcoma. submitted 13 august 2018; accepted 19 august 2018 summary no conflict of interest declared. ultrasound was inconclusive being unable to visualize the pelvic organ due to skeleton artifacts due to his bone pathology. due to the discovery of bilateral hydronephrosis, the inability of bladder visualizing and the presence of a pelvic bone tumor, the patient underwent to no-contrast computerized tomography (ct) in order to exclude ureteric compression by the tumor: no iodinated contrast material was given due to renal failure. the exam confirmed a voluminous bilateral hydronephrosis and hydroureter highly suggestive for chronic distal obstruction (figure 1). no signs of urinary stones in both ureters were described. the scan also revealed a total bladder dislocation due to the pelvic chondrosarcoma (figure 2) originating from left ischiopubic ramus and occupying almost the entire pelvis (figure 3). as compared with a previous computerized tomography, it resulted highly increased in size and the bladder, which was previously orthotopic, was now entirely located and compressed in the upper part of the right pelvis. no visceral metastases were detected on tomography. patient urgently underwent bilateral nephrostomy tubes placing in order to drain hydronephrosis, improve renal failure and alleviate the flank pain. doi: 10.4081/aiua.2018.4.293 case report a 52 years old feeble-minded male presented to our facility for bilateral flank pain poorly responsive to nonsteroidal anti-inflammatory therapy. the patient was previously diagnosed with pelvic chondrosarcoma but due to his general conditions, the advanced state of the tumor and its localization, no further therapies were offered to him just suggesting best supportive care. he has suffered for several months but pain intensified during last weeks: the pain was described as severe, originating in the flank bilaterally, irradiating anteriorly and associated to nausea and vomiting. anyway he did not give history of urolithiasis, haematuria or previous flank pain episodes: no bowel diseases were mentioned. he solely referred a contraction of the diuresis which occurred during the last four weeks without any lower urinary tract symptoms. on physical examination he was alert and afebrile. the abdomen was soft with giordano’s test fully positive on bilateral flank: no signs of acute urinary retention was found neither evoked pain in hypogastric region. blood examination revealed severe renal failure with creatinine on the high values; anyway white blood cells and haemoglobin were both normal. abdominal ultrasound showed a voluminous bilateral renal pelvis with short residual parenchyma, highly suggestive for chronic distal obstruction. moreover bladder figure 1. bilateral hydronephrosis due to urinary obstruction. de luca _stesura seveso 15/01/19 10:42 pagina 293 archivio italiano di urologia e andrologia 2018; 90, 4 v. olivieri, v. fortunati, s. annoscia, m. massarelli, l. bellei, m. ollino, e. manzi, a. maurizi, f. de luca 294 discussion chondrosarcoma is a malignant tumor of the bone originating from axial or appendicular skeleton. femur and proximal humerus are frequently involved as site of predilection: pelvis localization is also much common and this represent a major risk factor for pelvic organs compression. bladder, bowel or major vessels may be easily involved but to our knowledge this is the first case in literature associated with severe bilateral hydronephrosis and total bladder dislocation. many authors have shown how a wide tumor resection is essential in the therapy of primary bone neoplasms in order to ensure long-term survival particularly in chondrosarcoma but tumor localization and pelvic organs involving may result as a challenging surgical case (2). anyway proper selection of patient, preoperative planning and reconstruction provides good functional outcome also in patients affected by pelvic chondrosarcoma following internal hemipelvectomy (3). in our case, due to general conditions and tumor extension, the patient was considered as unfit for any major surgical approach simply receiving palliative nephrostomy. conclusions pelvic chondrosarcoma have been rarely shown to cause total bladder dislocation and bilateral hydronephrosis but according to the risk of obstructive renal failure, the work-up of patient affected by this tumor should include a regular monitoring of renal function and mass growth. references 1. mavrogenis af, angelini a, drago g, et al. survival analysis of patients with chondrosarcomas of the pelvis. j surg oncol. 2013; 108:19-27. 2. guder wk, hardes j, gosheger m, et al. osteosarcoma and chondrosarcoma of the pelvis and lower extremities. chirurg. 2015; 86:993-1003. 3. salunke aa, shah j, warikoo v, et al. surgical management of pelvic bone sarcoma with internal hemipelvectomy: oncologic and functional outcomes. j clin orthop trauma. 2017; 8:249-253. figure 3. pelvic chondrosarcoma originating from left ischiopubic ramus. correspondence valerio olivieri, md valerio.olivieri@uniroma1.it valentina fortunati, md valentina.fortunati@email.it scipio annoscia, md sannoscia@aslto4.piemonte.it massarelli massimo, md mmassarelli@gmail.com luca bellei, md lbellei@aslto4.piemonte.it massimo ollino, md mollino@aslto4.piemonte.it sandro guglielmetti, md gugls76@yahoo.it urology dpt, ivrea hospital asl to4, piazza credenza 2, 10015 ivrea, turin, italy emy manzi, md emymanzi@gmail.com department of general surgery, santa scolastica hospital manzi, via san pasquale, 03043 cassino (fr), italy angela maurizi, md angmau81@hotmail.com francesco de luca, md (corresponding author) francescodeluca.md@gmail.com department of gynaecological and urological sciences, sapienza university viale dell'università, 31/33, 00161 roma, italy figure 2. total bladder dislocation due to pelvic chondrosarcoma. de luca _stesura seveso 15/01/19 10:42 pagina 294 stesura seveso 183archivio italiano di urologia e andrologia 2014; 86, 3 original paper influence of hcg on inducible nitric oxide synthase gene expression in ram testicular arteries maria matteo 1, annalisa rizzo 2, ettore cicinelli 3, elvira grandone 4, giuseppe cardo 5, donatella colaizzo 4, giuseppe minoia 2, laura castellana 6, ugo indraccolo 7, sonia marrocchella 1, pantaleo greco 1, raffaele luigi sciorsci 2 1 operative unit of obstetric and gynecology, department of surgical sciences, university of foggia, italy; 2 department of animal production, university of bari, italy; 3 3rd unit of obstetrics and gynecology, department of biomedical and human oncological science (dimo), university of bari, italy; 4 atherosclerosis and thrombosis unit, irccs “casa sollievo della sofferenza”, s. giovanni rotondo, foggia, italy; 5 operative unit of urology “s. giacomo” hospital, monopoli, italy; 6 department of biomedical sciences, university of foggia, italy; 7 operative unit of gynaecology and obstetrics of civitanova marche area vasta 3, marche, italy. background. experimental evidence suggests a relationship between the vasodilatory effect of hcg and the nos system in the testis. the influence of hcg administration on testicular vascular nos gene expression has not been fully investigated. objective: this study aimed to evaluate the presence of the nitric oxide syntheses gene in ram testicular arteries and the influence of hcg administration on its expression. materials and methods: both testicular arteries of sixteen rams were extracted before and after i.v. administration of 5000 iu of hcg or placebo. the expression of the inos gene was investigated by real time pcr. data were analyzed by means of wilcoxon and mann-whitney tests. a p value of < 0.05 was considered statistically significant. results: pcr revealed the presence of inos mrna in all basal samples but the expression of the inos gene was significantly reduced in all arteries obtained 24 h after the administration of either hcg or placebo. a significant reduction in the expression of inos gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups. on the other hand hcg stimulation did not significantly influence inos expression following its administration compared to a placebo. conclusion: ram testicular arteries express the inos gene but hcg stimulation did not significantly influence inos expression. a significant reduction in the expression of this gene was observed in the testicular arteries extracted after 24 h in both treated and placebo groups, suggesting that inos expression on the testicular artery could be influenced by the spermatic vessel ligation of the controlateral testis. key words: inos gene, testicular artery; hcg; ram; intratesticular blood flow. submitted 17 january 2014; accepted 15 may 2014 summary no conflict of interest declared. introduction gonadotrophin treatment is capable of increasing intratesticular blood flow (1-3). several mechanisms are described in the literature for explaining hcg induced vasodilatation in the testicular arteries (4). hcg was found to increase the expression of angiogenic factors such as vascular endothelial growth factor (vegf) and angiopoietin 2 (ang2) (5, 6). hcg was also found to induce an inflammation-like response via a local increase of pro-inflammatory cytokines such as il1 by the leydig cells (7, 8). several authors have suggested that the nitric oxide syntheses (nos) system may play a pivotal role in increasing testicular blood flow after hcg administration (9). under basal conditions, the vasodilatory effect of no resulted of limited importance in the testis than in other tissues but, after hcg treatment, nos activity was found to be increased, suggesting that the increase in testicular blood flow observed in hormonally stimulated testis could be related to an increase in testicular no synthesis (9). although several studies have suggested a strong relationship between the vasodilatory effect of hcg and the activity of the nos system, the influence of hcg administration on testicular vascular nos gene expression has not been fully investigated. the aim of this study was to evaluate the influence of exogenous hcg administration on inos expression in the ram testicular vasculature. material and methods testicular arteries were collected from 16 rams aged 4 to 6 years and weighing between 60 and 90 kg using an approach approved by the local ethical committee, in accordance with the national research council's (nrc) publication (10). rams were randomly allocated into two groups: eight animals received 5000 iu of hcg i.v. (corulon, intervet, italy), eight rams (control group), received an i.v. injection of placebo. before surgery, sedadoi: 10.4081/aiua.2014.3.183 matteo_stesura seveso 08/10/14 12:07 pagina 183 archivio italiano di urologia e andrologia 2014; 86, 3 m. matteo, a. rizzo, e. cicinelli, e. grandone, g. cardo, d. colaizzo, g. minoia, l. castellana, u. indraccolo, s. marrocchella, p. greco, r.l. sciorsci 184 tion of the rams was achieved by means of an i.v. administration of 0.1 ml/20kg of xilazina cloridrato 2% (rompum, bayer ag, germany) combined with an i.m. injection of 0.44 mg/10 kg of atropina solfato (ati, italy) and of 0.04 ml/10 kg of butorfanolo (dolorex, intervet, italy). the spermatic funiculus was isolated after a longitudinal incision of the skin and the testicular arteries were isolated and extracted from the right testis (figure 1). arteries of the opposite testis were isolated and extracted from the same rams, 24 hours (h) after the administration of hcg or placebo. the vascular samples obtained were immediately incubated in tubes containing 3 ml of trizol reagent (invitrogen, san giuliano milanese, milano, italy) and stored at -80°c until the examination. total rna was isolated from the tissue according to the manufacturer's instructions. phenol-phase separation was performed with gel-phase tube (eppendendorf) in order to prevent protein contamination of the rna. rna was then dissolved in 20 µl of rnase-free water and exposed to 55°c for 5 min to increase solubility. the rna concentration was determined at 260 nm with a plate-reading spectrophotometer. for the cdna synthesis, a mixture of 0.5 µg of total rna and 0.25 µg oligo dt (invitrogen) per sample was subjected to 65°c for 5 min to promote primer annealing. a volume of 20 µl of rt reaction solution containing 200 u of moloney murine leukimia virus reverse transcriptase and 8 µl of rt master mix composed of 1× rt buffer, 25 mm dtt and 1.25 mm dntp was incubated at 37°c for 70 min. the quantity inos gene mrna expression was evaluated by the abi 7700tm quantitative real time pcr system (applied biosystems, warrington, uk) and compared to the ovis aries housekeeping ! actin gene. the mgb probes used for quantification of the targets and endogenous controls were designed according to the taqman technology (applied byosistems) employing the primer express (applied biosystems) computer software using published gene sequences. the fluorescent signal from the dye 6carboxyfluorescein (6-fam) at the 5' end of the probe was quenched by another fluorochrome, vic, at the 3' end. the quenching effect terminated as the probe was cleaved due to the 5' exonuclease activity of the amplitaq gold (applied biosystems) enzyme and a fluorescent signal was emitted. the emittance resulted proportional to the amount of amplified product, until it reached the lag phase of the pcr. a threshold value set above the baseline reflected the average change in emittance during the first pcr cycles. the real-time pcr reactions were performed on plates using adhesive seals as covers. to quantify the mrna levels we used a relative standard curve method in which the untreated control was used as an appropriate calibrator. the sequences of the primers and probe are shown in table 1. each sample contained: 3 μl of cdna, taqman universal pcr master mix (12.5 μl), ! actin primers 900 nm and probe 200 nm, inos primers 900 nm and probe 200 nm and rnase-free water to a volume of 25 μl. amplification was performed for 10 min at 95°c, 45 cycles of 15 seconds at 95°c, 60 seconds at 60°c. gene expression levels were calculated using standard curves generated by serial dilutions of cdna. a strong correlation between pcr efficiency of the internal control (! actin) and the target allowed the use of the ""ct-method (applied biosystems) to quantify comparable mrna levels (11). three independent analyses were performed with replicates. data were analyzed by means of wilcoxon and mann-whitney tests and a p value of < 0.05 was considered statistically significant. results were expressed as means + standard deviation. results the real time pcr revealed the expression of inos mrna in samples obtained from all the 16 rams, without surgical complications. the descriptive statistics of the data are reported in table 2. figure 1. testicular artery isolated and extracted from the spermatic funiculum of the ram. primers ! actin primers inos fw: tcaagatcatcgcgccc rev: gccgccaatccacacg fw: caacatcaggtcggccatc rev: agtcatgcttcccatcgct probe ! actin mgb (vic): probe inos mgb (fam): ctgagcgcaagtac cgtgttcccccagc table 1. quantitative real time pcr system. sequences of the primers and probe used to evaluate inos gene mrna expression. n mean std. deviation minimum maximum percentiles 25th 50th median) 75th basal 1 8 1.00 0.000 1.00 1.00 1.00 1.00 1.00 24h trattati 8 0.34 0,39 0.01 1.08 0.05 0.13 0.68 24h placebo 8 0.36 0.28 0.03 0.81 0.13 0.28 0.66 table 1. descriptive statistics: the mean and median inos mrna expression in the arteries extracted after 24 h in both the treated and placebo groups matteo_stesura seveso 08/10/14 12:07 pagina 184 the mean and median inos mrna expression in the arteries extracted after 24 h in both the treated and placebo groups were reduced compared to the basal samples. moreover the mean and median in the group exposed to 24 hours of treatment were lower than those in the group exposed to 24 hours of placebo. the wilcoxon rank test was performed to evaluate differences both between basal versus 24 h treated samples and basal versus 24 h placebo. we found a significant (p < 0.05) decrease in the inos mrna expression in the arteries extracted after 24 h both when we compared basal versus 24 h treated samples (p = 0.017) and basal versus 24 h placebo samples (p = 0.012). the mann-whitney test was performed to evaluate differences between treated and controls after 24 h, and no significant difference was found (p > 0.05). discussion the study demonstrates that the inos gene is expressed in the testicular artery of the ram and that inos activity is not influenced by i.v. administration of hcg. in fact the effects on inos gene expression observed after 24 h in the hcg group did not differ from that observed in the placebo group (figure 2). several reports have been published concerning the role of the nos system in the male reproductive tract (1214). no was found to be of importance for sperm quality and sperm fertilization potential (15-18) and to influence the testicular vascular relaxation by increasing cgmp levels (12). however, under basal condition, in the unstimulated intact testis only low levels of nos activity have been detected (21, 22). accordingly the vasoconstrictor response to l-name nos inhibition is weak (5) and acetylcholine does not increase testicular blood flow (19, 20). conversely, experimental evidence suggests that, after hormonal stimulation, the nos system could play a role in the regulation of the testicular vascular system since the intensity of nadph staining of the testicular artery, known to be directly correlated with the nos activity, was found to increase after hcg treatment (9, 23, 24). furthermore treatment with l-name nos was found to increase vascular resistance in the testis after stimulation with hcg (9). notably we did not observe any difference in the inos gene expression of the testicular artery extracted 24 h after hcg administration, compared with the placebo group (means 0.36 + 0.28 and 0.29 + 0.23 respectively) (figure 2). these findings suggest that hcg treatment does not have a direct effect on inos activity in the testicular artery but the effects on testicular blood flow could be mediated by other factors. several reports could support this discrepancy. firstly, hcg treatment is known to induce an increase in testicular blood flow, but this effect is not observed in leydig cell-depleted animals, suggesting that the effect on blood flow is mediated by the increase in sex steroid secretion via stimulation of the leydig cells (2). secondly, studies have reported that hcg treatment results in local secretion within the testis of potent vasoconstrictors such as serotonin and endothelin-1 and that the increase in no synthesis occurs to balance the effects of such local vasoconstrictors (25, 26). moreover, other authors have speculated upon the presence of a permeability-inhibiting factor in testicular microvessels that is down regulated by hcg (7, 27). finally, hcg was found to increase the expression of angiogenic factors such as vegf (6) and the ang2, which are associated with an increase in vascular permeability (5, 6). in a previous report we demonstrated the presence of thromboxane a2 (txa2) receptors, known as tp# receptor, in the testicular artery of the ram. in addition, our results showed that tp# receptor gene expression was completely suppressed in all samples 24 hours after i.v. administration of 5000 iu of hcg, suggesting that a down regulation of txa2 activity could be an additional mechanism explaining the vasodilatory effect of hcg in the testis (28). this study support the hypothesis that the testicular vascular relaxation observed after hcg administration is not related to a direct effect of hcg on the testicular nos system, but could be mediated by the up and down regulation of the inhibiting and stimulating factors described above. unexpectedly, a significant reduction in inos gene expression was observed in the testicular arteries extracted after 24 h in both groups (figure 3), suggesting that the decrease in inos activity could be related to the spermatic vessel ligation of the contralateral testis. only a limited number of studies have reported the effect 185archivio italiano di urologia e andrologia 2014; 86, 3 hcg, nitric oxide on spermatic vessels figure 2. inos mrna expression in arteries obtained after 24 hours from the hcg and placebo groups. figure 3. inos mrna expression before and 24 hours after the administration of hcg or placebo. matteo_stesura seveso 08/10/14 12:07 pagina 185 archivio italiano di urologia e andrologia 2014; 86, 3 m. matteo, a. rizzo, e. cicinelli, e. grandone, g. cardo, d. colaizzo, g. minoia, l. castellana, u. indraccolo, s. marrocchella, p. greco, r.l. sciorsci 186 of spermatic vessel ligation (named fowler-stephens maneuver) on inos expression and no levels in the ipsilateral and contralateral testis, although it is the most popular method in the surgical management of high testes (29-31). these studies showed an increase in no levels and in inos immunostaining in both testes, whereas moderate inos immunostaining expression and germ cell apoptosis were observed in the contralateral testis 24 hours after ligation (31). these findings are partially in agreement with the results of the present study which point to potentially important physiological implications of the nos system in the physiopathology of testicular germ cell apoptosis observed after the fowler stephens maneuver. moreover, it may be supposed that an ipsilateral flow obstruction (as it happens during testicular torsion) may cause a contralateral vascular injury (32). conclusion the ram testicular artery expresses the inos gene but its expression and functional activity is not directly influenced by hcg stimulation. further investigations are needed to confirm these results and to elucidate the functional role and the mechanisms involved in the regulation of the testicular vascular nos system. references 1. matteo m, cicinelli e, baldini d, et al. influence of human menopausal gonadotrophin treatment on testicular blood flow and on seminal plasma nitric oxide levels in infertile males int j androl. 2006; 29:441. 2. bergh a, damber je, et al. does follicle-stimulating hormone or pregnant mare serum gonadotrophin influence testicular blood flow in rats? int j androl. 1992; 15:365. 3. causio f, matteo m, cicinelli e, et al. variation of intratesticular blood flow in response to urinary folliclestimulating hormone treatment in men with severe oligoteratoasthenozoospermia fertil steril. 2002; 78:1133. 4. damber j.e, bergh a, fagrell b, et al. testicular microcirculation in the rat studied by videophotometric capillaroscopy, fluorescence microscopy and laser doppler flowmetry acta physiol scand. 1986; 126:371. 5. rudolfsson sh, johansson a, franck lissbrandt i, et al. localized expression of angiopoietin 1 and 2 may explain unique characteristics of the rat testicular microvasculature biol reprod. 2003; 69:1231. 6. rudolfsson sh, wikstrom p, jonsson a, et al. hormonal regulation and functional role of vascular endothelial growth factor a in the rat testis biol reprod. 2004; 70:340. 7. bergh a, damber je, hjertkvist m. human chorionic gonadotrophin-induced testicular inflammation may be related to increased sensitivity to interleukin-1 int j androl. 1996; 19:229. 8. assmus m, svechnikov k, von euler m, et al. single subcutaneous administration of chorionic gonadotropin to rats induces a rapid and transient increase in testicular expression of pro-inflammatory cytokines pediatr res. 2005; 57:896. 9. lissbrant e, lofmark u, collin o, bergh a. is nitric oxide involved in the regulation of the rat testicular vasculature? biol reprod. 1997; 56:1221. 10. nrc guide for the care and use of agricultural animals in agricultural research and teaching. consortium for developing a guide for the care and use of agricultural animals in agricultural research and teaching. champaign, il, 1988. 11. livak jk, schmittgen td. analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c (t)) methods. 2001; 25:402. 12. middendorff r, muller d, wichers s, et al. evidence for production and functional activity of nitric oxide in seminiferous tubules and blood vessels of the human testis j clin endocrinol metab. 1997; 82:4154. 13. battaglia c, giulini s, regnani g, et al. seminal plasma nitrite/nitrate and intratesticular doppler flow in fertile and infertile subjects hum reprod. 2000; 15:2554. 14. zini a, o'bryan m.k, magid m.s, schlegel pn. immu nohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death biol reprod. 1996; 55:935. 15. zhang h, zheng rl. possible role of nitric oxide on fertile and asthenozoospermic infertile human sperm functions free radic res. 1996; 25:347. 16. herrero mb, viggiano jm, perez-martinez s, et al. evidence that nitric oxide synthase is involved in progesterone-induced acrosomal exocytosis in mouse spermatozoa reprod fertil dev. 1997; 9:433. 17. o'bryan mk, zini a, cheng cy, schlegel pn. human sperm endothelial nitric oxide synthase expression: correlation with sperm motility fertil steril. 1998; 70:1143. 18. sengoku k, tamate k, yoshida t, et al. effects of low concentrations of nitric oxide on the zona pellucida binding ability of human spermatozoa fertil steril. 1998; 69:522. [19. noordhuizen-stassen en, beijer g, wensing cj. the effect of norepinephrine, isoprenaline and acetylcholine on testicular and epididymal circulation in the pig int j androl. 1983; 6:44. 20. whittle bj. nitric oxide in physiology and pathology histochem j. 1995; 27:727. 21. burnett al, ricker dd, chamness sl, et al. localization of nitric oxide synthase in the reproductive organ of the male rat biol reprod. 1995; 52:1. 22. ehren i, adolfsson j, wiklund np. nitric oxide synthase activity in the human urogenital tract urol res. 1994; 22:287. 23. brendt ds , hwang pm, synder s.h. localization of nitric oxide synthase indicating a neuronal role for nitric oxide nature. 1990; 347:768. 24. hope bt, michael gj, knigge km, vincent s. neuronal nadph diaphorase is a nitric oxide synthase proc natl acad sci usa 1991; 88:2811. 25. collin o, damber je, bergh a. 5-hydroyxytryptamine a local regulator of testicular blood flow and vasomotion in rats j reprod fertil. 1996; 106:17. 26. collin o, damber je, bergh a. effects of endothelin-1 on the rat testicular vasculature j androl. 1996; 17:360. 27. hjertkvist m, bergh a. the time response and magnitude of hcg induced vascular changes are different in scrotal and abdominal testes int j androl. 1993; 16:63. matteo_stesura seveso 08/10/14 12:07 pagina 186 28. matteo m, cicinelli e, sciorsci rl, et al. expression and hormonal modulation of the thromboxane a2 receptor gene in mammalian testicular arteries fertil steril 2006; 85:1276. 29. levy da, abdul-karim fw, miraldi f, elder js. effect of human chorionic gonadotropin before spermatic vessel ligation in the prepubertal rat testis j urol. 1995; 154:738. 30. taneli f, vatansever s, ulman c, giray g, genc a, tanel c. pre-ischemic administration of nitric oxide synthase inhibitors reduced germ cell apoptosis after spermatic vessel ligation in the rat testis urol int. 2005; 75:70. 31. taneli f, vatansever s, ulman c, et al. the effect of spermatic vessel ligation on testicular nitric oxide levels and germ cell-specific apoptosis in rat testis acta histochem. 2005; 106:459. 32. ozkan ku, küçükaydin m, muhtaroglu s, kontas o. evaluation of contralateral testicular damage after unilateral testicular torsion by serum inhibin b levels j pediatr surg. 2001; 36:1050. 187archivio italiano di urologia e andrologia 2014; 86, 3 hcg, nitric oxide on spermatic vessels correspondence maria matteo, md, phd (corresponding author) maria.matteo@unifg.it sonia marrocchella, md pantaleo greco, md institute of obstetrics and gynecology department of medical and surgical sciences, university of foggia, viale pinto 71100 foggia, italy annalisa rizzo, md giuseppe minoia, md raffaele luigi sciorsci, md department of animal production, university of bari, bari, italy ettore cicinelli, md 3rd unit of obstetrics and gynecology, department of biomedical and human oncological science (dimo) university of bari, bari, italy elvira grandone, md donatella colaizzo, md atherosclerosis and thrombosis unit, irccs “casa sollievo della sofferenza” s. giovanni rotondo, foggia, italy giuseppe cardo, md operative unit of urology “s. giacomo" hospital, monopoli, italy laura castellana, md department of biomedical sciences, university of foggia, foggia, italy ugo indraccolo, md operative unit of gynaecology and obstetrics of civitanova marche area vasta 3 civitanova marche, italy matteo_stesura seveso 08/10/14 12:07 pagina 187 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4280 original paper current approach for urinary system stone disease in pregnant women orcun celik, hakan türk, ozgur cakmak, rahmi gokhan ekin, mehmet zeynel keskin, guner yildiz, yusuf ozlem ilbey urology department, tepecik educational and research hospital, i̇zmir, turkey. urinary system stones can be classified according to size, location, x-ray characteristics, aetiology of formation, composition, and risk of recurrence. especially urolithiasis during pregnancy is a diagnostic and therapeutic challenge. in most cases, it becomes symptomatic in the second or third trimester. diagnostic options in pregnant women are limited due to the possible teratogenic, carcinogenic, and mutagenic risk of foetal radiation exposure. clinical management of a pregnant urolithiasis patient is complex and demands close collaboration between patient, obstetrician and urologist. we would like to review current diagnosis and treatment modalities of stone disease of pregnant woman. key words: urinary stone disease; pregnancy; hydronephrosis; renal colic. submitted 5 january 2015; accepted 31 march 2015 summary no conflict of interest declared. ment treatments and increased vitamin d level increase calcium excretion in the urine (13, 16-25). furthermore, uric acid, sodium, oxalate and other lithogenic factors show increase during pregnancy (7, 19, 20). calcium phosphate stones are observed in 75% of the pregnant women, whereas in general population usually calcium oxalate stones are prevalent (10, 14, 26-31). urinary stone disease involves some risks for the pregnant woman and her fetus. though data are contradictive, preterm delivery, miscarriage, premature rupture of membrane, recurrent miscarriages and preeclampsia might be included among these risks (9, 11, 31-36). importance of diagnosis and treatment of urinary stone disease is evident considering the complications that might be encountered. diagnosis the gold standard for the diagnosis of urinary stones in non-pregnant patients is computed tomography (37-42). however, its application in pregnant women is limited due to teratogenic effects of radiation. therefore, the most appropriate first-choice diagnostic tool in pregnant women, despite its 60-78% sensitivity, is gray scale ultrasonography (usg) (43-46). ureteral stones might be difficult to demonstrate with usg given to their localization; in this case, assessing resistive index (ri) (> 0.70) with doppler usg (cdusg), whose popularity has increased in recent years, will drive the sensitivity up to 90% in order to display the presemce of obstruction (although the stone cannot be shown) (47, 48). although ri evaluation will not reveal the cause of obstruction, it is crucial in terms of showing the necessity of intervention. in pregnancy, dilation is observed three times more in the right kidney than it is in the left and it mostly occurs in the mid-trimester. reasons for more frequent observation of dilation in the right kidney might be listed as: sigmoid colon’s relative protection of the left ureter from pressure in the left side, high stress and pressure in the right ureter due to the more proximal intercrossing of iliac veins by right ureter and as the most important factor, dextro-rotation of growing uterus in midtrimester (49-50). transvaginal usg might also be useful in distinguishing this physiological hydronephrosis, observed almost in 90% of the pregnant women, from doi: 10.4081/aiua.2015.4.280 introduction urinary system stone disease affects 10% of the population in a life time. the increase in this rate in the last decade is attributed to the developing imaging methods and more frequent use of imaging as well as to dietary habits, changing climate conditions, increasing obesity and diabetes mellitus (dm) (1-4). although urinary stone disease used to be more widespread amongst men, the difference between genders disappeared with the increase of urinary system stone incidence in women (2, 5). urinary stone disease is observed in one in 500 pregnant women, but there is no difference in prevalence when pregnant and non-pregnant groups of similar age are compared (6-13). in pregnant women, the most noticeable cause of admission to hospital for non-obstetric purposes is urinary system stone disease (14, 15). the causes of this condition are the anatomical and physiological changes observed in pregnant women in the structure of urinary system and in the chemical properties of urine. these changes were summarized in the table 1. increasing progesterone causes dilatation in the smooth muscles of urinary system and dilation and stasis occur in the urinary system as a result of mechanical pressure from the fetus. increasing glomerular filtration, calcium supple281archivio italiano di urologia e andrologia 2015; 87, 4 current approach for urinary system stone disease in pregnant women ureter stones in the distal part of ureter (13, 23, 51). if the accuracy of diagnosis is doubted, then magnetic resonance urography (mru) can be used as a second option. mru is comparable to ct and has the advantage of requiring safe and effective contrast media (52-55). at mru, stones appear as storage defects and at the same time mru may inform the physician of other causes that might lead to obstruction and about organs outside the urinary system. popularity of low dose ct (0.97-1.9 msv) with decreased radiation risk, as a last resort, has been increasing in the last years due to its high sensitivity (96.6%) and specificity (94.9%) (56-60). their insufficiency in diagnosis and the risk of complications they trigger during pregnancy, limit the use of direct urinary system graphy (dusg), intravenous urography (ivu), scintigraphic methods and magnetic resonance imaging (mri) (31, 61-65). as above reported, the sensitivity and specificity of imaging methods that can be applied during pregnancy are inadequate and the risks of those with high sensitivity limit their use during pregnancy. because of these reasons, urinary stone disease in pregnant women is already complicated at the stage of diagnosis. in a study, the rate of negative ureteroroscopy (urs) in pregnant women was found to be 14% (66). since the physiologic dilation (depending on fetal pressure especially in the right side) can be misdiagnosed as obstruction by a stone of the distal part of the ureter, the role of imaging methods become prominent to avoid invasive procedures based on false positive and the complications that could occur as a result. treatment modalities due to potential complications, diagnosis and treatment of urinary system stone disease in pregnant women should be closely followed with a multidisciplinary approach by an urologist, a neonatologist, an anesthetist and an obstetrician. in order to minimize the complications, the primary method should be the conservative treatment. in a study conducted by skolarikos et al., conditions that make patients eligible for conservative treatment are listed as: single stone, smaller than 1 cm and with no infection; effective pain management and conserved oral intake (67). most of the pregnant women with kidney stone can receive conservative treatment (17, 68, 69). ureter stones become symptomatic mostly in the midtrimester and this necessitates an intervention (45, 70). in non-pregnant patients spontaneous passage is reported to be 68% in patients with < 5 mm stone size and 47% in those with > 5 mm stone size (71), whereas during pregnancy spontaneous passage rate is 70-80%, with some women experiencing spontaneous passage after delivery at a rate of 50% (17, 11, 31, 34, 36, 69, 72, 73). although some authors argue that spontaneous passage during pregnancy would be higher due to physiologic ureteral dilatation, there are others who think otherwise (10). because of the limitations in diagnostic methods, the rate of false positive results is high and is reported as high as 23% according to the results of a study (74). for this reason, they argued that the high rate of spontaneous passage is based on misdiagnosis. in conservative approache, patients must be attentively followed with physical examination, vital findings, total blood count, blood biochemistry and usg. a) met (medical expulsive therapy) in addition to conservative treatment, spontaneous passage rate can be increased by medical expulsive therapy (met) in these patients. as a part of met, alpha blockers and calcium channel blockers can be safely used during pregnancy (75). as some patients are not eligible for met and conservative treatment, the treatment may also fail in others who fit. in particular, fever, infection and obstetric complications are indicative of intervention to the stone. also solitary kidney or occurrence of bilateral obstruction necessitate immediate intervention. finally, intervention must be taken into account in the case of intractable pain, oral intake problems and stones that are larger than 1 cm (76). cardio-pulmonary changes during pregnancy and limitations in imaging further complicate treatment environment (17). therefore, intervention team must be composed of an experienced urologist, an obstetrician, a neonatologist, a radiologist and an anesthetist and the patient should be closely followed and monitored. intervention is necessary in aforementioned conditions, however, another crucial point is whether it will be a temporary drainage or a definitive treatment. moreover, the question of whether the percutaneous drainage or the retrograde ureteral stenting is more convenient needs to be answered. with the technological advances in recent years definitive treatment became more prominent and ureterorenoscopy (urs) too is more frequently preferred (17, 77). however, extracorporeal shock wave lithotripsy (eswl) and percutaneous nephrolithotomy (pcnl) are still contraindicate in pregnant women (78-80). b) urs (ureterorenoscopy)+lithotripsy endourologic intervention is being increasingly preferred in line with the fast development of endourology in concert with technological advances. with the miniaturization of urs and enhancement of imaging quality, use of baskets, stone cone and lasers to this process was accelerated. in addition to this, development of monitoring methods used in post-operative follow-up of the patient and fetus also contributes to the process. besides all these developments, the risk of surgery and the complexity of the procedure should be kept in mind and shared explicitly with the patients. if the definitive treatment is decided, an experienced team, new equipment and post-operative monitoring must be provided. urs, which is a definitive treatment method, can be applied under spinal or general anesthesia and is a successful procedure considering the results. in a meta-analysis of 14 studies, complication rates of 108 pregnant women who were administered urs were found similar with that of general population and as a consequence the safety and efficiency of urs during pregnancy was highlighted (81). in recent years, records of pregnant women who were administered urs were published and results were reported in table 2 (26, 82-87). furthermore, a study carried out by johnson et al. involving 46 patients reported 2 premature labors, one resulting in delivery (86). if the patient suffers from an active infection or has archivio italiano di urologia e andrologia 2015; 87, 4 o. celik, h. türk, o. cakmak, r. gokhan ekin, m. zeynel keskin, g. yildiz, y. ozlem ilbey 282 fever, urs is contraindicate because in this case applying a procedure that would drive up the pressure in collecting tubules would aid to infection’s progress, and therefore the obstructed system must be immediately drained. temporary drainage methods should also be applied in case of oversized stone, complex anatomy, bilateral obstruction, obstetric complications, first trimester and being close to delivery (77, 88). in deciding the method, experience of the physician, preference of the patient and the available options are to be considered. c) temporary drainage: percutaneous nephrostomy (pcn) or double j stenting (djs) djs and usg with pcn are the most frequently employed methods in the treatment of urinary obstructions (89, 90). despite its advantages such as only requiring quick and minimal anesthesia, temporary drainage also has many disadvantages. in addition to inadequacy of temporary drainage in comparison to definitive treatment, disruption of the treatment, as the family focuses on the child, may also result in forgotten stent cases. physiologic changes during pregnancy involve the necessity of multiple procedures because encrustation of the catheter is accelerated requiring substitution every 4-6 weeks (91-93). this drives up the cost and endangers both the mother and the fetus. inability to tolerate temporary drainage, catheter migration and bacterial colonization makes it sometimes unbearable for the patient. percutaneous nephrostomy is a procedure first described by goodwin et al. in 1955 (94). up to today, it is effectively used under local anesthesia with 98-100% success rate in obstructed systems (95). major complication rate of pcn is 6% whereas minor complication rate is about 28% (96). according to these rastes, it is not at all an harmless procedure. therefore, patients that will undergo this procedure must be chosen with caution. if pcn has to be placed in an obstructed and infected system, a wide spectrum antibiotic treatment (ampiciline-sulbactam) is mandatory, in other cases a prophylaxis with first-generation cephalosporin is indicated (97, 98). important advantages of pcn are the absence of lower urinary system complaints and provides access for later definitive treatment (17, 99). djs can be applied with 94.2% success rate with local anesthesia (100). general opinion is that djs would be more tolerated since it cannot be viewed outside the body by the patient, however it is disadvantageous in terms of causing lower urinary system complaints. because it could be blocked and bacterial colonization could occur, djs must be changed every 4-6 weeks (9193). in fact djs encrustation and stone formation are physiologic changes in the kidney occurring during pregnancy stone-inducing factors * renal blood flow increases, leading to a 30% to 50% rise in glomerular filtration rate * increases the filtered loads of calcium, sodium, and uric acid (mcaleer and loughlin, 2004) * hypercalciuria is further enhanced by placental production of 1,25 (oh) 2d3, which increases intestinal calcium absorption and secondarily suppresses pth (gertner et al, 1986; biyani et al, 2002) * hyperuricosuria has also been reported as a result of increased filtered load of uric acid (swanson et al, 1995) physiologic changes in the kidney occurring during pregnancy stone inhibitors factors * increased excretion of citrate, magnesium, glycoproteins, uromodulin, and nephrocalcin (increased gfr) (maikranz et al, 1987; smith et al, 2001). table 1. physiologic changes in the kidney occurring during pregnancy. literature patients (n) complications n (%) semins et al. (81) meta-analysis of 14 studies 108 9 (8.3) – ureteral perforation (1), premature contractions (1), postoperative pain (2), uti (5) travassos et al. (83) 9 0 (0) rana et al. (84) 19 0 (0) polat et al. (82) 8 0 (0) table 2. complication rates of ureteroscopy during pregnancy. djs 1. catheters cannot be observed outside the body 2. lesser risk of hemorrhage (5c) 3. interventional radiologist is not needed, any urologist can apply 4. no need for anesthesia pcn 1. catheters can be placed in different sizes (8-12 fr) 2. catheter can be irrigated 3. urine can be followed from the implanted kidney 4. ureteral complications can be avoided 5. placement can be made with local anesthesia table 3. advantages of djs and pcn. 283archivio italiano di urologia e andrologia 2015; 87, 4 current approach for urinary system stone disease in pregnant women usually seen in patients that had the stent for more than 3 months (89). similar results were reported in studies that compare the success of dsj and pcn (101) and advantages of dsj and pcn were listed in table 3. disadvantages of temporary drainage methods emphasize the importance of definitive treatment. however, the most important factors in deciding the treatment are assessing the patient, considering the contraindications, experience of the physician and patient’s decision on treatment made in full awareness of the risks (77). conclusion both the diagnosis and the treatment of urinary system stone disease is difficult during pregnancy. in deciding the treatment, success of the method, its convenience and the risks that the mother and fetus may suffer from must be considered. after these considerations, patients must be informed of all possible risks, and decision should be made by taking into account the experience of the physician, available equipment and preference of the patient. even when all the conditions are favorable, natural complications of patient population must be regarded and attentively followed. references 1. pearle ms, calhoun ea, curhan gc. urologic diseases of america project. urologic diseases in america project: urolithiasis. j urol. 2005; 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89:819. 64. webb ja, thomsen hs, morcos sk, et al. the use of idoinated and gadolinium contrast media during pregnancy and lactation. eur radiol. 2005; 15:1234. 65. irving so, burgess na. managing severe loin pain in pregnancy. bjog. 2002; 109:1025. 66. white wm, johnson eb, zite nb, et al. predictive value of current imaging modalities for the detection of urolithiasis during pregnancy: a multicenter, longitudinal study. j urol. 2013; 189:931. 67. skolarikos a, laguna mp, alivizatos g, et al. the role for active monitoring in urinary stones: a systematic review. j endourol. 2010; 24:923-30. 68. mcaleer sj, loughlin kr. nephrolithiasis and pregnancy. curr opin urol. 2004; 14:123-127. 69. evans hj, wollin ta. the management of urinary calculi in pregnancy. curr opin urol. 2001; 11:379-384. 70. denstedt jd, ravzi h. management of urinary calculi during pregnancy. j urol. 1992; 108: 1072-1075. 71. preminger gm, tiselius hg, assimos dg, et al. american urological association education and research, inc; 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42:263. 92. kavoussi lr, albala dm, basler jw, et al. percutaneous management of uroltihiasis during pregnancy. j urol. 1992; 148:1069. 93. khoo l, anson k, patel u. success and short-term complication rates of percutaneous nephrostomy during pregnancy. j vasc interv radiol. 2004; 15:1469. 94. goodwin we, casey wc, woolf w. percutaneous trocar (needle) nephrostomy in hydronephrosis. j am med assoc. 1955; 157:891-894. 95. millward sf. percutaneous nephrostomy: a practical approach. j vasc interv radiol. 2000; 11:955-964 96. lee wj, patel u, patel s, pillari gp. emergency percutaneous nephrostomy: results and complications. j vasc interv radiol. 1994; 5:135-139 97. venkatesan am, kundu s, sacks d, et al. practice guidelines for adult antibiotic prophylaxis during vascular and interventional radiology procedures. written by the standards of practice committee for the society of interventional radiology and endorsed by the cardiovascular interventional radiological society of europe and canadian interventional radiology association. j vasc interv radiol. 2010; 21:1611-1630. 98. li ac, regalado sp. emergent percutaneous nephrostomy for the diagnosis and management of pyonephrosis. semin intervent radiol. 2012; 29:218-25. 99. van sonnenberg e, casola g, talner lb, et al. symptomatic renal obstruction or urosepsis during pregnancy: treatment by sonographically guided perctaneous nephrostomy. am j roentgenol. 1992; 158:91-94. 100. memon na, talpur aa, memon jm. indıcations and complications of indwelling ureteral stenting at nmch, nawabshah. pak j surg. 2007; 23:187-91. 101. pearle ms, pierce hl, miller gl, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol. 1998; 160:1260. correspondence orcun celik, md (corresponding autor) orcuncelik82@hotmail.com hakan türk, md ozgur cakmak, md rahmi gokhan ekin, md mehmet zeynel keskin, md guner yildiz, md yusuf ozlem ilbey, md tepecik educational and research hospital, urology department 35170, izmir, turkey stesura seveso 87archivio italiano di urologia e andrologia 2015; 87, 1 case report unusual case of locally advanced and metastatic paratesticular liposarcoma: a case report and review of the literature stefano chiodini 1, lorenzo g. luciani 1, tommaso cai 1, alberto molinari 2, luca morelli 3, chiara cantaloni 3, mattia barbareschi 3, gianni malossini 1 1 department of urology, santa chiara hospital, trento, italy; 2 department of urology, don calabria-sacro cuore hospital, negrar (vr), italy; 3 department of pathology, santa chiara hospital, trento, italy. liposarcoma accounts for 20% of all sarcomas and is a rare occurrence in the paratesticular region. we present the case of a 66-year-old man with a massive liposarcoma of the right scrotum invading the lower limb and the abdominal wall skin. the case concerns an unusually large and aggressive liposarcoma (25 cm), presenting with multiple lung and nodal metastases. the patient had an unfavourable evolution with rapid progression of metastases, although there were no signs of local disease. in this case, a wide local excision was performed in order to obtain local control of the disease. even though paratesticular sarcomas might have a more favourable evolution, the association with lung involvement carries an ominous prognosis. diagnosis of paratesticular sarcoma should be kept in mind in case of irregular necrotic masses in the inguinal and scrotal region. key words: liposarcoma; testicular neoplasms; case report; spermatic cord; orchiectomy. submitted 15 february 2015; accepted 2 march 2015 summary no conflict of interest declared. of the right inguinal and scrotal region associated with necrotic ulceration of the skin. general conditions at presentation were poor; the patient reported a slowly growing mass since one year. medical history included previous cholecystectomy, hypertension and mild lower urinary tract symptoms. physical examination revealed a large solid mass extending from the right scrotum to the inguinal region and to the ipsilateral thigh, associated with a deep necrotic ulceration at the root of the scrotum. the right testis was increased in volume and hard. the left testis and the penis were intact and dislodged laterally by the mass. beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase were normal, while creactive protein and leukocytes were elevated. staging ct scan showed a 25 cm paratesticular solid mass with colliquative areas, slightly increased nodes in the inguinal and external iliac region, and multiple pulmonary solid nodules ranging from a few mm to 3 cm. the patient underwent surgical wide excision of the mass, including the right testicle and all right inguinal canal contents up to the deep inguinal ring by inguinotomy access (inguinal incision). no postoperative complications were reported. histopathology revealed an undifferentiated liposarcoma infiltrating the testis abscessed to the overlying skin with extensive necrotic areas. adjuvant chemotherapy, initially suggested, was afterwards aborted due to cardiological complications and supportive care only was provided. at follow-up ct scan at 3 and 6 months, progression of lung metastases and right inguinal-external iliac lymph nodes was reported; surgical wound was regular. the patient died 9 months postoperatively for respiratory insufficiency due to further progression of lung metastases. discussion sarcomas of the genitourinary tract account for fewer than 5% of sarcomas. the first case of a spermatic cord sarcoma was reported in 1845 by lesauvage (6). sarcomas of soft tissue origin derive embryologically from mesodermal tissues and can occur in many organs. doi: 10.4081/aiua.2015.1.87 introduction liposarcoma accounts for 20% of all sarcomas and is a rare occurrence in the paratesticular region. approximately 200 cases of paratesticular liposarcoma (pls) have been reported in the literature (1). the optimal treatment of these tumours remains controversial, but there is a general consensus that all paratesticular sarcomas in adults should be managed with complete resection, including high ligation of the spermatic cord (2-5). we report one of the largest pls with an unfavourable prognosis in spite of aggressive surgical treatment. we present the case of a 66-year-old man with a massive liposarcoma of the right scrotum invading the lower limb and the abdominal wall skin. case report a 66-year-old man was referred for a bulky painless mass chiodini_stesura seveso 02/04/15 10:30 pagina 87 archivio italiano di urologia e andrologia 2015; 87, 1 s. chiodini, l.g. luciani, t. cai, a. molinari, l. morelli, c. cantaloni, m. barbareschi, g. malossini 88 although rare in the genitourinary tract, they can occur in spermatic cord, scrotum, and epididymis and resemble their counterparts in other organs. in adults, liposarcomas represent the most common soft-tissue sarcomas, and usually occur in patients older than 40 years. liposarcomas of the spermatic cord usually begin to grow directly below the external inguinal ring, so when the tumours reach a large size, they present as painless scrotal rather than inguinal mass (7). pls most commonly originates in the spermatic cord; however, because of the difficulty in determining the exact site of origin, pls include all liposarcomas rising in the structures around the testis, including the lower end of the cord. these tumours are often well-differentiated, and only 40% of the poorly differentiated liposarcomas metastasize (8). the diagnosis is usually obtained by ultrasound detection of an indolent scrotal or inguinal mass. additional radiologic studies might detect retroperitoneal or pulmonary involvement. sarcomas tend to infiltrate local tissues widely, making complete resection difficult. it has been suggested that at least a third of patients after local excision or orchidectomy occult local residual disease (4). therefore, primary treatment should consist of a wide local excision, orchiectomy and with re-excision, if needed, to ensure negative margins. retroperitoneal lymphadenectomy is used for some cases of rhabdomyosarcoma and for other sarcomas with proven lymphatic invasion. mortality and morbidity depend on histologic tumour type, tumour stage, and the presence of sarcoma at the surgical margin of the specimen. well-differentiated liposarcomas tend to recur over many years, but they do not metastasize. there are no large studies of liposarcomas with adequate follow-up, but myxoid/round cell and de-differentiated liposarcomas may persist, recur, or metastasize (7). recurrences are seen in 1/4 patients and metastases are seen in 1/10 patients with spermatic cord liposarcoma through lymphatic or haematogenous spread. if a sufficient tumour-free margin cannot be achieved, adjuvant radiotherapy covering the inguinal region and scrotum should be considered. the case we report concerns an unusually large and aggressive liposarcoma (25 cm), presenting with multiple lung and nodal metastases. the patient had an unfavourable evolution with rapid progression of metastases, although there were no signs of local disease. in this case, a wide local excision was performed in order to obtain local control of the disease. even though paratesticular sarcomas might have a more favourable evolution, the association with lung involvement carries an ominous prognosis. diagnosis of paratesticular sarcoma should be kept in mind in case of irregular necrotic masses in the inguinal and scrotal region. conclusion the relative paucity of cases reported in the literature makes it difficult to document the natural history for such a tumour. the information used to guide treatment is based on previous experiences from groups of few patients: no clear consensus exists regarding the proper treatment. radical orchiectomy with wide local excision provides ideally the best chance of eradicating this disfigure 1. the figure shows large solid mass with deep necrotic ulceration at the root of the right scrotum. panel a: patient at presentation. panel b: surgical specimen. figure 2. the figure shows microscopic findings. panel a: area of dedifferentiated liposarcoma. presence of large, round cells with nuclear abnormalities in a background of spindle and rounded cells (ee, 20x). panel b: particular of previous picture (ee, 40x). chiodini_stesura seveso 02/04/15 10:30 pagina 88 89archivio italiano di urologia e andrologia 2015; 87, 1 unusual case of locally advanced and metastatic paratesticular liposarcoma: a case report and review of the literature ease; however, the association with distant metastases implies an ominous prognosis. the diagnosis of liposarcoma should be kept in mind in case of a large solid mass in the paratesticular region with irregular margins. references 1. frank i, takahashi s, tsukamoto t, lieber mm. genitourinary sarcomas and carcinosarcomas in adults. in: vogelzang nj, shipley wu, scardino pt, coffey ds, eds. comprehensive textbook of genitourinary oncology. 2nd ed. philadelphia: lippincott williams & wilkins. 2000; 1110-3. 2. merimsky o, terrier p, bonvalot s, et al. spermatic cord sarcoma in adults. acta oncologica. 1999; 38:35-8. 3. catton cn, cummings v, fornasier b, et al. adult paratesticular sarcomas. a review of 21 cases. j urol. 1991; 146:342-5. 4. catton cn, jewett m, o’sullivan i, kandel r. paratesticular sarcoma: failure pattern after definitive local therapy. j urol. 1999; 161:1844-7. 5. fagundes ma, zietman al, althausen af, et al. the management of spermatic cord sarcoma. cancer. 1996; 77:1873-6. 6. f. hinman f, gibson te. tumors of the epididymis, spermatic cord and testicular tunics: a review of literature and report of three new cases. archives of surgery 1824; 8: article 100. 7. zhou m, magi-galluzzi c. genitourinary pathology: a volume in the series foundations in diagnostic pathology. first edition. chapter 10, pp.534-622. 8. stout ap. liposarcoma the malignant tumor of lipoblasts. ann surg. 1944; 119:86-107. correspondence stefano chiodini, md (corresponding author) stefano.chiodini@apss.tn.it lorenzo g. luciani, md tommaso cai, md department of urology, santa chiara hospital largo medaglie d’oro 9, 38122 trento, italy alberto molinari, md department of urology, don calabria-sacro cuore hospital, negrar (vr), italy luca morelli, md chiara cantaloni, md mattia barbareschi, md gianni malossini, md department of urology, santa chiara hospital, trento, italy chiodini_stesura seveso 02/04/15 10:30 pagina 89 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 2154 short communication lower urinary tract symptoms associated with neurological conditions: observations on a clinical sample of outpatients neurorehabilitation service fabrizio torelli 1, erica terragni 2, salvatore blanco 1, natale di bella 2, marco grasso 1, donatella bonaiuti 2 1 division of urology and. 2 division of neurorehabilitation, san gerardo hospital, monza, italy. objectives: the overall aims of this study were to investigate the lower urinary tract symptoms (luts) associated with neurological conditions and their prevalence and impact on a clinical sample of outpatients of a neurorehabilitation service. materials and methods: we reviewed the files of 132 patients treated in our neurorehabilitation service from december 2012 to december 2013. patients were divided into several subgroups based on the neurological diagnosis: multiple sclerosis (ms), other demyelinating diseases, peripheral neuropathy, neurovascular disorders (nd), neoplastic disease, traumatic brain injury (tbi), parkinson and parkinsonism, spinal cord injuries (sci). urinary status was based on medical evaluations of history of luts, type, degree, onset and duration of symptoms. we tried to analyze prevalence, kind of disorder, timing of presentation (if before or after the neurological onset) and eventual persistence of urological disorders (in the main group and in all subgroups). results: at the time of admission to our rehabilitation service, luts were observed in 14 out of 132 cases (11%). a high proportion of these outpatients (64.2%) presented bothersome urinary symptoms such as incontinence, frequency and urgency (storage luts). the most frequent symptom was urinary urge incontinence (42.8%). this symptom was found to be prevalent in the multiple sclerosis and neurovascular disorders. in 93% the urinary symptoms arose as a result of neurologic conditions and 78.5% did not present a complete recovery of urological symptoms in spite of improved selfreported functional activity limitations. none of these patients performed urological rehabilitation. conclusions: neurological disorders are a significant issue in rehabilitation services and it can lead to lower tract dysfunction, which causes luts. storage symptoms are more common, especially urge incontinence. current literature reports that a further optimization of the rehabilitation potential of neurologically ill patients is possible through an implementation of urological basic measures into the neurological treatment routine. key words: neurorehabilitation service; outpatient; neurovascular disorder; lower urinary tract symptoms (luts); lower urinary tract dysfunction (lutd ); urge incontinence. submitted 17 november 2014; accepted 28 january 2015 summary no conflict of interest declared. (cva),neurodegenerative disease due to parkinson’s disease (pd), multiple sclerosis (ms),spinal cord injury (sci),traumatic brain injury (tbi) or others are frequently associated with lower urinary tract dysfunction (lutd). it is a well-known fact that many different neurologic disorders can cause lutd through the development of lesions in different nerve centres. lower urinary tract symptoms (luts) can include storage, voiding, and post-micturition symptoms (1). although incomplete emptying/urinary retention can occur, generally storage disorders are the most common urinary symptoms (2). frequency, urgency and urinary incontinence can cause social embarrassment, reduce quality of life (qol) and may also cause difficulties in rehabilitative procedures (3). patients suffering from urological symptoms without adequate treatment may significantly lose quality of life , both at medical and at subjective assessment and to be qualified as a complex entity in terms of rehabilitation training and economical care (4). the purposes of this study were to describe the characteristics of the urological disorders associated with neurological conditions treated in outpatient setting in a service of neurorehabilitation and to identify the prevalence of specific urological disorders in the group, in order to improve cooperation between the medical specialist in rehabilitation and urologists. materials and methods we reviewed the files of 132 patients treated in our neurorehabilitation service from december 2012 to december 2013. details characteristics of the sample are outlined in table 1. patients were divided into several subgroups based on the neurological diagnosis: multiple sclerosis (ms), other demyelinating diseases, peripheral neuropathy, neurovascular disorders (nd), neoplastic disease, traumatic brain injury (tbi), parkinson and parkinsonism, spinal cord injuries (sci). urinary status was based on medical evaluations of history of luts, type, degree, onset and duration of symptoms. in general, symptoms and concurrent medical conditions are described during the patient interview. luts are defined following the international continence society standard terminology and so divided into three groups: storage, doi: 10.4081/aiua.2015.2.154 introduction in the practice of physical medicine and rehabilitation, neurologic conditions, such as cerebrovascular accident torelli_stesura seveso 02/07/15 11:27 pagina 154 155archivio italiano di urologia e andrologia 2015; 87, 2 urinary symptoms in neurorehabilitation voiding, and post micturition symptoms (5). functional status refers to an individual capability or level of skill in performing basic tasks to daily living. data on motor (self-care, sphincter control, locomotion and mobility) and cognitive domain (communication and social cognition scale) were collected to compare concurrent urological conditions. large cognitive impairment and functional disability were not included. we tried to analyze prevalence, kind of disorder, timing of presentation (if before or after the neurological onset) and eventual persistence of urological disorders (in the main group and in all subgroups). all the patients in this study using bladder catheter were classified as having urinary voiding symptoms. among the analyzed disorders, we excluded urinary tract infections (uti), because we considered those as a confounding factor. results at the time of admission to our rehabilitation service, luts were observed in 14 out of 132 cases (11%); 118 patients (89%) did not show relevant urological symptoms. among the 14 patients with urological symptoms, 8 presented storage symptoms, while 5 were affected by voiding and post-micturition symptoms. one patient showed both storage and voiding urinary symptoms. among those affected by voiding urinary symptoms, only one exhibited indwelling urinary catheter by hospital discharge. specific urinary symptoms are listed in table 2. in 13 out of 14 patients, the urinary disease was related to the acute neurological onset, while in one patient the problem was pre-existing. in 11 out of 14 patients the urinary disorders currently persist, in 3 out of them the urinary problem was solved. among the 14 affected patients, 6 presented ms, 7 nd and 1 sci. among all patients included in this study, 18 had been diagnosed ms (13.6%). between them 6 patients (33.3%) presented storage urinary symptoms, of which 3 (16.6% of the total) with incontinence, 2 (11.1%) with only urgency and increased daytime urinary frequency and 1 (5.5%) with both storage and voiding urinary symptoms. in all patients luts currently persists. seventy-one out of 132 (53, 8%) patients were treated in our service for the rehabilitation of cerebrovascular diseases. seven of them (10%) presented urinary disorders, of which 3 (42.8%) storage urinary symptoms (all of them suffer from incontinence as well). four of them (57%) voiding urinary symptoms (3 with straining, hesitancy and slow stream and another maintained bladder catheter for urinary retention at hospital discharge). only one patient presented the problem before the acute neurological event. among the 7 patients affected, in 3 the problem was solved, whereas in 4 the problem currently persists. another case of urinary disorder presented spinal cord injury. although this neurogenic bladder patient performed the combination treatment of the credé technique, tapping, and /or valsalva maneuver, the feeling of incomplete emptying, post micturition dribble are currently persisting. however, data on the prevalence and relationship of urinary symptoms with neurological conditions experienced in our retrospective study are further reported in table 3. characteristics sample (132 pts december 2012-2013) socio-demographics range age 26-81 mean age 68 gender females 86 males 46 table 1. characteristics of the sample (neurorehabilitation service, san gerardo hospital monza-italy). clinically urinary symptoms neurologic population (14 pts) n” % urinary urge incontinence 6 42.8 increased daytime frequency 2 14.3 urgency, frequency, straining, slow stream 1 7.1 straining, hesitancy, slow stream 4 28.5 feeling of incomplete emptying, post micturition dribble 1 7.1 diagnosis % of total diagnosis number affected type of urinary disorder timing evolution storage voiding/postmict both pre-existing post-acute event solved persisting ms 13.6% 6 3 2 1 0 6 0 6 nd 53.8% 7 5 2 0 1 6 3 3 pnp 5.3% 0 0 0 0 0 0 0 0 odd 2.3% 0 0 0 0 0 0 0 0 npl 6.1% 0 0 0 0 0 0 0 0 tbi 3.8% 0 0 0 0 0 0 0 0 pp 4.5% 0 0 0 0 0 0 0 0 sci 6.1% 1 0 1 0 0 1 0 1 other 3.8% 0 0 0 0 0 0 0 0 legend: ms = multiple sclerosis; odd = other demyelinating diseases; pnp = peripheral polyneuropathy; nd = neurovascular disorders; npl = neoplastic disease; tbi = traumatic brain injury; pp = parkinson and parkinsonism; sci = spinal cord injuries. table 2. details of storage and voiding urinary symptoms. table 3. prevalence and relationship of urinary symptoms among outpatients neurorehabilitation service compared with neurologic conditions. torelli_stesura seveso 02/07/15 11:27 pagina 155 archivio italiano di urologia e andrologia 2015; 87, 2 f. torelli, e. terragni, s. blanco, n. di bella, m. grasso, d. bonaiuti 156 discussion luts are a common problem in both sexes and increases with age. the pathogenesis may be multifactorial and can include lutd secondary to neurological disorders (6). in the setting of a neurorehabilitation service, it is difficult to estimate the prevalence of luts and estimates are varied. evidence suggests that it can depend on the validated questionnaires used and the different points in time when urinary symptoms are investigated in the neurological pattern disorder (7). however, there are gaps in the literature. kohler (8) stated, among 126 patients, 78 were afflicted by a disturbance of urinary extraction. zellner (4) claimed at the time of admission into the rehabilitation centre, 64.9% of patients presented relevant urological symptoms. in our experience, prevalence of luts was only 11% .this new investigation result is not unexpected because we must take into account, in first-order, that this could depend on the different kind of population studied in terms of neurological disorders, age and sex. second, we must take into account that luts following neurological illness may be influenced by multiple factors. for example, the incidence and prevalence of luts may rise with increasing progression of the underlying neurological disease (9) but also may vary due to the pattern expected based upon type of neurological lesion (10). moreover, attention should be paid to concomitant urological conditions, benign prostatic hyperplasia (bph), idiopathic overactive bladder (oab), urinary infection; such urological conditions are common in aging patients (11). on the other hand, several factors might influence luts as functional and cognitive impairment (grade of severe motor paresis, dysphasia and mental impairment), nocturnal poly-nocturia, diabetes, obesity, stool impaction, etc. (12). in our experience, luts appear to be related to neurological disorders. in general, 93% of urinary symptoms arise as a result of several neurologic conditions. we believe this high report could be attributed also to other associated factors such as age, sex or grade disability of the population sample examined. in fact many of these outpatients was elderly, females and with critical autonomy .in these cases the presence of neurologic deficits and functional disability more easily decreases the physiological competence of both the bladder function and the sphincter function of the urethra and pelvic floor muscles. it is well know that the process of micturition is controlled by the central nervous system (cns), which coordinates sympathetic, parasympathetic and somatic nervous system activity for normal micturition and urinary continence. damage to or diseases of the cns or within the peripheral or autonomic nervous system may lead to dysfunction in voiding that lead to an inability of the sphincter to appropriately increase or decrease its pressure when bladder pressure is increased (13). a high proportion of these outpatients (64.2%) presented bothersome urinary symptoms such as incontinence, frequency and urgency (storage luts). many neurogenic patients, especially those with multiple sclerosis, cerebrovascular accidents, and spinal cord injury, experience uninhibited bladder contractions (14, 15). the most frequent symptom was urinary urge incontinence (42.8%). this symptom was identified as prevalent in the multiple sclerosis and neurovascular disorders. the slight prevalence of this kind of urinary disorder in the subgroup of patient with cerebrovascular disease, although minor compared to multiple sclerosis, is nevertheless a relevant issue and is probably related with prevalence of neurovascular disorder cases in our neurorehabilitation service. in the literature urge incontinence has been reported in 29% of stroke patients at 3 month follow up (16) and in 19% at 6 month follow up (12). based on gelber (17) the major mechanism responsible for post stroke urinary incontinence may be the disruption of the neuromicturition pathways, resulting in bladder hyper-reflexia and urge incontinence. a variety of patterns may be seen, but detrusor overactivity of the bladder was identified in 50% to 90% of patients with multiple sclerosis too (18). most patients try to inhibit the involuntary bladder contraction by voluntary contraction of the striated sphincter. if this cannot be accomplished, urgency with incontinence may occur. in the period of at least one year of observation, the prevalence of this clinical sample (78.5%) did not present complete recovery of urological symptoms in spite of the self-reported functional activity limitations were improved. all these patients were referred to the urologist and they are currently in follow up. no one of these patients performed urological rehabilitation. it is a common belief that the medical specialist in neurorehabilitation focuses on only the performance of functional activities and that the urological parameters do not interfere with the outcomes of the rehabilitation process. current literature reports few data regarding the impact of the urinary symptoms on the outcomes rehabilitation process. lorenze (3) reported that persistent urinary incontinence was associated with delay or failure of the recovery process with respect to ambulation. zellner (4) declares that a further optimization of the rehabilitation potential of neurologically ill patients has been regarded as possible by an implementation of urological basic measures into the neurological treatment routine. likewise the literature data showed significant association between poor wellbeing and luts (19); also poor wellbeing includes serious problems of rehabilitation programme. subjects whose urinary incontinence persisted throughout their rehabilitation programme did not perform significant improvement in rehabilitation. moreover, they showed to be worsened if we consider barthel index. subjects who regained continence had higher weekly functional independence measure (fim) (20). therefore, we suggest an increased focus on luts in the neurorehabilitation unit and to stress the possibility of a first-line communication between specialist in neurorehabilitation and urologists to implement an earlier, appropriate diagnosis and treatment of luts. finally, the limitation of this study is that, being a retrospective study, it lacks a validated data collection instrument, as the international prostate symptom score (ipss), but it is based on the analysis of the files of the patients and for this reason urological problems may have been underestimated. conclusions neurological disorders are a significant issue in rehabilitation services and they can lead to lutd and luts. storage symptoms are more common, especially urge incontinence. not only an adequate neurological assesstorelli_stesura seveso 02/07/15 11:27 pagina 156 157archivio italiano di urologia e andrologia 2015; 87, 2 urinary symptoms in neurorehabilitation ment is important for the treatment of these patients, but also an increased attention on urological disorders is advisable to optimise overall outcomes. a multidisciplinary approach should be advised for the treatment of these patients, involving many different specialists and the whole rehabilitation team. references 1. gulur dm, drake mj. management: of overactive bladder. nat rev urol. 2010; 7:572-582. 2. li wj, oh sj. management of lower urinary tract dysfunction in patients with neurological disorders. korean j urol. 2012; 53:583592. 3. lorenze ej, simon hb, linden jl. urologic problems in rehabilitation of hemiplegic patients. jama 1959; 169:1042-1046. 4. zellner m. epidemiology of urological symptoms in neurological disorders. a prospective analysis in a center for neurological rehabilitation. urologe a. 2008; 47:675-84. 5. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society . neurourol urodyn 2002; 21:167-178. 6. wu mp, su th. do lower urinary tract symptoms (luts) predispose the individuals to more admissions in taiwanese women? a preliminary report. taiwan j obstet gynecol. 2012; 51:402-4. 7. brittain kr, perry si, peet sm, et al. prevalence and impact of urinary symptoms among community-dwelling stroke survivors. stroke. 2000; 31:886-891. 8. kohler m, franer m, ilko w. early rehabilitation measures in the area of urologic extraction. wien med. wochenschr. 1991; 141:235-41. 9. mehnert u, nehiba m. neuro/urological dysfunction of the lower urinary tract in cns diseases :pathophysiology, epidemiology, and treatment options. urologe a. 2012; 51:189-197. 10. panicker jn, menon l, anandkumar a, et al. lower urinary tract symptoms following neurological illness may be influenced by multiple factors: observations from a neurorehabilitation service in a developing country. neurourol urodyn. 2010: 29:378-81. 11. wehrberger c, madersbacher s, jungwirth s, et al. lower urinary tract symptoms and urinary incontinence in a geriatric cohort a population-based analysis. bju int. 2012; 110:1516-1521. 12. nakayama h, jorgensen hs, pedersen pm, et al. prevalence and risk factors of incontinence after stroke. the copenhagen stroke study. stroke. 1997; 28:58-62. 13. ginsberg d. the epidemiology and pathophysiology of neurogenic bladder. am j manag care. 2013; 19(10 suppl):191-6. 14.dorsher pt, mcintosh pm. neurogenic bladder.adv urol 2012; 2012:816274. 15..linsenmeyer ta, culkin d. aps recommendations for the urological evaluation of patients with spinal cord injury. j spinal cord med. 1999; 22:139-142. 16.sakakibara r, hattori t, yasuda k, yamanishi. micturition disturbance after acute hemispheric stroke: analysis of the lesion site by ct and mri. j neurol sci 1996; 137:47-56. 17. gelber da, good dc, laven lj, verhulst sj. causes of urinary incontinence after acut hemispheric stroke. stroke. 1993; 24:378-382. 18. manak a, lurvink m, barf ha, et al. epidemiology and healthcare utilization of neurogenic bladder patients in a us clims database. neurourol urodyn. 2011; 30:395-401. 19. tibaek s, dehlendorff c, iversen hk, et al. is well being associated with lower urinary tract symptoms in patient with stroke?.scand j. nephrol. 2011; 45:134-42. 20. gross jc. urinary incontinence and stroke outcomes. arch phys med rehabil. 2000; 81:22-7. correspondence fabrizio torelli, md (corresponding author) fatorelli@tiscali.it salvatore blanco, md sblanco_74@yahoo.it marco grasso, md m.grasso@hsgerardo.org division of urology, san gerardo hospital via g. pergolesi, 33 20052 monza (mb) erica terragni, md eri_eri66@hotmail.com natale di bella, md nataledibella@libero.it donatella bonaiuti, md dbonaiuti2@yahoo.it division of neurorehabilitation, san gerardo hospital via g. pergolesi, 33 20052 monza (mb) torelli_stesura seveso 02/07/15 11:27 pagina 157 archivio italiano di urologia e andrologia 2013; 85, 2104 introduction surgical treatment of female stress urinary incontinence (sui) has become very popular after respectable success with minimal invasive surgeries. however synthetic materials used in slings has some problems through their biocompatibility. among the different types of mesh, it seems they induce an inflammatory response (1). although tension-free vaginal tape (tvt) has been routinely used to treat female sui with a high success rate, there are concerns regarding its operative safety in relation to bowel and major blood vessel injuries, bladder and urethral perforation, and postoperative voiding difficulties. also, urethrovaginal and vesicovaginal fistulas were seen as a result of vaginal erosion leaded by mesh reaction. we documented a case presented 6 years after tvt sling operation with vaginocutenous fistula (vcf) and inguinal abcess. this is the first report of long term vcf plus inguinal abcess after propylene monofilament sling placement. case report vaginocutaneous fistula and inguinal abcess presented 6 years after tension-free vaginal tape sling ali feyzullah şahin 1, yusuf özlem i̇lbey 2, nur şahin 3 1 assistant professor in urology department of urology, şifa university medicine school, i̇zmir, turkey; 2 associative professor in urology department of urology, şifa university medicine school, i̇zmir, turkey; 3 specialist in gynecology and obstetrics department of gynecology and obstetrics, şifa university medicine school, i̇zmir, turkey. surgical treatment of female stress urinary incontinence (sui) has become very popular after respectable success with minimal invasive surgeries. this is the first report of long term vaginocutaneous fistula (vcf) plus inguinal abcess after tension-free vaginal tape (tvt). a 67 year-old woman with vaginal discharge lasting more than 3 years complained with a painful swelling in the left inguinal area for the last three months. she had a medical history of tvt sling procedure for sui six years ago. she had no history of pelvic surgery, cancer treatment or pelvic irradiation before or after tvt sling. no urethrovaginal or vesicovaginal fistula was found in physical examination and cystocopy. mri showed a vaginocutenaous fistula and inguinal abcess. this case highlights the need for a high index of suspicion for vcf after tvt. key words: abcess; fistula; tension-free vaginal tape; tvt; vaginocutaneous. submitted 11 february 2013; accepted 30 april 2013 no conflict of interest declared summary case a 67 year-old woman was referred to our urology clinic with vaginal discharge lasting more than 3 years and sometimes accompanying vaginal bleeding. for the last three months, a painful swelling in the left inguinal area was added to symptoms. she had a medical history of tvt sling procedure for sui six years ago. she had no history of pelvic surgery, cancer treatment or pelvic irradiation before or after tvt sling. in the physical examination, painful and hyperemic subcutaneous solid mass was present in the left inguinal area with 3 x 4 cm size. in the vaginal examination, there were two solid mass with pedicle in size of 4 x 4 cm which was originated from vaginal wall on both paraurethral areas seems like as entrance of sling trocars. both in vaginal or cystoscopic examination there was no urethravaginal or vesicovaginal fistula. mri showed a fistula tract originating from vagina to subcutaneous tissue of left inguinal area and mesh materials of tvt (figure 1a-c). both masses in the paraurethral areas were excised through vaginal approach at lithotomy position under sahin_stesura seveso 24/06/13 11:10 pagina 104 105archivio italiano di urologia e andrologia 2013; 85, 2 vaginocutaneous fistula and inguinal abcess presented 6 years after tension-free vaginal tape sling discussion tension-free vaginal tape is largely performed in the surgical treatment of sui as a minimal invasive treatment. the tvt procedure has been shown to have a cure rate of 90% and a low risk of complications (2). although tvt is minimally invasive surgical procedure, the blind passage of sharp trocars containing risk of injuries. also mesh has a risk of some inflammatory events because of foreign body reaction. the risk factors associated with genitourinary fistula formation are the same factors that predispose mesh erosion and include a history of pelvic surgery, pelvic irradiation or history or presence of cancer or infection (2). but in our case there was no history of these risk factors. also, quite long period was present between the tvt sling procedure and presentation of complications. it may depend on the ignorance of patient or very late reaction of body to mesh. urethrovaginal fistula is seen often after complication of pelvic floor surgery that is iatrogenic in developing countries. since tvt was commonly performed, many reports with urethrovaginal fistulas after tvt were published (2, 3). but there is no report of vcf after tvt. maffiolini and asteria (4) reported a 64 year-old woman patient with vcf 3 years after trans-obturator tape (tot) sling. patient had pre-obturatory abcess surfaced at the prepubic space of tape entry. firstly mesh was removed after tape exposure was found on the left side of vaginal wall. two months later pre-obturatory abcess was drained. the patient was referred to authors after worsening of symptoms, and they detected a vcf. marques et al. (1) reported 54-year-old woman with perineal cellulitis after tot sling. they have detected subugeneral anaesthesia. then, patient was switched to supine position and left inguinal incision was done. granulation tissue and abcess in the subcutenous tissue was excised. the sling mesh was dissected and removed from the fistula tract. fistula tract was removed lastly (figure 2a, b). skin and subcutaneous tissue was closed. she was discharged after removing urethral catheter and vaginal tampon at the first post operative day. clinical examination 6 weeks after procedure showed a perfect healing and no sui. figure 1. mri images of vaginocutaneous fistula and abcess. figure 2. images of fistula tract and tvt mesh after excision. 1c: transver axis, left inguinal abcess. 1b: transver axis, bilateral mesh and left vcf. 1a: saggital axis of the vcf. a b b a c 2a: mesh and inguinal abcess. 2b: distal part of fistula tract. sahin_stesura seveso 24/06/13 11:10 pagina 105 archivio italiano di urologia e andrologia 2013; 85, 2 ali feyzullah şahin, yusuf özlem i̇lbey, nur şahin 106 are underreported. the management of these complications is including removal of all tape, infectious tissue and, fistula tract, and also adjuvant antibiotic therapy. references 1. marques al, aparício c, negrão l. perineal cellulitis as a late complication of trans-obturator sub-urethral tape, obtape. int urogynecol j pelvic floor dysfunct. 2007; 18:821-2. 2. lowman j, moore rd, miklos jr. tension-free vaginal tape sling with a porcine interposition graft in an irradiated patient with a past history of a urethrovaginal fistula and urethral mesh erosion: a case report. j reprod med. 2007; 52:560-2. 3. estevez jp, cosson m, boukerrou m. an uncommon case of urethrovaginal fistula resulting from tension-free vaginal tape. int urogynecol j. 2010; 21:889-91. 4. maffiolini m, asteria cr. a cutaneous-vaginal fistula and myositis of the obturator muscle following placement of a trans-obturator tape for stress incontinence. eur j obstet gynecol reprod biol. 2010; 149:225-6. 5. marsh f, rogerson l. groin abscess secondary to trans obturator tape erosion: case report and literature review. neurourol urodyn. 2007; 26:543-6. rethral erosion allowed to see the tape. they removed the tape and infectious tissue after beginning intravenous antibiotic therapy. marsh and rogerson (5) reported a 46-year-old woman with groin abcess after tot erosion. the symptoms started with vaginal discharge 8 weeks after tot sling. they removed the tape, infectious and necrotic tissue after beginning antibiotic therapy. but their case was not late presentation and seems as an infectious complication. the patient had uncontrolled diabetes which could lead immune deficiency in her medical history. estevez (3) reported different pathologic mechanisms might affect due to presentation terms of fistula. they stated that short-term fistulas are probably due to an unknown intra-operative urethral injury or to an excessive tensioning of the sling, whereas, long-term fistulas, diagnosed after several months, may have a different complex physiopathology. vaginocutaneous fistula is a recognized, but rare, complication of tvt. this case highlights the need for a high index of suspicion for vcf after tvt. vaginal examination to identify any vaginal erosion and fistula is crucial in the follow-up of slings. most complications after slings correspondence ali feyzullah şahin, md, febu şifa üniversitesi bornova uygulama ve araştırma hastanesi, sanayi cad. no: 7 35100 bornova, i̇zmir, turkey uroali@yahoo.com sahin_stesura seveso 24/06/13 11:10 pagina 106 stesura seveso introduction the incidence of erectile dysfunction (ed) increases with age. it is reported that 35% of married men aged 60 years and older suffer from ed (1). from the prevalence rates reported in the massachusetts male aging study (mmas), between the ages of 40 and 70 years, the probability of complete ed increased from 5.1% to 15%, moderate dysfunction increased from 17% to 34%, and mild ed remained constant at about 17% (1). according to the study of the national health and social life survey (nhsls) the following prevalence rates for ed were reported (responses to questions regarding obtaining and maintaining erection): 7% for ages 18 to 29 years, 9% for ages 30 to 39,11% for ages 40 to 49, and 18% for 50 to 59 (1). obesity has become a worldwide public health problem, it may decrease life expectancy by 7 years at the age of 113archivio italiano di urologia e andrologia 2013; 85, 3 original paper caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats emin ozbek 1, abdulmuttalip simsek 1, mustafa ozbek 2, adnan somay 3 1 okmeydani research and education hospital, department of urology, istanbul, turkey; 2 diskapi research and education hospital, department of endocrinology, ankara, turkey; 3 fatih sultan mehmet research and education hospital, department of pathology, istanbul, turkey. because of the positive corelation between healthy cardiovascular system and sexual life we aimed to evaluate the effect of caloric restriction (cr) on endothelial and neuronal nitric oxide synthase (enos, nnos) expression in cavernousal tissues and enos expression in the internal iliac artery in young and aged rats. young (3 mo, n = 7) and aged (24 mo, n = 7) male sprague-dawley rats were subjected to 40% cr and were allowed free access to water for 3 months. control rats (n = 14) fed ad libitum had free access to food and water at all times. on day 90, rats were sacrified and internal iliac arteries and penis were removed and parafinized, enos and nnos expression evaluated with immunohistochemistry. results were evaluated semiquantitatively. enos and nnos expression in cavernousal tissue in cr rats were more strong than in control group in both young and old rats. enos expression was also higher in the internal iliac arteries of cr rats than in control in young and old rats. as a result of our study we can say that there is a positive link between cr and neurotransmitter of erection in cavernousal tissues and internal iliac arteries. cr has beneficial effect to prevent sexual dysfunction in young and old animals and possible humans. key words: rat; caloric restriction; nitric oxide synthase; internal iliac artery; penis. submitted 27 february 2013; accepted 30 april 2013 no conflict of interest declared summary 40 years: excess bodyweight is now the sixth most important risk factor contributing to the overall burden of disease throught the world. overweight and obesity may increase the risk of ed by 30-90% as compared with normal subjects. moreover, women with the metabolic syndrome have an increased prevalence of sexual dysfunctions as compared with matched controls. lifestyle changes reducing body weight induces amelioration of both erectile and endothelial functions in obese men (2). patients with ed show a higher body mass index (bmi), waist circumference (wc), and insulin-resistance (ir) and lower levels of total testosterone (tt ) and bioavailable testosterone (bt). there is a negative correlation between erectile function and ir and abdominal obesity. the tt levels are lower in patients with increased bmi, doi: 10.4081/aiua.2013.3.113 archivio italiano di urologia e andrologia 2013; 85, 3 e. ozbek, a. simsek, m. ozbek, a. somay 114 wc and ir. negative correlation was shown only between bt and abdominal obesity (3). androgen deficiency together with endothelial dysfunction may be responsible from ed in obesity (4). in animal experiments penile endonhelial nitric oxide synthase (enos) and neuronal nitric oxide synthase (nnos) expression were found decreased in hypercholesterolemic cavernousal tissue due to decrease activity of amp-activated protein kinase (ampk), which increases the expression of neuronal (n) nos and endothelial (e) nos (5). in another experiment we shown that mild to moderate exercise increases penile enos and nnos expression as well as serum total testosterone levels in young and aged rats (6). modifiable lifestyle factors such as obesity, lack of exercise and smoking play a role in the development, progression or remission not only of erectile dysfunction (ed), but also in cardiovascular disease and the metabolic syndrome. one-third of obese men with ed can regain their sexual activity after 2 y of adopting health behaviors, mainly regular exercise and reducing weight. western societies actually spend a huge part of their health care costs on chronic disease treatment and interventions for risk factors. the adoption of healthy lifestyles can reduce the prevalence of obesity and the metabolic syndrome, and hopefully the burden of sexual dysfunction (7). mediterranean-style diets and a reduction in caloric intake have been found to improve erectile function in men with the aspects of the metabolic syndrome. in addition, both clinical and experimental studies have confirmed that combining the two interventions provides additional benefit to erectile function, likely via reduced metabolic disturbances (e.g., inflammatory markers, insulin resistance), decreased visceral adipose tissue, and improvement in vascular function (e.g., increased endothelial function) (8). mediterranean-style diet might be effective in ameliorating sexual function in women with metabolic syndrome. lifestyle changes, mainly focussing on regular physical activity and a healthy diet, are effective and safe ways to reduce cardiovascular diseases and premature mortality in all population groups; they may also prevent and treat sexual dysfunctions in both sexes (9). taking all of these background into account, the objective of the our work was to investigate the role of caloric restriction on enos as well as nnos and enos expression in the internal iliac artery and cavernousal tissue of young and aged rats, respectively. materials and methods animals and diet 3-month-old young and 24-month-old aged male spraque-dawley rats were divided into four experimental groups (n = 7 rats per group). control rats in each group were fed ad libitum with pelleted standard diet. another two groups were subjected to 40% caloric restriction for three months (10). rats were housed induvidually with free access to water in wirebottom cages and acclimated at 22ºc with a 12h light/dark cycle. caloric restricted rats were fed on a daily basis at the beginning of the dark cycle and the amount of food was weekly updated. all animal experiments were approved by the animal ethics committee. isolation of samples and immunohistochemical staining at the end of 3 months rats were sacrificed and the and internal iliac arteries and penises were quickly removed, washed with saline and parafinized. all procedures were performed under general anaesthesia with 50 mg⁄ kg ketamine hcl administered intraperitoneally. enos, nnos expression in all tissues was evaluated with immunohistochemistry using specific antibodies. for the immunohistochemical evaluation, specimens were processed for light microscopy and sections incubated at +4°c overnight and then de-waxed in xylene for 30 min. after rehydrating in a decreasing series of ethanol, sections were washed with distilled water and phosphate buffered saline (pbs) for 10 min. sections were then treated with 2% trypsin in 50 mm tris buffer (ph 7.5) at 37°c for 15 min and washed with pbs. sections were delineated with a dako pen (dako, glostrup, denmark) and incubated in a solution of 3% h2o2 for 15 min to inhibit endogenous peroxidase activity. then, sections were incubated with enos ab-1 (rb-9279-r7, neomarkers, labvision, fremont, ca, usa) and nnos (sc-648, santa cruz biotechnology inc., santa cruz, ca, usa) antibodies. the ultra-vision (labvision) horseradish peroxidase⁄3amino-9-ethylcarbazole staining protocol was used at this stage. sections prepared for each case were examined by light microscopy. positive and negative controls were conducted in parallel with nos stained sections. staining of sections with commercially available antibodies served as the positive control. negative controls included staining tissue sections with omission of the primary antibody. the sections were evaluated for diffuseness and staining. penile enos and nnos were evaluated according to the diffuseness and intensity of staining in penile cavernousal smooth muscle. according to the diffuseness of the staining, sections were graded as 0 = no staining; 1 = staining < 25%; 2 = staining 25-50%; 3 = staining 50-75%; 4 = staining > 75%. according to staining intensity, sections were graded as follows: 0 = no staining; 1 = weak but detectable staining; 2 = distinct; 3 = intense staining (11, 6). immunohistochemical values were obtained by adding the diffuseness and intensity scores. results enos expression in internal iliac artery: in control young and aged rat internal iliac arteries there was focal mild to moderate e nos expression, but diffuse in caloric restricted young and aged rats (figure 1a-d). enos and nnos expression in cavernousal tissue: enos, nnos expression were weak in the cavernousal tissues of control rats. in caloric restricted group enos, nnos expression were more evident than in control young and aged rats (figure 2a-h). 115archivio italiano di urologia e andrologia 2013; 85, 3 caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats figure 1a-c. enos expression in internal iliac artery. a-b: young control group: focal mild internal iliac artery enos staining (ihc 400x). c-d: young caloric restriction group: diffuse internal iliac artery enos staining (ihc 400x). b: aged control group: focal mild penile enos staining (ihc 400x). d: aged caloric restriction group: diffuse penile enos staining (ihc 400x). f: aged control group: focal mild penile nnos staining (ihc 400x). h: aged caloric restriction group: diffuse penile nnos staining (ihc 400x). figure 2a-h. enos and nnos expression in cavernousal tissue. a: young control group: focal mild penile enos staining (ihc 400x). c: young caloric restriction group: diffuse penile enos staining (ihc 400x). e: young control group: focal mild penile nnos staining (ihc 400x). g: young caloric restriction group: diffuse penile nnos staining (ihc 400x). archivio italiano di urologia e andrologia 2013; 85, 3 e. ozbek, a. simsek, m. ozbek, a. somay 116 discussion erectile function is a multi system phenomenon involving vascular, neuronal and endocrin system. in this process nitric oxide (no) released from nerve endings and endothelial cells plays a key role. no is produced from l-arginine through an enzymatic reaction in which the enzyme nitric oxide synthase is involved. in the cavernousal tissue no stimulates guanilate cyclase enzyme present in the smooth muscle cells. guanylate cyclase induces the formation of cyclicguanosine monophosphate (gmpc) from guanosine triphosphate (gtp). phosphorilation of gmpc, results in cytoplasmic calcium release causing smooth muscle relaxation of the corpus cavernousum, with the subsequent penile tumescence (12, 13). the most common causes of ed are organic such as cardiovascular and endocrin diseases including obesity, type-2 diabetes mellitus (dm2) and metabolic syndrome.depression, hormonal changes and vascular or neurological damage after trauma or surgery are other factors aasociated with ed (3, 14). obesity causes insulin resistence and cardiovascular system diseases through disrupting in the signaling pathways required for nitric oxide production with subsequently endothelial dysfunction. nowadays obesity is a major health problem throught the world, especially in western countries. type 2 diabetes mellitus, hypertension, hyperlipidemia are comorbitidies associated with obesity that cause cardiovascular disease and endothelial dysfunction. these abnormalities are frequently clustered in the so called “metabolic syndrome”. obesity and metabolic syndrome may lead directly to endothelial dysfunction and subsequently erectile dysfunction (15). villalba et al. reported that endothelial relaxant responses were impaired in penile arteries of obese zucker rats (16). enhanced superoxide production and reduced basal no activity are the proposed underlying mechanism in this process. in human, obesity causes impaired indices of endothelial function and increases circulating concentrations of the proinflammatory cytokines interleukin-6 (il-6), interleukin-8 (il-8), interleukin-18 (il18), as well as c-reactive protein (crp) and no bioavailability (17). nos expression in highfat-fed obese rats has been found lower and restored by metformin (18). in our experiment we found e nos and n nos expression lower in hypercholesterolemic young and aged rats. caloric restiction restriction restores nos expression in both group. reduced caloric intake decreases arterial pressure in healthy induviduals and improeves endothelium vasodilatation in obese and overweight induviduals. in literature it is reported that caloric restriction promotes endotheliumdependent vascular relaxation by activating e nos activity in mice throught sirt1 (19). in our experiment we found that caloric restiction increases e nos expression in the internal iliac artery of rats. because penile arterial supply comes from internal iliac artery we can say that caloric restriction improves penile blood supply by increasing internal artery vasodilatation. in vitro experiments are required to demonstrate the effect of caloric restriction on the endothelial relaxant response of caloric restiction in the internal iliac artery. weight loss resulting from cr improves endotheliumdependent vascular relaxation in obese and overweight induviduals with hypertension (20, 21). in this experiment, authors show that sirt1 promotes endotheliumdependent vasodilation by targeting endothelial nitric oxide synthetase (enos) for deacetylation. sirt1 and enos co-localize and co-precipitate in endothelial cells, and sirt1 deacetylates enos, stimulating enos activity and increasing endothelial nitric oxide (no). these mechanisms may be effective in the internal ilac arteries and cavernousal endothelial cells. further studies are needed to confirm this suggestion. caloric restriction improves cardiovascular system through increase of systemic no release, increase of no bioavailability, upregulation of sirtuin-1 as well as reducing oxidative stress in animal models. recently, it is reported that 8 weeks 30% caloric restriction reverses vascular endothelial dysfunction in old mice by restoring no bioavailability, reducing oxidative stress (via reduced nadph oxidase-mediated superoxide production and stimulation of anti-oxidant enzyme activity) and upregulation of sirtuin-1 (22). in another study it was found that, cr reduce blood pressure by elevating no production and lowering ace activity in rats (23). shinmura et al. reported that prolonged (6 months) cr improves myocardial ischemic tolerance and restores the ischemic precontidioning effect in middle-aged rats through nitric oxide-dependent increase in nuclear sirt1 content (24). nisoli et al. report that caloric restriction for either 3 or 12 months induced endothelial nitric oxide synthase (enos) expression and 3',5'-cyclic guanosine monophosphate formation in various tissues of male mice. other authors stated that this was accompanied by mitochondrial biogenesis, with increased oxygen consumption, adenosine triphosphate production and enhanced expression of sirtuin 1 (25). in different experiments it was shown that cr increases aortic enos and no release as well as improves endotheliumdependent vasorelaxation to acetylcholine (26). in a clinical study caloric restriction improves endothelial-dependent vasodilation through an increased release of nitric oxide in obese hypertensive patients (27). as a conclusion, as it shown in literature, cr improves cardiovascular system by increasing no levels, no bioavailability as well as decreasing ros, proinflammatory and inflammatory cytokines. our study is the first to demonstrate the local effect of caloric restriction in the pathophysiology of ed at molecular level. further in vitro studies are needed to evaluate the contractionrelaxation responses of cavernousal and internal iliac artery strips in cr rats. in clinical practice we think that cr improves response to phosphodiesterase-5 inhibitors in aged and young subjects. further clinical studies are also needed to confirm this suggestion. references 1. wein aj, kavoussi lr, novick ac, et al. campbell-walsh urology, ninth edition, elsevier, philadelphia, vol. 1, p.738. 2. esposito k, giugliano f, ciotola m, et al. obesity and sexual dysfunction, male and female.int j impot res. 2008; 20:358-65. 3. knoblovits p, costanzo pr, rey valzacchi gj, et al. erectile dysfunction, obesity, insulin resistance, and their relationship with testosterone levels in eugonadal patients in an andrology clinic setting. j androl. 2010; 31:263-70. 4. traish am, feeley rj, guay a. mechanisms of obesity and related pathologies: androgen deficiency and endothelial dysfunction may be the link between obesity and erectile dysfunction. febs j. 2009; 276:5755-67. 5. kim yw, park sy, kim jy, et al. metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. j androl. 2007; 28:555-60. 6. ozbek e, tasci ai, ilbey yo, et al. the effect of regular exercise on penile nitric oxide synthase expression in rats. int j androl. 2010, 33:623-8. 7. esposito k, giugliano d. obesity, the metabolic syndrome, and sexual dysfunction. int j impot res. 2005; 17:391-8. 8. hannan jl, maio mt, komolova m, adams ma. beneficial impact of exercise and obesity interventions on erectile function and its risk factors. j sex med. 2009; 6(suppl 3):254-61. 9. esposito k, giugliano f, ciotola m, et al. obesity and sexual dysfunction, male and female. int j impot res. 2008; 20:358-65. 10. zanetti m, barazzoni r, vadori m, et al. lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction. atherosclerosis. 2004; 175:253-9. 11. moochhala s, chhatwal vj, chan st, et al. nitric oxide synthase activity and expression in human colorectal cancer. carcinogenesis 1996; 17:1171-1174. 12. barouch la, harrison rw, skaf mw, et al. nitric oxide regulates the heart by spatial confinement of nitric oxide synthetase isoforms. nature. 2002; 214:337-339. 13. trussell jc, legro rs. erectile dysfunction: does insulin resistance play a part? fertil steril. 2007; 88:771-777. 14. costanzo p, knoblovits p, rey valzacchi g, et al. erectile dysfunction is associated with a high prevalence of obesity and metabolic syndrome. rev argent endocrinol metab. 2008; 45:142-148. 15. fonseca v, jawa a. endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: common pathways and treatments? am j cardiol. 2005; 96(12b):13m-18m. 16. villalba n, martínez p, bríones am, et al. differential structural and functional changes in penile and coronary arteries from obese zucker rats. am j physiol heart circ physiol. 2009; 297:h696-707. 17. giugliano f, esposito k, di palo c, et al. erectile dysfunction associates with endothelial dysfunction and raised proinflammatory cytokine levels in obese men. j endocrinol invest. 2004; 27:665-9. 18. kim yw, park sy, kim jy, et al. metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. j androl. 2007; 28:555-60. 19. mattagajasingh i, kim cs, naqvi a, et al. sirt1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. proc natl acad sci usa. 2007; 104:14855-60. 20. raitakari m, ilvonen t, ahotupa m, et al. weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. arterioscler thromb vasc biol. 2004; 24:124-128. 21. sasaki s, higashi y, nakagawa k, et al. a low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. am j hypertens. 2002; 15:302-309. 22. rippe c, lesniewski l, connell m, et al. short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. aging cell. 2010; 9:304-12. 23. sharifi am, mohseni s, nekoparvar s, et al. effect of caloric restriction on nitric oxide production, ace activity, and blood pressure regulation in rats. acta physiol hung. 2008; 95:55-63. 24. shinmura k, tamaki k, bolli r. impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear sirt1. am j physiol heart circ physiol. 2008; 295:h2348-55. 25. nisoli e, tonello c, cardile a, et al. calorie restriction promotes mitochondrial biogenesis by inducing the expression of enos. science. 2005; 310:314-7. 26. zanetti m, barazzoni r, vadori m, et al. lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction. atherosclerosis. 2004; 175:253-9. 27. sasaki s, higashi y, nakagawa k, et al. a low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension. am j hypertens. 2002; 15:302-9. 117archivio italiano di urologia e andrologia 2013; 85, 3 caloric restriction increases internal iliac artery and penil nitric oxide synthase expression in rat: comparison of aged and adult rats correspondence emin ozbek, md (corresponding author) ozbekemin@hotmail.com abdulmuttalip simsek, md department of urology okmeydani research and education hospital darulaceze street, 34384, sisli, istanbul, turkey mustafa ozbek, md department of endocrinology diskapi research and education hospital ankara, turkey adnan somay, md department of pathology fatih sultan mehmet research and education hospital istanbul, turkey 71archivio italiano di urologia e andrologia 2017; 89, 1 original paper factors affecting surgical margin positivity in robotic assisted radical prostatectomy mustafa yuksel, kaan karamık, hakan anıl, ekrem islamoglu, mutlu ates, murat savas antalya training and research hospital, antalya, turkey. objectives: after radical prostatectomy, surgical margin positivity is an important indicator of biochemical recurrence and progression. in our study we want to compare the surgical margin positivity rates for retropubic radical prostatectomy (rrp) and robotic assisted radical prostatectomy (ralp) and investigate the factors affecting surgical margin positivity in ralp. materials and methods: data from 78 rrp and 62 ralp patients operated from 2011 may to 2016 march were retrospectively screened. patients in both groups were compared in terms of age, postop hematocrit reduction, hospital stay, duration of follow-up, surgical margin positivity, biochemical recurrence and oncologic parameters. in ralp group it was searched the relationship between the surgical margin positivity and prostate specific antigen (psa), positive biopsy core, biopsy gleason scoring, pathologic stage and gleason scoring, lymph node positivity, lymphovascular and perineural invasion, extracapsular extension, seminal vesicle invasion, prostate weight. results: patients in the ralp group had lower postop hematocrit reduction and shorter hospital stay (p < 0.001). there was no difference in surgical margin positivity between ralp and rrp groups (37.1% vs. 29.5%, p = 0.341). in ralp group there was a correlation between surgical margin positivity and positive biopsy core number (p = 0.011), pathologic stage (p < 0.001) and gleason score (p < 0.001), eau risk classification (p = 0.001), seminal vesicle invasion (p = 0.045), extraprostatic extension (p < 0.001). there was no correlation between prostate weight (p = 0.896), psa (p = 0.220), biopsy gleason score (p = 0.266), lymph node positivity (p = 0.140), perineural (p = 0.103) and lymphovascular invasion (p = 0.92) with surgical margin positivity. conclusions: positive biopsy core number, pathological stage and gleason score, eau risk classification, seminal vesicle invasion and extraprostatic extension are correlated with surgical margin positivity in ralp. key words: prostatectomy; surgical margin; prostate cancer. submitted 7 november 2016; accepted 11 january 2017 summary no conflict of interest declared. prostatectomy was first used by binder and kramer (4) in 2001 and is being applied at greater rates through time. among the advantages of robotic assisted radical prostatectomy (rarp) are technical details such as appropriate mimicking of the wrist maneuvers used in open surgery, 3-dimensional imaging and ability to perform surgery under magnification. in 2008, the open technique was chosen for 44% and the robotic technique was chosen for 53% of the procedures of radical prostatectomy in the usa (5). when the literature is investigated, it appears the hospital stay and transfusion rates are lower for the robotic technique compared to the open technique, though when functional and oncologic results are investigated contradictory results are found (6-9). additionally the high cost associated with robotic radical prostatectomy has led to questions about the necessity for use of this technique in developing countries such as ours (10). surgical margin positivity after radical prostatectomy is one of the important causes of biochemical recurrence and progression. when comparing retropubic radical prostatectomy (rrp) and rarp one of the important topics of interest is the effect on surgical margin positivity. in this study we compared the surgical margin positivity rates of rrp and rarp and aimed to investigate the factors affecting surgical margin positivity in rarp. materials and methods the data belonging to 173 patients who underwent rrp or rarp for prostate cancer, without neo-adjuvant therapy, at our center from may 2011 to march 2016 were retrospectively scanned. our study was in accordance with the helsinki declaration and did not gain ethics committee permission as it included retrospective data. while rrp was performed with the classic retropubic technique, the robotic technique used the da vinci robotic surgical system (intuitive surgical, sunnyvale, ca, usa) with 5 port transperitoneal approach. the operations were performed by 3 different surgeons experienced in open surgery and inexperienced in robotic surgery. patients with lymph node metastasis risk above 5% according to the briganti nomogram (11) had extended lymph node dissection (2) performed. for low risk prostate cancer (t1c, psa < 10, gleason < 7) patients, a nerve-sparing approach was chosen. patients who underwent rrp had a urethral foley catheter inserted for 2 weeks, while rarp patients had a catheter inserted for 1 week. the patient age, prostate doi: 10.4081/aiua.2017.1.71 introduction prostate cancer is the 2nd most common cancer type and is the 5th cause of cancer-related death in men (1). the gold standard treatment for localized prostate cancer currently is radical prostatectomy (2). much knowledge and experience of the open technique has been gained since radical prostatectomy was modernized by walsh (3) in 1982. the robotic technique for radical yuksel_stesura seveso 04/04/17 09:28 pagina 71 archivio italiano di urologia e andrologia 2017; 89, 1 m. yuksel, k. karamık, h. anıl, e. islamoglu, m. ates, m. savas 72 specific antigen (psa), positive core number on biopsy, biopsy gleason scoring, hospital stay, surgical pathology stage according to tnm classification, surgical gleason scoring, lymph node positivity, surgical margin condition, lymphovascular and perineural invasion, extracapsular extension and seminal vesicle invasion conditions, prostate weight, and biochemical recurrence during follow-up were recorded. patients were classified as low risk, moderate risk and high risk based on biopsy pathology and psa in accordance with the european association of urology (eau) prostate cancer guidelines. according to tnm surgical staging, patients were divided into t2 and t3-t4. biochemical recurrence was defined as postoperative psa rising above 0.2 ng/ml. thirty-three patients with incomplete data were excluded from the study. early oncologic results of 78 rrp and 62 rarp patients were compared in relation to the recorded parameters. additionally, the factors affecting surgical margin positivity in rarp patients were researched. statistical analysis descriptive statistics of data are given as mean, standard deviation, median, frequency and percentage. the distribution of variables was measured with the kolmogorov smirnov test. quantitative data were analyzed with the mann-whitney u test. analysis of qualitative data used the chi-square test, with the fisher test used when chi-square test conditions were not valid. analyses were completed using the spss 22.0 program (spss, chicago, il, usa). a value of p < 0.05 was accepted as statistically significant. results the data of patients undergoing retropubic radical prostatectomy and robotic assisted radical prostatectomy are shown in table 1. the follow-up duration for rrp group patients was clearly longer than for rarp patients (p < 0.05). patients in the rarp group had less postop hematocrit reduction and shorter hospital stays (p < 0.05). while there was no difference between patients of the two groups in terms of biopsy gleason score and psa (p > 0.05), surgical stage and gleason score in the rrp group were higher (p < 0.05). though surgical margin positivity was observed at a higher rate in the rarp group compared to the rrp group (37.1% vs. 29.5%), this difference did not reach statistical significance (p = 0.341). additionally, biochemical recurrence was observed at a higher rate in the rrp group (26.9% vs. 16.1%, p = 0.127). the factors affecting surgical margin positivity in patients treated by the robotic assisted radical prostatectomy group are investigated in table 2. when patients in the rarp group are investigated in terms of surgical margin positivity, a correlation was found between biopsy positive core number, eau risk classification, surgical stage, surgical gleason degree, seminal vesicle invasion and extraprostatic extension with surgical margin positivity (p < 0.05). additionally, surgical margin positivity increased the incidence of biochemical recurrence (p < 0.05). discussion surgical margin positivity in radical prostatectomy is one of the important factors affecting disease recurrence and progression. d’amico et al. reported that the 2 year biochemical recurrence rate in patients with surgical margin positivity (45-55%) was higher compared to patients with organ-limited disease (15-25%) (12). in our study investigating the data of 140 radical prostatectomy patients, surgical margin positivity in rarp group patients increased biochemical recurrence. though surgical stage and surgical gleason degree were higher in rrp patients, surgical margin positivity in rarp patients was still observed at a higher rate (although difference did not reach statistical significance). we believe this situation may be linked to still being in the learning stage for robotic radical prostatectomy operations. biochemical recurrence rates were observed to be higher in the rrp group (although difference was not statistically significant), but we believe that this observation may be due to the longer follow up period in the rrp group. when factors affecting surgical margin positivity in robotic radical prostatectomy are investigated, the results of literature appears to be very complex. a study by liss et al. in rarp patients, found a correlation of surgical margin positivity with psa (p = 0.012) and psa density (p = 0.005) table 1. comparison of rarp and rrp patients. robotic assisted retropubic radical radical prostatectomy prostatectomy p n = 62 n = 78 mean ± s.d/n-% med mean ± s.d/n-% med age (year) 63.4 ± 6.8 65.5 63.8 ± 6.3 64.0 0.850 m hematocrit decrease (%) 3.9 ± 2.2 4.3 7.7 ± 4.1 6.9 0.000 m hospitalization (day) 4.5 ± 2.1 4.0 8.4 ± 3.4 7.0 0.000 m follow up (month) 5.5 ± 5.0 3.5 22.6 ± 19.4 17.5 0.000 m psa (ng/ml) 0-4 4 6.5% 4 5.1% 4-10 37 59.7% 49 62.8% 0.520 x2 10-20 16 25.8% 14 17.9% 20 ˃ 5 8.1% 11 14.1% pathological stage t2 33 53.2% 55 70.5% 0.035 x2 t3 29 46.8% 23 29.5% pathology gleason ≤ 6 23 37.1% 44 56.4% 7 34 54.8% 24 30.8% 0.016 x2 8-10 5 8.1% 10 12.8% surgical margin (-) 39 62.9% 55 70.5% 0.341 x2 (+) 23 37.1% 23 29.5% seminal vesicle invasion (-) 51 82.3% 65 83.3% 0.867 x2 (+) 11 17.7% 13 16.7% lymph node (-) 58 93.5% 74 94.9% 0.738 x2 (+) 4 6.5% 4 5.1% biochemical recurrence (-) 52 83.9% 57 73.1% 0.127 x2 (+) 10 16.1% 21 26.9% m mann-whitney u test; x² chi-square test yuksel_stesura seveso 04/04/17 09:28 pagina 72 but no correlation was found with clinical stage and biopsy gleason score (13). ficarra et al. found a correlation between surgical margin positivity and biopsy gleason score, pathologic stage and gleason score and extraprostatic extension but did not find a correlation with psa (14). coelho et al. found a correlation between pathologic stage and pathologic gleason score with surgical margin positivity, while no correlation was found with psa, biopsy gleason score and biopsy positive core number (15). in our study we found a correlation of positive biopsy core number, pathologic stage and gleason score, eau risk classification, seminal vesicle invasion and extraprostatic extension with surgical margin positivity in rarp. additionally, no correlation was found with psa, biopsy gleason score, perineural and lymphovascular invasion and lymph node positivity. in the literature, there are some studies stating that a small prostate neck may increase the risk of surgical margin positivity (16), though in our study there was no correlation found between prostate weight and surgical margin positivity in rarp patients. when studies of the literature comparing surgical margin positivity rates in robotic assisted radical prostatectomy and retropubic radical prostatectomy are considered, contradictory results are found. a study in 2015 (17) investigated 282 rarp and 621 rrp operations and found no difference between the 2 techniques in terms of surgical margin positivity (24.5% vs. 23.1%, p = 0.51). a meta-analysis by soorikumaran et al. of data considering 22.393 patients showed that surgical margin positivity was higher in the open radical prostatectomy group (22.8%) compared to the rarp group (13.8%) (18). when assessing the results of this study, it should be noted that the patients in the open radical prostatectomy group had higher rates of high risk prostate cancer. tewari et al. investigated data from 286.876 radical prostatectomy patients obtained from 400 studies and found no difference between robotic rp and open rp in terms of surgical margin positivity (19). additionally, surgical margin positivity appeared to be lower in robotic rp compared to laparoscopic rp. experience is one of the most important factors affecting oncologic and functional results in robotic-aided radical prostatectomy. a study conducted in 2009 on the effects of surgical experience on rarp (20) investigated the results of 700 rarp operations. this study compared the results of the operations from 0300, 300-500 and 500-700 and observed that as experience increased the surgical margin positivity rates decreased. a study by kwon et al. investigating 286 patients compared the results of 165 rarp performed by surgeons with no experience of rarp and 121 rarp operations performed by surgeons with experience of rarp (21). in this study, experience of rarp appeared to directly affect surgical margin positivity (24% vs. 34.6%, p = 0.05). as we are still in the early stages of rarp surgery, we believe that our surgical margin positivity rates would decrease in course of time. there are studies investigating the effects of surgical technique on surgical margin positivity in robotic assisted radical prostatectomy. a study in 2009 did not find an effect on surgical margin positivity for nerve-sparing extrafascial and intrafascial techniques (22). chung et al. (23) investigated the effect of transperitoneal and extraperitoneal robotic prostatectomy on surgical margin positivity and obtained similar rates for both techniques. similarly bladder neck-sparing did not have an effect on surgical margin positivity (24). in a study published in 2009 (25) incision after suture ligation of the dorsal venous complex had greater rates of apical surgical margin positivity compared to only cold incision (p = 0.02). one of the points where rarp appears to be superior to 73archivio italiano di urologia e andrologia 2017; 89, 1 factors affecting surgical margin positivity in robotic assisted radical prostatectomy table 2. factors affecting surgical margin positivity in robotic assisted radical prostatectomy. surgical margin (-) surgical margin (+) robotik prostatectomy robotic prostatectomy p n = 39 n = 23 mean ± s.d/n-% med mean ± s.d/n-% med age (year) 63.2 ± 6.6 65.0 63.9 ± 7.3 66.0 0.672 m positive biopsy core number 3.3 ± 2.2 3.0 5.3 ± 3.0 5.0 0.011 m psa (ng/ml) 0-4 3 7.7% 1 4.3% 4-10 25 64.1% 12 52.2% 0.220 x2 10-20 11 28.2% 5 21.7% 20 ˃ 0 0.0% 5 21.7% biopsy gleason ≤ 6 29 74.4% 14 60.9% 7 10 25.6% 6 26.1% 0.266 x2 8-10 0 0.0% 3 13.0% risk high risk 0 0.0% 7 30.4% intermediate risk 19 48.7% 9 39.1% 0.001 x2 low risk 20 51.3% 7 30.4% prostatectomy gleason ≤ 6 21 53.8% 2 8.7% 7 14 35.9% 20 87.0% 0.000 x2 8-10 4 10.3% 1 4.3% lymphovascular invasion (-) 30 76.9% 13 56.5% 0.092 x2 (+) 9 23.1% 10 43.5% perineural invasion (-) 10 25.6% 2 8.7% 0.103 x2 (+) 29 74.4% 21 91.3% lymph node invasion (-) 38 97.4% 20 87.0% 0.140 x2 (+) 1 2.6% 3 13.0% seminal vesicle invasion (-) 35 89.7% 16 69.6% 0.045 x2 (+) 4 10.3% 7 30.4% biochemical recurrence (-) 37 94.9% 15 65.2% 0.002 x2 (+) 2 5.1% 8 34.8% stage t2 29 74.4% 4 17.4% 0.000 x2 t3 10 25.6% 19 82.6% t2a 10 25.6% 0 0.0% t2b 1 2.6% 0 0.0% t2c 18 46.2% 4 17.4% t3a 6 15.4% 12 52.2% t3b 4 10.3% 7 30.4% extraprostatic extension (-) 29 74.4% 0 0.0% 0.000 x2 (+) 10 25.6% 23 100% m mann-whitney u test; x² chi-square test yuksel_stesura seveso 04/04/17 09:28 pagina 73 archivio italiano di urologia e andrologia 2017; 89, 1 m. yuksel, k. karamık, h. anıl, e. islamoglu, m. ates, m. savas 74 rrp is the low rate of postoperative blood transfusion and shorter hospital stay (26, 27). in our study, the rarp group patients had lower postoperative hemoglobin decrease and shorter hospital stays compared to patients in the rrp group. one of the limitations of our study is that the functional results of both radical prostatectomy techniques were not included as it was retrospective. additionally due to the retrospective nature of the study, we could not investigate the effects on surgical margin positivity of standardizing the surgical technique. in addition to these points, our results reflect results from the learning stage. we believe that a future update will negate this problem. conclusions biopsy positive core number, surgical stage and gleason degree, eau risk classification, seminal vesicle invasion and extraprostatic extension are correlated with surgical margin positivity in rarp. references 1. world cancer report 2014. world health organization. 2014. chapter 1.1. 2. mottet n, bellmunt j, bolla m, et al. eau-estro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent. eur urol. 2016; pii: s03022838(16)30470-5. 3. walsh pc, donker pj. impotence following radical prostatectomy: insight into etiology and prevention. j urol. 1982; 128:492-7. 4. binder j, kramer w. robotically assisted laparoscopic radical prostatectomy. bju int. 2001; 87:408-10. 5. yu hy, hevelone nd, lipsitz sr, et al. use, costs and comparative effectiveness of robotic assisted, laparoscopic and open urological surgery. j urol. 2012; 187:1392-8. 6. rocco b, matei dv, melegari s, et al. robotic vs open prostatectomy in a laparoscopically naive centre: a matched-pair analysis. bju int. 2009; 104:991-5. 7. robertson c, close a, fraser c, et al. relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localised prostate cancer: a systematic review and mixed treatment comparison meta-analysis. bju int. 2013; 112:798-812. 8. farnham sb, webster tm, herrell sd, smith ja jr. intraoperative blood loss and transfusion requirements for roboticassisted radical prostatectomy versus radical retropubic prostatectomy. urology. 2006; 67:360-3. 9. thompson je, egger s, böhm m, et al. superior quality of life and improved surgical margins are achievable with robotic radical prostatectomy after a long learning curve: a prospective single-surgeon study of 1552 consecutive cases. eur urol. 2014; 65:521-31. 10. close a, robertson c, rushton s, et al. comparative cost-effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of men with localised prostate cancer: a health technology assessment from the perspective of the uk national health service. eur urol. 2013; 64:361-9. 11. briganti a, larcher a, abdollah f, et al. updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. eur urol. 2012; 61:480-7. 12. d’amico av, whittington r, malkowicz sb, et al. a multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. j urol. 1995; 154:131-8. 13. liss m, osann k, ornstein d. positive surgical margins during robotic radical prostatectomy: a contemporary analysis of risk factors. bju int. 2008; 102:603-7. 14. ficarra v, novara g, secco s, et al. predictors of positive surgical margins after laparoscopic robot assisted radical prostatectomy. j urol. 2009; 182:2682-8. 15. coelho rf, chauhan s, orvieto ma, et al. predictive factors for positive surgical margins and their locations after robot-assisted laparoscopic radical prostatectomy. eur urol. 2010; 57:1022-9. 16. link ba, nelson r, josephson dy, et al. the impact of prostate gland weight in robot assisted laparoscopic radical prostatectomy. j urol. 2008; 180:928-32. 17. alemozaffar m, sanda m, yecies d, et al. benchmarks for operative outcomes of robotic and open radical prostatectomy: results from the healthprofessionals follow-up study. eur urol. 2015; 67:432-8. 18. sooriakumaran p, srivastava a, shariat sf, et al. a multinational, multi-institutional study comparing positive surgical margin rates among 22393 open,laparoscopic, and robot-assisted radical prostatectomy patients. eur urol. 2014; 66:450-6. 19. tewari a, sooriakumaran p, bloch da, et al. positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy. eur urol. 2012; 62:1-15. 20. zorn kc, wille ma, thong ae, et al. continued improvement of perioperative, pathological and continence outcomes during 700 robotassisted radical prostatectomies. can j urol. 2009; 16:4742-9. 21. kwon eo, bautista tc, jung h, et al. impact of robotic training on surgical and pathologic outcomes during robot-assisted laparoscopic radical prostatectomy. urology. 2010; 76:363-8. 22. shikanov s, woo j, al-ahmadie h, et al. extrafascial versus interfascial nerve-sparing technique for robotic-assisted laparoscopic prostatectomy: comparison of functional outcomes and positive surgical margins characteristics. urology. 2009; 74:611-6. 23. chung js, kim wt, ham ws, et al. comparison of oncological results, functional outcomes, and complications for transperitoneal versus extraperitoneal robotassisted radical prostatectomy: a single surgeon’s experience. j endourol. 2011; 25:787-92. 24. freire mp, weinberg ac, lei y, et al. anatomic bladder neck preservation during robotic-assisted laparoscopic radical prostatectomy: description of technique and outcomes. eur urol. 2009; 56:972-80. 25. guru ka, perlmutter ae, sheldon mj, et al. apical margins after robot-assisted radical prostatectomy: does technique matter? j endourol. 2009; 23:123-7. 26. farnham sb, webster tm, herrell sd, smith ja jr. intraoperative blood loss and transfusion requirements for roboticassisted radical prostatectomy versus radical retropubic prostatectomy. urology. 2006; 67:360-3. 27. nelson b, kaufman m, broughton g, et al. comparison of length of hospital stay between radical retropubic prostatectomy and robotic assisted laparoscopic prostatectomy. j urol. 2007; 177:929-31. correspondence mustafa yuksel, md (corresponding author) drmustafayuksel@outlook.com kaan karamık, md hakan anıl, md ekrem islamoglu, md mutlu ates, md murat savas, md department of urology, antalya training and research antalya eğitimaraştırmahastanesi, varlıkmh. 07050 muratpaşa/antalya, turkey yuksel_stesura seveso 04/04/17 09:28 pagina 74 archivio italiano di urologia e andrologia 2013; 85, 114 introduction women are currently well informed and adequately counselled for both gynecological and sexually transmitted diseases. moreover womens’ perception of “body health” is original paper genital diseases awareness in young male students: is information necessary to protect them? nicola mondaini 1, mauro silvani 2, teo zenico 3, fabrizio gallo 4, franco rosso 4, tommaso cai 1, gianni ughi 5, pasquale scarano 6, vincenzo orlando 7, riccardo bartoletti 1 !u.o. urology, s. maria annunziata hospital, university of florence, italy; "department of surgery, division of urology, degli infermi hospital, biella, italy; #u.o. urology, morgagni pierantoni hospital, forlì, italy; 4 department of surgery, division of urology, san paolo hospital, savona, italy; 5 u.o. urology, morgagni pierantoni, ferrara, italy; 6 u.o. urology, civile hospital, rimini, italy; 7 stabilimento chimico farmaceutico militare, florence, italy. introduction: few studies on the prevalence of male sexual diseases are currently available due to difficult application of observational studies or andrological disease prevention campaigns on large series of apparently healthy subjects. the medical check-up linked to compulsory military service represented in italy a valid tool for epidemiological and observational study for 18 year old boys from 1861 to 2004. the stopping of compulsory military service and its related medical check-up could have determined an important social impact in terms of a lower level of attention and care on male genital/sexual diseases. the aim of the present observational study was to check the prevalence of genital/sexual diseases among young male high-school students and promote an alternative campaign of information among young students. methods: a prospective observational analytical study on young male students was conducted by 6 urological centres. genital and sexually transmitted diseases were presented with slides to students in a general assembly. some students were then counselled and filled out a short questionnaire on their lifestyle. results: 12,535 students (10,432 males-83.6%) followed the presentation. and 4,897 males (46.7%) decided to be checked-up by the urologist and out of them 1554 (31.7%) presented relevant andrological diseases. five-hundred students completed the questionnaire concerning their lifestyle. many of them had not yet experienced condom use during sexual intercourse (27.8%). drug abuse was reported by 39.6% of subjects and alcohol consumption in 80.8% of them. conclusions: these data suggest the need for a national information campaign on male sexual disorders to promote sexual health. key words: sexual dysfunctions; klinefelter syndrome; sexually transmitted diseases; sexual health awareness; fertility; andrologic disease; genital diseases; young male students. submitted 27 august 2012; accepted 31 december 2012 no conflict of interest declared summary more accurate and diligent than in men (1). the excess of reporting minor physical morbidity and affective disorders is probably related to specific subjective behaviours but mondaini_stesura seveso 18/04/13 10:59 pagina 14 15archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? the informed consent to participate in the study. the term “binge drinking” is the modern definition of drinking alcoholic beverages with the primary intention of becoming intoxicated by heavy consumption of alcohol over a short period of time. each male subject with evidence of andrological problems was counselled to receive subsequent adequate medical and/or surgical treatment. statistical analysis the prevalence of genital/sexual diseases was calculated as the proportion of young male high-school students with genital/sexual diseases over the specified period of study time. the differences between each parameter were evaluated by using t-test or chi-square test when appropriate. moreover, the mann-whitney test was also used to compare mean values of different parameters. statistical significance was achieved if p was < 0.05. all reported p values were two-sides. all statistical analyses were performed by using spss 11.0 for apple macintosh (spss, inc., chicago, illinois). results 12,535 students (10,432 males-83.6%) followed the presentation. the mean number of male subjects explored in relation with the total number of males (all ages) per area was about 3% (range 1-18,4%). the rate of participation was also related to both the number of schools explored per-area and the regional territory extent. 4,897 males (46.7%) decided to be checked-up by the urologist and 1554 (31.7%) of them presented relevant andrological diseases potentially related to a reduced rate of fertility (table 1). thus the prevalence of andrological diseases among young male students was 31.7% (25.28% if related x 100.000 subjects). the rate of male subjects asking for a medical consultation seemed to be strongly influenced and proportionally increased by the number of women present in the single class. when women exceeded 50% of the total students in the single class, about 90% of males accepted to be checked-up. in the class where the number of female students were less than 50%, only 37.9% of male students underwent further urological controls (p < 0.001; df = 2; f = 87.33). a wide range of andrological diseases such as varicocele, testis hypotrophy, mobile testis, epidydimal cyst, phimosis, short prepucial frenulum, hypospadia, congenital penile curvature, ambiguous genitalia, micro penis were collected (table 2). among these hypospadia and disorders of sex development (pseudo-hermaproditism) had already been fully diagnosed. no significant differences between the prevalence of diseases and geographical area were found (p = 0.12; df = 2; f = 7.2); the number of affected subjects enrolled in the study in different geographical areas ranged from 30.5 to 32.5% (mean 31.7%) of evaluated males. five-hundred students completed the questionnaire concerning their lifestyle. most them reported a continuous (35.2%) or occasional (37%) use of condom during sexual intercourse while 27.8% of them hadn’t yet experienced condom use. about 90% of condom users ascribed this practice to avoid undesired pregnancies in could be also related with confounding variables such as age, race, unemployment, marital status, income, social class and education (2). men are conversely oriented to underestimate their symptoms and maintain a more practical lifestyle (3). although systemic and hereditary diseases could be easily diagnosed by either the general practitioner or health care non-invasive diagnostic tools such as ultrasonography, new-born medical screening and genome analysis, genital and sexual disorders remained often undiscovered and untreated (4). few studies on the prevalence of male sexual diseases are currently available due to difficult application of observational studies or andrological diseases prevention campaigns on large series of apparently healthy subjects. the medical checkup linked to compulsory military service represented in italy a valid tool for epidemiological and observational study for 18 years old boys from 1861 to 2004. previous studies on a series of 80,000 young males evidenced a 40% prevalence of genital abnormalities (5). thus stopping compulsory military service and its related medical check-up could have determined an important social impact in terms of a lower level of attention and care on male genital/sexual diseases and couples’ infertility (6). the aim of the present observational study was to check the prevalence of genital/sexual diseases among young male high-school students and compare these data with those obtained by armed forces sanitary service during the compulsory military service period preliminary medical check-up (msmc) (5) and promote an alternative campaign of investigation among young students to reduce the risk of infertility and sexually transmitted diseases among future couples. materials and methods this is a prospective multi centre observational analytical cohort study on young male high-school students, specially those between 18 and 19 years old, organized under the aegis of the italian society of andrology (sia). urologists from six different urological centres throughout italy were involved in the study. high school head master assemblies were convened in each town to present the study project. each of them thus organized a special student assembly to introduce a slide presentation by the urologists showing the most frequent unrecognized andrological and sexually transmitted diseases. in particular, pictures from subjects with different clinical cases of varicocele, hydrocele, preputial phymosis, ambiguous genitalia, hypospadia, micropenis, penile congenital curvature were shown to the students presenting all possible complications overall related to infertility. women could participate in the assembly to obtain information on male genital diseases and exert a sort of counselling on male sexual partners inducing them to be evaluated by the urologist in a private consultation. all male students who were present at the assembly received the option of having a free clinical consultation either in a special room in the school the same morning or at the hospital thereafter. a smaller cohort of students who reported having had previous sexual intercourse, were then randomly selected to fill in an anonymous self-report questionnaire on the use of condoms, alcohol and drug abuse (appendix 1). all of them signed mondaini_stesura seveso 18/04/13 10:59 pagina 15 archivio italiano di urologia e andrologia 2013; 85, 1 n. mondaini, m. silvani, t. zenico, f. gallo, f. rosso, t. cai, g. ughi, p. scarano, v. orlando, r. bartoletti 16 their partners and 7.5% of them to avoid the risk of sexual infection transmission. drug abuse was reported by 198 out of 500 subjects (39.6%) with current use of cannabinoids in 66.6% of cases, cocain 6.6%, ecstasy mixed with cocain and cannabinoids 26.7%. alcohol consumption was documented in 404 out 500 subjects (80.8%) but 22.5% of them only reported repeated “binge-drinking” episodes. the term “specialist andrologist” was known only by 65 out of 500 subjects (13%) (table 3). discussion currently, there are a great variety of health care evaluation indicators in relation with different clinical disciplines such as radiology, cardiology, geriatrics, pediatrics and many others (7). andrology is a modern medical discipline that deals with male health, particularly relating to the problems of the male reproductive system and urological problems that are unique to men. it is the counterpart to gynaecology, which deals with medical table 1. distribution of check-ups in six different urological centres. table 2. the predominance of single diseases in 4897 male check ups. table 3. answers to an anonymous self-report questionnaire concerning student’s lifestyle. city residents: reale/total subjects male female male-visits andrological diseases florence 170.737/365.881 4434 3501 (78.9%) 933 (21.1%) 1545 (44.1%) 471 (30.5%) rimini 66.886/138.465 ferrara 62.590/133.980 forlì 56.661/117.550 3831 3831 (100%) 0 1302 (33.9%) 418 (32.1%) savona 28.868/61.916 300 230 (76.6%) 70 (23.4%) 100 (43.4%) 31 (31%) biella 21.508/46.128 3970 2920 (73.5%) 1050 (26.5%) 1950 (66.7%) 634 (32.5%) total 407.250/743.918 12.535 10.482 (83.6%) 2053 (16.4%) 4897 (46.7%) 1554 (31.7%) pathology cases % already diagnoses % varicocele 857 17.5 29 3.3 testis volume < 12 ml 61 1.2 0 0 mobile testis 202 4.1 0 0 epidymal cysts 57 1.1 0 0 hydrocele 24 0.5 5 20.8 phimosis 49 1 31 63.2 short preputial frenulum 160 3.2 14 8.7 hypospadias 16 0.3 16 100 congenital penile curvature 46 0.9 0 0 disorders of sex development 2 0.04 2 100 inguinal hernia 14 0.3 7 50 micropenis 5 0.1 0 0 gynecomastia 61 1.2 2 3.2 testicular cancer 0 0 0 0 total 1554 31.7% 106 6.8% use of condoms always 176/500 (36.2%) seldom 185/500 (37%) never used before 139/500 (27.8%) reason to avoid pregnancy in their partner 325/361 (90%) to avoid the risks of sexual infections 27/361 (7.5%) no answer 9/361 (2.5%) drugs abuse 198/500 (39.6%) cannabinoids 132/198 (66.6%) cocain 13/198 (6.6%) ecstasy+cannabinoids+cocain 53/198 (26.7%) alchool use 404/500 (80.8%) “binge-drinking” 91/404 (22.5%) awareness of the term “specialist andrologist” 65/500 (13%) mondaini_stesura seveso 18/04/13 10:59 pagina 16 17archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? issues which are specific to the female reproductive system (8). females are usually well informed and documented about infertility and sexually related diseases while many males have an urgent need to be counselled for sexual dysfunctions often related to relational and subjective psychological problems (9). the term “andrologist” is currently known by 13% of counselled males compared to 4% of males checked up during msmc, although the number of men aware of their personal situation decreased from 10-20% found during msmc (5, 10) to 6.8% found in the present study. moreover previous studies demonstrated that andrological disorders were found in about 30% of youngsters: these data have been confirmed by the mean rate of 31.7% found in the present series independently from the geographical area investigated.the logical explanation of this phenomenon could be that a lot of students are adequately informed on medical glossaries but not on their body health awareness to avoid subsequent complications on fertility and couples’s sexual problems. hypospadia and disorders of sex development such as pseudo-hermaphroditism, have always already been diagnosed in all cases found in both military and school check-ups while less evident diseases such as penile congenital curvature and short prepucial fraenulum have been diagnosed just after a projection of slides session (11). about 1% of subjects showed a substantial reduction of testicular volume and all of them were counselled to check a second level visit to test the presence of complicated diseases such as klinefelter syndrome (ks) (karyotipe 47, xxy). the time of first diagnosis in patients with ks is essential to test germ cell degeneration due to the presence of additional chromosome x and planning an adequate sperm collection. in the past 10 years, our knowledge about fertility chances of patients with ks has changed considerably, especially when regarding the possibility of ivf icsi treatment (in vitro fertilisation, intra cytoplasmic sperm injection) with single testicular spermatozoon. when entering puberty testicular volume of ks patients increases for a short time with rising testosterone and inhibin b levels at the same time. these decrease, however, and fsh increases during puberty. this seems to indicate a critical point in time when spermatogenetic function of the testicles could still be present. thus, in early puberty there could possibly be a time slot when spermatozoa could be detected in the ejaculate or-if not-at least in the testicular tissue. these could be extracted by testicular sperm extraction, cryopreserved and used for intra cytoplasmic sperm injection therapy later on. in the literature, a total of 133 births of children from klinefelter fathers have been reported. this early specific procedure could lead to a better acceptance of their diagnosis and also offer the option of not being incurably infertile (12). the high number of male students who have accepted to be checked-up seemed to be strictly related and proportional to the number of female students in the same classroom. female students are known to have a good perception of their bodies, careful to protect themselves against disease of all sorts,for future sexual activities. this could have determined a sort of inspiration for their male classmates to join the study. thirty-five percent of evaluated subjects only reported a persistent use of condoms during sexual intercourses and only 7.5% of them used condoms to avoid infections. these data sound alarming in relation to the opportunity of avoiding sexually transmitted diseases such as infections from human immunodeficiency virus (hiv) and human papilloma virus (hpv). foresta et al. found hpv dna in 10% young adult sperm cells who already had unprotected intercourse and its presence was associated with reduced sperm motility (13). thus male infection could determine the spread of the disease related to different sexual partners. due to these reasons the practice of safer sex, promoted in a sex-positive way, is necessary and should be included in a campaign of information directed at young male students. it includes the appropriate use of condoms (14). this is not just to prevent hiv, hpv and stds, but also to prevent unwanted pregnancy, sti-related infertility, and cervical cancer (15). a multifaceted intervention program that provided information and skills, as well as counselling and services, appears to have positive influence on contraceptive practice and condom use among unmarried young females and males (16). moreover the use of drugs (40%) and alcohol (80%) documented in our study could determine significant consequences on the students’ health by reducing their sexual function and desire and representing the first cause of death among young people due to car accidents. thus a good schoolbased prevention program should include a campaign on substance abuse related diseases. caria reported the effect of a new school-based prevention program against substance abuse on 7,079 students aged 12-14 years from 143 schools in seven european countries. the results demonstrated a subsequent decreased risk of alcohol-related problems (17). moreover faggiano reported a persistent positive effect over 18 months for alcohol abuse and for cannabis use, but not for cigarette smoking on the same sample of 7,079 students (18). these data stressed the importance of information, since the check-up enforcement could be difficult and socially expensive. on the other hand, all these data suggest the need for national information campaigns by media and other communication strategies such as internet website browsers and social networks (19-20). the world wide web is increasingly used by researchers, health care providers, and common people to seek medical information and could be also used to promote several opportunities of online communication, enhanced selfestimation, relationship formation, friendship quality, and sexual self-exploration (21-22). conclusions medical information remains one of the most useful tools to promote health. about 30% of male young students have undiagnosed genital and sexual dysfunctions compared to women who normally have a clear and safe perception of their bodies. this implies the need of campaigns for information to promote sexual health and protect future couples’ fertility. mondaini_stesura seveso 18/04/13 10:59 pagina 17 archivio italiano di urologia e andrologia 2013; 85, 1 n. mondaini, m. silvani, t. zenico, f. gallo, f. rosso, t. cai, g. ughi, p. scarano, v. orlando, r. bartoletti 18 references 1. popay j, bartley m, owen c. gender inequalities in health: social position, affective disorders and minor physical morbidity. soc sci med. 1993; 36:21-32. 2. mendoza-sassi ra, béria ju. gender differences in self-reported morbidity: evidence from a population-based study in southern brazil. cad saude publica. 2007; 23:341-6. 3. lai ch. major depressive disorder: gender differences in symptoms, life quality, and sexual function. j clin psychopharmacol. 2011; 31:39-44. 4. herlihy as, gillam l, halliday jl, mclachan ri. postnatal screening for klinefelter syndrome: is there a rationale? acta paediatr. 2011; 100:923-33. 5. mondaini n, bonafe’ m, di loro f, et al. andrologic disease in a population of 18 years old young men during conscription screening: how many were a first diagnosis? minerva urol nefrol. 2000; 52:63. 6. mondaini n, giubilei g, rizzo m, carini m. whither the andrologic pathology of italian lads with the end of medical check up to conscripts. arch ital urol androl. 2005; 77:121. 7. sans-corrales m, pujol-ribera e, gené-badia j, pet al. family medicine attributes related to satisfaction, health and costs. fam pract. 2006; 23:308-16. 8. lenzi a, jannini ea.the andrologist from medicine of reproduction to sexual medicine: the italian experience. int j androl. 2005; 28(suppl 2):9-13. 9. adegunloye oa, ezeoke gg sexual dysfunction-a silent hurt: issues on treatment awareness. j sex med. 2011; 8:1322-9. 10. campodonico f, michelazzi a, capurro a, carmignani g. andrologic disease detected during army medical visit. arch ital urol androl. 2003; 75:205. 11. mondaini n, ponchietti r, bonafè m, et al. hypospadias: incidence and effects on psychosexual development as evaluated with the minnesota multiphasic personality inventory test in a sample of 11,649 young italian men. urol int. 2002; 68:81-5. 12. kliesch s, zitzmann m, behre hm. fertility in patients with klinefelter syndrome (47,xxy). urologe a. 2011; 50:26-32. 13. foresta c, garolla a, zuccarello d, et al. human papilloappendix 1 how old are you? ______ do you use a condom? � always � seldom � never used before why do you use a condom? � to avoid pregnancy in your partner � to avoid the risks of sexual infections � no answer do you use drugs? � yes � no if, yes, what kind od drugs? � cannabinoids � cocain � ecstasy � cannabinoids + cocain � cannabinoids + ecstasy � cocain + ecstasy � cannabinoids + cocain + ecstasy do you use alcohol? � yes � no what kind of alcohol? � wine � beer � spirits do yu indulge in binge drinking? � yes � no do you know the term “specialist andrologist”? � yes � no mondaini_stesura seveso 18/04/13 10:59 pagina 18 19archivio italiano di urologia e andrologia 2013; 85, 1 genital diseases awareness in young male students: is information necessary to protect them? mavirus found in sperm head of young adult males affects the progressive motility. fertil steril. 2010; 93:802-6. 14. sartorius ga, nieschlag e. paternal age and reproduction. hum reprod update. 2010; 16:65-79. 15. kigbu jh, nyango dd. a critical look on condoms. niger j med. 2009; 18:354-9. 16. lou ch, wang b, shen y, gao es. effects of a community-based sex education and reproductive health service program on contraceptive use of unmarried youths in shanghai. j adolesc health. 2004; 34:433-40. 17. caria mp, faggiano f, bellocco r, et al. effects of a school-based prevention program on european adolescents' patterns of alcohol use. j adolesc health. 2011; 48:182-8. 18. faggiano f, vigna-taglianti f, burkhart g, et al. eu-dap study group. the effectiveness of a school-based substance abuse prevention program: 18-month follow-up of the eu-dap cluster randomized controlled trial. drug alcohol depend. 2010; 108:56-64. 19. http://www.salute.gov.it/resources/static/focus/307/presentazione.pdf 20. gosselin p, poitras p. use of an internet "viral" marketing software platform in health promotion. j med internet res. 2008; 10:e47. 21. tian h, brimmer dj, lin jm, et al. web usage data as a means of evaluating public health messaging and outreach. j med internet res. 2009; 11:e52. 22. valkenburg pm, peter j. online communication among adolescents: an integrated model of its attraction, opportunities, and risks. j adolesc health. 2011; 48:121-7. correspondence nicola mondaini, md (corresponding author) mondatre@hotmail.com tommaso cai, md riccardo bartoletti, md u.o. urology, s. maria annunziata hospital, university of florence, firenze, italy mauro silvani, md department of surgery, division of urology, ospedali degli infermi, biella, italy teo zenico, md u.o. urology, morgagni pierantoni hospital, forlì, italy fabrizio gallo, md franco rosso, md department of surgery, division of urology, san paolo hospital, savona, italy gianni ughi, md pasquale scarano, md u.o. urology, civile hospital, rimini, italy vincenzo orlando, md stabilimento chimico farmaceutico militare, firenze, italy mondaini_stesura seveso 18/04/13 10:59 pagina 19 archivio italiano di urologia e andrologia 2018; 90, 3172 original paper effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy ertugrul sefik, serdar celik, ismail basmaci, serkan yarımoglu, ibrahim halil bozkurt, tarık yonguc, bulent gunlusoy bozyaka training and research hospital, department of urology, izmir, turkey. objective: to evaluate the effect of variant histology on pathological and survival findings in patients undergoing radical cystectomy due to muscle invasive bladder cancer. materials and methods: data from 146 patients with radical cystectomy performed due to muscle-invasive urothelial carcinoma between january 2006 to november 2016 at our clinic were investigated. the preoperative and postoperative data of patients with variant histology were compared with nonvariant urothelial carcinoma patients. then of patients with variant histology only those with squamous differentiation (sqd) were compared with nonvariant urothelial carcinoma patients in terms of preoperative, postoperative and survival data. results: of the 146 patients, 23 had carcinoma with variant histology. of these, 17 had sqd, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant. in patients with variant histology, postoperative t stage and upstaging was higher, with no difference observed in terms of overall and cancer-specific survival compared with nonvariant urothelial cancer patients. sqd patients were observed to have higher postoperative t stage compared to nonvariant urothelial cancer patients, with no significant difference observed in terms of survival. conclusions: in cystectomy pathologies, patients with variant histology (especially sqd patients) were observed to have proportionally higher t stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival. key words: bladder cancer; radical cystectomy; squamous differentiation; variant histology; survival. submitted 26 march 2018; accepted 7 may 2018 summary no conflict of interest declared. of urothelial carcinoma is squamous differentiation (sqd), though other non-sqd variants may be observed (5). there are studies reporting that the survival for non-sqd histologic variants is lower (6). in our study in patients with radical cystectomy performed due to muscle-invasive bladder cancer, firstly we aimed to assess the effect of the presence of variant histology on oncologic results and survival results, and secondly we aimed to compare oncologic data and survival data between the most commonly observed histologic variant of sqd with nonvariant urothelial carcinoma. materials and methods the data belonging to 178 patients with radical cystectomy performed for bladder tumors from january 2006 to november 2016 at our clinic were retrospectively investigated. patients who undergone radical cystectomy due to high risk non-muscle-invasive bladder, patients with non-urothelial carcinoma pathology and patients who had missed data were excluded from the study. finally the study included 146 patients who undergone radical cystectomy operation due to muscle-invasive urothelial bladder carcinoma. pathologic staging of patients was performed according to the 2002 union for international cancer control (uicc) tnm staging system. all patients provided informed consent before the procedure. before radical cystectomy, patients had preoperative clinical staging with examination, transurethral resection (tur) and computed tomography. the age, gender, preoperative data (presence of hydronephrosis, clinical stage and tumor grade and presence of carcinoma in situ (cis) in tur pathology data, postoperative data (postoperative t stage, tumor grade, surgical margin positivity, lymph node metastasis, presence of prostate and urethra invasion and lymphovascular invasion), upstaging and overall and cancer-specific survival data were assessed. additionally patients with variant histology on radical cystectomy pathology and the histologic type of this variant were noted. patients with variant histology observed were called group 1, with patients with nonvariant histology called group 2. patients in group 1 with sqd were separately assessed. doi: 10.4081/aiua.2018.3.172 introduction the most common histologic type observed in bladder cancers is urothelial carcinoma. urothelial carcinoma is known to sometimes display extraordinary characteristics (variants) differentiated from normal morphology (1). the histologic variant differentiation rate for bladder urothelial carcinoma is reported as 7-81% in radical cystectomy series (2). there are some studies stating that oncologic results and especially survival results are worse for bladder cancers with variant histology (3, 4). the most commonly observed among histologic variants sefik2_stesura seveso 03/10/18 09:40 pagina 172 173archivio italiano di urologia e andrologia 2018; 90, 3 variant histology and survival after radical cystectomy statistical analysis patient data was first compared between group 1 and group 2 and then between patients with sqd and group 2 using the mann-whitney u test and the pearson x2 test. the cancer-specific survival and overall survival times in the groups were assessed with the kaplan-maier survival analysis. statistical analysis was completed using the statistical package for the social sciences (spss) version 20.0 (spss, chicago, illinois, usa). data are presented as mean and standard deviation, with statistical analysis calculated on the median values. the analysis results with p value < 0.05 were accepted as significant. results there were 13 females and 133 males with radical cystectomy performed due to muscle-invasive bladder cancer. the mean age of all patients was 64.4 ± 9 years. the mean follow-up time was 31.7 ± 31.8 months. a total of 23 patients had variant histology; 17 had sqd, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant. the preoperative, postoperative and survival data and comparison between group 1 (n = 23) and group 2 (n = 123) are given in table 1. when the comparison results are investigated, in the preoperative data, age, gender and clinical t stage and tur pathology tumor grade and cis presence were similar in group 1 and group 2. in the postoperative data, tumor grade, surgical margin positivity, prostate invasion, urethral invasion and presence of lymphovascular invasion were similar in both groups. however, the postoperative pathologic t stage and pathologic upstaging were significantly higher in group 1. there were no significant differences observed between the groups in terms of overall and cancer-specific survival. data for patients with urothelial carcinoma with the most commonly observed variant histology of sqd along with group 2 patient data were compared and results are given in table 2. patients with sqd had significantly higher rates of preoperative tumor grade (p = 0.020) and postoperative pathologic t stage (p = 0.040) compared with group 2. when survival data were examined, though patients with sqd had lower overall survival (52.3 ± 4.7 and 49.6 ± 10.4 months, respectively) and cancer-specific survival times (64.7 ± 5.3 and 58.4 ± 10.7 months, respectively) compared to group 2, no statistically significant difference was found between the two groups. discussion in our study, the rate of patients with variant histology on radical cystectomy pathology was 16%, while the sqd rate was 12%. in the literature, different studies show different rates for variant histology, with these rates reported between 7 and 81% (2). this large difference in variant histology rates may be explained by not using defined criteria for evaluation. sqd is reported to be most common among observed histologic variants, in fact in our study the rate of sqd among all histologic variants is 74% (17/23). though sqd is characterized by histologic intercellular bridges and keratinization, the world health organization (who) defines it is a urothelial carcinoma variant (7). among non-urothelial bladder cancers, squamous cell carcinoma and adenocarcinoma are known for their aggressive nature and low survival rates (8). however there is no consensus on the prognostic importance of histologic table 1. preoperative and postoperative patient characteristics and survival results for group 1 and group 2. variant variant p* histology (+) histology (-) n: 23 n: 123 age 63.7 ± 10.4 64.5 ± 8.7 0.119 gender female 4 9 0.136 male 19 114 preoperative hydronephrosis positive 11 40 0.158 negative 12 83 preoperative t stage t2 23 118 0.325 t3 0 5 preoperative tumor grade grade 1 1 0 0.065 grade 2 1 4 grade 3 21 119 cis positive 5 37 0.380 negative 18 83 postoperative t stage ≤ t1 0 19 0.035 t2 10 61 t3 10 17 t4 3 26 postoperative tumor grade 1 1 4 0.967 2 1 4 3 21 104 surgical margin positive 3 25 0.416 negative 20 98 lymph node metastasis positive 7 23 0.160 negative 16 93 invasion of prostate positive 2 15 0.606 negative 20 100 invasion of urethra positive 2 8 0.760 negative 21 108 lymphovasculer invasion positive 7 18 0.081 negative 16 100 perineural invasion positive 3 17 0.864 negative 17 101 upstaging positive 14 45 0.029 negative 9 78 overall survival 47.1 ± 8.6 52.3 ± 4.70 0.816 cancer spesific survival 52.8 ± 4.8 64.8 ± 5.3 0.824 *mann-whitney u test cis:carcinoma in situ. sefik2_stesura seveso 03/10/18 09:40 pagina 173 archivio italiano di urologia e andrologia 2018; 90, 3 e. sefik, s. celik, i. basmaci, s. yarımoglu, i. halil bozkurt, t. yonguc, b. gunlusoy 174 variants of urothelial carcinoma. studies of variant histologies and their clinical importance are examined, have generally heterogeneous populations and small scale. a study by monn et al. observed that generally patients with variant histology have high pathologic t stage. when subtypes are investigated, while plasmocytoid and micropapillary variants have high mortality, sqd and sarcomatoid variants were identified to have similar survival to nonvariant urothelial carcinoma (9). in our study, patients with variant histology had higher postoperative pathologic t stage and upstaging rate compared to nonvariant urothelial carcinoma patients, while survival rates were similar in accordance with the literature. there are studies showing that bladder cancers with variant histology forms are aggressive tumors with high tumor stage and high lymph node metastasis rates (10-12). xylinas et al. reported that patients with variant histology on radical cystectomy pathology were correlated with high tumor stage, high lymph node metastasis, lymphovascular invasion (lvi) presence, high recurrence risk and increased cancer-specific mortality. furthermore, they stated the patients with non-squamous differentiation were the worst prognostic group. in spite of this, they reported that variant histology was not an independent risk factor in terms of prognosis (13). in the present study, though the preoperative tumor grade and postoperative tumor stage were high among patients with sqd, the overall survival and cancer-specific survival were similar to nonvariant urothelial carcinoma. our findings support the report of moschini et al. who assessed 1067 radical cystectomy cases, observing sqd in 10.2% of patients with no effect of sqd on survival (14). our study has some limitations. the most important of these are that it is a retrospective study and the low number of patients. conclusions patients with variant histology on cystectomy pathology were observed to have high t stage compared to those with nonvariant urothelial cancer; however there were no significant differences in overall survival and cancerspecific survival. when the most commonly observed histologic variant of sqd is investigated, though there was higher stage disease compared to nonvariant urothelial cancers, there was no effect shown on overall survival and cancer-specific survival. references 1. shah rb, montgomery js, montie je, kunju lp. variant (divergent) histologic differentiation in urothelial carcinoma is underrecognized in community practice: impact of mandatory central pathology review at a large referral hospital. urol oncol. 2013; 31:1650-55. 2. chalasan i v, chin jl, izawa ji. histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. can urol assoc j. 2009; 3(6 suppl.4):s193-8. 3. cai t, tiscione d, verze p, et al. concordance and clinical significance of uncommon variants of bladder urothelial carcinoma in transurethral resection and radical cystectomy specimens. urology. 2014; 84:1141-6. 4. wasco mj, daignault s, zhang y, et al. urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection. urology. 2007; 70:69-74. 5. gluck g, hortopan m, stanculeanu d, et al. comparative study of conventional urothelial carcinoma, squamous differentiation carcinoma and pure squamous carcinoma in patients with invasive bladder tumors. j med life. 2014; 7:211. 6. soave a, schmidt s, dahlem r, et al. does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? urol oncol. 2015; 33:21.e1-21.e9. table 2. patient characteristics and survival results of urothelial carcinoma with squamous differentiation and nonvariant urothelial cancer patients. squamous nonvariant p* differantiation urothelial cancer n: 17 n: 123 age 66.9 ± 10 64.5 ± 8.8 0.219 gender female 3 9 0.154 male 14 114 preoperative hydronephrosis positive 7 40 0.479 negative 10 83 preoperative t stage t2 17 118 0.397 t3 0 5 preoperative tumor grade grade 1 1 0 0.020 grade 2 0 4 grade 3 16 119 cis positive 4 37 0.538 negative 13 83 postoperative t stage ≤ t1 0 19 0.040 t2 8 61 t3 6 17 t4 3 26 postoperative tumor grade 1 1 4 0.802 2 1 4 3 15 104 surgical margin positive 3 25 0.796 negative 14 98 lymph node metastasis positive 4 23 0.723 negative 13 93 upstaging positive 10 45 0.078 negative 7 78 overall survival 49.6 ± 10.4 52.3 ± 4.7 0.626 cancer specific survival 58.4 ± 10.7 64.7 ± 5.3 0.743 sefik2_stesura seveso 03/10/18 09:40 pagina 174 175archivio italiano di urologia e andrologia 2018; 90, 3 variant histology and survival after radical cystectomy 7. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998; 22:1435. 8. rogers cg, palapattu gs, shariat sf, et al. clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder. j urol 2006; 175:2048-53. 9. monn mf, kaimakliotis hz, pedrosa ja. contemporary bladder cancer: variant histology may be a significant driver of disease. urol oncol. 2015; 33:18.e15-18.e20. 10. shariat sf, karakiewicz pi, palapattu gs, et al. outcomes of radical cystectom y for transitional cell carcinoma of the bladder: a contemporary series from the bladder cancer research consortium. j urol. 2006; 176:2414-22. 11. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer:long-term results in 1,054 patients. j clin oncol. 2001; 19:666-75. 12. hautmann re, depetriconi rc, pfeiffer c, volkmer bg. radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. eur urol. 2012; 61:1039-47. 13. xylinas e, rink m, robinson bd. impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. eur j cancer. 2013; 49:1889-97. 14. moschini m, dell'oglio p, luciano' r, et al. incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. urol oncol. 2017; 35:335-41. correspondence ertugrul sefik, md (corresponding author) sefikanamur@yahoo.com serdar celik, md ismail basmaci, md serkan yarımoglu, md ibrahim halil bozkurt, md tarık yonguc, md bulent gunlusoy, md bozyaka training and research hospital, department of urology, izmir, turkey sefik2_stesura seveso 03/10/18 09:40 pagina 175 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 198 case report a very rare case of adult-type granulosa cell tumor roberto giulianelli 1, gabriella mirabile 1, giorgio vincenti 1, francesco pellegrino 2, giuseppe soda 2 1 roman urological association, division of urology, nuova villa claudia, rome, italy; 2 dipartimento di medicina sperimentale policlinico umberto i, università “sapienza” di roma, rome, italy. granulosa cell tumor (gst) of the testis is a rare neoplasm. here we describe a case of an adult type gst. more than a year after surgical treatment, without any other treatment, the patient is alive without sign of disease. key words: granulosa cells; tumor; testis; adult-type. submitted 19 october 2014; accepted 31 december 2014 summary no conflict of interest declared. surgical excision was decided and right inguinal orchiectomy was performed. the surgical specimen consisted of the right testis measuring 6 x 6 x 5 cm, in continuity with the spermatic cord measuring cm2 in length. on cross-sections the testis was totally replaced by a tumor partly solid, partly cystic, measuring 6 cm in diameter, with homogeneous appearance and yellowish colour. no necrosis or hemorrhage were seen. histologically, the tumor was composed of medium-size atypical cells with a diffuse growth pattern. the nuclei were round to oval, with evident nucleoli, sometimes with nuclear grooves, and scanty cytoplasm (figure 1). no other recognizable sex cord tumor component was identified. mitoses were approximately 4 x 10 hpf. there were no hemorrhage, necrosis or vascular invasion; the tunica albuginea, the spermatic cord and the margins of surgical resection were free of tumor. the remaining testicular parenchyma was atrophic. the immunoprofile of the neoplastic cells was vimentin positive, inhibin positive, cytokeratin negative, lca negative, cd99 negative, plap negative and melan-a negative. histochemical reticulum staining was also positive. the microscopic and immunohistochemical findings were consistent with the diagnosis of adult-type granudoi: 10.4081/aiua.2015.1.98 introduction sex cord-stromal tumors (scsts) comprise 4-5% of all testicular tumors. this group of tumors includes leydig cell, sertoli and granulosa cell tumors, in addition to mixed cell types and undifferentiated tumors, with the leydig cell group as the most frequent subtype (75% of all scsts) granulosa cell tumors (gsts) are even more rare, and they have been divided in two distinct groups: the juvenile type and the adult type. the adult-type is an extremely rare entity, with, to the best of our knowledge, only 31 cases reported in literature. here we describe a case of an 80 years old caucasian male with an adulttype gst located in the right testis. this is the oldest man with a diagnosis of gst of the testis reported. materials and methods an 80 year old white male presented with an inguinal swelling, during prostate cancer follow up, after a radical prostatectomy performed 14 years before. he also presented with a light painful gynecomastia, but he was taking bicalutamide. the physical examination was otherwise normal. palpation and ultrasound examination revealed a tumor of the right testis in the inguinal canal. the testis had an irregular morphology, with polilobulated hedges and disomogeneous ultrasound architecture. there were also multiple cysts, the biggest one located in the posterior wall (36 x 48 x 45 mm). the left testis was smaller than normal (7 cc). his preoperative blood tests (including tumor markers such as ldh, beta-hgc and afp) were normal. the abdominal and thoracic ct scans did not show any significant lymph node enlargements or distant metastases. figure 1. the tumor shows a diffuse growth pattern; the cells are characterized by round/oval nuclei, evident nucleoli, nuclear grooves and occasional mitoses. giulianelli_stesura seveso 02/04/15 10:35 pagina 98 99archivio italiano di urologia e andrologia 2015; 87, 1 a very rare case of adult-type granulosa cell tumor losa cell tumor. post-operative course was free of complications and after one-year of follow-up a total body ct scan confirmed that the patient is still disease-free. discussion scsts are rare neoplasms of the testis (1) and gcts are even more rare, especially if we consider the adult-type. generally more than half of the patients with adult type gsts presented with slow and painless testicular enlargement, with a variable period of growth (2) and with a range in age at presentation between 16 and 77 years (2). only in a small proportion of cases gynecomastia was reported. a specific diagnosis of adult-type granulosa cell tumor require that all or almost all the neoplasm have granulosa cell features (medium size, ovoid-elongated muclei, nuclear grooves). this because the presence of tubular differentiation in dicates that the tumor is of sertoli cell type, or mixed/unclassified sex-chord stromal tumor. obviously many differential diagnosis have to be considered. due to the rarity of these tumors, the optimal management of these patients is still difficult to establish, as does the clinica behaviour, which may be potentially malignant. kim et al. established six histopathological criteria for malignancy and metastatic potential for leydig cell tumors: tumor size > 5 cm, necrosis, angiolymphatic invasion, infiltrating margins, moderate/severe nuclear atypia, and > 5 mitoses per 10 hpf. afterwards all these criteria have been accepted for other scsts, and so they are valid for gcts as well. in our case, according to these criteria, the only histopathological feature predictive of metastatic potential was the major diameter of the lesion (6 cm). adult type gcts can follow an aggressive course; most frequently, metastases are found in the retroperitoneal lymph nodes, but also other sites have been described as liver, bones and lungs (1). however at present there is no consensus regarding discriminating criteria in order to predict a malignant behaviour of these tumors. silberstein et al. evaluated the management options of scsts of the testis, referring to the high-risk features mentioned above (3). they noticed that in their cohort of patients with ≤ 1 high risk factor, who received radical orchiectomy without adjuvant therapy, none of them developed disease recurrence or progression. other investigators, in a similar cohort of patients, most of them having zero risk factors, observed no cases of metastases after radical orchiectomy alone. all these data suggest that following orchiectomy, surveillance alone, is the preferred management for patients with ≤ 1 high risk factor, considering the very low likelihood of disease progression/recurrence (3) as in the case we described. given that our patient presented with only one high risk factor (i.e. a major diameter of tumor > 5 cm) and given and considering the reported data in the literature (3), in our opinion the most reasonable management following radical orchiectomy was a strict and long term surveillance alone. however initial treatment for these tumors is radical orchiectomy, with the option of a retroperitoneal lymphadenectomy in cases where metastases are suspected. conclusions in conclusion we reported a very rare case of adult type granulosa cell tumor of the testis, an entity that brings many problems in terms of management and outcome predictions. we recommend strict and long-term follow-up as recurrence and metastases have been reported years after diagnosis. references 1. colecchia m, mikuz g, algaba f. rare tumors of the testis and mesothelial proliferation in the tunica vaginalis. tumori. 2012; 98:270-273. 2. ditonno p, lucarelli g, battaglia m, et al. testicular granulosa cell tumor of the adult type: a new case and review of the literature. urologic oncol. 2007; 25:322-325. 3. silberstein jl, bazzi wm, vertosick e, et al. clinical outcomes of local and metastatic testicular sex cord-stromal tumors. j urol. 2014; 192:415-9. correspondence roberto giulianelli, md (corresponding author) roberto.giulianelli@virgilio.it gabriella mirabile, md giorgio vincenti, md roman urological association division of urology, nuova villa claudia via flaminia nuova 280 00100 rome, italy francesco pellegrino, md giuseppe soda, md dipartimento di medicina sperimentale policlinico umberto i, università “sapienza” di roma viale regina elena 324 00161 rome, italy giulianelli_stesura seveso 02/04/15 10:35 pagina 99 153archivio italiano di urologia e andrologia 2016; 88, 2 letter to editors about: a new ultrasound and clinical classification for management of prostatic abscess arch ital urol androl 2015; 87:246-9. key words: prostatic abscess; needle aspiration; classification. we really need a classification of prostatic abscess? no conflict of interest declared. doi: 10.4081/aiua.2016.2.153 dear editors, i read with interest the article by the esteemed collegue dell’atti (1). however, i would provide some questions about the topic. prostatic abscesses (pa) are now no longer a rare occurrence in clinical diagnostic urological practice. the wide use of antibiotics in patients with lower urinary tract symptoms (luts) and the high number of performed prostate biopsies could be responsible of the growing pa incidence in the last years (2). several are the cases reports or the short series published in the scientific literature, as recently i have done with my clinical group in this same journal (3). i agree with dell’atti about the lack of a standardized diagnostic and therapeutic routines but i disagree about the excessive use of sub-classification as part of the five types of prostatic abscesses recognized (1). this classification seems to start from a pioneering work presented some years ago by galosi et al. (4), in which the authors sought primarily to provide a tool for rapid employment to all those engaged to perform a prostatic ultrasound examination for routinary urological or andrological indications. i think that in case of pa the goal should be different. a classification should be characterized by morphological and clinical correlations but should allow an immediate approach since it is an urgent situation. what the urologist must be take into account is that the routine use of transrectal ultrasound (trus) evaluation in each case of luts associated to fever or predisposing factors for the development of pa may aid to avoid poor clinical evolutions of infection (5). in my opinion, the “dell’atti classification” does not reveal the exact correlation between the type of abscess and the type of treatment. in an urgent situation as the presence of a symptomatic prostatic abscess, which parameter should drive the therapeutic decision making? are the dimensions crucial? location into or around the gland may lead to an invasive or conservative therapeutic approach? i tried to apply the “dell’atti classification” in my local short series of prostatic abscesses realizing the impossibility of using the classes 1 and 3. from a prognostic point of view, only the pa dimensions and the associated symptoms had an extreme importance. as showed in table 1 (in the supplementary materials posted in www.aiua.it), in the last 30 months i prospectively collected 13 cases of symptomatic pa. independently from the abscess diameter, all cases were treated by a trus-guided needle aspiration as first approach. in one case, with extensive involvement of seminal vescicles, it was necessary to perform a radical cistoprostatectomy with urinary diversion due to the inefficient result of needle ultrasound guided aspiration regarding the septic status. recurrence were observed in four cases, which were managed by a second look of trus-guided needle aspiration. in two of these cases, a surgical adenomectomy was performed due to the persistence of bladder outlet obstruction. in this short series, the majors determinant factors of a poor prognosis were the pa dimensions and the seminal vesicles involvement. i believe that the approach of needle aspiration in the first place is essential for pathogenic diagnosis and then for the initial therapy. in the absence of symptoms, if a lesion is sonographically identified as pa, this lesion is only a cyst until proven otherwise, but because of the lack of symptoms the lesion should not be treated. what we need is a model of therapeutic management of the pa that allows us to treat it quickly and as best we can. in fact, we always keep in mind that pa is a potential life threatening condition that, when not adequately treated, may progress to sepsis and death. thus, an accurate and rapid diagnostic work up and an efficient treatment are both required. as suggested by vias et al. (5), a dimensional cut-off of 2 cm may aid to make a prompt therapeutic decision. in addition it is considered that the pa multilocularity could be an additional element of choice concerning the type of therapeutic approach considering that both transrectal needle aspiration and surgical approach (adenomectomy or transurethral deroofing) are viable comparable treatment option for pa (6). needle aspiration, when done for properly selected cases (solitary lesion or multifocal but accessible via transrectal route), could minimize the morbidity of the drainage procedure (6). references 1. dell’atti l. a new ultrasound and clinical classification for management of prostatic abscess. arch ital urol androl. 2015; 87:246-9. 2. granados ea, riley g, salvador j, et al. prostatic abscess: diagnosis and treatment. j urol. 1992; 148:80-2. 3. fabiani a, filosa a, maurelli v, et al. diagnostic and therapeutic utility of transrectal ultrasound in urological office prostatic abscess management: a short report from a single urologic center. arch ital urol androl. 2014; 86:344-8. 4. galosi ab, montironi r, fabiani a, et al. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation j urol. 2009; 181:647-657. 5. vias bj, ganpule sa, ganpule ap, et al. transrectal ultrasound-guided aspiration in the management of prostatic abscess: a single-center experience. indian j radiol imaging. 2013; 23:253-257. 6. elshal am, abdelhalim a, barakat ts, et al. prostatic abscess: objective assessment of the treatment approach in the absenceof guidelines. arab journal of urology. 2014; 12:262-268. andrea fabiani surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy correspondence andrea fabiani, md andreadoc1@libero.it surgery dpt, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy fabiani letter 1pagina_stesura seveso 01/07/16 11:14 pagina 153 191archivio italiano di urologia e andrologia 2018; 90, 3 original paper prognostic value of subclassification (pt2 stage) of pathologically organ-confined prostate cancer: confirmation of the changes introduced in the 8th edition of the american joint committee on cancer (ajcc) staging system hugo pontes antunes 1, belmiro parada 1, joão carvalho 1, miguel eliseu 1, roberto jarimba 1, rui oliveira 2, edgar tavares-da-silva 1, arnaldo figueiredo 1 1 department of urology and renal transplantation, coimbra university hospital center, portugal; 2 department of pathology, coimbra university hospital center, portugal. objective: the last edition of the ajcc staging system eliminated the pt2 subclassification of prostate cancer (pca). our objective was to evaluate the association of pt2 subclassification with the oncological results of patients with pca who underwent radical prostatectomy (rp). material and methods: we evaluated 367 patients who underwent rp between 2009 and 2016, with pt2 disease in the final pathological evaluation. we assessed differences in rates of biochemical recurrence (bcr), metastasis and mortality between t2 substages (pt2a/b vs pt2c). results: fifty-three (14.4%) patients presented pt2a/b disease and 314 (85.6%) pt2c disease. the mean follow-up time was 4.9 ± 2.6 years. grade group scores (p = 0.1) and prostate specific antigen (psa) (p = 0.2) did not differed between pt2 substages. the rate of bcr in pt2a/b and pt2c patients was 11.3% and 18.2%, respectively (p = 0.2). five (9.4%) patients with pt2a/b and 45 (14.3%) with pt2c substage underwent salvage radiotherapy (p = 0.3). the rate of positive surgical margins did not differ between groups (p = 0.2). seven (2.2%) patients with pt2c had lymph nodes or distant metastases. the overall survival was 92.5% and 93.6% in pt2a/b and pt2c, respectively (p = 0.2). conclusion: our results are in accordance with the changes introduced in the 8th edition of the ajcc staging system in which the pt2 subclassification was eliminated. key words: prostatic neoplasms; biochemical recurrence; prostatectomy; neoplasm staging. submitted 16 august 2018; accepted 19 august 2018 summary no conflict of interest declared. tem for prostate cancer, the american joint committee on cancer (ajcc) system, have been published reflecting progress in our understanding of prostate cancer biology and prognosis (1). the 8th edition of ajcc staging system, implemented in january 2018, has set some changes (2, 3). the major anatomic-based change is in the classification of organconfined disease. all organ-confined disease is now pathologically staged as t2 without further subcategorization by extent of involvement or laterality (3). this change was assigned a level of evidence iii, meaning that available evidence was not strong. in fact, there is no consensus whether pt2 subclassification has prognostic value in patients who underwent radical prostatectomy (4). nonetheless, the collective reasoning and data were deemed sufficient to support this change in pathologic stage. it is unknown how this updated staging classification will perform in different populations. given these changes have the potential to influence treatment decisions, and thus patient outcomes, independent validation is necessary to confirm the prognostic accuracy and to ensure generalizability across different settings (5, 6). the aim of this study was to assess the prognostic association of pt2 subclassification with the probability of biochemical recurrence (bcr), metastasis, cancer specific survival (css) and overall survival (os) in patients who had organ-confined disease in radical prostatectomy (rp) specimens. materials and methods we performed a cross-sectional analysis of patients who underwent rp between 2009 and 2016 in a single urology department with pt2 disease. patients with missing data and/or neoadjuvant treatments were excluded. the final study population consisted of 367 patients. surgeries were performed by different surgeons. patients who received previous treatments or had measurable doi: 10.4081/aiua.2018.3.191 introduction the tnm system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. the classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms. successive editions from the most common staging sysantunes2_stesura seveso 04/10/18 12:11 pagina 191 archivio italiano di urologia e andrologia 2018; 90, 3 h. pontes antunes b. parada, j. carvalho, m. eliseu, r. jarimba, r. oliveira, e. tavares-da-silva, a. figueiredo 192 psa values immediately after surgery were excluded. patients were followed with serum psa at 4-6 weeks, every 6 months for 5 years and annually thereafter. data were collected through the clinical information recorded in the database of our hospital. bcr was defined as the presence of a confirmed psa value of 0.2 ng/ml or greater. recurrence was based on clinical, laboratorial and radiological findings. data are expressed as mean ± standard deviation, number (%), or median with interquartile range as appropriate. ibm spss 24.0 software was used for all statistical analyses. normality of numerical variables was accessed with kolmogorov-smirnov test, and student t test or mann-whitney u test were properly used to assess differences in numerical variables. the chi-square or fisher exact probability tests were used for categorical data as appropriate. css and os were calculated using kaplanmeier analysis and tested for differences with the mantel-cox log-rank test. multivariate analysis was performed with a binary logistic regression. results were considered statistically significant if the p value was 0.05. for methodological reasons, we decided to focus the comparison between patients with unilateral (pt2a/b) and bilateral (pt2c) disease. results fifty-three (14.4%) patients presented pt2a/b disease and 314 (85.6%) pt2c disease. the mean age of our study population was 63.0 ± 6.8 years. demographics and disease characteristics by pt2 subclassification are shown in table 1. the mean follow-up time was 4.9 ± 2.6 years. we found no significant difference between the preoperative psa values of the two groups (p = 0.2, table 1). approximately twothirds of patients with pt2a/b and pt2c stage had a grade group 2 pca or higher (p = 0.1, table 1). the prostate volume did not show significant differences between the groups (p = 0.5, table 1). the rate of perineural invasion in rp specimens was higher in pt2c patients (p = 0.01, table 1). patients with pt2c substage showed no higher rates of positive surgical margins (p = 0.2, table 1). sixty-three (17.2%) patients had bcr in the entire cohort during follow-up. the rate of bcr in pt2a/b and pt2c patients was 11.3% and 18.2%, respectively (p = 0.2, table 1). there was no significant difference in time from rp to bcr between pt2a/b and pt2c patients (p = 0.7). five (9.4%) patients with pt2a/b and 45 (14.3%) with pt2c substage underwent salvage radiotherapy (p = 0.3, table 1). no patient with pt2a/b disease developed lymph node or distant metastases (table 1). in contrast, in the pt2c group 5 patients developed lymph node metastases and 2 prefigure 1. overall survival of patients with pt2a/b and pt2c prostate cancer in radical prostatectomy specimens. table 1. demographics and disease characteristics by pt2 subclassification. pt2a/b pt2c p value1 patients (%) 53 (14.4%) 314 (85.6%) psa pre-rp, ng/ml (mean ± sd) 7.4 ± 4.9 8.3 ± 8.3 n.s. age at rp, years (mean ± sd) 62.9 ± 6.9 63.0 ± 6.8 n.s. rp specimen grade group (%) grade group 1 17 (32.1%) 104 (33.1%) n.s. grade group 2 32 (60.4%) 190 (60.5%) grade group 3 2 (3.8%) 17 (5.4%) grade group 4 1 (1.9%) 3 (1.0%) grade group 5 1 (1.9%) 0 (0%) prostate size, cc (median) 45 (16-105) 45 (20-163) n.s. perineural invasion, n (%) 31 (58.5%) 245 (78.0%) 0.01 positive surgical margins (%) 5 (9.4%) 50 (15.9%) n.s. bcr rate (%) 6 (11.3%) 57 (18.2%) n.s. time to bcr, years (mean ± sd) 2.6 ± 1.8 2.3 ± 2.0 n.s. salvage radiotherapy (%) 5 (9.4%) 45 (14.3%) n.s. lymph node metastases (%) 0 (0%) 5 (1.6%) n.s. distant metastases (%) 0 (0%) 2 (0.6%) n.s. 1statistical significances: p < 0.05; abbreviations: bcr, biochemical recurrence; n.s., not significant; psa, prostate specific antigen; sd, standard deviation. antunes2_stesura seveso 04/10/18 12:11 pagina 192 sented bone metastases during follow-up. the overall survival was 92.5% and 93.6% in pt2a/b and pt2c, respectively (p = 0.2, figure 1). no cancer related deaths were identified in both groups. one (1.9%) patient in the pt2a/b group did androgendeprivation therapy. in the pt2c group, 7 (2.2%) patients were treated with androgen-deprivation. no patient was treated with docetaxel, abiraterone, enzalutamide or another new drug. in addition, we performed a binary logistic regression to access a multivariate analysis between isup grade, pt2 sub staging and surgical margins status from one side and survival or bcr on the other side. there was no association between these pathological variants and survival (p = 0.564; p = 0.748; p = 0.345) or bcr (p = 0.180; p = 0.246; p = 0.288), respectively. discussion pca grading has undergone significant evolution in the past half century (7, 8) and the ajcc staging system has been repeatedly revised with the current 2017 system eliminating the 3-tiered pt2 subclassification (4, 9). since the adoption of the 1992 ajcc/uicc tnm prostate cancer staging system, the pt2 subclassification has remained controversial due to the lack of robust evidence that it adds meaningful prognostic value (10). our results confirm the 8th edition ajcc staging system for pca. we confirmed that pt2 subclassification offers limited prognostic value, which supports its elimination. we found that the pt2 subclassification did not add prognostic information to the outcomes of bcr, distant metastases and overall survival. the subclassification of pt2 disease has been previously evaluated (4, 11-14). multifocal cancer has been noted in up to 80% of prostatectomy specimens and thus subclassification into pt2a/b/c may depend more on detection than underlying biology (5, 15). freeland et al. evaluated the rate of bcr in patients with unilateral and bilateral organ confined pca. they found no significant difference between both groups (16). other studies have observed results similar to those of our study (12, 13, 17, 18). nguyen et al. in a long follow-up study with 15.305 patients showed that the rates of metastases and cancer specific death at 10 years were relatively low in the pt2 population (4). the authors validate in their work the elimination of the pt2 subclassification and argue that the preoperative serum psa level and pathological grade remain the strongest prognostic factors in patients with pt2 disease. our results are similar to these previous studies. we observed higher rates of perineural invasion and positive surgical margins in patients with pt2c disease. however, these results had no significant impact on the development of bcr, metastases or survival. in agreement with the study of nguyen, we found a very low overall metastases rate (0.5%) (4). our study showed no cancer-specific deaths. this finding may be justified by a relatively short follow-up for a disease with a long natural history. however, other studies with longer follow-up time also show rates of cancerspecific death below 0.5% (4, 19). our work presents some limitations. first, it is a retrospective study which may introduce mis-classification or information bias. some data regarding patients were missing. another limitation is related to the sample size and duration of follow-up. a larger sample and length of follow-up would allow a further understanding of the prognostic value of the pt2 subclassification. conclusions the pt2 subclassification showed no prognostic value in patients with pca who underwent rp. our results are in accordance with the changes introduced in the 8th edition of the ajcc staging system in which the pt2 subclassification was eliminated. references 1. abdel-rahman o. assessment of the prognostic value of the 8 th ajcc staging system for patients with clinically staged prostate cancer; a time to sub-classify stage iv. plos one. 2017; 12:e0188450. 2. paner gp, stadler wm, hansel de, et al. updates in the eighth edition of the tumor-node-metastasis staging classification for urologic cancers. eur urol. 2018; 73:560-569. 3. fine sw. evolution in prostate cancer staging: pathology updates from ajcc 8th edition and ppportunities that remain. adv anat pathol. 2018; 25:327-332. 4. nguyen dp, vertosick ea, sharma v, et al. does subclassification of pathologically organ confined (pt2) prostate cancer provide prognostic discrimination of outcomes after radical prostatectomy? j urol. 2018; 199:1502-1509 5. bhindi b, karnes rj, rangel lj, et al. independent validation of the american joint committee on cancer 8th edition prostate cancer staging classification. j urol 2017; 198:1286-94. 6. bleeker se, moll ha, steyerberg ew, et al. external validation is necessary in prediction research: a clinical example. j clin epidemiol. 2003; 56:826-32. 7. bailar jc, mellinger gt, gleason df. survival rates of patients with prostatic cancer, tumor stage, and differentiation--preliminary report. cancer chemother reports 1966; 50:129-36. 8. gleason df, mellinger gt. prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. j urol. 1974; 111:58-64. 9. brierley jd, gospodarowicz mk, wittekind c (editors) tnm classification of malignant tumours 8th edition. union int cancer control. wiley blackwell, oxford 2017. 10. eichelberger le, cheng l. does pt2b prostate carcinoma exist? critical appraisal of the 2002 tnm classification of prostate carcinoma. cancer. 2004; 100:2573-6. 11. van der kwast th, amin mb, billis a, et al. international society of urological pathology (isup) consensus conference on handling and staging of radical prostatectomy specimens. working group 2: t2 substaging and prostate cancer volume. mod pathol. 2011; 24:16-25 12. chun fkh, briganti a, lebeau t, et al. the 2002 ajcc pt2 substages confer no prognostic information on the rate of biochemical recurrence after radical prostatectomy. eur urol. 2006; 49:273-8. 193archivio italiano di urologia e andrologia 2018; 90, 3 subclassification of pt2 stage prostate cancer antunes2_stesura seveso 04/10/18 12:11 pagina 193 archivio italiano di urologia e andrologia 2018; 90, 3 h. pontes antunes b. parada, j. carvalho, m. eliseu, r. jarimba, r. oliveira, e. tavares-da-silva, a. figueiredo 194 13. hong sk, han bk, chung js, et al. evaluation of pt2 subdivisions in the tnm staging system for prostate cancer. bju int. 2008; 102:1092-6. 14. may f, hartung r, breul j. the ability of the american joint committee on cancer staging system to predict progression-free survival after radical prostatectomy. bju int. 2001; 88:702-7. 15. andreoiu m, cheng l. multifocal prostate cancer: biologic, prognostic, and therapeutic implications. hum pathol. 2010; 41:781-93. 16. freedland sj, partin aw, epstein ji, walsh pc. biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: pt2a versus pt2b. cancer. 2004; 100:1646-9. 17. kordan y, chang ss, salem s, et al. pathological stage t2 subgroups to predict biochemical recurrence after prostatectomy j urol. 2009; 182:2291-5 18. caso jr, tsivian m, mouraviev v, et al. pathological t2 subdivisions as a prognostic factor in the biochemical recurrence of prostate cancer. bju int. 2010; 106:1623-7. 19. hruza m, bermejo jl, flinspach b, et al. long-term oncological outcomes after laparoscopic radical prostatectomy. bju int. 2013; 111:271-80. correspondence hugo antunes, md (corresponding author) hugoantunes4@gmail.com department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal belmiro parada, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal joão carvalho, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal miguel eliseu, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal roberto jarimba, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal rui oliveira, md department of pathology, coimbra university hospital center, coimbra, portugal edgar tavares-da-silva, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal arnaldo figueiredo, md department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal antunes2_stesura seveso 04/10/18 12:11 pagina 194 stesura seveso 233archivio italiano di urologia e andrologia 2015; 87, 3 original paper a two staged treatment procedure for the difficult to treat bladder neck contractures with concomitant incontinence. in the search of a solution to a complex problem ioannis adamakis, evangelos fragkiadis, ioannis katafigiotis, giorgos kousournas, konstantinos stravodimos, constantinos a. constantinides 1st university urology clinic, laiko hospital, greece. objective: to examine the efficacy of a two staged treating strategy with the use of a non-permanent urethral allium® stent for the management of recurrent bladder neck stenosis and subsequently the use of an artificial sphincter aus800® by ams for the management of the incontinence. materials and methods: we progressively identified patients eligible for the study creating a population of cases with recurrent bladder neck stenosis and concomitant incontinence occurring after the last intervention for the stenosis. efficacy for the treatment of the stenosis was defined as no recurrence both prior and post to the sphincter placement and efficacy for the treatment of the incontinence was defined as continence (0-1pads) after the sphincter placement. results and limitations: 14 white males with a mean age of 66.21, ranging from 59 to 73 years consisted the population of the study. all patients had severe stress incontinence following the last transurethral resection. the efficacy of the treatment of the bladder neck stenosis was 93% (13/14) while the efficacy for the treatment of the incontinence was 100%. a single patient had a recurrent bladder neck stenosis after the artificial sphincter placement and was treated with transurethral resection using a long pediatric 13 f resectoscope at 12 months. our limitations is the absence of a control group and the small number of patients enrolled, with a relatively short time of follow up. conclusions: in our series we propose the use of a non-permanent urethral allium® stent for 6 months in order to control the growth of fibrotic scar tissue, a further 6 months follow up for recurrence, and then placement of an artificial sphincter. the results are very promising both on stabilizing the vesicourethral stenosis, and on patient safety and tolerability. key words: vesicourethral anastomosis stenosis; bladder neck contracture; urethral stent. submitted 10 march 2015; accepted 30 april 2015 summary no conflict of interest declared. index, previous prostate surgeries, open surgical technique, postoperative haematuria, urinary leak and urinary retention, external beam radiation and biochemical recurrence (2, 3). the vast majority of anastomotic strictures manifest within the first year post operatively (4). different management approaches have been proposed according to the severity of each case, such as dilation, laser or cold cut incisions, use of corticosteroids, transurethral resection of fibrotic tissue, revision surgery and urinary diversion surgery. no consensus has been reached in their management and, despite the use of different and combined techniques, the need for repeat treatment remains as high as 70% depending on the method (5). in the more severe and relapsing cases, patients end up incontinent after multiple treatments, while obstruction is refractory to usual endoscopic modalities. it is evident that bladder neck contractures cause seriously morbidity and affect the quality of life of patients while the cost rises due to multiple procedures. we present the results of our prospective study of a new treatment modality for patients with severe symptoms caused by bladder neck obstruction, recalcitrant to multiple and different endoscopy treatment modalities. all patients had developed severe stress incontinence after previous endoscopic treatments for bladder neck obstruction. patients were treated with the placement of a non-permanent urethral allium® stent (6) for 6 months in order to control the growth of fibrotic scar tissue. after that the stent was removed and the patients were further followed up for 6 months and if remained unobstructed an artificial sphincter was placed to treat incontinence. materials and methods patient characteristics are depicted in table 1. fourteen white males with a mean age of 66.21, ranging from 59 to 73 years consisted the population of the study. ten patients were subjected to open radical prostatectomy as primary surgery, 1 patient to radical cystectomy and orthotopic neobladder, 2 patients to open transvesical adenomectomy and 1 patient to transurethral prostatectomy. patient inclusion criteria were recurrent bladder neck doi: 10.4081/aiua.2015.3.233 introduction vesicourethral anastomosis stenosis and bladder neck contracture is a deferred complication of prostate surgery, predominantly in radical prostatectomy, that occurs in 0.5% to 14.6% of the patients (1). a number of risk factors have been clearly described: age, increased body mass adamakis_stesura seveso 23/09/15 12:41 pagina 233 archivio italiano di urologia e andrologia 2015; 87, 3 i. adamakis, e. fragkiadis, i. katafigiotis, g. kousournas, k. stravodimos, c.a. constantinides 234 obstructions after at least 2 transurethral resections of fibrotic tissue post primary surgery, as well as multiple treatment modalities such as laser incision and use of corticosteroids. all patients had severe stress incontinence following the last transurethral resection. in all patients with a history of prostate and bladder cancer, a relapse was excluded through digital rectum examination (dre), prostatic specific antigen (psa) and pa tho logy report of the transurethral resection. the clinical study was approved by the scientific committee of our hospital and all the patients signed a written consent after a detailed presentation of our treatment approach the primary objective was to examine the efficacy in the treatment of the recurrent urethrovesical contracture after the placement of the sphincter in the 12 month follow up. the secondary objective was to examine the efficacy of the treatment of the severe stress incontinence induced over multiple recurrences and treatments after the placement of the sphincter in the 12 month follow-up.. all complications were re corded after patient evaluation and clinical examination and classified according to the clavien-dindo score (table 3). patients were treated by a single surgeon with an aggressive transurethral resection of obstructive fibrotic tissue. placement of the allium® stent was facilitated under sedation and fluorescence control for proper placement and stent measurement after 1 week. figure 1. the stent was removed after 6 months, and patients were followed up for stenosis recurrence at 1, 3 and 6 months with post voiding residual ultrasound and at 6 months with urethrography. if patients were unobstructed at 6 months, an artificial sphincter aus800® by ams was placed with open perineal surgery and patients were again followed up at 1, 3, 6 and 12 months (mean follow up time 12.93 months). treatment scheme is reported in figure 2. the allium® stent is a 45 f triangular polymer coated stent designed for high flexibility, low irritation, long indwelling time, reduced migration due to transsphincter anchor, acting as a wide mold to the development of scar tissue and allowing for time of fibrotic tissue to stabilise. allium® stent is provided in 45 mm and 55 mm length. results all 14 patients remained unobstructed for the complete time of follow up prior to sphincter placement, after the removal of the allium® stent. a single patient has relapsed after the artificial sphincter placement and was treated with transurethral resection using a long pediatric 13 f resectoscope at 12 months and as a result the patient characteristics number of patients 14 patients patient age 66,21 59-73 age range primary surgery 10 open rrp 1 open r-c 2 open tva 1tur-p number of transurethral resections prior to trial enrollment 3,64 2-7 patients with other treatments applied 3 laser incisions 3 application of corticosteroids severe incontinence 14 patients psa prior to enrollment < 0,01 results days after resection for stent placement 7 months of indwelling stent 6,25 6-7 follow up after stent removal and time of sphincter placement 6,14 6-6,5 bladder neck stenosis at sphincter placement 0/14 follow up after sphincter placement 12,93 11-16 continence achieved (0-1 pad per day) 14/14 recurrence of bladder neck stenosis 1/14 self reported at 12 months transurethral resection complications no of patients intervention clavien score stent migration 1/14 after 1 month replacement 3,1 acute urinary retention 1/14 immediately suprapubic urine drainage & nsaid 3,1 perineal pain 2/14 paracetamol 1 dysuria 8/14 self resolved 1 figure 1. stent placement. table 1. patient’s clinical details. table 2. results. table 3. complications. adamakis_stesura seveso 23/09/15 12:41 pagina 234 final efficacy was 93%. all 14 patients regained full continence after the application of the sphincter using 0-1 light pad per day (efficacy 100%). patients results are reported in table 2. in 1 patient, acute urinary retention occurred immediately after the stent placement, resolved by the use of suprapubic urine drainage and nsaid’s for one week, then suprapubic drainage was removed and patient was unobstructed. one case of stent migration at 1 month was reported with successful replacement of the stent. the stent was well tolerated with mild dysuria complaints in 8 cases, 2 patients further reported perineal pain, well controlled with paracetamol. all patients had no dysuria or pain after stent removal. complications are reported in table 3. discussion treatment of vesicourethral anastomosis stenosis is very challenging, due to the heterogeneity of the patients requiring different therapeutic approaches. furthermore the high relapse rates affect significantly patient’s quality of life adding both to the morbidity and the cost due to the demand for multiple operations. for cases with minimal fibrotic tissue the initial approach usually is the transurethral dilating balloon with success rates of 59%, but with recurrence rates of 70% with the occurrence of dense scar tissue as the cause of treatment failures (5). use of cold knife incision has also been suggested as the initial approach of strictures in continent patients, with good continence clinical results similar to patients with no strictures after radical prostatectomy in a 18.9 months follow up (7). giannarini et al. investigated the efficacy of balloon dilation compared to multiple cold cut incision over an extended follow up of 48 months, establishing the superiority of the cold cut approach, but also the frequent need of re-treatment (26%), the preservation of continence in all patients and the improvement of incontinence prior to treatment (4). in an attempt to improve long term results multiple treatment options have been proposed. the cold knife incision has been combined with the in situ injection of mitomycin c, reaching an 89% success rate, but still requiring multiple treatments (8). more complicated cases with contractures due to dense fibrotic tissue without sphincter involvement and without stress incontinence are usually treated with the facilitation of cautery incision and resection or laser. the use of the transurethral resection of bladder neck contractures has been proven safe when the obstruction was located below the bladder neck musculature, well above the distal urethral sphincter (9). comparing the resection of the stricture with a bipolar endoscopic resection and holmium laser treatment similar success results has been reported, but more durable in the case of bipolar use, with the same complication rates regarding continence (10). in the same principal, plasma vaporisation has been compared with transurethral resection in bladder neck sclerosis, post monopolar transurethral resection, with bipolar modality showing superior efficacy, a satisfactory safety profile in similar medium-term follow-up (11). collins knife incision has also been used in neovesical strictures over transurethral resection, but with the assistance of continuous intermittent catheterisation to preserve the results (12). the previous studies treated patients with mild obstruction and with none or mild to moderate incontinence, hence different than our group,which consisted of patients with severe obstruction and severe incontinence. an even more difficult to treat subset of patients have bladder neck contractures that involve the sphincter causing stress incontinence, that are due to previous endoscopic treatments affecting the sphincter so adding incontinence to the symptoms along with recurrence. a bladder neck incision technique with a collins knife electrocautery has been used for the treatment of these more challenging cases, as part of a two staged procedure dealing with the bladder neck contracture first, and at a deferred stage with the incontinence, but still with a high recurrence rate of 25% (13). the use of holmium laser incision with the adjuvant use of triamcinolone has been proposed for incontinent patients relapsing after previous treatment, with placement of the artificial sphincter as early as 2 months, but with a high retreatment rate of almost 29% (14). in patients refractory to endoscopic approach, more invasive solutions such as perineal reconstructive surgery or placement of urethral stents has been suggested (15). in similar populations with complicated strictures or contractures, but with concomitant incontinence, a two staged management of open reconstructive surgery and artificial sphincter placement seems to be the primary 235archivio italiano di urologia e andrologia 2015; 87, 3 difficult to treat blabber neck contractures figure 2. treatment scheme. adamakis_stesura seveso 23/09/15 12:41 pagina 235 archivio italiano di urologia e andrologia 2015; 87, 3 i. adamakis, e. fragkiadis, i. katafigiotis, g. kousournas, k. stravodimos, c.a. constantinides 236 choice (16). in order to avoid the copious reconstructive perineal surgery magera et al. opted for multiple stent placement and implantation of an artificial sphincter, achieving success rates of 76% (17). elliot et al. with the same approach and the use of a permanent stent, reported a success rate 89% with mild pain symptoms (18). this more complex patient subset with a history of multiple endoscopic treatments, high recurrence rate and severe stress incontinence, trapped in a vicious cycle of incontinence to retention and back, is closer to our case series. breyer et al. in an excellent review on the management of refractory bladder neck contractures after radical prostatectomy, summarised the shortcomings of stents (19). stents, being a foreign body, carry a lifelong infection risk. stent placement can induce urinary urgency, frequency or dysuria if it is near the trigone, and if it is placed too distally, perineal discomfort may occur in a sitting position. a restenosis of the stent may occur, due to either recurrent scar tissue or to calculi, requiring endoscopic excision. when stenosis recurs after the placement of the artificial sphincter the repeated endoscopic interventions may harm the artificial urinary sphincter (aus). finally, once placed, the stent is extremely difficult to remove, requiring an open surgical approach. most of these disadvantages are intrinsic to the permanent nature of stents, thus using a non permanent stent such as allium® stent we possibly can circumvent them. the two stage treatment seems to be well established in patients with severe anastomosis strictures and severe incontinence. the primary step of this two stage treatment is to establish a stable, open vesicourethral anastomosis and, in most cases, specialised perineal reconstructive surgery is being utilised. the use of permanent stents to replace complex open surgery is an intriguing possibility, with proven similar efficacy to reconstructive surgery. on the other hand the utilisation of a permanent stent has some disadvantages, inherent to the use of a foreign body including urgency, frequency, dysuria, pain, infection, and in some cases restenosis. the two stage treatment always facilitates placement of an artificial sphincter to successfully treat incontinence. in our series we propose the use of a non-permanent urethral allium® stent for 6 months in order to control the growth of fibrotic scar tissue, and, after a further 6 months follow up for recurrence, placement of an artificial sphincter. the results are very promising in order to stabilize the vesicourethral stenosis with patient safety and tolerability and the procedure is easy to apply in a standard facility setting. most important is the fact that no stent is left indwelling after the first 6 months, thus bypassing most of the disadvantages mentioned in relation to permanent stents ( i.e. risk of infection, pain, discomfort, difficulty of endoscopic procedures and removal) without compromising recurrent stenosis or successful long lasting results. as our series demonstrate, all 14 patients remained stable and unobstructed in the 6 month follow up period and the single recurrence 9 months after sphincter placement was readily resolved with a transurethral resection, thus 13/14 patients were recurrence free for the complete follow up period. all 14 patients regained continence after the application of the artificial sphincter. our limitations is the absence of a control group and the small number of patients enrolled, with a relatively short time of follow up. although this is an initial case series study, of a very complicated difficult to treat group of patients, with extended stenosis, multiple recurrence and severe incontinence, the follow up scheme is strict and comparable to similar studies. due to the solid promising results of our novel treatment modality it should be 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eur urol. 2008; 54:647-656. 5. ramchandani p, banner mp, berlin jw, et al. vesicourethral anastomotic strictures after radical prostatectomy: efficacy of transurethral balloon dilation. radiology 1994; 193:345-349. 6. yachia d, markovic z, markovic b, stojanovic v. endourethral prostheses for urethral stricture.acta chir jugosl. 2007; 54:105-14. 7. yurkanin jp, dalkin bl, cui h. evaluation of cold knife urethrotomy for the treatment of anastomotic stricture after radical retropubic prostatectomy j urol. 2001; 165:1545-1548. 8. vanni aj, zinman ln, buckley jc. radial urethrotomy and intralesional mitomycin c for the management of recurrent bladder neck contractures. j urol. 2011; 186:156-60. 9. popken g, sommerkamp h, schultze-seemann w, et al. anastomotic stricture after radical prostatectomy. incidence, findings and treatment. eur urol. 1998; 33:382-6. 10. brodak m, kosina j, pacovsky j, et al. bipolar transurethral resection of anastomotic strictures after radical prostatectomy. j endourol. 2010; 24:1477-81. 11. geavlete b, moldoveanu c, iacoboaie c, geavlete p. plasma vaporization versus standard transurethral resection in secondary bladder neck sclerosis: a prospective, medium-term, randomized comparison. ther adv urol. 2013; 5:75-83. 12. patel sg, cookson ms, clark pe, et al. neovesical-urethral anastomotic stricture after orthotopic urinary diversion: presentation and management. bju int. 2008; 101:219-22. 13. gousse ae, tunuguntla hs, leboeuf l. two-stage management of severe postprostatectomy bladder neck contracture associated with stress incontinence. urology. 2005; 65:316-9. adamakis_stesura seveso 23/09/15 12:41 pagina 236 14. eltahawy e, gur u, virasoro r, et al. management of recurrent anastomotic stenosis following radical prostatectomy using holmium laser and steroid injection. bju int. 2008; 102:796-8. 15. elliott sp, mcaninch jw, chi t, et al management of severe urethral complications of prostate cancer therapy. j urol. 2006; 176:2508-13. 16. simonato a, gregori a, lissiani a, carmignani g. two-stage transperineal management of posterior urethral strictures or bladder neck contractures associated with urinary incontinence after prostate surgery and endoscopic treatment failures. eur urol. 2007; 52:1499-504. 17. magera js jr, inman ba, elliott ds. outcome analysis of urethral wall stent insertion with artificial urinary sphincter placement for severe recurrent bladder neck contracture following radical prostatectomy. j urol. 2009; 181:1236-41. 18. elliott ds, boone tb. combined stent and artificial urinary sphincter for management of severe recurrent bladder neck contracture and stress incontinence after prostatectomy: a long-term evaluation. j urol. 2001; 165:413-5. 19. breyer bn, mcaninch jw. management of recalcitrant bladder neck contracture after radical prostatectomy for prostate cancer. endoscopic and open surgery. j urol. 2011; 185:390-1. 237archivio italiano di urologia e andrologia 2015; 87, 3 difficult to treat blabber neck contractures correspondence ioannis adamakis, md assistant professor yianton@hotmail.com evangelos fragkiadis, md urologist scientific associate e.fragkiadis@gmail.com giorgos kousournas, md resident giorgoskousournas@gmail.com konstantinos stravodimos, md associate professor kgstravod@yahoo.com constantinos a. constantinides, md professor of urology ckonstan@med.uoa.gr ioannis katafigiotis md, mls, phd (corresponding author) resident katafigiotis@yahoo.com department of urology, athens university medical school,greece laiko hospital 17 agiou thoma str., 11527, athens, greece adamakis_stesura seveso 23/09/15 12:41 pagina 237 stesura seveso 33archivio italiano di urologia e andrologia 2015; 87, 1 original paper is it possible to predict the need of inguinal lymphadenectomy in patients with squamous cell carcinoma of the penis? a clinical and a pathological study daniele minardi 1, guendalina lucarini 2, oriana simonetti 4, roberto di primio 2, rodolfo montironi 3, giovanni muzzonigro 1 1 institute of maternal and children’s sciences-urology, polytechnic university of the marche region, azienda ospedalierouniversitaria ospedali riuniti, ancona, italy; 2 department of molecular pathology and innovative therapies-histology, polytechnic university of the marche region, italy; 3 institute of pathological anatomy, polytechnic university of the marche region, azienda ospedaliero-universitaria ospedali riuniti, ancona, italy; 4 institute of dermatology, polytechnic university of the marche region, azienda ospedaliero-universitaria ospedali riuniti, ancona, italy. objective: to investigate the role of cd44 immunohistochemical expression within tumoural and non-tumoural tissue, aiming to understand if it can help us to predict the need of performing inguinal lymph nodes dissection to complete surgery of the penis. materials and methods: cd44 immunohistochemical expression was investigated in tissue specimens from 39 patients with squamous cell carcinoma of the penis who underwent partial or total penectomy between 1987 and 2008. patient age, tumour size, and grade; cd44 intensity score, cytological expression, topographic and distribution pattern were evaluated by immunohistochemistry on archived material and correlated with disease-specific survival. results: mean patients age was 67.7 years; mean followup was 130.44 months. bilateral inguinal lymphadenectomy was performed in 14 patients; there were 8 n+ patients (23.5%). ptis-pt1 vs. > pt1 and the eau classification of risk group resulted to be predictive of lymph nodal metastases at univariate analysis (respectively p = 0.006 and p = 0.045), but not the grading. the intensity score, cytological expression, topographic and distribution pattern of cd44 staining did not correlate with stage, grade and lymph nodes metastases. all disease related deaths occurred only in patients showing an high cd44 intratumoral expression, but this correlation is not statistically significant. multivariate analysis showed that only lymph node metastasis was an independent prognostic factor predictive of lymph nodes metastases. conclusions: cd44 expression in patients with squamous cell carcinoma of the penis is not able to predict the need of performing inguinal lymphadenectomy; staging and the eau classification of risk group resulted to be predictive of lymph nodal metastases. key words: penis; squamous cell carcinoma; cd44. submitted 3 march 2015; accepted 15 march 2015 summary no conflict of interest declared. introduction although squamous cell carcinoma of the penis is a rare disease, it is affected by an high mortality; many literature reports have pointed out that the presence of lymph nodal metastases are a determinant factor for disease specific survival (1); however, the correct treatment and the timing for inguinal lymph nodes dissection is still under debate. a number of studies are looking for prognostic factors able to distinguish patients who may benefit from inguinal lymph node dissection. in many fields of clinical oncology attention has been given to angiogenesis and lymphangiogenesis, that are biological processes induced by tumoural cells able to give neoplastic spread in blood and lymphatic vessels. cluster of differentiation 44 (cd44), a principal cell surface receptor for hyaluronic acid, has been implicated in tumourigenesis and metastasis. cd44 is a glycoprotein encoded on the short arm of the chromosome 11 (2). the genetic sequence can encode for a variety of different proteins by selecting certain exons within the sequence, that is, the gene contains constants and variable exons; it exists as a standard 90 kda form as well as several cd44 variant isoform produced through alternative splicing; it is a cell membrane molecule that was first identified on lymphocytes and was initially found to have cell adhesion and cell homing functions. since its initial discovery, the antigen has been identified in most human tissues and has been found to have a multiplicity of functions (3). cd44 has been defined as cancer-initiating cell marker in many tumour entities (4); the results from initial preclinical trials enforce the multiple benefits that cancerinitiating cells receive from cd44 and strengthen the point that their function might be disrupted by the blockade of this molecule. cd44 has also been implicated in metastasis. in this study, we evaluated a cohort of squamous cell penile carcinoma to investigate the role of cd-44 immu nohistochemical expression within tumoural and nondoi: 10.4081/aiua.2015.1.33 minardi1_stesura seveso 02/04/15 10:20 pagina 33 archivio italiano di urologia e andrologia 2015; 87, 1 d. minardi, g. lucarini, o. simonetti, r. di primio, r. montironi, g. muzzonigro 34 tumoural tissue, aiming to understand if it can help us to predict the need of performing inguinal lymph nodes dissection to complete surgery of the penis. materials and methods patients thirty-nine patients (mean age 67.7 years, range 50-88) with squamous cell penile carcinoma, operated on by partial or total penectomy at our institute of urology between 1987 and 2008, were retrospectively evaluated. of all the patients, 14 underwent to bilateral standard radical inguinal lymphadenectomy, performed in case of high clinical stage and grade (> t2 and/or > g3); in 2 of them palpable lymph nodes were detected. archived materials containing histological sections from patients were retrieved from the institute of pathological anatomy and used for the study purpose. histological grade was based on broders’ classification (5). tumor staging was based on the tnm system (6). positive lymph nodes were defined as the presence of histologically confirmed lymph nodes metastases in patients who underwent inguinal lymphadenectomy. the features considered in this study were patient age, tumour size and grade, cd44 intensity score, cd44 cytological expression, cd44 topographic pattern and cd44 distribution pattern. staging and eau classification of risk groups were also considered (7). all the considered parameters were correlated with patient specific survival. immunohistochemistry immunohistochemistry was performed on conventional 5 μm thick histological paraffin-embedded tissue sections on poly-l-lysine-coated glass slides. after heat-drying, sections were deparaffinized in xylene and sequentially rehydratated in gradients of ethanol. to better unmask antigenic sites, sections were treated with tuf solution (histoline laboratories, milano, italy) at 90°c for 10 min and incubated overnight at 4°c with the antibody cd44 (prediluted, signet laboratories inc., dedham, ma, usa). the reaction was revealed using the secondary antibody and streptoavidin-biotin-peroxidase technique (dako-lsab peroxidase kit, dako-cytomation, carpinteria, ca). after incubation with 3.3 diaminobenzidine (0.05 diaminobenzidine in 0.05 m tris buffer, ph 7.6 and 0.01% hydrogen peroxide), sections were counterstained with mayer’s hematoxylin, coverslipped with paramount and observed using a light microscope. positive controls were represented by paraffin-embedded sections, previously shown to react with primary antibodies, from gastric carcinomas. for negative controls primary antibodies were replaced with nonimmune sera; sections of human tonsil tissue and of squamous cell carcinoma of uterine cervix were used as positive controls for the reaction against anti-cd44. cd44 staining was assessed independently by two different operators (g.l., r.m.) counting individual microvessels on 10 fields at 200x magnification, i.e. a 20x objective lens and 10x ocular lens with 0.22 mm2 per field, on the invasive components of squamous cell carcinoma and normal epithelium. the intensity of intracellular expression has been semiquantitatively evaluated according to a 4 point scale: negative, low, medium and high; the cytological expression has been considered in the membrane and cytoplasm; the topographic distribution has been divided on the basis of positivity in different cellular layers: basal, epibasal, superficial and diffuse; the distribution pattern has been divided in focal and spread. statistical analysis statistical analysis was performed using the kolmogorovsmirnov normality test for all the considered parameters. the χ2 test, mann-whitney u and kruskal-wallis tests were used to compare nonparametric data. the values of cd44 staining were analysed with a model of classification by the roc curve to characterize sensibility, specificity and area under the curve to predict lymph node metastases. kaplan-meier curves were designed to compare survival parameters, the influence of each parameter on survival was assessed using cox proportional hazard models. the statistical significance has been considered with p < 0.05 with two tails. statistical analysis were performed with spss 16 and graph-pad prism 5.0. table 1. clinicopathologic features of tumors (34 patients). variable pts. (%) stage ta 3 (8%) tis 1 (2.9) t1 14 (41.2) t2 12 (35.3) t3 3 (8.8) t4 1 (2.9) grade g1 21 (61.8) g2 7 (20.6) g3 6 (17.6) nodes n0 10 (29.4) n+8 (23.5) nx 16 (47.1) table 2. cd44 characteristics in normal and tumoural tissue (chi-square). normal tumoral p cd44 intensity score absent 2 (7,7) 3 (6.9) 0.218 low 5 (19,2) 3 (6.9) medium 8 (30,8) 7 (20.7) high 11 (42,3) 21 (65.5) cd44 cytological expression membrane 18 (75) 27 (85.2) 0.334 cytoplasm 6 (25) 7 (14.8) cd44 topographic pattern basal 3 (12,5) 9 (25.9) 0.836 basal-epibasal 20 (83,3) 20 (63) epibasal 1 (4,2) 5 (11.1) cd44 dstribution pattern focal 6 (25) 12 (33.3) 0.211 spread 18 (75) 22 (66.7) minardi1_stesura seveso 02/04/15 10:20 pagina 34 35archivio italiano di urologia e andrologia 2015; 87, 1 is it possible to predict the need of inguinal lymphadenectomy in patients with squamous cell carcinoma of the penis? a clinical and a pathological study results of the 39 patients, 5 were lost to follow-up. the mean age of the remaining 34 patients was 67.7 years (range, 5088 years); mean follow-up was 100.44 months (range, 14-243 months). the clinicopathological features of the tumours are shown in table 1. no patient had distant metastases at the time of the diagnosis of the primary tumour. bilateral inguinal lympha denectomy was performed in 14 pa tients; there were 8 n+ patients (23.5%). none of the patients with non-palpable inguinal lymph nodes at diagnosis developed metastases (n0); for statistical purposes, they were therefore considered as n0. ptis-pt1 vs. > pt1 and the eau classification of risk group resulted to be predictive of lymph nodal metastases at univariate analysis (respectively p = 0.006 and p = 0.045), but not the grading, cd44 staining cd44 immunostaining was evaluated in cells in tumoural and normal tissue (figure 1a-c); a positivity has been detected also in normal tissue, while in 3 patients a positivity was not detected in the tumour (table 2); the intratumoral expression of cd44 has been observed mainly on cytoplasmic membrane (85.2%). we can observe that there is no statistically significant difference in normal and tumoural tissue when considering intensity score, cytological expression, topographic and distribution pattern. in table 3 the cd44 characteristics in cancer tissue of patient without and with nodal metastases are shown; there was no statistically significant difference in cancer tissue between patients with non-metastatic and metastatic lymph nodes when considering intensity score, cytological expression, topographic pattern and distribution pattern. the intensity score, cytological expression, topographic and distribution pattern of cd44 staining did not correlate with stage, grade and lymph nodes metastases. survival analysis mean 5-year disease-specific survival was 71%, with significant differences between n0 and n+ patients (96% versus 38%; p b .001, wilcoxon test). when evaluating patients survival, we could observe that all disease related deaths occurred only in patients showing an high cd44 intratumoral expression; but this correlation is not statistically significant (log rank p = 0.146) (figure 2). at univariate analysis, the presence of lymph nodes metastases resulted to be a risk factor for lower specific disease survival (p = 0.014, longrank test) (231.6 months vs. 71.5). multivariate analysis with the cox proportional model showed that only lymph node metastasis was an independent prognostic factor. discussion cd44 is a highly heterogeneous transmembrane glycoprotein that is involved in the growth and metastasis of many types of cancer, acting as a cellular adhesion molecule. in 1989, stamenkovic found that a variety of carcinoma cell lines and solid tumours expressed the cd44 gene (8). in 1991, günthert discovered that an isoform of cd44, when inserted into the genetic sequence of a non-metastasising tumour, gave it metastatic properties (9); these initial discoveries indicating that cd44 was involved in the metastatic process led to a large amount of research into the possible mechanisms and the degree of involvement of cd44. guo showed that monoclonal table 3. cd44 characteristics in cancer tissue of patient without and with nodal metastases (chi-square test). n0 n+ p cd44 intensity score medium 4 (80%) 1 (20%) 0.198 high 4 (44.4%) 5 (55.6%) cd44 cytological expression membrane 8 (61.5%) 5 (38.5%) 0.231 cytoplasm 0 (0%) 1 (100%) cd44 topographic pattern basal 4 (80%) 1 (20%) 0.277 basal-epibasal 4 (50%) 4 (50%) epibasal 0 (0%) 1 (100%) cd44 dstribution pattern focal 4 (66.7%) 2 (33.3%) 0.533 spread 4 (50%) 4 (50%) figure 1. cd44 immunostaining in scc of the penis. intratumoral tissue showed high intensity score in epithelial cell for cd44 (a, original magnification ×200), medium cell positivity (b, original magnification ×150) and low cell positivity (c, original magnification ×300). figure 2. patients survival in relation to cd44 intensity score (p = 0.1471). minardi1_stesura seveso 02/04/15 10:20 pagina 35 archivio italiano di urologia e andrologia 2015; 87, 1 d. minardi, g. lucarini, o. simonetti, r. di primio, r. montironi, g. muzzonigro 36 antibodies specific for cd44 can completely inhibit the binding of cells of a human melanoma cell line and also inhibit the metastatic capability of the tumour cell in vivo (10); in addition, if the monoclonal antibody to cd44 was given seven days after tumour inoculation, the primary tumour continued to grow, although the tumour’s metastatic capability was completely inhibited. hoffman noted that the expression of cd44 by rat embryonic fibroblast cells correlated with metastatic tumour behaviour (11). cd44 realizes its functions through multiple mechanisms, including inhibiting expression of fas (12), activating the mitogen-activated protein kinase (mapk) signalling pathway (13), binding to hyaluronic acid and regulating the activity of matrix metalloproteinases (mmps) (14). the presence of lymph nodes metastases in penile squamous cell carcinoma probably represents the most important prognostic factor for these patients. eau guidelines, regarding indications to inguinal lymphadenectomy in penile carcinoma, provide a stratification in 3 risk groups: low risk (tis, pta g1-g2, pt1 g1), intermediate risk (pt1 g2) and high risk (any g3 and > pt1) (7). nodal dissection is therefore recommended in patients with palpable inguinal lymph nodes or in those with unfavourable clinic and pathologic characteristics; this is based upon the need to select those patients who will undergo surgery, eventually missing those patients with non-palpable lymph nodes but who may present micro-metastases. it has already been observed that in 50-60% of patients palpable inguinal lymph nodes are only reactive (57% in our series), while in up to 20% non-palpable lymph nodes harbor occult metastases (15). furthermore, it is known that even the sentinel lymph node technique, performed by lymphography, is affected by 16% false negative results (16). therefore it has been looked for new prognostic factors for lymph nodes metastases. several authors have already looked for a pathologic or molecular marker able to predict lymph nodal metastases. in a series of 125 patients, campos et al. (17) studied prognostic factors linked to lymphatic diffusion, particularly e-cadherin and metalloproteinases 2 and 9. e-cadherin, a cell adhesion molecule, is involved in the mechanisms of diffusion in many tumors, low levels being correlated with metastases (p = 0.032); increased levels of metalloproteinases, enzymes able to cleave the basal membrane collagen, are correlated to disease recurrence. lopez et al. have studied p53 protein in a series of 82 patients operated on of partial penectomy and bilateral lymphadenectomy, with a mean follow up of 88.7 months, and showed that the nuclear storage of p53 was correlated with nodal involvement and that the absence of p53 brings out a better 5 and 10 years specific survival (18). recently a group from the shangai university confirmed the importance of p53, defining a significant role in determining the probability of nodal involvement in t1 patients (19). the aim of our study was to identify a pathologic factor able to predict the presence of nodal metastases; to our knowledge, this is the first report about the use of cd44 in penile squamous cell carcinoma. in our study, we have observed high levels of cd44 tumoural expression (83.1%); however, we were not able to detected any correlation between intensity of expression and tumour stage and grade. patients with nodal metastases did not show an increased cd44 expression. therefore, we can say that the study of cd44 expression in patients with squamous cell carcinoma of the penis is not able to predict the need of performing inguinal lymphadenectomy. in our study, staging (ptis-pt1 vs. > pt1) and the eau classification of risk group resulted to be predictive of lymph nodal metastases at univariate analysis (respectively p = 0.006 and p = 0.045), but not the grading; however the small number of cases does not allow us to draw definitive conclusions. by the univariate analysis of survival, the presence of nodal metastases represents the main influencing factor. we have already studied the expression of d2-40 in patients with squamous cell carcinoma of the penis, and we have observed that it is a useful marker to predict node metastasis; in particular, low intratumoral lvd and overexpression of d2-40 in cancer cells were associated with lymph node metastasis and a worse clinical prognosis (20). conclusions based on our study, we can say that the cd44 expression in patients with squamous cell carcinoma of the penis is not able to predict the need of performing inguinal lymphadenectomy; staging and the eau classification of risk group resulted to be predictive of lymph nodal metastases. the lack of a defined role of cd44 in our study may be mainly due to the small number of high stage cases, although relevant when considering that penile squamous cell carcinoma is a rare disease; our results need a confirmation by further multicentric studies including a greater number of cases. references 1. ornellas aa, nobrega bl, wei kin ce, et al. prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the brazilian national cancer institute. j urol. 2008; 180:1354. 2. goodfellow pn, banting g, wiles mv, et al. the gene, mic4, which controls expression of the antigen defined by monoclonal antibody f10.44.2, is on human chromosome 11. eur j immunol. 1982; 12:659. 3. sneath rjs, mangham dc. the normal structure and function of cd44 and its role in neoplasia. j clin pathol: mol pathol 1998; 51:191. 4. zöller m. cd44: can a cancer-initiating cell profit from an abundantly expressed molecule? nat rev cancer. 2011; 11:254. 5. broders ac. squamous-cell epithelioma of the skin: a study of 256 casi. ann surg. 1921; 73:141. 6. penis. in: edge sb, byrd dr, compton cc, et al., eds.: ajcc cancer staging manual. 7th ed. new york, ny: springer, 2010, pp 447-55. 7. solsona e, algaba f, horenblas s, et al. eau guidelines on penile cancer. eur urol. 46; 1:2004. minardi1_stesura seveso 02/04/15 10:20 pagina 36 8. stamenkovic i, amiot m, pesando j, seed b. a lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. cell. 1989; 56:1057. 9. günthert u, hofmann m, rudy w, et al. a new variant of glycoprotein cd44 confers metastatic potentials to rat carcinoma cells. cell. 1991; 65:13. 10. guo y, ma j, wang j, et al. inhibition of human melanoma growth and metastasis in vivo by anti-cd44 monoclonal antibody. cancer res. 1994; 54:1561. 11. hofmann m, rudy w, günthert u, et al. a link between ras and metastatic behavior of tumor cells: ras induces cd44 promoter activity and leads to low-level expression of metastasis-specific variants of cd44 in cref cells. cancer res. 1993; 53:1516. 12. manabu y, yoshiya t, koichi f, yasumoto k. cd44 stimulation down-regulates fas expression and fas-mediated apoptosis of lung cancer cells. int. immunol. 2001; 13:1309. 13. marhaba r, bourouba m, zoller m. cd44v6 promotes proliferation by persisting activation of map kinases. cell signal. 2005; 17:961. 14. en kajita m, itoh y, chiba t, et al. membrane-type 1 matrix metalloproteinase cleaves cd44 and promotes cell migration. cell biol. 2001; 153:893. 15. biedrzycki oj, hadway p, cooke a, et al. immunohistochemical analysis of negative inguinal lymph nodes in men with squamous cell carcinoma of the penis: are we missing micrometastases which could predict recurrence? bju int. 2006; 98:70. 16. kroon bk, horenblas s, meinhardt w, et al. dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience. eur urol. 2005; 47:601. 17. campos rs, lopes a, guimaraes gc, et al. e-cadherin, mmp2, and mmp-9 as prognostic markers in penile cancer: analysis of 125 patients. urology. 2006; 67:797. 18. lopes a, bezerra al, pinto ca , et al. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. j urol. 2002; 168:81. 19. zhu y, zhou xy, yao xd, et al. the prognostic significance of p53, ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. bju int. 2007; 100:204. 20. minardi d, d'anzeo g, lucarini g, et al. d2-40 immunoreactivity in penile squamous cell carcinoma: a marker of aggressiveness. human pathology. 2011; 42:1596. 37archivio italiano di urologia e andrologia 2015; 87, 1 is it possible to predict the need of inguinal lymphadenectomy in patients with squamous cell carcinoma of the penis? a clinical and a pathological study correspondence daniele minardi, md (corresponding author) d.minardi@univpm.it giovanni muzzonigro, md g.muzzonigro@univpm.it clinica urologica, università politecnica delle marche, a.o. ospedali riuniti via conca 71 60126 ancona, italy guendalina lucarini, md guendalina.lucarini@univpm.it roberto di primio, md r.diprimio@univpm.it dipartimento di scienze cliniche e molecolariistologia università politecnica delle marche, a.o. ospedali riuniti, ancona, italy oriana simonetti, md o.simonetti@univpm.it istituto di dermatologia, università politecnica delle marche, a.o. ospedali riuniti, ancona, italy rodolfo montironi, md r.montironi@univpm.it istituto di anatomia patologica università politecnica delle marche, a.o. ospedali riuniti, ancona, italy minardi1_stesura seveso 02/04/15 10:20 pagina 37 introduction eosinophilic cystitis is a rare inflammatory disease, that may affect adults and children. the aetiology and the treatment of this condition remains controversial. the pathological presentation of this disease is a eosinophilic infiltration, ranging from mild inflammation to bladder fibrosis. his clinical presentation includes lower urinary tract symptoms, thath can simulate an urinary tract infections. case report a 61-year-old man presented to the emergency room with a 1-week history of constant lower quadrant abdominal pain and lower urinary tract symptoms (1) characterized by increased daytime frequency, slow stream, nocturia, bladder and urethral pain increasing 99archivio italiano di urologia e andrologia 2013; 85, 2 case report a case of eosinophilic cystitis in patients with abdominal pain, dysuria, genital skin hyperemia and slight toxocariasis maria angela cerruto, carolina d’elia, walter artibani urology clinic, university of verona, italy. eosinophilic cystitis is a rare inflammatory disease with controversial aetiology and treatment. we report the case of a 61-year-old man presented with lower quadrant abdominal pain and lower urinary tract symptoms, non responsive to antibiotics and nonsteroidal antiinflammatory drugs. physical examination was substantially negative, such as laboratory parameters, microscopic, bacteriological and serological evaluations. cystoscopy revealed red areas involving the mucosa of the bladder and transurethral biopsies revealed infiltrating eosinophils. the patient was treated with corticosteroids and montelukast sodium with improving of the symptoms, and at 5 weeks postoperative pain score was reduced. after discontinuing corticosteroids dysuria recurred with the development of hyperemia at the genital skin; the specific enzyme-linked immunosorbent assay (elisa) to detect antibodies against several parasites was slightly positive for toxocara species. montelukast sodium was discontinued and corticosteroid therapy was started together with albendazole, with improving of patient’s symptoms and pain decreasing after one week. key words: eosinophilic cystitis; dysuria; genital skin hyperemia; toxocariasis. submitted 2 october 2012; accepted 31 december 2012 no conflict of interest declared summary with bladder filling and reducing during and after voiding, nonresponsive to antibiotics and nonsteroidal antiinflammatory drugs. the patient’s past medical history was notable for hypertension diagnosed 5 years earlier and well controlled with ramipril 5 mg daily. no history of allergy was obtained. he denied having any domestic pets, high-risk sexual behaviour, the use of tobacco, alcohol or illicit drugs, had no sick contacts and hat not travelled recently. he denied having any visual changes or respiratory symptoms, chest pain, nausea, vomiting, melena or hematochezia. he reported changes in bowel habits (an increasing stipsis). upon physical examination skin rash, upper quadrant abdominal tenderness or palpable liver, spleen or abdominal mass were all absent. only a slight tenderness to palpation in the lower abdominal quadrants, mainly in the suprapubic cerruto_cystitis_stesura seveso 24/06/13 11:08 pagina 99 archivio italiano di urologia e andrologia 2013; 85, 2 m.a. cerruto, c. d’elia, w. artibani 100 discussion the eosinophilic cystitis, although rare and mysterious, should be considered in adults with bowel and voiding symptoms associated to lower abdominal quadrant pain. its management is a challenge. and should be tailored to each patient. although leukotriene receptor antagonist (montelukast sodium) is useful in the treatment of eosinophilic cystitis in children, in adults this drug seems to be ineffective without corticosteroids (2). steroidal anti-inflammatory drugs have been reported also to improve symptoms related to allergic response to parasitic infection such as toxocariasis (3). in the present case a mild toxocara infection with antibody titres only midly elevated (4) might be responsible for bladder and genital skin allergic response to the parasite also in the absence of serum eosinophilia. conclusion the eosinophilic cystitis should be considered in adults with bowel and voiding symptoms associated to lower abdominal quadrant pain and its management should be tailored to each patient. in the present case a mild toxocara infection with only midly elevated antibodies might be responsible for bladder and genital skin allergic response to the parasite also in the absence of serum eosinophilia. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. urology. 2003; 61:37-49. 2. sterret s, morton j, perry d, donovan j. eosinophilic cystitis: successful long-term treatment with montelukast sodium. urology. 2006; 67:423.e19-423.e21. 3. despommier d. toxocariasis: clinical aspects, epidemiology, medical ecology, and molecular aspects. clin microbiol rev. 2003; 16:265-272. 4. leone n, baronio m, todros l, et al. hepatic involvement in larva migrans of toxocara canis: report of a case with pathological and radiological findings. dig liver dis. 2006; 38:511-514. region, was noted. digital rectal examination revealed an indolent regular prostate. urethral and bladder pain level was evaluated by a visual analogue scale in which 0 corresponded to “no pain” and 10 to “the worst pain imaginable”. patient’s score was 10. pelvic floor muscle examination was normal and neurologic examination did not reveal focal deficits. there was no lower extremity edema and there was no cervical, axillary or inguinal lymphadenopathy. laboratory parameters were all normal (including psa serum levels). microscopic and bacteriological evaluation of urine and expressed prostatic secretion were negative as well as coproculture. serological studies for viral hepatitis, hiv and syphilis were negative. a ct scan of the patient’s abdomen showed only the presence of small retroperitoneal lymph nodes at the celiac tripod level and a unique 6 mm calcific sigmoidal diverticulum, confirmed by colonoscopy and unable to justify alone the abdominal pain. cystoscopy revealed red areas involving the mucosa of the posterior and the left bladder walls. the prostatic urethra and the trigone appeared normal as did both ureteral orifices. bladder capacity under anaesthesia was 380 ml. after bladder hydrodistension the development of glomerulations did not occur. transurethral biopsies revealed infiltrating eosinophils (figure 1). postoperative course was unremarkable. patient’s postoperative symptoms decreased within 3 weeks taking corticosteroids (25 mg prednisone once-a-day) for 5 weeks. at 4 weeks postoperative he was given montelukast sodium. at 5 weeks postoperative pain score was 3 and bowel function improved. after discontinuing corticosteroids dysuria recurred (pain score 8) and itching, burning and hyperemia at the genital skin occurred. these symptoms temporarily resolved only at rest in a laying down position. in order to exclude parasitic origin of this dermatitis a specific enzyme-linked immunosorbent assay (elisa) to detect antibodies against several parasites was slightly positive for toxocara species. montelukast sodium was discontinued and 1 mg betamethasone dipropionate once-a-day was started together with albendazole 400 mg by oral route 2 times per day with food for 5 days. patient’s symptoms improved and the pain score decreased up to 4 within 1 week. figure 1. histopathology from the bladder biopsy specimen demonstrating a nodular cystitis with abundant eosinophilic cells infiltration (hematoxylin-eosin stain). correspondence maria angela cerruto, md mariaangela.cerruto@univr.it carolina d’elia, md, febu (corresponding author) karolinedelia@gmail.com walter artibani, md walter.artibani@univr.it urology clinic, department of surgery university of verona & aoui, p.le l scuro 10 37134 verona, italy cerruto_cystitis_stesura seveso 24/06/13 11:08 pagina 100 archivio italiano di urologia e andrologia 2013; 85, 18 introduction varicocele is one of the major causes of infertility in men, present in between 15-20% of the general male population (1, 2). it’s predominant in adolescents but found in 41% infertile men and 80% of those with secondary infertility (2). this anatomical abnormality due to the dilation of the venous plexus which covers the testicles (pampiniform plexus) is probably one of the most common causes of oligoasthenozoospermia (1, 3). the pathogenetic mechanism through which varicocele causes testicular dysfunction and subsequent alterations in spermatogenesis, is, however, not completely understood. although various factors may be involved (venous stasis which leads to testicular hypoxia) the increasing of internal testicular temoriginal paper the study of spermatic dna fragmentation and sperm motility in infertile subjects giuseppina peluso 1, alessandro palmieri 2, pietro paolo cozza 1, giancarlo morrone 1, paolo verze 2, nicola longo 2, vincenzo mirone 2 1 u.o.s. of andrology and physiophatology of reproduction-a.o. of cosenza, italy; 2 urological clinic, university federico ii of naples, italy. introduction: although the pathophysiology of the testicular damage associated with varicocele remains unclear, sperm dna damage has been identified as a potential explanation for this cause of male infertility. the current study was designed to determine the extent of sperm nuclear dna damage in patients with varicocele, and to examine its relationship with parameters of seminal motility. materials and method: semen samples from 60 patients with clinical varicocele and 90 infertile men without varicocele were examined. varicocele sperm samples were classified as normal or pathological according to the 1999 world health organizzation guidelines. sperm dna damage was evalutated using the halosperm kit, an improved sperm chromatin dispersion (scd) test. results: the dna fragmentation index (dfi: percentage of sperm with denatured nuclei) values was significantly higher in patients with varicocele, either with normal or abnormal (dfi 25.8 ± 3.2 vs 17.4 ± 2.8 p < 0,01) semen profiles. in addition, an inverse correlation was found between spermatic motility and the degree of spermatic dna fragmentation in patients with clinical varicocele. conclusions: varicocele is associated with high levels of dna-damage in spermatozoa. in addition, in subjects with varicocele, abnormal spermatozoa motility is associated with higher levels of sperm dna fragmentation. dna fragmentation may therefore be an essential additional diagnostic test that should be recommended for patients with clinical varicocele. key words: spermatic dna fragmentation; oxidative stress; varicocele; male infertility. submitted 18 march 2013; accepted 30 march 2013 no conflict of interest declared summary perature is probably the most likely link between varicocele and infertility. in fact, elevated scrotal temperature caused by vascular defects can cause altered production of spermatogenetic cells by germinal epithelium (1, 3). in fact, induced varicocele in laboratory animals leads to elevated intratesticular temperature and sperm dysfunction with decreased sperm motility (1, 3). another link between varicocele and infertility may arise from impairment of the hypothalamic-gonadal axis or oxidative stress (os) (4, 5). in fact, studies evaluating the role of oxidative stress in male infertility have recently shown that os could be considered as an important cause of sperm dysfunction in varicocele infertile men (6-8), peluso_stesura seveso 18/04/13 10:57 pagina 8 9archivio italiano di urologia e andrologia 2013; 85, 1 the study of spermatic dna fragmentation and sperm motility in infertile subjects and attending to andrology service for infertility diagnosis and other andrological problems. once consensus had been granted to be involved in this study, patients were given a thorough andrological analysis according to the guidelines provided by who 2001 which included complete anamnesis, scrotal scan, scrotal doppler ultrasound, hormonal profile based on serum/blood levels basal gonadotrophines (fsh, lh and total blood testo sterone), urethral sample for common microbes, two spermiograms at a week’s interval with a minimum of three days since sexual activity. considering the results of these analysis, it was possible to identify 80 patients with varying degrees of clinical varicocele but predominantly unilateral. all patients with urinary tract infections, leucocytospermia, hypogonadism (testicular volume < 15 ml), a history of excess of cigarette, alcohol or drug use were excluded from the study. the control group consisted of 100 healthy males with normal genitalia and normal seminal parameters, as defined by the who 2001 guidelines. for each patient included in the study, the spermatozoon population was determined. in addition, sperm dna fragmentation was quantified using the sperm chromatin dispersion (scd) test (halosperm kit-indas labora tories, madrid spain) which allows to express the spermatic dna fragmentation as a percentage index (dfi: dna fragmentation index). on the basis of the usual seminologic criteria, 34 patients with varicocele showed isolated asthenospermia, whereas spermatic concentration and morphology have normal values. patients with severe dispermia in conjunction with abnormal standard semen parameters such as oligoasthenotheratozoospermia (oat) where 3%: in such case high levels of damaged sperm dna are usually observed, consequently they were excluded from this study. patients considered in this phase of the study were therefore characterized by asthenozoospermia with various degrees of motility, ranging from 5-45% of the progressive linear a+b motility, according to the cut-off of normal sperm motility established by who, where a+b is greater than or equal to 50% values. the degree of dna damage in spermatozoa of these patients with only altered motility parameter was then correlated with the a+b motility seminal parameter. analysis of sperm dna fragmentation spermatozoon dna fragmentation was quantified using halosperm (diasint-cga, florence-italy) which has been used in the well-developed sperm chromatin dispersion (scd) test (16, 17). the basis of the technology lies in the differential response offered by the nuclei of spermatozoa with fragmented dna compared to those with their dna intact. the controlled denaturation of the dna followed by the extraction of the nuclear proteins, gives rise to partially deproteinized nucleoids in which the dna loops expand, forming halos of chromatin dispersion. the nucleoid, which corresponds to the massively deproteinized nucleus of the spermatozoon, is composed of two parts: spermatozoon nucleus silhouette, called the “core”, positioned centrally, and a peripheral halo of chrowith negative impact on sperm plasma membranes which contain higher amounts of polyunsaturated fatty acids (pufa) which easily experience lipid peroxidation by ros (9, 10). it is a result of cascade of events including lipid peroxidation (lpo) of sperm plasma membrane that ultimately affect an axonemal protein phosphorylation and sperm immobilization (9-11). these spermatozoa would therefore not only be particularly susceptible to reactive oxygen species (ros) (12), with compromised membrane fluidity and integrity and greatly reduced motility (11-13). metanalysis studies support this hypothesis, demonstrating that infertile patients with varicocele have higher levels of ros when compared to other typologies of infertility and controls (14, 15). in addition, the seminal plasma of varicocele patients exhibited reduced total antioxidant capacity (tac) (7, 15-18). recently, various studies have also demonstrated that an elevated presence of dna fragmentation is present in the spermatozoon nuclei of infertile patients with clinical varicocele (19, 18). interestingly, dna damage are higher when compared to spermatozoon of patients suffering from other types of infertility; moreover the spermatozoon of infertile varicocele patients exhibit higher levels of ros, suggesting correlation between oxidative damage and dna fragmentation. studies using rat models have confirmed this, demonstrating that nitric oxide (no) released by endothelial cells of dilated spermatic veins and peroxynitrites generated from reaction with superoxide radicals cause intracellular oxidative damage (20-22), particularly regarding membrane lipid peroxidation, thus altering the integrity of chromatin in spermatozoon nuclei which may be a direct expression of such oxidative damage (17). in addition, sperms of varicocele patients exhibit elevated levels of 8-hydroxy-2 deoxyguanosine which are associated with a deficiency in the pro-oxidant defense system which would cause oxidative damage to the dna by modifying the base, dna strand breaks and chromatin cross linking, since spermatozoa have limited defense mechanisms against oxidative attack on their dna mainly due to its exclusive structural composition for the complex packaging arrangement of dna (18, 23, 24). other indications of increased ros in patients with varicocele are elevated quantities of cytoplasmic droplets in the young spermatozoa. the droplets are indicative of immature and functionally defective spermatozoon (25-27) and, containing high concentrations of cytoplasmic enzymes such as g6pdh and sod, are additional sources of ros (21, 26). together, these studies indicate a positive correlation between spermatozoon immaturity, elevated levels of ros and increase of concentration of mature spermatozoa with damaged dna in ejaculates of these patients (21, 25-27). therefore, in this study, dna fragmentation in spermatozoa of infertile individuals diagnosed with clinical varicocele was quantified with respect to infertile men and controls. in addition, the amount of dna fragmentation was correlated to sperm motility. materials and methods one hundred and fifty subjects analyzed in this study ranged in age between 20-50 with the median age of 35 peluso_stesura seveso 18/04/13 10:57 pagina 9 archivio italiano di urologia e andrologia 2013; 85, 1 g. peluso, a. palmieri, p.p. cozza, g. morrone, p. verze, n. longo, v. mirone 10 sperm cells with very small halos, without halos, and without halo-degraded contain fragmented dna. nucleoids that do not correspond to sperm cells were separately scored. statistical analysis all data were calculated as average + standard deviation on experiments which were repeated and analyzed statistically using the statistical program spss. the statistical tests used were student’s t for continuous values and c2 for parametric values. in addition, statistical correlation was used to test non-linear regression with evaluation of the correlation coefficient. results the concentration of nemasperms in varicocele patients included in the study, was significantly lower than that of controls (19.8 + 6.5 e 39.7 + 7.1 respectively: p < 0.01. motility (type a+b) considered was also significantly lower than that of controls (30.4 + 9.7 and 49.9 + 8.5 respectively: p < 0.01). in addition, the frequency of dna damage in nemasperms of infertile patients with varicocele (% dfi) was statistically higher comparised with infertile patients without varicocele (25.8 + 3.2 and 17.4 + 2.8 respectively: p < 0.01: figure 1). besides the dfi of patients with varicocele was higher compared to values in patients with varicocele and infertile patients for other causes. as a whole the values measured is reported in figure 1. subsequently the values were grouped together, for everyone of the two categories of patients, referred to threshold values, established equal to 15, 20, 25, 30, 35, and 45. these values referred to conditions in a range from normality to extreme pathological condition. therefore the average values of groups under each threshold value were calculated, and the comparison is showed in the figure 2. the average of these groups were evaluated for differences matin/dna dispersion. likewise, when dna fragmentation is present, the nucleoid do not exhibit a dispersion hallow or, if present, is negligible. the tail of the spermatozoon is visible and serves as an important morphological parameter to distinguish the nuclei of nemaspermic cells from others. an aliquot of each sperm sample was diluted in phosphate buffer solution (pbs) to a concentration of 5 million/ml; 25 μl of each sample was mixed and resuspended in fused agarose microgel, as provided by the kit. 20 μl of semen-agarose mix was pipetted onto an agarose precoated slide, provided in the kit, and covered with a 22-x 22-mm coverslip. the slide was placed on a cold plate in the refrigerator (4°c) for 5 minutes to allow the agarose to produce a microgel with the sperm cells trapped. the coverslip was gently removed and the slide immediately immersed horizontally in a denatured solution, previously prepared by mixing 80 μl of hcl from an eppendorf tube in the kit, with 10 ml of distilled water, and incubated for 7 minutes at room temperature before transfer to 10 ml of lysing solution and left to incubate for 25 minutes. after washing 5 minutes in a tray with abundant distilled water, the slides were dehydrated in increasing ethanol bath (70%-90%-100%) for 2 minutes each and air dried at room temperature. for the latter, the slides were horizontally covered with a mix of wright’s solution (merck, darmstadt, germany) and phosphate buffer solution (merck) (1:1) for 5 to 10 minutes, with continuous airflow. then the slides were briefly washed in tap water and allowed to dry. strong staining is preferred to easily visualize the periphery of the dispersed dna loop halos. a minimum of 500 spermatozoa for sample were scored under the 100x objective of the microscope. scoring criteria the categorization of the different halo sizes is performed using the minor diameter of the core from the own nucleoid as a reference to which the halo width is compared. five scd patterns were established (28): a) sperm cells with large halos: those whose halo width is similar or higher than the smallest diameter of the core. b) sperm cells with mediumsize halos: the halo size is between those with high and with very small halo. c) sperm cells with very small-size halo: the halo width is similar or smaller than one third of the minor diameter of the core. d) sperm cells without a halo. e) sperm cells without a halo-degraded: similar to point d), but weakly or irregularly stained. figure 1. comparison of dna fragmentation index (dfi) experimentally evaluated for infertile men affected from varicocele (dots) or other causes (linees). peluso_stesura seveso 18/04/13 10:57 pagina 10 11archivio italiano di urologia e andrologia 2013; 85, 1 the study of spermatic dna fragmentation and sperm motility in infertile subjects such as varicocele-dfi infertile-dfi. such differences were correlated to the dfi values of the two categories and revealed that such differences were always positive and higher for patients with varicocele (fi gure 3). therefore, the most significant data of our study came from the analysis of correlation between the dfi values calculated and progressive a+b motility values expressed in % and calculated in patients with varicocele associated with the condition of isolated asthenozoospermia. statistical analysis of the data found a semi-empirical correlation of 0.9982 between the index of percentage fragmentation (dfi) and percentage sperm motility according to the: eq.1: dfi = 49,48*exp (0,022*motility), as seen in figure 4. discussion while varicocele is one of the most common adrological pathologies in the general population, it is particularly common in infertile men (2). that varicocele negatively influences spermatic function is well documented (29, 30), although the exact underlying mechanisms are still not understood. in fact, infertility may be associated to a variety of spermatogenetic conditions ranging from normozoospermia to moderate oligoasthenoteratozoospermia (oat), to azoospermia (4, 5). recently, several authors have suggested that human patients with varicocele have a significantly higher dna fragmentation index (27). studies show that varicocele samples contain a higher proportion of spermatozoa with abnormal dna and immature chromatin than those from fertile men as well as infertile men without varicocele (31). a cause of this phenomena may be the increased production of ros in varicocele patients which is significantly higher in patients diagnosed with 2° and 3° degree varicocele in whom altered sperm motility is common in these patients (8, 32). an enhancement in os, both due to an increase in ros production and a decrease in the antioxidant capacity, has been reported in men with varicocele (16, 17, 33, 34). no and peroxynitrite, a potent oxidant ros, have been demonstrated to be produced in high concentrations in the dilated spermatic veins, so they could be main contributors to the high os level in varicocele (20, 22, 35). in addition no can improve sperm dna fragmentation that is associated with infertility in men with varicocele (36). besides the dilated veins, ros may be released in the seminiferous tubules by the cytoplasmic droplets retained in immature spermatozoa, which seem to be frequent in the sperm samples from infertile men with figure 2. comparison of dna fragmentation index (dfi) experimental evaluated from different groups of infertile men. for each group, the threshold value has been selected on the basis of different relevance of the pathology. figure 3. detailed comparison of the relevance of the varicocele on the dna fragmentation index (dfi) for infertile men. it’s evident that dfi% is higher for varicocele infertile men. peluso_stesura seveso 18/04/13 10:57 pagina 11 archivio italiano di urologia e andrologia 2013; 85, 1 g. peluso, a. palmieri, p.p. cozza, g. morrone, p. verze, n. longo, v. mirone 12 varicocele (37). immaturity is a consequence of defective spermiogenesis that could also lead to differences in disulfide crosslinking and in susceptibility toward dna fragmentation (38, 39). because all the varicocele samples in this study showed abnormal standard semen parameters, we compared them with those from idiopathic infertility, either normozoospermic patients and from patients with abnormal semen parameters, all attending the infertility clinic. significant differences were found between the 3 groups in the frequency of sperm cells with fragmented dna using the halosperm kit, particulary between the varicocele group and the infertile group, except those samples with more intense and combined abnormalities that could have more frequency of sperm cells with fragmented dna. results of our study, on the higher frequency of dna fragmentation presented in the sperm cells of infertile patients with varicocele compared to patients suffering from other typologies of infertility and the fertile controls, supporting the hypothesis which has been proposed by other authors. besides, a higher proportion was evidenced in our varicocele samples in relation to the fertile controls. in addition, we also found a high inverse correlation between low sperm motility and index of dna fragmentation in sperms of varicocele patients and patients manifesting isolated asthenozoospermia. these findings suggest that a common pathological mechanisms underlies this pathological condition. this mechanism may be the presence of ros or other types of agents which compromise the energetic metabolism of gametes (32, 40). these can react negatively upon sperm membranes, probably by disrupting the equilibrium between antioxidants and prooxidant. in addition, these can also act upon genomic integrity and chromatin structure of the spermatozoon, damaging sperm cell dna (36, 41). the fact that sperms of subjects with varicocele exhibit higher levels of dna damage with respect to sperms from other typologies of infertility, even when normal seminal parameters are attained, clearly demonstrate the importance of studying sperm dna fragmentation (29). this evaluation can be included as a routine test in the clinical management of patients with varicocele, followed by suggestions regarding the potential negative effects that the elevated presence of damaged dna may have on eventual future fertility (30). future research is needed to better understand the exact mechanism by which dna is damaged in the spermatozoon of varicocele patients so that treatment to repair varicocele may be successful in the treatment of infertility and the reduction of such damage. references 1. naughton ck, nangia ak, agarwal a. varicocele and male infertility: part ii. pathophysiology of varicoceles in male infertility. hum reprod. 2001; 7:473-81. 2. kursh ed. what is the incidence of varicocele in a fertile population? fertil steril. 1987; 48:510-1. 3. hauser r, paz g, botchan a, et al. varicocele: effect on sperm functions. hum reprod updat.e 2001; 7:482-485. 4. hauser r, paz g, botchan a, et al. varicocele and male infertility: part ii. varicocele: effect on sperm function. hum reprod update. 2001; 7:482-5. 5. agarwal a, said tm. role of sperm chromatin abnormalities and dna damage in male infertility. hum reprod update. 2003; 9:331-45. 6. agarwal a, saleh ra, bedaiwy ma. role of reactive oxygen species in the pathophysiology of human reproduction. fertil steril. 2003; 79:829-843. 7. barbieri er, hidalgo me, venegas a, et al. varicocele-associated decrease in antioxidant defenses. j androl 1999; 20:713-717. 8. agarwal a, makker k, sharma r. clinical relevance of oxidative stress in male factor infertility: an update. am j reprod immunol. 2008; 59:2-11. 9. sakkas d, mariethoz e, manicardi g, et al. origin of dna damage in ejaculated human spermatozoa. rev reprod. 1999;4: 31-7. 10. zini a, kamal k, phang d, et al. biologic variability of sperm dann denaturation in infertile men. urology. 2001; 58:258-61. 11. barroso g, morshedi m, oehninger s. analysis of dna fragmentation, plasma membrane translocation of phosphatidylserine and oxidative stress in human spermatozoa. hum reprod. 2000; 15:1338-1344. figure 4. relationship estimated between dna fragmentation index (dfi) versus linear progressive motility (a+b) for varicocele infertile patients; (correlation = 0,9982). peluso_stesura seveso 18/04/13 10:57 pagina 12 13archivio italiano di urologia e 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22. romeo c, ientile r, impellizzeri p, et al. preliminary report on nitric oxide-mediated oxidative damage in adolescent varicocele. hum reprod. 2003; 18:26-9. 23. duru nk, morshedi m, oehninger s. effects of hydrogen peroxide on dna and plasma membrane integrity of human spermatozoa. fertil steril. 2000; 74:1200-7. 24. turner tt. the study of varicocele through the use of animal models. hum reprod update. 2001; 7:78-84. 25. evenson dp, jost lk, marshall d, et al. utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. hum reprod 1999; 14:1039-1049. 26. evenson dp, larson kl, jost lk. sperm chromatin structure assay: its clinical use for detecting sperm dna fragmentation in male infertility and comparisons with other techniques. j androl. 2002; 23:25-43. 27. irvine ds, twiggs jp, gordon el, et al. dna integrity in human spermatozoa: relationships with semen quality. j androl 2000; 21:33-44. 28. fernàndez jl, lourdes m, goyanes vj, et al. simple determination of sperm dna fragmentation with an improved sperm chromatin dispersion (scd) test. fertil steril. 2005; 84:833-842. 29. world health organization. the influence of varicocele on parameters of infertility in a large group of men presenting to infertility clinic. fertil steril. 1992; 57:1289-93. 30. villanueva-diaz ca, vega-hernandez ea, diaz-perez ma, et al. sperm dysfunction in subfertile patients with varicocele and marginal semen analysis. andrologia 1999; 31:263-7. 31. gonzález-marín c, gosálvez j, roy r. types, causes, detection and repair of dna fragmentation in animal and human sperm cells. int j mol sci. 2012; 13:14026-52. 32. armstrong js, rajasekaran m, chamulitrat w, et al. characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism. free rad biol med. 1999; 26:869-80. 33. naughton ck, nangia ak, agarwal a. varicocele and male infertility. hum reprod update. 2001; 7:473-81. 34. kamal k, phang d, willis j, jarvi k. biologic variability of sperm dann denaturation in infertile men. urology. 2001; 58:258-61. 35. turkyilmaz z, gulen s, sonmez k, et al. increased nitric oxide is accompanied by lipid oxidation in adolescent varicocele. int j androl. 2004; 27:183-187. 36. abbasi m, alizadeh r, abolhassani f, et al. effect of aminoguanidine in sperm dna fragmentation in varicocelized rats: role of nitric oxide. reprod sci. 2011; 18:545-50. 37. sakkas d, alvarez jg. sperm dna fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. fertil steril. 2010; 93:1027-36. 38. world health organization. who laboratory manual for the examination of human semen and semen-cervical mucus interaction. cambridge, united kingdom: cambridge university press; 1999. 39. zini a, defreitas g, freeman m, et al. varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa. fertil steril. 2000; 74:461-464. 40. aitken rj, krausz c. oxidative stress, dann damage and the y chromosome. reproduction 2001; 122:497-506. 41. hauser r, paz g, botchan a, et al. varicocele and male infertility: part ii. varicocele: effect on sperm function. hum reprod update 2001; 7:482-5. correspondence giuseppina peluso, md (corresponding author) via g. verdi 82/d 87036 rende (cs), italy pina.peluso@libero.it pietro paolo cozza, md giancarlo morrone, md u.o.s. of andrology and physiophatology of reproduction a.o. of cosenza, italy alessandro palmieri, md paolo verze, md nicola longo, md vincenzo mirone, md urological clinic, university federico ii of naples, italy peluso_stesura seveso 18/04/13 10:57 pagina 13 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 3118 introduction human follicle stimulating hormone (fsh) is a heterodimeric pituitary glycoprotein that regulates gonadal function in both male and female. in males, fsh stimulates sertoli cell proliferation and function. it shares with testosterone in the initiation and maintenance of spermatogenesis (1-3). several workers reported the positive outcome of fsh therapy on sperm quality and fertilizing capability (4-7), sperm production (5, 7-10), sperm fine construction (11, 12) and enhancement in conception rate after gamete micromanipulation (7, 13, 14). because of these obviously significant tasks on spermatogenesis, fsh has been original paper isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report nader salama 1, mohamed el-sawy 2 1 departments of urology and clinical pathology, 2 alexandria faculty of medicine, alexandria, egypt. objectives: high levels of follicle stimulating hormone (fsh) in infertile males received a significant attention and exploration. studies investigating the isolated deficiency of fsh in males are few, and its real prevalence is still unknown. therefore, the objectives of the current study was to report the prevalence of isolated low fsh in infertile males and highlight their demographics and standard sperm parameters. methods: records of 3335 infertile men were retrospectively checked. patients with isolated low fsh were retrieved. fsh levels were categorized into 3 groups based on the number of affected sperm parameter (s). study variables were also arranged into 2 groups in relation to smoking history. a control group was included to document the changes in sperm morphology. results: isolated low fsh (1.146 ± 0.219 miu/ml) was found in 29 (0.87%) patients. all patients showed at least one abnormal sperm parameter. the abnormal parameters were present in different combinations within the same patient but with no significant correlations with the fsh levels. the fsh levels got lower as the number of the affected sperm parameters increased although the decline was insignificant. the most frequent abnormal parameter presented was sperm morphology (86.2%). anomalous sperm morphology was highly and significantly demonstrated in the head; specifically in acrosome. abnormal sperm parameters were present in both smoking and nonsmoking groups but with no significant differences in between. conclusions: isolated low fsh among infertile males has a low prevalence. this may be associated with abnormality in semen parameters; particularly sperm morphology. these patients are suggested to be found as a primary entity. however, an additional work-up is highly recommended to validate this hypothesis.. key words: male infertility; low fsh; sperm parameters. submitted 15 april 2013; accepted 31 may 2013 no conflict of interest declared summary acknowledged as a regular laboratory test in the evaluation of the infertile male (2, 6). most reports dealing with fsh in males have focused on its high level associated with disorders of testicular structure and altered spermatogenesis, and how it can act as a predictor of retrieving sperms for subsequent in-vitro gamete micromanipulation (15, 16). in such situations, fsh altered level is often accompanied with changes in other requested hormones like testosterone and lh. on the contrary, studies investigating the isolated deficiency of fsh in males on clinical level are lacking. literature review shows mostly few case reports indicating such doi: 10.4081/aiua.2013.3.118 119archivio italiano di urologia e andrologia 2013; 85, 3 isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report unique deficiency in males (17-19). at best, isolated low fsh in men was cited at a glance on referring to a small study subgroup whose patients were extremely few, and only to reveal the beneficial effect of fsh therapy on these patients (20). infertile females were fortunate. their problems with isolated low fsh received better attention. there are several studies which reported this problem in females, and research was expedited to investigate polymorphism in fsh receptor (21) and fsh auto-antibodies (22, 23). therefore, the prevalence of isolated low fsh in infertile males have not yet been reported. this prompted us to assess this prevalence among egyptian infertile males, highlight their demographics and report the implication of the isolated low fsh on their standard semen parameters; with a special emphasis on sperm morphology. patients and methods study design this retrospective study was carried out at the departments of urology and clinical pathology, alexandria faculty of medicine, alexandria, egypt. evaluation of records of 3335 consecutive men consulting for delayed pregnancy, during the period between february 2004 to may 2012, was accomplished. patients with fsh value ≤ the lower limit of the normal range (1.5-12.4 miu/ml) given by our laboratory kits were recruited. the study was approved by the departmental review boards. inclusion criteria these criteria defined what we meant by isolated low fsh. so, male patients with low fsh but with normal levels of testosterone (t), luteinizing hormone (lh) and prolactin (prl) were enrolled in the study. the criteria included also absence of any clinically detectable varicocele, excess white blood cells (wbc) in semen, antibody-mediated sperm disorder or female factor. absence of varicocele was further confirmed by scrotal duplex scanning using 7.5 mhz probe (aloka,ssd-1700, dynaview ii, tokyo, japan). the presence of abnormally elevated wbc in semen (24, 25) was confirmed using peroxidase test (26). lack of sperm-associated antibody was indicated by mixed antiglobulin reaction (mar) which failed to demonstrate any antisperm antibodies in semen of these patients. hormonal assay blood samples were taken for hormonal assays in the morning at 9: 00-10: 00 o’clock in a heparinized syringe. serum fsh concentrations as well as other hormones (t, lh and prl) were measured using roche elycsys 4020 and cobas e411 automated electrochemiluminescence systems (roche diagnostics gmbh, mannheim, germany). the lower detection limit for fsh was 0.1 miu/ ml. fsh levels were confirmed by re-testing on 2 different occasions. the intra-assay and inter-assay coefficients of variation were < 10%. additional retrieved data after final recruitment of the study patients, additional data were retrieved from their files. these included socio-demographic features as age, occupation, body weight, alcohol intake and smoking habit. retrieved data also incorporated past, drug and family histories, duration of infertility, physical examination and semen analysis results. semen analysis at least, each patient had 3 previous semen reports when he was first seen in our university clinic. all these reports denoted abnormality in one or more of sperm parameters. then a recent semen analysis was accomplished in our facility using manual check up in 16 cases but computer assisted semen analysis (casa) in the subsequent 13 cases. the casa machine was sperm class analyser sca gii (barcelona, spain). the examination included assessment of semen volume, sperm concentration / ml, percentage total and active (scale a-b) motility of sperm and percentage normal sperm forms. the world health organization (who) sperm criteria were used to define normal or abnormal semen parameters using who 1992 handbook (24) for manual assessment and who 1999 handbook (25) for casa evaluation as the study patients were recruited along several years. for further study of the association between state of fsh in the current study and details of sperm morphology as assessed by casa for 13 patients (casa subgroup), a control group (n = 13) was included. statistics the raised data were analyzed using spss statistical software for windows release 20 (spss inc., chicago, usa) on a personal computer. the relationships between serum fsh and sperm parameters were quantified using the spearman rank correlation coefficient (r). fsh levels were categorized into 3 groups based on the number of affected sperm parameter (one, two or three) which included sperm count, total motility and morphology, and comparison between the resulting 3 groups was done using mann-whitney test. the sperm parameters were arranged into 2 groups (normal vs abnormal), and fsh of each resulting group was included. comparison between normal vs abnormal group per each sperm parameter was done using independent-samples t test. according to smoking history, patients’ data including fsh levels and sperm parameters were put into 2 groups (smoking vs nonsmoking). impact of smoking on these variables was also analyzed with independent-samples t test. the same test was also used to compare between the study patients and controls as regard detailed description of the sperm morphology. p-value < 0.05 was considered significant. results patients of 3335 checked files, 29 patients with isolated low fsh were recruited. this yielded a prevalence of 0.87% for this group of patients. at entry, the patients had age (30.55 yr ± 3.85), weight (76 kg ± 15.97) and fsh level (1.146 miu/ml ± 0.219). there was no significant correlation between patient fsh levels and ages (r = 0.1, archivio italiano di urologia e andrologia 2013; 85, 3 n. salama, m. el-sawy 120 p = 0.61). all patients had primary infertility with a duration (3 yr ± 2.8); except 3 who had secondary infertility with a duration (5.73 yr ± 4.94). all study patients were white collar employees. their partners were (16-29) yr old for the group of primary infertility and (21-37) yr old for the group of secondary infertility. fertility check up of the partners excluded female factor. past and family histories were irrelevant and the patients did not receive any prior hormonal treatment or medications which might affect testicular function. self-reported alcohol intake was nil. thirteen patients were smokers, another 13 were nonsmokers while no data were available for 3 patients. clinical examination showed no abnormalities. the 13 controls had comparable age ( 27.3 y ± 3.1 vs 30 y ± 2.8) to that of the casa-patients subgroup. they were clinically free and had normal fsh (4.9 miu/ml ± 1). their other hormones and lab data were normal. sperm parameters all the study patients presented normal semen volumes (2.87 ml ± 1.26). they showed abnormalities in their semen reports. these abnormalities involved one or more of the studied sperm parameter(s). the number of the patients presented with 2 combined abnormal parameters was higher than those of the patients who had either 1 or 3 abnormal parameters (table 1). the most frequently affected parameter was morphology (table 2). abnormal sperm morphology in the casa-patients subgroup this was seen involving the head, mid-piece and tail. the head was the part with the highest percentage of abnormalities (40% ± 4.4) compared with mid-piece (24.3% ± 6.5) or tail (29.3% ± 4.3). the most frequent head deformity was abnormal acrosome (49.2% ± 6.2). the controls showed significantly less anomalies in the sperm head (21.6% ± 5.2; p < 0.001) and acrosome (20.1% ± 3.5; p < 0.001). relation between fsh level and semen parameters the level of fsh declined as the number of affected sperm parameters increased. however, this decline in fsh level was not significant (table 1). it was of interest that the fsh levels were obviously lower in all the patients’ groups with abnormal sperm parameters compared to those levels of the patients’ groups with normal parameters (table 2). again, these differences in fsh levels were insignificant; except with total sperm motility. there were also no significant correlation between fsh level and semen volume (r = -0.27, p = 0.16) or any abnormally affected sperm parameter (table 3). no negative impact of smoking on the study variables no statistically significant differences were appreciated between the smoking and nonsmoking group in regard to any of the study variables (table 4). number of negative patient number fsh (mean ± sd) sperm parameter(s) (%) miu/ml 1 5 (17.2) 1.22 ± 0.29 2 14 (48.3) 1.17 ± 0.20 3 10 (34.5) 1.07 ± 0.20 sperm parameter normal levels abnormal levels p-value mean ± sd patient no. fsh mean ± sd patient no. fsh no. (%) (mean ± sd) (%) (mean ± sd) count (106/ml) 82.91 ± 40.46 11 (38) 1.16 ± 0.28 2.59 ± 3.3 18 (62) 1.14 ± 0.18 0.845 total motility (%) 54 ± 4.6 11 (38) 1.27 ± 0.13 23.42 ± 14.82 18 (62) 1.08 ± 0.23 0.011 active motility (%) 33.75 ± 7.44 8 (27.6) 1.17 ±0.14 6.76 ± 7.36 21 (72.4) 1.14 ± 0.25 0.683 morphology (%) who 1992 37.5 ± 9.6 4 (13.8) 1.18 ± 0.32 15.67 ± 6.73 12 (41.4) 1.15 ± 0.25 0.878 who 1999 6.39 ± 1.33 13 (44.8) 1.13 ± 0.18 25 (86.2) table 1. categorization of fsh levels in relation to the number of negative sperm parameter(s)*. table 2. normal and abnormal sperm parameters of the study patients and fsh levels (miu/ml) in each group*. p = 0.143 p = 0.515 p = 0.326 } } } * mann-whitney test * independent-samples ttest. 121archivio italiano di urologia e andrologia 2013; 85, 3 isolated low follicle stimulating hormone (fsh) in infertile males – a preliminary report discussion gonadotropin deficiency in men is rather uncommon. low fsh was reported previously; either in studies dealing with hypogonadotrophic hypogonadism (9, 27) or without any note about other reproductive hormones (28). so, such reported low fsh was not an isolated deficiency. recently, a study by efesoy et al. (20) included a subgroup of infertile men with a real isolated low fsh among its other subgroups while checking for response to fsh therapy. however, the sample was very small in number and just touched at a glance without detailed reporting of related demographical, clinical or laboratory findings. clinical studies investigating the isolated deficiency of fsh in males are lacking and mostly old case-reports (17-19, 29). enrollment of male patients to launch a study related to this isolated hormonal deficiency, either clinically or epidemiologically, is extremely difficult. therefore, the characteristic features of patients with this deficiency have not been well defined so far. in the present study out of 3335 infertile males, only 29 patients with isolated fsh deficiency were successfully recruited giving a prevalence of 0.87%. to the best of our knowledge, this is the first study documenting this prevalence of isolated low fsh in infertile males, and it included the largest number of infertile men with this deficiency so far in the literature. this rarity of selective fsh deficiency in males made some investigators to claim that existence of this deficiency as a primary entity is not clear (29). these investigators presented case reports for patients with remarkably low and sometimes undetectable levels of fsh. in the current study, we presented a complete and true degree of selective fsh deficiency, and we think that it could be found as a primary entity. three reasons may support our suggestion. first, the levels of fsh (1.146 ± 0.219 miu/ml) in our patients were obviously below the lower limit of normal laboratory range. this low level, a) was not due to spurious laboratory results as retesting fsh level confirmed the first result, and b) would remain low even on considering fsh periodicity which was documented in some studies to have an amplitude of 0.21 ± 0.03 miu/ml (30). the standardized chemiluminescence used in the present study was, therefore, suitable although it is less sensitive than other assays like delfia method (31). we wished also to test serum inhibin and anti-mullerian hormone levels which could have been used as a lab corollary to the low fsh but such testing was, unfortunately, not available in this country during the time when the study patients were first seen in the clinic, long years ago. second, we selected only the patients with really isolated low fsh. so, the potentially negative implications imposed by clinical or other reproductive hormonal disorders were excluded from the start. third, tobacco smoking, which was the only unavoidable factor in the current study, did not cause any further adverse effect on the already declined sperm parameters. however the declined parameters of the patients in the smoking group showed less drop than those of the non-smoking group patients. this current finding about lack of negative effect of tobacco smoking comes in line with other investigators who denied any effect of smoking on any sperm parameter (32) but it disagrees with others who reported negative implications on sperm parameters induced by smoking (33). this point may be criticized by some as the number of patients in the smoking group was 13 patients and might by relatively small to draw conclusion. however, recruitment of sufficient number of patients with isolated low fsh and also with negative history of smoking would be extremely difficult; if not impossible. we tried, in the present study, to exclude any factors with negative impact on sperm parameters as much as possible in order to demonstrate clearly the real relationship between isolated low fsh and sperm parameters. study point smoking group nonsmoking group p-value fsh level (miu/ml) 1.12 ± 0.24 1.14 ± 0.19 0.758 semen volume (ml) 2.89 ± 0.83 2.59 ± 0.74 0.352 sperm count (106/ml) 43.61 ± 57.19 19.52 ± 32.7 0.2 sperm total motility (%) 36.15 ± 18.61 33.08 ± 20.67 0.694 sperm active motility (%) 14.77 ± 12.94 16.92 ± 15.75 0.707 sperm normal forms (%) who 1992 23.29 ± 9.34 18.33 ± 17.22 0.548 who 1999 6.67 ± 1.63 6.14 ± 1.07 0.52 table 4. fsh levels and sperm parameters in relation to smoking *. * independent-samples ttest. sperm parameter mean ± sd correlation with fsh count (106/ml) 33.06 ± 46.52 p = 0.66 r = 0.09 total motility (%) 33.97 ± 19.15 p = 0.19 r = 0.25 active motility (%) 14.21 ± 14.26 p = 0.77 r = 0.06 morphology (%) who 1992 21.13 ± 11.11 p = 0.89 r = 0.04 who 1999 6.39 ± 1.31 p = 0.24 r = 0.35 table 3. sperm parameters of the 29 study patients and correlation with fsh levels *. * spearman rank correlation coefficient. archivio italiano di urologia e andrologia 2013; 85, 3 n. salama, m. el-sawy 122 pathogenic alterations in the hypothalamus or the pituitary have been incriminated as possible reasons for the defect in fsh secretion. in the current study, lh was within normal levels in all patients. so, a discrepancy in the levels of both hormones happened although different studies pointed out that both hormones are released from the same pituitary cell type (34). a possible explanation could be attributed to a change in the nature of gnrh pulse frequency and/or amplitude with a consequent abnormal fsh secretion by the pituitary cells (35). in support for this suggestion, recent studies demonstrated the differential interpretation ability of the same gonadotropin to the different gnrh inputs which depends mainly on signal-regulated mechanisms (36) as well as epigenetic factors (37) in maintaining these energetic responses of the gonadotropin. other causes which may decrease the fsh level alone may be attributed to multifaceted mutations in the coding region of the fsh gene (21). in the current study, screening for fsh-β gene has not been done due to financial reasons. these shortcomings in the present study may not unveil the exact reasons involved in the isolated fsh decline in the study patients. the present study is just a preliminary report, and we are starting now to collect new patients with similar abnormality who will be thoroughly screened for possible etiology in a new study. in the present work, isolated low fsh was associated with low percentage motile sperm in the majority of the patients. this comes in line with efesoy et al. (20) and novero et al. (28) although the number of patients in both studies were very limited. maroulis et al. have also reported similar abnormalities in sperm motility in their case reporting for 2 patients (18). this drop in sperm motility may be explained on the basis of the alteration in sertoli cell function due to the decline in fsh level which is known to stimulate its structure and function (3). this modification in function is expected to affect the growth factors secreted by the sertoli cell (38) where many of these factors are known to promote sperm motility (39). recent studies have addressed the existence of specific receptors for many of these factors on the sperm membrane itself (40). this may be a probable reason why some patients of the current work were infertile although they had sufficient number of motile sperms which may deal with their problem of asthenospermia. the drop in sperm concentration in the majority (62%) of the study patients is well accredited to the crucial role of fsh in the induction, regulation and maintenance of the spermatogenesis (3). the present study revealed also increased percentage abnormal forms as governed by who criteria (24, 25) in all patients, except only 4. this ranked the abnormal sperm morphology as the most prevailing anomaly associated with isolated low fsh. we agree, therefore, with novero and his co-workers (28) who showed a decline in normal forms in one of their patients and a borderline state in the second. the present study showed also an interesting finding, that is related to the sperm head anomalies. these anomalies represented the most frequent abnormalities in sperm morphology. they involved, in particular, the sperm acrosome. this may agree indirectly with bartoov et al. (41) who showed that abnormal forms, from infertile men who were kept on fsh therapy, were associated with significant improvement in acrosome shape with drop in its agenesis to reach normal frequency. the present finding of increased percentage of acrosome anomalies agrees also with courtens and courot (42) who showed that morphogenesis of the acrosome and its expansion in hypophysectomized ram was modulated by fsh and testosterone. recently, the enhancing effect of recombinant fsh on sperm morphology was also addressed in many studies which reported a significant increase in the sperm normal morphology after treatment (4, 6-8, 11, 14, 43). some of these studies indicated clearly the drop in head and acrosomal aberrations with this treatment (4, 11). conclusion isolated low fsh in infertile men has a low prevalence. disturbance in one or more sperm parameter (s) is (are) usually existent although abnormal sperm morphology was almost always present. anomalous sperm head with abnormal acrosome were the most eminent morphological findings. therefore, the need to measure serum fsh concentration in the infertile male has been reconfirmed. although the number of reported male patients with isolated low fsh in the literature is extremely limited so far, nevertheless, we believe that infertile men with isolated low fsh may be found as a primary entity in male infertility. extension of this work to thoroughly screen these patients for possible etiologies is highly recommended to validate this hypothesis. notes a master table containing the retrieved data of this study is documented, certified and saved at the department of urology, alexandria faculty of medicine, alexandria, egypt. statement of authorship nader salama: conception and design of the study, collection, analysis and interpretation of data, and drafting the article with final approval of its completed form. mohamed el-sawy: collection and interpretation of the data, and drafting the article with final approval of its completed form. references 1. matsumoto am, karpas ae, bremner wj. chronic human chorionic gonadotropin administration in normal men: evidence that follicle stimulating hormone is necessary for the maintenance of quantitatively normal spermatogenesis in man. j clin endocrinol metab. 1986; 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85, 3 n. salama, m. el-sawy 124 iniferrous epithelium during spermatogenesis. endocr rev. 2004; 25:747. 39. hermo l, oko r, morales c. secretion and endocytosis in the male reproductive tract: a role in sperm maturation. int rev cytol. 1994; 154:105. 40. naz rk, sellamuthu r. receptors in spermatozoa: are they real ? j androl. 2006; 27:627. 41. bartoov b, eltes f, lunenfeld e, et al. sperm quality of subfertile males before and after treatment with human follicle-stimulating hormone. fertil steril. 1994; 61:727. 42. courtens jl, courot m. acrosomal and nuclear morphogenesis in ram spermatids: an experimental study of hypophysectomized and testosterone-supplemented animals. anat rec. 1980; 197:143. 43. selice r, garolla a, pengo m, et al. the response to fsh treatment in oligozoospermic men depends on fsh receptor gene polymorphisms. int j androl. 2011; 34:306. correspondence nader salama, md (corresponding author) department of urology alexandria faculty of medicine alexandria, egypt nadersalama58@yahoo.com mohamed el-sawy, md department of clinical pathology alexandria faculty of medicine alexandria, egypt elsawymohamed@gmail.com archivio italiano di urologia e andrologia 2018; 90, 2112 original paper the effect of the american society of anesthesiology classification scores on complications associated with percutaneous nephrolithotomy erdem kisa 1, cem yücel 1, salih budak 2, murat ucar 1, mehmet zeynel keskin 1, ozgur cakmak 1, gokhan koc 1, zafer kozacioglu 1 1 tepecik training and research hospital, turkey; 2 sakarya training and research hospital, turkey. objectives: we aimed to evaluate the effect of american society of anesthesiology (asa) classification scoring and age on complications and surgical outcomes during and after percutaneous nephrolithotomy (pcnl) operation. material and methods: the records of 263 patients, above the age of 18 years, that underwent pcnl surgery between october 2014 and may 2017 were evaluated retrospectively. the patients were divided into three groups based on their asa risk scores (asa 1, 2, 3) and into two groups based on their age (younger and older than 65 years). postoperative complications were assessed according to the asa groups and age and according to the clavien classification system. results: the number of patients in the asa 1, 2, and 3 groups were 97 (36.8%), 131 (49.8%) and 35 (13.3%), respectively. four patients in asa4 were not included in the study. there was no significant difference in asa 1, 2, 3 groups in terms of changes in hgb values, mean duration of operation, and mean hospital stay. when asa1 was compared to asa3 and asa2 was compared to asa3, there was no significant difference in the incidence of all complication rates. there were 159 (60.4%) patients in the young group and 104 (39.5%) patients in the elderly group. postoperative pcnl complications of these 2 groups were compared according to clavien classification system and no significant difference was found in incidence of complications. conclusions: we believe that pcnl operation can be performed effectively and safely in both asa3 patients and patients above the age of 65 years. key words: american society of anesthesiologists’ scoring system; clavien classification system; percutaneous nephrolithotomy; surgical complications; geriatric. submitted 25 march 2018; accepted 29 april 2018 summary no conflict of interest declared. (pcnl) is a standard operation in following cases: staghorn stones larger than 20 mm, stones resistant to shock wave lithotripsy (swl), cystine stones, patients with anatomically anomalous upper urinary system, patients with anatomical defects (scoliosis, kyphosis or spasticity), lower pole stones larger than 15 mm and stones in transplant kidneys (2, 3). the reliability, efficacy and complication rates of the pcnl operation in elderly patients have been evaluated in many studies, just like the impact of the american society of anesthesiologist (asa) classification scores (4-10). the prevalence of systemic diseases increases with aging. the asa classification is a system in which patients are evaluated according to the risk of anesthesia prior to surgery. this system can be used to choose the type of anesthesia, to determine the monitoring method, and to assess the tolerance of patients to various surgical manipulations such as surgical position. staying in prone position during pcnl can lead to some difficulties; such as those in controlling the airway, maintaining the vascular access and ventilation of patients with lung diseases in particular (11, 12). in this study, we aimed to compare the effect of asa risk classification scores on complications during and after pcnl surgery. materials and methods we retrospectively reviewed the records of 263 patients over the age of 18 years who underwent pcnl surgery in our clinic between october 2014 and may 2017. patients were divided into three groups: asa1, asa2 and asa3. patients with an asa score of 4 were excluded from the study. patients were also divided into two groups according to their age: elderly (65 years and over) and young (18-65). local ethics committee approved our study. an expert anesthesiologist evaluated all the patients preoperatively. the risk of surgery was determined according to the asa classification score (table 1). demographic, surgical and perioperative anesthetic data and postoperative outcomes were obtained from patient records (table 2 and 3). patients with sterile urine culture were taken into operation. patients with urinary doi: 10.4081/aiua.2018.2.112 introduction nephrolithiasis is one of the most common diseases, affecting nearly one in thirteen women and one in seven men (1). certain factors such as location and composition of the stone, patients’ anatomy and comorbidities play an important role in the choice of treatment in urinary system stone disease. stone size is the most important factor in choosing the surgical modality for the removal of the stone. percutaneous nephrolithotomy kisa_stesura seveso 28/06/18 16:37 pagina 112 113archivio italiano di urologia e andrologia 2018; 90, 2 the effect of the american society of anesthesiology classification scores on complications associated with percutaneous nephrolithotomy tract infections were treated according to the antibiogram. all patients were assessed by direct urinary system rx-graphy and unenhanced computerized tomography (ct) preoperatively. the locations of the renal stones were identified as upper, middle or lower calyx, and pelvis. the stone size was calculated by multiplying the widest width and height of the stone. in patients with multiple stones in their urinary system, stone sizes were calculated separately and added. isolated stones in the upper, middle or lower calyces were classified as noncomplex, while partial or complete staghorn stones and stones located in both renal pelvis and a single calyx were classified as complex stones. all pcnl operations were performed in prone position and under general anesthesia and fluoroscopy. a single dose of appropriate intravenous antibiotic was used as antimicrobial prophylaxis. a ureteral catheter fixed to the foley catheter was placed. tract dilation up to 30-french was achieved with amplatz dilators and a 30-french plastic amplatz sheath was introduced. a 26french rigid nephroscope and ultrasonic lithotripter were used in all cases. a 24-french nephrostomy tube was used for drainage when necessary. the complications of the patients in asa risk groups were classified according to the modified clavien scoring system (table 4). same criteria were used to compare the patients in the age groups (table 5). all patients underwent noncontrast ct at first month postoperatively and overall stone-free rate was evaluated. since the numerical variables in the groups did not show normal distribution, the median (minimummaximum) was used as the descriptive statistic. moreover, the number (%) was used as a descriptive statistic for the categorical variables. a nonparametric kruskal-wallis test was used to determine whether there is a difference in numerical variables among the groups. the two proportions z test or the fisher exact test were used to assess the difference between the prevalence percentages of categorical variables within the groups, depending on the assumptions. for all tests, the probability of type i error was set to α = 0.05. the r project 3.2.5 package program was used for all statistical analyses. results the mean age of the groups, the stone dimensions, the ratio of complex to non-complex stones, the distribution of stone location, and the average number of accesses are shown in table 2. the changes in hemoglobin (hgb) levels before and after the operation, the mean duration of operation, and the mean hospital stay of the groups are shown in table 3. there was no statistically significant difference between the groups in terms of hgb change, mean duration of operation and mean hospital stay (p = 0.474, 0.389 and 0.674, respectively). the overall stone free rates in patients in the asa 3 group were compared with those in asa 2 and asa 1 groups (table 3). the overall stone-free rates of the groups were 71.1% for asa1, 67.9% for asa2, and 71.4% for asa3. the separate comparison table 1. asa scoring system. asa-i a completely healthy patient asa-ii a patient with mild systemic disease asa-iii a patient with severe systemic disease that is not incapacitating asa-iv a patient with incapacitating disease that is a constant threat to life asa-v a moribund patient who is not expected to live for 24 h with or without surgery table 2. the patients’ demographic data and stone locations. asa 1 asa 2 asa3 patients, n (%) 97 (36.9%) 131 (49.8%) 35 (13.3%) mean age ± standard deviation 44.4 ± 14.8 44 (18-75) 59.7 ± 11.6 median (min-max) 65 (29-87) 65.8 ± 8.8 66 (50-93) mean stone burden (mm2) 443.9 ± 364.3 500.2 ± 438.8 434.6 ± 311.7 ± standard deviation 322 375 399 median (min-max) (60-2275) (112-2772) (126-1880) complex stone, n (%) 54 (55.6%) 61 (46.5%) 20 (57.1%) noncomplex stone, n (%) 43 (44.3%) 70 (53.4%) 15 (42.8%) stone location superior n = 8 n = 8 n = 0 middle n = 13 n = 13 n = 2 inferior n = 45 n = 72 n = 21 pelvis n = 31 n = 38 n = 12 average access number 1.2 (117/97) 1.1 (152/131) 1.2 (42/35) table 3. study results by groups. asa 1 asa 2 asa3 p 1hgb preop-postop 1.70 (-0.80-8.70) 1.50 (-0.40-5.50) 1.50 (-0.30-6.10) 0.474 median (min-max) 1mean operative time (min) 93.0 ± 34.2 92.5 ± 37.3 100.5 ± 37.5 0.389 mean ± standard deviation 90 (40-230) 85 (45-210) 90 (55-225) median (min-max) 1mean hospitalization (days) 2.8 ± 1.3 3 ± 1.7 3.0 ± 1.9 0.674 mean ± standard deviation 2 (2-8) 2 (2-10) 2 (2-10) median (min-max) 2postop 1-month stone free (%) 69 (71.1) 89 (67.9) 25 (71.4) 0.974ac, 0.687bc complications 3grade1 n (%) 5 (5.1%) 5 (3.8) 1 (2.8) 0.999ac, 0.999bc 3grade2 n (%) 8 (8.1%) 16 (12.1%) 5 (14.2%) 0.356ac, 0.752bc 3grade3 n (%) 3 (3.0%) 6 (4.5%) 2 (5.7%) 0.608ac, 0.676bc 3grade4 n (%) 0 2 (1.5%) 1 (2.8%) 0.265ac, 0.511bc 2overall complication rates 16.4% 22.1% 25.7% 0.266ac, 0.664bc 1 kruskal-wallis test; 2 two proportion z test (bonferroni correction was made); 3 fisher exact test (bonferroni correction was made). kisa_stesura seveso 28/06/18 16:37 pagina 113 archivio italiano di urologia e andrologia 2018; 90, 2 e. kisa, c. yücel, s. budak, m. ucar, m. zeynel keskin, o. cakmak, g. koc, z. kozacioglu 114 between asa3 and asa1, asa3 and asa2 groups at 1-month follow-up did not reveal any statistically significant difference in terms of stone-free percentage (p = 0.974 and 0.687, respectively). the complications in patients in the asa 3 group were compared with those in asa 2 and asa 1 groups (table 3). there was no significant difference between asa1 and asa3 groups in terms of the separate incidence of grade 1, grade 2, grade 3, and grade 4 complications (p = 0.999, 0.356, 0.608, 0.265, respectively). the comparison of asa2 and asa3 groups also did not show any significant difference in terms of the separate incidence of grade 1, grade 2, grade 3, and grade 4 complications (p = 0.999, 0.752, 0.676, and 0.511 respectively). when asa1 and asa3, asa2 and asa3 groups were compared separately, there was no significant difference in terms of percentage of overall complication rates (bonferroni correction, p = 0.266 and 0.664, respectively). there were 104 patients (39.5%) in the elderly group and 159 patients (60.4%) in the young group. the post-pcnl surgery complications of these two groups were compared according to modified clavien classification system (table 5). there was no significant difference in the incidence of grade 1, grade 2, grade 3 complications between the age groups (> = 65 and < 65) (p = 0.689, 0.323, and 0.999, respectively). patients' comorbidities were divided according to the groups. the mean number of comorbidities in asa1 was 0.06 (6/97), in asa2 was 1.2 (158/131), and in asa3 was 2.1 (75/35). the most commonly observed comorbidity was hypertension (100/263, 38%). discussion the pcnl surgery is the standard treatment option for large kidney stones. many studies have shown that pcnl can be successful in high-risk patients (asa3 and asa4) (8-10). an increase in the rate of systemic disease is expected in patients with advanced age. in a study by kuzgunbay et al. the table 4. modified clavien classification according to asa groups. clavien complication rates asa 1 n (%) asa 2 n (%) asa3 n (%) grade 1 fever (over 38.5°c, requiring antipyretic treatment) 5 (5.1) 5 (3.8) 1 (2.8) grade 2 blood transfusion 6 (6.1) 13 (9.9) 4 (11.4) urinary tract infection requiring additional antibiotics (instead of prophylactics) 2 (2.0) 3 (2.2) 1 (2.8) grade 3a double-j stent placement for urine leakage > 24 h (local anesthesia) 1 (1.0) 3 (2.2) 1 (2.8) pleural effusion 0 1 (0.7) 0 pneumothorax 0 1 (0.7) 0 grade 3b double-j stent placement for urine leakage > 24 h (ureter stone, general anesthesia) 1 (1.0) 1 (%0.7) 1 (2.8) av fistula 0 perirenal hematoma needing intervention 1 (1.0) 0 0 perioperative bleeding requiring termination of the operation 0 0 0 0 0 grade 4a pulmonary emboli (requiring intensive care unit) 0 1 (0.7) 0 neighboring organ injury 0 0 0 nephrectomy 0 0 0 urosepsis 0 1 (0.7) 1 (2.8) grade 5 death 0 0 0 table 5. modified clavien scoring according to the age groups. clavien complication 65 < elderly 65> young p n = 104 n = 159 n (%) n (%) grade 1 0.6891 fever 5 (4.8) 6 (3.8) grade 2 0.3231 blood transfusion 12 (7.5) 11 (10.5) urinary tract infection requiring additional antibiotics (instead of prophylactics) 2 (1.2) 4 (3.8) total 14 15 grade 3a 0.9992 double-j stent placement for urine leakage > 24 h (local anesthesia) 1 (0.6) 1 (0.6) pleural effusion 0 4 (3.8) pneumothorax 2 (1.2) 0 grade 3b double-j stent placement for urine leakage > 24 h (ureter stone, general anesthesia) 0 1 (0.9) av fistula 0 1 (0.9) perirenal hematoma needing intervention 0 1 (0.9) perioperative bleeding requiring termination of the operation 4 0 total 0 7 grade 4a pulmonary emboli (requiring intensive care unit) 1 (0.6) 0 neighboring organ injury 0 0 nephrectomy 0 0 urosepsis 1 (0.6) 0 grade 5 death 0 0 1 two proportion z test; 2 fisher exact test kisa_stesura seveso 28/06/18 16:37 pagina 114 115archivio italiano di urologia e andrologia 2018; 90, 2 the effect of the american society of anesthesiology classification scores on complications associated with percutaneous nephrolithotomy patients who underwent pcnl surgery were divided into two groups based on their age: elderly (65 years and older) and the control group (18-36 years). the comparison of comorbidity prevalence showed that while 73% of patients in the elderly group had at least one comorbidity, there were no comorbidities in control patients (13). in a study by nouralizadeh et al. the number of co-morbidities in high-risk patients was 2, while this ratio was 5.4 in a study by patel et al. (8-10). in our study, we observed that the average number of co-morbidities increased from 0.06 to 2.1 when going from asa1 to asa3. this increased rate increases the number of medications used by patients, which in turn is an important factor to consider before, during and after the operation by both surgeons and the anesthesiologists, especially in asa3 patients. in the literature, the proportion of the elderly individuals among patients undergoing pcnl surgery ranges 10 to 12% (14). however, in a study by anagnostou et al., where they set the lower age limit to 70 years, 17% of the patients undergoing pcnl surgery were in that group (4). in our study, the ratio of elderly patients was 39%. we believe that our ratio is high because the age limit in our study was 65, our hospital is an institution that receives many referrals, and because the patients who need intensive care after operation were also treated in our hospital. bleeding and septic complications of pcnl may become more significant in elderly patients with impaired cardiopulmonary and renal function (15). for this reason, the risks associated with anesthesia may be more prevalent in older patients compared to younger patients. the anesthesiologists and surgeons are always concerned about invasive treatments such as pcnl when it comes to older patients with renal stones. therefore, when evaluating treatment alternatives in these patients, general health of the patient should be considered along with the size and location of the stone (16). careful pre-operative examinations can provide comprehensive safety for surgical procedures in elderly patients (4). higher prevalence of complex stones in elderly and highrisk patients can be explained by patients’ and surgeons’ initial reluctance to do surgery in favor of more conservative treatments and as a result stones get bigger and develop a staghorn formation (10). sahin et al. reported that stone sizes are larger in elderly patients compared to younger patients (1077.92 mm2 versus 920.85 mm2) (5). similarly, in our study, the median stone size and percentage of complex stone structures were higher in asa3 patient group. although pcnl surgery has been shown to be safe and effective in all age groups, minor and life-threatening complications can occur during and after surgery (7, 17, 18). pcnl related fever (0-32.1%), hemorrhage requiring transfusion (0-20%), embolization (0-1.5%), urinoma (01%), sepsis (0.3-1.1%), thoracic complications (0-1.6%), organ injury (0-1.7%), and death (0-0.3%) can be observed at varying rates (19). in 2007, tefekli et al. developed a modified clavien classification system for pcnl surgeries in order to better evaluate and inform patients about possible complications. this system also classifies complications seen during and after the operation by grading them (20). patel et al. found that the overall risk of complications was higher in the high-risk group compared to the lowrisk group (21.2% vs. 18.5%). the majority of complications in the high-risk group consisted of grade 2 complications (12.1%), while grade 1 complications made up 9.1%. however, there was no significant difference between the complication rates of high-risk group and the low risk group (8). similarly, the most common complication in our study was grade 2. when asa1 was compared with asa3 and asa2 was compared with asa3 there was no significant difference in terms of percentage of overall complication rates. moreover, the comparison of age groups (older and younger than 65 years) also did not show any significant difference in terms of percentage of overall complications. the studies on bleeding complications during and after pcnl operation in high-risk and elderly patients are controversial. resorlu et al. have shown that the probability of bleeding increases when comorbidity increases (21). similarly, nouralizadeh et al. found that the rate of blood transfusion was higher in in high-risk group compared to the low-risk (asa1, 2) groups, but hgb replacement was similar in all groups (10). however, patel et al. assessed the patients’ complications based on the modified clavien system, and found no difference in terms of bleeding and transfusion requirements between high and low risk groups (8). in the study by stoller et al. the patients were divided into groups: over and below the age of 65 years. although both groups had similar preoperative hgb levels, post-operative blood transfusion rates were higher in elderly group compared to the younger group (26% to 13.7%) (6). in our study, we did not find any differences in hgb exchange and blood transfusion requirements in both asa risk groups and in patients younger and older than 65 years. at the same time, there was no difference in terms of hgb exchange and blood transfusion requirements. comorbidities and older age have been shown to affect stone-free rates. karami et al. reported not seeing any significant difference in stone-free rates between patients younger and older than 65 years (7). resorlu et al. reported that the increase in the charlson comorbidity score had significantly reduced the stone-free rates (21). in the study by patel et al. the total stone-free rate was 61% in the high-risk group and 92% in the low-risk group, and this difference was significant (8). in our study, according to the results of the ct scans on 1month postoperative follow-up there was no significant difference in terms of complete stone-free percentage when we compared asa1 with asa3 and asa2 with asa3 groups (p = 0.974 and 0.687, respectively). the first limitation of this study is that it was performed retrospectively. our second limitation is that although the diameter of the access sheath is gradually reduced in pcnl surgeries, we have used 30f sheath in our study. however, since the blood transfusion rates in our study were compatible with the current literature, we decided not to change the sheet diameter. conclusions with increase in the life expectancy and aging of the world population improving quality of life has become kisa_stesura seveso 28/06/18 16:37 pagina 115 archivio italiano di urologia e andrologia 2018; 90, 2 e. kisa, c. yücel, s. budak, m. ucar, m. zeynel keskin, o. cakmak, g. koc, z. kozacioglu 116 very imperative. aging is associated with increased prevalence of comorbidity and other concomitant risks. we found that although the number of comorbidities and the risk of anesthesia are higher in asa3 risk group compared with patients in the asa1 and asa2 risk groups, there was no significant difference in terms of complete stone-free rates, complication rates, and hospitalization times following a pcnl surgery. therefore, we believe that pcnl surgery can be performed safely and effectively in both high-risk patients with comorbidities as well as elderly patients. references 1. stamatelou kk, francis me, jones ca, et al. time trends in reported prevalence of kidney stones in the united states: 1976 1994. kidney int, 2003; 63:1817. 2. morris ds, taub da, wei jt, et al. regionalization of percutaneous nephrolithotomy: evidence for the increasing burden of care on tertiary centers. j urol. 2006; 176:242-246. 3. srirangam sj, darling r, stopford m, et al. contemporary practice of percutaneous nephrolithotomy: a review of practice in a single region of the uk. ann r coll surg engl. 2008; 90:40-44. 4. anagnostou t, thompson t, ng cf, et al. safety and outcome of percutaneous nephrolithotomy in the elderly: retrospective comparison to a younger patient group.j endourol. 2008; 22:2139-45. 5. sahin a, atsu n, erdem e, et al. percutaneous nephrolithotomy in patients aged 60 years or older. j endourol. 2001; 15:489-491. 6. stoller ml, bolton d, st lezin m, et al. percutaneous nephrolithotomy in the elderly. urology. 1994; 44:651-654. 7. karami h, mazloomfard mm, golshan a, et al. does age affect outcomes of percutaneous nephrolithotomy? urol j. 2010; 7:17-21. 8. patel sr, haleblian ge, pareek g. percutaneous nephrolithotomy can be safely performed in the high-risk patient. urology. 2010; 75:51-55. 9. toksoz s, dirim a, kizilkan y, et al. the effect of american society of anesthesiology scores on percutaneous nephrolithotomy outcomes. urol int. 2012; 89:301-6. 10. nouralizadeh a1, lashay a, ziaee sa, et al. percutaneous nephrolithotomy in high-risk patients: a single-center experience with more than 350 cases urol int. 2013; 90:394-8. 11. ozturk e, yilmazlar t. factors affecting the mortality risk in elderly patients undergoing surgery. anz j surg. 2007; 77:156-159. 12. froehner m, koch r, litz r, et al. comparison of the american society of anesthesiologists physical status classification with the charlson score as predictors of survival after radical prostatectomy. urology. 2003; 62:698-701. 13. kuzgunbay b, turunc t, yaycioglu o, et al. percutaneous nephrolithotomy for staghorn kidney stones in elderly patients. int urol nephrol 2011; 43:639-643. 14. gentle dl, stoller ml, bruce je, et al. geriatric urolithiasis. j urol. 1997; 158:2221-2224. 15. tonner ph, kampen j, scholz j. pathophysiological changes in the elderly. best pract res clin anaesthesiol. 2003; 17:163-177. 16. akman t, binbay m, ugurlu m, et al. outcomes of retrograde intrarenal surgery compared with percutaneous nephrolithotomy in elderly patients with moderate-size kidney stones: a matched-pair analysis j endourol. 2012; 26:625-9. 17. de la rosette j, assimos d, desai m, et al. croes pcnl study group: the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5,803 patients. j endourol. 2011; 25:11-17. 18. kumar r, anand a, saxena v, et al. safety and efficacy of pcnl for management of staghorn calculi in pediatric patients. j pediatr urol. 2011; 7:248-251. 19. seitz c, desai m, häcker a, et al. incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. eur urol. 2012; 61:146. 20. tefekli a, karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008; 53:184. 21. resorlu b, diri a, atmaca af, et al. can we avoid percutaneous nephrolithotomy in high-risk elderly patients using the charlson comorbidity index? urology. 2012; 79:1042-1047. correspondence erdem kisa, md drerdemkisa@hotmail.com cem yücel, md murat ucar, md drmuratucar@hotmail.com mehmet zeynel keskin. md zeynel_akd@hotmail.com ozgur cakmak, md drozgurcakmak577@yahoo.com gokhan koc, md gokfekoc@gmail.com zafer kozacioglu, md zaferkozacioglu@gmail.com tepecik training and research hospital, urology department, izmir, turkey salih budak, md salihbudak1977@gmail.com sakarya training and research hospital, turkey kisa_stesura seveso 28/06/18 16:37 pagina 116 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4330 case report renal cell carcinoma in patient with crossed fused renal ectopia ozgur cakmak, cemal selcuk isoglu, ercument aziz peker, huseyin tarhan, ulku kucuk, orcun celik, ferruh zorlu, yusuf ozlem ilbey clinic of urology, tepecik research and education hospital, izmir, turkey. primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia. we presented a patient with right to left crossed fused kidney harbouring renal tumor. the most frequent tumor encountered in crossed fused renal ectopia is renal cell carcinoma. in this case, partial nephrectomy was performed which pave way to preservation of the uninvolved both renal units. due to unpredictable anatomy, careful preoperative planning and meticulous delineation of renal vasculature is essential for preservation of the uninvolved renal units. key words: crossed fused renal ectopia; renal cell carcinoma. submitted 23 may; accepted 30 september summary no conflict of interest declared. neys and tumor (figure 2). after catheterization of both ureters, partial nephrectomy was performed without any perioperative complication. pathologic examination revealed clear cell renal cell carcinoma, fuhrman grade 1 with negative surgical margins. patient was discharged at postoperative fifth day after uneventful postoperative period. no pathologic finding was observed during 7 months follow-up and her renal function has remained stable on routine surveillance. discussion crossed renal ectopia is an uncommon congenital anomaly and in most cases usually presents with fusion of both kidneys. the autopsy incidence has been reported as 1 in 2000 (1). there is a slight male predominance (3:2), and left-to-right crossover occurs more frequently (1). the doi: 10.4081/aiua.2015.4.330 introduction congenital anomalies of upper urinary tract include anomalies in number, location, collecting system and renal vasculature. crossed fused renal ectopia (cre) is an uncommon congenital anomaly in which both the kidneys lie on one side and are fused. this is the second most common congenital anomaly following horseshoe kidney (1). primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia (2-4). due to atypical arterial supply and venous drainage, surgery in these patients may become challenging. in this report we presented a patient with right to left crossed fused kidney harbouring renal tumor. case report a 42-year-old female patient presented complaints with left flank pain and dysuria. no family history of congenital anomalies and no systemic disease was present. laboratory tests were in normal ranges. right kidney was not visualized by ultrasonography and a 7 x 6 cm isoecoic mass was detected in the conjuction of both kidneys in left quadrant. contrast enhanced computerized tomography (ct) revealed right to left cross fused renal ectopia with 70 x 65 mm of solid mass arising from orthotopic left renal moiety (figure 1). no evidence of distant metastases was observed. magnetic resonance angiography was performed to delineate the renal vasculature of the kidfigure 1. ct scan demonstrating tumor arising from orthotopic left renal moiety and relation to crossed fused ectopic ‘right’ kidney. figure 2. ct angiography image delineating renal arteries of both renal moieties. 331archivio italiano di urologia e andrologia 2015; 87, 4 renal cell carcinoma in patient with crossed fused renal ectopia most common anomaly involves fusion between the lower pole of the orthotopic kidney and the upper pole of the ectopic kidney with the lower ureter crossing the midline to insert into a normal location within the bladder trigone in our case it was right to left crossover with two ureters ending in their normal positions. the association of malignant tumors with such anomalies is an extremely rare event. primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia (2-5). management typically involves complete nephrectomy of both renal moieties or excision of the tumor (4-6). due to the unpredictable anatomy and vascular anomalies which are observed in 70% of cases, careful preoperative planning using ct, magnetic resonance imaging (mri) or ct/mri angiography is advised (5). preoperative ureteral stenting may be helpful to avoid inadvertent ureteral injury during surgery. there are several surgical approaches which were described for renal fusion abnormalities. among these techniques anteriorlybased approachs such as subcostal or thoracoabdominal incisions provides the optimal exposure of the anomalous anatomy which enables nephron sparing surgery possible (5). in our case, left subcostal approach was performed to excise the tumor which pave way to preservation of the uninvolved both renal units. postoperative ct imaging of both kidneys was showed in figure 3. in the reviewed literature, rcc is the type of tumor most frequently associated with fusion anomalies. its incidence among fusion anomalies is similar to the general population and the prognosis of the disease depends on the same prognostic factors as in case of normal kidneys (6). compatibly the literature, pathologic examination of our case revealed rcc. conclusions primary malignancy in kidneys with fusion anomalies are very rare entity. the most frequent tumor encountered in crossed fused renal ectopia is renal cell carcinoma. due to unpredictable anatomy, careful preoperative planning and meticulous delineation of renal vasculature is essential for preservation of the uninvolved renal units. references 1. bauer sb. anomalies of the upper urinary tract. in: wein aj, kavoussi lr, novick ac, partin aw, peterseds ca, eds. campbell’s urology, 9th ed. philadelphia: saunders-elsevier; 2007; p. 3269304. 2. bolton dm, bowsher wg, costello aj. renal cell carcinoma in both moieties of crossed fused ectopia. aust n z j surg. 1993; 63: 662-3. 3. sugita s, kawashima h, nakatani t, et al. renal cell carcinoma in an l-shaped kidney. int j urol. 2000; 7: 236-8. 4. tsunoe h, yasumasu t, tanaka m, et al. resection of an l-shaped kidney with renal cell carcinoma using a microwave tissue coagulator. int j urol. 2001; 8:459-62. 5. carley m, davis manoj v, rao robert c, et al. renal cell carcinoma in two patients with crossed fused ectopic kidneys. urol int. 2008; 81:370-2. 6. stimac g, dimanovski j, ruzic b, et al. tumors in kidney fusion anomalies – report of five cases and review of literature. scand j urol nephrol. 2004; 38:485-9. figure 3. sample ct axial slice of patient depicting both kidneys in postoperative period. correspondence ozgur cakmak, md cemal selcuk isoglu, md ercument aziz peker, md huseyin tarhan, md ulku kucuk, md orcun celik, md orcuncelik82@hotmail.com ferruh zorlu, md fyzorlu@yahoo.com yusuf ozlem ilbey, md tepecik research and education hospital, clinic of urology, izmir, turkey 147archivio italiano di urologia e andrologia 2016; 88, 2 case report lymphoepithelioma-like carcinoma of the bladder: a case report konstantinos stamatiou 1, georgios christopoulos 2, aikaterini tsavari 3, kallirhoe koulia 3, kassiani manoloudaki 3, thivi vassilakaki 3 1 urology department, tzaneio hospital pireas, greece; 2 department of internal medicine, tzaneio hospital pireas, greece; 3 pathology department, tzaneio hospital pireas, greece. lymphoepithelioma is a rare histological type of low differentiated carcinoma of the nasopharyngeal region characterized by marked infiltration of lymphocytes in the area involved by tumor. however, carcinomas with this peculiar morphologic feature have been also described in various anatomic locations and they are generally designated «lymphoepithelioma-like carcinomas». those of the urinary bladder are uncommon as they account of 0.4%-1.3% of all bladder carcinomas. they may coexist with the conventional urothelial carcinoma. given their rarity, there is poor information regarding their behaviour. here we present a new case of lymphoepithelioma-like carcinoma in the bladder and we discuss its characteristics and prognosis. key words: lymphoepithelioma-like carcinoma; bladder; prognosis. submitted 24 april 2015; accepted 21 may 2015 summary no conflict of interest declared. according to the percentance of lymphoepithelioma component within the tumor. therefore three types of lelc are described: pure (100%), predominant (> 50%), or focal (< 50%) (3). their occurrence in the urinary system is very rare and in fact, the reported incidence of lelc in the bladder is between 0.4% and 1.3% of all bladder carcinomas (4). case presentation a 67-year-old woman suffering from recurrent urinary tract infections presented with macroscopic hematuria for 2 months. urinalysis was non diagnostic for infection while urine cytology analysis showed markedly atypical urothelial cells. the patient underwent cystoscopic examination, which revealed a large tumor with mixed polypoid and solidmorphology, located in the right lateral wall, the trigon and the dome of the bladder. a computed tomography (ct) scan suggested locally advanced disease (figure 1) however no lymph node involvement, non distant metastasis, and no hydronephrosis were shown. she refused surgical intervention; however, she subsequently agreed to receive treatment after an episode doi: 10.4081/aiua.2016.2.147 introduction lymphoepithelioma also known as “class iii nasopharyngeal carcinoma” is a rare form of undifferentiated carcinoma of the nasopharyngeal region that is considered a variant of undifferentiated non-keratinizing squamous cell carcinoma. it is characterized by excess inflammatory infiltrate of lymphocytes which appears to be intimately admixed with the carcinomatous cells. the last are large with vesicular nuclei and prominent nucleoli that are arranged in a dense growth pattern. this tumor displays a strong association with the epstein barr virus infection and its incidence exhibits a remarkable geographic variation (1, 2). reason explaining the above peculiarity is practically unknown. lymphoepithelioma-like carcinomas (lelc) arise outside of the nasopharynx, but resemble a lymphoepithelioma both morphologically and histologically. they may be found in almost any organ containing epithelial tissue such as the lung, thymus, breast, colon, endometrium, prostate, and skin, as well as urinary bladder, trachea, esophagus, stomach, salivary glands, vulva (3). they may coexist with the conventional adenocarcinomas of the abovementioned organs and therefore they are classified figure 1. computed tomography (ct) scan suggested locally advanced disease. stamatiou_stesura seveso 01/07/16 11:12 pagina 147 archivio italiano di urologia e andrologia 2016; 88, 2 k. stamatiou, g. christopoulos, a. tsavari, k. koulia, k. manoloudaki, t. vassilakaki 148 of recurrent gross hematuria accompanied by acute drop in hematocrit levels. the patient underwent an extensive transurethral resection of the bladder tumor (tur-bt) in a single session. sections of the tur-bt showed invasive carcinoma, composed of predominant lelc (50% of the specimen) with grade 3 urothelial carcinoma (figures 25). the patient was diagnosed with local invasive bladder tumor, and she was suggested to undergo cystectomy with ileal conduit formation. however due to special concerns regarding effects of surgery on her able-bodiedness she seeked organ-conserving approaches and she was referred to the oncological clinic. there she was advised that bladder-conserving approaches were not recommended because of the likely poor response to chemotherapy by the lelc elements, rendering thus radical cystectomy the standard of care. however, the woman continued to seek bladder preservation and presented to our institution to discuss bladder-sparing options. due to the limited experience regarding treatment of this particular tumor, the patient was further referred to the radiotherapy department. there she was advised to receive chemoradiation. uncertainty regarding the outcome and additional consulting helped the patient to choose radical cystectomy. she did not receive adjuvant therapy. she is now under close observation with regular clinical and radiologic follow-up. discussion given their rarity, there is poor information regarding leccs behaviour. however, urinary bladder carcinomas with a lymphoepithelioma-like component often manifest in t2-t3 stages and in 10% to 15% of the reported cases the cancer has spread to distant organs at the time of the first diagnosis. on the other hand, since these tumors constitute less than 1.5% of all carcinomas encountered at this anatomic location, no large systematically collected follow-up data exists and limited information regarding their biologic behaviour render treatment choice difficult (5). figure 2. lymphoepithelioma-like carcinoma of the bladder infiltrating tumours cells and nests in an inflamatory background (h-ex20). figure 3. the coexistent typical urothelial carcinoma in the same tumour (h-ex20). figure 4. strong immunoreactivity against ckae1-ae3 of tumours cells (x20). figure 5. ckae1-ae3 in typical urothelial carcinoma. comparative study (x20). stamatiou_stesura seveso 01/07/16 11:12 pagina 148 therefore, the fact that most leccs are discovered in advanced stages (t2-t3) could be rather attributed to the lack of specific symptoms than to a presuming aggressive behaviour. in fact, evidence suggests that lelcs of the urinary tract may exhibit less malignant potential than the conventional urothelial carcinoma: it has been demonstrated that pure or predominant type responds better to chemotherapy than conventional urothelial carcinoma (6). in mixed cases of urinary bladder carcinomas and lelcs, the more the presence of lymphoepithelioma-like elements, the less the risk of death from the disease. more precisely, a 5-year survival rate of 59% was reported for the predominant type while that of the pure type achieves 62% (7). favourable prognosis along with response to chemotherapy provides a potential to salvage bladder function in patients with locally advanced lelc. in a small number of patients with pure and predominant lelc treated with transurethral resection of bladder tumor (tur) and chemotherapy only, no evidence of disease was achieved in a follow-up period between 2 to 18 years (8-10). in most of the reported cases, the platinum-based chemotherapies were performed in the treatment of both locally advanced and metastatic disease (9). however, as with other variants of bladder tumors, there are no clear guidelines for the treatment of lelc. exactly because of the respectively favourable prognosis efforts should be given in the prompt diagnosis of this rare tumor, especially when occurs in the pure type. the differential diagnosis includes chronic cystitis, malignant lymphoma, and poorly differentiated carcinoma with a prominent stromal lymphocytic infiltrate (10). however, in our case lymphoplasmacytic infiltrate was not sufficiently dense as to obscure the epithelial component, while the presence of an epithelial malignancy was clearly apparent. in conclusion, more experience in the management of this rare tumour is needed in order to extract safe conclusions on its prognosis and provide clear guideline for its treatment. references 1. wenig bm. squamous cell carcinoma of the upper aerodigestive tract: precursors and problematic variants. mod pathol. 2002; 15:229-254. 2. terada t. epstein-barr virus associated lymphoepithelial carcinoma of the esophagus. int j clin exp med. 2013; 6:219-26. 3. mayer ek, beckley i, winkler mh. lymphoepithelioma-like carcinoma of the urinary bladder—diagnostic and clinical implications. nat clin pract urol. 2007; 4:167-71. 4. amin mb, ro jy, lee km. et al. lymphoepithelioma like carcinoma of the urinary bladder. am j surg pathol. 1994; 18:466-473. 5. samaratunga h, delahunt b. recently described and unusual variants of urothelial carcinoma of the urinary bladder. pathology. 2012; 44:407-18. 6. tamas ef, nielsen me, schoenberg mp, epstein ji. lymphoepi thelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases. mod pathol. 2007; 20:828-834. 7. singh ng, mannan ar, rifaat aa, kahvic m. lymphoepitheliomalike carcinoma of the urinary bladder: report of a rare case. ann saudi med. 2009; 29:478-481. 8. holmäng s, borghede g, johansson sl. bladder carcinoma with lymphoepithelioma-like differentiation: a report of 9 cases. j urol. 1998; 159:779-782. 9. amin mb, ro jy, lee km, ordóñez ng, et al. lymphoepi thelioma-like carcinoma of the urinary bladder. am j surg pathol. 1994; 18:466-473. 10. lopez-beltrán a, luque rj, vicioso l, et al. lymphoepitheliomalike carcinoma of the urinary bladder: a clinicopathologic study of 13 cases. virchows arch 2001; 438:552-557. 149archivio italiano di urologia e andrologia 2016; 88, 2 lymphoepithelioma-like carcinoma of the bladder correspondence konstantinos n. stamatiou, md (corresponding author) stamatiouk@gmail.com urology department, tzaneio hospital afendouli 1 ave 18536 pireas, attica, greece georgios christopoulos, md department of internal medicine, tzaneio hospital, pireas, greece aikaterini tsavari, md kallirhoe koulia, md kassiani manoloudaki, md thivi vassilakaki, md pathology department, tzaneio hospital, pireas, greece stamatiou_stesura seveso 01/07/16 11:12 pagina 149 49archivio italiano di urologia e andrologia 2019; 91, 1 case report blastoid variant of mantle cell lymphoma of the female urethra mimicking a caruncle: a rare but highly aggressive subtype case with literature review franco palmisano 1, 2, vito lorusso 1, 2, matteo giulio spinelli 1, paolo guido dell’orto 1, emanuele montanari 1, 2 1 fondazione irccs ca’ granda, ospedale maggiore policlinico, department of urology, milan, italy; 2 university of milan, milan, italy. primary urethral lymphoma is a rare entity without a standardized treatment protocol. we report a case of an elderly woman presenting with a caruncle associated with vaginal spotting and intermittent dysuria. she underwent surgical excision of the lesion. histological analysis revealed a blastoid variant of mantle cell lymphoma, a previously unreported subtype. the patient received chlorambucil assisting a rapid local disease progression. she died of disseminated disease 6 months after diagnosis. a review of the lymphomas of the urethra is included. key words: caruncle; lymphoma; urethra; genitourinary; mantle cell lymphoma; blastic variant. submitted 10 september 2018; accepted 27 september 2018 summary no conflict of interest declared. ination revealed a urethral mucosa characterized by squamous metaplasia, subjugated by a widespread growth pattern of lymphoid proliferation, consisting of mediumsized, blastic-shaped, b-cell phenotype elements. immunohistochemically, these cells were positive for cd20, cd5, cyclin d1 and bcl-2, negative for cd23, cd10, bcl6, mum1, cd3, cd30, tdt and cytokeratin. the ki-67 index was approximately 90%. a diagnosis of a primary blastoid variant of mantle cell urethral lymphoma was made. a chest, abdomen and pelvis contrast enhanced computed tomography (ct) was performed for the staging workup and revealed non-mediastinal lymphadenopathy, no focal lung lesions, a 2.5-mm angioma located at the right lobe of the liver, normal spleen, pancreas and kidneys, and no abdominal or pelvic lymphadenophaty. 18f-fluorodeoxyglucose positron emission tomography (fdg-pet) showed abnormal fdg uptake present in the external genitalia and vagina. the patient was then referred to the oncohematology department and underwent two cycles of chlorambucil, despite this a rapid local disease progression was seen (figire 1c). the patient died of disseminated disease six months after diagnosis. discussion caruncles commonly affect the postmenopausal female urethra, appearing as erythematous nodules at the posterior lip of the urethral meatus. this lesion is considered to be neither neoplastic nor preneoplastic, being composed of chronic inflammatory cells, dilated vessels and hyperplastic epithelium. in light of this, an incorrect diagnosis of lymphoma or sarcoma may occasionally be made based on the presence of bizarre stromal cells or lymphoid infiltrate (2). on the other hand, 2.3% of the caruncles were found to be malignant tumors upon histopathological analysis, usually a carcinoma or a bowen's disease (2). in this context, a caruncle-like primary lymphoma is exceptionally rare. since 1949, only 29 patients with urethral lymphoma have been reported (1-2), including the present case, with an age distribution ranging from 31 to 90 years old. of these, a female doi: 10.4081/aiua.2019.1.49 introduction non-hodgkin’s genitourinary lymphoma as a primary extra nodal invasion is a rare condition, with few reported cases affecting the urethra (1). the most common subtypes described are mucosa-associated lymphoid tissue-type (malt) lymphoma and diffuse large b-cell lymphoma. herein, we report the first documented case of a blastoid variant of mantle cell lymphoma resembling a caruncle. furthermore, to shed light on clinical features of primary urethral lymphoma, we reviewed previously reported cases. case report a 84-year-old woman presented with a recent onset, fastgrowing genital nodule associated with vaginal spotting and intermittent dysuria. her medical history was noncontributory, lacking fever, weight loss or any other systemic manifestations. there were no enlarged lymph nodes or organomegaly upon physical examination. pelvic examination revealed a urethral caruncle arising from the posterior wall of the urethral meatus (figure 1a, b). it was characterized by an erythematous appearance, firm at palpation, measuring approximately 4 cm at its maximum diameter. the patient underwent cystourethroscopy with a 21f cystoscope revealing no bladder involvement, and surgical excision of the urethral caruncle. histologic exampalmisano_stesura seveso 25/03/19 17:22 pagina 49 archivio italiano di urologia e andrologia 2019; 91, 1 f. palmisano, v. lorusso, m.g. spinelli, p.g. dell’orto, e. montanari 50 predominance has been shown, with 75.9% of cases affecting woman. when the female urethra is involved, a caruncle like aspect is the most common presentation, having been reported in 9 cases. other associated symptoms include spotting, hematuria, dysuria and vulvar pruritis. cancer-specific mortality is usually relegated to a disseminate disease at diagnosis, whereas the overall 4year survival rate of caruncle-like tumors is 55.5%. each of the previously reported 29 cases involved nonhodgkin’s lymphoma, with the most common subtypes being mucosa-associated lymphoid tissue-type lymphoma and diffuse large b-cell lymphoma. treatments include excision, radiotherapy and chemotherapy. to our knowledge, this is the first blastoid variant of mantle cell caruncle-like lymphoma to be reported. according to bernard et al. (3), the blastic variant form of mantle cell lymphoma is considered to be a very aggressive subtype of non-hodgkin's lymphoma with 46% of patients who do not respond to treatment dying quickly due to disseminated disease. the overall mortality rate is 66% with a 14.5month median survival time. reported frontline therapy includes chop-like regimen or chlorambucil. the blastic variant of mantle cell lymphoma is usually diagnosed upon initial presentation and more rarely in the course of common forms. patients are predominantly male, over 60 years of age, and one third have b symptoms. the majority of patients have an ann arbor stage iv disease (85%), lymphadenopathy (82%) and extranodal involvement (66%), especially in the lung and pleural cavities, more rarely with a gastro-intestinal infiltration. neither ann arbor staging nor bone marrow or blood involvement have been found to influence clinical outcome and there is currently no standard therapy for this disease. conclusions in conclusion, the correct recognition of a primary lymphoma of the urethra is of clinical importance and should be considered in the differential diagnosis of a caruncle. being the extranodal lymphoid infiltrate a diagnostic dilemma, it is of utmost importance that the pathologist has expertise concerning these tumors. an universally accepted treatment scheme is needed, and for subtypes of lymphoma with a less favorable prognosis an aggressive treatment strategy is strongly recommended. references 1. al zahrani a, abdelsalam m, al fiaar a, et al. diffuse large bcell lymphoma transformed from mucosa-associated lymphoid tissue lymphoma arising in a female urethra treated with rituximab for the first time. case rep oncol. 2012; 5:238-245. 2. chen yr, hung ly, chang kc. mucosa-associated lymphoid tissue-type lymphoma presenting as a urethral caruncle with urinary bladder involvement. int j urol. 2014; 21:1073-4. 3. bernard m, gressin r, lefrère f, et al. blastic variant of mantle cell lymphoma: a rare but highly aggressive subtype. leukemia. 2001; 15:1785-91. figure 1. a, b. polypoid, caruncle-like, flesh-colored lesion (images taken during cystoscopy). c. clinical presentation showing disease progression 3 months after diagnosis. correspondence franco palmisano, md (corresponding author) franco.palmisano@hotmail.it vito lorusso, md matteo giulio spinelli, md paolo guido dell’orto, md emanuele montanari, md department of urology, irccs ca’ granda ospedale maggiore policlinico via della commenda 15, 20122 milan, italy a. b. c. palmisano_stesura seveso 25/03/19 17:22 pagina 50 archivio italiano di urologia e andrologia 2017; 89, 3236 case report a case of seminoma presented with clinical manifestations of testicular torsion aytac sahin 1, caglar yildirim 1, serkan akan 1, ozgur haki yuksel 1, ahmet urkmez 2 1 fatih sultan mehmet research & training hospital, dept. of urology, istanbul, turkey; 2 haydarpasa numune research & training hospital, dept. of urology, istanbul, turkey. testicular tumors rarely manifest themselves with clinical picture of testicular torsion. in this presentation of ours, we reported a 30-year-old patient whose post-orchiectomy histopathology report revealed the presence of seminoma. the patient consulted us with acute scrotum whose physical examination and doppler ultrasonographic findings showed testicular torsion. though rarely seen patients, in cases who consulted with acute scrotum, the possibility of testicular tumor should not be discarded. for the establishment of differential diagnosis detailed anamnesis and physical examination findings should be supported with laboratory tests and imaging modalities. key words: testicular torsion; seminoma; orchiectomy. submitted 2 february 2017; accepted 5 may 2017 summary no conflict of interest declared. case report a 30 years-old male patient, has two children, applied to the emergency service due to left testicular pain lasted for a day. the patient stated that his pain started suddenly without any history of trauma. also there was not any similar attack before. besides the patient doesn’t have any known systemic comorbidity. on physical examination left testis seen oedematous and scrotal skin overlying the left testis was hyperaemic. left hemiscrotum was extremely tender on palpation and comparing with its counterpart, the left testis was seem to be elevated because of the inflammation. his urinalysis was unremarkable. leukocytosis (16.000/ml, normal range 460010200/ml), extremely high levels of serum lactic acid dehydrogenase (ldh) (650 u/l, normal range 125220u/l), and c-reactive protein (9 mg/dl, normal range 0-0,5 mg/dl) were detected. serum betahcg, and alfafetoprotein (afp) values were within normal limits. left testis demonstrated a heterogeneous structure on scrotal cdus obtained in the emergency service and blood flow was not detected. cdus images suggested testicular torsion. the spermatic cord manually detorsed prior to his surgical procedure but his clinical signs didn’t change. we talked about possible orchiectomy with the patient and his family. there was no suspicion of testicular tumor prior to orchiectomy. our main surgical intervention purpose was treatment of testicular torsion, so we performed scrotal exploration under general anesthesia immediately. testicular blood flow was not observed and no/any rotation wasn’t observed at cord. testis and spermatic cord were wrapped with warm compress for 15 minutes. then testicular parenchyma was controlled and any evidence of blood flowing was not detected. tunica vaginalis was incised with a surgical blade to detect if there is any bleeding. testicular bleeding on the exploration is important, because it shows that there is still circulation to the testis. but, just purulent and necrotic fluid was drained (figure 1). for microbiological analysis specimens were taken and then scrotal orchiectomy was performed. the patient was discharged on postoperative 1. day, there was not any complication depending on the surgery. histopathology results were reported as granulomatous inflammation and seminoma (figure 2). ct obtained at postoperative 2 weeks, metastatic lesion in the lungs was not detected. serum ldh levels regressed to 121 u/l. adjuvant chemotherapy was planned doi: 10.4081/aiua.2017.3.236 introduction testicular torsion is a scrotal emergency case occurs as a result of rotation of spermatic cord around its axis leading to impairment of testicular perfusion and testicular ischemia. scrotal pain spreading into the lower abdominal quadrant can cause concomitant symptoms of nausea and vomiting. the incidence rate of testicular torsion is around 3.5/100000. it is mostly idiopathic and 20% of the cases are related to trauma (1). torsion is a scrotal phenomenon, which can be observed in adolescents. 1-2% of all malignant tumors seen in men are testicular cancers and incidence rate of testicular cancers increases among young men aged between 15-40 years old. 80% of testicular tumors are seminomas, and most of them present themselves as clinical stage i disease. these two scrotal diseases can complicate each other, torsion due to testicular tumor may occur, however the possibility of simultaneous occurrence of these two diseases in the same testis is very low. scrotal color-doppler ultrasound (cdus) has a major role for differential diagnosis, however despite higher rates of diagnosis, in case of uncertainty, taking a decision to perform surgical exploration and orchiectomy without delay is essential. in this presentation of ours, we reported a 30-years-old patient whose post-orchiectomy histopathology report shows the presence of seminoma. the patient consulted to us due to acute scrotum. his physical examination and doppler ultrasonographic findings were consistent with testicular torsion. sahin2_stesura seveso 28/09/17 10:30 pagina 236 237archivio italiano di urologia e andrologia 2017; 89, 3 seminoma as testicular torsion for the patient with the diagnosis of pt1n0m0 seminoma and medical oncological treatment was initiated. now the patient is still monitored by the oncologist. discussion testicular torsion is a scrotal emergency disease, which occurs before the age of 20 and characterized by sudden onset of testicular pain. the ratio of testicular torsion among men aged over 20 years in the literature reported cases varies between percent 10 and 56 of all cases (2). our case was 30 years old who can be considered as over aged by comparing the average age mentioned in the literature of testicular torsion. acute testicular pain is considered as testicular torsion unless proved otherwise. testicular parenchyma damage starts to take effect within the first 4 hours of occlusion of testicular veins/arteries after the torsion of the spermatic cord. therefore in case of testicular torsion suspect, one should not hesitate to perform testicular exploration. on physical examination even some findings suggest testicular torsion, concomitant testicular swelling or hydrocele may mask testicular torsion. in testicular torsion the involved testis is solid, tender and tense and it can be elevated because of the shortening of the spermatic cord of the affected testis when compared with its counterpart. if testicular pain is relieved with testicular elevation then probability of epididymo-orchitis is present. in spermatic cord torsion cases, testicular pain is not relieved after manual elevation of the testis. cremaster reflex is not seen in testicular torsion, however cremaster reflex can be seen in the torsion of appendix testis, and it can show symptoms similar to those seen in cases with torsion of the spermatic cord. in our case the involved testis was tender to touch and elevated relative to other testis and there was no cremaster reflex. urinalysis is generally unremarkable and 50% leukocytosis can be seen. in our case leukocytosis was present, while results of urinalysis were within normal limits. since most of the scrotal diseases show similar symptoms, clinical diagnosis of testicular torsion is a challenging issue. cdus is a reliable method in the accurate diagnosis of scrotal pathologies. in addition to scrotal pathologies, cdus can also comparatively evaluate normal scrotal anatomy. becker et al. reported higher diagnostic sensitivity (90.5%), and specificity (98.3%) of scrotal cdus for testicular torsion (3). despite all physical examination findings and test results, if clinical suspicion still persists, then surgical exploration should not be declined. as is the case with other organ tumors, organ-preserving surgeries are revived for testicular tumors, however in cases with normal contralateral testis, this approach is not recommended. besides, biopsy is not a suitable option because of causing a possible shift in the lymphatic pathway and a risk of false positivity testicular. in patients for whom orchiectomy is decided, testicular tumor should be suspected, and spermatic cord should be clamped at the level of internal ring of the inguinal canal, and high-level orchiectomy should be performed. indeed cdus images of our patient did not demonstrate apparent characteristics of a testicular tumor, and any evidence of testicular blood flow was not detected. so we performed scrotal exploration to treatment of torsion. the patient underwent orchiectomy with the indication of torsion, and histopathology report of the specimen indicated pt1 seminoma. conclusion for the establishment of differential diagnosis detailed anamnesis, and physical examination findings should be reinforced with laboratory tests, and imaging modalities. even if all preoperative examinations and tests indicate testicular torsion, clinical common sense should never rule out the possibility of testicular cancer. references 1. huang wy, chen yf, chang hc, et al. the incidence rate and characteristics in patients with testicular torsion: a nationwide, population-based study: acta paediatr. 2013; 8:363-367. 2. althaffer lf. testicular torsion in men. j urol. 1980; 123:37. 3. becker d, burst m, wehler m, et al. differential diagnosis of acute testicular pain using color-coded duplex ultrasonography: difference between testicular torsion and epididymitis. dtsch med wochenschr. 1997; 122:1405-1409. correspondence aytac sahin, md caglar yildirim, md serkan akan, md ozgur haki yuksel, md fatih sultan mehmet research& training hospital,dept. of urology istanbul, turkey ahmet urkmez, md (corresponding author) ahmeturkmez@hotmail.com haydarpasa numune research& training hospital,dept. of urology uskudar tr34668 istanbul, turkey figure 1. during surgical exploration nontorsioned cord, heterogenous testicular structure, and necrotic, and purulent discharge observed when vaginal tunica was incised with a scalpel. figure 2. microscopic examination reveals patchy areas of diffuse groups of tumoral cells associated with small lymphocytes in a fibrous stroma. tumoral cells consist of atypical germ cells with clear or eosinophilic cytoplasm, generally uniform large round nuclei with thin chromatin, marked nucleoli, and mitotic figures. granulomatous reaction partly associated with tumor is seen. sahin2_stesura seveso 28/09/17 10:30 pagina 237 333archivio italiano di urologia e andrologia 2016; 88, 4 case report a singular case of polyorchidism giacomo di cosmo, tommaso silvestri, stefano bucci, michele bertolotto, carlo trombetta department of urology and radiology, university of trieste, italy. we report a case of polyorchidism, a rare congenital anomaly, frequently discovered by chance. at current knowledge is still not defined which is the best clinical and therapeutic approach as well the best follow-up scheme due to the unclear malignant potential and rate of complications if a conservative approach is used. mri (magnetic resonance imaging) seems to be a good method to discriminate this mass from others pathological findings but there is still not enough evidence to standardize the procedure. key words: polyorchidism; ultrasonography; magnetic resonance imaging; scrotal mass. submitted november 2016; accepted 15 december 2016 summary no conflict of interest declared. performed revealing no signs of torsion. after the complete remission of the pain, patient went home and performed a second scrotal ecography with contrast that revealed an epididymus tail isoechoic mass measuring about 1.3 cm, with a hypo-echoic area inside, with an increased vascular signal and good wash-out. first hypothesis was adenomatoid tumour, for which the patient underwent surgery by right inguinal incision and excision of a soft, grey mass at the border between testicle and epididymis, soft at the palpation and with a macroscopical similarity with a cyst. final histological exam revealed the pres-ence of a supernumerary testis classified as type ii in leung classification (1) and type a3 in bergholz classification (2). discussion this condition is a rare malformation believed to result from an abnormal division of the genital ridge and triorchidism is the most common type. depending on where the division occurs, a supernumerary testis will develop with either shared or individual vas deferens and epididymis. most of cases are incidental findings, painless, with a supernumerary testis sharing epididymis and vas deferens with the omolateral testis. the rarity of right-sided histologically proven polyorchidism and the bilateral scrotal pain were the reason why we presented this case. fundamental for diagnosis is the sonographic imaging or mri for better soft-tissue resolution and contrast and evaluation of the reproductive potential of the accessory testis (3) that could determine the thera-peutic approach. doi: 10.4081/aiua.2016.4.333 presented at 20th national congress sieun, sciacca 2016 introduction the histological finding of more than two testicles is called polyorchidism, a rare congenital anomaly with approximately 100 cases reported in the literature. most of the reported cases where incidental findings but this condition may be related with genital symptoms and pathologies as hydrocele, varicocele, testicular malignancy and torsion. about 75% of cases are reported on the left side in the age range from 15 to 25 years (1). case report a 45 years old man referred to our emergency service for acute bilateral scrotal pain, mostly on the left side, associated with nausea and vomit. at the visit the only evidence was painful palpation on both sides and a right testicle more cranially located in the emiscrotum. additionally, eco-fast of the abdomen and scrotum was figure 1. in the left image we can clearly notice the mass on the right epididymis tail. on the right mage we show the elastosonography performed during the second ceus, that gave us a first information about the consistence of the mass. di cosmo-a singular case of polyorchidism_stesura seveso 09/01/17 10:46 pagina 333 archivio italiano di urologia e andrologia 2016; 88, 4 g. di cosmo, t. silvestri, s. bucci, m. bertolotto, c. trombetta 334 conclusions polyorchidism is a rare condition, occurring in about 50% of cases between the age of 15 and 25 years. although rare, it should be considered in the differential diagnosis for intrascrotal masses by using sonography and mri. clinical management is still controversial and it depends on the supernumerary testis location, its relationship with the ipsilateral testis, its reproductive functionality and malignancy potential. in asymptomatic patients, with good reproductive function of the supernumerary testis it could be useful to follow-up by imaging. references 1. leung ak. polyorchidism am flam physician. 1988; 38:153-6. 2. bergholz r, koch b, spieker t, lohse k. polyorchidism: a case report and classification j pediatr surg. 2007; 42:1933-35. 3. danrad r, ashker l, smith w. polyorchidism: imaging may denote reproductive potential of accessory testicle. pediatr. radiol. 2004; 34:492-494. correspondence giacomo di cosmo, md (corresponding author) giacomo.dicosmo@gmail.com tommaso silvestri, md tommaso.silve@gmail.com stefano bucci, md urostef@yahoo.it michele bertolotto, md bertolot@univ.trieste.it carlo trombetta, md trombcar@units.it department of urology, university of trieste, trieste, italy di cosmo-a singular case of polyorchidism_stesura seveso 09/01/17 10:46 pagina 334 archivio italiano di urologia e andrologia 2016; 88, 3212 original paper retrograde intrarenal surgery (rirs), regular and small sized percutaneous nephrolithotomy (pcnl) in daily practice: european association of urology section of urolithiasis (eulis) survey stefano paolo zanetti 1, luca boeri 1, michele catellani 1, andrea gallioli 1*, alberto trinchieri 2, kemal sarica 3, emanuele montanari 4 1 ospedale san paolo, urological department, medical school university of milan, milan, italy; 2 ospedale alessandro manzoni lecco, urological department, lecco, italy; 3 dr. lutfi kirdar training and research hospital, urological department, semsi denizer cad. e-5 karayolu cevizli mevkii, 34890, kartal/istanbul, turkey; 4 fondazione irccs ca’ granda ospedale maggiore policlinico, urological department, medical school university of milan, milan, italy. objective: a wide selection of both anterograde and retrograde mini-invasive procedures exist for stones’ treatment. the 2016 european association of urology (eau) guidelines still don’t univocally define a best option. our purpose is to give an overview on some european stone centers’ customs and to compare real life clinical practice with statements of opinion leaders and guidelines. materials and methods: in 2015 we performed a survey in 3 step about the spread of retrograde intrarenal surgery (rirs) and percutaneous nephrolithotomy (pcnl) techniques among eau section of urolithiasis (eulis) members. the 1st and 2nd steps dealt with the definition of eulis urologist and department by collecting personal opinions about the endoscopic techniques. the third step was about clinical results. this paper presents data from the first two steps. results: ninety-one people answered. out of them, 80% are european and 42% work in centres fully dedicated to stone treatment. in particular, 50% of responders perform more than 80 rirs/year, 25% more than 80 pcnl/year, 48% more than 100 extracorporeal shock wave lithotripsy (swl)/year. rirs is mainly used to treat stones < 2 cm both as primary treatment and after swl failure. 73% don’t perform routine pre-stenting and 66% ordinarily use a ureteral sheath. hospital stay for rirs is 24h for 70% of responders. regular pcnl is performed by 87% of the responders, minipcnl by 58%, ultra-minipcnl by 23% and micropcnl by 28%. pneumatic balloon dilation is the favourite dilation technique (49%). 37% of responders perform pcnl always in the supine position, 21% always in the prone one. almost all the responders agree about using mini, ultra-mini and micropcnl for 1-2 cm stones. approximately 50% also use minipcnl for stones > 2 cm. conclusion: our survey confirms the great heterogeneity existing in stones’ treatment techniques in daily practice. key words: kidney calculi/surgery; nephrolithotomy; percutaneous; retrograde intrarenal surgery; pcnl; rirs. submitted 12 july 2016; accepted 19 august 2016 summary no conflict of interest declared. introduction urolithiasis management has changed over the past few decades due to the development of new mini-invasive instruments and techniques. the possibility to extract a stone through aa percutaneous access under fluoroscopic control was given by johanson and fernström in 1976 (1). between 1981 and 1984 p. alken, j.a.e. wickham and j. segura described endoscopic percutaneous nephrolithotomy (2-5) and perez castro in 1980 proposed and promoted rigid ureterorenoscopy in the stone treatment (6). since then, both the anterograde and retrograde techniques were perfected and miniaturized and nowadays we have a wide selection of procedures focused to the treatment of renal stones. in 1998 mini pcnl was mentioned for the first time in order to reduce the invasiveness of the percutaneous technique (7); in 2011 mahesh desai performed the first micro pcnl with a 4.8 charrier (ch) all seeing needle (8) and in 2013 janak desai described the ultra-mini pcnl (ump) with a 1113 ch access diameter (9). 2016 european association of urology (eau) guidelines contemplate all these techniques but still don’t give a clear indication in order to choose among the “small sized pcnl” the right one to treat the patient: in fact smaller instruments present some limitations in the choice of lithotripsy instruments and in clearing fragments, require a longer operation time, increase intrarenal pelvic pressure while their main advantage, “id est” less bleeding complications, needs to be confirmed. moreover, 2016 eau guidelines address pcnl as the first line treatment in kidney stones > 2 cm while they do not univocally define the best treatment for calculi between 1 and 2 cm, leaving the choice to the physician (10). many studies in literature make comparisons among the different techniques and try to suggest how to act in different situations but still many differences exist, according to single centre’s experiences and protocols, in terms of surgical indications and intra-technique applications. the doi: 10.4081/aiua.2016.3.212 zanetti_stesura seveso 21/09/16 08:58 pagina 212 213archivio italiano di urologia e andrologia 2016; 88, 3 retrograde intrarenal surgery (rirs), regular and small sized percutaneous nephrolithotomy (pcnl) in daily practice aim of the study is to give an overview on the uses and practices in some of the main european stone centers and on their indications for stones’ treatment. secondary objective is to compare the real life clinical practice with the indications and statements reported by opinion leaders and guidelines. material and methods we performed a survey approved by the eau section of urolithiasis (eulis) board in cape town in december 2014 about the spread of rirs and regular and small sized pcnl among physicians who attended copenhagen eulis meeting in 2013. the project was accomplished through the survey monkey online platform with a questionnaire in english in three steps and took place from february to may 2015. an introductory email was sent at the beginning with description and the aim of the survey and with the survey monkey site linked. participation was voluntary, without honorarium. the first step dealt with the definition of eulis urologist and department and the second step aimed to define personal opinions about rirs and pcnl. from the data we disposed of at the end of the first two steps, we tried to delineate eulis centres’ uses, practices and profiles in terms of instruments’ availability and techniques performed for stone treatment. moreover we collected opinions about efficacy and usefulness of the spreading small sized pcnl techniques. in the third step responders were asked to share the clinical results of the last 5 cases of each technique in study with at least one month follow-up. in this article we will describe and analyze the data resulting from the first two steps. results we sent the first and second step questionnaires to 360 people and the percentage of responders was 24% (88 responders). seventy-eight physicians agreed to receive the third step questionnaire and the 38% out of them (30 responders) shared their data. eulis physician and department 96% of eulis members are urologists and 80% are european, table 1. 47% of responders work in academic clinics, 44% in public hospitals and 9% in private ones. the distribution of the sample by age is fairly even in age groups from 35 to 65 years old, while a less represented group of responders (14%, 12 out of 88) is younger than 35. 43% (38 out of 88) of responders work in a stone centre dedicating all its activity to stone treatment. 92% of responders work in centres owning a laser dedicated to lithotripsy and 75% of them in centres owning an extracorporeal lithotripter. three responders out of 88 (3.41%) do not have any flexible ureterorenoscope in their armamentarium, while 39% of them have 2 or 3 and 42% have more than 4. 50% of responders work in departments performing more than 80 rirs/year while 25% of them in departments performing more than 80 pcnl/year, the most represented group (42%) performing 20-60 pcnl/year. 30% of the sample work in departments performing more than 200 extracorporeal shock wave lithotripsy (swl)/year and 18% in departments performing 100-200 swl/year. opinions about endoscopic techniques rirs indications to rirs, according to responders’ experience, are resumed in table 2. a double j stent is preoperatively placed in less than 1/3 of the cases by 73% of the eulis urologists and 66% use an ureteral access sheath in more than 2/3 of rirs. 42% of responders regularly obtain an informed consent for pcnl before a rirs and conversion rate from rirs to pcnl is lower than 2% for 68% of responders. the average hospital stay for rirs is 24 h for 70% of responders, 48 h for 22% and more than 2 days for 8%. pcnls the spread of the different pcnl techniques is summarized in table 3. country responders, no. (%) italy 14 (15,9) spain 12 (13,6) uk 10 (11,4) denmark, germany 8 each (9,2 each) greece 4 (4,6) japan, portugal, turkey 3 each (3,4 each) bulgaria, france, india 2 each (2,4 each) australia, austria, china, dubai, iraq, lithuania, morocco, netherlands, norway, pakistan, qatar, serbia, sweden, switzerland, thailand, uzbekistan 1 each (1,1 each) unknown 1 (1,1) table 1. distribution of responders for country of origin. options responders, no. (%) stones < 1cm (primary treatment) 39 (45) stones < 1 cm (after swl failure) 64 (74) stones 1-2 cm (primary treatment) 55 (64) stones 1-2 cm (after swl failure) 54 (63) stones > 2 cm (primary treatment) 14 (16) stones > 2 cm (after swl failure) 8 (9) table 2. which are your standard indications for rirs? (more than one option allowed; total of 86 responders to this question). techniques responders, no. (%) regular pcnl 75 (87) mini pcnl 50 (58) ultra-mini pcnl 20 (23) micro pcnl 24 (28) table 3. which size of pcnl access do you perform? (more than one option allowed; total of 86 responders to this question). zanetti_stesura seveso 21/09/16 08:58 pagina 213 archivio italiano di urologia e andrologia 2016; 88, 3 s.p. zanetti, l boeri, m. catellani, a. gallioli, a. trinchieri, k. sarica, e. montanari 214 technique skills pneumatic balloon dilation is the favourite dilation technique for 49% of the surgeons, followed by the alken progressive technique (29%), the amplatz progressive technique (16%) and the amplatz one shot technique (6%). 37% of responders always perform pcnl with the patient in any supine position, while 21% always perform the procedure with the patient in the prone position. 36% of responders also treat children by pcnl in their department. small size pcnls 58% of the interviewed urologists perform small sized pcnl (< 20ch), 88% of the others would be interested in, but they do not have the equipment. this interest is stronger regarding ump than micro pcnl (respectively 75% and 61% of the respondents who don’t perform these techniques would be interested in). the 79% of the responders believe it’s important, in terms of invasiveness, to move from regular to mini pcnl, 54% from mini pcnl to ump and 45% from ump to micro pcnl. indications to small sized pcnls and opinions about their relation with rirs are resumed in tables 4 and 5 respectively. the responders’ favourite stone-breaking energy in mini pcnl is laser, used by 90% followed by ballistic energy used by 32%. the perceptions of advantages and disadvantages of small sized pcnl techniques compared to regular pcnl are summarized in figure 1. discussion this paper presents the first survey inside eulis group. although eulis is a european society, 19,1% of responders come from extra-european countries (table 1) confirming the interest for the european scientific associations. rirs considering the departments’ armamentarium almost all the centres own a laser dedicated to stone treatment and more than one flexible ureteroscope, demonstrating the actual large spread of the retrograde technique. rirs diffusion is confirmed by the high proportions of centres performing more than 80 procedures per year (50%) that doubles the one of the centres performing the same number of pcnls. anyway swl appears to be the most popular technique for stone treatment: in almost 50% of the centres more than 100 shock-wave treatments per year are performed. it probably suggests that the most of the stone experts use swl as first approach for stones and this hypothesis is confirmed by the large proportions of responders considering swl as primary treatment for stones < 2 cm (table 2). less than 20% of the responders consider rirs a suitable technique for stones larger than 2 cm according to eau guidelines that consider pcnl the treatmini pcnl, ultra-mini pcnl , micro pcnl, responders no. (%) responders no. (%) responders no. (%) (84 responders (83 responders (83 responders to this question) to this question) to this question) 1-2 cm stones 71 (85) 83 (100) 82 (99) > 2 cm stones 44 (52) 7 (8) 3 (4) table 4. what are your indications to small sized pcnl techniques? mini pcnl, ultra-mini pcnl , micro pcnl, responders no. (%) responders no. (%) responders no. (%) (84 responders (83 responders (83 responders to this question) to this question) to this question) yes 38 (45) 41 (49) 27 (33) table 5. do you consider small sized pcnls and rirs alternative? figure 1. advantages and disadvantages of small sized pcnl techniques: responders were asked to score every proposed advantage (black bars) and disadvantage (dashed bars) for all the techniques. percentages in the graphics are the proportions of responders considering the proposed item as a real advantage or disadvantage. the perception of advantages in mini pcnl overwhelms the perception of disadvantages. this tendency is reduced for ump and inverted for micro pcnl, for which disadvantages are considered greater than advantages. zanetti_stesura seveso 21/09/16 08:58 pagina 214 215archivio italiano di urologia e andrologia 2016; 88, 3 retrograde intrarenal surgery (rirs), regular and small sized percutaneous nephrolithotomy (pcnl) in daily practice ment of choice. many studies in literature report high stone free rates with low morbidity in rirs performed for stones larger than 2 cm (11-12) but our survey shows that the majority of eulis departments don’t apply these statements in the daily clinical practice. the majority of responders preoperatively place a ureteral double j stent only in a small amount of cases according to expert opinions which don’t recommend routine pre-stenting unless necessary in order to insert a ureteral access sheath, when the force needed to insert the device in a prior procedure seems unreasonable (13). the ureteral access sheath is largely used by the eulis urologists performing rirs, as extensively suggested in literature (14) in order to reduce intrapelvic pressure. even if a discrete number of centres routinely obtain an informed consent for pcnl before a rirs, the reported conversion rate from rirs to pcnl is very low for the majority of the departments. hospital stay for rirs is 24 h for the greatest part of the departments and this datum confirms what pointed out by de et al (15). in their review and meta-analysis they observed, in the majority of the studies analysed, a mean hospital stay for rirs between 24 h and 48 h and an overall shorter length of stay for rirs than for pcnl. pcnls the great majority of the urologists perform regular pcnl while we observed a smaller diffusion of the pcnls procedures by reducing the percutaneous tract size (table 3). as a matter of facts only a few more than 50% of our responders perform small size pcnls even if almost all the other would be interested in, but they do not have the equipment. this interest appears stronger regarding mini pcnl than ump and micro pcnl, for which the importance in terms of invasiveness is considered progressively lower by reducing the percutaneous access diameter. about intraoperative technical manoeuvres, in contrast to the tendency of eulis people, who apparently do not appreciate the amplatz one shot dilation technique, the meta-analysis published by dehong et al. (16) shows that the one shot technique is safe and effective in all the patients. according to the same study the balloon dilation, the preferred technique among eulis group, is safer and more effective than the amplatz progressive dilation and the alken’s metal telescopic dilation in patients without previous open renal surgery, while the effectiveness and safety of balloon dilation are lower than the amplatz progressive and the metal telescopic dilation ones in patients with densely scarred tissue. yamaguchi et al, in their study on 5537 patients conducted of behalf of the clinical research office of the endourological society (croes), report a significantly higher bleeding rate in patients undergoing balloon dilation compared with telescopic/serial dilation (9.4% vs 6.7%; p < 0.0001). balloon dilation was also associated with significantly more transfusions (p = 0.001) and greater drops in haematocrit level (p < 0.0001) than telescopic/serial dilation, as well as significantly longer median operating times (p < 0.0001) (17). regarding patient’s position during pcnl, eulis physicians’ opinions are split, someone always performing the procedure with the patient in the prone position, someone always with the patient in the supine one and someone alternating. liu et al. review and meta-analysis (18) shows that pcnl in the supine position is as safe and efficacious as the conventional prone position and there’s not an overwhelming evidence indicating which one is better. as concluded by baard et al., considering the advantages of supine position in the morbidly obese, patients with skeletal deformities and patients with severe cardiorespiratory morbidity, it is important to have experience with several positions. the decision on position should be made on patient’s characteristics and surgeon’s preference and experience (19). we found in the literature only few articles defining precise indications to the different percutaneous techniques according to stone size. in their first paper on ump, j. desai and r. solanki conclude that their technique is safe and effective for stones up to 2 cm (9). ganpule et al., in their study on factors predicting outcomes of micro pcnl, assert that this technique appears to be a promising treatment method for solitary renal stones with volumes < 1000 mm3 and with low density (hounsfield units), regardless of stone location (20). our responders agree about treating 12 cm stones with mini, ultra-mini and micro pcnl. approximately the half of them also use mini pcnl for stones larger than 2 cm, while only a very small proportion of urologists consider ultra-mini and micro pcnl suitable techniques for this type of stones. de et al. review (15) reports that rirs can provide higher stone free rates with equal complication rate when compared with minimally invasive percutaneous procedures, including mini and micro pcnl. nevertheless, almost the half of our responders consider mini and ultra-mini pcnl alternative to rirs in stones treatment, while only a smaller proportion of urologists thinks the same regarding micro pcnl which is probably mainly used in highly selected cases. for what concerns responders’ perception of small size pcnl’s advantages and disadvantages summarized in figure 1, mini pcnl appears to be eulis urologists’ favourite technique among small size pcnls. conclusions our survey confirms the great heterogeneity existing in the treatment of urolithiasis both in the choice of the different endoscopic techniques and in the surgical steps of the procedures. moreover the real-life clinical practice is not always in line with the literature. in particular, while rirs technique seems to be quite well standardized, the debate appears to be open on pcnl techniques, in particular regarding the indications to the different access tract sizes. the impression is that micro and ultra-mini pcnl are considered suitable techniques for stones up to 2 cm, while mini pcnl could be used in larger stones too, but to assess evidence based indications further randomized prospective studies should be performed. acknowledgments are posted on www.aiua.it references 1. fernström i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976; 10:257. zanetti_stesura seveso 21/09/16 08:58 pagina 215 archivio italiano di urologia e andrologia 2016; 88, 3 s.p. zanetti, l boeri, m. catellani, a. gallioli, a. trinchieri, k. sarica, e. montanari 216 2. alken p, hutschenreiter g, günther r, marberger m. percutaneous stone manipulation. j urol. 1981; 125:463. 3. wickham jea, kellet mj. percutaneous nephrolithotomy. bmj 1981; 283:1571. 4. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones. preliminary report. mayo clin proc. 1982; 57:615. 5. patel s, nakada s. the modern history and evolution of percutaneous nephrolithotomy. j endourol. 2015; 29:153. 6. perez castro e, puigbert gorro a, cifuentes deatte l. la ureterorrenoscopia transuretral. un actual proceder urologico. arch esp urol. 1980; 23:5. 7. jackman sv, docimo sg, cadeddu ja, et al. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998; 16:371. 8. bader mj, gratzke c, seitz m, et al. the "all-seeing needle": initial results of an optical puncture system confirming access in percutaneous nephrolithotomy. eur urol. 2011; 59:1054. 9. desai j, solanki r. ultra-mini percutaneous nephrolithotomy (ump): one more armamentarium. bju int. 2013; 7:1046. 10. türk c. (2016) guidelines on urolithiasis. european association of urology. https://uroweb.org/guideline/urolithiasis/#note_1-6. accessed 15 april 2016. 11. aboumarzouk om, monga m, kata sg, et al. flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis. j endourol. 2012; 26:1257. 12. breda a, angerri o. retrograde intrarenal surgery for kidney stones larger than 2.5 cm. curr opin urol. 2014; 24:179. 13. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580. 14. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33. 15. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde internal surgery: a systematic review and meta-analysis. eur urol. 2015; 67:125. 16. dehong c, liangren l, huawei l, qiang w. a comparison among four tract dilation methods of percutaneous nephrolithotomy a systematic review and meta-analysis. urolithiasis. 2014; 41:523. 17. yamaguchi a, skolarikos a, buchholz np, et al. clinical research office of the endourological society percutaneous nephrolithotomy study group. operating times and bleeding complications in percutaneous nephrolithotomy: a comparison of tract dilation methods in 5,537 patients in the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011; 25:933. 18. liu l, zheng s, xu y, wei q. systematic review and meta-analysis of percutaneous nephrolithotomy for patients in the supine versus prone position. j endourol. 2010; 24:1941. 19. baard j, kamphuis gm, westendarp m, de la rosette jj. how well tolerated is supine percutaneous nephrolithotomy? curr opin urol. 2014; 24:184. 20. ganpule a, chhabra js, kore v, et al. factors predicting outcomes of micropercutaneous nephrolithotomy: results from a large single-centre experience. bju int. 2016; 117:478. correspondence stefano p. zanetti, md stefano.p.zanetti@gmail.com luca boeri, md dr.lucaboeri@gmail.com michele catellani, md michele.catellani@gmail.com andrea gallioli, md (corresponding author) andrea.gallioli@gmail.com ospedale san paolo, urological department, medical school university of milan via antonio di rudini 8, 20146 milan, italy alberto trinchieri, md a.trinchieri@ospedale.lecco.it ospedale alessandro manzoni lecco, urological department via dell’eremo 9/11, 23900 lecco, italy kemal sarica, md saricakemal@gmail.com dr. lutfi kirdar training and research hospital, urological department semsi denizer cad. e-5 karayolu cevizli mevkii, 34890, kartal/istanbul, turkey emanuele montanari, md emanuele.montanari@unimi.it fondazione irccs ca’ granda ospedale maggiore policlinico, urological department, medical school university of milan, via della commenda 15, 20122 milan, italy zanetti_stesura seveso 21/09/16 08:58 pagina 216 stesura seveso 245archivio italiano di urologia e andrologia 2014; 86, 4 original paper image guided robotic surgery: current evidence for effectiveness in urology anum pervez, kamran ahmed, stephen thompson, oussama elhage, m. shamim khan, prokar dasgupta mrc centre for transplantation, nihr biomedical research centre, king’s health partners, king’s college london and department of urology, guy’s hospital, st thomas street, london se1 9rt objectives: discussion of the evolution of image guided surgery (igs) and its fundamental components and current evidence for effectiveness of igs in clinical urology. methods: literature search for image-guided robotic urology. results: current literature in image-guided robotic urology with its use in robot assisted radical prostatectomy and robot assisted partial nephrectomy are shown. conclusions: image guided surgery can be a useful aid to improve visualisation of anatomy and subsurface structures during minimally invasive surgery. soft-tissue deformation makes it difficult to implement igs in urology but current studies have shown an attempt to address this issue. the feasibility of igs requires randomised control trials assessing in particular its accuracy and affect on clinical outcome. key words: robotic; iimage-guided surgery, registration; tracking; llocalisation error; augmented reality. submitted 6 april 2014; accepted 30 september 2014 summary no conflict of interest declared. intra-operatively. this article discusses the concept of igs and its effectiveness in the clinical urology. the evolution of igs the advent of igs began in the neurosurgical field. minimally invasive techniques were developed to overcome the high-risk of brain injury sustained during open neurosurgical procedures. by adapting various imaging modalities, it became possible to guide the surgery intraoperatively and hence improve the system accuracy (3). image-guided neurosurgery uses pre-operative mri or ct images of the patient’s brain, which show localisation of the tumour lesion to reconstruct a 3d model of the patient’s anatomy. the surgeon can then plan the procedure, viewing it from different angles and deciding on the exact point of entry, relative to other important structures, such as the brainstem. also, instruments used during the procedure can be tracked in real time to avoid damage to other tissue (3). neurosurgical procedures, which have shown success using this technique include, stereotactic biopsy, shunt placement and craniotomy. adapting igs for specialities other than neurosurgery has been challenging. however, early studies of igs in fields such as cardiac surgery and liver surgery have shown promise. in particular with the rapid development of robotic urology, there has been a need for better visualisation. hence the ability to combine igs and robotics could provide an essential technique for the future direction of urology (4). fundamental components of igs igs relies on several key engineering concepts, which must all be synchronized for the system to work. these are: 1) imaging 2) image processing (segmentation) 3) registration and tracking 4) user interface and display 1) imaging there are several different imaging modalities. tissue penetration, spatial resolution (ability to distinguish two doi: 10.4081/aiua.2014.4.245 introduction the benefits of minimally invasive surgery include shorter hospital stay, decreased intra-operative blood loss and less post-operative pain when compared to conventional open surgery. however, an advantage afforded to the open surgical technique is the ability to directly visualise structures. in minimally invasive surgery, the surgeon’s field of view becomes compromised as it is relies on scoped cameras to produce an display (1). recent advances in image-guided surgery (igs) may offer a solution to improve visualisation. igs technology merges pre-operative and/or intra-operative images in order to create a 3d reconstruction of the patient’s internal structures and subsurface anatomy. these images can be used alone with tracked surgical instruments or superimposed over a laparoscopic video feed to create a display referred to as augmented reality (ar). the principle benefit of such a system is the ability to see beyond the surgical plane and visualise internal structures such as organs, tissues, nerves and muscle (2). the use of igs is currently being explored in a number of surgical specialities and aims to improve surgical accuracy as well as guide procedures pervez_stesura seveso 15/01/15 12:53 pagina 245 archivio italiano di urologia e andrologia 2014; 86, 4 anum pervez, kamran ahmed, stephen thompson, oussama elhage, m shamim khan, prokar dasgupta 246 points) and tissue boundaries (contrast) are key features when choosing which approach to use. optical imaging has low tissue penetration and therefore would not be suitable for igs. ct, mri, x-ray and us on the other hand, have much better penetration of tissue structures and are therefore more suitable for igs. the most commonly used techniques in igs and their attributes are shown in table 1. along with the quality of the image produced, factors such as cost, radiation exposure and feasibility of use within the operating theatre will all come into play when creating an igs system (1, 5, 6). 2) image processing once the pre-operative images are acquired, a 3d model of the patient’s anatomy can be reconstructed using segments of the data. at present, the majority of cases require manual segmentation by radiologists. however, the need for faster automated segmentation is becoming more evident and in particular as a means to overcome the potential for human error (7). 3) registration and tracking registration aligns pre-operative images with the patients anatomy to create a 3d coordinated space (8). it is achieved by matching specific anatomical or fiduciary landmarks on the imaging with the corresponding points on the patient. for example, the tragus of the ear or the outer canthi of the eye are commonly used (9). these images can also be registered with intra-operative images or in the case of a laparoscopic procedure, superimposed over a video feed. image registration is classified into rigid and non-rigid categories. a rigid system assumes the position/shape of the subject remains unchanged and as such registration is relatively simple. for example in neurosurgery, the brain stays mostly unchanged between scans and when a stereotactic frame is attached to the patient’s skull, fiduciary markers can easily be aligned with ct/mri pre-operative images. another field, which has also been able to exploit igs, is orthopaedics because again the anatomy remains fixed (17). the need for non-rigid registration has developed because most structures in the body are in fact dynamic and susceptible to soft tissue deformation during surgery. non-rigid registration is much more complex and time-consuming (10). this has been the main challenge of using igs in surgical fields such urology, cardiac and general surgery. furthermore, many of the current registration models require manual overlay and hence the potential for human error can affect the accuracy of the system. in cases where there are no intraoperative images available, the pre-operative images are registered just to an instrument tracking system. tracking allows for the exact location of surgical instruments to be determined. the surgeon can therefore be guided in real-time during the procedure. the commonest tracking materials are optical and magnetic. the optical system uses a specialised tool with a camera and a tracker. the surgeon holds the proximal end of the tool with the camera and the distal tracker is placed inside the patient. however, direct line of sight is necessary between the camera and the tracker, which can be difficult in the operating theatre. the newer method of magnetic tracking does not require direct of line of sight but electromagnetic forces can vary with the presence of metallic objects in the operating room (8). the surgical accuracy of optical and magnetic tracking systems (< 3 mm considered good) was compared by mascott in 2005. the results of this study show the optical tracking system had an accuracy of 1.4 ± 0.8 mm and the magnetic system had 1.4 ± 0.6 mm (root mean square), and hence both systems are consider highly accurate (11). however accuracy of the tracking devices is application specific and can vary. 4) user interface and display the previous 3 steps must all be coordinated onto a user interface. it is important the user interface is designed for ease of control, rather than creating a distraction for the surgeon. the data is then available to view on a display console as an ar. this includes the imaging material, a view of the tracked surgical instruments and in the case of laparoscopic surgery it is superimposed over the video feed. the ar must also be able to provide real-time updates during the procedure. an example of a display screen is illustrated in figure 1 showing a robotic radical imaging technique tissue penetration spatial resolution tissue boundary differentiation advantages disadvantages ct complete 0.25 mm +++ 3-dimensional ionizing radiation ++++ can use contrast agent cheaper than mri mri complete 0.5 mm ++++ 3-dimensional expensive ++++ intrusive in operating room x-ray fluoroscopy complete 0.1 mm ++ low cost ionizing radiation ++++ can use contrast agent 2-dimensional us 2-20 cm, no bone 20 µm0.5 mm +++ non-ionising poor bone penetration +++ 3-dimensional user dependant dynamic imaging small portable device pet complete 5-10 mm can accurately define lesions ionising radiation ++++ when combined with ct/mri optical ≤ 5 mm 10 µm ++++ high quality images lack of penetration ++ of direct vision ct: computer tomography, mri: magnetic resonance imaging, us: ultrasound, pet: positive emission tomography, ct: computer tomography, mri: magnetic resonance imaging, us: ultrasound, pet: positive emission tomography. table 1. imaging modalities (1, 5, 6). pervez_stesura seveso 15/01/15 12:53 pagina 246 prostatectomy. the pre-operative mri scan is superimposed over the laparoscopic video screen (12). once all the components of igs are merged (shown in figure 2), the surgeon can then use the system to plan, guide and perform surgery. clinical effectiveness of image guided robotic urology the current application of igs in robotic urology has been analysed in table 2, with its consideration in robot assisted prostatectomy and robot assisted partial nephrectomy. a variety of imaging modalities have been considered, ranging from ct to ultrasound but development is in the early stages with relatively small studies, aimed mainly to assess the feasibility of igs in urology. a necessary attribute for the validity of the igs system is accuracy. accuracy becomes more difficult with non-rigid registration with dynamic and soft tissue deformation. this is a particular issue in urology because the soft tissue is in constant flux. teber et al. (13) proposed a technique to overcome the issue of tissue deformation by using navigation aids. needle-like markers were inserted directly into the target organ, in this case the kidney and could be tracked intra-operatively using a mobile c-arm with cone beam imaging. along with pre-operative ct images, all the information was integrated in real time as an image overlay over the endoscopic view. although this method is good at addressing the issue of tissue deformation, its downside is that 3d ar is superimposed over a 2d endoscopic view. another technology that has shown a great deal of promise is the firefly imaging system. patients are injected with intravenous indocyanine green (icg) dye, which binds to plasma proteins in the blood. a nearinfrared fluorescent (nirf) camera is integrated with the da vinci® surgical system and blood vessels are illuminated intra-operatively. not only does this improve tumour margins, but also allows for selective clamping of vessels to confine the area of ischemia. it is important to note fluorescent imaging is inadequate as a sole replacement for white light, rather it offers be to be a great adjunct that can be turned on/off as needed during the procedure (14). current research into igs explores the compatibility of various systems and their accuracy. however, the true effectiveness of igs will be based upon improvements to clinical outcome. evidence from table 2 show two studies, teber et al. (15) and hung et al. (16), in which the majority, if not all the patients had tumour-free margins. the ability to assess clinical outcome is limited in these cases because of the small sample size and the lack of 247archivio italiano di urologia e andrologia 2014; 86, 4 image guided robotic surgery: current evidence for effectiveness in urology figure 2. concept of the image guided surgery system. figure 1. display screen for laproscopic radical prostatectomy with pre-operative mri image overlay and surgical tool tracking (12). pre-operative imaging image processing user interface intra-operative intraoperative imaging image registration* & surgical tool tracking surgeon * stereotaxic rigid frame or non-rigid fiducial point alignment display workstation author speciality procedure sample size imaging modality accuracy clinical outcome thompson et al. (12) urology robot assisted 13 human patients pre-op mri rms error 5 mm no measureable change prostatectomy in clinical outcome but helpful to the surgeon teber et al. (13) urology robot assisted laparoscopic 10 porcine models and pre-op ct error margin 0.5 mm tumour-free margins partial nephrectomy 10 human patients in all 10 cases tobis et al. (14) urology robot assisted laparoscopic 11 human patients intra-op near infrared improved visualisation partial nephrectomy fluorescence imaging of renal vasculature & ability to differentiate renal tumours from normal parenchyma su et al. (15) urology robot assisted laparoscopic 2 human patients pre-op ct 1 mm partial nephrectomy hung et al. (22) urology robot assisted prostatectomy 10 human patients intra-op trus negative margins in 9/10 rms: root mean square, trus: transrectal ultrasound, pre-op: pre-operative, intra-op: ntra-operative. table 2. current literature in image-guided robotic urology. pervez_stesura seveso 15/01/15 12:53 pagina 247 archivio italiano di urologia e andrologia 2014; 86, 4 anum pervez, kamran ahmed, stephen thompson, oussama elhage, m shamim khan, prokar dasgupta 248 control groups. a study by thompson et al. (12) on the other hand reported no changes to clinical outcome. they did highlight however, that the igs system was found to be very helpful by the operating surgeon. challenges in image-guided robotic urology the igs system does have some challenges, which need to be addressed. one of the main considerations is creating a highly accurate system for image registration, which accounts for soft tissue deformation. as the majority of current igs requires manual processing and registration, it can be susceptible to human error. for example, if the image is aligned in the wrong location or the wrong blood vessels displayed, it can have devastating affects on the surgical outcome. furthermore, the computer interface must be relatively easy to operate by the surgeon. if the system is complex it may act as a rather dangerous distraction. therefore a simple but yet accurate system is as previously discussed, the current trials using igs have small sample sizes. this makes studying the efficacy of the system difficult. therefore randomised clinical trials comparing igs to non-igs are required to assess there is an improvement to clinical outcome. table 1 has also highlighted some issues with the imaging modalities that are currently being used for igs. for example radiation risk of intra-operative ct scans and the size of mri machines in the operating theatre. these issues create difficulty for igs to be adopted widely. a question yet to be considered, is the cost of these systems. the cost of implementing igs in most cases is negligible as the imaging modalities and surgical tools are already in common practise. however, the purpose of igs is to offer minimally invasive surgery to a patient who would have otherwise required open surgery. therefore analysing the improvement to clinical outcome will be difficult to perform. for example, if igs is successful in improving tumour resection margin, it could potentially improve cancer outcomes but this will require a long-term study design for conclusive evidence. future of igs igs has the potential to resolve the visibility issues encountered in robotic urology. however for the igs system to be adopted, further research must be performed on creating a successful automated system that can integrate with the intra-operative interface and account for soft tissue deformation. simulations and training may also be a future use of igs. the creation of an augmented virtual reality model could offer an excellent teaching tool. therefore procedures and therapies could be trialled on virtual reality simulators before being transferred to patients (9). acknowledgements nicholas chang, medical student, kings college london. this research was supported by the national institute for health research (nihr) biomedical research centre based at guy’s and st thomas’ nhs foundation trust and king’s college london. the project is also supported by the simulate (national initiative for simulation training in urology), the urology foundation (tuf) and the royal college of surgeons of england. the views expressed are those of the author(s), based on the research outcomes. references 1. perrin dp1, vasilyev nv, novotny p, et al. image guided surgical interventions: curr probl surg. 2009; 46:730-66.. 2. medtronic. image-guided surgery overview [cited 2012 24 november]. available from: http://wwwp.medtronic.com/newsroom/ linkeditemdetails.do?itemid=1101831118967&itemtype=backgrounder&lang=en_us. 3. de nigris d, collins d, arbel t. multi-modal image registration based on gradient orientations of minimal uncertainty. ieee trans med imaging. 2012; 31:2343-54. 4. ukimura o. image-guided surgery in minimally invasive urology. curr opin urol. 2010; 20:136-140. 5. voxelera. part i: commonly used radiological imaging modalities jan 2006 [cited 2012 dec 5th]. available from: http://www.voxelera.co.uk/downloads/tablepart1_jan2006.pdf. 6. voxelera. part ii: less commonly used in vivo imaging modalities may 2006 [cited 2012 dec 5th]. available from: http://www.voxelera.co.uk/downloads/tablepart2_may2006.pdf. 7. thompson s, penney g, buie d, et al. use of a ct statistical deformation model for multi-modal pelvic bone segmentation. in: medical imaging 2008: image processing.; vol. 6914 of proceedings of the spie. 2008. 8. herrell sd, galloway rl, su lm. image-guided robotic surgery: update on research and potential applications in urologic surgery. curr opin urol. 2012; 22:47-54. 9. peters tm. image-guided surgery and therapy: current status and future directions. in: mun sk, editor. medical imaging 2001: visualization, display, and image-guided procedures; san diego, cafebruary 17, 2001. 10. crum wr, hartkens t, hill dl. non-rigid image registration: theory and practice. br j radiol. 2004; 77 spec no 2:s140-53. 11. mascott cr. comparison of magnetic tracking and optical tracking by simultaneous use of two independent frameless stereotactic systems. neurosurgery. 2005; 57:295-301; discussion 295-301. 12. thompson s1, penney g, billia m, et al. design and evaluation of an image guidance system for robot assisted radical prostatectomy. bju int. 2013; 111:1081-90. 13. teber d, guven s, simpfendörfer t, et al. augmented reality: a new tool to improve surgical accuracy during laparoscopic partial nephrectomy? preliminary in vitro and in vivo results. eur urol. 2009; 56:332-338. 14. tobis s, knopf j, silvers c, et al. near infrared fluorescence imaging with robotic assisted laparoscopic partial nephrectomy: initial clinical experience for renal cortical tumors. j urol. 2011; 186:27-52. 15. su lm, vagvolgyi bp, agarwal r, et al. augmented reality during robot-assisted laparoscopic partial nephrectomy: toward real-time 3dct to stereoscopic video registration. urology. 2009; 73:896-900. 16. hung aj, abreu al, shoji s, et al. robotic transrectal ultrasonography during robot-assisted radical prostatectomy. eur urol. 2012; 62:341-8. 17. villavicencio at, burneikiene s, bulsara kr, thramann jj. utility of computerized isocentric floroscopy for minimally invasive spinal surgical techniques. j spinal disord tech. 2005; 18:369-75. correspondence kamran ahmed, mrcs, phd (corresponding author) kamran.ahmed@kcl.ac.uk anum pervez, bsc stephen thompson, phd oussama elhage, mrcs m shamim khan, obe, frcs (urol), febu prokar dasgupta. md, frcs (urol), febu mrc centre for transplantation, nihr biomedical research centre, king’s health partners, king’s college london and department of urology, guy’s hospital, st thomas street, london se1 9rt pervez_stesura seveso 15/01/15 12:53 pagina 248 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2162 case report no conflict of interest declared. doi: 10.4081/aiua.2020.2.162 complete blood count (cbc), c-reactive protein, and other biochemical tests were normal. ultrasonography (us) showed a cystic lesion localized on the right side of the urethra with a smoothly contoured, thin-walled, hypoechoic structure that was unrelated to the surrounding tissues. abdominopelvic us was normal. the patient’s oxygen saturation values returned to normal after cleaning nasal secretions with saline. following the evaluation of pediatric urology, the mass was thought to be a paraurethral cyst. after written informed consent was obtained from the family, the patient underwent puncture under sterile conditions. the content of the mass was mucoid and clear fluid. after the procedure, the urethra and vagina were normal. it was observed that the cyst did not recur during follow up at the neonatal unit or after the patient’s discharge. discussion paraurethral glands were first described by alexander johnston chalmers skene in 1880 (2). they are located in the distal part of the urethra and considered to be homologues of the prostate in females; they generate mucoid secretion with sexual stimulation (3). the distal urethra of an adult woman has between 6 and 30 ducts in the paraurethral glands, the largest of which is called the skene duct. paraurethral cysts are rare and occur with obstruction of the skene duct. although the etiology is not clear, it is thought that dislocation of the epithelium and inflammation may cause obstruction (4). the diagnosis of paraurethral cyst in newborns is based on the localization of the cyst and relationship with the urethra. in paraurethral cysts, the urethra is free, and the urethral meatus can displace with the mass effect. perineal ultrasound shows a smooth contoured simple cyst filled with mucoid fluid. on pathological examination, the internal surface of the cyst wall comprises transitional or squamous epithelium. differential diagnoses of paraurethral cysts in newborns include imperforate hymen, gardner canal cyst, muller canal cyst, urethral prolapse, vaginal rhabdomyosarcoma, ectopic ureterocele, condyloma, urethral polyp, congenital lipoma, and vaginal prolapse. if paraurethral cysts are accompanied by lower urinary tract obstruction, further urological evaluation should also be performed. there is no consensus about the treatment for paraurethral cysts because they are benign and often asymptoparaurethral cyst in a newborn raziye ergun 1, duran yildiz 2, cagri akin sekerci 3, hasan kahveci 2 1 erzurum regional training and research hospital, pediatric urology, erzurum, turkey; 2 erzurum regional training and research hospital, neonatology, erzurum, turkey; 3 marmara university pendik training and research hospital, pediatric urology, istanbul, turkey. introduction paraurethral cysts are a rare cause of intralabial mass in neonatal period. they develop due to congenital obstruction of the ducts of the paraurethral glands. the incidence of paraurethral cysts has been reported as 1.038 to 7.246 live births (1). paraurethral cysts are usually asymptomatic, 6-10 mm in size, cystic and soft masses in the physical examination. most of them spontaneously resolve. in this article, we aimed to present a case of paraurethral cyst which was treated by needle aspiration in early neonatal period. case report on the fourth day after birth, a baby girl was admitted to the neonatal intensive care unit with cyanosis. she was born from non-consanguineous parents, following an uneventful second pregnancy for her 40-year-old mother, by the normal spontaneous vaginal route at a private center. she was born at 37 weeks of gestation, with a weight of 2.200 grams (3rd-10th percentile) a height of 45 cm (25-50th percentile). in the systemic examination, the patient's general status was good. the neonatal reflexes were active and alive, and her vital signs were normal. moreover, the results of her respiratory, cardiovascular, neurological, and abdominal examinations were normal. in genital examination, a noninvasive mass measuring 2 × 1.5 cm was observed in the interlabial region, and the introitus was completely closed. the patient had spontaneous urine output. paraurethral cysts are rare and occur with obstruction of the skene duct. in this case, we aimed to present a paraurethral cyst in a baby girl. a 4-day-old newborn was consulted for pediatric urology because of an interlabial mass. in genital examination, a noninvasive mass measuring 2 × 1.5 cm was observed in the interlabial region, and the introitus was completely closed. ultrasonography showed a cystic lesion localized on the right side of the urethra with a smoothly contoured, thin-walled, hypoechoic structure. the patient underwent puncture under sterile conditions. the content of the mass was mucoid and clear fluid. paraurethral cysts are often asymptomatic and benign. there is no definitive consensus on treatment. key words: newborn; paraurethral cyst. submitted 26 july 2019; accepted 31 january 2020 summary 163archivio italiano di urologia e andrologia 2020; 92, 2 paraurethral cyst in a newborn matic. cyst excision, marsupialization, and needle aspiration, as in our case, are among the surgical methods that can be used in the treatment. because of spontaneous resolution in neonates, a conservative approach is another alternative to surgery. fujimoto et al. reported that the five neonates with paraurethral cysts who were followed conservatively showed spontaneous recovery after 150 days on average (5). the most common method for surgical procedures is needle aspiration, which can often be applied at the bedside with a local anesthetic cream without the need for general anesthesia. references 1.phupong v, aribarg a. management of skene's duct cysts in newborn girls. bju int. 2000; 86:562. 2. skene aj. the anatomy and pathology of two important glands of the female urethra. the american journal of obstetrics and diseases of women and children (18691919). 1880; 13:265. 3. costantino e, ganesan gs. paraurethral cysts in newborn girls. bmj case reports. 2016; 2016:bcr2016216689. 4. merlob p, bahari c, liban e, reisner s. cysts of the female external genitalia in the newborn infant. am j obstet gynecol. 1978; 132:607-10. 5. fujimoto t, suwa t, ishii n, kabe k. paraurethral cyst in female newborn: is surgery always advocated? j pediatr surg. 2007; 42:400-3. figure 1. view of the paraurethral cyst and aspirated fluid with the naked eye. a b c 1a: image of interlabial mass in vulva before operation. the mass was approximately 2 x 3 cm in size, covered with genital mucosa, ovoid, soft/elastic, and partially reddish but also generally creamy. 1b: content of the aspirated cyst during operation. 1c: image of vulva after operation (fifth day). correspondence raziye ergun, md raziye_ergun@hotmail.com erzurum regional training and research hospital, pediatric urology, erzurum (turkey) duran yildiz, md doktorduranyildiz@hotmail.com erzurum regional training and research hospital, neonatology, erzurum (turkey) cagri akin sekerci, febu, assoc. prof. (corresponding author) cagri_sekerci@hotmail.com marmara university pendik training and research hospital, pediatric urology, istanbul (turkey) hasan kahveci, assoc. prof. drhasankahveci@hotmail.com erzurum regional training and research hospital, neonatology, erzurum (turkey) 177archivio italiano di urologia e andrologia 2019; 91, 3 original paper chronic prostatic infection: microbiological findings in two mediterranean populations konstantinos stamatiou 1, vittorio magri 2, gianpaolo perletti 3, 4, vaia papadouli 5, nectaria recleiti 5, vassiliki mamali 5, olympia zarkotou 5 1 urology department, tzaneion hospital, piraeus, greece; 2 urology secondary care clinic, asst-nord, milan, italy; 3 department of biotechnology and life sciences, section of medical and surgical sciences, università degli studi dell'insubria, varese, italy; 4 faculty of medicine and medical sciences, ghent university, ghent, belgium; 5 microbiology department, tzaneion hospital, piraeus, greece. introduction/aim: despite accumulated knowledge, several microbiological aspects of chronic bacterial prostatitis (cbp) remain uncertain. the aim of our study was to determine microbiological characteristics on our cbp population. materials: the material of this retrospective study consisted in bacterial isolates from urine and/or prostatic secretions or sperm cultures (total ejaculate) obtained from individuals with prostatitis symptoms and from patients with febrile relapses of cbp visiting our department, from 03/2009 to 03/2015. retrospective data from an italian single-center database (years 2009-2015) were also collected for a tentative comparison of pathogen prevalence between chronic bacterial prostatitis cases assessed in greece and italy. results: a total of 389 bacterial isolates obtained from eligible greek patients constituted the material of the study. while e coli was the most frequent individual pathogen, gram-positive species were overly more frequent than gram-negative. besides the high frequency of e. coli and e. faecalis isolates the most remarkable similarity between greek and italian databases was the wide array of different gram-positive and gram-negative species isolated from cbp patients. conclusions: in greece, the incidence of cbp is possibly higher than that reported in international surveys. similarities between greek and italian databases suggest geographical trends in cbp epidemiology. key words: chronic prostatitis; prostate; infection; stameymeyers. submitted 19 june 2019; accepted 21 july 2019 summary no conflict of interest declared. methods material the material of this retrospective study consisted in bacterial isolates from urine and/or prostatic secretions or sperm cultures (total ejaculate) obtained from individuals with reported pelvic discomfort and genital pain, with or without lower urinary tract symptoms and sexual dysfunction, and from patients with febrile relapses of cbp, visiting our department from 03/2009 to 03/2015. retrospective data from an italian single-center database (years 2009-2015) were also collected for a tentative comparison of pathogen prevalence’s between cbp cases assessed in greece and italy. patients assessment demographic, microbiological and clinical history of each assessed patient were reviewed. patients suffering from conditions that influence bacterial virulence or host response (eg. immunodeficiency, abnormalities of the urogenital system) and patients who received antibiotics or immunosuppressive treatment within 4 weeks of the visit were excluded from the study. included patients were clinically evaluated and underwent the meares-stamey “4-glass” test. few cases underwent the “two-glass” test, assessing the sole vb2 and vb3 specimens. depending on medical history and specific symptoms, urethral smear cultures and total ejaculate cultures were additionally obtained from several patients. patients presenting with febrile prostatitis were investigated by a midstream urine culture (muc) only. appropriate antimicrobials were administered to confirmed cases of cbp accordingly to antibiogram for a period of 4 weeks. follow-up included interview, physical examination and the meares-stamey test. microbiological evaluation the meares-stamey test was considered positive when: 1) bacteria grew in the culture of expressed prostatic secretion (eps) and vb3 urine sample and did not in vb1 and vb2 sample; 2) bacterial colonies in vb3 were higher in numdoi: 10.4081/aiua.2019.3.177 introduction/aim chronic bacterial prostatitis (cbp) is an inflammatory condition of the prostate, characterized by pain in the genital or the pelvic area, which can lead to urinary disorders and may cause sexual dysfunction. despite the extensive knowledge accumulated over time, several microbiological aspects remain uncertain. the aim of our study was to describe the microbiological characteristics of patients referring to a single hellenic tertiary care center with symptoms of prostatitis combined with symptoms in the genitourinary tract. stamatiou_stesura seveso 30/09/19 18:23 pagina 177 archivio italiano di urologia e andrologia 2019; 91, 3 k. stamatiou, v. magri, g. perletti, v. papadouli, n. recleiti, v. mamali, o. zarkotou 178 ber compared to vb1 and vb2 samples. given that no standard cut-off level of the number of bacteria in both urine and prostate secretion samples is defined by consensus for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. cultures, identification and semi-quantitative assay for mycoplasma hominis and ureaplasma urealyticum were performed using the mycoplasma ist 2 kit (biomerieux). chlamydia trachomatis was detected by direct immune-fluorescence (monoclonal antibodies against lipopolysaccharide membrane, kallestad). urine samples were cultured undiluted in blood and macconkey agar plates (kallestad lab., tx, usa) and subjected to centrifugation for microscopic examination of the sediment. evaluation of culture results was performed by two specialist microbiologists. identification of traditional pathogens was performed by conventional methods and the vitek-2 compact (biomerieux, france) system and susceptibility testing was performed by disc diffusion and/or the vitek-2 system. interpretation of susceptibility results was based on clinical and laboratory standards institute (clsi) guidelines. the local ethical committee approved the research protocol for the present retrospective study. results a total of 548 bacterial isolates were obtained from eligible greek patients assessed in 1324 visits and recorded during a period of 6 years (2009-2015). in 114 cases the colonies counted in vb2 cultures were as many as those assessed in vb3. in 44 cases the eps/vb3 cultures were negative despite the presence of bacteria in the specimens. these cases were excluded from the study. finally, 389 bacterial isolates were recognized as cbp cases and constituted the material of our study. demographic and microbiological data are presented in table 1. microbiological findings a vast variety of pathogens, including rare bacteria, was found in both mono and polymicrobial cultures from both eps and vb3 samples. the most common were e. coli, coagulase negative staphylococci (cons) (mainly s. hominis and s. haemolyticus) and enterococcus faecalis. the most common combination in polymicrobial isolates composed of two different species was that of e. coli and cons (21 cases) while in polymicrobial isolates composed of three different species was that of escherichia coli, enterococcus faecalis and proteus mirabilis (4 cases). 29 out of 43 sperm cultures were performed complementary to eps/vb3. thirteen of them were identical to eps/vb3 cultures. the remaining 16 cultures allowed diagnosing bacterial infection while the eps/vb3 cultures were negative. the most frequently assessed isolates were enterococcus spp. (19 monomicrobial and 3 polymicrobial). urethral discharge cultures and cultures from urethral swab samples have diagnosed 48 cases of coexisting urethral infection mainly caused by cons and chlamydia trachomatis (table 2). follow-up visits and outcome as far as the outcomes of follow-up visits are concerned, 263 patients reported elimination of symptoms/clinical improvement, though only 149 were completely cured. bacterial persistence occurred in 111 cases. in 17 patients pus was found in eps and/or vb3 in the absence of symptoms. in 6 cases eps/vb3 cultures were negative despite the presence of bacteria in the same samples. six patients were diagnosed with another disease during follow-up. in most non-treated cases, the pathogens found in the follow-up cultures were different from those isolated in the initial visit (usually enterococcus faecalis, cons and e. coli). relapses occurred in 53 patients and almost half of them were caused by microorganisms other than those causing the initial infection. the average time interval between episodes of chronic prostatitis is 13.9 months (minimum 2 and maximum 56 months). the pathogens most commonly associated with clinical relapses were enterococcus faecalis, cons and e. coli. table 1. patient demographic and microbiological data. clinical sample number number of patients 389 median age 34.7 microbiological sample cultures of prostatic secretions 92 urine samples collected after prostate massage 343 mid-stream urine only cultures (febrile cases) 46 sperm cultures (total ejaculate) 43 monomicrobial infection 297 polymicrobial infection 92 table 2. pathogens found in monomicrobial and polymicrobial isolates. pathogen eps/vb3 sperm urethral escherichia coli 142 5 1 coagulase negative staphylococcus 108 15 enterococcus faecalis 102 16 4 streptococcus spp. 31 proteus spp. 28 1 staphylococcus aureus 21 1 klebsiella spp. 9 5 gemella morbilorum 4 1 raoultella planticola 3 haemophilus parainfluenzae 3 1 1 enterobacter aerogenes 2 citrobacter freundii 2 mycoplasma hominis 1 1 1 acinetobacter baumannii 1 staphylococcus lugdunensis 1 haemophilus influenzae 1 pseudomonas aeruginosa 1 brevundimonas diminuta/vesicularis 1 candida non albicans 2 candida albicans 2 chlamydia trachomatis 13 n. gonorrhoeae 4 total 465 30 40 stamatiou_stesura seveso 30/09/19 18:23 pagina 178 discussion epidemiological and diagnostical issues according to the general perception a progression of prostatic inflammation and its consequences from acute to chronic occur resulting on cbp pathogenesis (1). actually, after an episode of acute bacterial prostatitis approximately 5-10% of patients progress to chronic infection (2, 3). in accordance to the above, in our study 10.52% of the patients presented with episodic or persistent relapsing urinary tract infections and all reported a previous diagnosis of prostatitis. cbp is considered a relatively infrequent disease, since it comprises only 10% of all prostatitis cases (4). nevertheless, from the currently available epidemiologic studies, it appears that cbp is more common since many patients may have bacterial infection despite negative urine cultures: while less than 10% of men worldwide have a proven bacterial infection of the prostate, up to 25% receive a diagnosis of prostatitis in their lifetime (5). negative culture results occur for various reasons including, the presence of fastidious organisms, initiation of antibiotics prior to obtaining an eps sample, high bacterial count cut-offs established by laboratories (e.g., 50 000 cfu), or insufficient sample volumes. since we defined no lower acceptable level for bacterial colonies in both urine and prostate secretion samples for the diagnosis of chronic bacterial prostatitis, the bacteriologically proven incidence of cbp in this study was 29.45%. moreover, the fact that we recognised certain gram-positive bacteria as pathogenic may have also contributed to this difference. in fact, the literature strongly suggests that urologic diseases involving gram-positive bacteria may be easily overlooked due to limited culture-based assays typically utilized for urine in hospital microbiology laboratories (6). insufficient sample volumes explain the low number of assessable epss in this study. this fact may indicate the need of better preparing (e.g. abstain from sexual intercourse for 3 to 5 days) before the meares-stamey test. on the other hand, the presence of fastidious organisms, anaerobic pathogens or bacteria not detectable with the usual tests may explain the 44 cases whose eps/vb3 cultures were negative despite the presence of bacteria. as a matter of fact, traditional culture procedures show lower specificity and sensitivity in detection of bacteria in prostatic specimens than polymerase chain reaction (pcr)-based techniques. choi et al. found an 11.4% incidence of bacterial infection in routine eps or vb3 cultures, while pcr detected bacterial infection in 40.9% of cases (7). similarly, krieger and riley found a substantial proportion of positive broadspectrum pcr assays (8). regardless of its drawbacks, the four-glass test is currently considered the diagnostic standard for cbp, while pcr techniques are cumbersome and have little use in the daily clinical setting. for this reason magri et al. introduced the 'five-glass' test (four-glass plus post-vb3 semen culture), which showed 3.6or 6.5-fold increases in relative sensitivity and lesser reductions (-13.2% or 14.7%) in relative specificity for traditional and unusual pathogens (mycoplasmata and others) compared with the four-glass or two-glass test, respectively (9). the significance and diagnostic value of complementary semen culture is supported by two other studies (10. 11), though further studies are needed to determine whether a 'five-glass' test may represent a better diagnostic tool. similarities between greek and italian databases may indicate geographical trends in cbp epidemiology. in fact, similar policies in antibiotic usage and common factors that influence male sexuality and sexual behaviour may contribute to such trends. to our knowledge, a high cbp incidence (26.9%) has been also demonstrated in a previous greek study (12) while higher incidences were found in central and southern regions of italy (13). microbiological and pathophysiological issues besides the high frequency of e. coli and e. faecalis isolates the most remarkable similarity between greek and italian databases was the wide array of different species like coag. neg. staphylococcus, streptococcus spp., s. aureus, haemophylus spp., citrobacter spp., mycoplasma hominis, haemophylus spp., p. aeruginosa and candida spp. isolated from both greek and italian cbp patients (tables 2-4). in our study enterococcus faecalis was by far the most frequent bacterial isolate from sperm cultures. in the italian cohort, this species was the third most common isolate in sperm cultures after e. coli and u. urealyticum (tables 179archivio italiano di urologia e andrologia 2019; 91, 3 chronic prostatic infection: microbiological findings in two mediterranean populations table 3. monomicrobial isolates in an italian cohort of 151 consecutively assessed italian patients (years 2009-2015). pathogen isolated isolated isolated total from eps/vb3 from total from both only ejaculate only specimens escherichia coli 26 13 6 45 proteus mirabilis 2 1 / 3 klebsiella spp. 1 2 / 3 morganella morganii 1 5 / 6 pseudomonas aeruginosa / / 2 2 haemophilus parainfluenzae / 2 / 2 citrobacter koseri / 1 / 1 neisseria subflava / 1 / 1 enterococcus faecalis 11 6 3 20 staphylococcus aureus 3 / / 3 staphylococcus coagulase-negative 1 5 1 7 streptococcus beta-haemolyticus gr. b / / 1 1 streptococcus agalactiae 1 / / 1 steptococcus anginosus / 1 / 1 kocuria kristinae / / 1 1 chlamydia trachomatis 3 / / 3 ureaplasma urealyticum 4 21 2 27 mycoplasma hominis / 2 / 2 total 53 60 16 129 stamatiou_stesura seveso 30/09/19 18:23 pagina 179 archivio italiano di urologia e andrologia 2019; 91, 3 k. stamatiou, v. magri, g. perletti, v. papadouli, n. recleiti, v. mamali, o. zarkotou 180 3, 4). several other studies provided clear evidence of a gram-positive predomination in bacteriospermia (14, 15), while other found a very high proportion of gram-negative microorganisms with escherichia coli being the commonest isolate in positive cultures (22.2 to 75%) (16-18). urethral discharge cultures and cultures from urethral swab samples revealed coexisting cons and/or chlamydia trachomatis-induced urethral infection. interestingly, in the italian cohort, whereas mycoplasmata were found mainly in ejaculate cultures, c. trachomatis was isolated mainly from eps/vb3 samples (table 4). since the urinary tract acts as a nest of infection for the seminal tract, these microorganisms are capable of causing classical infections of the urogenital tract such as epididymitis and prostatitis as well as subclinical reproductive tract infections. outcome related issues differences in isolated microorganisms in vb3/eps cultures between follow-up and initial visits of untreated/relapsed cases reinforce the new appreciation of chronic prostatitis as a biofilm disease. pathogen eradication rates, as high as 80%, have been reported in the pastin cbp patients treated with various fluoroquinolones (19). our bacterial eradication rate (68.15%) is similar with that reported in a previous greek study (64.7%) (12) and this fact may be attributed to the quinolones overuse in greece. conclusions in greece, the incidence of cbp is possibly higher than that reported in international surveys. similarities between greek and italian databases suggest geographical trends in cbp epidemiology. the fact that gram-positive species were the most frequent isolates in both greek and italian databases support the role of gram-positive bacteria in cbps pathogenicity. regardless of its drawbacks, the meares-stamey is the main tool for the diagnosis of cbp. the significance and diagnostic value of complementary semen culture is supported by our findings, though further studies are needed to determine whether a 'five-glass' test may represent a better diagnostic tool. references 1. nickel jc, olson me, barabas a, et al. pathogenesis of chronic bacterial prostatitis in an animal model. br j urol. 1990; 66:47-54. 2. nickel cj. inflammatory and pain conditions of the male genitourinary tract: prostatitis and related pain conditions, orchitis, and epididymitis. campbell-walsh urology. 11th ed. elsevier; 2016. 3. yoon bi, kim s, han ds, et al. acute bacterial prostatitis: how to prevent and manage chronic infection? j infect chemother. 2012; 18:444-450. 4. krieger jn, egan kj. comprehensive evaluation and treatment of 75 men referred to chronic prostatitis clinic. urology. 1991; 38:11-19. 5. lipsky ba, byren i, hoey ct. treatment of bacterial prostatitis. clin infect dis. 2010; 50:164152. 6. kline ka, lewis al. gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. microbiol spectr. 2016; 4(2). 7. choi ys, kim ks, choi sw, et al. microbiological etiology of bacterial prostatitis in general hospital and primary care clinic in korea. prostate int. 2013; 1:133-8. 8. krieger jn, riley de. prostatitis: what is the role of infection. int j antimicrob agents. 2002; 19:475-9. 9. magri v, wagenlehner fm, montanari e, et al. semen analysis in chronic bacterial prostatitis: diagnostic and therapeutic implications. asian j androl. 2009; 11:461-77. table 4. polymicrobial isolates in an italian cohort of 151 consecutively assessed italian patients (years 2009-2015). pathogen isolated isolated isolated total from eps/vb3 from total from both only ejaculate only specimens e.coli + enterococcus faecalis 1 1 2 4 e.coli + klebsiella spp. / 1 / 1 e.coli + streptococcus beta-haemolyticus gr. b 1 / / 1 e.coli + ureaplasma urealyticum / / 1 1 e.coli + mycoplasma hominis / / 2 2 e.coli + peptostreptococcus spp. / / 1 1 e.coli + candida albicans / / 2 2 e. faecalis + klebsiella spp. / 2 / 2 e. faecalis + citrobacter spp. / / 1 1 e. faecalis + ureaplasma urealyticum / / 1 1 e. faecalis + staphylococcus coagulase negative 1 / / 1 p. aeruginosa + proteus mirabilis 1 / / 1 p. aeruginosa + staphylococcus coagulase negative / 1 / 1 m. morganii + haemophilus parainfluenzae / 1 / 1 streptococcus mitis + staphylococcus coagulase negative / / 1 1 chlamydia trachomatis + ureaplasma urealyticum / / 1 1 e. coli + e. faecalis + staphylococcus coagulase negative / / 1 1 total 4 6 12 22 table 5. clinical and microbiological outcome. cured 146 bacterial persistence symptom persistence 63 bacterial eradication symptom persistence 54 clinical improvement -unknown microbiological outcome 53 elimination of symptoms bacterial persistence 44 developed asymptomatic chronic nonbacterial prostatitis 17 non-recognizable bacteria in eps/vb3 cultured samples 6 diagnosed with another disease during follow-up 6 developed cystitis (vb3 cultures were identical to vb2) 4 total 389 stamatiou_stesura seveso 30/09/19 18:23 pagina 180 10. zegarra montes lz, sanchez mejia aa, loza munarriz ca, gutierrez ec. semen and urine culture in the diagnosis of chronic bacterial prostatitis. int braz j urol. 2008; 34:30-7. 11. cai t, pisano f, nesi g, et al. chlamydia trachomatis versus common uropathogens as a cause of chronic bacterial prostatitis: is there any difference? results of a prospective parallel-cohort study. investig clin urol. 2017; 58:460-467. 12. panagopoulos p, antoniadou a, kanellakopoulou k, et al. fluoroquinolone treatment of chronic bacterial prostatitis: a prospective cohort study. j chemother. 2009; 21:317-21. 13. rizzo m, marchetti f, travaglini f, et al. prevalence, diagnosis and treatment of prostatitis in italy: a prospective urology outpatient practice study. bju international. 2003; 92:955-959. 14. ibadin, ok, ibeh in. bacteriospermia and sperm quality in infertile male patient at university of benin teaching hospital, benin city, nigeria. mal j microbiol. 2008; 4:65-67. 15. sheikh af, mehdinejad m. identification and determination of coagulase-negative staphylococci spp and antimicrobial pattern of isolates from clinical specimens. afr. j. microbiol. 2012; 6: 16691674 16. panackal a, panackal a. semen culture a diagnostic tool in the diagnosis of bacterial prostatitis. transl biomed. 2017; 8:114. 17. budía a, luis palmero j, broseta e, et al. value of semen culture in the diagnosis of chronic bacterial prostatitis: a simplified method. scand j urol nephrol. 2006; 40:326-31. 18. ostrowski a, banas m, brzóska ret al. semen culture in bacterial prostatitis – retrospective analysis of microbiological profile, antibiograms and clinical utility eur urol suppl 2017; 1:e2949 19. weidner w, ludwig m, brähler e, schiefer hg. outcome of antibiotic therapy with ciprofloxacin in chronic bacterial prostatitis. drugs. 1999; 58 (suppl 2):103-6. 181archivio italiano di urologia e andrologia 2019; 91, 3 chronic prostatic infection: microbiological findings in two mediterranean populations correspondence konstantinos stamatiou, md stamatiouk@gmail.com urology dpt, tzaneion hospital, piraeus (greece) vittorio magri, md urology secondary care clinic, asst-nord, milan, italy gianpaolo perletti, phd department of biotechnology and life sciences, section of medical and surgical sciences università degli studi dell'insubria, varese (italy) vaia papadouli, md nectaria recleiti, md vassiliki mamali, md olympia zarkotou, md microbiology dpt, tzaneion hospital, piraeus (greece) stamatiou_stesura seveso 30/09/19 18:23 pagina 181 archivio italiano di urologia e andrologia 2017; 89, 3240 case report bladder carcinosarcoma: a case report with review of the literature ismail basibuyuk 1, ramazan topaktaş 2, fatih elbir 3 1 cizre state hospital, department of urology, sırnak, turkey; 2 haydarpasa numune training and research hospital, department of urology, istanbul, turkey; 3 mardin state hospital, department of urology, mardin, turkey. carcinosarcoma of the urinary bladder is a rare neoplasm that is histologically composed of malignant epithelial and mesenchymal components. the etiology of sarcomatoid tumors is unclear, but smoking and history of previous radiotherapy or chemotherapy may lead to bladder disorders and to the formation of sarcomatoid carcinoma. these neoplasms behave as highly aggressive tumors and optimal treatment is uncertain. herein, we report a case of sarcomatoid carcinoma of urinary bladder presenting as a giant intravesical mass in a 61-year-old man complaining of macroscopic hematuria. key words: bladder carcinosarcoma; urothelial carcinoma; prognosis. submitted 11 june 2017; accepted 19 july 2017 summary no conflict of interest declared. had a catheter without any other remarkable finding. laboratory test results were normal. whole abdominal ultrasonography (usg) showed a 9 x 8 cm mass which filled the bladder. abdominopelvic computerized tomography (ct) showed a 9 x 7 cm mass lesion, originating from the right lateral wall of the bladder and occupying the entire bladder (figure 1). a written informed consent was obtained from the patient and cystoscopic examination was performed under general anesthesia. the mass, which originated from the bladder neck and filled the bladder, was incompletely resected. pathological examination showed a biphasic pattern, and the result was reported as a sarcomatoid carcinoma. the epithelial component included an adenocarcinoma and squamous-cell carcinoma, whereas the sarcomatous component included a spindle-cell and chondrosarcoma. as the all resection specimen consisted of tumor tissues, we were unable to evaluate the depth of invasion. computed tomography showed no sign of lymph node or organ metastasis. four weeks after transurethral resection (tur-bt), radical cystoprostatectomy, lymph node dissection, and ileal conduit surgery were performed. cystoprostatectomy specimen had a 10 x 8.5 cm tumor in-diameter (figure 2). after histological examination, tumor was reported as a high-grade sarcomatoid carcinoma, pt2a, pn0, pmx. the histological pattern consisted of 70% sarcomatous component (spindle-cell and chondrosarcoma), and 30% epithelial component (adenocarcinoma and squamous-cell carcinoma). all surgical margin samples and lymph nodes were reported as normal. four days after the surgery, the patient died due to myocardial infarction. doi: 10.4081/aiua.2017.3.240 introduction the majority of bladder cancers (95 to 98%) originate from the urothelium (1). carcinosarcomas or sarcomatoid carcinomas are extremely rare malignancies, which have a biphasic character involving epithelial and mesenchymal components (2). loss of heterozygosity in stem cells is considered as the main factor in the underlying development of sarcomatoid carcinomas (2, 3). in addition, cyclophosphamide chemotherapy, smoking, and radiotherapy are considered to play a role in the etiology (4, 5). in most cases, epithelial component includes high gradeurothelial carcinoma, whereas mesenchymal component includes a chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, and rhabdomyosarcoma (5-7). herein, we present a paraplegic case who was diagnosed with a bladder carcinosarcoma in the light of literature data. case report a 61-year old, paraplegic male patient was admitted to our clinic with painless, gross hematuria with clots for three days. he had a history of coronary artery bypass grafting 12 years ago, spinal anesthesia-related paraplegia which developed two years before, and congestive heart failure (ejection fraction: 35%). he was a smoker. on examination, the paraplegic patient figure 1. a computed tomography image of a 9 x 7 cm heterogeneous mass within the bladder. basibuyuk_stesura seveso 28/09/17 10:32 pagina 240 241archivio italiano di urologia e andrologia 2017; 89, 3 bladder carcinosarcoma discussion bladder carcinomas are extremely rare tumors, which show polypoid character, and can reach large sizes, as assessed in gross examination. similar to other types of bladder cancer, these tumors are more common in males, and the incidence increases with age (8). tumors usually originate from the lateral walls, dome, trigon, and anterior wall (8). smoking, cyclophosphamide, and radiotherapy are considered to play a role in the etiology of carcinosarcomas due to their undesired effects on the cell proliferation (2, 4). similar to all other bladder cancers, these patients are admitted with painless gross hematuria. dysuria, increased need to urinate, and obstructive symptoms can be also seen (9). in our case, the patient was admitted with painless gross hematuria and a 10 cm mass originated from the right lateral wall of the bladder. in most cases, the epithelial component is reported as a high-grade papillary urothelial carcinoma (5, 6). sarcomatous component, on the other hand, usually include one or more of the followings: chondrosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma (5-7). in our case, pathological examination showed that the sarcomatous component consisted of a spindle-cell and chondrosarcoma, whereas the epithelial component consisted of an adenocarcinoma and squamous-cell carcinoma. furthermore, sarcomatoid tumors may affect several organs; however, clinical progression may vary according to the site (10). the best prognosis is seen, when the tumors involve the respiratory and gastrointestinal system, whereas tumors located in kidneys, bladder, prostate, and stomach have a poor prognosis (10). bladder carcinosarcomas are considerably aggressive, and there is no consensus on the standard treatment of these malignancies. however, tur-bt, radical cystectomy, radical cystectomy + radiotherapy, partial cystectomy + neoadjuvant radiotherapy followed by radical cystectomy are used for the treatment. although the efficacy of these methods is controversial, the main treatment methods are radical cystectomy and lymph node dissection (8, 11). aggressive surgery during early period is the only curative treatment option (5). in addition, radical cystectomy can be performed effectively in patients who have superficial or deep invasion, whereas transurethral resection and partial cystectomy are usually not preferred due to the increased risk of incomplete resection (8). recently, the combination of radical cystoprostatectomy and lymphadenoctomy with neoadjuvant or adjuvant chemotherapy and/or radiotherapy has been recommended (11). on the other hand, cancer-specific survival of carcinosarcomas is extremely poor, and tumor grade and subtype of epithelial component are the most important factors affecting survival (11, 12). while the majority of patients die within the first year, some patients live longer than 10 years (10). according to a recent study, one-, five-, and 10 years survival rates for bladder carcinosarcomas are 53.9%, 28.4%, and 25.8%, respectively (10). unfortunately, our case died due to myocardial infarction four days after radical cystoprostatectomy. conclusions due to aggressive and fatal nature of carcinosarcomas, a radical treatment approach should be implemented immediately as possible after the diagnosis. considering available data on carcinosarcomas in case reports, further large-scale studies should be carried out to gain a better understanding of the biological basis of this disease and to develop targeted therapies. references 1. erdemir f, uluocak n, tunc m, et al. sarkomatoid carcinoma of the urinary bladder. turk j urology. 2006; 32:462-6. 2. mukhopadhyay s, shrimpton ae, jones la, et al. carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss. arch pathol lab. 2004; 128:8-11. 3. halachmi s, demarzo am, chow nh, et al. genetic alterations in urinary bladder carcinosarcoma: evidence of a common clonal origin. eur urol. 2000; 37:350-7. 4. maestroni u, giollo a, barbieri a, et al. bladder carcinosarcoma: a case observation. acta biomed. 2004; 75:74-6. 5. lopez-beltran a, pacelli a, rothenberg hj, et al. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998; 159:1497-503. 6. lahoti c, schinella r, rangwala af, et al. carcinosarcoma of urinary bladder: report of 5 cases with immunohistologic study. urology. 1994; 43:389-93. 7. perret l, chaubert p, hessler d, guillou l. primary heterologous carcinosarcoma (metaplastic carcinoma) of the urinary bladder: a clinicopathologic, immunohistochemical and ultrastructural analysis of eight cases and a review of the literature. cancer. 1998; 82:1535-49. 8. wang j, wang fw, lagrange c, et al. clinical features of sarcomatoid carcinoma (carcinosarcoma) of the urinary bladder: analysis of 221 cases. sarcoma. 2010; 2010:454-792. 9. atilgan d, gencten y. carcinosarcoma of the bladder: a case figure 2. a gross view of a solid tumor invading the bladder completely. basibuyuk_stesura seveso 28/09/17 10:32 pagina 241 archivio italiano di urologia e andrologia 2017; 89, 3 i. basibuyuk, r. topaktaş, f. elbir 242 report and review of the literature. case rep urol. 2013; 2013:716704. 10. sreenan jj, hart wr. carcinosarcomas of the female genital tract. a pathologic study of 29 metastatic tumors: further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis. am j surg pathol. 1995; 19:666-74. 11. wright jl, black pc, brown ga, et al. differences in survival among patients with sarcomatoid carcinoma and urothelial carcinoma of the bladder. j urol. 2007; 178:2302-07. 12. rogers cg, palapattu gs, shariat sf, et al. clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder. j urol. 2006; 175:2048-53. correspondence ismail basibuyuk, md dr.ismailbb@gmail.com cizre state hospital, department of urology, sırnak, turkey ramazan topaktaş, md (corresponding author) ramazantopaktas@yahoo.com haydarpasa numune training and research hospital, department of urology tıbbiye street number:23, 34668 istanbul, turkey fatih elbir, md drfatihelbir@gmail.com mardin state hospital, department of urology, mardin, turkey basibuyuk_stesura seveso 28/09/17 10:32 pagina 242 109archivio italiano di urologia e andrologia 2020; 92, 2 case report management of a kidney stone in ectopic pelvic kidney with extracorporeal shockwave litothripsy: description of a case and revision of literature carmelo agostino di franco 1, maurizio burrello 1, francesco guzzardi 1, eva intagliata 1, irina oxenius 1, lavinia galvagno 2, calogero cordaro 1 1 department of urology, s. elia emergency hospital, caltanissetta, italy; 2 translation and language revision service, enna, italy. urolithiasis is one of the most frequent disease in the population and it represents one of the most frequent causes of access to emergency department. in addition. congenital anomalies occur more often in the kidney than in any other organ and the association of both renal abnormalities and stones is of clinical relevance. in this report, we discuss a case of a women with pelvic ectopic kidney affected by a large pyelic stone treated with eswl (extracorporeal shockwave lithotripsy). key words: pelvic ectopic kidney; urinary calculi; extracorporeal shockwave lithotripsy. submitted 24 november 2019; accepted 3 january 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.109 introduction urolithiasis is one of the most frequent diseases in the population and it represents one of the most frequent causes of access to the emergency department. for patients affected by kidney anomalies, stone treatment could be a strong challenge for the urologist. in addition, extracorporeal shockwave lithotripsy (eswl), is considered one of the first-line option treatment for kidney stones. in particular, retrograde intrarenal surgery (rirs) is not always available in all departments and it is associated to a higher complication rate than eswl. however, urinary stasis that usually is associated with kidney anomalies, could interfere with clearance of stone fragments after shockwave lithotripsy. in this report, we discuss a case of a woman with pelvic ectopic kidney affected by a large pyelic stone treated with eswl. case report we describe the case of a 63-years woman who presented to our emergency department with fever 39°c and abdominal pain. blood samples showed leukocytosis (wbc 21000) and increased c-reactive protein, normal kidney function. computed tomography (ct)-scan showed a right pelvic ectopic kidney with hydronephrosis and a large pyelic stone around 19 millimeters (figure 1). radiologist described increased peripyelic fat density secondary to phlogistic process. the patient was subjected to ureteral double j stenting into the ectopic kidney and bladder catheter with emission of pyuria. we treated the septic status with antibiotic (piperacillin/ tazobactam) and parenteral hydration. the patient was monitored with blood samples that showed a rapid improvement. in the first post-operative day the patient was afebrile. the patient was affected by diabetes mellitus type ii controlled with diet and she did not take any drug. after one month, the patient was subjected to first eswl treatment on the ectopic kidney stone; ureteral double j stent was maintained inside. in total, we performed two eswl treatments. we monitored stone changes after the first eswl with radiographic scans (figure 2). the position on the treatment-table was prone and we performed fluoroscopic control during the procedure. the shockwave lithotripsy was performed with a sonolith® device using electro-conductive shock head module. in both the procedures, we administered 3000 shocks, middle energy was 657 j, frequency 2 hz. fluoroscopy time was 02 minutes and 25 seconds with x-ray dose 3687 mgy/cm2 in first treatment and 02 minutes and 48 seconds with x-ray dose 3702 mgy/cm2 in second treatment. procedures were well tolerated; the patient did not need any antalgic drug during or after the procedure. no immediate complications were reported. we reported macrohaematuria during the first operative day in both procedures with spontaneous resolution and occasional dysuria during the two months with ureteral stent. after the second treatment, we performed outpatient ultrasound check and abdominal ct-scan. ct-scan showed complete stone free ectopic kidney as shown in figure 3. we removed ureteral stent after ct-scan check, two weeks from latest eswl treatment. the patient was enrolled to our outpatient service and metabolic study. discussion the introduction of eswl in 1980 revolutionized the treatment of kidney stones. it is a less invasive treatment for kidney stones, with low rate of complications and well accepted by patients. therefore, it is now used for almost 80% of patients with urinary stones. however, di franco_stesura seveso 17/06/20 10:14 pagina 109 archivio italiano di urologia e andrologia 2020; 92, 2 c. agostino di franco, m. burrello, f. guzzardi, e. intagliata, i. oxenius, l. galvagno, c. cordaro 110 today other minimally invasive techniques such as rirs or mini-perc (percutaneous stone surgery) represent good solutions for kidney stone treatment although they are not always available in all centers especially in secondary hospitals. as reported in literature, eswl can obtain good results in patients with malformed kidney, with an overall stonefree rate of 71.77% (1). for stones smaller than 1 cm, the stone-free rate was higher (up to 96.1%) demonstrating the importance of stone size for a successful treatment. brad et al. (2) reported retrospectively eswl results in a population with renal malformations; in their study average stone size was 10.23 mm and stone free-rate was 71.7%. they reported two cases of subcapsular hematoma (1.7%), two cases of acute pyelonephritis (1.69%) and two cases of haematuria which needed bladder washout and catheterization. overall complication rate in their report was 13.56%. in addition, the most severe complication is renal haematoma: it seems to be favoured in patients suffering of hypertension, liver diseases or anticoagulation drug use (2). in literature we found some studies related to the use of the ureteral stent in association with eswl. common idea is that ureteral stents compromise the results of eswl with a difference of around 22% in the stone-free rate in favour of non-stented patients as ureteral stents interfere with stone clearance because the presence of stent hinders the passage of fragments after eswl. in particular, a recent paper by ahmad et al. (3) reports that stone-free rate within patient without double j stent was 81,8% and within patients with jj stent was 16.7% (p < 0.05). regarding stone-free rate in the management of stones in anomalous kidneys with eswl, in literature some studies are reported, with a range from 31% to 100%. brad et al. (2) reported stone-free rate of 71.7% in 118 patients with kidney abnormalities and a medium stone size of 10.2 mm. the study of al-tawheed et al. (4) reported stone-free rate 83,9% with 9 patients with ectopic kidney an average stone-size of 1.5 cm. in ahmad et al. study (3) 50 patients with kidney malformations were evaluated and 22% of patients had ectopic kidney. in ectopic kidney group, stone-free rate was 100% with ectopic abdominal kidney, 75% with ectopic lumbar kidney and 0% with ectopic pelvic kidney. stone size was relevant, in particular stone-free rate was 74%; in patients with stone size below 1 cm, stone-free rate rose up to 91,6% demonstrating the importance of stone size for a successful eswl treatment. in our report, we describe a successful eswl treatment in a large stone (19 mm) in ectopic pelvic kidney. in our case patient had ureteral stent because she was first treated for septic status. however, in our routine we usually place the stent to patients with kidney calculi greater than 1.5 cm. conclusions eswl is a good treatment for kidney stones also in malformed kidneys achieving a good stone-free rate. figure 2. rxcheck showing stone modification after the 1st eswl treatment. figure 3. ct-scan after the 2nd eswl treatment showing 100% stonefree rate with ureteral jj stent inside. figure 1. preoperative ct-scan showing stone in ectopic pelvic kidney. di franco_stesura seveso 17/06/20 10:14 pagina 110 however, the success of eswl depend on many factors, in particular stone size, stone density and kidney position. the stone-free rate is related to patient compliance: in our case the patient was very collaborative and she did not need any analgesic drug. in addition, eswl treatment in selected cases could be an alternative to other stone treatments such us rirs or percutaneous nephrolithotomy (pcnl). references 1. tunc l, tokgoz h, tan mo, et al. stones in anomalous kidneys: results of treatment by shock wave lithotripsy in 150 patients. int j urol. 2004; 11:831-6. 2. brad a, et al. the place of eswl in the treatment of urinary stones in patients with renal malformations." romanian journal of urology. 2016; 15:28-32 3. ahmad mna, hussein abdallah galal ha, ayman kotb koritinah ak. outcome of extracorporeal shockwave lithotripsy in congenital malformed kidneys. the egyptian journal of hospital medicine 2019; 76:3963-3967. 4. al-tawheed, ar, al-awadi ka., kehinde eo, et al treatment of calculi in kidneys with congenital anomalies: an assessment of the efficacy of lithotripsy. urol res. 2006; 34:291-298. 111archivio italiano di urologia e andrologia 2020; 92, 2 stone in ectopic pelvic kidney treated with swl correspondence carmelo agostino di franco, md (corresponding author) carmelo_difranco@tiscali.it maurizio burrello francesco guzzardi eva intagliata irina oxenius calogero cordaro donc86@tiscali.it department of urology, s.elia emergency hospital, caltanissetta (italy) lavinia galvagno translation and language revision service, enna (italy) di franco_stesura seveso 17/06/20 10:14 pagina 111 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2108 original paper management of bladder stones associated with foreign bodies following incontinence and contraception surgery abdulmuttalip simsek 1, faruk ozgor 1, mehmet fatih akbulut 1, erkan sönmezay 1, bahar yuksel 2, omer sarılar 1, ahmet yalcın berberoglu 1, zafer gokhan gurbuz 1 1 haseki research and education hospital, department of urology, istanbul, turkey; 2 istanbul medical faculty, gynecology and obstetric department, istanbul, turkey. aim of the study: to investigate success of endoscopic lithotripsy for bladder stone following stress urinary incontinance surgery and contraception surgery. materials and methods: charts of patients admitted in two centers between january 2006 and march 2013 were retrospectively reviewed and seven women were enrolled in our study. patients demographic parameters including age, main complaint(s), previous surgery type, time to diagnosis were analyzed. also operative time, hospitalisation lenght, perioperative and postoperative complication(s) were evaluated. results: five patients had undergone tension free vaginal tape procedure and one patient had undergone transobturator tape procedure. median age was 62 (50-71) years. in one patient bladder stone formed around an intrauterine device. dysuria (85%), hematuria (57%) and recurrent urinary tract infection (57%) were the main complaints. the median diagnosis time was 44.1 months. abdominal ultrasonography and non contrast enhanced computer tomography were performed for five and two patients respectively and diagnosis was confirmed cystoscopically. endoscopic lithotripsy using holmium laser lithotripter or pneumatic lithotripter was used for all cases. the mean operation time was 41.2 minutes (20-70) and success was 100%. there was no intraoperative complication. only one patient had fever higher than 38ºc postoperatively and was treated by appropriate antibiotic. the median hospitalisation time was 1.57 day. conclusion: in conclusion endoscopic lithotripsy is a safe and effective approach to manage bladder stone associated with mid-urethral synthetic slings and intrauterine devices. key words: bladder stone; endoscopic cystolithotripsy; intrauterine device; mid urethral synthetic sling. submitted 17 september 2013; accepted 5 october 2013 summary introduction bladder stones (bs) are rare in women and consist 5% of all cases (1). generally stone formation in the bladder is no conflict of interest declared. related with an underlying pathology such as neurogenic bladder, pelvic organ prolapse or foreign bodies (2). benefits of intrauterin devices (iud) and mid-urethral synthetic slings (muss) were well described in contraception and stress urinary incontinence, respectively (3-4). migration of iud and muss into the bladder leads to dysuria, urgency, pelvic pain, recurrent urinary tract infection and bs (5). when bs occur, removal of bs and foreign body is mandatory. several authors have defined different approaches to solve this medico-legal problem. despite acceptable success rate of all techniques, open approaches as cystotomy and partial cystectomy are associated with new incision scar, painful post operative period and longer hospitalisation time when compared with endoscopic treatment modalities (6-7). in this paper we aim to present our experience about bs associated with iud and muss. materials and methods we conducted an observational study through chart review of patients who were treated for bs. from january 2006 to may 2013, eighteen patients were treated for bs in sultangazi goverment hospital and haseki training and research hospital. seven women had bs associated with iud or muss and were enrolled in the study. diagnosis was confirmed by imaging studies (ultrasonography or non-contrast enhanced computer tomography) and endoscopically. the operative procedure was similar for all patients. endoscopic cystolithotripsy was perfomed using holmium-yag laser or pneumatic lithotripter to expose iud or muss (figure 1). to disconnect the muss from the bladder wall, endoscopic scissors and transurethral resection (tur) with monopolar diathermy were used. when the foreign body was completely separated from the wall of the bladder, an endoscopic forcep was used to remove the iud or muss. patients’ age, main complaints, diagnosis method and time from surgery to diagnosis were evaluated. also operative time, treatment modality and lenght of hospitalization were analyzed. median diagnosis time was defined as the doi: 10.4081/aiua.2014.2.108 109archivio italiano di urologia e andrologia 2014; 86, 2 management of bladder stones associated with foreign bodies following incontinence and contraception surgery period from incontinence or contraception surgery to diagnosis of bs. all patients charts were rewieved by two author (fo and as). variables were defined before data collection. microsoft excel 2010 software (microsoft corporation, redmond, wa) was used for data entry. results demographic characteristics of the patients are presented in table 1. median age was 62 years. six patients had undergone stress incontinance surgery including tension free vaginal tape (tvt) and trans obturator tape (tot). one patients had an history of iud insertion (figure 2). all patients were symptomatic and had more than one complaint. main complaints were dysuria (85%), hematuria (57%) and recurrent urinart tract infection (uti) (57%). patients also reported urgency, frequency and pelvic pain. the median diagnosis time was 44.1 months (range from 9 to 218 months). pelvic x-ray was performed all patients. to evaluate upper urinary system and perivesical area abdominal ultrasonography was also performed in 5 patients and non contrast enhanced computer tomography was performed in other 2 patients (figure 3). median operative time was 41.2 minutes (range from 20 minutes to 70 minutes) and median hospitalisation time was 1.57 day (range from 1 day to 4 days). holmium laser was used in 3 cases and pneumatic lithotripter was used in 4 cases. there was no intra operative complication. post operative period was uneventfully for six patients. only one patient had fever > 38ºc on the first day of operation and ceftriaxone was started empirically at the dose of 2 g/day. in urine culture, ceftiraxone sensitive esbl producing escherichia coli was isolated. the patient was discharged at the 4th day after operation. in follow up, endoscopy was performed in six patients who underwent tur. cystoscopy revealed recovered bladder mucosa without protrusion of the tape into the bladder in each patient. recurrent stress urinary incontinence was developed in two patients but both of them refused new surgical manipulation. discussion bladder stones are uncommon in women and mostly result of pathological conditions such as neurogenic bladder, bladder diverticulum and foreign material. during storage of urine a foreign body is an ideal nidus for stone formation and encrustation by calcium oxalate. also infection in bladder accelerate the process (8). most of foreign bodies are related with complications of urogynecologic procedures. suture materials from bladder suspension procedures, sling procedures or iud insertion are the most common source of an intravesical foriegn body (9). insertion of muss or iud into the bladder leads to the development of significant symtomps and impact negatively on quality of life. dysuria, hematuria, urgency, frequency, resistant and recurrent uti are the most common symptoms (10). on the other hand stone formation requires time. it should be questioned why why the patients were not admitted to hospital despite they comfigure 1. bladder stone formed on tvt sling. pneumatic lithotripter was used to fragment the stone. figure 2. image of iud and fragmented stones after operation. endoscopic forceps was used to remove iud. figure 3. image of bladder stone at non-contrast enhanced computer tomography. archivio italiano di urologia e andrologia 2014; 86, 2 a. simsek, f. ozgor, m. fatih akbulut, e. sönmezay, b. yuksel, o. sarılar, a. yalcın berberoglu, z. gokhan gurbuz 110 plaints and why the diagnosis was so delayed. that may be explained by socio-cultural conditions of the country. all these symptoms are mostly considered as a natural sign of aging by patients. furthermore in rural areas its difficult to achieve health care and physicians tend to treat the symptoms without investigating underlying pathology. to prevent further complications, it is very important to recognize intraoperatively bladder injury during stress incontinance surgery. cystoscopy is a part of tvt procedure and the best method to evaluate the presence of bladder injury (11). nevertheless in this paper we present five cases who underwent tvt procedure. two hypothesis can explain the unfortunate event: sling mesh in the bladder was missed at cystoscopy or mesh was placed in the submucosal area close but outside to the bladder mucosa. experience of surgeon can affect recognizement of bladder injury at cystoscopy. to increase the accuracy of cystoscopy, bladder must be filled with at least 300 ml of fluid to have better vision and use of 7º or 12º optics allows a more extensive view (12). cystoscopy is not routinely performed after tot because of the low risk of bladder injury (13). tayrac et al. and abdel-fattah et al. found less than 1% incidence of lower urinary tract injury mostly associated with outin technique (14-15). due to longer operative time and requirement of endoscopic instruments, cystoscopic inspection after tot is not accepted by most surgeons. to avoid injury emptying the bladder completely is very important. we perform cystoscopy only if hematuria occurs intraoperatively or for persistance of irritative bladder symptoms. due to their safety and efficacy, iuds are the most preferred method of reversible contraception all over the world (16). however insertion of iud by paramedics and irregular followup evaluations can lead to serious complications such as uterine perforation (17). harrison et al. emphased on the experience of the surgeon to prevent uterine perforation (18). after perforation, iud could be found in any extrauterine location as rectum, omentum, peritoneum or wall of iliac vein but migration into the bladder is very rare (19-20). pathophysiology is still unknown but some authors believe that uterine and bladder contractions have a significant role in the migration of iud into the bladder. also uterin atrophy contributes to movement of iud (21). misplacement of iud can cause pain, bleeding and loss of its contraception ability. in our case, the patient was 32 years-old when the t-shape iud was placed. she had no pregnancies after insertion and symptoms were accepted as normal by the patient. treatment options are variable according to the experience of the physician and can be divided in open and endoscopic procedures. open cystotomy is an alternative for big and hard stones to shorten operation time. if the mesh or iud is very adherent and it is impossible to remove the foreign body from the bladder wall partial cystectomy may be performed (10). pikaart et al. performed laparoscopic stone removal by following the steps of open surgery (22). with the application of technological advances in medicine, endoscopic treatments is become equally effective and more comfortable than open surgeries. tyzortis et al. presented two case of bladder stone associated with tvt and both stones were treated endoscopically (23). also mustafa et al. used transurethral mesh resection and pneumotic lithotripsy for the same problem (24). feiner et al. used holmium laser to fragment bladder stones after tot procedure (25). endoscopic therapies are the first choice for us because most of bladder stones are easily fragmented. furthermore endoscopic manipulations are not affected from body mass index of the patient and by previous surgeries. in conclusion, misplacement of muss or iud into bladder during stress incontinance surgery or contraception surgery lead to several lower urinary tract symtomps. bladder stones are developed if the foreign material remains in the bladder. our experience with seven cases revealed that endoscopic lithotripsy using holmium laser and pneumotic lithotripter is a safe and effective method to manage these stones. references 1. stav k, dywer pl. urinary bladder stones in women. obstet gynecol surv. 2012; 67:715-25. 2. papatsoris ag, varkarakis i, dellis a, deliveliotis c. bladder lithiasis: from open surgery to lithotripsy. urol res. 2006; 34:163-7. 3. mwalwanda cs, black ki. immediate post-partum initiation of intrauterine contraception and implants: a review of the safety and guidelines for use. aust n z j obstet gynaecol. 2013; 53:331-7 4. ulmsten u, falconer c, johnson p, et al.. a multicenter study of tension-free vaginal tape (tvt) for surgical treatment of stress urinary incontinence. int urogynecol j pelvic floor dysfunct. 1998; 9:210-3. 5. tunn r, wildt b, rohne j, gauruder-burmester a. management of postoperative objectified intravesical position of the tvt tape two casereports. urologe a 2006; 45:347-50 6. irer b, aslan g, cimen s. development of vesical calculi following tension-free vaginal tape procedure. int urogynecol j pelvic floor dysfunct. 2005; 16:245-246. 7. minaglia s, ozel b, klutke c. bladder injury during transobturator sling. urology. 2004; 64:376-377. 8. chew r, thomas s, mantha ml, et al. large urate cystolith associated with proteus urinary tract infection. kidney int. 2012; 81:802-3. 9. peyromaure m, dayma t, zerbib m. development of a bladder stone following a tension-free vaginal tape intervention. j urol. 2004; 171:337. 10. deng dy, rutman m, raz s, rodriguez lv. presentation and management of major complications of midurethral slings: are complications under-reported? neurourol urodyn. 2007; 26:46-52. 11. gold rs, groutz a, pauzner d, et al. bladder perforation during tension-free vaginal tape surgery: does it matter? j reprod med. 2007; 52:616-8. 12. giri sk, drumm j, flood hd. endoscopic holmium laser excision of intravesical tension-free vaginal tape and polypropylene suture after anti-incontinence procedures. j urol. 2005; 174:13061307. 13. delorme e. transobturator urethral suspension: mini-invasive procedure in the treatment of stress urinary incontinence in women. prog urol. 2001; 11:1306-1313. 111archivio italiano di urologia e andrologia 2014; 86, 2 management of bladder stones associated with foreign bodies following incontinence and contraception surgery 14. detayrac r, deffieux x, droupy s, a prospective randomized trial comparing tension-free vaginal tape and transobturator suburethral tape for surgical treatment of stress urinary incontinence. am j obstet gynecol. 2004; 190:602-628. 15. abdel-fattah m, ramsay i, and pringle s. lower urinary tract injuries after transobturator tape insertion by different routes: a large retrospective study. bjog. 2006; 113:1377-1381. 16. xie zw, zhang yn, wan s, et al. levonorgestrel-releasing intrauterine device is an efficacious contraceptive for women with leiomyoma. j int med res. 2012; 40:1966-72. 17. ebel l, foneron a, troncoso l, et al. intrauterine device migration to the bladder: four case reports. actas urol esp. 2008; 32:530-532. 18. harrison-woolrych m, ashton j, coulter d. uterine perforation on intrauterine device insertion: is the incidence higher than previously reported? contraception. 2003; 67:53-56. 19. mosley fr, shahi n, kurer ma. elective surgical removal of migrated intrauterine contraceptive devices from within the peritoneal cavity: a comparison between open and laparoscopic removal jsls.. 2012; 16:236-41. 20. mccombie jj, le fur r. colonoscopic removal of an ectopic intrauterine device. anz j surg. 2012; 82:369-70. 21. atakan h, kaplan m, erturk e. intravesical migration of intrauterine device resulting in stone formation. urology. 2002; 60:911-913. 22. pikaart dp, miklos jr, moore rd. laparoscopic removal of pubovaginal polypropylene tension-free tape slings. jsls. 2006; 10:220-225 23. tzortzis v, mitsogiannis ic, moutzouris g. bladderstone formation after a tension-free vaginal tape procedure: reporton two cases. urol int. 2007; 79:181-182. 24. mustafa m, wadie bs. bladder erosion of tension-free vaginal tape presented as vesical stone; management and review of literature. int urol nephrol. 2007; 39:453-5. 25. feiner b, auslender r, mecz y, et al. removal of an eroded transobturator tape from the bladder using laser cystolithotripsy and cystoscopic resection. urol. 2009; 73:681.e15681.e16. correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com faruk ozgor, md mehmet fatih akbulut, md erkan sönmezay, md omer sarılar, md ahmet yalcın berberoglu, md zafer gokhan gurbuz, md haseki research and education hospital, department of urology, millet cad. no: 11 34000 fatih, istanbul, turkey bahar yuksel, md istanbul medical faculty, gynecology and obstetric department istanbul, turkey archivio italiano di urologia e andrologia 2016; 88, 3206 original paper telerounding & telementoring for urological procedures volkan sen, ozgu aydogdu, tarik yonguc, ibrahim halil bozkurt, deniz bolat izmir bozyaka training and research hospital, department of urology izmir, turkey. telemedicine is the use of medical information exchanged from one site to another via electronic communications to improve a patient’s clinical health status. telemedicine includes a growing variety of applications and services using two-way video, email, smart phones, wireless tools and other forms of telecommunications technology. starting out over forty years ago with demonstrations of hospitals extending care to patients in remote areas, the use of telemedicine has spread rapidly and is now becoming integrated into the ongoing operations of hospitals, specialty departments, home health agencies, private physician offices as well as consumer’s homes and workplaces. there’s also a current trend in the use of telemedicine in urology. in the present paper we aimed to review the recent literature about telemedicine and the use of telerounding and telementoring in urological procedures. key words: telemedicine; telementoring; telerounding. submitted 23 february 2016; accepted 3 march 2016 summary no conflict of interest declared. demonstrated high rates of patient satisfaction in telerounding arm (4). patients undergoing the following laparoscopic procedures were offered participation in this study: nephrectomy, partial nephrectomy, nephroureterectomy, retroperitoneal lymph node dissection, partial ureterectomy, and radical prostatectomy. forty-five percent of the patients assessed that their care was better because of telerounding, 67% said that it should be a regular part of patient care in the hospital, 86% could easily communicate with their doctor using the telerounding system, 76%, if hospitalized again, would feel comfortable with telerounding, and 67% claimed that if their doctor was out of town they would rather teleround with their doctor than be seen by another doctor. there were no significant differences in hospitalization time and complication rates between the two arms. kau et al. were evaluated the telerounding system by laptop computers with built-in webcam and video conferencing software in 2008 (5). ten physician, 14 nurses and 10 patients were included in the study; 90% of patients agreed that they could easily communicate with their physician using video-rounding system (vrs). all patients strongly agreed that vrs should be a regular part of patient care and that they would be comfortable using vrs if their physician was unable to be in direct contact with them. all physicians and nurses agreed that vrs was easy to use, enhanced patient care, would be a comfortable alternative if direct physician contact was not possible, and that it should be a regular part of institutional care. with the technological developments, the tablets had begun to be used for telerounding. kaczmarek et al. reported the first study with tablet telerounding in 2012 (6). totally 32 postoperative patients (25 robotic partial nephrectomy, 2 radical nephrectomy, 3 robotic-assisted radical prostatectomy, 1 adrenalectomy and 1 nephroure terectomy) were evaluated in this study. patients expressed a high level of satisfaction with 91% of patients stating that their care was better using telerounding and 97% of patients stating that telerounding should be a regular part of patient care in the hospital. additionally, 94% of patients stated that they could easily communicate with their doctor over the telerounding system, 84% of patients agreed that they would feel comfortable with telerounding daily if they were hospitalized again and 81% of patients would prefer telerounding communication with their doctor than be directly seen by another doctor. the results of the telerounding studies were summarized in table 1. by the technological developments, telerounding systems have become more cost-effective and more available and afforddoi: 10.4081/aiua.2016.3.206 introduction telemedicine had come to the fore with the report by aronson sh at 1977 about telephone using (1). subsequent studies about telemedicine were performed on e-mail (2, 3). johansen ma et al. investigated whether the parents of burns patients could capture suitable clinical images with a digital camera and add the necessary text information to enable the pediatric burns team to provide follow-up care via email and they suggested that this technique could be used as a low-cost telemedicine service in burns follow-up (2). telerounding is described as remote patient rounding by using computers, laptops, cameras and tablets. it was firstly reported in 2004 by ellison et al. using a computer with a camera for telerounding installed on a remotely controlled custom service robot platform with 85 patients (3). they emphasized that the patients in the telerounding arm demonstrated statistically substantial improvements in ratings of examination thoroughness, quality of discussions about medical information, postoperative care coordination, and attending physician availability. further trials supported the findings of these studies and telemedicine has been also widely used in urology clinics (4-6). the recent paper focused on the use of telemedicine in urology practice. telerounding in urology in 2007 a large multi-institutional randomized study by ellison et al., included 270 patients; 134 in the robotic telerounding arm and 136 patients in bedside round arm, sen_stesura seveso 21/09/16 08:55 pagina 206 207archivio italiano di urologia e andrologia 2016; 88, 3 telerounding & telementoring in urology able. in recent years especially the tablets has an advantage of lower purchase cost, widespread availability, uncomplicated setup. increased device portability inherent to its light weight and small size allows the device to be easily carried between floors and clinical locations. the increased patients’ satisfaction in kaczmarek’s study could be explained by these reasons. these studies showed us the telerounding system has potential benefit for the physician as well as the patient. doctors can gain convenience and flexibility with the potential for overseeing more patients. the average time of about 5 minutes is enough to facilitate communication and patient satisfaction. but we wish to emphasize that any telerounding systems could not replace the bedside rounding, they should be only an additional visits for bedsides rounds. telementoring in urology advances in technology have opened new avenues for long-distance communication through telemedicine. with this technology, an expert surgeon can observe and actively supervise a procedure performed by a trainee surgeon at another institution. telementoring is an application of telemedicine that involves the remote guidance of procedures when the operator has limited experience with the technique. the first instances of transcontinental urologic telesurgery performed using the da vinci system was reported by sterbis et al. in porcine model at 2007 (7). nephrectomy was successfully performed in 4 animals without any complication. robot-assisted radical prostatectomy (rarp) has a long learning curve. in recent studies this curve was reported in experienced open surgeons as 8 to 20 operations (8-10). this curve is higher in trainee surgeons therefore mentoring of trainee surgeons has become more important to ensure that they attain sufficient skill without compromising the safety of their initial patients. mentoring is usually done face-to-face, which presents practical difficulties when the mentor and trainee belong to different institutions. a telementoring system for robot-assisted surgery was firstly tested by hinata et al. in 30 patients which avoids expensive and time-consuming travel by mentors (11). they found that the perioperative outcome of rarp performed with telementoring was not inferior to direct mentoring. conclusion these studies showed us that the telerounding system has potential benefit for the physician as well as the patient. doctors can gain convenience and flexibility with the potential for overseeing more patients. however we wish to emphasize that any telerounding system could not replace the bedside rounding, but they should be only additional visits to bedsides rounds. the telementoring system for urological procedures seems to be reliable and feasible, however further comprehensive studies including larger patient cohorts are needed. references 1. aronson sh. the lancet on the telephone 1876-1975. med hist. 1977; 21:69-87. 2. johansen ma, wootton r, kimble r, et al. a feasibility study of email communication between the patient’s family and the specialist burns team. j telemed telecare 2004; 10 suppl 1:53-56. 3. ellison lm, pinto pa, kim f, et al. telerounding and patient satisfaction after surgery. j am coll surg. 2004; 199:523-530. 4. ellison lm, nguyen m, fabrizio md, et al. postoperative robotic telerounding: a multicenter randomized assessment of patient outcomes and satisfaction. arch surg. 2007; 142:1177-1181. 5. kau el, baranda dt, hain p, et al. video rounding system: a pilot study in patient care. j endourol. 2008; 22:1179-82. 6. kaczmarek bf, trinh qd, menon m, et al. tablet telerounding. urology 2012; 80:1383-8. 7. sterbis jr, hanly ej, herman bc, et al. transcontinental telesurgical nephrectomy using the da vinci robot in a porcine model. urology 2008; 71:971-3. 8. ahlering te, skarecky a, lee d, et al. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003; 170:1738-41. 9. patel vr, tully as, holmes r, et al. robotic radical prostatectomy in the community setting the learning curve and beyond: initial 200 cases. j urol. 2005; 174:269-72. 10. menon m, shrivastava a, kaul s, et al. vattikuti institute prostatectomy: contemporary technique and analysis of results. eur urol. 2007; 51:648-57. 11. hinata n, miyake h, kurahashi t, et al. novel telementoring system for robot-assisted radical prostatectomy: impact on the learning curve. urology 2014; 83:1088-92. ellison et al, 2004 ellison et al, 2007 kau et al, 2008 kaczmarek et al, 2012 number of patients 85 270 10 32 rate of patients who assessed that their care was better because of telerounding 42.4%* 45% 60% 91% rate of patients who said that it should be a regular part of patient care in the hospital 76.9% 67% 100% 97% rate of patients who could easily communicate with their doctor using the telerounding system 80.8% 86% 90% 94% rate of patients who, if hospitalized again, would feel comfortable with telerounding 66,6% 76% 84% rate of patients who claimed that if their doctor was out of town they would rather teleround with their doctor than be seen by another doctor 19.2%** 67% 100% 81% *: 53.9% patients answered this queston as ‘not sure’. table 1. summary of studies for telerounding systems. correspondence volkan sen, md (corresponding author) sen_volkan@yahoo.com ozgu aydogdu, md ozgucan@yahoo.com tarik yonguc, md tyonguc@gmail.com ibrahim halil bozkurt, md ihalilbozkurt@yahoo.com deniz bolat, md drbolat@hotmail.com department of urology, izmir bozyaka training and research hospital, izmir, turkey sen_stesura seveso 21/09/16 08:55 pagina 207 stesura seveso 7archivio italiano di urologia e andrologia 2016; 88, 1 original paper renal colic, where is it headed? an observational study paolo beltrami 1, andrea guttilla 1, lorenzo ruggera 2, patrizia bernich 3, filiberto zattoni 1 1 urology clinic, department of surgical, oncological and gastroenterological sciences, university of padova, padova, italy; 2 department of urology, s. maria degli angeli hospital, pordenone, italy; 3 department of nephrology, university of verona, verona, italy. aim: in the last thirty years, the treatment for renal and ureteral calculi has undergone profound variations. the objective of this study has been to evaluate the existence of parameters which can affect the spontaneous expulsion of a symptomatic ureteral stone in a reasonably brief period of time and to identify whether certain parameters such as sex, age, the location and dimension of the stone, the presence of dilation in the urinary tract together with the administered therapy, can be used for a correct clinical management of the patient. methods: in a period of 9 months, 486 cases of renal colic were registered at emergency department. results: the cases of renal colic due to ureteral calculus were 188 (38.7%). the patients’ charts, complete of all data and therefore, valid for this research, resulted to be 120 (64%). in the presence of a symptomatic ureteral stone, the correct approach must first of all, focalize on the dimension of the calculus itself; less importance instead, is given to the location, as reported in other studies, the presence of hydroureteronephrosis, sex and the side. conclusion: in the cases when the pain symptoms cannot be solved by means of the administration of analgesics, it is then reasonable to take into consideration an immediate endourological treatment. if the pain symptoms are promptly solved, an attentive wait of 4 weeks should be considered reasonable in order to allow spontaneous expulsion of the calculus. key words: renal colic; emergency treatment; stones; ureteroscopy; swl. submitted 25 april 2015; accepted 8 september 2015 summary no conflict of interest declared. would require frequent administration of analgesic and antispasmodic drugs, and often lead to the need of accessing emergency rooms. thus, the requirement on behalf of the patient is an immediate remedy and above all, a resolving one. after all, a long wait in the case of an urinary tract obstruction can damage the renal function thus, an immediate remedy is highly important (13, 14). the objective of this study has been to evaluate the existence of parameters which can affect the spontaneous expulsion of a symptomatic ureteral stone in a reasonably brief period of time so as not to damage the renal function and not to create an excessive discomfort in the patient due to the relapse of the symptoms. another objective has been to identify whether certain parameters such as sex, age, the location and dimension of the stone, the presence of dilation in the urinary tract together with the administered therapy, can be used for a correct clinical management of the patient. in the case of favorable parameters, to then consider whether reasonable, keeping the subject under observation while waiting for a spontaneous expulsion, or otherwise, to perform an immediate treatment or to defer it in a short time span. materials and methods in this observational study, emergency patients for renal colic were taken into consideration and then, only those in who a ureteral calculus was documentable at the moment of the imaging investigations, were evaluated, complete of an abdominal-pelvic ultrasonography (us), kidney, ureter, and bladder plain x-ray (kub), and in some cases, a computerized tomography (ct). in a period of 9 months, 486 cases of renal colic were registered at emergency department out of a total 41,796 accesses to the same (1.2%). the cases of renal colic due to ureteral calculus were 188 (38.7%). of each patient, the following aspects were evaluated: sex, age, the date of access to the emergency room, the emergency examinations carried out, the side of the stone, the location in the ureter, the dimension of the calculus (major and minor diameter), the radio-opacity, the presence of dilation in the urinary tract, the administered therapy, the results of the specialist’s examinations together with the treatment carried out. patients who required hospitalization, because presenting a concomitant, clinical situation such as urosepsis, acute doi: 10.4081/aiua.2016.1.7 introduction in the last thirty years, the treatment for renal and ureteral calculi has undergone profound variations, because of the development of extracorporeal lithotripsy, followed by the improvement of endourological instruments which have allowed to access the excretory cavities in a retrograde manner and have proved to be safe and effective (1-10). the “mini-invasive” therapies have even changed treatment indications of small sized stones, which apparently could be expelled spontaneously (11, 12). in fact, a patient affected by renal/ureteral calculi is not always likely to undergo a spontaneous expulsion, which could be achieved by means of relapsing colic that beltrami_stesura seveso 08/04/16 11:23 pagina 7 archivio italiano di urologia e andrologia 2016; 88, 1 p. beltrami, a. guttilla, l. ruggera, p. bernich, f. zattoni 8 renal failure and documented, perirenal fluid collection, were excluded. in patients who went through spontaneous expulsion, the same investigations that lead to the diagnosis were prescribed, so as to verify the complete expulsion and, analogously, for the treated patients, so as to confirm the therapy result. the patients’ charts, complete of all data and therefore, valid for this research, resulted to be 120 (64%). the data was inserted in a database created by means of excel. the non parametric values were considered in terms of the average ± standard deviation (sd) and the median one with an interquartile range (i.r.). the statistical analysis was carried out by means of spss software (statistical package for social sciences, version 12.0) using the t-student test in order to compare the average age between males and females, the mann-whitney test as to confront the major and minor diameter of the calculi, stratified on the basis of colic resolution and on the spontaneous expulsion, together with the chi-squared test for the comparison of the categorical variables taken into consideration. a value of p < 0.05 was considered significant (two-tailed test). results table 1 relates the general characteristics of the population. as concerns the characteristics of the calculi (table 2), no significant difference was found regarding the side (46.7% on the right and 53.3% on the left). in 8 cases, the calculus was localized at the pelvis or at the ureteropelvic junction, in 42 cases (35%), at the proximal ureter, in 36 (30%), at the mid ureter, in 13 (10.8%), at the distal ureter and in 21 (17.5%), at the terminal ureter. the average sizes were of 6.5 mm (range 115) as regards the major diameter and of 4.3 mm (range 1-10) as regards the minor one. 85.8% (103/120) of the calculi turned out to be radiopaque, while 8.4% (10/120) were poor radiopaque and 5.8% (7/120) were completely radiolucent. in 65.8% (79/120) of cases, dilation of the upper urinary tract was present. patients were treated with a single drug in 67.5% of cases (81/120) thus resolving the pain symptoms. in 32.5% (39/120) of cases, multiple drugs were administered. in 18 cases (15%), the symptoms could not be resolved, which lead to necessary hospitalization, while 102 patients were released from the hospital thanks to a pharmacologic treatment based on the administration of analgesics together with anti-inflammatory drugs, and in 40.2% of cases (41/102), an alpha-blocker was added. the statistical analysis was carried out on 119 patients instead of 120 due to one case of pregnancy, which required a different treatment compared to the traditionally used ones. from the analysis of the data, no significant differences came out between the dimensions of the calculus and the result of the colic, thus confirming the impression that the pain symptoms are independent from the size of the calculus (mann whitney test: p = ns) (figure 1). no significant statistical differences were noted neither between the n° of patients (%) 120 • male 88 (73.3%) • female 31 (26.6%) mean age years (range) 46.6 (21-85) • male 47.2 (24-85) • female 45.2 (21-77) colics n° (%) • first episode 55 (45.8%) • recurrence 65 (54.2%) imaging n° (%) • kub + us 104 (86.7%) • us 10 (8.3%) • ct 6 (5%) laterality of stone n° (%) 120 • right 56 (46.7%) • left 64 (53.3%) location of stone n° (%) • renal pelvis 3 (2.5%) • ureteropelvic junction 5 (4.2%) • proximal ureter 42 (35%) • mid ureter 36 (30%) • distal ureter 13 (10.8%) • terminal ureter 21 (17.5%) stone size mean mm (range) • major diameter 6.5 (1-15) • minor diameter 4.3 (1-10) radiopacity n° (range) • radiopaque 103 (85.5%) • poor radiopaque 10 (8.4%) • radiolucent 7 (5.7%) table 2. characteristics of the stones. table 1. demographics. figure 1. comparison between major (a) and minor (b) diameter (mean mm) of stones and outcome of renal colic (mann whitney test: p = ns). beltrami_stesura seveso 08/04/16 11:23 pagina 8 9archivio italiano di urologia e andrologia 2016; 88, 1 renal colic, where is it headed? an observational study location of the calculus and the relief from the pain symptoms, nor between the presence of hydroureteronephrosis and the relief from the pain symptoms (chi-square test: p = ns) (tables 3, 4). however, a statistically significant difference did appear between the emergency symptomatic treatment carried out and the breakdown of the colic (chi-square test: p ≤ 0.01). as a matter of fact, the patients who responded quickly to the administration of a single drug had a stronger possibility of long-lasting pain relief and fewer possibilities of hospitalization when compared to those who had undergone a multiple, pharmacological therapy (table 5). during the period of this research, 60.8% (73/120) of patients had spontaneously expelled the calculus responsible for the colic, in a time period ranging up to 4 weeks. in 14 cases (11.7%), emergency treatment with retrograde ureteroscopy (urs) was carried out with a complete resolution in all cases. for other 33 patients (27.5%), a deferred treatment was planned and then carried out: in 12 cases extracorporeal lithotripsy (swl) was done and its outcomes proved to resolve 10 cases (83.3%), while in other 21 cases, lithotripsy by ureteroscopy cured all cases (100%) (table 6). regarding the possibilities of spontaneous expulsion on the basis of sex, side and location of lithiasis (chi-square test; p = ns) (table 7), no relevant differences were observed. not even the presence of hydroureteronephrosis seems to have any effect on the probabilities of spontaneous expulsion (chi-square test; p = ns) (table 8). on the contrary of what has been reported in literature, in our casuistry, we were not able to statistically verify any significant differences between the various types of analgesic-antispasmodic treatments, which had been administered to the discharged patient, and the spontaneous expulsion of the calculus itself (chi-square test; p = ns) (table 9) (15-18). resolution of colic total yes hospitalization location pelvis 2 1 3 upj 3 2 5 proximal 36 6 42 mid 34 2 36 lower 12 1 13 terminal 15 5 20 total 102 17 119 table 3. comparison between location of the stone and resolution of colic (chi-square test: p = 0.147 ns). hydroureteronephrosis resolution of colic total yes hospitalization absent 35 5 40 present 67 12 79 total 102 17 119 table 4. comparison between hydroureteronephrosis and resolution of colic (chi-square test: p = 0.692 ns). medical therapy resolution of colic total diclofenac 5 0 5 ketorolac 49 4 53 other nsaid 17 1 18 antispasmodics 5 0 5 multiple drugs * 26 12 38 total 102 17 119 table 5. comparison between medical therapy and resolution of colic (chi-square test: * p = 0.007). stone expulsion total yes no location pelvis 1 2 3 upj 1 4 5 proximal 23 19 42 mid 25 11 36 distal 7 6 13 terminal 16 5 21 total 73 47 120 table 7. comparison between spontaneous stone expulsion and location of stones (chi-square test: p = 0.128 ns). hydroureteronephrosis stone expulsion total yes no absent 23 18 41 present 50 29 79 total 73 47 120 table 8. comparison between spontaneous stone expulsion and hydroureteronephrosis (chi-square test: p = 0.444 ns). home therapy stone expulsion total yes no flavoxate 9 8 17 other antispasmodics 1 1 2 α-blockers 7 7 14 nsaid 35 24 59 flavoxate + α-blocker 20 7 27 total 72 47 119 table 9. comparison between spontaneous stone expulsion of stones and home therapy (chi-square test: p = 0.515 ns). n° (%) resolution n° (%) spontaneous stone expulsion 73 (60.8%) immediate treatment (urs) 14 (11.7%) 14 (100%) elective treatment 33 (27.5%) • eswl 12 10 (83.5%) • urs 21 21 (100%) table 6. outcome of colics. beltrami_stesura seveso 08/04/16 11:23 pagina 9 archivio italiano di urologia e andrologia 2016; 88, 1 p. beltrami, a. guttilla, l. ruggera, p. bernich, f. zattoni 10 we noticed that the only parameter which seemed to be statistically significant, was the one relative to the size of the calculus. it must be pointed out that both the major and minor diameter had a strong impact on the probability of spontaneous expulsion of the calculus (figure 2). as concerns the chemical composition of the calculi, the statistical analysis underlined significant differences regarding the spontaneous expulsion between pure and mixed calculi (chi-square test; p < 0.01) (table 10). in particular, spontaneous expulsion proved to be more probable for mixed calculi of oxalate and calcium phosphate when compared to pure calculi of calcium oxalate and of uric acid. however, we believe that this result cannot be sufficiently representative due to the reduced sample size, which did not allow the evaluation of other parameter, and that is, by stratifying it even on the basis of size of the stone. it is known, in fact, that uric acid calculi are susceptible to litholytic therapy by means of allopurinol and urine alkalinization. the use of these drugs often permits to reduce the size of the uric acid calculi to such a point as to allow them to undergo spontaneous expulsion and sometimes, even the complete dissolution (19, 20). discussion urinary calculi constitute a relatively frequent pathology and 5% of the population is affected. renal colic represents the characteristic case history of the commitment of the stone as it goes down the urinary tract. as a matter of fact, it usually determines severe discomfort in the patient compelling the same to access the emergency room quite frequently. the lack of a clear and precise therapeutic plan may lead to further discomforts for the patient and furthermore, the increase of costs (21-23), considering that the risk of having renal colic, at least once in a lifetime, ranges between 8-15% (24, 25). clear and precise guidelines regarding the management of a patient with renal colic do not exist. concerning the diagnosis, several studies have reported that ct proves to be the method with the highest levels of sensitivity and specificity in the diagnostic procedures for renal colic. however, ct is not always possible in emergency situations therefore, in the majority of cases, the clinical diagnosis is frequently confirmed by means of a plain radiography of the abdomen, together with an abdominal ultrasonography, which are not always sufficient to correctly plan further procedures. on the other hand, the increase of ct use in patients with renal colic has not determined a corresponding, diagnostic increase of nephrolithiasis, which accounts for 20% of renal colic cases. thus, it must be underlined that an extensive use of ct does increase the costs together with the risks related to radiological exposition (26). once established that the cause of renal colic is the presence of a ureteral calculus, a further procedure to follow must still be chosen. dimension, location and form of a calculus have so far been considered as the determinant factors that mainly affect the decision relative to an active treatment of stones. the possibility of spontaneous expulsion, which occurs in 80% of cases for calculi with < 4 mm diameter, is reduced to 10%-53% in the presence of calculi ranging from 6-10 mm. the diagnosis of a ureteral calculus of a > 7 mm diameter instead, suggest an active treatment (27, 28). discharge of the patient with a prescription for an medical expulsive therapy is only possible in the case of complete resolution of the symptoms, if necessary with a prescription for an α-blocker therapy in the cases of distal ureter calculi, although many authors sustain that the α-blockers facilitates spontaneous expulsion above all (29-32). forced hydration has proved not to be more effective than normal hydration and, on the contrary, it does not seem to affect spontaneous expulsion at all (33). at the present, the therapeutic options regarding ureteral calculi include extracorporeal litho tripsy, ureteroscopic lithotripsy and surgical intervention meaning, laparoscopic ureterolithotostone composition stone expulsion total yes no ca-ox 7 16 23 ca-ox + ca-p* 42 15 57 ca-ox + ua 12 8 20 ua 3 5 8 nr 9 3 12 total 73 47 120 table 10. comparison between spontaneous stone expulsion and stone composition (ca-ox: calcium oxalate; ca-ox + ca-p: calcium oxalate + calcium phosphates; ca-ox + ua: calcium oxalate + uric acid; ua: uric acid; nr: not reported) (chi-square test: * p = 0.003). figure 1. comparison between major (a) and minor (b) diameter (mean mm) of stones and outcome of renal colic (mann whitney test: p = ns). beltrami_stesura seveso 08/04/16 11:23 pagina 10 11archivio italiano di urologia e andrologia 2016; 88, 1 renal colic, where is it headed? an observational study my. although, swl seems to be less effective than other techniques, it is nevertheless, considered as first choice therapy for calculi found at the proximal ureter, while its role, in the cases of calculi in the mid and lower ureter, still remains controversial (34-36). ureteroscopic lithotripsy is carried out extensively in the treatment of ureteral calculi with an effectiveness that exceeds 90% and furthermore, with a low incidence of complications (4, 37); as concerns surgical intervention, whether it is traditional or carried out by means of the laparoscopic procedure, it currently represents a therapeutic option that can only be recommended in selected cases (38-40). from the observational analysis about our series, regarding the spontaneous expulsion of the calculus, we can notice that the only valid and statistically relevant parameter proved to be the diameter of the calculus itself. both the major and minor diameter play an important role, meaning that even calculi with a small, transverse diameter may be difficult to expel if their major diameter is big (for example, long and thin calculi). other interesting data emerges from clinical cases where symptoms were resolved with the use of a single drug and no immediate hospitalization was needed. in these cases, if the patients had not spontaneously expelled the calculus in the following days after medical expulsive therapy, they would be treated with a planned elective treatment. as regards the patients in whose symptoms could not be solved by means of the administration of analgesics, relapsing colic was frequent, to the point of requiring hospitalization and emergency treatment. the emergency treatment chosen and carried out by us, was always ureterorenoscopy. although in literature, many studies have indicated extracorporeal lithotripsy as a possible and valid, urgency treatment, according to our experience, the limited results obtained by means of swl, do not justify the use of such option in emergency cases. in fact, subjects who suffer of relapsing renal colic, do not accept that a less invasive treatment such as swl, which actually ensures favorable results in only 60% of cases, could be associated with a further elevated incidence of colic during the expulsion of the fragments (41-44). thus, this study seems to confirm the validity of our choice treatment in the case of renal colic, meaning an immediate ureteroscopic lithotripsy when painful symptoms are present and cannot be solved by means of an analgesic-antispasmodic therapy. in patients in who the renal colic is solved, a wait of 4 weeks would be reasonable in order to safeguard the renal function. during these 4 weeks, it would thus be possible to plan for an elective treatment, if spontaneous expulsion of the calculus should not take place. the planned therapy, in these cases, could be an extracorporeal lithotripsy or an endourological one, according to the location and the dimension of the calculus together with the characteristics of the urinary tract. conclusions to conclude, in the presence of a symptomatic ureteral stone, the correct approach must first of all, focalize on the dimension of the calculus itself; less importance instead, should be given to the location, as reported in other studies, presence of hydroureteronephrosis, sex and the side. in the cases when the pain symptoms cannot be solved by means of the administration of analgesics, it is then reasonable to take into consideration an immediate endourological treatment, in relation to the choice of patient. if the pain symptoms are promptly solved, an attentive wait of 4 weeks should be considered reasonable in order to allow spontaneous expulsion of the calculus, hence, without excessively compromising the renal function and/or to program an elective treatment with of an endourological approach or of extracorporeal lithotripsy. acknowledgements sincerely thanks to prof. dunya bernardon for grammatical editing of the manuscript. references 1. chaussy c, schmiedt e, jocham d, et al. first clinical experience with extracorporeally induced destruction of kidney stones by shock waves. j urol. 1982; 127:417-420. 2. rassweiler jj, renner c, chaussy c, thüroff s. treatment of renal stones by extracorporeal shockwave lithotripsy: an update. eur urol. 2001; 39:187-199. 3. galvin dj, pearle ms. the contemporary 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johnson eb, monga m. emergency room management of ureteral calculi: current practices. j endourol. 2009; 23:1021-1024. 22. sterrett sp, moore nw, nakada sy. emergency room follow-up trends in urolithiasis: single-center report. urology. 2009; 73:11951197. 23. turkcuer i, serinken m, karcioglu o, et al. hospital cost analysis of management of patients with renal colic in the emergency department. urol res. 2010; 38:29-33. 24. tiselius hg. epidemiology and medical management of stone disease. bju int. 2003; 91:758-767. 25. amato m, lusini ml, nelli f. epidemiology of nephrolithiasis today. urol int. 2004; 72:1-5. 26. hyams es, korley fk, pham jc, matlaga br. trends in imaging use during the emergency department evaluation of flank pain. j urol. 2011; 186:2270-2274. 27. sandegard e. prognosis of stone in the ureter. acta chir scand suppl. 1956; 219:1-67. 28. masarani m, dinneen m. ureteric colic: new trends in diagnosis and treatment. postgrad med j. 2007; 83:469-472. 29. yilmaz e, batislam e, basar mm, et al. the comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010-2012. 30. hollingsworth jm, rogers ma, kaufman sr, et al medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 2006; 368:1171-1179. 31. beach ma, mauro ls. pharmacologic expulsive treatment of ureteral calculi. ann pharmacother. 2006; 40:1361-1368. 32. sterrett sp, nakada sy. medical expulsive therapy. curr opin urol. 2008; 18:210-213. 33. springhart wp, marguet cg, sur rl, et al. forced versus minimal intravenous hydration in the management of acute renal colic: a randomized trial. j endourol. 2006; 20:713-716. 34. lam js, greene td, gupta m. treatment of proximal ureteral calculi: holmium:yag laser ureterolithotripsy versus extracorporeal shock wave lithotripsy. j urol. 2002; 167:1972-1976. 35. ziaee sa, basiri a, nadjafi-semnani m, et al. extracorporeal shock wave lithotripsy and transureteral lithotripsy in the treatment of impacted lower ureteral calculi. urol j. 2006; 3:75-78. 36. kijvikai k, haleblian ge, preminger gm, de la rosette j. shock wave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an old discussion revisited. j urol. 2007; 178:11571163. 37. zattoni f. ureteroscopy. complications. in: smith ad et al (ed): smith’s textbook of endourology, london, bc decker inc, 2006. chapter 36, pp 295-303. 38. kane cj, bolton dm, stoller ml. current indications for open stone surgery in an endourological centre. urology. 1995; 45:218-221. 39. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. laparoscopic ureterolithotomy: technical considerations and long term follow up. bju int. 2002; 89:339-343. 40. kijvikai k, patcharatrakul s. laparoscopic ureterolithotomy: its role and some controversial technical considerations. int j urol. 2006; 13:206-210. 41. ghoneim ia, el-ghoneimy mn, el-naggar ae, et al. extracorporeal shock wave lithotripsy in impacted upper ureteral stones: a prospective randomized comparison between stented and non-stented techniques. urology. 2010; 75:45-50. 42. argyropoulos an, tolley da. failure after shockwave lithotripsy: is outcome machine dependent? int j clin pract. 2009; 63:14891493. 43. guercio s, ambu a, mangione f, et al. randomized prospective trial comparing immediate versus delayed ureteroscopy for patients with ureteral calculi and normal renal function who present to the emergency department. j endourol. 2011; 25:1137-1141. 44. yang s, qian h, song c, et al. emergency ureteroscopic treatment for upper urinary tract calculi obstruction associated with acute renal failure: feasible or not? j endourol. 2010; 24:1721-1724. correspondence paolo beltrami, md paolo.beltrami@sanita.padova.it andrea guttilla, md filiberto zattoni, md endourology unit, urology clinic, department of surgical oncological and gastroenterological sciences, university of padua via giustiniani, 2 35128 padova, italy lorenzo ruggera, md department of urology, s. maria degli angeli hospital, pordenone, italy patrizia bernich, md department of nephrology, university of verona, verona, italy beltrami_stesura seveso 08/04/16 11:23 pagina 12 7archivio italiano di urologia e andrologia 2017; 89, 1 original paper tadalafil once daily: narrative review of a treatment option for female sexual dysfunctions (fsd) in midlife and older women chiara borghi 1, lucio dell’atti 2 1 department of morphology, surgery and experimental medicine, institute of obstetrics and gynecology, university of ferrara, italy; 2 department of urology, s. anna university hospital, ferrara, italy. female sexual disorders (fsd) include a complex, multidimensional, individual experience that can change as an individual age, suggesting that these problems are caused by multiple factors including psychosocial factors, personal relationships, pathologic changes caused by diseases, and pharmacologic influences. menopause is an important time for middle aged women and postmenopausal physiological changes could have a significant role in the development of fsd. few is still known about their correct definition and treatment. their incidence, prevalence and risk factors are difficult to define because of a high level of overlap in the experience of problems with desire, arousal, and orgasm. little evidences are known about the best therapeutic approach, and both non-pharmacological and pharmacological treatment options have been described. among these, phosphodiesterase type 5 inhibitors could be an effective option for many subtypes of female sexual disorders, with an improvement in different aspects of sexual function, such as desire, arousal, orgasm and sexual satisfaction. in this paper authors reviewed what is already known about the use of these vasoactive agents, particularly tadalafil, as a treatment option for female sexual disturbances. key words: female sexual disorders; phosphodiesterase type 5 inhibitors; tadalafil; women. submitted 31 august 2016; accepted 24 december 2016 summary no conflict of interest declared. changes could have a significant role in the development of fsd. nevertheless, despite an increased awareness of its pathophysiology, studies didn’t find an agreement on what is the best therapeutic approach and currently there are no drugs approved for most of the complaints (3). phosphodiesterase type 5 inhibitors (pde5i) have been widely used for the treatment of male sexual dysfunction (4). in this paper authors review the current literature on fsd and analyse pde5i, particularly tadalafil, as a treatment option for this health issue. current knowledge of female sexual dysfunction the concept of fsd comprises a wide range of disorders, whose definition has undergone numerous changes and classifications in the past. different definitions included hypoactive sexual desire, impaired subjective or physical genital arousal, sexual pain and inability to achieve orgasm, which are multidimensional issues, often coexisting. the most frequently used classification systems are the international classification of diseases, 10th edition (icd-10) by the who (5) and the diagnostic and statistical manual of mental disorder, fifth edition (dsm-5) by the american psychiatric association (6). the former subdivides the disorders as organic or non organic. for female, organic disorders include vaginismus and dyspareunia of organic aetiology. non organic female sexual dysfunctions include lack of sexual desire, sexual aversion or lack of sexual enjoyment, failure of genital response, orgasmic dysfunction, non-organic vaginismus, non-organic dyspareunia, excessive sexual drive and two non-specific codes. these causes are summarized in table 1. the latter, introduced in 2013, defines the most prevalent subcategory of fsd with a global approach, namely female sexual interest/arousal disorders. the second group is called female orgasmic disorder, which includes marked delay in, marked infrequency of, or absence of orgasm and decreased intensity of orgasmic sensations. the other important branch of sexual pain disorders (vaginismus and dyspareunia) is also renamed into genito-pelvic pain/penetration disorders. according to this classification system, the diagnosis of a sexual dysfunction (except substance/medication-induced sexual dysfunction) requires a duration of symptoms of at least six months and an occurdoi: 10.4081/aiua.2017.1.7 introduction sexual and reproductive health and well-being are essential to guarantee responsible, safe and satisfying sexual lives, thus requiring an understanding of the complex factors that regulate human sexual behaviour. according to the world health organization (who) revised definition, sexual health is a state of physical, emotional, mental, and social wellbeing, underpinned by human rights, in relation to sexuality (1, 2). female sexual dysfunctions (fsd) are high prevalent, age-related and progressive problems, whose definition is complicated, and significantly less is understood in comparison to male sexual dysfunction. the sexual response cycle in women is done by complex interactions, psychological, social and biologic factors (hormonal, vascular and neuromuscular). menopause is an important time for middle aged women and postmenopausal physiological borghi_stesura seveso 04/04/17 09:03 pagina 7 archivio italiano di urologia e andrologia 2017; 89, 1 c. borghi, l. dell’atti 8 rence in approximately 75% of sexual occasions. the classification of fsd according to dsm-5 is summarised in table 2. further sub-classification includes lifelong versus acquired and generalized versus situational types (6). the literature on the incidence, prevalence and risk factors for female sexual dysfunction indicates a high level of overlap in the experience of problems with desire, arousal, and orgasm for women. because of these wide features, there are inherent difficulties in collection of data for epidemiological studies that can be significantly linked to clinically based definitions and classifications. furthermore, the lacking available literature is influenced by difficulties in comparing findings that include different recording systems and characteristics of the involved population in terms of age, cultural and socioeconomic background (7, 8). however, the most important epidemiological studies in the past found that fsd is considered a major complaint among women, involving approximately 43% of female population worldwide (9). its incidence ranges from 5.8% to 45% in different studies and percentages are higher in older women subgroups (20% in women younger than 25 and 70-80% in women aged between 55 and 74). the most common dysfunction is hypoactive sexual desire (25-45%), followed by low arousal (11-26%) and orgasm difficulties (11-21%). lower percentages of women reported combined symptoms. noticeably, females report sexual disorders more frequently than men (43% versus 31%) (8, 10). the prevalence (proportion of a given population that at a given time has a particular condition) of fsd also varies widely according to different age groups and countries. low sexual interest and desire involves percentages ranging from 17 to 55% of women younger than 59, and from 17 to 34% of women aged 40 to 80. more recent studies report an overall prevalence rate of 40-50% among women older than 65. epidemiologic data report considerable differences also regarding prevalence of lubrication and arousal dysfunction (12-41.9%), orgasmic dysfunction (11-72%) and genito-pelvic pain (1-68%) (8, 11-16). sexual function in women results from a complex neurovascular process that is controlled by psychological, psychosocial, inter-personal and endocrine inputs, consequently the aetiology and risk factors of fsd can be due to one or more systems and there is no consensus on the contribution of each of them (17). already known risk factors for fsd are of biological, psychological and socio-cultural origin and their role on the different aspects of sexual disorders is often unclear. as an example, biological factors seem to be related to disorders of desire and arousal, but their role in orgasm disorders is less clear. they include age, diabetes, heart disease, chronic health conditions, urinary tract symptoms, previous hysterectomy, female genital mutilation. overall, perceived poor health conditions are considered as predictors for women’s lack of sexual desire, arousal, orgasm and dyspareunia (7, 18-19). table 1. organic and non organic causes of fsd, according to icd-10*. organic sexual dysfunctions nonorganic sexual dysfunctions vaginismus of organic etiology lack of sexual desire dyspareunia of organic etiology sexual aversion lack of sexual enjoyment failure of genital response orgasmic dysfunction non-organic vaginismus non-organic dyspareunia excessive sexual drive not otherwise specified causes * icd-10: international classification of diseases, 10th edition. table 2. sexual dysfunctions in women, according to dsm-5°. etiologic subtype symptoms, disorders, difficulties female sexual interest-arousal disorder (at least three of the following characteristics) absent or decreased interest in sexual activity absent or decreased sexual or erotic thoughts or fantasies absent or decreased initiation of sexual activity and unreceptive to a partner’s attempts to initiate absent or decreased sexual excitement or pleasure during sexual activity in almost all or all sexual encounters absent or decreased sexual interest or arousal in response to any internal or external sexual or erotic cues absent or decreased genital or non-genital sensations during sexual activity in almost all or sexual encounters female orgasmic disorder (either of the following) marked delay in, marked infrequency of, or absence of orgasm markedly decreased intensity of orgasmic sensations genito-pelvic pain-penetration disorder (at least one of the following difficulties) vaginal penetration during intercourse marked vulvovaginal or pelvic pain during vaginal intercourse or penetration attempts marked fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of vaginal penetration marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration substanceor medication-induced sexual dysfunction sexual dysfunction etiologically related to a medication or substance (occurs in both men and women) other specified sexual dysfunction other unspecified sexual dysfunction unspecified ° dsm-5: diagnostic and statistical manual of mental disorder, fifth edition borghi_stesura seveso 04/04/17 09:03 pagina 8 in terms of psychological and psychiatric risk factors, anxiety and depression have confirmed association with sexual dysfunction, furthermore the medication used to treat them particularly affect orgasmic function (20). less is known about the role of social and cultural factors on fsd but it is clear that low education, low quality of the relationship, social and working difficulties, substance abuse and traumatic life experiences have a negative influence (7). epidemiologic studies will be more detailed and useful if standard definitions of sexual dysfunction, validated measurement instruments and uniform description of study design will be used in order to decrease all the variations reported in the current ones. because of this wide range of features, the therapeutic approach on fsd cannot be univocal and, in general, little evidence is known on both non-pharmacological treatment modalities (such as psychosexual treatments) and pharmacological treatment options (21). if possible, therapy should focus on the most likely causal factor, taking into consideration the frequent overlapping between biological, relational and psychological factors. among pharmacological possibilities, hormonal therapies with androgens, estrogens or selective estrogen receptor modulators are to be mentioned, psychotropic agents such as dopamine agonists have also been studied and herbal supplements or other nonmedical treatment have been used with unproven efficacy (22). interestingly, the success of vasoactive agents such as pde5i in the treatment of male sexual arousal dysfunction have encouraged the research of therapies that enhance women’s genital congestion and vaginal lubrication and pde5i have been used in several studies about fsd, with variable results (21). mechanism of action of phosphodiesterase type 5 inhibitors smooth muscle contraction and relaxation is regulated by a mechanism involving the nitric oxide (no) vasodilation pathway. no activates the guanylate cyclase enzyme, which converts guanosine triphosphate (gtp) into cyclic guanosine monophosphate (cgmp). cgmp is an important second messenger that plays a central role in signal transduction and regulation of many physiologic responses, such as smooth muscle tone. it is degraded by phosphodiesterase (pde) isoenzymes, a heterogeneous group of hydrolytic enzymes. pde5 inhibition should thus result in an increased no signal and improved vascular function (23). to date, eleven different pde families have been identified, each typically having several different isoforms and splice variants. among these, pde5 is specific for cgmp and pde5i have been proved to be of pharmacological relevance, widely studied and used (24). pde5i were originally designed to treat cardiovascular diseases and later used for the treatment of male erectile dysfunction with acceptable results (4). other fields of application have been analysed and, in spite of several studies, the exact mechanism of action and efficacy of pde5i in the treatment of fsd remain still unclear. pde5 enzymes and the no neurotransmitter mechanism have been detected in vaginal smooth muscle tissue, clitoral shaft and also in the uterine tissue and increased vaginal blood flow pulse amplitude has been detected after treatment with a pde5i. consequently, treatment with pde5i can decrease the catabolism of cgmp in females, thus resulting in the relaxation of clitoral and vaginal smooth muscle and increased blood flow in these sites (25). up to date, six oral pde5i are commercially available, which are sildenafil, vardenafil, tadalafil, avanafil, udenafil and mirodenafil. though success of pde5i in males with sexual dysfunction did stimulate interest in treating fsd, the same effectiveness of this drug class has not been found across genders (17). a few studies analysed the efficacy of sildenafil as a treatment for many subtypes of fsd (26) but even less is known about the role of other molecules belonging to the pde5i family. newly developed compounds may contain certain advantages over sildenafil, such as higher selectivity for pde5 compared with other isoenzymes, faster onset, longer duration of effect and absence of food effect on absorption, which consequently, allowing more flexibility in sexual activity (24). tadalafil tadalafil appears to be as effective as sildenafil but has a longer duration of action, between 24 and 36 hours, with a mean elimination half-life of 17.5 hours, compared to the 4-5 hours elimination half-life of sildenafil. this prolonged half-life, due to its pharmacokinetic properties, lets this drug available for once daily administration. this approach appeared to be as effective as taking higher doses on an as-needed basis in men with erectile dysfunction (27). this dosing regimen has the advantage of separating administration from sexual interaction and it could me more suitable also for female population. unlike sildenafil or vardenafil, tadalafil absorption is unaffected by food or alcohol consumption (28). tadalafil has been widely used in both sexes for the treatment of several pathologies, particularly its efficacy has been studied in lower urinary tract symptoms (24, 29) 9archivio italiano di urologia e andrologia 2017; 89, 1 treatment with tadalafil in elderly women table 3. published studies about female sexual disorders treated with tadalafil. reference treatment nr fsd outcome aston et al. 2006 tadalafil 20 mg on demand 3 sexual dysfunction induced by serotonin-enhancing medications resolution of sexual disorders lack of sexual desire. caruso et al. 2012 tadalafil 5 mg once daily for 12 weeks 33 premenopausal type 1 diabetic women resolution of sexual disorders genital arousal disorders nr = number of patients; fsd = female sexual disorders. borghi_stesura seveso 04/04/17 09:03 pagina 9 archivio italiano di urologia e andrologia 2017; 89, 1 c. borghi, l. dell’atti 10 for its metabolic and micro-vascular effects on skeletal muscle and adipose tissue in type 2 diabetic patients (23), for the treatment of pulmonary hypertension (30). little evidence is reported on its efficacy in the treatment of fsd, specially in particular populations such as women treated with antidepressant drugs (31) or women affected by type 1 diabetes mellitus (dm) with sexual arousal disorders (28). the first study described the use of tadalafil 20 mg prior to sexual activity by three women treated for anxiety disorder or panic disorder, who reported sexual dysfunction induced by serotoninenhancing medications. all these patients experienced resolution of the sexual disorders, and authors concluded that augmentation with tadalafil may help some women with serotonin-reuptaking inhibiting-induced sexual dysfunction (31). the second study analysed a population of 33 premenopausal type 1 diabetic women affected by sexual genital arousal disorder and treated with daily tadalafil 5 mg administration for 12 weeks. authors concluded that this therapeutic scheme seems to improve subjective sexual aspect in the analysed population and can be used to treat genital arousal disorder of premenopausal women with type 1 dm (28). in both studies tadalafil administration seems to improve subjective sexual aspects in the observed population, but they noticeably have some limitations, first of all the small sample, the lack of a placebo-control group and the lack of objective evaluation of the subtype of sexual aspects involved. conclusions female sexual disorders include a complex, multidimensional, individual experience that can change as an individual age, suggesting that fsd is caused by multiple factors including psychosocial factors, personal relationships, pathologic changes caused by diseases, and pharmacologic influences. furthermore, postmenopausal hormonal changes could have a significant role in the development of fsd. clinicians should correctly assess patients’ sexual health and provide open communication, medical understanding and education, in order to improve the medical assistance and let patients face sexual issues as they might arise. non pharmacologic interventions are the first choice in the approach to these disturbances, but they are often ineffective. pharmacotherapy for treating fsd is still under investigation and, to date, no treatments have been approved by the food and drug administration (32). pde5i have been used in the treatment of erectile dysfunction with acceptable results (33). the treatment with pde5i can decrease the catabolism of cyclic gmp also in female individuals, resulting in the relaxation of clitoral and vaginal smooth muscle, increasing local blood flow (32). although some researchers reported negative results, several authors demonstrated that treatment with pde5i, particularly sildenafil, could be an effective option for many subtypes of fsd if compared to placebo, with an improvement in different aspects of sexual function, such as sexual desire, sexual arousal, sexual orgasm and sexual satisfaction (26). pde5i administration can be related to known adverse effects, for example headache, nausea, flushing or vision changes, but all of them can be quickly solved with the discontinuation of therapy, thus implying that these medications could be safe. few is known about the use of tadalafil in this field and, since this molecule is well known and used in many different pathologies, we think that its administration should be studied deeper as a treatment option for fsd, with well designed randomized placebo controlled trials. therefore, well-designed randomized controlled trials should be performed to report results of the treatment with pde5i. references 1. hawkes s. sexual health: a post-2015 palimpsest in global health? lancet glob heal. 2014; 2:e377-e378. 2. world health organization. defining sexual health. report of a technical consultation on sexual health. sex heal doc ser. 2002. http://www.who.int/reproductivehealth/publications/sexual_health/d efining_sexual_health.pdf 3. belkin z, krapf j, goldstein a. drugs in early clinical development for the treatment of female sexual dysfunction. expert opin investig drugs. 2015;24:159-167. 4. doumas m, lazaridis a, katsiki n, athyros v. pde-5 inhibitors: clinical points. curr drug targets. 2015; 16:420-426. 5. world health organization. international statistical classification of diseases and related health problems. 10th ed. geneva: world health organization. 1992. http://www.who.int/classifications/icd/en/ 6. american psychiatric association. diagnostic and statistical manual of mental disorders. 5th ed. washington, dc: american psychiatric press. 2013. http://www.dsm5.org/pages/default.aspx 7. mccabe mp, sharlip id, lewis r, et al. risk factors for sexual dysfunction among women and men: a consensus statement from the fourth international consultation on sexual medicine 2015; j sex med. 2016; 13:153-167. 8. mccabe mp, sharlip id, lewis r, et al. incidence and prevalence of sexual dysfunction in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. j sex med. 2016; 13:144-152. 9. shifren jl, monz bu, russo pa, segreti a. sexual problems and distress in united states women. 2008; 112:970-978. 10. burri a, spector t. recent and lifelong sexual dysfunction in a female uk population sample: prevalence and risk factors. j sex med. 2011; 8:2420-2430. 11. de visser ro, richters j, rissel c, et al. change and stasis in sexual health and relationships: comparisons between the first and second australian studies of health and relationships. sexual health, 2014; 11:505-509. 12. amidu n, owiredu w, woode e, et al. incidence of sexual dysfunction: a prospective survey in ghanaian females. reprod biol endocrinol. 2010; 8:106. 13. dennerstein l, guthrie jr, hayes rd, et al. sexual function, dysfunction, and sexual distress in a prospective, population-based sample of mid-aged, australian-born women. j sex med. 2008; 5:2291-2299. 14. hayes rd, dennerstein l, bennett cm, fairley ck. what is the “true” prevalence of female sexual dysfunctions and does the way we assess these conditions have an impact? j sex med. 2008; 5:777-787. borghi_stesura seveso 04/04/17 09:03 pagina 10 15. mccabe mp, goldhammer dl. prevalence of women’s sexual desire problems: what criteria do we use? arch sex behav. 2013; 42:1073-1078. 16. safarinejadinal m. female sexual dysfunction in a populationbased study in iran: prevalence and associated risk factors. int j impot res. 2006; 18:382-395. 17. allahdadi kj, tostes rc, clinton webb r. female sexual dysfunction: therapeutic options and experimental challenges. cardiovasc hematol agents med chem. 2009; 7:260-269. 18. miles cl, candy b, jones l, et al. interventions for sexual dysfunction following treatments for cancer. cochrane database syst rev. 2007; cd005540. 19. clayton ah, harsh v. sexual function across aging. curr psychiatry rep. 2016; 18:28. 20. serretti a, chiesa a. a meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. int clin psychopharmacol. 2011; 26:130-40. 21. giraldi a, rellini ah, pfaus j, laan e. female sexual arousal disorders. j sex med. 2013; 10:58-73. 22. bonfim reis sl, abdo chn. benefits and risks of testosterone treatment for hypoactive sexual desire disorder in women : a critical review of studies published in the decades preceding and succeeding the advent of phosphodiesterase type 5 inhibitors. clinics. 2014; 69:294-303. 23. jansso pa, murdolo g, sjögren l, et al. tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes. diabetologia. 2010; 53:2205-2208. 24. zhang wh, zhang xh. clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update. asian j androl 2016; 18: 723-731. 25. chivers ml, rosen rc. phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? j sex med. 2010; 7:858-872. 26. gao l, yang l, qian s, et al. systematic review and meta-analysis of phosphodiesterase type 5 inhibitors for the treatment of female sexual dysfunction. int j gynecol obstet. 2016; 133:139-145. 27. porst h, giuliano f, glina s, et al. evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5mg and 10mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. eur urol. 2006; 50:351-359. 28. caruso s, cicero c, romano m, et al. tadalafil 5 mg daily treatment for type 1 diabetic premenopausal. j sex med. 2012; 9:2057-2065. 29. andersson k-e, nomiya m, sawada n, yamaguchi o. pharmacological treatment of chronic pelvic ischemia. ther adv urol. 2014; 6:105-114. 30. rusiecki j, rao y, cleveland j, et al. sex and menopause differences in response to tadalafil ì: 6-minute walk distance and time to clinical worsening. pulm circ. 2015; 5:701-706. 31. ashton a, weinstein w. tadalafil reversal of sexual dysfunction caused by serotonin enhancing medications in women. j sex marital ther. 2006; 32:1-3. 32. nappi re. why are there no fda-approved treatments for female sexual dysfunction? expert opin pharmacother. 2015; 16:1735-1738. 33. hakky ts, jain l. current use of phosphodiesterase inhibitors in urology. turkish j urol. 2015; 41:88-92. 11archivio italiano di urologia e andrologia 2017; 89, 1 treatment with tadalafil in elderly women correspondence chiara borghi, md department of morphology, surgery and experimental medicine, institute of obstetrics and gynecology, university of ferrara, ferrara, italy lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com department of urology university hospital s. anna, 8 a. moro street, 44124 cona, ferrara, italy borghi_stesura seveso 04/04/17 09:03 pagina 11 archivio italiano di urologia e andrologia 2017; 89, 2130 original paper correlation between lower urinary tract symptoms and objective measures of uroflowmetry hakan türk 1, sıtkı ün 2 1 dumlupınar university evliya celebi training and research hospital, turkey; 2 sivas state hospital, turkey. indroduction: benign prostate hyperplasia (bph) is the most commonly diagnosed benign adenoma which causes serious clinical symptoms by bladder outlet obstruction. bph patients suffer from negative changes in their quality of life and restriction of their daily activities due to the disease symptoms. our main objective in this study is to evaluate the relationship between bph and luts as described by international prostate symptoms score and objective non-invasive parameters related to bph. materials and methods: 238 patients over 40 years with clinical bph, luts and/or prostate volumes greater than 25 ml who presented to urology department were included in the study. all patients included in the study were subjected to a standardized diagnostic panel which included patient history, physical examination, biochemistry panels and urinalysis. results: results showed an increase in symptom scores with age. as symptom scores go from mild to severe; qmax values showed a decrease meanwhile prostate volume, psa and postvoid residue increased. again, in terms of erectile dysfunction, erectile dysfunction complaints increased with increased iief symptom scores. when all these results were evaluated, a positive correlation was seen between uroflowmetry parameters with patient symptoms, psa and iief scores. conclusion: from our study results, we can conclude that uroflowmetry is a very useful tool in monitoring lower urinary system complaints. key words: prostate volume; erectile dysfunction; uroflowmetry; urinary system complaints. submitted 15 march 2017; accepted 23 april 2017 summary no conflict of interest declared. toms (luts) (5, 6). uroflowmetry gives enough information in diagnosing boo. our main objective in this study is to evaluate the relationship between bph and luts as described by international prostate symptoms score (ipss) and objective non-invasive parameters related to bph. materials and methods 238 patients over 40 years with clinical bph, luts and/or prostate volumes greater than 25 ml who presented to urology department of dumlupinar university evliya celebi research and training hospital between 20 may 2015 and 13 november 2016 were included in the study. all patients included in the study were subjected to a standardized diagnostic panel which included patient history (including ipss), physical examination (including digital rectal examination), biochemistry panels (including prostate-specific antigen) and urinalysis. ipss and the international index of erectile function questionnaire (iief-5) were filled by all the patients. 113 patients who did not fill out these forms were excluded from the study. bmi of all patients were calculated by measuring their heights and weights. in addition, uroflowmetry (uroscan aymed) was performed in all patients. transabdominal prostate volume prior to uroflowmetry and pvr following voiding were measurers using usg (logiq 200 pro (ge) 7.5 mhz linear probe) (1/2 x transverse x anteroposterior x cephalocaudal diameter). patients on alpha blockers and 5α-reductase inhibitors, with acute urinary retention history, neurological disease, instrumental intervention history, urinary system or pelvic surgery history, recently catheterized and with clean intermittent catheterization history were all excluded from the study. all the other patients who met the inclusion criteria, following obtaining their consent to participate in the study, were included in the study. ethical approval for the study was obtained from the local ethics committee. statistical analysis was performed using statistical package for social sciences 20.0 (spss inc, chicago, usa). independent t-test was done for continuous variables whereas categorical variables were assessed using chi-square analysis and annova regression analysis. significance level was determined as p < 0.005. doi: 10.4081/aiua.2017.2.130 indroduction benign prostate hyperplasia (bph) is the most commonly diagnosed benign adenoma which causes serious clinical symptoms by bladder outlet obstruction (boo). about 40% of all men are under the risk of developing bph during their lifetime (1). bph patients suffer from negative changes in their quality of life and restriction of their daily activities due to the disease symptoms. although not lifethreatening, increased symptoms characterized by decreased quality of life, slow urine flows, increased prostate size and acute urinary retention cause this disease to be a major public health issue (2). boo was diagnosed in 60% of symptomatic and 52% of asymptomatic patients (3, 4). there was no significant connection between prostate enlargement, boo and lower urinary tract sympturk_stesura seveso 20/06/17 09:26 pagina 130 131archivio italiano di urologia e andrologia 2017; 89, 2 luts and uroflowmetry results the mean age of the patients was calculated as 60.83 ± 12.1. 35 (12.3%) patients were included in group 1 (ipss 0-7), 142 (50.2%) in group 2 and 106 (37.4%) in group 3. the patients were divided into 3 groups per their symptom scores. results showed an increase in symptom scores with age. as symptom scores go from mild to severe; qmax values showed a decrease meanwhile prostate volume, psa and post-void residue increased. again, in terms of erectile dysfunction (ed), erectile dysfunction complaints increased with increased iief symptom scores (table 1). in our review, we did not detect a direct relationship between body mass index (bmi) and patient symptoms. when all these results were evaluated, a positive correlation was seen between uroflowmetry parameters with patient symptoms, psa and iief scores. discussion today, we see an increase in male lower urinary tract symptoms (mluts) with increased life expectancy. this is starting to become important for both medical and socio-economical aspects (7). mluts include symptoms such as frequent urination, sudden urgency, difficulties in urinating, dysuria, straining to void, terminal dribbling and nocturia. although most of those symptoms are seen in prostate enlargement, they can also be caused by other conditions such as neurogenic bladder, urethral stricture or urinary tract infections (8-9). a large number of studies showed a correlation between mluts and prostate volume, peak flow speed, residual volume and psa (10, 11). however, there are also a few studies that say otherwise (i.e. no connection) (12, 13). in our study, our main objective was to evaluate the relationship between mluts and some non-invasive bphrelated parameters. luts severity was measured using ipss questionnaire, which consisted of 7 questions. patients with other severe diseases which might cause potential risk factors that might affect urinary symptoms were excluded from the study. in addition, patients who were treated for bph with medication were required to stop their treatments 3 months prior to the study for inclusion. uroflowmetry is the most commonly used tools today in urology for assessing luts (14). although there is a significant interest in the past decades for correlating uroflowmetry results with ipss scores, there is only a couple of studies that showed a significant but weak correlation between those two entities (14, 15). out of all uroflowmetry parameters, maximum flow rate is thought to be the most important variable in assessing luts. likewise, we also saw a significant correlation between ipss and uroflowmetry parameters in our study. with increased ipss scores, we detected a decrease in qmax values and total urine volume and an increase in post-void residue volume. therefore, we concluded that uroflowmetry can be used as an effective tool in mluts assessment of the patients. most community-based studies showed that age and symptom scores showed a positive correlation (16-20) as well as an increase in luts severity with age. despite some studies showing a negative correlation between age and symptom indexes (11, 21), the majority of the studies including ours showed an increase in symptom scores with age. patients often complaint about more severe symptoms as their daily-life activities are disrupted and consequently, their quality of life is reduced (22, 23). our study results were in accordance with the previous study results, with the strongest association between ipss and all variables assessed in uroflowmetry detected as quality of life. when total ipss scores and ipss severity were reviewed, we saw a global statistically significant association with a high post-void residue with ipss severity. moreover, we also found statistically significant correlations with increased post-void residue with the severity of symptoms in ipss questionnaire. likewise, another study in the literature showed a significant relationship between ipss and post-void residue (11). when ipss scores and prostate volume and psa were compared, we detected a significant correlation between those parameters. however, there is a slight difference in our study results. a study done by wang et al. on 803 patients showed no significant relationship between ipss, prostate volume and psa (26). other studies did not show a relationship between those parameters at table 1. parameters of three groups of patients divided according to ipss score (mild, moderate, and severe). parameters total group 1 group 2 group 3 p value p value (ipss 0-7) (ipss 8-19) (ipss 20-35) univariate analysis multivariate analysis number of patients (n) (%) 283 35 (12.3) 142 (50.2) 106 (37.4) urine volume (mean) (ml) 380 446 347 323 < 0.01 0.038 age 60.8 59.8 60.2 62.1 0.01 0.01 qmax (mean) (ml/sec) 11.1 15.7 10.3 8.7 < 0.001 0.01 qol (mean) 4 2 4 5 < 0,001 0.01 prostate volume (mean) (ml) 38.2 33 40.1 42.3 < 0.01 0.161 postvoid residue (mean) (ml) 101 78.1 110.3 124.2 < 0.01 0.155 significant postvoid residue (n) (ml) 283 5 40 41 < 0.001 0.01 psa (mean) (ng/ml) 1.6 1.2 1.9 2.6 < 0.01 0.072 iief (mean) 15 20 14 12 < 0.01 0.02 bmi (mean) (kg/m2) 29.2 29.8 29.6 28.9 0.07 qmax: maximum flow; qol: quality of life turk_stesura seveso 20/06/17 09:26 pagina 131 archivio italiano di urologia e andrologia 2017; 89, 2 h. türk, s. ün 132 all (27). the reason for discrepancy is still unclear. even though a correlation between ipss and objective parameters can be detected, it is still difficult to use those parameters as predictive factors for symptom severity assessment since they show a great overlap in groups with different ipss severity categories. mluts and sexual dysfunction complains are commonly seen in aging males. both of those two clinical situations which affect the patient’s quality of life share common etiological risk factors such as age, obesity and diabetes and their pathophysiological mechanisms are thought to be similar to each other. mluts itself is considered as an independent risk factor for ed (28). multinational aging male study (msam-7) is one of the most important studies which show the multifaceted epidemiological relations between mluts and ed in western male populations (29). the study, which included 14254 males from 7 different countries, reported that, contrary to popular belief, the aging males are indeed sexually active, however, mluts severity affected sexual activity rates, independent of age. the same study design, this time performed on asian countries, included 1155 males from 5 different countries and also reported that mluts severity affected sexual activity rates regardless of patient’s age (30). cologne study reviewed risk factors in ed patients such as mluts, diabetes, hypertension, pelvic surgery and such and reported that mluts was the most commonly seen risk factor for ed in 72% of ed group and 37% in control (non-ed) group patients (31). in the past, most lower urinary tract symptoms seen in males were thought to be related to benign prostate hyperplasia. however, recent studies showed that chronic diseases such as heart disease, diabetes and metabolic syndrome components, in addition to lifestyle risk factors such as smoking, alcohol consumption and lack of physical activity played important roles in lower urinary system symptom development (32-36). the cohort study of rohrmann et al. reported that there was a positive correlation between the increase in bmi and lower urinary tract symptoms in patients over 25 and there was an increase in frequency of lower urinary tract symptoms with increased bmi (32). bach study done by kupelian et al. on 1899 male patients assessed the relationship between metabolic syndrome components and lower urinary tract symptoms, and reported that there is a more significant relationship with voiding symptoms rather than filling symptoms in metabolic syndrome components (37). in our study, we were unable to show a significant relationship between bmi and ipss symptom scores. however, this is probably since our number of patients was low and we did not assess other parameters such as waist-to-hip ratio in our patients. some of the limitations of our study are the heterogenous patient population, that it is a single-center study and low number of patients. however, it is also one of the few studies that reflect the global population treated in urology departments with a prospective design. conclusion from all the data obtained in our study, we can argue that there are several significant correlations between symptom severity and objective bph-related parameters such as age, prostate volume, urine volume, residual urine, peak flow rate, iief and psa. yet still, it is quite difficult to use these parameters as predictive factors in symptom severity. from our study results, we can conclude that uroflowmetry is a very useful tool in monitoring lower urinary system complaints. references 1. fong yk, milani s, djavan b. natural history and clinical predictors of clinical progression in benign prostatic hyperplasia. curr opin urol. 2005; 15:35-8. 2. sarma av, jacobsen sj, girman, et al. concomitant longitudinal cahanges in frequency of and bother from lover urinary tract symptoms in community dwelling men. j urol. 2002; 168:1446-52. 3. reynard jm, yang q, donovan jl, et al. the 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international prostate symptom score bother question with the benign prostatic hyperplasia impact index in a clinical practice setting. bju int. 2008; 101:1531-5. 24. araki i, zakoji h, komuro m, et al. lower urinary tract symptoms in men and women without underlying disease causing micturition disorder: a cross-sectional study assessing the natural history of bladder function. j urol. 2003; 170:1901-4. 25. basri cakiroglu rg, sinanoglu o, aksoy sh, et al. the correlation of symptoms severity and objectivemeasures in patients with lower urinary tract symptoms. clin med res. 2013; 2:5.12. 26. li mk, garcia l, patron n, et al. an asian multinational prospective observational registry of patients with benign prostatic hyperplasia, with a focus on comorbidities, lower urinary tract symptoms and sexual function. bju int. 2008; 101:197-202. 27. zhang p, wu zj, gao jz. influence of bladder outlet obstruction and detrusor contractility on residue urine in patients with benign prostatic 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and sexual symptomps with common illnesses. eur urol. 2007; 52:407-12. 34. joseph ma, harlow sd, wei jt, et al. risk factors for lower urinary tract symptoms in a population based sample of africanamerican men. am j epidemiol. 2003; 157:906-12. 35. michel mc, mehlburger l, schumacher h, et al. effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. j urol. 2000; 163:1725-31. 36. chapple cr, roehrborn cg. a shifted paradigm for the further understanding, evaluation and treatment of lower urinary tract symptoms in men: focus on the bladder. eur urol. 2006; 49:651-8. 37. kupelian v, mcvary kt, kaplan sa, et al. association of lower urinary tract symptoms and the metabolic syndrome: results from the boston area community health survey. j urol. 2009; 182:616-24. correspondence hakan türk, md (corresponding author) hkntrk000@gmail.com dumlupınar university evliya celebi training and research hospital, turkey sıtkı ün, md sitki@doctor.com sivas state hospital, turkey turk_stesura seveso 20/06/17 09:26 pagina 133 25archivio italiano di urologia e andrologia 2020; 92, 1 original paper comparison of the patient’s satisfaction underwent penile prosthesis; malleable versus ambicor: single center experience omer bayrak, sakip erturhan, ilker seckiner, mehmet ozturk, haluk sen, ahmet erbagci department of urology, gaziantep university school of medicine, gaziantep, turkey. objective: to compare the surgical results, complications, and satisfaction levels of patients who underwent malleable penile prosthesis implantation (m-ppi) and ambicor penile prosthesis implantation (a-ppi). material and methods: one hundred forty two patients who underwent penile prosthesis implantation [m-ppi (promedontube®, cordoba, argentina): 81, and a-ppi (american medical systems, minnesota, usa): 61] between 2013-2018 were evaluated retrospectively. patients’ age, body mass index, smoking history, etiological factors, modified “erectile dysfunction inventory of treatment satisfaction (edits) questionnaire” scores, shortening of the penis, and complications were recorded. results: the patients who performed a-ppi implantation were younger (56.27 ± 10.81 vs. 51.47 ± 11.79, p = 0.009). the edits scores of 31(38.2%) patients who underwent m-ppi and 44 (72.4%) patients who underwent a-ppi were available. it was observed that the scores on the following questions were statistical significantly higher in the a-ppi group: “overall, are you satisfied with your penile prosthesis?, how much of your expectations did penile prosthesis meet?, how often do you use your penile prosthesis?” (p = 0.05, p = 0.048, p = 0.038). no difference was observed between the groups in terms of the scores on the other three questions (p = 0.447, p = 0.326, p = 0.365). a 61.3% of patients in mppi (19/31) group, and 56.8% of patients in a-ppi (25/44) group stated penile shortening (p = 0.417). mean shortening was reported as 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm, in m-ppi and a-ppi groups, respectively (p = 0.90). conclusion:it is remarkable that the patients who underwent a-ppi experienced higher satisfaction with their prosthesis. even though it has not been evidenced in the current literature data, patients who have had either m-ppi or a-ppi should be informed about the risk of penile shortening. key words: erectile dysfunction; penile prosthesis; satisfaction; complication. submitted 17 october 2019; accepted 12 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.25 introduction erectile dysfunction (ed) is the second most common male sexual disorder after premature ejaculation and is defined as “a man’s inability to achieve and/or maintain erection sufficient to have sexual intercourse, for at least six months” (1, 2). first and second-line conservative treatments, including medical therapies using either oral treatment or intracavernous injection as well as lifestyle changes, are the initial current methods suggested to patients with ed. phosphodiesterase type 5 inhibitors, intracavernous injections, intraurethral alprostadil and vacuum devices may cause treatment failure or lead the necessity to discontinue treatment in around 80% of the patients (3, 4). penile prosthesis implantation is recommended as a thirdline therapy in ed patients who do not respond to oral or non-surgical therapies or who are unable to accept such treatments for any reason (5). the surgical treatment has been modified many times in recent years to decrease the risk of complications, to reduce the mechanical dysfunction, and to increase patient/partner satisfaction. currently, penile prostheses are still commonly used as third line therapy in the treatment of ed (5, 6). in our study, we aimed to compare the surgical results, complications and satisfaction levels of patients who did not respond to firstand second-line therapies and who therefore underwent malleable penile prosthesis implantation (m-ppi) and ambicor penile prosthesis implantation (a-ppi). material and methods study participants following the approval of the local ethics committee, 142 patients with ed who underwent penile prosthesis implantation in our clinic between 2013-2018 were evaluated retrospectively. it was found that 81 patients had m-ppi (promedon-tube®, cordoba, argentina) and 61 patients had a-ppi (american medical systems, minnesota, usa). pre-operative informed consents were obtained from all patients. before the operations, the patients were given general information about the procedure and potential complications. detailed information on m-ppi or a-ppi prosthesis types was provided to the patients. a-ppi implantation was primarily recommended to patients who were able to pay the price gap for ppi (cost of m-ppi: approximately usd 1000, cost of a-ppi: approximately usd 2000), were in a good mental state, and had good manual dexterity. patients who had a history of unstable urethral or bladder neck stricture, abnormal psychiatric bayrak_stesura seveso 01/04/20 19:13 pagina 25 archivio italiano di urologia e andrologia 2020; 92, 1 o. bayrak, s. erturhan, i. seckiner, m. ozturk, h. sen, a. erbagci 26 condition, a genital or systemic infection, perineal wounds, severe liver failure, uncontrolled hypertension or diabetes were excluded from the study. efficacy and complication evaluations patients’ age, body mass index (bmi), smoking history, and etiological factors [diabetes mellitus (dm), coronary artery disease, hypertension, chronic kidney failure, neurological pathologies, radical prostatectomy and other pelvic surgeries] were recorded. the patients’ scores for the modified “erectile dysfunction inventory of treatment satisfaction (edits) questionnaire” at the post-operative 6th month, shortening of the penis, and complications (wound site infections, removal of prosthesis, hematoma, skin erosion and soft glans syndrome) were noted. the data on penile size was based only on the patient’s perception. the “erectile dysfunction inventory of treatment satisfaction questionnaire”, and modified edits forms are reliable and validated questionnaires, which were created by althof et al. to define satisfaction levels with ed therapies (7). the modified edits patient questionnaire is composed of six questions inquiring as level of satisfaction with ed treatment methods, level of expectations meet, suitability for continuous use, level of pleasure and confidence during sexual intercourse, and satisfaction of partners. overall satisfaction is measured on a 5-point scale: 1not satisfied at all, 3partially satisfied and 5very satisfied (7-9). surgical procedure after spinal or general anesthesia, the pubic area of the patient was shaved and the genital area was washed with a povidone iodine solution for 10 minutes. intravenous cefazolin and gentamicin were administered for prophylaxis simultaneously. after placement of a 18 f foley catheter, in a supine position, the corpora cavernosa were reached through a skin incision of approximately 3 cm from the penoscrotal region and a 2 cm bilateral corporotomy was performed. afterwards, the sites where the penile prosthesis would be placed were created in the corpora cavernosa with hegar dilators. measurements were undertaken to choose a suitable size for the cylinder. during these procedures, the corpora cavernosa were irrigated with solutions containing gentamicin. the prosthetic cylinders were inserted after the surgical site was prepared. a pump was placed by creating a subdartos pouch in the scrotum in patients who underwent a-ppi. following a hydraulic test, the corporotomies were closed with previously placed 2/0 vicryl sutures. the procedure was completed by suturing the subcutaneous tissue and skin. we recommended to patients, to start sexual intercourse after six weeks from the surgical procedure. statistical analyses the “spss 11 for windows” software package was used for the statistical calculations and the data was expressed as arithmetic mean and standard deviation. the chi-square distribution test and the mann-whitney u test were used to calculate categorical variables and compare mean values, respectively. the 95% confidence interval (p < 0.05) was accepted as statistical significance. table 1. demographic data. m-ppi a-ppi p (n = 81) (n = 61) age (year) 56.27 ± 10.81 51.47 ± 11.79 0.009 bmi (kg/m2) 27.19 ± 2.43 26.78 ± 2.25 0.211 cigarette consumption (n, %) 65 (80.2%) 46 (75.4%) 0.490 etiology (n, %) dm: 57 (70.3%) dm: 43 (70.4%) 0.569 cad: 22 (27.1%) cad: 5 (8.2%) ht: 18 (22.2%) ht: 9 (14.75%) crf: 2 (2.5%) crf: neurological pathologies : 3 (3.7%) neurological pathologies : 1 (1.6%) rp: 7 (8.6%) rp: 5 (8.2%) other pelvic surgeries : 6 (7.4%) other pelvic surgeries : 8 (13.1%) (tur-prostate, orchiectomy, radical (tur-prostate, orchiectomy, radical cystectomy, urethroplasty) cystectomy, urethroplasty) prosthesis replacement: 4 (4.93%) prosthesis replacement: 5 (8.1%) table 2. comparison of patients’ satisfaction according to modified ‘’erectile dysfunction inventory of treatment satisfaction questionnaire’’. modified edits grade of satisfaction m-ppi a-ppi p questionnaire (n, %) (n, %) overall, are you satisfied with your penile prosthesis? i am not satisfied 3 (9.6%) 1 (2.3%) 0.05* i’m partially satisfied 5 (16.1%) 3 (6.8%) i’m very satisfied 23 (74.2%) 40 (90.1%) how much of your expectations did penile prosthesis meet? did not meet 3 (9.6%) 1 (2.3%) 0.048* partially met 4 (12.9%) 2 (4.5%) fully met 24 (77.4%) 41 (93.1%) how often do you use use your penile prosthesis almost never 3 (9.6%) 1 (2.3%) 0.038* sometimes 10 (32.2%) 8 (18.2%) very often 18 (56.2%) 35 (79.5%) is it easy for you to use penile prosthesis? not easy 3 (9.6%) 1 (2.3%) 0.447 partially easy 3 (9.6%) 8 (18.2%) very easy 25 (80.6%) 35 (79.5%) do you trust your ability of pleasure during intercourse? no 3 (9.6%) 1 (2.3%) 0.326 partly 2 (6.4%) 3 (6.8%) fully 26 (83.8%) 40 (90.1%) how is the satisfaction of your partner? not satisfied 2 (6.45%) 1 (2.3%) 0.365 partially satisfied 2 (6.45%) 2 (4.5%) very satisfied 27 (87.1%) 41 (93.1%) n: number of patients. edits: erectile dysfunction inventory of treatment satisfaction questionnaire. m-ppi: malleable penile prosthesis implantation. a-ppi: ambicor penile prosthesis implantation. bayrak_stesura seveso 01/04/20 19:13 pagina 26 results the mean age of patients who underwent implantation of ambicor-ppi was lower than the mean age of patients who underwent implantation of m-ppi (51.47 ± 11.79 vs. 56.27 ± 10.81, p = 0.009). diabetes mellitus was as the most common etiological factor in both groups (70.3% vs. 70.4%). no differences were found between the two groups for body mass index and smoking history (p = 0.211, p = 0.490, respectively) (table 1). six-month scores of the edits forms were available in 31 (38.2%) patients who had m-ppi implantation, and 44 (72.1%) patients who had a-ppi. it was found that the scores for the following questions were statistical significantly higher in favor of the a-ppi group: “overall, are you satisfied with your penile prosthesis?, how much of your expectations did penile prosthesis meet?, how often do you use your penile prosthesis?” (p = 0.05, p = 0.048, p = 0.038, respectively). however, no significant difference was observed between the two groups in terms of the scores for the following questions: “is it easy for you to use penile prosthesis?, do you trust your ability of pleasure during intercourse?, how is the satisfaction of your partner?” (p = 0.447, p = 0.326, p = 0.365, respectively). additionally, it was evaluated if the length of the patients’ penis had shortened postoperatively or not. a 61.3% (19/31) of patients in m-ppi group, and 56.8% (25/44) of patients in a-ppi group stated that the length of their penis had shortened (p = 0.417). mean shortening was 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm in m-ppi group and a-ppi group, respectively (p = 0.90) (table 2, figure 1). there was no difference between the groups in terms of complications (p = 0.569); however, seven (77.7%) of nine patients who had wound site infection, and all (100%) three patients whose prostheses were removed, had a history of dm (table 3). tube kinking and skin erosion occurred in a patient at postoperative 6th week, and pump erosion occurred in another patient at postoperative 8th week. both patients were re-operated in collaboration with a plastic surgeon, the tube and pump were fixed to deeper tissue and a skin flap was rotated. the wound sites of both patients recovered without complication. 27archivio italiano di urologia e andrologia 2020; 92, 1 malleable versus ambicor penile prosthesis figure 1. comparison of patients’ satisfaction who underwent malleable penile prosthesis implantation (m-ppi) and ambicor penile prosthesis implantation (a-ppi). table 3. complications after penile prothesis implantation. m-ppi a-ppi p (n = 81) (n = 61) wound infection (n, %) 5 (6.17%) 4 (6.55%) 0.594 removal of prosthesis (n, %) 3 (3.7%) 0.183 hematoma (n, %) 1 (1.2%) 2 (3.2%) 0.394 skin erosion due to tube kinging (n, %) 1 (1.6%) 0.430 skin erosion due to pump (n, %) 1 (1.6%) 0.430 soft glans syndrome (n, %) 2 (2.4%) 0.324 overall complications (n, %) 11 (13.5%) 8 (13.1%) 0.570 n: number of patients. m-ppi: malleable penile prosthesis implantation. a-ppi: ambicor penile prosthesis implantation. bayrak_stesura seveso 01/04/20 19:13 pagina 27 archivio italiano di urologia e andrologia 2020; 92, 1 o. bayrak, s. erturhan, i. seckiner, m. ozturk, h. sen, a. erbagci 28 discussion in the literature, among the treatment options for ed, ppi has been reported to be the most successful surgical method with the highest level of satisfaction (10). different prostheses have different advantages and disadvantages that may affect the satisfaction of the patient (11). m-ppi has a structure that enables bending downwards during dressing, and urination and upwards during intercourse. the superior characteristics of m-ppi are: low mechanical failure rates, more easier operative procedure, shorter operation time, and relative costeffectiveness. however, as a disadvantage, it may cause difficulties during endoscopic procedures which may become necessary at later time. inflatable prostheses have cosmetic advantages and benefits such as increase in penile length, and girth that mimics a natural erection. the most important disadvantage of this prosthesis type is likelihood of mechanical damage (9). today, a three-piece ppi is recommended, and inserted as the first choice at many centers as its deflated appearance has a close to normal appearance, and it provides axial rigidity in various lengths. a-ppi constitutes almost 5% of all prostheses inserted (12). two-piece prostheses are generally preferred by surgeons who do not wish to place a reservoir in the abdomen or the retzius space (13). in our clinical practice, the patient’s choice is taken into consideration after informing the patients of all penile prosthetic choices. however, one of the most important factors that play a role in the selection of an inflatable prosthesis is the cost. in present circumstances in our country, the approximate cost of a one-piece ppi is usd 1000, a two-piece ppi is usd 2000, and a three-piece ppi is usd 3000. therefore, all patients referred to our clinic preferred mppi or a-ppi. another factor playing a role in the selection in our study is age. in particular, it has been seen that younger patients more often prefer a-ppi (51.47 ± 11.79 vs. 56.27 ± 10.81, p = 0.009). patient satisfaction depends on multiple factors including pre-operative expectations, post-operative pain and edema, undesired side effects, functionality of prosthesis, ease of use and acceptability by partners (9). in our series, penile prosthesis implantation has high rates of satisfaction due to being able to ensure rapid, and full rigidity. although our patients who underwent m-ppi implantation felt dissatisfied with constant rigidity in the first few days, this problem was accepted by patients over time. the most common side effects in patients who had an inflatable penile prosthesis implantation were pain, and discomfort associated with the pump in the scrotum, however, these patients learnt how to use the pump as a result of training provided by the clinic. none of the patients required the removal of the prosthesis as a result of dissatisfaction or inability to use. scores for high satisfaction with penile prostheses (90.1% vs. 74.2%, p = 0.05), meeting the expectations (93.1% vs. 77.4%, p = 0.048) and more frequent sexual intercourse (79.5% vs. 56.2%, p = 0.038) were significantly higher in the a-ppi group. in their series in 2007, lux et al. implemented a-ppi in 146 patients at two centers. the authors reported the rate of mechanical failure as 0.7% in a mean follow-up period of 38 months. 95% of patients reported to have had little or no problem in learning how to use the prosthesis, and 84% of them expressed that they were able to achieve good or excellent rigidity during coitus with a-ppi. patient and partner satisfaction were reported to be 85% and 76%, respectively. it is noteworthy that ambicor had a low rate of infection of 7%, despite the fact that it did not contain any topical antimicrobial agents or inhibizone (8). in previous studies reported by levine et al., it was seen that the prosthesis functioned without any problem in follow-ups over 70 months in 97% of 131 patients who had a-ppi. more importantly, 93% of patients and 90% of partners stated that they would suggest a-ppi to other couples. in this study, particularly in examining partner experience, 76% of partners reported to experience more satisfaction with a-ppi during sexual intercourse (14). in the current study, higher satisfaction rates were reported in the m-ppi group and a-ppi group, of 87.1% and 93.1%, respectively, although there was no statistically significant difference between the rates of satisfaction with intercourse (p = 0.365). the complication rates of ambicor-ppi were reported as 7.6%, 2.1% and 9.5% in studies by levine et al., lux et al. and gentile et al. (8, 14, 15). infection-related complications have been reported to be 2-3% in the existing literature (16). in our study, the overall complication rates were 13.5% in the m-ppi group, and 13.1% in the a-ppi group. the most feared complication, in particular with ppi, is infection (m-ppi: 6.17 vs. a-ppi: 6.55, p = 0.594). in the current study, in seven (77.7%) out of nine patients occurred wound site infection, and all three patients (100%) whose prostheses were removed had a history of dm. moreover, in one patient with a-ppi, tube kinking occurred at 6th week postoperatively, and pump erosion occurred in another patient at 8th week postoperatively. both patients were operated in combination with a plastic surgeon, and a reconstruction was performed. the tube and pump were fixed to deeper tissue, and a flap was rotated. the wound sites of both patients recovered without any complication. additionally, this study assessed whether the size of the patients’ penis had shortened compared to the period before implantation. a 61.3% of patients who had m-ppi (19/31), and 56.8% of patients who had a-ppi (25/44) stated that the length of their penis had shortened (p = 0.417). mean shortening was 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm in m-ppi group and a-ppi group, respectively (p = 0.90). lux et al. also reported a mean shortening of 1.5 inches in the size of the penis for 70% of patients, in their study (8). on the other hand, in a study by deveci et al., the stretched penile length was measured in patients who had undergone penile prosthesis surgery for the first time. deveci reported that the a-ppi did not affect the stretched penile length at 1 and 6 month postoperative follow up (17). the current study is one of the rare single-center investigations in the current literature comparing m-ppi and a-ppi over a large number of patients. however, its retrospective nature, the absence of randomization, and more edits scores available on the a-ppi group were significant limitations of our study. in addition, the data on penile shortening was based only on the patient’s perception. bayrak_stesura seveso 01/04/20 19:13 pagina 28 conclusions it is remarkable that patients who underwent a-ppi experienced higher satisfaction with their prosthesis. although no difference was observed between either ppis in terms of complications, patients who have diabetes should be particularly warned against post-operative complications. even though it has not been evidenced in the current literature, all patients who had either m-ppi or a-ppi should be informed about the risk of shortening of the penis. references 1. lindau st, schumm lp, laumann eo, et al. a study of sexuality and health among older adults in the united states. n engl j med. 2007; 357:762-74. 2. nih consensus conference. impotence. nih consensus development panel on impotence. jama. 1993; 270:83-90. 3. mulhall jp, bella aj, briganti a, et al. erectile function rehabilitation in the radical prostatectomy patient. j sex med. 2010; 7:1687-98. 4. gontero p, fontana f, zitella a, et al. a prospective evaluation of efficacy and compliance with a multistep treatment approach for erectile dysfunction in patients after non-nerve sparing radical prostatectomy. bju int. 2005; 95:359-65. 5. evans c. the use of penile prostheses in the treatment of impotence. br j urol. 1998; 81:591-8. 6. minervini a, ralph dj, pryor jp. outcome of penile prosthesis implantation for treating erectile dysfunction: experience with 504 procedures. bju int. 2006; 97:129-33. 7. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-9. 8. lux m, reyes-vallejo l, morgentaler a, et al. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007; 177:262-6. 9. kilicarslan h, kaynak y, gokcen k, et al. comparison of patient satisfaction rates for the malleable and two piece-inflatable penile prostheses. turk j urol. 2014; 40:207-10. 10. rajpurkar a, dhabuwala cb. comparison of satisfaction rates and erectile function in patients treated with sildenafil, intracavernous prostaglandin e1 and penile implant surgery for erectile dysfunction in urology practice. j urol. 2003; 170:159-63. 11. anafarta k, safak m, bedük y, et al. clinical experience with inflatable and malleable penile implants in 104 patients. urol int. 1996; 56:100-4. 12. henry gd, karpman e, brant w, et al. the who, how and what of real-world penile implantation in 2015: the propper registry baseline data. j urol. 2016; 427:195. 13. abdelsayed ga, levine la. ambicor 2-piece inflatable penile prosthesis: who and how? j sex med. 2018; 15:410-5. 14. levine la, estrada cr, morgentaler a. mechanical reliability and safety of and patient satisfaction with the ambicor inflatable penile prosthesis: results of a 2 center study. j urol. 2001; 166:9327. 15. gentile g, franceschelli a, massenio p, et al. patient’s satisfaction after 2-piece inflatable penile prosthesis implantation: an italian multicentric study. arch ital urol androl. 2016; 88:1-3. 16. goldstein i, newman l, baum n, et al. safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment. j urol. 1997; 157:833-9. 17. deveci s, martin d, parker m, et al. penile length alterations following penile prosthesis surgery. eur urol. 2007; 51:1128-31. 29archivio italiano di urologia e andrologia 2020; 92, 1 malleable versus ambicor penile prosthesis correspondence omer bayrak dromerbayrak@yahoo.com sakip erturhan mserturhan@yahoo.com ilker seckiner iseckiner@yahoo.com mehmet ozturk mehmetozturk000@hotmail.com haluk sen drhaluksen@gmail.com ahmet erbagci gantepuro@gmail.com department of urology, gaziantep university school of medicine, gaziantep, turkey. bayrak_stesura seveso 01/04/20 19:13 pagina 29 53archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.53 friend, lover) is rarely evaluated while, in our opinion, the ongoing relationship with the woman is crucial when the male must make the decision to undergo surgery to solve his ed (3). in our experience, patients with ed try to find a solution (psychotherapy, drugs, hormones, 5pdei, pge1, urethral alprostadil, low intensity extracorporeal shockwave therapy, penile implants) not only to manage to have an erection but, mainly, if not exclusively, to have the opportunity to have sex with their partners. if a male does not have sexual intercourses for religious choices, personal principles, lack of interest, limits of freedom, geographical factors (deportations, emigration, work shifts) probably he is not particularly bothered by his ed. if the male feels the need to have an orgasm and ejaculation, he can obtain it with masturbation, possible even with a not fully erect penis. many men over 50, of medium-high cultural level, with good profession, high work responsibilities, good income, one or more children, have no particular interest in having sex with their wives after 10-15 years of marriage (4-5) or even with a lover often because afraid of not being able to perform. until 30-40 years ago, males could have regular sex only after marriage; in married couples usually the male took the initiative and the woman had little chance of refusing. often, after giving birth to several children and as they became older, women might show a decline in sexual desire and, as menopause approached, the willingness to have sex might become less frequent and rewarding (6), due to the fatigue to take care of several children and the family and the lack of enough amusements and distractions. if a male complains ed and is less inclined to have sex, this doesn’t represent a problem for the wife and for the couple. a great number of patients, over 35 years of age, visiting our center, states that they have sexual intercourses with their wives, generally, every 7-10 days; the frequency of sexual intercourses with the lovers is the same. for the couple, generally, the working time and the travel back home is tiring; they have to check if the children did their “job” and spend time with them; after dinner they watch tv or prepare for the next day and generally, they go to sleep after 11-12 p.m. and are very tired; they have to wake up early next morning. generally, there isn’t enough time for sex. things are different in the weekend or during holidays when the frequency of sexual intercourses objective: we evaluated the role of women (wife, partner, girlfriend, lover) in the decision and the results of penile prostheses implants (ppi). material and methods: in a group of 355 pts (21-82 years, average age 50.3 years) submitted to ppi since 2007, we recorded data concerning the relationships with their partner and their role in the surgical decision. we implanted 97 semirigid (spp), 136 malleable (mpp) and 122 inflatable (ipp) prostheses. we collected data regarding some aspects of the sexual life of patients. we asked them if they were married, divorced or widowed; if they had a lover; if they go regularly to brothels; if they were satisfied of their actual couple’s life. after surgery we recorded data concerning their difficulties in utilizing the ppi and their level of satisfaction. results: most patients (93%) confirmed their satisfaction after ppi. relational aspects: 44 out of 46 unmarried patients with difficult sexual intercourses managed to have regular sex and decided to marry after ppi, including 5 younger patients (2130 years old) who were not able to penetrate their girlfriends. in the group of married patients 5 pts were not able to penetrate their wives; after ppi they managed to have regular intercourses and pregnancies. fifteen widowers and 22 divorced patients decided to have a ppi for possible sexual dating or stable relationships. ninety-six out of 271 (28.2%) married patients declared a stable extramarital relationship that represented the main reason for having a ppi. conclusions: in our opinion the simple act of penetrate and ejaculate in vagina, without considering the importance of personal, relational, emotional factors, often well linked to a specific woman, cannot be considered the ideal target of ppi. key words: penile prosthesis; penile prosthesis implant; psychosexual factors; couple. submitted 22 september 2020; accepted 22 november 2020 introduction penile prostheses implants (ppi) have been considered as one of the ultimate treatments of erectile dysfunction (ed) since 1972 (1, 2). in most cases, evaluation of the patients to be submitted to ppi included various parameters such as age, race, metabolic and general diseases, hormonal conditions, cardiovascular diseases, tobacco smoking, alcohol, drugs. the role of women (wife, partner, girlthe woman and the penile prosthetic implant. primary or secondary role? personal experiences on 355 implanted patients summary diego pozza 1, alberto berardi 2, mariangela pozza 1, augusto mosca 2, carlotta pozza 3 1 studio di andrologia e di chirurgia andrologica, rome, italy; 2 u.o. urologia, s. sebastiano hospital, frascati, italy; 3 department of fpm, sapienza university, rome, italy. archivio italiano di urologia e andrologia 2021; 93, 1 d. pozza, a. berardi, m. pozza, a. mosca, c. pozza 54 increases significantly. another factor influencing the frequency of marital intercourses, in the last 10-20 years, is represented by the sex-web with an increase of web-masturbation (7). many men report web-masturbation several times a week. after masturbation, males have no feeling or strength to have a sexual intercourse with their wives. today, most patients (> 40 years old) who visit our center for andrological problems generally refer sexual intercourses only in the weekend. the de is no longer a drama, but something missing that becomes important only if a male begins an affair or wants children and would like to increase the frequency of sexual intercourses. often only in these circumstances a male seeks an ultimate solution of his ed. for about 20 years we have been evaluating the relationships of our patients requiring a prosthetic solution for their ed. we started to consider the reactions of the partners; if they were informed of the surgical decision and if they supported or refused such a solution (8). in cases of married patients, we consider if they had extramarital relationships or if they buy prostitutes. in case of divorced or widowed patients, we investigated if the patients would prefer to remain alone in the future or if, instead, they would desire a new relationship both for domestic partnership and sexual activity. materials and methods since 1984 more than 39.000 patients presented to our private studio di andrologia for erectile or ejaculatory dysfunctions (about 40%), infertility (40%) and/or urologic problems (15%) (9). after diagnosis, specific therapies have been suggested. for patients affected by ed (a group of 9.200 pts) after the visit and specific diagnostic examinations (metabolic analyses, hormonal evaluations, often nocturnal penile tumescence test with rigiscan, dynamic penile duplex sonography, magnetic resonance imaging, neurological and cardiological examinations), we prescribed the available therapeutic modalities (psychotherapy, drugs, vasodilators, venous surgery, 5pdei, vasoactive injections, medical urethral system for erection or muse, urethral alprostadil creams, low intensity extracorporeal shockwave therapy or lieswt). we suggested the penile prosthetic solution to 750 pts who didn’t report any satisfactory results. out of them 577 accepted such option for treating their ed. in the first period (1984-2006) we recorded in our files only if the male was married or not. since 2007 (i.e. for the last 355 pts) we are recording more complete information dividing the patients in 6 groups: 1. single patients without no relationship and no sexual intercourses with women; 2. single patients with the opportunity to have sexual intercourses; 3. married patients with regular sexual activity; 4. married patients with wives who avoided or refused sexual intercourses; 5. married patients with sexual intercourses outside the marriage, with fixed relationships, lovers or prostitutes; 6. divorced or widowed patients who would like to start stable relationships for the future. we did not use validated and dedicated questionnaires about qol. the fact that medical visits had to be paid for limited the number of patients who mainly belonged to the middle or high class. normally, we did not use to send patients to a psychologist before surgery. patients were affected by various pathologies as venous or arterial and mixed vascular diseases; diabetes type 2; hypertension; peyronie’s disease; prostate and pelvic surgery outcomes; psychological and relational problems. we implanted a wide variety of ppi [semirigid, silicone: 97 (spp); malleable: 136 (mpp); inflatable: 122 (ipp)]. this was always justified by the search for low-cost ppi, because in italy patients had to pay for the clinic, prosthesis and surgeons. as a rule, we visited patients 710 days post-op and after about 1 and 12 months. a group of 36 pts did not comply to follow-up. many patients continued to carry out periodic and regular checks for many years afterwards. results results of ppi can be considered satisfying (1, 9) even if we recorded complications related to infections (14 pts, 3.9%) or malfunction of prosthetic cylinders and inflatable system (18 pts, 5.0%). in general, the patients who chose prosthetic surgery because they had ineffective sexual relationship, were able to have full sexual intercourses, although a share of them (15%) complained a shortening of the rod, a difficult penetration with semirigid and malleable prostheses (possible bending) and a significant loss of skin sensitivity. unmarried forty-four out of 46 unmarried patients with difficult sexual intercourses managed to have regular sex and decided to marry after ppi, including 5 younger patients (21-30 years old) who were not able to penetrate their girlfriends. only two patients continued to avoid sexual relationships for performance anxiety or for the lack of a stable partner. married all the married patients after ppi were able to have sexual intercourses, except three patients who reported a strong rejection by their wives who refused any kind of sexual intercourse. five patients who were never able to have penetrative intercourses after marriage managed to have a full and satisfying sexual life after ppi. we did not test the index of appraisal of the women (10) after their husbands’ ppi (11). extramarital relationships, divorced, widowed all pts who had a lover, referred good and improving sexual relationships. all divorced and widowed males who decided to have the ppi for a possible and new familial and sexual relationship referred to be fully satisfied of the ppi. obviously in this group of patients we were not able to analyze the reactions of their partners. psychological difficulties after ipp many males, after ppi, were often blocked by the fear that a new partner might notice the presence of the cavernous cylinders both semi-rigid and inflatable. in our experience, at least 5 patients with severe erectile dysfunction preventing sexual relationships, after the prosthetic implant admitted great difficulties in the first intercourses, because afraid of being discovered by their partner. most of our patients with mpp implants referred a better acceptance by their partners, because the penetration was easy after usual foreplay without particulars manoeuvres. patients with ipp could get better erection but they have to obtain it by inflating the ipp. a limited number of wives complained that the foreplay was compromised by these manoeuvres to have an artificial erection, thus changing the feeling about it. three out of 110 partners of patients with ipp (2.7%) considered this a reason for rejecting sexual intercourses with their husbands (12 were lost at follow up). on the contrary, 220 out of 223 patients with spp/mpp never referred that this was relevant (10 lost at follow up). in general, patients with partners who accepted or had been favourable to prosthetic surgery were able to use the prostheses earlier and with greater frequency of intercourses and satisfaction. this confirms the importance of the involvement and collaboration of the partner in the decision, preparation and post-op course of pps (12). in our clinical experience, 15 patients already personally convinced and just included in the program for penile prostheses implantation gave up or had to give up surgery due to the firm opposition of their no longer young wives, who considered the decision of their partner not absolutely relevant to modify or improve their relationship, that they considered optimal even if with scarce or no sexual activity. discussion the ppi is an effective option to treat ed especially in patients where pharmacological solutions have not provided satisfactory results. questionnaires, such as the female sexual function index (fsfi) (10, 13, 14), reporting the opinion of women on sexual function of their husbands or partners, are important to evaluate their sexual function and quality of life after ppi (15, 16). in the past, the literature addressed women sexual satisfaction in a generic way when reporting the satisfaction shown by women in relation to the penile prostheses of their partners. another problem begins to be observed in women with sexual dysfunction already existing before the resolution of the erectile dysfunction of their partners, who got used to the ed of their partners and after ppi begin to develop a high level of stress, as a result of the new requests and expectations made possible by the penile prosthetic implant (17). it has sometimes emerged that the wife, no longer young, begins to fear that the husband may be interested and involved in extramarital relationships, not possible as long as an ed was present. in those cases, it is important for the man to express his intention to integrate ppi into the sexual life of the couple. the man must make his wife understand, that the decision to have a ppi is aimed at restoring a correct sexuality in the couple. if this does not happen, it is probably too late to make that decision. the partner's decision should be understood and respected. obviously, it is essential to evaluate the sexual life of a couple before the decision to have a ppi implanted, because a woman who has not been having sexual intercourses for a long time, due to her husband's ed, or had a decrease in desire, might not be cooperative and participate in her partner's decision. it is often the surgeon's clinical ability and sensibility to illustrate the positive effects of ppi in the couple's life. until not long ago, the sexual life of menopausal women was culturally stigmatized. today, with the advent of hormonal therapies and the challenging and often rewarding social role, this perception has changed, and active desire and sexual life are universally accepted even at this stage of life. ppi is often considered as an "inconvenient third" in the intimacy of the couple even if it makes significant changes in the sexual health of the couple itself. in the literature, the importance of the women role in the treatment of patients is not taken into account. this can affect the overall vision about the surgery itself. in an italian survey (18) it was reported that about half of the sample (50.7% of men and 48.4% of women) was eager to choose (men) or to support (women) the choice of ppi in case of severe ed and the majority of both sexes (71.3% of males and 76.3% of females) did not oppose to the 55archivio italiano di urologia e andrologia 2021; 93, 1 woman and penile prostheses table 1. sexual activity and relationships of patients before surgery by age group. patients girlfriends marriage extramarital divorced widow years no. never had sex sex difficulties coexistence affairs < 21 6 3 3 0 0 0 0 21-30 30 3 22 5 2 0 0 31-40 44 2 13 28 3 0 0 41-50 75 0 0 69 23 5 1 51-60 98 0 0 92 34 4 2 61-70 64 0 0 54 26 6 4 71-80 33 0 0 22 8 5 6 81-90 5 0 0 1 3 2 2 total 355 8 38 271 96 22 15 table 2. protheses implanted in 355 patients. patients penile prostheses years semirigid malleable inflatable total < 21 6 0 0 6 21-30 18 6 6 30 31-40 16 18 10 44 41-50 17 34 24 75 51-60 20 38 38 96 61-70 14 18 32 64 71-80 5 20 10 35 81-90 1 2 2 5 51.20 mean 97 total 136 122 355 archivio italiano di urologia e andrologia 2021; 93, 1 d. pozza, a. berardi, m. pozza, a. mosca, c. pozza 56 choice of ppi. generally, the surgeon is not properly prepared, if not for personal factors and sensibility, to deal with the dynamics of the couple and, as a result, he/she often prefers not to involve the partner and to discuss all aspects only with the patient. adjusting false expectations and addressing the patient's doubts and concerns implies a willingness to dialogue and the involvement of various specialists, which is almost never possible. it would be important, after surgery, to join in sexological counselling sessions to help the couple regain the intimacy they lost after the ed and to recover after ppi. the recent clinical recommendations of the european society for sexual medicine points out that at present there are no standardized methods to determine the male and his partner expectations (19). careful and scrupulous sexological counselling seems to be fundamental to prevent the negative aspects of ppi on the couple relationship. even in these situations, the role of women is important in supporting the expectations of their partners and in driving the approach to consider having sex as a moment of intense couple relationship. conclusions in most cases, people tend to consider the penile prosthesis as a significant change in the man’s or couple’s life. for this change to be actually positive, it should promote the reinstatement of the psychosexual well-being of the patient and the couple. the clinician should take into account the necessary integration between surgical therapy and psychosexual counselling in the path leading to penile prosthesis. ppi can in fact allow penetrative intercourses and reduce the patient's discomfort in his sexual life in general, but at the same time, due to the irreversibility of prosthetic choice, it could trigger personal and couple dynamics related to the loss of sexual freedom and spontaneity. it would therefore be appropriate to involve, after the patient's first visit, the current partner who could provide important elements in the diagnostic phase and, therefore, help to reinforce the choice of the best therapeutic solution. in the case of ppi in particular, the involvement of women, who can be informed about the technical aspects of ppi and actually support their partners, could reduce the possibility of postoperative psychosexual complications. in addition, an indepth knowledge of the couple and their sexuality could allow a better monitoring of the subsequent results. in such cases, it is important for the partner to express her concerns considering the possibility of integrating the prosthesis into the couple's sexual life. the man must be able to reassure his partner that the decision to undergo surgery is something aimed at recovering the couple sexuality. if that does not happen, maybe it's a little late to make such an important decision. this article aims at emphasizing how important it can be to consider the impact of such an important "surgical solution" as a ppi, not only as a simple procedure but also as a factor with psychosexual consequences on the life of the man but also on the one of his partners. careful evaluation and psychosexual counselling are essential to prevent negative effects on the couple's life. in most cases the role of women is important, both to support the expectations of their partners and to adapt to the feasibility for sexual intercourses when the sexual life as a couple is not particularly intense. based on our over-35-year experience, we consider it important to be able to involve women from the very first steps, i.e. from the diagnosis and therapy phase of their partner's ed to the decision to undergo a ppi. women can help their partners to take this delicate and complex surgical decision, in order to find a new functional reality of the couple and be able to share the benefits and possible difficulties related to pps. aknowledgements we thank dr roberta rossi, phd, istituto di sessuologia clinica of rome for the invaluable advices and comments to the preparation of the article. references 1. wilson sk, delk jr. historical advances in penile prostheses. int j imp res. 2000; 12:101-7. 2. chevallier d, faix a, bettocchi c, et al. penile prosthesis in the treatment of erectile dysfunction: updates in 2020.rev med suisse. 2020; 16:525-30. 3. vakalopoulos i, kampantais s, ioannidis s, et al. high patient satisfaction after inflatable penile prostheses implantation correlates with female partner satisfaction. j sex med. 2013; 10:2774-81. 4. carter a, ford jv, luetke m, et al. ”fulfilling his needs, not mine”: reasons for not talking about painful sex and association with lack of pleasure in a national representative sample of women in the united states. j sex med. 2016; 16:1953-61. 5. beutel me, burghardt j, tibubos an, et al. declining sexual activity and desire in men-findings from representative german surveys 2005 and 2016. j sex med. 2018; 15:750-6. 6. simonelli c, eleuteri s, petruccelli f, et al. female sexual pain disorders: dyspareunia and vaginismus. curr opin psychiatry. 2014; 27:406-12. 7. duffy a, dawson dl, das nair r. pornography addiction in adults: a systematic review of definitions and reported impact. j sex med. 2016; 13:760-77. 8.barton gj, carlos ec, lentz ac. sexual quality of life and satisfaction with penile prostheses. sex med rev. 2019; 7:178-88. 9. pozza d, pozza m, musy m, et al. 500 penile prostheses implanted by a surgeon in italy in the last 30 years. arch ital urol andr. 2015; 87:216-23. 10. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000; 26:191-208. 11. rosen rc , riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-30. 12. özbay e, aydın a, salar rm, et al. sexual experiences between partners after penile prosthesis: who is more satisfied? andrologia. 2020; 52:13461-6. 13. awwad aa, aboseif af, fattag farag ma, et al. sexual functions of females married to males with semi-rigid penile implants: a cross-sectional study. urologia. 2019; 86:197-201. 57archivio italiano di urologia e andrologia 2021; 93, 1 woman and penile prostheses 14. isidori am, pozza c, esposito k, et al. development and validation of a 6-item version of the female sexual function index (fsfi) as a diagnostic tool for female sexual dysfunction. j sex med. 2010; 7:1139-46. 15. gittens p, moskovic jd, desiderio avila jr, et al. favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis implantation. j sex med. 2011; 8:19962001. 16. portman dj, gass mls. genitourinary syndrome of menopause: new terminology for vulvo vaginal atrophy from the international society for the study of women’s sexual health and the north american menopause societ. j sex med. 2014; 11:2065-72. 17. omonov d, christopher an, blecher ga. et al. clinical recommendations from the european society for sexual medicine exploring partner expectations, satisfaction in male and phalloplasty cohorts, the impact of penile length, girth and implant type, reservoir placement, and the influence of comorbidities and social circumstances. j sex med. 2020; 17:210-37. 18. pescatori es, baldini a, parazzini f, et al. how much do people know about male sexual problems? a survey in a selected population sample. arch ital urol androl. 2019; 91:182-6. 19. caraceni e, utizi l. a questionnaire for the evaluation of quality of life after penile prosthesis implant: quality of life and sexuality with penile prosthesis (qolspp): to what extent does the implant affect the patient's life? j sex med. 2014; 11:1005-12. correspondence diego pozza, md (corresponding author) diegpo@tin.it mariangela pozza, md mariangela.pozza@gmail.com carlotta pozza, md, phd carlotta.pozza@gmail.com via b. gozzoli, 82c, 00142 rome (italy) alberto berardi, md alberto.berardi@alice.it augusto mosca, md moscaugusto@gmail.com via tuscolana, 2, 00044 frascati-rm (italy) 277archivio italiano di urologia e andrologia 2017; 89, 4 original paper the correlation between biological activity and diffusion-weighted mr imaging and adc value in cases with prostate cancer bedriye koyuncu sokmen 1, dogukan sokmen 2, nese ucar 3, huseyin ozkurt 4, abdulmuttalip simsek 5 1 department of radiology, sisli florence nightingale hospital, istanbul, turkey; 2 department of urology, hospital derindere, istanbul, turkey; 3 department of radiology, gaziosmanpasa taksim training and research hospital, istanbul, turkey; 4 department of radiology, istanbul hamidiye sisli etfal training and research hospital, istanbul, turkey; 5 department of urology, bakirkoy dr. sadi konuk training and research hospital, istanbul, turkey. purpose: firstly, we aimed to investigate the correlation among dynamic contrasted magnetic resonance (mr) images, diffusion-weighted mr images, and apparent diffusion coefficent (adc) values in patients with prostate cancer. secondly, we aimed to investigate the roles of these variables on clinical risk classification and the biological behavior of the prostate cancer. methods: a total of sixty with prostatic adenocarcinoma patients diagnosed between january 2011 and may 2013 were retrospectively included in the study. risk classification of patients were evaluated as low-risk (group 1) (n = 20) (stage t1c-t2a, psa < 10 ng/ml, gleason score < 7), moderate-risk (group 2) (n = 18) (stage t1b-t2c, psa = 10-20 ng/ml, gleason score = 7) and high-risk (group 3) (n = 22) (stage > t3a, psa > 20 ng/ml, gleason score > 7). diffusion-weighted mr images, dynamic contrasted mr images, and adc values of the prostates were correlated. results: adc values of the cases in group 3 were lower than those of the other groups (p < 0.001). adc values of the areas without malignancy did not differ significantly between groups (p > 0.05). biological activity of the tumor tissue was determined by gs, while a negative correlation was observed between gss and adc values of the patients, (p < 0.001). conclusion: in tumors with higher gleason scores, lower adc values were obtained. these measured values can play a role in the noninvasive determination of the cellularity of the tumoral mass. key words: prostate cancer; dynamic contrasted mri; diffusion-weighted mri; apparent diffusion coefficient value. submitted 17 july 2017; accepted 23 september 2017 summary no conflict of interest declared. determination of its location have been realized and evaluated using serum prostate-specific antigen (psa) tests, digital rectal examination and transrectal ultrasound (trus) guided-biopsy which has a diagnostic accuracy of 36.8 percent (5, 6). imaging modalities, which provide individualized prognostic foresight are important for us. currently applied functional magnetic resonance (mr) modalities including conventional mr and diffusion-weighted imaging (dwi) provide more detailed information about location, size and activity, of the tumor and also a noninvasive identification method (7). since dwi is a technique used to demonstrate molecular diffusion due to brownian movements in biological tissues, diffusion is restricted in tumor cells because of increased cellularity. various studies based on lower apparent diffusion coefficent (adc) demonstrated that dwi could discriminate between benign and malignant prostatic tissue in comparison with normal prostatic tissue (8, 9). in our study, we aimed to investigate if determination of the biological behavior of the prostate cancer and the roles played by dynamic contrasted mri and dwi in clinical risk classification of prostate cancer is possible by correlating dynamic contrasted mri, dwi, adc values and histopathological diagnosis. in our study, firstly we aimed to investigate the correlation among dynamic contrasted mr images, diffusionweighted mr images, and adc values in patients with prostate cancer. secondly, we aimed to investigate the roles of these variables on clinical risk classification and the biological behavior of the prostate cancer. materials and methods study design the study has been conducted in accordance with the principles of the helsinki declaration and approved by the local institutional review board (25/11/2015, no:33). written informed consent was obtained from all subjects. a total of sixty patients with suspected prostate cancer doi: 10.4081/aiua.2017.4.277 introduction prostate cancer is the most frequently diagnosed type of cancer among men in the united states of america, while it ranks after lung and colorectal cancer in europe (1). however, it has the second most frequently seen cancerrelated mortality among men (2, 3). though the incidence of prostate cancer increases, it affects 15 and 4% of the male population in developed and developing countries, respectively (4). prostate cancer has a wide spectrum ranging from slowly progressing course and higher aggressivity. diagnosis of the prostate cancer and simsek_stesura seveso 03/01/18 09:43 pagina 277 archivio italiano di urologia e andrologia 2017; 89, 4 b. koyuncu sokmen, d. sokmen, n. ucar, h. ozkurt, a. simsek 278 based on clinical examination and psa measurements, and diagnosed as prostatic adenocarcinoma histopathologically between january 2011 and may 2013 were evaluated retrospectively. risk classification of 60 clinically localized prostate cancer patients who underwent radical prostatectomies were evaluated as low-risk (group 1) (n = 20) (stage t1c-t2a, psa < 10 ng/ml, gleason score < 7), moderate-risk (group 2) (n = 18) (stage t1b-t2c, psa = 10-20 ng/ml, gleason score = 7) and high-risk (group 3) (n = 22) (stage > t3a, psa > 20 ng/ml, gleason score > 7). outcome parameters t1-t2 axial, coronal section, axial diffusion-weighted mr images and dynamic contrasted mr images of the prostates of all cases were reviewed. in the present study “body” coil was used to obtain single shot images. diffusion-weighted sequences were obtained on axial plane at 3 gradients with different b values (b: 0 sec/mm², b: 500 sec/mm², b: 1000 sec/mm²). adc maps were constructed using automated devices. adc values and histopathological diagnoses of 60 cases were comparatively evaluated. patients with bleeding demonstrated on post-trus-bx mr images and inoperable advanced stage and metastatic cases were excluded from the study. in our study siemens avanto (erlangen germany) 1.5 tesla mr device of our radiology clinic was used. histopathological evaluations of radical prostatectomized cases were reported in consideration of prostate zone, tumor percentage, surgical margin, gleason score (gs), locations with/without malignancy. cases with low, moderate and high risk were classified as groups 1, 2, and 3, respectively (figures 1-3). adc values obtained individually using dwi techniques for regions of malignancy detected in pathology specimens and also for regions reported as benign lesions were determined. these values were compared with histopathological results and gss of patients who underwent radical prostatectomy. using this method, the correlation (if any) between biological activity detected by histopathological evaluation and dwi in prostate cancer patients was investigated. statistical analysis: all statistical analyses were realized using windows for spss v.13.0 (statistical package for social sciences) (spss inc. chicago, abd). adc values were expressed as mean ± standard deviation. student’s t test was used to compare adc values. for intergroup comparisons of age, psa values, gs one way anova (tukey) test was used. p < 0.05 was accepted as the level of statistical significance. results median age of 60 patients who underwent conventional mri and dwi was 60.95 (range, 45 to 73) years without any significant intergroup difference regarding age of the patients (p > 0.05). median psa value of the cases was 10.81 (range, 3.10 to 43.35) ng/ml. as a matter of fact, psa values were significantly higher in group 3 (p < 0.001). gs of 7 points was detected in groups 1 (n = 20) and 2 (n = 22). in group 3, gss of 8 (n = 7), 9 (n = 3) and 10 (n = 1) points were detected in respective number of cases (table 1). to calculate adc values of the cases circumscribed regions of interest (roi) of the cases were determined based on anatomical location of histopathologically detected adenocarcinoma foci in radical prostatectomy specimens of each patient. therefore, for each patient diagnosed as prostate cancer, foci of adenocarcinoma were on different locations. they were on peripheral zone (n = 51 foci), central zone (n = 5) and both central and peripheral zone (n = 4). a median roi of the prostatic area of 25 mm² containing adenocarcinoma foci based on histopathological examination of the table 1. prostate-specific antigen values and gleason scores according to groups. group 1 (n = 20) group 2 (n = 22) group 3 (n = 18) mean age (years) 58.45 61.59 62.94 mean psa (ng/ml) 6.79 8.80 18.08 gleason 6 (n) 20 5 2 gleason 7 (n) 17 5 gleason 8 (n) 7 gleason 9 (n) 3 gleason 10 (n) 1 table 2. apparent diffusion coefficient values of malign lesions according to groups. n (%) adc (×10ˉ6 mm2/sec) p value mean (min-max) group 1 20 (33.3%) 1130.30 ± 110.77 (931-1305) p < 0.001 group 2 22 (36.6%) 988.05 ± 141.54 (618-1241) group 3 18 (30%) 822.33 ± 141.11 (445-1034) total 60 (100%) 985.75 ± 179.03 (445-1305) table 3. apparent diffusion coefficient values of benign lesions according to groups. n (%) adc (×10ˉ6 mm2/sec) p value mean (min-max) group 1 20 (33.3%) 1541.50 ± 190.76 (1244-2002) p > 0.05 group 2 22 (36.6%) 1513.32 ± 132.64 (1337-1782) group 3 18 (30%) 1431.94 ± 163.87 (1196-1773) total 60 (100%) 1498.30 ± 166.67 (1196-2002) table 4. apparent diffusion coefficient values of malign lesions according to gleason scores. n (%) adc (×10ˉ6 mm2/sec) p value mean (min-max) gleason 6 27 (45%) 1105.78 ± 112.70 (898-1305) p < 0.001 gleason 7 22 (36.66%) 940.00 ± 139.19 (618-1241) gleason 8 7 (11.66%) 863.43 ± 114.75 (670-1034) gleason 9 3 (5%) 706.67 ± 67.26 (646-779) gleason 10 1 (1.66%) 445 (445-445) total 60 (100%) 985.75 ± 179.03 (445-1305) simsek_stesura seveso 03/01/18 09:43 pagina 278 prostate specimens of each patient was measured and average value of these measurements were taken into consideration as the basic reference value. therefore, adc values were determined based on the histopathology reports of the cases with prostate cancer. accordingly adc values of the cases in group 3 were lower than those of the other groups (p < 0.001) (table 2). adc values were determined based on rois of 25 mm² of prostates without malignancy as detected by histopathological evaluation. accordingly, adc values of the areas without malignancy (ie. benign areas) did not differ significantly between groups (p > 0.05) (table 3). biological activity of the tumor tissue was determined by gs, while a negative correlation was observed between gss and adc values of the patients, (p < 0.001) (table 4). discussion gleason score is the most widely used and accepted scoring system in the evaluation of the aggressivity of the prostate cancer d’amico classification of clinical risk has been developed by combining psa value and gs in order to evaluate tumor aggressivity more accurately (10, 11). using conventional imaging modalities, it is quiet difficult to make a diagnosis of locally advanced prostate cancer. besides because of the presence of benign diseases as bph and chronic prostatitis it is more difficult discriminate among these entities (12). magnetic resonance imaging can delineate the contours of the prostate and anatomical details of the internal zone can be disclosed. in addition, dwi, mr spectroscopy (mrs) and dynamic contrasted mri can also provide functional data. all of these data can determine the location of cancer, tumor volume and aggressivity more accurately when compared with other imaging modalities. in cases with suspect clinical prostate cancer patients with higher psa values, but negative recurrent negative biopsy results, mri demonstrates anatomic location of the tumor and functions as a road map for biopsies and surgery to be perform and also paves the way for focal radiotherapeutic approach (13, 14). many studies have been performed on the discrimination between normal and malignant prostate tissue using dwi technique. adc values reported in the literature for peripheral zone of the normal prostate (1.60-1.97 ×10-3 mm2/s), transitional zone (1.27-1.79 ×10-3 mm2/s) and prostate cancer (0.98-1.38 ×10-3 mm2/s) vary considerably. this variability may stem from the power of the diffusion gradient (300-1000 s/mm2) and magnetic area (1.5-3 t) (15-17). yagci et al. performed a study on 43 patients and reported that pre-biopsy dwi was valuable in the detection, localization and staging of the tumor in the peripheral zone and adc values would be a 279archivio italiano di urologia e andrologia 2017; 89, 4 the correlation between biological activity and diffusion-weighted mr imaging and adc value in cases with prostate cancer figure 1. a low-risk patient with psa = 8.3 ng/ml and gleason score of 6. t1a and t2 fat sat sequences showing hypointense central zone of the prostate (a, b, e). restricted dwi mri showing a malignant focus with adc value measured as 1013×106 mm2/sec which demonstrated marked contrast uptake during contrast-enhanced examination (c, d). figure 2. a moderate-risk patient with psa = 15 ng/ml and gleason score of 7. t1a and t2 fat sat sequences showing hypointense peripheral zone of the left half of the prostate (a, b, e). restricted dwi mri showing a malignant focus with adc value measured as 914×106 mm2/sec which demonstrated a mild contrast uptake during contrast-enhanced examination (c, d). simsek_stesura seveso 03/01/18 09:43 pagina 279 archivio italiano di urologia e andrologia 2017; 89, 4 b. koyuncu sokmen, d. sokmen, n. ucar, h. ozkurt, a. simsek 280 guiding tool for biopsy. in parallel with gss, they found adc values as 1.18 ± 0.44 × 10-3 mm2/s (gs 6); 1.05 ± 0.15 × 10-3 mm2/s (gs7) and 0.84 ± 0.16 × 10-3 mm2/s (gs ≥ 8) (18). differently from our study, they accepted a b value of 800 s/mm2 as a base value and used endorectal coil. tamada et al. used 1.5 t mr in their study group consisting of 90 prostate cancer patients and indicated the presence of a negative correlation between adc values and gss (19). similarly, mazaheri et al. and desouza et al. compared adc levels in cases with low and highrisk prostate cancer and found significant intergroup differences (20, 21). van as et al. followed up 86 patients for an average of 29 months and then evaluated psa, clinical stage and results of recurrent biopsy outcomes with the intention of detecting localized prostate cancer with a favorable prognosis. the authors revealed that adc value is an important prognostic factor demonstrating progression of the disease (22). gibbs et al. prospectively correlated 3t mri, t2 relaxation time and adc values in patients scheduled for radical prostatectomy and compared cellular density measurements in prostate cancer tissue in prostatectomy materials and adc values calculated for normal peripheral zone and cancer tissue. in conclusion, a negative correlation between cellular density, more markedly between gss and adc values was observed. in the light of the data obtained, it was concluded that via determination of cellular density, which is potentially related to gs, mri can have a prognostic role in the prediction of metastatic activity and aggressivity of the tumor tissue (23). in a study by türkbey et al., performed in the year 2011, the authors demonstrated a negative correlation between d’amico risk classification using 3t mr and endorectal coil gs of the tumor and adc values and indicated that adc values would help the clinicians in the evaluation of tumor aggressivity (24). in our study, a negative correlation was detected between adc values and gleason risk classification. in tumors with increased gss, a drop in adc values was observed due to altered structure of the tumor tissue in its location in the prostate gland because of tumoral cellularity and also restricted movement of water molecules in this location. besides, an important difference was detected in adc values of the tumors included in low, moderate and high clinical risk classification. treatment protocol effects the determination of biological aggressivity in prostate cancer. in some clinics, active surveillance is the most optimal follow-up strategy in the determination of biological aggressivity. it will be appropriate to evaluate aggressivity of prostate cancer and use it with the intention to follow-up the patients who will be included in the active surveillance protocol with adc mapping. this approach can provide us a noninvasive method of monitorization of the patients when compared with recurrent biopsies (25). conclusions since all regions of the prostate gland can be visualized and adc mapping can be obtained using diffusion-weighted mr, it can provide more advantageous evaluation when compared with trus biopsy. foci of malignancies, which can not be detected in trus biopsy, can be determined with attentive and detailed examination for the purpose of adc mapping. at the same time, in the patient group with persistently higher psa levels but without any detected adenocarcinoma foci in recurrent prostate biopsies, adc mapping with diffusion-weighted mr imaging of the prostate detects locations with lower adc values which can contribute significantly to the determination of targeted biopsy locations for recurrent biopsies to be performed in the future with resultant decrease in the number of unnecessary biopsies. in our study, the correlation between gleason scoring system and d’amico clinical risk classification which determines biological activity of the tumor, and adc values were revealed. in tumors with higher gss, lower adc values were obtained. these measured values can play a role in the noninvasive determination of the cellularity of the tumoral mass. discrimination between low and high gss using adc values may allow noninvasive specification of the disease prognosis. as the number of prospective studies performed with adc increase in the years to come, adc may have a guiding role in the selection of treatment for the cases with locally advanced stage and metastatic prostate cancer, in the monitorization of treatment response and also in determination of the disease-free survival. figure 3. a high-risk patient with psa = 21 ng/ml and gleason score of 8. t1a and t2 fat sat sequences showing hypointense peripheral zone of the right half of the prostate (a, b, e). restricted dwi mri showing a malignant focus with adc value measured as 651×106 mm2/sec which demonstrated a mild contrast uptake during contrast-enhanced examination (c, d). simsek_stesura seveso 03/01/18 09:43 pagina 280 references 1. jemal a, murray t, ward e, et al. cancer statistics, 2005. ca cancer j clin. 2005; 55:10-30. 2. boyle p, ferlay j. cancer incidence and mortality in europe 2004. ann oncol. 2005; 16:481-8, 3. jemal a, siegel r, ward e, et al. cancer statistics, 2008. ca cancer j clin. 2008; 58:71-96. 4. parkin dm, bray fi, devesa ss. cancer burden in the year 2000: the global picture. eur j cancer. 2001; 37(suppl 8):s4-66. 5. yagci ab, ozari n, aybek z, duzcan e. the value of diffusionweighted mri for prostate cancer detection and localization. diagn interv radiol. 2011; 17:130-4. 6. andriole gl, levin dl, crawford ed, et al. plco project team. prostate cancer screening in the prostate, lung, colorectal and ovarian (plco) cancer screening trial: findings from the initial screening round of a randomized trial. j natl cancer inst. 2005; 97:433-8. 7. woodfield ca, tung ga, grand dj, et al. diffusion-weighted mri of peripheral zone prostate cancer: comparison of tumor apparent diffusion coefficient with gleason score and percentage of tumor on core biopsy. ajr. 2010; 194:316-22. 8. kim ck, park bk, han jj, et al. diffusion-weighted imaging of the prostate at 3 t for differentiation of malignant and benign tissue in transition and peripheral zones: preliminary results. j comput assist tomogr. 2007; 31:449-54. 9. pickles md, gibbs p, sreenivas m, turnbull lw. diffusionweighted imaging of normal and malignant prostate tissue at 3,0 t. j magn reson imaging. 2006; 23:130-4. 10. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama 1998; 280:969-74. 11. d’amico av, moul j, carroll pr, et al. cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. j clin oncol 2003; 21:2163-2172. 12. ross r, harisinghani m. prostate cancer imaging what the urologic oncologist needs. to know. radiol clin north am. 2006; 4:711722. 13. turkbey b, albert ps, kurdziel k, choyke pl. imaging localized prostate cancer: current approaches and new developments. ajr am j roentgenol. 2009; 192:1471-1480. 14. mazaheri y, shukla-dave a, muellner a, hricak h. mr imaging of the prostate in clinical practice. magma 2008; 21:379-392. 15. pickles md, gibbs p, sreenivas m, turnbull lw. diffusionweighted imaging of normal and malignant prostate tissue at 3.0t. j magn reson imaging. 2006; 23:130-134. 16. kim ck, park bk, lee hm, kwon gy. value of diffusionweighted imaging for the prediction of prostate cancer location at 3t using a phased-array coil: preliminary results. invest radiol. 2007; 42:842-847. 17. ren j, huan y, wang h, et al. diffusion-weighted imaging in normal prostate and differential diagnosis of prostate diseases. abdom imaging. 2008; 33:724-8. 18. yagci ab, ozari n, aybek z, düzcan e. the value of diffusionweighted mri for prostate cancer detection and localization. diagn interv radiol. 2011; 17:130-4. 19. tamada t, sone t, jo y, et al. apparent diffusion coefficient values in peripheral and transition zones of the prostate: comparison between normal and malignant prostatic tissues and correlation with histologic grade . j magn reson imaging. 2008; 28:720-726 . 20. mazaheri y, hricak h, fine sw, et al. prostate tumor volume measurement with combined t2-weighted imaging and diffusionweighted mr: correlation with pathologic tumor volume . radiology. 2009; 252:449-457 21. desouza nm, riches sf, vanas nj, et al. diffusion-weighted magnetic resonance imaging: a potential non-invasive marker of tumor aggressiveness in localized prostate cancer. clin radiol. 2008; 63:774-782. 22. van as nj, de souza nm, riches sf, et al. a study of diffusionweighted magnetic resonance imaging in men with untreated localised prostate cancer on active surveillance. eur urol. 2009; 56:981-7. 23. gibbs p, liney gp, pickles md, et al. correlation of adc and measurements with cell density in prostate cancer at 3.0 tesla. invest radiol. 2009; 44:572-576. 24. turkbey b, shah vp, pang y, et al. is apparent diffusion coefficient associated with clinical risk scores for prostate cancers that are visible on 3-t mr images? radiology. 2011; 258:488-95. 25. gibbs p, pickles md, turnbull lw. repeatability of echo-planar-based diffusion measurements of the human prostate at 3 t. magn reson imaging. 2007; 25:1423-1429. 281archivio italiano di urologia e andrologia 2017; 89, 4 the correlation between biological activity and diffusion-weighted mr imaging and adc value in cases with prostate cancer correspondence bedriye koyuncu sokmen, md (corresponding author) bedriyekoyuncu@yahoo.com department of radiology, sisli florence nightingale hospital istanbul 34340, turkey dogukan sokmen, md department of urology, hospital derindere,istanbul, turkey nese ucar, md department of radiology, gaziosmanpasa taksim training and research hospital, istanbul, turkey huseyin ozkurt, md department of radiology, istanbul hamidiye sisli etfal training and research hospital, istanbul, turkey abdulmuttalip simsek, md department of urology, bakirkoy dr. sadi konuk training and research hospital, istanbul, turkey simsek_stesura seveso 03/01/18 09:43 pagina 281 stesura seveso 389archivio italiano di urologia e andrologia 2014; 86, 4 case report burned-out in a mixed germ cell tumor of the testis: the problem of pt0. case report carlos miacola, ottavio colamonico, carlo bettocchi, vito ricapito, silvano palazzo, marcello campagna, michele battaglia, pasquale martino policlinico di bari, divisione urologia universitaria i, bari, italy germ cell tumors constitute the majority of all testicular tumors, which are relatively rare overall and are mainly encountered in young adults and teenagers. the term ‘burned-out’ germ cell tumor refers to the presence of a metastatic germ cell tumor with histological regression of the primary testicular lesion. clinical examination of the testes and scrotal sonography is the initial diagnosis of such neoplasms. we report an unusual case of a burned-out testicular tumor with metastases to retroperitoneal lymphnodes in an asymptomatic patient with right testicular hypoechoic nodule associated with multiple calcifications of the testicular parenchyma. key words: burned-out tumor; germ cell tumor; testicular tumor. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. last ileal loop was unresectable at surgical exploration; a surgical biopsy reveled mixed germ cell tumor composed of yolk sac tumor, embryonal carcinoma and seminoma. in the following days the patient showed a rapid deterioration of lung function resulting in death from pulmonary embolism. discussion it is important to distinguish burned-out tumor of the testis from extragonadal germ cell tumor. in the first case, orchiectomy change prognostic outcome (1, 2). in this case report, the early diagnosis of a burned-out tumor of the testis was made difficult by the absence of symptoms and by the late raising oh neoplastic markers; microlithiasis at testicular ultrasound seems associated with burned-out tumor (3). the ‘burned-out’ phenomenon in germ cell tumors refers to a germ cell tumor in extra-gonadal tissues with spontaneous regression of an intra-gonadal tumor. extragonadal germ cell tumors are usually found in the retroperitoneal, supraclavicular, cervical, and axillary lymph nodes and occasionally in the lung and liver. there are two theories to explain this phenomenon. the first is spontaneous regression of a primary germ cell tumor after metastasis of the germ cell tumor. the mechanism of this regression is yet to be elucidated. possible explanations are an immune response or ischemia caused by the neoplasm outgrowing its blood supply due to its high metabolic rate. a second hypothesis is the denovo development of a primary germ cell tumor in extragonadal tissues (4). patients with extra-gonadal germ cell tumors with the burned out phenomenon usually complain of many vague symptoms, such as flank pain, abdominal mass, night sweating, or scrotal pain, and occasionally reveal an elevated testicular tumor marker. in our case, the patient complained of left-sided back pain without elevation of tumor markers (4). histological features that are helpful in establishing a diagnosis of a regressed testicular germ cell tumor include, apart from the scar formation, intratubular calcifications, lymphoplasmacytic infiltrate, hemosiderincontaining macrophages, and testicular atrophy (5). doi: 10.4081/aiua.2014.4.389 presented at 19th national congress sieun, fermo 2014 case report a 36 years old, asymptomatic and azoospermic patient, with secondary infertility and a testicular ultrasound detection of multiple calcifications distributed throughout the parenchyma associated an hypoechoic area of 22 mm with peripheral calcifications in the right testicle (a testicular nodule was appreciable at palpation with negative tumor markers). excision of the nodule was performed. extemporaneous histological examination showed fibrosis, while the definitive one showed seminiferous tubules transformed into areas of sclero-hyalinosis (95%), a micro-focal of adenomatous hyperplasia of rete testis and moderate interstitial fibrosis. the following year, the patient presented a rise of tumor markers (β-hcg 8.14 miu/ml and α-fp 125 iu/ml) without symptoms; testicular ultrasound showed an hypoechoic nodule of the right testicular with calcification of surrounding parenchyma; left testicle was normal. we performed a right orchiectomy with histological examination negative for testicular cancer. in the following weeks, there was a a further increase of tumor markers (β-hcg 15.79 miu/ml α-fp 705 iu/ml and ldh 909 u/l) associated with enlarged retroperitoneal lymph nodes at the ct scanning. a large tumor surrounding abdominal vessels and infiltrating the miacola_stesura seveso 16/01/15 11:41 pagina 389 archivio italiano di urologia e andrologia 2014; 86, 4 c. miacola, o. colamonico, c. bettocchi, v. ricapito, s. palazzo, m. campagna, m. battaglia, p. martino 390 conclusion the management of non-palpable lesions of the testis had to provide the execution of targeted multiple testicular biopsies to exclude the presence of cancer in the testicular tumor regression context in its primary site and, above all, a careful evaluation of the retroperitoneal lymph nodes in the suspicion of pt0 that, when not diagnosed in time as in the present case, can also evolve to the exitus. references 1. sahoo pk, mandal pk, mukhopadhyay s, basak sn. burned out seminomatous testicular tumor with retroperitoneal lymph node metastasis: a case report. indian j surg oncol. 2013; 4:390-2. 2. gurioli a, oderda m, vigna d, et al. two cases of retroperitoneal metastasis from a completely regressed burned-out testicular cancer. urologia. 2013; 80:74-9. 3. sidhu ps, muir gh. extragonadal tumor and testicular microlithiasis: "burned-out" tumors are represented by macrocalcification. j ultrasound med. 2011; 30:1604-5. 4. ha hk, jung sg, park sw, et al. retroperitoneal seminoma with the ‘burned out’phenomenon in the testis. korean j urol. 2009; 50:516-519. 5. bär w, hedinger c. comparison of histologic types of primary testicular germ cell tumors with their metastases: consequences for the who and the british nomenclatures? virchows arch a pathol anat histol. 1976; 370:41-54. figure 1. hypoechoic area on the right testis with multiple parenchyma calcifications. figure 2. retroperitoneal lymph node package surrounds aorta and invades cava. figure 3. bilateral massive pulmonary embolism. correspondence carlos miacola, md (corresponding author) cmiacola@hotmail.it ottavio colamonico, md ottaviocolamonico@gmail.com carlo bettocchi, md carlo.bettocchi@uniba.it vito ricapito, md vito.ricapito@uniba.it silvano palazzo, md silvano.palazzo@uniba.it marcello campagna, md marcecampagna@gmail.com michele battaglia, md michele.battaglia@uniba.it pasquale martino, md martino@urologia.uniba.it policlinico di bari – divisione urologia universitaria i piazza g. cesare 11 70124 bari, italy miacola_stesura seveso 16/01/15 11:41 pagina 390 cop+ed+fisse 2006 205archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.205 non-secreting adrenal myelolipoma in a middle-aged male patient manifesting with sudden onset of severe lower back pain carlo introini 1, fabio campodonico 1, marco ennas 1, antonia di domenico 1, luca foppiani 2 1 urology, 2 internal medicine, galliera hospital, genoa, italy. adrenal myelolipoma (aml) is a rare benign tumor, usually non-functioning and asymptomatic until it reaches large size. aml is mostly detected incidentally by imaging and is composed of adipose tissue and hematopoietic elements. only symptomatic tumor needs surgical excision. we report the case of a large non-functioning adrenal tumor discovered by means of combined imaging techniques in a middle-aged male patient who complained the sudden onset of severe lower back pain; successful laparoscopic removal was performed, and aml was diagnosed at histopathology. key words: adrenal myelolipoma; tumor size; laparoscopy. submitted 2 march 2020; accepted 15 march 2020 summary introduction adrenal myelolipoma (aml) is a benign tumor composed of variable amounts of mature adipose tissue and bone marrow (hematopoietic) elements. aml has an overall prevalence at autopsy of 0.0.8-0.2%, affects patients in their fifth to seventh decades of life, and is usually asymptomatic and non-functioning (1). with the widespread use of ultrasonography (us), computed tomography (ct) and magnetic resonance imaging (mri), the finding of aml has reached up to 7-15% of adrenal incidentalomas (2, 3). albeit mostly asymptomatic, huge aml may cause flank pain and abdominal discomfort/pain by causing pressure of surrounding structures and may present with rupture, haemorrhage, or hemorrhagic shock (1, 3). in patients with aml three distinct types of endocrine dysfunctions have been described: hormone secreting aml, aml occurring in patients with congenital adrenal hyperplasia (cah) and aml occurring in association with a secreting adrenal co-lesion. the rare secreting amls display cortisol or aldosterone secretion; nevertheless, a few reports of catecholamine and androgen secretion have been described (1, 3). we report the case of a large non-functioning aml which was discovered in a middle-aged male patient presenting with sudden lower back pain. case report a 47-year-old man was admitted to the emergency department for severe lower right back pain and vomiting. physical examination was unremarkable, and blood pressure and blood tests were normal. abdomen us showed a large 9 × 6 cm hyperechoic curved lesion with regular edge localized in the right suprarenal region. contrast-enhanced ct confirmed a large 9 cm elliptical heterogeneous neoplasm with regular margins localized in the right adrenal gland, which featured a hypodense part interspersed with more dense component (figure 1a), and proved suspicious for pheochromocytoma. the patient was admitted to the urology ward. in view of surgical removal of the adrenal mass, hormonal array was carried out on both plasma (acth, cortisol, 17-hydroxyprogesterone, dheas, upright renin and aldosterone) and urine (24-h free cortisol, 24-h metanephrines and normetanephrines); all values proved unremarkable. laparoscopic adrenalectomy was performed by transperitoneal approach. in lumbotomic position four trocars were placed by configuring a diamond draw. this technique offers a wide visualization of the operative field ensuring minimal morbidity. the 12-mm port was inserted at the lateral border of the rectus abdominis muscle just above the level of the umbilicus to accommodate the camera. two subcostal 5-mm ports were placed; one in the midclavicular line and the other in the lateral border of the rectus abdominis muscle. the third 5-mm subcostal trocar was inserted in the anterior axillary line. the upper pole of the right kidney was mobilised and the huge adrenal lesion was found (figure 1b, c). once the mobilization of the lesion was completed, the tumor was removed en-bloc by enlarging the pararectal incision. on gross examination, a 9 x 6 cm reddish yellow colored and friable mass was observed. histology showed normally shaped mature adipocytes mixed with hematopoietic cells and surrounded by a capsule; these features were compatible with the diagnosis of myelolipoma. postoperative course was uneventful and the patient was discharged after 5 days. discussion aml is discovered incidentally in 2-5% of population during imaging analysis performed for other reasons. tumor size varies from several millimeters to more than 40 centimeters (1, 3). the fat component of aml is postulated to be derived by the mesenchymal stem cells harbouring in the vessel wall of stromal fat of adrenal cortex. the mature adipocytes become inflammatory and stimulate adrenal cortex tissue to release substances (likely granulocyte colony stimulating factor) that recruit 11foppiani_stesura seveso 24/09/20 14:23 pagina 205 archivio italiano di urologia e andrologia 2020; 92, 3 c. introini, f. campodonico, m. ennas, a. di domenico, l. foppiani 206 circulating haematopoietic progenitors to anchor and differentiate (4). the diagnosis of aml is usually made by means of various imaging techniques (us, ct and mri). ct is considered the most sensitive way to detect these lesions, since amls show low attenuation values (-10 to -30 hounsfield units) and mixed density. although not diagnostic, the presence of fat density within the mass is a very useful feature to characterize a lesion as a myelolipoma (5). a recent review on 420 cases of aml ascertained that the average size was 10 cm; cah was present in 10% of patients, whereas cortisol or aldosterone secretion was found in 7.5% of cases (1). in our patient the size of the adrenal mass was in line with literature data and no hormonal secretion was ascertained. asymptomatic amls which measure less than 4 cm do not require further investigation (hormonal evaluation or follow-up imaging). surgical treatment becomes necessary in those rare tumours which are functional or increase in size or become symptomatic. amls larger than 6 cm are at high risk of spontaneous rupture with haemorrhage leading to acute abdomen and shock and should be removed (1, 3). in our patient, a large (9 cm) aml became symptomatic (severe back pain) and required surgery. however, the ct features of the right adrenal mass were initially deemed suggestive of pheochromocytoma: this tumor, in fact, may show homogeneous or variable enhancement as was found in our patient (5), and this may puzzle the diagnosis. hormonal work-up was therefore carried-out. the normality of 24-h urinary metanephrine and normetanephrine levels and blood pressure prompted us to exclude a pheochromocytoma. in addition, normal 17-hydroxyprogesterone levels ruled out cah; finally, normal acth and cortisol levels together with the absence of cushingoid’s features likely excluded a cortisol-secreting aml. the clinical practice guidelines of european society of endo cri no logy do not recommend in aml the endocrine/metabolic work-up deemed mandatory in other adrenal incidentalomas (2). however endocrine dysfunctions are reported in 7-10% of aml (1, 3). in our opinion, given the increasing number of aml reported as secreting hormones or occurring in association with either cah or adrenal collision tumors (adrenal carcinoma, cortisol-secreting adenoma, aldosterone-secreting adenoma), endocrine work-up seems advisable at least in those patients with hypertension, diabetes, or bilateral aml. from a urological point of view is consolidated that the organ most suitable for the laparoscopic approach is the adrenal gland; since it is deeply located in the retroperitoneum a large incision is required in case of open surgery. the right adrenalectomy, specifically in case of tumor diameter larger than 5 cm, can be more challenging due to the proximity with the inferior vena cava and the duodenum (6). a recent study compared the results in two groups of patients who underwent single-site transumbilical laparoendoscopic adrenalectomy (la) for adrenal tumors or standard multi-port la. no difference in terms of operative time, blood loss, analgesic requirement, and hospital stay was found; however in the first group 85% of patients did not require drainage compared to 25% of patients in the second group, and resumed normal diet earlier (7). conclusions aml is a rare, benign, and usually asymptomatic tumor of adrenal gland. hormonal work-up seems worthwhile at least in those patients at high metabolic risk or who are referred to surgery. in particular, rare catecholaminesecreting amls must be ruled out before surgery in order to prevent life-threatening hypertensive crisis during intraoperative tumor manipulation. the amls which are symptomatic owing to hormonal secretion or more frequently to mass effect should undergo surgical excision. laparoscopic adrenalectomy is nowadays the preferred and safe surgical option. informed consent was obtained from the patient. references 1. decmann a, perge p, tóth m, igaz p. adrenal myelolipoma: a comprehensive review. endocrine. 2018; 59:7-15. 2. fassnacht m, arlt w, bancos i, et al. management of adrenal incidentalomas: european society of endocrinology clinical practice guideline in collaboration with the european network for the study of adrenal tumors. eur j endocrinol. 2016; 175:g1-g34. 3. shenoy vg, thota a, shankar r, desai mg. adrenal myelolipoma: controversies in its management. indian j urol. 2015; 31:94-101. 4. feng c, jiang h, ding q, wen h. adrenal myelolipoma: a mingle of progenitor cells? med hypotheses. 2013; 80:819-22. 5. wale dj, wong kk, viglianti bl, et al. contemporary imaging of incidentally discovered adrenal masses. biomed pharmacother. 2017; 87:256-262. 6. gunseren ko, cicek mc, vuruskan h, et al. challenging risk factors for right and left laparoscopic adrenalectomy: a single centre experience with 272 case. int braz j urol. 2019; 45:747-753. 7. carvalho ja, nunes pt, antunes h, et al. transumbilical laparoendoscopic single-site adrenalectomy: a feasible and safe alternative to standard laparoscopy. arch ital urol androl. 2019; 91:1-4. figure 1. contrast-enhanced computed tomography scan demonstrating a huge inhomogeneous right adrenal mass containing amount of low attenuation tissue of fatty density (a, arrow), a large well capsulated round mass was found at surgery (b), the adrenal gland was entirely dissected along the capsule (c). correspondence carlo introini, md (corresponding author) carlo.introini@galliera.it fabio campodonico, md fabio.campodonico@galliera.it marco ennas, md marco.ennas@galliera.it antonia di domenico, md antonia.didomenico@galliera.it urology, galliera hospital, genova (italy) luca foppiani, md, phd (corresponding author) luca.foppiani@galliera.it internal medicine, galliera hospital mura delle cappuccine 14, 16128 genova (italy) 11foppiani_stesura seveso 24/09/20 14:23 pagina 206 archivio italiano di urologia e andrologia 2018; 90, 174 case report pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. a case report riccardo boschian 1, michele rizzo 1, lorenzo zandonà 2, carlo trombetta 1, giovanni liguori 1 1 department of urology, university of trieste, trieste, italy; 2 institute of pathological anatomy and histology, university of trieste, trieste, italy. we report a case of a 69-years-old man who presented with a solitary 1 cm nodule in the lower lobe of the left lung almost 3 years after radical prostatectomy for pt3an0m0, gleason score 4+3 disease, without evidence of osseous or lymphatic spread. surgical resection of the pulmonary lobe confirmed the metastatic nature of the lesion, with subsequent reduction of serum psa to undetectable levels. after 2 years from the metastasis resection, serum psa is still undetectable, without the necessity of additional treatments. solitary pulmonary metastases from prostate cancer (pca) are rare in clinical practice, with only 29 previous cases described besides the one that we present. key words: prostate cancer; recurrence; psa. submitted 9 august 2017; 21 september 2017 summary no conflict of interest declared. of the left lung, strongly suggesting a tumor. the patient was suspected to have a secondary lung metastasis. since there was no evidence of metastatic disease in the remaining workup, the patient elected to undergo a thoracoscopic segmental resection with lymph node dissection. histopathological examination revealed pca metastasis with negative lymph nodes (figure 1). subsequently, psa serum level dropped to undetectable levels (less than 0.05 ng/ml) and remained undetectable for more than 36 months. discussion the incidence of lung metastases from pca is reported from 5% to 27%; however, it is a very rare condition in the absence of gross osseous or lymphatic involvement (1). wallis and colleagues, in their recent literature review, found a total of only 18 cases of solitary metastatic pca to lung and 15 cases of multiple metastases without osseous or lymphatic involvement (2). until now, androgen deprivation therapy (adt) is the cornerstone of treatment for pca patients diagnosed with metastatic progression following primary treatment, although the optimal timing and schedule of adt is still under debate in this setting (3). doi: 10.4081/aiua.2018.1.74 introduction isolated lung metastases in prostate cancer (pca) has been reported in less than 1% of cases and its proper treatment is still debated (1). we report a case, of an isolated solitary pulmonary recurrence of pca after radical prostatectomy that was resected, resulting in a 3 years disease-free follow-up. case report a 69-year-old man comes to our observation after the diagnosis of a pg7 (4+3) prostate cancer. the psa level was 5.1 ng/ml. in february 2011, the patient underwent open radical prostatectomy with pelvic lymph node dissection. the pathology specimen demonstrated bilateral disease, gleason score 4+3, focal evidence of surgical margins infiltration, negative seminal vescicles and negative pelvic lymph nodes. there was no evidence of vascular invasion (pt3an0m0). the patient then underwent adjuvant radiotherapy at the dose of 70 gy in 35 fractions. for three years postoperatively, the patient’s psa serum level was undetectable. then it rose to 0.4 ng/ml. we then applied 18-fluoro-2-deoxyclucos positron emission tomography (fdg-pet-ct) which revealed selective accumulation in a 1 cm nodule in the inferior lobe figure 1. histopathological examination revealed prostate cancer metastasis. boschian_stesura seveso 27/03/18 09:34 pagina 74 75archivio italiano di urologia e andrologia 2018; 90, 1 pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. a case report as in other solid tumours, it is more likely that oligometastatic patients have a better prognosis and a better survival compared with patients with extensive metastatic disease. as a matter of fact, in a 2014 retrospective study on 1.206 patients referred for radiotherapy of the prostate (bed) following diagnosis of pca, patients with a single metastasis had a 5-yr cancer-specific survival of 90% (95% ci, 71-100) compared with only 32% (95% ci, 12-52) in patients with more than one metastasis (4). therefore, local cancer treatments could be curative in a proportion of patients with metastases. our patient had a solitary pulmonary metastasis that resulted in a complete response after surgical excision without androgen withdrawal. to date, only 6 cases of successful resection of a solitary lung metastases after radical prostatectomy for pca have been reported (5). to the best of our knowledge, this patient was the first in which metastases directed therapy was successfully performed only by surgery, without any adt. conclusion in conclusion, the diagnosis of a solitary pulmonary metastasis from pca with an otherwise negative metastatic workup is atypical and presents a therapeutic issue of the role of metastasectomy. metastasis-directed therapy is a promising approach and might be offered to selected patients with good results. this case focuses the importance of regular psa followup after pca therapies. however due to the low numbers of cases reported in literature, the absence of trials and the heterogeneity of patients treated, this should not be considered the standard therapy. references 1. bubendorf l, schöpfer a, wagner u, et al. metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. hum pathol. 2000; 31:578-83. 2. wallis cj, english jc, goldenberg sl. the role of resection of pulmonary metastases from prostate cancer: a case report and literature review. can urol assoc j. 2011; 5:e104-8. 3. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer. part ii: treatment of advanced, relapsing, and castration-resistant prostate cancer. eur urol. 2014; 65:467-79. 4. ost p, decaestecker k, lambert b, et al. prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. prostate 2014; 74:297-305. 5. maebayashi t, abe k, aizawa t, et al. solitary pulmonary metastasis from prostate cancer with neuroendocrine differentiation: a case report and review of relevant cases from the literature. world j surg oncol. 2015; 13:173. correspondence riccardo boschian, md (corresponding author) rboschian@gmail.com michele rizzo, md mik.rizzo@gmail.com carlo trombetta, md trombcar@units.it giovanni liguori, md gioliguori33@gmail.com department of urology, university of trieste, trieste, italy lorenzo zandonà, md lorenzan84@libero.it institute of pathological anatomy and histology, university of trieste, trieste, italy boschian_stesura seveso 27/03/18 09:34 pagina 75 261archivio italiano di urologia e andrologia 2019; 91, 4 case report preputial circumcision performed with a new mechanical stapling tool. the “langhe disposable circumcision suture device”. preliminary experiences diego pozza 1, carlotta pozza 2, augusto mosca 3, mariangela pozza 1 1 studio di andrologia e di chirurgia andrologica, rome, italy; 2 department of fpm, sapienza university, rome, italy; 3 u.o. urologia ed andrologia, osp. s. sebastiano, frascati, italy. the authors present their preliminary clinical experiences in performing preputial circumcision utilizing a new stapling tool. key words: circumcision; phimosis; stapling surgical tool. submitted 17 july 2019; accepted 29 july 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.261 introduction male circumcision was performed since 2300 bc in egypt (1) and is one of the most common surgical procedures performed on males for religious, ethical, sexual or medical reasons (2). circumcision is undertaken using a variety of surgical methods (3). since the years '80, "stapler" tools that allow to make sections and sutures of circular and longitudinal organs in very short time have become a "standard" for many surgical branches. genital surgery, due to the narrowness of the operative field and the limited dimensions of the organs, did not admit the use of these mechanical staplers. we want to present our preliminary experiences on the use of the "langhe disposable circumcision suture device" (ldcsd), which is an innovative mechanical "stapler" tool to carry out a circumcision (4). case report we utilized the ldcsd in 20 patients (pts) aged 14 to 80 years with congenital phimosis, redundant prepuce or balanopostitic outcome (figure 1). in the operating room local anesthesia or anesthesiological sedation is performed according to age and clinical data of the pts. after disinfection it is checked that the preputial frenulum is sufficiently extensible, otherwise it is engraved. the part of the instrument, conformed like a small cup with a stem, is introduced under the prepuce to completely cover the gland. the prepuce is fixed to the stem with a safety buckle, the stem of the instrument is introduced into the handpiece until it protrudes. the screw is turned until the handpiece is fixed to the cup under the prepuce. the two handles of the handpiece are firmly tightened so that there is a further compression and section of the cutaneous and mucosal layers. the compression of the handles determines their circular section and suture with 12 staples with perfect mechanical and hydraulic seal. after 1 minute the screw is unscrewed to distance the two parts and free the perfectly circumcised and sutured penis (figure 2). the prepuce is wrapped with sterile gauze and a strong circular pressure is maintained with the fingers for 4-5 minutes. the penis is tightly bendaged and the pt. is returned to bed with the bandage which is maintained for at least 2-3 hours for hemostatic purposes. if there are no signs of bleeding when the bandage is removed, the patient is sent home. if, on the other hand, a bleeding is observed, a local compression or an absorbable stitch should be applied. the first 3 cases required special prudence and attention; the 17 following pts were performed with simple local anesthesia and in 3 pts (< 20 years) with sedation. operating times varied between 5 and 7 minutes. figure 1. a. the box containing the ldcsd. b. the instrument ready for use. c. the 12 staples assembled in the circular resection part. pozza_stesura seveso 10/01/20 08:55 pagina 261 archivio italiano di urologia e andrologia 2019; 91, 4 d. pozza, c. pozza, a. mosca, m. pozza 262 we have never observed any major complications. no significant intraoperative blood loss. in 2 cases we have prudentially applied few absorbable suture stitches. metallic staples fell spontaneously after 15-25 days. in 2 cases after 30 days we removed some staples still present with a simple and painless ambulatory maneuver. all pts reported full satisfaction concerning operative, postoperative, aesthetic and functional results (figure 3). conclusions the ldcsd with his advantages of simple and easier manipulation, shorter operation time, fewer complications, better cosmetic results, could be considered a useful tool to carry out a rapid, aesthetic, effective and safe circumcision. references 1. meijer b, butzelaar rm. circumcision from a historical perspective. ned tijdchr geneeskd. 2000; 144:2504. 2. bronselaer ga, schober jm, meyer-bahlburg hf, et al. male circumcision decreases penile sensitivity as measured in a large cohort. bju. 2013; 111:820. 3. featherstone nc, murphy fl. paediatric suturless circumcision and modified circumcision: video demostration. j pediatr urol. 2012; 8:240. 4. lv bd, zhang sg, zhu xw, et al. disposable circumcision suture device: clinical effect and patient satisfaction. asian j androl. 2014; 16:453. figure 2. a. the prepuce is fixed around the metallic stem. b. the stem is introduced into the handpiece. c. the handpieces are strictly tightened. d. the system is disassembled; the prepuce has been cut. figure 3. a. result after 1 week in young patient with phimosis. b. result in a 80 years old patient after balanoposthitis. c. the metallic staples. d. result in a young patient after one month. correspondence diego pozza, md (corresponding author) diegpo@tin.it mariangela pozza, md studio di andrologia e di chirurgia andrologica via b. gozzoli, 62h 00142 roma (italy) carlotta pozza, md department of fpm, sapienza university, roma (italy) augusto mosca, md u.o. urologia ed andrologia, osp. s. sebastiano, frascati (italy) pozza_stesura seveso 10/01/20 08:55 pagina 262 stesura seveso 39archivio italiano di urologia e andrologia 2014; 86, 1 case report penile fracture: penoscrotal approach with degloving of penis after magnetic resonance imaging (mri) gabriele antonini 1, patrizio vicini 3, salvatore sansalone 4, giulio garaffa 4, antonio vitarelli 5, ettore de berardinis 1, magnus von heland 1, riccardo giovannone 1, emanuele casciani 2, vincenzo gentile 1 1 department of urology, “sapienza” rome university, rome, italy; 2 department of radiology, “sapienza” rome university, rome, italy; 3 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 4 department of experimental medicine and surgery, “tor vergata” rome university, rome, italy; 5 department of urology, bari university, bari, italy. fracture of the penis, a relatively uncommon emergency in urology, consists in the traumatic rupture of the tunica albuginea of the corpus cavernosum. examination and clinical history can be highly suspicious of penile fracture in the majority of cases and ultrasonography (uss) can be useful to identify the exact location of the tunical rupture, which is proximal in 2/3 of cases and therefore manageable through a penoscrotal approach. although expensive and not readily available in the acute setting, magnetic resonance imaging (mri) may play a role in the differential diagnosis with rupture of a circumflex or dorsal vein of the penis or when the tunical rupture is not associated with tear of the overlying buck’s fascia. this form of imaging is more sensitive than uss at identifying the presence of a tunical tear. the treatment of choice is immediate surgical repair, which allows preserving erectile function and minimizing corporeal fibrosis. key words: penile fracture; magnetic resonance imaging (mri); ultrasonography; fibrosis; erectile dysfunction. submitted 13 february 2014; accepted 28 february 2014 summary introduction fracture of the penis, which consists in the traumatic rupture of the tunica albuginea of the corpus cavernosum, is a relatively uncommon emergency in urology and it may be associated with urethral trauma in 1% to 38% of cases. it usually occurs when the erected penis hits the female pelvis during enthusiastic sexual intercourse. as the thickness of tunica albuginea decreases from 2 mm in the flaccid state to 0.25 mm during the erect state, a sudden increase in intracorporeal pressure due to blunt trauma during an erection could easily result in a rupture. all penile fractures occur on the shaft penis and in 2/3 of cases the tear is located at the level of the penoscrotal junction. no conflict of interest declared although trauma during intercourse is the most common cause of penile fracture in the western world, penile selfmanipulation to stop erection is the most common etiology in the middle east and the persian gulf (1-8). accurate history taking and clinical examination represent the mainstay in the diagnosis of penile fracture. typically the patient reports a “popping” sound followed by immediate detumescence. generally the penis appears diffusely swollen; if buck’s fascia is breached, a diffuse hematoma is visible on the penis (“eggplant deformity”) and may extend to the scrotum, groin and perineum (the “butterfly sign”). early surgical exploration is paramount to guarantee the preservation of the erectile function, to minimize the formation of corporeal fibrosis and to identify and repair an associated urethral rupture. although several reports suggest that diagnostic investigations, add little information to the clinical diagnosis, add extra costs to the treatment and potentially can delay surgery, penile ultrasonography (uss) is promptly available, reasonably cheap and allows to identify the exact location of the tunical tear (9). magnetic resonance imaging (mri) is not frequently performed, as uss can provide all the necessary information and may not be available in the out of hour settings. however, it guarantees superior image quality and allows better differentiating between penile fracture and other conditions such as rupture of the deep dorsal vein or circumflex veins, which produce a penile hematoma similar to the one present in case of tunical tear, but do not require surgical treatment. mri is also an adjunctive tool in the evaluation of atypical presentation of a suspected penile fracture, as has the ability to identify disruption of the corpus cavernosum due to excellent tissue contrast and visualization of soft tissue pathological processes (10). over the last 3 decades, management of penile fracture has progressively shifted from a conservative approach to early surgical repair, as non surgical management was associated with the formation of fibrosis of the corpora cavernosa and led invariably to a degree of curvature and erectile dysfunction (4). surgical treatment aims at repairing the torn tissue of tunica albuginea. although adequate expodoi: 10.4081/aiua.2014.1.39 antonini cr_stesura seveso 26/03/14 10:21 pagina 39 archivio italiano di urologia e andrologia 2014; 86, 1 g. antonini, p. vicini, s. sansalone, g. garaffa, a. vitarelli , e. de berardinis, m. von heland, r. giovannone, e. casciani, v. gentile 40 sure of the penile shaft can be achie ved through a subcoronal circumferential incision, 2/3 of penile fractures occur in the proximal third of the shaft and these pa tients would be the refore better ser ved with a pe no scrotal approach (7, 8). furthermore, de glo ving a bruised edematous penis can be quite challenging and a circumcision would be required to prevent preputial complications. imaging can be extremely helpful for the surgeon in order to identify distal fractures, which require a degloving, from proximal fractures, which can be easily dealt with through a penoscrotal approach. discussion penile fracture occurs during erection, as the expansion of the corpora stretches the tunica albuginea and renders it thinner and more vulnerable to trauma. although the diagnosis of penile fracture is often based on history and physical examination, imaging can be particularly useful when the clinical picture is not fully clear and when planning the type of surgical approach. among the radiological investigation, uss is the most widely used, as it is readily available and relatively inexpensive. however, although this form of imaging is highly specific in detecting a fracture, it is not very sensitive for detecting a cavernosal tear (6, 8, 9). on the contrary, mri scan of the penis is highly sensitive at detecting the exact location of the tunical tear and allows the surgeon to chose the best surgical approach. therefore, although more expensive and not always readily available in the acute setting, mri should be considered the gold standard diagnostic investigation in case of suspected penile fracture.although penile degloving is the most commonly used surgical approach, as it allows visualizing and inspecting adequately all the corpora cavernosa and urethra, it can be very morbid, due to the presence of diffuse bruising and edema of the dartos fascia. as 2/3 of fractures occur all the way down on the proximal aspect of the shaft, a complete degloving becomes an unnecessary procedure, as a penoscrotal approach would guarantee adequate exposure in these patients (7, 8). magnetic resonance imaging or uss of the penis play therefore a pivotal role for the identification of the exact location of the tear and therefore allow the surgeon to adequately choose the most appropriate surgical approach. surgery should be immediate, in order to preserve as much cavernosal tissue as possible and to minimize the formation of corporeal fibrosis, which would lead to ed, penile shortening and curvature (3-5). although patient history and clinical examination are highly sensitive and accurate in predicting the presence of a penile fracture, diagnostic imaging such as mri and uss of the penis can be very useful to confirm the diagnosis and to identify the exact location of the tunical tear and to plan the type of surgical approach (9). when readily available, mri should be the first choice modality of investigation due to its superior sensitivity in detecting tunical injuries (9). references 1. garcía gómez b, romero j, villacampa f, et al. early treatment of penile fractures: our experience. arch esp urol. 2012; 65:684-688. 2. murray ks, gilbert m, ricci lr, et al. penile fracture and magnetic resonance imaging. int braz j urol. 2012; 38:287-8. 3. wen j, li hz, ji zg, li hj. immediate surgical intervention for penile fracture: a case report and literature review. chin med sci j. 2011; 26:132-4. 4. garaffa g, raheem aa, ralph dj. penile fracture and penile reconstruction. curr urol rep. 2011; 12:427-31. 5. hatzichristodoulou g, dorstewitz a, gschwend je, et al. surgical management of penile fracture and long-term outcome on erectile and voiding. j sex med. 2013; 10:1424-30. 6. choi mh, kim b, ryu ja, et al. mr imaging of acute penile fracture. radiographics. 2000; 20:1397-405. 7. ozcan s, akpinar e. diagnosis of penile fracture in primary care: a case report. cases j. 2009; 2:8065. 8. srinivas bv, vasan ss, mohammed s. a case of penile fracture at the crura of the penis without urethral involvement.indian j urol. 2012; 28:335-337. 9. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-4575. 10. koifman l, barros r, júnior ra, et al. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology. 2010; 76:1488-92. case report and figures are posted in suppementary materials on www.aiua.it. correspondence gabriele antonini, md ettore de berardinis, md magnus von heland, md riccardo giovannone, md vincenzo gentile, md department of urology, “sapienza” university. rome, italy emanuele casciani, md department of radiology, “sapienza” university, rome, italy patrizio vicini, md (corresponding author) patriziovicini@gmail.com department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy salvatore sansalone, md giulio garaffa, md department of experimental medicine and surgery, “tor vergata” university, rome, italy antonio vitarelli, md department of urology, bari university, bari, italy figure. magnetic resonance imaging with gadolinium showing the interruption of tunica albuginea at the level of the proximal third of right corpus cavernosum without urethral involvement. antonini cr_stesura seveso 26/03/14 10:21 pagina 40 169archivio italiano di urologia e andrologia 2018; 90, 3 original paper comparison of an electromagnetic and an electrohydraulic lithotripter: efficacy, pain and complications grazia bianchi, diego marega, roberto knez, stefano bucci, carlo trombetta department of urology, university of trieste, cattinara hospital, trieste, italy. introduction. we analyzed efficacy and complications of extracorporeal shock wave lithotripsy (swl) and analgesia requirement during the treatment in two groups of patients treated with different lithotripters. materials and methods. the patients treated were 189, 102 between september 2016 and april 2017 with hmt lithotron® lits 172, electrohydraulic, and 87 between may and september 2017 with storz medical modulith® slk, electromagnetic. the main differences between the lithotripters are: type of energy source, patient position, frequency and number of shock waves. all the patients underwent sonography before and four to eight weeks after the treatment. the targeting was sonographic for renal stones and x-ray for ureteral stones. all the patients received ketorolac before the treatment with a supplement of pethidine if needed. people lost to follow-up and with incomplete data were excluded. results. we enrolled 173 patients, 94 treated with the electrohydraulic lithotripter and 79 with the electromagnetic one. 43 patients (54%) in the electromagnetic group and 31 (33%) in the electrohydraulic group were stone free or presented clinically insignificant residual fragments (cirfs), defined as asymptomatic, noninfectious, ≤ 3 mm. the association between cirfs and the kind of lithotripter was statistically significant (p = 0.004). an increased need for analgesia was found in 14.9% of patients in the electromagnetic group and in 81% of patients in the electrohydraulic group (p < 0.001). the access to emergency room (intractable pain, kidney failure, fever, steintrasse) after the treatment was similar in the two groups (p = 0.37). conclusions. the best results in stones fragmentation and less analgesia requirement were demonstrated in the electromagnetic lithotripter group. no differences were demonstrated considering the need for emergency room after the treatment. key words: lithotripter; stones; extracorporeal shock wave lithotripsy; electromagnetic; electrohydraulic. submitted 5 june 2018; accepted 3 august 2018 summary no conflict of interest declared. tially the same way (2). many studies compare different lithotripters or different energy source in order to evaluate efficacy (3, 4). in our institution, we used an electrohydraulic lithotripter and when it was no longer available, we used an electromagnetic one. materials and methods we retrospectively reviewed the data collected and compared the results obtained with the two lithotripters, using chi-square test, with significance considered at p < 0.05. the patients collected were 189. between september 2016 and april 2017 we treated with hmt lithotron® lits 172, an electrohydraulic lithotripter, 102 patients and when it was no longer available we use, between may and september 2017, a storz medical modulith® slk, electromagnetic, with 87 patients. all the patients underwent sonography before and four to eight weeks after the treatment, performed by the same urologists. the targeting during the treatment was sonographic for renal stones and x-ray for ureteral stones. all the patients received ketorolac (30 mg) before the treatment or paracetamol (1g) in case of allergy with a supplement of pethidine, according to weight, if needed. when we evaluated complications after the treatment, patients who visited the emergency room within 48 hours were included (5). people lost to follow-up and with incomplete data were excluded. results we enrolled 173 patients, 129 males and 44 females with a mean age of 58 ± 12 years. 94 were treated with the electrohydraulic lithotripter, 23 females and 71 males, and 79 with the electromagnetic one, 21 females and 58 males. in the group treated with the electromagnetic lithotripter the mean diameter of the stones was 9.59 ± 3.04mm and 16 patients had multiple stones. 73 had stones in the kidney and 6 in the ureter. the mean number of shock waves was 3079 (3043 in the kidney and 3516 in the ureter) with a 3-4hz frequency. in the group treated with the electrohydraulic one, the mean diameter of the stones was 10.39 ± 3.41 mm and 18 patients had multiple stones. 73 had stones in the kidney and 21 in the ureter. the mean number of shock doi: 10.4081/aiua.2018.3.169 introduction shock wave lithotripsy was introduced in the 1980s for the treatment of urinary stones and became a first line treatment option (1). since the introduction of the dornier hm3 lithotripter, there have been many changes to produce machines that were easier and more practical to use. three shock wave generating principles have been used in clinical lithotripters: electrohydraulic, electromagnetic and piezoelectric, but they work substanbianchi comp_stesura seveso 03/10/18 09:39 pagina 169 archivio italiano di urologia e andrologia 2018; 90, 3 g. bianchi, d. marega, r. knez, s. bucci, c. trombetta 170 waves was 2228 (2139 in the kidney and 2500 in the ureter) with a 1-2hz frequency (table 1). 43 patients (54%) in the electromagnetic group and 31 (33%) in the electrohydraulic group presented clinically insignificant residual fragments, defined as asymptomatic, noninfectious, ≤ 3 mm fragments (cirfs). the data were compared using chi-square test, demonstrating that the association between presence of cirfs or stone free status and kind of lithotripter was statistically significant (p = 0.004). an association between the kind of lithotripter and the need for more analgesia during the treatment was evaluated. 14.9% of people treated with electromagnetic (13 patients) and 81% of people treated with electrohydraulic (83 patients) asked for pethidine. people treated with electromagnetic lithotripter needed less analgesia (p < 0.001). the causes of access to the emergency room were intractable pain, kidney failure, fever (> 38°c) and steintrasse. 10 patients treated with electromagnetic an 8 treated with electrohydraulic went to emergency room within 48 hours and the difference was not statistically significant (p = 0.37) (table 2). discussion the electrohydraulic lithotripter has a source that generates a shock wave that is focused by an ellipsoidal reflector. the pressure pulse originates as a shock wave and remains a shock wave at all times. during shooting, there can be significant variation in the amplitude of the shock wave and there can be some shift in the position of the focal zone at the target. the electrodes wear out and must be replaced because this can affect their acoustic output. the electromagnetic lithotripter uses an electrical coil in proximity to a metal plate as an acoustic source. when the coil is excited by a short electrical pulse, an acoustic wave is generated. focusing is very reproducible and the variation in measured pressure waves is less than 10%. the shock waves generated by electromagnetic lithotripters are inherently more consistent than in electrohydraulic. an additional advantage is that there are no electrodes to replace (2). as seen above, there are inherent differences between the two kinds of lithotripter, but each brand has its own features (6-8). the position of the patient is different. with lithotron®, the patient is supine, with his flank lying on the therapy head and sometimes must be fixed to the bed to avoid involuntary movements (9). with modulith®, the patient is prone and the respiratory movements are smaller. in both, the therapy head is filled with water, covered by a thin rubber membrane pressed against the patient and through which the shock wave passes and gel is used as coupling agent (10). the number of the shock waves depends on the stone fragmentation. the frequency depends on the configuration of the lithotripter. for the lithotron® the frequencies available are 1 or 2 shock waves per second. for the modulith® the frequency depends on the energy delivered and with higher energy the frequency is 3 or 4 shock waves per second. in literature there are many studies that compare different lithotripters. some studies evaluate, as we did, the differences between electrohydraulic and electromagnetic lithotripters, however, the results are discordant (3, 4). in our series electromagnetic lithotripter has better results. another important argument about swl is pain management (11). discomfort during shock wave treatment is due primarily to the sensation of cutaneous pain over the area of shock wave entry at the surface of the body (2). analgesics used include opioids, nsaids and local analgesia, however, there is no consensus on standard analgesia for pain during swl (12). in our series, pain is better managed in patients treated with electromagnetic lithotripter. many complications after eswl are reported. the most dangerous are renal hematomas and injuries to adjacent organs, but the most frequent are flank pain, hematuria, fever, nausea with vomiting and acute urinary retention (5). we had no severe complication and in the two groups, the access to the emergency room was similar. conclusions all the treatments and the follow up were performed by the same group of urologists with years of experience. in the series we considered, the best results in stones fragmentation (p = 0.004) and less analgesia requirement (p < 0.001) were demonstrated in the electromagnetic lithotripter group. no differences were demonstrated considering the need for emergency room after the treatment (p = 0.37). table 1. characteristics of stones and treatments. electromagnetic electrohydraulic lithotripter lithotripter mean diameter of the stones 9.59 ± 3.04 mm 10.39 ± 3.41 mm patients with multiple stones 16 18 kidney stones 73 73 ureteral stones 6 21 mean number of shock waves 3079 2228 (3043 kidney (2139 kidney and 3516 ureter) and 2500 ureter) frequency of shock waves 3-4hz 1-2hz table 2. success rate,complications and analgesia requirement. electromagnetic electrohydraulic p lithotripter lithotripter cirfs 43 31 0.004 lithiasis > 3 mm 36 63 access to emergency room 10 8 0.37 no complications 69 86 analgesia requirement 13 83 0.00001 asymptomatic patients 74 19 bianchi comp_stesura seveso 03/10/18 09:39 pagina 170 references 1. tailly gg. extracorporeal shock wave lithotripsy today. indian j urol. 2013; 29:200-7. 2. cleveland ro, mcateer ja. the physics of shock wave lithotripsy. in: smith ad, badlani gh, preminger gm, et al., editors. smith’s textbook on endourology 3. vol. 1. hoboken: wiley-blackwell; 2012; pp. 529-558. 3. matin sf, yost a, streem sb. extracorporeal shock-wave lithotripsy: a comparative study of electrohydraulic and electromagnetic units. j urol. 2001; 166:2053-6. 4. bhojani n, mandeville ja, hameed ta, et al. lithotripter outcomes in a community practice setting: comparison of an electromagnetic and an electrohydraulic lithotripter. j urol. 2015; 193:875-9. 5. lu ch, kuo jy, lin tp, et al. clinical analysis of 48-h emergency department visit post outpatient extracorporeal shock wave lithotripsy for urolithiasis. j chin med assoc. 2017; 80:551-557. 6. ng cf, thompson tj, mclornan l, tolley da. single-center experience using three shockwave lithotripters with different generator designs in management of urinary calculi. j endourol. 2006; 20:1-8. 171archivio italiano di urologia e andrologia 2018; 90, 3 comparison of an electromagnetic and an electrohydraulic lithotripter: efficacy, pain and complications correspondence grazia bianchi, md (corresponding author) graziuccia88@libero.it diego marega, md roberto knez, md stefano bucci,md carlo trombetta, md trombcar@units.it università degli studi trieste, urology department – cattinara hospital, strada di fiume 447, trieste, italy bianchi comp_stesura seveso 03/10/18 09:39 pagina 171 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 3230 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.230 transperitoneal and retroperitoneal approach in laparoscopic partial nephrectomy for posterior ct1 renal tumors: a retrospective, two-centers, comparative study nikolaos ferakis 1, antonios katsimantas 1, nikolaos charalampogiannis 2, spyridon paparidis 1, jens jochen rassweiler 2, ali serdar gözen 2 1 department of urology, korgialenio-benakio hellenic red cross hospital, athens, greece; 2 department of urology, slk-kliniken heilbronn, university of heidelberg, heilbronn, germany. objectives: to compare perioperative, oncological and functional outcomes of laparoscopic transperitoneal partial nephrectomy (ltpn) and retroperitoneal laparoscopic partial nephrectomy (lrpn) for posterior, ct1 renal masses (rms). materials and methods: databases of two urologic institutions applying different laparoscopic surgical approaches on posterior ct1 rms between june 2016 and november 2018 were retrospectively evaluated. data on patient demographics, perioperative data and tumor histology were collected and further analyzed statistically. results: each group consisted of 15 patients. baseline characteristics were comparable in each group. when compared to ltpn, lrpn was associated with significantly shorter operative time (ot) (115 min versus 199 min, p < 0.05). no significant differences were detected in the other outcomes. conclusions: lrpn is associated with a significantly shorter ot compared to ltpn for posterior ct1 rms. both surgical approaches are safe, feasible and credible, demonstrating optimal results. key words: laparoscopy; partial nephrectomy; transperitoneal; retroperitoneal; renal tumor. submitted 2 march 2020; accepted 15 march 2020 summary introduction partial nephrectomy (pn) is as a valid surgical approach for ct1 renal masses (rms) and is strongly recommended whenever technically feasible (1-6). it can equally be performed by open (opn), pure laparoscopic (lpn) or robot-assisted laparoscopic approach (3, 7-9). a wide variety of endoscopic instruments and the steadily increasing laparoscopic experience rendered lpn a feasible treatment modality for ct1 rms (1, 7, 10-11). both routes, either transperitoneal (tp) or retroperitoneal (rp), can be equally advocated (1, 7, 11-15). a benefit of retroperitoneal lpn (lrpn) is the direct, rapid access to the posterior hilar structures and to posterior rms allowing for less kidney’s mobilization and rotation (1, 7, 12-18). lrpn avoids bowel mobilization, need for lysis of adhesions in patients with prior abdominal surgery and peritoneal cavity irritation through contamination of blood and urine (1, 3, 7, 11, 14, 15). moreover, the rp space may tamponade a possible postoperative bleeding and avoids peritonitis caused by a possible postoperative urinary fistula (5, 16). the presence of abundant rp fat (e.g. in obese patient) or the case of a large or anteriorly located tumor may render lrpn challenging (6, 10, 15, 16). in addition, lrpn is technically demanding, with a steep learning curve (19). tp route offers better spatial orientation due to the presence of more familiar anatomic landmarks (1, 7, 11, 14, 15, 19). ease in port placement due to larger skin surface, increased working space allowing for wider angulations and enhanced maneuverability are in favor of transperitoneal lpn (ltpn) (1, 3, 7, 11, 14, 15, 19). major drawbacks of the ltpn are the difficulty in dissection of posterior rms and subsequent reconstructive suturing, which may guide surgeon’s decision to perform opn instead of minimal invasive procedure, if he is not familiar with the steps for creating rp space (15, 17, 18). the aim of the present study is to analyze and present comprehensively the perioperative, oncological and functional outcomes of ltpn and lrpn for posterior ct1 rms in two urologic centers. materials and methods following institutional review board approval, we reviewed prospectively collected data of two centers to evaluate consecutive patients who underwent ltpn or lrpn for posterior, ct1 rm from june 2016 to november 2018. all tp procedures (group a) were performed by one experienced surgeon (nf) at a single institution in greece, where ltpn is the standard operative technique for ct1 rms. all rp procedures (group b) were performed by two experienced surgeons (jjr, asg) at a large german academic center, where lrpn is the usual operative technique for posterior rms. intraoperative findings were recorded systematically on surgical and video files and evaluated retrospectively. inclusion and exclusion criteria are listed in table 1. we excluded patients who underwent ethos chairassisted lrpn, as it was demonstrated that it significantly improves intraoperative parameters (16). preoperatively, all patients underwent routine laboratory testing, chest x-ray, cardiological evaluation and abdominal computed tomography scan or magnetic resonance imaging. informed consent was obtained by each patient. 231archivio italiano di urologia e andrologia 2020; 92, 3 transperitoneal vs retroperitoneal lpn our database included information on patient’s age, gender, body mass index (bmi), american society of anesthesiologists (asa) score, tumor characteristics, preand post-operative serum hemoglobin (hb) value, preand post-operative estimated glomerular filtration rate (egfr) according to the modification of diet in renal disease, tumor complexity evaluated by preoperative aspects and dimensions used for an anatomical classification (padua) score, operative time (ot), warm ischemia time (wit), length of hospital stay (los), tnm stage and histology, surgical margins (sm) status [positive sm (psm) defined as the presence of cancer cells at the level of the inked parenchymal excision surface] and intra-/post-operative complications (according to the modified clavien-dindo classification scale). the technique of lrpn has been described previously (16). in brief, under general anesthesia and in a full flank position, a rp space is created through a 16-18 mm transverse incision below the tip of the 12th rib in the ‘musclefree’ petit’s triangle. the rp space is entered bluntly by using the index finger and developed by using an optical dilatation balloon. a 12 mm trocar is placed with the guidance of index finger inside the rp space for the right hand and a 5 mm trocar for the left hand. optionally, another 5 mm trocar is placed under view medially to the rim of peritoneum when a retraction of the kidney and gerota’s fascia (gf) is needed. gf is incised horizontally parallel to the psoas muscle and the renal hilum is accessed for the dissection of the renal artery. the entire kidney is isolated from perirenal fat (except from the fat overlying the tumor) to localize the rm. the kidney is mobilized and the incision line around the tumor is scored with bipolar forceps. we clamp the renal artery with a bulldog clamp and we proceed to tumor’s excision according to the principles of enucleo-resection, preserving a 5-mm rim of normal renal tissue. the tumor is placed in an endoscopic specimen bag. subsequently, we perform inner renorrhaphy by continuous suturing with a barbed suture (v-loctm, covidien, sh, 20 cm) preloaded with an absorbable lapra-ty® clip supported by a vicryl patch or durapatch, which is stitched out on the contralateral side of the resection wound and fixed with a lapra-ty® clip. renal parenchyma is closed with a continuous suture secured at every loop using lapra-ty® clips, the bulldog clamp is removed and the suturing line is covered with perirenal fat. finally, the specimen bag is removed through the optic trocar incision and is grossly inspected, a drain (24 fr) is placed via 12 mm port incision and port incisions are closed. regarding ltpn, the patient is fixed in the lateral flank position with the table half flexed, under general anesthesia. we use open hasson technique to place the first trocar (12 mm) for the 30° laparoscope 2 fingerbreadths above and 8-10 cm lateral to the umbilicus. we place the rest of trocars (one 12 mm and one 5 mm at the midclavicular line according to the triangulation principle, serving as surgeon’s working channels, and one 12 mm 3 fingerbreadths medial to the superior anterior iliac spine and one 5 mm 8 cm lateral to the camera trocar for the first assistant) under direct vision. on the right side, we may place another 5 mm subxyphoid trocar to retract liver. we release colon’s lateral attachments, to deflect it medially, and splenorenal or hepatorenal ligaments. on the right side, we mobilize duodenum (kocher maneuver) medially, until we clearly visualize vena cava. gf is opened, the genital vessels, the proximal ureter, the psoas muscle and the renal pedicle are located and the kidney is defatted down to the renal capsule (preserving the fat overlying the tumor) and is mobilized. after locating the tumor, the margin of resection is marked with electrocautery. we use rummel tourniquet (rt) technique on renal artery in order to achieve wi, similarly to the technique described by shefler et al. (20). we create our tourniquet by using a 30 cm long 2 mm thick vessel loop, a 2 cm cylinder sheath prepared from a 16 fr levin tube and a large hem-o-lock clip. the tumor is excised [(enucleo)-resection] using cold scissors at 5 mm from the tumor’s edge. subsequently, we perform inner renorrhaphy using a 15 cm 3-0 v-loc running suture, we release rt (early unclamping technique) and we complete renorrhaphy using a 13 cm 1/0 polyglycolic acid running suture. we secure our running sutures using a large hem-o-loc clip at each exit point. we reapproximate perirenal fat over the cutting surface, the tumor is removed via a 12 mm port using an endoscopic specimen bag and is grossly inspected, a drain (16fr) is placed via a port incision and port incisions are closed. in both techniques, 2-dimensional high definition (hd) cameras were used, pneumo (retro) peritoneum was maintained at 12 mmhg and mannitol iv was administered prior to clamping the renal artery. in both departments, we apply similar perioperative protocols: bowel preparation is applied preoperatively, no antiemetic or opioid drugs are routinely administered postoperatively, nasogastric tube is removed immediately postoperatively, patients receive liquid diet and are mobilized and foley catheter is removed on the 1st postoperative day. the patients are discharged following drain’s removal and when they are medically stable, full ambulatory without assistance and need for intravenous analgesia and capable to tolerate a light diet. patients with malignant pathology are scheduled for 6-month imaging follow-up. all statistical analyses were performed using an spss25 statistical program. data were less than 35 (a = 15, b = 15), so standard normality assumptions did not meet. thus, non-parametric statistical tests were conducted. quantitative characteristics were compared using mannwhitney test and qualitative characteristics were compared using 2-tailed chi-square test. a p value < 0.05 was considered statistically significant. median values and table 1. inclusion and exclusion criteria. inclusion • single, unilateral, contrast-enhanced ct1n0m0 renal mass • localization of the tumor in the posterior renal surface • resection of the mass via transperitoneal or retroperitoneal laparoscopic partial nephrectomy exclusion • conversion to open partial or radical nephrectomy • lrpn using the ethos chair • missing data archivio italiano di urologia e andrologia 2020; 92, 3 n. ferakis, a. katsimantas, n. charalampogiannis, s. paparidis, j. jochen rassweiler, a. serdar gözen 232 range were calculated for quantitative continuous variables and proportions for nominal variables. results following exclusion, each cohort consisted of 15 patients. preoperative characteristics of both groups (demographic data and tumors’ characteristics) were comparable (table 2). peri-operative data of both groups are summarized on table 3. variation of serum hb value preand 10 hours post-operatively was comparable in both groups. however, 4 patients were transfused intra-operatively (1 unit of packed red blood cells each), being all of them from group a (3 pt1a, 1pt1b, 1 with no ischemia), although the difference between cohorts was not statistically significant. ot was shorter in group b (p < 0.05). three patients of group a (1 pt1a, 2 pt1b) and 5 patients of group b (3 pt1a, 2 pt1b) underwent clampless lpn. regarding postoperative complications, both groups were comparable. there were 5 patients of group a with minor postoperative complications (fever and bleeding which was managed conservatively with transfusion). one patient of group b presented prolonged drain excretion of serum fluid (biochemically confirmed). one patient of group a with a medical history of acute myocardial infarction died on the 4th postoperative day, following an episode of orthostatic hypotension, which resulted in fall on the ground, head injury and heart attack. no patient needed antiemetic drugs postoperatively or readmission following discharge. oncological data are demonstrated on table 4. psm rate was 13.3% in each cohort. there was solitary, focal, microscopic invasion of the tumor pseudocapsule in 3 cases [group a: 2 cases of ct1b, clear-cell renal cell carcinoma (ccrcc), fuhrman grade (fg) 2 and 3, group b: 1 case of ct1b, ccrcc, fg 2]. in addition, there was a case of pt1a, papillary type 2 rcc in group b with equivocal sm status (focally), which was interpreted as positive. psms were detected only in cases of clampless pn. there was no local or distant recurrence during the follow-up period. discussion in previous studies, the surgeon’s decision to perform tp or rp approach was usually influenced by tumor’s characteristics, patient’s history of previous intraperitoneal operations and by his discretion and experience (1, 3, 1113, 15, 17, 18). previous studies demonstrated that both approaches have comparable outcomes or that lrpn outperforms ltpn in several parameters (1, 3, 7, 11-15, 17, 18). however, to the best of our knowledge, this is the first comparative study of tp and rp approach on pure lpn, exclusively for posterior, ct1 rms of similar complexity, in patients with similar demographic data. table 2. baseline characteristics of the two groups. ltpn (na = 15) lrpn (nb = 15) number p gendera male/female 9/6 13/2 0.09 sidea right/left 5/10 10/5 0.07 median (25th-75th centile) p ageb (years) 70 (62–73) 68 (53–75) 0.95 bmib (kg/m2) 25.0 (24.2–27.3) 28.1 (26.1–30.8) 0.05 asa scoreb 2.0 (1.0–2.0) 2.0 (2.0–3.0) 0.140 preop. hbb (g/dl) 14.4 (12.7–15.1) 13.0 (11.8–14.4) 0.201 preop. egfrb (ml/min/1.73m2) 76.3 (69.7–85.1) 68.0 (63.8–87.8) 0.458 padua scoreb 7.5 (6.8–9.0) 7.0 (6.0–10.0) 0.798 tumor sizeb (cm) 3.5 (2.5–3.8) 4.5 (2.2–5.0) 0.271 ltpn/lrpn: laparoscopic transperitoneal/retroperitoneal partial nephrectomy; bmi: body mass index; asa score: american society of anesthesiologists score; preop.: preoperative, hb: hemoglobin; egfr: estimated glomerular filtration rate; padua score: preoperative aspects and dimensions used for an anatomical classification score. a x2 test, fisher’s test; b mann-whitney test, 2-sided fisher exact test. table 3. perioperative data of the two groups. ltpn (na = 15) lrpn (nb = 15) median (25th-75th centile) p hb postop.a (g/dl) 11.8 (11.3–13.5) 11.1 (10.5–13.3) 0.256 variation of hb preand postop.a (g/dl) 1.4 (0.8–3.4) 1.35 (0.675–1.925) 0.646 variation of egfr preop. and at dischargea (ml/min/1.73m2) 6.8 (0.0–14.1) 0.0 (-5.0–13.8) 0.352 operative timea (minutes) 199 (150.0–220.0) 115 (100.0–180.0) < 0.05 wita (minutes) 16 (14.0–20.0)* 23 (20.0–28.5)** 0.160 length of hospital staya (days) 5 (4–7) 6 (5–6) 0.233 number p wib yes/no 12/3 10/5 0.68 intraoperative transfusionb yes/no 4/11 0/15 0.10 postop. complicationsb yes/no 6/9 1/14 0.06 minor complications (grade 1 & 2)b yes/no 5/10 1/14 0.17 postop. fever (%) 2 (13.3) (-) postop. bleeding-transfusion (%) 3 (20) (-) prolonged drain excretion (%) (-) 1 (6.7) major complications (≥ grade 3)b yes/no 1/14 0/15 0.31 death (%) 1 (-) ltpn/lrpn: laparoscopic transperitoneal/retroperitoneal partial nephrectomy; hb: hemoglobin; egfr: estimated glomerular filtration rate; wi(t): warm ischaemia (time). a mann-whitney test; 2-sided fisher exact test; b x2 test, fisher’s test. table 4. oncological data of the two groups. ltpn (na = 15) lrpn (nb = 15) median (25th-75th centile) p tumor’s sizea (cm) 3.5 (2.5–3.8) 4.5 (2.2–5.0) 0.271 follow-up perioda (months) 23.0 (19.8–22.3) 17.0 (15.0–24.3) 0.137 number p malignancyb yes/no 12/3 14/1 0.28 smb neg./pos. 13/2 13/2 1.00 number p benign lesions oncocytoma 3 (20) 1 (6.7) malignant lesions ccrcc 9 (60) 9 (60) fg 1 (-) 5 (55.6) fg 2 6 (66.7) 4 (44.4) fg 3 2 (22.2) (-) fg 4 1 (11.1) (-) prcc type 2 1 (6.7) 4 (26.7) chrcc 2 (13.3) 1 (6.7) t stage pt1a 8 (66.7) 7 (50) pt1b 3 (25) 7 (50) pt3a 1 (8.3) (-) ltpn/lrpn: laparoscopic transperitoneal/retroperitoneal partial nephrectomy; sm: surgical margins, rcc: renal cell carcinoma; fg: fuhrman grade; neg./pos.: negative/positive; ccrcc: clear cell rcc; prcc: papillary rcc; chrcc: chromophobe rcc. a mann-whitney test; 2-sided fisher exact test; b x2 test, fisher’s test. 233archivio italiano di urologia e andrologia 2020; 92, 3 transperitoneal vs retroperitoneal lpn in our study, lrpn was associated with shorter ot. the difference in ot is probably due to the rapid access of lrpn to the tumor, avoiding bowel and extensive kidney mobilization, and due to the need for lysis of adhesions in the first cohort (1, 3, 7, 11-18). it is worth-mentioning that we noticed intrabdominal adhesions in more patients of the group a than anticipated by the history of previous intraperitoneal operation and this might prolong ot. commonly, wi is applied during pn in order to control bleeding, facilitating tumor excision and renorrhaphy and avoiding complications (9, 17, 21-23). wit below 20-25 minutes is generally considered safe (9). efforts to minimize wit resulted in the introduction of terms such as early unclamping technique, selective renal artery clamping technique, clampless pn and selective renal parenchymal ischemia (9, 16, 22, 23). we commonly occlude renal artery without occluding renal vein in both centers. although the occlusion of both renal vessels reduces bleeding from the tumor bed and offers better visualization by preventing venous backflow, animal studies revealed that selective renal artery clamping is superior in preserving renal function postoperatively, as it allows the retrograde irrigation of the normal renal parenchyma by venous blood at lower oxygen tension (23). we used different techniques in order to achieve wi. as expected, group a (early unclamping technique) had shorter median wit than group b. however, the difference was not statistically significant. in cases where we met favorable conditions intraoperatively, we proceeded in clampless pn in order to complete resection and renal reconstruction. hd view and increased intrabdominal pressure due to pneumoperitoneum in laparoscopy facilitate clampless pn offering higher control of bleeding (2, 9). solitary kidney model demonstrated lower incidence of acute kidney injury and chronic kidney disease when ischemia is not applied, although comparison of long-term results on renal function following on-clamp or off-clamp lpn did not demonstrate any benefit in favor of clampless technique in the case of normal contralateral renal function preoperatively (21, 23). in fact, all patients who underwent clampless lpn had no change in egfr postoperatively. in any case, the possible benefit of clampless pn has to be balanced against the risk of intraoperative bleeding, which may affect the oncological outcome and the complication rate (9). any other techniques except conventional wi are technically challenging and should not be popularized (5). transient vascular occlusion exposes the remnant kidney to wi-reperfusion injury, mitigating the renoprotective character of pn (9, 10, 21-23). in addition, postoperative renal function is determined by the preoperative renal function, the volume of the resected rm and the suturing in order to perform renorrhaphy (22). the variation of egfr preoperatively and at discharge in each cohort results from the patients who received wi, as patients who underwent clampless lpn demonstrated no change in egfr. however, we did not notice any benefit in favor of early unclamping technique. as tumor size and complexity are comparable between the two groups, this result may be due to the quality of renorrhaphy of each approach in posterior tumors or due to the quality of remaining parenchyma in each group (24, 25). usual intraoperative complications of lpn are bleeding and injuries of adjacent viscera (10). bleeding (postoperative or delayed) and urine leak are the most common postoperative complications (10). previous studies demonstrated that lrpn is related to lower intraoperative blood loss, as it provides excellent hilar control and demands lesser extent of dissection (1, 11, 15). the intraoperative transfusion rate of group a and the fact that preoperative serum hb value and variation of serum hb value preand post-operatively were similar may confirm the result of previous studies. nevertheless, this may be due to differences in clamping technique between cohorts (1). the majority of our complications were minor, while the only death was unrelated to the operation. an advantage of lrpn is the avoidance of peritoneal entry and bowel mobilization, resulting in earlier bowel recovery postoperatively (1, 7, 15, 19). we did not observe any complications or readmissions related to bowel dysfunction in both cohorts, no patient needed antiemetic drugs postoperatively and we applied similar feeding protocols. in any case, intrabdominal adhesions following ltpn are usually of minor clinical importance (1, 14). we did not notice difference in los, although previous studies favored lrpn (1, 3, 7, 12, 14, 15, 17). this result may be due to the application of similar perioperative care and discharge criteria, although different hospital settings and postoperative complications may affect outcome (11). psm rate was similar between approaches. psm status was noticed only in patients who underwent clampless lpn and there may be a relationship between them. our psm rate is relatively high compared to previous studies, but this may be affected by the small sample size (4, 8, 9, 14, 23). psms may increase the likelihood of recurrence, although their role in natural history of rcc is still under investigation and tumor’s multifocality, grade and stage may be more important factors than psm on the development of local recurrence (4). nevertheless, microscopic psms do not seem to influence survival (4, 8). although our follow-up period is relatively short, none of the patients presented recurrence. in the cases of psm, we schedule our patients in shorter follow-up time intervals, in order to manage a possible recurrence on time (8). our research has several limitations. the statistical power of the sample size is possibly capable to detect only the largest differences between cohorts. it was a retrospective study and patients were not randomly allocated to treatment groups. however, we believe that it is difficult to design randomized, prospective studies with larger sample to compare ltpn and lrpn exclusively for posterior rms in order to draw definitive conclusions, as there are already a lot of approaches and there is a rapid progress in technology and surgical equipment. our results reflect the experience of high-volume laparoscopic surgeons and it may be difficult to replicate them in a different setting. moreover, differences in hospital settings may affect outcomes. finally, longer follow-up period is required for our functional and oncological results to mature. archivio italiano di urologia e andrologia 2020; 92, 3 n. ferakis, a. katsimantas, n. charalampogiannis, s. paparidis, j. jochen rassweiler, a. serdar gözen 234 conclusions lrpn is associated with shorter ot compared to ltpn for patients with posterior ct1 rms. ultimately, good results can be achieved with either approach in experienced hands and the choice should be based on surgeon’s experience and judgment in order to achieve the optimum outcome for the patient. references 1. ren t, liu y, zhao x, et al. transperitoneal approach versus retroperitoneal approach: a meta-analysis of laparoscopic partial nephrectomy for renal cell carcinoma. plos one. 2014; 9:e91978. 2. porpiglia f, mari a, bertolo r, et al. partial nephrectomy in clinical t1b renal tumors: multicenter comparative study of open, laparoscopic and robot-assisted approach (the record project). urology. 2016; 89:45-51. 3. ouzaid i, xylinas e, pignot g, et al. laparoscopic partial nephrectomy: is it worth still performing the retroperitoneal route? adv urol. 2012; 2012:473457. 4. minervini a, campi r, sessa f, et al. positive surgical margins and local recurrence after simple enucleation and standard partial nephrectomy for malignant renal tumors: systematic review of the literature and meta-analysis of prevalence. minerva urol nefrol. 2017; 69:523-38. 5. marconi l, challacombe b. robotic partial nephrectomy for posterior renal tumours: retro or transperitoneal approach? eur urol focus. 2018; 4:632-635. 6. paulucci dj, beksac at, porter j, et al. a multi-institutional propensity score matched comparison of transperitoneal and retroperitoneal partial nephrectomy for ct1 posterior tumors. j laparoendosc adv surg tech a. 2019; 29:29-34. 7. fu j, ye s, ye hj. retroperitoneal versus transperitoneal laparoscopic partial nephrectomy: a systematic review and meta-analysis. chin med sci j. 2015; 30:239-44. 8. vartolomei md, foerster b, kimura s, et al. oncologic outcomes after minimally invasive surgery for ct1 renal masses: a comprehensive review. curr opin urol. 2018;28:132-138. 9. mearini l, nunzi e, vianello a,et al. margin and complication rates in clampless partial nephrectomy: a comparison of open, laparoscopic and robotic surgeries. j robotic surg. 2016; 10:135-44. 10. zhao pt, richstone l, kavoussi lr. laparoscopic partial nephrectomy. int j surg. 2016; 36:548-553. 11. gin ge, maschino ac, spaliviero m, et al. comparison of perioperative outcomes of retroperitoneal and transperitoneal minimally invasive partial nephrectomy after adjusting for tumor complexity. urology. 2014; 84:1355-1360. 12. fan x, xu k, lin t, et al. comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy for renal cell carcinoma: a systematic review and meta-analysis. bju int. 2013; 111:611-621. 13. muñoj-rodriguez j, prera a, dominguez a, et al. laparoscopic partial nephrectomy: comparative study of the transperitoneal pathway and the retroperitoneal pathway. actas urol esp. 2018; 42:273-279. 14. marszalek m, chromecki t, al-ali bm, et al. laparoscopic partial nephrectomy: a matched-pair comparison of the transperitoneal versus the retroperitoneal approach. urology. 2011; 77:109-13. 15. wright jl, porter jr. laparoscopic partial nephrectomy: comparison of transperitoneal and retroperitoneal approaches. j urol. 2005; 174: 841-845. 16. rassweiler jj, klein j, tschada a, gözen as. laparoscopic retroperitoneal partial nephrectomy using an ergonomic chair: demonstration of technique and matched-pair analysis. bju int. 2017; 119:349-357. 17. ng cs, gill is, ramani ap, et al. transperitoneal versus retroperitoneal laparoscopic partial nephrectomy: patient selection and perioperative outcomes. j urol. 2005; 174:846-849. 18. kieran k, montgomery js, daignault s, et al. comparison of intraoperative parameters and perioperative complications of retroperitoneal and transperitoneal approaches to laparoscopic partial nephrectomy: support for a retroperitoneal approach in selected patients. j endourol. 2007; 21:754-9. 19. klap j, butow z, champy cm, et al. 1,000 retroperitoneoscopic procedures of the upper urinary tract: analysis of complications. urol int. 2019; 102:406-412. 20. shefler a, ghazi a, zimmermann r, janetschek g. renal hilus clamping with tourniquet during laparoscopic partial nephrectomy. bju int. 2011; 107:1688-93. 21. shah ph, george ak, moreira dm, et al. to clamp or not to clamp? long-term functional outcomes for elective off-clamp laparoscopic partial nephrectomy. bju int. 2016; 117:293-9. 22. bagheri f, puztai c, farkas l, et al. impact of parenchymal loss on renal function after laparoscopic partial nephrectomy under warm ischemia. world j urol. 2016; 34:1629-1634. 23. ng am, shah ph, kavoussi lr. laparoscopic partial nephrectomy: a narrative review and comparison with open and robotic partial nephrectomy. j endourol. 2017; 31:976-984. 24. corongiu e, grande p, di santo a, et al. safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. arch ital urol androl. 2019;91:157-162. 25. tiscione d, cai t, luciani lg, et al. sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. arch ital urol androl. 2019; 91:30-34. correspondence nikolaos ferakis, md ferakis@otenet.gr antonios katsimantas, md antonioskatsimantas@gmail.com spyridon paparidis, md sppap1986@gmail.com department of urology, korgialenio-benakio hellenic red cross hospital, athens (greece) nikolaos charalampogiannis, md nickharas@yahoo.gr jens rassweiler, md jens.rassweiler@slk-kliniken.de ali s gozen, md (corresponding author) asgozen@yahoo.com department of urology, slk-kliniken heilbronn, university of heidelberg, heilbronn, germany stesura seveso 215archivio italiano di urologia e andrologia 2014; 86, 3 short communication association of erectile dysfunction and urolithiasis alper otunctemur 1, emin ozbek 2, suleyman sami cakir 3, murat dursun 4, emre can polat 5, levent ozcan 6, osman kose 2, huseyin besiroglu 1 1 okmeydani training and research hospital, department of urology, istanbul, turkey; 2 katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey; 3 bayburt state hospital, department of urology, bayburt, turkey; 4 bahcelievler state hospital, department of urology, istanbul, turkey; 5 !stanbul medipol university, faculty of medicine, department of urology, istanbul, turkey; 6 derince training and research hospital, department of urology, kocaeli, turkey. objectives: in recent years, it has been shown that there is association between metabolic syndrome and urinary stone disease. stone disease and erectile dysfunction (ed) are considered as systemic diseases which are associated with hormonal and metabolic disorders. therefore we investigated the relationship between ed and urinary tract calculi. material and methods: 98 male patients with urolithiasis and 59 randomly selected male patients without stone disease were included in the study. serum testosterone (t) levels were measured and international index of erectile function (iief)-15 questionnaire forms were used to assess ed. results: the prevalence of ed was found 29% (29 patients) in the urolithiasis group. sixty-nine patients (71%) had no ed; 16 (16.3%) had mild, 5 (5.1%) had moderate and 8 (8.2%) had severe ed. none of the patients in the control group had severe or modarete ed, six patients (10.2%) had mild ed. serum t levels were detected at the level of biochemical hypogonadism on 13 patients with stones (13.3%) and t levels were detected at the lower limit in 18 (18.3%) patients. conclusion: in our study we have shown that ed and low t levels are significantly associated with urolithiasis. we propose that the patients with urolitiasis should be evaluated for ed and hypogonadism. key words: urolithiasis; erectile dysfunction; metabolic syndrome; testosterone; hypogonadism; iief. submitted 29 june 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction erectile dysfunction (1) is defined as the consistent inability to obtain and/or maintain a penile erection which is sufficient to permit satisfactory sexual intercourse (2). it is estimated that more than 150 million men worldwide have ed and the global prevalence is increasing along with aging population trends (3, 4). ed has been associated with signs of generalized arterial disease, as it frequently coexists with diseases with a high component of endothelial dysfunction, such as coronary artery disease, idiopathic systemic arterial hypertension, doi: 10.4081/aiua.2014.3.215 atherosclerosis and end-stage chronic kidney disease. ed is also associated with cardiovascular disease risk factors, such as diabetes mellitus, dyslipidemia, and smoking (1, 5-7). low testosterone levels are significantly associated with prevalence of mets (8, 9). obesity and components of metabolic syndrome have been associated with nephrolithiasis, and several studies have suggested that metabolic syndrome is linked directly to the formation of urolithiasis (10-12). the higher prevalence of stone disease in patients with metabolic syndrome suggests that insulin resistance might have a role in the pathophysiology of nephrolithiasis (13, 14). although, stone disease and ed are defined as systemic diseases which are associated with hormonal and metabolic disorders, there are few studies on the association of ed and stone disease. we estimated the association of ed with urolithiasis and testosterone levels in the patients who were admitted to our clinic. material and methods this study assessed the prevalence rate of ed in men with urolithiasis. we identified as the study group 98 male patients with urolithiasis who had experienced spontaneous stone passage or surgery for urolithiasis (percutaneous nephrolithotomy, ureterorenoscopy) or whose stones were radiologically (ultrasonography, computed tomography or intravenous urography) visible at the onset of clinical symptoms and 59 randomly selected male patients as the controls. mean age of the study group was 48.49 ± 10.87! years (range: 28-67) and mean age of controls was 47.28 ± 8.62 years (range:31-64). there was no significant difference between mean age of patients and control group. the study population for this case-control study consisted of patients who were admitted to our clinic. subjects having severe cardiovascular disease, endocrine or neurological disease were excluded from study. serum testosterone (t) levels were evaluated on blood samples taken between 08.00 and 10.00 in the fasting state. serum t was measured using enzymatic methods with an autoanalyzer. international index of erectile function (iief)-15 questionnaire which was validated for use in turkey was otunctemur sc_stesura seveso 08/10/14 12:14 pagina 215 archivio italiano di urologia e andrologia 2014; 86, 3 a. otunctemur, e. ozbek, s. sami cakir, m. dursun, e. can polat, l. ozcan, o. kose, h. besiroglu 216 applied to all patients. according to the iief-15 questionnaire, we evulated scores between 6 and 10 as severe dysfunction, between 11 and 18 as moderate dysfunction, between 19 and 24 as mild dysfunction and between 25-30 no dysfunction. low testosterone level was considered when < 110 ng/dl whereas levels from 110 to 285 ng/dl were considered as the lower limit of testosterone level. local ethics committee approval had been obtained before the commence of the study. statistics analyses were completed using chi-square tests. odds ratios (or) were calculated. statistical determinations were within the 95% confidence interval (ci). all p values were two-tailed, and p 0.05 was considered statistically significant. the data were analyzed with an spsstm (spss version 13.0, chicago, il) statistical software package. results the prevalence of ed was found 29% (29 patients) in the urolithiasis group. sixty-nine patients (71%) had no ed, 16 (16.3%) mild ed, 5 (5.1%) moderate ed and 8 (8.2%) severe ed. none of the patients in the control group had severe or modarete ed and six patients (10.2%) had mild ed (p = 0.0084). a significantly higher proportion of ed was found among patients with urolithiasis compared with controls (table 1). serum t levels were detected at the level of biochemical hypogonadism on 13 (13.3%) of patients with stones and t levels were detected at the lower limit in other 18 (18.3%) patients. biochemical hypogonadism was never observed in the controls whereas t levels at the lower range were detected in only 8 patients (p = 0.018) (table 2). serum t levels were dedected at the lower limit in 3 patients with mild ed and at the level of biochemical hypogonadism in 7 patients with severe ed. conclusions in our study we have shown that ed and low t levels are significantly associated with urolithiasis. we suggest that the patients with urolitiasis should be evaluated for ed and hypogonadism, and consequently life-style arrangements are to be planned for treatment. references 1. mesquita jf, et al. prevalence of erectile dysfunction in chronic renal disease patients on conservative treatment. clinics (sao paulo) 2012; 67:181-3. 2. santos t, drummond m, botelho f erectile dysfunction in obstructive sleep apnea syndrome prevalence and determinants. rev port pneumol. 2012; 18:64-71. 3. lewis rw, et al. definitions/epidemiology/risk factors for sexual dysfunction. j sex med. 2010; 7:1598-607. 4. ayta ia, mckinlay jb, krane rj the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-6. 5. vlachopoulos c, et al. arterial function and intima-media thickness in hypertensive patients with erectile dysfunction. j hypertens. 2008; 26:1829-36. 6. koca o, et al vasculogenic erectile dysfunction and metabolic syndrome. j sex med. 2010; 7:3997-4002. 7. lee yc, et al. the potential impact of metabolic syndrome on erectile dysfunction in aging taiwanese males. j sex med. 2010; 7:3127-34. 8. kupelian v, et al. inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. j clin endocrinol metab. 2008; 93:3403-10. 9. goncharov np, et al. three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone. aging male 2008; 11:118-22. 10. taylor en, stampfer mj, curhan gc obesity, weight gain, and the risk of kidney stones. jama 2005; 293:455-62. 11. taylor en, stampfer mj, curhan gc. diabetes mellitus and the risk of nephrolithiasis. kidney int. 2005; 68:1230-5. 12. curhan gc. et al. body size and risk of kidney stones. j am soc nephrol. 1998; 9:1645-52. 13. west b, et al. metabolic syndrome and self-reported history of kidney stones: the national health and nutrition examination survey (nhanes iii) 1988-1994. am j kidney dis. 2008; 51:741-7 14. obligado sh, goldfarb ds the association of nephrolithiasis with hypertension and obesity: a review. am j hypertens. 2008; 21:257-64. correspondence alper otunctemur, md alperotunctemur@yahoo.com huseyin besiroglu, md okmeydani training and research hospital, department of urology, 34384, sisli, istanbul, turkey emin ozbek, md osman kose, md katip celebi university, ataturk training and research hospital, department of urology, izmir, turkey suleyman sami cakir, md bayburt state hospital, department of urology, bayburt, turkey murat dursun, md bahcelievler state hospital, department of urology, istanbul, turkey emre can polat, md !stanbul medipol university, faculty of medicine, department of urology, istanbul, turkey levent ozcan, md derince training and research hospital, department of urology, kocaeli, turkey iief-5 iief-5 iief-15 iief-15 severe ed moderate ed mild ed no ed (6-10) (11-18) (19-24) subject with stone 8 (9.2%) 5 (5.1%) 16 (16.3%) 69 (71%) subject without stone 6 (8.2%) 53 (89%) p 0.0084 table 1. iief-15: international index of erectile function. stl < 110 ng/dl stl between 110 to 285 ng/dl subject with stone 13 (13.3%) 18 (18.3%) subject without stone 8 (13.5%) p = 0.018 table 2. stl: serum testosterone level. otunctemur sc_stesura seveso 08/10/14 12:14 pagina 216 151archivio italiano di urologia e andrologia 2017; 89, 2 case report metastasis of renal cell carcinoma to the thyroid gland 9 years after nephrectomy: a case report and literature review zeki bayraktar, selami albayrak istanbul medipol university, school of medicine, department of urology, istanbul, turkey. we report a case presenting with thyroid and lung metastases of renal cell carcinoma that was treated with molecular targeted therapy followed metastasectomy. a 52-year-old female underwent radical nephrectomy of right renal cell carcinoma in 2007. the patient presented 9 years after nephrectomy at the age of 61 years with sudden loss of vision on the left side and a mass on the neck. on magnetic resonance imagining, there was a mass on the midline of the neck, extending to the left, measuring 46 x 31 mm and containing central cystic-necrotic areas. fine-needle aspiration biopsy was performed. the histopathological examination of the biopsy specimen revealed a lesion composed of malignant epithelial cells compatible with metastasis of renal carcinoma. computed tomography showed multiple metastases in bilateral lungs. metastasectomy and total tiroidectomy were performed. thyroid and lung metastasis of renal cell carcinoma were pathologically confirmed. but on the first computed tomography after metastasectomy, there was residual tumor in the thyroid. interferon-alpha therapy was given for 8 weeks. after that, pazopanib therapy started. three months later, on computed tomography, residual metastatic foci were regressed. the patient was followed up for 1 year after metastasectomy. the patient is currently receiving a single dose of pazopanib per day (400 mg/day) and the general condition is good. thyroid metastasis should be considered in patients with a thyroid nodule and positive history for renal cell carcinoma. successful results can be obtained with metastasectomy and systemic targeted therapy. key words: renal cell carcinoma; metastasis; thyroid; metastasectomy; targeted therapy. submitted 14 april 2017; accepted 24 april 2017 summary no conflict of interest declared. in this article, we presented a case with ocular emboli and metastasis of renal cell carcinoma to the thyroid gland and to the lung 9 years after nephrectomy. case report the patient was 52 years old when she suffered from a 5.2 cm right renal mass with no evidence of metastasis for which right radical nephrectomy was performed. histopathology revealed clear-cell renal cell carcinoma (crcc), grade iii, stage pt1bn0m0, with negative surgical margins. the patient was followed regularly for the first 7 years after nephrectomy, although she disrupted her follow-up in the 8th year. she presented with sudden loss of vision on the left side and a mass in the neck at the age of 61 years, 9 years after the operation. ophthalmologic disturbances were interpreted as left ocular embolism. at magnetic resonance imaging (mri), a mass on the midline of the neck was demonstrated, which extended to the left, measuring 46 x 31 mm and containing central cystic-necrotic areas. the mass showed diffuse restriction and peripheral heterogeneous enhancement. the plan between the mass and the posterior thyroid cartilage was not clearly visible. the mass was invasive to the isthmus of the thyroid gland inferiorly and showed diffuse restriction and peripheral heterogeneous contrast enhancement (figure 1). on positron emission tomography/computed tomogra phy (pet/ct), there was a nodular lesion with increased 18 f-fluorodeoxyglucose (fdg) uptake of approximately 2.4 x 2.2 cm located in thyroid gland isthmus (suv max: 8,7). in the mediastinum, there were numerous lymph nodes in the right paratracheal region. the largest was 2.1 x 1.4 cm and some showed increased fdg uptake (suv max: 7.7). in the anterior segment of the upper lobe of the left lung there was a nodular lesion of 2.2 x 1.5 cm with increased fdg uptake (suv max: 7.0). in the superior segment of the lower lobe of the right lung, there were subpleural localized nodular lesions, which showed increased fdg uptake. in addition, there was a parenchymal nodular lesion in the lower laterobasal segment of the right lobe, 5 mm in diameter and without increased fdg uptake. these lesions in the lung and in the thyroid gland were evaluated radiologically as rcc metastases due to the doi: 10.4081/aiua.2017.2.151 introduction renal cell carcinoma (rcc) is the most frequent renal malignancy and comprises approximately 2-3% of all adult malignancies (1). metastases of rcc usually occur in the lungs, bones, lymph nodes, brain, liver, and skin, with other sites (such as the thyroid gland) described less frequently (2). thyroid metastasis is an uncommon entity despite its rich vascular supply. metastatic thyroid nodules comprise only 2-3% of all thyroid malignancies (3). although secondary involvement of the thyroid gland by rcc is rare (< 0.1%), rcc is one of the more common neoplasms that metastasize to the thyroid gland (2). bayraktar_stesura seveso 20/06/17 09:59 pagina 151 archivio italiano di urologia e andrologia 2017; 89, 2 z. bayraktar, s. albayrak 152 medical history of the patient. subsequently, a fine-needle aspiration biopsy (fnab) of the nodule of the thyroid that was metabolically active node on pet/ct was performed. on fnab, there were solid areas composed of cells with large, oval-round nucleus, some with nuclei, eosinophilic cytoplasm, and common coagulation necrosis. neoplastic cells were antigenically positive with vimentin and pax8, and showed focal positivity with pansitokeratin, ema and cd10. there was no immunoreactivity with thyroglobulin, thyroid transcription factor-1 (ttf-1), parathormone (pth), calcitonin and ck7. thus, the clinical and radiological diagnosis of mrcc was also confirmed pathologically. hormonal status of the patient was euthyroid (t3, t4 and tsh hormone levels were normal). on color doppler ultrasonography of the patient, there was no thrombus in the bilateral carotid arteries and jugular veins. metastasectomy and systemic targeted therapy was planned after oncologic consultation. two separate operations were planned for metastatic foci in the lung. first, metastasectomy was performed for the foci in the left lung. two weeks later, the right lung foci and mediastinal lymph nodes were resected. but after thoracic lymphadenectomy, lymphatic leakage occurred due to thoracic duct injury. percutaneous drainage was performed and it revealed milky fluid consistent with chylous leakage of 1200 ml per day. conservative treatment including oral feeding with medium chain triglycerides or cessation of oral feeding and total parenteral nutrition was initiated in order to treat the lymphatic leak. although the lymphatic leakage initially decreased, it gradually increased back to former levels. with the aim of stopping the leakage, percutaneous intervention was planned to embolize the leakage site. for this purpose, intranodal lymphangiogram and ct-guided percutaneous thoracic duct embolization was performed in the department of radiology, interventional radiology section. one day after embolization, the catheter drainage reduced from 1200 ml to 500 ml daily and stopped on day 7. the pathological diagnosis of lung and mediastinal lesions was confirmed as rcc metastasis. but, because of the complication of lymphatic leakage, total thyroidectomy could be performed 10 weeks after thoracic lymphadenectomy. in the pathological examination of thyroidectomy material, there were solid and diffuse necrotic-neoplastic proliferations and neoplastic cells had a large and oval-round nucleus, distinct nucleolus and clear cytoplasm, and occasionally glandular growth pattern (figures 2, 3). on immunohistochemical examination, neoplastic cells were positive with cd10 and showed focal positivity with ema and pax-8, but were negative with ck7, ck20, ttf-1, thyroglobulin, calcitonin and pth. tumor involved the surgical margin. pet/ct at 6 weeks after thyroidectomy showed significant findings for postoperative residual tumor in thyroidectomy area. two new nodules were also demonstrated, one of which retained fdg in the upper lobe of the right lung and the other of which did not retain fdg in the right lung apex. the 4 mm nodule in the right lower lobe of the lung observed in the previous pet/ct also enlarged to 5 mm, athough no fdg uptake of this nodule was still observed. the patient started interferon-alpha (inf-α) for 8 weeks as first-line adjuvant systemic therapy for mrcc. after 8 figure 1. magnetic resonance imaging showing a solid a mass on the midline of the neck, extending to the left, measuring 46 x 31 mm and containing central cystic-necrotic areas. figure 3. renal cell carcinoma with clear cytoplasm showing nest growth in normal thyroid tissue (hex200). figure 2. renal cell carcinoma metastasis with clear cytoplasm in the vicinity of normal thyroid tissue (hex40). bayraktar_stesura seveso 20/06/17 09:59 pagina 152 weeks, inf-α was stopped and pazopanib was started as second-line adjuvant systemic therapy for mrcc (2 x 400 mg/day). three weeks after the start of pazopanib therapy, on pet/ct, there were nodular densities in the right upper lobe of the lung and in the lower lobe of the left lung that were millimeter in size, faintly confined, and without significant fdg uptake. at the mediastinum there were two hypermetabolic lymphadenopathies with suspected subcarinal and retrotracheal metastases. the patient is currently receiving one dose of pazopanib per day (400 mg/day) after 12 months of thyroidectomy and the general condition is very good. conclusions rcc can metastasize to the thyroid gland even years after nephrectomy. in patients with a history of rcc, both past and present, a thyroid mass, especially co-existing with adenomatous goiter, should prompt a work-up for thyroid metastasis. if thyroid metastasis is present, metastasectomy and systemic targeted therapy may prolong the patient's survival. this is also true for lung and other organ metastases of rcc. because despite multiple morbidities and treatment-related side effects, long-term survival can be reached in cases of mrcc with metastasectomies and systemic targeted therapies. acknowledgements because of the contributions, i would like to thank dr. mustafa soytas from department of urology, dr. belgin karan from department of radiology, and asli cakır from department of pathology, school of medicine, istanbul medipol university. references 1. siegel r, naishadham d, jemal a. cancer statistics. ca cancer j clin. 2013; 63:11-30. 2. heffess cs, wenig bm, thompson ld. metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study of 36 cases. cancer. 2002; 95:1869-78. 3. cilengir ah, kalayci to, duygulu g, et al. metastasis of renal clear cell carcinoma to thyroid gland mimicking adenomatous goiter. pol j radiol. 2016; 81:618-621. 153archivio italiano di urologia e andrologia 2017; 89, 2 thyroid metastasis in rcc correspondence zeki bayraktar, md (corresponding author) zbayraktar@medipol.edu.tr selami albayrak, md salbayrak@medipol.edu.tr istanbul medipol university, school of medicine, department of urology istanbul, turkey bayraktar_stesura seveso 20/06/17 09:59 pagina 153 stesura seveso 93archivio italiano di urologia e andrologia 2020; 92, 2 original paper intensive simulation training on urological mini-invasive procedures using thiel-embalmed cadavers: the iamsurgery experience guglielmo mantica 1, 2, giovannalberto pini 2, 3, davide de marchi 2, 3, irene paraboschi 4, francesco esperto 5, andré van der merwe 6, heidi van deventer 6, massimo garriboli 7, nazareno suardi 1, carlo terrone 1, rosario leonardi 2, 3 1 department of urology, policlinico san martino hospital, university of genova, genova, italy; 2 iamsurgery, international accademy of miniinvasive surgery; 3 department of urology, san raffaele turro hospital, milan, italy; 4 department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health (dinogmi), university of genova, genova, italy; 5 department of urology, campus bio-medico university of rome, rome, italy; 6 department of urology, stellenbosch university and tygerberg academic hospital, cape town, south africa; 7 department of pediatric urology, evelina children hospital, london, uk. introduction: the objective of the study was to evaluate the benefits perceived by the use of cadaver models by iamsurgery attendees and to define indications to standardize future similar training camps. materials and methods: a 25-item survey was distributed via e-mail to all the participants of previous training courses named as “urological advanced course on laparoscopic cadaver lab" held at the anatomy department of the university of malta, for anonymous reply. participants were asked to rate the training course, the thiel’s cadaveric model, and make comparison with other previously experienced simulation tools. results: the survey link was sent to 84 attendees, with a response rate of 47.6% (40 replies). there was improvement in the median self-rating of the laparoscopic skills before and after the training camp with a mean difference of 0.55/5 points in the post-training skills compared to the basal (p < 0.0001). the 72.2% of the urologists interviewed considered thiel's hcm better than other training methods previously tried, while five urologists (27.8%) considered it equal (p = 0.00077). globally, 77.5% (31) of attendees found the training course useful, and 82.5% (33) would advise it to colleagues. conclusions: thiel’s fixed human cadaveric models seem to be ideal for training purposes, and their use within properly structured training camps could significantly improve the surgical skills of the trainees. an important future step could be standardization of the training courses using cadavers, and their introduction into the standardized european curriculum. key words: training; cadaver model; urology; thiel fixation; simulation. submitted 22 november 2019; accepted 7 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.93 introduction surgical ethics requires that surgical procedures should be performed on patients only after having reached adequate skills that ensure high standards in terms of quality and safety for the patient himself (1, 2). for this reason, in recent years, we have witnessed the multiplication of theoretical, technological, synthetic, and biological simulation/training models of varying utility for urologists and post-graduates (3-7). although often useful, many of these models have significant limitations in terms of realism, accessibility, and ethics. as trivial as it sounds, nothing is more like the human body as the human body itself. for this reason, a solution in terms of education and pre-real patient surgical training could be provided by increased use of human cadaver models. currently, there is little (but increasing) literature on the use of human cadaveric models (hcm) for training purposes, and there are a few experiences of training camps with a standardized format reported (8-14). the iamsurgery has been organizing laparoscopic urological surgery training camps for several years using human cadaveric models. the objective of the study is, therefore, to evaluate the benefits perceived by the use of cadaver models by iamsurgery attendees and to define indications to standardize future similar training camps. materials and methods from january 2016 to october 2019, the iamsurgery (international academy of mini-invasive surgery) organized six editions of a training camp called “urological advanced course on laparoscopic cadaver lab". the courses were held at the anatomy department of the university of malta, an expert in the advanced preparation of the bodies following the thiel’s soft-fix embalming method. preparation of the thiel’s cadaveric models the “thiel method” 15 consists of the application of an intravascular injection formula, and submersion for a determinate time in a stainless steel tank in a particular solution that lacks toxic or irritating gases due to minimum formaldehyde concentrations. thiel fixation provides “reusable” cadavers on which, in some cases, several procearchivio italiano di urologia e andrologia 2020; 92, 2 g. mantica, g. pini, d. de marchi, i. paraboschi, f. esperto, a. van der merwe, h. van deventer, m. garriboli, n. suardi, c. terrone, r. leonardi 94 dures might be performed, being more cost-effective than fresh and fresh frozen cadavers. format of the course the course starts with six hours of face-to-face interactive lectures on embalming technique, preparation of the corpses, pelvic and retroperitoneal anatomy, patient positioning, followed by step-by-step modular videos on pelvic and kidney surgery. the hands-on practice began early on the second day. the course, supported by the expert faculty, allows practising simultaneously on three cadavers for a total time of 24 hours. two four-hour modules were focused on laparoscopic radical prostatectomy, two four-hour modules on laparoscopic partial nephrectomy, and two four-hour modules on laparoscopic radical nephrectomy. the philosophy of the course was to maintain small groups for each procedure, favoring a modular rotation regulated by the tutor, to teach not only surgical technique but also non-technical skills and encouraging the team building, a fundamental requirement in the operating room and real life. study design and data analysis a 25-item survey (table 1) was designed by two of the course tutors (r.l. and g.p.) and checked by a third urologist (g.m.) not previously involved in the organization of the courses. the survey was designed following the checklist for reporting results of internet e-surveys (cherries) guidelines, 16 uploaded on google form, and was distributed via e-mail to all the participants of the previous courses, for anonymous reply. the survey was distributed in november 2019. before circulating, we tested the survey for usability and technical functionality. the survey consists of two parts: – part one: general information of the responder (including age, trainee vs. specialist, nationality). – part two: ratings of the training course, the thiel’s cadaveric model, and comparison with other previously experienced simulation tools. some questions had a free answer option while others a ranking scale from 1 (very low) to 5 (very high). only surveys with section one completed, and more than 90% completed in section two, were included in the analysis. data were entered into a microsoft excel (version 14.0) database and transferred to sofastatstm for windows. a descriptive statistical analysis was performed. variables are presented as median (1st-3rd interquartile range) or as a percentage (%). the statistical analysis of nominal variables was done using the t-test calculator and the chi-square calculator for goodness of fit. the level of significance was set at p < 0.05. results the survey link was sent to 84 attendees, with a response rate of 47.6% (40 replies). all attendees were italian, specialized in urology, and with a median age of 50 years (4357.5). twenty-seven (67.5%) were already performing laparoscopy at their institution (either as first operator or assistant). ten (76.9%) out of the 13 who were not performing laparoscopy started with this minimally invasive approach after the training course. the ratings given to the training course and the usefulness and realism of the hcm for training purposes are summarized in table 2. there was improvement in the median selfrating of the laparoscopic skills before and after the training camp with a mean difference of 0.55/5 points in the post-training skills compared to the basal (p < 0.0001). twenty-one (52.5%) attendees did not have experience with any other simulator models, while 18 (45%) had tried at least one other method (one surveyed colleague did not reply to this question). porcine and virtual models were both tried by eight urologists while a synthetic model was tried by five urologists. the presence of bleeding was stated in favor of porcine models by seven urologists (87.5%) while the realism of anatomy 13 (72.2%) and better tissue consistency 8 (44.4%) was in favor of thiel’s hcm. thirteen (72.2%) urologists considered thiel's hcm better than other training methtable 1. iamsurgery malta training course on thiel cadaver models. 1) age 2) working position at the time of the training course 3) nationality 4) were you already performing laparoscopy before the training camp? (yes/no) 5) if no; have you started to perform laparoscopy after the training camp? (yes/no) 6) please give a mark to the team of tutors (1 to 5) 7) please give a mark to the course concept (1 to 5) 8) please give a mark to the time planning (was the training course too short/long?) (1 to 5) 9) usefulness of cadaver training model for radical nephrectomy (1 to 5) 10) realism of cadaver training model for radical nephrectomy (1 to 5) 11) usefulness of cadaver training model for partial nephrectomy (1 to 5) 12) realism of cadaver training model for partial nephrectomy (1 to 5) 13) usefulness of cadaver training model for prostatectomy (1 to 5) 14) realism of cadaver training model for prostatectomy (1 to 5) 15) do you have any experience with other training models (i.e. porcine, synthetic, etc)? (yes/no) 16) if yes; please state what other type of training model have you tried 17) if yes; please explain the differences/advantages/disadvantages of the cadaveric model compared to the others that you have experienced (i.e. any difference in bleeding?) 18) how would you rate the thiel cadaveric model? (1 to 5) 19) if you do have experiences with other training models, how do you consider thiel cadaver model? (worse-equal-better) 20) please rate your laparoscopic skills confidence before the training (1 to 5) 21) please rate your laparoscopic skills confidence after the course (1 to 5) 22) were your couse expectations fullfilled? (yes/no/not completely) 23) have you found the training camp useful for your clinical and surgical practice? (yes/no/not completely) 24) how would you rate the training course? (1 to 5) 25) would you advice it to a colleague? (yes/no/i don’t know) ods previously tried, while five urologists (27.8%) considered it equal (p = 0.00077). globally, 77.5% (31) of attendees found the training course useful, and 82.5% (33) would advise it to colleagues (figure 1). discussion surgical training is very delicate and for ethical reasons cannot be performed directly on the patient but requires a structured modular training first in the dry lab, then on animal or cadaveric models (17) the "urological advanced course on laparoscopic cadaver lab" is a three-day training camp that combines theory, surgical practice, and team building. the cadaveric model is designed to bridge the gap between simulation and live surgery. in literature, there are other training camp reports on cadavers in different fields of urology with excellent feedback from the participants who generally perceive an improvement in their operating skills at the end of the course itself (10-14). in such courses, the importance of the tutors is fundamental (18). the preparation, the ability to teach, and the passion of an excellent tutor can affect the quality of the contents. the quality of the cadaver models is also fundamental. due to biological risk, human cadavers are often used after an embalming process (15). the most common method of embalming is formalin fixation. however, a new method called "thiel fixation" provides an alternative to fresh or formalin-fixed specimens and can be ideal for training purposes (8). the thiel method provides cadavers that can be re-used and on which many procedures can be performed. the re-usability is of paramount importance, considering the scant supply of human bodies available for research and training in some settings. moreover, from our survey, it emerges how most of the interviewees consider the cadaver model globally superior compared to the other tested models (porcine, synthetic, and virtual). the only flaw is the absence of bleeding, which compromises complete realism in particular in some procedures such as partial nephrectomy. similarly, the thiel method has already been tested in urology and showed to be suitable for training and testing purposes within minimally-invasive approaches (19-20). surgical training in adult cadaveric models may be useful also for pediatric urologists regarding some specific procedures such as nephrectomies (i.e., performed for wilms 'tumors). the anatomy of an infant is different; however, a teenager often presents with an anatomy similar to an adult. furthermore, while taking into account the limits as mentioned earlier, the pediatric surgeon could benefit from confidence-building with tissue consistency and surgical planning. from an educational point of view, thiel’s model might be a perfect tool to be introduced into standardized european curricula for urologists and pediatric urologists. the future perspective of iams is to make the training even more realistic by mimicking a real surgical environment through a live cadaver model, and the anatomy department of the university of malta is already at work to provide a cadaver perfusion system. the model will combine the realistic conditions of the living body with the real human anatomy in one model and is the only training model available that provides such a combination (21, 22). conclusions thiel’s fixed human cadaveric models seem to be ideal for training purposes, and their use within properly structured training camps could significantly improve the surgical skills of the trainees. an important future step could be standardization of the training courses using cadavers, and their introduction into the standardized european curriculum. acknowledgements a kind and sincere thank you to dr. heidi van deventer for the english editing. 95archivio italiano di urologia e andrologia 2020; 92, 2 urological mini-invasive training using cadavers table 2. overall and specific course rating. figure 1. variable: respondent numbers (%) 1 2 3 4 5 tutors rating 1 (2.5%) 13 (32.5%) 26 (65%) course concept rating 1 (2.5%) 6 (15%) 33 (82.5%) time planning rating 8 (20%) 16 (40%) 16 (40%) useful of hcm for rn 10 (25%) 30 (75%) the realism of hcm for rn 2 (5%) 19 (47.5%) 19 (47.5%) useful of hcm for pn 2 (5%) 8 (20%) 20 (50%) 10 (25%) the realism of hcm for pn 4 (10%) 12 (30%) 18 (45%) 6 (15%) useful of hcm for rp 7 (17.5%) 17 (42.5%) 16 (40%) the realism of hcm for rp 6 (15%) 17 (42.5%) 17 (42.5%) thiel hcm rating 3 (7.5%) 21 (52.5%) 16 (40%) pre-course personal lap skills 8 (20%) 6 (15%) 16 (40%) 10 (25%) post-course personal lap skills 8 (20%) 14 (35%) 18 (45%) overall course rating 3 (7.5%) 16 (40%) 21 (52.5%) would you advice it to a colleague? have you found the training camp useful for your clinical and surgical practice? archivio italiano di urologia e andrologia 2020; 92, 2 g. mantica, g. pini, d. de marchi, i. paraboschi, f. esperto, a. van der merwe, h. van deventer, m. garriboli, n. suardi, c. terrone, r. leonardi 96 references 1. carrion dm, rodriguez-socarrás me, mantica g, et al. current status of urology surgical training in europe: an esru-esu-esut collaborative study. world j urol. 2019 apr 13. 2. de oliveira tr, cleynenbreugel bv, pereira s, et al. laparoscopic training in urology residency programs: a systematic review. curr urol. 2019; 12:121-126. 3. tawfik am, el-abd as, el-enen ma, et al. validity of a sponge trainer as a simple training model for percutaneous renal access. arab j urol. 2017; 15:204-210. 4. monda sm, weese jr, anderson bg, et al. development and validity of a silicone renal tumor model for robotic partial nephrectomy training. urology. 2018; 114:114-120. 5. mantica g, pacchetti a, aimar r, et al. developing a five-step training model for transperineal prostate biopsies in a naïve residents' group: a prospective observational randomised study of two different techniques. world j urol. 2019; 37:1845-1850. 6. setia s, feng c, coogan c, et al. urology residents' experience with simulation: initial evaluation of mri/us fusion biopsy workshop. urology 2019; pii: s0090-4295(19)30817-9. 7. mantica g, balzarini f, dotta f, et al. development of a photographic handbook to improve cystoscopy findings during resident's training: a randomised prospective study. arab j urol. 2019; 17:243-248. 8. mantica g, leonardi r, pini g, et al. the current use of human cadaveric models in urology: a systematic review. minerva urol nefrol. 2019 nov 11. doi: 10.23736/s0393-2249.19.03558-6. 9. healy se, rai bp, biyani cs, et al. thiel embalming method for cadaver preservation: a review of new training model for urologic skills training. urology. 2015; 85:499-504. 10. yiasemidou m, roberts d, glassman d, et al. a multispecialty evaluation of thiel cadavers for surgical training. world j surg. 2017; 41:1201-1207. 11. mains e, tang b, golabek t, et al. ureterorenoscopy training on cadavers embalmed by thiel's method: simulation or a further step towards reality? initial report. cent european j urol. 2017; 70:81-87. 12. bele u, kelc r. upper and lower urinary tract endoscopy training on thiel-embalmed cadavers. urology. 2016; 93:27-32. 13. özcan s, huri e, tatar i, et al. impact of cadaveric surgical anatomy training on urology residents knowledge: a preliminary study. turk j urol. 2015; 41:83-7. 14. ahmed k, aydin a, dasgupta p, et al. a novel cadaveric simulation program in urology. j surg educ. 2015; 72:556-65. 15. thiel w. the preservation of the whole corpse with natural color. ann anat. 1992; 174:185-95. 16. eysenbach g. improving the quality of web surveys: the checklist for reporting results of internet e-surveys (cherries). j med internet res. 2004; 6:e34. 17. somani bk, van cleynenbreugel b, gozen a, et al. the european urology residents education programme hands-on training format: 4 years of hands-on training improvements from the european school of urology. eur urol focus. 2019; 5:1152-1156. 18. mantica g, fransvea p, virdis f, et al. surgical training in south africa: an overview and attempt to assess the training system from the perspective of foreign trainees. world j surg. 2019; 43:2137-2142. 19. rai bp, stolzenburg ju, healy s, et al. preliminary validation of thiel embalmed cadavers for laparoscopic radical nephrectomy. j endourol. 2015; 29:595-603. 20. veys r, verpoort p, van haute c, et al. thiel-embalmed cadavers as a novel training model for ultrasound guided supine endoscopic combined intrarenal surgery. bju int. 2019 nov 16. doi: 10.1111/bju.14954. [epub ahead of print] 21. aboud et, aboud g, aboud t. "live cadavers" for practicing airway management. mil med. 2015; 180 (3 suppl):165-70. 22. held jm, mclendon rb, mcevoy cs, polk tm. a reusable perfused human cadaver model for surgical training: an initial proof of concept study. mil med. 2019;184(suppl 1):43-47. correspondence guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com department of urology, policlinico san martino hospital, university of genova largo rosanna benzi 10, 16132, genova (italy) giovannalberto pini, md davide de marchi, md rosario leonardi, md department of urology, san raffaele turro hospital, milan (italy) irene paraboschi, md department of neuroscience, rehabilitation, ophthalmology, genetics, maternal and child health (dinogmi), university of genova, genova (italy) francesco esperto, md department of urology, campus bio-medico university of rome, rome (italy) andré van der merwe, md department of urology, stellenbosch university and tygerberg academic hospital, cape town (south africa) massimo garriboli, md department of pediatric urology, evelina children hospital, london (uk) nazareno suardi, md carlo terrone, md department of urology, policlinico san martino hospital, university of genova, genova (italy) archivio italiano di urologia e andrologia 2017; 89, 2134 original paper the role of an herbal agent in treatment for escherichia coli induced bacterial cyctitis in rats murat tuken 1, mustafa zafer temiz 1, emrah yuruk 1, asuman orcun kaptanagasi 2, kayhan basak 3, fehmi narter 4, ahmet yaser muslumanoglu 1, kemal sarica 4 1 bagcilar training & research hospital, dept. of urology, istanbul, turkey; 2 kartal lütfi kirdar training & research hospital, dept. of biochemistry, istanbul, turkey; 3 kartal lütfi kirdar training & research hospital, dept. of pathology, istanbul, turkey; 4 kartal lütfi kirdar training & research hospital, dept. of urology, istanbul, turkey. objectives: the aim of this study is to evaluate the effects of the herbal agent in the prevention and treatment of bacterial cystitis in a rat model. material and methods: a total of twenty-eight male spraguedawley rats were divided into four groups. group-1 constituted the control group (operated and normal saline injected into the bladder, received only drinking water for 7 days); group-2 constituted the no-treatment group (operated, e.coli j96 strain injected into the bladder, received only drinking water for 7 days); group-3 constituted the short-term treatment (operated, e.coli j96 strain injected into the bladder, received the herbal agent added into drinking water for 7 days) and group-4 constituted the long-term treatment (operated, e. coli j96 strain injected into the bladder, received herbal agent added into drinking water for 14 days). at the end of the pre-defined treatment periods of duration, the rats were sacrificed, urine samples collected from the bladder for culture and bladders were harvested for histopathological evaluation. urine culture results and histopathological findings were comparatively evaluated between the groups. results: urine cultures were positive for implanted e. coli strains in 0%, 85.7%, 42.8% and 0% of rats in group 1, group 2, group 3 and group 4, respectively (p = 0.001). although histopathological evaluation revealed increased vascular dilation in the bladder specimens obtained from group 2 and group 3 (p = 0.028) no significant difference was noticed in level of inflammation (p = 0.610), edema (p = 0.754) and thickness of uroepithelium (p = 0.138). conclusion: while long term (14 days) treatment with an herbal agent added into the drinking water resulted in complete clearance of urine from e. coli; shorter application of the agent revealed partial clearance. further clinical studies are needed to support our results. key words: antibiotics; bacterial cystitis; herbal agent. submitted 3 february 2017; accepted 3 april 2017 summary no conflict of interest declared. use, related antimicrobial resistance and the spread of bacterial resistant strains make the problem more serious than ever. like other infectious diseases, the early and proper treatment of cystitis decreases the incidence of disease related morbidity and this situation necessitates the initiation of an empirical antimicrobial treatment in the majority of cases (2). on the other hand, with this approach, the antimicrobial resistance patterns of the hospital and the country are generally ignored by the responsible physicians. administration of an inappropriate empirical antimicrobial therapy may eventually result in the accelerated rates of antimicrobial resistance (3). moreover, these agents are also being used for the antimicrobial prophylaxis in the prevention of urinary tract infections particularly in patients with anatomical abnormalities or increased tendency for serious urinary tract infections. however, the long term prophylactic use of antimicrobial agents has the potential risk of not only the drug resistance but also the development of drug related adverse events. taking all these facts and difficulties in antimicrobial treatment of infections into account, natural remedies composed of herbal agents have been used as an alternative treatment to antimicrobial medications in an attempt to maintain similar efficacy and lower the side effects. studies with such agents did show that some of these herbal remedies may treat uti by several favorable effects. furthermore, some of them may also be helpful in the prevention of future recurrent attacks (4). in present study we aimed to evaluate the potential protective effects of ‘tutukon’ application in the management of bacterial cystitis in rat model. material and methods study design after approval by the local ethical committee of bagcilar training and research hospital, twenty-eight male sprague-dawley rats weighting approximately 300-350 g were randomly divided into 4 groups. a 12/12-hour day&night cycle animal housing cage and ad libitum access to food and water were maintained to all rats doi: 10.4081/aiua.2017.2.134 introduction being responsible for 95% of all symptomatic urinary tract infections (uti), uncomplicated cystitis is the most common type of uti (1). although it can be treated in an effective manner with proper antibiotic selection, cystitis is now accepted as a major public health issue due to its high prevalence. moreover, the antimicrobial mistuken_stesura seveso 20/06/17 09:35 pagina 134 135archivio italiano di urologia e andrologia 2017; 89, 2 treatment of cystitis with an herbal agent throughout the study. group-1 constituted the control group (0.6 ml sterile saline injected into the bladder and fed with normal drinking water for 7 days). group-2 constituted the no-treatment group (0.3 ml of sterile saline and 0.3 ml of escherichia coli [e. coli] j96 strain with a dose of 108 colony forming units [cfu] injected into the bladder and fed with normal drinking water for 7 days). group-3 and group-4 represented the short and long term treatment groups, while rats in both groups received 0.3 ml of sterile saline and 0.3 ml of e. coli j96 strain with a dose of 108 cfu injected into the bladder and fed with 15 ml/day of tutukon. tutukon was applied by adding it into the drinking water for 7 and 14 days, in the last two groups respectively. at the end of study, the urine samples were collected for culture and the bladders were harvested for pathological evaluation. operative technique following 6-hours of fasting, a single intramuscular injection of 60 mg/kg katemine and 10 mg/kg xylazine was applied to anesthetize the rats. loss of reflex response to pinching of paws was used to control the efficacy of anesthesia. thenafter, the abdominal wall of each rat was shaved with electric clippers and the skin was cleansed with 10% povidine iodine (poviodine, dioagnokim inc., istanbul, turkey). after a 1.5 to 2 cm lower abdominal wall incision, the abdominal wall muscles were separated with blunt dissection. the urinary bladders were isolated and exposed. using a 2 ml syringe, the urine inside the bladder was removed and the predefined amount of sterile saline or e. coli was injected into the bladder. after the replacement of the bladder to its original location, the abdominal muscles were approximated using 3/0 absorbable polyglactine (vicryl, ethicaon inc., somerville, nj, usa) and the skin was closed with 2/0 silk (permahand silk, ethicon inc., somerville, nj, usa). the wounds were cleansed using 10% povidine iodine. at the end of the predefined period, the rats in each group were anesthetized using 60 mg/kg katemine and 10 mg/kg xylazine and the bladders were exposed applying the same technique used at the beginning of the study. using a 1ml syringe, the urine in the bladder was aspirated in a sterile condition and sent for culture. the bladder was then harvested for further pathological examination. while the harvested bladders were fixed in 4% neutral formaldehyde, embedded in paraffin blocks and 4-6μm sections were stained with haematoxylin and eosin, theurine samples were kept and transferred at 4°c and cultured for microbiological evaluation. the rats were then sacrificed. herbal agent tutukon (laboratorio miquel y garriga, s.a., barcelona, spain) is a plant based herbal agent compromised with a fixed dose of essential fatty acids, flavonoid quercatin, polysaccharides, rosamarinic acid, boldin and flavonglicozides. it has been used as resolutivo regium for its antioxidant, anti-inflammatory, diuretic, spasmolytic, antibacterial and nephro-protective effects. the drug is available as hidrolate form in bottles of 600 ml. the recommended adult dose is 45 ml three times daily. every 100 ml of the drug is composed aqueous distillate of the dried parts of 570 mg enguisetum arvensis stem, 330 mg of whole plant of spergularia rubra, 280 mg of peumus boldus leaves, 170 mg of flowers of opuntia ficus indica, 170 mg of flowers of sideritis angustifolia, 170 mg of rozmarinus officinales leaves, 170 mg of cynodon dactylon rhizomes and 170 mg of melissa officinalis leaves. microbiological evaluation urine cultures were performed by inoculating the 0.01 ml of rat urine aerobically at 35°c for 24 h on to mac conkey agars and streaking the entire plate surface to obtain quantitative colony counts. histopathological examination all examinations were performed by a single experienced genitourinary pathologist. all samples were examined under the light-microscopy and level of edema (none, mild, moderate and severe), vascular congestion (none, mild, moderate and severe), level of inflammation (none, mild, moderate and severe), changes in transitional epithelium (fibrosis, calcification, mitosis, dysplasia), thickness of the epithelium (in millimeters) and epithelial cell layer (≤ 7 or > 7) were recorded. statistical analysis number cruncher statistical system 2007 statistical software (ncss, llc, kaysville, ut, usa) was used for data analyses and statistical evaluation. the data were expressed as mean ± standard error of mean. statistical comparisons between the groups were performed by the kruskal-wallis multiple comparison test and dunn's multiple comparison test was used for comparisons of subgroups. fisher's exact test and chi-square test were used for analysis of qualitative data. the differences were considered to be significant at a p value less than 0.05. results the pathologic evaluation of the bladder tissue samples with respect to the possible inflammatory changes induced by e. coli injection demonstrated a statistically significant difference regarding the degree of vascular dilation between the groups (p = 0.028) (table 1). dunn’s multiple comparison test revealed that degree of vascular dilation was lower in group-1 when compared to group-2 (p = 0.045), group-3 (p = 0.048) and group-4 (p = 0.044). on the other hand however, we were not able to note any significant difference with respect to the degree of edema, inflammation, the presence of fibrosis and the degree of calcification among the groups evaluated (table 1). although the uroepithelial thickness of the bladder was decreased in group-2 rats; this difference was not statistically significant (p = 0.138) (table 2). on the other hand, the number cell layer in bladder uroepithelium was significantly lower in group-2 when compared with the group-1 (p = 0.024), group-3 (p = 0.024) and group-4 (p = 0.045). last but not least as an important parameter for urinary infection; the urine culture test results were negative for all rats of group-1 and group-4; while positive urine cultures were detected in 85.71% and 42.86% of rats in group-2 and group-3, respectively (p = 0.001). tuken_stesura seveso 20/06/17 09:35 pagina 135 archivio italiano di urologia e andrologia 2017; 89, 2 m. tuken, m. zafer temiz, e. yuruk, a. orcun kaptanagasi, k. basak, f. narter, a. yaser muslumanoglu, k. sarica 136 discussion uti, especially in the form of bacterial cystitis, is one of the most common bacterial infections, affecting the women more frequently than men. e. coli is the most common causative agent and histopathological findings of e. coli cystitis include infection induced interstitial edema, inflammatory cell infiltration and a decrease in the thickness of transitional epithelium of the bladder wall. moreover, utis tend to recur. recurrent uti defines a condition in which the urinary tract is recurrently infected with a pathogen causing inflammation. while e. coli is the predominant uropathogen responsible for approximately 80% of recurrent disease, other causative organisms are staphylococcus, klebsiella, enterobacter and enterococci species (5-7). although antibiotics are quite effective at providing clinical cure for utis in most of the cases, antibiotic resistance is globally increasing (8). there is a growing concern regarding antimicrobial resistance of pathogenic bacteria, particularly of e. coli with repeated antibiotic usage (9, 10). although the resistance was initially described for agents limited to ampicillin, trimethoprim, sulphur-based antimicrobials or tetracyclines, it is now relevant to large families of agents including most ß-lactam antibiotics, aminoglycosides and fluoroquinolones (10, 11). besides high resistance rates, antimicrobial agents also have side effects including disruption of the protective flora of the mouth, anal area, urethra and vagina, which results an increased risk of recurrent infections (12, 13). in addition, antibiotics can cause general adverse effects including palpitations, flushes, nausea, vomiting, diarrhoea, abdominal pain, rashes, headache and dizziness (13, 14). the presence of a natural alternative that could prevent and treat uti is preferable to any other treatment (8). phytotherapeutic and herbal agents are well-studied alternatives to antimicrobial agents with documented efficacies. the most studied natural agent for uti management is vaccinium macrocarpon (cranberry). its benefical effects comes from hippuric acid content which acidifies the urine. it also has the potential antiadhesive properties (5). stothers enrolled 150 sexually active women for a one-year period in a randomized trial to evaluate the prophylactic effects of cranberry in the prevention of uti. he showed that the cranberry prophylaxis resulted in a decrease in antibiotic use compared to placebo group and a statistically significant decrease in symptomatic uti episodes (15). haverkorn et al. also showed that 15 ml cranberry juice twice daily for one month resulted in decreased rates of bacteriuria (16). in a randomized, double-blind, placebo controlled trial including 153 elderly women revealed that usage of cranberry has resulted in significantly less bacteriuria with pyuria (17). a meta-analysis of 10 studies investigated the benefits of cranberry juice or tablets compared to a placebo control in 1049 patients susceptible to uti. the study revealed that the cranberry products reduced the incidence of uti by 35%, a statistically significant amount, over a 12-month period (18). cranberry has been found to specifically inhibit hemagglutination of e. coli by expression of type 1 and p adhesin through the component compounds fructose and proanthocyanidins (19). other natural treatment alternatives for uti are hydrastis canadensis (golden seal or ground raspberry), coptis chinensis (coptis or goldenthread), berberis aquifolium (oregon grape; mahonia aquifolium), berberis vulgaris (barberry), and berberis aristata (tree turmeric). the common characteristic of these herbal agents is berberine content. berberine is a plant alkaloid with a significant antimicrobial activity against a variety of organisms, including bacteria, viruses, fungi, protozoans, helminths, and chlamydia. cernakova et al. showed the growth inhibition effect of berberine on several bacteria, including both sensitive and resistant e. coli, staphylococcus aureus, pseudomonas aeruginosa and bacillus subtilis strains (20). in an ex vivo/in vitro study, it has been demonstrated that presence of 200 mcg/ml berberine sulfate in a culture medium consisting of a urinary pathogenic strain of e. coli isotable 1. comparative evaluation of the pathologic findings of the rat bladders in all groups. parameter group-1 group-2 group-3 group-4 p vascular dilation none 4 (57.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0.028 mild 1 (14.3%) 4 (57.1%) 2 (28.6%) 3 (42.9%) moderate 2 (28.6%) 2 (28.6%) 3 (42.9%) 4 (57.1%) severe 0 (0.0%) 1 (14.3%) 2 (28.6%) 0 (0.0%) edema none 5 (71.4%) 3 (42.9%) 3 (42.9%) 3 (42.9%) 0.754 mild 1 (14.3%) 2 (28.6%) 3 (42.9%) 2 (28.6%) moderate 1 (14.3%) 1 (14.3%) 0 (0.0%) 2 (28.6%) severe 0 (0.0%) 1 (14.3%) 1 (14.3%) 0 (0.0%) inflammation none 5 (71.4%) 2 (28.6%) 3 (42.9%) 0 (0.0%) 0.610 mild 1 (14.3%) 3 (42.9%) 3 (42.9%) 5 (71.4%) moderate 0 (0.0%) 1 (14.3%) 1 (14.3%) 1 (14.3%) severe 1 (14.3%) 1 (14.3%) 0 (0.0%) 1 (14.3%) fibrosis negative 7 (100%) 7 (100%) 7 (100%) 7 (100%) positive 0 0 0 0 calcification negative 7 (100%) 7 (100%) 7 (100%) 7 (100%) positive 0 0 0 0 table 2. histopathologic evaluation of the structural changes in the uroepithelium of rat bladders in all groups. group-1 group-2 group-3 group-4 p thickness of uroepithelium (mm) 0.009 ± 0.025 0.063 ± 0.033 0.079 ± 0.03 0.096 ± 0.016 0.138 number of cell layer in the uroepithelium 4.43 ± 0.79 2.86 ± 1.35 4.43 ± 0.98 4.29 ± 0.49 0.019 tuken_stesura seveso 20/06/17 09:35 pagina 136 137archivio italiano di urologia e andrologia 2017; 89, 2 treatment of cystitis with an herbal agent lated from infected patients results in complete inhibition of fimbrial synthesis (21). arctostaphylos uva ursi (bearberry) is another well studied herbal medicine for uti. it has a direct antimicrobial effect due to its arbutin content which changes the bacterial cell surface characteristics. arbutin is released in alkaline urine and for optimum treatment results, the urine ph should be alkaline (5). turi et al. demonstrated that arbutin significantly increased the hydrophobicityof the bacterial cell surface of e. coli strains with decreasing the ability of bacteria to adhere to the host (22). sharma et al. demonstrated that ethanol extract of some herbs such as zingiber officinale, punica granatum, terminalia chebula, ocimum sanctum, cinnamomum cassia, azadirachta indica and ocimum sanctum have potential antimicrobial effects against uti pathogens such as e. faecalis, gram-negative e. coli, k. pneumoniae and p. aeruginosa. the authors suggested that plants are potential sources of antimicrobial compounds (23). many other herbals such as barosma betulina (buchu), apium graveolens (celery seed), agrimonia eupatoria (agrimony), arctium lappa (burdock), elymus repens (couchgrass), hydrangea aborescens (hydrangea), althea officinalis (marshmallow), mentha piperita (peppermint) have been used successfully for treatment of uti without comprehensive scientific researches (5). tutukon is a medication composed of 8 different herbal ingredients including equisetum arvensis, spergularia rubra, peumus boldus, opuntia ficus indica, sideritis angustifolia, rosmarinus officinalis, cynodon dactylon and melissa officinalis with certain biological effects. the anti-inflammatory effect is an important property of the drug (24). equisetum arvensis has been traditionally used as a mild diuretic, anti-edematous, anti-inflammatory compound. it was also used for treating prostatitis, urinary incontinence and gonorrhea in the early 19th century (25, 26). spergularia rubra is commonly used as diuretic and antiseptic agent for treating diseases related to the renal systems in some regions (27, 28). peumus boldus has strong inhibitory activities and strong antibacterial activity against staphylococcus aureus strains and streptococcus pyogenes due to its antimicrobic components including ethanol (29). opuntia ficus indica commonly known as nopal is called prickly pear cactusin the united states. nopal is used for diabetes, hypercholesterolemia, obesity, alcohol-induced hangover, colitis, diarrhea, benign prostatic hypertrophy (bph) and atherosclerosis (30). sideritis angustifolia is used to relieve the cramping that occurs commonly during menstruation, prepared alone or mixed with sideritis foetens, in spain (31). rosmarinus officinalis has promising results in the case of urinary infections with gram-positive bacteria and it is considerable alternative for the treatment of urinary infections (32). cynodon dactylon possess antimicrobial, and antiviral activity and it has also been used to treat urinary tract infection, urinary calculi and prostatitis. cynodon dactylon has been also used as an antidiabetic agent in traditional system of medicine in india (33). melissa officinalis usually known as lemon balm is one of the oldest and it has been used traditionally to prepare tea in order to calming and anti-spasmolytic effects. pharmacological investigations have shown that the most commonly known therapeutic properties of melissa officinalis extract are sedative, carminative, antispasmodic, antibacterial, antiviral, anti-inflammatory, antioxidant, and neuroprotective (34). the present study shows that both short and long term oral administration of tutukon has a potential effect against e. coli j96 strain induced bacterial cystitis while the effect is more prominent with the long term usage. the drug not only resulted in the eradication of pathogenic bacteria, but also increased the number of uroepithelial cell layer. despite its beneficial effects on the uroepithelium, tutukon treatment did not alter the inflammatory response of the bladder mucosa. in addition, when comparing pyuria among the groups, the results clearly show that oral administration of tutukon resulted in bacterial clearance. application of oral tutukon may be advantageous in situations where a high bacterial load exists in the urinary bladder. conclusion tutukon can be used as an alternative agent for the treatment of uti. in addition to eradication of e. coli j96 strain, tutukon also protects the uroepithelial cell layers. further clinical trials are needed to evaluate the safety and efficacy of tutukon treatment for management of uti in humans. references 1. moura a, nicolau a, hooton t, azeredo j. antibiotherapy and pathogenesis of uncomplicated uti: difficult relationships. j appl microbiol. 2009; 106:177. 2. francesco ma, ravizzola g, peroni l, et al. urinary tract infections in brescia, italy: etiology of uropathogens and antimicrobial resitance of common uropathogens. med sci monit. 2007; 6:136. 3. linhares i, raposo t, rodrigues a, almeida a. frequency and antimicrobial resistance patterns of bacteria implicated in community urinary tract infections: a ten-year surveillance study (20002009). bmc infect dis. 2013; 13:19. 4. geetha rv, anıtha r, lakshmı t. nature’s weapon against urinary tract infections. int j drug dev & res. 2011; 3:85. 5. head ka. natural approaches to prevention and treatment of infections of the lower urinary tract. altern med rev. 2008; 13:227. 6. dineshkumar b, krishnakumar k, menon js, et al. natural approaches for treatment of urinary tract infections: a review sch acad j pharm. 2013; 2:442. 7. tasdemir c, tasdemir s, vardi n, et al. evaluation of the effects of ozone therapy on escherichia coli-induced cytitis in rat. ir j med sci. 2013; 182:557. 8. othman m. cysticlean and recurrent urinary tract infection. webmed central urology. 2013; 4:4203. 9. chakupurakai r, ahmed m, sobithadevi dn, et al., urinary tract pathogens and resistance pattern. j clin pathol. 2010; 63:652. 10. rogers b, sidjabat h, paterson d. escherichia coli o25b-st131: a pandemic, multiresistant, community-associated strain. j antimicrob chemother. 2011; 66:1. 11. matoo t. are prophylactic antibiotcs indicated after urinary tract infection? curr opin pediatr. 2009; 21:203. tuken_stesura seveso 20/06/17 09:35 pagina 137 archivio italiano di urologia e andrologia 2017; 89, 2 m. tuken, m. zafer temiz, e. yuruk, a. orcun kaptanagasi, k. basak, f. narter, a. yaser muslumanoglu, k. sarica 138 12. reid g, howard j, gan b. can bacterial interference prevent infection? trends in microbiology. 2001; 9:424. 13. yost n, cox s, infection and preterm labour. clin obstet gynecol. 2000; 43:759. 14. reid g, burton j, devillard e. the rationale for probiotics in female urogenital healthcare. medscape general medecine. 2004; 6:49. 15. stothers l. a randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. can j urol. 2002; 9:1558. 16. haverkorn mj, mandigers j. reduction in bacteriuria and pyuria using cranberry juice. jama. 1994; 272:590. 17. avorn j, monane m, gurwitz jh, et al. reduction of bacteriuria and pyuria after ingestion of cranberry juice. jama. 1994; 271:751. 18. jepson rg, craig jc. cranberries for preventing urinary tract infections. cochrane database syst rev. 2008; 1:cd001321. 19. zafriri d, ofek i, adar r, et al. inhibitory activity of cranberry juice on adherence of type 1 and type p fimbriated escherichia coli to eucaryotic cells. antimicrob agents chemother. 1989; 33:92. 20. cernakova m, kostalova d. antimicrobial activity of berberine – a constituent of mahoniaaquifolium. folia microbiol (praha). 2002; 47:375. 21. sun d, abraham sn, beachey eh. influence of berberine sulfate on synthesis and expression of pap fimbrialadhesin in uropathogenic escherichia coli. antimicrob agents chemother. 1988; 32:1274. 22. turi m, turi e, kotjalg s, mikelsaar m. influence of aqueous extracts of medicinal plants on surface hydrophobicity of escherichia coli strains of different origin. apmis. 1997; 105:956. 23. sharma a, chandraker s, patel vk, ramteke p. antibacterial activity of medicinal plantsagainst pathogens causing complicated urinary tract infections. indian j pharm sci. 2009; 71:136. 24. sahin c, sarikaya s, basak k, et al. limitation of apoptotic changes and crystal deposition by tutukon following hyperoxaluriainduced tubular cell injury in rat model. urolithiasis. 2015; 43:313. 25. carneiro dm, tresvenzol lmf, jardim pcbv, cunha lc. equisetum arvense: scientific evidences for clinical use. ijbpas. 2013; 2:1579. 26. geetha rv, lakshmı t, anıtha r. in vitro evaluation of anti bacterıal activity of equısetum arvense linn on urinary tract pathogenes. int j pharm pharm sci. 2011; 3:323. 27. al-quran s. taxonomical and pharmacological survey of therapeutic plants in jordan. j nat prod. 2008; 1:10. 28. gonzalez-tejero mr, casares-porcel m, sanchez-rojas cp, et al. medicinal plants in the mediterranean area: synthesis ofthe results of the project rubia. j ethnopharmacol. 2008; 116:341. 29. wendakoon c, calderon p, gagnon d. evaluation of selected medicinal plants extracted in different ethanol concentrations for antibacterial activity against human pathogens. jmap 2012; 1:60. 30. rodriguez-fragoso l, reyes-esparza j, burchiel s, et al. risks and benefits of commonly used herbal medicines in méxico toxicol appl pharmacol. 2008; 227:125. 31. bojovic d, jankovic s, potpara z, tadic v. summary of the phytochemıcal research performed to date on sideritis species. ser j exp clin res. 2011; 12:109. 32. petrolini fv, lucarini r, de souza mg, et al. evaluation of the antibacterial potential of petroselinum crispum and rosmarinus officinalis against bacteria that cause urinary tract infections. braz j microbiol. 2013; 44:829. 33. bharti d, jagtap p, undale v, bhosale a. aerial parts of aqueous extract of cynodondactylon shows hypotensive effect in high fructose treated wistar rats. int j res pharm biomed sci international journal of research in pharmaceutical and biomedical sciences. 2012; 3:585. 34. hosseini r, kaka g, joghataei mt, et al. assessment of neuroprotective properties of melissa officinalis in combination with human umbilical cord blood stem cells after spinal cord injury. asn neuro. 2016; 8:1. correspondence murat tuken, md murattuken@hotmail.com mustafa zafer temiz, md dr_mustafazafertemiz@hotmail.com emrah yuruk, md (corresponding author) emrah.yuruk@yahoo.com ahmet yaser muslumanoglu, md ymuslumanoglu56@hotmail.com bagcilar training & research hospital, dept. of urology merkez m mimar sinan c 6. sok. bagcilar, istanbul, turkey asuman orcun kaptanagasi, md kartal lütfi kirdar training & research hospital, dept. of biochemistry, istanbul, turkey asumanorcun@yahoo.com kayhan basak, md kartal lütfi kirdar training & research hospital, dept. of pathology, istanbul, turkey drkayhanbasak@yahoo.com fehmi narter, md fehminarter66@gmail.com kemal sarica, md saricakemal@gmail.com kartal lütfi kirdar training & research hospital, dept. of urology, istanbul, turkey tuken_stesura seveso 20/06/17 09:35 pagina 138 stesura seveso 7archivio italiano di urologia e andrologia 2020; 92, 1 original paper adjustable bulbourethral male sling: experience after 30 cases of moderate to severe male stress urinary incontinence michele cotugno 1, daniel martens 1, giacomo pirola 2, martina maggi 2, carmelo destro pastizzaro 1, michele potenzoni 1, bernardo maria cesare rocco 3, salvatore micali 3, andrea prati 1 1 dipartimento chirurgico, u.o. di urologia, ospedale di vaio-fidenza, fidenza, italy; 2 dipartimento di chirurgia generale e specialistica, u.o.c urologia, ospedale di arezzo, arezzo (italy); 3 dipartimento di chirurgia generale e specialità chirurgiche, u.o di urologia, azienda ospedaliero-universitaria di modena, italy. objective: to report our experience using the argus perineal sling from july 2015 to april 2018 for male stress urinary incontinence (sui) after prostatic surgery. to evaluate the safety, efficacy and healthrelated quality of life in patients undergoing this procedure. patients and methods: the positioning of an adjustable bulbourethral male sling provides a perineal incision, exposure of the bulbospongiosus muscle and the application of the sling bearing on it with transobturator passage of the two extremities with out-in technique. to modulate the bearing tension on the urethra, with a rigid cystoscope the retrogade leak point pressure is measured, increasing it by 10-15 cm of h20 from baseline. we retrospectively evaluated the results of this implant performed by the same operator on 30 patients who presented post-operative sui from medium to severe (> = 2 pads/day, pad test at one hour > = 11 g). mean operative time and possible intra and postoperative complications were evaluated. postoperatively each patient was reassessed according to the following parameters: number of pads consumed/die, pad tesy at one hour, icqs-f, any related side effects. results: after the intervention, 21 of 30 patients (70% of the total) were totally continent (< 1 pad / day, pad test at 1 h < 1-2 g, icqs-f < 11), out of them 4 required a single adjustment at 3 months in order to achieve this result. 9 of 30 patients (30 %) achieved a clinically significant improvement without obtaining total continence (mean reduction of the n° pads/day: -2.5 ± 1 ds; average reduction of the pad test at 1 h: -20 g ± 4 ds; icqs-f average reduction: -6 points ± 2 ds), out of them 5 required a 3 month adjustment to obtain these improvements resulting, 4 needed 2 adjustments resulting because the first adjustment was not satisfactory and one who ameliorated from severe to moderate incontinence decided to live in this clinical condition. conclusions: the results of our study show that the positioning of this sling represents a valid treatment for the moderate and severe post-surgical male sui. the possibility of adjusting the tension of the sleeve in a "second look" makes the intervention adaptable according to the results obtained. only multicentric clinical trials on larger series would clarify and eventually confirm the clinical benefits of this sling in post-surgical male sui. key words: male stress urinary incontinence; sling; prostatectomy. submitted 30 july 2019; accepted 21 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.7 introduction stress urinary incontinence (sui), defined according to international continence society (ics) as leakage from the urethra synchronously with exertion/effort or sneezing/coughing (1), can be listed within iatrogenic complications following different prostatic surgeries. this condition represents a major issue since it has been proven that its occurrence negatively impacts patients’ quality of life (qol), leading to withdrawal from social activities (2-6) and affecting primary disease treatments outcomes (7, 8). in these cases, according to different surgical technique implemented, the incidence of male sui widely ranges, showing 0-2% rate following benign prostatic surgery and 5-35% after radical prostatectomy (rp) (9, 10). these high differences in sui incidences can be due to a wide variation within different continence definitions, variable diagnostic evaluation, inclusion/exclusion criteria and type of surgical procedures performed among available literature evidence (11). it is important to remember that the incidence of this disorder will also depend on the general condition of the patient before surgery (26). this can change the risk that each individual patient will have to develop post-operative ius. according to the european association of urology (eau) guidelines, surgical treatment is recommended when initial conservative treatments (i.e. floor muscle training, biofeedback and behavioral modifications) failed. artificial urinary sphincter (aus, ams 800®, american medical systems, usa) represents the gold standard to treat sui, achieving continence rate of 59-90% with high patient satisfaction and best long-term outcomes (10, 12-14). nevertheless, mechanical failure, infection or erosion have been documented within 25% at 10 years (15). implantation of male sling either fixed (advance®, american medical systems, minnetonka, mn, usa) or adjustable (argus®, promedon sa, cordoba, argentina; reemex®, neomedic international, barcelona, spain; atoms®, agency for medical innovations a.m.i., feldkirch, austria) has been considered an option for surgical treatment of sui following prostatic surgery (13). even if the aus demonstrated superior long-term outcomes, slings are attractive to patients since these devices showed sevcotugno_stesura seveso 06/04/20 17:39 pagina 7 archivio italiano di urologia e andrologia 2020; 92, 1 m. cotugno, d. martens, g. pirola, m. maggi, c.d. pastizzaro, m. potenzoni, b.m.c. rocco, s. micali, a. prati 8 eral advantages: absence of mechanical parts, no need for device training, immediate efficacy and no need to cycle device before micturition (16). argus® (promedon sa; cordoba, argentina) adjustable male sling system is a minimally invasive device developed to treat male sui and to achieve urinary continence. the possibility of intraoperative adjustments and postsurgical readjustments represent its main advantage allowing the necessary coaptation of the bulbar urethra, with low tension, reaching the needs of each patient and at the same time minimizing risks of erosion, ischemia and urine retention. the aim of the present study was to report our preliminary results with the implementation of argus male perineal sling for male sui after prostatic surgery. to this purpose, we evaluated efficacy, safety and patients’ health-related qol outcomes in our retrospective cohort of patients suffering from sui. materials and methods the following analysis represents a single-center study in which 30 men who underwent male argus sling implant as treatment for sui following prostatic surgery were retrospectively reviewed from july 2015 to april 2018. the study received formal institutional review board. written informed consent was obtained from all enrolled patients. patients were informed about the opportunity for aus implantation as well as risks and benefits of the argus sling positioning, including the possible need of additional surgeries over the time. all patients were suffering from moderate to severe sui as result of prostatic surgery as follows: 23 (76.7%) post radical prostatectomy (rp), 5 (16.7%) post rp followed by adjuvant radiotherapy (rt), 1 (3.3%) post transurethral resection of the prostate (turp) and 1 (3.3%) post holmium laser enucleation of the prostate (holep) (table 1). three out of 30 patients (10%) had previously undergone an adjustable non-circumferential constrictor that was simultaneously explanted during the sling placement. all patients presenting with persistent moderate to severe sui (≥ 2 pads/day, pad test at one hour ≥ 11 g) for > 1 year after surgery, despite conservative treatments, were enrolled in our study. patients previously diagnosed with urethral stricture, bladder neck sclerosis and/or bladder overactivity were excluded. all procedures were performed by the same single surgeon. according to romano et al, the technique was previously described (17). the positioning of the argus sling (promedon sa, cordoba, argentina) consisted in a perineal incision followed by exposure of the bulbospongiosus muscle and the application of the sling bearing on it with transobturator passage of the two extremities with out-in technique. two vials of gentamicin 80 mg were distributed at the level of the exposed tissues following the 3 incisions and always after positioning the sling. to modulate the bearing tension on the urethra, with a rigid cystoscope (optic 0°) the retrogade leak point pressure was measured, increasing it by 10-15 cm of h20 from baseline without exceeding 40 cm of h20. all patients were evaluated at baseline before surgery, and then every 3 months for 2 years. pre-operative assessment included: number of pads used/day; pad-test at one hour (mild sui < 10 g, moderate between 11 and 50 g, severe > 50 g); administration of the international consultation on incontinence questionnaire short form (icqs-f) (pathological value > 11, score 021); cystoscopy (to assess the presence and extent of the sphincter deficiency and to exclude post-surgical neck sclerosis or urethral stricture); urodynamic examination. mean operative time and possible intra and post-operative complications were collected. post-operatively each patient was evaluated according to the following parameters: number of pads used/day, padtest at one hour, icqs-f, any related side effects. we defined patients as either totally continent if they were using no pads to 1 security pad/day or a urinary leakage of < 1-2 g at 1 h, or with a significant improvement if there was a reduction of > 50% in number of pads used/day or urinary leakage at 1 h. results overall, 30 men with median age of 73.5 years (range 5179) undergone our male sling implant and were evaluated with a median follow-up of 13.5 months (range 3-24). results reported are those obtained from the last follow-up visit of each patient. surgical procedures were carried out within median operative time of 58 minutes (range 38-95) and no intraoperative complications were reported. postoperatively 21 out of 30 patients (70%) were totally continent (< 1 pad/day, pad-test at 1 h < 1-2 g, icqs-f < 11); of these 4 (13.3%) required a single adjustment of the sling 3 months after the intervention in order to achieve continence. nine out of 30 patients (30%) found a clinically significant improvement in their continence, with a mean reduction of the number of pads used/day of -2.5 ± 1, a mean reduction of the pad-test at 1 h of -20 ± 4 g and a mean reduction of icqs-f of -6 ± 2 points. out of these, 5 (16.7%) required single adjustment of the sling at 3 months to obtain this result, while 4 (13.3%) needed 2 revisions (at 3 and 6 months, respectively) since they were not satisfied after the first adjustment. all of these 9 patients presented with a severe pre-operative sui (> 5 pads/die, pad-test at 1 h > 50 g, iciq-sf score 21), and 5 out of 9 were previously submitted to rt. the mean operative time for surgical revisions (increase of sleeve tension on the urethra) was 35 ± 8 min. early post-operative complications to report included: difficulties in emptying the bladder, which occurred in 3 table 1. causes of sui and previous surgery characteristics of the 30 men who underwent male argus sling implant. parameter number (%) rp 23 (76.7) rp+rt 5 (16.7) turp 1 (3.3) holep 1 (3.3) rp = radical prostatectomy; rt = radiotherapy; turp = transurethral resection of the prostate; holep = holmium laser enucleation of the prostate. cotugno_stesura seveso 06/04/20 17:39 pagina 8 patients (10%) and resolved spontaneously within 18 days (range 14-21); perineal and/or inguinal pain, which occurred in 17 patients (56.6%) and was conservatively managed with the use of nsaids (none required sling removal) within a maximum of 45 days (range 18-45). discussion male sui almost exclusively recognizes prostatic surgery as a leading cause responsible for the majority of the cases. injuries of the distal urethral sphincter are the basis of the pathophysiology of this form of incontinence. turp, holep and open adenomectomy give relatively low 1-year incontinence rates achieving 1% at 12 months after surgery (18). on the contrary rp has a higher percentage of risk, especially in elderly patients and associated with pelvic radiation or a previous turp (14). ficarra et al in their recent systematic review found that the mean continence rates at 12 months were 89-100% for patients treated with robotic-assisted laparoscopic prostatectomy (ralp) and 80-97% for patients treated with radical retropubic prostatectomy (rrp) (19). a prospective controlled non-randomized trial of patients undergone rp in 14 centers using ralp or rrp showed an incontinence rate of 21.3% and 20.2% at 12 months for ralp and rrp respectively (or 1.08, 95%ci: 0.87-1.34) (20). regardless of the considered studies it seems that increased surgical experience has lowered the complication rates of rp and improved cancer cure (21). the placement of an aus represents today the first line treatment for male sui. despite it is the most established surgical procedure, with a high degree of patients’ satisfaction and success (59-90%), it has shown a risk of revision due to mechanical failure, infection or erosion of 25% at 10 years (15). according to these considerations, over the last decade, a raising interest in male sling to treat sui has been developed. in 2007, rehder and gozzi published their pilot study on the use of advance®, transobturator fixed sling which aimed to re-establish the anatomical position of the external sphincter (22, 23). in order to avoid overcorrection and to enable the sling to adapt to functional or anatomical changes in the patients, adjustable systems have been developed. the argus system has become a valid option since it has countless advantages: minimally invasive approach, no exposure of the urethra, average learning curve and, above all, the possibility of adjusting the tension of the sleeve on the urethra, which allows us to "customize the sling" for each type of urinary incontinence. in our series the percentage of patients with total postoperative continence was 70% with a median follow-up of 13.5 months. this percentage is similar to those reported by the current literature. hubner wa et al. demonstrated a total continence rate of 79.2% in their 101 patient series after a 2.1 year mean follow-up (24). romano sv et al. obtained 73% of continence rate in 48 patients after a mean follow-up of 7.5 months (17). regarding readjustments of the sling tension, the extreme ease and the reduced operating time reported in our series (mean operative time 35 ± 8 min), make this treatment extremely personalized and adaptable to each single case. in the present study, post-operative sling adjustments (one or more) were necessary in 43.3% of patients, due to either persistence of incontinence or patient’s dissatisfaction. this percentage is higher than those experienced by romano sv et al. (4 cases, 8%) and hubner wa et al. (39 cases, 38.6%) (17, 24). the most frequent complication experienced in our patient series was inguinal and/or perineal pain (56.6% of patients), which has always been transient and never required explant of the device. interestingly, in our study, none of the cases experienced erosion and/or infection of the sling that required removal of the device. this data significantly differs from other available evidences in which infection and device removal rates of the sling are 5.4-8% and 10-15%, respectively (24, 25). this result could be explained by several factors: 1. the sling was opened only after the needle has passed through the obturator foramen; 2. the routinary use of 2 vials of gentamicin 80 mg for each operation; 3. the positioning of the sling was always performed by the same operator who already had therefore a considerable experience. in men who underwent adjuvant pelvic rt, the efficacy of the sling is unclear and results in the literature are still conflicting. hubner et al in their series with 22 radiated men reported a good success rate of 90.9% (20 of 22 patients were dry) and a sling explantation rate of 9.1% (2 of 22 patients) (24); differently, bochove-overgaauw and schrier in a series of 13 radiated men found a significantly worse success rate (15%, 2 of 13 patients) and sling explantation rate (27%, 4 of 15 patients) (25). in our study all 5 cases with a prior rt found a clinically significant improvement in their continence, thus demonstrating the feasibility of this surgery also in radiated patients. several limitations of our study should be acknowledged. our sample size was limited to 30 cases, thus affecting clinical deducible implications from our analysis. the design of the present study is retrospective without a control arm for comparison. all surgical procedures were performed by a single experienced urologist and results may be a related to the surgical skills of the surgeon and may not be similar for naïve operators. our follow-up does not allow an evaluation of efficacy and complications occurred 24 months after surgery, thus a longer follow-up should be necessary to report efficacy and safety data over the time. conclusions results from our study show that implantation of this type of sling represents a valid option to treat moderate and severe post-surgical male sui. the technique by not providing exposure to the urethra minimizes the risk of iatrogenic damage, erosion and infection of the device and is feasible in radiated patients, especially if performed by experienced surgeons. on the other hand, the possibility to adjust postoperatively the tension of the sleeve makes the intervention adaptable according to the obtained results, thus achieving better patients’ compliance and continence rate. only multi-centric clinical trials with a larger cohort of patients could clarify and eventually confirm the clinical benefits of this sling in postsurgical male sui. 9archivio italiano di urologia e andrologia 2020; 92, 1 adjustable bulbourethral male sling cotugno_stesura seveso 06/04/20 17:39 pagina 9 archivio italiano di urologia e andrologia 2020; 92, 1 m. cotugno, d. martens, g. pirola, m. maggi, c.d. pastizzaro, m. potenzoni, b.m.c. rocco, s. micali, a. prati 10 references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology in lower urinary tract function: report from the standardization sub-committee of the international continence society. urology. 2003; 61:37-49. 2. fosså sd, bengtsson t, borre m, et al. reduction of quality of life in prostate cancer patients: experience among 6200 men in the nordic countries. scand j urol. 2016; 50:330-337. 3. wagner th, patrick dl, bavendam tg, et al. quality of life of persons with urinary incontinence: development of a new measure. urology 1996; 47:67-71. 4. powel ll. quality of life in men with urinary incontinence after prostate cancer surgery. j wound ostomy continence nurs. may 2000; 27:174-178. 5. sciarra a, gentilucci a, salciccia s, et al. psychological and functional effect of different primary treatments for prostate cancer: a comparative prospective analysis. urol oncol. 2018; 36:340.e7340.e21. 6. maggi m, gentilucci a, salciccia s, et al. psychological impact of different primary treatments for prostate cancer: a critical analysis. andrologia. 2019; 51:e13157. 7. cornu jn, sèbe p, ciofu c, et al. mid-term evaluation of the transobturator male sling for post-prostatectomy incontinence: focus on prognostic factors. bju int. 2011; 108:236-40. 8. stothers l, thom dh, calhoun ea. urinary incontinence in men. urologic diseases in america. us department of health and human services, public health service, national institutes of health, national institute of diabetes and digestive and kidney disease. available at: <http://kidney. niddk.nih.gov/statistics/uda/urinary_ incontinence_in_men-chapter06.pdf>. 9. aagaard mf, khayyami y, hansen fb, et al. implantation of the argus sling in a hard-to-treat patient group with urinary stress incontinence. scand j urol. 2018; 52:448-452. 10. kirkeby hj, nordling j. urinary incontinence after prostatic surgery. danish medical journal. 2007; 169:1910-1912. 11. bauer rm, bastian pj, gozzi c, stief cg. postprostatectomy incontinence: all about diagnosis and management. eur urol. 2009; 55:322-33. 12. trost l, elliott ds. male stress urinary incontinence: a review of surgical treatment options and outcomes. adv urol. 2012; 2012:287489 13. thuroff jw, abrams p, andersson k-e, et al. eau guidelines on urinary incontinence. eur urol.urol. 2011; 59:387-400. 14. herschorn s, bruschini h, comiter c, et al. surgical treatment of stress incontinence in men. neurourol urodyn. 2010; 29:179190. 15. abrams p, andersson ke, birder l, et al. 4th international consultation on incontinence. recommendations of international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse and fecal incontinence. neurourology and urodynamics. 2019; 29:213-240. 16. welk bk, herschorn s. the male sling for post-prostatectomy urinary incontinence: a review of contemporary sling designs and outcomes. bju int. 2012; 109:328-44. 17. romano v, metrebian se, vaz f, et al. an adjustable male sling for treating urinary incontinence after prostatectomy: a phase iii multicentre trial bju int. 2006; 97:533-9. 18. van melick hh, van venrooij ge, eckhardt md, boon ta. a randomized controlled trial comparing transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with ipb: analysis of subjective changes, morbidity and mortality. j urol. 2003; 169:1411-6. 19. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012; 62:405. 20. haglind e, carlsson s, stranne j, et al. urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. eur urol. 2015. 68:216. 21. augustin h, hammerer p, graefen m, et al. intraoperative and perioperative morbidity of contemporary radical retropubic prostatectomy in a consecutive series of 1243 patients: results of a single center between 1999 and 2002. eur urol. 2003; 43:113. 22. rehder p, gozzi c. transobturator sling suspension for male urinary incontinence including post radical prostatectomy. eur urol. 2007; 52:860-6. 23. rehder p, gozzi c. re: surgical technique using advance sling placement in the treatment of post-prostatectomy urinary incontinence. int braz j urol. 2007; 33:560-1. 24. hubner, w.a, gallistl h, rutkowski m, et al. adjustable bulbourethral male sling: experience after 101 cases of moderate-tosevere male stress urinary incontinence. bju int. 2011; 107:777-82. 25. bochove-overgaauw dm, schrier bp. an adjustable sling for the treatment of all degrees of male stress urinary incontinence: retrospective evaluation of efficacy and complications after a minimal followup of 14 months. j urol. 2011; 185:1363-8. 26. padilla-fernández b, virseda-rodríguez áj, valverde-martínez ls, et al. influence of secondary diagnoses in the development of urinary incontinence after radical prostatectomy. arch ital urol androl. 2017; 89:34-38. correspondence michele cotugno, md (corresponding author) mikcot88@libero.it daniel martens, md dmastens@ausl.pr.it pastizzaro carmelo destro, md pdestro@ausl.pr.it michele potenzoni, md mpotenzoni@ausl.pr.it andrea prati, md aprati@ausl.pr.it dipartimento chirurgico, u.o.c di urologia, ospedale di vaio-fidenza, fidenza (italy) giacomo pirola, md gmo.pirola@gmail.com martina maggi, md martina.maggi@uniroma.it dipartimento di chirurgia generale e specialistica, u.o.c urologia, ospedale di arezzo, arezzo (italy) bernardo maria cesare rocco, md bernardo.rocco@gmail.com salvatore micali, md smicali@unimore.it dipartimento di chirurgia generale e specialità chirurgiche, u.o di urologia, azienda ospedaliero-universitaria di modena, modena (italy) cotugno_stesura seveso 06/04/20 17:39 pagina 10 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 3212 short communication evaluation of depression and self-esteem in children with monosymptomatic nocturnal enuresis: a controlled trial orhan koca 1, mehmet akyüz 1, bilal karaman 1, zeynep yeşim özcan 2, metin öztürk 1, zülfü sertkaya 1, muhammet ihsan karaman 1 1 haydarpasa numune training and research hospital, department of urology, istanbul, turkey; 2 haydarpasa numune training and research hospital, department of family medicine, istanbul, turkey. objectives: nocturnal enuresis (ne) is very common and is one of the most common causes for patients to be admitted to urology, pediatrics, child psychiatry and child surgery departments. we aimed to investigate the effect on depression and self-esteem of this disorder that can cause problems on person's social development and human relations. material and methods: 90 patients who were admitted to our clinic with complaints of nocturnal enuresis were enrolled. investigations to rule out organic causes were performed in this group of patients. out of them 38 children and adolescents (age range 8-18 years) with primary monosymptomatic nocturnal enuresis (pmne) agreed to participate in the study in the same period 46 healthy children and adolescents with a similar age range without bed wetting complaint were included in the study as a control group. the age of the family, educational and socioeconomic level were questioned and piers-harris children's self-concept scale (phcscs) and children's depression inventory (cdi) forms were filled out. results: mean age of the cases (18 females or 47.4% and 20 males or 52.6%) was 10.76 ± 3.82 years whereas mean age of controls (26 females or 56.5% and 20 males or 43.5%) was 10.89 ± 3.11 years. depression scale was significantly higher (p = 0.001) in the case group than in the control group (10.42 ± 4.31 vs 7.09 ± 4.35). in both groups there was no statistically significant difference by age and sex in terms of depression scale (p > 0.05). conclusion: ne is widely seen as in the community and is a source of stresses either for children and for their families. when patients were admitted to physicians for treatment, a multidisciplinary approach should be offered and the necessary psychological support should be provided jointly by child psychiatrists and psychologists. key words: depression; self-esteem; nocturnal enuresis. submitted 13 june 2014; accepted 1 august 2014 summary introduction nocturnal enuresis (ne) is very common in the society and is one of the most common causes for patients to be admitted to urology, pediatrics, child psychiatry and child no conflict of interest declared. surgery departments. ne is recurrent urinary incontinence in children over the 5 years old that is observed during the sleep (1). the prevalence of nocturnal enuresis has been reported as 5.5-16.8% (2,3). ne is classified as primary and secondary. ne may cause stress and emotional problems in person and families. on the other hand ne may develop secondary to stress on patients and families (4). however, there are conflicting results as to whether these stressful situations cause psychological problems in enuretic children. some authors assert that there is no difference of the psychological problems between the normal population and monosymptomatic enuretic children, but some others have argued that ne cause clinical or subclinical psychological problems (5). in a study of bed wetting and behavioral problems, conduct problems and deficits in attention up to age 13 and internalizing problems up to age of 15 have been reported more frequently in children whose bedwetting continue over 10 years of age (6). it may seem that there is a relationship between ne and behavioral problems increasing with age, but cause and effect relationship has not been clearly elucidated (7). we aimed to investigate the effect on depression and selfesteem of this disorder that can cause problems on person's social development and human relations. material and method ninety patients who were admitted to our clinic with complaints of nocturnal enuresis were enrolled. out of them 38 children and adolescents (age range 8-18 years) with primary monosymptomatic nocturnal enuresis (pmne) agreed to participate in the study and filled out questionnaires. in the same period 46 healthy children and adolescents with a similar age range without bed wetting complaint were included in the study as a control group. investigations (history, urinalysis, urine culture, urinary tract ultrasonography) were performed in the case group patients to rule out organic causes. age and educational and socioeconomic levels were questioned in both groups and piers-harris children's self-concept scale (phcscs) and children's depression inventory (cdi) forms were filled out. patients in both groups were classified accorddoi: 10.4081/aiua.2014.3.212 koca sc_stesura seveso 08/10/14 12:14 pagina 212 213archivio italiano di urologia e andrologia 2014; 86, 3 depression and self-esteem in enuretic children ing to age in 2 groups 8-11 years and > 12 years. nonpmne wetting bed or patients on any type of treatment were excluded from the study. patients who missed to fill all or a part of the questionnaire were excluded from the study. student t test via spss 13 for windows was used for statistical analyzes. p value < 0.05 was considered statistically significant. results mean age of the cases (18 females or 47.4% and 20 males or 52.6%) was 10.76 ± 3.82 years whereas mean age of controls (26 females or 56.5% and 20 males or 43.5%) was 10.89 ± 3.11 years. twenty six patients (68.4%) out of the case group were 8-11 years of age and 12 (31.6%) were > 12 years whereas 32 (69.6%) out of the control group were 8-11 years of age, and 14 (30.4%) were > 12 years. there were statistically significant differences between the two groups in self-esteem scale (table 1). no statistically significant difference in term of gender was found (p > 0.05). in the case group no statistically significant difference of the total score was found by age (p > 0.05), but a statistically significant difference was detected in in term of behavior and comply (p = 0.022). in the control group, no statistically significant difference of the total score was found by age (p > 0.05). depression scale was significantly higher (p = 0.001) in the case group than in the control group (10.42 ± 4.31 vs 7.09 ± 4.35). in both groups there was no statistically significant difference by age and sex in terms of depression scale (p > 0.05). in both groups, occupation of parents, education and socioeconomic status didn't affect phcscs and cdi scores (p > 0.05). discussion ne is fairly common all over the world and this disease averagely affects one in 10 children. effects on children's social and psychological development are frequently observed. self-identity and sexual identity are acquired during childhood and adolescence, therefore a number of additional problems like mood disorders are seen with ne. ne is fairly common in our country and causes many negative effects on individuals and families. this condition may cause the fear of being noticed by others, humiliation, anxiety, social withdrawal, high anxiety levels and behavior problems (8). in a study that investigated how children see enuresis it was reported that bedwetting is the most stressful events after family fights and divorce (9). adverse effects on mothers have also been described (11). ne has depressive effects on children and their families (10). in our study, a statistically significant difference of depression scores (cdi) was detected between enuretic patients and controls without difference by age, gender, education and socio-economic level. decreased self-esteem, social adjustment problems in school and with friends and behavior problems have been reported in children with enuresis (12). in our study, a statistically significant difference of self-esteem phcscs scores was detected between patients with enuresis and controls with significant difference of sub-titles of happiness, anxiety and popularity. in contrast hirasing et al reported no significant relationship between nocturnal enuresis and behavioral and emotional problems (13). decreased self-esteem was detected in enuretic adults as in children (14). liu et al. reported that there were more problems with behavior, emotional, and academic achievement in children with ne and observed that they increased with age (15). delay of the family to apply to health institutions for therapy increases children self-esteem problems. in our study, only the behavior and adaptation sub-title was significantly different in terms of age whereas age-related differences were not observed by other parameters although this could be explained by insufficient size of the sample. in fact a limitation of our study could be low number of patients from a single center and lack of graduation of the severity of ne. conclusions in conclusion, ne that is frequently observed in the community is a source of stresses for either children or their families. it should be considered that ne may cause loss of self-confidence and depression in children. trust should be provided for children and families and training should be given according to treatment planning. when patients were admitted to physicians for treatment, a multidisciplinary approach should be offered and the necessary psychological support should be provided jointly by child psychiatrists and psychologists. references 1. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international children's continence society. j urol. 2006; 176:314-24. case group n= 38 control group n=46 p value happiness 9.26 ± 3.1 10.71 ± 1.96 0.012 anxiety 7.47 ± 2.64 9.35 ± 2.0 < 0.001 popularity 7.95 ± 1.99 9.41 ± 1.44 < 0.001 behavior and compliance 9.97 ± 3.19 11.28 ± 2.86 0.051 physical appearance 8.05 ± 1.87 8.22 ± 1.74 0.677 mental and school 5.13 ± 1.3 5.65 ± 1.12 0.052 total 54.26 ± 12.98 63.41 ± 9.14 < 0.001 table 1. comparison of the two groups in terms of self-confidence. koca sc_stesura seveso 08/10/14 12:14 pagina 213 archivio italiano di urologia e andrologia 2014; 86, 3 o. koca, m. akyüz, b. karaman, z.y. özcan, m. öztürk, z. sertkaya, m.i. karaman 214 2. bower wf, moore kh, shepherd rb, adams rd. the epidemiology of childhood enuresis in australia. br j urol. 1996; 78:602-6. 3. kalo bb, bella h. enuresis: prevalence and associated factors among primary school children in saudi arabia. acta paediatr. 1996; 85:1217-22. 4. chang ss, ng cf, wong sn. behavioural problems in children and parenting stres associated with primary nocturnal enuresis in hong kong. acta pediatr. 2002; 91:475-9. 5. butler rj. impact of nocturnal enuresis on children and young people. scand j urol nephrol. 2001; 35:169-76. 6. fergusson dm, horwood lj. nocturnal enuresis and behavioral problems in adolescence: a 15-year longitudinal study. pediatrics. 1994; 94:662-8. 7. rocha mm, costa nj, silvares ef. changes in parents' and selfreports of behavioral problems in brazilian adolescents after behavioral treatment with urine alarm for nocturnal enuresis. int braz j urol. 2008; 34:749-57. 8. hägglöf b, andrén o, bergström e, et al. self-esteem in children with nocturnal enuresis and urinary incontinence: improvement of self-esteem after treatment. eur urol. 1998; 33 suppl 3: 16-9. 9. van tijen nm, messer ap, namdar z. perceived stress of nocturnal enuresis in childhood. br j urol. 1998; 81 suppl 3:98-9. 10. hjalmas k, arnold t, bower w, et al. nocturnal enuresis: an international evidence based management strategy. j urol. 2004; 171:2545-61. 11. egemen a, akil i, canda e, et al. an evaluation of quality of life of mothers of children with enuresis nocturna. pediatr nephrol. 2008; 23:93-8. 12. hägglöf b, andrén o, bergström e, et al. self-esteem before and after treatment in children with nocturnal enuresis and urinary incontinence. scand j urol nephrol. suppl. 1997; 183:79-82. 13. hirasing ra, van leerdam fj, bolk-bennink lb, bosch jd. bedwetting and behavioural and/or emotional problems. acta paediatr. 1997; 86:1131-4. 14. theunis m1, van hoecke e, paesbrugge s, et al. self-image and performance in children with nocturnal enuresis. eur urol. 2002; 41:660-7. 15. liu x, sun z, uchiyama m, et al. attaining nocturnal urinary control, nocturnal enuresis, and behavioral problems in chinese children aged 6 through 16 years. j am acad child adolesc psychiatry. 2000; 39:1557-64. correspondence orhan koca, md (corresponding author) drorhankoca@hotmail.com mehmet akyüz, md bilal karaman, md metin öztürk, md zülfü sertkaya, md muhammet ihsan karaman, md haydarpasa numune training and research hospital department of urology tıbbiye st. no:2 üsküdar zip:34718 istanbul, turkey zeynep yeşim özcan, md haydarpasa numune training and research hospital department of family medicine, istanbul, turkey koca sc_stesura seveso 08/10/14 12:14 pagina 214 stesura seveso 105archivio italiano di urologia e andrologia 2015; 87, 2 original paper dietary treatment of urinary risk factors for renal stone formation. a review of clu working group domenico prezioso 1, pasquale strazzullo 1, tullio lotti 1, giampaolo bianchi 2, loris borghi 3, paolo caione 4, marco carini 5, renata caudarella 6, giovanni gambaro 7, marco gelosa 8, andrea guttilla 9, ester illiano 1, marangella martino 10, tiziana meschi 3, piergiorgio messa 8, roberto miano 11, giorgio napodano 12, antonio nouvenne 3, domenico rendina 1, francesco rocco 8, marco rosa 2, roberto sanseverino 12, annamaria salerno 13, sebastiano spatafora 14, andrea tasca 15, andrea ticinesi 3, fabrizio travaglini 5, alberto trinchieri 16, giuseppe vespasiani 11, filiberto zattoni 9 1 università federico ii napoli; 2 azienda ospedaliera-policlinico di modena; 3 università degli studi di parma; 4 ospedale pediatrico bambino gesù di roma; 5 azienda ospedaliero universitaria di careggi, firenze; 6 casa di cura villalba, bologna; 7 università cattolica sacro cuore di roma; 8 fondazione irccs ca' granda ospedale maggiore policlinico, milano; 9 università degli studi di padova; 10 a.o. ordine mauriziano di torino; 11 fondazione irccs ca' granda ospedale maggiore policlinico, milano; 11 università di roma tor vergata; 12 ospedale umberto i, nocera inferiore, salerno; 13 università campus biomedico, roma; 14 arcispedale santa maria nuova, reggio emilia; 15 ospedale san bartolo di vicenza; 16 ospedale a. manzoni di lecco. objective: diet interventions may reduce the risk of urinary stone formation and its recurrence, but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi. the aim of this study was to review the studies reporting the effects of different dietary interventions for the modification of urinary risk factors in patients with urinary stone disease. materials and methods: a systematic search of the pubmed database literature up to july 1, 2014 for studies on dietary treatment of urinary risk factors for urinary stone formation was conducted according to a methodology developed a priori. studies were screened by titles and abstracts for eligibility. data were extracted using a standardized form and the quality of evidence was assessed. results: evidence from the selected studies were used to form evidencebased guideline statements. in the absence of sufficient evidence, additional statements were developed as expert opinions. conclusions: general measures: each patient with nephrolithiasis should undertake appropriate evaluation according to the knowledge of the calculus composition. regardless of the underlying cause of the stone disease, a mainstay of conservative management is the forced increase in fluid intake to achieve a daily urine output of 2 liters. hypercalciuria: dietary calcium restriction is not recommended for stone formers with nephrolithiasis. diets with a calcium content ≥ 1 g/day (and low protein-low sodium) could be protective against the risk of stone formation in hypercalciuric stone forming adults. moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. a low-normal protein intake decrease calciuria and could be useful in stone prevention and preservation of bone mass. omega-3 fatty acids and bran of different origin decreases calciuria, but their impact on the urinary stone risk profile is uncertain. sports beverage do not affect the urinary stone risk profile. hyperoxaluria: a diet low in oxalate and/or a calcium intake normal to high (800-1200 mg/day for adults) reduce the urinary excretion of oxalate, conversely a diet rich in oxalates and/or a diet low in calcium increase urinary oxalate. a restriction in protein intake may reduce the urinary excretion of oxalate although a vegetarian diet may lead to an increase in urinary oxalate. adding bran to a diet low in oxalate cancels its effect of reducing urinary oxalate. conversely, the addition of supplements of fruit and vegetables to a mixed diet does not involve an increased excretion of oxalate in the urine. the intake of pyridoxine reduces the excretion of oxalate. hyperuricosuria: in patients with renal calcium stones summary no conflict of interest declared. doi: 10.4081/aiua.2015.2.105 the decrease of the urinary excretion of uric acid after restriction of dietary protein and purine is suggested although not clearly demonstrated. hypocitraturia: the administration of alkaline-citrates salts is recommended for the medical treatment of renal stone-formers with hypocitraturia, although compliance to this treatment is limited by gastrointestinal side effects and costs. increased intake of fruit and vegetables (excluding those with high oxalate content) increases citrate excretion and involves a significant protection against the risk of stone formation. citrus (lemons, oranges, grapefruit, and lime) and non citrus fruits (melon) are natural sources of dietary citrate, and several studies have shown the potential of these fruits and/or their juices in raising urine citrate levels. children: there are enought basis to advice an adequate fluid intake also in children. moderate dietary salt restriction and implementation of potassium intake are useful in limiting urinary calcium excretion whereas dietary calcium restriction is not recommended for children with nephrolithiasis. it seems reasonable to advice a balanced consumption of fruit and vegetables and a low consumption of chocolate and cola according to general nutritional guidelines, although no studies have assessed in pediatric stone formers the effect of fruit and vegetables supplementation on urinary citrate and the effects of chocolate and cola restriction on urinary oxalate in pediatric stone formers. despite the low level of scientific evidence, a low-protein (< 20 g/day) low-salt (< 2 g/day) diet with high hydration (> 3 liters/day) is strongly advised in children with cystinuria. elderly: in older patients dietary counseling for renal stone prevention has to consider some particular aspects of aging. a restriction of sodium intake in association with a higher intake of potassium, magnesium and citrate is advisable in order to reduce urinary risk factors for stone formation but also to prevent the loss of bone mass and the incidence of hypertension, although more hemodynamic sensitivity to sodium intake and decreased renal function of the elderly have to be considered. a diet rich in calcium (1200 mg/day) is useful to maintain skeletal wellness and to prevent kidney stones although an higher supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases. a lower content of animal protein in association to an higher intake of plant products decrease the acid load and the excretion of uric acid has no particular contraindications in the elderly patients, although overall nutritional status has to be preserved. key words: urinary calculi; dietary treatment; urinary risk factors; hypercalciuria; hyperoxaluria; hypocitraturia; children; elderly. submitted 1 february 2015; accepted 30 april 2015 prezioso_stesura seveso 02/07/15 11:18 pagina 105 archivio italiano di urologia e andrologia 2015; 87, 2 prezioso, strazzullo, lotti, bianchi, borghi, caione, carini, caudarella, gambaro, gelosa, guttilla, illiano, marangella, messa, miano, et al. 106 introduction (domenico prezioso, pasquale strazzullo, domenico rendina, ester iliano) nephrolithiasis (nl) affects 5-15% of the population worldwide with a recurrence rate higher than 50%. it does not spare any geographical, cultural, or racial group. an increase in nl incidence and prevalence has been observed in the final quarter of the last century in both genders (1, 2). approximately 80% of all kidney stones are composed of calcium salts, namely calcium-oxalate (caox) and calcium phosphate (cap) (3). the tendency to form caox stones is directly related to urinary concentrations of calcium, oxalate and urate, and inversely associated with those of magnesium and citrate. in addition to these metabolic risk factors, also the urinary concentrations of phosphate and hydrogen ions (ph) plays a role in the pathogenesis of cap stones (3, 4). a significant percentage of the remaining stones is composed of uric acid (ua), which accounts for over 10% of all kidney stones. ua stones form in the presence of an abnormally low urine ph (4). recent epidemiological data indicate that nl is a significant risk factor for chronic and end stage kidney disease (5-6).both environmental and genetic factors synergistically contribute to the pathogenesis of the different types of stones (2-4). the role of inheritance is obvious in monogenic diseases such as cystinuria, dent’s disease and primary hyperoxaluria (4), but also “idiopathic” stone formation show a familial tendency (7). among environmental factors, dietary habits appear to play an important role in the pathogenesis of nl and are likely responsible for its growing incidence in the last few decades (8-9). indeed, nl is considered a systemic disorder associated with a group of cardio-metabolic conditions such as obesity, diabetes, hypertension, metabolic syndrome and coronary artery disease (10-13), all of them in turn related to nutritional inadequacies. the nldirectly related costs exceed 5 billion dollars each year in the united states. thus, the development of (scientifically sound) dietary recommendations for primary and secondary nl prevention should be seen as one of the most promising cost-saving actions in the clinical management of nl (5). patient evaluation each patient with nl should undertake appropriate morpho-functional evaluation (3, 7, 14, 15). the classification of nl is based on the composition of renal calculi because the different types of stones present different etiologies and pathogeneses that require a different therapeutic approach. based on the clinical history of the disease, it is also important to distinguish relapsing forms, from those associated with metabolic syndrome (ms) and those at particularly risk of systemic complications such as chronic kidney disease (ckd) and metabolic bone disease (mbd). relapsing nl is diagnosed if the patient experienced ≥ 3 new episodes of kidney stones in the past 5 years, although even a patient with first-episode, showing more calculi in one or both kidneys, should be classified as a relapsing patient. the general practitioner (gp) is the professional figure most often involved in the initial diagnostic evaluation of the patient. indeed, a well conducted history and a limited number of step one laboratory tests allow to identify several secondary forms of nl and to select patients with ms and those at increased risk of ckd or mbd. the medical history will provide information on i) degree of disease activity over the past 5 years, ii) familiarity of the disease, iii) dietary habits and lifestyle. although a comprehensive nutrition survey must be attended by skilled personnel and requires the use of dedicated software, the formulation of a few questions may provide in most cases enought information about the lithogenic risk associated with the patient’s dietary habits. information should be obtained about average caloric intake, amount and type of ingested liquids and the habitual intake of salt, animal protein, carbohydrates, potassium, calcium and oxalate-rich foods. step 1 metabolic investigation includes: blood tests (creatinine, urea, glucose, uric acid, na, k, cl, calcium, phosphorus, lipid profile); urine tests (complete urinalysis and urine culture for common germs); ultrasound abdomen examination; analysis of stone composition. this step thanks to execution simplicity and low costs, may be applied on almost all nl patients and allows one to select patients requiring more advanced step two assessment. step 2 evaluation may more often require collaboration with a specialist. it will include again: blood tests (parathyroid hormone (pth), 25 and possibly 1,25 vitamin d, magnesium, alkaline phosphatase); 24 hour urine collection for creatinine, urate, sodium, potassium, chloride, calcium, phosphate, magnesium, citrate, ph, sulphate and ammonium. the 24 hour urine analysis should be repeated annually to assess the patients adherence to treatment. in the case of calcium nl a bone mineral density assessment by dexa may be of value. diagnostic imaging workup is based on: abdomen x-ray and ultrasonographic examination, which in combination allow to recognize 90% of cases of nl; echo-color-doppler examination with measurement of the resistance index to detect urine flow obstruction; urography, currently used only before surgical treatment, endoscopy and lithotripsy or in other particular circumstances; non contrast computed tomography (nc ct, used for diagnostic emergency in patients with renal colic, allowing detection of all types of calculi or their indirect signs; uro ct, which consists in a normal ct scan of the abdomen exploiting the early stage of impregnation for the study of the kidneys and the bladder; ascending or descending pielography, to be performed only in the context of operating procedures, e.g. ureterorenoscopy; sequential renal scintiscan, that is still the most reliable method for the assessment of impairment of individual renal unit and degree of obstruction, if present; magnetic resonance imaging (mri) to be preferred whenever the radiation burden involved with other procedures is of concern (e.g. pregnant and pediatric patients). stone analysis there are two main categories of urinary stones: calcium stones and no-calcium stones, which are both the consequence of crystallization and aggregation of highly concentrated urinary components. although stone composition analysis is not always feasible or achievable, there is helpful information from such an investigation that can aid for prevention of recurrences. for instance, as shown by a well performed randomized controlled trial (16), calcium phosphate or brushite stones may be associated to primary prezioso_stesura seveso 02/07/15 11:18 pagina 106 hyperparathyroidism (hpt) and renal tubular acidosis (rta), calcium oxalate stones may be associated to chronic diarrhoea, acid uric stones to gouty diathesis, struvite stones to urinary infection and cystine stones to urinary cystine excretion. these associations are particularly evident in the case of non-calcium stones, as also shown by kourambas et al. (17), who found that patients with no-calcium stones were found to have specific metabolic disorders according to the type of analysed calculi, whereas patients with calcium stones were more heterogeneous with regard to concomitant metabolic disorders. knowledge of the calculus composition may help the physician to prescribe of the most appropriate diagnostic workup and with the implementation of adequate dietary and therapeutic measures (18). namely, should the urine be alkalinized? will the stone be amenable to extracorporeal shock wave lithotripsy or should ureteroscopy or percutaneous lithotripsy be attempted? stone composition analysis should be performed in all first-time stone formers and repeat stone analysis is needed in case of recurrence under pharmacological prevention, early recurrence after interventional therapy with complete stone clearance, late recurrence after a prolonged stone-free period (19). the methods currently available for the of stone composition analysis are: i) chemical analysis (now deemed obsolete because of its major limitations), thermogravimetry, emission spectroscopy, polarizing spectroscopy, x-ray diffraction, x-ray coherent scatter/crystallography, scanning electron microscopy, and infrared spectroscopy (20). the ones preferred are infrared spectroscopy and x-ray diffraction (21-23). x-ray diffraction uses monochromatic x-rays for identifying the constituents of a renal stone based on the unique diffraction patterns produced by a crystalline material (24). infrared (ir) spectroscopy uses ir radiation in order to cause atomic vibrations energy absorption and final appearance of absorption bands in the ir spectrum of stone samples 24). equivalent results can be obtained by polarisation microscopy, based on the interaction of polarized light with stone crystals, which however is limited to centers with special expertise (25). in addition to the above mentioned commonly used techniques, there are other techniques which may unravel more detailed information on the molecular structure of the stone nuclear region (26). these techniques are not used in routine diagnostic laboratories for being costly and requiring special expertise or sample preparation. studies involving the use of single-energy ct technology have shown that valuable information about stone composition may be gained, enabling differentiation between uric acid and calcium stones on the basis of their different attenuations (27). dual-energy ct by low and high-energy scanning is capable to differentiate various materials with similar electron densities but different photon absorption (27), thus contributing to the chemical characterization of stones for the purpose of surgical or medical treatment decision. water intake for all nl patients, regardless of the underlying cause of the stone disease, a mainstay of conservative management is to force the increase in fluid intake to achieve a daily urine output of 2 litres (28). theoretically, increased urine output may have two effects. first, the ensuing mechanical diuresis may prevent urine stagnation and formation of symptomatic stones. more important, the dilute urine alters the supersaturation of stone components. modification of the concentration of lithogenic factors is indeed the focus of stone prevention. the effect of urinary dilution on crystallization of stone-forming salts was first evaluated by pak et al. (2), who showed that an increased fluid intake and the subsequent urine dilution had a protective effect on the crystallization of calcium salts (29). currently, no evidence is available with regard to the actual benefit of increasing water intake for primary prevention of urinary stones, however there is a randomised controlled trial evidence of benefit from increasing water intake for the prevention of stone recurrences (30). in the trial by borghi and co-workers, participants randomized to > 2 l/d of water intake were significantly less likely to have stone recurrence over 5 years and a much longer time to recurrence compared with the untreated control group (30). in another study by sarica et al. on nl patients who underwent shockwave lithotripsy and were currently stone-free, those randomized to increased fluid intake to achieve a urine output of > 2.5 l/d for 2-3 years had a stone recurrence rate of 8% compared with 56% of those allocated to no treatment (31). a study by frank et al. compared the incidence of urinary stones in two desert towns after an educational program had been run in one of them for increasing water intake as a preventive measure against the risk of nl. upon a 3-yr follow-up, the prevalence of urinary stones was significantly lower in the intervention town (0.28% versus 0.85%) (32). similar findings have been provided by a long-term study in the us (33). it has long been debated whether differences in drinking water characteristics, namely water hardness, fixed residue and saline components may impact on the risk of renal stones. whereas coen et al. reported that an increase in water hardness resulted in higher incidence of nl (34), in most other studies greater water hardness, i.e, mineral content, has been associated with beneficial effects in preventing stone events, probably through different mechanisms, including the increase in urinary citrate (35-38). confounding factors may explain the discrepancies in results. karagülle et al., found that bicarbonate-rich mineral water had a positive effect on calcium oxalate urine supersaturation (38), probably due to increased ph (in a range opposing calcium oxalate stone formation) and to greater concentration of the inhibitory factors citrate and magnesium. this finding was confirmed in the study by bertaccini et al. who showed that the intake of a water with medium mineral (calcium 119.7 mg/l) and high bicarbonate (412 mg/l) content causes specific changes of urinary composition that could be beneficial to prevent stone formation (39), the bicarbonate load increasing urinary ph and urinary citrate excretion. the latter can indeed be helpful for prevention of both uric acid lithiasis, thanks to the higher urinary ph with increased solubility of uric acid, and calcium lithiasis, as a consequence of the increased urinary citrate concentration, with inhibition of calcium crystal formation and aggregation. the higher potassium content of mineral water also promoted urinary alkalization and led to further increase in urinary citrate excretion (39). according to siener et al. also the magnesium content of mineral water results in favourable 107archivio italiano di urologia e andrologia 2015; 87, 2 dietary treatment of urinary risk factors for renal stone formation prezioso_stesura seveso 02/07/15 11:18 pagina 107 archivio italiano di urologia e andrologia 2015; 87, 2 prezioso, strazzullo, lotti, bianchi, borghi, caione, carini, caudarella, gambaro, gelosa, guttilla, illiano, marangella, messa, miano, et al. 108 changes in urine composition, namely a higher urinary magnesium concentration (40). materials and methods the clu working group conducted a systematic search of the pubmed database literature up to july 1, 2014 for studies on dietary treatment of urinary risk factors for urinary stone formation.reviewers were divided in 5 groups for searching about dietary intervention for treatment of hypercalciuria (group 1), hyperoxaluria and hyperuricosuria (group 2), hypocitraturia (group 3) and about dietary prevention of urinary calculi in the child (group 4) and in the elderly (group 5). search terms were reported in table 1. according to a methodology developed a priori meta-analyses, randomized controlled trials, case control and cohort studies were included. review studies and case reports were excluded. additional articles were identified from reference lists of relevant articles or, if necessary, by other more specific search strategies. three or more reviewers for each group independently screened titles and abstracts of studies for potential eligibility. the quality of evidence was assessed using the grading of recommendations assessment, development and evaluation (grade) framework. the reviewers extracted data using a standardized form. the following data were abstracted: type of study, characteristics of trial participants (number, gender, healthy/rsfs); type of intervention; outcomes and quality of evidence. results summary of findings tables were built for defined outcomes (posted in supplementary materials on www.aiua.it). results of the selected studies were used to form evidencebased guideline statements. in the absence of sufficient evidence, additional statements were developed as expert opinions. discussion and conclusions dietary treatment of hypercalciuria (marco rosa, giovanni gambaro, p. manuel ferraro, giampaolo bianchi, domenico rendina, andrea tasca) generally speaking available literature is of very low quality data. quite few randomized clinical trials (rcts) have been done, most of them with significant methodological limitations. they are addressed in depth by a recent cochrane review (1) which concluded that “…no compelling evidence was identified to support the use of dietary interventions to reduce the risk of complications [essentially the effect on stone rate or on the urinary stone risk profile] among people with idiopathic hypercalciuria….” also noticing that “…overall, the quality of the evidence supporting dietary interventions is poor…”. the cochrane review considered 5 rct; however, in the present systematic review of the literature we decided not to consider 2 of them because the dietary intervention was indeed a “pharmacological” treatment with the herbal extract phyllantus niruri (2) or because the total intake of calcium was not controlled (3). however, a number of observational or non-controlled interventional studies, either retrospective or prospective on urinary stone risk-factors (mainly variations in calciuria and/or oxaluria) can be retrieved. we obtained from specialized registers 374 articles of which 26 have been considered in the present statement. 1. dietary calcium restriction is not recommended for stone formers with nephrolithiasis. diets with a calcium content ≥ 1 g/day (and low protein-low sodium) could be protective against the risk of stone formation in hypercalciuric stone forming adults. a cross-sectional study in stone formers has shown that higher calcium intakes at levels typically observed in freeliving individuals are associated with only small increases in calciuria (3). a previous observational cohort prospective study in healthy men had disclosed that a high dietary calcium intake decreases the risk of symptomatic kidney stones (4). a retrospective, uncontrolled longitudinal study (very low quality data) on the effect of a calcium restricted diet in hypercalciuric and normocalciuric stone formers concluded that secondary rise in urinary oxalate occurring from calcium restriction can be avoided by concurrent dietary oxalate restriction; the effect on urinary saturation of calcium oxalate was modest (6). another uncontrolled longitudinal study (retrospective of very low quality) in hypercalciuric stone formers reported that low calcium diet only marginally decrease calciuria and did not modify fasting hypercalciuria (7). in an uncontrolled descriptive study, in 50% of patients who were hypercalciuric on a free diet, when assuming a 1000 mg/d calcium diet (higher content than in the free diet) calcium excretion fell markedly or normalized (8). an uncontrolled longitudinal, prospective study has shown that, on a low-calcium diet, absorptive hypercalciuric patients are particularly prone to develop hyperoxaluria (9). in an observational cohort study (prospective) oxaluria group search terms papers n° selected added 1 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and hypercalciuria 374 26 0 2 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and hyperoxaluria 183 37 3 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and hyperuricosuria 75 6 0 3 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and hypocitraturia 54 5 19 4 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and children 197 38 0 5 (urinary calculi or kidney stones or renal stones or nephrolithiasis or urolithiasis) and diet and elderly 597 3 19 table 1. search pubmed terms. prezioso_stesura seveso 02/07/15 11:18 pagina 108 was significantly reduced after one week treatment with calcium 1 g/day in stone formers who were usually on a regular low calcium diet (< 500 mg/day) but not in those with diet-dependent hypercalciuria (10). with a similar experimental design in hypercalciuric stone patients, the same group did not show a significant additional increase in urinary calcium (11). in an uncontrolled longitudinal prospective study in hypercalciuric idiopathic stone formers an intake of a high-calcium diet for 5-6 days reduced urinary oxalate and the probability of being a stone former according to psf index (12). in a 4 weeks randomized controlled trial (rct) in absorptive hypercalciuric stone formers, a low calcium (< 500 mg/day), normal protein and salt diet did not significantly modify the urine risk profile for stone formation while possibly inducing an increased bone turn-over (13). in an uncontrolled longitudinal 4-week prospective study in calcium stone formers a low calcium diet (440 mg/day) decreased calciuria but increased the urine supersaturation for calciumoxalate also in hypercalciuric patients (14). in an uncontrolled longitudinal prospective study on idiopathic hypercalciuria, a combined low calcium, low oxalate diet did not significantly decreased the psf (15). a rct has shown that in hypercalciuric stone formers with a 2-3 l/day water intake, a diet with calcium 1200 mg/day, together with reduced protein (less than 15% caloric intake) and salt (< 50 mmol/day) was superior in reducing stone recurrences versus a 400 mg/day low calcium diet (16). in this study, however, it is difficult to dissect the preventive role of the different components of the diets (normal calcium versus low protein versus low salt). furthermore, it is difficult to understand if the positive results were due to the favourable effects of this latter diet alone, or the results were magnified by a particularly unfavourable diet as the low-calcium diet. 2. moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. a rct trial in hypercalciuric stone formers with high baseline sodium intake, a low-salt (< 60 mmol/d sodium, or < 3.5 g/d nacl) normocalcic (800-1000 mg/d) diet reduced calcium excretion (17). 3. a low-normal protein intake decreases calciuria and could be useful in stone prevention and preservation of bone mass. in a short term uncontrolled longitudinal prospective study on a small cohort of hypercalciuric stone formers a diet with an intake of 0.8 g of protein per kg of body weight and normal calcium intake decreased calciuria and a number of bone and stone risk factors possibly because of a reduced acid load (18). this observation is in keeping with the study by borghi at al. (16) and with a number of observations in healthy non-stone forming people. 4. omega-3 fatty acids decrease calciuria, but the impact on the urinary stone risk profile is uncertain. although an observational cohort study of moderate quality disclosed in healthy non-stone forming people that greater levels of arachidonic and linoleic acid intake do not increase the risk for developing a kidney stone, and greater intake of omega-3 fatty acids does not reduce the risk (based on a food frequency questionnaire) (19), very low quality data may suggest that the administration omega-3 fatty acids of fish oli alone or combined with empiric dietary counseling decrease urinary calcium in hypercalciuric stone formers (20-22). however, the impact of omega-3 administration on the risk profile for recurrent nephrolithiasis may be limited (20). 5. bran of different origin decreases calciuria, but the impact on the urinary stone risk profile is uncertain. in a descriptive study on idiopathic hypercalciuric patients, rice bran (10 g twice daily) for 1 month to 3 years decreased calciuria (23). in a very small uncontrolled longitudinal, prospective study farmolith (a granular powder consisting of different dietary fibres) decreased calciuria and oxaluria in absorptive hypercalciuric stone patients (24). wheat bran (14 g) assumed in each of the 2 main meals in stone formers with absorptive hypercalciuria decreased calciuria without changing oxaluria in a small uncontrolled longitudinal 90 days study (25). in a small rct on hypercalciuric stone formers, 30 g of dietary fiber as unprocessed wheat bran in association with a low calcium-low oxalate diet induced a 23.5% decrease in calciuria in comparison with only a 5.6% reduction obtained with diet alone; however, oxaluria was decreased 21.4% by diet alone compared with only 3.9 % in the diet and fiber treatment group (26). 6. sports beverage do not affect the urinary stone risk profile. carbohydrate-electrolyte sports beverages (gatorade) in a prospective crossover study on healthy and stone forming patients had no effect on urinary calcium or other urine stone risk parameters (27). dietary treatment of hyperoxaluria (martino marangella, fabrizio travaglini, alberto trinchieri) dietary oxalate and its precursors 1. in human experiments, the intestinal absorption of oxalate is greater on a diet high in oxalate (600 mg) compared to that on a diet poor in oxalate (63 mg), although there is an adaptation with lower rate of absorption if the diet with a high content of oxalate continues for over 6 weeks (zimmermann 2005 experimental controlled study m) (1). 2.. a diet rich in oxalate causes a significant increase in urinary oxalate levels (butz 1980 experimental study m, massey 1993experimental study m, siener 2003 observational study l, de o g mendonça 2003 rct m) (2-5). 3. a diet low in oxalate is effective in reducing urinary excretion of oxalate and urinary saturation for calcium oxalate with respect to a basal free choice diet (kirac 2013 experimental non controlled m; laminski 1991 experimental non controlled m) (6, 7). 4. in patients with idiopathic calculi an intake of ascorbic acid > 1 g/day is more frequent than in controls (griffith 1986 case-control observational study l) (8). a load of ascorbic acid may lead to an increase in serum and urinary levels of oxalate by increasing the intestinal absorption and endogenous synthesis. in total parenteral nutrition (tpn) an increase of ascorbic acid infusion from 100 to 200 mg induces an increase of oxaluria of about 0.10 mmol/day. (pena de la vega, 2004 experimental study m) (9). 5. the increase of oxaluria after oral ingestion of large 109archivio italiano di urologia e andrologia 2015; 87, 2 dietary treatment of urinary risk factors for renal stone formation prezioso_stesura seveso 02/07/15 11:18 pagina 109 archivio italiano di urologia e andrologia 2015; 87, 2 prezioso, strazzullo, lotti, bianchi, borghi, caione, carini, caudarella, gambaro, gelosa, guttilla, illiano, marangella, messa, miano, et al. 110 amounts of ascorbic acid is not well predictable and has not been confirmed unanimously but it was suggested that patients at risk of kidney stones should not exceed an intake of 500 mg/day (butz 1980, massey 2005 m experimental studies m) (2, 10). dietary calcium (and magnesium) 6. epidemiological studies have shown that the excretion of oxalate is inversely related to dietary intake of magnesium (eisner 2012 observational cohort study l) (11) and calcium (trinchieri 1998 observational cohort study l) (12). 7. the rate of intestinal absorption of oxalate, evaluated with [ 13c2] oxalate in healthy volunteers on a diet containing 800 mg of calcium, ranges between 2.2 and 18.5%. the intra-individual variation is wide (3.4 ± 1.7%) (von unruh, 2003 experimental study m) (13). 8. the intestinal absorption of radioactive [13c2] oxalate in a diet containing 1200 mg of calcium (diet + supplements of calcium citrate and calcium carbonate) is 2%, but it increases to 17% at 200 mg of dietary calcium. the increase is linear with the decrease of dietary calcium, but there is no further reduction of intestinal absorption of oxalate when dietary calcium increases > 1200 mg (von unruh, 2004 experimental study m) (14). 9. in healthy subjects and calcium renal stone formers a low-calcium diet causes a significant decrease in the levels of urinary calcium but increases urinary excretion of oxalate and the risk of renal stone formation (bataille 1983 experimental non controlled study m) (15). 10. in idiopathic renal calcium stone formers with hypercalciuria a low calcium diet increases urinary oxalate excretion more than in normocalciuric. on low calcium diet urinary oxalate excretion is related to the degree of intestinal absorption of calcium (jaeger 1985 experimental non controlled m) (16). 11. in renal stone formers with idiopathic hypercalciuria a high-calcium diet (900-1070 mg/day) decreases the excretion of oxalate, the oxalate/creatinine ratio and the lithogenic risk in comparison with a normal-calcium diet (700 mg/day) (brown 1987 experimental non controlled study l, nakada 1988 experimental non controlled study m) (17, 18). 12. in calcium oxalate renal stone patients with hyperoxaluria the addition of supplements of calcium citrate to the low-oxalate diet did not result in a greater decrease of urinary excretion of oxalate than diet alone, although the supersaturation for calcium oxalate decreases more significantly (penniston, 2009 experimental non controlled m) (19). vegetarian 13. vegetarians have higher urinary oxalate levels than controls on a free-choice mixed mediterranean diet with significantly higher calcium/oxalate ratio resulting from an higher intake of oxalate and increased fractional intestinal absorption of oxalate (marangella 1989 observational study l) (20). 14. in vegetarians the risk of calcium oxalate crystallization is not decreased (increase in urinary ph, citrate and magnesium excretion and decline in calcium excretion, but increase in urinary oxalate by 30%) (siener r, 2002 experimental non controlled study m) (21). fruit and vegetables 15. in patients with hyperoxaluria (> 40 mg), the diet rich in fruits, vegetables, whole grains and low-fat dairy products and low in total fat and saturated fat, cholesterol, refined carbohydrates and sweets and meat, which is recommended for patients with hypertension (dietary approaches to stop hypertension dash) results in a slight increase in urinary excretion of oxalate compared with a diet low in oxalates, but decreases the supersaturation with respect to calcium oxalate due to the concomitant increase in excretion of magnesium and citrate and increase of urinary ph (noori 2014 rct h) (22). 16. in normal healthy subjects the abolition of fruits and vegetables induces a slight increase of calcium oxalate and calcium phosphate saturation as it reduces excretion of citrate, magnesium, potassium and also oxalate, while increasing urinary excretion of calcium and ammonium. in hypocitraturic calcium renal stone formers, adding fruits and vegetables increases excretion of magnesium and citrate, urinary ph and urinary volume, without changing excretion of oxalate and calcium. the result is a significant reduction of lithogenic risk for calcium salts and for uric acid (meschi 2004 experimental non controlled study m) (23). protein 17. a moderate load of glycine (4.5 g daily) or protein (50 g daily, 50% animal protein) has no effect on serum or urinary oxalate (butz 1980 experimental non controlled study m) (2). 18. a diet very rich in meat (700 g of meat or fish daily, 2.26 g of protein/kg daily) increases urinary oxalate in approximately one third of patients with calcium nephrolithiasis, with an average increase of 73 μmol/24 h whereas no change is observed in normal subjects. patients with mild hyperoxaluria have a more substantial increase of urinary oxalate (+100 μmoli). the mechanism of sensitivity is not clear, but does not involve deficit in vitamin b6 (nguyen 2001 experimental non controlled study m) (24). 19. the effect of a reduction in dietary protein on urinary excretion of oxalate is controversial. changing calcium stone-formers from a high to a low animal protein intake causes no variation in urinary oxalate (marangella 1989 observational study l) (20). in renal stone formers with idiopathic hypercalciuria a moderate restriction of protein intake causes a reduction of urinary calcium, urate and oxalate and improves the profile of lithogenic patients (giannini 1999 experimental non controlled study m) (25). a diet with reduced intake of protein (< 93 g) and salt (50 mmol) results in a significant reduction of urinary oxalate excretion and calcium oxalate product (borghi et al. 2002 rct h) (26). in patients with idiopathic calcium oxalate nephrolithiasis and mild hyperoxaluria (> 40 mg/day), a diet low in protein and salt with normalized calcium intake for the duration of three months proved to be more effective in reducing oxaluria in comparison with a diet low in oxalate administered to a historical control group of hyperoxaluric patients (nouvenne et al. 2009 observational study l) (27). wheat bran 20. in hypercalciuric renal stone formers the addition of 30 g of dietary fiber as unprocessed wheat bran to a low-calcium and low-oxalate diet results in a 23.5% decrease of urinary calcium with respect to the 5.6% decrease obtained prezioso_stesura seveso 02/07/15 11:18 pagina 110 with the diet alone whereas the addition of fiber results in a 3.9% decrease of urinary oxalate compared to the 21.4% on diet alone (gleeson 1990 experimental study m) (28). pyridoxine 21. the administration of pyridoxine in oral doses of 250500 mg daily to both normoor hyperoxaluric calcium renal stone formers decreases urinary oxalate excretion (nakada 1988 experimental study m, mitwalli 1988 experimental non controlled study m, ortiz-alvarado 2010 experimental non controlled study m) (18, 29, 30). probiotics (lactobacilli) 22. the administration of lactobacilli has not proved to be effective in reducing the levels of urinary excretion of oxalate in renal calcium stone patients with idiopathic hyperoxaluria and calcium (> 40 mg/day) (goldfarb 2007, lieske 2010 randomized controlled studies h) (31, 32), in healthy subjects consuming an high-oxalate diet (siener 2013 experimental non controlled study m) (33) and in renal stone formers without hyperoxaluria on a diet rich in oxalate (ferraz 2009 experimental non controlled m) (34). general measures 23. hyperoxaluric patients shows higher lipid intake and lower glucidic and calcium intake (mahe 1993 observational study vl) (35). dietary counseling according to recommended dietary allowance results in a reduction of intakes of total protein, animal protein, fat, and carbohydrates and it is associated to a reduction of the excretion of oxalate. (nomura 1995 observational study vl) (36). the effect of general dietary measures (balanced diet, specific diet) on urinary oxalate has not always proven effective in reducing urinary oxalate (kocvara 1999 controlled study l, siener 2005 experimental non randomized m; schwen 2013 observational study l) (37-39). the dietary approach is particularly recommended after eswl because it induces an increase of urinary oxalate and calcium (oehlschläger 2003 observational study l) (40). dietary treatment of hyperuricosuria (martino marangella, fabrizio travaglini, alberto trinchieri) protein and purine 1. in patients with renal calcium stones the decrease of the urinary excretion of uric acid after restriction of dietary protein and purine is not well demonstrated. in patients with hyperuricosuria on free diet, the reduction of dietary purine normalized the excretion of uric acid in approximately 45% of cases (mateos anton 1984 experimental non controled study l) (1). complex dietary intervention that included a reduction in protein and purine, such as a diet tailored on metabolic risk factors and a diet based on reduction of animal protein intake (56-64 g/day) and foods high in purine (75 mg/day) in combination with an increased intake of fruits, vegetables and cereal grains (including ¼ cup of bran per day) have not achieved variations of the excretion of uric acid (kocvara 1999 rct l, hiatt 1996 rct h) (2,3), conversely a standardized balanced diet decreased the excretion of uric acid in others (siener 2005, experimental study m) (4). 2. a standardized artificial diet (ensure) in an amount adjusted for the individual caloric needs is not associated with higher levels of uric acid excretion in patients with calcium stones compared with controls (pais 2007 experimental study m) (5). sodium intake 3. a diet with a high sodium intake (240 meq.di sodium for 10 days) to cause an expansion of chronic volume compared to a diet with a low sodium content (10 meq.di sodium for 10 days) results in increased clearance of acid uric acid, decreased serum uric acid and unchanged uric acid excretion (breslau and pak 1984 observational study of good quality m) (6). dietary treatment of hypocitraturia (renata caudarella, andrea guttilla, sebastiano spatafora) introduction hypocitraturia is common metabolic alteration in kidney stone-formers with a prevalence ranging from 20 to 60%; hypocitraturia may be found alone or associated with other metabolic alterations promoting stone formation. the acid-base status of the patient significantly modulates renal citrate excretion with systemic acidosis promoting citrate absorption in the proximal renal tubule with its subsequent incorporation into the krebs cycle (1). instead, alkalosis induces a decrease in citrate absorption, resulting in increased urinary citrate excretion. conditions associated with a lower value of intracellular and urinary ph, such as metabolic acidosis or hypokalemia, cause a decrease in citrate excretion in urine (2). acid-base balance, under physiological conditions, is strictly controlled by the net endogenous acid production related to acid and alkali dietary intake, and the incomplete metabolism of organic acids. the main dietary source of alkali is the conjugate base of potassium salts present in fruits and vegetables whereas the non dairy animal proteins, such as those present in meat, poultry, fish and eggs, which contain amino acids with sulfur moieties, represent the principal intake of dietary acid. the administration of alkaline-citrates (such as sodium-citrate, potassium citrate, potassium-magnesium citrate, especially potassium citrate) for the medical treatment of stone-formers with hypocitraturia and prevention of stone recurrence is recommended by most international guidelines. prospective randomized trials exist regarding the treatment of stone recurrence by means of alkali citrate therapy lasting at least 1 year (3, 4). the results of these trials seem to suggest that the correction of this metabolic alteration using medical therapy reduces stone risk recurrence. gastrointestinal side effects are quite common in these patients (approximately 10%) with a consequent decrease in compliance of up to 25% (16). the reduced compliance is also due to other factors, such as cost. vegetables the relationship between a diet rich in vegetables and urinary citrate excretion has also been examined. increased intake of fruit and vegetables (excluding those with high oxalate content) increases citrate excretion and consequently decreases urinary saturation for calcium oxalate and calcium phosphate. in fact hypocitraturic subjects have a lower fruit intake (domrongkitchaiporn et al. 2006, observational study l) (5) and an high consumption of vegetables involves a significant protection against the 111archivio italiano di urologia e andrologia 2015; 87, 2 dietary treatment of urinary risk factors for renal stone formation prezioso_stesura seveso 02/07/15 11:18 pagina 111 archivio italiano di urologia e andrologia 2015; 87, 2 prezioso, strazzullo, lotti, bianchi, borghi, caione, carini, caudarella, gambaro, gelosa, guttilla, illiano, marangella, messa, miano, et al. 112 risk of stone formation (hess et al. 1994, observational study l, siener et al. 2005, observational non controlled study l, trinchieri a et al. 2006 and 2013, observational studies l, meschi et al. 2004, interventional study m) (6-10). citrus and non citrus juices several authors had studied the possible influence of the consumption of fruit juices (both citrus and non citrus) on urinary citrate excretion. information on citrate concentrations in citrus juices, non citrus juices and commercially available citrus based beverages are now available (haleblian et al. 2008) (11). lemon juice drinking lemonade or freshly squeezed lemon juice significantly raised urinary citrate levels at least twofold (seltzer 1996, interventional non controlled m; aras et al. interventional non randomized m; kang observational l) (12-14). a decrease in urinary calcium excretion and no changes in urine oxalate levels were also observed. in some studies, the authors were not able to find a significant change in the urinary excretion induced by lemon therapy (koff, et al 2007 experimental non controlled m) (15) or they found lower increases with respect to potassium citrate or orange juice (penniston et al 2007 observational l, odvina et al. experimental non randomized m) (16, 17). orange juice orange juice consumption resulted in a significantly higher urinary citrate excretion when compared to lemonade. on the contrary urinary oxalate was significantly higher during orange juice consumption, a finding which was not observed with the lemonade consumption. the saturation ratio of calcium oxalate tended to be lower during orange juice consumption compared with lemonade, but the difference was not significant. (penniston et al. 2007 observational l: wabner et al. 1993) (16, 18). grapefruit juice grapefruit juice significantly increased urinary citrate and urinary oxalate levels. these events were not associated with an increased risk of supra-saturation of calcium oxalate, calcium phosphate or uric acid. in other words, the increase in oxalate excretion, which would promote lithogenicity, was offset by the increase in citrate excretion (goldfarb et al. 2001, experimental m) (19). lime juice in renal stone formers a solution containing lime powder significantly increased urine citrate, potassium, and ph (tosukhowong et al. 2008 experimental m) (20). non citrus juices cranberry juice had controversial effect on urine citrate (no effect or increase of 31%), but resulted in a significantly increased concentration of urinary calcium and oxalate (gettman et al. 2005 experimental non controlled m, mcharg et al. 2003 experimental cross over m) (21, 22). unsweetened blackcurrant diluted juice increased urinary citrate by 25% over baseline (kessler et al. 2002 experimental m) (23). the consumption of a non citrus alkaline fruit (melon) also has a positive effect in increasing citraturia as compared to citrus fruit consumption (baia et al. 2012 experimental m) (24). other drinks in non stone-formers the citrus-based sport drink performance® increased citrate excretion and urine ph, but the other sport drink gatorade® did not change either parameter significantly. thus, performance® appears to have effects on urine citrate which are similar in magnitude to those observed in some studies using homemade lemonade (goodman et al. 2009, experimental m) (25). consumption of soda showed no significant variations of citrate urinary excretion (passman et al. 2009 experimental m) (26). despite the efficacy of these different types of drinks in raising urine citrate, practitioners must be cautious in recommending high volumes of juices or sports beverages for long-term citrate replacement, due to the high caloric content of many preparations that might be associated with unwanted carbohydrate consumption. conclusions several patients require modification of their dietary regimen instead of medical treatment as a first option for the prevention of stone recurrence. both citrus fruits (lemons, oranges, grapefruit, and lime) and non citrus fruits (melon) are natural sources of dietary citrate, and several studies have shown the potential of these fruits and/or their juices in raising urine citrate levels. nevertheless, future prospective randomized trials having hypocitraturia dietary treatment as the primary endpoint and also comparing pharmacologic therapy with dietary interventions are needed. dietary prevention in the child renal stone patient background nephrolithiasis in children is most prevalent between 3 and 5 years old, even if it can arise from early childhood to late adolescence. it affects males more frequently than females (1). the most frequent causes of nephrolithiasis in children are urinary tract infections (up to 60% of cases in some records), metabolic abnormalities (including idiopathic hypercalciuria), congenital urogenital malformations, and cystinuria (2-3). the most frequent composition of stones in children is calcium oxalate (45%), followed by calcium phosphate (25%), struvite (17%) and cystine (8%), while uric acid stones are very rare (4). metabolic abnormalities, like hypercalciuria and hypocitraturia, are less prevalent than in adults, although this difference attenuates in adolescents (4). more recent reports however state that their prevalence is rising (5). a complete metabolic evaluation of urinary risk factors is nowadays considered mandatory also in young children (6). hypercalciuria is traditionally considered the most important urinary risk factor for lithogenesis in children (4, 79), especially in recurrent patients (7). however, recent reports state that hypocitraturia is nowadays the most prevalent risk factor (8, 10) and probably the major responsible for kidney stone formation in children (11). a poor hydration is often another fundamental risk factor (12-13). urinary calcium excretion is generally higher in stone forming children than in healthy ageand sexmatched controls (14). in some cases, hypercalciuria may be caused by excessive vitamin d intake for rickets preprezioso_stesura seveso 02/07/15 11:18 pagina 112 vention (15-16) or by genetic polymorphisms inducing an abnormal vitamin d metabolism (17). hyperoxaluria is the leading metabolic risk factor in about 20% of pediatric patients (4) and is often geneticallydetermined (primary hyperoxaluria type 1 and 2), although almost half of cases have a dietary origin (18). the relationship between overweight/obesity and nephrolithiasis in children is controversial, with some studies reporting a higher prevalence of hyperoxaluria and hypocitraturia in obese children (19) and others denying any association between body mass index and urinary factors of lithogenic risk (20). there are also data stating that underweight, rather than overweight, is a risk factor for nephrolithiasis in children (21). dietary treatment of hypercalciuria in children 1. diets with a high calcium content (up to 1 g/day) are not harmful for urinary calcium excretion, both in stone forming and in control children. therefore, dietary calcium restriction is not recommended for children with nephrolithiasis. a diet with 1 g of calcium per day induces a significant (20%) rise in urinary calcium excretion lasting only 3 days in stone forming children, compared to a calcium restriction (400 mg/day). after this period, urinary calcium excretion returns to basal levels. moreover, dietary calcium restriction may promote urinary calcium excretion by inducing a rise in calcitriol levels (22). moreover, children that are used to a low calcium intake are more sensitive to variations in dietary calcium content (23). 2. moderate dietary salt restriction and implementation of potassium intake are useful in limiting urinary calcium excretion and thus for primary and secondary prevention of nephrolithiasis. a direct correlation between urinary sodium and urinary calcium excretion and an inverse correlation between urinary potassium and calcium have been demonstrated in children. these correlations are even stronger in adolescents, who are probably more prone to eat large amounts of salty foods and to avoid fruit and vegetables (24). a study carried out on 11 children with idiopathic hypercalciuria has demonstrated that potassium supplementation, through fruit and vegetable intake or potassium citrate ingestion, is associated to a drop in urinary calcium and lithogenic risk (25). another study, carried out on a small sample of calcium stone formers, found that a diet with a low salt (1-2 mg/kg/day) and a high potassium intake (1 meq/kg/day) is able to treat hypercalciuria in virtually all patients (26). however, another study from the same research group found that a low-salt high-potassium protein-balanced diet is effective in resolving hypercalciuria only in 33% of cases (27). these results have been confirmed by a more recent study, where the above mentioned diet proved to be effective in treating hypercalciuria in only 24% of 46 hypercalciuric children aged more than 4 (28). the largest study carried out on dietary treatment of hypercalciuric pediatric calcium nephrolithiasis has instead showed that dietary salt restriction alone (1-2 mg/kg/day) is effective in reducing calcium excretion in 65 out of 131 (49,6%) subjects (29). 3. the best therapeutical approach for treating hypercalciuria in children is to prescribe a 3-month period of lowsalt high-potassium diet, followed by personalized pharmacological therapy if hypercalciuria does not resolve. almost every study carried out on pediatric hypercalciuria adopted this approach (a 3-month run-in period with dietary therapy followed by a new metabolic evaluation and pharmacologic therapy if metabolic abnormalities do not resolve), which has proven to be very effective (2730). this sequential therapeutic schedule is also very effective in preventing kidney stone recurrences on a long-term follow-up (30). the main limitation of these studies is the fact that data are analyzed in an aggregate way, so that the effects of dietary therapy alone are not discernible from that of dietary therapy plus pharmacological intervention. dietary treatment of hypocitraturia in children 4. hypocitraturia in children is most likely due to a high salt and sugar intake and to a consumption of fruit and vegetables lower than recommended. like in adult stone formers, also in children salt and sugar intake is inversely correlated with urinary citrate excretion (31). moreover, hypocitraturic children with kidney stones have low levels of urinary phytate, which is a reliable marker of fruit and vegetable consumption (32). in western countries, it has been demonstrated that children have an extremely low average intake of vegetables, while the consumption of fruit is slightly increasing in recent years, anyhow lower than recommended (33-34). 5. no studies have assessed the effect of fruit and vegetable supplementation and/or dietary salt and sugar restriction on urinary citrate excretion in pediatric calcium stone formers so far. therefore, at the moment there is no scientific evidence to recommend this dietary intervention in hypocitraturic children. even in those studies who have evaluated the possible therapies for pediatric nephrolithiasis in a combined way, hypocitraturia was always treated with pharmacological supplementation with potassium citrate (27, 30). this treatment has however proven effective both in raising urinary citrate levels and in diminishing recurrence rates (35). 6. despite the lack of specific studies, given the wellknown benefits of fruit and vegetable intake, it seems reasonable to advice a balanced consumption of these foods, according to general nutritional guidelines. dietary treatment of hyperoxaluria in children 7. apart from genetic hyperoxaluria, a high urinary oxalate excretion in children and adolescents is most likely due to a high consuption of oxalate-rich foods such as chocolate and cola. a dietary load of chocolate is able to cause transient hyperoxaluria in adults (36-37). the habitual consumption of cola has also been linked to hyperoxaluria (38). intake of other oxalate-rich foods does not automatically result in hyperoxaluria, due to lower bioavalaibility (39). it has been demonstrated that children and adolescents have significantly higher intake of chocolate and cola than adults (40-42). 8. no studies have assessed the effects of chocolate and cola restriction on hyperoxaluric pediatric stone formers so far. therefore, at the moment there is no scientific evidence to recommend this dietary intervention in hyperoxaluric children. all studies that have considered hyperoxaluric pediatric patients have tested dietary interventions combined with pharmacologic approach (vitamin b6), 113archivio italiano di urologia e andrologia 2015; 87, 2 dietary treatment of urinary risk factors for renal stone formation prezioso_stesura seveso 02/07/15 11:18 pagina 113 archivio italiano di urologia e andrologia 2015; 87, 2 prezioso, strazzullo, lotti, bianchi, borghi, caione, carini, caudarella, gambaro, gelosa, guttilla, illiano, marangella, messa, miano, et al. 114 demonstrating that this therapy is effective in reducing hyperoxaluria and preventing stone recurrences (24,30). 9. despite the lack of specific studies, given the wellknown benefits of limiting cola and chocolate intake, it seems reasonable to advice a low consumption of these foods, according to general nutritional guidelines. importance of urinary volume in children 10. there are no studies assessing the effectiveness of water therapy alone in the prevention of kidney stone recurrences in pediatric patients. however, given the availability and strength of data in adults, there are sufficient basis to advice an adequate fluid intake also in children. in adults, water therapy alone, as to maintain urinary volume over 2 litres per day, is able to prevent 44% of recurrences in patients with a first episode of renal colic (43). no data are available for children, but all studies carried out on pediatric nephrolithiasis have prescribed an adequate fluid intake in addition to dietary and pharmacological treatments. these recommendation may be crucial in pediatric subjects where no metabolic abnormalities are present (12-13). diet for the obese children with kidney stones 11. no studies have assessed specific dietary treatments to prevent nephrolithiasis in obese children. therefore, in this category of patients, it seems reasonable to recommend the usual diets for childhood obesity. dietary treatment in children with cystinuria 12. despite the low level of scientific evidence, a low-protein (< 20 g/day) low-salt (< 2 g/day) diet with high hydration (> 3 litres/day) is strongly advised in children with cystinuria.in a study carried out on one patient with cystinuria many years ago, a 20 g/day protein intake proved to reduce basal cysteine levels by 31% compared with a 117 g/day protein intake (44). it is probable that cystine excretion is strongly influenced also by the specific type of proteins of foods. a diet with a high glutamine but with normal overall protein intake is actually able to diminish cystine excretion (45). however, this dietary manipulation is effective only when salt intake is liberal (46). salt restriction itself is highly effective in diminishing cystine excretion, provided that it is very strict (< 2 g/day) (46-47). in a study carried out on 5 patients, a salt intake < 2 g/day has been associated to a 50% reduction in urinary cystine (47). however, such a strict salt restriction is very difficult to achieve and maintain in western countries. dietary therapy in cystinuria has only a supportive role 13. low-protein low-salt high-fluid diet alone is poorly effective in preventing kidney stone recurrences in cystinuria. association with urinary alkalinization and pharmacological treatment with thiola is often mandatory to achieve an acceptable prevention (48). final considerations and conclusions highor fair-quality intervention studies on dietary treatment of pediatric nephrolithiasis are lacking. available studies have in fact several important limitations, including: low number of patients; poor characterization of the precise diagnosis of patients (i.e., idiopathic calcium nephrolithiasis vs secondary calcium nephrolithiasis vs asymptomatic crystalluria); poor characterization of metabolic phenotype; no stratification of data and results for metabolic phenotype; multiple treatments (dietary interventions are often studied together with drug therapy); lack of stratification for age groups (some studies consider together patients younger than 2 years old and adolescents); poor characterization of basal dietary habits; poor definition of outcomes; short term follow-ups. moreover, some of these studies were carried out many years ago, and thus did not take into account epidemiologic changes that occurred in the last decade(s). therefore, it is not possible to express any highor fairlevel recommendation on dietary therapy in pediatric nephrolithiasis. all advices reported above are thus relying on poor-quality data or on expert opinion. dietary prevention in the elderly renal stone patient background definition of elderly patient: the chronological age of 65 years as a definition of 'elderly' patient has conventionally been accepted. however, this convention is not exhaustive and is rather restrictive, not taking into account the large inter-individual biological variability within the same chronological age. therefore it would be more appropriate to take into consideration some parameters referring to biological aging, as regressive change of the structure and the function of different organs and systems of the human body. the elderly, however defined, has a lower functional reserve and increased fragility compared to the young (1-2). therefore during the biological process of aging changes of the body occur that affect clinical and diagnostic aspect in the elderly. epidemiology of nephrolithiasis in the elderly: in the case series reported by various studies on nephrolithiasis, 1012% (3-4) of the patients with urinary stones are over 65 years. however, in the general population over the age of 65, it has been shown a ratio of stone formation ranging 0.1-2%, that is not higher compared to that found in the younger population (5-6). an increase of crystalluria, which is known to represent a potential early stage of lithiasis, has also been described in the urine of elderly subjects (7). in the elderly recurrence and severity of the stone disease is the same than in the general population (4). stone composition and metabolic aspects of nephrolithiasis in the elderly: before dealing with the presence of metabolic risk factors for stone formation in the elderly population, it has to be pointed out that the average level of renal function in the elderly is reduced compared to younger patients. this aspect by itself may contribute to metabolic changes in the older patient with nephrolithiasis. for example, it is known that there is a reduction of calcium excretion in relation to the decrease of glomerular filtration and associated to a reduced intestinal absorption of this mineral. well-known alterations of bone metabolism and intermediary metabolism can influence both some typical parameters of mineral metabolism (pth, calcium, phosphorus) and of intermediary metabolism (uric acid).moreover, it has to be pointed out that the style of life, in particular for what concerns the food habits, is changed significantly with increasing age. accordingly, the larger series show that calcium oxalate prezioso_stesura seveso 02/07/15 11:18 pagina 114 stones are the more frequent also in elderly patients as in the general population but the rate of uric acid stones is greater in the elderly (4, 8, 9). some studies show that about 10-20% of patients suffering from gout form uric acid stones and conversely that 40% of patients with uric acid stones develop gout (10, 11). about 50% of elderly people suffering from kidney stones show an isolated metabolic defect in 24 hour urine (12). the most frequent is hypocitraturia with a rate in stone patients from 29% to 56% (4, 13). this figure would seem correlated to a physiological metabolic acidosis related to the progressive decrease of renal function with age. a urine ph below 5.5 promotes uric acid stone formation more than hyperuricosuria or hyperuricemia (10). in elderly people suffering from kidney stones, the values of pth are significantly increased and the values of 1,25-hydroxyvitamin d reduced (4). furthermore, especially in the elderly patients on long-term care, lower levels of natural vitamin d were found (14, 15). metabolic abnormalities are equally represented in both sexes in the elderly. in addition to the different prevalence of some metabolic disorders, other factors that are potentially lithogenic, could contribute to renal stone formation in the elderly. among these factors, infections of the urinary tract and reduced mobility could play a major role. in fact infections of the urinary tract are common in the elderly. however, although some studies show that in the elderly there is an increased risk of urinary tract infection, such data are not correlated to an higher rate of infection stones, that account for only 1% in the elderly (4-8). the reduction of ambulation in the elderly could cause an increased excretion of calcium in the urine. however, this condition is described only after prolonged periods of immobilization. diet dietary counseling for renal stone prevention in the elderly has to consider some particular aspects of aging. 1. about sodium intake, it is well known that diets high in sodium expose renal stone patients, especially if overweight and hypercalciuric, to an increase in urinary calcium excretion (taylor 2006 prospective study, evidence l) (16) which may increase the lithogenic risk and the risk to develop hypertension and bone demineralization. however, it should be considered that the elderly patient is particularly sensitive to sodium intake from a hemodynamic point of view. consequently, effects of any other concomitant therapy have to be attentively considered in relation to this aspect. 2. it is also known that a diet with a higher content of potassium, magnesium and citrate, is particularly effective not only in reducing the incidence of urinary risk factors for stone formation (hypercalciuria, hypocitraturia) but also in preventing the loss of bone mass and the incidence of arterial hypertension (ettinger 1997 prospective study, evidence l) (17). there are no particular additional problems in recommending such a diet in the older patient. 3. an important aspect to be considered is the calcium content in the diet. in the past, patients with calcium nephrolithiasis were given advice to avoid foods with an high calcium content. in recent decades more data have accumulated showing that a diet with a normal calcium content, but with reduced intake of animal protein (taylor, 2009, prospective, evidence l) (18) would be more protective on the lithogenic risk compared to a diet with reduced intake of calcium and oxalate, in particular in subjects with hypercalciuria. in fact, the reduced availability of calcium in the intestine would favor the increase of intestinal absorption of oxalate (messa, 1997 prospective study, evidence l) (19). moreover, a low-calcium diet expose patients to an increased risk of osteoporosis. this risk is certainly higher in the elderly, especially if female. there is no general indication in the renal stone patient to a low-calcium diet and even less in the elderly. therefore a diet rich in calcium (1200 mg/day) would be useful for the proper maintenance of both the musculoskeletal wellness and the prevention of kidney stones. in contrast a further supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases (20). 4. diets high in animal protein have been recognized to increase the risk of stone formation, probably by increasing the acid load (which reduces the excretion of citrate and rises calcium excretion secondary to increased removal from the bone) and the production and excretion of uric acid. although there are no prospective randomized studies that provide clear evidence of its clinical effects on prevention of renal stone disease and hypertension, some observational studies suggest that the adoption of a low-sodium diet, with increased intake of fruits and vegetables and reduced fat intake can be effective in the prevention of nephrolithiasis (taylor, 2009, prospective, evidence l) (18). in any case, a diet with lower content of animal protein and higher intake of plant products has no particular contraindications in the elderly patient with nephrolithiasis, although overall nutritional status of such patients must be always evaluated with great attention. 5. the available information about the usefulness of the reduction in the content of dietary oxalate is poor (taylor, 2007, prospective, evidence l) (21). therefore, in the elderly, it remains a questionable. in renal stone patients with high disease activity, when diet is not effective, use of drugs and dietary supplements (thiazide diuretics, allopurinol, citrate salts, etc.) is often advisable. there are no differences in prescribing pharmacological treatment in the elderly with respect to younger renal stone patients, although greater caution should be maintained in the use of diuretics (sonnenblick, 1993 observational study, evidence l) (22) for the obvious hemodynamic reasons and the greater frequency of decreased renal function in this range of age. in the case of elderly patients with nephrolithiasis on therapy with inhibitors of the renin-angiotensin-aldosterone system, attention should also be taken in the use of potassium citrate salts. references introduction 1. romero v, akpinar h, assimos dg. kidney stones: a global picture of prevalence, incidence, and associated risk factors. rev urol. 2010; 12:86-96. 2. sakhaee k, maalouf nm, sinnott b. clinical review. kidney stones 2012: pathogenesis, diagnosis, and management. j clin endocrinol metab. 2012; 97:1847-1860. 3. worcester em, coe fl. clinical practice. calcium kidney stones. n engl j med. 2010; 363:954-963. 115archivio italiano di urologia e andrologia 2015; 87, 2 dietary treatment of urinary risk factors for renal stone formation prezioso_stesura seveso 02/07/15 11:18 pagina 115 archivio italiano di urologia e andrologia 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gentle dl, stoller ml, bruce je, leslie sw. geriatric urolithiasis. j urol. 1997; 158:2221-4. 5. asper r. epidemiology and socioeconomic aspects of urolithais. urol res. 1984; 12:1. 6. hiatt ra, dales lg, friedman gd, hunkeler em. frequency of urolithiasis in prepaid medical care program. amer. j. epidemiol. 115:255-1982. 7. moesch c, charmes jp, gaches f, et al. crystalluria prevalence in the elderly. eur j med. 1993; 2:512. 8. knoll t, schubert ab, fahlenkamp d, et al. urolithiasis through the ages: data on more than 200,000 urinary stone analyses.j urol. 2011; 185:1304-11. 9. krambeck ae1, lieske jc, li x, et al. effect of age on the clinical presentation of incident symptomatic urolithiasis in the general population. j urol. 2013; 189:158-64. 10. stoller ml. gout and stones or stones and gout? j. urol. 1995; 154:1670. 11. riese rj, sakhaee j. uric acid nephrolithiasis: dathogenesis and treatment. j urol. 1992; 148:7657. 12. yagisawa t, hayashi t, yoshida a, et al. metabolic characteristics of the elderly with recurrent calcium oxalate stones. bju int. 1999; 83:924-8. 13. freitas junior ch, mazzucchi e, danilovic a, et al. metabolic assessment of elderly men with urolithiasis. clinics (sao paulo). 2012; 67:457-61. 14. fardellone p, sebert jl, garabedian m, et al. prevalence and biological consequences of vitamin d deficiency in elderly institutionalized subjects. rev rheum. 1995; 62:576. 15. komar l, nieves j, cosman f, et al. calcium homeostasis of an elderly population upon admission to a nursing home. j amer ger soc. 1993; 41:1057. 16. taylor en, fung tt, curhan gc. dash-style diet associates with reduced risk for kidney stones. j am soc nephrol. 2009; 20:2253-9. 17. ettinger b, pak cy, citron jt, et al. potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. j urol. 1997; 158:2069-73. 18. taylor en, curhan gc. body size and 24-hour urine composition. am j kidney dis. 2006; 48:905-15. 19. messa p, marangella m, paganin l, et al. different dietary calcium intake and relative supersaturation of calcium oxalate in the urine of patients forming renal stones. clin sci (lond). 1997; 93:257-63. 20. ross ac, manson je, abrams sa, et al. the 2011 report on dietary reference intakes for calcium and vitamin d from the institute of medicine: what clinicians need to know. j clin endocrinol metab. 2011; 96:53-8. 21. taylor en, curhan gc. oxalate intake and the risk for nephrolithiasis. j am soc nephrol 2007; m18: 2198-2204. 22. sonnenblick m, friedlander y, rosin aj. diuretic-induced severe hyponatremia. review and analysis of 129 reported patients. chest. 1993; 103:601-6. correspondence domenico prezioso, md dprezioso@libero.it (corresponding author) pasquale strazzullo, md strazzul@unina.it tullio lotti, md tulliolotti@hotmail.it giampaolo bianchi, md bianchi.giampaolo@unimore.it loris borghi, md loris.borghi@unipr.it paolo caione, md paolo.caione@opbg.net marco carini, md carini@unifi.it renata caudarella, md renata.caudarella@alice.it giovanni gambaro, md giovanni.gambaro@rm.unicatt.it marco gelosa, md marco.gelosa@yahoo.it andrea guttilla, md andrea.guttilla@gmail.com ester illiano, md ester.iliano@inwind.it martino marangella, md mmarangella@alice.it tiziana meschi, md tiziana.meschi@unipr.it piergiorgio messa, md pmessa@policlinico.mi.it roberto miano, md mianor@virgilio.it giorgio napodano, md antonio nouvenne, md antonio.nouvenne@alice.it domenico rendina, md domenico.rendina@libero.it francesco rocco, md francesco.rocco@unimi.it marco rosa, md marcorosa1983@gmail.com roberto sanseverino, md roberto.sanseverino@alice.it annamaria salerno, md annamaria.salerno@unicampus.it sebastiano spatafora, md s.spatafora@me.com andrea tasca, md andrea.tasca@ulssvicenza.it andrea ticinesi, md andrea.ticinesi@studenti.unipr.it fabrizio travaglini, md effetrava@hotmail.com alberto trinchieri, md a.trinchieri@ospedale.lecco.it giuseppe vespasiani, md vespasiani@uniroma2.it filiberto zattoni, md filiberto.zattoni@unipd.it prezioso_stesura seveso 02/07/15 11:18 pagina 120 archivio italiano di urologia e andrologia 2016; 88, 4330 case report rare presentation of a testicular angiofibroma treated with testis sparing surgery luca leone 1, paola fulvi 1, giulia sbrollini 1, alessandra filosa 2, enrico caraceni 3, angelo marronaro 3, andrea b. galosi 1 1 clinica urologica, scuola di specializzazione in urologia, università politecnica delle marche, ancona, italy; 2 uoc urologia civitanova marche, av 3, asur marche, italy; 3 anatomia patologica, av 3, asur marche, italy. introduction: testicular benign tumors are very rare (< 5%). testicular angiofibroma (af) is one of those, however the gold standard of treatment and follow-up is still unclear. case report: a 47 years-old man with only one functioning testis was referred to our clinic for a palpable right testicular mass and atrophic contralateral testis. patient underwent testis-sparing surgery with inguinal approach and intraoperative frozen sections examination with diagnosis of af. final histology confirmed af. post-operative follow-up was uneventful. clinical and ultrasonographic follow-up was negative after 8 months. conclusion: we report a conservative surgery in a patient with af of the solitary testis. af is a benign para-testicular fibrous neoplasm that could be misinterpreted as malignant tumor and treated with orchiectomy. testis-sparing surgery is recommended in this case with intraoperative pathological examination. the excision of the mass is enough but in front of a possible recurrence a long follow-up is advisable. key words: testicular neoplasms; angiofibroma; testis-sparing surgery; small testicular tumors. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. fetoprotein, human chorionic gonadotropin, lactate dehydrogenase) were normal. the ultrasonography described an 1.1 cm isoechoic nodule of the right testis with extratesticular growth located in the upper third, associated with thinning of the scrotal sac and a moderate hydrocele; a posterior acoustic shadowing behind the lesion was evident, suggesting the presence of fibrous tissue in the mass (figures 1-2). patient underwent inguinal approach with externalization of right testis. the lesion appeared superficial, firmly attached to the tunica albuginea (figure 3). considering that patient was monorchid, it was performed a testis-sparing surgery of the lesion using an enucleation technique plus biopsies of the surrounding parenchyma. at the frozen section a fibrous benign lesion was found. the wound was closed. definitive hisdoi: 10.4081/aiua.2016.4.330 presented at 20th national congress sieun, sciacca 2016 figure 1. testicular mass at ultrasonography. figure 2. testicular mass at colordoppler. introduction angiofibroma (af) is a benign neoplasm arising mainly in vulvo-vaginal region in woman and in inguino-scrotal region in men; it is very rare in male genitalia (1). because of the variability of clinic findings and uncertain classification, the gold standard of treatment and followup are still unclear. testis-sparing surgery (tss) with intraoperative frozen sections of small testicular lesions is recommended (2) to avoid over-treatment of benign tumors like af, despite those are uncommon. we present a case of an af in a young man with an only one functioning testis. case report a 47 years old man was referred to our department for a palpable and painless right testicular mass found incidentally during a shower. the left testis was atrophic because of a torsion at age of 15. he had not further previous medical or surgical history. tumor markers (alphaleone-rare presentation of a testicular _stesura seveso 09/01/17 10:45 pagina 330 331archivio italiano di urologia e andrologia 2016; 88, 4 primitive angiofibroma treated with testis sparing surgery tological examination confirmed the af. any complication was observed in the post-operative time. clinic and ultrasonographic follow-up after 3 and 8 months was negative for recurrence. discussion testicular and para-testicular benign fibromatous lesions are rare, arise in most cases from tunica vaginalis and the 15% of cases from tunica albuginea (like this one) (2, 3). the aetiology is uncertain: while some authors consider them non-neoplastic and reactive process, others consider them true neoplasms arising from the cellular tunics if inflammatory cells are not present; these lesions can arise from the testis (fibromas of gonadal stromal origin) or from testicular tunics (3). in particular, angiomyofibroblastoma-like (amf-like) tumors are benign mesenchymal neoplasm with extremely low incidence (4), initially described in women by nucci et al. (5), and then in men by laskin et al. (6). iwasa concluded that cellular af and amf-like tumors are very similar but they differ in the stroma/cellular ratio in favour of af (7). no cases of metastatic disease or recurrence are described (8). af arises mainly in inguino-scrotal region in men but is very rare in the testis; it originates from perivascular stem cells that differentiates into fatty and myofibroblastic cells (9); it is composed by prominent blood vessels, low cellularity with spindle cells (9) within collagenous stroma, without mitotic activity, necrosis, nuclear pleomorphisms. testicular parenchyma is not remarkable inside the lesion and a vascular axis is described in the center. the histological differential diagnosis includes aggressive angiomyxoma, angiomyofibroblastoma, spindle cell lipoma, solitary fibrous tumor, perineurioma and leiomyoma (5). the ultrasonography findings of these lesions are not frequently described, and there is a large variation of characteristics: fibromatous tumors are described as hyperor isoor hypoechoic, with or without posterior acoustic shadowing (10). in some paper are described also magnetic resonance imaging (mri) findings: are lesions with intermediate signal intensity in all sequences, more hypointense on t2than in t1weighted sequences and failed to enhance after gadolinium administration (10). the differentiation of an inflammatory fibrous pseudotumor from a true neoplasm is based on clinical, radiographic, gross and microscopic features. clinical and ultrasonography features (as the appearance of extratesticular masses) may indicate the benignity of the lesion, but the specificity isn’t sufficient to permit confident differentiation between benign and malignant process; therefore, a histological evaluation of the lesion is mandatory. testis-sparing surgery is indicated in selected cases (bilateral testicular tumor or monorchid patient) (11); in cases of endophytic masses intraoperative ultrasound (iu) and collaboration with the pathologist can help to detect and enucleate the entire lesion (12); in this case a wedge resection was performed without iu because tumor was mostly exophytic and margins were clearly detectables. the major concern for tss is the small size of lesions send for frozen sections: the low quantity of tissue and the missing of intraoperative immunoistochemistry can affect the diagnosis (1, 13). the definitive histologic report is the only one to comply the final diagnosis. follow-up is still important also if the diagnosis is a benign tumor. we don’t have many data in literature about follow-up of these lesions, because are very rare and most of papers report only a case report, like our experience; in the largest case series published composed by 40 (1) and 9 (3) men were negative for recurrence. best strategy for testicular follow-up is ultrasound, because the sensibility for small and not palpable lesions. conclusions frozen sections are recommended in case of tss that is an effective treatment for small testicular lesions to avoid over-treatment, limiting functional outcomes in cases of benign tumor, mostly in monorchid patients. further studies and biggest series are needed to confirm the right follow-up to detect any recurrence. references 1. iwasa y, fletcher cd. cellular angiofibroma: clinicopathologic and immunohistochemical analysis of 51 cases. am j surg pathol. 2004; 28:1426-35. 2. jones ma, young rh, scully re. benign fibromatous tumors of the testis and paratesticular region. a report. am j surg pat. 1997; 21:296-305. 3. jones ma, young rh, scully re. benign fibromatous tumor of the testis and paratesticular region: a report of 9 cases with a proposed classification of fibromatous tumors and tumor-like lesions. am j surg pathol. 1997; 21:296-305. 4. galosi ab, scarpelli m, mazzucchelli r, et al. adult primary paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of spermatic cord leiomyosarcoma. diagnostic pathology. 2014, 9:90. 5. nucci mr, granter sr, flecther cd. cellular angiofibroma: a benign neoplasm distinct from angiomyofibroblastoma and spindle cell lipoma. am j surg pathol. 1997; 21:636-44. 6. laskin wb, fetsch jf, mostofi fk. angiomyofibroblastoma-like tumor of the male genital tract: analysis of 11 cases with comparison to female angiomyofibroblastoma and spindle cell lipoma. am j surg pathol. 1998; 22:6-16. figure 3. intra-operative picture of the testicular mass. leone-rare presentation of a testicular _stesura seveso 09/01/17 10:45 pagina 331 archivio italiano di urologia e andrologia 2016; 88, 4 l. leone, p. fulvi, g. sbrollini, a. filosa, e. caraceni, a. marronaro, a.b. galosi 332 7. canales bk, weiland d, hoffman n, et al. angiomyofibro blastoma-like tumors (cellular angiofibroma). int j urol. 2006; 13:177-9. 8. maciel de lima m jr, maciel de lima, granja f. angiofibroma testicular a case report. int j med phar sci. 2014; 4:01-03. 9. miyajima k, hasegawa s, oda y, et al. angiomyofibroblastomalike tumor (cellular angiofibroma) in the male inguinal region. radiat med. 2007, 25:173-177. 10. sadowski ea, salomon cg, wojcik em, albala d. fibroma of the testicular tunics. j ultrasound med. 2001; 20:1245-1248. 11. sbrollini g, mazzaferro d, ettamimi a, et al. diagnostic-therapeutic pathway for small lesions of the testis. arch ital urol androl. 2014; 86:397-399. 12. fabiani a, filosa a, fioretti f, et al. diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules. a single institution experience. arch ital urol androl. 2014; 86:373-377. 13. borghesi m, brunocilla e, schiavina r, et al. role of testis sparing surgery in the conservative management of small testicular masses: oncological and functional perspectives. actas urol esp. 2015; 39:57-62. correspondence luca leone, md luca.leone.1985@gmail.com paola fulvi, md paola.fulvi19@gmail.com giulia sbrollini, md giuliasbrollini@libero.it andrea b galosi, md (corresponding author) galosiab@yahoo.it clinica urologica, scuola di specializzazione in urologia, università politecnica delle marche ancona, italy alessandra filosa, md uoc urologia civitanova marche, av 3, asur marche civitanova marche, italy enrico caraceni, md ecarace@libero.it angelo marronaro, md ang6marr@yahoo.it anatomia patologica, av 3, asur marche, italy leone-rare presentation of a testicular _stesura seveso 09/01/17 10:45 pagina 332 archivio italiano di urologia e andrologia 2017; 89, 160 original paper renal extracapsular hypoechoic rim and kidney cortical thickness simone brardi 1, gabriele cevenini 2, roberto ponchietti 3, giuseppe romano 4, ennio duranti 1 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of surgery and bioengineering, university of siena, italy; 3 professor of urology, university of siena, italy; 4 urology unit, s. maria della gruccia hospital, montevarchi, italy. objectives: a renal extracapsular hypoechoic rim was previously recognized and interpreted as a typical sonographic finding of renal failure. subsequently it was hypothesized that the hypoechoic rim could be produced by a state of sodium retention and oedema caused by nephropathy but not necessarily associated with renal failure. in order to get this cleared we performed a retrospective analysis of 80 renal ultrasound examinations, carried out at our center, in 41 of which it was found a renal extracapsular hypoechoic rim. materials and methods: for each patient we recorded the glomerular filtration rate, the diameters in the longitudinal axis, the resistive indexes and the cortical thickness of each kidney, the possible presence and thickness of the hypoechoic rim and yet the possible coexistence of diabetes mellitus, proteinuria and clinical signs of fluid overload as peripheral oedema, distended jugular veins, ascites, increased caliber and reduced respiratory excursion of the vena cava. results: the f value calculated to assess the weight/influence on the hypoechoic rim of each of the variables showed as all variables, except the sex, significantly weighed on the hypoechoic rim although the greatest weight was reached by a glomerular filtration rate < 60 ml/min/1.73 m2 and a renal cortical thickness between 7 and 12 mm. the hypoechoic rim was found only when cortical thickness was between 7 and 12 mm while it was absent if the cortical thickness was less than 7 or greater than 12 mm. we also found numerous cases of sidedness of the hypoechoic rim. conclusions: it is our opinion that in case of unilateral finding of an hypoechoic rim, the association between the hypoechoic rim and the cortical thinning is consistent and therefore more accurate than the correlation between the presence of the hypoechoic rim and the reduction of the glomerular filtration rate. key words: renal ultrasonography; renal extracapsular hypoechoic rim; cortical thinning; kidney failure; retrospective analysis. submitted 20 february 2017; accepted 2 march 2017 summary no conflict of interest declared. interpreted renal extracapsular hypoechoic rim as an ultrasound finding exclusive of patients with renal impairment because they didn’t find any trace of it in any of 172 kidney ultrasound scans performed in patients who had no clinical or laboratory signs of kidney failure. subsequently haddad et al. (2) by a series of only 9 patients advanced the hypothesis that the renal extracapsular hypoechoic rim could be constituted by a transudate that may occur in patients suffering from a state of sodium retention and oedema resulting from some form of nephropathy although not necessarily associated with renal impairment. however, haddad et al. (2) observed the hypoechoic rim also in patients affected by parenchymal renal disease but without renal failure. in order to find more evidence to settle, if possible, this different interpretations we performed a retrospective analysis of 41 renal ultrasound examinations, carried out over the last six months at our center and reporting the presence of an unilateral or bilateral renal extracapsular hypoechoic rim, in association with a retrospective analysis of 39 controls, randomly selected, among the patients who underwent renal ultrasound exam in the same six months and who didn’t show any renal extracapsular hypoechoic rim. of these 80 patients we recorded sex and age, the actual glomerular filtration rate estimated from the serum creatinine by the chronic kidney disease epidemiology collaboration (ckd-epi) equation (3), the longitudinal axis diameters of each of the two kidneys, the resistive indexes of both kidneys, the cortical thickness of each of the two kidneys, the presence or not, for each kidney, of an extracapsular hypoechoic rim and, if present, its thickness, presence of diabetes mellitus, presence of proteinuria and its amount, presence of any clinical signs of fluid overload such as peripheral oedema, distended jugular veins, ascites, increased caliber and reduced respiratory excursion of the vena cava. materials and methods from june 2016 to december 2016 we found at renal ultrasound examination an unilateral or bilateral renal extracapsular hypoechoic rim in 41 patients. subsequently we randomly selected 39 patients as control group, among who underwent renal ultrasound doi: 10.4081/aiua.2017.1.60 introduction the presence of a renal extracapsular hypoechoic rim (that was called “kidney sweat” sign) (figures 1, 2) for the first time was recognized by yassa et al. (1) in 1999 by a series of 502 ultrasound examinations, 330 of those were performed in patients with renal insufficiency. yassa et al. (1) brardi_stesura seveso 04/04/17 09:24 pagina 60 61archivio italiano di urologia e andrologia 2017; 89, 1 renal extracapsular hypoechoic rim and kidney damage examination in the same six months and who didn’t show any renal extracapsular hypoechoic rim. all kidney nephrology ultrasound examinations were performed by logiq s7 (ge medical systems italy s.p.a. milan, italy) sonographic system using 3 to 5 mhz transducers. for every patient were recorded sex, age and glomerular filtration rate (gfr) estimated by the ckd-epi equation (3) from serum creatinine as found during the blood test closer to the time of the ultrasound examination. subsequently four classes of renal function were recognized: severe renal insufficiency when the gfr was lower than 30 ml/min/1.73 m2, moderate renal impairment when the gfr was equal or greater than 30 ml/min/1.73 m2 and less than 60 ml/min/1.73 m2, mild renal impairment when the gfr was equal or greater than 60 ml/min/1.73 m2 and less than 90 ml/min/1.73 m2 and finally normal renal function when the gfr proved equal or greater than 90 ml/min/1.73 m2. we recorded the diameters in the longitudinal axis of each kidney, the resistive indexe of each kidney by sampling intrarenal segmental and interlobar arteries and finally the cortical thickness of each kidney by measuring the portion closer to the upper pole and the lower pole of the same kidney. four grades of cortical thickness were recognized: severe reduction of cortical thickness when the thickness of the cortex was less than 7 mm, moderate reduction of cortical thickness when the thickness of the cortex was greater than 7 mm and less than 10 mm, mild reduction in cortical thickness when the cortical thickness was greater than 10 mm and less than 12 mm and normal cortical thickness when the thickness of the cortex was equal or greater than 12 mm. of course was recorded the presence or absence, for each kidney, of a renal extracapsular hypoechoic rim and, if present, its thickness; presence of diabetes mellitus or presence of proteinuria and its amount , presence of any clinical signs of fluid overload such as peripheral oedema, distended jugular veins, ascites, increased the caliber and reduced respiratory excursion of the vena cava. since the perirenal spaces can collect fluid collections that may be related to acute renal disorders or related to adjacent retroperitoneal structures (4) we excluded patients with renal trauma, spontaneous rupture of renal cysts, hydronephrosis or mass lesions (5) and patients with acute pancreatitis which may cause pancreatic exudates going to gather in front pararenal spaces. descriptive statistics of the quantitative data was reported as the mean and standard deviation, while qualitative data as frequency and/or percentage. it was used a univariate logistic regression to evaluate the weight of each variable on the presence of the renal extracapsular hypoechoic rim, using the f statistic of fisher. the groups were statistically compared, using the analysis of variance (anova) for quantitative variables distributed in a gaussian manner. where it had to reject the statistical assumptions of normality, checked using the kolmogorov-smirnov test, was used the nonparametric kruskal-wallis test. when the anova or kruskal-wallis test provided statistically significant differences between the test groups, we used, respectively, the post-hoc test bonferroni or dunn for pairwise comparisons. the comparison between groups for qualitative variables was performed with fisher's exact test for 2 x 2 contingency tables, otherwise, with chi-square test for the greater dimension tables. finally, the correlations between quantitative variables were performed by calculating the pearson correlation coefficient and evaluating statistical significance. for all statistical analyzes, performed with the spss software package version 10, it was chosen a significance level of 95% and thus were considered statistically significant p < 0.05 values. results a renal extracapsular bilateral hypoechoic rim was observed in 21 patients (18 males and 3 females), mean age 78.1 ± 10.1 years with an average renal cortical thickness of 0.52 ± 0.17 cm, a minimum thickness of 0.24 cm and a maximum thickness of 0.94 cm; these 21 patients had a mean glomerular filtration rate of 34.5 ± 12.2 ml/min/1.73 m2 and a renal cortical thickness greater of 7 mm and less than 10 mm in 31% of the cases and a renal cortical thickness greater than 10 mm and less than 12 mm in the remaining 69%. the mean diameter in longitudinal axis was 98.3 ± 11.6 mm with a maximum of 130 mm and a minimum of 71 mm. the average of resistive indexes were 0.73 ± 0.06; proteinuria was found in 62% of patients (13 of 21 patients) and the average amount was 0.33 ± 0.59 g/24h. finally signs of fluid overload were observed in 19% of patients while diabetes was present in 33% of the same patients. instead a renal extracapsular unilateral hypoechoic rim was found in 20 patients (10 males and 10 females), mean age 81.1 ± 7.2 years, with an average renal cortical thickness of 0.27 ± 0.29 cm, a minimum of 0.24 cm and a maximum of 0.79 cm; these patients had a mean glomerular filtration rate of 34.7 ± 12 ml/min/1.73 m2 while cortical thickness was greater than 7 mm and less than 10 mm in 55% of kidneys with unilateral hypoechoic rim and greater than 10 mm and less than 12 mm in the remaining 45% of the same kidneys, while in the other 20 kidneys without extracapsular hypoechoic rim was found a renal cortical thickness smaller than 7 mm in a percentage of 55% and a cortical thickness equal or greater than 12 mm in the remaining 45%. the average diameter of the kidneys with an unilateral hypoechoic rim in the longitudinal axis was 90.6 ± 17.8 mm with a maximum of 126 mm and a minimum 55 mm. the mean resistive index was 0.76 ± 0.07; proteinuria was found in 63% of patients and the average amount was 0.21 ± 0.35 g/24h. finally signs of fluid overload were found in 10% of patients with unilateral hypoechoic rim while diabetes was found in a 30% of these same patients. the patients without both unilateral or bilateral extracapsular hypoechoic rim were 39, 22 males and 17 females, with a mean age of 57.5 ± 15.1 years while the glomerular filtration rate was 77 ± 22.8 ml/min/1.73 m2. the mean diameter in the longitudinal axis was 108.1 ± 16.6 mm with a maximum of 143 mm and a minimum of 92 mm; the average resistive index was 0.63 ± 0.06. the cortical thickness was less than 7 mm in 18% of the total of the kidneys and equal or greater than 12 mm in brardi_stesura seveso 04/04/17 09:24 pagina 61 archivio italiano di urologia e andrologia 2017; 89, 1 s. brardi, g. cevenini, r. ponchietti, g. romano, e. duranti 62 the remaining 82%. signs of fluid overload and diabetes were not found in anyone of the patients. the f value calculated to assess the weight on the presence of unilateral or bilateral renal extracapsular hypoechoic rim of each of the variables taken into account (age, sex, glomerular filtration rate, diameter of each kidney, cortical thickness of each kidney, resistive index of each kidney, presence of proteinuria, presence of signs of fluid overload, presence of diabetes mellitus) allowed us to demonstrate that all the variables except gender (which showed a p-value > 0.05) weighed significantly on yhe presence of an hypoechoic rim (table 1). however the greater weight on the presence of the renal extracapsular hypoechoic rim was equally reached by both the presence of a glomerular filtration rate lower than 60 ml/min/1.73 m2 and by the presence of a cortical thickness greater than 7 and less than 12 mm (table 1). furthermore it was found in a statistically significant manner that the renal extracapsular hypoechoic rim was present only when cortical thickness was greater than 7 mm and less than 10 mm or greater than 10 and less than 12 mm while it was not found any extracapsular hypoechoic rim when the cortical thickness was less than 7 mm or greater than 12 mm. it was not found any correlation between severe reduction of the glomerular filtration rate (i.e. < 30 ml/min/1.73 m2) or moderate reduction of the glomerular filtration rate (i.e. ≥ 30 and < 60 ml/min/1.73 m2) and the respective mean thickness of the extracapsular hypoechoic rim. it was also confirmed the presence of a statistically significant correlation between the presence of signs of fluid overload and the coexistence of renal extracapsular hypoechoic rim although this association was found in only 6 of the 41 patients with an unilateral or bilateral renal extracapsular hypoechoic rim that is the 15% of the cases. a similar statistically significant correlation was found between the presence of hypoechoic rim and the coexistence of diabetes mellitus or proteinuria. discussion the kidney is encased by the anterior and posterior pararenal fascia, also known as gerota's fascia, forming the perirenal space. between the anterior pararenal fascia and the posterior peritoneum there is the anterior pararenal space while between the posterior pararenal fascia and the transversalis fascia there is the posterior pararenal space (6-8). the fascia cannot be recognized by sonography so the perirenal and pararenal spaces appear as a single compartment filled with fat (6, 7). the fat is variable in amount and is usually hyperechoic but occasionally may become hypoechoic, when the water content of the fat tissue is low (6, 9), so appearing as a hypoechoic rim (figures 1, 2) that mimics a perirenal fluid (6, 10, 11). table 1. weight/influence of the variables on the hypoechoic rim (unilateral and/or bilateral). variables score statistical (fisher f) significance (p-value) age (years) 28.219 .000 sex 2.262 .133 gfr (ml/min/1.73 m2) 37.556 .000 right kidney diameter (mm) 7.305 .007 left kidney diameter (mm) 13.262 .000 right kidney cortical thickness (mm) 42.134 .000 left kidney cortical thickness (mm) 50.699 .000 right kidney resistive indexes 28.916 .000 left kidney resistive indexes 26.900 .000 proteinuria (gr/24h) 4.590 .032 right kidney hypoechoic rim thickness (cm) 32.259 .000 left kidney hypoechoic rim thickness (cm) 41.944 .000 clinical findings of fluid overload 5.628 .018 diabetes mellitus 13.867 .000 right kidney cortical thickness > 7 < 12 (mm) 45.490 .000 left kidney cortical thickness > 7 < 12 (mm) 49.568 .000 gfr < 60 (ml/min/1.73 m2) 49.568 .000 figure 1. renal extracapsular hypoechoic rim (arrows). figure 2. renal extracapsular hypoechoic rim (arrow). brardi_stesura seveso 04/04/17 09:24 pagina 62 63archivio italiano di urologia e andrologia 2017; 89, 1 renal extracapsular hypoechoic rim and kidney damage moreover the ultrasound appearance of the kidneys under chronic renal failure (6, 12, 13) it is characterized by a reduction in renal size, thinning of the parenchyma (especially of the cortex) and increased echogenicity of the same cortex. in these cases when cortical thickness cannot be determined with precision because the medullary pyramids are not visible, thinning of the cortex can be appreciated as thinning of the entire parenchyma (6). with respect to normal cortical thickness, although there are limited data, a cutoff of 12 mm can be considered appropriate (6, 14) while a value of less than 7 mm is probably abnormal (6). among the all characteristics of cortical atrophy, the most reliable is just the cortical thinning (6) since the renal size varies with body size and increased echogenicity is a subjective determination that may be affected by artifacts (6). consequently echogenicity should not be taken into account among the parameters which can weigh on the hypoechoic rim. more in detail the renal cortex is the subcapsular portion of the kidney composed mainly of glomeruli and convoluted tubules, extending in columns between the pyramids that constitute the renal medulla. renal ultrafiltration, which occurs in the glomeruli, takes place therefore in the cortex of the kidney. given the above, we note that, consistently with the findings of yassa et al. (1) and haddad et al. (2), also our study shows a statistically significant close correlation between the presence of the hypoechoic rim and a reduced glomerular filtration rate below 60 ml/min/1.73 m2, as well as a correlation between the presence of the hypoechoic rim and the coexistence of fluid overload although this latter correlation, in the light of the limited number of the cases of fluid overload (which were only the 15% of all patients with unilateral or bilateral hypoechoic rim), certainly weighs less in statistical terms on hypoechoic rim if compared to the presence of above-mentioned renal insufficiency as shown by the specific statistical analysis (table 1). it is also widely known as the ascites is a common cause of widening of the space between the right kidney and the liver (6). indeed, quite peculiar of this retrospective analysis, it is the close correlation that was found between the presence of the hypoechoic rim and a thinning of the renal cortex between 7 and 12 mm so that the reduction in cortical thickness weighs on the hypoechoic rim as the presence of a glomerular filtration rate less than 60 ml/min/1.73 m2. furthermore we found in our series numerous cases of unilaterality of the hypoechoic rim equal to the 49% of all patients that showed the hypoechoic rim, quite differently from what found by yassa et al. (1) who observed a bilateral hypoechoic rim in all cases but accordingly to haddad et al. (2) and orofino et al. (16) who reported cases unilaterality of the hypoechoic rim. the association between the hypoechoic rim and a reduction in cortical thickness, excluding conditions of excessive reduction of cortical thickness (as when below to 7 mm or absent ) or ortical thickness ≥ 12 mm is consistent and in the frequent cases where the presence of the hypoechoic rim is inilateral this associaytion is undoubtedly more accurate when compared to the simplest correlation between the presence of the hypoechoic rim and reduction of glomerular filtration rate below 60 ml/min/1.73 m2. although it is true that a reduction in the glomerular filtration rate below 60 ml/min/1.73 m2 it is often accompanied by a cortical thinning it is equally true that in many cases the kidney damage (of all kinds) may be unilateral or otherwise more expressed in one of the two kidneys involving a different cortical thickness between a kidney and the other (as observed in our series, in a kidney cortical thickness may be even normal and in the other completely lost i.e less than 7 mm) while renal function (as assessed by estimated glomerular filtration rate which is calculated from serum creatinine) it is given by the sum of the glomerular filtration rate of each kidney, one of which can compensate completely or in part to the failure of the other. finally our series showed that the hypoechoic rim was absent when the cortical thickness was completely lost i.e less than 7 mm, as is the case of end-stage kidneys, in fact the hypoechoic rim, likewise the thinning of the renal cortex, may be a finding of kidney damage that will disappear when renal function will become negligible or lost and the cortical thickness, at the same time, will shrink. conclusions it is our opinion that, except in cases of fluid overload, the hypoechoic rim, accordingly to the thinning of renal cortex to which it is very well correlated, can be regarded as an expression of damage, probably chronic, of the single kidney in which it is found and therefore it is associated, of course, with a reduction of renal function. to explain the absence of the hypoechoic rim in case of complete loss of cortical thickness (i.e. < 7 mm), we can hypothesize that the presence of the hypoechoic rim may be associated only with an initial phase of renal injury that still has not hesitated in a complete functional loss of the single kidney. it is clear, however, that further trials are needed to confirm this hypothesis. references 1. yassa na, peng m, ralls pw. perirenal lucency (`kidney sweat'): a new sign of renal failure. ajr am j roentgenol. 1999; 173:1075-1077. 2. haddad mc, medawar wa, hawary mm, et al. perirenal fluid in renal parenchymal medical disease (`floating kidney'): clinical significance and sonographic grading. clinical radiology. 2001; 56:979-983. 3. levey as, stevens la, schmid ch, et al. a new equation to estimate glomerular filtration rate. ann intern med. 2009; 150:604-12. 4. haddad mc, hawary mm, khoury nj, et al. radiology of perinephric fluid collections. clinical radiology. 2002; 57:339-346. 5. balci nc, akun e, erturk m, et al. renal-related perinephric fluid collections: mri findings. magnetic resonance imaging. 2005; 23:679-684. 6. o'neill w. c. atlas of renal ultrasonography. 2001 w.b. saunders company. brardi_stesura seveso 04/04/17 09:24 pagina 63 archivio italiano di urologia e andrologia 2017; 89, 1 s. brardi, g. cevenini, r. ponchietti, g. romano, e. duranti 64 7. belli a-m, joseph aea. the renal rind sign: a new ultrasound indication of inflammatory disease in the abdomen. br j radiol. 1988; 61:806. 8. chen j-j, changchien c-s, kuo c-h. causes of increasing width of right anterior extrarenal space seen in ultrasonographic examinations. j clin ultrasound. 1995; 23:287. 9. behan m, kazam e. the echographic characteristics of fatty tissues and tumors. radiology. 1978; 129:143. 10. brammer hm, smith ws, lubbers pr. septated hypoechoic perirenal fat on sonograms: a pitfall in renal ultrasonography. j ultrasound med. 1992; 11:361. 11. heinz-peer g, oettl c, mayer g, et al. hypoechoic perirenal fat in renal transplant recipients. radiology. 1994; 193:717. 12. paivansalo m, huttunen k, suramo i. ultrasono graphic findings in renal parenchymal diseases. scan j urol nephrol. 1985; 19:119. 13. hricak h, cruz c, romanski r, et al. renal parenchymal disease: sonographic-histologic correlation. radiology. 1982; 144:141. 14. emamian sa, nielsen mb, pedersen jf, et al. kidney dimensions at sonography: correlation with age, sex and habitus in 665 adult volunteers. ajr. 1993; 160:83. 15. raj dsc, hoisala, somiah s, et al. quantitation of change in the medullary compartment in renal allograft by ultrasound. j clin ultrasound. 1997; 25:265. 16. orofino l, herrero a, quereda c, et al. perirenal subcapsular fluid collection in a patient with membranous nephropathy and renal vein thrombosis. j urol. 1986; 136:1287-1289. correspondence simone brardi, md sibrardi@gmail.com ennio duranti, md ennio.duranti@libero.it hemodialysis unit, s. donato hospital, arezzo, italy gabriele cevenini, md cevenini@unisi.it department of surgery and bioengineering, university of siena, siena, italy roberto ponchietti, md ponchietti@unisi.it professor of urology, university of siena, siena, italy giuseppe romano, md giuseppe.romano@usl8.toscana.it urology unit, s. maria della gruccia hospital, montevarchi, italy brardi_stesura seveso 04/04/17 09:24 pagina 64 125archivio italiano di urologia e andrologia 2017; 89, 2 original paper influence of hiv virus in the hospital stay and the occurrence of postoperative complications classified according to the clavien-dindo classification and in comparison with the charlson comorbidity index in patients subjected to urologic and general surgery operations. our preliminary results dimitrios dimitroulis 1, georgios karaolanis 2, ioannis katafigiotis 3, ioannis anastasiou 2, viktoria-varvara palla 2, athanasios kontos 4, mordechai duvdevani 5, konstantinos kontzoglou 1 1 2nd department of surgery, laikon general hospital, medical school of athens, greece; 2 1st department of surgery, vascular surgery unit, laikon general hospital, medical school of athens, greece; 3 1st university urology clinic, laiko hospital, medical school of athens, greece; 4 department of pathophysiology, laikon general hospital, greece; 5 department of urology, hadassah hebrew university medical center, greece. objectives: from the first time that human immunodeficiency virus (hiv) was discovered, till today both the quality of life and survival expectancy of hiv-infected patients have markedly improved. as the life expectancy of these patients increases due to the use of highly active anti-retroviral therapy (haart) also increases the number of hiv-positive patient to be subjected to an operation. different studies have examined the occurrence of complications in this particular group of patients and their possible susceptibility to infections or other complications that could lead to increased hospital stay, morbidity and mortality with controversial results. material and methods: we retrospectively analyzed the data of 25 hiv-patients that were subjected to general surgery and urologic operations and we also examined in comparison with the charlson score and their comorbidities the occurrence of complications and subsequently the possibility of an increase hospital stay due to their hiv infection. alongside we classified their complications according to the clavien-dindo and compared these complications in relation to their charlson score and cd4 count. results: 10/25 (40%) of the population had prolonged hospital stay and from this population 6 (6/25) (24%) patients had less than 200 cd4 constituting the aids subpopulation. the decline of the cd4 count showed a tendency for the occurrence of a complication and comorbidities to hiv-positive patients seem to affect more the aids subpopulation. conclusions: although this is a small retrospective study, we tried to classify our complications according to the claviendindo classification and combine the classification to the age adjusted charlson score index of comorbidities. key words: hiv-positive patients and postoperative complications; hiv-positive patients and surgery; hiv-positive patients and clavien-dindo; aids and postoperative complications; hospital stay and surgery to aids patients. submitted 19 february 2017; accepted 23 april 2017 summary no conflict of interest declared. introduction from the first time that human immunodeficiency virus (hiv) was discovered, till today both the quality of life and survival expectancy of hiv-infected patients have markedly improved (1). as the life expectancy of these patients increases due to the use of highly active antiretroviral therapy (haart) also increases the number of hiv-positive patient to be subjected to an operation (2). different studies have examined the occurrence of complications in this particular group of patients and their possible susceptibility to infections or other complications that could lead to increased hospital stay ,morbidity and mortality with controversial results (2-5). we retrospectively analyzed the data of 25 hiv-patients that were subjected to general surgery and urologic operations and we also examined in comparison with the charlson score and their comorbidities the occurrence of complications and subsequently the possibility of an increase hospital stay due to their hiv infection. alongside we classified their complications according to the clavien-dindo and compared these complications in relation to their charlson score and cd4 count. materials and methods results patients characteristics (tables 1, 2) we retrospectively analyzed from the archives of our clinic (general surgery and unit of special infections-laiko hospital) the data of 25 hiv-positive patients (mean age 54.32 years) that were subjected to general surgery and urologic operations operations (tables 1, 2). for the classification of the comorbidities of our patients we used the age-adjusted charlson score and for the classification of our complications the clavien-dindo doi: 10.4081/aiua.2017.2.125 katafigiotis_stesura seveso 20/06/17 09:24 pagina 125 archivio italiano di urologia e andrologia 2017; 89, 2 d. dimitroulis, g. karaolanis, i. katafigiotis, i. anastasiou, v.-varvara palla, a. kontos, m. duvdevani, k. kontzoglou 126 classification. the mean cd4 count was 390.72 and 9/25 (36%) patients (table 1) had less than 200 cd4 preoperatively constituting the aids subpopulation of the hiv positive patients. according to the protocol (table 2) used in the surgery and urology clinic of our hospital the expected hospital stay for the operations of our population is fluctuating between 0 (day cases) to 3 days. two patients were subjected to two operations at the same time, one to cervical lymph node biopsy and radical orchiectomy and the other to cervical lymph node biopsy and hydrocelectomy (table 2). all the comorbidities were classified according to the charlson score (mean charlson score 4.04) and the complications were classified according to the clavien-dindo classification of surgical complications (mean clavien 0.6). the highest clavien score in this population was 3. in total 10/25 (40%) of the population had prolonged hospital stay and from this population 6(6/25) (24%) patients had less than 200 cd4 constituting the aids subpopulation. nine out of 25 (36%) of the total population had 2 additional days of hospital stay and 1/25 (4%) had 3 additional days of hospital stay. the operations in which the prolonged stay occurred are depicted in table 2. all the aids patients with the prolonged stay, 6 out of 25 (24%) had 2 additional days of prolonged stay according to the protocol of the hospital for the specific operations. complications (table 3) our complications are depicted in table 3. twelve out of 25 (48%) patients had postoperatively fever requiring prolonged hospital stay -> (40%). three of these patients had wound infection as the site of the infection and one of them required an opening of the wound at the bedside and a change in the antibiotic from a cephalosporine of 2nd generation to piperacillin and tazobactam while the other two responded to the everyday wound care and to the change of the antibiotic as previously. in total 10 patients (40%) (table 1) had prolonged hospital stay due to fever, including the 3 patients with the wound infection. seven patients had fever without a specific infection and from the 10 patients with fever 5 of them needed not only antipyretics but also an upgrade of the antibiotic from cephalosporin of 2nd generation to piperacillin and tazobactam to stay without a fever while the other 5 responded well only to antipyretics without the need of an antibiotic change. complications in combination with charlson score and clavien (tables 4, 5) even though there wasn’t an absolute relationship between the charlson score and the complications, there was a clear tendency of an occurrence of a complication as the charlson score was higher. six of the 10 patients (60%) (table 4) with complication had more than five points to the charlson score. three of 5 patients with clavien 2 had more than 5 points to the charlson score with the highest having eleven. the lack of an absolute relationship between charslon score and clavien can be depicted from the fact that there was 3 (3/25, 12%) patients with charlson score 6, 9, and 7 respectively without complication and clavien 0, and also there were 2 patients with charlson score 2 and 3 that had a complication with clavien 2. table 1. patients characteristics. number of patients 25 mean age 54.32 years (31-74) mean charlson score 4.04 (0-11) mean clavien 0.6 (0-2) mean cd4 count 390.72 (0-1249) aids/hiv 9/25 (36%) patients (hiv + aids) with prolonged hospital stay 10/25 (40%) patients with hiv (no aids) and prolonged stay 4/25 (16%) patients with aids and prolonged stay 6/25 (24%) patients with 2 days additional stay 9/25 (36%) patients with 1 day additional stay 1/25 (4%) table 2. type of operations. typeof operation patients protocol hospital stay operations with the prolonged stay prolonged hospital stay biopsy of cervical or inguinal 14 0 (daycase) 4 3 patients 2 days (2 additional days or axillary lymph nodes 2 aids patients 1 patient 3 days (3 additional days) biopsy of cervical or inguinal or axillary lymph nodes + radical orchiectomy 1 1 1 1 patient 3 days (2 additional days) aids patient biopsy of cervical or inguinal or axillary lymph nodes + hydrocele 1 0 (daycase) 1 1 patient 2 days (2 additional days) radical orchiectomy 2 1 1 1 patient 3 days (2 additional days) aids patient hydrocele 2 0 (daycase) 1 1 patient 2 days (2 additional days) radical nephrectomy 2 3 1 1 patient 5 days (2 additional days) aids patient perirectal abscess 2 2 1 1 patient 4 days (2 additional days) aids patient circumcision 1 0 (daycase) 0 0 table 3. complications. fever 10/25 (40%) wound infection 3/25 (12%) katafigiotis_stesura seveso 20/06/17 09:24 pagina 126 cd4 count, charlson score, complications and clavien (tables 5, 6) the impact of the cd4 count to the complications and clavien score showed again a clear tendency but not an absolute relationship. the majority of the aids patients that is 6/9 (66.67%) had a complication. aids population with less than 200 cd4 cell/μl automatically had 6 points to the charlson score meaning that the impact of the cd4 count of the aids population to the charlson score was very important regardless the existence of other comorbidities to these patients. even though there were 3 aids patients (< 200 cd4) with no complication and clavien 0, the decline of the cd4 cells showed a tendency for the occurrence of a complication and also for a higher clavien (table 5). seven out of 25 (28%) of the patients with a complication had less than 500 cd4 cells, while only 3 patients (12%) with more than 500 cd4 cells had a complication one with clavien 2 and two with clavien 1. eleven out of 25 (44%) patients didn’t have both comorbidities and complications and only 4/25 (16%) had both comorbidities and complications (table 6). comorbidities seem to affect more the aids population since from the 4 aids patients with comorbidities 3 (75%) had complications, while from the 4 hiv-positive (no aids) patients with comorbidities only one (25%) had complication (table 6). discussion surgical operations to hiv-positive patients constitute a challenge both for the safety of the surgeon and an uneventful postoperative period. in early decades, surgeons were hesitant to perform elective and emergency procedures to this group of patients due to high complication rates (3, 6). the development of haart in the mid-1990s, presented as the cornerstone for the decrease of the morbidity and mortality rates associated with hiv infection in these patients. based on this scientific evolution, several studies continued to estimate the postoperative complication rates according to the clinical status of the patient and the type of operation performed. various risk factors have been implicated and examined for the occurrence of complications to the hiv-patients subjected to operations. the viral load and the history of opportunistic infections may play a significant role in the patient’s assessment. both of these factors depend on the cd4+ lymphocyte counts, the overall immune status, and the survival rate (7). several studies demonstrated that the cd4+ lymphocyte count is clinically relevant with the risk stratification in hiv patients. grubert et al. compared 235 patients with hiv undergoing obstetric and gynecological procedures with 235 hiv-negative patients (8). they came to the conclusion that patients with cd4+ counts of < 200 cells/μl, had a three to four times greater risk of complications after abdominal procedures. later, lin et al. came to support these findings after analysis of 48 hiv-seropositive patients, who underwent abdominal aortic surgical treatment (9). moreover, they found that cd4+ values < 200 cells/μl resulted in an increase in the overall operative morbidity and mortality. we also found a clear tendency of an occurrence of complications as the number of cd4 cells was decreasing (tables 5, 6).the majority of the aids population 6/9 (66,67%) had a complication (table 5). however, the role of cd4+ count as a significant prognostic factor remains debatable, because not all studies have reproduced these findings. harrison et al. have reported differences in the incidence of postoperative wound infections based on cd4+ lymphocyte counts (10). moreover, the cd4+ cell count did not affect the incidence of infection (r = 0.16). even though we had 3 aids patients (< 200 cd4cells/ μl) with no complication (table 5) in our study the decrease of the cd4 cells affected both the charlson score and the occurrence of a complication and as a result the clavien score (tables 4-6). earlier, paiement et al. in a retrospective study came to the conclusion that hiv-seropositive patients had a postoperative infection rate of 16.7% when in the seronegative group the postoperative infection rate was 5.4% (11). when the 127archivio italiano di urologia e andrologia 2017; 89, 2 hiv virus and postoperative complications table 6. aids-hiv patients, comorbidities and complications. aids patients without comorbidities and without complications 2/25 (8%) aids patients with comorbidities without complications 1/25 (4%) aids patients without comorbidities and with complications 3/25 (12%) aids patients with comorbidities and with complications 3/25 (12%) hiv (no aids) patients without comorbidities and without complications 9/25 (36%) hiv (no aids) patients with comorbidities without complications 3/25 (12%) hiv (no aids) patients without comorbidities and with complications 3/25 (12%) hiv (no aids) patients with comorbidities and with complications 1/25 (4%) table 4. charlson and clavien cassification in hiv patients. charlson 0 1 2 3 4 5 6 7 8 9 10 11 clavien 0 5 (20%) 2 (8%) 4 (16%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 2 (8%) 1 (4%) 1 (4%) 1 (4%) 2 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 3 table 5. cd4 count and clavien comparison in hiv patients cd4 cell/μl < 200 200-500 > 500 clavien 1 3 (16%) 0 (0%) 2 (8%) 2 3 (8%) 1 (4%) 1 (4%) 3 katafigiotis_stesura seveso 20/06/17 09:24 pagina 127 archivio italiano di urologia e andrologia 2017; 89, 2 d. dimitroulis, g. karaolanis, i. katafigiotis, i. anastasiou, v.-varvara palla, a. kontos, m. duvdevani, k. kontzoglou 128 hiv-patients suffered from open trauma the estimated infection rate increased at 55.6%. therefore they came to a conclusion that is important to properly identify and optimize the status of cd4+ deficient patients before any elective surgery. in our study the majority of the aids patients 6/9 (66,67%) (table 6) had a complication and even though 3 aids patients with < 200 cd4 had no complication and clavien 0, the decline of the cd4 cells showed a tendency for the occurrence of a complication and also for a higher clavien (table 5). another significant point that many studies underline is the correlation between postoperative wound infections and the length of hospital stay. ferrero et al. in a retrospective study evaluated the complications associated with caesarean section in hiv-infected women (12). because of a higher incidence of major (pneumonia, anaemia) and minor (wound infections) postoperative complications, the median duration of hospital stay (median value 7 days) was significantly higher in the hiv-infected patients compared with the hiv negative. later, drapeau et al. reported that hiv-infected patients who underwent different surgical procedures, had the tendency to develop more surgical site infections (ssi) compared to the general population (13). this complication was the cause for longer hospital stay in this patient group. morrison et al. supported the previous study coming to the conclusion that hiv-infected patients are more likely to develop certain infectious complications and require a longer hospital stay (median value 7.6 days) (14). in our study 10/25 (40%) of the population had prolong hospital stay and from this population 6 (6/25) (24%)patients had less than 200 cd4 constituting the aids subpopulation (table 1). 10/25 (40%) of our patients had postoperatively fever requiring prolong hospital stay (tables 1, 2). 3 of these patients had wound infection as the site of the infection and 1 of them required an opening of the wound at the bedside and a change in the antibiotic from a cephalosporine of 2nd generation to piperacillin and tazobactam while the other two responded to the everyday wound care and to the change of the antibiotic as previously (tables 1-3). hiv patients are more likely to develop infectious complications after surgery due to their immune function deficiency. pneumonia, anaemia, urinary tract infection, surgical wound infection and sepsis are the most common (12). also in our study fever of unknown origin mainly 10/25 (40%) and wound infection were the complications 3/25 (12%) which occurred more frequently (table 3). surgical site infection is the third most frequently reported nosocomial infection and one of the main factors causing patient mortality after surgery (15). the mortality rate of patients with sepsis is 30% to 40% and up to 50% for those with severe sepsis or septic shock (1, 16). in an attempt to reduce the postoperative complications in hiv-patients, a recent study reported specific guidelines for treatment (17). patients with preoperative cd4+ counts < 200 cells/μl, antibiotic and antifungal medication (sulfamethoxazole and fluconazole) should be administrated preoperatively as a prophylaxis against pneumocystis carinii pneumonia and fungal infection. moreover, in those with deep incisional or organ space infections, administration of appropriate antibiotics in combination with the removal the purulent tissue, is needed. patients with incisional infections do not require long term use of antibiotics but their incisions should be kept clean (17). 5 of our 10 patients with fever needed an upgrade to the antibiotic from cephalosporin of 2nd generation to piperacillin and tazobactam while the other 5 remained without a fever with the use only of antipyretics. finally it is important to highlight that the presence of comorbidities though showed a clear tendency to increase the occurrence of a complication (tables 5, 6) since 6 of the 10 patients (60%) (table 4) with complication had more than five points to the charlson score, this wasn’t an absolute relationship since 3 (3/25, 12%) patients with charlson score 6, 9, and 7 respectively had no complication and clavien 0, and also 2 patients with charlson score 2 and 3 that had a complication with clavien 2. aids population was affected more from the presence of comorbidities and 3 out of 4 aids patients (75%) with comorbidities had complications, while 1 out 4 hiv-positive (no aids) patients (25%) with comorbidities had a complication (table 6). conclusions although this is a small retrospective study, we tried to classify our complications according to the claviendindo classification and combine the classification to the age adjusted charlson score index of comorbidities. our hiv-positive patients stayed 2.08 days more than expected, the decline of the cd4 count showed a tendency for the occurrence of a complication and comorbidities to hiv-positive patients seem to affect more the aids subpopulation. as far as we have reviewed the literature this is the first paper submitted concerning hiv virus and postoperative complications. references 1. drapeau cm, pan a, bellacosa c, cassola g, et al. surgical site infections in hiv-infected patients: results from an italian prospective multicenter observational study. infection. 2009; 37:455-60. 2. abalo a, patassi a, james ye, et al. risk factors for surgical wound infection in hiv-positive patients undergoing surgery for orthopaedic trauma. j orthop surg. 2010; 18:224-7. 3. emparan c, iturburu im, ortiz j, mendez jj. infective complications after abdominal surgery in patients infected with human immunodeficiency virus: role of cd4+ lymphocytes in prognosis. world j surg. 1998; 22:778-782. 4. davis pa, corless dj, gazzard bg, wastell c. increased risk of wound complications and poor healing following laparotomy in hiv-seropositive and aids patients. dig surg. 1999; 16:60-7. 5. morandi e, merlini d, salvaggio a, et al. prospective study of healing time after hemorrhoidectomy: influence of hiv infection, acquired immunodeficiency syndrome, and anal wound infection. dis colon rectum. 1999; 42:1140-4. 6. huang wc, kwon eo, scardino pt, eastham ja. radical prostatectomy in patients infected with human immunodeficiency virus. bju int. 2006; 98:303-307. 7.mellors jw, rinaldo cr jr, gupta p, et al. prognosis in hiv-1 katafigiotis_stesura seveso 20/06/17 09:24 pagina 128 infection predicted by the quantity of virus in plasma. science. 1996; 272:1167-70. 8. grubert ta, reindell d, kastner r, et al. rates of postoperative complications among human immunodeficiency virus-infected women who have undergone obstetric and gynecologic surgical procedures. clin infect dis. 2002; 34:822-30. 9. lin ph, bush rl, yao q, et al. abdominal aortic surgery in patients with human immunodeficiency virus infection. am j surg. 2004; 188:690-7. 10. harrison wj, lewis cp, lavy cb. wound healing after implant surgery in hiv-positive patients. j bone joint surg br. 2002; 84:802-6. 11. paiement gd, hymes ra, ladouceur ms, et al. postoperative infections in asymptomatic hivseropositive orthopedic trauma patients. j trauma. 1994; 37:545-51. 12. ferrero s1, bentivoglio g. post-operative complications after caesarean section in hiv-infected women. arch gynecol obstet. 2003; 268:268-273. 13. morrison ca, wyatt mm, carrick mm. effects of human immunodeficiency virus status on trauma outcomes: a review of the national trauma database. surg infect. 2010; 11:41-7. 14. owens cd, stoessel k. surgical site infections: epidemiology, microbiology and prevention. j hosp infect. 2008; 70(suppl 2):3-10. 15. shapiro ni, howell m, talmor d. a blueprint for a sepsis protocol. acad emerg med. 2005; 12:352-359. 16. cheng b, xie g, yao s, et al. epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in china. crit care med. 2007; 35:2538-2546. 17. liu bc, zhang l, su js, et al. treatment of postoperative infectious complications in patients with human immunodeficiency virus infection. world j emerg med. 2014; 5:103-6. 129archivio italiano di urologia e andrologia 2017; 89, 2 hiv virus and postoperative complications correspondence dimitrios dimitroulis, md dimitroulisdimitrios@yahoo.com konstantinos kontzoglou, md kckont@med.uoa.gr 2nd department of surgery, laikon general hospital, medical school of athens, athens, greece georgios karaolanis, md drgikaraolanis@gmail.com ioannis anastasiou, md viktoria-varvara palla, md vickypalla21@gmail.com 1st department of surgery, vascular surgery unit, laikon general hospital, medical school of athens, athens, greece ioannis katafigiotis md, mls, phd, febu (corresponding author) katafigiotis.giannis@gmail.com 1st university urology clinic, laiko hospital, medical school of athens ag. thoma 17 11527 athens, greece athanasios kontos, md medkontos@gmail.com department of pathophysiology, laikon general hospital, athens, greece mordechai duvdevani, md moti_duv@yahoo.com department of urology, hadassah hebrew university medical center, athens, greece katafigiotis_stesura seveso 20/06/17 09:24 pagina 129 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2142 original paper short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence aybuke ersin 1, sule b. demirbas 2, fatih tarhan 3 1 istanbul medipol university, institute of health sciences, department of physiotherapy and rehabilitation, istanbul, turkey; 2 yeditepe university, faculty of health sciences, department of physiotherapy and rehabilitation, istanbul, turkey; 3 health sciences university, dr. lutfi kirdar training and research hospital, urology clinic, istanbul, turkey. aim: the aim of this non-controlled trial was to investigate the effects of a homebased pelvic floor muscle training (pfmt) and bladder training (bt) in urinary incontinence (ui) among women. patients and methods: the study included 25 individuals who were diagnosed with ui. pfmt which strengthens pelvic floor muscles was described to patients in litotomy position with using digital palpation method. pfmt was given as homebased exercise program for six weeks, 7 days a week and ten times a day. bt was planned according to the symptoms of the patients. assessments were done at the beginning and at the end of the six weeks exercise program. the outcome measures were ui severity measured by pad test and qol measured by king’s health questionnaire. the secondary outcome measure was lower urinary tract symptoms and sexual health measured by bristol female lower urinary tract symptoms index. results: preand post-treatment assessments done with pad test showed that there was a statistically significant decrease in the severity of ui (p = 0.002). the difference between pre and post-treatment qol scores (p = 0.001) and lower tract symptom scores were also statistically significant (p = 0.000). conclusions: when pfmt and bt were given together there was a decrease in the symptoms and increases the qol. key words: urinary incontinence; pelvic floor muscle training; bladder training; physiotherapy. submitted 25 october 2019; accepted 12 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.142 introduction international urogynecological association and the international continence society (iuga/ics) defined urinary incontinence (ui) as the complaint of involuntary loss of urine. there are three main types of ui in women: stress urinary incontinence (sui), urgency urinary incontinence (uui), and mixed urinary incontinence (mui). sui is defined as the involuntary loss of urine during sneezing, coughing, or other types of physical effort; uui is characterized by involuntary loss of urine related with urgent conditions; mui is the mixture of stress and urge ui (1). although ui is not a life-threatening problem among women, it effects the physical and psychological aspects of social life. because of these reasons the problem should be handled meticulously (2). ui is more common in women than in men. studies from different countries report a prevalence of ui in the range of 25% to 45% in adult women (3). ui was reported as 38.7% of women and 9.9% of men in turkey (4). although many conservative approaches are available for treating female ui, pelvic floor muscle training (pfmt) and bladder training (bt) are the most popular, of which pfmt is recommended as the first-line therapy. numerous studies have reported the effectiveness of either bt or pfmt singly for treating the female ui. at present, only one randomized clinical trial and one pragmatic non-randomized controlled trial have been conducted regarding the efficacy of adding pfmt to bt for treating ui (5, 6). in this study, we aimed to investigate the effects of a six week home based pfmt and bt program in women with ui. materials and methods design the study was approved by the local ethics committee of health sciences university dr. lutfi kirdar training and research hospital (istanbul, turkey; approval no: 2014/05, 514/43/6), and all participants submitted written informed consent. our study started with thirty-six patients and ended up with twenty five patients who completed the 6-week program (figure 1). the ui was diagnosed by the urologist and the assessment and the therapy were done by the physiotherapist. patients women in the 25-75 age range, with ui diagnoses were included in the study. those who had cancer, neurological disorders, pregnancy, pelvic organ prolapse, mental retardation or uro-gynecologic operation in the last six months were excluded. evaluation patients age as year and body mass index (bmi) as kg/cm2 were recorded. patients were questioned about their education, profession and smoking habits. their obstetric histories were also recorded. quality of life (qol) and 143archivio italiano di urologia e andrologia 2020; 92, 2 short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence ui effects were tested by king’s health questionnaire (khq), severity of incontinence by pad test, lower urinary tract symptoms and sexual health conditions by bristol female lower urinary tract symptoms index (b-fluts). the patients were assessed in the beginning and at the end of the program. they filled out an exercise follow up chart during home exercises and these charts were examined at the end of the 6-week program. khq consists of 8 sections. these are role limitation, physical limitation, social limitation, personal relationship, emotions, sleep, energy and incontinence severity (5). b-fluts is a questionnaire used for the assessment of lower track urinary system symptoms, sexual health and qol (7). pad test is one of the most objective tests which shows the existence of ui and its severity. it is used extensively in the diagnosis of incontinence and in the evaluation of the therapy. the 1-hour pad test which was standardized by ics in 1983 is the most frequently used test (8). the patients, after taking 500 cc water, were asked to use pre-weighed pads during the test period. during the test period the patients were asked to cough, sit to stand and climb stairs several times which increase the abdominal pressure or stimulate detrusor contractions. at the end of the test, if the weight difference of the pad was less than 2 grams it was rated as normal; if it was between 2-10 grams as mild, 10-50 grams as moderate, over 50 grams as severe incontinence (9). treatment the patients were informed about the structure and function of the lower urinary system. pfmt which strengthens pelvic floor muscles was described to patients in lithotomy position by using digital palpation method. patients completed a home-based exercise program consisting of strength and endurance training. they were taught both fast (5-s) and slow voluntary pelvic floor muscle contractions (vpfmcs). one slow contraction took 15 s (5-s contraction, 5-s hold, 5-s relaxation). one set of exercises involved ten fast and ten slow vpfmcs. during the program, patients were instructed to perform ten sets of exercises per day. the patients were asked to do the exercise in the supine, seated, and upright positions. they were supposed to integrate these exercises into their daily living activities. pfmt chart was given to every patient to remind them of exercise and to discipline them. the aim was to decrease the frequency of urination and to increase the capacity of the bladder. special bt was planned according to the patients’ urgency symptoms. in bt the patients were asked to keep away from bladder irritant fluids (coffee, tea, coke, lemonade etc.) and not to limit the water intake. extension of the urination intervals were done gradually during the six weeks period. in order to help increase the intervals, the patients were taught some control techniques for urgencies. in these techniques the patients were asked to contract the pelvic floor, to take deep and slow breaths and to think of something different in order to repress the feeling of urgency. statistical analyses statistical analyses were performed using spss software (statistical package for social sciences) version 21.0. during the evaluation of the data student’s t-test, paired sample t-test, wilcoxon signed-rank test were used for comparison of quantitative data along with descriptive statistical methods (mean, standard deviation, frequency). mcnemar’s test was used for comparison of qualitative data. multiple regression analysis was used to determine risk factors. confidence interval which was 95% and p < 0.05 were considered significant. results mean age, bmi, number of births, abortions and miscarriage were respectively: 47.6 ± 10.12 years (min 28 max 73); 30,8 ± 5,88 kg/m2 (min 20.2 max 42.97); 3 ± 2.1 (0-10); 1.04 ± 1.24 (0-4); 0.2 ± 0.64 (0-3). 92% gave birth at least one child with 76% giving natural birth and 16% with sectio. 8% did not give birth (table 1). 15 women had sui, 7 women uui, 8 women mui. preand post-treatment assessments with pad test showed that the incontinence severity decreased statistically and khq showed significant increase in the qol (table 2). the difference between preand post-treatment scores of ui was statistically significant. statistical analyses figure 1. flow of participants. archivio italiano di urologia e andrologia 2020; 92, 2 a. ersin, sule b. demirbas, f. tarhan 144 showed us that an increase in bmi can cause increased of incontinence severity. participants reported that their urination frequency had decreased and sexual health had improved as well. discussion the aim of the study was to investigate the effects of a home-based pfmt and bt in ui among women. it was found that 6-week pfmt and bt was effective in the decrease of ui symptoms and increase in qol. in a study by fan et al. the mean of age was 52.3 years and they found that age did not have any influence on the effectiveness of pfmt. our mean age was 47.6 years and we found similar results as far as the mean age and the effectiveness were concerned (10). in their study kaya et al. compared bt with the bt+ pfmt complex and showed that a short term (6 weeks) complex approach was more effective, which was also supported by our results (5). ahlund et al. chose digital palpation technique in order the teach their patients to contract their pelvic floor muscle in the most accurate way. in their study they also gave information about anatomy and physiology of the pelvic floor and ui to their patients. they informed that they achieved accurate muscle contraction in 66% of their patient (11). moen et al. informed that they achieved accurate muscle contraction in 70% of their patients by digital palpation (12). in our study we used digital palpation in order to teach pelvic floor muscle contraction. we gave information about anatomy and physiology of the pelvic floor. even though it was not evaluated statistically, we observed that our patients learned accurate contraction of pelvic floor muscle. mommsen et al. showed that bmi was related to ui values (13). our study showed that bmi increases severity of ui and supported the literature. kaya et al. reported an increase in the qol of the patients (5) and our study showed the same result. vaz et al. conducted a combined pfmt and ct program in the same manner as us and reported positive results in the quality of life and incontinence in 6 weeks. they also stated that there was no difference in efficacy between home-based program and health center treatment. our study similarly demonstrated the success of the 6-weeks home-based program (6). in our study, we used the khq to evaluate the symptomspecific qol. the validity and reliability of the turkish version of this questionnaire, which was first developed in urinary incontinence, had been proved by akkoç et al. (7). the khq was used in studies in pelvic floor muscle strengthening exercises designed similarly to our study. neumann et al. used the khq to determine changes in the qol before and after treatment (14). b-fluts, which we used to evaluate filling, voiding and incontinence symptoms and sexual functions, was found to be valid and reliable by gökkaya et al. it is an effective index to determine the success of the treatment (8). bø et al. used bfluts to investigate the effects of pelvic floor muscle exercises in qol and sexual problems (15). also ahlund et al. used bfluts to evaluate urinary incontinence symptoms and sexual functions (10). in our study, bfluts was used to evaluate the symptoms of lower urinary tract before and after treatment and a statistically significant difference was observed which also supported by the literature. ahlund et al. reported that their patients had decreased ui symptoms based on their feedback based on their patients’ feedbacks ahlund et al. reported that the ui symptoms had reduced (10). we also had the same results from the feedbacks of our participants that reported that they were feeling better. when we overviewed the limitations of our study, one of them was that the patients were not statistically classified and evaluated according to their incontinence type. if we had greater number of patients we would have stronger statistical results. the other limitation of our therapy program was that long-term results were not evaluated along with the short-term results. in order to reach a definitive conclusion, randomized controlled trials with larger sample numbers are needed. conclusions to sum up, pelvic floor muscle training and bladder training, together result in reducing the symptoms and in increasing the quality of life. by combining these two approaches a home based exercise program, the therapy becomes more effective, cheaper, safer and quicker in achieving the result. acknowledgments the authors would like to thank ayse ardali and burcu ardali gurcay for editing the english translation of this article. funding: the authors declare no funding about this project. table 1. characteristics of individuals. characteristic mean sd* age (years) 47.6 10.12 bmi (kg/m2) 30.8 5.88 parity 3 2.1 abortion 1.04 1.24 misscarriage 0.2 0.64 *standard deviation. table 2. outcomes of pre&post treatment on incontinence severity, quality of life and lower urinary tract symptom. before treatment after treatment mean s.d. min max mean s.d. min max p* pad test (g) 36.24 46.19 0 213 13.28 16.65 0 70 0.002 khq scores 544.26 185.14 150 888.8 361.31 237.73 0 900 0.001 b-fluts scores 51.04 13.3 18 72 37.04 14.2 11 72 0.000 *comparison between pre and post treatment. s.d: standard deviation. khq: king’s health question. b-fluts: bristol female lower urinary tract symptoms index. 145archivio italiano di urologia e andrologia 2020; 92, 2 short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence conference presentation: part of this paper was presented at the iuga (international urogynecological association) 40th annual scientific meeting 9-13 june 2015, nice, france. references 1. haylen bt, de ridder d, freeman rm, et al. international urogynecological association (iuga)/international continence society (ics) joint report on the terminology for female pelvic floor dysfunction. neurourol urodyn. 2010; 29:4-20. 2. can t, yagci n, cavlak u. effects of urinary incontinence on depressive symptoms and quality of life in women with reproductive age. fizyoter rehabil. 2012; 23:83-89. 3. milsom i, altman d, cartwright r, et al. epidemiology of urinary incontinence (ui) and other lower urinary tract symptoms (luts), pelvic organ prolapse (pop) and anal (ai) incontinence. in: abrams p, cardozo l, wagg a, wein, a. (eds) incontinence 6th edition. iciics. international continence society, bristol uk, isbn: 978 0956960733; 2017. 4. zumrutbas ae, bozkurt ai, tas e, et al. prevalence of lower urinary tract symptoms, overactive bladder and urinary incontinence in western turkey: results of a population-based survey. int j urol. 2014; 21:1027-1033. 5. kaya s, akbayrak t, gürsen c, beksac s. short-term effect of adding pelvic floor muscle training to bladder training for female urinary incontinence: a randomized controlled trial. int urogynecol j. 2015; 26:285-93. 6. vaz ct, sampaio rf, saltiel f, figueiredo em. effectiveness of pelvic floor muscle training and bladder training for women with urinary incontinence in primary care: a pragmatic controlled trial. braz j phys ther. 2019; 23:116-24. 7. akkoc y, karapolat h, eyigor s, et al. quality of life in multiple sclerosis patients with urinary disorders: reliability and validity of the turkish version of king’s health questionnaire. neurol sci 2011; 32:417-421. 8. gokkaya cs, öztekin cv, doluoglu og, et al. index validation of turkish version of bristol female lower urinary tract symptom index. j clin anal med. 2012; 3:415-8. 9. kaya s. comparison of different treatment modalities in patients with idiopathic detrusor overactivity: physical therapy and rehabilitation, medical treatment. degree msc., hacettepe university, ankara, turkey; 2008. 10. fan hl, chan ssc, law tsm, et al. pelvic floor muscle training improves quality of life of women with urinary incontinence: a prospective study. aust n z j obstet gynaecol. 2013; 53:298-304. 11. ahlund s, nordgren b, wılander e, et al. is home-based pelvic floor muscle training effective in treatment of urinary incontinence after birth in primiparous women? a randomized controlled trial. nordic federation of societies of obstetrics and gynecology, acta obstet gynecol scand. 2013; 92:909-915. 12. moen md, noone mb, vassallo bj, elser dm. pelvic floor muscle function in women presenting with pelvic floor disorders. int urogynecol j pelvic floor dysfunct 2009; 22:654-8. 13. mommsen s, foldspang, a. body mass index and adult female urinary incontinence. world j urol 1994; 12:319-322. 14. neumann pb, grımmer ak, grant re, gill va. physiotherapy for female stress urinary incontinence: a multicentre observational study. aust n z j obstet gynaecol. 2005; 45:226-232. 15. bø k, talseth t, vınsnes a. randomized controlled trial on the effect of pelvic floor muscle training on quality of life and sexual problems in genuine stress incontinent women. acta obstet gynecol scand 2000; 79:598-603. correspondence aybuke ersin, md istanbul medipol university göztepe mah. atatürk cad. no: 40/16, 34815 beykoz, !stanbul aybukeu2011@gmail.com sule b. demirbas, md yeditepe university, faculty of health sciences, department of physiotherapy and rehabilitation, istanbul, turkey fatih tarhan, md health sciences university, dr. lutfi kirdar training and research hospital, urology clinic, istanbul, turkey 203archivio italiano di urologia e andrologia 2017; 89, 3 original paper etiological factors and management in priapism patients and attitude of emergency physicians mehmet giray sönmez 1, leyla öztürk sönmez 2, hakkı hakan taşkapu 1, cengiz kara 3, zerrin defne dündar 2, yunus emre göğer 1, togay evrin 4, ahmet öztürk 1 1 department of urology, meram medical faculty, necmettin erbakan university, konya, turkey; 2 department of emergency medicine, meram medical faculty, necmettin erbakan university, konya, turkey; 3 department of urology, medical park ankara hospital, ankara, turkey; 4 department of emergency medicine, ufuk university medical faculty, ankara, turkey. objective: to present the underlying etiological factors in patients referring with priapism, sharing how they are managed according to etiology and priapism type together with our experiences, creating awareness so that urologists and emergency physicians may play a more active role together in priapism management. materials and methods: patients referring to emergency service with priapism were examined. penile doppler ultrasonography (pdu) and/or corporeal aspiration and blood gas analysis were made in order to determine priapism type after anamnesis and physical examination. the most appropriate treatment option was chosen and applied on the patients considering priapism type, underlying etiological factors and priapism time. presence of a statistical difference between etiological factors causing priapism, priapism type and applied treatment methods was calculated using chi square (χ2) test. results: a total of 51 patients referring to emergency service with priapism attacks for 53 times were included in the evaluation.when compared to other etiological factors, number of priapism cases developing secondary to papaverine after pdu was found statistically significantly high (p < 0.001). ischemic priapism ratio was detected statistically higher compared to other groups (p < 0.001). aspiration and/or irrigation treatment were the most common method used for treatment at a statistically significant level (p < 0.001). all patients (100%) were hospitalized in urology service without applying any treatment in emergency service and had treatment and intervention under the control of the urologist. conclusions: application of non-invasive treatments in suitable priapism patients would protect patients from invasive painful interventions. we believe that emergency physicians should be more effective in priapism phase management and at least noninvasive treatment phase. key words: priapism; prolonged erection; emergency. submitted 14 june 2017; accepted 15 july 2017 summary no conflict of interest declared. result in permanent erectile dysfunction unless treated quickly. even though the incidence is rare (0.31.5/100.000), it is more common in males than females. it is frequent in 20-50 age group of males (3, 4). although the possible causes of priapism differ according to priapism types, it is observed that they are mostly related to idiopathic and iatrogenic causes. alcohol, medicine, drug use (21%), perineal trauma (12%) and sickle cell nephropathy (5%) are other possible etiological causes in order (4). among iatrogenic priapism causes, penile papaverine application made for penile doppler ultrasonography (pdu) used most commonly for erectile dysfunction diagnosis and use of phosphodiesterase 5 enzyme (pde5) inhibitors used for erectile dysfunction treatment are responsible (5, 6). in order to be able to start priapism treatment, it is required to present priapism etiology primarily. there are three different types of priapism: ischemic (veno-occlusive, low flow), non-ischemic (arterial, high flow) and stuttering (recurrent) priapism. pathophysiological causes and treatment methods of every priapism type are different (3). although priapism patients routinely refer to emergency service, patient management is frequently made by urologists. it is observed that generally emergency physicians demand urology consultation before intervening these patients. the aim of this study is to present underlying etiological factors causing pathology in patients referring with priapism and sharing how these patients are managed according to the etiology and priapism type together with our experiences. at the same time, our aim was to create awareness so that emergency physicians may also actively participate in priapism management together with urologists. materials and methods without any relief through orgasm and ejaculation, erection state lasting longer than 4 hours was defined as priapism. patients referring to emergency services between october 2006 and november 2016 were examined. a total of 51 patients referring to emergency service in two centers with a total of 53 priapism attacks were included doi: 10.4081/aiua.2017.3.203 introduction priapism takes its name from god priapus who is the symbol of virility and fertility in ancient greek culture and is constantly in the state of erection (1). priapism is a painful erection condition of penis or clitoris lasting more than four hours without sexual desire. glans and corpus spongiosum do not participate in this period (2). although observed rarely, it is one of the urological emergency pathologies. it is an urgency which may sonmez_stesura seveso 28/09/17 10:20 pagina 203 archivio italiano di urologia e andrologia 2017; 89, 3 m. giray sönmez, l. öztürk sönmez, h. hakan taşkapu, c. kara, z. defne dündar, y. emre göğer, t. evrin, a. öztürk 204 in the evaluation. in the anamnesis of these patients, erection duration, previous priapism story, medicine, drug, alcohol use, phosphodiesterase type 5 inhibitor use (pde5 inh), penile doppler ultrasonography (pdu) story, penile papaverine and intracavernosal medicine application during or apart from pdu, presence of sickle cell anemia, trauma history, previous penile surgery, urinary system surgery and vertebra surgery story were questioned. all patients were examined physically after anamnesis. continuation/discontinuation of erection, accompanying pain, presence of rigid erection, color of the penis, color and tissue changes for considering permanent circulation disorder in penis were evaluated. penile doppler ultrasonography and/or corporeal aspiration and blood gas analysis were made in order to determine priapism type. blood count, prothrombin time and activated partial thromboplastin time were studied in order to evaluate possible hematological parameters in patients. the most appropriate treatment option was chosen and applied on the patients considering priapism type, underlying etiological factors and priapism time. statistical analysis statistical analysis was performed with spss 15.0 for windows version 15.0 (spss inc., chicago, il, usa). presence of a statistical difference between etiological factors causing priapism, priapism type and applied treatment methods was calculated using chi square test (x2). p < 0.05 was used as a threshold for statistical significance. results a total of 51 patients referring to emergency service in two centers with a total of 53 priapism attacks between october 2006 and november 2016 were included in the evaluation. mean age of the patients was measured as 47.2 (10-69). mean priapism duration was detected as 17.68 (5-104) hours. in relation to etiology, priapism was observed after doppler ultrasonography (secondary to intracavernosal 60 mg papaverine application) in 31 patients (60.7%), after pde5 inhibitor use in nine patients (17.6%), secondary to urethral intervention in two patients (3.9%), after pelvic trauma in two patients (3.9%), pelvic mass related in one patient (1.88%), antipsychotic drug use related in one patient (1.88%) and related to unexplainable idiopathic causes since no cause was found in five patients (9.8%). when compared to other etiological factors, number of priapism cases developing secondary to papaverine after pdu was found statistically significantly more frequent (p < 0.001). according to the penile doppler ultrasonography and/or corporeal aspiration with blood gas analysis and the patient's clinic, four out of 53 priapism attacks (7.5%) were stutter (two attacks each for two patients), three (5.6%) were non-ischemic and 46 were ischemic priapism (86.7%). ischemic priapism ratio was detected statistically more frequently compared to other groups (p < 0.001). in the etiology of non-ischemic type of patients, two patients had pelvic trauma and one patient had urethral intervention. among two stutter type of patients, one had overdose pde5 use and one had idiopathic etiology. general information for priapism patients are available in table 1. all patients (100%) had urology consultation, were hospitalized in urology service without applying any treatment in emergency service and had treatment and intervention under the control of the urologist. during the treatment of 53 priapism attacks, one nonischemic priapism patient with pelvic trauma etiology was treated with pudendal artery micro-embolization by interventional radiology, two patients with 4 stutter attacks were orally given pseudoephedrine 60 mg+diazepam 5 mg+ketoconazole 200 mg and two non-ischemic priapism patients were orally given pseudoephedrine 60 mg. four ischemic priapism patients were given pseudoephedrine 60 mg+ diazepam 5 mg medical treatment. but since detumescence was not provided, corporeal aspiration and/or phenylephrine irrigation were applied to a total of 46 patients including these four patients (200 mcg/ml, maximum: 1 mg). for corporeal aspiration and irrigation, a transcavernosal 18 gauge needle was placed percutaneously into the lateral aspect of the proximal penile shaft. aspiration and evacuation of blood from the corpora cavernosa were performed with irrigation of normal saline followed by irrigation with phenylephrine (200 ug/ml) in saline and administered intermittently as 1.0 ml, every 35 min to a maximum dosage of 1 mg. detumescence was provided in 39 patients through aspiration and/or irrigation. spongiocavenous (distal) shunt was applied to seven patients unresponsive to aspiration and irrigation. winter shunt and t shunt were applied as spongiocavernous shunt. safenocavernous (proximal) shunt was applied to three patients not benefitting from this approach. aspiration and/or irrigation treatment were the most common method used for treatment at a statistically significant table 1. general information of patients. p value* number of patients 51 number of priapism attacks 53 mean age (years) 47.2 (10-69) mean priapism duration (hours) 17.68 (5-104) mean hospitalization duration (hours) 19.2 (4-215) etiology (n = 51) pdu: 31 (60.7%) < 0.001 pde 5 inh.: 9 (17.6%) idiopathic: 5 (9.8%) urethral intervention: 2 (3.9%) pelvic trauma: 2 (3.9%) pelvic mass: 1 (1.88%) antipsychotic drugs: 1 (1.88%) priapism type (n = 53) ischemic: 46 (86.7%) non-ischemic: 3 (5.6%) stutter: 4 (7.5%) < 0.001 pdu: penile doppler ultrasonography; pde5: phosphodiesterase 5 enzyme inhibitors; *chi square(χ2) test. sonmez_stesura seveso 28/09/17 10:20 pagina 204 level (p < 0.001). mean hospitalization time of the patients was measured as 19.2 hours (4-215). number of the patients and the study flow chart in each step are demonstrated in figure 1. discussion priapism was published in 1845 for the first time in modern medicine literature (7). recurrent priapism was defined in 1980 together with sickle cell anemia cases (8). after that it became a pathology covering a wide range of the studies in literature. during the first referral of priapism patient, priapism duration, possible etiological factors, previous priapism story, presence of accompanying pain should be questioned and penile doppler ultrasonography and/or corporeal aspiration with blood gas analysis should definitely be made in order to determine priapism type (2, 3). there are three different types of priapism: ischemic (veno-occlusive, low flow), non-ischemic (arterial, high flow) and stuttering (recurrent) priapism. pathophysiological causes and treatment methods of every priapism type are different. there is no or very low arterial flow in corpus cavernosum in ischemic priapism (ip). in non-ischemic priapism, cavernosal flow can be normal, high or irregular and arteriosinusoidal fistule or pseudoaneurism may be observed. stuttering priapism has repetitive, spaced erections (1-4). ischemic priapism 205archivio italiano di urologia e andrologia 2017; 89, 3 priapism management figure 1. number of the patients and the study flow chart in each step. sonmez_stesura seveso 28/09/17 10:20 pagina 205 archivio italiano di urologia e andrologia 2017; 89, 3 m. giray sönmez, l. öztürk sönmez, h. hakan taşkapu, c. kara, z. defne dündar, y. emre göğer, t. evrin, a. öztürk 206 is the most common type among priapism types. ischemic priapism constitute 95% of all priapism cases. it is characterized by painful erection accompanied by significant permanent hardness in corpus cavernosum due to venous blood exit disorder. occurrence of hypoxia, hypercapnia and acidosis is similar to penile compartment syndrome and this situation may cause tissue damage. in ischemic priapism, the ultrastructural changes in cavernosal flat muscle are observed 12 hours later, focal necrosis 24 hours later and finally necrosis and transformation of wide necrosis and fibroblast-like cells are observed 48 hours later. thus emergency inspection and management are required and delayed treatment may cause total erectile dysfunction (ed) (2-4). in the patient group in this study, ischemic priapism ratio was detected as 86.7%. there is an increase in priapism cases recently due to the frequent use of phosphodiesterase 5 enzyme (pde5) inhibitors in ed treatment and to penile doppler ultrasonography (pdu) generally accompanied by intracavernosal papaverine injection used for erectile dysfunction (ed) diagnosis. prolonged erections after intracavornosal injection may be seen with a ratio of 5-35% (9). in our priapism patient group, intracavernosal injection related priapism accounted for 60.7% and priapism developing after pde 5 use for 17.6% of cases. all patients were using papaverine in priapism occurring due to intracavernosal injections. idiopathic causes with a ratio of 9.8%, urethral intervention and pelvic trauma with 7.5%, antipsychotic drug use with 1.96% and pelvic mass with 1.96% played a role in etiology in this order. one of the most common causes of priapism is sickle cell disease (10). interestingly, sickle cell disease was not detected as etiology in any of the patients in our group. this may be due to the fact that these patients were generally followed up by hematology department and were referred to their own hematologists or to child emergency service since they had their first attack between the ages 15 and 18 generally. suggestions of european association of urology guidelines and american urological association guidelines were used for the treatment of all patients (2, 11). spontaneous resolution ratio is 62% with follow-up in non-ischemic priapism treatment and selective artery embolization can be made on demand (12). we followed up one patient with selective artery embolization and two patients with pseudoephedrine treatment in this group. a complete response was obtained in all three patients. it is recommended to manage stutter priapism like priapism (13). medical agents such as pseudoephedrine, ketoconazole, gnrh agonists and 5-alpha reductase inhibitors were used for priapism attack and for preventing the attack (2, 12, 14). we applied pseudoephedrine+benzodiazepine+ketoconazole medical treatment for our stutter priapism patients and we were successful in the treatment of four attacks. time is important in ischemic priapism since serious complications may occur. so aspiration and/or irrigation should be the primary treatment. primarily distal and then proximal shunt treatments should be used in irresponsive cases. penile prosthesis may provide an effective treatment to preserve penile length in ischemic priapism patients not responding to conventional treatment (15). penile prosthesis application was not required in any of the patients in this study. non-invasive treatment approaches are recommended for ischemic priapism in current studies. habous et al. provided detumescence in 34% of priapism patients in 60 minutes with salbutamol 4 mg oral treatment which is a β2 adrenergic agonist (9). lowe and jarow compared terbutaline which is a x2 adrenergic agonist and pseudoephedrine which is βand β2-adrenergic agonist in priapism patients and with a respond ratio of 38% with terbutaline and 28% with pseudoephedrine (16). due to their antiandrogenic effect, gonadotropin-releasing hormone agonists, estrogens, antiandrogens and 5α-reductase inhibitors can also be used as non-invasive medical treatment of priapism (2, 3). we recommend the use of these medicines in early-period priapism and stutter type priapism especially. this is due to the fact that delay in ischemic priapism treatment especially may result in permanent erectile dysfunction in the patient. especially in case of the patient being responsive to the application of symptomatic medicines such as terbutaline, salbutamol and pseudoephedrine during the first intervention in emergency service, the patient would be saved from an invasive intervention. emergency physicians generally leave priapism intervention to urologists in turkey. in our study, treatment of all patients were managed by urologists. since patients primarily refer to emergency service for priapism which is among the important urological emergencies, we believe that emergency physicians should have a good mastery of non-invasive and invasive treatment protocols for priapism and have equipment to provide required intervention on this. conclusions underlying etiological factors and priapism type should definitely be determined before starting priapism management. application of non-invasive treatments in suitable patients would protect patients from invasive painful interventions. we believe that emergency physicians be more effective in priapism first phase management and at least in non-invasive treatment. deficiencies during this phase may be made up through common education programs in urology and emergency medicine clinics. references 1. kadıoglu a, sanlı ö, ersay a, et al. practical management of priapism. turkish j urol. 2006; 32:182-192. 2. salonia a, eardley i, giuliano f, et al. european association of urology guidelines on priapism. eur urol. 2014; 65:480-9. 3. shigehara k, namiki m. clinical management of priapism: a review. world j mens health. 2016; 34:1-8. 4. song ph, moon kh. priapism: current updates in clinical management. korean j urol. 2013; 54:816-23. 5. coombs pg, heck m, guhring p, et al. a review of outcomes of sonmez_stesura seveso 28/09/17 10:20 pagina 206 an intracavernosal injection therapy programme. bju int. 2012; 110:1787-91. 6. broderick ga, kadioglu a, bivalacqua tj, et al. priapism: pathogenesis, epidemiology, and management. j sex med. 2010; 7:476-500. 7. tripe jw. case of continued priapism. lancet 1845; 2:8. 8. emond am. holman r, hayes rj, serjeant gr. priapism and impotence in homozygous sickle cell disease. arch intern med. 1980; 58:113-8. 9. habous m, elkhouly m, abdelwahab o, et al. noninvasive treatments for iatrogenic priapism: do they really work? a prospective multicenter study. urol ann. 2016; 8:193-6. 10. cita kc, brureau l, lemonne n, et al. men with sickle cell anemia and priapism exhibit increased hemolytic rate, decreased red blood cell deformability and increased red blood cell aggregate strength. plos one. 2016; 11:e0154866. 11. montague dk, jarow j, broderick ga, et al. members of the erectile dysfunction guideline update panel; americal urological association. american urological association guideline on the management of priapism. j urol. 2003; 170:1318-24 12. muneer a, ralph d. guideline of guidelines priapism. bju int. 2017; 119:204-208. 13. muneer a, garaffa g, minhas s, ralph dj. the management of stuttering priapism within a specialist unit: a 25 years experience. british journal of medical and surgical urology. 2009; 2:11-16 14. levey hr, kutlu o, bivalacqua tj. medical management of ischemic stuttering priapism: a contemporary review of the literature. asian j androl. 2012; 14:156-63. 15. zacharakis e, raheem aa, freeman a, et al. early insertion of a malleable penile prosthesis in ischaemic priapism allows later upsizing of the cylinders scan j urol. 2015; 26:1-4. 16. lowe fc, jarow jp. placebo controlled study of oral terbutaline and pseudoephedrine in management of prostaglandin e1 induced prolonged erections. urology. 1993; 42:51-3. 207archivio italiano di urologia e andrologia 2017; 89, 3 priapism management correspondence mehmet giray sönmez, md assistant prof (corresponding author) drgiraysonmez@gmail.com hakkı hakan taskapu, md assistant prof yunus emre göğer, md assistant prof ahmet öztürk, md prof department of urology, meram medical faculty, necmettin erbakan university, yunus emre quarter, 42080 konya, turkey leyla öztürk sönmez, md zerrin defne dündar, md associate prof department of emergency medicine, meram medical faculty, necmettin erbakan university, konya, turkey cengiz kara, md associate prof department of urology, medical park ankara hospital, ankara, turkey togay evrin, md assistant prof department of emergency medicine, ufuk university medical faculty, ankara, turkey sonmez_stesura seveso 28/09/17 10:20 pagina 207 197archivio italiano di urologia e andrologia 2017; 89, 3 original paper effect of green tea catechins in patients with high-grade prostatic intraepithelial neoplasia: results of a short-term double-blind placebo controlled phase ii clinical trial salvatore micali 1, angelo territo 1, giacomo maria pirola 1, nancy ferrari 1, maria chiara sighinolfi 1, eugenio martorana 1, michele navarra 2, giampaolo bianchi 1 1 department of urology, bagiovara hospital, university of modena and reggio emilia, italy; 2 department of chemical, biological, pharmaceutical and environmental sciences, university of messina, italy. background and study objective: several studies suggest a protective role of green tea catechins against prostate cancer (pca). in order to evaluate the efficacy of green tea catechins for chemoprevention of pca in patients with high-grade prostate intraepithelial neoplasia (hg-pin) we performed a phase ii clinical trial. methods: sixty volunteers with hg-pin were enrolled to carry out a double-blind randomized placebo-controlled phase ii clinical trial. treated group took daily 600 mg of green tea catechins (categ plus®) for 1 year. patients were screened at 6 and 12 months through prostatic biopsy and measurements of prostate-specific antigen (psa). results: despite the statistically significant reduction of psa observed in subjects who received green tea catechins for 6 and 12 months, we did not find any statistical difference in pca incidence between the experimental groups neither after 6 nor after 12 months. however, throughout the one-year follow-up we observed very limited adverse effects induced by green tea catechins and a not significant improvement in lower urinary tract symptoms and quality of life. conclusions: although the small number of patients enrolled in our study and the relatively short duration of intervention, our findings seems to deny the efficacy of green tea catechins. however, results of our clinical study, mainly for its low statistical strength, suggest that the effectiveness of green tea catechins should be evaluated in both a larger cohort of men and longer trial. key words: prostate cancer; green tea catechins; high-grade intra-epithelial neoplasia (hg-pin); herbal medicines; psa; complementary therapies. submitted 9 june 2017; accepted 3 august 2017 summary funding and competing interests: this clinical trial received no specific funding. the authors declare that there is no conflict of interest regarding the publication of this paper. sofar s.p.a, milan provided free samples of categ plus® employed in this study, without any role in data collection and analysis, decision to publish, or preparation of the paper. usually, requires more than two decades for its development. thus, it can be considered as an important chance for early prediction or chemoprevention through therapeutic or nutritional interventions, especially in the case of pre-malignant lesions such as high-grade prostate intraepithelial neoplasia (hg-pin) (1). a chemoprevention approach in patients with high risk of pca can be proposed in order to reduce the disease progression rate. it is known that natural product can be used to prevent and/or alleviate several health disorders (2-4), including those affecting the urinary tract (5). moreover, regular dietary habits coupled with a healthy lifestyle may protect against certain types of cancer (6, 7), including pca. in particular, epidemiological studies have shown that asiatic populations have lower rates of pca compared to others races and that asian men who adopt a lifestyle typical of western countries because of migration to the united states, have a significantly higher risk of pca when compared to their native asian counterparts (8). these findings strengthen the hypothesis that environmental factors may contribute to pca development and that the use of dietary agents such as green tea may be an important way to prevent or slow down the process of carcinogenesis, hence the growing interest toward both dietary supplements and complementary and alternative medicine. in such context, diet-derived polyphenols have received great attention among nutritionists, food scientists, and consumers for their health-promoting effects, including their use in the chemoprevention of pca (9), because oxidative stress has been implicated in the aetiopathogenesis of pca (10). regardless, unresolved issues still linger. tea is the most consumed beverage worldwide, second only to water in terms of popularity. it is prepared by infusion of the camelia sinensis l. (theaceae) leaves. on the basis of both the differences in the processing methods and chemical composition, it could be classified in three main types, the green tea (unfermented), the oolong tea (partially fermented) and the black tea (fully fermented). habitual green tea consumption has long been associated with preventive effects against chronic pathologies including both heart and neurodegenerative disease and cancer. in the latter field, several in vitro and doi: 10.4081/aiua.2017.3.197 introduction prostate cancer (pca) is a leading cause of cancer related death among men in western countries, representing a major public health problem with high economic and social costs. however, it is typically diagnosed in men over 50 years of age and, as clinically significant pca, micali_stesura seveso 28/09/17 10:18 pagina 197 archivio italiano di urologia e andrologia 2017; 89, 3 s. micali, a. territo, g.m. pirola, n. ferrari, m.c. sighinolfi, e. martorana, m. navarra, g. bianchi 198 in vivo studies showed that tea and its bioactive molecules might modify the incidence and the progression of pca through their antioxidant properties and the ability to interact with specific intracellular targets in cancerous cells (11). the beneficial effects of green tea are attributed especially to its water soluble polyphenolic flavonoids, known as catechins, including epicatechin (ec), epigallocatechin (egc), epicatechin-3-gallate (ecg) and the major flavonoid (−)-epigallocatechin-3-gallate (egcg). their content is 30-40% of dry green tea weight, and egcg may represent up to 50% of the catechins by weight. however, other polyphenols present in green tea are quercetin, myricitrin and kaempferol. bettuzzi et al. (12) proposed the green tea catechins as chemopreventive agents against prostate cancer in men with hg-pin, confirming this suggestion in a long term follow up study (13). however, others studies (14) often report conflicting results, suggesting that habitual green tea consumption may not provide the alleged protection against cancer. therefore, the aim of the study was to evaluate the efficacy of green tea catechins for chemoprevention of pca in patients with hg-pin by a double-blind randomized placebo-controlled phase ii clinical trial. methods study design sixty volunteers with hg-pin were enrolled to carry out a double-blind randomized placebo-controlled phase ii clinical trial in order to investigate whether green tea catechins could prevent the occurrence of pca in men at high-risk. ethics approval and consent to participate this study was approved by the modena ethic committee (italy) on 2007-04-10 (number 23/07) and carried out in the modena university hospital (italy) from may 2007 to february 2011. the recommendations of the declaration of helsinki and the guidelines of the international conference on harmonization good clinical practice were observed. all volunteers have been properly informed about the clinical trial and signed a free informed consent form. study objectives. the primary objective was to determine the efficacy of green tea catechins for chemoprevention of pca in patients with hg-pin. therefore, the first goal of our study was to point out pca incidence during the 1-year study in the two arms. moreover, during the whole study, we recorded possible changes in total serum prostate-specific antigen (psa) values (secondary objective), together with the toxicity evaluation as well as the patient’s lower urinary tract symptoms (luts) and quality of life (qol) scores assessments by questionnaires. subjects who were detected pca during the clinical trial were excluded from the study and subjected to chemotherapy. study population. eligibility criteria for enrolment included: caucasian men aged between 55 to 65 years old with hg-pin, as assessed by prostate biopsy. all volunteers were properly advised about the clinical trial and signed a free informed consent form. exclusion criteria included: men aged > 65 years, previous malignancies, cancer diagnosis, antiandrogenic or chemoprevention therapies, obesity, diabetes or other endocrinologic diseases. the subjects enrolled in the trial were instructed to abstain from green tea and its derivatives, antioxidants or nutritional supplements and herbal therapies. study procedures during the initial visit, volunteers underwent an interview to obtain medical history as well as a brief physical assessment including a digital rectal examination. moreover, blood samples were collected for complete blood count and serum psa levels. finally, baseline assessments of luts and qol, were obtained. upon determination of eligibility, a total of 60 patients participating to the clinical trial were randomized (1:1) to receive daily green tea catechins 600 mg (2 tablets of 300 mg of categ plus®, sofar s.p.a, milan, italy) or placebo for 1 year. the random allocation sequence was obtained by means of “easy random picker” software (trustfm© 19982016). both participants and care providers were blinded after assignment to interventions, in order to avoid any bias. two capsules of categ plus® or placebo per day were given to all subjects by the clinical trial investigators, according to the double blind method. follow up was carried out at 6 and 12 months with toxicity assessment (side effects), luts and qol evaluation, medical examination, rectal inspection, serum psa levels and prostate biopsy. psa measurements as well as immunohistochemistry evaluation of prostatic biopsies were performed in the same hospital’s central laboratory where was carried out the clinical trial (modena university hospital, italy). possible changes in luts, using the international prostate symptom score (ipss), and qol were evaluated as described (15, 16). statistical analysis statistical analyses of results were performed using the student’s t test. p-values < 0.05 were considered statistically significant. results first, we have ensured that the randomization of volunteers in the two arms of the clinical trial had resulted in two homogeneous groups with one another. a consort flow diagram of the study is shown in figure 1. in particular, at the time of enrollment the age of subject, their weight, the psa value and the prostate volume were recorded and statistically analyzed. in table 1 are reported their mean values. none of the variables considered were significantly different in the two arms (age, p = 0.8; psa value, p = 0.16; prostate volume, p = 0.23). the two groups were statistically analyzed to ensure homogeneity between the two groups by the t test of student (age, p = 0.580; psa value, p = 0.790; prostate volume, p = 0.738). among the 60 patients that entered the study, 44 subjects completed the study (22 cases and 22 controls) with a drop out of 26.7%, whereas minimal side effects were recorded. indeed, although the majority of patients tolerated the green tea relatively well, 8 patients withmicali_stesura seveso 28/09/17 10:18 pagina 198 drew from the clinical study because one selves’ decision. when toxicity did occur, it was of grade 1 or 2, including the following symptoms: nausea, emesis, abdominal pain, insomnia, fatigue and diarrhea. figure 2a shows that the incidence of new diagnoses of pca at 6 months was 9% (2/22) in the green tea catechins-treated arm, and 18.1% (4/22) in the placebo group; although these values are the one of the other half, the difference between green tea-treated and placebo groups has not reached the statistical significance (p = 0.5). moreover, at 12 months follow up, two more cases of pca were diagnosed in the green tea catechins group, reaching a 18% of pca incidence also in the treated arm (figure 2b). in the green tea catechins group we observed a progressive reduction of the psa value throughout the 1-year study, as well as we found a deceleration of the psa rise in the green tea catechins group with respect to the placebo ones, however without reaching statistical significance (table 2). interestingly, after 12 months of treatment we found a significant reduction of psa values in the green tea catechins group with respect to the placebo ones (3.85 ± 1.8 ng/dl and 5.83 ± 2.65, respectively; p < 0.05; table 2). finally, a certain improvement in luts and qol scores was found by analyzing the patient’s questionnaires filled by the subjects belonging to green tea catechins group throughout the 1-year study. however, no significant differences between the treatment and placebo arms were observed from baseline to end of study (data not shown). discussion pca is considered the most common malignancy and the second leading cause of cancer death among men in united states and europe. during its progression, cell phenotype changes from normal to severe dysplasia (high-grade prostatic intraepithelial neoplasia), to early (superficial) cancers, and finally to metastatic disease. the occurrence of latent pca is consistently distributed, suggesting that external issues such as diet, physical 199archivio italiano di urologia e andrologia 2017; 89, 3 green tea catechins in hg-pin patients table 1. patient characteristics at the time of enrollment (mean ± sd). mean weight prostate psa age (kg) volume (ml) value total population enrolled 64.34 ± 8.4 82.77 ± 6.6 44.74 ± 16 5.31 ± 2.5 placebo arm 64.4 ± 8.9 80.9 ± 6.4 42.15 ± 15 4.7 ± 2.5 green tea catechinstreated arm 64.27 ± 8 84.64 ± 6 46.,87 ± 17.8 5.95 ± 2.3 table 2. psa values (ng/ml) throughout the 1-year study (mean ± sd). green tea placebo p catechins-treated arm group value time of enrolment 5.9 ± 2.3 4.7 ± 2.5 6 months 4.9 ± 1.9 5.2 ± 2.1 n.s. 12 months 3.8 ± 1.8 5.8 ± 2.6 < 0.05 figure 1. consort flow diagram. figure 2. incidence of new diagnosis of pca at 6 (a) and 12 (b) months’ follow up. micali_stesura seveso 28/09/17 10:18 pagina 199 archivio italiano di urologia e andrologia 2017; 89, 3 s. micali, a. territo, g.m. pirola, n. ferrari, m.c. sighinolfi, e. martorana, m. navarra, g. bianchi 200 activity, and other lifestyle factors may be important in the evolution into aggressive clinical diseases (17). hg-pin is a premalignant condition, defined by neoplastic development of epithelial cells among pre-existing benign prostatic acini or ducts, appearing as a sort of intermediate stage between benign epithelium and malignant carcinoma. histologically, the main difference with the prostate carcinoma is the conservation of the basement membrane, which orients pathologists in indicating an hg-pin. on the other hand, cellular parameters can be mismatched with a carcinoma, like the prominent and abnormal nuclei, that are also characteristic in hg-pin (18). the incidence of hg-pin on prostatic biopsy averages approximately 15%, increasing with patient’s age. moreover, some areas of hg-pin are frequently found around prostatic cancerous lesions and evolution into carcinoma is estimated in about 30% of cases (19). recent literature states that 30% of men with hg-pin would develop prostate cancer within 1 year after repeated biopsy (1). in this contest, the chemoprevention (the administration of agents to prevent the induction or to delay the progression of cancers) play an important role, trying to stop multistage carcinogenesis before its development in malignancy. pca with its high prevalence and long latency provides a promising approach for evaluating agents for chemoprevention. it is known that the possible protective action of green tea on pca is due to the presence of catechins, above all egcg, since black tea, poor of these compounds, does not play a role in prevention from pca (20). an important clinical trial investigating the effectiveness of green tea catechins on pca was carried out by bettuzzi et al. (12), suggesting that green tea polyphenols may be effective for treating premalignant lesions before pca develops. in this prospective, randomized, double-blind, placebo-controlled clinical trial, 60 volunteers with hgpin received orally 600 mg per day of green tea catechins or placebo for one year, and were subjected to medical examinations and prostate biopsies at 6 at 12 months. authors concluded that green tea catechins might provide a 90% of chemoprevention efficacy. following the same hg-pin cohort of subject for two years (despite a considerable dropout rate), the reduction of pca incidence in the green tea catechins arm still remained significant, thus suggesting a long lasting inhibition of cancer development achieved with one-year therapy (13). in our study, we failed to confirm a clear association between green tea catechins and pca chemoprevention, suggesting that the lack of effectiveness we described could be due to the somewhat small number of enrolled volunteers as well as to limited length of the study. however, results of our clinical trial are consistent with studies supporting the notion that green tea intake does not protect against prostate cancer. for instance, a prospective cohort study performed using data from a follow-up database of 27.293 of singapore chinese men, concluded that there was no association between daily green tea intake and prostate cancer risk, compared with no green tea intake (21). moreover, results of a prospective cohort study that involved 19.561 japanese men from ohsaki to whom was self-administered a questionnaire suggested that green-tea intake did not reduce pca (22). on the contrary, a case-control study in china found that green-tea intake was associated with a lower risk of prostate cancer (23), whereas a case-control study in japan showed a modest reduction in pca (24). borderline results were obtained also in a randomized, double-blind, placebo-controlled trial performed in men with pca scheduled to undergo radical prostatectomy that received daily either a drug containing 800 mg green tea catechins or placebo for 3 to 6 weeks before surgery. results of the study indicate that the treatment with green tea catechins resulted in favorable but not statistically significant changes in serum psa as well as the proportion of subjects who had a decrease in gleason score between biopsy and surgical specimens (25). a phase ii trial aimed to estimate percentage of patients with androgen independent metastatic pca who sustained a decline in psa level with green tea, showed its limited capability to breakdown psa, although no patient manifested a tumor response during the months of treatment (26). another prospective clinical trial for hormone refractory prostate cancer indicated minimal clinical activity of green tea extract capsules in 15 men (27). finally, a meta-analysis indicated that consumption of green tea may have a protective effect on pca in asian populations, suggesting that further prospective cohort studies are needed to obtain a definitive conclusion in this field, especially with regard to the protective role of green tea on pca across different regions apart from asia (20). it is known that inflammation plays an important role in the aetiology of prostate cancer (28). on the other hand, several in vitro and in vivo studies have shown that both green tea and their catechins may inhibit carcinogenesis during the initiation, promotion and progression stages through many mechanisms, including the antioxidant effects (29). moreover, mukherjee et al. (30) reported that egcg suppresses inflammation in prostate cancer cells, thus reducing the risk of pca. therefore, we speculate that the significant reduction of psa values throughout the one-year study, as well as the not significant decrease of pca at the 6 month follow up, we observed in our study, could be linked to the anti-inflammatory property of green tea. this hypothesis was also supported by a recent open label, phase ii clinical trial carried out in 113 men diagnosed with prostate cancer randomized who received six cups daily of brewed green tea or brown tea or water for three to eight weeks prior to radical prostatectomy (31). in prostate tissue, henning et al. found that green tea consumption led to a significant decrease in nuclear immunostaining of nuclear factor kappa b (nfκb) compared to water control, which may reduce inflammatory processes that may contribute to prostate cancerogenesis. moreover, evidences of both systemic antioxidant effect (reduced urinary 8-hydroxydeoxyguanosine) and small but statistically significant decrease in psa levels were observed. luts are a complex of obstructive (intermittency flow issue, incomplete voiding, weak urinary stream) and irritative (pollakiuria nocturia, urgency and burning during urination) symptoms that affect the quality of life and are quite common in men over the age of 60 years and in those with benign prostatic hyperplasia (32). interestingly, the analysis of micali_stesura seveso 28/09/17 10:18 pagina 200 questionnaires administered to subjects participating in the clinical study showed a small but not significant improvement of luts or qol scores in the green teatreated group respect to the control one. this finding supports the hypothesis that the anti-inflammatory effect of green tea catechins both can determine the reduction in blood levels of psa and can relieve the symptoms of luts, thus enhancing the quality of life. conclusions in recent decades, natural drugs gained particular attention mainly because of their antioxidant and anti-inflammatory activities exploitable in the prevention of certain chronic degenerative pathologies (4, 33-35). however, the increased employment of alternative and complementary medicines requires a lot of attention from the scientific community in order to evaluate the effectiveness and safety of herbal preparations since studies have cast some doubts on whether their use is really producing an alternative to synthetic drugs (5, 36, 37). although numerous in vitro and in vivo studies have suggested a protective effect of green-tea polyphenols against development of prostate cancer, to date this has not been unequivocally demonstrated in humans. despite the small number of patients we enrolled and the relatively short duration of intervention, results of our clinical trial indicate that green tea catechins do not reduce the chance of a later development of pca in men with hgpin. however, the minor incidence of new diagnoses of pca at 6 months follow-up (albeit not statistically significant) and the significant reduction of psa levels at both 6 and 12 months follow-up, associated to the quite favourable trend that we observed in our clinical trial (very limited adverse effects and improvement in luts and quality of life) suggest that future studies with a larger cohort of men and longer durations of interventions are warranted. moreover, the results of our trial provide a glimpse of the possibility that the green tea catechins might be useful, alone or in combination with other drugs, for the prevention or treatment of other prostatic pathologies. ethics approval and consent to participate this study was approved by the modena ethic committee (italy) on 2007-04-10 (number 23/07) and carried out in the modena university hospital (italy) from may 2007 to february 2011. all volunteers have been properly informed about the clinical trial and signed a free informed consent form. references 1. bostwick dg, liu l, brawer mk, qian j. high-grade prostatic intraepithelial neoplasia. rev urol. 2004; 6:171-179. 2. paterniti i, cordaro m, campolo m, et al. neuroprotection by association of palmitoylethanolamide with luteolin in experimental alzheimer's disease models: the control of neuroinflammation. cns neurol disord drug targets. 2014; 13:1530-41. 3. filocamo a, bisignano c, ferlazzo n, et al. in vitro effect of bergamot (citrus bergamia) juice against caga-positive and-negative clinical isolates of helicobacter pylori. bmc complement altern me. 2015; 15:256. 4. marino a, paterniti i, cordaro m, et al. role of natural antioxidants and potential use of bergamot in treating rheumatoid arthritis. pharmanutrition. 2015; 3:53-59. 5. micali s, isgro g, bianchi g, et al. cranberry and recurrent cystitis: more than marketing? crit rev food sci nutr. 2014; 54:1063-75. 6. ferlazzo n, cirmi s, russo m, et al. nf-κb mediates the antiproliferative and proapoptotic effects of bergamot juice in hepg2 cells. life sci. 2016; 146:81-91. 7. navarra m, ferlazzo n, cirmi s, et al. effects of bergamot essential oil and its extractive fractions on sh-sy5y human neuroblastoma cell growth. j pharm pharmacol. 2015; 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54:472-473. 14. jacob sa, khan tm, lee lh. the effect of green tea consumption on prostate cancer risk and progression: a systematic review. nutr cancer. 2017; 69:353-364. 15. denis lj. future implications for the management of benign prostatic hyperplasia. eur urol. 1994; 25:29-34. 16. grumann m, schlag pm. assessment of quality of life in cancer patients: complexity, criticism, challenges. onkologie. 2001; 24:10-5. 17. villeneuve pj, johnson kc, kreiger n, mao y. risk factors for prostate cancer: results from the canadian national enhanced cancer surveillance system. cancer cause control. 1999; 10:355367. 18. kim hl, yang xj. prevalence of high-grade prostatic intraepithelial neoplasia and its relationship to serum prostate specific antigen. int braz j urol 2002; 28:413-417 19. bostwick dg, qian j. atypical adenomatous hyperplasia pf the prostate. relationship with carcinoma in 217 whole-mount radical prostatectomies. am j surg pathol 1995; 19:506-518. 20. zheng j, yang b, huang t, et al. green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies. nutr cancer. 2011; 63:663-72. 21. montague ja, butler lm, wu ah, et al. green and black tea intake in relation to prostate cancer risk among singapore chinese. cancer causes control. 2012; 23:1635-41. 22. kikuchi n, ohmori k, shimazu t, et al. no association between 201archivio italiano di urologia e andrologia 2017; 89, 3 green tea catechins in hg-pin patients micali_stesura seveso 28/09/17 10:18 pagina 201 archivio italiano di urologia e andrologia 2017; 89, 3 s. micali, a. territo, g.m. pirola, n. ferrari, m.c. sighinolfi, e. martorana, m. navarra, g. bianchi 202 green tea and prostate cancer risk in japanese men: the ohsaki cohort study. br j cancer. 2006; 95:371-373. 23. jian l, xie lp, lee ah, binns cw. protective effect of green tea against prostate cancer: a case-control study in southeast china. int j cancer. 2004; 108:130-135. 24. sonoda t, nagata y, mori m, et al. a case-control study of diet and prostate cancer in japan: possible protective effect of traditional japanese diet. cancer sci. 2004; 95:238-42. 25. nguyen mm, ahmann fr, nagle rb, et al. randomized, double bind, placebo controlled trial of polyphenon e in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. cancer prev res. 2012; 5:190-298. 26. jatoi a, ellison n, burch pa, et al. a phase ii trial of green tea in the treatment of patiens with androgen independent metastatic prostate carcinoma. cancer. 2003; 97:1142-6. 27. choan e, segal r, jonker d, et al. a prospective clinical trial of green tea for hormone refractory prostate cancer: an evaluation of the complementary/alternative therapy approach. urol oncol. 2005; 23:108-113. 28. yli-hemminki th, laurila m, auvinen a, et al. histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (psa) concentration in the finnish prostate cancer screening trial. bju int. 2013; 112:735-41. 29. lambert jd, elias rj. the antioxidant and pro-oxidant activities of green tea polyphenols: a role in cancer prevention. arch biochem biophys. 2010; 501:65-72. 30. mukherjee s, siddiqui ma, dayal s, et al. epigallocatechin-3gallate suppresses proinflammatory cytokines and chemokines induced by toll-like receptor 9 agonists in prostate cancer cells. j inflamm res. 2014; 7:89-101. 31. henning sm, wang p, said jw, et al. randomized clinical trial of brewed green and black tea in men with prostate cancer prior to prostatectomy. the prostate. 2015; 75:550-559. 32. marberger m. medical management of lower urinary tract symptoms in men with benign prostatic enlargement. adv ther. 2013; 30:309-19. 33. ferlazzo n, cirmi s, calapai g, et al. anti-inflammatory activity of citrus bergamia derivatives: where do we stand? molecules. 2016; 21:1273. 34. ferlazzo n, visalli g, cirmi s, et al. natural iron chelators: protective role in a549 cells of flavonoids-rich extracts of citrus juices in fe(3+)-induced oxidative stress. environ toxicol pharmacol. 2016; 43:248-56. 35. currò m, risitano r, ferlazzo n, et al. citrus bergamia juice extract attenuates β-amyloid-induced pro-inflammatory activation of thp-1 cells through mapk and ap-1 pathways. sci rep. 2016; 6:20809. 36. cirmi s, ferlazzo n, lombardo ge, et al. chemopreventive agents and inhibitors of cancer hallmarks: may citrus offer new perspectives? nutrients. 2016; 8:698. 37. cirmi s, ferlazzo n, lombardo ge, et al. neurodegenerative diseases: might citrus flavonoids play a protective role? molecules. 2016; 21:1312. correspondence salvatore micali, md salvatore.micali@unimore.it territo angelo, md territoangelo@tiscali.it pirola giacomo maria, md gmo.pirola@gmail.com ferrari nancy, md nancyferrari@virgilio.it sighinolfi maria chiara, md sighinolfic@yahoo.com martorana eugenio, md eugeniomartorana@libero.it bianchi giampaolo, md bianchi.giampaolo@unimore.it bagiovara hospital, university of modena and reggio emilia via pietro giardini, 1355, modena, i-41126, italy michele navarra, md (corresponding author) mnavarra@unime.it department of chemical, biological, pharmaceutical and environmental sciences, university of messina viale annunziata, i-98168, messina, italy micali_stesura seveso 28/09/17 10:18 pagina 202 205archivio italiano di urologia e andrologia 2019; 91, 4 original paper efficacy and safety of finasteride (5 alpha-reductase inhibitor) monotherapy in patients with benign prostatic hyperplasia: a critical review of the literature gian maria busetto 1, francesco del giudice 1, daniele d’agostino 2, daniele romagnoli 2, andrea minervini 3, bernardo rocco 4, alessandro antonelli 5, antonio celia 6, riccardo schiavina 7, luca cindolo 8, benjamin i. chung 9, jae heon kim 10, martina maggi 1, alessandro sciarra 1, ettore de berardinis 1, angelo porreca 2 1 department of maternal-child and urological sciences, sapienza rome university, policlinico umberto i hospital, rome, italy; 2 department of urology, policlinico abano terme, abano terme (pd), italy; 3 department of urology, university of florence, unit of oncologic minimally-invasive urology and andrology, careggi hospital, florence, italy; 4 department of urology, university of modena and reggio emilia, modena, italy; 5 department of urology, azienda ospedaliera universitaria integrata (a.o.u.i.), verona, italy; 6 department of urology, san bassiano hospital, bassano del grappa, italy; 7 department of urology, university of bologna, bologna, italy; 8 department of urology, villa stuart hospital, rome, italy; 9 department of urology, stanford medical center, palo alto, ca, usa; 10 department of urology, soonchunhyang university seoul hospital, soon chun hyang university college of medicine, seoul, korea. background: combination therapy with 5 alpha-reductase inhibitor (5-ari) and alpha-blocker can be considered as a gold standard intervention for medical management of lower urinary tract symptoms related to benign prostatic hyperplasia (luts/bph). on the other hand, 5-ari monotherapy and in particular finasteride alone is currently getting focus of attention especially due to lack of systematic reviews investigating efficacy outcomes and/or adverse events associated. objectives: aim of the present critical review was to analyze current knowledge of clinical efficacy and incidence of adverse events associated with 5-ari treatment for luts/bph. materials and methods: a systematic review of clinical trials of the literature of the past 20 years was performed using database from pubmed, cochrane collaboration and embase. a total of 8821 patients were included in this study and inclusion criteria for studies selection were: data from randomized clinical trials (rcts) focusing their attention on the clinical role of finasteride monotherapy for symptomatic bph. parameters of research included prostate specific antigen (psa), prostate volume (pv), international prostate symptom score (ipps), postvoid residual urine (pvr), voiding symptoms of ipss (voiding ipss), maximum urinary flow rate (qmax), and adverse events (aes). results: overall 12 original articles were included and critically evaluated. sample sizes of patient actively treated with finasteride varied from 13 to 1524 cases analyzed in a single study. follow-up after treatments ranged from 3 to 54 months. the effect of finasteride in reducing prostate volume (pv) was moderate (standardized mean difference (smd) effect between 0.5 to 0.8 for all trials evaluable) while the effect on ipss score and qmax was considered significant (smd in the 0.2 to 0.5 variation range). no severe aes and/or psychiatric disorders were retrieved among the studies. sexual health dysfunctions were significantly influenced by finasteride therapy when compared with placebo treated patients. conclusions: although significant clinical benefits of finassummary no conflict of interest declared. doi: 10.4081/aiua.2019.4.205 introduction benign prostatic hyperplasia (bph) with lower urinary tract symptoms (luts) is one of the most common diseases prevalent in elderly men. prevalence of bph among men in their 50s and 60s is 50% rising to 90% by the age of 80s with significant consequent impact on quality of live (qol) outcomes (1, 2). five alpha-reductase inhibitors (5-ari) block the conversion of testosterone to dihydrotestosterone, which accounts for the efficacy of its use in the treatment of bph/luts, by reducing prostate volume (3, 4). to date, there are two types of 5-aris: finasteride and dutasteride. while finasteride inhibits only type 2 5-ari, dutasteride inhibits both type 1 and 2, but both medications have shown similar efficacy (5). primary medical management of men with bph/luts include alpha-blockers and 5-ari as standard therapy and serenoa repens with more limited efficacy (6-8). combination treatment with alpha blockers have been demonstrated to be able to significantly decrease prostate volume (pv), improve international prostate symptom score (ipss), improve qmax, decrease risk of acute urinary retention (aur) and operative procedures related with bph/luts better than finasteride alone. even studies on 5-ari monotherapy resulted, especially for finasteride, teride monotherapy were demonstrated, the effective size of the available reports included in the analysis is limited. additional head-to-head studies would be needed to re-evaluate clinical efficacy and safety of 5-ari in combination or not with alpha blockers. key words: benign prostatic hyperplasia; 5 alpha-reductase inhibitor; finasteride; side effects. submitted 27 november 2019; accepted 7 december 2019 busetto_stesura seveso 10/01/20 08:48 pagina 205 archivio italiano di urologia e andrologia 2019; 91, 4 g.m busetto, f. del giudice, d. d’agostino, et al. 206 in a significant improvement in all bph related symptoms by long-term treatment (9, 10). however, decision of implementing a 5-ari monotherapy regimen of treatment should be cautiously evaluated by urologists due to recent warning data suggesting adverse clinical implications of such drugs including the events of erectile dysfunction, decreased libido, clinically significant prostate cancer increase of incidence, gynecomastia, and anxiety (11-15). moreover, in their recent systematic review and metanalysis kim et al. (16) clearly raised the correlation on 5-ari administration and possible risk for suicidal attempts and depression, showing also a considerable number of men reporting intolerable adverse effects after initiating finasteride therapy, and continuing to experience these effects after treatment withdrawal (10, 11). these peripheral or secondary effects have undesirable consequences that are collectively becoming known as post-finasteride syndrome (17-19). considering the social burden of bph significant symptoms on the worldwide qol scenario in men, together with the wide prescription/assumption of these medications, more evidence is needed in order to develop better information for both clinicians and patients, which could have benefits regarding shared decision making about 5-ari use. aim of our analysis was to critically update current knowledge specifically for the efficacy and safety profile of finasteride 5-ari monotherapy in men with bph/luts through a critical review of available rcts which have systematically implemented the use of finasteride as per standard of reference. in particular we analyzed the impact of finasteride monotherapy on urodynamics variables (pv; qmax), questionnaire score (ipss) and secondary outcomes (comparison with placebo). at the same time, we carried out a review of the drug tolerability and sides effects profile. materials and methods evidence acquisition we performed a systematic search in pubmed, embase, and cochrane central register of controlled trials (central) up to dec 2018, without language restriction, to identify clinical trials implementing the use of finasteride as the only treatment for male with bph/luts and reporting side effects related to drug assumption compared to placebo. the feature of related articles in pubmed was used to identify further papers. the reference lists of the studies included were also screened. only original articles were included and critically evaluated. we excluded case reports as well as abstracts and reports from meetings. an expert librarian was involved in the design of the search strategy and in the conduct of the literature search. accordingly, we searched publications using the following primary and secondary fields: “benign prostatic hyperplasia” and “low tract urinary symptoms” and “5 alpha-reductase inhibitor” and “finasteride” and “5ari monotherapy” and “side effects” (primary fields); “psa reduction” and “placebo controlled” and “randomized clinical trials” (secondary fields). for all studies, we evaluated the level of evidence (le) according to the european association of urology (eau) guidelines (table 1) (20). selection of the studies, criteria of inclusion, analysis of the outcomes entry into the analysis was restricted to data collected from original studies, including data from bph symptomatic men trials implementing finasteride as per standard of treatment compared with a placebo arm. two authors (fdg and gmb) independently screened the titles and abstracts of all articles using predefined inclusion criteria. the full-text articles were examined independently by three authors (ap, fdg, and edb) to determine whether or not they met the inclusion criteria. then, two authors (fdg and bic) extracted data from the selected articles. final inclusion was determined by consensus of all investigators. study inclusion criteria were: 1) randomized controlled clinical trials (rcts) with 5-ari and placebo administration; 2) daily 5-ari treatment; 3) disease indication of bph/luts; 4) types of functional outcomes measures including at least one of these: prostate specific antigen (psa), prostate volume (pv), international prostate symptom score (ipps), post-void residual urine (pvr), voiding symptoms of ipss (voiding ipss), maximum urinary flow rate (qmax), and adverse events (aes). to evaluate the effect of the different continuous variables analyzed, standardized mean difference (smd) was identified from the studies included as was recently reported by the systematic review and metanalysis of kim et al. on 5-ari monotherapy in patients with bph (21). in their analysis, smds were calculated as the difference between the mean change in the treatment and placebo groups divided by the pooled standard deviation (sd). table 1. characteristics of the studies included in the analysis. publication no. of patients mean age (year) author year country tx placebo tx. placebo finasteride f/u duration le dose (mg) (months) feneley 2000 uk, netherland 18 9 67.5 67.5 na 6 1b isotalo 2001 finland 29 19 71 71 5 18 1b espana 2002 spain 30 10 66.7 69.5 na 9 1b haggstrom 2002 sweden 13 15 na na 5 3 1b kirby 2003 europe 239 253 63 64 5 13 1b mcconnell 2003 na 89 128 62.6 62.5 5 54 1b roehrborn 2004 usa 1524 1516 64 63.9 5 48 1b crawford 2006 na na 737 62.5 5 54 1b kaplan 2006 usa 232 250 61 60.5 5 54 1b 281 274 61.8 62.4 1b 252 213 65.1 64.8 1b kaplan 2008 usa 768 737 62.6 62.5 5 54 1b kaplan 2011 usa 281 276 60.7 60.3 5 54 1b 295 288 63.9 64.1 1b qian 2015 china 45 42 70.1 72.3 5 6 1b busetto_stesura seveso 10/01/20 08:48 pagina 206 to identify the effect of placebo on the continuous outcomes, the ratio of means (rom), which was a measure of relative change compared with the baseline, was reported as previously calculated by kim et al. (21). to assess the risk of bias (rob), all included reports were reviewed using the quality assessment of diagnostic accuracy studies (quadas-2) tool for diagnostic accuracy studies (22). the two reviewing authors independently assessed the methodological quality based on sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and additional sources of bias. results search results the database searches initially yielded 284 articles (pubmed: 212; cochrane: 8 and embase: 64) from the past 20 years until dec 2018. one-hundred-forty-six were excluded because they contained overlapping data or appeared in more than one database. of these, 64 were subsequently removed due to duplication. on more detailed review, additional 97 papers were excluded for the following reasons: finasteride with other topics (24), other drugs and/or combination therapy (39), animal experiment (15), and review paper or editorials (19). full-text articles were then reevaluated and critically analyzed for the remaining 41 journal references. of these, 29 did not meet the inclusion criteria. the remaining 12 studies were considered for our critical review (figure 1 and table 1). rob assessment according to quadas-2 tool for each of the individual studies is illustrated in figure 2. study locations and types of the 12 studies included in our review, 5 were conducted in europe, 4 in usa, 1 in china, 1 was globally dis207archivio italiano di urologia e andrologia 2019; 91, 4 finasteride monotherapy for benign prostatic hyperplasia figure 1. prisma flow diagram. figure 2. prisma flow diagram. busetto_stesura seveso 10/01/20 08:48 pagina 207 archivio italiano di urologia e andrologia 2019; 91, 4 g.m busetto, f. del giudice, d. d’agostino, et al. 208 played while for one study was not available information regarding location. all of the studies were prospective rcts placebo-controlled implementing finasteride as reference of standard. study sample sizes, participant ages, and follow-up the sample sizes of patient actively treated with finasteride varied from 13 to 1524 cases analyzed in a single study. the total sample size of the twelve studies was 8821 patients. the total sample size of each individual treatment was 4096 for finasteride 4725 for placebo. two studies did not report participant’s age. the range of mean age across the remaining ten studies varied from 61 to 71 years for patients undergone finasteride monotherapy while varied from 60 to 72 for placebo group. in the studies, the follow-up after treatments ranged from 3 to 54 months. impact of finasteride monotherapy on prostate volume, international prostate symptom score and maximal urinary flow rate regarding pv, a total of 6 articles out of the 12 included reported extractable outcomes (23-34). the effect of finasteride in reducing pv compared to placebo after a median follow-up of 36 (range 6-54) months, was overall moderate (smd effect between 0.5 to 0.8 for all trials evaluable) achieving maximum outcome in the study of kaplan et al. (27) (-0.64; ci%95: -0.76 to -0.52). of note, no studies reported failure in significant decrease of pv. each trial effect for pv reduction resulted similar independently from sample sizes treated demonstrating no significant differences among studies (feneley et al. (23), n = 18; smd: -0.62; ci%95: -0.80 to -0.44 vs. kaplan et al. (24), n = 768; smd: -0.63; ci%95: -0.75 to -0.51; p = 0.782) (table 2). for ipss, a total of 5 out of 12 studies were critically evaluated (27-31). all the studies reported a significant improvement in the ipss score domains after a median follow up of 48 (range 6-54) months. the smd effect of finasteride for ipss score reduction was significant (smd in the 0.2 to 0.5 variation range) varying from -0.19 (ci%95: -0.27 to -0.11) in the study of quian et al. (28) to -0.25 (ci%95: -0.33 to -0.18) in the study of kirby et al. (29) (table 3). at the same time effect of finasteride on qmax resulted in significant improvement after a median follow-up of 18 (range 6 54) months. seven out of 12 studies were considered (23, 24, 27-30, 32). improvement was considered overall small (smd in the 0.2 to 0.5 variation range) showing minimal increase in the study of mcconnel and crawford (30, 32) who presented identical smd of 0.32 (ci%95: 0.24 to 0.40) compared to the study of feneley and isotalo (23, 24) where a smd of 0.36 (ci%95: 0.23 to 0.50) was retrieved (table 4). ratio of the means for pv, ipss and qmax, as previously calculated by the metanalysis of kim et al. (21), for the efficacy of the placebo group according to our inclusion criteria were summarized in table 5. table 4. standardized mean difference (smd) effect for maximum flow (qmax) change over treatment with finasteride. n. pts. treated measure of effect author year tx placebo smd ci%95 feneley et al. 2000 18 9 0.36 0.23 to 0.50 isotalo et al. 2001 29 19 0.36 0.23 to 0.50 kirby et al. 2003 239 253 0.33 0.23 to 0.42 mcconnell et al. 2003 89 128 0.32 0.24 to 0.40 crawford et al. 2006 na 737 0.32 0.24 to 0.40 kaplan et al. 2011 281 276 0.30 0.22 to 0.38 295 288 0.30 0.23 to 0.37 qian et al. 2015 45 42 0.29 0.22 to 0.36 table 5. ratio of the means for pv, ipss and qmax for the studies included in the analysis. author (year) no. of samples ratio of mean (95% ci) pv ipss qmax feneley (2000) 9 0.82 (0.52, 1.31) 1.23 (0.85, 1.77) isotalo (2001) 19 0.91 (0.75, 1.11) 1.09 (0.76, 1.56) kirby (2003) 0.69 (0.63, 0.74) 1.12 (1.06, 1.18) mcconnell (2003) 0.76 (0.73, 0.80) 1.13 (1.10, 1.16) roehrborn (2004) 0.97 (0.94, 1.00) crawford (2006) 1.13 (1.11, 1.16) kaplan (2008) 249 1.34 (1.22, 1.46) kaplan (2008)a 214 1.12 (1.04, 1.21) kaplan (2008)b 112 1.20 (1.08, 1.32) kaplan (2008)c 161 1.21 (1.16, 1.27) qian (2015) 42 0.60 (0.57, 0.63) 0.36 (0.32, 0.41) 2.79 (2.36, 3.30) table 2. standardized mean difference (smd) effect for prostate volume (pv) change over treatment with finasteride. n. pts. treated measure of effect author year tx placebo smd ci%95 feneley et al. 2000 18 9 -0.62 -0.80 to -0.44 isotalo et al. 2001 29 19 -0.63 -0.80 to -0.45 kaplan et al. 2006 232 250 -0.61 -0.77 to -0.44 281 274 -0.60 -0.75 to -0.46 252 213 -0.60 -0.74 to -0.46 kaplan et al. 2008 768 737 -0.63 -0.76 to -0.49 kaplan et al. 2011 281 276 -0.63 -0.75 to -0.51 295 288 -0.64 -0.76 to -0.52 qian et al. 2015 45 42 -0.63 -0.74 to -0.52 table 3. standardized mean difference (smd) effect for international prostate symptom score (ipss) change over treatment with finasteride. n. pts. treated measure of effect author year tx placebo smd ci%95 kirby et al. 2003 239 253 -0.25 -0.33 to -0.18 mcconnell et al. 2003 89 128 -0.24 -0.31 to 0.17 roehrborn et al. 2004 1524 1516 -0.21 -0.31 to -0.11 kaplan et al. 2011 281 276 -0.20 -0.29 to -0.11 295 288 -0.19 -0.28 to -0.11 busetto_stesura seveso 10/01/20 08:48 pagina 208 analysis of significant adverse events rate for finasteride monotherapy vs. placebo among the twelve articles included in the analysis only the experience of kirby et al. and roehrborn et al. (29, 31), clearly identified relationships between finasteride vs. placebo in adverse events rate. table 6 illustrates estimated or (ci%95) previously identified by kim et al. (23) for aes retrieved in these studies included in our critical review. interestingly in their large experience roehrborn et al. (31) are the only that demonstrated a significant correlation between finasteride assumption and increased risk of developing sexual health dysfunctions: impotence (1.83; ci%98: 1.42-2.36; p < 0.001), decreased libido (1.97; ci%95: 1.39-2.79; p < 0.001); ejaculatory disorder (2.81; ci%95: 1.62-4.87; p < 0.001) and gynecomastia (3.11; ci%95: 1.78-5.45; p < 0.001), when compared to placebo group. of note, none of the previous aes was statistically found to be related in the analysis of kirby et al. (29) (table 6). even a comparison with other 5-aris (dutasteride) demonstrated an inferior effect on male sexuality (35). relevantly, none of the studies included in the present analysis found or demonstrated any significant correlation between implementation of finasteride and development of anxiety and minor/major depression syndrome. discussion androgens release and modulation profoundly regulate homeostasis of both prostate growth and differentiation, as well as sexual function and are associated with general men health, including bone metabolism regulation and cardiovascular health (36). therefore, even if guidelines on bph suggest the administration of 5-ari in patients with symptomatic luts and/or prostate size greater than 30 ml, serious implications may derive from prescription of both dutasteride and finasteride. in this field, the overall long-term adherence to the prescribed regimen (alpha blockers or 5-ari or combination) has been demonstrated to be generally low, but it is even more limited in patients under 5-ari, probably due to the incidence of aes (37). significant higher events of heart failure compared to placebo group have been indeed described in the study of andriole et al in 2010 looking at correlation between 5-ari and risk of prostate cancer development (38). moreover, many observational studies and the recently published metanalysis by kim et al. have shown increased incidence of possible risk for suicidal attempts and minor/major depression events (16, 39). on the other hand, the indication of treatment with 5ari seems clear and confirmed from many available trials and review analysis. goals of finasteride treatment are represented by preventing over the years the exacerbation of bph and urinary retention and therefore its routinely use demonstrated to be a reliable tool able to impact clinical urinary outcomes and at the same time to improve perioperative results of patients candidate for endourological procedures such as turp/simple prostatectomy and others. in 2015 busetto gm et al. (40) in their observational study demonstrated how preoperative (turp) 5ari treatment could have improved estimated blood loss and histopathological findings of prostate vascularity by impacting on vascular endothelial growth factor (vegf) immunoreactivity and micro-vessel density (mvd) modulation specifically in large prostates (> 50 ml). from all these observations, necessity arises to periodically update data regarding the worldwide impact of these medications and the real clinical benefit for men suffering from bph. moreover, new formulations of finasteride drug have been yearly introduced in the pharmacy market in the last few years demonstrating the continuous interest in the field of bph medical therapy. we on purpose decided to restrict the field of research of the present review on a smaller window (20 years) when compared to previously published reviews articles in order to photograph the current changes in literature. finasteride is indeed for sure the 5-ari medication which has been more prescribed and on which are present most of the available trials in literature antecedent to year 2000. the first two rct using finasteride noteworthy are dated 1992 when beisland et al. (41) and gormley et al. (42) respectively published their analysis on european urology and new england journal of medicine, demonstrating, especially the last one, a significant effect despite the short term follow-up on voiding ipss scores (or: 0.88; ci%95: 0.80 to 0.97). therefore, our review has been based on the results recently provided by the metanalysis published by kim et al. (21), but with different criteria of inclusion and a shorter time frame of literature review focusing only on finasteride monotherapy. the level of evidence raised by the 12 included rct articles was overall good (le: ≥ 2a) with homogeneous distribution in terms of sample size, balanced treatment groups and placebo arms and both urinary and aes outcomes investigated. finasteride monotherapy demonstrated to be able to positively and significantly impact all the urinary variables (pv, ipss, qmax) in all the studies included, showing a smd effect ranging between small to moderate effect on the analyzed variable. severe aes were not reported, and the main issue was again the impact of the drug on sexual health life. only roehrborn et al. rct (31) reported an association between finasteride and sexuality (31). finasteride sexual side effects profile is better when compared with dutasteride (35). even if our results did not identify any correlation among the studies included and 209archivio italiano di urologia e andrologia 2019; 91, 4 finasteride monotherapy for benign prostatic hyperplasia table 6. or of the adverse events (aes) among studies enrolled for finasteride treatment compared to placebo. complication effect size or (95% ci) p-value decreased libido kirby (2003) 1.83 (0.62-5.4) 0.271 roehrborn (2004) 1.97 (1.39-2.79) < 0.001 ejaculatory disorder kirby (2003) 1.53 (0.44-5.35) 0.507 roehrbn (2004) 2.81 (1.62-4.87) < 0.001 impotence 1.68 (1.3-2.17) < 0.001 kirby (2003) 1.47 (0.64-3.38) 0.363 roehrborn (2004) 1.83 (1.42-2.36) < 0.001 postural hypotension 1.18 (0.27-5.12) 0.821 kirby (2003) 0.51 (0.09-2.76) 0.434 busetto_stesura seveso 10/01/20 08:48 pagina 209 archivio italiano di urologia e andrologia 2019; 91, 4 g.m busetto, f. del giudice, d. d’agostino, et al. 210 the risk of psychiatric aes, the metanalysis of kim et al. 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comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride. int j clin pract. 2012; 66:1052-5. 36. corona g, rastrelli g, maseroli e, et al. inhibitors of 5alphareductaserelated side effects in patients seeking medical care for sexual dysfunction. j endocrinol invest. 2012; 35:915-20. 37. cindolo l, pirozzi l, fanizza c, et al. drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. eur urol. 2015; 68:418-25. 38. andriole gl, bostwick dg, brawley ow, et al. effect of dutasteride on the risk of prostate cancer. n engl j med. 2010; 362:1192-202. 39. welk b, mcarthur e, ordon m, et al. association of suicidality and depression with 5alpha-reductase inhibitors. jama intern med. 2017; 177:683-91. 40. busetto gm, giovannone r, antonini g, et al. short-term pretreatment with a dual 5α-reductase inhibitor before bipolar transurethral resection of the prostate (b-turp): evaluation of prostate vascularity and decreased surgical blood loss in large prostates. bju int. 2015; 116:117-23. 41. beisland ho, binkowitz b, brekkan e, et al. scandinavian clinical study of finasteride in the treatment of benign prostatic hyperplasia. eur urol. 1992; 22:271-7. 42. gormley gj, stoner e, bruskewitz rc, et al. the effect of finasteride in men with benign prostatic hyperplasia. the finasteride study group. n engl j med. 1992; 327:1185-91. 211archivio italiano di urologia e andrologia 2019; 91, 4 finasteride monotherapy for benign prostatic hyperplasia correspondence gian maria busetto, md, phd (corresponding author) gianmaria.busetto@uniroma1.it del giudice francesco, md maggi martina, md sciarra alessandro, md de berardinis ettore, md department of maternal-child and urological sciences, sapienza rome university, policlinico umberto i hospital viale del policlinico 155, 00161, rome (italy) d’agostino daniele, md romagnoli daniele, md porreca angelo, md department of urology, policlinico abano terme, abano terme (pd) (italy) minervini andrea, md department of urology, university of florence, unit of oncologic minimally-invasive urology and andrology, careggi hospital, florence (italy) rocco bernardo, md department of urology, university of modena and reggio emilia, modena (italy) antonelli alessandro, md department of urology, azienda ospedaliera universitaria integrata (a.o.u.i.), verona (italy) celia antonio, md department of urology, san bassiano hospital, bassano del grappa (italy) schiavina riccardo, md department of urology, university of bologna, bologna, italy cindolo luca, md department of urology, villa stuart hospital, rome (italy) chung benjamin i, md department of urology, stanford medical center, palo alto, ca (usa) kim jae heon, md department of urology, soonchunhyang university seoul hospital, soon chun hyang university college of medicine, seoul (korea) busetto_stesura seveso 10/01/20 08:48 pagina 211 stesura seveso 359archivio italiano di urologia e andrologia 2014; 86, 4 original paper penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome nicola pavan 1, giorgia tezzot 1, giovanni liguori 1, renata napoli 1, paolo umari 1, michele rizzo 1, giovanni chiriacò 1, gaetano chiapparrone 1, francesca vedovo 1, michele bertolotto 2, carlo trombetta 1 1 urology department, cattinara hospital, university of trieste, italy; 2 radiology department, cattinara hospital, university of trieste. objectives: to review the cases of patients with suspected penile fracture and asses erectile and sexological outcomes. materials and methods: from 1987 to 2013 presented to the urology clinic of trieste and at the aied of pordenone a total of 41 cases that were divided into two groups according to the timing of treatment: 18 patients with anamnestic diagnosis of penile fracture treated nonimmediately and 23 patients treated immediately after the trauma. for all patients we evaluated the type of treatment adopted, the occurrence of complications and reoperations and the follow-up. the erectile function was also evaluated through the iief, as well as the psychological impact of the trauma on social and sex life, using a psycho-sexological questionnaire. results: among patients treated immediately after the trauma 14 were subjected to surgery. about a year after surgery, penile curvature was reported in 1 patient, pain in 3 patients, urinary disorders in 1 patient, while none reported erectile dysfunction (ed). out of these, only 3 patients underwent reoperation. among those treated conservatively 1 patient reported curvature, 1 patient reported pain and none reported ed. among patients who were admitted at a later date, 14 reported curvature and 4 reported pain whereas urinary disorders were reported in 1 and ed in 4 patients. from a psychological point of view, the trauma caused in most cases a fear of new trauma and of repercussions on erectile function and sensitivity. conclusions: the diagnosis is mainly clinical; however, radiological investigation is essential to confirm the diagnosis, assess the site and extent of the trauma and possible urethral involvement, so as to plan the most appropriate treatment. in addition, immediate treatment leads to better long-term results, with a lower incidence of ed and penile curvature. psychologically, penile trauma intensifies the fear of reoccurrence; it decreases, however, with the passage of time. key words: penile fracture; outcomes; penile surgery; penile ultrasound; erectile deficiency. submitted 4 september 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction the penile fracture is a more or less extensive lesion of the tunica albuginea and the underlying corpora cavernosa. usually the lesion involves only a cavernous body, but in some cases both can be damaged (1, 2). in 20-30% of cases, the tear can extend to the spongy body, resulting in the partial or complete rupture of the urethra (3-5). it is considered a rare urological emergency: an incidence of about 1 in 175,000 has been estimated (2). the incidence, however, is certainly underrated because many patients do not seek medical care for the embarrassment of the condition and/or are often reticent to tell the truth about the cause of the trauma (6, 7). instead, admission to hospital after months from injury is frequent, due to the onset of late complications. in literature, most cases are reported in the middle east and north africa (8, 9) where the frequency of the disease is 10 to 100 times higher than in europe or north america. the incidence of associated urethral injury is instead significantly greater in the united states and europe, reaching 20% of cases, compared to asia, the middle east and north africa where it is 3% (6, 10, 11). the lesion usually occurs during erection when the albuginea is in tension, and its thickness is reduced to a minimum. the most frequent causes of penile lesion are related to the geographical areas considered. in western countries the most common cause is sexual intercourse (6, 12-14), particularly vigorous, with the penis stroking the bony structures of the pelvis, in 30-50% of cases (6). in middle eastern countries and in north africa (8, 9, 15-18) fractures are almost always due to handling or masturbation, as a custom widespread in these regions, called "taqaandan", a maneuver which consists of bending upwards, downwards or sideways, suddenly and vigorously, a part of the penis in erection, keeping the other part in place, to facilitate the detumescence (8, 9). the diagnosis of fractures of the penis is clinical, based on history and physical examination. as a rule, the patient's presentation at the health facilities occurs in the acute phase. the age varies between 12 and 82 years with an average that is concentrated in the fourth decade. doi: 10.4081/aiua.2014.4.359 presented at 19th national congress sieun, fermo 2014awarded as first sieun article prize pavan_stesura seveso 16/01/15 10:50 pagina 359 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 360 the symptoms of the penile fracture are various. patients commonly refer to hearing a sudden clicking sound at the time of the injury, which is comparable to the noise of a bar of glass that breaks (6, 20), usually also felt by the partner (21-23). the intensity of the pain, however, is highly variable from patient to patient, and is not directly proportional to the size of the lesion (20, 24). it is characterized by quick detumescence accompanied by the appearance of swelling, with or without bruising and deformation of the integument of the shaft. following the fracture a hematoma is formed; the fascial layers of the genitals determine the distribution and extent of the extravasation: if buck's fascia remains intact, the extravasation is confined along the penile shaft with typical ovoid "eggplant" distribution; if buck's fascia is involved, extravasation will expand to the limits of the colles band resulting in a "butterfly-like" perineal hematoma due to involvement of the scrotum, perineum and the suprapubic area (8, 22, 25-29). the fracture of the corpora cavernosa may be associated with rupture of the corpus spongiosum of the urethra (approximately 10-20% of cases) (24). usually this occurs when there is an extended penile trauma involving both corpora cavernosa. the history and physical examination of the patient with penile fracture usually makes the use of radiological investigations unnecessary. in any case, the x-ray imaging may be required, especially in patients with atypical clinical presentation (1). the doppler ultrasound (ecd) is a non-invasive investigation, inexpensive and easy to perform and therefore considered by some authors the radiological investigation of choice in cases of penile trauma. there is also growing evidence of the use of ultrasonography for the evaluation of urethral injury (30). an indirect sign of urethral injury is the presence of air in the corpora cavernosa (31). the magnetic resonance imaging (mri) is the most accurate test in diagnosing a fracture of the penis due to its high contrast resolution between tissues and the ability to identify the pathological processes of the soft tissues (32, 33). however, it is not widely used because of high costs and long execution times. conservative treatment was considered the conduct of choice in case of penile fracture (22, 34). however, several studies comparing the long-term results of conservative treatment with the surgical one have demonstrated the superiority of the latter in terms of late complications, in particular the appearance of curvature and erectile dysfunction, better results and shorter hospitalization time (19, 24). therefore, currently immediate surgery is considered the treatment of choice. it allows the evacuation of the hematoma with hemostasis of the blood vessels (21, 35, 36), the proper cleaning of the injured area and the suture of the albuginea (22, 37). the surgery also consists of exploration of the urethra with possible stenting (37, 38) or suture of the urethral wound with end-to-end anastomosis (39). one of the most frequent complications is the penile curvature, secondary to the fibrosis at the site of the trauma; it has been estimated to affect more than 10% of patients with conservative treatment, percentage reduced to less than a half in patients who undergo surgical treatment (9). the incidence of plaque formation similar to those of la peyronie disease (induratio penis plastica), abscesses and penile tissue necrosis reaches up to respectively 25% and 30% in patients treated conservatively. materials and methods in this retrospective study were included all patients with suspected penile fracture that, from january 1987 to june 2013, were admitted to the urology clinic at the hospital of trieste and the urology ambulatory of associazione italiana per l’educazione demografica (aied) in pordenone. a total of 41 patients were examined, then divided into two groups on a clinical basis (signs and symptoms of acute trauma and post-traumatic long-term complications) and according to the time elapsed between the occurrence of the trauma and the urologic evaluation: • group 1 (g1): 23 patients referred from the emergency department with a clinical diagnosis of penile fracture, treated "acutely" or shortly after the trauma (hours-days); • group 2 (g2): 18 patients with anamnestic diagnosis of penile fracture, treated at a distance of time from the trauma for the onset of complications (months). each patient was evaluated in the following manner: 1. cause of the trauma; 2. clinical presentation (signs and symptoms); 3. radiological imaging (performed or not, type, reliability); 4. site of the lesion; 5. urethral involvement; 6. type of treatment adopted (surgical or conservative); 7. complications in the short and long term; 8. reinterventions; 9. follow-up one year after the first visit; 10.international index of erectile function (iief) 15 preand post-trauma; 11.psychological impact of the trauma on the social and sex life of the patient one year after the trauma, evaluated by psycho-sexological questionnaire created “ad hoc” (satisfaction during sexual intercourse, sexual habits, fear and feelings before and after the trauma, coital pain, interpersonal relationships/anxiety before and after the trauma). the patients of g1 were subdivided into two subgroups according to the type of treatment adopted (surgical/conservative). for the surgically treated patients, the following data were also taken into consideration: 1. type of surgery; 2. incision; 3. suture (albugineal, buck's fascia, urethral, dermal); 4. catheter; 5. drainage; 6. dressing and medication. most of the data (points 1 to 9) were collected from the analysis of medical records in the general archive and the g2 system of insiel for patients consulted in trieste, and from internal archives of patients consulted at the aied of pordenone. since the follow-up data resulted often incomplete, patients were contacted via telephone pavan_stesura seveso 16/01/15 10:50 pagina 360 and/or e-mail and invited to the urology clinic of the hospital of cattinara in trieste, for an andrological examination. on this occasion it was decided to administer the iief 15 questionnaire and also a psycho-sexological questionnaire, which was created specifically after specialist consultation in order to assess the psychological impact of the trauma on the social and sex life of the patient one year after its occurrence. a total of 9 patients of those contacted joined the study. in g1, the diagnosis of penile fracture was made on a clinical basis, with the exception of two cases with atypical presentation, in which radiological imaging was used, in one case, and surgical exploration, in the other. in more than half of the patients, both to confirm the diagnosis and to evaluate the extent of damage and then decide the most suitable treatment for the situation, radiological examinations were performed (penile ecd in 16 cases; cavernography in 2 cases one intraoperative; mri of the lower abdomen in 3 cases, always in association penile ecd). based on clinical and imaging findings, 3 patients were found to be false positives. of the 5 patients with suspected tear in the tunica albuginea with concomitant urethral injury, all patients except one reported hematuria. in the latter case, the radiological imaging result was negative, but the surgery confirmed the diagnosis of urethral involvement. uretrography was not performed in any of the cases in order to confirm the diagnosis of urethral injury, unlike what is reported in literature. in 5 cases, a conservative approach was adopted. of the remaining patients, 14 underwent surgical exploration with evacuation of the hematoma, suture of the albugineal laceration and eventual closure of the urethral gap, while one patient refused surgery. to patients undergoing conservative treatment medical therapy was set, variable from case to case, consisting mostly of antibiotics, antiinflammatory drugs, and heparin cream for topical use, ice bags, compression bandages, and anti-androgens. in all cases, a one-month long abstinence from sexual intercourse was recommended. 3 of the 5 patients with lesion of the tunica albuginea associated with suspected urethral injury were candidates for repair surgery and the diagnosis was confirmed during surgical exploration. patients in g2, with anamnestic trauma and admitted for onset of late complications, have been investigated by medical history and physical examination and subsequently with radiological examinations (dynamic penile ecd in 9 cases; cavernography in 2 cases; ecd + cavernography in 3 cases; mri of the lower abdomen + ecd in 1 case; ecd + cavernography + mri in 1 case), which confirmed previous trauma to the corpora cavernosa. of these 18 patients, 5 were submitted to surgery for the appearance of curvature: in 2 cases corporoplasty for straightening according to the technique of nesbit was performed; in 1 case the technique of yachia was employed and in 2 cases patches were used (lyophilized dura patch in one patient, and a venous patch from the right saphenous vein in the other patient). in order to assess the impact of the fracture on the erectile function and other areas of sexual function, and since the study was retrospective, the patients were asked to fill out two iief 15 questionnaires (international index of erectile function): one in reference to the period before the trauma, the other in reference to the year following the penile fracture. to complete the assessment of the impact of penile trauma on social life and sex life of the patient, an ad hoc questionnaire was drawn up with the help of a sex therapist, in order to be understandable and completed by the patient himself. with this questionnaire, we tried to investigate the possible difference in satisfaction during sexual relations between preand posttrauma, the position taken during fracture in cases of post-coital trauma, possible changes in sexual habits and numerical differences in sexual and/or emotional relationships after the trauma (qualitative analysis with yes/no answers). in addition, the following aspects were evaluated quantitatively by using 7-point likert scales: fear (of a new trauma, of repercussions on erectile function, of losing sensitivity, of pain during intercourse), penile sensitivity, pain during sexual intercourse, anxiety (in social relations, of performance, of position). results a total of 41 patients were included in the study, of which 23 belonging to g1 and 18 to g2. in g1 the average age was 40.2 years (range: 26-65) with a prevalence of cases in the third decade (8/23: 34.7%); in g2, the average age was 42 years (range: 23-62) with a prevalence of cases in the fifth decade (5/18: 27.8%). the two groups are therefore age-homogenous. a detailed summary of the characteristics of patients, symptoms, diagnosis and intraoperative findings is described in table 1. diagnosis of penile fracture in g1 the diagnosis of penile fracture was suspected in 23 cases, of which 20 (87%) had a typical clinical presentation (hematoma, swelling, pain, detumescence, noise). in two of these patients (10%), however, the diagnosis was not confirmed by radiological examinations (negative ecd), which therefore were considered to be false positives (fp). in the 3 cases (13%) with atypical clinical appearance (pain, detumescence, urethral bleeding), the diagnosis of penile fracture was confirmed in only 2 patients (66.7%), one case with surgical exploration and the other with radiological imaging, the third resulting therefore fp. thus excluding from the total count the three fp cases, overall the penile fracture was diagnosed in 20/23 (87%) patients. the diagnosis was clinical in 18/20 (90%) cases and radiological imaging was performed in 14/20 (70%) (10/14 ecd, 1/14 ecd + cavernography, 3/14 ecd + mri), which in 13/14 (92.9%) of the patients confirmed the diagnosis of penile fracture, while 1/14 (7.1%) cases was negative (negative ecd). in the latter case, the diagnosis of penile fracture was confirmed by surgery. 14 of 20 patients (70%) underwent surgical exploration; one patient refused the recommended surgery, while 5 of 20 patients (25%) were treated conservatively. the decision for surgical repair was made on the basis of clinical findings and imaging of the extent of the damage, in cases in which it was performed. 361archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 361 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 362 in all cases of g2, i.e. 18 patients, the diagnosis was based on remote case history and clinical presentation. we performed a radiological examination in 16 of 18 patients (88.9%) (9/16 ecd, 2/16 cavernography, 3/16 ecd + cavernography, 1/16 ecd + mri, 1/16 ecd + cavernography + mri) confirming the diagnosis of penile fracture in 16/16 (100%) of the cases. five of 18 patients (27.8%) were submitted to surgery and in all cases, corporoplasty was performed for straightening of the penile curvature. even in this case, the decision for the corrective action was taken based on clinical and imaging findings. patients with urethral lesion the urethral involvement associated with the laceration of the tunica albuginea was diagnosed in 5/20 (25%) patients in g1. in 4 (80%) cases, the cause of the trauma was sexual intercourse, while in 1 (20%) case it was non assessable. four of these 5 patients (80%) reported urethral bleeding; one out of five (20%) had no suggestive signs or symptoms of urethral injury and even the x-ray imaging (ecd) resulted negative, a fact contradicted by the surgical findings. of the 16 patients with unilateral rupture of the tunica albuginea, 1 also had a urethral laceration (6.3%) and 4/4 (100%) of the patients with bilateral rupture of the albuginea had a concomitant urethral injury. three of 5 (60%) patients with suspected urethral involvement associated with rupture of the tunica albuginea underwent surgical treatment with simultaneous suturing of the tunica and the urethral mucosa; in 3/3 (100%) of the cases the urethral rupture was confirmed by surgical exploration. among patients treated surgically only one reported post-operative urinary disorders. this patient complained of recurrent urinary tract infections and difficulty in urination; through targeted radiological investigations (voiding cystourethrogram and ecd), he was diagnosed with a urethral stenosis due to the presence of a foreign body granuloma (suture). the patient was re-operated for the removal of the granuloma. two of 5 patients (30%) with suspected urethral trauma treated conservatively showed no complications during the follow-up. of the 18 patients in g2 none had concomitant urethral involvement, as confirmed by the clinical appearance (due to the absence of urethral bleeding in all cases), and by imaging findings. follow-up of patients in acute care immediately after the trauma of the 20 patients receiving acute care immediately after the trauma (g1), 14 underwent surgery; no patients (100%) showed post-surgical complications in the short term. in addition, 9/14 (64.3%) patients during followup did not show long-term complications, whereas 5/14 (35.7%) patients had at least one complication. in particular, in 5 cases out of 14 (35.7%) on examination it was possible to appreciate plaques/nodules along the penile shaft, and 3 out of 14 patients (21.4%) reported pain and paresthesia during sexual intercourse; 1/14 (7.1%) presented penile curvature, secondary to the corpora cavernosa suturing at surgery, and 1/14 (7.1%) complained of urinary disorders. of the 14 surgically treated patients 3 were re-operated (21.4%) for the correction of complications: the patient with penile curvature was subjected to corporoplasty, another patient had removal of a foreign body granuloma causing urethral stricture and urinary disorders, patients with suspected penile fracture (n) 23 average age of patients with range (years) 40,2 (26-65) causes of trauma • sexual intercourse 18/23 (78,6%) • masturbation 1/23 (4%) • non assessable 4/23 (17,4%) clinical signs and symptoms • penile hematoma 19/23 (82,6%) • penile swelling 10/23 (43,5%) • pain 14/23 (60,9%) • detumescence 19/23 (82,6%) • noise 8/23 (34,8%) • curvature 3/23 (13%) • urethral bleeding 5/23 (21,7%) • erectile dysfunction (ed) 0/23 (0%) diagnosis of penile fracture 20/23 (87%) • clinical 18/20 (90%) • clinical (-) with radiological imaging (+) 1/20 (5%) • clinical (-) with surgical exploration (+) 1/20 (5%) • radiological imaging 14/20 (70%) • radiological confirmation of penile fracture diagnosis 13/14 (92,9%) false positives 3/23 (13%) • atypical clinical presentation 1/3 (33,3%) • clinical presentation (+), radiological imaging (-) 2/3 (66,7) patients subjected to surgery 14/20 (70%) access to the tunica albuginea • degloving with circumcision 11/14 (78,6%) • peno-scrotal skin incision on the median raphe 1/14 (7,1%) • degloving+second access 2/14 (14,3%) penile fracture confirmed by surgical exploration 14/14 (100%) rupture of the tunica albuginea • unilateral 16/20 (80%) • bilateral 4/20 (20%) unilateral rupture of the tunica albuginea • right corpus cavernosum 10/16 (62,5%) • left corpus cavernosum 6/16 (37,5%) urethral involvement 5/20 (25%) average of hospitalization days 4,5 (0-11) • average of hospitalization days of patients with surgical treatment 5,6 (15-3) • average of hospitalization days of patients with conservative treatment 2,5 (4-0) re-intervention 3/14 (21,4%) table 1. characteristics, clinical symptoms, intraoperative findings of patients in g1. • absence of complications 12/19 (63,1%) • plaques/nodules along the penile shaft 7/19 (36,8%) • pain/paresthesia 4/19 (21%) • curvature 2/19 (10,5%) • urinary disorders 1/19 (5,3%) • erectile dysfunction (ed) 2/7 (28,6%) table 2. long term complications of patients in acute care immediately after the trauma. pavan_stesura seveso 16/01/15 10:50 pagina 362 while the third was subjected to dorsal incision of the prepuce for the onset of phimosis, secondary to ischemia of the skin flaps for excessive devascularization linked to degloving, since he had not been circumcised during the repair surgery of the tunica albuginea. among the 5 patients treated conservatively in g1, 3 (60%) did not present long-term complications. in 2 of 5 patients with late complications (40%), on physical examination plaques/nodules along the penile shaft were palpable in both cases, and in 1 patient (20%) penile curvature was also present. in the latter case, the patient also complained of pain and paresthesia during sexual intercourse. overall, 19 of 20 patients were available for follow-up, as for one patient with clinical diagnosis of penile fracture, which had refused surgical treatment, it was not possible to collect the documentation. of these, 12 patients (63.1 %) did not report any complications, while 7/19 presented plaques/nodules, 4/19 (21%) pain/paresthesia during sexual intercourse, 2/19 (10.5%) curvature, and 1/19 (5.3%) reported urinary disorders. with regard to follow-up about erectile deficiency (ed), 7 of the 20 patients contacted (35%) agreed to fill out two iief 15 questionnaires. the analysis of the pretrauma iief data showed that 7/7 (100%) patients had no disorder of the sexual sphere, with a total score of 72 to 54 and in all patients the erectile function was between 27 and 30 points. taking into account the iief post-trauma (about 1 year), 2 out of 7 patients (28.6%) developed post-traumatic ed: mild in one case (24 points) and moderately severe in the other (16 points) (table 2). follow-up of patients treated at a distance of time fromthe trauma due to the onset of complications of the 18 patients treated at a distance of time from the trauma (g2) all have manifested long-term complications, as they reported to the urologist just for the onset of symptoms/signs related to the complications. in particular, 8/18 (44.4%) presented penile plaques/nodules, 4/18 (22.2%) reported pain and paresthesia during sexual intercourse, 14/18 (77.8%) had penile curvature and 1/18 (5.6%) complained of urinary disorders. in one case of 18 (5.6%), herniation of the corpora cavernosa was present. in this group of patients, the data related to the ed were collected by consulting the medical records and it was found that 6 patients (33.3%) experienced an ed (table 3). four of the 18 patients contacted responded to the iief questionnaire and of these, 3 had an ed. in one case the dysfunction was moderately severe (score of 15) and in two cases mild (score of 19 and 21 respectively). follow-up of patients subject to the psycho-sexological questionnaire nine of the 41 patients contacted (22%) attended the psycho-sexological evaluation. of these, 7 belonged to g1 and 2 to g2. four out of 9 (44.4%) patients interviewed have not noticed any difference in preand posttrauma sexual intercourse. the 5 patients (55.6%) who noticed a difference, responded however in different manners, mentioning: changes in their sexual habits (1 pt.), fear of a new trauma (1 pt.), fear of their partner to cause further trauma (1 pt.), fear of the trauma itself (1 pt.), and one patient was not able to answer . the cause of trauma was in 8 out of 9 cases (88.9%) sexual intercourse and in 1 case (11.1%) related to masturbation. with regard to the position that led to penile fracture, 4 of 8 patients (50%) reported having had trauma while the woman stood over the man, 3 of 8 (37.5%) while the man penetrated the woman from behind and 1 in 8 (12.5%) while the man stood over the woman. among patients with post-coital trauma, 4 (50%) still practice the position that caused the fracture, while 4 (50%) avoid it: 2/4 (50%) because they are afraid of a second trauma, 1/4 (25%) because their partner is afraid to cause a new fracture and in 1/4 (25%) because of both coexisting fears. none of the patients surveyed, however, reported a variation in the number of emotional and/or sexual relationships before and after the trauma and none has attributed the cause of the trauma to their personal sex knowledge. seven out of 9 (77.8%) patients in the year following fracture reported that they had been afraid of a new trauma, fear that has however diminished with the passage of time. by classifying the level of fear according to a 7-point likert scale, the level of fear was maximum (7 on the likert scale) in 2 patients, mediumhigh (4 and 5) in 3 patients and average low (3 and 2) in 2 patients. at the time of completing the questionnaire, therefore over a year after the trauma, the level of fear had lowered by about two points in all patients. eight of 9 post-trauma patients (88.9%) were afraid of repercussions on the erectile function, such fear in 2 cases was "very high" (7 on the likert scale), high in 1 case (6), medium-high in 2 cases (4) and medium-low and low in the other 2 cases (2 and 1). the fear of losing penile sensitivity after trauma was reported in 7 out of 9 patients (77.8%); in these 7 cases the fear was highest in 2 (7 on the likert scale), high in 1 (6), medium-high in another one (5), medium-low in 2 (3 and 2) and low in one other case (1). six of 9 patients (66.7%) had fear of experiencing pain during sexual intercourse after the trauma: in 1 patient the fear was high (7 on the likert scale), in 2 patients medium-high (5 and 4), in 1 medium-low (2) and in 2 cases low (1 on the scale). the questionnaire also investigated the penile sensitivity preand posttrauma, which in 6 of 9 patients (66.7%) was found to be unchanged. in the three cases in which a change was reported, for two patients the cause was attributed to surgery, and for one patient to both surgery and trauma itself. within one year from the trauma, five of 9 patients (55.6%) experienced pain during sexual intercourse. the intensity of pain varied from patient to patient: in 1 patient it was very high (7 on the likert 363archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome • absence of complications 0/18 (0%) • plaques/nodules along the penile shaft 8/18 (44,4%) • pain/paresthesia 4/18 (22,2%) • curvature 14/18 (77,8%) • urinary disorders 1/18 (5,6%) • hernation of the corpora cavernosa 1/18 (5,6%) • erectile dysfunction (ed) 6/18 (33,3%) table 3. long term complications in patience treated at a distance of time after the trauma. pavan_stesura seveso 16/01/15 10:50 pagina 363 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 364 scale), in 1 patient medium-high (4) and in 3 patients very low (1). the penile fracture in 3 out of 9 patients (33.3%) increased anxiety in social relations: in 1 patient the anxiety level increased by 2 points on the likert scale, from 0 (corresponding to "no anxiety") at 2 ("low anxiety"); in 1 patient it augmented from 1 ("very low") to 4 ("moderately high"); in 1 patient the trauma increased anxiety in social relations with a shift from 0 to 7 (corresponding to "very high"). five of 9 patients (55.6%) reported an increase in anxiety from performance in response to the trauma: in 1 patient, the increase was from 0 to 1; in another patient from 2 to 3 ("moderately low"); in one other case the increase was from 6 ("very high") to 7. in 2 cases, however, the increased anxiety from performance was more significant, from a score of 0 to 6 in one case and from 0 to 5 in the other case. the penile trauma also induced in 6 of 9 patients (66.7%) an increase in anxiety from position (meaning as "anxiety from position” a fear of experiencing certain positions during intercourse). of these 6 patients: one patient has gone from 1 to 2; 1 from 0 to 2; 1 other increased from 1 to 7; another from 0 to 3, and finally 2 patients shifted from 0 to 4. comparison between surgically treated patients and conservatively treated patients in group 1 the average age of patients treated surgically in g1 was 35.9 years (27-63) and that of the treated conservatively was 43.4 years (26-65). analyzing the incidence rate of complications developed in the long-term by patients in g1, it was showed that there is no difference comparing the surgically treated patients (35.7%, ie 5/14 pcs.) with those treated conservatively (40%, ie 2/5 pcs.). the data relative to each type of complications are summarized in the table below (table 4). in particular, an erectile dysfunction (ed) of mild severity (iief of 24) occurred in 25% (1/4) of the surgically treated patients who responded to the iief 15, unlike patients treated conservatively in which the ed was of modest severity (iief of 16 ) in 33.3% (1/3). the results were compared using fisher's exact test; from the general analysis and that of each single complication. no statistically significant information was revealed (p > 0.05) with regard to the correlation between the type of treatment adopted and the onset of complications. three out of 14 patients (21.4%) treated surgically were re-operated for the onset of a complication, while none of the patients to whom medical therapy was prescribed has been subjected to surgery for the onset of complications at a distance of time. comparison between patients treated "acutely" and the patients treated at a distance of time for the onset of complications the average age of patients in g1 was 40.2 years (26-65) and in g2 of 42 years (23-62): the two groups therefore are fairly homogeneous in respect to age. the incidence rate of long-term complications was 36.8% (7/19) and 100% (18/18) in g1 and g2 respectively. erectile dysfunction (ed) of medium/mild severity occurred in 28.6% (2/7) of patients in g1 and of medium/high severity in 33.3% (6/18) of patients in g2. the results were compared using fisher's exact test; from the general analysis of long-term complications in the two groups a p value < 0.0001 with a relative risk (rr) equal to 0.3684 were obtained. with these data, it may be concluded that patients treated at a distance of time from the trauma have the probability of manifesting long-term complications 36.8 times higher than those receiving care immediately after the trauma. the specific analysis of each individual complication has not revealed anything statistically significant, except for the occurrence of penile curvature. in this case, in fact, comparing with fisher's exact test the occurrence rates of this complication in the two different groups, we obtained a p value < 0.0001 (rr of 0.1353 and confidence interval (ci) between 0.03564 and 0.5139). based on these data it can be stated that the treatment at a distance of time from the trauma is likely to lead to penile curvature 13.5 times more than the immediate treatment. regarding the ed, according to the results obtained, one cannot assert that patients with treatment at a distance of time have a greater risk of developing ed compared to patients treated immediately after the trauma. the only difference was the degree of ed (mild to moderate in patients of g1/moderate to severe in patients of g2), but other assessments in this matter cannot be made because a few patients were available for completing the iief 15 questionnaire and this was the only method used in this study for the evaluation of erectile function. finally, again from the data obtained, it can be concluded that an inevitable long-term complication in the healing of the rupture of the tunica albuginea, reported in almost all patients, including those undergoing surgical treatment, is the permanent but clinically irrelevant formation of fibrotic scar nodules on the side of the repaired tissue. discussion the fracture of the penis is rare urological emergency, even if the total number of cases is certainly underestimated, as many patients do not seek medical care because of embarrassment or report to the urologist belatedly for the occurrence of complications (penile curvature, erectile dysfunction). however, the number of patients long-term complications patients in acute care patients treated at a distance of time p presence of complications 7/19 (36,8%) 18/18 (100%) < 0,0001 • plaques/nodules 7/19 (36,8%) 8/18 (44,4%) n.s. • pain/paresthesia 4/19 (21%) 4/18 (22,2%) n.s. • curvature 2/19 (10,5%) 14/18 (77,8%) < 0,0001 • herniation 0/19 1/18 (5,6%) n.s. • urinary disorders 1/19 (5,3%) 1/18 (5,6%) n.s. • ed 2/7 (28,6%) 6/18 (33,3%) n.s. table 4. comparison of long-term complications. pavan_stesura seveso 16/01/15 10:50 pagina 364 in our case archive is in line with european case studies. the penile fracture or traumatic rupture of the corpora cavernosa is an injury that occurs in the erect penis. many authors (17, 24, 25, 37) in fact recommend that the term "fracture" should be restricted to cases of trauma that occur during penile erection. in western countries it is mainly caused by sexual intercourse (6, 14), in middle-eastern countries instead the predominant cause is masturbation (8, 14, 40, 41). the etiological difference in these two regions may be explained by the strict prohibition in the muslim areas of sexual relations outside of marriage (6, 23) resulting in increased frequency of masturbation among the population. the high incidence of penile fracture in these regions of the mediterranean could be because the time to reach orgasm with penile manipulation is longer than with sexual intercourse, and thus the risk of tearing the tunica albuginea increases. in addition, the preponderance of post-coital penile trauma in western countries, including the united states, could reflect a more permissive culture in relation to sexual intercourse (6). in this study, the causes of trauma have been sexual intercourse and masturbation in 31/41 (75.6%) and 2/41 (4.9%) patients, respectively, reflecting the situation in western countries. in most cases, the coital trauma occurred while the woman was on top of the man, when the full weight of the partner presses on the erect penis or when the erect penis, out of the vagina, is accidentally pushed against the woman’s perineum. in 8 of 41 patients (19.5%) it was not possible to investigate the etiology of the trauma, and this reflects the natural embarrassment to which this condition can lead (14, 42). in the 23 patients of g1 with suspected penile fracture who reported immediately after the trauma, 19/23 (82.6%) showed a hematoma along the penile shaft, and in 10 of these (43.5%) a swelling of the penis was associated. pain and detumescence were reported in 14/23 (60.9%) and 19/23 (82.6%) cases, respectively. however, only 7 of the 20 patients (35%) with a confirmed diagnosis of penile fracture confirmed by radiological imaging and/or surgical exploration presented the classical clinical triad (hematoma, noise and immediate detumescence). in literature, noise is reported in 47.7 to 100% of patients, while pain is present in 48.5 to 100% of cases, demonstrating a variable constellation of symptoms associated with this condition (7, 9, 12, 14, 34, 40, 43). in addition to the clinical diagnosis in doubtful cases with atypical clinical appearance, radiological imaging can be made use of to obtain a differential diagnosis of diseases that can mimic penile fracture and thus avoid an unnecessary surgery (33, 34, 44). in this study the radiological investigations were performed both in clinically typical and atypical cases, for a total of 16 of 23 patients (69.6%) with suspicion of penile fracture, and this data comes in contrast with information reported in literature. in our case study, we preferred to investigate and ascertain the rupture of the tunica albuginea, drawing on the advice of a great team of radiology specialists with high experience in the field of urology, before subjecting the patient to surgical exploration. all 16 patients who underwent xray examination were also subject to penile ecd, the radiological technique of choice for evaluating patients with penile trauma (1, 31). the anatomy and the penile vasculature can in fact be accurately described by the shades of gray of the doppler ultrasound technique, so that the nature and extent of the lesion can be fully accounted for in many cases (1). the ecd is able to detect the location of the lesion through the interruption of the echogenic line of the tunica albuginea (1, 31). however there have been reports of false-negative results (1, 45, 46), as pronounced in the presence of a hematoma or edema which render the interpretation difficult (6). in this retrospective analysis, the ecd has confirmed the diagnosis of penile fracture in 13 of 16 cases (81.3%), while in 2 cases (12.5%) it excluded the rupture of the tunica albuginea and in 6.3% of cases (1/16), penile edc was found to be a false negative. the cavernography is an easy procedure to perform on the operating table, with or without anesthesia (37); however, being a noninvasive diagnostic technique with potential complications such as priapism (25, 47), infection (14) and allergic reactions (6), which could lead to cavernous fibrosis (1, 37), it was performed in only 2 out of 16 cases (12.5%): in one case in combination with edc and intraoperative in the other one. the mri is a noninvasive procedure, very accurate in the evaluation of penile fracture and that can help determine the most appropriate type of treatment; however because of its high cost (6), it is rarely used in acute situations and many penile trauma cases are been diagnosed only with clinical presentation and ecd. in this study, it has been employed only in 18.8% (3 /16) of cases and always in combination with edc. the prevalence of urethral lesions in this study was 25% (5 /20) and this is in line with literature, which reports a proportion of cases of urethral involvement between 20% and 25% (24). four out of 5 (80%) patients with urethral involvement reported urethral bleeding, demonstrating that the lesion of the urethra occurs very commonly with an initial macroscopic presence of red blood cells in the urine. urethral bleeding (25), hematuria and voiding difficulties (3, 24) indeed indicate urethral rupture, however the absence of these signs and symptoms does not exclude possible urethral involvement (3, 5, 43, 48). in medical literature, there have been reports of urethral laceration even in the absence of a rupture of the corpora cavernosa (13, 49). the clinical presentation in these cases of isolated urethral injury differs from typical penile fractures for the absence of noise, penile deformity and for the absence of palpable penile defects (49). as reported in the literature (6, 24), in this study the bilateral fracture of the corpora cavernosa is very frequently associated with urethral injury; in fact, 100% of patients with bilateral rupture of the tunica albuginea had a concomitant urethral injury. in the case of bilateral laceration of the albuginea, the urologist should always give in the operating room special attention to the urethra (6, 14, 24). fergany et al. also suggest exploring the other cavernous body when one is broken and the urethra is injured simultaneously. three out of 5 (60%) patients with urethral injury were subjected to surgical repair, but the type of treatment, surgical or conservative, of partial lesions of the urethra remains controversial (14, 42). 365archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 365 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 366 in our series of patients with urethral involvement, 1 in 5 (20%) developed a urethral stenosis with associated urinary disorders. patients with rupture of the tunica albuginea with concomitant urethral injury are much more likely to develop post-operative complications, so a close follow-up is recommended (42). some authors recommend the use of retrograde cystourethrography or urethroscopy in cases of suspected urethral injury (1, 30); an indirect sign of urethral injury is the presence of air in the corpus cavernosum (1, 31). however, false negative results may be reported (5, 7), since the urethrography has limitations and might not detect the tear in the case of post-coital urethral bleeding (6, 23, 19). none of our cases with suspicion of concomitant urethral involvement, however, has been subjected to such radiological investigations. a direct approach was preferred, looking intraoperative urethral injury (7, 12). kamdar et al. (7) recommend, in the case of high suspicion of urethral injury, to use a flexible cystoscopy in the operating room prior to inserting the bladder catheter, in order to allow the examination of the urethral mucosa and display the extension of the rupture before placing the catheter. the urethral injury is much more common when the fracture occurs during sexual intercourse, compared to other causes of penile fracture, and this is because on this occasion the force applied is stronger than during masturbation (7, 8, 12, 23, 24). this finding was also confirmed by our study. in literature it is widely confirmed that immediate surgical repair of the albugineal rupture is the best method of treatment of a penile fracture, leading to excellent results with less time and less risk of hospitalization for erectile dysfunction and curvature in the long term (24). in our case study, 14 of 20 patients (70%) underwent surgical exploration; of these, 5 patients (35.7%) had complications during follow-up. specifically, all 5 patients (35.7%) presented plaques/nodules along the penile shaft; in addition, 3 of these (21.4%) reported paresthesia and pain during sexual intercourse, 1 (7.1%) reported penile curvature and 1 (7.1%) complained of urinary disorders. in this study, 1 in 4 (25%) patients with confirmed diagnosis of penile fracture treated surgically immediately after the trauma, to whom it was possible to administer the iief questionnaire, developed post-traumatic ed. this percentage is much higher than the 0-17% reported in literature (5, 12, 14, 40). this discrepancy may be due to many reasons, first the lack of availability of patients contacted to participate in the study and, consequently, to the scarcity of data obtained from the compilation of the iief questionnaire by patients themselves. in addition, the average age of patients treated surgically immediately after the trauma was 35.9 years in our study, an age higher than that reported in several case studies (27-29 years) (10, 34, 43). an older age may be associated with a higher prevalence of ed before the trauma and consequently this data in our study may have led to a higher percentage of post-traumatic ed. in this context, therefore, the erectile function before the trauma should always be assessed to monitor more precisely any posttraumatic changes, because patients with a preexisting ed are much more prone to deterioration after surgery (14). in our study, erectile function, both pre-and posttrauma, was assessed through the administration of two iief questionnaires to the patients. although the pretrauma state was estimated retrospectively, and thus represents a source of bias in the study, it is still useful as a reference, although in our series of 4 patients who completed the iief, no one had a pretrauma ed. in any case, this data, albeit limited to the small sample size, cannot be compared in literature, since all of the studies examined lack a preevaluation of the erectile function domain of trauma patients who underwent surgical exploration, and there is only sporadic data on this important issue (14). none of our patients with post-traumatic ed, however, necessitated therapy. this suggests that these patients, still able to have satisfactory sexual intercourse, may not seek the attention of the urologist after surgery, even if they suffer from ed, assuming a higher percentage of ed than that reported in literature. another important aspect is the adequate evaluation of ed, since in medical literature there is a high variability of measurement criteria (9, 12, 41), which means that adopting different systems of evaluation leads to equally diverse results and therefore not comparable with each other. the best way to classify ed is the iief and penile dynamic ecd (14), but in our study, the penile ecd during follow-up was not performed in all patients. some patients may show a normal ecd but with a pathological iief score in a context of psychological ed (12). in the study of ibrahiem et al., 36.4% of men with erectile dysfunction after penile fracture had a normal penile ecd. these patients reported extreme fear of incurring another trauma, and this led to a very limited sex life despite the absence of erectile dysfunction (12). in this regard, the psycho-sexological questionnaire administered to our patients revealed that the only patient with post-traumatic ed in our case series had a very strong fear of impact on the erectile function, of losing penile sensitivity and experiencing pain during sexual intercourse. he also reported, again after the trauma, high social and performance anxiety and a moderate anxiety from position. taking these data into consideration, therefore, we may consider the ed of this patient is not so much organic, thus linked to the alterations caused by trauma to the erectile tissue and the tunica albuginea, but especially psychological, as described by ibrahien. considering the period of follow-up of patients who have suffered a fracture of the penis, it should long enough, to the point of unmasking any ed (40, 43). in a recent study led by gamal et al., ed appeared in 4% of cases after a mean follow-up of 20.8 months (34), while other studies with a longer follow-up of 90 months showed an ed incidence of between 6.6% and 17% (5, 12). this relationship is not clear and should be evaluated in future studies (14). finally, many reports on penile fracture are based on a patient population of the middle east (12, 41). in the different ethnic groups, however, considering the different etiology of penile fractures, there might be a different percentage of post-traumatic ed, which might explain the higher rate of ed in our study. pavan_stesura seveso 16/01/15 10:50 pagina 366 only one case in 14 (7.1%) treated surgically developed a penile curvature. in 13 cases out of 14 (92.8%), a subcoronal incision with degloving of the penile skin was performed. this surgical technique allows in fact an excellent exposure of both the corpora cavernosa and the corpus spongiosum of the urethra (6, 29). in 2 cases, however, a second incision was necessary because the lesion was proximal. in only 1 case a penoscrotal cutaneous incision was performed on the median raphe, a procedure which avoids excessive disconnection from degloving and delivers good cosmetic results. this incision allows the evacuation of the hematoma and repair of the corpora cavernosa and is recommended in case of widespread edema and hematoma that prevent degloving (7). in addition, it can also serve as a guide for the proximal degloving (50). while the laceration of the tunica albuginea is usually sutured longitudinally along the axis of the penis, the skin closure in the case of peno-scrotal incision could be performed transversely if the longitudinal closure should cause a throttling (51). the need for catheterization should be evaluated carefully to reduce the risk of infection and possible urethral trauma (15), but in all patients in our study a bladder catheter was positioned to identify the urethra and thus prevent accidental injuries during inspection of the corpora cavernosa to search the albugineal breach, and also to allow possible repair of a concomitant urethral injury. in the absence of urethral laceration in our patients, the catheter was removed in the first post-operative day, while in patients with concomitant urethral injury the catheterization time was longer, in order to allow the urethral suture to stabilize. according to medical literature, in case of simultaneous rupture of the albuginea and the urethra, the catheter may also be left for 7-10 days after surgery (7). the search for the albugineal lesion and therefore the state of the corpora cavernosa and further the sealing of the suture were investigated on the operating table by means of the intracavernous injection of isotonic saline, sometimes mixed with methylene blue dye, causing an artificial tumescence. this is achieved by placing a tourniquet at the base of the penis. all patients in our case study was finally given a semicompressive dressing after surgery. the post-surgical therapy consisted, in all cases, of abstinence from sexual intercourse for a month, of administration of antibiotics, painkillers/analgesics. only in one case, an anti-androgen was administered, as normally the postoperative pain prevents erection. in literature, conservative treatment today is more the exception than the rule, because its results are less satisfactory than those of surgical treatment (6). conservative therapy is recommended when the corpora cavernosa are intact, but in the case of acute penile fracture, it may be difficult to exclude the complete rupture of the corpora cavernosa, even with a diagnostic radiological procedure (25, 48). in our study, five of 20 (25%) patients were treated conservatively. one of these had atypical clinical presentation, but the ecd and mri were suggestive of penile fracture. medical therapy adopted involved in the majority of cases the administration of anti-inflammatory/pain relievers, antibiotics, anti-androgens, topical heparin gels, ice bags and the positioning of a compressive dressing which allowed exposure of the glans so as to prevent or detect any penile ischemia (38, 52). two patients, 1 with clinical diagnosis of penile fracture confirmed by ecd and 1 with only a radiological diagnosis of penile trauma (ecd and positive mri), have developed long-term complications such as plaques/nodules along the penile shaft in both cases, pain and paresthesia during intercourse and penile curvature in one case (20%); ed was reported in only 1 patient (20%). these data are in contrast with what is described in literature, as the penile curvature and ed following conservative treatment are reported in 50-80% of cases, for a total of long-term complications after conservative therapy of 80% (34, 41). in the group treated “acutely” the average number of days of hospitalization (4.5 days overall) was higher in patients who underwent surgical exploration (5.6 days) compared to patients treated conservatively (2.5 days) and this is in stark contrast to the literature that shows the average number of days of hospitalization for patients treated conservatively to be 14 (24). a longer stay in operated patients enrolled in our study may be sought in the presence of cases with concomitant urethral injury, whose post-operative course was linked to the need to maintain the bladder catheter in place for longer, even if the incidence of urethral lesion in our patients was in line with other studies reported in literature. in a study by el-sherif (15), patients treated conservatively spent on average 2.3 days in the hospital, while those treated surgically 4.1 days. the author explains this finding by showing that the conservatively treated group had not been catheterized and did not require special medical treatment. the most common long-term complications of penile trauma are: plaques/nodules along the penile shaft at the site of injury, pain and paresthesia during sexual intercourse, painful erections, penile curvature, erectile dysfunction and urinary disorders. they can occur both in patients treated conservatively and in patients treated surgically (6). in our study, the incidence rate of long-term complications was similar in patients treated surgically immediately after the trauma and in those treated conservatively. in fact, in the first group (treated surgically), the complication rate was 35.7%, while in patients treated conservatively was 40%. this difference in our study is not statistically significant. in light of this data, we can state that the acute conservative treatment does not have a higher risk of long-term complications compared to acute surgical treatment, and that the type of treatment adopted does not affect the overall incidence of long-term complications, which depend on the trauma itself, unlike what is instead reported in literature (22, 34). in this study we also took into consideration 18 patients treated at a distance of time from the trauma for the onset of complications. these patients had not resorted to urological examination immediately after the trauma and therefore had not been subjected to any kind of acute care. they have turned to the doctor in the moment in which long-term complications related to anamnestic penile fracture appeared. one hundred percent of these patients experienced a complication and 367archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 367 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 368 therefore this finding fits with what has been described in literature, as the overall rate of complications after conservative treatment corresponds to 80% (34, 41). in 77.8% of cases penile curvature was reported, which in 35.7% of patients was treated surgically because it constituted an obstacle in their intimate life; 33.3% of cases developed ed. the ratio of penile curvature in this group of patients was in line with the data for post-conservative treatment curvature reported in the literature (50-80%) (34, 41), while the incidence of ed was lower (50-80%). this can be explained by the fact that many patients with previous penile trauma, who had a mild ed that did not prevent normal sexual relations, have not felt the need for a urological examination. comparing the incidence rates of long-term complications of patients receiving acute care (g1) and patients treated at a distance of time (g2), it was shown that nonimmediate treatment after the trauma has a 36.8% risk of leading to complications and in particular a 13.5% risk of generating a penile curvature. from these data it may be concluded that the acute treatment of a penile fracture would be more suitable, reducing the overall risk of long-term complications secondary to trauma, particularly the risk of penile curvature. the immediate treatment, whether surgical or conservative, then turns out to be the ideal treatment of penile fractures, but it the choice does not depend on the doctor, but rather the patient, which for the embarrassment generated by the situation does not seek medical care immediately and requires specialist advice only when complications are already notable. given the small number of patients who responded to the iief, we do not have sufficient data to enable us to assess the post-traumatic ed. however, the lack of participation in completing the iief questionnaire may presume a certain well-being of patients, who then have no interest in contacting the urologist. from the analysis of the psycho-sexological questionnaire no conclusions can be drawn, as only few patients from an already small group, were available to answer the questions submitted. this might also indicate a reluctance to face again the traumatic event, perhaps to relive the negative experience, or, on the contrary, it could indicate a certain well-being of the patient, who does not feel the need to undergo a medical evaluation. considering all the above, the interpretation of the data can be very variable. this questionnaire, not being validated, but purposebuilt by a sex therapist to investigate certain personal aspects not investigated by the iief, does not allow for a quantitative analysis of data; it only allows a qualitative analysis of data that differ greatly from patient to patient. however, we can affirm that the penile fracture definitely has a psychological impact on the patient, especially in the year following the trauma. the psychological sphere that is mainly affected is that of fear. the majority of patients admitted in fact that in the year following the trauma they experienced fear of new trauma, fear that in several cases was experienced also by the partners. the same thing can be said about the fear of the repercussions on erectile function, fear of losing penile sensitivity and fear of experiencing pain during intercourse. however, all these fears diminish with the passage of time, perhaps for the reacquisition by the patient of selfconfidence, and having ascertained that despite the trauma “everything was back to normal". despite the fear, patients have not noticed differences in sexual relationships before and after the trauma; the few patients who have noticed these differences, however, gave very different answers, so it was difficult to make a quantitative analysis of the data. in general, even anxiety in social relationships, anxiety from position and performance have not undergone much change between the preand posttrauma states. limitations of the study this study is limited by the number of patients, especially in comparison with other studies from the middle east or the mediterranean basin (9, 12, 41). in our case series, already numerically limited from the start, it was possible to evaluate the erectile function and psychosexological impact of the trauma on the emotional and sex lives of the patients only in 9 cases out of a total of 41; therefore, the interpretation of the data obtained has proven difficult in some respects. many patients with penile fracture have not turned to the doctor for their possible welfare and/or the non-occurrence of complications. however, this is not clear and must be taken into account when interpreting the results of this study. in addition, the retrospective evaluation of patient status before the injury might have caused some bias, but this should be considered as a benefit of the study, since the evaluation before the occurrence of a penile fracture is not possible. conclusions the fracture of the penis is a rare urological emergency, even if underestimated, probably because of socio-cultural inhibition of the patients, who are ashamed to report to the doctor. sexual intercourse and penile manipulation are the most frequent causes of this type of trauma, depending on the geographical area analyzed. the radiological imaging does not replace clinical evaluation, but in our experience, it is very useful in cases with atypical clinical presentation and in cases of doubt, especially because it allows assessing the need for surgical exploration. the penile doppler ultrasound is the radiological technique of choice, given its diagnostic accuracy, non-invasiveness, speed of execution and low cost. a concomitant urethral injury must always be taken into account especially in case of urethral bleeding or bilateral lesion of the corpora cavernosa. in the literature, the surgical technique most recommended is the incision with sub-glandular de-gloving of the penile skin, which allows a good exposure and viewing of the corpora cavernosa and the corpus spongiosum of the urethra, in order to simultaneously repair the tunica albuginea and the eventual urethral injury. in our study, in contrast to what is reported in literature, we found no difference in the onset of long-term complications among patients treated surgically compared to those treated conservatively. instead, comparing patients treated "acutely" with those treated at a distance of time after the trauma, it was found that the latter have a higher probability of experiencing complications, and in parpavan_stesura seveso 16/01/15 10:50 pagina 368 ticular of experiencing penile curvature. however, taking into account the small number of patients who were available for filling the iief 15 questionnaire, we cannot state that patients treated after a long time have a higher risk of developing ed than those treated immediately after the trauma. from the results obtained, we can only say that in the two groups ed occurred with varying severity: 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2000; 20:1397-405. 33. murray ks, gilbert m, ricci lr, et al. penile fracture and magnetic resonance imaging. int braz j urol. 2012; 38:287-8. 34. gamal wm, osman mm, hammady a, et al. j trauma 2011; 71:491-3. 35. nehru-babu m, hendry d, ai-saffar n. rupture of the dorsal vein mimicking fracture of the penis. bju int. 1999; 84:179-80. 36. sant gr. rupture of the corpus cavernosum of the penis. arch surg. 1981; 116:1176-8. 37. klein fa, smith mj, miller n. penile fracture: diagnosis and management. j trauma. 1985; 25:1090-2. 369archivio italiano di urologia e andrologia 2014; 86, 4 penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome pavan_stesura seveso 16/01/15 10:50 pagina 369 archivio italiano di urologia e andrologia 2014; 86, 4 n. pavan, g. tezzot, g. liguori, r. napoli, p. umari, m. rizzo, g. chiriacò, g. chiapparrone, f. vedovo, m. bertolotto, c. trombetta 370 38. kowalczyk j, athens a, grimaldi a. penile fracture: an unusual presentation with lacerations of bilateral corpora cavernosa and partial distruption of the urethra. urology. 1994; 44:599-601. 39. de rose af, giglio m, carmignani g. traumatic rupture of the corpora cavernosa: new physiopathologic acquisitions. urology. 2001; 57:319-22. 40. ateyah a, mostafa t, nasser ta, et al. penile fracture: surgical repair and late effects on erectile function. j sex med. 2008; 5:1496502. 41. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 352 patients from kermanshah, iran. j sex med. 2009; 6:1141-50. 42. sawh sl, o'leary mp, ferreira md, et al. fractured penis: a review. int j impot res. 2008; 20:366-9. 43. mydlo jh. surgeon experience with penile fracture. j urol 2001; 166:526-8. 44. kachewar s, kulkarni d. ultrasound evaluation of penile fractures. biomed imaging interv j. 2011; 7:e27. 45. martinez perez e, arnaiz esteban f, perez arbej ja, et al. fractura de pene: dos nuevos casos. revision de literatura. utilidad de la ecografia. arch esp urol. 1997; 50:1099-1102. 46. koga s, saito y, arakaki y, et al. sonography in fracture of the penis. br j urol. 1993; 72:228-9. 47. de stefani s, stubinski r, ferneti f, et al. penile fracture and associated urethral injury. scientific world journal. 2004; 4 suppl 1:92-9. 48. mydlo jh, hayyeri m, macchia rj. urethrography imaging in a small series of penile fractures: a comparison with surgical findings. urology. 1998; 51:616-19. 49. mohapatra tp, kumar s. reverse coitus: mechanism of urethral injury in male partner. j urol. 1990; 144:1467-8. 50. su lm, sutaria pm, eid jf. repair of penile rupture through a high-scrotal midline raphe incision. urology. 1998; 52:717-9. 51. karadeniz t, topsakal m, airman a, et al. penile fracture: differential diagnosis, management and outcome. br j urol. 1996; 77:279-81. 52. orvis br, mcaninch jw. penile rupture. urol clin north am. 1989; 16:369-75. correspondence nicola pavan, md (corresponding author) nicpavan@gmail.com giorgia tezzot, md giorgiatez@hotmail.it giovanni liguori, md gioliguori@libero.it renata napoli, md renata.napoli@libero.it paolo umari, md paoloumari@alice.it; michele rizzo, md mik.rizzo@gmail.com giovanni chiriacò, md gio.chiriaco@gmail.com gaetano chiapparrone, md g.chiapparrone@gmail.com francesca vedovo, md superv@libero.it carlo trombetta, md trombcar@units.it urology department, cattinara hospital, university of trieste strada di fiume 447 34149 trieste, italy michele bertolotto, md bertolot@units.it radiology department, cattinara hospital, university of trieste strada di fiume 447 34149 trieste, italy pavan_stesura seveso 16/01/15 10:51 pagina 370 stesura seveso 391archivio italiano di urologia e andrologia 2014; 86, 4 case report bladder neck disease and kidney damage anna mudoni 1, francesco caccetta 1, maurizio caroppo 1, fernando musio 1, antonella accogli 1, maria dolores zacheo 1, domenica maria lucia burzo 1, giancamillo carluccio 2, vitale nuzzo 1 1 department of nephrology and dialysis, “cardinale g. panico” hospital, tricase (lecce), italy; 2 department of urology “cardinale g. panico” hospital, tricase (lecce), italy. primary bladder neck obstruction (pbno) was first described in men by marion in 1933. the precise cause of pbno has not been clearly elucidated. this paper review the theories on etiology, clinical presentation, diagnostic evaluation and treatments for pbno. also this paper focuses on management of patients with complications like acute urine retention, hydroureteronephrosis and severe renal failure. the treatment options for men and women with pbno include careful clinical evaluation, pharmacotherapy with alpha-blockers and surgical intervention. key words: primary bladder neck obstruction; acute urine retention; renal failure; ultrasound; videourodynamics; alpha-blockers. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. pended, for his own initiative, any type of medical treatment. the physical examination revealed: blood pressure 130/80 mmhg, rhythmic heart rate 105 bpm, breaks free, no lung stasis nor peripheral edema. the skin was pale and there was no signs of fluid overload. in the suprapubic area there was a hard mass, tense, sore from probable globe bladder. the diuresis was present. the laboratory tests showed a mild anemia (hematocrit 31.9 vol.%, hemoglobin 11.4 g/dl) and a severe renal impairment (blood urea 174 mg/dl, s-creatinine 7.4 mg/dl). blood gas analysis revealed metabolic acidosis (ph 7.3, bicarbonate 18 mmol/l, be ecf-5.6 mmol/l). serum electrolytes were normal. erythrocyte sedimentation rate was 24 mm, and urine analysis showed a density of 1010, ph 5.0, hemoglobin 0.10 mg/dl, absence of protein and some erythrocytes in the sediment. urineculture was negative. there were not bleeding disorders, and liver and thyroid function were normal. the electrocardiogram highlighted sinus rhythm, tachycardia. the chest x-ray was negative. abdominal ultrasound, performed at the admission to our department of nephrology, showed an increase in right kidney size (figure 1), with a 138 mm longitudinal diameter (ld), and a normal size left kidney (ld 103 mm). the parenchymal thickness was bilaterally slightly reduced with bilateral severe hydroureteronephrosis. the bladder appeared very relaxed, with thickened walls, jagged mucous design and there were presence of large particulate matter in suspension (estimated volume of 4500 ml) (figure 2). the urologist consulted, after an unsuccessful attempt to bladder catheterization, placed suprapubic transcutaneous foley catheter, resulting an abundant outflow of urine hyperpigmentated. the patient underwent a hydration therapy with sodium bicarbonate and polysaline solution, and antibiotic therapy with levofloxacin 500 mg/day was started. during hospitalization, indices of renal function gradually improved, as shown in figure 3, with a correction of acid-base balance. in the following days, the patient was submitted to retrograde and voiding cystourethrography that showed the bladder retrogradely filled with finely serrated walls. in the voiding phase only a thread-like opacification of the doi: 10.4081/aiua.2014.4.391 presented at 19th national congress sieun, fermo 2014 introduction the bladder neck disease is a cervico-urethral obstruction that results in an obstructed flow of urine due to the incomplete opening of the bladder neck during urination. to date, the etiopathogenesis is still unclear and may be given to an abnormality in the development of the bladder neck and the detrusor musculature, whereby the bladder neck, during urination, remains contracted (1-4). the present paper focuses on pbno complicated by acute urine retention and severe renal failure, treated with surgery and shows clinical, laboratory and instrumental long-term follow-up. case report we describe the clinical history of a 48 years old male, sent to our attention from emergency room where he presented for marked asthenia, general malaise, and oliguria. his history was positive for nocturnal occasional urinary incontinence from childhood. for this reason he had been treated with alpha blockers for an unspecified time. since 38 years he had not carried out clinical, chemistry, and instrumental inspection and he had susmudoni_stesura seveso 16/01/15 11:51 pagina 391 archivio italiano di urologia e andrologia 2014; 86, 4 a. mudoni, f. caccetta, m. caroppo, f. musio, a. accogli, m.d. zacheo1, d.m.l.burzo, g. carluccio, v. nuzzo 392 the sequential renal scintigraphy showed the ability of glomerular filtration rate less than the norm, with functional prevalence of the right kidney and absence of signs of obstructive disease. uroflowmetry revealed flow values and flow control in the standard curve. introduction, discussion, conclusions and other figures are posted in supplementary materials in www.aiua.it references 1. marion g. surgery of the neck of the bladder. br j urol. 1933; 5:351-357. 2. leadbetter gw, leadbetter wf. diagnosis and treatment of congenital bladder neck obstruction in children n engl. j med.1959; 260:633. 3. nitti vw. primary bladder neck obstruction in men and women. rev urol. 2005; 7 suppl 8:s12-7. 4. padmanabhan p, nitti vw. primary bladder neck obstruction in men,women, and children. curr urol rep. 2007; 8:379-84. figure 1. bilateral severe hydroureteronephrosis, right kidney increased size (ld 138 mm), left kidney normal size (ld 103 mm). the parenchymal thickness bilaterally slightly reduced. figure 2. bladder over dilated at diagnosis with thickened walls (left); post-voiding residual volume after treatment (about 100 ml) (right). urethra was appreciated, whereas, in the retrograde opa ci fication, signals stricture of the membranous urethra was detected. subsequently, in general anesthesia, he was submitted to urethrocystoscopy with evidence of obstructive bladder neck. endoscopic incision of the bladder neck by laser fiber was performed with urinary catheter placement and subsequent removal of the suprapubic foley catheter. the postoperative course was uneventful, so the urinary catheter was removed and a valid resumption of spontaneous voiding occurred. at discharge the patient was in good general condition, with valid urination of normochromic urine and improvement in renal function (s-creatinine 2.5 mg/dl, cgfr 27 ml/min/m2mdrd formula). the patient underwent a regular clinical, laboratory and instrumental follow-up (renal and bladder ultrasonography, uroflowmetry, renal scintigraphy) and, after more than a year, resolution of symptoms, absence of urinary tract infections and improvement in renal function (s-creatinine 1.64 mg/dl, cgfr 88 ml/min/m2) were observed. sonographically, the right kidney presented a normal size (ld 108 mm), regular shape, normal cortico-medullary thickness, resistive intrarenal index (ri) equal to 0.6 and pyelo-caliceal cavity not dilated without stone. left kidney presented a small size (ld 81 mm), regular shape, thickness cortico-medullary reduced, (ri 0.9), with a ii-iii degree hydro nephrosis, without stones (figure 4). bladder showed thickened walls and a post-voiding residue was present (about 100 ml) (figure 2). correspondence anna mudoni, md (corresponding author) mudonia@libero.it francesco caccetta, md maurizio caroppo, md fernando musio, md antonella accogli, md maria dolores zacheo, md domenica maria lucia burzo, md vitale nuzzo, md department of nephrology and dialysis, “cardinale g. panico” hospital via s. pio x 4, 73039 tricase (lecce), italy giancamillo carluccio, md department of urology, “cardinale g. panico” hospital via s. pio x 4 73039 tricase (lecce), italy mudoni_stesura seveso 16/01/15 11:51 pagina 392 archivio italiano di urologia e andrologia 2017; 89, 2148 short communications pharmacological/dynamic rehabilitative behavioural therapy for premature ejaculation: results of a pilot study franco mantovani clinica san giovanni, milan, italy. objectives: premature ejaculation (pe) is a sexual disorder characterised by excessive rapidity of orgasm. it is defined as either primary (60%), present since the onset of sexual activity, or secondary (40%), manifesting later in life. to date, dapoxetine is the only preparation approved for the on-demand treatment of pe. however, side effects, costs associated with the treatment of chronic pe, drug dependence and its variable effectiveness leads to a not insignificant drop-out rate. dynamic rehabilitative/behavioural therapy may be a viable therapeutic option, working alongside pharmacological treatment, as long as the participation and involvement of both the individual and the couple is optimal. materials and methods: 18 patients were enrolled, aged between 25 and 55 (mean: 40), all with primary pe, free of comorbidities and with their partners involved. six patients were prescribed 30 mg dapoxetine two hours before sexual relations for 3 months (group a); 6 patients began the dynamic rehabilitative treatment (group b); 6 other couples were assigned to pharmacological treatment in association with dynamic rehabilitative behavioural treatment for 3 months (group c). division of subjects was carried out by simple randomisation, excluding patients with a short frenulum, phimosis, ed, chronic prostatitis or experiencing results from previous treatment. results: outcomes of treatment were evaluated at the end of the 3 months of treatment and 3 months after discontinuing treatment. in group a 75% of patients were cured at 3 months and 25% at 6 months. in group b 25% patients were cured at 3 months and 25% at 6 months. in group c 75% of patients were cured 3 months and 50% at 6 months. "cured" means a premature ejaculation diagnostic tool (pedt) score reduced from an average of 12 to an average of 6 and intravaginal ejaculation latency time (ielt) values from < 1 to > 6 minutes. conclusions: the integration of pharmacological treatment with dynamic behavioural rehabilitation has the specific aim of optimising and stabilising the results, supporting a more efficient recovery of ejaculatory control. the close involvement of the partner is extremely useful for all results. key words: premature ejaculation; dapoxetine; perineal rehabilitation; vacuum device; sex-therapy. submitted 14 april 2017; accepted 23 april 2017 summary no conflict of interest declared. ondary (30%), manifesting later in life. they share the symptoms of reduced ejaculation latency times, a lack of control and/or subjective perception of the time of ejaculation. the etiopathogenesis may be somatic and/or neurobiological, which is often is associated with a significant psychosexual component and intimate discomfort. our diagnosis was based mainly on anamnesticclinical and laboratory data (hormones, meares-stamey tests, semen cultures). pedt questionnaires (premature ejaculation diagnostic tool) and ielt tests (intravaginal ejaculation latency time) were very useful during the research, while electrophysiological tests presented more difficulties in terms of execution and interpretation (1, 2). assuming that the treatment of choice should be causative, the vast majority of patients will be excluded from treatment, because a precise identification of the causes is lacking in most of the patients that often are not able to completely resolve the disease (3). in the pharmacological field dapoxetina is, to date, the only preparation approved for the on-demand treatment of pe. unlike conventional selective serotonin reuptake inhibitors (ssri), it allows for use on an as-needed basis (not requiring a window to take effect), has a good safety profile, and does not present the risk of developing a withdrawal syndrome after discontinuation (4). however, the side effects (nausea, headaches, dizziness, diarrhoea), the costs associated with the treatment of chronic pe, drug dependence and its variable effectiveness leads to a not insignificant drop-out rate. although there are no clinical studies of sufficient quality to generate high levels of scientific evidence, dynamic rehabilitative/behavioural therapy may be a viable therapeutic option, working alongside pharmacological treatment, as long as the participation and involvement of both the individual and the couple is optimal following simple, precise and controlled explanations, examples and training (5). materials and methods eighteen patients were enrolled, aged between 25 and 55 (mean: 40), all with primary pe, free of comorbidities and with their partners involved. six patients were prescribed 30 mg dapoxetine two hours before sexual relations for 3 months, six patients began dynamic rehabilitative treatment consisting of toning the pubococcygeus (the fundadoi: 10.4081/aiua.2017.2.148 introduction premature ejaculation (pe) is a sexual disorder characterised by excessive rapidity of orgasm. on average, from international case studies, it affects 25% of the male population aged 25 to 55. it is defined as either primary (70%), present since the onset of sexual activity, or secmantovani2_stesura seveso 21/06/17 10:04 pagina 148 149archivio italiano di urologia e andrologia 2017; 89, 2 rehabilitation for premature ejaculation mental perineal muscle for ejaculation control) by means of daily home physiotherapy following outpatient demonstration and by weekly application (for 3 months) in an outpatient clinic of extracorporeal magnetic innervation (exmi-neocontrol) followed by functional electrical stimulation (fes) and biofeedback (bfb) with rectal probe (myoplus 40hz) in a dynamic setup with erection induced and maintained using a vacuum device (rapport-medis) (figure 1). over the 3 month period the couple was also trained in home behavioural therapy (sensate squeeze stop and start). six other couples were assigned to pharmacological treatment associated with dynamic rehabilitative behavioural treatment for 3 months. assignment of subjects to treatment was carried out by simple randomisation, after excluding patients with a short frenulum, phimosis, erectile dysfunction, chronic prostatitis or experiencing results from previous treatment. the muscle rehabilitation procedure is largely adapted from the established procedure for urinary incontinence, but it is carried out during a vacuum-induced erection for identification with the condition of the penis when ejaculatory control is required. the behavioural therapy, through various dedicated exercises, is targeted at the acquisition of greater control over levels of arousal and ejaculation times, rebuilding their self-esteem, which translates into greater confidence during sexual intercourse, thereby reducing anxiety, causing increased ejaculation latency times and offering the possibility of greater ease of penetration. results pedt questionnaires were filled and ielt values were evaluated by interviews with the couples at the end of the 3 months of treatment and 3 months after the discontinuation of treatment; fortunately no subjects dropped out or failed to follow-up. in group a (pharmacological treatment) 75% of patients were cured at 3 months and 25% at 6 months. in group b (dynamic rehabilitative behavioural therapy) 25% of patients were cured at 3 months and 25% at 6 months. in group c (pharmacological associated with dynamic rehabilitative behavioural therapy) 75% of patients were cured at 3 months and 50% at 6 months. positive results were considered a reduction in the pedt score from an average of 12 to an average of 6 (figure 2) or an increase of ielt from < 1 to > 6 minutes on average (figure 3). from the baseline to the evaluation at 3 and 6 months, all groups presented a significant (p < 0.0001) increase in ielt values and a reduction in pedt score. the difference between group a and group c is particularly significant. in group a (dapoxetine alone) the increase in ielt (in seconds) was significantly lower (84.8-170.9-120.7) compared to group c (complete integrated treatment) (86.2-370.7-232.5) and similarly the decrease in the reduction in pedt scores was lower in group a than in group c (18.16-9.88-14.68) vs (19.56-5.92-8.96). figure 1. dynamic electro-stimulation (fes) associated with use of vacuum device. figure 2. changes in pedt score. figure 3. changes in ielt values. group a group b group c group a group b group c baseline 3 months 6 months baseline 3 months 6 months pe dt s co re ie lt v al ue in m in ut es mantovani2_stesura seveso 21/06/17 10:04 pagina 149 archivio italiano di urologia e andrologia 2017; 89, 2 f. mantovani 150 discussion the integration of pharmacological treatment (6) with a dynamic rehabilitative behavioural approach (7) has the specific aim of optimising and stabilising the results, supporting the patient in a more efficient recovery of lasting ejaculatory control (8). to that effect, the involvement of the partner in the therapeutic process is extremely useful, as the establishment of greater involvement in the sexual relationship provides further stimulus for the patient in the recovery of their self-esteem, virility and sense of adequacy of their sexuality. (9) in addition, the involvement of the couple is extremely useful in mitigating the drop-out rate associated with the pharmacological treatment and effectively reducing the difficulty of keeping the patient committed to the integrated treatment plan. the limits of this study, despite the prospective nature of the study and the use of three treatment groups, include the reduced number of patients enrolled in the study and the limited time of the followup. further comparative studies are necessary to assess in more detail the actual significance of the therapeutic approaches to be proposed for pe. in conclusion, these integrated treatments, alternating concentration and relaxation, create an impression of real control in overcoming this issue. excluding the cases with comorbidities that have to be resolved first, the administration of dapoxetine is beneficial in terms of immediate results. its use in conjunction with dynamic perineal rehabilitation and behavioural therapy offers significant advantages and a more appreciable stability along time of the results. references 1. althof se, et al. international society for sexual medicine’s guidelines for the diagnosi and treatment of premature ejaculation. j sex med. 2010; 7:2947-2969. 2. jannini ea, maggi m, lenzi a. evaluation of premature ejaculation. j sex med. 2011; 8:328-34. 3. rowland d, mcmahon cg, abdo c, et al. disorders of orgasm and ejaculation in men. j sex med. 2010; 7:1668-86. 4. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 5. waldinger md, quinn p, dilleen m, et al. a multinational population survey of intravaginal ejaculation latency time. j sex med. 2005; 2:492-7. 6. buvat j, tesfaye f, rothman m. et al. dapoxetine for the treatment of premature ejaculation: results from a randomized, doubleblind, placebo-controlled phase 3 trial in 22 countries. eur urol. 2009; 55:957-67. 7. la pera g awareness and timing of pelvic floor muscle contraction, pelvic exercises and rehabilitation of pelvic floor in lifelong premature ejaculation: 5 years experience. arch ital urol androl. 2014; 86:123-5. 8. steggall m, fowler c, pryce a. combination therapy for pe: results of a small-scale study. sex and relationship therapy. 2008; 23:365-76. 9. perelman m. a new combination treatment for premature ejaculation. a sex therapist’s prospective. j sex med. 2006; 3:1004-1. correspondence franco mantovani, md mantovanifranco@yahoo.it clinica san giovanni via civitali 71, milano, italy mantovani2_stesura seveso 21/06/17 10:04 pagina 150 archivio italiano di urologia e andrologia 2017; 89, 2120 original paper psychologic and sexual dysfunction in primary and secondary infertile male patients aytac sahin 1, ahmet urkmez 2, ayhan verit 1, ozgur haki yuksel 1, fatma ferda verit 3 1 fatih sultan mehmet research & training hospital, department of urology, istanbul, turkey; 2 haydarpasa numune research & training hospital, department of urology, istanbul, turkey; 3 suleymaniye maternity, research & training hospital, department of obstetrics and gynecology, center of assisted reproduction, istanbul, turkey. objective: the aim of this study was to compare depression and sexual dysfunctions observed in primary and secondary infertile patients. material and method: the study was performed in 39 primary and 31 secondary infertile male patients. male sexual health was evaluated using the international index of erectile function (iief) score and depression with beck depression inventory (bdi). results: mean age of the participants and their partners were 31.54 ± 5.37 (range, 24-48 yrs), and 28.16 ± 5.58 (range, 2046 yrs) years, respectively. mean duration of their marriage ranged between 1 and 17 years (mean, 5.06 ± 4.15 yrs). a statistically significant intergroup difference was detected between groups as for bdi scores (p = 0.015; p < 0. 05). bdi scores of the primary group were significantly lower than those of the secondary group. a statistically and extremely significant difference was detected between iief scores of the groups (p = 0.006; p < 0.01). iief scores of the primary infertile group were higher than those of the secondary group. conclusion: our study, frequency of the depression and erectile dysfunction seen in the patients with secondary infertility was seen significantly higher than the patients with primary infertility. key words: infertility; male sexual dysfunction; depression; secondary infertile man. submitted 2 february 2017; accepted 23 april 2017 summary no conflict of interest declared. clear definition of this time, the 12 months period is also accepted for the secondary infertility by many authors. diagnosis of infertility can be made in nearly 15% of the couples who want to have a baby and primary or secondary infertility are detected in 90 and 10% of them (3). one of the basic and primitive instincts in human beings is reproductive instinct. reproductive deficiency frequently creates a social stigma, which is perceived as a disgraceful condition (4). infertility emerges from a sudden and unexpected life crisis, which can be diagnosed in the long run. it results in excessive stressful problems, which strain adjustment mechanisms (5). studies analyzing the association between infertility and psychological functions have used one of the following models. one of them is psychological infertility model, which asserts the role of an existing psychopathology on the etiology of infertility and the other model (psychological result) claims that psychological problems arise as a result of infertility (6). recently direct correlation of mental stress with infertility problems and its impact on the outcomes of infertility treatment has been demonstrated. for example it has been revealed that during natural disasters like earthquakes, sperm quality activities of seminal plasma superoxide dismutase and arginine decrease, and nitric oxide levels increase in men under stress (7, 8). since psychiatric disorders are more frequently analyzed during infertility investigations, scales specific to infertility process haven’t been developed yet (9). in developed countries, it appears to be appropriate to take a detailed history about psychological status of the infertile couple. the rationale of this approach is to predict problems, which might arise during the treatment period and be prepared to confront them. since patients with severe pathological conditions will affect compliance to treatment, these patients will not be included in this costly and prolonged management process. in this study we analyzed and discussed the possible difference mechanisms of psychologic and sexual dysfunction of primary and secondary infertile male patients. material and methods this study was performed in 39 primary and 31 secondary infertile male patients. after institutional review board doi: 10.4081/aiua.2017.2.120 introduction according to criteria of world health organization (who) infertility is defined as inability of a sexually active, non-contracepting couple to achieve conception after 12 months of regular sexual intercourse (1). infertility affects 10-15% of the couples in their reproductive age. infertility is related to male and female factors in 40 and 40% of the cases. infertility is caused by both male and female factors in 20% of the cases. the culprit factor cannot be identified (2) in nearly 10-20% of infertile couples. failure to become pregnant after 12 months despite regular unprotected sexual intercourse is called primary infertility. secondary infertility is defined as the inability to become pregnant a time after the birth of one or more biological children. although there is no sahin_stesura seveso 20/06/17 09:34 pagina 120 121archivio italiano di urologia e andrologia 2017; 89, 2 psychological/sexual dysfunction and infertility (irb) approval was received, all patients gave detailed medical history and underwent physical examinations. on physical examination, especially dimensions of both testes, presence of vas deferentia were evaluated. patients with a history of psychiatric disorders and suspect diagnoses of hepatic, renal, cardiovascular and metabolic diseases, users of drugs affecting prolactin levels including cimetidine and anxiolytic drugs were excluded from the study. at admission, routine seminal analyses of all patients were performed and serum fsh, lh, prolactin and total testosterone levels were checked. all of our patients had olgoasthenozoospermia without varicocele or previous surgery who were under medical treatment and surveillance in our clinic. the patients were questioned as for ejaculatory disorders, decreased libido, erectile dysfunction, depression and anxiety. male sexual health was evaluated using international index of erectile function (iief) scores and depression with beck depression inventory (bdi). the iief form was used for the evaluation, but for the erectile functions, 1, 2, 3, 4, 5 and 15 questions were taken into consideration and the evaluation was made on 30 points. statistical analysis for statistical analysis ncss (number cruncher statistical system) 2007&pass (power analysis and sample size) 2008 statistical software (utah, usa) program was used. study data were evaluated by using descriptive statistical methods and for intergroup comparisons of quantitative data related to parameters with normal or non-normal distribution student t test and mann whitney u test were used, respectively. for comparisons of 3 or more than 3 groups with non-normal distribution kruskal wallis test was employed. for the comparison of qualitative data pearson chi-square test, fisher’s exact test, and yates continuity correction test were utilized. for the evaluation of correlations between parameters, pearson correlation analysis and spearman’s correlation analysis were used. statistical significance was evaluated at a level of p < 0.01 and p < 0.05. finally, multiple logistic regression analysis was used to determine whether sociodemographic characteristics, and depression were associated with male sexual dysfunction. data were considered significant at p < 0.05. ethical standard this study procedures were reviewed and approved by the regional ethical vetting board (istanbul) and have therefore been performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. results mean age of the patients and their partners were 31.54 ± 5.37 (range, 24-48 years) and 28.16 ± 5.58 (range, 2046 years) years, respectively. mean duration of their marriage ranged between 1 and 17 years (mean, 5.06 ± 4.15 years). bmi measurements of the cases ranged between 20.15 and 37.96 kg/m2 (mean; 26.09 ± 3.65 kg/m2). bdi scores of the cases changed between 0 and 26 points (mean; 8.49 ± 6.79 pts). iief scores of the cases varied between 7 and 30 points (mean; 26.33 ± 4.61 pts). a statistically and extremely significant difference was detected between groups as for age of the cases (p = 0.001; p < 0.01). ages of the cases in the primary infertile group were significantly lower than the secondary infertile group. statistically and extremely significant difference was found between groups as for ages of the partners of the infertile male patients (p = 0.001; p < 0.01). ages of the partners were significantly lower than those of the secondary infertile group. a statistically and extremely significant difference was found between duration of marriage of the cases (p = 0.001; p < 0.01). cases of the primary infertile group stayed married for significantly shorter periods when compared with the secondary group. bmi measurements of the cases did not demonstrate statistically significant differences between groups (p>0.05). a statistically significant difference was detected between groups regarding bdi scores (p = 0.015; p < 0.05). bdi scores of the primary infertile group were significantly lower than those of the secondary group. a statistically, and extremely significant difference was detected between groups regarding iief scores (p = 0.006; p < 0.01). iief scores of the primary infertile group was significantly higher than the secondary infertile group. the patients’ place of residence was either rural (5.7%; n = 4) or city (94.3%; n = 66) areas. when educational levels of the cases were considered, the cases were either primary school (31.4%; n = 22), high school (48.6%: n = 54) or university (20%; n = 14). the distribution of monthly income of our cases was low in 18.6% (n = 13) and moderate to high in 81.4% (n = 57). places of residence and educational level of the cases did not differ significantly between groups (p > 0.05). there were positive relationship between male sexual dysfunction (erectile dysfunction) and age (r = 0.28, p = 0.018), partner’s age (r = 0.28, p = 0.015), duration of marriage (r = 0.25, p = 0.033), depression (r = 0.28, p = 0.017) and low income (r = 0.28, p = 0.016). multivariate logistic regression analysis showed that depression [exp(β) = 9.8, 95% ci: 1.274.3; p = 0.027] and low income [exp(β) = 9.8, 95% ci: 1.951.3; p = 0.007] were the independent predictors that were associated with sexual dysfunction. hosmer-lemeshow goodness of fit test was found to be well calibrated in this final model (p = 0.77) (table 1). in primary infertile group, a statistically significant correlation was not detected between bdi scores and ages of the study participants (p > 0.05). between bdi scores and duration of marriages, a statistically significant negative correlation was found at a level of 32.4% (ie. shorter marriages with increased bdi scores) (r = -0.324; p = 0.044; p < 0.05). a statistically significant correlation was not found between bdi scores and bmi measurements (p > 0.05). between bdi and iief scores a negative correlation (bdi scores increase with decreasing of iief scores) at a level of 32.3% was detected. (r = -0.323; p = 0.045; p < 0.i05). in secondary infertile group, a statistically significant positive correlation (parallel increases in bdi scores and ages) was detected between bdi scores and ages of the participants at a level of 35.8% (r = 0.358; p = 0.048; p < 0.05).a statistically significant correlation was not found between bdi scores and duration of marriages (p > 0.05). a statistically significant differsahin_stesura seveso 20/06/17 09:34 pagina 121 archivio italiano di urologia e andrologia 2017; 89, 2 a. sahin, a. urkmez, a. verit, o. yuksel, f. verit 122 ence was not detected between bdi scores and bmi measurements (p > 0.05). a statistically significant negative correlation was noted between bdi and iief scores (bdi scores increased concurrently with a decrease in iief scores) at a level of 39.7% (r = -0.397; p = 0.027; p < 0.05) (table 2). in primary infertile group a statistically significant correlation was not found between iief scores and ages of the participants scores (p > 0.05). a statistically significant correlation was not found between iief scores and duration of marriages (p > 0.05). a statistically significant correlation was not found between iief scores and bmi measurements (p > 0.05). a statistically significant negative correlation was noted between iief and bdi scores at a level of 32.3% (iief scores increased as bdi scores decreased: r = -0.323; p = 0.045; p < 0.05). in secondary infertile group, a statistically significant correlation was not found between iief scores and ages of the participants.(p > 0.05). a statistically significant correlation was not detected between iief scores and duration of marriages (p > 0.05). a statistically significant correlation was not detected between iief scores and bmi measurements (p > 0.05). a statistically significant negative correlation was noted between iief and bdi scores (iief scores increased in parallel with a decrease in bdi scores) at a level of 39.7% (r = -0.397; p = 0.027; p < 0.05) (table 3). in primary infertile group, bdi and iief scores of the cases according to their income level did not significantly differ statistically (p > 0.05). in secondary infertile group, a statistically significant difference was not found between bdi scores of the cases. (p > 0.05), but iief scores of the cases were significantly different statistically in consideration of their income levels (p = 0.015; p < 0.05). discussion even though erectile dysfunction and ejaculatory disorders manifest themselves as psychogenic effects caused by their inability to have a child, it should not be forgotten that common organic factors may induce infertility itself and psychosexual disorders. in cases where conditions of hormonal imbalance, like prolactinoma or primary hypogonadism as cause infertility, this endocrinologic disorder is also the etiological factor of associated sexual dysfunction. therefore, before resorting to psychogenic factors, organic causes should be ruled out. in the differential diagnosis process in infertile couples, complete anamnesis, physical examination, hormonal evaluation and if required nocturnal penile tumescence test should be used. in our study the patients observed in our clinic with the diagnosis of infertility were interrogated with respect to sexual and ejaculatory dysfunction. the patients with organic disorders and, in consideration of surgical stress, those who had undergone any surgical intervention were excluded from the study. older theories related to infertility focused on psychological factors as cause of infertility, however during 1970s, manning’s psychological strain theory revealed that psychological problems were not the cause but the effect of infertility. infertility is a stressful life experience and depressive symptoms are normal manifestations of reactive behaviors (10). in nearly 37% of infertile women manifest depressive symptoms 2 times more frequently relative to the control group as evaluated with bdi (11). in another similar study, the authors detected mildmoderate (28%), moderate-severe (7%) or very severe (1%) degrees of depression in infertile women (12). in a separate study 2 of 3 of the infertile women had comtable 1. comparative evaluation between groups. table 2. intragroup correlation for age, duration of marriage, bmi and iief scores. table 3. intragroup correlations for iief scores, age, duration of marriage, bmi and beck-d scores. parameters primary infertile men secondary infertile men p (mean ± sd) (n = 39) (mean ± sd) (n = 31) age (y) 29.2 ± 3.1 34.3 ± 6.2 < 0.0001 partner’s age (y) 25.6 ± 3.5 31.2 ± 6.1 < 0.0001 body mass index (kg/m2) 25.4 ± 2.8 26.9 ± 4.3 0.11 duration of marriage (y) 2.5 ± 1.8 8.1 ± 4.1 < 0.0001 current settlement type rural 1 (2.6%) 3 (9.7%) city 38 (97.4%) 28 (90.3%) 0.20 educational status primary school 13 (33.3%) 9 (29.0%) high school 20 (51.3%) 14 (45.2%) university 6 (15.4%) 8 (25.8%) 0.55 monthly income low income 7 (17.9%) 6 (19.4%) moderate to high income 32 (82.1%) 25 (80.6%) 0.88 beck-d score 6.7 ± 6.0 10.6 ± 7.1 0.017 iief score 27.7 ± 2.1 24.4 ± 6.0 0.002 beck-d scores primary (n = 39) secondary (n = 31) r p-value r p-value age (years) 0.037 0.825 0.358 0.048* duration of marriage (years) -0.324 0.044* 0.260 0.157 bmi (kg/m2) -0.226 0.167 0.168 0.366 iief score -0.323 0.045* -0.397 0.027* r = spearman’s correlation coefficient; *p < 0,05 bmi: bodymass index; iief: international index of erectile dysfunction. iief score primary (n = 39) secondary (n = 31) r p-value r p-value age (year) a0.243 0.135 a-0.041 0.825 duration of marriage b0.214 0.191 b-0.267 0.147 bmi (kg/m2) a-0.062 0.708 a0.054 0.773 beck-d score b-0.323 0.045* b-0.397 0.027* ar=pearson correlation coefficient; br=spearman’s correlation coefficient; *p < 0.05 bmi: bodymass index; iief: international index of erectile dysfunction. sahin_stesura seveso 20/06/17 09:34 pagina 122 123archivio italiano di urologia e andrologia 2017; 89, 2 psychological/sexual dysfunction and infertility plaints of anxiety (13). in a similar study by oddens et al., the authors detected depressive disease in a quarter of their patients (14). in an anxiety survey study performed on 130 infertile women in china, the results obtained demonstrated that 83% of infertile women had emotional disorder of various degrees and 25% of them demonstrated moderate or severe type of anxiety. global incidence rates of depressive disorders and anxiety among infertile women range between 24 and 36% and 6784%, respectively (15). in some studies, authors have demonstrated that infertile men had demonstrated better emotional function index scores relative to women. it is not known whether this observation might be due to introverted nature of men on this issue. one of the most important criteria seen among women is that emotional statuses of infertile women are more deeply affected than infertile men (16). a study analyzed the impact of psychological stress on male hormones and sperm quality of male partners. seventy infertile male partners were investigated as for psychological stress levels using anxiety and depression scale scoring system and with measurements of total serum testosterone, serum gnrh, fsh, lh levels and spermiograms. the researchers indicated that psychological stress firstly lowers serum total testosterone levels, and secondarily increases serum lh and fsh levels, which suggest that stress management might have an important place in male infertility (17). we included only infertile male patients in our study and found depression rates in primary and secondary infertile groups as 22 and 38%, respectively. ed rates in primary and secondary infertile groups were 15 and 45% respectively. all of our patients had normal levels of fsh, lh, and testosterone. similar study that was conducted on infertile women with primary and secondary infertility and in parallel with an our previous study, sexual dysfunction in infertile patients with secondary infertility was seen significantly higher than the patients with primary one (18). in a study that investigated association between ed and socio-economic parameters, lowincome was found a predictive parameter (19). in our study, multivariate logistic regression analysis showed that depression and low income were independent predictors that were associated with sexual dysfunction. long-lasting infertility, and failed treatment attempts aggravate psychological problems as stress and especially depression (20). in infertile women depression and anxiety worsen with advanced age and prolonged duration of infertility (21). in our study, duration of infertility differed statistically with extreme significance between groups. duration of infertility is significantly shorter in the primary infertile group when compared with the secondary infertile group. a statistically significant difference was detected between groups regarding bdi scores of the cases. bdi scores of the primary infertile group was significantly lower than those of the secondary infertile group. on the other hand immunological investigations on psychoneurosis have demonstrated the potential impact of psychological factors on immunity (22, 23). for instance, natural killer cell (nk) activity has been determined as the main factor in premature termination of pregnancy (24, 25). provided that these studies have taken psycho-neuro-endocrine-immune system into consideration, the authors indicated that stress induced by infertility concerns would worsen the psychological status of the couple, and objective evaluation of emotional reactions of the couples to infertility, and appropriate psychosomatic approach might be as fruitful as pharmacological therapy of infertility. limbic system is considered as ‘emotional brain’. every type of mental exercise has demonstrated an increase in hippocampal volume and neurogenesis. besides, sustained stressful conditions cause a decrease in hippocampal volume and neurogenesis of hippocampal neurons (26). as an adaptive response to stress, blood cortisol levels peak suddenly. however excessive and prolonged cortisol release creates a neurotoxic effect on brain leading to decreases in synaptic plasticity and neurogenesis and hippocampal atrophy. probably these deleterious effects deteriorate memory and cognitive functions with resultant sexual dysfunction. in depressive states, a correlation has been indicated between hippocampal atrophy, plasma cortisol levels, and duration of depression. resolution of atrophy has been reported in line with amelioration of depression (27). in some studies performed, the authors stated that a negative correlation between depression and testosterone in men and cortisol in women may be associated with biological pathophysiology of male and female depression, respectively (28). adrenal androgens, dehydroepiandrosterone (dhea) and its sulfate derivative are known to play important roles in controlling emotions, mood and anxiety. a relevant study has demonstrated that in male patients, serum dhea-s levels decreased significantly when compared with the male control subjects, however in infertile female patients an important difference was not observed relative to the control group. since dhea therapy was effective treatment for depression, increased levels of serum dhea can be associated with biological pathophysiologic mechanisms of depression. however, dhea/dhea-s levels have been reported as a weak marker of the severity of depression (29). in our study, we observed that secondary infertile group was more negatively affected in terms of bdi and iief scores. when the groups were evaluated separately; duration of marriage was negatively correlated with bdi in primary infertile group, on the other hand patient age and low-income were positively correlated with bdi in secondary group. we think that the secondary infertility patients felt extra pressure on their moods because they had already achieved the fertility award at least once in their previous life but they could not manage this again, however all intra or extra motivations directed at this focus. our study was the pioneer one, which was conducted on the infertile men with primary and secondary infertility in regard to find out the differences of psychologic and sexual dysfunction patterns of both groups. for a successful infertility management, elimination of psychological stress factors might be required. in certain patient groups, treatment of sexual dysfunction may achieve fertility and eliminate infertility related problems. however, we are of the opinion that as a study sahin_stesura seveso 20/06/17 09:34 pagina 123 archivio italiano di urologia e andrologia 2017; 89, 2 a. sahin, a. urkmez, a. verit, o. yuksel, f. verit 124 design, men and women factors should be evaluated together in infertile pairs and we think that our subject study will make a greatest contribution to the literature. references 1. world health organization. who manual for the standardized investigation and diagnosis of the infertile couple. cambridge: cambridge university press, 1999. 2. freidman t. infertility and assisted reproduction. bailiere’s clinical obst. andgyne. scandinavica. 1989; 66:517-21. 3. eau guidelines on male infertility, 2010. 4. herz ek. infertility and bioethical issues the new reproductive technologies. the psychiatric clinics of north america. 1989; 12:117-31. 5. forrest l, gilbert lg. infertility: an unanticipated and prolonger life crisis. j mental health counsel. 1992; 14:42-58. 6. berg bj, wilson jf. psychiatric morbidity in infertile population. fertility and sterility. 1990; 53:654-61. 7. collodel g, moretti e, fontani v, et al. effect of emotional stress on sperm quality. indian j med res. 2008; 128:254-61. 8. abu-musa aa, nassar ah, hannoun ab, et al. effect of the lebanese civil war on sperm parameters. fertilsteril. 2007; 88:1579-1582. 9. greil al, mcquillan j, lowry m, shreffler km. infertility treatment and fertility-specific distress: a longitudinal analysis of a population-based sample of u.s. women soc sci med. 2011; 73: 87-94. 10. wroolie te, williams ke, keller j, et al. mood and neuropsychological changes in women with midlife depression treated with escitalopram. j clin. psychopharmacol. 2006; 26:361-6. 11. domar ad, broome a, zuttermeister pc, et al. the prevalence and predictability of depression in infertile women. fertil steril. 1992; 58:1158-63. 12. thiering p, beaurepaire j, jones m, et al. mood state as a predictor of treatment outcome after in vitro fertilization/embryo transfer technology. j psychosom res. 1993; 37:481-91. 13. guerra d, liobra a, veiga a, et al. psychiatric morbidity in couples attending a fertility service. hum.reprod. 1998; 13:1733-6. 14. oddens bj, tonkelaar id, nieuwenhuyse h. psychosocial experience in women facing fertility problems a comparative survey. hum.reprod. 1999; 14:255-61. 15. lu y, yang l, lu g. mental status and personality of infertile women. zhonghua fu chan kezazhi 1995; 30:34-7. 16. franco jg jr, razerabaruffi rl, mauri al, et al. psychological evaluation test for infertile couples. j assist report genet. 2003; 19:269-73. 17. bhongade mb, prasad s, jiloha rc, et al. effect of psychological stress on fertility hormones and seminal quality in male partners of infertile couples. andrologia. 2015; 47:336-42. 18. keskin u, coksuer h, gungor s, et al. differences in prevalence of sexual dysfunction between primary and secondary infertile women. fertil steril. 2011; 96:1213-7. 19. laumann eo, paik a, rosen rc. sexualdysfunction in the united states: prevalenceandpredictors.jama. 1999; 281:537-44. 20. lok ih, lee dt, gheung lp, et al. psychiatric morbidity amongst infertile chinese women undergoing treatment with assisted reproductive technology and the impact of treatment failure. gynecol. obstet. invest. 2002; 53:195-9. 21. guz h, ozkan a, sarisoy g, et al. psychiatric symptoms in turkish infertil women. j psychosom obstet gynaecol. 2003; 24:267-71. 22. strauman tj, lemieux am, coe cl. self-discrepancy and natural killer cell activity: immunological consequences of negative selfevaluation. j pers soc psychol. 1993; 64:1042-52. 23. ishihara s, nohara r, makita s, et al. immune function and psychological factors in patients with coronary heart disease. jpn circ j. 1999; 63:704-9. 24. aoki k, kajiura s, matsumoto y, et al. preconceptional naturalkiller-cell activity as a predictor of miscarriage. lancet. 1995; 345:1340-2. 25. matsubayashi h, hosaka t, sugiyama y, et al. increased natural killer-cell activity is associated with infertile women. am j reprod immunol. 2001; 46:318-22. 26. czeh b, michaelis t, watanabe t, et al. stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. proc natl acad sci. usa. 2001; 98:12796-801. 27. spolsky rm. glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. arc gen psychiatry. 2000; 57:925-35. 28. wischmann t. sexual disorders in infertile couples: an update. curr opin obstet gynecol. 2013; 25:220-2. 29. matsuzaka h, maeshima h, kida s, et al. gender differences in serum testosterone and cortisol in patients with major depressive disorder compared with controls. int j psychiatry med. 2013; 46:203-11. correspondence aytac sahin, md ayhan verit, md ozgur haki yuksel, md fatih sultan mehmet research & training hospital, department of urology, istanbul, turkey ahmet urkmez, md (corresponding author) ahmeturkmez@hotmail.com haydarpasanumune research and training hospital, dept. of urology, uskudar, tr34668 istanbul, turkey fatma ferda verit, md ffverit@gmail.com suleymaniye maternity, research & training hospital, department of obstetrics and gynecology, center of assisted reproduction, istanbul, turkey sahin_stesura seveso 20/06/17 09:34 pagina 124 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4400 case report primary b-cell lymphoblastic lymphoma of the testis flavia tombolini 1, vito lacetera 1, guido gini 2, debora capelli 2, pietro leoni 2, rodolfo montironi 3, andrea benedetto galosi 4, giovanni muzzonigro 1 1 institute of urology, 2 institute of hematology, 3 institute of pathological anatomy and histopathology, aou united hospitals, polytechnic university of marche region, ancona, italy; 4 division of urology, a. murri hospital, fermo, italy. . we present a rare case of primary lymphoblastic b-cell lymphoma of the testis focusing on ultrasonographic and pathological features and clinical implications. pathological examination revealed primary testicular lymphoblastic b-cell lymphoma which was treated with adjuvant chemotherapy, including rachicentesis with administration of chemotherapy and with radiotherapy of contralateral testis. primary testicular lymphoblastic b cell lymphoma is an aggressive disease and it is necessary a multimodal therapy (surgery, chemotherapy and radiotherapy) to prevent metastasis. key words: b-cell lymphoblastic lymphoma; primary testicular lymphoma; testicular ultrasound. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. no history of traumatic events in the inguinal and scrotal region. he underwent surgical correction of left varicocele 12 years before with a complete resolution of the problem. scrotal ultrasound showed an hypoechoic area with homogeneous aspects in the inferior part of the left testicle, size 2.7 x 1.3 cm. scrotal eco-power-doppler showed high blood perfusion (figure 1) and increased vascularization of the left epididymis if compared to the right one. tumoral markers were normal. patient underwent left orchifunicolectomy and implantation of testicular prosthesis. intraoperative pathological evaluation described an extended cellular neoplastic population with mitotic aspects, high nucleocytoplasmic ratio and irregular nucleus. definitive pathological report described a creamy white nodular proliferation of 2,8 x 2,5 cm in lower pole of testis; microscopic examination was positive for lymphoblastic b-cells with intermediate size and irregular nucleus (figure 2). immunohistochemical expression pattern was: cd45 positive, cd79a-cd10-cd38 positive, bcl1, bcl6, cd57, mum 1 cd99 and cd117 negative; focal areas were cd20, bcl 2, tdt and cd3 positive (figu re 3). the proliferation index, as detected by mib1 antipresented at 19th national congress sieun, fermo 2014 introduction primary testicular lymphoblastic b-cell lymphoma is a rare tumor, it represents 7% of all testicular cancer (< 2% in men under 50 years of age) and it accounts for 1% of all non-hodgkin’s lymphomas. it is the most common bilateral testicular tumor, with 10-18% cases of synchronous or asynchronous involvement of contralateral testis (1-4). it has no pathognomonic clinical and ultrasonographic features and a diagnosis before surgery is uncommon. it needs specific adjuvant chemotherapy and radiotherapy because of the high risk of metastatic process at skin, central nervous system, contralateral testis and other organs. a multidisciplinary care is the key of treatment. case report a 39 years old man was referred to our clinic with acute pain at the left testis; a swelling hard mass in the inferior part of the left testicle was palpable; the right testis was normal without any associated symptoms of lower urinary tract infection. after a first clinical evaluation an infective orchiepididymitis was suspected and antibiotics were administered for 2 weeks. he had no comorbidities and figure 1. high blood perfusion at colour-doppler examination in the inferior part of testis. doi: 10.4081/aiua.2014.4.400 tombolini_stesura seveso 16/01/15 12:13 pagina 400 401archivio italiano di urologia e andrologia 2014; 86, 4 primary testicular b-cell lymphoblastic lymphoma body, was 70%. this lesion was classified as a primary testicular lymphoblastic b-cell lymphoma with focal expression of cd3, confined to the testicle. patient underwent total-body computed tomography (ct), which resulted negative for metastasis. a multidisciplinary discussion with urologists, oncologists, radiation oncologists and hematologists was done. after a negative bone marrow biopsy the patient underwent to 6 cycles of hyper-cvad chemotherapy (cyclophosphamide, vincristine, doxorubicin, and dexamethasone given as course a, followed by methotrexate and cytarabine given as course b), rachicentesis with administration of methotrexate 12 mg and cytarabin 100 mg (2 for each cycle), and radiotherapy of contralateral testis. we proposed also cryoconservation of sperm before starting adjuvant treatment. after 6 months of follow-up the patient is alive and without disease. discussion is posted in supplementary materials in www.aiua.it conclusions primary testicular lymphoma is not associated to pathognomonic findings at ultrasound and is not different from other testis neoplasms. primary testicular lymphoblastic b lymphoma is an aggressive disease and it is necessary a multimodality therapy (surgery, chemotherapy and radiotherapy) to prevent metastasis. references 1. emura a, kudo s, et al. testicular malignant lymphoma: imaging and diagnosis. radiat med. 1996; 14:121-126. 2. mazzu d, jeffrey rb, et al. lymphoma and leukemia involving the testicles: findings on grey scale and colour-doppler sonography. am j roentgenol. 1995; 164:645-647. 3. ahmad ss, idris sf, et al. primary testicular lymphoma. clin oncol. 2012; 24:358-65. 4. cheah cy, wirth a, seymour jf. primary testicular lymphoma. blood. 2014; 123:486-93. figure 2. a. macroscopical aspect of tumor with creamy white nodular proliferation. b. histological findings: tumor cells penetrate diffusely into testicular tissue with loss of intact seminiferous tubules. figure 3. c. histological findings: cells demonstrated enlarged nucleii with little nucleoli and decrement of cytoplasm. d. hematoxylin and eosin). immunihistoche mical panel with tdt positive antibodies. correspondence flavia tombolini, md, resident in urology flavia.tombolini@virgilio.it vito lacetera, md vlacetera@gmail.com giovanni muzzonigro, md g.muzzonigro@univpm.it guido gini, md, hematologist guido.gini@ospedaliriuniti.marche.it debora capelli, md, hematologist debora.capelli@ospedaliriuniti.marche.it pietro leoni, md, hematologist p.leoni@univpm.it rodolfo montironi, md, pathologist r.montironi@univpm.it aou united hospitals polytechnic university of marche region, ancona, italy andrea b. galosi, md (corresponding author) galosiab@yahoo.it division of urology, dept. of surgery, “augusto murri” general hospital area vasta 4, az. sanitaria unica regione marche 63900 fermo (fm), italy tombolini_stesura seveso 16/01/15 12:13 pagina 401 345archivio italiano di urologia e andrologia 2016; 88, 4 case report an unusual case of primary intrascrotal lipoma andrea fabiani 1, emanuele principi 2, alessandra filosa 3, tiziana pieramici 3, fabrizio fioretti 1, valentina maurelli 1, lucilla servi 1, gabriele mammana 1 1 urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche, italy; 2 urologic clinic, polytechnic university of marche region, ancona, italy; 3 pathologic unit asur marche area vasta 3, macerata civic hospital, italy. in daily clinical practice, intrascrotal lesion are commonly detected, both by clinical examination either by ultrasound scan. while 95% of testicular lesions are malignant, most paratesticular lesions are benign. among these, intrascrotal lipomas must be take into account in differential diagnosis. when they originate from scrotal wall, they named “primary scrotal lipoma”. we describe a case of a primary intrascrotal lipoma diagnosed after surgical excision in a young man presented at our urological department complaining a painful left scrotal mass. key words: scrotal lipoma; paratesticular tumor; scrotal ultrasound. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. due to the difficult interpretation and to the symptoms complained, it was decided to perform a scrotal surgical exploration. after a local anesthesia with left funicular and median raphe infiltration (lidocaine 2% 10 ml and ropivacaine 7,5 mg 10 ml), a longitudinal median scrotal incision was made. an ovoid intrascrotal mass was externalized (figure 2). doi: 10.4081/aiua.2016.4.345 presented at 20th national congress sieun, sciacca 2016 figure 1. scrotal ultrasound shows a slightly hyperechoic homogeneous nodule without color signal expression. figure 2. nodule appearance at surgical exploration. introduction intrascrotal lipomas are lesions rarely observed in common clinical practice. they are benign mesenchymal tumours that can arise from the paratesticular structures as the spermatic cord, epididymis, tunica vaginalis or from the subcutaneous adipose cell of the scrotum (1). in most cases it is not easy to identify the precise source site of these tumors . when lipomas originate from scrotal wall they are named “primary scrotal lipomas” (2) such in the case reported herein. case presentation a 22-years-old patient presented to our hospital with a painful nodule of a left scrotal region, that was first noticed about 3 months before but gradually and slowly became symptomatic. no others symptoms were reported in anamnesis. at palpation, the nodule showed an elastic non tender consistency and it resulted regularly shaped on the left side of the scrotum apart of the lower ipsilateral testicular pole. it was easily distinguishable from testicle and epidydimus that appeared normal for shape and size and not painful. the contralateral testicle and epidydimus were normal. the scrotal ultrasound, performed with a 7,5 mhz linear probe, showed a slightly hyperechoic homogeneous nodule, that does not show any infiltrative character and was 3 x 2 cm in size (figure 1). no echocolor signal was present. therefore, fabiani1_stesura seveso 09/01/17 10:51 pagina 345 archivio italiano di urologia e andrologia 2016; 88, 4 a. fabiani, e. principi, a. filosa, t. pieramici, f. fioretti, v. maurelli, l. servi, g. mammana 346 the yellowish mass of about 3 cm in major diameter, was completely excised from the scrotal wall. the left testicle and epidydimus were normal. after excision and eversion of tunica vaginalis, scrotal wall was sutured with absorbable stiches. a drainage was placed in paratesticular space to avoid haematocele. the microscopic pathologic evaluation of the surgical specimen highlighted the presence of mature adipocytes constituting the totality of the tissue examined in the absence of other types of connective tissue and an obvious abnormal vascular proliferation vascular with steatonecrosis areas and, at the periphery of the lesion, a reactive vascular proliferation like a granulation tissue (figure 3a, b). the diagnosis of primary scrotal lipoma was made. discussion in daily clinical practice, intrascrotal lesion are commonly detected, both by clinical examination either by ultrasound scan. while 95% of testicular lesions are malignant, most paratesticular lesions are benign. among these, the intrascrotal lipomas are rare lesion. the region of origin are not always detectable and they may originate from the adipose tissue of spermatic cord, spermatic cord structures and the scrotal wall (3). the patient age may be a guide to clinical diagnosis (1). they may also be malignant and vary in size. consequently symptoms are caused by growth. ultrasound imaging play an important role in the initial evaluation of these lesions. providing information about localization, cystic or solid nature of the lesion (3). then, these lesions can be distinguished from most other testicular lesions, such as fibrous pseudotumor, adenomatoid tumor or cystic lesions, according to ultrasound findings, anatomic location, and negative tumor markers. however, even using these findings it is difficult to radiologically determinate the nature of these lesions (benign or malignant). although the majority of solid extratesticular masses are benign, it is hard to distinguish malignancy (4). in conditions like these, magnetic resonance imaging may be of use. the histopathology of primary scrotal lipoma may be confused with lipomatosis, lipoblastoma and liposarcoma. being the mass encapsulated and not infiltrated to the surrounding tissues helped us to differentiate it from lipomatosis, and the presence of mitosis and atypia to differentiate it from liposarcoma. no malignancy was present in the case reported. on the third and sixth month follow-up no local relapse was seen. conclusion scrotal lipomas are rare, benign paratesticular tumors. surgical excision is the treatment of choice. there is no evidence that scrotal lipomas differ in terms of management and prognosis from other variants of lipoma. although the sonographic appearance of these tumors is variable and non-specific, ultrasound is the first exam in the clinical management as for all scrotal masses and it has a key role in the initial management. authors’ contributions all authors participated in the design and conduct of the study. all authors reviewed and approved the final version of the manuscript. references 1. algaba f, mikuz g, boccon-gibod l, et al. pseudoneoplastic lesions of the testis and paratesticular structures. virchows arch. 2007; 451:987-97. 2. fujimura n, kurokawa k. primary lipoma of the scrotum. eur urol. 1979; 5:182-183. 3. galosi ab, scarpelli m, mazzucchelli r, et al. adult paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of spermatic cord leiomyosarcoma. diagnostic pathology. 2014; 9:90. 4. basal s, malkoç e, aydur e, et al. fibrous pseudotumors of the testis: the balance between sparing the testis and preoperative diagnostic difficulty. turkish journal of urology. 2014; 40:125-9. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md phd fa.fioretti@libero.it valentina maurelli, md valentinamaurelli@hotmail.it lucilla servi, md lucilla.servi@sanita.marche.it surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, macerata, italy emanuele principi, md, urology resident principie@tiscali.it urologic clinic, polytechnic university of marche region, ancona, italy alessandra filosa, md, phd alessandrafilosa@yahoo.it tiziana pieramici, md t.pieramici@libero.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy gabriele mammana, md gabriele.mammana@sanita.marche.it head surgery dpt, chief of section of urology asur marche area vasta 3, macerata hospital, macerata, italy figure 3. hystological features of the nodule. a. b. fabiani1_stesura seveso 09/01/17 10:51 pagina 346 53archivio italiano di urologia e andrologia 2019; 91, 1 case report does right-sided varicocele indicate a right-sided kidney tumor? miguel bonfitto 1, leandro shogo matuy kimura 2, josé maria pereira godoy 3, miguel zerati filho 4, luis cesar fava spessoto 4, fernando nestor facio junior 4 1 urology, hospital de base de são josé do rio preto/famerp/funfarme, brazil; 2 general surgery, hospital de base de são josé do rio preto/famerp/funfarme, brazil; 3 vascular surgery division, são josé do rio preto school of medicine, famerp/funfarme, brazil; 4 urology division, são josé do rio preto school of medicine, famerp/funfarme, brazil. varicocele is a dilation of the pampiniform venous plexus, mainly affecting the left side of the scrotum. in rare cases, however, the right side is affected. when this occurs, a retroperitoneal disease should be suspected, such as right-sided renal neoplasm. the present case report highlights the importance of right-sided varicocele in the diagnostic investigation of neoplasm of the right kidney. key words: acute right-sided varicocele; right-sided renal neoplasm; renal tumor. submitted 11 september 2018; accepted 25 september 2018 summary no conflict of interest declared. flaccid, depressible, painless abdomen with no palpable masses. the scrotal veins on the right side were dilated and an increase in caliber was observed during the valsalva maneuver (figure 1). doppler ultrasound of the scrotum confirmed accentuated right-sided varicocele. the complementary examination of the abdomen revealed a mass in the right kidney. the patient was submitted to computed tomography of the abdomen and pelvis, which revealed a solid, heterogeneous, expansive formation with circumscribed and lobulated contours, occupying nearly the entire right kidney, measuring 14.6 x 10.9 cm, with invasion of the right renal vein causing ectasia of the gonadal vein and accentuated varicocele (figure 2). the patient was submitted to right nephrectomy with lymphadenectomy. the anatomo-pathological analysis confirmed the occurrence of kidney cell carcinoma (stage pt2 nx mx). following good clinical evolution, the patient was discharged from hospital on the fourth day of the postoperative period and is currently in outpatient follow up. discussion we report a rare case of a right kidney neoplasm associated with right-sided varicocele. this is an uncommon finding and documented little in the literature. approximately 0.2% of patients present right-sided varicocele, which should lead to the hypothesis of ipsilateral kidney tumor (1, 5-10). in the present report, the diagnostic investigation initiated with the observation of varicose veins in the right side of the scrotum. subsequent doppler ultrasound and computed tomography of the abdomen confirmed the diagnosis of right kidney neoplasm and the patient was submitted to nephrectomy. cases of renal cell carcinoma in patients with right-sided varicocele are rare in the literature. we found only two case reports (11, 12). ates et al. (13) reported an association between right-sided varicocele and retroperitoneal paraganglioma exerting extrinsic pressure on the inferior vena cava and causing grade 3 dilation of the right pampiniform plexus. dewitt et al. (6) performed a retrospective investigation of 337 cases of right-sided varicocele, but found no statistically significant association with the diagnosis of a malignancy. these studies condoi: 10.4081/aiua.2019.1.53 introduction varicocele is defined as a dilation of the pampiniform venous plexus, affecting 10 to 15% of urology patients (1-6). the left side of the scrotum is affected in up to 85% of cases (6). in rare cases of presentation on the right side, a neoplasm or a retroperitoneal mass in the right kidney should be the diagnostic hypothesis (3, 6). a physical examination is the gold standard for the diagnosis of varicocele, which is characterized by the dilation of veins in the spermatic cord (7). currently, doppler ultrasound is the main complementary exam (7). right-sided varicocele may be explained by an increase in hydrostatic pressure due to compression of the renal or spermatic vein caused by a tumor or the formation of thrombi (1, 8). this condition is scored as grade i when the varicose cord is palpated only during the valsalva maneuver, grade ii when it is palpable in the standing position and grade iii when it is visible without palpation (1, 4). in this paper, we report a rare case of right-sided varicocele associated with a neoplasm in the right kidney and highlight the importance of this finding in the investigation of kidney tumors. case report a 49-year-old male patient with no previous comorbidities sought care due to a varicose cord on the right testicle that had appeared 40 days earlier. the patient reported no pain, local swelling, weight loss, abdominal pain or urinary problems. during the physical examination, the patient presented a good general health state and bonfitto_stesura seveso 25/03/19 17:22 pagina 53 archivio italiano di urologia e andrologia 2019; 91, 1 m. bonfitto, l. shogo matuy kimura, j.m. pereira godoy, m. zerati filho, l.c. fava spessoto, f. nestor facio junior 54 firm the initial aim of the present report of describing a rare association and highlighting the importance of the diagnostic investigation of an abdominal disease following the confirmation of right-sided varicocele. right-sided varicocele is rare and should alert physicians to the possibility of compression of the inferior vena cava (14). varicocele in the left side of the scrotum is more frequent due to the anatomic relationship between the left spermatic vein and left renal vein. therefore, rightsided varicocele should be seen as a possible indicator of neoplasm in the right kidney (14-17). conclusions as the majority of cases of varicocele occur on the left side, right-sided varicocele is a potential indicator for the clinical investigation of a concomitant abdominal disease. the present report underscores the need for a discerning investigation of right kidney neoplasm following the diagnosis of right-sided varicocele. references 1. clavijo ri, carrasquillo r, ramasamy r. varicoceles: prevalence and pathogenesis in adult men. fertility and sterility. 2017; 108:364-369. 2. marte a. the history of varicocele: from antiquity to the modern era. 2017; 44:563-576. 3. vanlangenhove p, dhondt e, everaert k, defreyne l. pathophysiology, diagnosis and treatment of varicoceles: a review. min urol nefrol. 2014; 66:257-82. 4. molly a, dewitt e, greene dj, et al. isolated right varicocele and incidence of associated cancer. urology. 2018; 117:82-85. 5. baden lr. acute varicocele revealing renal cancer. n engl j med. 2016; 374:21. 6. woldu s, nees s, batavia jv, et al. physical exam and ultrasound characteristics of right varicocoeles in adolescents with left varicocoeles. andrology. 2013; 1; 936-942. 7. belay re, huang go, ken j, et al. diagnosis of clinical and subclinical varicocele: how has it evolved? asian j androl. 2016; 18:182-185. 8. georgiades f, stylianides a, grange p, kouriefs c. images in clinical urology point to sinister causes. urology. 2016; 97:e23-e24. 9. robson j, wolstenhulme s, knapp p. is there a co-association between renal or retroperitoneal tumours and scrotal varicoceles? a systematic review. ultrasound. 2012; 20:182-191. 10. hanna gb, byrne d, townell n. right-sided varicocele as a presentation of right renal tumours. br j urol. 1995; 75:798-799. 11. hadad z, norup k, petersen c. right-sided varicocele testis as the only sign of right-sided renal tumour. ugeskr læger. 2016; 178:2-3. 12. fernández-pello s, gonzález i, pérez-carral jr, et al. right varicocele as finding of right renal mass. arch esp urol. 2015; 68:641-2. 13. ates n, habibi m, ipekci t. retroperitoneal paraganglioma presenting as right-sided varicocele: case report. ann saudi med. 2016; 36:148-151. 14. cheungpasitporn w, horne jm, howarth cb. adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report. j med case rep. 2011; 5:337-41. 15. roy cr, wilson t, raife m, horne d. varicocele as the presenting sign of an abdominal mass. j urol. 1989; 141:597-599. 16. thompson jn, abraham k, jantet h. metastasis to pampiniform plexus from left renal adenocarcinoma presenting with acute varicocele. urology. 1984; 24:621-622. 17. shinsaka h, fujimoto n, matsumoto t. a rare case report of right varicocele testis caused by a renal cell carcinoma thrombus in the spermatic vein. int j urol. 2006; 13:844-845. figure 1. physical examination revealing grade 3 right-sided varicocele. figure 2. computed tomography of abdomen revealing tumor in right kidney. correspondence miguel bonfitto, resident physician of urology, hospital de base de são josé do rio preto/famerp/funfarme, (brazil) leandro shogo matuy kimura, resident physician of general surgery, hospital de base de são josé do rio preto/famerp/funfarme (brazil) josé maria pereira godoy, professor, vascular surgery division, são josé do rio preto school of medicine, famerp/funfarme (brazil) 5416 brig. faria lima ave. 15090-000 são josé do rio preto, sp, brazil miguel zerati filho, luis cesar fava spessoto, fernando nestor facio junior, md, phd (corresponding author) fnfacio@yahoo.com.br professor, urology division, são josé do rio preto school of medicine, famerp/funfarme (brazil) bonfitto_stesura seveso 25/03/19 17:22 pagina 54 63archivio italiano di urologia e andrologia 2019; 91, 1 case report pubis bone osteomyelitys after robotic radical cystectomy with continent intracorporeal urinary diversion: multidisciplinary approach to a complex situation daniele romagnoli 1, federico mineo bianchi 2, paolo sadini 2, andrea angiolini 2, daniele d'agostino 1, marco giampaoli 1, sergio candiotto 3, riccardo schiavina 2, eugenio brunocilla 2, angelo porreca 1 1 robotic urology and mini invasive urologic surgery unit, abano terme hospital, abano terme (pd), italy; 2 urology unit, s. orsola malpighi university hospital alma mater studiorum, bologna (bo), italy; 3 orthopaedic unit, abano terme hospital, abano terme (pd), italy. pubic bone osteomyelitis is a rare infectious condition which is characterized by a complex diagnostic and therapeutic workup, due to its various clinical manifestations. among the many causes of this condition, urinary fistula is the most common in case of previous urological procedures. in order to solve this complication, it is crucial to treat both the fistula and (moreover) the infectious locus arising from it, because treating the fistula alone does not provide any control on the infectious noxa. we present the first case of pubic bone osteomyelitis arising from a urinary fistula after a robotic radical cystectomy with intra corporeal continent neobladder, which has been successfully treated through a multidisciplinary approach. key words: osteomyelitis; cystectomy; urinary fistula; robotic; multidisciplinary. submitted 28 december 2018; accepted 8 february 2019 summary no conflict of interest declared. case description we describe the case of a male patient, aged 69, who had undergone a robot-assisted radical cystectomy (rarc) with extended pelvic lymph node dissection (plnd) and intracorporeal orthotopic neobladder substitution (ons) according to the studer-wiklund technique, due to a pt2 high grade bladder carcinoma. local staging was performed either with ct scan and mri in order to plan a better approach to a safe nerve sparing cystectomy, as described for prostate cancer clinical t staging (8). the operation was performed at our institution in march 2018, and no early postoperative complication was documented. barbed sutures were used for neo-bladder reconstruction and muscle-fascial-reconstruction as described in prostatic surgery for bladder neck-urethral anastomosis (9). patient was discharged in 7th post-operative day (pod), catheter was removed after 30 postoperative days, and 3 months later, during the scheduled control visit at one month, he described persistent suprapubic pain and recent presentation of 38°c fever. oral empiric antibiotic therapy (prulifloxacin 600 mg daily for seven days) was administered, but neither fever nor suprapubic pain resolved. thus, patient was hospitalized at our institution, to rule out a diagnostic work-up. abdominal ultra sound (us) was negative for abdominal free fluid (suggestive for lymphocele or pelvic haematoma), and neobladder voiding was confirmed complete at ultrasound. under the suspicion of an infection supported by neovescico-ureteric reflux (para-physiological in case of neobladder), we started intravenous antibiotic therapy (cefotaxime 1 g twice a day for 7 days) and 3-way urinary catheter was inserted. patient experienced a quick symptom relief and was discharged after 3 days. a week later catheter was removed, but after two more weeks the patient reported the recurrence of the afore mentioned symptoms. moreover, the suprapubic pain was described as intensifying during ambulation, and was in some cases associated with mixed urinary incontinence. patient was readmitted at our institution, where we performed a contrast enhanced computed tomography (ct), which revealed the presence of a filidoi: 10.4081/aiua.2019.1.63 introduction pubic bone osteomyelitis (pbo) is a rare complication that may occur after either radical prostatectomy, radical radiotherapy of the prostatic bed or other ablative techniques for the treatment of prostate cancer or benign hyperplasia (1-4). due to its extremely low incidence, its initial cause is still uncertain. this clinical syndrome is characterized by pelvic and thigh pain, difficulty with ambulation, and recurrent urinary tract and pelvic infection. the pain associated with this condition can significantly impact the quality of life of patients and impede participation in the activities of daily living. several authors reported urinary fistulation (uf) into the bone symphysis to be the main culprit of this condition (5-7). common presentation includes chronic and debilitating suprapubic pain, fever, voiding disorders, recurrent urinary tract infections and sometimes impairment and pain during ambulation. our aim is to present a case of pbo which arose from a urinary fistula after robotic assisted radical cystectomy with continent urinary diversion, and how we managed it in order to solve the chronic inflammatory process. romagnoli_stesura seveso 25/03/19 17:26 pagina 63 archivio italiano di urologia e andrologia 2019; 91, 1 d. romagnoli, f. mineo bianchi, p. sadini, a. angiolini, d. d'agostino, m. giampaoli, s. candiotto, r. schiavina, e. brunocilla, a. porreca 64 form fistula between the neobladder anastomosis (at 11 o’clock) and the pubic bone. considering the thin length (1.5 cm) and width (0.5 cm) of the fistula, and the unwillingness of the patient to be submitted to another surgical operation, conservative management was adopted. a neobladder catheter was inserted, in order to grant an adequate drainage of the neobladder, and oral empiric antibiotic therapy (ciprofloxacin 500 mg twice a day for 1 week every month) was administered. a follow up ct scan was performed two months later, and no residual fistula was apparently documented, thus the catheter was removed. two weeks later a flexible neo-cystoscopy was performed, and none remnant of the fistula was documented, except for an area of edematous tissue in a location correspondent to the previous leakage. the absence of any residual fistula was confirmed also by a subsequent retrograde uretrography. however, six months after rarc, the patient was admitted at the emergency department of our institution, reporting persisting strong inguinal pain, particularly focused in the pubic symphysis. pain was reported to have begun one month before, with a subsequent constant increase, associated with a significant impairment in the ambulation of the medial side of the right leg. moreover, the patient reported to suffer from a significant worsening of urinary continence, using about 3 pads/day, with a steep decrease of his whole quality of life. a third uro-ct was performed showing the recurrence of the fistula, which resulted to be larger than before (figures 1-4). physical examination confirmed intense pain at the palpation of the inguinal region, bilaterally. due to the intense pain, the patient refused consent to the urinary catheter, so bilateral percutaneous nephrostomies were placed with combined ultrasonographic and radiologic technique, to reduce the urinary leakage from the fistula. multidisciplinary evaluation was carried out, by a team made up by the members of the urology unit and orthopedic unit. we agreed that the clinical situation was the result of a chronic pubic osteomyelitis, which had originally been started by the urinary fistula. the recurrence of the urinary fistula appeared to be the result of the reactivation of the bone chronic inflammatory process, and the extirpation of the tissue involved was planned. intravenous administration of meropenem 1 g twice a day was administered 3 days before the surgical operation, in order to reduce the septic load. the operation began with a semicircle incision of the skin from pubis to the groin, and subsequent section of the rectus abdominis muscle. the pubic symphysis was figure 1. ct scan showing fistulous tract in the context of the pubis symphysis. figure 2. pre-operative ct urographic phase highlighting pubo-vesical fistula. figure 3. mri scan (t1w) showing focus of pubis osteomyelitis. figure 4. mri scan (t2w) documenting pubis osteomyelitis focus. romagnoli_stesura seveso 25/03/19 17:26 pagina 64 isolated, and aggressive scarring of the inflammatory tissue surrounding the fistula was performed (figure 5). the pubic tissue was deeply removed until obtaining vital, well vascularized and bleeding tissue. moreover, we noted the involvement of the origin of the right longus adductor muscle by the inflammatory process, thus explaining ambulation impairment. then retrograde removal of the fistulous path was performed. neobladder filling with a solution made up of saline and methylene blue was performed, in order to check the presence of any residual fistula. the check resulted negative, as confirmed by a flexible cystoscopy. then the rectus abdominis muscle was fixed to the remnant part of the symphysis. double laminar drainages were positioned at the level of the symphysis, and the surgical incision was closed. operative time was 120 minutes, with estimated blood loss less than 100 ml. drainages were removed on first and third postoperative day, and length of hospital stay (los) was 7 days. the patient experienced a quick relief from the symptoms previously reported, also due to an adequate antalgic therapy made up by nonsteroidal-anti-inflammatory drugs (nsaids). one month after surgery a retrograde and anterograde radiological study was performed and resulted negative for any recurrence of the fistula. the patient reported to be fine, thus catheter was removed, and nephrostomies were closed. the patient was revaluated two weeks later and was confirmed symptoms free. retrograde uretrography was performed resulting negative for any urinary leakage, so both nephrostomies were removed. at 3 and 6 months post-operative control visits, the patient confirmed full continence and no further symptoms. discussion osteomyelitis of the symphysis pubis is a rare entity, accounting for less than 1% of all cases of osteomyelitis (10). the presenting signs and symptoms are mainly pubic pain, antalgic gait, pain with hip motion, and occasional presence of fever. postoperative pain after radical cystectomy is expected; nevertheless, pain lasting for more than 6 months is not usual and may suggest other etiologies (11, 12). osteomyelitis of the symphysis pubis has been reported after renal transplantation (13), inguinal herniorraphy (14), procedures for urinary stress incontinence such as tension free vaginal/transobturator taping (15), and ablative treatments for prostate cancer, such as high intensity focused ultrasound treatment for prostate cancer (16), pelvic radiation therapy and radical prostatectomy (1). several theories lie behind the pathogenesis of pbo. this includes infection, trauma secondary to haematogenous spread or complex regional pain syndrome (17). the most common pathogen causing pubic symphysis osteomyelitis is staphylococcus aureus. however, other organisms such as pseudomonas aeruginosa, escherichia coli, enterococcus species, mycobacterium tuberculosis, and salmonella species have also been reported in the literature (18). there have been several reports of pubic bone osteomyelitis secondary to pubosymphyseal fistula, in patients who underwent radical prostatectomy, followed by adjuvant radiation therapy. matsushita et al. reported 12 patients, from two centers over an 11-year period, who developed a pubovesical fistula, following treatment of prostate cancer (19). all those patients had radiation therapy either as the primary treatment or as salvage therapy and subsequently developed bladder neck contracture. the median interval to develop pubovesical fistula was 37 months after treatment for bladder neck contracture. broad-spectrum antibiotics were initiated in all patients, and only one patient had resolution of his osteomyelitis. the remaining patients either needed diversion of their urinary tract or insertion of bilateral percutaneous nephrostomies, to achieve resolution of symptoms. despite such a small sample size, the longtime frame, extending over 11 years, reflects the rarity of this disease and as such the absence of any existing guidelines, for treating those fistulas. pelvic bone pain and gait instability, after radical prostatectomy, reflect multiple bone etiologies, to contemplate in our differential diagnosis (20-22). other than osteomyelitis of the pubic symphysis, pelvic insufficiency fracture (pif), osteonecrosis (on), and osteitis pubis (op) are among the others to consider (14). op is usually mistaken by osteomyelitis. it is defined by a painful inflammatory process resulting in bone destruction of the margins of the symphysis pubis. nevertheless, op is a self-limiting process, treated conservatively by anti-inflammatory drugs. the main difference between osteitis pubis and osteomyelitis is the negative culture on biopsy (7). noteworthy here is that delay in diagnosis or treatment of symphysis pubis osteomyelitis can further manifest as bilateral thigh pain and adductor muscle abscesses, necessitating percutaneous drainage (23, 24). as part of pain relief, pubic bone resection has been shown to provide immediate and sustained improvement in pain, along with the long course of antibiotics administered (25). in a cohort of 16 patients, a statistically significant decrease in the median pain intensity score was noted, over a median follow-up of 9.4 months, after performing pubic bone resection (5.5 versus 0; p = 0.0005). suturing of the dorsal venous complex (dvc), during the robotic radical prostatectomy procedure, using a type of 65archivio italiano di urologia e andrologia 2019; 91, 1 pubis bone osteomyelitys after robotic radical cystectomy figure 5. intra-operative image of the combined orthopaedic and urologic surgical procedure with removal of the osteomyelitis focus. romagnoli_stesura seveso 25/03/19 17:26 pagina 65 archivio italiano di urologia e andrologia 2019; 91, 1 d. romagnoli, f. mineo bianchi, p. sadini, a. angiolini, d. d'agostino, m. giampaoli, s. candiotto, r. schiavina, e. brunocilla, a. porreca 66 needle called v-lock suture needle, and then fixing it at the level of the pubic bone, has been postulated to be the cause for osteomyelitis. indeed, the use of barbed suture for urethral anastomosis in safe and efficacious but repeated needle injury to the pubic symphysis, during the urethral vesical anastomosis, may as well inadvertently cause contiguous-focus osteomyelitis (26). yet, the possibility of an even rarer etiology of the pubic bone osteomyelitis cannot be excluded, given the negative urine culture at time of surgery. in our experience we count only 3 cases of pubo-urinary fistula in over 15 years of high volume surgery, but the one we reported was the first after rarc (2 cases of uf were recorded after open radical prostatectomy). this is the first surgical complication of our series of rarc (27) whose control have been achieved through an open approach, having adopted a less invasive approach in the remaining cases (28). in our opinion, uf and pbo have mutual cause-effect relation. pbo originally arose from a urinary leakage from the neo-bladder, with urinary extravasation as the main responsible for the subsequent bacterial colonization of the pubic bone. despite long-term antibiotic therapy along with bladder catheter placement to drain urine, with further negative ct that excluded any residual urinary fistula, the patient was nonetheless readmitted in hospital 3 months later due to further recurrence of intense suprapubic pain and ambulation impairment. despite resolution of systemic infection, antibiotic therapy could not reach and fully turn off the primary osteomyelitis focus, thus impairing tissue repairing processes and causing an additional urinary leakage. an early diagnosis of pubic osteomyelitis is often difficult: the lack of typical acute osteomyelitis symptoms due to the deep position of pelvic bone and the limitation of its motion, along with unspecific symptoms and hematologic findings often lead to a late acknowledgement of this serious condition (29, 30). x-rays have been used for early diagnosis though appearance of bone destruction and periosteal reaction occur typically 7-14 days after onset, thus limiting their role in the early phase of disease (25). a definitive diagnosis of pubic osteomyelitis is usually made through mri and ct examination. mri displays a 94% sensitivity and 97% specificity in detecting this clinical condition, as it represents the most suitable imaging technique to distinguish between infected and normal bone marrow and to detect edematous changes and abscess formation. mri should be in fact considered as pbo is suspected (29, 30). the treatment for pbo is based on antibiotic therapy and surgical debridement. when recognized early, antibiotic therapy alone could guarantee a complete resolution of this clinical condition, due to the rich vascularization of the pelvis. del busto et al. reviewed 7 patients diagnosed with pbo, who didn’t require any surgical debridement after complete response to 3-to-12 weeks of antibiotic therapy (31). surgical debridement is nonetheless recommended after primary antibiotic therapy and consists in a wide removal of necrotic and infected tissues until vital and bleeding ones are reached. intravenous antibiotics should be prolonged for 6 more weeks after surgery, with 3 additional weeks of oral antibiotics in case of haematogenous origin of pbo (29, 32). in our case direct and prolonged urinary leakage from the orthotopic neobladder resulted in a chronic infection with a slowly increasing inflammatory process that could be identified only when osteomyelitis had already destroyed pubic bone and the abscess was already formed. uro-ct and mri imaging were decisive to correctly identifying pbo, as symptoms reported by the patient and hematologic findings were inconclusive. antibiotic therapy alone was not enough to resolve pbo. despite complete resolution of urinary fistula and apparent symptom relief, the inflammatory process recurred 2 months later. persistence of chronic inflammation caused an impairment of tissue reparation, that translated in a recurrent urinary fistula from the neobladder. multi-disciplinary management was critic for choosing the proper management of this peculiar clinical condition: extensive surgical debridement of the necrotic and infected tissues along with prolonged antibiotic therapy led to a definitive resolution of the chronic inflammation. no signs of recurrence were identified at 3 and 6 months follow up visits, with a complete continence recover and any additional symptoms were reported. conclusions osteomyelitis of the symphysis pubis is a rare condition, quite uncommon to occur after radical cystectomy. it can be often missed due to vague non-specific symptoms. its clinical presentation might be confused by the presence of concurrent urinary fistula, which might be its origin, but also its effect. in case of urinary fistula, it is very important to rule out, via mri, the presence of any concurrent pbo focus, because curative goal might be achieved only if both conditions are treated, preferably through a multidisciplinary approach. referemces 1. gupta s. et al., pubic symphysis osteomyelitis in the prostate cancer survivor: clinical presentation, evaluation, and management. urology, 2015; 85:684. 2. moore dc, et al. a 57-year-old man with a history of prostatectomy and pelvic irradiation presents with recurrent urinary tract infections, hematuria, and pelvic pain. urology. 2013; 81:221. 3. kats e, et al. diagnosis and treatment of osteitis pubis caused by a prostate-symphysis fistula: a rare complication after transurethral resection of the prostate. br j urol. 1998; 81:927. 4. hutchinson rc, et al. magnetic resonance imaging to detect vesico-symphyseal fistula following robotic prostatectomy. int braz j urol. 2013; 1:288. 5. bugeja s, et al. fistulation into the pubic symphysis after treatment of prostate cancer: an important and surgically correctable complication. j urol, 2016; 195:391. 6. matsushita k, et al. pubovesical fistula: a rare complication after treatment of prostate cancer. urology, 2012; 80: 46. 7. knoeller, et al. osteitis or osteomyelitis of the pubis? a diagnostic romagnoli_stesura seveso 25/03/19 17:26 pagina 66 and therapeutic challenge: report of 9 cases and review of the literature, acta orthop belg, 2006; 72:541. 8. schiavina r, et al. mri displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. j endourol. 2018; 32:315. 9. porreca a, et al. bidirectional barbed suture for posterior musculofascial reconstruction and knotless vesicourethral anastomosis during robot-assisted radical prostatectomy, minerva urol nefrol. 2018; 70:319 10. lavien g, et al, pubic bone resection provides objective pain control in the prostate cancer survivor with pubic bone osteomyelitis with an associated urinary tract to pubic symphysis fistula, reconstructive urology. 2017; 100:234. 11. mchenry mc, alfidi rj, wilde ah, hawk wa. hematogenous osteomyelitis: a changing disease, cleve clin q. 1975; 42:125-53. 12. moore dc1, keegan ka, resnick mj, et al. a 57-year-old man with a history of prostatectomy and pelvic irradiation presents with recurrent urinary tract infections, hematuria, and pelvic pain, urology. 2013; 81:221. 13. jindal rm, idelson b, bernard d, cho si.r. m. osteomyelitis of symphysis pubis following renal transplantation, postgrad med j. 1993; 69:742. 14. mader r, yeromenco e. pseudomonas osteomyelitis of the symphysis pubis after inguinal hernia repair, clini rheumatol. 1999; 18:167. 15. goldberg rp, tchetgen mb, sand pk, et al. incidence of pubic osteomyelitis after bladder neck suspension using bone anchors, urology, 2004; 63:704. 16. robison cm, gor ra, metro mj. pubic bone osteomyelitis after salvage high-intensity focused ultrasound for prostate cancer. curr urol. 2013; 7:149-51. 17. sexton dj, heskestad l, lambeth wr, et al. postoperative pubic osteomyelitis misdiagnosed as osteitis pubis: report of four cases and review. clin infect dis. 1993; 17:695-700. 18. alqahtani sm, jiang f, barimani b, gdalevitch m. symphysis pubis osteomyelitis with bilateral adductor muscles abscess. case rep orthop. 2014; 2014:982171. 19. matsushita k, ginsburg l, mian bm, et al. pubovesical fistula: a rare complication after treatment of prostate cancer. urology, 2012; 80:446. 20. pauli s, willemsen p, declerck k, et al. osteomyelitis pubis versus osteitis pubis: a case presentation and review of the literature. br j sports med. 2002; 36:71-3. 21. trubiano ja, yang n, mahony aa. bilateral thigh pain after treatment for prostate cancer. bmj case rep. 2013; 2013 pii: bcr2013008784. 22. lavien g, chery g, zaid ub, peterson ac. pubic bone resection provides objective pain control in the prostate cancer survivor with pubic bone osteomyelitis with an associated urinary tract to pubic symphysis fistula. urology. 2017; 100:234-239. 23. kitaguchi d, et al. pubic osteomyelitis after surgery for perforated colonic diverticulitis with fecal peritonitis: a case report. int j surg case rep. 2017; 38:50. 24. rosenthal re, et al. osteomyelitis of the symphysis pubis: a separate disease from osteitis pubis. report of three cases and review of the literature. j bone joint surg am. 1982; 64:123. 25. kozlowski k, hochberger o, povysil b. swollen ischiopubic synchondrosis: a dilemma for the radiologist. australas. radiol. 1995; 39:224. 26. porreca a, et al. robotic-assisted radical prostatectomy with the use of barbed sutures. surg technol int. 2017; 30:39. 27. porreca a, et al. robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon's experience after a modified modular training, minerva urol nefrol. 2018; 70:193. 28. schiavina r, et al. laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. j robot surg. 2016; 10:323. 29. carek pj, et al. diagnosis and management of osteomyelitis. am fam phys. 2001; 63:2413. 30. sammak b, et al. osteomyelitis: a review of currently used imaging techniques. eur. radiol. 1999; 9:894. 31. del busto r, et al. osteomyelitis of the pubis. report of seven cases. jama. 1982; 248:1498. 32. wilmes d, et al. osteomyelitis pubis caused by kingella kingae in an adult patient: report of the first case, bmc infect. dis. 2012; 12:236. 67archivio italiano di urologia e andrologia 2019; 91, 1 pubis bone osteomyelitys after robotic radical cystectomy correspondence daniele romagnoli, md (corresponding author) danieleromagnoli87@gmail.com daniele d'agostino, md marco giampaoli, md angelo porreca, md robotic urology and mini invasive urologic surgery unit, abano terme hospital piazza cristoforo colombo, 2 abano terme (pd) (italy) federico mineo bianchi, md paolo sadini, md riccardo schiavina, md eugenio brunocilla, md andrea angiolini, md urology unit, s. orsola malpighi university hospital alma mater studiorum via pelagio palagi, 9 bologna (italy) sergio candiotto, md orthopaedic unit, abano terme hospital piazza cristoforo colombo, 2 abano terme (pd) (italy) romagnoli_stesura seveso 25/03/19 17:26 pagina 67 43archivio italiano di urologia e andrologia 2019; 91, 1 case report management of erosion of inflatable penile prosthesis reservoir into bladder. a different approach volkan izol, mutlu deger, bahattin kizilgok, ibrahim atilla aridogan, mustafa zuhtu tansug department of urology, faculty of medicine, university of çukurova, adana, turkey. we report a rare case of erosion of an inflatable penile prosthesis reservoir into the bladder that was managed with a different approach from the literature by preserving the existing reservoir. inflatable penile implant was applied to a 54-year-old male patient who had undergone with a robot-assisted radical prostatectomy operation due to localized prostate cancer 2 years before. two months after the operation, the patient referred to our clinic with predominant symptoms of lower urinary tract system associated with scrotal pain and swelling. the urinary system ultrasonography (usg) and the lower abdomen magnetic resonance imaging (mri) demonstrated that the reservoir of the penile prosthesis was in the bladder. cystoscopy confirmed that the reservoir was in the bladder. according to literature the reservoir was surgically removed from bladder. after bladder repair, the rectus muscles were repaired creating a space between the rectus muscle and the skin, where the reservoir was placed. after postoperative observation, the patient was discharged without any infection and regression of the lower urinary tract symptoms. no problem was referred by using the penile prosthesis when at 1-month and 3-month follow up and the patient was not uncomfortable in this regard. in conclusion no drawback occurred by using the old reservoir. key words: penile prosthesis; reservoir; erosion; bladder. submitted 31 december 2018; accepted 26 january 2019 summary no conflict of interest declared. an area under the skin above the rectus muscles. the relevance of this case report is the demonstration of a different approach for the treatment of this condition. case report a 54-year-old male patient underwent a robot-assisted radical prostatectomy operation due to localized prostate cancer two years before our observation, because of erectile dysfunction after operation, the patient received sildenafil therapy without benefit from the treatment, so inflatable penile implant was placed in another center. two months after the operation, the patient referred to our clinic with predominant symptoms of lower urinary tract system associated with scrotal pain and swelling. on physical examination, the right testicle was normal at palpation with minimal hydrocele and penile prosthesis was detected. left testicle was normal and minimal hydrocele was observed. scrotal ultrasonography reported a bilateral complicated chronic hydrocele. laboratory findings showed at urinalysis the presence of 1605 leukocytes, with positive leukocyte esterase (++) and nitrite (+); blood count showed wbc 6900/mm3; serum procalcitonin level was 0.09 n/ml and erythrocytes sedimentation rate (esr) 59 mm/h; urine culture was negative. meropenem 500 mg ter in die treatment was started after consultation with infectious diseases and clinical microbiology clinic. in addition to antibiotic therapy, diclofenac sodium, scrotal elevation and cold application were also provided. despite the treatment, due to the persistence of the patient's complaints, urinary system ultrasonography (usg) and lower abdomen magnetic resonance imaging (mri) were performed and it was demonstrated that the reservoir of the penile prosthesis was in the bladder (figure 1). cystoscopy confirmed the presence of the reservoir in the bladder. surgical procedure a pfannenstiel incision was made to expose the bladder and perivesical space and the bladder anterior wall was released, to reach where the reservoir entered in the bladder. the bladder wall was opened to remove the reservoir and afterthat bladder repair was performed. after bladder repair, the rectus muscles were repaired and a space was created between the rectus muscle and the skin (figure 2a). the reservoir was kept in saline doi: 10.4081/aiua.2019.1.43 introduction erectile dysfunction (ed) is defined as the inability to achieve and or maintain a penile erection sufficient for satisfactory sexual performance (1). surgical implantation of penile prosthesis can be recommended as a third-line treatment in patients who have failed pharmacotherapy or require a permanent solution (2). complications of penile prostethesis include postoperative infection, bleeding, hematoma and device malfunction. in the literature, complications of reservoir of inflatable penile prosthesis are rarely reported, such as reservoir herniation, migration, erosion into the adjacent structure (e.g. bladder, bowel), ectopic reservoir location, hematoma, bowel obstruction and vascular compression with arterial or venous thrombosis (3). we report a rare case of erosion of the reservoir of inflatable penile prosthesis into bladder. in the present case, the reservoir was not removed as in other cases in the literature and differently from published cases it was placed in izol_stesura seveso 25/03/19 17:18 pagina 43 archivio italiano di urologia e andrologia 2019; 91, 1 v. izol, m. deger, b. kizilgok, i. atilla aridogan, m. zuhtu tansug 44 with diluted 180 mg of gentamicin for 10 minutes. then the reservoir was placed in the space formed (figures 2b3). after the operation, the patient was treated with vancomycin and meropenem for 2 weeks. after postoperative observation, the patient was discharged without any infection and regression of symptoms of lower urinary tract. no problem in using the penile prosthesis was reported by the patient at 1-month and 3-month follow up. the patient was not uncomfortable in this regard because the patient's reservoir was not visible under the skin and computed tomography (ct) at 3 months did not show any infection status or abscess around the reservoir (figure 4). discussion surgical implantation of penile prosthesis can be recommended as a third-line treatment in patients who have failed pharmacotherapy or require a permanent solution (2). there are two types of penile prosthesis used by urologists for erectile dysfunction: malleable (semi-rigid, non-inflatable) and inflatable. the first penile implant was introduced by lash et al. in 1964 and scott et al. introduced the first inflatable penile prosthesis (ipp) in 1973 (4). inflatable penile prostheses (ipps) consist of 3 pieces (two intracorporal cylinders, a scrotal pump and a fluid reservoir). these reservoirs may be placed in the space of retzius, however, scarring after pelvic surgeries (such as radical prostatectomy, cystectomy, renal transplantation) destroys this space. in the literature, erosions of reservoir of inflatable penile prostheses into bladder have been reported. possibly the first published case of ipp reservoir erosion into the bladder was described by leach et al. in 1984. the patients were treated with complete explantation (5). in 1986, fitch reported a case of reservoir erosion into bladder, but differently of leach et al., he removed the old reservoir and placed a new reservoir with a successful outcome (6). in 1988, dupont et al. reported an erosion of reservoir of ipp into the bladder after 4 years from initial implantation with formation of bladder calculi on the reservoir: a complete explantation was carried out (7). park et al. reported a case of erosion of penile prosthesis reservoir into the bladder due to shortened tubing by multiple revision surgeries and suggested, as rescue surgery, the reposition of a new reservoir on the contralateral side to the erosion (8). in 2009, kramer et al. report two cases of intravesical reservoir displacement presenting with gross hematuria in the recovery room following repair of a cylinder to pump tubing break of their inflatable penile prostheses (ipps): they removed reservoirs and a new reservoir was placed in the contra-lateral space of retzius (9). in 2012 garber et al. report a case of erosion of a penile prosthesis reservoir into the bladder in a patient undergone four prior ipp surgeries and reported a literature review of intravesical erosions of penile implant reservoirs reporting that all penile implant reservoirs in the bladder mentioned in figure 1. mr scan showing erosion of the reservoir into bladder. figure 2. a. space was created between the rectus muscle and the skin. b: the reservoir was placed in the space formed. figure 3. the reservoir was placed in the space formed and semirigid penile erection was obtained. a. b. figure 4. ct scan at 3 months after operation showing the reservoir in the area formed without problem. izol_stesura seveso 25/03/19 17:18 pagina 44 the literature were treated with complete explantation or placement of a new reservoir (10). in 2013, tran et al. present the case of a 75-year-old male with history of bladder cancer requiring radical cystoprostatectomy who had erosion of the inflatable penile prosthesis reservoir into the neobladder: the patient underwent removal of the ipp reservoir (11). we report the case of the erosion of ipp reservoir into the bladder in a patient who had undergone robot assisted radical prostatectomy due to localized prostate cancer. unlike other cases in the literature, we put the same reservoir in a space we had prepared after previous treatment of the infection without removal of the reservoir. the reservoir was placed in a space under the skin above the rectus muscle. this case is relevant because it offers a different new approach. conclusions in conclusion the use of the old reservoir was safe. in addition, due to destruction of retzius in pelvic surgery of some patients, such as those submitted to radical prostatectomy, we demonstrated that the reservoir could be placed in a safer area. references 1. nih consensus development panel of impotence. jama. 1993; 270:83-90. 2. hatzimouratidis k, amar e, eardley i, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol. 2010; 57:804-14. 3. hartman rp, kawashima a, takahashi n, et al. inflatable penile prosthesis (ipp): diagnosis of complications. abdom radiol (ny). 2016; 41:1187-96. 4. o'rourke tkjr, erbella a, zhang y, wosnitzer ms. 'prevention, identification and management of postoperative penile implant complications of infection, hematoma, and device malfunction. transl androl urol. 2017; 6(suppl 5):s832-s848. 5. leach ge, shapiro ce, hadley r, raz s. erosion of inflatable penile prosthesis reservoir into bladder and bowel. j urol. 1984; 131:1177 8. 6. fitch wp 3rd, roddy t. erosion of inflatable penile prosthesis reservoir into bladder. j urol. 1986; 136:1080. 7. dupont mc, hochman hi. erosion of an inflatable penile prosthesis reservoir into the bladder, presenting as bladder calculi. j urol. 1988; 139:367-8. 8. park jk, jang sw, lee sw, cui y. rare complication of multiple revision surgeries of penile prosthesis. j sex med. 2005; 2:735-6. 9. kramer ac, chason j, kusakabe a. report of two cases of bladder perforation caused by reservoir of inflatable penile prosthesis. j sex med. 2009; 6:2064-2067. 10. garber bb, morris a. intravesical penile implant reservoir: report, literature review, and strategiesfor prevention. int j impot res. 2013; 25:41-4. 11. tran cn, boncher n, montague dk, angermeier kw. erosion of inflatable penile prosthesis reservoir into neobladder. j sex med. 2013; 10: 2343-6. 45archivio italiano di urologia e andrologia 2019; 91, 1 erosion of penile prosthesis reservoir into bladder correspondence volkan izol, md mutlu deger, md, febu (corresponding author) drmutludeger@gmail.com bahattin kizilgok, md ibrahim atilla aridogan, md mustafa zuhtu tansug, md department of urology, faculty of medicine, university of çukurova, adana 01330 (turkey) izol_stesura seveso 25/03/19 17:18 pagina 45 archivio italiano di urologia e andrologia 2021; 93, 164 case report no conflict of interest declared. doi: 10.4081/aiua.2021.1.64 world health organization (who) classification distinguishes testicular neoplasms into germ cell-derived (95%) and non-germ cell neoplasms (2). the most frequent germ-cell tumours (gcts) are seminoma (40-50% of cases). in about 80% of the cases, seminoma presents in a typical form (4). tts are often localized (68%) and confined to the testis. locally advanced tumours usually remain confined to the scrotum. although rare, extension of the primary tumour to the inguinal canal can be observed, mostly among non-germ cell tts (ngctts) (5). to the best of our knowledge, no previous case of large seminoma spreading in the retroperitoneum through inguinal canal has been described. in this study we report the first case of testicular cancer presenting as a voluminous ulcerated testicular mass. case report a 44-year-old man self-referred to the emergency room of our hospital because of a voluminous scrotal mass associated to abdominal and pelvic pain. the patient had no fever, poor nutritional conditions and pale skin. clinical history included smoke and thyroid goitre. physical examination showed a voluminous scrotal mass likely with colliquative necrotic phenomena and abdominal extension (figure 1a). the abdomen was tense and slightly painful on deep palpation. laboratory tests showed an anaemia with reduction in red blood cell (rbc) count (3.1 × 106 mm3; normal range 4.55.3 × 106 mm3), haemoglobin (hgb) of 6.9 g/dl (normal range 13-16 g/dl), hct of 24 % (normal value 37-49%). tumour markers were elevated, in particular b-hgc was 4873 miu/ml (normal range between 0-5 mui/ml), a-fetoprotein was 33.4 ng/ml (normal values less than 6 ng/ml were evaluated) and ldh was 9047 u/l (normal range 313-618 u/l). complete blood tests are shown in the table 1. the patient underwent an abdominal ct scan, showing a voluminous scrotal sac (28 x 13 x 12 cm) with solid tissue sized 16 x 16 cm, occupying the scrotum with extension to the left inguinal canal and to the retroperiintroduction: testicular cancers represent about 5% of all urological malignancies and 1-1.5% of all male neoplasms. most of the testicular cancers are localized (68%) at diagnosis. bulky masses in the scrotum are rare. we present a rare case of bulky testicular cancer with retroperitoneal spread through the inguinal canal. case report: a 44-year-old man came to the emergency department referring weakness and the presence of a scrotal mass. at physical examination, a voluminous mass was found, with necrotic phenomena within the scrotum. abdomen was tense and sore. abdominal ct scan revealed a bulky testicular mass spreading to the retroperitoneal space through the inguinal canal with node enlargement. patient underwent orchiectomy with excision of infiltrated scrotum skin. histologic diagnosis confirmed a typical form seminoma. the patient was then treated with a cisplatin-based chemotherapy, with a partial response. the patient recently relapsed and he is being treated with a new line of chemotherapy and subsequent surgery with or without radiotherapy. conclusions: we described a rare presentation of testicular cancer. this case highlights the importance of a multidisciplinary approach to rare testis tumour presentation and early diagnosis for testicular cancers. key words: testicular cancer; large seminoma; retroperitoneal space; inguinal lymph nodes. submitted 2 june 2020; accepted 6 july 2020 introduction testicular tumours (tts) represent about 5% of all urological malignancies and 1-1.5% of all male neoplasms (1). the incidence of testicular cancers is 3-6 new cases per 100.000 males in western countries, with an increase observed in the past 30 years (2), probably as a consequence of pollution. these rare tumours are more frequent between 18 and 35 years and in scandinavian countries (1, 3). risk factors include the presence of a tumour in the contralateral testicle, germ cell neoplasia in situ (gcnis), klinefelter's syndrome, cryptorchidism or undescended testicle, family history of testicular cancer (2). retroperitoneal extension of massive ulcerated testicular seminoma through the inguinal canal: a case report summary alessio antonaci 1, daniela fasanella 1, vikiela galica 2, nicola tinari 3, jamara giampietro 4, pietro di marino 4, andrea delli pizzi 5, raffaella basilico 5, luigi schips 1, michele marchioni 1 1 department of medical, oral and biotechnological sciences, g. d'annunzio university of chieti, urology unit, ss. annunziata hospital, chieti, italy; 2 department of biotechnological and applied clinical sciences, university of l’aquila “san salvatore” hospital, l’aquila, italy; 3 department of medical, oral and biotechnological sciences and center for advance studies and technology (cast), g. d'annunzio university of chieti, italy; 4 clinical oncology unit, ss annunziata hospital, chieti, italy; 5 department of neuroscience, imaging and clinical sciences, g. d'annunzio university of chieti, chieti, italy. 65archivio italiano di urologia e andrologia 2021; 93, 1 retroperitoneal seminoma toneal space. moreover, there was a pathological involvement of the left inguinal (11 x 7 cm) and iliac-obturator (10 x 6 cm) lymph nodes infiltrating the external iliac vein. in addition, pathologic retroperitoneal lymphatic tissue was documented along the abdominal aorta for a longitudinal extension of about 20 cm, resulting in compression of the inferior vena cava and infiltration of the external iliac vein, left renal vein and left ureter with signs of post-renal obstructive uropathy. no distant lesions to parenchymal organs were detected (figure 1d-f). in the context of reduced hgb, the patient underwent a transfusion and was hospitalized in the urology department. unilateral orchiectomy with lymph node dissection was performed (figure 1b). first, an inguinal incision was made and the enlarged nodes of left inguinal chain were identified. there was no clear distinction between metastatic lymph nodes and the testicular mass. after cautious isolation left inguinal nodes were dissected. subsequently the inguinal portion of the tumour was also isolated and, after incision enlargement to the scrotum, was removed. finally, scrotal portion of the mass was resected alongside with the surfacing necrotic skin (figure 1c). the right testis and penile shaft were preserved (figure 2). histological examination showed a typical seminoma. the neoplasm infiltrated the skin up to ulcerating it and involved lymph nodes (pt4, pn3, pm1, s3). the presence of an intra-tumour phlogistic infiltrate was also revealed. molecular morphology investigations with immunohistochemical characterization of the tumour showed positivity for octamer-binding transcription factor (oct) 3/4, placental alkaline phosphatase (plap), b-hgc, cd117, leukocyte common antigen (lca, in the intra tumour inflammatory component) and cd30. following surgery, the patient received four three-weekly cycles of standard bep (bleomycin 30 ui iv weekly on days 1.8 and 15; etoposide 100 mg/m² iv on days 1-5; cisplatin 20 mg/m² iv on days 1-5 (6). ct scan taken one month after the completion of chemotherapy showed a great deal of reduction in the retroperitoneal lymph node masses (6 x 4 cm current vs 17 x 12 cm prior). serum level of tumour markers was also decreased (table 2). subsequently, the patient underwent ct-scan at 3-month intervals. abdominal and chest imaging showed a stable disease (sd) according to the response evaluation criteria in solid tumors (recist) (7) with no parenchymal metastases for one year and half. a progressive disease (pd) was documented after 18 months. ct-scan showed a new dimensional increase in the left periaortic lymph node tissue (55 x 35 mm current vs 50 x 25 mm prior), along the left external iliac chains (57 x 44 cm current vs 47 x 37 cm prior) and the appearance of infiltration of the left iliac and table 1. blood tests. result reference values haemoglobin (g/dl) 6.9 13.0-16.0 red blood cells (mmc) 3.1 4.5-5.3 x 10˄6 hematocrit (%) 24 37.0-49.0 mch (pg) 21.8 25.0-35.0 mchc (g/dl) 28 32.0-36.0 white blood cells (u/l) 8.97 4.00-10.0 x 10˄3 platelets (mmc) 479 150-450 x 10˄ fibrinogen (mg/dl) 542 189-400 glucose (mg/dl) 117 74-106 creatinine (mg/dl) 0.90 0.66-1.25 urea (mg/dl) 20.0 9.0-20.0 albumin (g/dl) 2.6 2.5-5.2 sodium (mmol/l) 138 136-146 potassium (mmol/l) 5.40 3.50-5.10 calcium (mmol/l) 2.3 2.1-2.55 ast (u/l) 35 15-46 alt (u/l) 21 11-66 amylase (u/l) 73 30-110 lipase (u/l) 157 313-618 cpk (u/l) 21 55-170 total bilirubin (mg/dl) 0.60 0.20-1.30 ldh (u/l) 9047 313-618 beta-hcg (mui/ml) 4873 0-5 alpha-fetoprotein (ng/ml) 33.4 < 6 mch: mean cell hemoglobin, mchc: mean cell hemoglobin concentration, ast: aspartate aminotransferase, alt: alanine aminotransferase, cpk: creatin phosphokinase, ldh: lactate dehydrogenase, hcg: human chorionic gonadotropin. figure 1. (a) voluminous and necrotic scrotum at the diagnosis. (b) intra-operative photograph. (c) post-operative photograph of resected scrotal mass. (d-f) computed tomography shows extensive abdominal diffusion of tumour. archivio italiano di urologia e andrologia 2021; 93, 1 a. antonaci, d. fasanella, v. galica, et al. 66 psoas muscles by the pathological lymph node tissue (7). moreover, the patient underwent a pet-ct scan that showed an intense metabolic activity corresponding to a voluminous lymph node masses (10 x 13 cm) in the left iliac region, infiltrating the left ileo-psoas muscle. after considering the disease progression, we had a multi-disciplinary meeting. as salvage chemotherapy the patient is being treated with four three-weekly cycles of standard tip (paclitaxel 175 mg/m² iv on day 1; cisplatin 20 mg/m² iv on days 1-5; ifosfamide 1000 mg/m² iv on days 1-5). in case of mass reduction, a combined surgical retroperitoneal lymph node dissection (rplnd) and radiotherapeutic approach will be evaluated. discussion in this report, we described a rare case of large seminoma extending to the inguinal canal with diffuse retroperitoneal spreading and skin ulceration. presentation at advanced stage or even metastatic at diagnosis is more common for ngctts (5). our case is paradigmatic for several reasons. first of all, the age of diagnosis. our patient presented a primary testicular cancer in the absence of risk factors and at an age older than usual. this highlights the importance of genital examination at every age, even when the probability of a testicular tumour is low. moreover, our patient had a very unusual presentation. indeed, while most of testis cancers are diagnosed as localized tumours of few centimeters in diameter, in our case the patient turned to physicians only when symptomatic. when investigating the reasons why the patient delayed the primary intervention, a complex mix of personal, familiar and social causes emerged. several studies have shown a detrimental effect of low socio-economic and familiar status on cancer awareness and intervention timing (8, 9). in a recent analysis macload et al. showed that socio-economic status was associated with poorer oncological outcomes and a more difficult access to primary treatment in patients with testicular cancer (10). our case corroborates these evidences and suggests the importance of a social tissue that could led to prompt access to primary care and early diagnosis. it is of note that the italian one is a single payer healthcare system. in consequence, cure costs are not one of the major barriers to early diagnosis and treatment. however, even in this context weaker social strata still exist. within this strata population could be more susceptible to experiment worse oncological outcomes. in fact, even after a wide surgical excision and associated chemotherapy, as recommended by international guidelines (11), we obtained only a partial response with a subsequent relapse of the disease. furthermore, in our case is evident how, even if cisplatin-based regimen is effective on testis cancer, a multidisciplinary approach should be warranted. early diagnosis, a multidisciplinary approach and a close follow-up remain mandatory to improve prognosis of testicular cancer (12, 13). after relapse, our patient will undergo four cycles of tip (14). surgery and radiotherapy should be considered in the case of mass reduction and resectable masses with small residual tumour (15). moreover, a close follow-up of all psychological aspects was planned in consideration of the high psychological burden of testis cancer. conclusions in conclusion, we reported an extremely rare presentation of locally advanced testis cancer, resulting from the combination of cancer and patient related conditions. early diagnosis is fundamental to guarantee a good oncological prognosis for testis cancer. moreover, a multidisciplinary approach is important to guarantee a good oncological outcome. references 1. chia vm, quraishi sm, devesa ss, et al. international trends in the incidence of testicular cancer, 1973-2002. cancer epidemiol biomark prev. 2010; 19:1151-9. 2. huyghe e, matsuda t, thonneau p. increasing incidence of testicular cancer worldwide: a review. j urol. 2003; 170:5-11. 3. shanmugalingam t, soultati a, chowdhury s, et al. global incidence and outcome of testicular cancer. clin epidemiol. 2013; 5:417-27. 4. moch h, cubilla al, humphrey pa, et al. the 2016 who classification of tumours of the urinary system and male genital organspart a: renal, penile, and testicular tumours. eur urol. 2016; 70:93-105. 5. palumbo c, mistretta fa, mazzone e, et al. contemporary incidence and mortality rates in patients with testicular germ cell tumors. clin genitourin cancer. 2019; 17:e1026-35. 6. saxman sb, finch d, gonin r, einhorn lh. long-term follow-up of a phase iii study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the indian university experience. j clin oncol. 1998; 16:702-6. table 2. tumour markers in the eighteen months following chemotherapy. figure 2. (a) post-operative photograph. an inguinal and scrotal incision was made and the voluminous necrotic scrotal mass was removed. (b) photograph of inguino-scrotal region on follow-up at 12 months. november 2018 march 2019 june 2019 april 2020 alpha-fetoprotein (ng/ml) 9 3.20 1.60 60.79 beta-hcg (mui/ml) < 1 < 1 < 1 < 1 ldh (u/l) 422 179 216 2580 67archivio italiano di urologia e andrologia 2021; 93, 1 retroperitoneal seminoma 7. eisenhauer ea, therasse p, bogaerts j, et al. new response evaluation criteria in solid tumours: revised recist guideline (version 1.1). eur j cancer 1990. 2009; 45:228-47. 8. mihor a, tomsic s, zagar t, et al. socioeconomic inequalities in cancer incidence in europe: a comprehensive review of populationbased epidemiological studies. radiol oncol. 2020; 54:1-13. 9. marchioni m, martel t, bandini m, et al. marital status and gender affect stage, tumor grade, treatment type and cancer specific mortality in t1-2 n0 m0 renal cell carcinoma. world j urol. 2017; 35:1899-905. 10. macleod lc, cannon ss, ko o, schade gr, et al. disparities in access and regionalization of care in testicular cancer. clin genitourin cancer. 2018; 16:e785-93. 11. honecker f, aparicio j, berney d, et al. esmo consensus conference on testicular germ cell cancer: diagnosis, treatment and follow-up. ann oncol. 2018; 29:1658-86. 12. warde p, specht l, horwich a, et al. prognostic factors for relapse in stage i seminoma managed by surveillance: a pooled analysis. j clin oncol 2002;20:4448-52. 13. aparicio j, germà jr, garcía del muro x, et al. risk-adapted management for patients with clinical stage i seminoma: the second spanish germ cell cancer cooperative group study. j clin oncol. 2005; 23:8717-23. 14. park s, lee s, lee j, et al. salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (tip) in relapsed or cisplatin-refractory germ cell tumors. onkologie. 2011; 34:416-20. 15. oldenburg j, fosså sd, nuver j, et al. testicular seminoma and non-seminoma: esmo clinical practice guidelines for diagnosis, treatment and follow-up. ann oncol off j eur soc med oncol. 2013; 24 suppl 6:vi125-132. correspondence alessio antonaci, md luigi schips, md michele marchioni, md daniela fasanella, md (corresponding author) danielafasanella@libero.it department of medical, oral and biotechnological sciences, g. d'annunzio university of chieti, urology unit, ss annunziata hospital via dei vestini, 66100, chieti (italy) vikiela galica, md department of biotechnological and applied clinical sciences, university of l’aquila “san salvatore” hospital, l’aquila (italy) nicola tinari, md department of medical, oral and biotechnological sciences and center for advance studies and technology (cast), g. d'annunzio university of chieti, chieti (italy) jamara giampietro, md pietro di marino, md clinical oncology unit, ss annunziata hospital, chieti (italy) andrea delli pizzi, md raffaella basilico, md department of neuroscience, imaging and clinical sciences, g. d'annunzio university of chieti, chieti (italy) stesura seveso 291archivio italiano di urologia e andrologia 2014; 86, 4 case report peripheral primitive neuroectodermal tumor of seminal vesicles: is there a role for relatively aggressive treatment modalities? alessandro crestani 1, andrea guttilla 1, mario gardi 2, marina gardiman 3, fabrizio dal moro 1, claudio valotto 1, filiberto zattoni 1 1 department of gastroenterological, oncological and surgical sciences, urology clinic, university of padua, italy; 2 department of urology, s. antonio hospital, padua, italy; 3 department of oncological and surgical sciences, division of pathology, university hospital of padua, italy. a 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. a ct scan showed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle. he had been followed by the removal of the right seminal vesicle and both the cystic lesion. the histological findings of the specimen documented the presence of small round cells compatible with ewing’s sarcoma/ppnet. the patient received also adjuvant chemotherapy and radiation treatment. after 10 years, the follow-up is still negative. key words: seminal vesicles, sarcoma, peripheral primitive neuroectodermal tumor. submitted 27 august 2013; accepted 30 september 2014 summary no conflict of interest declared. urine analysis were all normal. the general physical examination did not reveal anything particular. at dre, a palpable mass was recognized at the level of the right portion of the anterior rectal wall dislocating the prostate gland. the abdominal ultrasound examination of the pelvis showed a roundish cyst within the right seminal vesicle of 8 cm in the widest diameter, with septa and corpuscular material, inside (figure 1). the further imaging diagnostic work up consisted in a pelvic computed tomography (ct) scan and intravenous pyelography (ivp). the ct scan confirmed the presence of a 7.8 cm roundish cyst, originating from the right seminal vesicle; the urinary bladder resulted compressed and anteriorly dislocated (figure 2). no wall contrast enhancement was detected and a plane of dissection was appreciable from the bladder, rectum and the lateral pelvic wall (internal obturator muscle). ct scan revealed another oval-shaped cyst of 3 cm in the widest diameter originating from the right seminal vesicle with the same densitometric features. the ivp confirmed also that the right supero-external margin of the bladder wall was compressed (figure 3). the patient underwent a tc guided fine needle agobiopsy (fnab) of the larger lesion that gave no significant findings. therefore the patient was surgically explored through a midline incision of the lower abdomen. a cystic lesion was found against the right seminal vesicle that raised-up the bladder. frozen section biopsies of the cystic lesion documented fibrous tissue with chronic inflammation. the removal of the right seminal vesicle and both the cystic lesions was performed. the post operative period was uneventful and the patient was discharged in few days. the histological findings of the specimen documented the presence of small round cells compatible with ewing’s sarcoma/ppnet (figures 4-5). after surgery the patient received adjuvant chemotherapy with a total of 13 cycles (adriamycin, vincristine, cyclophosphamide, actinomycin d, ifosfamide, etopo side), as well as radiation treatment (48 gy) on the pelvis. after 10 years, the follow-up is still negative: pet total body was always negative and the patient is in a good general condition with normal urinary continence and good erectile function. doi: 10.4081/aiua.2014.4.291 introduction the seminal vesicles are an unusual site of primary malignancy in the urinary tract and primary malignant ewing’s sarcoma or its variant peripheral primitive neuroectodermal tumor (ppnet) are even more rare (1-2). the prognosis of extraskeletal ppnet is generally poor and an aggressive, multimodal approach is usually required (3). at our knowledge only one case of ppnet involving the seminal vesicles has been reported, with scarce information about the follow-up. herein is described a case of ppnet arising from the right seminal vesicle with a ten year follow-up. case report a 50 year old white man received an incidental ultrasound diagnosis of hypoechoic mass interesting the right seminal vesicle. at the time, he was 174 cm in height, 82 kg in weight and the body surface area was 1,97 m2; the performance status was grade 0. the family and his own personal medical history was not significant. he did not refer any professional exposure to carcinogens and used to smoke 7-8 cigarettes per day. complete blood cell count, routine chemistry profile and crestani_stesura seveso 14/01/15 13:00 pagina 291 archivio italiano di urologia e andrologia 2014; 86, 4 a. crestani, a. guttilla, m. gardi, m. gardiman, f. dal moro, c. valotto, f. zattoni 292 way was related to ct scan images that showed only roundish cystic lesions without any contrast enhancement in the cystic wall and the presence of a well defined plane of dissection from the bladder, rectum and lateral pelvic wall. usually in case of sarcoma of the seminal vesicles, they are treated by means of an aggressive surgical approach as radical prostatectomy or radical cystectomy with an inevitably negative impact on the quality of life of the patients. in the case here described, the very conservative surgical approach was followed by an adjuvant therapy: such a treatment provided good clinical results, lasted in the long term period. figures are posted in supplementary materials” on www.aiua.it references 1. agrawal v, kumar s, sharma d, et al. primary leiomyosarcoma of the seminal vesicle. int j urol. 2004; 11:253-5. 2. baschinsky dy, niemann th, maximo cb, bahnson rr. seminal vesicle cystadenoma: a case report and literature review. urology. 1998; 51:840-5. 3. lawrentschuk n, appu s, chao i, et al. peripheral primitive neuroectodermal tumor arising from the seminal vesicle. urol int. 2008; 80:212-5; discussion 216. 4. llombart-bosch a, machado i, navarro s, et al. histological heterogeneity of ewing's sarcoma/pnet: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. virchows arch. 2009; 455:397-411. 5. berg t, kalsaas ah, buechner j, busund lt. ewing sarcomaperipheral neuroectodermal tumor of the kidney with a fus-erg fusion transcript. cancer genet cytogenet. 2009; 194:53-7. 6. zanetti g, gazzano g, trinchieri a, et al. a rare case of benign fibroepithelial tumor of the seminal vesicle. arch ital urol androl. 2003; 75:164-5. discussion ppnet, histologically characterized by the presence of small round cells extracranially in soft tissues and bones. ewing’s sarcoma and primitive peripheral neuroectodermal tumor (ppnet) have been originally described as two distinct pathologic entities (4). because of their similar histologic and cytogenetic characteristics, these tumors are now considered to derive from a common origin cell and to be a part of a spectrum of neoplastic diseases known as the ewing sarcoma family of tumors (esft), which also includes extraosseous ewing sarcoma (ees), adult neuroblastoma, malignant small-cell tumor of the thoracopulmonary region (askin tumor), paravertebral small-cell tumor, and atypical ewing’s sarcoma. they all derive from embryonal neural crest cells. the essential feature to diagnose ppnet or ewing’s sarcoma is the histoimmunochemistry with cd99. ewing family of tumors (efts) represents a neoplastic entity characterized by specific chromosomal rearrangements. the most commonly detected translocation involves the fusion of ewsr1 to one of the genes encoding ets family of transcription factors, usually fli1 or erg. the detection of specific translocations by fluorescence in situ hybridization (fish), reverse transcription-polymerase chain reaction (rt-pcr), or both has become the diagnostic hallmark for the efts (5). ppnets are uncommon and the primary ppnet of the seminal vesicles is quite exceptional. differential diagnosis must include rhabdomyosarcomas, leyomiosarcomas, phylloides tumors, malignant fibrous histiocytomas, chondrosarcomas. differential diagnosis must also include benign conditions like benign fibroepithelial tumor (6), prostatic utricle cyst, the prostatic abscess, the hydrops, the cyst and the empyema of seminal vesicles or the ectopic ureterocele. usually surgical treatment of sarcomas of the pelvis is extremely aggressive. the choice to treat the present patient in a conservative correspondence alessandro crestani, md (corresponding author) alessandro.crest@gmail.com andrea guttilla, md fabrizio dal moro, md claudio valotto, md filiberto zattoni, md department of gastroenterological, oncological and surgical sciences urology clinic, university of padua via giustiniani, 2 padova, italy mario gardi, md department of urology, s. antonio hospital, padova, italy marina gardiman, md department of oncological and surgical sciences, division of pathology, university hospital of padua via giustiniani, 2 padova, italy crestani_stesura seveso 14/01/15 13:00 pagina 292 145archivio italiano di urologia e andrologia 2018; 90, 2 case report surgical approach to adrenal ganglioneuroma: case report and literature review danilo abate, giuseppe giusti, nicola caria, marco lucci chiarissi, antonello de lisa clinica urologica, università degli studi di cagliari, ospedale ss. trinità, cagliari, italy. objective: ganglioneuroma (gn) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus. it is usually asymptomatic or with nonspecific symptoms. tc and rm scan are helpful to study gn. it is usually represented by an ovalshaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. surgical treatment is mandatory. literature shows how the laparoscopic approach is the most used, especially in lesions that are 6 cm or smaller. our purpose is to describe our experience on an incidental adrenal gn of about 5 cm treated by the laparoscopic transperitoneal approach. materials and methods: a 33-year-old male had ultrasound occasional finding of an about 4 cm adrenal mass. tc and rm scan identified a retroperitoneal mass (max diameter 48 mm). the lesion was removed with a transperitoneal laparoscopic approach. results: no intraoperative or postoperative complications occurred. the patient was discharged 3 days after surgery. conclusions: up to the present laparoscopic surgery is the best approach for gn treatment. key words: adrenal ganglioneuroma. submitted 17 april 2018; accepted 29 april 2018 summary no conflict of interest declared. the laparoscopic approach is the most used, especially in less than 6 cm lesions. the majority of authors consider transperitoneal approach as best solution because it guarantees a good retroperitoneal access and maximum adrenal and big vessels exposition (3). according to this technique, with a patient in right lateral posture, zofragos et al. have completed right adrenalectomy in a 33-year-old female with a 13 cm gn, whereas abraham et al. have performed the same surgery in a 33-year-old female with a 17 cm gn. low intraoperative blood loss and no postoperative complications occurred in both studies. the open approach should be preferred when the tumor is close to big vessels or other organs. case description a 33-year-old male was hospitalized in march 2016 for urinary calculi. during ultrasound abdominal study, we occasionally found a 40 mm left adrenal mass. in november 2016 he underwent tc abdomen scan with radiological contrast media. the lesion was an ovalshaped gross and homogeneous mass of about 46 mm. its radiological aspect was compatible with low adipose tissue adenoma (median density was 45 hu). on 3 january 2017 he underwent an abdomen rm without radiological contrast media and the left adrenal lesion (48 x 30 mm) was featured by low hyperintensity in t-2 weighted scans and signal hypointensity during t1 weighted ones. in the beginning, the mass was described as low lipidic adenoma. plasmatic values of cortisol, aldosterone, renin, and tsh were in range and plasmatic acth was not suppressed. aldosterone/renin ratio was 4,86 pg/ml. daily urinary metanephrine and normetanephrine were normal. we performed laparoscopic transperitoneal adrenalectomy. the patient was placed in right lateral posture. pneumoperitoneum was induced with open hasson technique. an optical port was placed at the umbilicus, the other 2 trocars were placed respectively in left iliac fossa and in the left pararectal region. the left paracolic gutter was incised and renal loggia was exposed. then, the anterior membrane of gerota fascia was incised and renal vascular hilum isolated. an accurate craniocaudal dissection was performer till the adrenal gland exposition. adrenal vesdoi: 10.4081/aiua.2018.2.145 introduction ganglioneuroma (gn) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus but can occasionally develop in the adrenal medulla. it is usually asymptomatic or with nonspecific symptoms related to mass effect causing diaphragmatic compression, upper urinary tract or gastrointestinal upset and, rarely, spinal cord compression or bone erosions. sometimes gn produces catecholamines or other hormones so patients can have hypertension, diarrhea or flushing. tc and rm scan are helpful to study gns. they are usually represented by an oval-shaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. rm study is characterized by signal hypointensity during t-1 weighted scans and a non uniform hyperintensity in t-2 weighted scans (1). from the histopathologic point of view, gn presents mature schwann cells, ganglion cells and nerve fiber (2). surgical treatment is mandatory. literature shows how caria2_stesura seveso 28/06/18 16:43 pagina 145 archivio italiano di urologia e andrologia 2018; 90, 2 d. abate, g. giusti, n. caria, m. lucci chiarissi, a. de lisa 146 sels were isolated and adrenal vein was cut between 3 hem-o-lok clips just at the confluence with the renal vein. the adrenal artery was cut by a vessel sealing device. then, adrenalectomy was completed and adrenal gland was extracted into 10 mm endo-bag. no drainage was placed. a urinary catheter was placed and then removed after 24 hours. routine blood samplings were taken. the difference between pre-surgery and 6 hours later hemoglobin values was 0.8 g/dl. the patient was discharged 3 days after surgery. histopathological analysis showed an adrenal ganglioneuroma with isolated mature ganglion cells, packaged in 3-4 elements with no cellular atypia. immunohistochemistry was positive for s100 and nse (figure 1). conclusions our case report and a literature review confirm feasibility, efficacy, and safety of surgical management of this disease. a laparoscopic approach can reduce invasivity, blood loss, and hospital stay. references 1. ichikawa t, ohtomo k, araki t, et al. ganglioneuroma: computed tomography and magnetic resonance features. brit j radiol. 1996; 69:114-121. 2. chang cy, hsieh yl, hung gy, et al. ganglioneuroma presenting as an asymptomatic huge posterior mediastinal and retroperitoneal tumor. j chin med assoc. 2003; 66:370-374. 3. zografos gn, kothonidis k, ageli c, et al. laparoscopic resection of large adrenal ganglioneuroma. j soc laparoendoscopic surg, 2007; 11:487-492. figure 1. histology showed "adrenal ganglioneuroma with isolated mature ganglion cells, packaged in 3-4 elements with no cellular atypia”. section 1 highlights in h&e stain 100x aggregates of ganglion cells, section ii low positivity on ki67 immunohistochemistry, section iii & iv strong positivity on nse and s100 respectively. correspondence danilo abate, md giuseppe giusti, md (corresponding author) giuseppegiusti.med@gmail.com nicola caria, md (corresponding author) nicolacaria1@gmail.com marco lucci chiarissi, md antonello de lisa, md clinica urologica, università degli studi di cagliari, ospedale ss. trinità via is mirrionis, cagliari, italy caria2_stesura seveso 28/06/18 16:43 pagina 146 319archivio italiano di urologia e andrologia 2017; 89, 4 case report incidentally discovered pelvic paraganglioma: a case report vittorio imperatore 1, massimiliano creta 1, sergio di meo 1, roberto buonopane 1, lorenzo spirito 2, ferdinando fusco 2, nicola longo 2, nicola rosario forte 3, vincenzo mirone 2 1 operative unit of urology, buon consiglio hospital fatebenefratelli, naples, italy; 2 urological clinic, federico ii university of naples, naples, italy; 3 operative unit of pathological anatomy, fatebenefratelli hospital, benevento, italy. paragangliomas (pgl) are rare neuroendocrine tumors of the autonomic nervous system originating from paraganglia. although pgl may arise at any site where physiologic paraganglionic tissue exists, the localization in the small pelvis is extremely rare. pgl may be hormonally active and release surplus catecholamines into the blood or inactive. the asymptomatic cases pose a diagnostic dilemma. we describe the case of an asymptomatic pgl arising in the small pelvis sidewall presenting as an incidentally discovered asymptomatic mass in a male subject. key words: magnetic resonance imaging; paraganglioma. submitted 1 august 2017; accepted 16 september 2017 summary no conflict of interest declared. lesion at the level of the left paravesical space on abdominal ultrasound imaging. his past medical history was relevant for simple prostatectomy performed 1 year before. his prostate specific antigen value was 2.9 ng/dl. physical examination including digital rectal examination was unremarkable. his arterial blood pressure and heart rate were within the normal ranges. he denied systemic symptoms, lower urinary tract symptoms, pain, and hematuria. a computed tomography of the abdomen revealed the presence of a 38 mm nodular mass located at the level of the left obturator space characterized by internal inhomogeneity and an intense peripheral enhancement in the portal phase with rapid washout. no significant abnormalities of other abdominal organs were detected. a magnetic resonance imaging (mri) with contrast medium of the pelvis confirmed the presence of an inhomogeneous 38 x 35 mm extraperitoneal mass located into the left obturator space in the proximity of the vesicoprostatic junction characterized by an intense contrast enhancement in the arterial phase and expansive growth pattern (figure 1). although suggestive of probable benign disease, radiological findings were inconclusive, and an exploratory laparotomy with excision of mass was planned. the procedure was technically challenging due to the adherence of the mass to the vascular structures of the doi: 10.4081/aiua.2017.4.319 introduction paragangliomas (pgl) are rare tumors of the autonomic nervous system that originate from paraganglia which are neuroendocrine organs characterized by catecholamine and peptide-producing cells deriving from the neural crest (1). the role of normal paraganglia is homeostasis, either by acting directly as chemical sensors or by secreting catecholamines in response to stress (1). the paraganglionic system comprises the adrenal medulla and the extra-adrenal paraganglia. in 2004 the world health organization defined a pheochromocytoma as an intraadrenal pgl, whereas related tumors of extraadrenal sympathetic or parasympathetic paraganglia are defined as extraadrenal pgl (1). although extra-adrenal pgl may arise at any site where physiologic paraganglionic tissue exists, the localization in the small pelvis is extremely rare. from a functional point of view pgl may be hormonally active or inactive. functional pgl result in symptoms of excess catecholamine production. non-functional pgl pose a significant diagnostic challenge. we describe the case of an asymptomatic pgl of the small pelvis sidewall incidentally discovered in a male patient. case report a 69-year-old man came to our attention for an incidentally discovered 32 mm hypoechoic figure 1. transverse (a) and coronal (b) mri section of the pelvis showing a well-defined, rounded, heterogeneous enhancing mass measuring 3.8 x 3.5 cm at the level of the left obturator space (arrow). no regional lymphadenopathy or invasion of the adjacent structures were evident. imperatore1_stesura seveso 03/01/18 09:48 pagina 319 archivio italiano di urologia e andrologia 2017; 89, 4 v. imperatore, m. creta, s. di meo, r. buonopane, l. spirito, f. fusco, n. longo, n.r. forte, v. mirone 320 small pelvis and to the ureter. the post-operative course was uneventful and the patient was discharged home on post-operative day 5. histological examination revealed a proliferation of neoplastic cells arranged in solid nests. immunohistochemistry revealed positivity for synaptophysin and s-100 which was located at the periphery of the clusters of cells. immunostaining for ck 7, ck 20 and prostate specific antigen was negative. the ki 67 proliferative index was 7%. the histological and immunohistochemical findings were compatible with the diagnosis of pgl. post-operative staging with whole body contrast enhanced computed tomography showed no residual tumor or distant metastases. 24-h urinary excretion of catecholamines, were within normal limits. discussion extra-adrenal pgl are rare tumors that can occur in isolation or as a part of multisystem disorders such as multiple endocrine neoplasia, neurofibromatosis or von hippel-lindau disease (1). clinical presentation of extraadrenal pgl is highly variable and depends on the location, the size, and the functional status of the tumor. pgl may present at all ages but the peak incidence is around 30-50 years. although most pgl are benign, the probability of malignant pgl reaches up to 25% depending on the presence of genetic mutations. commonly, extraadrenal pgl arise from the para-aortic region at the level of the renal hila, the organ of zukerkandl, the thoracic paraspinal region, head, and neck (2). rarely, pgl occur in the small pelvis and may arise from the bladder, the seminal vesicles, or the pelvis sidewall (2). if the tumor is hormonally active, the patient may experience symptoms and signs of catecholamine overproduction, such as hypertension, headaches, palpitations, sweating, tachycardia, and anxiety (2). symptoms of excess catecholamine production, as well as elevated urine vanillylmandelic acid levels and serum and urine norepinephrine levels, are highly diagnostic for pgl (3). unfortunately, most cases of pgl arising in the small pelvis are nonfunctional and the diagnosis is made in cases of advanced stage, nonspecific symptoms or incidentally (2). to our knowledge, we described the second case of pelvic pgl arising from the pelvis sidewall. mri represents an optimal diagnostic modality in cases of uncommon pelvic retroperitoneal masses in adults thanks to the multiplanar capability and the high-resolution imaging thus permitting better tumor localization and internal characterization (3-5). moreover, mri provides useful data to plan surgical resection (3). at mri, pgl appear as areas of low t1 and high t2 signal intensity and show avid enhancement following the administration of gadoliniumbased contrast material (3). the differential diagnosis for pgl in the pelvic retroperitoneum includes nerve sheath tumors, hypervascular lymphadenopathy (metastases or castleman disease), and hypervascular soft-tissue sarcomas (3). percutaneous biopsy of a hypervascular pelvic retroperitoneal mass may be harmful since it can result in hypertensive crisis or even death (3). in the present case, the pre-operative suspicious of pgl was very low due to the lack of specific symptoms. the definitive diagnosis is made by histopathological examination of the removed tumor and is confirmed by immunohistochemistry. treatment options for pgl include, surgery, radiotherapy, chemotherapy, radiofrequency ablation and cryoablation. the standard treatment for localized or locally advanced pgl is surgical resection of the tumor (2). surgical tumor excision is in most cases curative. however, pgl can represent a surgical challenge due to their tight relation to vessels. the prognosis of extra-adrenal pgl is a matter of debate as the definitive diagnosis of malignancy is difficult. tumor size > 5 cm, occurrence of invasion or metastatic disease and hormonal activity are considered predictors of malignancy. although uncommon, late tumor recurrences in the surgical bed or systemic may occur and close follow-up is required. conclusions pgl are rare tumors that should be included in the differential diagnosis of incidentally found pelvic hypervascular masses. hormonally inactive pgl pose diagnostic challenges and surgical excision requires extensive surgical skills. references 1. lefebvre m, foulkes wd. pheochromocytoma and paraganglioma syndromes: genetics and management update. curr oncol. 2014; 21:e8-e17. 2. sahdev a, sohaib a, monson jp, et al. ct and mr imaging of unusual locations of extra adrenal paragangliomas (pheochromocytomas) eur radiol. 2005; 15:85-92. 3. shanbhogue ak, fasih n, macdonald db, et al. uncommon primary pelvic retroperitoneal masses in adults: a pattern-based imaging approach. radiographics. 2012; 32:795-817. 4. creta m, mirone v, di meo s, et al. a rare case of male pelvic squamous cell carcinoma of unknown primary origin presenting as perineal abscess and urethral stenosis. arch ital urol androl. 2017;89:154-155. 5. cennamo p, montuori n, trojsi g, et al. biofilms in churches built in grottoes. sci total environ. 2016; 543:727-38. correspondence vittorio imperatore, md (corresponding author) v.imperatore@alice.it massimiliano creta, md max.creta@gmail.com sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it operative unit of urology, buon consiglio hospital fatebenefratelli, naples, italy via a. manzoni, 220, 80123 napoli lorenzo spirito, md ferdinando fusco, md nicola longo, md vincenzo mirone, md urological clinic, federico ii university of naples, naples, italy via s.pansini, 5, 80131 napoli nicola rosario forte, md operative unit of pathological anatomy, fatebenefratelli hospital, benevento, italy viale principe di napoli, 14, 82100 benevento imperatore1_stesura seveso 03/01/18 09:48 pagina 320 archivio italiano di urologia e andrologia 2019; 91, 116 original paper the role of anticholinergic therapy based on the upoint system in the treatment of chronic prostatitis kamil fehmi narter 1, utku can 2, alper coşkun 2, kubilay sabuncu 2, fatih tarhan 2 1 acibadem mehmet ali aydinlar university, urology, istanbul/turkey; 2 department of urology, university of health sciences, kartal dr. lütfi kırdar training and research hospital, istanbul/turkey. objective: chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a common problem and severely impairs the quality of life (qol). we aimed to investigate the effects of different treatment options on voiding symptoms and qol in patients with urinary phenotype according to the upoint system. matherial and methods: ninety-six patients with nih category ii,iii cp/cpps were included in the study prospectively. after the diagnosis, the questionnaires including nih chronic prostatitis symptom index (nih-cpsi), international prostate symptom score (ipss), overactive bladder screening questionnaire (oab-v8), and beck depression inventory were filled by the patients. the patients with urinary phenotype were treated by alpha-blocker, antimuscarinic or both therapy modalities (combined) considering the specific therapy recommendations by upoint. the questionnaires applied on the first visit were reapplied after one month and treatment success was evaluated. results: seventy-three patients were included in ‘urinary phenotype’ group (76%) and 23 were included in ‘other phenotypes’ (24%) group of the patients according to the upoint classification. significant improvements of symptoms were observed with the all treatment modalities when the nih-cpsi, ipss and oab-v8 scores were compared before and after treatment in the ‘urinary phenotype’ group. significant differences in the percentage of change in values were obtained in the anticholinergic group for pain subdomain of nih-cpsi and ipss scores. conclusion: u-point clasification is useful for deciding on the treatment modality in cp/cpss patients. we showed anticholinergic therapy might be effective option. addition to the symptomatic recovery, there is need more further studies about effectivity cholinergic system in the prostate tissue. key words: chronic prostatitis; anticholinergic therapy, upoint system. submitted 28 august 2018; accepted 25 september 2018 summary no conflict of interest declared. of this problematic disease is only on the basis of symptoms such as pain/discomfort in the pelvic area or lower urinary tract symptoms (luts) like storage symptoms frequency and urgency (3, 4). antibiotics, alpha-adrenergic blockers, and anti-inflammatory drugs may be chosen in the treatments for cp/cpss, but anticholinergic treatment for cp/cpss has not been preferable yet adequately, and there are few references about this topic (5). according to the national institutes of health (nih), inflammation of the prostate can be classified as acute bacterial prostatis (category i), chronic bacterial prostatitis (category ii), chronic prostatitis/chronic pelvic pain syndrome (cp/cpps, category iii) and asymptomatic prostatitis (category iv) (6). cpss are further subdivided by the presence of inflammation in the extraprostatic secretions or semen (category iiia) or the absence of it (category iiib). although there is no symptoms of disease, chronic prostatitis can be declared histologically on many prostate biopsy reports. the upoint system was described in 2008. patient's symptoms were seperated into six phenotypes as (u)rinary symptoms, (p)sychological dysfunction, (o)rgan specific symptoms, (i)nfectious causes, (n)eurologic dysfunction and (t)enderness of the pelvic floor muscles according to the this system (7). moreover, comorbidities are often present along with cp/cpss such as irritable bowel syndrome and fibromyalgia. recently, a (s)exual dysfunction domain (upoint(s)) was described as an additional content to the clinical phenotyping of cp/cpps (8). until today, anticholinergic therapy for patients with cp/cpss has been very few reported as a symptomatic treatment option for voiding problems. our theory are based on cholinergic system effective on the infectious/inflammation process in the prostate tissue. so that, anticholinergic therapy can be a new alternative and additional therapy option for these patients. many patients with cp/cpss may have luts and genital/pelvic pain. it depend on this, new individualized treatment modalities for patients with cp/cpps has been considered as a multimodal therapy based on upoint sysytem. for this reason, we aimed to classify patients with cp/cpss according to the upoint system and investigate the effects of different treatment modalities such as anticholinergic treatment on voiding symptoms and quality of life in a prospective clinical trial. doi: 10.4081/aiua.2019.1.16 introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a common disease especially seen in men younger than 50 years old. its prevalence was reported from 2 to 16% in the male population (1, 2). cp/cpps has a significant negative impact on quality of life and it may cause depresssion and anxiety due to pyschological effects. this syndrome has not been well described yet and its optimal treatment is not clear. moreover, there is no standard diagnostic test for cp/cpps. the diagnosis narter_stesura seveso 25/03/19 17:14 pagina 16 17archivio italiano di urologia e andrologia 2019; 91, 1 anticholinergic therapy for chronic prostatitis materials and methods ninety-six patients with symptoms of cp/cpps who were referred to our outpatient clinic between march 2014 and may 2015 were enrolled in this prospective study. all patients were evaluated with a detailed medical history, physical examination, and laboratory tests (urine analysis, two glass test, urinary sonographic evaluation, uroflowmetry, and postvoid residual urine volume-pvr). all patients were also asked to fill out national institutes of health chronic prostatitis symptom index (nih-cpsi) (9), international prostate symptom score (ipss) (10), overactive bladder screening qustionare version 8 (oabv8) (11), and beck depression inventory (12). validated turkish versions of these all questionnaries are used in the study. nih categories was designated by the number of leucocytes and culture analysis in the expressed prostate secretion (eps) examination (modified meares and stamey test/two glass test-1968). national institutes of health chronic prostatitis symptom index (nih-cpsi), international prostate symptom score (ipss), overactive bladder screening questionnaire version 8 (oabv8), and beck depression inventory were used to grade the symptoms. patients aged 20 to 50 years and patients with cp/cpss (nih category ii, iiia and iiib) with pelvic pain/discomfort for 3 or more months, negative urine culture, maximum urinary flow rate of 15 ml/sec or greater were included to study. patients with medical history of pelvic surgery/previous prostate surgery, benign prostate hyperplasia (bph), urinary obstruction or high postvoid residual volume (> 100 cc), urinary tract infection, prostatic cancer, urethral stricture, diabetes mellitus, neurogenic lower urinary tract dysfunction and patients who had 5-alpha reductase inhibitors or anticholinergics were excluded from the study. after the nih-cpsi, ipss, oab-v8 and beck depression inventory evaluations, patients were clinically classified as ‘urinary phenotype’ or ‘other phenotypes’ according to upoint system. alpha blocker (silodosin 8 mg/daily), antimuscarinic (propiverin 30 mg/daily), or combination therapies have been ordered for patients with urinary phenotype, taking into consideration failure of treatments and allergy records in medical history. all patients were classified into the treatment groups as patients with high voiding subdomain of ipss score were treated with the alpha blocker, patients with high oab-v8 score were treated with the anticholinergic or patients with both criteries were treated with the alpha blocker and anticholinergic in combined group. addition to these cut off (ipss ≥ 8 and oabv8 ≥ 8) values, for the patients with modest and severe depression, cut off value of beck depression inventory was accepted 17 or higher. nih-cspi score was evaluated as a succesful with at least a 6-point improvement and experienced improvements in every domain. when similar questionnaire results were obtained, treatment option were selected according to preference of clinician. one month later, all patients were recalled for control, then all questionnaires were applied again and effectiveness of treatment was evaluated. this study was approved by our instutional review board (03.06.2014/8) and was conducted according to the declaration of helsinki. all patients gave informed consent. data were presented as median + standard deviation (sd). stastical analysis was performed by mann-whitney u, kruskal-wallis and wilcoxon tests with spss 12.0 (spss inc. chicago, il, usa) and p < 0.05 was considered to indicate significance. the difference in values before and after treatments was defined as ‘∆’ and (∆/value before treatment) x100 was defined as ‘% change’. results based on the u-point scoring system, patients were classified as ‘urinary phenotype’ (n: 73, 76%) and ‘other phenotypes’ (n: 23, 24%). the mean age, duration of symptoms, voiding volume and prostate volume were similar between two groups. luts were found to be more frequent in the group of ‘urinary phenotype’. maximum flow rate at voiding in the ‘urinary phenotype’ group was significant lower than the ‘other phenotypes’. nih-cpsi, ipss and oab-v8 scores were statistically significant higher in the ‘urinary phenotype’ group (p < 0.001). stastistically difference was obtained in urinary and qol subdomain of nih-cpsi, except pain subdomain between urinary and other phenotypes group. significant differences were also obtained in ipss subdomain between ‘urinary phenotype’ and ‘other phenotypes’. but beck depression inventory scores were similar between two groups (table 1). three patients with positive prostatic secretion culture (category ii) were treated with antibiotics and the remaining 73 patients with non-bacterial prostatitis (25 patients with category iiia, 48 patients with category iiib) were treated with appropriate medical agents. moreover, alphablockers (n: 19), anticholinergics (n: 16) and combination therapies (n: 38) were initiated to patients in the ‘urinary phenotype’ group, while psychotherapy or physiotheraphy (n: 6) and food supplements contain quercetin (n: 13) were preferred in the group of ‘other phenotypes’. lifestyle changing and dietery modifications was recommended for all patients (table 2). table 1. evaluation of clinical and demographic data of patients with and without predominant urinary symptoms according to u-point score. u-point urinary other p* phenotype (n = 73) phenotypes (n = 23) median + sd median + sd age 37 + 9.6 36.5 + 9 0.708 duration of symptoms (months) 12 + 47 12 + 15.5 0.235 qmax 21 + 8 27 + 6.3 0.002 prostate volume (cc) 22 + 7.5 20 + 8.1 0.860 nih-cpsi 24 + 7.3 19 + 5.8 < 0.001 pain 10.5 + 4.9 10 + 4.3 0.45 urinary 7 + 2.7 2 + 1.4 < 0.001 qol 8 + 2.3 6 + 2 0.002 ipss ipss 15.5 + 8.1 5.5 + 5.9 < 0.001 qol 5 + 2.3 3 + 1.3 < 0.001 oab-v8 18 + 8.4 7 + 5.6 < 0.001 beck 8.5 + 8.1 9..5 + 7.1 0.968 *mann-whitney u. narter_stesura seveso 25/03/19 17:14 pagina 17 archivio italiano di urologia e andrologia 2019; 91, 1 k. fehmi narter, u. can, a. coşkun, k. sabuncu, f. tarhan 18 significant improvements were observed in the three treatment groups (alpha blockers, anticholinergic and combined) when comparing the pre and post treatment values of the nih-cpsi, ipss and oab-v8 scores in the ‘urinary phenotype’ group. recovery in all three groups was observed according to beck depression scale, but it was not statistically significant difference in anticholinergic group (p = 0.387). the best improvement in the pain subdomain of nih-cpsi and ipss scores were obtained from the anticholinergic group compared to the others (table 3). discussion the prostate is innervated by rich supply of mixed autonomic postganglionic neurons that arise from the pelvic (inferior hypogastric) and the preganglionic parasympathetic neurons joining the pelvic plexus from the pelvic nerve arising from the sacral spinal cord segment (13). cholinergic innervation is found in the both stromal and glandular epithelial areas of the human prostate for secretion and contraction (14). the prostate secretes many substances into the seminal plasma that includes psa (serine protease), zinc, citric acid, magnesium, spermine, prostatic acid phosphatase calcium, and accounts for approximately 15% of volume of the normal human ejaculate. moreover, in vitro contraction of isolated prostate can be inhibited by muscarinic receptor antagonists in the human (15-17). recently, anticholinergic (antimuscarinic) treatment has become more actual for treatment of male luts because such drugs work not only bladder but also on the prostate (18). muscarinic receptors are intensely represented, especially those belonging to the m1 subtype, on glandular epithelial cells whereas m2 subtype receptors are more represented on the stromal cells. animal data suggest that muscarinic receptors may be important in the genesis of prostatic secretions (19), smooth muscle contraction of the prostatic capsule (15, 17) and prostatic growth (18, 20). cholinergic fibres were found in various regions of the prostate including the anterior capsule, peripheral zone, proximal and distal central zones and their density was more than adrenergic fibers (21). moreover, muscarinic receptors with binding characteristics of table 3. assessment of pre and post treatment nih-cspi, ipss, oab-v8 and beck depression inventory scores according to the treatment groups in ‘urinary phenotype’ group. table 2. treatment chart for patients with and without predominant urinary symptoms according to u-point score. u-point treatment urinary phenotype (n = 73) other phenotypes (n = 23) n (%) n (%) antibiotics 0 3 (13) alpha blocker 19 (26) 0 anticholinergic 16 (22) 1 (4) combined 38 (52) 0 quercetin 0 13 (57) others 0 6 (26) total 73 (100) 23 (100) nih-cspi total pretreatment posttreatment δ * % change* 1p pain pretreatment posttreatment δ * % change* 1p urinary pretreatment posttreatment δ * % change* 1p qol pretreatment postreatment δ * % change* 1p ipss pretreatment posttreatment δ * % change* 1p oab-v8 pretreatment posttreatment δ * % change* 1p beck pretreatment posttreatment δ * % change* 1p alpha blocker n = 19 20.9 + 6.6 15.6 + 5.1 -5.3 + 5 -12.2 + 11.6 < 0.001 8.4 + 5.2 6.3 + 3.8 -2.1 + 2.2 -9.8 + 10.7 0.002 6.2 + 2.9 4.6 + 2.2 -1.5 + 2.2 -15.3 + 22.2 0.012 6.4 + 2.3 4.7 + 2 -1.7 + 2.2 -14 + 18 0.003 14.8 + 7.2 11.3 + 6.5 -3.6 + 4.2 -10.2 + 11.9 0.003 13.5 + 8 9.7 + 6 -3.8 + 3.6 -10.5 + 10.1 0.001 9.5 + 6.4 6.3 + 4.8 -3.2 + 2.9 -5 + 4.6 0.001 antimuscarinic n = 16 27.2 + 7.5 20.1 + 6.3 -7.1 + 5.8 -16.6 + 13.5 0.001 11.8 + 5.2) 8 + 3.6 -3.8 + 3 -18.1 + 14.5 0.001 7.3 + 2.8 5.5 + 2.6 -1.8 + 2 -17.5 + 19.8 0.003 8.1 + 1.5 6.6 + 2.1 -1.6 + 2.6 -13 + 21.9 0.008 16.4 + 8.7 10.5 + 6.3 -5.9 + 4.9 -17 + 14 0.001 20 + 6 14.8 + 6.2 -5.3 + 4.5 -14.6 + 12.5 0.001 11 + 8.8 9.4 + 8.7 -1.6 + 5.1 -2.5 + 8.1 0.387 combined n = 37 25.1 + 7.3 20 + 7.3 -5.1 + 6.2 -11.8 + 14.3 < 0.001 9.8 + 4.5 8.1 + 3.4 -1.8 + 2.9 -8.5 + 13.7 < 0.001 7.1 + 2.6 5.3 + 2.8 -1.9 + 2.2 -18.6 + 22.1 < 0.001 8.1 + 2.2 6.7 + 2.6 -1.4 + 2.6 -11.7 + 18.8 0.001 16.8 + 8.6 13.9 + 7.7 -2.9 + 3.8 -8.3 + 10.9 < 0.001 19.7 + 8 16.9 + 7.4 -2.8 + 4.1 -7.9 + 11.4 < 0.001 11.6 + 8.7 8 + 6.4 -3.7 + 6.1 -5.8 + 9.6 < 0.001 2p 0.267 0.031** 0.894 0.858 0.053 0.190 0.223 1 wilcoxon 2 kruskal wallis *δ : the difference in values before and after treatments **% change: percentage of change in values before and after treatments; (δ /the maximum score of relevant questionnaire) x100 narter_stesura seveso 25/03/19 17:14 pagina 18 19archivio italiano di urologia e andrologia 2019; 91, 1 anticholinergic therapy for chronic prostatitis the m3 subtype are predominant in the rat ventral prostate (22), and m1 subtype is dense in the rabbit vas deferens (23). despite of the only small acute urinary retention risk, muscarinic antagonists may be helpful in men with luts as well as overactive bladder (oab). the expression of muscarinic receptors can be correlated with cp/cpss. recently, a possible etiological pathway has been described. according to this mechanism, an unfavorable event as trauma or infection leads to an injury-response of the tissue. inflammation and upregulation of cytokines may lead to additional organ damage involving nerves, blood vessels, smooth muscles, and the loss of urothelium integrity. as we well know, urothelium is a whole unit especially in the trigonum and prostatic ürethra, and some muscle fibers in detrusor and sphincter region continue in the prostatic area, so that it is a functional and anatomic whole unit. the resulting pain may produce contraction of pelvic smooth and skeletal muscles, finally leading to luts, ejaculatory pain or pain in other regions such as back and abdomen. prolonged pain may sensitize central and peripheral nervous systems and finally cause hyperalgesia and allodynia. for this reason, the primary symptoms of cp/cpps can be pelvic pain and frequency and few physicians prefer anticholinergics empirically for treatment, and there are only hints of treatment with anticholinergics in some of the guidelines (9). in our study, anticholinergic therapy improved the pain subdomain score associated with cp/cpss more than the others (p = 0.031). according to this result, anticholinergic therapy is the best succesful option for treatment of pain subdomain of nih-cpsi. in some actual studies, muscarinic receptors have also been suggested to be implicated in the control of inflammation, cell growth and proliferation (24, 25). the muscarinic receptors are also present in the urethra, but their function have not been clarified adequately. the urethral sphincter tone is predominantly regulated by adrenergic nerves, but muscarinic receptors also modulate the tone (26). muscarinic receptor mediates contraction of the proximal urethra whilst mediating relaxation of the distal urethra (27). all muscarinic receptor subtypes (m1-5) are located on the urinary system, especially m2 receptors mostly occur in the circular muscle layers, and muscarinic m3 receptors in the longitudinal layer. during inflammation expression of muscarinic m5 receptors is increased, especially in the epithelium and cholinergic induced production of nitric oxide (no) increase (28). we chose propiverine as an anticholinergic in this study because of it is a competitive antagonist with similar affinity for all muscarinic receptor subtypes (29). kim et al. presented their results about efficacy of anticholinergics for cp/cpss at american urological association's (aua) 2010 annual meeting and then confirmed this finding with a prospective study in 2011 (30, 31). in that study, ninety six patients with cp/cpps were randomly assigned in a single-blind fashion and received either ciprofloxacin or ciprofloxacin and solifenacin (5 mg/d) for 2 months. ipss, nih-cpsi, iief-5 questionnaires and assessment of qol were used in that study. according to the results of the study, 67% of patients had urinary symptoms. similarly, in our study 76% of patients showed urinary phenotype. on the other hand, the ipss assessment appears to be a good indicator follow-up in the management of cp/cpps especially in many patients with severe luts. statistically significant differences in the total score, the pain and sub-domain scores of nih-cpsi and total score and storage domain score of ipss were reported according to kim’s research. moreover, they reported a statistically non significant increase of the total score of iief-5 and no statistically significant difference in residual urine. as a result of the study, the efficacy of anticholinergic treatment in cp/cpps was demonstrated by the improvements in the nih-cpsi and ipss total and storage scores. similar to the results of that study, the nihcpsi and ipss total and storage scores improved significantly in the anticholinergic treatment group for patients with cp/cpss in our study (p = 0.053). more than 90% of cases of cp are not associated with a significant bacteriuria, a condition referred to as chronic pelvic pain syndrome (cpps) and may not respond to antibiotics or other classical treatment options. many hypotheses have been suggested for the physiopathology of cp/cpss including infection, inflammation, autoimmunity, neuromuscular spasm or intraprostatic urinary reflux. cp/cpss is a syndrome, not a disease and patients may have a wide array of symptoms. for this reason, symptomatic treatment is essential for these patients. symptom severity should be assessed using the nih chronic prostatitis symptom index (cpsi), which is a validated nine question survey that covers the three domains of pain, urinay symptoms and quality of life (32). the upoint system was developed to identify clinical phenotypes according to the symptoms and decide for combined multimodal treatment strategies. the upoint system (www.upointmd.com) was validated in several clinical trials (33-35). in this system each category has its own treatment. use of this treatment strategy is starting to become more widespread and is proving its effectiveness. a strong correlation between the number of positive upoint domains and the worse total score of the cpsi measured in patients was shown (36). shoskes et al demostrated that a majority (84%) of patients treated based on the upoint phenotype had a clinical improvement of cp/cpss symptoms measured by an at least a 6-point or greater decrease in nih-cpsi score (33, 34, 37). another study about upoint clinical phenotyping reported that 75% of patients had at least a 6-point improvement in cpsi and experienced improvements in every domain (38). in our study, many patients with cp/cpss had luts and we evaluated to all patients according to upoint classification. in addition to the correlation between the upoint and cp/cpss, sexual dysfunction (ed) was added as a specific domain to create upoint(s) (12). in this study, the authors suggested that adding sexual dysfunction to the domain system may be helpful, as a sexual dysfunction is a frequent complaint of patients suffering from cp/cpss. according to this study, the prevalence of sexual dysfunction is 65% in these patients. multimodality treatment strategies that provides superior outcomes over other treatment strategies for this disnarter_stesura seveso 25/03/19 17:14 pagina 19 archivio italiano di urologia e andrologia 2019; 91, 1 k. fehmi narter, u. can, a. coşkun, k. sabuncu, f. tarhan 20 ease and it aims to offer a personalized combination therapy. at least combined therapy may show synergistic effects in the management of cp/cpps. in our study, nih-cpsi, ipss and oab-v8 scoring values were calculated at statistically significant higher level in the ‘urinary phenotype’ group (p < 0.001). we found statistically significant differences between the two groups in the total score and urinary domain of the nih-cpsi and the total score and storage symptom score of the ipss. as a result of nih-cpsi, ipss and oab-v8’s data, we can suggest that cp/cpss is a complex problem and it can effect bladder, prostate and lower urinary tract functions as a whole system. however to prove the effective of anticholinergics in cp/cpps decrease of absolute values between two groups should be considered during the study. our data suggest that anticholinergics are effective in the management of cp/cpss, especially for the treatment of storage symptoms. in our study, total and storage scores of nih-cpsi and ipss improved significantly in the anticholinergic treatment group for patients with cp/cpss (p = 0.053). as we well know, upoint system may recommends all treatment options for ‘urinary phenotype’ according to patient’s symptoms and preference of the clinician. according to our results, anticholinergics may be a treatment option for many patients with cp/cpss who have high ipss scores with modarate or severe luts symptoms. moreover, this effect of antimuscarinics may be explain by the influence of anticholinergic system on the prostate tissue. many treatment options for this disease have been used such as alpha blockers, antibiotic therapy, anti-inflammatory drugs and analgesics, antispasmodics, 5-alpha reductase inhibitors (5-ari), lifestyle changing, psychotherapy, physiotheraphy, local thermotherapy, neuroleptics and anti-anxiolitics, narcotics, acupuncture, extracorporeal shockwave therapy, myofascial trigger point release, biofeedback, food supplements (quercetin, zinc etc), phytotherapy (bioflavonoids), botulinum toxin a injection or occasionally surgical therapy. there have been few studies of the efficacy of anticholinergics for these patients. at least for a symptomatic relief of complaints, anticholinergic treatment may be tried according to the results of our study. but there is a need for a long term, randomized, controlled study to confirm the efficacy of this treatment. the limitations of the our study are the lack of a questionnaire to assess the sexual performance of the patients such as iief-5 and of an evaluation of long-term treatment outcomes. furthermore, our study was not a large scale and long term research. so that, more randomized, controlled, long-term and large-scale clinical trials are needed. on the contrary, our study was the first to include beck depression scale together with upoint system in patients with cp/cpss. although there was a decrease in beck score after treatment in patients treated with anticholinergics, the change was not significant (p = 0.387). this positive but statistically insignificant result can be pioneer for entegration of beck depression scale and upoint system that could be named as upoint(d; depression) similarly to upoint(s) modification. conclusions as we well know, cp/cpps is a common, worrisome problem especially for the young men population. until today, anticholinergic therapy is not a choice for the treatment of this problem according to classical treatment algorithms, but after the introduction of upoint system this option has been considered, especially for patients belong urinary phenotype based on upoint system. if patients with cp/cpss according to subgroup of the nih categorization have lower urinary symptoms (luts) such as urgency, frequency, nocturia, increased postvoid residual urine, dysuria, they have to be evaluated with upoint system and they are best candidate for anticholinergic treatment. in this study, we showed that anticholinergic therapy was an effective and preferable option for these patients. in the near future anticholinergic treatment of patients with cp/cpss will be accepted and take a place in classical treatment algorithms. in addition to the symptomatic recovery in this disease, we believe that it is possible a physiopathological improvement in the tissue of prostate due to anticholinergic effect, because cholinergic system is well reprsented in the whole prostate tissue. there is need for more randomised prospective clinical trials and histological/molecular researches to evaluate tissue receptors in the prostate. references 1. krieger jn, lee sw, jeon j, et al. epidemiology of prostatitis. int j antimicrob agents. 2008; 31(suppl 1):s85-90. 2. marszalek m, wehrberger c, hochreiter w, et al. symptoms suggestive of chronic pelvic pain syndrome in an urban population: prevalence and associations with lower urinary tract symptoms and erectile function.j urol. 2007; 177:1815-9. 3. luzzi ga. chronic prostatitis and chronic pelvic pain in men: aetiology, diagnosis and management.j eur acad dermatol venereol. 2002; 16:253-6. 4. liang cz, zhang xj, hao zy, et al. an epidemiological study of patients with chronic prostatitis. bju int. 2004; 94:568-70. 5. fall m, baranowski ap, elneil s, et al. european association of urology. eur urol. 2010; 57:35-48. 6. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999; 282:236-7. 7. shoskes da, nickel jc, dolinga r, et al. clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity. urology. 2009; 73:538-42. 8. magri v, wagenlehner f, perletti g, et al. use of the upoint chronic prostatitis/chronic pelvic pain syndrome classification in european patient cohorts: sexual function domain improves correlations. j urol. 2010; 184:2339-45. 9. litwin ms, mcnaughton-collins m, fowler fj jr, et al. the national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. chronic prostatitis collaborative research network. j urol. 1999; 162:369-75. 10. barry mj, fowler fj jr, o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549-57. narter_stesura seveso 25/03/19 17:14 pagina 20 21archivio italiano di urologia e andrologia 2019; 91, 1 anticholinergic therapy for chronic prostatitis 11. acquadro c, kopp z, coyne ks, et al. translating overactive bladder questionnaires in 14 languages. urology. 2006; 67:536-40. 12. beck at, ward ch, mendelson met al. an inventory for measuring depression. arch gen psychiatry. 1961; 4: 561-71. 13. vaalasti a, hervonen a. autonomic innervation of the human prostate. invest urol. 1980; 17:293-7. 14. chapple cr, crowe r, gilpin sa, et al. the innervation of the human prostate gland-the changes associated with benign enlargement. j urol. 1991; 146:1637-44. 15. caine m, raz s, zeigler m. adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. br j urol. 1975; 47:193-202. 16. hedlund h, andersson ke, larsson b. alpha-adrenoceptors and muscarinic receptors in the isolated human prostate.j urol. 1985; 134:1291-8. 17. gup di, shapiro e, baumann m, et al. contractile properties of human prostate adenomas and the development of infravesical obstruction. prostate. 1989; 15:105-14. 18. ventura s, pennefather j, mitchelson f. cholinergic innervation and function in the prostate gland.pharmacol ther. 2002;94:93-112. 19. bruschini h, schmidt ra, tanagho ea. neurologic control of prostatic secretion in the dog.invest urol. 1978; 15:288-90. 20. witte lp, chapple cr, de la rosette jj, et al. cholinergic innervation and muscarinic receptors in the human prostate.eur urol. 2008; 54:326-34. 21. crowe r, chapple cr, burnstock g. the human prostate gland: a histochemical and immunohistochemical study of neuropeptides, serotonin, dopamine beta-hydroxylase and acetylcholinesterase in autonomic nerves and ganglia.br j urol. 1991; 68:53-61. 22. latifpour j, gousse a, yoshida m, et al. muscarinic receptors in diabetic rat prostate.biochem pharmacol. 1991; 42 suppl:s113-9. 23. levey ai, kitt ca, simonds wf, et al. identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. j neurosci. 1991; 11:3218-26. 24. profita m, giorgi rd, sala a, et al. muscarinic receptors, leukotriene b4 production and neutrophilic inflammation in copd patients.allergy. 2005; 60:1361-9. 25. kawashima k, fujii t. expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function.front biosci. 2004; 9:2063-85. 26. mattiasson a, andersson ke, andersson po, et al. nerve-mediated functions in the circular and longitudinal muscle layers of the proximal female rabbit urethra.j urol. 1990; 143:155-60. 27. nagahama k, tsujii t, morita t, et al. differences between proximal and distal portions of the male rabbit posterior urethra in the physiological role of muscarinic cholinergic receptors. br j pharmacol. 1998; 124:1175-80. 28. giglio d, tobin g. muscarinic receptor subtypes in the lower urinary tract. pharmacology. 2009; 83:259-69. 29. maruyama s, oki t, otsuka a, et al. human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. j urol. 2006; 175: 365-9. 30. kim hj, kyung ys, woo sh, et al. the efficacy of anticholinergics for chronic prostatitis/chronic pelvic pain syndrome in young and middle aged patients -single-blinded, prospective, multi-center study aua annual meeting program abstracts 796, 2010, volume 183, issue 4, supplement, page e311. 31. kim ds, kyung ys, woo sh, et al. efficacy of anticholinergics for chronic prostatitis/chronic pelvic pain syndrome in young and middle-aged patients: a single-blinded, prospective, multi-center study.int neurourol j. 2011; 15:172-5. 32. litwin ms, mcnaughton-collins m, fowler fj jr, et al. the national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. chronic prostatitis collaborative research network. j urol. 1999; 162:369-75. 33. shoskes da, hakim l, ghoniem g, et al.long-term results of multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome. j urol. 2003; 169:1406-10. 34. magri v, marras e, restelli a, et al. multimodal therapy for category iii chronic prostatitis/chronic pelvic pain syndrome in upoints phenotyped patients. exp ther med. 2015; 9:658-666. 35. polackwich as, shoskes da. chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy.prostate cancer prostatic dis. 2016; 19:132-8. 36. zhao z, zhang j, he j, et al. clinical utility of the upoint phenotype system in chinese males with chronic prostatitis/chronic pelvic pain syndrome (cp/cpps): a prospective study. plos one. 2013; 8:e52044. 37. shoskes da, nickel jc, kattan mw. phenotypically directed multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome: a prospective study using upoint. urology. 2010; 75:1249-53. 38. guan x, zhao c, ou zy, et al. use of the upoint phenotype system in treating chinese patients with chronic prostatitis/ chronic pelvic pain syndrome: a prospective study. asian j androl. 2015; 17:120-3. correspondence fehmi narter, md, phd, assoc prof (corresponding author) fehminarter66@gmail.com acibadem mehmet ali aydinlar university, urology kızıltoprak istasyon cad. murat apt. 24/15 kadikoy 34724 istanbul (turkey) utku can, md utkucan99@yahoo.com alper coşkun, md dr.alper05@gmail.com kubilay sabuncu, md kubilaysabuncu@yahoo.com fatih tarhan, md, assoc prof tarhanf@yahoo.com department of urology, university of health sciences, kartal dr. lütfi kırdar training and research hospital, istanbul (turkey) narter_stesura seveso 25/03/19 17:14 pagina 21 stesura seveso 395archivio italiano di urologia e andrologia 2014; 86, 4 case report capillary hemangioma of the scrotum mimicking an epididymal tumor: case report antonio vavallo 1, francesco lafranceschina 1, giuseppe lucarelli 1, carlo bettocchi 2, pasquale ditonno 2, michele battaglia 2, francesco paolo selvaggi 1 1 casa bianca hospital (gvm), cassano delle murge, bari, italy; 2 urology, andrology and kidney transplantation unit, department of emergency and organ transplantation (deto), university of bari, italy. we report a case of capillary hemangioma of the scrotum. a 52-year-old male presented with a left scrotum swelling that had arisen suddenly two months before. scrotal ultrasound revealed a dishomogeneous mass in the left scrotum. the mass demonstrated blood flow in the color doppler mode. scrotal mass excision was performed. pathological evaluation revealed a capillary hemangioma. key words: capillary; hemangioma; scrotum. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. in the lesion. the patient was diagnosed with a suspected epididymal neoplasm and a left inguinal approach was performed. the mass was dissected with testicular and epididymal sparing surgery and found to be a nodular, dark red conglomerate of distended blood vessels measuring 7 x 5 x 2 cm. the mass was not attached to the testis or the spermatic cord, but was adherent to the epididymis. pathological examination identified a capillary hemangioma and immunohistochemical staining for cd31, actin, s100 protein and ki67 confirming the vascular nature of this tumor. on the basis of the morphological characteristics and immunohistochemical findings, the diagnosis of scrotal capillary hemangioma was rendered. at the last follow-up, 12 months after the operation, the patient was healthy without any clinical evidence of complication or recurrence. discussion hemangiomas are benign vascular tumors, which may develop in any part of the body and they are most common in the musculoskeletal system, liver and spleen. hemangiomas are classified into capillary, cavernous, arteriovenous, venous and mixed subtypes and may be composed of vessels whose walls are abnormal and cannot be identified as arterial or venous (3). the occurrence of capillary hemangioma in the scrotum is rare and scrotum enlargement, with or without tenderness, is the chief presenting symptom. only a few number of articles describing intrascrotal hemangioma have been reported. an interesting point of our case is the age; our patient was a 52-year-old male and, as far as we know, this is the first case in which the patient is older than 50 years in the literature. ultrasonography is useful for diagnosing scrotal hemangiomas, but rarely definitive. it can determine the extent of the lesion, delineate its relationship with adjacent structures, demonstrate the nature of the mass and help plan therapy. in sonography, hemangiomas vary from hypoechoic to hyperechoic, or they may be heterogeneous. color doppler may demonstrate blood flow within these lesions but the absence of flow doi: 10.4081/aiua.2014.4.395 presented at 19th national congress sieun, fermo 2014 introduction scrotal hemangioma is a very rare benign vascular neoplasm, mostly seen in children and young adults and comprises less than 1% of all hemangiomas (1). malignant tumors of the epididymis constitute 25% of the tumors of this area (2). in the current study, we report a case of capillary hemangioma of the left scrotum, which mimicked an epididymal tumor, and discuss the diagnostic and therapeutic problems. case report a 52 years old man referred to our department for painless enlargement in the left hemiscrotum for two months. personal and familiar history were unremarkable. the patient denied any history of fever, scrotal trauma or epididymitis. at physical examination, the mass was discriminated from the testis, but not from epididymis and spermatic cord. the patient had a normal blood cell count and urinalysis. laboratory examinations, including relevant tumor markers, particularly α-fetoprotein and β-human chorionic gonadotrophin, were normal. scrotal ultrasound revealed a dishomogeneous mass, lying on the border between epididymal tail and lower pole of the left testis without any disruption of the architecture of the testicular parenchyma. color doppler sonography showed increased blood flow withvavallo_stesura seveso 16/01/15 12:01 pagina 395 archivio italiano di urologia e andrologia 2014; 86, 4 a. vavallo, f. lafranceschina, g. lucarelli, c. bettocchi, p. ditonno, m. battaglia, f.p. selvaggi 396 does not rule out the presence of the lesions. magnetic resonance imaging (mri) may provide more useful information for differentiation. when the diagnosis is established, eradication of the lesion is recommended and the lesion must be complete removed to avoid recurrence. since it is impossible to differentiate a hemangioma from a malignant tumor before the operation, intra-operative frozen section examination may be requested as tumor enucleation with testicular and epididymal sparing surgery is considerate adequate. conclusion in summary, capillary scrotal hemangioma is a very rare neoplasm with different morphologies having in common an infiltrative growth pattern. clinical and radiologic findings may preoperatively suggest a vascular tumor; however any scrotal solid masses of uncertain diagnostic significance require surgical approach to define the nature by hystological examination. references 1. lin cy, sun gh, yu ds, et al. intrascrotal hemangioma. arch androl. 2002; 48:259-65. 2. dell'atti l. ultrasound diagnosis of unusual extratesticular mass: case report and review of the literature. arch ital urol androl. 2013; 85:41-3. 3. rastogi r. diffuse cavernous hemangioma of the penis, scrotum, perineum, and rectuma rare tumor. saudi j kidney dis transpl. 2008; 19:614-8. figure 1. macroscopic specimen of the dissected mass, which appeared as a nodular, dark red conglomerate of distended blood vessels. correspondence antonio vavallo, md (corresponding author) antoniovavallo@hotmail.com francesco lafranceschina, md giuseppe lucarelli, md francesco paolo selvaggi, md casa bianca hospital (gvm) cassano delle murge, bari, italy carlo bettocchi, md pasquale ditonno, md michele battaglia, md urology, andrology and kidney transplantation unit, department of emergency and organ transplantation (deto), university of bari piazza g. cesare 11 70124 bari, italy vavallo_stesura seveso 16/01/15 12:01 pagina 396 stesura seveso 397archivio italiano di urologia e andrologia 2014; 86, 4 short communication diagnostic-therapeutic pathway for small lesions of the testis giulia sbrollini 1, 2, daniele mazzaferro 1, asim ettamimi 1, rodolfo montironi 3, marco cordari 1, guevar maselli 1, giacomo tucci 1, gaetano donatelli 1, francesco pellegrinelli 1,2, alessandro conti 1,2, andrea benedetto galosi 1 1 division of urology, “augusto murri” hospital, asur marche, fermo, italy; 2 institute of urology, 3 institute of pathology, polytechnic university of the marche region, united hospitals, ancona, italy. objective of our study was to define a diagnostic-therapeutic pathway for proper treatment of not-palpable testicular masses, that may be benign in 38% of cases. since the intraoperative diagnosis is difficult to reach in particular in small lesion (< 8 mm) and the risk of tissue loss in frozen section analysis occurs frequently, we propose a diagnostic flow chart for the best management of small testis lesions. this proposed protocol has to be shown in details to physicians and patients, who must understand the clinical implications and the risk to undergo a second radical surgery. key words: small masses; testis neoplasms; partial orchiectomy; ultrasound; pathology. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. clinical protocol to not-palpable testis lesions we present a diagnostic-therapeutic protocol for patients affected by not-palpable testicular masses, with maximum diameter lower than 15 mm and negative testicular markers. this approach follows our clinical practice. ultrasound all men underwent scrotal ultrasound in our hospital to confirm type, dimension and localization of the lesion. ultrasound characteristics of the lesion were then verified at the confirmatory ultrasound by expert operator and last generation of ultrasound machine. if the lesion was not confirmed by confirmatory ultrasound or it is extra-testicular lesion, the patient was proposed for ultrasound follow-up. once the small testicular mass was confirmed at our hospital, the therapeutic indication for all cases was testicular exploration with inguinal access. this technique can be associated to intraoperative ultrasound, equipped with linear probe, in order to obtain the relative certainty of the size of the nodule and negative surgical margins, which of course will be subsequently verified by the pathologist. in figures, we report ultrasound images of three cases of our who underwent surgery for epidermoid cyst (figure 2), leydig tumor (figure 3), and seminoma (figure 4). surgery surgical exploration, using intraoperative ultrasound was done without clamping the spermatic cord. the surgical technique involved the removal of the neoplastic nodule and 3 additional biopsies of the surrounding parenchyma (two distant and one next to the mass) sent for definitive histology. smaller masses (< 8 mm) were usually sent for definitive histology, while larger masses (8-15 mm) were sent to the pathologist for intraoperative frozen sections. pathologist confirmed size and completeness of surgical margins, by macroscopic view. if the nodule was large enough to be cut for frozen section, then a microscopic description of malignant pattern was reported. doi: 10.4081/aiua.2014.4.397 presented at 19th national congress sieun, fermo 2014 introduction incidentally discovered small testicular lesions are increasing since ultrasound use increased in particular for infertility work up. although small lesion of the testis are benign in 38% of cases (1, 2), there is no agreement on criteria for testissparing surgery. guidelines give indication for testis-sparing surgery only in selected cases (bilateral testicular tumor or monorchid patient) (3). however, testis-sparing surgery has been performed also in patients with contralateral normal testis with a good oncological outcome (2, 4-8). several concerns on conservative approach are debated: intraoperative diagnosis is not always reliable in relation to the small size of the lesion and also difficulties in pathological diagnosis related to the missing immunoistochemistry during intraoperative analysis. the aim of this study is to establish a diagnostic-therapeutic pathway that allows to perform an effective testissparing surgery for impalpable testicular masses. archivio italiano di urologia e andrologia 2014; 86, 4 g. sbrollini, d. mazzaferro, e. asim, r. montironi, m. cordari, g. maselli, g. tucci, g. donatelli, f. pellegrinelli, a. conti, a.b. galosi 398 masses of mean size (8-9 mm) were sent to the pathologist, who evaluated whether to perform the frozen section or to move directly to the definitive exam, in order to reduce the risk of losing tissue for definitive histology and immunoistochemistry. if feasible, the intraoperative frozen section histology gives real time information about macroscopic (localization, surgical margins, size of the lesion) and microscopic features. such information can guide the surgical management. in case of benign or doubtful lesion there was the indication to keep on conservative management. in case of malignancy at the frozen section, inguinal orchiectomy was performed. all removed testicular lesion are subjected to definitive histological examination, including immunohistochemistry of the surgical specimen, that allowed to have a definitive histologic diagnosis. definitive paraffin-embedded tissue analysis is the main diagnostic tool for testicular cancer. if definitive histology confirmed that the mass was benign, the patient was submitted to periodic ultrasound follow up. in case of definitive malignancy inguinal orchiectomy was done. the presence of isolated intraepithelial neoplasia (tin) in one or more of the biopsies of the surrounding parenchyma, posed indication to radiotherapy. before undergoing this protocol, the patient has to be informed in detail about the various benefits, risks and implications: first of all the possibility of being subjected to a second surgery as soon as the urologist is in possession of the definitive histological result. our protocol has been approved by different specialists involved in the diagnosis and treatment (urologist, pathologist, radiologist and oncologist) and used in different departments of urology. figure 1 shows the flow chart of the protocol for diagnosis, treatment and therapy of small not-palpable testicular masses. figure 1. flow chart of diagnostic-therapeutic protocol for the management of non-palpable testicular masses. figure 2. testis ultrasound: hyper-echoic lesion, not palpable, inside the testis. after surgical partial orchiectomy, a dermoid cyst was described. figure 3 testis ultrasound: small non palpable hypo-echoic lesion inside the testis. a leydig tumor was identified after partial resection and definitive histology. figure 4 testis ultrasound: small non palpable hypo-echoic lesion close to the epididymis. a seminoma was identified after partial resection and definitive histology. the histological diagnosis on frozen sections is difficult in small testicular masses and raises the risk of loss of tissue useful for the final histology and ancillary immunohistochemistry. intraoperative ultrasound allows the surgeon to orient with more confidence in the surgical practice and then to decide whether to send the specimen for intraoperative histological examination or for definitive examination. in the masses of border-line size a key role in this decision is covered by the pathologist, who must be able to evaluate the tumor volume and then to act in a way to have an definitive histologic diagnosis as accurate as possible. conclusions frequency of benign tumors is higher in small testicular masses. intraoperative diagnosis of non-palpable testicular lesions with frozen sections is difficult in particular for very small lesions (< 8 mm) also for the risk of loss of tissue for definitive histology and ancillary immunoistochemistry. for these reasons, our protocol allows the surgeon to perform testis-sparing surgery in selected cases, reaching an oncologic out-come similar to standard surgery. references 1. shilo y, zisman a, raz o, et al. the predominance of benign histology in small testicular masses. urol oncol. 2012; 30:719-22. 2. shilo y, zisman a, raz o, et al. testicular sparing surgery for small masses. urol oncol. 2012; 30:188-91. 3. albers p, albrecht w, algaba f, et al. guidelines on testicular cancer. eur urol. 2011; 60:304-19. 4. de stefani s, isgrò g, varca v, et al. microsurgical testis-sparing surgery in small testicular masses: seven years retrospective management and results. urology 2012; 79:858-62. 5. subik mk, gordetsky j, yao jl, et al. frozen section assessment in testicular and paratesticular lesions suspicious for malignancy: its role in preventing unnecessary orchiectomy. hum pathol. 2012; 43:1514-9. 6. muller t, gozzi c, akkad t, pallwein l, et al. management of incidental impalpable intratesticular masses of < or = 5 mm in diameter. bju int. 2006; 98:1001-4. 7. gentile g, brunocilla e, franceschelli a, schiavina r, et al. can testis-sparing surgery for small testicular masses be considered a valid alternative to radical orchiectomy? a prospective single-center study. clin genitourin cancer. 2013; 11:522-6. 8. brunocilla e, gentile g, schiavina r, et al. testis-sparing surgery for the conservative management of small testicular masses: an update. anticancer res. 2013; 33:5205-10. 9. galosi ab, lacetera v, muzzonigro g. clinica delle malattie testicolari di interesse ecografico. urologia 2008; 75s12:s59-66. 399archivio italiano di urologia e andrologia 2014; 86, 4 pathway for small testicular lesions correspondence giulia sbrollini, md, urologist (corresponding author) giuliasbrollini@libero.it alessandro conti, md, urologist alessandro.conti@hotmail.com daniele mazzaferro, md, urologist mazzaferro.dr@gmail.com ettamimi asim, md ettamimi.asim@tiscali.it marco cordari, md, urologist m.cordari@tin.it guevar maselli, md, urologist guevarmaselli@katamail.com giacomo tucci, md, urologis tucci.giacomo@virgilio.it gaetano donatelli, md, urologist francesco pellegrinelli, md, urologist asaga@hotmail.it alessandro conti, md, urologist alessandro.conti@hotmail.com clinica urologica, azienda ospedaliero-universitaria ospedali riuniti ancona via conca 71, 61100 torrette di ancona, italy rodolfo montironi, md, pathologist r.montironi@univpm.it institute of pathology, polytechnic university of the marche region, united hospitals, ancona, italy andrea benedetto galosi, md, phd galosiab@yahoo.it division of urology, “augusto murri” hospital asur marche, fermo, italy 9archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.9 introduction urothelial carcinoma of the upper urinary tract (utuc) is among the ten most common cancers, is more frequent in males and diagnosis is generally done in the sixth decade (1, 2). established risk factors are exposure to tobacco, arsenic, and aristolochic acid, as well as alcohol consumption (3). some genetic polymorphisms are also associated with an increased risk of utuc or faster disease progression that introduces variability in the inter-individual susceptibility to the risk factors previously mentioned (4). the disease has high mortality, with more than 150.000 patients dying each year worldwide (1). extirpative surgery with removal of kidney, entire ureter and bladder cuff – radical nephroureterectomy (rnu) – is the treatment of choice for non-metastatic high-risk utuc. conversely, low-risk cases (unifocal, < 2 cm, lowgrade and superficial cancers) are amenable of kidneysparing treatments providing equal survival outcomes but better preservation of renal function (4). despite this recommendation, a relevant rate of low-risk cases still undergo rnu for several reasons, mainly concerns on clinical understaging or challenging anatomical locations with inherent risk of tumor spillage and complications (4). the issue of renal function impairment after rnu is generally postponed to the need for radicality, but utuc patients are at high risk of chronic kidney disease (ckd) because of patient’s age and comorbidities, smoking exposure, potential impairment of contralateral kidney due to diagnostic procedures or bilateral utuc. indeed, despite adjuvant chemotherapy might prolong survival (5) and reduce the risk of disease recurrence in locallyadvanced utuc (6), nearly only 50% of patients are still eligible for platinum-based protocols, due to post-operative renal failure (7, 8). finally, it should be noted that ckd might determine worse mortality due to non-cancer but also cancer-related causes, as found in patients treated for renal cell carcinoma (rcc) (9-11). thus, the identification of patients at risk of significant renal function decline may allow clinicians to better assess the opportunity of kidney-sparing rather than objective: the aim of our study was to investigate frequency and predictors both of postoperative acute kidney injury (aki) and renal function decline in a population of consecutive upper tract urothelial carcinoma (utuc) patients who underwent radical nephroureterectomy (rnu). materials and methods: between october 2014 and february 2020, 93 patients underwent rnu at our institution. after considered exclusion criteria, 89 patients were selected. perioperative clinical factors were retrospectively collected. estimated glomerular filtration rate (egfr) was calculated using the chronic kidney disease epidemiology collaboration (ckdepi) equation. we defined aki as an increase in serum creatinine by ≥ 0.3 mg/dl or a 1.5-1.9-fold increase in serum creatinine from baseline to i post-operative day (pod). a significant renal function reduction was defined as an egfr reduction of 40% from baseline at discharge and at last clinical evaluation. frequency of aki and egfr decline was investigated. association between perioperative clinical factors and aki and egfr reduction at discharged and last follow-up was studied using univariate and multivariate models. results: aki was detected at i pod in 45 patients. on multivariate analysis, pre-operative egfr was an independent predictor of aki (or 1.03; p = 0.042). further, aki was found to be a significant predictor of egfr reduction ≥ 40% at discharge at univariate analysis (or 19.42; p = 0.005) and at multivariate analysis (or 12.49; p = 0.02). in a multivariate logistic regression model post-operative aki (or 5.18; p = 0.033), lack of ipsilateral preoperative hydronephrosis (or 0.17; p = 0.016), preoperative egfr (or 1.04; p = 0.047) and antiplatelet therapy (or 5.14; p = 0.018) were found to be independent predictors of an egfr reduction higher than 40% at last clinical evaluation made at a median of 15 (iqr 5-30) months. conclusions: in our cohort, aki was present in almost 50% of patients after rnu and it was a strong predictor of renal function decline after rnu. key words: upper tract urothelial carcinoma; radical nephroureterectomy; acute kidney injury; renal function reduction; chronic kidney disease. submitted 26 september 2020; accepted 15 october 2020 acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: a single-centre experience summary alessandro tafuri 1, 2, katia odorizzi 1, giacomo di filippo 1, 3, clara cerrato 1, giulia fassio 1, emanuele serafin 1, alessandro princiotta 1, damiano d’aietti 1, alessandra gozzo 1, antonio b. porcaro 1, matteo brunelli 4, maria angela cerruto 1, alessandro antonelli 1 1 department of urology, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy; 2 department of neuroscience, imaging and clinical science, physiology and physiopathology division, “g. d’annunzio” university, chieti, italy; 3 department of general and hepatobiliary surgery, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy; 4 department of pathology, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy. archivio italiano di urologia e andrologia 2021; 93, 1 a. tafuri, k. odorizzi, g. di filippo, et al. 10 extirpative surgery when feasible, to adopt appropriate protective strategies during the peri-operative period and to adequately schedule controls during the follow up. the aim of our study is to investigate the prevalence of aki and ckd, as well as the degree of renal functional impairment, in a population of patients submitted to rnu, in order to identify the most significant predictors of these events. materials and methods data were retrospectively collected in our institutional review board (irb) approved utuc dataset prospectively compiled since october 2014. at admission, each patient provided written informed consent for data collection and analysis. between october 2014 and february 2020, 93 consecutive patients underwent rnu at our institution as primary treatment for utuc. patients who underwent primary neo-adjuvant chemotherapy were not considered. for the purposes of the present study 4 patients with solitary kidney were excluded, leaving 89 patients, 10 of which previously submitted to radical cystectomy. in total 87 patients were submitted to open rnu and 2 to robot-assisted rnu. the following data were considered: gender, age at surgery, body mass index (bmi), performance status [american society of anesthesiologists (asa) classification and eastern cooperative oncology group (ecog) score], comorbidities (presence of coronary artery disease (cad), pulmonary disease, hypertension, hyperlipidemia, diabetes mellitus), smoking exposure, hydronephrosis, operative time, blood loss, intraoperative transfusions, pathological tnm stage (8th edition) (12), grade, presence of tumor necrosis, surgical margins status, length of hospital stay. according to an internal protocol regulating postoperative management, estimated glomerular filtration rate [egfr, calculated by the ckd-epi equation (13)] and blood chemistry were collected in all cases on post-operative day (pod) 1, 3 and at discharge. acute kidney injury was defined as an increase in serum creatinine with respect to baseline by ≥ 0.3 mg/dl or a 1.5-1.9-fold at i pod, according to the acute kidney injury network (akin) classification (14). according to previous reports, a renal function decline was considered significative when egfr reduction got over 40% with respect to the baseline (15). based on our internal protocol for low risk patients, follow-up controls were scheduled after 3 months from surgery performing cystoscopy and blood samples. if negative, subsequent cystoscopy and urinary cytology, abdominal ultrasound, and blood samples were scheduled 9 months later and then yearly, for 5 years. for high-risk patients, cystoscopy and urinary cytology at 3 months were performed. if negative, cystoscopy and cytology every 3 months for a period of 2 years, and every 6 months thereafter until five years, and then yearly were considered. additionally, yearly computed tomography (ct) urography and chest ct was scheduled. however, many patients traveled to our tertiary center from far away only for surgery, and the follow-up controls were often performed elsewhere. table 1. study population's characteristics (n = 89). n, % / median [iqr] age at surgery, years follow up, months gender male female side right left bmi smoking status no yes ex asa score ≤ 2 > 2 ecog score 0 1 2 preoperative hydronephrosis no yes cad no yes hypertension no yes preoperative hb, mg/dl preoperative albumin, mg/dl preoperative creatinine, mg/dl preoperative egfr, ml/min/1.73 m2 preoperative ckd stage 1 2 3 4 5 hb i pod, mg/dl hb iii pod, mg/dl egfr i pod, ml/min/1.73 m2 egfr iii pod, ml/min/1.73 m2 hyperlipidemia no yes diabetes no yes antiplatelet therapy no yes anticoagulant therapy no yes antidiabetic therapy no yes operation time, min blood loss, ml transfusions no yes intraoperative complications no yes pt stage ≤ 1 > 1 grade low high tumour necrosis no yes lymph node status pn0 pn+ pnx margin status r0 r1 length of stay, days egfr at discharge, ml/min/1.73 m2 egfr at last follow up, ml/min/1.73 m2 egfr reduction i pod (%) egfr reduction at iii pod (%) egfr reduction at discharge (%) egfr reduction at last follow up (%) aki i pod no yes egfr reduction at discharge, from baseline ≤ 39,9% > 40% egfr reduction at last follow up, from baseline ≤ 39,9% > 40% aki: acute kidney injury; asa: american society of anesthesiology; bmi: body mass index; cad: coronary artery disease; ckd: chronic kidney disease; ecog: eastern cooperative oncology group; egfr: estimated glomerular filtration rate; hb: haemoglobin; pod: postoperative day. 71 [66-76] 15 [5-30] 61 (68.5%) 28 (31.5%) 43 (48.3%) 46 (51.7%) 25.6 [23.14-28] 24 (27%) 20 (22.5%) 45 (50.6%) 64 (71.9%) 25 (28.1%) 38 (42.7%) 39 (43.8%) 12 (13.5%) 38 (42.7%) 51 (57.3%) 77 (86.5%) 12 (13.5%) 39 (43.8%) 50 (56.2%) 13.4 [11.8-14.36] 38 [35.9-40.4] 1.1 [0.96-1.37] 58.39 [45.32-76.17] 9 (10.1%) 35 (39.3%) 38 (42.7%) 6 (6.7%) 1 (1.1%) 11.8 [10.5-12.9] 11.2 [10.3-12.6] 43.18 [33.49-52.99] 48.5 [36.63-57.23] 74 (83.1%) 15 (16.9%) 68 (76.4%) 21 (23.6%) 58 (65.2%) 31 (34.8%) 82 (92.1%) 7 (7.9%) 68 (76.4%) 21 (23.6%) 200 [178-252] 380 [250-600] 78 (87.6%) 11 (12.4%) 85 (95.5%) 4 (4.5%) 41 (46.1%) 48 (53.9%) 16 (18%) 73 (82%) 72 (83.7%) 14 (16.3%) 32 (36%) 16 (18%) 41 (46.1%) 83 (93.3%) 6 (6.7%) 10 [8-12] 51.16 [41.8-61.09] 48.45 [38.36-55.68] 25.14 [5.5-41.9] 17.7 [ -2.22-34.88] 8.57 [-7.42-32.53] 16.83 [-4.14-34.88] 44 (49.4%) 45 (50.6%) 74 (83.1%) 15 (16.9%) 69 (77.5%) 20 (22.5%) categorical variables were expressed as frequencies and relative percentages. continuous variables were expressed as median and interquartile range. patients were divided into two groups according to the presence of i pod aki. categorical variables were compared between groups using the !2 test. continuous variables were tested between subgroups with the independent samples t-test or mannwhitney test after testing for normality of distributions using shapiro-wilk test, as appropriate. univariate logistic regression was used to identify outcomes’ predictors, and odds ratios and 95% confidence intervals were calculated for each significant variable. significant variables at univariate analysis were entered into a multivariate regression model to identify independent predictors. a p value < 0.05 was considered statistically significant. the analysis was carried out using spss software version 25.0 (spss inc, chicago, il). results demographics, clinical, operative and pathological data of the entire population are summarized in table 1. the median age of the cohort was 71 years (iqr 66-76), 61 were males, 28 females; median follow-up time was 15 months (iqr 5-30). median preoperative hb was 13.4 g/dl (iqr 11.8-14.36) and median baseline egfr was 58.39 ml/min/1.73 m2 (iqr 45.32-76.17). 51 patients (57.3%) had preoperative ipsilateral hydronephrosis. histology found pt1 or less in 41 patients (46.1%) and pt2 or higher in the other 48 (53.9%). lymph node invasion in the pathological specimen was found in 16 (18%) cases. post-operative median egfr at 1, 3 pod and at discharge were 43.18 ml/min/1.73 m2 (iqr 33.49-52.99), 48.5 ml/min/1.73 m2 (iqr 36.63-57.23) and 51.16 ml/min/1.73 m2 (iqr 41.8-61.09) respectively. at the same timepoints, median relative egfr reduction was equal to 25.14%, 17.7%, and 8.57%. at discharge and last available follow up egfr reduction was > 40% from the baseline in 15 (16.9%) and 20 (22.5%) patients, respectively. overall, 45 patients (50.6%) developed aki after surgery. the clinicopathological characteristics of the two groups (aki compared to non-aki) are reported in table 2. on univariate analysis aki was found significantly related to preoperative hb value (or 1.44; p = 0.003), preoperative egfr (or 1.04; p = 0.002), preoperative creatinine serum level (or 0.23, p = 0.018) and ckd stage < 2 (or 0.29, p = 0.005). 11archivio italiano di urologia e andrologia 2021; 93, 1 rnu and renal function decline table 2. clinicopathological characteristics stratified according i pod aki. group 1 (no, n = 44) group 1 (yes, n = 45) p value n (%); median [iqr] n (%); median [iqr] age at surgery, years follow up, months gender male female side right left bmi smoking status no yes ex asa score ≤ 2 > 2 ecog score 0 1 2 preoperative hydronephrosis no yes cad no yes hypertension no yes preoperative hb, mg/dl preoperative albumin, mg/dl preoperative creatinine, mg/dl preoperative egfr, ml/min/1.73 m2 preoperative ckd stage 1 2 3 4 5 hb i pod, mg/dl hb iii pod, mg/dl egfr i pod, ml/min/1.73 m2 egfr iii pod, ml/min/1.73 m2 hyperlipidemia no yes diabetes no yes antiplatelet therapy no yes anticoagulant therapy no yes antidiabetic therapy no yes operation time, min blood loss, ml transfusions no yes intraoperative complications no yes pt stage ≤ 1 > 1 grade low high tumour necrosis no yes lymph node status pn0 pn+ pnx margin status r0 r1 length of stay, days egfr at discharge, ml/min/1.73 m2 egfr at last follow up, ml/min/1.73 m2 egfr reduction i pod (%) egfr reduction at iii pod (%) egfr reduction at discharge (%) egfr reduction at last follow up (%) egfr reduction at discharge, from baseline ≤ 39,9% > 40% egfr reduction at last follow up, from baseline ≤ 39,9% > 40% aki: acute kidney injury; asa: american society of anesthesiology; bmi: body mass index; cad: coronary artery disease; ckd: chronic kidney disease; ecog: eastern cooperative oncology group; egfr: estimated glomerular filtration rate; hb: haemoglobin; pod: postoperative day. 71 [66-79] 16 [5-35] 26 (59.1%) 18 (40.9%) 14 (31.8%) 30 (68.2%) 25.63 [22.99-27.65] 12 (27.3%) 8 (18.2%) 24 (54.5%) 29 (65.9%) 15 (34.1%) 18 (40.9%) 22 (50%) 4 (9.1%) 15 (34.1%) 29 (65.9%) 41 (93.2%) 3 (6.8%) 22 (50%) 22 (50%) 12.65 [11.05-13.9] 37.7 [35.55-40.35] 1.21 [0.98-1.68] 51.34 [40.97-65.89] 3 (6.8%) 12 (27.3%) 23 (52.3%) 5 (11.4%) 1 (2.3%) 11.6 [10.35-12.6] 11.45 [10.5-12.5] 51.13 [41.67-62] 51.01 [41.31-68.16] 36 (81.8%) 8 (18.2%) 32 (72.7%) 12 (27.3%) 33 (75%) 11 (25%) 40 (90.9%) 4 (9.1%) 32 (72.7%) 12 (27.3%) 200 [161-251] 400 [275-600] 39 (88.6%) 5 (11.4%) 44 (100%) 0 (0%) 15 (34.1%) 29 (65.9%) 7 (15.9%) 37 (84.1%) 35 (83.3%) 7 (16.7%) 17 (38.6%) 9 (20.5%) 18 (40.9%) 38 (86.4%) 6 (13.6%) 10 [8-11] 53.7 [44.49-64.32] 50.43 [39.41-59.84] 5.44 [-7.94-12.75] -0.35 [-18.41-13.48] -3.16 [-16.63-4.68] -1.31 [-10.62-17] 43 (97.7%) 1 (2.3%) 41 (93.2%) 3 (6.8%) 72 [66-76] 15 [5-29] 35 (77.8%) 10 (22.2%) 29 (64.4%) 16 (35.6%) 25.6 [23.4-28.8] 12 (26.7%) 12 (26.7%) 21 (46.7%) 35 (77.8%) 10 (22.2%) 20 (44.4%) 17 (37.8%) 8 (17.8%) 23 (51.1%) 22 (48.9%) 36 (80%) 9 (20%) 17 (37.8%) 28 (62.2%) 13.9 [13-15.2] 38 [36.3-40.9] 1.05 [0.91-1.24] 69.37 [53.46-80.37] 6 (13.3%) 23 (51.1%) 15 (33.3%) 1 (2.2%) 0 (0%) 12 [10.5-13.4] 10.9 [10.1-12.7] 38.44 [31.66-45.42] 45.42 [36.31-54.13] 38 (84.4%) 7 (15.6%) 36 (80%) 9 (20%) 25 (55.6%) 20 (44.4%) 42 (93.3%) 3 (6.7%) 36 (80%) 9 (20%) 200 [180-252] 365 [250-650] 39 (86.7%) 6 (13.3%) 41 (91.1%) 4 (8.9%) 26 (57.8%) 19 (42.2%) 9 (20%) 36 (80%) 37 (84.1%) 7 (15.9%) 15 (33.3%) 7 (15.6%) 23 (51.1%) 45 (100%) 0 (0%) 10 [9-13] 46.98 [41.35-54.67] 46.98 [38.32-54.67] 41.9 [35.50-48.89] 34.83 [22.90-42.15] 30.69 [10.66-43.09] 33.17 [13.36-44.92] 31 (68.9%) 14 (31.1%) 28 (62.2%) 17 (37.8%) 0.663 0.660 0.058 0.002 0.159 0.908 0.213 0.355 0.105 0.069 0.245 0.001 0.042 0.001 0.001 0.044 0.007 0.003 0.001 0.001 0.741 0.419 0.054 0.671 0.419 0.928 0.388 0.778 0.043 0.025 0.615 0.924 0.615 0.010 0.993 0.004 0.001 0.001 0.001 0.001 0.001 0.001 0.001 archivio italiano di urologia e andrologia 2021; 93, 1 a. tafuri, k. odorizzi, g. di filippo, et al. 12 on multivariate analysis, preoperative egfr was the only independent predictor to the occurrence of aki (or 1.03; p = 0.042) (table 3). on univariate analysis aki (or 19.42; p = 0.005), preoperative egfr (or 1.05; p = 0.004), preoperative hb (or 1.43; p = 0.036), the lack of ipsilateral hydronephrosis (or 0.30; p = 0.047), iii pod creatinine serum level (or 3.00; p = 0.018), i pod hb (or 1.57, p = 0.019) were predictors of egfr reduction > 40% at discharge. on multivariate analysis only aki retained its significance (or 12.49; p = 0.02) (table 4). among several factors predicting egfr reduction > 40% at last follow-up on univariate analysis, aki (or 5.18, p = 0.033), preoperative egfr (or 1.04, p = 0.047), the lack of ipsilateral hydronephrosis (or 0.17; p = 0.016), and antiplatelet therapy (or 5.14; p = 0.018) were found significantly associated to the outcome also on multivariate analysis (table 5). discussion the present study shows that patients with utuc candidate to rnu have baseline poor renal function, with median egfr values close to 60 ml/min, and post-operatively suffer from further relevant decline given that an impairment exceeding 40% of baseline function was noted in 22.5% of cases at a median follow-up of 15 months. the factors associated with worse functional outcome were preoperative egfr, lack of ipsilateral hydronephrosis, antiaggregating therapy and the presence of post-operative aki, which represent the strongest predictor of ckd after rnu in the present cohort. definitely these patients have major determinants of baseline impaired function and relevant risks to develop ckd, with inherent effects on non-cancer (11), but also cancer-related survival outcomes, firstly concerning the access to platinum-based chemotherapy regimens that showed significantly improved disease-free survival in locally advanced utuc (6). although renal function preservation in utuc represents a major issue it has been poorly investigated, with sparse reports in the literature. the main reason of this is that utuc is often featured by aggressiveness and multifocality, so that extirpative treatment is commonly privileged, except for very selected low risk cases for whose kidney-sparing approaches might be preferred (16, 17). in 2006, meyer et al. retrospectively analyzed 131 rnu patients reporting a 18% deterioration in egfr after a median follow-up of 5 years. such deterioration was found to be greater in patients with older age, and comorbidities as diabetes mellitus, hypertension, pre-existing renal impairment and analgesic nephropathy (18). in a multicentric retrospective study evaluating 388 patient who underwent rnu for utuc, kaag mg et al. showed a mean 24% of egfr decrease after surgery. they also reported that eligibility to platinum-based chemotherapy decreased from 49% before surgery to 19% post-surgery using a cut-off of 60 ml/min/1.73 m2, and from 80% to 55% using a cut-off of 45 ml/min/1.73 m2 (19). kaag m. and his group identified age and preoperative egfr as a predictors of renal function decline after rnu (20). they retrospectively enrolled 374 rnu patients and assessed early (1-5 months) and late (> 5 months) egfr after surgery: multivariable analysis identified preoperative egfr lower than 60 ml/min/1.73 m2 and age > 70 years as preoperative predictors of clinically relevant egfr loss after rnu, considering clinically relevant a loss of renal function compromising the possibility of chemotherapy recruitment. shao et al. recently reported that among 242 rnu cases, 42.1% was eligible to cisplatin-based therapy prior to rnu whereas, following surgery, only 15.2% remained eligible, because of the worsening of renal function (8). in the present study, we also investigated the role of postoperative aki, finding that a half of patients experienced this event. interestingly, preoperative hemoglobin and preoperative egfr predicted aki, but only preoperative egfr remained an independent predictor of aki on multivariate analysis. the prevalence of aki after rnu was previously unreported and resembles the data after radical nephrectomy for rcc (15). the most relevant finding of our analysis table 3. logistic regression analysis for i pod aki predictors assessment. univariate multivariate or 95% ci p value or 95% ci p value preoperative ckd stage 0.285 0.12-0.68 0.005 preoperative creatinine 0.234 0.07-0.78 0.018 preoperative egfr 1.038 1.01-1.06 0.002 1.027 1.00-1.05 0.042 preoperative hb 1.441 1.13-1.83 0.003 1.295 0.99-1.68 0.051 aki: acute kidney injury; ckd: chronic kidney disease; egfr: estimated glomerular filtration rate; hb: haemoglobin; pod: postoperative day. table 4. logistic regression analysis for the assessment of egfr reduction > 40% from baseline to discharge. univariate multivariate or 95% ci p value or 95% ci p value preoperative hb 1.43 1.02-2 0.036 1.091 0.76-1.57 0.636 hb i pod 1.567 1.08-2.28 0.019 preoperative egfr 1.053 1.02-1.09 0.004 1.036 0.99-1.08 0.108 aki i pod 19.419 2.42-155.54 0.005 12.491 1.48-105.40 0.02 creatinine iii pod 3.004 1.21-7.45 0.018 preoperative hydronephrosis 0.304 0.09-0.98 0.047 0.519 0.13-2.02 0.344 aki: acute kidney injury; ckd: chronic kidney disease; egfr: estimated glomerular filtration rate; hb: haemoglobin; pod: postoperative day. table 5. logistic regression analysis for the assessment of egfr reduction > 40% from baseline to the last follow-up. univariate multivariate or 95% ci p value or 95% ci p value preoperative hb 1.359 1.02-1.81 0.037 1.085 0.75-1.57 0.663 hb i pod 1.598 1.13-2.26 0.008 hb iii pod 1.768 1.21-2.58 0.003 preoperative egfr 1.055 1.02-1.09 0.001 1.043 1-1.09 0.047 aki i pod 8.298 2.22-31 0.002 5.183 1.14-23.54 0.033 creatinine iii pod 67.524 8.45-539.64 0.0001 creatinine at discharge 72.359 9.87-530.65 0.0001 preoperative hydronephrosis 0.167 0.05-0.52 0.002 0.172 1.14-23.55 0.016 antiplatelet therapy 3.947 1.4-11.16 0.01 5.139 1.32-19.93 0.018 aki: acute kidney injury; ckd: chronic kidney disease; egfr: estimated glomerular filtration rate; hb: haemoglobin; pod: postoperative day. 13archivio italiano di urologia e andrologia 2021; 93, 1 rnu and renal function decline is that aki affects long-term renal function impairment, indicating that any effort should be done to prevent aki, especially in patients at risk. identification of such patients would allow to optimize the perioperative management in order to reduce the incidence of aki after surgery and its consequences. a dedicated pre-, intraand postoperative management with avoidance of potentially nephrotoxic agents, close monitoring of serum creatinine and urine output (remembering that urine output and serum creatinine are changing very late during the development of aki), optimization of volume status and hemodynamic parameters and use of alternatives to radio contrast agents, represent the best aki preventative measure to adopt in perioperative time (2123). also, anesthesiologist may contribute to renal damage prevention avoiding the reduction of renal blood and renal hypoxia, and preventing hypotension during surgery (21). the median percentage egfr reduction we sought was 8.6% at discharge, 16.8% at last follow-up after a median of 15 months from surgery. the rate of patients experiencing an egfr decline ≥ 40% at last follow-up was 22.5%. the factors independently associated to this event were post-operative aki, the lack of preoperative hydronephrosis, preoperative hemoglobin, and antiplatelet therapy. the interpretation of these findings is that already established contralateral hypertrophy due to hydronephrosis of the affected urinary tract, as well as better post-operative course, with less blood loss and without aki, facilitate the compensatory role of the remnant solitary kidney. additionally, antiplatelet drugs represent a risk factors for renal function impairing, especially after rnu. as we already mentioned, these patients should be properly managed pre-operatively and accurately followed after surgery. after nephrectomy utuc patients showed larger egfr reduction than those with parenchymal tumors, reasonably because the latter are generally younger and with less comorbidities. however, there are some intrinsic differences between these two conditions still to be investigated. tae et al. indeed investigated by matched-pair comparison 554 patients who underwent nephrectomy for utuc (n = 277) or parenchymal tumor (n = 277), balanced in terms of age, bmi, baseline egfr and comorbidities. a significant larger decline in postoperative egfr was found in utuc cases (73.3% vs. 66.1%, p = 0.039) and multivariate analysis showed that the indication to nephrectomy due to utuc (or 1.84; p = 0.006) was an independent predictor of postoperative impaired renal function (24). lee et al. showed similar findings in 616 patient who underwent nephrectomy for renal cancer (n = 319), or utuc (n = 297), with the latter older and more comorbid. the authors reported that utuc patients had an increased risk of serum creatinine doubling and need for dialysis after radical nephrectomy, and the predictor of these unfavorable outcomes were old age, diabetes, low baseline egfr and indication to nephrectomy due to utuc (25). other tools have been proposed for identifying and monitoring patients at risk of renal failure. brardi et al. investigated the role of doppler ultrasound derived renal resistive index (rri) in a ckd population in the monitoring of renal function after a therapeutic and dietetic intervention to ameliorate the renal impairment. the authors found that rri was a key parameter in monitoring patients with ckd and a helpful tool to drive clinical efforts to contrast renal function decline (26). the same team recently found that variation in time of egfr positively correlates to sonographic measurements of average right and left kidney diameters and percentage variations of right and left renal cortical thickness in a population of 80 adult patients with various degrees of chronic kidney disease after received of a therapeutic and dietetic intervention to improve renal function. patients were not dialysis-dependent, they did not undergo renal surgery, nor they were affected by any of the pathological conditions that can increase kidney size (27). according to these pieces of evidence, renal ultrasound derived parameters together with clinical factors could represent a useful tool for evaluating patients before rnu and subsequent follow up. the present study is a retrospective evaluation of a small population. however, our results are innovative. we showed that aki at i pod is a strong predictor of renal function decline in patients who underwent rnu for utuc who might need an adjuvant platinum-based chemotherapy. identifying patients at high-risk of renal function decline has a pivotal role to provide a correct peri-operative management. a tailored pre-operative management and surgical procedure should be provided to patients at high risk of developing aki. additionally, when utuc patients are counseled before treatment, the risk of renal function decline should be extensively explained. further higher-level studies are needed to confirm our results. conclusions in our cohort, almost 50% of patients developed aki after rnu. acute kidney injury was a strong predictor of renal function decline after radical nephroureterectomy at discharged and a 15 months follow-up. identifying patients at high-risk of renal function decline is essential to provide a correct peri-operative management. references 1. siegel rl, miller kd, jemal a. cancer statistics. ca cancer j clin. 2019; 69:7-34. 2. horstmann m, witthuhn r, falk m, stenzl a. gender-specific differences in bladder cancer: a retrospective analysis. gend med. 2008; 5:385-94. 3. colin p, koenig p, ouzzane a, et al. environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary 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radical nephroureterectomy for upper tract urothelial carcinoma. eur j surg oncol. 2016; 42:16251635. 18. meyer jp, delves gh, sullivan me, et al. the effect of nephroureterectomy on glomerular filtration rate. bju international. 2006; 98: 845-848. 19. kaag mg, o'malley rl, o'malley p, et al. changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. eur urol. 2010; 58:581-587. 20. kaag m,trost l, thompson rh, et al. preoperative predictors of renal function decline after radical nephroureterectomy for upper tract urothelial carcinoma. bju international. 2014; 114:674-679. 21. zarbock a, koyner jl, hoste eaj, et al. update on perioperative acute kidney injury. anesth analg, 2018; 127:1236-1245. 22. kdigo clinical practice guideline for acute kidney injury. kidney int suppl. 2012; 2:1-138. 23. bell s, prowle j. postoperative aki-prevention is better than cure? j am soc nephrol. 2019; 30:4-6. 24. tae bs, ku jh, kwak c, et al. comparison of renal function after radical surgery for upper tract urothelial carcinoma versus renal cell carcinoma: propensity score matching. urologia internationalis. 2018; 101:400-408. 25. lee, kh, chen yt, chung hj, et al. kidney disease progression in patients of upper tract urothelial carcinoma following unilateral radical nephroureterectomy. renal failure. 2016; 38:77-83. 26. brardi s, cevenini g, giovannelli v, romano g. longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients treated with conventional medical and dietetic therapy. arch ital urol androl. 2017; 89:305-309. 27. brardi s, cevenini g. time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients. arch ital urol androl. 2020; 92:21-24. correspondence alessandro tafuri, md aletaf@hotmail.it katia odorizzi, md katia.odorizzi@virgilio.it giacomo di filippo, md giacomo.difilippo90@gmail.com clara cerrato, md clara.cerrato01@gmail.com giulia fassio, md fassio.giulia@gmail.com emanuele serafin, md serafin.mnl@gmail.com alessandro princiotta, md alessandroprinciotta0@gmail.com damiano d’aietti, md damiano.daietti@gmail.com alessandra gozzo, md la.ale.gozzo@gmail.com antonio b. porcaro, md antoniobenito.porcaro@aovr.veneto.it maria angela cerruto, md mariaangela.cerruto@univr.it alessandro antonelli, md (corresponding author) alessandro.antonelli@univr.it department of urology, university of verona, azienda ospedaliera universitaria integrata verona, piazzale stefani 1, 37126, verona (italy) matteo brunelli, md matteo.brunelli@univr.it department of pathology, university of verona, azienda ospedaliera universitaria integrata verona, verona (italy) introduction high grade prostatic intraepithelial neoplasia (hgpin) is a cytoarchitectural modification of the prostatic tissue, with pre-existing acini and ducts lined by cytologically atypical cells (1). it has long been considered the pre-neoplastic lesion of prostate cancer (pca) (1, 2) and is considered a risk factor for pca on subsequent biopsy (3-7). the prognostic value of hgpin in prostate biopsy cores however has been questioned and controversy has arisen on whether patients with a diagnosis of hgpin should 59archivio italiano di urologia e andrologia 2013; 85, 2 original paper widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer: a 12 months analysis after three consecutive prostate biopsies cosimo de nunzio 1, simone albisinni 1, antonio cicione 1, mauro gacci 2, costantino leonardo 1, francesco esperto 1, andrea tubaro 1 1 department of urology, ospedale sant’andrea, university “la sapienza”, rome, italy; 2 department of urology, ospedale careggi, university of florence, italy. purpose: to evaluate the risk of prostate cancer (pca) on a third prostate biopsy in a group of patients with two consecutive diagnoses of high grade intraepithelial neoplasia (hgpin). materials and methods: from november 2004 to december 2007, patients referred to our clinic with a psa ! 4 ng/ml or an abnormal digital rectal examination (dre) were scheduled for trans-rectal ultrasound (trus) guided 12-core prostate biopsy. patients with hgpin underwent a second prostate biopsy, and if the results of such procedure yielded a second diagnosis of hgpin, we proposed a third 12-core needle biopsy regardless of psa value. crude and adjusted logistic regressions were used to assess predictors of pca on the third biopsy. results: a total of 650 patients underwent 12 cores transrectal ultrasound prostatic biopsy in the study period. of 147 (22%) men with a diagnosis of hgpin, 117 underwent a second prostatic biopsy after six months and 43 a third biopsy after other six months. after the third biopsy, 19 patients (34%) still showed hgpin, 15 (35%) were diagnosed with pca and 9 (21%) presented with chronic prostatitis. widespread hgpin on a second biopsy was significantly associated with pca on further biopsy (!2 = 4.04, p = 0.04). moreover, the presence of widespread hgpin significantly predicted the risk of pca on crude and adjusted logistic regressions. conclusions: widespread hgpin on second biopsy is associated with the presence of pca on a third biopsy. nonetheless, the relationship between hgpin and pca remains complex and further studies are needed to confirm our findings. key words: prostate cancer; high grade prostatic intraepithelial neoplasia; biopsy; gleason score; widespread. submitted 5 november 2012; accepted 31 january 2013 no conflict of interest declared summary undergo further biopsies (2, 8, 9). widespread hgpin, defined as ! 4 biopsy cores involved with the intraepithelial lesion, has been found to be significantly associated with pca diagnosis on further biopsy by different investigators (6, 10-15), including our group (16). other predictors of pca on a subsequent biopsy in patients with isolated hgpin, such as age, an abnormal digital rectal examination (dre), an abnormal prostate volume, psa, psa ratio or psa density values have been examined, yet no de nunzio_stesura seveso 24/06/13 10:57 pagina 59 archivio italiano di urologia e andrologia 2013; 85, 2 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro 60 consensus on their predictive role has been reached (5, 7, 14, 17). to date, the prognostic value of hgpin, clinical markers (age, digital rectal examination, psa, etc) and widespread hgpin in men after multiple diagnoses of isolated hgpin remains controversial, and little is available on long term follow-up of these patients. data confirming a positive association of widespread hgpin and pca diagnosis on repeat biopsy have already been published by our group (16). we now report the results after the third biopsy in men with two consecutive diagnoses of isolated hgpin. we explored the association of hgpin, widespread hgpin and clinical markers (age, digital rectal examination, psa, etc) and pca risk on a third biopsy, in order to elucidate the potential predictive role of hgpin on pca and further help to indentify the correct clinical management for patients with hgpin. materials and methods from november 2004 to december 2007, after receiving institutional review board approval, patients referred to our clinic with a psa ! 4 ng/ml or an abnormal digital rectal examination (dre) were scheduled for trans-rectal ultrasound (trus) guided 12-core prostate biopsy after informed consent was signed. in every patient diagnosed with hgpin, a second biopsy was proposed after 6 months regardless of psa values. finally, in patients with a second diagnosis of hgpin a third and final biopsy was proposed 6 months after the second procedure, for a total of 12 months follow-up. biopsy was performed as an outpatient procedure and the methodology has been throughout fully described in previously published peer-reviewed manuscripts (16, 18). all biopsies were performed following the same 12-core scheme. before each procedure, blood specimens were obtained and free and total psa were measured. prostate volume was calculated by trus. patients on finasteride or dutasteride and men who had undergone prostate surgery were excluded from the study. a single uro-pathologist performed the histological evaluation for all biopsy series. the histological/architectural threshold used to assign the various diagnoses was that proposed by the who (19, 20). in areas suspicious for asap or hgpin, immunohistochemical staining of sequential sections was used to confirm the eventual loss of basal cells using a mix of anti-p63 and 34"12 cytokeratin antibodies. as defined by netto and epstein, widespread hgpin was defined as 4 or more cores involved with hgpin (21). statistical analysis widespread hgpin on the second biopsy was examined as a categorical variable. the presence or absence of cancer on the third biopsy specimens defined our main categorical outcome variable. we performed chi-square test to evaluate the association between widespread hgpin on the second biopsy and the diagnosis of pca on the subsequent biopsy. crude and adjusted logistic regressions were used to evaluate the association of clinical and pathological predictors and the risk of pca on the third biopsy. however, given the small number of events in our model, we executed separate multivariate analyses for each predictor other than widespread hgpin: multivariate analyses constantly included the presence of widespread hgpin on the second biopsy (categorical) plus a second term as age, psa, trus volume, dre, psa ratio and psa density. due to non-parametrical distribution, psa values and derivates (psa ratio and density) were logarithmically transformed in the multivariate logistic regression tests. mann-whitney test was used to explore differences in age, prostate volume, psa concentration, psa ratio and psa density across our two outcome groups and between men with and without widespread hgpin at second biopsy. wilcoxon signed rank sum test was used to evaluate significant modifications of psa concentration, ratio and density between the second and third biopsy. statistical analysis was performed using stata 11 (statacorp, college station, tx). results during the study period 650 men underwent primary prostate biopsy. of these, 147 (22%) were diagnosed with hgpin. as 30 men refused further procedures, a second biopsy was performed in 117 men, six months later. data regarding the second biopsy have already been published (16). out of 117 re-biopsies, 75 (64%) yielded a second diagnosis of hgpin and to these men a third prostate biopsy was proposed, 6 months after the second biopsy. 22 of these patients refused to undergo the third biopsy and 10 underwent prostate surgery for bladder outlet obstruction; no cancer was found in any of the pathological specimens examined after surgery in these 10 patients. 43 men were therefore available for final analysis. patients characteristic are illustrated in table 1. after the third biopsy, 19 patients (44%) still showed hgpin, 15 (35%) were diagnosed with pca and 9 (21%) presented with chronic prostatitis. a flow chart (figure 1) clearly illustrates the results of the biopsies. the 10 men who underwent prostate resection for bladder outlet obstruction were all diagnosed with benign prostatic hypertrophy. median (iqr) age (yrs) 65 (61-70) prostate volume (ml) 56 (42-64) psa (ng/ml) 7.53 (5.87-10.8) psa ratio (%) 15 (12-22) psa density (ng/ml2) 0.14 (0.10-0.22) dre negative 37 (86%) positive 6 (14%) widespread hgpin at second biopsy (! 4 cores) 17/43 (40%) table 1. clinical characteristics of the cohort (43 patients). de nunzio_stesura seveso 24/06/13 10:57 pagina 60 of the 15 patients with pca, 9 had a low grade gleason 6 (3 + 3) adenocarcinoma, 4 men had a gleason 7 (3 + 4) tumor, while only one gleason 8 (4+4) and one gleason 9 (4 + 5) cancers were diagnosed. a single core was involved in 10 of the men with cancer, with a 15% median core cancer extension. of these, 7 were gleason 6 (3 + 3) and the remaining 3 were gleason 7 (3 + 4). two cores were positive for cancer in 4 patients with a median extension of 15%. in one patient, diagnosed with a gleason 8 (4 + 4), 4 cores were involved with cancer, for a maximum of 60% of their length. no significant difference in the distribution of age, psa, prostate volume, dre, psa ratio and psa density (at the time of third biopsy) was found across the two outcome groups (table 2). widespread hgpin on a second biopsy was significantly associated with pca on further biopsy (!2 = 4.04, p = 0.04) (table 2). moreover, the presence of widespread hgpin significantly predicted the risk of pca on crude logistic regression (or 3.75, 95%ci 1.00-14.02, p = 0.049). widespread hgpin remained a significant predictor of pca on all 61archivio italiano di urologia e andrologia 2013; 85, 2 widespread high grade prostatic intraepithelial neoplasia on biopsy predicts the risk of prostate cancer no cancer cancer p-value1 < 4 cores involved ! 4 cores involved p-value1 (widespread hgpin) number of patients 28 (65%) 15 (35%) ----26 (60%) 17 (40%) ----age (yrs) median (iqr) 66 (60-70) 65 (61-71) 0.86 66 (62-71) 64 (57-70) 0.30 prostate volume (ml) median (iqr) 58 (43-65) 51 (38-64) 0.31 57 (40-65) 51 (45-63) 0.80 dre negative 25 (89%) 12 (80%) 0.402 22 (85%) 15 (88%) 0.742 positive 3(11%) 3 (20%) 4 (15%) 2 (12%) psa (ng/ml) median (iqr) 6.86 (5.66-9.3) 8.84 (6.75-13.5) 0.14 7.8 (5.88-11.7) 6.86 (5.87-8.89) 0.39 psa ratio (%) median (iqr) 16 (12-24) 15 (10-19) 0.27 16 (12-25) 15 (12-20) 0.72 psa density (ng/ml2) median (iqr) 0.13 (0.10-0.21) 0.15 (0.1-0.26) 0.24 0.145 (0.10-0.23) 0.14 (0.10-0.18) 0.57 widespread hgpin 8/28 (29%) 9/15 (60%) 0.042 ----------prostate cancer ----------6/26 (23%) 9/17 (53%) 0.042 table 2. clinical and pathological differences across groups. figure 1. study design. 1 mann-whitney test. 2 !2 test. de nunzio_stesura seveso 24/06/13 10:57 pagina 61 archivio italiano di urologia e andrologia 2013; 85, 2 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro 62 epstein as ! 4 cores involved with hgpin (21). this pathological entity has been positively associated with a significantly increased risk of pca in numerous studies (6, 7, 10-14, 16), ranging from 36% to 39%. to date only few studies (12, 14, 22-25) have explored the risk of cancer following multiple biopsies (> 2 procedures) diagnosing hgpin; moreover only two manuscripts have examined the cancer risk at third biopsy after diagnosing multiple cores involved with hgpin on a second prostate biopsy (12, 14). in this manuscript we addressed this issue by conducting a prospective trial with a minimum 12 month follow-up, during which men with two consecutive diagnoses of hgpin underwent a third prostate biopsy. widespread hgpin on the second biopsy was significantly associated with the risk of pca. no clinical parameter such as age, dre, prostate volume, psa, psa density or psa ratio was able to significantly predict cancer. if validated, these results strengthen the prognostic value of widespread hgpin, with impact on the need for further oncologic surveillance in patients with such diagnosis. we found a significant association between widespread hgpin on second biopsy and pca (!2 = 4.04, p = 0.04), and men with widespread hgpin had a 4-fold, significant increase in risk of detecting pca on subsequent biopsy compared to men with 3 or less cores involved with hgpin. the overall cancer risk on the third biopsy for men with widespread hgpin on second prostate biopsy was 53%, higher that the risk if widespread was present at the time of the first biopsy (36-39% risk). in line with these findings are the results reported by bishara et al, who found a 50% cancer risk if multiple cores (! 2) involved with hgpin had been found on second biopsy (12). abdel-khaled et al. reported a similar 58% risk in patients with multifocal hgpin (14). whether these results justify the need to perform an early re-biopsy (6 months) in patients with widespread hgpin at the second biopsy cannot be fully determined by our data. however we feel that repeat biopsy should be advised after diagnosing widespread hgpin on second biopsy, after adequately counseling patients on the risks and benefits of undergoing further prostate biopsies. moreover, we explored the prognostic value of other clinical and laboratory parameters on pca. all parameters measured, including age, prostate volume, dre, psa, psa ratio psa density were not significant predictors of pca on subsequent biopsy. most studies have yielded similar results (5, 26-29), in that there does not appear to be any clinical parameter that helps identify men who are more likely to have cancer on further biopsies. given these results, a finding of widespread hgpin, especially on second biopsy, may be crucial in planning patients’ future follow-up and should draw the urologist’s attention, as it appears to be a significant predictor of pca on further testing. of the neoplasms diagnosed on the third biopsy of our cohort, 9/15 (60%) were low-grade, gleason 6 (3 + 3), 7 of which showed a single core, 10-15% core involvement. thus, 7/15 (47%) of the tumors identified are probably clinically insignificant and of 43 biopsies only 6 men had pca with gleason score ! 7. it could be argued multivariate models (all p < 0.05). all clinical parameters evaluated, such as age, psa, dre, prostate volume and psa ratio were not significant predictors of cancer at the time of the third prostate biopsy (table 3). no significant differences in age, prostate volume, dre, psa, psa ratio and psa density were found between men with and without widespread hgpin (table 2). psa concentration was not significantly modified between the second and third biopsy (median [iqr]: 7.83 [5.3410.50] vs. 7.53 [5.87-10.80], p = 0.34). the presence or absence of widespread hgpin on the second biopsy did not significantly differ across patients with chronic prostatitis and patients with hgpin on third biopsy (p = 0.12). finally, of the 43 patients who underwent the full set of three biopsies, 12 had a diagnosis of widespread hgpin at the time of the first biopsy. of these, 9 (75%) were rediagnosed with widespread hgpin on the second biopsy, while the remaining 3 (25%) had focal hgpin at that time. cancer was found on third biopsy only in the first 9 patients (those with widespread lesions on both biopsies, in particular in 5 of these 9 men (56%), while none of the 3 patients with widespread hgpin only on the first biopsy had a diagnosis of pca on the third biopsy. discussion hgpin is a common pathological finding on prostate biopsy and has been associated with an increased risk of pca on subsequent biopsies (3-6, 9). initially this risk was estimated around 50% (4), however studies performed after 2000, in the era of extended prostate biopsy, have shown that this risk is approximately 23%, compared to a 19% risk of detecting cancer after a benign diagnosis (2). the impact of hgpin on the need for further biopsies has thus been redimensioned, and numerous studies have explored pathological features of hgpin in order to predict pca on subsequent biopsies (2, 21). in this context, the denomination of widespread or multifocal hgpin has arisen, defined by netto and or 95% ci p-value widespread hgpin 3.75 1.00-14.02 0.04 age 1 1.04 0.93-1.15 0.51 psa 1, 2 3.98 0.83-19.02 0.08 prostate volume 1 1.00 0.97-1.04 0.81 dre 1 2.53 0.39-16.19 0.98 psa ratio 1, 2 0.37 0.10-1.35 0.13 psa density 1, 2 2.89 0.84-9.94 0.09 table 3. multivariate logistic regressions: exploring the risk of prostate cancer on third biopsy. 1 due to the small number of events separate regressions were performed, adding each single term to the initial model with our main predictor variable (widespread hgpin) (see text). 2 psa, psa ratio and psa density were log-transformed due to non-parametrical distribution. de nunzio_stesura seveso 24/06/13 10:57 pagina 62 therefore that performing a third biopsy in men all with two diagnoses of hgpin it may not be legitimate, as too many biopsies should to be performed to find one clinically significant cancer. however, if we restrict the analysis to patients with widespread lesions on second biopsy (17 men of 43), 9 tumors were identified, of which 4 were gleason ! 7. as such, 17 men underwent prostate biopsy to uncover 4 clinically significant high-grade cancers: these results in four men being biopsied to find one clinically significant cancer (4:1). these results suggests that, if not all men with two hgpin biopsies should undergo further procedures, it may be appropriate to perform a repeat biopsy in men with widespread lesions on the second biopsy specimens, in order to uncover clinically significant prostate cancer. it is correct to point out some limitations of this study as the small sample size (n = 43). given the singularity of this group of patients, as it represents a second subset group of our initial study population, we believe that these results express the impact that widespread hgpin on pca. 10 patients who underwent prostate resection for bladder outlet obstruction were excluded from final analysis: given the different accuracy in pca detection of trus-guided prostate biopsy vs. histologic analysis of resected specimen during transurethral prostatic surgery, we feel that such exclusion is justified (30). the follow-up period was limited to 12 months, time elapsed between the first and third biopsy: such period of time may seem inappropriate to evaluate the evolution of hgpin on pca, but patients are still under evaluation and the results of biopsies performed at 24 months will be soon available. moreover, a significant number of patients failed to return for rebiopsy and unfortunately data on their follow-up was not available for analysis: however, if we consider these drop outs to be random, the results of this study should not have been significantly biased by such loss of data. this finding underlines the importance of patient follow-up after a diagnosis of hgpin (3). nevertheless, we must acknowledge that our study firstly confirmed in a homogeneous population that widespread hgpin is associated with a significant higher risk of pca even in patients with two previous biopsies. furthermore another peculiar characteristics of our group is that our patients underwent three prostate biopsies in 12 months time regardless of psa value, using the presence of hgpin a mandatory indication for prostate biopsy. the lower cancer detection rate on initial biopsy and the high incidence of multiple isolated hgpin areas may depend on our study population: our academic hospital operates under the italian national care system which does not support screening programs for pca. furthermore, our clinical facility opened in 2002, and we can assume that our patient population had limited access to pca centers and screening programs in the past. conclusions the results of our study suggest that hgpin and in particular widespread hgpin are associated with an increased risk of pca on a repeat biopsy in men with two previous diagnoses of hgpin. no clinical parameter evaluated such as age, psa, prostate volume, dre and psa derivates was able to significantly predict pca in this particular group of patients. further studies are needed to confirm these findings in other populations and to evaluate which possible biological factors related to widespread hgpin are responsible for the observed results. references 1. montironi r, mazzucchelli r, lopez-beltran a, et al. prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance bju int. 2011; 108:1394-401. 2. epstein ji, herawi m. prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci 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md acicione@libero.it costantino leonardo, md costantino.leonardo@gmail.com francesco esperto, md francescoesperto@gmail.com andrea tubaro, md department of urology, ospedale sant’andrea, università “la sapienza” via di grottarossa 1035 00198 roma, italy mauro gacci, md department of urology, ospedale careggi, università di firenze largo brambilla 3 50134 firenze, italy maurogacci@yahoo.it 64 c. de nunzio, s. albisinni, a. cicione, m. gacci, c. leonardo, francesco esperto, a. tubaro archivio italiano di urologia e andrologia 2013; 85, 2 16. de nunzio c, trucchi a, miano r, et al. the number of cores positive for high grade prostatic intraepithelial neoplasia on initial biopsy is associated with prostate cancer on second biopsy j urol. 2009; 181:1069-74; discussion 1074-5. 17. raviv g, janssen t, zlotta ar, et al. prostatic intraepithelial neoplasia: influence of clinical and pathological data on the detection of prostate cancer j urol. 1996; 156:1050-4; discussion 1054-5. 18. de nunzio 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[epub ahead of print]. 19. sakr wa d. m. a., montironi r, humphrey, et al. prostatic intraepithelial neoplasia in: who classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon, france: iarc press. 2004; 193:198. 20. epstein ji hb, algaba f, humphrey pa, et al. acinar adenocarcinoma in: who classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. edited by jn eble, g sauter, ji epstein and ia sesterhenn. lyon, france: iarc press. 2004; 162-192. 21. netto gj, epstein ji. widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma am j surg pathol. 2006; 30:1184-8. 22. goeman l, joniau s, ponette d, et al. is low-grade prostatic intraepithelial neoplasia a risk factor for cancer? prostate cancer prostatic dis. 2003; 6:305-10. 23. gokden n, roehl ka, catalona wj, humphrey pa. high-grade prostatic intraepithelial neoplasia in needle biopsy as risk factor for detection of adenocarcinoma: current level of risk in screening population urology. 2005; 65:538-42. 24. moore ck, karikehalli s, nazeer t, et al. prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era j urol. 2005; 173:70-2. 25. park s, shinohara k, grossfeld gd, carroll pr. prostate cancer detection in men with prior high grade prostatic intraepithelial neoplasia or atypical prostate biopsy j urol. 2001; 165:1409-14. 26. kamoi k, troncoso p, babaian rj. strategy for repeat biopsy in patients with high grade prostatic intraepithelial neoplasia j urol. 2000; 163:819-23. 27. postma r, roobol m, schroder fh,van der kwast t. h. lesions predictive for prostate cancer in a screened population: first and second screening round findings prostate. 2004; 61:260-6. 28. roscigno m, scattoni v, freschi m, et al. monofocal and plurifocal high-grade prostatic intraepithelial neoplasia on extended prostate biopsies: factors predicting cancer detection on extended repeat biopsy urology 2004; 63:1105-10. 29. langer je, rovner es, coleman bg, et al. strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy j urol. 1996; 155:228-31. 30. jones js, follis hw, johnson jr. probability of finding t1a and t1b (incidental) prostate cancer during turp has decreased in the psa era prostate cancer prostatic dis. 2009; 12:57-60. de nunzio_stesura seveso 24/06/13 10:57 pagina 64 stesura seveso introduction the bacterial adhesiveness to the bladder walls is important virulence factor in the pathogenesis of urinary tract infections. the development of a biofilm that prevents bacterial adhesion plays an important role in prophylaxis of recurrent urinary tract infections (utir). aim of this study is to evaluate the efficacy of a phytotherapic which includes solidago, orthosiphon and birch extract (cistimev®) in association with the antibiotic prophylaxis in female patients affected by (utir) materials and methods all the female patients affected by utir who referred to our urogynaecological unit between september 2010 and 197archivio italiano di urologia e andrologia 2013; 85, 4 original paper role of phytotherapy associated with antibiotic prophylaxis in female patients with recurrent urinary tract infections emanuela frumenzio, daniele maglia, eleonora salvini, silvia giovannozzi, manuel di biase, vittorio bini, elisabetta costantini clinica urologica e andrologica di perugia, università degli studi di perugia, italy objective: aim of this study is to evaluate the efficacy of a phytotherapic which includes solidago, orthosiphon and birch extract (cistimev®) in association with antibiotic prophylaxis in female patients affected by recurrent urinary tract infections (utir). materials and methods: patients affected by utir older than 18 years started a 3-months antibiotic prophylaxis (prulifloxacin 600 mg, 1 cps/week or phosphomicyn 1 cachet/week) according to antibiogram after urine culture. the patients were divided in 2 groups: group a: antibiotic prophylaxis plus phytotherapy (1 cps/die for 3 months) and group b: antibiotic prophylaxis alone. results: 164 consecutive patients were studied: 107 were included in group a (mean age 59 ± 17.3 years) and 57 (mean age 61 ± 15.7) in group b. during the treatment period the relapse frequencies between the two groups were not significantly different (p = 0.854): 12/107 (11.21%) patients interrupted the treatment for utir in group a and 6/57 (10.52%) in group b. in the long term follow-up the relapse uti risk was significant different in the two groups with a relapse risk 2.5 greater in group b than in group a (p < 0.0001). conclusion: our study demonstrated that in female patients affected by recurrent uti, the association between antibiotic prophylaxis and of a phytotherapic which includes solidago, orthosiphon and birch extract reduced the number of uti in the 12 months following the end of prophylaxis and obtained a longer relapsing time, greatly improving the quality of life of the patients. key words: recurrent urinary infection; phytotherapy; antibiotc prophylaxis. submitted 28 february 2013; accepted 30 april 2013 no conflict of interest declared summary january 2012 were included in a retrospective study comparing antibiotic prophylaxis alone or combined with solidago, birch e ortosiphon (cistimev®). utir was defined as at least three episodes of uncomplicated infection documented by urine culture (eau guidelines) (1). paatients affected by utir older than 18 years started a 3-months antibiotic prophylaxis (prulifloxacin 600 mg, 1 cps/week or phosphomicyn 1 cachet /week) according to antibiogram after urine culture. the patients were divided in 2 groups: group a: antibiotic prophylaxis plus phytotherapy (1 cps/die for 3 months) and group b: antibiotic prophylaxis alone. exclusion criteria were patients with less than three doi: 10.4081/aiua.2013.4.197 archivio italiano di urologia e andrologia 2013; 85, 4 e. frumenzio, d. maglia, e. salvini, s. giovannozzi, m. di biase, v. bini, e. costantini 198 uncomplicated utis in the previous year; significant (> 50 ml) residual urine; pregnancy; intolerance or allergy to drug compounds, pelvic organ prolapse more than stage ii (pop-q quantification). all patients were assessed by history, clinical examination, urine culture, uroflowmetry parameters and postvoid residual volume evaluation. the patients in both groups were followed-up with urine analysis and urine culture during the treatment every month and after the end of therapy at 3, 6 and 12 months. primary outcome was the efficacy in preventing infection recurrences during the treatments and the evaluation of uti relapse risk in the year after the end of therapy in both groups. statistical analysis: chi2 test was used for comparisons of categorical variables; kaplan-meier estimation with logrank test was applied to compare the relapse-free survival time in both groups. results 164 consecutive patients were studied: 107 were included in group a (mean age 59 ± 17.3 years) and 57 (mean age 61 ± 15.7) in group b. both groups were equivalent: there were no statistically significant difference, as regards the type of antibiotic chosen (prulifloxacin or phospho micyn), menopausal status, sexual activity, urinary incontinence and residual urine (table 1). no patients reported side effects in both groups. during the treatment the relapse frequencies between the two groups were not significantly different (p = 0.854): 12/107 (11.21%) patients interrupted the treatment for utir in group a and 6/57 (10.52%) in group b. in the long term follow-up the relapse uti risk was significant different in the two groups with a relapse risk 2.5 greater in group b than in group a (p < 0.0001). the survival curves (figure 1) demonstrated that 25% of patients that underwent the antibiotic prophylaxis plus phytotherapy had no recurrence at 1 year, while all the patients in group b had at least one recurrence within 1 year. it is also evident that the time to recurrence is always longer in group a, in fact the mean survival time was 10.4 months in group a and 3.6 months in group b (log-rank test p < 0.0001) discussion a major problem today in public health economy is the increase in multi-resistant micro-organisms in patients with recurrent cystitis. new therapeutic and behavioural strategies are needed to prevent recurrences. using drugs based on natural substances which are free of side effects may have a place in the armentarium for these very hard to treat patients. figure 1. kaplan-meier survival analysis. table 1. group a group b p antibiotic prophylaxis 55/107(51.4%) pts 52/107(48.6%) pts 29/57(50.9%) pts 28/57 (49.1%) pts prulifloxacin phosphomicyn prulifloxacin phosphomicyn < 0.540 sexual activity 62/107(57.9%) pts 45(42.1%) pts 30/57 (52.6%) pts 27/57 (47.4%) pts sexual activity no sexual activity sexual activity no sexual activity <0.312 menopause 72/107(67.3%) pts 35/107 (32.7%) pts 44/57(77.2%) pts 13/57 (22.8%) pts menopause no menopause menopause no menopause < 0.125 incontinence 56/107(52.3%) pts 51/107 (47.7%) pts 36/57 (63.2%) pts 21/57 (36.8%) pts incontinence no incontinence incontinence no incontinence < 0.122 survival plot (pl estimates) antibiotic prophylaxis has been reported to prevent recurrent episodes for as long as it is continued, with uti usually recurring as soon as it is suspended (2). when antibiotics are combined with drugs that inhibit bacterial adhesion it appears that the dose can be reduced and recurrences are not as frequent. the present study demonstrates that long-term results are better with a drop in the number of recurrences after prophylaxis was suspended. conclusions our study demonstrated that in female patients affected by recurrent uti, the association between antibiotic prophylaxis and cistimev® reduced the number of uti in the 12 months following the end of prophylaxis and obtained a longer relapsing time, greatly improving the quality of life of the patients. references 1. naber kg, bergman b, bishop mc, at all. eau guidelines for the management of urinary and male genital tract infections. urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau); urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau). eur urol. 2001; 40:576-88. 2. costantini e, salvini e, lazzeri m, et al. prulifloxacin vs phosphomycin: prophylaxis in patients with recurrent uti. preliminary results of a randomized multi-centre study. eur urol 2011; (suppl 10):480. 199archivio italiano di urologia e andrologia 2013; 85, 4 role of phytotherapy associated with antibiotic prophylaxis in female patients with recurrent urinary tract infections correspondence emanuela frumenzio, md (corresponding author) emanuela.frumenzio@virgilio.it daniele maglia, md eleonora salvini, md silvia giovannozzi, md manuel di biase, md vittorio bini, md elisabetta costantini, md clinica urologica e andrologica di perugia, università degli studi di perugia, perugia, italy stesura seveso 393archivio italiano di urologia e andrologia 2014; 86, 4 case report perivascular epithelioid cell tumor (pec-ome) of the prostate: ultrasound feature in case report giulia sbrollini 1, 2, alessandro conti 1,2, andrea benedetto galosi 1, vito lacetera 2, rodolfo montironi 3, lorenzo montesi 2, giovanni muzzonigro 2 1 department of urology, “augusto murri” general hospital, asur marche, fermo, italy; 2 institute of urology, ospedali riuniti, politechnic university of the marche, ancona, italy; 3 institute of pathology, ospedali riuniti, politechnic university of the marche, ancona, italy. introduction: we describe a rare tumor arising from the prostate gland: perivascular epithelioid cells tumor (pec-ome). a 54-years old was treated for acute urinary retention with alpha-blockers at presentation due to benign prostate enlargement (65 cc) with asymmetric middle lobe and regular psa (0.92 ng/ml). after 5 months, patient developed a second acute urinary retention episode and nodules in the left lung; he was treated with transurethral resection of the prostate and left lobectomy. results: histological examination of prostate and lung tissue gave the same diagnosis: leiomyosarcoma with atypical morphological features and patient was observed for 4 months. considering the uncommon diagnosis, pathological review by the uro-pathologist at our hospital was done. additional immunohistochemistry was done and both tumors showed similar and typical features of metastatic pec-ome (t1b n0 m1). therefore a new staging showed local and distant progression with prostatic mass and small lung metastasis. three cycles of gemcitabine and pazopanib were administered, but 2 months later a new urinary retention occurred, despite chemotherapy. patient referred to our hospital for salvage pelvic surgery with lymph node dissection. final pathological diagnosis was pecome of the prostate stage pt4 pn0 r0 m1. conclusions: pec-ome is a rare but rapidly invasive mesothelial tumor with early metastatic potential. when this tumors originates from the fibromuscular stroma of the prostate it mimics benign prostatic enlargement and causes luts. expert pathology aided by immunoisthochemistry is the cornerstone of diagnosis. there are no pathognomonic imaging on ultrasound or symptoms suggesting the presence of pecome in early stage. a multidisciplinary approach is necessary and radical surgery should be done to treat this aggressive cancer. key words: perivascular epithelioid cell neoplasms; ultrasound; prostate neoplasms; diagnosis; surgery. submitted 3 october 2014; accepted 31 october 2014 summary no conflict of interest declared. introduction perivascular epithelioid cell tumor (pec-ome) is a peri vascular epithelioid neoplasia, that is a mesothelial tumor (1-3). introduction, figures and conclusions are posted are posted in supplemmentary materials on www.aiua.it case presentation we describe a case of a 53-yrs old man affected by pecoma of the prostate, presented with lung metastasis at the diagnosis. the patient was first hospitalized in december 2012 for an episode of acute urinary retention after a period of dysuria, nocturia and urinary symptoms. a urinary catheter was placed for a week. chest xray and renal ultrasonography performed at admission were negative. trus highlighted an increased prostate volume, not homogeneous ultrasound pattern with two solid nodular formations of 24 mm, compatible with benign hyperplasia of the middle lobe, with large periurethral and parenchymal calcifications. the posterior profile of the gland, as well as the structure of the seminal vesicles appeared regular. psa was always normal (psa tot = 0.9 ng/ml; psa free = 0.2 ng/ml). four months later a second episode of acute urinary retention occurred and endoscopic transurethral resection of the prostate (turp) was performed. preoperative chest x-ray emphasized the presence of a rounded lung opacity, confirmed by contrast-enhanced computed tomographyb (ct), that documented an ovoidshape solid nodule, with sharp margins (40 mm) and contemporary similar small imagines, bilaterally. histological analysis of the resected prostatic tissue showed cellular proliferation of partly spindled epithelioid elements with clear cytoplasm, marked irregular atypias, necrotic areas with high mitotic index with atypical mitoses. ihc staining showed positivity for muscle-specific and connective tissue markers as desmin, caldesmonin, calponin, smooth-muscle actin and vimentine, orienting the diagnosis to a grade iv leiomyosarcome. nevertheless, contemporary positivity for some epithedoi: 10.4081/aiua.2014.4.393 presented at 19th national congress sieun, fermo 2014 sbrollini_stesura seveso 16/01/15 11:56 pagina 393 archivio italiano di urologia e andrologia 2014; 86, 4 g. sbrollini, a. conti, a.b. galosi, v. lacetera, r. montironi, l. montesi, g. muzzonigro 394 lial markers as citokeratin 18, cam5.2, ema, as far as cd10 posed the differential diagnosis with a metastasis of sarcomatoid clear cell renal cell carcinoma. after a total body positron-emission tomography (pet)ct scan that confirmed the metabolically active nature of the nodule (suv max 5.38) and the thoracic surgeon performed in a left lower pulmonary lobectomy. histological examination of pulmonary mass showed a tumor with large cells characterized from a clear cytoplasm, severe atypical cyto-morphology and high mitotic activity. in consideration of the similarities between the two pathological features, the urologist submitted the case along with the respective histological samples (lung and prostate) to an expert uro-pathologist (rm), who confirmed the morphological and ihc similarity between pulmonary and prostatic lesions, with the constant presence of cells with clear cytoplasm and polymorphic nuclei and, to a lesser degree, of spindle cells. the prostate specimen showed an infiltrative appearance of the tumor, with a ihc positivity for smooth muscle–specific actin, focal hmb45 and melana, as well as positivity for tfe3 (figure 1). it leads to the definitive confirmation of the diagnosis of pec-ome with prostatic and pulmonary localization at the onset, t1b n0 m1. molecular study of the specimens, performed at the john hopkins institute, permitted to further support tumor identification. staging total body ct scan, after 4 months without treatment, showed an increase in the number and size of some of the pulmonary lesions and some lymph nodes enlargements in the mediastinum (max: 1.1 cm). the residual prostate appeared increased in size, elevating the bladder floor. it finally ruled out the renal nature of the tumor. after oncological evaluation, indication to 3 cycles chemotherapy (ctx) with gemcitabine was given. two months ct scan, during ctx treatment, showed progression with solid tissue of the prostate (7 x 5.4 cm) projecting into the lumen of the bladder. prostate tissue appeared to be infiltrating the bladder walls. all the documentation of the case was sent for counseling to the national referring center for tumors (irccs, milano, director roberto salvioni). considering also the discomfort associated with the presence of the indwelling bladder catheter, it was held for reasonable to propose the patient an intervention of cystoprostatectomy. the patient was then referred to our hospital for cystoprostatectomy with extended lymphadenectomy. a control trus performed preoperatively, confirmed, in b mode, dyshomogeneous periurethral tissue, with diffuse calcifications and a hypo-anechoic nodular formation of the anterior portion of the prostate. the margins in the peripheral zone of the gland were apparently safe, failing to show any sonographic signs of infiltration of the pelvic structures surrounding the bladder (figure 2-a). the power-doppler mode let us see a massive vascularization, with the presence of a central artery, going from the apex of the prostate to the bladder neck, spraying the tumor mass itself (figure 2-b). the postoperative course was uneventful. the definitive histological examination confirmed the diagnosis of prostate pec-oma, infiltrating the bladder, pt4 pn0 r0 m1. the surgical margins and all the 39 lymph nodes removed were free from the tumor. complementary therapy with pazopanib was then performed. in the diagnosis of malignant prostate tumors, a series of diseases with extremely low incidence but significantly unfavorable prognosis should be considered in addition to the most common histology of adenocarcinoma. although the initial diagnostic path is difficult, imaging techniques, if properly interpreted, can provide elements that address the clinical suspicion of an unusual variant. nevertheless, a final guideline is still missing and the possibility of early treatment is left to the skill and intuition of the clinician and the expertise of the pathologist. references 1. vang r, kempson rl. perivascular epithelioid cell tumor ('pecoma') of the uterus: a subset of hmb-45-positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. am j surg pathol. 2002; 26:1-13. 2. folpe al. neoplasms with perivascular epithelioid cell differentiation (pecomas). in: fletcher cdm, unni kk, epstein j, mertens f (eds) pathology and genetics of tumours of soft tissue and bone. series: who classification of tumours. iarc press, lyon, 2002; pp 221–222. 3. martignoni g, pea m, reghellin d, et al. pecomas: the past, the present and the future. virchows arch. 2008; 452:119-132. correspondence giulia sbrollini, md, resident in urology (corresponding author) giuliasbrollini@libero.it alessandro conti, md, urologist alessandro.conti@hotmail.com vito lacetera, md lorenzo montesi, md, resident in urology lorenzomontesi@yahoo.it giovanni muzzonigro, md, urologist g.muzzonigro@univpm.it rodolfo montironi, md, pathologist r.montironi@univpm.it aou united hospitals polytechnic university of marche region, ancona, italy andrea benedetto galosi, md, urologist galosiab@yahoo.it department of urology, “augusto murri” general hospital, asur marche, fermo, italy sbrollini_stesura seveso 16/01/15 11:56 pagina 394 archivio italiano di urologia e andrologia 2018; 90, 4276 original paper low-intensity shock wave therapy for erectile dysfunction and the influence of disease duration pedro simoes de oliveira, tiago ribeiro de oliveira, álvaro nunes, francisco martins, tomé lopes sci-centro de urologia, lisbon, portugal. objective: low-intensity shock-wave treatment (liswt) is a therapy for erectile dysfunction (ed) with good results reported in the literature. the aim of this study was to evaluate the results of liswt on patients treated for ed and the influence of ed duration in treatment outcomes. material and methods: we performed an open-label single-arm prospective study of patients treated with liswt for ed. patients were assessed with the iief-5 at baseline and at six weeks and three months after liswt, and with penile dynamic doppler ultrasound before treatment and six weeks after. patients were divided into two groups accordingly to ed evolution time: ≤ 24 months and > 24 months. results: twenty-five patients were enrolled, 13 had ed ≤ 24 months and 12 > 24 months. median baseline iief-5 was 14, at 6 weeks post liswt was 16 (p < 0.001) and at 3 months post liswt was 18 (p < 0.001). mean baseline peak systolic velocity (psv) was 29.3 ± 13.0 cm/s, after liswt was 35.9 ± 15.2 cm/s (p 0.001). mean baseline end-diastolic velocity (edv) was 2.6 ± 4.8 cm/s and after liswt was 1.3 ± 4.3 cm/s (p 0.015). no statistical significative difference was identified between the two groups. conclusions: liswt is a safe, harmless and repeatable treatment tool for ed with good outcomes reported. our results suggest that length of disease duration doesn´t negatively influences treatment results. key words: erectile dysfunction; penis; shock wave therapy; time-to-treatment; treatment outcome. submitted 4 october 2018; accepted 15 november 2018 summary no conflict of interest declared. and, therefore improvement in erectile function (3). published studies have different samples, different protocols and different inclusion criteria. there is still no evidence of which patient is the best candidate for liswt. the aim of our study was to evaluate the results of liswt on patients treated for ed and looking for cofounding factors that could influence treatment outcomes, specially duration of ed. materials and methods we performed an open-label single-arm prospective study of all patients who underwent liswt for ed, at a single center from june 2016 to march 2018. patients were assessed with the simplified international index of erectile function (iief-5) before starting the treatment and at six weeks and three months after. assessment included also penile dynamic doppler ultrasound (pddu) before treatment and six weeks after. inclusion criteria included, age over 18 years-old, a total iife-5 score < 22, no psychiatric disturbance and no active skin lesion at the treatment site. treatment was performed using the piezowave2 (richard wolf gmbh, knittlingen, germany) device with a linear probe. treatment protocol included a weekly session for six weeks. each session delivered 2000 shocks on the perineum plus 2000 shocks on dorsum penis with an energy flux density (efd) of 0.160 mj/mm2. during treatment every patient had tadalafil 5 mg daily. patients were divided into two groups accordingly to ed evolution time, defined by time-to-treatment since the beginning of symptoms: ≤ 24 months (group 1) and > 24 months (group 2). other analyzed variables included, age, type of ed (arteriogenic, arteriogenic + venous leak, post radical prostatectomy and, venous leak), ed risk factors and pde5i treatment necessity and response. an increase in the iief-5 after liswt was considered “improvement”. regarding pddu, an increase in peak systolic velocity (psv) and/or decrease in end-diastolic velocity (edv) after liswt was considered “improvement”. regarding pde5i treatment, “improvement” was defined when a patient previously on pde5i, was able to leave medication. “improvement” in pdei5 response was considered whenever a patient subjectively improved the response to medication after liswt considering three categories: “good”, “moderate” and “bad”. doi: 10.4081/aiua.2018.4.276 introduction erectile dysfunction (ed) is a common condition affecting more than 50% of men aged 40-70 years (1). available treatments include phosphodiesterase type 5 inhibitors (pde5i), vacuum devices, topical, intraurethral or intracavernosal, administration of vasoactive agents or, in the most severe cases, penile prosthesis. although many patients are satisfied with these treatments, others are not, due to poor response or impossibility of using them. low-intensity shock wave therapy (liswt) is another available first line therapy for ed. since vardi et al. (2) first described its use on ed, several reports have been published with encouraging results. although the mechanism of action is poorly understood, it is suggested that liswt can induce neovascularization, anti-inflammation and tissue regeneration leading to structural changes de oliveira_stesura seveso 10/01/19 16:09 pagina 276 277archivio italiano di urologia e andrologia 2018; 90, 4 low-intensity shock wave therapy the primary endpoint was any observed change in iief-5 and pddu associated with liswt and comparing results between groups 1 and 2 regarding the influence of disease duration in treatment response. the secondary endpoint was to evaluate the response to treatment with pde5i associated with liswt and comparing results between groups 1 and 2. also, liswt results were evaluated accordingly with ed type and risk factors. adverse events, patient satisfaction and recommendation were also assessed. clinical data was analyzed using ibm spss statistics, version 24.0 (ibm corp., armonk, ny, usa). descriptive statistics were reported as frequencies for categorical variables and, mean, median (first quartile third quartile) and standard deviation for continuous variables. comparison between pre-treatment and posttreatment and between groups 1 and 2 results was performed using the wilcoxon signed-rank test. χ2-test (two-sided pearson χ2-test with two degrees of freedom) was used between iief-5, pddu, pde5i, ed type and ed risk factors. fisher's exact test was used when the expected frequency was of five or less. statistical significance was considered for p values < 0.05. results twenty-five patients were enrolled, 13 had ed ≤ 24 months (group 1) and 12 > 24 months (group 2). fifteen patients had arteriogenic ed, four arteriogenic and venous leak ed, three post-radical prostatectomy ed and, three venous leak. median age was 61 years-old (range: 27-73). patient demographics are described in table 1. table 2 shows the results of the total study sample. median baseline iief-5 was 14, at 6 weeks post liswt was 16 (p < 0.001) and at 3 months post liswt was 18 (p < 0.001), with an improvement of 68% and 72% respectively. mean baseline psv was 29.3 ± 13.0 cm/s, after liswt was 35.9 ± 15.2 cm/s (p 0.001) representing an 84% improvement. mean baseline edv was 2.6 ± 4.8 cm/s, after liswt was 1.3 ± 4.3 cm/s (p 0.015) representing an 68% improvement. there was no significative result in pde5i treatment, nevertheless, pde5i response had an improvement of 36% (p 0.004). tables 2a and 2b show the specific results of group 1 and group 2 respectively and separately. table 1. patient demographics. total number 25 patients total 13 patients ed ≤ 24 months 12 patients ed > 24 months age at liswt (years) median (range) total 61 (27-73) ed ≤ 24 months 56 (42-73) ed > 24 months 62.5 (27-73) ed type n (%) n (%) n (%) total ed ≤ 24 months ed > 24 months arteriogenic 15 (60) 9 (69) 6 (50) arteriogenic + venous leak 4 (16) 1 (8) 3 (25) post-radical prostatectomy 3 (12) 2 (15) 1 (8) venous leak 3 (12) 1 (8) 2 (17) ed risk factors n (%) n (%) n (%) total ed ≤ 24 months ed > 24 months hypertension 16 (64) 8 (62) 8 (67) dyslipidemia 15 (60) 8 (62) 7 (58) diabetes 7 (28) 5 (39) 2 (17) tobacco 5 (20) 4 (31) 1 (8) obesity 8 (32) 5 (39) 3 (25) ed evolution time median (months) range (months) total 24 5 192 ed ≤ 24 months 18 5 24 ed > 24 months 66 30 -192 liswt: low-intensity shock wave therapy; ed: erectile dysfunction. table 2. results. iief-5 summary statistics pre-liswt 6 weeks post-liswt p value 3 months post-liswt p value min-max 5-21 5-24 5-25 median (iqr) 14 (10.0-16.5) 16 (11.0-20.5) *< 0.001 18 (11.5-22) *< 0.001 mean ± sd 13.3 ± 4.9 15.6 ± 5.9 16.6 ± 6.3 improvement % (n) 68.0 (17) 72.0 (18) penile dynamic duplex ultrasound summary statistics psv psv p value edv edv p value pre-liswt post-liswt pre-liswt post-liswt min-max 4,7-59.2 8.0-70.0 -6.0-13.8 -7.3-8.0 median (iqr) 27.4 31.6 *0.001 2.1 2.6 *0.015 (21.0-32.4) (27.2-42.1) (-0.9 -6.3) (-2.2 -4.9) mean ± sd 29.3 ± 13.0 35.9 ± 15.2 2.6 ±4.8 1.3 ± 4.3 improvement % (n) 84.0 (21) 68.0 (17) pde5i treatment pre-liswt % (n) post-liswt % (n) p value yes 72.0 (18) 52.0 (13) 0.063 no 28.0 (7) 48.0 (12) improvement % (n) 20.0 (5) pde5i response pre-liswt % (n) post-liswt % (n) p value good 16.0 (4) 20.0 (5) moderate 32.0 (8) 20.0 (5) *0.004 bad 24.0 (6) 12.0 (3) improvement % (n) 36.0 (9) iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; iqr: interquartile range; sd: standard deviation; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 de oliveira_stesura seveso 10/01/19 16:09 pagina 277 archivio italiano di urologia e andrologia 2018; 90, 4 p. simoes de oliveira,t. ribeiro de oliveira, á. nunes, f. martins, t. lopes 278 table 3 shows the results of the total study sample accordingly with type of ed. statistical significance was seen only in the iief-5 at 6 weeks after liswt, presenting the best response patients with arteriogenic and/or venous leak ed (p 0.021). table 4 shows the results of the total study sample accordingly with ed risk factors. statistical significance was seen in the pde5i response improvement, where diabetic patients presented the worse response (p 0.027). table 5 compares the results and treatment improvement between the two groups. no statistical significative difference was identified beside a better pde5i response in patients with ed > 24 months. at the end of the study, overall patient satisfaction with liswt was 76% and, 80% of patients would recommend it (table 6). no adverse effect was reported. discussion ed is a common medical condition and epidemiological data have shown a high incidence and prevalence worldwide (1). this greatly disseminated and progressive condition has great impact in patient´s quality of life and it´s no wonder efforts have been made in order to find a successful treatment. although the true mechanism of action is not well understood, according to basic science evidences it can be hypothesized that liswt may act by several pathways leading to cell proliferation, angiogenesis, nerve regeneration and anti-inflammation (3). it is theorized that energy carried by liswt compresses the tissue and the following negative pressure originates tensile forces leading to shear stress on cell membranes. this phenomenon is called “cavitation” and triggers a chain of events that cause the release of angiogenic factors such as endothelial no synthase, vascular endothelial growth factor and proliferating cell nuclear antigen (3). following this rationale, vardi et al pioneered the first study using liswt for ed. twenty men with vasculogenic ed were included in their study: at one-month posttable 2a. results ed ≤ 24 months. table 2b. results ed > 24 months. iief-5 summary statistics pre-liswt 6 weeks post-liswt p value 3 months post-liswt p value min-max 5-21 5-24 5-25 median (iqr) 15.0 (10.5-16.5) 17 (11.5-22) *0.008 17 (11.5-22.5) *0.012 mean ± sd 13.8 ± 4.6 16.4 ± 5.9 16.9 ± 6.2 improvement % (n) 69.2 (9) 61.5 (8) penile dynamic duplex ultrasound summary statistics psv psv p value edv edv p value pre-liswt post-liswt pre-liswt post-liswt min-max 4,7 59.2 8.0-70.0 -6.0 – 10.1 -7.3-8.0 median (iqr) 27.0 30.1 *0.017 1.5 2.6 *0.630 (21.0-36.9) (25.2-40.6) (-2.2 -4.2) (-0.1 -4.2) mean ± sd 29.6 ± 14.5 34.6 ± 15.5 1.6 ±4.0 2.2 ± 4.0 improvement % (n) 84.6 (11) 61.5 (8) pde5i treatment pre-liswt % (n) post-liswt % (n) p value yes 46.2 (6) 38.5 (5) 1.000 no 53.8 (7) 61.5 (8) improvement % (n) 7.7 (1)) pde5i response pre-liswt % (n) post-liswt % (n) p value good 15.4 (2) 7.7 (1) moderate 7.7 (1) 15.4 (2) 0.500 bad 23.1 (3) 15.4 (2) improvement % (n) 15.4 (2) iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; iqr: interquartile range; sd: standard deviation; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 iief-5 summary statistics pre-liswt 6 weeks post-liswt p value 3 months post-liswt p value min-max 5-21 5-22 5-24 median (iqr) 12.5 (9.3-17.3) 15 (10.3-20.8) *0.008 18 (10.5-22.0) *0.018 mean ± sd 12.8 ± 5.4 14.8 ± 6.1 16.2 ± 6.6 improvement % (n) 66.7 (8) 83.3 (10) penile dynamic duplex ultrasound summary statistics psv psv p value edv edv p value pre-liswt post-liswt pre-liswt post-liswt min-max 13.2-58.8 14.7-68.2 -5.1-13.8 -7.3-6.9 median (iqr) 28.5 32.7 *0.016 5.6 1.7 *0.005 (20.5-29.6) (28.5-47.5) (-1.3 -7.2) (-5.1 -5.5) mean ± sd 29.0 ± 11.7 37.3 ± 15.5 3.8 ± 5.4 0.3 ± 5.4 improvement % (n) 83.3 (10) 75.0 (9) pde5i treatment pre-liswt % (n) post-liswt % (n) p value yes 100 (12) 66.7 (8) 0.125 no 0.0 (0) 33.3 (4) improvement % (n) 33.3 (4) pde5i response pre-liswt % (n) post-liswt % (n) p value good 16.7 (2) 33.3 (4) moderate 58.3 (7) 25.0 (3) *0.016 bad 58.3 (7) 25.0 (3) improvement % (n) 58.3 (7) iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; iqr: interquartile range; sd: standard deviation; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 de oliveira_stesura seveso 10/01/19 16:09 pagina 278 279archivio italiano di urologia e andrologia 2018; 90, 4 low-intensity shock wave therapy treatment, mean iief-ed (erectile function domain) significantly improved from 13.5 ± 4.1 to 20.9 ± 5.8 (p < 0.001) (2). later, this group conducted a randomized, double-blind, sham controlled study with 67 men. at one-month post-treatment, the mean iief-ed increased by 6.7 points in the treated group while in the sham group increased by 3.0 points (p 0.0322) (4). another randomized, doubleblind, placebo-controlled study by yee et al, with 58 men, concluded that liswt presented significant improvement at 4 weeks post-treatment only in patients with severe ed (iief-ed improvement in liswt group was 10.1 ± 4.1, in placebo group was 3.2 ± 3.3 (p 0.003)) (5). ruffo et al reported a study with 31 patients with mild to moderate ed.that achieved significant improvement in iief-ed: baseline mean iief-ed was 16.54 ± 6.35, at one-month post-treatment was 21.13 ± 6.31 (p 0.0075) and, at three-month was 21.03 ± 6.38 (p 0.0096) (6). a meta-analysis conducted by lu et al., comprising 14 studies including 833 patients revealed that liswt could significantly improve iief (mean difference 2.00; p < 0.0001) (7). another meta-analysis conducted by clavijo et al., comprising seven randomized controlled trials involving 602 patients, also reported a statistically significant improvement in pooled change in iief-ed score from baseline to follow-up in men treated with liswt compared with those receiving sham therapy (6.40 points; 95% ci 1.78-11.02; p < 0.001 vs 1.65 points; 95 ci 0.92-2.39; p < 0.0001; between-group difference p 0.047) (8). our results are in line with previous reported studies. overall baseline median iief-5 was 14, at six weeks post-treatment was 16 (p < 0.001) and, at 3 months 18 (p < 0.001), corresponding to an improvement of 68% and 72% respectively. at 3 months, median iief-5 actually changed category from mild-to-moderate to mild. lu et al. (7) in his metaanalysis also reported a good therapeutic effect by 3 months, suggesting that changes induced by liswt may not be immediate but table 3. results by ed type. iief-5 improvement 6 weeks post-liswt p value 3 months post-liswt p value arteriogenic 80.0 (12) 73.3 (11) arteriogenic + venous leak 50.0 (2) *0.021 75.0 (3) 0.459 post-rp 0.0 (0) 33.3 (1) venous leak 100 (3) 100 (3) penile dynamic duplex ultrasound improvement psv post-liswt % (n) p value edv post-liswt % (n) p value arteriogenic 86.7 (13) 60.0 (9) arteriogenic + venous leak 75.0 (3) 0.532 100 (4) 0.133 post-rp 66.7 (2) 33.3 (1) venous leak 100 (3) 100 (3) pde5i treatment improvement % n p value arteriogenic 20.0 3 arteriogenic + venous leak 25.0 1 1.000 post-rp 0 0 venous leak 33.3 1 pde5i response improvement % n p value arteriogenic 20.0 3 arteriogenic + venous leak 75.0 3 0.119 post-rp 33.3 1 venous leak 66.7 2 ed: erectile dysfunction; iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; post-rp: post radical prostatectomy; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 table 4. results by ed risk factor. iief-5 improvement 6 weeks post-liswt p value 3 months post-liswt p value hta 58.8 (10) 0.661 55.6 (10) 0.208 diabetes 29.4 (5) 1.000 22.2 (4) 0.355 tobacco 17.6 (3) 1.000 16.7 (3) 0.597 dyslipidemia 58.8 (10) 1.000 55.6 (10) 0.659 obesity 35.3 (6) 0.680 38.9 (7) 0.362 penile dynamic duplex ultrasound improvement psv post-liswt % (n) p value edv post-liswt % (n) p value hta 57.1 (12) 0.260 64.7 (11) 1.000 diabetes 23.8 (5) 0.548 23.5 (4) 0.640 tobacco 23.8 (5) 0.549 29.4 (5) 0.140 dyslipidemia 61.9 (13) 1.000 70.6 (12) 0.194 obesity 38.1 (8) 0.269 35.3 (6) 0.680 pde5i treatment improvement % n p value hta 40.0 2 0.312 diabetes 0.0 0 0.274 tobacco 20.0 1 1.000 dyslipidemia 60.0 3 1.000 obesity 20.0 1 0.642 pde5i response improvement % n p value hta 44.4 4 0.200 diabetes 0.0 0 *0.027 tobacco 22.2 2 1.000 dyslipidemia 55.6 5 1.000 obesity 22.2 2 0.661 ed: erectile dysfunction; iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; post-rp: post radical prostatectomy; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 de oliveira_stesura seveso 10/01/19 16:09 pagina 279 archivio italiano di urologia e andrologia 2018; 90, 4 p. simoes de oliveira,t. ribeiro de oliveira, á. nunes, f. martins, t. lopes 280 rather delayed in time. our subgroups analysis by length of disease duration showed no significant difference improvement in iief-5 between groups at 6 weeks or at 3 months follow-up post-treatment (p 1.00 and p 0.378 respectively), suggesting that time of ed do not alter treatment outcomes. pelayo-nieto et al, in a study with 15 patients reported an overall improvement in iief-ed of 80% (14.23 vs 19.69; p < 0.0013) and no influence of ed duration was found using a cut-off of 3 years (p < 0.20) (9). in a multicenter open-label prospective study with 58 patients, reisman et al. reported an overall improvement of 81.03% in iief-ed (iief-ed average increase 7.5 ± 4.7; p < 0.001). furthermore, a only moderate negative pearson correlation coefficient of -0.62 was found between the duration of ed and success of treatment, showing satisfactory success rates in cases of ed up to 10 years of duration (10). also, bechara et al, in a study with 50 patients, concluded that time of ed did not influenced the results (11). our study evaluation relied not only in subjective patient questionnaire like iief-5, but also assessed penile hemodynamics with a tangible tool like penile doppler ultrasound. our overall results showed a significant improvement both in mean psv (29.3 cm/s vs 35.9 cm/s; p 0.001) and mean edv (2.6 cm/s vs 1.3 cm/s; p 0.015) with both post-treatment values within normal ranges. also, subgroups analysis by length of disease duration showed no significant difference between the two groups (psv improvement in group 1 was 84.6% vs 83.3% in group 2; p 1.000 and edv improvement in group 1 was 61.5% vs 75.0% in group 2; p 0.673).the majority of published studies addressed treatment outcomes with sexual function and quality of live questionnaires but not many have assessed penile hemodynamics in patients treated with liswt for ed. kalyvianakis et al., in a doubleblinded, randomized, sham controlled trial with 46 patients, like in our study, used pddu to evaluate patients at 3 months post-treatment and reported a mean change in psv of 4.5 cm/s and 0.6 cm/s for the treatment and sham-control groups, respectively (p < 0.001) (12). other studies, namely vardi et al (4) and kitrey et al. (13) also assessed penile hemodynamics with another technique using the flow mediated dilation. both groups reported significant improvement (p < 0.0001). these results show that liswt indeed produces changes in penile vascularization associated with improved hemodynamics. another endpoint of our study was to evaluate the influence of liswt in pde5i response and if patients were able to leave this medication after treatment. significant results were seen in patients who still needed pde5i after treatment, because their response to medication improved (overall improvement of 36.0%; p 0.004). significant difference was present between groups (p 0.041), being group 2 the major responsible for this improvement, showing that patients with longer ed responded better to pde5i after liswt. it is a fact that these patients were all on pde5i previously, thus, more used to it and more aware, and this might have influenced the results. at the end of the study 5 patients (20%) were able to leave permanently pdei5 and achieve spontaneous erections, nevertheless this was not statistically significative (p 0.063). others have evaluated the effect of liswt on pde5i response. grueenwald et al., in a study with 29 men with severe ed and poor response to pdei5, showed that one month post-treatment, 34% of patients returned to sexual activity without the necessity for pharmacotherapy (14). our protocol included having tadalafil 5 mg daily. although it could induce a bias in the results, following the concept of angiogenesis and neovascularization associated with liswt, concomitant pde5i produces a continuous local stimulus that might contribute to a synergic effect with liswt and potentiate global response in the best interest for the patient. kitrey et al., in a prospective randomized, double-blind sham-controlled study with 55 patients, also used pdei5 during liswt and showed that 54% of these patients achieved erections hard enough for penetration, in comparison of 0% of the sham group (pde5i only) (13). the meta-analysis pertable 5. results comparison. iief-5 improvement 6 weeks 6 weeks p value 3 months 3 months p value post-liswt % (n) post-liswt % (n) post-liswt % (n) post-liswt % (n) ed > 24 months ed ≤ 24 months ed > 24 months ed > 24 months 69.2 (9) 66.7 (8) 1.000 61.5 (8) 83.3 (10) 0.378 penile dynamic duplex ultrasound improvement psv psv p value edv edv p value post-liswt % (n) post-liswt % (n) post-liswt % (n) post-liswt % (n) ed > 24 months ed ≤ 24 months ed > 24 months ed > 24 months 84.6 (11) 83.3 (10) 1.000 61.5 (8) 75.0 (9) 0.673 pde5i treatment improvement post-liswt % (n) post-liswt % (n) p value ed ≤ 24 months ed > 24 months 7.7 (1) 33.3 (4) 0.160 pde5i response improvement post-liswt % (n) post-liswt % (n) p value ed ≤ 24 months ed > 24 months 15.4 (2) 58.3 (7) *0.041 iief-5: international index of erectile function (5 questions); liswt: low-intensity shock wave therapy; iqr: interquartile range; sd: standard deviation; psv: peak systolic velocity; edv: end-diastolic velocity; pde5i: phosphodiesterase type 5 inhibitors. * statistical significance with p < 0.05 table 6. patient questionnaire. satisfaction recommendation adverse effects % (n) % (n) % (n) total 76.0 (19) 80.0 (20) 0.0 (0) ed ≤ 24 months 76.9 (10) 84.6 (11) 0.0 (0) ed > 24 months 75.0 (9) 75.0 (9) 0.0 (0) de oliveira_stesura seveso 10/01/19 16:09 pagina 280 281archivio italiano di urologia e andrologia 2018; 90, 4 low-intensity shock wave therapy formed by lu et al. showed that the iief increased more significantly in the group with liswt combined with pde5i use (mean difference: 4.20; 95% ci, 0.16-8.24; p 0.04), supporting the use of combination therapy (7). when stratified by type of ed, our results showed that patients with vasculogenic ed, whether arteriogenic and/or venous leak, presented the best results, regarding iief-5 at 6 weeks post-treatment and, patients with ed post radical prostatectomy, the worse results (p 0.021). there is a consensus in the literature that the major suggested mechanism of action of liswt is by angiogenesis and neovascularization, and that explains why patients with vasculogenic ed are expected to be the best candidates to this treatment. nevertheless, assuming mechanisms of action like nerve regeneration, other patients may be candidates. frey et al., in a study with 16 patients who underwent nerve-sparring robotic radical prostatectomy, reported significant changes in iief-5 post-liswt, with a median increase of +3.5 at one-month (p 0.0049) and, +1 at one-year post-treatment (p 0.046), nevertheless, the majority of patients achieved only marginal improvements in ed category (15). ed postprostatectomy is usually a severe and complex side-effect, caused by direct trauma, stretching, heating, ischemia and local inflammation of the cavernous nerves (16). nerve damage results in impaired erections and inadequate penile oxygenation, leading to smooth muscle apoptosis and fibrosis (17). in this setting, it may be too ambitious expecting evident results with liswt, but it may have a role as adjunctive therapy in penile rehabilitation. when looking for the influence of ed risk factors on liswt outcomes, our study showed that diabetic patients presented the worse results. in fact, statistical significance was found in pdei5 response, where diabetic patients didn´t show any improvement (p 0.027). reisman et al., comparing diabetic and non-diabetic patients, had a success rate 25% higher in the latter group (70.83% vs 88.24% respectively) (10). hisasue et al, in subgroup analysis by comorbidities, found worse results in diabetic patients with only 3/10 achieving a score of 3 in erection hardness score (18). these results all together suggest a negative impact of diabetes on the efficacy of liswt. contemporary liswt machines can be divided into 3 main types based on the mechanism of shock waves namely electrohydraulic, electromagnetic and piezoelectric. the majority of studies have used the first two types. the piezoelectric device differs from the others in that it offers full organ coverage and higher treatment parameters. motil et al., like in our study, used a piezoelectric machine and reported an average iief-5 score improvement from 14.4 baseline to18.6 at 1-month post-treatment. a total of 75 patients were treated and they had pde5i during treatment (19). fojecki et al., in a randomized, double-blinded, sham-controlled study with 126 patients, also used a piezoelectric device, and reported success rates based on the iief-ef score of 38.3% in the sham group and 37.9% in the active group (or = 95, 95% ci = 0.45-2.02, p 0.902), showing no clinical relevant effect of liswt (20). although using the same device, fojecki et al., delivered less energy to the penis, using an efd of 0.09 mj/mm2, in contrast motil et al., like in our study an efd of 0.160 mj/mm2 was used. also, in the fojecki study, patients had a 4-weeks wash-out period of pdei5 and medication was not allowed during treatment. this protocol differences may be responsible for different outcomes between these studies, reinforcing the benefit of using adjuvant pdei5 with liswt. limitations of our study are the absence of a sham-control arm, a small number of patients and the short follow-up period. also, the concomitant use of pde5i could induce a bias. nevertheless, the strengths include being prospective, having evaluated penile hemodynamics in all patients with a tangible and reliable tool as pddu, no limitation in inclusion criteria regarding type of ed and looking for cofounding factors that could influence treatment outcomes, specially duration of ed. liswt is a safe, harmless, repeatable treatment modality for ed with good functional outcomes reported. our results suggest that length of disease duration doesn´t negatively influences treatment results. also, concomitant use of pde5i should be considered. references 1. feldman ha, goldstein i, hatzichristou dg, et al. impotence 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patients who do not respond to phosphodiesterase type 5 inhibitors. sex med. 2016; 4:e225-e232. de oliveira_stesura seveso 10/01/19 16:09 pagina 281 archivio italiano di urologia e andrologia 2018; 90, 4 p. simoes de oliveira,t. ribeiro de oliveira, á. nunes, f. martins, t. lopes 282 12. kalyvianakis d, hatzichristou d. low-intensity shockwave therapy improves hemodynamic parameters in patients with vasculogenic erectile dysfunction: a triplex ultrasonography-based shamcontrolled trial. j sex med. 2017; 14:891-897. 13. kitrey nd, gruenwald i, appel b, et al. penile low intensity shock wave treatment is able to shift pde5i nonresponders to responders: a double-blind, sham controlled study. j urol. 2016; 195:1550-1555. 14. gruenwald i, appel b, vardi y. low-intensity extracorporeal shock wave therapy–a novel effective treatment for erectile dysfunction in severe ed patients who respond poorly to pde5 inhibitor therapy. j sex med. 2012; 9:259-264. 15. frey a, sonksen j, fode m. low-intensity extracorporeal shockwave therapy in the treatment of postprostatectomy erectile dysfunction: a pilot study. scand j urol 2016; 50:123-127. 16. burnett al. rationale for cavernous nerve restorative therapy to preserve erectile function after radical prostatectomy. urology 2003; 6:491-497. 17. iacono f, gianella r, somma p, et al. histological alterations in cavernous tissue after radical prostatectomy. j urol. 2005; 173:1673-1676. 18. hisasue s, china t, horiuchi a, et al. impact of aging and comorbidity on the efficacy of lowintensity shock wave therapy for erectile dysfunction. int j urol. 2016; 23:80-84. 19. motil i, kubis i, sramkova, t. treatment of vasculogenic erectile dysfunction with piezowave2 device. application of low intensity shockwaves using novel linear shockwave tissue coverage (lstced®) technique. a prospective, multicentric, placebo-controlled study. adv sex med. 2016; 6:15-18. 20. fojecki gl, tiessen s, osther pjs. effect of low-energy linear shockwave therapy on erectile dysfunction – a double-blinded, shamcontrolled, randomized clinical trial. j sex med 2017; 14:106-1. correspondence pedro simoes de oliveira, md (corresponding author) pedrosimoesdeoliveira@gmail.com tiago ribeiro de oliveira,md tiagoribeirooliveira@sapo.pt álvaro nunes, md alvaronunes@portugalmail.pt francisco martins, md faemartins@gmail.com tomé lopes, md tomematoslopes@gmail.com sci-centro de urologia av. defensores de chaves, 83, 1º, 1000-115, lisbon, portugal de oliveira_stesura seveso 10/01/19 16:09 pagina 282 stesura seveso 295archivio italiano di urologia e andrologia 2014; 86, 4 case report intestinal perforation after radical cystectomy due to drain: case report salih budak 1, hüseyin aydemir 2, hasan salih saglam 2, oztuğ adsan 2 1 tepecik training and research hospital, urology clinic, izmir, turkey; 2 sakarya university training and research hospital, urology clinic, sakarya, turkey the current standard treatment for nonmetastatic invasive bladder cancer is radical cystectomy with urinary diversion. radical cystectomy surgery carries a serious potential risk of complications. in this case report, an intestinal perforation which was thought to be occurred due to a foley catheter placed as a drain after the cystectomy is presented. key words: cystectomy; intestinal perforation; drainage. submitted 28 july 2014; accepted 30 september 2014 summary no conflict of interest declared. approximately 5 cm in size on the anterior wall of the bladder, was performed. the histopathological evaluation report of the surgical material demonstrated a muscle invasive urethral carcinoma (t2g3). a radical cystectomy with urinary diversion by an ileal reservoir was proposed to the patient. radical cystectomy, bilateral pelvic lymphadenectomy and ileal conduit diversion were performed. urethra, uterus, cervix, ovaries and anterior wall of the vagina were removed with the bladder due to the involvement of the bladder neck. bricker technique was applied for uretero-ileal anastomosis. as an abnormal finding during the surgery, there was a tumor extension from the bladder anterior wall to the symphysis pubis. at the end of the operation, a silicon drain was placed into the abdomen and a foley balloon catheter was placed into the urethrectomy region as drainage. the patient was mobilized in the postoperative 1st day and the nasogastric tube was removed. the oral feeding (regime 1) started in the postoperative third day, total parenteral nutrition was discontinued and the vaginal tampon was removed. defecation occurred in the postoperative forth day and regime 2 was started, the abdominal drain was removed, but the foley drain was left in place because it drained 300 cc. the deep vein thrombosis prophylaxis was ended in the postoperative fifth day and there was stool outflow. in the fifth postoperative day nausea, abdominal pain and sensitivity occurred with increased white blood cell count. oral nutrition was stopped and intravenous liquid replacement was started. a general surgery consultation was requested. the patient was followed with blood count evaluations, direct abdominal radiograph and findings of abdominal examinations. at the abdominal ct (with oral contrast) presence of free contrast between the intestinal loops was shown.. the patient was surgically explored in the postoperative fifth day. at surgical exploration at approximately 20 cm apart from the ileocecal junction, the 15 cm long ileum wall including the intestinal anastomosis line was thickened and there was a perforation of both the proximal and the distal ileum with respect to the anastomosis, although the anastomotic line was still intact (figure 1). doi: 10.4081/aiua.2014.4.295 introduction the current standard treatment for the non-metastatic invasive bladder cancer is radical cystectomy with urinary diversion. despite of the technical improvements, nowadays, radical cystectomy surgery carries a serious potential risk of complications. although the improvements in the perioperative and postoperative care decrease the complication risks in years, the mortality rate of cystectomy is still 3% and the post-surgical morbidity rate is 30% (1). cystectomy with urinary diversion is a serious surgical procedure for the physiological reserve. in this article, we presented a case of intestinal (ileum) perforation complicating the postoperative period of a patient who underwent radical cystectomy and urinary diversion. case report a sixty-five year-old female patient presented with a recurrent macroscopic hematuria complaint. it was learned from her history that the patient was a smoker at a rate of 40 packets/year and that she did not have any other disease. at initial evaluation, there was no abnormal finding at physical examination and serum biochemical and hematological investigations were in the normal range. at ultrasonography of the urinary tract, both kidneys were normal but an approximately 4-5 cm large mass lesion was detected in the anterior wall of the bladder. a complete resection of the tumor formation, which was budak2_stesura seveso 15/01/15 13:22 pagina 295 archivio italiano di urologia e andrologia 2014; 86, 4 s. budak, h. aydemir, h. salih saglam, o. adsan 296 !leum resection was performed in a way to include the two perforation areas and the anastomotic line (figure 2). !leostomy was anastomosed to the skin. discussion in the cases of bladder tumors invasive to the muscle, cystectomy is the most effective treatment choice with a disease-free survival rate of 87% (2). postoperative close follow-up is important for the diagnosis and treatment of early complications. since cystectomy and urinary diversion operations are serious operation for the physiological functions, the hospitalization periods of the patients might be approximately more than one week. complications of the early period after radical cystectomy occurs approximately at a rate of 6-30% and consist mostly in bleeding, intestinal obstruction, urinary extravasation, urinary reflux and infection (1). in our clinics, we restore oral nutrition and mobilization in the patients who underwent cystectomy in our clinics as soon as possible after the operation. the intestinal epithelium is quite sensitive to anoxia and necrosis and they can easily occur in the areas of the operation resulting in perforation. intestinal perforation may occur as a result of pressure or ischemic necrosis (3). although the early period of follow-up after the operation was in the normal course in our case, we think that the foley drain that we placed into the urethrectomy region might have led to the necrosis of the ileum wall by making a physical pressure. as can be understood from figure 3, erosion developed in the areas that had a contact with the foreign body. in conclusion, it should be taken into account that in the patients who had urinary diversion by using intestinal segments, the fragility of the intestinal structures increase. thus, one should be careful in the placement of stents, drains and catheters. the early follow-up after the radical cystectomy should be carefully and drains and catheters should be removed as soon as possible. references 1. maffezzini m, gerbi g, campodonico f, parodi d. multimodal perioperative plan for radical cystectomy and intestinal urinary diversion. effect on recovery of intestinal function and occurrence of complications. urology. 2007; 69:1107-1111. 2. stein jp, leiskowsky g, cote r, et al. radical cystectomy in treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2002; 19: 666-675. 3. kulaylat mn, doerr rf. small bowel obstruction. holzhimer rg, mannick ja (eds) surgical treatment: evidence-based and problemoriented. 2001. figure 1. white arrow: distal perforation, green arrow: anastomotic line, blue arrow: proximal perforation, yellow arrow: ileal loop orifice. figure 2. exploration finding, two perforations in the ileum segment, white arrow: distal perforation, green arrow: anastomose line, blue arrow: proximal perforation. figure 3. blue arrow: proximal perforation, green arrow: urethrectomy region drain (foley catheter). correspondence salih budak,md (corresponding author) salihbudak1977@gmail.com tepecik training and research hospital, urology clinic, izmir, turkey hüseyin aydemir, md husaydemir@yahoo.com hasan salih saglam, md associate. prof. hasanss@hotmail.com oztuiğ adsan, md professor oztugadsan@yahoo.com sakarya eah, uroloji kliniği, sakarya, turkey budak2_stesura seveso 15/01/15 13:22 pagina 296 347archivio italiano di urologia e andrologia 2016; 88, 4 case report ultrasound features of a metastatic seminal vesicle melanoma: a case report andrea fabiani 1, emanuele principi 2, alessandra filosa 3, fabrizio fioretti 1, valentina maurelli 1, lucilla servi 1, gabriele mammana 4 1 urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche, italy; 2 urologic clinic, polytechnic university of marche region, ancona, italy; 3 pathologic unit asur marche area vasta 3, macerata civic hospital, italy. in this report we describe what we consider to be the second case of seminal vescicle (sv) metastasis from an unknown primary melanoma. only presenting symptom was a palpable firm nodule of the right prostate base on digital rectal examination (dre). the diagnosis, after prostatic transrectal ultrasound examination (trus), was performed by ultrasound guided biopsy. we underline that prostatic trus evaluation is mandatory in case of abnormal digital rectal examination. seminal vesicle must be always evaluated. key words: metastatic melanoma; seminal vesicle; transrectal ultrasound; cup-syndrome. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. and mmb45 expression on immunohistochemical examination, suggesting a melanoma metastasis (figure 3a, b, c). further extension assessment by cistoscopy, wholebody computed tomography, dermatologic, ophthalmologic and gastroenteric examinations showed no primary tumor. since he had a single localization, surgical resection was proposed. doi: 10.4081/aiua.2016.4.347 presented at 20th national congress sieun, sciacca 2016 figure 1. inhomogeneous nodular lesion of 3 cm in major diameter, occupying the site of right seminal vesicle normal location. the aspect is similar to that of advanced prostate cancer. figure 2. echocolor signal was present in the retrovesical solid mass. introduction metastatic melanoma of the seminal vesicles is extremely rare (1). only one case has been reported of metastatic malignant melanoma to the male genital organs, in patients with an unknown primary melanoma (2). in other two cases reports a metastasis to the seminal vesicle from a primary cutaneous malignant melanoma has been described (3). we report the second case of seminal vesicle (sv) metastasis from an unknown primary melanoma. case presentation a 78-years-old man presented for an urologic screening during the follow up of a gastric carcinoma, surgically resected some years ago. his serum prostate-specific antigen level was 2,06 ng/ml. international prostatic index score was 6. at digital rectal examination, the prostate resulted modestly increased in volume with a firm nodule palpable at the right base. transrectal ultrasound (trus) examination, performed with a 6-12 mhz ultrasound end fire probe (8818 bk medical, denmark), revealed an hypo-echoic inhomogeneous nodular lesion of 3 cm in major diameter, occupying the site of seminal vesicle normal location (figure 1). ecocolor signal was present (figure 2). transrectal ultrasound guided prostate biopsy was performed. pathology revealed seminal vesicle invasion by a malignant tumor with s-100 fabiani2_stesura seveso 09/01/17 10:52 pagina 347 archivio italiano di urologia e andrologia 2016; 88, 4 a. fabiani, e. principi, a. filosa, f. fioretti, v. maurelli, l. servi, g. mammana 348 the patient denied any further treatment. he was lost at 6 months visit follow-up. discussion metastatic solid tumor in the male genital urinary tract are under diagnosed. they are considered uncommon but an accurate diagnosis is important because of its aggressiveness and possible functional impact (1). clinical manifestations are usually lower urinary tract symptoms, haematuria, pelvic pain, haemospermia, melanospermia. in our case, the absence of sexual activity by the patient has not allowed the identification of the lesion before digital rectal exploration (dre) was performed. in case of dre abnormality, trus is the initial diagnostic tool of choice. performing a trus, it must be taken into account that the prostate must be analyzed on two orthogonal planes, transverse and longitudinal. in this study it is essential to examine the juxtavesical ureters, bladder, prostate and seminal vesicles (4). in cases of suspicious masses of the sv, trus allows an excellent visualization. at the same time it offers the opportunity of performing a trus-guided biopsy for histological confirmation (5). additional radiological evaluation with magnetic resonance imaging and computed tomography is required to visualize the exact extent of metastases and concomitant pelvic pathology (6). normally, at trus evaluation, sv are seen as elongated septate cystic structures above the prostate. the distal portion of the vas deferens (vd) is seen as a slightly dilated tubular structure (the ampulla of the vd) medial to the sv. if scanned obliquely, the sv and the terminal portion of the vd can be seen joining to form the ejaculatory duct (ed), which may be traced to the region of the veru montanum (7). ultrasound features in case of sv diseases are not specific. primary neoplasms are extremely rare. they are classically classified as benign or malignant, primary or secondary. benign tumors of the sv are even rarer and the reported histology types in the literature are cystic dysplasia, fibroepithelial tumor, leiomyoma, cystadenoma and schwannoma (8). primary adenocarcinoma is the most common neoplasm of the sv. other histology types of the primary neoplasms of the sv that have been recorded in the literature are sarcomas, squamous cell carcinoma, yolk salk tumor, neuroendocrine carcinoma, paraganglioma, epithelial stromal tumors, lymphoma (burkitt, b-cell), extragastrointestinal stromal tumor (egist), myxoid solitary fibrous tumor, and seminoma peripheral primitive neuroectodermal tumor (ppnet) (9). secondary sv involvement is most frequent from the prostate but other tumors of adjacent organs such as the bladder and rectum, as well as metastasis from distant organs or peritoneal carcinomatosis, may also affect the sv (10). these tumors may appear as a retrovesical mass with or without prostatic or ureteral obstruction or as an infiltrating lesion in the sv with enhancement similar to that of advanced prostate cancer (7). also in our reported case, the ultrasound findings were not specific. only hystolopathological evaluation on biopsy cores obtained by trus, associated to ancillary immunohistochemical procedures (s-100 and mmb45) allowed the diagnosis. the primary melanoma was not recognized. we are in presence of a so called cup-syndrome that comprises a heterogenous group of metastatic tumors for which no primary site can be detected. although most cupsyndromes derive from neuroendocrine carcinomas, also metastatic melanomas are sporadically detected by metastasis only (11, 12). performing a brief literature review using the term “seminal vesicle melanoma”, we found only three cases reported. in two cases (3, 13), primary melanoma was identified. in one case (2), as reported in our experience, the initial localization of the melanoma remained unknown. anyway, genito-urinary locations of metastatic malignant melanoma have a poor prognosis. surgical excision with no margin should always be discussed as first-line management whenever possible, with or without systemic therapy. figure 3. the microscopic features of transrectal bioptic core obtained from the solid lesion; three different grade of magnifications. a. b. c. fabiani2_stesura seveso 09/01/17 10:52 pagina 348 conclusion diseases involving the sv are rare. owing to their close proximity to the prostate gland, these organs are most commonly affected by disease arising from the prostate. secondary tumor invasion is often seen in patients with prostate, bladder, or rectal cancer. rarely, primary neoplasms can also occur. metastatic solid tumor involvement of sv is probably under-diagnosed. transrectal ultrasound prostatic evaluation is mandatory in case of abnormal digital rectal examination. seminal vesicle must be always evaluated. at our knowledge, this is the second case of metastatic malignant melanoma of the seminal vescicle in a patient with an unknown primary melanoma. references 1. morichetti d, mazzucchelli r, lopez-beltran a, et al. secondary neoplasms of the urinary system and male genital organs. bju int. 2009; 104:770-6. 2. meng mv, werboff lh. hematospermia as the presenting symptom of metastatic malignant melanoma of unknown primary origin. urology. 2000; 56:330. 3. foahom kamwa ad, mateus c, thanigasalam r, et al. seminal vesicle metastasis of cutaneous malignant melanoma: an unusual and challenging presentation. can urol assoc j. 2015; 9:e220-3. 4. martino p. galosi ab, bitelli m, et al. practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl: 2014; 86:56-88. 5. zhang k, li sq, he zj, et al. long term efficacy of trus-giuded transperineal needle aspiration and irrigation on persistent hematospermia. zhonghua nan ke xue. 2005; 11:452. 6. cho i, lee m, rha k, et al. magnetic resonance imaging in hemospermia. j urol. 1997; 157:258. 7. kim b, kawashima a, ryu ja, et al. imaging of the seminal vesicle and the vas deferens. radiographics 2009; 29:1105-1121. 8. sandlow ji, winfield hn, goldstein m. surgery of the scrotum and seminal vesicles. in: wein aj, kavoussi lr, novick ac, partin aw, peters ca, eds. campbell-walsh urology. 9th ed, vol 1. philadelphia, pa: saunders elsevier. 2007; 1098-1127. 9. katafigiotis i, sfoungaristos s, duvdevani m. primary adenocarcinoma of the seminal vesicles. a review of the literature. arch ital urol androl. 2016; 88:47-51. 10. king bf, hattery rr, lieber mm, williams b jr, et al. seminal vesicle imaging. radiographics. 1989; 9:653-676. 11. pavlidis n, briasoulis e, hainsworth j, et al. diagnostic and therapeutic management of cancer of unknown primary. eur j cancer. 2003; 39:1990. 12. anbari kk, schuchter lm, bucky lp, et al. melanoma of unknown primary site, presentation treatment and prognosisa single institution study. cancer. 1997; 79:1816. 13. papoutsoglou n, burger m, riedmiller h. persistent painless hemospermia due to metastatic melanoma of the right seminal vesicle bmc urology. 2013; 13:43. 349archivio italiano di urologia e andrologia 2016; 88, 4 ultrasound features of a metastatic seminal vesicle melanoma: a case report correspondence andrea fabiani, md andreadoc1@libero.it fabrizio fioretti, md phd fa.fioretti@libero.it valentina maurelli, md valentinamaurelli@hotmail.it lucilla servi, md lucilla.servi@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3 macerata hospital, italy emanuele principi, md, urology resident principie@tiscali.it urologic clinic, polytechnic university of marche region, ancona, italy alessandra filosa, md phd alessandrafilosa@yahoo.it gabriele mammana, md gabriele.mammana@sanita.marche.it head surgery dpt, chief of section of urology asur marche area vasta 3, macerata hospital, italy fabiani2_stesura seveso 09/01/17 10:52 pagina 349 81archivio italiano di urologia e andrologia 2016; 88, 2 original paper prognostic impact of returb in high grade t1 primary bladder cancer roberto sanseverino 1, giorgio napodano 1, antonio campitelli 1, maria addesso 2 1 u.o.c. di urologia, ospedale umberto i, asl salerno, nocera inferiore, italy; 2 u.o.c. di anatomia patologica, ospedale umberto i, asl salerno, nocera inferiore, italy. purpose: to evaluate whether pathological outcomes of returb have a prognostic impact on recurrence and progression of primitive t1hg bladder cancer. material and methods: patients affected by primitive t1hg tcc of bladder underwent restaging turb (returb). patients with muscle invasive disease at returb underwent radical cystectomy; those with non-muscle invasive residual (nmi-rt) and those with no residual tumour (nrt) received an intravesical bcg therapy. we compared recurrence and progression in nmirt patients and nrt patients at restaging turb. patients were followed every 3-6 months with cystoscopy and urine cytology. results: 212 patients were enrolled in the study. at returb, residual cancer was detected in 92 of 196 (46.9%) valuable patients: 14.3% of these were upstaged to t2. at follow up of 26.3 ± 22.8 months, there were differences in recurrence and progression rates between nrt and nmirt patients: 26.9% and 45.3% (p < 0.001), 10.6% and 23.4% (p 0.03), respectively. recurrence-free and progression-free survivals were significantly higher in nrt compared to nmirt patients: 73.1% and 54.7% (p < 0.001), 89.4% and 76.6 (p 0.03), respectively. conclusions: returb allows to identify a considerable number of residual and understaged cancer. patients with nmirt on returb have worse prognosis than those with nrt in terms of recurrence and progression free survival. these outcomes seem to suggest a prognostic impact of findings on returb that could be a valid tool in management of high grade t1 tcc. key words: bladder cancer; returb; prognosis. submitted 20 november 2015; accepted 11 february 2016 summary no conflict of interest declared. to t2 at the second resection (16). high grade t1 tcc present a high risk of progression and represent a controversial therapeutic issue. it has been demonstrated that restaging turb (returb) is a valid tool to improve recurrence-free and progression-free survival, and, improving staging accuracy, to identify understaged t2 cancer that could benefit from an early radical treatment (17). however, it is not clear whether or not patients with no residual cancer at returb have a better prognosis than those with residual cancer. we have evaluated the usefulness of second turb and whether pathological outcomes of returb have a prognostic impact on recurrence and progression of primitive t1g3 bladder cancer. materials and methods patients affected by primitive t1g3 transitional cell carcinoma of bladder were enrolled in this study and underwent second look turb 4-6 weeks following the initial turb informed consent was obtained from each patient. patients who refused returb and those who have undergone incomplete resection were excluded from the study. restaging turb consisted of fractioned resection of all visible lesions, depth resection of base and borders of previous resection area, biopsy of any abnormal mucosal area; it was performed by the same urologist who performed the first turb. pathological evaluation was carried out according to the tnm system of uicc and to the who grading classification. patients with muscle invasive disease underwent radical cystectomy; those with non-muscle invasive residual (nmi-rt) and those with no residual tumour (nrt) received an induction 6 weeks course of intravesical bcg followed by maintenance swog schedule (table 1). all patients were followed with cystoscopy and voiding urine cytology every 3-4 months for the first and second year, every 6 months for the third and fourth year, and annually thereafter. diagnostic imaging of the upper tract and chest x ray were performed at least annually or when clinically indicated. in order to evaluate the prognostic significance of returb outcomes, we compared recurrence and progression rate, and recurrence and progression free survival in nmi-rt and nrt patients at restaging turb. recurrence was defined as first evidence of any tumour at follow up; progression was defined as doi: 10.4081/aiua.2016.2.81 introduction bladder cancer includes tumours of extremely heterogeneous biological behaviour. approximately 75-85% of all patients present with non muscle invasive (nmi) bladder cancer (1). transurethral resection of the bladder (turb) is the cornerstone approach in the diagnosis, initial staging and therapy of transitional cell carcinoma (tcc). however the rate of residual tumour after turb of neoplasms invading the lamina propria (t1 tcc) ranges from 28% to 76% at any site (2-11) and from 22 to 74% at the same site of first turb (12-15). moreover 9 to 49% of tumours after turb are understaged; particularly, up to 28% of t1 tcc are upstaged sanseverino_stesura seveso 01/07/16 10:58 pagina 81 archivio italiano di urologia e andrologia 2016; 88, 2 r. sanseverino, g. napodano, a. campitelli, m. addesso 82 muscle invasive tumour or evidence of metastasis. categorical variables are presented as numbers and frequency values and compared by chi-square and fisher exact test as appropriate. continuous variables are expressed as mean ± standard deviation and compared by t student test. a cumulative survival curve for recurrence-free and progression-free survival was drawn using the kaplan-meier method, log-rank test was used to compare differences between nmirt and nrt patients. a p value ≤ 0.05 with the 2-tailed test was considered to be statistically significant. statistical analysis was carried out by statistical package for social sciences software package version 16.0 (spss, chicago, ill. usa). results from january 2002 to september 2013, 212 eligible patients were enrolled in the study. were excluded from the study, 11 patients who refused restaging turb and 5 who underwent incomplete resection. the average age of 196 valuable patients (173 males and 23 females) was 69.5 ± 9.5 years. of the entire cohort of 196 patients, 146 (74.5%) had a solitary tumour and 50 (25.5%) had multiple lesions, at first turb; 6 patients showed concomitant carcinoma in situ (cis). in 19 patients (9.7%) pathological analysis revealed absence of muscle in specimen. the turb was performed by 6 experienced urologists and pathological evaluation was carried out by 1 dedicated uropathologist. at restaging turb residual cancer was histologically detected in 92 patients (46.9%). in 5 cases (2.5%) was observed prolonged bleeding (> 24 hours), but not requiring any blood transfusion. there was no significant statistical association between primitive tumour focality and evidence of residual cancer at returb: 35.5% (44/124) of patients with solitary tumour had residual cancer compared to 45.4% (20/44) of patients with multiple lesions (p 0.28). among the 92 patients with residual cancer at returb, 41 (20.9%) presented identical stage and grade, while 28 (14.3%) were upstaged to t2. histological outcomes of the remaining patients with residual cancer are listed in table 2. patients with muscle invasive cancer underwent radical cystectomy. of the remaining 168 patients with no residual tumour (nrt) and those with non muscle invasive residual tumour (nmirt), 57 (33.9%) had recurrence and 26 (15.5%) progressed to muscle invasive disease after a mean follow up of 26.3 ± 22.8 months. there was statistically significant difference in recurrence rate between nrt patients and nmirt patients: 26.9% vs 45.3% respectively (p < 0.001) (table 3). estimated actuarial recurrence-free survival rate was significantly higher in nrt group (73.1%) compared to nmirt patients (54.7%) (log-rank 10.64; p < 0.001) (figure 1). progression of the disease occurred in 10.6% of nrt patients and in 23.4% of nmirt patients (p = 0.03); estimated actuarial progression-free survival rate was higher in nrt group (89.4%) compared to nmirt patients (76.6%) (log-rank 4.58; p = 0.03) (figure 2). follow up of nrt patients was significantly longer than that of nmi-rt patients (34.8 (± 24.0) vs 22.8 (± 15.6) months, p = 0.005). discussion t1hg tcc are high risk tumours and they represent a great challenge for the urologists; they can present with various biological behaviour, so it is not easy to identify those with worse prognosis that could benefit by early radical cystectomy. recurrence within 3 months of turb is one of the most important prognostic factors for time to progression and progression free survival of nmi bladder cancer (18, 19). this rate depends on several factors such as stage, tumour size, number of lesions, use of adjuvant therapy, surgeon’s experience (20). however it is essential to distinguish between patients with true early recurrence and those with residual tumour due to an incomplete resection. it has been demonstrated that residual cancer after turb of t1 bladder cancer ranges from 28 to 76% at any site (2-11) and from 22 to 74% at the same site of first turb (12-15), depending on stage, grade, multiplicity, appearance of tumour, surgeon’s experience and modality of resection (2, 3, 10, 11, 21). moreover several studies, assessing the staging value of returb, proved that 9-49% of nmi bladder cancer had been underestimated at first turb (3, 4, 7, 8), and, parno residual tumour [nrt] (104 pts; 53.1%) residual tumour muscle invasive residual (92 pts; 46.9%) tumour (28 pts; 14.3%) non muscle invasive residual tumour [nmirt] (64 pts; 32.7%) table 1. groups of patients. stage and grade pts (n) t0 104 tag1 (+cis) 6 (1) t1g1 4 t1g2 (+cis) 1 (2) tag3 1 t1g3 (+cis) 39 (2) cis 8 t2 28 table 2. histological outcomes of returb. nrt nmirt p value pts (n) 104 64 age (years) 69.3 ± 9.9 70.6 ± 9.0 0,38 mean follow up (months) 34.8 ± 24.0 22.8 ± 15.6 0.005 multifocality at first turb (%) 23.1 31.2 0.28 recurrence rate % (n) 26.9 (28/104) 45.3% (29/64) < 0.001 progression rate % (n) 10.6 (11/104) 23.4 (15/64) 0.03 table 3. outcomes of nrt and nmirt patients. total (196 pts) sanseverino_stesura seveso 01/07/16 10:58 pagina 82 83archivio italiano di urologia e andrologia 2016; 88, 2 prognostic impact of returb in high grade t1 primary bladder cancer ticularly, up to 28% of t1 tcc had been upstaged to t2 by second turb (16). the accuracy of histological evaluation depends on several factors related to cancer characteristics, experience of pathologist and quality of samples (24,25). for a thorough and accurate histological evaluation it is necessary to achieve adequate specimens containing muscularis propria. mulders et al. showed that in only 121 of 155 (78%) patients, who underwent turb for t1g3 tcc, the specimens were suitable for complete pathological assessment (26). in the study of bernardini et al. muscularis propria was absent in 55 of 149 (36%) patients (27); likewise cheng et al. reported absence of muscle in turb samples in 66% of patients with t1 tcc (28). herr et al. demonstrated understaging in 49% of t1 patients without and in 14% of those with muscularis propria in the specimens of first turb. in this study 8% of ta/cis tumours and 27.6% of t1 were upstaged to muscle invasive cancer by returb (29). in our study, we have evaluated the usefulness and the prognostic significance of second turb in patients affected by primitive high grade t1 tcc. the second turb was safe and only 5 self-limiting bleeding occurred. however, though resection of bladder was performed by experienced surgeons, residual cancer occurred in 46.9% of patients. histological evaluation revealed muscle invasive disease in 28 (14.3%) patients and cis in 13 (6.6%). particularly, 6 of 19 (31.6%) patients without muscularis propria in samples of first turb were classified as t2 tcc on second turb; these data underline relevance of adequate samples containing muscularis propria, as yet demonstrated in other series. the prognostic value of second look turb on natural history of bladder cancer has not enough been elucidated; in fact, only few studies have investigated impact of pathological outcomes of returb on recurrence and progression of primitive t1 bladder cancer. in a study on 42 patients affected by primitive t1g2-3 tcc, restaging turb revealed 64% of residual tumours, 4.8% of muscle invasive cancers and 19% of cis. at mean follow up of 60 months the recurrence rate of no residual tumour (nrt) patients was 33% compared to 57%, 75% and 87.5% of ta, cis and t1 residual cancer (tr) patients, respectively; moreover, organ preservation rate was 100% for nrt patients and 64% for tr patients (8). in a prospective randomized trial, divrik et al. compared outcomes of returb plus intravesical mmc (group 1) with turb plus intravesical mmc (group 2) in 210 patients affected by t1 tcc of bladder; at mean follow up of 66.1 months, recurrence rate was 37/93 % in group 1 and 70/98 2% in group 2. median recurrence free survival (rfs) was 47 months for group 1 compared to 12 months for group 2. progression was figure 1. figure 2. sanseverino_stesura seveso 01/07/16 10:58 pagina 83 archivio italiano di urologia e andrologia 2016; 88, 2 r. sanseverino, g. napodano, a. campitelli, m. addesso 84 observed in 6.5% of patients for group 1 and in 23.5% of patients for group 2 (p = 0.001). median progression free survival (pfs) was 73 months for group 1 compared to 53.5 months for group 2. overall survival of two groups was 67.7% and 64.3% (log rank 0.363), respectively. this study demonstrated that the differences in terms of recurrence between two groups were due to the presence of residual tumour in group 2 rather than true recurrence and that intravesical chemotherapy did not compensate for inadequate resection (17). in a recent study on 352 t1 tcc patients with a 7.5 years of median follow up, those with t1 residual cancer on returb presented higher bcg failure rate (53%), recurrence rate (88%) and progression rate (82%) than patients with no residual cancer (3%, 48% and 8%, respectively). the authors suggest that early cystectomy may be advised for patients with t1 residual cancer on restaging turb (30). our data revealed a statistical significant difference in recurrence rate, recurrence free survival, progression rate and progression free survival between patients with and without residual cancer on returb. patients with no muscle invasive residual tumour on returb have higher recurrence (45.3% vs 26.9%), progression rates (23.4% vs 10.6%) and worse recurrence and progression free survival than those with no residual tumour, though they presented significant shorter follow up (22.8 vs 34.8 months). these outcomes seem to suggest a prognostic impact of findings on returb that could be a valid tool in identify patients at high risk of progression that could be ideal candidates for an early radical cystectomy. however, evidences of our study are limited by retrospective data evaluation and relatively short follow up. conclusions complete tumour eradication and correct staging are of paramount importance in primary diagnosis and treatment of bladder cancer. it has been clearly shown that persistence of tumour can negatively affect recurrence and even progression free survival. understaging with delay of appropriate treatment can affect overall patient survival after radical cystectomy. turb still remains the cornerstone modality for staging and primary treatment of bladder cancer. however, even in experienced hands, it is far from being perfect, with a consistent percentage of residual disease or tumour understaging left behind. second look turb in a short delay appears to be very useful in case of t1 and/or high grade tumours and mandatory whenever the tissue specimen does not allow a correct evaluation of the muscular layer. in our study patients with non muscle invasive residual tumour on returb show worse prognosis than those with no residual tumour in terms of recurrence and progression of disease. a longer follow up and a larger series of patients are essential to confirm the prognostic value of findings on returb and to demonstrate whether returb outcomes can identify patients at high risk of progression that could benefit from early cystectomy. references 1. oosterlinck w, van der meijden a, sylvester r, et al. guidelines on ta-t1 (non muscle-invasive) bladder cancer. in: guidelines, european association of urology 2006; pp 3-17. 2. klan r, loy v, huland h. residual tumor discovered in routine second transurethral resection in patients with stage t1 transitional cell carcinoma of the bladder. j urol. 1991; 146:316-8. 3. mersdorf a, brauers a, wolff jm, et al. 2nd turb for superficial bladder cancer: a must? j urol 1998; 159:143, abstract 542. 4. herr hw. the value of a second transurethral resection in evaluating patients with bladder tumors. j urol. 1999; 162:74. 5. schips l, augustin h, zigeuner re, et al. is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer? urology 2002; 59:220. 6. grimm m-o, steinhoff c, simon x, et al. effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. j urol. 2003; 170:433. 7. vögeli ta, grimm m-o, ackermann r. prospective study for quality control of turb of bladder tumors by routine 2nd turb (returb). j urol. 1998; 159:143, abstract 543. 8. brauers a, buettner, r, jakse, g. second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? j urol. 2001; 165:808. 9. rigaud j, karam g, braud, g, et al. t1 bladder tumors: value of a second endoscopic resection. prog urol. 2002; 12:27. 10. schwaibold h, treiber u, kubler h, et al. significance of 2nd transurethral resection for t1 bladder cancer. eur urol. 2000; 37 (suppl 2):11. 11. divrik t, yildirim u, eroglu a, et al. is a second transurethral resection necessary for newly diagnosed pt1 bladder cancer? j urol. 2006; 175:1258 -61. 12. jakse g, loidl w, seeber g, hofstadter f. stage t1, grade 3 transitional cell carcinoma of the bladder: an unfavourable tumor? j urol. 1987; 137:39-43. 13. lundbeck f, jacobsen t, vaeth m. impact of the category of early tumor recurrence on tumor progression in bladder tumors treated by transurethral resection. eur urol. 1989; 16:291-4. 14. wolf h, iversen hg, rosenkilde p, schroder t. transurethral surgery in the treatment of invasive bladder cancer (t1 and t2). scand j urol nephrol. 1987; 104:127-32. 15. schwaibold h, sivalingam s, may f, hartung r. the value of a second transurethral resection for t1 bladder cancer. brit j urol int. 2006; 97:1199-201. 16.miladi m, peyromaure m, zerbib m, et al. the value of a second transurethral resection in evaluating patients with bladder cancer. eur urol. 2003; 43:241-5. 17. divrik t, sahin a, yildirim u, et al. impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pt1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. eur urol. 2010; 58:185-90. 18. fitzpatrick jm, west ab, butler mr, et al. superficial bladder tumors: the importance of recurrence pattern following initial resection. j urol. 1986; 135:920-4. 19. kurth kh, schroeder fh, debruyne f, et al. long-term followup in superficial transitional cell carcinoma of the bladder: prognostic factors for time to first recurrence, recurrence rate, and survival. sanseverino_stesura seveso 01/07/16 10:58 pagina 84 85archivio italiano di urologia e andrologia 2016; 88, 2 prognostic impact of returb in high grade t1 primary bladder cancer final results of a randomized trial comparing doxorubicin hydrochloride, ethoglucid, and transurethral resection alone. eortc genitourinary tract cancer cooperative group. prog clin biol res 1989; 303:481. 20. brausi m, collette l, kurth k, et al. variability in the recurrence rate at first follow up cystoscopy after turb in stage ta t1 transitional cell carcinoma of the bladder: a combined analysis of seven eortc studies. eur urol 2002; 41: 523-31. 21. kohrmann ku, woeste m, kappers jh, rassweiler j, alken p. der wert der transurethralen nachresektion beim oberflachlichen harnblasenkarzinom. akt urol. 1994; 25:208-13. 22. zurkirchen ma, sulser t, gaspert a, hauri d. second transurethral resection of superficial transitional cell carcinoma of the bladder: a must even for experienced urologists. urol int. 2004; 72:99102. 23. pathologists of the french association of urology cancer committee. lamina propria microinvasion of bladder tumors, incidence or stage allocation (pta vs pt1): recommended approach. world j urol. 1993; 11:161-4. 24. grigor km, bollina. interpathologist variartion in the assessment of g3pt1 bladder carcinoma. eur urol. 1996; 30 (suppl 2):a850. 25. witjes ja, kiemeney la, schaafsma he, debruyne fm. the influence of review pathology on study outcome of a randomized multicenter suprerficial bladder cancer trial. br j urol. 1994; 73:172-6. 26. mulders pfa, hoekstra wj, heybroek rpm, et al. prognosis and treatment of t1g3 bladder tumours. a prognostic factor analysis of 121 patients. eur j cancer 1994; 30:914-7. 27. bernardini s, billerey c, martin m, et al. the predictive value of muscularis mucosae invasion and p53 over expression on progression of stage t1 bladder carcinoma. j urol. 2001; 165:42-6. 28. cheng l, neumann rm, weaver al, et al. grading and staging of bladder carcinoma in transurethral resection specimens. am j clin pathol. 2000; 113:275-9. 29. herr hw. does cystoscopy correlate with histology of recurrent papillary tumours of the bladder? bju int. 2001; 88:83-685. 30. herr hw, donat sm, dalbagni g. can restaging transurethral resection of t1 bladder cancer select patients for immediate cystectomy? j urol 2007; 177:75-9. correspondence roberto sanseverino, md roberto.sanseverino@libero.it giorgio napodano, md giorgio.napodano@gmail.com antonio campitelli, md u.o.c. di urologia, ospedale umberto i, asl salerno nocera inferiore, italy maria addesso, md u.o.c. di anatomia patologica, ospedale umberto i, asl salerno nocera inferiore, italy sanseverino_stesura seveso 01/07/16 10:58 pagina 85 archivio italiano di urologia e andrologia 2020; 92, 164 case report case reports of benign intrascrotal tumors: two epidermoid cysts and one scrotal calcinosis tuncay toprak 1, cagri akin sekerci 2 1 department of urology, fatih sultan mehmet training and research hospital, istanbul, turkey; 2 marmara university pendik training and research hospital, pediatric urology, istanbul, turkey. background: the aim this study was to explain the underlying etiology of unknown scrotal masses. case presentation: this study included 3 patients with a intrascrotal mass. one patient was over 50 years. the remaining patients were between the ages of 30-50. patients had no serious complaints (two complained about having 3 testicles and one complained of swelling in the scrotum for the last 6 months). all patients underwent scrotal exploration under general anesthesia and the specimen was sent for pathological examination. all masses were mobile and encapsulated. the masses were not associated with the testicle. two cases had classical histologic features of epidermoid cyst and one had scrotal calcinosis in the pathological report. physical examination, operation, magnetic resonance and histological images of scrotal masses were shown in the figures. conclusions: this study is important in terms of showing the underlying etiology of the rare scrotal masses. key words: intrascrotal; epidermoid cyst; calcinosis cutis. submitted 29 november 2019; accepted 30 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.64 introduction epidermoid cysts (ecs), also known as sebaceous cysts, are most common encapsulated cysts and usually these cysts have no potential for malignancy (1). the cyst filled with keratin and inflammatory reaction develops due to the outflow of keratin, and many practitioners mistakenly diagnose abscesses and prescribe antibiotics. although it is known as benign, it has been reported that approximately 1% of these cysts may develop into squamous or basal cell carcinoma. ecs may be found in autosomal dominant gardner and gorlin syndrome but most cases are seen as sporadic (2). scrotal calcinosis (sc), another benign lesion in the scrotum, is a rare disease characterized by multiple papules or calcification nodules in scrotal skin (3). in this study we discussed two cases of epidermoid cysts and one scrotal calcinosis. this study showed the etiology of the rare intrascrotal masses and contributing to the literature about the diagnosis, follow-up and treatment of these masses. case reports written informed consent was obtained from patients for the publication of this case reports. this study included 3 patients who underwent surgery due to the intrascrotal mass between 2018-2019. the laboratory data and tumor markers of all patients were within normal limits in this study. two was complaining about having 3 testicles and one was complaining of swelling in the scrotum for the last 6 months. the patients were 60, 40, and 35 years old, respectively. all patients had no history of comorbidity, drug use or history of operation. all masses on the physical examination were mobile and well limited. two on the right side and one on the left side. all patients underwent scrotal exploration under general anesthesia. the masses were not associated with the testicle. during the operation, the adherent skin was dissected and the skin was separated from the mass in two patients. the specimen was sent for pathological examination. two of the patients had pathological results of ec and one had calcinosis cutis. pathological images of patients were presented in figures 3, 4 and 5. figure 1 shows preoperative, intraoperative and postoperative images of a intrascrotal mass which is later diagnosed histologically with ec. figure 2 shows preoperative t1, t2 and diffusion-weighted magnetic resonance (mr) images of ec separated from the testis. following resection of the intrascrotal mass two patients had no recurfigure 1. preoperative (left), intraoperative (right) and postoperative (below) images of the epidermoid cyst. toprak2_stesura seveso 01/04/20 19:01 pagina 64 65archivio italiano di urologia e andrologia 2020; 92, 1 rare intrascrotal masses rence up to 8 months and one patient had no recurrence up to 5 months and no complication was observed. discussion ecs are epithelial cysts and are generally known as nonmalignant (1). in general, these cysts are caused by the occlusion of the follicular orifice. in addition, ecs may occur after traumatic or penetrating injuries leading to epithelial implantation (4).these cysts are composed of a sac surrounded by a stratified squamous epithelium filled with debris, keratin and cholesterol crystals (5). a granular layer is present that is filled with keratohyalin granules (figure 3). the ec may be associated with the testicle in the scrotum or may be completely separate. in t2-weighted magnetic resonance imaging (mri), these cysts are observed as high-density, well-limited solid masses surrounded by a low-signal capsule (6). the patients in the study showed the same mri findings. due to the suspicion of testicular cancer, the preoperative diagnosis of an ec is very difficult. complete surgical excision with the cyst wall is considered the the most effective treatment for an ec. generally, cysts are asymptomatic but when rupture as in one patient in the study, an inflammatory reaction occurs because of the displacement of the keratin into the dermis and surrounding tissue (figure 4). the evalution is largely based on history and physical examination. physical examination usually shows a non-fluctuant, compressible mass between 0.5 cm and several centimeters. although laboratory examination is not necessary, it can be recommended to take tumor markers when there is a suspicion of testicular cancer. scrotal mri was performed in the first few patients. however, it was concluded that it did not benefit much. calcinosis cutis, another intrascrotal mass in the study, was characterized by multiple papules or calcification nodules on the scrotal skin, but in our patient this was larger than normal sc nodules and was a single lesion in the scrotum. the pathology showed classical histologic features of sc with a granular calcified material in the dermis and fibroblastic proliferation around it (figure 5). it could be traced to originate from calcification of epidermal cyst or hair follicular and then the epithelial elements disappeared, leaving behind residual areas of calcification. conclusions this study is valuable in terms of showing the etiology of the rare intrascrotal masses and contributing to the literature about the diagnosis, follow-up and treatment of ecs. figure 2. t1 (left), t2 (right) and diffusion-weighted mr images of the epidermoid cyst. figure 4. epidermoid cyst; surrounded with stratified squamous epithelium. h & e x40 (left figure). ruptured area, granulomatous reaction is observed under the multilayer squamous epithelium (right figure). figure 5. calcinosis cutis; the epidermis on the surface is regular. granular calcified material is surrounded by fibrosis in the dermis h & ex40 (left figure). granular calcified material is observed in the dermis and fibroblastic proliferation is observed around it h & ex100 (right figure). figure 3. epidermoid cyst; surrounded with stratified squamous epithelium. lamellar keratinous material is observed in the lumen. h & ex40 (left figure). granular layer in stratified squamous epithelium. lamellated keratinous material is observed on the surface of the epithelium. h & ex400 (right figure). toprak2_stesura seveso 01/04/20 19:01 pagina 65 archivio italiano di urologia e andrologia 2020; 92, 1 t. toprak, c. akin sekerci 66 acknowledgements: we would like to thank to fatih sultan mehmet hospital pathology department for providing histological images. references 1. prasad kk, r. manjunath r multiple epidermal cysts of scrotum. indian j med res. 2014; 140:318. 2. zito pm, scharf r. cyst, epidermoid (sebaceous cyst), in statpearls (internet). 2019, statpearls publishing. 3. tareen a, ibrahim rm. idiopathic scrotal calcinosis–a case report. int j surg case rep. 2018; 44:51-53. 4. karaci s, kulaksiz d, sekerci ca. a rare cause of clitoromegaly: epidermoid cyst. arch ital urol androl 2019: 91:137-8. 5. shah kh, maxted wc, chun b. epidermoid cysts of the testis: a report of three cases and an analysis of 141 cases from the world literature. cancer. 1981; 47:577-582. 6. cho jh, chang jc, park bh, et al.. sonographic and mr imaging findings of testicular epidermoid cysts. ajr am j roentgenol. 2002; 178:743-8. correspondence tuncay toprak, md (corresonding author) drtuncay55@hotmail.com department of urology, fatih sultan mehmet training and research hospital anabilim dalı atasehir, istanbul (turkey) cagri akin sekerci, md cagri_sekerci@hotmail.com marmara university pendik training and research hospital, pediatric urology, istanbul (turkey) toprak2_stesura seveso 01/04/20 19:01 pagina 66 stesura seveso 271archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.271 cylinder rerouting for lateral extrusion after inflatable penile prosthesis implantation surgical technique revision paulo jorge pinto pe leve, joão pedro cardoso felício, pedro simões de oliveira, josé manuel palma dos reis, francisco alves estrócio martins urology department, centro hospitalar universitário lisboa norte, lisboa, portugal. lateral cylinder extrusion is a potential complication of penile prosthesis implantation. several methods have been proposed for repairing this complication. we present a case where a cylinder re-routing technique, first described by dr. john mulcahy, was used and a revision of the literature. key words: penile prosthesis; lateral extrusion; surgery. submitted 2 march 2020; accepted 15 march 2020 summary introduction implantation of an inflatable penile prosthesis (ipp) is the definitive solution for the treatment of organic erectile dysfunction (ed) in patients who have failed or are unfit for medical treatment and are motivated to pursue continued erectile function and sexual activity (1). although ipp patient satisfaction rates are high, 7.5% of these devices are subject to reoperation, often as a result of mechanical failure. other common indications for reoperation include patient dissatisfaction, chronic ipp pain, and impending distal or lateral cylinder extrusion. ipp extrusion comprises approximately 5-33% of reoperations (2). the risk of ipp extrusion appears to be associated with increased time from initial prosthesis placement, prior history of ipp placement, and the presence of corporal fibrosis or deformity. several methods have been proposed for repairing ipp extrusion such as closure of the distal corpus cavernosum with replacement of the penile prosthesis in its original position or the use of a patch in order to reinforce the corpus cavernosum (3). if there is no skin erosion this complication can be solved by a cylinder rerouting technique, a technique first described by dr. john mulcahy in 1999 (4). his method has been adopted as an elegant and effective approach that avoids the use of foreign material. we present a case where this surgical approach was used and a revision of the literature. clinical case a 67-year-old male patient, with a past history of hypertension, type 2 diabetes mellitus, hypothyroidism and ed refractory to medical treatment underwent ipp implantation (ams 700 cx®) 2 years ago. in the last year he started to complain of inability to deflate the prosthesis and penile axis deviation. he was submitted to a prosthesis surgical revision and a cylinder lateral extrusion was identified. he underwent a cylinder re-routing with replacement of both pump and cylinders by the modified mulcahy technique (4). the surgery was carried out under general anesthesia and lasted 75 minutes. a 14 fr foley catheter was inserted into the bladder and was removed 24 hours after the procedure. there were no intraoperative complications. the prosthesis was maintained inflated for 24 hours post operation. the patient was discharged on the first postoperative day. he resumed sexual intercourse 3 months after the surgery. at the moment he is satisfied with the functional outcome. no postoperative complications were documented. surgical technique description after flexible urethroscopy was performed to ensure that there was no cylinder erosion through the urethra, a subcoronal penile degloving was made and the affected cylinder was exposed (figure 1a). a lateral longitudinal corporotomy was made over the cylinder. the cylinder was then exposed through the corporotomy (figure 1b). then, a penoscrotal incision was made and prosthesis cylinders and pump were removed. the back wall of the fibrotic sheath (pseudocapsule) containing the cylinder was incised transversely, and a new plane of dissection was developed through homolateral corpus cavernosum behind the sheath, distally to the glans (figure 1c). a new space in the distal end of the corpus cavernosum was created and dilated to fit the appropriate cylinder caliber. in this manner, the pseudocapsule back wall that formerly comprised the medial wall of the capsule became the lateral aspect of the new capsule. the new cylinder was introduced into the new space in the corpus cavernosum by the penoscrotal approach using a keith needle and furlow inserter (figure 1d). the incision of the fibrotic sheath and corporotomy were then closed with absorbable suture. the cylinder is now protected by 2 though layers comprising the back wall of the fibrotic sheath and the wall of the corpus cavernosum albuginea. discussion this technique was first described by mulcahy et al. (4) he reported a series of 14 patients with a follow-up of about 2 years with optimal functional outcomes. carson and noh compared corporoplasty using mulcahy archivio italiano di urologia e andrologia 2020; 92, 3 p.j. pinto pe leve, j.p. cardoso felício, p.s. de oliveira, j.m. p. dos reis, f. alves estrócio martins 272 technique with gore-tex windsock repair based on their experience with 28 patients who presented with impending extrusion. mulcahy rerouting technique was performed in 18 men, with the remaining 10 undergoing repair with gore-tex windsock. the authors reported that the operative time was shorter for corporoplasty (mean 53 minutes, range 36-81) compared to the windsock repair (mean 90 minutes, range 64-142). there were no infections or recurrences among men underwent distal corporoplasty. one patient who had a windsock repair developed postoperative infection and two had recurrence of extrusion (6 and 18 months, respectively). functional results were similar in both groups. the authors concluded that distal corporoplasty is an overall superior method because of fewer major complications and reduced surgical time (5). shindel et al. developed a transglanular repair method but reported only 6 cases and identified some limitations such as small working space and brisk bleeding of the glans (6). we opted for the mulcahy procedure because of its technical simplicity, less operating time, and avoidance of synthetic material which increases the infection risk and surgical cost (1). recently, carrino et al. evaluated 18 consecutive patients with this corporoplasty technique. the operative time was 85 (± 13.1) minutes. no intraoperative complications were reported. one patient (5.55%) had postoperative infection (7). this technique is a simple and safe procedure in the treatment of lateral cylinder extrusion when the prosthetic material is not exposed to the outside surface. it also avoids the costs of the use of additional artificial material. references 1. levine la, becher e, bella a, et al. penile prosthesis surgery: current recommendations from the international consultation on sexual medicine. j sex med. 2019; 13:489-518. 2. fuentes jl, yi ya, davenport mt, et al. long-term sequelae of inflatable penile prosthesis: clinical characteristics of patients who develop distal cylinder tip extrusion. transl androl urol. 2020; 9:38-42. 3. stember ds, kohler ts, morey af. management of perforation injuries during and following penile prosthesis surgery. j sex med. 2015; 12(suppl 7):456-461. 4. mulcahy j. distal corporoplasty for lateral extrusion of penile prosthesis cylinders. j urol. 1999; 161:193-195. 5. carson cc, noh ch. distal penile prosthesis extrusion: treatment with distal corporoplasty or gortex windsock reinforcement. int j impot res. 2002; 14:81-4. 6. shindel aw, brant wo, mwamukona k, et al. transglanular repair of impending penile prosthetic cylinder extrusion. j sex med. 2010; 7:2884-90. 7. carrino m, chiancone f, battaglia g, et al. distal corporoplasty for distal cylinders extrusion after penile prosthesis implantation”. actas urol esp. 2016; 84:38-39. figure 1. a. affected cylinder exposition. b. cylinder retraction through the corporotomy. c. dissection of the posterior plane beneath the pseudocapsule. d. introduction of the new cylinder in the new cavity by penoscrotal incision. correspondence paulo jorge pinto pe leve, md (corresponding author) paulo.peleve@gmail.com rua jaime cortesão, nº 21, 7050-250 montemor-o-novo (portugal) joão pedro cardoso felício, md praceta fernando valle, nº6 8ºb, 1750-489 lisboa (portugal) pedro simões de oliveira,md pedrosimoesdeoliveira@gmail.com rua maria lamas, 2, 9º direito, 1500-438 lisboa (portugal) josé manuel palma dos reis, md jpalmareis@gmail.com francisco alves estrócio martins, md faemartins@gmail.com avenida professor egas moniz, 1649-028 lisboa (portugal) 25archivio italiano di urologia e andrologia 2019; 91, 1 original paper subjective and objective results in surgical correction of adult acquired buried penis: a single-centre observational study andrea cocci 1, gianmartin cito 1, marco falcone 2, marco capece 3, fabrizio di maida 1, girolamo morelli 4, nim christopher 5, david ralph 5, giulio garaffa 5 1 careggi hospital, department of urology, university of florence, florence, italy; 2 molinette hospital, department of urology, university of turin, turin, italy; 3 department of urology, university of naples, naples, italy; 4 department of urology, university of pisa, pisa, italy; 5 the institute of urology, uclh, and international andrology, london, uk. objective: the purpose of this study was to provide a detailed analysis of surgical and functional outcomes after correction of acquired buried penis in the adult. materials and methods: from 2006 to 2016, we retrospectively reviewed 47 patients undergoing surgical treatment for the correction of buried penis. functional and surgical outcomes, as well as patients’ satisfaction were the main endpoints. results: the most common complains at presentation were recurrent uro-genital infections, sexual dysfunction, voiding dysfunction and lichen sclerosus (ls). surgical management steps included: circumcision (27.66%), scrotoplasty (19.14%), v-y skin plasty (4.25%), split thickness skin graft (stsg) 12.76%, full thickness skin graft (ftsg) 36.17%, suprapubic fat pad excision (57.44%), abdominoplasty (25.53%), division of the suspensory ligament (36.17%). postoperative complications were recorded in 15% of patients. vaginal penetration and erectile function ended up being more effective in 97.87% (46/47) and 42.55% (20/47) of patients. improvement in penile erogenous sensation was in 6.38% (3/47). aesthetic appearance of genitalia fully satisfied 36.17% of patients (17/47). overall patients’ satisfaction rate resulted 76.59% (36/47). conclusion: management of adult acquired buried penis still remains a challenging task to achieve, however excellent cosmetic results can be obtained by surgical reconstruction. key words: buried penis; erectile dysfunction; circumcision; scrotoplasty. submitted 4 september 2018; accepted 26 october 2018 summary no conflict of interest declared. lichen sclerosus (ls) (7); in the majority of patients more conditions coexist. the development of buried penis occurs thanks to the elasticity of penile skin and dartos, which can slide and migrate distally while the corpora remain firmly attached to the pubic branches (8). in obese patients as well as in case of diffuse lymphoedema, the pre-pubic tissue progressively envelopes the penis rendering local hygiene impossible (9). similarly, excessive removal of penile shaft skin during circumcision, either due to surgical error or because all penile shaft skin was affected by ls, may trap the penile shaft in the pre-pubic adiposity. moreover, diabetes mellitus, which is a relatively common finding on obese patients, may impair immunity response to local and systemic infections and therefore worsen patients’ prognosis (10). buried penis profoundly impacts patients’ quality of life, as sexual and voiding function are severely compromised. in particular, during micturition, the pooling of urine and the lack of hygiene leads to skin maceration and to recurrent urinary tract infections. moreover, the maceration of skin, which is not meant to be in contact with urine for prolonged time, may be responsible of the development of permanent degenerative changes such as ls and carcinoma of the penis (cp). substantial quality of life improvement has been consistently reported after definitive surgical management (11). the rationale of the current study was to provide a detailed analysis of surgical and functional outcomes after surgical management of acquired buried penis in the adult, in order to describe the better choice of treatment. materials and methods after institutional review board approval, we retrospectively identified in this single-centre observational study all patients who have undergone surgical management of acquired buried penis between january 2006 and december 2016. demographic characteristics of patients, comorbidities, surgical procedures carried out, intraand postoperative complications and functional outcomes after penile reconstruction were retrospectively reviewed. doi: 10.4081/aiua.2019.1.25 introduction buried penis is a congenital or acquired condition, in which the phallus is partially or totally hidden below the surface of the skin. keyes in 1919 first stated that “absence of the penis exists when the penis, lacking its proper sheath of skin, lies buried beneath the integument of the abdomen, thigh or scrotum” (1). concealed penis (2), webbed penis (3) and inconspicuous penis (4) are sometimes used as synonyms (5). in most cases adult acquired buried penis is secondary to morbid obesity (6), diffuse lymphedema and skin contracture due to scarring of degenerative conditions like cocci_stesura seveso 26/03/19 09:44 pagina 25 archivio italiano di urologia e andrologia 2019; 91, 1 a. cocci, g. cito, m. falcone, m. capece, f. di maida, g. morelli, n. christopher, d. ralph, g. garaffa 26 the type of surgical procedure was decided according to the extent of the suprapubic adiposity and the availability and quality of penile skin. overall, abdominal and scrotal skin quality was determined preoperatively, while the characteristics of penile skin were assessed intraoperatively after surgical exposure of the penis. each patient signed a written fully informed consent statement to the surgical procedure. in case of phimosis, surgery always began with a dorsal incision of the phimotic ring, in order to guarantee adequate exposure of the penis and to assess the quality of the glans penis mucosa. a circumcising incision was then performed around the corona to free the penile shaft from the surrounding tissues. apronectomy was carried out through a transverse abdominal incision including a lozenge of skin, in order to remove the excess of skin and adipose tissue in the prepubic region. following apronectomy, a suction drain was left in the cavity to reduce the risk of haematoma formation. a thick split thickness skin graft (stsg) harvested from a relatively non-hair bearing area of the abdomen was applied on the denuded dartos to reconstruct the shaft skin. when affected by ls, the mucosa of corona and glans were reconstructed with a thin stsg (0.016 inch) harvested from the inner thigh with air dermatome, as previously described by garaffa et al. (12). postoperatively, a compressive penile dressing and an indwelling urethral catheter were left in place for 1 week to optimize graft take. patients were routinely discharged after removal of dressing and urethral catheter. from 2 weeks postoperatively, patients undergoing skin grafting were advised to introduce phosphodiesterase type 5inhibitors (pde5-i) therapy, in order to encourage nocturnal erections and to promote the stretching of the graft. in this way, the scar contracture that would naturally occur during the graft healing, was minimized. upon discharge, patients were routinely reviewed in the follow-up period at the fourth and eighth week after surgery. surgical outcomes were assessed at the postoperative follow-up visits using the patient global impression of improvement (pgi-i) questionnaire, in order to evaluate the functional outcomes and their satisfaction rate after surgery (13). pgi-i estimated the score that best described the postoperative condition, from 1 (very much better) to 7 (very much worse). moreover, the international index of erectile function (iief-5) was used to assess preoperative and postoperative sexual function (14). we used the abbreviated version, also known as iief-5 in the validated italian version (15). the scale considered the presence of the erectile dysfunction, classified as follow: severe (iief-5 ≤ 10), moderate (iief-5 between 11 and 16) and mild (iief-5 between 17 and 25). the hospital anxiety and depression scale (hads) questionnaire determined the levels of anxiety and depression that a patient was experiencing pre and postoperatively, with a score from 0 to 21, categorized as follow: normal (0-7), borderline abnormal (8-10), abnormal (11-21) (16). the differences between preand postoperative iief-15 and hads score were compared using a paired samples student t test. all tests were two-sided with a significance set at p ≤ 0.05. results overall, 47 patients were eligible in the study. the mean age at the time of surgery was 51.8 ± 18.38 years (range 43-69 years). patients’ demographics are reported in table 1. the average bmi was 30 ± 2.32. 16/47 (34.0%) patients were diabetics. the most frequent reported complaints included recurrent genital infections (8.51%), sexual dysfunction (27.66%), voiding dysfunction (27.66%), ls (10.63%) and a combination of both sexual and urinary dysfunction (25.54%) (figure 1). the type of surgical approach was tailored on the individual characteristics of each patient. surgical procedures included circumcision (27.66%), scrotoplasty (19.14%), v-y plasty of the pre-pubic region (4.25%), skin grafting of the penile shaft (thin stsg 12.76% thick stsg 36.17%), suprapubic fat pad excision (57.44%), abdominoplasty (25.53%) and division of the suspensory ligament (36.17%) (figures 2-6). the average hospital stay was 7 ± 2 days (range 2-14 days). no intraoperative complications were recorded. postoperative surgical complications occurred in 14.9% (7/47) of cases. complications were managed conservatable 1. patient’s characteristics (n = 47). parameter value mean age, years (sd) 51.8 (± 18.38) mean bmi, kg/m2 (sd) 30 (± 2.32) dm type i, n (%) 10 (21.27) dm type ii, n (%) 6 (12.76) hypertension, n (%) 18 (38.29) cardiovascular diseases, n (%) 8 (17.0) mean operative time, minutes (sd) 185 (± 91.12) mean blood loss, ml (sd) 180 (± 240.2) mean hospital stay, days (sd) 7 (± 6.36) intraoperative complications, n (%) 0 (0) postoperative complications, n (%) 7 (14.89) dm: diabetes mellitus; bmi: body max index; sd: standard deviation. figure 1. the most frequent symptoms reported by patients with clinical presentation of buried penis. cocci_stesura seveso 26/03/19 09:44 pagina 26 tively in 5 patients while surgical intervention was necessary in the remainder, as summarized in table 2. functional results after reconstructive surgery are reported in table 3. comparing preand postoperative hads score we found a statistically significant difference (p = 0.03). equally, comparing preand postoperative iief-5 score, a trend of significance (p = 0.09) was detected. vaginal penetration became possible in 97.87% of patients (46/47), while erectile function improved in almost half of them (42.55%). 23 patients (48.93%) needed to take pde5i to enhance their nocturnal erections. improvement in penile erogenous sensation was recorded in 6.38% (3/47) of patients. overall, 36 patients were satisfied with the outcome of surgery (17 fully satisfied and 19 partially satisfied) while 8.51% (4/47) declared to be dissatisfied, due to the small size of the discovered penis. 27archivio italiano di urologia e andrologia 2019; 91, 1 surgical correction of buried penis in adults table 2. postoperative complications and treatment (n = 47). complication patient (n) treatment wound infection 3 antibiotics apronectomy site dehiscence 2 surgical repair myocardial infarction 1 angioplasty respiratory failure 1 re-intubation table 3. functional outcomes after surgery (n = 47). questionnaire value (sd) p value preoperative iief-5 15 (±12.72) p = 0.09 postoperative iief -5 18 (± 12.02) preoperative hads score 18 (± 8.48) p = 0.03 postoperative hads score 8 (± 7.77) postoperative pgi-i score 2 (± 2.12) sd: standard deviation; iief: international index of erectile function; hads: hospital anxiety and depression scale; pgi-i: patient global impression of improvement. figure 2. one case showing the starting clinical presentation of buried penis. figure 3. one case showing the starting clinical presentation of buried penis. figure 4. skin grafting of the penile shaft. figure 5. immediate post-operative period. figure 6. clinical presentation three months after surgery. cocci_stesura seveso 26/03/19 09:44 pagina 27 archivio italiano di urologia e andrologia 2019; 91, 1 a. cocci, g. cito, m. falcone, m. capece, f. di maida, g. morelli, n. christopher, d. ralph, g. garaffa 28 discussion buried penis is a non-specific term indicating both a pediatric and adult morbid condition characterized by the complete entrapment of phallus secondary to congenital or acquired etiologies. acquired buried penis is becoming increasingly common, in concurrence with the prevalence of obesity (17). nonetheless, no reliable data about the exact incidence of buried penis in adults are available. in fact, this condition can significantly affect patients’ quality of life as it compromises sexual and urinary function and renders urogenital hygiene almost impossible (10, 18). furthermore, buried penis can be secondary to excessive pre-pubic adiposity or lymphoedematous tissue or to excessive penile shaft skin removal during circumcision (6). during micturition, urine from the buried urethral meatus drips over the scrotum and the thigh resulting in tissue maceration, infection, inflammation, scarring and chronic skin changes (19). the main proposal for the management of adult buried penis is surgical correction. several surgical techniques have been described, depending on the etiology of the buried penis. when insufficient penile skin is available, either due to previous overzealous circumcision or because all skin is affected by ls and therefore needs to be removed at the time of surgery, adequate cover can be achieved with a stsg (20). in case of excessive penoscrotal lymphoedema, all the lymphoedematous tissue has to be excised down to buck’s fascia on the penis and spermatic fascia on the testicles. genital skin cover of the penis is achieved with preputial flaps, as they are never affected by lymphoedema, and stsg while scrotal reconstruction is achieved with craniodorsal flaps (21). if excessive suprapubic adiposity is the cause of the buried penis, the excessive adipose tissue has to be completely removed, either through an open suprapubic fat pad excision or liposuction. if excessive abdominal skin is present, the patient needs also to undergo an apronectomy to allow adequate exposure of the genitalia. suspensory ligament division can be performed in combination with suprapubic fat pad excision in order to gain some extra penile length (17). donatucci et al. described a treatment algorithm ranging from release of scar contracture and primary closure (10). if insufficient release of the phallus through scar release occurs, then panniculectomy is justified. depending on the adequacy of skin or soft tissue for closure, the next step would be to use primary skin closure versus z-plasty. if native skin is not available and/or of poor quality, then split thickness skin grafts or flaps may be necessary. skin flaps should only be used when an inadequate graft bed exists (14). as a common rule, in case of ls, genital skin should not be used for repair, as it can potentially develop ls in the future and stsg are the solution of choice (12). generally, thick stsg tend to heal with less contracture and dyschromia than their thin counterparts and therefore are ideal for penile shaft cover in patients who are keen to resume sexual activity. on the other hand, thin stsg tend to have a better take and are therefore the solution of choice for coronal and glans reconstruction (9, 22). the current series confirms the importance of surgically addressing buried penis in order to improve sexual and urinary function, which translates in a significant improvement in overall quality of life. in particular, according to literature, sexual penetration became possible in about 98% of cases and more than 90% of patients were satisfied with the outcome of surgery (9, 23). however, the main limitation of the current study was represented by the small number of the study cohort. conclusions surgical management of acquired adult buried penis is necessary as this condition can have a profound negative impact on quality of life. in expert hands, excision of excessive adipose/lymphoedematous tissue and of genital skin affected by ls followed by reconstruction with stsg yields satisfactory functional results and allows restoration of sexual and urinary function in most patients. references 1. keyes el. phimosis-paraphimosis-tumors of the penis. appleton & co, new york, ny, usa 1919. 2. wollin m, duffy pg, malone ps, ransley pg. buried penis. a novel approach. br j urol. 1990; 65:97-100. 3. crawford bs. buried penis. br j plast surg. 1977; 30:96-99. 4. maizels m, zaontz m, donovan j, et al. surgical correction of the buried penis: description of a classification system and a technique to correct the disorder. j urol. 1986; 136:268-271. 5. cromie wj, ritchey ml, smith rc, zagaja gp. anatomical alignment for the correction of buried penis. j urol. 1998; 160:14821484. 6. mattsson b, vollmer c, schwab c, et al. complications of a buried penis in an extremely obese patient. andrologi.a 2012; 44(suppl 1): 826-828. 7. tausch tj, tachibana i, siegel ja, et al classification system for individualized treatment of adult buried penis syndrome. plast reconstr surg. 2016; 138:703-711. 8. frenkl tl, agarwal s, caldamone aa. results of a simplified technique for buried penis repair. j urol. 2004; 171:826-828. 9. fuller tw, theisen k, rusilko p. surgical management of adult acquired buried penis: escutcheonectomy, scrotectomy, and penile split-thickness skin graft. urology. 2017; 108:237-238. 10. donatucci cf, ritter ef. management of the buried penis in adults. j urol. 1998; 159:420-424. 11. rybak j, larsen s, yu m, levine la. single center outcomes after reconstructive surgical correction of adult acquired buried penis: measurements of erectile function, depression, and quality of life. j sex med. 2014; 11:1086-1091. 12. garaffa g, shabbir m, christopher n, et al. the surgical management of lichen sclerosus of the glans penis: our experience and review of the literature. j sex med. 2011; 8:1246-1253. 13. yalcin i, bump rc. validation of two global impression quescocci_stesura seveso 26/03/19 09:44 pagina 28 tionnaires for incontinence. am j obstet. gynecol. 2003; 189:98101. 14. rosen rc, cappelleri jc, gendrano n, 3rd. the international index of erectile function (iief): a state-of-the-science review. int j impot res 2002; 14:226-244. 15. d'elia c, cerruto ma, cavicchioli fm, et al. critical points in understanding the italian version of the iief 5 questionnaire. arch ital urol androl. 2012; 84:197-201. 16. zigmond as, snaith rp. the hospital anxiety and depression scale. acta psychiatr scand. 1983; 67:361-370. 17. adham mn, teimourian b, mosca p. buried penis release in adults with suction lipectomy and abdominoplasty. plast reconstr surg. 2000; 106:840-844. 18. tang sh, kamat d, santucci ra. modern management of adultacquired buried penis. urology. 2008; 72:124-127. 19. burns h, gunn js, chowdhry s, et al. comprehensive review and case study on the management of buried penis syndrome and related panniculectomy. eplasty. 2018; 18:e5. 20. triana junco p, dore m, nunez cerezo v, et al. penile reconstruction with skin grafts and dermal matrices: indications and management. european j pediatr surg rep. 2017; 5:e47-e50. 21. garaffa g, christopher n, ralph dj. the management of genital lymphoedema. bju int. 2008; 102:480-484. 22. white n, hettiaratchy s, papini rp. the choice of split-thickness skin graft donor site: patients' and surgeons' preferences. plast reconstr surg. 2003; 112:933-934. 23. hughes db, perez e, garcia rm, et al. sexual and overall quality of life improvements after surgical correction of "buried penis". ann plast surg. 2016; 76:532-535. 29archivio italiano di urologia e andrologia 2019; 91, 1 surgical correction of buried penis in adults correspondence andrea cocci, md, ph.d (corresponding author) cocci.andrea@gmail.com gianmartin cito, md fabrizio di maida, md careggi hospital, department of urology, university of florence largo brambilla 3 – 50139 florence (italy) marco falcone, md molinette hospital, department of urology, university of turin, turin (italy) marco capece, md department of urology, university of naples, naples (italy) girolamo morelli, md department of urology, university of pisa, pisa (italy) nim christopher, md david ralph, md giulio garaffa, md the institute of urology, uclh, and international andrology, london (uk) cocci_stesura seveso 26/03/19 09:44 pagina 29 11archivio italiano di urologia e andrologia 2019; 91, 1 original paper factors associated with urinoma accompanied by ureteral calculi ercan öğreden 1, ural oğuz 1, mehmet karadayı 1, erhan demirelli 1, alptekin tosun 2, mücahit günaydın 3 1 giresun university, faculty of medicine, department of urology, giresun, turkey; 2 giresun university, faculty of medicine, department of radiology, giresun, turkey; 3 giresun university, faculty of medicine, department of emergency medicine, giresun, turkey. objective: urinoma is a rare entity and mainly occurs due to acute obstruction such as ureteral stone. we aimed to demonstrate factors associated with urinoma accompanied by ureteral calculi. material and methods: data of 550 patients who were diagnosed with ureteral stone by computed tomography (ct) were analyzed retrospectively. in 20 patients perirenal urinoma was associated with ureteral calculi (group i), whereas in other 530 patients no urinoma was detected (group ii). gender, age, size, side and localization of the stone, hydronephrosis, fever, sepsis, urinary tract infections (utis), hematuria, serum creatinine, blood urea nitrogen (bun), white blood cell (wbc), c-reactive protein (crp), presence of diabetes mellitus (dm), hypertension (ht) and cronic kidney disease (ckd) of the two groups were compared. results: the average age of the patients were 46.2 (20-71) and 44.9 (10-82) years in group i and group ii, respectively (p > 0.05). according to our results leukocytosis, microscopic and macroscopic hematuria, utis, increase of serum creatinine, bun and crp, diagnosis of dm and ht were significantly associated with urinoma (p < 0.05). in addition, patients with distal ureteral stones are more prone to urinoma (p = 0.001). an interesting finding of the study was that the stone size in group i (median 5 mm [range 3-8]) was significantly smaller than in group ii (9.3 mm [4-25]; p = 0.001). conclusions: small stone size, distal localisation of the stone in ureter, leukocytosis, hematuria, utis, increase of serum creatinine, bun and crp, presence of dm and ht are associated with perirenal urinoma. key words: computerized tomography; factors associated with urinoma; prevalence; ureteral calculi; urinoma. submitted 26 august 2018; accepted 11 october 2018 summary no conflict of interest declared. noma (2). when the intraluminal pressure exceeds 35 cm/h2o, rupture develops from the fornix, which is the weakest part of the collecting system, resulting in urinoma. in this case, the urine is first spread to the subcapsular area, then to the perirenal region and the retroperitoneal area (3). urinoma leads to local irritation, inflammatory side effects, fever, malaise, sepsis, acute abdomen and deterioration of general condition (4). computed tomography (ct) is adequate for definitive diagnosis of urinoma. at ct, fluid collection around the kidney and imaging of the stone within the ureter is sufficient for the diagnosis of spontaneous urinoma. it may also document the contrast extravasation from the collecting system and determine the location of the rupture (5, 6). ureterorenoscopic stone surgery and ureteral stent placement are recommended in the current treatment of spontaneous urinoma (7). there is no specific finding of urinoma and this may lead to delayed diagnosis and treatment causing increased morbidity and mortality in patients who have admitted to emergency clinics with colic pain. in this study, it was aimed to identify the risk factors for urinoma, to define parameters that would facilitate the diagnosis and help in choosing appropriate treatment, and to discuss the topic under light of current literature. material and methods between may 2010 and march 2018, 11,000 patients were diagnosed with ureteral stone at our center. the diagnosis of stone was made by direct x-ray, intravenous pyelogram (ivp), ultrasonography (usg), unenhanced ct and contrast-enhanced ct. the data of 2100 patients who underwent ureterorenoscopy (urs) due to ureteral stone were retrospectively reviewed. electronic and conventional medical records, including demographic information, laboratory data, electronic notes, operative reports and radiological reports, were reviewed for each patient. a total of 550 patients who were diagnosed with ureteral stone by ct and whose data were complete were included in the study. patients with kidney trauma and patients with a history of kidney surgery were excluded from the study. vital findings were also queried from the medical records and doi: 10.4081/aiua.2019.1.11 introduction urinoma is defined as an extravasated urine collection with surrounded fibrous capsule. urinary stones, surgical ligation of ureters, tumors, posterior urethral valve (puv) and blunt or penetrating traumas are involved in the etiology of urinoma (1). spontaneous urinoma is rare and ureteral stones are among the most common causes of spontaneous urinoma. high hydrostatic pressure applied on the ureter wall by the impacted ureteral stone and formation of micro-tears in the mucosa during stone passage play an important role in the mechanism of uriogreden_stesura seveso 25/03/19 17:13 pagina 11 archivio italiano di urologia e andrologia 2019; 91, 1 e. öğreden, u. oğuz, m. karadayı, e. demirelli, a. tosun, m. günaydın 12 presence of utis, fever and urosepsis were recorded. patients' age, gender, stone localization, presence of hydronephrosis, fever, sepsis, utis, microscopic and macroscopic hematuria, serum creatinine, bun, wbc and crp values were evaluated. chronic diseases such as diabetes mellitus (dm), hypertension (ht) and chronic kidney disease (ckd) were recorded. urine cultures were obtained from patients with asymptomatic bacteriuria and appropriate empirical treatment was initiated. symptomatic utis criteria included fever, costovertebral angle sensitivity, pyuria (≥ 10 white blood cells per highpower field), and positive urine culture [≥ 105 colonyforming units (cfu) of uropathogen/ml]. findings of urosepsis included at least 2 signs of sirs (systemic inflammatory response syndrome) in the presence of infection (fever > 38°c or < 36°c, heart rate > 90 beats/min, respiratory rate > 20/min or paco2 < 32 mm/hg, wbc > 12,000/mm3 or < 4.000/mm3). appropriate antibiotic therapy was started according to results of antibiotic susceptibility testing in patients who were diagnosed with urosepsis. patients were classified as group i (n = 20; 3,6%) if were diagnosed with spontaneous urinoma secondary to ureteral stone and group ii (n = 530; 96,4%), if without urinoma (figure 1). patients diagnosed with urinoma and ureteral stone were treated with ureteroscopy (urs) and lithotripsy and ureteral double j stent placement. the stents were removed after 4 weeks as treatment was completed. both groups were compared in terms of gender, age, stone size and stone localization, fever, sepsis, utis, hematuria, serum cratinine, bun, wbc, ckd values as well as presence of dm, ht and ckd. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. statistical analysis the data obtained in this study were analyzed with the spss 20 (ibm spss statistics; armonk, ny, usa) package program. results are presented as frequency and percentage (%). the abnormal distribution of data from each group was confirmed with the kolmogorov-smirnov test, thus statistical comparisons were performed using mann whitney-u test. chi-square test was used to examine the dependency between the groups. a p value less than 0.05 was considered statistically significant. results in this study, we found urinoma in 20 (0.2%) of 11000 patients diagnosed with ureteral stones in our clinic. the mean age of the patients was 46.2 (20-71) years in group i and 44.91 (10-82) years in group ii (p > 0.005). gender distributions of the patients were 16 (80%) male, 4 (20%) female in group i and 339 (63.96%) male and 191 (36.04%) women in group ii (p > 0.005). gender distributions of the patients were similar in both groups. upper ureter was considered as the segment from renal pelvis to the upper border of the sacrum, middle ureter is as the segment from the upper to the lower border of the sacrum, and lower ureter as the segment which extends from lower border of the sacrum to the bladder. proximal ureteral stones were not observed in group i, while they were present in 345 (65.1%) patients in group ii. middle ureteral stones were found in 5 (25%) patients in group i and 126 (23.8%) patients in group ii. distal ureteral stone distributions in group i and group ii were 15 (75%) and 59 (11.1%), respectively (p = 0.001). the difference of distribution of stone localizations between the groups was statistically significant. pyuria was found in 5 (25%) patients in group i and in 47 (8.9%) patients in group ii (p = 0.032). microscopic hematuria was detected in 16 patients (80%) in group i and in 42 (7.9%) patients in group ii (p = 0.001). macroscopic hematuria was positive in 9 (45%) and 42 (7.9%) patients, respectively (p = 0.001). fever was found in 12 (60%) patients in group i and in 30 (5.7%) patients in group ii (p = 0.001) and utis were detected in figure 1. the image of spontaneous urinoma. a: perirenal urinary leak; b: retroperitoneal urinary leakage; c: stones of millimetric size in the distal ureter; d: sagittal section view of urinoma and distal ureteral stone. a. b. c. d. ogreden_stesura seveso 25/03/19 17:13 pagina 12 5 (25%) and 24 (4.5%), respectively (p = 0.003). the difference between the two groups was statistically significant in terms of pyuria, hematuria, fever and utis. urosepsis was observed in 2 (10%) patients in group i and in 10 (1.9%) patients group ii, however the difference was not statistically significant (p > 0.05). crp was higher in 14 (70%) patients in group i and in 22 (4.1%) patients in group ii (p = 0.001). wbc was high in 10 (50%) patients in group i and in 24 patients (4.53%) in group ii (p = 0.001). bun was high in 7 (35%) patients in group i and in 38 (7.2%) patients in group ii (p = 0.001). creatinine was high in 10 (50%) patients in group i than and in 25 (4.7%) patients in group ii (p = 0.001). dm was detected in 7 (35%) and 23 (4.3%) patients in group i and group ii, respectively (p = 0.001). ckd was not seen in any patients in group i, whereas 7 (1.3%) patients had ckd in group ii (p > 0.05). however, this difference was not statistically significant. ht was found in 10 (50%) patients in group i and in 24 (4.5%) patients in group ii (p = 0.001). the difference between the two groups in terms of crp, wbc, bun and high serum creatinine values and presence of chronic diseases such as dm and ht was statistically significant. there was no statistically significant difference between the patient groups in term of presence of ckd (table 1). the mean stone size was 5 (38) mm in group i and 9.3 (425) mm in group ii (p = 0.001). the difference in stone size between the two groups was statistically significant (table 2). according to logistic regression analysis results, 1 mm increase in stone length reduced the risk for urinoma 2.022-fold. the presence of microscopic hematuria and high serum crp 13archivio italiano di urologia e andrologia 2019; 91, 1 urinoma and ureteral calculi table 1. factors associated with urinoma accompanied by ureteral calculi. mann whitney u test n mean median min max sd rank avarage z p age group i 20 46.2 45 20 71 13.88 274.89 -0.465 0.642 group ii 530 44.9 44 10 82 13.95 291.73 total 550 45 44 10 82 13.94 stone size/mm group i 20 5 4 3 8 1.78 283.07 -5.785 0.001 group ii 530 9.3 9 4 25 3.56 74.9 total 550 9.1 8 3 25 3.6 table 2. the differences between groups with/without urinoma in terms of age and stone size. group i group ii total chi square test n % n % n % chi square p gender male 16 80 339 64.0 355 64.6 1.522 0.217 female 4 20 191 36.0 195 35.4 total 20 100 530 100 550 100 localization proximal 0 0 345 65.1 345 62.7 * 0.001 middle 5 25 126 23.8 131 23.8 distal 15 75 59 11.1 74 13.5 total 20 100 530 100 550 100 pyuria absent 15 75 483 91.1 498 90.5 fisher's exact 0.032 exist 5 25 47 8.9 52 9.5 total 20 100 530 100 550 100 microscopik hematuria absent 4 20 488 92.1 492 89.5 fisher's exact 0.001 exist 16 80 42 7.9 58 10.5 total 20 100 530 100 550 100 gross hematuria absent 11 55 488 92.1 499 90.7 fisher's exact 0.001 exist 9 45 42 7.9 51 9.3 total 20 100 530 100 550 100 fever absent 8 40 500 94.3 508 92.4 fisher's exact 0.001 exist 12 60 30 5.7 42 7.6 total 20 100 530 100 550 100 uti absent 15 75 506 95.5 521 94.7 fisher's exact 0.003 exist 5 25 24 4.5 29 5.3 total 20 100 530 100 550 100 urosepsis absent 18 90 520 98.1 538 97.8 fisher's exact 0.067 exist 2 10 10 1.9 12 2.2 total 20 100 530 100 550 100 crp normal 6 30 508 95.9 514 93.5 fisher's exact 0.001 high 14 70 22 4.1 36 6.5 wbc normal 10 50 506 95.5 516 93.8 fisher's exact 0.001 high 10 50 24 4.5 34 6.2 total 20 100 530 100 550 100 bun normal 13 65 492 92.8 505 91.8 fisher's exact 0.001 high 7 35 38 7.2 45 8.2 total 20 100 530 100 550 100 creatinin normal 10 50 505 95.3 515 93.6 fisher's exact 0.001 high 10 50 25 4.7 35 6.5 total 20 100 530 100 550 100 dm absent 13 65 507 95.7 520 94.6 fisher's exact 0.001 exist 7 35 23 4.3 30 5.5 total 20 100 530 100 550 100 ckd absent 20 100 523 98.7 543 98.7 fisher's exact 1 exist 0 0 7 1.3 7 1.3 total 20 100 530 100 550 100 ht absent 10 50 506 95.5 516 93.8 fisher's exact 0.001 exist 10 50 24 4.5 34 6.2 total 20 100 530 100 550 100 uti: urinary tract infection; crp: c-reactive protein; wbc: white blood cell; bun: blood urea nitrogen, dm: diyabetes mellitus; ckd: chronic kidney disease; ht: hypertension. ogreden_stesura seveso 25/03/19 17:13 pagina 13 archivio italiano di urologia e andrologia 2019; 91, 1 e. öğreden, u. oğuz, m. karadayı, e. demirelli, a. tosun, m. günaydın 14 level were both detected high in patients with urinoma. logistic regression analysis revealed that distal localization of the stones also increased the risk for urinoma 3.806-fold. discussion as a result of the collecting system disruption at any level from calyces to urethra, the urine that extravasates the urinary system is called urinoma. urinomas may sometimes, although rare, occur spontaneously. the most common etiological cause of spontaneous urinomas is the ureteral stones (8). hydronephrosis, utis, and increased pressure due to obstruction, provide a basis for rupture. the intraluminal pressure increases on the collecting system as a result of obstruction elsewhere in the system due to a stone and extravasation occurs at the calyceal fornix, the weakest part of the collecting system. the kidneys have mechanisms to protect themselves against increasing pressure in the collecting system. these mechanisms include pyelo-sinus, pyelo-venous, and pyelo-lymphatic backflow. an increase of more than 35 cmh2o in intrapelvic pressure results in the failure of these mechanisms and leads to forniceal rupture (9). furthermore, small-sized ureteral stones cause microtears during spontaneous passage; this in turn plays a facilitating role in the rupture of collecting system mucosa, resulting in extravasation of urine (10, 11). in their latest study, gershman et al. (12) reported that 75.7% of distal ureteral stones cause primary urinoma. in the same study, the mean stone size was 4.09 mm with stone size decreasing significantly from proximal ureteral to distal ureteral locations, and urinoma incidence was found to be more frequent in distal ureteral stones. in our present study, 75% of the patients with urinoma had distal ureteral stones and this finding was consistent with the literature. we found that the mean stone size was 5 mm and a 1 mm increase in stone length reduced the urinoma risk of 2.022 fold, whereas the distal localization of stones increased the urinoma risk of 3.806 fold. apart from obstruction and stasis caused by the stone in the ureteral lumen, in addition utis constitute a facilitating factor for development of the urinoma. spontaneous urinomas that develop due to an ureteral stone may cause side-pain, reno-ureteral pain, renoabdominal pain, as well as vasovagal nausea and vomiting. ureterovesical junction (uvj) stones and utis can cause urinary urgency, fever, abdominal pain and pain in genital organs. besides these symptoms, urinomas can result in serious complications. possible complications include hydronephrosis, paralytic ileus and acute abdomen, electrolyte imbalances, abscess formation, sepsis, and chronic renal failure in delayed cases (11). gershman et al. (12) reported a utis ratio of 5.2% in a retrospective study. the rate of utis in our study was 5.3% in accordance with previous reports. utis trigger the collecting system rupture and result in the accumulation of infected urine in the retroperitoneal space. this picture sets a ground for urosepsis and retroperitoneal abscess formation in delayed cases (13). in our study, we found that the rate of patients diagnosed with urosepsis was 2.2%, a rate not statistically different from that observed in absence of urinoma. furthermore, retroperitoneal abscess was not observed in any of the patients who were diagnosed with urosepsis. we think that early diagnosis of urinoma along with early surgical and medical treatment were effective in this respect. sterile urine in contact with the retroperitoneum can trigger an inflammatory response, whereas infected urine may lead to acute abdomen, retroperitoneal abscess formation and retroperitoneal fibrosis in later stages. in patients with urinary infection and pyuria, these complications may be more aggressive and may result in a clinical picture with progression to sepsis by disturbing the general condition in the patients. in many case reports published to this time, it has been reported that urinary infection, pyuria, hematuria and sepsis were present in patients who had diagnosis of urinoma in the emergency room. blood tests of these cases revealed high wbc, bun and elevated serum creatinine levels (14). in our study pyuria, hematuria, fever, utis and urosepsis were significantly common in the patients with urinoma and crp and wbc values were also high in these patients. although urinoma has been reported to play a protective role in renal function, it has been shown an impaired kidney function in several recent case reports. heikkila et al. (15) demonstrated that urinoma affects renal function and leads to progressive renal damage in 25% of patients. in our study, bun and plasma creatinine values were significantly higher in the cases with urinoma but ckd did not develop in our patients, probably because of early treatment and early surgical intervention. ht, dm and ckd are common comorbid diseases. comorbidities are important for the patient in terms of bearing an additional disease to the existing disease and facing an increased morbidity. especially, the suppression of the current clinical picture by these comorbid diseases may delay the diagnosis and increase the complication rates. many case reports published in the literature have reported that diagnosis of urinoma might be delayed with accompanied ckd and dm and as a result, the complication rates were increased (11, 15). in our present study, the dm rate was 35% vs 4.3% and the ht rate was 50% vs 4.5% in patients with and without urinoma (p < 0.05). ckd was not seen in any of the patients who had been diagnosed with urinoma. spontaneous urinoma is a rare disease and most commonly caused by ureteral stones. until recently, literature about urinoma mainly consisted of case reports only and there was no study on prevalence of urinoma. however, the development of imaging modalities, availability of spiral ct and the widespread use of contrast agents in the clinical settings have led to a relative increase in the number of diagnosed spontaneous urinomas (16, 17). in fact, in the present study, we found urinoma in 0.2% of patients diagnosed with ureteral stones. conclusions infection related parameters such as crp and wbc elevation, pyuria, hematuria, fever, and high creatinine levels were found to be higher in patients with ureteral stones and urinoma. interestingly, urinomas were more ogreden_stesura seveso 25/03/19 17:13 pagina 14 common in the smaller-sized and distally ureter-located stones. in addition, chronic diseases such as ht and dm have attracted attention as factors that increase urinoma risk in patients with ureteral stones. references 1. nouira y, ben younes a, rekik h, et al. spontaneous perirenal urinoma during nephritic colic. ann urol (paris) 2000; 34:156-7. 2. ay d, yencilek e, celikmen mf, et al. spontaneous rupture of ureter: an unusual cause of acute abdominal pain. am j emerg med. 2012, 30:1-2. 3. miller nl, lingeman je. management of kidney stones. bmj. 2007; 334: 468-72. 4. patil kk, wilcox dt, samuel m, et al. management of urinary extravasation in 18 boys with posterior urethral valves. j urol. 2003; 169:1508-11. 5. chen gh, hsiao pj, chang yh, et al. spontaneous ureteral rupture and review of the literature. am j emerg med. 2014; 32:772-4. 6. pampana e, altobelli s, morini m, et al. spontaneous ureteral rupture diagnosis and treatment. case rep radiol. 2013; 2013:851859. 7. stravodimos k, adamakis i, koutalellis g, et al. spontaneous perforation of the ureter: clinical presentation and endourologic management. j endourol. 2008; 22:479-84. 8. jeon ch, kang jh, min jh, et al. spontaneous ureteropelvic junction rupture caused by a small distal ureteral calculus. chin med j (engl) 2015; 128:3118-19. 9. georgieva m, thieme m, pernice w, et al. urinary ascites and perirenal urinoma-a renoprotective "complication" of posterior urethral valves. aktuelle urol. 2003; 34:410-12. 10. ferri e, casoni gl, morabito g, et al. rupture of the renal pelvis complicating a renal colic: report of a case. am j emerg med. 2006; 24:383-5. 11. gayer g, zissin r, apter s, et al. urinomas caused by ureteral injuries: ct appearance. abdom imaging. 2002; 27:88-92. 12. gershman b, kulkarni n, sahani dv, et al. causes of renal forniceal rupture. bju int. 2011; 108:1909-12. 13. titton rl, gervais da, hahn pf, et al. urine leaks and urinomas: diagnosis and imaging-guided intervention. radiographics. 2003; 23:1133-47. 14. pace k, spiteri k, german k. spontaneous proximal ureteric rupture secondary to ureterolithiasis. j surg case rep. 2017, 2016. 15. heikkilä j, taskinen s, rintala r. urinomas associated with posterior urethral valves. j urol. 2008; 180:1476-78. 16. murawski m, gołebiewski a, komasara l, et al. rupture of the normal renal pelvis after blunt abdominal trauma. j pediatr surg. 2008; 43:e31-33. 17. ashebu sd, elshebiny yh, dahniya mh. spontaneous rupture of the renal pelvis. australas radiol. 2000; 44:125-27. 15archivio italiano di urologia e andrologia 2019; 91, 1 urinoma and ureteral calculi correspondence ercan öğreden, md (corresponding author) ercanogreden@gmail.com ural oğuz, md mehmet karadayı, md erhan demirelli, md giresun university, faculty of medicine, department of urology, giresun (turkey) alptekin tosun, md giresun university, faculty of medicine, department of radiology, giresun (turkey) mücahit günaydın, md giresun university, faculty of medicine, department of emergency medicine, giresun (turkey) ogreden_stesura seveso 25/03/19 17:13 pagina 15 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 4300 short communication primitive robotic procedures: automotions for medical liquids in 12th century asia minor necmettin penbegul 1, murat atar 1, muammer kendirci 2, yasar bozkurt 1, namık kemal hatipoglu 1, ayhan verit 3, ateş kadıoglu 4 1 dicle university, medical faculty, dept. of urology, diyarbakir, turkey; 2 liv hospital hospital, dept. of urology, istanbul, turkey; 3 fatih sultan mehmet research and training hospital, dept. of urology, istanbul, turkey; 4 istanbul university, istanbul medical faculty, dept. of urology, istanbul, turkey. this study was presented at 30th world congress of endourology & swl congress, poster no: up-473, 4-8 sept. 2012, istanbul, turkey. in recent years, day by day, robotic surgery applications have increase their role in our medical life. in this article, we reported the discovery of the first primitive robotic applications as automatic machines for the sensitive calculation of liquids such as blood in the literature. al-jazari who wrote the book “elcâmi ‘beyne’l ‘ilm ve’l ‘amel en-nâfi ‘fi es-sınaâ ‘ti’l hiyel”, lived in anatolian territory between 1136 and 1206. in this book that was written in the twelfth century, al-jazari described nearly fifty graphics of robotic machines and six of them that were designed for medical purposes. we found that some of the robots mentioned in this book are related to medical applications. this book reviews approximately 50 devices, including water clocks, candle clocks, ewers, various automata used for amusement in drink assemblies, automata used for ablution, blood collection tanks, fountains, music devices, devices for water lifting, locks, a protractor, a boat-shaped water clock, and the gate of diyarbakir city in south-east of turkey, actually in northern mesopotamia. we found that automata used for ablution and blood collection tanks were related with medical applications; therefore, we will describe these robots. key words: robots; history of urology; robotic surgery. submitted 21 october 2014; accepted 31 october 2014 summary no conflict of interest declared. the “da vinci robotic surgical platform”, is the most commonly mentioned such device nowadays. the platform was named after leonardo da vinci (1452-1519), who is generally recognized in the literature as the first to design a robot. however, based on in-depth research into the history of robots, it is highly possible to see that the first mechanism of a robot and the relationship between robots and medical sciences occurred in anatolian territory in the twelfth century. al-jazari (1136-1206), who is known to have had a distinctive knowledge of mechanics, engineering, and automation, was a turkish scholar known to have been “the ancestor of automation and robots” and lived in the twelfth century (4). al-jazari was born in cizre, mardin province, and lived in the city of amid, now known as diyarbakir, in the period of the artuqids. as a scientist, he served for 32 years as chief engineer in artuqid palace. he wrote his book, ‘el-câmi ‘beyne’l-‘ilm ve’l-‘amel en-nâfi ‘fi es-sınaâ ‘ti’l-hiyel (the book of knowledge of ingenious mechanical devices)’ in the name of the throne of the artuqids. in this article, we discuss al-jazari and explain that he has recently been credited with the design of nearly fifty robots in the twelfth century; six of these were designed for medical purposes. materials methods this book by al-jazari was described as a work forming a keystone of world technological history and a work ahead of its time (5). however, the first explanatory english translation of this book was by donald r. hill in 1974 (6). then, in 2002, sevim tekeli and her colleagues translated and edited it into turkish (5). the mechanisms that gave this reputation to al-jazari could be described as follows: robot serving drink to sultan, robot drinking on feet, robot drinking leftovers of sultan’s chalice, clocks that ring alarms for the hours with a series of events occurring automatically and combination lock mechanisms (with 3.55 x 1015 probability of unlock) that are similar/better to today’s combinadoi: 10.4081/aiua.2014.4.300 introduction the word robot was first used by czech playwriter čapek, in his play ‘rossum’s universal robots’ (1920), wherein he described a population dependent on mechanical workers, which he called robots (1). these robots were capable of performing every kind of intellectual and physical function (2). by the 1980s, surgical robots were in use for neurosurgery and orthopedic surgery (3). recently, robot-assisted surgeries have been involved in surgical applications and are becoming more widespread as well as they improve with each passing day. verit_stesura seveso 15/01/15 13:24 pagina 300 301archivio italiano di urologia e andrologia 2014; 86, 4 medical robots in 12th century tion locks (5). in another work, al-jazari drew peacocks from whose mouths water flowed and robot men of machinery that poured abluting water into the hands of his beloved sultan who wished to avoid employing slaves in the palace. results we especially evaluated robot designed as ewers, blood collection tanks, and washbowls for ablution which we think were pioneering automatic mechanisms for the health sector. ewers, washbowls for ablution, and automata designed for hand washing sink with peacock used for ablution (figure 1a) the device consists of a sink placed on the ground, four columns rising above the sink, and, on these columns, a castle with two gates carrying the peacock. the neck of the bird is laid like a spring and its beak is toward the sink. its tail is vertical. water flows through the beak of the bird. at that moment, one of the gates opens and a robot child appears holding a soap pot in his hand. when the water flow is stopped, another gate opens, and from there another robot child holding a towel emerges. automat designed for hand washing (figure 1b-c) this mechanism consists of a platform with a child holding an ewer in the right hand and a comb and towel in the left hand. in addition to the platform are a tank with a peacock adjacent to a platform, its beak pointing toward the floor, and a dome, which is placed on four columns on top of the platform and is capped with a bird. water flows through the ewer and the bird sings as long as it flows. flowing water is collected in the tank and the bird drinks it. when the water runs out, the child passes the towel and the comb using his left hand. blood collection tanks among al-jazari’s works are blood collection tanks that measure the blood collected from a patient. no record has been found related to the blood collection tanks designed on the base of principles of equilibrium before al-jazari (7). in this automaton, floats rise with the help of a liquid that is collected in a pot and causes a counterweight to be lowered. the device described here and illustrated with a picture serves for the measurement of blood collected by cupping (8). tank with a monk indicating the amount of blood flow (figure 2a-b) the machinery is shaped like a sink and is placed on the ground. a monk stands on the platform in the middle of the tank. there is a “c” hole through which blood flows to the collector in the bottom of the tank. the blood drained into the tank flows to the collector from the hole. the collector has a “d” float and there is a rope “e” bound to the top of it. the rope coils up the “f,” “g,” and “h” reels inside the platform that carries the monk and the “j” weight is bound to its end. the shaft of the “g” reel, “k,” comes out of the platform and is fixed to the feet of the monk. the monk has a rod and it reaches the edge of the tank, which is numbered from 1 to 120. the device is located in front of the individual from whom the blood will be collected. when the blood figure 1. (a) sink with peacock used for ablution. (b-c) automat designed for hand washing. figure 2. (a-b) tank with a monk indicating the amount of blood flow. (c) blood collection tank with two clerks. (d) calculator tank by which collected blood amount can be measured. (e) blood collection tank with a castle. verit_stesura seveso 15/01/15 13:24 pagina 301 archivio italiano di urologia e andrologia 2014; 86, 4 n. penbegul, m. atar, m. kendirci, y. bozkurt, n. kemal hatipoglu, a. verit, a. kadıoglu 302 has been drained into the tank, the float rises and the “g” reel spins. in accordance with the spinning of the reel, the monk and its rod spin in a way that shows the amount of blood taken. the rod in the hand of the monk reaches the first sign once 1 dirham (dirham = 3.207 gr) of blood has been collected in the tank (5). blood collection tank with two clerks (figure 2c) this mechanism consists of a sink placed on the ground. four columns rise from the tank’s floor, and a platform on the column supports two seated clerks. in the hand of one of the clerks, there is a pen, and the tip of the pen is on the arc of a circle numbered to 120. the other clerk holds a segmented plate in one hand, and in the other a pen is positioned close to the surface of this plate. the clerk holding the pen spins accordingly as the blood drains off to the tank and the plate in the hand of the other clerk rises. the blood amount collected is indicated by the segments indicated by the pens of both of the clerks (5). calculator tank in which the amount of collected blood can be measured (figure 2d) the mechanism consists of a tank placed on the ground and having four columns located on a floor. there is a platform on the columns on which two clerks are seated. one of them holds a pen, while the other has a plate. there is a castle between the two clerks in which the chest, head, and two hands of a third man can be seen. as long as the blood is flowing into the tank, the pen of the clerk continuously shows the amount, while the plate of the other clerk shows the same amount. when the blood amount is 10 dirhams, the man in the castle shows this with his hands and shows 20 when the amount reaches 20 dirhams (5). blood collection tank with a castle (figure 2e) the mechanism consists of a tank with six columns on the floor, at the top of which is positioned a castle with twelve gates and two wings at each gate. two clerks are seated atop the castle. one of them holds a pen and the other has a plate. the appearance of the mechanism is similar to that of the other blood collection tanks. the movements of the clerk’s plate, of the clerk holding the pen, and the hand seen at the “p” window are the same as those of the figures in the previous tanks. however, ten figures of children emerge from the gates to show each amount of 10 dirhams of blood and show 10, 20, 30 . . . and 120 dirhams with their hands that are positioned on this device (5). discussion al-jazari described many machine parts that are included in the european engineering terminology of the current time, plus he mentioned these long before leo nardo da vinci, who first referred to the cone valve in the 1500s (4). in the machines he designed, al-jazari was the first to use the systems that are reminiscent of “the crankshaft” and “camshaft” that are now used in all motor vehicles (9-11). these automatic ablution machines and automata de signed for hand washing can be accepted as the first design draft of the hand-washing sinks and automatic towel-holding apparatuses used especially in surgery rooms today and it is astonishing that this level could be reached in the circumstances of the twelfth century. al-jazari invented a blood-letting measuring device that contained a maximal amount of 120 dirhams (120 dirhams = 120 x 3.207 = 380 g), which, interestingly, corresponds to one unit of blood. probably the maximal amount of blood to be transfused at one time had been kept at that level, which is nowadays used as a cut-off value. al-jazari started to fabricate a blood-letting measuring device with a simple design and then invented more sophisticated models. in the first of his blood collection devices, the amount of blood drawn was indicated with only one robot (figures 2a-b), while he mounted four indicators in his latest robots (figure 2e). to us, this contrivance suggests transmission from a one-armed robotic telescoping grasper system to four-armed robotic surgical systems. based on literature reviews, robotic surgery was firstly employed in 1983 during an orthopedic procedure; however, al-jazari is the scientist who designed the first robot, which he used in medical procedures in the twelfth century. in fact, his peculiar automation of a blood-letting measuring device displayed the amount of the blood drawn at a given moment during a phlebotomy procedure (2). even though some devices were fabricated that resembled the automata made by al-jazari in the twelfth century, the crank gears designed and used by al-jazari that were depicted in his works were quite distinct from any others. it is known that the crank system was firstly used by leonardo da vinci in the twelfth century (10). thus, the name of the robotic system used in urologic surgery is dedicated to him (da vinci robots). but in fact, al-jazari used this system 300 years before da vinci and depicted its three-dimensional design, which we still admire today. even in the article in which the historical background of the “da vinci” robot was told, al-jazari was credited as the first scientist to have invented the first programmable humanoid robot (2). inventions of al-jazari are still in vogue in modern engineering (12), and with his everlasting designs of automata, he is regarded as the “father of robots” (13-14). not only did he invent automata that were not surpassed for centuries, he also described their construction process step by step. robots fabricated based on his instructions in his works, are still functioning perfectly well. in conclusion, we think that robots were firstly described, and even used in medical procedures, by the famous scientist al-jazari even three hundered years before leonardo da vinci, thus recently, popularized as “da vinci” robotic surgical systems. even though he depicted his robotic systems in his books, al-jazari’s robotic contrivances could not pass his name on to future generations. this heritage should be transferred to future generations, and his life and his inventions should be better recognized. verit_stesura seveso 15/01/15 13:24 pagina 302 303archivio italiano di urologia e andrologia 2014; 86, 4 medical robots in 12th century references 1. shah j, mackay s, rockall t, et. al. urobotics: robots in urology. bju int. 2001; 88:313. 2. yates dr, vaessen c, roupret m. from leonardo to da vinci: the history of robot-assisted surgery in urology. bju int. 2011; 108:1708-13; discussion 1714. 3. buckingham ra, buckingham ro. robots in operating theatres. bmj 1995; 311:1479. 4. mahsereci n: ebû’l-izz el-cezerî. bilim ve ütopya 2002; 91:6-11. 5. tekeli s, dosay m, unat y. el-câmi ‘beyne’l – ‘ilm ve’l – ‘amel en-nâfi ‘fi es-sınaâ ‘ti’l –hiyel. ankara, türk tarih kurumu basımevi (turkish historical establishment press) 2002. 6. hill dr. the book of knowledge of ingenious mechanical devices (kitâb fî ma’rifat al-hiyal al-handasiyya) by ibn al-razzâz aljazzarî. dordrecht and boston 1974. 7. unat y. cezerî’nin yapıtı. bilim ve ütopya. 2002; 91:19. 8. sezgin f. islam’da bilim ve teknik (science and technique in islam). istanbul, istanbul büyüksehir belediyesi kültür a.s. yayınları, 2008, pp 35. 9. ifrah g: the universal history of computing: from the abacus to the quatum computer. wiley, 2001. 10. romdhane l, zeghloul s. al-jazari (1136-1206), in ceccarelli m: distinguished figures in mechanism and machine science springer netherlands, 2010, pp 1-21. 11. hill dr. mechanical engineering in the medieval near east. scientific american. 1991:64-69. 12. hill dr. studies in medieval islamic technology. brookfield usa, 1998. 13. chapius a, droz e. automota: a historical and technological study. france, neuchatel: éditions du griffon, 1958. 14. nocks l. the robot: the life story of a technology. greenwood press, westport, ct, 2007. correspondence necmettin penbegul, md murat atar, md yasar bozkurt, md namık kemal hatipoglu, md dicle university, medical faculty, dept. of urology, diyarbakir, turkey muammer kendirci, md liv hospital hospital, dept. of urology, istanbul, turkey ayhan verit, md veritayhan@yahoo.com fatih sultan mehmet research and training hospital, dept. of urology, içerenköy/atasehir tr34752 istanbul, turkey verit_stesura seveso 15/01/15 13:24 pagina 303 archivio italiano di urologia e andrologia 2018; 90, 4270 original paper lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl volkan caglayan, efe onen, sinan avci, murat sambel, metin kilic, sedat oner, mustafa murat aydos, halil emre yıldız university of health sciences, bursa yuksek ihtisas training and research hospital, bursa, turkey. objective:to evaluate the diagnostic value of serum inflammation markers derived from complete blood count in diagnosis of prostate cancer (pca). methods: we retrospectively analyzed the data of 621 patients who underwent prostate biopsy between march 2013 and april 2018. age, prostate specific antigen (psa), free psa, platelet count, neutrophil count, lymphocyte count, monocyte count, prostate volume (pv) and pathology result of the patients were recorded. patients were grouped as benign prostatic hyperplasia (bph), prostatitis and pca. patients were also grouped according to psa values, as psa < 4 , psa 4-10 and psa > 10 ng/dl. results: the mean lymphocyte-to-monocyte ratio (lmr) value of the patients with pca was significantly lower in the entire cohort (p = 0.047). in the psa 4-10 ng/dl range, lmr value wassignificantly lower in patients with pca than those with bph or prostatitis ( p = 0.012). in this psa range, free/total psa ratio and lmr were significant factors to predict pca. the cut-off values of lmr, free/total psa were 3.05 and 0.15 respectively. the sensitivities, spesificities, positive predictive values (ppv) and negative predictive values using lmr cut-off, free/total psa cut-off and their combination were assessed. specificity and ppv of the combination group were higher (97.2%, 83.3% respectively) compared to free/total psa cut-off group (91.6%, 76.6%) and lmr cut-off group (67.8%, 43.7%). conclusions: lmr is a useful tool at detecting pca especially in patients with psa value between 4 and 10 ng/dl. the combination of free/total psa ratio and lmr improves the diagnostic accuracy more than the use of free/total psa ratio alone. key words: lymphocyte-to-monocyte ratio; prostate cancer. aubmitted 19 august 2018; accepted 19 august 2018 summary no conflict of interest declared. pca and reduced the associated mortality. however, the low specificity of psa can lead to unnecessary biopsies, overdiagnosis and overtreatment (3). psa is organ but not cancer-specific, therefore it may be elevated in benign conditions such as benign prostate hyperplasia (bph), prostatitis, urinary tract infections and trauma. after detection of elevated psa, it is recommended to perform prostate biopsy (pbx) which is still the gold standard method for diagnosis of pca. however pbx is associated with several complications, including pain, hematospermia, haematuria, hematochezia, and potentially severe infectious complications, ranging from urinary tract infections (utis) and prostatitis to sepsis (4). although psa is a useful tool at detecting pca, concern about performing unnecessary pbx considering overdiagnosis and complications is the crucial problem for urologists. some psa-related testing parameters (e.g., psa density, free/total psa ratio, psa doubling time, and prostate health index test) have been used to improve the accuracy of pca prediction (5). thus, new biomarkers may be needed to improve decision-making regarding initial management, including whether to biopsy. over the last decade, it has become clear that systemic inflammation plays an important role in the development and progression of cancer. the markers of the systemic inflammatory response are usually based around composite ratios or cumulative scores of different circulating white blood cells representing the systemic responses of lymphoid/myeloid tissue. the main approach is to take the ratio of different white blood cells and then apply a prognostic threshold to the ratio such that outcome is effectively stratified. the most repeatedly validated examples of this approach are the neutrophil-lymphocyte ratio (nlr) based on the ratio of circulating neutrophil and lymphocyte counts, the platelet-lymphocyte ratio (plr) based on the ratio of circulating platelet and lymphocyte counts and the lymphocyte-monocyte ratio (lmr) based on the ratio of circulating lymphocyte and monocyte counts. in this study, we aimed to investigate the role of the systemic inflammatory response markers prior to pbx at predicting histologic≠al outcomes. doi: 10.4081/aiua.2018.4.270 introduction prostate cancer (pca) is the second most frequently diagnosed cancer and the fifth most common cause of cancer-associated death in men worldwide (1). despite the recent advances in diagnostic and therapeutic approaches, it is still a major health concern especially in developed countries and especially in elderly men (2). serum prostate-specific antigen (psa) is widely used as a biomarker for this cancer, and its widespread introduction has undoubtedly enhanced the early detection of caglayan_stesura seveso 10/01/19 16:08 pagina 270 271archivio italiano di urologia e andrologia 2018; 90, 4 lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl. methods we retrospectively analyzed the data of 621 patients who underwent 12-core pbx between march 2013 and april 2018. pbx was performed within 4 weeks after blood tests. age, total psa level, free psa level, hemoglobin level, platelet count, neutrophil count, lymphocyte count, monocyte count, prostate volume and pathology result of the patients were recorded. patients with symptomatic prostatitis or urinary tract infection or systemic inflammatory disease or any history of anti-inflammatory drug use within 2 weeks before pbx were excluded. also patients with high grade intraepithelial neoplasia (h-pin) and atypical small acinar proliferation (asap) were excluded due to the low number of cases. finally the patients whose psa was less than 100 ng/ml and those had no evidence of metastasis in imaging reports were included. the patients were laid down in left lateral decubitus position and in the flexion of knees and hips. general electric logiq 100 pro series ultrasound device was used with 6.5 mhz rectal probe, the widest diameter of which was 23 mm. biopsy samples were taken as 12 cores with the use of 30 cm 18 gauge full automatic biopsy needle. data analysis biopsy results, gleason scores, psa, free/total psa ratio, prostate volume, age, nlr results, plr results, lmr results were assessed using the chisquare test or mann-whitney u-test to determine statistically significant differences. after adjusting for confounding factors, univariate and multivariate logistic regression analyses were performed to determine the factors effecting pca diagnosis. the predictive accuracy of the multivariate model was assessed using receiver operating characteristic (roc)-derived area under the curve (auc) analysis. the ibm spss software package version 21.0 (statistical package for social sciences™, chicago, il, usa) weas used for statistical analysis. a two-tailed p < 0.05 was considered as significant for all analyses. results a total of 800 patients who underwent transrectal ultrasound guided pbx were recorded. of these, 179 did not meet inclusion criterias and were excluded (lack of data regarding cbc in 77 patients, presence of hpin or asap in 30 patients, presence of metastasis in the imaging reports in 47 patients and presence of psa higher than 100 ng/dl in 25 patients). finally the data of 621 patients were investigated. the mean age was 64.97 ± 6.36 years. the mean prostate volume was 71.64 ± 39.9 cc. the mean psa and free/total psa value were 9.86±7.43 ng/dl and 0.23 ± 0.10, respectively. the mean nlr, plr and lmr values were 2.50 ± 1.17, 124.94 ± 51.81 and 3.84 ± 1.44, respectively. additionally, patients were grouped with regard to histology of the biopsy. among all table 1. comparison of the study parameters of 3 histology groups in entire cohort. bph (n = 357) prostatitis (n = 24) pca (n = 240) p value age, years (mean ± sd) 64,45 ± 6,08 64 ± 5,87 65,85 ± 6,74 0,004 total psa, ng/dl (mean ± sd) 8,82 ± 6,61 6,27 ± 2,46 11,79 ± 8,68 0,001 free/total psa (mean ± sd) 0,25 ± 0,10 0,29 ± 0,06 0,18 ± 0,10 0.000 prostate volume, cc (mean ± sd) 82,82 ± 43,49 72,75 ± 51,14 54,90 ± 24,30 0.000 comparison of the study parameters of 3 histology groups in psa 4-10 range bph (n = 252) prostatitis (n = 18) pca (n = 150) age, years (mean ± sd) 64.58 ± 5.89 63.17 ± 6.5 66.64 ± 6.04 0.000 total psa, ng/dl (mean ± sd) 6.6 ± 1.63 6.13 ± 1.72 6.86 ± 1.72 0.106 free/total psa (mean ± sd) 0.25 ± 0.09 0.30 ± 0.06 0.19 ± 0.11 0.000 prostate volume, cc (mean ± sd) 80.3 ± 39.6 80.17 ± 54.75 50.78 ± 19.08 0.000 pca: prostate cancer; bph: benign prostate hyperplasia; sd: standart deviation; psa: prostate spesific antigen. table 2. mean ± sd values of the inflammation markers and p values for comparison of the histological groups in the entire cohort. bph (n = 357) prostatitis (n = 24) pca (n = 240) nlr value bph = 2,50 ± 1,22 1 0,529 0,543 (mean ± sd) prostatitis = 2,34 ± 0,96 0,529 1 0,207 pca = 2,51 ± 1,10 0,543 0,207 1 plr value bph = 124,02 ± 49,25 1 0,480 0,669 (mean ± sd) prostatitis = 108,93 ± 39,05 0,480 1 0,512 pca = 127,89 ± 56,30 0,669 0,512 1 lmr value bph = 3,92 ± 1,45 1 0,485 0,047 (mean ± sd) prostatitis = 4,11 ± 1,19 0,485 1 0,098 pca = 3,67 ± 1,44 0,047 0,098 1 pca: prostate cancer; bph: benign prostate hyperplasia; sd: standart deviation; psa: prostate spesific antigen; nlr: neutrophile to lymphocyte ratio; plr: platelet to lymphocyte ratio; lmr: lymphocyte to monocyte ratio. bph (n = 252) prostatitis (n = 18) pca (n = 150) nlr value bph = 2.52 ± 1.31 1 0.439 0.295 (mean ± sd) prostatitis = 2.64 ± 0.94 0.439 1 0.982 pca = 2.55 ± 1.10 0.295 0.982 1 plr value bph = 123.64 ± 49.58 1 0.910 0.743 (mean ± sd) prostatitis = 114.06 ± 28.13 0.910 1 0.782 pca = 124.13 ± 48.79 0.743 0.782 1 lmr value bph = 3.95 ± 1.54 1 0.536 0.012 (mean ± sd) prostatitis = 3.80 ± 1.19 0.536 1 0.533 pca = 3.56 ± 1.33 0.012 0.533 1 pca: prostate cancer; bph: benign prostate hyperplasia; sd: standart deviation; psa: prostate spesific antigen; nlr: neutrophile to lymphocyte ratio; plr: platelet to lymphocyte ratio; lmr: lymphocyte to monocyte ratio. table 3. mean ± sd values of the inflammation markers and p values for comparison of the histological groups in the cohort psa 4-10 ng/dl range. caglayan_stesura seveso 10/01/19 16:08 pagina 271 archivio italiano di urologia e andrologia 2018; 90, 4 v. caglayan, e. onen, s. avci, m. sambel, m. kilic, s. oner, m. murat aydos, h. emre yıldız 272 the individuals, bph was detected in 357 patients, prostatitis was detected in 24 and pca was detected in 240. the mean age and the mean psa value of the pca group were significantly higher when compared to the other groups. also the mean prostate volume and free/total psa ratio were significantly lower (table 1). nlr, plr and lmr values of the histological groups were compared. any statistically significant difference was not observed for nlr and plr values. mean lmr value of the patients with pca was significantly lower than patients with bph and prostatitis (p = 0.047) (table 2). the patients were divided into 3 groups as; with psa lower than 4 ng/dl, with psa between 4 and 10 ng/dl and with psa higher than 10 ng/dl. in the patients with psa between 4 and 10 ng/dl, lmr value was significantly lower in patients with pca than those with bph or prostatitis (p = 0.012) (table 3). any statistically significant difference between the groups was not observed in nlr and plr in the psa 410 ng/dl range. in the group of the patients with psa higher than 10 ng/dl, there was not any statistically significant variation for nlr, plr and lmr (table 4). in this group, the presence of prostatitis could not be compared due to the low number of patients. the patients with pca were seperated into 2 groups as patients with gleason score 6 and patients with gleason score 7 and above. there was no statistically significant difference between the groups in nlr, plr and lmr value (table 5). in the patients with psa between 4 and 10 ng/dl, age, free/total psa ratio and lmr were significant factors to predict pca. based on the auroc curve, the cut-off points of lmr, free/total psa and age were 3.05, 0.15 and 65.5 respectively (figure 1). multivariate analysis showed that lmr (hr = 1.65), age (hr = 2.77) and free/total psa ratio (hr = 12.3) were independent risk factors to predict pca (table 6). the sensitivities, spesificities, positive predictive values and negative predictive values using lmr cut-off, free/total psa cut-off and their combination were showed in table 7. specificity and positive predictive value of the combination group were higher (97.2%, 83.3% respectively) compared to the free/total psa cut-off group (91.6%, 76.6% respectively) and lmr cut-off group (67.8%, 43.7% respectively) (table 7). table 4. mean ± sd values of the inflammation markers and p values for comparsion of the histological groups in the patients with psa higher than 10 ng/dl. bph (n = 78) pca (n = 72) nlr (mean ± sd) bph = 2.63 ± 1.0 1 0.839 pca = 2.66 ± 1.1 0.839 1 plr (mean ± sd) bph = 133.3 ± 51.1 1 0.965 pca = 143±71 0.965 1 lmr (mean ± sd) bph = 3.76 ± 1.1 1 0.892 pca = 3.69 ± 1.3 0.892 1 pca: prostate cancer; bph: benign prostate hyperplasia; sd: standart deviation; psa: prostate spesific antigen; nlr: neutrophile to lymphocyte ratio; plr: platelet to lymphocyte ratio; lmr: lymphocyte to monocyte ratio. table 5. mean ± sd values of the inflammation markers and p values for comparsion of the gleason score groups in the entire cohort. gleason 6 (n = 173) gleason > 7 (n = 67) nlr (mean ± sd) gs 6 = 2.5 ± 1.05 1 0.454 gs > 7 = 2.57 ± 1.23 0,454 1 plr (mean ± sd) gs 6 = 122.1 ± 46.8 1 0.082 gs > 7 = 142.8 ± 73.8 0,082 1 lmr (mean ± sd) gs 6 = 3.7 ± 1.15 1 0.177 gs > 7 = 3.6 ± 2.02 0,177 1 sd: standart deviation; nlr: neutrophile to lymphocyte ratio; plr: platelet to lymphocyte ratio; lmr: lymphocyte to monocyte ratio; gs: gleason score. table 6. univariate and multivariate analyses for predicting prostate cancer. n univariate analysis multivariate analysis hr 95% ci p hr %95 ci p age (year) < 65.5 186 1 1.14-1.86 0.01 1 1.68-4.56 < 0.001 > 65.5 216 1.45 2.77 lmr value > 3.05 258 1 0.99-1.37 0.04 1 1.02-2.6 0.037 < 3.05 144 1.17 1.65 free/total psa value > 0.15 1 1.45-1.97 < 0.001 1 6.80-22.22 < 0.001 < 0.15 1.69 12.3 psa: prostate spesific antigen; lmr: lymphocyte to monocyte ratio; hr: hazard ratio; ci: confidence interval. sensitivity specificity ppv npv free/total psa < 0.15 46% (69 of 150) %91.6 (231of 252) %76.6 (69 of 90) %71.7 (231 of 322) lmr < 3.050 %42 (63 of 150) %67.8 (171 of 252) %43.7 (63 of 144) %73 (171 of 234) free/total psa < 0.15 & lmr < 3.050 %16.6 (25 of 150) %97.2 (247 of 252) %83.3 (25 of 30) %66.4 (247 of 372) ppv: positive predictive value; npv: negative predictive value; psa: prostate spesific antigen; lmr: lymphocyte to monocyte ratio. table 7. mean ± sd values of the inflammation markers and p values for comparison of the histological groups in the cohort psa 4-10 ng/dl range. caglayan_stesura seveso 10/01/19 16:08 pagina 272 273archivio italiano di urologia e andrologia 2018; 90, 4 lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl. discussion the immune system plays an important role in cancer pathogenesis. serum biomarkers which can be easily derived from complete blood count (cbc) are useful tools to estimate the prognosis and survival in many solid cancers. the presence of low lmr, high plr and high nlr values were associated with poor overall survival (os) in the published systemic reviews (6-8). in the study performed by gu et al., elevated nlr was closely associated with poor os in pca (9). also a similar study in japan, revealed that elevated nlr was correlated with both poor cancer-spesific survival (p = 0.018) and os (p = 0.008) in patients with metastatic pca.10 besides, nonsteroidal anti-inflammatory drug medications have been suggested to reduce the development risk of pca (11, 12). additionally to the prognostic value of serum inflammation markers, there are also many studies assessing the diagnostic value of those prior to the pbx with controversial results in the literature. in the study performed by kamali et al., 500 patients who underwent pbx were evaluated but statistically significant difference was obtained between the nlr of the patients with positive biopsy and those with negative biopsy p = 0.112): nlr was not described as a predictive factor for positive pca biopsy (13). in another study, 3913 men who underwent pbx were analyzed retrospectively. the nlr value was higher in the biopsy-positive group than in the biopsy-negative group (p < 0.001). also the nlr value was significantly higher in high-grade gleason pca group than the biopsy-negative group and low-grade pca group (p < 0.001). on multivariate analyses, a higher nlr was associated with pca detection (or = 1.37, 95% ci: 1.017-1.850, p = 0.038) (14). kawahara et al. investigated the data of 810 men with psa value between 4 and 10 ng/ml who underwent pbx. nlr value was significantly higher in men with positive biopsy than in those with negative biopsy (p < 0.001). using nlr cut-off point of 2.40 determined by the auroc curve, positive/negative predictive values of nlr alone and nlr combined with free/total psa ratio (cut-off: 0.15) were 56.6%/60.8% and 80.7%/60.1%, respectively (15). huang et al. analyzed a total of 662 patients who underwent transperineal template guided pbx. in the entire cohort, any significant difference was not found in nlr when patients were grouped with regard to histology of the biopsy (cancer and no cancer) (p = 0.424). however, they observed additional significant difference in nlr figure 1. auroc for variables to predict prostate cancer. caglayan_stesura seveso 10/01/19 16:08 pagina 273 archivio italiano di urologia e andrologia 2018; 90, 4 v. caglayan, e. onen, s. avci, m. sambel, m. kilic, s. oner, m. murat aydos, h. emre yıldız 274 value (p = 0.002) when analyses were restricted to patients with psa ranged from 4 to 10 ng/ml (cut-off value was set at 2.44). accordingly the patients were classified into high-nlr and low-nlr group. the highnlr showed significantly high pca detection rate in the entire cohort and in the cohort with psa ranged from 4 to 10 ng/ml (175/338, 142/324, p = 0.041 and 36/77, 14/87, p < 0.001 respectively) (16). gokce et al. investigated the data of 1836 patients. patients were divided as follows: the group with bph, the group with prostatitis and the group with pca. pre-biopsy mean nlr value of the prostatitis group was significantly higher compared to the pca and bph groups (p = 0.0001). the mean nlr of pca group was significantly higher compared to the bph group (p = 0.002). also, the pca patients with high gleason score (gs) (gs 8 and above) had a significantly higher mean nlr compared to the pca patients with gs 5-6 and gs 7 (p = 0.0001) (17). in the present study; when evaluating the nlr, any statistically significant difference was not observed based on the biopsy results. also, cohort were seperated into 3 groups as men with psa value of < 4, psa between 4 and 10 and psa of > 10 ng/dl. no statistically significant nlr difference was observed based on the biopsy results in any psa range. we divided the pca patients into 2 groups as the group with gs 6 and gs 7 and above. there was not a statistically significant difference between the gs groups. additionally, controversial to the study performed by gokce et al., we did not observe a significant highness in the prostatitis group compared to the pca and bph group. our data showed that chronic prostatitis does not effect the inflammation markers derived from cbc considerably. kaynar et al. retrospectively reviewed the data of 201 patients. pathological sample results were categorized as chronic prostatitis, bph and pca. psa levels were also categorized as 0-4 ng/ml, 4-10 ng/ml, and 10 ng/ml and above.any statistically significant difference was not observed between benign or malign groups in terms of age, nlr and mean prostate volume. statistically significant differences were present only in the psa 10 ng/ml and above group related to mean plr values (p: 0.044) (18). in another study, plr value was statistically higher in pca group than in bph group while nlr value was not (19). in our study, pre-biopsy plr value was not associated with higher pca detection rate in any psa range or in any gleason score range. to our knowledge, there is not any study assessing the predictive value of lmr for pca risk. in the present study, lmr was the only inflammation marker associated with pca diagnosis (p = 0.047 ). interestingly, in the 4-10 ng/dl psa range lmr value was extremely lower in patients with positive biopsy than those with negative biopsy (p = 0,012). in this group free/total psa ratio lower 0.15 and age higher than 65.5 were also risk factors to predict pca. additionally our data showed that, when lmr and free/total psa cut-off values were combined, the specificity and positive predictive value were higher compared to the use of lmr or free/total psa ratio alone. there are many limitations in our study. firstly, our data derived from retrospective cohort. the next, we could not evaluate the factors, such as body mass index, smoking, metabolic syndrome which may be associated with the inflammatory response. also the number of patients was relatively low. especially, the low number of the patients with prostatitis inhibited some analysis. however we think that, regarding our limited data, asymptomatic prostatitis does not effect cbc parameters. furthermore, the initial pbx may miss cancer in some men and 20% of men may be diagnosed as pca in repeated biopsy (20). conclusions regarding our data lmr value is a useful tool at detecting pca especially in patients with psa value between 4 and 10 ng/dl. the combination of free/total psa ratio and lmr improves the diagnostic accuracy more than the use of free/total psa ratio alone. this model can assist urologists in deciding whether prostate biopsy is advisable. references 1. ferlay j, 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caglayan_stesura seveso 10/01/19 16:08 pagina 274 275archivio italiano di urologia e andrologia 2018; 90, 4 lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl. 12. ishiguro h, kawahara t. nonsteroidal anti-inflammatory drugs and prostatic diseases. biomed research international. 2014; 2014:436123. 13. koosha kamali, mojtaba ashrafi, pejman shadpour, et al. the role of blood neutrophil count and the neutrophil-to-lymphocyte ratio as a predictive factor for prostate biopsy results. urologia. 2018 apr 1:391560318766822. 14. jong jin oh, ohsung kwon, jung keun lee, et al. association of the neutrophil-to-lymphocyte ratio and prostate cancer detection rates in patients via contemporary multi-core prostate biopsy. hongasian j androl. 2016; 18:937-941. 15. takashi kawahara, sachi fukui1, kentaro sakamaki, et al. neutrophil-to-lymphocyte ratio predicts prostatic carcinoma in men undergoing needle biopsy. oncotarget 2015; 6:32169-76. 16. tian-bao huang, shi-yu mao, sheng-ming lu,et al. predictive value of neutrophil-to-lymphocyte ratio in diagnosis of prostate cancer among menwho underwent template-guided prostate biopsy. medicine 2016; 95:44(e5307). 17. gokce mi, hamidi n, suer e, et al. evaluation of neutrophil-tolymphocyte ratio prior to prostate biopsy to predict biopsy histology: results of 1836 patients. can urol assoc j. 2015; 9:e761-e765. 18. kaynar m, yıldırım me, gul m, et al. benign prostatic hyperplasia and prostate cancer differentiation via platelet to lymphocyte ratio. cancer biomark. 2015; 13:317-23. 19. ozgur haki yuksel, ahmet urkmez, serkan akan,et al. predictive value of the platelet-to-lymphocyte ratio in diagnosis of prostate cancer. asian pac j cancer prev. 2015; 16:6407-6412. 20. ploussard g, nicolaiew n, marchand c, et al. risk of repeat biopsy and prostate cancer detection after an initial extended negative biopsy: longitudinal follow-up from a prospective trial. bju int. 2013; 111:988-996. correspondence volkan caglayan volkantuysuz@hotmail.com efe onen efe17@yahoo.com sinan avci sinavci@yahoo.com murat sambel muratsambel@hotmail.com metin kilic kilicmetin@yahoo.com sedat oner sedatoner@yahoo.com mustafa murat aydos mudos16@hotmail.com halil emre yıldız halilemreyldz@gmail.com university of health sciences, bursa yuksek ihtisas training and research hospital, bursa, turkey caglayan_stesura seveso 10/01/19 16:08 pagina 275 301archivio italiano di urologia e andrologia 2017; 89, 4 original paper a rare cause of acute post renal failure: retroperitoneal fibrosis kamil gokhan seker, mithat eksi, yunus colakoglu, mustafa gürkan yenice, fatih gokhan akbay, volkan tugcu, abdulmuttalip simsek bakirkoy sadi konuk research and training hospital, department of urology, istanbul, turkey. retroperitoneal fibrosis is an inflammatory process which may cause acute renal failure. in patients who admitted to emergency services with obstructive uropathy, retroperitoneal fibrosis should be considered in the differential diagnosis. we present our ten cases who admitted to emergency department with obstructive acute renal failure related to retroperitoneal fibrosis. key words: retroperitoneal fibrosis; postrenal acute renal failure; obstructive uropathy. submitted 18 july 2017; accepted 23 september 2017 summary no conflict of interest declared. my tube (pnt). further medical treatments were consulted with nephrology department. demographic data, physical examination findings, laboratory data, radiological examinations, treatments modalities and follow-up data were retrospectively analyzed. patients were followed up with 3-monthly laboratory tests and radiological observations. at the end of the one-year follow-up period, the patients were evaluated by comparing their initial and recent ct. statistical analysis was performed using spss (ibm statistical package for the social sciences, new york, usa) 17.0 program. results the mean age was 65.2 ± 20.2 years. male/female ratio was 8/2. the demographic data of the patients were shown in table 1. the side pain was the most frequent presenting symptom. ct scan revealed increase in retroperitoneal soft tissue density at the periaortic and periureteral area in 8 patients with addition perinephritic area in 2 patients. unilateral renal atrophy was observed in two patients as a result of fibrosis. after the initial intervention, medical therapy was applied. corticostreoids (cs) were used as a first line therapy for all patients. the antihypertensive treatment of the patient who admitted with beta-blocker toxicity was changed to another antihypertensive drug. for maintenance therapy, additionally to corticosteroids; seven patients were treated with azathioprine (aza) and one doi: 10.4081/aiua.2017.4.301 introduction retroperitoneal fibrosis (rf) is a clinical entity that causes inflammatory and fibrotic reactions in retroperitoneal organs and produces obstruction in ureters. it was first described by albarran in 1905 and in 1948, the idiopathic form was described as ormond's disease (1, 2). recently, an international consensus has begun to use the term "igg4-related disease (igg4-rd)" which defines several organ-related disorders (3). the incidence is about 0.1-1.3/100.000. rf generally seen over 50 years of age and 3 times more often in men (4, 5). two-thirds of rf cases are idiopathic. other causes include such as drugs, malignancies, infectious processes, radiotherapy, trauma and previous abdominal surgery (6). rf may cause the symptoms of hydronephrosis and uremia resulting from the external pressure of the retroperitoneum and the deterioration of the ureteral passage. in this study, we aimed to present the diagnosis and treatment management of ten patients who were admitted to the emergency department (ed) with postrenal acute renal failure (arf). materials and methods we retrospectively analyzed the records of patients diagnosed with postrenal arf caused by rf in our clinic between 2013 and 2016. the rf was diagnosed according to the computed tomography (ct) images taken at the ed. biopsy was not performed due to absence of atypical appearance and no need of surgical intervention during follow-up. urinary system decompression was made by placement of double j (dj) stent or percutaneous nephrostotable 1. demographic datas and serum creatinine levels during follow up. no. total patients 10 male/female (n) 8/2 age mean ± sd (year) 65.2 ± 20.2 idiopathic/secondary 9/1 serum creatinine levels (mg/dl) mean ± sd initial 5.7 ± 3.5 after urinary system decompression 1.1 ± 0.2 after medical therapy 0.9 ± 0.1 simsek5_stesura seveso 03/01/18 12:24 pagina 301 archivio italiano di urologia e andrologia 2017; 89, 4 k. gokhan seker, m. eksi, y. colakoglu, m. gürkan yenice, f. gokhan akbay, v. tugcu, a. simsek 302 patient was treated with tamoxifen (tmx). total regression and regression were observed in two and five patients respectively. the mean initial serum creatinine level was 5.7 ± 3.5 mg/dl. after the first intervention by decompressing urinary system, mean serum creatinine level regressed to 1.1 ± 0.2 mg/dl. at the end of medical therapy, the mean serum creatinine level was 0.9 ± 0.1 mg/dl. demographic data, presenting symptoms, laboratory and radiological findings, follow-up times and treatment data are summarized in table 2. patient's radiological images were shown in figures 1-5. discussion two-thirds of rf patients are idiopathic and the remaining are secondary to causes including infection, trauma, previous surgery and malignancy. in the literature, presence of figure 3. significant regression of the hydronephrosis and soft tissue density after steroid therapy. figure 5. bilateral medial retraction due to periureteral fibrosis. figure 1. a. bilateral hydroureteronephrosis due to periureteral fibrosis. b. soft tissue density that extends from paraaortic area to caudal. figure 4. left atrophic kidney. grade 2 hydronephrosis on the right kidney. soft tissue enlargement and calcification extending around the large vessels and extending from the periureteral area to the pelvic region. figure 2. a. right dj stent and left percutaneous nephrostomy tube. b. bilateral dj stents. table 2. demographic datas and serum creatinine levels during follow up. patient no. gender symptom urinary system decompression medical therapy follow-up (month) status 1 m side pain, weakness pnt + d-j cs + aza 42 full regression 2 f hypotension d-j cs + tmx 27 regression 3 m bilateral side pain d-j cs + aza 12 stable 4 m bilateral side pain pnt + dj cs + aza 12 regression 5 f side pain, weakness pnt cs + aza 18 regression 6 m bilateral side pain pnt + dj cs + aza 24 stable 7 m bilateral side pain pnt cs 18 regression 8 m fever, weakness pnt + dj cs + aza 30 full regression 9 m fever, side pain pnt cs + aza 12 stable 10 m abdominal pain pnt + dj cs 18 regression simsek5_stesura seveso 03/01/18 12:24 pagina 302 retroperitoneal fibrosis following high doses of beta-blockers usage have been reported (7). in this study, we found that in 9 patients rf was idiopathic (90%) and in one patient (10%) it was related to drug overdose. diagnosis of idiopathic rf is generally delayed due to atypical symptoms of the disease and patients may be diagnosed with postrenal arf in ed. urologically, the most frequent and most serious complication of the disease is arf due to bilateral ureteral obstruction (8, 9). in two large studies in the literature, pain was the most common presenting symptom, and additionally undefined symptoms such as fatigue, weakness, myalgia were observed (4, 10). renal failure due to bilateral ureteral obstruction is seen in 4295% of the cases. patients may also be referred to the urology clinic with scrotal edema, hydrocele or varicocele due to the involvement of the gonadal vessels (11). erythrocyte sedimentation rate (esr), c-reactive protein (crp), which are non-specific inflammation markers, are laboratory parameters used for diagnosis and follow-up (12, 13). in our study, side pain and uremic symptoms due to bilateral ureteral involvement were observed in 8 patients. the other two patients had different symptoms: one patient had hypotension and the other had fever and weakness. initial inflammation markers were found to be high in all patients. non-contrast abdominal ct and magnetic resonance imaging (mri) provide limited information in the diagnosis of the disease (14). in non-contrast ct, rf usually appears as an increase in soft tissue density, surrounding the abdominal aorta and iliac vessels, and usually surrounding the ureter and inferior vena cava (15). positron emission tomography (pet-ct) provides more comprehensive clinical information as it includes whole-body metabolic studies. it shows active inflammation and post-treatment relapses, and reveals occult malignancies (16, 17). in our cases, we used non-contrast ct in consideration of the risk of contrast nephropathy due to the presence of arf. during follow-up, if the creatinine level was in the normal range; contrast-enhanced mri and ct examinations were performed. in patients with radiologically diagnosed rf, which typically have mild symptoms and considered as a benign disease, medical treatment can be started without biopsy. biopsy is usually preferred in cases of partial response or failure to the medical therapy (18). we did not perform biopsy because no progression was observed in any of our patients and ct had no atypical appearance. the aim of the treatment is to relieve the fibro-inflammatory reaction, in order to reduce ureteral obstruction and prevent recurrence (19). after the urinary system decompression by pnt or dj stent, there are two options as first line medical treatment (20). cs alone or cs with tamoxifen (tmx) can be used as first line therapy (21). the second step is the addition of drugs such as immunosuppressive azathioprine (aza), mycophenol mofetil, rituximab, bortezomip, cyclophosphamide, cyclo spo rine in the course of treatment or relapse (22). in the case of failure to respond to medical treatment, the treatment approach is adjuvant cs therapy after surgical obstruction is reduced by ureterolysis. secondary rf is treated for the underlying cause (8). urinary system decompression was achieved by dj stent in two of our patients, by pnt in three patients and by both dj stent and pnt placement in five other patients. in two of the 5 patients treated by both dj and pnt, a dj stent was inserted firstly but a pnt had to be inserted subsequently because of the lack of adequate radiological and clinical regression. after initial treatment, cs was initially administered with additionally aza and tmx. in a randomized controlled trial, after achieving remission with high-dose prednisolone as an induction therapy, patients were divided into 2 groups and followed up with cs (prednisone) or tmx mono therapy for 8 months. in this study, maintenance therapy with cs was associated with lower relapse rates, with a higher side effect profile than tmx group (21). van der bilt et al. reported that css were superior to tmx for induction therapy, but the rate of recurrence was lower in patients treated with tmx for the maintenance therapy (23). surgical treatment may be applied in case of non response to medical treatment or interruption of medical treatment due to side effects. open, laparoscopic and robotic ureterolysis can be performed as a salvage procedure in case of failure with medical therapy (24). in our management, all patients were treated by consecutive three line therapy, initial decompression and achieving of improved renal function, induction with corticosteroids and maintenance therapy with cs or addition of aza or tmx. with the success of this third line therapy, surgical treatment was not performed during the follow-up period. our study has some limitations such as the small sample size and as the retrospective design. in addition, there were no long-term follow-up results of patients. conclusions retroperitoneal fibrosis should be kept in mind in patients who admitted to the ed with hydroureteronephrosis and uremic symptoms. after the initial treatment with urinary system decompression, remission can be achieved with appropriate medical treatments. references 1. albarran j. retention renale par periureterite: liberation externe uretere. ass fr urol. 1905; 9:511. 2. ormond jk. bilateral ureteral obstruction due to development and compression by an inflammatory retroperitoneal process. j urol. 1948; 59:1072. 3. fairweather j, jawad as. immunoglobulin g4 related retroperitoneal fibrosis: a new name for an old disease. urology. 2013; 82:505 7. 4. van bommel ef, jansen i, hendriksz tr, aarnoudse al. iodiopathic retroperitoneal fibrosis: prospective evaluation of incidence and clinicoradiologic presentation. medicine (baltimore) 2009; 88:193-201. 5. nakada sy, hsu ths. retroperitoneal fibrosis. campbellwalsh urology, 10th edition. editör: wein aj, kavoussi lr, novick ac, partin aw, peters ca. philadelphia, elseviersaunders, 2012; 1165-1168 6. palmisano a, vaglio a. chronic periaortitis: a fibro-inflammatory disorder. bestpract res clin rheumatol 2009; 23:339-53. 7. bullimore dw. retroperitoneal fibrosis associated with metoprolol. br med j (clin res ed). 1982; 284:664. 303archivio italiano di urologia e andrologia 2017; 89, 4 a rare cause of acute post renal failure: retroperitoneal fibrosis simsek5_stesura seveso 03/01/18 12:24 pagina 303 archivio italiano di urologia e andrologia 2017; 89, 4 k. gokhan seker, m. eksi, y. colakoglu, m. gürkan yenice, f. gokhan akbay, v. tugcu, a. simsek 304 8. ross jc, tinckler lf. renal failure due to periureteric fibrosis. br j surg. 1958; 46:58. 9. ha yj, jung sj, lee kh, lee sw, et al. retroperitoneal fibrosis in 27 korean patients: single center experience. j korean med sci. 2011; 26:985-90. 10. scheel pj jr, feeley n. retroperitoneal fibrosis; the clinical, laboratory, and radiographic presentation. medicine (baltimore) 2009; 88:202-207. 11. vaglio a, buzio c. chronic periaortitis: a spectrum of diseases. curr opin rheumatol. 2005; 17:34-40. 12. magrey mn, husni me, kushner i, calabrese lh. do acutephase reactants predict response to glucocorticoid therapy in retroperitoneal fibrosis? arthritis rheum. 2009; 61:674-679. 13. an lm, xu yf, zhang zl. clinical features and prognostic analysis of retroperitoneal fibrosis in 32 patients (in chinese). j peking univ (health sci). 2012; 44:265-9. 14. horger m, lamprecht hg, bares r, et al. systemic igg4-related sclerosing disease: spectrum of imaging findings and differential diagnosis. ajr am j roentgenol 2012; 199:w276-w282. 15. george v, tammisetti v, surabhi v, shanbhogue a. chronic fibrosing conditions in abdominal imaging. radiographics. 2013; 33:10531080. 16. zhang j, chen h, ma y, et al. characterizing igg4-related disease with 18f-fdg pet/ct: a prospective cohort study. eur j nucl med mol imaging. 2014; 41:1624-1634. 17. caiafa ro, vinuesa as, izquierdo rs, et al. retroperitoneal fibrosis: role of imaging in diagnosis and follow up. radiographics. 2013; 33:535-52. 18. surcel c, mirvald c, pavelescu c, et al. management of idiopathic retroperitoneal fibrosis from the urologist’s perspective. ther adv urol. 2015; 7:85-99. 19. fry ac, singh s, gunda ss, et al. successful use of steroids and ureteric stents in 24 patients with idiopathic retroperitoneal fibrosis: a retrospective study. nephron clin pract. 2008; 108:213-220. 20. urban ml, palmisano a, nicastro m, et al. idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach. rev med interne. 2015; 36:15-21. 21. vaglio a, palmisano a, alberici f, et al. prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomised controlled trial. lancet. 2011; 378:338-346. 22. khosroshahi a, wallace zs, crowe jl, et al. international consensus guidance statement on the management and treatment of igg4-related disease. arthritis rheumatol. 2015; 67:1688-1699. 23. van der bilt fe, hendriksz tr, van der meijden wa, et al. outcome in patients with idiopathic retroperitoneal fibrosis treated with corticosteroid or tamoxifen monotherapy. clin kidney j. 2016; 9:184-91. 24. omer a, esen t retroperitoneal fibroziste cerrahi tedavi: nelere dikkat edilmeli? endoüroloji bülteni 2013; 6:10-15. correspondence kamil gokhan seker, md mithat eksi, md yunus colakoglu, md mustafa gürkan yenice, md fatih gokhan akbay, md volkan tugcu, md abdulmuttalip simsek, md simsek76@yahoo.com bakirkoy sadi konuk research and training hospital, department of urology, zuhuratbaba, tevfik saglam cad. no:11 bakirkoy, istanbul, turkey simsek5_stesura seveso 03/01/18 12:24 pagina 304 archivio italiano di urologia e andrologia 2017; 89, 3226 original paper renal access in pnl under sonographic guidance: do we really need to insert an open end ureteral catheter in dilated renal systems? a prospective randomized study bilal eryildirim, murat tuncer, emre camur, fatih ustun, fatih tarhan, kemal sarica dr. lütfi kirdar training and research hospital urology clinic, istanbul, turkey. purpose: to evaluate the true necessity of open end ureteral catheter insertion in patients with moderate to severe pelvicalyceal system dilation treated with percutaneous nephrolithotomy (pnl) under sonographic guidance. patients and methods: 50 cases treated with pnl under sonographic guidance in prone position for solitary obstructing renal stones were evaluated. patients were randomly divided into two groups; group 1: patients in whom a open end ureteral catheter was inserted prior to the procedure; group 2: patients receiving no catheter before pnl. in addition to the duration of the procedure as a whole and also all relevant stages as well, radiation exposure time, hospitalization period, mean nephrostomy tube duration, mean drop in hb levels and all intra and postoperative complications have been evaluated. results: mean size of the stones was 308.5 ± 133.2 mm2. mean total duration of the pnl procedure in cases with open end ureteral catheter was significantly longer than the other cases (p < 0.001). evaluation of the outcomes of the pnl procedures revealed no statistically significant difference between two groups regarding the stone-free rates (86% vs 84%). additionally, there was no significant difference with respect to the duration of nephrostomy tube, hospitalization period and secondary procedures needed, complication rates as well as the post-operative hb drop levels in both groups (p = 0.6830). conclusions: our results indicate that the placement of an open end ureteral catheter prior to a pnl procedure performed under sonographic access may not be indicated in selected cases presenting with solitary obstructing renal pelvic and/or calyceal stones. key words: percutaneous nephrolithotomy; ureteral catheter; renal stone; ultrasonographic access. submitted 12 july 2017; accepted 7 august 2017 summary no conflict of interest declared. oroscopic and/or ultrasonographic guidance. although fluoroscopic guidance has been used as the most common method for a long period of time, increasing experience in sonographic applications has enabled endourologists to use this method more commonly than ever to get an access to the renal collecting system. use of sonography will allow the surgeon to identify the pelvicalyceal system as well as the surrounding organs in a safe manner (particularly in relatively dilated systems) to reduce the radiation exposure in a meaningful manner (10, 11). on the other hand, an open end ureteral catheter has been commonly used during percutaneous stone removal procedures to visualise the renal collecting system, avoiding the passage of small stone fragments into the ureteric lumen and lastly but most importantly to dilate the renal collecting system to ease the puncture when needed. despite all these wellestablished advantages however, insertion of an “open end ureteral catheter” may certainly be associated with some possible problems. first of all, a certain injury to the urethra particularly in male cases as well as to the mucosa of the relevant ureter could be caused. additionally, loss of time due to the insertion of the catheter first in supine position and turning of the case into prone position will further prolong the duration of the procedure (the duration of the anesthesia as well). thus, in the light of the safe and practical renal puncture in a quick manner in dilated kidneys as well as the problems related to the placement of a catheter use of an open end ureteral catheter in all cases becomes really questionable. in this present study we aimed to evaluate the true necessity of open end ureteral catheter insertion prior to pnl for a succesful procedure as well as the safety of renal puncture performed under sonographic guidance in patients with pelvicalyceal system dilation (grade 2 or higher) by comparing two group of cases treated with and without insertion of an open end ureteral catheter before pnl. patients and methods study population between january 2015 and january 2017, of all the 236 cases undergoing pnl, procedure in our department, 72 patients meeting the inclusion criteria were included into study program and randomized. upon randomization doi: 10.4081/aiua.2017.3.226 introduction following its first application in 1976, percutaneous nephrolithotomy (pnl) technique has evolved substantially over the last three decades and became the preferred choice in the management of larger stones (> 2 cm) both in adults and children (1-3). although the procedure is safe and successful with stone-free rates of > 90 %, certain complications may develop during all stages as well as early and late follow-up period of this procedure (4-9). related to this subject, an appropriate initial puncture of the most desirable calyx of the kidney is of paramount importance and access can be established either under flueryildirim _stesura seveso 28/09/17 10:27 pagina 226 227archivio italiano di urologia e andrologia 2017; 89, 3 do we really need ureteral catheter in dilated systems during pnl? while 27 cases in group 1 and 28 cases in group 2 were operated with pnl technique, cases who were not operated due to some certain reasons were excluded from the study program. moreover, 2 cases in group 1 and 3 cases in group 2 were lost to follow-up for several reasons and finally 50 cases (31 males, 19 females) were analyzed. patients’ enrollment algorithm has been illustrated in figure 1. in an attempt to assess the sample size, power analysis was made by using g*power (v3.1.7) program. depending on the index of effect size of cohen; supposing that the evaluations between two independent groups will have the highest effect size (d = 0.85), our calculations did show that at least 23 cases should be included into each group. additionally, taking the possibility of patient drop-out risk during the study program, final number of the cases in each group has been proposed to be 25. while cases presenting with pelvicalyceal system dilation (grade 2 or higher) due to moderate sized solitary renal pelvic and/or calyceal stones were included into the study program, all other cases with a detectable pathology with respect to the integrity of the ureter prior to the pnl were excluded from the study program. patients with renal anomalies, non-dilated renal collecting systems and younger than 18 years of age were also excluded from the study program. study design this study is a prospective single center, randomized clinical trial with balanced randomization [1:1] which was performed in the referral hospital dr. lutfi kirdar kartal training and research hospital. for randomization procedure a simple randomization method by generating a random digit (0-60 in each group) has been used. even numbers have been used for cases in whom an open end ureteral catheter was inserted and odd numbers have been used for cases whom operated without an open end ureteral catheter. study protocol was approved by the ethics committee of the relevant hospital (september 08, 2016-2016/514/91/3). all steps of the study were planned and applied carefully according to helsinki declaration. all pnl procedures were performed in prone position by experienced urologists and access to the renal collecting system was performed under sonographic guidance. depending on the placement of an open end ureteral catheter, the patients were divided into two different groups namely; group 1: patients in whom a 5 french (f) open end ureteral catheter was inserted prior to the procedure; group 2: patients not receiving an open end ureteral catheter insertion before pnl. following a complete biochemical and radiological evaluation; patients with urinary tract infections were treated with appropriate culture test based antibiotics. regarding the radiological evaluation, ultrasonography (usg), kidney-ureter-bladder (kub) film and low-dose computed tomography (ct) have been performed to assess the renal anatomy, degree of hydronephrosis, position of the relevant kidney with neighboring organs and location, burden of the stone(s) to be treated. stone area has been calculated by using the two dimensions of the stone(s) from ct images. while the primary outcome of our study was to evaluate and compare the ultimate stone free rates after both approaches¸ secondary end points were the evaluation of operational duration, complication rates, mean fluoroscopy time and hospital stay period in both groups in a comparative manner. figure 1. consort flow diagram of study. eryildirim _stesura seveso 28/09/17 10:27 pagina 227 archivio italiano di urologia e andrologia 2017; 89, 3 b. eryildirim, m. tuncer, e. camur, f. ustun, f. tarhan, k. sarica 228 surgical technique of pnl procedure following general anesthesia, while performing cystoscopy, a 5 f open end ureteral catheter was placed into the relevant ureter till ureteropelvic junction area in group 1 cases in the lithotomy position, no open end ureteral catheter was inserted in group 2 cases and a prone position has been given directly in these cases. an appropriate calyceal puncture under full sonographic guidance was done with a 18 gauge percutaneous entrance needle (boston scientific, natick, ma, usa). following puncture of the kidney, a 0.038 inch guide wire was inserted into the collecting system (into the ureter when possible) and amplatz mechanical dilatators were used for percutaneous tract dilatation (amplatz sheath, boston scientific, natick, ma, usa) until 28-30 f. following the placement of an appropriate access sheath a standard 26 f nephroscope (karl storz, tuttlingen, germany) was placed directly into the kidney through the tract and the stone disintegrated using an ultrasonic lithotripsy probe (swiss lithoclast®, ems electro medical system, nyon, switzerland). fragments were removed by suction, tipless basket, or grasping forceps. at the end of the procedures, a re-entry nephrostomy catheter (14 f) was placed, and an antegrade pyelography was performed to check for possible complications in all cases. the open end ureteral catheter was removed at the end of the operation in group 1 cases. the nephrostomy tube was removed postoperatively on the first or second day as soon as the urine became clear. outcome assessment all patients were re-evaluated by a plain abdominal film and/or sonography after 24 hours and by a non-contrast abdominal tomography at the end of a 4 weeks period. the operation was considered successful if there were no fragments at all or if the size of the residual fragments were smaller than 4 mm. in addition to the duration of the procedure as a whole and also all relevant stages as well, the duration of radiation exposure, hospitalization period along with the mean duration of nephrostomy tube, mean drop in hemoglobin (hb) levels, all intraoperative, and postoperative complications have been evaluated and recorded. statistical analysis the prism 5.0 (graphpad software, san diego, ca) was used for the statistical analysis. data are presented as mean standard deviation of mean. mann whitney u test was used for both comparison of descriptive statistical methods and evaluation of quantitative data and fisher exact test were used to compare the qualitative data between two groups, a twosided p < 0.05 was considered statistically significant. results a total of 50 cases (31 males/19 females m/f: 1.63) were treated with standard pnl for moderate sized solitary calyceal or pelvic stones and sonographic guidance was used for renal puncture. while the age of the cases ranged from 22-72 years (mean 44.90 +/12.32 years, 95% ci: 41.00-48.40), the mean size of the treated stones was 308.5 +/-133.2 mm2, (95% ci: 270.7-346.4). demographic as well as radiologic characteristics of the cases are given in table 1. the stones were located in the calyceal system in 28 cases (6 cases upper, 9 cases middle, 13 cases lower calyx) and in the renal pelvis in 22 cases. there was no significant difference regarding the size of the stones in both groups. evaluation of our findings in both groups revealed following data. regarding the duration of the treatment as a whole or in certain parts of the procedure, our results show clearly that the mean total duration of the pnl procedure in cases with open end ureteral catheter was significantly longer than the other cases (85.80 +/16.18 vs 60.84 +/13.21 minute respectively, p < 0.001). the mean duration for an open end ureteral catheter insertion in group 1 was 27.96 +/5.86, (95% ci: 25.54-30.38) min. and this time period was the main cause for prolonged total operative time in these cases. on the other hand however, there was no statistically significant difference with respect to the mean duration of other isolated stages of pnl procedure (renal puncture, access sheath placement, stone disintegration and removal) as shown in table 2. as an important parameter again, although the mean fluoroscopic exposure time was relatively longer in cases treated with an open end ureteral catheter, this difference was not statistically significant (p = 0.3595). evaluation of the outcomes of the pnl procedures in terms of success rates as well as early post-operative follow-up data revealed no statistically significant difference between the two groups regarding the stone-free rates (84 % vs 88 %) and also the percentage of the cases with residual fragments sizing > 4 mm (p = 1.00) (table 3). additionally, when we evaluated the cases with respect to the duration of nephrostomy tube, hospitalization period and secondary procedures needed double j stent placement and ureteroscopy (urs) again we were not able to show any significant difference in these table 1. evaluation of patient and stone characteristics in both groups. variablesa overall group 1 group 2 p value n = 50 ureteral catheter (+) ureteral catheter (-) n = 25 n = 25 age, year; mean ± sd 44.90 12.32 47.00 11.05 42.80 13.36 0.2175 (range) (22-72) (26-60) (22-72) bmi, kg/m2; mean ± sd 27.18 4.14 28.52 4.20 25.84 3.69 0.0380 (range) (18.2-38.0) (22.3-38.0) (18.2-34.5) stone burden, mm2; mean ± sd 308.5 133.2 297.8 106.5 319.2 157.0 0.7784 (range) (195-570) (195-570) (200-530) hu, hounsfield unit; mean ± sd 812 198.3 766.3 164.5 857.5 202.4 0.1276 (range) (450-1500) (450-1480) (470-1500) degree of hydronephrosis, grade; mean ± sd 2.22 0.50 2.16 0.47 2.28 0.54 0.3024 (range) (2-4) (2-4) (2-4) bmi: body mass index; hu: hounsfield unit. a continuous variables were compared by mann whitney u test. eryildirim _stesura seveso 28/09/17 10:27 pagina 228 229archivio italiano di urologia e andrologia 2017; 89, 3 do we really need ureteral catheter in dilated systems during pnl? values. last but not least as another important parameter to be evaluated, there was also no notable difference regarding the post-operative drop in hb levels in both groups (p = 0.6830). finally, evaluation of the complications in the light of modified clavien grading system demonstrated no statistically significant difference between the two groups particularly concerning bleeding after pnl (table 4). as summarized in this table, while one case in each group required double j stent insertion due to the prolonged urine leakage after nephrostomy tube removal, a stone passing into the ureter despite open end ureteral catheter placement was removed with urs in one case of group 1. relocation of the disintegrated stone fragments down into the ureteric lumen could be a significant drawback of this approach however, as we tend to remove all relatively larger fragments during the procedure with great care, there will be very limited chance for fragment relocation in these cases with moderate sized calculi. moreover, it is clear that passage of the fragments down into the ureteric lumen might occur despite given care and open end ureteral catheter insertion (like the case in group 1 of our study) in a certain percentage of the cases. discussion percutaneous nephrolithotomy has been performed as a minimally invasive method of removing kidney stones since 1976. as a result of the improvements in operative technique and miniaturization of the available equipment, this approach is now commonly performed as a safe and successful management option in larger stones. however, despite the high stone free rates obtained in a single session; pnl could be associated with certain types of complications like bleeding, organ perforation and sepsis (12). such complications could be encountered during all steps of pnl among which the access to the renal collecting system seems to be the most important one (13). related to this subject, an appropriate initial puncture of the most desirable calyx of the kidney is extremely important for a successful and safe procedure by limiting the chance of both bleeding as well as injury to the surrounding organs (e.g. colon, spleen, liver, pleura, lung). access to the renal collecting system from the most suitable calyx can be established either under fluoroscopic and/or sonographic guidance. main aim of these two different guiding procedures should be a direct path which will be identified and used from the skin through the papilla of the desired calyx (14). accumulated experience so far has clearly demonstrated that each of these methods could be associated with certain advantages as well as disadvantages. related to this subject, during fluoroscopic guidance renal puncture is usually done after the placement of an open end ureteral catheter through cystoscopy. use of this catheter will in turn allow the table 4. evaluation of the type and grade of complications according to modified clavien classification in both groups. grade complication overall group 1 group 2 b p value n = 50 ureteral ureteral catheter (+) catheter (-) n = 25 n = 25 1 fever > 38 0c; n, (%) 5 (10.0) 3 (12.0) 2 (8.0) 1.0000 hemorrhage not requiring blood transfusion; n, (%) 4 (8.0) 2 (8.0) 2 (8.0) 2 hemorrhage requiring blood transfusion; n, (%) 2 (4.0) 1 (4.0) 1 (4.0) 1.0000 3a double j stent placement for urine leakage > 24 h; n, (%) 2 (4.0) 1 (4.0) 1 (4.0) 1.0000 3b endoscopic treatment for ureteral stone; n, (%) 1 (2.0) 1 (4.0) 1.0000 a continuous variables were compared by mann whitney u test. b continuous variables were compared by fisher exact test. table 3. evaluation of the outcomes of the procedures in terms of success rates as well as early post-operative follow-up data. variablesa, b overall group 1 group 2 p value n = 50 ureteral catheter (+) ureteral catheter (-) n = 25 n = 25 b stone free rate; n, (%) 43 (86.0) 21 (84.0) 22 (88.0) 1.0000 b residual stone > 4 mm n, (%) 7 (14.0) 4 (16.0) 3 (12.0) 1.0000 a mean drop in hb levels (g/dl) 1.52 0.68 1.60 0.69 1.45 0.57 0.6830 a mean duration of nephrostomy (day) 1.86 0.88 1.83 0.79 1.92 0.92 0.7246 a mean hospital stay (day) 2.88 0.96 2.84 0.96 2.92 1.03 0.9010 b secondary intervention; n, (%) 3 (6.0) 2 (8.0) 1 (4.0) 1.0000 a continuous variables were compared by mann whitney u test. b continuous variables were compared by fisher exact test. table 2. evaluation of the procedure related parameters with an emphasis on the duration of the interventional steps in both groups. variablesa overall group 1 group 2 p value n = 50 ureteral catheter (+) ureteral catheter (-) n = 25 n = 25 mean duration of the procedure (min) 73.12 18.90 85.80 16.18 60.84 13.21 < 0.0001 mean duration of open end catheter insertion (min) 27.96 5.86 mean duration of access to the collecting system (min) 5.42 2.32 5.28 2.08 5.76 2.45 0.4909 mean duration of dilation and access sheath placement (min) 10.34 3.96 10.08 3.22 10.67 4.02 0.5118 mean duration of fragmentation and stone removal (min) 27.38 12.53 25.96 11.80 28.80 12.86 0.3896 mean fluoroscopy time (sec.) 18.20 9.60 19.60 11.08 17.36 7.63 0.3595 a continuous variables were compared by mann whitney u test. eryildirim _stesura seveso 28/09/17 10:27 pagina 229 archivio italiano di urologia e andrologia 2017; 89, 3 b. eryildirim, m. tuncer, e. camur, f. ustun, f. tarhan, k. sarica 230 surgeon to dilate the collecting system with saline injection for an easy puncture particularly in cases with minimal or no dilation and also to visualize the pelvicalyceal system with contrast medium. to accomplish this task however, patients are initially placed into a lithotomy position for the placement of the ureteral catheter and then brought into the prone position to perform the kidney puncture and access to the renal collecting system. it is clear that these procedures and maneuvers will certainly lengthen the total operational time for these cases being operated under general anesthesia. additionally and more importantly a certain injury to the urethra particularly in male cases as well as to the mucosa of the relevant ureter could be caused. on the other hand again, the administration of contrast agent may cause severe, contrast-related complications and the contrast agent may affect the opacity of the stone, causing challenges for the endourologist during stone manipulation. moreover, the fear of injuring structures during a ‘blind’ approach under fluoroscopic guidance up to the renal capsule constitutes another major concern. last but not least, using fluoroscopy during percutaneous access to the kidney is accompanied by the exposure of the operators, patients as well as the other working staff to radiation. long-term ionizing radiation may lead to considerable hazardous effects on certain organs (15). taking the above mentioned problems related to fluoroscopic access into account, endourologists began to use sonographic guidance more commonly then ever in an attempt to avoid such certain problems with some certain advantages. first of all, this approach is totally free of ionizing radiation with shorter operating duration (16). additionally, this form of guidance allows the endourologist to identify the neighboring organs in an accurate manner to minimize the risk of injury (17). lastly, the european association of urology recommends the initial puncture under sonographic guidance because it reduces radiation hazards (18). as stated above use of sonographic guidance in gaining access to the renal collecting system gained more importance than ever in the last decade. related with this issue, in a prospective and randomized study zu w et al., aimed to compare the safety and efficacy of fluoroscopic (fg), total ultrasonographic (usg) and combined (cg) guidance for percutaneous renal access during mini-percutaneous nephrolithotomy (mini-pcnl) in a total of 450 consecutive patients with renal stones larger than 2 cm. while the overall complication rates using the clavien grading system as well as stone free rates were similar between the three groups; multiple-tracts pnl were used more frequently in the fg and cg group than usg group and the mean access time was longer in cg than for fg and usg group patients. mean total radiation exposure time however was significantly greater for fg than for cg (19). in another study again, 45 children with unilateral stones underwent pnl procedures under totally sonographic guidance with a mean time to establish access as 2.9 (range 2.1-5) min. blood loss requiring transfusion, sepsis, adjacent organ injury and kidney loss were not observed in any case and the authors concluded that the ultrasound-guided mini-pcnl is feasible and safe in patients aged < 3 years, without major complications or radiation exposure (20). last but not least, in their well organized systematic literature review including 18 studies with 2919 patients, liu q et al. stated in the final analysis that when compared with fluoroscopic guidance, use of ultrasonography provided shorter puncture time, higher success rate of fist puncture, less blood loss, and less complications as the main advantages of this approach (21). on the other hand again, sonographic access to the kidney will be more practical and safe in relatively dilated renoureteral units in experienced hands. easy and quick identification of the renal structures but most important the desired calyx in such dilated kidneys will allow the endourologist to establish the puncture in a safe manner which will diminish the importance of open end ureteral catheter insertion to a certain extent. thus, taking the advantages of renal puncture in a safe and quick manner under sonographic guidance in dilated kidneys as well as the problems related to open end ureteral catheter placement into account use of an open end ureteral catheter in all cases becomes really questionable. regarding the performance of percutaneous nephrolithotomy without open end ureteral catheter insertion, there is highly limited data reported so far in the literature. only one study conducted by tabibi et al. compared the outcomes of renal calyceal system puncture with and without retrograde pyelography in 55 patients with opaque renal calculi. they were able to show no differences in outcome, infection, operative time, duration of hospital stay, and radiation exposure, indicating that ureteral catheter placement may be precluded (22). we believe that our current study is a comprehensive one focusing on this critical issue in a detailed manner. in this present study we aimed to evaluate the true necessity of open end ureteral catheter insertion in terms of the success as well as safety of renal puncture in patients with diated pelvicalyceal system (grade 2 or higher) performed under sonographic guidance by comparing them with the cases in whom the catheter was inserted. our results demonstrate clearly that the mean total duration of the pnl procedure in cases with open end ureteral catheter was significantly longer than the other cases. however, use of open end ureteral catheter did not shorten the renal access time in both groups of cases indicating that the presence of a dilated system doesn’t require a catheter placement particularly in the light of the disadvantages mentioned above. evaluation of the outcomes of the pnl procedures in terms of success rates as well as early post-operative follow-up data revealed no statistically significant difference between the two groups regarding the stone-free rates (84% vs 88%). additionally, when we evaluated our cases in both groups with respect to nephrostomy tube duration, hospitalization period and percentage of secondary procedures, no statistically significant difference again could be demonstrated from these aspects. last but not least, as an important parameter again, although the mean fluoroscopic exposure time was relatively longer in cases treated with open end ureteral catheter, this difference was not statistically significant. our results demonstrate clearly that despite its wellknown advantages during pnl procedure performed under fluoroscopic guidance; placement of an open end ureteral catheter may not really be necessary particularly in selected cases with a dilated renal collecting system eryildirim _stesura seveso 28/09/17 10:27 pagina 230 231archivio italiano di urologia e andrologia 2017; 89, 3 do we really need ureteral catheter in dilated systems during pnl? operated under sonographic guidance. renal puncture under sonographic guidance can be done in a safe and practical manner in experienced hands in such cases without any need for such a catheter placement. furthermore visualisation of the entire collecting system could be done via antegrade way in all these cases whenever needed. it should be kept in mind that; open end ureteral catheter insertion is a time consuming procedure which will in turn definitely prolong the total duration of a certain procedure during which the patient receives anesthesia in an unusual position. additionally, when we add the time period needed for the change of the position from lithotomy to prone in the majority of the cases again the total duration of the intervention (as well as the anesthesia) will further increase in these cases. additionally, it is very clear that urethra as well as ureter are both exposed to a certain degree of trauma during stent placement particularly in male cases. taking all these facts into account, we believe that an open end ureteral catheter may not be inserted in selected cases treated with pnl under sonographic access for solitary renal pelvic and/or calyceal stones causing dilatation in the upper urinary tract. our study may have one limitation: the number of cases included and evaluated may be small. but taking the lack of publications regarding this issue and comprehensive evaluation of the necessity for an open end ureteral catheter performing pnl in dilated renal systems under sonographic guidance, we believe that our current findings will certainly be contributive enough to the existing literature on this critical subject. conclusions in the light of the findings obtained in our current study and the above mentioned well known associated problems, we believe that placement of an open end ureteral catheter prior to a pnl procedure performed under sonographic access may not be indicated in selected cases presenting with solitary renal pelvic and/or calyceal stones causing dilatation in the upper urinary tract. references 1. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976; 10:257-9. 2. tanriverdi o, boylu u, kendirci m, et al. the learning curve in the training of percutaneous nephrolithotomy. eur urol. 2007; 52:206-11. 3. tiselius hg, ackermann d, alken p, et al. working party on lithiasis, european association of urology. guidelines on urolithiasis. eur urol. 2001; 40:362-71. 4. kim sc, kuo rl, lingeman je. percutaneous nephrolithotomy: an update. curr opin urol. 2003; 13:235-41. 5. basiri a, tabibi a, nouralizadeh a, et al. comparison of safety and efficacy of laparoscopic pyelolithotomy versus percutaneous nephrolithotomy in patients with renal pelvic stones: a randomized clinical trial. urol j. 2014; 1:1932-7. 6. de la rosette j, assimos d, desai m, et al. the clinical research office of the endourological society percutaneous nephrolithotomy global study: indications, complications, and outcomes in 5803 patients. j endourol. 2011; 25:11-7. 7. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007; 51:899-906. 8. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008; 53:184-90. 9. mousavi-bahar sh, mehrabi s, moslemi mk. percutaneous nephrolithotomy complications in 671 consecutive patients: a singlecenter experience. urol j. 2011; 8:271-6. 10. desai m, ridhorkar v, patel s, et al. pediatric percutaneous nephrolithotomy: asssessing impact of technical innovations on safety and efficacy. j endourol. 1999; 13:359-64. 11. zegel hg, pollack hm, banner mc, et al. percutaneous nephrostomy. comparison of sonographic and fluoroscopic guidance. am j roentgenol. 1981; 137:925-7. 12. el-nahas ar, eraky i, shokeir aa, et al. factors affecting stonefree rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. urology. 2012; 7:1236-41. 13. aslam mz, thwaini a, duggan b, et al. urologists versus radiologists made pcnl tracts: the uk experience. urol res 2011; 39:217-21. 14. agarwal m, agrawal ms, jaiswal a, et al. safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy. bju int. 2011; 108:1349. 15. hellawell go, mutch sj, thevendran g, et al. radiation exposure and the urologist: what are the risks? j urol. 2005; 174:948-52. 16. basiri a, ziaee sa, nasseh h, et al. totally ultrasonography guided percutaneous nephrolithotomy in the flank position. j endourol. 2008; 22:1453-7. 17. basiri a, ziaee a, kianian h, et al. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008; 22:281-4. 18. european association of urology. guidelines on urolithiasis. 2012 http://www.uroweb.org/gls/pdf/21_urolithiasis_lr.pdf 19. zhu w, jiasheng l, jian y, et al. a prospective and randomized trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. bju int. 2017; 119:612-8. 20. xiao b, hu w, zhang x, et al. ultrasound-guided mini-percutaneous nephrolithotomy in patients aged less than 3 years: the largest reported single-center experience in china. urolithiasis. 2016; 44:179-83. 21. liu q, zhou l, cai x, et al. fluoroscopy versus ultrasound for image guidance during percutaneous nephrolithotomy: a systematic review and meta-analysis. urolithiasis. 2016 nov 22. [epub ahead of print]. 22. tabibi a, akhavizadegan h, nouri-mahdavi k, et al. percutaneous nephrolithotomy with and without retrograde pyelography: a randomized clinical trial. int braz j urol. 2007; 33:19-22. correspondence bilal eryildirim, md (corresponding author) bilaleryildirim@yahoo.com murat tuncer, md murattuncer77@hotmail.com emre camur, md emre.camur@outlook.com fatih ustun, md drfatihustun@gmail.com fatih tarhan, md tarhanf@yahoo.com kemal sarica, md saricakemal@gmail.com dr. lütfi kirdar training and research hospital urology clinic istanbul, turkey eryildirim _stesura seveso 28/09/17 10:27 pagina 231 163archivio italiano di urologia e andrologia 2018; 90, 3 original paper role of the gonadal vessels on the stone lodgment in the proximal ureter: direct observation during laparoscopic ureterolithotomy mohammad hadi radfar 1, reza valipour 2, behzad narouie 3, mehdi sotoudeh 1, hamid pakmanesh 4 1 department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran; 2 department of urology, tehran medical sciences branch, islamic azad university, tehran, iran; 3 department of urology, zahedan university of medical sciences, zahedan, iran; 4 department of urology, shahid bahonar hospital, kerman university of medical sciences (kmu), kerman, iran. introduction: previous radiological studies revealed that stones lodge more frequently in the ureterovesical junction (uvj) as well as the proximal ureter. factors that prevent stone passage from the proximal ureter are not well studied. aim: to explore the site of the lodged stones in the proximal ureter with direct observation during laparoscopic ureterolithotomy. materials and methods: between november 2014 and february 2015, we included 26 patients including 18 men and 8 women with stones larger than 10 millimeters in the proximal ureter who were candidate for laparoscopic ureterolithotomy. we prospectively recorded the site of the lodged stones in the ureter during laparoscopic ureterolithotomy in relation with the sites of ureteral stenosis as well as the gonadal vessels. results: among 26 patients with ureteral stone, in 19 cases stone was found close to the gonadal vein compared with seven cases that stone was in other locations of the ureter (p = 0.02). the characteristics of patients and stones were not different in cases that the stone was close to gonadal vessels compared with other locations. conclusions: this study showed that most of the stones lodged in the proximal ureter were in close proximity with gonadal vessels. gonadal vessels may be an extrinsic cause of ureteral narrowing. key words: ureter; urolithiasis; laparoscopy; pathophysiology; gonadal vessels. submitted 11 december 2017; accepted 12 january 2018 summary no conflict of interest declared. ureteral calculus revealed that stones lodge more frequently in two sites: uvj and proximal ureter. uvj is known unanimously as the narrowest part of the ureter (8); however, we have not a clear response to the question that why large stones that pass the upj, lodge in the proximal ureter. ureteroscopy (tul) or shock wave lithotripsy (swl) or are the first line treatment for more ureteral stones (9). for large stone burden or when previous options have failed, laparoscopic ureterolithotomy is a less invasive technique with excellent success rate (10). in this study, we prospectively investigated the location of the lodged stones in the proximal ureter under direct laparoscopic vision in patients who were candidate for laparoscopic ureterolithotomy. to the best of our knowledge, this is the first study that report intraoperative data of lodged ureteral stones in relation with the gonadal vessels. materials and methods we prospectively evaluated patients who undergo laparoscopic transperitoneal ureterolithotomy for upper ureteral stones. between november 2014 and february 2015, we included 26 patients. the inclusion criteria was stones larger than 10 millimeters in the proximal ureter (from ureteropelvic junction to the iliac vessels) in the nonenhanced spiral abdominopelvic computed tomography scan (ct-scan), that failed to response with shock wave lithotripsy (swl). we excluded patients who had previously underwent open stone surgery. a negative urine culture and normal coagulation tests was attained. the studied variables were patient demographic data including age, gender, height, weight, body mass index as well as stone characteristics including size, number and laterality and data of previous interventions. urology and nephrology research center board of ethical approval approved the study. all procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. surgical technique after induction of the general anesthesia, we inserted a doi: 10.4081/aiua.2018.3.163 introduction ureteral stone is a common presentation of the urinary tract stone disease that usually is associated with an excruciating pain (1). most of urinary tract stones pass spontaneously; however, some stones lodge in the ureter and require intervention (2, 3). anecdotally, three constrictions in the ureter are told to be the potential site of stone impaction including ureteropelvic junction (upj), the crossing of the ureter over iliac vessels and the ureterovesical junction (uvj) (4). in contrast with this theory, data of clinical studies did not show increased rate of stone lodgment at the level of the iliac vessels (5-7). in addition, upj is not a frequent location for lodged stones. actually, studies that reviewed imaging of the patients with impacted radfar_stesura seveso 04/10/18 11:11 pagina 163 archivio italiano di urologia e andrologia 2018; 90, 3 m. hadi radfar, r. valipour, b. narouie, m. sotoudeh, h. pakmanesh 164 foley catheter and orogastric tube. then, we placed the patients in flank position and flexed the operating table at umbilical level. one surgeon, trainee fellowship of laparoscopy, under supervision of one attending staff performed all operations. we inserted a 10-millimeter trocar in the umbilicus or lateral to the rectus muscle at the umbilicus level. after insufflation, we inserted two or three working ports in a rhomboid style. the ipsilateral colon was mobilized. then, we explored the ureter based on preoperative imaging to find the stone. then, we evaluated the location of the stone in relation with the gonadal vessels. (figure 1) then, we extracted the stone through a longitudinal ureteral incision. we placed a double-j stent in all cases and repaired the ureteral incision with separate absorbable 4-0 vicryle sutures. statistical analysis data are presented as mean ± standard deviation, range, numbers and percentages. we analyzed data using nonparametric binominal test with the test proportion of 0.50 to evaluate whether the ureteral stones are randomly distributed in the ureter or not. p value less than 0.05 was considered significant. results we evaluated 26 patients including 18 men and 8 women with mean age of 48±14 years (25 to 75). mean bmi was 26 ± 3 kg/m2 (21 to 32). regarding previous history of intervention, two patients had previous history of percutaneous nephrolithotomy. in sixteen cases (61%), stone was located in the right side. considering the location of the stone in relation with gonadal vessels, among 26 patients with ureteral stone, in 19 cases stone was found close to the gonadal vein compared with seven cases that stone was in other locations of the ureter (p = 0.02). the characteristics of patients and stones were not different in cases that the stone was close to gonadal vessels compared with other cases (table 1). discussion to the best of our knowledge, this is the first report that consider the gonadal vessels as a cause of stone lodgment in the proximal ureter. upj is told to be one of the three constrictions of the ureter; however, there is large body of evidence that shows many stones pass the upj but lodge in the proximal ureter (5, 3, 11, 7). nevertheless, no one has explained an etiological factor for this finding yet. actually, stones that lodge in the proximal ureter are less likely to pass spontaneously with medical expulsive therapy (met) compared with lower ureter stones (12). we think that, presence of gonadal vein as an extrinsic compression against ureteral peristalsis may explain these findings. there are some examples that a vessel can compress the ureter and produce obstruction in the upper urinary tract. ureterovascular hydronephrosis is an example of upper tract obstruction secondary to the pressure effect on the ureter by the lower pole arterial branches. this obstruction leads to hydronephrosis resembling uretero-pelvic junction obstruction especially in children (13, 14). this obstruction may be successfully resolved by laparoscopic transposition of the lower pole crossing vessels (15). likewise, thrombosis of the ovarian vein may compress the ureter, a condition known as ovarian vein syndrome (16, 17). the aforementioned conditions corroborate our finding that gonadal vessels may cause extrinsic narrowing in the ureter sufficient to prevent spontaneous stone expulsion. ordon et al. reviewed kidney-ureter-bladder (kub) and ct-scan of the patients referred for swl. they found that in this group of patients most stones were lodged at the level of the lower l2 and upper l3 vertebra followed by at the level of the iliac spine. larger stones and stones in female patients were located more proximally (6). they concluded that the stones at the level of the l2-l3 vertebra is compatible with the upj. they did not considered that the gonadal vessels traverse the ureter at the same level of the vertebra. gonadal arteries arise from the abdominal aorta at the l2 vertebral level (18) and traverse laterally and cross the ureter at l3 vertebral level. namely, stone lodgment at the l2-l3 level may be a consequence of the extrinsic pressure of the gonadal vessels rather than functional narrowing of the upj. additionally, some other studies have shown that stones usually lodge at the upper ureter rather than upj. eisner et al. retrospectively reviewed ct-scan imaging data of 94 patients referred to the emergency department and reported that upper ureter (23%) stone was the second most frequent site of the stone lodgment after uvj table 1. demographic and stone characteristics of patients considering the relation of the lodged stone with gonadal vessels. location of stone close to gonadal other locations p value vessels (n = 19) (nn = 7) laterality right 12 (63.2) 4 (57.1) 0.78  left 7 (36.8) 3 (42.9) gender male 13 (68.4) 5 (71.4) 0.88 female 6 (31.6) 2 (28.6) stone size (mm) 16.3 ± 6.1 15 ± 2.9 0.59 age (years) 47.8 ± 13.8 50 ± 14.1 0.74 height (cm) 167.7 ± 7.2 170.7 ± 9.8 0.48 bmi (kg/m2) 25.9 ± 3.4 26.7 ± 3.5 0.6 data are presented as count (column percent) or mean ± standard deviation. figure 1. the location of the lodged stone in the proximal ureter in relation with the right gonadal vessels. radfar_stesura seveso 04/10/18 11:11 pagina 164 (60%). in their study, stone lodged at the upj level in 10 percent of cases (5). similarly, jong song et al. reviewed ct-scan imaging of 95 patients with acute renal colic and found that upj stone was present in only 5% of patients. in contrast, 30% of stones were detected in the proximal ureter. interestingly, only in one case in both aforementioned studies stone was detected in the level of ureter crossing iliac vessels (5, 7). this data confirms that upj itself is not the leading cause of stone lodgment, the stones lodge in the proximal ureter instead. el-barky et al. published result of their prospective study on ureteral stone location in cases that were candidate for intervention due to failed met. they reported that uvj followed by proximal ureter were the more frequent sites of stone lodgment in this cohort. twenty two percent of the stones were at the level of the l3-l4 vertebra in the proximal ureter whereas only 10% of stones were in the upj level (3). recently, moon et al. reviewed the finding of the computed tomography scans of the patients with ureteral stone that failed to pass the ureteral calculi after two weeks of met. this study showed that 37% of patients that failed to response with two weeks of met had stone in the proximal ureter, 36% in the uvj and 2% in the upj. further, stones lodged in the upper ureter were larger than the lower ureter stones and showed lower response rate to met (11). these findings more attest our theory that some pathophysiological factor should be present that create a constriction on the proximal ureter that interfere with stone passage. our finding may explain this difference likewise. in this study, for the first time we introduce the gonadal vessels as an extrinsic factor that induce stone lodgment in the proximal ureter. previous studies evaluated imaging studies of the patients whereas this is the first report that investigate the real place of the stone lodged in the ureter by direct laparoscopic vision. in addition, results of this study may help during laparoscopy of the ureteral stone to find the stone by focusing on the site that gonadal vessels traverse the ureter. further studies including more patients is needed to validate our findings in the present study. conclusions this study showed that most of the stones lodged in the proximal ureter were in close proximity with gonadal vessels. gonadal vessels may be a cause of extrinsic ureteral narrowing. references 1. basiri a, shakhssalim n, khoshdel ar, et al. drinking water composition and incidence of urinary calculus: introducing a new index. iranian journal of kidney diseases. 2011; 5:15-20. 2. deliveliotis c, chrisofos m, albanis s, et al. management and follow-up of impacted ureteral stones. urol int. 2003; 70:269-272. 3. el-barky e, ali y, sahsah m, et al. site of impaction of ureteric calculi requiring surgical intervention. urolithiasis. 2014; 42:67-73. 4. ai d. anatomy and surgical approach to the urogenital tract in the male. in: campbell m (ed) urology. wb saunders company, philadelphia/london 1954, (1st edn.), p.12 5. eisner bh, reese a, sheth s, stoller ml ureteral stone location at emergency room presentation with colic. j urol. 2009; 182:165-168. 6. ordon m, schuler td, ghiculete d, et al. stones lodge at three sites of anatomic narrowing in the ureter: clinical fact or fiction? j endourol. 2013; 27:270-276. 7. song hj, cho st, kim kk. investigation of the location of the ureteral stone and diameter of the ureter in patients with renal colic. korean journal urol. 2010; 51:198-201. 8. abdel razzak om. ureteral anatomy. in: smith ad b, g bd, et al, eds. smith’s textbook of endourology., 2nd ed. lewiston: bc decker inc, pp 213-216. 9. porpiglia f, fiori c, poggio m, et al. ureteroscopy: is it the best? urologia. 2014; 81:99-107. 10. wu t, duan x, chen s, et al. ureteroscopic lithotripsy versus laparoscopic ureterolithotomy or percutaneous nephrolithotomy in the management of large proximal ureteral stones: a systematic review and meta-analysis. urol int 2017 doi:10.1159/000471773. 11. moon yj, kim hw, kim jb, et al. distribution of ureteral stones and factors affecting their location and expulsion in patients with renal colic. korean j urol. 2015; 56:717-721. 12. choi t, yoo kh, choi sk, et al. analysis of factors affecting spontaneous expulsion of ureteral stones that may predict unfavorable outcomes during watchful waiting periods: what is the influence of diabetes mellitus on the ureter? korean j urol. 2015; 56:455-460. 13. stephens fd. ureterovascular hydronephrosis and the "aberrant" renal vessels. j urol. 1982; 128:984-987. 14. pesce c, campobasso p, costa l, et al. ureterovascular hydronephrosis in children: is pyeloplasty always necessary? eur urol. 1999; 36:71-74. 15. gundeti ms, reynolds ws, duffy pg, mushtaq i. further experience with the vascular hitch (laparoscopic transposition of lower pole crossing vessels): an alternate treatment for pediatric ureterovascular ureteropelvic junction obstruction. j urol. 2008; 180(4 suppl):1832-1836. 16. jc c. the right ovarian vein syndrome. clinical urography: an atlas end texbook of roentgenologic diagnosis 2ª ed, 1964, pp.1227-1236. 17. derrick fc jr., turner wr, house ee, stresing ha. incidence of right ovarian vein syndrome in pregnant females. obst gynecol. 1970; 35:37-38. 18. ahlberg ne, bartley o, chidekel n. right and left gonadal veins. an anatomical and statistical study. acta radiologica: diagnosis. 1966; 4:593-601. 165archivio italiano di urologia e andrologia 2018; 90, 3 location of the lodged proximal ureter stones correspondence mohammad hadi radfar, md mehdi sotoudeh, md department of urology, shahid labbafinejad medical center, shahid beheshti university of medical sciences, tehran, iran reza valipour, md department of urology, zahedan university of medical sciences, zahedan, iran behzad narouie, md departement of urology, tehran medical sciences branch, islamic azad university, tehran, iran hamid pakmanesh, md (corresponding author) h_pakmanesh@yahoo.com; h_pakmanesh@kmu.ac.ir department of urology, shahid bahonar hospital, kerman university of medical sciences (kmu), kerman, iran radfar_stesura seveso 04/10/18 11:11 pagina 165 stesura seveso 293archivio italiano di urologia e andrologia 2014; 86, 4 case report intraperitoneal stone migration during percutaneos nephrolithotomy akif diri 1, tolga karakan 1, mustafa resorlu 2, mucahit kabar 1, cankon germiyanoglu 1 1 department of urology, ankara training and research hospital, ankara, turkey; 2 department of radiology, canakkale onsekiz mart university, faculty of medicine, canakkale, turkey. percutaneos nephrolithotomy (pnl) is the standard care for renal stones larger than 2 cm. the procedure has some major and minor complications. renal pelvis laceration and stone migration to the retroperitoneum is one of the rare condition. we report the first case of intraperitoneal stone migration during pnl. key words: complications; percutaneous nephrolithotomy; renal pelvis rupture; renal stone. submitted 20 july 2014; accepted 30 september 2014 summary no conflict of interest declared. tive first day, the patient showed abdominal distension due to free fluid in the abdomen. vital signs and biochemical examinations of the patient were normal. the patient was followed closely and at the end of the seventh day the urinary tract was checked with antegrade pyelography that showed no extravasation and that the collecting system was intact. the re-entry catheter was removed and the patient was discharged and referred to our clinic. at plain radiograph there was a 2 cm stone at the level of the pelvic bone (figure 2). ct scan demonstrated that the stone was posterior to the bladder on the right side. we planned laparoscopic exploration but intraoperatively we found many adhesions and we had to switch to open surgery. the stone was found in the vesicouterine pouch and extracted (figure 3). after the operation the patient was discharged without complicationa at the fourth postoperative day. doi: 10.4081/aiua.2014.4.293 introduction percutaneos nephrolithotomy (pnl) should be the firstline treatment for large or multi-calyxeal stones (1). pnl is a safe treatment option and associated with low complication rate (2). the procedure has some major and minor complications like extravasation, renal hemorrhage, colonic injury and pleural injury (3). clayman et. al. reported extravasation during pnl at a 26% rate (4). lee et al. reported 0.9% renal pelvis laceration, 1% retroperitoneal stone migration and 0.3% urinoma in their series (5). they conservatively treated the migrated stones and urinomas observed in their series. segura et al reported 0.1% retroperitoneal stone migration in their series (6). in this study, we report an intraperitoneal stone migration case that occurred during pnl procedure. to our knowledge, after revision of the literature, stone migration to the peritoneum was not previously described. case report a 38 years female patient presented with right renal colic at a different center. urogenital system examination revealed only right costovertebral sensitivity. the patient had previously two pyelolithotomy operations. radiological examination showed a 3 cm right renal pelvis stone (figure 1) and pnl was performed. during the procedure pelvic rupture occurred with stone migration into the peritoneum. the procedure was terminated with placing a re-entry catheter. at postoperafigure 1. plain radiograph of the renal stone before pnl operation. diri_stesura seveso 15/01/15 13:21 pagina 293 archivio italiano di urologia e andrologia 2014; 86, 4 a. diri, t. karakan, m. resorlu, m. kabar, c. germiyanoglu 294 discussion the most common complications of pnl are extravasation (7.2%), transfusion (11.2-17.5%) and fever (2132.1%) (3). lacerations may occur during dilatation or manipulation with nephroscope and during lithotripsy. fluoroscopic monitoring during dilatation and gentle manipulations may reduce the risk of collecting system injury. the inflow and outflow of the irrigation fluid must be measured. if there is a inequality that exceeds 500 ml, the procedure must be stopped and a nephrostomy must be placed (3). stone migration in the peritoneum is a rare condition. especially for operated kidneys pnl can be a complicated proedure and collecting system perforation with stone migration may occur like in the presented case. references 1. lingeman je, newmark jr, wong myc: classification and management of staghorn calculi. in: smith ad (editor) controversies in endourology. saunders, philadelphia 1995, pp. 136-44. 2. rudnick dm, stoller ml. complications of percutaneous nephrostolithotomy. can j urol. 1999; 6:872-5. 3. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007; 51:899-906. 4. wolf js jr, clayman rv. percutaneous nephrostolithotomy: what is its role in 1997?. urol clin north am. 1997; 24:43-58. 5. lee wj, smith ad, cubelli v, et al. complications of percutaneous nephrolithotomy. ajr am j roentgenol. 1987; 148:177-80. 6. segura jw, preminger gm, assimos dg, et al. nephrolithiasis clinical guidelines panel summary report on the management of staghorn calculi. the american urological association nephrolithiasis clinical guidelines panel. j urol. 1994; 151: 1648-51. correspondence akif diri, md tolga karakan, md mucahit kabar, md cankon germiyanoglu, md department of urology, ankara training and research hospital ankara, turkey mustafa resorlu,md (corresponding author) mustafaresorlu77@gmail.com department of radiology,faculty of medicine, canakkale onsekiz mart universitesi, terzioglu yerleskesi, barbaros mh, 17100, canakkale, turkey figure 2. plain radiograph of the migrated stone. figure 3. intraoperative stone extraction. the stone is located in the vesicouterine pouch. diri_stesura seveso 15/01/15 13:21 pagina 294 stesura seveso 227archivio italiano di urologia e andrologia 2014; 86, 3 case report localised prostate cancer and hemophilia a (aha): case report and management of the disease francesco celestino 1, cristian verri 2, francesco de carlo 2, savino mauro di stasi 2 1 urologic oncology unit, policlinico casilino, rome, italy; 2 department of experimental medicine and surgery, tor vergata university, rome, italy. acquired hemophilia a (aha) is a rare bleeding diathesis characterized by the development of autoantibodies against factor viii (fviii). about half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . aha is associated with malignancies in 7-15% of cases. we report a case of aha in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (rp). key words: activated partial thromboplastin time; factor viii; hemophilia a; prostate cancer; radical prostatectomy. submitted 14 july 2014; accepted 1 august 2014 summary no conflict of interest declared. introduction aha is a bleeding disorder in which autoantibodies, usually igg, are produced against factor viii (fviii). the clinical presentation varies from light bleeding to acute and life-threatening hemorrhages. the mortality rate ranges from 7.9 to 22% (1, 2). case report a 65-year-old caucasian male, with no significant medical history, underwent retropubic radical prostatectomy (rp) for prostatic carcinoma. his psa was 5.2 ng/ml, hb was 14.6 g/dl. coagulation studies revealed an elevated activated partial thromboplastin time (aptt) of 37.4 seconds (20.0-35.0 sec.) and normal prothrombin time (pt). in the immediate postoperative period, hb was 10.7 g/dl. on 7th postoperative day, hb was 6.7 g/dl, the urine was clear and surgical drainage showed no significant traces, whereas the patient had a ct scan showing active bleeding in the prostate bed anterior to the rectum. the patient underwent surgical revision that showed no major bleeding. on the 11th postoperative day, massive hematuria was noted in the patient. the endoscopic revision showed multiple and small hemorrhagic areas at the bladder neck and posterior bladder wall, which were coagulated. doi: 10.4081/aiua.2014.3.227 the aptt was 61.0 seconds. two days later there was another massive hematuria, for which the patient underwent selective angiography that showed spreading of the contrast medium from a very thin and tortuous branch of the vesical artery. after several failed attempts at selective cannulation of the vesical artery branch, the patient underwent surgical revision. ten days later, following another massive hematuria, the patient underwent endoscopic revision. on the 34th postoperative day, he was diagnosed with autoantibodies against fviii (6 u bethesda; normal range 0.55 u bethesda) by a specialized hematological laboratory. the fviii assay was 20% (normal range 60-140%). initial management was aimed at controlling acute bleeding and then eradicating the inhibitor. recombinant factor viii (rfviia, novoseven®, novo nordisk, bagsvaerd, denmark) was adopted as a primary agent, using the dose of 90 µg/kg every 4 hours when major bleeding occurred and prior to planned invasive procedures. immunosuppression was initiated with 1 mg/kg of prednisone daily. six weeks after immunosuppressive therapy, fviii autoantibodies were measured at < 0.55 u bethesda. discussion aha is a bleeding disorder in which autoantibodies, usually igg, are produced against fviii. its incidence ranges from 0.2-4 cases/million/year, but this figure may be underestimated, given the difficulty in achieving its diagnosis. when preoperative coagulation studies reveal an elevated aptt and normal pt, aha should be suspected. some patients may show a normal aptt and no bleeding during and immediately after surgery. in this cases, the development of fviii inhibitors can be viewed as a paraneoplastic phenomenon. aha is confirmed by detecting the fviii inhibitor in laboratory tests, but these tests are available only at specialized hematological laboratories. this lengthens the time needed for diagnosis, resulting in a delay in administering the appropriate anti-hemorrhagic treatment. therefore, the patient often undergoes surgical or invasive diagnostic procedures that can cause complications requiring blood transfusions. celestino cr_stesura seveso 09/10/14 10:20 pagina 227 archivio italiano di urologia e andrologia 2014; 86, 3 f. celestino, c. verri, f. de carlo, s.m di stasi 228 management principles entail controlling bleeding and then eradicating autoantibodies through immunosuppression using a combination of steroids, immunoglobulins, cyclophosphamide and monoclonal antibodies (table 1). the treatment of acute bleeding episodes involves the use of different bypassing agents, such as recombinant activated factor vii (rfviia), activated prothrombin complex concentrate (apcc, feiba®), desmopressin and human or porcine fviii concentrates. fresh frozen plasma is often ineffective, because it contains a low concentration of fviii that is quickly inactivated by antibodies. in patients with a low fviii antibody titer, desmopressin (minirin®, ferring, sweden), synthetic vasopressin analogues can be used to stop bleeding. this is due to the ability of desmopressin to release fviii from the vascular endothelium to the circulatory system. there is no optimal regimen for inhibitor eradication. the most common strategy is to use steroids alone or steroids in combination with cyclophosphamide. the average time to remission with steroids is about 5 weeks. references 1. franchini m, gandini g, di paolantonio t, mariani g. acquired hemophilia a: a concise review american journal of hematology. 2005; 80:55-63. 2. shetty s, bhave m, ghosh k. acquired hemophilia a: diagnosis, aetiology, clinical spectrum and treatment options autoimmun rev. 2011; 10:311-6. 3. reitter s, knoebl p, pabinger i, lechner k. postoperative paraneoplastic factor viii auto-antibodies in patients with solid tumours. haemophilia. 2011; 17:e889-94. correspondence francesco celestino, md (corresponding author) frapichi@libero.it policlinico casilino via casilina, 1049 00169 rome, italy home: via g. rossini, 26 81040 curti (ce), italy cristian verri, md verricris@tiscali.it francesco de carlo, md francescodecarlo03@yahoo.it savino mauro di stasi, md sdistas@tin.it department of experimental medicine and surgery tor vergata university, rome, italy table 1. algorithm of acquired hemophilia a patient management (rfviia recombinant activated factor vii (novoseven®); apcc activated prothrombin complex concentrate; vwf von willebrand factor). celestino cr_stesura seveso 09/10/14 10:20 pagina 228 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2136 original paper the importance of psa-density in active surveillance for prostate cancer caner ediz, serkan akan, muhammed cihan temel, omer yilmaz department of urology, sultan abdulhamid han education and research hospital, istanbul, turkey. objective: in this study, we aimed to determine the predictive factor for additional treatment requirement in active surveillance (as) for patients with low or very low-risk prostate cancer (pca) and we investigated the effect of tumor burden by total core involvement rate in biopsy to predict of need for additional treatment. material and methods: 107 patients with pca in as between 2005 and 2018 have been evaluated retrospectively. groups were divided into two groups according to the need for additional treatment. group 1 received additional treatment, group 2 did not receive additional treatments and active surveillance was continued. patient’s total prostate-specific antigen (tpsa), prostate-specific antigen density (psa-d), total core involvement count, quantity and rate at biopsy pathology results and follow-up period were recorded and compared in the two groups. results: the current cohort includes 107 patients. mean age at diagnosis was 63.01years. mean tpsa values at diagnosis were 6.09 ng/ml and 5.2 ng/ml in the group 1 and group 2, respectively. mean follow-up period was 38.1 months (range, 12 to 134 months). only psa-d measurement significantly predicted need for additional treatment (p = 0.017). roc analysis showed that the optimal threshold was 0.13 ng/ml/cc (sensitivity: 70.8%; specificity: 57.1%). additional treatment requirement was not detected in patients with psa-d cut-off level less than 0.07 ng/ml/cc. conclusions: total tumor burden of less than 5% is safe for patients with low or very low-risk pca in as. a 0.13 ng/ml/cc cut-off level of psa-d can predict to need for additional treatment in patients managed by as. key words: prostate cancer; active surveillance; prostate specific antigen density; definitive treatment. submitted 12 december 2019;accepted 3 january 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.136 introduction prostate cancer (pca) is the most common cancer in men (1) and has a high mortality rate like lung cancer. psa screening and early diagnosis have led to a decrease in the mortality rates (2). there are many changes in the treatment of prostate cancer over the years and one of the most significant changes is active surveillance (as) protocol. the time from the diagnosis of low-risk disease to the clinical progression is generally long and progression signs are detectable during the follow-up period. for this reason, as is applied at low-risk pca because definitive treatment can be offered when needed. another reason for choosing as, is to prevent overtreatment by selecting patients with low-risk prostate cancer in order to preclude possible side effects of the definitive treatment. in 2003, this point was emphasized to avoid or delay definitive treatment and its associated morbidity without compromising survival (35). as provides these benefits to patients and it is extremely cost effective compared to definitive treatment (6). active surveillance has been used for many years in the follow-up of pca. unfortunately, we do not know the answer to questions such as “which patients will need additional treatment?” or “when the definitive treatment should be started?” we aimed to evaluate whether total core involvement count, quantity and rate were the correct parameter and we analyzed the efficacy of prostate-specific antigen density or total core involvement rate to predict tumor burden and possible additional treatment needs. we reported outcomes of as in patients with very low and low-risk pca. materials and methods study population and design 1695 patients with prostate biopsy performed due to high prostate-specific antigen (psa) or significant digital rectal examination findings in our clinics between june 2005 and june 2018 were enrolled. the data were collected retrospectively. no ethical committee approval was required owing to the retrospective nature of our study. a total of 117 patients with pca were managed by as. the current cohort with available data includes 107 patients. patient’s age, digital rectal examination (dre) findings, prostate volumes (pv), total psa (tpsa), psadensity (psa-d), in biopsy; total core involvement count (tcic), quantity (tciq) and rate (tcir), pathology results and follow-up period were recorded. the criteria for inclusion in the study was as follows: patients with the low risk of cancer progression: > ten years life expectancy, ct1/2, psa ≤ 10 ng/ml, biopsy gleason score of </= 6, ≤ 2 positive biopsies, minimal biopsy core involvement (≤ 50% cancer per biopsy). the criteria for exclusion in the study were: patients who started follow-up before 2003 and patients whose data could not be reached. patients who voluntarily opted to leave the active surveillance protocol were not included in this study. the patient's medical records were reviewed. patients’ age, grading and findings of digital rectal examination, 137archivio italiano di urologia e andrologia 2020; 92, 2 psa-density and active surveillance prostate volumes (pvs) calculated by transrectal ultrasound (trus) with the ellipse method (length x depth x width x π/6) by using height obtained by transaxial scanning, tpsa, psa-d that was calculated as tpsa (ng/ml) divided by pv, were eveluated in all patients. in each biopsy. tcic, tciq and tcir were calculated by total core number (n), total tumor length in all cores (mm) and ratio of total tumor length to total length of biopsy tissues detected within the tumor (%), respectively. recurrent pathology results and follow-up time were eveluated. pathological specimens were reviewed by a single genitourinary pathologist based on the 2005 and 2014 international society of urological pathology (isup) consensus conference grading of prostate cancer (7, 8). the patients who were diagnosed with prostate cancer before 2014 were evaluated using 2005 isup grading criteria and patients who were followed-up after 2014 were classified using the 2014 isup new grading system. the follow-up protocol included a minimum of four reexaminations per year. tpsa measurement was performed every 3 months for 2 years and then every 6 months in suitable patients. dre were routinely performed in all patients. possible tpsa changes were confirmed at least two times. a confirmation biopsy was recommended for all patients within the first year after diagnosis. confirmation biopsies generally involve more core assessment than standard biopsies. multiparametric magnetic resonance imaging of the prostate (mpmri) was performed in patients who do not want to have a second biopsy or before recurrent biopsies. patient-based modalities are preferred in the definitive treatment decision. definitve treatment was planned primarily in patients who were found to be unsuitable for as. however, androgen deprivation treatment was prefered in patients who did not accept surgical treatment or radiotherapy. statistical analysis in the analysis of the data, pspp and microsoft excel computer programs were used. as a statistical method in the analysis of data in the research, descriptive analyzes (mean and standard deviation) were applied. in the analysis of the data, the normality hypothesis was first investigated using the kolmogorov-smirnov test and mann whitney u test was used for data analysis after the normal distribution test. the statistically significant parameters were analyzed by the receiver operating characteristic (roc) that allowed for the determination of the cutoff value by the combination of the greater specificity and sensitivity by the definition of the area under the curve. the results were evaluated at 95% confidence interval and p < 0.05 significance level. results for the 107 patients included in analyses, the mean age at diagnosis was 63.01 years (range, 47 to 74 years). the distributions of all patients by age, pv, tpsa and psa-d were shown in table 1 and by tcic, tciq and tcir in table 2. an abnormal dre findings were found in 32 of 107 patients (such as asymmetric growth of lateral lobes, nodule or stiffness). mean follow up period was 38.1 table 1. evaluation of descriptive characteristics in patients with pca were managed by as. table 4. evaluation of descriptive characteristics according to the patients with or without additional treatment requirement (surgical or medical). table 3. 5-year average of pca patients who underwent psa follow-up with active surveillance. table 2. total core involvement count. quantity and rate of patients according to number of biopsy procedures. variable mean ± sd (min-max) age (years) 63.01 ± 5.85 (47-74) prostate volume (ml) 43.47 ± 17.92 (10-114) tpsa (ng/ml) 5.35 ± 1.96 (1.24-10) psa density (ng/ml/cc) 0.14 ± 0.09 (0.02-0.83) sd: standard deviation. as: active surveillance. first biopsy n = 107 second biopsy n = 68 third biopsy n = 23 mean ± sd (min-max) mean ± sd (min-max) mean ± sd (min-max) tcic (n) 1.18 ± 0.39 (1-2) 2.2 ± 1.06 (1-5) 2.3 ± 1.84 (1-7) tciq (mm) 1.89 ± 1.25 (0.1-7) 5.31 ± 4.22 (1-18) 6.31 ± 7.2 (1-20) tcir (%) 14.78 ± 11.24 (0.55-50) 26.23 ± 19.19 (2.5-90) 20.59 ± 25.8 (1-85.8) sd: standard deviation. tcic: total core involvement count. tciq: total core involvement quantity. tcir: total core involvement rate. follow-up period n (overall) tpsa (ng/ml) (min-max) first year (initial) 107 5.35 (1.24-10) second year (confirmation) 100 5.88 (0.43-28.1) third year 69 5.86 (1.04-12.2) fourth year 48 6.88 (0.84-22) fifth year 32 6.56 (1.64-19.08) additional treatment (-) n = 24 additional treatment (+) n = 83 p mean ± sd (min-max) mean ± sd (min-max) age (years) 63.92 ± 5.79 (57-74) 62.76 ± 5.84 (47-74) 0.74 prostate volume (ml) 40.5 ± 12.16 (15-70) 43.95 ± 19.45 (10-114) 0.72 tpsa (ng/ml) 6.09 ± 1.83 (3.36-9.47) 5.2 ± 2.02 (1.24-10) 0.7 psa density (ng/ml/cc) 0.16 ± 0.06 (0.07-0.28) 0.14 ± 0.12 (0.03-0.83) 0.017* tcic (n) 1.16 ± 0.38 (1-2) 1.19 ± 0.39 (1-2) 0.79 tciq (mm) 1.88 ± 1.36 (1-6) 1.96 ± 1.34 (0.1-7) 0.64 tcir (%) 15.56 ± 11.93 (5-50) 15.31 ± 12.81 (0.55-50) 0.75 sd: standard deviation. tcic: total core involvement count. tciq: total core involvement quantity. tcir: total core involvement rate. * < 0.05. archivio italiano di urologia e andrologia 2020; 92, 2 c. ediz, s. akan, m. cihan temel, o. yilmaz 138 months (range, 12 to 134 months); tpsa changes in the following years after diagnosis were shown in table 3. there was no difference in tcic, tciq and tcir levels between the 2 groups as reported in table 4 (p > 0.05). the psa-d was less than 0.13 ng/ml/cc in 58/107 patients and only 7 (12.06%) of them required additional treatment; in 49/107 patients psa-d was more than 0.13 ng/ml/cc and 17 (34.69%) of them required additional treatment (table 5). when the cut-off level of psa-d was based on 0.13 ng/ml/cc, the follow-up period until the decision to start additional treatment was 26.14 months for psa-d ≤ 0.13 and 25.4 months for psa-d > 0.13) months, respectively. two patients with psa-d > 0.13 ng/ml/cc lost their chance of definitive treatment. psa-d was associated with predicting of additional treatment requirement for active surveillance (p = 0.017) and roc analysis showed that the optimal threshold was 0.13 ng/ml/cc (sensitivity: 70.8%; specificity: 57.1%). twenty patients underwent radical prostatectomy (rp) as additional treatment in follow-up. average follow-up time until rp was 25.47 months (range, 12 to 60 months). in patients with prostate cancer managed by active surveillance, annual changes of tpsa levels in follow-up according to patients with psa-d > 0.13 or 0.13 ≤ ng/ml/cc are shown in figure 1. pathology results of radical prostatectomy specimens according to the isup classification are reported in table 6. twelve out of 20 (60%) radical prostatectomy specimens were graded isup 1. two patients preferred radiotherapy (rt) and another two received androgendeprivation therapy (rt not approved by radiation oncologist) as additional treatment (figure 2). additional treatments were offered to other two patients, but the patients refused to additional treatments and were removed from the treatment protocol of their own volition. additional cancers were observed in 3 of 107 patients under follow-up, one patient was diagnosed with bladder cancer and two patient diagnosed with renal cell cancer. two patients died due to non-cancerous causes (chronic heart failure and lymphoma). table 5. number of patients managed with additional treatments in different psa-density levels and grouping of patients with radical prostatectomy by isup grade. table 6. number of pca patients managed with active surveillance according to isup grades. figure 1. in patients with prostate cancer managed by active surveillance. annual changes of psa levels in follow-up according to patients with psa-density > 0.13 or 0.13 ≤ ng/ml/cc. psa: prostate specific antigen. psad: prostate-specific antigen density. tpsa1.2.3.4.5: first, second, third, fourth and fifth year total prostate specific antigen levels in follow-up. psa-d ≤ 0.13* (n = 58) psa-d > 0.13* (n = 49) mean ± sd mean ± sd age (years) 63.06 ± 5.41 62.93 ± 6.39 atr atr n = 7 (%) n = 17 (%) treated with radical prostatectomy isup 1 6 (85.71) 6 (35.29) isup 2 0 5 (29.41) isup 3 0 1 (5.88) isup 4 0 0 isup 5 1 (14.28) 0 pt0** 0 1 (5.88) treated with rt 0 2 (11.76) treated with adt 0 2 (11.76) psa-d: psa-density. atr: additional treatment requirement. isup: international society of urological pathology. rt: radiotherapy. adt: androgen-deprivation therapy. *: ng/ml/cc. **: tumor tissue was not detected in pathology specimen after radical prostatectomy. isup grades (pca in rp) n (overall) % isup 1 12 60 isup 2 5 25 isup 3 1 5 isup 5 1 5 pt0* 1 5 *: tumor tissue was not detected in pathology specimen after radical prostatectomy. isup: international society of urologic pathologists. pca: prostate cancer. 139archivio italiano di urologia e andrologia 2020; 92, 2 psa-density and active surveillance discussion active surveillance is a well-recognized option in patients with low (clinical stage t1-t2a and tpsa < 10 ng/ml and grade group 1) and very low-risk (clinical stage t1-t2a and tpsa < 10 ng/ml and grade group 1 and psa-density < 0.15 ng/ml/cc and < 34% of biopsy cores positive and no core with > 50% involved) pca (9). there are different protocols and selection criterias to select the appropriate patient. tpsa, clinical stage, and number of positive cores, each core involvement, psa-d and a life expectancy of at least 10 yr are the basis of different protocols. prostate specific antigen threshold values in as are variable, but generally less than 10 ng/ml, in a study conducted by royal marsden clinic in 2008, tpsa threshold was determined ≤ 15 ng/ml (10). clinical stage t1c or t2a is accepted as eligible for as guidelines. the tpsa threshold values for as suggested by the guidelines have a low risk potential. however, we think that the low gleason score is more valuable than the low psa, and the threshold value of high psa values (above 10 ng/ml) should be preferred in appropriate patients. in our clinical practice, we apply as more flexibly in informed patients (information including detailed explanations about their condition and the likely outcomes of treatment) than the guidelines suggest. psa-density is a predictor of upgrading of isup degree after radical prostatectomy and it is used safely in as (11-13). the threshold value of psa-d is 0.15 ng/ml/cc in current guidelines, but nowadays, in some studies, the cut-off value of psa-d of 0.08 ng/ml/cc indicates significant risk for disease progression (14). jin et al. found that optimal cut-off level of psa-d was 0.13 ng/ml/cc (11). barayan et al. found that a psa-d > 0.15 ng/ml/cc is an important predictor for disease progression (15). in our cohort, psa-d was the only factor that was statistically significant in predicting the need for additional treatment and optimal cut-off level was 0.13 ng/ml/cc. in patients with psa-d > 0.13 ng/ml/cc, a larger part of the patients needed additional treatment and follow-up period until the decision to start surgical or hormonal theraphy was shortened when the psa-d was increased. in patients with psa-d greater than 0.13 ng/ml/cc, high gleason scores (from 3+4 to 4+5) were detected when radical prostatectomy was performed as definitive treatment. in a study by camur et al., upgrading was seen in 35 (44.8%) of 78 patients included in the study, but pv had no significant effect on upgrading in as appropriate patients (16). although pv is ineffective, as criterias may include psa-d. patients with psa-d levels < 0.07 ng/ml/cc were not upgraded and needed no additional treatment. especially very low psa-d levels (< 0.07) are extremely safe. we think that risk classifications according to psa-d levels will contribute to the determination of secondary or tertiary biopsy requirements in follow-up protocols of patients and believe that the cutoff value of the recommended psa-d in the guidelines should be updated to below 0.15 ng/ml/cc. the number of positive cores is limited by two according to many authors. in california university, this value should not exceed 33% of the total number of cores taken (17). many guidelines and authors have suggested that involvement rate in cores should be limited to 50%. soloway et al. suggested a rate of 20% (18) and porten et al. of 33% (19). we think that 50% is an optimal value, but this rate cannot be evaluated in inadequate biopsy samples. the ideal core length should be more than 1.5 cm. tumor measurements such as number of positive cores, fraction of positive cores, linear percentage of carcinoma in each core or across all sites and linear millimeters of carcinoma in each core or across all sites are used for patient selection in as (20). the actual area of the tumor in millimeters is used to calculate percentage (21). the percent of needle biopsy cores and surface area are the strongest predictors of tumor volume and pathological stage (22). in the literature, many articles found that maximum percent core involvement at diagnosis was associated with progression (23-26). sternberg et al. (27) and iremashvili et al. (28) created nomograms that include number of positive cores and percent of positive cores at diagnosis. however, disease progression and extent of cancer on biopsy are not associated significantly in some studies (29, 30). in this area; open to different interpretations, tcic, tciq and tcir measurements are optional and we thought that the tcic, tciq and tcir would be more significant than the amount of tumor rate in each core. quintal et al found that tcic and tcir were significantly stronger than linear percentage of cancer or greatest millimeter length in each core to predict biochemical recurrence (31). brimo et al. found that tcir is closely associated with stage and biochemical failure (32). however, park et al. found that figure 2. the flowchart includes patients who remained on surveillance or moved to active treatment (rp, rt or adt) and annual change of tpsa for 5-year in the study population. archivio italiano di urologia e andrologia 2020; 92, 2 c. ediz, s. akan, m. cihan temel, o. yilmaz 140 these paramaters were not significant in predicting pt3 disease (33). russo et al. found a cut-off value of 0.4 mm for each core (34). today, clearly defined and accepted values are still not available to predict total tumor burden. in this study, we found that the measurements except than psa-d were insufficient in predicting the need for additional treatment. one of the most important points in as is patient compliance to follow-up periods. patients may want to withdraw from the as protocol because they can not accept living with recurrent psa measurements, examinations, biopsies and diagnosis of tumor. for this reason, followup of this protocol with non-invasive methods such as mpmri is extremely valuable. alberts et al found that prostate imaging reporting and data system score of 13 and psa-d of < 0.15 ng/ml/cc did not show gleason score upgrading in biopsies at each time point of surveillance (35). as may be more preferable to patients with low risk pca due to reduced biopsy requirements in the future. especially combination of psa-d and mpmri may be the future of this therapy management. the limitations of the study are the evaluation of data retrospectively, the relatively patients’ low compliance with the follow-up protocol, the comparatively short mean follow-up period and the lack of multiparametric mri findings. more studies are needed to predict total tumor burden at diagnosis and additional treatment requirement over time. conclusions active surveillance in the treatment of prostate cancer is a proven protocol and there is a high degree of consensus on its criterias. although tcic, tciq and tcir measurements are thought to help us to have an idea about the total tumor burden and progression, there is no contribution to predict the need for additional treatment. therefore, we don't think they need to be measured routinely. cut-off value of psa-d as a 0.13 ng/ml/cc may be effective in determining the risk group and may be predictive of the need for additional treatment in the follow-up. acknowledgements of financial support the authors would like to thank the entire staff of the department of urology, sultan abdulhamid han education and research hospital and certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin 2018; 68:7-30. 2. jemal a, siegel r, ward e, et al. cancer statistics, 2007. ca cancer j clin. 2007; 57:43-66. 3. klotz l. active surveillance with selective delayed intervention: a biologically nuanced approach to favorable-risk prostate cancer. clin prostate cancer. 2003; 2:106-110. 4. koo kc, lee ks, jeong jy, et al. pathological and oncological features of korean prostate cancer patients eligible for active surveillance: analysis from the k-cap registry. jpn j clin oncol. 2017; 47:981-985. 5. lee dh, koo kc, lee sh, et al. low-risk prostate cancer patients without visible tumor (t1c) on multiparametric mri could qualify for active surveillance candidate even if they did not meet inclusion criteria of active surveillance protocol. jpn j clin oncol. 2013; 43:553-558. 6. corcoran at, peele pb, benoit rm. cost comparison between watchful waiting with active surveillance and active treatment of clinically localized prostate cancer. urology. 2010; 76:703-707. 7. egevad l, delahunt b, srigley jr, et al. international society of urological pathology (isup) grading of prostate cancer an isup consensus on contemporary grading. apmis. 2016; 124:433-435. 8. epstein ji, allsbrook wc jr., amin mb, et al. the 2005 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma. am j surg pathol. 2005; 29:1228-1242. 9. thostrup m, thomsen fb, iversen p, et al. active surveillance for localized prostate cancer: update of a prospective single-center cohort. scand j urol. 2018; 52:14-19. 10. van as nj, norman ar, thomas k, et al. predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance. eur urol. 2008; 54:1297-1305. 11. jin bs, kang sh, kim dy, et al. pathological upgrading in prostate cancer patients eligible for active surveillance: does prostate-specific antigen density matter? korean j urol. 2015; 56:624-629. 12. kotb af, tanguay s, luz ma, et al. relationship between initial psa density with future psa kinetics and repeat biopsies in men with prostate cancer on active surveillance. prostate cancer prostatic dis. 2011; 14:53-57. 13. loeb s, bruinsma sm, nicholson j, et al. active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. eur urol. 2015; 67:619-626. 14. san francisco if, werner l, regan mm, et al. risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance. j urol. 2011; 185:471-476. 15. barayan ga, brimo f, begin lr, et al. factors influencing disease progression of prostate cancer under active surveillance: a mcgill university health center cohort. bju int. 2014; 114:e99-e104. 16. camur e, coskun a, kavukoglu, et al. prostate volume effect on gleason score upgrading in active surveillance appropriate patients. arch ital urol androl. 2019; 91:93-96 17. cooperberg mr, cowan je, hilton jf, et al. outcomes of active surveillance for men with intermediate-risk prostate cancer. j clin oncol. 2011; 29:228-234. 18. soloway ms, soloway ct, eldefrawy a, et al. careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. eur urol. 2010; 58:831-835. 19. porten sp, whitson jm, cowan je, et al. changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. j clin oncol. 2011; 29:2795-2800. 20. amin mb, lin dw, gore jl, et al. the critical role of the pathologist in determining eligibility for active surveillance as a management option in patients with prostate cancer: consensus statement with recommendations supported by the college of american pathologists, international society of urological pathology, association of directors 141archivio italiano di urologia e andrologia 2020; 92, 2 psa-density and active surveillance of anatomic and surgical pathology, the new zealand society of pathologists, and the prostate cancer foundation. arch pathol lab med. 2014; 138:1387-1405. 21. draisma g, boer r, otto sj, et al. lead times and overdetection due to prostate-specific antigen screening: estimates from the european randomized study of screening for prostate cancer. j natl cancer inst. 2003; 95:868-878. 22. sebo tj, bock bj, cheville jc, et al. the percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy. j urol. 2000; 163:174-178. 23. tseng ks, landis p, epstein ji, et al. risk stratification of men choosing surveillance for low risk prostate cancer. j urol. 2010; 183:1779-1785. 24. bul m, zhu x, valdagni r, et al. active surveillance for low-risk prostate cancer worldwide: the prias study. eur urol. 2013; 63:597-603. 25. eggener se, mueller a, berglund rk, et al. a multi-institutional evaluation of active surveillance for low risk prostate cancer. j urol. 2013; 189:s19-25. 26. venkitaraman r, norman a, woode-amissah r, et al. predictors of histological disease progression in untreated, localized prostate cancer. j urol. 2007; 178:833-837. 27. sternberg ia, yu c, keren paz ge, et al. predicting progression in patients followed with active surveillance for low-risk prostate cancer. american society of clinical oncology; 2014. 28. iremashvili v, burdick-will j, soloway ms. improving risk stratification in patients with prostate cancer managed by active surveillance: a nomogram predicting the risk of biopsy progression. bju int. 2013; 112:39-44. 29. cary kc, cowan je, sanford m, et al. predictors of pathologic progression on biopsy among men on active surveillance for localized prostate cancer: the value of the pattern of surveillance biopsies. eur urol. 2014; 66:337-342. 30. adamy a, yee ds, matsushita k, et al. role of prostate specific antigen and immediate confirmatory biopsy in predicting progression during active surveillance for low risk prostate cancer. j urol. 2011; 185:477-482. 31. quintal mm, meirelles lr, freitas ll, et al. various morphometric measurements of cancer extent on needle prostatic biopsies: which is predictive of pathologic stage and biochemical recurrence following radical prostatectomy? int urol nephrol. 2011; 43:697-705. 32. brimo f, vollmer rt, corcos j, et al. prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue. histopathology. 2008; 53:177-183. 33. park ea, lee hj, kim kg, et al. prediction of pathological stages before prostatectomy in prostate cancer patients: analysis of 12 systematic prostate needle biopsy specimens. int j urol. 2007; 14:704-708. 34. russo gi, cimino s, castelli t, et al. percentage of cancer involvement in positive cores can predict unfavorable disease in men with low-risk prostate cancer but eligible for the prostate cancer international: active surveillance criteria. urol oncol. 2014; 32:291-296. 35. alberts ar, roobol mj, drost fh, et al. risk-stratification based on magnetic resonance imaging and prostate-specific antigen density may reduce unnecessary follow-up biopsy procedures in men on active surveillance for low-risk prostate cancer. bju int. 2017; 120:511-519. correspondence caner ediz, md (corresponding author) drcanerediz@gmail.com serkan akan, md drserkanakan@hotmail.com muhammed cihan temel, md dr.cihantemel@gmail.com omer yilmaz, md dr_omeryilmaz@yahoo.com department of urology, sultan abdulhamid han education and research hospital, istanbul, turkey tibbiye street. selimiye neighborhood. uskudar/istanbul stesura seveso 297archivio italiano di urologia e andrologia 2014; 86, 4 short communication viburnum opulus: could it be a new alternative, such as lemon juice, to pharmacological therapy in hypocitraturic stone patients? devrim tuglu 1, erdal yılmaz 1, ercan yuvanc 1, imge erguder 2, ucler kisa 3, fatih bal 1, ertan batislam 1 1 university of kirikkale, faculty of medicine, department of urology and 3 biochemistry, 2 university of ankara faculty of medicine, department of biochemistry, turkey. objective: citrate, potassium, and calcium levels in viburnum opulus (v. opulus) and lemon juice were compared to evaluate the usability of v. opulus in mild to moderate level hypocitraturic stone disease. materials and methods: v. opulus and lemon fruits were squeezed in a blender and 10 samples of each of 100 ml were prepared. citrate, calcium, sodium, potassium, magnesium, and ph levels in these samples were examined. results: potassium was found to be statistically significantly higher in v. opulus than that in lemon juice (p = 0.006) whereas sodium (p = 0.004) and calcium (p = 0.008) were found to be lower. there was no difference between them in terms of the amount of magnesium and citrate. concusions: because v. opulus contains citrate as high as lemon juice does and it is a potassium-rich and calciumand sodium-poor fluid, it can be an alternative to pharmaceutical treatment in mild-to-moderate degree hypocitraturic stone patients. these findings should be supported with clinical studies. key words: viburnum opulus; hypocitraturic; urinary stone; lemon juice. submitted 24 october 2014; accepted 31 october 2014 summary no conflict of interest declared. recurrence. however, patient compliance to pharmacotherapy with potassium citrate can be difficult. due to gastrointestinal side effects and the high number of tablets to take throughout the day, 3-year treatment dropout rates of patients are as high as 25 percent (2, 5). natural citric acid intake can be used as an alternative to pharmacotherapy in patients who are incompatible, or who cannot tolerate potassium citrate. there are studies that have used lemonade, orange, grapefruit, lime, or tomato to aim this target (6-11). these studies emphasize that they can be a good alternative to pharmacotherapy in mild to moderate hypocitraturia. oxidative stress and renal tubular cell injury are observed in urinary tract stone patients. lipid peroxidation begins in the cell membrane as a consequence of the toxicity of free radicals. when cell membrane integrity breaks down, cell balance begins to disappear, and cell death starts. antioxidants may be used in order to avoid this situation (12). viburnum opulus (v. opulus) has antioxidant properties (13-15) and we think that it may have a place in the medical treatment of stone disease. not only with its antioxidant properties, but also with its content of potassium and citrate, it suggests being beneficial in the prevention of stone disease. in our study, v. opulus is compared in terms of citrate, calcium, phosphorus, magnesium, sodium, potassium and ph to lemon, which is known as a source of natural citrate, and the usability of v. opulus in hypocitraturic stone disease patients is discussed. material and method because v. opulus has a bitter taste when first collected, the fruit was kept in brine water for a month to make it lose its bitterness. after having made it drinkable, it was squeezed in a blender and 10 samples of each of 100 ml were collected. ten samples of 100 ml each were taken from lemons in the same manner. during evaluation, no dilutions were made with water or any other solution and no sugar was added to prevent the direct effect of a liquid or sugar to the variables to evaluate. the resulting extract was centrifuged for 15 min at 2000 g. citrate, oxalate, calcium, phosphorus, magnesium, sodidoi: 10.4081/aiua.2014.4.297 introduction urinary tract stone disease affects 12% of the world's population and its recurrence can be as high as 50% at 10 year follow up (1). with the widespread use of swl and introduction of endoscopic techniques, studies on medical stone treatment have been reduced and pushed to the background (2). urinary tract stones are formed through a marked increase in the saturaton of a solute substance in the urine. one of the changeable factors affecting solubility is ph. increase in the value of urinary ph raise the point of solubility and may prevent stone formation (3). the agents commonly used to treat hypocitraturia and alkalinizing urine are sodium citrate and potassium citrate (4, 5). many studies have shown that citrate replacement reduces rates of stone tuglu_stesura seveso 14/01/15 13:02 pagina 297 archivio italiano di urologia e andrologia 2014; 86, 4 d. tuglu, e. yılmaz, e. yuvanc, i. erguder, u. kisa, f. bal, e. batislam 298 um, potassium, chloride, and ph levels were examined in all samples. samples were grouped as follows: group 1. v. opulus juice held in brine; group 2. fresh lemon juice an enzyme-spectrophotometric method was used to determine citrate in biological fluids it is based on citrate lyase and phenylhydrazine reactions. the enzyme converts citrate into oxaloacetate, which, in the presence of phenylhydrazine, is transformed into the corresponding phenylhydrazone. the ultraviolet-absorbing product is determined by absorbance measurement at 330 nm (16). the method is based on the following reactions: citrate lyase citrate oxaloacetate + acetate malate dehydrgenase oxaloacetate + nadh + h+ malate + nad+ calcium, phosphorus and magnesium (roche diagnostics gmbh, mannheim) were colorimetrically measured by a hitachi p800 autoanalyser (hitachi high-technologies co., japan). sodium and potassium were analyzed in the hitachi p800 autoanalyser using ion-selecting electrodes. a ph meter precisa ph 900 device was used to verify ph. wilcoxon rank-sum test was used in the statistical evaluations for comparison of the parameters. results the citrate and magnesium contents of v. opulus have been found not statistically different from than of lemon juice. potassium has been found statistically higher than in lemon juice (p: 0.006) whereas sodium (p: 0.004) and calcium (p: 0.008) were lower. table 1 shows the citrate, calcium, sodium, potassium, phosphorus, magnesium and ph values in lemon juice and v. opulus contents. discussion a well known inhibitor of calcium-based stones is citrate. citrate reduces calcium oxalate and phosphate saturation by forming calcium-soluble complexes and by inhibiting crystal nucleation and growh (4). with an incidence of 16-63%, hypocitraturia is an important etiological factor in recurrent calcium nephrolithiasis (3). it has been demonstrated that pharmacological potassium citrate intake increases urine citrate levels and reduces urine calcium excretion as well as relative saturation of calcium oxalate in hypocitraturia (2). alternatives to potassium citrate have been sought in recent years due to patient non-compliance, particularly due to gastrointestinal poor tolerance (17-45%), and to the severe financial burden (a daily dose price of $ 3.90 in turkey) (5). significant increases in urinary volume, ph, potassium, magnesium and citrate excretion have been obtained in patients with hypocitraturic stone disease by the addition of fruit and vegetable juices to the diet (7, 17, 18). in addition, this has also been reported to provide dilution of lithogenic risk factors in the urine without affecting the concentration of potassium and citrate (19). in particular, various studies have established that the use of citrate extracts and juices as a natural source of citrate can be an alternative to potassium citrate (6, 8). it has been shown that high concentrations of citrate in citrus products may affect urine citrate excretion (20, 21). orange juice causes an alkali load by increasing net gastrointestinal alkali absorption, increases urinary ph and citrate and reduces ammonium and net acid excretion. it is also reported that daily consumption of one liter of orange juice increases citraturia and ph and prevents stone formation and reduces crystallization risk factors for calcium phosphate (8, 22, 23). although grapefruit juice has been shown to have higher citrate content, it has not been possible to demonstrate that it reduces urinary risk factors (24, 25). in addition, grapefruit juice may affect metabolism of commonly used drugs by inhibiting the cytochrome p-450 (24). the citraturic effect of lemonade have been established by a variety of studies. an advantage of lemonade to orange juice is that its citric acid content is high and calcium content is low (9, 20, 26). v. opulus is known to be widely used in turkey, especially in stone disease. this plant is a species within the caprifoliaceae (honeysuckles) family within the dipsacales order. the plant's trunk, bark and fruits are utilized in pharmacology and as food in the form of pickles, jams, and in various other ways (27). in central anatolia, turkey, especially in the city of kayseri, it is widely termed as gilaburu. there are no studies in literature about the mechanism of action of v. opulus in stone disease. we believe that it may be active by two ways: 1. antioxidant properties 2. possible citrate and potassium content of the plant. several studies have been carried in recent years establishing that v. opulus has a high potential of antioxidant activity and antimicrobial characteristics depending on the composition of the substances it contains (13-15, 28). it has also been shown to have beneficial effects in the gastrointestinal mucosa thanks to its antioxidant properties (29). comparison of citrate and potassium content of v. opulus, which has also antioxidant properties, to citrate and potassium content in lemon juice was the purpose of this study. we demonstrated that if v. opulus is citrateand potassium-rich, therefore in relation to both its antioxidant properties and its high content in citrate and potassium, it could be argued that it can be an alternative to pharmacological agents in the treatment of hypocitraturic stone patients. in our study it has been found that potassium content in v. opulus content is higher than that of lemon juice whereas calcium content is lower. no statistically sigv. opulus lemon juice citrate (mmol/l) 65.22 ± 5.86 54.04 ± 5.05 potassium (mmol/l) 40.51 ± 2.78 27.55 ± 2.12 calcium (mmol/l) 0.05 ± 0.01 1.52 ± 0.02 magnesium (mmol/l) 1.57 ± 0.26 1.44 ± 0.21 sodium (mmol/l) 2.54 ± 0.19 6.35 ± 0.98 ph 4.02 ± 0.16 4.03 ± 0.18 table 1. concentration of solutes and ph value in the two fluids. tuglu_stesura seveso 14/01/15 13:02 pagina 298 nificant difference from lemon juice in terms of the content of citrate was observed. this result suggests us that v. opulus may have a citraturic effect as much as lemon juice and can also provide an alkali load due to its high content of potassium. this alkali load increases urinary citrate excretion by reducing renal tubular reabsorption and citrate metabolism. in addition to alkalinizing urine, alkali load also affects citrate reabsorption from the kidneys. the low calcium and sodium content of v. opulus could also be considered as an advantage for stone patients. conclusions in our study, we have identified citrate and potassium v. opulus content as high as that in lemon juice. due to its antioxidant properties as well as to its high content of both citrate and potassium, v. opulus can be recommended to stone patients. we think that it is advisable just as lemon or orange juice in mild-to-moderate hypocitraturia as an alternative to potassium citrate. however, clinical trials on this subject are desirable. references 1. menon m, parulkar bg, drach gw. urinary lithiasis: etiology, diagnosis and medical management. in: walsh pc, retik ab, vaughan ed jr, wein aj, editors. campbell’s urology. 7th 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mcdonald m, et al. dietary manipulation with lemonade to treat hypocitraturic calcium nephrolithisis. j urol. 1996; 156:907-909. 10. tosukhowong p, yachantha c, sasivongsbhakdi t, et al. citraturic, alkalinizing and antioxidative effects of limeade-based regimen in nephrolithiasis patients. urol res 2008; 36:149-155. 11. yilmaz e, batislam e, basar m, et al. citrate levels in fresh tomato juice: a possible dietary alternative to traditional citrate supplementation in stone-forming patients. urology. 2008; 71:379-383. 12. selvam r. calcium oxalate stone disease: role of lipid peroxidation and antioxidants. urol res. 2002; 30:35-47. 13. rop o, reznicek v, valsikova m, et al. antioxidant properties of european cranberrybush fruit (viburnum opulus var. edule) molecules. 2010; 15:4467-4477. 14. altun ml, citoglu gs, yılmaz bs, coban t. antioxidant properties of viburnum opulus and viburnum lantana growing in turkey. int j food sci nutr. 2007; 5:1-6. 15. andreeva ti, komarova en, yusubov ms, korotkova ei. antioxidant activity of cranberry tree (viburnum opulus l.) bark extract. pharma chem j. 2004; 38:548-550. 16. petrarulo m, facchini p, cerelli e, et al. citrate in urine determined with new citrate lyase method. clin chem. 1995; 41:15181521. 17. parivar f, low rk, stoller ml. the influence of diet on urinary stone disease. j urol. 1996; 155:432-440. 18. siener r, hesse a. the effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects. eur urol. 2002; 42:289-296. 19. borghi l, meschi t, maggiore u, prati b. dietary therapy in idiopathic nephrolithiasis. nutr rev. 2006; 64:301-312. 20. aras b, kalfazade n, tugcu v, et al. can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? a prospective randomized study. urol res. 2008; 36:313-317. 21. gettman mt, ogan k, brinkley lj, et al. effect of cranberry juice consumption on urinary stone risk factors. j urol. 2005; 174:590-594. 22. campoy martínez p, arrabal martín m, blasco hernández p, et al. orange juice in the prevention of calcium oxalate lithiasis. acta urol esp. 1994; 18:738-743. 23. wabner cl, pak cy. effect of orange juice consumption on urinary stone risk factors. j urol. 1993; 149:1405-1408. 24. goldfarb ds, asplin jr. effect of grapefruit juice on urinary lithogenicty. j urol. 2001; 166:263-267. 25. hönow r, laube n, schneider a, et al. influence of grapefruit-, orangeand apple-juice consumption on urinary variables and risk of crystallization. br j nutr. 2003; 90:295-300. 26. kang de, sur rl, haleblian ge, et al. lemonade-based dietary manipulation in patients with hypocitraturic nephrolithiasis. j urol. 2007; 177:1358-1362. 27. soylak m, elci l, saracoglu s, divrikli u. chemical analysis of fruit juice of european cranberry bush (viburnum opulus) from kayseri, turkey. asian j chem. 2002; 14:135-138. 28. cesonienè l, daubaras r, viškelis p, sarkinas a. determination of the total phenolic and anthocyanin contents and antimicrobial activity of viburnum opulus fruit juice. plant foods hum nutr. 2012; 67:256-61 29. zayachkivska os, gzhegotsky mr, terletska oi, et al. influence of viburnum opulus proanthocyanidins on stress-induced gastrointestinal mucosal damage. j physiol pharmacol. 2012; 57 suppl 5:155-67. 299archivio italiano di urologia e andrologia 2014; 86, 4 viburnum opulus: could it be a new alternative, such as lemon juice, to pharmacological therapy in hypocitraturic stone patients? correspondence devrim tuglu, md (corresponding author) devrimtuglu@gmail.com erdal yılmaz, md ercan yuvanc, md fatih bal, md ertan batislam, md university of kirikkale, faculty of medicine, department of urology saglik sokak, 71100, kirikkale, turkey imge erguder, md university of ankara faculty of medicine, department of biochemistry ankara, turkey ucler kisa, md university of kirikkale, faculty of medicine, department of biochemistry kirikkale, turkey tuglu_stesura seveso 14/01/15 13:02 pagina 299 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 150 review the impact of non-urologic drugs on sexual function in men ferdinando fusco, marco franco, nicola longo, alessandro palmieri, vincenzo mirone department of neurosciences, reproductive science and odontostomatology federico ii university, naples, italy. sexual dysfunctions have commonly been reported as the resulting side effects of many drugs. to understand the impact of a single drug, the mechanism of action of the most commonly prescribed drugs and the physiological mechanisms of sexual function have to be taken into dual consideration. psychotropic drugs (antidepressants, antipsychotics and antiepileptic) in particular result in both short and long-term effects on sexual function. antihypertensive drugs have also produced evidence certifying their role in determining sexual dysfunction. patients affected with sexual dysfunction are often aged and assume several drugs and, while iatrogenic sexual dysfunction is prevalent in men, urological drugs are not the only drugs to be held accountable. many different drugs acting on different sites and with several mechanisms of action can induce sexual dysfunction. the drug classes involved are widely diffused and frequently assumed in combination therapies. key words: sexual dysfunctions; psychotropic drugs; antihypertensive drugs. submitted 17 february 2014; accepted 28 february 2014 summary introduction sexual function is our physiological capacity to experience desire, arousal and orgasm. male sexual activity is a multifaceted activity, involving complex interactions between the nervous system, the endocrine system, the vascular system and a variety of structures that are instrumental in sexual excitement, intercourse and satisfaction (1). as defined by kaplan, this process consists of three phases: desire, arousal (excitement) and orgasm (2). however, the division between the three is arbitrary and only assists in organizing clinical and research oriented problems involving sexuality. in clinical practice sexual desire, arousal and orgasmic difficulties more often than not coexist, suggesting an integration of phases. in males, arousal basically the ability to achieve and maintain an erection. the orgasm is the mental and physical phenomenon that signifies the climax of coital no conflict of interest declared activity and is accompanied by the ejaculation of seminal fluid (3). normal sexual functioning requires not only an ability to interact with others (i.e. a certain level of social skills) but also a combination of different physiological factors, such as the integrity of the genitalia, the reliable co-ordination of blood flow, the activation of various smooth and skeletal muscles and the stimulation of local secretions (3) sexual dysfunction can result from a wide variety of psychological and physical causes. pathophysiology of sexual dysfunction involves derangements in the levels of sex hormones and neurotransmitters (4), and different drugs affect sexual function in different ways depending on their mechanism of action. drugs that affect libido usually act on the central nervous system and may reduce desire by causing sedation or hormonal disturbance. likewise, drugs that interfere with the autonomic system will have negative effects on erectile function, ejaculation and orgasm (5). many drug classes, other than “prostatic” drugs, have the potential to interfere with the physiology of sexual function. knowledge of the normal biology of sexual function may allow one to predict whether a medication might potentially cause sexual dysfunctions. furthermore, clinical experience acquired on different drug classes and molecules can confirm this potential. the purpose of this article is to review the impact of non-urologic drugs on sexual function in men. materials and methods in june 2013 a literature search was conducted from medline to identify original articles published up to this date with no time limitation and analysis was conducted on previously published reviews and any other relevant articles suitable for the purposes of this review. the search was limited to articles published in english and was conducted by combining the following terms: ed and/or sexual dysfunction; aexual dysfunction and/or drugs, and or antidepressant, antiepileptics, antihypertensive, antipsycothic, antiparkinsonian, proton pump inhibitors, recreational drugs. the retrieval was then extended to the reference list and to the related articles. in the case of the availability of more than one publicadoi: 10.4081/aiua.2014.1.50 fusco_stesura seveso 26/03/14 10:50 pagina 50 51archivio italiano di urologia e andrologia 2014; 86, 1 the impact of non-urologic drugs on sexual function in men tion sharing the same information, the most recently published article was included in this review. two independent reviewers evaluated the output listings to identify the references matching the selection criteria and checked each article to ensure consideration of further relevant published articles from the respective reference lists. drugs that affect sexual function several drug classes are reported to interfere with sexual function. evidence was found for medications that differed greatly both for their indications and mechanisms of action, e.g.: antihypertensive, as beta blockers and thiazides, acting on peripheral blood flow and the sympathetic autonomous nervous system; proton pump inhibitors, acting on testosterone metabolism; drugs acting on the central nervous system as antidepressants, antiepileptics and antipsychotics, with their central mechanism of action on ions channels or nervous transmission (table 1). antidepressants treatment-emergent sexual dysfunction caused by antidepressants is a considerable issue with a large variation across compounds (6). this is primarily due to the activation of 5-ht2 receptors which inhibit both noradrenergic and dopaminergic transmission. generally, antidepressants with fewer 5-ht2 effects tend to cause less treatmentemergent sexual dysfunctions (7). depression itself can cause sexual problems, thus it is sometimes difficult to recognize what is causing any occurring sexual dysfunction (8). it is therefore useful to try to get some idea of a person’s sexual functioning prior to starting antidepressants. serretti et al. (6) showed in a recent work on depressed men treated with antidepressants, that there was a significantly higher rate of total and specific treatment-emergent sd and specific phases of dysfunction compared with placebo for the following drugs in decreasing order of impact: sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine, with sd ranging in 25.8% to 80.3% of patients. no significant difference with placebo was found for the following antidepressants: agomelatine, amineptine, bupropion, moclo bemide, mirtazapine, and nefazodone. in conclusion the use of antidepressant therapy associated with the depression itself, has to be carefully considered in patients with a history of sexual dysfunction. as different antidepressants may have a different impact on sexual function, in the case of antidepressantinduced sd, a switch to an alternative antidepressant may be worth trying. anti-epileptics epileptic men may experience hormonal changes and altered levels of biologically active testosterone; changes that could alter semen quality and sexual function. in addition, 22% to 67% of men with epilepsy have been found to have reduced sexual interest and an impaired quality of sex life (9) moreover, men with epilepsy are at a five-fold higher risk of erectile dysfunction (ed) than men without epilepsy (10). alterations in male sexual and reproductive parameters may also be due to treatment with antiepileptic drugs (aeds) to control seizures (11, 12). carbamazepine: adverse effects of carbamazepine (cbz) use including impaired hepatic p450 enzyme system function and changes in serum sex hormone have been reported. moreover, epileptic men taking cbz present altered semen quality, ed, and a reduction in coital frequency (9). these aeds related effects are explicable if considered as sexual hormonal changes. levetiracetam: the relationship between the older antiepileptic drugs (aeds) and sexual dysfunction has long been known and is likely to be related to sexual hormonal changes. instead, rare reports on sexual disorders related to new aeds suggest the possibility of complex and poorly understood mechanisms as well as alterations of the central nervous system neurotransmitters table 1. different classes and single drugs causing sexual dysfunction. medication class subclasses and single drugs antidepressants tricyclic antidepressants selective serotonin reuptake inhibitors (ssris) monoamine oxidase inhibitors (maois) viloxazine, nefazodone, venlafaxine, reboxetine, mirtazepine, trazodone, duloxetine antipsychotics typical: aliphatic phenothiazines (e.g. chlorpromazine), thioridazine atypical: risperidone, quetiapine, aripiprazole olanzapine clozapine antihypertensives thiazide diuretics beta blockers anti-parkinsonian drugs l-dopa ssris recreational drugs psychostimulants, amphetamine, ecstasy, crystal methamphetamine, alcohol, anabolic steroids, cannabis opiates, poppers, tobacco proton pump inhibitors esomeprazole fusco_stesura seveso 26/03/14 10:50 pagina 51 archivio italiano di urologia e andrologia 2014; 86, 1 f. fusco, m. franco, n. longo, a. palmieri, v. mirone 52 such as glutamate, serotonin, and dopamine. in this regard calabrò et al. (13) reported two men affected by epilepsy in which levetiracetam (lev) intake appeared to induce a severe loss of libido and anhedonia. topiramate: common side effects of topiramate (tpm) comprise of fatigue, somnolence, dizziness, paresthesias and loss of appetite, but sexual dysfunctions including ed and anorgasmia are rarely reported (14, 15) civardi et al. hypothesized that the inhibition of carbonic anhydrase could interfere with production of vip and nitric oxide, two known intracavernosal vasoactive compounds that play a key role in the peripheral erectile mechanism, leading to a reduction in genital blood flow (16). indeed, calabrò et al. (17) have suggested that tpminduced ed may be secondary to a blockage of ampa receptors with inhibition of the glutamatergic pathway, whereas glutamate is considered a candidate neurotransmitter of reflexive erection. to support this hypothesis, recent studies have shown the presence of both ampa and nmda glutamatergic receptor subunits in the lumbosacral spinal cord. moreover, ampa and nmda receptor antagonists are known to block reflexive erection (18). in conclusion, the data reported in literature confirms the alteration of hormonal levels as mechanism of sexual dysfunction in men taking antiepileptic drugs and shows possible different mechanisms for the sexual effects caused by new anti-epileptics drugs. antihypertensives several reports collectively spanning more than three decades indicate that 2.4%-58% of hypertensive males experience one or more symptoms of sexual dysfunction of varying degrees of severity during antihypertensive drug therapy. it is also true, however, that hypertensive patients experience sexual dysfunction prior to taking medication, when compared to normotensive subjects. this finding, while quite consistent with the physiologic changes noted in hypertensive individuals, is often neglected in the overall assessment of subjects and in the formulation of a therapeutic scheme (19). the different anti hypertensive drugs have peculiar mechanisms through which sexual dysfunction is caused. beta blocker: beta blockers (e.g., atenolol and propranolol) may potentially impact sexual functioning through a variety of mechanisms, including a reduction in central sympathetic outflow, impairment of vasodilatation of the corpora cavernosa, effects on luteinizing hormone and testosterone secretion, and a tendency to produce sedation or depression thereby causing a loss of libido (19). an italian study (20) on sexual activity and plasma testosterone in hypertensive men, evaluated the effects of the beta 1-selective beta-blocker atenolol on sexual activity and plasma testosterone levels in newly diagnosed, previously untreated essential hypertensive, sexually healthy men. one of the proposed mechanisms inducing sexual dysfunction is represented by an inhibition of the sympathetic nervous system which is involved in the integration of erection, emission and ejaculation in the regulation of luteinising-hormone secretion and the stimulation of release of testosterone (21). in this study atenolol significantly reduced plasma testosterone values thus confirming previous observations about the depression in testosterone levels in patients receiving this beta-blocker (22, 23). in contrast, a recent important review by ko et al. (24) showed that the conventional wisdom that beta-blocker therapy is associated with substantial risks of sexual dysfunction is not supported by data from clinical trials and that the risk of sexual dysfunction is only minimally increased. the risk of these adverse effects, therefore, should be seen within the context of the documented benefits of these medications. moreover, nebivolol seems to have a beneficial effect on ed, possibly due to increased nitric oxide availability (25). the possible occurrence of ed with metoprolol has, for the most part, been attributed to the prejudice (the so called “hawthorne effect”) on the “easy incidence” of this side-effect in hypertensive men. since the etiology of this ed is largely psychological, it is not surprising that placebo is as effective as a pde5inhibitor, namely tadalafil, in reversing this side effect (26). thiazides: the associations that have been noted between the clinical use of the thiazide diuretics and impairment of male sexual performance remain enigmatic. a medical research council working party in 1981 reported a 16% incidence of impotence in patients taking thiazide diuretics after 12 weeks of treatment (medical research council working party, 1981). a later study of diuretics in mild hypertension showed a significant increase in sexual dysfunction compared with placebo. the disorders noted included a reduction in libido, difficulty in obtaining and maintaining erection and problems with ejaculation. patients on diuretics were 2 to 6 times more likely to experience sexual dysfunction than those on placebo (27). recent studies investigated aspects of the male sexual dysfunction in hypertensive men following treatment with thiazide diuretics. the results suggest that penile erectile defects and decrements in sexual activities are specifically related to thiazide administration. a rodent model of thiazide-induced male sexual dysfunction, that documents dose-related impairment by hydrochlorothiazide of penile erectile reflexes and male copulatory performance is available (28). the etiology of thiazide-induced male sexual dysfunction is hypothesized to result from alterations in sodium excretion that alter afferent renal nerve input to hypothalamic areas regulating male sexual responses. other antihypertensive drugs calcium channel blockers (ccb) and angiotensin-converting enzyme (ace) inhibitors have not been associated with major negative impact on ed. it has also been suggested that angiotensin ii type 1 receptor blockers (arb) would affect sexual function less than other antihypertensive treatment. some data even suggests that sexual function and ed may improve during treatment with arb (29). in conclusion, two groups of antihypertensive drugs were examined in this review which have produced evidence on their role in determining sexual dysfunction. however, in both groups of drugs, individual mechanisms of action through which such alterations of sexual function was perpetrated, have not yet been well defined. antipsychotics human sexual function is affected in many different ways by schizophrenia and the antipsychotic drugs used in its fusco_stesura seveso 26/03/14 10:50 pagina 52 53archivio italiano di urologia e andrologia 2014; 86, 1 the impact of non-urologic drugs on sexual function in men treatment. the evaluation of the effects of antipsychotics on sexual function in patients with schizophrenia is also complex because the deleterious effects of conventional antipsychotics are superimposed on the effects of the disease itself (30). studies have suggested that, although antipsychotic drugs often restore sexual desire lost due to schizophrenia, they may impair patients’ sexual performance (30, 31). in a recent study evaluating a sample of male psychotic patients, both sexual dysfunction and hyperprolactinemia were very prevalent (32). based on their findings in 72 patients, 45.9% of the patients reported diminished sexual desire, whereas 35.9% and 36.1% reported erectile and ejaculatory dysfunction, respectively. a total of 20 patients used risperidone, 26 olanzapine, 9 quetiapine, 13 ziprasidone, and 1 aripiprazole. more than half the sample was hyperprolactinemic, and about one fifth had prolactin levels more than 3 times the upper threshold, none of which were caused by the biologically inert macroprolactin fraction. differences were noted among the drug groups, with risperidone-treated patients having the highest prolactin levels and the highest rate of hyperprolactinemia. hyperprolactinemia has received new attention lately as potential long-term complications have been identified, including osteoporosis and carcinogenic effects (32). no association was found in the present study between prolactin levels and sexual dysfunction. in many case reports and few non-systematic reviews priapism was found to be associated with antipsychotic drug administration (33-38). particular interest should be given to the frequency of priapism. drug-induced priapism accounts for as many as 15% to 41% of all cases, and antipsychotics are the most frequently involved drugs, followed by antidepressants and antihypertensive medications (39). in conclusion, a therapy with antipsychotics medications have to be thoroughly considered in patients reporting sexual dysfunction. there is no definitive evidence that correlates hyperprolactinemia and sexual dysfunction, however since a high incidence of both conditions in treated psychotic patients has been reported, prolactin levels should be measured irrespective of whether sd symptoms are present or not. anti-parkinsonian drugs the reported prevalence of sexual symptoms in men with parkinson disease (pd) ranges from 37% to 65% (40). bronner et al. (41) reported that use of medications (selective serotonin reuptake inhibitors used for comorbid depression), and advanced pd stage contributed to the development of ed. it is possible that levodopa and other antiparkinsonian medications may affect sexual function in pd. however, it is not entirely clear to what extent levodopa influences sexual dysfunction in pd. pathological hypersexuality may occur together with (42) or without delirium (43), which is attributed to the dopamine dysregulation syndrome in this disorder. deep brain stimulation in the subthalamic nucleus has produced either improved sexual wellbeing (44) or transient mania with hypersexuality (45) in patients with pd (40). more studies are needed to better understand the etiology and probable mechanism of action of levodopa in determining sexual dysfunction in men with parkinson disease. proton pump inhibitors a case report recently described a 42-year-old woman with previously normal sexual function who gradually developed loss of libido during treatment with esomeprazole. while taking esomeprazole, the patient's loss of libido improved with oral testosterone supplementation and deteriorated after testosterone withdrawal. steady improvement in both sexual function and serum free testosterone concentration after discontinuation of esomeprazole was observed. based on this evidence, proton pump inhibitors (ppi) could determine sexual dysfunction by modulation of the isoformes of cytochrome enzymes involved in testosterone metabolism (46). only 1 case report was found regarding sexual dysfunction induced by ppi (46). given the large number of prescription and administrations of these medications, further investigation of the role that these drugs may play in sexual dysfunction should be conducted. pde5 and combination therapy: interaction and patient’s safety the phosphodiesterase-5 inhibitors (pde5i) sildenafil, vardenafil, and tadalafil are considered first-line therapy for the treatment of patients with erectile dysfunction (ed). the widespread application of pde5i, that causes the potential for drug-drug interactions emerges as a relevant factor in determining the safety profile of pde5i. the use of nitrates remains the only contraindidcation for all 3 pde5i. vardenafil is also not recommended in patients taking type 1a (such as quinidine, or procainamide) or type 3 antiarrhythmics (such as sotalol, or amiodarone) while no other major limitations have been reported for tadalafil and sildenafil. in contrast to previously reported labeling, recent studies have suggested only precaution, but not contraindication, with the concomitant use of alpha-blockers agents. in addition, precaution is also suggested in the presence of potent cyp3a inhibitors such as azole antifungals, antiretroviral protease inhibitors, or macrolide antibiotics. this is because sildenafil, vardenafil, and tadalafil are metabolized mainly via the cyp3a4 pathway. on the other hand, statins and testosterone seem to have synergic effects with pde5i on sexual activity (47). the safety and efficacy of the 3 currently available pde5 inhibitors (sildenafil, tadalafil, and vardenafil) have been evaluated extensively in patients with ed and concomitant cardio vascular disease (cvd), hypertension, dyslipidemia, or diabetes with or without additional risk factors. overall, these studies have shown similar efficacy for the 3 agents resulting in significant improvement of erectyle function in patients with any of these comorbid conditions. their safety profile was also similar. no adverse effects on cardiac contraction, ventricular repolarization, or ischemic threshold was noted, and there was no evidence of increased cardiovascular risk from using any of these agents. however, because ed is known to be a harbinger of cardiovascular events in some men, the presence of ed should prompt investigation and intervention for cardiovascular risk factors (48). lastly, in a recent study of men with high systolic blood pressure who had initiated ed therapy, was showed an improvement in the systolic blood pressure control. fusco_stesura seveso 26/03/14 10:50 pagina 53 archivio italiano di urologia e andrologia 2014; 86, 1 f. fusco, m. franco, n. longo, a. palmieri, v. mirone 54 after initiating therapy with pde5i, patients were more likely to start an antihypertensive medication (17.3%) versus stop therapy (2.3%) and add additional antihypertensive medication to their existing therapy (42.2%) versus decrease the number of medications (17.3%). surveillance also increased with total number of systolic bp measurements increasing by 42%. in conclusion, men with high systolic bp who initiated ed therapy had improvements in systolic bp control that may be related to clinically relevant behaviors, such as more aggressive monitoring and treatment with antihypertensive medications. future research should further explore the underlying reasons and mechanisms for the observed improvements in systolic bp and whether cessation of ed therapy results in worsening bp control (49). conclusions patients affected with sexual dysfunction are often aged and assume several drugs (figure 1). slabaugh et al. published a study reporting that 39.4% of patient over 65 years were exposed to multi-drug consumption during the study period (50). elderly people are substantial consumers of medications and communitybased surveys reveal that they take an average of 2.7 to 3.9 prescription and nonprescription medications (51). coadministration of drugs may be a factor for sexual dysfunction in single patients, and effects on sexual function may be unforeseeable. in our search we did not find any trial exploring the effects of multiple drugs prescription on sexual function. however, considering the results of available data, a negative synergic effect on sexual function is plausible. when evaluating an elderly man with ed, medical history should be attentively focused on pharmacological therapies. the “myth” of sex-killer drugs, e.g. 5alpha reductase inhibitors or beta-blockers, that should be identified amongst a number of several “innocent” drugs possibly assumed by a single patient should be put into perspective. many widely diffused drug classes that would most commonly be defined as “unsuspectable” have the potential to affect sexual function on their own, and even more so when the number of co-administered drugs makes a synergistic, multidrug impact plausible. while iatrogenic sexual dysfunction is prevalent in men, urological drugs are not the only drugs to be held accountable for this. many different drugs acting on different sites and with several mechanisms of action can induce sexual dysfunction. the drug classes involved are widely diffused and frequently assumed in combination therapies. therefore, both general practitioners and specialists must consider the importance of pharmacological therapy in their clinical practices. references 1. bancroft j. the biological basis of human sexuality. in: human sexuality and its problems. edinburgh: churchill livingstone. 1989; 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34:209-10. 36. kirshner a, davis rr. priapism associated with the switch from oral to injectable risperidone. clin psychopharmacol. 2006; 26:626-8. 37. torun f, yılmaz e, gümüs e. priapism due to a single dose of quetiapine: a case report. turk psikiyatri derg. 2011; 22:195-9. 38. sinkeviciute i, kroken ra, johnsen e. priapism in antipsychotic drug use: a rare but important side effect. case rep psychiatry. 2012 ;2012:496364. 39. sinkeviciute i, kroken ra, johnsen e. priapism in antipsychotic drug use: a rare but important side effect. case rep psychiatry. 2012; 2012:496364. 40. sakakibara r, kishi m, ogawa e, et al. bladder, bowel, and sexual dysfunction in parkinson's disease. parkinsons dis. 2011; 2011:924605.9. 41. bronner g, royter v, korczyn ad, giladi n. sexual dysfunction in parkinson’s disease. journal of sex and marital therapy. 2004; 30:95-105. 42. klos kj, bower jh, josephs ka, et al. pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in parkinson’s disease and multiple system atrophy. parkinsonism and related disorders. 2005; 11:381-386. 43. kessel bl. a case of hedonistic homeostatic dysregulation. age and ageing. 2006; 35:540-541. 44. castelli l, perozzo p, genesia ml, et al. sexual well being in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. journal of neurology, neurosurgery and psychiatry. 2004; 75:1260-1264. 45. romito lm, raja m, daniele a, et al. transient mania with hypersexuality after surgery for high-frequency stimulation of the subthalamic nucleus in parkinson’s disease. movement disorders. 2002; 17:1371-1374. 46. rosenshein b, flockhart da, ho h. induction of testosterone metabolism by esomeprazole in a cyp2c19*2 heterozygote. am j med sci. 2004; 327:289-93. 47. corona g, razzoli e, forti g, maggi m. the use of phosphodiesterase 5 inhibitors with concomitant medications. endocrinol invest. 2008; 31:799-808. 48. nehra a. erectile dysfunction and cardiovascular disease: efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. mayo clin proc. 2009; 84:139-148. 49. scranton re, lawler e, botteman m, et al. effect of treating erectile dysfunction on management of systolic hypertension. am j cardiol. 2007; 100:459-63. 50. slabaugh sl, maio v, templin m, abouzaid s. prevalence and risk of polypharmacy among the elderly in an outpatient setting: a retrospective cohort study in the emilia-romagna region, italy. drugs aging. 2010; 27:1019-28. 51. hanlon jt, landerman lr, wall we jr, et al. is medication use by community-dwelling elderly people influenced by cognitive function? age ageing. 1996; 25:190-6. correspondence ferdinando fusco, md ferdinando-fusco@libero.it marco franco, md (corresponding author) marcofranco87@gmail.com nicola longo, md alessandro palmieri, md vincenzo mirone, md department of neurosciences, reproductive science and odontostomatology federico ii university, naples, italy fusco_stesura seveso 26/03/14 10:50 pagina 55 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4392 case report no conflict of interest declared. doi: 10.4081/aiua.2020.4.392 an urological cause of hypoglycaemia: a case report of the doege-potter syndrome nuno ramos 1, rodrigo ramos 2, celso marialva 2, eduardo silva 2 1 urology department, garcia de orta hospital, almada, portugal; 2 urology department, portuguese institute of oncology, lisbon, portugal. level was 33 mg/dl (normal range 70-109 mg/dl), being administrated continuous glucose infusion and glucocorticoid. the hypothesis of insulinoma was ruled out by serum insulin level of 12.3 µui/ml (normal < 28.0 µui/ml) and serum c-peptide level of 3.6 ng/ml (normal range 0.9-7.1 ng/ml). plasma igf-i and igf-ii levels were measured being respectively 29.00 ng/ml (normal: 55166 ng/ml) and 458 ng/ml (normal: 288-736 ng/ml). the ratio igf-ii/igf-i was higher than 10, suggestive of hypoglycaemia caused by non-islet cell tumor, the doegepotter syndrome. computed tomography (ct) demonstrated a large renal exophytic mass in the left kidney of 19 x 17 x 18.7 cm, heterogeneous, with little contrastenhancement, without signs of renal vein invasion neither areas of necrosis (figure 1). open left radical nephrectomy was performed. the postoperative course was uneventful, and hypoglycemic symptoms disappeared immediately after surgery. histopathological analysis revealed a tumor composed of spindle cells without atypia neither mitoses or areas of necroses. immunohistochemical staining revealed a tumor positive for activators of transcription 6 (stat6), cd34 and igf-ii, and negative for mdm2, ae1/ae3, ema, s-100, sma, and desmin (figure 1). based on the histological and immunohistochemical findings, a diagnosis of sft of the kidney was made. the tumor secreted igf ii, which caused hypoglycaemia, but did not present malignant potential. on the first year of followup, the patient was observed in consultation every 3 months, remaining tumor-free based on ct scan at 6 and 12 months. patient reported no episodes of hypoglycaemia during this period. due to the rarity of this tumor, there are no specific guidelines available to monitor these patients. therefore, we have used the european association of urology (eau) guidelines for renal cell carcinoma for subsequent follow-up. conclusions sfts can arise from a wide range of anatomic sites, both intrapleural or extrapleural, as the retroperitoneum. refractory hypoglycaemia may occur in 4% of sft and is reported as doege-potter syndrome (6). it is caused by the inappropriate secretion of a high molecular-weight form of igf-ii (hmw igf-ii). this molecule is an incompletely processed molecule of igf-ii, derived from the tumor, which fails to form a complex with igf-binding proteinthe doege-potter syndrome is a rare paraneoplastic syndrome presenting with hypoglycaemia due to ectopic secretion of insulin-like growth factor ii (igf-ii) from a solitary fibrous tumor. the underlying tumor can be benign or malignant and rarely present in extrapleural sites. we describe the case of a 83-year-old male diagnosed with a doege-potter syndrome due to a kidney tumor. key words: hypoglycaemia; insulin-like growth factor; solitary fibrous tumor. submitted 19 june 2020; accepted 24 july introduction solitary fibrous tumor (sft) was first reported by klemperer and rabin in 1931 as a lesion that originated in the pleura (1, 2). nevertheless, sfts are rare mesenchymal tumors, found in various anatomic locations, with approximately 20% in extrapleural locations like liver, orbit, lung and gastrointestinal tract. these tumors occur mainly in adults, with a peak age of 60-80 years and are equally distributed between genders (3) . sfts are rarely symptomatic and the vast majority are incidentally found. however, these tumors may also potentially cause symptoms, such as refractory hypoglycaemia, due to the production of insulin-like growth factor (igf-ii). when hypoglycaemia is associated with an sft, it is referred as the doege-potter syndrome, a potentially life-threatening condition (2, 4). majority of the tumors are benign, but 10%-20% can be malignant. malignancy is determined by invasive growth with an unclear boundary, high cell density, mitoses, pleomorphism and the presence of bleeding or necrosis (5). benign sfts can be cured by complete surgical resection. the role of chemotherapy and radiotherapy is still unclear. we describe the case of an 83-year-old man, who underwent a surgical resection for a sft, associated with refractory hypoglycaemia. case report a male 83 years old male patient was referred to our hospital due to a progressive increase of abdominal volume, in association with frequent episodes of syncope, as a result of hypoglycaemia. the patient had a history of arterial hypertension and was medicated with lisinopril. physical examination revealed the presence of a palpable mass in the left flank. on admission, his blood glucose summary 393archivio italiano di urologia e andrologia 2020; 92, 4 the doege-potter syndrome in urology 3. this leads to higher bioavailability compared to mature igf-ii, with activation of insulin receptors, inhibiting hepatic gluconeogenesis and increasing peripheral glucose uptake which results in hypoglycaemia (7). the detection of hmw igf-ii requires immunoblot analysis, not available at our institute. the patients with doege-potter syndrome, usually presents suppressed serum insulin, c peptide and low igf-i against normal or elevated levels of igf-ii (8). ct scan and magnetic resonance imaging (mri) are effective tools for identifying sft, determining the invasion of the surrounding structures, revealing information on distant metastasis and for follow-up. ct imaging typically shows a smooth, well circumscribed, homogeneous mass with or without necrosis or calcifications (2). mri presents as a tumor with high signal intensity on t2weighted images and iso-intensity or low intensity on t1weighted images (6). fluorodeoxyglucose positron emission tomography (fdg-pet) can also offer benefit in the diagnosis but is less often used. definitive diagnosis of an sft depend upon histological identification of a spindle cell tumor with alternating areas of cellularity and hypocellular collagen rich areas, as well as consistent cd34 expression and negative expression patterns for cytokeratin ae1/ae3, desmin and s-100. although the majority of sfts are benign, 20% may present local recurrence and metastases (9, 10). malignant criteria include: hypercellularity (> 4 mitotic figures/10 high power fields), atypia, infiltrative growth pattern and necrosis (11). complete tumor resection is the only definitive treatment. due to its rarity, there are no guidelines for the treatment of metastatic or nonresectable sft. chemotherapy and consecutive selective embolization of the feeding vessels of the tumor can be tried to alleviate symptomatic hypoglycaemia in irresectable tumors, but they are not effective treatments. radiotherapy has limited value, although it has been used as an adjuvant treatment in case of incomplete surgical resection (3, 12). symptomatic medical treatment of hypoglycaemia has been tried with some success for patients unfit for surgery (8). in our patient, hypoglycaemia disappeared after the complete radical resection. however, the return of this symptom can be a sign of tumor recurrence, which can happen in an estimated rate of 9.9% (2). in conclusion doege-potter syndrome should be considered as a differential diagnosis in a patient with a known malignancy if accompanied by hypoglycaemia and sfts have a favourable clinical outcome if complete resection is performed. references 1. wada y, okano k, ando y, et al. a solitary fibrous tumor in the pelvic cavity of a patient with doege-potter syndrome: a case report. surg case rep. 2019; 5:60. 2. forster c, roumy a, gonzalez m. solitary fibrous tumor of the pleura with doege-potter syndrome: second recurrence in a 93-year-old female. sage open med case rep. 2019; 7:2050313x18823468. 3. qian x, zhou d, gao b, wang w. metastatic solitary fibrous tumor of the pancreas in a patient with doege-potter syndrome. hepatobiliary surgery and nutrition. 2020; 9:112-5. 4. moreira bl, monarim ma, romano rf, et al. doege-potter syndrome. radiol bras. 2015; 48:195-6. )5) kim dw, na kj, yun js, song sy. doege-potter syndrome: a report of a histologically benign but clinically malignant case. j cardiothorac surg. 2017; 12:64. 6. han g, zhang z, shen x, et al. doege-potter syndrome: a review of the literature including a new case report. medicine (baltimore). 2017; 96:e7417. 7. pant v, baral s, sayami g, sayami p. doege-potter syndrome, cause of nonislet cell tumor hypoglycemia: the first case report from nepal. int med case rep j. 2017; 10:275-8. 8. kalebi ay, hale mj, wong ml, et al. surgically cured hypoglycemia secondary to pleural solitary fibrous tumour: case report and update review on the doege-potter syndrome. j cardiothorac surg. 2009; 4:45. 9. antonella d, loren d, maria c, et al. doege-potter syndrome by malignant solitary fibrous tumor of the liver: a case report and review of literature. world j gastrointest surg. 2019; 11:348-57. 10. chen s, zheng y, chen l, yi q. a broad ligament solitary fibrous tumor with doege-potter syndrome. medicine (baltimore). 2018; 97:e12564. 11. fung ec, crook ma. doege-potter syndrome and 'big-igf2': a rare cause of hypoglycaemia. ann clin biochem. 2011; 48:95-6. 12. urbina-lima ad, roman-martin aa, crespo-santos a, et al. solitary fibrous tumor of the urinary bladder associated with hypoglycemia: an unusual case of doege-potter syndrome. urol int. 2019; 103:120-4. figure 1. figure 1 imaging, histopathological, and immunohistochemical findings. (a, b) computed tomography demonstrated a large tumor in the left kidney with little contrastenhancement, (c) histopathological findings: the mass is a spindle cell tumor (100×) (d, e, f) immunohistochemical findings: (d) immunohistochemistry shows positive staining for cd34 (100x), (e) positive staining for stat6 (100x), (f) negative staining for mdm2, ae1/ae3, ema, s100, sma, and desmin (100x). correspondence nuno ramos, md (corresponding author) nuno.ramos@hgo.min-saude.pt garcia de orta hospital , av. torrado da silva, 2801-951, almada (portugal) rodrigo ramos, md celso marialva, md eduardo silva, md urology department, portuguese institute of oncology, lisbon (portugal) stesura seveso archivio italiano di urologia e andrologia 2016; 88, 14 original paper results of tadalafil treatment in patients following an open nerve-sparing radical prostatectomy erkan hirik 1, aliseydi bozkurt 1, mehmet karabakan 1, özkan onuk 2, mustafa bahadır can balcı 2, memduh aydın 2, murat çakan 1, barış nuhoğlu 1 1 erzincan university mengücek gazi education and research hospital, urology clinic, turkey; 2 gaziosmanpaşa taksim education and research hospital, urology clinic, turkey. purpose: to evaluate the effect of postoperatively administering a low daily dose of tadalafil on the erectile function of patients who underwent a nerve-sparing radical prostatectomy(nsrp) due to localized prostate cancer (pca). materials and methods: of 138 patients, who underwent nsrp due to pca between 2012 and 2014, 55 patients who had not had pre-operative erectile dysfunction (ed) were included in the study. the mean age of the patients was 64 (54-72). on the 15th day after surgery, after ultrasound evaluation, all 55 patients started on a daily dose of 5 mg tadalafil that was continued for 2.5 months. the erectile function of patients was evaluated pre-operatively, post-operatively, and at the 3rd and 6th month after surgery using the international index of erectile function (iief-5) test. none of the patients was treated with hormonal therapy or radiotherapy before or after surgery. results: three patients were excluded from the study due to the adverse effects of tadalafil and two patients elected to discontinue the treatment. of the remaining 50 patients whose pre-operative erectile function had been found normal, at 3 months after surgery, 36 (72%) had normal erectile function; of the remaining patients in the study six (12%) presented with mild, two (4%) with moderate, and six (12%) with severe ed. six months after surgery, 35 patients (70%) had normal erectile function while seven (14%) had mild, three (6%) moderate and five (10%) severe ed. there was no statistically significant difference between the results obtained at the 3rd and 6thmonth follow-up (p > 0.05). three patients reported adverse effects with tadalafil including flushes in 2 (3.6%) and a headache in 1 (1.8%). conclusions: the administration of a 5 mg post-operative dose of tadalafil to patients that had undergone a bilateral nsrp was found to have a positive effect on the recovery and maintenance of erectile function. however, there is still a need to investigate a larger series of cases. key words: radical prostatectomy; tadalafil; erectile function. submitted 28 july 2015; accepted 13 october 2015 summary no conflict of interest declared. prostatectomy (rp) is a gold standard treatment for organ-confined pca (2). erectile dysfunction (ed) developing after an rp (ed) is one of the most significant problems that affect the quality of life (3). the definition of anatomic rp and the development of a better understanding of the neuroanatomy of prostate in the last 20 years have resulted in a significant improvement in retaining sexual functions after rp, however, the prevalence of post-operative ed is still above 50% (4, 5). to eliminate the negative outcomes of the treatment for pca, ‘ed treatment and penile rehabilitation after rp’ has become a widely investigated topic in preclinical and clinical studies (6). even though the first-line therapy for ed is phosphodiesterase type 5 (pde5) inhibitors, there is still not a standard treatment program. in this study, we evaluated the safety and effects of a low-dose of postoperative tadalafil on the erectile functions of patients who had undergone an nsrp due to localized pca. material and methods of 138 cases that were treated with nsrp due to pca between 2012 and 2014, 55 patients, who had not had pre-operative erectile dysfunction (ed) and had undergone a bilateral nsrp, were included in the study. the erectile function of the patients was evaluated pre-operatively and post-operatively by the international index of erectile function (iief-5) test. an open rp was performed using the classical technique and nerve-sparing approach. following an ultrasound examination on the post-operative 15th day, all patients were prescribed a daily dose of 5 mg tadalafil to be continued for 10 weeks. the erectile functions of patients were evaluated at the 3rd and 6th postoperative month. potency was defined as the ability to achieve unassisted sexual intercourse through vaginal penetration. none of the patients received hormone therapy or radiotherapy before or after surgery. in addition, to exclude the possibility of androgen insensitivity syndrome, the pre-operative serum total testosterone and body mass index (bmi) of the patients were measured. results the mean age of patients was 64 years (54-72) and the mean bmi was calculated as 24.3 (18.1-33.4). table 1 doi: 10.4081/aiua.2016.1.4 introduction prostate cancer (pca) is the most frequent type of cancer in men aged over 50 and the second most common reason for cancer-related deaths (1). for cases in which there is a life expectancy of more than 10 years, radical hirik_stesura seveso 08/04/16 11:22 pagina 4 5archivio italiano di urologia e andrologia 2016; 88, 1 results of tadalafil treatment in patients following an open nerve-sparing radical prostatectomy presents the demographic information on patients. of the 55 patients who had not had ed prior to the operation and had undergone a bilateral nsrp, three patients were excluded from the study due to the adverse effect of tadalafil and two patients discontinued the treatment. of the remaining 50 patients whose pre-operative erectile function was found to be normal, at 3-month post-operative follow up, 36 (72%) had normal erectile function while six (12%) presented with mild, two (4%) with moderate, and six (12%) with severe ed. at 6 month follow up after surgery, 35 patients (70%) had normal erectile function while seven (14%) had mild, three (6%) moderate and five (10%) severe ed. there was no statistically significant difference between the results obtained at 3and 6month follow-up (p > 0.05). three patients reported adverse effects with tadalafil; including flushes in two (3.6%) and headache in one (1.8%). discussion our results show that most patients (72%) who were treated with 5 mg tadalafil daily following a bilateral nsrp had normal erectile function at 3-month postoperative follow up while severe ed was observed in 12% of the patients. similar results were obtained from the evaluation at 6-month post-operative follow up. considering the 50% prevalence of ed reported in the literature in patients who received no post-operative treatment, the results of the current study indicate that tadalafil treatment after rp contributes to the early recovery of erection and the retention of this function even after 6 months (24, 25). the development of ed after rp has been reported to be the result of an injury to cavernous nerves and pudendal arteries (11-13). factors that are known to have an effect on the post-operative erectile function of patients are age, pre-operative potency, and surgery with nerve sparing intent. when surgical modalities are compared, no significant difference has been observed in the prevalence of ed between the results of laparoscopic and open nsrp whereas robotic surgery has been found to produce much better post-operative results compared to the other two methods (13). most patients who are diagnosed with localized pca are in the advanced age group. diseases that have already developed or will possibly develop due to old age increase the process of ed (14). since after rp it takes a long time to recover normal erection function there is a need to seek for a treatment option that will shorten this period. in the literature, the first study that monitored the results of patients after nsrp for more than 5 years was conducted by zippe et al. this study showed the importance of ed treatment but it has been commented that the process is like a marathon race. according to the last report of zippe et al. after a follow-up of 6.4 ±1.8 years, only 50% of the patients were sexually active, and of these patients, only 23% had a natural normal erection function with the remaining 77% needing oral or other treatments (7). many papers have reported on various post rp treatments; for example, pde5 inhibitors induce cgmp accumulation in corporal smooth muscles resulting in the relaxation of these muscles. goldstein et al. (15) reported a success rate of 43% after the use of pde5 inhibitors in patients who had undergone rp. raina et al. (16) showed that bilateral nsrp produced better results than unilateral nsrp and other treatments that do not involve the use of nerve-sparing technique. in experimental studies, pde5 inhibitors have been reported to be effective in preventing ed due to cavernous nerve trauma (17). kovanecz et al. investigated the effect of sildenafil on rats who underwent a cavernosal nerve resection and found that the treatment group had significantly better intracavernosal pressure/mean arterial pressure (icp/map); the cell content of smooth muscles and endothelial factors were retained and apoptosis was reduced; there was also an improvement in venous leak in the long term (17). similarly, studies conducted with vardenafil and tadalafil reported that the use of these drugs prevent corporal fibrosis, reduce collagen production and retain the content of smooth muscles (18-20). pde5 inhibitors have been found to be effective in recovering and retaining the erectile function in patients after nsrp (21-23). the use of pde-5 inhibitors for erection rehabilitation after rp has recently become a widely discussed topic. the reason for using these drugs is to make it easy for the patient in the recovery period to have sexual intercourse, also, as much as possible, reduce cavernosal hypoxia and protect the penis from apoptosis and cavernosal fibrosis. since these drugs also increase corporal oxygenation, they will ease night-time erections and protect the basal functions of corpus cavernosum (8). raina et al. reported that starting the treatment of pde5 inhibitors earlier than 6 months after surgery significantly improves the response to pde5, and therefore, the authors suggested the use of sildenafil post-operatively for a period of 3 to 6 months (9). as the rp-related neuropraxia heals over age 64 (54-72) body mass index (bmi) 24.3 (18.1-33.4) comorbidity dm 8 (16%) ht 32 (64%) hepatitis 3 (6%) psa 7.2 (2.5-18) biopsy gleason score 4-6 31 (62%) 7 17(34%) 8 2 (4%) erectile function 3-month post-operative 6-month post-operative (n = 50) (n = 50) normal 36 (72%) 35 (70%) mild ed 6 (12%) 7 (14%) moderate ed 2 (4%) 3 (6%) severe ed 6 (12%) 5 (10%) table 1. demographic information on patients. table 2. erectile function after prescribing 5 mg tadalafil daily to patients without pre-operative ed who underwent bilateral nsrp. hirik_stesura seveso 08/04/16 11:22 pagina 5 archivio italiano di urologia e andrologia 2016; 88, 1 e. hirik, a. bozkurt, m. karabakan, ö. onuk, m. bahadır can balcı, m. aydın, m. çakan, b. nuhoğlu 6 time, cavernosal smooth muscles respond better to pde5 inhibitors. this is due to the increase in the nitric oxide (no) released by the nerve that starts to heal. since recovery is dependent on time, even when the response to sildenafil is lower within the first 6 months after surgery, over time it starts improving (10). similarly, in the current study, treatment with a daily 5 mg dose of tadalafil for 10 weeks was found to be efficient. however, there is a need for further studies that will comparatively evaluate larger series of cases over a longer period of time. conclusions a 5 mg post-operative dose of tadalafil was found to have a positive effect on patients that had undergone a bilateral nsrp in terms of the recovery and maintenance of erectile function. however, there is still a need to conduct studies on larger series of cases and including a control group for comparative purposes. references 1. landis sh, murray t, bolden s, wingo pa. canser statistics, 1999, ca cancer j clin. 1999; 49:8-31. 2. partin aw, mangold la, lamm dm, et al. contemporary update of prostate cancer staging nomograms (partintables) for the new millennium. urology. 2001; 58:843-8. 3. burnett al, aus g, canby-hagino ed, et al. erectile function outcome reporting after clinically localized prostate cancer treatment. j urol. 2007; 178:597-601. 4. walsh pc, donker pj.impotence following radical prostatectomy:insight into etiology and prevention. j urol. 1982; 128:492-7. 5. talcott ja, rieker p, propert kj, clark ja, et al. patient-reported impotence and incontinence after nerve-sparingradical prostatectomy. j natl cancer inst. 1997; 89:1117-23. 6. montorsi f, briganti a, salonia a, et al: current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy. eur urol. , 2004; 45:123-33. 7. zippe c, nandipati k, agarwal a, et al. sexual dysfunction after pelvic surgery. int j impot res. 2006; 18:1-18. 8. montorsi f, briganti a, salonia a, et al. current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy review. eur urol. 2004; 45:123-33. 9. raina r, lakin mm, agarwal a, et al: efficacy and factors associated with successful outcome of sildenafil citrate use for erectile dysfunction after radical prostatectomy urology. 2004; 63:960-966. 10. padma-nathan h. pde-5 inhibitor therapy for erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy. rev urol. 2005; 7 (suppl 2): 33-8. 11. carrier s, zvara p, nunes l, et al. regeneration of nitric oxide synthase containing nerves after cavernous nerveneurotomy in the rat. j urol. 1995; 153:1722-7. 12. zippe cd, pahlajani g. penile rehabilitation following radical prostatectomy: role of early intervention and chronic therapy. urol clinnorth am 2007; 34: 601-18. 13. akbal c, simsek f. radikal prostatektomi sonrası erektil disfonksiyonönlenebilir mi? cerrahi ve medikal alternatifler var mı? üroonkoloji bülteni 112-6. 14. martin-morales a, sanchez-cruz jj, saenz de tejada i, et al. prevalence and independent risk factors for erectile dysfunction in spain: results of theepidemiologia de la disfuncion erectil masculina study. j urol. 2001; 166:569-75. 15. goldstein i, lue tf, padma-nathan h, et al. oral sildenafil in the treatment of erectile dysfunction. sildenafilstudy group. n engl j med .1998; 338:1397-404. 16. raina r, lakin mm, agarwal a, et al. long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy: 3year follow-up. urology. 2003; 62:110-5. 17. kovanecz i, rambhatla a, ferrini m, et al. long-term continuous sildenafil treatment ameliorates corporalveno-occlusive dysfunction (cvod) induced by cavernosal nerve resection in rats. int j impot res. 2008; 20:202-12. 18. ferrini mg, davila hh, kovanecz i, et al. vardenafil prevents fibrosis and loss of corporal smoothmuscle that occurs after bilateral cavernosal nerve resection in therat. urology. 2006; 68:429-35. 19. kovanecz i, rambhatla a, ferrini mg, et al. chronic daily tadalafil prevents the corporal fibrosis and venoocclusive dysfunction that occurs after cavernosal nerve resection.bju int. 2008; 101:203-10. 20. lysiak jj, yang sk, klausner ap, et al. tadalafil increases akt and extracellular signal-regulated kinase 1/2activation, and prevents apoptotic cell death in the penis followingdenervation. j urol. 2008; 179:779-85. 21. nakano y, miyake h, chiba k, fujisawa m. impact of penile rehabilitation with low-dose vardenafil on recovery of erectile function in japanese men following nerve-sparing radical prostatectomy. asian j androl. 2014; 16:892-6. 22. gandaglia g, gallina a, suardi n, et al. preoperative erectile function is the only predictor of the use of a high number of phosphodiesterase type-5 inhibitors after bilateral nerve-sparing radical prostatectomy.nt j impot res. 2014; 26:2014. 23. cathala n1, mombet a, sanchez-salas r, et al. evaluation of erectile function after laparoscopic radical prostatectomy in a single center. can j urol. 2012; 19:6328-35. 24. stolzenburg ju, graefen m, kriegel c, et al. effect of surgical approach on erectile function recovery following bilateral nervesparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo. bju int. 2015; 116:241-51. 25. moncada i1, de bethencourt fr, lledó-garcía e, et al. effects of tadalafil once daily or on demand versus placebo on time to recovery of erectile function in patients after bilateral nerve-sparing radical prostatectomy. world j urol. 2015; 33:1031-8. correspondence erkan hirik ehirik@gmail.com aliseydi bozkurt mehmet karabakan murat çakan barış nuhoǧlu erzincan university mengücek gazi education and research hospital, urology clinic, turkey özkan onuk, mustafa bahadır can balcı, memduh aydın, gaziosmanpaşa taksim education and research hospital, urology clinic, turkey hirik_stesura seveso 08/04/16 11:22 pagina 6 stesura seveso archivio italiano di urologia e andrologia 2013; 85, 4190 introduction prostatitis is a common urological disorder mainly affecting males 18-35 years of age, but also constitutes a frequent diagnosis in those aged over 65 primarily as a histological finding or in relation to benign prostatic hypertrophy symptoms (1-3). between 1990 and 1994, more than 2 million outpatient visits in the usa related to chronic prostatitis cases, whereas currently 15% of men who visit a doctor due to urinary tract symptoms are diagnosed with prostatitis (4). this particular disease has been characterized as a significant and developing clinical enigma given that its aetiopathogenesis remains to a great extent unclear. its presentation is related to an infective focus in the distant (mainly) prostatic glandular element and ducts involving gram-negative uropathogens and less frequently grampositive bacteria (5). it exhibits an array of symptoms, most notably pelvic pain (at various sites and of varying intensity), urinary symptoms (obstructive and irritative) original paper serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis. the preliminary results of a long term observational study konstantinos stamatiou, nikolaos pierris urology department, tzaneio hospital, pireas, greece. introduction: chronic prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). the purpose of this article is to briefly present the preliminary results of our study examining the role of phytotherapeutic agents in the treatment of chronic prostatitis patients. materials and methods: the study included in total fifty-six consecutive patients who visited the outpatient department. subjects were randomized into two groups. subjects in the first group (28 patients) received prulifloxacin 600 mg for 15 days, while subjects in the second group (28 patients) received prulifloxacin 600 mg for 15 days and serenoa repens extract for 8 weeks. the response was tested using laboratory and clinical criteria. results: we found statistically significant differences between the two groups regarding pain regression and no statistically significant regarding bacterial eradication. moreover however while sexual dysfunction improvement was equally achieved in both groups, improvement of urinary symptoms was more evident in the 2nd group especially after the completion of the antibiotic treatment. conclusions: serenoa repens extract for 8 weeks seems to improve prostatitis related pain. further randomized, placebo-controlled studies are needed to substantiate safer conclusions. key words: chronic prostatitis, phytotherapeutics; quinolones; pain; serenoa repens. submitted 6 june 2013; accepted 20 june 2013 no conflict of interest declared summary as well as erectile and sexual dysfunction. similar symptoms are also encountered in benign prostatic hypertrophy and are attributed to both obstruction and secondary inflammation. the effectiveness of phytotherapeutic agents used for symptoms related to benign prostatic hypertrophy justifies their use in the treatment of chronic prostatitis (6). the best known phytotherapeutic is serenoa repens, a constituent of the acid-loving plant saw palmetto. it contains fatty acids, phytosterols and vitamins. its mechanism of action has not been fully elucidated, however is attributed to hormonally and non-hormonally mediated anti-inflammatory activity (6). the former is related to the inhibition of conversion of testosterone to the more potent antiandrogen dihydrotestosterone at the level of androgen receptors. this results in a reduction of the hormonal response of macrophages and leukocytes and the inhibition of their migration to the site of inflammation. as a consequence doi: 10.4081/aiua.2013.4.190 stamatiou_stesura seveso 20/12/13 11:04 pagina 190 191archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis there is a reduction in the release of myeloperoxidase which causes destruction of the inflamed tissue and of platelet-derived growth factor and growth factor-beta which induce inflammation. existing evidence regarding serenoa repens’ antiandrogenical antiproliferative and/or antiapoptotic action through inhibition of 5-alpha reductase is probably conflicting (7, 8). there is experimental proof of inhibition of signaling of growth factors such as igf-1 (insulin-like growth factor) as well as cytokines such as mcp-1/ccl2 (monocyte chemotactic protein1/chemokine cl2) a fact which interferes with inflammatory activity in human prostate epithelial cells (9, 10). the aim of the study is to assess the effectiveness of phytotherapeutics in the management of these symptoms. materials and methods the study was designed as a prospective randomized study and was conducted at “tzaneio” general hospital of piraeus. patients enrolled in the study had symptoms and signs of chronic prostatitis and visited the specialist clinic between 1 may 2011 and 30 may 2012. patients suffering from neurological disorders, those with anatomic abnormalities of the urinary tract and immunosuppressed patients were excluded from the study, as these are all conditions which can affect the clinical manifestation of the disease and could alter the outcome of the study. patients were randomized into two groups depending on the date of attendance (odd/even day of the month). patients in the first group (group a) received prulifloxacin 600 mg for 15 days and patients in the second group (group b) received prulifloxacin 600 mg for 15 days and an extract of serenoa repens for 8 weeks. urine specimens from all patients were collected before and after prostatic massage and were cultured while, depending on the medical history, urethral discharge or urethral swabs were also sent to the laboratory for examination in a number of patients. all patients filled in questionnaires relating to chronic prostatitis (nhi-cpsi), urinary symptoms (ipss) and sexual function (iief-5). initial evaluation (1st and 2nd follow up visit) was performed 15 days after the completion of antimicrobial therapy and during the course of treatment with serenoa repens microbial response was assessed by urine culture before and after prostatic massage and the response to symptoms by questionnaires nhi-cpsi, ipss, iief-5 at 4 weeks from the beginning of the study (1st follow up) and 8 weeks from the beginning of the study (2nd follow up). the final outcome was assessed 3-6 months later (3rd follow up visit). microbiological assessment: the stamey-meares test was deemed positive if: 1) bacteria were cultured in the prostatic secretion (eps) and the vb3 urine specimens (or ppm) and were not cultured in the vb1 and vb2 (or pm) specimens, 2) bacterial colony count in the vb3 specimen was 10 times that in the vb1 and vb2 specimens, 3) leukocyte numbers in the eps and vb3 were 10 times those in the vb1 and vb2. no lower cut-off value for the number of colonies was set. cultures for gonococcus, mycoplasma and ureaplasma and the semi-quantitative assessment were performed using biomerieux reagents. chlamydia trachomatis was detected using direct immu nofluorescence (kallestad anti-membrane lipopoly saccharide monoclonal antibodies). urine specimens were centrifuged and cultured in blood and macconkey agar for aerobic and anaerobic gram-positive and negative bacteria (biomerieux culture media). all processing and final assessment of samples in this study were performed by the same specialist microbiologist to whom the medical history of the patients was not disclosed. questionnaires: the chronic prostatitis nhi-cpsi questionnaire includes 9 questions in 3 sections (character-site of pain, urinary symptoms, effect on quality of life). the resultant sum ranges from 0 to 43 (character-site of pain: 0-21, urinary symptoms: 0-10 and quality of life: 0-12). the greater the resulting sum the greater the disturbance. however, questions with the highest scores affect the final result as they contribute more to the total sum of the nihcpsi. the ipss questionnaire includes 8 questions in 8 fields (incomplete bladder voiding, frequency, intermittency, urgency, poor urine flow, dribbling, nocturia and effect on quality of life) each question scoring 0-5 points. results from the first 7 questions are used to assess urination. a final score of less than 7 indicates mild disturbance, a score of 8-19 indicates moderate disturbance and a score of 20-35 severe disturbance. finally, the iief-5 questionnaire includes 5 questions each scoring 0-5 points. a sum score of 1-7 points suggests serious erectile dysfunction, a score of 8-11 moderate dysfunction, a score of 12-16 suggests moderate to mild dysfunction, a score of 17-21 indicates mild erectile dysfunction, whereas a score of 22-25 does not indicate erectile dysfunction. statistical analysis: analysis was performed using the spss 12 program and fisher’s exact test of significance was used. the accepted statistical significance cut-off value was 0.05 (p value < 0.05). differences between study groups n mean p value group 2 group 1 group 2 group 1 age (years) 28 28 41,9643 45,5714 ,223 prostatitis related history 28 28 ,4643 ,5714 ,415 baseline nih-cpsi score 28 28 26,96 26,64 ,843 baseline ipss score 27 28 10,6296 14,70 ,140 baseline iief score 28 28 20,57 19,4643 ,172 table 1. difference between groups 1 and 2 with regard to age, prostatitis related history and baseline questionnaire scores. stamatiou_stesura seveso 20/12/13 11:04 pagina 191 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 192 age main symptom microorganism 28 haemospermia, suprapubic pain chlamydia trachomatis 53 dysuria, raised psa e. coli 42 perineal pain proteus 52 suprapubic, perineal pain, luts e. coli 36 scrotal pain cons 47 penile pain e. coli 52 suprapubic, scrotal pain e. coli 48 perineal pain proteus, cons 51 suprapubic, perineal pain, dysuria gonococcus 50 irritative luts chlamydia 49 febrile prostatitis, epididymitis proteus 39 perineal, testicular pain 4 types of gram + cocci 41 scrotal, penile pain e. coli 44 perineal pain e. coli 56 penile pain, erectile dysfunction e. coli 56 dysuria, irritative symptoms of urination 3 types of gram + cocci 35 perineal pain, raised psa cons 52 perineal pain, irritative luts e. coli 45 perineal pain, malaise e. coli 36 perineal, testicular pain e. coli 44 perineal pain e. coli 58 perineal, testicular pain cons 56 luts, haemospermia, suprapubic pain e. coli, proteus 43 testicular pain cons 37 scrotal, perineal pain, luts proteus 44 perineal, penile pain e. coli 44 suprapubic, scrotal pain klebsiella, staphylococcus 38 perineal pain, erectile dysfunction e. coli table 2. age, main symptoms and pathogens of patients of group 1 (prulifloxacin) at baseline. results in 16 of the 72 patients initially included in the study no pathogen was cultured and these patients were excluded from the study. the remaining 56 patients were equally assigned to the first group and the second group. the average age in the first group was 45.5 years and in the second group was 41.9 years. no statistically significant difference was noted between groups 1 and 2 with regard to mean age (table 1) and prior history of prostatitis (table 1) upon introduction into the study. the primary symptom for patients in both groups was pain, while urinary disturbances as a primary symptom were reported by 7 patients in group a and 6 in group b and erectile dysfunction as a primary symptom was reported by 2 patients in group a and 2 patients in group b (tables 2, 3). assessment of the questionnaires revealed moderate to severe urinary symptoms (obstructive or irritative) in more than 50% of patients in both groups (17 patients in the 1st group and 14 in the 2nd group) and erectile or sexual dysfunction in less than 30% of patients in both groups (9 patients in the 1st group and 7 patients in the 2nd group). no significant difference was noted between groups 1 and 2 with regard to individual questionnaire fields upon introduction into the study (table 1). 1st follow up visit: at the first follow-up 16/28 patients in the first group reported persistence of symptoms compared to 10/28 patients in the second group. four patients in group 1 and 3 patients in group 2 age main symptom microorganism 27 haemospermia, suprapubic pain 3 types of gram + cocci 62 luts, perineal pain, raised psa cons 34 penile, scrotal pain mycoplasma 58 scrotal pain e. coli 45 perineal, scrotal pain mycoplasma 35 suprapubic, perineal pain, dysuria unknown 47 febrile prostatitis e. coli 32 febrile prostatitis proteus 28 febrile prostatitis enterococcus 34 perineal pain e. coli 25 perineal pain, irritative luts e. coli 47 penile pain, erectile dysfunction enterococcus 32 scrotal pain streptococcus mitis oralis 61 perineal pain cons 25 irritative luts enterococcus 52 dysuria, irritative symptoms of urination e. coli, cons 49 suprapubic, perineal pain e. coli 38 haemospermia e. coli 48 testicular pain cons, staphylococcus aureus 31 perineal pain e. coli 21 scrotal, testicular pain enterococcus 27 penile, scrotal pain e. coli 56 suprapubic pain proteus 65 perineal pain, luts cons, enterococcus 37 suprapubic, perineal pain e. coli 61 penile, suprapubic pain, e. coli erectile dysfunction 64 haemospermia enterococcus 34 febrile prostatitis e. coli table 3. age, main symptoms and pathogens of patients of group 2 (prulifloxacin and serenoa repens) at baseline. stamatiou_stesura seveso 20/12/13 11:04 pagina 192 193archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis outcome (table 7). in contrast, symptoms questionnaire analysis revealed statistically significant differences between the two groups with regard to symptoms regression (table 7). 3rd follow up visit: at the third follow-up, 5/23 patients in the first group (5 patients did not attend) reported persistence of symptoms (3 of these patients were asymptomatic at the 2nd follow-up) whereas only 1/22 patients in the second group (6 patients did not attend) reported persistence of symptoms. only one patient from the 1st group had a positive culture (tables 4, 5). comparison of symptoms questionnaire results before and after treatment analysis revealed statistically significant differences between the two groups with regard to outcome while comparison of culture results not (table 8). notably, in most cases the microorganism grown was different to that of the initial culture. comparison of the ipss and iief-5 questionnaire scores revealed statistically significant differences with regard to improvement of urinary symptoms (p < 0.05) and no statistically significant differences with regard to erectile and sexual dysfunction (p > 0.05). 1st 2nd 3rd 1 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 2 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 3 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 4 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 5 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 6 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic morganella 7 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 8 symptomatic proteus asymptomatic bacterial eradication asymptomatic bacterial eradication 9 symptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 10 symptomatic cons symptomatic bacterial eradication symptomatic bacterial eradication 11 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 12 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 13 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 14 symptomatic proteus symptomatic enterococcus asymptomatic bacterial eradication 15 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 16 symptomatic bacterial eradication symptomatic bacterial eradication symptomatic bacterial eradication 17 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 18 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 19 asymptomatic bacterial eradication did not attend did not attend 20 symptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 21 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 22 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 23 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 24 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 25 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 26 asymptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 27 symptomatic chlamydia asymptomatic bacterial eradication asymptomatic bacterial eradication 28 asymptomatic bacterial eradication did not attend did not attend table 4. outcome at follow-up in group 1. had positive cultures. bacterial eradication was achieved in 24 patients in group 1 and 25 patients in the second group (tables 4, 5). comparison of culture results before and after treatment as well as symptoms questionnaire analysis revealed not statistically significant differences between the two groups with regard to outcome (table 6). in contrast, symptoms questionnaire analysis revealed statistically significant differences between the two groups with regard to symptoms regression (table 6). 2nd follow up visit: at the second follow-up 7/26 patients in the first group and 1/25 in the second group (5 patients did not attend) reported persistence of symptoms. of note, two of these patients (one in each group) reported recurrence of the symptoms despite being asymptomatic at the first follow-up. since, only one patient from each group had a positive culture, bacterial eradication was achieved in 25/26 patients of the first group and 24/25 patients of the second group (tables 4, 5). comparison of culture results before and after treatment as well as symptoms questionnaire analysis revealed not statistically significant differences between the two groups with regard to stamatiou_stesura seveso 20/12/13 11:04 pagina 193 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 194 1st 2nd 3rd 1 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 2 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 3 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 4 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 5 asymptomatic bacterial eradication asymptomatic bacterial eradication symptomatic bacterial eradication 6 symptomatic proteus asymptomatic bacterial eradication asymptomatic bacterial eradication 7 asymptomatic cons asymptomatic cons asymptomatic bacterial eradication 8 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 9 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 10 asymptomatic bacterial eradication did not attend asymptomatic bacterial eradication 11 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 12 asymptomatic bacterial eradication asymptomatic bacterial eradication did not attend 13 symptomatic enterococcus symptomatic bacterial eradication asymptomatic bacterial eradication 14 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 15 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 16 asymptomatic bacterial eradication did not attend did not attend 17 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 18 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 19 asymptomatic bacterial eradication symptomatic bacterial eradication asymptomatic bacterial eradication 20 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 21 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 22 symptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 23 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend 24 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 25 asymptomatic bacterial eradication asymptomatic bacterial eradication asymptomatic bacterial eradication 26 asymptomatic bacterial eradication did not attend asymptomatic bacterial eradication 27 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend 28 symptomatic bacterial eradication asymptomatic bacterial eradication did not attend table 5. outcome at follow-up in group 2. n mean p value group 2 group 1 group 2 group 1 differences in symptom regression between group 1 and 2 28 28 ,64 ,46 ,022 differences in bacterial eradication between group 1 and 2 28 28 ,1429 ,1071 ,326 table 6. statistical evaluation of outcomes at 1st follow up. ranks n p value differences in symptom regression between group 1 and 2 negative ranks 5(a) ,025 positive ranks 0(b) ties 20(c) total 25 differences in bacterial eradication between group 1 and 2 negative ranks 0(a) ,317 positive ranks 1(b) ties 24(c) total 25 table 7. statistical evaluation of outcomes at 2nd follow up. stamatiou_stesura seveso 20/12/13 11:04 pagina 194 195archivio italiano di urologia e andrologia 2013; 85, 4 serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis ranks n p value differences in symptom regression between group 1 and 2 negative ranks 4(a) ,046 positive ranks 0(b) ties 18(c) total 22 differences in bacterial eradication between group 1 and 2 negative ranks 1(a) ,317 positive ranks 0(b) ties 21(c) total 22 table 8. statistical evaluation of outcomes at 3rd follow up. discussion the most widely known phytotherapeutic is saw palmetto. its fruit are rich in fatty acids and phytosterols and its extract known as serenoa repens is prescribed in many countries (mainly in europe) under different brand names (permixin, prostamol uno, permixon etc). it has been the object of intense research into the treatment of symptoms of benign hypertrophy and (lately) of infections of the urinary tract, having been used as a sole agent, in combination with or in comparison to other phytotherapeutics, combined with antibiotics, with alpha-blockers, anti-inflammatory agents and 5-alpha reductase inhibitors. results are conflicting given that in these studies the outcomes measured as well as the materials and methods used differ. on the other hand, conditions such as chronic bacterial and chronic nonbacterial prostatitis and prostatic hypertrophy overlap, many of the symptoms are common, while conditions and diseases of organs other than the prostate can contribute towards the presentation or deterioration of these symptoms. a prospective multi-centre double-blind randomized trial by debruyne et al. compared tamsulosin (0.4 mg/24 h) to permixon (320 mg/24 h) in a substantial number of patients (542) suffering from symptomatic prostatic hypertrophy (ipss ! 10). after 12 months of follow-up no differences in ipss were noted (average reduction of 4.4 in each group, with a respective improvement in both irritative and obstructive symptoms) and the improvement in qmax (1.8 ml/s permixon vs. 1.9 ml/s tamsulosin) and psa fluctuations were similar in both groups. by contrast, a small reduction in prostate size was noted in the permixon group. both treatments were well tolerated (11). a multicenter trial by the italian society of oncological urology studied the effectiveness of serenoa repens in patients with chronic non-bacterial prostatitis comparing it to a combination of serenoa repens and alpha-blocker. after a 6 month follow-up, similar changes in the uroflowmetry parameters of both groups were found and no changes were noted in the iief-5 sexual function questionnaire (a fact which may be related to both the lack of antiandrogen activity as well as reduced effectiveness in erectile dysfunction). a notable improvement in findings relating to inflammation was reported (on digital rectal examination, ultrasound and prostate biopsy) (12). aliaev et al. retrospectively studied the effectiveness of prostamol uno (320 mg/24 h) as complementary treatment in the prevention of relapses of chronic bacterial prostatitis. after 5 years the improvement in both subjective (ipss) and objective (reduction in percentage of relapse and progression, improvement in sexual function) measures of the study was greater with the addition of prostamol uno to the standard therapy consisting of anti-inflammatory and antimicrobial agents (13). similar results are reported by reissigl et al. with permixin used for chronic pelvic pain syndrome, while the safety profile noted was equivalent to studies mentioned above (14). in addition to the findings of the above mentioned studies, we demonstrated the early onset of the effect of serenoa repens on symptoms regression as well as the maintenance of this effect during the study period. of note, barry et al. researched any potential clinical benefit in increasing the dose administered to patients with lower urinary tract symptoms. according to their results a gradual increase in the dose administered (3 times the standard dose in 16 months) does not reduce urinary symptoms more than placebo. interestingly, no negative effects were observed which could distinctly be attributed to serenoa repens (15). on the other hand, kaplan et al. in a prospective study comparing the extract of saw palmetto against finasteride found no appreciable long term improvement (at 1 year follow-up) in type iii prostatitis symptoms (16), while pavone et al. noted a greater reduction in pain and irritative symptoms (albeit with no changes in flow rate and prostate volume) using combinations of phytotherapeutic agents (serenoa repens, urtica dioica and pinus pinaster) (17). based on the above we expect the effectiveness of serenoa repens in an array of symptoms related to prostatitis to depend on the type of prostatitis, the presence of prostatic hypertrophy, any preexisting obstruction, coadministered treatments and the duration of treatment. this hypothesis explains the differences between the present study and what has been discussed above. however, the small number of patients included in the above mentioned studies as well as differences in methodology and outcomes render the drawing of conclusions problematic. conclusions serenoa repens extract is effective in the treatment of pain symptoms in chronic bacterial prostatitis. an adminisstamatiou_stesura seveso 20/12/13 11:04 pagina 195 archivio italiano di urologia e andrologia 2013; 85, 4 k. stamatiou, n. pierris 196 activated protein kinase/c-jun n-terminal kinase phosphorylation in human prostate epithelial cells. endocrinology 2004; 145:3205-3214 10. latil a, libon c, templier m, et al. hexanic lipidosterolic extract of serenoa repens inhibits the expression of two key inflammatory mediators, mcp-1/ccl2 and vcam-1, in vitro. bju int. 2012; 110:e301-7. 11. debruyne f, koch g, boyle p, et al. (groupe d'étude permal). comparison of a phytotherapeutic agent (permixon) with an alphablocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. prog urol. 2002; 12:384-92. 12. bertaccini a, giampaoli m, cividini r, et al. observational database serenoa repens (dosser): overview, analysis and results. a multicentric siuro (italian society of oncological urology) project. arch ital urol androl. 2012; 84:117-22. 13. aliaev iug, vinarov az, et al. treatment of chronic prostatitis in prophylaxis of prostatic adenoma. urologiia. 2012; 39-40, 42-3. 14. reissigl a, djavan b, pointner j. prospective placebo-controlled multicenter trial on safety and efficacy of phytotherapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome. program and abstracts of the american urological association 2004 annual meeting; may 8-13, 2004; san francisco, ca. abstract 233. 15. barry mj, meleth s, lee jy, et al. (complementary and alternative medicine for urological symptoms study group). effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. jama. 2011; 306:1344-51. 16. kaplan sa, volpe ma, te ae. a prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category iii prostatitis/chronic pelvic pain syndrome. j urol. 2004; 171:284-8. 17. pavone c, abbadessa d, tarantino ml, et al. associating serenoa repens, urtica dioica and pinus pinaster. safety and efficacy in the treatment of lower urinary tract symptoms. prospective study on 320 patients. urologia. 2010; 77:43-51. tration period of 8 weeks appears to improve the effect of antibacterial therapy on pain while a longer duration of administration possibly alleviates the remaining symptoms. more randomized placebo-controlled studies are required to substantiate safer conclusions. references 1. cheah py, liong ml, yuen kh, et al. chronic prostatitis: symptom survey with follow-up clinical evaluation. urology. 2003; 61:60-64. 2. nickel jc, elhilali m, vallancien g. alf-one study group. benign prostatic hyperplasia (bph) and prostatitis: prevalence of painful ejaculation in men with clinical bph. bju int. 2005; 95:571-574. 3. de la rosette jj, hubregtse mr, karthaus hf, debruyne fm. results of a questionnaire among dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes. eur urol. 1992; 22:14-19. 4. collins mm, stafford rs, o'leary mp, barry mj. how common is prostatitis? a national survey of physician visits. j urol. 1998; 159:1224-1228. 5. nickel jc, moon t. chronic bacterial prostatitis: an evolving clinical enigma. urology. 2005; 66:2-8. 6. levin rm, das ak. a scientific basis for the therapeutic effects of pygeum africanum and serenoa repens. urol res. 2000; 28:201-9. 7. hill b, kyprianou n. effect of permixon on human prostate cell growth: lack of apoptotic action. prostate. 2004; 61:73-80. 8. marks ls, hess dl, dorey fj, et al. tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. urology. 2001; 57:999-1005. 9. wadsworth t, carroll j, mallinson r, et al. saw palmetto extract suppresses insulin-like growth factor-i signaling and induces stresscorrespondence konstantinos stamatiou, md (corresponding author) urology department, tzaneio hospital, pireas, greece stamatiouk@gmail.com nikolaos pierris, md urology department, tzaneio hospital, pireas, greece stamatiou_stesura seveso 20/12/13 11:04 pagina 196 11archivio italiano di urologia e andrologia 2018; 90, 1 original paper intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus calmette-guerin-induced chemical cystitis: preliminary experience with one-year follow-up vittorio imperatore 1, massimiliano creta 2, sergio di meo 1, roberto buonopane 1, nicola longo 2, ferdinando fusco 2, lorenzo spirito 2, ciro imbimbo 2, vincenzo mirone 2 1 unità operativa di urologia, ospedale buon consiglio fatebenefratelli, napoli, italy; 2 clinica urologica, università federico ii di napoli, napoli, italy. objective: we investigated the efficacy of intravesical instillations of combined hyaluronic acid (ha) and chondroitin sulphate (cs) in patients with bacillus calmette-guérin (bcg)-induced chemical cystitis unresponsive to first-line therapies. patients and methods: we retrospectively reviewed the clinical records of patients with grade 2 bcg-induced chemical cystitis unresponsive to first line therapeutic options performed according to the international bladder cancer group guidelines who underwent intravesical instillations of ha/cs. bladder pain, urinary urgency, voiding volume and number of voids/24 hours recorded prior to treatment, at the end of the treatment, at six months and at one-year follow-up were recorded and analyzed. results: the records of 20 patients were identified. all patients underwent eight weekly instillations of ha/cs. mean baseline visual analogue scale (vas) scores ± standard deviation (sd) for urinary urgency and bladder pain were 7.8 ± 0.5 and 7.2 ± 1.0, respectively. mean number of voids/24 hours ± sd was 15.4 ± 2.3 and mean urine volume per void ± sd was 85.8 ± 21.0 ml. at the end of the treatment, mean vas scores ± sd for urgency and pain significantly decreased to 4.7 ± 1.1 and 4.2 ± 0.9, respectively (p < 0.05 in both cases). mean number of voids/24 hours ± sd decreased to 9.6 ± 1.4 (p < 0.05) and mean urine volume per void ± sd significantly increased to 194.1 ± 59.5 ml (p < 0.05). at six months and one-year followup, all outcome measures remained stable. conclusions: bladder instillations of ha/cs provide significant and durable improvement of bladder pain, urinary urgency, urinary volume per void and urinary frequency in patients with refractory bcg-induced chemical cystitis. key words: bacillus calmette-guérin; bladder cancer; chondroitin sulphate; cystitis; hyaluronic acid. submitted 25 august 2017; accepted 23 october 2017 summary no conflict of interest declared. and has been reported in in up to 80% of patients (2-4). histologically, bcg-induced chemical cystitis is characterized by an intense inflammatory reaction involving the lamina propria associated with nonspecific reactive atypia of the overlying urothelium that may be partially or entirely denuded (5). clinically, it is characterized by storage lower urinary tract symptoms and hematuria with negative urine cultures. reduced functional bladder capacity has been also reported. most patients experience self-limiting symptoms that usually begin 2 to 4 hours after instillation and resolve rapidly over the next 24 to 48 hours (5). however, symptoms may persist or worsen and can become a troubling problem for some patients during bcg therapy and in the post-bcg observation period (5). the management of bcg-related side effects should reflect their type and grade and involves a stepwise approach according to the recommendations provided by the international bladder cancer group (ibcg) (1, 6). first-line therapeutic options for patients with bcg-related cystitis include phenazopyridine, propantheline bromide or non-steroidal anti-inflammatory drugs (1, 6). if symptoms persist or worsen, guidelines recommend postponing therapy, perform a urine culture, and start empirical antibiotic therapy with subsequent adjustments in case of positive culture (1, 6). in cases of negative culture, quinolones and potentially analgesic anti-inflammatory instillations are recommended (1, 6-8). a defective glycosaminoglycan (gag) barrier has recently emerged as the key factor in the pathogenesis of many pathophysiological processes that involve multiple biological systems including the bladder (i.e. biofilm formation, chemical and radiation damage) (9, 10). the gags best represented within the urothelial coating are hyaluronic acid (ha) and chondroitin sulfate (cs). the balanced association of ha and cs is indicated to treat chronic inflammatory diseases of the bladder originated from damage of the gag layer of the bladder epithelium. studies on bladder instillations of ha/cs as gag replenishment therapy suggest that this formulation is efficacious in a wide range of clinical conditions characterized by chronic bladder inflammation including interstitial cystitis/painful bladder syndrome, doi: 10.4081/aiua.2018.1.11 introduction intravesical immunotherapy with bacillus calmetteguérin (bcg) is the most effective prophylactic treatment for patients with non-muscle invasive bladder cancer (bca) at intermediate and high risk of recurrence and/or progression after complete tumor removal (1). bcg-related toxicity is a great concern for these patients and it can occur locally and/or systemically (1). chemical cystitis is the most common local side effect imperatore.e$s_stesura seveso 27/03/18 09:16 pagina 11 archivio italiano di urologia e andrologia 2018; 90, 1 v. imperatore, m. creta, s. di meo, r. buonopane, n. longo, f. fusco, l. spirito, c. imbimbo, v. mirone 12 recurrent urinary tract infections, radiation cystitis (11, 12). to date, only few studies evaluated the benefits of bladder instillations with ha/cs in patients with chemical cystitis induced by bcg (8, 13). we aimed to investigate the efficacy of intravesical instillations of combined ha/cs in patients with bcg-induced chemical cystitis unresponsive to first-line treatments. patients and methods the clinical records of patients with diagnosis of bcginduced grade 2 chemical cystitis unresponsive to first line therapeutic options performed according to ibcg recommendations who underwent intravesical instillations of combined ha/cs between january 2010 to january 2015 were retrospectively reviewed (6). grade 2 chemical cystitis was defined as severe and/or > 48 hours cystitis according to the world health organization grading scale (14). patients with systemic side effects related to bcg, active genitourinary tract infections, actinic bladder, follow-up < 1 year, or incomplete data were excluded. the followings were considered outcome measures: urinary urgency, bladder pain, urinary volume per void, number of voids/24 hours. urinary urgency and bladder pain were investigated through a 0-10 visual analogue scale (vas) score. urinary volume per void and number of voids/24 hours were investigated through frequency/volume charts. demographic and clinical data were collected including ethnicity, age, gender, tumor characteristics, previous therapies, symptoms onset, oncologic follow-up. for all outcome measures, values recorded at baseline, at the end of the treatment, at six months and one-year follow-up were collected and compared. moreover, treatment related adverse event were also collected. continuous variables were reported as mean, standard deviations (sd) and ranges. categorical variables were reported as absolute values and percentages. data were analyzed using the student’s t test, the mannwhitney and the wilcoxon test, as appropriate. p values < 0.05 were considered statistically significant. analyses were performed with spss version 17.0 (spss inc, chicago, il, usa). the study was performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. results a total of 20 caucasian patients were identified who met the study criteria. mean age was 61.8 years (range 4877), 9 patients were males (45%) and 11 (55%) were females. bca risk stratification revealed highand intermediate-risk tumors in 14 and 6 patients, respectively. bcg-induced grade 2 chemical cystitis occurred after a mean of 3.5 instillations (range: 2-6). symptoms persisted in all patients despite therapy with non-steroid antiinflammatory drugs and quinolones. the treating physician decided to definitively stop bcg instillations in all cases. patients were counseled about early cystectomy and refused. all patients received intravesical instillations of combined ha and cs (ha 1.6% 800 mg/50 ml and cs 2% 1000 mg/50 ml) weekly for eight weeks. all patients underwent follow-up investigations for bca according to recommendations provided by european urology guidelines. at baseline, mean vas scores ± sd for bladder pain and urinary urgency were 7.2 ± 1.0 and 7.8 ± 0.5, respectively. while mean number of voids/24 hours ± sd, and mean urinary volume per void ± sd were 15.4 ± 2.3 and 85.8 ± 21.0 ml, respectively. at the end of the treatment (8 weeks), symptoms improved in all but one patient. mean vas scores ± sd for bladder pain and urinary urgency significantly decreased to 4.2 ± 0.9 and to 4.7 ± 1.1, respectively (figure 1). mean number of voids/24 hours ± sd, and mean urinary volume per void ± sd significantly improved to 9.6 ± 1.4 and 194.1 ± 59.5 ml, respectively (figures 2 and 3). at six months follow up, mean vas scores ± sd for bladder pain and urinary urgency were 4.4 ± 1.1 and 4.5 ± 1.0, respectively. mean number of voids/24 hours ± sd, and mean urinary volume per void ± sd were 9.1 ± 1.6 and 210.8 ± 58.3 ml, respectively. at one year follow up, mean vas scores ± sd for bladder pain and urinary urgency were 4.2 ± 0.8 and 4.3 ± 0.9, figure 1. mean visual analogue scale (vas) scores for symptoms of urinary urgency and bladder pain at baseline, at the end of the treatment 8 weeks), at six-months and at one-year follow-up. (*: p < 0.05 with respect to baseline). figure 2. mean number of voids/24 hours at baseline, at the end of the treatment (8 weeks), at six-months and at one-year follow-up. (*: p < 0.05 with respect to baseline). imperatore.e$s_stesura seveso 27/03/18 09:16 pagina 12 respectively. mean number of voids/24 hours ± sd, and mean urinary volume per void ± sd were 9.0 ± 0.9 and 220.7 ± 55.3 ml, respectively (figures 2 and 3). not statistically significant differences were evident when comparing values recorded at eight weeks, six months and one-year follow-up for all outcome measures. we did not observe any side effect due to the treatment. at one-year follow-up none of the patients had bca recurrence. discussion bca is the most common malignancy of the urinary tract, the seventh most common cancer in men and the 17th in women (1, 15-17). transurethral resection of bladder tumors is the gold standard for removal of bca, to allow diagnosis and, in many cases, definitive treatment (1, 1517). however, tumor may recur or progress to muscle invasive disease and further adjuvant intravesical therapies are often needed (1). bcg intravesical immunotherapy is the most effective prophylactic management for bca in situ as well as for ta and t1 bca at intermediate and high risk of recurrence and progression after complete transurethral resection (1). morbidity secondary to intravesical bcg represents a great clinical concern. toxicities requiring treatment discontinuation or interruption are frequently seen during the first year of therapy and chemical cystitis represents the most common local side effect (18, 19). chemical cystitis is characterized by negative urine cultures and symptoms resemble to those of the urgency/frequency and painful bladder syndromes (8, 18). symptoms are generally self-limited. however, they can persist or worsen in some cases (18). the ibcg published recommendations for the treatment of intravesical therapy-associated adverse events (6). the management of bcg-related side-effects should reflect their type and grade and involves a stepwise approach (1). analgesic and anti-inflammatory intravesical instillations are recommended as an adjunctive option for patients with symptoms of cystitis that persist despite first-line antiinflammatory therapies (1, 6). to date, however, evidences about the efficacy of intravesical instillations in this clinical scenario are limited. palou et al. treated 16 patients with severe bcg cystitis unresponsive to systemic medical treatments with an anaesthetic anti-inflammatory solution administered by intravesical instillations (19). authors obtained good results in 94% of the cases with immediate clinical improvement in terms of pain and urinary symptoms, and no side effects (19). chuang et al. investigated, in a retrospective review, the potential utility of botulinum toxin a bladder injections in two patients with bcginduced chemical cystitis who had failed conventional therapies (20). the authors reported significant symptomatic improvements in both patients. the bladder capacity increased from 110 to 230 ml, urinary frequency decreased from 16 to 12 episodes per day, and using a 10point visual analogue pain scoring system, the perceived pain score decreased from 8 to 2 (20). however, theoretical risks of the injection procedure of botulinum toxin a exist, including hematuria, perforation, urinary tract infections, and injection-site pain (20). the role of gag replenishment therapy in patients with chemical cystitis was investigated by sommariva et al. (8). authors evaluated the efficacy of intravesical instillations with sodium hyaluronate in 55 male patients with acute iatrogenic cystitis secondary to bladder chemo-immunoinstillation or pelvic radiotherapy. of these, 17 patients received bcg. after 16 weeks vas for pain improved in every case of chemical cystitis from an initial mean value of 8.6 to a final mean value of 1. bladder capacity increased in all cases of chemical cystitis from a mean value of 56 ml to 276 ml. however, the study population was highly heterogeneous as 12 patients were treated with contemporary bladder hyperthermia. moreover, patients also received dexamethasone intravesical (8). results from the present study showed statistically significant improvements of bladder pain, urinary urgency, number of voids/24 hours and voided volume in patients with chemical cystitis secondary to intravesical immunotherapy with bcg and unresponsive to anti-inflammatory and quinolone therapies who received intravesical instillations of ha/cs. these results are in line with those reported by sommaviva et al. (8) moreover, for the first time, we observed a persistence of benefits after treatment discontinuation up to one year. the rationale behind the clinical benefits of intravesical instillations of ha/cs in patients with diagnosis of chemical cystitis secondary to intravesical immunotherapy with bcg is unknown. however, some potential mechanisms can be hypothesized. evidences exist suggesting that a defective urothelial barrier is involved in the pathogenesis of several chronic bladder conditions, such as interstitial cystitis/painful bladder syndrome, recurrent urinary tract infections, chemical and radiation cystitis (20). the surface of the urothelial cells carries a thick layer of glycoproteins and proteoglycans, together forming a gag layer, which constitutes a hydrophilic mucosal coating and a barrier against solutes or noxious substances in the urine. a defect in this layer may be the first step in the development of urothelial dysfunction (9). bladders lacking the apical layer of cells become more permeable, but impermeability can be restored with exogenous gags (21). moreover, ha/cs may act in the context of chemical cystitis secondary to bcg by interfering with the inflammatory process. indeed, studies have demonstrated that cs and ha may inhibit leukocyte migration, adherence of immune complexes, and binding to specific receptors (22). moreover, reduction 13archivio italiano di urologia e andrologia 2018; 90, 1 bcg-induced cystitis figure 3. mean urine volume per void at baseline, at the end of the treatment (8 weeks), at six-months and at one-year followup. (*: p < 0.05 with respect to baseline). imperatore.e$s_stesura seveso 27/03/18 09:16 pagina 13 archivio italiano di urologia e andrologia 2018; 90, 1 v. imperatore, m. creta, s. di meo, r. buonopane, n. longo, f. fusco, l. spirito, c. imbimbo, v. mirone 14 of local production of proinflammatory cytokines has been also described (9). however, further studies are needed to specifically address these issues. other authors have investigated the benefits of gag replenishment therapy in patients receiving bcg in a preventive setting. in their pilot study, topazio et al. evaluated the role of the sequential administration of ha and bcg (22). authors found significantly lower vas scores for pain, number of daily micturitions, and international prostate symptom scores in patients receiving ha and bcg with respect to patients receiving bcg alone (22). however, cost/benefits issues and potential interaction between bcg and ha deserve careful evaluations (22). interestingly, none of the subjects in the present study had bca recurrence at one-year follow-up despite bcg interruption. to date, little is known about the optimal treatment in patients with high-risk tumors who could not complete bcg instillations because of intolerance (1). although gag replenishment therapy may potentiate the protective barrier of the urothelium to prevent implantation of bca tumor cells, the role of intravesical ha/cs in terms of bca recurrence and progression is poorly understood and this issue deserves well designed pre-clinical and clinical studies (9). we acknowledge potential limitations of the present study. first, it was a retrospective study thus selection bias cannot be avoided. moreover, the number of patients was low and there was not a control group. therefore, formal randomized controlled trials and wider series are required to confirm these preliminary data and to draw definitive conclusions. conclusions intravesical instillations of ha/cs combination can improve urinary urgency, bladder pain, urinary frequency, and voided volume in patients with refractory bcginduced chemical cystitis. clinical benefits can persist up to one year after the suspension of the treatment. references 1. babjuk m, böhle a, burger m, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017; 71:447-461. 2. shang pf, kwong j, wang zp, et al. intravesical bacillus calmette-guérin versus epirubicin for ta and t1 bladder cancer. cochrane database syst rev. 2011; (5):cd006885. 3. bohle a, balck f, von wietersheim j, jocham d. the quality of life during intravesical bacillus calmette-guerin therapy. j urol. 1996; 155:1221-6. 4. braasch mr, bohle a, o’donnell ma. intravesical instillation treatment of non-muscle-invasive bladder cancer eur urol suppl. 2009; s8:549-555. 5. vogelzang nj, scardino pt, shipley wu, et al. (eds). comprehensive textbook of genitourinary oncology third edition. philadelphia, lippincott williams & wilkins. 2006; isbn: 0-7817-4984-0. 6. witjes ja, palou j, soloway m, et al. clinical practice recommendations for the prevention and management of intravesical therapyassociated adverse events. eur urol suppl. 2008; 7:667-674. 7. rischmann p, desgrandchamps f, malavaud b, chopin dk. bcg intravesical instillations: recommendations for side-effects management. eur urol suppl. 2000; 37:33-6. 8. sommariva ml, sandri sd, ceriani v. efficacy of sodium hyaluronate in the management of chemical and radiation cystitis. minerva urol nefrol. 2010; 62:145-50. 9. bassi pf, costantini e, foley s, palea s. glycosaminoglycan therapy for bladder diseases: emerging new treatments. eur urol suppl. 2011; 10: 451-459. 10. cennamo p, caputo p, giorgio a, et al. biofilms on tuff stones at historical sites: identification and removal by nonthermal effects of radiofrequencies. microb ecol. 2013; 66:659-68. 11. damiano r, cicione a. the role of sodium hyaluronate and sodium chondroitin sulphate in the management of bladder disease. ther adv urol. 2011; 3:223-32. 12. nordling j, van ophoven a. intravesical glycosaminoglycan replenishment with chondroitin sulphate in chronic forms of cystitis. a multi-national, multi-centre, prospective observational clinical trial. arzneimittelforschung. 2008; 58:328-35. 13. finazzi agro e, bove p, perugia c, et al. could hyaluronic acid reduce bacillus calmette guerin (bcg) local side effects? a preliminary report. j urol. 2012; 187(4 supplement:s):230-230. 14. saint f, irani j, patard jj, et al. tolerability of bacille calmetteguerin maintenance therapy for superficial bladder cancer. urology. 2001; 57:883-8. 15. longo n, imbimbo c, fusco f, et al. complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. bju int. 2016; 118:521-6. 16. imbimbo c, mirone v, siracusano s, et al. quality of life assessment with orthotopic ileal neobladder reconstruction after radical cystectomy: results from a prospective italian multicenter observational study. urology. 2015; 86:974-9. 17. creta m, mirone v, di meo s, et al. endoscopic spatulation of the intramural ureter: a technique to prevent stenosis of the ureterovesical junction in patients undergoing resection of the ureteral orifice. j endourol. 2016; 30:913-7. 18. anastasiadis a, de reijke tm. best practice in the treatment of nonmuscle invasive bladder cancer. ther adv urol. 2012; 4:13-32. 19. palou j, rodríguez-villamil l, andreu-crespo a, et al. intravesical treatment of severe bacillus calmette-guerin cystitis. int urol nephrol. 2001; 33:485-9. 20. chuang yc, kim dk, chiang ph, chancellor mb. bladder botulinum toxin a injection can benefit patients with radiation and chemical cystitis. bju int. 2008; 102:704-6. 21. hauser pj, buethe da, califano j, et al. restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. j urol. 2009; 182:2477-82. 22. topazio l, miano r, maurelli v, et al. could hyaluronic acid (ha) reduce bacillus calmette-guérin (bcg) local side effects? results of a pilot study. bmc urol. 2014; 14:64. correspondence vittorio imperatore, md (corresponding author) v.imperatore@alice.it sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it unità operativa di urologia, buon consiglio fatebenefratelli hospital, via a. manzoni, 220, 80123, napoli, italy massimiliano creta, md max.creta@gmail.com nicola longo, md ferdinando fusco, md lorenzo spirito, md ciro imbimbo, md vincenzo mirone, md clinica urologica, università federico ii di napoli via s.pansini, 5, 80131 napoli, italy imperatore.e$s_stesura seveso 27/03/18 09:16 pagina 14 stesura seveso archivio italiano di urologia e andrologia 2021; 93, 168 case report no conflict of interest declared. doi: 10.4081/aiua.2021.1.68 two weeks later, the patient underwent left radical nephrectomy. the histopathological examination reported clear-cell renal cell carcinoma. tnm staging was t3a with g3 fuhrman grade. she was followed up by the oncologist for 10 years without evidence of recurrence. after ten years, a pet/ct was performed demonstrating a metabolically active area in the thyroid right lobe. ultrasound imaging confirmed the presence of a solid hypoechoic, well-demarcated nodule of 2.2 cm. decision was made to perform a radical thyroidectomy in november 2014. the histopathological examination showed metastatic rcc of clear cell type (figure 1a). three year after thyroidectomy, in a further follow-up, two pulmonary nodules were detected and consequently the patient underwent thoracotomy for atypical double resection of the upper lobe and left pulmonary lingula. tnm staging was t1a and histology showed lung lipid adenocarcinoma (figure 1e, f) while the other nodule instead was comparable with metastasis from rcc (figure 1g, h). the subsequent follow-up was negative. the average latency time before the detection of thyroid metastases was 10 years (4). case 2 a76-year-old male underwent a right radical nephrectomy for a solid mass clear cell renal carcinoma in march 2016. tnm staging was t3an0m0. in april 2018 he underwent laparoscopy and subsequently to lower pole resection of the left kidney. the histopathological examination reported papillary carcinoma. tnm staging t1b g2. one year after surgery, a solid nodule in the right lobe of the thyroid gland (4.5 x 3 x 3.5 cm) was detected. the patient presented a painful mass associated with cough and dysphagia. size of metastases was significantly higher in this patient compared to those with painless mass. ultrasound imaging followed by computed tomography (ct) showed a well-defined hypodense nodule in the right lobe of the thyroid gland. our 79-year-old patient underwent thyroidectomy, after fna cytology, in 2019. the histopathological examination reported metastatic rcc of clear cell type which developed in his third follow-up year. the subsequent follow-up was negative. the average latency time before the detection of thyroid metastases was 3 years. renal cell carcinoma (rcc) is known to cause metastasis to unusual sites, which can be both synchronous or metachronous. thyroid gland is a rare site for metastasis. however, rcc is the most common primary neoplasm to metastasize to the thyroid gland. report of three cases and review of the literature. key words: renal cell carcinoma; thyroid; metastasis. submitted 26 june 2020; accepted 20 august 2020 introduction kidney cancer accounts for 5% and 3% of all adult malignancies in men and women, respectively, representing the 7th most common cancer in men and the 10th most common cancer in women. renal cell carcinoma (rcc) accounts for 80% of all kidney cancers. common metastatic sites of rcc are lung, lymph nodes, bone and liver. rcc is responsible of unusual metastatic sites, although it is the most common primary neoplasm that metastasizes to thyroid gland (1). the incidence of thyroid metastasis has been reported to be higher on autopsy studies (2) and ranges from 0.5% to 24% in high stage malignancies. metastasis can occur many years after initial diagnosis, but are extremely rare in clinical practice. a thyroid nodule in a patient with a history of rcc should be considered potentially metastatic. we retrospectively reviewed our database searching patients who developed recurrence of rcc with thyroid metastases. the total number of rcc patients observed from 2004 to 2019 in our institution was of about 208 cases. out of these, only three cases developed recurrence of rcc with thyroid metastases many years after nephrectomy in a 15 year follow-up range (3). case report/case presentation case 1 a 61-year-old female admitted to our hospital in april 2004, presented with left flank pain and history of weight loss. an mri was performed showing an exophytic, hypervascular, solid mass, measuring 7 x 8 cm. the mri findings were in keeping with a malignant renal tumor. clear-cell renal cell carcinoma single thyroid metastasis: a single-center retrospective analysis and review of the literature summary isabella ricci 1, francesco barillaro 2, enrico conti 2, donatella intersimone 3, paolo dessanti 3, carlo aschele 1 1 department of oncology, ospedale s. andrea, la spezia, italy; 2 department of urology, ospedale s. bartolomeo, sarzana, italy; 3 department of pathology, ospedale s. andrea, la spezia, italy. 69archivio italiano di urologia e andrologia 2021; 93, 1 unusual presentation of single thyroid metastasis case 3 a 78 year-old female presented with a history of a lump on the neck for the last 3 months in may 2014. the past medical history encompassed rcc on the right side around 10 years before. at that time she has been treated surgically undergoing left radical nephrectomy and left adrenalectomy for a large renal mass measuring 11 x 7 x 7 cm. the histology showed clear cell rcc g2 sec fuhrman. tumor was not infiltrating through the capsule. surgical margins were free of tumor and tnm staging t2bn0m0. she was followed-up by the oncologist for almost 10 years and no evidence of recurrence was noted. the examination of the neck revealed evidence of a 3 cm nodule in the right thyroid lobe. on positron emission tomography/computed tomography there was a metabolically active area in the thyroid right lobe. ultrasound imaging confirmed a solide hypoechoic nodule. the patient subsequently underwent fine needle aspiration cytology which showed borderline neoplastic cells, although it poses the diagnostic doubt. a thyroidectomy was therefore carried out. the istopathological examination showed metastatic rcc of clear cell type (figure 1b). mean latency time before the detection of thyroid metastases was 10 years. the subsequent follow-up was negative. discussion rcc accounts for approximately 3-4% of all adult malignancies. it is more common in males and occurs predominantly in the 6th to 8th decade of life. major histopathological subtypes include clear cell carcinoma, papillary carcinoma, chromophobe carcinoma, medullary carcinoma. the metastasis may be detected at the time of diagnosis (synchronous) or may be found years after the diagnosis and treatment (metachronous) (5-11). it has been estimated that 20-30% of patients including those who have undergone nephrectomy with curative intent will develop recurrence and out of these 50% will relapse distantly (6). moreover, solitary metastasis from rcc occurs with an incidence rate of about 1-4% of which about 1% occur in the thyroid gland. most of the recurrences appears within 3 years from surgery, but delayed recurrences even after decades have been reported (7). characteristics of patients described in literature are reported in table 1 (11). rcc metastasis to thyroid generally are symptomatic or painless mass but can be also completely asymptomatic and discovered incidentally during follow-up. size of metastases was higher in symptomatic patients compared to those with painless mass and asymptomatic ones. rarely may present dysphagia, dysphonia or dyspnea. moreover, there was a weak correlation between lag time and size of metastases. table 1. characteristics of patients described in literature. characteristics of patients age (yr) mean ± sd male 64 ± 10 female 64 ± 11 sex percentage (number of patients) male 47% (69) female 53% (77) initial ccrcc stage stage i ccrcc 32% (21) stage ii ccrcc 29% (19) stage iii ccrcc 31% (20) stage iv ccrcc 8% (5) lag time (years) from initial diagnosis of ccrcc 8.7 ± 6.5 mean ± sd symptoms asymptomatic 30% (33) symptomatic or painless mass 70% (76) surgery total thyroidectomy 62% (75) subtotal thyroidectomy 38% (46) figure 1. a: thyroid (bottom left) with metastasis of adult renal cell carcinoma clear cell (conventional) (top right). hematoxylin eosin 40x. b: thyroid (upper half) with nodular hyperplasia and with metastasis of adult renal cell carcinoma (lower half). hematoxylin eosin 20x. c-d: renal cell metastasis showed immunoreactivity for rcc/renal cell carcinoma marker (c) and negativity for thyroglobulin (d), which was positive in the thyroid parenchyma. e-f: lung metastasis (lingular lobe left lung) of renal cell carcinoma. hematoxylin eosin 20x (e). lung metastasis (lingular lobe left lung) of renal cell carcinoma. hematoxylin eosin 20x (f). g-h: lung adenocarcinoma (lower lobe left lung) with predominantly lepidic type growth. napsin a 40x (g). the neoplastic cells show intense nuclear immunoreactivity for pax 8 confirming their renal origin. pax 8, 20x (h). archivio italiano di urologia e andrologia 2021; 93, 1 i. ricci, f. barillaro, e. conti, d. intersimone, p. dessanti, c. aschele 70 regarding the tests performed for the diagnosis of rcc metastases to the thyroid gland, ultrasound of the neck was the most frequently used imaging tecnique followed by computed tomography (ct scan) and positron emission tomography (pet scan). usually metastatic thyroid lesions appear as solid hypoechoic, well-demarcated nodules with irregular vascularity on ultrasound imaging and cold nodules on radioisotope uptake studies. these radiological features are not specific and it is not possible to distinguish between primary and secondary thyroid neoplasms on imaging. only a case demonstrated incidental thyroid abnormalities on positron emission tomography/computed tomography and ultrasound later confirmed as a metastases of renal cell carcinoma. fine needle aspiration (fna) cytology is necessary to establish preoperative diagnosis. a challenge it is sometimes distinguishing metastasis from tumors of thyroid, because can have clear cell component on fna cytology alone. in these cases, immunohistochemistry is helpful and aids in differential diagnosis. in our cases cytocheratin, vimentin and cd 10, traditional immunohistochemical markers for renal cell carcinoma, were positive; thyroglobulin, thyroid transcription factor-1 (ttf-1), and calcitonin, markers used for identifying primary thyroid malignancies, were negative (figure 1c, d). definitive diagnosis of metastatic rcc is usually made by histopathological examination after thyroidectomy (8). surgical resection with either partial or radical thyroidectomy should be performed if thyroid gland is the only site for metastasis. prognosis is good in this group (9, 10). thyroid metastasis from rcc has a better survival rate according to the literature. patients with disseminated disease have poor prognosis and should undergo thyroidectomy only for palliation for compressive symptoms. treatment choice in metastatic renal cell carcinoma depends on different factors including the extent of the disease and prognostic risk factors such as karnofsky performance status, diagnosis timeline and laboratory findings. direct treatments to the thyroid metastasis result in prolonged survival especially in solitary thyroid gland metastasis where surgical treatment is recommended. it is demonstrated a favorable prognosis in patients treated with radical surgery (average 5-year survival rate 30-60%). clinically it has been observed that the overall survival rate in patients undergoing thyroidectomy for metastases of rcc is more affected by general health status rather than by tumor-related factors. sunitinib could be effective for the treatment of these metastases. his mechanism of action is based on causing reduction in thyroid volume. negative adverse reaction of this drug can results in a various grade of thyroid dysfunction from hypothyroidism to thyroid atrophy, in particular in patients who receive the drug over a long period of time, and that could result in irreversible hypothyroidism. this is thought to be a result of a possible sunitinib-induced thyrotoxicosis along with a direct effect of the drug which could cause degeneration of thyroid follicular cells. to understand the possible effectiveness of sunitinib on thyroid further investigations are needed. conclusions a thyroid nodule in a patient with a history of rcc should be considered as potentially metastatic. it’s challenging to distinguish between primary and secondary thyroid neoplasms on imaging, and clinical manifestation and radiographic findings are non-specific. fna cytology and immunohistochemistry are helpful in establishing diagnosis and should be obtained in suspected cases. the average latency time before the detection of thyroid metastases was variable. however, a lifelong follow-up is recommended. our cases demonstrate the importance of considering rcc metastases to the thyroid even years after nephrectomy to avoid potential delays in diagnosis (11). references 1. chen h, nicol tl, udelsman r. clinically significant, isolated metastatic disease to the thyroid gland. world j surg. 1999; 23:177-80. 2. willis ra. metastatic tumours in the thyroid gland. am j pathol. 1931; 7:187-208.3. 3. bayrakter z, albayrak s. metastasis of renal cell carcinoma to the thyroid gland 9 years after nephrectomy: a case report and literature review. arch ital urol androl. 2017; 89:151-153. 4. cilengir ah, kalayci to, duygulu g, et al. metastasis of renal clear cell carcinoma to thyroid gland mimicking adenomatous goiter. pol j radiol. 2016, 81:618-621. 5. motzer rj, bander nh, nanus dm. renal cell carcinoma. nejm. 1996. 335:865-875. 6. flanigan rc, campbell sc, clark ji, et al. metastatic renal cell carcinoma curr treat options oncol. 2003; 4:385-390. 7. eggener se, yossepowitch o, pettus ja, et al. renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence, jco. 2006; 24:3101-3106. 8. aljiabri ks, bokhari sa, fadag rb, et al. thyroid metastasis from renal cell carcinoma, archives of endocrinology and diabetes care. 2018; 1:65-70. 9. chung ay, tran tb, brumund kt, et al. metastases to the tyroid: a review of the literature from the last decade, thyroid. 2012; 22:258-68. 10. de stefano r, carluccio r, zanni e, et al, management of thyroid nodules as secondary involvement of renal cell carcinoma case report and literature review, anticancer research. 2009; 29:473-6. 11. khaddour k, marernych n, ward wl, et al. characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: a systematic review, world j clin cases. 2019; 7:3474-3485. correspondence isabella ricci, md (corresponding author) isabella.ricci@asl5.liguria.it carlo aschele, md carlo.aschele@asl5.liguria.it department of oncology, ospedale s. andrea, la spezia (italy) francesco barillaro, md francesco.barillaro@asl5.liguria.it enrico conti, md enrico.conti@asl5.liguria.it department of urology, ospedale s. bartolomeo, sarzana (italy) donatella intersimone, md donatella.intersimone@asl5.liguria.it paolo dessanti, md paolo.dessanti@asl5.liguria.it department of pathology, ospedale s. andrea, la spezia (italy) 55archivio italiano di urologia e andrologia 2019; 91, 1 case report large primary leiomyosarcoma of the seminal vesicle: a case report and literature revision emanuele corongiu 1, pietro grande 2, valerio olivieri 3, giorgio pagliarella 1, flavio forte 1 1 department of urology, m.g. vannini hospital, rome, italy; 2 sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris, france; 3 department of urology, ivrea hospital asl to 4, ivrea, italy. primary leiomyosarcoma of the seminal vesicle is a very rare condition. we report a case of a 74-year-old man with a tumour detected by rectal symptoms with pelvic pain and dysuria at ultrasonography. computed tomography and magnetic resonance imaging suggest an origin in the left seminal vesicle and did not show a clear cleavage plan with the rectum and a right hydroureteronephrosis was also present. a radical vesiculo-cystoprostatectomy with ileal conduit and bilateral pelvic lymphadenectomy was performed, a sigmoidectomy with end colostomy was performed also. pathological examination showed a high grade (g3) leiomyosarcoma of the seminal vesicle. key words: seminal vesicle; leiomyosarcoma; oncology; rare tumors. submitted 25 october 2018; accepted 4 november 2018 summary no conflict of interest declared. revealed no specific findings, and rectal examination was totally negative for rectal or prostatic bulging masses. ultrasonography (us) discovered a bulky mass located in the right portion of the pelvis compressing the urinary bladder and causing omolateral hydronephrosis. serum prostate-specific antigen (psa) levels were normal. a computed tomography (ct) confirmed a massive abdominal mass (14 x 13 x 12 cm) with considerable contrast enhancement, determining a compression on the distal part of the right ureter with omolateral hydroureterone phrosis (figure 1). there was no evidence of a clear cleavage plan between mass and surrounding organs (sigma, bladder and prostate). furthermore, a nodal involvement at level of the right iliac and obturator lymph nodes was reported. magnetic resonance (mri) confirmed the findings of the ct scan (figure 2), giving no supplemental information. based on these data, a surgical approach was decided. doi: 10.4081/aiua.2019.1.55 introduction the localization in the genitourinary tract of soft tissue sarcoma (sts) is a very rare condition (less than 5% of these neoplasms) (7), among these a localization at the level of the seminal vesicles is even more rare (7). to our knowledge, only few cases have been reported to date in the literature but no one with large dimension as in our case (1-7). the diagnosis of the real anatomical origin of this type of neoplasia is made difficult by invasive and compressive phenomena on adjacent organs, so for a correct diagnosis the use of ct-scan and mri are fundamental. considering the rarity of these conditions, the role of radiotherapy and chemotherapy seems to remain uncertain, and the treatment of choice remains a radical surgical removal. case report a 74-year old caucasian man, with previous history of hypertension showed up at the emergency department of our hospital in may 2018 due to the acute onset of pelvic pain, dysuria, and partial occlusion of the intestine. physical examination figure 1. ct scan of the patient. figure 2. mri scan of the patient. corongiu1_stesura seveso 26/03/19 09:48 pagina 55 archivio italiano di urologia e andrologia 2019; 91, 1 e. corongiu, p. grande, v. olivieri, g. pagliarella, f. forte 56 the treatment consisted of a radical vesiculo-cystoprostatectomy with ileal conduit and bilateral pelvic lymph node dissection (iliac, obturator and hypogastric nodes). during the surgery the dissection of the mass from the sigma resulted unfeasible, so a sigmoid colon resection with end colostomy was performed (figure 3). the patient was transferred to intensive care unit for 24 hours after surgery, the post-operative course was without complications and the patient was discharged on the 7th post-operative day. results the final pathological analysis showed a small prostate (5 x 4 x 5 cm) with outbreaks of bilateral adenocarcinoma [pt2c, gleason 6 (3 + 3)]. no neoplastic invasion of bladder or sigmoid colon and no nodal involvement were found and both ureteral margins were free of tumor. the right seminal vesicle was unscathed, while the left vesicle was not recognizable, as it was included in a large mass with a polylobate appearance measuring of 14 cm on the longest axe and having a hard-elastic consistency and yellowish-white color. microscopically, the mass consisted of fused cellular elements, organized in short bundles with marked cell polymorphism and foci of necrosis. neoplastic cells were positive for the histochemical reaction for smooth muscle actin, desmin and vimentin, negative for immunohistochemically reaction for s100, determining the final diagnosis of leiomyosarcoma of the seminal vesicle. discussion/conclusion primary tumors of the seminal vesicle are a very rare condition. among them, carcinomas are much more frequent than sarcomas (8). at present only 8 cases of primary leiomyosarcoma of seminal vesicles have been described in the literature (1-7). our case represents the ninth patient, and one with the largest dimensions and the last one described since 2011. no specific risk factor has been identified. the clinical detection of tumors of the seminal vesicles is very difficult, both for the extreme rarity of this neoplasm and for the extreme variability of the symptoms: in some cases the patient is totally asymptomatic, in other cases it has non-specific symptoms (pelvic-abdominal pain, dysuria, rectal symptoms) depending on the size of the tumor and the relationships it contracts with the adjacent organs (7). radiological imaging is essential for a correct diagnosis, usually the first step is represented by an ultrasound (abdominal or trans-rectal) but it is undoubtedly crucial the use of ct scan and we have seen that in our case as in the last two cases described in literature (6, 7). further investigation with mri is very useful to identify the organ of origin of the neoplasm. the histological diagnosis of sarcoma is obtained on the anatomical specimens. in some of the previously reported cases it was preferred to proceed first to a tissue biopsy, but in our case we preferred to perform the surgery immediately considering the poor results obtained from chemotherapy on soft tissue sarcomas (sts) (7) and consequently the improbability of any reduction in the mass following neoadjuvant chemotherapy. the differential diagnosis should be made with leiomyosarcomas originating from the neighbouring organs (prostate, bladder, rectum) and which secondarily invade the seminal vesicles. the prognosis of leiomyosarcoma of seminal vesicles is negative, less favorable than other urogenital sarcomatoid lesions from the bladder or paratesticular areas (4), this is probably partly due to the delay in diagnosis and the difficulty to perform a radical excision of the neoplasm. given the rarity of this condition the treatment of choice is uncertain, but the only therapeutic option that offers a chance of cure in sts is radical surgery, in all reported cases the surgical approach consisted in a cystoprostatectomy with a pelvic lymphadenectomy, except in the last case where prostatectomy with removal of seminal vesicles was done. the role of adjuvant radiation therapy in visceral sts is not clear (9), and only two out of 8 reported cases (two with positive margins and one with very close margins) received such treatment. also, the role of adjuvant chemotherapy is discussed (10), in literature only one patient received adjuvant combination of doxorubicin, fosfamide and dacarbazine (maid) (7). concluding our case of primary leiomyosarcoma of the seminal vesicles is only the ninth described, at the time, in the literature and the first in which the extension and compression of the neoplasm has also necessitated a resection of the sigmoid and the creation of a colostomy. considering the exceptional nature of these neoplasm, the sharing of knowledge and a multimodal approach are fundamental to improve the prognosis that is still poor. references 1. agrawal v, kumar s, sharma d, et al. primary leiomyosarcoma of the seminal vesicle. int j urol. 2004, 11:253-255. 2. amirkhan rh, molberg kh, wiley el, et al. primary leiomyosarcoma of the seminal vesicle. urology. 1994, 44:132-135. 3. muentener m, hailemariam s, dubs m, et al. primary leiomyosarcoma of the seminal vesicle. j urol. 2000, 164:2027. figure 3. surgical specimen. corongiu1_stesura seveso 26/03/19 09:48 pagina 56 4. russo p, brady ms, conlon k, et al. adult urological sarcoma. j urol 1992, 147:1032-1036, discussion 1036-1037. 5. schned ar, ledbetter js, selikowitz sm. primary leiomyosarcoma of the seminal vesicle. cancer. 1986; 57:2202-2206. 6. upreti l, bhargava sk, kumar a. imaging of primary leiomyosarcoma of the seminal vesicle. australas radiol. 2003; 47:70-72. 7. cauvin c, moureau-zabotto l, chetaille b, et al. primary leiomyosarcoma of the seminal vesicle: case report and review of the literature.bmc cancer. 2011; 11:323. 8. thiel r, effert p. primary adenocarcinoma of the seminal vesicles. j urol. 2002; 168:1891-1896. 9. swallow cj, catton cn. local management of adult soft tissue sarcomas. semin oncol. 2007; 34:256-269. 10. blay jy, le cesne a. adjuvant chemotherapy in localized soft tissue sarcomas: still not proven. oncologist. 2009; 14:1013-1020. 57archivio italiano di urologia e andrologia 2019; 91, 1 large seminal vesicle leiomyosarcoma correspondence emanuele corongiu, md giorgio pagliarella, md flavio forte, md phd flavioforte@hotmail.com g.m. vannini hospital, department of urology via di acqua bullicante 4, 00177, rome (italy) pietro grande, md sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris (france) valerio olivieri, md dept. of urology, ivrea hospital asl to 4, ivrea (italy) corongiu1_stesura seveso 26/03/19 09:48 pagina 57 archivio italiano di urologia e andrologia 2017; 89, 3212 original paper effect of superoxide dismutase supplementation on sperm dna fragmentation luciano negri 1, renzo benaglia 1, emanuela monti 1, emanuela morenghi 2, alessandro pizzocaro 3, paolo e. levi setti 1 1 humanitas research hospital, department of gynecology, division of gynecology and reproductive medicine, humanitas fertility center, rozzano, milan, italy; 2 biostatistics unit, humanitas research hospital, rozzano, milan, italy; 3 endocrinology unit, irccs, humanitas research hospital, rozzano, milan, italy. background: antioxidants supplementation improves sperm quality, but few trials have analyzed the effects on sperm dna fragmentation (sdf). this study compares the effectiveness of sod-based antioxidant supplementation plus hydroxytyrosol and carnosol in reducing sdf with other antioxidants without sod, hydroxytyrosol, and carnosol. materials and methods: men with high sdf at baseline were selected in our clinical database. the patients taken into account had a 2-month control. sdf was measured by sperm chromatin dispersion test (scd). untreated men were used as a control group. the remaining subjects received some oral antioxidant supplements (12 different combinations of both hydrophilic and lipophilic antioxidants), with some of them receiving nutritional support with a sod-based antioxidant supplementation plus hydroxytyrosol and carnosol. results: 118 men were selected for a retrospective study. mean age 39.3 ± 5.4 years. fifteen had no treatment, 55 were treated with a sod-based antioxidant supplementation plus hydroxytyrosol and carnosol, and 48 took some antioxidant supplements for 2 months. clinically, variations of at least 10% in baseline values of classic semen parameters and sperm dna fragmentation were taken into consideration. classic seminal parameters did not vary significantly in the three groups, with the exception of viability (p = 0.001). we assessed which of the active substances (no. 19) in different formulations were associated with variations in sdf. in the multivariable analysis of the 7 active substances that passed the univariable analysis, only the sod molecule appeared to be linked to an improvement in sdf (< 0.0001). in detail, only one patient in the control group showed a spontaneous improvement in sdf (6%), compared to 16/48 (33%) of those taking various oral antioxidant supplements, and 31/55 (56%) of those taking a sod-based antioxidant supplementation plus hydroxytyrosol and carnosol. conclusions: sod-based antioxidant supplementation plus hydroxytyrosol and carnosol seems to provide a better chance of improving sperm dna integrity than other classical antioxidant molecules. key words: sperm dna fragmentation: male infertility; superoxide dismutase; hydroxytyrosol; carnosol. submitted 19 july 2017; accepted 3 august 2017 summary no conflict of interest declared. with pregnancy in natural cycles (1), intrauterine inseminations (2), and in-vitro procedures (3). sdf is also associated with recurrent miscarriage (4), both during in-vivo and in-vitro procedures. it is well known that sdf may be present in men with both normal and abnormal semen analysis (5) and that infertile men have higher proportions of sperm with dna damage compared to fertile men (6). cohen-bacrie et al. (2009) (7) found elevated levels of sperm dna damage in over 60% of men attending fertility clinics, with 30% being severe. because conventional semen analysis is a poor predictor of sperm dna damage (8), sdf assays have been suggested in selected cases of infertility, e.g. unexplained infertility, recurrent miscarriages, and asthenoteratozoospermia. abortive apoptosis, infection, defective spermatogenesis, and oxidative stress (os) are thought to be causes of sdf (9), with the latter being the most common cause (10). oxidative stress occurs when reactive oxygen species (ros) overcome the semen’s natural antioxidant defenses. in physiological conditions, oxidative stress is suitably balanced by the action of endogenous enzymatic antioxidants, including superoxide dismutase (sod), catalase, and glutathione peroxidase⁄reductase, as well as non-enzymatic antioxidants such as ascorbate, urate, vitamin e, pyruvate, glutathione, albumin, vitamin a, ubiquinol, taurine, and hypotaurine (11). these endogenous antioxidants scavenge both intracellular and extracellular superoxide radicals, preventing the lipid peroxidation of plasma membranes (12). pathological stressors that generate endogenous ros include infections, varicocele, aging, cancer, drugs, cigarette smoking, obesity, pharmaceutics, industrial chemicals, radio-frequency electromagnetic radiation and, lastly, abnormal spermatozoa (13, 14). all these stressors decrease sperm motility and viability, while stimulating dna base adduct formation and, ultimately, dna fragmentation. physiologically, homeostasis between free radicals and antioxidant substances is guaranteed by very complex systems. the most efficient seems to be the system mediated by the nrf2 (nuclear factor [erythroid-derived 2]-like 2 transcription factor) pathway. the latter regulates a wide variety of antioxidant cytoprotective enzymes through a promotion sequence known as are (antioxidant response element) (15). doi: 10.4081/aiua.2017.3.212 introduction sperm dna fragmentation (sdf) is an important factor in the etiology of male infertility. sdf negatively correlates negri_stesura seveso 28/09/17 10:23 pagina 212 213archivio italiano di urologia e andrologia 2017; 89, 3 effect of superoxide dismutase supplementation on sperm dna fragmentation at present, several tests have been developed to evaluate sperm dna fragmentation. these include the sperm chromatin dispersion test (scd) (16), a simple and inexpensive test for basic diagnosis in clinical practice. when no clear sdf etiological factors exist, antioxidants drugs are empirically prescribed (17, 18). numerous combinations of hydrophilic and lipophilic antioxidants are available in drugstores and online, e.g. vitamin c, vitamin e, folic acid, dha, l-acetyl carnitine, l-carnitine, astaxanthin, ethyl cysteine, coenzyme q10, zinc, and selenium. in view of the fact that recent in-vitro and in-vivo trials support the theory that nrf2 activation strategies could effectively combat oxidative stress, the purpose of our retrospective study is to match the effectiveness of sodbased antioxidant therapy plus hydroxytyrosol and carnosol (fertiplus® sod) in reducing sperm dna fragmentation with other antioxidants without sod, hydroxytyrosol, and carnosol. materials and methods selection of participants and data collection male partners of infertile couples referred to our fertility center were selected by a query in our clinical database (june 2014 november 2016). inclusion criteria were oligo-normozoospermia, according to the 2010 world health organization criteria for the evaluation of human semen (5th edition) (19); sperm dna fragmentation > 15%; no current seminal infections according to sperm culture and/or seminal leucocyte (< 106 x ml); no sperm antibodies (sperm mar igg; ferti pro, n.v., origio, florence, italy); no varicocele. these patients had i) mildly or severely high levels of dna fragmentation at baseline examination and ii) scd control after 2 months. the medical histories of all patients were taken into consideration and physical examinations plus ultrasonography of reproductive apparatus were conducted by three clinical andrologists (ln, rb and ap). semen analyses, as well hormone profiles, were evaluated in our hospital. the presence of previous cryptorchidism, long-term medication use (e.g. selective serotonin reuptake inhibitors, tranquilizers, antihypertensives, substances for the prevention of fatty acid metabolism disorders, mesalazine), and idiopathic hypogonadism were not considered exclusion factors as they are representative of everyday real-life clinical practice. table 1 shows the clinical characteristics of patients. this retrospective study was approved by our hospital’s institutional ethical committee and all patients provided written informed consent for the scientific use of their clinical data. the primary endpoint of the study was to analyze the improvement in sperm integrity (sdf reduction) after antioxidant oral supplementation. the secondary endpoints were the effects on classic semen parameters (sperm count, progressive motility, normal forms, viability) and the presence of adverse events. pregnancy, miscarriage, and live birth rates were not considered due to the short duration of treatment (2 months). semen processing semen samples were obtained in a collection room located in the same facility as the andrology laboratory after 3-5 days of sexual abstinence. after liquefaction at 37°c in sterile cups, seminal volume and ph, sperm concentration, motility, morphology, and viability were evaluated according to world health organization guidelines (2010) (19). we analyzed the total sperm count instead of the concentration/ml, as it is more representative of actual testicular function. scd test the method used was halosperm g2® (halotech, madrid, spain), in keeping with the manufacturer’s protocol (http://www.halotechdna.com/wp-content/uploads/2015/ 04/iu-halosperm-g2_10det_v2.pdf). the scd test is based on the principle that sperm with fragmented dna fail to produce the characteristic halo of dispersed dna loops observed in sperm with non-fragmented dna, following acid denaturation and removal of nuclear proteins. sperm cells with very small halos or without halos are to be considered as containing fragmented dna. the extent of dna damage for each semen sample is expressed as the sperm dna fragmentation index (sdf). in humans, a threshold of 30% sdf is suggested as a cutoff to distinguish between a potentially fertile vs infertile semen sample, although a threshold of 18% has been suggested as predictive of a poor fertilization rate. in order to understand whether the patient achieved a clinically useful improvement in sdf, we arbitrarily selected a cut-off of 10% dna fragmentation percentage change, calculated as: statistics the data were described as number and percentage, or mean and standard deviation, as appropriate. differences were explored with the wilcoxon test for paired data when comparing data at baseline and 2 months control, or the kruskal-wallis test when comparing improvements in sdf or integrator type. the association between the percentage variation and the commercial product table 1. conventional seminal parameters and clinical characteristics of patients tpmc means total progressively motile sperm count [(volume x sperm concentration x progressive motility)/10-8]. at baseline 2 months control p patients 118 118 infertility duration (months) 32.9 ± 24.8 male age (yrs.) 39.4 ± 5.4 female age (yrs.) 35.1 ± 4.3 male bmi 25.7 ± 3.0 total orchidometry (ml) 28.7 ± 8.2 active smoking 27 (22.88%) fsh (mu/ml) 5.43 ± 3.07 comorbidities 35 (29.66%) medication use 25 (21.19%) semen volume (ml) 3.52 ± 1.51 3.43 ± 1.55 0.393 total sperm count (106) 70.4 ± 63.2 80.9 ± 78.4 0.159 tpmc (106) 13.9 ± 15.4 17.2 ± 20.0 0.160 progressive motility (%) 18.3 ± 10.2 19.3 ± 11.4 0.738 normal forms (%) 3.49 ± 2.09 3.64 ± 1.86 0.334 viability (%) 63.6 ± 11.9 66.6 ± 10.4 0.014 negri_stesura seveso 28/09/17 10:23 pagina 213 archivio italiano di urologia e andrologia 2017; 89, 3 l. negri, r. benaglia, e. monti, e. morenghi, a. pizzocaro, p.e. levi setti 214 was explored with an univariable linear regression; all the products with a p less than 0.1 were then subjected to a multivariable linear regression. all analyses were made with stata13 software (statacorp lp, 4905 lakeway drive, college station, tx 77845, usa). a p < 0.05 was considered as significant. results 118 male partners of infertile couples treated from june 2014 november 2016 were selected for a retrospective study. mean age was 39.3 ± 5.4 years, infertility duration was 32.9 ± 24.8 months. female age on examination was 35.1 ± 4.3 years. conventional seminal parameters and clinical characteristics of patients are reported in table 1. none of the patients reported any adverse events after oral antioxidant supplementation. of these men, 15 had received no medical or surgical treatment and were used as a control group. the remaining 103 had received some oral antioxidant supplementation (12 different combinations of both hydrophilic and lipophilic antioxidants), whose composition is shown in table 2. fifty-five were treated with sod-based antioxidant fertiplus® sod, whose formulation contains orisod®, extramel®, α-lipoic acid, glutathione, folic acid, zinc, and vitamins b2, b3, b6, b12. fertiplus® sod is a balanced combination of enzymatic and non-enzymatic antioxidants (sod micro encapsulated [extramel®]), alpha lipoic acid, glutathione (low dose), zinc, b vitamins, a micronutrient complex (orisod®) containing substances of plant origin, hydroxytyrosol, and carnosol, identified as substances able to activate the antioxidant system and detoxify intracellular endogenous nrf-2 (nuclear transcription factor-erythroid 2). five patients had a clinical history of juvenile orchidopexy and one had a history of previous unilateral seminoma without chemoradiotherapy; one had testicular microlithiasis, one reported a low birth weight, one had unilateral absence of the vas deferens and ipsilateral renal agenesis, and one had unilateral testicular torsion without antisperm antibodies. another 25 patients were taking medication for anxiety and depression (n. 1), asthma (n. 6), behçet’s disease (n. 1), gastroesophageal reflux (n. 5), nasal polyposis (n. 1), hypertension (n. 3), hypothyroidism (n. 1), crohn’s disease (n. 1), juvenile diabetes (n. 1), epilepsy (n. 1), mild chronic renal insufficiency (n. 1), hypercholesterolemia (n. 1), and pudendal nerve entrapment (n. 1). one patient was using cannabis. we then assessed which of the active substances were associated with variations in dna fragmentation, individually considered and corrected on an individual basis for the statistically significant cases. the results are shown in table 2. in the multivariable analysis of the seven active substances that passed the univariable analysis, only the sod molecule appears to be linked to an improvement in sdf. clinically, variations of at least 10% in baseline values of classic semen parameters and sperm dna fragmentation were taken into consideration. variations between the two limits were not considered clinically relevant. table 3a shows the clinical and seminal parameters compared to the percentage change in sdf. no seminal parameters were associated with the variation in dna fragmentation, except for the improvement in sperm viability (p = 0.001) and, to a slight extent, the improvement in progressive motility (p = 0.07). the distribution of comorbidities and medication use is homogeneous in the three analyzed groups. furthermore, no differences in age, bmi, active smoking, fsh, and total testicular volume were observed in the three groups. classic seminal parameters (total sperm count, progressive motility, and morphology) do table 2. the table lists the substances contained in 12 commercial products. the second column shows the number of prescriptions in the 103 patients evaluated in the study. the fourth and fifth columns report the percentage variation in dna fragmentation for each individual active substance. data are expressed as mean ± sd. ingredients commercial no. patients absent present p p products (n. 12) (n. 118) (mean ± sd) (mean ± sd) (univariable) (multivariable) vit. e 7 28 6.96 ± 27.83 -4.66 ± 28.47 0.1189 vit. c 6 33 7.21 ± 26.90 -3.57 ± 30.69 0.0920 0.2505 zinc 6 82 -7.54 ± 28.93 9.36 ± 26.60 0.0024 0.3565 arginine 6 23 6.18 ± 28.64 -3.96 ± 25.84 0.1404 selenium 5 16 5.87 ± 28.44 -6.43 ± 25.74 0.1141 l-carnitine 5 17 5.57 ± 28.11 -3.91 ± 28.90 0.2902 folic acid 5 71 -7.36 ± 27.23 11.86 ± 26.50 0.0002 0.6156 coenzyme q10 3 17 5.3 ± 29.63 -3.70 ± 17.11 0.1341 inositol 3 8 5.18 ± 27.90 -9.30 ± 32.36 0.2702 vit. b 2 57 -6.54 ± 26.55 15.69 ± 25.65 < 0.0001 0.2226 astaxanthine 2 8 4.77 ± 28.85 -3.56 ± 18.80 0.2941 α-lipoic acid 2 57 -6.54 ± 26.55 15.69 ± 25.65 < 0.0001 -* dha 2 8 4.33 ± 28.04 2.47 ± 33.80 0.4799 sod 1 55 -7.13 ± 26.65 17.18 ± 24.46 < 0.0001 < 0.0001 l-taurine 1 12 4.81 ± 27.78 -1.14 ± 33.47 0.7997 aspartic acid 1 10 5.02 ± 28.95 -4.60 ± 18.90 0.2308 glutathione 1 60 -7.06 ± 25.45 15.09 ± 26.78 < 0.0001 0.6537 tryptophan 1 2 4.71 ± 28.11 -25.06 ± 33.09 0.1961 maca 1 6 4.22 ± 27.98 3.93 ± 36.88 0.5648 any treatment 103 -16.15 ± 22.39 7.17 ± 27.93 0.0028 * α-lipoic acid omitted from multivariable analysis for collinearity. negri_stesura seveso 28/09/17 10:23 pagina 214 215archivio italiano di urologia e andrologia 2017; 89, 3 effect of superoxide dismutase supplementation on sperm dna fragmentation not vary significantly in the three groups, except for sdf, showing an improvement in the group receiving sod (table 3b). in particular the post-hoc evalution of sdf variation test power (by cohen’s d) is greater than 0.98 confirming the adeguacy of sample size. in greater detail, only one patient in the control group showed a spontaneous improvement in sdf (6%), compared to 16/48 (33%) of those taking various oral antioxidant suppletable 3a. clinical and seminal parameters compared to the percentage change in sdf. the δ are calculated as (post-pre)/pre and expressed as a percentage. table 3b. clinical and seminal parameters in the three groups. classic seminal parameters (total sperm count, progressive motility, and morphology) do not vary significantly in the three groups, except for viability and sdf, showing an improvement in the group receiving sodthe δ are calculated as (post-pre)/pre and are expressed as a percentage. sdf variation > 10% unchanged > 10% p deterioration improvement n 36 34 48 male age (yrs.) 38.6 ± 4.2 39.9 ± 4.8 39.6 ± 6.5 0.640 female age (yrs.) 35.2 ± 4.3 34.8 ± 4.2 35.1 ± 4.4 0.923 male bmi 25.5 ± 2.9 26.1 ± 2.8 25.5 ± 3.2 0.364 total orchidometry (ml) 30.6 ± 7.9 27.8 ± 8.8 27.8 ± 7.9 0.302 infertility duration (months) 32.8 ± 28.6 33.7 ± 22.7 32.5 ± 23.7 0.587 active smoking 6 (16.67%) 7 (20.59%) 14 (29.17%) 0.419 fsh (mu/ml) 5.20 ± 2.90 5.87 ± 3.53 5.28 ± 2.87 0.512 medication use 6 (16.67%) 6 (17.65%) 13 (27.08%) 0.471 comorbidities 8 (22.22%) 9 (26.47%) 18 (37.50%) 0.296 antioxidants < 0.001 none 8 (22.22%) 6 (17.65%) 1 (2.08%) other 21 (58.33%) 11 (32.35%) 16 (33.33%) sod 7 (19.44%) 17 (50.00%) 31 (64.58%) baseline semen volume (ml) 3.47 ± 1.40 3.65 ± 1.68 3.45 ± 1.50 0.918 δ semen volume (%) 11.5 ± 28.7 2.5 ± 34.7 -5.6 ± 28.1 0.025 baseline total sperm count (106) 80.2 ± 79.1 57.1 ± 52.2 72.4 ± 56.3 0.299 δ total sperm count (%) 68.4 ± 163.1 18.3 ± 77.5 16.0 ± 68.9 0.307 baseline tpmc (106) 17.1 ± 19.7 10.3 ± 9.5 14.1 ± 14.8 0.4971 δ tpmc (%) 98.6 ± 179.1 27.0 ± 124.1 83.9 ± 269.7 0.204 baseline progressive motility (%) 19.8 ± 11.5 17.0 ± 7.7 18.3 ± 10.8 0.6110 δ progressive motility (%) 11.8 ± 55.0 -3.4 ± 43.4 43.3 ± 115.6 0.074 baseline normal forms (%) 3.36 ± 2.17 3.32 ± 2.40 3.71 ± 1.82 0.2039 δ normal forms (%) 10.2 ± 54.0 25.0 ± 70.0 54.6 ± 161.0 0.717 baseline viability 63.4 ± 11.6 65.5 ± 8.2 62.4 ± 14.2 0.8646 δ viability (%) 2.9 ± 21.9 -0.4 ± 12.5 20.0 ± 47.5 0.001 no drugs other drugs sod p n 15 48 55 male age (yrs.) 38.7 ± 4.4 38.9 ± 5.5 40.0 ± 5.6 0.454 female age (yrs.) 34.3 ± 5.2 35.1 ± 3.5 35.2 ± 4.6 0.709 male bmi 24.8 ± 2.1 25.6 ± 2.7 26.0 ± 3.4 0.441 total orchidometry (ml) 30.7 ± 7.4 29.6 ± 8.9 27.3 ± 7.7 0.421 infertility duration (months) 34.7 ± 21.5 32.3 ± 24.8 33 ± 26.1 0.754 active smoking 1 (6.67%) 14 (29.17%) 12 (21.82%) 0.202 fsh (mu/ml) 4.39 ± 1.16 5.72 ± 3.59 5.46 ± 2.91 0.464 medication use 3 (20.00%) 12 (25.00%) 10 (18.18%) 0.703 comorbidities 3 (20.00%) 13 (27.08%) 19 (34.55%) 0.521 baseline sdf 34.9 ± 12.5 37.0 ± 9.5 40.0 ± 12.6 0.3728 δ sdf (%) 16.1 ± 22.4 4.3 ± 27.5 -17.2 ± 24.5 < 0.001 baseline semen volume (ml) 3.64 ± 1.26 3.60 ± 1.55 3.40 ± 1.56 0.639 δ semen volume (%) 8.7 ± 27.5 2.5 ± 31.4 -0.5 ± 31.5 0.596 baseline total sperm count (106) 76.4 ± 90.0 62.4 ± 50.8 75.7 ± 64.9 0.825 δ total sperm count (%) 52.1 ± 78.2 45.5 ± 145.4 16.1 ± 75.7 0.165 baseline tpmc (106) 15.1 ± 15.7 11.8 ± 11.7 15.5 ± 17.9 0.857 δ tpmc (%) 74.6 ± 144.5 63.1 ± 155.4 79.0 ± 263.4 0.644 baseline progressive motility (%) 22.2 ± 13.4 17.7 ± 8.5 17.9 ± 10.6 0.473 δ progressive motility (%) 11.1 ± 57.1 9.2 ± 49.2 32.2 ± 111.7 0.529 baseline normal forms (%) 2.53 ± 1.41 3.60 ± 2.16 3.65 ± 2.15 0.229 δ normal forms (%) 45.5 ± 98.1 15.1 ± 58.9 44.9 ± 150.3 0.483 baseline viability 68.1 ± 11.0 63.6 ± 10.1 62.4 ± 13.5 0.161 δ viability (%) -5.8 ± 11.4 6.8 ± 17.8 14.6 ± 46.4 0.029 negri_stesura seveso 28/09/17 10:23 pagina 215 archivio italiano di urologia e andrologia 2017; 89, 3 l. negri, r. benaglia, e. monti, e. morenghi, a. pizzocaro, p.e. levi setti 216 ments and 31/55 (56%) of those taking oral antioxidant supplements with sod. nevertheless, it should be considered that although fragmentation can also improve spontaneously in patients with risk factors for comorbidities or drug therapy, the positive impact of the integrator administration persists, succeeding in combatting the oxidative damage caused by free radicals and highly reactive oxygen species, which have been identified as the agents responsible for sperm dna damage. discussion it is believed that about 80 million people worldwide are affected by the inability to have children (20), with male factor subfertility accounting for up to 50% of these cases (21). some 30-80% of male factor subfertility cases are believed to be due to the damaging effects of oxidative stress (21). oral supplementation with antioxidants is thought to improve sperm quality by reducing oxidative stress (22) and these products are widely available and inexpensive when compared to other fertility treatments. this suggestion is so widely spread by the media that, currently, a high percentage of couples turning to our fertility center are already taking antioxidants, prescribed by gynecologists, general practitioners, or even self-prescribed. at present, several tests have been developed to evaluate sperm dna fragmentation, e.g. tunel (tdt-mediated dutp nick-end labeling) (23), comet assay (24), sperm chromatin structure assay (scsa) (25) and sperm chromatin dispersion test (scd) (16). while tunel and comet assay directly detect dna damage (the latter also finding single and double strand breaks), scsa and scd measure dna fragmentation after a mild denaturation process. tunel and scsa employ flow cytometry, with little intra-technician variability. however, they are complex, time consuming, and expensive (flow cytometer). comet assay is not suited for rapid diagnosis and requires highly specialized personnel to analyze the results. the scd test is a simple and inexpensive technique, but could have higher intra-individual variation. there are currently six meta-analyses of antioxidant treatment for male infertility available (22, 26-30) and all report improvements in pregnancy rate and sperm quality after therapy. ross et al. (2010) (29) report improvement in at least one semen variable in 13 out of 17 studies analyzed. in a more recent cochrane meta-analysis (22), comprising 48 studies, 4.179 men were analyzed; of these, 2.466 received oral antioxidant supplementation and 1.713 received no treatment. the patient population was made up of the male partners of couples who had attended a fertility clinic. surprisingly, only two trials performed on a total of 100 patients (64 + 36) analyzed the effects of oral antioxidant supplementation on sdf (31, 32) and both observed a reduction in sdf when compared to placebo (mean difference: -13.85, 95% ci -17.28 to -10.41, p < 0.00001). one investigator used vitamin c + vitamin e, while the other used docosahexaenoic acid (dha). menezo et al. (2007) (33) (not included in the meta-analysis) treated 58 men with an sdf > 15% with oral antioxidant therapy (vitamins c and e, beta carotene, zinc and selenium) for 13 weeks and reported a significant improvement in dna fragmentation (-19.1%, p < 0.0004). our data are not all consistent with those reported in literature, not providing a significant improvement in classic seminal parameters (total sperm count, progressive motility, and morphology). basic semen parameters do not vary significantly in the three groups (antioxidants, fertiplus® sod, no medication), except as regards viability. the reasons may be related to the older age of our population (39.4 ± 5.4 yrs.), which reflects the later age at which couples are deciding to have children. secondly, the selection of patients was as close as possible to everyday real-life clinical practice. indeed, we only excluded patients with varicocele and seminal infections, as diseases associated with sdf, but susceptible to effective specific treatment (antibiotics and surgery). patients with antisperm antibodies were excluded as in other studies, although the two available cases did not have a high degree of dna fragmentation (data not shown). most of the studies published to date did not enroll men with a considerable number of risk factors, such as smoking, recreational drug use, systemic diseases, longterm medication use, alcohol, oligozoospermia, high serum gonadotropins, previous orchidopexy, and anatomic abnormalities of the genital tract. while this approach permits a better appreciation of the effect of medical treatment, it also drastically reduces the number of candidates for oral antioxidant treatment. at our fertility center, perfectly healthy, young patients without any bad habits are really very few. our selection criteria could, therefore, justify unsatisfactory results in terms of classic sperm parameters. antioxidants not containing sod led to an improvement of at least 10% in tpmc in 43.8% patients vs 45.5% in men treated with fertiplus® sod (n.s.). in the same two groups sperm morphology increased by at least 10% to 31.3% and 36.4%, n.s.), respectively, while oral antioxidant supplementation proved effective in reducing sperm dna fragmentation. as mentioned in the results section, only one patient in the control group showed a spontaneous improvement in sdf (6%), compared to 16/48 (33%) of those taking various oral antioxidant supplements and 31/55 (56%) of those taking oral antioxidant supplements with sod (p < 0.0001). from a clinical viewpoint, the possibility to reduce sperm dna fragmentation in 56% of otherwise untreatable infertile patients is certainly an ethically and economically sound approach. we must therefore consider that almost one quarter of our patients had untreatable diseases, requiring long-term treatment; 13 had high fsh (7.6-21.1 mu/ml), 17 had a testicular volume of less than 12 ml, 10 had class 1 obesity, and 27 were active smokers. nevertheless, we were surprised to observe that the presence of co-morbidities, signs of testicular impairment and bad habits did not affect the chances of improving dna fragmentation. while oral sod supplementation seems to work better than any other antioxidant molecules analyzed, it remains unclear why the benefit is observed in just over half of the cases treated. one could assume that 2 months intake are insufficient to fully express the therapeutic effect. another possible explanation may be that antioxidant therapy could be ineffective if given to males whose subfertility is not caused by oxidative stress (34) and, in this respect, no negri_stesura seveso 28/09/17 10:23 pagina 216 217archivio italiano di urologia e andrologia 2017; 89, 3 effect of superoxide dismutase supplementation on sperm dna fragmentation patients underwent an objective test indicating that oxidative stress was the key factor behind their condition. our study has a number of limitations. firstly, it is retrospective, meaning that neither a causality hypothesis nor mechanistic models can be drawn up due to the nature of our study. secondly, the data derive from patients entering an ivf-icsi program, who could have different characteristics from the general male population. in addition, another limitation is the low number of subjects examined. lastly, the seminal os levels were not assessed. although to be confirmed in a randomised trial this result is a new and relevant data in patient’s counselling. conclusions oral sod supplementation appears to produce a better reduction in sperm dna fragmentation in the infertile population than other commonly used antioxidant formulations. when used in unselected infertile patients, representative of daily clinical practice, fertiplus® sod reduces dna fragmentation in 56% of cases compared to 33% of cases using other antioxidant formulations. therefore, given the absolute tolerability of the product and the affordable cost, this approach is to be considered clinically and ethically acceptable. author contributions nl provided the study design concept, drafted the article and interpreted the data. nl, rb and ap recruited the subjects, compiled the medical records, performed physical examinations and the color-doppler ultrasound evaluations. em performed the scd test and semen analyses em performed the statistical analyses pels made a substantial contribution to critically revising the article. ethics approval and consent to participate we declare that our study has been conducted according to the helsinki declaration on clinical research and to the ethical code on animal research set forth by who (who chronicle 1985; 39:51) and that has been approved by irccs istituto clinico humanitas independent ethics committee, reference number 1/17, on january 17, 2017. a written informed consent was obtained from each participant before study. references 1. spano m, bonde j, hjøllund hi, et al. sperm chromatin damage impairs human fertility. fertil steril. 2000; 73:43-50. 2. bungum m, humaidan p, axmon a, et al. sperm dna integrity assessment in prediction of assisted reproduction technology outcome. hum reprod. 2007; 22:174-9. 3. osman a, alsomait h, seshadri s, et al. the effect of sperm dna fragmentation on live birth rate after ivf or icsi: a systematic review and meta-analysis. rbm online. 2015; 30:120-7. 4. lewis se, aitken rj. dna damage to spermatozoa has impacts on fertilization and pregnancy. cell tissue res. 2005; 322:33-41. 5. erenpreiss j, elzanaty s, giwercman a. sperm dna damage in men from infertile couples. asian j androl. 2008; 10:786-90. 6. saleh ra, agarwal a, nelson de, et al. increased sperm nuclear dna damage in normozoospermic infertile men: a prospective study. fertil steril. 2002; 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94:s235-236. 33. menezo yj, hazout a, panteix g, et al. antioxidants to reduce sperm dna fragmentation: an unexpected adverse effect. rbm online. 2007; 14:418-21. 34. bolle p, evandri mg, saso l. the controversial efficacy of vitamin e for human male infertility. contraception. 2002; 65:313-5. correspondence luciano negri, md luciano.negri@humanitas.it renzo benaglia, md renzo.benaglia@humanitas.it emanuela monti, md emanuela.monti@humanitas.it paolo e. levi setti, md paolo.levi_setti@humanitas.it humanitas research hospital, department of gynecology, division of gynecology and reproductive medicine, humanitas fertility center, rozzano-milan, italy emanuela morenghi, md emanuela.morenghi@humanitas.it biostatistics unit, humanitas research hospital, rozzano-milan, italy alessandro pizzocaro, md alessandro.pizzocaro@humanitas.it endocrinology unit, irccs, humanitas research hospital, rozzano-milan, italy negri_stesura seveso 28/09/17 10:23 pagina 218 archivio italiano di urologia e andrologia 2016; 88, 4320 original paper testicular sparing surgery in small testis masses: a multinstitutional experience andrea b. galosi 1, paola fulvi 1, andrea fabiani 2, lucilla servi 2, alessandra filosa 3, luca leone 1, angelo marronaro 4, enrico caraceni 4, rodolfo montironi 5 1 clinica urologica, dipartimento scienze cliniche e odontostomatologiche, università politecnica delle marche, ao ospedale riuniti, ancona, italy; 2 uoc urologia macerata, area vasta 3, asur marche, italy; 3 uoc anatomia patologica, area vasta 3, asur marche, italy; 4 uoc urologia, civitanova marche, area vasta 3, asur marche, italy; 5 uoc anatomia patologica, università politecnica delle marche, ancona, italy. introduction: the incidence of benign testicular tumors is increasing in particular in small lesion incidentally found at scrotal ultrasonography. primary aim of this study was to perform radical surgery in malignant tumor. secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery in benign lesions. materials and methods: in this multicenter study, we reviewed all patients with single testis lesion less than 15 mm at ultrasound as main diameter. we applied the diagnostic-therapeutic pathway described by sbrollini et al. (arch ital urol androl 2014; 86:397) which comprises: 1) testicular tumor markers, 2) repeated scrotal ultrasound at the tertiary center, 3) surgical exploration with inguinal approach, intraoperative ultrasound, and intraoperative pathological examination. definitive histology was reviewed by a dedicated uro-pathologist. results: twenty-eight patients completed this clinical flowchart. the mean lesion size was 9.3 mm (range 2.5-15). testicular tumor markers were normal except in a case. intraoperative ultrasound was necessary in 8/28 cases. we treated 11/28 (39.3%) with immediate radical orchiectomy and 17/28 (60.7%) with testis-sparing surgery. definitive pathological results were: malignant tumor in 6 cases (seminoma), benign tumor in 10 cases (5 leydig tumors, 2 sertoli tumors, 1 epidermoid cyst, 1 adenomatoid tumor, 1 angiofibroma), benign disease in 11 (8 inflammation with haemorragic infiltration, 2 tubular atrophy, 1 fibrosis), and normal parenchyma in 1 case. we observed a good concordance between frozen section examination and definitive histology. any malignant tumor was treated conservatively. any delayed orchiectomy was necessary based on definitive histology. conclusions: the incidence of benign lesions in 60% of small testis lesions with normal tumor markers makes orchiectomy an overtreatment. testicular sparing surgery of single testicular nodules below 15 mm is a safe option, but requires a standardized pathway in diagnosis. our pathway has shown good reliability and security profile to be applied in a multicenter management for small scrotal masses. our study has shown the reliability of the diagnostic-therapeutic pathway in the management of single testicular masses. the higher incidence of benign lesions in 60% of patients makes often orchiectomy an overtreatment. key words: testis neoplasms; ultrasound; surgery; small testis masses. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. introduction scrotal ultrasound increased detection of small and not palpable testicular lesions. the incidence of benign tumors is clinically relevant in lesions smaller than 15 mm (1, 2). this suggest organ-sparing surgery rather than radical orchiectomy (3, 4). the first step to diagnose testicular cancer is the clinical examination, principally with scrotal palpation, that can give to the physician the first suspect of tumor. but it is possible only for masses which have a large volume. consequently patients must undergo scrotal ultrasound, that confirms the presence of the neoplasia. the definitive histologic diagnosis of testicular cancer can only be achieved through exploration and inguinal orchiectomy and subsequent histological examination (5). in fact, the gold standard for the treatment of palpable testicular lesions is inguinal exploration and orchiectomy. meanwhile, the diagnostic-therapeutic pathway for small and not palpable small testicular lesions exclusively identified by ultrasonography is still under debate. according to international guidelines testis-sparing surgery can be performed only in special and selected cases: bilateral testicular tumors (synchronous bilateral testicular tumors or metachronous contralateral tumors) or monorchid patient with normal pre-operative testosterone levels when tumor volume is less than 30% of testicular volume (2-4). for some years the testis sparing surgery is being practiced with success, with good oncologic out-comes, but there is not currently internationally agreed protocol for management and treatment of small non-palpable testicular masses. our team published a flow chart including ultrasound diagnosis and surgical management of lesion with maximum diameter of 15 mm (6). this protocol was established with agreement of pathology, radiology, urology and oncology units. however application of this clinical protocol is not yet published. primary aim of this study was to perform radical surgery in all malignant tumor. secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery only in benign lesions. doi: 10.4081/aiua.2016.4.320 presented at 20th national congress sieun, sciacca 2016 galosi3_stesura seveso 09/01/17 10:43 pagina 320 321archivio italiano di urologia e andrologia 2016; 88, 4 testicular sparing surgery materials and methods in this multicenter study, we recruited patients with single testicular lesion of 15 mm as main diameter, based on scrotal ultrasound. we applied the diagnostic-therapeutic pathway described by sbrollini et al. (6) which comprises: 1) normal testicular tumor markers, 2) repeated scrotal ultrasound at the tertiary center to confirm size, localization and ultrasound characteristics, 3) surgical exploration with inguinal approach using intraoperative ultrasound, and intraoperative pathological examination. the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery is summarized in figure 1. definitive histology was reviewed by a dedicated uro-pathologist. after their identification, the nodule was removed and 3 additional biopsies were perfomed in surround normal-looking parenchyma. if the pathologist considered the nodule size with enough amount of tissue, the intraoperative frozen was done, otherwise if not the specimen was sent for definitive histology. in case of benign or doubtful histology on frozen section, the specimen were submitted to definitive exam. delayed orchiectomy was suggested only if malignant neoplasia was confirmed. in case of testicular intraepithelial neoplasia, patients were addressed to radiotherapy or orchyfuniculectomy. the protocol suggests that small masses (< 8 mm) are sent to the pathologist for histological definitive examination, avoiding the extemporaneous examination, which due to the small volume of the tumor, might subtract material necessary for definitive histological diagnosis. the masses of diameter between 8 and 15 mm are sent to the pathologist for the extemporaneous histological examination of frozen sections, which determines: histological nature, size and relationship with the surrounding pa renchyma. all testicular masses were submitted to definitive histological examination including im munohistochemistry. results we recruited 28 patients, mean age was 38 years (18-68) and mean lesion size was 9.3 mm (range 2.5-15). baseline clinical features are summarized in table 1 and 2. oncological testicular markers were normal except in a case who had small increase beta-hcg (9.0). intraoperative ultrasound was necessary in 8/28 cases to identify the exact cancer location. in particular, 10/28 (36%) patients had testicular nodules smaller than 8 mm and 18/28 (64%) between 8 and 15 mm (figure 3-6). concerning nodules smaller than 8 mm, 2/10 underwent definitive histological examination (because of low volume of the sample). primary aim of this study was to perform radical surgery in malignant tumor. we performed 11 table 1. overall baseline clinical and pathological characteristics of all patients (tss = testis sparing surgery, iro = intraoperative orchiectomy). case age size (mm)/ tumor definitive intraoper. tipe of side markers histology histology surgery 1 25 6/left normal sertoli tumor not done tss 2 33 8/right normal seminoma malignant io 3 25 5/right normal leydig tumor benign tss 4 41 15/right normal haemorrhagic infiltration no tumor io 5 37 10/left normal haemorrhagic infiltration no tumor tss 6 53 12/left normal fibrosis and normal parenchyma no tumor tss 7 53 11/left normal haemorrhagic infiltration no tumor tss 8 57 10/right hcg 9 haemorrhagic infiltration no tumor tss 9 47 11/right normal angiofibroma benign tss 10 34 15/right normal epidermoid cyst benign tss 11 39 15/right normal normal parenchyma no tumor io 12 34 10/left normal fibrosis with tubular atrophy no tumor tss 13 68 10/left normal leydig tumor benign tss 14 20 8/left normal haemorrhagic infiltration no tumor tss 15 38 7/left normal haemorrhagic infiltration no tumor io 16 18 5/left normal haemorrhagic infiltration no tumor io 17 36 4/left normal seminoma and intratubular neoplasia malignant io 18 42 6/right normal seminoma and intratubular neoplasia malignant io 19 23 6,5/left normal leydig tumor benign tss 20 27 6/right normal leydig tumor benign tss 21 38 2.5/right normal sertoli tumor benign tss 22 30 2.7/right normal seminoma and intratubular neoplasia malignant io 23 60 8.8/right normal adenomatoid tumor not done tss 24 45 13/left normal haemorrhagic infiltration no tumor tss 25 30 14/right normal leydig tumor benign tss 26 19 10/left normal seminoma malignant io 27 46 15/right normal fibrosis with tubular atrophy no tumor io 28 43 15/right normal seminoma malignant io table 2. summary of results. total patients 28 mean age 38 (18-68) mean lesion size (mm) 9.3 (2.5-15) high alfa feto protein 0 high lattic dehidrogenasi 0 high beta-human corionic gonadot. 1 (3.6%) intraoperative ultrasound 8 (28.6%) intraoperative orchiectomy 11 (39.3%) delayed orchiectomy 0 testis sparing surgery 17 (60.7%) malignant tumor 6 (21.4%) benign tumor 10 (35.7%) benign disease 11 (39.3%) normal parenchyma 1 (3.6%) (39.3%) radical orchiectomy and 17 (60.7%) testis-sparing procedures. secondary aim was to verify the efficacy of the diagnostic-therapeutic pathway recently adopted in management of small masses with testis sparing surgery in benign lesions: any delayed orchiectomy was necessary and any radical surgery was performed in benign lesions (figure 2). eight of 10 nodules smaller than 8 mm underwent frozen section examination. all the 18 nodules between 8 and 15 have been subjected to frozen section histological examinagalosi3_stesura seveso 09/01/17 10:43 pagina 321 archivio italiano di urologia e andrologia 2016; 88, 4 a.b. galosi, p. fulvi, a. fabiani, l. servi, a. filosa, l. leone, a. marronaro, e. caraceni, r. montironi 322 tion. 19/26 masses subjected to frozen section examination resulted benign tumors: 14/19 of them have been treated conservatively, while 5/19 underwent intraoperative radical orchiectomy. we observed a good concordance between frozen section examination and definitive histology, without any false positive results at frozen section. one of 26 mass resulted as healthy parenchyma. six of 26 masses resulted as malignant tumors and underwent radical orchiectomy. we have had no cases of benign tumor associated with testicular intraepithelial neoplasia. definitive pathological results were: malignant tumor in 6 cases (seminoma), benign tumor in 10 cases (5 leydig tumors, 2 sertoli tumors, 1 epidermoid cyst, 1 adenomatoid tumor, 1 angiofibroma), benign disease in 11 (8 inflammation with hemorragic infiltration, 2 tubular atrophy, 1 fibrosis), and normal parenchyma in 1 case (table 2). discussion our study has shown the reliability of the diagnostic-therapeutic pathway suggested by sbrollini et al. in the management of single testicular masses below 15 mm. the higher incidence of benign lesions in this group of tumors (60%) makes often orchiectomy an overtreatment. we observed a complete concordance between frozen section examination and definitive histology regarding malignant cell. previous experience in high volume centers had same results with dedicated pathologist (7, 8), pointing out that in our center there was always a dedicated uro-pathologist too. in our experience the definitive intraoperative diagnosis of non-palpable testicular lesions was always reliable even in very small lesions (< 8 mm). however in case of uncertain diagnosis or small tissue, the definitive histology is recommended. this protocol is useful also for centres were the frozen section is not available: very small lesions could be managed with definitive histology and any subsequent decision can be delayed. in our experience, intraoperative histology on frozen section was possible in 8 of 10 small nodules with diameter less than 8 mm, figure 1. diagnostic and surgical flow chart for management of not-palpable testis masses modified from sbrollini et al.(6). figure 2. oncological results in 28 patients submitted to surgery according to flow chart. galosi3_stesura seveso 09/01/17 10:43 pagina 322 323archivio italiano di urologia e andrologia 2016; 88, 4 testicular sparing surgery without any false positive results and without wasting tissue for the final histology and ancillary immunohistochemistry. only 20% of the specimens were considered unsuitable for frozen section analysis. unusual malignant tumor has been observed also arising from stromal cells tumors (e.g. malignant leydig cells tumors, malignant sertoli cells tumors). the differential diagnosis may be not easy among malignant and benign testis tumor such as sertoli tumor, leydig cells tumors, epidermoid cyst, brenner tumor, adenomas of the ducts. testis sparing surgery is adopted also in selected cases in children (9). during surgery the surgeon should use loop for optical magnification and use palpation to detect the nodule. in case of soft nodule, were the palpation is not helpful, the intraoperative ultrasound is mandatory. this protocol should be shared in the first instance by the involved specialists, such as the urologist, as an active operator in the operating room, the pathologist, the oncologist and the radiologist. high resolution and high frequency ultrasound (12 mhz) with adequate focusing, fine-tunig and grayscale regulation should be ready available in operating room. machine with low resolution and frequency (8 mhz) with inadequate tuning are not enough to have a good imaging and could be misleading (10). the patient, before being subjected to this type of approach has to be informed in detail about the various benefits, risks and implications, first of all the possibility of being subjected to a second surgery as soon as the urologist is in possession of the definitive histological result. conclusion testicular sparing surgery of single testicular nodules below 15 mm is a safe option, but requires a standardized figure 6. leydig tumor with irregular bordered and irregular content with very small anechoic lacunas. figure 5. epidermoid cyst with circular calcifications (a longitudinal view; b axial). the follow-up ultrasound: 8 years later after testis sparing surgery (c, arrows show surgical scar). figure 4. cyst of the testis (a) that was only observed, compared to irregular solid hypoecoic (b, arrowhead) confirmed at the referral center before surgey, that contained a sertoli tumor. figure 3. small solid hypoechoic lesion (5 x 3 mm) well defined compared to normal parenchyma: leydig cell tumor. galosi3_stesura seveso 09/01/17 10:43 pagina 323 archivio italiano di urologia e andrologia 2016; 88, 4 a.b. galosi, p. fulvi, a. fabiani, l. servi, a. filosa, l. leone, a. marronaro, e. caraceni, r. montironi 324 pathway in diagnosis. our pathway has shown good reliability and security profile to be applied in a multicenter management for small scrotal masses. our study has shown the reliability of the diagnostic-therapeutic pathway in the management of single testicular masses. the higher incidence of benign lesions in 60% of patients makes testis-sparing surgery a reliable option, where orchiectomy could be considered an overtreatment. references 1. ates f, malkoc e, zor m, et al. testis-sparing surgery in small testicular masses not suspected to be malignant. clin genitourin cancer. 2016; 14:e49-53. 2. shilo y, zisman a, raz o, et al. testicular sparing surgery for small masses. urol oncol. 2012; 30:188-91. 3. brunocilla e, gentile g, schiavina r, et al. testis-sparing surgery for the conservative management of small testicular masses: an update. anticancer res. 2013; 33:5205-10. 4. palermo g, antonucci m, recupero sm, et al. focal surgery in testis cancer: current state of the art. urologia 2013; 80:290-6. 5. galosi ab, lacetera v, muzzonigro g. clinica delle malattie testicolari di interesse ecografico. urologia 2008; 75,4, s12: 59-66. 6. sbrollini g, mazzaferro d, ettamimi a, et al. diagnostic-therapeutic pathway for small lesions of the testis. arch ital urol androl. 2014; 86:397-9. 7. fabiani a, filosa a, pieramici t, mammana g. testicular nodules suspected for malignancy. does the pathologist make the difference for organ-sparing surgery? anal quant cytopathol histpathol. 2015; 37:147-52. 8. steiner h, höltl l, maneschg c, et al. frozen section analysisguided organ-sparing approach in testicular tumors: technique, feasibility, and long-term results. urology. 2003; 62:508-13. 9. friend j, barker a, khosa j, samnakay n. benign scrotal masses in children: some new lessons learned. j pediatr surg. 2016; 51:1737-42. 10. martino p, galosi ab, bitelli m, et al. imaging working group societa italiana urologia and societa italiana ecografia urologica andrologica nefrologica. practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. correspondence andrea b galosi, md galosiab@yahoo.it paola fulvi, md, resident in urology paola.fulvi19@gmail.com luca leone, resident in urology lucaleone85@virgilio.it clinica urologica, dipartimento science cliniche e odontostomatologiche,università politecnica delle marche, ao ospedale riuniti, ancona, italy andrea fabiani, md urologist andreadoc1@libero.it lucilla servi, md urologist uoc urologia macerata, area vasta 3, asur marche, macerata, italy alessandra filosa, md pathologist uoc anatomia patologica, area vasta 3, asur marche, italy angelo marronaro, md urologist enrico caraceni, md urologist ecarace@libero.it uoc urologia, civitanova marche, area vasta 3, asur marche, civitanova marche, italy rodolfo montironi, md, pathologist r.montironi@univpm.it uoc anatomia patologica, università politecnica delle marche, ancona, italy galosi3_stesura seveso 09/01/17 10:43 pagina 324 archivio italiano di urologia e andrologia 2020; 92, 130 original paper influence of dietary energy intake on nephrolithiasis a meta-analysis of observational studies gianpaolo perletti 1,2, vittorio magri 3, pietro manuel ferraro 4,5, emanuele montanari 6, alberto trinchieri 7 1 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 2 faculty of medicine and medical sciences, ghent university, belgium; 3 urology secondary care clinic, asst-nord, milan, italy; 4 u.o.c. nefrologia, fondazione policlinico universitario a. gemelli irccs, roma, italy; 5 università cattolica del sacro cuore, roma, italy; 6 department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy; 7 school of urology, university of milan, milan, italy. objective: obesity has been associated with an increased risk of kidney stone formation. the presence of obesity is due to an imbalance between energy intake and energy consumption resulting from physical activity and resting metabolic rate. the purpose of this meta-analysis was to assess the differences in dietary energy intake levels between patients developing urinary stones versus healthy individuals. materials and methods: medline/pubmed and embase databases search was performed using the terms “urolithiasis”, “kidney stones*”, “calcul*”, “energy”, “calor*”, “intake”, “food”, “kilojoule/kjoule”, “kilocal*/kcal” from january 1st, 2000, and were assessed as up to date on september 30th, 2019. results: after having screened 1.782 records, four studies were included in the meta-analysis. the total population was 467.063, including 453.078 healthy men and/or women and 13.985 men and/or women affected by nephrolithiasis. when energy intake data were pooled irrespective of the sex of participants, mean calory intake values were significantly higher in nephrolithiasis patients, compared to healthy individuals. the mean difference (md) was 39.16 kcal (95% ci 18.53 to 59.78, p = 0.0002, random-effects model, inverse-variance weighing). the odds ratio for this comparison – calculated from the standardized mean difference – is significant (or = 1.946; 95% ci: 1.869 to 5.561). conclusions: patients affected by urolithiasis show a significantly higher energy intake in various patient populations (usa, china and korea) including subjects of both sexes. the relevance of this finding should be confirmed by studies in populations showing different and diverse dietary patterns, and by evaluating energy consumption linked to physical activity and metabolic rate in renal stone formers. key words: urinary calculi; energy intake; obesity; nutrition; diet. submitted 14 october 2019; accepted 29 february 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.30 introduction a recent meta-analysis (1) confirmed that obesity is associated with an increased risk of renal stone formation. however, it has not been clarified which of the factors determining obesity are directly implicated in increasing the risk of formation of kidney stones. in fact, obesity is due to the altered balance between dietary energy intake and energy consumption resulting from physical activity and resting metabolic rate. the meta-analysis by aune et al. (1) showed that renal stone formers do not have a lower level of physical activity when compared to non-stone forming subjects, but the impact of dietary energy intake on the risk of stone formation was not assessed in that study. the purpose of this meta-analysis was to investigate whether there were any differences between dietary energy intake levels in patients affected by urolithiasis versus healthy individuals, thus pointing to a possible association between dietary energy intake and the risk of renal stone formation. materials and methods types of studies we included only full-text articles written in english, reporting prospective cohort studies evaluating the relationship between daily dietary energy intake and the incidence of kidney stones in subjects of any age, men and/or women. we excluded case-control studies. primary outcomes the single outcome considered for this review is the assessment of differences in dietary energy intake (mean daily kilocalories intake) between subjects developing kidney stones versus healthy individuals. search strategy and study selection records were identified by searching the medline/pubmed, cochrane and embase databases, using the terms urolithiasis, kidney stone*, calcul*, energy, calor*, intake, food, kilojoule/kjoule kilocal*/kcal. hand searching was performed by browsing the references of published papers on the matter. database searches were performed starting from january 1st, 2000, and were assessed as up to date on december 31st, 2019. this time frame has been chosen according to the meta-analysis of aune et al. who selected studies published after 2000. data extraction and analysis data extraction was performed by two independent perletti_stesura seveso 01/04/20 18:54 pagina 30 31archivio italiano di urologia e andrologia 2020; 92, 1 influence of dietary energy intake on nephrolithiasis a meta-analysis of observational studies researchers (gp, at). when energy intake data in women (w) and men (m) were presented separately (e.g. the shu 2017 study) (2) the combined mean energy intake and combined variance of the entire population (women and men) were calculated with the formulas: x = (nwxw+nmxm)/(nw+nm) and s = nwsw = nmsm+nw(xw-x)^2+nm(xm-x)^2/(nw+nm) (n = number of observations, x = mean, and s = variance). when energy intake data were expressed as median kcal intake and interquartile ranges (iqrs) (e.g., the kim 2018 study) (3), data were converted into means and standard deviations according to wan et al. (4). differences in energy intake between nephrolithiasis patients and healthy subjects to analyze differences in continuous data from the included studies (average daily energy intake, expressed as kilocalories/day) we calculated crude mean differences (md) and standardized mean differences (smd). odds ratios for the comparisons were calculated with the formula: or = antilnsmd*π/√3. analysis included the calculation of 95% confidence intervals (ci) and z statistics. for meta-analysis we adopted a random-effects model and the inverse variance weighing method. heterogeneity was assessed by calculating the i^2 value. pooled analysis was performed using the revman 5.3 software. funnel plots, the egger’s and begg’s tests, and “trim and fill” effect size adjustments were performed with the meta-essentials excel workbook 1.0 (erasmus research institute of management, erasmus university, rotterdam, the netherlands). optimal information size for metaanalysis was calculated with the c*power 3.1 software (assuming as an α level equal to 0.05 and 1-β error equal to 0.95). assessment of risk of bias in included studies quality assessment the risk of bias (rob) of included studies was assessed independently by two researchers (gp, at). this meta-analysis included non-randomized studies, and the cochrane rob tool had limited application. we identified two main possible biases for the included studies: recall bias and reporting bias. since recall and reporting biases may overlap to some extent, we adopted the following definitions: in the included studies, recall bias may have occurred when study participants forgot to recall past episodes of kidney stones (or the number of such episodes) during follow-up visits, whereas reporting bias may have occurred when patients gave inaccurate account of their food and energy intake by selectively revealing or omitting essential information. the risk of bias was classified as low, high or unknown according to cochrane criteria (5). publication bias and small-study effect were investigated by visually assessing funnel plots and by performing both the egger’s regression test and the begg’s rank correlation analysis. the “trim and fill” missing study imputation approach was applied to funnel plots and adjusted overall effect sizes were calculated according to duval and tweedie (6). the quality of evidence resulting from analysis of pooled data was evaluated according to grade criteria (7). results description of studies after having screened 1.782 records, four studies (2, 3, 8, 9) including data from 6 cohorts were included in the meta-analysis (table 1). the total population was 467.063, including 453.078 healthy men and/or women and 13.985 men and/or women affected by nephrolithiasis. from the studies by shu et al. (2) and sorensen et al. (8) the data regarding women only could be extracted (total: 153.391; healthy 149.548; nephrolithiasis: 3.843). men strata could be extracted only from the shu study (2) (total: 58.054; healthy 56.852; nephrolithiasis: 1.202). meta-analysis when energy intake data were pooled irrespective of the sex of participants (men and women, or women only), mean energy intake values were significantly higher in urolithiasis patients, compared to healthy individuals. the mean difference (md) was 39.16 calories (95% ci: 18.53 to 59.78, p = 0.0002; figure 1). this comparison showed “considerable” heterogeneity (i^2 = 79%; p = 0.002). the study of ferraro et al. (9) was identified as a source of heterogeneity. when this study was excluded from analysis, the overall effect remained significant (md: 49.57; 95% ci: 37.73 to 61.40, p < 0.00001) and the heterogeneity was eliminated (i^2 = 0, p = 0.37). sensitivity analysis was completed by excluding one by one the remaining studies, and the result remained significant (not shown). since the methods used to measure energy intake may have differed among studies, we confirmed the results of this analysis by calculating the standardized mean difference for the same comparison. the standardized mean difference was found to be equally significant (smd: 0.07 units of standard deviation; 95% ci: 0.03 to 0.12, p = 0.001). the approximate odds ratio for the comparison is also significant (or = 1.946; 95% ci: 1.869 to 5.561). pooled comparison in women (2, 8) was devoid of statistical significance (md: 21.41; 95% ci: -23.95 to 66.78, p = 0.35, figure 1). being based on only two: studies, this analysis does not allow further investigation. table 1. characteristics of included studies. study reference, location study design patients ferraro 2015, usa prospective cohort study (20 years follow up) men and women; 25-75 years; healthy: 209778; nephrolithiasis: 5355: total: 215133 kim 2018, korea prospective study (2011-2014) men and women; healthy: 59728; nephrolithiasis: 2363: total: 62091 shu 2017, china prospective cohort study (1996-2006) men and women; 40-70 years; healthy: 124567; nephrolithiasis: 2653: total: 127220 sorensen 2014, usa longitudinal prospective cohort study (1993-2006) postmenopausal women; < 50 years; healthy: 81833; nephrolithiasis: 2392: total: 84255 total healthy: 475906; nephrolithiasis: 12763: total: 488669 perletti_stesura seveso 01/04/20 18:54 pagina 31 archivio italiano di urologia e andrologia 2020; 92, 1 g. perletti, v. magri, p.m. ferraro, e. montanari, a. trinchieri 32 recall bias the recall in bias was rated as high in the sorensen et al. (8) and shu et al. (2) studies, as in both cases nephrolithiasis episodes were self-reported and not confirmed using a validated method. in the kim et al. study (3) the risk of recall bias was low, since measures were taken (periodical ultrasonography) to confirm the self-reported occurrence of nephrolithiasis, as well to detect asymptomatic cases. the recall bias was rated as low in the ferraro et al. study (9), as self-reported episodes of kidney stones were confirmed by official medical records in over 97% of patients. reporting bias the risk of reporting bias was reputed to be low in the ferraro et al. study (9), as validated questionnaires were periodically administered to participants, and their analysis took into consideration corrections for energy-adjusted nutrients. in the sorensen et al. study (8), attempts were made to correct some of the biases associated with reporting, as for energy intake was concerned. however, the authors admit that self-reported dietary intake in their study might have been prone to bias. thus, the bias was rated as unknown. a validated food intake questionnaire was also administered by shu et al. (2), but the authors do not disclose whether any bias correction was attempted (unknown rob). in the kim et al. study report (3), the authors did not disclose whether validated systems were implemented to assess the energy intake of patients (high risk of reporting bias). in the methods section, kim et al. (3) refer to “standardized, self-administered questionnaires”. however, such questionnaires assessed medical history, medication use, family history, physical activity, alcohol intake, smoking habits, and education level, but not dietary/energy intake. publication bias funnel plots were generated to analyze the publication bias for the comparison of data in the overall population (men and or women).the funnel plot indicated symmetry of the data distribution and such visual impression was confirmed by the egger’s test or by begg’s rank correlation analysis, as neither test reached statistical significance (egger’s, p = 0.36; begg’s, p = 0.49). the “trim and fill” method applied to the funnel plot imputed no missing studies (figure 2), and no adjusted estimate of the overall effect size could be calculated for this comparison. discussion the results of the present meta-analysis demonstrate a higher dietary energy intake in renal stone formers compared to non-stone forming subjects. this might be an important finding because it would better explain the association between obesity and the risk of renal stone formation. however, we still have limited data on the energy consumption in renal stone formers, which is linked to physical activity but especially to the resting metabolic rate, which is the largest component of daily energy consumption and is characterized by significant inter-individual differences (10). furthermore, the energy intake of food nutrients that is calculated experimentally through direct calorimetry as thermal energy could differ from the net energy that is extracted through human metabolism. efficiency of digestion for different foods depends on their coefficient of digestibility. notably, energy loss occurs during the process of metabolism. the present findings should be considered provisional and should be interpreted conservatively, since our meta-analysis was based on a limited number of observational studies from three countries (usa, china and korea) that are characterized by very diverse dietary patterns. the typical us diet is based on abundant consumption of meat and animal fats, sugar, carbonated beverages, and insufficient consumption of fruits and vegetables. on the other hand, china and korea are charfigure 1. pooled analysis of energy intake values in urolithiasis patients compared to healthy individuals. perletti_stesura seveso 01/04/20 18:54 pagina 32 33archivio italiano di urologia e andrologia 2020; 92, 1 influence of dietary energy intake on nephrolithiasis a meta-analysis of observational studies acterized by dietary patterns that have a balanced intake of animal and plant-derived foods, at the same time based on a high sodium intake (11, 12). the association between dietary energy intake and the risk of renal stone formation could be different in other countries with healthier dietary patterns, with limited consumption of animal fats and meat and reduced salt consumption. in particular, in countries consuming a mediterranean diet, an increase in dietary energy intake could have a different effect on the risk of stone formation, as it is related to a higher intake of healthy foods such as cereals, nuts, fruit, vegetables, fish, olive oil, and dairy products. hence, such food could cause an increase in body weight without concurrently increasing the risk of renal stone formation. in fact, it was shown that adherence to the mediterranean diet (13) or the dash diet (14), a diet suggested for the prevention of hypertension that provides for a reduction in the consumption of animal proteins and fats in favor of increased consumption of fruits and vegetables, is associated with a reduction in the risk of renal stone formation. in conclusion, the present meta-analysis, based on a large pool of subjects from the united states of america, china and korea, showed that the mean energy intake of patients affected by urolithiasis is significantly higher than the corresponding intake in healthy individuals. assessment of the standardized mean difference allowed the calculation of the odds ratio for such comparison. such odds ratio (or = 1.946 (95% ci: 1.869 to 5.561) is significant and points to an association between higher dietary energy intake and urolithiasis. the extensive significance of this finding could be better evaluated when data from other populations with different dietary patterns and more data on energy consumption linked to physical activity and metabolic rate in renal stone formers will be collected. references 1. aune d, mahamat-saleh y, norat t, riboli e. body fatness, diabetes, physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies. eur j epidemiol. 2018; 33:1033-1047. 2. shu x, cai h, xiang yb, et al. nephrolithiasis among middle aged and elderly urban chinese: a report from prospective cohort studies in shanghai. j endourol. 2017; 31:1327-34. 3. kim s, chang y, sung e, et al. association between sonographically diagnosed nephrolithiasis and subclinical coronary artery calcification in adults. am j kidney dis. 2018; 71:35-41. 4. wan x, wang w, liu j, tong t. estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. bmc med res methodol. 2014; 14:135. 5. higgins jp, altman dg, gøtzsche pc, et al. cochrane bias methods group; cochrane statistical methods group. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011; 343: d5928. 6. duval s, tweedie r. trim and fill: a simple funnel-plot based method of testing and adjusting for publication bias in meta-analysis. biometrics. 2000; 56:455-63. 7. https://training.cochrane.org/handbook 8. sorensen md, chi t, shara nm, et al. activity, energy intake, obesity, and the risk of incident kidney stones in postmenopausal women: a report from the women’s health initiative. j am soc nephrol. 2014; 25:362-9. 9. ferraro pm, curhan gc, sorensen md, et al. physical activity, energy intake and the risk of incident kidney stones. j urol. 2015;193:864-8. 10. goran mi. energy metabolism and obesity. med clin north am. 2000; 84:347-62. 11. zhang r, wang z, fei y, et al. the difference in nutrient intakes between chinese and mediterranean, japanese and american diets. nutrients. 2015; 7:4661-88. 12. shu x, calvert jk, cai h, et al. plant and animal protein intake and risk of incident kidney stones: results from the shanghai men's and women's health studies. j urol. 2019; 202:1217-1223. 13. leone a, fernández-montero a, de la fuente-arrillaga c, et al. adherence to the mediterranean dietary pattern and incidence of nephrolithiasis in the seguimiento universidad de navarra followup (sun) cohort. am j kidney dis. 2017; 70:778-786. 14. taylor en, fung tt, curhan gc. dash-style diet associates with reduced risk for kidney stones. j am soc nephrol. 2009; 20:2253-9. correspondence gianpaolo perletti, dr. sci, m.clin. pharmacol. (corresponding author) gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy vittorio magri, md vittorio.magri@virgilio.it urology secondary care clinic, asst-nord, milan, italy pietro manuel ferraro, md pietromanuel.ferraro@unicatt.it u.o.c. nefrologia, fondazione policlinico universitario a. gemelli irccs, roma, italy emanuele montanari, md emanuele.montanari@unimi.it department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, italy alberto trinchieri, md alberto.trinchieri@gmail.com school of urology, university of milan, italy figure 2. the “trim and fill” method applied to the funnel plot imputed no missing studies. perletti_stesura seveso 01/04/20 18:54 pagina 33 stesura seveso 275archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.275 reported worldwide in 2018 (1). this is generally associated with high levels of morbidity and mortality especially in patients over 70yrs. in the united states about 47% are estimated to be ta/tis at initial presentation, 21% stage i, 11% stage ii, 4% stage iii, and 6% stage iv disease (2). the cornerstones of bc surgical treatments are represented by trans-urethral resection of bladder tumours (turbt) and radical cystectomy (rc). some papers were recently published regarding mortality risk from covid-19 and bc: 63% of patients (pts) had one comorbidity (such as hypertension, cardiovascular, or pulmonary), 32% had two or more comorbidities, and the risks of dying from bc or from a competing disease were similar at 5 yrs after diagnosis (3, 4). on march 11th, 2020, after the world health organization declared the disease caused by the novel coronavirus sars-cov-2 a pandemic, the exponential increase in the number of affected individuals led to a rapid reallocation of economic, infrastructural and health care resources, with redistribution of those medical/surgical, including urologic oncology, prioritizing urgent and emergent needs (5). this takes into consideration the evidence that almost 30% of individuals older than 65 years are at risk for developing acute respiratory distress syndrome after contracting covid-19 and approximately 20% of asymptomatic individuals infected with covid-19 may die after an elective operation (6, 7). however, the effect of this prioritization, as well as the clinical consequences of postponing surgical procedures, on patients and health care systems remains actively debated, despite recently published recommendations (7-12) (table 1). additionally, as demonstrated by liang et al. and moschovas et al., the increasing risk of covid-19 related complications in cancer patients has to be considered specifically, noting that a significantly higher proportion of patients will require ventilation in the intensive care unit (icu), with some dying as a consequence of these complications (13, 14). moreover, 25% of pts requiring high-priority surgery are considered at increased perioperative risk, which can be partially defined by cancer-related immunocompromised state and consequent higher susceptibility to objective: overview of bladder cancer (bc) management in italy during the first month of the covid-19 pandemic (march 2020) with head to head comparison of the data from march 2019, considered “usual activity” period. the aim is to analyze performance of different italian centers in north, center and south, with a special eye for lombardy (the italian epicenter). patients and methods: during april 2020, a survey containing 14 multiple-choice questions focused on general staffing and surgical activity related to bc during the months of march 2019 and march 2020 was sent to 32 italian centers. statistical analysis was performed using ibm spss statistics (v26) software. a medline search was performed, in order to attempt a comparative analysis with published papers. results: 28 centers answered, for a response rate of 87.5%. most of the urology staff in the lombardy region were employed in covid wards (p = 0.003), with a statistically significant reduction in the number of radical cystectomies (rc) performed during that time (p = 0.036). the total amount of rc across italy remained the same between 2019 and 2020, however there was an increase in the number of surgeries performed in the southern region. this was most likely due to travel restrictions limiting travel the north. the number of trans-urethral resection of bladder tumors (turbt) (p = 0.046) was higher in academic centers (ac) in 2020 (p = 0.037). conclusions: the data of our survey, although limited, represents a snap shot of the management of bc during the first month of the covd-19 pandemic, which posed a major challenge for cancer centers seeking to provide care during an extremely dynamic clinical and political situation which requires maximum flexibility to be appropriately managed. key words: covid-19; urology; pandemic; outbreak; bladder cancer; non-muscle invasive bladder cancer; trans-urethral resection of bladder tumor; cystectomy; hematuria. submitted 2 june 2020; accepted 20 july 2020 introduction bladder cancer (bc) represents 3% of all malignancies, with 549.000 new cases and 199.000 deaths were overview of the italian experience in surgical management of bladder cancer during first month of covid-19 pandemic summary carmen maccagnano 1, lorenzo rocchini 2, emanuele montanari 2, giario natale conti 1, giovanni petralia 3, federico dehò 4, kadi-ann bryan 5, roberto contieri 6, rodolfo hurle 6 1 department of surgery, section of urology, asst lariana, nuovo ospedale sant’anna, san fermo della battaglia (co), italy; 2 department of surgery, division of urology, fondazione irccs ca' granda ospedale maggiore policlinico, milan, italy; 3 urology unit, niguarda hospital, milan, italy; 4 unit of urology, asst sette laghi-circolo e fondazione macchi hospital; 5 rogue-valley urology, medford, oregon, us; 6 department of urology, istituto clinico humanitas irccs clinical and research hospital, rozzano (mi), italy. maccagnano_stesura seveso 16/12/20 19:27 pagina 275 archivio italiano di urologia e andrologia 2020; 92, 4 c. maccagnano, l. rocchini, e. montanari, g.n. conti, g. petralia, f. dehò, k.-a. bryan, r. contieri, r.hurle 276 infections, compared to general population (5, 15). furthermore, it is important to consider the most valuable resource that is personnel, as we observed a 30% shortage of health care workers due to hospital-acquired covid-19 infection (16, 17). we report on the surgical management of bc in different regions of italy (with focus on lombardy, as the italian epicenter) during the first month of covid-19 outbreak (march 2020), with head to head comparison with data from march 2019. materials and methods a survey containing 14 multiple choice questions, focused on surgical activity related to bc carried out in march 2019 and march 2020, was sent to 32 italian centers (see appendix 1) during the first week of april 2020. we also queried medical staffing at these facilities: total amount of urologists (including resident physicians) and percentage dedicated to covid wards for each institute. 28 centers answered (table 2). to note, non covid-centers (ncc) were defined as hospitals where only pts with negative nasopharyngeal swab and negative chest ct-scans were admitted. statistical analysis of the data was performed using ibm spss statistics (v26) software. we evaluated the geographic differences between lombardy (the epicenter of pandemic), northern centers outside lombardy, center and south. moreover, we evaluated differences between academic (ac) and non-academic centers (nac), according to location. we evaluated the number of rc, turbt, operative blocks (ob) dedicated to urology and number of surgical procedures performed during march 2019 and march 2020. we also compared the differences between ac and nac. all the variables in this survey are nominal (categorical), so we tested the statistical differences between centers and location using chi-square test through crosstab function in our software. results table 3 reported data about centers and their distribution across italy. several different statistical differences emerged comparing lombardy hospitals and rest of northern italy in march 2020: number of ob dedicated to urology (p = 0.027); number of surgical procedures per ob (p = 0.018); number of turbt (p = 0.012); number of hemostatic transurethral resection (htur) (p = 0.010). these differences were no relevant considering lombardy centers among northern group. table 1. international scientific societies recommendations about surgical management of bc during pandemic. scientific society turbt cystectomy italian society of urology (siu) low priority (deferrable) never postpone (https://www.siu.it) (9) • turbt after instillations • turbt in low risk pts for progression intermediate priority turbt in pts with small recurrences high priority: • pts with high risk of progression • 2nd look turbt for hg or t1 european association of urology (eau) low priority (defer by 6 months): cystectomy has to be performed within 3 months since (https://uroweb.org/wp-content/uploads/eau• small papillary recurrences (< 1 cm) and history of ta/1 low grade tumour; the diagnosis in case of: guidelines-office-rapid-reaction-group-an-organisation• 2nd turbt in pts with visibly complete initial turbt of t1 lesion • pts with highest risk nmibc; wide-collaborative-effort-to-adapt-the-eau-guidelineswith muscle in the specimen. • pts with bcg unresponsive tumor or bcg failure. recommendations-to-the-covid-19-era.pdf) (10) intermediate priority (treat before end of 3 months): any primary tumour or recurrent papillary tumour > 1 cm and without hematuria or without history of hg nmibc high priority (treat within 6 weeks) • pts with bladder lesion and intermittent macroscopic hematuria or history of high-risk nmibc; • 2nd turbt in pts with visibly residual tumour after initial resection and large or multiple t1hg at initial resection without muscle in the specimen national comprehensive cancer network (nccn) possible postponing low risk pts (https://www.nccn.org/covid-19/pdf/cancer_services_ not postponing high risk pts patient_prioritization_guidelines.pdf) (11) american urological association high risk: high risk cancer: (https://www.facs.org/covid-19/clinical-guidance/triage) (12) turbt as scheduled cystectomy as scheduled nothigh risk: nothigh risk cancer: postpone in 4-12 weeks postpone in 4-12 weeks table 2. main characteristics of centers who answered to survey. characteristic number total amount of centers who answered 28/32 (87.5%) academic centers 15/28 (53.6%) emergency room 24/28 (85.7%) non covid-centers (ncc) 4/28 (14.3%) institutes located in north 14/28 (50%) institutes in lombardy 11/28 (39.3%) institutes located in centre 7/28 (25%) institutes located in south 7/28 (25%) maccagnano_stesura seveso 16/12/20 19:27 pagina 276 compared to other hospitals across italy during march 2020, lombardy was the only region where a consistent number of urology staff were reassigned to covid wards (p = 0.003) and four centers had no ob dedicated to urology (p = 0.027). table 4 describes differences in surgical activity, as well as patients with hematuria referred to emergency room (er) in different parts of italy in march 2019 and march 2020. a statistically significant reduction of the amount of rc in lombardy (p = 0.036) was seen, as well as an increasing number of rc performed in the south (p = 0.030). the total amount of rc remained the same in 2019 and 2020, as more centers performed these opera277archivio italiano di urologia e andrologia 2020; 92, 4 bladder cancer and pandemic in italy in march 2019 table 3. lombardy vs north vs centre and south italy centers. lombardy north italy central italy south italy total numbers p number 11/28 (39.3) 3/28 (10.7%) 7/28 (25%) 7/28 (25%) covid free yes 2/11 (18.2%) 0/3 2/7 (28.6%) 0/7 4/28 (14.3%) 0.518 no 9/11 (81.8%) 3/3 5/7 (71.4%) 7/7 24/28 (85.7%) academic hospital yes 4/11 (36.4%) 2/3 (66.7%) 5/7 (71.4%) 4/7 (57.1%) 15/28 (53.6%) 0.140 no 7/11 (63.6%) 1/3 (33.3%) 2/7 (28.6%) 3/7 (42.9%) 13/28 (46.2%) emergency room: yes 9/11 (81.8%) 3/3 5/7 (71.4%) 7/7 24/28 (85.7%) 0.518 no 2/11 (18.2%) 0/3 2/7 (28.6%) 0/7 4/28 (14.3%) staff: < 10 5/11 (45.5%) 1/3 (33.3%) 3/7 (42.9%) 1/7 (14.3%) 10/28 (35.7%) 0.288 10-20 5/11 (45.5%) 0/3 1/7 (14.3%) 5/7 (71.4%) 11/28 (39.3%) > 20 1/11 (9.1%) 2/3 (66.7%) 3/7 (42.9%) 1/7 (14.3%) 7/28 (25%) medical doctors employed in covid wards: < 30% 5/11 (45.5%) 3/3 7/7 7/7 22/28 (78.6%) 0.003 30%-50% 3/11 (27.3%) 0/3 0/7 0/7 3/28 (10.7%) > 50% 3/11 (27.3%) 0/3 0/7 0/7 3/28 (10.7%) operating block dedicated to urology division during march 2020: 0 4/11 (36.4%) 0/3 0/7 0/7 4/28 (14.3%) 0.027 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 2/7 (28.6%) 4/28 (14.3%) > 2 6/11 (54.5%) 3/3 6/7 (85.7%) 5/7 (71.4%) 20/28 (71.4%) operating block dedicated to urology division during march 2019: 0 0/11 0/3 0/7 0/7 0/28 0.329 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 3/7 (42.9%) 5/28 (17.9%) > 2 10/11 (90.9%) 3/3 6/7 (85.7%) 4/7 (57.1%) 23/28 (82.1%) number of operation performed per operating block during march 2020: 1 4/11 (36.4%) 0/3 0/7 0/7 4/28 (14.3%) 0.018 2-3 4/11 (36.4%) 3/3 5/7 (71.4%) 5/7 (71.4%) 17/28 (60.7%) > 3 3/11 (27.3%) 0/3 2/7 (28.6%) 2/7 (28.6%) 7/28 (25%) number of operation performed per operating block during march 2019: 1 0/11 0/3 0/7 1/7 (14.3%) 1/28 (3.6%) 0.688 2-3 7/11 (63.6%) 2/3 (66.7%) 3/7 (42.9%) 6 (85.7%) 18/28 (64.3%) > 3 4/11 (36.4%) 1/3 (33.3%) 4/7 (57.1%) 0/7 9/28 (32.1%) number of trans-urethral resection performed during march 2020: <5 6/11 (54.5%) 0/3 0/7 1/7 (14.3%) 7/28 (25%) 0.012 5-15 4/11 (36.4%) 3/3 4/7 (57.1%) 3/7 (42.9%) 14/28 (50%) >15 3/11 (27.3%) 0/3 3/7 (42.9%) 3/7 (42.9%) 7/28 (25%) number of trans-urethral resection performed during march 2019: < 5 0/11 0/3 0/7 1/7 (14.3%) 1/28 (3.6%) 0.664 5-15 4/11 (36.4%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) 11/28 (39.3%) > 15 7/11 (63.6%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) 16/28 (57.1%) number of cystectomy performed during march 2020: 0 6/11 (54.5%) 0/3 0/7 3/7 (42.9%) 9/28 (32.1%) 0.123 1-5 3/11 (27.3%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) 12/28 (42.9%) > 5 2/11 (18.2%) 1/3 (33.3%) 3/7 (42.9%) 1/7 (14.3%) 7/28 (25%) number of cystectomy performed during march 2019: 0 4/11 (36.4%) 0/3 2/7 (28.6%) 6/7 (85.7%) 12/28 (42.9%) 0.688 1-5 2/11 (18.2%) 1/3 (33.3%) 2/7 (28.6%) 1/7 (14.3%) 6/28 (21.4%) > 5 5/11 (45.5%) 2/3 (66.7%) 3/7 (42.9%) 0/7 10/28 (35.7%) number of patients evaluated for hematuria during march 2020: < 5 7/11 (63.6%) 0/3 1/7 (14.3%) 3/7 (42.9%) 11/28 (39.3%) 0.072 5-10 1/11 (9.1%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) 8/28 (28.6%) > 10 3/11 (27.3%) 1/3 (33.3%) 4/7 (57.1%) 1/7 (14.3%) 9/28 (32.1%) number of patients evaluated for hematuria during march 2019: < 5 2/11 (18.2%) 0/3 2/7 (28.6%) 2/7 (28.6%) 6/28 (21.4%) 0.937 5-10 3/11 (27.3%) 0/3 1/7 (14.3%) 3/7 (42.9%) 7/28 (25%) > 10 6/11 (54.5%) 3/3 4/7 (57.1%) 2/7 (28.6%) 15/28 (53.6%) number of patients undergone to tur for hemostatic/diagnostic purpose during march 2020: 0 7/11 (63.6%) 0/3 1/7 (14.3%) 1/7 (14.3%) 9/28 (32.1%) 0.010 < 50% 4/11 (36.4%) 3/3 4/7 (57.1%) 4/7 (57.1%) 15/28 (53.6%) > 50% 0/11 0/3 2/7 (28.6%) 2/7 (28.6%) 4/28 (14.3%) number of patients undergone to tur for hemostatic/diagnostic purpose during march 2019: 0 2/11 (18.2%) 0/3 2/7 (28.6%) 1/7 (14.3%) 5/28 (17.9%) 0.412 < 50% 7/11 (63.6%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) 14/28 (50%) > 50% 2/11 (18.2%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) 9/28 (32.1%) table 4. comparison of 2019 and 2020 activity in lombardy, north, centre and south of italy. lombardy p north p central p south p operating block dedicated to urology division during march 2020: 0 4/11 (36.4%) 0/3 0/7 0/7 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 2/7 (28.6%) > 2 6/11 (54.5%) 0.382 3/3 n.a. 6/7 (85.7%) 0.143 5/7 (71.4%) 0.714 operating block dedicated to urology division during march 2019: 0 0/11 0/3 0/7 0/7 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 3/7 (42.9%) > 2 10/11 (90.9%) 3/3 6/7 (85.7%) 4/7 (57.1%) number of operation performed per operating block during march 2020: 1 4/11 (36.4%) 0/3 0/7 0/7 2-3 4/11 (36.4%) 3/3 5/7 (71.4%) 5/7 (71.4%) > 3 3/11 (27.3%) 0.441 0/3 n.a. 2/7 (28.6%) 0.286 2/7 (28.6%) 0.286 number of operation performed per operating block during march 2019: 1 0/11 0/3 0/7 1/7 (14.3%) 2-3 7/11 (63.6%) 2/3 (66.7%) 3/7 (42.9%) 6 (85.7%) > 3 4/11 (36.4%) 1/3 (33.3%) 4/7 (57.1%) 0/7 number of trans-urethral resection performed during march 2020: < 5 6/11 (54.5%) 0/3 0/7 1/7 (14.3%) 5-15 4/11 (36.4%) 3/3 4/7 (57.1%) 3/7 (42.9%) >15 3/11 (27.3%) 0.125 0/3 n.a. 3/7 (42.9%) 0.629 3/7 (42.9%) 0.629 number of trans-urethral resection performed during march 2019: < 5 0/11 0/3 0/7 1/7 (14.3%) 5-15 4/11 (36.4%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) > 15 7/11 (63.6%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) number of cystectomy performed during march 2020: 0 6/11 (54.5%) 0/3 3/7 (42.9%) 9/28 (32.1%) 1-5 3/11 (27.3%) 2/3 (66.7%) 3/7 (42.9%) 12/28 (42.9%) > 5 2/11 (18.2%) 0.036 1/3 (33.3%) 0.667 1/7 (14.3%) 0.327 7/28 (25%) 0.030 number of cystectomy performed during march 2019: 0 4/11 (36.4%) 0/3 6/7 (85.7%) 12/28 (42.9%) 1-5 2/11 (18.2%) 1/3 (33.3%) 1/7 (14.3%) 6/28 (21.4%) > 5 5/11 (45.5%) 2/3 (66.7%) 0/7 10/28 (35.7%) number of patients evaluated for hematuria during march 2020: < 5 7/11 (63.6%) 0/3 1/7 (14.3%) 3/7 (42.9%) 5-10 1/11 (9.1%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) > 10 3/11 (27.3%) 0.264 1/3 (33.3%) n.a. 4/7 (57.1%) 0.068 1/7 (14.3%) 0.421 number of patients evaluated for hematuria during march 2019: < 5 2/11 (18.2%) 0/3 2/7 (28.6%) 2/7 (28.6%) 5-10 3/11 (27.3%) 0/3 1/7 (14.3%) 3/7 (42.9%) > 10 6/11 (54.5%) 3/3 4/7 (57.1%) 2/7 (28.6%) number of patients undergone to tur for hemostatic/diagnostic purpose during march 2020: 0 7/11 (63.6%) 0/3 1/7 (14.3%) 1/7 (14.3%) < 50% 4/11 (36.4%) 3/3 4/7 (57.1%) 4/7 (57.1%) > 50% 0/11 0.166 0/3 n.a. 2/7 (28.6%) 0.190 2/7 (28.6%) 0.033 number of patients undergone to tur for hemostatic/diagnostic purpose during march 2019: 0 2/11 (18.2%) 0/3 2/7 (28.6%) 1/7 (14.3%) < 50% 7/11 (63.6%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) > 50% 2/11 (18.2%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) maccagnano_stesura seveso 16/12/20 19:27 pagina 277 archivio italiano di urologia e andrologia 2020; 92, 4 c. maccagnano, l. rocchini, e. montanari, g.n. conti, g. petralia, f. dehò, k.-a. bryan, r. contieri, r.hurle 278 tions in 2020, due to travel restrictions. some statistically significant difference was observed comparing ac and nac, with number of medical doctors, including residents, employed in covid wards being greater in ac (p = 0.001). to note, the number of turbt (p = 0.046) and number of rc was superior in ac in march 2020 (p = 0.037). moreover, the ac differed in the number of interventions performed per ob (p = 0.015) and number of htur (p = 0.014), in favor of 2019. on the other hand, in nac we did not observe any statistically differences in term of surgical performance from 2019 to 2020, except for the number of turbt, which was higher in march 2019 (p = 0.022). finally, we tested the differences between ac and nac in the different parts of italy. in lombardy, we did not find any statistical differences between ac and nac in 2019 and in 2020 regarding: number of ob per week, number of interventions performed per ob, number of turbt nor number of rc. we did not observe any differences in lombardy between ac and nac about patients referred to er with hematuria requiring htur during march 2020 and 2019. we did not find any statistical differences regarding the aforementioned parameters in the other three centers in the north (outside lombardy). in the center regions, we saw statistical differences only in number of pts evaluated for hematuria (p = 0.030) and number of htur in 2019 (p = 0.030), with higher numbers performed in ac. of note, 2 nac included in this survey did not have emergency rooms. finally, there was no statistical differences in the aforementioned items in the southern regions. discussion general performance of italian centers during the first month of pandemic in italy, from february, 27th to april 28th, 199,470 cases and 25.215 confirmed covid-19-related deaths were reported (18). at the same time, a significant shortage of health care personnel was observed, with 20.831 health workers (10%) being affected by confirmed covid-19 infection (5, 15, 18, 19). the rapidly increasing number of pts affected by the sars-cov-2 virus have exerted significant pressure on the healthcare systems of western countries in general, with an emphasis on maintaining emergency and essential services. the need to dedicate major economic, infrastructural and health care resources to assist sars-cov2 patients during the first weeks of the outbreak resulted in a rapid reallocation of staff, wards and equipment from several medical disciplines not primarily involved in the management of these pts (5, 20). as a result, several facilities had to retrain or re-assign personnel to covid-related activities (cra), even if this was outside of their primary designation. the majority of hospital wards were converted to covid-dedicated units and surgical were cases reduced because personnel and resources were reassigned. in our study, all centers maintained 70% of their urological staff for “usual” urological activities and only 30% were reassigned for cra. overall more physicians at ac, including residents, were assigned to covid wards (p = 0.001). it is important underlying that, in the global emergency scenario caused by covid-19 pandemic, the urology residents’ training has been critically affected (especially for residents attending the final year of training), with a significant proportion of residents experiencing a severe reduction (> 40%) or complete suppression (> 80%) of training both for “clinical” activities and “surgical” activities, as reported by amparore et al. (21). while this involvement was particularly evident in lombardy, with urologists involved in cra in more than 50% of the hospitals, in the centre and southern italy, < 30% of urologists were assigned to cra. we can therefore hypothesize that the greater the number of physicians on staff during the usual activity period, the greater the number assigned to cra during the pandemic. the data of our survey supports the findings of naspro (8) and montorsi (22), from giovanni xxiii hospital in bergamo and san raffaele hospital in milan, respectively (two of the primary centers for covid-19 management during the pandemic). naspro reported that, during the 10 days of the first cases of sars-cov2, two-thirds of the hospital beds were occupied by pts with covid-19. within two weeks, urological surgical volume was reduced to 30%, then 15% and then totally halted as of march 19. with the progression of the outbreak, all nonemergent urology surgeries were cancelled, with few exceptions for emergent and some urgent cases (8). during our investigation we identified four non-covid centers (ncc): two in the north and two in the center. as expected, the number of urological procedures in ncc was almost identical to that of the same period in 2019. referring pts to high-volume centers and surgeons potentially allows fast discharge and reduced number of complications (14, 23, 24). this organization also allowed for the residency program to proceed without interruptions in teaching program (25, 26). there were no ncc in the south in our survey, but we know that they have been created. this may be partly justified by the reduced number of covid pts in southern italy (18). except in the south, where numbers were mildly increased, the total amount of surgical procedures were comprehensively reduced during 2020, with a wider geographic distribution of urological procedures. these is likely a direct result of strict travel restrictions during pandemic, which prevented patients living in the south from seeking medical care in the north of italy, which was prevoiusly the norm. a structural reorganization is essential during this time, as key elements, such as the duration of emergency, economic and social consequences, or the viral persistence in the population, are unknown (5). therefore, rationing resources becomes mandatory, in order to ensure continuity of healthcare for covid-free patients (27). nevertheless, the italian situation has to be considered as peculiar: preservation of covid-19-free areas within mixed facilities turned out to be impossible: both caregivers and pts can bring the infection while asymptomatic, contributing to further nosocomial spread. maccagnano_stesura seveso 16/12/20 19:27 pagina 278 279archivio italiano di urologia e andrologia 2020; 92, 4 bladder cancer and pandemic in italy in march 2019 overview on surgical management of bladder cancer during pandemic when the covid-19 outbreak expanded into western countries during the last weeks of february 2020, there were no recommendations about management of oncological surgical procedures, including urology. during the following weeks, several international and national scientific societies have published suggestions based on experts’ opinions, using limited data available and with currently unknown impact on urologic practice (table 1) (9-12). campi et al. recently found that approximately two thirds of pts with genitourinary malignancies do not require high-priority surgery, and 25% of pts requiring high-priority surgery are considered at high perioperative risk. this increasing risk is partially defined by the immunocompromised cancer-related state, which leads to increased susceptibility to infectious diseases compared to general population (15). during this pandemic, the risk of covid-19 related complications, including icu admissions, requiring mechanical ventilation and death, has been calculated to be 3.5 folds higher than usual (28). conversely, wang et al. have highlighted the risk for cancer pts who do not receive adequate and timely medical treatments during an outbreak, resulting in a potentially dangerous delay of uro-oncologic surgeries, with a final impact on the short and intermediate-term progression and mortality rates (19, 29, 30). trans-urethral resection of bladder tumor according to the aforementioned recommendations, turbt for low grade non muscle invasive bladder cancer (lg nmibc) can be delayed in maximum 6 months during the covid-19 outbreak. in case of high grade (hg) nmibc, the recommendations of all societies advise against postponing interventions, due to the risk progression to muscle invasion/metastases in 15-40% and the cancer specific mortality of around 10-20% (30, 31). in case of re-resection, the indications should be carefully evaluated, considering covid-19 local incidence, patients’ risk factors, bc risk, characteristics of initial turbt, not forgetting the limited surgical capacity during pandemic. the potential risk of stage migration due to postponing turbt should always be taken into consideration. finally, most nmibc patients should be considered at high risk of presenting with severe forms of covid-19 that might require admission to an icu and invasive ventilation. in this particular context, the urologist has a responsibility to evaluate the potential benefits and risks of performing turbt at the time (32). naturally, our results showed a decrease in total amount of turbts in march 2020 when compared to march 2019, especially in nac (p = 0.022). these data agree with those recently published by oderda et al. who reported a a restriction for turbt of about 46% (15, 33). to note, the number of turbt performed (p = 0.046) was superior in ac in 2020 (p = 0.037), probably due to superior number of medical staff and/or the presence of residents. unfortunately, we did not collect detailed data about turbt; thus, we cannot comment on this specific issue. radical cystectomy rc should be prioritized to other urologic oncology procedures and never be postponed according to all recommendations during the crisis (table 1). delays exceeding 90 days between diagnosis/turbt and rc are associated with worse survival (7, 34). the intervention should be considered in patients at low risk of covid-19 mortality and with high-risk disease features: presence of high-grade pt1 plus tis, or tumors with lympho-vascular invasion, variant histology (eg, micro-papillary disease), residual grade 3/high-grade urothelial carcinoma on re-resection, or pt1 stage (3537). the total amount of rc was decreased during the pandemic in italy, consistent with a reduction of 46% in major uro-oncological surgeries across europe. nevertheless, rc remained the second most common procedure performed during the covid-19 outbreak (11.7% of all urological procedures) (15, 33). in our survey, more centers performed this operations in 2020 vs 2019, with an increase in geographic availability of rc across italy. to note, the number or rc performed in the south centers during march 2020 did not decrease comparing to 2019; in common times italian pts move routinely from the southern regions to the north to address medical needs, as aforementioned. this trend was impacted by travel restrictions during outbreak, leading especially ac to perform rc. surgical management of emergency room accesses due to hematuria the total amount of pts with hematuria and htur have generally decreased during covid-19 outbreak, perhaps attributable to avoidance of the er during the pandemic. in fact, while all the hospitals have performed htur in < 50% of cases during both 2019 and 2020, during 2019 more centers performed htur in up to 50% of cases. considering differences in centres, there was a difference in the number of pts evaluated for hematuria (p = 0.030) and number of htur in 2019 (p = 0.030) in favor of ac. of note, two centers in this area did not have emergency rooms. the number of htur increased only in the south centers and these data can be explained by the access to er only in case of life-threatening hematuria and by travel restrictions. all these data can be justified by the general reduction of er admissions because of non-covid reasons. lombardy overview during pandemic, most of the centers were dedicated to the management of covid-19 and had an er with medicals staff involved in cra in more than 50% of the hospitals (p = 0.003). consequently, the number of urological ob diminished, also considering that four centers had not any ob dedicated to urology, comparing to other hospitals across italy (p = 0.027). on the other hand, there were more than two ob per week dedicated to urology in the most of the hospitals. however, the total amount of turbt and rc diminished, similarly to the rest of italy, even if these operations were more homogeneously distributed across the region, and this is demonstrated by the fact the number of centers which performed from 1 to 5 procedures increased. maccagnano_stesura seveso 16/12/20 19:27 pagina 279 archivio italiano di urologia e andrologia 2020; 92, 4 c. maccagnano, l. rocchini, e. montanari, g.n. conti, g. petralia, f. dehò, k.-a. bryan, r. contieri, r.hurle 280 conclusions the survey data supports the findings of the most recent papers, showing a global reduction in number of bc surgical procedures due to the prioritization given to covid19 pts management. however, we can affirm that the reduction was not so significant if we look at the different regions, especially the southern ones. in fact, during pandemic, patients seek care at the nearest medical institution, not only for covid-19 related reasons, overriding the strict travel limitations and leading to an improvement of “local” bc surgical management in the south. altogether, these data demonstrate the significant efforts were made by italian urologists to proceed with urgent surgical procedures despite covid-19 outbreak. in our opinion, the improvement of management of pts may be optimized by having covid-dedicated hospitals to guarantee high-quality, timely, and safe treatments to oncological patients. this leads to appropriate cure both for covid and covid-free pts who are affected with urologic cancer and should not have a delay in definitive management. the “overlapping” of covidand noncovid wards could not ameliorate the management of all pts, because of the risk of transmitting infections by both pts themselves and medical/nursing staff, despite all the strict preventive measures. finally, covid-19 pandemic represents an important challenge and learning opportunity for cancer centers, in the context of an extremely dynamic clinical and political situation which requires maximum flexibility to be appropriately faced. for example, telemedicine can represent an alternative for both multidisciplinary and follow-up visits, as suggested by the preliminary experience of ambrosini et al. 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67:74-82. 37. veskimae e, espinos el, bruins hm, et al. what is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? a european association of urology muscle invasive and metastatic bladder cancer guidelines panel systematic review. eur urol oncol. 2019; 2 :625-642. 38. ambrosini f, di stasio a, mantica g, et al. covid-19 pandemic and uro-oncology follow up: a “virtual” multidisciplinary team strategy and patients’ satisfaction assessment arch ital urol androl. 2020; 92:78-79. correspondence carmen maccagnano, md, febu (corresponding author) carmen.maccagnano@gmail.com giario natale conti, md giario.conti@gmail.com department of surgery section of urology asst lariana, nuovo ospedale sant’anna via ravona, 20, 22042 san fermo della battaglia (co) lorenzo rocchini, md lorenzo.rocchini@gmail.com department of surgery division of urology emanuele montanari, md, professor of urology emanuele.montanari@unimi.it department of surgery – division of urology and department of clinical sciences and community health fondazione irccs ca' granda ospedale maggiore policlinico padiglione cesarina riva via della commenda 15 20122 milan, italy giovanni petralia, md giovannipetralia@hotmail.com urology unit, niguarda hospital piazza ospedale maggiore, 3 20132, milan, italy federico dehò, md federico.deho@asst-settelaghi.it unit of urology; asst sette laghi-circolo e fondazione macchi hospital viale luigi borri, 57 1100 varese, italy kadi-ann bryan, md kadiann.bryan@gmail.com rogue-valley urology providence plaza, suite 280 1698 e. mcandrews road medford, oregon 97504 roberto contieri, md contieri.ro@gmail.com rodolfo hurle, md rodolfo.hurle@humanitas.it department of urology istituto clinico humanitas irccs clinical and research hospital via manzoni, 56 20089, rozzano (mi), italy maccagnano_stesura seveso 16/12/20 19:27 pagina 281 cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2020; 92, 3186 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.186 penile-scrotal flap vaginoplasty versus inverted penile skin flap expanded with spatulated urethra: a multidisciplinary single-centre analysis giorgio gentile 1, ardigò martino 2, daniela nadalin 3, martina masetti 4, brigida lilia marta 5, franco palmisano 1, alessandro franceschelli 1, patrizia stella 3, anna paola sanfelici 3, eugenio brunocilla 4, fulvio colombo 1 1 andrology unit, university hospital s.orsola-malpighi, bologna, italy; 2 institute for integrated health, federal university of mato grosso do sul, campo grande ms, brazil; 3 health centre gender dysphoria at movement for transsexual identity – agreement with local health care unit, city of bologna, italy; 4 department of urology, university of bologna, bologna, italy; 5 department of anthropology, medical anthropology research center, rovira i virgili university , tarragona, spain. this study is aimed to compare outcomes of penile-scrotal flap vaginoplasty to inverted penile skin flap expanded with spatulated urethra as a singlecentre experience. data regarding vaginoplasty performed between may 2003 and january 2014 were reviewed. subjects were divided into two groups according to the surgical technique performed: perineal-scrotal flap vaginoplasty (group a), and inverted penile skin flap expanded with spatulated urethra vaginoplasty (group b). all patients underwent to psychological analysis before surgery. functional follow-up was based on a modified validated female sexual function index. overall, 67 patients with a mean (sd) age of 34 (±9.38) years underwent to surgery. 41 patients were included into the group a and 26 into the group b. mean operative time among groups a and b was 316 (±101.65) and 594 (±89.06) minutes, respectively (p<0.0001). longer postoperative hospitalization was shown in group b (14 days ± 4,51) than in group a (10 days ± 2,49); (p<0.0001). group b patients showed a higher anemization rate requiring blood transfusion (p=0.00014) as well as compressive neuropathy (p=0.038). in addition to this, necrosis of the skin flap was reported in 8 patients of group b (p<0.0001). comprehensive functional follow-up data was included; spontaneous vaginal lubrication was not reported in 82.4% of group a vs 12.5% cases of group b (p=0.0085). when compared to penile-scrotal flap vaginoplasty, inverted penile skin flap expanded with spatulated urethra technique shows an increased risk of complications with comparable satisfaction rates whereas a higher spontaneous vaginal lubrication is reported. sexological support is of utmost importance in this setting. key words: transgender; penile inversion; vaginoplasty; techniques; outcomes, sexologist. submitted 2 march 2020; accepted 16 march 2020 summary ture of one gender rather than other within a specific social and cultural background (2-3). the term gi disorder appeared in the dsm-iv in 1994 (4-5) and was renamed “gender dysphoria” (gd) in the 2013 dsm-v revised version (6), whereas biological sex ("feeling of being trapped in the wrong body") (7) is not perceived as wrong by patients but the gender assigned at birth. in the light of this, transsexualism treatment necessarily requires the change of the nominally assigned gender rather than sexual characters (6). besides being of utmost importance the psychological evaluation in gd diagnosis, patient should be managed in a multidisciplinary setting taking into account hormone replacement therapy, psychological support and, if required, sex reassignment surgery (srs) (8). regarding the technical aspects of srs, the principal surgical goal is the creation of aesthetically natural and functionally effective external female genitalia, with a sufficiently deep and compliant neovagina allowing normal sexual intercourse without anatomical hindrance (8). in the 1950s, pioneers of srs used invagination of the inverted penile skin sheath to form the neovagina, in order to maintain optimal vascularization (9). almost two decades later, jones et al. described the principles of male-to-female (mtf) srs using a double cutaneous flap obtained from penile, perineal and scrotal skin for the configuration of the neovagina (10). this technique was the starting point for the development of several other procedures for mtf-srs. particularly, perovic et al. proposed to use a cylinder sharped by inverted penile skin widened with spatulated urethra for the neo-vaginal cavity’s lining allowing an increased vaginal sensitivity with urethral secretionsrelated autonomous lubrication (11-12). since the comparison of the different techniques is still the subject of debate in relation to the different surgical outcomes particularly those related to complications and satisfaction rate, the aim to this study was to compare results of penile-scrotal flap vaginoplasty to inverted penile skin flap expanded with spatulated urethra as a single-centre experience. introduction the concept of "gender identity" (gi) in male-to-female people refers to the individual's awareness of belonging to female rather than to male gender (1). in this context, stoller postulated the existence of gi distinguishing it from the “role identity”, defined as the behavioral struc06gentile-palmisano_stesura seveso 24/09/20 14:18 pagina 186 187archivio italiano di urologia e andrologia 2020; 92, 3 vaginoplasty: surgical-sexological comparison of two techniques patients and methods in this retrospective cohort study we identified patients within the department of andrology of our centre who underwent vaginoplasty between may 2003 and january 2014. patients were divided into two groups according the surgical technique performed: perineal-scrotal flap vaginoplasty (group a), and inverted penile skin flap expanded with spatulated urethra vaginoplasty (group b). for both groups, we recorded intraoperative features including, if present, a modification of the technique proposed by our center for the creation of the mons veneris and of the neoclitoris, introduced from may 2010. before surgery, all patients underwent to psychological analysis performed by consultants working within the transsexual identity movement (mit), an italian non-profit association that offers counselling assistance to transsexuals; this service was created in 1994 acknowledging emilia romagna government’s financial support. all patients were previously treated with estrogens and androgen antagonists and lived for at least two years in the role of a person belonging to the desired gender. psychological aspects were recorded, such as the type of followed pathway, the observation of real-life experience, the examination of areas of the individual’s global functioning such as the emotional, social and working areas and her defense mechanisms. all patients underwent a detailed medical history intake, as well as a general physical and andrological examination. the procedure was performed by the same experienced surgical team. intraoperative and post-operative adverse events were recorded. surgical complications were divided into three groups: intraoperative complications; short-term complications, noticed during the post-operative hospital stay; and long-term complications, noticed during follow up after patient discharge. long-term complications were further divided according their aesthetical and functional concern. functional follow-up based on a standard internal protocol consisted of a modified validated female sexual function index (13-15), the questionnaire was administered through interviews during outpatient visits or by telephone to all the patients with at least 6 months of post-operative revaluation. this questionnaire was modified according to psychoclinical/sexological indications (see also supplementary file). r software was used for statistical analysis (r: a language and environment for statistical computing; r core team, 2014; r foundation for statistical computing, vienna, austria). statistical significance for the tests was set at a < .05. descriptive statistics and test statistics were used to compare the 2 groups in terms of clinical variables. one-way kolmogorov-smirnov statistical tests were applied to assess the normality of variables. continuous variables were presented as mean ± standard deviation (sd) and compared using chi squared, fisher’s exact and wilcoxon tests, where normality could not to be assumed. this retrospective study was conducted according to the guidelines and principles of the declaration of helsinki and standard ethical conduct for research involving humans; after approval of our ethical committee for clinical research, all patients signed an informed consent agreeing to supply their own anonymous data for this and future studies. table 1. surgical complications. intra operative complications group a resolution group b resolution rectum’s injuries 1 (2.4%) simple suture 1 (3.9%) protective stoma recanalized after two months anemization (calo di hb > 2 g) 5 (12.2%) transfusion 14 (53.8%) transfusion bulbar urethra’s injuries 2 (4.9%) simple suture — — short-term post operative complications group a resolution group b resolution hyperpyrexia (t > 38°c after the 4th postoperative day) 11 (26.8%) antibiotic therapy 13 (50%) antibiotic therapy anemization 12 (29.3%) transfusion 20 (76.9%) transfusion compressive neuropathy 3 (7.3%) physiotherapy 7 (26.9%) physiotherapy urethro-neovaginal fistula * 1 (2.4%) urinary catheter kept for 3 weeks — — prolonged urethral bleeding 1 (2.4%) surgical revision — — infection of the surgical wound associated with hyperpyrexia 3 (7.31%) 1 antibiotic therapy and 1 surgical revision to remove necrotic material — — clitoral ischemic necrosis — — 1 (3.9%) loss of clitoris necrosis of the skin flaps with dehiscence of the wound sutures — — 8 (30.8%) courettage and sutures * probably due to urethral necrosis. long-term postoperative complications group a resolution group b resolution functional complications stenosis of the neourethral meatus 5 (12.2%) later meatoplasty 1 (3.9%) urinary catheter placed and maintained for two weeks neovaginal atresia (reduction in vaginal depth up to less than 5 cm) 4 (9.8%) enteric vaginoplasty (1/4 patients) 2 (7.7%) enteric vaginoplasty (1/2 patients) vaginal prolapse 1 (2.4%) colpopexy 1 (3.9%) — recto-vaginal fistula ** — — 1 (3.9%) — ** the patient had previously undergone left hemicolectomy due to colorectal cancer followed by pelvic radiotherapy. aestethical complications group a group b reconfiguration of the labia majora due to asymmetries of them or to the presence of dog-ear residual. 2 (4.9%) _ clitoroplasty for a clitoral hypertrophy 1 (2.4%) 2 (7.7%) labia minora and/or clitoral hood’s reconfiguration 3 (7.3%) 1 (3.9%) lower neo-vaginal commissure’s reconfiguration 3 (7.3%) 1 (3.9%) scar tissues’ removal 2 (4.9%) _ 06gentile-palmisano_stesura seveso 24/09/20 14:18 pagina 187 archivio italiano di urologia e andrologia 2020; 92, 3 g. gentile, a. martino, d. nadalin, m. masetti, b.l. marta, f. palmisano, a. franceschelli, p. stella, a.p. sanfelici, e. brunocilla, f. colombo. 188 results overall, 67 patients with a mean (sd) age of 34 (± 9.38) years underwent to surgery. according to the technique performed, 41 patients were included into the group a and 26 into the group b. our modified technique was applied to 26 subjects of group a whereas was performed in all patients of group b. mean (sd) operative time among groups a and b was 316 (± 101.65) and 594 (± 89.06) minutes, respectively; this result was statistically significant (p < 0.0001). similarly, postoperative hospitalization revealed longer in group b (14 days ± 4.51) than in group a (10 days ± 2.49); (p < 0.0001). surgical complications are reported in table 1; group b patients showed a higher blood transfusion rate (p = 0.00014) as well as compressive neuropathy (p = 0.038). in addition to this, necrosis of the skin flap was reported in 8 patients of group b (p < 0.0001). functional questionnaire was administered in 19 subjects in group a (46.3%) and 17 patients in group b (65.4%); 46.3% of the whole cohort resulted unreachable or refused the questionnaire administration. in terms of sexual orientation, 18 patients of group a (94.7%) declared to be mainly attracted to men and 1 (5.3%) has defined herself as bisexual, while 14 (82.3%) cases of group b were mainly attracted to men, 1 was mainly attracted to women (5.9%) and 2 were bisexual (11.8%). all patients with a stable partner, 12 (68.4%) in group a and 4 (23.5%) in group b, resulted to be attracted to men, and all their partners resulted to be attracted to women. among group a subjects with a stable relationship, 6 (46.1%) reported to have sex once or twice a month, 6 (46.1%) several times a week and 1 patient (7,8%) daily. regarding group b patients, 1 (25%) reported to have sexual intercourses once or twice per month while 3 having sex (75%) several times per week. additionally, 61.5% of group a (8) declared to be satisfied with their couple sexuality, 4 (30.8%) revealed moderately satisfied whilst 1 case (7.7%) demonstrated very dissatisfied with her couple sexuality. among group b, 1 patient (25%) declared to be very satisfied while 75% of cases (3) reported to be moderately satisfied with couple's sex life. in terms of emotional complicity with the partner during sexual intercourse, 10 patients of group a (76.9%) declared to be very satisfied and 3 patients (23.1%) showed themselves moderately satisfied, while all 4 cases in group b declared to be very satisfied about the couple emotional complicity. functional questionnaire results concerning autoerotism, sexual intercourses and sex arousal are reported in table 2. when asked how often they managed to have a spontaneous vaginal lubrication during sexual activity, 82.4% of group a answered to be never or almost never able to lubricate; significantly higher than 2 (12.5%) cases of group b (p = 0.0085). in addition to this, 62.5% of group b patients claimed to be able to lubricate always or most of the time. summarizing the overall sexual satisfaction in group a and b, patients defined as very satisfied in 10 and 11 (52.6% vs. 64.7%; p > 0.05) cases. moreover 6 (31.6%) patients of group a declared to be moderately satisfied while 1 (5.3%) was really dissatisfied, whereas in group b 3 (17.6%) patients were neither satisfied nor dissatisgroup a (n,%) group b (n,%) how often do you masturbate? never 12 (63.1) 5 (29.4) less than once a month 1 (5.3) 2 (11.8) one or two times a month 2 (10.5) 4 (23.5) several times a week 3 (15.8) 6 (35.3) daily 1 (5.3) how often do you have sexual intercourses? never 3 (15.8) 2 (11.8) less than once a month 2 (11.8) one or two times a month 8 (42.1) 4 (23.5) several times a week 7 (36.8) 9 (52.9) daily 1 (5.3) over the last 4 weeks how often have you felt sexual desire or sexual interest? always or almost always 2 (10.5) 3 (17.6) often 3 (15.8) 7 (41.2) sometimes 10 (52.6) 7 (41.2) never or almost ever 4 (21.1) over the past 4 weeks, how would you rate your level of sexual desire or interest? very high 5 (26.3) 4 (23.5) high 5 (26.3) 4 (23.5) moderate 5 (26.3) 9 (53) low 1 (5.3) very low or none at all over the past 4 weeks, how often did you feel sexually aroused ("turned on") during sexual activity or intercourse? no sexual activity 2 (10.5) 5 (29.4) almost always or always 8 (47.1) 8 (66.7) most times (more than half the time) 5 (29.4) 3 (25) sometimes (about half the time) 3 (17.6) 1 (8.3) a few times (less than half the time) almost never or never 1 (5.9) how often did you reach orgasm through masturbation? i don’t masturbate 5 (26.3) 3 (17.6) almost always or always 5 (26.3) 10 (71.4) most times (more than half the time) 1 (7.1) 1 (7.1) sometimes (about half the time) 3 (21.4) a few times (less than half the time) 1 (7.1) almost never or never 4 (28.6) 3 (21.5) how often did you reach orgasm through sexual intercourses? i don’t have sexual intercourses 1 (5.3) 1 (5.9) almost always or always most times (more than half the time) 7 (38.9) 7 (43.8) sometimes (about half the time) 2 (11.1) 4 (25) a few times (less than half the time) 5 (28.7) 2 (12.5) almost never or never 4 (22.2) 3 (18.8) did you notice a change in the orgasmic feeling between before and after surgery? yes 13 (81.3) 13 (92.9) no 3 (18.8) 1 (7.1) i haven’t had orgasm yet 3 (15.8) 3 (17.6) over the past 4 weeks, how satisfied were you with your ability to reach orgasm during sexual activity or intercourse? no sexual activity 2 (10.5) 1 (5.9) very satisfied 10 (58.8) 12 (75) moderately satisfied 5 (29.4) 1 (6.3) moderately dissatisfied 1 (5.9) 1 (6.3) very dissatisfied 1 (5.9) 2 (12.5) table 2. functional questionnaire investigating desire and sexual interest, frequency of sexual intercourses and masturbation, sex arousal. 06gentile-palmisano_stesura seveso 24/09/20 14:18 pagina 188 189archivio italiano di urologia e andrologia 2020; 92, 3 vaginoplasty: surgical-sexological comparison of two techniques fied and 2 (11.8%) declared to be moderately satisfied. other post-operative problems revealed through questionnaire are reported in figure 1. discussion vaginoplasty is often the final stage in the gender-confirming process for transgender women. being gender affirmation surgery paramount in the treatment of gender dysphoria, vaginoplasty offers the opportunity for removal of masculine-appearing genitalia and replacement with a gender-congruent appearance (16). the aim of our study was to compare two different techniques, from a surgical and functional point of view, in a cohort of transgender patients who underwent vaginoplasty, in the real-life setting. we found significant differences in terms of short-term adverse events with good aesthetic and functional results. in decades of experience at our center, an original technical modification which involves the preservation of tunica albuginea below the neurovascular bundle was introduced in 2007, allowing a faster and safer clitoroplasty and providing a more natural aspect of mons veneris; this modification was adopted by jones and subsequently by perovic (17). outcomes of penile inversion vaginoplasty are generally in the form of large case series from high volume institutions. buncamper et. al reported a retrospective series of 475 patients who underwent penile inversion vaginoplasty, of whom 85% required additional full-thickness skin grafts (18). the most frequently observed intraoperative complication was rectal injury (n = 11-2.3%) whereas short-term postoperative bleeding that required transfusion and/or reoperation was shown in 6.7% of the cohort. among other vaginoplasty techniques, salgado et al. reported a small case series of transwomen who underwent primary sigmoid vaginoplasty (19); among 12 patients, 2 major complications were reported (1 deep venous thrombosis, 1 suspected pulmonary embolism). from an aesthetical and functional point of view, it is important to emphasize that imperfections are extremely subjective: women with minor imperfections may suffer from issues in their sexual life to the point of requiring further surgery, whereas other patients with serious blemishes decide not to undergo re-intervention. clitoral dimensions are inevitably related to original gland size, since the necessity of saving the marginal portion of the gland for vascularization and innervation of the neo-clitoris (20-21). moreover, depending on the surgical technique, the morphology of the lower commissure varies: jones technique results in a u-shaped commissure while the perovic strategy results in a v-shaped commissure, which has a more natural aspect and can allow hinder penetration (8). in our experience, more patients within group a than group b were subjected to surgical reconfiguration of the lower commissure (7% group a 3% group b): this may be dependent to an interindividual variability. concerning the sexual functionality and sensitivity evaluation, a different time lapse between two groups should be taken into account. in fact, follow-up of the patients of group a is longer than that of group b, whereas the type b procedure has been performed in our center only since 2010. this may significantly influence the quality of sexual life reported by patients: in fact, the capability of re-balancing personal sexuality on a different reproductive system and of reaching orgasm frequently requires a long period (22). an important element which emerged from the questionnaire relates to the high ability to reach an autonomous vaginal lubrication after appropriate sexual stimulation in the patients of group b, due to the mucous secretions of the urethral flap that forms the neovaginal roof, confirming the data in literature (11-12). stable partner was reported more commonly in group a, this can be due to a longer follow-up, as well as by a quicker post-surgery recovery; in addition to this, the emerging trend in group b concerning low sexual satisfaction may be related to the more challenging surgery and therefore to a longer process of integration of body parts with the symbolic expectations (23). the widely shared results within two cohorts about the high emotional complicity of the couples during intercourse are likely motivated by issues due to stigma and prejudice as experienced by transsexual couples that, once overcome, tend to favor emotional sharing and lead to an increase of intimacy (24). concerning the sexual desire levels, higher scores reported in the patient of group b may be hypothetically due to their more consistent effort in post-surgery recovery phase and their interest into the expression of a sexual activity. neovaginal moisture is perceived by these patients as crucial, because it allows to be closer to a standard ideal of femininity, as it matches the symbolic component of figure 1. supplementary data about post-operative problems. 06gentile-palmisano_stesura seveso 24/09/20 14:18 pagina 189 archivio italiano di urologia e andrologia 2020; 92, 3 g. gentile, a. martino, d. nadalin, m. masetti, b.l. marta, f. palmisano, a. franceschelli, p. stella, a.p. sanfelici, e. brunocilla, f. colombo. 190 representation with anatomical reality also in its functioning (25). independently of the well-known benefits of srs on the patients general and sexual life-related quality of life, as well as on cosmesis and sexual functioning (26, 31), it is reasonable to offer sexologic consultation in order to favor the integration of physical and anatomical parts and to sustain and encourage the subject undergoing surgery to achieve a satisfying sexuality. several limitations to this study should be acknowledged, of which the single institution design is probably the most evident. another limitation of the present study lies in the fact that the two different types of intervention were performed by two different surgeons, and this may affect the data collected. on the other hand, this aspect is a good representation of a real-life situation in contrast to single surgeon series. in this context, regardless of the surgeon who performed surgery, it is important to consider that the longer duration of the surgical intervention, the longer post-surgery hospitalization and the higher rate of anemia and hyperpyrexia in the case of group b patients may be related to the greater technical complexity of this procedure, and to the fact that more vascularized tissues – such as the urethra – are handled. moreover, the questionnaire used is not standardized; nevertheless, its essential purpose is to answer a purely surgical and clinical interest rather than to report objective measures of sexual satisfaction. in the light of this, there are more variables involved in sexual satisfaction compared to the biological subset, which is essentially linked to the type of surgery and its clinical consequences. therefore, the impact of body transformation on sexuality should be evaluated by qualitative methods, rather than quantitative, involving couples and not only individuals since that may interfere with subjective evaluation of surgery outcomes. lastly, it should be noted that this analysis focuses on an outdated case series; this is due to the fact that after 2014 the state funds destined for this setting were suspended; in this sense, we hope that this analysis will be a signal for the restoration of this public activity answering to a real need in the transgender community of our region. conclusions when compared to penile-scrotal flap vaginoplasty, inverted penile skin flap expanded with spatulated urethra technique shows an increased risk of complications with a higher spontaneous vaginal lubrication and comparable satisfaction rates. references 1. stoller rj. sex and gender. vol.2: the transsexual experiment. london: hogarth press, 1975. 2. stoller rj. presentations of gender. new haven: yale university press, 1985. 3. stoller rj. the gender disorders. in: rosen i, ed. sexual deviations. third edition. oxford: oxford university press, 1997. 4. american psychiatric association. diagnostic and statistical manual of mental disorders, 4th ed. washington, dc: apa, 1965. 5. american psychiatric association. diagnostic and statistical manual of mental disorders. fourth edition, text revision (dsm-ivtr). washington, 2000. 6. american psychiatric association, diagnostic and statistical manual of mental disorders (5th ed.) arlington, 2013 va: american psychiatric publishing. 7. prosser j. second skins: the body narratives of transsexuality. new york: columbia university press, 1998. 8. belgrano e, fabbris b, trombetta c. il transessualismo, iden tificazione di un percorso diagnostico e terapeutico. milano: ed. kurtis 1999; 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18:178-184. 28. klein c, gorzalka b. sexual functioning in transsexuals following hormone therapy and genital surgery: a review. j sex med. 2009; 6:2922-2939. 29. marecek j, crawford m, popp d. on the construction of gender, sex, and sexualities. the psychology of gender. 2004; 2:192-216. 30. bevan te. the psychobiology of transsexualism and transgenderism: a new view based on scientific evidence. santa barbara, ca: praeger, 2015, p. 257 pp, isbn-13: 978-1440831263. 31. epstein s. a queer encounter: sociology and the study of sexuality. sociological theory. 1994; 12:188-202. correspondence giorgio gentile, md franco palmisano, md (corresponding author) franco.palmisano@hotmail.it fulvio colombo, md alessandro franceschelli, md andrology unit, university hospital s.orsola-malpighi, via pelagio palagi 9, 40138 bologna (italy) ardigò martino, md institute for integrated health, federal university of mato grosso do sul, campo grande ms (brazil) daniela nadalin, md patrizia stella, md anna paola sanfelici, md health centre gender dysphoria at movement for transsexual identity agreement with local health care unit, city of bologna (italy) martina masetti, md eugenio brunocilla, md department of urology, university of bologna, bologna (italy) brigida lilia marta, md department of anthropology, medical anthropology research center, rovira i virgili university, tarragona, (spain) 06gentile-palmisano_stesura seveso 24/09/20 14:18 pagina 191 archivio italiano di urologia e andrologia 2016; 88, 4304 original paper prostatic calculi detected in peripheral zone of the gland during a transrectal ultrasound biopsy can be significant predictors of prostate cancer lucio dell’atti 1, andrea b. galosi 2, carmelo ippolito 1 1 division of urology, university hospital “st. anna”, ferrara, italy; 2 division of urology, marche polytechnic university, ancona, italy. purpose: prostatic calculi (pc) are usually associated with benign prostatic hyperplasia or chronic inflammation. however, in several studies prostatic inflammation and calcification have been implicated in the pathogenesis of prostate cancer (cap). we evaluated the prevalence of pc during transrectal ultrasound (trus) and correlate the ultrasonographic patterns with histological findings. methods: a prospective study of 664 patients undergoing trus and prostate biopsy was planned. a standardized reproducible technique was used with using a ge logiq 7 machine equipped with a 5-9mhz multi-frequency convex probe “end-fire”. we defined marked presence of pc as multiple hyperechoic foci with significant area (≥ 3 mm in the largest diameter). pc were classified according to zone distribution into the gland: transitional zone (tz), central zone (cz), and peripheral zone (pz). results: no significant difference was noted between the patients with pc and without pc, when comparing age, preoperative psa level, prostate volume, and biopsy number, except for dre findings. 168 patients (25.3%) had marked presence of pc on trus: 50.6% in tz, 20.2% in cz, and 29.2% in pz. 31 patients (63.3%) with presence of pc in pz had cap on biopsy. the correlation observed between cap and the presence of pc in pz was statistically significant (p < 0.001). however, among patients in the cap group there was no statistical association between pc and moderate or high gleason grade. conclusions: this study suggests that chronic prostatic inflammation and pc have a role in the biogenesis of cancer. cap was more frequent in patients with pc in pz of the gland, but was not associated with higher gleason grade among these patients (p < 0.001). key words: prostatic calculi; prostate cancer; inflammation; ultrasound; risk factors. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. with age (3, 4). the study of prostate with transrectal ultrasound (trus) provides the evaluation of the number, location, and dimension of the pc through axial and sagittal views. pc are usually accepted associated with benign prostatic hyperplasia (bph) or chronic prostatitis (5). however, in several studies prostatic inflammation and calcification have been implicated in pathogenesis of prostate cancer (cap) (6-8). in this study we wished to evaluate the prevalence of pc during trus and correlate the ultrasonographic patterns with histological findings. materials and methods a single center prospective randomized study of 664 consecutive patients referred for transrectal ultrasoundguided prostate biopsy (trusbx) to our department was performed between november 2013 to april 2016. all patients underwent an initial trusbx for abnormal digital rectal examination (dre), high prostate-specific antigen (psa) levels (≥ 4 ng/ml), or both. patients with a history of biopsy, surgical treatment for prostatic disease or neoadjuvant therapy were excluded from our study. all patients enrolled in the study signed a consent form for the procedure. trusbx was performed with the patient in the left lateral decubitus using a general electric logiq 7 machine (ge healthcare, milwaukee, wi, usa) equipped with a 5-9mhz multi-frequency convex probe “end-fire”. the patients were treated under local anaesthesia with lidocaine spray 10 gr/100 ml (ecocain®, molteni dental, fi, italy) applied two minutes before the procedure (9). each trus performed included an assessment of the prostatic diameter, the volume of the whole prostate, the transition zone, capsular, seminal vesicle characteristics, presence/absence of prostatic calcification, and a morphological description of potential pathological features. the prostate volume was invariably calculated using prostate ellipse formula (0.52 x length x width x height). we defined moderate/marked presence of pc as multiple (≥ 3 in number) hyperechoic foci with significant area (≥ 3 mm in the largest diameter) and coarse shadow detected in both dimensions (figure 1). mild calcifications were defined as 1 or multiple small foci without doi: 10.4081/aiua.2016.4.304 presented at 20th national congress sieun, sciacca 2016 introduction prostatic calculi (pc) are usually ovoid bodies, with variable sizes and shapes, and they are found in alveoli of prostatic glands (1). pc are created as a result of deposition of calcareous calcium salts on corpora amylacea (2). their incidence is believed to begin after puberty and increase dell'atti-prostatic calculi detected_stesura seveso 09/01/17 10:04 pagina 304 305archivio italiano di urologia e andrologia 2016; 88, 4 relation between prostatic calculi and cancer coarse shadow. pc were classified according to zone distribution into the gland [transitional zone (tz), central zone (cz), and peripheral zone (pz)]. all measurements were analysed and recorded by an experienced urologist. after having images of the prostate, sampling was carried out with a 18-gauge tru-cut (bard biopsy systems, tempe, az, usa) needle powered by an automatic spring-loaded biopsy disposable gun. a 14-core biopsy scheme was performed in each patient, as first intention, including 2 basal samples (lateral and medial), 2 parasagittal samples (lateral and medial), 2 apical samples (lateral and medial), and 1 transitional zone sample on each side. all biopsy cores were analysed internally by our pathology department specializes in genitourinary pathology. the gleason grading was based on the recommendations of the 2005 international society of urological pathology consensus conference. statistical analysis comparisons between patients with pc and without pc were performed using the mann-whitney u test for continuous variables and the chi-square test or fisher’s exact test for categorical variables. univariate logistic regression analysis was used to identify the individual clinical factors predictive of cap presence. all statistical analyses were conducted on microsoft excel 2010 platform version 10.1. a p < 0.05 was considered to indicated statistical significance. results the mean ± standard deviation age of enrolled patients was 61.4 ± 6.6 years, with a prostate volume (pv) of 46.2 ± 18.9 ml, initial psa levels of 7.5 ± 5.3 ng/ml. the number of biopsy cores was 11.4 ± 4.6. no significant difference was noted between the patients with pc and without pc, when comparing age, preoperative psa level, prostate volume, and number of biopsy fragments, except for dre findings. in patients with pc more frequently abnormal dre findings were observed. cap was detected in 213 patients (32.1%) and their gleason scores were ≤ 6 (51.2%), 7 (32.4%), and ≥ 8 (16.4%) (table 1). high-grade prostatic intraepithelial neoplasia (pin) was shown in 81 patients (12.2%), and atypical small acinar proliferations (asap) in 55 patients (8.3%). one hundred and sixty eight patients (25.3%) had marked presence of pc on trus: 85 patients (50.6%) in tz, 34 patients (20.2%) in cz, and 49 (29.2%) in pz (table 2). prostatic calculi in tz were frequently associated with histological findings of inflammation (55.3%; p < 0.002) and bph (41.2%; p < 0.001). however, in 31 patients (63.3%) with presence of pc in pz had cap on biopsy (p < 0.001). the frequency of cap increased as table 1. demographic, clinic-pathologic features and outcomes of patients undergoing transrectal ultrasound biopsy. patients with patients without p prostatic calculi prostatic calculi (n: 168) (n: 496) age (year), mean ± sd* 61.1 ± 6.3 62.4 ± 6.5 ns** prostate volume (ml), mean ± sd* 45.4 ± 17.7 47.2 ± 18.3 ns** psa’’ level (ng/ml), mean ± sd* 6.9 ± 5.8 7.7 ± 5.1 ns** n° biopsy cores, mean ± sd* 11.2 ± 4.4 11.9 ± 4.6 ns** abnormal dre+, n (%) 91 (54) 156 (31) < 0.001 prostate cancer, n (%) 45 (26.8) 168 (33.9) ns** biopsy gleason score, n (%) ≤ 6 31 (68.9) 78 (46.4) < 0.001 7 10 (22.2) 59 (35.1) < 0.001 ≥ 8 4 (8.9) 31 (18.5) < 0.001 sd* = standard deviation; psa’’ = prostate-specific antigen; ns** = not significant; dre+= digital rectal examination. table 2. distribution of prostatic calculi and histological findings in patients undergoing transrectal ultrasound biopsy. prostatic calculi distribution transitional central peripheral p histological findings, zone zone zone n (%) (n: 85) (n: 34) (n: 49) hyperplasia 35 (41.2) 10 (29.5) 10 (20.4) < 0.001 inflammation 47 (55.3) 13 (38.2) 8 (16.3) < 0.002 cancer 3 (3.5) 11 (32.3) 31 (63.3) < 0.001 figure 1. transrectal ultrasound in axial section of the prostate gland: middle (a) and apex (b) zone show marked calcifications with multiple hyperechoic foci, and significant area (≥ 3 mm) with coarse shadow. dell'atti-prostatic calculi detected_stesura seveso 09/01/17 10:04 pagina 305 archivio italiano di urologia e andrologia 2016; 88, 4 l. dell’atti, a.b galosi, c. ippolito 306 patient age increased. in addition, patients with cap had higher psa levels and smaller prostates than men without cap (p < 0.001). the correlation observed between cap and the presence of pc in pz of the prostatic gland was statistically significant (p < 0.001). however, among patients in the cap group there was no statistical association between pc and moderate or high gleason grade. discussion in literature, no studies have systematically looked for pc in a general population. however, it is generally accepted that the incidence of pc increases with age (10). in one study of 612 trus, pc were seen in 47.2% of patients younger than 50 years old and in 86% of those older than 50 years. the authors showed that calcifications are associated with chronic inflammation (11). geramoutsos et al. (12) screened 1374 men younger than 50 years old and found 101 cases of pc (7.4%). the patients with larger significant calcifications were much more likely to have chronic inflammation. a casual connection between chronic inflammation and carcinogenesis was supposed for the first time by virchow in 1863 (13). today it is accepted that almost 25% of all cancers are associated to chronic inflammatory diseases. standard examples are gastric cancer occurring on a history of helicobacter pylori infection or colon carcinoma after history of crohn’s disease (14). in the last years, the casual link between inflammation and pca has been investigated (15). however, the cause of chronic prostatic inflammation as well as its presumed role in carcinogenesis remain unclear. inflammation and pc are often histologically apparent in the examination of the cap specimens from older men (4). histologically, chronic inflammatory cell infiltrates are commonly observed in prostate specimens in the peripheral and transitional zone of the gland (7). immune surveillance may clarify the association between the inflammation and cap. the prostate gland is clearly an immunocompetent organ. besides epithelial and stromal cells, the prostate also contains a small number of immunocompetent cells (lymphocytes, macrophages and granulocytes), which are collectively known as human prostate-associated lymphoid tissue (16). vignozzi and maggi demonstrated that prostate stromal cells can act as antigen-presenting cells, stimulating alloreactive cd4+ t cells to produce several inflammatory cytokines, chemokines and growth factors (including il 8, il 6 and bfgf) in response to a variety of inflammatory stimuli (17). the formative mechanism of pc is not well understood, but is usually observed more often in an inflammation of prostate gland than in the prostates of men with cap. prostatic stones are hypothesized to be calcifications of prostatic secretions, with a core of calcium apatite surrounded by concentric layers (18). multiple different aetiological agents are thought to contribute to initiation of pc, including infections, bacterial biofilm production, dietary factors, physical trauma, hormonal changes, desquamation of prostatic epithelium with obstruction of intraprostatic ducts and urine reflux (3, 8, 19). griffiths et al. (20) reported 63% correlation between pc and cap on trus. similar results were found by hwang et al. (21). in their study the authors deduced that, although not statistically significant, pc were more common in men with cap and were associated with higher gleason grade among these patients. contrary to the aforementioned researches woods et al. (8) showed that pc were less commonly associated with cap than with bph. epidemiological, genetic, molecular and rodent model studies have suggested an association between pc and cap. zhang et al. (22) further examined the relation between inflammation, pc and pca in surgical specimens. inflammation was more common in radical prostatectomy specimens. the limitation of this tissue source relates to the fact that these prostates were removed from patients with an established diagnosis of pca, and their aggressiveness warranted surgery. however, in our study, inflammation was presented histologically in association with pc in 46.4% of patients who were diagnosed pca on prostate biopsy. this proportion of positive findings for cap in the biopsy specimens is relatively high compared with those in previous studies. to our knowledge, this is the first prospective study based on a large number of patients to show a link between cap and pc. however, it had several limitations. a first limitation, we had no data available regarding the ethnic background of the patients. this details could be of special interest, because in multiethnic populations, some subgroups might have more unfavourable cap characteristics than others (23). however, although we did not expressly documented race, the majority of the patients of our study cohort were white and italian population. thus, the number of asian and black patients was very small and surely did not exceed 1% of the entire cohort. second in this study only a visual assessment of pc was performed. the description of pc, calcification size, hyperechoic prostatic images as signs of an inflammation is not usually accepted in the urological community (24). we did not quantify the extent of pc and distinguished only 2 distinct types of severity. to clarify the actual role of pc on cap development more molecular research, cytokines and inflammatory markers are required, and would provide a more accurate measure of inflammation. finally, long term follow-up of patients with pc might clarify the possible association between pc, inflammation and cap. there is no evidence confirming a temporal relationship between tissue inflammation and prostatic carcinogenesis. conclusions although we don’t completely understand the role of the pc in the development of bph or cap. there is emerging evidence that inflammation is crucial for the etiology of bph, whether inflammation has a role in the pathogenesis of cap remains unclear. chronic prostatic inflammation may result from the immunologic response of different pathogenic causes that produce a tissue damage and subsequent vulnerability to developing cancer. however, further studies are necessary to more fully elucidate the relationship between inflammation, pc, and cap. references 1. sfanos ks, wilson ba, de marzo am, et al. isaacs wb. acute inflammatory proteins constitute the organic matrix of prostatic cordell'atti-prostatic calculi detected_stesura seveso 09/01/17 10:04 pagina 306 307archivio italiano di urologia e andrologia 2016; 88, 4 relation between prostatic calculi and cancer pora amylacea and calculi in men with prostate cancer. proc natl acad sci. 2009; 106:3443-8. 2. shoskes da, lee ct, murphy d, kefer j, et al. incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. urology. 2007;70:235-8. 3. park sw, nam jk, lee sd, chung mk. are prostatic calculi independent predictive factors of lower urinary tract symptoms? asian j androl. 2010; 12:221-6. 4. suh jh, gardner jm, kee kh, et al. calcifications in prostate and ejaculatory system: a study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens. ann diagn pathol. 2008; 12:165-70. 5. kim wb, doo sw, yang wj, et al. influence of prostatic calculi on lower urinary tract symptoms in middle-aged men. urology. 2011; 78:447-9. 6. yun bh, hwang ec, yu hs, et al. is histological prostate inflammation in an initial prostate biopsy a predictor of prostate cancer on repeat biopsy? int urol nephrol. 2015; 47:1251-7. 7. smolski m, turo r, whiteside s, et al. prevalence of prostatic calcification subtypes and association with prostate cancer. urology. 2015; 85:178-81. 8. woods je, soh s, wheeler tm. distribution and significance of microcalcifications in the neoplastic and non neoplastic prostate. arch pathol lab med. 1998; 122:152-5. 9. dell’atti l. lidocaine spray administration in transrectal ultrasound-guided prostate biopsy: five years of experience. arch ital urol androl. 2014; 86:340-3. 10. delongchamps nb, de la roza g, chandan v, et al. evaluation of prostatitis in autopsied prostates--is chronic inflammation more associated with benign prostatic hyperplasia or cancer? j urol. 2008; 179:1736-40. 11. bock e, calugi v, stolfi v, et al. calcifications of the prostate: a transrectal echographic study. radiol med. 1989; 77:501-3. 12. geramoutsos i, gyftopoulos k, perimenis p, et al. clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. eur urol. 2004; 45:333-7. 13. woenckhaus j, fenic i. proliferative inflammatory atrophy: a background lesion of prostate cancer? andrologia. 2008; 40:134-7. 14. lu h, ouyang w, huang c. inflammation, a key event in cancer development. mol cancer res. 2006; 4:221-33. 15. sfanos ks, de marzo am. prostate cancer and inflammation: the evidence. histopathology. 2012; 60:199-215. 16. de marzo am, platz ea, sutcliffe s, et al. inflammation in prostate carcinogenesis. nat rev cancer. 2007; 7:256-69. 17. vignozzi l, maggi m. prostate cancer: intriguing data on inflammation and prostate cancer. nat rev urol. 2014; 11:369-70. 18. gu m, li w, chen q, et al. prostate calculi can higher urinary retention probability and worsen uncomfortable feeling after prostate biopsy but not predict cancer. int j clin exp med. 2015; 8:6282-6. 19. irani j, levillain p, goujon jm, et al. inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. j urol. 1997; 157:1301-3. 20. griffiths gj, clements r, jones dr, et al. the ultrasound appearances of prostatic cancer with histological correlation. clin radiol. 1987; 38:219-27. 21. hwang ec, choi hs, im cm, et al. prostate calculi in cancer and bph in a cohort of korean men: presence of calculi did not correlate with cancer risk. asian j androl. 2010; 12:215-20. 22. zhang w, sesterhenn ia, connelly rr, et al. inflammatory infiltrate (prostatitis) in whole mounted radical prostatectomy specimens from black and white patients is not an etiology for racial difference in prostate specific antigen. j urol. 2000; 163:131-6. 23. ravery v, dominique s, hupertan v, et al. prostate cancer characteristics in a multiracial community. eur urol. 2008; 53:533-538. 24. ludwig m, weidner w, schroeder-printzen i, et al. transrectal prostatic sonography as a useful diagnostic means for patients with chronic prostatitis or prostatodynia. br j urol. 1994; 73:664-8. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com carmelo ippolito, md department of urology university hospital “st. anna” 8 a. moro street, 44124 cona, ferrara, italy andrea b galosi, md division of urology, marche polytechnic university ancona, italy dell'atti-prostatic calculi detected_stesura seveso 09/01/17 10:04 pagina 307 stesura seveso 217archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.217 clear cell carcinoma of the urinary bladder, a case report: surgical and oncological management emanuele corongiu 1, pietro grande 2, emanuele liberati 1, roberto iacovelli 3, mostafà amini 4, paola mascioli 4, giorgio pagliarella 1, stefano squillacciotti 1, angelo di santo 1, flavio forte 1, valerio olivieri 5 1 division of urology, hospital “madre giuseppina vannini”, rome, italy; 2 sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris, france; 3 oncologia medica, fondazione policlinico universitario gemelli irccs, rome, italy; 4 division of histopathology, bios spa, roma, italy; 5 division of urology, ivrea hospital (asl to4), ivrea (turin), italy. introduction: bladder cancer is a condition characterized by a broad spectrum of histological variants and clinical courses. the morphological description of histological variants is becoming increasingly important. the 75% of cases of these cancers are classified as pure urothelial carcinoma, while the remaining 25% is represented by other histological variants. the clear cell carcinoma is part of urothelial group and is a very rare entity. oncological outcomes of this variant are still uncertain, but seems to be worst than for patiens with pure urothelial carcinoma. moreover it seems to metastasize more easily to the lymph nodes. case report: we present a case of a caucasian 73 year old woman who, after an episode of gross hematuria, underwent an ultrasound of the urinary system, a cystoscopy and a total body computed tomography (ct) which confirmed the presence of a bladder neoformation. a transurethral resection of the bladder (turb) was performed: the result of the histological examination was "poorly differentiated clear cell carcinoma". given the rarity of histological characterization, we required a pet ct scan for more accurate staging, at which a suspected right pelvic lymph node was detected. we proposed a radical cystectomy with hysteroannessiectomy and extended lymphadenectomy. during the pre-hospitalization process, the patient developed anuria, with acute renal failure and bilateral hydronephrosis, which required the placement of bilateral nephrostomies; we performed the planned surgical procedure and the histological exam confirmed: high grade urothelial carcinoma with a high percentage (more than 70%) of clear cell carcinoma, with a strong local aggression and lymphnode metastates. we referred the patient to the oncologist who suggested a treatment plan within an immunotherapy based clinical trial and cisplatin. conclusions: the morphological description of histological variants in bladder cancer is gaining increasing importance, especially for infiltrating and aggressive forms. the clear cell carcinoma is a very rare entity part of the urothelial group; they would seem more aggressive forms with an early lymph node involvement. this evidence is confirmed by the clinical case described, in which we have seen a large local aggression with an involvement of the lymph nodes of the right side of the pelvis of the pre-sacral ones. in these cases, the multimodal approach is crucial. key words: bladder cancer; oncology; uro-oncology; rare tumors; cistectomy. submitted 2 march 2020; accepted 15 march 2020 summary introduction bladder cancer is a condition characterized by a broad spectrum of histological variants and clinical courses. indicatively 75% of cases of these cancers are classified as pure urothelial carcinoma, while the remaining 25% is represented by other histological variants (1). the morphological description of histological variants is becoming increasingly important as underlined by the who 2016 classification (2), which introduced a particular category: “invasive urothelial carcinoma with divergent differentiation” for tumours showing a component of urothelial carcinoma combined with other morphologies (2-3). the real clinical importance of the histological variant is still under discussion, in fact the data are still insufficient to demonstrate a different clinical course compared to the conventional urothelial bladder carcinoma of the same stage and grade (2). currently we can distinguish the histological viariants in two large subgroups: urothelial and non-urothelial. the clear cell carcinoma is part of urothelial group and is a very rare entity, characterized by a glycogen-rich cytoplasmic pattern with tubulocystic, papillary, or diffuse growth patterns. this histological pattern must be distinguished from clear cell adenocarcinoma of the urethra or bladder, or metastatic carcinoma originating from the kidney, prostate, or female genital tract; oncological outcomes of this variant are still uncertain, both for the rarity and for the short follow-up period, but seems to be worst than for patients with pure urothelial carcinoma (3-5). moreover it is also one of the variants (together with the micropapillary histotype) that seems to metastasize more easily to the lymph nodes, suggesting theses variants are associated with lymphatic spread (6). case report we present a case of a caucasian 73 year old woman with a history of breast cancer, treated with left mastectomy and subsequent chemotherapy, diabetes mellitus and high blood pressure on medical therapy. she reported an episode of macrohematuria for which she underwent ultrasound of the urinary tract, which showed a thickening of the posterior wall of the bladder. it was therefore decided to perform a cystoscopy, which showed a large 17corongiu3_stesura seveso 05/10/20 14:54 pagina 217 archivio italiano di urologia e andrologia 2020; 92, 3 e. corongiu, p. grande, e. liberati, r. iacovelli, m. amini, p. mascioli, g. pagliarella, s. squillacciotti, a. di santo, f. forte, v. olivieri 218 solid-looking outward bending of the bladder that involved the posterior wall towards the trigone (figu re 1). a transurethral resection of the bladder (turb) was scheduled, and a pre-operatory total body computed tomography (ct) scan with contrast was required. the ct scan did not show hydroureteronephrosis and any enlargement of the regional lymphnodes, but only a thickening of the posterior wall of the bladder without a clear cleavage plan between bladder and uterus. the turb was performed: the ureteral openings did not seem included in the neoformation, but the cutting surface seemed solid and it was not possible to identify healthy muscle tissue. the result of the histological examination was "poorly differentiated clear cell carcinoma". given the rarity of histological characterization, we required a pet ct scan for more accurate staging, at which a suspected right pelvic lymph node was detected but no distant lesions were found. after discussing the case within the uro-oncology team we proposed a radical cystectomy with hysteronannessiectomy and extended lymphadenectomy with ileal conduit urinary diversion (bricker conduit). during the pre-hospitalization process, the patient developed anuria, with acute renal failure and bilateral hydronephrosis, which required the placement of bilateral nephrostomies; this clinical condition was due to the involvement of the bladder trine by the neoplasm.we performed the planned surgical procedure, finding significant adhesions during lymphadenectomy from the right side. the post-operative course was regular and the patient was discharged on the fifth day. post-operative blood tests showed a progressive recovery of renal function, up to obtaining values of creatinine and gfr in the normal range. the result of the histological exam confirmed: high grade urothelial carcinoma with a high percentage (more than 70%) of clear cell carcinoma (figure 2), infiltrating the full thickness of bladder wall, uterus, both ovaries and vagina; metastases were present in the obturator and iliac lymph nodes of the right side and in the presacral ones; both ureteral stumps were infiltrated, with negative proximal margin, ptnm pt4a n2; immunohistochemistry revealed immuno positivity of pan cytokeratin (ck), gata3, p40, ck. on the basis of this finding, we referred the patient to the onco logist who suggested a treatment plan within an immuno therapy based clinical trial and cisplatin; unfortunately the patient rapidly worsened developing loss of appetite, constipation and pain in her right side. she underwent a total body ct scan that showed disease recurrence at the peritoneum, pelvis and ileal conduit which determined intestinal sub-occlusion and right hydroureteronephrosis. the clinical picture further worsened and the patient died almost four months after surgery. conclusions the morphological description of histological variants in bladder cancer is gaining increasing importance, especially for infiltrating and aggressive forms. the role of this more accurate histological characterization in clinical practice is still under discussion. the clear cell carcinoma is a very rare entity part of the urothelial group, the oncological outcomes of this histotype are still uncertain, but they would seem more aggressive forms with an early lymph node involvement; this evidence is confirmed by the clinical case described, in which we have seen a large local aggression (with a rapid involvement of the ureteral hosts, the uterine cervix and the annexes) with an involvement of the lymph nodes of the right side of the pelvis of the pre-sacral ones. we have also witnessed a rapid recurrence of disease which quickly led to patient’s death. in these cases, the multimodal approach could be fundamental to improve the prognosis. references 1. cai t, et al. concordance and clinical significance of uncommon variants of bladder urothelial carcinoma in transurethral resection and radical cystectomy specimens. urology. 2014; 84:1141-1146. 2. ulbright tm, reuter ve. the 2016 who classification of tumours of the urinary system and male genital organs-part b: prostate and bladder tumours. eur urol. 2016; 70:106-119. 3. moschini m, d'andrea d, korn s, et al. characteristics and clinical significance of histological variants of bladder cancer. nat rev urol. 2017; 14:651-668. 4. sefik e, celik s, basmaci i, et al. effect of variant histology presence and squamous differentiation on oncological results and patient's survival after radical cystectomy. arch ital urol androl. 2018; 90:172-175. 5. rice kr, et al. lymph node metastases in patients with urothelial carcinoma variants: influence of the specific variant on nodal histology. urol. oncol. 2015; 33:20.e23-20.e29. figure 1. image of pre-operative cistoscopy. figure 2. the microscopic finding showing clear cell carcinoma of the bladder (original magnification x 400). correspondence emanuele corongiu, md (corresponding author) emanuele.corongiu@libero.it emanuele liberati, md emanuele.liberati@libero.it flavio forte, md flavioforte@hotmail.com giorgio pagliarella, md giorgiopagliarella@hotmail.com stefano squillacciotti, md stefanosquillacciotti@gmail.com angelo di santo, md adisanto1978@gmail.com division of urology, hospital “madre giuseppina vannini”, rome (italy) pietro grande, md grandepietro@gmail.com sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris (france) roberto iacovelli, md roberto.iacovelli@policlinicogemelli.it oncologia medica, fondazione policlinico universitario gemelli irccs, rome (italy) mostafà amini, md mostamini@gmail.com paola mascioli, md paola.mascioli@tiscali.it division of histopathology, bios spa, roma (italy) valerio olivieri, md valerio.oliveri@uniroma1.it division of urology, ivrea hospital (asl to4), ivrea (turin) (italy) 17corongiu3_stesura seveso 05/10/20 14:54 pagina 218 archivio italiano di urologia e andrologia 2017; 89, 4316 case report partial nephrectomy in horseshoe kidney: primary carcinoid tumor kamil gokhan seker 1, emre sam 1, selcuk sahin 1, mustafa gürkan yenice 1, ayse gul aktas 2, abdulmuttalip simsek 1, volkan tugcu 1 1 department of urology, bakırkoy dr.sadi konuk training and research hospital, istanbul, turkey; 2 department of pathology, bakırkoy dr.sadi konuk training and research hospital, istanbul, turkey. primary neuroendocrine carcinoma of the kidney is a rarely observed clinical condition because neuroendocrine cells are not found in kidney parenchyma. it’s not clinically and radiologically possible to distinguish from other kidney tumors. incidence with horseshoe kidney anomaly, it should be considered as a definitive diagnosis for the patients with this condition. in this case report, we reported about a carcinoid tumor in horseshoe kidney in a 37-year-old woman. key words: carcinoid tumor; neuroendocrine tumor; horseshoe kidney; partial nephrectomy. submitted 8 june 2017; accepted 4 august 2017 summary no conflict of interest declared. my zero ischemia with modified chevron incision (figure 2). no complication was observed during intraoperative and postoperative periods. at macroscopic pathological examination of the specimen, a 2 cm in diameter and cream color mass was observed, at microscopic examination, negative surgical borders, mitotic index 1/50 high-power fields (hpf) and no necrosis were observed. from immunohistochemical tests, cdx2 (-), cd10 (-), vimentin (-), ck7 (-),epithelial membrane antigen (ema) (-), chromogranin focal (+), synaptophysin: common (+) and 8% ki-67 were observed. microscopic and immunohistologic findings were in comply with primary neuroendocrine tumor of the kiddoi: 10.4081/aiua.2017.4.316 introduction carcinoid tumors are low-grade tumors, exhibiting differentiation from neuroendocrine cells, with malignancy potential. neuroendocrine cells in the body are also known are enterochromoffin cells or amine precursor uptake and decarboxylation cells (apud) and they present in glandulous endocrine organs (like hypophysis, parathyroid, adrenal medulla). neuroendocrine tumors (nets) are most commonly present at gastrointestinal system by 73.7% and respiratory system by 25.1% where they rarely present in ovary, testis, cervix, breast, biliary tract and gall bladder (1, 2). however, primary renal carcinoid tumor is a rare case and was firstly reported by resnick in 1966 (1). in this case report, we aimed to focus on a case with welldifferentiated primary neuroendocrine carcinoma of the kidney pathologically diagnosed after partial nephrectomy in horseshoe kidney. case report in a 37-year-old woman patient, examined due to incidentally diagnosed splenomegaly, a horseshoe kidney with a hypodense area 18 x 12.5 mm in size at left kidney lower pole was observed by abdominal computed tomography (ct) scans. abdominal magnetic resonance imaging (mri) confirmed a pathological area 18 x 12.5 mm in size at left kidney lower pole, in venous phase monitoring at t2 sequence with mild hypointense signal, with a mild suspicious contrast and exhibiting diffusion limitation in diffusional examination (figure 1). the patient was operated by left-open partial nephrectofigure 1. a. horseshoe kidney formation and hypodense area 18 x 12.5 mm in size at left kidney lower pole (red, lower arrow). isthmus in the patient with horseshoe kidney anomaly (blue,upper arrow). b. monitoring at t2 sequence with mild hypointense signal of the area exhibiting diffusion limitation. figure 2. exophytic mass lesion. borders were determined by cautery at left kidney lower pole. simsek6_stesura seveso 03/01/18 09:48 pagina 316 317archivio italiano di urologia e andrologia 2017; 89, 4 partial nephrectomy in horseshoe kidney: primary carcinoid tumor ney diagnosis (well-differentiated carcinoid tumor with trabecular and solid pattern) (figure 3). no pathology was observed at gastrointestinal system endoscopy, thorax computed tomography and 68gadotatate positron emission tomography/computed tomography (pet/ct). neuroendocrine tumor markers were not found in urine and blood. the patient was followed by diagnosis of primary neuroendocrine carcinoma of the kidney and during 6 months follow-up period no local relapse or systemic metastasis was observed. discussion primary neuroendocrine carcinomas of the kidney are rare and their pathogenesis is still unknown as these tumors do not usually present in adult normal renal parenchyma, renal pelvis and ureter (2). unlike renal cell carcinoma, renal carcinoid tumor is observed at an early age and in most cases the age at diagnosis is about 49 years and no gender dominance is present. symptoms (e.g. carcinoid syndrome) are rare and it is incidentally diagnosed in 25-30% of cases (2-4). they are clinically misdiagnosed with type 1 papillary renal cell carcinoma, mesonephric tumors, urothelial tumors, wilms tumor and undifferentiated carcinoma (3). primary neuroendocrine carcinoma of the kidney do not have specific ct or mri imaging. in general, primary renal neuroendocrine tumors show a mild contrast uptake as it’s observed in radiological examinations of our case. apart from this, it’s characterized by cystic mass and sometimes by calcification at ct (5, 6). the most dominant histological types of carcinoid tumors are trabecular or ribbon-like types. as a result of immunohistochemical studies, synaptophysin, chromogranin and cd56 showed positive and thyroid transcription factor (ttf-1), wilms tumor protein (wt-1) and cdx2 showed negative (2, 7). chromogranin, synaptophysin and cd56 positivities and cdx2 negativities of our case supported our neuroendocrine tumor diagnosis, and thus, we discarded renal cell carcinoma diagnosis. it’s known that primary neuroendocrine carcinomas of the kidney are frequently presented in kidneys with anomaly. so far in studies in the literature, 100 patients have been diagnosed by similar cases and it has been observed that tumor development mostly occurs in horseshoe kidney. the incidence of neuroendocrine carcinoma in horseshoe kidney is 62 times higher than in normal kidneys (8). in their report examining clinical characteristics of 21 renal carcinoid tumors, hansel et al. reported horseshoe kidney formation in 19% of the patients (7). other kidney anomalies apart from horseshoe kidney are found as renal teratoma or teratoid malformation and polycystic kidney anomalies (1). our case of primary neuroendocrine tumor 2 cm in size, diagnosed in horseshoe kidney supports the literature. primary neuroendocrine carcinomas of the kidney are known to stem from neuroendocrine cells and be lowgrade malignancy potential tumors. to determine prognostic state of these tumors, some indicators and clinical findings are proposed. aung et al. reported about morphologic and molecular structures of 11 well-differentiated renal carcinoid tumors showing that distant metastasis were not present in tumors 5 cm in size or ≤ 2 mitotic 10 hpf (3). in an other review, romero et al. reported that 50% of cases was metastatic and of which 45.6% was at the time first diagnosis. they also stated that the risk of metastasis increases especially in patients over 40 years of age and with solid characterized and high mitotic activity tumors (2). complete surgical resection is the primary treatment against primary neuroendocrine tumors of the kidney. partial nephrectomy might be applied depending on the size of the tumor (9). octreotide or 68ga-dotatate pet/ct is offered during follow-up as useful diagnostic tool in order to diagnose residual or hidden metastatic carcinoid tissue after surgical resection (10). patients may develop local lymph node or distant organ metastasis after a long period of clinical course (7). in our study, a local tumor 2 cm in size with low mitotic index was diagnosed and no distant metastasis was present. during follow-up after partial nephrectomy, no local or systemic relapse was observed. conclusion primary neuroendocrine carcinoma of the kidney are rarely observed and treated by curative treatment after complete surgical resection and show low-grade malignancy potential. its presence in kidneys with anomalies should be kept in mind and, if there is not a clear definitive diagnosis of other kidney masses, it should be taken into consideration. references 1. zhang q, ming j, zhang s, qiu x. primary micro neuroendocrine tumor arising in a horseshoe kidney with cyst: report of a case and review of literature. diagn pathol. 2012; 7:126. figure 3. a. synaptophysin positive tumor cells. b. association of normal kidney tissue with tumor hex4. c. neuroendocrine tumor hex20. d. neuroendocrine tumor hex40. simsek6_stesura seveso 03/01/18 09:48 pagina 317 archivio italiano di urologia e andrologia 2017; 89, 4 k. gokhan seker, e. sam, s. sahin, m. gürkan yenice, a. gul aktas, a. simsek, v. tugcu 318 2. romero fr, rais-bahrami s, permpongkosol s, et al. primary carcinoid tumors of the kidney. j urol. 2006; 176:2359-66. 3. aung pp, killian k, poropatich co, et al. primary neuroendocrine tumors of the kidney: morphological and molecular alterations of an uncommon malignancy. hum pathol. 2013; 44:873-80. 4. murali r, kneale k, lalak n, delprado w. carcinoid tumors of the urinary tract and prostate. arch pathol lab med. 2006; 130:1693-706. 5. quinchon jf, aubert s, biserte j, et al. primary atypical carcinoid of the kidney: a classification is needed. pathology. 2003; 35:353-5. 6. motta l, candiano g, pepe p, et al. neuroendocrine tumor in a horseshoe kidney. case report and updated follow-up of cases reported in the literature. urol int. 2004; 73:361-4. 7. hansel de, epstein ji, berbescu e, et al. renal carcinoid tumor: a clinicopathologic study of 21 cases. am j surg pathol. 2007; 31:1539-44. 8. krishnan b, truong ld, saleh g, et al. horseshoe kidney is associated with an increased relative risk of primary renal carcinoid tumor. j urol. 1997; 157:2059-66. 9. lane br, chery f, jour g, et al. renal neuroendocrine tumours: a clinicopathological study. bju int. 2007; 100:1030-5. 10. gabriel m, oberauer a, dobrozemsky g, et al. 68ga-dotatyr3-octreotide pet for assessing response to somatostatin-receptormediated radionuclide therapy. j nucl med. 2009; 50:1427-34. correspondence kamil gokhan seker, md emre sam, md selcuk sahin, md mustafa gürkan yenice, md volkan tugcu, md abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com bakirkoy dr.sadi konuk education and research hospital department of urology tevfik saglam caddesi no:11 zuhuratbaba/bakirkoy istanbul 34147, turkey ayse gul aktas, md bakirkoy dr.sadi konuk education and research hospital department of pathology tevfik saglam caddesi no:11 zuhuratbaba/bakirkoy istanbul 34147, turkey simsek6_stesura seveso 03/01/18 09:48 pagina 318 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4302 original paper penile prosthesis and complications: results from 577 implants diego pozza 1, andrea marcantonio 1, augusto mosca 2, carlotta pozza 3 1 studio di andrologia e di chirurgia andrologica, roma, italy; 2 urology and andrology unit, s. sebastiano hospital, frascati, italy; 3 department of experimental medicine, sapienza university, roma, italy. objective: penile prosthetic surgery is already well characterized but the problems connected with possible complications still need to be evaluated and discussed. material and methods: the authors revaluated their experience in penile prosthetic surgery involving 577 patients (18 86 years, mean age 51.3 years) operated by the same surgeon since 1984. we implanted 199 silicone-semi-rigid (small carrion, implantal, eurogest, subrini, ssda gs), 200 malleable (jonas, omniphase, duraphase, ams600, mentorcoloplast genesis, vedise) and 178 inflatable (mentor: mark ii, alpha i, titan otr; ams: mono-component hydroflex, dynaflex; bi-component ambicor; multicomponent: 700 ultrex, 700 cx, 700 lgx) prostheses. operative, postoperative, infectious and malfunctioning complications have been recorded. a total of 156 patients drop out at follow-up and we may not exclude possible late complications treated at different hospitals. results: the recorded complications and the therapeutic modalities utilized to treat them are examined. operative complications were recorded in 2 malleable prostheses (mpp) and in one inflatable prosthesis (ipp). postoperative complications have been recorded in three cases of mpp (1.5%) and in 9 ipp (5.0%) and were strictly connected to general medical co-morbidities as diabetes mellitus (dm), coronary artery dysfunction (cad), and peyronie’s disease (pd). in three cases of ipp implantation, hematomas were related to the blunt surgical maneuvers utilized to insert the reservoir or the scrotal pumps. infectious complications were mostly observed in patients with dm: 4 patients with mpp (1.0%) and 15 patients with ipp (8.4%). malfunction rate of the prostheses in our series was really disappointing considering that 13/17 cases (77%) of mono-component ipp broke while in patients with multicomponent ipp the percentage of malfunction has been of 13/161 (8%) and malfunction was observed in only one case of mpp. we were forced to explant the prostheses in 2 patients with mpp (0.5%) and 40 with ipp (22%). however, after excluding 17 mono-component ipps, the percentage of explants of multicomponent ipp (23 patients, 4.2%) is in line with other significative experiences. conclusion: the number of complications of pps are similar to those reported by well qualified urological institutions. in our experience a scrupulous antibiotic therapeutic schedule, avoiding direct contact between the prostheses and the patient’s skin, reduced time of surgery with surgeon’s experience positively influenced the results. summary no conflict of interest declared. doi: 10.4081/aiua.2020.4.302 introduction since the first penile prosthetic implants, in 1972 (1-3), the relevant problems related to surgical technique, durability of materials and prosthetic mechanisms (4-7), the high risk of infections (8-11) and the possible traumas related to an incorrect use of the prostheses continue to be object of medical consideration (12). with the increase of operated cases (13, 14), the surgical ability has significantly improved; in parallel medical companies have introduced new materials that last longer over time and are less subject to wear and tear. despite these improvements, the possibility that the insertion of a prosthesis could lead to dangerous and harmful maneuvers still exists. we have to consider that the particular weakness of the cavernous and perineal tissues such as may occur after pelvic surgery or radiation therapy, the structural alterations in peyronie’s disease (pd) and the presence of comorbidity such as diabetes mellitus (dm) or coronary artery disease (cad) continue to make penile prosthetic surgery (pps) a risky surgery (15-17). materials and methods from 1984 to 2020 over 39,000 patients (pts) (age 6-90 years) with urological and/or andrological problems presented to our outpatient clinic for consultation. out of them, 9540 patients (25.1%) complained of erectile dysfunction (ed). after an accurate taking of medical history and clinical evaluation we requested appropriate diagnostic tests (routine blood tests, hormonal evaluation, colorduplexsonography, sometimes magnetic resonance imaging, cavernometry and neurologic tests). we then prescribed currently available therapies (psychotherapy, hormones, venous surgery, vasoactive intracavernous injections, oral phosphodiesterase type 5 in a limited number of patients medical treatment or minimal surgical acts allowed to solve the complications preserving the prostheses and avoiding the prosthetic explant. key words: penile prosthesis surgery; complications; infections. submitted 14 june 2020; accepted 26 august 2020 303archivio italiano di urologia e andrologia 2020; 92, 4 penile prostheses complications inhibitors, medical urethral system for erection (muse) or alprostadil urethral creams, vacuum). to 952 patients who had no satisfactory results with the first line therapies used, we suggested a penile prosthesis (pp). the italian national health system did not refund the costs of such surgery and therefore, until a few years ago, patients had to cover the not-negligible expenses for the cost of prostheses, clinics, and surgeons. for these reasons, the type of prosthesis to implant was selected also considering their economic cost. of 952 patients, 577 (age 18-86 years) accepted the prosthetic solution of their ed. we began to implant pp in 1984 performing the surgical procedures in different private clinics in rome. we implanted 199 silicone semi-rigid (small carrion, implantal, eurogest, subrini, ssda gs), 200 malleable (jonas, omniphase, duraphase, ams600, mentor/ coloplast genesis, vedise) and 178 inflatable (mentor: mark ii, alpha i, titan otr; ams: hydroflex, dynaflex, ambicor, 700 ultrex, 700 cx, 700 lgx) prostheses. we systematically used an antibiotic therapy (abthe) with ciprofloxacin 1 g/day since 34 days before surgery until 7-10 days after; gentamicin sulfate 150 mg/bid starting from the day of surgery until the day after, ceftriaxone 2gr/iv just before surgery and 1gr/day until 7 days after (16). patients were hospitalized the night before or the morning of surgery. genital skin was shaved 1-2 hours before surgery. spinal anesthesia was mostly used; local anesthesia with sedation, for semi-rigid or malleable prostheses, was performed in 40 patients. the time of the surgery varied between 35 to 120 minutes. in cases of pd with significant curvature wilson’s maneuver (14), plaque’s incision or excision with heterologous grafting were performed. patients were discharged the day after surgery; patients implanted with inflatable prosthesis (ipp) or living outside rome 2-3 days later. follow-up visits were performed, generally, after 7 days, 4 weeks and 1 year. a total of 156 patients dropped out at followup and we cannot exclude possible late complications. results we recorded a series of operative, late postoperative, mechanical, infectious and removal complications that we report below. operative complications perforation of the cavernosal septum in 2 patients, during cavernosal dilation we perforated the septum inserting the two cylinders in the same cavernous space. in one case we were immediately aware of the incorrect location of the cylinders. in the second case, we discovered the incorrect insertion during the final suture steps. we managed to correct the defect by placing the cylinder in the correct cavernous space. in both cases, no significant immediate or postoperative complications were recorded. in 1 case of ams 700cx ipp implantation, the rear part of the right cylinder was improperly positioned in the left cavernous root. the ipp functioned regularly and the patient was discharged after 2 days. after 3 months, the scrotal pump malfunctioned and the ipp had to be removed. at that time, during surgery, we discovered the erroneous placement of the right cylinder. the new ipp was correctly replaced and the postoperative course had no problems. after 8 years the patient is still fine and satisfied with the ipp. crural perforation during the cavernous dilation in a young patient suffering from corporal veno occlusive dysfunction (cvod), we caused the perforation of the right crus with pathological progression of scissors and hegar’s dilators beyond the crus. no evident perineal hematoma happened. we decided to conclude the procedure inserting a rear tip extender (rte) into the cavernous crus and, through a small perineal incision, we affixed it with stitches to the albugineal tunica. we inserted the eurogest cylinders, 21 cm into the left and 19 cm into the right space. we did not record significant postoperative complications. the patient after 6 years continues to be satisfied. postoperative complications superficial ecchymosis – hematomas postoperative formation of blood effusions or hematomas is a common surgical complication. for this reason, the patient is always advised to suspend anticoagulants and/or aspirin 7-10 days before surgery. cutaneous bruising and superficial hematomas tend to disappear in a few weeks (figure 1). we recorded scrotal hematomas in 6 patients: 3 patients after peno-scrotal access and 3 patients after blunt dilation performed to place the scrotal pump after infra-pubic incision. until 1992, we did not use any suction drainage, but after the first episode of voluminous hematoma we begun to place a suction drainage (12) that we generally remove 16-24 hours after surgery in all cases of ipp. we do not use drainage in cases of malleable prostheses (mpp) (13). figure 1. postoperative local and diffuse ecchymosis. simple medical treatment. case 1 a 52 year-old patient had to remove an ipp for malfunction after 8 years. the removal and repositioning of a new ams700cx prosthesis did not present any problem. after 16 hours, next morning, the drainage had aspirated 15-20 cc of blood. we deflated the cylinders that had been left swollen since operation. the patient had to be dismissed archivio italiano di urologia e andrologia 2020; 92, 4 d. pozza, a. marcantonio, a. mosca, c. pozza 304 in the late afternoon so we maintained the drainage. in the hours after we noticed an abundant blood collection in the vacuum cleaner and hematic suffusion at the base of the penis. we brought the patient back to the operating room (or) but we did not find any bleeding vessel. blood was seeping out of an incomplete suture of the cavernous body. we applied a stitch, inflated the prosthetic cylinders and the bleeding completely stopped. the drainage was removed after 24 hours and the patient was discharged maintaining fully inflated cylinders for 15 days. after 5 years the patient is satisfied. case 2 a 31 years-old patient, developed a voluminous hematoma of the penis and scrotum after ipp with drainage in suction. after 10 hours, at night, the volume of the scrotum and the base of the penis begun to increase for a voluminous hematoma (figure 2). we immediately checked him in the or but we failed to identify obvious sources of bleeding. multiple local and scrotal washes were performed. we kept fully inflated the cylinders and maintained the drainage for 3 days until the patient was discharged. the cylinders were kept inflated for 10 days. after surgery, the patient was diagnosed with an unknown coagulative disease. detected the extrusion of the right prosthetic cylinder, however, not in contact with the outside (figure 3a). a small medium-penile incision was performed and the right prosthetic cylinder was fully removed (figure 3b). we changed the 2 cm rte with a 1 cm rte. the apex of the right cavernous body was closed by applying a patch of marlex tissue like a hood. after reinserting the cylinder the corporotomy was sutured and the glans fixed to the albuginea. the cylinders were maintained inflated for 10 days. in 2020, the patient continues to be satisfied. figure 2. relevant hematoma after coloplast inflatable penile prosthesis with drainage due to unrecognized coagulation’s problem. an immediate surgical revision was performed. no damages to the patient and the inflatable penile prosthesis. case 3 & 4 two patients (72 and 74 years old) with dm and cad, after radical prostatectomy (rp), received an ipp. in the 2 cases the drainage was negative at discharge but after 7-10 days, with the resumption of aspirin and anticoagulant treatment (coumadin), they complained of scrotum bulge with pain and difficulty in finding the scrotal pump. in one case we preferred to operate on to drain a scrotal hematoma with rapid healing. in the second, less evident, case, we solved the problem after a month with medical therapy. apical extrusion after 4 years from implantation of an ams700cx ipp for pd with mild dorsal curvature, a 56 years old patient complained of persistent pain in the glans. the glans appeared deformed. suspecting an apex extrusion, it was decided to operate on. after sub-coronal incision, we figure 3. a: extrusion of the right cylinder of inflatable penile prosthesis under the glans; b: removal and shortening of right cylinder’s rear tip extender. repairing of the cavernous tip with marlex hood. apical extrusion with removal case 1 in a 56 years old patient with dm, an hydroflex cylinder perforated the apex of the right cavernous body after 8 months from implantation (figure 4a). the ipp did not work so we removed the 2 cylinders. after dismissal, the patient was lost at follow-up. case 2 in a 36 years old patient, with dm and cad and cvod, we implanted a couple of implantal 120 mpp in 2003. the patient got married, he fathered a son and after 6 years he began to feel a constant pain in the glans. in a few days the cylinder came out. we extracted the prosthetic cylinder, washed with antibiotic solution and did not insert a new cylinder for the risk of infection. after 3 months the patient reported that he had no more pain being able to have penetrative intercourses with his wife. he refused a possible re-intervention to reposition the missing prosthetic cylinder mainly for economical reasons (figure 4b). case 3 in a 65 years old patient with dm, an infection of the ipp begun to develop after 35 days. the evolution of the infection was aggressive, not modified by complex antibiotic treatment, till the extrusion of the right cylinder due to necrosis of cavernous body. it was immediately explanted (figure 4c). skin erosion due to connection tubes a 66 years old patient with dm received in 1999 an ipp with penoscrotal incision. after 7 years he begun to feel pain near the peno-scrotal scar where the presence of the connecting tubes was always felt. after the pain, local bulging appeared with leakage of serous not infected 305archivio italiano di urologia e andrologia 2020; 92, 4 penile prostheses complications material (figure 5). a lozenge incision was made, under local anesthesia and sedation; the tube, after antibiotic washes, was sunk into the dartos tissue of the scrotum. the skin was closed. antibiotic therapy was started. after discharge, the patient did not complain any local and general symptoms. urinary urethral stones a 76 years old patient with cad and hyperuricemia, had an ipp in 2004. he had a frequent sexual activity being very satisfied. in 2017 he had an episode of renal colic with hematuria. the medical practitioner (mp) who visited him during the first episode, unaware of the hydraulic prosthesis, at sonography excluded kidney stones but diagnosed a “paravesical liquid cyst”. the patient the next day continued to suffer pain and hematuria and presented to our clinic. the ipp worked properly. the “paravesical liquid cyst” at sonography revealed to be the prosthetic reservoir that emptied and filled normally. through palpation and sonography we found 2 round stones obstructing the urethra. local anesthesia with lidocaine was performed, followed by a small meatal incision that made possible the extraction of the urinary stones (figure 6). a foley catheter was inserted till the bladder without any obstacle. after 2 days a flexible cystoscopy excluded other bladder stones. in 2020 the patient continues to utilize the prosthesis. preputial edema in the last 3 years we begun again to utilize the infrapubic incision to implant ipp. in 7/ 12 patients we observed, in the first post-op week a significant edema of the foreskin with patient’s discomfort and difficulties in discovering the glans. general and local steroid therapy determined a normalization of the edema in a few weeks. in one patient (coloplast ipp), the difficulty in discovering the glans persisted after one month and the patient preferred to be submitted to circumcision. we observed this problem also in several patients operated in the past for different indications utilizing the infrapubic incision. we cannot exclude an interruption of lymphatic vessels draining of the penile foreskin due to the “pubic” incision (figure 7). altered position of the scrotal pump in 3 patients we observed, during the first visit after surgery, an irregular positioning of the scrotal pump with difficulty to find and activate it. case 1 a 54 years-old patient, after ipp, wasn’t able to perceive the pump, to activate and to deflate the cylinders. after several controls without obtaining a correct position of the pump we decided to re-operate on the patient; after antibiotic therapy, re-incision of the scrotum and freeing of the pump from adhesions we positioned it in the correct way. we did not observe any postoperative complication, neither infections. case 2 a 72 years-old patient, after ipp, wasn’t able to activate the prosthesis because one tube was fixed to the pump and was not possible to detach it even with physical maneuvers performed after local anesthesia. we perfigure 4. a: apical extrusion of hydroflex penile prosthesis covered by the glans, probably without infection. b: complete extrusion of implantal cylinder. c: complete extrusion of inflatable penile prosthesis after severe cavernosal infection in a patient with diabetes mellitus. figure 5. scrotal superficial extrusion of inflatable penile prosthesis tubing without infection. simple surgical repair of the scrotal tissues. figure 6. two urethral stones extracted in a patient with inflatable penile prosthesis after renal colic. figure 7. preputial edema in ipp due to infra-pubic incision. figure 8. scrotal pump surrounded by clear fluid under the neocapsule. archivio italiano di urologia e andrologia 2020; 92, 4 d. pozza, a. marcantonio, a. mosca, c. pozza 306 cations (14-16). in our series we recorded 22 cases of severe infections in 6/399 mpp (1.5%) and in 16/177 ipp (8.9%) that were not managed with complex antibiotic treatment. we reported most of our complications in patients with dm (16/22, 73%) even if we tried to perform penile implant after regularization of glycemic values with insulin or oral antidiabetics. scrotal pump abscess case 1 a 72 years-old patient with dm, 2 years after an ipp implantation, begun to report scrotal pain, fever, and leakage of purulent material from the peno-scrotal scar. we informed the patient of the possible removal of the prosthesis but we started the treatment by cleaning the scrotal wound with gentamicin 80 mg and iodopovidone solution twice a day for 7 days and by starting systemic antibiotic treatment. after 7 days the leakage of purulent secretion stopped and the wound closed. the patient begun to utilize the pump after 15 days. since then he has no further complaints (figures 10a, b). case 2 a 58 years-old patient with dm and cad, after an ipp for pd and ed, begun to experience pain in the scrotum formed a surgical revision after usual antibiotic therapy. the pump was repositioned in the right way. the patient had no complications. after 4 years the ipp is functioning (figure 8). case 3 a 66 years-old patient after radical prostatectomy had in 2012 an ipp with infrapubic access. he observed that the pump was positioned transversally, at the base of the scrotum, bur normally functioning. in front of the proposal to re-operate on to position the pump in the correct way, the patient refused due to the risks of infection. after 3 years the patient was however satisfied. case 4 a 60 years-old hypertensive patient, after ipp observed a progressive formation of a painful liquid swelling of the scrotum. the ultrasound was not conclusive so we performed surgery, after antibiotic therapy, and we found a very large amount of clear fluid collected into the pseudo capsule covering the pump (figure 9). we removed the capsule and repositioned the pump between the testicles. no complication was registered. pump malfunction and substitution two patients (56 and 60 years old) after ipp complained of malfunction of the pump that doesn’t inflate the cylinders. in or, after incision of the scrotum, we observed that the tubes were broken at their base, near the pump, with leaking of the fluid. in both patients we disconnected the pumps, checked the correct function of cylinders and reservoir and we substitute only the pump making three new tube connections. no infection occurred; the ipps worked perfectly and the patients were both satisfied after 2 and 4 years (figure 9). infections the risk of infection continues to be the main problem for pps. surgeons and medical companies tried to find the better strategy, the medical behavior, the drugs, the instruments to reduce the incidence of infective complifigure 9. removal of the pumps of inflatable penile prosthesis and their substitution after 3 years. figure 10. a: painful scrotum and purulent secretion from the pump; b: after local infusion of gentamicin for 7 days closure of the skin with complete recovery; c: purulent abscess of the scrotal pump in a patient with diabetes mellitus after 36 days from implantation of inflatable penile prosthesis. removal of the inflatable penile prosthesis. 307archivio italiano di urologia e andrologia 2020; 92, 4 penile prostheses complications and septic fever after 30 days. in few days, scrotal pump appeared outside with purulent secretion. we decided to remove the entire ipp on suspicion of contamination of the whole system. the patient for economical reasons refused a new ipp (figure 10c). case 3 a 62 years-old patient with dm and cad, in 2004 was submitted to ams700 implant. usual antibiotic treatment was administered. after 15 days the patient begun to complain pain at the basis of the penis, septic fever, and a yellowish lesion at the basis of the penis. a yellowish creamy purulent secretion begun to drain. when we inflated the cylinders the volume of purulent fluid drain increased. suspecting an infection of the ipp we suggested to the patient the possibility to explant the ipp. the patient, mainly for economical reasons, refused such an immediate hypothesis. we started with a local injection of iodopovidone and gentamicin 150 mg. after injecting fluid we inflated the cylinders forcing the fluid to exit. we repeated this maneuver several times, every 8 hours. the quantity of drain was reduced and we injected only gentamicin. after 12-15 days the skin opening closed and we maintained the cylinders fully inflated for 10 days without secretion, fever and pain. we had the possibility of checking the patient regularly till 2012 (figures 11a, b, c). case 4 a 45 years-old patient presented with pd, curvature and ed. he was submitted to subcoronal incision, excision of the plaque, heterologous grafting and mpp. after 2 weeks he developed fever, pain at the glans and pouring of purulent fluid. we organized an explant and in meanwhile, we decided to inject a solution of gentamicin and iodopovidone every 8 hours into the hole of the suture. after one week, pain and fever were decreased and the fluid drainage stopped. after 2-3 days without secretion we closed the hole. (figures 12a, b). after 2 years the patient is fully satisfied. malfunction we recorded malfunctions in 13/17 mono-component ipp (2 leakings of fluid from the cylinders, 3 ruptures of the outer layer and 8 ineffective pumps). in multi-component ipp we recorded aneurysmatic dilation (figure 13a) of the cylinders in 2 ams700ultrex, 3 leakage of fluid at the cylinder level (figure 13b, d), 3 ruptures of the connecting tubes and 4 ruptures on the outer layer (figure 13c). figure 11. a: purulent secretion at the basis of the penis 15 days after implantation of inflatable penile prosthesis; b: repeated local instillations of antibiotic; c: complete resolution after 20 days. figure 12. malleable penile prosthesis implantation and plaque grafting in a 42 years old patient with peyronie’s disease. initial leakage of serous-corpusculated secretion. repeated instillations of antibiotic with complete resolution. figure 13. malfunction of inflatable penile prosthesis. a: aneurism of inflatable penile prosthesis ams700ultrex cylinder; b: leakage of fluid from one cylinder of amshydroflex; c: rupture of the outer layer of ams700ultrex; d: leakage of fluid from one cylinder of ams700. archivio italiano di urologia e andrologia 2020; 92, 4 d. pozza, a. marcantonio, a. mosca, c. pozza 308 removal we had to remove most (13/17; 76.4%) of single component ipp (ams hydroflex and dynaflex), for malfunction. for the high percentage of malfunctions these prostheses have been retired from the market (19). we explanted in only 2 patients the broken pump of ipp reconnecting the tubes and refilling the reservoir. in 23/160 (14.3%) ipp the whole system was removed for malfunction or infections. in 15/168 (8.9%) cases we observed infections non treatable with medical therapy. in 6/144 (4.1%) mpp and in 23/177 (12.9%) ipp we registered infections with subsequent removal of all parts of the ipp. in 2 pts we re-implanted the ipp after 3 months and mpp in 2 pts. in the last 3 years, probably due to the selection of the patients, the skill of the surgical team, the shortening of operating procedures and the improved prosthetic materials the number of complications has greatly reduced. conclusions the event of complications related to pps is still present. our clinical and surgical experience confirms that with experience some complications tend to decrease as is the case of all surgical practices. particularly, we never observed major complications reported in other series as perforations of adjacent organs (20). the problem of infections and malfunctions of ipp persists and could always lead to the removal of prostheses which for the patient and surgeon always represents a bad and sad defeat. we were able to verify that some technical or infectious complications could be resolved with a limited surgery without necessarily having to perform an explant. we also believe that a close relationship between patient and surgeon is extremely important both to manage the course of the patient with penile prosthesis and to face and resolve possible complications. references 1. pearman ro. insertion of a silastic penile prothesis for the treatment of organic sexual impotence. j urol. 1972; 107:802-6. 2. scott fb, bradley we, timm gw. management of impotence erectile. use of inflatable prostheses. urology. 1973; 2:80-82. 3. small mp, carrion hm, gordon ja. small carrion penile prosthesis. new implant for management of impotence. urology. 1975; 5:479-86. 4. pozza d, rossello barbara m, carrion h. l’utilizzazione del cavernotomo di carrion-rossello per l’impianto di protesi intracavernose. acta urol ital. 1993; 2:87-8. 5. ehlers m, mccormick b, coward rm, figler bd. innovating incrementally: development of the modern inflatable penile prosthesis. curr urol rep. 2019; 20:4. 6. scherzer nd, dick b, gabrielson at, alzweri lm, hallstrom wjg. penile prosthesis complications: planning, prevention, and decision making. sex med rev. 2019; 7:349-59. 7. bayrak o, erturhan s, seckiner i, et al. comparison of the patient’s satisfaction underwent penile prosthesis; malleable versus ambicor: single center experience. arch ital uro androl. 2020; 92:25-9. 8. mulcahy jj, kramer a, brant wo, et al. current management of penile implant infections, device reliability, and optimizing cosmetic outcome. curr urol rep. 2014; 15:413-6. 9. dhabuvala c. in vitro assessment of antimicrobial properties of rifampicin-coated titan coloplast penile implants and comparison with inhibizone. j sex med. 2010; 7:3516-9. 10. lokeshwar sd, madhusoodanan v, kava b, ramasamy r. a surgeon guide to various antibiotic dips available during penile prosthesis implantation. curr urol rep. 2019; 20:11. 11. christodoulidou m, pearce i. infection of penile prostheses in patients with diabetes mellitus. surg infect. 2016; 17:2-8. 12. jani k, smith c, delk jr 2nd, et al. infection retardant coating impact on bacterial presence in penile prosthesis surgery: a multicenter study. urology. 2018; 119:104-8. 13. madiraju sk, wallen jj, rydelek sp, et al. biomechanical studies of the inflatable penile prosthesis: a review. sex med rev. 2019; 7:369-75. 14. wilson sk, delk jr. historical advances in penile prostheses. int j imp res. 2000; 12:101-7. 15. whelan p, levine la. additional procedures performed at time of penile prosthesis implantation: a review of current literature. int j impot res 2020; 32:89-98. 16. pozza d, pozza m, musy m, pozza c. 500 penile prostheses implanted by a surgeon in italy in the last 30 years. arch ital urol androl. 2015; 87:216-21. 17. hebert kj, kohler ts. penile prosthesis infection: myths and realities. world j mens health. 2019; 37:276-87. 18. kramer a, goldmark e, greenfield j. is a closed-suction drain advantageous for penile implant surgery? the debate continues. j sex med. 2011; 8:601-12. 19. anafarta k, yaman o, aydos k. clinical experience with dynaflex penile prostheses. urology. 1998; 52:1098-100. 20. deger m, kizilgok b, aridogan ia, tansug mz. management of erosion of inflatable penile prosthesis reservoir into bladder. a different approach. arch ital urol androl. 2019; 91:43-45. correspondence diego pozza, md (corresponding author) studio di andrologia e di chirurgia andrologica via b. gozzoli, 82c, 00142 roma (italy) diegpo@tin.it andrea marcantonio, md via b. gozzoli, 82, 00142 roma (italy) md.andreamarcantonio@gmail.com augusto mosca, md via tuscolana 2, 00040 frascati (italy) moscaugusto@gmail.com carlotta pozza, md via b. gozzoli, 82, 00142 roma (italy) carlotta.pozza@gmail.com 259archivio italiano di urologia e andrologia 2017; 89, 4 original paper the association between prostatitis and prostate cancer. systematic review and meta-analysis gianpaolo perletti 1, 2, elena monti 1, vittorio magri 3, 4, tommaso cai 5, anne cleves 6, alberto trinchieri 7, emanuele montanari 4 1 department of biotechnology and life sciences, università degli studi dell'insubria, busto a., italy; 2 department of human structure and repair, faculty of medicine and medical sciences, ghent university, ghent, belgium; 3 urology secondary care clinic, asst-nord, milan, italy; 4 department of urology, university of milan fondazione ca' granda irccs ospedale maggiore policlinico, milan, italy; 5 department of urology, santa chiara regional hospital, trento, italy; 6 velindre nhs trust library, cardiff university, velindre cancer centre, cardiff, uk; 7 urology unit, a. manzoni hospital, lecco, italy. objective: the main outcome of this review was the association between a history of clinical chronic prostatitis (nih category ii or iii) and a histologically confirmed diagnosis of prostate cancer. materials and methods: crude odds ratios and 95% confidence intervals (ci) were calculated to analyze dichotomous data. for analysis of pooled data we adopted a random-effects model and the inverse variance weighing method. heterogeneity was assessed by calculating the i2 value. results: out of 2794 screened records, we retrieved 16 full-text articles written in english, reporting the data of 15 case-control studies, involving 422.943 patients. pooled analysis resulted in a significant crude odds ratio of 1.83 (95% ci: 1.43 to 2.35; p < 0.00001). the total set of data showed considerable heterogeneity (i2 = 91%). both the egger’s test and the begg's test for funnel plot asymmetry did not reach statistical significance. the ‘trim and fill’ method applied to the funnel plot imputed 3 missing studies and the resulting adjusted estimate of the odds ratio was 2.12 (95% ci: 1.38 to 3.22). according to grade criteria, the overall quality of the meta-analysis data is low, mainly due to the presence of bias, confounders and extreme effect size outliers. five among the included studies reported data assessed in 8015 african-american subjects. pooled analysis resulted in a non-significant crude odds ratio of 1.59 (95% ci: 0.71 to 3.57; p = 0.26), and considerable heterogeneity (i2 = 90%). conclusions: meta-analysis of 15 case-control studies shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer in the general population, whereas such association in african-american individuals remains uncertain. key words: prostate cancer; prostatitis; chronic prostatitis; chronic pelvic pain syndrome; meta-analysis; case-control study. submitted 13 july 2017; accepted 20 october 2017 summary no conflict of interest declared. ulcerative colitis, h. pylori gastritis, acid reflux-related esophagitis/barrett’s syndrome and hepatitis can significantly increase the risk of developing malignant neoplasms. in the urological setting, the association between inflammation and urothelial bladder cancer has been recently demonstrated (3), and the interest for the role of inflammation in urolo-genital oncogenesis is increasing. in the last two decades, considerable effort has been devoted to investigate the linkage between inflammation and prostate cancer. for example, at the molecular and cellular level a model has been proposed whereby overexpression of the vav3 oncogene plays a key role in the transduction of aberrant signals leading to both chronic prostatitis and prostate cancer (4). at the tissue level, inflammation in the prostate can modify the organization of the glands and generate early cancer precursor lesions. postatrophic hyperplasia, a variety of ‘proliferative inflammatory atrophy’, is believed by some authors to be ‘fertile ground’ for development of preneoplastic lesions, as it appears to be implicated in lethal prostate cancer (5). at the clinical level, a number of studies investigated whether a history of clinical prostatitis may increase the risk of developing prostate cancer. the results of these studies have been meta-analyzed by jiang et al. (6). this work, based on a literature search performed up to july 2012, confirmed previous findings (7) and indicated that clinical prostatitis may be significantly associated with prostate cancer. in subsequent years and up to the present day, new case-control studies have been performed on large patient populations. this systematic review is aimed to update and complement the meta-analytic data so far produced, focusing on the relationship between a diagnosis of prostate cancer (any grade) and previous exposure to clinical prostatitis. patients and methods no funding was received to support the present research. eligibility criteria we included only full-text articles written in english, reporting case-control studies evaluating with various doi: 10.4081/aiua.2017.4.259 introduction advanced age, family history, brca gene mutations and african descent are established risk factors for prostate cancer (1, 2). inflammation is known to be a major risk factor for various types of cancer. strong epidemiological evidence demonstrates that chronic inflammatory diseases like perletti print_stesura seveso 03/01/18 09:35 pagina 259 archivio italiano di urologia e andrologia 2017; 89, 4 g. perletti, e. monti, v. magri, t. cai, a. cleves, a. trinchieri, e. montanari 260 epidemiological and statistical approaches the relationship between a history of ‘prostatitis’ and a subsequent diagnosis of prostate cancer. self-reported or physician-assessed clinical ‘prostatitis’ might include different symptomatic inflammatory conditions, characterized by chronic pain in the pelvic region, lower urinary tract symptoms (luts) and sexual dysfunction. these conditions are currently classified as nih category ii chronic bacterial prostatitis (cbp) and nih category iii chronic prostatitis/chronic pelvic pain syndrome (cp/cpps, formerly prostatodynia) (8). studies based exclusively on acute bacterial prostatitis were not included in this review and meta-analysis, as this condition is characterized by short duration and by prompt post-therapy remission. subgroup data of patients affected by acute prostatitis were excluded from odds-ratio calculation and meta-analysis. studies focusing exclusively on the assessment of inflammatory cell infiltrates in biopsy or radical prostatectomy specimens (‘histological prostatitis’, nih category iv) were not included in the present analysis. patients of any ethnicity with a history of prostate cancer of any grade were eligible for the present study. prostate cancer diagnosis could be documented by inspection of patient records or could be retrieved from community, hospital, medicare or other national private or public health insurance program databases/registers. outcomes the main and single outcome considered for this review is the association between a history of clinical chronic prostatitis and prostate cancer of any grade. search strategy and study selection search of published reports was performed by an information specialist (ac). records were identified by searching international databases and trial registers including medline, premedline, embase, cochrane library, web of science, lilacs; scopus, opengrey, who international clinical trial registry and clinicaltrials.gov. all searches were performed starting from january 1st, 2000, and were assessed as up to date on january 31st, 2017. this time frame has been chosen to minimize the use of different definitions of prostatitis in included studies, as a new classification for clinical prostatitis was implemented in year 1999 and almost universally adopted thereafter (8). in the text of the present review, included studies are referred to by the first author and year of publication. quality assessment the risk of bias (rob) of included studies was assessed independently by two researchers (gp, em). the quality of individual studies was rated using the case-control study version of the newcastle-ottawa scale (nos) (9), as recommended in chapter 13 of the cochrane collaboration handbook, addressing the inclusion of non-randomized studies in systematic reviews and meta-analyses (cochrane handbook for systematic reviews of interventions, version 5.1.0) (10). the thresholds for converting the nos scores to agency for healthcare research and quality (ahrq) standards were: good quality: 3 or 4 stars in selection domain and 1 or 2 stars in comparability domain and 2 or 3 stars in outcome/exposure domain. fair quality: 2 stars in selection domain and 1 or 2 stars in comparability domain and 2 or 3 stars in outcome/exposure domain. poor quality: 0 or 1 star in selection domain or 0 stars in comparability domain or 0 or 1 stars in outcome/ exposure domain. the nos allowed to evaluate ascertainment bias/recall bias (exposure item of the nos) and hospital control bias (hospital control section of the selection item of the nos), according to sutton-tyrrel (11). detection bias was evaluated separately, according to cochrane guidelines (10). publication bias and small-study effect were investigated by visually assessing funnel plots and by performing both the egger’s regression test and the begg's rank correlation analysis (12, 13). the quality of the evidence resulting from analysis of pooled data was evaluated according to grade criteria, modified as recommended in chapter 13 of the cochrane handbook (10). briefly, grade recommends rating as ‘low’ all meta-analytic evidence generated by pooling nonrandomized studies. evaluation may be upgraded to ‘moderate’ only in the presence of a large magnitude of effects or of lack of concern about confounders. data collection and statistical analysis data extraction was performed by two independent researchers (gp, em). to analyze dichotomous data we calculated crude (unadjusted) odds ratios (or) and log-odds ratios. analysis included the calculation of 95% confidence intervals (ci), and z statistics. for meta-analysis we adopted a randomeffects model and the inverse variance weighing method. heterogeneity was assessed by calculating the i2 value. we performed galbraith’s plot analysis to identify outliers contributing substantially to heterogeneity. heterogeneity was tentatively investigated by excluding from meta-analysis studies showing small sample sizes, major effect estimate outliers, or specific study design characteristics deviating from the rest of included studies. the ‘trim and fill’ missing study imputation approach was applied to funnel plots, and adjusted overall effect sizes were calculated according to duval and tweedie (14). in the presence of a prevalence of exposure in controls (pctr) higher than 10%, a risk-ratio (rr) approximation was calculated according to vanrhee and suurmond (15). pooled analysis was performed using the revman 5.3 software. funnel plots, galbraith’s plots, the egger’s and begg's tests, and ‘trim and fill’ effect size adjustments were performed with the meta-essentials excel workbook 1.0 (erasmus research institute of management, erasmus university, rotterdam, the netherlands). optimal information size for meta-analysis was calculated with the g*power 3.1 software (assuming an α level equal to 0.05 and a 1-β error equal to 0.95). results a prisma flow-chart of the search and screening process is shown in figure 1 of supplementary materials. a total of 2794 deduplicated records were identified using our perletti print_stesura seveso 03/01/18 09:35 pagina 260 261archivio italiano di urologia e andrologia 2017; 89, 4 prostate cancer and prostatitis, meta-analysis search strategy. from 29 potentially relevant articles selected by two independent reviewers on the basis of title and abstract content, 16 articles met the inclusion criteria for the present review (16-31). these articles report the results of 15 case-control studies including a total population of 422.943 subjects. the cheng 2010 and chao 2010 articles (20, 21) contained essential data from a single study (the california men’s health study), whereas it was not sure whether the rosenblatt 2001 study and the rothman 2004 study focused on the same case and control populations (28, 30). the sample size of our meta-analysis complied “optimal information size” criteria, as recommended by the grade guidelines (32, not shown). table 1 of supplementary materials summarizes the main characteristics of the 15 included studies and the data extracted for the present systematic review. table 2 of supplementary materials presents the quality and bias assessments for the present review. the median score and mode of the newcastle-ottawa scale were 5* and 5*, respectively (nos range: 0 to 9). nos scores were converted to ahrq standards. 11 studies were rated as ‘poor’, 2 studies were rated as ‘fair’ and 2 studies were rated as ‘good’ (is shown in table 2 of supplementary materials). detection bias, evaluated separately, was present in virtually all included studies, mainly due to the increased probability of prostate cancer detection in prostatitis patients subjected to intensive follow-up assessments. the prostate cancer cases were 13.942, of which 1,806 were previously exposed to clinical chronic prostatitis;, whereas controls were 409.001, of which 57.203 had a history of clinical chronic prostatitis. pooled analysis resulted in a significant crude odds ratio of 1.83 (95% ci: 1.43 to 2.35; p < 0.00001). figure 1 (panel a) shows the forest plot, study data and statistics. the total set of data shows ‘considerable’ heterogeneity (cochrane handbook, chapter 9) (10), as the calculated value of i2 was 91%. the hosseini 2010 study (22) appeared to be the major determinant of heterogeneity. this study yielded an odds ratio equal to 32.3, and thus appeared to be an extreme outlier in our analysis. a galbraith plot was generated, and the hosseini 2010 study was confirmed to be an effect size outlier (is shown in figure 2 of supplementary materials). the authors of the study were asked to verify whether any error in data analysis/reporting had occurred, or whether exposure vs. non-exposure data had been accidentally swapped. hosseini et al. collaborated fully in this investigation by re-assessing the study database and statistics, and confirmed the original results of their study. to assess to which extent the pooled effect size might have been inflated by the presence of extreme outliers, sensitivity analysis was performed by excluding the hosseini 2010 study. the resulting pooled effect size (crude odds ratio) was 1.55, and retained statistical significance (95% ci: 1.30 to 1.85, p < 0.00001) (figure 1, panel b). exclusion of hosseini 2010 from meta-analysis decreased the i2 value to 81% (‘substantial’ heterogeneity). the weinmann 2010 study differed from all other thirteen studies, as it included only lethal prostate cancer cases (19). however, tentative exclusion of this study from the meta-analysis did not modify the i2 value (i2 = 91%). to further explore heterogeneity, the pelucchi 2006 study was excluded, as data were collected as early as 1985, and exposure might be partly based on a dated definition and understanding of prostatitis (26). the sutcliffe study was also tentatively excluded, as analyses in this study included participants with missing prostatitis exposure information. in addition, case data were collected as early as 1985, and might be partly based on a pre-1999 definition of prostatitis (24). exclusion of individual studies (pelucchi 2006 or sutcliffe 2006) did not substantially alter heterogeneity, as the i2 values were 92% and 91%, respectively. the sarma 2006 study was also tentatively excluded as it included exclusively african-american patients (25), but also in this case heterogeneity was not substantially decreased (i2 = 90%). five among the included studies reported data assessed in african-american men (17, 20, 23, 25, 27), and metaanalysis in this specific ethnic subgroup was attempted. the total population included 8015 subjects; prostate cancer cases were 1066, of which 135 had a history of clinical chronic prostatitis, whereas the controls were 6949, of which 436 had been previously exposed to the disease. pooled analysis resulted in a non-significant crude odds ratio of 1.59 (95% ci: 0.71 to 3.57; p = 0.26, figure 2). when a fixed-effect model was applied to this analysis, the resulting odds ratio was 1.58 (95% ci: 1.23 to 2.03; p = 0.0003). in the frame of the present meta-analysis, the statistical significance of the odds-ratio calculated with such model should be interpreted conservatively. heterogeneity was ‘considerable’ (i2 = 90%), and appeared to be mainly generated by the sarma 2006 study (25), as its exclusion yielded a i2 value of 73% (‘substantial’ heterogeneity). in this study, age distributions differed substantially between cases and controls, with older patients being present in the case cohort. this may imply that confounding factors (e.g., bph confounder symptoms or higher number of ‘historical’ sexual partners in the cases cohort) might have played a role in the generation of the outlier odds ratio assessed in this study (crude or: 5.02). heterogeneity was not further explored, due to the small number of included studies. funnel plots were generated to analyze publication bias and small-study effects. the funnel plot (figure 3, panel a) suggested a certain degree of asymmetry of the data distribution, though such visual impression was not confirmed by the egger’s test or by the begg's rank correlation analysis, as neither test reached statistical significance (egger’s, p = 0.631; begg’s, p = 0.125). the ‘trim and fill’ method applied to the funnel plot imputed 3 missing studies (figure 3, panel a), and the resulting adjusted estimate of the overall effect size was 0.75 log-odds ratio (95% ci: 0.32 to 1.17), whose natural anti-logarithm is 2.12 (95% ci: 1.38 to 3.22). such adjusted effect size is greater compared to the original finding of the pooled analysis (log 1.83 = 0.60). again, the hosseini 2010 study (22) was a significant outlier in the funnel plot (figure 3, panel a). since hosseini 2010 shows the smallest sample size among all included studies (137 cases and 137 controls), a small-study effect may account for such a drift, in addition to other unique perletti print_stesura seveso 03/01/18 09:35 pagina 261 archivio italiano di urologia e andrologia 2017; 89, 4 g. perletti, e. monti, v. magri, t. cai, a. cleves, a. trinchieri, e. montanari 262 figure 2. subgroup analysis performed on patients of african ethnicity (african-american). data are plotted according to the increasing weight of each study (top to bottom). figure 1. meta-analysis of case-control studies investigating the association between prostate cancer and a previous history of clinical chronic prostatitis. a, pooled analysis of the general population of included prostate cancer cases and controls; b, sensitivity analysis performed by excluding the hosseini 2010 study (22) from the pooled effect size estimate. the number of subjects allocated to cases or control groups, crude odds ratios, the 95% confidence intervals, the z value for the overall effect, the significance of the pooled comparisons and heterogeneity data (chi2, i2), are presented. data to the right of the vertical no-effect line of forest plots represent increased odds for prostate cancer in patients exposed to prostatitis. diamonds represent overall effect sizes extending to the limits of the 95% confidence intervals of odds ratios. data are plotted according to the increasing weight of each study (top to bottom). total study population _______________________________a b sensitivity analysis (hosseini 2010 study excluded) _______________________________ perletti print_stesura seveso 03/01/18 09:35 pagina 262 263archivio italiano di urologia e andrologia 2017; 89, 4 prostate cancer and prostatitis, meta-analysis figure 3. funnel plot for publication bias analysis. a, ‘trim and fill’ method (14) applied to the analysis of the total study population. the combined effect size (ces, green) and the adjusted estimate of the combined effect size (red) resulting from the imputation of three additional studies (orange) are shown. b, funnel plot analysis performed after excluding the hosseini 2010 study (22). in these plots the effect sizes are expressed as the natural logarithms of the odds ratios. !"!! !"#! !"$! !"%! !"&! 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' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 9.40 4.40 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 #!'" 10/.-+, 8.06/5423 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 0;/+,:0998 +82.0,1-=<. ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 1,6/3?@,@..0,-?>4 ' ' ' ' ' ' ' ' ' 7 7 7 7 7 ' ' ' ' ' ' ' ' ' 6 6 6 6 6 perletti print_stesura seveso 03/01/18 09:35 pagina 263 archivio italiano di urologia e andrologia 2017; 89, 4 g. perletti, e. monti, v. magri, t. cai, a. cleves, a. trinchieri, e. montanari 264 features of the study. exclusion of hosseini 2010 from the funnel plot analysis (figure 3, panel b) confirmed the nonsignificance of the plot asymmetry tests (egger’s, p = 1.0; begg’s, p = 0.352). the ‘trim and fill’ analysis imputed 2 missing studies, and the adjusted estimate of the overall effect size was 0.49 log-odds ratio (95% ci: 0.25 to 0.74), whose natural anti-logarithm is 1.63 (95% ci: 1.28 to 2.09) (figure 3, panel b). such adjusted odds ratio is slightly higher compared to the original finding of the pooled analysis (without hosseini 2010, log 1.55 = 0.44). we did not assess for publication bias in the subgroup analysis of african-american patients, due to the small number of included studies. according to grade criteria (32), the overall quality of the meta-analysis data is ‘low’, mainly due to the presence of bias, confounders and extreme outliers. moreover, the magnitude of the effect size generated from meta-analysis and the assessed heterogeneity did not justify upgrading the quality evaluation to ‘moderate’. discussion the present meta-analysis of fifteen case-control studies performed between year 2000 and january 31st, 2017 shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer of any grade (or = 1.83, 95% ci: 1.43 to 2.35). our results support and update previous findings, pointing to a significant association between prostate cancer and exposure to prostatitis (dennis et al., or = 1.6, 95% ci 1.0 to 2.4; jiang et al., or = 1.64, 95% ci: 1.36 to 1.98) (6, 7). although calculation of the odds ratio is the most appropriate strategy to retrospectively quantify the association between a disease and a hypothetical risk factor, its interpretation is not always straightforward, and the perception of risk can be often overestimated by readers not familiar with its underlying statistics. thus, we converted the 1.83 odds ratio resulting from our meta analysis to a risk-ratio estimate equal to 1.63 (95% ci: 1.23 to 2.17) (15). subgroup meta-analysis focusing on men of african descent did not yield significant results when a randomeffects model was adopted. it is indeed crucial to assess whether prostatitis may be a risk factor for prostate cancer in this population, as its incidence is approximately 60% higher and the mortality rate is 2-3 times greater compared with caucasian men (33). thus, additional studies performed on large patient populations are warranted to provide unequivocal evidence in this respect. included studies were characterized by high risk of bias, mainly due to the presence a number of confounding factors, such as comorbidities (e.g., bph) in both cases and controls, different intra-study or inter-study proportions of african-american subjects, difficulty in obtaining medical documentation of previous exposure to risk factors, different interand intra-study age ranges, issues in the selection of control populations, population size issues, etc. increased digital rectal examination, psa or ultrasound assessment rates may expose patients affected by prostatitis or sexually-transmitted diseases to increased detection of indolent, clinically irrelevant cancers, thus potentially generating detection biases between cases and controls. in addition, recalling bias, due to subjective reporting of prostatitis exposure, might be universally present in the studies included in this review, also because prostatitis and bph (likely prevalent in older subjects) are known to be cross-confounders, due to partial symptom overlap (34). these biases are intrinsically present in most case-control investigations, independently of the rigorousness of the study design. clinical diagnosis of chronic prostatitis presumes the presence of chronic inflammation of the prostatic tissue in diagnosed patients. however, the presence of inflammatory mononuclear cells is a very common finding in histological prostate specimens (up to 77%), especially in men beyond the age of 50 (35). moreover, it has been demonstrated that the distribution of prostatic inflammation is similar for patients with and without chronic prostatitislike symptoms (36). however, histological chronic inflammation has been associated to increased prostate cancer risk in several studies (e.g., 37), though this issue is controversial, as other studies have shown that inflammation may actually decrease the risk for prostate cancer (38-40). thus, from our point of view clinical, symptomatic chronic prostatitis and histological evidence of chronic inflammation of the prostate should be provisionally investigated as separate entities, whose impact on prostatic oncogenesis may be based on distinct mechanisms of action at the tissue, cellular or molecular levels. clinical implications and key points the prognostic and therapeutic implications of our findings, together with the findings of dennis et al. and jiang et al. (6, 7), may be of considerable importance. in this respect, it might be interesting to investigate whether aggressive therapeutic management of chronic prostatitis syndromes may have cancer-preventive potential. conclusions meta-analysis of 15 case-control studies shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer in the general population, whereas such association in african-american individuals remains uncertain. references 1. modena a, iacovelli r, scarpa a, et al. investigating brca mutations: a breakthrough in precision medicine of castrationresistant prostate cancer. target oncol. 2016; 11:569-577. 2. rebbeck tr. prostate cancer genetics: variation by race, ethnicity, and geography. semin radiat oncol. 2017; 27:3-10. 3. nesi g, nobili s, cai t, et al. chronic inflammation in urothelial bladder cancer. virchows arch. 2015; 467:623-33. 4. liu y, mo jq, hu q, et al. targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. cancer res. 2008; 68:6396-406. 5. davidsson s, fiorentino m, andrén o, et al. inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer. cancer epidemiol biomarkers prev. 2011; 20:2280-7. 6. jiang j, li j, yunxia z, et al. the role of prostatitis in prostate cancer: meta-analysis. plos one 2013; 8:e85179. perletti print_stesura seveso 03/01/18 09:35 pagina 264 265archivio italiano di urologia e andrologia 2017; 89, 4 prostate cancer and prostatitis, meta-analysis correspondence gianpaolo perletti, phd (corresponding author) gianpaolo.perletti@uninsubria.it università degli studi dell’insubria department of biotechnology and life sciences via a. da giussano, 12 21052 busto a., italy elena monti, phd università degli studi dell’insubria department of biotechnology and life sciences via a. da giussano, 12 21052 busto a., italy vittorio magri, md urology secondary care clinic, asst-nord, milan, italy tommaso cai, md department of urology, santa chiara regional hospital, trento, italy anne cleves, mrs velindrencer nhs trust library, cardiff university, velindre cancer centre, cardiff, uk alberto trinchieri, md urology unit, a. manzoni hospital, lecco, italy emanuele montanari, md department of urology, university of milan fondazione ca' granda irccs ospedale maggiore policlinico, milan, italy 7. dennis lk, lynch cf, torner jc. epidemiologic association between prostatitis and prostate cancer. urology. 2002; 60:78-83. 8. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama 1999; 282:236-7. 9. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp 10. http://handbook.cochrane.org/ 11. sutton-tyrrell k. assessing bias in case-control studies. proper selection of cases and controls. stroke. 1991; 22:938-42. 12. egger m, davey smith g, schneider m, minder c. bias in metaanalysis detected by a simple, graphical test. bmj. 1997; 315:629-34. 13. begg cb, mazumdar m. operating characteristics of a rank correlation test for publication bias. biometrics. 1994; 50:1088-101. 14. duval s, tweedie r. trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. biometrics. 2000; 56:455-63. 15. https://www.erim.eur.nl/fileadmin/erim_content/images/metaessentials/meta-analyze_dichotomous_data.pdf 16. nair-shalliker v, yap s, nunez c, et al. adult body size, sexual history and adolescent sexual development, may predict risk of developing prostate cancer: results from the new south wales lifestyle and evaluation of risk study (clear). int j cancer. 2017; 140:565-574. 17. rybicki ba, kryvenko on, wang y, et al. racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer. prostate cancer prostatic dis. 2016; 19:145-50. 18. boehm k, valdivieso r, meskawi m, et al. prostatitis, other genitourinary infections and prostate cancer: results from a populationbased case-control study. world j urol. 2016; 34:425-30. 19. weinmann s, shapiro ja, rybicki ba, et al. medical history, body size, and cigarette smoking in relation to fatal prostate cancer. cancer causes control. 2010; 21:117-25. 20. cheng i, witte js, jacobsen sj, et al. prostatitis, sexually transmitted diseases, and prostate cancer: the california men's health study. plos one 2010; 5:e8736. 21. chao c, haque r, van den eeden sk, et al. red wine consumption and risk of prostate cancer: the california men's health study. int j cancer. 2010; 126:171-9. 22. hosseini m, seyed alinaghi s, mahmoudi m, mcfarland w. a case-control study of risk factors for prostate cancer in iran. acta med iran. 2010; 48:61-6. 23. huang wy, hayes r, pfeiffer r, et al. sexually transmissible infections and prostate cancer risk. cancer epidemiol biomarkers prev. 2008; 17:2374-81. 24. sutcliffe s, giovannucci e, de marzo am, et al. gonorrhea, syphilis, clinical prostatitis, and the risk of prostate cancer. cancer epidemiol biomarkers prev. 2006; 15:2160-6. 25. sarma av, mclaughlin jc, wallner lp, et al. sexual behavior, sexually transmitted diseases and prostatitis: the risk of prostate cancer in black men. j urol. 2006; 176:1108-13. 26. pelucchi c, talamini r, negri e, et al. genital and urinary tract diseases and prostate cancer risk. eur j cancer prev. 2006; 15:254-7. 27. patel da, bock ch, schwartz k, et al. sexually transmitted diseases and other urogenital conditions as risk factors for prostate cancer: a case--control study in wayne county, michigan. cancer causes control. 2005; 16:263-73. 28. rothman i, stanford jl, kuniyuki a, berger re. self-report of prostatitis and its risk factors in a random sample of middle-aged men. urology. 2004; 64:876-9. 29. roberts ro, bergstralh ej, bass se, et al. prostatitis as a risk factor for prostate cancer. epidemiology. 2004; 15:93-9. 30. rosenblatt ka, wicklund kg, stanford jl. sexual factors and the risk of prostate cancer. am j epidemiol. 2001; 153:1152-8. 31. wright jl, lin dw, stanford jl. circumcision and the risk of prostate cancer. cancer. 2012; 118:4437-43. 32. guyatt gh, oxman ad, kunz r, et al. grade guidelines 6. rating the quality of evidence imprecision. j clin epidemiol. 2011; 64:1283-93. 33. kheirandish p, chinegwundoh f. ethnic differences in prostate cancer. br j cancer. 2011; 105:481-5. 34. collins mm, meigs jb, barry mj, et al. prevalence and correlates of prostatitis in the health professionals follow-up study cohort. j urol. 2002; 167:1363-6. 35. nickel jc, roehrborn cg, o'leary mp, et al. the relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the reduce trial. eur urol. 2008; 54:1379-84. 36. nickel jc, roehrborn cg, o'leary mp, et al. examination of the relationship between symptoms of prostatitis and histological inflammation: baseline data from the reduce chemoprevention trial. j urol. 2007; 178:896-900. 37. benedetti i, bettin a, reyes n. inflammation and focal atrophy in prostate needle biopsy cores and association to prostatic adenocarcinoma. ann diagn pathol. 2016; 24:55-61. 38. porcaro ab, novella g, mattevi d, et al. chronic inflammation in prostate biopsy cores is an independent factor that lowers the risk of prostate cancer detection and is inversely associated with the number of positive cores in patients elected to a first biopsy. curr urol. 2016; 9:82-92. 39. moreira dm, nickel jc, gerber l, et al. baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the reduce study. cancer. 2014; 120:190-6. 40. kryvenko on, jankowski m, chitale da, et al. inflammation and preneoplastic lesions in benign prostate as risk factors for prostate cancer. mod pathol. 2012; 25:1023-32. perletti print_stesura seveso 03/01/18 09:35 pagina 265 stesura seveso 237archivio italiano di urologia e andrologia 2019; 91, 4 original paper does duration of stenting increase the risk of clinical infection? tuncay toprak, aytaç şahïn, musab ali kutluhan, korhan akgul, yavuz onur danacioglu, mehmet akif ramazanoglu, ayhan verit department of urology, fatih sultan mehmet training and research hospital, istanbul, turkey. objective: we investigated when an indwelling ureteral catheter should be withdrawn for infection and evaluated the importance of urinary cultures in identifying colonized microorganisms and define the bacterial flora encountered in the study. moreover, this study tried to determine the clinical role of stent culture in clinical practice. material and methods: the study was conducted between june 2018 and february 2019. patients with ureteral stent implantation after endoscopic ureteral stone treatment were divided into two groups and each group consisted of 45 patients. ureteral catheter was removed 15 and 30 days after ureteral stone treatment in group 1 and 2, respectively, and transferred for microbiological examination. the urine culture was obtained before and after ureteral stent implantation. the groups were compared in terms of demographics, urine and catheter cultures results. urine analysis and catheter culture results were also compared. results: demographic data of patients were similar in both groups. 3 patients in group 1 and 12 patients in group 2 had positive urine culture before catheter retraction; 2 of 45 and 6 of 45 patients had positive catheter culture in group 1 and 2, respectively. although 2 patients in group 1 and 4 patients in group 2 had urine culture sterile, they had growth in catheter culture. in group 1, 1 of the microorganisms was e. fecalis and 1 was e. coli. in group 2, 2 cases were e. fecalis, 3 were e. coli and 1 was mrse. there was no significant difference between the urine analysis results of the patients before catheter retraction and catheter culture positivity. conclusions: pre-operative urine culture does not exclude catheter colonization, and the prolonged duration of the catheter associated with greater colonization and may be associated urinary tract infection. ureteral catheter should be removed as early as possible. key words: duration; ureteral stents; colonization. submitted 15 june 2019; accepted 23 july 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.237 introduction ureteral stenting is commonly used for drainage of the obstructed or infected upper urinary tract. although ureteral stent application is not routinely recommended after each ureteroscopy (1) ureteral stents were inserted before the procedure to relieve pain to 7 to 68% of patients who underwent ureteroscopy (2). ureteral stent is often colonized and incrustated, because it is in direct contact with urine after insertion (3) and sterile urine cultures do not exclude bacterial colonization on ureteral stents and postoperative urinary tract infection (4). many studies indicated there is no significant difference between stents and urine cultures, complicating the selection of appropriate antibiotics even when bacteria are identified in urine culture (5, 6). we investigated when an indwelling ureteral catheter should be withdrawn for infection and evaluated the importance of urinary cultures in identifying colonized microorganisms and define the bacterial flora encountered in the study. moreover, this study tried to determine the clinical role of stent cultures in clinical practice. material and methods this prospective study was approved by the institutional ethics committee of fatih sultan mehmet training and research hospital (fsm eah-kaek 2019/13) and was conducted between june 2018 and february 2019. all patients gave an informed consent for participation in the study. patients who underwent ureteral stent implantation after endoscopic ureteral stone treatment were included in this study. the patients who had positive urine culture before ureteral stone treatment and who underwent ureteroscopy for other reasons and patients who had diabetes mellitus, chronic renal diseases, or immune suppression were not included in this study. patients were divided into two groups and each group consisted of 45 patients. at the beginning and before catheter retraction urine culture were obtained from mid-stream voided urine. stents were inserted and removed under aseptic conditions with 22 fr rigid cystoscope. intravenous second-generation cephalosporin was given 30-60 minutes before stent placement. a polyurethane double j stents (djs; uromed, oststeinbek, germany) was used for insertion. ureteral catheters were removed 15 and 30 days after ureteral stone treatment in group 1 and 2, respectively. the ureteral stents were transferred to the microbiological examination immediately. post-operative antibiotics were not given. urine culture and ureteral catheter culture results of patients were compared between groups. urine analysis results and catheter culture results were also compared. statistical analysis when evaluating the findings obtained in this study, ibm spss statistics 22 for statistical analysis (spss ibm, turkey) toprak_stesura seveso 14/01/20 12:44 pagina 237 archivio italiano di urologia e andrologia 2019; 91, 4 t. toprak, aytaç şahïn, m. ali kutluhan, k. akgul, y. onur danacioglu, m. akif ramazanoglu, a. verit 238 programs were used. the conformity of the parameters to the normal distribution was evaluated by shapiro wilks test. for evaluation of study data, chi-square test was used to compare qualitative data as well as descriptive statistical methods. significance was evaluated as p < 0.05. results a total of 90 patients were included in this study. patients were randomized into two groups. patients’ characteristics are summarized in table 1. male/female ratio was 1.5 in group 1 and 1.25 in group 2. the mean age was 45.6 in group 1 and 42.7 in group 2. no significant difference was observed between the groups in terms of age and gender. the urine culture of all patients was sterile before catheter insertion. urine culture taken before catheter retraction was positive in 3 patients in group 1 and 12 patients in group 2. table 2 shows comparison of bacterial growth between groups. patients with positive urine culture were treated with appropriate antibiotics before ureteral catheter withdrawal. three patients with positive urine culture in group 1 had no bacterial growth in catheter culture after antibiotic treatment. two of 12 patients with positive urine culture in group 2 had the same microorganisminduced growth in catheter culture after antibiotic treatment. although 2 patients in group 1 and 4 patients in group 2 had urine culture sterile, they had growth in catheter culture. as shown in table 3; one of the microorganisms isolated from urine culture in group 1 was e. fecalis and one of was e. coli. in group 2, 2 cases were e. fecalis, 3 were e. coli and 1 was mrse. the urine analysis of the patients before the procedure was investigated for nitrite positivity, leukocyte esterase positivity and pyuria and compared with catheter culture results. as shown in table 4 no statistically significant difference was found between catheter culture and urine analysis results. the duration of surgical procedures ranged from 9 to 37 minutes, but the relationship between the duration of surgery and colonization was not investigated. discussion ureteral stents are usually effective and safe in order to deliver urine from kidney to the bladder. however, they can lead to various complications, one of them being urinary infection (7). after stent insertion biofilm formation starts immediately, however, the time required for bacteria to colonize the stent has not yet been defined (3). several studies showed the ability of uropathogens such as e. coli, proteus mirabilis, staphylococcus epidermidis, and enterococcus faecalis to form biofilms on ureteral stents within 24 hours (8, 9). biofilm formation process on a ureteral catheter is well defined by some studies (10), and begins with the early development of the first membrane on the catheter. bacteria on this membrane can more easily adhere and multiply. this environment protects bacteria from antibacterial factors (3) and bacteria appear to be more resistant to antibiotics by developing resistance genes to antibiotics (11). consequently, it is not surprising that stent colonization is frequently encountered. in our study approximately 9% of our patients hosted one microorganism and 87.5% of these colonies included gram-negative bacteria. this rate is similar to rates described by other publications that are below 50% for a mean catheterization time between 2 and 9 weeks (6, 12-14). stent retention time in the ureter increases the likelihood of biofilm formation and so the duration of stenting is considered to be a critical factor for bacterial proliferation (13). however, some reports (6, 15) didn’t find a meaningful relationship between positive cultures and catheterization time. in our study, patients in group 2 had more bacterial growth in ureteral stent cultures than group 1 patients. female gender in table 1. comparison of demographic characteristics between groups. group 1 (n = 45) group 2 (n = 45) p value m/f (%) 60/40 55.5/44.5 > 0.05 age, years, mean 45.6 (min 19 , max 73) 42.7 (min 23, max 76) > 0.05 table 2. comparison of bacterial growth between groups. group 1 (n = 45) group 2 (n = 45) p value urine culture (at the all of them sterile all of them sterile beginning or before ureteral catheter placement) urine culture (after ureteral 3 positive (6.6%) (2 of them women) 0.01 catheter placement or before 12 positive (26.6%) (8 of them women) ureteral catheter retraction) catheter culture results 3 of them sterile 10 of them sterile of patients with positive urine culture before catheter retraction (after antibiotic treatment) catheter culture in total 2 positive (4.4%) 6 positive (13.3%) 0.14 (1 of them women) (4 of them women) table 4. comparison of catheter culture and urine analysis. group 1 group 1 p value group 2 group 2 p value positive catheter negative catheter positive catheter negative catheter culture (n = 2) culture (n = 43) culture (n = 6) culture (n = 39) pyuria (> 5 leukocytes) 1 (%50) 18 (%41.8) 0.82 3 (%50) 21 (%53.84) 0.86 leukocyte esterase positivity 0 (%0) 4 (%9.3) 0.65 1 (%16.6) 3 (%7.6) 0.47 nitrite positivity 0 (%0) 3 (%6.9) 0.69 2(%33.3) 5 (%12.8) 0.19 table 3. bacteriology of the cultured ureteral stents. group 1 n (%) group 2 n (%) enterococcus fecalis 1(%2.2) 2(%4.4) mrse 0(%0) 1(%2.2) e. coli 1(%2.2) 3(%6.6) sterile 43(%95.5) 39(%86.6) total 45(%100) 45(%100) toprak_stesura seveso 14/01/20 12:44 pagina 238 various studies was found to be associated with a high rate of sepsis as a result of the high infection rate in this population (16). as expected, in our study 62.5% of patients with positive ureteral catheter culture were women, but we have not encountered symptomatic infection or sepsis. the relationship between urine and ureteral catheter cultures is not well defined. lojanapiwat (17) published urine culture results showing colonization in approximately two-thirds of patients, whereas klis et al. (5) indicated a large inconsistency between urine and ureteral catheter cultures. our data supports the discordance between preoperative urine and intraoperative stent culture. in this study, 6 patients had positive stent culture despite sterile urine culture. sterile urine culture in the presence of foreign bodies doesn’t prevent stent colonization, and this may cause urinary tract infection (18). although some studies have reported the opposite (15), in our study, the most common pathogen in ureteral catheter cultures were e. coli and enterococci. in literature, there are also other publications reporting that e. coli (4, 17) and enterococci (6) are most common in ureteral catheter culture. kehinde et al. (19) showed that bacteriuria and ureteral stent colonization increased significantly with a longer stenting time, female gender and presence of systemic diseases such as diabetic nephropathy, chronic renal failure and diabetes mellitus and recommended that patient of these categories should have shorter stenting time and antimicrobial prophylaxis to minimize infectious complications. another study (20) emphasized that early removal of the ureteral stent, 2 weeks after renal transplantation, reduced the rate of urinary tract infection. although not statistically significant our study gave similar results: longer duration of stenting was associated to higher colonization rate (4.4% for stents left for 15 days versus 13.3% for those left for 30 days). none of our patients had any systemic disease therefore the study of the correlation between presence of pathologies and colonization was not made. in conclusion, our study shows that results of urine cultures do not represent the results of ureteral stent cultures. e. coli is usually isolated and should be coated with preoperative antibiotics. our study demonstrates that the stents are colonized under natural conditions and that more awareness should be necessary before using these stents. our findings also showed that colonization of ureteral stents was not associated with the development of symptomatic infection. we didn’t found any symptomatic infection after stent removal and we found a colonization rate of 4.4% within 15 days and 13.3% within 30 days. limitations of our study we have given preoperative antibiotic treatment which may have affected bacterial flora. although a study (5) showed that colonization throughout the stent is consistent, we didn’t investigate different ureteral stent segments which could be colonized by different pathogens. our bacterial profile depends from local flora and could be not transferable to other centers. finally, stone culture was not done although bacteria within the stone could affect ureteral colonization. conclusions the clinical significance of bacterial colonization of ureteral stent seems to be low, and it seems that ureteral stents are safer, especially within 15 days when colonization is very low. urine analysis and urine culture results are not related with ureteral stent culture and prolongation of ureteral stent increases colonization. further studies are needed to determine the optimal indwelling time of ureteral stent after endoscopic ureter stone treatment. knowing the bacteriological flora of an institution is useful for evidence-based prophylactic and therapeutic application. it is not recommended to routinely send the stents to microbiological examination because it is not cost effective and increases the workload to the microbiology laboratory. stents should be withdrawn immediately if no more required. informed consent ureteral stent is frequently inserted after ureteral stone treatment. our study named ‘does stent duration increase the risk of clinical infection?’ will investigate the relationship between the duration of these ureteral stents with infection. the ureteral stent of some patients will be taken 15 days after the stone treatment and some of them will be taken 30 days later and sent to the microbiological examination. our research is multicentered and will be between september 2018 and january 2019. a total of 100 patients were planned to be included in the study. patients will be randomized into two groups. in the event of any unintended or unexpected health problems directly or indirectly related to the research, any medical intervention will be provided by us without any charge. you are completely free to participate in the research. failure to participate in this study will not necessarily affect your current treatment or relationship with your physician. you have the right to withdraw from the work by giving notice at any time; and if deemed necessary, you may be excluded from research by the investigator, provided that your medical condition is not harmed. if you participate in the research, you will not be charged any fees or charges for any expenses incurred in the study. the sample taken from you for research will be used only for this study. in addition, your information at the end of the research will serve only scientific purposes without your identity being disclosed. author's contribution toprak: project development, data collection, manuscript writing; şahin: data collection, statistical analysis; kutluhan: manuscript writing; akgul: revision; danacıoglu: data collection; ramazanoglu: data collection; verit: revision. references 1. blackmur jp, maitra nu, marri rr, et al., analysis of factors' association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. j endourol. 2016; 30: 963-969. 239archivio italiano di urologia e andrologia 2019; 91, 4 duration of stenting and infection toprak_stesura seveso 14/01/20 12:44 pagina 239 archivio italiano di urologia e andrologia 2019; 91, 4 t. toprak, aytaç şahïn, m. ali kutluhan, k. akgul, y. onur danacioglu, m. akif ramazanoglu, a. verit 240 2. sivalingam s, stormont im, nakada sy. contemporary practice patterns in the management of acute obstructing ureteral stones. j endourol. 2015; 29: 736-740. 3. zumstein v, betschart p, albrich wc, et al. biofilm formation on ureteral stents-incidence, clinical impact, and prevention. swiss med wkly. 2017; 147:w14408. 4. farsi hm, mosli ha, al-zemaity mf, et al. bacteriuria and colonization of double-pigtail ureteral stents: long-term experience with 237 patients. j endourol. 1995; 9:469-72. 5. klis r, korczak-kozakiewicz e, denys a, et al. relationship between urinary tract infection and self-retaining double-j catheter colonization. j endourol. 2009; 23:1015-1019. 6. lifshitz da, winkler hz, gross m, et al. predictive value of urinary cultures in assessment of microbial colonization of ureteral stents. j endourol. 1999; 13:735-8. 7. vallejo jh, burgos fr, alvarez ja, et al. double j ureteral catheter. clinical complications. arch esp urol. 1998; 51:361-373. 8. stickler dj. bacterial biofilms in patients with indwelling urinary catheters. nature reviews urology. 2008; 5:598. 9. gabi m, hefermehl l, lukic d, et al. electrical microcurrent to prevent conditioning film and bacterial adhesion to urological stents. urol res, 2011; 39:81-88. 10. reid g, denstedt jd, kang ys, et al. microbial adhesion and biofilm formation on ureteral stents in vitro and in vivo. j urol. 1992; 148:1592-1594. 11. kiran md, giacometti a, cirioni o, balaban n. suppression of biofilm related, device-associated infections by staphylococcal quorum sensing inhibitors. int j artif organs. 2008; 31:761-70. 12. paick sh, park hk, oh sj, kim hh. characteristics of bacterial colonization and urinary tract infection after indwelling of double-j ureteral stent. urology. 2003; 62:214-217. 13. kehinde eo, rotimi vo, al-hunayan a, et al. bacteriology of urinary tract infection associated with indwelling j ureteral stents. j endourol. 2004; 18:891-896. 14. aydin hr, irkilata l, aydin m, et al. incidence of bacterial colonisation after indwelling of double-j ureteral stent. arch ital urol androl. 2016; 87:291-4. 15. kozyrakis d, perikleous s, chatzistamou s-e, et al. is there a role for double j stent culture in contemporary urology? urol int. 2018; 100:203-208. 16. de la rosette j, denstedt j, geavlete p, et al., the clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. j endourol. 2014; 28:131-139. 17. lojanapiwat b. colonization of internal ureteral stent and bacteriuria. world j urol. 2006; 24:681-683. 18. grabe m, botto h, cek m, et al. preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. world j urol. 2012; 30:39-50. 19. kehinde eo, rotimi vo, al-awadi ka, et al. factors predisposing to urinary tract infection after j ureteral stent insertion. j urol. 2002; 167:1334-7. 20. coskun ak, harlak a, ozer t, et al. is removal of the stent at the end of 2 weeks helpful to reduce infectious or urologic complications after renal transplantation? transplant proc. 2011; 43:813-5 correspondence tuncay toprak, md (corresponding author) drtuncay55@hotmail.com aytaç şahïn, md draytacsahin@gmail.com musab ali kutluhan, md dr.musab151@gmail.com korhan akgul, md korhanakgul@gmail.com ayhan verit, md veritayhan@yahoo.com department of urology, fatih sultan mehmet training and research hospital, istanbul (turkey) yavuz onur danacioglu, md dr_yonur@hotmail.com department of urology, bakirkoy dr. sadi konuk training and research hospital, istanbul (turkey) mehmet akif ramazanoglu, md maramazanoglu@hotmail.com urology, rize state hospital, rize (turkey) toprak_stesura seveso 14/01/20 12:44 pagina 240 stesura seveso 97archivio italiano di urologia e andrologia 2019; 91, 2 original paper increased neutrophil/lymphocyte ratio in testicular cancer aytaç şahin, tuncay toprak, musab ali kutluhan, yasin vural, ahmet ürkmez, ayhan verit sbu fatih sultan mehmet training and research hospital, istanbul. objective: testicular cancers, which are less common than other cancers, are important in terms of being seen in young people. physical examination, imaging, laboratory and tumor markers are used for diagnosis. there are some studies of some blood parameters that can be involved in inflammation and tumorogenesis. we retrospectively compared hematological values measured in our patients who were diagnosed with testicular tumor in comparison with patients with similar age group who underwent varicocelectomy repair. materials and methods: this cross-sectional retrospective study included 120 patients who underwent radical inguinal orchiectomy for testicular tumor between january 2010 and december 2018, and 171 patients who underwent varicocelectomy as a control group. patients with an active infection and hematological disorders were excluded from the study. we evaulated hematological parameters including neutrophil (neu), lymphocyte (lym), platelet (plt) count, and mean platelet volume. the study was conducted on 291 patients. divided in two groups: tumor (n = 120) and varicocele (n = 171). results: there was no statistically significant difference between the groups in terms of plt / lymphocyte ratio and mean platelet volume (mpv) levels (p > 0.05). the neutrophil /lymphocyte ratio (nlr) of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05). there was a statistically significant difference between the tumor stages in terms of plt / lymphocyte ratios (p = 0.006; p < 0.05). conclusions: there was only a statistically significant increase in nlr values in the testicular tumor group compared to the varicocele group. larger, randomized controlled studies are needed at this field. key words: testis; cancer; mean platelet volume (mpv); neutrophil/lymphocyte ratio (nlr). submitted 13 january 2019; accepted 2 april 2019 summary no conflict of interest declared. diagnosis more effective treatment schedules can be applied contributing to better survival. at this point, simple, inexpensive and easily applicable markers can be useful in the clinical approach. there are some studies that some blood parameters can be associated to inflammation and tumorogenesis. studies have shown that inflammatory response is closely related to tumorigenesis and tumor invasion (2). interactions occur between the tumor and inflammation according to complex and various mechanisms. at each stage of carcinogenesis; inflammation has an important role (3). changes in systemic inflammatory response can be assessed by hematological parameters. for example, changes in c-reactive protein (crp) and neutrophil to lymphocyte ratio (nlr) show signs of systemic inflammatory response in various malignancies (4). there are also reports that elevated nlr is associated with poor prognosis in some urothelial cancers (5). the vast majority of studies have reported that the increase in nlr is associated with poor prognosis in many malignant tumors. for this reason, nlr can be used not only as a marker of systemic inflammatory response, but also in various tumor types and inflammatory conditions (6). in order to predict cancer prognosis and inflammatory conditions, there is a growing interest in simple blood methods such as nlr. nlr, lymphocytemonocyte ratio (lmr), platelet-lymphocyte ratio (plr) and mean platelet volume (mpv) can be used as factors to determine the prognosis of patients in various clinical situations (7). platelets are seedless cells derived from megakaryocytes in the bone marrow. platelets, an element of the immune system, also play a role in cancer formation, progression and metastatization. it is known that activated platelets have critical roles in tumor proliferation, neoangiogenesis and release of mitogenic mediators in the microenvironment of cells that exhibit tumoral behavior, although their production, maturation and clearance from circulation are still not fully elucidated (8). yun zy et al. reported that decreased mpv may be a marker of poor prognosis in renal cell cancer (9). because it is known that mpv is an index of bioactive platelets activated for any reason and incorporated into the inflammation process, rather than platelet count (10). these markers, which are easily applicable in practice, were retrospectively analyzed in our patients who were diagnosed with testicular tumor and compared with the values of patients with similar age group of patients who underwent varicocelectomy repair. doi: 10.4081/aiua.2019.2.97 introduction testicular cancers, which are less common than other cancers, are important because they are often seen in young people. it is the most common solid organ cancer in men between the ages of 15-35 while it contitutes 11.5% of all male cancers. in developed countries there is an increase incidence for testicular cancer (1). both testes can be easily examined and results of early diagnosis of testicle tumours are very favorable enhancing the importance of early diagnosis and treatment of testicular tumors. physical examination, imaging, laboratory and tumor markers are used for diagnosis. with early archivio italiano di urologia e andrologia 2019; 91, 2 a. şahin, t. toprak, m. ali kutluhan, yasin vural, a. ürkmez, a. verit 98 materials and methods this cross-sectional retrospective study included 120 patients who underwent radical inguinal orchiectomy for testicular tumor between january 2010 and december 2018, and 171 patients who underwent varicocelectomy as a control group. patients with acute infections, chronic inflammatory disease, malignancies or hematological disorders, those using anticoagulant treatment, and subjects with a history of hormonal treatment in the last 12 months or blood product administration in the last month were excluded. hematological parameters were evaluated with peripheral blood samples taken preoperatively. these hematological parameters include neutrophil (neu), lymphocyte (lym), platelet count, and mean platelet volume (mpv). the staging of patients with testicular tumors was performed by examining the computed tomography and by measurement of beta human chorionic gonadotropin, alpha fetoprotein and lactate dehydrogenase (ldh) as tumor markers. statistical analysis to evaluate the findings obtained in this study, ibm spss statistics 22 for statistical analysis (spss ibm, turkey) program was used. conformity of the parameters to the normal distribution was evaluated by the shapiro wilks test. descriptive statistical values were computed (mean, standard deviation, frequency) and the comparison of quantitative data were done by kruskal wallis test and the mann whitney u test was used for the determination of the group causing the difference. mann-whitney u test was used for the two-group comparisons of the parameters that did not show normal distribution, and student's t test was used for the parameters with normal distribution. the cut-off point was chosen based on the roc curve analysis. a p < 0.05 was considered significant. results the study was conducted on 291 patients with ages ranging from 1 to 85 years. the mean age was 34.25 ± 16.56 years. the cases were divided into two groups: tumor (n = 120) and varicocele (n = 171). there was no statistically significant difference between the groups in terms of plt/lymphocyte ratio and mpv levels (p > 0.05). the neutrophil/lymphocyte ratio of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05) (table 1, figure 1). there was a statistically significant difference between the tumor stages in terms of plt/lymphocyte ratios (p = 0.006; p < 0.05). paired comparisons demonstrated that plt/lymphocyte ratio of pt3 group was significantly higher than pt1 and pt2 (p1 = 0.002; p2 = 0.003; p < 0.05). there was no significant difference between pt1 and pt2 stages (p > 0.05). there was no statistically significant difference in neutrophil/lymphocyte ratio and mpv levels between tumor stages (p > 0.05) (table 2). the roc curve for neutrophil/lymphocyte ratio (nlr) was plotted in the diagnosis of testicular tumor. the area table 1. evaluation of groups in terms of plt/lymphocyte, neutrophil/lymphocyte ratio and mpv. tumor varicocele p mean ± sd (median) mean ± sd (median) plt/lymphocyte 128.91 ± 95.19 (110.4) 125.45 ± 63.3 (110.8) 0.9071 neutrophil/lymphocyte 4.22 ± 3.54 (3.5) 3.49 ± 2.79 (2.7) 0.001*, 1 mpv 8.05 ± 1.46 8.28 ± 1.56 0.2142 1 mann whitney u test; 2 student t test; * p < 0.05. table 2. evaluation of groups in terms of plt/lymphocyte, neutrophil/lymphocyte ratio and mpv. pt1 (n = 60) pt2 (n = 43) pt3 (n = 5) p mean ± sd (median) mean ± sd (median) mean ± sd (median) plt/lymphocyte 115.57 ± 58.01 (108.1) 140 ± 135.35 (110.4) 231.27 ± 74.21 (212.5) 0006* neutrophil/lymphocyte 3.83 ± 2.58 (3.4) 4.62 ± 4.94 (3.5) 5.78 ± 1.87 (6.3) 0.108 mpv 8.26 ± 1.62 (7.9) 7.92 ± 1.19 (7.8) 7.24 ± 0.82 (7.2) 0.107 kruskal wallis test; * p < 0.05. note: since the number of patients with pt3 was 5, kruskal wallis test was used despite the normal distribution of mpv. figure 1. stone expulsion duration in the groups. under the curve is 0.612 and the standard deviation is 0.03. the area under the roc curve was significantly higher than 0.5 (p = 0.001; p < 0.05). the cut-off point for nlr in the diagnosis of testicular tumor is > 3.16. the sensitivity of this value was 63.87% and the specificity was 63.16% (figure 2). discussion inflammation plays an important role in tumor development and progression. the relationship between inflammation and cancer has long been known. in 1863, virchow put forward the hypothesis that cancer occurs in the areas of chronic inflammation, and that some irritants increase cell proliferation along with inflammation leading to tissue injury (11). although the effect of this proliferation is clear, cells alone do not cause cancer. continuous cell proliferation, inflammatory cells, growth factors, activated stroma and dna-damage enhancing agents increase or promote neoplastic risk. neutrophils mediate inflammation through various biochemical mechanisms such as release of arachidonic acid metabolites and platelet aggravating factors (12). neutrophilia could represent a consequence of ectopic production of myeloid growth factors as part of a paraneoplastic syndrome (13) or, more likely, a nonspecific response to cancer-related inflammation secondary to tissue destruction and cytokine releases. lymphopenia is associated with cortisol induced stress response (12). high nlr occurring as a result of the added effect of increased neu response to lym suppression can support the development of cancer by inhibiting the antitumor immune response (14). experimental data have shown that active neutrophils can stimulate tumor growth directly and indirectly (15). nlr and platelet/lymphocyte ratio (plr) have also been shown to be reliable markers of systemic inflammation by many studies (16). according to the type of malignancy, inflammatory and immune responses to systemic tumor cells and secreted peptides can vary. today, systemic inflammatory response indicators such as cytokine, crp, albumin, serum amyloid a and leukocytes have gained importance in the patients with malignancy and it has been thought that they can be independent prognostic factors (17). the immune system has a positive and negative effect on cancer development and progression. it can eliminate tumor cells or increase the metastatic ability and invasion capacities of active malignant cells, leading to tumor progression. the excess of circulating neus is thought to play an important role in tumor progression and angiogenesis. therefore, increased number of neus should be associated with poor prognosis (18). mpv represents the mean platelet size in the blood. it can be altered in various diseases such as cancer, thrombosis, sepsis, respiratory distress syndrome, and acute appendicitis (19). plts are frequently observed in the cancer microenvironment and are thought to stimulate proliferation and transformation of cancer cells by platelet derived growth factor (pdgf) release (20). in the study of russell et al., it was reported that increased pdgf alpha receptor expression was associated with bone metastasis in castration-resistant pca (21). even in the current literature, anti-platelet therapy has been reported to have a role in pca adjuvant therapy (22). mpv measurement is a useful method in determining the presence of these activated plts (9). a high mpv means that your platelets are larger than average. this is sometimes a sign that you're producing too many platelets. platelets are produced in the bone marrow and released into the bloodstream. larger platelets are usually young and more recently released from the bone marrow. smaller platelets are more likely to have been in circulation for a few days. when someone has a low platelet count and a high mpv level, it suggests that the bone marrow is rapidly producing platelets. this may be because older platelets are being destroyed, so the bone marrow is trying to compensate. increased mpv is associated with platelet activation, which can happen when platelets encounter tumor byproducts. still, a high mpv doesn't mean you have cancer. the diagnostic role of mean platelet volume (mpv) is reported in various malignant tumors such as ovary (23), pancreas (24), and colon (25) cancers, the diagnostic and prognostic role of mpv cannot be precisely demonstrated for testicular tumors. in a study conducted by gokcen k et al., 36 patients with testicular tumors were investigated. wbc, neu, plr, and nlr values were significantly higher in testicular tumors however mpv was significantly lower than the control group p < 0.05). also differences between hematological parameters of patients with testicular cancer according to the stages were examined, and differences were observed between mean corpuscular volume (mcv), mean corpuscular hemoglobin (mch) and mean platlet volume (mpv) (p < 0.05). mcv was significantly higher in stage 1 compared 99archivio italiano di urologia e andrologia 2019; 91, 2 increased neutrophil/lymphocyte ratio in testicular cancer figure 2. roc curve for nlr in the diagnosis of testicular tumor. cut off point determination for nlr in the diagnosis of testicular tumors. archivio italiano di urologia e andrologia 2019; 91, 2 a. şahin, t. toprak, m. ali kutluhan, yasin vural, a. ürkmez, a. verit 100 to stage 2 or 3 tumour (p = 0.035 and p = 0.025, respectively). mch was significantly higher in stage 1 compared to stage 3 (p = 0.022). mpv was significantly lower in stage 1 compared to stage 3 (p = 0.016) (26). in our study, the neutrophil/lymphocyte ratio of the tumor group was significantly higher than the varicocele group (p = 0.001; p < 0.05), but there was no statistically significant difference between the groups in terms of plt/lymphocyte ratio and mpv levels (p > 0.05). on the other hand we found that there was no statistically significant difference between the tumor stages in terms of neutrophil/lymphocyte ratio and mpv levels (p > 0.05). in contrast, there was a statistically significant difference in terms of plt/lymphocyte ratios (p: 0.006; p < 0.05). as a result of paired comparisons plt/lymphocyte ratio of pt3 group was significantly higher than pt1 and pt2 (p1: 0.002; p2: 0.003; p < 0.05). there was no significant difference between pt1 and pt2 stages (p > 0.05). limited numbers of reports are available on immune resistance in patients with testicular cancer. considerable evidence supports the view that the biological behavior of tumors and in particular, their capacity to metastasize are in part determined by immunological factors requiring participation of t lymphocytes, b lymphocytes, macrophages and natural killer cells. immunological reactivity has been analyzed in a wide spectrum of solid tumors and a vast literature indicates a correlation between depressed cell-mediated immunity and the stage of the disease. on the contrary, there is little evidence about the role of immunological factors in the development and spread of testicular tumors. conclusions in this study, there was only statistically significant increase in nlr values in the testicular tumor group compared to the varicocele group. there was no statistically significant result for mpv and plr. in the evaluation of patients with testicular tumors according to their stages, the plt/lymphocyte ratio of the pt3 group was found to be significantly higher than the pt1 and pt2 stages. although there are many studies on hematological parameters related to other cancers, there is limited data for testicular tumors in the literature. the limitations of our study were that it was a retrospective one with limited study group and had not a prognostic predictive design. larger, randomized controlled studies are needed at this field. references 1. borghesi m, brunocilla e, schiavina r, et al. role of testis sparing surgery in the conservative management of small testicular masses: oncological and functional perspectives. actas urol esp. 2015; 39:57-62. 2. gregory ad, houghton am. tumor associated neutrophils: new targets for cancer therapy. cancer res. 2011; 71:24116. 3. grivennikov si, greten fr, karin m. immunity, inflammation, and cancer. cell 2010; 140:88399. 4. duan h, zhang x, wang fx, et al. prognostic role of neutrophil lymphocyte ratio in operable esophageal squamous cell carcinoma. world j gastroenterol. 2015; 21:55917. 5. viers br, boorjian sa, frank i, et al. pretreatment neutrophil to lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. eur urol. 2014; 66:115764. 6. templeton aj, mcnamara mg, šeruga b, et al. prognostic role of neutrophil to lymphocyte ratio in solid tumors: a systematic review and metaanalysis. j natl cancer inst. 2014; 106:dju124. 7. lee js, kim ny, na sh, et al. reference values of neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, and mean platelet volume in healthy adults in south korea. medicine (baltimore) 2018; 97:e11138. 8. goubran ha, stakiw j, radosevic m, et al. platelet-cancerinteractions. semin thrombhemost. 2014; 40:296-305. 9. yun zy, zhang x, liu zp, et al. association of decreased mean platelet volume with renal cell carcinoma. int j clin oncol. 2017; 22;1076-1080. 10. gasparyan ay, ayvazyan l, mikhailidis dp, et al.meanplateletvolume: a link between thrombosis and inflammation. curr pharm des. 2011; 17:47-58. 11. balkwill f, mantovani a. inflammation and cancer: back to virchow? lancet. 2001; 357:539-545. 12. tamhane uu, aneja s, montgomery d, et al. association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. am j cardiol. 2008; 102:653-7. 13. vassilatou e, fisfis m, morphopoulos g, et al. papillary thyroid carcinoma producing granulocyte-macrophage colony-stimulating factor is associated with neutrophilia and eosinophilia. hormones (athens). 2006; 5:303-9. 14. schaider h, oka m, bogenrieder t, et al. differential response of primary and metastatic melanomas to neutrophils attracted by il 8. int j cancer. 2003; 103:33543 15. fridlender zg, sun j, kim s et al. polarization of tumor-associated neutrophil phenotype by tgf-beta: “n1”versus “n2” tan. cancer cell. 2009; 16:183-94. 16. guthrie gj, charles ka, roxburgh cs, et al. the systemic inflammation-based neutrophil lymphocyte ratio: experience in patients with cancer. crit rev oncol hematol. 2013; 88:218-30. 17. moore mm, chua w, charles ka, clarke sj. inflammation and cancer: causes and consequences. clin pharmacol ther. 2010; 87:5048. 18. kusumanto yh, dam wa, hospers ga, et al. platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. angiogenesis. 2003; 6:2837. 19. albayrak y, albayrak a, albayrak f, et al. mean platelet volume: a new predictor in confirming acute appendicitis diagnosis. clin appl thromb hemost. 2011; 17:362-6. 20. ustach cv, taube me, hurst nj, et al. a potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. cancer res. 2004; 64:1722-9. 21. russell mr, liu q, fatatis a. targetingthe {alpha} receptor for platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis. clin cancer res. 2010; 16:5002-10. 22. mezouar s, frere c, darbousset r, et al. role of platelets in cancerandcancer-associated thrombosis: experimental and clinical evidences. thromb res. 2016; 139: 65-76. 23. kemal y, demirag g, ekiz k, et al. mean platelet volume could be a useful biomarker for monitoring epithelial ovarian cancer. j obstet gynaecol. 2014; 34:515-8. 24. karaman k, bostanci eb, aksoy e, et al. the predictive value of mean platelet volume in differential diagnosis of non functional pancreatic neuroendocrine tumors from pancreatic adenocarcinomas. eur j intern med. 2011; 22:e95-8. 25. kilincalp s, çoban s, akinci h, et al. neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as potential biomarkers for early detection and monitoring of colorectal adenocarcinoma. eur j cancer prev 2015; 24:328-3. 26. gokcen k, dundar g, gulbahar h, et al. can routine peripheral blood counts like neutrophil to lymphocyte ratio be beneficial in prediagnosis of testicular cancer and its stages? j res med sci. 2018; 23:64. 101archivio italiano di urologia e andrologia 2019; 91, 2 increased neutrophil/lymphocyte ratio in testicular cancer correspondence aytaç şahin md (corresponding author) draytacsahin@gmail.com tuncay toprak, md drtuncay55@hotmail.com musab ali kutluhan, md dr.musab151@hotmail.com yasin vural, md yasin_vural@windowslive.com ahmet urkmez, md ahmeturkmez@hotmail.com ayhan verit, prof. veritayhan@yahoo.com urology clinic sbu fatih sultan mehmet training and research hospital atasehir, i̇stanbul 34752 turkey 199archivio italiano di urologia e andrologia 2018; 90, 3 original paper serenoa repens extracts: in vitro study of the 5α-reductase activity in a co-culture model for benign prostatic hyperplasia daniela buonocore 1, manuela verri 1, laura cattaneo 1, sara arnica 1, michele ghitti 2, maurizia dossena 1 1 university of pavia, pavia (italy), department of biology and biotechnology “l. spallanzani”; 2 university of pavia, pavia (italy), department of earth and environmental sciences (dsta) unit of statistical analyses (unistat). objectives. benign prostatic hyperplasia (bph) is a form of benign tumor that occurs in humans mainly with ageing. it affects more than 50% of over 50 years old males and it is characterized by an increased synthesis of dihydrotestosterone (dht), due to the 5α-reductase activity. the bph therapeutic approach mainly uses 5α-reductase inhibitors, such as the active compounds present in the extracts deriving from species serenoa repens. many lipidosterolic extracts are available on the market, which are obtained with different solvents, among them ethanol is recognized as non-toxic and has less handling risks than hexane. the purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of s. repens comparing it with an n-hexane one. materials and methods. two different lipido-sterolic extracts of s. repens have been tested: ethanol extract and n-hexane extract, two batches for each one. the inhibitory action of the extract was evaluated estimating in-vitro the activity of enzyme 5α-reductase type i (5α-ri), which was mainly active under the experimental condition of ph 7.5. dht amount, synthesized from testosterone (1 μm), was evaluated in a co-culture model of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with bph. results. the analysis of the resulting dose-response curves showed that the entire s. repens extracts inhibited the 5α-ri showing no difference between the two kinds of extract or between the batches. the resulting ic50 values were the following: 8.809 (95% ci = 5.133-15.56) and 9.464 (95% ci = 5.09418.27) for ethanol extracts; 11.08 (95% ci = 6.389-19.98) and 12.72 (95% ci = 7.758-21.53) for n-hexane extracts. conclusions. the potency of ethanol extracts of s. repens was comparable with the one of n-hexane extracts. key words: benign prostatic hyperplasia; dihydrotestosterone; ethanol extracts; in-vitro study; 5α-reductase; serenoa repens. submitted 7 may 2018; accepted 12 july 2018 summary no conflict of interest declared. action of enzyme 5α-reductase, which leads to an increase of the prostate size and causes various disorders, especially in the lower urinary tract (1, 2). the approach for the treatment and therapy of bph is mainly based on the use of inhibitors of 5α-reductase enzyme, in particular natural inhibitors, such as the active compounds present in the alcoholic extracts deriving from species serenoa repens, a typical palm common in the subtropical sandy soils and in the southern coasts of the united states. although the sure mechanism of action of s. repens is not yet fully understood, numerous mechanisms have been proposed (3) and the presence of specific fatty acids (saturated and unsaturated fatty acids) and phytosterols in its alcoholic extracts confers upon s. repens an anti-inflammatory and above all antiproliferative action on prostatic tissue (4). both a systematic cochrane review of the literature (5) and a meta-analysis (6) assessed the safety profile and the clinical efficacy of s. repens in the treatment of symptoms in patients with bph. these studies have shown an improvement of urinary tract disorders, with a mild to moderate effect and, therefore, a lack of therapeutic equivalence between s. repens extracts of different brands and between extracts of a single brand, but belonging to different manufacturing batches (5, 6). many lipido-sterolic extracts are commercially available, which were obtained with different solvents, among them ethanol is recognized as non-toxic and it has less handling risks than hexane (7, 8). the purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of s. repens comparing it with an n-hexane one. in particular, the activity of enzyme 5α-reductase was estimated invitro concerning the inhibitory action of the extracts, using co-cultures of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with bph. materials and methods samples two extracts, belonging to commercial brands saba® (lampugnani farmaceutici) and permixon® (pierre fabre pharma), supplied with marketing authorization in doi: 10.4081/aiua.2018.3.199 introduction benign prostatic hyperplasia (bph) is a form of benign tumor that occurs in humans mainly with ageing. in fact, it affects more than 50% of over 50 years old males, with an incidence rate directly proportional to age (1). it is characterized by an increased synthesis of dihydrotestosterone (dht) starting from testosterone, due to the buonocore_stesura seveso 03/10/18 09:45 pagina 199 archivio italiano di urologia e andrologia 2018; 90, 3 d. buonocore, m. verri, l. cattaneo, s. arnica, m. ghitti, m. dossena 200 several eu member states (including italy) and belonging to the class of drugs employed to counter the increase in prostatic volume in males with bph, have been tested. the two branded drugs contained the lipid-sterolic extract of s. repens (320 mg/soft capsule) as active ingredient and particularly, ethanol extract (saba®) and hexane extract (permixon®). two different batches of each brand were tested: saba® (g08363 and g08364); permixon® (f 11917 and g07340), mentioned below as “samples”. the content of one soft capsule was weighed (10 mg) and dissolved in n-hexane; then the solvent was evaporated to leave the solid extract that was dissolved in ethanol (70%) to give a concentration of 10 mg/ml. this stock solution was further diluted in appropriate media to provide a working solution of 1 mg/ml (9). co-culture cell model two types of primary cells were used: epithelial cells and fibroblasts, previously isolated from prostatic tissue obtained during a biopsy from a patient with established bph. informed consent of the patient was obtained. primary cultures of fibroblast and epithelial cells were obtained as previously described (2). both the epithelial and fibroblast cells were cultured separately in flasks with culture medium, complete with fetal bovine serum (10%), dmem and rpmi 1640 respectively, and kept in an incubator in a humidified atmosphere (37°c and 5% co2). corresponding to the third generation step, both the epithelial cells and fibroblasts, were transferred into multiwell plates of 12 wells provided with transwell® (3470 clear-corning), or supports consisting of a microporous polystyrene membrane. this enabled to keep the two cell populations separate but, at the same time, to allow their interactions. in particular: epithelial cells were sown in the number of 50,000 on the bottom of each well; on the contrary, fibroblasts were sown in the number of 5,000 on the microporous polystyrene membrane. co-cultures were maintained in dmem:rpmi-1640 (1:1 v/v) media + 10% fetal calf serum at 37°c in 5% co2 (10). furthermore, in order to verify that the fibroblasts were correctly adhering to the membrane, the quantitative technique teer (transepithelial transendothelial electrical resistance) was applied; this technique enabled to examine the integrity of the cell junctions (tight junctions) by measuring the resistance that the monolayer of fibroblasts opposed to the passage of electric current (11). measurement of the trans-epithelial resistance value, expressed in ohms and normalized for the polystyrene membrane area (ω/cm²), was performed using a voltmeter (millicell® ers-2, merck millipore) equipped with two electrodes of different length (data not reported). 5α-reductase activity assay the co-culture cells were pre-treated for a period of four days with a non-toxic concentration (10 μg/ml) of each sample (saba®: g08363 and g08364; permixon®: f 11917 and g07340). afterwards the cells were harvested by trypsinization, centrifuged and the pellet was suspended in rpmi-1640, supplemented with 10% fetal calf serum, and then counted. the ph value of the medium solution was 7.85, an optimum value for the activity of 5 α-reductase type i (12). cell suspensions were added into tubes containing testosterone (1 μm) as substrate, a nadph-regenerating system (0.5 mm glucose-6-phosphate, 0.06 u glucose-6-phosphate dehydrogenase, 50 μm nadph) (h+ donor) (13) and different concentrations of each sample: 1 mg/ml, 100 μg/ml, 10 μ /ml, 5 μg/ml, 1 μg/ml, 0.1 μg /ml, 0.01 μg/ml; these concentrations were chosen basing on the cytotoxicity results, previously obtained in laboratory applying the mtt test (14)) and in agreement with data present in the literature (9, 10). the tubes were then incubated at 37° c for 30 min in a stirring water bath. the reaction was stopped by dipping the tubes into liquid nitrogen (9, 10, 12). the 5α-reductase type i activity was assessed by measuring the conversion of testosterone to dihydrotestosterone (dht) applying a qualitative/quantitative enzyme-linked immunosorbent assay (abnova ka1886), as previously described (15). enzyme activity is expressed as a percentage of the control. the conversion of 1 μm of testosterone in the absence of inhibitors is defined as 100% activity (2.953.63 nmol of dht/106 cells/min for type i isoenzyme). dose-effect response curves were analyzed using a sigmoid maximum-effect model with a variable slope (graphpad, prism7). inhibitory potency was assessed by estimating the ic50 value that represented the concentration (μg / ml) capable of determining the 50% of the maximal effect (enzymatic inhibition). the highest ic50 value was then divided by the ic50 values obtained for each sample for the relative potency (rp) (the relative potency value = 1 was considered the lowest value). statistical analysis the nonlinear-regression curves were analyzed applying two different linear mixed models, one to analyze the commercial brands (saba® vs permixon®) and one for the batches. the analyses were performed with software r. results all the samples of s. repens extracts (f 11917; g07340; g08363; g08364) were found to be capable of inhibiting 5α-reductase (5α-ri) in a prostatic co-cultured epithelial and fibroblast cells, as shown by dose-effect curves in figure 1 (enzyme activity (%) as a function of the logarithm of concentrations). regarding the potency of each sample, evaluated by ic50 value (table 1) and highlighted by the relative potency (table 2), saba® (ic50 = 8.809 and 9.464) showed a higher efficacy on 5α-ri than permixon® (ic50 = 11.08 and 12.72), but there were non-significant differences between the two brands and batches, as mentioned below. regarding the comparison between the two brands (saba® vs permixon®), the analysis of deviance (type iii tests) for 5α-ri data set showed that the model was non-significant (response: enzyme; chisq df pr (> chisq); (intercept) 28.3600 1 1.007e-07 ***; brand 2.9228 1 0.08734; signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1). buonocore_stesura seveso 03/10/18 09:45 pagina 200 regarding the comparison between the batches (f 11917; g07340; g08363; g08364), the analysis of deviance (type iii tests) showed that the model was non-significant [response: enzyme; chisq df pr (> chisq); (intercept) 28.0176 1 1.202e-07 ***; batch 2.9326 3 0.4021; signif. codes: 0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1]. regarding the relative potency (table 2), both saba® and permixon® showed comparable potencies between the two batches and permixon® showed the lowest values. discussion all the extracts of s. repens that we tested, saba® (g08363 and g08364) and permixon® (f 11917 and g07340), have shown to inhibit enzyme 5α-reductase in a co-culture model of human prostatic cells (epithelial and fibroblasts), as reported also in the literature (9, 10). even though the potency of saba samples of inhibiting the activity of enzyme 5α-reductase type i showed higher values than permixon’s values, there were no significant statistical differences between the two brands or the batches. these in-vitro results pointed out that the s. repens ethanol extract (saba®) was equivalent to the nhexane one (permixon®). this conclusion is important because basing on the equivalence of efficacy for both tested extracts, obtained with different extraction methods, it would be better to use organic solvents (ethanol) recognized as environmentally safer and alternative to hexane, which is a solvent obtained from petrochemical sources that can remain in potential traces in edible oils after refining and can be emitted during extraction and recovery and that has been identified as an air pollutant since it can react with other pollutants to produce ozone and photochemical oxidants (7, 8, 16). moreover, data that we obtained allow us to speculate on the possible effects of the ethanol extract from s. repens on the pathology of bph: it is known that clinical benefits are generally associated with the free fatty acid content, along with a small contribution from unsaponifiable components (17, 18). particularly, the relative inhibitory efficacy of the various free fatty acids seems to depend on the length of the carbon chain and its saturation state (17). for example, lauric acid (short saturated, c12 chain) inhibits both 5 α-reductase type i and ii, while oleic acid with a c18 unsaturated chain (c18 ∆9) and linoleic acid (c18 ∆9, 12) have a good activity on type i but not on type ii (15). saba® and permixon® (19) were analyzed in 201archivio italiano di urologia e andrologia 2018; 90, 3 s. repens inhibits 5α-reductase table 1. comparative potency of the two extracts on 5α-reductase type i, given by ic50 value and related 95% ci. permixon saba f11917 g07340 g08363 g08364 ic50 (5α-ri)1 11.08 12.72 8.809 9.464 95% ci2 6.39 to 19.98 7.76 to 21.53 5.13 to 15.56 5.09 to 18.27 15α-ri: 5α-reductase type i. 2ci: confidence interval. table 2. relative potency of the various extracts on 5α-reductase type i (considering rp = 1 as the lowest potency). 5α-ri1 saba saba permixon permixon batch g08363 g08364 f11917 g07340 rp2 1.444 1.344 1.148 1 15α-ri: 5α-reductase type i. 2rp: relative potency. figure 1. inhibition of 5α-reductase type i. enzyme activity, depending on the logarithm of concentrations, is expressed in percentage as compared with the positive control (100% of enzyme activity converting testosterone 1μm, in the absence of inhibitors). buonocore_stesura seveso 03/10/18 09:45 pagina 201 archivio italiano di urologia e andrologia 2018; 90, 3 d. buonocore, m. verri, l. cattaneo, s. arnica, m. ghitti, m. dossena 202 terms of concentration in free fatty acids, methyl and ethyl esters, long-chain esters and glycerides. these analyses revealed that each of the individual ffas analyzed was found in similar proportions in the tested products, with lauric and oleic acids present at the highest concentrations in every tested sample and similar concentrations of methyl and ethyl esters were found. instead, glyceride content was particularly high (420%) in saba® and not in permixon®. generally, a similar content composition was observed between saba® and permixon® (19). so, our results are explained by data reported above: similar content composition is associated with the same potency of ethanol and hexane extracts. conclusions ethanol extract of s. repens has shown in vitro a potency of inhibiting the activity of enzyme 5α-reductase comparable with potency of n-hexane extract of s. repens. references 1. rył a, rotter i, grzywacz a, et al. molecular analysis of the srd5a1 and srd5a2 genes in patients with benign prostatic hyperplasia with regard to metabolic parameters and selected hormone levels. int j environ res public health. 2017; 14:1318. 2. bayne cw, donnely f, chapman k, et al. a novel coculture model for benign prostatic hyperplasia expressing both isoforms of 5α-reductase. jcem. 1998; 83:206. 3. buck ac. is there a scientific basis for the therapeutic effects of serenoa repens in benign prostatic hyperplasia? mechanisms of action. j urol. 2004; 172:1792. 4. capasso f, de pasquale r, grandolini g. droghe contenenti lipidi. in: farmacognosia. botanica, chimica e farmacologia delle piante medicinali. italia: ed. springer verlag, 2014. 5. wilt t, ishani a, macdonald r. serenoa repens for benign prostatic hyperplasia. cochrane database syst rev. 2002; cd001423. 6. boyle p, robertson c, lowe f, roehrborn c. updated metaanalysis of clinical trials of serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. bjui. 2004; 39:751. 7. johnson la & lusas ew. comparison of alternative solvents for oils extraction. j am oil chem soc. 1983; 60:229. 8. ferreira-dias s, valente dg, abreu jmf. comparison between ethanol and hexane for oil extraction from quercus suber l. fruits. grasas y aceites. 2003; 54:378. 9. scaglione f, lucini v, pannacci m, et al. comparison of the potency of different brands of serenoa repens extract on 5αreductase types i and ii in prostatic co-cultured epithelial and fibroblast cells. pharmacology. 2008; 82:270. 10. bayne cw, donnely f, ross m, habib fk. serenoa repens (permixon®): a 5α-reductase types i and ii inhibitor-new evidence in a coculture model of bph. prostate. 1999; 40:232. 11. srinivasan b, kolli reddy a, esch mb, et al. teer measurement techniques for in vitro barrier model systems. j lab autom. 2015; 20:107. 12. smith cm, ballard sa, worman n, et al. 5 alpha-reductase expression by prostate cancer cell lines and benign prostatic hyperplasia in vitro. j clin endocrinol metab. 1996; 81:1361. 13. weisser h, tunn s, behnke b, krieg m. effects of the sabal serrulata extract ids 89 and its subfractions on 5 alpha-reductase activity in human benign prostatic hyperplasia. prostate. 1996; 28:300. 14. mosmann t. rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. j immunol methods. 1983; 65:55. 15. di silverio f, d'eramo g, lubrano c, et al. evidence that serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. eur urol. 1992; 21:309. 16. wan pj, pakarinen dr, hron rjsr, et al. alternative hydrocarbon solvents for cottonseed extraction. j am oil chem soc. 1995; 72:653. 17. paubert-braquet m, cousse h, raynaud jp, et al. effects of the lipido-sterolic extract of serenoa repens (permixon ®) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. eur urol. 1998; 33:340. 18. raynaud jp, cousse h, martin pm. inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of permixon®. j steroid biochem mol biol. 2002; 82:233. 19. habib fk & wyllie mg. not all brands are created equal: a comparison of selected components of different brands of serenoa repens extract. prostate cancer prostatic dis. 2004; 7:195. correspondence daniela buonocore, md (corresponding author) daniela.buonocore@unipv.it manuela verri, md manuela.verri@unipv.it laura cattaneo, md laura.cattaneo02@universitadipavia.it sara arnica, md sara.nica90@gmail.com maurizia dossena, md maurizia.dossena@unipv.it via ferrata, 9-27100 pavia, italy michele ghitti, md ghitti.michele@gmail.com via ferrata, 1-27100 pavia, italy buonocore_stesura seveso 03/10/18 09:45 pagina 202 archivio italiano di urologia e andrologia 2017; 89, 2154 case report a rare case of male pelvic squamous cell carcinoma of unknown primary origin presenting as perineal abscess and urethral stenosis massimiliano creta 1, vincenzo mirone 2, sergio di meo 1, roberto buonopane 1, nicola longo 2, ferdinando fusco 2, nicola rosario forte 3, vittorio imperatore 1 1 unità operativa di urologia, ospedale buon consiglio fatebenefratelli, napoli, italy; 2 clinica urologica, università federico ii di napoli, napoli, italy; 3 unità operativa di anatomia patologica, ospedale fatebenefratelli, benevento, italy. carcinomas of unknown primary origin (cup) represent a diagnostic and therapeutic challenge. squamous cell cup located in the male pelvis are very rare. we describe a case of a locally advanced squamous cell cup occurring in the male pelvis presenting as perineal abscess and urethral stenosis and diagnosed by means of transperineal needle biopsy. key words: squamous cell carcinoma; perineal abscess; urethral stenosis. submitted 21 january 2017; accepted 18 february 2017 summary no conflict of interest declared. tioned, the perineal abscess was drained and a suspect urethrocutaneous fistula was excised. histological examination showed a fibromuscular tissue with chronic inflammation and squamous epithelium. the patient was discharged home and a magnetic resonance imaging (mri) of the pelvis was prescribed. six months later, the patient presented at our institution with intense perineal pain and persistent bleeding from the perineal surgical wound. liver function tests were within the normal ranges. serum creatinine level was 1.91 mg/d. physical examination revealed a bleeding perineal wound. digital rectal examination was very painful and revealed a firm mass in the small pelvis and rectal bleeding. white blood cells count was within the normal range. hemoglobin level was 9.0 g/dl. a contrast enhanced pelvic mri showed a large (11 cm) inhomogeneous lesions with heterogeneous contrast enhancement infiltrating the prostate apex, the proximal corpora cavernosa, and the urethra (figure 1). serum levels of ca 15-3, ca 19-9, cea, ca-125, nse tumor markers were within the normal range. prostate specific antigen (psa) level was 1.8 ng/ml. a contrastenhanced total body computed tomography excluded other neoplasms. doi: 10.4081/aiua.2017.2.154 introduction carcinomas of unknown primary origin (cup) represent a heterogeneous group of tumors for which a standardized diagnostic work-up fails to identify the site of origin and account for about 3-5% of all malignancies (1). squamous cell cup account for 5-10% of cup and their occurrence in the male pelvic cavity is extremely rare (1). initial presenting symptoms include buttock pain, rectal urgency, constipation, diarrhea, and urinary frequency (1). we describe a case of a locally advanced squamous cell cup occurring in the male pelvic cavity and presenting as perineal abscess and urethral stenosis. case report a 78-years old men presented to another hospital complaining of acute urinary retention, perineal pain and purulent perineal discharge. his past medical history was irrelevant. transurethral catheterization of the bladder was impossible and cystoscopy revealed a severe urethral stenosis that made impossible the advancement of the instrument. a perineal abscess secondary to urethral stenosis was suspected. a suprapubic catheter was posifigure 1. contrast-enhanced mri of the pelvis demonstrating a 11 cm inhomogeneous pelvic lesion with heterogeneous contrast enhancement infiltrating the prostate apex, the proximal corpora cavernosa, and the urethra. a) transverse section, b) sagittal section. creta_stesura seveso 20/06/17 10:01 pagina 154 155archivio italiano di urologia e andrologia 2017; 89, 2 carcinoma of unknown primary origin a colonscopy revealed an edematous rectal mucosa with signs of extrinsic compression. rectal biopsies were taken showing chronic inflammation and absence of malignancy. a transperineal needle biopsy of the pelvic mass was then performed showing fibro-muscular and adipose tissue with chronic inflammation and squamous cell carcinoma displaying solid tumor nests. patients’ general conditions rapidly worsened and he underwent colostomy for the urgent management of distal large bowel obstruction two months later. the patient was lost to follow-up after 3 months. discussion cup represent a diagnostic and therapeutic challenge. according to some authors, the criteria for cup diagnosis include a biopsy-proven malignancy for which the anatomic origin is unknown after a medical history has been obtained, a detailed physical examination has been performed, and liver and kidney function tests, blood tests, chest radiography, abdomen and pelvis computed tomography, and a psa test have been performed (2). squamous cell cup located in the male pelvis represent a rare entity, so the ideal diagnostic work-up, the optimal treatment strategies and prognosis are not well determined (1). in the present case, a primary anal neoplasm was unlikely as no anal lesions were noted on targeted biopsies. moreover, other neoplasms were excluded on the basis of computered tomography and serum tumor markers results. transperineal biopsy proved to be a valid option for histological diagnosis. in experienced hands, the transperineal route allows to access to the small pelvis in complex situations (3). however, we acknowledge that, due to the locally advanced disease, the diagnostic work-up was suboptimal. indeed, urethral infiltration prevented to perform a detailed endoscopic study of the lower urinary tract. moreover, due to the small amount of neoplastic tissue in the biopsy specimen, immunostaining was not performed. however, immunostaining is not generally helpful in differentiating metastatic squamous cell cup (1). in general, cup have a poor prognosis, with a median survival time of less than six months (1). based on the limited literature data, it appears that squamous cup outside of the head and neck region have a more favorable prognosis compared to other cup and that these malignancies may respond well to a combination of surgical resection, when feasible, local radiotherapy, and platinum-based systemic chemotherapy (1). due to the locally advanced disease and the rapidly worsened general conditions, the patient described in the present report could not undergo local surgical therapy or systemic chemotherapy. conclusions squamous cell cup may arise in the male pelvic cavity and present, even in advanced stage, with non-specific signs and symptoms. the present case underlines the misleading clinical course and the complex diagnostic work-up. further studies are needed to determine ideal strategies for diagnosis, treatment, and prognostication of these neoplasms. references 1. chiec l, verma s, kendler a, abdel karim n. male pelvic squamous cellcarcinoma of unknown primary origin. case rep oncol med. 2014; 2014:953698. 2. varadhachary gr. carcinoma of unknown primary origin. gastrointest cancer res. 2007; 1:229-35. 3. imperatore v, creta m, di meo s, et al. transperineal repair of a persistent rectourethral fistula using a porcine dermal graft. int j surg case rep. 2014; 5:800-2. correspondence massimiliano creta, md (corresponding author) max.creta@gmail.com sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it vittorio imperatore, md v.imperatore@alice.it unità operativa di urologia, ospedale buon consiglio fatebenefratelli, napoli via a. manzoni, 220 80123, napoli, italy vincenzo mirone, md, professor of urology nicola longo, md ferdinando fusco, md clinica urologica, università federico ii di napoli via s.pansini, 5, 80131 napoli, italy nicola rosario forte, md unità operativa di anatomia patologica, ospedale fatebenefratelli, benevento viale principe di napoli, 14, 82100, benevento, italy creta_stesura seveso 20/06/17 10:01 pagina 155 archivio italiano di urologia e andrologia 2016; 88, 4308 original paper transrectal ultrasound (trus) guided prostate biopsy: three different types of local anesthesia giuseppina anastasi, enrica subba, rosa pappalardo, luciano macchione, gioacchino ricotta, graziella muscarà, francesco lembo, carlo magno unit of urology, department of human pathology, university of messina, messina, italy. transrectal ultrasound (trus) guided prostate biopsy is regarded as the gold standard for prostate cancer diagnosis. the majority of patients perceive trus-guided prostate biopsy as a physically and psychologically traumatic experience. we aimed to compare in this paper the efficacy of three different anesthesia techniques to control the pain during the procedure. materials and methods: 150 patients who underwent transrectal ultrasound (trus) guided prostate biopsy were randomly divided into three groups. group a included 50 patients who received one hour before the procedure a mixture of 2.5% lidocaine and 2.5% prilocaine, group b: 50 patients who received intrarectal local anesthetic administration (lidocaine 5 ml 10%) and lidocaine local spray 15 % and group c included 50 patients who received periprostatic block anesthesia (lidocaine 10 ml 10%). visual analogue scale (vas) of patients in different groups was evaluated at the end of the biopsy and 30 minutes after the procedure. results: the vas of patients in group a was 1.32 ± 0.65 (vas i) and 2.47 ± 0.80 (vas ii). in group b the vas of patients was 1.09 ± 0.47 (vas i) and 1.65 ± 0.61 (vas ii). in group c the vas of patients was 2.63 ± 0.78 (vas i) and 1.70 ± 0.85 (vas ii). there was no statistically significant difference in term of vas i between group a and b. a statistically significant difference was determined in terms of vas ii between group a and b. there was no statistically significant difference in term of vas between group b and c. conclusions: the most effective of the three methods for pain control we used was intrarectal local anesthetic administration and lidocaine local spray 15% that enables an ideal patient comfort. key words: biopsy; local anesthesia; pain control; prostate. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (2). two factors are usually responsible for pain during transrectal prostate biopsy: anal pain due to ultrasound probe, that causes pressure and stretching of muscle fibers, and pain at insertion of the needle through the prostate (3). all of the pain-rating scales are reliable and valid. the well-known visual analogue scale (vas) and numeric rating scale (nrs) for assessment of pain intensity agree well and are equally sensitive in assessing acute pain after surgery, and they are both superior to a fourpoint verbal categorical rating scale (vrs). early studies conducted on sextant biopsy without anesthesia showed that 65% to 90% of patients reported discomfort (1) and 19% would not agree to undergo it again without some form of anesthesia. various kinds of local anesthesia have been used before trus-guided prostate biopsy, but there is no agreement about the most effective one. trus-guided biopsy is commonly performed with intrarectal local anesthetic (irla), but one study has shown that > 50% of patients reported moderate-tointolerable pain even with intrarectal lidocaine application before the procedure (4). the most commonly used anesthetic is lidocaine either in gel suspension or as an injectable preparation (periprostatic nerve block ppnb) (5) although there is no strong evidence to recommend the different types of anesthetics that may be used. some authors doesn’t use any types of anesthetics during transrectal prostate biopsy. aim of our study was to compare the efficacy of three types of anesthesia methods for a painless transrectal ultrasound (trus) guided prostate biopsy. materials and methods 150 patients who underwent transrectal ultrasound (trus) guided prostate biopsy (12 cores) were randomly divided into three groups of 50. group a included 50 patients who receive one hour before mixture of 2.5% lidocaine and 2.5% prilocaine, group b included 50 patients who received intrarectal local anesthetic administration (lidocaine 5 ml 10%) and lidocaine local spray 15% and group c included 50 patients who received periprostatic block anesthesia (lidocaine 10 ml 10%). after transrectal ultrasound examination, assessing the doi: 10.4081/aiua.2016.4.308 presented at 20th national congress sieun, sciacca 2016 introduction prostate cancer is the second leading cause of cancer death behind only lung cancer with more than 180.000 new cases/year and 25.000 deaths per year. transrectal ultrasound (trus) guided prostate biopsy is regarded as the gold standard for prostate cancer diagnosis as demonstrated by recent studies. the majority of patients perceive trus-guided prostate biopsy as a physically and psychologically traumatic experience (1). the international association for the study of pain has offered the following definition of pain: “pain is an unpleasant anastasi-transrectal ultrasound (trus) _stesura seveso 09/01/17 10:05 pagina 308 309archivio italiano di urologia e andrologia 2016; 88, 4 local anesthesia for prostate biopsy prostatic diameter, the volume of the whole prostate, the transition zone, capsular and seminal vesicle characteristics, a sampling was carried out with a 18gauge tru-cut needle powered by an automatic spring-loaded biopsy disposable gun. visual analog scale (vas) of patients in groups was evaluated at the end of the biopsy (vas i) and 30 minutes after the procedure (vas ii). the pain level was scored between 1 and 10. in vas scale, number 0 represented absence of pain and number 10 the maximum pain perceived in life. results in group a, group b, and group c, the mean age of patients included into the study was 61.4 ± 7.9 (47-82), 59.7 ± 6.3 (49-72), and 63.4 ± 7.5 (48-77) years, respectively. the mean age of patients in all groups was 61.5 ± 7.4 (47-82) years. no statistically significant difference was observed in terms of age distribution between groups (p = 0.16). the mean serum total psa (tpsa) level of patients in group a, group b, and group c was 11.2 ± 25.9 (4.9052) ng/ml, 8.9 ± 5.3 (4.3-43.2) ng/ml, and 7.6 ± 4.1 (5.2-36.8) ng/ml, respectively. no statistically significant difference was also observed in terms of serum tpsa level distribution between groups (p = 0.658). mean fpsa/tpsa ratio in group a, group b, and group c was 17 ± 12 (10-50), 18 ± 8 (5-33), and 20 ± 10 (355), respectively. no statistically significant difference was observed in terms of fpsa/tpsa ratios between groups (p = 0.598).the mean serum free psa (fpsa) level of patients in group a, group b, and group c was 4.53 ± 8.10 (0.8-5.0) ng/ml, 2.40 ± 2 (0.50-8.57) ng/ml, and 3.10 ± 2.14 (0.30-7.6) ng/ml, respectively. no statistically significant difference was observed in terms of serum fpsa level distribution between groups (p = 0.714). the mean trus prostate volume of those in group a was 42 ± 12.5 (30-65) ml, those in group b was 48 ± 17.3 (32-69) ml, and those in group c was 45.6 ± 15.7 (30-63) ml. total trus prostate volume was 42 ± 36.7 (30-69) ml. no statistically significant difference was determined in terms of trus prostate volume between groups (p = 0.681) (table 1). the vas of patients in group a was 1.32 ± 0.65 (vas i) and 2.47 ± 0.80 (vas ii). in group b the vas of patients was 1.09 ± 0.47 (vas i) and 1.65 ± 0.61 (vas ii). in group c the vas of patients was 2.63 ± 0.78 (vas i) and 1.70 ± 0.85 (vas ii). there was no statistically significant difference in term of vas i between groups a and b. there was a statistically significant difference in term of vas i between group c and groups a and b. there was a statistically significant difference in term of vas ii between groups a and groups b and c. there was no statistically significant difference in term of vas ii between groups b and c. the vas of patients in group a was 1.32 ± 0.65 (vas i) and 2.47 ± 0.80 (vas ii). in group b the vas of patients was 1.09 ± 0.47 (vas i) and 1.65 ± 0.61 (vas ii). in group c the vas of patients was 2.63 ± 0.78 (vas i) and 1.70 ± 0.85 (vas ii) (table 2). there was no statistically significant difference in term of vas i between groups a and b. there was a statistically significant difference in term of vas i between group c and groups a and b. there was a statistically significant difference in term of vas ii between groups a and groups b and c. there was no statistically significant difference in term of vas ii between groups b and c. the cost of anesthesia was 12.90 for patient in group a; 0.25 for patient in group b; 8.50 for patient in group c (anesthesia and chiba needle). in group a 55% of patients in group a would agree to undergo another prostate biopsy; 65% in group b and 60% in group c. discussion it is now well accepted that trus-guided prostate biopsy causes significant pain and discomfort in patients and that some form of pain relief should be administered. however, given the two-way origin of pain; that is, probe-related anorectal discomfort and prostate capsule punctures, neither of the methods alone provides sufficient pain control throughout the whole process. since first introduced by obek et al., who showed a significantly decreased level of pain with local lidocaine gel application before ppnb, various kinds of local analgesics (local anesthetics, myorelaxants, nsaids, etc.) have been introduced to supplement ppnb. as the current standard technique recommended, periprostatic nerve block involved direct anesthetic infiltration of the neurovascular bundle within the denonvilliers’ fascia, which innervates the prostate (6). meta-analytic studies have shown its efficacy compared with intrarectal local analgesia or placebo (7). as suggested by giannarini et al. (8), the variability of perceived discomfort might be related to differences in table 1. patients’ characteristics. group a group b group c patients 50 50 50 age 61.4 ± 7.9 (47-78) 59.7 ± 6.3 (49-72) 63.4 ± 7.5 (48-77) serum total psa ng/ml 11.2 ± 25.9 (4.90-52) 8.9 ± 5.3 (4.3-43.2) 7.6 ± 4.1 (5.2-36.8) fpsa/tpsa 17 ± 12 18 ± 8 20 ± 10 serum free psa ng/ml 4.53 ± 8.10 (0.8-5.0) 2.40 ± 2 (0.50-8.57) 3.10 ± 2.14 (0.30-7.6) trus prostate volume ml 42 ± 12.5 (30-65) 48 ± 17.3 (3269) 45.6 ± 15.7 (3063) table 2. results for mean pain scores. vas i vas ii group a 1.32 ± 0.65 2.47 ± 0.80 group b 1.09 ± 0.47 1.65 ± 0.61 group c 2.63 ± 0.78 1.70 ± 0.85 anastasi-transrectal ultrasound (trus) _stesura seveso 09/01/17 10:05 pagina 309 archivio italiano di urologia e andrologia 2016; 88, 4 g. anastasi, e. subba, r. pappalardo, l. macchione, g. ricotta, g. muscarà, f. lembo, c. magno 310 anorectal compliance. they suggested the possibility of omitting anesthesia in those patients with high anorectal compliance. ultrasound probe geometry may influence pain perception during the prostate biopsy procedure and may be determinant in selecting patients in which some form of analgesia is needed (9). however, ppnb grants little effect in alleviating the pain associated with ultrasound probe manipulation, which was found to be a major source of discomfort during the procedure (10). wang et al. evaluated the analgesic efficacy and safety of different combined modalities of irla + ppnb versus ppnb alone, showing the better analgesic efficacy of combined anesthesia with respect to ppnb alone (11). in the study performed by raber et al. comparing intrarectal gel and placebo before biopsy, they reported that there is a statistically significant reduction in the group where anesthesia is applied with lidocaine gel during insertion of probe into rectum and taking needle biopsies compared with placebo group and that the rates of complication were similar (12). lidocaine was the most used local anesthetic. results of studies using lidocaine gel for irla showed a significantly reduced vas score of proberelated pain; however, anesthetic infiltration and needle biopsy pain were not significantly reduced. this could be partly attributed to the short-acting nature of lidocaine. a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine has recently been evaluated in several studies, and was found to be superior to typical anesthetic agents with intrarectal local administration, probably for its much longer anesthesia duration (2-5 h) and deeper tissue infiltration (13). in our experience combined intrarectal local anesthetic administration (lidocaine 5 ml 10%) and lidocaine local spray 15% reduced the pain. according to cost evaluation this method appears less expensive. conclusion there are various forms of analgesia performed by many authors in the literature in order to remove pain and discomfort of trus-guided prostate biopsy. we determined that the most effective method for pain control among the three methods tested in our study was intrarectal local anesthetic administration + lidocaine local spray 15 % and that it enables an ideal patient comfort. references 1. nazir b pain during transrectal ultrasound-guided prostate biopsy and the role of periprostatic nerve block: what radiologists should know korean j radiol. 2014; 15:543-553. 2. merskey h, bogduk n. classification of chronic pain, iasp task force on taxonomy. iasp press; seattle: 1994. 3. maccagnano c, scattoni v, roscigno m, et al. anaesthesia in transrectal prostate biopsy: which is the most effective technique. urol int. 2011; 87:1-13. 4. nash pa, bruce je, indudhara r, shinohara k. transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the prostate. j urol. 1996; 155:607-609. 5. el-hakim a, mouss s. cua guidelines on prostate biopsy methodology can urol assoc j. 2010; 4:89-94. 6. obek c, ozkan b, tunc b, et al. comparison of 3 different methods of anesthesia before transrectal prostate biopsy: a prospective randomized trial. j urol. 2004; 172:502-5. 7. hergan l, kashefi c, parsons jk. local anesthetic reduces pain associated with transrectal ultrasound-guided prostate biopsy: a meta-analysis. urology. 2007; 69:520-5. 8. giannarini g, autorino r, valent f, et al. combination of perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerveblock for pain control during transrectal ultrasound guided prostate biopsy: a randomized, controlled trial. j urol. 2009; 181:585-91. 9. fabiani a, tallè m, mammana g, et al. may ultrasound probe size influence pain perception of needle piercing during transrectal prostate biopsy? a prospective evaluation. arch ital urol androl. 2016; 88:223-227. 10. mccabe je, hanchanale vs, philip j, javle pm. a randomized controlledtrial of topical glyceryl trinitrate before transrectal ultrasonography-guidedbiopsy of the prostate. bju int. 2007; 100:536-9. 11. wang j, wang l, du y, et al. addition of intrarectal local analgesia toperiprostatic nerve block improves pain control for transrectal ultrasonography-guided prostate biopsy: a systematic review and meta-analysis. int j urol. 2015. 12. raber m, scattoni v, roscigno m, et al. perianal and intrarectal anaesthesia for transrectal biopsy of the prostate: a prospective randomized study comparing lidocaine-prilocaine cream and placebo. bju int. 2005; 96:1264-7. 13. cormio l, lorusso f, selvaggio o, et al. noninfiltrative anesthesia for transrectal prostate biopsy: a randomized prospective study comparing lidocaine-prilocaine cream and lidocaine-ketorolac gel. urol oncol. 2013; 31:68-73. correspondence giuseppina anastasi, md enrica subba, md rosa pappalardo, md luciano macchione, md gioacchino ricotta, md graziella muscarà, md francesco lembo, md carlo magno, md unit of urology, department of human pathology, university of messina, messina, italy anastasi-transrectal ultrasound (trus) _stesura seveso 09/01/17 10:05 pagina 310 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4340 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.340 protective effect of cordycepin on experimental renal ischemia/reperfusion injury in rats hasan riza aydin 1, cagri akin sekerci 2, ertugrul yigit 3, hatice kucuk 4, huseyin kocakgol 1, seyfi kartal 5, yiloren tanidir 2, orhan deger 6 1 department of urology, university of health sciences, trabzon kanuni training and research hospital, turkey; 2 marmara university school of medicine, department of urology, istanbul, turkey; 3 karadeniz technical university, department of biochemistry, trabzon, turkey; 4 department of pathology, university of health sciences, trabzon kanuni training and research hospital, turkey; 5 department of anesthesia and reanimation, university of health sciences, trabzon kanuni training and research hospital, turkey; 6 karadeniz technical university, department of biochemistry, trabzın, turkey. worldwide (1). hypotension, shock, sepsis, renal artery embolism, trauma, renal transplantation, and partial nephrectomy are the main conditions that cause renal ischemia. renal tissue damage develops with the failure of oxygen and nutritional support of kidney cells due to a complete stop or decrease of blood flow. ischemia/reperfusion (i/r) is defined as restoring blood flow after it is interrupted. in the case of reperfusion following renal ischemia, tissue damage continues. necrosis, apoptosis, free oxygen radicals, and inflammation have been described as the main mechanisms that are responsible for i/r kidney damage. however, the mechanism of development of i/r kidney damage is not clear (2, 3). various agents have been studied to protect the kidney from i/r damage. doxycycline (by decreasing pro-inflammatory cytokine levels), ascorbic acid (by reducing antioxidant activity), leptin (by decreasing tnf alpha level and by increasing nitric oxide levels), iloprost (by suppressing lipid peroxidation) and levosimendan (antioxidant and no/release) have been shown to have protective effects on i/r kidney damage (4). cordycepin (c) is an adenosine analog and reported as the first nucleoside antibiotic isolated from cordycepin militaris culture. cordycepin has been shown to have protective effects on testicular i/r injury in rats, and its anti-inflammatory, anti-tumor and antioxidant properties have been reported (5-7). in this study, we aimed to investigate the effects of cordycepin on experimental renal i/r injury. materials and methods 24 male sprague-dawley female rats (8 weeks old, weight 230-300 g) were obtained from the karadeniz technical university laboratory animals research centre (trabzon, turkey). the study was approved from the animal experiments local ethics committee of karadeniz technical university (trabzon, turkey) (approval number/id: 2018/21). the same environment and nutritional conditions were provided for all animals. rats were entrained under a 12:12 h dark: light cycle (lights on 6 am-6 pm) with stable temperature (21 ± 2°c) and aim: to date, various molecules have been investigated to reduce the effect of renal ischemia/reperfusion (i/r) injury. however, none have yet led to clinical use. the present study aimed to investigate the protective effect of cordycepin (c) on renal i/r injury in an experimental rat model. materials and methods: twenty-four mature sprague dawley female rat was randomly divided into three groups: sham, i/r, i/r+c. all animals underwent abdominal exploration. to induce i/r injury, an atraumatic vascular bulldog clamp was applied to the right renal pedicle for 60 minutes (ischemia) and later clamp was removed to allow reperfusion in all rats, except for the sham group. in the i/r + c group, 10 mg/kg c was administered intraperitoneally, immediately after reperfusion. after 4 hours of reperfusion, the experiment was terminated with right nephrectomy. histological studies and biochemical analyses were performed on the right nephrectomy specimens. egti (endothelial, glomerular, tubulointerstitial) histopathology scoring and semi-quantitative analysis of renal cortical necrosis were used for histological analyses and superoxide dismutase (sod), catalase (cat), malondialdehyde (mda), total oxidant status (tos) for biochemical analyses. results: histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. the i/r group had higher histopathological scores than the i/r + c group. in the biochemical analysis of the tissues, sod, mda, tos values were found to be statistically different in the i/r group compared to the i/r + c group (p: 0.004, 0.004, 0.001 respectively). conclusions: intraperitoneal cordycepin injection following ischemia preserve renal tissue against oxidative stress in a rat model of renal i/r injury. key words: cordycepin; ischemia/reperfusion injury; kidney; rat. submitted 19 october 2020; accepted 27 october 2020 introduction renal ischemia is one of the important causes of acute renal failure. acute renal failure is an important public health problem with high morbidity, mortality, and cost summary 341archivio italiano di urologia e andrologia 2020; 92, 4 effect of cordycepin on renal i/r injury humidity (60 ± 5%). the rats had sterile water and food available ad libitum. experimental protocol and surgical procedure the protocol is described in the previous study (8). rats were randomly and equally divided into 3 groups; sham group, i/r group, i/r+c group. ketamine hydrochloride (100 mg/kg, ketalar, eczacibasi, turkey) and xylazine (10 mg/kg) were used intraperitoneally for anesthesia. a midline laparotomy incision was performed, and the right renal pedicle was dissected. then, right renal ischemia was performed with bulldog clamp for 60 minutes in i/r and i/r+c groups. the clamp was removed for reperfusion and the renal artery pulse was visually confirmed. in the i/r+c group, 10 mg/kg cordycepin was administered intraperitoneally following the beginning of reperfusion and saline in the i/r group. after controlling the bleeding, the skin layers were sutured. in the sham group, rats underwent a similar surgical procedure without renal occlusion. the rats were sacrificed 4 hours after reperfusion and the right nephrectomy was performed. renal tissues were prepared for biochemical analyses and histopathological examination. histological analysis after the kidney tissue samples were fixed in 10% formaldehyde for 24-48 hours, routine histological followup was performed. serial sections of 5-micron thickness were taken from the paraffin-embedded tissues. subsequently, the samples were stained with hematoxylin-eosin and i/r related changes were evaluated under the light microscope. besides, sections were taken from each paraffin block, and periodic acid-schiff (pas) and masson trichrome stain were applied for evaluation of fibrosis and bowman capsule thickening. the histological evaluations of the renal tissue damage were graded as described in the study of medeiros et al. (table 1) (9). egti scoring system was also used (table 2) for histological analyses (10). this system examines histological damage in 4 separate sections: endothelial, glomerular, tubular, and interstitial. the histological evaluations were made by examining each section one by one and considering the areas where the damage was most severe. biochemical analysis the tissues were first cleaned by saline solution and stored at -80 °c until the analysis time. in the analysis process, first they were homogenized in cold phosphate buffer solution (pbs) (0.05 m, ph 7.4), and were centrifuged at 3000 rpm for 10 min to remove debris and to obtain clear supernatant fraction. then, the analyses were performed in this fraction. malondialdehyde (mda), total oxidant status (tos), as well as enzyme activities of superoxide dismutase (sod) and catalase (cat) were measured in this fraction. mda levels in tissue samples were determined using the method described by mihara and uchiyama. tetramethoxypropane was used as a standard, and tissue mda levels were calculated as nmol/g wet tissue (11). tos levels were determined using a colorimetric tos kit as previously described by erel (12). cat activity was measured by modifying the method based on the measurement of the absorbance of ammonium molybdate with h2o2 at 405 nm. cat standard (sigma c9322) was used as a standard, and tissue cat activity was calculated as nmol/g protein (13). the sod enzyme activity was determined by the method of sun and oberley. this method is based on the measurement of the absorbance of the purple-colored formazan molecule at 560 nm resulting from the reduction of nitroblue tetrazolium of o2.formed by the xanthine-xanthine oxidase system. tissue sod activity was calculated as nmol/g protein by using sod standard (sigma s8160) (14). statistical analysis the data were transferred to spss 22 (statistical package for the social sciences) computer package program and evaluated statistically. compliance with normal distribution was checked by the kolmogorov-smirnov test. one way anova and post-hoc tukey tests were used for the evaluation of more than two independent groups that fit the normal distribution, and the kruskal-wallis test was used for the evaluation of more than two parameters that did not fit the normal distribution, and mann whitneyu test was used for the binary parameter that did not fit the normal distribution. the values obtained were expressed as mean ± standard deviation (x ± sd) and p < 0.05 was considered statistically significant. table 1. scoring system for renal histopathology. score histopathological pattern 0 normal 0.5 small focal damaged areas 1 < 10% cortical damaged zone 2 10–25% cortical damaged zone 3 25–75% cortical damaged zone 4 > 75% cortical damaged zone table 2. the egti histological (endothelial, glomerular, tubular, interstitial) scoring system. tissue type damage score tubular no damage 0 0 loss of brush border (bb) in less than 25% of tubular cells. integrity of basal membrane 1 loss of bb in more than 25% of tubular cells, thickened basal membrane 2 (plus) inflammation, cast formation, necrosis up to 60% of tubular cells 3 (plus) necrosis in more than 60% of tubular cells 4 endothelial no damage 0 endothelial swelling 1 endothelial disruption 2 endothelial loss 3 glomerular no damage 0 thickening of bowman capsule 1 retraction of glomerular tuft 2 glomerular fibrosis 3 tubulo/interstitial no damage 0 inflammation, haemorrhage in less than 25% of tissue 1 (plus) necrosis in less than 25% of tissue 2 necrosis up to 60% 3 necrosis more than 60% 4 archivio italiano di urologia e andrologia 2020; 92, 4 h. riza aydin, c. akin sekerci, e. yigit, h. kucuk, h. kocakgol, s. kartal, y. tanidir, o. deger 342 results all rats in the sham group had normal renal tissue in the histopathologic examination. however, as shown in table 3, 2 (25%) rats in the i/r group had small focal damaged areas, 3 (47.5%) < 10% cortical damage, 2 (12.5) had 10-25 % cortical damage and 1(12.5%) had 25-75% cortical damage. in i/r+c group, 5 (62.5%) had small focal damaged areas, 1 (12.5%) had < 10% cortical damage and 2 (25%) had 10-25% cortical damage. egti scores of the rats in each group are shown in table 4, separately. histological images are shown in figure 1. the biochemical analysis results are shown in table 5. sod in the i/r group decreased significantly compared to the i/r+c group (p = 0.004) but was similar in the sham and i/r+c groups (p: 0 = 749). cat in the i/r group was lower than the sham and i/r+c groups but not statistically significant (p = 0.056). mda and tos in the i/r group increased significantly compared to the i/r+c group (p = 0.004, p = 0.001) but were similar in the sham and i/r+c groups (p = 0.055, p = 0.324). discussion ischemia-reperfusion injury of the kidney continues to be an important clinical condition since it is not an effective agent that has been used in the treatment (1). although the formation of i/r damage is a complex process that is not fully understood, significant progress has been made in this regard. the main components of this complex pathophysiological condition are inflammation, oxidative stress-lipid peroxidation, mitochondrial dysfunction, nitrite, and nitric oxide, the complement system, and the renin-angiotensin system. homeostatic control of kidney functions is dependent on the production of mitochondrial adenosine triphosphate (atp), nitric oxide (no), and reactive oxygen species (ros), but is only possible with adequate oxygen supply to the kidney tissue (15). circulatory impairment causes hypoxia and oxidative stress in the kidney tissue and subsequent no, ros, and oxygen imbalance. ischemic damage inhibits the na-k atpase enzyme bound to the cell membrane, as a result, intracellular h2o and sodium increase and edema develop (16). interstitial edema and vascular permeability cause a further reduction in blood flow. in addition, oxidative stress and increased prostaglandin synthesis in damaged tubules further disrupts oxygen transmission and causes the local no-reflow phenomenon (17, 18). the long-term consequence of microvascular circulation disorder is the development of hypoxia and finally renal fibrosis as a result of transforming growth factorbeta (tgf-β) stimulation with decreased vascular endothelial growth factor (vegf) response secondary to the decrease in peritubular capillary density (19). the inflammatory cascade is triggered with i/r damage, which further aggravates the kidney damage. the main mediators of inflammatory damage are chemokines. chemokines regulate pro-inflammatory cytokine activity, adhesion molecule expression, leukocyte infiltration and activation. il 6 and tnf-alpha are cytokines that play a major role in the development of renal dysfunction (4). activation of the janus kinase/signal transducer and activator of transcription (jak/stat) pathway mediates the release of multiple proinflammatory cytokines that table 3. cortical damage score of all rats according to the groups. rats sham group i/r group i/r+c group 1 0 0.5 0.5 2 0 1 2 3 0 3 0,5 4 0 2 0.5 5 0 2 0.5 6 0 0.5 0.5 7 0 1 1 8 0 1 2 figure 1. histological images of the rat renal cortex sections. a) glomerular damage: glomerular fibrosis (x40 masson trichrome) (score: 3), b) glomerular damage: glomerular retraction (x40 masson trichrome) (score: 2), c) tubular damage: necrosis up to 60% in tubule cells, tubular dispersion (x40 he) (score: 3), d) tubulo/interstitial damage: inflammation, hemorrhage in less than 25% (x40 he) in tubulo/interstitial damage area (score: 1), e) normal cortex (x20 he)) (score: 0). a b c d e table 4. ecti scores of all rats according to the groups. rats sham group i/r group i/r+c group 1 0 6 5 2 0 5 3 3 0 4 3 4 0 6 5 5 0 5 5 6 0 6 2 7 0 4 4 8 0 4 7 table 5. results of superoxide dismutase (sod), catalase (cat), malondialdehyde (mda), total oxidant capacity (toc) of groups. mean ± sd sham group i/r group i/r+c group p value (n: 8) (n: 8) (n: 8) sod (u/gprotein) 46.39 ± 2.65 28.84 ± 6.74 45.76 ± 6.91 0.004* 0.749** cat (u/gprotein) 7.19 ± 1.02 4.37 ± 0.74 6.46 ± 1.16 0.056 mda (nmol/gtissue) 39.8 ± 4.9 65.5 ± 3.5 45.6 ± 2.8 0.004* 0.055** tos (µmol/l) 8.5 ± 1.74 17.8 ± 3.33 15.83 ± 1.53 0.001* 0.324** * i/r vs i/r+c. ** sham vs i/r+c. 343archivio italiano di urologia e andrologia 2020; 92, 4 effect of cordycepin on renal i/r injury cause progression of renal i/ r injury (20). various agents have been studied in reducing inflammation in i/r injury. dexmedetomidine (a highly selective α2-adrenoreceptor agonist) has a cytoprotective effect by reducing the level of il6 and tnf alpha by inhibiting the phosphorylation of jak/stat proteins (21). nicotine has a renoprotective effect by reducing leukocyte infiltration and chymokine release with its anti-inflammatory cholinergic properties (22). celastrol (tripterygium wilfordii), also found in china (china herb), is used in chronic nephritis and autoimmune diseases with its anti-inflammatory and antioxidant properties. although celastrol has been reported to have a positive effect on i/r damage by suppressing neutrophil infiltration, lipid peroxidation, and proinflammatory mediator synthesis such as cyclooxygenase-2 (cox2), there are also counter studies reporting that it increases i/r damage by cox-2 upregulation and prostaglandin e2 synthesis (23, 24). ros produced in excess during i/r injury causes changes in mitochondrial oxidative phosphorylation, atp consumption, intracellular calcium increase and membrane phospholipid protease activation (25-27). this process causes damage to the lysosome membrane, leakage of lysosome enzymes and deterioration of the cell structure (28). free oxygen radicals that cause lipid peroxidation are generated during the reperfusion phase of i/r injury. lipid peroxidation and oxidative damage contribute to apoptosis and cell death by making dna and protein damage. in addition, down-regulation of the antioxidant enzyme system consisting of catalase, superoxide dismutase and glutathione peroxidase enzymes may be responsible for i/r damage (25-27). studies have shown that free radical scavengers and antioxidants can be beneficial in protecting against i/r damage. propofol, melatonin, ulinastatin, picroliv, naringin, and aqueous garlic extract, are some of the antioxidants and radical scavengers that have been of interest to researchers (4). in our study, the biochemical and histopathological effects of cordycepin (3'-deoxyadenosine) on renal i/r injury in a rat model were investigated. cordycepin is widely used in the treatment and prevention of many diseases (circulatory, immune, respiratory, and glandular systems illness) in east asian countries (29). cordycepin has been reported to be an effective antiinflammatory and antioxidant (7). cordycepin exerts its anti-inflammatory and analgesic effect by inhibiting il1β, il-6, tnf-α, induced nitric oxide synthase (inos), and cyclooxygenase-2 (cox-2) enzymes (5). it has been reported that ros production induced by plateletderived growth factor (pdgf) can be reduced by cordycepin and it attenuates neointima formation in vascular smooth muscles in rats (29, 30). also, li et al. reported that cordycepin showed a renoprotective effect by inhibiting myofibroblast activation (31). in previous studies, cordycepin's protective effect on the brain and testis in ischemia-reperfusion injury was reported (7, 32). in the study of han f et al., the effectiveness of cordycepin at different doses (2 mg/kg, 4 mg/kg, 8 mg/kg) in rats with renal ischemia-reperfusion injury was investigated (33). in this study, in which cordycepin was administered with oral gavage for 7 days, it was reported that increasing doses reduce pathological damage, oxidative stress, and apoptosis. in the same study, serum creatinine and bun values were observed to be statistically lower in the cordycepin treated groups compared to the i/r group. in our study, unlike the study of han et al., 20 mg/kg cordycepin was administered intraperitoneally at the beginning of reperfusion, and nephrectomy was performed 4 hours later. in the biochemical analysis, sod, mda, and tos values were found to be statistically different in the c + i/r group compared to the i/r group. as a limitation of the study, serum creatinine and bun values were not measured since we did not perform left nephrectomy. conclusions intraperitoneal cordycepin administration has been shown to support the endogenous antioxidant defense system and reduce oxidative stress in renal ischemia/reperfusion injury in rats. acknowledgement we would like to thank the scientific research council of the university of health sciences, turkey (bap) for the financial support. the bap project number assigned to this study is 2018/065. the project leader of the study is assoc. prof. hasan riza aydin. references 1. zuk a, bonventre jv. acute kidney injury. annual review of medicine. 2016; 67:293-307. 2. wang l, liu x, chen h, et al. effect of picroside ii on apoptosis induced by renal ischemia/reperfusion injury in rats. experimental and therapeutic medicine. 2015; 9:817-22. 3. zhang j, zou yr, zhong xet al. erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating pi3k/akt signalling. nephrology. 2015; 20:266-72. 4. malek m, nematbakhsh m. renal ischemia/reperfusion injury; from pathophysiology to treatment. j renal inj prev .2015; 4:20. 5. yue k, ye m, zhou z, et al. the genus c ordyceps: a chemical and pharmacological review. j pharm pharmacol. 2013; 65:474-93. 6. nakamura k, shinozuka k, yoshikawa n. anticancer and antimetastatic effects of cordycepin, an active component of cordyceps sinensis. j pharmacol sci 2015; 127:53-6. 7. okur mh, arslan s, aydogdu b, et al. protective effect of cordycepin on experimental testicular ischemia/reperfusion injury in rats. j invest surg 2018; 31:1-8. 8. toprak t, sekerci ca, aydın hr, et al. protective effect of chlorogenic acid on renal ischemia/reperfusion injury in rats. arch ital urol androl. 2020; 92:153-157. 9. medeiros pjd, villarim neto a, lima fp, et al. effect of sildenafil in renal ischemia/reperfusion injury in rats. acta cir bras 2010; 25:490-5. 10. chavez r, fraser dj, bowen t, et al. kidney ischaemia reperfusion injury in the rat: the egti scoring system as a valid and reliable tool for histological assessment. journal of histology and histopathology. 2016; 3. archivio italiano di urologia e andrologia 2020; 92, 4 h. riza aydin, c. akin sekerci, e. yigit, h. kucuk, h. kocakgol, s. kartal, y. tanidir, o. deger 344 11. uchiyama m, mihara m. determination of malonaldehyde precursor in tissues by thiobarbituric acid test. anal biochem 1978; 86:271-8. 12. erel o. a new automated colorimetric method for measuring total oxidant status. clin biochem 2005; 38:1103-11. 13. goth l. a simple method for determination of serum catalase activity and revision of reference range. clin chim acta. 1991; 196:143-51. 14. sun y, oberley lw, li y. a simple method for clinical assay of superoxide dismutase. clin chem 1988; 34:497-500. 15. aksu u, demirci c, ince c. the pathogenesis of acute kidney injury and the toxic triangle of oxygen, reactive oxygen species and nitric oxide. contrib nephrol 2011; 174:119-128. 16. salvadori m, rosso g, bertoni e. update on ischemia-reperfusion injury in kidney transplantation: pathogenesis and treatment. world j transplant. 2015; 5:52. 17. ferenbach da, bonventre jv. mechanisms of maladaptive repair after aki leading to accelerated kidney ageing and ckd. nat rev nephrol. 2015; 11:264-76. 18. molitoris ba. therapeutic translation in acute kidney injury: the epithelial/endothelial axis. j clin invest 2014; 124:2355-63. 19. basile dp, donohoe d, roethe k, osborn jl. renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. am j physiol renal physiol. 2001; 281:f887-99. 20. yang n, luo m, li r, et al. blockage of jak/stat signalling attenuates renal ischaemia-reperfusion injury in rats. nephol dial transplant. 2008; 23:91-100. 21. si y, bao h, han l, et al. dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the jak/stat signaling activation. j transl med. 2013; 11:141. 22. yeboah m, xue x, duan b, et al. cholinergic agonists attenuate renal ischemia–reperfusion injury in rats. kidney int. 2008; 74:62-9. 23. chu c, he w, kuang y, et al. celastrol protects kidney against ischemia-reperfusion-induced injury in rats. j surg res. 2014; 186:398-407. 24. hwang hs, yang kj, park kc, et al. pretreatment with paricalcitol attenuates inflammation in ischemia–reperfusion injury via the up-regulation of cyclooxygenase-2 and prostaglandin e2. nephrol dial transplant 2013; 28:1156-66. 25. johnson kj, weinberg jm. postischemic renal injury due to oxygen radicals. curr opin nephrol hypertens. 1993; 2:625-35. 26. paller ms. the cell biology of reperfusion injury in the kidney. j investig med. 1994; 42:632-9. 27. bonventre jv. mechanisms of ischemic acute renal failure. kidney int 1993; 43:1160-78. 28. sugiyama s, hanaki y, ogawa t, et al. the effects of sun 1165, a novel sodium channel blocker, on ischemia-induced mitochondrial dysfunction and leakage of lysosomal enzymes in canine hearts. biochem biophys res commun. 1988; 157:433-9. 29. ramesh t, yoo s-k, kim s-w, et al. cordycepin (3αdeoxyadenosine) attenuates age-related oxidative stress and ameliorates antioxidant capacity in rats. exp gerontol. 2012; 47:979-87. 30. won k-j, lee s-c, lee c-k, et al. cordycepin attenuates neointimal formation by inhibiting reactive oxygen species–mediated responses in vascular smooth muscle cells in rats. j pharmacol sci. 2009; 109:403-12. 31. li l, he d, yang j, wang x. cordycepin inhibits renal interstitial myofibroblast activation probably by inducing hepatocyte growth factor expression. j pharmacol sci. 2011; 117:286-94 32. cheng z, he w, zhou x, et al. cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro. eur j pharmacol. 2011; 664:20-8. 33. han f, dou m, wang y, et al. cordycepin protects renal ischemia/reperfusion injury through regulating inflammation, apoptosis, and oxidative stress. acta biochim biophys sin. 2020; 52:125-32. correspondence hasan riza aydin, md, assoc. prof. hrizaaydin@gmail.com huseyin kocakgol, md hsynkocakgl@gmail.com department of urology, university of health sciences, trabzon kanuni training and research hospital (turkey) cagri akin sekerci, md, assoc. prof. (corresponding author) cagri_sekerci@hotmail.com yiloren tanidir, md, assoc. prof. yiloren@yahoo.com marmara university school of medicine, department of urology fevzi çakmak mah., muhsin yazicioglu cad. no:10 ust kaynarca/ pendik/istanbul (turkey) ertugrul yigit, md ertugrulyigit@ktu.edu.tr orhan deger, md, prof. odeger@ktu.edu.tr karadeniz technical university, department of biochemistry, trabzon (turkey) hatice kucuk, md dr.hatice.kucuk@hotmail.com department of pathology, university of health sciences, trabzon kanuni training and research hospital (turkey) seyfi kartal, md drseyfikartal@gmail.com department of anesthesia and reanimation, university of health sciences, trabzon kanuni training and research hospital (turkey) archivio italiano di urologia e andrologia 2019; 91, 3196 case report a complicated case of recurrent cowper’s gland abscess pietro pepe, ludovica pepe, astrid bonaccorsi, paolo panella, michele pennisi urology unit, cannizzaro hospital, catania, italy. a caucasian man 64 years old was admitted to our department for fever, strangury, frequency and pain in the perineum secondary to the relapse of cowper’s gland abscess previously treated by antibiotic therapy and trans-perineal ultrasound-guided aspiration. at admission, the clinical parameters were suggestive of sepsis; moreover, the trans-perineal ultrasound detected an hypoechoic mass suspicious for the recurrence of cowper’s gland abscess. a suprapubic catheter was positioned and a targeted antibiotic therapy (colistin 9000.000 u intravenously every day for 8 days plus meropenem 500 mg intravenously every 8 hours for 10 days) was administered. the patient during the follow up presented long fibers of mucus in the urine and recurrent positive urine culture, therefore two months later underwent trans-perineal surgical asportation of the left cowper’s gland. one month after surgery the patient was readmitted for the presence of a urinary fistula between bulbar urethra and perineum. a new suprapubic catheter was positioned and after three months was removed because a complete restitutio ad integrum was shown by retrograde cystourethrogram and uroflowmetry. in conclusion, the abscess of cowper’s gland could represent a very rare but severe clinical event that need aggressive therapy and close follow up for its potentially high rate of early and late clinical complications; in the presence of recurrence the surgical asportation of the cowper’s gland should be considered. key words: cowper’s gland abscess; urinary perineum fistula; transperineal ultrasound; cowper's gland surgery. submitted 17 february 2019; accepted 9 april 2014 summary no conflict of interest declared. urine. the patient had been treated with three cycles of antibiotics during hospitalization about nine months before for the presence of sepsis secondary to an abscess of the left cowper’s gland; in addition, for the persistence of symptoms, a culture of trans-perineal ultrasound-guided aspiration of cowper’s gland abscess showed the presence of pseudomonas aeruginosa sensitive to ciprofloxacin. a suprapubic catheter was positioned and antibiotic therapy (oral ciprofloxacin 1000 mg per day) was administrated for 4 weeks with apparent restitutio ad integrum (urine and urethral swab cultures were negative) and absence of clinical symptoms for the following three months from hospital discharge (3). at last hospital readmission, psa was 1.8 ng/ml, kidney and bladder ultrasound were normal (absence of postvoid urinary residual); urological examination was characterized by normal prostate, penis and testicular findings with pain and skin redness in correspondence of the perineum. the trans-perineal ultrasound detected a hypoechoic mass suggestive for the relapse of the left cowper’s gland abscess that was confirmed by pelvic magnetic resonance imaging. a suprapubic catheter was positioned; blood culture found presence of escherichia coli and the patient underwent targeted antibiotic therapy (colistin 9000.000 u intravenously every day for 8 days plus meropenem 500 mg intravenously every 8 hours for 10 days) according to antibiogram results; seven days from the end of the therapy and in the absence of urinary symptoms the patient underwent 3 blood culture (negative), urine culture (negative), serum pro-calcitonin (negative) and was discharged from the hospital. the patient during the follow up presented again long fibers of mucus in the urine and recurrent positive urine cultures, therefore two months later underwent transperineal surgical asportation of the left cowper’s gland. after the incision of perineum the gland was identified during surgery by metilene blue dye that was previously injected trans-perineally under transrectal ultrasound guidance; the cowper’s gland was removed and the duct between the gland and the bulbar urethra was identified and closed in correspondence of the urethra (figure 1). the transcutaneous drain was removed after four days and the patient was discharged after two weeks from surgery; two weeks later the urethral and suprapubic catheters were removed. definitive histological specimen showed an abscess of the cowper’s gland. one month from surgery the patient was readmitted again for the presence of a urinary fistula between bulbar urethra and doi: 10.4081/aiua.2019.3.196 introduction the abscess of the cowper gland (1, 2) is associated with fever, malaise and severe pain in the perineum combined frequency, urgency, painful defecation and sometime acute urinary retention. we, previously, showed a case of cowper’s gland abscess complicated by sepsis treated conservatively (targeted antibiotic therapy, trans-perineal ultrasound-guided aspiration of the abscess and suprapubic catheter) with an apparent restitutio ad integrum (3). we now report the clinical evolution and relapse of the same clinical case that needed the surgical asportation of the cowper’s gland subsequently complicated by a urinary perineum fistula. case report a caucasian man 64 years old was readmitted to our hospital for the presence of fever (40°c), strangury, frequency, pain in the perineum and long fibers of mucus in the pepe_stesura seveso 30/09/19 18:27 pagina 196 197archivio italiano di urologia e andrologia 2019; 91, 3 cowper’s gland abscess perineum (figure 2). a new suprapubic catheter was positioned and after three months was removed after complete restitutio ad integrum was showed (absence of fistula or urethral stenosis) by retrograde cystourethrogram and uroflowmetry. discussion cowper’s gland abscess has been rarely reported (1, 2) but it should be considered in any male presenting with long persistent irritative or obstructive symptoms following many cycles of antibiotic therapy. cowper's gland defect (i.e. syringocele) could be a focal point for bacterial persistence in the urinary tract following acute prostatitis (4-7). the treatment is appropriate antibiotic therapy, but in the presence of abscess direct aspiration is the most efficacious procedure; when underestimated, cowper’s gland abscess could induce a perineal fistula (8). in the clinical case previously showed, to our knowledge the first reported in literature, we observed multiple acute recurrences requiring removal of the cowper’s gland that was also complicated by a urinary fistula between bulbar urethra and perineum. conclusions the abscess of cowper’s gland could represent a very severe clinical event that need aggressive therapy and close follow up for its potentially high rate of early and late clinical complications; in the presence of relapse the surgical asportation of the cowper’s gland should be considered. references 1. chwallar r. cowperitis: a rarely diagnosed frequent disease, its diagnosis and treatment. zeitschrift fur urologie. 1963; 56:155-166. 2. martínez-sagarra jm, cuervo j, cortiñas jr. cowperitis. actas urológicas españolas. 1981; 5:255-258. 3. pepe p, pepe l, bonaccorsi a, et al. sepsis secondary to cowper's gland abscess. urol case rep. 2017; 15:48-49. 4. lo a, upadhyay v, teele rl. syringocoele of the bulbourethral duct with additional lower genito-urinary anomalies. pediatric radiolology. 2011; 41:1201-1204. 5. blasl f, rösch wh, koen m, et al. cowper's syringocele: a rare differential diagnosis of infravesical obstruction in boys and young adults. j pediatr urol. 2017; 13:52.e1-52.e5. 6. arena s, scuderi mg, arena f, di benedetto v. management of "open" syringocele based on urodynamic findings. pediatr med chir. 2008; 30:35-40. 7. maizels m, stephens fd, king lr, firlit cf. cowper's syringocele: a classification of dilatations of cowper's gland duct based upon clinical characteristics of 8 boys. j urol. 1983; 129:111-114. 8. birnstingl j, griffiths d, nicol cs, redmond a. two cases of perineal fistula following cowperitis. br j vener dis. 1957; 33:246-248. figure 1. left cowper’s gland (a) was removed by transperineal surgical approach (b). figure 2. transperineal ultrasound during urethral echography (saline solution injected through the urethra). in the correspondence of the spongiosum corpus is clearly showed a large hypoechoic zone (arrow) secondary to a cutaneous fistula between bulbar urethra and perineum. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md astrid bonaccorsi, md paolo panella, md michele pennisi, md urology unit cannizzaro hospital via messina 829, catania (italy) pepe_stesura seveso 30/09/19 18:27 pagina 197 241archivio italiano di urologia e andrologia 2019; 91, 4 original paper evaluation of sexual dysfunction prevalence in infertile men with non-obstructive azoospermia taha numan yıkılmaz, erdem öztürk, nurullah hamidi, !smail selvi, halil başar, levent peşkircioğlu department of urology, dr. abdurrahman yurtaslan oncology training and research hospital, ankara. objectives: to determine the prevalence of sexual dysfunction in male partners of infertile couples and evaluate the effect of childlessness on erectile dysfunction (ed) and sexual relationship stress. materials and methods: we collected datas of couples who attended our clinics for infertility between 2009 and 2016. erectile dysfunction was investigated with the questionnaires of international index of erectile function-15 (iief-15) whereas premature ejaculation (pe) status with the premature ejaculation diagnostic tool (pedt). the stress status of the childlessness in terms of sexual intercourse was scored by the visual analogue scale (vas) questionnaire. these scores were measured before and after a successful assisted reproductive treatment with the birth of the child. results: the median age of the 193 male patients was 31 years (range 23-48). erectile dysfunction was found in 68 (35.2%) and pe in 42 (21.7%) subjects. one hundred and forty-one couples were treated with assisted reproductive treatments. forty eight couples had successful pregnancy. the iief-15 test was repeated after the birth of the child to the male partners of these couples. we observed that the iief-15 scores increased from 16 to 21 (p = 0.014). however there were no significant improvement on their ejaculation status (p > 0.05). the mean vas scores of male partners was 5.2 (3-10) in the treatment period while it decreased to 4.1 (0-8) after the birth of the chils (p = 0.02). statistically analysis showed a correlation between vas and infertility as did iief-15. conclusions: we observed that having children has a reducing effect on sexual relationship stress. infertility is absolutely blamed on the women and men. this condition may have negative effects on male sexual performance and it is closely related with some emerging female sexual disorders. it should be taken into consideration that infertile couples may have sexual dysfunction. key words: andrology; infertility; childlessness; anxiety; erectile dysfunction. submitted 12 may 2019; accepted 2 august 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.241 introduction infertility is the inability to have child after 1 year of unprotected intercouse. fifteen percent of couples experience difficulty conceiving a child. in between one-third and one-half of these, an abnormality can be found in the male partner (1). infertility has been described as a stressor and a life crisis for individuals or couples, which results in a lower life quality and enhanced marital conflicts (2-5). these stresses play havoc with the couple’s sex life. the physical health and emotional well-being of many individuals and couples of reproductive age are significantly affected by infertility. sexual function is one of the important components of health and overall quality of life (6). thus, couples with infertility may have abnormalities of sexual function, reduced sexual activity and this leads to an increase in the numbers of past years without a baby owner (7). the relationship between sexual problems and infertility is unclear. infertility causes many psychosexual problems such as loss of libido (with a consequent decrease in sexual activity), impotence, inhibition of orgasm and premature ejaculation (little or no control over ejaculatory response withnejaculation that may occur before vaginal entry achieved) or retarded ejaculation (difficulty ejaculating intravaginally, or at all) in male (8). in contrast, sexual dysfunction may have an etiological role on infertility. several studies from the united states (us) have suggested that infertility does not impact on sexual or erectile function after controlling for differences in intercourse frequency and/or socio-economic factors (9-11). one the other hand, many studies from us have suggested that infertility is often associated with sexual problems in men (12). the aim of this study is determining the prevalence of sexual dysfunction in male partners of infertile couples and evaluating the effect of childlessness on erectile dysfunction (ed) and sexual relationship stress in male partners. materials and methods we collected data of couples who attended our clinics for infertility from 2009 to 2016. age of couples, educational status of couples, duration of marriage, timing of obtaining first sexuality education, the number of successful or unsuccessful conception history of prior paternity, number of intercourse and sexual function were enrolled. sexual function involved erectile dysfunction and premature ejaculation for men. erectile dysfunction was investigated with the questionnaires of international index of erectile function-15 (iief-15) (11), in its turkish translation. male participants were invited to complete several selfreported questionnaires including modified the iief-15 and the modified international index of erectile function (iief-5) which consists 5 questions: 2 regarding erectile function, 1 concerning orgasmic function, 1 question on sexual desire, and 1 on satisfaction with intercourse. yikilmaz_stesura seveso 10/01/20 08:52 pagina 241 archivio italiano di urologia e andrologia 2019; 91, 4 t. numan yıkılmaz, e. öztürk, n. hamidi, !. selvi, h. başar, l. peşkircioğlu 242 iief-15, a 15-item questionnaire for the evaluation of 5 domains of male sexual function (desire, erectile function, intercourse satisfaction, orgasmic function and overall satisfaction) (13, 14). the questionnaire investigated both spontaneous sex for pleasure and sex intended to lead to pregnancy. an iief-15 erectile function domain score less than 26 was used as a cut-off for the presence of erectile dysfunction (15). according to iief15, score was categorized as: (score 6-10) severe ed; (score 11-16) moderate ed; (score 17-21) mild to moderate ed; (score 22-25) mild ed; (score 26-30) no ed. premature ejaculation (pe) was determined by a questionnaire consisting of 5 separate questions called premature ejaculation diagnostic tool (pedt) (16). a pedt score less than 8 indicates no pe, on the contrary pe was diagnosed. the subjects underwent standard semen analysis, according to world health organization criteria. semen samples obtained by masturbation after 3-5 days of sexual abstinence. azoospermic men were evaluated according to the clinical parameters (testicular volume and structure, serum fsh levels and testicular biopsy) and only non-obstructive azoospermia patients were included in the study. the stress status of the childlessness in terms of sexual intercourse was scored by the visual analogue scale (vas) questionnaire. the scores before and after the birth of the child were compared. patients with known systematic and psychiatric diseases, taking a medicine that may cause sexual dysfunction or the ones complaining of secondary infertility were excluded from the study. all the data provided were enrolled as part of a routinely clinical procedure and, ethical approval for the study was received from the ethics commitee. written informed consent was obtained from patients who participated in this study. statistical analysis all statistical analyses were performed with statistical package for the social science (spss inc, chicago, illinois, usa) version 16.0. normality of tests was analyzed with the kolmogorov-smirnov and shapiro-wilk tests. the independent samples t test was used for pairwise comparisons of parameters that were distributed normally, and the mann whitney u-test was used for parameters that were not distributed normally. differences were considered significant when p < 0.05. results the median age of the 193 male patients and their partners were 31 (range 23-48) and 27.2 (range 18-43) years, respectively. when the socio-cultural levels of male partners were examined, 59% of them were graduated from high school or university. couples have been married for an average of 45 months (range 12-193) and the median period of infertility in these couples was 27 months (range 12-180). the average number of weekly frequency of coitus was around 2.5 (range 0.5-7). in this study, all of the cases consisted of primarily infertile couples, whereas a previously successful birth was not observed in any case. the mean number of treatments of couples prior to involvement in study was 0.6 (range 07) including oral medications, injectable fertility drugs, intrauterine insemination (iui).the majority of men was in their first marriage (93%), while a minority was in their second (6%) or third marriage (1%) (table 1). the results of the iief-15 questionnaire showed that 68 (35.2%) men reported an overall ed. of these, 31 (15.5%) patients reported a mild ed (score 22-25), 25 (12.9%) patients a mild to moderate (score 17-21), 9 (4.6%) patients a moderate ed (score 11-16) and 3 (1.5 %) patients have reported a severe form (score 6-10). premature ejaculation was seen in 42 (21.7%) patients according to pedt score. in patients with a pedt score > 8 acquired and lifelong pe was reported by 56.2% and 43.8% of the patients, respectively. erectile dysfunction was not seen in 50% of cases with pe, whereas pe was not observed in cases with severe ed. patients were divided into two groups according to presence of ed, (group 1: iief-15 ed score < 26 [n:68]; group 2: no ed [n:125]). the mean age of the patients was 33.1 ± 6.55 and 31.3 ± 4.93, respectively (p = 0.14). when comparing two groups there was no relationship between ed presence and education level but the education levels of men with severe and moderate ed were significantly lower than men with mild ed (p < 0.05). age of partners was 29.4 ± 6.02 and 27.5 ± 5.15, respectively, and weekly frequency of coitus was 2.1 ± 0.84 and 2.5 ± 0.97 respectively; differences were statistically significant (p = 0.053 and 0.002, respectively). the mean number of treatment protocols applied to these couples was 2.1 (0-4). one hundred and forty-one of the couples were treated with different treatment modalities such as oral drugs, injectable fertility drugs, intrauterine insemination (iui). successful pregnancies were obtained in 61 cases with assisted reproduction treatments after a mean of 10 months (3-18 months). thirteen pregnancies were terminated due to different reasons. after the treatment period, the iief-15 test was repeated to 48 male partners of couples having children. we observed that iief-15 scores increased from 16 to 21 and that improvement in iief-15 scores was statistically table 1. sociodemographic and clinical characteristics of the subjects. all patients (n: 193) age (years) 31 ± 4.2 partner’s age (years) 27.2 ± 3.1 education (%) primary/secondary 41 high/university 59 duration of marriage (months) 45 (12-193) number of marriage (%) first 93 second 6 third 1 duration of infertility (months) 27 (12-180) frequency of coitus (per week) 2.5 (0.5-7) erectile dysfunction n (%) 68 (35.2) iief-15 score n (%) no ed (26-30) 125 (64.8) mild ed (22-25) 31 (15.5) mild to moderate (17-21) 25 (12.9) moderate (11-16) 9 (4.6) severe (6-10) 3 (1.5) premature ejaculation n (%) 42 (21.7) yikilmaz_stesura seveso 10/01/20 08:52 pagina 242 significant (p = 0.014). at the same time pe was questioned by pedt in this group of patients, but no statistical difference was observed. we evaluated the effect of having children on stress levels by vas score. the visual analogue scale (vas) questionnaire was filled during the period of the use of assisted reproduction methods and in the next period after having children in order to evaluate the stress related to infertility. their stress levels regarding sexual function in these two periods were scored as follows; 0: no stress, 10: very stressful. the mean vas scores of male partners was 5.2 (3-10) in treatment period while the same group mean score decreased to 4.1 (0-8) when they had children (p = 0.02). statistical analysis showed a correlation between vas and infertility like iief-15 (table 2). discussion sexual dysfunctions are common problems in society. premature ejaculation (29.3%) is the main sexual displeasure in men in the general population; ed (14.5%) follows as the second sexual health problem (17). the prevalence of infertile couples ranges from 4% to 17% and sexual dysfunction may play an etiological role in these couples (18, 19). in one study, investigating presence of ed and pe in infertile men, lotti et al. proved that both ed and pe were higher in them compared to fertile men (20). another study in infertile men on in vitro fertilisation treatment, found no significant difference in infertile men in terms of ed, but these patients had more depressive mood (21). in a community research by jain et al. premature ejaculation (66%) was the most common problem and it was followed by erectile dysfunction (15%), decreased libido (11%) and orgasmic failure (8%) among the infertile men (22). in a similar study by lotti et al. erection and ejaculation status of infertile men were evaluated with iief and pedt (12). they also researched psychological status with middlesex hospital questionnaire (mhq) and prostatitis symptoms with national institutes of health-chronic prostatitis symptom index (nih-cpsi). lotti et al. found lower rates of pe and ed (15.6% and 17.8%) than in our study (21.7% and 34.7%, respectively). also depression was significantly associated with ed and they found a positive relationship between pe and prostatitis symptoms and phobic anxiety. according to these rates, it was obvious that men who had known that they were infertile, came across with more sexual problems such as pe and ed than fertile ones. these male partners, especially living in conservative societies, have a feeling of guiltiness and weakness so sexual fuction can not be fully performed by them (23). there are many factors that can lead to the relation between infertility and sexual dysfunction such as age, race, religion, social status, employment status, level of education and previous paternity experience. in our study, we found that education levels of men with severe and moderate ed were significantly lower than in men with mild ed, similarly to the literature (23). kızılay et al. found a close correlation between sperm parameters and sexual dysfunction in infertile couples. according to this study, poor sperm quality for count, morphology and motility were associated with severe ed in men and a parallel increase of female sexual dysfunction was observed (24). they also reported that worse sperm parameters accompanied declines in testosterone and iief scores. this comparison is not possible in terms of the azoospermia of all the cases in our study. however, known azoospermic group had the worst erectile function, higher pe prevalence, lower sexual desire, orgasmic function and general health condition among all infertile males (25). in 2014, bayar et al. examined sexual dysfunction before and after treatment in patients who received ivf treatment (26). iief form for male partners and fsfi form for female partners were used for determining sexual dysfunction. at the third month of ivf treatment, severity of sexual dysfunction increased to 72% of female partners and 48% of male partners. but in the subgroup analysis, there were not found significant differencies in erection status and pe. in our study we investigated the changes in ed and pe in case of couple’s having a baby and we observed that iief-15 scores increased from 16 to 21 in male partners after having a baby after treatment. this improvement in iief-15 scores was statistically significant (p = 0.014). at the same time pe was questioned by pedt in this group of patients, but no statistical difference was observed. it had been observed that psychosexual problems rise at the maximum level when duration of childlessness lasted less than two years or more than eight years (14). song et al. searched stress related to infertility and timed intercourse during fertile periods of male partners in infertile couples with vas questionnaires (8). the mean vas score of sexual relationship stress was significantly higher during fertile than non-fertile periods (3.4 vs 2.1). as the fecundity of healthy couples is about 20% per cycle, the wife and the environment create stress on men' sexual function during fertile periods (8). we investigated the effect of sexual relationship stress in infertile couples who had children after assisted reproduction procedures. to our knowledge, this is the first study to quantitatively investigate stress levels of male partners of infertile couples between the periods before after the birth of the child. in our study, after having child the vas scores of male partners showed a statistically significant decrease to 4.1 from 5.2 during sexual intercourse. furthermore this significant improvement was also observed on sexual functions. we observed a statistically significant increase in the mean iief-15 levels from 16 to 21 in case of having a baby although the same improvement was not seen in pe. our study has some limitations. firstly, sexual functions of female partners were not investigated. a decrease in female sexual desire may cause a negative effect on sexual function of their male partners. secondly, we did not eval243archivio italiano di urologia e andrologia 2019; 91, 4 sexual dysfunction and non-obstructive azoospermia table 2. comparison of stress levels of 48 male partners with childhood by using vas questionnaire and ed and pe scores between childlessness and after having child. childlessness having child p iief (0-30) 16 21 0.014 pe (0-20) 6.3 ± 2.1 5.9 ± 1.7 vas (0-10) 5.2 (3-10) 4.1 (0-8) 0.02 yikilmaz_stesura seveso 10/01/20 08:52 pagina 243 archivio italiano di urologia e andrologia 2019; 91, 4 t. numan yıkılmaz, e. öztürk, n. hamidi, !. selvi, h. başar, l. peşkircioğlu 244 uate the psychological or somatic status of patients with psychiatric tests such as middlesex hospital questionnaire (mhq) or short form health survey 36 (sf-36) which can effect patients’ sexual functions. lastly, our study did not include fertile couples as a control group. also the retrospective design of our study is an important bias. therefore, randomised prospective studies with large groups of infertile and fertile groups are needed to understand the main pathogenesis of male sexual dysfunction. conclusions we aimed to investigate the prevalence of sexual dysfunction which included ed and pe in infertile men. erectile dysfunction was more common in our patient group than the literature. we consider this as a repercussion of communicative obstacles encountered in conservative societies. moreover another finding, contrasting the literature, was related to the assessment of ed, pe and quantitative stress degree related to infertility (vas scores) after having a baby through assisted reproduction treatments. we observed that having children is a reducing effect on sexual relationship stress. sexuality can be deprived of its amusement and erotic value in case of a known infertility status. this condition may have negative affects on male sexual performance and it is closely related with occuring female sexual disorders. it should not be forgotten that infertile couples may have sexual dysfunction. references 1. lee ty, sun gh, chao sc. the effect of an infertility diagnosis on the distress, marital and sexual satisfaction between husbands and wives in taiwan. hum reprod 2001; 16:1762-7. 2. nene ua, jindal un, dhall gi. infertility: a label of choice in the case of sexually dysfunctional couples. patient educ couns 2005; 59:234-8. 3. brugh vm iii, lipshultz li. male factor infertility: evaluation and management. med clin north am 2004; 88:367-85. 4. chevret m, jaudinot e, sullivan k, et al. impact of erectile dysfunction (ed) on sexual life of female partners: assessment with the index of sexual life (isl) questionnaire. j sex marital ther 2004; 30:157-72. 5. speckens ae, hengeveld mw, lycklama a nijeholt g, et al. psychosexual functioning of partners of men with presumed nonorganic erectile dysfunction: cause or consequence of the disorder? arch sex behav 1995; 24:157-72. 6. khademi a, alleyassin a, amini m, ghaemi m. evaluation of sexual dysfunction prevalence in infertile couples. j sex med. 2008; 5:1402-10. 7. lapane kl, zierler s, lasater tm, et al. is a history of depressive symptoms associated with an increased risk of infertility in women? psychosom med 1995; 57:509-13. 8. song sh, kim ds, yoon tk, et al. sexual function and stress level of male partners of infertile couples during the fertile period. bju int. 2016; 117:173-6. 9. hurwitz mb. sexual dysfunction associated with infertility. a comparison of sexual function during the fertile and the nonfertile phase of the menstrual cycle. s afr med j. 1989; 76:58-61. 10. shindel aw, nelson cj, naughton ck, mulhall jp. premature ejaculation in infertile couples: prevalence and correlates. j sex med. 2008; 5:485-91. 11. cappelleri jc, rosen rc, smith md, et al. diagnostic evaluation of the erectile function domain of the international index of erectile function. urology. 1999; 54:346-51. 12. lotti f, corona g, rastrelli g, et al. clinical correlates of erectile dysfunction and premature ejaculation in men with couple infertility. j sex med. 2012; 9:2698-707. 13. saleh ra, ranga gm, nelson dr, agarwal a. sexual dysfunction in men undergoing infertility evaluation: a cohort observation study. fertil steril. 2003; 79:909-12. 14. jindal un, dhall gi. psychosexual problems of infertile women in india. int j fertil. 1990; 35:222-5. 15. soykan a. the reliability and validity of arizona sexual experiences scale in turkish esrd patients undergoing hemodialysis. int j impot res. 2004; 16:531-4. 16. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 17. yilmaz e, zeytinci ie, sari s, et al. investigation of sexual problems in married people living in the center of konya. turk psikiyatri derg. 2010; 21:126-34. 18. tuttelmann f, nieschlag e. classification of andrological disorders. in: nieschlag e, behre hm, nieschlag s, eds. andrology. male reproductive health and dysfunction. 3nd edition. berlin: springer, verlag; 2010; 87-92. 19. krausz c. male infertility: pathogenesis and clinical diagnosis. best pract res clin endocrinol metab. 2011; 25:271-85. 20. lotti f, corona g, castellini g, et al. semen quality impairment is associated with sexual dysfunction according to its severity. human reproduction. 2016; 31:2668-2680. 21. ozkan b, orhan e, aktas n, coskuner er. depression and sexual dysfunction in turkish men diagnosed with infertility. urology. 2015; 85:1389-1393. 22. jain k, radhakrishnan g, agrawal p. infertility and psychosexual disorders: relationship in infertile couples. indian j med sci. 2000; 54:1-7. 23. smith jf, walsh tj, shindel aw, et al. sexual, marital, and social impact of a man’s perceived infertility diagnosis. j sex med. 2009; 6:2505-2515. 24. kızılay f, sahin m, altay b. do sperm parameters and infertility affect sexuality of couples? andrologia. 2018; 50. 25. lotti f, corona g, castellini g, et al. semen quality impairment is associated with sexual dysfunction according to its severity. hum reprod. 2016; 31:2668-2680. 26. bayar u, basaran m, atasoy n, et al. sexual dysfunction in infertile couples: evaluation and treatment of infertility. j pak med assoc. 2014; 64:138-45. correspondence taha numan yıkılmaz, md (corresponding author) numanyikilmaz@gmail.com erdem öztürk, md drerdemozturk@gmail.com halil başar, md drhalilbasar@gmail.com !smail selvi, md drismailselvi@gmail.com department of urology, ankara dr. abdurrahman yurtaslan oncology training and research hospital, ankara 06200, turkey nurullah hamidi, md drnurullahhamidi@gmail.com atatürk training and research hospital, ankara 06200, department of urology levent peşkircioğlu, md drlevent@gmail.com baskent university ankara education and research hospital, department of urology, ankara, turkey yikilmaz_stesura seveso 10/01/20 08:52 pagina 244 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 4296 original paper mri/us fusion prostate biopsy: our initial experience vito lacetera 1, bernardo cervelli 1, antonio cicetti 1, giuliana gabrielloni 1, michele montesi 1, roberto morcellini 1, gianni parri 1, emilio recanatini 1, gianluca giglioni 2, andrea benedetto galosi 2, valerio beatrici 1 1 azienda ospedaliera ospedali riuniti marche nord, pesaro, italy; 2 clinica urologica, università politecnica delle marche, azienda ospedaliera ospedali runiti, ancona, italy. aim: the objective of this study is to present our initial experience with magnetic resonance imaging/ultrasound (mri/us) fusion biopsy using the koelis trinity device after the first consecutive 59 patients. materials and methods: 59 consecutive patients with suspected prostate cancer (pca) underwent prostate biopsy using trinity koelis® (koelis, grenoble, france). we divided the patients into 2 groups: patients with a previous negative mapping underwent to a mri/us fusion re-biopsy (group a); and biopsy-naïve patients who underwent to a first stereotactic 3-d mapping of the prostate (group b). group a (22 patients):mean age 64 years (ci 48-73), mean psa = 7.7 ng/ml (ci 4.29.9); mean prostate volume 55 ml(ci 45-82), digital rectal examination (dre) positive in 2/22, number of lesions detected by mri 1.4, mean cores from each mri target lesion 3 (ci 2-5), mean total cores 15 ( ci 12-19). group b (37 patients): mean age 66 years (ci 49-77), mean psa= 4.7 (3.27.9); mean prostate volume 45 ml (33-67), dre positive in 5/37, mean total cores 14 ( ci 10-16) results: in group a 10/22 patients were positive for pca (overall detection rate of 45.5%): 6 pca were detected by target biopsy and 4 cancer by random biopsy. significant prostate cancer (defined as the presence of gleason pattern 4) was detected in 4/10 patients (significant pca detection rate of 40%) and all significant pca were detected by mri target biopsy. all pca detected by random biopsy had gleason score 3 + 3 = 6. in group b (biopsy naïve patients) 14/37 patients were positive for pca (overall detection rate of 37.8%), significant prostate cancer was detected in 5/14 patients (significant pca detection rate of 35,7%). no significant side effects were recorded. conclusions: our overall detection rate was 45.5% and 37.8% in group a (patients with previous negative biopsy and persistent suspicion of pca) and in group b (biopsy naïve patients) respectively; clinical significant pca detection rate was respectively 40% and 35.7%. these results are similar to current literature and promising for the future. we believe that using platforms of co-registered mri/us fusion biopsy can potentially improve risk stratification and reduces understaging, undergrading and the need for repeat biopsies in biopsy naïve patients (using a stereotactic first mapping) and in patients with previous negative biopsy and persistent suspicion of pca ( using a second mri/us fusion biopsy). key words: mri/us fusion biopsy; prostate cancer; prostate biopsy. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. introduction transrectal ultrasound-guided random biopsy of the prostate (trusb) is still the recommended standard tool for the diagnosis of prostate cancer (pca) (1). this approach is a blindly sample of the prostate without focus on any specific lesion; there are several limitations in this approach, including failure to detect clinically significant pca (due to undersampling); imprecise tumor risk stratification (undergrading) and detection of small, low risk clinically insignificant cancers (overdiagnosis) (2). undersampling can occur in up to 30% of cases with clinically significant tumors being missed on initial biopsy; undergrading is exstimated at 46% of cases considered at low risk of progression candidates for active surveillance, based on preoperative systematic biopsy, but with an upgraded gleason score of 7 or greater at final histopathology (3). these diagnostic limitations can lead to repeat biopsies (with related side effects and costs), delayed detection of significant pca and over treatment. efforts to overcome sampling error include performing multiple repeat biopsies and increasing the core number; this resulted in the overdetection of indolent cancers, morbidity attributed to unnecessary biopsies and an increase in cost. several studies have shown that when serial biopsies are indicated, most cancers that are detected are clinically insignificant and the rate of indolent cancer detection increases (4, 5). recently, a 3-d stereotactic mapping of the prostate has been proposed in order to have a threedimensional histological mapping of the gland: this technique can be made by a templated-guided transperineal biopsy that requires anaesthesia (spinal or sedation) and hospitalization, or by a software based transrectal biopsy that records all tracks of the needle on a 3-d map with only a local anaesthesia. this technique should allow not overlapping needle’s tracks with a better 3-d volumetric distribution of the biopsies into the prostatic gland and than a better determination of the extent and location of cancer before definitive therapy (6). advances in imaging have led to the application of magnetic resonance imaging (mri) for the detection of pca (7-12) with subsequent development of software-based co-registration allowing for the integration of mri with real-time trus during prostate biopsy. a number of fusion-guided methods and platforms are now commercially available doi: 10.4081/aiua.2016.4.296 presented at 20th national congress sieun, sciacca 2016 297archivio italiano di urologia e andrologia 2016; 88, 4 fusion prostate biopsy with common elements in image and analysis and planning (13-15). we present our initial experience with one of these platforms after the first consecutive 59 patients. materials and methods between may 2016 and october 2016, we prospectively evaluated the first consecutive 59 patients who underwent to trus biopsy using trinity koelis® (koelis, grenoble, france) mri/us fusion machine. we divided the patients into 2 groups: patients with a previous negative mapping who underwent to a mri/us fusion re-biopsy (group a); and biopsy-naïve patients who underwent to a first stereotactic 3-d mapping of the prostate (group b). mri images were obtained using a 1.5 t scanner with a pelvic phased array coil, each suspicious area was further characterized according to the esur pi-rads v.1 global score (12), mri were done in different hospital without a central review. two different urologists made all the biopsies. all biopsy core specimens were examined by 2 urogenital pathologists and graded according to the 2005 international society of urological pathology modified gleason grading system (16). characteristics of the patients (summarized in table 1) were in group a: n° of patients = 22, mean age 64 years (ci 48-73), mean psa = 7.7 ng/ml (ci 4.29.9), mean prostate volume = 55 ml (ci 45-82), digital rectal examination (dre) positive ratio = 2/22, number of lesions detected by mri 1.4 (17 pirads 3, 4 pirads 4, 1 pirads 5), mean cores from each mri target lesion = 3 (ci 2-5), mean total cores = 15 (ci 12-19). in group b: n° of patients = 37, mean age 66 years (ci 49-77), mean psa = 4.7 (3.27.9); mean prostate volume = 45 ml (33-67), dre positive ratio = 5/37, mean total cores = 14 (ci 10-16). we standardized our mri/us fusion biopsy technique using koelis trinity in 5 steps: first step: mri t2 and/or dwi images are loaded into the trinity, we manually border the prostate signing the apex, the base the mid gland and additional landmarks of the prostate obtaining a 3-d mri volume; than we target the suspected areas described in the mri report in a semiautomatic process. this step is usually done the day before procedure second step: a 3d trus volume is obtained by a real-time trus examination in 3 planes (transversal, 60 degree longitudinal turning the probe on the right and on left) by an end fire probe with a rotating 360 degree head. we border the prostate volume in a similar way to mri process. third step: automatic elastic fusion of the mri and ultrasound volumes is done by the machine’s software pressing a button. we check the correct fusion of the volumes fourth step: virtual simulation of bioptical tracking with a visual feedback on the fused target volume is done fifth step: if the virtual simulation of the track is inside the target lesion, we press the button of the needle and a real biopsy is done followed by 3d-trus acquisition of the real track with the needle still in the gland. a mean of 2 cores were obtained from each mri-target area. then at least a 12-core random biopsy were performed in all patients. in case of stereotactic first round biopsy in biopsy naïve patient (group b) step 1 and 3 are avoided, we recorded all real track in a 3-d trus map. results our results are summarized below and displayed in table 2. group a (22 patients): 10/22 positive for pca (overall detection rate of 45.5%). 6 pca were detected by target biopsy and 4 cancer by random biopsy. significant prostate cancer (defined as the presence of gleason pattern 4) was detected in 4/10 patients (significant pca detection rate of 40%), all significant pca were detected in mri target biopsy (1/17 pirads 3, 2/4 pirads 4, 1/1 pirads 5). all pca detected by random biopsy had gleason score 3 + 3 = 6. group b (37 biopsy naïve patients): 14/37 positive for pca (overall detection rate of 37.8%), significant prostate cancer was detected in 5/14 patients (significant pca detection rate of 35,7%). the mean time of the procedure was 42 min (c.i. 22-55) in the initial 10 patients and 27 min in the following 10 patients (c.i. 19-35) in group a, 27 min (c.i. 19-45) in the initial 10 patients and 17 min in the following 10 patients (c.i. 10-25) in group b. no significant side effects were recorded in either group (such as fever, urinary retention, urosepsis, and hospitalization). table 1. characteristics of the patients. group a: patients with a previous negative mapping who underwent to a mri/us fusion re-biopsy. group b: biopsy-naïve patients who underwent to a first stereotactic 3-d mapping of the prostate. group a group b number of patients 22 37 mean age 64 66 mean psa 7.7 4.7 dre positive 2/22 5/37 mean prostate volume 55 46 total cores 15 14 mean core from each target 3 pirads 3 17/22 pirads 4 4/22 pirads 5 1/22 table 2. results. group a group b overall pca detection rate 10/22 ( 45.5%) 14/37 (37.8%) significant pca detection rate 4/10 (40%) 5/14 (35.7%) pca in target lesion 6/10 pca in random biopsy core 4/10 significant pca detected in target lesion 4/6 pirads 3 1 /6 pirads 4 2 /6 pirads 5 1/6 significant pca in random biopsy core 0/4 archivio italiano di urologia e andrologia 2016; 88, 4 v. lacetera, b. cervelli, a. cicetti, g. gabrielloni, m. montesi, r. morcellini, g. parri, e. recanatini, g. giglioni, a.b. galosi, v. beatrici 298 discussion we considered many commercial platforms of co-registered mri/us fusion biopsy devices commercially available. these devices vary by method of co-registration (mechanical, electromagnetic or real-time) and use a different hardware platform to align the biopsy with the co-registered image. we chose trinity koelis because we considered this option to be the best compromise between accuracy, reproducibility and feasibility in our daily practice. a recent systematic review shows that mri-trus image fusion targeted biopsies detect more clinically significant cancers compared with standard biopsy techniques: the median detection rate of any cancer was 43.4% and 50.5% in the standard biopsy strategy versus mri-trus image fusion biopsy; the median detection of clinically significant disease was 23.6% (range: 4.8-52%) for standard biopsy and 33.3% (range: 13.2-50%) for mritrus image fusion targeted biopsy however, patient populations differ quite a bit between the different studies regarding the amount of patients with a previous negative biopsy or patients that were biopsy naïve (17). our overall detection rate was 45.5% and 37.8% in mri-us fusion biopsy (patients with previous negative biopsy and persistent suspicion of pca) and in stereotactic biopsy (biopsy naïve patients); clinical significant pca detection rate was respectively 40% and 35.7%. these results are similar to those reported in the current literature and promising for the future. the main limitations of our study were the small number of patients, difference in expertise of the radiologists, our learning curve of at least the first 10 cases. until now our main problems using this technique are the following: it is not easy to border the target lesion without radiologist’s help if it is visible only in dwi sequence; because this is a freehand procedure (operator dependent technique) without a probe stepper, even a little movement of the probe in the passage from virtual track simulation to real biopsy could miss the target lesion (especially if the diameter is < 1 cm). conclusions mri/us fusion biopsy in patients with a previous negative mapping but persistent suspicion of pca represents a useful tool to address many of the limitations of contemporary systematic re-biopsy (reduce false-negatives, improve risk classification, contribute to the reduction of repeat biopsies and overdetection). among men with no previous biopsy its role is poorly defined, but we believe that at least a stereotactic first bioptical mapping (recording all bioptical tracks in a 3-d map) can not only increase cancer detection rate but, if a re-biopsy will be necessary, a mri-us fusion biopsy can be done using the previous recorded 3-d map, avoiding the same tracks of first mapping and improving the results of this technique.we believe that among men with suspicion of pca, stereotactic first mapping and mri/us fusion rebiopsy potentially improves risk stratification and reduces understaging, undergrading and the need for repeat biopsies. the optimal method for mr targeted biopsy has not yet been established; further comparative studies with standard of practice and evaluation of cost-effectiveness are warranted. figure 1. first stereotactic 3-d mapping of the prostate in a biopsynaïve patient. figure 2. mri/us fusion re-biopsy in a patients with a previous negative mapping (4 target cores from a mri lesion with a pirads score 3 at right apex plus 9 random cores). figure 3. automatic elastic fusion of the mri and ultrasound volumes is done by the machine’s software. figure 4. mri/us fusion target and random re-biopsy: 2 mri lesions with a pirads score of 3 (orange) and 2 mri lesions with pirads 4 (red). 299archivio italiano di urologia e andrologia 2016; 88, 4 fusion prostate biopsy references 1. bjurlin ma, carter hb, schellhammer p, et al. optimization of initial prostate biopsy in clinical practice: sampling, labeling and specimen processing. j urol. 2013; 189:2039. 2. serefoglu ec, altinova s, ugras ns, et al. how reliable is 12-core prostate biopsy procedure in the detection of prostate cancer? can urol assoc j. 2013; 7:e293-e298 3. mufarrij p, sankin a, godoy g, et al. pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy. urology. 2010; 76:689. 4. walz j, et al. high incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series. eur urol. 2006; 50:498. 5. eichler k, et al. diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. j urol. 2006; 175:1605. 6. moran bj, et al. re-biopsy of the prostate using a stereotactic transperineal technique. j urol. 2006; 176:1376. 7. futterer jj, et al. can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? a systematic review of the literature. eur urol. 2015; 68:1045. 8. schoots ig, et al. magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasoundguided biopsy: a systematic review and meta-analysis. eur urol. 2015; 68:438. 9. panebianco v, et al. multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study. urol oncol. 2015; 33:17 e1. 10. barentsz jo, weinreb jc, verma s, et al. synopsis of the pirads v2 guidelines for multiparametric prostate magnetic resonance imaging and recommendations for use. eur urol. 2016; 69:41-49. 11. vache t, et al. characterization of prostate lesions as benign or malignant at multiparametric mr imaging: comparison of three scoring systems in patients treated with radical prostatectomy. radiology. 2014;. 272:446. 12. barentsz jo, et al. esur prostate mr guidelines 2012. eur radiol. 2012; 22:746. 13. moore cm, robertson nl, arsanious n, et al. image-guided prostate biopsy using magnetic resonance imaging-derived targets: a systematic review. eur urol. 2013; 63:125. 14. van hove a, et al. comparison of image-guided targeted biopsies versus systematic randomized biopsies in the detection of prostate cancer: a systematic literature review of well-designed studies. world j urol. 2014; 32:847. 15. siddiqui mm, et al. comparison of mr/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. jama. 2015; 313:390. 16. epstein ji, allsbrook wc, amin mb, egevad ll, grading isup, isup grading committee the 2005 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma. am j surg pathol. 2005; 29:1228-1242. 17. valerio m, donaldson i, emberton m, et al. detection of clinically significant prostate cancer using magnetic resonance imagingultrasound fusion targeted biopsy: a systematic review. eur urol. 2015; 68:8-19. correspondence vito lacetera, md, urologist vito.lacetera@gmail.com bernardo cervelli, md, urologist bernardo.cervelli@ospedalimarchenord.it antonio cicetti, md, urologist antonio.cicetti@ospedalimarchenord.it giuliana gabrielloni, md, urologist giuliana.gabrielloni@ospedalimarchenord.it gianluca giglioni, md gianluca.giglioni@ospedalimarchenord.it piallu88@gmail.com michele montesi, md, urologist michele.montesi@ospedalimarchenord.it roberto morcellini, md, urologist roberto.morcellini@ospedalimarchenord.it gianni parri, md, urologist gianni.parri@ospedalimarchenord.it emilio recanatini, md, urologist emilio.recanatini@ospedalimarchenord.it valerio beatrici, md, urologist valerio.beatrici@ospedalimarchenord.it azienda ospedaliera ospedali riuniti marche nord piazzale cinelli 4, 61121 pesaro, italy andrea benedetto galosi, md, associate professor of urology galosiab@yahoo.it clinica urologica, università politecnica delle marche, azienda ospedaliera ospedali runiti, ancona, italy archivio italiano di urologia e andrologia 2016; 88, 4292 original paper cognitive zonal fusion biopsy of the prostate: original technique between target and saturation andrea b. galosi 1, guevar maselli 3, giulia sbrollini 1, gaetano donatelli 3, lorenzo montesi 1, matteo tallè 1, rodolfo montironi 2 1 department of clinical sciences and dentistry, urology clinic, 2 pathology, az. ospedaliera polytechnic university of marche, ancona, italy; 3 division of urology, asur marche, fermo, italy. we describe our experience in prostate biopsy using a new standardized cognitive fusion techniques, that we call “cognitive zonal fusion biopsy”. this new technique is based on two operative options: the first based on target biopsies, the cognitive target biopsy (ctb) if the same target was detected with transrectal ultrasound (trus) and multiparametric magnetic resonance (mpmri); the second based on saturation biopsies, the zonal saturation biopsy (zsb) on anatomical zone/s containing the region of interest if the same target was not evident with trus and mri. we evaluated results of our technique compared to standard biopsy in order to identify clinically relevant prostate cancer. methods: this is a single-center prospective study conducted in 58 pts: 25 biopsy-naïve, 25 with previous negative biopsy and in 8 with cancer in active surveillance. based on mpmri and transrectal ultrasonography (trus), all patients were scheduled for standard 12-core trus-guided biopsy. if mpmri was suggestive or positive (pi-rads 3, 4 or 5): patients underwent additional targeted 2 to 6 cores using cognitive zonal fusion technique. results: 31/58 (53.4%) patients had a cancer. our technique detected 80.6% (25 of 31) with clinically significant prostate cancer, leading to detection of insignificant cancer in 20%. using standard mapping in mr negative areas we found 5 clinically significant cancer and 4 not significant cancers. mri cancer detection rate was 18/31 (58.1%), and 9/18 (50%) in high grade tumors. therefore mri missed 50% of high grade cancers. the mean number of cores taken with cognitive zonal fusion biopsy was 6.1 (2-17), in addition biopsy sampling was done outside the roi areas. overall 15.4 cores (12-22) were taken. cancer amount in zonal biopsy was larger than 7.3 mm (1-54.5) in comparison with 5.2 mm (1-23.5) in standard mapping. largest percentage of cancer involvement with cognitive zonal fusion technique was detected in 19.4% vs 15.9%. conclusions: cognitive zonal saturation biopsies should be used to reduce operator variability of cognitive fusion biopsy in addition to standard biopsy. cognitive zonal biopsy based on mpmri findings identifies clinically relevant prostate in 80%, has larger cancer extension in fusion biopsies than in random biopsies, and reduce the number of cores if compared to saturation biopsy. key words: prosate neoplasms; prostate biopsy; fusion imaging; ultrasound; prostatectomy. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. introduction magnetic resonance imaging (mri) is now becoming the imaging of choice for men with suspected prostate cancer, in particular index lesion detected by multiparametric mr (mpmr) may help us in risk-stratification. several approaches have been explored to improve the accuracy of image-guided targeted prostate biopsy, including inbore mri-guided, cognitive fusion, and mri/transrectal ultrasound fusion-guided biopsy (1). image-guided biopsy on mri-target rather than ultrasound-target improves amount of tumor in biopsy cores and reduces the number of cores to harvest diagnosis (2). however, it has been recently observed that standard 12-cores biopsy still maintains the same cancer detection rate (53.1%) if compared to targeted in bore mri procedures, even in the rate of clinically significant cancer (3). the debate is open on the question that we can't answer right now is whether we should omit the systematic conventional 12-core biopsies in patients with negative mpmr. we attempt to advance our extensive experience in prostate biopsy using a new standardized cognitive fusion techniques, that we call “cognitive zonal fusion biopsy”. in the standard cognitive fusion biopsy, the target is based on target biopsy of the the area supposed by operator after reading the mri. this technique is extremely dependent on operator, his experience and imaging interpretation. our technique, cognitive zonal fusion, is based on the following principles: 1) ultrasound target biopsy using endfire probe (4), that is performed if a target could be clearly showed comparing transrectal ultrasonography (trus) and mri, 2) saturation biopsy principle, that is the standard method suggested by guideline to systematic detect or exclude prostate cancer (5). therefore applying this principles to daily practice, if a target lesion is evident comparing trus and mri, the saturation biopsy is limited to the target using 2-4 cores: this is called cognitive target biopsy (ctb). whereas, in prostate without target lesion detectable by trus if compared to mri, the saturation biopsy is extended to anatomical zone or zones described by mr: this is called zonal saturation biopsy (ztb). thus we supposed to reduce variability linked to cognitive fusion biopsy. based on this hypothesis, aim of doi: 10.4081/aiua.2016.4.292 presented at 20th national congress sieun, sciacca 2016 galosi1-cognitive zonal fusionbiopsy _stesura seveso 09/01/17 10:01 pagina 292 293archivio italiano di urologia e andrologia 2016; 88, 4 cognitive zonal fusion biopsy of the prostate the study is to describe the technique and evaluate the benefits of the cognitive zonal fusion biopsy in addition to standard biopsy in order to identify clinically relevant prostate cancer. furthermore, we evaluated cancer detection rate of cognitive target biopsy which is used in case of a suspicious finding on ultrasound associated to mpmr suspicious finding, and zonal saturation biopsy which is performed when there is no suspicious finding on ultrasound associated to mpmri results. materials and methods this is a single-center prospective study conducted in 58 pts (mean age of 64 years, 46-79): 25 biopsy-naïve men with elevated levels of psa, 25 men with previous negative biopsy (including 8 with atypical small acinar proliferation) and 8 prostate cancer in active surveillance. digital rectal examination was positive in 9 men (15%), mean serum psa was 6.8 ng/ml (0.7-22.6). thirty-three patients (56.9%) had already had 1 up to 6 previous prostate biopsy (mean 1.6). patients features are listed in table 1. all the participants underwent contrast enhanced mpmri in several centers with different degree of experience in public and private italian hospitals, however all with adequate technical instrumentations most of them using 1.5 tesla. prostate imaging report and data system (pirads) and zonal anatomical identification of the region of interest (roi) were available in all reports. if mpmri was negative (pi-rads 1-2), subjects received at least a standard 12-core trus-guided biopsy plus additional cores according to prostate volume up to 20 cores. if mpmri was suggestive (pi-rads 3) or positive of cancer (pi-rads 4 or 5) underwent 12-core biopsy plus targeted 2 to 6 cores using cognitive zonal fusion technique. cognitive target biopsy (ctb) on roi (region of interest) was done on a target if a correspondence was found between mri and ultrasound (figure 1). in addition the ctb was done if a anatomic ultrasound marker was close to the roi identified by mr images (example: cyst or calcification, figure 2). if any ultrasound lesion or anatomic marker was detected comparing ultrasound with mr imaging, or a missing correspondence was found, the zonal saturation biopsy (zsb) was done. zonal saturation was performed using an uniform spatial distribution of random biopsies (2 up to 6) to cover the anatomic zone identified by mri. based on mr images, prostate gland was divided in 14 areas according to standardized mri prostate reporting scheme according to pi-rads reporting (2), therefore a whole random sampling of the roi was done including one or more anatomic zone which harbors the suspected mri area. also additional cores in adjacent areas can be taken in large gland (volume ≥ 60 cc). trained operator in trus imaging and mr imaging performed all procedures. definition of clinically significant tumor based on biopsy and radical prostatectomy specimen was defined by a dedicated uro-pathologist. definition of clinically significant tumor based on biopsy was based on: tumor grade (gleason grading 3+4, or who grade grouping ≥ 2), tumor involvement > 50% of each biopsy core, cancer extension in more than 2 different anatomic zones, tumor marker above the upper limit (psa > 10 ng/ml and/or psa-density > 0.15). perineural and ductal invasion detected on biopsy specimens was recorded by a expert uro-pathologist. definition of clinically significant tumor based on radical prostatectomy specimen: for grading (any gleason grade pattern 4, or grade grouping 2), tumor volume > 0.50 cc based on stereological (i.e. grid) method on histologic slides (6), local invasion of seminal vesicle (t3b) or extracapsular disease (t3a). results in our study, 31/58 (53.4%) patients had a cancer, 18/31 had high grade tumors (gleason pattern 4 or 5). twentyfive of 31 (80.6%) patients had a clinically significant prostate cancer and 6/31 (19.3%) had not significant cancer. cancer detection rate of mpmr was 18/31 (58.1%), and 9/18 (50%) for high grade tumors: sensitivity was 18/22 (81.8%) for all tumors and 11/19 (58.9%) for high grade tumors. cancer detection rate inside zsb/ctb was 14/25 (56%) table 1. patients characteristics at fusion biopsy. tot patients 58 median age (years) 64 (46-79) naive biopsy for elevated psa 25 (43%) n pts with previous biopsy 25 (43%) • pts in active surveillance 8 (13.8%) mean number of previuos biopsies 1.6 (1-6) dre + 9 (15%) psa (mean, ng/ml) 6.8 (0.7-22) patients with positive mpmri (pirads 3-5) 53 (91%) pi-rads 3 36 pi-rads 4-5 17 patients with negative mpmri (pirads 1-2) 5(8%) table 2. biopsy features after cognitive zonal fusion biopsy. tot n° of pts with cancer in biopsy 31 (53,4%) •high grade ca. 18/31 (58%) •clinically significant ca. 25/31 (80,6%) •not significant ca. 6/31 (19,3%) mpmri detection rate for all ca. 18/31 (58,1%) mpmri detection for high grade ca. 9/18 (50%) mpmri sensitivity 18/22 ca. detection in the cfb 14/25 (56%) ca. detection outside cfb 5/13 (38.5%) ca. detection in pi-rads 4/5 8/17 (47%) ca. detection in pi-rads 3 16/36 (44%) n° of cores in ctb (mean) 6.1 (2-17) histology core length (mean, cm) 1.5 (0.8-1.9) •large cancer inside cfb 19.44% (0-67.53%) •large cancer outside cfb 15.9% (0-50.7%) galosi1-cognitive zonal fusionbiopsy _stesura seveso 09/01/17 10:01 pagina 293 archivio italiano di urologia e andrologia 2016; 88, 4 a.b. galosi, g. maselli, g. sbrollini, g. donatelli, l. montesi, m. tallè, r. montironi 294 for clinically significant cancer and 4/6 (66.7%) for not significant cancers. outside the zsb/ctb results 5/13 (38.5%) for clinically significant cancer and 4/7 (57.1%) for not significant cancers. cancer detection rate was 8/17 (47%) in pi-rads 4/5 cancers, 16/36 (44%) in pirads 3 and 0/5 in pirads 0-2. the mean number of cores taken with cognitive zonal fusion biopsy was 6.1 (2-17), in addition biopsy sampling was done outside the roi areas. overall a mean of 15.4 cores (12-22) were taken. mean core length was 1.5 cm (0.8-1.9) measured in histology slide. amount of cancer in zonal biopsy resulted 7.3 mm (154.5) in zsb or ctb and 5.2 mm (1-23.5) outside zsb or ctb. cancer according to prognostic grading group was grouped as 2-5 in 11/23 inside the zsb/ctb and in 13/23 outside the zsb/ctb. largest percentage of cancer involvement was detected in 19.44% (0-67.53%) inside zsb or ctb and 15.9% (0-50.7%) outside zsb or ctb. discussion cognitive zonal fusion biopsy may be considered an improvement of cognitive fusion biopsy. cognitive zonal fusion is based on the principles of ultrasound target biopsy using end-fire probe and saturation biopsy applied to a zone of the prostate containing the target lesion. therefore applying this principles to daily practice, if a target lesion is evident comparing trus and mri, we performed cognitive target biopsy limited to the target using 2-4 cores in 26 %. in prostate without ultrasound target lesion compared to mri, the zonal saturation biopsy was performed in 74% cases. thus we supposed to reduce variability linked to cognitive fusion biopsy. whereas the pure cognitive biopsy may be extremely dependent on operator experience and imaging interpretation, the zonal saturation biopsy limits these factors causing a limited increase in number of cores (+ 6 in our experience). cognitive plays a key role in the decision-making process of therapeutic choice, because an increased detection rate of clinically significant cancer can drive the choice between active surveillance and surgery. based on our data, we can confirm that systematic 12core biopsies in patients with negative or positive mpmri should not be omitted. this may be valid in our area where the experience with mpmri was not uniform. in agreement with the study presented by quentin et al. (3), trus-guided biopsy can be as good if done well. in 128 men, prostate cancer detection rate comparing inbore target mri with trus guided biopsies was 60.9%. when used alone, the mri and trus biopsies had an identical detection rate (53.1%) and a similar ability to detect clinically significant intermediateand high-risk cancer (22 vs 23 patients). they did not find any significant difference in gleason score of tumours diagnosed by the two methods. however, more than half of the lesions missed by trus-guided biopsy were located in the interior part of the prostate gland. for tumors with equivalent gleason grading, the mean tumor infiltration of biopsy cores was also greater with mri biopsy (61.4% vs 48.4%; p < .0001). multiparametric mri should be used to identify anatomical zones containing suspected lesions. zsb is a technique useful in increasing the detection rate of clinically significant cancers in comparison to target biopsy. zonal saturation has been done when the ultrasound is not enough to identify the suspected lesion found to mpmri or any abnormal imaging was reported. in the few cases (5) with negative mri an extended biopsy were done, figure 1. patient who underwent zonal saturation biopsy. mismatch between target area on transrectal ultrasound (a, arrow) and the mpmri in t2 (b, arrow on the roi). figure 2. patient who underwent cognitive target biopsy (ctb). extact matching between target area on transrectal ultrasound (a, yellow arrow) and the mpmri in t2 (b, yallow arrow). furthermore a midline cyst (red arrow) helps in the lesion using a spatial correlation with us and mri. galosi1-cognitive zonal fusionbiopsy _stesura seveso 09/01/17 10:01 pagina 294 295archivio italiano di urologia e andrologia 2016; 88, 4 cognitive zonal fusion biopsy of the prostate without any evidence of tumor. mri is the best tool we have to find clinically relevant cancer reducing overdetection, however mr has bias in interpretation and instrumentation leading to not uniform definition of pirads among different centers and operator. advantage of trus guided biopsy using end-fire probe over biplane probe has been validated (7, 8). also significance of hypoechoic lesion on trus during cognitive fusion biopsy was recently outlined by shkir et al. (8). limitations of our study are bias in instrumentation and interpretation of mr, even if pi-rads classification was used in different centers by several operators; in order to reduce this bias we included also suspect lesion (pirads 3). however the low detection rate observed for mpmr may reflect the “real life” value of a center with initial experience in mpmri, such as in our region, rather than detection rate observed in referral centers with dedicated mri. another methodological limitation is based on limited number of cases and absence of a control group evaluated using mr/us fusion machine. conclusions cognitive zonal biopsy based on mpmri findings plus standard extended biopsy identifies clinically relevant prostate cancer in 80%. cognitive zonal biopsy contains more cancer extension rather than random biopsies, and reduce the number of cores if compared to saturation biopsy. systematic 12-core biopsies in patients with negative or positive mpmri should not yet be omitted. references 1. dickinson l, ahmed hu, allen c, et al. magnetic resonance imaging for the detection, lo-calisation, and characterization of prostate cancer: recommendations from a european conensus meeting. eur urol. 2011; 59:477-94. 2. barentsz jo, richenberg j, clements r, et al. esur prostate mr guidelines 2012. eur radiol. 2012; 22:746-57. 3. quentin m, blondin d, arsov c, et al. prospective evaluation of magnetic resonance imaging guided in-bore prostate biopsy versus systematic transrectal ultrasound guided prostate biopsy in biopsy naïve men with elevated prostate specific antigen. j urol. 2014; 192:1374-9. 4. galosi ab, tiroli m, cantoro d, et al. biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. arch ital urol androl. 2010; 82:248-252. 5. bertaccini a, fandella a, prayer-galetti t, et al. italian group for developing clinical practice guidelines on performing prostate biopsy: systematic development of clinical practice guidelines for prostate biopsies: a 3-year italian project. anticancer res. 2007; 27:659-666. 6. scattoni v, montironi r, rigatti p, et al. pathological changes of high-grade prostatic intraepithelial neoplasia and prostate cancer after monotherapy with bicalutamide 150 mg. bju int. 2006; 98:54-58. 7. ploussard g, aronson s, pelsser v, et al. impact of the type of ultrasound probe on prostate cancer detection rate and characterization in patients undergoing mri-targeted prostate biopsies using cognitive fusion. world j urol. 2014; 32:977-83. 8. shakir na, siddiqui mm, george ak, et al. should hypoechoic lesions on trus be sampled during mri-targeted prostate biopsy? urology. 2016. correspondence andrea b. galosi, md (corresponding author) a.b.galosi@univpm.it galosiab@yahoo.it chief institute of urology, marche polytechnic university azienda ospedaliera universitaria “united hospitals” 60020 ancona, italy giulia sbrollini, md giuliasbrollini@libero.it lorenzo montesi, md lorenzomontesi@yahoo.it matteo tallè, md matteo.talle@gmail.com resident, institute of urology, azienda ospedaliera universitaria “united hospitals” 60020 ancona, italy guevar maselli, md guevarmaselli@katamail.com gaetano donatelli, md gaetanodonatelli@hotmail.com division of urology, “murri” hospital 63900 fermo, italy rodolfo montironi, md r.montironi@univpm.it institute of pathology, marche polytechnic university azienda ospedaliera universitaria “united hospitals” 60020 ancona, italy galosi1-cognitive zonal fusionbiopsy _stesura seveso 09/01/17 10:01 pagina 295 archivio italiano di urologia e andrologia 2018; 90, 2136 original paper predictive factors of successful salvage microdissection testicular sperm extraction (mtese) after failed mtese in patients with non-obstructive azoospermia: long-term experience at a single institute cem yücel, salih budak, mehmet zeynel keskin, erdem kisa, zafer kozacioglu department of urology, tepecik training and research hospital, izmir, turkey. objective: to observe the clinical practice of salvage microdissection testicular sperm extraction (mtese) in patients with non-obstructive azoospermia (noa) and to determine the factors that may predict the presence of spermatozoa in preoperative salvage mtese. methods: we retrospectively reviewed the medical records of 445 patients with the diagnosis of noa, who had undergone the mtese operation consecutively in our institution between the dates of march 2008 and june 2017. the study included a total of 49 patients with failure to detect spermatozoa in the first mtese and who had then undergone salvage mtese. in order to investigate the factors that predict the result of salvage mtese, the patients were classified into two groups according to the outcome of salvage mtese, as those with and without spermatozoa retrieval. patients in these two groups were compared with regard to age, body mass index, history of varicocele, history of cryptorchidism, duration of infertility, outcomes of genetic analysis, results of hormone profiles and the testicular histopathology results of the first mtese. results: the sperm retrieval rate following salvage mtese was observed to be 42.8%. statistically a significant difference was determined between the mean follicle stimulating hormone (fsh) values of the groups (p = 0.013). no significant difference was observed between the groups with regard to the remaining parameters. conclusion: it was observed that among the factors that predict the success of sperm retrieval in salvage mtese in patients with noa and previous unsuccessful sperm retrieval in mtese operation, only the pre-operative fsh level was observed to significantly correlate with the success in salvage mtese. key words: azoospermia; salvage; testicular sperm extraction; spermatozoa. submitted 11 january 2018; accepted 20 february 2108 summary no conflict of interest declared. the current treatment of noa is sperm retrieval from the testes via testicular sperm extraction (tese) and using these sperms in intracytoplasmic sperm injection (icsi) to obtain a healthy pregnancy (2). currently, tese operations are performed in the guidance of a microscope (mtese). although it was initially reported that retrieval rate following a first tese attempt in a well-defined noa population was around 50%, recovery rates reported subsequently in literature were inconsistent (3). unsuccessful sperm retrieval from the first tese operation results in negative emotional and financial effects. salvage tese offers a further chance of pregnancy for whom the first tese has been unsuccessful. there is no clinical finding or test that precisely predicts the outcome of tese preoperatively. knowing the clinical characteristics that help predicting the outcomes of salvage tese would be facilitative for the preoperative counseling and clinical management of patients undergoing salvage tese. currently, there are not many studies that have published the clinical application of salvage tese in the literature. the aim of this study was to observe the clinical practice of salvage mtese in patients with noa and to determine the factors that may predict the presence of spermatozoa in preoperative salvage mtese, and help physicians determine the best candidates for this procedure. materials and methods patients and study design we retrospectively reviewed the medical records of 445 patients with the diagnosis of noa, who had undergone the mtese operation in our institution between the dates of march 2008 and june 2017. the diagnosis of noa was confirmed by clinical findings, medical history, physical examination, serum hormone levels, genetic analysis and as suggested by the who guideline, 2 semen analysis. semen analyses were obtained by masturbation after 3-4 days of sexual abstinence. the levels of serum total testosterone, follicular stimulating hormone (fsh), luteinizing hormone (lh), estradiol, prolactin of the patients and the genetic analyses doi: 10.4081/aiua.2018.2.136 introduction azoospermia is described as the absence of spermatozoa in the ejaculate and is observed in 1% of all men and 1015% of those with the complaint of infertility (1). azoospermia is examined in two groups according to its etiology as obstructive and non-obstructive azoospermia. non-obstructive azoospermia (noa) is accepted as the absence of spermatozoa in the ejaculate due to minimally developed or unproduced cells in the testicles. yucel2_stesura seveso 28/06/18 16:40 pagina 136 137archivio italiano di urologia e andrologia 2018; 90, 2 predictive factors of successful salvage mtese after failed mtese (karyotype analysis and y chromosome micro-deletion analysis) results were evaluated. for the hormone profile, blood was drawn from the antecubital vein of the patients after at least 8 hours of fasting. the micro-particle enzyme immuno-assay method (roche/hitachi, cobas e601, indianapolis, in, usa) was used to determine all the hormone levels. for the chromosome analysis, the peripheral venous blood samples of the patients were subjected to 72 hours of phytohemagglutinin-induced cell culture. the study included a total of 49 patients with noa, who had previously mtese and no sperm retrieval could be available. all patients included in the study had undergone tese operations according to the mtese procedure both in the previous attempt and in the second attempt. in order to ascertain wound healing following the first operation, salvage tese was planned for a minimum of 3 months afterwards. no hormone therapy was administered to the patients in the time between the first tese and salvage tese. those with a y chromosome micro-deletion analysis revealing azfa or azfb, history of malignancy, those who were morbidly obese, those who had obstruction-related azoospermia, those who had undergone mtese prior to the second icsi attempt despite sperm retrieval being possible in the first tese, and undergone multiple mteses, and those whose first tese operation was conventional, were excluded from the study. the patients were classified into two groups as those with or without sperm retrieval in order to investigate the factors that predict the outcome of salvage mtese. patients in these two groups were compared with regard to age, body mass index (bmi), history of varicocele, history of cryptorchidism, duration of infertility, results of genetic analysis, results of hormone profiles and testicular histopathology results of the first mtese. tese technique on the day that the tese operation was planned, additional sperm samples were obtained and it was confirmed that there were no sperms present. informed consent was obtained from all of the patients before tese. all of the patients underwent spinal anesthesia for tese. a midline scrotal incision was made and the scrotal content was pushed out from the side with the larger testis. the tunica vaginalis was opened and the tunica albuginea that surrounds the testicle was visualized. after this stage, the operation was handled under operating microscope. as described by schlegel, an avascular area was selected from the antimesenteric area to the tunica albuginea and a 3 cm incision was made with a thin scalpel (4). small samples were obtained from opaque, large, white tubules in the testicular parenchyma. each sample was placed in a petri dish filled with human tubal fluid. all samples were immediately evaluated by an embryologist using a 200 x magnification microscope in order to investigate the presence of spermatozoa. the operation was terminated when suitable spermatozoa were found for icsi. if spermatozoa were not detected in the first samples, additional samples were obtained from the same testicle. in cases where the spermatozoa were not found in the samples sent from the larger testis, the samples were also obtained from the contra-lateral testis. the biopsy specimen was sent to the pathology laboratory intraoperatively in order to determine the testicular histopathology. histopathological analysis in order to define the testicular histopathology, all testicular biopsy samples were fixed within bouin's solution, and embedded into paraffin blocks following the tissue processing steps. 4 µm-thick sections were obtained, stained using hematoxylin and eosin dye, and evaluated under a microscope with 400 x magnification by the same pathologist who was experienced in this field for more than 10 years. germinal epithelia of at least 100 seminiferous tubules were evaluated for each biopsy sample. in the presence of germinal epithelium, the spermatogenetic situation was assessed using the johnsen's score (js). according to js, the tissue maturation and spermatogenetic situation of the germinal epithelia of each sample were scored between 1 and 10. in this scoring system, tubular necrosis was scored as 1, sertoli cell only was scored as 2, spermatogonia only was scored as 3, arrest at primary spermatocyte was scored as 4 or 5, arrest at the early spermatid stage was scored as 6 or 7, arrest at the late spermatid stage was scored as 8 or 9, and full spermatogenesis was scored as 10 (5). the mean js was calculated for each sample. testicular biopsy specimens were classified according to the histopathological criteria as follows: normal spermatogenesis (ns) (mean js; 10), hypospermatogenesis (hs) (mean js; 8-9), late maturation arrest (lma) (mean js; 6-7), early maturation arrest (ema) (mean js; 3-4-5), sertoli cell only (sco) (mean js; 2) and hyalinization of tubules (ht) (mean js; 1). statistical analysis the conformity of the variables to the normal distribution was assessed with the shapiro wilk test. the categorical variables were described using frequencies with percentages, and the numerical variables were described using the mean and standard deviation values. the student’s t-test and the chi-square test were used for the intergroup analyses of the continuous variables. the chi-square test or the fisher’s exact chi-square was used to for the categorical variables. more than two independent averages were compared with the anova test and the kruskal wallis test. we performed the univariate and the multivariate analysis to identify the factors associated with and predictive of positive sperm retrieval during a salvage mtese. multiple logistic regression analysis was performed using a model including age, fsh and lh levels, and js. the data analysis was carried out using the statistical package for the social science (spss inc, chicago, illinois, usa) version 22.0 and a p value of < 0.05 was considered significant. results in 21 of the 49 participants (42.8%), sperm retrieval was possible via salvage mtese. a statistically significant difference was observed between the groups with and without sperm retrieval, with regard to fsh levels (20.4 ± 9.7 vs. 31.2 ± 10.4, respectively; p = 0.013) (table 1). yucel2_stesura seveso 28/06/18 16:40 pagina 137 archivio italiano di urologia e andrologia 2018; 90, 2 c. yücel, s. budak, m. zeynel keskin, e. kisa, z. kozacioglu 138 no significant difference was observed for the remaining hormone parameters, age, bmi, and duration of infertility. the clinical and laboratory findings of the patients have been presented in table 1. no history of cryptorchidism was observed in any of the patients included in the study. non-mosaic klinefelter’s syndrome was observed in a patient prior to salvage mtese, and no sperm could be obtained in this patient in salvage mtese. grade 1-2 varciocele was detected in the physical examination of 4 patients in the sperm retrieval group and 5 patients in the no sperm retrieval group. no serious complication was observed during mtese or within the post-operative 3 weeks. the mean js of the 49 participants was found to be 5.4 ± 1.1. the js among the sperm retrieval group and the no sperm retrieval group were 4.2 ± 1.0 and 6.4 ± 1.1, respectively. the sperm retrieval rates in patients with ht, sco, ma and hs histopathologies were 25% (2/8), 36% (4/11), 38% (8/21) and 60% (3/5), respectively. the sperm retrieval rate among patients with ns histopathology in the first mtese was 100% (4/4). no statistically significant difference was observed between two groups with regard to testicular histopathology and mean js (p = 0.621; p = 0.246, respectively). the multiple logistic regression analysis was performed by constructing a model including age, fsh and lh levels, and js. this model has been presented in table 2. it was observed that fsh was a significant and independent predictive factor for positive sperm retrieval in salvage mtese (p = 0.032). discussion in this study, the factors predicting the success of positive sperm retrieval in salvage mtese in patients with noa and previous unsuccessful retrieval in mtese were investigated, and a statistical correlation was observed only between the preoperative fsh level and the success in salvage mtese. herein, we have summarized our experience of salvage mtese in patients with noa in our single unit within an 9-year interval. there are only five studies investigating the factors predicting the success of salvage mtese in patients with noa and previous unsuccessful mtese in the literature. in these studies, the sperm retrieval rates were reported to be between 30% and 46%. table 1. comparison between the successful and unsuccessful sperm retrieval in salvage mtese. variables overall spermatozoa no spermatozoa p value (n=49) were retrievied were retrievied (n = 21) (n = 28) age (years) 35.7 ± 5.1 35.4 ± 5.9 36.0 ± 4.9 0.817 duration of infertility (years) 6.82 ± 3.67 6.58 ± 3.94 7.01 ± 3.63 0.844 bmi 22.8 ± 1.2 23.7 ± 1.3 22.1 ± 1.2 0.902 t (ng/dl) 401.1 ± 186.5 406.3 ± 279.0 397.3 ± 135.8 0.694 e2 (pg/ml) 31.3 ± 12.4 30.0 ± 9.9 32.4 ± 13.3 0.729 fsh (miu/ml) 26.5 ± 10.2 20.4 ± 9.7 31.2 ± 10.4 0.013 lh (miu/ml) 11.3 ± 7.1 8.7 ± 5.4 13.4 ± 9.1 0.161 prl (ng/ml) 10.3 ± 3.8 10.5 ± 4.0 10.2 ± 3.9 0.834 mean js 5.4 ± 1.1 4.2 ± 1.0 6.4 ± 1.1 0.246 histopathology (n/%) ht 8 (16.3) 2 (9.5) 6 (21.4) 0.621 sco 11 (22.4) 4 (19.0) 7 (25) ema 11 (22.4) 3 (14.2) 8 (28.5) lma 10 (20.4) 5 (23.8) 5 (17.8) hs 5 (10.2) 3 (14.2) 2 (7.1) ns 4 (8.1) 4 (19.0) 0 (0) t, testosterone; e2, estradiol; fsh, follicle-stimulating hormone; lh, luteinizing hormone; prl, prolactin; ht, hyalinization of tubules; sco, sertoli cell only; ema, early maturation arrest; lma, late maturation arrest; hs, hypospermatogenesis; ns, normal spermatogenesis; table 2. logistic regression analysis model for successful sperm retrieval in salvage mtese. variables or 95% ci p value age 0.992 0.938-1.136 0.657 fsh 0.963 0.944-0.982 0.032 lh 0.786 0.857-1.089 0.356 js 0.763 0.865-0.979 0.812 js, johnsen's score; fsh, follicle-stimulating hormone; lh, luteinizing hormone; or, odds ratio; ci, confidence interval. table 3. summary of the studies investigating the factors predicting the success of salvage tese in patients diagnosed with noa, who had previously undergone unsuccessful tese. variables initial tese salvage tese n srr in srr in the srr in the srr in the srr in the srr in the procedure procedure the study ht group sco group ma group hs group ns group okuba et al. (2002) conventional microscopic 13 30.7% tsujimara et al. (2006) conventional microscopic 46 45.7% 39.1% 41.7% 100% ramasamy and schlegel (2007) conventional microscopic 20 45% 34.3% 61.55% 93.3% kalsi et al. (2015) conventional microscopic 58 46.55% 40% 36.36% 75% xu et al. (2016) conventional microscopic 52 38.5% 25% 5.5% 25% 83.3% this study microscopic microscopic 49 42.8% 25% 36% 38% 60% 100% ht, hyalinization of tubules; sco, sertoli cell only; ema, early maturation arrest; lma, late maturation arrest; hs, hypospermatogenesis; ns, normal spermatogenesis; srr, sperm retrieval rate; tese, testicular sperm extraction; n, number of patients included in the study. yucel2_stesura seveso 28/06/18 16:40 pagina 138 139archivio italiano di urologia e andrologia 2018; 90, 2 predictive factors of successful salvage mtese after failed mtese among those, the widest study included 58 patients. the outcomes of these studies have been summarized in table 3 (6-10). in all of these studies, the first unsuccessful tese was performed via the conventional procedure, whereas salvage tese was performed with the guidance of a microscope. therefore, our study is the first to investigate the factors affecting the success of salvage mtese in patients with noa and previous unsuccessful tese performed using the microscopic procedure. although empirical medical treatments may be given in patients with noa prior to mtese in order to increase the success rates, the efficacies of these treatments have not been confirmed via randomized controlled studies (11). some authors claim that the possibility to retrieve sperm in salvage tese may be increased via hormone therapies using clomiphene or human chorionic gonadotropin (hcg) following unsuccessful tese (12). however, due to the low level of evidence and lack of recommendations for these therapies in the guidelines, no hormone therapy was performed in the time between the first unsuccessful and salvage mteses. there are conflicting data about the effect of fsh level on the success of mtese in the literature. there are studies demonstrating no effect of fsh on the success of mtese, whereas there are others demonstrating the contrary (13). fsh acts by binding to its receptors on the sertoli cells, which are important for spermatogenesis in the testis. therefore, it tends to decrease in patients with impaired spermatogenesis. although high fsh levels were related to global impairment of spermatogenesis, there may be normal foci of spermatogenesis in the testicles of these patients (14). xu et al. and kalsi et al. have reported no significant difference between the fsh levels of the patients with or without sperm retrieval in salvage tese (9, 10). on the contrary, in our study, the fsh levels in patients with no sperm retrieval in salvage tese was observed to be higher. tese is an invasive procedure that may lead to complications such as hematoma, infection, fibrosis and even permanent devascularisation. diagnostic testicular biopsy has complications similar to the mtese operation. furthermore, sperm retrieval in subsequent mtese cannot be assured by retrieved sperm in diagnostic testicular biopsy in patients with noa. diagnostic testicular biopsy has not been recommended in clinical practice due to the additional cost, repetitive surgical procedures and the invasive nature of the procedure that increase the risk of complications (15). thus, the diagnostic testicular biopsy procedure is not being performed in our clinics prior to tese. testicular biopsy samples have been obtained during the initial tese surgery. additionally, one of the strong aspects of our study was that the testicular histopathology was evaluated by the same and experienced pathologist.tsujimara et al., ramasay et al., and kalsi et al. have evaluated testicular histopathology by classifying into sco, ma and hs subgroups in order to assess its predictive value for the outcome of salvage tese (7-9). in addition to these three studies, xu et al. have evaluated ht testicular histopathology as an individual subgroup (10). in contrast to these studies, the ns testicular histopathology subgroup was individually evaluated in our study, and patients with ma were divided into the lma and ema groups. this classification was made using the js in our study and therefore, testicular histopathology is believed to be subgrouped more accurately. tsujimara et al., ramasay et al. and kalsi et al. compared testicular histopathologies, and determined the sperm retrieval rates of 39.1%, 34.3% and 40%, respectively, in patients with sco histopathology prior to salvage tese (7-9). in our study, the sperm retrieval rate was 36% in patients with sco histopathology. in the study of xu et al., sperm retrieval was possible in 25% of the patients with ht histopathology in salvage tese (10). similiarly, in our study, the sperm retrieval rate among patients with ht histopathology was 25%. these results demonstrate that the possibility of sperm retrieval continues in salvage mtese even after a previous unsuccessful tese. in our study, the sperm retrieval rate in salvage mtese in patients with ns histopathology was 100% and it was 60% in patients with hs histopathology. compared to the other studies in the literature, the sperm retrieval rate among patients in the hs subgroup of our study was lower. the reason for this difference may be the different subgrouping in our study to that in the literature. it was also concluded that the testicular histopathology was not a predictive factor for the success of salvage tese. the sample size in our study and those in other studies in the literature were small, it is believed that accurate results may be accessed via meta-analyses performed in the future. our study has some limitations. first, it was a retrospective study. the effects of cryptorchidism and klinefelter’s syndrome could not be evaluated in salvage tese, since there was no history of cryptorchidism and only one patient had a history of klinefelter’s syndrome in our study. although short-term complications following salvage tese were evaluated, no long-term evaluation was carried out, which is the second limitation of our study. not all sperms retrieved in tese can be used in the icsi procedure. reproductive analysis of the patients following icsi was not included in our study, which may be considered as another limitation; however, the outcomes of icsi are affected by many factors including those of the women as well, and since the priority of our study was the factors affecting the success in salvage mtese, the icsi results were not included in the study. conclusions our study suggests that salvage mtese is a safe alternative treatment method in patients with noa and previous unsuccessful tese, since the sperm retrieval rate was relatively higher. evaluation of the preoperative fsh levels may be useful in determining the best candidates for this patient group. further multi-center, prospective studies with larger sample sizes should be conducted in order to better understand the subject. acknowledgements we would like to thank to mustafa karabicak, ertan can, ozgur cakmak for their contribution to the statistical analysis and can kose, ulku kucuk, gokhan koc for their contribution to the acquisition of data. yucel2_stesura seveso 28/06/18 16:40 pagina 139 archivio italiano di urologia e andrologia 2018; 90, 2 c. yücel, s. budak, m. zeynel keskin, e. kisa, z. kozacioglu 140 references 1. keskin mz, budak s, aksoy ee, et al. investigation of the effect of body mass index (bmi) on semen parameters and male reproductive system hormones. arch ital urol androl. 2017; 89:219-21. 2. yucel c, keskin mz, cakmak o, et al. predictive value of preoperative inflammation-based prognostic scores (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-toeosinophil ratio) in testicular sperm extraction: a pilot study. andrology. 2017; 5:1100-4. 3. vloeberghs v, verheyen g, haentjens p, et al. how successful is tese-icsi in couples with non-obstructive azoospermia? hum reprod. 2015; 30:1790-1796. 4. schlegel pn. testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. hum reprod. 1999; 14:131-5. 5. ustuner m, yılmaz h, yavuz u, et al. varicocele repair improves testicular histology in men with nonobstructive azoospermia. biomed res int. 2015; 709452. 6. okada h, dobashi m, yamazaki t, et al. conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. j urol. 2002; 168:1063-7. 7. tsujimura a, miyagawa y, takao t, et al. salvage microdissection testicular sperm extraction after failed conventional testicular sperm extraction in patients with nonobstructive azoospermia. j urol. 2006; 175:1446-9. 8. ramasamy r, schlegel pn. microdissection testicular sperm extraction: effect of prior biopsy on success of sperm retrieval. j urol. 2007; 177:1447-9. 9. kalsi js, shah p, thum y, et al. salvage micro-dissection testicular sperm extraction; outcome in men with non-obstructive azoospermia with previous failed sperm retrievals. bju int. 2015; 116:460-5. 10. xu t, peng l, lin x, et al. predictors for successful sperm retrieval of salvage microdissection testicular sperm extraction (tese) following failed tese in nonobstructive azoospermia patients. andrologia. 2017; 49: e12642. 11. patel dp, chandrapal jc, hotaling jm. hormone-based treatments in subfertile males. curr urol rep. 2016; 17:1-8. 12. hussein a, ozgok y, ross l, et al. optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study. bju int. 2013; 111:110-4. 13. ramasamy r, lin k, gosden lv, et al. high serum fsh levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009; 92:590-3. 14. hung aj, king p, schlegel pn. uniform testicular maturation arrest: a unique subset of men with nonobstructive azoospermia. j urol. 2007; 178: 608-12. 15. haimov-kochman r, lossos f, prus d, et al. the value of repeat testicular sperm retrieval in azoospermic men. fertil steril. 2009; 91:1401-3. correspondence cem yücel, md (corresponding author) meclecuy@hotmail.com salih budak, md salihbudak1977@gmail.com mehmet zeynel keskin, md zeynel_akd@hotmail.com erdem kisa, md drerdemkisa@hotmail.com zafer kozacıoglu, md associate prof. zaferkozacioglu@gmail.com tepecik training and research hospital yenisehir mah, gaziler cad. no:468, konak/izmir, turkey yucel2_stesura seveso 28/06/18 16:40 pagina 140 archivio italiano di urologia e andrologia 2018; 90, 170 case report conservative management of a bladder leiomyosarcoma in a 43-year-old patient aikaterini anastasiou, ioannis katafigiotis, spyridon skoufias, ioannis anastasiou, constantinos constantinides 1st university urology clinic, laiko hospital, athens, greece. leiomyosarcoma of the bladder is an aggressive and rare tumor, with less than 200 reported cases. the treatment of bladder leiomyosarcoma is controversial although in most cases an aggressive surgical therapy is preferred. usually, a radical cystectomy is performed, as it is considered to have a better disease-specific survival rate. a 43-year-old man presented to our urology department with painless macroscopic hematuria. he was submitted to transurethral resection of the tumor. the transurethral resection was complete and revealed only this small single lesion and the rest of the bladder was normal with no other lesion or suspicious lesion. the final histology revealed leiomyosarcoma of the bladder. due to his age and the aggressiveness of the tumor after a thorough and detailed discussion with the patient a conservative management with aggressive follow up was decided. the patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes. key words: bladder leiomyosarcoma; bladder carcinoma; rare bladder tumor; non urothelial bladder cancer. submitted 13 october 2017; accepted 19 november 2017 summary no conflict of interest declared. the urine cytology was negative for malignancy. he was submitted to flexible cystoscopy, during which a single small exophytic lesion in the left lateral bladder wall, was revealed. the patient also underwent computed tomography (ct), which was negative for metastases. he was submitted to transurethral resection of the tumor. the transurethral resection was complete and revealed only this small single lesion and the rest of the bladder was normal with no other lesion or suspicious lesion. the final histology revealed leiomyosarcoma of the bladder (figure 1). due to his age and the aggressiveness of the tumor after a thorough and detailed discussion with the patient a conservative management with aggressive follow up was decided. one month after the surgery, a new biopsy from the scar of the previous operation and random biopsies were also performed, all of which were negative. three months postoperatively the cystoscopy was negative for recurrence. he was submitted to a third cystoscopy with random biopsies after six months again with negative results for malignancy (10 months after the first operation). the patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes. the next cystoscopy and ct tomography of the abdomen are planned in six months. doi: 10.4081/aiua.2018.1.70 introduction leiomyosarcoma of the bladder is an aggressive and rare tumor, with less than 200 reported cases (1). it relates to 1% of all bladder malignancies (1). patients have a median age of 65 years, at diagnosis (2), with no clear evidence of any sex prevalence. the prognosis of the tumor is poor, with an approximately 46 months survival (1). we present a case of a 43-year-old man with leiomyosarcoma of the bladder. case report a 43-year-old man presented to our urology department (1st university urology clinic, laiko hospital) with painless macroscopic hematuria. he had no other symptom and no other co morbidities. the patient was a heavy smoker, but he did not have any other risk factors. the ultrasound of the bladder was normal and the rest of the general examinations of the blood and urine were normal apart from the presence of blood in the urine. figure 1. neoplastic spindle cells with concomitant neo-vascular angiogenesis and sparks lymphocytic presence. anastasiou_stesura seveso 27/03/18 09:33 pagina 70 71archivio italiano di urologia e andrologia 2018; 90, 1 bladder leiomyosarcoma discussion leiomyosarcoma of the bladder is a very rare type of bladder tumor. the annual age-adjusted incidence rate is only 0.23 cases per 1,000,000 and there is no significant change over time (2). it is considered to be the most common bladder sarcoma, however it only accounts for 0.1% of all non-urothelial tumors (2). different risk factors as the use of cyclophosphamide and ketamine may lead to the development of the disease (1). furthermore, the exposure to local pelvic radiotherapy or systemic chemotherapy and the use of tobacco seems to be the most common etiological factors, due to genetic alterations (1). our patient was a heavy smoker without any other co-morbidity. the pathophysiology of bladder leiomyosarcoma is not clear. the main symptoms are gross hematuria, dysuria, urinary frequency and abdominal pain (2). hematuria is the most common symptom, and in our case, was the main and only symptom. the treatment of bladder leiomyosarcoma is controversial although in most cases an aggressive surgical therapy is preferred. usually, a radical cystectomy is performed, as it is considered to have a better disease-specific survival rate (1, 2). other treatment modalities that have been suggested are the partial cystectomy, the transurethral resection of a bladder tumor (turbt) for small local tumors usually as a part of a multimodality treatment, or radiotherapy (2). neoadjuvant or adjuvant chemotherapy is also applied (2). neoadjuvant chemotherapy is used in patients with locally advanced disease. the most common neoadjuvant regimens are doxorubicin, ifosfamide, cisplatin, adriamycin, and vincristine with favorable outcomes (1). for the treatment of smaller leiomyosarcomas (< 4 cm) a partial cystectomy is preferred, as it provides therapeutic efficacy, but also a better quality of life to the patient, compared to more radical surgeries (1, 3). in our case, considering the young age of our patient (43 years old), after a thorough discussion a conservative management avoiding aggressive surgical methods but combined with a close follow-up was decided. finally, there is no consensus regarding the prognosis of the disease or the follow-up of the patients. patients with bladder leiomyosarcomas usually have a very poor prognosis with a median survival time of 46 months, with a survival rate of 62% in 5 years (1, 3). important prognostic factors are the presence of tumorfree margins, local invasiveness, tumor size and the tumor grade. the poor prognosis of leiomyosarcoma is attributed to the fact that more than 60% of tumours are aggressive, and lead to metastasis, some of them even in a low stage. the overall local recurrence percentage of the disease is 16% recurring mainly in the pelvis . our patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes. conclusion leiomyosarcoma of the bladder is a rare tumor that is difficult to diagnose and treat. the disease is considered to be highly aggressive. as a result a radical treatment, with detrimental effects to the quality of life of the patient is usually considered as necessary. however, a more conservative management of the patient should be considered, when treating a young person especially with small solitary lesions, but with a strict follow-up. prognosis is generally poor. references 1. fakhoury m, hwang rr, silletti j, bjurlin ma. bladder leiomyosarcoma: a rare, but aggressive diagnosis. curr urol. 2016; 9:166-168. 2. rodríguez d, preston ma, barrisford gw, et al. clinical features of leiomyosarcoma of the urinary bladder: analysis of 183 cases. urol oncol. 2014; 32:958-65. 3. slaoui h, sanchez-salas r, validire p, et al. urinary bladder leiomyosarcoma: primary surgical treatment. urol case rep. 2014; 2:137-8. correspondence aikaterini anastasiou, md (corresponding author) aikatianast@gmail.com ioannis katafigiotis, md katafigiotis.giannis@gmail.com spyridon skoufias, md spyskouf@hotmail.com ioannis anastasiou, md ekati2@otenet.gr constantinos constantinides, md ckonstan@med.uoa.gr 1st university urology clinic, laiko hospital agiou thoma 17, athens 11527, greece anastasiou_stesura seveso 27/03/18 09:33 pagina 71 stesura seveso archivio italiano di urologia e andrologia 2016; 88, 164 case report vesico-vaginal fistula and bladder stone caused by a protruding spiral tacker 4 years after a laparoscopic sacrocolpopexy: case report gabriella mirabile 1, alfonso rossetti 2, barbara cristina gentile 1, roberto giulianelli 1, manlio schettini 1 1 department of urology, nuova villa claudia rome, italy; 2 department of gynecology, nuova villa claudia rome, italy. our case report demonstrates that the use of tackers or other devices in a improper way should be avoid and it can be correlated with late complication of laparoscopic colposacropexy. key words: tacker; bladder stone; vesico-vaginal fistula; sacrocolpopexy. submitted 3 september 2015; accepted 8 december 2015 summary no conflict of interest declared. maintained for 15 days more, but cystography confirmed the persistence of the fistula. a combined vaginal and laparoscopy approach was performed. from the vagina a 12 f foley catheter was inserted in the fistula to “mark” it for the laparoscopic approach. once visualized, the fistula was repaired with a suture, and the water-tightness of the bladder proved. the catheter was removed without complication 30 days after. one year after surgery the patient was asymptomatic and completely dry. conclusions mesh fixation with tacker systems is common in laparoscopic inguinal and ventral hernia repair but it is described also for promontofixation. complications due to tackers are rare. there are reports of tacker related complications of adhesions, pain, hernia, intestinal obstruction, perforation of doi: 10.4081/aiua.2016.1.64 introduction we report a case of bladder mesh erosion resulting in a stone and vesico-vaginal fistula due to spiral tacker used for vaginal wall mesh fixation during laparoscopic sacrocolpopexy. to our knowledge, this is the first described case of such a complication. case report a 67-year-old female presented for an urodynamic study for incontinence. in the 2010 she underwent laparoscopic sacrocolpopexy for vaginal vault prolapse. she complained of urinary symptoms, burning sensation and urgency since 3 years. a month before severe incontinence appeared, so that she used about 4 pads/day. at ultrasonography a hyperecogenic formation was noticed, attributed to a 4 cm bladder stone. the urethro-cystoscopy confirmed the presence of the stone attached to the posterior bladder wall at the point of mesh erosion. we also performed a uretro-cystography (figure 1) which showed the presence of tackers behind the stone and a vesico-vaginal fistula. a laparotomy and cystolithotomy was performed and showed a big stone developed on the eroded mesh, which resulted to have been fixed with spiral tackers. the spiral tacker, had eroded into the bladder resulting in a stone and a vesico-vaginal fistula. the stone was removed with the mesh and all the tackers, and the fistula had been repaired with the interposition of omentum. fifteen days after surgery, the incontinence due to the fistula persisted, and the catheter was figure 1. radiography pre cystography. mirabile_stesura seveso 08/04/16 11:47 pagina 64 65archivio italiano di urologia e andrologia 2016; 88, 1 vesico-vaginal fistula and bladder stone caused by a protruding spiral tacker 4 years after a laparoscopic sacrocolpopexy: case report the bowel or urinary bladder and death. several cases of spondylodiscitis were reported after use of tackers to the promontory; however this complication also occurs if sutures are utilized. the length of a tacker is 4 mm long and depending on the thickness of tissue it may penetrate the neighboring structures with disastrous complications. alternative techniques of suture fixation of mesh may avoid the tacker related complications. references 1. boukerrou m, orazi g, nayama m, et al. promontofixation procedure: use of non-absorbable sutures or tackers? j gynecol obstet biol reprod. 2003; 32:524-8. 2. hazard report. patient injury or death could result from improper use of u.s. surgical helical tacks, health devices. 2004; 8:293-295. 3. de tayrac r, sentilhes l. complications of pelvic organ prolapse surgery and methods of prevention. int urogynecol j. 2013; 24:1859-1872. correspondence gabriella mirabile, md (corresponding author) gabriella.mirabile@urorua.it barbara cristina gentile, md roberto giulianelli, md manlio schettini, md department of urology, nuova villa claudia via flaminia nuova 280, rome, italy alfonso rossetti, md department of gynecology, nuova villa claudia via flaminia nuova 280, rome, italy mirabile_stesura seveso 08/04/16 11:47 pagina 65 archivio italiano di urologia e andrologia 2018; 90, 172 case report metastasis of the epididymis and spermatic cord from pancreatic adenocarcinoma: a rare entity. description of a case and revision of literature carmelo agostino di franco 1, bruno rovereto 1, daniele porru 1, valeria zoccarato 1, cesare regina 1, tiziano cebrelli 1, nicolò fiorello 1, alessandra viglio 2, lavinia galvagno 3, carlo marchetti 1, andrea ringressi 1, davide barletta 1, giovanni giliberto 1 1 department of urology, university hospital irccs policlinico s.matteo of pavia, italy; 2 department of pathology, university hospital irccs policlinico s.matteo of pavia, italy; 3 language and translation services, enna, italy. introduction: metastatic epididymal and spermatic cord adenocarcinoma from epithelial tumors are a rare condition. the most frequent primary cancers are prostate, lung, kidney, gastrointestinal tumors and breast. in literature, there are very low number of cases reporting metastasis from pancreatic cancer to epididymis and spermatic cord. case description: we report a case of 70-years old man with history of left orchiectomy for undescended testicle, who presented to our department with a palpable nodule in the right scrotum. scrotal ultrasound revealed an inhomogeneous hypoechoic nodule of epididymis and/or spermatic cord. neoplastic markers showed high levels of cea (carcinoembryonic antigen) and bhcg (beta human chorionic gonadotropin). the patient underwent right surgical scrotal exploration with orchifunicolectomy. pathologic examination revealed pathologic tissue showing rare glandular structures. immunohistochemistry profile was compatible with malign epithelial neoplasm with glandular differentiation. total body ct-scan revealed pathologic tissue in pancreas between head and body and a suspect pathologic lesion in liver and 18-fdg pet-scan confirmed the pancreatic neoplastic mass and a suspect secondary hepatic lesion. biopsy of pancreatic pathologic area was positive for ductal pancreatic adenocarcinoma. the patient was sent to oncologic evaluation and started chemotherapy. conclusions: malignancies of epididymis and spermatic cord are rare entities and, in literature, very low number of cases of metastasis from pancreatic carcinoma to epididymis and spermatic cord are described. early differential diagnosis is fundamental mostly in those patients with age range unusual for testis cancers. key words: spermatic cord cancer; metastasis; pancreatic cancer; adenocarcinoma; epididymis cancer; scrotal tumour. submitted 6 january 2018; 24 february 2018 summary no conflict of interest declared. there are few reports regarding epididymis and spermatic cord metastasis in gastric cancers (3-5), colorectal cancers (6-8), prostate cancer (9) and pancreatic adenocarcinoma (2). in particular, very low number of cases reported metastasis from pancreatic cancer to epididymis and spermatic cord. we report a case of 70-years old man with history of left orchiectomy for undescended testicle in young age, who presented to our department with a palpable nodule in right scrotum. the patient underwent right radical orchifunicolectomy finding adenocarcinoma of epididymis and spermatic cord probably secondary to gastrointestinal cancer; a total body ct-scan showed a suspect pancreatic lesion that a biopsy confirmed to be a ductal pancreatic adenocarcinoma. case report a 70-years old man presented with right scrotal palpable nodule without pain or other symptoms, with history of left orchiectomy in young age for undescended testis. scrotal ultrasound revealed an inhomogeneous hypoechoic nodule of epididymis and/or spermatic cord with small calcifications. neoplastic markers showed carcinoembryonic antigen (cea) and beta human chorionic gonadotropin (bhcg) respectively 9,7 ng/ml (reference ≤ 5.5 ng/ml) and 6.7 mui/ml (reference ≤ 2.5 mui/ml). the patient underwent right surgical scrotal exploration with orchifunicolectomy. pathologic examination revealed a neoplastic mass of around 2 centimetres at epididymis and spermatic cord. microscopically, pathologic tissue showed rare glandular structures, with slit-like and papillary pattern and presence of mitosis with associated desmoplastic reaction. immunohistochemistry profile was positive for cytokeratin ae1 ae3, polyclonal cea, cytokeratin 7, berep4 (ep-cam/ epithelial specific antigen) and negative for alpha-fetoprotein, oct3/4 (octamer-binding transcription factor), d240, placental alkaline phosphatase (plap), cd30. this histopathologic pattern was compatible with malign epithelial neoplasm with glandular differentiation. based on rarity of primary epididymis and spermatic cord doi: 10.4081/aiua.2018.1.72 introduction metastatic epididymal and spermatic cord adenocarcinoma from epithelial tumors are a rare condition. the most frequent primary cancers with metastasis to epididymis and spermatic cord are prostate, lung, kidney, gastrointestinal tumors and breast cancers (1-2). in literature, di franco_stesura seveso 27/03/18 09:33 pagina 72 73archivio italiano di urologia e andrologia 2018; 90, 1 metastasis of the epididymis and spermatic cord tumors, the pathologist suggested a differential diagnosis with other epithelial cancers. we performed a total body ct-scan that revealed pathologic tissue in pancreas between head and body and a suspect pathologic lesion in the left hepatic lobe of 26 millimetres and another suspect metastatic hepatic lesion in vii segment of 12 millimetres (figure 1). 18-fdg pet-scan confirmed the pancreatic neoplastic mass and a suspect secondary hepatic lesion (figure 2). patient performed endoscopic ultrasound and biopsy of pancreatic pathologic area that was positive for ductal pancreatic adenocarcinoma. the patient was sent to oncologic evaluation and started chemotherapy with gemcitabine and abraxane i.v according the scheme day 1, 8, 15 of a 28 days cycle. conclusion generally, malignancies of epididymis and spermatic cord are rare entities, with few cases of both primary cancers and secondary ones. in literature, very low number of cases of metastasis from pancreatic carcinoma to epididymis and spermatic cord are described and usually they are associated with a poor prognosis. early differential diagnosis is fundamental mostly in those patients with age range unusual for testis cancers. in these cases, at the time of diagnosis, it would be correct to suspect and exclude an “extra-scrotal” origin of the disease. references 1. algad f, santaularia jm, villavicencio h. metastatic tumour of the epididymis and spermatic cord. eur urol. 1983; 9:56-9. 2. kanno k, ohwada s, nakamura s, et al. epididymis metastasis from colon carcinoma: a case report and a review of the japanese literature. jpn j clin oncol. 1994; 24:340-4. 3. irisawa c, yamaguchi o, shiraiwa y, et al. a case of metastatic tumor of the spermatic cord from gastric carcinoma. hinyokika kiyo. 1989; 35:1807-1809. 4. pozzobon d, caldato c, pavanello m, di falco g. metastatic gastric neoplasm in the spermatic cord: report of a case. chirital. 2001; 53:729-32. 5. schaefer i. m, sauer u, liwocha m, et al. occult gastric signet ring cell carcinoma presenting as spermatic cord and testicular metastases: “krukenberg tumor” in a male patient. pathol res pract. 2010; 206:519-521. 6. shida y, miyata y, igawa t, et al. a case of metastatic tumor of spermatic cord from ascending colon carcinoma. hinyokika kiyo. 2006; 52:733-5. 7. polychronidis a, tsolos c, sivridis e, et al. spermatic cord metastasis as an initial manifestation of sigmoid colon carcinoma: report of a case. surg today. 2002; 32:376-7. 8 melone f, olmastroni m, petacchi d, et al. metastatic tumor of the spermatic cord from a primary silent colorectal adenocarcinoma. minerva urol nefrol. 1997; 49:57-61. 9. bawa as, singh r, bansal vk, punia rs. spermatic cord metastasis from prostatic cancer. j postgrad med. 2003; 49:97-98. figure 1. contrast ct-scan showed a pancreatic neoplastic lesion between the pancreatic head and body and suspect hepatic secondary lesions. figure 2. 18 fdg pet-scan showed a pancreatic metabolic lesion compatible with neoplastic mass. correspondence carmelo agostino di franco, md (corresponding author) carmelo_difranco@tiscali.it bruno rovereto, md daniele porru, md valeria zoccarato, md cesare regina, md tiziano cebrelli, md nicolò fiorello, md carlo marchetti, md andrea ringressi, md davide barletta, md giovanni giliberto, md bruno rovereto, md department of urology, university hospital irccs policlinico s.matteo, pavia, italy alessandra viglio, md department of pathology, university hospital irccs policlinico s.matteo, pavia, italy lavinia galvagno, prof. language and translation services, enna, italy di franco_stesura seveso 27/03/18 09:34 pagina 73 archivio italiano di urologia e andrologia 2017; 89, 3222 original paper evaluation of per-operative cough stress test during transobturator mid-urethral sling surgery abdulmuttalip simsek 1, sinan levent kirecci 2, goksel bayar 2, kaya horasanli 2, faruk ozgor 3, zafer gokhan gurbuz 3 1 bakirkoy sadi konuk research and training hospital, department of urology, turkey; 2 sisli etfal research and training hospital, department of urology, turkey; 3 haseki research and training hospital, department of urology, turkey. this study has been presented in eau 2015 meeting in madrid. purpose: currently, it is unclear how the mesh tension should be adjusted on the transobturator tape surgery (tot) for improving continence. the aim of this study was to evaluate the effects of per-operative cough stress test on tot. materials and methods: between march 2007 and december 2011, 206 women with sui were enrolled in this study. patients were randomly categorized to treatment with tot (96) or tot with cough stress test (110). the iiq-7 and the udi-6 were used to identify satisfaction level. at the end of 1st year, two groups were compared patient characteristics, operation time, duration of hospital stay, cure and complication rates. results: the cure rate was 84.37% 81/96) versus 83.63% (92/110) in tot and tot with cough test groups, respectively. postoperatively ten patient (10/110, 9.09%) suffered voiding difficulties (> 250 ml residual urine) in tot with cough stress test group. five patients were discharged with transurethral catheter, whereas, in traditional tot group, two patients (2/96, 2.1%) had transient postoperative voiding difficulty and two patients were treated with repeated catheterization for 1 week (p < 0.05). postoperative groin pain was present in 7/96 (8%) versus 24/110 (22%) in tot and tot with cough test groups, respectively (p < 0.05). tot with cough stress test group had an higher rate of complications like, retention of urine, necessitating to cut the tape, mesh erosion and pain in groin or leg. no patient had resistant voiding difficulty or prolonged urinary retention (> 1 week) in traditional tot group. conclusions: we believe that per-operative cough stress test leads to overtreatment of stress urinary incontinence when the complication rates were considered. key words: cough stress test; transobturator tape; stress urinary incontinence (sui). submitted 26 april 2017; accepted 26 april 2017 summary no conflict of interest declared. time and hospitalisation time, tot has a high success rate up to 90% with lower complication rate (6-7). although tot is a safe and favorable for surgery for sui, success of procedure is related with age, body mass index (bmi), diabetes mellitus, intrinsic sphincter deficiency and concomitant prolapsus surgery (8-9). also urodynamic parameters including qmax, maximum urethral closure pressure and valsalva leak point pressure have effects on operation success (10). additionally, achieve adequate mesh tension is the one of most important point to prevent urinary incontinence. for assessment of the mesh tension, cough stress test (cst) is used intreoperatively while tot procedure (11). as less tension is associated with leaving the patient incontinent, more tension may cause voiding disorders (12). in this study, we evaluated affect of cst on tot procedure success rate and patients quality of life with using the incontinence impact questionnaire and urinary distress inventory questionnaire. also we assessed the effect of the adjustment of mesh tension with using cst on postoperative voiding disorders. materials and methods from march 2007 to december 2011, 206 patients diagnosed with either pure sui or mixed incontinence with predominance sui symptoms in two urogynecologic centers were enrolled into the study. patients were randomly categorized to two groups as tot procedure without using cst (group 1) and tot procedure with using cst (group 2). full medical histories and bladder diary were requested from all patients. demographic characteristics of patients, including age, bmi, number of pregnacies and comorbidities were recorded. physical examination including stress test and q-tip test were performed. urine analysis, urine culture and urinary ultrasonography for measurement of post voiding residue were completed. in the urodynamic assessment, filling cystometry, uroflowmetry and abdominal leak point pressure were evaluated before the tot procedure. intrinsic sphincter deficiency (isd) was defined as maximal urethral clossure pressure of 20 cm h20 or less and urethral mobility is defined as q-tip test results of 300. the 1 h pad doi: 10.4081/aiua.2017.3.222 introduction stress urinary incontinence (sui) is a condition of involuntary urine leakage due to increased abdominal pressure without detrusor muscle contraction and affect nearly 25% women population all around the world (12). further, 4% of women will undergo sui surgery in their lifespan (3). since introduction of urology practise by delorme, transobturator tape (tot), has became a most preffered method for the treatment of sui (4-5). in addition to short learning curve, decreased operative simsek2_stesura seveso 28/09/17 10:26 pagina 222 223archivio italiano di urologia e andrologia 2017; 89, 3 cough stress test for tot weighing test was used to define sui as a loss of 1 gr of urine in 1 h, as explained by the eau guidelines on urinary incontinence. severety and impact of incontinence on quality of life were analysed by using incontinence impact questinnaire (iiq-7) and the urinary distress inventory (udi-6). patients with overactive bladder, neurogenic bladder, immobile urethra, gynecologic malignancies and concomitant prolapsus surgeries were excluded from the study. all procedure were performed by two exprienced surgeon under spinal or epidural anesthesia. after placing mesh, mesh tension was adjusted by using a right angle clamp or long scissor. mesh tension was assessed by cst in group 2 and if necesssary mesh tension was reduced or increased. duration of operation, hospitalisation day, intraoperative and post operative complications were registered as well. the first day after operation, the foley catheter was removed. uroflowmetry and post voiding residue were evaluated before discharged. if patient inability of voiding or post voiding residue was > 250 cc, foley catheter was indwelled again for a week. voiding disorders were defined as postoperative voiding difficulties and pain while voiding, high post voiding residue (> 250 ml) and retention of urine needed catheterization or mesh cutting. follow up visits were scheduled on 7th day, 1st month and 1st year. at the end of 1st year, the two groups were compared in relation to patients characteristics, operation time, cure and complication rates. statistical analysis data analysis was performed using the software spss® version 13.0 for windows (spss inc., chicago, il, usa). data are presented as number, mean, and standard deviation, and comparisons were performed using the chisquare test and mann whitney u test. results in 96 patients tot procedure was performed without cst (group 1) and in other 110 patients cst was done (group 2). the mean age and bmi of 206 patients was 52.3 ± 9.2 years and 27.8 ± 3.6 kg/m2, respectively. most common comorbidities were smoking (in 52/ 206,25.2%) and diabetes mellitus (dm)(in 27/206, 13.1%). preoperative characteristics of patients and physical examination findings were summarized in table 1. the mean operation time was 26.4 ± 8.4 minutes. none of patients required blood transfusion. duration of hospital stay was similar between two groups. any lethal intraoperative or postoperative complication occured. the most common postoperative complaints were voiding difficulties and pain. postoperatively, ten patients (9.09%) suffered voiding difficulties in group 2, five patients were discharged with transurethral catheter, whereas, in group 1, two patients (2.1%) had transient voiding difficulty and two patients were treated with repeated catheterization for 1 week (p < 0.05). postoperative groin pain was present in 7 patients (8%) versus 24 patients (22%) in group 1 and in group 2, respectively (p < 0.05). no patient had resistant voiding difficulty or prolonged urinary retention (> 1 week) in group 1. mesh excision was performed in 2 patients in group 2. the mean follow up period was 16.4 (12.221.3) months with no significant difference between groups. the cure rate was 84.37% (81/96) versus 83.63% (92/110) in group 1 and group 2, respectively (at the end of 1st year ). all women completed the iiq-7 and udi-6 questionnaire at the first year follow up. the symptoms scores were significantly better at follow up, when compared to preoperative assesment (table 2). discussion according to delancey and asthon-miller, damage of pelvic floor muscle and endopelvic fascia, the supportive layer under urethra, is related with delayed closure of urethral lumen (13, 14). if abdominal pressure increase as in cough, urethra is displaced in a dorsocaudal line and the anterior edge of urethra move longer interval than posterior edge of urethra, so sui would be occur (15). to prevent the movement of urethra and support urethra against increased abdominal pressure, polyprolen mesh is placed in the obturator foramen in tot procedure with a route of the trocar that avoid potential complications as bladder, bowel and vessels injuries (16). stav et al. demonstrated a 86% success rate after tot surgery in their series of 1225 patients (17). some surgeon reported up to 91% cure rate after one year follow up (18). in this study, we achive 84 % cure rate after one year follow up period. to assess mesh tension intraoperatively, some maneutable 1. demographic characteristics of patients. parameters mean ± standard deviation age (years) 52.3 ± 9.2 bmi (kg/m2) 27.8 ± 3.6 dm 27/206 (13.1%) smoking 52/ 206 (25.2%) ht 22/206 (10.67%) table 2. postoperative parameters in group 1 and group 2. group 1 group 2 number of patients 96 110 cure rate 84.37% ( 81/96) 83.63% (92/110) voiding difficulty (≥ 250 ml post voiding residue) (2/96, 2.1%) (10/110, 9.09%) postoperative pain (7/96, 8%) (24/110, 22%) mesh excision 2 mesh erosion 1 iiq-7 preoperative 22.8 ± 2.7 23.2 ± 1.9 after first week 3.8 ± 1.8 3.4 ± 1.4 after first year 2.7 ± 1.5 2.5 ± 1.2 p value 0.001 0.001 udi-6 preoperative 13.7 ± 1.9 14.1 ± 1.7 after first week 1.7 ± 0.8 1.9 ± 0.9 after first year 1.9 ± 0.4 2.0 ± 0.6 p value 0.001 0.001 simsek2_stesura seveso 28/09/17 10:26 pagina 223 archivio italiano di urologia e andrologia 2017; 89, 3 a. simsek, s. levent kirecci, g. bayar, k. horasanli, f. ozgor, z. gokhan gurbuz 224 vers were developed. some authors apply manual suprapubic pressure or the credè maneuver on full bladder to create conditions simulating increased intra-abdominal pressure (19). however, standardization of this methods is difficult and affected by surgeon experience and patients bmi. to date, cst is the most preferred method to adjust mesh tension intraoperatively in mid urethral sling surgeries until patient does not leak urine (20). there only few reports about the effect of cst on tot success but technique and results of cst on tvt are well described and there is no reason to believe cst will have different characteristic between tvt and tot. murphy has demonstrated significant improvement in sui after tvt procedure with cst (21). in contrast, lavy et al. compared women who undergone tvt with cst and without cst and reported no diffrence in success rate (22). in this study we found 84.37% (81/96) versus 83.63% (92/110) success rate of tot without and with cst, respectively. our results demostrated that cst does not affect on tot success. voiding dysfunction is one of the most common complication of mid urethral sling surgeries that requires surgical intervention (23). however, there is no standard definition of voiding dysfunction after tot making difficult to compare the results of different studies. in literature, postoperative retention rates in tot were between 2.0% and 10% (1, 10, 19). according to ulmsten, minimal tissue dissection, appropriate positioning of the sling and proper mesh tension were the essential for prevention of urinary retention (24). schreiner et al. reported that performing valsalva maneuver during preoperative assessment increased voiding dysfunction nearly seven fold (25). similarly, we believe that intraoperative cst leads to more mesh tension with associated postoperative voiding disorders. preoperative urodynamic parameters are considered important to estimate tot success and voiding disorders. kawashima et al. reported that preoperative detrusor contractility failure is significantly related with postoperative voiding difficulty (26). dawson found that preoperative flow urine flow and low peak urinary flow were associated with postoperative voiding disorders (27). on the other side, mostafa and lemack showed that there were no urodinamic parameter to predict postoperative voiding disorders (28, 29). in our study urodynamic assessment were evaluated before the tot procedure. most voiding dysfunction after tot are transient and improved with intermittent catheterization, behavioral or drug therapy (30). if these treatments fail, tape incision is the best way to solve voiding problem. however, sui recurs in almost 60% of patients (31). in our study, among patients which had tot performed without cst, two patients (2.1%) had transient voiding difficulties and two patient were treated with repeated catheterization for 1 week. postoperatively ten patient (9.09%) suffered voiding difficulties in tot with cst group and five patients were discharged with transurethral catheter. mesh excision was performed in two patients and these patients suffered from sui again. incontinence-related quality of life is measured with udi-6 and iiq-7, as they can be validated in the turkish population (32). heinonen et al. used them to assess the outcome of tot, and confirmed a significant improvement in quality of life (33). another large study evaluated quality of life in women who underwent tot, with a 1-year follow-up. postoperatively, udi-6 and iiq-7 were shown to be improved, so the authors concluded that the tot procedure significantly improved health-related symptoms during daily life (34). in this study, there were benefits in postoperative scores with each assessment tool. we also concluded that tot surgery improved quality of life at the first year follow-up. this study had some limitations. first we did not assess preoperative incontinence grade and included it in statical analysis. further we did not have postoperative urodinamic parameters such as detrusor pressure, flow rate and urethral resistance to compare with preoperative assessment. small number of patients and short-term follow-up are other limitations of the study. our study showed that tot is a safe and effective treatment modality for sui. additionally, we believe that perioperative cst leads to overtreatment of stress urinary incontinence when the complication rates were considered. references 1. bullock tl, ghoniem g, klutke cg, staskin dr. advances in female stress urinary incontinence: mid-urethral slings. bju int 98. 2006; suppl 1:32-40. 2. minassian va, drutz hp, al-badr a. urinary incontinence as a worldwide problem. int j gyneco obstet. 2003; 82:327-338. 3. barber md, kleeman s, karram mm, et al. risk factors associated with failure 1 year after retropubic and transobturator midurethral slings. am j obstet gynecol. 2008; 199:666.e1-666.e7. 4. delorme e, droupy s, de tayrac r, delmas v. transobturator tape (uratape) a new minimally-invasive procedure to treat female urinary incontinence. eur urol. 2004; 45:203-207. 5. novara g, artibani w, barber md, et al. updated systematic review and meta-analysis of the comparative data on colposuspensions, pubovaginal slings, and midurethral tapes in the surgical treatment of female stress urinary incontinence. eur urol. 2010; 58:218-238. 6. giberti c, gallo f, cortese p, schenone m. transobturator tape for treatment of female stress urinary incontinence: objective and subjective results after a mean follow-up of two years. urology. 2007; 69:703-707. 7. poza jl, pla f, sabadell j, et al. trans-obturator suburethral tape for female stress incontinence: a cohort of 254 women with 1-year to 2-year follow-up. acta obstet gynecol scand. 2008; 87:232-239. 8. long cy1, hsu cs, wu mp, et al. comparison of tension-free vaginal tape and transobturator tape procedure for the treatment of stress urinary incontinence. curr opin obstet gynecol. 2009; 21:342-7. 9. latthe pm, foon r, toozs-hobson p. transobturator and retropubic tape procedures in stress urinary incontinence: a systemic review and meta-analysis of effectiveness and complications. bjog. 2007; 114:522-531. 10. barber md, kleeman s, karram mm, et al. risk factors associated with failure 1 year after retropubic and midurethral slings. am j obstet gynecol. 2008; 199:666-670. 11. murphy m, heit mh, fouts l, et al. effect of anesthesia on voidsimsek2_stesura seveso 28/09/17 10:26 pagina 224 225archivio italiano di urologia e andrologia 2017; 89, 3 cough stress test for tot ing function after tension-free vaginal tape procedure. obstet gynecol. 2003; 101:666-70. 12. kim s, bae j, cho m, et al. effect of preoperative flow rate on postoperative retention and voiding difficulty after transobturator tape operation. 2014; 55:190-5. 13. delancey jol, trowbridge er, miller jm, et al. stress urinary incontinence: relative importance of urethral support and urethral closure pressure. urology. 2008; 179:2286-90. 14. ashton-miller j, delancey jol. functional anatomy of the female pelvic floor. ann ny acad sci. 2007; 1101:266-96. 15. barbic m, kralj b, cor a. compliance of the bladder neck supporting structures: importance of activity pattern of levator ani muscle and content of elastic fibers of endopelvic fascia. neurourol urodyn. 2003; 22:269-76. 16. mischinger j, amend b, reisenauer c, et al. different surgical approaches for stress urinary incontinence in women. minerva ginecol. 2013; 65:21-28. 17. stav k, dwyer pl, rosamilia a, et al. repeat synthetic mid urethral sling procedure for women with recurrent stres urinary incontinence. j urol. 2010; 183:241-246. 18. abdel-fattah m, ramsay i, pringle s, et al. randomised prospective single-blinded study comparing ‘inside-out’ versus ‘outside-in’ transobturator tapes in the management of urodynamic stress incontinence: 1-year outcomes from the e-tot study. bjog. 2010; 117: 870-878. 19. lazarou g, miller c, gupta n, et al. intraoperative crede maneuver for tape adjustment during transobturator sling placement: does it improve continence. female pelvic medicine and reconstructive surgery 2013; 6:369-372. 20. takacs p, medina ca. tension-free vaginal tape: poor intraoperative cough test as a predictor of postoperative urinary retention. int urogynecol j. 2007; 18:1445-47. 21. murphy m, culligan pj, arce cm, et al. is the cough-stress test necessary when placing the tension-free vaginal tape? obstet gynecol. 2005; 105:319-324. 22. lavy y, lev-sagie a, hamani y, et al. cough stress test during the tension-free vaginal tape procedure: is it necessary? in proceedings of the 32nd annualmeeting of the international continence society, ics office publications, heidelberg, germany, 2002. 23. petri e, ashok k. complications of synthetic slings used in female stress urinary incontinence and applicability of the new iuga-ics classification. eur j obstet gynecol. 2012; 165:347-51. 24. ulmsten u, henriksson l, johnson p, varhos g. an ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence, internationalurogynecology journal and pelvic floor dysfunction. 1996; 7:81-5 25. schreiner l, peterson tv, karp d, davila gw. predictive factors for voiding dysfunction after transobturator slings. 2013; 35:290-4. 26. kawashima h, hirai k, okada n, et al. the importance of studying pressure-flow for predicting postoperative voiding difficulties in women with stress urinary incontinence: a preliminary study that correlates low pdet x qave with postoperative residual urine. urol res. 2004; 32:84-8. 27. dawson t, lawton v, adams e, richmond d. factors predictive of post-tvt voiding dysfunction. int urogynecol j pelvic floor dysfunct. 2007; 18:1297-302. 28. mostafa a, madhuvrata p, abdel-fattah m. preoperative urodynamic predictors of short-term voiding dysfunction following a transobturator tension-free vaginal tape procedure. int j gynaecol obstet. 2011; 115:49-52. 29. lemack ge, krauss s, litman h, et al. normal preoperative urodynamic testing does not predict voiding dysfunction after burch colposuspension versus pubovaginal sling. j urol. 2008; 180:2076-80. 30. segal j, steele a, vassallo b, et al. various surgical approaches to treat voiding dysfunction following anti-incontinence surgery. int urogynecol j pelvic floor dysfunct. 2006; 17:372-7. 31. viereck v, rautenberg o, kociszewski j, et al. midurethral sling incision: indications and outcomes. int urogynecol j. 2013; 24:645-53. 32. cam c, karateke a, sakallı m. validation of the short forms of incontinence impact questionnaire (iiq-7) and urogenital distress inventory (udi-6) in a turkish population. neurourology urodynamics. 2006; 26:129-133. 33. heinonen p, ala-nissilä s, räty r, et al. objective cure rates and patient satisfaction after the transobturator tape procedure during 6.5-year follow-up. j minim invasive gynecol. 2013; 20:73-8. 34. domingo s, alamá p, ruiz n, et al. transobturator tape procedure outcome: a clinical and quality of life analysis of a 1-year follow-up. int urogynecol j pelvic floor dysfunct. 2007; 18:895-900. correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com bakirkoy sadi konuk research and training hospital, department of urology, zuhuratbaba, tevfik saglam cad. no:11 bakirkoy, istanbul, turkey sinan levent kirecci, md goksel bayar, md kaya horasanli, md sisli etfal research and training hospital, department of urology, turkey faruk ozgor, md zafer gokhan gurbuz, md haseki research and training hospital, department of urology, turkey simsek2_stesura seveso 28/09/17 10:26 pagina 225 archivio italiano di urologia e andrologia 2018; 90, 4254 original paper the aging male: relationship between male age, sperm quality and sperm dna damage in an unselected population of 3124 men attending the fertility centre for the first time alessandro colasante, maria giulia minasi, filomena scarselli, valentina casciani, vincenzo zazzaro, alessandra ruberti, pierfrancesco greco, maria teresa varricchio, ermanno greco centre for reproductive medicine, european hospital, rome, italy. objective: the aim of our study was to put forward insights to treat any possible correlation among sperm quality, sperm dna damage and male age as they may have fertility implications for men who choose to delay fatherhood. materials and methods: our study is a non-interventional retrospective analysis of 3124 semen samples from patients that were investigated for the conventional semen parameters. tunel test assay was set up for the evaluation of the sperm dna fragmentation index (dfi). we applied the kappa index to compare both the 1999 and the 2010 world health organization (who) reference criteria to evaluate the competence of such semen parameters categorization during the standard routine of our laboratory. results: with regards to our findings, it is possible to underline a significant relationship between aging and semen volume (p = 0.001), motility (p = 0.009), semen viscosity (p < 0.003) and sperm dna damage (p < 0.009). we found a trend when focusing on the semen concentration (p = 0.05). the analysis of sperm morphology did not show any influence with advancing age (p = 0.606). when comparing both the 1999 and the 2010 who scales we found no accordance in the appraisal of sperm morphology but a very good one in the evaluation of the other parameters. conclusions: conventional semen analysis represents the opportunity to draw up a proxy insight on the male fertility status even if semen quality can only indirectly assess the probability of pregnancy. several studies have verified a decay in the male reproductive system, sperm quality and fertility with advancing age although the reported results are not yet conclusive. our results substantially agree with those findings outlined in the literature. moreover we find that the discrepancy between the two who reference scales would eventually lead to an improper diagnosis of infertility. key words: aging; male; semen; analysis; who; infertility. submitted 25 june 2018; accepted 31 july 2018 summary no conflict of interest declared. tions of an overwhelming course marked by the achievement of individual goals such as education and economic solidity prior to attempting conception (2). aging is explained by biological and demographic topics characterized by the impairment of several physiological functions and to what concern human reproduction, age related decrease of couples fertility potential is usually associated to female aging (1, 3). female germ cells are lessened during life span and do not replace (4). therefore, as ovary grow older, the total number of oocytes and their quality decrease, lowering female fecundity (5). female age has been explained as a predictor of poor reproductive success resulting in decreased fertilization and implantation rates as well as in increased abortion rates (5). efficient reproduction and early embryonic development mostly rely on oocyte quality with those from older women being more prone to nondisjunction caused by meiotic errors and therefore impaired by an increased occurrence of aneuploid abnormalities (4, 5). male reproductive functions do not suddenly come to an end as spermatogenesis continues into advanced ages. consequently men can conceive children at later ages (6). anyway a large number of studies have marked a linkage between advanced male age and the decrease in fertility potential status (1, 3, 7). the effect of advanced paternal age on embryo quality, miscarriage rate or pregnancy rate has been assessed for the general population and for infertile patients outlining an increased time-to-pregnancy disorder (2, 8). older fathers are reported to imply higher rates of miscarriages and several diseases in the new generations: altered designs of genetic expression in aged male are related to a wide range of genetic disorders through descendants as the rate of denovo inheritable mutations is strictly linked to the male age (8). substantial interest exists in studying effects of aging on semen quality and sperm dna damage (1, 3, 7, 9). conventional semen analysis represents the opportunity to draw up an insight on the male fertility status even if semen quality is an indirect measure of the probability of pregnancy (7). advanced paternal age is related to a decline in sperm quality and to an increased sperm dna damage referring to a combination doi: 10.4081/aiua.2018.4.254 introduction infertility has a wide impact on public health. in developed countries, where expectancy of a prolonged life is well established, modern trends have enforced the delay of first parenthood (1). it partly reflects the complicacolasante_stesura seveso 10/01/19 16:04 pagina 254 255archivio italiano di urologia e andrologia 2018; 90, 4 aging and sperm quality of genetic and environmental factors which can lead to a condition of oxidative stress impairing the integrity of sperm dna (1, 10). several studies tried to fix an age effect on semen quality indicating a broad trend in age ranges (1) but the effect of advanced paternal age on semen parameters is not yet conclusive and its impact on fertility is still debated (1, 2). our study is then meant to put forward stronger insights to help clarify any possible correlation among sperm quality, sperm dna damage and male age as they may have fertility implications for men who choose to delay fatherhood. materials and methods patients enrolled in this study were recruited from january 2009 to december 2012. semen samples were obtained from unselected males attending, for the first time in their life, the andrology laboratory both for infertility problems as well as for a spontaneous screening provided for free, during the so-called “fertility days” arranged at our centre. each patient produced a semen sample by masturbation into a sterile plastic container. as the number of days of abstinence may have influence on semen parameters, patients included in this study were previously taught to observe 2 up to a maximum of 5 days of abstinence from intercourse before their planned analysis. semen samples were collected in a room next to the laboratory. all the samples were allowed to liquefy for at least 20 minutes at 37°c, prior to be processed. analysis of semen samples, liquefaction, viscosity and volume were recorded. a 10 µl drop was examined using phase contrast microscopy to assess sperm concentration, motility and morphology according to who guidelines for the examination and processing of human semen (11). we both used the 2010 and the 1999 reference cutoff values to evaluate the competence of such semen categorization during the standard routine of our laboratory (12). a raw portion of the semen sample was then taken out at the time of the semen evaluation. it was immediately processed for the subsequent assessment of the dfi (dna fragmentation index) setting up the tunel test assay. visualization of fragmented sperm nuclear dna was performed with the use of cell death detection kit with tetramethylrhodamine-labelled dutp (roche, monza, italy), according to the manufacturer’s instructions. ejaculated sperm samples were washed from seminal plasma by low-speed centrifugation, smeared on microscope slides, air-dried, fixed with 4% paraformaldehyde in phosphate-buffered saline at 4°c for 25 minutes, and permeabilized with 0.1% triton x-100 in 0.1% sodium citrate. spermatozoa with fragmented dna were detected in an epifluorescence microscope with a x100 oil immersion objective and the percentage of tunelpositive spermatozoa was determined (13). statistical analysis shapiro-wilk test was used to test normality assumption. chi square test (or fisher exact test when appropriate), was used to compare categorical variable. to set up the evaluations, records were ranked by age brackets to create three consecutive age groups each containing suitable observations to be analysed as described in previous studies. bonferroni correction was used to adjust multiple comparisons. non parametric mann-withney test was used for continuous variables. to compare classification of same subjects with two different scale, mc nemar test was used. kappa index was then calculated to evaluate accordance between the two scale using the landis-koch reference model (14). such model ranges from 0 to 1 to point out respectively “no-accordance” (value = 0) and “overlapping conformity” (value = 1) between the used examiners (table 1). a p value < 0.05 was considered statistically significant. results population characteristics our study is a non-interventional retrospective analysis of 3124 semen samples from patients that were investigated for the conventional semen parameters and the dfi. none of the men included in the study revealed having or having suffered cryptorchidism, hypospadias or testicular cancer. all the patients enrolled in the study were investigated for smoking habits and none of them has disclosed a heavy consumption of cigarettes. when considering the whole sample, a share of around 65% of the men investigated were found to be pathological for at least one of the features investigated: concentration, motility or morphology as well. the remaining 35% was normozoospermic. the age of the patients ranged from 21 to 65 with a mean of 40 years (sd 5, 9). the results of our study were allocated to three age groups: younger than 35 years (n = 775, 25%); 36-40 years (n = 1110, 35%); 41 years and older (n = 1239, 40%). semen volume the median semen volume was 3 ml (table 2). patients with normal volume values were 87% of the entire samtable 2. median and interquartile range (iqr, 25th-75th percentile) of semen parameters. n volume (ml) sperm concentration 106/ml sperm motility % (a+b+c) sperm morphology % sperm dna damage 3124 3 (2,4) 24 (12, 38) 60 (50, 70) 4 (3, 7) 5 (2, 10) table 1. landis-koch model. < 0 poor 0-20 slight 0.2-0.40 fair 0.41-0.60 moderate 0.61-0.80 substantial 0.81-1.00 almost perfect colasante_stesura seveso 10/01/19 16:04 pagina 255 archivio italiano di urologia e andrologia 2018; 90, 4 a. colasante, m.g. minasi, f. scarselli, v. casciani, phd, vincenzo zazzaro, a. ruberti, p. greco, m.t. varricchio, e. greco 256 ple. those with abnormal ones were 13%. when referring to the whole sample we found a weak relationship between the two variables investigated (r = 0,1). on the contrary, when we focused attention only on the subjects who were estimated having abnormal volume values, we found a significant trend toward age groups (p = 0,001) and the number of patients with abnormal semen volume raising up as age increased. sperm concentration and total sperm count the median sperm concentration was 24*106/ml (table 2). patients with normal sperm concentration were 66% of the entire sample, those with abnormal ones were 34%. we found a trend when focusing on the whole population (r = 0.04, p = 0.05) and a trend (p = 0.037) across the three groups but no clear post-hoc analysis confirmation emerged. total sperm count analysis failed to point out any relationship with age (p = 0.769) among groups. motility the median motility was 60% (table 2). patients with normal motility values were 80% of the entire sample, those with abnormal ones were 20%. no clear trend was revealed for the whole sample analysis (r = -0.01). quite the opposite emerged when we analyzed only the subjects who were estimated having abnormal values. we found a significant trend toward age groups (p = 0,009) and the number of subjects with abnormal assessments raised up as age increased. morphology the analysis of sperm morphology, with the sample equally divided in normal and abnormal estimations, (median value = 4, r = 0.01) did not show any influence by advancing age (p = 0.606). semen viscosity twenty-eight percent of our sample reported an increased semen viscosity estimation. it was possible to point out a clear deviation within age groups (p < 0.001) toward the older one (p < 0.003). sperm dna damage the analysis for the three age groups point out a clear trend toward older subjects (p < 0.009). when we have analysed the relationship between sperm morphology linked to sperm dna fragmentation, we found a negative correlation between the variables investigated both for the whole sample (r = -0.16, p < 0.001) and for all the three age groups respectively: r = -0.17; r = -0.16; r = -0.18 (p < 0.001). comparison between who 2010 and who 1999 once the primary data analysis was concluded (table 3), we have reloaded the data of the whole population. to this, we have applied the older who reference values scale (12) for semen analysis (table 4). in this subsequent investigation we found again that the third group, that including men at older ages, still issued a significant difference regarding semen values if referred to the other two groups and mainly, when evaluating concentration and motility, toward the first group of younger subjects. considering the amount of difference between the scale currently in use and the 1999 replaced one, we have decided to match them up, so to evaluate any possible divergence which could reveal a clinical weight in the ivf treatment of couples. to this purpose, mcnemar test table 3. median and interquartile range (iqr, 25th-75th percentile) of semen parameters. n < 35 years 36-40 years >= 41 years n % n % n % p value n 775 1110 1239 volume 77 9.9 130 11.7 189 15.3 0.001 concentration 281 36.3 396 35.7 390 31.5 0.037 motility 138 17.8 202 18.2 279 22.5 0.009 morphology 397 51.2 546 49.2 631 50.9 0.606 viscosity (augmented) 195 25.2 287 25.9 398 32.1 < 0.001 table 4. number of subjects with abnormal values (who, 1999). n < 35 years 36-40 years >= 41 years n % n % n % p value n 775 1110 1239 volume 170 21.9 260 23.4 359 29.0 0.001 concentration 376 48.5 524 47.2 531 42.9 0.023 motility 216 27.9 332 29.9 416 33.6 0.018 morphology 758 97.8 1072 96.6 1203 97.1 0.295 viscosity (augmented) 195 25.2 287 25.9 398 32.1 < 0.001 colasante_stesura seveso 10/01/19 16:04 pagina 256 257archivio italiano di urologia e andrologia 2018; 90, 4 aging and sperm quality was applied to the entire sample and then to the three different groups (table 5). kappa index was then used to evaluate the accordance between the two different who reference values scales (table 5). it is possible to highlight greater percentages of subjects with pathological semen evaluations when the 1999 who scale is applied due to its stringent criteria of estimation. moreover, kappa index exhibits a valuable accordance between the two guidelines if referred to the estimation of volume, concentration and motility. on the contrary, such correspondence failed when we analyzed the morphology parameters determining the misidentification of a remarkable infertility male factor (table 5). discussion several studies have demonstrated a decline in the male reproductive system, sperm quality and fertility with advancing age but many of the biological mechanisms of such processes are poorly understood and the reported results are not conclusive (2). in the present analysis, methods, personnel, and instrumentation were consistent throughout the study period because study settings represent a topic of wide importance: earlier attempts to draw conclusions from pooled data from different publications or from the same investigators at different locations have been troubled by differences in methods, personnel, and instrumentation. the lack of standardization in analytic techniques weakened statistical analysis of pooled data by compounding the existent inherent variability in measured semen characteristics. moreover, in our study we enrolled subjects at older ages preventing the loss of statistical power as occurred in some of the past clinical studies, where older patients (e.g. > 50 years) were under-represented (3, 15). in this way a limited age range may have improved the possibility to ignore the threshold age at which the biological consequences of aging are disclosed. with regards to our current findings, it is possible to underline a significant relationship between advancing age and semen volume, viscosity, motility and sperm dna damage and a trend for sperm concentration. despite other previous findings we could underline no significant relationship emerging when age and sperm morphology were linked (3). quite a lot of mechanisms have been suggested to explain how advancing age may influence semen quality (3). for instance abnormal semen volume alterations could be caused by seminal vesicle deficiency as vesicle fluid itself largely provides most of the ejaculate volume (16). variations in the prostate arise with aging and the related decay in protein and water contents can clarify the negative impact on semen volume, motility and viscosity (16). once more, the epididyms have a valuable importance: considering sperm acquiring its straight motility only during the transition through the epididymal tract, any alteration may negatively restrict this parameter (3). aging may regulate tubular lumen suffering a condition of sclerosis determining a decline in the spermatogenic activity, loss of germ cells proliferation and a deficiency of leydig cells functions (7). testes compromised responsiveness to the endocrinological stimuli can possibly explain the alterations of sperm concentration and the increase in sperm count with age may be also explained by urogenital infections (9). spermatozoa are constantly produced by the testes as germ cells and go through enduring replication, meiosis and spermiogenesis. cell selection is a major process during early years. it has been speculated that when dna damage is induced in cells of young men equally levels of apoptosis also increase to eliminate cells with table 5. two scale comparison (who, 1999 vs. who, 2010). who (1999) who (2010) total n % n % p value* kappa whole sample volume 3124 789 25.3 396 12.7 < 0.001 0.601 concentration 3124 1431 45.8 1067 34.2 < 0.001 0.761 motility 3124 964 30.9 619 19.8 < 0.001 0.713 morphology 3124 3033 97.1 1574 50.4 < 0.001 0.059 < 35 years volume 775 170 21.9 77 9.9 < 0.001 0.564 concentration 775 376 48.5 281 36.3 < 0.001 0.753 motility 775 216 27.9 138 17.8 < 0.001 0.719 morphology 775 758 97.8 397 51.2 < 0.001 0.046 36-40 years volume 1110 260 23.4 130 11.7 < 0.001 0.605 concentration 1110 524 47.2 396 35.7 < 0.001 0.766 motility 1110 332 29.9 202 18.2 < 0.001 0.685 morphology 1110 1072 96.6 546 49.2 < 0.001 0.066 > =41 years volume 1239 359 29.0 189 15.3 < 0.001 0.612 concentration 1239 531 42.9 390 31.5 < 0.001 0.760 motility 1239 416 33.6 279 22.5 < 0.001 0.730 morphology 1239 1203 97.1 631 50.9 < 0.001 0.060 *mc nemar test. colasante_stesura seveso 10/01/19 16:04 pagina 257 archivio italiano di urologia e andrologia 2018; 90, 4 a. colasante, m.g. minasi, f. scarselli, v. casciani, phd, vincenzo zazzaro, a. ruberti, p. greco, m.t. varricchio, e. greco 258 irreversible dna damage (17). on the contrary, when dna damage is induced in cells from older men, apoptosis do not increase, implying that the ability to remove damaged cells decrease (17). in such a way it can be assumed the existence of age-induced anomalies in the apoptotic pathway leading to an age-linked increase in sperm cells with higher dna damage (17). confirming the contradiction of the literature published results and in spite of what other authors reported (2, 3, 16, 17), we found no decline in sperm concentration levels with advancing age. sperm dna damage has been associated to both male aging and infertility and it has been linked to several factors such as oxidative stress, abortive apoptosis and deviations in the process of recombination and protamine replacement during spermatogenesis (8). oxidative stress occurs when the generation of free radicals and the scavenging ability of antioxidants become unbalanced. the performance of antioxidant enzymes from older men may be reduced if compared to those of younger ones leading spermatozoa to be more suitable for mutational changes due to the endogenous activity of ros (8). high dna fragmentation is linked to diminished sperm concentration, motility and morphology. decreased fertilization rates and implantation rates are associated to dna fragmentation (8). higher levels of sperm dna damage are associated to decreased embryo quality and pregnancy rates (10). several studies dealt with the relationship between sperm damaged dna and the impairment of embryonic developmental stages and it has been marked a strong evidence of lowered quality in embryo development at later stages (4). as a final point, it has been long recognized that the female aging increases the odds for meiotic errors in oogenesis resulting in offspring with chromosome affected by aneuploid abnormalities (4, 5, 18). therefore, there seems to be a lesser impact for paternal than maternal age on the couple fertility potential (4, 18). nevertheless, various authors have pointed out that the oocytes are able to mend up dna damages of paternal origin thus saving the aging spermatozoa (19). consequently, repairing mechanisms of oocytes from older women may be less competent and may give rise to a condition of infertility or to a prolonged time to pregnancy (19). in conclusion there are lots of difficulties in using semen parameters to screen and clear male health condition when considering the wide impact of the physiological variations of spermatogenesis combined with the distinct lifestyle habits and the growing effects of a lifelong exposure to those factors usually considered as exogenous pollutants (20). conclusions the semen analysis stands for one of the first essential steps in the assessment of the male fertility condition (3). starting from 2010 renewed semen standard thresholds has been defined for the who reference manual (11). this resulted in the statement of lower cutoffs than the previously practiced to handle semen analysis. comparing both the 1999 and the 2010 reference values in the evaluation of broad semen parameters, we found no accordance in the appraisal of sperm morphology but a very good one in the evaluation of the other parameters. we can therefore speculate that, based on such innovation, a large number of couples previously detected with male factor infertility would now be ranked as having normozoospermia. in such a way, we find that the discrepancy between the two who reference scales would eventually lead to an improper diagnosis of infertility. as the new reference values are almost similar to the previous ones, it has become quite difficult to clearly set apart fertile from infertile male patients and it therefore seems of pressing utility to manage a more comprehensive clinical approach when couples with problems of infertility come up to a fertility center. references 1. winkle t, rosenbusch b, et al. the correlation between male age, sperm quality and sperm dna fragmentation in 320 men attending a fertility center. j assist reprod genet. 2009; 26:41-46. 2. bellver j, garrido n, et al. influence of paternal age on assisted 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with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. hum reprod. 2000; 15:1703-8. 10. bungum m, humaidan p, axmon a, et al. sperm dna integrity assessment in prediction of assisted reproduction technology outcome. hum reprod. 2007; 22:174-9. 11. world health organization. laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 2010; world health organization, cambridge, uk. 12. world health organization. laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 1999; world health organization, cambridge, uk. 13. greco e, romano s, iacobelli m, et al. icsi in cases of sperm dna damage: beneficial effect of oral antioxidant treatment. hum reprod. 2005; 20:2590-4. 14. landis j, koch g. the measurement of observer agreement for categorical data. biometrics. 1977; 33:159-174. 15. stewart tm, liu d, garrett c, et al. recruitment bias in studies of semen and other factors affecting pregnancy rates in fertile men. human reprod. 2009; 24:2401-2408. 16. ausmees k, korrovits p, et al. decline of seminal parameters in colasante_stesura seveso 10/01/19 16:04 pagina 258 259archivio italiano di urologia e andrologia 2018; 90, 4 aging and sperm quality middle.aged males is associated with lower urinary tract symptoms, prostate enlargement and bladder outlet obstruction. int braz j urol. 2013; 39:727-40. 17. brahem s, mehdi m, et al. the effects of male aging on semen quality, sperm dna fragmentation and chromosomal abnormalities in an infertile population. j assist reprod genet. 2011; 28:425-432. 18. angell rr. aneuploidy in older women. higher rates of aneuploidy in oocytes from older women. human reprod. 1994; 9:11992000. 19. ashwood-smith mj, edwards rg. dna repair by oocytes. mol hum reprod. 1996; 2:46-51. 20. de rosa m, zarrilli s, et al. traffic pollutants affect fertility in men. hum reprod. 2003; 18:1055-1061. correspondence alessandro colasante, phd, msc (corresponding author) a.colasante@tiscali.it maria giulia minasi, msc mg.minasi@gmail.com filomena scarselli, msc filomenascarselli@virgilio.it valentina casciani, phd valcasciani@gmail.com vincenzo zazzaro, phd enzozazzaro@yahoo.it alessandra ruberti, bsc alessandra.ruberti@virgilio.it pierfrancesco greco, md piergreco@hotmail.it maria teresa varricchio, md mtvarricchio@gmail.com ermanno greco, md ergreco1@virgilio.it centre for reproductive medicine, european hospital, rome, italy colasante_stesura seveso 10/01/19 16:04 pagina 259 archivio italiano di urologia e andrologia 2018; 90, 168 case report bilateral synchronous testicular seminoma: a rare presentation of a rare disease pedro simões de oliveira, tiago ribeiro de oliveira, sérgio pereira, david martinho, tomé lopes hospital de santa maria, urology department, lisbon, portugal. objective: to present a case of a bilateral synchronous testicular seminoma in a young male clinical stage iib. material and method: a 37 years old man presented a bilateral testicular mass with elevated tumoral markers. histology of frozen section revealed bilateral seminoma and bilateral radical orchiectomy was performed. result: enhanced chest and abdominopelvic staging ct scan revealed a lymphadenopathy of 30 mm within the inter-aortocava nodal chain (stage iib). patient received three cycles of bep. three months later 18f-fdg pet showed no evidence of hypermetabolic activity and serum tumoral markers were normal. conclusion: bilateral testicular germ cell tumors are a rare disease. management of this tumors is controversial. bilateral radical orchiectomy is the standard of care, nevertheless, in order to preserve fertility and androgen production, an organsparing surgery can be attempted in selected cases. although prognosis is good, with overall survival rates similar to patients with unilateral disease, life-long close follow-up may be advocated due to relapse risk. key words: seminoma; bilateral; synchronous. submitted 28 october 2017; 19 november 2017 summary no conflict of interest declared. terone levels (1). in order to preserve fertility and androgen production, organ-sparing surgery can be attempted when tumor volume is less than 30% of the testicular volume and surgical rules are respected (1). in those cases, the rate of associated germ cell neoplasia in situ (cis) is high (up to 82%). follow-up schedule is the same for patients with unilateral testis cancer (1). life-long follow-up may be advocated because of a small risk for late relapse and close clinical control, with ultrasound of the testis, may be recommended for patients undergoing testis-preserving surgery (1). we present a rare case of a young male with bilateral voluminous testicular masses representing synchronous seminoma clinical stage iib. case report a 37 years old man, without any known risk factor, presented as an outpatient with chief complaints of bilaterdoi: 10.4081/aiua.2018.1.68 introduction testicular germ cell tumors (tgcts) are the most common malignancy diagnosed in males aged 20 to 40, nevertheless they are a rare disease representing only 5% of all urologic tumors (1). risk factors in the development of testicular tumors include history of cryptorchidism or undescended testis, klinefelter syndrome, testicular cancer in the first-degree relatives, presence of tumor or intratubular germ cell neoplasia (tin) in the contralateral testis, and infertility (1). bilateral tgcts (btt) are even more rare, representing 1-2% of all cases at diagnosis. approximately 35% of these bilateral tumors are synchronous and the majority are seminomas, being histologically identical almost always (1). management of this tumors is controversial. bilateral radical orchiectomy via an inguinal incision is considered the standard of care in cases of synchronous testis cancer with impaired pre-operative testosfigure 1. a) intra-operative image showing bilateral radical orchiectomy via inguinal incision; b) pathological examination: nests of seminoma surrounded by bands of fibrous tissue infiltrated with lymphocytes (arrow); c) enhanced chest and abdominopelvic ct scan revealing a lymphadenopathy of 30 mm within the inter-aorto-cava nodal chain (arrow); d) 18f-fdg pet showing no evidence of hypermetabolic activity. oliveira_stesura seveso 27/03/18 09:31 pagina 68 69archivio italiano di urologia e andrologia 2018; 90, 1 bilateral synchronous seminoma al scrotal swelling and heaviness, since last three months. on local examination swelling was present over bilateral hemiscrotum, hard in consistency, surface was irregular and it was associated with restricted mobility. transillumination was negative. there were no palpable inguinal neither supraclavicular lymph nodes. testis ultrasound revealed multiple bilateral solid nodules occupying about 50% of each testicle. serum tumor markers were ldh 322 u/l, afp 1.3 ng/ml and hcg 29 u/l. testosterone was 453 ng/dl. patient underwent inguinal exploration and bilateral testicular biopsy for frozen section histological examination which revealed bilateral seminoma (figure 1a). a bilateral radical orchiectomy was performed with insertion of bilateral testicular prosthesis. pathological examination confirmed bilateral seminoma with invasion of tunica albuginea and vascular and lymphatic invasion (pt2) (figure 1b). postoperatively, serum tumoral markers were normal (ldh 166 u/l, afp 1.3 ng/ml and hcg 0.3 u/l). patient initiated testosterone replacement therapy. enhanced chest and abdominopelvic staging ct scan revealed a lymphadenopathy of 30 mm within the interaorto-cava nodal chain (stage iib) (figure 1c). patient was referred to oncology and received three cycles of bep (bleomycin, etoposide and cisplatin). three months later 18f-fdg pet showed no evidence of hypermetabolic activity (figure 1d) and serum tumoral markers were normal. conclusions btt are rare and therefore literature is scarce, mainly case reports or small series, restricting management strategies for these patients. patients with btt, present with different problems requiring careful management to permit a good quality of life. bilateral radical orchiectomy is the standard of care treatment, nevertheless this approach has a vast impact on fertility and can render patients dependent on life-long testosterone supplementation (1). in 1997 heidenreich et al. (2) presented a series of 13 patients with btt who underwent testis-sparring surgery. six of the 13 patients underwent testicular radiation for cis and five patients had adjuvant local therapy. a testicular biopsy was taken 6 months post-operatively and revealed sertoli cells only in all patients who had received radiation therapy. only one patient had local recurrence 9 months after tumor enucleation. testis-sparing surgery must be performed whenever possible, when tumor volume is less than 30% of the testicular volume and surgical margins are respected (1), although multiple testicular biopsies are advocated in this setting in order to identify the presence of cis and tumor multifocality (1). the occurrence of cis is a factor suggesting the need for irradiation therapy which can result in loss of fertility and hormonal function of the remaining part of the testicle, the important factors affecting patients’ quality of life (1). holzbeierlein et al. (3) reported a series of 58 patients with bilateral testicular tumors treated at the memorial sloan kettering cancer center between 1950 and 2001, ten had synchronous tumors while 48 had metachronous tumors, being seminoma the most frequent histology. the authors suggested that these patients had favorable outcomes when compared with patients with unilateral tumors and the prognosis was mainly determined by tumor histology and metastatic disease. although these patients usually present with a higher stage disease, they have an excellent prognosis with overall survival rates comparable with those with unilateral disease. follow-up is the same as unilateral disease, nevertheless life-long close follow-up is advisable due to the small risk of late relapse (1). references 1. campobasso d, ferretti s, frattini a. synchronous bilateral testis cancer: clinical and oncological management. contemp oncol (pozn). 2017; 21:70-76. 2. heidenreich a, höltl w, albrecht w, et al. testis-preserving surgery in bilateral testicular germ cell tumours. br j urol. 1997; 79:253-7. 3. holzbeierlein jm, sogani pc, sheinfeld j. histology and clinical outcomes in patients with bilateral testicular germ cell tumors: the memorial sloan kettering cancer center experience 1950 to 2001. j urol. 2003; 169:2122-5. correspondence pedro simões de oliveira, md (corresponding author) pedrosimoesdeoliveira@gmail.com tiago ribeiro de oliveira, md tiagoribeirooliveira@sapo.pt sergio pereira, md sergioahpereira@gmail.com david martinho, md martinho_david@hotmail.com tomè lopes, md tomematoslopes@gmail.com avenida professor egas moniz 1649-035 lisbon, portugal oliveira_stesura seveso 27/03/18 09:32 pagina 69 stesura seveso 335archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.335 effects of butein on renal ischemia/reperfusion injury: an experimental study mehmet akif ramazanoglu 1, tuncay toprak 2, mehmet remzi erdem 3, gulistan gumrukcu 4, hatice kucuk 5, feridun sengor 6 1 department of urology, rize state hospital, rize, turkey; 2 university of health sciences, turkey. fatih sultan mehmet training and research hospital, department of urology, istanbul, turkey; 3 department of urology, istanbul kolan hospital, istanbul, turkey; 4 department of pathology, haydarpaşa numune training and research hospital, istanbul, turkey; 5 department of pathology, kanuni training and research hospital, trabzon, turkey; 6 department of pathology, university of kırklareli, faculty of kırklareli, turkey. mation, reactive oxygen radicals, apoptosis and necrosis (3, 4). tissues that have undergone i/r are subjected to pro-inflammatory processes of cytokine release and the production of reactive oxygen radicals (ror) by neutrophils (5). the production of ror is considered a key reason for uncontrolled oxidative stress during the reperfusion period (4). thus, oxidative stress is extremely important in renal i/r injury (6), and targeting its processes is an ideal therapeutic approach. the importance of i/r injury preventing during nephron sparing surgery is major issue in urology practice. serum creatinine can increase and glomerular infiltration rate can decrease after nephron sparing surgery even in the patients who have healthy contralateral kidney. to preserve better kidney function leads lowering the risk of development of metabolic or cardiovascular disorders (7). to date, many pharmacological agents such as nacetylcysteine (8), allopurinal (9) or mannitol (10) have been identified to decrease i/r injury after nephron sparing surgery. another potential compound that can target i/r injury is butein, a polyphenolic compound which has reported biological activities ranging from antioxidant properties (11) to anti-fibrogenic, anti-inflamatory (12). it can also exert a protective effect on ischemia or i/r damage (13). against this background, we hypothesized that butein using may reduce i/r injury in rats by its anti-oxidative effects. to the best of our knowledge, there is no information about of the anti-oxidative effects of butein in rat model of renal i/r injury. materials and methods all experimental and surgical procedures were approved by the institutional animal care and use committee of university of bezmialem (istanbul, turkey) (approval number/id: 2016/134). the procedures complied with the guide for the care and use of laboratory animals and were conducted according to animal care guidelines (14). a total of 27 male wistaralbino (wa) rats (8 weeks old, weight 220-250 g) were purchased from the university of bezmialem (istanbul, objectives: renal ischemia/reperfusion (i/r) injury is a common cause of acute kidney injury. the aim of this study was to investigate the effect of butein on renal i/r injury. materials and methods: twenty-seven rats were randomly allocated to three groups (n = 9): a sham group, a renal i/runtreated (control) group, and a renal i/r-butein group. the sham group underwent only opening and closing of the peritoneum. in the control group, an experimental i/r model was created and 1 cc isotonic saline was applied to the peritoneum. in the butein group, the experimental i/r model was created and 1 mg/kg butein was administered intraperitoneally 15 minutes before the beginning of ischemia. the left kidneys of the rats were histopathologically examined for tissue damage caused by i/r. results: histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. by contrast, 2 in the control group (22.2%) had small focal damaged areas, 1 (11.1%) had < 10% cortical damage, 5 (55.6%) had 10-25% cortical damage, and 1 (11.1%) had 25-75% cortical damage. the butein group had 1 (11.1%) normal kidney, 2 (22.2%) with small focal damaged areas, 4 (44.4%) with < 10% cortical damage, and 2 (22.2%) with 10-25% cortical damage. tissue damage was significantly lower in the sham group than in the control and butein groups (p < 0.01). no statistically significant differences were observed in the histopathology of the control and butein groups (p > 0.05). conclusions: intraperitoneal administration of butein had no significant effect on renal tissue injury. key words: butein; oxidative stress; renal ischemia; reperfusion injury; rat. submitted 19 june 2020; accepted 28 july 2020 introduction ischemia/reperfusion (i/r) injury is a common cause of renal injury arising from a variety of clinical circumstances, including partial nephrectomy, renal transplantation, renal artery angioplasty, hydronephrosis and iatrogenic trauma (1, 2). the pathologic processes underlying this injury are complex and involve inflamsummary archivio italiano di urologia e andrologia 2020; 92, 4 mehmet akif ramazanoglu, tuncay toprak, mehmet remzi erdem, gulistan gumrukcu, hatice kucuk, feridun sengor 336 turkey). the animals were kept in captivity under the same nutritional and environmental conditions. rats were entrained under a 12:12 h light: dark cycle with stable temperature (21 ± 2°c) and humidity (60 ± 10%). the rats had food and sterile water available ad libitum. experimental design the wa rats were randomly divided into three groups (n = 9 in each group): 1. sham group: after sterile conditions were obtained, a midline laparotomy was performed. the left kidney pedicle was then dissected. no other procedure was performed, and the incision was closed in two layers. 2. control group (renal i/r injury and plasebo group): after sterile conditions were obtained, a midline laparotomy was performed. isotonic saline (1 mg/kg) was applied intraperitoneally 15 minutes before the beginning of arterial clamping. the left kidney pedicle was clamped with an artery clamp for 45 minutes. after 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed in two layers. 3. renal i/r injury and butein group: after sterile conditions were obtained, a midline laparotomy was performed. butein (1 mg/kg) was applied intraperitoneally 15 minutes before the beginning of arterial clamping. the left kidney pedicle was clamped with an artery clamp for 45 minutes. after 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed in two layers. butein was sourced from farmasina medical and chemical products company (kayışdağı, ataşehir, istanbul). induction of renal i/r injury the rats were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg, ketalar, eczacıbasi, turkey) and xylazine (10 mg/kg). the midline laparotomy and dissection of the left kidney pedicle were then performed as already described, followed by the i/r procedure for the control and butein groups. all procedures were performed under sterile conditions. the rats were sacrificed 24 h after completion of the reperfusion procedure and kidney samples were obtained. histological analysis renal tissues were extracted from rats in all groups (24 h after surgery), as well as following intraperitoneal injection of butein (1 mg/kg) in the butein group. kidney tissue was embedded in paraffin and 5 μm tissue sections were taken for hematoxylin and eosin (h&e) staining. an independent pathologist blinded to the treatment groups, analyzed three different tissue sections from rats in each treatment group, using a zeiss axio imager a2 microscope (carl zeiss ag, germany). the histological evaluations of the renal tissue were graded as follows: 0, normal; 0.5, small focal damage areas; 1, areas of tubular epithelial cell necrosis and desquamation, including < 10% of cortical tubules; 2, similar changes, including 10-25% cortical tubules; 3, similar changes including 25-75% cortical tubules; and 4, similar changes including > 75% cortical tubules. this scoring system is shown in table 1 (15). statistical analysis statistical analysis was performed using the spss 22 software. before starting to study, we performed power analysis. the power analysis showed that 9 subjects per group would be needed to have a 80% chance of achieving statistical significance at the p < 0.05 level. the kolmogorov-smirnov test was performed to determine the normality of data. the results are expressed as mean ± sd. mann-whitney u and kruskal-wallis tests were performed for comparison of two and three independent samples, respectively. a p value below 0.05 was considered statistically significant. results histopathological examination of tissue damage revealed that all rats in the sham group had normal kidneys. by contrast, 2 rats in the control group (22.2%) had small focal damaged areas, 1 (11.1%) had < 10% cortical damage, 5 (55.6%) had 10-25% cortical damage, and 1 (11.1%) had 25-75% cortical damage. the butein group had 1 rat (11.1%) with normal kidneys, 2 (22.2%) with small focal damaged areas, 4 (44.4%) with < 10% cortical damage, and 2 (22.2%) with 10-25% cortical damage. renal cortical damage was significantly lower in the sham group than in the control and butein groups (p < 0.01). no statistically significant difference was noted in the histopathology of the control and butein groups (p > 0.05). histopathologic results for the experimental animals were shown in table 2. histological images of the damage according to the scoring system for the rat renal cortex sections after ir injury were shown in figures 1-4 table 1. scoring system for renal histopathology. table 2. histopathologic results for the experimental animals. score histopathological pattern 0 normal 0.5 small focal damaged areas 1 < 10% cortical damaged zone 2 10–25% cortical damaged zone 3 25–75% cortical damaged zone 4 > 75% cortical damaged zone sham control butein total group n (%) group n (%) group n (%) normal 9 (100) 0 1 (11.1) 10 (37.0) small focal damaged areas 0 2 (22.2) 2 (22.2) 4 (14.8) < 10% damaged cortical zone 0 1 (11.1) 4 (44.4) 5 (18.5) 10–25% damaged cortical zone 0 5 (55.6) 2 (22.2) 7 (25.9) 25–75% damaged cortical zone 0 1 (11.1) 0 1 (3.7) min-max (median) 0–0 (0) 0.5-3 (2) 0-2 (1) 0-3 (0.5) pa 0.001** sham-control groupb 0.001** sham-butein groupb 0.001** control-butein groupb 0.105 a kruskal-wallis test; b mann-whitney u test; **p < 0.01. 337archivio italiano di urologia e andrologia 2020; 92, 4 effects of butein in renal i/r injury and dissociation of histopathologic tissue damage according to groups was shown in figure 5. discussion the complicated pathogenesis of renal i/r injury is due to the broad range of effects on vascular endothelial and tubular epithelial cells (16). these effects are characterized by the cellular accumulation of waste products, imbalances in electrolytes and acid-base levels (17). renal i/r injury induces an inflammatory response by triggering the immune systems. an infiltration of leukocytes then occurs in the site of inflammation, followed by activation of tubular epithelial cells (18, 19). the influx of neutrophils and macrophages into injured renal tissue results in the secretion of pro-inflammatory cytokines, including tnf-a, hmgb1, il-6, and il-1b (20), while the infiltrated cells themselves reduce blood flow in the kidney and disrupt microcirculation (21). significant increases in pro-inflammatory cytokine levels have been reported following renal i/r injury in rats (22). in the present study, butein was examined for its potential effects on regulating renal i/r injury. we considered that butein may serve a protective role in the rat model of renal i/r injury model by regulating the level of inflammatory cytokines. butein is an important herbal polyphenol in traditional japanese and korean medicine, where it has been used as an analgesic, antibiotic, antithrombotic, anticancer, and anti-inflammatory medicine (23). it has demonstrated a broad spectrum of activity in both in vivo and in vitro models, including antineoplastic, anti-inflammatory, and antioxidant effects (24), but the mechanism underlying its antiinflammatory properties is unclear. the present evidence suggests that butein inhibits many enzymes and pro-inflammatory mediators and that it also suppresses macrophage-mediated inflammation. one study performed in macrophage culture showed suppression of lipopolysaccharide-dependent nitrite and pge2 production by butein and a pronounced antiinflammatory effect (25). application of butein to cell cultures resulted in cox-1 and cox-2 inhibition (11). lee and colleagues suggested the use of butein as a treatment for intestinal inflammation, as butein reduced the expression of il-8 in intestinal epithelial cell cultures (26). butein also reduced e-selectin expression in human umbilical vein cells and expression of icam-1 and vcam-1 in endothelial cells (27). in addition, butein inhibited proinflammatory gene activity by inhibiting nfkbeta activation and inhibited the release of tnf-a, il-6 and il-8 (28). many studies have shown that butein neutralizes and inhibits production of ror and protects the cells from ror damage. in living organisms, ror arise as a result of normal biological metabolism and they can distort the structures of dna, fats, proteins and carbohydrates. the best known of these oxygen figure 1. normal cortex (histopathologic score = 0). figure 2. cortical focal necrose areas (histopathologic score = 1). figure 3. more common cortical necrose areas (histopathologic score = 2). figure 4. extensive cortical necrose areas (histopathologic score = 3). figure 5. dissociation of histopathologic tissue damage according to groups. archivio italiano di urologia e andrologia 2020; 92, 4 mehmet akif ramazanoglu, tuncay toprak, mehmet remzi erdem, gulistan gumrukcu, hatice kucuk, feridun sengor 338 radicals are the superoxide anion, hydrogen peroxide, and hydroxyl radicals. cheng et al. used ccl4 to cause cellular damage to the liver and then tried to repair this cellular damage using butein and a-tocopherol. butein showed a similar antioxidant effect to that of a-tocopherol, but butein had the advantage of eliciting an effect at lower doses (11). i/r-induced damage differs histologically in some respects from chemically induced damage. for example, the arterial circulation in the renal cortex is somewhat suppressed following i/r, due to tubulo-glomerular arteriolar vasoconstriction, cellular swelling, tubular obstruction, and vascular occlusion arising from extravasation of white blood cells and erythrocytes from the external medulla. the proximal tubules affected by i/r are damaged due to warm ischemia during recirculation and this leads to regression of the renal function when circulation returns to its original state. during re-infusion, the tubular lumen diameter increases, while punctures from the proximal tubules block the tubules, creating resistance to fluid ingestion in the handle and proximal tubules. the result is a decrease in tubular reabsorption due to cellular damage, while capillary expansion increases the intratubular pressure in the external medullary collecting tubes. subsequently, in addition to a 12% reduction in blood flow, the gfr is also reduced by 90% (29). the tubular tissue undergoes atrophy, the tubular lumen diameter increases, the tubules undergo hyalinization, and reactive atypia, brushy edge loss, cellular swelling, nucleus deformity, and leukocyte infiltration are observed. in our study, histopathologic evaluation of the tissue response to butein in the renal i/r rat model was compared with the non-butein control group and the sham group. histopathologically significant differences were found between the sham group and the other groups, but no statistically significance was noted histopathologically between the i/r rats treated with butein or the saline control (p > 0.05). the current study has two major limitations: plasma concentrations of creatinine and urea were not measured, and no biochemical analysis of renal tissue was performed. conclusions the intraperitoneal administration of butein to the rat experimental i/r model did not result in a statistically significant effect on renal tissue i/r injury. nevertheless, this study is important since, to the best of our knowledge, it is the first study in the literature to test butein for effects on renal i/r. further meaningful results can be obtained in comparative studies of different applications of butein. references 1. sagiroglu t, torun n, yagci m, et al. effects of apelin and leptin on renal functions following renal ischemia/reperfusion: an experimental study. exp ther med. 2012; 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300:f721-f33. 17. huber tb, edelstein cl, hartleben b, et al. emerging role of autophagy in kidney function, diseases and aging. autophagy. 2012; 8:1009-31. 18. land wg. the role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. transplantation. 2005; 79:505-14. 19. serteser m, koken t, kahraman a, yilmaz k, akbulut g, dilek on. changes in hepatic tnf-a levels, antioxidant status, and oxidation products after renal ischemia/reperfusion injury in mice. j surg res. 2002; 107:234-40. 20. ysebaert dk, de greef ke, vercauteren sr, et al. identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. nephrol dial transplant. 2000; 15:1562-74. 21. bolisetty s, agarwal a. neutrophils in acute kidney injury: not neutral any more. kidney int. 2009; 75:674-6. 339archivio italiano di urologia e andrologia 2020; 92, 4 effects of butein in renal i/r injury 22. dessing mc, pulskens wp, teske gj, et al. rage does not contribute to renal injury and damage upon ischemia/reperfusioninduced injury. j innate immun. 2012; 4:80-5. 23. kang dg, lee as, mun yj, et al. butein ameliorates renal concentrating ability in cisplatin-induced acute renal failure in rats. biol pharm bull. 2004; 27:366-70. 24. wang y, chan fl, chen s, leung lk. the plant polyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase. life sci. 2005; 77:39-51. 25. jung ch, kim jh, hong mh, et al. phenolic-rich fraction from rhus verniciflua stokes (rvs) suppress inflammatory response via nf-kb and jnk pathway in lipopolysaccharide-induced raw 264.7 macrophages. j ethnopharmacol. 2007; 110:490-7. 26. lee sh, seo gs, jin xy, et al. butein blocks tumor necrosis factor a-induced interleukin 8 and matrix metalloproteinase 7 production by inhibiting p38 kinase and osteopontin mediated signaling events in ht-29 cells. life sci. 2007; 81:1535-43. 27. takano-ishikawa y, goto m, yamaki k. inhibitory effects of several flavonoids on e-selectin expression on human umbilical vein endothelial cells stimulated by tumor necrosis factor-a. phytother res. 2003; 17:1224-7. 28. jang jh, yang es, min k-j, kwon tk. inhibitory effect of butein on tumor necrosis factor-a-induced expression of cell adhesion molecules in human lung epithelial cells via inhibition of reactive oxygen species generation, nf-kb activation and akt phosphorylation. int j mol med. 2012; 30:1357-64. 29. yin m, kurvers hm, tangelder g, et al. intravital microscope studies of the ischemically injured rat kidney during the early phase of reperfusion. transplant proc. 1995; 27:2847-8. correspondence mehmet akif ramazanoglu, md (corresponding author) maramazanoglu@hotmail.com rize state hospital, department of urology eminettin mah. atatürk caddesi, merkez, 53020 rize (turkey) tuncay toprak, md drtuncay55@hotmail.com university of health sciences, turkey. fatih sultan mehmet training and research hospital, department of urology, istanbul (turkey) mehmet remzi erdem, md remzierdem@gmail.com department of urology, istanbul kolan hospital, istanbul (turkey) gulistan gumrukcu, md department of pathology, haydarpasa numune training and research hospital, istanbul (turkey) hatice kucuk, assistant professor dr.hatice.kucuk@hotmail.com department of pathology, kanuni training and research hospital, trabzon (turkey) feridun sengor, professor fsengor2004@yahoo.com department of urology, university of kırklareli, faculty of kırklareli, (turkey) stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4314 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.314 from the neuropathophysiological point of view, the importance of the condition is not yet entirely specified. diabetic neuropathy is the most common and disturbing complication of diabetes, it leads to the highest morbidity and mortality rates, therefore producing an enormous economic burden in treatments. clinical evaluation and treatment of diabetic peripheral neuropathy has multiple options and patients with diabetic neuropathy should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications (1). nevertheless, this disease is also of great interest in relation to the high morbidity and occasional fatal consequences (2). this assumption motivated the investigation to verify the rate of diabetic cystopathy in relation to the type of diabetes and the correlation or not with a neuro-urological subjective symptomatology (3). while diabetes as a metabolic disease is of easy recognition, diabetic cystopathy develops insidiously and symptoms may not appear until the disease is already in an advanced stage (1). the consequences of diabetes on bladder function have been known since 1864 (4), but subsequently in literature often conflicting data were reported, due to both the selection of patients according to different diabetic and urological criteria, as to the occasional diversity in definitions of diabetic cystopathy, not always compliant and identical. in fact, the incidence of “bladder dysfunction” in diabetic patients varies from 37% to 67% (5). before presenting the study and making assessments on the incidence of diabetic cystopathy it is relevant to consider some predictive factors such as age, gender, type and degree of diabetes, factors that may have caused a (unintended) patient selection, linked to the characteristics of the study population. only with this foresight, it will be possible to attempt comparative assessments between the various authors who have so far treated the problem. some studies include in the definition of diabetic cystopathy sensory impairment (1), others sensory and sensory-motor impairment (6), others in addition to the previous also consider the apparently isolated motor impairment of the detrusor (hyperreflexia, contractility devoid) without compulsory and prevailing sensory impairment (7). in the present case study, patients suffering from diabetic cystopathy (in the broad interpretation of the term as diabetic autonomic neuro-bladder) were considered as patients that had sensitive impairment, sensitive-motor impairment, isolated motor impairment and detrusor “hyperreflexia”. particular attention was paid to identify objective: to investigate the incidence of diabetic cystopathy in relation to age, gender, type of diabetes, duration of diabetic disease and clinical evidence of peripheral neuropathy and to analyze the physiopathology of the various forms of diabetic cystopathy due to sensory impairment, motor-sensory impairment, motor impairment and hyperreflexia. materials and methods: in a retrospective multicenter cohort study the medical records of a cohort of 126 diabetic patients with (128 patients) or without (48 patients) urological symptoms were analyzed. patients were observed at the città di alessandria clinic of policlinico di monza and/or at the outpatient clinic of alessandria hospital from june 2018 to june 2020. the study excluded patients with central and/or peripheral neuropathy, spina bifida (mylomeningocele or meningocele) or spina bifida occulta; with persistent urinary infections; in anticholinergic treatment for enteric dysfunctions; in medical treatment for cervical-prostatic-urethral obstruction; with vaginal and/or rectal prolapse of ii, iii, iv degree; with previous spinal or pelvic surgery including radical prostatectomy, wertheim hysterectomy or colorectal surgery. all the patients were studied with computed tomography (ct) scan of the urinary tract, voiding cystourethrography (vcug), uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (emg) of the anal sphincter, pressure flow analysis, urethral pressure profile and, when advised, pharmacological tests. results: out of 126 diabetic patients, 48 did not show any signs or symptoms of urine voiding dysfunction; 30 were men and 18 women with an average age of 62.6 years; 20 had type i diabetes and were in treatment with insulin and 28 type ii diabetes treated with oral hypoglycemic medication. the remaining 78 patients (48 men and 30 women), with an average age of 64.8 years, presented urological symptoms; 31 had type i diabetes and 47 had ii type diabetes. conclusions: diagnosis of the various forms of diabetic cystopathy and early treatment decreases complications and consequently accesses to outpatient facilities and hospital admissions, resulting in an improved quality of life. key words: diabetic neuropathy; neurological bladder; diabetes mellitus; urodynamics. submitted 13 october; accepted 16 november physiopathology of the diabetic bladder summary tatiana bolgeo 1, antonio maconi 1, marinella bertolotti 1, annalisa roveta 1, marta betti 1, denise gatti 1, carmelo boccafoschi 2 1 azienda ospedaliera ss. antonio e biagio e c. arrigo, alessandria, italy; 2 clinica città di alessandria policlinico di monza, alessandria, italy. introduction changes in diabetic patients’ bladder functions are part of the wider field of autonomic diabetic neuropathy, but boccafoschi_stesura seveso 14/12/20 20:36 pagina 314 315archivio italiano di urologia e andrologia 2020; 92, 4 diabetic bladder other coexistent illnesses and diseases, especially the presence of cervical-prostatic-urethral obstructions. the diagnostic tools used to evaluate the type of diabetic cystopathy include urodynamic evaluation (uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (emg) of the anal sphincter, pressure-flow study, urethral pressure profile and when advised pharmacological tests), ultrasound and computed tomography (ct) scan of the urinary tract and voiding cysto-urethrography. when assessing the association between autonomic neuropathy and cervical-prostatic obstruction, differential urodynamic diagnosis can be difficult and maybe sometimes even impossible. conversely after the removal of the obstruction (clinically and urodynamically proven) it is easier to evaluate bladder sensitivity and residual detrusorial contraction function associated to diabetic cystopathy. during follow up, ultrasound examinations were used to assess the post-void residue. patients were separately evaluated according to the type of diabetes and time-period of onset or first clinical diagnosis. from literature, it does not emerge a precise nosology of diabetic neuropathies and even less of diabetic cystopathy that was generically considered as an alteration of bladder function that can be independent or linked to autonomic visceral neuropathy. the aim of this study was to assess in a cohort of patients the incidence of the above described bladder dysfunctions (diabetic cystopathy) in relation to predictive factors such as age, gender, type and timing of diabetic onset. methods in this retrospective multicentre cohort study, the clinical records of 126 diabetic patients treated at “città di alessandria clinic” and/or at out-patient clinic of the alessandria hospital from june 2018 to june 2020 were reviewed. exclusion criteria included: patients with central and/or peripheral neuropathy (parkinson. multiple sclerosis, stroke, etc.); patients with spina bifida (mylomeningocele or meningocele) or spina bifida occulta; patients with persistent urinary infections; patients in anticholinergic treatment for enteric dysfunctions; patients in medical treatment for cervical-prostatic-urethral obstruction; patients with vaginal and/or rectal prolapse of ii, iii, iv degree; patients with previous spinal or pelvic surgery including radical prostatectomy, wertheim hysterectomy or colorectal surgery. results out of the 126 diabetic patients observed, 48 did not show signs or symptoms of dysfunctional voiding; 30 were men and 18 women; the average age was 62.2 years; 20 presented type i diabetes and were on treatment with insulin and 28 had type ii diabetes and were on oral hypoglycemic treatment. the remaining 78 patients showed urological symptoms; 48 were men and 30 women; average age was 64.8 years; 31 presented type i diabetes and 47 type ii diabetes. the 78 diabetic patients with urological symptoms were divided into subgroups according to the type of diabetes and the presence or not of diabetic cystopathy that was differentiated in its various forms by urodynamic evaluation (table 1). sensory impairment was identified in 11 patients with type i diabetes and in 12 patients with type ii diabetes (a prostatic obstruction not pharmacologically treated was associated in 2 patients with type i diabetes and in 3 patients with type ii diabetes, respectively). a mixed motor-sensory impairment was identified in 5 patients with type i diabetes and in 5 patients with type ii diabetes (in 2 of the latter, a non-pharmacologically treated cervical-prostatic obstruction was also identified). isolated motor impairment without sensory implication were identified in 5 type i diabetic patients and in 6 type ii diabetic patients (in 1 of the latter a non-pharmacologically treated cervical-prostatic obstruction was also present). in total, the association between diabetic cystopathy and cervical-prostatic-urethral obstructive disease was present, in 8 patients. the diagnosis of bladder outlet obstruction was conveyed on clinical and radiological data, pressure flow studies and urethral pressure profilometry (upp), although in presence of hypocontractility or acontractility of the detrusor the flow-pressure relationship was not very significant. in 5 out of 8 cases, postvoiding residue was more than 10% (sign of decompensation). in these cases the presence of neuropathy was outstanding because when they were urodynamically studied after the removal of the cervical-prostatic obstruction hypo-contractility or a-contractility of the detrusor responded to treatment with parasympatheticmimetic drugs. detrusor hyperreflexia (with unstable contractions but with normal urethral resistances) was present in 1 patient with type i diabetes and in 8 type ii diabetic patients. urodynamic examination was essential to identify this group, because it allowed to exclude obstructive anatomical and/or functional factors. the urodynamic examination also played an important role in evaluating a group of 17 patients with cervicalprostatic-urethral obstruction without any sign of diabetic cystopathy, these patients evidenced normal bladder sensitivity but detrusor hyper-contractility. in 8 other patients (5 with type i and 3 with type ii diabetes) the urodynamic evaluation did not identify any impairment allowing to consider these patients as normal for bladder function. table 1. results of urodynamic evaluation in patients with diabetes type i and ii. urodynamic results type i diabetes type ii diabetes sensory impairment 11 12 motor sensory impairment 5 5 motor impairment 5 6 hyperreflexia without obstruction 1 8 22 31 tot 53 obstruction 4 13 normal 5 3 totale 31 47 tot 78 boccafoschi_stesura seveso 14/12/20 20:36 pagina 315 archivio italiano di urologia e andrologia 2020; 92, 4 t. bolgeo, a. maconi, m. bertolotti, a. roveta, m. betti, d. gatti, c. boccafoschi 316 altogether, diabetic cystopathy was present in 71% (22/31) of patients with type i diabetes and 66% (31/47) of patients with type ii diabetes. peripheral somatic neuropathy was clinically present in 20 out 78 patients with urological symptoms. fifteen of these (75%) also had diabetic cystopathy, while only 65% of the remaining 58 patients without clinically detectable signs and symptoms of somatic neuropathy, evidenced bladder dysfunctions indicative of diabetic cystopathy. only in 15 of patients with diabetic cystopathy (about 28%) a peripheral somatic neuropathy was clinically demonstrated. to evaluate the relationship between the duration of diabetic disease and the incidence of autonomic cystopathy, the patients included in the present study, were divided into two groups according to whether the diabetic disease had been diagnosed for less than 5 years (28 patients) or more than 5 years (50 patients). the average age of the two groups was not significantly different being respectively 62 and 66 years. of the recently diagnosed patients, 16 out of 28 (57%) presented diabetic cystopathy, while 37 out of 50 (74%) of the remaining with long-lasting diabetes showed signs of cystopathy. in 37/53 (70%) of the patients with diabetic cystopathy, the diabetic disease was present from more than 5 years. discussion the multiple aspects of the diabetic bladder can be due to both the variety of neurological impairments specific of the disease that affect the nervous system at various levels, as to the altered pathophysiology of the organ affected by neuro-impairment (8). the autonomic and somatic diabetic neuropathy has probably a multifactorial origin. the multiplicity of locations and extent of impairment can therefore explain why there are different types of diabetic neurological bladder (9). in our case study of diabetic patients with urological symptoms, a neurogenic bladder dysfunction was identified in 66% of cases. the total of the patients included 23 patients who presented exclusively sensory impairment, 10 patients with motor-sensory impairment, 11 patients with exclusive motor impairment and 9 patients with hyperreflexia (without obstruction) (figures 1-4). seventeen of the remaining patients presenting with urological symptoms (22%) had cervical-prostatic obstruction and 8 patients (10%) were urodynamically normal. diabetic cystopathy, as neurogenic bladder dysfunction caused by autonomic diabetic neuropathy, occurs with remarkable frequency (42% of the 126 diabetic patients studied) particularly if urological symptoms are present (68% of this group of 78 patients). in our series, type of diabetes (insulin dependent versus non-insulin dependent) was not associated with an higher risk of diabetic cystopathy, that was observed in 71% of symptomatic patients with type i diabetes and 66% of symptomatic patients with type ii diabetes. consequently, it seems that the insulin dependence of diabetes is not the determining factor of onset of autonomic cystopathy. on the contrary, frimodt-møller (10), figure 1. urodynamic trace of a case of diabetic cystopathy with impairment restricted only to the sensory pathways (modified by boccafoschi c, maurel a appunti sui parametri e le metodiche in urodinamica. minerva medica; 1986) figure 2. urodynamic trace in a case of diabetic cystopathy with impairment of the motor-sensory pathways (modified by boccafoschi c, maurel a appunti sui parametri e le metodiche in urodinamica. minerva medica; 1986) figure 3. urodynamic trace in a case of diabetic cystopathy with impairment restricted only to the motor pathways (modified by boccafoschi c, maurel a appunti sui parametri e le metodiche in urodinamica. minerva medica; 1986). figure 4. urodynamic trace in a case of diabetic cystopathy with detrusor hyperreflexia (modified by boccafoschi c, maurel a appunti sui parametri e le metodiche in urodinamica. minerva medica; 1986). boccafoschi_stesura seveso 14/12/20 20:36 pagina 316 317archivio italiano di urologia e andrologia 2020; 92, 4 diabetic bladder evaluating a different series, obtained different results showing a higher incidence of cystopathy in insulin dependent diabetics (48%) than in diabetics on oral hypoglycemic treatment or treated only with diet (25%). conversely, their series was not comparable with our series because of lower mean age of patients, higher prevalence of patients treated with insulin (80%) and longer duration of the diabetic disease. the most relevant neurological disease related to diabetes in addition to autonomic neuropathy is peripheral somatic neuropathy, with the association between diabetic cystopathy and peripheral neuropathy reported in percentages varying from 14% to 80% (11-13). the association between peripheral neuropathy and diabetic cystopathy was demonstrated in 19% of the cases with symptomatic diabetes. the rate of cystopathy was high in neuropathic patients (75%) but this was not true for the opposite. in fact, only 28% of patients with diabetic cystopathy showed clinically demonstrable peripheral neuropathy as if the impairment of the visceral autonomic nervous system precedes in time that of the peripheral autonomic system or that of the somatic nerves. this is confirmed by the data relating the rate of cystopathy (and neuropathy) and the duration of the diabetic disease, especially if it is above 5 years. cystopathy is in fact, present in 74% of diabetic patients that have been afflicted with the disease for more than 5 years, compared to only 57% of the patients who have been afflicted with diabetes for less than 5 years. conclusions in literature, up to the present day, all the studies have addressed symptomatic and non-symptomatic diabetic patients from an urological perspective. urodynamic techniques can successfully study the pathophysiology of the diabetic bladder and allow identifying four types of diabetic cystopathy: sensory pathway impairment, motor-sensory pathway impairment, motor pathway impairment and impairment to control detrusorial reflex resulting in hyperreflexia. the urodynamic evaluation can also identify cases of simple cervical-prostatic obstruction without signs of diabetic cystopathy. nevertheless, particular problems arise when there is an association between diabetic cystopathy and cervical-prostatic-urethral obstruction. the urodynamic evaluation of detrusor contractility function, urethral function and bladder sensitivity makes it possible to convey a precise diagnosis, even if in a number of cases it becomes necessary to repeat the test after having surgically removed the cervical-prostatic-urethral obstruction. in the assessment of bladder sensitivity, the urodynamic evaluation is limited and it may be useful to integrate it with the measurement of the threshold of electrical perception or with the study of evoked potentials. the complexity of nerve structures that control bladder functioning and the possibility that diabetes can impair them with multiple mechanisms (dis-metabolic, toxic, microor macroangiopathic) and at multiple levels of the central and peripheral nervous system, makes questionable the claim that the impairment responsible for diabetic cystopathy is due exclusively to peripheral impairment. conversely, being central impairment alone not confirmed, mixed forms should be accepted as the more frequent. in the future, it could be worthwhile the use of dynamic brain magnetic resonance studies. these results may have clinical applicability in identifying patients with diabetic cystopathy and guide patient counselling with treatment decision-making. references 1. feldman el, callaghan bc, pop-busui r, et al. diabetic neuropathy. nat rev dis primers. 2019; 5:42. 2. deli g, bosnyak e, pusch g, et al. diabetic neuropathies: diagnosis and management. neuroendocrinology. 2013; 98:267-80. 3. ziegler d. painful diabetic neuropathy: treatment and future aspects. diabetes metab res rev. 2008; 24 suppl 1:s52-7. 4. tanik n, tanik s, albayrak s, et al. association between overactive bladder and polyneuropathy in diabetic patients. int neurourol j. 2016; 20:232-239. 5. duby jj, campbell rk, setter sm, et al. diabetic neuropathy: an intensive review. am j health syst pharm. 2004; 61:160-73. 6. bossi l, caffaratti e. bladder complications in neuropathic diabetic patients. clinical and radiological study. minerva radiol. 1968; 13:40-7. 7. bradley we. cerebro-cortical innervation of the urinary bladder. tohoku j exp med. 1980; 131:7-13. 8. bolgeo t. caring for bladder dysfunctions in patients with parkinson’s disease. arch ital urol androl. 2011; 83:112-5. 9. boccafoschi c, maurel a. appunti sui parametri e le metodiche in urodinamica. minerva medica; 1986. 10. frimodt-møller c. diabetic cystopathy: epidemiology and related disorders. ann intern med. 1980; 92:318-21. 11. freeman r. diabetic autonomic neuropathy. handb clin neurol. 2014; 126:63-79. 12. carone r, frea b, tizzani a, borgno m. neurologic bladder in diabetes. etiopathogenetics and treatment. minerva urol. 1979; 31:91-3. 13. kiani j, moghimbeigi a, azizkhani h, kosarifard s. the prevalence and associated risk factors of peripheral diabetic neuropathy in hamedan, iran. arch iran med. 2013; 16:17-9. correspondence tatiana bolgeo antonio maconi marinella bertolotti annalisa roveta marta betti denise gatti azienda ospedaliera ss antonio e biagio e c. arrigo, alessandria (italy) carmelo boccafoschi, md (corresponding author) cboccafoschi@virgilio.it clinica città di alessandria policlinico di monza, alessandria (italy) boccafoschi_stesura seveso 14/12/20 20:36 pagina 317 311archivio italiano di urologia e andrologia 2016; 88, 4 original paper the role of intraoperative ultrasound in small renal mass robotic enucleation roberta gunelli 1, massimo fiori 1, cristiano salaris 1, umberto salomone 1, marco urbinati 1, vici alexia 1, teo zenico 1, mauro bertocco 2 1 urology unit, forlì hospital, romagna local health service, italy; 2 radiology unit, romagna local health service, italy. introduction: as a result of the growing evidence on tumor radical resection in literature, simple enucleation has become one of the best techniques associated to robotic surgery in the treatment of renal neoplasia, as it guarantees minimal invasiveness and the maximum sparing of renal tissue, facilitating the use of reduced or zero ischemia techniques during resection. the use of a robotic ultrasound probe represents a useful tool to detect and define tumor location, especially in poorly exophytic small renal mass. materials and methods: a total of 22 robotic enucleations were performed on < 3 cm renal neoplasias (padua score 18 pz 6/7 e 4 pz 8) using a 12-5 mhz robotic ultrasound probe (bk drop-in 8826). results: once kidney had been isolated from the adipose capsule at the site of the neoplasia (2), the exact position of the lesion could be easily identified in all cases (22/22), even for mostly endophytic lesions, thanks to the insertion of the ultrasound probe through the assistant port. images were produced and visualized by the surgeon using the tilepro feature of the davinci surgical system for producing a picture-in-picture image on the console screen. the margins of resection were then marked with cautery, thus allowing for speedy anatomical dissection. this reduced the time of ischemia to 8 min (6-13) and facilitated the enucleation technique when performed without clamping the renal peduncle (6/22). no complications due to the use of the ultrasound probe were observed. conclusions: the use of an intraoperative robotic ultrasound probe has allowed for easier identification of small, mostly endophytic neoplasias, better anatomical approach, shorter ischemic time, reduced risk of pseudocapsule rupture during dissection, and easier enucleation in cases performed without clamping. it is noteworthy that the use of intraoperative ultrasound probe allows mental reconstruction of the tumor through an accurate 3d vision of the hidden field during surgical dissection. key words: robotic ultrasound probe; renal tumor; simple enucleation; psychomotor skills. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. (se) is one of the partial nephrectomy techniques that mostly combines functional sparing with radical tumor resection (1-3). in addition, nss has been encouraged by the recently introduced robotic technique for the conservative treatment of renal neoplasias, assuring minimal invasiveness through the sparing of renal tissue and enabling the use of reduced or zero ischemia techniques during surgery. in the present paper we report our experience of the use of intraoperative ultrasound imaging in se, showing how, besides providing more accurate anatomic detection of neoplasias, it may improve the surgeon’s spatial proprioception, thus facilitating se performance. materials and methods since april 2013 we have performed in our unit a total of 22 robotic enucleations on < 3 cm renal tumor (padua score 18 pz 6/7 e 4 pz 8) through a 12-5 mhz robotic probe (bk drop-in 8826) (figure 1). we used the davinci xi system in the three-armed configuration, connected to a 5-mm port utilized for suction and retraction of the bowel, and a 12-mm assistant port for inserting the drop-in ultrasound probe and for applying the vascular bulldog clamps and the hem-o-lok clips. a proart robotic trasducer 8826 (bk medical) was used for the intraoperative ultrasonography. the tilepro was selected to observe the images on the robotic console, which allowed simultaneous vision of both the operative field and the ultrasound images (4). the probe was managed by the prograsp forceps; image quality was optimal also thanks to the large field of view. tumor excision was performed with scissors and the prograsp forceps (intuitive surgical). no patient had positive surgical margins detected at the pathologic examination. after excision, the renal cortex was closed using the sliding clip renorrhaphy technique (5). results once kidney had been isolated from the adipose capsule at the site of the neoplasia (2), the exact position of the lesion could be easily identified in all cases (22/22), even for mostly endophytic lesions. doi: 10.4081/aiua.2016.4.311 presented at 20th national congress sieun, sciacca 2016 introduction the widespread use of little invasive imaging tools such as ultrasound has lead to a growing number of diagnosed small renal masses treatable with nephron sparing surgery (nss) in the past decades. on the basis of literature evidence, simple enucleation gunelli-the role of intraoperative ultrasound _stesura seveso 09/01/17 10:06 pagina 311 archivio italiano di urologia e andrologia 2016; 88, 4 r. gunelli, m. fiori, c. salaris, u. salomone, m. urbinati, vici alexia, t. zenico, m. bertocco 312 the margins of resection were marked with cautery allowing for speedy anatomical dissection, reducing either time of ischemia to 8 min (6-13) or facilitating enucleation when performed without clamping the renal peduncle (6/22). no complications due to the use of the ultrasound probe were observed. discussion a comparison of the different types of intraoperative ultrasound probe has shown that handling issues of laparoscopic probes impede an accurate spatial evaluation of the tumor, while robotic drop-in probes combined with prograsp forceps enable fast and efficacious ultrasound exploration on 3d planes (6). in addition, while assistant-controlled laparoscopic probes limit the autonomy of the surgeon, only robotic drop-in probes can be handled directly by the surgeon at the console. picture-in-picture vision technology (tilepro) on the davinci robotic system enables routine simultaneous live vision of both operation field and ultrasound images (figure 2), while the attached surgeon-controlled dropin ultrasound probe improves the operator’s sensation of the tool. a possible limitation might be that the methodology is highly operator-dependent: adequate ultrasound imaging training should therefore be included in the operator’s preparation. the presence of a radiologist in the initial phases of the training might accelerate the learning curve itself. in a recently published study (7) 87% of interviewees highlighted the potential usefulness of augmented reality, especially during rapn for detecting the neoplasia, and during mass resection. as yet, however, such technology has not been insufficiently mastered to be transferred to clinical practice (8). it has also been suggested to display overlapped 3d images using the open source processing software (osirix) on the surgeon’s console screen through tilepro display for identifying the tumor and vascularization sites, and performing a selective arterial clamping. the combination of this technique with the use of an ultrasound probe will allow for an accurate drawing of the neoplasia profile (9). augmented reality techniques, however, are still far from being perfect (10): since augmented reality cannot be used in fine anatomy until adequate technique development and mastering has been accomplished, it is all the more crucial to optimize the use of a modality which is safe and reproducible, such as intraoperative ultrasound, possibly implemented by the contrast enhanced ultrasound (ceus). in our experience, both the easily-handled ultrasound probe and the freedom of movement of the robotic tool have enabled the correct vision of the morphology especially in the deep planes, indicating the best tumor dissection way, reducing time, risk of pseudocapsule rupture during dissection, and ultimately surgical invasiveness (11). a possible limitation of the methodology might be the application of the ultrasound probe to the renal parenchyma after it has been removed from the adipose capsule, especially in case of high renal sclerolipomatosis. despite the easier handling of the ultrasound probe and the more focused dissection of the sclerolipomatosic capsule thanks to the ct scan images, a higher chance of bleeding and a longer operating time indisputably represent major weaknesses. future use of ceus will partly overcome these issues. efficacy of ceus has been demonstrated by several studies: ultrasound scan can be performed without adipose capsule removal, limiting the dissection of the capsule to the precise site of the neoplasia (12). evaluation of renal vascularization by means of ceus has also been described. this methodology assists zeroischemia partial nephrectomy techniques providing several more advantages than the fire-fly technology, including non defatted kidney, good control of medullary blood flow, no toxicity (potential risk of allergic reactions to sodium iodide). rapn was performed with selective clamping and evidence of a nonperfused segment of kidney (occlusion angiography) using intraoperative ceus (13-14). evidence has been reported on the higher safety of selective ischemia than total ischemia (15). to optimize this technique, the use of a robotic ultrasound probe represents a useful tool to detect and define tumors, especially in poorly exophytic small renal mass, which is usually difficult to identify, and to better assess vascularization. it is noteworthy that the use and the easy handling of the ultrasound probe result in a more accurate identification of the neoplasia site, and in the improvement of psychomotor skills, in particular visuospatial skills, enabling a 3d mental image of the tumor with defined profiles, depth and relationship with other structures (16). figure 1. ultrasound robotic probe. figure 2. picture-inpicture vision technology (tilepro). gunelli-the role of intraoperative ultrasound _stesura seveso 09/01/17 10:06 pagina 312 the ability to build a mental image of the neoplasia improves both accuracy and awareness of the surgeon’s gesture, consequently optimizing execution time, reducing warm ischemia time (wit), and facilitating se, partly compensating the lack of force feedback, which is still a major limitation in robotic technology. conclusions the use of a robotic ultrasound probe has allowed easier identification of small, mostly endophytic neoplasias, better anatomical approach, shorter ischemic time, reduced risk of pseudocapsule rupture during dissection and easier enucleation in cases performed without clamping. reduced wit and intraoperative ultrasound allowed accurate excision with sparing of normal parenchyma in an nss perspective. ultrasound methodology using contrast medium will be the natural evolution of intraoperative ultrasound in mininvasive robotic surgery. the major oncological and function sparing results are obtained through the combination of the benefits derived from all available imaging techniques: drop-in ultrasound probe for identifying and mentally reconstructing the neoformation, ceus for reducing time and avoiding bleeding in case of sclerolipomatosis, fire-fly for an intuitive evaluation of the exact ischemia area, and virtual reality in the near future. interestingly, such ultimate technologies have not succeeded in superseding the human being: rather, in this way greater importance is conveyed to the surgeon himself who employs such techniques for a more comprehensive 3d mental vision which includes also depth. references 1. carini m, minervini a, masieri l, et al. simple enucleation for the treatment of pt1a renal cell carcinoma: our 20-year experience. eur urol. 2006; 50:1263-1271. 2. alenezi a, motiwala a, eves s, et al. robotic assisted laparoscopic partial nephrectomy using contrast-enhanced ultrasound scan to map renal blood flow, int j med robot. 2016 mar 7. doi: 10.1002/rcs.1738 3. longo n, minervini a, antonelli a, et al. simple enucleation versus standard partial nephrectomy for clinical t1 renal masses: perioperative outcomes based on a matched-pair comparison of 396 patients (record project) ejso 2014; 40:762-768. 4. rogers cg, laungani r, bhandari a, et al. maximizing console surgeon independence during robot-assisted renal surgery by using the fourth arm and tilepro. j endourol. 2009; 23:115-121. 5. benway bm, wang aj, cabello jm, bhayani sb. robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. eur urol. 2009; 55:592-599. 6. kaczmarek bf, sukumar s, kumar rk, et al. comparison of robotic and laparoscopic ultrasound probes for robotic partial nephrectomy. endourol. 2013; 27-9:1137-1140. 7. hughes-hallett a, mayer ek, pratt p, et al. the current and future use of imaging in urological robotic surgery: a survey of the european association of robotic urological surgeons. int j med robotics comput assist surg. 2015; 11:8-14. 8. cheung cl, wedlake c, moore j, et al. fused video and ultrasound images for minimally invasive partial nephrectomy: a phantom study. med image comput comput assist interv. 2010; 13:40815. 9. furukawa j, miyake h, tanaka k, et al. console-integrated realtime three-dimensional image overlay navigation for robot-assisted partial nephrectomy with selective arterial clamping: early singlecentre experience with 17 cases. int j med robotics comput assist surg. 2014; 10:385-390. 10. hughes-hallett a, pratt p, mayer e, et al. using preoperative imaging for intraoperative guidance: a case of mistaken identity. int j med robot. 2016; 12:262-7. 11. kaczmarek bf, sukumar s, petros f, et al. robotic ultrasound probe for tumor identification in robotic partial nephrectomy: initial series and outcomes. int j urol. 2013; 20:172-176. 12. curtiss km, ball mw, gorin ma, et al. perioperative outcomes of robotic partial nephrectomy for intrarenal tumors. j endourol. 2015; 29:3. 13. rao ar, gray r, mayer e, et al. occlusion angiography using intraoperative contrast-enhanced ultrasound scan (ceus): a novel technique demonstrating segmental renal blood supply to assist zero-ischaemia robot-assisted partial nephrectomy. eur urol. 2013; 63:913-919. 14. alenezi a, karim o. role of intra-operative contrast-enhanced ultrasound (ceus) in robotic-assisted nephron-sparing surgery. j robotic surg. 2015; 9:1-10. 15. gill is, patil mb, de castro abreu al, et al. zero ischemia anatomical partial nephrectomy: a novel approach. j urol. 2012; 187:807-815. 16. nicholls d, sweet l. psychomotor skills in medical ultrasound imaging an analysis of the core skill set. j ultrasound med. 2014; 33:1349-135. 313archivio italiano di urologia e andrologia 2016; 88, 4 the role of intraoperative ultrasound in small renal mass robotic enucleation correspondence roberta gunelli, md massimo fiori, md cristiano salaris, md umberto salomone, md marco urbinati, md vici alexia, md teo zenico, md urology unit, forlì hospital, romagna local health service, forlì, italy mauro bertocco, md radiology unit, forlì hospital. romagna local health service, forlì, italy gunelli-the role of intraoperative ultrasound _stesura seveso 09/01/17 10:06 pagina 313 stesura seveso 127archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. american urological association (aua) white paper (4) determined that transrectal ultrasound guided biopsy (trusbx) is associated with 5 to 7% of risk of infection and 2 to 4% of hospital admission despite giving prophylactic antibiotics. for the last decade, transperineal trus guided prostate biopsy (ttpb) is gaining popularity in the diagnosis of prostate cancer (5). as there is no intrusion of gastrointestinal or urogenital tract, ttpb is relatively considered a clean procedure. there is an ample published evidence that ttpb carried a very low risk of infection and hospital re-admission rate as compared to trusbx (6-8). ttpb is mostly performed under general anaesthesia but some centres have even reported under local anaesthesia (9). similarly, there is an increasing evidence that multiparametric magnetic resonance imaging (mpmri) of prostate can helps diagnosing high risk prostate cancer and decreases number of unnecessary biopsies (30). in order to increase cancer detection rate, concept of mpmri detected suspicious areas were targeted with transrectal ultrasound guidance biopsy (10). transperineal mpmrius fusion biopsy has advantage of detecting more cancers in anterior prostate as compare to transrectal mpmri-us fusion biopsy (11). as for as targeted or systematic biopsy is concerned, although mpmri has highest detection rate of clinically significant prostate cancer, combination of targeted and systematic mpmri-us fusion transperineal biopsy are still required (12, 13). in spite of highest detection rate, mpmri may still miss 8-24% of clinically significant prostate cancer (cspca) if we compare total foci detected on prostatectomy specimen with mpmri detected lesions (14, 15). in this prospective study we will report our experience of first hundred patients with mpmri-us fusion transperineal prostate biopsy under general anaesthesia. primary aim of this study is to detect infectious complications and cancer detection rate. the ultimate goal is to reduce infectious complications, increase detection rate of cspca and reduce unnecessary biopsies. materials and methods this prospective study was approved by office of research assistant (ora) an institutional review board of king background: post-biopsy urosepsis is a major concern for patient morbidity and cost. trasperineal biopsy is reported to have less complications and higher detection rate of clinically significant prostate cancer (cspca). objectives: to determine the diagnostic efficacy and safety of transperineal prostate biopsy in patients with elevated prostatic specific antigen (psa). material and methods: a prospective study included men with elevated psa > 3 ng/ml and previous negative biopsy from january 2018 to april 2019. all patients had multiparametric magnetic resonance imaging (mpmri) and suspicious lesions reported as prostate imaging reporting and data system (pirads) score version 2. average twelve systematic and two targeted cores were biopsied under general anaesthesia. patients received single dose of antibiotic prebiopsy. results: 100 consecutive patients having median age 64.0 years and median psa of 6.1ng/ml were included for mpmri-us fusion transperineal biopsies. cancer detection rate was 45% (targeted 38% and systematic 22%) and cspca were detected in 75.55% (targeted 86.84% and systematic 59.09%). mri-us fusion targeted biopsies detected 63.88% cspca in pirads 5, 33.33% in pirads 4 and 5.88% in pirads 3 lesions. psa > 10 (p = 0.012), psa density > 0.15 (p = 0.0002), and pirads 5 (0.0001) were significantly associated with pca. factors like age (0.0001), initial psa (0.022) and psa density (0.006) were significant on univariate analysis while age (0.0001) was significant on multivariate analysis. there was no case of urinary tract infection. conclusions: transperineal prostate biopsy is safe and effective in diagnosing cspca. there is no risk of sepsis and major complications. key words: multiparametric mri; transperineal; urosepsis; targeted biopsy; systematic biopsy. submitted 19 october 2020; accepted 28 december 2020 introduction prostate cancer (pca) is the most common solid cancer in men and third leading cause of death in developed world (1). traditionally, pca is diagnosed with transrectal ultrasound guided biopsy (trusbx) in a patient with high prostatic specific antigen (psa) and or abnormal digital rectal examination. however, most studies (2, 3) and diagnostic efficacy and safety of transperineal prostate targeted and systematic biopsy: the preliminary experience of first 100 cases shahbaz mehmood, khalid ibraheem alothman, abdulaziz alwuhaibi, samia mohamed alhashim king faisal specialist hospital & research center, riyadh, ksa. doi: 10.4081/aiua.2021.2.127 summary archivio italiano di urologia e andrologia 2021; 93, 2 s. mehmood, k. ibraheem alothman, a. alwuhaibi, s. mohamed alhashim 128 faisal specialist hospital & research centre riyadh. informed written consent was taken from every patient before mri-us fusion transperineal biopsy. from january 2018, we converted to transperineal mri-us fusion prostate biopsy from trusbx in all patient with elevated psa and suspicious mpmri. between january 2018 and july 2019, an hundred consecutive patients were recruited prospectively for transperineal prostate biopsy. all patients who had high psa > 3.0 ng/ml with reference to age and previous negative conventional biopsy were included and subjected to pre biopsy multiparametric mri (mpmri) by our dedicated uro-radiologist. patients in whom mri was contraindicated or refused by patients either for mpmri or for transperineal biopsy were excluded from study. patient in whom normal mpmri [< prostate imaging reporting and data system (pirads) score 3] and high psa were also included for systematic biopsy. mpmri and biopsy protocol all patients underwent pre biopsy mpmri of prostate. mri images were reviewed by our dedicated uro-radiologist and reported with pirads version 2 (16). these mpmri images were stored in hospital computer icis network and imported for fusion with real-time trus via localized network system. mri/us fusion-guided biopsy was performed with the biojet fusion system and software (d&k technologies, barum, germany). a minimum of one and preferably 2-4 cores were taken from each target lesion. a systematic 12 core transperineal biopsies were performed in every patient after targeted biopsy. all patients received only single one-gram cephazolin intravenously at the time of induction of general anaesthesia and procedure was performed under dorsal lithotomy position. patients were only given analgesics in the form paracetamol and no oral postbiopsy antibiotics. biopsies were done by a single urologist who had an experience in transperineal mpmri-us fusion prostate biopsy. outcome we investigated the clinical safety in term of complications like urinary tract infection, sepsis, hospital admission rate, urinary retention, pain and perineal hematoma. moreover, overall cancer detection and clinically significant prostate cancer detection rate in targeted and systemic biopsies were analysed. a clinically significant prostate cancer was defined as gleason score of ≥ 7, gleason score ≥ 2 positive cores, and bilateral cancer on prostate biopsy (17). statistical analysis analysis of patient demographics along with clinical and pathologic variables using descriptive statistics was performed. fisher’s exact test and chi-square test were used for statistical analysis for categorical variables and student’s t-test for continuous variable and are specified as percentage. statistical analysis was done using the sas software package, version 9.4 (statistical analysis system, sas institute inc., cary, nc, usa). univariate logistic regression analysis was used to determine the association between baseline patient characteristics like age, body mass index (bmi), psa, psa density and detection of pca. multivariable regression analysis was used to investigate the association between pca detection and variables which were significant in univariate regression model. a p-value of < 0.05 was considered statistically significant. results between january 2018 and june 2019, 100 consecutive patients with clinically and biochemically suspected for pca were recruited for transperineal mpmri-us fusion prostate biopsy. median age of patients was 64.0 (60.072.0) and median initial psa and psa density were 6.1 (4.8-11.5) ng/ml and 0.12 (0.10-0.27) ng/ml2 respectively. mean time from mpmri to transperineal targeted biopsy was 4.1 ± 3.6 months. average two targeted and 12 systematic biopsies were taken in every patient. a total of 45 patients (45.0%) were diagnosed as prostate cancer. among these, 22 patients were diagnosed as cancer on systematic biopsy while 38 patients were found to have cancer on targeted biopsy. similarly, detection rates of cspca were 13/22 patients (59.09%) in systematic biopsy while 33/38 patients (86.84%) were in targeted arm and 34/45 patients (75.55%) in combination. systematic biopsy detected more (10%) insignificant prostate cancer than targeted biopsy (5%). among 45 patients, 16 patients had a prostate cancer diagnosed on both systematic and targeted biopsy and 3 of them had discordant gleason score between systematic and targeted biopsies and these patients were upgraded to targeted biopsy cores because of gleason score. similarly, 22 (22%) patients were exclusively diagnosed on targeted biopsy while systematic biopsy diagnosed exclusively 7 (7.0%) patients. prostate cancer detection and mpmri pirads score among mpmri and its reporting on the basis of pirads version 2, 20 patients (20.0%) without suspicious lesion on mpmri (pirads < 3) and high psa, systematic biopsies revealed none of the patient with prostate cancer; 17 (17.0%) patients had pirads 3, targeted biopsies detected only 2 patients of whom one cancer of clinically significant and one with insignificant pca while systematic biopsies confirmed 3 cancer patients, of whom only one patient was having cspca; 27 patients (27.0%) had pirads 4 lesions, targeted biopsies diagnosed 11 cancer patients (40.74%), of whom 3 had gs 6, 6 gs 3+4, and 2 gs 4+3 while systematic biopsies detected 6 patients (18.51%), of whom 4 had gs 6 and 2 gs 3+4; lastly 36 patients (36.0%) were reported as pi-rads 5, targeted biopsies detected 25 patients (69.44%) cancer, of whom 2 patients had gs 6, 6 gs 3+4, 3 gs 4+3, 3 gs 8, 9 gs 9, and 2 gs 10 while systematic biopsies diagnosed cancer in 14 patients (38.88%), of whom 4 patients had gs 6, 3 gs 3+4, one gs 4+3, 2 gs 8, 2 gs 9, and 2 with gs 10. a total of 8 patients had prior negative prostate biopsy with conventional trusbx, three (37.5%) were diagnosed as cancer on transperineal mpmri-us fusion biopsy. all 3 patients were having cspca, found in anterior prostate and none had cancer diagnosed on systematic biopsy as shown in table 1. we categorised psa into < 4, 4-10 and > 10 ng/ml and found that higher the psa, more patients with pca were diagnosed (p = 0.0127). similarly, psa density > 0.15 was significantly associated with pca as in table 2. in order to identify factors associated with prostate cancer, univariate logistic regression analysis was done. factors like age, initial psa and psa density were significant associated with prostate cancer. when these significant factors were analysed by multivariate regression analysis, only age was the significant factor for pca as in table 3. transperineal biopsy and complications in our series of 100 cases of mpmri-us fusion tpbx, few minor and no major complication was reported following tpbx. five patients (5.0%) presented with urinary retention in emergency room; 3 of them were already having lower urinary tract symptoms pre biopsy and taking alpha blocker. these patients had significantly greater mean prostatic volume (70.2 cm3) than patient who did not develop (49.8 cm3) (p = 0.024). similarly, more systematic biopsy cores (15.5) than patients who did not develop retention (12.0) (p = 0.012). urine cultures were negative in these patients. all had temporary catheterization, of whom 4 had successful trial without catheter and one ended up transurethral resection of prostate. almost all patient had mild temporary hematuria which settled down in 48-72 hours while complaint of hematospermia remained for 2-3-month post biopsy. temporary skin bruising was noted in almost all patients. all patients received single intravenous dose of antibiotics at induction of anaesthesia. none of patient received postoperative oral antibiotics. most importantly, there was not a single case of urosepsis who needed hospital admission. discussion traditionally, psa has been used for prostate cancer screening and trus guided 10-12 cores systematic biopsy was considered a diagnostic method for prostate cancer for more than two decades. however, this diagnostic method no doubt detects prostate cancer but also detect insignificant prostate cancer which leads to over diagnosis. therefore, systematic biopsies have low sensitivity and tend to diagnose more insignificant pca (18). in order to improve detection of clinically significant pca and reduce rate of negative biopsies, mpmri targeted biopsies has been reported a high sensitivity and specificity in many studies (19, 20). pirads version 2 categories were assigned prospectively to all lesions in our series. this system was established in 2012 and updated in 2014 as pirads version 2. pirads v2 dictates that scores 3-5 lesions should be subjected to mri image guided targeted biopsies and found to have excellent detection rate for pca and cspca (21, 22). in our study, we found highest overall pca (40.74% & 69.44%) and cspca (33.33% & 63.88%) detection rate for pirads 4 & 5 respectively. twenty patients with pirads score < 3 with high psa > 4 underwent systematic biopsies, all turned out to be negative. similarly, in our series with relatively low rate of pca detection, mpmri-us fusion biopsies diagnosed cancer in 45.0% of the patients; 75.55% of these cancers were clinically significant, and targeted biopsies alone detected 33/80 (41.25%) of cspca. moreover, mri-us fusion targeted biopsies missed seven cases, including two having cspca which were diagnosed on systematic biopsies. this stresses the essentiality of systematic cores during prostate biopsy. there are inconsistent results in detection rates of targeted and systematic biopsies. one of the prospective study of mri/us fusion targeted versus concurrent systematic transperinel biopsy showed that detection rate of cspca was higher in systematic biopsy arm compared to targeted biopsy 57.1% vs 48.0%, p = 0.088 (23). in contrast valerio et al. performed a systemic review on 15 studies and found a consistent results that mri-us fusion targeted biopsies diagnosed more cspca (median: 33.3% vs 23.6%) compared to conventional random biopsy technique and even mri-us fusion targeted biopsies detect cspca (median: 9.1%; range: 5-16.2%) that would have been missed by conventional biopsy (24). in our series, we had only eight cases with high psa and prior negative conventional trus guided biopsies. of whom 3 cases diagnosed with cspca on mri-us fusion targeted biopsy and all were anteriorly located suggesting the necessity of mri-us fusion targeted transperineal 129archivio italiano di urologia e andrologia 2021; 93, 2 transperineal mpmri-us fusion prostate biopsy table 1. pi-rads score and pca detection rate. variables total systematic biopsy p-value targeted biopsy p-value benign cispca cspca benign cispca cspca pirads < 3 20 20 0 0 20 0 0 pirads 3 17 14 02 01 0.0214 15 01 01 < 0.0001 pirads 4 27 22 03 02 16 02 09 pirads 5 36 22 04 10 11 02 23 prior negative biopsy 08 08 0 0 05 0 03 pi-rads: prostate imaging reporting and data system; pca: prostate cancer, cispca: clinical insignificant prostate cancer; cspca: clinically significant prostate cancery. table 2. psa, psa density and overall malignancy rate. variables total benign malignant pvalue psa < 4 11 9 2 4-10 60 36 24 0.0127 > 10 29 10 19 psa density <= 0.15 66 45 21 0.0002 > 0.15 34 10 24 psa: prostate specific antigen. table 3. univariate and multivariate analysis of variables for overall detection of prostate cancer. variables univariate analysis multivariate analysis or 95%ci p value or 95% ci p value age 1.181 1.097-1.272 < 0.0001 1.193 1.098-1.295 0.0001 bmi 1.018 0.921-1.124 0.7318 initial psa 1.071 1.010-1.136 0.0228 0.947 0.868 -1.033 0.5127 prostate vol. 0.996 0.979-1.014 0.6934 psa density 109.41 3.761->999.99 0.0063 500.29 0.695–>999.99 0.0641 psa: prostate specific antigen; od: odd ratio; bmi: body mass index; vol.: volume; ci: confidence interval. archivio italiano di urologia e andrologia 2021; 93, 2 s. mehmood, k. ibraheem alothman, a. alwuhaibi, s. mohamed alhashim 130 approach for prostate biopsy in these anterior located lesions. similarly, d'agostino et al. (25) found that mri-us fusion targeted biopsy is safe and highly accurate for diagnosing cspca especially in patients with prior negative trus guided prostate biopsy in their 155 patients. the primary objective of this study was to determine diagnostic efficacy and safety of transperineal mpmri-us fusion prostate biopsy. from safety perspective, we have not found a single case of urosepsis in our series. five patients developed urinary retention, received temporary catheterization and one of them ended up turp as he was on alpha blocker and having preoperative lower urinary tract symptoms. similarly, vyas et al. (26) found a similar result in relatively large series. there was not a single case of urosepsis and 1.7% of cases developed temporary urinary retention post transperineal biopsies. it is well recognised that infectious complications and after trusbx is steadily increasing worldwide. multidrug resistant organisms are also increasing due to repeated use of antibiotics (27, 28) lack of infectious complications makes transperineal prostate biopsy alternative to transrectal biopsy. transperineal biopsy should be considered a clean procedure as neither gastrointestinal nor urinary tract is traversed. similarly, pepe et al. (31) presented the morbidity and clinical complications of transperinal biopsy in 3000 patients and found that complications are directly related with number of biopsy cores taken our study is strengthened because of its prospective nature, single institution and single surgeon performed the biopsy. there are also limitations of our study. first, there was no control arm like patients with systematic trus guided non fusion biopsies. although mpmri reporting were done by our dedicated uro-radiology team but mpmri reporting and practical use of mri for prostate biopsies obviously needs a learning curve (29). moreover, this study is limited due to nonvalidation of biopsy results with histopathological finding of whole gland prostatectomy specimen. although we have got cspca and index lesions correspond to targeted biopsy results, it cannot be said with certainty that all cspca has been detected without histological analysis of whole gland specimens. next, the number of patients in our study was relatively low to accurately determine the cancer detection rate. in addition, transperineal prostate biopsy is safer than transrectal biopsy with regards to lower risk of sepsis and hospital re admission. although some centres have published transperieal biopsy under local anaesthesia successfully but this is a disadvantage in our series by using general anaesthesia. conclusions transperineal mpmri-us fusion prostate biopsy is highly accurate and safe in diagnosing clinically significant prostate cancer. there is no risk sepsis or major complications. references 1. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 2. loeb s, carter hb, berndt si, et al. complications after prostate biopsy: data from seer-medicare. j urol. 2011; 186:1830. 3. bennett hy, roberts mj, doi sa, et al. the global burden of major infectious complications following prostate biopsy. epidemiol infect. 2016; 144:1784-91. 4. liss ma, ehdaie b, loeb s, et al. an update of the american urological association white paper on the prevention and treatment of the more common complications related to prostate biopsy. j urol. 2017; 198:329. 5. davis p, paul e, grummet j. current practice of prostate biopsy in australia and new zealand: a survey. urol ann. 2015; 7:315-9. 6. grummet j, pepdjonovic l, huang s, et al. transperineal vs. transrectal biopsy in mri targeting. transl androl urol. 2017; 6:368. 7. roberts mj, bennett hy, harris pn, et al. prostate biopsy-related infection: a systematic review of risk factors, prevention strategies, and management approaches. urology. 2017; 104:11-21. 8. pepdjonovic l, tan gh, huang s, et al. zero hospital admissions for infection after 577 transperineal prostate biopsies using singledose cephazolin prophylaxis. world j urol. 2017; 35:1199. 9. murphy dg and grummet jp. planning for the post-antibiotic era why we must avoid trus-guided biopsy sampling. nat rev urol. 2016; 13:559-60. 10. d'amico av, tempany cm, cormack r, et al. transperineal magnetic resonance image guided prostate biopsy. j urol. 2000; 164:385-7. 11. pepe p, garufi a, priolo gd, et al. multiparametric mri/trus fusion prostate biopsy: advantages of a transperineal approach. anticancer res. 2017; 37:3291-3294. 12. hansen nl, kesch c, barrett t, et al. multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image fusion guided transperineal prostate biopsy in patients with a previous negative biopsy. bju int. 2017; 120:631-8. 13. radtke jp, schwab c, wolf mb, et al. multiparametric magnetic resonance imaging (mri) and mri-transrectal ultrasound fusion biopsy for index tumor detection: correlation with radical prostatectomy specimen. eur urol. 2016; 70:846-53. 14. tan n, margolis dj, lu dy, et al. characteristics of detected and missed prostate cancer foci on 3-t multiparametric mri using an endorectal coil correlated with whole-mount thin-section histopathology. ajr am j roentgenol. 2015; 205:w87-92. 15. le jd, tan n, shkolyar e, et al. multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. eur urol. 2015; 67:56976. 16. seo jw, shin sj, taik oh y, et al. pi-rads version 2: detection of clinically significant cancer in patients with biopsy gleason score 6 prostate cancer. ajr am j roentgenol. 2017; 209:w1-9. 17. matoso a, epstein ji. defining clinically significant prostate cancer on the basis of pathological findings. histopathology. 2019; 74:135-145. 18. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and treatment of clinically localised disease. eur urol. 2011; 59:61-71. 19. thompson je, moses d, shnier r, et al. multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. j urol. 2014; 192:67-74. 131archivio italiano di urologia e andrologia 2021; 93, 2 transperineal mpmri-us fusion prostate biopsy 20. arumainayagam n, ahmed hu, moore cm, et al. multiparametric mr imaging for detection of clinically significant prostate cancer: a validation cohort study with transperineal template prostate mapping as the reference standard. radiology. 2013; 268:761-9. 21. zhao c, gao g, fang d, et al. the efficiency of multiparametric magnetic resonance imaging (mpmri) using pi-rads version 2 in the diagnosis of clinically significant prostate cancer. clin imaging. 2016; 40:885-8. 22. rosenkrantz ab, verma s, choyke p, et al. prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a prior negative biopsy: a consensus statement by aua and sar. j urol. 2016; 196:1613-8. 23. hakozaki y, matsushima h, kumagai j, et al. a prospective study of magnetic resonance imaging and ultrasonography (mri/us) fusion targeted biopsy and concurrent systematic transperineal biopsy with the average of 18-cores to detect clinically significant prostate cancer. bmc urology. 2017; 17:117. 24. valerio m, donaldson i, emberton m, et al. detection of clinically significant prostate cancer using magnetic resonance imagingultrasound fusion targeted biopsy: a systematic review. eur urol. 2015; 68:8-19. 25. d'agostino d, mineo bianchi f, romagnoli d, et al. mri/trus fusion guided biopsy as first approach in ambulatory setting: feasibility and performance of a new fusion device. arch ital urol androl. 2020; 91:211-217. 26. vyas l, acher p, kinsella j, et al. indications, results and safety profile of transperineal sector biopsies (tpsb) of the prostate: a single centre experience of 634 cases. bju int. 2014; 114:32-37. 27. loeb s, van den heuvel s, zhu x, et al. infectious complications and hospital admissions after prostate biopsy in a european randomized trial. eur urol. 2012; 61:1110-4. 28. chang dt, challacombe b, lawrentschuk n. transperineal biopsy of the prostate-is this the future? nat rev urol. 2013; 10:690-702. 29. gaziev g, wadhwa k, barrett t, et al. defining the learning curve for multiparametric magnetic resonance imaging (mri) of the prostate using mri-transrectal ultrasonography (trus) fusionguided transperineal prostate biopsies as a validation tool. bju int. 2016; 117:80-6. 30. donato p, morton a, yaxley j, et al. improved detection and reduced biopsies: the effect of a multiparametric magnetic resonance imaging-based triage prostate cancer pathway in a public teaching hospital. world j urol. 2020; 38:371-379. 31. pepe p, aragona f. morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. urology. 2013; 81:1142-1146. correspondence shahbaz mehmood, md assistant consultant urologist shahbazmalik49@gmail.com khalid ibraheem alothman, md (corresponding author) consultant urologist kialothman@gmail.com abdulaziz alwuhaibi, md senior resident urology abdulaziz.a.w@hotmail.com samia mohamed alhashim, md biostatistician samia@kfshrc.edu.sa king faisal specialist hospital & research center riyadh (ksa) stesura seveso archivio italiano di urologia e andrologia 2016; 88, 166 case report transperitoneal laparoscopic treatment for recurrence of a giant multilocular prostatic cystadenoma: a case report and review of the literature davide abed el rahman 1, tiziano zago 1, giuseppe verduci 1, gianpaolo baroni 1, marco lorenzo berardinelli 1, umberto pea 2, eugenio morandi 3, marco castoldi 3 1 urology department, “guido salvini” hospital, asst rhodense, rho (mi), italy; 2 urology department, “fatebenefratelli e oftalmico” hospital, asst fatebenefratelli sacco, milano, italy; 3 surgery department, “guido salvini” hospital, asst rhodense, rho (mi), italy. giant multilocular prostatic cystadenomas (gmpc) are very rare benign tumors that originate from the prostate with extensive spread into the pelvis. the lesion may present as large abdominal mass causing obstructive voiding dysfunction and usually not invading adjacent structures. all of the previously reported patients with gmpc underwent open surgery. although the natural history of prostatic cystadenoma remains unknown, complete surgical excision may not always be necessary. we report the case of a 74-year-old male who presented a retrovesical recurrence of prostatic cystoadenoma after 16 years, treated with a laparoscopic approach. to our knowledge this is the first case of laparoscopic management of gmpc. in this article we review the current literature about this rare tumor and discuss the diagnostic and management dilemmas posed by this rare pathologic condition. we believe that physicians should at least be aware of the existence of this disease in the differential diagnosis of pelvic cavity tumours and, considering the benignity of gmpc, they should propose -as firsta minimally invasive approach. key words: cystadenoma; prostate; multilocular; laparoscopy. submitted 11 july 2015; accepted 11 september 2015 summary no conflict of interest declared. and cuboid cells with basally located nuclei and pale cytoplasm. the epithelial cells usually show positive prostatic spe cific antigen (psa) staining (4). different therapeutic approaches can be employed since some authors describe total surgical excision as therapy of choice (5) due to the risk of recurrence in case of partial resection, while many others think that radical surgery is not necessary (6); it is also described a “medical” treatment using gnrh antagonists with excellent results (3). we report the first case – to our knowledge – of laparoscopic treatment for a recurrent giant multilocular prostatic cystadenoma. case report we report the case of a 74 years old patient with an history of hypertension and of laparotomy 16 years before for a prostatic cystoadenoma with diameter of 20 cm completely excised (figure 1), who presented to our hospital complaining hypogastric pain since 3 months associated with obstructive voiding symptoms (weak urinary stream with intermittent flow) and constipation. rectal examination revealed a large elastic mass compressing the right side of the anterior rectal wall. the patient did not report any episode of hematuria, fever or loss of weight. baseline blood parameters at presentation identified a moderately raised c-reactive protein level with a normal renal biochemistry profile and an elevated serum prostate specific antigen (psa) of 20.5 ng/ml. a needle core biopsy showed benign prostatic tissue with no evidence of malignancy. computed tomography (tc) scan showed a 11.6 x 9 x 8 cm multiloculated cystic pelvic mass with a well-defined wall compressing the right side of rectum and with heterogeneous and predominantly peripheral contrast enhancement (figures 2-5). an exploratory laparoscopy performed through 3 trocars (12 mm prerectal right and left and 5 mm in left iliac fossa) and periumbilical camera, revealed, by using a laparoscopic ultrasound probe, a large multiloculated cystic mass arising from pelvic floor until mesosigma origin; the bladder was displaced anteriorly. doi: 10.4081/aiua.2016.1.66 introduction giant multilocular prostatic cistoadenoma is a rare benign tumor of the prostate gland (1, 2); it is usually characterized by large multilocular cysts located between rectum and bladder, attached to the prostate via a pedicle or, rarely, entirely separated from the prostate. it is not always possible to determine the exact point of origin of these multilocular cystic neoplasms because of their large size at the time they are diagnosed. the clinical presentation includes obstructive voiding symptoms such as poor stream, intermittency, sensation of incomplete emptying, acute urinary retention and sometimes constipation symptoms due to mechanical compression of the lower intestine (1, 3). the age of patients ranges from 15 (6) to 80 (1) years. microscopically it is characterized by typical prostatic glands and cysts lined with double layers of columnar el rahman_stesura seveso 08/04/16 11:32 pagina 66 67archivio italiano di urologia e andrologia 2016; 88, 1 giant multilocular prostatic cystadenoma after blunt dissection of the superior part of the cystic mass, we opened it draining more than 150 cc of dense brown liquid, we removed a large dome of the cyst (negative for malignancy at histological examination) and we proceeded with its marsupialization; similar treatment was performed for smaller neighboring cysts. the pathologic findings were consistent with giant multilocular prostatic cystadenoma. at follow up 48 months later, the patient remained free of lower urinary tract symptoms and there were no signs of recurrence. references 1. watanabe j, konishi t, et al. a case of giant prostatic cystadenoma. hinyokika kiyo. 1990; 36:1077-9. 2. maluf hm, king me, et al. giant multilocular prostatic cystadenoma: a distinctive lesion of the retroperitoneum in men. a report of two cases. am j surg pathol. 1991; 15:131-5. 3. datta mw, hosenpud j, et al. giant multilocular cystadenomaof the prostate responsive to gnrh antagonists. urology. 2003; 61:225. discussion, tables and supplementary refe rences are posted on www.aiua.it figure 1. previous prostatic cystadenoma (16 years before). figures 2-5. recurrence of prostatic cystadenoma. 2. 3. 4. 5. correspondence tiziano zago, md (corresponding author) tzago@aogarbagnate.lombardia.it davide abed el rahman, md giuseppe verduci, md gianpaolo baroni, md marco lorenzo berardinelli, md urology department, “guido salvini” hospital, asst rhodense, corso europa, 250 rho (mi), italy umberto pea, md urology department, “fatebenefratelli e oftalmico” hospital, asst fatebenefratelli sacco via g.b. grassi, 74 milano, italy eugenio morandi, md marco castoldi, md surgery department, “guido salvini” hospital, asst rhodense corso europa, 250 rho (mi), italy el rahman_stesura seveso 08/04/16 11:32 pagina 67 181archivio italiano di urologia e andrologia 2018; 90, 3 original paper association between large prostate calculi and prostate cancer cem yucel 1, salih budak 2 1 department of urology, tepecik training and research hospital, izmir, turkey; 2 department of urology, sakarya training and research hospital, sakaraya, turkey. objective: we investigated the relationship between large prostate calculi and prostate cancer (pca) risk. materials and methods: the medical records of 340 patients who received a prostate biopsy at our institution between january 2015 and august 2016 were reviewed retrospectively. of the patients, 82 had large prostatic calculi visualised by transrectal ultrasonography and 88 did not or had scarce prostatic calculi. we divided these patients into two groups: patients with large prostatic calculi (group 1) and patients without prostatic calculi (group 2). these groups were compared according to age, total prostate specific antigen (psa) level, prostate volume, and final pathological diagnosis. results: the mean age of all patients was 61.4 ± 6.2 years, the mean total psa was 12.3 ± 17.4 ng/ml, the mean prostate volume was 41.7 ± 17.6 ml, and the overall cancer detection rate was 31.5%. the cancer detection rates were 41.3% and 22.6% in groups 1 and 2, respectively (p = 0.018). no significant differences in mean age, mean total psa, or mean prostate volume were observed between the groups. conclusions: in the present study, large prostatic calculi were associated with pca. however, more study is needed to examine the relationship between large prostatic calculi and pca in more detail. the effects of particularly large prostate calculi in the development of pca will be a necessary focus of future research. key words: prostatic calculi; prostate cancer; ultrasound; risk factors. submitted 21 january 2018; accepted 21 february 2018 summary no conflict of interest declared. whereas type 2 calculi are larger, multifaceted, and situated mainly in the prostatic ducts (5, 6). larger prostate calculi are reportedly related to clinical prostatitis (5). transrectal ultrasonography (trus)-guided prostate biopsy remains the gold-standard method for diagnosing pca, and prostatic calculi are frequently diagnosed by trus (1, 7). although prostatic calculi are commonly seen in trus-guided prostate biopsy, the relationship between pca and prostatic calculi is unclear. in the present study, we investigated the relationship between large prostate calculi and pca risk. materials and methods the medical records of 340 patients who received a prostate biopsy at our institution between january 2015 and august 2016 were reviewed retrospectively. indications for prostatic biopsy included an abnormal digital rectal examination and/or an elevated serum prostate specific antigen (psa) concentration (≥ 4.0 ng/ml). after informed consent was obtained from patients, all biopsies were taken transrectally with ultrasonographic guidance using a 25 cm, 18 gauge, sidenotch cutting (tru-cut) needle. the biopsy was obtained from patients in the lateral decubitus position with periprostatic nerve blockage. prostatic calculi and prostate volume were measured by trus. prostate volume was calculated using the prostate ellipse formula (0.52 × length × width × height). we defined large prostatic calculi as multiple (≥ 3) or large (≥ 3 mm largest diameter) hyperechoic zones. in the present study, among 340 patients, we included only patients who have large prostate calculi or have not prostate calculi. we excluded patients who have fewer than three prostatic calculi or < 3 mm prostatic calculi (67 cases). we also excluded patients who have chronic diseases (diabetes, hyperlipidemia, hypertension, cardiovascular disease) (49 cases), malignancy (9 cases), psychiatric disorders (9 cases), acute infections (8 cases), a history of urinary tract surgery (15 cases), a prior diagnosis of pca (11 cases) and a history of irradiation (2 cases). a total number of 170 patients were enrolled in this study. patients were divided into two groups, group 1 included 82 patients with large prostatic calculi visualised by trus, whereas group 2 included 88 patients without doi: 10.4081/aiua.2018.3.181 introduction prostatic calculi are presumed to form by precipitation of prostatic secretions and desquamated acinar cells under inflammatory conditions (1). however, the clinical significance of prostatic calculi for evolution of cancer is unknown, immunological and inflammatory reactions may contribute to the carcinogenic process (2). histopathological and molecular biology studies have shown that inflammation of the prostate gland may contribute to the development of prostate cancer (pca) (3). inflammation may affect the development of pca in patients with prostate calculi compared to patients without prostate calculi (4). two kinds of calculi exist in the prostate. type 1 are discrete, multiple small echoes and are usually diffusely distributed throughout the gland, yucel_stesura seveso 03/10/18 09:42 pagina 181 archivio italiano di urologia e andrologia 2018; 90, 3 c. yucel, s. budak 182 prostatic calculi. these groups were compared according to age, total psa level, prostate volume, and final pathological results. we identified the pca detection rates and gleason scores of the two groups. we also compared the patients according to their final pathological diagnosis. statistical analysis the conformity of variables to a normal distribution was assessed with the kolmogorov-smirnov test. descriptive statistics for variables with a normal distribution and categorical variables are shown as means ± standard deviations and percentages, respectively. student’s t test and the chi-square test were used for intergroup analyses of continuous variables. more than two independent averages were compared using analysis of variance and the kruskal-wallis test. data were analysed using spss ver. 22.0 (spss inc., chicago, il, usa), and a p-value < 0.05 was considered significant. results a total of 170 patients participated in this study. the mean age of all patients was 61.4 ± 6.2 years, the mean total psa was 12.3 ± 17.4 ng/ml, the mean prostate volume was 41.7 ± 17.6 ml, and the overall cancer detection rate was 30%. the clinical and demographic characteristics of the study patients are listed in table 1. according to the final pathological diagnosis, in group 1, 18 patients (21.9%) had prostatitis, 31 patients (37.8%) had benign pathology, 33 patients (40.2%) had pca; in group 2, 34 patients (38.6%) had prostatitis, 36 patients (40.9%) had benign pathology and 18 patients (20.5%) had pca (table 2). the gleason score was 6 in 23 (69.7%), 7 in three (9.1%) and ≥ 8 in seven (21.2%) patients in group 1 who were diagnosed with pca; it was 6 in 16 (88.9), 7 in one (5.6%) and ≥ 8 in one (5.6%) patients who were diagnosed with pca in group 2 (table 2). the cancer detection rates were 40.2% and 20.5% in groups 1 and 2, respectively (p = 0.018). no differences in mean age, mean total psa, or mean prostate volume were observed in group 1 compared to group 2. the comparisons of the patients according to their final pathological diagnosis, is summarized in table 3. discussion prostatic calculi are generally detected while performing trus (8). prostate calculi occur during the aging process and may not produce any symptoms (9). the definition of prostatic calculi has not been well described in the literature, so the incidence of prostatic calculi may differ by definition; it is about 30% in histological studies and increases to 71% in radiological-histological correlational studies. prostatic calculi exist in about 99% of autopsy specimens (10). in our study, large prostate calculi were found in 48.2% of participants. a limited number of studies are available on the correlation between pca and calculi (4, 8, 11, 12). griffiths et al. analysed the ultrasound images of 221 patients with diagnosed pca and observed a 63% association between pca and prostatic calculi (11). hwang et al. reviewed the medical records of 417 patients who underwent a trusguided prostate biopsy and reported that prostatic calculi were found more often in patients diagnosed with pca (4). they also reported that prostatic calculi are correlated with a higher gleason score when pca is proven. in another study, smolski et al. found that 78.1% of peripheral zone calculi were associated with pca (8). this percentage was higher than in our study. we did not assess the prostate zones separately. a specific zone assessment of the prostate may be more useful for detecttable 1. clinical and biological characteristics of all patients (n = 170). variables mean (sd) age (years) 61.4 (± 6.2) psa (ng/ml) 12.3 (± 17.4) prostate volume (ml) 41.7 (± 17.6) pathology (n, %) prostatitis 52 (30.6) bph 67 (39.4) pca 51 (30.0) gleason score (n, %) 6 39 (76.4) 7 4 (7.6) ≥ 8 8 (15.6) psa: prostate specific antigen, bph: benign prostatic hyperplasia, pca: prostate cancer table 2. clinical variables for patients with and without prostatic calculi. variables group 1 (n = 82) group 2 (n = 88) p value (with calculi) (without calculi) age (years) 60.5 (± 8.1) 61.8 (± 7.2) 0.946 psa (ng/ml) 12.8 (± 15.1) 11.3 (± 7.8) 0.439 prostate volume (ml) 42.5 (± 10.7) 39.2 (± 18.5) 0.345 pathology (n, %) prostatitis 18 (21.9) 34 (38.6) 0.438 bph 31 (37.8) 36 (40.9) 0.790 pca 33 (40.2) 18 (20.5) 0.018 gleason score (n, %) 6 23 (69.7) 16 (88.9) 0.289 7 3 (9.1) 1 (5.6) 0.302 ≥ 8 7 (21.2) 1 (5.6) 0.041 psa: prostate specific antigen, bph: benign prostatic hyperplasia, pca: prostate cancer table 3. comparisons of patients according to the final pathologic diagnosis. variables prostatitis bph pca p value (n = 52) (n = 67) (n = 51) age (years) 58.8 (± 7.3) 60.2 (± 6.6) 65.2 (± 7.2) 0.686 psa (ng/ml) 8.7 (± 9.1) 7.9 (± 8.5) 21.7 (± 12.3) < 0.01 prostate volume (ml) 40.2 (± 9.4) 43.6 (± 11.2) 40.7 (± 8.1) 0.867 large prostate calculi (n, %) 18 (34.6) 31 (46.2) 33 (64.7) < 0.01 absent prostate calculi (n, %) 34 (65.3) 36 (53.7) 18 (35.2) < 0.01 psa: prostate specific antigen, bph: benign prostatic hyperplasia, pca: prostate cancer yucel_stesura seveso 03/10/18 09:42 pagina 182 ing pca. contrary to the aforementioned studies, woods et al. analysed the histological material of 266 radical prostatectomy and 10 cystoprostatectomy cases and suggested that prostatic microcalculi were less commonly associated with pca (12). in our study we observed that pca was more common in patients with large prostatic calculi, and, similar to hwang et al., we found that prostatic calculi were correlated with high-grade pca. chronic inflammation damages the prostate cells and promotes proliferation, so pca can develop from the damaged cells. mutations in prostate cells also contribute to the development of pca. although the relationship between inflammation and pca remains unclear, antiinflammatory drugs (e.g., aspirin) potentially reduce the incidence of pca and pca-specific mortality (13). a meta-analysis of 11 studies revealed a 60% increased risk of pca in patients with prostatitis (14). contrary to the aforementioned studies, the reduction by dutasteride of prostate cancer events trial reported that patients with inflammation in an initial negative biopsy had a lower risk of pca than those who received a repeat prostate biopsy. inflammation can elevate psa levels, and these patients are selected more often for repeat prostate biopsy; thus, these patients have a lower risk of being diagnosed with pca (15). in our study, patients with large prostatic calculi tended to have higher psa levels than patients who had no prostatic calculi, but this difference was not significant. the prostate cancer prevention trial (pcpt) found that pca, in particular high-grade pca, was more common in patients with chronic inflammation (16). in the present study, we observed that pca was more common in patients with large prostatic calculi. although our study had a small sample size, we achieved similar results to those reported in the pcpt trial. conclusions prostate calculi are a common finding on ultrasonographic evaluation of the prostate, but their role in the development of pca is not fully understood. in the present study, large prostatic calculi were associated with pca. however, more work is needed to examine the relationship between large prostatic calculi and pca in more detail. the effects of particularly large prostate calculi in the development of pca will be a focus of further research. references 1. park sw, nam jk, lee sd, et al. are prostatic calculi independent predictive factors of lower urinary tract symptoms? asian j androl. 2010; 12:221-226. 2. coussens lm, werb z. inflammation and cancer. nature. 2002; 420:860-867. 3. palapattu gs, sutcliffe s, bastian pj, et al. prostate carcinogenesis and inflammation: emerging insights. carcinogenesis. 2005; 26:1170-1181. 4. hwang ec, choi hs, im cm, et al. prostate calculi in cancer and bph in a cohort of korean men: presence of calculi did not correlate with cancer risk. asian j androl. 2010; 12:215-220. 5. geramoutsos i, gyftopoulos k, perimenis p, et al. clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. eur urol 2004; 45:333-338. 6. peeling wb, griffiths gj. imaging of the prostate by ultrasound. j urol. 1984; 132:217-224. 7. lee se, ku jh, park hk, et al. prostatic calculi do not influence the level of serum prostate specific antigen in men without clinically detectable prostate cancer or prostatitis. j urol. 2003; 170:745-748. 8. smolski m, turo r, whiteside s, et al. prevalence of prostatic calculi subtypes and association with prostate cancer. urology. 2015; 85:178-81. 9. hong cg, yoon bi, choe hs, et al. the prevalence and characteristic differences in prostatic calculi between health promotion center and urology department outpatients. korean j urol. 2012; 53:330-334. 10. suh jh, gardner jm, kee kh, et al. calculis in prostate and ejaculatory system: a study on 298 consecutive whole mount sections of prostate from radical prostatectomy or cystoprostatectomy specimens. ann diagn pathol. 2008; 12:165-170. 11. griffiths gj, clements r, jones dr, et al. the ultrasound appearances of prostatic cancer with histological correlation. clin radiol. 1987; 38:219-227. 12. woods je, soh s, wheeler tm. distribution and significance of microcalculis in the neoplastic and nonneoplastic prostate. arch pathol lab med. 1998; 122:152-155. 13. liu y, chen jq, xie l, et al. effect of aspirin and other nonsteroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis. bmc med. 2014; 12:55. 14. dennis lk, lynch cf, torner jc. epidemiologic association between prostatitis and prostate cancer. urology. 2002; 60:78-83. 15. moreira dm, nickel jc, gerber l, et al. baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the reduce study. cancer. 2014; 120:190-196. 16. gurel b, lucia ms, thompson im, et al. chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. cancer epidemiol biomarkers prev. 2014; 23:847-856. 183archivio italiano di urologia e andrologia 2018; 90, 3 prostate calculi and cancer correspondence cem yucel, md meclecuy@hotmail.com department of urology, tepecik training and research hospital, izmir, turkey salih budak, md salihbudak1977@gmail.com sakarya training and research hospital, sakaraya, turkey yucel_stesura seveso 03/10/18 09:42 pagina 183 cop+ed+fisse 2006 31archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.31 surgical treatment remains the most effective option in patients with lower urinary tract obstructive symptoms who did not respond to medical therapy and have moderate to severe symptoms. evaluation of prostate specific antigen (psa) and digital rectal examination (dre) constitute the routine urological evaluations before surgery for benign prostatic hyperplasia (bph) to exclude pca; psa density, psa velocity, free/total psa and psa according to age could be utilized if required. a transrectal ultrasound-guided prostate biopsy is the gold standard to rule out pca in these patients and have been used extensively. neoplastic tissue may not be detected in sample when biopsy is performed with transrectal ultrasound (trus) guidance, even if the psa levels are high or dre findings are positive (11). incidental prostate cancer (ipca) is the diagnosis of pca with histopathological examination of resected prostate tissue, which was previously considered benign. ipca rates after both open prostatectomy (op) and transurethral resection of prostate (turp) have been reported to be vary between 5% and 41% in the literature (3-8). despite normal psa values, dre findings, and normal prostate biopsy results before surgery; ipca is still a challenge for physicians and patients with high expectations. in this study, we aimed to evaluate rate of ipca after benign prostate surgery and to determine if there is a psa cut-off value indicating ipca in turkish population. materials and methods the study protocol was approved by the institutional review board of turkiye yuksek ihtisas training and research hospital (approval number: 15.03.201829620911-929-e.2475). the data of all consequent patients who underwent turp or op with the pre-diagnosis of bph between 2008-2018 were evaluated retrospectively. patients with normal dre and psa levels in preoperative evaluation as well as patients who underwent trus guided prostate needle biopsy prior to surgery due to abnormal dre and/or high serum psa values and were reported to have not pca were included the study. patients who had a history of pca or patients who received any treatment aim: to investigate incidental prostate cancer (ipca) rate and to determine prostate specific antigen (psa) cut-off value indicating pca in patients who underwent surgery by being diagnosed with benign prostatic hyperplasia (bph) clinically or by standard prostate biopsy. methods: data of 317 patients, who underwent transurethral resection of the prostate (turp) or open prostatectomy (op) with pre-diagnosis of bph, were evaluated retrospectively. the examined parameters included patients’ demographics, preoperative serum psa values, digital rectal examination (dre) findings, surgical method, histopathological findings and gleason scores. results: a total of 317 patients were included the study. the median age of patients was 69 years (min: 51-max: 79) and the median psa value was 3.24 ng/dl (min: 0.17-max: 34.9). in 21 patients (6.6%); dre findings were in favor of malignancy, but prostate biopsy resulted as bph. while 281 (88.6%) of the patients underwent turp, 36 (11.4%) underwent open prostatectomy. pca was detected in 21 (6.6%) patients. psa was statistically higher in patients who underwent op compared to patient who underwent tur-p, 5.9 (min: 1.2 max: 27.6, ir: 8.7) vs. 2.8 (min: 0.1-max: 34.9, ir: 4.2) ng/dl, p < .001. the rate of ipca among four psa group was similar (p = 0.46). there was no difference between the rate of ipca in patients younger and older than 70 years, (p = 0.11). please change whole sentence as 'the median psa level was slightly higher in patients diagnosed with bph compared to patients diagnosed with ipca, 3.2 (min: 0.1-max: 34.9) vs. 2.7 (min: 0.3-max: 26.5) ng/dl, p = 0.9. conclusions: ipca still remains an important clinical problem. we were not able to find any correlation of psa and age with incidental pca. key words: incidental; prostate cancer; open prostatectomy. submitted 19 october 2020; accepted 1 december 2020 introduction prostate cancer (pca) is the most commonly diagnosed cancer in men and the most common cause of cancer deaths following lung cancer. according to autopsy studies, the risk of pca in men > 50-year-old is about 30% (1, 2). is there a psa cut-off value indicating incidental prostate cancer in patients undergoing surgery for benign prostatic hyperplasia? summary senol tonyali 1, cavit ceylan 2, erdogan aglamis 3, serkan dogan 4, sedat tastemur 2, mustafa karaaslan 2 1 department of urology, istanbul university istanbul school of medicine, istanbul, turkey; 2 department of urology, university of health sciences, ankara city hospital, ankara, turkey; 3 department of urology, university of health sciences, elazig city hospital, elazig, turkey; 4 department of urology, sancaktepe sehit prof. dr. ilhan varank training and research hospital, istanbul, turkey. archivio italiano di urologia e andrologia 2021; 93, 1 s. tonyali, c. ceylan, e. aglamis, s. dogan, s. tastemur, m. karaaslan 32 due to pca were excluded from the study. the examined parameters included patients’ demographics, preoperative serum psa values, dre findings, surgical method, histopathological findings and gleason scores. the relationship between these parameters and ipca was investigated. tha patients were divided into 4 groups according to psa values: group 1: psa < 2.5 ng/dl, group 2: psa = 2.5-4 ng/dl, group 3: psa = 4.10 ng/dl, group 4: psa > 10 ng/dl. statistical analysis statistical analysis was performed using ibm spss statistical package program v 21.0. continues variables were given in median (minimum-maximum) and categorical variables were given in numbers and percentage. roc curve analysis was used to determine cut-off value for psa. spearman correlation test was performed for the relationship between psa, age and ipca. chi-square test was used to determine the differences between frequencies in two categorical variables. mann-whitney u test was used to compare the age and psa of the patients with and without prostate cancer when there was not a normal distribution after kolmogorov-smirnov test. results a total of 317 patients were included the study. the median age of patients was 69 years (min: 51, max: 79) and the median psa value was 3.24 ng/dl (min: 0.17, max: 34.9). in 21 patients (6.6%) dre findings were in favor of malignancy, but prostate biopsy resulted as bph. while 281 (88.6%) of the patients underwent turp, 36 (11.4%) underwent open prostatectomy. pca was detected in 21 (6.6%) patients (table 1). the gleason scores of the patients with ipca were as follow: g6 (n = 10), g7 (3 + 4) (n = 2), g7 (4 + 3) (n = 1), g8 (n = 2), g9 (n = 3) and g10 (n = 3). four patients with gleason scores > 6 underwent radical prostatectomy. a patient in high-risk group after this radical prostatectomy and a patient with low-surgical performance who had a gleason score > 9 were referred to the oncology clinic for adjuvant hormone therapy and radiotherapy. psa was statistically higher in patients who underwent op compared to patient who underwent tur-p, 5.9 (min: 1.2max: 27.6, ir: 8.7) vs. 2.8 (min: 0.1-max: 34.9, ir: 4.2) ng/dl, p < .001. the rate of ipca among four psa group was similar (p = 0.46). there was no difference between the rate of ipca in patients younger and older than 70 years, (p = 0.11). the median psa level was slightly higher in patients diagnosed with bph compared to patients diagnosed with ipca, 3.2 (min: 0.1-max: 34.9) vs. 2.7 (min: 0.3-max: 26.5) ng/dl, p = 0.9. discussion today, the rate of ipca is still found to be high in patients diagnosed with bph clinically or after prostate biopsy under the guidance of trus. the widespread use of new biopsy techniques such as multiparametric magnetic resonance imaging (mri) targeted biopsy may decrease the rate of ipca. in our study, 6.6% ipca was detected in patients who underwent open prostatectomy or tur-p with the diagnosis of benign prostatic hyperplasia. prostate cancer incidence and cancer-related mortality are more common in european countries than in asian countries (12, 13). the rate of diagnosis of ipca reaches up to 16% in parallel with the increase in life expectancy and might not to be underestimated (5). the use of psa and its derivatives in daily urology practice, the increase in the number of prostate needle biopsy cores and the improvement in technical methods have decreased the rate of ipca cases over the years but it has not been minimalized (5). rohr et al. reported a rate of 15% ipca in 457 turp operations in 1987 and merril et al., reported in their study that the rate of ipca determined by turp gradually decreased between 1980 and 1999. they also reported that ipca rates decreased from 39% to 7% from 1980s to 2000 (14, 15). in a study that emphasized the importance of age-specific psa, ipca was observed in 13% of patients who underwent turp and open prostatectomy, whereas this rate was decreased to 6.3% with age-specific psa assessment (16). in a study by zigeuner et al., it was reported that preoperative dre and psa test combination caused a 50% reduction in the detection rate of ipca (16). in our study, we detected ipca in 6.6% of patients that underwent turp and open prostatectomy. our rate is consistent with the literature and we think that the decrease in the rate of ipca is related to early diagnosis with the advances in diagnostic tests and biopsy techniques we utilized in the light of the technological developments. on the other hand, with increase in life expectancy, it is obvious that ipca that can be newly diagnosed is that was previously named as hidden prostate cancer. perhaps the rate of 19.9% ipca detected by abedi et al. might be the best example of this. this demonstrates that ipca diagnosis rate cannot be minimized and is not constantly reduced (4). the lack of table 1. patient characteristics and comparison of patients with and without incidental prostate cancer. total benign prostate incidental prostate p value (n = 317) hyperplasia (n = 296) cancer (n = 21) median age (years) 69 (51-79) age < 70 years 178 170 8 0.11^ age > 70 years 139 126 13 median psa (ng/dl) 3.2 (0.1-34.9) psa < 2.5 118 (37.2%) 109 9 0.46^ psa: 2.5-4.0 73 (23%) 71 2 psa: 4-10 93 (29.3%) 85 8 psa > 10 33 (10.4%) 31 2 gleason score gleason 3+3 10 (3.15%) gleason 3+4 2 (0.63%) gleason 4+3 1 (0.31%) gleason 4+4 1 (0.31%) gleason 4+5 2 (0.63%) gleason 5+4 1 (0.31%) gleason 5+5 3 (0.94%) gleason 5+3 1 (0.31%) homogeneous study cohorts and inter-racial differences might explain the wide range of this rate in literature. zigeuner et al., reported an ipca of 7.9% in 445 patients who underwent turp or open prostatectomy after transrectal prostate biopsy due to high psa level and/or abnormal dre. the rate of ipca reported in this study is similar to our results, however the inclusion of patients who underwent transrectal prostate biopsy prior to surgery might affect obtaining a low ipca rate (17). in a study conducted by otto et al., 771 patients who underwent turp were retrospectively analyzed and ipca was detected in 11 patients (1.4%). among 11 patients, ten had a (91%) gleason score of 3+3 = 6 and one (9%) patient had a gleason score of 3+4 = 7. of 11 patients with ipca, nine had t1a disease and two had t1b disease. (18). when compared with this study, the rate of ipca was found to be higher in our study. however, in their study, otto et al., only included patients who underwent turp and the mean resected tissue weight was 8.1 g. the amount of prostate sample examined may affect the ratio of ipca. in our study, 47.6% of ipca cases had a gleason score of ≤ 6, which is lower than the rate reported by otto et al. in another study by abedi et al., authors reported higher ipca rates detected via open prostatectomy compared to turp (4). although, ipca ratios detected via open prostatectomy were higher compared to turp in our study, it was not statistically significant. this might be due to the low number of patients in the open prostatectomy group. in pca diagnosis, various methods have been developed to prevent unnecessary repeated biopsies and to detect pca that need to be treated. multiparametric magnetic resonance imaging (mri) fusion biopsy is one of these methods gaining importance day by day (19). several researchers reported that mri-targeted biopsy is superior to standard transrectal ultrasonography (trus)-guided biopsy in detection of pca (20, 21). european association of urology (eau) guidelines favor mri guided biopsy to systematic biopsy in detecting isup grade ≥ 2 pca in the repeated-biopsy setting. however, in biopsy-naïve patients this difference was stated to be less significant (22). in their retrospective multicenter study, porreca et al. investigated the utility of ‘in-bore’ mri prostate biopsy to exclude significant pca in patients with bph scheduled for transurethral laser enucleation of prostate. the authors concluded that including mpmri and mri guided biopsy prior to surgery for bph might lead to low pca and avoid unnecessary standard trus-guided biopsies (23). in our study, prostate biopsy was performed only with conventional trus which might be considered a limitation of our study. incidental pca detection still remains as a troublesome problem for the patients, urologists and the pathologists. according to the collage of american pathologists statement, it was suggested to sample all prostate tissue left behind when t1a pca was detected (8). in routine practice of pathologists, it is not possible to sample all of the turp or open prostatectomy materials. this may cause ipca cases to be overlooked. for this reason, the determination of preoperative clinical parameters that may predict ipca may change the preoperative approach of the urologists, and may also help the pathologists to determine the required pathological sample amount for an accurate examination. however, this may also lead to over diagnosis and over treatment risk. our study is not without limitations. the retrospective nature of our study and the inclusion of patients treated with different surgical methods are the main limitations of our study. in addition, the absence of patients to whom multiparametric mri-targeted biopsy was applied might be another issue. prospective multicenter studies with large patient number comparing standard trus prostate biopsy and new biopsy techniques such as mri-targeted prostate biopsy might improve our knowledge in this topic. conclusions incidental pca detection rate is considerably high in patients undergoing surgery for benign prostatic hyperplasia, which was diagnosed clinically or via standard trus-guided prostate needle biopsy. thus, ipca still remains an important clinical problem. we were not able to find any correlation of psa and age with incidental pca. determination of new parameters that can predict ipca detection and the widespread use of new biopsy techniques such as mri-targeted biopsy may decrease the rate of ipca. references 1. jemal a, murray t, ward e, et al. cancer statistics. ca cancer j clin. 2005; 55:10-30. 2. stangelberger a, waldert m, djavan b. prostate cancer in elderly men. rev urol. 2008; 10:111-119. 3. yoo c, oh cy, kim sj, et al.. preoperative clinical factors for diagnosis of incidental prostate cancer in the era of tissue-ablative surgery for benign prostatic hyperplasia: a korean multi-center review. korean j urol. 2012; 53:391-395. 4. abedi ar, fallah-karkan m, allameh f, et al. incidental prostate cancer: a 10-year review of a tertiary center, tehran, iran. res rep urol. 2018; 10:1-6. 5. stamey ta, kabalin jn, mcneal je. prostate specific antigen in the diagnosis and treatment of adenocarcinoma of prostate. j urol. 1989; 141:1076. 6. voigt s, hüttig f, koch r, et al. risk factors for incidental prostate cancer who should not undergo vaporization of the prostate for benign prostate hyperplasia? prostate. 2011; 71:1325-1331. 7. helfand bt, anderson cb, fought a, et al. postoperative psa and psa velocity identify presence of prostate cancer after various surgical interventions for benign prostatic hyperplasia. urology. 2009; 74:177-183. 8. trpkov k, thompson j, kulaga a, yilmaz a. how much tissue sampling is required when unsuspected minimal prostate carcinoma is identified on transurethral resection? arch pathol lab med. 2008; 132:1313-6. 9. jahn jl, giovannucci el, stampfer mj. the high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the prostate-specific antigen-era. int j cancer. 2015; 137:2795-2802. 10. mcconnell jd. epidemiology, etiology, pathophysiology, and diag33archivio italiano di urologia e andrologia 2021; 93, 1 incidental prostate cancer archivio italiano di urologia e andrologia 2021; 93, 1 s. tonyali, c. ceylan, e. aglamis, s. dogan, s. tastemur, m. karaaslan 34 nosis of benign prostatic hyperplasia. in: walsh pc, retik ab, vaughan jr ed, wein aj, eds. campbell’s urology. 7thed. philadelphia: wb saunders company. 1998, p.1429-52. 11. fernández re, gómez vf, alvarez cl, et al. clinicopathological study of incidental cancer prostate in patients undergoing surgery for symptomatic diagnosis of bph. actas urol esp. 2006; 30:33-37 12. parkin dm, bray f, ferlay j, pisani p. 2005. global cancer statistics. ca cancer j clin. 2002; 55:74-108. 13. landis sh, murray t, bolden s, wingo pa. cancer statistics. ca cancer j clin. 1999; 49:8-31. 14. rohr lr. incidental adenocarcinoma in transurethral resections of prostate. am j surg pathol. 1987; 11:53-8. 15. merril rm, wiggins cl. incidental detection of population based prostate cancer incidence rates trough transurethral resection of the prostate. urol oncol. 2002; 7:213-9. 16. zigeuner re, lipsky k, rieder i, et al. did the rate of incidental prostate cancer change in the era of psa testing? a retrospective study of 1127 patients. urology; 2003; 62:451-5. 17. zigeuner r, schips l, lipsky k, et al. detection of prostate cancer by turp or open surgery in patients with previously negative transrectal prostate biopsies. urology; 2003; 62:883-887. 18. otto b, barbieri c, lee r, et al. incidental prostate cancer in transurethral resection of the prostate specimens in the modern era. adv urol. 2014; 2014:627290. 19. borkowetz a, platzek i, toma m, et al. comparison of systematic transrectal biopsy to transperineal mri/ultrasound-fusion biopsy for the diagnosis of prostate cancer. bju int. 2015; 116: 873-9. 20. kasivisvanathan v, rannikko as, borghi m et al. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med, 2018; 378:1767-77. 21. kasivisvanathan v, stabile a, neves jb et al. magnetic resonance imaging-targeted biopsy versus systematic biopsy in the detection of prostate cancer: a systematic review and meta-analysis. eur urol. 2019; 76:284-303. 22. mottet n, cornford p, van der bergh rcn, et al. eaueanmestroesursiog guidelines of prostate cancer 2020. available at: https://uroweb.org/guideline/prostate-cancer/ 23. porreca a, d'agostino d, vigo m, et al. "in-bore" mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation. arch ital urol androl. 2020; 91:224-229. correspondence senol tonyali, md (corresponding author) senoltonyali@hotmail.com cavit ceylan, md ceylancavit@yahoo.com sedat tastemur, md sedattastemur@yahoo.com department of urology, istanbul university istanbul school of medicine surgery monobloc floor:1, 34104 çapa fatih, istanbul (turkey) mustafa karaaslan, md mustafakaraaslan23@gmail.com erdogan aglamis, md uroloji23@yahoo.com department of urology, university of health sciences, elazig city hospital, elazig (turkey) serkan dogan, md sdogan1907@yahoo.co.uk department of urology, sancaktepe sehit prof. dr. ilhan varank training and research hospital, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2016; 88, 168 case report 3t mr-guided minimally-invasive penile fracture repair giovanni rosi 1*, paolo fontanella 2*, giordano venzi 2, fernando jermini 2, filippo del grande 1 1 radiology department, ospedale regionale di lugano, switzerland. 2 urology department, ospedale regionale di lugano, switzerland. * these authors equally contributed to the development of this paper. we present the case of a 21 year old patient with an incomplete tear of the tunica albuginea occurred after violent masturbation. the diagnostic assessment was performed first clinically, then with ultrasound and with 3 tesla mri. 3 tesla mri, owing to its high resolution, allowed to exactly detect the tear location leading to precise preoperative planning. after adequate diagnosis through imaging and proper planning, we were able to perform a selective minimally invasive surgical approach to repair the lesion. key words: penile fracture; magnetic resonance imaging; minimally invasive penile surgery. submitted 10.august.2015; accepted 13.october 2015 summary no conflict of interest declared. discussion penile fracture is a rare urologic emergency characterized by the rupture of one or both corpora cavernosa, associated with the tear of tunica albuginea. it is difficult to estimate the incidence of penile fractures: a review of 1,600 cases reported in the literature, showed an higher prevalence in asian and middle-eastern countries. vigorous sexual intercourse is considered to be the main cause of penile fractures in the western world. other causes are the following: non-physiologic penile bending, rolling over in bed with an erect penis and sport injuries with flaccid penis. in middle eastern countries the most frequent reported cause of penile fracture is a self-inflicted practice called taghaandan which consists of snapping and bending the erect penis to achieve a rapid detumescence (1). similarly to our case, penile fracture occurs with an audible popping or cracking sound followed by intense pain and rapid detumescence of the broken corpus cavernosus, followed by a briefly delayed generalized penile detumescence. the common clinical presentation of a penile fracture is the so-called "eggplant deformity", (i.e.: asymmetrical swelling of the penis with purple bruises over the entire shaft possibly extending to the scrotum and perineum). hematuria, urethrorrhagia and voiding difficulties are common signs of urethral involvement, which is estimated to be as high as 38% with a prevalence of 20% of urethral bleeding. in order to achieve adequate treatment planning, it is very important to differentiate false ruptures from real ones, as the latter requires surgical treatment. the false rupture is the presence of a hematoma confined in the soft tissues due to rupture of a superficial or deep dorsal vein and not to actual sheaths rupture. the intracavernous hematoma is considered false rupture and needs conservative treatment. ultrasound, cavernosography, retrograde urethrography and mr are the diagnostic imaging tools to assess penile fractures. ultrasound is most commonly used for early diagnosis, to evaluate the integrity of the tunica albuginea, and the presence and dimensions of a hematoma. however, the low sensitivity for small lesions of the tunica albuginea and the high operator dependence are major limitations. retrograde urethrography and cavernosography are rarely performed and have been generally replaced by mr. today, mr represents the gold standard to show the extension and the exact location of the lesions of the doi: 10.4081/aiua.2016.1.68 case report a twenty-one year-old caucasian male presented to our emergency department with an asymmetric penile swelling, penile-scrotal hematoma, and severe localized pain. the patient reported a cracking sound followed by sudden pain and rapid detumescence of the penis after violent masturbation 48 hours before presenting to the emergency room. clinical examination showed a painful and swollen penis, mainly on the right ventral side. purple colored penile skin extended from the proximal penile shaft to right side of scrotum, without association of urethrorrhagia. on clinical examination no significant “gaps” were palpated. an ultrasound exam was performed to evaluate the integrity of the tunica albuginea and the extension of the hematoma. the exam confirmed the presence of a large hematoma extending from the right central-third penile shaft to the region of the glans penis. no clear evidence of discontinuity of the tunica albuginea was detected. in order to plan the best surgical approach, the patient underwent a 3 tesla magnetic resonance (mr) of the penis. the mr showed a tear in the proximal-third of the right ventral tunica albuginea with a large surrounding hematoma in the soft tissues of the right penile shaft. the hematoma appeared to be enclosed between the tunica albuginea, torn, and the overlying buck's fascia, intact. mr findings allowed to approach the lesion directly, suture the sheath tear and drain the hematoma. fontanella_stesura seveso 05/04/16 15:27 pagina 68 69archivio italiano di urologia e andrologia 2016; 88, 1 3t mr-guided minimally-invasive penile fracture repair tunica albuginea, the presence of an intra or extra-cavernous hematoma, and the possible involvement of the corpus spongiosum and the urethra (3). in an uninjured penis, mr doesn’t allow to distinguish the tunica albuginea from buck’s fascia; only by isolate rupture of the tunica albuginea, an hematoma interposes between the two fascia, granting a vision of the two separate layers. surgical treatment is mandatory in cases of rupture of the tunica albuginea and urethral involvement (3). mr plays a key role for treatment planning. high resolution images permit to distinguish a real tunica albuginea rupture, from a false rupture due to a dorsal vein tear or an isolated intracavernous hematoma. in case of real rupture conservative approach often leads to penile curvature and erectile dysfunctions, urethral stricture, and infection of the hematoma (4). in our patient, after detecting the location of the rupture with mr, we opted for a minimally-invasive ventral approach instead of a degloving procedure, to preserve the integrity of the foreskin, avoiding unnecessary circumcision, reducing the risk for necrotic and sensitivity complications. the ventral approach was preferred as it's less traumatic and determines rapid healing, while granting ideal exposure of both the hematoma and the damaged area of tunica albuginea, allowing for proper repair (figure 1). conclusions penile fracture is an uncommon condition that requires accurate diagnosis for treatment planning. high resolution mr imaging provides the key information to offer the best treatment minimizing risks of complications. with high resolution 3 tesla mr imaging, we were able to properly plan and optimally treat, obtaining excellent functional and aesthetic result. references 1. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164:364-6. 2. choi mh, kim b, ryu ja, et al. mr imaging of acute penile fracture. radiographics. 2000; 20:1397-405. erratum in: radio gra phics. 2000; 20:1818. 3. parker ra 3rd, menias co, quazi r, et al. mr imaging of the penis and scrotum. radiographics. 2015; 35:1033-50. 4. lumen n, kuehhas fe, djakovic n, et al. review of the current management of lower urinary tract injuries by the eau trauma guidelines panel. eur urol. 2015; 67:925-9. figure 1. a. upon arrival at emergency department: markedly swollen, purple and painful penis with clinically suspected penile fracture. b. coronal fat suppressed t2 tse (tr/te 6000/120 ms) showing the interruption of the right tunica albuginea consistent with a tear (white arrow). c. intraoperative picture shows the rupture of the right tunica albuginea (black arrow), with a minimal-invasive surgical approach. d. post-surgical control after 14 days shows the penis with regular shape and appearance. correspondence giovanni rosi, md filippo del grande, md ospedale regionale di lugano, radiology department via tesserete 46, 6900 lugano, switzerland paolo fontanella, md (corresponding author) p.fontanella@outlook.com giordano venzi, md fernando jermini, md ospedale regionale di lugano, urology department via tesserete 46, 6900 lugano, switzerland fontanella_stesura seveso 05/04/16 15:27 pagina 69 stesura seveso 373archivio italiano di urologia e andrologia 2021; 93, 3 letter to editor no conflict of interest declared. to the editor, we have been very pleased to read the interesting work proposed by salemi et al. (1) regarding the expression of specific fragments of microrna (mirna), particularly mir-132 and mir-212, as potential key regulators in prostate cancer (pca). as outlined by the authors, the altered expression of mirnas in cancer pathogenesis represents a well-consolidated knowledge in the current literature (2, 3). more specifically, both mir-212 and mir-132 regulate subsets of genes involved in tumor progression in several tumor cell types as pca, proving a central role in tumorigenesis, cell adhesion, and angiogenesis. in addition, a strong association between mir-132 expression and high gleason score pca has been lately depicted. several studies have identified specific mirna expression profiles in the serum of cancer patients, as well as an increased expression of certain mirnas in the blood of patients with metastatic pca compared with non-metastatic pca (4). thus, mirna expression profiles could act as potential biomarkers for pca diagnosis and prognosis. in this context, data achieved by salemi et al. remarked an increased expression of mir-132 and mir-212 in pca tissue compared to control and, by contrast, a reduced expression of mir132 and mir-212 in metastatic lymph node. the intriguing findings obtained by this case are likely to suggest a different biologic behavior between the primary pc and metastatic lymph nodes. recently, we described the outcomes obtained in a real-world setting by the biggest cohort of mcrpc patients undergoing 223-ra radiometabolic treatment in our country and one of the most extensive in the whole of europe (5). the risk of developing metastatic localizations during follow-up ranges from 26% to 38% after primary radical approaches and about 4% of the patients are ex-novo diagnosed with metastatic disease. bone-metastatic pca occurs in up to 90% of mcrpc patients and represents a leading cause of morbidity in these subjects, being associated with significant clinical complications and quality of life impairment. although there is no consensus regarding the very optimal treatment of high-risk or locally advanced pca, in the last years, multi-modal therapy has demonstrated a clinical advantage and many clinical trials are ongoing to evaluate the best clinical therapeutic approach for each patient. thus, there is an urgent need to better understand high-risk pca prognosis using new biomarkers (i.e., histological and molecular genetics patterns), aiming to reach the most appropriate optimization of current treatment strategies to improve outcomes, avoid or postpone complications, and accordingly to enhance the patient's overall quality of life. currently, it is still unequivocal how to best apply them in a real clinical practice setting, particularly in case of decisions concerning treatment sequencing and combination options (6). in general, for mcrpc patients, androgen deprivation therapy with or without chemotherapy was recommended by eau guidelines (7, 8). with the successful application of cytoreductive surgery for metastatic cancers and the signs of progress achieved in surgical and radiotherapy techniques, the role of the cytoreductive prostatectomy approach for mcrpc has gained great interest. as pointed out by the results of our study (9), cytoreductive prostatectomy may have the potential to enhance mcrpc disease control, however, the lack of randomized controlled trials and the low level of evidence in the current literature preclude any firm conclusions on the benefit of cytoreductive strategy in mcrpc and to clearly identify the patients who would benefit most from their primary pca ablation. based on this growing experience and believing in the great potential of the integration of the perspective emerged from molecular findings by salemi et al. with our pca patients cohort, we focus on the opportunity to cross-reference the mir expression analysis in mcrpc enrolled for 223-ra treatment, to evaluate the clinical and prognostic relevance of mir aberrations in this peculiar group of pca patients. more in detail, different groups of patients clustered for multiple pca biological (gleason score, histopathologic and molecular patterns), biochemical (psa, ldh, talp) (10), and clinical features (tnm score, performance status, secondary skeletal burden) could be designed, aiming to assess the precise relation, if any, between mir expression with every single variable. the final goal would consist of the achievement of the most effective treatment sequence possible, relying on the individual potential prognostic value of mir-132 and mir-212 expression in mcrpc patients mariano pontico 1, viviana frantellizzi 2, luca cindolo 3, giuseppe de vincentis 2 1 program in morphogenesis & tissue engineering, department of medico-surgical sciences and biotechnologies, sapienza university of rome, rome, italy; 2 department of radiological sciences, oncology and anatomical pathology, sapienza, “sapienza” university of rome, rome, italy; 3 department of urology, "villa stuart" private hospital, rome, italy. submitted 13 november 2020; accepted 11 january 2021 doi: 10.4081/aiua.2021.3.373 archivio italiano di urologia e andrologia 2021; 93, 3 m. pontico, v. frantellizzi, l. cindolo, g. de vincentis 374 clinical and biomolecular characteristics specific of each patient, in a real patient-centered treatment approach (11). in this direction, it would be very interesting other than useful to assess molecular mirnas patterns of pca bone secondary localizations, investigating whether these peculiar pathological entities act like the lymph nodal ones rather than the primary pca discussed in the case reported by salemi et al., thus respectively showing underor over-expression of mir132 and mir-212. a detailed analytical assessment of these new molecular variables in mcrpc patients could eventually lead to a clinically useful prognostic stratification of which kind of pca patient would rather benefit from a specific treatment strategy, such as 223-ra treatment. the outcomes of molecular mirnas expression assessment in skeletal pca metastases could potentially help to shed light on the role of primary tumor cytoreduction in mcrpc and its still enigmatic biological causes. several studies are suggesting the existence of a critical interaction between primary tumors, their circulating and disseminated cells, and the development and maintenance of secondary lesions, via a complex connecting network. this tangled connection could justify how primary tumor ablation is demonstrated in many cases to prevent the development of new metastases and even promote their regression in a phenomenon known as the abscopal effect (12, 13). even if the biological mechanisms underlying this hypothesis are not yet known in detail, most of the actual evidence confirm that ablative treatment of the primitive tumor, purposing to reduce the local load of disease, is able to positively influence the biological behavior of secondary locations too, along with their response to systemic therapies. whether these theories apply to all or only specific solid tumors remains still to be determined. in this regard, we hope in the development of further detailed studies with a larger number of pca patients that could definitely lead to many solid achievements, with the purpose to help the determination of peculiar mirna expression profiles for pca, supporting its early diagnosis, stratification, and prognosis clinical workup. references 1. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl. 2020; 92:209-210. 2. hassan o, ahmad a, sethi s, and sarkar fh. recent updates on the role of micrornas in prostate cancer. j hematol oncol. 2012; 5:9. 3. zhang w, edwards a, fan w, et al. mirna-mrna correlation-network modules in human prostate cancer and the differences between primary and metastatic tumor subtypes. plos one. 2012; 7:e40130. 4. chen zh, zhang gl, li hr, et al. a panel of five circulating micrornas as potential biomarkers for prostate cancer. prostate. 2012; 72:144352. 5. frantellizzi v, monari f, mascia m, et al. radium-223 in mcprc patients: a large real-life italian multicenter study. minerva urol nefrol 2020. doi: 10.23736/s0393-2249.20.03808-4. epub ahead of print. 6. frantellizzi v, lazri j, pontico m, et al. bone pain palliation outcomes and possibility of radium-223 re-treatment in mcrpc. arch ital urol androl. 2020; 92:196-199 7. de vincentis g, follacchio ga, frantellizzi v, et al. 223ra-dichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature. aging clinical and experimental research. 2017; 30:677-80. 8. ricci m, frantellizzi v, bulzonetti n, de vincentis g. reversibility of castration resistance status after radium-223 dichloride treatment: clinical evidence and review of the literature. int j radiat biol. 2019; 95:554-561. 9. frantellizzi v, costa r, mascia m, et al. primary radical prostatectomy or ablative radiotherapy as protective factors for patients with mcrpc treated with radium-223 dichloride: an italian multicenter study. clin genitourin cancer. 2020; 18:185-91. 10. de vincentis g, follacchio ga, frantellizzi v, et al. prostate-specific antigen flare phenomenon during 223ra-dichloride treatment for bone metastatic castration-resistant prostate cancer: a case report. clinical genitourinary cancer. 2016; 14:e529-e33. 11. prelaj a, rebuzzi se, buzzacchino f, et al. radium-223 in patients with metastatic castration-resistant prostate cancer: efficacy and safety in clinical practice. oncol lett. 2019; 17:1467-76. 12. abuodeh y, venkat p, kim s. systematic review of case reports on the abscopal effect. curr probl cancer. 2016; 40:25-37. 13. yilmaz mt, elmali a, yazici g. abscopal effect, from myth to reality: from radiation oncologists' perspective. cureus. 2019;11:e3860. correspondence mariano pontico, md mariano.pontico@uniroma1.it program in morphogenesis & tissue engineering, department of medico-surgical sciences and biotechnologies, sapienza university of rome, rome (italy) viviana frantellizzi, md, phd (corresponding author) viviana.frantellizzi@uniroma1.it department of radiological sciences, oncology and anatomical pathology, sapienza, “sapienza” university of rome viale regina elena 324, 00161 rome (italy) luca cindolo, md, phd lucacindolo@virgilio.it department of urology, "villa stuart" private hospital, rome (italy) giuseppe de vincentis, md, phd giuseppe.devincentis@uniroma1.it department of radiological sciences, oncology and anatomical pathology, sapienza, “sapienza” university of rome, rome (italy) 25archivio italiano di urologia e andrologia 2018; 90, 1 original paper comparison of three most frequently used alpha blocker agents in medical expulsive therapy for distal ureteral calculi, result of a retrospective observational study aykut buğra sentürk 1, cemil aydin 1, musa ekici 1, muhammet yaytokgil 2, ali akkoc 3, mehmet murat baykam 1 1 hitit university corum training and research hospital, turkey; 2 rize state hospital, turkey; 3 alanya alattin keykubat university, turkey. purpose: in this study, we compared the effects of three agents frequently used in daily life for medical expulsive therapy. materials and methods: a total of 143 patients meeting the criteria were included in the study. patients were divided into three homogeneous drug groups which were tamsulosin group (n:48), alfuzosin group (n:47) and silodosin group (n:48). the time of stone expulsion, analgesic needs, side effects of the medicine and endoscopic intervention needs of the patients were recorded. results: the rate of stone expulsion was 70.8% (n:34) in tamsulosin group, 70.2% (n:33) in alfuzosin group, and 75% (n:36) in silodosin group. no significant difference was observed among the rates of stone expulsion in three groups, and the rates of stone expulsion were similar (p = 0.778). the duration of stone expulsion was significantly different in the groups (p = 0.012): the time of stone expulsion for tamsulosin was 2.33 ± 0.78 days longer than for silodosin, indicating a significant difference. there was no significant difference between tamsulosin-alfuzosin and silodosin-alfuzosin (respectively p = 0.147, p = 0.925). conclusions: the results of this study showed that medical expulsive therapy by using alpha blocker agents is safe and efficacious. this option must be kept in mind for patients who do not ask for surgery as the first-step treatment for eligible patients. key words: urology; ureter; stone. submitted 13 february 2018; 24 february 2018 summary no conflict of interest declared. expulsive therapy, extracorporeal shock wave and lithotripsy (eswl), retrograde ureterorenoscopy, antegrade percutaneous ureterorenoscopy, and laparoscopic and open ureterolithotomy (3). the location and the size of the stone, the availability of the technology, the treatment cost, the experience of the surgeon, and the preference of the patients are considered when a treatment is chosen among the other alternatives (4). the probability of spontaneous expulsion of the ureteral calculi has two factors: the size of the calculi and the anatomic location of the calculi. according to a metaanalysis, the rate of spontaneous expulsion of the stones smaller than 5 mm is 68% while it is 47% for the stones bigger than 5 mm and smaller than 10 mm (5). when anatomic location is considered, it is seen that 71% of the distal ureteral calculi and 22% of the proximal ureteral calculi expulse spontaneously (6). therefore, spontaneous expulsion of the stone protects the patient from surgical intervention, anesthesia risk and additional costs, who does not have infection history and who has pain control and small size of calculi. by this way, with the understanding of the ureter physiology in detail, the concept of medical expulsive therapy has been developed in order to make the spontaneous expulsion of the stone easier. the purpose of the medical expulsive therapy is to increase the spontaneous probability of the stone expulsion by enabling relaxation in the ureter smooth muscle structure and eventually it reduces the pain level and frequency felt by the patient, shorten the time of stone expulsion, reduces the need of operation, prevents the risk and complications related with the operation and reduces the cost of the treatment. some main points need attention during the medical expulsive treatment. the most important two factors of them are the location of the calculi in the ureter and the size of the calculi. the maximum upper limit recommended for the treatment of the medical expulsive is 10 mm (7). many treatment alternatives are available for medical expulsive treatment. calcium channel blockers, alpha blockers, phosphodiesterase type 5 inhibitors and corticosteroids are the most frequently used drugs. in the guide of european society of urology, it is mentioned that doi: 10.4081/aiua.2018.1.25 introduction urolithiasis is one of the most common disorders of urinary tract affecting about 5%-10% of the population. renal stones are most prevalent between the ages of 20 and 40 years and are three times greater in men than women (1). women typically excrete more citrate and less calcium than men, which may explain the higher incidence of stone diseases in men. twenty-two percent of all urinary tract stones are found in ureter, of which 68% are seen in the distal ureter (2). the treatment of urinary stones basically varies depending on the anatomic location of the stone, the size of the stone and the factors related with the patient. the treatments of the ureteral calculi are observation, medical senturk_stesura seveso 27/03/18 09:19 pagina 25 archivio italiano di urologia e andrologia 2018; 90, 1 a. buğra sentürk, c. aydin, m. ekici, m. yaytokgil, a. akkoc, m. murat baykam 26 alpha blockers are more successful for medical expulsive treatment and calcium channel blockers are successful only when nifedipine is used for medical expulsive treatment. also corticosteroids are recommended to be used not alone but with other drugs for medical expulsive treatment purpose (8). in the various studies, it was shown that phosphodiesterase type 5 inhibitors increase the spontaneous stone expulsion by causing the relaxation of ureter smooth muscles; however, there is no sufficient data for its clinical use (9). although alpha adrenergic receptors are available in all ureter segments, these receptors are usually located at distal ureter (10). density order in distal ureter is alpha1d> alpha-1a>alpha-1b (11). in this retrospective study, we investigated the effects of three agents frequently used in daily life for medical expulsive therapy on each other. materials and methods the study was undertaken retrospectively in accordance with the principles of the declaration of helsinki. between january 2013 and october 2017, the data of 365 patients who were admitted to a polyclinic with distal ureter calculi size between 4-10 mm were investigated retrospectively. they were grouped homogeneously in terms of calculi size, patient age and gender. those patients who had bilateral ureter calculi, severe urinary tract infection, severe colic attack, fever, severe hydronephrosis, renal impairment, history of endoscopic surgery due to ureter calculi, and history of drug which interact with alpha blockers were excluded from the study. urine analysis, blood urea and creatinine values and complete blood count of all the patients were recorded before the treatment. those patients who had calculi with the size of 410 mm which were located under the common iliac arteries and confirmed by computarized tomography, and those responding to the analgesic treatment were included in the study. a total of 143 patients meeting the criteria were included in the study. patients were divided into three homogeneous drug groups which were tamsulosin group (n:48), alfuzosin group (n:47) and silodosin group (n:48). the patients in tamsulosin group received one dose of 0.4 mg/day tamsulosin orally, the patients in alfuzosin group received one dose of 10 mg/day alfuzosin orally, and those in silodosin group received one dose of 8 mg/day silodosin orally. in each group, the medical treatment was maintained until the patients expulsed the stone or for four weeks. when the patients had pain, they were administered analgesic. the time of stone expulsion, analgesic needs, side effects of the drug and endoscopic intervention needs of the patients were recorded. the expulsion of the non-transparent stones was confirmed by ultrasonography and transparent stones were confirmed by unenhanced tomography. all statistical analysis were performed with spss statistical software (version 22.0, spss inc., chicago, il, usa). descriptive statistics were presented as mean ± standard deviation (sd) values. shapiro-wilk test was used to check for normality of distribution. patient characteristics in the three age groups were compared using pearson's chi-squared test in case of discrete variables. the significance of the difference between three groups were assessed by using one-way analysis of variance (anova) in case of normal data distribution, or kruskalwallis test (non-parametric analysis of variance) in case of non-normal distribution for continuous variables. bonferroni post hoc test was applied to determine the differences between the pairwise groups. p values < 0.05 were considered to be statistically significant. results in each group, the sizes of the stones were similar (p = 0.224) (table 1). the sizes of the stones were 7.10 ± 1.80 mm in tamsulosin group, 6.55 ± 1.58 mm in alfuzosin group, and 6.65 ± 1.57 mm in silodosin group. the rate of stone expulsion was 70.8% (n:34) in tamsulosin group, 70.2% (n:33) in alfuzosin group, and 75% (n:36) in silodosin group. no significant difference was observed among the rates of stone expulsion in the three groups, and the rates of stone expulsion were similar (p = 0.778). despite the medical expulsive treatment lasting for four weeks, the rates of ureterorenoscopy operations due to non-expulsing stone was 29.2% (n:14) in tamsulosin group, 10.6% (n:14) in alfuzosin group and 25% (n:12) in silodosin group. the duration of stone expulsion was 10.41 ± 3.61 days in tamsulosin group, 8.87 ± 3.54 days in alfuzosin group, and 8.09 ± 3.66 days in silodosin group. the duration of stone expulsion was significantly different in the groups (p = 0.012). according to post hoc test results, the difference between silodosin and tamsulosin groups was (p = 0.010). so, the time of stone expulsion in tamsulosin was 2.33 ± 0.78 days longer than the one in silodosin, indicating a significant difference. there was no significant difference between tamsulosinalfuzosin and silodosin-alfuzosin (respectively p = 0.147, p = 0.925). no statistical difference was found between 3 drug groups in terms of frequency of colic attack and analgesic usage (respectively p = 0.25, p = 0.45). hypotension which is a major adverse effect of the drug was 8.5% in tamsulosin group, 4.5% in silodosin group, and 6.4% in alfuzosin group. although retrograde ejaculation was seen more frequently in silodosin group than the other groups, there was no statistical difference (p = 0.35). table 1. demographic values of groups. tamsulosin alfuzosin silodosin p value mean age ± sd (year) 40.37 ± 12.43 41.15 ± 12.15 41.46 ± 15.04 p = 0.919 mean stone diameter ± sd (mm) 7.10 ± 1.80 6.55 ± 1.58 6.65 ± 1.57 p = 0.224 male/female (n) 24/24 27/20 26/22 p = 0.778 senturk_stesura seveso 27/03/18 09:19 pagina 26 discussion due to risk of complications for ureteral stones less than 10 mm in size during minimal invasive treatments and their high costs, nowadays the treatment of ureteral stones vary in the direction of conservative treatment. management of ureteral stones depends on the size, location, number, structure of the stone and presence of the symptoms. ureteral spasm, ureteral anatomy and mucosal edema by inflammation affect the rate of stone expulsion. watchful waiting for distal ureteral stones is a good option in patients with no infection, tolerable colic attacks and small stone size. the aim of medical expulsive therapy is to facilitate spontaneous stone expulsion by relaxing ureteral smooth muscle without any disruption of ureteral peristalsis and to reduce the severity of pain of the patient. this idea depends on good spontaneous expulsion rates of small ureteral stones. natural spontaneous expulsion rate of distal ureteric calculi is 68% for stones less than 5 mm in size. and this rate is about 47% for stones with sizes between 5 and 10 mm (5). besides of the size, the localization of the calculi is also an important factor for spontaneous expulsion. the spontaneous expulsion rate of proximal ureter stone is 21%, of middle ureter stone 46%, and of distal ureteral stone 71% (6). alpha-1 receptors have been classified into three subtypes, which are alpha-1a, alpha-1b and alpha-1d. alpha-1d and alpha-1a are the most common adrenoceptors found in the ureter (12) and the distributions of these receptors are alpha-1d > alpha-1a > alpha-1b (11). alpha-1d receptors are found predominantly in the intramural ureter and detrusor muscle and they are the target of medical expulsive therapy as they are found generally in the distal ureter (13). itoh et al. reported that the distal part of the ureter expresses the higher amount of alpha-1 adrenoceptor than the other parts. also it was demonstrated that alpha-1d adrenoceptor mrna is much more common than alpha-1a adrenoceptor mrna in each part of the ureter. therefore, alpha-1d adrenoceptor blocker can be more useful than alpha 1a adrenoceptor blocker to facilitate expulsion of ureteral calculi according to their study (11). but in contrast, tatemichi et al. reported that ureteral motility is medicated more commonly by alpha 1a adrenoceptors (14). a study comparing the efficacy of silodosin to tamsulosin including 136 patients with proximal ureter stone which are in diameter of 4-10 mm showed that the patients treated with silodosin demonstrated a significant increase in expulsion rate and a decrease in expulsion duration of lower ureteral stones (61.2 versus 80.3%) (19). a meta-analysis involving eight publications from huang w et al. indicated that silodosin was superior to placebo or tamsulosin in the efficacy for distal ureteral calculi treatment with better control of pain (18). also, a multi-institutional, randomized, double-blinded, placebo-controlled trial from sur rl et al. reported that silodosin was found to be well tolerated and beneficial in facilitating the expulsion of distal ureteral stones (17). in our study, we found a similar effect between silodosin and tamsulosin groups in terms of stone expulsion (p = 0.010). stone expulsion duration was 10.41 + 3.61 days in tamsulosin group and 8.09 + 3.66 days in silodosin group. the stone expulsion duration of tamsulosin was significantly longer than the duration with silodosin (2.33 ± 0.78 days). as mentioned in similar studies, we consider that this finding is associated with the selective alpha 1-a adenoceptor antagonist effect of silodosin rather than the alpha-1 adrenoceptor antagonist effect of tamsulosin. we also did not found any statistical difference between tamsulosin-alfuzosin and silodosin-alfuzosin in terms stone expulsion duration (p = 0.147, p = 0.925 respectively). in the study of imperatore v et al., it was reported that both tamsulosin and silodosin are equally effective as medical expulsive treatment (met) for distal ureteral calculi sized < 10 mm. stone-expulsion rate was 88% in silodosin group and 82% in tamsulosin group (20). similarly, while stone expulsion rate was 70.8% in tamsulosin group, 70.2% in alfuzosin group and 75% in silodosin group in our study, we found no statistical difference between three groups in terms of stone expulsion rates (p = 0.778). increase in intraureteral pressure due to obstruction causes colic pain attacks. alpha blockers which are used predominantly for stone expulsion may also decrease analgesic drug usage by expulsion of ureteral calculi (16). kumar et al. reported that stone expulsion by an alpha 1 adrenoceptor on the obstructed ureter is facilitated by increasing the intaureteral pressure gradient around the stone and decreasing peristalsis below the ureter (13) and alpha blockade may decrease ureteric colic attacks by blocking c fibers which are responsible for pain (15). although we could not find any statistical difference between three groups in terms of the frequency of colic attack in our study (p = 0.45). the medical expulsive treatment should be discontinued in case of severe urinary infection and hydronephrosis, and endoscopic surgery should be considered. in our study, the rate of patients who needed endoscopic procedure due to nonexpulsing stones was 29.2% (n:14) in tamsulosin group, 10.6% (n:14) in alfuzosin group, and 25% (n:12) in silodosin group. medical expulsive therapy is a cost-effective non-surgical treatment for ureteral calculi less than 10 27archivio italiano di urologia e andrologia 2018; 90, 1 alpha blockers in medical expulsive therapy figure 1. stone expulsion duration in the groups. senturk_stesura seveso 27/03/18 09:19 pagina 27 archivio italiano di urologia e andrologia 2018; 90, 1 a. buğra sentürk, c. aydin, m. ekici, m. yaytokgil, a. akkoc, m. murat baykam 28 mm in size. several studies showed that alpha-1 adrenoceptor blockers can facilitate spontaneous passage of distal ureteral calculi with minimal side effects. a study from bensalah k et al. reported that medical expulsive therapy using tamsulosin resulted in a cost advantage for 1,132 usd over observation in usa. since the cost of tamsulosin is only 2.08 usd per day whereas the estimated cost of ureteroscopy is 4973 usd in usa (4). according to a systematic review and meta-analysis based on 21 studies, of which the main topic was to understand the effect of medical expulsive treatment (met) of ureter stone, by picozzi sc et al., it was reported that medical expulsive therapy should be offered to patients who are complaining about distal ureteral calculi (21). our study have some limitations. one of them is that we do not have a control group since the main objective of the study was to compare the effects of these three different type of alpha blockers. other limitation was the small number of the samples. however, the results of the power analysis during the design of the study showed that current numbers were not statistically problematic. conclusion no significant difference was found between the three groups in terms of the rate of stone expulsion (p = 0.778). however, the duration of stone expulsion had a significant difference among the groups (p = 0.012). stone expulsion duration for tamsulosin was 2.33 ± 0.78 days longer than for silodosin, which is a considerable difference (p = 0.010). there was no significant difference between tamsulusin-alfuzosin and silodosin-alfuzosin (p = 0.147 and p = 0.925, respectively). the results of this study showed that medical expulsive therapy by using alpha blocker agents are safe and efficacious. this option must be kept in mind who do not ask for surgery as the first-step treatment for eligible patients. references 1. manglaviti g, tresoldi s, guerrer cs, et al. in vivo evaluation of the chemical composition of urinary stones using dual-energy ct. ajr am j roentgenol. 2011; 197:w76-83. 2. hollingsworth jm, rogers ma, kaufman sr, et al. medical therapy to facilitate urinary stone passage: a meta-analysis. lancet. 2006; 368:1171-1179. 3. ergun o, gonen m. üriner sistem tas hastalıgında medikal ekspulsif tedavi: kime, nasil, ne kadar? endoüroloji bülteni 2014; 7:74-76. 4. bensalah k, pearle m, lotan y. cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. eur urol. 2008; 53:411-8. 5. preminger gm, tiselius hg, assimos dg, et al. eau/aua nephrolithiasis guideline panel. 2007 guideline for the management of ureteral calculi. j urol. 2007; 178:2418-34. 6. morse rm, resnick mi. ureteral calculi: natural history and treatment in an era of advanced technology. j urol. 1991; 145:263-5. 7. singh a, alter hj, littlepage a. a systematic review of medical therapy to facilitate passage of ureteral calculi. ann emerg med. 2007; 50:552-63. 8. türk c, petrík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016; 69:468-74. 9. gratzke c, uckert s, kedia g, et al. in vitro effects of pde5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. urol res. 2007; 35:49-54. 10. atan a. medikal ekspulsif tedavi: yeni olan nedir? endoüroloji bülteni. 2015; 8:78-80. 11. itoh y, kojima y, yasui t, tet al. examination of alpha 1 adrenoceptor subtypes in the human ureter. int j urol. 2007; 14:749-53. 12.sigala s, dellabela m, milanese g, et al. evidence for the presence of alpha 1adrenoceptor subtypes in the human ureter. neurourol urodyn. 2005; 24:142-148. 13. kumar s, kurdia kc, ganesamoni r, et al. randomized controlled trial to compare the safety and efficacy of naftopidil and tamsulosin as medical expulsive therapy in combination with prednisolone for distal ureteral stones. korean j urol. 2013; 54:311-5. 14. tatemichi s, tomiyama y, maruyama i, et al. uroselectivity in male dogs of silodosin (kmd-3213), a novel drug for the obstructive component of benign prostatic hyperplasia. neurourol urodyn. 2006; 25:792-9; discussion 800-1. 15. kinnman e, nygards eb, hansson p. peripheral alpha-adrenoceptors are involved in the development of capsaicin induced ongoing and stimulus evoked pain in humans. pain. 1997; 69:79-85. 16. kumar s, jayant k, agrawal mm, et al. role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). urology. 2015; 85:59-63. 17. sur rl, shore n, l'esperance j, et al. silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, doubleblinded, placebo-controlled trial. eur urol. 2015; 67:959-64. 18. huang w, xue p, zong h, zhang y. efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta-analysis. br j clin pharmacol. 2016; 81:13-22. 19. dell'atti l. silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. urologia. 2015; 82:54-7. 20. imperatore v, fusco f, creta m, et al. medical expulsive therapy for distal ureteric stones: tamsulosin versus silodosin. arch ital urol androl. 2014; 86:103-7. 21. picozzi sc, marenghi c, casellato s, et al. management of ureteral calculi and medical expulsive therapy in emergency departments. j emerg trauma shock. 2011; 4:70-6. correspondence aykut buğra sentürk, md (corresponding author) aykutbugra@gmail.com cemil aydin, md cemilaydin78@yahoo.com.tr musa ekici, md musaekici40@gmail.com hitit university corum training and research hospital, turkey senturk_stesura seveso 27/03/18 09:19 pagina 28 stesura seveso 345archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.345 which factors affect the success of pediatric pcnl? single center experience over 20 years volkan izol 1, nihat satar 1, yildirim bayazit 1, fatih gokalp 2, nebil akdogan 1, ibrahim atilla aridogan 1 1 department of urology, faculty of medicine, university of çukurova, adana, turkey; 2 clinic of urology, osmaniye government hospital, osmaniye, turkey. rograde intrarenal surgery (rirs) are the treatments of choice in children (2). additionally, over the last two decades, percutaneous nephrolitotomy (pcnl), with low complications and high success rates, has become the standard treatment of choice for kidney stones > 2 cm and is an alternative procedure for stone size between 12 cm at lower pole (2, 3). pcnl is an effective and safe procedure in pediatric patients (4-7). nevertheless, serious complications such as bleeding requiring transfusion, organ injuries, pneumothorax, infection, and sepsis, still have been reported for this procedure (7). there are a few factors identified as affecting complications, including stone size, sheath size, number of punctures, presence of hydronephrosis, and prolonged operation time (8, 9). recent studies of stone disease treatment showed increased success rates, and also decreased complication rates in association with increase of expertise in high volume centers (7, 8). in this retrospective study, we aimed to evaluate the impact of surgeons’ experience on complication rates, success rates, and the management of complications along a period of more then 20 years. materials and methods between june 1997 and june 2018, 573 pediatric patients with a total of 654 renal units underwent pcnl for renal stone disease. the patients with bilateral kidney stones were treated with staged procedures. all patients were assessed preoperatively with excretory urography, renal ultrasound, and/or non-enhanced spiral computerized tomography, and urine was collected for culture analysis before surgery. written informed consent was achieved for all participants. after approvel by cukurova university ethics committee, june 2018/78, preoperative data were obtained, including gender, age, operation time, sheath size, laterality, stone burden, hematocrit, and serum creatinine. the stone burden was calculated by the stone surface area formula. intraoperative and postoperative data were obtained including pre/postoperative variation of glomerular filtration rate (gfr) (calculated with cockcroft gault equations), drop of hemoglobin levels, transfusion rate, complications according to the clavien classification, operative time, length of hospital stay and stone-free rate (sfr) (10, 11). objective: we aimed to investigate the impact of surgeons’ experience on pediatric percutaneous nephrolithotomy (pcnl) outcomes. materials and methods: between june 1997 and june 2018, 573 pediatric patients with 654 renal units underwent pcnl for renal stone disease by senior surgeons. data were divided into two groups, group-1 (n = 267), first ten years period, group-2 (n = 387); second ten years period. results: mean ± sd age of patients was 7.6 ± 4.9 (1-17) years. the stone-free rates (sfr) assessed after 4 weeks were 74.9% vs. 83.4% in group-1 vs. group-2, respectively (p = 0.03). the mean operation time, fluoroscopy time, and the number of patients requiring blood transfusion significantly decreased in group 2 (100.4 ± 57.5 vs. 63.63 ± 36.3, 12.1 ± 8.3 vs. 8.3 ± 5.4, and 24.3% vs. 2.9%; p < 0.001, p < 0.001, and p = 0.002 in group-1 versus group-2, respectively). on multivariate analysis, increasing stone size increased operation time (p < 0.001), fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion rates (p = 0.006 and p = 0.018, respectively), and hospital stay (p = 0.002) but was not associated with change of glomerular filtration rate (gfr) (p = 0.71). sheath size also correlated with increased fluoroscopy time (p < 0.001), operation time (p < 0.001), intraoperative blood transfusion (p < 0.001) and hospital stay, but sheath size did not affect postoperative blood transfusion (p = 0.614) or gfr change (p = 0.994). conclusions: the percutaneous nephrolithotomy (pcnl) is a minimally invasive procedure and is well accepted because of its lower complication rate and high efficiency for pediatric patients. stone and sheath size are predictive factors for blood loss and hospital stay. during 20 years, our fluoroscopy time, operation time, blood loss, and complication rates decreased, and stone-free rate increased. key words: pediatric; percutaneous; urinary calculi; endourology. submitted 24 may 2020; accepted 30 july 2020 introduction pediatric stone-disease is widespread in developing countries and turkey (1). the surgical management of stone disease has changed because of technological advances in recent years. for renal stones smaller than 2 cm, extracorporeal shock wave lithotripsy (swl) and retsummary archivio italiano di urologia e andrologia 2020; 92, 4 v. izol, n. satar, y. bayazit, f. gokalp, n. akdogan, i. atilla aridogan 346 additionally, we divided the data into two groups. in group-1, pcnl was performed in the first ten years period (1997-2007); in group-2, pcnl was performed in the second ten years period from 2008 to the present. surgical technique all procedures were performed by four experienced surgeons who had been working for at least 20 years in our clinic and staff surgeons under supervision of mentors. all patients received prophylactic antibiotics preoperatively during anesthesia induction. after the placement of a 5 fr ureteral open-end catheter, patients were positioned in a prone position with proper constructional support by silicone rolls. the pelvicalyceal system was visualized by injecting the radiographic contrast dye through the ureteric catheter. the collecting system was punctured with a needle under fluoroscopy, a guidewire was inserted, and then the urinary tract was dilated with metal or amplatz dilatators. after placement of an 18-30 fr sheath, a 15fr-19fr rigid nephroscope or 9.5 fr rigid ureteroscope was inserted into the collecting system. stones were fragmented with a pneumatic lithotripter or laser and retrieved with rigid or flexible forceps or graspers. a 10 fr nephrostomy tube was left in place if needed. we preferred the tubeless technique for selected cases such as those with short operation time, a single puncture for a tract, undamaged pelvicalyceal system, no major bleeding or residual stones at the end of the procedure. on the second postoperative day, the patient underwent antegrade pyelography, or the nephrostomy tube was clamped if there was no residual fragment or extravasation detected by imaging. then, the nephrostomy tube was extracted. patients were discharged after drainage from the nephrostomy tract was stopped. if the drainage from the nephrostomy tract continued longer than seven days, it was defined as prolonged drainage, and we inserted a double j stent. when drainage was stopped for several days, patients were discharged. follow up the first visit for follow up was done at 4-6 weeks after discharge, including urinalysis, metabolic examination of 24-hour urine specimens, and urinary ultrasonography. stone free rates (sfr) were evaluated at 4 week follow. we reported the result as a failure in presence of any asymptomatic residual stone fragment > 4 mm at 4 week follow up. we confirmed the result by using intravenous urography in the first-year period and nonenhanced computerized tomography in the second ten years period. statistical analysis spss, version 20.0, was used to perform statistical analysis. the kolmogorov smirnov test was used in the numerical computations provided the assumption of a normal distribution. for comparing the categorical measurements between the groups, the chi-square test was used. mann-whitney u, chi-square, anova, and logistic regression were used for multivariate analysis. statistical significance was defined as a p-value of less than 0.05. results demographic data five hundred seventy-three pediatric patients with 654 renal units were evaluated in the study. the mean ± sd age of patients was 7.6 ± 4.9 years. the mean stone burden was 371.8 ± 459.4 (95% ci: 343.0-415.5) mm3. there were 343 (52.5%) renal units with a single calyceal stone and 311 (47.5%) patients with multiple calyceal or staghorn stones. sfr was found 81.4% (n = 533). the mean hospital stay was 4.6 ± 4.2 days. in our practice, the usual hospital course for pcnl is 3-4 days in pediatric patients, but 173 (26.4%) patients stayed longer (7 to 27 days) due to leakage drainage, bleeding, infections, or other complications (table 1). operative outcomes on multivariate analysis, the perioperative parameters such as fluoroscopy time, bleeding, and operation time were associated with stone size and sheath size. increasing stone size increased operation time (p < 0.001), fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion rate (p = 0.006 and p = 0.018, respectively), and hospital stay (p = 0.002) but was not associated with gfr change (p = 0.71). sheath size also correlated with th parameters and increased fluoroscopy time (p < 0.001), operation time (p < 0.001), intraoperative blood transfusion (p = 0.002) and hospital stay, but sheath size did not affect postoptable 1. demographic data of patients. value no. of patients 654 age (years)a 7.6 ± 4.9 genderb m 167 (62.5%) f 100 (37.5%) lateralityb left 326 (49.8%) right 328 (50.2%) site of stoneb single calyx 343 (52.5%) multiple calyces 311 (47.5%) operation timea 78.3 ± 49.0 stone free rateb 533 (81.4%) adata was presented as mean ± sd; bdata was presented as n (%). table 2. complications causing prolonged hospital stay. group 1 group 2 p value (1997-2007) (2008-2018) infection and fever 26 (9.7%) 15 (3.8%) 0.02 leakage drainage 10 (3.7%) 11 (2.8%) 0.52 requiring stenting 6 (2.2%) 7 (1.8%) 0.69 colon perforation 2 (0.7%) 1 (0.2%) 0.79 collecting system perforation 1 (0.3%) 4 (1.0%) 0.34 bleeding 78 (29.2%) 22 (5.6%) < 0.001 requiring blood transfusion 65 (24.3%) 11 (2.8%) < 0.001 transcathateter angiography 2 (0.7%) 1 (0.2%) 0.36 all data was presented as n (%). 347archivio italiano di urologia e andrologia 2020; 92, 4 success of pediatric percutaneous nephrolithotomy erative blood transfusion (p = 0.614) or gfr change (p = 0.994). furthermore, prolonged operation time increases fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion (p < 0.001 and p = 0.008, respectively), and hospital stay (p < 0.001), but not associated with gfr change (p = 0.55). stone size and sheath size were not associated with postoperative changes of gfr. sfr was correlated with operation time (b: -0.013, p = 0.02) (table 3). table 4 shows the comparison of the outcomes of two subgroups of patients treated in two different period of time using different-sized instruments. mean operation time, fluoroscopy time, and blood transfusion rate were significantly lower in group-2 (p < 0.001, p < 0.001, and p = 0.002, respectively). however, stone volume and sheath size also significantly decreased in group-2 (p < 0.001). sfr were 74.9% and 86.4% in group-1 and group-2, respectively (p = 0.03). reoperation rates were 18 (6.7%) versus 11 (2.9%) in group-1 vs. group-2, respectively (p = 0.01). there was no significant change between preoperative and postoperative mean gfr in both groups (2.51 ± 0.2 ml/min and 3.83 ± 0.3 ml/min; p = 0.584, p = 0.536 in group1 and group-2, respectively). the most common complications were low-grade complications, grade i (21.3%), and grade ii (29.6%). grade i and ii complications were significantly higher group-1 than group-2 (p = 0.001 and p < 0.001). grade iii-a and iii-b complications were seen in 16 (2.4%) and 5 (0.7%) patients, respectively, and there was no significant difference between groups (p = 0.45, p = 0.34). complications and management the most common complication was bleeding in both groups (29.2% and 5.6% in group-1 and group-2, respectively). rates of hemorrhages requiring transfusions were significantly different between the two groups (24.3% and 2.9% in group-1 and group-2, respectively, p = 0.02). three patients underwent angiography for severe bleeding after the procedure, and a ten-year-old child underwent embolization for a pseudoaneurysm of the kidney. twenty-six (9.7%) children in group-1 and fifteen (3.8%) in group-2 had a fever after pcnl (p = 0.07). patients took different antibiotic regimens after a positive urine culture. twenty-one patients were followed up for prolonged drainage after removal of the nephrostomy tube. thirteen patients, six (2.2%) in group-1 and seven (1.8%) in group-2, required double-j stenting. one patient required stenting for perirenal urinoma that resolved spontaneously. collecting system perforations were seen in five patients, one (0.3%) in group-1 and four (1.0%) in group-2. three patients had a long-staying nephrostomy tube from four to seven days, which was extracted after no extravasation was demonstrated at anterograde pyelography. two cases required open surgery, one underwent pyeloplasty for damaged ureter-pelviv junction (upj) and the other underwent a primary repair of the renal pelvis. two (0.7%) patients in group-1 and one (0.2%) in group2 had a colon perforation. one of them was treated with open surgery and a colostomy by the pediatric surgeon. the colostomy was closed after three months when anastomosis was done successfully. two patients were treated conservatively, by withdrawal of the nephrostomy tube outside the kidney into the colon as a percutaneous colostomy tube and by insertion of a double-j ureteral stent for separating nephron-colic communication. patients took intravenous broad-spectrum antibiotics and total parenteral nutrition. after 7-10 days, the patients started receiving oral feeding. the tube was removed after complete healing of the colon. one month after, the j stent was extracted under control of retrograde pyelography. one child underwent nephrectomy for a nonfunctioning kidney that was not producing urine in the table 4. difference characteristics of two chronological groups. 1997-2007 2008-2018 p value (n = 267) (n = 387) age (years)a 8.5 ± 4.9 6.9 ± 4.7 genderb m 167 (62.5%) 210 (54.2%) f 100 (37.5%) 177 (45.8%) sideb left 128 (47.9%) 198 (51.1%) right 139 (52.1%) 189 (48.9%) stone sizea (mm2): 480.8 ± 380.0 295.8 ± 196.5 p < 0.001 sheath sizea: 27.87 ± 2.8 24.41 ± 2.6 p < 0.001 gfr change (mg/dl): 2.6 ± 0.2 3.8 ± 0.3 p = 0.425 serum creatinine changea (mg/dl): 0.013 ± 0.0 0.001 ± 0.0 p = 0.717 operation timea (min): 100.4 ± 57.5 63.63 ± 36.3 p < 0.001 fluoroscopy timea (min): 12.19 ± 8.3 8.31 ± 5.4 p < 0.001 hemorrhage requiring transfusionb: 65 (24.3%) 11 (2.9%) p = 0.002 stone free ratesb sf 200 (74.9%) 323 (83.4%) p = 0.03 failure 64 (24.2%) 56 (14.8%) nephrostomy removal time (day): 2.93 2.57 p = 0.133 postoperative complications: clavien dindob p = 0.842 1 39 (14.6%) 26 (6.7%) p = 0.001 2 69 (25.8%) 15 (3.8%) p < 0.001 3a 8 (2.9%) 8 (2.0%) p = 0.45 3b 1 (0.3%) 4 (1.0%) p = 0.34 4a 2 (0.7%) 1 (0.2%) p = 0.36 5 0 0 adata was presented as mean ± sd; bdata was presented as n (%). table 3. multivariate analysis of sfr compared to demographic and perioperative parameters. unstandardized coefficients 95% confidence interval b std. error p lower upper age .047 .056 .399 .939 1.170 gender -.024 .300 .936 .543 1.756 laterality -.264 .301 .380 .426 1.385 weight -.017 .014 .226 .956 1.011 stone size -.001 .001 .108 .998 1.000 operation time -.013 .006 .021 .976 .998 fluoroscopy time .000 .000 .781 .999 1.001 sheath size .079 .070 .259 .944 1.241 constant 1.367 1.614 .397 *depended variable was sfr. archivio italiano di urologia e andrologia 2020; 92, 4 v. izol, n. satar, y. bayazit, f. gokalp, n. akdogan, i. atilla aridogan 348 postoperative days. histopathological evaluation revealed xanthogranulomatous pyelonephritis. discussion pediatric stone disease is an important issue, and the critical point for preventing recurrence and relative complications after surgery is stone clearance. there still is not a consensus on describing stone-free rates. sfr varied in the studies due to the differences between pediatric and adult kidney anatomy, variable stone size, use of different-sized instruments, and inclusion or exclusion of clinically insignificant residual fragment (cirf) cases. a recent study by çıtamak et al. presented their results at four years intervals over 17 years, and stone-free rates were 73.5%, 68.1%, 75.5%, and 74.0%, with no significant difference among the groups (p = 0.65) (12). our study showed that our increasing clinical experience and use of small instruments incresed sfr after pediatric pcnl. our sfr was significantly higher in group-2 than group-1 and reoperation rates were similar into groups. similar to our study, yadav et al. study reported that stone-free rates were increased over 15 years from 84.6% to 89.9% (13). the early pediatric pcnl series were performed using adult-size instruments. the improvements in the devices and techniques of pcnl facilitated urologists to perform this procedure (14, 15). in our study, the mean sheath size decreased from 28 fr to 24 fr over the years. bilen et al. compared three different sized nephroscope, and stone-free rates were 69.5%, 80%, and 90% in the 26fr, 20fr, and miniperc groups, respectively (p < 0.005). the authors emphasized that the 26fr and 20fr groups include more patients with semi-staghorn and staghorn calculi (16). a novel systematic review showed that the minimal invasive pcnl (micro-ultra mini) success rate ranged between 85-100% (17). in our study, the total complication rate (clavien i-iv) was 28.4%, and there was no significant difference between the two groups. similar results were found in the croes study which showed that the complication rate was 23.3% (7). novel research showed the complications were decreased over the years (33.8%, 23.6%, 19.6%, and 11.5%, respectively, for every four years, p < 0.001) (12). in the literature, the studies compared pcnl complications in children using different instruments, and the complications were graded according to the modified clavien system, and similar to our research, most of the complications were grade i and ii (5, 18, 19). ozden et al., in a study of 100 patients using pediatric instruments, reported an overall complication rate of 25% (18). another study by guven et al. reported that the total complication rate was 29.1% (n = 140), and there was no significant difference between pediatric and adult instruments (p = 0.52) (5). additionally, bilen et al. also showed that complication rates were not significantly different in their study comparing three different sized instruments (16). mishra et al. examined the outcomes of miniperc (mpcnl) versus standard conventional pcnl and concluded that the mpcnl is significantly superior to pcnl in bleeding and hospital stay time (19). similar to our study, novel papers showed that recently presented small size percutaneous accesses, such as mpcnl and micro percutaneous method (micro-pcnl), are safer than classic pcnl in children (2, 20). our study demonstrated that there had been no significant change in the treatment of complications until today, but we became less invasive due to our increased knowledge of complications. the most common complications were bleeding and fever. types and frequencies of complications were similar to those in adults (8, 17, 21). zeren et al. study showed correlation of intraoperative bleeding with operation time, sheath size, and stone size (8). our research demonstrated that stone size and operation time correlated with intraoperative and postoperative blood transfusion. we also found that a larger sheath size is related to higher intraoperative blood transfusion rates and longer hospital stay. similar to our study, altintaş et al. study compared three different sheath sizes (17 fr, 24 fr, and 26 fr) showing that sheath size was related to increased intraoperative bleeding although there was no significant difference of preoperative and postoperative creatinine levels (p = 0.873) (22). however, controversial to our study, the literature also reported that sheath size did not affect transfusion rates (12, 16, 23). fever was the second common complication in our study. previous studies reported that the postoperative fever rate was approximately present in 29% (18, 21). bayrak et al. reported that postoperative fever rates in their study, comparing children to adults, were 5.4% and 5.6%, respectively (24). çelik et al. showed that postoperative fever rates were similar and reported rates of 5.9% and 6.8% using pediatric (18fr) and adult-sized (24fr) nephroscope, respectively (25). in our study, postoperative fever rates were not significantly different in the two groups and similar to published literature. herein, we compared different-sized instruments and experience time and found that pcnl is an operatordependent procedure, which improves its results, presumably due to increased operator experience and the involvement of a team with substantial prior knowledge. furthermore, our results depend on advances to technology that shifted the management of stone disease to minimal invasive modalities. we realized that we treated smaller stones in the second ten years period. the main reasons for this finding are: • increasing of diagnosis of patients with small stone size due to the novel radiological tools and easier access to health care services. • in our clinic, use of a eswl machine that uses fluoroscopy for stone localization (with no ultrasoundguided eswl machine around the region) • technological advancement with development of small instruments for urologic endoscopic procedures. limitations of the study included its retrospective nature and the absence of a metabolic evaluation and chemical analysis of the composition of the stone. the second significant limitation was insufficient data of follow up, especially on group-1 and no standardization of timing or use of imaging tools at follow up. another limitation of the study was the performance of percutaneous pro349archivio italiano di urologia e andrologia 2020; 92, 4 success of pediatric percutaneous nephrolithotomy cedures by more surgeons using different instruments at different periods being the experience of each surgeon a possible source of bias. however, a strenght of the study is that the data and results were obtained from a single large volume center. conclusions our study showed that the patient cohort became younger with smaller stone sizes over time. concordantly, the fluoroscopy time, operation time, blood loss, and complications rates were decreased, and stone free-rates were increased with use of smaller instruments. the stone and sheath size are major factors to predict blood loss and hospital stay. references 1. bartosh sm. medical management of paediatric stone disease. urol clin north am. 2004; 31:575-87. 2. türk c, neisius a, petr̆ík a, et al. eau guidelines on interventional treatment for urolithiasis. eau guidelines. edn. presented at the eau annual congress london 2018. isbn 978-94-92671-01-1. 3. matlaga br, kim sc, lingeman je. improving outcomes of percutaneous nephrolithotomy: access. eur urol. eau update ser. 2005; 3:37-43. 4. woodside jr, stevens gf, stark gl, et al. percutaneous stone removal in children. j urol. 1985; 134:1166-7. 5. guven s, istanbulluoglu o, gul u, et al. successful percutaneous nephrolithotomy in children: multicentre study on current status of its use, efficacy and complications using clavien classification. j urol. 2011; 185:1419-24. 6. unsal a, resorlu b, kara c, et al. safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. urology. 2010; 76:247-52. 7. guven s, farttini a, onal b, et al. behalf of the croes pcnl study group. percutaneous nephrolithotomy in children in different age groups: data from the clinical research office of the endourological society (croes) percutaneous nephrolithotomy global study. bju international. 2012; 111:148-56. 8. zeren s, satar n, bayazit y, et al. percutaneous nephrolithotomy in the management of pediatric renal calculi. j endourol. 2002; 16:75-8. 9. desai m. endoscopic management of stones in children. curr opin urol. 2005; 15:107-12. 10. cockcroft dw, gault mh. prediction of creatinine clearance from serum creatinine. nephron. 1976; 16:31-41. 11. dindo d, demartines n, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 12. cıtamak b, altan m, bozacı ac, et al. percutaneous nephrolithotomy in children: 17 years of experience. j urol. 2016; 195:1082-7. 13. yadav p, madhavan k, syal s, et al. technique, complications, and outcomes of pediatric urolithiasis management at a tertiary care hospital: evolving paradigms over the last 15 years. j pediatr urol. 2019; 15:665.e1-665.e7 14. goyal nk, goel a, sankhwar sn, et al. a critical appraisal of complications of percutaneous nephrolithotomy in paediatric patients using adult instruments. bju int. 2014; 113:801-10. 15. smaldone mc, docimo sg, ost mc. contemporary surgical management of paediatric urolithiasis. urol clin north am. 2010; 37:253-67. 16. bilen cy, kocak g, kitirci o, et al. percutaneous nephrolithotomy in children: lessons learned in 5 years at a single institution. j urol. 2007; 177:1867-71. 17. jones p, bennett g, aboumarzouk om, et al. role of minimally invasive percutaneous nephrolithotomy techniques-micro and ultramini pcnl (< 15f) in the pediatric population: a systematic review. j endourol. 2017; 31:816-24. 18. ozden e, mercimek mn, yakupoglu yk, et al. modified clavien classification in percutaneous nephrolithotomy: assessment of complications in children. j urol. 2011; 185:264-8. 19. mishra s, sharma r, garg c, et al. prospective comparative study of miniperc and standard pnl for treatment of 1 to 2 cm size renal stone. bju int. 2011; 108:896-9. 20. karatag t, tepeler a, sılay ms, et al. comparison of 2 percutaneous nephrolitotomy technique for the treatment of pediatric kidney stones of sized 10-20 mm: microperc vs miniperc. urology. 2015; 85:015-8. 21. onal b, dogan hs, satar n, et al. factors affecting complication rates of percutaneous nephrolithotomy in children: results of a multi-institutional retrospective analysis by the turkish pediatric urology society. j urol. 2014; 191:777-82. 22. altintas r, oguz f, tasdemir c, et al. the importance of instrument type in paediatric percutaneous nephrolithotomy. urolithiasis. 2014; 42:149-53. 23. traxer o, smith 3rd tg, pearle ms, et al. renal parenchymal injury after standard and mini percutaneous nephrostolithotomy. j urol. 2001; 165:1693-5. 24. bayrak o, erturhan s, seckiner i, et al. reliability of percutaneous nephrolithotomy in pediatric patients: comparison of complications with those in adults. korean j urol. 2013; 54:383-7. 25. celik h, camtosun a, dede o, et al. comparison of the results of pediatric percutaneous nephrolithotomy with different sized instruments. urolithiasis. 2017; 45:203-8. correspondence volkan izol, md nihat satar, md yildirim bayazit, md nebil akdogan, md ibrahim atilla aridogan, md department of urology, faculty of medicine, university of çukurova, adana (turkey) fatih gokalp, md, febu (corresponding author) fatihgokalp85@gmail.com osmaniye government hospital, urology clinic, 80020, osmaniye (turkey) archivio italiano di urologia e andrologia 2017; 89, 2164 case report kaposi’s sarcoma: an unusual penile lesion in a hiv negative patient aldo franco de rose, matteo justich, guglielmo mantica, nicolò testino, carlo terrone department of urology, ospedale policlinico san martino istituto di ricerca e cura a carattere scientifico per l’oncologia, university of genova, genoa, italy. kaposi's sarcoma (ks) of the penis is a very rare lesion and it is usually observed in hiv-infected patients. we introduce a case of ks of the penis in a 75 years old hiv negative patient with a peripheral t-cell lymphoma. he came to our attention with a painful ulcerated red lesion on the glans that stretched from the urethral meatus to the coronal skin. this lesion was found to be a ks balanopreputial in the classical variant. penile ks must be included in the differential diagnosis of genital diseases especially when the clinical features of the lesion are aspecific and diagnosis can be made histologically by performing a biopsy. key words: kaposi sarcoma; penile lesion; hiv negative; hhv-8; t-cell lymphoma. submitted 17 january 2017; accepted 1 march 2017 summary no conflict of interest declared. the abdominal ct scan showed no inguinal lymph nodes or other suspected lesions. due to an extended lesion and to the absence of a clear diagnose it was decided to perform a glansectomy. the histopathology examination described a classical balanopreputial ks. six months later the patient was negative for local recurrence but a secondary gastrointestinal lesion was detected during a whole body ct scan and a gastric biopsy was performed. the patient is currently under therapy with interferon. discussion ks, described for the first time by moritz kaposi in 1872, is a rare neoplasm that origins from the endovascular cells in a multifocal way (1). the behavior of the disease varies from a singular indolent lesion localized in the skin, to a fleeting extensive respiratory and gastrointestinal visceral involvement (2). four clinical variants have been described: classic, african endemic, iatrogenic or transplanted associated and hiv-related (3). before the 1980s classic ks was rare and it increased because of the aids epidemic. nowadays the introduction of highly active anti-retroviral therapy (haart) resulted in a reduction of the ks incidence (4, 5). primary classical ks of the penis is rare in hiv negative patients (6) and in the literature has been reported only in doi: 10.4081/aiua.2017.2.164 introduction kaposi's sarcoma (ks) is a malignant neoplasm that typically arises in the skin of the extremities but any area of the face and trunk could be involved. furthermore it often occurs in the lymph nodes and in the visceral organs (1-3). penile occurrence is very uncommon so the diagnose and the treatment could be a hard challenge to the urologist. we introduce a very rare case of penile ks in a patient with peripheral t-cell lymphoma without hiv infection. case report a 75 year-old man came to our attention with a paraphimosis arisen 2 days earlier. he reported a 5 month painless ulcerated red lesion on the glans extending from the urethral meatus to the coronal skin. (figure 1). he did not complain urethral discharge nor there were palpable inguinal lymph nodes. he was diabetic, hypertensive and in 2014 it was diagnosed a t-cell lymphoma. so he was treated with comp 6 cycles, then bendamustin 4 cycles and finally romidepsin 6 cycles with the remission of the disease. a subtotal circumcision and a glans biopsy were performed. the histological examination could only provide evidence of immunohistochemical staining for hhv-8 both in the stromal cells and in the endothelial ones. there were no localizations of t-cell lymphoma. urinary exam and blood laboratory tests were normal. hiv antibody test by elisa was negative. figure 1. ulcerated red lesion on the glans extending from the urethral meatus to the coronal skin. de rose_stesura seveso 20/06/17 10:05 pagina 164 165archivio italiano di urologia e andrologia 2017; 89, 2 a rare case of penile kaposi’s sarcoma 19 cases (7). it usually affects patients between the fifth and eighth decade of life living on the mediterranean coastal areas where the hhv-8 infection is widespread (6). the pathogenesis of the disease is unclear but hhv-8 infection seems to be an essential cofactor for the development of the ks irrespective of the variant, clinical presentation or prognosis (1, 8). beside a ks our patient presented an immunological t cell disorder and an hhv-8 infection. probably the t-cell immunity plays a major role in the hhv-8 control and in the development of ks both in viral immunosuppressed patients both in iatrogenic ones. however no studies have shown a clear correlation between the presence of an immunological t disorder and a ks (9). the typical clinical feature of a penile ks is a purple papule or macule located on the glans, foreskin, frenulum, urethral meatus or coronal sulcus (6, 10). it rarely affects the shaft or the scrotum. nodules, plaques, multiple papules, wart-like or pedunculated lesions are less common (5-6). the differential clinical diagnosis includes pyogenic granuloma, moluscum contagiosum, condiloma acuminate, glomus tumor, bowenoid papulosis, nevi, mela noma and lymphoma (7). the conclusive diagnosis is made by biopsy. the histological pattern is not so different from ks seen in other areas of the body showing groups of spindle cells, extravascular erythrocytes, and macrophages filled with hemosiderin (1). the main target of therapies is to decrease the symptoms, reduce the size, the number of the lesions and to delay the disease progression (11). many therapeutic approaches have been described: surgical excision, cryosurgery, radiation therapy, thermo-photoablative, laser therapy, local and systemic chemoterapy, αand β-interferon (6). for small and single lesions surgical excision is recommended, while for multiple skin lesions or large-size is recommended radiation therapy. systemic chemotherapy has been employed in systematic forms (10). in the case of radical surgical excision, local recurrence is rare (6). however it is important not to neglect the patient’s follow-up because a penile unique lesion could be the manifestation of a disseminated kaposi's sarcoma. as reported by a greek author, 82% of patients with classic ks refer a gastric asymptomatic lesion. they recommend therefore the execution of a gastroscopy in every patient with a new diagnose of ks (11-12). conclusions in conclusion the spectrum of penile lesions is broad and the clinical assessment is often insufficient to reach a diagnosis and an adequate choice of treatment. penile ks must be included in the differential diagnosis of the genital diseases in particular when there are not specific-feature penile lesions so a biopsy is advisable for reaching a histological diagnosis. references 1. seleit i, attia a, maree a, et al. isolated kaposi sarcoma in two negative patients. j dermatologic case rep. 2011; 2:24-26. 2. schwartz ra, micali g, nasca mr, et al. kaposi sarcoma: a continuing conundrum. j am acad dermatol. 2008; 59:179-206 3. tschachler e. kaposi sarcoma. in: wolff k, goldsmith la, katz si, et al, editors, fitzpatrick’s dermatology in general medicine, 7th ed., new york: mcgraw-hill. 2008; p. 1183-7. 4. pinto-almeida t, torres t, rosmaninho a, et al. penile kaposi sarcoma: a case of complete resolution with highly active antiretroviral therapy alone. dermatology online journal. 2011; 17:12. 5. ho kim k, il choi j, ho ryu k, et al. primary classic kaposi's sarcoma of the penis in an hiv-negative patient korean j urol. 2010; 51:803-806. 6. micali g, nasca mr, de pasquale r, et al. primary classic kaposi’s sarcoma of the penis: report of a case and review. j eur acad derm venereol. 2003; 17:320-323. 7. attwa e, gharib k, albalat w, et al.classical kaposi sarcoma: case reports with unusualpresentation on the penis and scrotum int. j dermatol. 2016; 55:533-538. 8. fatahzadeh m. kaposi sarcoma: review and medical management. oral surg oral med oral pathol oral radiol. 2012; 113:2-16. 9. sabbah s. jagne yj, zuo j, et al. t-cell immunity to kaposi sarcoma-associated herpesvirus: recognition of primary effusion lymphoma by lana-specific cd4+ t cells. blood 2012; 119:2083-92. 10. zargari o. exclusive penile kaposi's sarcoma: report of an hivnegative man successfully treated with radiotherapy. j eur acad dermatol venereol. 2006; 20:318-20. 11. kolios g, kaloterakis a, filiotou a, et al. gastroscopic findings in mediterranean kaposi’s sarcoma (non-aids). gastrointest endosc 1995; 42:336-339. 12. balachandra b, tunitsky e, dawood s, et al. classic kaposi’s sarcoma presenting first with gastrointestinal tract involvement in a hiv-negative inuit male a case report and review of the literature. pathol res pract. 2006; 202:623-6. correspondence aldo franco de rose, md aldofrancoderose@gmail.com matteo justich, md teojus@gmail.com guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com nicolò testino, md nicolo.testino@live.it carlo terrone, md carlo.terrone@med.unipo.it department of urology, ospedale policlinico san martino istituto di ricerca e cura a carattere scientifico per l’oncologia, university of genova largo rosanna benzi 10 16132 genova, italy de rose_stesura seveso 20/06/17 10:05 pagina 165 165archivio italiano di urologia e andrologia 2016; 88, 3 original paper chronic obstructive pulmonary disease (copd) and erectile dysfunction (ed): results of the bred observational study stefano lauretti 1, vittorio cardaci 2, francesco barrese 3, luigino calzetta 4 1 center of sexual medicine and urological rehabilitation. day surgery unit, pscr s. caterina della rosa, asl roma c, italy; 2 physiopathology and respiratory rehabilitation unit ircss san raffaele pisana, rome, italy; 3 unit of urology, fabia mater, rome, consultant in urology ircss san raffaele, rome, italy; 4 laboratory of systems approaches, ircss san raffaele pisana, rome, italy. most patients with chronic obstructive pulmonary disease (copd) share many risk factors and similar aetiological agents with erectile dysfunction (ed). both conditions also cause serious interference with quality of life and sexual relationships. in general, ageing and chronic illness decrease sexual interest, sexual function, and testosterone levels. this observational study included 66 male patients referred to our centre with different grades of copd. we studied the different correlations between copd and ed. the data collected from each patient regarded the following features: demographic and social condition; smoking status; clinical status; spirometric measurements. in this group, copd was diagnosed in 78.8% and ed was present in 83.3% with increased severity in presence of luts and nicotinism. key words: chronic obstructive pulmonary disease (copd); erectile dysfunction; endothelial dysfunction, chronic inflammation. submitted 18 august 2015; accepted 13 october 2015 summary no conflict of interest declared. ed shares several risk factors (4-5) with hypertension (two-fold risk), chronic cardiovascular disease (four-fold risk) (6), diabetes (three-fold risk) (7) and the resulting predisposing factors such as hypercholesterolemia (8), obesity as well as a sedentary lifestyle with contextual nicotinism, irrespective of the abuse entity, further increase the weight of the cause/effect relationship. in a consistently stable fashion, wider epidemiological studies reveal how men between 50 and 59 years are the most frequently represented category, while below 40 years of age, the prevalence of the disorder is between 1% and 10%, with an increase between 2 and 9% in the following decade, with a maximum of 15%, then up to 50-100%, from 70 years onwards. the association with various chronic conditions confirms an overall average increase of prevalence, which in the relationship between ed and diabetes, for example, is between 25 and 33%, with peaks up to 77% (9-10-11). other predominantly chronic conditions may be associated with erectile disorder both in terms of cause and maintenance: renal or hepatic impairment; endocrinopathies such as hypogonadism, hypothyroidism and hyperprolactinemia; various neurological diseases such as postischemic outcomes, multiple sclerosis or parkinson's disease and psychiatric disorders with particular regard to anxious and depressive syndromes (12-13). more recently, increasing importance has been attributed to the common association with obesity and metabolic syndrome (14), although it is not yet clear whether these two conditions are to be understood as a separate entity or an additional risk to diabetes or cardiovascular diseases and lower urinary tract symptoms (luts) (15), which in the results of the cologne male survey correlate with ed at a rate of 72% (16). copd and ed are two conditions that apparently have little in common. certainly it is virtually impossible to compare their consequences on overall health and longterm prognosis (quod vitam), the therapeutic commitment in drug, instrument, rehabilitation and – consequently – economical terms, inevitably involves the entire family sphere. in the face of all this, however, both of these conditions not only present numerous pathodoi: 10.4081/aiua.2016.3.165 introduction chronic obstructive pulmonary disease (copd) is the persistent obstruction of airways (bronchiolitis) associated with the usually progressive destruction of lung areas (emphysema) associated with medical history of chronic inflammation, related to exposure to various pathogens including the prominent role attributed to cigarette smoking. clinically it occurs with progressive shortness of breath, at first under stress and later – in severe cases – even at rest, cough and chronic catarrh (1). erectile dysfunction (ed), or the “persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse” (2), not only implies a more or less severe deficit from a male biological functional point of view, but has also a particularly significant impact on relationships and the quality life of the man who is affected as well as on his partner. currently epidemiological data still comply with the incidence values reported in the mmas study, between 5 and 20% of men, with mild to severe medical history (3). lauretti_stesura seveso 21/09/16 08:37 pagina 165 archivio italiano di urologia e andrologia 2016; 88, 3 s. lauretti, v. cardaci, f. barrese, l. calzetta 166 physiological mechanisms in common, and hence the possibility of shared approach. furthermore, if we consider the population suffering from respiratory disease, what emerges is the constant demand for support in order to live a rewarding relationship and gratifying sexuality, which are extremely important in the early phases of the disease. in chronic disabling diseases, in fact, the sexual function can be otherwise altered, with negative consequences on the relationship, and more generally on the so-called quality of life (17-18). in men whose lives are often strongly affected by the disabling effects of chronic disease, sexuality can be a crucial moment of intimacy and a powerful source of pleasure, as well as of self-esteem and gratification and can help revive a positive affirmation of their role with their partner, whereas, in other contexts, such as work, sport, the social life, this role is limited or may have failed (19-21). copd is not a single nosological entity, but is rather a definition that gathers and describes chronic pulmonary conditions that cause a more or less important limitation of respiratory flow (22). thus ed recognizes numerous aetiopathogenetic factors in common with chronic illnesses and, overall, an increased risk of incidence as has clearly emerged from various epidemiological investigations (23). materials and methods at the unit of pathophysiology and respiratory rehabi litation at the ircss san raffaele in rome, an observational study on broncopathy and erectile dysfunction –bred was conducted from february 1 to july 30, 2015. 66 patients were studied in order to study the different correlations between copd and ed. a database was designed and implemented in visual basic for excel: data were then statistically evaluated using spss/v. 13. information gathered from each patient concerns the following features: – demographic and social: reason for visit, age, place of residence, marital status, type of work involving exposure or non-exposure to risk of respiratory diseases, perceived quality of life (st. george's scale); – smoking habits: active smoker, number of cigarettes smoked daily, years as smoker or ex-smoker; – clinical: co-morbidity/comorbidities, body mass index (bmi), blood glucose, total cholesterol, dyspnoea (mrc), copd, erectile function (international index of erectile function, iief), enlarged prostate (international index symptoms of prostate, ipss); – spirometric measurements: ph, co2, o2, forced expiratory volume (fev1), forced total capacity (fvc), tiffenau index (ti), forced expiatory flow fef75%, pef, vital capacity (vc), total lung capacity (tlc ). the reference ranges are summarized in table 1. copd is expressed as a dichotomous categorical variable, while ed is also expressed as continuous. it should be specified that the latter is one of several fields of sexuality under investigation by the iief. the score obtained from particular applications allows to classify ed as shown in table 2. the distribution of absolute frequencies and percentages of categorical variables and descriptive statistics for continuous variables were used to summarize the characteristics of the sample as a whole, according to the severity of ed and copd. to assess differences in the various characteristics of patients in the different groups, the chi-square test (or fisher's exact test) for categorical explanatory variables and non-parametric tests were used, given the non-normality of the data in question for the constant explanatory variables. in particular, kruskal-wallis allowed the comparison of the various degrees of severity of the disease, while the mann-whitney test assessed the presence or absence of diagnosis of the disease. both tests assess the function of divers variables. these variables were further explored through spearman nonparametric correlation coefficients, to identify possible relationships with the diagnosis and severity of ed and copd. correlations were calculated first for the entire sample and subsequently for the stratified sample according to the following category variables: active smoker, years smoked, years as former smoker, number of cigarettes per day, comorbidity/co-morbidities, bmi, dyspnoea. ultimately a logistic regression model was applied in order to identify possible predictors of ed and copd. critical limit for significance was set at 5%. the software used for the data analysis is spss/v 13.0. results the sample from 39 to 72 year-olds, had a mean age of 62.4 ± 6.9. ed was present in 55 subjects (83.3%): 32 were severe (48.5%), 6 moderate (9.1%), 17 light (25.8%) table 1. blood gas analysis and spirometric parameters and relative normality ranges. parameters normality ranges ph 7.35-7.45 co2 35%-45% o2 > 70% fev1 > 80% fvc > 80% it > 80% fef75% > 80% pef > 80% cv > 80% tlc < 100% table 2. classification of ed. score dysfunction 1-10 severe 11-16 moderate 17-25 light 26-30 absent lauretti_stesura seveso 21/09/16 08:37 pagina 166 and the remaining 11 (16.7%) had a negative diagnosis. 40.9% (n = 27) of the patients had undergone medical examination for dyspnoea, 45.5% (n = 30), for cough, 12.1% (n = 8) for causes related to erectile functionality, one patient (1.5%) for a generic check up. copd was diagnosed in 52 patients (78.8%), among whom 10 (15.2%) had slight copd, 19 (28.8%) moderate, 13 (19.7%) severe, 10 (15.2%) very serious and the remaining 14 (21.2 %) were at risk. 13.6% (n = 9) of the patients had hypertension, 19.7% (n = 13), hypercholesterolemia, 15.2% (n = 10) suffered from several other diseases, and the remaining 51.5% did not have co-morbidities. 90.9% (n = 60) of the patients lived in cities while the rest of them lived in the country; 7 (10.6%) had a job that exposed them to lung disease risks; 56.1% (n = 37) were married or cohabiting, 31.8% (n = 21), were celibate, the remaining 12.2% were separated (n = 4) or widowed (n = 4). according to the st. georges questionnaire it was found that these patients perceived a low quality life (86.4 ± 19.3). the mean sample of patients had 28.3 ± 6.7 bmi, 2 were underweight (3.0%) while 3 suffered severe obesity (4.5%). taking into account the smoking habits, 21.2% (n = 14) had never smoked, 24.2% (n = 16) were smokers and the remaining 54.5% (n = 36) had a history of smoking, including 30.6% (n = 11) who had stopped smoking for less than a year, and 16.7% (n = 6) for over five years. considering the sample as a whole, 12.1% (n = 8) smoked for less than ten years, and 28.8% (n = 19) for more than twenty years. only one subject (1.5%) smoked less than 5 cigarettes a day, one-third of the remaining (30.8%) smoked between five and ten cigarettes a day, another third (34.6%) between ten and twenty, while the last third (32.7%) over twenty cigarettes per day. 24.2% (n = 16) had no dyspnoea, 39.4% (n = 26) light dyspnoea, 18.2% (n = 12) moderate, 16.7% (n = 11) severe and only one case (1.5%) suffered from extremely severe dyspnoea. according to the ipss scale, in the cases that showed lower urinary tract disorders, 39.4% (n = 26) of the cases had light symptoms, 10.6% (n = 7) of patients were seriously affected, while 50.0% (n = 33) were seriously compromised only under certain circumstances. with regard to the spirometric parameters, 87.9% (n = 58) of the patients had normal values of ph, 3% (n = 2) lower than normal and 9.1% (n = 6) higher than the threshold of normality (average = 7.4; sd = 0.0). half of the patients had co2 levels above the normal range, while none had lower values (average = 47.8; sd = 12.9). 62.1% (n = 41) had normal oxygen levels while the remaining 37.9% (n = 25) had low levels (average = 73.8; ds 11.3). almost 70% (n = 46) of patients had low fvc, the remaining 30% (n = 20) had normal (average = 69.4; sd = 22.6). 84.8% (n = 56) were found to have too low fev1 values, while the remaining 15.2% (n = 10) had normal (average = 53.5; sd = 26.9). only 12.1% (n = 8) fulfilled the tiffenau index normality parameter, against 87.9% (n = 58) who were below the threshold (average = 57.7; sd = 21.3). slightly fewer than 30% (n = 19) had a normal vital capacity, compared with 71.2% (n = 47) (mean = 70.6; sd = 21.7). most patients, 51 (77.3%), had a total lung capacity that was higher than 100%, while only 22.7% (n = 15) was below the threshold (average = 145.4; sd = 64.5). studying the distribution of the subjects characteristics related to the severity degrees of ed and copd, it was found that: 56.8% (n = 21) of married or cohabiting patients had severe ed, while the single men were affected by the disease only in 37.9% (n = 11) of the cases and in 41.4% (n = 12), the ed was light (χ2(3) = 7.9, p = 0.048); 42.3% (n = 11) of the patients with absence or light urinary tract disorder suffered from light ed, while 63.6% (n = 21) of those who presented a median symptomatology, and 57.1% (n = 4) of those with severe symptoms, had severe ed (χ2(6) = 14.9, p = 0.021); among subjects who had stopped smoking from less than a year, none had severe or very severe copd, while among those who had stopped smoking for more than 5 years, 83.3% (n = 5) were suffering from severe copd (χ2(12) = 33.2, p = 0.001); there was no case of severe or very severe copd among patients with fvc in the normal range, while an equal distribution of patients with fvc was observed to be below the normality threshold among the different degrees of copd (χ2(4) = 15.5, p = 0.004). the kruskal-wallis test has revealed a weak connection between ed and age, while copd seems to be associated with most of the spirometric parameters, bmi, quality of life perception and ed expressed as absolute score (table 3 shows the medians and statistics of the test). according to the mann-whitney test, there is no statistical difference between the characteristics of patients without ed, or at risk of copd and those who had already developed the disease. the degree of ed has been correlated in a statistically significant way with the severity levels of copd (ρ = -0.28, p = 0.024) and age (ρ = -0.33, p = 0.007), or rather a more serious form of copd and at an older age corresponds to a more important ed. as expected, copd seems related to many spirometric parameters and quality of life. in particular, more severe copd corresponds to poorer values of spirometric parameters, but a better sense of well-being. the results are reported in table 4. in order to complete the study, a more thorough analysis of the stratified correlation for the main characteristics of the patients has been performed both for copd as well as for ed. based on the logistic regression analysis none of the monitored parameters emerged as a predictor of the presence of ed. statistical evidence has led to the identification of forced expiatory volume corruption as the sole predictor of copd. specifically, it has been estimated that patients with fev1 lower than 80% had about 5fold higher odds of presenting pathology than patients with normal parameters (or = 5.22, ci95 = 1.25, 21.82, p = 0.023). 167archivio italiano di urologia e andrologia 2016; 88, 3 chronic obstructive pulmonary disease (copd) and erectile dysfunction (ed): results of the bred observational study lauretti_stesura seveso 21/09/16 08:37 pagina 167 archivio italiano di urologia e andrologia 2016; 88, 3 s. lauretti, v. cardaci, f. barrese, l. calzetta 168 discussion on the basis of an analysis of correlation, the severity degree of ed and copd appear to be associated: severe levels of copd correspond to poorer erectile function (24). however, it was not possible to identify the predictors of ed through the analysis of logistic regression, although it appeared that both married patients as well as those with medium to severe urinary disorders suffered from a higher level of dysfunction. furthermore, patients with mild disease or absence of disease had a lower mean age. the only predictive parameter of copd was found to be forced expiatory volume lower than 80%. many of the other spirometric parameters, although not predictory, resulted to be significantly correlated to a more severe form of copd, as well as having a more positive perception of life quality. in addition to the previous results, the number of years as ex-smoker seems associated with the severity of copd, or rather the greater part of those who had stopped smoking for more than 5 years had severe or very severe forms. finally, according to the kruskal-wallis test, patients with varied degrees of pathology differ significantly in many of the spirometric parameters, for body mass index, for the perception of quality of life and for ed, expressed as a continuous variable. the need to study the pathologies on the basis of certain characteristics of patients, such as smoking habits, requires subdividing them into small samplesized groups. this limits the efficacy of the study, as it does not allow generalization and the extension of the results to an entire population. a more appropriate study would provide for a stratified sample regarding both degrees of copd severity, so as to obtain an equitable number of subjects suffering from the disease and at risk for copd, as well as the different smoking habits. at present, ed is increasingly establishing itself as the “sentinel symptom” of chronic diseases (hypertension, diabetes, ischemic heart disease): in this sense, it may paradoxically be a real “life saver” by which we can identify and eventually correct early phases of disease or hazardous lifestyles. it has also been emphasized how copd is a “modifiable” condition before it becomes irreversible. karadag (25) has shown how in patients with copd, a high level of cytokines tnf-α, the recognized marker of chronic inflammation, is in turn correlated with body weight, chronic hypoxemia and cigarette smoking. in the relationship between the two pathological conditions, moderate and severe levels of tnf-α are particularly high in ed, suggesting that even chronic inflammation may play a causative role in the onset of ed in patients with copd (26), resulting in alterations in the vascular endothelium (27-30). however, the high levels of plasma cytokines related to the degree of obesity in patients with ed had already been evaluated by giuliano (31). copd, as other diseases of the lung, can result in a condition, shared with the ed, of vasoconstriction and microvascular occlusion. in the lung, this leads to changes in the ventilation/perfusion ratio, intrapulmonary shunting, arterial hypoxemia and pulmonary hypertension, especially in the later stages of the disease. in both primary and secondary pulmonary hypertension, there is a decreased expression of e-nos absent (median) light (median) moderate (median) severe (median) χ2(3) p-value ed categorical age 61 61 67 66 7.98 0.046 at risk (median) light (median) moderate (median) severe (median) very serious (median) χ2(4) p-value copd category bmi 27 29 25 31 23 13.0 0.011 fvc 68 78 79 55 51 18.5 0.001 fev1 68 54 63 41 25 29.7 0.000 it 63 52 61 53 40 12.1 0.017 fef75% 39 44 29 16 10 27.4 0.000 pef 49 57 66 41 28 27.3 0.000 cv 63 66 77 67 50 18.8 0.001 st.george 97 100 93 73 74 15.8 0.003 de score 16 10 18 6 4 9.6 0.048 table 3. distribution of the variable medians associated with erectile dysfunction and copd, for the different severity degrees of the disease, and kruskal-wallis test (χ2, p-value). variables ρ p-value ed category (n = 66) copd category -0.278(*) 0.024 age 0.327(**) 0.007 copd category (n = 66) o2 -0.244(*) 0.048 fvc -.359(**) 0.003 fev1 -.510(**) 0.000 it -.254(*) 0.040 fef75% -.490(**) 0.000 pef -.394(**) 0.001 quality of life (st. george) -.405(**) 0.001 table 4. variables associated with erectile dysfunction and copd, both categorical (ρ, p-value). lauretti_stesura seveso 21/09/16 08:37 pagina 168 (endothelial nitric oxide synthase), pulmonary vascular endothelium. the three aetiopathogenetic hypotheses are common in the two conditions: inflammatory, vascular and endo crine. following sexual stimulation, non-adrenergic and non-cholinergic nerve endings (nanc) release no, which through the second messenger, cgmp, induces the relaxation of the smooth muscles in the corpora cavernosa. the levels of cgmp are regulated by the action of pde5, the enzyme responsible for the hydrolysis of cgmp in gmp. for the same functional cascade, this could also represent the rationale of treatment with pde5 inhibitors, aimed at improving the ventilatory lung flow (32). conclusions both ed and copd conditions share several risk factors and physiopathological mechanisms. these correlations can lead to some interesting assumptions of treatment, common to both diseases, although the importance of proper prevention, especially in younger patients, cannot be ignored. ed and copd may finally determine important ingravescence as well as often cause emotional, relational, social and sexual issues, with potentially depressive tendencies, not only in the patient but also, and especially, in the couple. these conclusions confirm, once again, the need for a multi-speciality health policy for the prevention and management (33). references 1. global initiative for chronic obstructive lung diseases: global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease (copd). update january: 2, 2014. 2. nih consusus development conference statement: impotence. 1992; 10:1-31. 3. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 4. schouten bw, bohnen am, dohle gr, groeneveld fpm, et al. risk factors for deterioration of erectile function: the krimpen study. int j androl. 2007; 32:166-175. 5. cazzola m, bettoncelli g, sessa e, et al. prevalence of comorbidities in patients with chronic obstructive pulmonary disease. respiration; international review of thoracic diseases 2010; 80:112-119. 6. gandaglia g, briganti a, jackson g, et al. a systematic review of the association between erectile dysfunction and cardiovascular disease. eur urol. 2014; 65:968-978. 7. tamler r. diabetes, obesity and erectile dysfunction. gender medicine 2009; vol. 6 theme issue; 4-16. 8. roumeguère th, wespes e, carpentier y, et al. erectile dysfunction is associated with high prevalence of hyperlipidemia and coronary heart disease risk. eur urol. 2003; 44:355-359. 9. benet ae, melman a. the epidemiology of erectile dysfunction. urol clin north am. 1995; 22:699-709. 10. parazzini f, menchini fabris f, bortolotti a, et al. on behalf of gruppo italiano studio deficit erettile, frequency and determinants of erectile dysfunction in italy. eur urol. 2000; 37:43-49. 11. gareri p, castagna a, francomano d, et al. erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. int j endocrinol. 2014; 2014; 873760. 12. krane rj, mckinlay jb. impotence and its medical and psychological correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 13. giuliano f, droupy s. erectile dysfunction. prog urol. 2013; 23:629-637. 14. tiengo a, fadini gp, avogaro a. the metabolic syndrome, diabetes and lung dysfunction. diabetes metab. 2008; 34:447-454. 15. huang wj, chen kk, chang ls. correlation between voiding and erectile function in patients with symptomatic benign prostatic hyperplasia. j clin med assoc. 2005; 68:178-182. 16. braun m, wassmer g, klotz t, et al. epidemiology of erectile dysfunction: results of the ‘cologne male survey’. int j impot res. 2000; 12:305-311. 17. mcinnes ra. chronic illness and sexuality. real life. 2003; 179:263-266. 18. lauretti s, cardaci v. broncopneumopatia cronica ostruttiva (bpco) e disfunzione erettile (de): implicazioni eziopatogenetiche multifattoriali. urologia. 2008; 75:s11-s15. 19. paap m, bode c, lenferink l, et al. identifying key domains of health-related quality of life for patients with chronic obstructive pulmonary disease: the patient perspective. health qual life outcomes. 2014; 1:106-123. 20. kaptein aa, van klink rc, de kok f, et al. sexuality in patients with asthma and copd. respir med. 2008; 102:198-204. 21. collins eg, halabi s, langston m, et al. sexual dysfunction in men with copd: impact on quality of life and survival. lung. 2012; 190:545-556. 22. vijayan vk. chronic obstructive pulmonary disease. indian j med res. 2013; 137:251-269. 23. fletcher ec, martin ri. sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease. chest. 1982; 81:413-421. 24. koseoglu n, koseoglu h, ceylan e, et al. erectile dysfunction prevalence and sexual function status in patients with chronic obstructive pulmonary disease. j urol. 2005; 174:249-252. 25. karadag f, ozcan h, karul ab, et al. correlates of erectile dysfunction in moderate-to-severe chronic obstructive pulmonary disease patients. respirology. 2007; 12:248-253. 26. carneiro fs, saiprazad zemse b, et al. tnf-α infusion impairs corpora cavernosa reactivity. j sex med. 2009; 6 suppl 3:311-319. 27. aversa a. strategies to improve endothelial function and its clinical relevance to erectile dysfunction. eur urol. suppl. 2009; 8:71-79. 28. rajfer j. endothelial dysfunction as a cause of erectile dysfuction. misdiagnosis or misnomer? urology. 2004; 64:193-194. 29. deanfild je, halcox jp, rabelink tj. endothelial function and dysfunction: testing and clinical relevance. circulation. 2007; 115:1285-1295. 30. foresta c, caretta n, lana a, et al. relationship between vascu169archivio italiano di urologia e andrologia 2016; 88, 3 chronic obstructive pulmonary disease (copd) and erectile dysfunction (ed): results of the bred observational study lauretti_stesura seveso 21/09/16 08:37 pagina 169 archivio italiano di urologia e andrologia 2016; 88, 3 s. lauretti, v. cardaci, f. barrese, l. calzetta 170 lar damage degrees and endothelial progenitor cells in patients with erectile dysfunction: effect of vardenafil administration and pde5 expression in the bone marrow. eur urol. 2007; 51:1411-1417. 31. giugliano f, esposito k, di palo c, et al. erectile dysfunction associates with endothelial dysfunction and raised pro-inflammatory cytokine levels in obese men. j endocrinol invest. 2004; 27:665-66. 32. toque ha, teixeira ce, priviero fb, et al. vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. br. j. pharmacol 2008; 154: 787-796. 33. vincent ee, singh sj. addressing the sexual health of patients with copd: the needs of the patient and implications for health care professionals. chronic respiratory disease. 2007; 4:111-115. correspondence stefano lauretti, md stefanolauretti@gmail.com center of sexual medicine and urological rehabilitation. day surgery unit, pscr s. caterina della rosa, asl roma c, rome, italy vittorio cardaci, md vittorio.cardaci@sanraffaele.it physiopathology and respiratory rehabilitation unit ircss san raffaele pisana, rome, italy francesco barrese, md fbarrese.urologo@gmail.com unit of urology. fabia mater, roma. consultant in urology ircss san raffaele rome, italy luigino calzetta, md luigicalz@gmail.com laboratory of systems approaches, ircss san raffaele pisana rome, italy lauretti_stesura seveso 21/09/16 08:37 pagina 170 archivio italiano di urologia e andrologia 2016; 88, 4314 original paper azoospermic patient’s treatment: an experience of a pma hospital unit and role of ultrasonography paolo panella 1, pietro pepe 1, placido borzì 2, maria elena vento 2, michele pennisi 1, paolo scollo 2 1 urologic unit, 2 obstetrics and gynecology unit, pma service, cannizzaro hospital, catania, italy. introduction: azoospermia causes about 10% of male infertility and the best therapeutic option is the retrieval of sperm from testis or epididymis. material and methods: from juanary 2008 to june 2016, 92 men (median 36 years; range: 25-54 years) were submitted in 47 cases to tese (testicular sperm extraction) and in 45 cases to pesa (percutaneous epididymal sperm aspiration) for secretory and obstructive azoospermia, respectively; moreover, all the patients previously underwent color doppler ultrasound of the testis and transrectal ultrasound of the prostate. results: serum fsh values were 9.4 ml/ui and 36.4 ml/ui (median 18.2 ml/ui) with an estimated volume of the testis equal to 5 ml; 40 men had the mutation for cystic fibrosis with bilateral agenesis of the deferentia vasa, 4 men had a cyst of the prostatic utricle, 1 man had retrograde ejaculation, 7 had an epididymis cyst and 2 had anejaculation secondary to traumatic neurologic spinal cord injury. the retrieval of sperm was performed in 39 (83%) and 36 (80%) of the patients submitted to tese and pesa, respectively. the pregnancy rate was equal to 28% and 33% in men with secretory and obstructive azoospermia, respectively. discussion: assisted reproduction technology with a multidisciplinary team is provided of a pregnancy rate equal about 30% in men with azoospermia; ultrasound allows to evaluate abnormalities of the testis and prostate improving the percentage of pregnancy. key words: azoospermia; sperm retrieval techniques; ultrasound of male genital tract; treatment of azoospermia. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. tese (testicular sperm extraction) and in 45 cases to pesa (percutaneous epididymal sperm aspiration) for secretory and obstructive azoospermia, respectively; moreover, all the patients previously underwent cdu of the testis and prostate. the pesa was performed under local anesthesia (mepivacaine 2% without adrenaline) using a 21 gauge butterfly. all the patients underwent to general and genital physical examination, evaluation of two semen analysis, culture of semen performing pcr (amplification of dna) for chlamidya trachomatis, mycoplasma hominis and mycetes. in addition, the karyotype with the evaluation of microdeletion for cromosoma y and mutation of fibrosis cistyc genes was done. a ge logiq e9 and p6 with small part and biplanar transrectal probes were used to perform cdu evaluation of testis and prostate; in detail, the ecopattern and the vessels maps of the testis were evaluated to improve the detection of sperm during biopsy procedure. all the patients underwent to blood evaluation for fsh, lh, testosterone, cmv, hbv, hcv e hiv. the biopsy testicular parenchyma was delivered to the biologists team to retrieval the sperm and perform in real time icsi procedure; finally, testicular parenchyma underwent definitive histological evaluation. results serum fsh values were 9.4 ml/ui and 36.4 ml/ui (median 18.2 ml/ui) with an estimated volume of the testis equal to 5 ml; 40 men had the mutation for cystic fibrosis with bilateral agenesis of the deferentia vasa, 4 men had a cyst of the prostatic utricle, 1 man had retrograde ejaculation, 7 had and epididymis cyst and 2 had anejaculation secondary to traumatic neurologic spinal cord injury. the recovery of sperm was performed in 39 (83%) and 36 (80%) of the patients submitted, respectively, to tese and pesa. the pregnancy rate was equal to 28% in men with secretory azoospermia and to 33% in those with obstructive azoospermia. the culture of semen was negative in all patients. four men underwent transperineal ultrasound guided prostatic cyst aspiration before testis biopsy (figure 1); none had abnormal ultrasound suspicious area of the testis. three patients had hematocele and orchiepididymitis following biopsy those did not required hospitalization. definitive specimens did not found neoplastic lesions of the testis. doi: 10.4081/aiua.2016.4.314 presented at 20th national congress sieun, sciacca 2016 introduction about 20% of the couples is unable to have a pregnancy. the obstructive and non obstructive azoospermia constitutes the 10% of male infertility; in these cases the icsi (intracytoplasmatic sperm injiection) allows to have a pregnancy in about 30% of the cases (1). the sperm could be retrieval in the semen or directly in the testis or epididymis performing a percutaneous or open procedure (2-4). the role of color doppler ultrasound (cdu) in the clinical evaluation of azoospermic men, has been reported (5). material and methods from january 2008 to june 2016, 92 men (median 36 years; range: 25-54 years) were submitted in 47 cases to panella-azoospermic patient’s treatment_stesura seveso 09/01/17 10:07 pagina 314 315archivio italiano di urologia e andrologia 2016; 88, 4 ultrasonography in azoospermic patient discussion assisted reproduction technology (art) is the treatment used to achieve pregnancy in procedures such as fertility medication, artificial insemination, in vitro fertilization and surrogacy. it mainly belongs to the field of reproductive endocrinology and infertility, and may also icsi and cryopreservation (6, 7). some forms of art are also used with regard to fertile couples for genetic reasons (preimplantation genetic diagnosis). transvaginal ovum retrieval is the process whereby a small needle is inserted through the back of the vagina and guided via ultrasound into the ovarian follicles to collect the fluid that contains the egg cells. the icsi is beneficial in the case of male factor infertility where sperm counts are very low, in the presence of azoospermia or failed fertilization occurred with previous ivf attempt. the icsi procedure involves a single sperm carefully injected into the center of an egg cell using a microneedle (8, 9). before performing art clinical evaluation of the couple is mandatory; in this respect, cdu of the testis and prostate improve sperm retrieval rate guiding testis biopsy in the areas with better parenchymal microcirculation (10, 11). in addition, transrectal ultrasound detect seminal obstruction secondary to cistys or stenosis of ejaculatory ducts those could be successfully cured (12, 13). the pesa is a technique used to determine sperm counts in the event of a possible blockage of the deferentia vasa; it is an alternative to microepidydimal sperm aspiration (mesa), and aims to address the technical difficulty and cost of mesa. a small needle (butterfly 23 o 21 g) is inserted through the skin of the scrotum to collect sperm from the epididymis or testis (tefna “testicular fine needle aspiration tesa “testicular sperm aspiration”). the tese is the process of removing a small portion of tissue from the testicle, under local anesthesia, and extracting the few viable sperm cells present in that tissue for icsi (figure 2). mesa refers to retrieval of sperm-containing fluid from optimal areas of the epididymis that are selected and sampled using highpower optical magnification provided by an operating microscope (14). the percutaneous approach is less invasive then surgical techniques and could be performed under local anesthesia; tese and microtese procedures allows to reach a sperm retrieval rates equal to 30-70% and 80% per cycle, respectively. in our series, we obtained a sperm retrieval rate equal to 78% with a pregnancy rate of 28% (15). in conclusion, assisted reproductive department needs a multidisciplinary team to improve the clinical couple evaluation and the pregnancy rate; cdu of testis and prostate allows to improve the percentage of pregnancy. references 1. timpano m, fontana d, rolle l, et al. prelievo di spermatozoi per la procreazione medicalmente assistita in pazienti affetti da azoospermia. urologia 2014; 81:27-31. 2. esteves sc, miyaoka r, agarwal a. sperm retrieval techniques for assisted reproduction. int braz j urol. 2011; 37:570-583. 3. colpi gm, piediferro g, nerva f, et al. sperm retrieval for intracytoplasmic sperm injection in nonobstructive azoospermia. minerva urol nefrol. 2005; 57: 99-107. 4. tsujimura a, matsumiya k, koga m, et al. outcome of surgical treatment for obstructive azoospermia. arch androl. 2002; 48:2936. 5. lotti f, maggi m. ultrasound of the male genital tract in relation to male reproductive health. hum reprod update. 2015; 21:56-83. 6. hong-tao jiang, qian yuan, yu liu, et al. multiple advance surgical techniques to treat acquired seminal duct obstruction. asian j androl. 2014; 16:912-916. figure 1. transperineal percutaneous aspiration of prostatic cyst. figure 2. testicular sperm extraction. panella-azoospermic patient’s treatment_stesura seveso 09/01/17 10:07 pagina 315 archivio italiano di urologia e andrologia 2016; 88, 4 p. panella, p. pepe, p. borzì, m.e. vento, m. pennisi, p. scollo 316 7. tsujimura a. microdissection testicular sperm extraction: prediction, outcome and complications. int j urol. 2007; 14:883889. 8. schroeder-printzen i, ludwig m, köhn f, weidner w. surgical therapy in infertile men with ejaculatory duct obstruction: technique and outcome of a standardized surgical approach. hum reprod. 2000; 15:1364-1368. 9. watkins w, nieto e, bourne h, et al. testicular and epididymal sperm in a microinjection program: methods of retrieval and results. fertil steril. 1997; 67:527-535. 10. colpi gm, colpi em, piediferro g, et al. microsurgical tese versus conventional tese for icsi in non-obstructive azoospermia: a randomized controlled study. reproductive biomedicine online. 2009; 3:315-319. 11. glander hj, horn lc, dorschner w, et al. probability to retrieve testicular spermatozoa in azoospermic patients. asian j androl. 2000; 2:199-205. 12. cytron s, avrech om, pinkas h, et al. preliminary experience with ultrasound-guided percutaneous perineal aspiration of spermatozoa for icsi in azoospermic patients with obstructed ejaculatory ducts. hum. reprod. 1996; 11 (suppl. 1), abstract t069. 13. xu chen, hua wang, rong pei wu, et al. the performance of transrectal ultrasound in the diagnosis of seminal vesicle defects: a comparison with magnetic resonance imaging. asian j androl. 2014; 16:907-911. 14. safran a, reubinoff be, porat-katz a, et al. assisted reproduction for the treatment of azoospermia. hum reprod. 1998; 13:4. 15. heshmat s, lo kc. evaluation and treatment of ejaculatory duct obstruction in infertile men. can j urol. 2006; 13:18-21. correspondence paolo panella, md (corresponding author) p.panella@alice.it pietro pepe, md michele pennisi, md urologic unit, cannizzaro hospital, catania, italy placido borzì, md maria elena vento, md paolo scollo, md obstetrics and gynecology unit pma service, cannizzaro hospital, catania, italy panella-azoospermic patient’s treatment_stesura seveso 09/01/17 10:07 pagina 316 archivio italiano di urologia e andrologia 2017; 89, 3208 original paper comparison of conventional dressings and vacuum-assisted closure in the wound therapy of fournier’s gangrene fatih yanaral 1, can balci 2, faruk ozgor 1, abdulmuttalip simsek 3, ozkan onuk 2, muammer aydin 2, baris nuhoglu 2 1 department of urology, haseki teaching and research hospital, istanbul, turkey; 2 department of urology, gaziosmanpasataksim teaching and research hospital, istanbul, turkey; 3 department of urology, bakirkoy dr. sadikonuk teaching and research hospital, istanbul, turkey. objective: the purpose of our study was to compare vacuum-assisted closure (vac) and conventional dressings in the wound therapy of fournier’s gangrene (fg). materials and methods: the study evaluated 54 patients, retrospectively. following initial removal of necrotic and devitalized tissue, in group i patients the wounds were covered with conventional antiseptic dressings and patients continued to be treated with conventional dressings. in group ii patients vac therapy was initiated. the collected data were compared between groups. results: the difference between two groups were statistically significant in terms of number of daily dressing (group i: 2, group ii: 0,5), vas (group i: 8, group ii: 5), number of daily analgesics (group i: 4, group ii: 2), number of daily narcotic analgesics (group i: 1, group ii: 0), duration of mobilization per day (group i: 40, group ii: 73 minutes) (p < 0.05). conclusions: our study does not determine that a vac therapy is better than conventional dressings in terms of clinical outcome. however, vacuum dressing appears an effective and successful method, which offers fewer dressing changes, less pain, and greater mobility comparing to conventional dressings in the management of fg patients. key words: debridement; gangrene; prognosis; treatment outcome; wound closure techniques. submitted 26 april 2017; accepted 2 june 2017 summary no conflict of interest declared. rates (3). classical treatment consists of radical excision of all necrotic tissue, broad-spectrum antibiotics and intensive care. usually repeated debridement is necessary. for this reason wounds of the patients remain open for a long time, and require frequent dressing. different protocols have been proposed for postoperative open wound care: unprocessed honey, hyperbaric oxygenation, grown hormones, growing agents, and vacuumdressing technologies (4). vacuum-assisted closure (vac) device (kci usa, inc. san antonio, tx usa) is a wound care system that works on the basis of negative pressure vacuuming; removes exudate and infectious materials, reduces edema and promotes healing. the purpose of our study was to comparevac and conventional dressingsin the wound therapy of fg. materials and methods the study evaluated 54 patients who diagnosed of fg and received treatment between june 2001 and october 2014 at our urology department. all data and parameters were analyzed retrospectively. fg was diagnosed by evidence of a necrotizing fasciitisin the scrotal or perineal region. patients with a simple inflammation without involvement of the fascia, necrotizing fasciitis at other locations and patients with incomplete clinical data were excluded from the analysis. intravenous replacement of fluid and electrolytes, thirdgeneration cephalosporin and metronidazole antibiotherapy were started at admission. all patients underwent surgical debridement during admission day (figure 1). empiric antimicrobial therapy was revised according to the results of bacterial culture and drugsensitive tests of the removed tissue samples. following initial removal of necrotic and devitalized tissue, in group i patients the wounds were covered with conventional antiseptic dressings and patients continued to be treated with conventional dressings by washing repeatedly with saline until healthy granulation tissue was formed in the wound. wound dressings were changed twice a day. after surgical debridement, in group ii patients vac therapy was initiated. silver nitrate sponge was used for the wounds then drape was placed over the doi: 10.4081/aiua.2017.3.208 introduction in 1883, jean alfred fournier described a syndrome with necrosis of the perineum in five men; this type of necrotizing fasciitis was subsequently given his name and is known as fournier’s gangrene (fg) (1). fg is a potentially life-threatening progressive infection necrotizing fasciitis of the perineal, genital, or perianal regions. it is characterized by thrombosis of the nutrient vessels leading to tissue ischemia and tissue ischemia promotes infectious dissemination leading to skin necrosis. in most cases, fg is a polymicrobial infection, with both aerobic and anaerobic organisms, which originates from a urogenital, colorectal, or cutaneous source (2). in spite of aggressive management; it is associated with high morbidity and mortality (3-67%) and a delay in diagnosis and treatment is known to increase mortality yanaral_stesura seveso 28/09/17 10:21 pagina 208 209archivio italiano di urologia e andrologia 2017; 89, 3 vacuum-assisted closure in fournier’s gangrene results all the 54 patients were male, with a mean age of 55.8 ± 14.9 in conventional dressings group and 61.6 ± 7.6 in vac group (p > 0.05). group i consisted of thirty-one patients and group ii consisted oftwenty-three patients. the two groups were similar in the distribution of history of diabetes mellitus (group i: 41.9%, group ii: 60.9%), wound diameter (group i: 17, group ii: 15 cm), duration of operation (group i: 55, group ii: 48 minutes), number of surgical debridement (group i: 1, group ii: 2), and length of hospital stay (group i: 14, group ii: 17 days) (p > 0.05). the origin of fg was anorectal diseases in 13 patients in group i (41.9%) and 10 patients in group ii (43.5%). the other origin was urogenital diseases in 18 patients in group i (58.1%) and 13 patients in group ii (56,5%), time from initial surgical debridement to wound closure (group i: 12 (7-25), group ii: 13 (11-21) days) (p > 0.05) (table 1). however the difference between two groups were statistically significant in terms of number of daily dressing (group i: 2, group ii: 0.5), vas (group i: 8, group ii: 5), number of daily analgesics (group i: 4, group ii: 2), figure 1. patient during surgical debridement with fournier’s gangrene. figure 2. vac therapy at negative pressure. figure 3. same patient as in figure 1 and 2. a: after the second session of vacuum therapy. b: after the third session of vacuum therapy. c: three months after wound closure. sponge, suction was inserted and continuous negative pressure was applied to the wounds (figure 2). initially, the pressure is set to 50 mm hg and increased to a maximum of 125 mm hg. vac dressings were changed every 48-72 hours. additional changes were performed in both groups if the dressings became wet due to blood or fluid from the wounds. in the case of progressive necrosis, surgical debridement was repeated. after the wounds were clinically healed, in small residual defects tertiary wound closure was performed; otherwise, skin flap or graft surgery was performed (figure 3). we collected data on patient age, gender, history of diabetes mellitus, origin, wound diameter, duration of operation, use of vac, the number of daily dressing, visual analogue scale for pain (vas), need for analgesics, the duration of mobilization per day, number of surgical debridement, time from initial surgical debridement to wound closure, wound closure technique, length of hospital stay (los), number of deaths. the independent-samples t-test, the mann-whitney u test, chi-square test and fisher’s exact test were used for statistical analysis. results were considered statistically significant if the p value was less than 0.05. yanaral_stesura seveso 28/09/17 10:21 pagina 209 archivio italiano di urologia e andrologia 2017; 89, 3 f. yanaral, c. balci, f. ozgor, a. simsek, o. onuk, m. aydin, b. nuhoglu 210 number of daily narcotic analgesics (group i: 1, group ii: 0), duration of mobilization per day (group i: 40, group ii: 73 minutes) (p < 0.05). wound closure was performed by tertiary closure in 19 and 11 patients among group i and group ii, respectively. on the other hand, the wounds of twenty patients (group i: 10, group ii: 10) were reconstructed with skin flap or graft (p > 0.05). the mortality rate was lower in the group i at 6.5% (2/31) compared with the group ii, which was 8.7% (2/23). but this difference was not statistically significant (p > 0.05) (table 2). discussion fg is an uncommon but life-threatening condition. males are reported to be ten times more likely than females to develop the disease.the predisposing factors include diabetes mellitus, alcohol abuse, immunodeficiency, malignant neoplasms, and liver and renal diseases. multiple predisposing factors represent a poor prognosis and high mortality (5). the most frequent comorbidity in patients with necrotizing fasciitis is diabetes mellitus (10-60%). in the literature the incidence is highest in the sixth decade of life and patient age in our study groups was similar to that reported (6). fg maybe the result of surgical wounds, skin abscess drainage, and pressure sores. it can also present as a complication of colorectal disease due to anorectal infection, ischiorectal abscesses, and colon perforations. other causes include a possible urethral stricture and a trauma from an indwelling foley catheter (7). previous studies from general surgery departments reporting perianal abscess as the most common etiological factor (8). as a urology department we found that the most common origin of fg was urogenital diseases (57.4%). the two groups were similar in origin of disease (p = 1). timing and the extent of the first debridement are the most important risk factors in terms of increased mortality rate. the relative risk of death was 7.5 times greater in cases of restricted primary debridement (9). surgical removal of necrotic tissue caused halting the progress of the infection and eliminating the systemic effects of necrotic material, toxins, and bacteria (10). after initial surgical debridement, management of the wound is important, along with proper nutrition of the patient. in most cases, wounds are managed with conventional dressings that contain a wide variety of active agents such as saline, povidone iodine, potassium permanganate, dakin’s solution, enzymatic agents for wound cleansing, or polyhexanide. the other proposed protocols are unprocessed honey, hyperbaric oxygenation, grown hormones, growing agents, and vacuum-dressing technologies (4). vac is a device used in the general surgery, orthopedic, and gynecology in wound care management. it is also applied in the management of large wounds resulting from fg. vac therapy has several benefits with wound area reduction and formation of granulation tissue being the most prominent. other benefits, such as effective wound cleaning and the ability to remove the exudate render vac a promising adjuvant therapy for wound closure (7). since the conventional dressings require painful changes twice a day, this has a large negative impact on the patient’s quality of life. patients in the group ii reported less pain and less need for analgesics, had greater mobility, needed fewer dressing changes than the patients in the group i. since patients did not need significant sedation and analgesia every day, oral intake was not limited. thus vac therapy can be more comfortable for patients. in a study faster discharge-using vac device was found however, in another study no difference was reported in wound healing time comparing conventional dressing with vac (4, 11). in the present study, vac therapy does not decrease wound healing time when compared with conventional dressing techniques. however, vac effectively converts an open wound into a temporarily closed and controlled environment an it is possible to obtain much cleaner wounds without exudate by draining stagnant fluid and the debris. these devices stimulate angiogenesis and lead to an improvement of nourishment and tissue formation and create a favorable environment for healing in wound beds (12). the length of hospitalization can be exacerbated by large tissue defects or sepsis-induced complications. the mean hospital stay was similar between group i (14 days) and in group ii (17 days). the mean length of stay for all 54 patients was 16 days, which is shorter to the result reported by czymek et al. (40 days) (13).this is due to our patients have smaller soft-tissue defects. death is caused by coagulopathy, acute renal failure, diabetic ketoacidosis, severe sepsis, or multi-organ failurtable 1. preoperative characteristics of patients. conventional dressings vac group p group (n: 31) (n: 23) mean age, years 55.8 ± 14.9 61.6 ± 7.6 > 0.05 dm 13 (41.9%) 14 (60.9%) > 0.05 origin (anorectal/urogenital) 13/18 10/13 > 0.05 median wound diameter, cm 17 (10-45) 15 (9-44) > 0.05 dm = diabetes mellitus. table 2. clinical characteristics of patients. conventional dressings vac group p group (n: 31) (n: 23) duration of operation, minutes 55 (30-110) 48 (30-98) > 0.05 no. of daily dressing 2 (2-3) 0.5 (0.5-1) < 0.05 vas 8 (4-10) 5 (4-10) < 0.05 no. of daily anelgesics 4 (3-5) 2 (2-3) < 0.05 no. of daily narcotic anelgesics 1 (0-2) 0 (0-1) < 0.05 duration of mobilization per day, minutes 40 (0-70) 73 (30-120) < 0.05 no. of surgical debridement 1 (1-3) 2 (1-3) > 0.05 time from initial surgical debridement to wound closure, day 12 (7-25) 13 (11-21) > 0.05 wound closure technique (tertiary/flap or graft) 19/10 11/10 >0.05 length of hospital stay, days 14 (2-32) 17 (4-32) > 0.05 no. of deaths 2 (6.5%) 2 (8.7%) > 0.05 vas = visual analogue scale for pain. yanaral_stesura seveso 28/09/17 10:21 pagina 210 211archivio italiano di urologia e andrologia 2017; 89, 3 vacuum-assisted closure in fournier’s gangrene erather than local tissue defects.in the present study, there was no significant difference between the groups in mortality rate (p = 1). fifty of the 54 patients survived and the mortality rate of all patients was 7%. the deaths of these four patients were at 6, 4, 2 and 8 days. this is compatible with mortality from fg increase within the acute sepsis phase (14). conclusions our study does not determine that a vac therapy is better than conventional dressings in terms of clinical outcome. however, vacuum dressing appears an effective and successful method, whichoffers fewer dressing changes, less pain, and greater mobility comparing to conventional dressings in the management of fg patients.the present study’s outcomes should be supported by further prospective studies with a larger patient volume. references 1. fournier ja. gangrene foudroyante de la verge. med pract. 1883; 4:589-97. 2. zagli g, cianchi g, degl'innocenti s, et al. treatment of fournier's gangrene with combination of vacuum-assisted closure therapy, hyperbaric oxygen therapy, and protective colostomy. case rep anesthesiol. 2011; 2011:430983. 3. shyam dc, rapsang ag. fournier’s gangrene. surgeon. 2013; 11:222-32. 4. tucci g, amabile d, cadeddu f, milito g. fournier's gangrene wound therapy: our experience using vacdevice. langenbecks arch surg. 2009; 394:759-60. 5. li c, zhou x, liu lf, et al. hyperbaric oxygen therapy as an adjuvant therapy for comprehensive treatment of fournier's gangrene. urol int. 2015; 94:453-8. 6. ferreira pc, reis jc, amarante jm, et al. fournier’s gangrene: areview of 43 reconstructive cases. plast reconstr surg. 2007; 19:175-84. 7. misiakos ep, bagias g, patapis p, et al. current concepts in the management of necrotizing fasciitis. front surg. 2014; 1:36. 8. yılmazlar t, isık ö, öztürk e, et al. fournier’s gangrene: review of 120 patients and predictors of mortality. ulus travma acil cerrahi derg. 2014; 20:333-7. 9. mok my, wong sy, chan tm, et al. necrotizing fasciitis in rheumatic diseases. lupus. 2006; 15:380-3. 10. vaz i. fournier gangrene. trop doct. 2006; 36:203-4. 11. czymek r, frank p, limmer s, et al. fournier's gangrene: is the female gender a risk factor? langenbecks arch surg. 2010; 395:173-80. 12. cuccia g, mucciardi g, morgia g, et al. vacuum-assisted closure for the treatment of fournier's gangrene. urol int. 2009; 82:426-31. 13. czymek r, schmidt a, eckmann c, et al. fournier's gangrene: vacuum assisted closure versus conventional dressings. am j surg. 2009; 197:168-76. 14. furr j, watts t, street r, et al. contemporary trends in the inpatient management of fournier's gangrene: predictors of length of stay and mortality based on population-based sample. urology. 2017; 102:79-84. correspondence fatih yanaral md (corresponding author) fyanaral@yahoo.com faruk ozgor, md md.farukozgor@gmail.com haseki training and research hospital, urology department millet street, fatih, istanbul (turkey) can balci, md mbcbalci@gmail.com gaziosmanpasataksim training and research hospital, urology department karayollarimah. osmanbey cad. gaziosmanpasa, istanbul, turkey ozkan onuk, md drozkanonuk@gmail.com muammer aydin, md maydinmd@yahoo.com baris nuhoglu, md drbnuhoglu@gmail.com abdulmuttalip simsek, md simsek76@yahoo.com bakirkoy dr. sadikonuk training and research hospital, urology department zuhuratbabamah. tevfiksaglam cad. bakirkoy, istanbul, turkey yanaral_stesura seveso 28/09/17 10:21 pagina 211 133archivio italiano di urologia e andrologia 2016; 88, 2 review the role of cajal cells in chronic prostatitis ozgur haki yuksel 1, ahmet urkmez 2, ayhan verit 1 1 department of urology, fatih sultan mehmet research & training hospital, istanbul, turkey; 2 haydarpasa numune research and training hospital, dept. of urology, istanbul, turkey. types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. etiopathogenesis of chronic prostatitis is not well defined. moreover, its treatment outcomes are not satisfactory. presence of c-kit positive interstitial cells in human prostate is already known. it has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. in the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. we think that in this neuromuscular mechanism interstitial cajal cells have an important role in chronic prostatitis. our hypothesis is that curability of prostatitis is correlated with the number of cajal cells not subjected to apoptosis. key words: prostatitis; cajal cells; mast cells. submitted 17 october 2015; accepted 8 january 2016 summary no conflict of interest declared. the physicians (7). patients with cp typically have longlasting genitourinary/pelvic pain and obstructive and/or irritative voiding symptoms. sexual dysfunction and psychological symptoms are frequently added to these symptoms. interstitial cells of cajal (iccs) were firstly demonstrated in the urinary system in 1999 (8). in two separate studies performed by exintaris and shafik, the authors suggested presence of spontaneous contractile activity in the stromal layers of prostates of the guinea pig and dogs (9, 10). similarly, presence of c-kit positive cells has been demonstrated in human prostate (11). mast cells belong to a multifunctional immune system, which secretes proinflammatory cytokines such as histamine, serotonin, leukotriene and protease with increased immunoglobulin e receptor affinity (12). experimental studies have shown their roles in the development of autoimmune and cp (13, 14). mazzoli et al. evaluated the role of interleukin 8 (il-8) and chlamydia trachomatis infections in patients with cp. anti-chlamydia trachomatis immunoglobulin a (iga) and il-8 were detected in 69.2% and 75.6% of patients. moreover, the patients with higher levels of il-8 and higher positivity for iga reported the worst symptoms. their results emphasize the role of immune system activation in the pathophysiology of cp (15). besides, studies related to diseases with contractility disorder as achalasia have demonstrated that mast cells are closely associated with iccs. these cells degranulate and lead the related cells to death via cytokine release and autophagy. we think that in cp, prostatic ductal contractility disorder occurs. therefore medical treatment of prostatitis should be evaluated accordingly and appropriate treatment with mast cell degranulation inhibitors at an optimal time before total cajal cell apoptosis occurs will achieve permanent treatment response. evaluation of the hypothesis high-pressure voiding dysfunction, intraprostatic ductal reflux (chemical mechanism), microbial etiology, autoimmune and neuromuscular mechanisms are thought to play a role in the etiopathogenesis of cp. cp is defined and classified with culture and microscopic examination of prostatic secretions and segmental urine samples as described by meares and stamey in addition to its peculiar symptoms (16). bartoletti et al. evaluated the role of doi: 10.4081/aiua.2016.2.133 introduction chronic prostatitis (cp) is classified as chronic bacterial prostatitis (category 2), inflammatory chronic pelvic pain syndrome (category 3a), non-inflammatory chronic pelvic pain syndrome (category 3b) and asymptomatic inflammatory prostatitis (category 4). prostatitis affects 10-14% of men of all ages and ethnicities (1, 2). more than 50% of the men experiences episodes of prostatitis at one time of their lives (3). prostatitis is the most frequently established diagnosis in men younger than 50 years of age and every year nearly 2 million people consult for examination (4). in most of the patients despite negative antibiogram results, more than one cycle of antibiotic therapy is applied (5, 6). in patients with unstable angina pectoris, newly developed myocardial infarction or active crohn disease, cp becomes a disappointing experience for patients and frustrating for haki-yuksel_stesura seveso 01/07/16 11:09 pagina 133 archivio italiano di urologia e andrologia 2016; 88, 2 o. haki yuksel, a. urkmez, a. verit 134 biofilmproducing bacteria in patients with negative microbiological results and persistent cp symptoms. they found that biofilmproducing bacteria were commonly isolated and had a significant negative effect on clinical response to antibiotic treatment (17). the presence of bacterial biofilm could be the “primum movens” of the flogosis process in the prostatic tissue. the role of cajal cells in continuing this process could be interesting to evaluate. cp can also occur without any evidence of bacterial or demonstrable prostatic infection (18). many investigators have proposed neuromuscular etiology in inflammatory and non-inflammatory prostatitis (19, 20). chronic pain associated with these syndromes is definitively of neuropathic type. according to one hypothesis, non-inflammatory prostatitis can emerge as a form of reflex sympathetic dystrophy. if perineum/pelvic wall is thought as a distal extremity, then this opinion deserves to be evaluated. symptoms of all patients with noninflammatory prostatitis closely resemble to those with cases of reflex sympathetic dystrophy. this perspective should be investigated and validated in further more sophisticated studies (18). in recent studies, presence of spontaneous contractile activities in the prostatic stroma of guinea pig and dogs has been suggested (9, 10). it has been demonstrated that this spontaneous contractile activity enhances with entry of calcium into l-type calcium (ca++) channels and that these short-acting spontaneous depolarizations at 5-15 mv amplitude trigger one or more than one nifedipine sensitive ca++ voltage increments. these slow-waves have myogenic origins and they are not effected by blockers of conduction of action potential, sympathetic, parasympathetic, sensorial and synaptic nerve impulse transmission or prostaglandin synthetase inhibitors. in the prostates of guinea pigs, conduction networks of c-kit positive cells have been located between glandular and stromal muscle layers of prostate acini and in the stromal smooth muscle layer (9). similarly, presence of c-kit positive cells has been shown in the human prostate (11). discovery of slow-waves and iccs in the prostate gland of guinea pigs has suggested that activities of these slowwaves may be responsible for spontaneous tonus of the human prostate. according to these experimental animal models, in patients with diseases which progress with decreased intestinal motility including diabetes, chronic or inflammatory bowel diseases, and in those with defective interstitial cell network, there is higher probability of development of benign prostatic hyperplasia (bph) due to icc-like cell dysfunction (21). in another study, it is stated that intraprostatic slow wave activity may be important role in the etiology of bph and symptoms related to bph (22). up to now, embryological origin of iccs has not been understood and in consideration of their resemblance to neural cells, they have been probably thought to originate from neural crest. however, many studies have demonstrated that they do not stem from neural crest, but develop independently from enteric neurons. in recent literature, cajal cells are thought to be originated from mesenchymal precursor cells that have gained momentum (23). iccs have been found to be promising in the elucidation of motor physiology and pathophysiology of luminal organs. in recent years, thanks to advances in the developments in histopathological and immunohistochemical diagnostic methods, studies investigating location, function and the role of icc in the pathophysiology of urinary system diseases are still continuing. in a study where total urinary system postmortem tissue samples harvested from pigs were investigated, three groups of cells with c-kit receptor (cd 117) positivity were detected. spindle-shaped interstitial cells included in the first cell group had been demonstrated to have oval nuclei, bipolar cytomorphological structure and two thin wavy extensions; the second group consisted of cd 177 positive mast cells and the third group comprised of vertically aligned cells located on the epithelial basal layers (24). in a study where intramural ureters of the patients with vesicoureteral reflux of various degree were compared as for the presence of c-kit positive cells, marked decrease in interstitial cells interposed between muscle fascicles, which are replaced by connective tissue in relation with the degree of vesicoureteral reflux was detected. in the ureteral unit with reflux, decrease in baseline and maximum intraureteral pressures and associated decrease in c-kit positive interstitial cells were detected (25). in a study performed on human urethra, the presence of c-kit positive cells was demonstrated between smooth muscle fibers and in the border layer between urothelium and lamina propria (26). in another study where distribution of iccs was compared in patients with congenital obstructive megaureter, a prominent decrease both in the smooth muscle ratio and the number of c-kit positive cells were detected (27). as it was noted previously, literature studies on iccs have been performed involving a wide spectrum of anatomical sites extending from renal calyces to urethra or even spontaneous contractile activity of vas deferens and spermatogonia. absence of iccs has been associated with both relative obstruction and also mechanism of reflux. still in various studies the role of mast cells in prostatitis and interstitial cystitis has been indicated (28, 29) and supported by experimental studies (14). theoretically, mast cells increase regeneration capacity of cajal cells and subsequent increase in the density of cajal cells is perceived as a tumoral activity by immune system and the process terminates dramatically with apoptosis of all cajal cells. studies in achalasia have demonstrated that iccs modulate electrical activity generated by nitrergic and vipergic neurons, which also control muscular contractions before transmitting this activity to the muscle cells by delaying its transport in micronsized gaps between iccs. this modulation is realized in various frequencies and it is valid for all digestive systems. this is called ‘gap function’, which operates just like a condenser in physics and delays the transport of ‘directives’ set forth so as to control muscular contractions. therefore, various medical treatments that can regulate activation of mast cells will obviously provide infinite benefits in the treatment of diseases presumably associated with icc-related contractility disorders. in literature reviews, iccs have been analyzed in cases of many urological pathologies including ureteropelvic junction obstruction, primary obstructive megaureter, congenital vesicoureteral junction obstruction and overactive haki-yuksel_stesura seveso 01/07/16 11:09 pagina 134 detrusor and were evaluated as a urological pacemaker. we have observed that clinical findings of these abovementioned diagnoses are generally associated with infections, which are pathophysiologically explained with a mechanism of stasis (29-32). our hypothesis points a similar mechanism that should present in the prostate tissue, which produces nearly 30% of seminal fluid (33). conclusion our hypothesis confirmed the infective etiology of cp as the result of the intraprostatic stasis due to the icc deficiency. pathophysiologic mechanism of cp and the presence of intraprostatic icc may explain the etiology of this pathology and identify the therapeutic target of this seemingly challenging disease encountered in the urology practice. references 1. mehik a, hellstrom p, lukkarinen o, et al. epidemiology of prostatitis in finnish men: a populationbased cross sectional study. bju. 2000; 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519:867-884. 9. exintaris b, klemm fm, lang jr. spontaneous slow wave and contractile activity of the guinea pig prostate. j urol. 2002; 168:315-322. 10. shafik a. electroprostatogram: an experimental study. mol androl. 1996; 8:73-79. 11. van der a, roskans t, blyweert w. interstitial cells in the human prostate: a new therapeutic target? prostate. 2003; 56:250-255. 12. ren s, sakai k, schwartz lb. regulation of human mast cell beta-tryptase: conversion of inactive monomer to active tetramer at acid ph. j immunol. 1998; 160:4561-4569. 13. donadio ac, depiante-depaoli m. inflammatory cells and mhc class ii antigens expression in prostate during time-course experimental autoimmune prostatitis development. clin immunol immunopathol. 1997; 85:158. 14. keith im, jin j, neal d jr, et al. cell relationship in a wistar rat model of spontaneous prostatitis. j urol. 2001; 166:323-328. 15. mazzoli s, cai t, rupealta v, et al. interleukin 8 and antichlamydia trachomatis mucosal iga as urogenital immunologic markers in patients with c. trachomatis prostatic infection. eur urol. 2007; 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156:1098-106. 23. metzger r, neugebauer a, rolle u. c-kit receptor (cd117) in the porcine urinary tract. pediatr surg int. 2008; 24:67-76. 24. arena s, fazzari c, arena f. altered ''active'' antireflux mechanism in primary vesico-ureteric reflux: a morphological and manometric study. bju int. 2007; 100:407-412. 25. hyo jk, hye yl, mei h. decreased interstitial cells of cajal-like cells, possible cause of congenital refluxing megaureters: histopathologic differens in refluxing and obstructive megaureters. ped urol. 2009; 74:318-323. 26. van der a, roskans t, blyweert w. identification of kit positive cells in the human urinary tract. j urol. 2004; 171:2492-2496. 27. pontari ma, ruggieri mr. mechanisms in prostatitis/chronic pelvic pain syndrome. j urol. 2004; 172:839. 28. elbadawi a. interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis. urology. 1997; 49:14-40 29. di benedetto a, arena s, nicotina pa, et al. pacemakers in the upper urinary tract. neurourol urodyn. 2013; 32:349-353. 30. apoznanski w, koleda p, wozniak z, et al. the distribution of interstitial cells of cajal in congenital ureteropelvic junction obstruction. int urol nephrol. 2013; 45:607-612. 31. juszczak k, maciukiewicz p, drewa t, thor pj. cajal-like interstitial cells as a novel target in detrusor over activity treatment: true or myth? cent european j urol. 2014; 66:413-417. 32. eken a, erdogan s, kuyucu y. immunohistochemical and electron microscopic examination of cajal cells in ureteropelvic junction obstruction. can urol assoc j. 2012; 10:1-6. 33. turunc t, bayazit y, doran f, bal n, doran s. effects of vas deferens obstruction on cajal-like cells in rats. urol int. 2009; 83:86-91. 135archivio italiano di urologia e andrologia 2016; 88, 2 the role of cajal cells in chronic prostatitis correspondence ozgur haki yuksel, md (corresponding author) ozgurhaki@gmail.com ayhan verit, md, prof. department of urology, fatih sultan mehmet research & training hospital içerenköy/atasehir tr34752 istanbul, turkey ahmet urkmez, md haydarpasa numune research and training hospital, dept. of urology istanbul, turkey haki-yuksel_stesura seveso 01/07/16 11:09 pagina 135 archivio italiano di urologia e andrologia 2020; 92, 282 original paper holmium laser prostatectomy in a tertiary italian center: a prospective cost analysis in comparison with bipolar turp and open prostatectomy riccardo schiavina 1, 2, lorenzo bianchi 1, 2, marco giampaoli 3, marco borghesi 1, 2, hussam dababneh 1, 2, francesco chessa 1, 2, cristian pultrone 1, 2, andrea angiolini 1, umberto barbaresi 1, matteo cevenini 1, fabio manferrari 1, 2, alessandro bertaccini 1, 2, angelo porreca 3, eugenio brunocilla 1, 2 1 department of urology, university of bologna, bologna, italy; 2 department of experimental, diagnostic and specialty medicine (dimes), cardio-nephro-thoracic sciences doctorate, university of bologna, bologna, italy; 3 department of urology, abano terme hospital, padua, italy. objective: to assess the economic impact of holmium laser enucleation of prostate (holep) in comparison with transurethral resection of prostate (turp) and open prostatectomy (op). methods: between january 2017 and january 2018, we prospectively enrolled 151 men who underwent holep, turp or op at tertiary italian center, due to bladder outflow obstruction symptoms. patients with prostate volume ≤ 70 cc and those with prostate volume > 70 cc were scheduled for turp or holep and op or holep, respectively. intraoperative and early post-operative functional outcomes were recorded up to 6 months follow up. cost analysis was carried out considering direct costs (operating room [or] utilization costs, nurse, surgeons and anesthesiologists’ costs, or disposable products costs and or products sterilization costs), indirect costs (hospital stay costs and diagnostics costs) and global costs as sum of both direct and indirect plus general costs related to hospitalization. cost analysis was performed comparing patients referred to turp and holep with prostate volume ≤ 70 cc and men underwent op and holep with prostate volume > 70 cc respectively. results: overall, 53 (35.1%), 51 (33.7%) and 47 (31.1%) were scheduled to holep, turp and op, respectively. both turp, holep and op proved to effectively improve urinary symptoms related to bpe. considering patients with prostate volume ≤ 70 cc, median global cost of holep was similar to median global cost of turp (2151.69 € vs. 2185.61 €, respectively; p = 0.61). considering patients with prostate volume > 70 cc, median global cost of holep was found to be significantly lower than median global cost of op (2174.15 € vs. 4064.97 €, respectively; p ≤ 0.001). conclusions: global costs of holep are comparable to those of turp, offering a cost saving of only 11.4 € in favor of holep. conversely, holep proved to be a strong competitor of op because of significant global cost sparing amounting to 1890.82 € in favor of holep. key words: holep; xost analysis; turp; open prostatectomy; prostatic enlargement. submitted 15 may 2019; accepted 15 june 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.82 introduction benign prostatic enlargement (bpe) is one of the most common age-related medical disease in men, with troublesome impact on quality of life and a non-negligible social burden (1-3). the wide panorama of medical treatments developed over years has increasingly reduced the proportion of patients scheduled to surgical treatments (4). as a consequence, the economic impact of lower urinary tract symptoms (luts) is relevant, with costs exceeding 3 billion $ annually in us (5), 320 million € for pharmacological treatment and 74.834 days off work every year in italy (6), and this trend is increasing over time (7). surgical and endoscopic techniques, such as transurethral resection of prostate (turp) and open prostatectomy (op) have been the standard of care for many years in patients with drug-refractory disease. however, the surgical management of bpe has been changed in the last decade while laser prostatectomy increased in popularity (5). although different laser techniques are available for surgical treatment of bpe, holmium laser enucleation of prostate (holep) has been the most rigorously studied (8) and has emerged as a viable minim-invasive option in patients with symptomatic bpe regardless prostate volume (9). several studies including randomized controlled trials demonstrated equivalent earlyand long-term functional outcomes as compared to turp (10-13) and op (14, 15), even in case of large prostate volume (16). therefore, holep is currently defined by international european guidelines (17) as an effective alternative to turp and op, with several advantage of minim invasive approach including shorter catheterization time and hospital stay, reduced blood loss and lower blood transfusions (10, 11, 14, 15). despite the initial non negligible costs, holep could be less expensive by shortening the hospital stay and lowering the perioperative complications’ rate if compared to turp (18, 19) and op (2, 16). since rigorous data on comparative costs of surgical treatments for bpe is limited in literature (20), we hereby aimed to assess the economic impact of holep in comschiavina_stesura seveso 17/06/20 10:12 pagina 82 83archivio italiano di urologia e andrologia 2020; 92, 2 cost analysis of surgical approach for bph parison with turp and op performed at single tertiary italian center. furthermore, we investigated and compared the surgical and early functional outcomes of the three surgical approaches. material and methods population between january 2017 and january 2018, we prospectively enrolled 151 men who underwent surgical or endoscopic treatment for bpe at single tertiary italian referral center (s. orsola-malpighi hospital). indications for surgical treatment consisted of persistent bladder outflow obstruction symptoms, international prostatic symptoms score (ipss) higher than 8, independent peak urinary flow rate (qmax) ≤ 15 ml/s, or individuals non-responder to medical therapies including alfa blockers and 5α-reductase inhibitors (5-ari). the baseline assessment of bpe consist of digital rectal examination (dre), transrectal ultrasound of prostate (trus) reporting the overall prostate volume and prostatic adenoma's volume, ipss score, quality of life score (qol), qmax, total psa value and post void residual (pvr) measured with suprapubic ultrasound. patients diagnosed with prostate cancer, those with history of previous prostatic or urethral surgery and with concomitant surgery needed (namely, bladder diverticulum excision and bladder stones removal) were excluded. surgical techniques patients with prostate volume ≤ 70 cc and those with prostate volume > 70 cc were scheduled for turp or holep and op or holep according to surgeon attitude and patient’s preference, respectively. turp was carried out with a 26fr continuous-flow storz bipolar resectoscope, as previously described (21). all procedures were performed by 2 surgeons with more than ten years’ experience with endoscopic surgery of both lower and upper urinary collecting system. a 22 fr three-way catheter was positioned at the end of the procedure with continuous irrigation. holep was performed by using lumenis versa pulse® holmium laser at 2.0 j and 50 pulses per second with a maximum average power of 100 w and 26fr continuous-flow storz laser resectoscope. laser energy was delivered with a 550-μm fiber. the enucleation of prostatic adenoma was performed according to gilling's technique (22). the enucleated prostatic lobes were removed by using lumenis versacut™ morcellator system. all procedures were performed by a single surgeon at the end of learning curve with three years’ experience with holep technique and more than 200 procedures performed. a 22 fr three-way catheter was positioned at the end of the procedure with continuous irrigation. op was performed though trans-vesical approach as previous described (23). all procedures were performed by 4 surgeons with more than ten years’ experience within op techniques. a suprapubic drain and a 24fr three-way catheter were positioned; the catheter was inflated in the prostatic fossa with a continuous irrigation. collected data each patient had complete preoperative data including ipss and qol scores, qmax and psa values, prostate volume and pvr at trus and suprapubic ultrasound, respectively. recorded intraoperative data were as follows: surgical time, anesthesia time, total operating room (or) usage time and removed tissue weight. moreover, we measured early post-operative outcomes: hemoglobin (hg) loss at 24 hours after surgery, catheterization time, hospital stay and early complications including re-catheterization, clot irrigation, transfusion and urinary tract infection according to clavien-dindo classification (24). after discharge, patients were scheduled to follow up examination at 3, 6 and 12 months including ipss and qol scores, pvr and qmax. moreover, urge and stress incontinence rates were recorded after discharge, at 3,6 and 12 months follow up. urinary incontinence was defined as usage of ≥ 1 pad per day. at time of analyses, all patients had complete follow up data up to 6 months after surgery. cost analysis was carried out thought delta analysis considering direct costs related to surgical procedure, indirect costs related to post-surgical hospitalizations and global costs as sum of both direct and indirect plus general costs related to hospitalization. those data were obtained with the collaboration of the finance department with our center. direct costs consist of or utilization costs (2,01 €/minute) plus nurse cost (0,5 €/minute, considering 3 nurses in op and 2 nurses in holep and turp), o.r. personnel costs including surgeons (1,33 €/minute, considering 2 surgeons in op and 1 surgeon in holep and turp) and anesthesiologists (1,33 €/minute), o.r. disposable products costs and o.r. products sterilization costs. indirect costs included hospital stay costs, diagnostics costs and costs of complications (including additional drugs, transfusions and medications). general costs included several costs of different services for each patient calculated by the hospital’s administration and related to the hospital stay (including insurance, water and electricity). data analysis and statistical assessments first, preoperative patients’ characteristics and mildterm (≤ 6 months) postoperative data were compared between patients referred to the three surgical approaches (namely, op, turp and holep): anova test was used to compare continuous variables between the three groups. second, postoperative stress and urge incontinence rates were reported at discharge, at 3 and 6 months after surgery and were compared between the three surgical techniques using chi-square test. third, intraoperative and early postoperative data as well as intraoperative surgical times and surgical costs were analyzed comparing patients referred to holep and turp and those scheduled to holep and op, respectively. since surgical indication to turp or op was respectively carried out in case of prostate volume ≤ 70 cc and > 70 cc at preoperative trus, while the indication to holep was carried out regardless prostate volume, individuals referred to holep with prostate volume ≤ 70 cc (holep ≤ 70 cc) and those with prostate volume > 70 cc (holep > 70 cc) were compared with men underwent turp and op, respectively, in order to assess whenever holep technique could represent a direct competitor of both standard surgical procedures according to prostate volume. schiavina_stesura seveso 17/06/20 10:12 pagina 83 archivio italiano di urologia e andrologia 2020; 92, 2 r. schiavina, l. bianchi, m. giampaoli, et al. 84 statistical analysis was conducted with ibm spss 21 with a 2-sided significance level set at p < 0.05. the local institutional ethical committee approved the study (approval code stud-of by the s. orsola-malpighi hospital, irb september 11, 2012). results preoperative data overall, 151 patients were prospectively enrolled. of them, 53 (35.1%), 51 (33.7%) and 47 (31.1%) were scheduled to holep, turp and op, respectively. among patients submitted to holep, 27 (50.1%) individuals had a preoperative prostatic volume ≤ 70 cc, while 26 (49.9%) had a preoperative prostatic volume > 70 cc. between patients referred to op, turp and holep, the preoperative clinical characteristics including age, ipss and qol scores, qmax and pvr were found to be similar between the three groups, except for prostate volume that was significantly higher in men treated with op and holep as comtable 1. preoperative patients’ characteristics according to the surgical techniques (namely, op, turp and holep). op turp holep p value number of patients (%) 47 (31.1) 5 1(33.7) 53 (35.1) age (years) mean ± sd (range) 71.1 ± 7.3 (56-85) 69.0 ± 9.7 (46-86) 70.2 ± 6.8 (51-84) 0.4 prostate volume (cc) mean ± sd (range) 109.8 ± 45.8 (75-280) 43.3 ± 13.1 (27-70) 75.4 ± 25.6 (32-140) < 0.001 qmax (ml/sec) mean ± sd (range) 8.5 ± 4.4 (2-15) 9.5 ± 4.9 (4-15) 9.1 ± 3.6 (4-15) 0.9 ipss mean ± sd (range) 15.6 ± 8.2 (8-33) 19.6 ± 7.7 (8-34) 17.2 ± 7.2 (8-30) 0.07 qol mean ± sd (range) 3.6 ± 1.5 (1-6) 4.1 ± 1.3 (1-6) 3.8 ± 1.4 (1-6) 0.2 pvr (cc) mean ± sd (range) 96.7 ± 65.3 (10-300) 87.1 ± 55.8 (10-250) 88.7 ± 60.9 (10-220) 0.9 psa (ng/ml) mean ± sd (range) 6.73 ± 3.29 (1.5-15.8) 2.55 ± 2.34 (0.5-11.0) 3.27 ± 2.46 (0.6-12.0) < 0.001 op: open prostatectomy; turp: transuretral resection of prostate; holep: holmium laser enucleation of prostate; ipss: international prostate symptoms score; pvr: post voided residual; qol: quality of life; sd: standard deviation. table 2. preoperative, surgical and early post-operative outcomes according to the surgical techniques (namely, turp vs. holep with preoperative prostatic volume ≤ 70 cc and op vs holep with preoperative prostatic volume >70 cc). turp holep ≤ 70 cc p value op holep > 70 cc p value number of patients (%) 51(33.7) 27 (17.9) 47 (31.1) 26 (17.2) preoperative characteristics age (years) mean ± sd (range) 69.0 ± 9.7 (46-86) 70.9 ± 6.7 (51-83) 0.3 71.1 ± 7.3 (56-85) 69.5 ± 7.03 (57-84) 0.6 prostate volume (cc) mean ± sd (range) 43.3 ± 13.1 (27-70) 47.8 ± 8.3 (32-70) 0.06 109.8 ± 45.8 (75-280) 96.8 ± 18.8 (75-140) 0.06 qmax (ml/sec) mean ± sd (range) 9.5 ± 4.9 (4-15) 8.7 ± 2.7 (5-15) 0.6 8.5 ± 4.4 (2-15) 9.7 ± 4.5 (3.7 – 15) 0.6 ipss mean ± sd (range) 19.6 ± 7.7 (3-34) 16.1 ± 6.5 (3-27) 0.06 15.6 ± 8.2 (3-33) 18.3 ± 7.8 (3-30) 0.06 qol mean ± sd (range) 4.1 ± 1.3 (1-5) 3.8 ± 1.2 (1-5) 0.2 3.6 ± 1.5 (1-5) 4.3 ± 1.5 (1-5) 0.2 pvr (cc) mean ± sd (range) 87.1 ± 55.8 (10-250) 95.4 ± 72.3 (15-220) 0.3 96.7 ± 65.3 (10-300) 96.6 ± 62.8 (10-220) 0.3 psa (ng/ml) mean ± sd (range) 2.55 ± 2.34 (0.5-11.0) 2.50 ± 1.80 (0.6-7.6) 0.9 6.73 ± 3.29 (1.5-15.8) 4.00 ± 2.80 (1.1-12.0) 0.9 intraoperative data removed tissue weight (gr) mean ± sd (range) 21.6 ± 11.1 (5-50) 26.4 ± 12.2 (20-55) 0.09 62.2 ± 32.7 (30-180) 50.2 ± 23.2 (31-90) 0.09 intra-perioperative complications according to clavien-dindo classification (%) overall 5 (10) 1 (4) 0.3 11 (23) 2 (8) 0.04* grade 1 3 (6) 0 (0) 3 (6) 1 (4) grade 2 2 (4) 1 (4) 6 (13) 0 (0) grade 3 0 (0) 0 (0) 2 (4) 1 (4) early post-operative outcomes hb loss at 24 hours (g/dl) mean ± sd (range) 1.1 ± 0.7 (0-3.9) 2.1 ± 3.4 (0.3-3.6) 0.1 2.1 ± 1.4 (0-6.2) 1.9 ± 1.2 (0-5.2) 0.2 catheterization time (hr) mean ± sd (range) 74.4 ± 21.4 (48-144) 57.2 ± 43.9 (20-183) 0.003* 146.9 ± 55.6 (60-448) 68.1 ± 53.8 (20-200) < 0.001* hospital stay (hr) mean ± sd (range) 84.4 ± 10.5 (60-104) 72.2 ± 37.4 (27-168) 0.01* 184.2 ± 78.7 (84-554) 83.9 ± 42.3 (47-192) < 0.001* op: open prostatectomy; turp: transuretral resection of prostate; holep: holmium laser enucleation of prostate; hb: hemoglobin; sd: standard deviation. schiavina_stesura seveso 17/06/20 10:12 pagina 84 85archivio italiano di urologia e andrologia 2020; 92, 2 cost analysis of surgical approach for bph pared to those referred to turp (table 1; p < 0.001). however, no significant differences were found between men referred to turp and those underwent holep with prostate volume ≤ 70 cc and between patients referred to op as compared with those submitted to holep with prostate volume > 70 cc, concerning preoperative characteristics (table 2). perioperative data concerning mean removed tissue weight, we found no significant difference between patients referred to turp as compared with those submitted to holep with prostate volume ≤ 70 cc and between patients referred to op as compared with those submitted to holep with prostate volume > 70 cc (table 2). men in turp group and those in op group revealed higher catheterization and hospital stay times as referred to individuals scheduled to holep regardless prostate volume (all p ≤ 0.01; table 2). in men with prostate volume ≤ 70 cc, both holep and turp revealed to be safety procedures with 4% and 10% overall complications, respectively (p = 0.3). on the contrary, in men with prostate volume > 70 cc, those referred to op experienced higher rates and higher grade of complications as referred to those underwent to holep (p ≤ 0.04). postoperative functional outcomes both turp, holep and op proved to effectively improve urinary symptoms related to bpe at short term follow up, since no significant differences were found in term of ipss score, qmax, qol score and pvr at time of discharge, at 3 and 6 months after surgery, between the three groups (table 3). patients in holep group revealed higher stress incontinence rate at 3 months after surgery as compared to men in turp and op group, despite not significant difference (8% vs. 4% vs. 2%; figure 1; p = 0.2); however, only 1 (2%) patients referred to holep and 1 (2%) men underwent op, experienced stress incontinence at 6 months follow up. irritative symptoms were comparable between the three surgical approach and only 1 patient (2%) had urge incontinence at 6 months after holep (figure 2). intraoperative times and costs analyses o.r usage, anesthesiology and surgery time and disposable products' costs revealed to be significantly higher in patients referred to holep ≤ 70cc, as compared to those treated with turp (all p ≤ 0.001). accordingly, median direct costs of holep in men with prostate volume ≤ 70 cc were significantly higher as compared to median direct table 3. short-term functional outcomes of the three surgical techniques (namely, op, turp and holep). 3 months 6 months op (47) turp (51) holep (53) p value op (47) turp (51) holep (53) p value ipss mean ± sd 7.6 ± 4.2 9.6 ± 7.0 9.5 ± 5.8 0.3 7 ± 4.5 8.57 ± 5.7 8.3 ± 5.6 0.5 qmax (ml/s) mean ± sd 23.8 ± 10.6 21.5 ± 8.5 22.8 ± 10.5 0.7 23.2 ± 10.8 22.8 ± 9.7 22.7 ± 9.6 0.2 qol mean ± sd 1.2 ± 1.3 1.8 ± 1.6 1.5 ± 1.5 0.5 0.9 ± 1.0 1.4 ± 1.1 1.4 ± 1.3 0.2 pvr (cc) mean ± sd 3.5 ± 2.1 10.9 ± 22.8 20.8 ± 12.1 0.4 4.1 ± 2.5 10.8 ± 25.3 24.5 ± 16.6 0.4 op: open prostatectomy; turp: transuretral resection of prostate; holep: holmium laser enucleation of prostate; ipss: international prostate symptoms score; pvr: post voided residual; qol: quality of life; sd: standard deviation. figure 1. postoperative stress urinary incontinence rate according to the three surgical techniques (namely, op, turp and holep) at discharge, 3 and 6 months follow up. figure 2. postoperative urge urinary incontinence rate according to the three surgical techniques (namely, op, turp and holep) at discharge, 3 and 6 months follow up. schiavina_stesura seveso 17/06/20 10:12 pagina 85 archivio italiano di urologia e andrologia 2020; 92, 2 r. schiavina, l. bianchi, m. giampaoli, et al. 86 costs of turp (866.62 € vs. 650.90 €, respectively; p ≤ 0.001; table 4). on the contrary, indirect costs were found to be inferior in holep ≤ 70 cc group as compared to turp group (all p ≤ 0.002), mainly due to lower hospitalization time. as a matter of fact, considering patients with prostate volume ≤ 70 cc, median global cost of holep was similar to median global cost of turp (2151.69 € vs. 2185.61 €, respectively; p = 0.61; table 3). despite significant difference in terms of o.r usage, anesthesiology and surgery time and disposable products' costs between patients referred to holep > 70 cc and op in favor of op (all p < 0.001), median direct costs revealed to be similar between op and holep in men with prostate volume > 70 cc (948.89 € vs. 803.31 €; p = 0.09; table 4). this could be explained with higher surgeon costs in op which is related to the involvement of two surgeons per procedure, although the surgical time is lower in op as referred to holep which is a single surgeon procedure. on the other side, indirect costs were found to be significantly lower in holep > 70 cc group as compared to op group (p < 0.001), mainly due to lower hospitalization time and lower complications rates. therefore, considering patients with prostate volume > 70 cc, median global cost of holep was found to be significantly lower than median global cost of op (2174.15 € vs. 4064.97 €, respectively; p ≤ 0.001; table 4). discussion thanks to unquestionable efficiency, early and long terms functional outcomes and safety profile, turp represents nowadays the gold standard (17), (25) for surgical treatment of patients affected by bpe. on the other hand, laser technology has been worldwide increasingly diffused as safe minim invasive surgical treatment for bpe. among different laser adopted in urology, holmium laser has been the most rigorously studied (8) and holep has passes the test of the time. on the other side, op has been the first choice of surgical treatment in men with a substantially enlarged prostate (namely, prostate volume > 80 cc) in the last 50 years, despite more invasive approach and higher operative morbidity. however, contrarily to turp, the rate of open procedures varies among different countries and cultures, because of different national health systems, variable economic pressure and available resources. in fact, analysis of direct and indirect costs suggests that op is the most expensive surgical procedure for bpe (23). taken together these considerations support that op is a technique of the past which would be progressively abandoned. contrarily, holep proved to be a safe alternative to turp (10-13) and op (14, 15) with equivalent early and long term functional outcomes (10, 11, 14, 15), that render holep an attractive competitor of both standard techniques. despite such benefits, two main drawbacks including a steep learning curve and the costs related to initial laser equipment (holmium laser, a dedicated laser resectoscope sheath, fibers and morcellator) could have limited diffusion of this technique. nevertheless, it has been postulated that holep is a cost-sparing procedure since fibers can be reused multiple times and holmium laser can be used for several other urological procedures (26). moreover, previous authors showed that holep is more table 4. cost analysis including direct, indirect and total costs according to surgical procedure (namely, turp vs. holep with preoperative prostatic volume ≤ 70 cc and op vs holep with preoperative prostatic volume > 70 cc). turp holep ≤ 70 cc p value op holep > 70 cc p value number of patients (%) 51 (33.7) 27 (17.9) 47 (31.1) 26 (17.2) o.r. usage time (min) median (iqr) 105 (89.75-125) 140 (113.25-176) < 0.001* 110 (90-119) 140 (117-175) < 0.001* o.r usage cost (€) median (iqr) 306.23 (270.14-376.25) 421.40 (332.61-535.78) < 0.001* 386.10 (315.90-417.69) 421.40 (349.91-527.50) 0.04* anesthesiology time (min) median (iqr) 88 (74.5-111) 123 (103-161.5) < 0.001* 93 (80-110) 117 (100-160) < 0.001* anestesiology cost (€) median (iqr) 117.23 (99.09-147.63) 167.58 (129.01-214.13) < 0.001* 123.69 (106.40-146.30) 154.94 (133.00-215.13) < 0.001* surgery time (min) median (iqr) 63 (47-85.25) 96 (70.5-123.25) < 0.001* 68 (58-89) 96 (72-120) 0.001* surgeon cost (€) median (iqr) 84.78 (62.51-113.38) 141.00 (89.76-161.60) < 0.001* 180.88 (154.28-236.74) 114.38 (95.76-162.26) < 0.001* disposable products (€) 34.80 134.04 < 0.001* 34.8 134.04 < 0.001* sterilization costs (€) 103.86 103.86 103.86 103.86 1.0 direct costs (€) median (iqr) 650.90 (559.46-760.41) 866.62 (717.94-1040.52) < 0.001* 948.89 (813.15-1054.59) 803.31 (723.30-1074.98) 0.09 indirect costs (€) median (iqr) 1218.29 (1214.36-1272.83) 889.13 (797.77-1433.61) 0.002* 2542.87 (2194.06-2885.68) 867.20 (794.12-1203.39) < 0.001* direct + indirect costs (€) median (iqr) 1868.19 (1771.48-2058.04) 1772.33 (1418.25-2234.13) 0.37 3507.33 (3205.78-3895.28) 1905.60 (1509.39-2132.37) < 0.001* general costs (€) median (iqr) 317.42 (301.15-348.17) 301.29 (241.10-379.80) 0.38 596.24 (544.98-662.19) 323.95 (256.59-362.50) < 0.001* total cost (€) median (iqr) 2185.61 (2072.64-2396.20) 2151.69 (1735.79-2618.85) 0.61 4064.97 (3636.36-4557.47) 2174.15 (1765.23-2465.19) < 0.001* op: open prostatectomy; turp: transuretral resection of prostate; holep: holmium laser enucleation of prostate; or: operating room; iqr: interquartile range. schiavina_stesura seveso 17/06/20 10:12 pagina 86 87archivio italiano di urologia e andrologia 2020; 92, 2 cost analysis of surgical approach for bph cost-effective as compared to turp (18, 19) and op (2, 16), giving a cost savings of 24.5% (18) and 9.6% (2), respectively. our cost-analysis attempted to evaluate and compare the financial burden of different procedures for surgical treatment of bpe performed at single italian institution, in order to define a future perspective concerning surgical management of patients with bpe. indeed, several findings are noteworthy. first, holep proved to be as efficient as turp and op in term of removed tissue weight. second, our study provides further evidence to support optimal functional outcomes of holep at short follow up. moreover, holep confirmed to be a safe procedure, since similar intraoperative and perioperative complications were found as compared to turp. conversely, holep proved to be a safer approach than op, considering lower complications rates compared to op (8% vs. 23%; table 2). precisely, no men in holep>70cc and 6 patients in op group required blood transfusions; moreover, only 1 holep > 70 cc and 2 op needed re-intervention in order to achieve control of bleeding. third, according to literature (25), patients submitted to holep experienced faster recovery due to significantly lower catheterization time and hospital stay as compared to those underwent turp and op regardless prostate volume (table 2). fourth, direct costs, including or surgical setup, disposables, fibers and surgical staff costs (namely, unitary cost of surgeon, anesthesiology and operating room nurses) of holep ≤ 70 cc procedures, were found to be significantly higher as related to turp's costs. a sub-analysis of direct costs shows as disposable costs and sterilization costs are similar between two techniques. conversely, higher direct costs within holep ≤ 70 cc group, seems to be related mainly to increased operating room usage time, that leads to augment costs of surgeon, anesthesiologists and all staff involved. however, indirect costs found to be significantly lower in patients referred to holep ≤ 70 cc as compared to those treated with turp, due to lower hospital stay. in fact, laser technology allows to spare almost 1 day of hospitalization, thanks to optimal hemostatic proprieties and earlier catheter removal. therefore, global holep’s costs found to be comparable to global turp's costs considering patients with similar prostate volume (≤ 70 cc). this implies an overall cost saving of 11.4 € per procedure, in favor of holep. our findings differ from previous costeffectiveness analysis reported by fraundorfer et al. (18) comparing holmium laser prostatectomy (namely, holmium laser resection of prostate) and turp, by suggesting a net economic benefit of 24.5% (651 new zeland dollars) in favor of laser. however, the authors did not include in their analysis the medical salary costs (urologist and anesthesiologist), that could reduce the cost-saving difference between two techniques. fifth, our economic analysis shows that holep could be an attractive competitor of op. in fact, direct costs of holep were found to be comparable to op, considering patients with similar prostate volume (> 70 cc). despite lower operating room usage time and related costs, in favor of op, that would reduce surgeon cost, the median surgeon cost of op (180.88 €) is significantly higher as compared with those of holep (114.38 €) since it is influenced by the number of surgeons involved in each procedure (namely, two surgeons in op and one surgeon in holep). indeed, the higher costs of disposable products in holep group, mainly related to the costs of fibers, can be amortized during time, since a single fiber can be re-used at least 10 times. moreover, the main aspect that renders holep an attractive and preferable procedure as referred to op, consists of lower hospital stay and faster recovery to daily life. in fact, in our cohorts, patients treated with holep > 70 cc have been discharged more than 4 days earlier than those referred to open surgery. it implies a significant reduction of indirect cost (867.20 € in holep group vs. 2542.87€ in op group; p < 0.001), due to lower hospitalization time and lower complications rates, that leads to spare 1661.05€ per patients, in favor of holep. indeed, considering the global cost of both procedures, holep offers a net total cost saving of 1890.82 € per patient as compared to op, that assumes an important economic impact in health systems. these findings are even more impressive than those reported by salonia and colleagues (2), reporting a significant hospital net cost savings of 9.6% in favor of holep as compared with op. however, the medical salary costs (including urologist and anesthesiologist), that could increase the cost-saving difference between two techniques, has not been included in their analyses. despite several strength, our study is not avoided from limitations. first, number of patients included in our analyses is limited and it could affect statistical strength. second, our cohort consists of single italian center population with bpe submitted to most common surgical procedures (namely, holep, turp and op) recognized as standard procedures by international guidelines (17). however, we did not include patients referred to other diffused minim invasive techniques for surgical treatment of bpe. as consequence, our cohort could not be representative of the experience of other centers both in italy and worldwide. third, at baseline preoperative assessment of patients with bpe, we did not provide routine urodynamic study. fourth, our cost effectiveness analysis did not include initial costs of laser equipment that may consist of main limitation to start the procedure: the initial global costs of holmium laser and morcellator in our department was 150.000 € and 50.000 €, respectively. of note, the economic impact of holep could be overestimated, since the amount of initial financial charge, that would increase global cost of procedures, was not reported. moreover, we did not consider how many cases are needed to amortize the initial costs of laser equipment. conclusions holep is a safe and valuable alternative to turp and op. lower indirect costs and higher direct costs within patients treated with holep, imply that global costs of holep are comparable to global costs of turp, offering a cost saving of only 11.4 € in favor of holep. conversely, holep proved to be a strong competitor of op because of consistent reduction of indirect cost, mainly due to lower hospitalization time, that leads to significant global cost sparing amounting to 1890.82 € in favor of holep. however, further evaluations including schiavina_stesura seveso 17/06/20 10:12 pagina 87 archivio italiano di urologia e andrologia 2020; 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53:160-6. 16. elshal am, mekkawy r, laymon m, et al. holmium laser enucleation of the prostate for treatment for large-sized benign prostate hyperplasia; is it a realistic endourologic alternative in developing country? world j urol. 2016; 34:399-405. 17. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015; 67:1099-109. 18. fraundorfer mr, gilling pj, kennett km, dunton ng. holmium laser resection of the prostate is more cost effective than transurethral resection of the prostate: results of a randomized prospective study. urology. 2001; 57:454-8. 19. fayad as, elsheikh mg, zakaria t, et al. holmium laser enucleation of the prostate versus bipolar resection of the prostate: a prospective randomized study. "pros and cons". urology. 2015; 86:1037-41. 20. mathieu r, lebdai s, cornu jn, et al. perioperative and economic analysis of surgical treatments for benign prostatic hyperplasia: a study of the french committee on lut. prog uro. 2017; 27:362-8. 21. rassweiler j, schulze m, stock c, et al. bipolar transurethral resection of the prostate--technical modifications and early clinical experience. minim invasive ther allied technol. 2007; 16:11-21. 22. gilling pj, kennett k, das ak, et al. holmium laser enucleation of the prostate (holep) combined with transurethral tissue morcellation: an update on the early clinical experience. j endourol. 1998; 12:457-9. 23. tubaro a, de nunzio c. the current role of open surgery in bph. eau-ebu update series. 2006;4:191-201. 24. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 25. cornu jn, ahyai s, bachmann a, et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol. 2015; 67:1066-96. 26. vincent mw, gilling pj. holep has come of age. world j urol. 2015; 33:487-93. correspondence riccardo schiavina, md rschiavina@yahoo.it lorenzo bianchi, md (corresponding author) lorenzo.bianchi3@gmail.com marco borghesi, md mark.borghesi1@gmail.com hussam dababneh, md drdababneh@gmail.com francesco chessa, md francesco.chessa@live.it cristian pultrone, md cristian28@libero.it andrea angiolini, md dr.angiolini@gmail.com umberto barbaresi, md ubarbaresi@libero.it matteo cevenini, md matteoceve@gmail.com fabio manferrari, md fabio.manferrari@unibo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it alessandro bertaccini, md alessandro.bertaccini@gmail.com department of urology, university of bologna, bologna (italy) marco giampaoli, md giampaoli.marco85@gmail.com angelo porreca, md angelo.porreca@gmail.com department of urology, abano terme hospital, padua (italy) schiavina_stesura seveso 17/06/20 10:12 pagina 88 117archivio italiano di urologia e andrologia 2020; 92, 2 case report feasibility of a single session retrograde endoscopic laser lithotripsy of two large stones located in a bifid urinary tract. presentation of a rare case diomidis kozyrakis 1, 2, anastasios zarkadas 1, ilias katsaros 1, vasileios mourkas 3, zisis kratiras 1 1 “achillopoulio” general hospital of volos, department of urology, volos, greece; 2 “metropolitan general” health clinic, department of urology, athens, greece; 3 “achillopoulio” general hospital of volos, department of anesthesiology, volos, greece. a 76 year-old male presented with urosepsis and acute renal injury secondary to obstruction by a 13 mm stone located in the common segment of a bifid left ureter. a second 10 mm stone was detected in the mid calyx of the lower moiety of the kidney. drainage of both moieties with two double-j stents was initially performed. following recovery from urosepsis a retrograde endoscopic semirigid and flexible laser lithotripsy of the distal and proximal stone respectively was performed resulting in stone clearance. although retrograde ureterolithotripsy has been presented in the past, to the best of the authors’ knowledge, this is the first description of flexible retrograde intrarenal lithotripsy performed through a bifid ureter. key words: bifid ureter; lithiasis; lithotripsy; rirs; ureteroscopy; duplication. submitted 11 february 2020; accepted 2 march 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.117 case report a 76 year-old male presented in the emergencies due to fever (up to 39° c), chills, mild hematuria and cloudy urine that lasted for 48 hours and also dyspnea of 24 hours duration. he had a history of non-insulin dependent diabetes mellitus, hyper-lipidemia and arterial hypertension; all of them under control with oral treatment. the diagnostic work-up revealed urosepsis due to e. coli with acute renal injury due to obstruction by a 13 mm stone in the common segment of an incomplete duplicated left ureter. another 10 mm stone was detected in the mid calyx of the lower moiety of the ipsilateral kidney. incidentally, an atrophic contralateral kidney was detected. intravenous administration of antibiotics and drainage of both moieties was performed using two double-j stents (figure 1). recovery from urosepsis and renal injury was quick and uneventful. fifty days later the patient was readmitted for lithotripsy. prior to treatment he signed informed consent and also gave a written permission to record the procedure and to use the material for scientific presentations. the procedure and the conduct of the study were approved by the institution’s scientific committee. fragmentation of the proximal stone was performed using a 8/9.5f semirigid scope with a 30w ho:yag laser and a 325 micron laser fiber (figure 2). the catheterization of the second limb of the bifid ureter was made under direct vision of the joint by the ureteroscope (figure 3). then retrograde intrarenal surgery (rirs) of the 10 mm intrarenal stone was performed using a 7.5f flexible scope and 200 micron fiber for stone fragmentation facilitated by a 45 cm long, 10/12 f access sheath (figure 4). two stents were postoperatively placed in each ureter. surgical time was 67 minutes. after 36 hours of hospital staying, the patient was discharged. postoperative recovery was uneventful. the stents were left in place for 14 days. three months after lithotripsy the patient was stone free having normal renal function. discussion complete and incomplete (bifid) ureteral duplication (ud) represent different clinical manifestations of the same embryologic disorder. during the 4th-5th gestation week, the mesenchymal ureteral bud starts its development to form the ureter. if two buds arise separately from the mesenchyme, two different ureters are developed and complete ureteral duplication is encountered. if a single bud splits later during various stages of metanephric tissue development a bifid collecting system is generated (1). ud usually has an uneventful clinical course, though obstruction of a bifid ureter by stones has been reported in the literature. a recent case report underscored the role of the contrast enhanced computed tomography (ct) imaging in the correct diagnosis of ureteral duplication. plain kidney ureter bladder (kub) x-ray is unreliable in detecting this anatomical disorder. only in ct scan images the bifid ureter can be recognized, and the size and location of stones if any, can be clearly determined contributing to the appropriate delivery of treatment (2). in our case, due to the patient’s critical condition, the ct scan was performed in emergency settings. although a contrast agent was not administered due to renal dysfunction, the anatomy of the dilated collecting system was adequately delineated and the presence of ureteral duplication was identified. bhatia and biyani reported on 8 lithiasic cases in ud, five of which were located in a bifid ureter. all of them were treated with shock wave lithotripsy (swl) with excellent kozyrakis_stesura seveso 17/06/20 10:15 pagina 117 archivio italiano di urologia e andrologia 2020; 92, 2 d. kozyrakis, a. zarkadas, i. katsaros, v. mourkas, z. kratiras 118 results (2). migliari and usai were the first to perform endoscopic treatment in incomplete ud in 1991. they used a semirigid scope to gain access to a 1 cm stone located in the pelvic portion of the lower limb of a bifid ureter. fragmentation was performed using an ultrasonic lithotripter with optimal stone clearance (3). to the best of our knowledge, the present study is the first to report on flexible retrograde intrarenal surgery (rirs) and laser lithotripsy with the scope inserted into the kidney through the joint of a bifid ureter. initially, to ensure adequate drainage, both moieties of the kidney had to be decompressed with stents. the presence of a double-j stent also facilitated the retrograde endoscopic treatment. intraoperatively, a safety guidewire was inserted in each limb of the ureter and after the disintegration of the distal stone, an access sheath was advanced up to the ureteropelvic junction of the moiety hosting the stone. the use of the sheath allowed an easy detection of the stone and a safe and quick operation under low intrarenal pressure. the sheath also facilitated the immediate removal of stone fragments. despite the large lithiasic burden, the duration of the procedure was approximately one hour. this brief operation time eliminates the risks of surgical complications, particularly postoperative sepsis, and shortens the duration of hospital staying. in conclusion, the present study is the first to report the performance of flexible rirs in a bifid collecting system. preoperative ct scan, stenting of both limbs, use of safety guidewires and placement of ureteral access sheath under fluoroscopic guidance were crucial for a successful outcome. with the use of semirigid and flexible ureteroscopy the disintegration of a large lithiasic burden in the ureter and in the pyelo-calyceal system is feasible to be performed in one session, within a reasonable operation time and a minimum risk of complications. references 1. xiao n, ge b, wang j, zhao h. obstruction of bifid ureter by two calculi: a case report. medicine (baltimore). 2018; 97. 2. bhatia v, biyani cs. calculus disease in duplex dystem role of extracorporeal shockwave lithotripsy. urol int. 1993; 50:164-169. 3. migliari r, usai e. ureteroscopic removal of ureteral calculi in bilateral ureteral duplications. urol int. 1991; 46:79-81. figure 1. preoperative kub x-ray of stented ureters. the intrarenal stone is not clearly shown. figure 2. a 13 mm hard stone (mean 970 hounsfield units) located in the common segment of the bifid ureter. figure 3. appearance of joint of the bifid ureter under endoscopic vision with the semirigid ureteroscope. the arrow shows the entrance to the other limb of the ureter. the asterisk shows lithiasic dust. figure 4. an intrarenal 10 mm stone (mean hounsfield units 785). correspondence diomidis kozyrakis, md (corresponding author) dkozirakis@yahoo.gr anastasios zarkadas, md ilias katsaros, md zisis kratiras, md “achillopoulio” general hospital of volos, department of urology 134 polymeri str., volos, gr 38222 (greece) vasileios mourkas, md “achillopoulio” general hospital of volos, department of anesthesiology, volos, greece kozyrakis_stesura seveso 17/06/20 10:15 pagina 118 1archivio italiano di urologia e andrologia 2020; 92, 1 original paper free prostate-specific antigen outperforms total prostate-specific antigen as a predictor of prostate volume in patients without prostate cancer sinan avci, efe onen, volkan caglayan, metin kilic, murat sambel, sedat oner university of health sciences, bursa yuksek ihtisas training and research hospital, department of urology, bursa, turkey. objective: in the management of benign prostatic hyperplasia (bph), urology guidelines recommend medical or surgical treatments according to different prostate volumes (pv). the aim of this study was to analyze the relationships between pv and age, total and free prostate specific antigen (tpsa, fpsa) and fpsa/tpsa ratio in patients without histologically proven prostate cancer. materials and methods: a retrospective analysis was made of the data of 1334 patients who underwent transrectal ultrasound (trus)-guided prostate biopsy between january 2016 and october 2018. a total of 438 patients with available data for age, tpsa and fpsa levels and pv calculated by trus were enrolled in the study. patients with chronic prostatitis pathology in addition to bph were also noted and evaluated as a separate group. results: there were significant correlations between pv and age, tpsa, fpsa, fpsa/tpsa ratio (r = 0.210, r = 0.338, r = 0.548, r = 0.363 respectively). in multivariate linear regression analysis, fpsa was found to be the only predictor for pv (p < 0.001) when compared to age (p = 0.097), tpsa (p = 0.979) and fpsa/tpsa ratio (p = 0.425). in patients with chronic prostatitis pathology there were significant correlations between pv and age, tpsa, fpsa, fpsa/tpsa ratio (r = 0.279, r = 0.379, r = 0.592, r = 0.359, respectively). the multivariate linear regression analysis showed a significant correlation only between pv and tpsa and fpsa/tpsa ratio but not with fpsa and age (p = 0.008, p = 0.015, p = 0.430, p = 0.484, respectively). in men with only bph pathology there were significant correlations between pv and age, tpsa, fpsa, fpsa/tpsa ratio (r = 0.223, r = 0.385, r = 0.520, r = 0.287, respectively) in multivariate linear regression model the significant correlation was shown only between pv and fpsa (p < 0.001). conclusions: although tpsa was significantly correlated with pv in patients without prostate cancer, the correlation between fpsa and pv was much stronger. however, it should be kept in mind that the efficacy of fpsa may be limited in patients with clinically unknown prostatic inflammation. key words: benign prostatic hyperplasia; chronic prostatitis; free prostate-specific antigen; free prostate-specific antigen/total prostate-spesific antigen ratio; prediction; prostate-specific antigen; prostate volume. submitted 18 july 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.1 introduction lower urinary tract symptoms (luts) have traditionally been related to bladder outlet obstruction, which is often caused by benign prostatic enlargement resulting from the histological condition of benign prostatic hyperplasia (bph) (1, 2). prostate volume (pv) predicts symptom progression and the risk of complications such as urinary retention (3). pv may also be determinative in the decision for bph treatment. for example, in urology guidelines the use of 5 alpha reductase inhibitors in prostate volumes > 40 cc is recommended for medical treatment. surgical treatment options also vary according to the prostate volume in guidelines (4). therefore, it is important to know the pv correctly for the prognosis and treatment of the disease. digital-rectal examination (dre) is the simplest way to assess pv, but the correlation to pv is poor. underestimation of pv by dre increases with increasing transrectal ultrasound (trus) volume, particularly where the volume is > 30 ml (5). trus is more accurate in determining pv than dre and transabdominal ultrasound so it is the standard method recommended for measurement of pv (6, 7) however, it is an expensive, time-consuming, and uncomfortable modality for the initial evaluation of men with luts. therefore, another cheaper and simply applicable method, other than dre is needed to predict the pv correctly in our daily practice. the prediction of pv can be based on total and free prostate specific antigen (psa). both psa forms predict the trus prostate volume (± 20%) in > 90% of cases (8, 9). the aim of this study was to analyze the relationships between total psa, free psa, age and prostate volume in patients with histologically proven bph. furthermore, the implication of the use of free psa as a proxy marker to estimate pv was analyzed. materials and methods the data of 1334 men who underwent transrectal ultrasound (trus) guided prostate biopsy between january 2016 and october 2018 were analyzed retrospectively. approval for the study was granted by the local ethics committee (reg. no: 2011-kaek-25 2018/11-03). patients with pathological results of cancer, prostatic intraepithelial neoplasia (pin) or atypical small acinar proliferation (asap), aged < 40 years, with psa levels > 30 ng/dl, with a history of 5alpha-reductase inhibitor therapy, phytotherapy or any invasive therapy for bph were excluded. patients who had a cystoscopy, colonoscopy, trus, prostate biopsy, acute prostatitis, sinan_stesura seveso 01/04/20 18:51 pagina 1 archivio italiano di urologia e andrologia 2020; 92, 1 sinan avci, efe onen, volkan caglayan, metin kilic, murat sambel, sedat oner 2 urinary tract infection and urinary retention during the previous month were also omitted. those with a subsequent positive prostate biopsy were also excluded, and those with negative prostate biopsies were included. the pathology reports with chronic prostatitis in addition to bph were also noted. the pv of the patients were calculated by measuring three dimensions of the prostate with trus, and using the ellipsoid formula (pv=height*width*length*0.52). for prostate enlargement, a volume of 40 ml was considered as the cut-off value. serum psa levels were measured using the chemiluminescent microparticle immunoassay (cmia) method prior to any prostate manipulation, including dre, trus and biopsy. a total of 438 patients who met the inclusion criteria, with the available data of age, total-free psa levels and pv calculated by trus were enrolled in the study. patients were stratified by age into three groups: < 60 years, 60-70 years and > 70 years. patients with psa levels < 10ng/dl and psa levels between 10 ng/dl and 30ng/dl were also evaluated as two separate groups. data obtained in the study were analysed using spss version 15.0 software (spss, inc., chicago, il, usa). correlation and linear regression analyses were performed to evaluate the relationships between age, total psa, free psa and pv. receiver operating characteristics (roc) curves were constructed to evaluate the ability of free psa to predict pv for the entire cohort and each subgroup. a value of p < 0.05 was accepted as statistically significant. results a total of 896 patients with any exclusion criteria or with incomplete data were excluded from the study. the remaining 438 patients had a mean age of 64.82 ± 7.18 years, median total psa value of 6.82 ng/dl (minmax = 2.75-29.85), median free psa value of 1.68 (minmax = 0.24-11.25), median free psa/total psa ratio of 0.235 (min-max = 0.02-0.82) and median pv of 74 cc (min-max = 40-422). the baseline characteristics of the entire cohort and each subgroup are shown in table 1. statistically significant correlations were determined between pv and age, total psa, free psa, free psa/total psa ratio when the entire cohort was analyzed (p < 0.001 and r = 0.210, p < 0.001 and r = 0.338, p < 0.001 and r = 0.548, p < 0.001 and r = 0.363 respectively) (table 2). free-psa was found to be the only predictor for pv (p < 0.001) in the multivariate linear regression model when compared to age (p = 0.097), total psa (p=0.979) and free psa/total psa ratio (p = 0.425) (table 3). patients with chronic prostatitis pathology and patients with pathology reported as bph only were evaluated separately. in the chronic prostatitis group there were significant correlations between pv and age (p = 0.011 and r = 0.279), total psa (p < 0.001 and r = 0.379), and free psa (p < 0.001 and r = 0.592), fpsa/tpsa ratio (p < 0.001 and r = 0.359) (table 2). in the multivariate linear regression model, a significant correlation was shown only between pv and tpsa, fpsa/tpsa (p = 0.008, p = 0.015 respectively) (table 3). in the bph only group, there were significant correlations between pv and age (p < 0.001 and r = 0.223), total psa (p < 0.001 and r = 0.385), free psa (p < 0.001 and r = 0.520) and fpsa/tpsa ratio (p < 0.001 and r = 0.287) (table 2). in the multivariate linear regression model, a significant correlation was shown only between pv and fpsa (p < 0.001) (table 3). there were correlations between free psa and pv in all three age groups (< 60 years p < 0.001 and r = 0.546, 6070 years p < 0.001 and r = 0.506, > 70 years p < 0.001 and r = 0.483) (table 4). there were correlations between free psa and pv when the cohort was separated according to total psa value as below or above 10 ng/dl table 1. characteristics of the patient population. number age (years) total psa (ng/dl) free psa (ng/dl) fpsa/tpsa ratio prostate volume (cc) of patients (mean ± sd) (median, min-max) (median, min-max) (median, min-max) (median, min-max) age groups < 60 121 56.05 ± 3.66 5.59 1.20 0.208 61 (28%) (2.75-29.85) (0.24-7.74) (0.03-0.69) (40-290) 60-70 224 65.43 ± 2.72 7.19 1.70 0.24 80 (51%) (2.9-28.62) (0.36-9.56) (0.02-0.82) (40-422) > 70 93 74.72 ± 2.94 9.05 2.21 0.26 83 (21%) (2.75-28.63) (0.50-1.25) (0.07-0.55) (40-297) pathology results chronic 114 65.69 ± 6.19 6.37 1.71 0.252 81 prostatitis group (26%) (2.9-24.09) (0.48-9.56) (0.09-0.69) (40-297) only bph group 324 64.39 ± 7.09 6.86 1.805 0.248 79.5 (74%) (2.75-29.85) (0.24-0.26) (0.03-0.82) (40-422) tpsa levels < 10 ng/dl 325 63.93 ± 7.09 5.995 1.43 0.239 68.50 (74%) (2.75-9.91) (0.24-5.28) (0.03-0.82) (40-234) > 10 ng/dl 113 67.34 ± 6.91 13.84 3.05 0.230 95.0 (26%) (10.04-29.85) (0.36-1.25) (0.02-0.56) (40-422) total cohort 438 64.82 ± 7.19 6.82 1.69 0.235 74 (100%) (2.75-29.85) (0.24-1.25) (0.02-0.82) (40-422) tpsa: total prostate-specific antigen; fpsa: free prostate-specific antigen; bph: benign prostatic hyperplasia; sd: standard deviation; min: minimum; max: maximum. sinan_stesura seveso 01/04/20 18:51 pagina 2 (psa < 10 ng/dl p < 0.001 and r = 0.494, psa > 10 ng/dl p < 0.001 and r = 0.512) (table 4). the cut-off level for free psa was determined as 1.285 ng/dl for the prediction of prostate volume > 40 cc (table 5). the cut-off levels are shown in table 5 for the other subgroups in which free psa was significant in predicting pv. the receiver operating characteristic (roc) curves of each group for fpsa in the prediction of prostate volume < 40cc or > 40cc are shown in figure 1. discussion in the management of benign prostatic hyperplasia (bph), urology guidelines recommend medical or surgical treatments according to different prostate volumes (pv). therefore, accurate determination of pv is crucial for the choice of treatment and for the prediction of treatment outcomes such as the probability of urinary retention and the need for surgery (10-13). nevertheless, bph is a progressive disease and that progression is related to prostatic enlargement (14-16). transrectal ultrasound (trus) is more accurate in determining pv than transabdominal ultrasound so it is the reference method used to measure pv (6, 7). however, it is an expensive, time-consuming and uncomfortable method, and the equipment is not available in most primary settings. moreover, in the initial evaluation of bph patients, neither trus nor transabdominal ultrasound is recommended according to the urology guidelines. digitalrectal examination (dre) is simple to perform and useful for estimating the pv but it may assess small prostates as larger, and large ones as smaller. therefore, there is a need for a reliable, practical and cheap method as an alternative to ultrasonography and dre in daily practice (17). several independent investigators have verified the log-linear relationship between serum total psa and pv in different populations and races with similar results (18). hochberg et al. (19) and coban et al. (20) found the correlation coefficient between total psa and pv to be 0.39 and 0.41, respectively. similarly, in the present study, a significant correlation was determined between total psa and pv (r = 0.33) but this result was not confirmed in the multivariate analysis (table 3, p: 0.979). in agreement with the current study multivariate analysis findings, some investigators have proposed that the variability in the relationship between total psa and pv can preclude the accurate prediction of the prostate volume using the total psa alone for an individual patient (9, 21). 3archivio italiano di urologia e andrologia 2020; 92, 1 free psa as useful tool to predict prostate volume table 3. multivariate analysis of factors effecting the pv. unstandardized standardized 95% ci coefficients coefficients t p ß se ß lower bound upper bound total cohort age 0.450 0.265 0.075 1.696 -0.71 0.972 0.091 tpsa 0.023 0.890 0.003 0.026 -1.726 1.772 0.979 fpsa 11.640 3.178 0.427 3.663 5.394 17.886 < 0.001 fpsa/tpsa ratio 25.800 31.322 0.067 0.824 -35.763 87.363 0.411 chronic prostatitis group age 0.476 0.677 0.068 0.703 -0.873 1.825 0.484 tpsa 7.312 2.706 0.671 2.702 1.924 12,699 0.008 fpsa -6.615 8.341 -0.224 -0.793 -23.220 9.991 0.430 fpsa/tpsa ratio 169.948 68.279 0.456 2.489 34.015 305.880 0.015 only bph group age 0.494 0.385 0.076 1.283 -0.265 1.252 0.201 tpsa -1.437 1.387 -0.158 -1.036 -4.169 1.295 0.301 fpsa 17.079 4.879 0.615 3.500 7.465 26.692 < 0.001 fpsa/tpsa ratio -27.425 46.072 -0.067 -0.595 -118.201 63.351 0.552 pv: prostate volume; tpsa: total prostate-specific antigen; fpsa: free prostate-specific antigen; se: standart error; ci: confidence interval. table 5. receiver operating characteristic (roc) curves for free psa to predict whether prostate volume is > 40cc or < 40cc. auc se p 95% ci sensitivity (%) specificity (%) cutoff levelt total cohort 0.780 0.036 < 0.001 0.709-0.851 72.8 73.5 1.285 only bph group 0.749 0.054 < 0.001 0.643-0.855 66.5 76.0 1.495 age < 60 years 0.782 0.059 < 0.001 0.667-0.897 77.0 71.4 0.875 age 60-70 years 0.738 0.067 0.001 0.606-0.869 71.8 72.2 1.365 age > 70 years 0.854 0.074 < 0.001 0.708-0.999 90.4 80.0 1.325 psa < 10 ng/dl 0.753 0.044 < 0.001 0.666-0.840 75.5 71.8 1.105 psa > 10 ng/dl 0.892 0.054 < 0.001 0.787-0.998 89.3 80.0 1.660 avauc: area under curve; se: standart error; ci: confidence interval. table 4. correlations between free psa and pv in different age groups and total psa levels. age tpsa levels < 60 years 60-70 years > 70 years < 10 ng/dl > 10 ng/dl n = 121 (28%) n = 224 (51%) n = 93 (21%) n = 325 (74%) n = 113 (26%)  correlation correlation correlation correlation correlation coefficient p coefficient p coefficient p coefficient p coefficient p pv-fpsa 0.546 < 0.001 0.506 < 0.001 0.487 < 0.001 0.494 < 0.001 0.473 < 0.001 pv: prostate volume; tpsa: total prostate-specific antigen; fpsa: free prostate-specific antigen. table 2. correlations between prostate volume and age, total psa, free psa, free psa/total psa ratio. total cohort chronic prostatitis group only bph group correlation p correlation p correlation p coefficient coefficient coefficient pv age 0.210 < 0.001 0.279 0.011 0.223 < 0.001 pv tpsa 0.338 <0.001 0.379 < 0.001 0.385 < 0.001 pv fpsa 0.548 < 0.001 0.592 < 0.001 0.520 < 0.001 pv-fpsa/tpsa 0.363 < 0.001 0.359 < 0.001 0.287 < 0.001 pv, prostate volume; tpsa, total prostate-specific antigen; fpsa, free prostate-specific antigen. sinan_stesura seveso 01/04/20 18:51 pagina 3 archivio italiano di urologia e andrologia 2020; 92, 1 sinan avci, efe onen, volkan caglayan, metin kilic, murat sambel, sedat oner 4 although there have been numerous studies investigating the correlation of total psa and pv in patients with bph, the relationship between free psa and pv has received little attention. to the best of our knowledge, there have only been seven studies that have examining the relationship between free psa and pv (8, 9, 20, 2225). all of these studies showed that free psa was superior to total psa for predicting pv, and this result was also demonstrated in the multivariate analyses in five of the aforementioned studies (8, 9, 20, 24, 25). in the current study, both total psa and free psa were correlated with pv (r = 0.33, r = 0.54, respectively) but multivariate analysis showed a significant relationship only between free psa and pv (p < 0.001). the superiority of the free psa to total psa found in the current study is consistent with findings in literature (8, 9, 20, 22-25). there were significant correlations between total psa and pv in the multivariate analysis of 3 of the 5 previously mentioned studies (8, 20, 24), whereas in the other two studies, a significant relationship was found only between free psa and pv, as was the case in this current study (9, 25). prostatic inflammation appears to play a role in bph pathogenesis and progression (26, 27) but in the aforementioned studies (8, 9, 20, 22, 24, 25), other than mao et al. (23), who reported that patients with pathological results of only bph were included in the study, there is no information about the presence of inflammatory conditions such as chronic prostatitis in the pathology results of patients. according to the pathology results of the current study, patients were divided into two groups as only bph and bph with chronic prostatitis. significant correlations were found between free psa and pv in both groups. however, in multivariate analysis, the bph only group showed a significant correlation between free psa and pv, similar to the entire cohort, but that correlation was not found in bph with chronic prostatitis group, whereas there was a significant correlation between total psa and pv. it can be hypothesized that free psa may be less influenced by prostatic inflammation in which serum total psa elevation may occur as a result of disruption of the normal prostatic architecture, in other words, the greater increase in free psa may result from a larger benign prostate tissue and prostatic inflammation contributes a greater increase to total psa than free psa. in the above-mentioned studies (8, 20, 24) where a significant correlation was determined between total psa and pv in multivariate analysis, this result could be attributed to possible prostatic inflammation. however, as prostatic inflammation is a pathological diagnosis, it may not be known before biopsy, especially in patients without symptoms associated with such a pathological condition. according to the current study results, the correlation between free psa and prostate volume was comparatively decreased in the case of inflammation in the prostate. therefore, the recommendations of previous studies and the current one for the use of free psa to predict pv may be relatively limited in men with clinically unknown prostatic inflammation. in this respect, the importance of defining this point, which has not been explored in previous studies, should be emphasized. the relationship between free psa and pv according to different age ranges and total psa values was also examined in this study. the patients were stratified into three age groups of < 60 years, 60-70 years and > 70 years. figure 1. roc curves of each group for free psa to predict whether prostate volume is > 40 or < 40 cc. the areas under curve and p values of each group are shown in table 5. sinan_stesura seveso 01/04/20 18:51 pagina 4 in all three age groups a significant correlation was determined between free psa and pv and the highest degree of correlation was found in the group aged < 60 years (r = 0.54, r =0.50, r = 0.48 respectively). in three previous studies where patients were similarly classified according to age, a correlation between free psa and pv was shown in all age groups (22-24). however, the age groups with the highest correlations were different from the current study. in two of the studies (23, 24) the highest correlations were seen in the group aged 60-70 years, while in the other study (22) it was the group of patients > 70 years. in some studies (20, 22, 23) patients with total psa values > 10 ng/dl have been excluded to reduce the possibility of including patients with prostate cancer. nevertheless, in some studies (8, 24) there is no information about the upper limit of total psa while in another study (9), patients with total psa > 10 ng/dl were included. in addition, no study has evaluated the correlation between free psa and pv in patients with total psa values > 10 ng/dl. in the current study, the correlation was analysed between free psa and pv in total psa-stratified cohorts as total psa above or below 10ng/dl. the data obtained showed that the value of the correlation coefficient was slightly greater for the total psa < 10 ng/dl cohort than for the total psa > 10 ng/dl cohort, suggesting that free psa may correlate better to pv when the possibility of patients with prostate cancer decreases (r = 0.494, r = 0.473, respectively). however, from another perspective, because of the small difference in the correlation values between the groups, it can be said that in patients with total psa > 10 ng/dl, free psa can be used safely for the prediction of pv. in the current study, the diagnostic performance of free psa as a proxy for pv was evaluated using roc curves for each group, and free psa was determined to be significant for pv with auc values ranging from 0.73 to 0.89 for all subgroups (table 5). in these analyses, the pv threshold was 40cc, which is of great importance as guidelines have suggested not prescribing 5α-reductase inhibitors to patients with a prostate volume < 40cc (4). in the roc curves of the current study, when the cutoff value of free psa was taken as 1.28 ng/dl to predict prostate volume > 40cc, sensitivity and specificity were determined as 72.8% and 73.5%, respectively and the auc was 0.78 for the entire cohort. this result of auc as 0.78 for free psa to predict whether pv was > 40cc or < 40cc was slightly better than the values reported in previous studies (aucs for references 8, 20, 22-24 were 0.72, 0.75, 0.71, 0.75, 0.75, respectively). there continues to be value in the use of free/total psa for the stratification of the risk of prostate cancer and to decide on a biopsy for patients with 4-10 ng/ml total psa and negative dre. a previous study reported that prostate cancer was detected by biopsy in 56% of men with free/total psa < 0.10, but in only 8% with free/total psa > 0.25 ng /ml (28). those studies indicate that the probability of bph increases as free psa levels increase. therefore, free psa is more closely related to bph and this link is parallel to the current study results. in the multivariate analysis results, the patients with chronic prostatitis pathology showed a significant relationship between free/total psa and pv. this finding can be considered to be related to inflammation-induced total psa increase, as discussed above. when the results were evaluated of the relationship between age and pv, a significant correlation (r = 0.21) was determined, similar to other studies in the literature (8, 9, 20, 22, 23) but that correlation was not seen in the multivariate analysis (p: 0.091). this was consistent with the study of morote et al. (9) whereas the opposite was reported in studies by kayikci et al. (7) and coban et al. (20) (p: < 0.01 and < 0.01, respectively). the present study is one of a limited number of trials suggesting that free psa is a strong predictor for pv and that it is better than total psa. initially, the efficacy of free psa at predicting pv in patients with inflammatory pathology reports in addition to bph and total psa levels >10ng/dl were reported. these conditions were then evaluated as separate groups to eliminate any bias. in addition, separate cut-off levels for free psa in the prediction of pv were established for different subgroups of patients. this study had some limitations, primarily the retrospective nature of the study, the probability of occult cancers that could not be detected by biopsy and the criteria used for subject recruitment on the basis of the indications for prostate biopsy rather than a clinical diagnosis of bph. nevertheless, the data suggest that because of the ability to obtain more accurate estimates of the pv without the help of more expensive, invasive diagnostic evaluations, free psa could provide a more reasonable contribution in the proper management of patients with bph. conclusions although total psa was significantly correlated with pv, this correlation was not shown in multivariate analyses unlike free psa. the superiority of free psa may be used to estimate pv with easily obtained serum tests and could be a useful tool for therapeutic decison-making and longitudinal follow-up in patients with bph. however, in patients with prostatic inflammation, considering that there is a significant relationship between free psa and pv only in univariate analysis, it should be kept in mind that the efficacy of free psa may be limited in this group of patients. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn 2002; 21:167-178. 2. kupelian v, wei jt, o’leary mp, et al. prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the boston area community health (bach) survey. arch intern med. 2006; 166:2381-2387. 3. wilkinson ag, wild sr. is pre-operative imaging of the urinary tract worthwhile in the assessment of prostatism?. br j urol. 1992; 70:53-57. 4. gravas s, cornu jn, drake mj, et al. guidelines on the management of non-neurogenic male luts. uroweb 2018. available from:http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/. 5archivio italiano di urologia e andrologia 2020; 92, 1 free psa as useful tool to predict prostate volume sinan_stesura seveso 01/04/20 18:51 pagina 5 archivio italiano di urologia e andrologia 2020; 92, 1 sinan avci, efe onen, volkan caglayan, metin kilic, murat sambel, sedat oner 6 5. roehrborn cg. accurate determination of prostate size via digital rectal examination and transrectal ultrasound. urology. 1998; 51:19-22. 6. terris mk, stamey ta. determinetion of prostate volume by transrectal ultrasound. j urol. 1991; 145:984-987. 7. trop-pedersen s, juul n, jakobsen h. transrectal prostatic ultrasonography: equipment, normal findings, benign hyperplasia and cancer. scand j urol nephrol. suppl 1988; 107:19-25. 8. kayikci a, cam k, kacagan c, tekin a, ankarali h. free prostate-specific antigen is a better tool than total prostate-specific antigen at predicting prostate volume in patients with lower urinary tract symptoms. urology. 2012; 80:1088-1092. 9. morote j, encabo g, lopez m, de torres im. prediction of prostate volume based on total and free serum prostate-specific antigen: is it reliable?. eur urol. 2000; 38:91-95. 10. jacobsen sj, jacobsen dj, girman cj, et al. natural history of prostatism: risk factors for acute urinary retention. j urol. 1997; 158:481-487. 11jacobsen sj, jacobsen dj, girman cj, et al. treatment for benign prostatic hyperplasia among community dwelling men: the olmsted county study of urinary symptoms and health status. j urol. 1999; 162:1301-1306. 12. bosch jl, bohnen am, groneveld fp. validity of digital rectal examination and serum prostate specific antigen in the estimation of prostate volume in community-based men aged50 to 78 years: the krimpen study. eur urol. 2004; 46:753-759. 13. marberger mj, andersen jt, nickel jc. prostate volume and serum prostate-specific antigen as predictors of acute urinary retention: combined experience from three large multinational placebocontrolled trials. eur urol. 2000; 38:563-568. 14. kaplan sa, roehrborn cg, mcconnell jd, et al. long-term treatment with finasteride improves results in a clinically significant reduction in total prostate volume compared to placebo over the full range of baseline prostate sizes in man enrolled in the mtops trial. j urol. 2008; 180:1030-2. discussion 1032-1033. 15. kaplan sa, lee jy, meehan ag, et al. long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged versus a smaller prostate: data from the mtops trial. j urol. 2011; 185:1369-1373. 16. emberton m, andriole gl, de la rosette j et al. benign prostatic hyperplasia: a progressive disease of aging men1. urology 2003;61:267-273. 17. roehrborn cg, girman cj, rhodes t, et al. correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. urology. 1997; 49:548-557. 18. trivedi mr, choudhary ba. digital rectal examination, transrectal ultrasound and prostate specific antigen as a triple assessment diagnostic tool for benign enlargement of prostate. natl j med res. 2015; 5:244-248. 19. hochberg da, armenakas na, fracchia ja. relationship of prostate-specific antigen and prostate volume in patients withbiopsy proven benign prostatic hyperplasia. prostate. 2000; 45:315-319. 20. coban s, doluoglu og, keles i, et al. age and total and free prostate-specific antigen levels for predicting prostate volume in patients with benign prostatic hyperplasia. the aging male. 2016; 19:124-127. 21. roehrborn cg, boyle p, gould al, waldstreicter j. serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. urology. 1999; 53:581-589. 22. choi h, park jy, shim js, et al. free prostate-specific antigen provides more precise data on benign prostate volume than total prostate-specific antigen in korean population. int neurourol j. 2013; 17:73-77. 23. mao q, zheng x, jia x, et al. relationships between total/free prostate-specific antigen and prostate volume in chinese men with biopsy-proven benign prostatic hyperplasia. int urol nephrol. 2009; 41:761-766. 24. masuda h, kawakami s, sakura m, et al. performance of free psa better than total psa for estimation of prostate volume in elderly men without prostate cancer (abstract). eur urol suppl. 2011; 10:32. 25. canto ei, singh h, shariat sf, et al. serum bpsa outperforms both total psa and free psa as a predictor of prostatic enlargement in men without prostate cancer. urology. 2004; 63:905-910. 26. ficarra v, rossanese m, zazzara m, et al. the role of inflammation in lower urinary tract symptoms (luts) due to benign prostatic hyperplasia (bph) and its potential impact on medical therapy. curr urol rep. 2014; 15:463. 27. he q, wang z, liu g, et al. metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links. prostate cancer and prostatic dis. 2016; 19:7. 28. catalona wj, partin aw, slawin km, et al. use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. jama 1998; 279:1542-1547. correspondence sinan avci, md (corresponding author) sinavci@yahoo.com efe onen, md efe17@yahoo.com volkan caglayan, md volkantuysuz@hotmail.com metin kilic, md kilicmetin@hotmail.com murat sambel, md muratsambel@hotmail.com sedat oner, associate professor sedatoner@yahoo.com university of health sciences, bursa yuksek ihtisas training and research hospital, department of urology, bursa, turkey sinan_stesura seveso 01/04/20 18:51 pagina 6 65archivio italiano di urologia e andrologia 2018; 90, 1 case report robotic perineal radical prostatectomy with high prostate volume volkan tugcu, abdulmuttalip simsek, i • smail yigitbasi, mustafa gürkan yenice, selcuk sahin, ali i • shsan tasci bakirkoy dr. sadi konuk research and training hospital, department of urology, istanbul, turkey. background: minimally invasive techniques are ever improving and are preferred more. many techniques were developed in radical prostatectomy operations. robotic radical prostatectomy with the perineal approach is a new technique. case presentation: a 66-year-old male patient presented because of lower urinary tract symptoms, a psa value of 5.5 ng/ml was detected, prostate biopsy was performed under transrectal ultrasound guide, a gleason 3+3 adenocarcinoma on 3/12 foci was reported at pathology. robotic perineal radical prostatectomy (r-prp) operation was performed in the patient who had a prostate volume of 130 cc with middle lobe and a body mass index of 32 without additional disease. the duration of operation was 140 minutes in total and the duration at the console was 95 minutes, the amount of bleeding was 85 cc and no intraoperative complication was detected. conclusion: r-prp is a technique that can be applied safely without prolonging the operation period and without additional morbidity to the patient, preserving the oncologic and functional outcomes in patients with surgical history and large prostate volume. key words: robotic perineal radical prostatectomy; high prostate volume. submitted 15 january 2018; 20 january 2018 summary no conflict of interest declared. (rrp) showed prolonged operation time and hospitalization (3). since each technique has its own difficulties and limitations, it is only when the factors of the prostate do not affect the operation and when the comorbidities of the patient are also taken into account, the situation becomes more difficult and the development of new techniques will be inevitable. robotic perineal radical prostatectomy (r-prp) was developed and applied by tugcu et al to 15 patients, indicated that this technique can be safely applied in centers with advanced robotic surgery experience (4). this technique with the perineal approach, is applied to a narrow surgical field without incision of endopelvic fascia and without abdomen involvement. when evaluating the surgical steps, a question comes to mind whether this technique is applicable to large prostates. in this case report, we aimed to prove that this technique can be safely applied to prostates with a large volume. presentation of case a 66-year-old male patient presented because of lower urinary tract symptoms, a psa value of 5.5 ng/ml was detected, prostate biopsy was performed under transrectal ultrasound guide and a gleason 3+3 adenocarcinoma on 3/12 foci was reported at pathology. at multiparametric magnetic resonance imaging (figure 1a) of the patient, who had a laparotomy history due to ileus (figure 1b), there was no extraprostatic spread when the pirads 3 lesion was detected, radical-prp doi: 10.4081/aiua.2018.1.65 introduction and background since description of radical prostatectomy technique which has high morbidity and mortality, many methods have been used up to that time and the results have been presented. with the acquisition experience, the morbidity and mortality are reduced in parallel with the development of the technology and these operations can be performed safely in experienced centers with minimally invasive techniques. despite the introduction of many new methods, some factors of the disease may cause this surgical technique to change, to apply another surgical technique or to give up the surgeon. one of these factors is the size of the prostate and when applied with different methods, prostate size can affect the duration of operation, amount of bleeding, postoperative urinary incontinence and erectile dysfunction (1). when open radical prostatectomy (orp) compared to other techniques, it has been reported that the amount of bleeding is significantly increased as a negative factor (2). according to the data of the literature, laparoscopic radical prostatectomy (lrp) and robotic radical prostatectomy figure 1a. screening middle lobe. figure 1b. laparotomy incision due to ileus. simsek_stesura seveso 27/03/18 09:31 pagina 65 archivio italiano di urologia e andrologia 2018; 90, 1 v. tugcu, a. simsek, i • smail yigitbasi, m. gürkan yenice, s. sahin, a. i • hsan tasci 66 operation was performed in the patient who had a prostate volume of 130 cc with middle lobe and a body mass index of 32 without additional disease. the duration of operation was 140 minutes in total and the duration of the console was 95 minutes, the amount of bleeding was 85 cc and no intraoperative complication was detected. the drainage catheter and urethral catheter of the patient with no postoperative complication were removed on 2nd and 7th postoperative day, respectively, and the patient was discharged the same day of catheter removal.the pathology score was gleason 3 + 3 adenocarcinoma and the surgical margin was negative. surgical technique the patient is taken to the exaggerated lithotomy position with 15 degrees of trendelenburg. a urethral catheter is placed and the bladder is emptied. a sterile glove is placed in the rectum and the sides of the glove are stitched to the perineal skin. thus, we aim to avoid rectum damage by using digital rectal examination during perineal dissections. a 6 cm semilunar incision is bilaterally made between tubercula ischiadica. the perineal dissection is terminated when the dissection margin reaches to the membranous urethra and the apex of the prostate is seen. subcutaneous tissue laying under the incision borders is dissected deeply over the superficial perineal fascia to place the gelpoint® (applied medical, rancho santa margarita, ca, usa). once the robotic system is docked (figure 2), dissection is started from prostate apex and extended in to the lateral sides of the prostate and then deepened inferiorly to reveal the denonvilliers’ fascia covering the seminal vesicle compartment. once the denonvilliers’ fascia is incised, vasa deferentes are bilaterally revealed, dissected and cut. seminal vesicles are completely dissected and revealed. then the membranous urethra is dissected and cut. the lateral prostatic pedicles are dissected and controlled using hem-o-lock® clips. after completing the lateral dissections of prostate bilaterally, the bladder neck is identified and incised with monopolar scissors, sparing and leaving intact the dorsal vein complex. dissection was extended towards the bladder neck. anterior bladder neck was incised using monopolar scissors. after dissection the bladder neck, the middle lobe of the prostate was observed and a vicryl suture was placed for traction of the middle lobe of the prostate (figure 3a). with proper resection margin, posterior border of the bladder neck was cut and prostate fully dissected from the bladder (figure 3b). two of 4/0 v-loc™ (covidien, mansfield, ma, usa) sutures are used in a running fashion starting from the retzius side to rectal side of the bladder neck. the first suture is started at 12 o'clock on the bladder neck from outside to inside and then continued the urethra from inside to outside clockwise down to 6 o’clock. a second barbed suture is used in the same setting but in reverse clockwise. once the anastomosis is completed a 22 ch urethral catheter is replaced. the bladder is filled by 200 cc saline to test the anastomosis for leakage. after observing the anastomosis is water tight, robotic system is undocked and a jackson pratt drain is placed. specimen was sent to the pathology laboratory for examination (figure 4). discussion today, despite the large prostate volumes, in the experienced centers, radical prostatectomy has been successfully applied with many techniques. when we look at risk factors for prostate cancer, obesity and hypertension are at the forefront, therefore radical prostatectomy for large prostate volumes often is accompanied by obesity, hypertension and other comorbid factors. consequently it is necessary to cope with the additional comorbidities and the negative factors related to previous abdominal surgery. sarle et al. reported that with retropubic approach the posterior border of the prostate base is very difficult to view, especially in patients with large median lobes, ureteral orifices are almost impossible to view and the risk of injury is high, especially in the antegrade approach, and seminal vesicle dissection prolonged the duration of the operation (5). despite the narrow surgical field with perineal approach, in our technique, large prostate was easily dissected with appropriate surgical margins on the apex, base and lateral planes, even if a large median lobe was present. approaching the posterior borders of the prostate from the inferior side allows to safely dissect them by using used strap vicryl suture without affecting the operation time with the ureters protected by direct vision. figure 2. docking of the robotic system. figure 3a. strap vicryl suture. figure 3b. dissection from the bladder neck. figure 4. specimen. simsek_stesura seveso 27/03/18 09:31 pagina 66 when large prostates are dissected from the bladder, large defects may form in the bladder neck and require additional reconstructive intervention to anastomose bladder neck to the urethra and can adversely affect continence (6). eden et al. have proposed 60 cc as the highest prostate volume for open perineal radical prostatectomy (7). regardless of how large the prostate, in our technique the anterior and posterior borders of the bladder can be easily visualized from perineal approach and the prostate can be easily dissected without creating large defects in the bladder neck. our technique allows to visualize the trigone and bilaterally the ureteral orifices. in patients who have large prostate, orifices can be protected by direct vision and bladder neck resection can be safely performed. at the same time, the endopelvic fascia is completely preserved, the bladder neck defect is optimal for anastomosis and is not dissected from the surrounding tissues. all these advantages facilitate radical prostatectomy of large prostates in order to preserve the anatomic structure at the maximum extent and contribute to functional outcomes. this technique is safely applied to large prostates with maximum respect for anatomy with its advantages. conclusion robotic-prp is a technique that can be applied safely without prolonging the operation period and without additional morbidity to the patient, preserving the oncologic and functional outcomes in patients with previous surgical history and large prostate volume. references 1. smith ja jr, chan rc, chang ss, herrell sd, et al. a comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical prostatectomy. j urol. 2007; 178:2385-2389. 2. hsu ei, hong ek, lepor h. influence of body weight and prostate volume on intraoperative, perioperative, and postoperative outcomes after radical retropubic prostatectomy. urology. 2003; 61:60-1. 3. link ba, nelson r, josephson dy, et al. the impact of prostate gland weight in robot assisted laparoscopic radical prostatectomy. j urol. 2008; 180:928. 4. tugcu v. akca o, simsek a, yigitbasi i, et al. robot-assisted radical perineal prostatectomy: first experience of 15 cases. turk j urol, 2017; 43:476-83. 5. sarle r, tewari a, hemal ak, menon m, robotic-assisted anatomic radical prostatectomy: technical difficulties due to a large median lobe. urol int. 2005; 74:92-94. 6. zorn kc, orvieto ma, mikhail aa, et al. effect of prostate weight on operative and postoperative outcomes of robotic-assisted laparoscopic prostatectomy. urology. 2007; 69:300-305. 7. eden cg. minimal access radical prostatectomy: how is it shaping up? bju int. 2008; 101:791-792. 67archivio italiano di urologia e andrologia 2018; 90, 1 robotic perineal radical prostatectomy correspondence volkan tugcu, md abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com i • smail yigitbasi, md mustafa gürkan yenice, md selcuk sahin, md ali i • hsan tasci, md bakirkoy dr. sadi konuk research and training hospital, department of urology zuhuratbaba, tevfik saglam cad. no:11, bakirkoy, istanbul, turkey simsek_stesura seveso 27/03/18 09:31 pagina 67 325archivio italiano di urologia e andrologia 2016; 88, 4 original paper who “apparently” more spends, “in reality” spends less. spending “a little” more for the rental of the extracorporeal lithotripter can save “a lot” about the days of hospitalization for urinary stones giuseppe albino 1, francesco albergo 2 1 uoc of urology, “l. bonomo” hospital, andria, asl bat, italy; 2 school of management, università lum “jean monnet”, italy. objective: the right to health (according to the article 32 of the italian republic constitution) is financially conditioned; for this reason the national health system (nhs) has the objective of rationalize health expenditure according to the criteria of efficiency, effectiveness and economy. this paper is an example of rationalization concerning the extracorporeal shock wave lithotripsy (eswl). materials and methods: hospital admissions for urinary stones were taken into account. "edotto", the database of the puglia region has identified 23 inpatient admissions during which was performed eswl. a single operator performed eswls with a storz lithotripter, modulith slk. results: the average hospital stay is conditioned by days "to wait" lithotripsy. in 2014 the hospitalization days "waiting for" lithotripsy were 100. the results were subjected to swot analysis and discussed with the boston consulting group matrix. discussion: constant availability of the lithotripter would spare 100 days of hospitalization, amounting to € 88,200.00. this waste of resources corresponds to an additional cost equal to 98.3% on the cost for the rental of the lithotripter. instead, reducing "unnecessary" hospitalization days would get a saving of 79.3% on the rental cost. it is as if for 46 days of the lithotripter rent were paid 46 days, while for 365 days of the lithotripter rent were paid only 11.8 sessions per year. conclusions: rationalization of resources is not necessarily a synonym of "reduction" of resources, but of reduction of waste in the nhs. a good plan is the most important rational basis to get more resources. about the process taken into account it is seen as an investment of € 21,450.00 would keep unchanged the effectiveness of lithotripsy service but would add efficiency and economy (increase of sessions/year, increase in the active mobility, increase in orthopedic treatments) and would drastically reduce the number hospital days (a waste). key words: eswl; efficiency; effectiveness; economy. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. a fundamental right of the individual and as collective interest, and guarantees free medical care to the indigent" (1). but this right/interest is financially conditioned, therefore, by law 833 of 1978 that introduced in the national health system (nhs) also the objective of rationalization of health expenditure through the analysis based on long-term planning and short and medium term programming, as tools for controlling the use of resources. the asls (local health agency) have the "objectives" to be pursued as in a "business management model", focused on the achieved results and used resources (2). the asls as "companies" do not realize the profit, but must operate in maximum economy in order to make the best use of scarce resources and to positively improve results/resources ratio. the company control techniques do not want to assert the primacy of the economic aspects on the technical and professional, ethical and social, but have the function of identifying the mechanisms able to improve the economic management, so more and more qualified services can be offered (3). in fact, the management control committee (mcc) is the means by which managers ensure that the management is working effectively in conditions of efficiency and effectiveness (3), such as to enable the achievement of business objectives set in the strategic planning (4, 5). when talking about "control" the focus should not only be focused on the "ex post" aspects, performing a control approach on employed conducts and reached results by different organizational units (eg. the operating units or departments of a hospital), but above all on improving the "ex ante" decision-making processes (3). this work takes inspiration from this integral vision of the concept of "control": starting from ''analysis of processes" (3) of hospital admissions with a diagnosis of urolithiasis useful data "ex post" are obtained which become the basis for proposing a program aimed to improve the "ex ante" decision making, by putting the emphasis on making more efficient the process, minimizing waste and optimizing resources to be used, with the possibility to obtain an increase of the output volume (of the provided services), maintaining their quality. doi: 10.4081/aiua.2016.4.325 presented at 20th national congress sieun, sciacca 2016 introduction the topic of this paper has origin in a distant time but still present in the article 32 of the constitution of the italian republic of 1947: "the republic protects health as albino_stesura seveso 09/01/17 10:44 pagina 325 archivio italiano di urologia e andrologia 2016; 88, 4 g. albino, f. albergo 326 materials and methods to verify the carried out activity in 2014 by u.o. urology in "l. bonomo" hospital andria asl bat, "edotto", a data processing platform, was consulted. edotto (6) is the new health information system of the puglia region, in operation since 2012. the system is a tool of the information communication technology (ict); it facilitates greater interaction between actors at various levels of health organization (welfare department, regional health agency, healthcare companies, general pratictioners, pharmacies, hospital physicians, etc.). the edotto system is available without functional limitations only by authorized terminals connected to the rupar network (7). the application area on the "the hospital admissions management" was consulted to get the data. in this application area it is possible to search by setting the search criteria; the result can be printed or stored in pdf or excel format. research was performed in relation to drgs and to performances (icd-9-cm code). drg (8) the drg system (diagnosis related group: homogeneous diagnostic groupings) is derived from the research begun in 1967 by the team at yale university (united states), coordinated by robert fetter (9). the initial idea of fetter was to identify the hospital product in terms of classes or categories of homogeneous patients for clinical and care characteristics, and therefore also with respect to the expected treatment from which it derives the consumption of resources and, therefore, a cost. these features make the drg classification system suitable for use as a reference to specify the performance of hospitalization to which to attribute specific predetermined rates. in this paper the drgs 323 and 324 have been taken into account; they represent respectively: "urinary stones, with complications and comorbidities and/or ultrasonic lithotripsy" for drg 323 and "urinary stones, without complications and comorbidities" for drg 324. within these two drg the advanced search filter has been set for the 9851 procedure according to the icd-9cm code, corresponding to the "extracorporeal lithotripsy of kidney, ureter and/or bladder". icd-9-cm (10) the international classification of diseases (icd) is a system that organizes diseases and injuries into groups. in 1893, the international institute of statistics conference, which took place in chicago, approved the international classification of causes of death. since 1948 (6th revision) international classification was also adopted to detect the causes of morbidity. in 1975, in geneva, in the course of the 29th assembly of the world health organization it was approved the 9th revision of the classification (icd-9). since 1979, in the united states, the national center for health statistics (nchs), section of the center for disease control (cdc) (where are represented the professional and academic associations of physicians, associations of hospitals, the regional office of the world health organization, the hcfa agency) provides for annually updating a revised and extended version of the classification system, with the introduction of interventions and diagnostic and therapeutic procedures: the icd-9-cm (international classification of diseases, 9th revision, clinical modification). since then, in october of each year, the icd-9-cm updates are published. since january 2009, the 2007 version of the icd-9-cm classification is adopted throughout the italian territory. this is the italian translation of the us classification, prepared by the health section of the ministry of labour, health and social affairs and published by the istituto poligrafico e zecca of state. eswl the procedure object of our reflection, classified as the 9851 icd-9-cm, is the extracorporeal shock wave lithotripsy or eswl currently, extracorporeal shock wave lithotripsy is performed electively in day service regime (which it is a day hospital with the patient's economic sharing who pays the ticket). only patients admitted from the emergency department for renal colic and/or hydronephrosis and/or urosepsis may undergo extracorporeal shock wave lithotripsy in ordinary admission. the lithotripter storz modulith slk is a third-generation lithotripter. it is composed of an electromagnetic generator, it uses a dual-pointing system, ultrasonographic "in line" and radiological, with computerized "video track". the strongest point of this machine is constituted by "the degrees of freedom" of the arm on which the generator (called "head") is installed, that allow to perform ultrasonographic pointing of the stone by maneuvering the generator in a similar way and with the same inclinations of a ultrasound probe when it is used "free hand” for a diagnostic examination. for this reason there are very few stones that you cannot point and in any case all treatable keeping the patient in a "comfortable" position, lying prone or supine as needed. lease the extracorporeal lithotripter used in asl bat is not owned by the asl, but is entrusted in rent. the rental was awarded at the price per session of € 1,950.00 plus vat (inclusive of all equipment, works and services, as well as technical support and maintenance). in the same resolution, it is written that the rental would be held for 4 sessions monthly. stakeholders among the external stakeholders of lithotripsy ambulatory there is also the supplier of the lithotripter rental. the price per session also includes the cost of transport, assembly at the beginning of the session and disassembly at the end of the session. if the asl were to ask an additional monthly day of the lithotripter rental (5th session), the supplier company would ask to be able to permanently leave the lithotripter at the ambulatory of lithotripsy, making it available to carry out the treatments even on days above 5 monthly, required by possible new rental request. in doing so, the supplier company would save on transport costs and the asl would have the lithotripter available for 365 days a year. results edotto system was questioned about the number of hospitalizations between 1 january 2014 and 31 december 2014 in the urology unit of the hospital of andria, in the albino_stesura seveso 09/01/17 10:44 pagina 326 asl bat. in the urology unit in the year 2014 they were performed 510 hospital admissions. they were taken into account admissions corresponding to drg 323 (“urinary stones, with cc (13) and/or ultrasonic lithotripsy”) and the drg 324 ("urinary stones, without cc"). the edotto system indicated 37 hospital admissions with drg 323 and 11 hospital admissions with drg 324 (48 hospital admissions in total). for both drgs was performed advanced search by entering the procedure with the code 9851 icd-9-cm, corresponding to the "extracorporeal lithotripsy of kidney, ureter and/or bladder”. twenty-three ordinary admissions for urinary stones during which the extracorporeal shockwave lithotripsy (eswl) was performed were selected. this data was summarized on the excel worksheet with date of admission and date of discharge (table 1). the day when eswl was performed was also inserted. it has been calculated, for each admission, the number of hospital days "to wait" for the lithotripsy session, -1 day (minus one day), corresponding to the day when the admission from the emergency department occurred, during which the patient completed the clinical evaluation and the examinations necessary for treatment. in 2014, "the days of hospitalization -1" waiting for the lithotripsy session were 100 in total (the excel worksheet, once set, automatically calculates the result). the following observations were made (table 2). – according to the reporting of the asl bat the total average cost of one day of hospitalization at the urology unit in 2014 was € 882.00 (11); – if the extracorporeal lithotripter was constantly in the clinic, the patient once admitted from the emergency department should not have to wait for the scheduled day for the session of lithotripsy, but he would be treated on the day of admission or at the latest the following day. it follows that in 2014 at least 100 days of hospitalization would be spared, amounting to € 88,200.00; – the rental price per session of lithotripsy is € 1,950.00 plus vat; the asl bat is actually requiring the rental of the extracorporeal lithotripter for 4 sessions per month; – if the asl bat would require an additional session per month (the fifth), the supplier company declared that they would consider cheaper to leave the lithotripter on the spot in the andria hospital to save the cost of transportation, so making the device available every day of the year; – an additional cost per year would be added ( considering that in august only 2 sessions are performed, the number of extra sessions per year would be 11 x € 1,950.00 = 21,450.00/year) but 100 days of hospitalization (882 x 100) would be saved because patients with urinary stones could be subjected to extracorporeal shock wave lithotripsy already on the day of admission or the next day to their admission, with a net saving of € 66,750.00 (€ 88,200.00 21,450.00); – the current number of lithotripsy sessions for year is 46; adding one session a month (except in august) the number of session per year will be increased by 11 and the total number of sessions per year would become 57; – since the lithotripter would remain constantly on site, 100 hospitalization days would be spared, amounting to € 88,200.00, that should be deducted from the expenditure for 57 rental days (€ 111,150.00), resulting in an overall net expenditure for the asl of € 22,950.00 equivalent to 11.77 lithotripsy sessions, to the price of € 1,950.00. each. in other words, at present the asl bat would pay 46 lithotripsy sessions "apparently" for the price of € 1,950.00/session, but in reality taking into account the cost of 100 hospitalization extra days, it is as if each lithotripsy session would cost € 3,860.00, that is 98.3% more. otherwise, acquiring 11 sessions of lithotripsy extra, "apparently" the asl would have an increase of 23.9% on spending for the lithotripter rental, but taking into account the savings that would be achieved on the days of hospitalization, it is as if it paid each rental day at the price of € 403.00/session, with a saving of 79.3% on the current price. the total cost of "operation" would be € 22,950.00, equivalent to 11.8 sessions of lithotrip327archivio italiano di urologia e andrologia 2016; 88, 4 who “apparently” more spends, “in reality” spends les... table 1. ordinary admission for eswl. table 2. economic analyses. albino_stesura seveso 09/01/17 10:44 pagina 327 archivio italiano di urologia e andrologia 2016; 88, 4 g. albino, f. albergo 328 sy. it is as if, to have on site the lithotripter for 46 days, the asl had to pay 46 sessions a year, whereas to have in place the lithotripter for 365 days a year the asl should pay only 11.8 sessions per year, equivalent to the cost of the extra sessions to require, while the rest of the sessions would be "at no cost" (table 2). discussion the "process analysis" which represents the first phase of the control protocol of the care path that we are reviewing (“what leads to extracorporeal lithotripsy after hospitalization from the emergency department”) should be initially performed. the "ex post" direction (analysis of the historical data) and the “ex ante” direction (planning and development assumptions) should follow. finally, the preliminary stages should be completed with some analysis tools (3) before submitting the project under review by the general directorate and by the management control (table 3). strengths 1. lithiasis is an endemic disease. according to istat data (13), to 01 january 2015, the resident population in puglia was 4,090,105 persons, while the population resident in the barletta-andria-trani province was 394,387 inhabitants. according to the most recently published data (14), showing a prevalence of urolithiasis in puglia of 4.69% and an incidence of 2.53‰ it can be estimated that in puglia 191,826 people are suffering for urinary stones, of which 18,497 in the bat province, and that every year in puglia 10,348 new cases of urolithiasis may arise, of which 998 only in the bat province. it is likely that many of them will go to the emergency room of the hospital of andria, the only hospital in the province with the urology unit. 2. 80% of the cases of urolithiasis will continue to be treated by eswl despite technological advances the treatment algorithm of urolithiasis still includes the extracorporeal lithotripsy as the reference treatment for most of the stones, as stated by the most recent international guidelines (15). 3. active mobility. from the records of lithotripsy service it appears that 249 eswl treatments were carried out in 2014, of which 14% to extra asl patients, 10% to patients from puglia but of other provinces and 4% to patients outside the region. opportunity 4. it can become a good basis for developing a stone center. careful management of the health system should take account of directions of the population migrations, indicated by the data relating to the active and passive mobility, to enhance what the statistics show as reference centers. weaknesses 5. to accept that the cost of the lithotripter extracorporeal rental increases of 23.9% in a year. 6. the need to wait a year before checking the effective savings in hospital admissions related to drgs 323 and 324. threats 7. insurance for any theft or damage of the lithotripter that will be left in the hospital. a suitable area will be needed to the machine housing; where it can be left mounted and ready for use. 8. increased wear. to introduce the maintenance service on 24 hours for 365 days/year in the lease. boston consulting group matrix another tool that can be used in the preliminary stages of the control protocol is growth/share matrix that was designed in the seventies by bcg (boston consulting group) bcg (16). this matrix is able to rank strategic business areas or activities of a company. it can also be used to evaluate the services and products of a local health organization. the parameters used for classification are: market growth rate, on the vertical axis (it is a measure of market attractiveness) and relative market share, on the horizontal axis (measuring the company's strength in that market). the combination of these two elements can be used to identify four categories: question mark, star, cash cow, dog. for each of the described combinations exists a recommended behavior during the evaluation. if we take into account the path of the patient suffering from urolithiasis that is hospitalized from the emergency department for renal colic (3), identified by drgs 323 and 324, it is immediate to place these activities in the dog category. in fact, these are "medical" drgs treated in a "surgical department" with debatable appropriateness, which will be "at a loss", but that can never completely avoided. what can be do is to minimize the number of hospital days (minimize waste), where it is always available on site the extracorporeal lithotripter. the lithotripsy service, which takes place as day service (with the participation of the patient through the payment of the ticket), may instead be classified in the "cash cow” category that is a strategic area of clinical performances which lead to constant cash flows obtained at the price of a few investments with a high profit margin. it is not a new strategic area, but an area well established in the health service, although still very profitable. the cash cows should be carefully cared by the asl, because the gain is practically guaranteed. they are "cows" from which "milking" money to finance other activities. the recommended behavior to the management is to "realize" (make a minimum investment in the face of a table 3. swot analysis [12]. albino_stesura seveso 09/01/17 10:44 pagina 328 high gain by the day service and a net reduction of losses by the ordinary hospitalization). if implemented, the stone center would be classified in the star category: the star activities are characterized by a high market share (the urolithiasis is endemic in puglia). they require investment to continue to grow, and then transform themselves into stars. the behavior recommended to the management is to "maintain". the crucial point is to make clear to the management control that to realize a stone center does not fall at all in the "enigma" category (question mark). this category indicates a strategic business area that is located in an expanding market, without owning a significant share of this market. typically question marks require massive investments in order to increase the market share. in the case of urolithiasis there is a "market" and it is in expansion. there is not uncertainty about the possibility to increase the market share, as in the question mark category and, as we have seen, investment in a stone center, where there is already a lithotripsy service, are not massive. in any case, the recommended behavior to management in front of a product of the enigma category is to "develop". conclusions planning within the national health system is essential to rationalize the use of resources. when budgeting, the directions can follow the top-down or bottom-up model. this case is an example of a budget proposal that follows the bottom-up model. consequently a good plan becomes the most important rationale with which to get approval for more resources. the plan accurately identified that the key objectives continue to remain within the fold of effectiveness, efficiency and economy. in the path in question is clearly seen how, with an investment of € 21,450.00, the effectiveness of lithotripsy services would remain unchanged, but it would add efficiency and economy, because the use of the lithotripter would be optimized (increase in sessions/year, increase in the active mobility, increase in orthopedic treatments with shockwaves) and the number of hospital days related to drgs 323 and 324 would be reduced drastically with a considerable saving on hospital days. it would also be a solid basis for the institution of a stone center. the role played by the persons is important in achieving objectives; they are precisely the behaviors of managers, rather than the measures and the accounts, to represent the essence of the planning and control systems. references 1. costituzione della repubblica italiana in gazzetta ufficiale, nº 298, roma, istituto poligrafico dello stato, dicembre 1947, pp. 3801-3816 2. antonelli v, d’alessio r. casi di controllo di gestione, metodi, tecniche, casi aziendali di settore. ipsoa, 2007, 2nd, p.418 3. albergo f. strumenti del controllo e analisi del rischio nelle aziende sanitarie. cacucci editore bari, 2014, p. 51. 4. brusa l. sistemi manageriali di programmazione e controllo. giuffrè editore, milano, 2000, p.2. 5. garzoni a. il controllo della realizzazione della strategia. scritti in onore di vittorio coda, milano, 2010, egea. 6. http://www.sanita.puglia.it/portal/page/portal/saussc/sistemi% 20informativi/edotto/ulteriori%20informazioni%20edotto.pdf 7. http://archivio.cnipa.gov.it/site/_files/linee%20guida_pa.pdf 8. http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano& id=1349&area=ricoveriospedalieri&menu=vuoto 9. thompson jd, averill rf, fetter rb. planning, budgeting, and controlling--one look at the future: case-mix cost accounting. health serv res. 1979; 14:111-25. 10. international classification of diseases, 9th revision, clinical modification (icd-9-cm). http://www.salute.gov.it/portale/temi/ p2_6.jsp?lingua=italiano&id=1277&area=ricoveriospedalieri&me nu=classificazione. 11. data of the asl bat corporate reporting provided by dr. reda rosario. 12. armstrong m. a handbook of human resource management practice (10th edition) 2006, kogan page, london isbn 0-74944631-5. 13. istat data. http://dati.istat.it/index.aspx?datasetcode=dccn _pilprodt 14. prezioso d, illiano e, et al. urolithiasis in italy: an epidemiological study. arch it urol androl 2014; 86 (2), 99-102. 15. http://uroweb.org/wp-content/uploads/eau-guidelines-urolithiasis -2015-v2.pdf 16. http://www.bcg.it/ 329archivio italiano di urologia e andrologia 2016; 88, 4 who “apparently” more spends, “in reality” spends les... correspondence giuseppe albino, md, phd (corresponding author) peppealbino@hotmail.com uoc of urology, “l.bonomo” hospital, asl bat, andria, italy francesco albergo, phd albergo@lum.it school of management, università lum “jean monnet”, italy albino_stesura seveso 09/01/17 10:44 pagina 329 archivio italiano di urologia e andrologia 2021; 93, 186 letter to editor red man syndrome caused by intracavernous irrigation with vancomycin at the time of placing penile implants submitted 8 december 2020; accepted 20 december 2020 no conflict of interest declared. doi: 10.4081/aiua.2021.1.86 to the editor, erectile dysfunction is a condition that affects more than half of men between 40 and 70 years of age. penile prosthesis (pp) implant is recognized, at present, as the most effective option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which the pharmacological approach is contraindicated or ineffective (1). postoperative infection is the most feared complication of genitourinary prosthetic surgery. the literature contains several interventions that have been shown to reduce the rate of pp infection. one of the intraoperative approaches is to use an antiseptic washout solution containing vancomycin and gentamycin (2). we report a case of a 65-year-old male patient who developed red man syndrome (rms) soon after the initiation of intracavernous irrigation of vancomycin during the implantation of a pp. the case was successfully managed with diphenhydramine. rms is an idiopathic pseudo-allergic drug reaction that may develop after the administration of vancomycin. it is frequently observed with the infusion of vancomycin. the patient shows signs and symptoms of an allergic reaction, but without any classic allergy immunologic mechanism (3). discontinuation of the vancomycin infusion and administration of diphenhydramine can abort most of the reactions. slow intravenous administration of vancomycin should minimize the risk of infusion-related adverse effects (4). a 65-year-old male with poorly controlled diabetes mellitus type 2 presented for inflatable pp insertion. he has no known food or drug allergies. on pre-procedure assessment, his blood pressure was 110/80 mmhg, heart rate 72 beats per minute, respiratory rate 13 per minute, and temperature 37.1c°. in the supine position, prepping and draping in the usual sterile manner done. under spinal anesthesia, a penoscrotal incision was made. the dartos fascia is now exposed and incised. skin hooks are placed. the tunica albuginea of both corporas is exposed and the urethral catheter is palpated in the midline. a stab wound is made with a scalpel into each corpora and, using metzenbaum scissors, a 3-cm vertical corporotomy is performed between two 2-0 stay sutures. corporal dilatation is performed. vigorous intracavernous washout was done using an antimicrobial solution (500 mg vancomycin and 80 mg gentamicin sulfate diluted in a 1 liter of normal saline solution). after 5 minutes, erythema developed along the patient’s right forearm. at the same time, the patient developed redness of his right neck and itching of his scalp, mainly on his left side. adequate oxygenation by a face mask was initiated. vital signs were stable. this was identified as rms secondary to vancomycin. the adverse reaction was resolved after the discontinuation of intracavernous irrigation with vancomycin and administration of diphenhydramine. the planned procedure was completed. this report of rms after intracavernous irrigation with vancomycin is believed the first in the literature. the patient’s symptoms disappeared within one hour after the medication was discontinued. this case demonstrates the need to closely monitor for side effects of intracavernous irrigation with vancomycin and to carefully consider this approach. references 1. bettocchi c, palumbo f, spilotros m, et al. penile prostheses. ther adv urol. 2010; 2:35-40. 2. swanton ar, munarriz rm, gross ms. updates in penile prosthesis infections. asian j androl. 2020; 22:28-33. 87archivio italiano di urologia e andrologia 2021; 93, 1 red man syndrome caused by intracavernous irrigation with vancomycin at the time of placing penile implants 3. arroyo-mercado f, khudyakov a, chawla gs, et al. red man syndrome with oral vancomycin: a case report. am j med case rep. 2019; 7:16-17. 4. sivagnanam s, deleu d. red man syndrome. crit care. 2003; 7:119-20. correspondence mohamad moussa, md mohamadamoussa@hotmail.com head of urology department, zahraa hospital, university medical center, lebanese university, beirut, lebanon mohamad abou chakra, md (corresponding author) mohamedabouchakra@hotmail.com faculty of medicine, department of urology, lebanese university, beirut, lebanon, 1108 athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece. athanasios dellis, md aedellis@gmail.com department of urology/general surgery, areteion hospital, athens, greece yasmine moussa, md moussa.yasmin@yahoo.com clinic of dermatology, dr. brinkmann, schult & samimi-fard barbarastraße 15, 45964 gladbeck, germany mohamad moussa 1, mohamad abou chakra 2, athanasios papatsoris 3, athanasios dellis 4, yasmine moussa 5 1 urology department, zahraa hospital, university medical center, lebanese university, beirut, lebanon; 2 faculty of medicine, department of urology, lebanese university, beirut, lebanon 3 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece; 4 department of urology/general surgery, areteion hospital, athens, greece; 5 clinic of dermatology, dr. brinkmann, schult & samimi-fard, gladbeck, germany. stesura seveso 215archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. introduction end-stage renal disesase (esrd) is a disabling disease that forces patients to a radical change of their lifestyle and habits, causing physical and important psychological disorders. sexual male dysfunction is an extremely common condition that manifests itself with erectile disorder (ed) and premature ejaculation (ep) (1), often present at the same time. in everyday clinical practice, both pathologies require a multidisciplinary approach in the diagnostic phase and in the therapeutic management (2, 3) due to their multifactorial genesis, such as psychological factors and endothelial dysfunction. female sexual dysfunctions objectives: incidence and prevalence of patients in dialytic therapy increased considerably in recent years. the onset of new issues, once overshadowed, linked to a lower quality of life like sexual dysfunction became increasingly common. the first study in this area, dating back to the 1970s, shows the high prevalence of sexual dysfunction among patients in dialytic therapy of both sexes. later studies proved an association of sexual dysfunction with psyche disorders, anxiety, depression and lack of self-confidence. the aim of this study is to describe the incidence of male and female sexual main dysfunctions, the latter not least in literature, in patients in hemodialytic therapy. with this aim two dialytic centers have been compared, one located in northern italy and one in southern italy, and the different prevalence has been compared to the general population. methods: we conducted a prospective cross-sectional observational study in patients undergoing dialytic therapy in two hemodialysis centers, one located in palermo and one in lecco. male sexual dysfunction was investigated by the international index of erectile function-15 (iief15) questionnaire and the premature ejaculation diagnotic tool (pedt) questionnaire, and the female dysfunction by female sexual function index (fsfi) questionnaire. criteria for inclusion in our study were: age < 75 years and dialytic age > 3 months; exclusion criteria were: advanced cancer diseases, life expectancy < 6 months, previous urological manipulation, anti-androgenic therapy, sexual dysfunction unrelated to kidney disease, psychiatric disorders. data were compared with mean-standard deviation (sd) and with the variance analysis (anova). a value of p < 0.05 is considered significant. discrete data were analyzed with contingency analysis. a chi2 < 0.05 was considered significant. results: data of 78 patients have been collected. mean age and dialytic time were 54 ± 12 years and 42 ± 35 month; 33 patients were from palermo and 24 from lecco; 21 patients were excluded. age and dialytic age of the two subgroups did not demonstrate statistically significant differences. between the two centers there was a statistically significant difference (p < 0.005) in the distribution of basic nephropathy: an higher incidence of diabetic and obstructive nephropathy has been observed in the southern center compared to northern center, while glomerulonephritis and polycystic kidney disease had an higher incidence in the northern center compared to southern one. the main sexual dysfunctions in both sexes, erectile dysfunction (ed) and premature ejaculation (pe) in men and orgasm disorder and pelvic pain in women, have been investigated. ed was present in 70% sexual dysfunction in dialytic patients. a prospective cross-sectional observational study in two hemodialysis centers carlo pavone 1, antonio simone di fede 1, piero mannone 1, gabriele tulone 1, arjan bishqemi 1, alberto abrate 2, vincenzo la milia 3, vincenzo serretta 1, alchiede simonato 1 1 department of surgical, oncological and oral sciences, section of urology, university of palermo, palermo, italy; 2 department of surgery, urology unit, asst valtellina e alto lario, sondrio, italy; 3 nephrology and dialysis department, lecco, italy. doi: 10.4081/aiua.2021.2.215 summary of hemodialyzed patients, which is an higher incidence compared to the general population. the severity of ed between patients of the two groups was significantly different (chi2 < 0.001) with higher incidence of moderate/severe forms in northern italy. the score, in addition to discrete data (severe, moderate, mild, absence), of ed was significantly different (p < 0.001) between patients of the two centers (22 ± 7 palermo vs. 9 ± 8, lecco). the pe was absent in 20 patients (54%), present in 12 patients (32%) and probable in 5 patients (14%) (scores of 7.6 ± 4.0 and 8.9 ± 6.8, respectively in palermo and lecco patients). for women, orgasmic dysfunction was severe in 10 patients (50%), mild in 4 patients (20%), very mild in 5 patients (25%), while it was normal in 1 patient (5%), with a statistically significant difference (p< 0.05) between palermo and lecco patients (3.0 ± 1.4 vs 1.2 ± 2.0). sexual pain in women was severe in 11 patients (55%), moderate in 4 patients (20%) and mild in 5 patients (25%). sexual pain was present in all patients (p < 0.05). conclusions: regardless of sex, sexual dysfunction is one of the most common side effect in patients with end stage renal disease in dialytic therapy. our study confirms literature data. the growing number of the dialytic population with sexual disorders needs specialist support to improve quality of life of these patients. key words: dialysis; end-stage renal disease; sexual male dysfunction; erectile disorder; premature ejaculation; female sexual dysfunctions; international index of erectile function; premature ejaculation diagnostic tool. submitted 4 november 2020; accepted 28 december 2020 archivio italiano di urologia e andrologia 2021; 93, 2 c. pavone, a.s. di fede, p. mannone, g. tulone, a. bishqemi, a. abrate, v. la milia, v. serretta, a. simonato 216 are understudied, despite the incidence being alarmingly high: in a 30 years ago study, 76% of women were living with some symptoms of sexual dysfunction (4), while more recent literature suggest that prevalence is around 43% (5). most common symptoms in women are dyspareunia, vaginismus, and noncoital sexual pain disorder (6). since population undergoing hemodialysis (hd) treatment for esrd significantly increased in the last few years, attention is focused on its sexual disease (7). the greater longevity of these patients and the association with dialytic therapy has led to new problems that in the past were not highlighted in an incisive way and that today have been noticed to have a significant influence on the quality of life among esrd patients. first studies on sexual dysfunction in dialysis patients, date back to the 1970s, highlighted the high prevalence of sexual dysfunction among patients of both sexes (8). following studies confirmed that sexual dysfunction is very common in men and women with esrd, associated with anxiety and depression, affecting the quality of life with impact on self-confidence, self-esteem and selfimage (9, 10). the aim of this study is to describe the incidence of male and female main sexual dysfunctions, in patients undergoing hemodialytic therapy, considering modern dialytic techniques. two dialytic centers have been compared, one in northern italy and another one in southern italy. different prevalence has been compared to the general population. methods a prospective cross-sectional observational study amongst two hemodialysis centers has been conducted. the presence of sexual dysfunctions has been assessed by questionnaires administered to patients on chronic haemodialysis treatment in both examined haemodialysis centers, one in southern italy (palermo) and one in northern italy (lecco). questionnaires were administered and returned anonymously. andrological or gynecological evaluation was offered when requested by patients. inclusion criteria are age < 75 years and dialytic age > 3 months. exclusion criteria are advanced neoplastic diseases, life expectancy < 6 months, radical prostatectomy, anti-androgenic therapy, sexual dysfunctions unrelated to kidney disease, any previous surgical manipulation of the urogenital system, use of drugs to improve sexual performance, psychiatric disorders, and people who refused to participate to the study. dialytic patients were recruited for the study regardless of the cause that led to end-stage renal failure. data were collected from january 2018 to december 2018. questionnaires administered to male patients are international index of erectile function 15 (iief) 15 (11) and premature ejaculation diagnostic tool (pedt) (12). the female sexual function index test (fsfi) (13) was administered to female patients. data are compared with mean standard deviation (sd) and with the variance analysis (anova). a value of p < 0.05 is considered significant. discrete data are analysed with contingency analysis. a chi2 < 0.05 value is considered significant. in our study, the sample size was not calculated and this represents a limitation for results. results 78 patients were recruited into the study: 5 of them were excluded for psychiatric issues, 6 refused to answer and 10 did not complete the questionnaire. therefore, our study was carried out on 57 patients. patients underwent chronic hemodialysis treatment, aged 54 ± 12 years, 37 males and 20 females, with dialysis age 42 ± 35 months, of which 33 patients were hemodialyzed in a dialysis center in southern italy (palermo) and 24 patients in a dialysis center in northern italy (lecco). in the dialysis center of palermo, 23 male patients were recruited. patient ages range from a minimum of 25 to a maximum of 72 years, with an average of 54 ± 14 years. we also analyzed the dyalisis ages of patients from a minimum of 4 to a maximum of 84 months, with an average of 37 ± 24 months. in the dialysis center of lecco, 14 male patients were recruited. patient ages range from a minimum of 36 to a maximum of 70 years, with an average of 55 ± 10 years. we also collected informations about the dyalisis ages of patients ranging from a minimum of 5 to a maximum of 106 months, with an average of 45 ± 33 months. furthermore, we paid attention to the anamnesis and chronic pathologies that led patients to need dialysis treatment in the respective center (table 1). the average age of male patients on hemodialysis treatment in palermo is not significant different from those in lecco (54 ± 14 years vs 55 ± 10 years, respectively) and there is not significant difference in dialysis age, either (37 ± 24 months vs 45 ± 33 months, respectively). on the other hand, there is a difference in the most common underlying disease between the two centers: diabetic nephropathy (39%) in palermo and polycystic kidney (29%) in lecco. in the dialysis center of palermo, 10 female patients were recruited. the ages of the patients range from a minimum of 39 to a maximum of 71 years, with an average of 54 ± 11 years. 60% (n. 6) of these patients were in menopause. we also collected informations about the dyalisis ages of the patients ranging from a minimum of 10 to a maximum of 72 months, with an average of 35 ± 20 months. in the center of lecco, 10 female patients were recruited. the ages of the patients range from a minimum of 34 to a maximum of 63 years, with an average of 53 ± 10 years. 80% (n. 8) of these patients were in menopause. we also collected the dyalisis ages of the patients ranging from a minimum of 9 to a maximum of 209 months, with an average of 57 ± 62 months. table 1. cause of esrd. cause of esrd male male female female palermo lecco palermo lecco hypertensive nephropathy 3 (13%) 0 1 (10%) 0 diabetic nephropathy 9 (39%) 3 (21%) 4 (40%) 2 (20%) obstructive nephropathy 3 (13%) 1 (7%) 1 (10%) 0 glomerulonephritis 4 (17%) 2 (14%) 1 (10%) 3 (30%) polycystic kidney 1 (4%) 4 (29%) 1 (10%) 4 (40%) recurrent urinary tract infections 3 (13%) 1 (7%) 2 (20%) 0 nephroangiosclerosis 0 3 (21%) 0 1 (10%) tot 23 14 10 10 we also paid attention to the anamnesis and chronic pathologies that led patients to need dialysis treatment in the respective center (table 1). the average age of female patients on hemodialysis treatment in palermo is not significant different from those in lecco (54 ± 11 years vs 53 ± 10 years, respectively) while there is a significant difference in dialysis age, either (35 ± 20 months vs 57 ± 62 months, respectively). as in the case of male patients, there is a difference in the most common underlying disease between the two centers: diabetic nephropathy (40%) in palermo and polycystic kidney (40%) in lecco. esrd influence on sexual function is analyzed using questionnaires. for male patients following parameters are taken into account: erectile dysfunction, orgasmic dysfunction, libido reduction, dissatisfaction of sexual relations and premature ejaculation (table 2). erectile dysfunction is present in 70% of patients with different severity level distributed with a significant difference (chi2 < 0.001). data show prevalence of severe dysfunction among patients on hemodialysis treatment at the center of lecco, while at the hemodialysis center of palermo this dysfunction is absent in most patients. we documented a different score (p < 0.001) among patients of the center of palermo compared to those of the center of lecco (9 ± 2 vs 3 ± 4, respectively). the reduction in sexual desire is absent in 2 patients (5%), very slight in 5 patients (14%), mild in 19 patients (51%), moderate in 8 patients (22%) and severe in 3 patients (8%). libido reduction is statistically different (chi2 < 0.05) between the male patients of the two hemodialysis centers, with a clear prevalence of severe and moderate dysfunction among the patients on hemodialysis treatment at the center of lecco, whereas it is mild in most patients in treatment at the hemodialysis center in palermo. we documented a significantly different score (p < 0.05). the general sexual well-being is also statistically different (chi2 < 0.05) with a clear prevalence of severe and moderate impairment among the patients on hemodialysis treatment at the center of lecco, while this impairment is mild or very mild in most patients in treatment at the hemodialysis center in palermo. we documented significantly different score (p < 0.05) among patients of the center of palermo, compared to those of the center of lecco (7 ± 0 vs 5 ± 1, respectively). there is a statistically significant difference (chi2 = 0.03) regarding premature ejaculation: this alteration of sexuality is more frequent in male patients on dialysis at the center of lecco, compared to male patients of the hemodialysis center in palermo. however, when considering the total score of responses on premature ejaculation, instead of considering the discrete variables (present, absent and probable), this difference is no longer significant; in particular, the total score is 7.6 ± 4.0 and 8.9 ± 6.8 in patients being treated at the hemodialysis center in palermo and lecco, respectively (figu re 1) (table 2). 217archivio italiano di urologia e andrologia 2021; 93, 2 sexual dysfunction in dialytic patients table 2. males’ sexual dysfunctions. figure 1. male's main sexual dysfunctions. patients features patients (n.) 57 males: 37 females: 20 age (years) 54 ± 12 (palermo 54 ± 14; lecco 55 ± 10) dialysis age (month) 42 ± 35 (palermo 37 ± 24; lecco 45 ± 33 males sexual disfunctions palermo lecco severe moderate mild light very light absent severe moderate mild light very light absent p value erectile dysfunction (%) 2 (8.7%) 2 (8.7%) 10 (43.5%) 9 (39.1%) 9 (64.3%) 3 (21.5%) 0 2 (14.2%) < 0.001 orgasmic dysfunction (%) 1 (4.3%) 1 (4.3%) 2 (8.7%) 19 (82.7%) 9 (64.3%) 0 3 (21.5%) 2 (14.2%) < 0.001 libido reduction (%) 0 3 (13%) 15 (65.3%) 3 (13%) 2 (8.7%) 3 (21.5%) 5 (35.8%) 4 (28.5%) 2 (14.2%) 0 < 0.05 dissatisfaction of sexual relations (%) 2 (8.7%) 0 12 (52.1%) 9 (39.2%) 10 (71.4%) 2 (14.2%) 1 (7.1%) 1 (7.1%) < 0.001 present probable absent present probable absent premature ejaculation (%) 5 (21.7%) 5 (21.7%) 13 (56.6%) 7 (50%) 0 7 (50%) archivio italiano di urologia e andrologia 2021; 93, 2 c. pavone, a.s. di fede, p. mannone, g. tulone, a. bishqemi, a. abrate, v. la milia, v. serretta, a. simonato 218 here below female patients’ data were then analyzed. through the scores we investigated parameters such as reduction of sexual desire, reduction of sexual arousal, lubrication, orgasmic dysfunction, sexual disatisfaction and sexual pain (table 3). the reduction in sexual desire is statistically significant (chi2 < 0.05) in female patients in hemodialysis treatment in the two hemodialysis centers, with it being severe or moderate in patients in hemodialysis treatment in lecco, while in patients in hemodialysis treatment in palermo it presented in a milder form. however, the analysis of the score, i.e. the continuous variable, do not show a statistically significant difference between patients of palermo and those of lecco (2.2 ± 0.9 vs 2.8 ± 0.9). the reduction in sexual arousal is not statistically significant in female patients in hemodialysis treatment at the two hemodialysis centers, although the reduction in sexual arousal is more severe in hemodialysis patients in lecco than in hemodialysis patients in palermo. the score shows a statistically significant difference (p < 0.005) between patients of palermo and those of lecco (3.2 ± 1.1 vs 1.3 ± 1.7) with a greater dysfunction of sexual arousal in the latter. the reduction in lubrication is statistically significant (chi2 < 0.01) in female patients in hemodialysis treatment at the two hemodialysis centers, being severe or moderately severe among patients in hemodialysis treatment in lecco, while in patients in hemodialysis treatment in palermo it manifested itself in a milder form. the analysis of the score, i.e. the continuous variable, do not show a statistically significant difference between the patients of palermo and those of lecco (3.2 ± 1.2 vs 1.5 ± 2.5, respectively). orgasmic dysfunction is not statistically significant in female patients in hemodialysis treatment at the two hemodialysis centers, although there is a greater tendency for severe dysfunction in patients in hemodialysis treatment at the center of lecco than in patients in hemodialysis treatment in palermo. the score shows a statistically significant difference (p < 0.05) between the patients of palermo and those of lecco (3.0 ± 1.4 vs 1.2 ± 2.0, respectively). sexual dissatisfaction is statistically significant (chi2 < 0.001) in female patients in hemodialysis treatment at the two hemodialysis centers, with a greater tendency for severe sexual dissatisfaction in patients in hemodialysis treatment at the center of lecco, compared to patients in treatment hemodialysis in palermo. the analysis of the score, i.e. of the continuous variable, also shows a statistically significant difference (p < 0.001) between the patients of palermo and those of lecco (3.8 ± 0.4 vs 0.7 ± 0.4, respectively). finally, sexual pain presents a statistically significant difference (chi2 < 0.05) in female patients in hemodialysis treatment at the two hemodialysis centers, with a greater tendency to severe sexual pain in patients in hemodialysis treatment at the center of lecco, compared to patients in hemodialysis treatment in palermo. the analysis of the score, i.e. the continuous variable, also shows a statistically significant difference (p < 0.05) between the patients of palermo and those of lecco (2.2 ± 0.7 vs 0.8 ± 1.8, respectively) (figure 2, table 3). discussion analyzing available data, the two main male and female typical sexual dysfunctions of the chronic hemodialytic patient were compared with those present in the general population, also making a comparison with data obtained throughout this study. table 3. females’ sexual dysfunctions. females sexual disfunctions palermo lecco p value severe moderate mild very mild absent severe moderate mild very mild absent reduction of sexual desire (%) 2 (20%) 1 (10%) 7 (70%) 3 (30%) 5 (50%) 2 (20%) reduction in sexual arousal (%) 1 (10%) 2 (20%) 5 (50%) 2 (20%) 0 6 (60%) 1 (10%) 2 (20%) 1 (10%) 0 < 0.005 female lubrication reduction (%) 1 (10%) 2 (20%) 2 (20%) 5 (50%) 0 7 (70%) 0 0 1 (10%) 2 (20%) orgasmic dysfunction (%) 3 (30%) 3 (30%) 4 (40%) 0 7 (70%) 1 (10%) 1 (10%) 1 (10%) < 0.05 sexual dissatisfaction (%) 1 (10%) 0 3 (30%) 6 (60%) 7 (70%) 2 (20%) 1 (10%) 0 < 0.001 sexual pain (%) 3 (30%) 4 (40%) 3 (30%) 0 8 (80%) 0 2 (20%) 0 < 0.05 figure 2. female's main sexual dysfunctions. 219archivio italiano di urologia e andrologia 2021; 93, 2 sexual dysfunction in dialytic patients by evaluating erectile dysfunction (ed) we can show how this dysfunction has increased in the chronic hemodialytic population, compared to the general one, as we expected. according to general data, erectile dysfunction in italy is present in about 3-5 million men, with a prevalence percentage ranging from 10% to 17%. according to an italian study by parazzini et al. (14), the prevalence of ed assessed by questionnaire in the general population was 12.8%, with 70% partial ed, while 30% is complete. these epidemiological data increase in the chronic hemodialytic population, as reported in the literature. in fact, according to a study by savadi et al. (15), the prevalence of ed in patients with chronic renal failure was reported in the range of 22-88% and more specifically it is 87.5% in patients on hemodialysis. analyzing our data, ed prevalence of 70% is observed, considering also the mild form, and it is more frequent in the population of northern italy than in that of southern italy. evaluating premature ejaculation, it has been observed that in the italian general population it is present in about 4-5 million men with a prevalence ranging from about 15 to 20%; while according to the literature, and more precisely according to aslan, the prevalence of premature ejaculation is determined in 31.6% of patients (16). analyzing our data, it was observed that the prevalence of premature ejaculation in our population is 46%. assessing the alterations of the female sexual sphere, although data from female hemodialytic patients are very limited, it has been observed that according to one of the largest study carried out worldwide, the prevalence of these disorders is around 84%, confronted with a general population prevalence of about 45% (more precisely, in the general population there is, for example, a dyspareunia ranging from 12% in women of childbearing age up to 31% in those in menopause; or vaginismus that is about 0.5-15%) (9). data reported by our study, however, show that sexual dysfunctions in women receiving hemodialysis are around in 100% of patients, in almost all assessed items. furthermore, comparing data of these sexual dysfunctions between the population of northern italy and that of southern italy, in the two hemodialysis centers, it is evident that they are different, with a greater prevalence in the northern population compared to the southern one. this could be due to different reasons. these differences allow us only to be able to formulate diagnostic hypotheses underlying the different results obtained by our study. a definitely important aspect to explain these differences is basic nephropathy: our data show a significant difference between basic nephropathy in the population assessed in the north and in the south; it cannot be excluded that the underlying pathology may contribute to these differences in sexual dysfunction between the two italian populations. even the dialysis age, slightly higher in lecco patients than in palermo patients, could explain this difference between the two populations. the cultural differences between the two regions of the country could also have influenced the test results by changing the approach to the questions and altering the answers. in addition, by assessing the prevalence of male and female sexual dysfunctions, it is evident that these are more frequent in the male than in the female sex. this difference could be due to different pathogenetic factors in the male sex compared to the female one. finally, psychological factors in these differences cannot be excluded. conclusions our study confirms literature data, according to which chronic renal failure is a disabling disease, also from a sexual functionality point of view, of both male and female patients, and confirms the need for specialist andrological or gynecological advice, in addition to dialysis. the growing number of dialytic populations with sexual disorders needs specialist support to improve their quality of life. conflict of interest statement authors declare that they have no competing interests. the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the helsinki declaration of 1975, as revised in 2000. informed consent was obtained from all patients for being included in the study. references 1. verze p, arcaniolo d, palmieri a, et al. premature ejaculation among italian men: prevalence and clinical correlates from an observational, non-interventional, cross-sectional, epidemiological study (iper). sex med. 2018; 6:193-202. 2. iacona r, bonomo v, di piazza m, et al. five-year prospective study on cardiovascular events, in patients with erectile dysfunction and hypotestosterone. arch ital urol androl. 2017; 89:313-315. 3. pavone c, abbadessa d, gambino g, et al. premature ejaculation: pharmacotherapy vs group psychotherapy alone or in combination. arch ital urol androl. 2017; 89:114-119. 4. frank e, anderson c, rubinstein d. frequency of sexual dysfunction in “normal” couples. n engl j med. 1978; 299:111. 5. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama 1999; 281:537. 6. allahdadi kj, tostes rc, webb rc. female sexual dysfunction: therapeutic options and experimental challenges. cardiovasc hematol agents med chem. 2009; 7:260-269. 7. mccullough kp, morgenstern h, saran r, et al. projecting esrd incidence and prevalence in the united states through 2030. jasn. 2019; 30:127-135. 8. milne jf, golden js, fibus l. sexual dysfunction in renal failure: a survey of chronic hemodialysis patients. int j psychiatry med. 1977; 8:335-345. 9. strippoli gf. collaborative depression and sexual dysfunction (cds) in hemodialysis working group, vecchio m, et al. sexual dysfunction in women with esrd requiring hemodialysis. clin j am soc nephrol. 2012; 7:974-981. 10. edey mm. male sexual dysfunction and chronic kidney disease. front med (lausanne). 2017; 4:32. 11. rosen rc, riley a, wagner g, et al. the international index of archivio italiano di urologia e andrologia 2021; 93, 2 c. pavone, a.s. di fede, p. mannone, g. tulone, a. bishqemi, a. abrate, v. la milia, v. serretta, a. simonato 220 erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-830. 12. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 13. meston cm. validation of the female sexual function index (fsfi) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder. j sex marital ther. 2003; 29:39-46. 14. parazzini f, menchini fabris f, bortolotti a, et al. frequency and determinants of erectile dysfunction in italy. eur urol. 2000; 37:43-9. 15. savadi h, khaki m, javnbakht m, pourrafiee h. the impact of hemodialysis on sexual function in male patients using the international index of erectile function questionnaire (iief). electron physician. 2016; 8:2371-2377. 16. aslan g, arslan d, cavdar c, et al. analysis of premature ejaculation in hemodialysis patients using the international index of erectile function. urol int. 2003; 70:59-61. correspondence carlo pavone, md, professor (corresponding author) carlo.pavone@unipa.it antonio simone di fede, md piero mannone, md gabriele tulone, md arjan bishqemi, md vincenzo serretta, md alchiede simonato, md department of surgical, oncological and oral sciences, section of urology, university of palermo, palermo (italy) alberto abrate, md department of surgery, urology unit, asst valtellina e alto lario, sondrio, (italy) vincenzo la milia, md nephrology and dialysis department, lecco (italy) archivio italiano di urologia e andrologia 2017; 89, 4266 original paper evaluation of the complications in laparoscopic retroperitoneal radical nephrectomy; an experience of high volume centre ali serdar gozen 1, vitalie gherman 1, 3, yigit akin 1, mustafa suat bolat 1, muhammad elmussareh 2, jens rassweiler 1 1 department of urology, slk-kliniken, university of heidelberg, heilbronn, germany; 2 department of urology, mid yorkshire hospitals nhs trust, wakefield, uk; 3 department of urology, “iuliu hatieganu” university of medicine and pharmacy, cluj-napoca, romania. objectives: to provide a standardised report of complications after retroperitoneal laparoscopic radical nephrectomy (rlrn) in a high-volume centre using clavien-dindo classification. materials and methods: we analysed records maintained in a prospective database of 330 consecutive patients that underwent rlrn between march 1995 and september 2016. all complications were graded according to the modified clavien-dindo classification. three generations of surgeons were defined and the learning curve in rlrn was evaluated by comparing the first 100 cases (group a) performed by firstgeneration surgeons with the last 100 cases (group b) by thirdgeneration surgeons. results: the mean age of our cohort was 66 ± 11.9 years. the overall complication rate was 19.7%. the majority of complications (12.7%) were clavien 1 (5.1%) and clavien 2 (7.6%) and did not require any interventions; blood transfusion was the most frequently encountered intervention (4.8%). half of which were because of major intraoperative bleeding. mortality rate was 0.9%. we found a trend towards lower complication rate in group b (19%) compared to group a (23%); this was mainly because of the reduction in the incidence of clavien 1 and 2 complications. the pathological stage varied significantly in the two groups while the rate of negative surgical margins was comparable. conclusions: rlrn is a safe procedure with an acceptable rate of complications. the learning curve was shorter for the thirdgeneration surgeons (group b); although these surgeons operated on a significantly higher number of patients with more advanced diseases. the clavien-dindo classification is suitable for assessing rlrn complications. adopting this standardised system can help in the evaluation and comparison of surgical quality of lrn series. key words: laparoscopy; kidney cancer; complications; clavien-dindo classification. submitted 19 july 2017; accepted 3 august 2017 summary no conflict of interest declared. kidney (1). radical nephrectomy (rn) remains the gold standard surgical treatment for patients with rcc when nephron-sparing procedures are not feasible (2). over the past two decades, with advancements in laparoscopic surgery, laparoscopic rn (lrn) has become a widely available surgical option that has been shown to provide similar oncological outcomes to open surgical techniques with the well-known benefits of laparoscopic approach (3-5). at present, it is regarded as a standard treatment worldwide with up to 80% of urologists offering lrn to patients with localised rc (6). lrn can be performed by two different approaches, namely the retroperitoneal route or the transperitoneal route. the retroperitoneal approach, which was developed to mimic open-flank nephrectomy, allows rapid and direct access to the renal pedicle without violating the peritoneal cavity. thus, retroperitoneal lrn (rlrn) can minimise the risk of some complications, such as visceral organ injuries. the european guidelines on reporting and grading of complications after urologic surgical procedures were recently published (7). the key recommendations of these guidelines include the use of a standardised system, such as the clavien-dindo grading system (8), and the provision of a table of all complications and corresponding scores or a list of the complications by scores. complication rates are still one of the most frequently used surrogate indicators for the quality of surgery. however, to the best of our knowledge, no data have been published on rlrn complications using standardised classifications. in this study, we report on our large, single-institution rlrn series, representing over 15 years of experience. the purpose of the study is to determine the complication rates after rlrn using a standardised method, namely the clavien-dindo classification, in a large cohort at a pioneering institution. materials and methods between march 1995 and september 2016, 380 consecutive lrn surgeries were performed for patients with renal tumours (stage t1-t4) at our institution. all patients were counselled appropriately about the treatdoi: 10.4081/aiua.2017.4.266 introduction renal cell carcinoma (rcc) is the most common malignant tumour of the kidney parenchyma, representing approximately 2% of all new cases of cancer and accounting for over 80% of all neoplasms that affect the gozen_stesura seveso 03/01/18 11:01 pagina 266 267archivio italiano di urologia e andrologia 2017; 89, 4 complications in laparoscopic nephrectomy ment and the aim of this study with written informed consent obtained prior to the surgery. in our centre, the preferred laparoscopic approach is the retroperitoneal route which was first described by gaur (9) and later modified and developed by rassweiler et al. (10, 11). all data were recorded prospectively using a microsoft office excel spreadsheet. we excluded cases that were performed via transperitoneal laparoscopic approach or open surgery, those with less than 12 months of followup or missing follow-up data and patients with additional cancer or bilateral renal tumours. thus, 330 patients with complete follow up were enrolled in the study. the review board of our certified cancer centre approved our prospective collection of patients’ data. in the first 50 cases, the specimen was entrapped in an organ retrieval bag and extracted via a flank incision without prior morcellation. afterwards, we preferred to extract the specimen through a gibson incision. all patients stayed in the intensive care unit (icu) for the first 24 hours after the operation and received antibiotics for a minimum of 3 days in the postoperative period. three generations of surgeons were defined as follows: first-generation surgeons had previous experience in open surgery but no laparoscopic training; second-generation surgeons had experience in open surgery, and they were trained by first-generation surgeons; and third-generation surgeons had no or limited experience in open surgery, and they were trained by first-or second-generation surgeons (12). the learning curves of the firstand third-generation surgeons were compared and analysed based on the results of the first 100 and last 100 cases. data collection demographic data, including age (years), gender, comorbidities, body mass index (bmi; kg/m2), operation history, tumour size (mm), tumour side and preoperative clinical stage, were recorded. operative and postoperative data, including operation time; estimated blood loss; conversion to open surgery; length of hospital stay and duration of surgical drains; were also noted. all pathological specimens were reviewed by a single, experienced pathologist; the pathology results, including tumour staging, were evaluated according to the revised 2009 tnm classification (13). complications were noted in detail, including treatment and outcomes, as part of our internal quality management system. complication assessments and follow-up schedule all the charts, including the medical records, of patients with identified postoperative complications were reviewed and grouped according to the modified clavien-dindo classification (table 1). medical and surgical complications during the first 6 weeks were evaluated at the end of this period using our institution’s medical records and reports from the rehabilitation centre and other physicians. patients were followed up every 3 months for the first 2 years after surgery then 6 monthly thereafter. statistical analyses all data were recorded in microsoft excel files. for statistical analysis, we used a commercially available software package (spss v16.0; spss, chicago, il, usa) table 1. complication assessment according to modified clavien-dindo classifications. grade definition clavien 1 any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions. acceptable therapeutic regimens are: drugs as anti-emetics, antipyretics, analgesics, diuretics and electrolytes and physiotherapy. this grade also includes wound infections opened at the bedside. clavien 2 complications requiring pharmacological treatment with drugs other than such allowed for grade i complications. blood transfusions and total parenteral nutrition are also included. clavien 3a complications needing surgical, endoscopic, or radiologic intervention under local anaesthesia. clavien 3b complications needing surgical, endoscopic, or radiologic intervention under general anaesthesia (including dialysis). clavien 4a life-threatening complications requiring icu management: single organ dysfunction. clavien 4b life-threatening complications requiring icu1 management: multiorgan dysfunction. clavien 5 death of the patient. suffix ’d’ if the patient suffers from a complication at the time of discharge, the suffix “d” (for ‘disability’) is added to the respective grade of complication. this label indicates the need for a follow-up to fully evaluate the complication. icu1 = intensive care unit. including the pearson x2 test. a p-value < 0.05 was considered statistically significant. results patient clinico-pathological characteristics and distribution of complications this study included 330 patients who underwent rlrn performed by one of six surgeons at a single centre. the median follow-up time was 33 ± 9.8 months. demographic, intraoperative and pathological data are presented in table 2. seventy-three postoperative complications were identified in 63 patients (19.1%). in 52 patients (82.5%), only one complication was recorded, while 11 patients (17.5 %) had two or more complications. as recommended by dindo et al. (8), when one complication was clearly related to another, only the more severe one was labelled and reported. hence, we reported a complication rate of 19.7% (65 complications), as eight patients had received concomitant blood transfusion with more severe complications (four conversions and four open revisions). minor complications that needed no or non-interventional treatments represented 12.7% of all those reported (clavien 1: 5.1%; clavien 2: 7.6%; table 1). complications requiring reintervention with or without anaesthesia occurred in 6% of cases (clavien 3a: 1.5%; clavien 3b: 2.1%; clavien 4a: 2.1%; clavien 4b: 0.3%). the mortality rate was 0.9% (clavien 5). the conversion rate was 2.1%, with half the cases requirgozen_stesura seveso 03/01/18 11:01 pagina 267 archivio italiano di urologia e andrologia 2017; 89, 4 a. serdar gozen, v. gherman, y. akin, m. suat bolat, m. elmussareh, j. rassweiler 268 ing open conversion because of uncontrollable intraoperative bleeding. the most frequent complication was anaemia requiring transfusions, which occurred in 4.8% of cases. detailed information on each category of complications and their management is presented in table 3. analysis of the learning curve to analyse the learning curves of the firstand third-generation surgeons, we compared the first 100 cases (group a) with the last 100 cases (group b). there was no significant difference in demographic data in these groups (table 4); the intraoperative records were also similar. the operative time was comparable between the two groups (135 min vs. 128 min in group a and group b, respectively), with no significant difference in average tumour size (46 mm vs. 62 mm) or estimated blood loss (140 ml vs. 100 ml). there was, however, a significant difference in pathological tumour stage between the two groups. in group a, 73% (68 patients) of patients that had malignant pathology were found to have pt1-tumours compared to only 30% of cases in group b. whereas, third-generation surgeons treated significantly more patients with pt3 disease (45.6% vs. 12.9%; p < 0.001). despite the increased complexity of cases performed by the last generation of surgeons, the rates of negative surgical margins were similar in both groups (98.9% vs. 94.6%), and the total complication rates were comparable (23% vs. 19%), (p = 0.04%). the conversion rates were similar in both groups, while blood transfusion rates were higher in the first 100 cases. this trend in reduction of overall complication rates was mainly because of the lower incidence of clavien 1 and clavien 2 complications (blood transfusions, infections, etc.) (figure 1). the complication rates were higher for the first 40 cases in the first group and the first 25 cases in the second group. complication rates and institutional learning curves are also influenced by technical and technological developments over time. discussion in the present study, we summarised rlrn complications according to the clavien-dindo classification. to the best of our knowledge, this is the first detailed report on this issue. it is well-accepted that successful operative and patients’outcomes can be supported through standardised postoperative complication classifications. comparison with other series in 2004, the clavien-dindo classification system for reporting postoperative complications was introduced and successfully validated in general surgery (8). it has been successfully employed in case series for reporting complications in urological procedures such as transurethral prostate resection; percutaneous nephrolithotomy; laparoscopic live-donor nephrectomy; and laparoscopic, robotic-assisted and retropubic radical prostatectomy (12, 14-20). however, after more than a decade, it is still not frequently used in all fields of minimally invasive urological surgeries. using the modified claviendindo classification, we observed a complication rate of 19.7% in a prospective series of 330 consecutive rlrn. abbou et al. (5) reported similar findings: their rlrn overall complication rate was 8%. however, they may have observed lower complication rates because they used the old version of the clavien classification system. similarly, gill et al. (21) observed a complication rate of 13% in a series of 34 rlrn surgeries for suspected kidney cancer. the complications in this study were only table 2. demographic, operative and postoperative data of patients. age (year) mean (± sd): 66 ± 11.9 gender male: 207 (62.7%), female: 123 (37.2%) bmi1, kg/m² (%) ≤ 25 (normal weight): 141 (42.7%) 26-30 (obesity i°): 133 (40.3%) 31-40 (obesity ii°): 47 (14.2%) > 41 (obesity iii°): 9 (2.7%) mean bmi (± sd): 27.1 ± 5.1 tumour side: left: 177 (53.6%), right: 153 (46.3%) tumour size (mm): mean (± sd): 58 ± 15.3 range: 30-120 operation time (min): mean (± sd): 143 ± 46.3 mean estimated blood loss (ml): 155 blood transfusion rate: 32 (9.6%) concomitant adrenalectomy 154 (46.6%) tumour histology clear cell rcc2 254 (76.9%) papillary 26 (7.9%) chromophobe 12 (3.6%) tcc3 5 (1.5%) other malignancies 8 (2.4%) benign 25 (7.5%; oncocytoma 14 [4.2%]) pathological t stage (pt), no. (%) pt1 147 (48.2%) pt2 62 (20.3%) pt3 89 (29.2%) pt4 7 (2.3%) fuhrman grade, no. (%) fuhrman i 54 (18.5%) fuhrman ii 155 (53.1%) fuhrman iii 73 (25%) fuhrman iv 10 (3.4%) surgical margins, no. (%) nsm4 (r0) 298 (97.7%) psm5 (r1) 7 (2.3%) bmi1: body mass index; rcc2: renal cell carcinoma; tcc3: transitional cell carcinoma; nsm4: negative surgical margin; psm5: positive surgical margin. figure 1. complication rates by grade in first and last 100 cases. gozen_stesura seveso 03/01/18 11:01 pagina 268 269archivio italiano di urologia e andrologia 2017; 89, 4 complications in laparoscopic nephrectomy summarised as minor and major complications, without using a standardised classification system to define the complications; nevertheless, the study underlines rlrn’s feasibility, reproducibility and relatively low complication rate compared to open retroperitoneal approach. finally, clavien and dindo (8) revised and externally validated the pre-existing classification system for postoperative complications in 2004. the new system was considered to be simple, logical, reproducible, useful and comprehensive. permpongkosolet al. (22) used claviendindo classification to assess the complications associated with urological laparoscopic surgery. in this study, the authors observed a total complication rate of 22.1% after more than 2700 laparoscopic procedures. in the lrn group, complications occurred in 20% of the patients. conversion to open surgery occurred in 2.9% (16 patients) of cases, while the mortality rate was 0.2%. we reported seven open conversions (2.1%) that we graded as clavien 3b. a collaborative review by breda et al. (23) concluded that although the retroperitoneal approach has the disadvantage of a smaller working space with no anatomical landmarks, it offers the clear advantage of rapid and direct access to the renal hilum. in addition, as in our experience, the incidence of adjacent organ injuries is extremely low. most major intra operative complications encountered in the retroperitoneal approach were related to vascular injuries. in previous studies, the complication rates ranged from 8 to 22% (5, 21-23). however, the common limitation of these studies is difficulty in comparing similar surgical techniques in terms of postoperative complications due to a lack of a consensus on reporting postoperative complications in the literature. because our study used a standardised system, it can address this limitation. another point to consider is that all these complication rates may show a learning curve (24). indeed, rlrn has a relatively steep learning curve; we found that a surgeon could reach a plateau after 40 cases in the first generation, where as a third-generation surgeon could reach a plateau after 25 cases. this shortening of the learning curve may have resulted from our standardized laparoscopic training table 3. detailed analysis of clavien-dindo complications. complication clavien grade 1 surgical site hematoma recurrent pain at surgical site ileus minor bladder tamponade allergic exanthema diarrhoea caused by antibiotics pneumopericardium urinary retention after catheter removal subcutaneous emphysema total n/n, (%) clavien grade 2 anaemia without additional complications urinary tract infection other site infection persistent postoperative fever total n/n, (%) clavien grade 3a infection of the surgical site/ delayed healing recurrent nausea and vomiting, reflux oesophagitis grade 1 acute gastritis, duodenal ulcer, due to an increased need for analgesics over time total n/n, (%) clavien grade 3b major intraoperative bleeding (vascular injury, vena cava rupture) intraoperative visceral injury lymph nodes; vena cava adhesion total n/n, (%) clavien grade 4a major postoperative bleeding (1 patient with intracerebral bleeding and left hemip hemiparesis) cardiac decompensation, potentially lethal arrhythmias allergic shock caused by changes in antihypertensive medication (enalapril) massive bleeding from oesophageal ulcers total n/n, (%) clavien grade 4b asystole, acute renal failure, thrombocytopenia respiratory insufficiency total n/n, (%) clavien grade 5 cardiogenic shock, perioperative nstemi3, acute renal failure acute-on-chronic renal failure, sirs4, left kidney infarct fulminant pulmonary embolism 2nd day after the procedure total n/n, (%) ppi1: proton pump inhibitors, icu2: intensive care unit, nstemi3: non-st segment elevation myocardial infarction, sirs4: systemic inflammatory response syndrome. management of complications no special therapy (topic ointment) oral analgesics laxatives, parenteral alimentation bladder irrigation through catheter antibiotic discontinuation antibiotic discontinuation, fluid replacement, imodium no special therapy re-catheterization without cystoscopy no special therapy transfusion parenteral antibiotics parenteral antibiotics parenteral antibiotics secondary suture gastroscopy and ppi1 therapy (esomeprazol 20 mg-7 days) gastroduodenoscopy. ppi therapy (pantoprazole 20 mg-5 days) conversion conversion conversion open revision, transfusions, treatment in icu2 implantation of a permanent cardiac pacemaker, treatment in the icu medical treatment in the icu endoscopic clipping of the bleeding sites, transfusion, treatment in icu successful cardio-pulmonary resuscitation, hemodyalisis, tracheostomy, artificial respiration, treatment in icu failed bradycardia resuscitation, circulatory insufficiency failed cardio respiratory resuscitation failed cardio respiratory resuscitation n, (%) 6 (1.8) 2 (0.6) 2 (0.6) 2 (0.6) 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 17/330 (5.1) 16 (4.8) 3 (0.9) 4 (1.2) 2 (0.6) 25/330 (7.5) 3 (0.9) 1 (0.3) 1 (0.3) 5/330 (1.5) 4 (1.2) 1 (0.3) 2 (0.6) 7/330 (2.1) 3 (0.9) 2 (0.6) 1 (0.3) 1 (0.3) 7/330 (2.1) 1 (0.3) 1/330 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) 3/330 (0.9) gozen_stesura seveso 03/01/18 11:01 pagina 269 archivio italiano di urologia e andrologia 2017; 89, 4 a. serdar gozen, v. gherman, y. akin, m. suat bolat, m. elmussareh, j. rassweiler 270 patient risk profile [comorbidities status, american society of anesthesiologists (asa) score, tumour characteristics] and postoperative complications. this may be the subject of a future study. a further limitation of this study is that we only reported the standardised complications of rlrn. the institutional learning curve may have a limited informative value because our data represent results from several surgeons working in a pioneering academic training centre with residents and fellows attending certain procedural steps. conclusions rlrn is a safe, reproducible technique associated with a relatively low incidence of complications. the learning curve was shorter for the third-generation surgeons; although these surgeons operated on significantly more patients with advanced diseases. the clavien-dindo classification is suitable for assessing rlrn complications and adopting this standardised system can help in the evaluation and comparison of surgical quality of lrn series. references 1. weikert s, ljungberg b. contemporary epidemiology of renal cell carcinoma: perspectives of primary prevention. world j urol. 2010; 28:247. 2. merseburger as, herrmann trw, shariat sf, et al. eau guidelines on robotic and single-site surgery in urology. eur urol. 2013; 64:277. 3. ljungberg b, cowan nc, hanbury dc, et al. eau guidelines on renal cell carcinoma: the 2010 update. eur urol. 2010; 58:398. 4. dunn md, portis aj, shalhav al, et al. laparoscopic versus open radical nephrectomy: a 9-year experience. j urol. 2000; 164:1153. 5. abbou cc, cicco a, gasman d, et al. retroperitoneal laparoscopic versus open radical nephrectomy. j urol. 1999; 161:1776. 6. gerber gs, stockton br. update on laparoscopic nephrectomy and nephroureterectomy. j endourol. 2005; 19:1151. 7. mitropoulos d, artibani w, graefen m, et al. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. eur urol. 2012; 61:341. 8. dindo d, demartines n, clavien p. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205. 9. gaur dd, agarwal dk, purohit kc. retroperitoneal laparoscopic nephrectomy: initial case report. j urol. 1993; 149:103. 10. rassweiler jj, henkel to, stock c, et al. retroperitoneoscopic surgery — technique, indications and first experience. minim invasive ther. 1994; 3:179. 11. rassweiler jj, seemann o, frede t, et al. retroperitoneoscopy: experience with 200 cases. j urol. 1998; 160:1265. 12. hruza m, weiss ho, pini g, et al. complications in 2200 consecutive laparoscopic radical prostatectomies: standardised evaluation and analysis of learning curves. eur urol. 2010; 58:733. table 4. demographic, operative and postoperative data of first 100 cases and last 100 cases. parameters group a group b p value (first 100) (last 100) age (years) 65 ± 12.6 67 ± 11.1 0.2 gender 0.4 male 59 66 female 41 34 bmi (kg/m2) 0.5 ≤ 25 (normal weight) 46 41 26-30 (obesity i°) 42 44 31-40 (obesity ii°) 9 10 > 41 (obesity iii°) 3 5 tumour size (mm) 46 ± 2.3 62 ± 3.2 0.3 tumour side 0.4 left 56 61 right 44 39 operation time (min) 135 ± 41.5 128 ± 43.4 0.2 ebl (ml) 140 ± 38.4 100 ± 43.7 0.5 blood transfusion rate (n) 9 6 0.2 tumour histology clear cell rcc 84 71 0.5 chromophobe 5 3 papillary 2 9 tcc 2 6 benign 7 7 liposarcoma 1 metastasis 2 nephroblastoma 1 pathological t stage no. (%) 0.001* pt1 68 (73.1%) 27 (30%) pt2 13 (14%) 16 (17.8) pt3 12 (12.9%) 41 (45.6%) pt4 0 6 (6.5%) fuhrman grade, no. (%) 0.07 grade i 32 (35.2%) 10 (12%) grade ii 49 (53.8%) 44 (53%) grade iii 8 (8.8%) 21 (25.3%) grade iv 2 (2.2%) 8 (9.6%) surgical margins, no. (%) 5 (5.4%) nsm (r0) 92 (98.9%) 88 (94.6%) psm (r1) 1 (1.1%) bmi: body mass index, ebl: estimated blood loss, rcc: renal cell carcinoma, tcc: transitional cell carcinoma, nsm: negative surgical margin, psm: positive surgical margin. *statistical significant p value. programme supported by continuous technological development and improvement (25). we believe that our study can help beginners in laparoscopy, and the most experienced hands should also know about the standardised complication rates. limitations of the study our prospective database was created over a long period of over 20 years. during this period, the clavien classification only changed twice. as such, the probability of bias in recording the complications is inherent. minor complications (clavien 1 and 2) could have been easily overlooked at the beginning of laparoscopic surgery when the method was emerging as a safe and viable alternative to open surgery. another limitation is that we did not evaluate the association between the gozen_stesura seveso 03/01/18 11:01 pagina 270 271archivio italiano di urologia e andrologia 2017; 89, 4 complications in laparoscopic nephrectomy 13. sobin lhgmk, wittekind c. tnm classification of malignant tumours. in: uicc international union against cancer. 7th ed. wiley-blackwell. 2009; 255-257. 14. gozen as, akin y. are structured curriculums for laparoscopic training useful? a review of current literature. curr opin urol. 2015; 25:163. 15. harper jd, breda a, leppert jt, et al. experience with 750 consecutive laparoscopic donor nephrectomies--is it time to use a standardized classification of complications? j urol. 2010; 183:1941. 16. mamoulakis c, efthimiou i, kazoulis s, et al. the modified clavien classification system: a standardized platform for reporting complications in transurethral resection of the prostate. world j urol. 2011; 29:205. 17. zuazu jr, hruza m, rassweiler jj, de la rosette jjmch. the clavien classification system to optimize the documentation of pcnl morbidity. arch ital urol androl. 2010; 82:20. 18. de la rosette jjmch, opondo d, daels fpj, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246. 19. novara g, ficarra v, d’elia c, et al. prospective evaluation with standardised criteria for postoperative complications after robotic-assisted laparoscopic radical prostatectomy. eur urol. 2010; 57:363. 20. rabbani f, yunis lh, pinochet r, et al. comprehensive standardized report of complications of retropubic and laparoscopic radical prostatectomy. eur urol. 2010; 57:371. 21. gill is, schweizer d, hobart mg, et al. retroperitoneal laparoscopic radical nephrectomy: the cleveland clinic experience. j urol. 2000; 163:1665. 22. permpongkosol s, link re, su l-m, et al. complications of 2,775 urological laparoscopic procedures: 1993 to 2005. j urol. 2007; 177:580. 23. breda a, finelli a, janetschek g, et al. complications of laparoscopic surgery for renal masses: prevention, management, and comparison with the open experience. eur urol. 2009; 55:836. 24. rassweiler j, fornara p, weber m, et al. laparoscopic nephrectomy: the experience of the laparoscopy working group of the german urologic association. j urol. 1998; 160:18. 25. furriel ftg, laguna mp, figueiredo ajc, et al. training of european urology residents in laparoscopy: results of a paneuropean survey. bju int. 2013; 112:1223. correspondence ali serdar gozen, md, febu (corresponding author) assoc. prof. of urology ali.goezen@slk.kliniken.de vitalie gherman, md vitaliegherman@gmail.com yigit akin, md yigitakin@hotmail.com mustafa suat bolat, md msbolat@gmail.com jens rassweiler, md jens.rassweiler@slk-kliniken.de department of urology, slk kliniken heilbronn, am gesundbrunnen 20-25, 74078 heilbronn, germany muhammad elmussareh, md elmussareh@googlemail.com department of urology, mid yorkshire hospitals nhs trust, wakefield, uk gozen_stesura seveso 03/01/18 11:01 pagina 271 archivio italiano di urologia e andrologia 2021; 93, 182 letter to editor movember in a pandemic it matters, more than ever submitted 4 november 2020; accepted 1 december 2021 no conflict of interest declared. doi: 10.4081/aiua.2021.1.82 dear editor, in recent years there has been an increase in the number of new cases of cancer. this increase, in part, is closely related to the increase in average life expectancy, as well as more accurate diagnostic techniques and well-defined screening programs. nowadays, the world faces a new challenge, a pandemic, an outbreak of a new beta-coronavirus. who has declared the new coronavirus disease (covid-19), caused by sars-cov-2, an international public health emergency. given the unprecedented situation of the pandemic, those programs may begin to slow down. movember is the leading charity changing the face of men´s health on a global scale, focusing on mental health and suicide prevention, prostate cancer and testicular cancer. commenced in 2003 with the dual aims of raising funds and awareness of prostate cancer and mental health, incorporating testicular cancer and physical inactivity in recent years, the term was created from the combination of “mo” – australian slang for mustache – and november. the strength of the movember campaign is in its fundraising capacities. to date, has raised millions and funded over thousands programmes worldwide. the campaign makes outstanding use of social media with accounts on facebook, twitter and instagram, but most of their marketing focus on encouraging men to grow facial hair. with a trademark combination of humor, companionship, and competitive nature they managed to do the seemingly impossible: turn huge numbers of men into energetic fundraisers, much as women do for breast cancer. movember in a pandemic does it matters? coronavirus disease 2019 (covid-19) is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and first emerged in december 2019 in wuhan, hubei province, china. since then, the virus has rapidly spread to many countries with a daily increase in the number of confirmed cases and infection-related deaths. covid-19 morbidity and mortality has been associated with factors such as age and comorbidities. infection in frail patients assumes a worse prognosis, resulting more often in hospitalization, admission to intensive care units with a consequent need for invasive mechanical ventilation. among these, cancer patients represent a large subgroup with a high risk of developing infection associated with coronavirus and, consequently, serious complications. the challenges caused by the covid-19 pandemic required an enormous effort to adapt and reorganize medical services. the consequent internal restructuring to respond to the new demands determined by covid-19 had to be done simultaneously taking care of people and working as a team, focusing on identifying the most appropriate solutions at all times for the different contexts of the dynamics. the question of how to organize the screening programs during the covid-19 pandemic is crucial it is indisputable to join efforts to fight the sars-cov-2 pandemic, but let us not agree that the virus contaminates our national health system. the emergency committee of the world health organization (who) anticipated that the covid-19 pandemic will last a long time and, therefore, it is necessary to continue efforts to contain it worldwide. the challenges are immense, but there are lives beyond covid-19 that need to be taken on account. by this we mean that the pandemic caused by covid-19 has not made the illnesses of these potential patients disappear, who continue to need our attention and care. if, on the one hand, it is more than clear that we should be aware that with the current pandemic situation it is impossible to maintain all normal activity and simultaneously treat covid-19 patients; on the other hand, we cannot ignore the remaining problems in our health system in addition to this virus. 83archivio italiano di urologia e andrologia 2021; 93, 1 movember in a pandemic it matters, more than ever "the pandemic is a health crisis that occurs once in a century and its effects will be felt in the decades to come," said who director-general tedros adhanom ghebreyesus. these effects are valid for both covid and non-covid patients. so, the answer to whether the movember movement makes sense in times as troubled as those we currently live in, our answer is a categorical yes. references 1. movember foundation (us). mo history. < https://us.movember.com > 2. ambrosini f, di stasio a, mantica g, et al. covid-19 pandemic and uro-oncology follow-up: a "virtual" multidisciplinary team strategy and patients' satisfaction assessment. arch ital urol androl. 2020; 92. doi: 10.4081/aiua.2020.2.78. pmid: 32597103. correspondence joão vasco barreira (corresponding author) joaovascobarreira@gmail.com medical oncologist, lisbon, portugal gil falcão urologist, lisbon, portugal mariana amaral pedro barreira family doctor, lisbon, portugal joão vasco barreira 1, gil falcão 2, mariana amaral 3, pedro barreira 3 1 medical oncologist, lisbon, portugal; 2 urologist, lisbon, portugal; 3 family doctor, lisbon, portugal. all the authors contributed equally to the paper. 287archivio italiano di urologia e andrologia 2017; 89, 4 original paper ureteroscopy in pregnant women with complicated colic pain: is there any risk of premature labor? salvatore butticè 1, antonio simone laganà 2, salvatore giovanni vitale 2, christopher netsch 3, yiloren tanidir 4, francesco cantiello 5, laurian dragos 6, michele talso 7, esteban emiliani 8, rosa pappalardo 1, tarik emre sener 4 1 department of human pathology section of urology, university of messina, messina, italy; 2 unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina, italy; 3 department of urology, asklepios hospital barmbek, hamburg, germany; 4 department of urology, school of medicine, marmara university, istanbul, turkey; 5 department of urology, magna graecia university, catanzaro, italy; 6 clinical emergency county hospital "pius branzeu" timisoara, university of medicine and pharmacy "victor babes" timisoara, romania; 7 department of urology, irccs ca' granda ospedale maggiore policlinico, università degli studi di milano, italy; 8 department of urology, hôpital tenon, université pierre et marie curie paris vi, paris, france; groupe de recherche clinique sur la lithiase urinaire, grc n° 20, sorbonne universités, paris vi, france. objective: clinical presentation of ureteral stones during pregnancy is generally with renal colic pain. the aim of this study is to present our experience in the management of renal colic during pregnancy in emergency settings. materials and methods: 208 pregnant patients who presented to emergency department with renal colic pain and underwent ureteroscopy (urs) due to failed conservative therapy were enrolled in the study. urinary tract stones were diagnosed either with ultrasound (us) examination or during urs. laser lithotripsy and double j (dj) stent placement were routinely done in all patients with ureteral stones. the incidence of infective complications and premature uterine contractions (puc) due to urs were compared. results: no stone was identified in 36.1% (n = 75) of patients with using us and diagnostic urs. of the remaining 133 patients, 30 (22.6%) had no stone at us but stones were diagnosed during diagnostic urs. the type of anesthesia had no significant effect on puc. an increased risk of sepsis and puc was found in patients with fever at the initial presentation. interestingly, puc was more frequent in patients with lower serum magnesium levels. there was a significant correlation with time delay until the intervention and the risk of urosepsis and puc, individually. conclusions: ureteroscopy is a safe option for evaluation of pregnant patients with unresolved renal colic. according to the current findings, timing of the operation is the most important factor affecting the septic risks and abortion threat. surgical intervention with urs must be planned as soon as possible. key words: pregnancy; urinary calculi; renal colic. submitted 31 august 2017; accepted 18 october 2017 summary no conflict of interest declared. 0.02-0.53%, complicating from 1:200 to 1:2000 pregnancies, and urolithiasis may also be a contributing factor in up to 40% of premature births (2). several elements are capable of increasing the risk of urolithiasis and hydronephrosis during pregnancy, including the mass-effect of gravid uterus, reduced peristalsis and dilation of the urinary tract due to elevated progesterone levels, and increased risk of infection and electrolyte imbalance (decreased secretion of urinary stone inhibitors, such as citrate and magnesium) (3). renal colic is the most common non-obstetric cause of abdominal pain and subsequent hospitalization during pregnancy (3). the clinical presentation of ureteral stones during pregnancy is primarily after 20 weeks of gestation; alongside renal colic, tenderness, fever, dull aching pain and hematuria (4). as is the case with the general population, a conservative approach that makes use of analgesia and monitoring for spontaneous passage is often the most appropriate initial treatment for acute renal colic in the pregnant patient. however, if spontaneous passage does not occur or if complications develop, placement of a ureteral stent or a percutaneous nephrostomy is necessary. in such cases, ureteroscopy (urs) has also become a reasonable alternative due to patients’ low tolerance for these devices (5). the aim of this study is to present our experience managing renal colic during pregnancy in emergency settings. materials and methods from november 2000 to august 2014 pregnant patients who presented to emergency departments (eds) of university of messina and magna graecia university with complicated renal colic were included in the study. we refer to as complicated when it is unresponsive to condoi: 10.4081/aiua.2017.4.287 introduction the management of urinary stones during pregnancy is a major challenge for urologists (1). the incidence of urolithiasis during pregnancy is estimated to be between butticè_stesura seveso 03/01/18 12:21 pagina 287 archivio italiano di urologia e andrologia 2017; 89, 4 s. butticè, a.s. laganà, s.g. vitale, c. netsch, y. tanidir, f. cantiello, l. dragos, m. talso, e. emiliani, r. pappalardo, t. emre sener 288 servative analgesic treatment or there is leucocytosis, fever and vomiting. patients were endoscopically treated with either a double j (dj) stent placement or semirigid ureterolithotripsy. data were retrospectively analyzed. as standard protocol at the university hospitals in which the study was carried out, each patient signed an informed consent agreement upon admission allowing data collection for research purposes. the study design is in accordance with the helsinki declaration, conforms to the committee on publication ethics (cope) guidelines and was approved by the institutional review board (irb) of the university hospitals in which the study was conducted. all design, analysis, interpretation of data, drafting and revisions followed the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies, available through the equator (enhancing the quality and transparency of health research) network (6). assessment included general evaluation at presentation, routine urine and blood tests, urine culture, blood culture if necessary, urinary system ultrasonography (usg), and consultation with the department of obstetrics & gynecology. no computed tomography (ct) scan, kidneyureter-bladder (kub) graphy, or other ionizing radiation study was performed due to risk of foetal radiation exposure. all patients presented to the ed with complicated hn received analgesics and intravenous (iv) hydration treatment in a conservative approach; those who failed to respond and still had renal colic underwent ureteroscopy and were included in the study. stones were fragmented using a holmium:yttrium-aluminum-garnet (holmium:yag) laser and dj stents were routinely placed in all patients. all operations were performed by two surgeons with a large amount of experience in endourology (performing more than 500 procedures each). follow-up protocols included obstetric examination and ultrasound, to check both maternal and fetal health status, and urological follow-up consisted of clinical assessment of general well-being and symptomatology, usg examination, routine urine and blood tests, and urine culture. dj stents were removed four weeks after post-op. the primary endpoints of the study were to examine whether urs increases premature uterine contractions (puc) and the rate of premature labor, defined as regular uterine contractions that induce thinning and shortening of the uterine cervix before 37 weeks of pregnancy according to nice guidelines (7). uterine contractions were specifically defined as regular if they were of high intensity and occurred 3 or more times in 10 minutes measured by cardiotocography. modification of the uterine cervix was evaluated by vaginal examination and, in case patients were 30 weeks pregnant or more, by transvaginal ultrasound and if cervical length was more than 25 mm we excluded the diagnosis of preterm labor (8). we also evaluated whether delaying the operation increases the risk of premature labor and whether early intervention is beneficial over delayed urs in terms of urosepsis, sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and organ dysfunction can be identified as an acute change in total sequential (sepsis-related). organ failure assessment score (sofa) score ≥ 2 points consequent to the infection. urosepsis is mainly due to obstructed uropathy of the upper urinary tract (9). the secondary endpoints were to evaluate whether the rate of preterm labor and sepsis are effected by having a urinary stone and undergoing laser lithotripsy or by having a negative diagnostic urs, to see if there are parameters that can be used to determine the risk of preterm labor and urosepsis. statistical analysis statistical analyses were performed using original spss software, version 20.0 (ibm corp, ny, usa). statistical significance was set at p < 0.05. baseline variables were described using means and standard deviations or percentages, as appropriate. mann-whitney u tests were used to evaluate the difference between quantitative measurements that have non-parametric distribution. chi-squared tests were used for categorical data. cut off values for quantitative measurements were found by using receiver operating characteristics (roc). sensitivities, specificities, and predictive values with 95% confidence intervals were calculated. results a total of 208 patients were included in the study. all enrolled patients were in the second (from the 13th to the 27th week) or third trimester (from the 28th week onward) of pregnancy. patients in the second trimester had a gestational age of 26.1 ± 0.8 weeks, whereas patients in the third trimester had a gestational age of 31.8 ± 2.2 weeks. the grade of hydronephrosis was 1, 2 and 3 in 102 (48.1%), 75 (35.4%), 35 (16.5%) patients, respectively. a total of 133 of these patients had a ureteral stone diagnosed with urinary system ultrasonography (usg) or during diagnostic ureteroscopy and underwent laser lithotripsy and dj stent placement. the mean stone size was 8.3 ± 2.2 mm. the stone was in the lower, middle and upper ureter in 78 (58.6%), 46 (34.6%) and 9 (6.7%) patients, respectively. in 10 patients, stone retropulsion occurred during laser lithotripsies and only two of these patients had puc. the remaining 75 patients underwent diagnostic ureteroscopy, no stone was encountered, and a dj stent was placed. the mean duration of the operation was 29.4 ± 4.6 minutes. different parameters about patients with and without puc are given in table 1. 8.7% of patients with a stone (encountered before or during urs and treated) underwent preterm labour something they are at higher risk of than patients in whom no stone is revealed during either preoperative evaluation or diagnostic urs (1.4% of these patients underwent preterm labour, p < 0.05, odd’s ratio: 3.8, confidence interval: 1.113.2). patients with signs of urinary tract infection (uti) are considered to have a fever at the time of diagnosis, as they have positive urine culture and urosepsis after ureteroscopy and were at greater risk for the presence of puc when compared to patients without signs of uti (p < 0.005, odd’s ratio: 6.6, confidence interval: 1.8-12.1). nine out of 35 patients (25.7%) with and 12 out of 173 patients (6.9%) without signs of uti underwent preterm labour. butticè_stesura seveso 03/01/18 12:21 pagina 288 the number of patients with signs of uti experiencing preterm labour was not statistically different in subgroups where the patients were operated upon for an existing stone or where they had a diagnostic urs and dj stent placement (p: 0.488). however when patients without signs of uti were considered, having a stone and undergoing lithotripsy increased the risk of preterm labour more than in patients with no urinary stone (p < 0.05, odd’s ratio: 7.3, confidence interval: 0.9-57.6). when we analyze the data, having a fever at the time of diagnosis is the highest risk factor for preterm labour (odd’s ratio: 19.3, confidence interval: 6.1-60.8). additionally, delaying operation by more than 36 hours increases the risk by a factor of 10 (odd’s ratio: 10, confidence interval: 1.8-12.1). however being stone-free at operation’s end increases the risk of preterm labour (odd’s ratio: 6.2, confidence interval: 2.8-13.5). this situation may indicate that, to be stone-free, patients need complete stone removal which may require longer operation times and can therefore lead to a risk of increased preterm labour. upon univariate analysis of the data, having a fever at time of diagnosis, being stone-free at the end of the procedure and a delay of > 36 hours until operation have a statistically significant relationship with having puc (p < 0.0001). the mean time elapsed until operation was significantly longer in patients with preterm labour than in both subgroups of patients without preterm labour; in whom a stone was not revealed (p < 0.05) or whom had a diagnosed stone either with us or urs (p < 0.001). the cutoff value of a 30.5 hour-delay till operation in patients without a stone has a sensitivity of 75% and specificity of 71% on a roc curve analysis (auc: 0.792). on the other hand, for patients with a urinary stone, the cut-off value of 29.5 hours has a sensitivity of 83% and a specificity of 79% (auc: 0.86). additionally, the serum magnesium levels of patients who had a stone were significantly lower in patients with preterm labour than in patients without preterm labour (p < 0.01). interestingly, when patients without a stone were considered, the opposite relationship is encountered; patients in this group with a puc had significantly higher levels of serum magnesium (p < 0.05). the data is reported in table 2. for patients with a diagnosed urinary stone (either with us or during urs) who subsequently underwent laser lithotripsy, elapsed time until operation (p < 0.05), urine density (p < 0.05), serum uric acid (ua) level (p < 0.05) and serum glucose level (p < 0.05) all have statistically significant relationships to urosepsis. the median values for all these parameters are given in table 3. however, these parameters did not have statistically significant relationships in patients without urinary stones. discussion hydronephrosis and the accompanying persistent renal colic during pregnancy is a urological and obstetric emergency. it is a relatively rare occurrence in 0.05% of all pregnancies (10). different urological, obstetrical, gynecological and general surgical evaluations are needed to make a differential diagnosis and exclude other emergency situations such as an acute twisted ovarian cyst, aortic aneurysms or appendicitis (11). the first diagnostic step is an ultrasonographic examination. real-time usg demonstrates the renal parenchyma, calyceal system, dilated ureter, and occasionally the offending calculus, without radiation exposure. there are limitations of usg however; the first being low sensitivity of standard usg for urolithiasis which is between 34-86% (12, 13). the second limitation is the impossibility of evaluating the ureter below the level of the pelvic brim/iliac artery in most cases as well as situations in which the 289archivio italiano di urologia e andrologia 2017; 89, 4 ureteroscopy in pregnant women and premature labor table 1. time elapsed prior to operation (hours) and serum magnesium level (mmol/l) of patients diagnosed and treated for urinary stone disease and patients who underwent diagnostic ureteroscopy, subgrouped by having premature uterine contrations (puc). values are expressed as median (minimum, maximum). (*p < 0.05, **p < 0.01, ***p < 0.001, when compared with patients having puc). time elapsed until operation serum magnesium level stone + puc + 37.5 (min 19, max 43) 0.73 (min 0.62, max 0.84) puc 21 (min 6, max 42)*** 0.78 (min 0.54, max 1.86)** stone puc + 34.5 (min 30, max 42) 0.96 (min 0.83, max 1.17) puc 22 (min 6, max 47) * 0.82 (min 0.58, max 1.36)* table 2. median values of time elapsed prior to operation (hours), urine density, serum uric acid level (μmol/l) and serum glucose level (mmol/l) in patients with diagnosed urinary stone who had urosepsis. values are expressed as median (minimum, maximum). (*p < 0.05, when compared with patients who didn’t have urosepsis). urosepsis + urosepsis stone + time elapsed until operation 38 (min 32, max 40) 21 (min 6, max 43)* urine density 1010 (min 1000, max 1020) 1015 (min 1010, max 1030)* serum uric acid level 350 (min 260, max 430) 238 (min 121, max 2785)* serum glucose level 4.28 (min 4.03, max 4.48) 4.82 (min 3.45, max 8.07)* butticè_stesura seveso 03/01/18 12:21 pagina 289 archivio italiano di urologia e andrologia 2017; 89, 4 s. butticè, a.s. laganà, s.g. vitale, c. netsch, y. tanidir, f. cantiello, l. dragos, m. talso, e. emiliani, r. pappalardo, t. emre sener 290 investigator is unable to differentiate between secondary ureteral obstruction from calculi and the physiologic hydronephrosis of pregnancy (14). transvaginal usg is another diagnostic tool that can be used to accurately detect distal ureteral stones as demonstrated in the literature and can be performed to evaluate the length of the uterine cervix in a one-step procedure (15). in pregnant patients, ionizing radiation may have teratogenic effects on the fetus and should be avoided, diminishing clinicians’ diagnostic options in complicated cases. however, european association of urology (eau) guidelines permit the use of a low-dose ct as a last resort in selected cases. magnetic resonance imaging (mri) can also be used as it may define the level of urinary tract obstruction and visualize stones as filling defects (5). in our cohort of patients we did not use low-dose ct, kub x-ray, intravenous urography (ivu) or mri. in patients with complicated hydronephrosis with colic pain, ureteroscopy can be used as a diagnostic procedure thanks to low complication rates in this patient group and due to a potentially high number of diagnosed ureteral stones in carefully selected patients, something that was reflected by our results in this study (16-18). according to wymer et al. study, ureteroscopy is less costly and more effective than routine stenting, especially in early pregnancy (19). of all the patients presented to the emergency department, 133 were found to have a ureteral stone. ultrasonography revealed the stone in 103 patients (77.4%), and 30 patients (22.6%) were found to have ureteral calculi during ureteroscopy. this finding demonstrates that usg is a decisive diagnostic method for patients with renal colic during pregnancy and that ureteroscopy can be used as an auxiliary measure (20). about 20-30% of ureteral stones during pregnancy are not expelled spontaneously and need active treatment (21). the first step in active treatment is the placement of a ureteral dj stent or percutaneous nephrostomy. dj stent placement is a rapid way to decompress the urinary system, and can be performed with a retrograde or antegrade approach (22). retrograde approach may be performed under local anesthesia using usg guidance, thus avoiding fluoroscopic radiation exposure. limited fluoroscopic imaging can only be performed if there is any difficulty advancing the guidewire up the ureter (23). however, denstedt and razvi suggest that a ureteral stent should be reserved for the later stages of pregnancy (24). in cases where a dj stent is placed during the first trimester of pregnancy, it is advised that the stent be changed on a monthly basis (21). percutaneous nephrostomy insertion in pregnant patients has several advantages. it’s a minimally invasive procedure, provides immediate and effective decompression of the kidney cavities and can be performed even in sepsis situations and under local anesthesia without the need for ionizing radiation. the procedure also allows urine collection for culture, and permits access for future percutaneous nephrolithotomy procedures (25). percutaneous nephrostomy may be preferred over dj stents during early pregnancy due to easier replacement techniques if necessary (21, 26). ureteroscopy and laser lithotripsy for ureteral calculi during pregnancy has gained popularity in the last few years and studies on urinary tract stones in pregnant patients are increasing. zhang et al. reported that out of 117 pregnant patients, 12 had puc and 5 had renal colic for more than 24 hours a statistically significant condition (18). in our study, we found that time elapsed until operation is a major risk factor for puc and that there is a significant difference between patients with and without puc in both groups as well as with and without urinary system stones. the delay is caused by the need to perform tocolysis and maternal corticosteroid administration to induce fetal lung maturation according to royal college of obstetricians and gyneacologists guidelines (27-30). however, early intervention should be suggested in cases of complicated hn patients. the delayed operation was also found to be a risk factor for urosepsis in our cohort of patients. the situation becomes a two-sharp-edged sword; delay is necessary but can be a risk factor for sepsis. a delay is associated with increased sepsis risk, especially in patients who had urinary stones. this delay is not significant in patients without stones, which may depend on the duration of the operation (in patients with a stone, operation time may be longer due to the additional procedure of laser lithotripsy). unfortunately operation times are not recorded, so statistical analysis could not be performed. so, we can potentially suggest that a simple dj stenting may be preferred over laser lithotripsy in cases where the operation can be performed after > 36 hours of admission to the ed or in patients with signs of uti upon admission, in order to reduce the rate of puc. mitrovic-jovanovich et. al. reported in their study how serum levels of magnesium and calcium can be predictors of preterm delivery (31). in our study cohort, we observed that serum levels of magnesium are significantly lower in patients who had uterine contractions during urs. however, the serum levels of calcium did not differ in patients with or without uterine contractions. the significant differences in serum glucose levels in patients with and without sepsis can be attributed to increased catabolic activity. jeon et al. found that an increased glucose level upon hospital admission is associated with increased blood stream infections (32). similarly, in our study, the serum glucose levels were significantly higher in patients who had urosepsis. although the mechanism is not clear, the serum levels of ua increased in cases of severe sepsis. this is either caused by an increase in production due to hypoxia and ischemia, which results in increased conversion of xantine and hypoxantine to ua; or is caused by decreased excretion from the kidneys due to decreased renal perfusion in sepsis (33, 34). it was hypothesized by chuang et al. that serum ua levels are correlated with total antioxidant capacity of patients and helps to counterbalance increased proinflammatory cytokines. whether hyperuricemia is a risk factor for sepsis is unknown, but it is shown that higher levels of ua are associated with poorer outcomes in sepsis patients (35). butticè_stesura seveso 03/01/18 12:21 pagina 290 our study has some limitations. the first limitation is the retrospective nature of the study and the second is that duration of time prior to operation wasn’t exactly recorded but classified into categories so the analyses with this parameter could not be carried out to provide exact mean values. conclusions ureterolitotripsy and dj stent placement are valid and safe choices in pregnant patients with complicated hydronephrosis. in our opinion, the most important issue is timing, evaluating all the parameters including blood tests, radiology, general status of the fetus and patient. delaying an operation can lead to an over exposure to septic risks and puc may increase. the perfect timing should be planned step-by-step with a multi-disciplinary approach. author contributions concept and design: salvatore butticè, tarik emre sener, rosa pappalardo, michele talso. acquisition of data: antonio simone laganà, salvatore giovanni vitale, christopher netsch, francesco cantiello. analysis and interpretation of data: salvatore butticè, tarik emre sener, yiloren tanidir. drafting the article: salvatore butticè, tarik emre sener, esteban emiliani, laurian dragos. revising the article for important intellectual content: salvatore butticè, tarik emre sener, rosa pappalardo. references 1. fregonesi a, dias fg, saade rd, et al. challenges on percutaneous nephrolithotomy in pregnancy: supine position approach through ultrasound guidance. urol ann. 2013; 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148(3 pt 2):1072-4; discussion 1074-5. 25. pearle ms, pierce hl, miller gl, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol. 1998; 160:1260-4. 26. wang z, xu l, su z, et al. invasive management of proximal ureteral calculi during pregnancy. urology. 2014; 83:745-9. 27. gyetvai k, hannah me, hodnett ed, ohlsson a. tocolytics for preterm labor: a systematic review. obstet gynecol. 1999; 94(5 pt 2):869-77. 28. magee la, dawes gs, moulden m, redman cw. a randomised controlled comparison of betamethasone with dexamethasone: effects on the antenatal fetal heart rate. br j obstet gynaecol. 1997; 104:1233-8. 291archivio italiano di urologia e andrologia 2017; 89, 4 ureteroscopy in pregnant women and premature labor butticè_stesura seveso 03/01/18 12:21 pagina 291 archivio italiano di urologia e andrologia 2017; 89, 4 s. butticè, a.s. laganà, s.g. vitale, c. netsch, y. tanidir, f. cantiello, l. dragos, m. talso, e. emiliani, r. pappalardo, t. emre sener 292 29. mushkat y, ascher-landsberg j, keidar r, et al. the effect of betamethasone versus dexamethasone on fetal biophysical parameters. eur j obstet gynecol reprod biol. 2001; 97:50-2. 30. roberts d, dalziel s. antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth (review). cochrane database syst rev. 2006; 19:cd004454. 31. mitrovic-jovanovic a, dragojevic-dikic s, zamurovic m, et al. comparison of electrolytic status (na+, k+, ca2+, mg2+) in preterm and term deliveries. clin exp obstet gynecol. 2012; 39:479-82. 32. jeon cy, furuya ey, smaldone a, larson el, post-admission 292c, chi ch, et al. serum total antioxidant capacity reflects severity of illness in patients with severe sepsis. crit care. 2006; 10:r36. correspondence salvatore butticè, md (corresponding author) salvobu@gmail.com rosa pappalardo, md gattoparto@hotmail.it department of human pathology section of urology, university of messina, via consolare valeria 1, 98125, messina, italy antonio simone laganà, md antlagana@unime.it salvatore giovanni vitale, md vitalesalvatore@hotmail.com unit of gynecology and obstetrics, department of human pathology in adulthood and childhood "g. barresi", university of messina, messina, italy christopher netsch, md c.netsch@asklepios.com department of urology, asklepios hospital barmbek, hamburg, germany yiloren tanidir, md yiloren@yahoo.com department of urology, school of medicine, marmara university, istanbul , turkey francesco cantiello, md cantiello@unicz.it department of urology, magna graecia university, catanzaro, italy laurian dragos, md lauriandragos@yahoo.com clinical emergency county hospital "pius branzeu" timisoara, university of medicine and pharmacy "victor babes" timisoara, romania michele talso, md michele.talso@gmail.com department of urology. irccs ca' granda ospedale maggiore policlinico, università degli studi di milano, milano, italy esteban emiliani, md emiliani@gmail.com department of urology, hôpital tenon, université pierre et marie curie paris vi, paris, france.; groupe de recherche clinique sur la lithiase urinaire, grc n° 20, sorbonne universités, paris vi, france tarik emre sener, md dr.emresener@gmail.com department of urology, school of medicine, marmara university, istanbul , turkey butticè_stesura seveso 03/01/18 12:21 pagina 292 stesura seveso 69archivio italiano di urologia e andrologia 2019; 91, 2 original paper running suture hemostatic technique versus standard reconstruction of the surgical bed in zero ischemia time mini-flank open partial nephrectomies. retrospective, match-paired case-control study petar kavaric, aleksandar magdelinic, marko vukovic faculty of medicine, university of montenegro, podgorica, montenegro. objective: to estimate the efficacy of our technique of zero ischemia time partial nephrectomy (ztpn) with hemostatic running suture and compare it to the standard technique, in terms of perioperative complications, operative time (ot) and estimated blood loss (ebl). materials and methods: we retrospectively analysed 180 consecutive patients who underwent ztpn using a supra 11th or supra 12th rib mini flank approach. first group numbered 90 patients treated with running suture hemostatic technique (rsht), while the control group enrolled 90 patients in whom we performed standard reconstruction technique (srt). according the propensity score, both groups were similar in terms of tumor size, age and padua score. patients with solitary tumour limited to the kidney (t1-t2a) were included. our technique included a running suture of surgical bed edges and closure of the renal cortex by the positioning of peri-renal fat within the cortical bed and fixation with interrupted sutures. results: padua score and tumor size were comparable between groups (7.12 ± 1.33 vs 7.1 ± 2.11, p = 0.4 and 52.9 ± 14.8 vs 50.0 ± 13.2, p = 0.3). the mean operative time (ot) was significantly longer in first group (165.2 vs 95, p = 0.04), while median estimated blood loss (ebl) was significantly reduced (250 vs 460 ml, p = 0.02). surgical resection margins were negative in 100% of cases and no patient developed a local or distant recurrence during follow up. there was significant difference in postoperative gfr value between groups (p < 0.05). conclusions: our technique could be safely performed in local, low volume facilities, thus reducing the need for expensive and more challenging minimal invasive surgical techniques.. key words: nephrectomy; ischemia time; hemostatic technique. submitted 12 february 2019; accepted 13 february 2019 summary no conflict of interest declared. oped the supra 11th rib mini flank approach and supra 12th rib approach (2, 3). these techniques provide optimum anatomical exposure and better aesthetic outcomes with a low risk of long-term complications (2). typically, for a lower pole tumor, a supra 12th rib incision is more appropriate, while for mid and upper pole tumors a supra 11th incision ispreferred (3). clamping of the hilar vessels during partial nephrectomy may cause ischemic damage to the kidney and subsequent chronic renal impairment, which implies the necessity for improving zero-ischemia time techniques, especially for long lasting procedures, where ischemia time can be more than 25-30 minutes (4, 5). this led to the development of techniques such as zero ischemia time partial nephrectomy (ztpn) (6). there are however difficulties with this approach, which include increased intraoperative blood loss compared with on-clamp procedure, hence requiring new, technically less demanding haemostatic techniques with comparable blood loss. the aim of this study was to present our approach – open ztpn using a running suture hemostatic technique for surgical bed – in order to reduce intraoperative blood loss and maintain stable renal function (rf), comparing to standard reconstruction technique. patients and methods from 543 patients who underwent tumour nephrectomy in our clinic between january 1997 and march 2017, we retrospectively analysed 186 consecutive patients who underwent pn using supra 11th or supra 12th rib mini flank approach (2, 3). first group numbered 96 patients with running suture hemostatic technique (rsht), while the control group enrolled 90 patients in whom we performed standard reconstruction technique (srt). the patients who underwent rsht were matched to control group according to the following variables: tumor size, age and anatomic classification of renal tumors (padua) score. finally, 90 patients from the first group were matched to 90 patients from the control group. the indication for surgery was solitary renal tumor limited to the kidney (ct1-ct2a). we used preoperative ct or mri tumor staging according to the doi: 10.4081/aiua.2019.2.69 introduction partial nephrectomy (pn) for localized kidney tumor has oncological outcomes similar to that of radical surgery (1). according to current guidelines, patients with low grade renal cell carcinoma (rcc) should undergo nephron-sparing surgery rather than radical nephrectomy whenever possible (eau guidelines). utilizing minimally invasive surgical approaches to open nephrectomy, two mini-flank open techniques have been develarchivio italiano di urologia e andrologia 2019; 91, 2 p. kavaric, a. magdelinic, m. vukovic 70 2004 world health organization (who) classification of renal epithelial tumors (7). patients with the following criteria were excluded: those with blood disorders; evidence of locally advanced or systemic disease; regional adenopathy or previous kidney surgery. the presence of hereditary renal cancers was no contraindication for surgery. the variables we examined when reviewing our database were demographics (age, gender, body mass index), lesion characteristics (location, centrality and size), pathological stage and histological subtype, perioperative variables operative time (ot), estimated blood loss (ebl), postoperative glomerular filtration rate (pgfr), length of hospital stay and intraoperative and postoperative complications (poc) (3). poc were classified according to the modified clavian system (8). • the primary end points evaluated included ebl, postoperative creatinine and pgfr, poc and hospital stay. • the secondary end points evaluated included ot, transfusion rate and surgical margin status. tumour histology was evaluated using modified heidelberg histopathological classifications of renal tumors (9). surgical approach and hemostatic technique after positioning a patient in a standard flank position, we then perform a supra 11th or supra 12th skin and subcutaneous incision, using the mini-flank technique as described by diblasio et al. (2). after the transection of abdominal wall muscle layers and division of the transverses abdominis fibers, we use a combination of blunt and sharp dissection (finger and metzenbaum scissors) to divide the transversalis and lumbodorsal fascia, with displacement of the pleura using a sponge stick. we use a self-retaining retractor with an additional bladder blade or morris retractor to retract the 10th or 11th rib superiorly. typically, we do not perform resection of the 12th rib. after accessing the retroperitoneal space using bluntdissection and reflecting the kidney with surrounding fat tissue medially, we create the plane between the quadrates lumborum and psoas muscle. in the case of upper pole tumours, after medial and lateral mobilisation of the kidney we isolate the ureter from the lower pole and place it in a yellow vessel loop. when operating upper pole tumors, the adrenal gland would be inspected & palpated, and if there is no indication for adrenalectomy we proceed with mobilization of the upper pole of the kidney using ligasure bipolar current (ligasuretm, covidien, minneapolis, usa). after mobilization of surrounding fat, the kidney is carefully inspected to determine the depth and proximity of the tumour to the renal vessels and collecting system (2). for centrally located tumors and for endophitic ones, we use intraoperative ultrasonography in order to accurately identify tumour borders. upon demarcation of tumor contours with monopolar current (figure 1a), we use sharp dissection of tumour tissue together with resection of an approximately 0.5 cm thick rim of tissue from the tumour bed (figure 1b-c ). we do not perform tumour margins frozen section routinely, even for deep renal tumour specimen. prominent arterial branches within the tumor bed are ligated with 2/0 vicryl ligature or clipped using surgical microclips, in order to selectively devascularize the tumour without interruption of normal renal perfusion (6). with incidental break (what do you mean) within the collecting system, the calyces are sutured with 4/0 pds suture (figure 1d). after the excision of tumour tissue, we utilize running 4/0 pds suture of surgical bed edges, with additional hemostatic sutures in case of minor bleeding within the surgical bed (figure 1e). at the end, we close the renal cortex by placing perirenal fat within the cortical bed and placing size 0 chromic liver interrupted sutures (figire 1f). standard reconstruction technique consists of tumor resection and reconstruction of the surgical bed with single, interrupted sutures, followed by application of hemostatic agents within resection cavity (surgicel; johnson and johnson, new brunswick, new jersey). the renal capsule is reaproximated using 0 vicryl sutures pledged with surgicel to prevent tearing of the renal cortical capsule and further bleeding (10). the surgical incision is closed using 3/0 absorbable sutures in a subcuticular fashion (2). during the early postoperative period (48h), blood pressure is tightly controlled (e.g. mean arterial pressure (map) between 60 100 mmhg) in order to avoid additional bleeding from renal parenchyma, but also to maintain safe tissue perfusion and oxygenation, preserving normal postoperative rf. figure 1. surgical technique of ztpn using running suture technique for surgical bed with fat tissue tamponade: demarcation of tumor with monopolar current (a); sharp dissection of tumor tissue with approximately 0.5 cm thick rim of renal tissue (b); tumor appearance after c); suturing of ruptured calyces and tumor bed (d); hemostatic running suture of wound edges (e); fat tamponade (f). a. b. c. d. e. f. statistical analysis for statistical analysis we used spps v16.0, spps, chicago, il, usa. methods of statistical description and significance included the student t test and mann whitney u test. descriptive analyses were also generated and some data are reported as median, interquartile range (iqr), or number (%). the difference of the obtained values was considered to be significant when p < 0.05, and highly significant when p < 0.01. results following exclusion criteria and score matching, 180 patients were eligible for this study. according the propensity score, both groups were similar in terms of tumor size, age and padua score (52.9 ± 14.8 vs 50.0 ± 13.2 mm, p = 0.3; 57 ± 17.26 vs 55 ± 12.19 years, p = 0.5 and 7.12 ± 1.33 vs 7.1 ± 2.11, p = 0.4, respectively) (table 1). median follow up time was 52.75 months in first group and 59.25 within control group (p = 0.3). additionally, hospital stay and surgical margin status did not differ between the groups. the mean padua score in first group was 7.12 ± 1.33 where 14.7% of patients had a score > 8 and 5 patients (5.25%) had a score > 10. the majority of masses (55.5%) were malignant with predominance of the clear cell subtype (67.7%) and exophitic growth (78.9%). the demographic data are given in table 2. intraoperatively, three patients (3.3%) from the first group and 7 from the control group (7.77%) required radical nephrectomy due to hilar or deeply penetrating endophytic tumours. concomitant radical tumor nephrectomy of the other kidney was required in 9 and 7 patients (10% vs 7.77%), with no clinical confirmation of hereditary cancer occurence. no other complications were recorded during surgery. there were 11.2 % and 23.3% poc during follow-up, which were predominantly clavien grade ii (table 1). postoperative transfusion rate was 1.1% and 2.2% with a maximum of 1 blood unit required; mean ebl was 250 and 460 ml, while average ot was 165.2 and 95 min. intraoperative ultrasound was used in 26 patients (28.8%). surgical resection margins were negative in 100% of all cases (table 1) and no patient developed a local or distant recurrence during follow up. table 3 shows pre and postoperative parameters between groups. there was no significant difference in preoperative creatinine value, gfr or haemoglobin (hgb) between groups (p = 0.43; p = 0.51 and p = 0.6). nevertheless, gfr was significantly increased in first group during the early postoperative period (98.86 ± 8.4 vs 77 ± 6.8, p = 0.01). discussion the primary goal of this study was to determine whether rsht could substantially decrease the morbidity associated with srt, regarding ebl, postoperative creatinine and pgfr. our results showed that ebl and poc were sig71archivio italiano di urologia e andrologia 2019; 91, 2 open partial nephrectomy with specific hemostatic technique table 1. comparison of perioperative outcomes between two groups. table 2. demographic data within first group. mean (sd)/median (iqr) n group i control group 90 patients 90 patients age (years) 57 (17.26) 55 (12.19) padua score 7.12 (1.33) 7.1 (2.11) tumor size (mm) 52.9 (14.8) 50 (13.2) operative time 165.2 (47.31) 95 (32.1) * estimated blood loss (ml) 250 (100-350) 460 (170-530)* hospital stay (days) 5 (2.5) 7 (1.5) number (%) surgical margin 0 (100) 0 (100) transfusion rate 1 (1.1) 2 (2.2) complications 11 (12.22) 21 (23.3)* clavien i 3 7 clavien ii 5 8 clavien iii 2 4 clavien iv 1 2 * statistically significant difference between corresponding groups (p < 0.05). mean (sd)/median (iqr) n 90 patients male, n (%) 60 (66.6) female, n (%) 30 (33.3) median body mass index, kg/m2 30.75 (7.45) asa class 3 (1-4) indication for pn number (%) elective 80 (88.2) solitary kidney 4 (4.4) bilateral tumors 6 (6.6) tumor location number (%) upper pole 45 (50) mid pole 9 (10) lower pole 31 (34.4) renal hilus 5 (5.6) tumor histology number (%) clear cell 61 (67.7) papillary 15 (16.7) oncocytoma 7 (7.8) chromophobe 3 (3.4) multilocular cystic 4 (4.4) table 3. comparison of several parameters before and after surgical treatment between groups. mean (sd)/median (iqr) first group before treatment 72 h after the treatment creatinine (mg/dl) 1.16 (0.5) 1.10 (0.46) gfr (ml/min) 91.66 (9.5) 95.86 (8.4)** control group before treatment 72 h after the treatment creatinine (mg/dl) 1.10 (0.3) 1.55 (0.76) gfr (ml/min) 88.25 (8.7) 77 (6.8) * statistically significant difference comparing preoperativeand postoperative values within first group (p < 0.05). ** statistically significant difference comparing postoperative values between first and control group (p < 0.05). archivio italiano di urologia e andrologia 2019; 91, 2 p. kavaric, a. magdelinic, m. vukovic 72 nificantly reduced within first group, while postoperative gfr increased, compared to control group of patients. nevertheless, ot was significantly prolonged using rsht. the main goal in pn is to achieve negative tumor margins with a minimal decrease in renal function (rf) and minimal blood loss. since warm ischemia may be detrimental to rf and cold ischemia may be difficult to achieve during minimally invasive pn, several techniques have been developed in order to avoid clamping of the renal artery (6). anatomical zero-ischemia pn, introduced by gill et al. (11) was based on clipping of tumor-specific arterial branches, in order to devascularize the tumor without interruption of normal renal perfusion. this technique led to low ebl (206 ml) with 100% negative surgical margins and a transfusion rate of 21% with poc grade > 3 of 3.5%. we used a similar concept during excision of tumour tissue and after final hemostasis of the surgical bed, mean ebl was 250 ml in first and 460 ml in control group, with a transfusion rate of 1.1% and 2.2% and a 100% negative surgical margin. although we performed open pn in both groups, mean ebl was significantly lower in group treated with rsht, which could be associated with meticulous surgical technique and suturing of surgical bed edges with additional fat tissue tamponade. the importance of the improving outcomes of rf through technical modification of resection techniques has already been emphasized (12), with an emphasis on minimization of resection margins and amount of tissue incorporated into renorrhaphy. desai et al. (13) shares our attitudes on ‘tissue-sparing’ technique using running suture for wound edges through their reporting of point-specific hemostasis of the parenchymal defect. however, it is worth noting limitations in comparing these techniques with simple interrupted renorrhaphy, as our study describes open technique of pn, while majority of other studies outline a laparoscopic or robotic assisted minimal invasive approach. one of the few papers comparing perioperative and functional outcomes for patients treated with open, off-clamp pn, is research made by smith et al. (14), where authors retrospectively evaluated 192 patients and reported long operative times (226.5 min), significant ebl (500 ml) and a high transfusion rate (42%). our study however, found a significantly better outcome in all above mentioned perioperative parameters, which reinforces the importance of the applied surgical technique. moreover, lack of standardization in off-clamp surgical approach requires more comprehensive studies in order to establish proper technique with adequate hemostasis and preservation of surrounding parenchyma (15). this concept is strongly emphasized by maurice mj et al. (16), where volume loss of renal parenchyma was recognized to be the most important modifiable determinant of long term renal function. tissue sparing technique with simple hemostatic principles could assist in achieving this goal. kreigmar mc et al. (17) identified 40 cases of open partial nephrectomies, performed without clamping of the renal artery. the mean operative time was shorter compared to our study (106 vs 162.5 min), but ebl was significantly higher (521 vs 250 ml); nevertheless, their study included patients with padua scores > 8 and more complexity of tumour localization. this indicates that our surgical technique could be improved, since more favourable padua scores and tumour positions should lead to shorter operative time. however, complication rate and surgical margin status were comparable between studies. the most common tumour location in our study was upper pole and the majority of patients were elective, with a normal contralateral kidney. this is an important prerequisite for normal postoperative kidney function. serum creatinine is the easiest and most commonly used tool to assess rf after pn; however, it is not reliable since its value is significantly affected by age, sex, and muscle mass, especially in the presence of a healthy contralateral kidney (18). nevertheless, determination of gfr has been shown to reflect rf more accurately than serum creatinine. our study showed significant improvement in rf in the early postoperative period after using rsht, comparing gfr values between groups. this confirms effectiveness of our technique, even in patients with solitary or bilateral kidney tumours. the impact of different resection and renorrhaphy techniques on postoperative rf and perioperative blood loss has not been sufficiently investigated, and standardized reporting of these techniques for future pn series is warranted (19). our technique consisted of nephron sparing pn with running suture of the surgical edges and fat tissue tamponade of the surgical bed and showed promising results. operative time and ebl were at least comparable to other studies using open or minimal invasive ztpn, with preservation of renal function, negative surgical margins and no signs of tumour recurrence during a median of three years follow up time, with additional low transfusion rate and relatively short hospital stay. our research could be a starting point for future, so that more comprehensive studies comparing different surgical approaches could be developed. this research, however, has its limitations. first of all, our study concerned only patients treated with an open approach, a single technique and performed by one surgeon. additionally, our study included only one patient with t2 stage rcc with a relatively low padua score. only few patients had a solitary kidney tumour, so postoperative rf could not be accurately estimated without renal scintigraphy. finally, the majority of tumours had polar localization (84.4%) and exophitic growth (78.9%), therefore, the risk of complications in our study population may have been inherently lower. during pn surgery, the most important considerations in preserving rf are efforts at minimizing blood loss and reducing operative time, while maximizing renal parenchyma volume. our surgical technique showed satisfactory results regarding all perioperative outcomes, with no additional technical requirements. it could be safely performed in local, low volume facilities, thus reducing the need for expensive and more challenging minimal invasive surgical techniques. statement of ethics each subject signed the acceptance of the study protocol, in which the ethical principles for medical research involving human subjects (the helsinki declaration) were clearly stated. they all signed the written consent form. the national ethical committee at the university of montenegro approved this study. references 1. peycelon m, hupertan v, comperat e, et al. long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. j urol. 2009; 181:35-41. 2. diblasio cj, snyder me, russo p. mini-flank supra 11-th rib incision for open partial or radical nephrectomy. bju int. 2006; 97:149-56. 3. wang h, sun la, wang y, et al. mini-flank supra-12th rib incision for open partial nephrectomy for renal tumor with renal nephrometry score ≥10: an innovation of traditional open surgery. medicine. 2015; 94:692. 4. browne c, lonergan pe, bolton em, et al. a single centre experience of zero-ischaemia laparoscopic partial nephrectomy in ireland. ir j med sci. 2017; 186:1023-1026. 5. rod x, peyronnet b, seisen t, et al. impact of ischaemia time on renal function after partial nephrectomy: a systematic review. bju int. 2016; 118:692-705. 6. simone g, gill is, mottrie a, et al. indications, techniques, outcomes and limitations for minimally ischemic and off-clamp partial nephrectomy: a systematic review of the literature. eur urol. 2015; 68:632-40. 7. lopez-beltran a, scarpelli m, montironi r, et al. 2004 who classification of the renal tumors of the adults. eur urol. 2006; 49:798-805. 8. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 9. lopez-beltran a, carrasco jc, cheng l, et al. 2009 update on the classification of renal epithelial tumors in adults. int j urol. 2009; 16:432-43. 10. russo p, mano r, kimm s. open partial nephrectomy. in: kean te and graham sd, editors. glenn’s urologic surgery. lippincott williams & wilkins, wolters kluwer; 2016, p. 7-16. 11. gill is, patil mb, abreu al, et al. zero ischemia anatomical partial nephrectomy: a novel approach. j urol. 2012; 187:807-15. 12. minervini a, ficarra v, rocco f, et al. simple enucleation is equivalentto traditional partial nephrectomy for renal cell carcinoma: results of a nonrandomized, retrospective, comparative study. j urol. 2011; 185:1604-10. 13. desai m, de castro abreu al, leslie s, et al. robotic partial nephrectomy with superselective versus main artery clamping: a retrospective comparison. eur urol. 2014; 66:713-9. 14. smith gl, kenney pa, lee y, et al. non-clamped partial nephrectomy: techniques and surgical outcomes. bju int. 2011; 107:1054-8. 15. kopp rp, mehrazin r, palazzi k, et al. factors affecting renal function after open partial nephrectomy a comparison of clampless and clamped warm ischemic technique. urology. 2012; 80:865-70. 16. maurice mj, ramirez d, maloc e, et al. predictors of excisional volume loss in partial nephrectomy: is there still room for improvement? eur urol. 2016; 70:413-5. 17. kriegmar m.c, pfalzgraf d, hacker a, et al. zirk -technique: zero ischemia resection in the kidney for high-risk renal masses: perioperative outcome. urol int. 2015; 95:216-222. 18. volpe a, blute ml, ficarra v, et al. renal ischemia and function after partial nephrectomy: a collaborative review of the literature. eur urol. 2015; 68:61-74. 19. minervini a, carini m, uzzo rg, et al. standardized reporting of resection technique during nephron sparing surgery: the surfaceintermediate-base margin score. eur urol. 2014; 66:803-5. 73archivio italiano di urologia e andrologia 2019; 91, 2 open partial nephrectomy with specific hemostatic technique correspondence petar kavaric, md, phd petar.kavaric@kccg.me aleksandar magdelinic, md acomgd@yahoo.com marko vukovic, md (corresponding author) marko.vukovic09@gmail.com department of urology, clinical centre of montenegro ljubljanska bb, 81000 podgorica, montenegro 49archivio italiano di urologia e andrologia 2018; 90, 1 original paper seminal transferrin in the seminal quality evaluation of hemodialytic patients gilmar pereira silva 1, fabiana pirani carneiro 1,vitor pereira xavier grangeiro 2 1 university of brasilia, brasilia, federal district, brazil; 2 faculty of medical sciences, joão pessoa, paraiba, brazil. objective: to verify the association between seminal quality and seminal transferrin (st) level and fertility index in patients undergoing chronic hemodialysis (ch). material and methods: this is a cross-sectional study in a group of 60 men (case) undergoing ch for more than 6 months, and a group of 30 healthy men (control), aged 18-60 years, without clinical or laboratory signs of infection/inflammation. spermiogram was performed, fertility index (fi) was calculated and st and sex hormones (sh) levels were measured, including follicle-stimulating hormone, luteinizing hormone, total testosterone, and prolactin. results: all individuals were eugonadal. no differences for age (49.47 ± 5.56, 47.90 ± 6.2, p = 0.22) were observed between cases and controls, whereas there were significant differences between the individuals in the case and control groups with respect to the mean fi (p = 0.000), seminal parameters (sp) (p = 0.000), and st levels (40.12 ± 08.25 vs 73.32 ± 06.8, p = 0.000). st levels were correlated with fi (r = 0.787, p = 0.00) and sp (motility: r = 0.857, p = 0.000; vitality: r = 0.551, p = 0.000; density: r = 0.850, p = 0.000; normal morphology: r = 0.386, p = 0.000). linear regression model showed relationship of st levels with total sperm motility (r2 = 0.701; p = 0.000) and and fi (r2 = 0.569; p = 0.000). conclusions: our results suggest that seminal quality is associated with st levels and fi and that it can be used the initial investigation of subfertility/infertility of patients undergoing chronic hemodialysis.. key words: chronic kidney disease; hemodialysis; male infertility; seminal transferrin; seminal quality; seminal parameters. submitted 8 january 2018; 20 february 2018 summary no conflict of interest declared. patients with hypogonadism and clinical conditions that could alter st levels such as recent history of genitourinary tract infection, clinical signs of acute or chronic infection/inflammation, positive serology for hepatitis b, c and human immunodeficiency virus (hiv), vascular access infection, leukocytosis, fever, hypoproteinemia were not included in the study. sample consisted of 60 men (cases) in high flow hd by vascular fistula access, 3x week with duration of 4 hours/hd session and 30 healthy men (control) from the health promotion outpatient clinic of the same hospital without injury of renal function (glomerular filtration rate ≥ than 90 ml/min per 1.73 m2) and sperm without changes. routine collection of blood and semen the blood sample for analysis was collected from the arteriovenous fistula immediately before the first weekly hemodialysis session in the case group and on a previously scheduled day for the control group, always between 8:00 and 10:00 a.m. in the clinical laboratory of the same hospital to assay st, follicle stimulating hormone (fsh); luteinizing hormone (lh) and total testosterone (tt). on the same day of blood collection, the semen was collected by voluntary masturbation in an appropriate environment to perform spermiogram by manual method according to the guidelines of the world health organization (who) laboratory manual for the examination and processing of human semen 5th ed (1). the seminal plasma was prepared by centrifuging at 3500 × g for 20 min after 30 minutes liquefaction. the supernatant was collected into a new tube and held at -20 ° c for the measurement of st levels. st and hormones were measured by enzyme immunochemiluminescence using the immulite 2000/siemens automatic analyzer. specific kits were used for quantification, as well as calibrators and controls recommended by the manufacturer. fertility index (fi) fi was calculated according to harvey (2) as follows: fi = sperm concentration (x 106/ml) x sperm motility x percentage of spermatozoa with normal morphology. statistical analysis after the normal distribution curve of the sample was verified by normality tests (shapiro-wilk), for differences doi: 10.4081/aiua.2018.1.49 materials and methods recruitment, inclusion and exclusion a cross-sectional study was realized in the hemodialysis sector of the university hospital of the university of brasília, between july 2016 and december 2016, after approval by the research ethics committee of the faculty of health sciences of the university of brasília under number 53172316.9.0000.0030. inclusion criteria were: age between 18 to 60 years, has been in hemodialysis (hd) for more than 6 months (cases) and absence of acute or chronic liver disease. exclusion criteria were the presence of hemochromatosis or diseases of iron metabolism. silva_stesura seveso 27/03/18 09:27 pagina 49 archivio italiano di urologia e andrologia 2018; 90, 1 g. pereira silva, f. pirani carneiro, v. pereira xavier grangeiro 50 between two independent quantitative variables was used t-test and pearson correlation analysis. statistical significance was set at p < 0.05 to reject the null hypothesis. spss® for windows, version 24.0 was used. results all sample of patients were eugonadics (normal lh, fsh, tt). no difference for afe was observed between cases and controls (49.47 ± 5.56, 47.90 ± 6.2, p = 0.229), whereas significant differences between case and control means were observed for fi (p = 0.000), seminal parameters (sps) (p = 0.000) and st levels (40.12 ± 08.25 vs 73.32 ± 06.8, p = 0.000). st maintained correlation (table 2) with fi (r = 0.787 , p = 0.00) and sps (motility r = 0.857 and p = 0.000; vitality r = 0.551 and p = 0.000; density r = 0.850 and p = 0.000 and normal morphology r = 0.386 and p = 0.000) and without hormones corrections (p > 0,05). the positive relationships between st and sperm concentration and fertility index in group case can be explained by the linear regression model in up to 72.2% and 56.9%, respectively. discussion this study is of great importance because it is the first to verify the association between st levels and sp and fi in patients undergoing hd. the practicality and low cost of the st measurement can be attractive for the initial evaluation of semen quality in patients undergoing hd with suspected subfertility/infertility. st is an isoform of the human transferrin family that is found abundantly in human seminal plasma; it is produced and secreted (80%) by sertoli cells (3). it is sensitive to systemic and site inflammatory changes, and is involved in transport of iron ions in the systemic or site compartments (4). distribution of the mean values of the parameters evaluated in case and control groups can be observed in figure 1. the similar age (p = 0.229) and eugonadal status (p = 0.000) (table 1) of the studied individuals ensures greater reliability, and it lowers the impact on the analysis and interpretation of these variables. the male hormonal profile most commonly observed in patients in hd includes elevated serum levels of fsh, lh, and decreased levels of tt in response to the inhibitory action of one or more hypothalamic-pituitary-gonadal axis sites (5). these changes are promoted by factors such as uremia, oxidative stress (os) and pro-inflammatory cytokines present in hd (4). the hormones profile (table 1) in the case group in our study followed partially the pattern described above and found by other authors (6, 7) that is high levels of fsh and lh although tt levels were within the limits of normality (eugonadics). absence of clinical hypogonadism, in thesis, minimizes the effect of hormonal factor in the pathophysiology of the changes found in the st level and seminal parameter. in the present study there was no relationship (p > 0.05) between st levels and hormones (table 2) which is corroborated by studies of fuse (8) and ber (9). however, there are studies that show as tfs was inversely correlated with serum levels of lh, fsh and prolactin (10, 11). st levels found were significantly lower in the cases in relation to control in agreement with previous studies conducted by different researchers in non-uremic populations with suspected sub/infertility. kosar et al. (12) found values of 58.1± 14.4 μg/ml vs 108.4 ± 17.5 μg/ml (p < 0.0001); bharshankar and bharshankar (13) 2.63 ± 1.76 mg/dl vs 5.35 ± 2.07 mg/dl (p < 0.001) and saeed et al. (14) 54.0 μg/ml (50.0-60, 0) vs 74.0 μg/ml (69.080.0) (p < 0.01). the explanation of the decrease in mean st levels in unhealthy men in sub/infertility studies are not well known, but it is hypothesized that it is due to the action of interleukin-6 (il6) in testis to reduces transferrin secretion in sertoli cells (15). all sperm cell parameters evaluated (table 1) were significantly lower in the case group than in the control group (p = 0.000), corroborating partially the results of other authors (16, 17) that did not found significant differences for all the elements of the sp (16, 17). however there is a study that did not show a significant difference in st levels between healthy subjects and those with seminal quality alterations (18). there was a statistically significant correlation (table 2) between st and all eletable 1. comparative evaluation of age, semen and hormone parameters, fertility index and transferrin seminal levels among case and control groups (x ± sd). observed parameters case n (60) control n (30) p values age (y) 49,47 ± 5,56 47,90 ± 6,22 0,229 semen volume (ml) 01,33 ± 00,36 02,77 ± 0,44 0,000 total motility (pr + np %) 34,00 ± 06,24 71,31 ± 7,86 0,000 sperm vitability (%) 47,49 ± 07,31 64,41 ± 2,89 0,000 sperm density (x 106/ ml) 14,95 ± 06,18 50,21 ± 8,57 0,000 morphology sperm (%) 25,40 ± 07,87 59,76 ± 10,58 0,000 fsh (miu/ml) 06,30 ± 01,21 03,40 ± 00,48 0,000 lh (miu/ml) 15,91 ± 02,62 02,84 ± 00,54 0,000 testosterone (ng/ml) 04,11 ± 00,58 05,10 ± 00,92 0,000 prolactin (ng/ml) 16,38 ± 02,92 05,86 ± 01,93 0,000 fertility index 0, 85 (0,57) 5,54 (1,3) 0,000 seminal transferrin(ng/ml) 40,12 ± 08,25 73,32 ± 06,81 0,000 pr progressive motility; np non-progressive motility; fsh follicle-stimulating hormone; lh luteinizing hormone; at tests. table 2. correlational evaluation pearson’ between seminal transferrin and fertility index and seminal parameters in case group. observed parameters case n (60) r p fertility index 0,787 0,000 seminal sperm motility 0,857 0,000 transferrin sperm viability 0,551 0,000 versus sperm density 0,850 0,000 sperm morphology 0,386 0,002 silva_stesura seveso 27/03/18 09:27 pagina 50 ments of the sp (p < 0.05). however, these correlations were not linear in comparative studies with non-uremic population of other authors. bharshankar and bharshankar (13) found only a statistically significant correlation between st and percent of motile sperms (p < 0.05). fuse et al. (8) found only a statistically significant correlation between sperm concentration and st level (r = 0.56; p < 0.05). the fi is a general index to evaluate the semen quality, which was better than any single semen parameter (2). in the present study we found a fi significantly lower in the case group than in the control group (table 1) in according with the results of other authors in uremic populations as xu et al. (16) who found a value of 0.68 (2.08) vs 7.72 (13.51) (p < 0.05) and xu et al. (17) who reported a value of 0.23 (0.76) vs 13.02 (14.26) (p < 0.001). the positive relationship of st with sperm concentration and fertility index in the present study can explain up to 72.2% (r2) (p = 0.000) and 61.9% (r2) (p = 0.000) of the cases, respectively, by the simple linear regression model. this reinforces the hypothesis of its association with sps. the explanation for changes identified in spa and st level are multifactorial (19). but there is evidence of the importance of cytokines and other immune regulatory factors in 51archivio italiano di urologia e andrologia 2018; 90, 1 seminal transferrin and seminal quality figure 1. distribution of mean values of all parameters tested in the group and control group. fsh: follicle stimulating hormone; lh: luteinizing hormone. silva_stesura seveso 27/03/18 09:27 pagina 51 archivio italiano di urologia e andrologia 2018; 90, 1 g. pereira silva, f. pirani carneiro, v. pereira xavier grangeiro 52 the regulation of testicular function (steroidogenesis and spermatogenesis) during pathophysiological states as well as under normal physiological conditions (20). cytokines are interconnected with multiple factors, including steroid hormones, the redox system, and systemic or local inflammation (15). the hd patients are characterized by increased levels of oxidative stress and inflammation with the relationship between inflammation and oxidative stress leading to overproduction of reactive oxygen species (ros) (21). these factors are likely to represent an important component for the development of sp changes (21). it is postulated that hypercytokinemia generated in patient hd can profoundly affect vascular testicular permeability and to achieve interstitial compartment of the testis (22). this causes directly profound changes in the physiology of the blood-testis barrier (btb) and/or stimulate the testicular macrophages to produce differents pro and anti-inflammatory cytokines, promoting blockage of the paracrine/autocrine testicular regulation systems (22). in the male reproductive system there is a variety of cytokines in human seminal plasma, with differences in cytokine concentrations between fertile and infertile men and negative correlations between some cytokine levels and sp (22). the relationship between inflammation and oxidative stress is confirmed and both processes contribute with adverse effects on the structural and functional integrity of sperm, resulting in changes in the sperm function and in male infertility by protein, glycogen, lipid and dna peroxidation that can partially justify changes in the seminal parameters (15). proand anti-inflammatory cytokines and other inflammatory mediators are largely responsible for the changes observed in seminal plasma (23). il-6 is a multifunctional cytokine involved in many changes identified in the tubular and interstitial compartments testicular with reflection on the seminal quality (23). it has been suggested that it is a potent inhibitor of the seminiferous epithelium (23), modulating st production by sertoli cells (20) and inducing persistent testicular resistence to lh action and/or suppression of cell steroidogenesis in the leydig cells (24), on the other hand, il-6 has other important functions which play an important role in maintaining the function of sertoli cells, germ cells, regulating the dynamics of btb via delaying btb-constituent proteins degradation (22). overexpression of il-6 (systemic inflammation) could disrupt the integrity of the sertoli cell and btb, making foreign molecules to reach germ cells (22). alteration of the permeability of btb seems to be the most important event in the pathophysiology of changes in the semen of patients with seminal parameter changes (22). the cytokines produced by the complex systemic inflammation/oxidative stress, frequently observed in these patients might modulate the activity of the prooxidative and antioxidative systems (25). the oxidative stress is responsible for permanent peroxidative damage to spermatozoa by means of protein complexes called ion-responsive elements and ion regulatory proteins (eris/pris) (25). these proteins are responsible for the post-transcriptional regulation of proteins linked to uptake iron (transferrin receptor 1 -rtf1) and storage iron (ferritin) (25). when altered, they promote changes in intracellular iron ion levels and morpho-functional changes in seminal quality by toxic effect on germ cells (25). that breakdown of the intratesticular pro-and antiinflammatory cytokine balance promoted by different cytokines as the il-6 contributes significantly by changes in the permeability of btb to important alterations in autocrine/paracrine autoregulation mechanisms of interaction between surrounding germ cells, sertoli and leydig cells (26). the changes promoted by cytokines result in an immunopathological microenvironment that can change the testicular immune privilege and justify partially the changes in st levels and their association with seminal quality and fertility index in this group of patients. conclusion although the multifactoriality in etiology of sub/infertility, our results suggest that seminal quality is associated with st levels and what st can be used the initial investigation of subfertility/infertility of patients undergoing chronic hemodialysis with alteration in seminal quality. this study presents the limitations of the absence of supplementary measurement of total seminal antioxidant capacity and of the reduced sample. references 1. organization wh. who laboratory manual for the examination and processing of human semen. 2010. 2. harvey c. a fertility index derived from semen analysis. j clin pathol. 1953; 6:232-6. 3. franca lr, hess ra, dufour jm, et al. the sertoli cell: one hundred fifty years of beauty and plasticity. andrology. 2016; 4:189212. 4. akchurin om, kaskel f. update on inflammation in chronic kidney disease. blood purif. 2015; 39:84-92. 5. palmer bf, clegg dj. gonadal dysfunction in chronic kidney disease. rev endocr metab disord. 2017; 18:117-130. 6. zedan h, kamal ee, el shazly a, et al. impact of renal failure and haemodialysis on semen parameters and reproductive hormones. human andrology. 2013; 3:16-20. 7. lehtihet m, hylander b. semen quality in men with chronic kidney disease and its correlation with chronic kidney disease stages. andrologia. 2015; 47:1103-8. 8. fuse h, satomi s, okumura m, katayama t. seminal plasma transferrin concentration: relationship with seminal parameters and plasma hormone levels. urol int. 1992; 49:158-62. 9. ber a, vardinon n, yogev l, et al. transferrin in seminal plasma and in serum of men: its correlation with sperm quality and hormonal status. hum reprod. 1990; 5:294-7. 10. irisawa c, nakada t, kubota y, et al. transferrin concentration in seminal plasma with special reference to serum hormone levels in infertile men. arch androl. 1993; 30:13-21. 11. meeker jd, godfrey-bailey l, hauser r. relationships between serum hormone levels and semen quality among men from an infertility clinic. j androl. 2007; 28:397-406. silva_stesura seveso 27/03/18 09:27 pagina 52 12. kosar a, sarica k, ozdiler e. effect of varicocelectomy on seminal plasma transferrin values: a comparative clinical trial. andrologia. 2000; 32:19-22. 13. bharshankar rn, bharshankar jr. relationship of seminal plasma transferrin with seminal parameters in male infertility. indian j physiol pharmacol. 2000; 44:456-60. 14. saeed s, khan fa, rahman sb, et al. biochemical parameters in evaluation of oligospermia. j pak med assoc. 1994; 44:137-40. 15. fraczek m, kurpisz m. cytokines in the male reproductive tract and their role in infertility disorders. j reprod immunol. 2015; 108:98-104. 16. xu l, xu h, zhu x, et al. effect of uremia on semen quality and reproductive function in humans. cell biochem biophys. 2012; 62:29-33. 17. xu lg, xu hm, zhu xf, et al. examination of the semen quality of patients with uraemia and renal transplant recipients in comparison with a control group. andrologia. 2009; 41:235-40. 18. eneroth p, lizana j, bygdeman m. lactoferrin and transferrin levels in the seminal plasma of infertile men. protides of the biological fluids. 1984; 31:149-53. 19. coutton c, fissore ra, palermo gd, et al. male infertility: genetics, mechanism, and therapies. biomed res int. 2016; 2016:7372362. 20. guazzone va, jacobo p, theas ms, lustig l. cytokines and chemokines in testicular inflammation: a brief review. microsc res tech. 2009; 72:620-8. 21. tucker ps, scanlan at, dalbo vj. chronic kidney disease influences multiple systems: describing the relationship between oxidative stress, inflammation, kidney damage, and concomitant disease. oxid med cell longev. 2015; 2015:806358. 22. zhang h, yin y, wang g, et al. interleukin-6 disrupts bloodtestis barrier through inhibiting protein degradation or activating phosphorylated erk in sertoli cells. sci rep. 2014; 4:4260 23. salman dta-wd. evaluation the effect of interleukin-6 and tumor necrosis factor in semen quality of infertile men with varicocele. kufa journal for nursing sciences | ةلجم ةفوكلا مولعلل .6 ;2016 .ةيضيرمتلا 24. tremblay jj. molecular regulation of steroidogenesis in endocrine leydig cells. steroids. 2015; 103:3-10. 25. zhao s, zhu w, xue s, han d. testicular defense systems: immune privilege and innate immunity. cell mol immunol. 2014; 11:428-37. 26. fijak m, bhushan s, meinhardt a. the immune privilege of the testis. immune infertility: springer; 2017; p. 97-107. 53archivio italiano di urologia e andrologia 2018; 90, 1 seminal transferrin and seminal quality correspondence gilmar pereira silva (corresponding author) gilpsilva2006@gmail.com urologist physician phd, university of brasilia hotel sector north, block d, apartment 1716, fusion building, 70701040 brasilia, federal district, brazil fabiana pirani carneiro fabianapirani@hotmail.com professor phd, faculty of medicine of the university of brasília brasilia, federal district, brazil vitor pereira xavier grangeiro vitorpxavierg10@gmail.com academic of the faculty of medical sciences joão pessoa, paraiba, brazil silva_stesura seveso 27/03/18 09:27 pagina 53 stesura seveso 135archivio italiano di urologia e andrologia 2019; 91, 2 case report malignant solitary fibrous tumor of urinary bladder: a rare clinical entity zisis kratiras 1, 2, 3, vasileios spapis 1, efthymios koniaris 2, diomidis kozyrakis 3, konstantinos skriapas 4 1 department of urology, hippokratio general hospital of athens, athens, greece; 2 department of pathology, hippokratio general hospital of athens, athens, greece; 3 department of urology, general hospital of volos, volos, greece; 4 department of urology, general hospital of larisa, larisa, greece. solitary fibrous tumors (sfts) are mesenchymal tumors occurring in several sites. urinary bladder sfts are quite rare. eighteen cases are described in the literature and only two of them had malignant features. sfts comprise a histologic spectrum of mesenchymal neoplasms that show fibroblastic differentiation. the signs and symptoms are non specific. immunohistochemistry plays a pivotal role in the diagnosis, differentiating sfts from other spindle cell mesenchymal tumors. malignant criteria are considered the large size, increased mitotic activity, focal necrosis or hemorrhage, nuclear atypia, hypercellularity and infiltrative margins. clinical and biological behavior of bladder sfts is usually not aggressive but cannot be safely predicted based on the pathologic features. complete surgical resection is the cornerstone of treatment. we present the third bladder sft case with malignant features and a mini literature review. key words: solitary fibrous tumor; hemangiopericytoma; bladder tumors; mesenchymal tumors. submitted 17 february 2019; accepted 11 march 2019 summary no conflict of interest declared. lymph nodes or distant metastasis. patient was driven to theatre and an urgent transurethral resection was performed, revealing a solid looking bladder tumor occupying the bladder dome and part of the left lateral wall. the pathology revealed that the tumor was composed of ovoidto spindle-shaped cells with alternating hypercellular and hypocellular areas. they had a staghorn vascular pattern with a mixed variable with evidence of necrosis and hemorrhage. nuclear atypia was present with increased mitotic activity, focally up to 23/10 hpf, and a proliferation rate ki67 positive 30-35% (figure 1). immunohistochemistry revealed that the tumor was positive for vimentin, bcl-2, cd99 and cd34 and negative for actin, desmin, cd117 and ckae1/ae3. patient underwent a magnetic resonance imaging (mri) for local staging followed by an uneventful radical cystectomy and ileal conduit as diversion. the tumor was completely removed with clear surgical margins. he had a successful recovery doi: 10.4081/aiua.2019.2.135 introduction: in 1931 klemperer and rabin were the first to describe the solitary fibrous tumor (sft) as a mesothelial tumor arising from the pleura. since then numerous extrapleural sites of sft had been described (1). sfts originating from the urinary bladder are uncommon; only 18 cases have been described in the english literature. we report a case of a snt of the bladder with malignant features in a 31-year old male patient. case report a 31year old male patient self-presented to the accident and emergency department of our hospital reporting frank heamaturia, accompanied with dysuria, dull abdominal pain and blood clots. he denied any systemic symptoms and his clinical examination was unremarkable. from his past medical history, he was an ex-smoker but otherwise fit and healthy. his blood chemistry was in the normal range. a computed tomography (ct) that was performed revealed a 42 x 53 mm solid mass at the left lateral wall and the bladder dome without any evidence of figure 1. pathology revealed ovoidto spindle-shaped cells with a staghorn vascular pattern. archivio italiano di urologia e andrologia 2019; 91, 2 z. kratiras, v. spapis, e. koniaris, d. kozyrakis, k. skriapas 136 without any immediate post operative complication. he was discharged home at day 9 post op and he was reviewed in clinic after 3 months. his final pathology verified the initial diagnosis of snt of the bladder with malignant features. discussion solitary fibrous tumors comprise a histologic spectrum of rarely metastasizing mesenchymal neoplasms that show fibroblastic differentiation and can occur in any anatomical position. extrapleural sfts are usually diagnosed between the 5th and the 6th decade of life, having an equal distribution between races and sexes. they are normally slowly growing and symptoms arise due to local invasion of the tumor. the usual presenting symptoms are abdominal pain along with palpable abdominal mass. heamaturia and dysuria might also be the first symptoms of a bladder sft as in our case. symptomatic hypoglycemia might occur as paraneoplasmatic syndrome in a small subset of tumors (2). there is no diagnostic or treatment algorithm. imaging plays the most contemporary role in the diagnosis. certain, but not specific, imaging features have been described. ct usually reveals an enhancing heterogenous, well defined mass demonstrating the vascular nature of the tumor. areas of hemorrhage or necrosis might be present. mri usually reveals heterogenous and variable signals depending on the vascularity and the fibrous stroma of the neoplasm. macroscopically the tumor is usually a well circumscribed, tan colored mass that may be encapsulated by a thin and vascular pseudocapsule. it usually arises from the bladder submucosa although cases arising from bladder serosa have been described. microscopically it consists of hypocelullar and hypercellular areas consisting of ovoid and spindle-shaped cells (2, 3). staghorn configuration of blood vessels is common. immunohistochemistry plays a pivotal role in differentiating sfts from other spindle cell mesenchymal tumors. sfts are immunoreactive to vimentin, cd34, cd99 and bcl-2 and they are negative for actin, desmin (in smooth muscle tumors), keratin and cd117 (in gists) (2, 3). malignant criteria are considered the large size, increased mitotic activity (more than 4 mitosis in 10 high power fields), focal necrosis or hemorrhage, nuclear atypia, hypercellularity and infiltrative margins. clinical and biological behavior of bladder sfts is usually not aggressive but cannot be safely predicted based on the pathologic features. even benign tumors can act aggressively by invading structures at the proximity of the tumor or reoccurring, while malignant ones might have a less aggressive behavior without recurrence or metastasis (2, 3). complete surgical resection is the cornerstone of treatment. adjuvant radiotherapy is a useful asset for the local control of the disease, while adjuvant chemotherapy appears to have limited efficacy. chemoradiotherapy has been used for non-resectable tumors with variable success. high quality evidence is not available due to the rarity of the disease and the data are from only small case series. in our case the tumor was completely excised with radical cystectomy. unfortunately the patient returned to his homeland 5 months after the operation and longer follow is not available. conclusions bladder sfts are extremely rare mesenchymal neoplasms, usually arising from the bladder submucosa. although they usually have benign features, their clinical behavior cannot be safely predicted. signs and symptoms are non specific, while radiology findings are indictive of an enhancing bladder lesion. immunohistochemistry is pivotal for the diagnosis of sfts. although the literature is sparse and the level of evidence is low, radical surgical excision is the mainstay of treatment. references 1. cheng sh, wang ss, lee ch, et al. malignant solitary fibrous tumor of the urinary bladder. j chin med assoc. 2012; 75:479-82. 2. varaldo m, ferrarazzo c, tunesi g, et al. solitary fibrous tumor. solitary fibrous tumor. rare tumors. 2010; 2:e64. 3. spairani c, squillaci s, pitino a, et al. a case of concomitant occurrence of solitary fibrous tumor and urothelial high-grade invasive carcinoma of the urinary bladder. int j surg path. 2014; 22:252-9. correspondence zisis kratiras, md (corresponding author) zkratiras@gmail.com diomidis kozyrakis, md dkozirakis@yahoo.gr department of urology, general hospital of volos dimokratias 126, 37300 volos (greece) vasileios spapis, md vspapis@hotmail.com department of urology, hippokratio general hospital of athens, athens (greece) efthymios koniaris, md ethimiok@hotmail.com department of pathology, hippokratio general hospital of athens, athens (greece) konstantinos skriapas, md kostas.skriapas@hotmail.com department of urology, general hospital of larisa, larisa (greece) 223archivio italiano di urologia e andrologia 2016; 88, 3 original paper may ultrasound probe size influence pain perception of needle piercing during transrectal prostate biopsy? a prospective evaluation andrea fabiani 1, lucilla servi 1, alessandra filosa 2, fabrizio fioretti 1, valentina maurelli 1, flavia tombolini 3, matteo tallè 3, gabriele mammana 1 1 surgery department, section of urology, asur marche area vasta 3, macerata hospital, macerata, italy; 2 section of pathological anatomy, department of clinical pathology, asur marche area vasta 3, macerata hospital, macerata, italy; 3 urologic clinic, polytechnic university of marche region, italy. introduction and objective: transrectal ultrasound guided prostate biopsy (trus-bx) is the definitive step in the diagnosis of prostate cancer (cap). patients (pts) generally experience significant pain during the procedure at the point that biopsy should be accompanied by some form of anesthesia. several different factors influence pain perception (pp) during trus-bx. in our study we want to assess that the use of an ergonomic smaller sized probe reduces pp during the procedure independently from the administration of local anesthesia or pain relieving drugs. materials and methods: this was a prospective, randomized study in which 114 pts who underwent trus-bx due to abnormal psa and/or to digital rectal examination (dre) suspicious findings were considered eligible. pts were split in two trus-bx groups into which we used two different sized ultrasound probes. in group 1, 61 pts underwent trus-bx with aloka end fire probe (size 74 mm). in group 2, 53 pts underwent trus-bx with b-k type 8818 probe (size 58 mm). both groups were treated with no local anesthesia or pain relieving drugs. pain was evaluated three times using a 10-point visual analogue scale (vas), during the dre (vas 1), during the insertion of the probe (vas 2) and during the needle piercing (vas 3). results: mean age of pts was 68.03 (sd 8.51); mean tpsa and mean prostate volume was 7.75 (sd 4.83) and 45.17cc (sd 17.7), respectively. the two groups were homogeneous respect to tpsa (p = 0.675) and to prostate volume (p = 0.296); age was significantly different (p = 0.04) between group 1 (65.93) and group 2 (70.43), whereas no statistically significant correlation between vas 3 and age was observed (p = 0.179). analyzing pain perception, we found no statistically significant difference between the two groups in dre (vas 1; p = 0.839); on the contrary, patients in group 1 experienced on average more pain than other in group 2 both during the insertion of the probe (vas 2 3.49 vs 1.09; p < 0.001) and during the needle piercing vas 3 (2.8 vs 2.00; p < 0.05). the discomfort during probe insertion and manipulation was perceived as very high (vas 2 > 5) in 42.6% of patients in group 1 and in 9.4% in group 2. globally, the procedure was well tolerated (mean vas score < 3) in 77% of patients in group 1 and in 90% in group 2. the proportion of patients who experienced more than moderate pain (vas > 5) during needle piercing ranged 24.6 % in group 1 to 18.9 % in group 2. summary no conflict of interest declared. introduction prostate biopsy is one of the most common procedures performed in the urologist’s office today. despite developments in the field of prostate imaging recently reached, it is still considered the standard procedure for diagnosing prostate cancer (1-2). during the years, the minimization of the sampling error has been the goal of urologic community. however, the increase in the number and location of cores, if on the one hand it led to an improvement of prostate cancer detection rate, on the other led to an increase of patient discomfort. patients may generally experience a significant pain during the procedure at the point that biopsy should be accompanied by some form of anesthesia (3). conversely, improvements in anesthesia techniques have allowed physicians to sample with a great number of cores and at different locations in the gland, achieving patient compliance and, finally, being able to perform the procedure in an office setting. however, despite these considerations, the use of anesthesia is still under debate because of doubt of its real benefits and the associated costs (4). two factors are usually responsible for pain during transrectal prostate biopsy: anal pain due to ultrasound probe, that causes pressure and stretching of muscle fibers, and pain at insertion of the needle through the prostate (5). are these factors related? may ultrasound probe geometry influence pain perception of needle piercing during transrectal prostate biopsy? to contribute in the answers of these questions, we present a prospective randomized doi: 10.4081/aiua.2016.3.223 conclusions: patients who underwent a trus-bx with the 58-mm circumference probe were found to experience lower degree of pain not only during the insertion of the probe through the anal sphincter, but also in the moment of needle piercing. key words: transrectal ultrasound; prostate biopsy; end fire probe; pain; size. submitted 1 november 2015; accepted 4 december 2015 fabiani_stesura seveso 21/09/16 09:02 pagina 223 archivio italiano di urologia e andrologia 2016; 88, 3 a. fabiani, l. servi, a. filosa, f. fioretti, v. maurelli, f. tombolini, m. tallè, g. mammana 224 evaluation assessing the role of the use of an ergonomic smaller sized probe on reducing pain perception during ultrasound guided prostate biopsy, independently from the administration of local anesthesia or pain relieving drugs. material and methods in this prospective randomized study, 114 patients underwent trus guided prostate biopsy. they had no history of previous prostate biopsy, chronic prostatic pain or pelvic pain syndrome, anal surgery, concomitant analgesic medication or any other medical condition that could potentially interfere with pain assessment. indications to prostate biopsy were an abnormal psa and/or a suspicious findings on digital rectal examination (dre). patients was randomized into two groups in which we used two different sized ultrasound probes. in group 1 (n = 61) patients underwent trus biopsy using an aloka machine with a 5-12 mhz multi-frequency convex probe “end-fire” sized 74 mm. in group 2 (n = 53) patients underwent trus biopsy with bk medical machine equipped with an end fire probe (type 8818) sized 58 mm. as explained to any patient in informed consensus, both groups were treated with no local anesthesia or pain relieving drugs. only an aqueous gel was used to perform dre and probe insertion. the procedures were performed by the same operator on the patients in the left lateral decubitus (“sims position”) after emptying of the bladder, according to believed that the state of bladder repletion may be an element of discomfort during the prostate mapping biopsy performance (6). antibiotic prophylaxis was given to the patients (oral fluoroquinolone 1-2 h before the procedure and three days after). twelve random cores biopsies were obtained, 6 from each lobe of the prostate gland, according to gore scheme (7). after transrectal ultrasound performance, conducted assessing the prostatic diameter, the volume of the whole prostate, the transition zone, capsular and seminal vesicle characteristics, as well as morphological description of potential pathological features (8), sampling was carried out with a 18-gauge tru-cut needle powered by an automatic spring-loaded biopsy disposable gun. pain was evaluated after procedure asking the patient to sign in a 10-point visual analogue scale (vas) the pain degree felt during each phase of procedure. in vas scale, number 0 represented absence of pain and number 10 the maximum pain perceived in life. the vas evaluation was differentiated in three scales considering the pain perceived during the dre (vas 1), during the insertion of the probe and the movements associated (vas 2), and during the needle piercing (vas 3). additionally, we determined the relationship between the level of pain, prostate volume, age and psa. statistical evaluation was performed student test t by med calc system. p value less than 0.05 was considered statistically significant. results the study groups were comparable in psa and prostate size. age was significantly high in group 2. (table 1). the mean pain scores in group 1 during dre (vas1), probe insertion and ultrasound procedure (vas2) and during biopsy (vas3) were 0.42 ± 0.66, 3.49 ± 3.17 and 2.8 ± 2.22 respectively. the same mean pain scores in group 2 were 0.45 ± 0.72, 1.09 ± 1.68 and 2 ± 2.03 respectively (table 2). while age had shown a significant difference (p = 0.04) between group 1 (65.93) and group 2 (70.43), no statistically significant correlation patients characteristics total (n = 114) group 1 (n = 61) group 2 (n = 53) p-value mean age (yr) 68.03 ± 8.51 (range 50-85) 65.93 ± 7.54 (range 51-81) 70.43 ± 8.98 (range 50-85) 0.04 mean prostate size (ml) 45.17 ± 17.70 (range 20-120) 46.79 ± 19.86 (range 20-120) 43.30 ± 14.79 (range 20-78 ml) 0.296 mean psa (ng/ml) 7.75 ± 4.83 (range 0.66-31) 7.93 ± 4.69 (range 0.66-24.81) 7.55 ± 5.03 (range 0.82-31) 0.675 table 1. patients characteristics. group 1 group 2 p value mean pain score during edr (vas 1) 0.42 ± 0.66 0.45 ± 0.72 0.839 mean pain score during probe manipulation (vas 2) 3.49 ± 3.17 1.09 ± 1.68 0.001 mean pain score during biopsy (vas 3) 2.8 ± 2.22 2.0 ± 2.03 0.05 table 2. results for mean pain scores. figure 1. correlation between patient age and pain perceived during probe insertion. legend. vassonda: visual analogue pain score in probe manipulation; etàtot: total age. fabiani_stesura seveso 21/09/16 09:02 pagina 224 between vas 3 and age was observed (p = 0.179) (figures 1-3). globally, the procedure was well tolerated (mean vas score < 3) in 77% of patients in group 1 and in 90% in group 2. probe insertion or manipulation during the procedures (vas2) were felt by patients as more than a moderate pain (vas > 5) in 42.6% in group 1 and 9.4% in group 2. the pain perception during needle piercing (vas 3) was high (vas > 5) for 15 patients in group 1 (24.6%) and 10 patients in group 2 (18.9%). there were only minor complications and were managed on an outpatient basis without admission. both groups were comparable in terms of complications. there was no significant difference in the cancer detection rate (65.6% in group 1; 66% in group 2). discussion it is the experience of every urologist that most patients experience moderate to severe pain during the prostate biopsy procedure (9) and their discomfort appears to be proportional to the number of cores taken (10-11). there is now a strong evidence in the current literature that anesthesia and/or analgesia improves patient tolerance and comfort (5). therefore, it is suggested that all urologists should introduce it in clinical practice as a routine part of the procedure whatever the patient characteristics and biopsy scheme (12-13). of the various methods of peri-prostatic nerve block alone or associated with lidocaine gel has been shown to be safe, easy to perform and highly effective. with limitations, it can be considered the gold standard at the moment even if the optimal technique remains to be established (14-15). however, several different factors contribute to discomfort and pain during ultrasound guided transrectal biopsy. omitting the psychological patients stress attributable to fear of the potential diagnosis of cancer, to the anal route of penetration and to the fact that the examined organ is part of the male sexual system, it is recognized that the introduction and movement of trus probe into the rectum, the geometry of the ultrasound probe itself, the needle piercing through the rectal wall, the needle passage through the prostate capsule and the number of biopsy cores taken are the most determinant etiologic factors of pain during the procedure (5). as suggested by giannarini et al. (16) the variability of perceived discomfort might be related to differences in anorectal compliance. they suggested the possibility of omitting anesthesia in those patients with high anorectal compliance. others (2) have stated that pressing the probe against the rectum might minimize the discomfort of the biopsy needle traversing the rectal mucosa. we think that anorectal tone is the most determinant factor of perceived pain during ultrasound guided transrectal prostate biopsy. similarly to what happened with the transition from rigid to flexible cystoscopy, the use of an ergonomic probe may greatly may reduce the patient discomfort during the procedure. as suggested by moussa et al. (17) it must be focalized into the role of transrectal probe configuration, the probe design and needle guide in determining pain during the ultrasound guided prostate biopsies. they analysed prospective data on 1114 patients undergoing the procedure in a three years period. from results derived from analysis of patient’s responses of a 10-point visual analogue pain scale related to the consecutive steps of prostate biopsy (probe insertion, application of periprostatic nerve block and the obtaining of prostate biopsies cores), they concluded that probe configuration may affect pain during each step of trus-guided prostate biopsy. rochester et al. (18), in his double-blind randomized controlled trial of topical glyceryl trinitrate use during ultrasound guided transrectal prostate biopsy, concluded that although decreasing anal sphincter tone is effective for decreasing pain associated with biopsy, its role may be in combination with local anesthetic infiltration, which together address two different aspects of pain associated with biopsy. in the other hand, the use of anesthesia in performing prostate biopsy is still under debate because of doubt of its real benefits and the associated costs (4). moreover, periprostatic 225archivio italiano di urologia e andrologia 2016; 88, 3 may ultrasound probe size influence pain perception of needle piercing during transrectal prostate biopsy? a prospective evaluation figure 2. correlation between patient age and pain perceived during needle piercing. legend. vasprelievo: visual analogue pain score during biopsy; etàtot: total age. figure 3. correlation beetween patient age and pain perceived during digital rectal examination. legend. vasedr; visual analogue pain score during digital rectal examination; etàtot: total age. fabiani_stesura seveso 21/09/16 09:02 pagina 225 archivio italiano di urologia e andrologia 2016; 88, 3 a. fabiani, l. servi, a. filosa, f. fioretti, v. maurelli, f. tombolini, m. tallè, g. mammana 226 nerve block causes a lengthening of the procedure and requires the patient to undergo additional injections. these considerations led us to the idea to investigate if the reduction of the mechanical stretching of sensory fibers innervating the part of the anal canal distal to the dentate line using an ergonomic probe might cause a discomfort reduction to the patient not only during the introduction of the probe itself but also in pain perception of needle piercing. few studies have accessed the influence of size probe on pain perception during trus guided prostate biopsy. koprulu et al. (19) asserted that under adequate local anesthesia there is no difference in pain perception between a larger or a smaller probe. they evaluated one hundred and seventy patients who underwent trus guided biopsies, divided into three trus biopsies groups. group i (60 pts) underwent trus biopsy with newer bk type 8808 probe (circumference 58 mm) under injectable periprostatic anesthesia, group ii (60 pts) underwent trus biopsy with bk type 8551 probe (circumference 74 mm) under injectable periprostatic anesthesia, and group iii (50 pts) underwent trus biopsy with bk type 8551 probe (circumference 74 mm) without local anesthesia. peri-prostatic injection anesthesia was performed with 10 cc, 1% lidocaine (5 cc on each side) 10 min before procedure. pain was assessed using a 10-point modified visual analog scale (vas) 15 min after the biopsy procedure. most of the patients experienced no pain to slight pain in groups i and ii, but 66% of the patients had more than moderate pain (vas ≥ 5) in group iii with mean vas score statistically higher than the other two groups (group i vs. iii, p = 0.0001; group ii vs. iii, p = 0.0001). mean vas score was not statistically different between group i and ii (p = 0.126). no statistically significant difference in vas pain perception was observed between different age categories within the group i, ii, and iii. authors concluded that in the absence of injectable local anesthesia, larger probe (74 mm) results in much higher vas pain perception than same size and smaller (58 mm) probe used under injectable local anesthesia. however, under injectable local anesthesia, the size of the transrectal probe (58 mm vs. 74 mm) does not result in any different pain perception during trus biopsy. in our part, we investigated how the ergonomic smaller sized probe can reduce pain perception, making the procedure more comfortable and well tolerated by the patients, without performing any form of anesthesia. we built the randomization of the study in order to eliminate some possible confounders. the patients in both group underwent the same number of needle piercing (twelve) avoiding to perform a periprostatic nerve block. the pain perceived was the result of digital rectal examination (during which the same operator provide to insert a lubricant gel), the probe insertion and/or movements and the prostatic tissue biopsy. the two groups were similar in terms of clinical data (psa, prostate volume, dre). we noted a difference in terms of age. group 2 (smaller sized probe) was characterized by an older age than group 1. some literature data demonstrated age > 65 years as “a natural anesthetic” in pain perception during the transrectal ultrasound-guided prostate biopsy procedure (20). in our data, mean age was > 65 years in both group and statistical analysis revealed no significant correlation between vas 3 (pain perceived during needle piercing) and age (p = 0.179) (figure 3). the only significant different variable between the two groups was the size of the probe used. as we expected, using a 58 mm probe instead of 74 mm reduced very significantly pain perception during the insertion of the probe (vas 2). moreover pain perception is reduced not only during the insertion of the probe, but also during needle piercing biopsy (vas 3), always significantly. in effect, there are several data in scientific literature supporting the evidence that probe insertion is more painful than prostatic biopsy performed under peri-prostatic nerve block. for example, philip et al. (21), evaluating in a prospective manner the efficacy of bi-apical vs bibasal periprostatic nerve block during 12 core ultrasound guided prostate biopsy, found that patients who experienced greater pain with the introduction of the probe also reported more pain with the biopsy procedure. these data may suggest that most of the pain the patients experienced during trus guided prostate biopsy is not just related to the piercing itself, but the insertion of the probe has some key role on overall pain, probably due to the tone of anal sphincter. if the only ergonomic geometry of the probe in a compliant anus reduces also the perceived pain during cores sampling, then it is not so necessary a peri-prostatic nerve block but a maneuver that locally augment anal compliance with the opportunity to select the cases in which is necessary a form of analgesia, just during anal tone assessment with digito-rectal examination as suggested by onur et al. (22). we need further studies to evaluate that. conclusion performing a trus guided prostate biopsy with the 58mm circumference probe patients were found to experience lower degreesof pain not only during the insertion of the probe trough the anal sphincter, but also at the moment of needle piercing. ultrasound probe geometry may influence pain perception during the prostate biopsy procedure and may be determinant in selecting patients in which it is needed some form of analgesia. authors’ contributions all authors participated in the design and conduct of the study. all authors reviewed and approved the final version of the manuscript. references 1. barentsz jo, richenberg j, clements r, et al. esur prostate mr guidelines 2012. eur radiol. 2012; 22:746-757. 2. ramey cr, halpern ej, gomella lj. ultrasonography and biopsy of the prostate: prostate biopsy techniques and outcomes; in wein aj, kavoussi lr, novick ac, partin aw, peters ca (eds): campbellwalsh urology, ed 9. philadelphia, saunders. 2007, pp 2887-2892. 3. luscombe cj, cooke pw. pain during prostate biopsy. lancet. 2004; 363:1840-1841. 4. shinohara k, master va, chi t, et al. prostate needle biopsy techniques and interpretation; in vogelzang nj, scardino pt, shipley fabiani_stesura seveso 21/09/16 09:02 pagina 226 wu (eds): genitourinary oncology. philadelphia,lippincott, williams & wilkins, 2006, pp 111-119. 5. maccagnano c, scattoni v, roscigno m, et al. anaesthesia in transrectal prostate biopsy: which is the most effective technique. urol int. 2011; 87:1-13. 6. dell’atti l. lidocaine spray administration in transrectal ultrasound guided prostate biopsy: five years of experience. arch ital urol androl. 2014; 86:340-3. 7. gore jl, shariat sf, miles . et al. optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. j urol. 2001; 165:1554-9. 8. martino p, galosi ab, bitelli m, et al. imaging working groupsocieta italiana urologia (siu); società italiana ecografia urologica andrologica nefrologica (sieun). practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. 9. irani j, fournier f, bon d, et al. patient tolerance of transrectal ultrasound-guided biopsy of the prostate . br j urol. 1997; 79:608-10. 10. lee-elliott ce, dundas d, patel u. randomized trial of lidocaine vs lidocaine/bupivacaine periprostatic injection on longitudinal pain scores after prostate biopsy. j . 2004; 171:247. 11. rabets jc, jones js, patel ar et al. bupivacaine provides rapid, effective periprostatic anaesthesia for transrectal prostate biopsy. bju int. 2004, 93:1216. 12. damiano r, cantiello f, sacco, et al. randomized placebocontrolled study of periprostatic local anaesthesic for transrectal ultrasound guided prostate biopsy. arch ital urol androl. 2004; 76:163. 13. kaver i, mabjeesh nj, matzkin h. randomized prospective study of periprostatic localanesthesia during transrectal ultrasoundguided prostate biopsy. urology. 2002; 59:405-8. 14. rodriguez a, kyriakou g, leray e, et al. prospective study comparing two methods of anaesthesia for prostate biopsies: apex periprostatic nerve block versus intrarectal lidocaine gel: review of the literature. eur urol. 2003; 44:195-200. 15. kumar a, griwan ms, singh sk, et al. is periprostatic nerve block a gold standard in case of transrectal ultrasound-guided prostate biopsy? urol ann. 2013; 5:152-6. 16. giannarini g, autorino r, valent f. et al. combination of perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block for pain control during transrectal ultrasound guided prostate biopsy: a randomized, controlled trial. j urol. 2009; 181:585-91. 17. moussa as, el-shafei a, diaz e, et al. identification of the variables associated with pain during transrectal ultrasonography-guided prostate biopsy in the era of periprostatic nerve block: the role of transrectal probe configuration. bju int. 2013; 111:1281-6. 18. rochester ma, karena m, brewster sf. a double-blind, randomized, controlled trial of topical glyceryl trinitrate for transrectal ultrasound guided prostate biopsy. j urol. 2005; 173:418-420. 19. koprulu s, cevik i, unlu n, et al. size of the transrectal ultrasound probe makes no difference in pain perception during trus-bx under adequate local anesthesia. int urol nephrol. 2011; 44:29-33. 20. dell’atti l, borea pa, russo gr. age: “a natural” in pain perception during the transrectal ultrasound-guided prostate biopsy procedure. urologia. 2011; 78:257-61. 21. philip j, mccabe je, dutta roy s, et al. site of local anaesthesia in transrectal ultrasonography-guided 12–core prostate biopsy: does it make a difference? bju int. 2006; 97:263-5. 22. onur k, gurdal i, metin t, et al. can pain during digital rectal examination help us to decide the necessity and the method of anesthesia for transrectal ultrasound guided prostate needle biopsy? international braz j urol. 2007; 33:470-476. 227archivio italiano di urologia e andrologia 2016; 88, 3 may ultrasound probe size influence pain perception of needle piercing during transrectal prostate biopsy? a prospective evaluation correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it lucilla servi, md lucilla.servi@sanita.marche.it fabrizio fioretti, md phd fa.fioretti@libero.it valentina maurelli, md valentinamaurelli@hotmail.it gabriele mammana, md gabriele.mammana@sanita.marche.it surgery dpt., section of urology asur marche area vasta 3 macerata hospital, macerata, italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, macerata, italy flavia tombolini, md, urology resident flavia.tombolini@gmail.com matteo tallè, md, urology resident matteo.talle@gmail.com urologic clinic, polytechnic university of marche region fabiani_stesura seveso 21/09/16 09:02 pagina 227 93archivio italiano di urologia e andrologia 2017; 89, 2 original paper comparison of robotic and laparoscopic partial nephrectomy for small renal tumours abdulmuttalip simsek, abdullah hizir yavuzsan, yunus colakoglu, arda atar, selcuk sahin, volkan tugcu bakirkoy sadi konuk research and training hospital, department of urology, istanbul, turkey. objective: to evaluate a single surgeon oncological and functional outcomes of laparoscopic partial nephrectomy (lpn) compared to robotic partial nephrectomy (rpn) for pt1a renal tumours. materials and methods: between 2006 and 2016, a retrospective review of 42 patients who underwent lpn (n = 20) or rpn (n = 22) by same surgeon was performed. patients were matched for gender, age, body mass index (bmi), american society of anaesthesiologists (asa) score, tumour side, renal and padua scores, peri-operative and post-operative outcomes. results: there was no significant differences between the two groups with respect to patient gender, age, bmi, asa score, tumours side, renal and padua scores. mean operative time for rpn was 176 vs. 227 minutes for lpn (p = 0.001). warm ischemia time was similar in both groups (p = 0.58). estimated blood loss (ebl) was higher in the lpn. there was no significant difference with preoperative and postoperative creatinine and percent change in egfr levels. only one case in lpn had positive surgical margin. conclusions: rpn is a developing procedure, and technically feasible and safe for small-size renal tumours. moreover rpn is a comparable and alternative operation to lpn, providing equivalent oncological and functional outcomes, as well as saving more healthy marginal tissue and easier and faster suturing. key words: partial nephrectomy; robotic; laparoscopic; small renal tumour. submitted 18 march 2017; accepted 23 april 2017 summary no conflict of interest declared. tion of renal function that can have long term association with patients overall health (3). the laparoscopic approach has been performed since 1993, showing to provide functional and oncologic outcomes equivalent to those of open surgery and affording the patients a shorter hospital stay and more rapid recovery time (4, 5). however, the laparoscopic technique remains difficult for the average urologist, because of the technical challenge of intracorporeal suturing. therefore, complex laparoscopic partial nephrectomy is only limited to experienced surgeons at high volume centres (6). the introduction of robotic technology allows for complex procedures to be performed more easily by most of surgeons without experience than the conventional laparoscopic approach. this technology has revolutionized the surgical management of prostate cancer, then has been successfully utilized for pyeloplasty, radical and partial nephrectomy (7-9). robotic surgery has some technical advantages such as magnified visualization, 3dimensional visualization, fully articulating instruments under precise control, absence of the fulcrum effect, and elimination of tremors. these details decrease the technical difficulty associated with critical portion of partial nephrectomy including tumour dissection and pelvicalyceal renal reconstructions. in the present study we aimed to retrospectively compare a single surgeon experience with laparoscopic and robotic partial nephrectomy for suspected rcc. we evaluated intraoperative and postoperative parameters to compare the two methods. materials and methods clinical data of patients who underwent robotic assisted laparoscopic partial nephrectomy (rpn) or laparoscopic partial nephrectomy (lpn) by a single surgeon between 2006 and 2016 at bakirkoy dr. sadi konuk training and research hospital were obtained from medical record system. we reviewed data of 60 patients who underwent robotic or laparoscopic partial nephrectomy. inclusion criteria were a single renal mass ≤ 4 cm and follow up for ≥ 3 months after surgery. of the 60 patients, 17 cases were excluded from the study because of > 4 cm tumour, zero ischemia tumour excision, conversion to open surgery, metastatic disease, a solitary kidney, multiple tumours, or doi: 10.4081/aiua.2017.2.93 introduction renal cell carcinoma (rcc) is one of the common cancer and represents 2-3% of all cancers (1), with the highest incidence in western countries. there is a male predominance with a peak incidence between 60-70 years. aetiology factors include smoking, obesity, hypertension, acetaminophen, and viral hepatitis (2). using new diagnostic tools the tumour size has decreased throughout the years and open partial nephrectomy has become an efficacious alternative to radical nephrectomy for small rcc. partial nephrectomy, in patients who have a solitary kidney, bilateral rcc, genetic disease with rcc, and small sized tumour with a normal function contra lateral kidney, has an important advantage for preservasimsek_stesura seveso 20/06/17 08:58 pagina 93 archivio italiano di urologia e andrologia 2017; 89, 2 a. simsek, a. hizir yavuzsan, y. colakoglu, a. atar, s. sahin, v. tugcu 94 loss to follow up. retrospective analysis was performed for 42 patients, of which 22 (52.3%) and 20 (47.7%) underwent rpn and lpn, respectively. we reviewed medical data's for patient age, sex, body mass index, consumption of tobacco, previous surgical history, american society of anaesthesia physical status score (asa score), charlson comorbidity index, tumor laterality, preoperative and postoperative 3th month serum creatinine level. renal nephrometry score (10) and padua score (11) were calculated by preoperative contrast-enhanced computed tomography. operation time, warm ischemic time (wit) and estimated blood loss (ebl) were evaluated. estimated glomerular filtration rate (egfr) was calculated to evaluate renal function preoperatively and at 3th month after the surgery (mdrd-gfr) (12). perioperative and postoperative complications were assessed using the clavien-dindo classification (13). surgical technique for all cases, the patient is placed in flank position. for robotic procedures, a 4-arm approach was used, and the da vinci s hd and the da vinci xi systems (intuitive surgical, sunnyvale, ca) were used. for the da vinci s hd system we used the same technique that has been previously described (14). after starting to use the da vinci xi system we have changed the port placement because of lesser clashing of the robotic arms. all four robotic trocars were inserted through the midaxillary line. assistant port was located medially near the umbilicus. for laparoscopic procedures traditional laparoscopic port configuration for renal surgery was used. after starting the operation, the renal hilum was dissected and the tumour was identified. renal arteries were clamped with laparoscopic bulldog clamps. in the robotic cases the assistant surgeon replaced the bulldog clamps. then tumour was excised by cold scissors. the tumour bed was continuously sutured by 3-0 selfretaining absorbable barbed suture. parenchymal defect was sutured by 1-0 vicryl suture with hemolock clips attached (15). a silicone drain was replaced and the operation was finished. statistical analysis was performed using spss software programme. date are expressed as the mean ± standard deviation or as a percentage of baseline, chi-square and independentsample t-test were used and a p value of < 0.05 was considered to indicate statistically significance. results a total of 42 patients (20 robotic, 22 laparoscopic partial nephrectomy) participated in the study. the mean follow-up of the robotic and laparoscopic groups were 35.4 ± 7.3 and 49.1 ± 12.6 months, respectively. the patient’s demographic characteristics are summarized in table 1. there were not any statistically significant differences in the baseline characteristics among the groups regarding age, body mass index (bmi), cci, asa class, tumour size, renal, and padua scores. table 2 presents the perioperative features and change in serum creatinine levels and egfr of the two groups. patients in the robotic group had shorter operative time in comparison to laparoscopic groups (176 vs. 227.5, p < 0.01). subjects in the lpn group had greater ebl (182.5 vs. 218.8, p < 0.05) and shorter hospital stay (4.4 vs. 6.1, p < 0.05) compared to the robotic approach. we did not detect any statistical significant differences between the groups including postoperative hb, transfusion rates, days of drain preservation, egfr changes, percent of patients with clavien-dindo complications and mortality rates (figure 1). there was only one major complication in lpn group. this patient had urinary leakage at the first day of the operation. table 1. pre-operative patients data. lpn rpn p value patients (n) 20 22 male 15 12 0.20 female 5 10 mean age (y) 50.2 ± 11.3 54.8 ± 9.6 0.16 mean bmi (kg/m2) 27.7 ± 3.5 27.3 ± 4.9 0.76 cci 2.3 ± 0.8 2 ± 0.4 0.12 asa score 1.9 ± 0.4 1.9 ± 0.7 0.99 smokers (n) 14 16 surgical history (n) 8 6 side (n) left 6 9 0.53 right 14 13 mean renal score 5.2 ± 1.4 4.6 ± 1.2 0.14 mean padua score 6.4 ± 2.1 6.2 ± 1.6 0.72 bmi: body mass index; cci: charlson comorbidity index; asa score: american society of anesthesia physical status score. table 2. peri-operative and post-operative outcomes. rpn lpn p value operation time, min 176 ± 23.6 227.5 ± 56.3 0.001 wit, min 16.2 ± 6.7 17.6 ± 9.4 0.58 ebl, cc 182.5 ± 50.4 218.8 ± 60.7 0.04 hospital stay (days) 6.1 ± 2.4 4.4 ± 1.9 0.01 positive surgical margin 0 1 transfusion 0 1 serum creatinine, mg/dl preoperative 0.81 ± 0.12 0.85 ± 0.19 0.42 postoperative 3th month 0.95 ± 0.35 0.97 ± 0.24 0.82 egfr preoperative 104.65 ± 28.6 89.2 ± 24.5 0.06 postoperative 3th month 85 ± 19.3 75.2 ± 14.5 0.06 figure 1. postoperative complication cdc grade i-ii. simsek_stesura seveso 20/06/17 08:58 pagina 94 at first the patient followed conservatively then ureteral stent was replaced because of the continuation of urinary leakage. discussion the number of renal cell carcinoma that are diagnosed each year is increasing owing to development and increased use of new imaging modalities. at the same time the number of small rcc cases has also risen. following recent development of surgical instruments and techniques, partial nephrectomy has become the method of choice for the management of t1 renal masses. nephron sparing surgery has many advantages for preservation of renal function and overall survival in cases of t1a cases (16). laparoscopic partial nephrectomy (lpn) offers a shorter convalescence, reduced need for analgesia, and comparable outcomes to open partial nephrectomy in the expert surgeons (17). on the other hand, lpn can be particularly challenging for complex tumours, such as endophytic, and hilar masses. for these cases tumour resection and repairing the defect under the time constraints of warm ischemia is difficult (7). rpn is a viable alternative of more technical challenging lpn, since the da vinci robot system has advantages such as the seven degree of freedom, high definition imaging, easily movement, stable motion for tremor, resection and suturing can be performed easier and faster (18). disadvantages of robotic surgery are lack of tactile feedback, high cost, and time consumed for the setting up the robot (19). moreover, the surgeon is unscrubbed in the operation console and thus could not proceed to the operating table immediately in an emergent situation (20). lpn or rpn has the following three main goals: oncologic control, preservation of renal function and a low morbidity. in 2012, buffi et al. proposed a simple classification system to identify patients with the optimal outcomes after pn procedures. they combined the three main goals of pn into the margin, ischemia and complication system. the background of the this system was as follows: (1) the margin is a surrogate for determining whether the primary tumour is completely removed; (2) ischemia (in particular, the warm ischemia time) is the surgical variable that influences the postoperative renal function, and (3) the modified clavien-dindo classification is a measure of the safety profile of pn. according to this system, the goal of pn is achieved when (1) the surgical margins are negative, (2) the wit is < 20 min and (3) no major complications (grade 3-4 according to clavien classification) are observed (21). warm ischemia time in the partial nephrectomy is one of the main concerns. clamping of the renal vascular supply reduces bleeding from the resection margin, however can cause permanent ischemia injury in the renal parenchyma. for this reason warm ischemia time should be less than 30 minutes (7). large intraparenchymal or hilar tumour usually needs more time, and can be resected efficiently and repair faster with robotics. in the series of haber et al. study comparing lpn and rpn cases, they concluded that there were no significant differences with respect to warm ischemic time (18.2 minutes vs 20.3 minutes, respectively) (22). in our study rpn was associated with shorter operation time and warm ischemic time, but wit was not statistically significant. oncologic outcome with negative surgical margin is the primary focus of partial nephrectomy. however, impact of positive margin on the oncological outcome of patients with rcc remains controversial (23). our single institution, single surgeon series demonstrated that lower positive margin rate were seen in the rpn group. we found no difference in the incidence of psm when comparing the clampless procedures, and no preor perioperative parameters predicted the psm in both groups. the more widespeared use of grading system for reporting complications has developed by dindo et al. (13) to facilitate standardization. the safety of clampless pn emerged from analysis of the postoperative complications. the overall complication rates were similar for the clampless lpn and rpn groups in terms of the incidence of serious, in particular grade iii-iv complications according to clavien-dindo classification have not seen in lpn or rpn. the padua and renal scores are important predictor of the overall complication. this study confirms that the anatomical and topographical characteristics of the tumour expressed by the padua or renal score did not affect the outcomes of rcc less than 4 cm. retrospective study design was the main limitation of this study. another limitation is that all results were based on same surgeon’s experiences. a third limitation is that the study group is too small. to better elucidate comparison of lpn and rpn, a sample of large size studied in a prospectively randomized controlled design with long term follow up data will be necessary to determinate whether lpn or rpn is safe, reproducible and effective according to renal function and oncological outcomes. in conclusion, robotic surgery in urology is increasingly replacing the conventional urological techniques. our results demonstrated that favourable results of rpn compared to lpn in the perioperative outcomes of estimated blood loss, shorter warm ischemia time, and less positive margin rate. besides higher costs, rpn is safe, feasible, and associated low morbidity for small-sized renal tumours. references 1. lindblad p epidemiology of renal cell carcinoma. scand j surg. 2004; 93:88-96. 2. sun m, becker a, tian z, et al. management of localized kidney cancer: calculating cancer-specific mortality and competing risks of death for surgery and nonsurgical management. eur urol. 2014; 65:235-41. 3. snow dc, bhayani sb. rapid communication: chronic renal insufficiency after laparoscopic partial nephrectomy and radical nephrectomy for pathologic t1a lesions. j endourol. 2008; 22:337-41. 4. mcdougall em, elbahnasy am, clayman rv. laparoscopic wedge resection and partial nephrectomy--the washington university experience and review of the literature. jsls. 1998; 2:15-23. 5. gill is, kavoussi lr, lane br, et al. comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. j urol. 2007; 178:41-6. 95archivio italiano di urologia e andrologia 2017; 89, 2 rpn vs. lpn for small renal tumours simsek_stesura seveso 20/06/17 08:58 pagina 95 archivio italiano di urologia e andrologia 2017; 89, 2 a. simsek, a. hizir yavuzsan, y. colakoglu, a. atar, s. sahin, v. tugcu 96 6. desai mm, gill is, kaouk jh, et al. laparoscopic partial nephrectomy with suture repair of the pelvicaliceal system. urology. 2003; 61:99-104. 7. gettman mt, blute ml, chow gk, et al. robotic-assisted laparoscopic partial nephrectomy: technique and initial clinical experience with davinci robotic system. urology. 2004; 64:914-8. 8. peschel r, neururer r, bartsch g, gettman mt. robotic pyeloplasty: technique and results. urologic clin north am. 2004; 31:737-41. 9. guillonneau b, jayet c, tewari a, vallancien g. robot assisted laparoscopic nephrectomy. j urol 2001; 166:200-1. 10. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009; 182:844-53. 11. ficarra v, novara g, secco s, et al. preoperative aspects and dimensions used for an anatomical (padua) classification of renal tumours in patients who are candidates for nephron-sparing surgery. eur urol. 2009; 56:786-93. 12. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis. 2002; 39:s1-266. 13. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 14. sb1 b. da vinci robotic partial nephrectomy for renal cell carcinoma: an atlas of the four-arm technique. j robot surg. 2008; 1:279-85. 15. benway bm wa, cabello jm, bhayani sb. robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. eur urol. 2009; 55:592-9. 16. zini l, perrotte p, capitanio u, et al. radical versus partial nephrectomy: effect on overall and noncancer mortality. cancer. 2009; 115:1465-71. 17. riggs sb, larochelle jc, belldegrun as. partial nephrectomy: a contemporary review regarding outcomes and different techniques. cancer j. 2008; 14:302-7. 18. wang aj, bhayani sb. robotic partial nephrectomy versus laparoscopic partial nephrectomy for renal cell carcinoma: singlesurgeon analysis of > 100 consecutive procedures. urology. 2009; 73:306-10. 19. phillips ck, taneja ss, stifelman md. robot-assisted laparoscopic partial nephrectomy: the nyu technique. j endourol. 2005; 19:441-5. 20. stifelman md, caruso rp, nieder am, taneja ss. robot-assisted laparoscopic partial nephrectomy. jsls 2005; 9:83-6. 21. buffi n, lista g, larcher a, et al. margin, ischemia, and complications (mic) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery. eur urol. 2012; 62:617-8. 22. haber gp, white wm, crouzet s, et al. robotic versus laparoscopic partial nephrectomy: single-surgeon matched cohort study of 150 patients. urology. 2010; 76:754-8. 23. khalifeh a kj, bhayani s, rogers c, et al. positive surgical margins in robot-assisted partial nephrectomy: a multi-institutional analysis of oncologic outcomes (leave no tumor behind). j urol. 2013; 190:1674-9. correspondence abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com abdullah hizir yavuzsan, md hiziryavuzsan@yahoo.com yunus colakoglu, md yunuscolakoglu@gmail.com arda atar, md ardatar@yahoo.com selcuk sahin, md selcuksahin@yahoo.com volkan tugcu, md volkantugcu@yahoo.com department of urology, bakirkoy sadi konuk research and training hospital zuhuratbaba, tevfik saglam cad. no:11 bakirkoy, istanbul, turkey simsek_stesura seveso 20/06/17 08:58 pagina 96 141archivio italiano di urologia e andrologia 2018; 90, 2 case report skin flap squamous cell carcinoma developed after urethroplasty danilo abate, giuseppe giusti, nicola caria, giuseppe de vita, marco lucci chiarissi, antonello de lisa clinica urologica, università degli studi di cagliari, ospedale ss. trinità, cagliari, italy. objectives: to describe our experience in diagnosis and treatment of urethral carcinoma following urethroplasty with a orandi penile skin flap. material and methods: our patient underwent to orandi penile skin flap urethroplasty then developed a urethral epidermoid carcinoma on the flap approximately 15 years later. we treated this case with a partial penectomy surgery and perineostomy. surgery was followed by chemotherapy with cisplatin and 5-fluorouracil. the progression of the disease led to a salvage surgery of total penectomy and asportation of testicles and scrotum. results: despite the success of the surgery, the disease progressed and three months after the last surgical operation the patient died. conclusions: urethral carcinoma on skin flap is a rare complication of the urethroplasty surgery but with severe consequences, so we recommend to undertake a long-term urological follow up in patients undergone such kind of surgery. key words: skin flap; squamous cell carcinoma; urethroplasty. submitted 13 april 2018; accepted 29 april 2018 summary no conflict of interest declared. recurrences of urethral stenosis. so in july 2001 an orandi flap urethroplasty with penile skin was performed. subsequently in july 2016 the patient presented multiple scrotal and penile urinary fistulae accompanied by urosepsis. then an abdominal-pelvic mri identified a multi-segmented abscess of the left inguinal scrotal region and a solid neoplasm involving the urethra and corpora cavernosa in their proximal part. the micturition cystography pointed out also a severe stenosis of the penile urethra, confirmed by an endoscopic exam. so, a partial penectomy and distal ureterectomy were therefore performed with a perineal urethrostomy. the operation was accomplished by a median incision of the penile shaft, from the external urethral meatus down to the perineum. the presence of hard tissue, sometimes ulcerated and with the presence of purulent material, which incorporated the urethra up to the bulbar section, made the correct distinction of the surgical planes difficult. in order to better guide the surgical choice, a tissue sample was taken and sent for extemporaneous histological examination which disclosed for "epidermoid carcinoma, affected by moderate interstitial leukocyte exudation, with granulomatous aspects similar to a foreign body". given the histological report, it was decided to proceed with total urethrectomy and the forging of a perineal urethral meatus. in september 2016, the patient undertook an oncological assessment and subsequent cycle of systemic chemotherapy with cisplatin and 5-fu, which was completed in january 2017. unfortunately, no significant therapeutic response to systemic therapy was observed. due to the progression of the disease, the patient began to accuse diffuse pain in the hypogastric and inguinal regions. the mri restaging demonstrated a neoplastic extension of the disease into the corpora cavernosa up to the bulbs and neighboring regions. in march 2017 the patient underwent new surgery. we proceeded with a median longitudinal incision at the level of the pubic symphysis and extended caudally down to the perineal urethral meatus, also invaded by neoplastic tissue. the proximal cavernous bodies appeared rigid and hard, deeply affected by the neoplasia. even the tissues nearest to the corpora cavernosa bulbs appeared to be affected by the neoplasm. for this reason we proceeded to a detachment of the doi: 10.4081/aiua.2018.2.141 introduction according to the american association of urology (aua) guidelines, male urethral stenosis can be treated with urethral dilatation, endoscopic urethrotomy, and surgical urethroplasty. urethroplasty should be performed in patients that presented a post-dilatation relapse or a recurrence after an endoscopic urethrotomy for stenoses less than 2 cm in length. urethroplasty is also the preferred treatment for patients with long (≥ 2 cm) bulbar urethral strictures, given the low success rate of direct visual internal urethrotomy (dviu) or dilation. the surgical reconstruction of the urethral strictures can be carried out using oral mucosal grafts, penile fascia-cutaneous flaps or a combination of these techniques. in literature are reported isolated cases of urethral carcinoma following urethroplasty (1, 2). we report our experience in order to increase the scientific evidence. case description the patient was a 69 years old male who had in the previous year's several endoscopic surgeries for multiple caria_stesura seveso 28/06/18 16:41 pagina 141 archivio italiano di urologia e andrologia 2018; 90, 2 d. abate, g. giusti, n. caria, g. de vita, m. lucci chiarissi, a. de lisa 142 neoplastic plate from the periosteum of the pubis and its excision up to the bulbar section of the urethral stump and so on to a total penectomy, en-block removal of external genitalia and scrotal sac. given the extent of the tumor and its degree of infiltration, it was not possible to guarantee oncological radicalness. the intervention was completed by accomplishing a definitive suprapubic urinary derivation. the definitive histological report showed a "moderately differentiated spinocellular carcinoma with horn pearl formations of the periurethral tissue and the corpora cavernosa, focally extended to the testicular albuginea without infiltrating the pulp. the neoplastic involvement includes the tissues of the scrotum up to the dermis". the rapid progression of the disease and the state of clinical impairment of the patient did not allow to consider treatments with an adjuvant intent. the patient died in june 2017. conclusions although extremely rare, the malignant transformation of the skin flaps used during urethroplasty is possible. such carcinoma if not early recognized can have harmful consequences as documented. it is therefore important to undertake a long urological follow-up in patients subjected to this kind of urethral surgery. references 1. williams g, ashken mh. urethral carcinoma following urethroplasty. j r soc med. 1980; 73:370-1. 2. sawczuk i, acosta r, grant d, et al. post urethroplasty squamous cell carcinoma. n y state j med. 1986; 86:261-3. figure 1. histology reports: "moderately differentiated spinocellular carcinoma with horn pearl formations of the periurethral tissue and the corpora cavernosa” h&e stain. 100x. correspondence danilo abate, md giuseppe giusti, md (corresponding author) giuseppegiusti.med@gmail.com nicola caria, md (corresponding author) nicolacaria1@gmail.com giuseppe de vita, md marco lucci chiarissi, md antonello de lisa, md clinica urologica, università degli studi di cagliari, ospedale ss. trinità via is mirrionis, cagliari, italy caria_stesura seveso 28/06/18 16:41 pagina 142 archivio italiano di urologia e andrologia 2019; 91, 158 case report minimally invasive management of a symptomatic case of zinner’s syndrome: laparoscopic seminal vesiculectomy and ipsilateral nephroureterectomy emanuele corongiu 1, pietro grande 2, valerio olivieri 3, giorgio pagliarella 1, flavio forte 1 1 department of urology, m.g. vannini hospital, rome, italy; 2 sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris, france; 3 department of urology, ivrea hospital asl to 4, ivrea, italy. introduction: zinner syndrome is a rare developmental anomaly of the wolffian (mesonephric) duct which is characterized by a triad of obstruction of the ejaculatory duct, the ipsilateral seminal vesicle cyst, and the ipsilateral renal agenesis. usually is totally asymptomatic, however it can also determine symptoms such as lower urinary tract symptoms, perineal pain, ejaculatory disorders such as painful ejaculation or hematospermia, and infertility. case report: we present a case of a 51 years old men with a 3-year history of lower urinary tract symptoms, perineal pain, obstructed defecation, recurrent urinary tract infections and infertility. ct scan showed a voluminous cystic neoformation of the left seminal vesicle, hypoplasia of the left kidney and ipsilateral ureteronephrosis. the mass was removed using laparoscopic “en block” seminal vesiculectomy with associated ipsilateral nephroureterectomy. no post-operative complications occurred. at 2-month post-operative control the patient reported an improvement of urinary and rectal symptoms.. key words: seminal vesicle cyst; zinner’s syndrome; nephroureterectomy; seminal vesciculectomy; laparoscopy. submitted 2018; accepted 2019 summary no conflict of interest declared. infections and infertility. uroflowmetry, showed reduced maximal flow (9 ml/s), irregular flow pattern and a consistent postvoid residue (150 ml). the evaluation was completed by an abdominal ultrasound which showed a voluminous cystic formation of the left seminal vesicles together with agenesis of the left kidney. accordingly, ct scan with excretory phase, revealed a small pelvis completely occupied by a voluminous cystic formation dislocating the rectum and the urinary bladder and causing right ureteronephrosis, with ureteral outlet at the level of the cystic mass (figure 1). additionally, hypoplasia of the left kidney was noticed (figure 1). based on these data, a minimally-invasive surgical approach was planned, as previously reported as a safe and feasible option (3). a laparoscopic left nefroureterectomy and cystic mass ablation was subsequently planned. the patient was placed in trendelenburg position: a 12 mm optical trocar was inserted 1 cm above the umbilical fold. pneumoperitoneum was obtained and three other trocars (two of 5 and one of 10 mm) were placed. the douglas fold was completely obliterated by the engorged left seminal vesicle underlying the parietal pelvic peritoneum. the extra-peritoneal space was accessed and the seminal tangle carefully dissected, taking care to avoid direct damages to rectal walls and moreover to the hovealque plexus located at both lateral rectal sides. special attention was taken to retract laterally the sacro-recto-genito-pubic ligaments (delbet bands) in which prostatic and vesical vessels roots are contained. the right ductus deferens was identified and spared, while the left one was necessarily transacted at the point in which it seemed to fuse with the left ureter on the engorged dome of the seminal vesicle, configuring a disturbance of the paramesonephric wolffian duct development. once the seminal vesicle removed, the patient was moved in right flank position to perform nephroureterectomy. one more 5 mm trocar was inserted at the cross between the pararectal and infracostal left lines. via detaching the mesosigma and gaining the jonnesco space, 3-5 cm above the left common iliac vessels, the aplastic kidney with its small vascular pedicle was found and it was possible to remove the left kidney, the dilated ureter and the cystic mass "en block", with an doi: 10.4081/aiua.2019.1.58 introduction zinner syndrome is a very rare condition, first described in 1914 (1), with less than 200 cases reported worldwide, characterized by unilateral renal agenesis, ipsilateral seminal vesicle cyst and ejaculatory duct obstruction. the association between upper urinary tract abnormalities and seminal vesicle malformation are based on the shared origin of the ureteral buds and seminal vesicles from the mesonephric (wolffian) duct (2). in most cases, these anomalies are completely asymptomatic and the diagnosis is often incidental. however, the association with lower urinary tract symptoms, perineal pain, ejaculatory disorders such as painful ejaculation or hematospermia, and infertility may help unveil the syndrome. case report we report the case of a 51-year old caucasian man, presenting with lower urinary tract symptoms (luts), perineal pain, obstructed defecation, recurrent urinary tract corongiu2_stesura seveso 25/03/19 17:24 pagina 58 59archivio italiano di urologia e andrologia 2019; 91, 1 nephroureterectomy e seminal vesciculectomy in zinner’s syndrome ta d operative time of about 2 hours (figure 2). the postoperative course was without complications and the patient was discharged on the 4th post-operative day. conclusions final pathological analysis revealed a small polycystic left kidney in the absence of residual parenchyma. the cystic mass (measured at 33 cm in diameter) was compatible with a polycystic and ectopic seminal vesicle (figure 2). the patient was subsequently followed-up in outpatient setting, reporting a progressive and continuous improvement luts and rectal symptoms. approximately 60 days after the surgical procedure, the patient underwent a new uroflowmetric check which showed a more regular pattern and significantly improved urinary indices (qmax 15 ml/s) and a reduction of post-void volume (60 cc). references 1. zinner a. ein fall von intravesikaler samenblasenzyste. wein med wochenschr. 1914; 64:605-609. 2. kao cc, wu cj, sun gh, et al. congenital seminal vesicle cyst associated with ipsilateral renal agenesis mimicking bladder outlet obstruction: a case report and review of the literature. kaohsiung j med sci. 2010; 26:30-4. 3. kiremit mc, acar o, sag aa, et al. minimally invasive management of zinner’s syndrome with same-session robot-assisted seminal vesiculectomy and ipsilateral nephroureterectomy using a single geometry of trocars, j endourol case rep. 4: 1, 186-189. figure 1. ct scan. correspondence emanuele corongiu, md (corresponding author) emanuele.corongiu@libero.it giorgio pagliarella, md flavio forte, md g.m. vannini hospital, department of urology via di acqua bullicante 4, 00177, rome (italy) pietro grande, md sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris (france) valerio olivieri, md department of urology, ivrea hospital asl to 4, ivrea (italy) figure 2. hypoplasia of the left kidney and voluminous seminal cystic formation. corongiu2_stesura seveso 25/03/19 17:24 pagina 59 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 280 letter to editor comment on hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19 submitted 7 may 2020; accepted 13 may 2020 no conflict of interest declared. doi: 10.4081/aiua.2020.2.80 to the editor the covid-19 outbreak dramatically changed hospital everyday life, impairing the course of previous routine activity, also in urology (1, 2). in the next months, together with keeping the focus on the prevention of contagion recrudescence, the health care system will face another stringent issue, i.e. to restore all the services not covid-related. leonardi et al. in their paper (3) report an equilibrate overview on the incoming “phase 2”, in order to set up so-called covid-free hospitals and departments. the authors offer an insight from a practical point of view, detailing protocols for any of the steps of the path of care, from the outpatient visit to surgery. the aim is to ensure a safe healthcare flow, based on the early identification of the positive subjects and the rigorous protection of the negative ones. the cornerstones of this framework are: microbiological and instrumental covid screening for patients but also for healthcare workers; furniture of personal protective equipment to the medical and administrative staff; re-definition of outpatient and inpatient scheduling to guarantee distancing; regulation of operating theaters by general protocols (as intubation in dedicated rooms, adoption of filters and smoke evacuation devices, etc), but also others dedicated to specific procedure (endoscopic, open, minimally-invasive). although these actions will undoubtedly be pivotal to prevent virus contagion, to date no solid evidence is available on the safety of contemporarily hospitalization (4). furthermore, the feasibility and sustainability of such measures have still to be established, first of all concerning economical resources. secondly, many hospitals will be required to engage structural works in order to create appropriate spaces for distancing patients and personnel. thirdly, the dilution of scheduling and increasing intervals between procedures will result in a significant extension of sessions and need for additional personnel, otherwise posing conflicts with the regulatory on shift and rest. similarly, restricting surgical teams to a few operators periodically screened for covid will result in the escalation of workload. fourthly, academic institutions shall conjugate safety requirements with their educational mission; this objective will become even more challenging considering the emerging calls to increase the number of residency positions, already initiated before the covid emergency. besides these considerations there are several issues related to the patient side, mainly due to the withdrawal of procedures and consequent delay in execution of adequate new diagnostical examination (5) and in choice of best treatments occurred in this emergency period (6), with consequent repercussions on the quality of life of the patients (7). all these points should be read taking into account the peculiarities of italian scenario, where marked differences in the epidemiology and effects of the pandemic have occurred (8). additionally, our universalistic health systems, articulated in independent regional subsystems, count on institutions of various nature (academic, public, private), with different facilities, delivery capacity and attractiveness towards patients and investors. such disparities have been already dramatically highlighted by the covid emergency, but could be more and more emphasized if further phases will be managed on a local basis. reasonably, supra-regional and, hopefully, supra-national coordination are needed to control such heterogeneity, sharing protocols and regulating funding allocation, in order to ensure that each institution could handle with both covid and non-covid patients. references 1. puliatti s, eissa a, eissa r, et al. covid-19 and urology: a comprehensive review of the literature. bju int. 2020. 2. rocco b, sighinolfi mc, sandri m, et al. the dramatic covid 19 outbreak in italy is responsible of a huge drop of urological surgical activity: a multicenter observational study. british journal of urology international. 2020; in press. 3. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. archivio italiano di urologia e andrologia. 2020; 92(1). 4. maida fd, antonelli a, porreca a, et al. letter to the editor: "clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of covid-19 infection". eclinicalmedicine. 2020:100362. 5. vagnoni v, brunocilla e, bianchi l, et al. state of the art of pet/ct with 11-choline and 18f-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. arch esp urol. 2015; 68:354-70. 81archivio italiano di urologia e andrologia 2020; 92, 2 hospital care in departments defined as covid-free 6. grasso aa, cozzi g, de lorenzis e, et al. multicenter analysis of pathological outcomes of patients eligible for active surveillance according to prias criteria. minerva urol nefrol. 2016;68:237-41. 7. gacci m, noale m, artibani w, et al. quality of life after prostate cancer diagnosis: data from the pros-it cnr. eur urol focus. 2017; 3:321-324. 8. simonato a, giannarini g, abrate a, et al. pathways for urology patients during the covid-19 pandemic. minerva urol nefrol. 2020 mar 30. correspondence alessandro tafuri, md alessandro antonelli, md department of urology, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy andrea minervini, md department of urology, careggi hospital, university of florence, florence, italy. antonio celia, md department of urology, st. bassiano hospital, bassano del grappa, italy luca cindolo, md department of urology, "villa stuart" private hospital, rome, italy riccardo schiavina, md department of urology, university of bologna, st. orsola-malpighi hospital, bologna, italy bernardo rocco, md department of urology, university of modena and reggio emilia, modena, italy angelo porreca, md (corresponding author) angeloporreca@gmail.com department of urology, policlinico abano terme, abano terme, italy alessandro tafuri 1, andrea minervini 2, antonio celia 3, luca cindolo 4, riccardo schiavina 5, bernardo rocco 6, angelo porreca 7, alessandro antonelli 1 1 department of urology, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy; 2 department of urology, careggi hospital, university of florence, florence, italy; 3 department of urology, st. bassiano hospital, bassano del grappa, italy, 4 department of urology, "villa stuart" private hospital, rome, italy; 5 department of urology, university of bologna, st. orsola-malpighi hospital, bologna, italy; 6 department of urology, university of modena and reggio emilia, modena, italy; 7 department of urology, policlinico abano terme, abano terme, italy. 1archivio italiano di urologia e andrologia 2017; 89, 1 original paper the role of nutraceuticals and phytotherapy in the management of urinary tract infections: what we need to know? tommaso cai 1, irene tamanini 1, ekaterina kulchavenya 2, tamara perepanova 3, béla köves 4, florian m.e. wagenlehner 5, zafer tandogdu 6, gernot bonkat 7, riccardo bartoletti 8, truls e. bjerklund johansen 9 1 department of urology, santa chiara regional hospital, trento, italy; 2 tb research institute, medical university, novosibirsk, russian federation; 3 n. lopatkin scientific research institute of urology and interventional radiology branch of the national medical research radiological centre of the ministry of health of the russian federation; 4 jahn ferenc south pest teaching hospital, budapest, hungary; 5 klinik und poliklinik für urologie, kinderurologie und andrologie, universitätsklinikum giessen und marburg gmbh, justus-liebig-universität, giessen, germany; 6 northern institute for cancer research, newcastle university, ne1 7ru newcastle upon-tyne, uk; 7 alta uro ag, merian iselin klinik, center of biomechanics & calorimetry (cob), university basel, basel, switzerland; 8 department translational research and new technologies, university of pisa, pisa, italy: 9 oslo university hospital and univeristy of oslo, oslo, norway. urinary tract infections (utis) are amongst the most common infectious diseases and carry a significant impact on patient quality of life and health care costs. despite that, there is no well-established recommendation for a “standard” prophylactic antibiotic management to prevent uti recurrences. the majority of patients undergoes long-term antibiotic treatment that severely impairs the normal microbiota and increases the risk of development of multidrugresistant microorganisms. in this scenario, the use of phytotherapy to both alleviate symptoms related to uti and decrease the rate of symptomatic recurrences is an attractive alternative. several recently published papers report conflicting findings and cannot give confident recommendations for the everyday clinical practice. a new approach to the management of patients with recurrent uti might be to use nutraceuticals or phytotherapy after an accurate assessment of the patient`s risk factors. no single compound or mixture has been identified so far as the best preventive approach in patients with recurrent uti. we reviewed our non-antibiotic approach to the management of recurrent uti patients in order to clarify the evidence-base for the commonly used substances, understand their pharmacokinetics and pharmacodynamics in order to tailor the best way to improve patient’s quality of life and reduce the rate of antibiotic resistance. lack of a gold-standard recommendation and the risk of increasing antibiotic resistance is the reason why we need alternatives to antibiotics in the management of urinary tract infections (utis). a tailored approach according to bacterial characteristics and the patient risk factors profile is a promising option. key words: nutraceuticals; phytotherapy; urinary tract infections. submitted 13 january 2017; accepted 28 january 2017 summary no conflict of interest declared. introduction urinary tract infections (utis) are amongst the most common community-acquired infectious diseases, with annual costs estimated to be higher than $1.5 billion in the united states (1-2). the impact on public health is significant due to the high recurrence rate and the effect on patients’ quality of life (4). the mortality rate must also be taken into account (reported to be as high as 1% in men and 3% in women due to development of pyelonephritis and urosepsis). in particular, after an initial uti, approximately 20-30% of women with a uti will have a second uti within 6 months, and 3% will experience a third uti during that time period (4-5). in consequence, women with recurrent utis (rutis) reported a high indirect cost as a result of the number of working days lost (6). the majority of these patients are women with recurrent bacterial cystitis or acute pyelonephritis, and the causative pathogens can usually be eradicated with a short course of oral antimicrobial therapy. however, the antibiotic treatment can lead to long term impairment of the normal microbiota of the vagina and gastrointestinal tract and to the development of multidrug-resistant micro-organisms (7-9). moreover, there is no well-established recommendation for a ‘standard’ prophylactic antibiotic management to prevent uti recurrence (10). furthermore, many women have a number of signs and symptoms of utis without any evidence of bacterial presence (11). in this sense, the use of phytotherapy to alleviate symptoms related to uti and decrease the rate of symptomatic recurrence seems a good alternative which is nowadays more commonly used. there are many good reasons for this approach e.g. the low side-effects, low costs and a high level of compliance. also important are the low rate of efficacy of doi: 10.4081/aiua.2017.1.1 cai_stesura seveso 04/04/17 09:01 pagina 1 archivio italiano di urologia e andrologia 2017; 89, 1 t. cai, i. tamanini, e. kulchavenya, t. perepanova, b. köves, f.m.e. wagenlehner, z.tandogdu, g. bonkat, r. bartoletti, t.e. bjerklund johansen 2 standard preventive measures with subsequent patient disappointment and drop-outs (3, 12). traditionally, nutraceuticals and phytotherapy have been used to prevent rutis in otherwise healthy women. although the results from a number of clinical studies have supported their benefits, the efficacy of nutraceuticals and phytotherapy on prevention of rutis remains controversial, due to heterogeneity of published studies in terms of methodology and the reported findings such as trial design; inclusion/exclusion criteria; patient characteristics; outcome measures, as well as heterogeneity of the compounds used. the latest cochrane reviews on uti management concluded as follows: – chinese herbal medicine alone or in conjunction with antibiotics may be beneficial for treating recurrent utis during the acute phase of infection and may reduce the recurrent uti incidence for at least six months post-treatment (13). – no significant benefit was demonstrated for probiotics compared with placebo or no treatment, but a benefit cannot be ruled out as the data were few, and derived from small studies with poor methodological reporting (3). – given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and poor evidence for prevention of uti, cranberry juice cannot currently be recommended for the prevention of utis (14). the lack of a standard approach for the management of patient with recurrent uti and the need to reduce the use of antibiotics suggest to re-think current practice in uti management. in this perspective, the nutraceutical or phytotherapic approach to recurrent utis should be based on a full evaluation of the clinical situation, patient risk factors and the characteristics of the bacteria (e.g. escherichia coli, adherent to vaginal and bladder epithelial cells). this includes assessment of symptomatic or asymptomatic bacteriuria; the disease symptoms/characteristics themselves (number or recurrences); the patient’s behavior (use of a spermicide, diaphragm, delayed postcoital micturition, hormonal status; other risk factors); such as abo-blood-group non-secretor phenotype, bowel function and water intake (4, 15-17). a comprehensive assessment may guide and suggest the best nutraceutical or phytotherapic approach and improve the treatment outcome. the aim of the present manuscript is to review the published data about the role of nutraceuticals and phytotherapy in the management of patients affected by recurrent uti and also to address compounds that can modify the patient’s related risk factors and improve the treatment outcome. state of the art: international guidelines recommendations the latest version of european association of urology (eau) guidelines on urological infections states that there are many non-antimicrobial measures for prevention of recurrent utis but only a few of them are based on well designed studies which are needed to make evidence-based recommendations (18). in particular, eau guidelines highlight that there is no convincing benefit for lactobacillus products or cranberry extracts as prophylaxis of recurrent uti (18). the scottish intercollegiate guidelines network confirmed the recommendations from the eau guidelines, highlighting that cranberry products (juice, tablets, capsules) are not standardized and the concentrations of active ingredients are not known; hence the concentration may also fluctuate between batches of the same product (19). there is no evidence to support the effectiveness of cranberry products for treating symptomatic episodes of uti (19). the society of obstetricians and gynaecologists of canada`s guidelines suggest to inform the patients about the efficacy of cranberry products in reducing recurrent urinary tract infections (ia) (20). moreover, they suggest to not use probiotics and vaccines due to lack of demonstrated efficacy (ii-2c) (20). take home message • international guidelines agree that there is no convincing benefit for the use of nutraceuticals and/or phytotherapy as prophylaxis of recurrent utis. • new rcts are needed. actual scenario: alternative non-antibiotic measures contemporary reviews identify four alternative compounds for non-antibiotic management of recurrent utis: – cranberry – probiotics – chinese herbal medicine – d-mannose cranberry extracts a cochrane review from 2008 concluded that cranberry products significantly reduced the incidence of utis at 12 months (rr 0.65, 95% ci 0.46-0.90) compared with placebo/control in women with recurrent utis (21). in a more recent cochrane review it was concluded that cranberry products did not significantly reduce the occurrence of symptomatic uti in women with recurrent utis (14). the changed view is based on the inclusion of two additional trials in their meta-analysis (14). in these two rcts the effectiveness of cranberry extract was compared with low-dose antibiotic prophylaxis (14). mcmurdo et al. concluded that trimethoprim had a limited advantage over cranberry extract in the prevention of recurrent utis in older women (22). in addition beerepoot et al. showed that cranberry capsules are less effective than low-dose (480 mg) trimethoprim/sulfamethoxazole in the prevention of recurrent utis in premenopausal women (23). vaccinium macrocarpon, named also american cranberry, is a rich source of polyphenols that show several in vitro properties, including antibacterial, antiviral, antimutagenic, anticarcinogenic, antitumorigenic, antiangiogenic, anti-inflammatory, and antioxidant effects (27). moreover, cranberry extract is a promising therapy due to the fact that it is cai_stesura seveso 04/04/17 09:01 pagina 2 an anti-adhesive agent against e. coli strains and thus prevent the development of antibiotic resistance (2). on the other hand, it has been demonstrated that uropathogenic bacteria may have an intestinal origin and the intestinal tract could be an alternative site where the active components of cranberry extract may interact with e. coli decreasing its infectivity (24). several authors demonstrated that some extracts from cranberry decrease the pathogenicity of proteus mirabilis by limiting urothelial cell invasion and improving the mucosal immunity to uropathogens (25-26). probiotics probiotics are defined as “a preparation of, or a product containing viable, defined micro-organisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a host compartment and by that exert beneficial health effects in this host” (3, 28). the hypothesis is that probiotics are able to establish a barrier against infectious pathogens ascending the urinary tract, colonizing, and subsequently causing infection (3, 29). the latest cochrane review showed that probiotics were not superior to placebo in reducing the risk of recurrent symptomatic bacterial uti. the conclusion was based on 6 studies with (352 participants (rr 0.82, 95% ci 0.60 to 1.12; i2=23%). hence the data were derived from small studies with poor methodological quality (3). on the other hand the reported evidences could not rule out a reduction or increase in recurrent uti in women with recurrent uti who use prophylactic probiotics. one rct did not provide sufficient evidence to conclude on the effect of probiotics versus antibiotics (3). chinese herbal medicine chinese herbal medicine is a part of traditional chinese medicine and represents a complex of herbal formulae usually comprising 10 to 15 different herbs (13). chinese herbal medicine formulae may be standardized or individualized according to specific needs and patients’ characteristics (13). the hypothesis supporting the efficacy of chinese herbal medicine is based on in vitro research suggesting that some commonly used chinese herbs may confer significant diuretic, antibiotic, immune enhancing, antipyretic, anti-inflammatory and pain relieving effects (13). the latest cochrane review, including 7 rcts with a total of 542 women, concluded that chinese herbal medicine alone or in conjunction with antibiotics may be useful in treating recurrent utis during the acute phase of an infection and may reduce the incidence of recurrent uti for at least six months post-treatment (13). however, this evidence is based on a small number of poor quality studies with severe bias that should be taken into account. d-mannose d-mannose is a sugar that has an important role in human metabolism, especially in the glycosylation of certain proteins. the hypothesis is that d-mannose inhibits bacterial adherence to uroepithelial cells (30). in fact, in vitro and in vivo animal studies demonstrated that d-mannose can inhibit the adhesion of type 1 fimbriae of the uropathogenic bacteria to uroepithelial cells (31). only one rct evaluated its effect as preventive agent in recurrent uti. kranjc̆ec et al., in a study of 98 women, showed that patients in d-mannose group and nitrofurantoin group had a significantly lower risk of recurrent uti episode during prophylactic therapy compared to patients in the no prophylaxis group (rr 0.239 and 0.335, p < 0.0001) (30). these preliminary findings are promising, but supplementary clinical trials are essential. take home messages • cranberry products did not significantly reduce the occurrence of symptomatic uti in women with recurrent utis. • probiotics are not superior to placebo in reducing the risk of recurrent symptomatic bacterial uti. • chinese herbal medicine may be useful for treating recurrent utis during the acute phase of infection and may reduce the incidence of recurrent uti for at least six months post-treatment. this evidence is based on a small number of patients and low quality studies. • no well-done studies have been performed about the use of d-mannose in preventing recurrence among uti patients. too many antibiotics: doctors need to change course! increasing antimicrobial resistance has stimulated interest in non-antibiotic prophylaxis of recurrent urinary tract infections. this is particularly due to the recent alarming increase of the extended spectrum beta-lactamase (esbl)-producing enterobacteriaceae prevalence among outpatients with uti (32-33). thus, antimicrobial resistance has become a major worldwide health problem during recent years. several strategies have been developed to reduce the alarming increase of resistant bacteria (34-36). phytotherapy and nutraceuticals may be considered an alternative approach for reducing the recurrences among uti patients. in fact, patients with recurrent utis are increasingly asking their healthcare professionals about the value of taking non-antibiotic products. the non-antibiotic approach, however, should be based on a correct and deep knowledge about the real efficacy and tolerability of phytotherapy compounds. all physicians should update themselves on the latest evidences on non-antibiotic approaches to recurrent utis and suggest products according to international guidelines and latest reviews. the main arguments for using a non-antibiotic approach to prevent recurrence among uti patients are as follows: the use of antibiotic prophylaxis for recurrent uti is not generally accepted; the risk of bacterial resistance is already high and still increasing; the tolerability and the compliance to nonantibiotic products is high; preliminary study findings are promising. while long-term antibiotic prophylaxis might efficiently inhibit new intravesical bacterial growth during the treatment period, infections are likely to reccur when the prophylactic treatment ends (37-38). take home messages • contemporary antimicrobial resistance rate is alarming. 3archivio italiano di urologia e andrologia 2017; 89, 1 nutraceuticals and urinary tract infection management cai_stesura seveso 04/04/17 09:01 pagina 3 archivio italiano di urologia e andrologia 2017; 89, 1 t. cai, i. tamanini, e. kulchavenya, t. perepanova, b. köves, f.m.e. wagenlehner, z.tandogdu, g. bonkat, r. bartoletti, t.e. bjerklund johansen 4 • phytotherapy and nutraceuticals may be considered a feasible strategy to reduce indiscriminate use of antibiotics. assessment of patients’ behaviour and bacterial related risk factors hooton et al. developed a simple risk prediction model based on the number of days with intercourse per week and the use of contraceptives (diaphragm and spermicide) for predicting the risk of uti recurrence (39). hooton showed that an unmarried, 24-year-old female university student who had sexual intercourse had a risk of uti that was 2.6-fold greater than that of a similar student who had no intercourse in the previous week (39). hooton was a pioneer in highlighting the role of riskpredicting tools in the management of women with recurrent uti1. recently, cai et al. developed and validated a nomogram that accurately predicts the recurrence risk of urinary tract infection at 12 months, and which can assist in identifying women at high risk of symptomatic recurrence that can be suitable candidates for a prophylactic strategy (40). in this model they found the following independent predictors of uti recurrence: number of sexual partners, bowel function, type of pathogens isolated (gram-positive/negative), hormonal status, number of uti recurrences and previous treatment of asymptomatic bacteriuria (40). in this model they excluded use of food supplements because of the high variability of products used. cai et al. also found that the most important factors affecting the risk of new recurrences were: bowel function, presence of gram negative strains, asymptomatic bacteriuria treatment and having had 3 or more than 3 uti episodes (40). the importance of bowel function for development of uti is well known and is related to the fecal-perineal-urethral contamination by enteric bacteria (40). the risk is of uti is increased by constipation as demonstrated by loeningbaucke et al. (41). the same authors demonstrated that constipation treatment results in the disappearance of recurrent urinary tract infections in all patients who had no anatomical abnormality of the urinary tract (41). what about gram negatives? cai et al. found that the presence of gram-negative bacteria (e. coli) is associated with a higher likelihood of recurrence (40) due to three reasons: – e. coli is the most common pathogen in uti patients (1). – e. coli isolated from recurrent uti has the greatest propensity of the uropathogenic bacteria to adhere to the uroepithelial cells of women with recurrent uti as compared with bacteria from women without recurrent infection (42). – e. coli is able to adhere to the bladder epithelium, invade the cells and form intracellular bacterial communities, which can remain quiescent reservoirs able to cause new recurrences when reactivated (38). recently, cai et al. found that antibiotic treatment of asymptomatic bacteriuria in young women with recurrent uti is not only unnecessary, but harmful (8-9). this is due to the fact that in women undergoing antibiotic treatment, the rate of e. coli decreased over time, whereas the prevalence of e. faecalis increased gradually, suggesting that e. faecalis might be an important defense mechanism that effectively interferes with the establishment of many important enteric pathogens, such as e. coli (8-9). in this sense, the use of non-antibiotic approach should be preferred because it doesn’t interfere with the normal commensal bowel flora. risk factor assessment as a guide to treatment assessment of the risk for recurrence is not only important for predicting the probability of a new recurrence but also for the development of a tailored therapeutic approach on the basis of patient’s characteristics. a constipated patient, for example, should be informed about the relationship between the constipation and the risk of new uti. a nutraceutical or phytotherapic approach acting on the bowel function should be preferred. moreover, a patient who reported more than 3 episodes of previous uti and correlation with sexual intercourses should be treated with nutraceutical products that are able to interfere with the e. coli adhesion to urothelial cell and invasion. furthermore, a correct non-antibiotic approach should work against one or more of the following infection mechanisms: – reduction of the bacterial load in the intestinal reservoir with concomitant correction of the constipation – reduction of the spread of e. coli from the perineal zone to the urethra and bladder. – reduction of the adhesion and invasion of uropathogens to the urothelial cells. – mobilization of the immune system against the intracellular bacterial communities avoiding reactivation and new symptomatic recurrences. we have no an ideal nutraceutical or phytotherapic compound so far that is able to act in all the above ways to decrease the risk of recurrence. even if cranberry extracts seem to be able to act along more than one pathway, there are limitations due to the pharmacokinetic and pharmacological characteristics of this compound. as discussed above, cranberry extracts are able to reduce the adherence of e. coli to the urothelial cells and reduce the adherence of bacterial strains also to the intestinal cells. however, possible reasons for the inefficacy of cranberry extracts found in the cited rcts should also be taken into account. firstly, multi-step processing of cranberry production leads to a substantial loss of phytochemicals (through elimination of rich fractions like skin and seeds), which are further damaged by thermal degradation, as well as oxidation by polyphenol oxidase and peroxidase (38). moreover, the exact concentration of active metabolites on the action site and the pharmacokinetics of cranberry extracts is unknown. there are other plant extracts that have shown interesting results in the prevention of uti recurrences. rafsanjany et al. demonstrated that a mixture of extracts from betula spp. (birch), orthosiphon stamineus (java tea) and urtica spp. (nettles) is able to reduce the adherence of the pathogen to the host cell. the same results have been obtained by cai et al. who demonstrated that a compound with solidago, orthosiphon, birch and cranberry extracts is able cai_stesura seveso 04/04/17 09:01 pagina 4 to reduce the microbial colonization in patients with indwelling urinary catheters (43). however, this mixture is not able to cover all mechanisms of infection. conclusions the lack of a gold-standard for the treatment of recurrent utis and the risk of provoking resistances among the pathogenic bacteria are two important reasons why we need non-antibiotic alternatives for the management of recurrent utis. a promising alternative is a tailored approach based on a comprehensive assessment of patient related risk factor and the characteristics of the causative pathogen. better knowledge about the action of natural substances will 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transcinnamaldehyde decreases attachment and invasion of uropathogenic escherichia coli in urinary tract epithelial cells by modulating virulence gene expression. j urol. 2011; 12:1526-1531. 27. blumberg jb, camesano ta, cassidy a, et al. cranberries and their bioactive constituents in human health. adv nutr. 2013; 4:618-32. 5archivio italiano di urologia e andrologia 2017; 89, 1 nutraceuticals and urinary tract infection management cai_stesura seveso 04/04/17 09:01 pagina 5 archivio italiano di urologia e andrologia 2017; 89, 1 t. cai, i. tamanini, e. kulchavenya, t. perepanova, b. köves, f.m.e. wagenlehner, z.tandogdu, g. bonkat, r. bartoletti, t.e. bjerklund johansen 6 28. schrezenmeir j, de vrese m. probiotics, prebiotics, and synbiotics approaching a definition. am j clin nutr. 2001; 73(2 suppl):361s-364s. 29. bruce aw, reid g. intravaginal instillation of lactobacilli for the prevention of recurrent urinary tract infections. can journal microbiol. 1988; 34:339-43. 30. kranjc̆ec b, papeš d, altarac s. d-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. world j urol. 2014; 32:79-84. 31. altarac s, papes d. use of d-mannose in prophylaxis of recurrent urinary tract infections (utis) in women. bju int. 2014; 113:9-10. 32. al-mayahie s, al kuriashy jj. distribution of esbls among escherichia coli isolates from outpatients with recurrent utis and their antimicrobial resistance. j infect dev ctries 2016; 10:575-83. 33. gupta k, scholes d, stamm we. increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. jama. 1999; 281:736-738. [ 34. cai t, verze p, brugnolli a, et al. adherence to european association of urology guidelines on prophylactic antibiotics: an important step in antimicrobial stewardship. eur urol. 2016; 69:276-83. 35. charani e, cooke j, holmes a. antibiotic stewardship programmes--what's missing? j antimicrob chemother. 2010; 65:2275-7. 36. cai t, mazzoli s, mondaini n, et al. the role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? clin infect dis. 2012; 55:771-7. 37. eells sj, bharadwa k, mckinnell ja, miller lg. recurrent urinary tract infections among women: comparative effectiveness of 5 prevention and management strategies using a markov chain monte carlo model. clin infect dis. 2014; 58:147-160. 38. lüthje p, brauner a. novel strategies in the prevention and treatment of urinary tract infections. pathogens. 2016; 27:5. 39. hooton tm, scholes d, hughes jp, et al. a prospective study of risk factors for symptomatic urinary tract infection in young women. n engl j med. 1996; 335:468-74. 40. cai t, mazzoli s, migno s, et al. development and validation of a nomogram predicting recurrence risk in women with symptomatic urinary tract infection. int j urol. 2014; 21:929-34. 41. loening-baucke v. urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. pediatrics. 1997; 100:228-32. 42. schaeffer aj, jones jm, falkowski ws, et al. variable adherence of uropathogenic escherichia coli to epithelial cells from women with recurrent urinary tract infection. j urol. 1982; 128:1227-30. 43. cai t, caola i, tessarolo f, et al. solidago, orthosiphon, birch and cranberry extracts can decrease microbial colonization and biofilm development in indwelling urinary catheter: a microbiologic and ultrastructural pilot study. world j urol. 2014; 32:1007-14. correspondence tommaso cai, md (corresponding author) ktommy@libero.it irene tamanini, md department of urology, santa chiara regional hospital, largo medaglie d'oro 9 38123 trento, italy ekaterina kulchavenya, md tb research institute, novosibirsk 630040, russia tamara perepanova, md s.r. urology institute, moscow 105425, russia béla köves, md jahn ferenc south pest teaching hospital, 1204 budapest, hungary florian m.e. wagenlehner, md klinik und poliklinik für urologie, kinderurologie und andrologie, universitätsklinikum giessen und marburg gmbh, justus-liebiguniversität, 35392, giessen, germany zafer tandogdu, md northern institute for cancer research, newcastle university, ne1 7ru newcastle upon-tyne, uk gernot bonkat, md department of urology, university hospital basel, university of basel, basel, switzerland riccardo bartoletti, md dept. translational research and new technologies, university of pisa, 56121 pisa, italy truls e. bjerklund johansen,md department of urology, oslo university hospital, 0424 oslo, norway cai_stesura seveso 04/04/17 09:01 pagina 6 stesura seveso 371archivio italiano di urologia e andrologia 2020; 92, 4 review no conflict of interest declared. doi: 10.4081/aiua.2020.4.371 erectile dysfunction in common neurological conditions: a narrative review mohamad moussa 1, athanasios g. papatsoris 2, mohamed abou chakra 3, baraa dabboucy 4, youssef fares 5 1 urology department, zahraa hospital, university medical center, beirut, lebanon; 2 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece; 3 department of urology, faculty of medical sciences, lebanese university, beirut, lebanon; 4 department of neurosurgery, faculty of medical sciences, lebanese university, beirut, lebanon; 5 department of neurosurgery, neuroscience research center, faculty of medical sciences, lebanese university, beirut, lebanon. 8-11 moderate ed, 12-16 mild-moderate ed, 17-21 mild ed and 22-25 no ed (2). risk factors for ed are numerous, with patients over 40 years old demonstrating a significant association between ed and cardiovascular risk factors including hypertension, dyslipidemia, diabetes mellitus (dm), coronary artery disease, and the metabolic syndrome (3). organic causes are responsible for about 60% to 90% of all causes of ed. most frequent pathologies involved are vasculogenic. the most common etiologies are due to low blood inflow (large vessel atherosclerosis), dm, endocrinologic disorders, neurogenic, trauma, penile disease, iatrogenic, and drugs. it was estimated that 10-19% of the organic ed are neurogenic. the main causes are intracerebral (parkinson's disease, cerebrovascular disease, stroke, encephalitis, or temporal lobe epilepsy) or spinal cord etiologies (trauma, multiple sclerosis, myelodysplasia). peripheral nerves are also affected in alcoholic neuropathy, diabetic neuropathy, after surgery (radical pelvic surgery), and trauma (4). the first distinction of ed that should be established is psychogenic from organic. clues to suggest a psychogenic etiology include sudden onset, good quality spontaneous or self-stimulated erections, major life events, or previous psychological problems. conversely, gradual onset, lack of tumescence, and normal libido are more suggestive of an organic etiology (5). identification of ed can be made through questionnaires or a complete medical and sexual history. anamnesis and laboratory tests are sufficient in most cases to identify ed and to manage the treatment. supplementary tests are used in special cases or where confirmation of an etiological diagnosis is required (6). the current standard of care for ed consists of lifestyle changes such as management of diet, diabetes, hypertension, and weight loss, along with pharmacotherapies. the current gold standard treatment is the use of phosphodiesterase 5 inhibitors (pde5i) (7). pde5i are the most effective oral drugs for the treatment of ed, including ed associated with dm, spinal cord injury, and antidepressants. intraurethral and intracavernosal injections (ici), vacuum pump devices, and surgically implanted penile prostheses are alternative therapeutic options neurogenic erectile dysfunction (ned) can be defined as the inability to achieve or maintain an erection due to central or peripheral neurologic disease. neurologic diseases can also affect the physical ability and psychological status of the patient. all these factors may lead to a primary or secondary ned. medication history plays an important role since there are many drugs commonly used in neurologic patients that can lead to ed. the assessment of ned in these patients is generally evolving with the application of evoked potentials technology in the test of somatic and autonomic nerves, and functional magnetic resonance imaging. with the electrophysiological examinations, neurogenic causes can be determined. these tools allow to categorize neurologic lesion and assess the patient prognosis. the first-line treatment for ned is phosphodiesterase inhibitors. second-line treatments include intracavernous and intraurethral vasoactive injections. third-line treatments are penile prostheses. the efficacy and safety of each treatment modality depend on the specific neurologic condition. this review discusses the physiology, pathophysiology, diagnosis, and treatment of ed in multiple peripheral and central neurologic conditions, as well as for future research. key words: erectile dysfunction, neurogenic, neurologic disability, management. submitted 19 may 2020; accepted 6 august 2020 introduction erectile dysfunction (ed) is common (affecting 10-20 million men in the usa) and multifactorial disease due to organic and/or psychological factors that strongly impair the quality of life in man. during the past decade, many advances in the understanding of the pathophysiology of ed have been made and new therapeutic strategies have become available (1). ed is the inability to achieve or maintain an erection that is sufficient for satisfactory sexual performance and affects a considerable proportion of men at least occasionally. the severity of ed is often described as mild, moderate or severe according to the five-item international index of erectile function (iief-5) questionnaire, with a score of 1-7 indicating severe ed, summary archivio italiano di urologia e andrologia 2020; 92, 4 m. moussa, a.g. papatsoris, m. abou chakra, b. dabboucy, y. fares 372 when pde5i fail. testosterone supplementation in men with hypogonadism improves ed and libido (8). more invasive options exist for patients who do not respond to pde-5 i therapy or in whom it is contraindicated. alprostadil (prostaglandin e1) causes smoothmuscle relaxation and subsequent vasodilation by acting on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate (camp) concentration. prostaglandin e1 may be administered intraurethrally, where it is absorbed and transported throughout the erectile bodies. vasoactive drugs may also be injected intracavernosally. such therapy represents an important second-line therapy for ed. it is the most effective pharmacologic treatment but has a high dropout rate because of the associated pain (9). penile prostheses are the only surgical therapy option maintaining its significance as a cure for ed. there are convincing long-term results with a high degree of patient and partner satisfaction, high patient acceptance, and good functional durability of the mostly three-piece inflatable devices (10). in patients where pharmacological therapy is unhelpful or contraindicated, another option is the surgical approach. penile vascular surgery is suitable only for healthy men with acquired ed due to isolated stenosis of extra-penile arteries without any kind of generalized vascular disease. penile prosthesis implant is recognized, at present, as the most effective option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which the pharmacological approach is contraindicated or ineffective (11). we performed a narrative review to discuss the physiology, pathophysiology, diagnosis, and treatment of ed in multiple peripheral and central neurologic conditions. we also presented the novel therapies for ed in some neurologic diseases. materials and methods we searched electronic databases including pubmed, the scopus database for published studies that analyzed the role of the following medical subject headings terms: erectile dysfunction (or) ‘sexual dysfunction’ (or) ‘erection’ (or) ‘neural control’ (and) ‘erection’ (or) ‘electrodiagnostic test’ (and) ‘erectile dysfunction’ (or) ‘spinal cord injury’, ‘cerebrovascular accident’, ‘parkinson’s disease’, ‘multiple sclerosis’, ‘epilepsy’, ‘herniated disc’, ‘multiple system atrophy’, ‘peripheral neuropathy’ (and) ‘erectile dysfunction’ (or) ‘neurogenic erectile dysfunction’(and) ‘management’. this was done in order to ensure the comprehensive inclusion of articles related to neurogenic erectile dysfunction. the initial search resulted in 230 articles. after review, we initially excluded papers that were not relevant (85). at completion of review, articles were selected based on their clinical relevance related to the aim. data extraction was performed by three authors (ap, mm, ma). neurogenic erectile dysfunction overview neural control of erection erectile function requires the participation of autonomic and somatic nerves (sacral parasympathetic [pelvic], thoracolumbar sympathetic [hypogastric and lumbar chain], and somatic [pudendal] nerves), with the hypothalamic and limbic pathways playing significant roles. neurologic diseases can also challenge the physical ability of the individual to embrace, stimulate, engage in intercourse, and maintain urinary and bowel continence during sexual activity. all these factors may lead to a primary or secondary neurogenic ed (12). from the neurons in the spinal cord and peripheral ganglia, the sympathetic and parasympathetic nerves merge to form the cavernous nerve. the somatic nerves are primarily responsible for sensation and the contraction of the bulbocavernosus and ischiocavernosus muscles. the sympathetic pathway originates from the 11th thoracic to the 2nd lumbar spinal segments and passes through the white rami to the sympathetic chain ganglia. the parasympathetic pathway arises from neurons in the intermediolateral cell columns of the second, third, and fourth sacral spinal cord segments. the preganglionic fibers pass in the pelvic nerves to the pelvic plexus. the cavernous nerves are branches of the pelvic plexus that innervate the penis. no psychogenic erection occurs in patients with lesions above t9; the efferent sympathetic outflow is thus suggested to be at the levels t11 and t12 (13). sensory information from the genitals is a potent activator of pro-erectile spinal neurons and elicits reflexive erections. some pre-motor neurons of the medulla, pons and diencephalon project directly onto spinal sympathetic, parasympathetic, and pudendal motoneurons. they receive in turn sensory information from the genitals (14). the somatic sensory and motor innervation of the male genitalia is carried via branches of the pudendal nerve. the pudendal nerve arises from sacral spinal segments 2-4 (s2-s4). there are three branches of the pudendal nerve (dorsal nerve of the penis, perineal and inferior rectal), each carrying sensory input to the s2-s4 spinal levels from the genital structures, which is relayed through the central nervous system via ascending spinal tracts. the skeletal pelvic floor muscles receive somatic innervation mainly from the motor branches of the pudendal nerve (15). penile erection can be elicited by various stimuli integrated into the spinal cord and/or higher central nervous structures. the medial preoptic area (mpoa) of the hypothalamus is known to play a key role in the regulation of male sexual behavior (16). spinal erectile centers may be activated by genital afferents or by descending commands from higher central sites. an important inhibitory pathway from the nucleus paragigantocellularis has been demonstrated. the mpoa has been demonstrated to be crucially involved in sexual behavior. it is likely that it participates in the integration of hormonal and sensory cues necessary for sexual behavior. the medial amygdala and paraventricular nucleus of the hypothalamus have also been shown to play key roles (17). centrally as well as peripherally, many transmitters and transmitter systems are involved. dopamine, nitric oxide, oxytocin, and acth/alpha-msh, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. peripherally, the balance between contractant (noradrenaline, endothelins, angiotensins) and relaxant (no, vip, 373archivio italiano di urologia e andrologia 2020; 92, 4 neurogenic erectile dysfunction and related peptides, prostanoids) factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis (18). psychogenic erection is a result of audiovisual stimuli or fantasy. impulses from the brain modulate the spinal erection centers (t11-l2 and s2-s4) to activate the erectile process. reflexogenic erection is produced by tactile stimuli to the genital organs. the impulses reach the spinal erection centers; some then follow the ascending tract, resulting in sensory perception, while others activate the autonomic nuclei to send messages via the cavernous nerves to the penis to induce erection. this type of erection is preserved in patients with upper spinal cord injury. nocturnal erection occurs mostly during rapid-eye-movement (rem) sleep (13). electrodiagnostic test of genital nerves the sympathetic skin response (ssr) tests have been applied to evaluate the autonomic innervation of the genital skin. ssr are helpful in the evaluation of sexual impotence and of disorders affecting the pelvic floor as well as of well-known neuropathies (19). the ssr was useful as an indicator of the effect on efferent c fibers. despite ssr being a polysynaptic potential of long latency and regulated by the cerebral cortex, the present results show that it is advisable to record the latencies of ssr in the penis, where it seems to be more useful as a marker of lumbosacral and/or pudendal alterations (20). corpus cavernosum electromyography (cce) has been widely done to evaluate autonomic dysfunction in patients with ed. due to false-negative results on cce and penile ssr testing evoked cavernous activity (eca) seems more reliable for determining autonomic involvement in the pathophysiology of ed (21). eca can be recorded following a brief, startling stimulus. the noxious stimulus results in a generalized, sympathetic nervous system discharge that manifests throughout the body, including the corpus cavernosum. when the discharge is carried through the cavernous nerves, it can be recorded in the corpora cavernosa. if the sympathetic innervation to the corpus cavernosum is disrupted, then eca will not be present following the startling stimulus (22). in the last decade, several investigators have tried to develop corpus cavernosum electromyography (cc-emg) as a direct clinical method to evaluate the state of the penile autonomic innervation and the cavernous smooth muscle. both basic and clinical studies have shown promising results. however, its application as a diagnostic tool with clinical relevance was hindered by insufficient knowledge of cavernous smooth muscle electrophysiology, lack of standardization, technical and practical difficulties (23). erectile dysfunction (ed) in patients with spinal cord injury spinal cord injury (sci) is not as common as many other injuries, yet its physical and psychosocial consequences are devastating. very few people experience complete neurologic recovery after sci. the most common etiologies of sci were automobile crashes (31.5%) and falls (25.3%), followed by gunshot wounds (10.4%), motorcycle crashes (6.8%), diving incidents (4.7%), and medical/surgical complications (4.3%) (24). sci causes organic changes in men leading to ed, impaired ejaculation, and changes in genital orgasmic perception. a vast majority of men with both complete and incomplete sci will require treatment for ed (25). the effect of sci on the sexual response depends on the level and severity of the injury, as well as personal attributes. the level and completeness of sci are major determinants of sexual functioning. in the immediate postinjury period, both men and women lose the ability to have reflexive sexual responses. once reflexes return, reflexive arousal in men can be achieved with genital stimulation if the sacral spinal segments and peripheral pathway conveying sensations (cauda equina) are intact. however, these reflexive responses are usually short-lived, limited to the duration of stimulation, and often do not achieve a fully satisfactory response. if the injury is caudal to the 12th thoracic cord segment men can be expected to experience psychogenic arousal in response to visual, auditory, imaginative, tactile, and gustatory stimuli (26). sacral sparing refers to the preservation of sensory and/or motor function at the s4-s5 sacral segments and is used to refer to an incomplete sci; complete sci do not exhibit sacral sparing. one hundred percent of the men retained reflexogenic erections when the complete lesion was above the sacral segments. subjects with injury to the conus medularis and cauda equina were able to generate erections using psychogenic and reflexogenic stimuli in 90% and 80% of cases, respectively. the production of reflexogenic erections in this group is likely because lesions to the conus medularis or cauda equina are often partial. lesions below t11 generally only allow filling of the corpora cavernosa via reflexogenic erections (27). there are social and clinical factors associated with sexual dysfunction (sd) in men with traumatic sci, as well as predictive factors for sd. fixed partner, ejaculation, masturbation are protective factors for sd. ed, orgasmic, and infrequent sex dysfunction are predictors of sd (28). for most men with sci, the basic mechanisms for erection are preserved, including normal vasculature and an intact s2-4 reflex arc. they are often able to have reflex erections, but not psychogenic erections. these men typically respond well to pharmacological treatments used for the management of ed in men without sci, namely oral pde-5i such as sildenafil, vardenafil, and tadalafil (29). recommendations for the management of ed in sci men, if it is possible to obtain a satisfactory erection but of insufficient duration, use a venous constrictor band to find out if this is sufficient to maintain the erection. otherwise, it is recommended to use sildenafil. if sildenafil is not satisfactory then use ici with prostaglandin e (30). sildenafil seems more effective in the treatment of neurogenic ed secondary to upper motor neuron (umn) sci compared with that secondary to lower motor neuron (lmn) injury. its efficacy on lmn injuries does not seem different from placebo and administration of this treatment may not be effective in sci which has caused lmn symptoms (31). a review was conducted to assess the efficacy and safety of sildenafil treatment of ed in men with sci. as for the general efficacy, the proportion of archivio italiano di urologia e andrologia 2020; 92, 4 m. moussa, a.g. papatsoris, m. abou chakra, b. dabboucy, y. fares 374 patients who reported improved erections and ability to have intercourse was as high as 94%. up to 72% of intercourse attempts were successful. for measures of erectile function, 5 of the 6 studies showed statistically significant improvements among sildenafil-treated versus placebo-treated patients. erectile response rates were generally higher in patients with incomplete versus complete sci and patients with umn versus lmn lesions (32). a post hoc analysis of pooled data from two randomized, controlled trials (rct) of sildenafil was conducted in europe, australia, and turkey. it was found that all international index of erectile function outcomes, including achieving and maintaining erections and ejaculation frequency, were statistically significantly greater with sildenafil vs. placebo, including the subgroup with complete sci (p < .01 for all comparisons). the percentage of successful intercourse attempts with sildenafil (53% vs 12%) and preference for sildenafil (96% vs. 4%) vs. placebo were significant (p < .001), including the subgroup with complete sci (33). a rct was implemented to assess the efficacy of sildenafil in men with ed associated with complete or incomplete sci and to assess its effects on quality of life (qol). results showed that compared with placebo, sildenafil produced higher levels of successful sexual stimulation, intercourse success, satisfaction with sexual life and sexual relationship, erectile function, overall sexual satisfaction, and an improved erectile dysfunction inventory of treatment satisfaction score, with no clinically relevant effects on vital signs. sildenafil seemed more effective in patients with incomplete sci than in those with complete sci (34). another study was done by giuliano et al. to assess the efficacy and safety of oral sildenafil in men with ed caused by traumatic sci. a total of 178 men received placebo or sildenafil 1 hour before sexual activity for 6 weeks. the 50-mg starting dose could be adjusted to 100 or 25 mg based on efficacy and tolerability. of 143 men with residual erectile function at baseline, 111 (78%) reported improved erections and preferred sildenafil to placebo. for all men (including those who reported no residual erectile function at baseline), 127 of 168 (76%) reported improved erections and preferred sildenafil to placebo (35). a study done by gans et al. reported that there was significant improvement in quality of erection (p < .05) if sildenafil used in sci patients, but no change in satisfaction (36). another study was done determine the efficacy and safety of tadalafil when taken on demand by men with ed secondary to sci. it conclude that tadalafil (10 mg and 20 mg) improved erectile function and was well tolerated by men with ed secondary to traumatic sci. the 2 most common treatment-emergent adverse events in the tadalafil group compared with placebo were headache (8.5% vs. 4.5%) and urinary tract infection (7.7% vs. 6.8%) (37). del popolo et al. compared the safety, time/duration effectiveness, and the impact on the qol of tadalafil 10 mg vs. sildenafil 50 mg in the treatment of ed in sci patients. tadalafil allowed a majority of men in their trial to achieve both normal sexual functioning up to 24 h postdosing compared to sildenafil (p < 0.01) and improved overall sex life satisfaction as well as sexual relations with a partner (38). soler et al. compared the efficacy and safety of sildenafil (viagra), tadalafil (cialis) and vardenafil (levitra) for ed in sci patients. pde5i were effective in 85% of the patients on sildenafil, 74% of the patients on vardenafil, and 72% of the patients on tadalafil. the mean duration of erection was 34, 28, and 26 min, respectively. adverse effects were mild, usually attenuated with continued dosing. more than 70% of the patients on vardenafil and tadalafil required higher doses of 20 mg, whereas 50 mg of sildenafil was effective in 55% of the patients. their data indicate that sildenafil is more effective in treating ed in sci patients (39). studies have shown improvements in erectile function based on iief score compared to placebo when pde5i used in the treatment of ed in patients with sci, results are summarized in table 1 (31, 34-41). sánchez ramos et al. reported that sildenafil is an effective, well-tolerated treatment for ed caused by sci, regardless of the cause, neurological level, american spinal injury association (asia) grade, and time since table 1. clinical trials testing the efficacy of pde5i to treat ed in patients with sci. authors n. of patients treatment main results khorrami et al. (31) 105 50-100 mg sildenafil vs. placebo sildenafil was effective in 82% of patients umn disease and its efficacy was statistically higher than placebo (82 vs. 25%, p < 0.05) ergin et al. (34) 50 50-100 mg sildenafil vs. placebo sildenafil produced higher levels of successful sexual stimulation, intercourse success, erectile function, vs. placebo giuliano et al. (35) 178 50-mg starting dose of sildenafil adjusted 132 of 166 (80%) of men reported that sildenafil improved sexual intercourse compared with 17 of 166 men (10%) to 100 or 25 mg vs. placebo reporting improvement with placebo gans et al. (36) 17 sildenafil 25mg increased by 25 mg as needed erectile function significantly improved (p < .05) after 5.3 +/2.2 months when compared with baseline or previous therapies (p < .05) giuliano et al. (37) 186 tadalafil, 10 mg titrated to 20 mg vs. placebo tadalafil group compared with the placebo group was significantly greater (p < .001) in mean per-patient percentage of successful penetration attempts and percentage of improved erections del popolo et al. (38) 28 tadalafil 10 mg vs. sildenafil 50 mg tadalafil 10 mg significantly increased the percentage of successful intercourse attempts at 12–24 hours compared with sildenafil soler et al. (39) 240 50 to 100 mg for sildenafil, from 10 pde5 inhibitors were effective (rigidity enough for penetration) in 85% of the patients on sildenafil, 74% of the patients on vardenafil to 20 mg for vardenafil and tadalafil and 72% of the patients on tadalafil lombardi et al. (40) 65 10-20 mg of tadalafil patient using tadalafil maintained significant statistical improvement in erectile function, sexual satisfaction, and overall satisfaction compared with baseline (p < 0.05) sánchez ramos et al. (41) 170 sildenafil 50 mg it was reported by 88.2% of the patients and 85.3% of their partners that treatment with sildenafil had improved their erections, regardless of the baseline characteristics of the spinal cord injury and erectile function ed: erectile dysfunction, sci: spinal cord injury, pde5i: phosphodiesterase inhibitors, umn: upper motor neuron. 375archivio italiano di urologia e andrologia 2020; 92, 4 neurogenic erectile dysfunction injury (41). rizio et al. reviewed 10 articles, which used the iief to study satisfaction and/or efficacy of pde5is sildenafil, tadalafil, and vardenafil in the treatment of ed. minimal adverse effects were reported in the articles. of the 739 patients studied in the 10 articles, only 102 patients reported any adverse effects, most of which were mild. headache, flushing, hypotension, nasal congestion, and dyspepsia were the most commonly noted adverse reactions. these side effects are not only found in men with sci but also in men without sci who have ed (42). patients with sci, especially those with lesions above t6, are at great risk for hypotension. sildenafil, can exacerbate this hypotension. sildenafil induces significant hypotension in people with cervical level injuries more so than in thoracic level injuries and can cause dizziness in both populations (43). in another study, tadalafil use in people with sci above t6 is safe with concerning not causing hypotension; hemodynamic changes that occurred 12-36 h post-administration were compensated for by elevations in heart rate (44). ici of vasoactive agents and intraurethral injection has been successfully used in the treatment of ed in patients with sci. trial results were summarized in table 2 (4556). a pharmacologic erection program was given to the patient with sci, using a fixed combination of prostaglandin e1 (pge1) and papaverine. the dosage range was 0.10 to 0.50 cc. this simplified pharmacologic erection program offers safe, well-accepted, and effective therapy for ed to sci population with very high patient satisfaction (45). intracavernosal papaverine injection treatment was used to treat ed in sci patients. satisfactory erection sufficient for coital penetration was possible in 97% of patients (46). the ici and self-injection of papaverine-phentolamine technique offer the possibility of achieving a full erection which continues for a few hours and disappears afterward in a group of sci patients with erectile impotence (47). intraurethral prostaglandin e1 (alprostadil, muse) appears to be somewhat effective in creating erections; however, these were less rigid erections than those obtained with ici and provided less overall satisfaction. it should always be used in the patient with sci after the placement of a constriction ring to prevent hypotension (48). a prospective study concerns 36 spinal cord injured men was implemented to confirm the efficiency of ici in the treatment of ed in sci patients and to determine the mean necessary dose to obtain a functional erection. the findings confirm the efficiency of ici in the management of ed in sci. the average doses required to obtain a functional erection was 12.3 (+/4.8) microgram with alprostadil and 14 (+/5.4) mg with moxisylyte (49). in another study, ici of prostaglandin e1 had significantly improved the erectile condition of the patient with sci. patients received testing dosage starting from 5 micrograms with increasing dosage (maximum 20 micrograms) no systemic side effect or any other complication was noted except that pain at the injection site was complained of in two patients with an incomplete lesion (50). vacuum erection devices (ved) can be presented to sci men along with other options for treatment of ed. a study done by denil et al. showed that after 3 months of the use of a ved, 93% of the men and 83% of the women reported rigidity sufficient for vaginal penetration, with an average duration of 18 minutes. ved is effective in many couples in the treatment of ed in sci patients (57). a data from another trial suggest that ved is a feasible, safe, noninvasive alternative and possibly a better initial treatment for the management of impotence secondary to sci (58). ved use is not without a risk, two cases of subcutaneous penile hemorrhage in patients using anticoagulant therapy and one case of penile gangrene occurred in three different sci males (59). penile prostheses, introduced as the first effective organic treatment for ed over three decades ago, have an important role in the treatment of ed when other nonprosthetic treatment options have proven unsatisfactory (60). the insertion of malleable penile prostheses in patients with sci is associated with low complication rates and good patient satisfaction. multiple studies showed its efficacy for ed in sci patients, results are summarized in table 3 (61-65). a trial implemented by kim et al., where a total of 48 patients with a sci, who underwent malleable penile prosthesis (ams 600) insertion from 1990 to 2004 were evaluated. the overall patient satisfaction rate was 79.2%. complications occurred in eight patients. wound infections in four patients. two patients were treated with conservative management, and two were managed through prostheses removal. other complications were erosion in two patients, uncontrolled table 2. clinical trials testing the efficacy of pde5i to treat ed in patients with sci. authors agents used mode of effective administration or not for ed zaslau et al. (45) combination of pge1 ici effective and papaverine kapoor et al. (46) papaverine injection ici effective wyndaele et al. (47) papaverine-phentolamine ici effective bodner et al. (48) pge1 (alprostadil, muse) iua effective lebib ben achour et al. (49) alprostadil, moxisylite, papaverine ici effective tang et al. (50) pge1 ici effective hirsch et al. (51) pge1 ici effective earle et al. (52) papaverine, papaverine plus phentolamine or pge1 ici effective sidi et al. (53) papaverine hydrochloride ici effective or papaverine and phentolamine mesylate beretta et al. (54) papaverine ici effective sønksen et al. (55) papaverine ici effective momose et al. (56) papaverine hydrochloride ici effective pge1: prostaglandin e1, ici: intracavernosal injection, sci: spinal cord injury, ed: erectile dysfunction, iua: intraurethral administration. table 3. clinical trials testing the efficacy of penile prosthesis in patients with sci. authors type of prosthesis effective or not for ed kim et al. (61) malleable effective iwatsubo et al. (62) shirai-type silicone penile implants partially effective green et al. (63) semi-rigid and inflatable prostheses effective gross et al. (64) semi-rigid, semi-flexible or flexible prostheses effective sci: spinal cord injury, ed: erectile dysfunction. archivio italiano di urologia e andrologia 2020; 92, 4 m. moussa, a.g. papatsoris, m. abou chakra, b. dabboucy, y. fares 376 penile pain owing to excessive prosthesis length in one patient, and supersonic transporter deformity in one patient (61). iwatsubo et al. reported that the prosthesis improved sexual function in 15 (41%) patients, 18 (48%) patients were unchanged and four (11%) patients were dissatisfied (62). gross et al. reported that when paraplegic patients are able to regain sexual activity after successful implantation of a penile prosthesis, their self-confidence is increased (64). in men with sci, sildenafil is the most effective treatment and is widely accepted. ici, ved therapy in sci patients should be used according to the patient's preference and choice (65). in sci patients, penile implants may help to keep an external condom catheter in place and provide more penile stability for intermittent catheterization. however, they have an increased risk of infection. semirigid rods have an increased risk of erosion. although convenient to use, pde5i are usually not effective in lower motor injuries. the hypotensive effects of intraurethral prostaglandins and pde inhibitors need to be considered in sci men with injuries at or above t6. ici is very effective modality of therapy (66). the brindley procedure consists of a stimulator for sacral anterior-root stimulation and a rhizotomy of the dorsal sacral roots to abolish neurogenic detrusor overactivity. the brindley procedure is suitable for a selected group of skeletally mature patients with complete sci and detrusor overactivity. erections can be evoked in a substantial number of patients, but results vary considerably. this can be explained by the relatively low number of patients that actually use the stimulator to evoke erections for sexual intercourse (0-32%) (67). lombardi et al. showed that 45% of men with incomplete sci who were submitted to sacral neuromodulation reached and maintained a normal iief-5 score for > 3 years (68). erectile dysfunction (ed) in patients with cerebrovascular accident a marked decline in sexual activity has been reported in stroke patients. sd and dissatisfaction with sexual life seem to be common both in male and female stroke patients and in their spouses. decreased libido, sexual arousal, and satisfaction are related particularly to the presence of the hemisensory syndrome. the etiology for sd after stroke is multifactorial including both organic and psychosocial factors (69). a study found that the occurrence of ed after ischemic stroke was 77.8%, significantly higher than the common ed. stroke and ed have common risk factors, including hypertension and hyperlipidemia (70). acute ischaemic stroke in brain areas contributing to male sexual function may impair erectile function depending on the lesion site. there are an associations between stroke-related ed and lesion sites in the right occipito-parietal cortex and thalamus, as well as in the left insula and adjacent temporo-parietal areas. it was demonstrated associations between the deterioration of erectile function and lesion sites in the right occipital and thalamic region, and the left parietal association area (71). jung et al. concluded in their study that the sexual desire, erectile function, and ejaculatory function were impaired after stroke. a lack of sexual desire was the major cause of an absence of sexual intercourse (72). if the right hemisphere is dominant for activation and this capacity is critical for normal sexual function, a greater incidence of impaired sexual function is occurred after right than after left hemisphere stroke (73, 74). the presence of post stroke emotional incontinence (excessive/inappropriate laughing/crying) is a factor related to decreased post stroke sexual activity, more so in chronic than in subacute stages (75). sexual disorders after stroke are thought to be due to multiple etiologies, including both organic (lesion localization, premorbid medical conditions, and medications) and psychosocial (fear of recurrences, loss of self-esteem, role changes, anxiety, and depression) (76). as the sexual function is an important component to quality of life and activities of daily living, physicians and rehabilitation specialists, including physical, occupational, and speech therapists, should receive training in addressing sexuality in the treatment of post-stroke patients (77). sexual rehabilitation needs to be an integrative part of stroke patients' rehabilitation process, preferably at the interdisciplinary level (78). exploring individual stroke survivor counseling preferences periodically for recovery may be a useful strategy for delivering the desired information at the most appropriate time (79). there is a lack of studies that assessed a pharmacological intervention for ed post-stroke. a rct was implemented to assess the effectiveness of a structured sexual rehabilitation program compared with written information alone regarding sexual and psychological functioning. it concludes that the provision of written information alone appears to be as effective as a 30-min individualized sexual rehabilitation program in an inpatient setting (80). a study was done by tibaek et al. to evaluate the effect of pelvic floor muscle training (pfmt) on measured erectile function as an indicator of sexuality in men with lower urinary tract symptoms after stroke. the data was insufficient to provide any reliable indication of benefit or risk of physical therapy targeted towards pelvic floor muscles for improving erectile function following stroke (81). besides pharmacological treatment, one of the most important, but underestimated, success factors of ed therapy are undeniably a proper counseling, which is mandatory to provide correct information on post-stroke sexuality (82) a systemic review had demonstrated that both neuroprotective and neurorestorative effects of pde5i in animal models of stroke, though the specific underlying signaling pathways relating to pde5 inhibition and cgmp may remain serendipitous in some studies. there is currently limited evidence on the effects of selective pde5i in human stroke patients (83). erectile dysfunction(ed) in patients with parkinson’s disease parkinson's disease (pd) is the second most common progressive neurodegenerative disorder affecting older american adults and is predicted to increase in prevalence as the united states population ages. resulting from a pathophysiologic loss or degeneration of dopaminergic neurons in the substantia nigra of the midbrain and the development of neuronal lewy bodies. characterized by 377archivio italiano di urologia e andrologia 2020; 92, 4 neurogenic erectile dysfunction both motor and non-motor symptoms, pd patients classically display rest tremor, rigidity, bradykinesia, and stooping posture (84). sexual dysfunction is one of the more disabling and poorly investigated aspects of pd. several variables should be considered when evaluating sd in a disease in which physical, psychological, neurobiological, and pharmacological features merge and are not easily distinguishable (85). dopamine has a fundamental role in the mediation of erectile function, whereas testosterone deficiency has been shown to be more common among pd patients than age-matched controls. central regulation of erectile function is dependent on dopaminergic stimulation (86). in addition, hypothalamic dysfunction is mostly responsible for sd (decrease in libido and erection) in pd, via altered dopamine-oxytocin pathways, which normally promote libido and erection (87). the risk of pd was higher for patients with ed along with dm or hypertension than for patients without ed or counterpart comorbidities. ed has been reported as a risk factor for the development of pd (88). hypersexuality (hs) is usually considered to constitute a marked increase in sexual interest, arousal, and behavior, which has adverse consequences for the patient and their partner. hs, as a complication of treated pd, is rare in absolute terms, with estimates of prevalence from postal questionnaires and clinical surveys of approximately 2% to 4%( 89). sildenafil citrate may be considered to treat ed in patients with pd as concluded in multiple studies, results are summarized in table 4 (90-94). a study was implemented by raffaele et al. to assess the efficacy and safety of oral sildenafil, in depressed men with idiopathic pd and ed. thirty-three men were enrolled in a 4month prospective, open-label, fixed-dose study, and received 50 mg of sildenafil in the home setting approximately 1 hour before sexual activity, not more than once daily. at the end of the study, improved erections were reported by 84.8% of patients. sildenafil significantly increased patients' ability to achieve and maintain erections. a clear improvement of depressive symptoms was observed in 75% of patients. sildenafil was well tolerated in all the patients (91). in another study, there was statistically significant improvement in total sexual health inventory for men scores (23.8 +/2.0 vs 16.6 +/2.8; p = 0.01), overall sexual satisfaction (p = 0.03), satisfaction with sexual desire (p = 0.04) with use of sildenafil citrate for patients with pd (92). sildenafil has no treatment effects for quality of life (p = 0.3) or pd symptoms (p = 0.86) (93). hussain et al. assess the efficacy and safety of sildenafil citrate in men with ed and parkinsonism due either to pd or multiple system atrophy (msa). sildenafil citrate (50 mg) is efficacious in the treatment of ed in both conditions; however, it may unmask or exacerbate hypotension in msa. as pd may be diagnostically difficult to distinguish from msa, especially in the early stages, measurement of lying and standing blood pressure before prescribing sildenafil to men with parkinsonism was recommended (94). there were no clinical trials have studied the potential effectiveness of the other pde-5 i (vardenafil or tadalafil) in the treatment of ed for the patient with pd. apomorphine, a short-acting d1and d2-like receptor agonist, is the only drug proven to have efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. dopaminergic side effects such as nausea, somnolence, and hypotonia, are often mild (95). the benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in pd (96). a study was done by heaton et al. evaluating the efficacy and side effects of apomorphine in men with no documentable organic cause of ed. men with primarily psychogenic impotence were tested with one of four protocols of an apomorphine preparation (preliminary sublingual liquid, preliminary 5 mg tablet, aqueous nasal spray, and new 3 and 4 mg controlled absorption tablets). seven of 10 evaluable patients responded to the sublingual liquid preparation but the majority experienced significant nausea. the preliminary 5 mg tablet and aqueous forms did not produce useful responses. the newly formulated controlled absorption 3 and 4 mg tablets were tested in 12 men. eight of 12 (67%) developed erections (97). its role in the management of ed has been suggested for men with pd but not totally validated. testosterone deficiency is associated with a decline in erectile function and testosterone levels are inversely correlated with increasing severity of ed. a significant proportion of men who fail to respond to a pde5i are testosterone deficient (98). testosterone deficiency may cause signs and symptoms of the nonmotor symptoms seen in pd. in a prospective open-labeled pilot study, testosterone topical gel was administered daily to testosteronedeficient men with pd. a daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with pd. although there were trends in improvement in other nonmotor and motor symptoms of pd (99). in contrast, the results of the test-pd study demonstrated that testosterone therapy was generally well-tolerated in elderly men with pd and probable testosterone deficiency. while there was no significant difference in the motor and nonmotor scales between the testosterone therapy and placebo groups at the end of 8 weeks compared with baseline (100). urologist should be particularly cautious in the treatment of low testosterone concentrations in men with pd until more definitive studies were done. pergolide substantially improved sexual function in the younger male patients who were still interested in sexual activities. in such cases, the introduction of pergolide might be a better choice than treatment with sildenafil, which usually meets several contraindications in the comtable 4. clinical trials testing the efficacy of sildenafil for ed in patients with pd. authors n. of patients dosage of sildenadil effective or not for ed raffaele et al (91) 33 50 mg effective zesiewicz et al (92) 10 50-100 mg effective bernard et al (93) 20 started at 50 mg and adjusted effective to 25, 50, or 100 mg after 2 weeks hussain et al (94) 12 50 mg effective ed: erectile dysfunction, pd: parkinson's disease. archivio italiano di urologia e andrologia 2020; 92, 4 m. moussa, a.g. papatsoris, m. abou chakra, b. dabboucy, y. fares 378 mon pd male population (101). dose reduction or discontinuation of a dopamine agonist is recommended when patients experience hypersexuality. despite the lack of therapeutic options, discussing sexuality with pd patients remains essential. the hesitation of both patients and neurologists to discuss sexuality is what may cause an ongoing circle of avoidance. routine screening for ed may break this vicious circle (102). erectile dysfunction (ed) in patients with multiple sclerosis multiple sclerosis (ms) is a chronic demyelinating disease of the central nervous system. the main autonomic nervous system disorders include sweating abnormalities, lower urinary tract dysfunctions, gastrointestinal symptoms and, sd. among these, sd is common, but often underestimated symptom (103). the most common complaints of sexual dysfunction in men with ms are ed (50%-75%). one well-accepted hypothesis is that sd arises from spinal cord damage due to autoimmune responses. recently, however, experts have suggested that sd in ms may be due not only to lesions affecting the neural pathways involved in physiologic function but also to psychological factors (104). ed in men with ms is related to neurological dysfunction, psychological factors, side effects of medication, or generalized ms symptoms, such as fatigue or micturition problems, usually in combination. the question of sexual dysfunction should always be broached during routine follow-up, regardless of age and social status (105). sildenafil treatment for ed in men with ms was effective and well-tolerated. a study implemented by fowler et al. to assess the efficacy and safety of sildenafil citrate in men with ms and ed. overall, 217 men received sildenafil (25-100 mg; n = 104) or placebo (n = 113) for 12 weeks. after 12 weeks, patients receiving sildenafil had higher mean scores for iief achieving and maintaining an erection compared with those receiving placebo (p < 0.0001), and 89% (92/103) reported improved erections compared with 24% of patients receiving placebo (p < 0.0001) (106). another trial was enrolling 203 patients with ms, 102 into the sidenafil group, and 101 in the placebo group. improved erections were reported by 32.8% of patients receiving sildenafil and 17.6% of those receiving placebo. compared with placebo, sildenafil has little effect on ms emergent ed (107). sildenafil cannot be recommended for the routine treatment of ed in every patient with ms. tadalafil was proved as an effective and safe treatment for males with ms suffering from ed (108). intracavernous self-injection of vasoactive drugs is a wellaccepted therapy for the management of ed in neurogenic disorders. vidal et al. presented the results of a selfinjection program in seven ms patients. all patients showed an excellent erectile response and had penile rigidity sufficient for sexual intercourse during an acceptable time, with minimal complications (109). ici of papaverine was tested in a group of 29 patients with ms and ed. acceptable rigidity was obtained in 27 patients of whom 23 started to use self-injections as treatment. minor hematomas or ecchymoses were reported in 16 cases. two patients developed penile indurations after 6 and 19 injections respectively (110). a study confirms the safety and efficacy of self-administered intracavernous pge-1 for neuropathic impotence including the ms patients (111). counseling intervention is crucial for patients with ms and ed. those interventions consist of counseling sessions, communication with the ms medical treatment team, education, and tailoring symptomatic treatments so they interfere less with sexual function (112). erectile dysfunction (ed) in patients with epilepsy sd is a common comorbidity in people with epilepsy that adversely affects their quality of life. nearly one-half of men and women with epilepsy have sd. there is limited evidence to indicate that sexual function improves in patients rendered seizure-free following epilepsy surgery. multiple mechanisms including direct effects of epilepsy, effects of antiepileptic drugs (aed), and psychosocial factors contribute to sd in epilepsy. circumstantial evidence indicates that seizures and interictal epileptiform discharges can directly affect the hypothalamic-pituitary axis as well as the production of gonadal steroids. enzyme-inducing antiseizure drugs cause sd by affecting the metabolism of gonadal steroids (113). clinicians need to investigate such problems carefully, both because of their multifactorial nature and because patients and physicians alike may often fail to recognize or be reluctant to acknowledge them (114). epileptic men have been found to have an increased risk of ed of up to 57%. certain sd have been associated with specific periods of seizure activity, and fall into two discrete categories: those directly related to the epileptic discharge period (ictal), and those unrelated in time to seizure occurrence (interictal). hypersexuality has been connected to ictal seizure activity while hyposexuality has been linked to interictal seizure activity (115). various studies have described an unusually common incidence of sexual and reproductive dysfunction in patients affected by temporal lobe epilepsy (tle). the results of a study done by daniele et al. suggests a reduction of sexual interest in patients with right tle as compared with left tle in both men and women. no significant difference was found between right and left tle groups concerning most aspects of sexual performance (116). evidence suggests that people with temporal lobe epilepsy have reduced genital blood flow in response to erotic stimulation; the etiology of this phenomenon is not well understood, but disruption of the limbic and frontal cortex by epileptic activity may be implicated (117). epileptic discharges from the temporal lobe may influence the release of hormones from the hypothalamic-pituitary axis. serum androgen concentrations in men with epilepsy are significantly low in men with seizures (118, 119). it is noticeable that aeds may also alter endocrine function in both men and women with epilepsy and this alteration may lead to clinically significant reproductive endocrine disorders in certain cases. in recent years, the effects of enzyme-inducing aeds on androgen metabolism have been evoked as a possible etiologic factor. these drugs have been found to cause an increase in total testosterone and sex hormone-binding globulin 379archivio italiano di urologia e andrologia 2020; 92, 4 neurogenic erectile dysfunction (shbg), but a decrease in free testosterone (120). the enzyme stimulating aeds (phenytoin, topiramate, phenobarbital, and carbamazepine) raise the hepatic synthesis of shbg that lessens the accessibility of testosterone. additionally, enhanced sex hormone metabolism and contraceptive hormones are not found with the use of aeds that do not stimulate hepatic enzymes (lamotrigine, valproate, gabapentin, and vigabatrin) (121). management of sd thought to be caused by anti-convulsants should include the cessation of the offending drug, and consideration of switching to alternative anti-convulsants that have been reported to improve sexual function such as oxcarbazepine, and lamotrigine (122). a study showed that switching aed treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ed side effects observed with carbamazepine (123). adding testosterone for a short time in cases of low-normal testosterone levels (300 to 400 ng/dl) seems helpful in some men who did not respond to initial treatment with pde-5i alone and in whom testosterone therapy is not contraindicated (124). concentrating on hormone levels alone as an explanation of sd in epilepsy represents an overly simplistic approach to the problem (125). the therapy of sd in epilepsy depends on its cause. in cases of hormonal alterations, the first step is a change of antiepileptic regimen. instead of enzymeinductor antiepileptics and valproate, new antiepileptic drugs should be prescribed. at present, the most investigated antiepileptic drug is the oxcarbazepine with a positive effect on antiepileptic-induced male sd, however, lamotrigine seems to be also beneficial. if the hormonal and sd cannot be eliminated by drug changes, androgenic therapy or bromocriptine may be required. testosterone may not only be beneficial on sexual functions but can reduce also the seizure frequency (126). evidence suggests an influence of pde5i on seizure susceptibility in humans. in addition, preclinical studies have demonstrated the role of nitric oxide metabolites in the facilitation of the paroxysmal phenomenon (127). recent evidence indicates that sildenafil may exert some central effects through the enhancement of nitric oxide (no)-mediated effects. no is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through nomediated mechanisms (128). although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. a study was to investigate the effect of tadalafil on seizure threshold in three acute seizure tests in mice. it concludes that tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine (129). in summary, pde5i should be used with great caution in men with epilepsy. erectile dysfunction (ed) in patients with herniated disc lumbar disc herniation (ldh) is the most common pathologic condition that is responsible for radicular pain. in patients non-responsive to medical therapy disc surgery is indicated. lumbosacral disc disease may interfere with the nerve transmission for erection through multiple autonomic and somatic pathways (129). braun et al. reported that herniated disc was seen in 23.2% of 8000 men with ed (130). akbas et al. implemented a study to evaluate patients' sexual problems and sexual behavior patterns before and after surgical treatment of ldh. forty-three patients were included in the study (mean age 41.4 years). the frequency of sexual intercourse before the operation was reduced by 78% of cases compared with the pain-free period. the frequency of intercourse was found to have increased (p = 0.01), while the description of any type of sexual problem had decreased (p = 0.005) significantly (131). ldh largely impacted sexual desire, activity, and satisfaction. adjustment in sexual position was required in a large number of patients to avoid discomfort during sexual activities. surgical treatment improved the quality of sexual activities (132). in another study, ed was more frequent in patients with ldh, the treatment of ldh had positive effects on ed (133). akca et al. reported four patients with sexual and sphincter dysfunction, including two women and two men, aged between 20 and 52 years. all patients had a perianal sensory deficit and sexual and sphincter dysfunction. magnetic resonance imaging (mri) of three patients displayed a large extruded disc fragment at the l5-s1 level. a syndrome with a perianal sensory deficit, paralysis of the sphincter, and sd may occur in patients with lumbar l5-s1 disc disease. the improvement of perianal sensory deficit after surgery was counteracted by a trend toward disturbed sexual function (134). xu et al. studied 90 male patients with intervertebral disc herniation treated by a lumbar discectomy, who were divided into three age groups of equal number: groups a (< 45 yr), b (45 55 yr) and c ( > 55 yr). they obtained the iief-5 scores of the patients preoperatively and at 12 months after surgery. the iief-5 scores at 12 months after surgery were 21.3 +/3.3, 16.8 +/1.3 and 14.1 +/1.0 in groups a, b and c. group a showed better improved erectile function than b and c ([51.17 +/6.25 ]% vs [36.31 +/4.28]% and [22.71 +/5.68]%, p < 0.05). early decompression surgery according to different etiological factors is very important for erectile function recovery in young and middle-aged male patients (135). one of the consequences of the discopathy is pressure on the spinal cord or nerve roots that supply the genitals and sexual centers located in the cord. in addition, the accompanying pain and limitation of mobility can lead to the occurrence of sd. the pain and neurological symptoms associated with intervertebral disc disease reduce the patients' satisfaction with their sex lives. patients with lumbosacral discopathy noted a change in sexual performance, often resulting in passivity, discouragement, weakness, or a complete lack of interest in sex. the disorders also affect the emotional state (136). there is significant sexual impairment in men with lesions of the cauda equina or conus medullaris. this is poorly correlated with neurological and emg findings and has received insufficient medical attention (137). choy et al. describe the case of two patients with ed who were treated with percutaneous laser disc decompression as outpatients. in addition to the early return of erectile function in both cases, immediate pain relief was archivio italiano di urologia e andrologia 2020; 92, 4 m. moussa, a.g. papatsoris, m. abou chakra, b. dabboucy, y. fares 380 achieved in the second case. follow-up visits confirmed continued normal sexual function and lack of pain (138). orlin et al. reported a case of a 35-year-old male with normal erectile function up until the age of 18 years subsequently suffered permanent ed for the next 17 years. ct of the lumbar spine showed a large protrusion of the intervertebral disc l5-s1. after operative removal of the protrusion, a normal erection was achieved after 15 days and urine flow improved at 1 and 2 months and became normal after 3 months. both erectile and bladder functions continued to be normal 10 years later. thus, the effects of long-lasting mechanical compression of parasympathetic nerves need not be irreversible (139). kulaksizoglu et al. assessed the effect of lumbar disc herniation surgery for low back pain on the erectile functioning. they reported that ed rates have improved in 31.7% of those previously with ed in a 3 month period after the surgery. best results were obtained in those patients with mild ed preoperatively. moderate and severe ed may be related to a more severe nerve injury or to vascular and/or psychiatric factors. evaluation of erectile functioning should routinely be performed in patients with lumbosacral disc disease (140). erectile dysfunction (ed) in patients with multiple system atrophy multiple system atrophy (msa) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with parkinsonism or cerebellar ataxia. novel therapeutic options targeting disease modification have been investigated in clinical trials. these include riluzole, recombinant human growth hormone, and minocycline (141). urinary and ed symptoms are prominent early features in men with msa. autonomic failure, considered until recently to be the cause of ed in these men, is commonly expressed through symptoms of orthostatic hypotension. in a study conducted by kirchhof et al., the onset of ed had preceded the onset of bladder symptoms in 58% and the onset of hypotension symptoms in 91% of these men. the earlier occurrence of ed in men with msa suggests a lack of a causal relationship to hypotension (142). there is an ongoing debate on the causes of ed in msa. impairment of dopaminergic mediated pathways in the central nervous system, which is heavily implicated in erectile function, is most likely involved. other diseaserelated factors such as psychosocial stress, the burden of chronic illness, changed appearance, fatigue, and relative immobility contribute to ed (143). sildenafil citrate (50 mg) is efficacious in the treatment of ed in parkinsonism due to pd or msa; however, it may unmask or exacerbate hypotension in msa (94). its administration may not be recommended in patients with symptomatic orthostatic hypotension. the use of direct injections of alprostadil, either intracavernosal or intraurethral is another option (144). erectile dysfunction (ed) in patients with peripheral neuropathy peripheral nervous system (pns) disorders may cause sd in patients of both genders. these disorders include mainly polyneuropathies (particularly those affecting the autonomic nervous system and localized lesions affecting the innervation of genital organs. impaired neural control may produce a malfunction of the genital response consisting of loss of genital sensitivity, ed, ejaculation disorder, and orgasmic disorder (145). diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms decreased or disappeared achilles tendon reflex and/or abnormal vibration perception. a study that included 287 male japanese patients with dm type 2, age (19-65 years) was implemented to demonstrate that diabetic neuropathy is positively associated with severe erectile dysfunction among japanese dm type 2 patients aged < 65 years (146). the proposed mechanisms of ed in diabetic patients are represented by vasculopathy, neuropathy, visceral adiposity, insulin resistance, and hypogonadism. both somatic and autonomic neuropathies may contribute to diabetes-induced ed due to the impairment of sensory impulses from the penis to the reflexogenic erectile center (147). in an attempt to understand better the role of vascular and neurogenic alterations in the pathophysiology of diabetic impotence, benvenuti et al. studied 29 impotent male patients with dm. results confirm that vascular obstruction, more than nerve damage, plays a primary role in the pathophysiology of diabetic erectile failure, and stress the importance of psychogenic factors. the observation that some patients presented marked involvements of both arterial supply and neurological pathways only a few years, or even 1 year, after the diagnosis of the disease, indicates the need for an early screening of the vascular and neurological status, even in asymptomatic patients (148). while hecht et al. found that the tests indicating neuropathy showed abnormalities in men with diabetic ed as frequently as in men with neuropathic ed. some tests even suggested neuropathy more often in diabetic than in neuropathic ed (149). the microvascular deficit in the vasa nervorum of nerve trunks and ganglia is a major trigger for a cascade of events that eventually lead to diabetic neuropathy and autonomic neuropathy. ed is a consequence of these events and if not treated early may become irreversible. diabetes-induced ed are often resistant to pde5i treatment (150). first-, secondand third-line therapy may be applied. pde5i treatment from the first-line options leads to smooth muscle relaxation in the corpus cavernosum and enhancement in blood flow, resulting in erection during the sexual stimulation. the use of pde-5i in the presence of oral nitrates is strictly contraindicated in diabetic men. all pde-5i have been evaluated for ed in diabetic patients with convincing efficacy data. second-line therapy includes intracavernosal, transor intraurethral administration of vasoactive drugs or application of a vacuum device. third-line therapies are the implantation of penile prosthesis and penile revascularization (151). gene therapy strategies that can enhance no production or no-mediated signaling pathways, growth factormediated nerve regeneration, or k+ channel activity in the smooth muscle could be promising approaches for the treatment of ed. for the neurogenic type of ed induced by diabetes or cavernous nerve injury, genes 381archivio italiano di urologia e andrologia 2020; 92, 4 neurogenic erectile dysfunction encoding different types of neurotrophic factors, which can enhance nerve regeneration, have been proposed for ed gene therapy. the recent clinical study using nonviral gene therapy of the ca2+ activated bk (max-k) channel for ed patients shows great promise for future development of gene-based therapy of ed (152). the adoption of anatomic radical prostatectomy (rp) with cavernous nerve preservation by many surgeons, the rate of postoperative recovery of erectile function sufficient for sexual intercourse has improved dramatically. pharmacologic rehabilitation has rapidly emerged as a clinical strategy to reduce the incidence of ed after radical prostatectomy (153). post prostatectomy ed appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. in this novel approach, it affected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation (154). preclinical data and several prospective randomized trials have demonstrated the value of treating patients with oral pde5i after surgery, with the concomitant potential benefit of early re-oxygenation of the erectile tissue. for patients who do not properly respond to pde5is, proper counseling regarding intracavernous treatment should be considered, along with the further possibility of surgical treatment for ed involving the implantation of a penile prosthesis (155). a proper algorithm or a clinical guideline for the post rp-ed has not been established until 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secondary to nerve-sparing radical retropubic prostatectomy: comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies. curr urol rep. 2004; 5:467-71. 155. capogrosso p, salonia a, briganti a, montorsi f. postprostatectomy erectile dysfunction: a review. world j mens health. 2016; 34:73-88. correspondence mohamad moussa, md mohamadamoussa@hotmail.com head of urology department, zahraa hospital, university medical center, beirut (lebanon) athanasios g. papatsoris, md (corresponding author) agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens (greece) mohamed abou chakra, md mohamedabouchakra@hotmail.com department of urology, faculty of medical sciences, lebanese university, beirut (lebanon) baraa dabboucy, md baraa.dabboucy@gmail.com department of neurosurgery, faculty of medical sciences, lebanese university, beirut (lebanon) youssef fares, md yfares@ul.edu.lb department of neurosurgery, neuroscience research center, faculty of medical sciences, lebanese university, beirut (lebanon) archivio italiano di urologia e andrologia 2016; 88, 4300 original paper detection rate for significant cancer at confirmatory biopsy in men enrolled in active surveillance protocol: 20 cores vs 30 cores vs mri/trus fusion prostate biopsy pietro pepe 1, sebastiano cimino 3, antonio garufi 2, giandomenico priolo 2, giorgio ivan russo 3, raimondo giardina 3, giulio reale 3, michele barbera 1, paolo panella 1, michele pennisi 1, giuseppe morgia 3 1 urology and 2 imaging unit, cannizzaro hospital, catania, italy; 3 department of urology, university of catania, italy. introduction: the detection rate for significant prostate cancer of extended vs saturation vs mmri/trus fusion biopsy was prospectively evaluated in men enrolled in active surveillance (as) protocol. mterials and methods: from may 2013 to september 2016 75 men aged 66 years (median) with very low risk pca were enrolled in an as protocol and elegible criteria were: life expectancy greater than 10 years, ct1c, psa below 10 ng/ml, psa density < 0.20, 2 < unilateral positive biopsy cores, gleason score (gs) equal to 6, greatest percentage of cancer (gpc) in a core < 50%. all patients underwent 3.0 tesla pelvic mpmri before confirmatory transperineal extended (20 cores) or saturation biopsy (spbx; 30 cores) combined with mpmri/trus fusion targeted biopsy (4 cores) of suspicious lesions (pi-rads 3-5). results: 21/75 (28%) patients were reclassified by spbx based on upgraded gs ≥ 7; mpmri lesions pi-rads 4-5 vs pi-rads 3-5 diagnosed 9/21 (42.8%) vs 16/21 (76.2%) significant pca with 2 false positives (6.5%). the detection rate for significant pca was equal to 76.2% (mpmri/trus fusion biopsy) vs 81% (extended) vs 100% (spbx) (p = 0.001); mpmri/trus targeted biopsy and extended biopsy missed 5/21 (23.8%) and 4/21 (19%) significant pca which were found by spbx (p = 0.001) being characterised by the presence of a single positive core of gs ≥ 7 with gpc < 10%. conclusions: although mpmri improve the diagnosis of clinically significant pca, spbx is provided of the best detection rate for pca in men enrolled in as protocols who underwent confirmatory biopsy. key words: active surveillance; prostate cancer; confirmatory prostate biopsy; mri/trus fusion biopsy. submitted 15 nivember 2016; accepted 15 december 2016 summary no conflict of interest declared. ing (4). recently, multi-parametric magnetic resonance imaging (mpmri) and mpmri/trus fusion targeted biopsy have improved the accuracy of standard prostate biopsy schemes in the diagnosis of clinically significant pca especially if located in the anterior prostate (5-7); therefore many authors suggest including mpmri in as follow up (8-13). however, the time of confirmatory biopsy has been established 6-12 months from initial diagnosis there are no data regarding the number of cores and the best procedure to diagnose exclusively clinically significant pca. in our study, the detection rate for pca at confirmatory prostate biopsy has been prospectively evaluated performing mpmri/trus fusion targeted biopsy vs extended or saturation prostate biopsy in men enrolled in a as protocol study. materials and methods from may 2013 to september 2016 75 men aged between 58 and 73 (median age 66) with very low risk pca were enrolled in our as protocol study. presence of the following criteria defined eligibility: life expectancy greater than 10 years, clinical stage t1c, psa below 10 ng/ml, psa density (psa-d) < 0.20, < 2 unilateral positive biopsy cores, gleason score (gs) equal to 6, maximum core percentage of cancer (gpc) < 50%. all patients were requested to sign a written informed consent, and six months after pca diagnosis underwent digital rectal examination, total psa, psa-d, psa doubling time measurement and pelvic mpmri 3.0 tesla evaluation before confirmatory trans-perineal prostate saturation biopsy (spbx); the procedure was performed with the use of a ge logiq p6 ecograph (general electric; milwaukee, wi) supplied with a bi-planar trans-rectal probe (5-7.5 mhz) using a tru-cut 18 gauge needle (bard; covington, ga) under sedation and antibiotic prophylaxis (14). all mpmri examinations were performed using a 3.0 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16 channels phasedarray coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo t2doi: 10.4081/aiua.2016.4.300 presented at 20th national congress sieun, sciacca 2016 introduction active surveillance (as) has become an alternative (1-3) to definitive treatment of low/very low risk prostate cancer (pca), focusing on prevention of overtreatment (1) and strict monitoring over time of patients to establish potential risk reclassification. however, follow-up in the majority of as protocols is still short, and prospective validation of criteria for selecting low-risk disease is still lackpepe-detection rate for significant cancer_stesura seveso 09/01/17 10:03 pagina 300 301archivio italiano di urologia e andrologia 2016; 88, 4 active surveillance and confirmatory biopsy weighted (t2w), axial diffusion weighted imaging (dwi), axial dynamic contrast enhanced (dce) and spectroscopy were performed for each patient. the mpmri lesions characterized by a pi-rads (prostate imaging-reporting and data system) score of 4 and 5 were considered highly suspicious for cancer (6, 7); two radiologists (af, gp) blinded to pre-imaging clinical parameters evaluated the mri data separately and independently. in the presence of mpmri lesions suggestive of cancer (pi-rads 3-5), targeted mri/trus fusion guided-biopsies were added to standard spbx using a ge logiq e9 (general electric; milwaukee, wi) or hitachi arietta 70 ecograph (hitachi medico, chiba, japan) supplied with a end-fire (figure 1) or biplanar transrectal (figure 2) probe, respectively. risk reclassification at repeat biopsy triggered the recommendation for active treatment and defined as over 3 or more than 10% of positive cores, gs > 6, gpc > 50%; patients being reclassified underwent definitive treatment (radical prostatectomy or external radiotherapy). we evaluated the detection rate for clinically significant pca performing extended biopsy (20 cores: 16 in the periphery and 4 in the anterior zone) vs saturation biopsy (30 cores: 24 in the periphery and 6 in the anterior zone) vs mpmri/trus fusion guided-biopsies (4 targeted cores of the suspicious lesions with pi-rads 3-5). probability level of p < 0.05 was considered statistically significant. results the clinical parameters of the 75 patients enrolled in the as protocol are listed in the table 1. 21/75 (28%) patients had unfavourable repeat spbx and were reclassified based on upgraded gs (15 cases gs = 3 + 4; 4 cases gs = 4 + 3; 2 cases gs = 4 + 4) and number of positive cores (range: 3-5 positive cores; 50% of the cases). in detail, 8 (38%) pca were located only in the anterior zone of the gland, 8 (38%) in the periphery zone and 5 (24%) in both zones. of the remaining 54 (72%) patients, 33 were found to have very low-risk pca and in 21 cancer was absent; pca was located in the periphery in 22 cases and in the anterior zone in 11 cases. a total of 124 (mpmri/trus fusion targeted biopsy) vs 2250 (spbx) vs 1500 (extended biopsy) cores were performed and the detection rate of pca for single core was equal to 22.5% vs 5% vs 6.8%, respectively. no-one suffered significant complication from standard biopsy (extended or spbx) or mpmri/trus fusion targeted biopsy requiring admission to hospital. multiparametric pmri was suspicious (pirads 3-5) in 31 of 75 cases (41.3%); in detail, mpmri showed a lesion with pi-rads 4-5 in all the patients with gs 4 + 4 (2/2 cases) and gs 4 + 3 (4/4 cases), in 3/15 (20%) men with gs 3 + 4 and in 2 patients who were not reclassified. in addition, mpmri found lesions with pi-rads 3 in the 7/15 (46.6%) patients with gs 3 + 4 and in the remaining 13 (17.4%) cases who were not reclassified. high level of concordance in the diagnosis of pi-rads 3-5 between the two radiologists was found (cohen’s kappa 0.85). diagnostic accuracy, sensitivity, specificity, positive and negative predictive value (npv) of mpmri in diagnosing significant pca in the presenc of pi-rads 3-5 vs pi-rads 4-5 were: 83.4 vs 84.3%, 76.5 vs 42.8%, 84.3 vs 96.4%, 51 vs 81%, 96.4 vs 100%, respectively. twelve upgraded patients underwent radical prostatectomy (6 open surgery, 2 laparoscopic and 4 robotic prostatectomies); in every case, definitive pathology report found organ confined pca of gs 7 with negative surgical margins and nodes (pt2cn0); in addition, 4 men with negative mpmri who chose radical prostatectomy (through anxiety), were found to have clinically insignificant pca (cancer volume < 0.5 ml and a 6 gs) (15). summing up, mpmri lesions pi-rads 4-5 vs pi-rads 3-5 diagnosed 9/21 (42.8%) vs 16/21 (76.2%) significant pca (8) characfigure 1. multiparametric transrectal mri/trus fusion targeted prostate biopsy of a suspicious lesion located in the left (target 1) of the gland (pi-rads 3). figure 2. multiparametric transperineal mri/trus fusion targeted prostate biopsy of a suspicious lesion located in the anterior prostate (target lesion: pi-rads 4). pepe-detection rate for significant cancer_stesura seveso 09/01/17 10:03 pagina 301 archivio italiano di urologia e andrologia 2016; 88, 4 p. pepe, s. cimino, a. garufi, g. priolo, g. ivan russo, r. giardina, g. reale, m. barbera, p. panella, m. pennisi, g. morgia 302 terised by gs ≥ 7 (100% of the cases) and a number of positive core > 3 (50% of the cases) with 2 false positives (6.5%). the detection rate for significant pca was equal to 76.2% (mpmri/trus fusion biopsy) vs 81% (16 p) (extended) vs 100% (spbx 21) (p = 0.001); in detail, mpmri/trus targeted biopsy and extended biopsy missed 5/21 (23.8%) vs 4/21 (19%) significant pca which were found by spbx being characterised by the presence of a single positive core of gs ≥ 7 with gpc < 10%. discussion there are many published active surveillance series, varying in size of population and duration of follow-up (1-4) those have mostly restricted this approach to favourable-risk patients; there is considerable variation regarding patient selection, follow-up policies and when active treatment should be offered. although biological markers appear promising as does genomics on the tissue sample itself, follow up in as should be based on serial psa measurements, psa kinetics (psa doubling time), clinical examination and, in particular, repeat prostate biopsy; in this respect, the percentage of patients reclassified at confirmatory prostate biopsy reported in the prostate cancer research international active surveillance (prias) study (1) is equal to 28% (415/2494 cases). although the optimal number of cores (extended vs saturation biopsy) and approach of prostate biopsy (trans-rectal vs trans-perineal) has not been established (16), the criteria of reclassification include upgrading (gs ≥ 7) and modification of biopsy quantitative histology (number of positive cores, gpc > 50%). spbx in comparison with extended biopsy (17) demonstrated more accurate assessment of the extent and grade of disease in men enrolled in as protocol; in addition, the trans-perineal free hand or template spbx increases progression to treatment in as (18) improving the detection rate of pca located solely in the anterior zone of the gland (about 10% of the cases) (19, 20). in the last years, mpmri and mpmri/trus fusion targeted biopsy have a good degree of accuracy in diagnosing clinically significant pca secondary to the high sensitivity for lesion upgrading, especially when the cancer is located in the anterior prostate (6, 7); mpmri targeted biopsy allows to reclassify about 10% of patients eligible for as in comparison with standard trans-rectal biopsy (21, 22). in addition, if confirmed by larger studies, mpmri could be useful to better define those having very low risk pca allowing for a greater interval of time for prostate biopsy re-evaluation (23) and reducing the risk of clinical complications secondary to repeat biopsy (24). on the other hand, false negative rate of mpmri in diagnosing significant pca is equal to 15-30% of the cases especially in the presence of low volume of pca with gs ≥ 7 (25); in this respect, a combination of systematic and mri/trus fusion targeted cores increase detection on significant pca (26-28). in our series, we found mpmri to have a 83.4% (pirads 3-5) diagnostic accuracy rate with a 94.6% npv rate in predicting the presence of clinically significant pca; mpmri/trus targeted biopsy and extended biopsy missed 5/21 (23.8%) and 4/21 (19%) significant pca which were found by spbx (p = 0.001) being characterised by the presence of a single positive core of gs ≥ 7 with gpc < 10%. these data suggest that mpmri/trus fusion biopsies alone could miss small but significant pca because mpmri accuracy significantly correlates with the diameter of the suspicious lesions (7, 29); moreover, in a selected population of men with very low-risk pca in as with an expected negative mpmri, the suspicious lesions with pi-rads 3 should undergo targeted biopsy to improve the reclassification of the patients. in definitive, spbx detect the highest percentage of pca allowing to better define the best therapeutic clinical strategy for each patient. limitations and considerations of the present study need mention. firstly, a greater number of patients need to be examined; secondly, we do not know the true diagnostic accuracy of mpmri and biopsy procedure in pca diagnosis because the detection rate for cancer was compared only in 16/75 (21.3%) cases with definitive specimen. finally, we cannot establish if the two mpmri false positives were possibly re-assignable to false-negative repeat prostate biopsy procedures (30). in conclusion, although mpmri improve the diagnosis of clinically significant pca, spbx is provided of the best detection rate for pca in men enrolled in as protocols who underwent confirmatory biopsy. references 1. schröder fh, hugosson j, roobol mj, et al: prostate-cancer mortality at 11 years of follow-up. n engl j med. 2012; 366:981-990. 2. bokhorst lp, zappa m, carlsson sv, et al. correlation between stage shift and differences in mortality in the european randomised study of screening for prostate cancer (erspc). bju int. 2016; 118:677-680. 3. richard po, alibhai sm, panzarella t, et al. the uptake of active surveillance for the management of prostate cancer: a populationbased analysis. can urol assoc j. 2016; 10:e342-e346. 4. kim th, jeon hg, choo sh, et al. pathological upgrading and upstaging of patients eligible for active surveillance according to currently used protocols. int j urol . 2014; 21:377-381. 5. pepe p, garufi a, priolo g, pennisi m. can 3 tesla pelvic phasearray mri avoid unnecessary repeat prostate biopsy in patients with psa below 10 ng/ml? clinical genitourinary cancer. 2015; 13:e27-30. table 1. clinical parameters of the 75 men enrolled in the active surveillance protocol who underwent confirmatory prostate biopsy. median psa (range) 6.5 ng/ml (3.7-10 ng/ml) median psa-d (range) 0.15 (0.09-0.20) dre negative gleason score 6 (3 + 3) gpc (range) 20% (5-50%) prostate weight (range) 48 grams (30-115 grams) median number of positive cores 1.5 (range; percentage) (1-2; 5%) pepe-detection rate for significant cancer_stesura seveso 09/01/17 10:03 pagina 302 303archivio italiano di urologia e andrologia 2016; 88, 4 active surveillance and confirmatory biopsy 6. pepe p, garufi a, priolo g, et al. prostate cancer detedtion at repeat biopsy: can pelvic phased-array multiparametric mri replace saturation biopsy? anticancer research. 2013; 33:1195-1199. 7. pepe p, garufi a, priolo g, pennisi m. 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[epub ahead of print] correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital via messina 829, catania, italy sebastiano cimino, md giorgio ivan russo, md raimondo giardina, md giulio reale, md michele barbera, md paolo panella, md michele pennisi, md giuseppe morgia, md department of urology, university of catania, catania, italy antonio garufi, md giandomenico priolo, md imaging unit, cannizzaro hospital, catania, italy pepe-detection rate for significant cancer_stesura seveso 09/01/17 10:03 pagina 303 stesura seveso 13archivio italiano di urologia e andrologia 2016; 88, 1 original paper non-muscle invasive high grade urothelial carcinoma of the bladder. which factors can influence understaging at the time of radical cystectomy? daniele minardi, giulio milanese, gianni parri, vito lacetera, giovanni muzzonigro department of clinic and specialistic sciences, urology, polytechnic university of the marche region, azienda ospedaliero-universitaria ospedali riuniti, ancona, italy. objective: to evaluate the main factors which influence understaging in patients with t1g3 non-muscle invasive bladder cancer (nmibc). materials and methods: 109 patients with t1/g3 underwent transurethral resection of bladder tumor (turbt) and then radical cystectomy (rc) with pelvic lymph nodes dissection. a number of variables were considered when evaluating the detection of understaging. we considered the patients age and gender, as well as the size, number, location and morphology of their tumor. we also considered coexistence of bladder carcinoma in situ (cis), microscopic vascular invasion and deep lamina propria invasion. the level of experience of the surgeon was also analyzed. results: in rc samples muscle invasion, that is understaging, was detected in 74 (67.9%) patients, while 35 (32.1%) patients were appropriately staged. in these cohort of patients with high grade tumors, understaging was associated with deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor; age, gender, tumor morphology, cis associated, and experience of urological surgeon were not associated with clinical understaging. conclusions: in our study, evaluating patients with high grade nmibc at first turbt, we identified some risk factors that need to be considered and that are able to increase the risk of understaging: deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor. when these risk factors are present, performing an early cystectomy, and not a re-turbt, could lower the risk of worse pathological finding due to rapid disease progression of the high grade tumors, and can prolong survival. key words: bladder tumor; high grade bladder carcinoma; non-muscle invasive bladder carcinoma; understaging. submitted 7 march 2015; accepted 29 march 2015 summary no conflict of interest declared. are included, that have a high risk of recurrence and stage progression (1). transurethral resection of the bladder tumor (turbt) is the standard treatment for non-muscle-invasive cancer, by which the urologist should provide to the pathologist complete sampling of the tumor, the underlying bladder wall, and the edges of the resection (2). the pathologist should report specifically the histology type, the grade, the depth of lamina propria invasion, and the presence of muscle in the specimen (3). the main objective of the initial turbt is a correct staging of the tumor; while turbt alone, with intravesical immuneor chemotherapy is the standard of care in nmibc, muscle-invasive tumors (mibc) (≥ t2 or pn1) will require radical approaches; turbt is the key diagnostic modality to determine whether patients have bladder cancer that can be treated locally or requires more aggressive, surgical treatment (3). in a significant number of cases the carcinoma at pathologic examination results to be understaged in specimens obtained from turbt compared to those after radical cystectomy (rc); understaging is therefore defined as the presence of mibc at rc; muscular invasion can more likely happen in high grade bc (4). the aim of our study was to evaluate the main factors that influence disease understaging in patients with high grade nmibc. methods the study patients were identified from an existing prospective database of all patients who underwent rc at our institution between december 1998 and june 2008 (685 patients). institutional review board approved the study design. 109 patients were selected from the database; they had nmibc t1/g3 after the first turbt; t1 tumors were subclassified into pt1a (tumor invasion to the lamina propria above the level of the muscularis mucosa) and pt1b (tumors invading up to or beyond the muscularis mucosa without involving the muscularis propria) (5). after turbt, all the considered patients underwent rc and extended bilateral pelvic lymph nodes dissection; we did not perform a re-turbt because in the bladder there doi: 10.4081/aiua.2016.1.13 introduction bladder cancer is a frequent malignancy of the lower urinary tract, showing an incidence of 10.1 per 100,000 for men and 2.5 per 100,000 for women (1). the majority of patients with bladder cancer at first diagnosis have non-muscle-invasive bladder tumors (nmibc) (tcis, ta, and t1); but in this group also high-risk bladder cancers minardi1_stesura seveso 08/04/16 11:26 pagina 13 archivio italiano di urologia e andrologia 2016; 88, 1 d. minardi, g. milanese, g. parri, v. lacetera, g, muzzonigro 14 was extensive and/or multiple disease, and/or residual disease. rc was performed within 6 weeks from turbt in all patients. for the purpose of the study, only patients who did not undergo neoadjuvant chemotherapy before rc, and those who did not receive adjuvant intravesical or systemic therapy after the turbts were considered. five urological consultants and 5 urologists in training at our institution performed the turbts. stage was assigned according to the american joint committee of cancer (ajcc) guidelines (6); and the grade was defined according to the who grading system (7). all our turbt cases were performed under spinal anesthesia; both a 70and 30-degree lens to evaluate the entire bladder surface fully have been used; all abnormal areas were recorded and then biopsied separately; a complete cystoscopic exam was repeated at the end of the turbt to ensure that all tumors and abnormal areas have been resected. patients pathologically staged t1 at the time of rc were considered appropriately staged; those who resulted to have a > t2 were considered understaged. for all the patients, we considered the following parameters: age, gender, tumor size, depth of lamina propria invasion, tumor morphology (solid vs. papillary) (8), associated carcinoma in situ, multiplicity, location of the tumor (lateral wall, trigone, dome), and microscopic vascular invasion. we also considered the surgeon’s experience when performing turbt (operations performed by experienced consultants or by registrars); all of these parameters were evaluated for detection of understaging. statistical analysis the mannwhitney u test or student’s t-test methods were used to compare differences among categories as appropriate. the nonparametric wilcoxon signed-rank test was used on calculated pair difference values. survival curves were assessed using the kaplan-meier method and differences were calculated with the log-rank statistic. multivariate analysis was performed with cox proportional hazard model analyses to identify predictors of clinical understaging. two-tailed tests were used for all comparisons and p < 0.05 was considered statistically significant. spss 11.0 software was used for all calculations results the characteristics of the patients who took part in the study are listed in table 1. the mean age of patients (sd) was 69.4 (11.2) years; 87 of them were males and 22 females; mean tumor diameter was 5.8 + 1.5 cm; 39 patients were staged as t1a and 70 as t1b; in 35 patients the tumor was solid and in 74 it was papillary; cis was associated in 12 patients; in 32 patients the tumors were single and in 77 multiple; 63 tumors were in the lateral bladder walls, 21 in the trigone, and 25 in the bladder dome; microscopic vascular invasion was present in 65 patients; 63 operations were undertaken by consultants and 46 by registrars; in 83 patients there was residual tumor after turbt. final pathologic specimens from rc revealed muscle invasion, i.e. understaging, in 74 (67.9%) patients; therefore 35 (32.1%) patients were appropriately staged; nine patients had lymph nodes metastases at final pathological examination. understaging was associated with deep lamina propria (stage t1b) and microscopic vascular invasion, multiple tumors, tumor size (tumors > 6 cm are more likely to be understaged), tumor location (tumors in the trigone and in the bladder dome are more likely to be understaged), residual tumor; age, gender, tumor morphology, bladder cis associated did not result to be important. the type of urological surgeon (consultant or registrar) was not associated with clinical understaging at final pathology. by multivariate analysis the most important factor predictive of understaging is the presence of microscopic vascular invasion. survival analysis (figure 1) showed a significantly higher survival rate in those patients who were appropriately staged compared to those who were understaged at final pathology (73,5% vs. 42%; log rank p = 0.001; chi-square = 10,560). characteristics after turbt understaged appropriately p at rc staged at rc n. patients 109 74 35 mean age 69.4 + 11.2 70.1 + 9.8 68.5 + 10.9 0.619 male 87 64 23 female 22 10 12 0.282 tumor size 5.8 + 1.5 6.8 + 1.9 4.5 + 1.8 0.025 t1a 39 11 28 0.002 t1b 70 63 7 tumor morphology solid 35 20 15 0.081 papillary 74 54 20 bladder carcinoma in situ associated 12 4 8 0.284 single 32 3 29 0.003 multiple 77 71 6 location lateral wall 63 38 25 0.008 trigone 21 17 4 dome 25 19 6 microscopic vascular 65 58 7 0.001 invasion surgeon’s experience consultant 63 45 18 0.5 registrar 46 29 17 residual tumor 83 50 33 0.002 table 1. patients characteristics. p relative risk 95% ci age 0,210 1,378 0,71,7 gender 0,161 4,206 0,817,6 depth of lamina propria invasion 0,810 3,591 0,36,2 tumor size 0,890 0,899 0,3-1,1 tumor morphology 0,251 1,335 0,5-1,8 solitary vs multiple tumor 0,530 0,924 0,4-1,4 ca in situ associated 0,368 1,322 0,7-1,7 location 0.134 0.432 0,1-1,5 microscopic vascular invasion 0,001 1,885 0,71,5 surgeon’s experience 0,121 1,320 0,8-2,1 residual tumor 0,030 1,474 0,4-1,9 table 2. multivariate analysis of factors predictors of understaging. minardi1_stesura seveso 08/04/16 11:26 pagina 14 15archivio italiano di urologia e andrologia 2016; 88, 1 cystectomy in non-muscle invasive bladder cancer discussion one of the problems of turbt for the diagnosis and staging of bc is the inability to accurately identify all cases of mibc (9). due to the significant risk of understaging, a second turbt is to be considered for all patients with high-grade t1 urothelial carcinoma (10); to improve the accuracy, separate biopsies from the tumor base and random bladder biopsies can provide additional prognostic informations (3, 11); a restaging turbt is strongly advised for those patients diagnosed with t1 disease, where muscularis propria is not present in the initial histological specimen. a restaging turbt is considered for patients with highgrade ta or t1 disease even when muscle is present in the resection specimen, due to the considerable risk of understaging, up to 70% (12-14). some studies have observed that a delay in doing a radical cystectomy is associated with an higher pathological stage at cystectomy; some have shown that delaying surgery more than 90 days results in a worse pathologic stage with locally advanced disease (15); others have demonstrated similar results when cystectomy is delayed of more than 12 weeks, and also a decreased survival (16). the timing of radical surgery is therefore most important. several studied have highlighted the importance of surgeon experience on the outcomes of turbt. mariappan et al. (17) observed that surgery performed by people with less than 5 years of experience was also an independent predictor of early recurrence; on the contrary, zurkirchen et al. (18) found that trainees had less percentage of residual tumor than experienced surgeons; vasdev et al. (19) did not observe that the surgeon experience was associated with the prognosis tag2 tumors after restaging. it has been observed that survival is high in patients with superficial bladder cancer after rc; survival is better in patients treated with early rc compared to those having radical surgery after recurrence of tumors (20); although rc is important when intravesical therapy fails, it might be too late even if the tumor remains clinically superficial. in this study we have shown that understaging is present in 67.9% of high grade nmibc, while 32.1% of high grade nmibc were appropriately staged; we considered a selected group of patients, who underwent cystectomy after the first turbt. this was because of the presence of locally extensive and/or multiple disease and/or residual tumor, and this fact could be responsible for the high rate of understaging we have found. in our report all the patients underwent rc within 6 week from turbt, therefore a delay in performing radical surgery cannot be considered responsible for disease progression; the rate of understaging is higher compared to other studies, but we have considered a very selected cohort of patients with high grade tumors. our finding unusual compared to the results found in the literature, and because of this we think that our findings are interesting. we have also observed that surgeon’s experience is not important in determining the rate of understaging. in our study we have observed that there are some factors predictive of understaging: tumor size is an important factor, and tumor understaged have a significantly higher mean diameter (6.8 + 1.9) compared to those appropriately staged (4.5 + 1.8); tumor in the trigone are frequently understaged (probably due to early invasion of adjacent tissues), as those in the dome of the bladder (probably due to incomplete resection for technical difficulties); depth of lamina propria invasion and microscopic vascular invasion are also factors predictive of understaging. high grade nmibc can be treated with turbt and intravesical chemoimmunotherapy, but this treatment is absolutely insufficient if there is an error in stage determination, that can lead to a delay in radical surgery and figure 1. survival in patients understaged and appropriately staged minardi1_stesura seveso 08/04/16 11:26 pagina 15 archivio italiano di urologia e andrologia 2016; 88, 1 d. minardi, g. milanese, g. parri, v. lacetera, g, muzzonigro 16 worse prognosis. defining the exact stage of bladder tumor is essential for planning appropriate treatment and determining the patient’s prognosis. in this study we have considered a selective group of patients with highgrade bladder tumor, who were staged t1 at first turbt; the second turbt was not performed in our patients, since the bladder was extensively affected by the tumor, and residual tumor was present in 76.14% of cases. according to our observation, when evaluating patients with nmibc at first turbt, we believe that it is important to consider the following factors that are able to increase the risk of understaging: high grade tumor, deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor. when these risk factors are present, we suggest to examine carefully the case and consider whether avoiding delays with performing a second turbt and proceed straight to radical cystectomy could be a possible option; in this situation, performing an early cystectomy could lower the risk of worse pathological finding due to rapid disease progression of the high grade tumors, and can prolong survival. references 1. ploeg m, aben kk, kiemeney la. the present and future burden of urinary bladder cancer in the world. world j urol. 2009; 27:28993. 2. babjuk m, burger m, zigeuner r, et al. eau guidelines on nonmuscle-invasive urothelial carcinoma of the bladder: update 2013. eur urol. 2013; 64:639-53. 3. ramírez-backhaus m, domínguez-escrig j, collado a, et al. restaging transurethral resection of bladder tumor for high-risk stage ta and t1 bladder cancer. curr urol rep. 2012; 13:109-14. 4. poulsen al, horn t, steven k. radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. j urol. 1998; 160:2015-9. 5. edge sb, compton cc. the american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. ann surg oncol. 2010; 17:1471-4. 6. sauter g, algaba f, amin m, et al. tumours of the urinary system: non-invasive urothelial neoplasias. in: eble jn, sauter g, epstein jl, sesterhenn i, eds. who classification of classification of tumours of the urinary system and male genital organs. lyon: iarcc press, 2004, pp. 29-34. 7. kirkali z, chan t, manoharan m, et al. bladder cancer: epidemiology, staging and grading, and diagnosis. urology. 2005; 66:4-34. 8. ark jt, keegan ka, barocas da, et al. incidence and predictors of understaging in patients with clinical t1 urothelial carcinoma undergoing radical cystectomy. bju int. 2014; 113:894-9. 9. nieder am, brausi m, lamm d, et al. management of stage t1 tumors of the bladder: international consensus panel. urology. 2005; 66:108-25. 10. dutta sc, smith ja, shappell sb, et al. clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. j urol. 2001; 166:490-3. 11. hall mc, chang ss, dalbagni g, et al. guideline for the management of nonmuscle invasive bladder cancer (stages ta, t1, and tis): 2007 update. j urol. 2007; 178:2314-30. 12. montie je, clark pe, eisenberger ma, et al. national comprehensive cancer networkl. bladder cancer. j natl compr canc netw. 2009; 7:8-39. 13. mclaughlin s, shephard j, wallen e, et al. comparison of the clinical and pathologic staging in patients undergoing radical cystectomy for bladder cancer. international braz j urol. 2007; 33:25-32. 14. dalbagni g, herr hw, reuter ve: impact of a second transurethral resection on the staging of t1 bladder cancer. urology. 2002; 60:822-4. 15. chang ss, hassan jm, cookson ms, et al. delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. j urol. 2003; 170:1085-7. 16. sanchez-ortiz rf, huang wc, mick r, et al. an interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. j urol. 2003; 169:110-5. 17. mariappan p, zachou a, grigor km. detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. eur urol. 2010; 57:843-9. 18. zurkirchen ma, sulser t, gaspert a, hauri d. second transurethral resection of superficial transitional cell carcinoma of the bladder: a must even for experienced urologists. urol int. 2004; 72:99-102. 19. vasdev n, dominguez-escrig j, paez e, et al. the impact of early re-resection in patients with pt1 high-grade non-muscle invasive bladder cancer. ecancermedicalscience. 2012; 6:269. 20. solsona e, iborra i, rubio j, casanova j, almenar s. the optimum timing of radical cystectomy for patients with recurrent highrisk superficial bladder tumour. bju int. 2004; 94:1258-62. correspondence daniele minardi, md d.minardi@gostec.net giulio milanese, md gianni parri, md vito lacetera, md giovanni muzzonigro, md clinica urologica, università politecnica delle marche, a.o. ospedali riuniti via conca 71 60020 ancona, italy minardi1_stesura seveso 08/04/16 11:26 pagina 16 stesura seveso 125archivio italiano di urologia e andrologia 2019; 91, 2 original paper relationships between sperm dna integrity and bulk semen parameters in bulgarian patients with varicocele viktor alargkof 1, larissa kersten 2, romil stanislavov 3, zdravko kamenov 4, panagiotis nikolinakos 1 1 medical university sofia, sofia, bg; 2 university of essex, uk; 3 genika, genetic and medico-diagnostic laboratory, sofia, bg; 4 clinic of endocrinology, alexandrovska university hospital, sofia, bg. objective: this exploratory retrospective study aimed to compare the level of sperm dna fragmentation (sdf) and investigate its association with bulk semen parameters, for the first time in bulgarian patients with varicocele, using a distinct methodology. material and methods: standard semen analysis was performed according to the 2010 criteria of the european society of human reproduction and embryology nordic association for andrology (eshre-nafa-2010) and dna fragmentation was assessed using the halosperm® kit. the total sample included 28 males: the control group consisted of men with normal genital examination and unknown fertility (n = 10), group one consisted of men with varicocele, normozoospermia and dna fragmentation > 15% (n = 9) and group two consisted of men with varicocele, abnormal sperm parameters and dna fragmentation > 15% (n = 9). results: dna fragmentation was found to be higher in patients with abnormal sperm parameters (43.78 ± 30.78) compared to the normozoospermic group (21.22 ± 3.93) (p = 0.008). in normozoospermic patients, no statistically significant correlations were observed between sdf and bulk semen parameters. in patients with abnormal sperm parameters, dna fragmentation exhibited significant very strong negative association with motility (a+b), vitality and typical morphology (p < 0.001). conclusions: dna integrity assays could be used for a better evaluation and management of male infertility, particularly in normozoospermic varicocele patients. key words: male infertility; sperm dna fragmentation; sperm dna damage; varicocele; semen analysis. submitted 26 november 2018; accepted 15 december 2018 summary no conflict of interest declared. clinically evident varicocele may present with normal values on primary semen assays. on the other hand, patients may present with altered spermatogenesis, poor bulk seminal parameters and oligoasthenoteratozoospermia (oat syndrome) (4). the mechanisms by which varicoceles lead to spermatogenic failure are not completely elucidated. however, most authors investigating how varicoceles impair the reproductive function consider the primary event to be an increase in intratesticular temperature secondary to interruption in the counter-current heat exchange provided in the plexus pampiniformis with opposing flow vectors in a central arterial system and surrounding veins. the proposed mechanisms by which male fertility is impaired by this effect mainly include dna fragmentation, apoptosis and oxidative stress. other associated factors include testicular hypoxia secondary to venous stasis, reflux of renal/adrenal toxic metabolites and hypertension in the internal spermatic veins (5). numerous researchers have recently examined the association between varicocele and sperm dna fragmentation (sdf). although a cause-and-effect relationship is not established, multiple reviews and meta-analyses conclude that there is indeed evident association between varicocele and increased dna fragmentation (6). although sperm dna damage represents a reproducible sperm function marker, the american society for reproductive medicine and the american urological association (aua) do not recommend routine clinical use of sperm dna testing (7). the utility of sdf testing is currently appreciated by the aua and the european association of urology (eau) for the evaluation of assisted reproductive technology (art) success (8, 9). studies have shown that sperm dna damage is associated with negative influence on embryo development and lower pregnancy rates (lower natural pregnancy rates and lower pregnancy rates after intrauterine insemination and in vitro fertilization) (10, 11). a significant finding is the increased risk for spontaneous abortions with increasing sperm dna fragmentation. comprehensive meta-analyses have shown that higher levels of dna fragmentation are linked with an approximately double risk ratio (rr) of miscarriages (12). the current study included bulgarian men clinically doi: 10.4081/aiua.2019.2.125 introduction varicocele, an abnormal dilation and tortuosity of the internal spermatic veins within the plexus pampiniformis, is the most frequently identified lesion in males undergoing infertility evaluation (1). it is a common condition in men with normal spermatogenesis but also in men with abnormal semen parameters. it is found in approximately 15% of the general population and is reported in 35% of men with primary infertility and 75 to 81% of men with secondary infertility (2). varicocele is a complex entity as its effects on sperm quality are both difficult to define and predict. not all men with varicocele are infertile (3) and patients with archivio italiano di urologia e andrologia 2019; 91, 2 v. alargkof, l. kersten, r. stanislavov, z. kamenov, p. nikolinakos 126 diagnosed with varicocele and sdf level higher than 15%, which is defined as the normal threshold for in vivo fertilization using the halosperm® kit (13). the objective was to compare the levels of dna fragmentation between varicocele patients with normozoospermia and abnormal sperm parameters and to investigate the correlation of sdf and bulk semen parameters as well as describe the relationships between them, for the first time in the bulgarian population. at the same time a secondary aim was to collect data using a distinct methodology which is not utilized as frequently in literature. namely, the normozoospermic patients in the current study are defined according to the eshrenafa-2010 criteria which are stricter in defining normal parameters and make the additional distinction of borderline parameters in comparison to the who manual. finally, there is great variability in literature in the methods used to determine sdf, which renders making correlations and drawing conclusions difficult (14). sdf in the present study was analyzed using the halsoperm® kit, aiming to add to the pool of data acquired via sperm chromatin dispersion. materials and methods study group the study included 28 men assessed by the andrology laboratory department at genika, genetic and medicodiagnostic laboratory in sofia, bulgaria. a retrospective study was designed involving one control group of men with unknown fertility, normal genital examination and normal bulk semen parameters (n = 10) and two groups of patients with clinically diagnosed varicocele and infertility. the varicocele was diagnosed by palpation and doppler ultrasound examination. among the patients with varicocele, the first group (n = 9), presented with normozoospermia and levels of dna fragmentation higher than 15%. the second group (n = 9) presented with abnormal sperm parameters and levels of dna fragmentation higher than 15%. in all men, medical history was obtained, including occupation, smoking habits, alcohol intake and the use of prescription medication. exclusion criteria for all groups were: current or previous systemic diseases that would lead to testicular alterations such as cancer and endocrinopathies (and their treatments) and a history of excessive alcohol and drug consumption. according to the laboratory’s protocol, informed consent is acquired from all patients at the time of registration for the anonymous inclusion of their sperm analysis results in potential medical studies and research. sperm collection and semen analysis semen samples were collected by masturbation after three to seven days of ejaculatory abstinence and were analyzed within one hour of collection. additionally, patients were instructed to abstain from alcohol consumption for three to seven days and maintain a good general status for three months before the examination as well as present afebrile on the day of the analysis, without having consumed any antibiotics (they were instructed to report any received medications). in all patients, the semen sample was (up to 25 minutes post ejaculation) retained in a 37 °c thermostat for circa 15 minutes. after complete semen liquefaction, ph and volume were measured and a standard seminal analysis was performed according to the criteria of the european society of human reproduction and embryology nordic association for andrology 2010 (eshre-nafa-2010). analysis was performed on the computer microscopic fluorescent platform sperm class analyzer (sca v.5.0) and the parameters measured included total sperm count, motility, vitality and morphology. sperm morphology was assessed using kruger’s strict criteria. sperm vitality was assessed using eosin y to stain spermatozoa and negrosin to stain the background. in comparison to who-5, 2010, the criteria of eshre-nafa-2010 interpret results in three categories: normal, borderline and pathologic. the borderline results represent a buffer zone of clinical importance. patients in this zone are regarded as having the potential to shift to either normal or pathological spectra depending on the persistence of offending factors. determination of dna integrity sperm nuclear dna integrity was evaluated by use of the halosperm® kit (halotech® dna sl, madrid, spain). this test is a modified and improved version of the sperm chromatin dispersion (scd) test (15). the clinical threshold for percentage of spermatozoa with dna fragmentation has been established as (1) < 15% for in vivo fertilization, (2) < 30% for in vitro fertilization. the kit included: 10 super coated slides, 10 eppendorf agarose tubes, one tube with denaturizing solution (1 ml), and two bottles of lysis solution (60 ml ×2). the first step included inserting the semen sample in agarose microgel. the lysis solution was first left in room temperature. the semen sample was diluted with an extender or pbs until a concentration of 5-10 ×106/ml. the eppendorf tube with the agarose was placed in a float for five minutes at 90 to 100 °c until the agarose melted. the tube was then moved along with the float into a water bath with a temperature of 37 °c and was left there for five minutes. 60 ml of the semen sample were transferred to the eppendorf tube and were gently mixed. the super-coated slide to be used was placed on a cold surface area (glass plate) at 4 °c. once the slide had been cooled, cell suspension was transferred from the eppendorf tube to the slide, towards the side that was treated and marked by a dark point. a coverslip was placed on top very carefully, to avoid creating bubbles. a drop of 14, 20 or 50 μl for the slides is used for the respective magnifications of 18×18mm, 22×22 mm or 24×60 mm. the slides were maintained in horizontal orientation throughout the whole procedure. the cooled glass plate with the slide was then placed in the fridge and the sample was left to jellify for five minutes. processing the sample followed. the denaturizing agent was prepared by adding 80 μl from the acid denaturizing solution to 10 μl distilled water and was placed in an incubator tray. the cover slip was slid off the slide and the slide was immediately immersed in the denaturizing solution in horizontal orientation, leaving it to incubate for seven minutes at room temperature (22°c). after putting on gloves, the slide was picked up with the help of pincers. while remaining in horizontal position it was placed in another incubation tray containing 10 μl of lysis solution. it was left to incubate for 25 minutes. the slide was picked up and placed in a petri dish filled with distilled water in order to wash off the lysis solution. it was left to incubate for five minutes. the slide was picked up and was placed horizontally in a petri dish with 70% ethanol for two minutes, 90% ethanol for two minutes and 100% ethanol for two minutes. the slide was left to dry and once completely dried the prepared slide was stained for observation under light microscopy. wright’s staining solution was mixed with phosphate-buffered saline (pbs) in 1:1 ratio and one layer of the staining solution was placed horizontally in order to cover the wet slide. the slide was left to stain for five to 10 minutes. the slide was carefully rinsed with running water and was left to dry. subsequently direct microscopic visual analysis was performed. the nucleoid that corresponds to deproteinized nuclei of spermatozoa is made up of two parts: a core located centrally and a peripheral halo of chromatin/dna dispersion. the spermatozoa tails are also visible. a minimum of 500 spermatozoa are studied per sample and scored according to the following criteria. sperm classification the categorization of the different halo sizes is performed using the minor diameter of the core from the own nucleoid as a reference to which the halo width is compared. the scd patterns established are the following (15): sperm cells without dna fragmentation a) sperm cells with large halo: those whose halo width is similar or higher than the minor diameter of the core. b) sperm cells with medium-size halo: the halo size is between: maximum one third of the minor diameter of the core and minimum the length of the minor diameter of the core. sperm cells with dna fragmentation c) sperm cells with small halo: the halo width is similar or smaller than one third of the minor diameter of the core. the core may have irregular form or barely distinguishable (< 150 μm2). d) sperm cells without halo e) sperm cells without halo-degraded: there is no halo and the core presents granule-like fragmentation and is weakly stained. ’’others’’ nucleoids that do not correspond to spermatozoa. one of the morphological characteristics that distinguish them is the absence of tail. these cells are not included in the estimation of frequency of sperm with fragmented dna. statistical analysis data analysis was performed using the r software environment for statistical computing and graphics. for each variable the mean, the standard deviation and interquartile range (ir) are presented to indicate the relevant distribution. the shapiro-wilk test was applied to test whether variables are normally distributed. for normally distributed data a student’s test was conducted to test whether means differ across groups. in the case of not normally distributed variables a mannwhitney-wilcoxon test was applied to test whether the distribution across two groups differs. for both tests, the null-hypothesis (difference in means/populations) was rejected if the p-value was smaller than 0.05. correlation coefficients were calculated according to the pearson method. statistically significant correlation coefficients were interpreted as: weak from 0.20 to 0.39 (or -0.20 to -0.39); moderate from 0.40 to 0.59 (or -0.40 to -0.59); strong from 0.60 to 0.79 (or -0.60 to -0.79); very strong from 0.80 to 1.0 (or -0.80 to -1.0). if the p-value was smaller than 0.05 then the correlation coefficient was interpreted as being statistically significant. results all 18 patients entering the study presented varicocele in the left testis, which was detected by physical examination and confirmed by doppler ultrasound. the median age (years) was 31 ± 6.182 (26.25-34.5) for controls, 32 ± 6.648 (30-37) for patients with normal semen parameters (g1) and 36 ± 6.464 (35-42) for patients with abnormal semen parameters (g2). no statistically significant difference was found between the groups with respect to age apart from between the controls age and the g2 age, p = 0.01905. standard semen analysis parameters the main sperm parameters of controls and varicocele patients are presented in table 1. g1 (n = 9) had normal 127archivio italiano di urologia e andrologia 2019; 91, 2 sdf and bulk semen parameters in varicocele table 1. comparison of standard sperm parameters between control subjects, varicocele patients with normal sperm parameters (g1) and varicocele patients with abnormal sperm parameters (g2). numbers represent mean ± standard deviation and range is shown in parentheses. control (n = 10) normal sperm parameters abnormal sperm parameters a: p value b: p value (g1) n = 9 (g2) n = 9 between controls between controls and g1 and g2 ph 7.54 ± 0.07 (7.5-7.575) 7.611 ± 0.078 (7.6-7.7) 7.733 ± 0.132 (7.6-7.8) 0.052 0.002 volume (ml) 3.87 ± 2.465 (2.525-4.4) 3.944 ± 1.474 (2.7-5.1) 3.889 ± 2.070 (2.6-5.5) 0.595 0.744 number (x 106/ml) 448.4 ± 317.518 (251.2-651.7) 293.9 ± 109.582 (214.6-362.3) 117.3 ± 115.782 (41.1-169.3) 0.488 0.008 motility (% a+b) 57.8 ± 3.225 (56-60.5) 57 ± 3.640 (55-58) 24.89 ± 13.897 (26-32) 0.594 <0.001 vitality (%) 78.2 ± 3.676 (78-81) 76.67 ± 3.464 (73-79) 48.89 ± 19.127 (46-62) 0.337 < 0.001 morphology: typical (%) 17.7 ± 1.947 (16-18) 16.56 ± 1.667 (16-17) 4.111 ± 2.028 (4-5) 0.256 < 0.001 archivio italiano di urologia e andrologia 2019; 91, 2 v. alargkof, l. kersten, r. stanislavov, z. kamenov, p. nikolinakos 128 sperm parameters. g2 (n = 9) showed an abnormality in one or more of the bulk semen parameters. particularly, five patients had oligoasthenoteratozoospermia and four had asthenoteratospermia. furthermore, six patients presented with more than 20% decapitated forms. sperm dna fragmentation measured by the halosperm® kit in the control group the mean sdf percentage was calculated as 11.4 ± 1.35 (10.25-12). this was lower in comparison to g1 (p < 0.001) and g2 (p < 0.001). sdf was found to be higher in patients with abnormal sperm parameters 43.78 ± 30.78 (26-38) compared to the normozoospermic group 21.22 ± 3.93 (18-23) (p = 0.008). sdf by group is presented in figure 1. relationships between dna fragmentation and bulk semen parameters in patients with varicocele and normal sperm parameters, dna fragmentation was negatively correlated with sperm ph (r = -0.54, p = 0.135) and motility (a+b) (r = -0.31, p = 0.410), and positively correlated with sperm volume (r = 0.10, p = 0.799), number (r = 0.14, p = 0.713), vitality (r = 0.05, p = 0.894) and typical morphology (r = 0.38, p = 0.314). in all cases the strength of association ranges from very weak to moderate only, of which none is significant (i.e., p > 0.05). on the other hand, in the group of patients with abnormal sperm parameters, dna fragmentation was positively correlated with ph (r = 0.08, p = 0.840) and volume (r = 0.15, p = 0.706); and negatively correlated with number (r = -0.47, p = 0.204), motility (a+b) (r = -0.94; p < 0.001), vitality (r = -0.93; p < 0.001) and typical morphology (r = -0.89; p < 0.001). the latter three indicate a very strong association. discussion this exploratory study aimed to answer the following question: do varicocele patients with abnormal sperm parameters have higher levels of sdf than varicocele patients with normozoospermia? according to the literature research performed by the authors, it was impossible to identify other studies using the same design: directly comparing the dna fragmentation levels, by use of the halosperm® kit, between varicocele patients with normozoospermia and varicocele patients with abnormal sperm parameters, while performing semen analysis according to the eshrenafa-2010 criteria. the results of our study indicate that there is clearly a higher degree of sdf in patients with varicocele. furthermore, in our study varicocele patients with abnormal sperm parameters were found to have higher levels of sdf than varicocele patients with normozoospermia. this finding is consistent with what other authors have also demonstrated regarding infertile men (16). the fact that the levels of fragmentation in the group of patients with abnormal sperm parameters are higher, could reflect the more advanced effects of varicocele on spermatogenesis. moreover, in men with abnormal sperm parameters, we established statistically significant, very strong correlations between dna fragmentation and three semen parameters: progressive motility, vitality and typical morphology. these results are comparable to what other authors have observed (17). weaknesses of this study are the limited number of participating patients as well as the absence of data regarding the grade of varicocele which do not allow the drawing of any major conclusions. this being an exploratory study, the authors urge other researchers both in bulgaria and abroad to collect more data using the methodology described, to obtain a more thorough understanding of the correlations between sdf and bulk semen parameters in patients with varicocele. criticisms regarding the utility of sdf tests to evaluate male infertility include: that the minimum number of spermatozoa without fragmentation required for in vivo conception is unknown, that a simple sperm vitality assessment could suffice given its correlation to sdf (18), and that more studies investigating the cost effectiveness of sdf testing are required to determine its role alongside the standard sperm analysis. while the halosperm® kit is only available in a few laboratories in figure 1. dna fragmentation by group. abnormal sperm control normal sperm parameters parameters group pe rc en ta ge 20 40 60 80 10 0 our country, it can be argued that it is cost-and-time effective, since the results are produced on the same day and the average price of 100 eur for the combined standard semen and sdf analysis is affordable. in conclusion, it has already been proven by numerous studies that sperm dna damage is associated with decreased pregnancy rates in both in vivo and in vitro fertilization. there is an association of sdf with miscarriage and some studies have demonstrated the potential of reversing it by varicocelectomy (19). in patients with abnormal sperm parameters, sdf levels could be expected to be higher. in normozoospermic patients, sdf testing could potentially alter management as increased levels of sdf could present a therapeutic target. dna fragmentation testing can be another arrow in the quiver of the clinician for the better understanding of male infertility and the management of selected patients with varicocele. references 1. jarow j. effects of varicocele on male fertility. hum reprod update. 2001; 7:59. 2. gorelick j, goldstein m. loss of fertility in men with varicocele. fertil steril. 1993; 59:613. 3. kursh e. what is the incidence of varicocele in a fertile population?. j urol. 1988; 139:665. 4. world health organization. the influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. fertil steril. 1992; 57:1289. 5. masson p, brannigan r. the varicocele. urol clin north am. 2014; 41:129. 6. zini a, dohle g. are varicoceles associated with increased deoxuribonucleic acid fragmentation?. fertil steril. 2011; 96:1283 7. practice committee of american society for reproductive medicine. the clinical utility of sperm dna integrity testing. fertil steril. 2008; 90:178. 8. jarrow j, sigman m, kolettis p, et al. optimal evaluation of the infertile male. aua best practice statement reviewed and validity confirmed. 2011. 9. jungwirth a, giwercman a, tournaye h, et al. european association of urology guidelines on male infertility: the 2012 update. eur urol. 2012; 62:324. 10. giwercman a, lindstedt l, larsson m, et al. sperm chromatin structure assay as an independent predictor of fertility in vivo: a case-control study. int j androl. 2010; 33:221. 11. collins j, barnhart k, schlegel p. do sperm dna integrity tests predict pregnancy with in vitro fertilization?. fertil steril. 2008; 89:823. 12. robinson l, gallos i, conner s, et al. the effect of sperm dna fragmentation on miscarriage rates: a systematic review and metaanalysis. hum reprod, 2012; 27:2908. 13. evenson d, wixon r. meta-analysis of sperm dna fragmentation using the sperm chromatin structure assay. reprod biomed online. 2006; 12:466. 14. evgeni e, lymberopoulos g, touloupidis s, et al. sperm nuclear dna fragmentation and its association with semen quality in greek men. andrologia. 2015; 47:1166. 15. fernandez j, muriel l, goyanes v, et al. halosperm® is an easy, available, and cost-effective alternative for determining sperm dna fragmentation. fertil steril. 2005; 84:860. 16. moskovtsev s, willis j, white j, et al. sperm dna damage: correlation to severity of semen abnormalities. urology. 2009; 74:789. 17. omran h, bakhiet m, dashti m. dna integrity is a critical molecular indicator for the assessment of male infertility. mol med rep. 2013; 7:1631. 18. mitchell la, de iuliis gn, aitken rj. the tunel assay consistently underestimates dna damage in human spermatozoa and is influenced by dna compaction and cell vitality: development of an improved methodology. int j androl. 2011; 34:2. 19. roque m, esteves s. effect of varicocele repair on sperm dna fragmentation: a review. int urol nephrol. 2018; 50:583. 129archivio italiano di urologia e andrologia 2019; 91, 2 sdf and bulk semen parameters in varicocele correspondence viktor alargkof, md valargoff@yahoo.gr 24 rue du bugnon, lausanne, 1005, ch larissa kersten, md larissa.kersten@gmail.com 4 theodor-heuss str, 45731 waltrop, de romil stanislavov, md rstanik@abv.bg 84 ami bue str. 1000, sofia, bg, zdravko kamenov, md zkamenov@hotmail.com 1 sveti georgi sofiyski str, 1431, sofia, bg panagiotis nikolinakos, md pnikolinakos@yahoo.gr 139 pentelis ave, 15127, athens, gr archivio italiano di urologia e andrologia 2018; 90, 144 original paper erectile dysfunction in patients taking psychotropic drugs and treated with phosphodiesterase-5 inhibitors rossella mazzilli 1, gloria angeletti 2, soraya olana 1, michele delfino 1, virginia zamponi 1, chiara rapinesi 2, antonio del casale 2, georgios d. kotzalidis 2, jlenia elia 1, gemma callovini 2, paolo girardi 2, fernando mazzilli 1 1 andrology unit, sant’andrea hospital, sapienza university of rome, school of medicine and psychology, rome, italy; 2 nesmos (neurosciences, mental health, and sensory organs) department, sant’andrea hospital, sapienza university of rome, school of medicine and psychology, rome, italy. objectives: the aim of this study was to assess the prevalence of patients with erectile dysfunction (ed) receiving psychotropic drugs, the impact of these drugs on hormonal profile, and the efficacy of pde5-i in these patients. materials and methods: we recruited 1872 patients referring for ed to our andrology unit. assessment included serum testosterone, gonadotropins, tsh, prolactin, and psa, and the iief-5 questionnaire for ed diagnosis. inclusion criteria were age 21-75 years and iief-5 total score ≤ 21; exclusion criteria included hypogonadism, diabetes mellitus, previous prostatectomy, other medication intake, and ed diagnosis prior to psychotropic drug treatment. efficacy was rated with the iief-5 (remission: total score ≥ 22). results: the prevalence of ed patients treated with psychotropic drugs since ≥ 3 months was 9.5% (178/1872), subdivided according to the drugs used into: group a, 16 patients treated with atypical antipsychotics (9.0%); group b, 55 patients with benzodiazepines (30.9%); group c, 33 patients with antidepressant drugs (18.5%); and group d, 74 patients with multiple psychotropic drugs (41.6%). patients in group a were significantly younger than other groups (p < 0.05). the hormonal profile presented only higher prolactin level in patients treated with antipsychotics, alone or in combination (p < 0.05). overall, 146 patients received pde5-i. remission rate, after three months of treatment, was significantly higher in group b compared to c and d groups (p < 0.05). conclusions: a substantial portion of patients receiving psychotropic drugs show ed. sexual performance in these patients benefits from pde5-i. age, effects of psychiatric disorders, psychotropic drugs, and pde5-i treatment modality accounted for variability of response in this sample. key words: erectile dysfunction; psychotropic drugs; phosphodiesterase 5-inhibitors; antipsychotic drugs; antidepressant drugs; benzodiazepines. submitted:14 december 2017; accepted 20 february 2018 summary no conflict of interest declared. alpha-blockers, proton pump inhibitors and psychotropic drugs, especially antidepressants and antipsychotics. there are many ways by which drugs can interfere with the neuro-vascular and sensory mechanisms of sexual function (2). in particular, antipsychotics and serotonin reuptake inhibitors (ssris), in addition to anorgasmia and decreased libido, may induce ed, mainly through dopamine inhibition and the consequent increase in prolactin levels. however, antipsychotics differ in their hyperprolactinemic effect; risperidone, olanzapine, ziprasidone, and amisulpride have all been associated with hyperprolactinemia, quetiapine, clozapine and aripiprazole with both hyperprolactinemia and its reversal, and lurasidone has shown no hyperprolactinemizing potential. furthermore, combining antidepressants with antipsychotics was associated with increased prolactin level (3). there are several reports and studies dealing with the treatment of ed with pde5-i in patients receiving psychotropic medication, mainly in patients who developed ed secondary to antidepressant or antipsychotic intake. antidepressants are long known to be associated with sexual side effects (2) and more than half of the patients who receive antidepressants (ads) develop sexual side effects. the main mechanisms by which antidepressants affect sexual function are monoaminergic, i.e., serotonergic, noradrenergic, and dopaminergic. almost all currently used antidepressants acutely increase the concentration of biogenic amines in the synaptic cleft and in the longer term down-regulate serotonergic and noradrenergic receptors in the synapses. in man, cavernosal serotonin mediates contraction, hence reduced penile blood influx, with 5-ht1a, 5-ht2a, and 5-ht4 serotonin receptor stimulation inducing detumescence that may be blocked by antagonists of these receptors. to further add to this complexity, dopamine d1 and d2like receptor agonists strain-dependently induce penile erection (4). antipsychotic drugs, both classical and atypical, are able to block dopaminergic function by inhibiting all types of dopamine receptors, so their ability to cause ed is not surprising (5). increased intracellular cgmp is crucial for erection; various phosphodiesterases (pdes) hydrolyze cgmp (pde5, 6 and 9 specifically) to 5’-gmp thereby decreasing its intracellular concentration and consequently, erection, thus providing an adequate rationale for pde inhibitors in the treatment of ed. the effects of doi: 10.4081/aiua.2018.1.44 introduction erectile dysfunction (ed) is defined as the persistent inability to achieve or maintain penile erection that is sufficient for satisfactory sexual performance. organic (neurological, endocrine-metabolic disorders, diabetes, vascular, and mechanic), psychological and pharmacological (e.g., drug interference) factors may lead to ed (1). the drug classes most frequently associated with ed are antihypertensive, mazzilli_stesura seveso 27/03/18 09:26 pagina 44 45archivio italiano di urologia e andrologia 2018; 90, 1 erectile dysfunction and psychotropic drugs sildenafil have been evaluated and found satisfactory in patients treated with antipsychotics who had developed ed, including atypical antipsychotics, such as olanzapine and risperidone or antidepressant drugs; in all studies, sildenafil was effective and well-tolerated (6-9). tadalafil was also found to be effective in patients treated with antidepressants, like serotonin reuptake inhibitors (ssris) (10). however, no studies to date focused conjointly on how many patients with ed were treated with psychotropics and on their endocrine derangement. we aimed to retrospectively investigate: a) the prevalence of patients who are treated with psychotropic drugs among men with ed; b) the impact of these drugs on their hormonal profile; and c) the efficacy of pde5-i in relieving ed in patients with psychotropic-associated ed who continue on their psychotropic medication. materials and methods patients we recruited 1872 patients with ed between 21 and 75 years of age who referred to our andrology unit (sant'andrea hospital-sapienza university, rome, italy) between january 2006 and july 2017. patients were explained the purpose of the study and signed free, informed consent. assessment comprised medical history collection, physical examination, in particular andrological, and the completion of a sociodemographic data collection sheet. all patients completed the international index of erectile function (iief-5) questionnaire (11). those scoring ≤ 21 were eligible for the study. exclusion criteria comprised previous radical prostatectomy, hypogonadism in treatment with testosterone, diagnosis of diabetes mellitus (dm), based on fasting plasma glucose and glycosylated hemoglobin-hba1c levels, a previous pde5-i treatment, a concomitant treatment with other, non -psychotropic medications. at baseline we obtained blood to evaluate luteinizing hormone (lh), follicle stimulating hormone (fsh), testosterone, thyroid stimulating hormone (tsh), prolactin, and prostate specific antigen (psa). hormonal assays. between h 08:00 and 11:00 we withdrew from each patient 5 ml of blood in 5 ml vials. the vials were centrifuged at 3,000 r.p.m. for 10 min and kept at 20°c until the day of the assay. assays were carried-out using enzyme-linked fluorescence assay (elfa); we investigated serum testosterone, ft4, tsh, and prolactin. psychometric assessment. the patients completed the validated italian version of the abridged iief-5 questionnaire, consisting of five items each rated on a 5-point likert scale ranging from 1 (low on sexuality) to 5 (normal sexual performance) (11). a score of ≤ 21 is considered as showing the existence of ed, while scores of ≥ 22 are considered as remission. treatment. in the absence of contraindications, included ed patients had the option to choose between an “on demand” schedule of a pde5-i, i.e., 50-100 mg oral sildenafil, 10-20 mg vardenafil, 10-20 mg tadalafil, and (since 2013) 100-200 mg avanafil, or a 5 mg/day oral tadalafil “once a day” schedule. in particular, the “on demand” drug was chosen with the patient, according to time of onset, duration of action, and interactions with food and alcohol, which are specific for each pde5-i. the study adhered to the hospital’s ethics committee guidelines and to the ethical principles for medical research involving human subjects as adopted at the 18th wma general assembly, helsinki, finland, june 1964, and amended by the 55th wma general assembly, tokyo, japan, october 2004 and subsequent modifications when enforced (last, fortaleza, brazil, october 2013). statistics given the large sample size, we used parametric statistics to analyze our data. we used the paired t-test and fisher's exact test for continuous and categorical data, respectively. continuous data were described as absolute values, mean ± standard deviation (sd), and range. categorical data were described as absolute, percentage frequency, and 95% confidence intervals (cis). we set statistical significance at p < 0.05. analyses were carriedout with the statistical package for the social sciences (spss), version 24 (international business machines corporation [ibm], armonk, new york, us). results of the 1872 evaluated patients, 1642 were not receiving any psychotropic medication, while 230 patients (12.3%) were receiving psychotropic drugs; of them, 52 were excluded, 9 because they were previously prostatectomized, 8 were hypogonadic in treatment with testosterone, 14 had dm, and 47 were taking also non-psychotropic medications, thus leaving a final sample of 178 (9.5%). the sample’s sociodemographic characteristics are shown in table 1. the 178 patients were distributed into 4 groups, according to the psychotropic drugs they used (table 2): • group a: 16/178 patients (9.0%) were treated with atypical antipsychotics (olanzapine, aripiprazole, risperidone and quetiapine); table 1. sociodemographic characteristics of the included men (n = 178). sd, standard deviation. mean (range) sd age 51.6 (21-75) 13.1 n (%) marital status single 43 24.2 married 97 54.5 divorced 25 14.0 widowed 13 7.3 educational level primary school 3 1.7 high school 15 8.4 superior high school 83 46.7 college/university 54 30.3 specialization/master/ph.d. 23 12.9 occupational status unemployed 21 11.8 blue collar worker 28 15.7 employee 44 24.8 entrepreneur 28 15.7 free-lance professional 42 23.6 executive 15 8.4 mazzilli_stesura seveso 27/03/18 09:26 pagina 45 archivio italiano di urologia e andrologia 2018; 90, 1 r. mazzilli, g. angeletti, s. olana, m. delfino, v. zamponi, c. rapinesi, a. del casale, g.d. kotzalidis, j. elia, g. callovini, p. girardi, f. mazzilli 46 • group b: 55/178 patients (30.9%) treated with benzodiazepines (alprazolam, lorazepam, clonazepam, bromazepam); • group c: 33/178 patients (18.5%) treated with antidepressant drugs in monotherapy (ssris, i.e., fluoxetine, sertraline, citalopram, escitalopram, or paroxetine; serotonin-norepinephrine reuptake inhibitors (snris), i.e., duloxetine and venlafaxine; and tricyclic antidepressants (tcas), i.e., amitriptyline and clomipramine); • group d: 74/178 patients (41.6%) in polytherapy with antidepressant drugs (citalopram, paroxetine, and clomipramine) and/or atypical antipsychotics (olanzapine, aripiprazole, and risperidone) and/or benzodiazepines (alprazolam, lorazepam, and clonazepam) and/or mood stabilizers (lithium carbonate, carbamazepine, and valproic acid). no patient was on monotherapy with monoamine oxidase inhibitors (maois) or mood stabilizers. age. patients in group a were significantly younger compared to the other groups (p < 0.05) (table 2). hormonal profile. the four groups did not differ in hormone levels, except for prolactin, that was higher in patients treated with antipsychotics alone or those in polytherapy with respect to the groups treated with benzodiazepines or antidepressants alone (p < 0.05) (table 2). ed treatment. of the 178 patients, 146 (82.0%) accepted pde5-i treatment; patients in group a adhered to treatment significantly more than patients in group b (p < 0.05). the remaining 32 (18.0%) patients refused pde5-i treatment for various reasons. response/remission of ed, as assessed after three months of treatment through the iief-5 questionnaire (i.e., a total score of ≥ 22), was significantly higher in group b compared to groups c and d (p < 0.05) (tables 3-4). regarding pde5-i treatment modality, 113/146 (77.4%) patients chose “on demand” while 33/146 (22.6%) chose “once a day” administration. “on demand” and “once a day” groups showed no significant differences in positive response rates (47.8% vs. 41.2%; p = n.s.). however, considering individual groups, response/remission in patients who chose an “on demand” modality was significantly higher in group b, compared to groups c and d (p < 0.05). regarding the “once a day” modality, no between-groups differences were shown. of the 146 patients who adhered to pde5-i treatment, 67 (45.9%) responded positively to treatment (final iief-522). the iief-5 total score varied from 12.5 ± 3.8 (range 621) at baseline to 19.8 ± 3.8 (range 8-25) at the threemonth follow-up. the difference was statistically significant (p < 0.01). table 2. age and hormonal profile in the different groups considered [mean values ± sd (min.-max)]. table 3. therapeutic efficacy of pde5-i in the various psychotropic treatment groups (iief-5: total score ≥ 22) [n (%, 95%ci)]. table 4. pde5-i “on demand” or “once a day” treatment and efficacy (iief-5: total score ≥ 22) per psychotropic treatment [n (%, 95%ci)]. n = 178 age (years) lh fsh testosterone tsh prolactin psa (range) (mlu/ml) (mlu/ml) (ng/ml) (mlu/ml) (ng/ml) (ng/ml) group a 16 42.5 ± 14.1* 5.2 ± 2.8 5.1 ± 2.6 5.3 ± 2.0 1.6 ± 0.5 16.9 ± 2.8* 1.4 ± 1.1 (25-59) (2.7-9.2) (3.1-8.0) (3.1-8.0) (0.92-2.3) (14.0-21.3) (0.58-2.15) group b 55 54.0 ± 13.5 4.9 ± 2.3 4.4 ± 1.5 5.9 ± 2.3 1.6 ± 0.8 6.8 ± 3.2 1.7 ± 1.2 (24-75) (2.3-8.7) (1.8-7.4) (2.7-8.8) (1.1-3.4) (4.0-11.2) (0.3-3.3) group c 33 55.3 ± 11.7 5.8 ± 2.7 6.6 ± 2.6 5.9 ± 1.5 1.0 ± 0.8 7.2 ± 3.7 1.6 ± 1.1 (0.6-2.9) (36-75) (2.0-11.2) (3.4-12.6) (4.6-7.9) (0.3-1.9) (4.9-13.3) group d 74 50.2 ± 12.4 6.0 ± 4.3 7.3 ± 3.9 4.1 ± 2.3 2.0 ± 0.9 15.8 ± 5.5* 1.8 ± 1.0 (21-75) (1.4-12.6) (2.5-12.1) (1.6-8.9) (0.9-3.1) (6.8-25.4) (0.7-1.9) *p < 0.01 vs group b, c e d; **p < 0.01 vs groups b and c. legend for groups: a, receiving only atypical antipsychotics; b, receiving only benzodiazepines; c, receiving only antidepressants; d, receiving any combination of the above. luteinizing hormone (lh), follicle stimulating hormone (fsh), thyroid stimulating hormone (tsh), prostate specific antigene (psa). n treated patients responders (%) total 178 146/178 (82.0%; 75.7 to 87.0) 67/146 (45.9%; 38.0 to 54.0) group a 16 9/16 (56.3%; 33.2 to 76.9) 5/9 (55.6%; 26.6 to 81.2) group b 55 47/55 (85.5%; 73.6 to 92.7)* 31/47 (66.0%; 51.6 to 77.9)** group c 33 27/33 (81.8%; 65.2 to 91.8) 11/27 (40.7%; 24.5 to 59.3) group d 74 62/74 (83.8%; 73.6 to 90.6) 20/62 (32.3%; 21.9 to 44.7) * p< 0.05 vs a; ** p<0.05 vs groups c and d. legend for groups: a, receiving only atypical antipsychotics; b, receiving only benzodiazepines; c, receiving only antidepressants; d, receiving any combination of the above. on demand once a day n responders (%) n responders (%) total 113 54/113 (47.8%; 38.8-56.9) 33 14/33 (41.2%; 26.3-57.8) group a 7/10 3/7 (42.9%; 15.8 to 75.0) 3/10 2/3 (66.7%; 20.2 to 94.4) group b 42/47 29/42 (69.1%; 53.9 to 81.0)* 5/47 3/5 (60.0%; 22.9 to 88.4) group c 16/27 6/16 (37.5%; 18.4 to 61.5) 11/27 4/11 (36.4%; 15.0 to 64.8) group d 48/62 16/48 (33.3%; 21.6 to 47.5) 14/62 5/14 (35.7%; 16.2 to 61.4) *p < 0.05 vs groups c and d. legend for groups: a, receiving only atypical antipsychotics; b, receiving only benzodiazepines; c, receiving only antidepressants; d, receiving any combination of the above. mazzilli_stesura seveso 27/03/18 09:26 pagina 46 47archivio italiano di urologia e andrologia 2018; 90, 1 erectile dysfunction and psychotropic drugs discussion in this study we focused on identifying the prevalence of psychotropic drug use in ed patients, on observing psychotropic drug impact on ed patient’s hormonal profile, and on the efficacy of pde5-i in such patients. about 12.3 % of patients with ed in our sample were receiving psychotropic medication and about 9.5% met criteria for inclusion; of them, about half achieved remission in response to pde5-i treatment added on their psychotropic drug(s). in this cross-sectional study, we found the group receiving only benzodiazepines to fare better than groups receiving other drugs or combinations, even after splitting the sample into “on demand” or “once a day” modalities. we also found higher serum prolactin only in patients receiving antipsychotics, alone or in combination, as well as age differences among the four groups. a possible pathogenic factor of ed is represented by drug interference. among drugs, psychotropics have an important role, even if, in the presence of ed, the line between effect of drug therapy and psychopathology is undefined. in fact, in patients with depressive symptoms, symptoms like apathy or anhedonia, and in those with schizophrenia, specifically anhedonia, could negatively shape sexual life (5-9). we are aware of no studies investigating the prevalence of psychotropic drug use in an ed population. here we found a 9.5% prevalence involving patients developing ed after at least 3-month psychotropic drug use. studies investigating psychotropic drug prescription/use in the general population worldwide have produced different results depending on the period of investigation and on the country where the search was conducted (supplementary table). comparing our data with the last european data on general populations (12.3%), our proportion of patients with ed who are on psychotropics is similar. however, given that in most studies significantly more women than men use psychotropics, and considering that our sample was composed of men only, we might suppose that psychotropic drug use in ed populations may be higher than in the general population. we divided our sample into 4 groups according to the type of drugs they used, i.e., atypical antipsychotics, benzodiazepines, and antidepressant drugs in monotherapy and those who were on polytherapy. these subsamples differed for age, in that patients receiving antipsychotics were significantly younger than those in the other groups, probably because the psychoses have an earlier onset and an earlier treatment initiation than other psychiatric disorders. in fact, schizophrenia has an onset around adolescence and early adulthood, while anxiety disorders and depression have a later onset and a later initiation of treatment (12). the hormonal profile (gonadotropins, testosterone and tsh levels) was similar in the different groups; on the other hand, prolactin levels, a hormone related to sexual dysfunction, was significantly higher in the groups treated with atypical antipsychotics, alone or in combination, in line with literature (3, 13). there are few reports on the use of sildenafil and tadalafil in patients treated with atypical antipsychotic or antidepressant drugs in monotherapy, and they showed variable efficacy (6, 14-15). our study included also people treated with benzodiazepines and polytherapy, and, among pde5-i, also vardenafil and avanafil. there are few, sporadic reports on the use of these two pde5-is in psychotropic-associated ed. the only controlled study regarded vardenafil vs. placebo and found effectiveness for both ed and mild depression in patients receiving no psychotropic drugs, that could mean either intrinsic antidepressant properties for pde5-is or that improved sexual performance acted on depression to decrease it (16). acceptance to be treated was higher in patients treated with benzodiazepines, compared to the other groups. in particular, people on benzodiazepines were significantly more likely to endorse pde5-i treatment than patients on antipsychotics and responders among the former were significantly more likely to have endorsed pde5-i treatment than those who received either antidepressants or polytherapy. while we are not able to demonstrate why should this occur, we could speculate that people with anxiety, who usually receive benzodiazepines (although antidepressant treatment is the standard for most anxiety disorders), experience less side effects (other than dependence) than those who receive other classes of psychotropics, thus they are more open to further drug treatment to improve their ed. help-seeking was found to be the most important factor in benzodiazepine and antidepressant use in europe (17), but factors prompting to further drug use were not examined. we did not investigate help-seeking specifically, but most of our patients were motivated for resolving their ed. furthermore, people with psychosis tend to be suspicious about drug treatment and doctors and show poor adherence (18). furthermore, we found significantly more improvement in the group receiving benzodiazepines, indicating their ed was due to an underlying anxiety disorder rather than to their medication. although benzodiazepines may differ in their ed-inducing potential, results from large cohorts show benzodiazepines to be associated with ed, even after adjusting for comorbidities and health behaviors or addressing possible confounders (19). benzodiazepine increase gabaa receptor function and gabaa receptor stimulation has been shown to reduce penile erection in rats through central mechanisms, so we could expect that people on benzodiazepines could show similar rates of ed to people taking other ed-associated psychotropic drugs (20). it is possible that in conditions of extreme anxiety, in which gabaergic activity is low, its normalization through benzodiazepines could alleviate impaired erection caused by anxiety itself. better response in the benzodiazepine group was present also when subdividing the sample according to “on demand” or “once a day” modalities, with better response in the former, while in the latter no significance could be shown, probably due to reduced sample size. on the other hand, the unsatisfactory response of the other groups (antidepressants, antipsychotics and polytherapy) could be possibly due to both the psychopathological condition and to persistent drug interference with erectile function. the limitations of this study is that it included only patients without prior ed who underwent psychotropic drug treatment. thus, we cannot investigate the extent to which pde5-i treatment may benefit patients with ed mazzilli_stesura seveso 27/03/18 09:26 pagina 47 archivio italiano di urologia e andrologia 2018; 90, 1 r. mazzilli, g. angeletti, s. olana, m. delfino, v. zamponi, c. rapinesi, a. del casale, g.d. kotzalidis, j. elia, g. callovini, p. girardi, f. mazzilli 48 who need psychotropic treatment for their psychological condition. furthermore, the design was cross-sectional and retrospective. obviously, a prospective cohort study would be more accurate and specific. conclusions this study underlines the significant prevalence of patients with ed treated with psychotropic drugs, and confirms, in line with the literature, the possibility of pde5-i to improve the sexual performances of these patients. the variability of the therapeutic efficacy appears to depend on age, on the effects of psychiatric disorders, on the psychotropic drugs used, and on the choice of pde5-i treatment modality. acknowledgments the authors wish to thank ms mimma ariano, ms ales casciaro, ms teresa prioreschi, and ms susanna rospo, librarians of the sant’andrea hospital, school of medicine and psychology, sapienza university, rome, for rendering precious bibliographical material accessible. references 1. foresta c, caretta n, corona g, et al. clinical and metabolic evaluation of subjects with erectile dysfunction: a review with a proposal flowchart. int j androl. 2009; 32:198-211. 2. waldinger md. psychiatric disorders and sexual dysfunction. handb clin neurol. 2015; 130:469-489. 3. pacchiarotti i, murru a, kotzalidis gd, et al. hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice. eur neuropsychopharmacol. 2015; 25:10451059. 4. melis mr, argiolas a, gessa gl. apomorphine-induced penile erection and yawning: site of action in brain. brain res. 1987; 415:98-104. 5. liu-seifert h, kinon bj, tennant cj, et al. sexual dysfunction in patients with schizophrenia treated with conventional antipsychotics or risperidone. neuropsychiatr dis treat. 2009; 5:47-54. 6. gopalakrishnan r, jacob ks, kuruvilla a, et al. sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. am j psychiatry. 2006; 163:494-499. 7. atmaca m, kuloglu m, tezcan e. sildenafil use in patients with olanzapine-induced erectile dysfunction. int j impot res. 2002; 14:547-549. 8. aviv a, shelef a, weizman a. an open-label trial of sildenafil addition in risperidone-treated male schizophrenia patients with erectile dysfunction. j clin psychiatry. 2004; 65:97-103. 9. nurnberg hg, hensley pl, gelenberg a, et al. treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. jama. 2003; 289:56-64. 10. segraves rt, lee j, stevenson r, et al. tadalafil for treatment of erectile dysfunction in men on antidepressants. j clin psychopharmacol. 2007; 27:62-66. 11. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abriged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999; 11:319-326. 12. kessler rc, amminger gp, aguilar-gaxiola s, et al. age of onset of mental disorders: a review of recent literature. curr opin psychiatry. 2007; 20:359-364. 13. park ym, lee sh, lee bh, et al. prolactin and macroprolactin levels in psychiatric patients receiving atypical antipsychotics: a preliminary study. psychiatry res. 2016; 239:184-189. 14. fava m, nurnberg hg, seidman sn, et al. efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. j clin psychiatry. 2006; 67:240-246. 15. de boer mk, oolders jm, van den heuvel er, et al. efficacy of tadalafil on erectile dysfunction in male patients using antipsychotics: a double-blind, placebo-controlled, crossover pilot study. j clin psychopharmacol. 2014; 34:380-382. 16. rosen r, shabsigh r, berber m, et al. vardenafil study site investigators. efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study. am j psychiatry. 2006; 163:79-87. 17. demyttenaere k, bonnewyn a, bruffaerts r, et al. clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the european study of the epidemiology of mental disorders (esemed). j affect disord. 2008; 110:84-93. 18. garcía s, martínez-cengotitabengoa m, lópez-zurbano s, et al. adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: a systematic review. j clin psychopharmacol. 2016; 36:355-371. 19. kupelian v, hall sa, mckinlay jb. common prescription medication use and erectile dysfunction: results from the boston area community health (bach) survey. bju int. 2013; 112:1178-1187. 20. melis mr, argiolas a. reduction of drug-induced yawning and penile erection and of noncontact erections in male rats by the activation of gabaa receptors in the paraventricular nucleus: involvement of nitric oxide. eur j neurosci. 2002; 15:852-860. correspondence rossella mazzilli, md rossella.mazzilli@uniroma1.it sant’andrea hospital, sapienza university of rome, school of medicine and psychology via di grottarossa 1035-1039, 00189 rome, italy soraya olana, md michele delfino, md, phd virginia zamponi, md jlenia elia, md fernando mazzilli, md andrology unit, sant’andrea hospital, sapienza university of rome, school of medicine and psychology, rome, italy gloria angeletti, md chiara rapinesi, md antonio del casale, md, phd georgios d. kotzalidis, md, phd gemma callovini, md paolo girardi, md nesmos (neurosciences, mental health, and sensory organs) department, sant’andrea hospital, sapienza university of rome, school of medicine and psychology, rome, italy mazzilli_stesura seveso 27/03/18 09:26 pagina 48 stesura seveso 343archivio italiano di urologia e andrologia 2016; 88, 4 case report the importance of citrates in the treatment and prophylaxis of calcium oxalate urinary stones michele barbera 1, andreas tsirgiotis 1, mauro barbera 2, quintino paola 1 1 operative unit of urology, ospedale giovanni paolo ii, sciacca, italy; 2 university of palermo, palermo, italy. about 10% of the people is the subject of an episode of kidney stones during their lifetime, about 70% of these people undergoes relapses. about 80% of the urinary stones contains calcium, of wich 80% is formed of calcium oxalate, in pure form or associated with calcium phosphate. therefore we can saythat in most cases (about 65%) the urinary stones are composedof calcium oxalate. use of supplements of potassium citrate and magnesium citrate can help in the prevention of kidney stones of calcium oxalate, but mostly they can be used in the days before a shockwaves lithotripsy treatment to make the stones more fragile to the effect of the shock waves. a case of successful treatment with magnesium potassium citrate of a swl resistant ureteral stone is presented. key words: calcium oxalate stones prophylaxis. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. – family history of kidney stones: is the case for example of cystine stones, due to a congenital defect of the kidney which cause high concentration of a poorly soluble amino acid in the urine (cystine) which precipitates forming crystals; – chronic urinary tract infections; – abuse of certain drugs or saline and vitamin supplements; – hyperthyroidism (catabolic effect on bone) and hyperparathyroidism (increased blood calcium); – incongruous diet; – ethnicity: increased incidence of kidney stones in white and asian race; – climate (during the hot summer period the increased of evaporation, if not supplemented by appropriate fluid intake, increases urine concentration and the formation of stones). case report a man of 28 years was diagnosed with a 15 mm radiopaque stones located in the first tract of the left lumbar ureter (figure 1). the patient was subjected to a shockwaves litothripsy (swl) (2) treatment that did not achieve fragmentation of the stone (3). after that, he underwent left ureterolithotripsy with limited fragmentation of the stone and migration of the fragdoi: 10.4081/aiua.2016.4.343 presented at 20th national congress sieun, sciacca 2016 figure 1. introduction kidney stones are very common in the population, they affect about 3% of people on average. particularly at risk are males aged between twenty and forty years. in this age group, because of the simultaneous presence of multiple risk factors, the incidence of the disease is over 15%. the causes of the origin of the stones have not yet been fully clarified, although some predisposing factors significantly increase the likelihood the formation of the stones: – male gender: males have a 3 fold increased risk than women to develop kidney stones in the urinary tract (the highest concentration of citrate in women's urine, closely related to the estrogen rate, would explain the lower incidence of the disease in the females); – poor fluid intake: a reduced flow of urine favors the stagnation of the urine and then the precipitation of the salts contained in the urine as in the case of dehydration due to the increase of fluids loss (diarrhea, sweating); – age: kidney stones are formed mainly between twenty and forty years; – acidity of urine: urinary ph below 5 (with respect to some types of stones, such as uric acid, cystine, and xanthine); archivio italiano di urologia e andrologia 2016; 88, 4 m. barbera, a. tsirgiotis, m. barbera, q. paola 344 ments in the lower pole of the left kidney (figure 2). a left ureteral stent was placed. he started oral therapy with magnesium and potassium citrate for 30 days as pre-treatment for subsequent swl (1). after the second swl treatment fragmentation of the stones in small concretions more evident at the lower calyceal group level was achieved (figure 3). the patient continued the treatment with oral magnesium potassium citrate and hydratation. a further reduction of the size of the fragments and the spontaneous expulsion of most of them was observed (figure 4). discussion citrates have an important role in the prevention of kidney stones because they promote formation in the urine of soluble complexes with calcium which determine a reduction of the concentration of calcium ions and of the urinary saturation of calcium oxalate and calcium phosphate. furthermore citrates are capable of inhibiting the crystallization, the growth and aggregation of lithogenic crystals that constitute the stone. the magnesium potassium citrate treatment improves the clearance of residual fragments after swl. recommended daily intake: ranges 40 to 60 meq in two/three divided doses in a continuous manner and for cycles of at least three months. references 1. marangella m, bagnis c, bruno m, et al. crystallization inhibitors in the pathophysiology and treatment of nephrolithiasis. urol int. 2004; 72(suppl 1):s6-10. 2. baggio b, borghi l, caudarella r, et al. linee guida per la nefrolitiasi. g ital nefrol. 2000; 17:59-64. 3. fine jk, pak cyc, preminger gm. effect of medical management and residual fragments on recurrent stone formation following shock-wave lithotripsy. j urol. 1995; 153:27-33. correspondence michele barbera, md barbera.mic@gmail.com andreas tsirgiotis, md atsirgiotis@alice.it paola quintino, md q.paola@inwind.it operative unit of urology, ospedale giovanni paolo ii, sciacca, italy mauro barbera, mb barbera.mau@gmail.com university of palermo, palermo, italy figure 2. figure 4. figure 3. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2206 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.2.206 37% in developing countries with a prevalence rate of nearly 8% in usa (3, 4). prior trials have assessed the incidence of uti in other developing countries. in nigeria, the prevalence of uti is 11%, and it is 12% in india, 6% in kenya and 20% in south africa. saudi arabia has a different ethnic and diverse population. apart from saudi citizens, it has egyptians, syrians, yemeni, indians, pakistani, bangladeshi, and philippians. the study of alanazi et al. estimated the prevalence of uti in saudi arabia at 24% (5-10). risk factors associated with uti include child age, lack of circumcision, urinary obstructive conditions, such as, hydronephrosis, posterior urethral valve occlusion, ureteropelvic junction obstruction, neurological conditions including myelomeningocele with neurogenic bladder, bladder and bowel dysfunction, vesicoureteral reflux (vur), renal scarring, and/or bladder catheterization. also, the prevalence increases in children with malnutrition. online calculators have developed to estimate the risk for uti, such as, the calculator from the university of pittsburgh (3, 11-14). escherichia coli is the commonest pathogen in paediatric uti and it causes 70% of infections. other pathogens include proteus, klebsiella, enterococcus, citrobacter, and pseudomonas aeruginosa (5, 11). uti manifests as either pyelonephritis which tends to present with fever and loin pain. cystitis and urethritis usually present with urine soreness and increased frequency. it is difficult to distinguish pyelonephritis from cystitis in children below the age of two (3). early identification and appropriate antibiotic use are essential to avoid the long-term sequels of uti including introduction: urinary tract infection (uti) is a common disorder in childhood. early identification and appropriate antibiotic use are essential to avoid long-term sequels. the trial objective was to identify the prevalence of uri in children, and the risk factors. methods: this is an analytical cross-sectional study conducted in the saudi arabia, from april 4th 2020 till july 30th 2020. the sample was randomly selected from children who presented to the ministry of health tertiary hospitals. people answered a questionnaire of 10 items. results: 1083 people participated in the current trial. the prevalence of uti was 25.8%. the mean age was 4.5-5 years. uti was commoner in females than males. urethritis was the main presenting complaint. western region was the commonest identified area. those with multivitamin deficiency had the highest prevalence. conclusion: uti is not a very common problem for children in saudi arabia. western region had the highest prevalence and the peak age ranged from 4.5 to 5 years. additionally, nearly a sixth of children could develop severe/complicated uti. key words: urinary tract infection; saudi; pyelonephritis; cystitis; urethritis. submitted 18 november 2020; accepted 1 december 2020 introduction urinary tract infection (uti) is a common clinical problem in childhood (1, 2). internationally, it is anticipated that 150 million uti cases occur annually, and it costs more than 6 billion dollars, yearly. the prevalence of uti ranges from 6% in more developed countries to prevalence of urinary tract infection in children in the kingdom of saudi arabia summary mariam alrasheedy 1, hoda jehad abousada 2, mutaz mansour abdulhaq 3, raghad abdulelah alsayed 4, khalid abdullah alghamdi 5, fayez dhyefallah alghamdi 5, abdullah faisal al muaibid 5, refal ghassan ajjaj 6, seham salem almohammadi 7, sarah salem almohammadi 7, wajd adnan alfitni 8, abdulrahman mohamed homsi 9, meqbel majed alshelawi 10, hassan ali alshamrani 11, abdulrauf abdulatif tashkandi 11, sara mohammed mannan 12, salihah attiah alsamiri 13 1 pediatric nephrology, east jeddah hospital, ksa; 2 obstetrics & gynecology physician, kamc, ksa; 3 east jeddah hospital, ksa; 4 ohod hospital, madinah, ksa; 5 baha university, baha, ksa; 6 isnc, jeddah, ksa; 7 kfh, jeddah, ksa; 8 batterjee medical college, jeddah, ksa; 9 uqu university, mecca, ksa; 10 medical university of silesia, katowice, poland; 11 taif university, taif, ksa; 12 king abdulaziz university, jeddah, ksa; 13 rcsi, dublin, ireland. 207archivio italiano di urologia e andrologia 2021; 93, 2 urinary tract infection in children kidney scarring, chronic renal impairment and hypertension. on the other hand, the inappropriate use of antibiotics is one of the major reasons for antimicrobial resistance which represents a serious global problem. this is because it causes significant impacts on health-care costs, and patient morbidity, and mortality (15, 16). the current trial main objective is to identify the prevalence of uti in children in saudi arabia. also, the research aims to know the risk factors for uti including the region with the highest prevalence, the most common types of presentation, and the risk factors for the development of uti. patients and methods study design and setting this is an analytical cross-sectional study which was carried out in the period between april 4th 2020 and july 30th 2020 in the ministry of health hospitals in the kingdom of saudi arabia. study population the sample was randomly selected, through the computer, from children who presented to both general inpatient and outpatient departments in the ministry of health tertiary hospitals between april 4th 2020 and july 30th 2020. the authors aimed to contact 1600 families. selection was done by the computer to ensure that the selected sample was accurately representing the population in terms of their age, gender, and residency region. for inclusion in the current study, the surveyed sample should be either citizens or residents in the country with their family. to avoid including cases with hospital acquired uti, for inpatients, the authors included only patients up to 2 days of their admission. people answered a survey of 10 items about their residency region (eastern, western, central, southern, or northern); if they have a child who developed urinary tract infection; the age of that child when having uti; the gender of the child; the type of presentation; if the child had a risk factor including hydronephrosis, diabetes mellitus, autism, congenital abnormalities, diseases of the immune system, or vitamin deficiency; if the child was hospitalised because of uti, people’s definition for uti; whether uti recurred within a period of one month after the first diagnosis. finally, the survey asked about the person who answered the questionnaires (father or mother). people who fit with the inclusion criteria of the study were included in the current trial. additionally, the criteria included age of children between 1 and 10 years. collection dates were from april 4th, 2020, to june 30th. 2020. study measurements the prevalence of uti was defined as the proportion of children with the target disease among all the number of children. the current study examined the link between uti and certain predefined factors including the region of residency, age, gender, and other comorbidities. also, severe/complicated uti was defined as that which required hospitalisation, presented with pyelonephritis, or recurrent uti within 30 days after the initial diagnosis (17). statistical analysis statistical analysis was carried out by statistical package for the social sciences (spss) version 17. continuous data were presented in terms of mean, median, mode and 95% confidence interval (ci). univariate analysis with or using chi-squared test and mann-whitney test was performed to investigate the association between uti, severe/complicated uti and predefined factors including their region of residency, age, gender, and comorbidities. multivariate analysis with hr was performed using binary logistic regression. p-value was set at a significance level of < 0.05. ethical consideration ethical approval was sought from the biomedical ethics research committee of the faculty of medicine, ministry of health, kingdom of saudi arabia. prospective informed consent was taken from all participants. the authors confirmed that they did not receive any funding from agencies in the public, commercial, or not-for-profit sectors. table 1. sample characteristics. number percentage % p-value age: (years) 1-3 249 23 0.06 3.1-6 401 37 6.1-8 103 9.5 8.1-10 217 20 unknown 113 10.5 mean 4.5-5 years 95% ci 1-10 years gender: male 454 41.9 0.05 female 629 58.1 region: western 417 38.5 0.04 eastern 343 31.7 central 105 9.7 northern 36 3.3 southern 182 16.8 table 2. patient’s characteristics. number percentage % p-value age: (years) 1-3 64 23% 0.06 3.1-6 101 36% 6.1-8 27 9.7% 8.1-10 57 20.5% unknown 30 10.8% mean 4.5-5 years 95% ci 1-10 years gender: male 118 42 0.05 female 162 58 region: western 109 39 0.04 eastern 90 32 central 15 5.4 northern 25 8.9 southern 41 14.7 mean western archivio italiano di urologia e andrologia 2021; 93, 2 m. alrasheedy, h. jehad abousada, m. mansour abdulhaq, et al. 208 results one thousand sixhundred people were contacted and the authors got responses from 1083 of them. 280 people stated that their child had uti, and the prevalence of uti in the sample was 25.8%. tables 1 and 2 summarised the sample characteristics and patient characteristics. one hundred and thirty-one (47%) children presented with urethritis, 93 (33%) children had cystitis, 28 (10%) children had pyelonephritis, and for the remaining 28 (10%) children location of infection was unknown. seven (2.2%) children had hydronephrosis; 16 (5.8%) children had diabetes mellitus; one (0.4%) child had autism; three (1.1%) children had congenital abnormalities; three (1.1%) children immune disorders; 24 (8.6%) children had a vitamin deficiency; the remaining 226 (80.8%) had no comorbidities. as shown in figure 1, 540 (49.9%) of the responders defined uti as infection in the kidneys, ureter, urethra, or urinary bladder; 478 (44.1%) of the sample defined uti as infection in the urethra or urinary bladder; 31 (2.9%) of people defined uti as infection in the kidneys only; 34 (3.1%) of people defined it as infection in the urethra only. twenty-eight (10%) of patients required admission for their uti, and 24 (8.5%) of patients developed recurrent uti within 30 days of their initial uti. accordingly, 51 (18%) of children with uti developed severe/complicated uti. to note, eight patients had recurrent uti and they did not require admission, so they did not meet the current criteria for severe/complicated uti. tables 3 and 4 showed univariate analysis for uti and severe/complicated uti, respectively. multivariate analysis for uti and severe/complicated are shown in tables 5 and 6 respectively. finally, 54.5% of questionnaires were answered by mothers and the rest was answered by fathers. discussions the current study aims to identify the prevalence of urinary tract infection (uti) in children in the kingdom of saudi arabia and the risk factors for uti. the authors believe that the health of children has always been the health of future generations. children are more susceptible to uti than other age groups. perhaps this is related to their low immunity, lack of family attention to their child hygiene and malnutrition. saudi arabia has a diverse ethnic population, and it depends on two sources of water, which are groundwater and water from desalination plants which remove salt from seawater. also, serum vitamin d level is low among 40% of the saudi population. knowing the prevalence of the disease and identifying the risk group could help physicians in selecting patients who benefit from an additional diagnostic test and prioritise patients who require an additional care (18, 19). the current study is a cross-sectional study that was based on interviewing families of children who presented to the outpatient department and inpatient wards in the tertiary ministry of health hospitals over 3-month period. the tertiary ministry of health hospitals represents 81% of health care services in the country and represents the well-established care level for patients. the authors decided to conduct a cross-sectional survey which evaluates the prevalence of certain diseases and their risk factors at the same point in time. cross-sectional survey provides the best way to identify a disease and its risk factors in a predefined population (20, 21). previous research was conducted in the area of paediatric uti in saudi arabia. the study of garout et al. (22) investigated the prevatable 3. univariate analysis for uti. factor uti no uti or (95% ci) p-value age 1-6 years 165 485 0.00 (0.00-2.00) 0.04 age 6.1-10 84 320 0.035 (0.02-2.2) 0.05 regions western, and eastern 199 561 0.02 (0.00-2.00) 0.04 other regions 81 242 0.04 (0.02-2.1) 0.05 male 118 336 0.04 (0.02-2.2) 0.06 female 162 467 0.03 (0.02-2.0) 0.05 comorbidities 54 31 1.1 (1.00-2.3) 0.04 figure 1. the frequency of surveyors who responded to the question “how to define uti”. what do you think is the correct definition for urinary tract infection? frequency percent valid percent cumulative percent valid an infection of the kidney, ureter, bladder, or urethra 540 49.9 49.9 49.9 an infection of the kidney only 31 2.9 2.9 52.7 an infection of the ureter only 34 3.1 3.1 55.9 an infection of the bladder, or urethra only 478 44.1 44.1 100.0 total 108.3 100.0 100.0 table 4. univariate analysis for severe/complicated uti. factor uti no uti or (95% ci) p-value age 1-6 years 30 620 0.00 (0.00-2.00) 0.03 age 6.1-10 21 383 0.03 (0.02-2.1) 0.05 regions western, and eastern 35 725 0.03 (0.02-2.00) 0.04 other regions 16 307 0.04 (0.03-2.1) 0.03 male 20 434 0.05 (0.03-2.1) 0.04 female 31 598 0.04 (0.02-2.0) 0.06 comorbidities 31 53 1.05 (1.0-2.8) 0.05 table 5. multivariate analysis for uti. factor hr (95% ci) p-value age 1-6 years 0.5 (0.09-1.00) 0.03 regions western, and eastern 0.7 (0.5-1.1) 0.04 male 1.3 (0.9-2.1) 0.06 comorbidities 1.1(0.9-2.0) 0.05 table 6. multivarte analysis for severe/complicated uti. factor hr (95% ci) p-value age 1-6 years 0.6 (0.1-1.00) 0.03 regions western, and eastern 0.6 (0.4-1.0) 0.04 male 1.4 (1.1-2.1) 0.04 comorbidities 1.1(0.8-2.0) 0.05 209archivio italiano di urologia e andrologia 2021; 93, 2 urinary tract infection in children lence of uti in riyadh, the research conducted by alibrahim et al. (23) studied the prevalence of uti in a tertiary hospital in riyadh over a 3-year period, the study of al-otaibi and bukhari (24) investigated the incidence of hospital-acquired uti in a hospital in riyadh and alanazi (25) evaluated the prevalence of uti in emergency departments amongst adults, elderly and children. however, until the time of publication, there has not been any available data stratifying uti prevalence based on gender, age, region, or comorbidities, and to the knowledge of the authors, this was the first study that examined the prevalence of uti on a wide scale of people across the country. the current study focused on community-acquired uti which is a major problem worldwide. also, it included 1083 responders who fit with its inclusion criteria (22-25). the current study showed the prevalence of uti of 25.8% in children aged 1 to 10 years. the study of alanazi et al. (25) showed comparable results. similarly, the study of shisana et al. (10) showed the prevalence of uti in south africa at 20%. other trials showed different rates about 8%. the prevalence of uti varies widely among countries and in different regions in the same country, due to many factors including age, gender, socioeconomic status and health condition (6, 10, 23). this trial showed that the prevalence of uti varied widely by age, gender and regional place and comorbidities. the mean age of uti was 4.5-5 years. the study of garout et al. (22) showed a mean age of incidence of 5 years. the difference could be related to the majority of cases in the latter trial coming from the central region rather than the western area as in the current trial. also, uti was more common among females. the study of garout (22) agreed with our findings. the main presenting complaint was urethritis. the study of alanazi (25) showed a similar finding. those with vitamin deficiency as comorbidity had the highest prevalence. wald (26) agreed with the current finding as the author mentioned that low vitamin levels, including low vitamin d, increased the risk for uti. the current trial revealed that western region had the highest prevalence rate. this is probably related to the fact that the western region had the highest number of participants in the current trial. also, the majority of responders did not have any comorbidity. additionally, the majority of respondents selected the correct definition for urinary tract infection. moreover, nearly a sixth of children developed severe uti. this is the first trial that addresses these observations, but further trials are required to confirm the current findings. the current trial defined severe/complicated uti as uti which requires admission, recurrent uti within 30 days, and uti presenting with pyelonephritis. the study of colgan and mozella (27) agreed with these definitions in adult population, although there is not any clear definition for severe uti in paediatric population. the authors believe that there should be a consensus among physicians about the definition of complicated/severe uti in childhood. the current study has some limitations. it was conducted amongst patients who visited the ministry of health hospitals which provide the majority of health services in the country. further research is required to cover patients who visit community services and private hospitals. also, the current study was conducted over a 4-month period. further research is required with a longer duration to confirm the current study results. conclusions urinary tract infection (uti) is not very common for children in the kingdom of saudi arabia. western region had the highest disease prevalence and the peak age for uti ranged from 4.5 to 5 years. the most common presenting symptom was urethritis and almost a sixth of children developed severe/complicated uti. references 1. subcommittee on urinary tract infection, steering committee on quality improvement and management, roberts kb. urinary tract infection: clinical practice guideline for the diagnosis and management of the initial uti in febrile infants and children 2 to 24 months. paediatrics. 2011; 128:595-610. 2. national institute for health and clinical excellence. urinary tract infection in children. london (uk): nice; 2007. 3. shaikh n, morone ne, bost je, farrell mh. prevalence of urinary tract infection in childhood: a meta-analysis. pediatr infect dis j. 2008; 27:302-308. 4. foxman b. urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. infect dis clin north am. 2014; 28:1-13. 5. the total population in 2018. general authority for statistics (saudi arabia). archived from the original on 2019-04-03. 6. alanazi mq, al-jeraisy mi, salam m. prevalence and predictors of antibiotic prescription errors in an emergency department, central saudi arabia. drug healthc patient saf. 2015; 7:103-111. 7. ghorashi z, ghorashi s, soltani-ahari h, nezami n. demographic features and antibiotic resistance among children hospitalized for urinary tract infection in northwest iran. infect drug resist. 2011; 4:171-176. 8. rabasa ai, shattima d. urinary tract infection in severely malnourished children at the university of maiduguri teaching hospital. j trop pediatr. 2002; 48:359-361. 9. kala uk, jacobs dw. evaluation of urinary tract infection in malnourished black children. ann trop paediatr. 1992; 12:75-81. 10. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence and behaviour survey, 2014. cape town, south africa: hsrc press; 2014. 11. alshamsan l, al harbi a, fakeeh k. the value of renal ultrasound in children with a first episode of urinary tract infection. ann saudi med. 2009; 29:46-49. 12. shaw kn, gorelick m, mcgowan kl, et al. prevalence of urinary tract infection in febrile young children in the emergency department. pediatrics. 1998; 102:e16. 13. singh-grewal d, macdessi j, craig j. circumcision for the prevention of urinary tract infection in boys: a systematic review of randomised trials and observational studies. arch dis child. 2005; 90:853. archivio italiano di urologia e andrologia 2021; 93, 2 m. alrasheedy, h. jehad abousada, m. mansour abdulhaq, et al. 210 14. wald er. cystitis and pyelonephritis. in: feigin and cherry’s textbook of pediatric infectious diseases, 8th ed, cherry jd, harrison g, kaplan sl, et al. (eds), elsevier, philadelphia 2018. p.395. 15. shim yh, lee jw, lee sj. the risk factors of recurrent urinary tract infection in infants with normal urinary systems. pediatr nephrol. 2009; 24:309. 16. caksen h, cesur y, uner a, et al. urinary tract infection and antibiotic susceptibility in malnourished children. int j urol nephrol. 2000; 32:245-247. 17. haynes rb, sackett dl, guyatt gh, tugwell p. clinical epidemiology: how to do clinical practice research. 3rd ed. philadelphia, pa: lippincott williams & wilkins, 2006. 18. abderrahman wa water management in arriyadh, international journal of water resources development 2006; 22:277-289. 19. amer kamel, et al., editors. the water, energy, and food security nexus in the arab region. 1st ed., ser. 2017, 2367-4008, springer international publishing. 20. health indicators, ministry of health, department of statistics, 2006. 21. schmidt co, kohlmann, t. when to use the odds ratio or the relative risk? int j public health. 2008; 53:165-7. 22. garout wa, kurdi hs, shilli ah, and kari ja. urinary tract infection in children younger than 5 years. saudi med j. 2015; 36:497-501. 23. al-ibrahim aa, girdharilal rd, jalal ma, et al. urinary tract infection and vesicoureteral reflux in saudi children. saudi j kidney dis transpl. 2002; 13:24-28. 24. al-otaibi fe, bukhari ee. clinical and laboratory profiles of urinary tract infections caused by extended-spectrum beta-lactamase-producing escherichia coli in a tertiary care center in central saudi arabia. saudi med j. 2013; 34:171-176. 25. alanazi mq. an evaluation of community-acquired urinary tract infection and appropriateness of treatment in an emergency department in saudi arabia. ther clin risk manag. 2018; 14:2363-2373. 26. wald er. cystitis and pyelonephritis. in: feigin rd, cherry j, demmler-harrison gl, kaplan sl, editors. feigin and cherry's text book of infectious diseases. 6th ed. philadelphia (pa): elsevier saunders; 2009, pp. 554-569. 27. colgan r, mozella wm. diagnosis and treatment of acute pyelonephritis in women. am fam physician. 2011; 84:519-526. correspondence mariam alrasheedy, md ma-rasheedy@moh.gov.sa consultant pediatric nephrology, east jeddah hospital (ksa) hoda jehad abousada, md (corresponding author) dr.huda1992@outlook.com obstetrics & gynecology physician, kamc (ksa) mutaz mansour abdulhaq, md pediatric resident, east jeddah hospital (ksa) raghad abdulelah alsayed, md raghadalsayed148@gmail.com resident, ohod hospital, madinah (ksa) khalid abdullah alghamdi, md iikldxii@gmail.com fayez dhyefallah alghamdi, md fayezn96@gmail.com abdullah faisal al muaibid, md almuaibid.96@gmail.com intern, baha university, baha (ksa) refal ghassan ajjaj, student refal.g@outlook.com isnc, jeddah (ksa) seham salem almohammadi, md seham92.sm@gmail.com sarah salem almohammadi, md saroon.sm1@gmail.com intern, kfh, jeddah (ksa) wajd adnan alfitni, md wajd.alfattani@hotmail.com intern, batterjee medical college, jeddah (ksa) abdulrahman mohamed homsi, md abdurrahman.homsi@gmail.com intern, uqu university, mecca (ksa) meqbel majed alshelawi, md l.10.m@hotmail.com intern, medical university of silesia, katowice (poland) hassan ali alshamrani, md h.alshomrani1416@gmail.com intern,taif university, taif (ksa) abdulrauf abdulatif tashkandi, md abdulrauf.t@hotmail.com intern, taif university, taif (ksa) sara mohammed mannan, medical student king abdulaziz university, jeddah (ksa) salihah attiah alsamiri, medical student s.at.alsamiri@gmail.com rcsi, dublin (ireland) archivio italiano di urologia e andrologia 2019; 91, 146 case report a rare complication of inguinal hernia repair: total testicular ischemia and necrosis erhan ates, hakan gorkem kazici, akin soner amasyali department of urology aydin adnan menderes university school of medicine, aydin, turkey. testicular ischemia and necrosis are quite rare complications following inguinal hernia repair. there is still no consensus on the mechanism of infarction and necrosis in the literature. we present a case with total testicular ischemia and necrosis in the early period following the inguinal hernia repair with prolene mesh, ending up with orchiectomy. key words: testis; ischemia; necrosis; hernia repair. submitted 2 january 2018; accepted 20 january 2018 summary no conflict of interest declared. crp was 93.4 mg/l. the laboratory examination of the total urine revealed results within normal levels. during the ultrasound examination of scrotums, it was observed that the right testis was 29 x 25 x 44 mm in size with a normal blood supply, however, the left testis was larger (40 x 35 x 52 mm) with a decreased echogenicity compared to the right one. doppler examination revealed that there is no blood supply to the left testis (figure 1). in addition, there was some free fluid of about 2 mm height around the left testis. upon these findings, on the same day, the patient underwent left inguinal exploration in the region of the former incision scar. following the exposure through the suture line towards the inguinal canal, a 100 cc serous and hemorrhagic fluid was drained. the left spermatic cord was edematous. the left testis was dissected, reaching the level of the internal ring. the left spermatic cord was strangulated at the level of the internal ring by the mesh. at this level, an intracordal necrosis was present. then, the tunica vaginalis was opened. the testis was necrotic (figure 2). the incision of the tunica albuginea did not result in arterial bleeding. spermatic cord was clamped and a left orchiectomy was performed. the operation was finalized by placing a hemovac drain after revision of the mesh graft by a general surgeon. the hemovac drain was removed on the 2nd day following the operation and the patient was discharged without any complications. doi: 10.4081/aiua.2019.1.46 introduction currently, prosthetic meshes are used commonly in inguinal hernia repair procedures as the duration of hospital stays are shorter, postoperative pain is less intense, and relapse rates are lower compared to the direct tissue to tissue repair surgeries (1). however, the direct contact of the mesh with the vessels in the inguinal canal or perimesh fibrosis can cause adverse effects on the testicular blood flow. these may result in some troublesome complications such as testicular atrophy, ischemic orchitis, a partial or total testicular ischemia and necrosis. testicular atrophies are observed at a rate of 0.5% after open inguinal hernioplasties, and the rate increases to 5% after recurrent hernioplasty surgeries, although the rates may vary depending on the experience level of surgeons (2). we present a case with total testicular ischemia and necrosis in the early period following the inguinal hernia repair with prolene mesh, ending up with orchiectomy. case presentation a 30-years-old male patient presented with pain and swelling in the left testis on the 5th day following a herniorrhaphy with a prolene patch, in another healthcare facility, due to a strangulated hernia in the groin. upon the consultation request of the emergency department, the patient was examined. the physical examination revealed that the left testis was slightly hard and tender and the spermatic cord was coarse on palpation. there was mild edema cutaneously and subcutaneously. the phren's sign was negative. laboratory investigation results were 14.1 gr/dl for hemoglobin, 12700 mcl for leukocytes, the platelet count was 288 000 mcl, and figure 1. image of scrotal doppler ultrasonography. there is no blood flow to the left testis. ates_stesura seveso 26/03/19 09:22 pagina 46 47archivio italiano di urologia e andrologia 2019; 91, 1 testicular necrosis after hernia repair the patient presented with normal findings on the follow-up visit in the second postoperative week. the pathological examination reported some testis tissue with disseminated ischemic necrosis and bleeding. informed consent was taken from the patient. discussion testicular atrophy, ischemia, and necrosis are rare complications after inguinal hernia operations. while testicular atrophy is observed at a rate of 0.5% after primary open inguinal hernioplasty, the incidences may reach up to rates of 5% following open recurrent hernioplasties (2). this is considered to be due to an acute thrombosis of the pampiniform venous plexus rather than an acute artrial injury because of the collateral blood supply to the testis via the inferior epigastric, vesical, prostatic and scrotal arterial (3). furthermore, there are studies reporting that testicular ischemia will not develop even, in onethird of the cases, in which the spermatic cord is ligated intentionally (4). in a study, evaluating a total of 6500 patients, it has been determined that, following surgical traumas to the spermatic cord during inguinal hernioplasties, venous congestions develop, leading to thrombosis, which was considered to be the cause of consequent ischemic orchitis and testicular atrophies (5). especially in large hernias extending to the scrotum and in recurrent hernias, wider dissections of the spermatic cord or dislocation of the testis from the scrotum during surgery increase the rates of ischemic orchitis and testicular atrophy. therefore, it is argued that medial and inferior dissections extending beyond the pubic tubercle should be avoided during open repair surgeries (6). the testicular veins may be affected mechanically as well as by inflammatory reactions due to prosthetic meshes. peiper et al. (7), demonstrated inflammatory changes and testicular venous congestion following mesh implementations in animal studies. inflammation was considered to be due to a fibrotic reaction, triggered by the mesh. in peiper’s study, thrombosis in the spermatic cord was identified, additionally. however, there is no consensus in the literature on the relation of the factors including the spermatic cord structures, testicular volumes, and changes in the arterial blood flow; to the direct contact of the prosthetic mesh or to perimesh fibrosis. uzzo et al. (8) observed decreases in the arterial perfusion of the testis and in its temperature. the ultrasonographic examination demonstrates decreases in the systolic blood flow and increases in the resistive index in testicular ischemia (9). on the contrary, there are other studies arguing that testicular blood flow and perfusion does not change after hernia surgeries like the study by zieren et al. (10). ischemic orchitis in the testis manifests on the 2nd or 3rd day following an inguinal hernia surgery and progresses to the develop an infarction. the physical examination and doppler ultrasonography are the initial diagnostic methods in cases, of which testicular ischemia is suspected (9). the testicular arterial blood flow and the testicular perfusion should be evaluated by a scrotal doppler ultrasonography. in these cases, the possibility of a torsioned testis should be considered as well, despite the history of recent inguinal hernioplasty. in our case, the decision of exploration was made when it was determined that there was no blood supply to the testis. the method of treatment is an emergency surgical intervention. surgical methods vary depending on the observation of testicles during the surgery and on the duration of ischemia. the necrotic regions of the testis are excised and repaired by earlier surgical interventions, however, orchiectomy is inevitable when the early stage ischemia, following inguinal surgeries, is recognized later as it was in our case. figure 2. intraoperative images. left testis and spermatic cord (a). mechanical effect of prolene mesh (black arrow) on left spermatic cord (b), left necrotic testis (c). a. b. c. ates_stesura seveso 26/03/19 09:22 pagina 47 archivio italiano di urologia e andrologia 2019; 91, 1 e. ates, h. gorkem kazici, a. soner amasyali 48 conclusions all kinds of symptoms such as scrotal pain, redness, and swelling should be evaluated immediately and with care after inguinal surgeries. in addition, it must be considered that this type of complications may develop in any surgery adjacent to the spermatic cord. references 1. huang cs, huang cc, lien hh. prolene hernia system compared with mesh plug technique: a prospective study of shortto mid-term outcomes in primary groin hernia repair. hernia 2005; 9:167-71. 2. reid i, devlin hb. testicular atrophy as a consequence of inguinal hernia repair. the british journal of surgery 1994; 81:91-3. 3. fong y, wantz ge. prevention of ischemic orchitis during inguinal hernioplasty. surg gynecol obstet, 1992; 174:399-402. 4. heifetz cj. resection of the spermatic cord in selected inguinal hernias. twenty years of experience. arch surg. 1971; 102:36-9. 5. wantz ge. testicular atrophy. a risk of inguinal hernioplasty. chirurgie. 1991; 117:645-51. 6. wantz ge. open repair of hernias of the abdominal wall, surgical techniques. sci am surg. 1995; 2:1-19. 7. peiper c, junge k, klinge u, et al. is there a risk of infertility after inguinal mesh repair? experimental studies in the pig and rabbit. hernia. 2006; 10:7-12. 8. uzzo rg, lemack ge, morrissey kp, goldstein m. the effects of mesh bioprothesis on the spermatic cord structures: a preliminary report in a canine model. j urol. 1999; 161:1344-9. 9. kupczyk-joeris d, kalb a, hofer m, et al. doppler sonography of testicular circulation following reconstruction of inguinal hernia. chirurg. 1989; 60:536-40. 10. zieren j, beyersdorff d, beier km, müller jm. sexual function and testicular perfusion after inguinal hernia repair with mesh. am j surg. 2001; 181:204-6. correspondence erhan ates, md drerhanates@yahoo.com hakan gorkem kazici, md hgkazici@yahoo.com akin soner amasyali, md drakinsoner@gmail.com department of urology aydin adnan menderes university school of medicine, 09010 aydin (turkey) ates_stesura seveso 26/03/19 09:22 pagina 48 stesura seveso 67archivio italiano di urologia e andrologia 2020; 92, 2 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.2.67 introduction this document was based on the review of information materials from agenas (agenzia nazionale per i servizi sanitari), siu (italian society of urology), sages (american rosario leonardi 1, piera bellinzoni 2, luigi broglia 2, renzo colombo 3, davide de marchi 2, lorenzo falcone 1, guido giusti 2, vincenzo grasso 1, guglielmo mantica 4, giovanni passaretti 2, silvia proietti 2, antonio russo 2, giuseppe saitta 2, salvatore smelzo 2, nazareno suardi 4, franco gaboardi 2, urop executive committee * 1 musumeci gecas clinic, gravina di catania, catania, italy; 2 department of urology, san raffaele turro hospital, milan, italy; 3 department of urology, san raffaele hospital, milan, italy; 4 department of urology, irccs policlinico san martino hospital, university of genova, genova, italy; hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19 the covid-19 pandemic influenced the normal course of clinical practice leading to significant delays in the delivery of healthcare services for patients non affected by covid-19. in the near future, it will be crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients. all the staff involved in the project of a covid-free hospital should be subjected to a diagnostic swab for covid-19 before the beginning of healthcare activity and then periodically in order to avoid the risk of contamination of patients during the process of care. the modifications of various activities involved in the process of care are described: outpatient care, reception of inpatients, inpatient ward and operating room. for outpatient care, modality of appointment procedure, characteristics of waiting room and personal protective equipment (ppe) for healthcare professionals and administrative staff are presented. reception of inpatients shall be conditional on a negative swab for covid-19 obtained with a drive-in procedure. the management of the operating room represents the most crucial step of the patient's care process. the surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. adequate personal protective equipment and measures to reduce aerosolization in the operating room (closed circuits, continuous cycle insufflators, fume extraction) should be adopted. prevention of possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate ppe (ffp3 plus surgical mask and protective visor for all the staff working in the operating room) and smoke evacuation devices with a suction and filter system. key words: covid-19; pandemy; surgery; endoscopy; filtration. submitted 20 april 2020; accepted 21 april 2020 summary society of gastroenterology endoscopic surgery), eaes (european society of endoscopic surgery) and italian society of endoscopic surgery. prevention measures, personal protective equipment (ppe) and protocols for healthcare professional, administrative staff and patients have been included trying to implement the best prevention measures against covid-19 infection in public or private healthcare facilities. the covid-19 pandemic influenced the normal course of clinical practice through multiple mechanisms leading to significant delays in the delivery of healthcare services. the possibility of meeting the demand for healthcare in the near future will depend on the duration of the epidemic, its economic and social consequences, and also on changes of the population caused by the infection itself. in consideration of the awareness that for many months we will still have to live with the presence of the virus among the population, it becomes mandatory an immediate rationalization of resources in order to ensure continuity of healthcare for patients not affected by covid-19. it is crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients who need medical treatment. the triage of medical and surgical procedures must take into account the heterogeneity of the pathologies to be treated, the variability of the timing useful for effective treatment, the different surgical approaches and non-surgical alternatives. it should not be forgotten that the epidemic has heterogeneous loco-regional outbreaks with differentiated measures from local government authorities. although there is no official data, it has been reported that a new health migration is underway, with a flow of patients moving from high endemic areas to areas where they can obtain adequate care (agenas-siu). this document aims to provide indications in the triage of patients and in the optimization of the resources available in this difficult moment. as a precondition, all the staff involved in the project of a covid-free hospital should be subjected to a diagnostic swab for covid-19 before the beginning of healthcare activity. the swab should be archivio italiano di urologia e andrologia 2020; 92, 2 r. leonardi, p. bellinzoni, l. broglia, et al. 68 repeated every two weeks in order to avoid the risk of contamination of patients during the process of care. if reliable tests will be validated, able to replace the swab in the diagnosis of covid-19, these tests could be considered as faster and less expensive screening procedure to monitor the absence of infection in the medical staff and hospital nursing. we divided the text into several chapters concerning the various activities involved in the process of care: – outpatient care – reception of inpatients – inpatient ward – operating room. outpatient visits appointment procedure the outpatient visit should be booked through a telephone triage. exclusion criteria: – coming from high endemic areas (red areas) – referred flu symptoms (sore throat, cough, rhinorrhea) – temperature – state of quarantine or cohabitation with subjects in compulsory quarantine. patients must be informed that they must access to the office equipped with a surgical mask. the patient can be accompanied by a person who however will not enter in the office at the time of the visit. if it is necessary to provide information to the companion, this will be convened separately so that the criteria for social distancing are respected within the office. upon entering in the facility it would be useful to perform a body temperature measurement. waiting room in relation to the size of the waiting room, one or more patients can be accepted. it is mandatory to maintain a distance between the patients and their companions of at least two meters. healthcare professionals healthcare professionals must be equipped with personal protective equipment (ppe) including ffp3 mask and protective goggles or visors. administrative staff (payment of outpatient service) must be equipped with ppe (ffp2 mask). note: it is important that the area of the consultations must be separated from the area of hospitalization. hospitalization of the patient for surgery indispensable condition for taking care of the patient (swab testing) an indispensable condition for the patient to be candidate for surgical treatment is that of being subjected to a swab for covid-19 before entering the facility. how and how long before admission, it depends on the structural and organizational characteristics of the hospital and the time needed to obtain the result of the swab. our suggested option is the drive-in swab. a protected area (parking) must be identified where the car with the patient on board can stop for the time necessary to perform the swab. the staff responsible for the procedure must be provided with the maximum individual protection (suit, ffp3 mask, protective visor and gloves). in the case that the hospital could arrange a special area for pre-hospitalization the patient could be accepted after the swab in this area of the hospital to wait for the response. general criteria protect the patient from potential covid infections in the hospital setting. protect staff and other patients from contamination, including mutual. the surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. admission of the patient to the hospital for elective surgery the call of patients for elective surgery must take place through a telephone interview to rule out a possible contagion from coronavirus sars-cov-2: – clinical criteria: cough, rhinorrhea, body temperature rise, pharyngodynia, abdominal pain, conjunctivitis – epidemiological criteria: direct contact with positive covid-19 patient (cohabitation/interview for more than 15 minutes in the same environment, attendance at hospital facilities); origin from high endemic geographic areas identified by current epidemiological data the patient must be informed that the following steps will be followed on the day of the call to enter the hospital: – arrival at the facility will take place starting at 7.30 with a staggering between one patient and the other of about 15 min – arrival by car and parking in the drive-in swab area. – return to his/her home where the patient must respect strict self-isolation until he/she receives the call from the triage staff who communicates the outcome of the swab – as an alternative (especially for patients domiciled far away from the hospital), the hospital could offer hospitality in a separate area with hotel service in individual rooms with private bathroom (nursing and service staff of this area must wear suitable personal protective equipment including gloves, ffp2 mask, plus surgical masks, if the former are equipped with an exhalation valve, waterproof gown for contacts, and protective visor) – any kind of personal contact of the patient with the other patients has to be avoided – in the case of a delayed result of the swab, food must be delivered out of the room in disposable tray with a sealable bag where the patient should pour food waste including the tray – food waste must be handled as special hazardous waste – room must undergo sanitization at the end of the stay – in the event of a negative outcome of the swab, the patient can be admitted to the ward, staying fasting, to start the acceptance and hospitalization procedure – in the event of a positive outcome, the patient is invited to inform the competent health authorities to arrange for self-isolation at home or hospitalization in the covid ward. the patient can be accompanied by a family member or friend who will be able to assist him/her in the swab procedure and in the subsequent phase of hospitalization but who will not be admitted to the wards. both the patient and the companion, in the various stages of the swab procedure and hospitalization must be equipped with a mask. entry of the patient to the facility waiting room waiting room must be organized taking into account social distancing. administrative staff appointed to accept the patient front-office administrative staff must carry out their activity protected by a transparent glass barrier and equipped with ppe (ffp2 mask). medical and nursing staff appointed to accept the patient collection of clinical history, compilation of the clinical records and administration of the informed consent must be done with compliance of the distancing measures. discussion of consent to surgery should include an illustration of the risk of covid-19 exposure and its potential consequences on clinical outcomes. personnel dedicated to blood sampling for blood chemistry and to cardiological and anesthesiological evaluation must be equipped with ppe (ffp2 masks with or without surgical mask based on the presence or absence of an exhalation valve, protective visor, gloves and waterproof gown). everything can take place in a dedicated area where the rules of social distancing are respected or directly in the hospital room. note: the attending physician and/or the patient's reference specialist should be invited to inform the head of the anesthesia department or his/her delegate, before the hospitalization phase, if there are, in his/her opinion, pathologies that may contraindicate the intervention or that could request diagnostic investigations before hospitalization. in this case, the patient should be booked for an anesthesiological outpatient visit in a reasonable time before admission. entry of the patient into the ward after the acceptance phase and the first phase of evaluation in preparation for the surgical procedure, the patient is sent to the hospital ward and housed in a single room with personal bathroom. the medical and nursing staff, in this phase, must always wear suitable personal protective equipment (gloves, ffp2 mask, plus surgical masks, if the former are equipped with an exhalation valve, waterproof gown for contacts, protective visor). management of the operating room general considerations management of the operating room represents the most crucial step of the patient's care process. even if the patient underwent a swab the day before with a negative result, this is not sufficient to safely exclude a positivization in the following day. in the operating room for a whole series of conditions related to intubation and to the use of endoscopic and laparoscopic surgical instruments, the risk of transmission is maximum. for this reason, the most effective ppe systems must be adopted and it is necessary to implement well-coded behaviors that can be summarized as follows: – the surgical team should be restricted, monitored with periodic swabs and subjected to restrictive measures to limit the risk of infection – there should be no change of staff in the room – surgical procedures should be performed by experienced surgeons to reduce operating times and the risk of complications (therefore, the suspension of surgical training is recommended – the standard approach should be maintained, in order not to compromise the outcome and standardize the operating room times – surgical staff should not stay in the operating room during intubation maneuvers, waiting a few minutes from their conclusion before entering, leaving any infected droplets to settle – it would be desirable for intubation and extubation to take place inside a negative pressure room (https://www.asahq.org/in-the-spotlight/coronaviruscovid-19-information) (1, 2) – all measures should be put in place to reduce the risk of contagion among healthcare professionals by adopting adequate personal protective equipment. all members of the operating room staff must use ppe (ffp3 mask). appropriate clothing and face shields must be used. these measures should be used during all pandemic surgical procedures, regardless of known or suspected covid status. the positioning and removal of ppe must be performed according to the world health organization (who) and centre for disease control and prevention (cdc) guidelines (https://www.cdc.gov) – measures to reduce aerosolization in the operating room should be considered (closed circuits, insufflators continuous cycle, fume extraction). note: remember that the virus has been isolated very frequently in respiratory secretions, saliva and feces, rarely in the blood, exceptionally in the urine. specific technical considerations there is very little evidence regarding the risks of virus spread related to the use of the laparoscopic surgical technique compared to the open approach (3). emerging evidence and regular updates are provided by the website https://siceitalia.com/covid19/ it is recommended, however, to seriously consider the possibility of viral contamination of operating room personnel during surgery, be it open, laparoscopic or robotic. it is advisable to actively monitor strict application of protective measures for the safety of the operating room staff. although previous research has shown that the laparoscopic technique can favor the aerosolization of pathogens present in the blood (corynebacteria, papillomavirus and hiv) (4-6), there is no evidence to indicate that this effect 69archivio italiano di urologia e andrologia 2020; 92, 2 hospitalization during covid emergency archivio italiano di urologia e andrologia 2020; 92, 2 r. leonardi, p. bellinzoni, l. broglia, et al. 70 is also possible for the coronavirus, nor that the risk can be confined exclusively to minimally invasive surgical procedures. however, as a precaution, coronavirus should potentially be considered capable of aerosolizing. for this reason, the use of devices to filter co2 should be strongly considered. for further information https://eaes.eu/eaesand-sages-recommendations-regarding-surgical-response-to-covid-19-crisis/ the proven benefits of minimally invasive treatment in terms of reduced duration of hospitalization and reduction of complications, as well as the potential advantages in terms of ultrafiltration of most or all aerosol particles, must be strongly considered. in fact, the filtration of aerosolized particles can be more difficult during open surgery. there may be an increased risk of virus exposure for endoscopists during upper gastrointestinal tract and airway procedures. when these procedures are necessary, the rigorous use of ppe of greater protection is recommended. the complete mask with ffp 3 should be considered for the whole team, following the guidelines of cdc (https://www.cdc.gov) or who (https://www. who.int) (5, 6). filtration the smaller droplets, in contact with the ambient air (aerosol) can transmit the infection from one individual to another via the respiratory tract (within a certain distance). currently, the "droplet" diameter classification system (from 5 to 10 μm) represents the unit of measurement used to evaluate the transmission mode of an infectious disease. filtration can be an effective means of protection from virus release during minimally invasive surgery and endoscopy. masks such as n95 respirators are designed to filter 95% of 0.3 micron and larger particles. respiratory masks of protection class ffp3 offer the maximum possible protection from the pollution of breathing air with a protection of at least 99% from particles up to 0.6 μm in size. purified air respirators (papr) can be useful for intubation, extubation, bronchoscopy, endoscopy and tracheostomy. intraoperatively, filters are used to remove smoke and particles including viruses. air particulate filters (hepa) have a minimum efficiency index of 99.97% for the removal of particles with a diameter greater than or equal to 0.3 microns (6). ulpa (ultra-low particulate air) filters can remove 99.999% of airborne particles with a minimum particle penetration size of 0.05 microns. the association of perioperative registered nurses (aorn) guidelines define ulpa as filters capable of removing particles of 0.1 microns (7). filtration is also essential on a large scale in positive pressure operating rooms. hepa filters positioned in the ceiling provide terminal cleaning. currently, the best practice to reduce the possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate ppe (ffp3 plus surgical mask, plus protective visor for all staff working in the operating room) and smoke evacuation devices with a suction and filter system (8). practical filtration measures during laparoscopic surgery 1. the pneumoperitoneum must always be safely evacuated from the trocar connected to the filtration device before removing the trocars, extracting the operating piece or converting by laparotomy. 2. once the trocars are positioned, their valves should not be opened during surgery, if possible. if it is necessary to change the insufflation site on another trocar, the valve must be closed before disconnecting the tubing and the valve of the new trocar must remain closed until the insufflation tubing has been connected. the insufflator must be activated before the new insufflation valve is open. this is to prevent the backflow of gas into the insufflator itself. 3. during the desufflation phase, all gas and exhaust fumes must pass through an ultra-filtration system, possibly activating the desufflation mode on the insufflator, if this mode is available. 4. if the insufflator in use does not have a desufflation function, it must be ensured that the valve that is used for insufflation has been closed before the co2 flow is deactivated (even if there is a filter in line with the tube). without taking this precaution, contaminated intra-abdominal co2 can be pushed into the insufflator when the intra-abdominal pressure is higher than the pressure inside the insufflator. 5. the patient must be on the level at the time of desufflation. 6. the workpiece(s) must be extracted once all the co2 gas and smoke have been evacuated. 7. drainage pipes should only be used if absolutely necessary. 8. the methods of closing the accesses of the trocars with the use of sutures that allow the escape of gas and residual fumes must be avoided. the fascial plane must be closed after complete desufflation. 9. laparoscopic hand-assisted techniques can lead to significant co2 and smoke losses and should therefore be avoided. a protection system can be positioned after complete desufflation to remove more voluminous operating pieces and protect the wound. the piece can then be removed and closed. systems for the evacuation of smoke and gas below is a list of commercially available products that could potentially be used to filter co2 gas or smoke evacuated during surgical procedures (table 1). the list was provided by sages and eaes that stated they do not promote any of the following products. sages and eaes specify that they have sought information by contacting the known manufacturers, but the possibility is recognized that there are many other companies that may have similar products on sale. surgeons should be aware of the characteristics of the products used in their facility and contact the product representative or refer to the product instructions for their use. for a consultation of the smoke and gas evacuation systems currently on the market, refer to the links: https://www.sages.org/resources-smoke-gas-evacuation-duringopen-laparoscopic-endoscopicprocedures/https://www.sages. org/wp-content/uploads/2020/03/summary-of-commerciallyavailablepneumoperitoneum-smoke-evacuation-systems.pdf in addition to the smoke evacuation products, the ultravision system can minimize aerosolized particles inside the pneumoperitoneum (https://www.sages.org/ wpcontent/uploads/2020/03/ultravision-as-an-adjunct. pdf). electrosurgical and laser units the electrosurgical units and lasers must be programmed to the lowest possible settings for the desired effect and for the correct execution of the surgery. the use of monopolar electrosurgery, ultrasound dissectors and advanced bipolar devices and lasers can lead to aerosolization of the particles. if available, the use of monopolar electrosurgical units with integrated smoke aspirator is recommended (9-15). during their use, the rules of maximum protection of the medical nursing staff apply as required for all procedures in the operating room. measures to be put into practice during laparoscopic surgery 1. the skin incisions should be as small as possible to allow trocars to pass and at the same time prevent co2 losses around the trocars. 2. the co2 insufflation pressure should be kept to a minimum and, if available, ultra-filtration (smoke evacuation or filtration system) should be used (https://www.sages.org/resources-smoke-gas-evacuationduring-open-laparoscopic-endoscopicprocedures/). 3. all pneumoperitoneum must be safely evacuated through a filtration system before removal of the trocars, extraction of the surgical piece, or conversion by open surgical procedure. measures to be put into practice during digestive endoscopy procedures (https://www.asge.org/home/joint-gi-society-message-covid19) (16, 17). 1. in the absence of the ability to control the aerosolized virus during endoscopic procedures, all members of the endoscopy room or operating room must wear appropriate ppe (ffp3 mask, appropriate clothing and face shields). the positioning and removal of ppe must be carried out according to the cdc guidelines (https://www.cdc.gov). 2. since patients can present with gastrointestinal manifestations of covid-19, all endoscopic procedures in an emergency regime should be considered high risk. 3. since the virus has been found in multiple cells of the gastrointestinal tract and in all fluids (saliva, enteric content, feces and blood) surgical energy must be minimized. 4. endoscopic procedures that require additional insufflation of co2 or ambient air should be avoided until we have a better understanding of the aerosolization properties of the virus. this includes many of the endoscopic mucosal resection procedures and endoluminal procedures. 5. removing the caps on the endoscopes could release fluid and/or air and should be avoided. references 1. wax rs, christian md. practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019ncov) patients. can j anaesth. 2020 feb 12 [epub ahead of print]. 2. zucco l, levy n, ketchandji d, et al. anesthesia patient safety foundation. https://www.apsf.org/news-updates/perioperativeconsiderations-for-the-2019-novel-coronavirus-covid-19/. visited the 14th april 2020. 3. zheng mh, boni l, fingerhut a. minimally invasive surgery and the novel coronavirus outbreak: lessons learned from italy. annals of surgery. 2020. [accepted for publication]. 4. alp e, bijl d, bleichrodt rp, hansson b, voss a. surgical smoke and infection control. j hosp infect. 2006; 62:1-5. 5. kwak hd, kim sh, seo ys, et al. detecting hepatitis b virus in surgical smoke emitted during laparoscopic surgery. occup environ med. 2016; 73:857-863. 6. choi sh, kwon tg, chung sk, kim th. surgical smoke may be a biohazard to surgeons performing laparoscopic surgery. surg endosc. 2014; 28:2374-80. 7. repici a, maselli r, colombo m, et al. coronavirus (covid-19) outbreak: what the department of endoscopy should know. gastrointest endosc. 2020; pii: s0016-5107(20)30245-5. 8. zucco l, levy n, ketchandji d, et al. perioperative considerations for the 2019 novel coronavirus (covid-19) https://www.apsf.org/ news-updates/perioperative-considerations-for-the-2019-novel-coronavirus-covid-19/. visited the 15th april 2020. 9. parsa rs, dirig nf, eck in, payne iii wk. surgical smoke and the orthopedic implications. the internet journal of orthopedic surgery 2015; volume 24 number 1. 10. gloster hm jr, roenigk rk. risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts. j am acad dermatol. 1995, 32:436-41. 11. garden jm, o‘banion mk, shelnitz ls, et al. papillomavirus in the vapor of carbon dioxide laser-treated verrucae. jama. 1988; 259:1199-1202. 12. ferenczy a, bergeron c, richart rm. human papillomavirus 71archivio italiano di urologia e andrologia 2020; 92, 2 hospitalization during covid emergency table 1. commercially available systems for the evacuation of smoke and gas. company conmed cooper ethicon medtronic olympus stryker northgate commercial brand airseal® (lap) seeclear® plume-away megadyne valleylab rapidvac™ uhi-4 pneumoclear™ nebulae™ i plumepen® (open) mega vac plus pureview™ buffalo filter® mega vac™ smoke management mini vac™ open yes no yes yes no no no archivio italiano di urologia e andrologia 2020; 92, 2 r. leonardi, p. bellinzoni, l. broglia, et al. 72 dna in co2 laser-generated plume of smoke and its consequences to the surgeon. obstet gynecol. 1990; 75:114-118. 13. baggish ms, poiesz bj, joret d, et al. presence of human immunodeficiency virus dna in laser smoke. lasers surg med. 1991; 11:197-203. 14. in sm, park dy, sohn ik, et al. experimental study of the potential hazards of surgical smoke from powered instruments. br j surg. 2015; 102:1581-1586. 15. wisniewski pm, warhol mj, rando rf, et al. studies on the transmission of viral disease via the co2 laser plume and ejecta. j reprod med. 1990; 35:1117-23. 16. gu j, han b, wang j. covid-19: gastrointestinal manifestations and potential fecal-oral transmission. gastroenterology. march 3 2020 [epub ahead of print]. 17. joint gi society message on covid-19. clinical insights for our community of gastroenterologists and gastroenterology care providers. https://www.asge.org/home/joint-gisociety-message-covid-1. visited the 15th april 2020. correspondence rosario leonardi, md (corresponding author) leonardi.r@tiscali.it lorenzo falcone, md vincenzo grasso, md department of urology and andrological surgery musumeci gecas clinic gravina of catania, catania (italy) piera bellinzoni, md luigi broglia, md davide de marchi, md guido giusti, md giovanni passaretti, md silvia proietti, md antonio russo, md giuseppe saitta, md salvatore smelzo, md franco gaboardi, md department of urology, san raffaele turro hospital, milan (italy) renzo colombo, md department of urology, san raffaele hospital, milan (italy) guglielmo mantica, md guglielmo.mantica@gmail.com nazareno suardi, md department of urology, irccs policlinico san martino hospital, university of genova, genova (italy) * urop executive committee giuseppe ludovico 1, angelo cafarelli 2, ottavio de cobelli 3, ferdinando de marco 4, giovanni ferrari 5, stefano pecoraro 6, angelo porreca 7, domenico tuzzolo 8 1 department of urology, “f. miulli” hospital, acquaviva delle fonti (ba), italy; 2 department of urology, villa igea clinic, ancona, italy; 3 department of urology, european institute of oncology, irccs department of oncology and hemato-0ncology, university of milan, milan, italy; 4 department of urology, “ini” italian neurotraumatological institute, grottaferrata (roma), italy; 5 department of urology, cure, modena, italy; 6 department of urology, malzoni clinic neuromed, avellino, italy; 7 department of urology, policlinico abano terme, abano terme (pd), italy; 8 department of urology, “casa del sole” clinic, formia (lt), italy. stesura seveso archivio italiano di urologia e andrologia 2016; 88, 2122 original paper insist-ed: italian society of andrology registry on penile prosthesis surgery. first data analysis edoardo pescatori 1, giovanni alei 2, gabriele antonini 2, antonio avolio 3, carlo bettocchi 4, marco bitelli 5, francesco boezio 6, tommaso cai 7, enrico caraceni 8, maurizio carrino 9, fulvio colombo 10, enrico conti 11, antonio corvasce 12, federico dehò 13, stefano fiordelise 14, nicola ghidini 1, emilio italiano 15, giuseppe la pera 16, giovanni liguori 17, carlo maretti 18, nicola mondaini 19, alessandro natali 20, carlo negro 21, alessandro palmieri 22, fabrizio palumbo 4, matteo paradiso 21, massimo polito 23, diego pozza 24, mauro silvani 25, aldo tamai 26, massimiliano timpano 27, lilia utizi 8, francesco varvello 28, patrizio vicini 29, antonio vitarelli 4, giorgio franco 2 1 hesperia hospital, modena, italy; 2 policlinico umberto i, roma, italy; 3 ospedale mazzoni, ascoli piceno, italy; 4 policlinico bari, bari, italy; 5 ospedale s. sebastiano martire, frascati, italy; 6 ospedale tatarella, cerignola, italy; 7 ospedale santa chiara, trento, italy; 8 area vasta 3, civitanova marche, italy; 9 ospedale cardarelli, napoli, italy; 10 policlinico s.orsola-malpighi, bologna, italy; 11 ospedale san bartolomeo, sarzana, italy; 12 ospedale bonomo, andria, italy; 13 ospedale san raffaele, milano, italy; 14 ausl piacenza, italy; 15 ospedali riuniti, palermo, italy; 16 san camillo forlanini, roma, italy; 17 ospedali riuniti, trieste, italy; 18 cirm, piacenza, italy; 19 ospedale s.m. annunziata, firenze, italy; 20 auoc, firenze, italy; 21 ospedale cardinal massaia, asti, italy; 22 università federico ii, napoli, italy; 23 ospedali riuniti, ancona, italy; 24 wojtyla hospital, roma, italy; 25 ospedale infermi, biella, italy; 26 casa di cura eretenia, vicenza, italy; 27 ospedale molinette, torino, italy; 28 ospedale san lazzaro, alba, italy; 29 rome american hospital, roma, italy. objectives: the italian society of andrology, i.e. “società italiana di andrologia” (s.i.a.), launched on december 2014 a prospective, multicenter, monitored and internal review board approved registry for penile implants, the “insist-ed” (italian nationwide systematic inventarisation of surgical treatment for ed) registry. purpose of this first report is to present a baseline data analysis of the characteristics of penile implant surgery in italy. material and methods: the insist-ed registry is open to all surgeons implanting penile prostheses (all brands, all models) in italy, providing anonymous patient, device, surgical procedure, outcome, follow-up data, for both first and revision surgeries. a registry project board overviews all the steps of the project, and a registry monitor interacts with the registry implanting surgeons. results: as by april 8, 2016, 31 implanting surgeons actively joined the registry, entering 367 surgical procedures in its database, that comprise: 310 first implants, 43 prosthesis substitutions, 14 device explants without substitution. implanted devices account for: 288 three-component devices (81,3%), 20 two-component devices (5,4%), 45 non-hydraulic devices (12,3%). leading primary ed etiologies in first implant surgeries resulted: former radical pelvic surgery in 111 cases (35,8%), peyronie’s disease in 66 cases (21,3%), diabetes in 39 cases (12,6%). two intraoperative complications have been recorded. main reasons for 57 revision surgeries were: device failure (52,6%), erosion (19,3%), infection (12,3%), patient dissatisfaction (10,5%). surgical settings for patients undergoing a first penile implant were: public hospitals in 251 cases (81%), private environments in 59 cases (19%). conclusions: the insist-ed registry represents the first european experience of penile prosthesis registry. this baseline data analysis shows that: three-pieces inflatable prosthesummary no conflict of interest declared. introduction penile prosthetic surgery is a strategic and highly qualifying surgical tool for both patients with severe erectile dysfunction and urologists devoted to sexual medicine. the penile prosthesis option is the ed treatment presently reported to score the highest in terms of satisfaction among both patients and partners, compared to all the other available ed treatments (1, 2). the paradox of the penile prosthesis is that, despite being an excellent solution for the patient with severe ed, majority of candidates to this treatment do not have access to it. in italy the overall prevalence of ed in the adult population is 12,8% (3), accounting for about 3 million men. while a conservative estimate would predict not less than 200.000 men with severe ed, market data report that only roughly 500 penile implant surgeries are yearly performed in italy. several are the barriers to the penile prosthesis solution, among them paucity of proper patient information, and costs of penile implants: often public hospitals doi: 10.4081/aiua.2016.2.122 sis is the most implanted device, leading etiology of erectile dysfunction (ed) in patient receiving a prosthesis is former radical pelvic surgery, primary reason for revision surgery is device failure, primary settings for first penile implant surgery are public hospitals. evaluation of penile implant impact on recipients quality of life is presently ongoing. key words: penis; penile prosthesis; surgery; surgical procedures; implant; registry; quality of life; impotence; erectile dysfunction. submitted 30 april 2016; accepted 6 may 2016 123archivio italiano di urologia e andrologia 2016; 88, 2 italian registry on penile prosthesis surgery have no or few units/year available, with long waiting lists, while in private settings device costs are prohibitive for several patients. furthermore, public health authorities seldom have reliable figures on the dimensions of penile implant surgery field, at least partly due to a significant number of procedures performed in the private environment; it is accordingly complicated to pursue negotiations with health authorities, for instance to improve reimbursement for this surgery. two key interventions appear to be strongly needed to change the present landscape of limited access by patients (pts) that qualify for penile prosthesis surgery. firstly, to produce reliable data on the phenomenon “penile implant surgery” at national levels, and possibly on the benefits that this surgical intervention produces on recipients quality of life (qol); secondly, to soundly inform the lay public of the penile prosthesis option existence, of the appropriate indications for this kind of surgery, and of real pros and cons. the italian society of andrology, i.e. “società italiana di andrologia” (s.i.a.), launched the “registry project” on december 2014 (4) to address both those interventions: the project comprises in fact both a prospective registry for penile implants, the italian nationwide systematic inventarisation of surgical treatment for ed (insist-ed) registry, and a institu tional informative website aimed to the lay public: www.androprotesi.it. given the short life of the insist-ed registry, the purpose of this first report is to present a baseline data analysis of the characteristics of penile implant surgery in italy. material and methods registry project board and registry coordinator s.i.a. executive committee appointed a project board (ep, gf, eca, fc, fd) that has the tasks to evaluate before approval all the requests of implanting surgeons to adhere to the registry, to deal with potential issues arising in the registry, and to overview for ethics all the materials submitted by surgeons for the informative website www.androprotesi.it (see below). the project coordinator (ep) directly interacts with the project monitor for the best functioning of the registry. registry characteristics the insist-ed registry is a prospective registry of penile prostheses (all brands, all models) open to all implanting surgeons operating in italy. registry surgeons agree to provide anonymous patient, device, surgical procedure, outcomes, follow-up (fu) data, for both first and revision surgeries. they also agree that device companies could send the registry monitor (see below) periodic reports of number and type of implants performed by each specific surgeon since the date of his/her adhesion to the registry. the registry database has the following structure: surgery data, data at 1 month fu with report of possible complications, 1 year fu with data on patient qol by means of the qolspp questionnaire (5), optional further fus. details of the database fields are reported in supplementary materials posted in www.aiua.it. the insist-ed registry can be accessed in its demo version at www.registro.andrologiaitaliana.it (username: demo@registrosia.it; password: regsia2015_demo). data analysis registry data have been organized in a dedicated excel format (microsoft excel 2011 for mac, version 14.6.3); mean and standard deviation (sd) have been calculated. registry monitor a registry monitor (lu) has been appointed by the registry board. monitor tasks are: to interact with new registry implanting surgeons briefing and supporting them on data entry, to interact with device companies to verify the completeness of number of surgeries inserted by implanting surgeons. privacy protection and ethical issues the registry protects patient privacy; no sensible data (i.e. patient name, date of birth, address, etc.) are present in the registry. for the protection of the privacy of each implanting surgeon individual surgical data inserted in the registry can be accessed solely by the national registry coordinator and the registry monitor; registry data are elaborated and circulated in a aggregated fashion only: no implanting surgeon can access data produced by individual implanting surgeons. similarly, it has been the choice of the registry board, on behalf of s.i.a., to report device data in an aggregated fashion only: three-component hydraulic devices, two-component hydraulic devices, non-hydraulic devices. the “registry project” has been evaluated, before approval, by s.i.a, legal office, in particular under the profile of the patient privacy and anonymity protection law, and it has been found sound in this perspective. institutional informative website s.i.a. concurrently created an institutional website (www.androprotesi.it) aimed to provide lay public with sound information on the penile prosthesis option; only implanting surgeons adhering to the registry and active on it (i.e. with at least one case entered in the registry) are present in such website with a personal page. the term “institutional” refers to the fact that the project board, appointed by the scientific society s.i.a., overviews the contents present in the informative website. the purpose of www.androprotesi.it is both to correctly inform the lay public regarding the penile prosthesis option, and to motivate implanting surgeons to adhere to the registry, as only surgeons active in the registry are eligible to be present in the website with a personal page and contributions. results the insist-ed registry as by april 8, 2016 accounts for 31 implanting surgeons active in the registry, and for 367 surgical procedures in the registry database. geographic distribution of performed surgeries the overall 367 surgical procedures related to penile prostheses resulted scattered through italy in the following fashion: north = 139 cases (piedmont n. 70, lombardy n. 8, friuli n. 5, veneto n. 8, emilia-romagna n. 48); centre = 139 cases (tuscany n. 30, marche n. 26, lazio n. 83); archivio italiano di urologia e andrologia 2016; 88, 2 e. pescatori, g. alei, g. antonini, et al. 124 figure 1. geographic distribution of performed surgeries. south = 89 cases (campania n. 26, puglia n. 61, sicily n. 2) (figure 1). patient characteristics (age, type of surgery, and ed etiology) age and type of surgery. the mean age of the overall 367 pts is 60,5 years (sd 9,6). of them 310 pts underwent first penile implant surgery; they have a mean age of 60,4 years (sd 9,2); 43 patients underwent device explant and substitution (mean age: 59,6; sd 11). fourteen patients underwent device explant only (mean age 63,6; sd 13) (figure 2). ed etiology. the 310 patients undergoing first penile implant surgery have the following primary diagnoses for their ed: status-post (s/p) radical pelvic surgery n. 111 (35,8%), peyronie’s disease n. 66 (21,3%), diabetes n. 39 (12,6%), vascular disease n. 29 (9,4%), neuropathy n. 5 (1,6%), other n. 60 (19,3%). surgery data (device type, surgical approach, reasons for revision, intraoperative complications) device type. the overall 367 surgeries comprise: implant of three-component hydraulic devices in 288 cases (78,5%), implant of two-component hydraulic prostheses in 20 cases (5,4%), implant of non-hydraulic prostheses in 45 cases (12,3%), device explant only in 14 cases (3,8%). the models of implanted devices are reported in table 1. in patients undergoing a first implant (n. 310), devices comprise: three-component hydraulic prostheses in 252 cases (81,3%), two-component hydraulic prostheses in 16 cases (5,2%), non-hydraulic prostheses in 42 cases (13,5%). in the 43 device substitution cases the newly implanted devices comprise: three-component hydraulic prostheses in 36 cases (83,7%), two-component hydraulic prostheses in 3 cases (7%), non-hydraulic prostheses in 4 cases (9,3%). surgical approach. in patients undergoing a first implant with a three-component hydraulic prosthesis (n. 252) the surgical approach is penoscrotal in 132 cases (52,4%), infrapubic in 53 cases (21%). type of approach information are missing in 67 cases (26,6%). a single incision is performed in 196 cases (77,8%), a second incision in 40 cases (15,9%), incision information are missing in 16 cases (6,3%). reasons for revision. device substitution occurred in 43 patients, for the following reasons: fluid loss (n. 19), patient dissatisfaction (n. 6), erosion (n. 5), mechanical failure (n. 5), infection (n. 3), cylinder aneurism (n. 2), crossover (n. 1), reason not reported (n. 2). device explant without substitution occurred in 14 patients, for the following reasons: erosion (n. 6), infection (n. 4), mechanical failure (n. 4). intraoperative complications. in first penile implant surgeries (n. 310) intraoperative complications occurred in 2 cases (0,6%): one cross-over (intra-operatively recognized and corrected), and urethral lesion (surgery concluded with placement of a single cylinder only). surgery focus 1: first penile implant in patients s/p radical pelvic surgery (n. 111) these pts received a hydraulic device in 94 cases (84,7%), two-component hydraulic prostheses in 9 cases (8,1%), non-hydraulic prostheses in 8 cases (7,2%). patients receiving a three-component prosthesis (n. 94). surgical approach resulted penoscrotal in 80 cases (85,1%) and infrapubic in 14 cases (14,9%); reservoir was placed in retzius space in 67 cases (71,3%), intraperitoneally in 15 cases (15,9%), ectopically in 12 cases (12,8%). a single incision was performed in 61 cases (64,9%), a second incision in the remaining 33 cases (35,1%). penile curvature was present at surgery in 13 patients (13,9%), was not present in 77 patients (81,9%), information missing in 4 cases (4,2%). surgery focus 2: first penile implant in patients with peyronie’s disease (n. 66) these patients received a hydraulic device in 50 cases (75,8%), non-hydraulic prostheses in 16 cases (24,2%); in no case a two-component hydraulic prosthesis was implanted. patients receiving a three-component prosthesis (n. 50). a single incision was performed in 36 cases (72%), a second incision in the remaining 14 cases (28%). concerning intraoperative strategies aimed at curvature three-component hydraulic prostheses ams 700 (cx, cxr, lgx) coloplast titan (otr, otr zero degree, otr narrow-base) zephyr zsi 475 two-component hydraulic prostheses ams ambicor non-hydraulic prostheses ams spectra coloplast genesis gis (ssda, subrini) eurogest table 1. models of implanted devices. 125archivio italiano di urologia e andrologia 2016; 88, 2 italian registry on penile prosthesis surgery figure 2. ages of the 367 patients in the three groups first implant, substitution surgery, and explant only. archivio italiano di urologia e andrologia 2016; 88, 2 e. pescatori, g. alei, g. antonini, et al. 126 correction, wilson maneuver (6) was performed in 31 cases (72%), relaxing corporotomies without defect coverage were performed in 7 cases (14%), relaxing corporotomies with defect coverage were performed in 6 cases (12%); in 6 cases (12%) no intraoperative procedure was needed. surgery settings (public vs. private) and respective waiting times from indication to surgery patients that underwent first penile implant (n. 310) had their surgery performed in public hospitals in 251 cases (81%), in private settings in the remaining 59 cases (19%). waiting time from indication to surgery resulted: 8,2 months (sd 6,8) in public hospitals, 2,3 months (sd 6,2) in private settings. patients treated in private settings paid out of their pocket in 49 cases (83%), had insurance coverage in 10 cases (17%). discussion the insist-ed registry is the first european experience of a registry devoted to penile implants. it provides for the first time a real-world picture of penile implant surgery in italy, thanks to the adhesion of surgeons performing penile implants (all brands, all types, all models) in italy, with no restrictions in terms of surgeon implant volumes and of society affiliation. launched on december 2014 by the italian society of andrology (1), the registry as by april 8, 2016 has been joined by 31 active implanting surgeons, and accounts for 367 procedures inserted in the database. the short life of the insist-ed registry at present allows for a baseline data analysis only, but the structure of the registry should provide shortly data also on surgical outcomes, postoperative complications, follow-up. presently, the only other existing registry of penile implants is the u.s.a. propper registry (7). the two registries have several structural differences, chief ones being: propper addresses american medical systems (ams) penile implants only, ams is responsible for the database and statistical analysis, implanting surgeons have been selected among high volume implanting surgeons; the insist-ed registry addresses all brands/types/models of penile implants, the scientific society s.i.a. is responsible for the database and statistical analysis, all implanting surgeons operating in italy could adhere to the registry regardless of their implant volumes. such differences mandate caution in making comparisons between the outcomes of the two registries, nonetheless some general considerations can be proposed. the first data analysis of the insist-ed registry shows that the geographic distribution of the performed procedures is overall even across the three italian macro-areas of north, centre, south. distribution becomes anyhow uneven when considering the different regions: 7 regions have 26-70 procedures in the registry, 4 regions have 2-8 procedures, 11 regions have none. this may reflect both a selective adhesion of implanting surgeons to the registry, and/or a real different regional availability/access to the penile prosthesis option across different italian regions. mean age of patients in our series is 60 years (sd 9,6), that appears similar to that recorded in the propper study (mean 63,6; sd 10). the leading primary causes for severe ed in first implant surgeries were: former radical pelvic surgery (35,8%), peyronie’s disease (21,3%) and diabetes (12,6%), respectively. in this aspect there is an apparent difference with data of the propper study that describe as leading ed causes, besides former radical prostatectomy (28%): diabetes (21%), cardiovascular disease (19,6%), and peyronie’s disease (8,9%). we suggest that such differences may reflect the different prevalence of metabolic syndrome in italy and u.s.a. (8, 9). the most popular device type resulted the three-component hydraulic prosthesis in all the patient groups considered (overall, first implant, substitution, subgroup of s/p radical pelvic surgery, peyronie’s disease), followed by non-hydraulic devices, with the exception of the subgroup s/p radical pelvic surgery, where two-component hydraulic prostheses were by little preferred over nonhydraulic prostheses. two-component hydraulic prostheses were never used in peyronie’s cases. also in the propper study the three-component model was the most popular, but to a higher extent (96,5%) compared to the insist-ed registry (83,7% in first implant cases). differently from propper we record in italy a certain degree of popularity for the non-hydraulic models: 13,5% in first implant surgery versus 1% in u.s.a.. such difference might reflect both: differences in implanting surgeons (in insist-ed: not selected according to surgery volume, i.e. possibly including also less experienced surgeons), and device costs: in italy three-component hydraulic prostheses are marketed with a roughly double price compared to the u.s.a. the preferred surgical approach for three-component devices (first implant) resulted by far the penoscrotal one, with a single incision only, similar to the propper study. in cases of former radical pelvic surgery the reservoir of three-pieces devices has been placed ectopically in the minority of cases, as in propper, but to a lesser extent (12,8% in insist-ed vs. 31,8% in propper). in such cases, i.e. s/p radical pelvic surgery, penile curvature was observed in 13,9% of cases, consistently with the report of tal et al. (10). in cases of peyronie’s disease the most popular approach to solve the curvature resulted the wilson maneuver (6). in the 310 first penile implant surgeries intraoperative complications occurred in 2 cases (0,6%) only, implying that implanting surgeons that adhere to the insist-ed registry are appropriately skilled. majority of first implants were performed in public settings (81%), but with a significant waiting time from indication to surgery. furthermore, the vast majority of patients undergoing surgery in private settings were not covered by medical insurance. it accordingly appears that there is a definite need in italy for better public health policies for the penile implant surgery area; for instance, more favorable reimbursements and more prosthesis units/year available in public hospitals. we hope that present and future outcomes of the insist-ed registry will be instrumental in negotiations with health authorities on such aspects. 127archivio italiano di urologia e andrologia 2016; 88, 2 italian registry on penile prosthesis surgery conclusions the insist-ed registry represents the first european experience of penile prosthesis registry; it has the purpose to produce objective, real world hard data on the landscape of penile implant surgery in italy. the first baseline analysis of 367 procedures entered in the registry by 31 implanting surgeons operating in italy shows chiefly that three-pieces inflatable prosthesis is the most implanted device, the leading etiology of ed in patient receiving a prosthesis is former radical pelvic surgery, the primary reason for revision surgery is device failure, primary settings for first penile implant surgery are public hospitals. we do hope that the first experiences of penile prosthesis surgery registries, insist-ed in italy and propper in u.s.a., will be soon followed by other countries, so to generate a great amount of prospective, multicenter, multinational, comparable data for the benefit of patients and physicians: better public health policies and definition of the best surgical standards. acknowledgment authors wish to thank dott. ilaria stanghellini and dr. alberto strano for their support in statistical data analysis. references 1. rajpurkar a,dhabuwala cb. comparison of satisfaction rates and erectile function in patients treated with sildenafil, intracavernous prostaglandin e1 and penile implant surgery for erectile dysfunction in urology practice. j urol. 2003; 170:159-63. 2. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. advances in urology, 2012, article id 707321, http://dx.doi.org/10.1155/2012/707321. 3. parazzini f, menchini fabris f, bortolotti a, et al. frequency and determinants of erectile dysfunction in italy. eur urol. 2000; 37:43-9. 4. pescatori e, franco g. introducing the first registry for penile implants: the insist-ed registry (italian nationwide systematic inventarisation of surgical treatment for ed). j sex med 2015; 12(suppl 3):216.240 hp-06-005 5..caraceni e, utizi l. a questionnaire for the evaluation of quality of life after penile prosthesis implant: quality of life and sexuality with penile prosthesis (qolspp): to what extent does the implant affect the patient's life? jsm 2014; 11:1005-12. 6. wilson sk, delk jr. a new treatment for peyronie’s disease: modeling the penis over an inflatable penile prosthesis. j urol. 1994; 152:1121-1123. 7. henry gd, karpman e, brant w, et al. the who, how and what of real-world penile implantation in 2015: the propper registry baseline data. j urol. 2016; 195:427-33. 8. balkau b, charles ma, drivsholm t, et al. frequency of the who metabolic syndrome in european cohorts, and an alternative definition of an insulin resistance syndrome. diabet metab 2002; 28:364-76. 9. ford es, giles wh, dietz wh. prevalence of the metabolic syndrome among us adults: findings from the third national health and nutrition examination survey. jama 2002; 287:356-9. 10. tal r, heck m, teloken p, et al. peyronie’s disease following radical prostatectomy: incidence and predictors. j sex med. 2010; 7:1254-1261. correspondence edoardo pescatori, md (corresponding author) info@andrologiapescatori.it hesperia hospital, modena giovanni alei, md info@giovannialei.it policlinico umberto i, roma gabriele antonini, md dottgabrieleantonini@gmail.com policlinico umberto i, roma antonio avolio, md antonio.avolio@gmail.com ospedale mazzoni, ascoli piceno carlo bettocchi, md carlo.bettocchi@uniba.it policlinico bari marco bitelli, md marcobitelli@yahoo.com ospedale s. sebastiano martire, frascati francesco boezio, md francescoboezio@alice.it ospedale tatarella, cerignola tommaso cai, md ktommy@libero.it ospedale santa chiara, trento enrico caraceni, md ecarace1@gmail.com area vasta 3, civitanova marche maurizio carrino, md cris63@libero.it ospedale cardarelli, napoli fulvio colombo, md fulvio.colombo@aosp.bo.it policlinico s.orsola-malpighi, bologna enrico conti, md econti@aslcn2.it ospedale san bartolomeo, sarzana antonio corvasce, md a.corvasce@katamail.com ospedale bonomo, andria federico dehò, md deho.federico@gmail.com san raffaele, milano stefano fiordelise, md stfiorde@tin.it ausl piacenza nicola ghidini, md hesperia hospital, modena info@nicolaghidini.it emilio italiano, md eitaliano@gmail.com ospedali riuniti, palermo giuseppe la pera, md lapera@libero.it san camillo forlanini, roma giovanni liguori, md gioliguori33@gmail.com ospedali riuniti, trieste carlo maretti, md carlomaretti@tin.it cirm, piacenza nicola mondaini, md info@nicolamondaini.it ospedale s.m. annunziata, firenze alessandro natali, md info@profnatali.it auoc, firenze carlo negro, md carlo.negro@gmail.com ospedale cardinal massaia, asti alessandro palmieri, md info@alessandropalmieri.it federico ii, napoli fabrizio palumbo, md palumbo.fab@gmail.com policlinico bari matteo paradiso, md m.paradiso2014@gmail.com ospedale cardinal massaia, asti massimo polito, md max_polito@virgilio.it ospedali riuniti, ancona diego pozza, md diegopo@tin.it wojtyla hospital, roma mauro silvani, md dr.silvani@libero.it ospedale infermi, biella aldo tamai, md aldotamai@libero.it casa di cura eretenia, vicenza massimiliano timpano, md info@andrologiatorino.it ospedale molinette, torino lilia utizi, md lilia16@libero.it area vasta 3, civitanova marche francesco varvello, md francesco.varvello@me.com ospedale san lazzaro, alba patrizio vicini, md patriziovicini@inwind.it rome american hospital, roma antonio vitarelli, md antoniovitarelli@hotmail.com policlinico bari giorgio franco, md giorgio.franco@libero.it policlinico umberto i, roma archivio italiano di urologia e andrologia 2017; 89, 2162 case report hutch bladder diverticulum unusual cause of adult obstructive uropathy pedro simões de oliveira, tiago ribeiro de oliveira, david martinho, tomé lopes hospital de santa maria, urology department, lisbon, portugal. objective: to present a case of a hutch bladder diverticulum containing the ureteral opening. material and methods: an 83-year-old man presented a giant bladder diverticulum causing obstructive azotemia due to bilateral ureteral compression. endoscopy revealed an unusual and potentially harmful anatomical alteration: the left ureteral orifice was inside in the diverticulum. despite bladder emptying, the diverticulum remained full, causing bilateral ureteral compression. the patient underwent diverticulectomy with ureteroneocystostomy. result: post-operative follow-up showed renal and voiding functions restoration. conclusion: although clinical watching is a valid option in patients with hutch diverticulum, reconstructive surgical approach, especially when complications are present, should be the standard of care. key words: bladder; diverticulum; ureteral obstruction. submitted 26 april 2017; accepted 26 april 2017 summary no conflict of interest declared. before, presented in the emergency department with acute renal failure (creatinine 4.7 mg/dl). physical examination showed a distended abdomen, dull to percussion at low quadrants and painless to palpation. reno-vesical echography showed bilateral ureterohydronephrosis, a voluminous formation containing fluid occupying the lower abdominal quadrants in continuity with the bladder. after inserting an indwelling catheter, the patient maintained the bilateral obstruction, despite emptying the bladder, with diverticular repletion. he then underwent percutaneous catheterization of the diverticulum. cystoscopy showed a voluminous bladder diverticulum with a narrow neck localized in the posterior left wall of the bladder, right ureteral ostium was correctly visualized in the anatomic position, and left ureteral ostium was located inside de diverticulum. the patient underwent diverticulectomy with left ureteral reimplantation by ricard-puigvert technique. post-operative follow-up presented with no complications, with resolution of the obstructive uropathy, normal renal function (creatinine 1.1 mg/dl), qmax 18 ml/s in the uroflowmetry performed 2 months later. conclusions bladder diverticulum usually appear in patients with infra-vesical obstruction that causes intra-vesical high pressure (1). the congenital weakness of the detrusor in the peri-ostium location seems to contribute to the high frequency in this area. bauer et al. proposed that the doi: 10.4081/aiua.2017.2.162 introduction bladder diverticulum results from de herniation of the urothelium through the muscular layer of the bladder wall, being formed by mucosa, lamina propria, few muscular fibers and adventitia. bladder diverticula are classified as congenital or acquired. congenital ones usually appear in young ages with a maximum incidence before 10 years. usually unique, almost exclusively in males, located posteromedially to the ureteral ostium and resulting from the weakness of the bladder wall in this portion. acquired ones generally are due to high intra-vesical pressure caused by infra-vesical obstruction or detrusorsphincter dyssynergia. more rarely are due to wall debility after bladder surgery. often develop in males after sixth decade, in about 12% of patients with infra-vesical obstruction (1). usually multiple and associated with important trabeculation of the bladder wall. if the ureteral ostium is included in the bladder diverticulum, it is called hutch diverticulum, which is a rare entity, typically in young ages, with few cases identified in the adult. case report an 83-year-old previous healthy man who underwent a trans-urethral resection of the prostate three months figure 1. echography: voluminous bladder diverticulum 1a. diverticulectomy: intradiverticular ureteral meatus 1b. (b bladder; d diverticulum; uc left ureteral catheter). oliveira_stesura seveso 20/06/17 10:04 pagina 162 163archivio italiano di urologia e andrologia 2017; 89, 2 hutch bladder diverticulum bladder and the trigone have different embryological development, which can lead to weakness in this point (ureteral ostium) (2). also johnson et al. posted that diverticula occur mainly in this area due to muscular weakness in the ureteral junction with the trigone (3). with progressive diverticular growth, the ureteral ostium may be incorporated (hutch diverticulum), as described in our case (1). despite being often small, asymptomatic and with no need for treatment, some diverticula may cause high morbility. these usually are in association with ipsilateral vesicoureteral reflux, and sometimes may cause uni or bilateral obstruction. apart from these complications, it can also be related with infection or calculi formation (1). rarely it can be in association with cancer (< 5%), due to the chronic irritation of the mucosa. in the described case, the obstructive uropathy was caused by extrinsic ureteral compression due to the difficulty in voiding de diverticulum because of the narrow neck. diagnose evaluation should include, beside echography, intravenous urography and cystoscopy in order to best characterize anatomic location and identification of the intradiverticular ureteral ostium, as described in our case. ct with contrast and urodynamics can also be performed. clinical watching is a valid option in patients with hutch diverticulum, but if in association with complications, diverticulectomy with reimplantation of the ureter should be performed. infravesical obstruction should always be treated previously or at the same time as surgery. references 1. rovner es. bladder and urethral diverticula. in: kavoussi lr, novick ac, partin aw, peters ca (ed), campbell walsh urology, 9th ed. philadelphia: wb saunders company, 2007; 2361. 2. bauer sb, retik ab. bladder diverticula in infants and children. urol. 1974; 3:712. 3. johnson jh. bladder disorders. in: william di, johnston jh (ed). pediatric urology. london: butterworth scientific. 1982; p.225. correspondence pedro simões de oliveira, md (corresponding author) pedrosimoesdeoliveira@gmail.com tiago ribeiro de oliveira, md tiagoribeirooliveira@sapo.pt david martinho, md martinho_david@hotmail.com tomè lopes, md tomematoslopes@gmail.com avenida professor egas moniz 1649-035 lisbon, portugal oliveira_stesura seveso 20/06/17 10:04 pagina 163 archivio italiano di urologia e andrologia 2018; 90, 134 original paper injection therapy for chronic prostatitis: a retrospective analysis of 77 cases attila toth, frederico maria guercini, dawn marta feldthouse, jun chao zhang the macleod laboratory, weill-cornell medical college, new york presbyterian hospital, new york, us. objective: to compare preand post-therapy symptom scores reported on the national institute of health chronic prostatitis symptom index (nihcpsi) after trans-rectal antibiotic injections therapy for men suffering from chronic prostatitis. materials and methods: retrospective analysis of nihcpsi symptom scores obtained from chart reviews of 77 treated males suffering from chronic prostatitis before and after trans rectal injections for the treatment of chronic prostatitis. results: most patients reported a 40% to 60% improvement in symptom scores. in subgroups comparing scores in patients with less than 5 injections, the improvement was less than in patients who received 10 or more injections. patients’ responses after a shorter (3 months) follow up showed better pain scores than patient’s scores after longer, over one-year or more, follow-up periods. conclusion: our findings show that direct antibiotic injection for chronic prostatitis is a viable addition to standard therapies. improvements in symptom scores are long lasting. discomfort is minimal and side effects are rare and avoidable. key words: chronic prostatitis; bacterial prostatitis; injection therapy of prostatitis. submitted 14 october 2017; 17 december 2017 summary no conflict of interest declared. in response to failure of oral antibiotics to eradicate pathogens from the genital secretions of male patients being treated for infertility, we adopted direct antibiotic injections to the prostate and offered this treatment to patients for the last 17 years. histology showing scarring, calcification, and sealed off bacteria in the prostate supported this approach. for the last 10 years, injection therapy has been also offered to patients suffering from symptoms of chronic prostatitis without infertility issues. this work aims to compare national institute of health chronic prostatitis symptom index (nihcpsi) scores of patients suffering from prostatitis before and after injection therapy. materials and methods eligible candidates for this retrospective study were 77 patients who presented to us for the treatment of prostatitis symptoms during a five-year period, between july 1st, 2008 and july 1st, 2013. the mean duration of prostatitis in the study group was 83.91 and the range was 2-360 (in months). the mean age at first visit was 40.51 and ranged from 20-to 67 (in years). the study was conducted with the approval of the institutional review board at weill cornell medical college new york presbyterian hospital on 07/16/2014 (irb protocol number: 130814262). all patients had been given the diagnosis of chronic prostatitis by a urologist prior to our consultation. except for a few patients presenting with previous cultures showing mostly enteric bacteria, all others’ cultures were negative or not done, yet all had received courses of oral antibiotics prior. the patients signed a written informed consent for the injection therapy and were asked to fill out an nihcpsi questionnaire and undergo physical and microbiological examinations prior to the start of the injection therapy. the patients were free to interrupt the injection therapy if they did not feel improvement of symptoms after the first two injections or anytime during the therapy course if there was no further improvement with subsequent injections. subgroups: follow up nihcpsi questionnaires were completed by 9 of the 77 patients within three months after the last injection, 29 subjects completed the questionnaire not more than 12 months and not less than three months following the completion of the therapy and for 38 patients the time for filling out the follow up questionnaire was longer than one year. doi: 10.4081/aiua.2018.1.34 introduction prostatitis accounts for approximately 2 million outpatient visits per year in the united states, including 8% of all visits to urologists and 1% of those to primary care physicians. the direct costs of care approach $4,000 per patient per year (1). the clinical syndrome encompasses a wide range of male pelvic conditions from the well-defined bacterial prostatitis to the ill-defined chronic pelvic pain syndrome (cpps). only in about 5% of all cases is there a documented bacterial origin. still, a very high percentage of patients receive antibiotic therapy at the first visit (2). about half of all patients presenting with prostatitis are in the reproductive age (3) and they have worse scores on questions related to mental and physical health-related quality of life issues than patients with congestive heart failure, diabetes mellitus or crohn’s disease (4, 5). it has been known for a long time that chronic prostatitis affects sperm quality, fertility and pregnancy rates (6). symptomatic prostatitis and asymptomatic leucospermia make the treatment of infertility more challenging (7). toth_stesura seveso 27/03/18 09:21 pagina 34 35archivio italiano di urologia e andrologia 2018; 90, 1 injection therapy for prostatitis office evaluation: the physical examination included manual and ultrasound evaluations of the prostate and seminal vesicles and taking of a urethral swab specimen for chlamydia direct fluorescent antibody (dfa) testing. expressed prostatic secretion (eps) or seminal fluid samples were used for microscopic examination and for bacteria cultures. microbiological examination of genital secretions: chlamydia trachomatis was tested using the pathfinder direct antigen detection system from bio rad laboratories. a7 differential agar was used to identify mycoplasma, and application program interface (api) systems were used for aerobic bacteria identification. remel rapid ana (anaerobic) ii system was used to identify anaerobic bacteria. the api 20c aux system (brand name from biomerieux for yeast identification system) was used to identify yeast. the rapid nh (neisseria hemophilus) system identified neisseria and hemophilus. trichomonas vaginalis was identified by directly observing the fresh secretion for moving parasites with flagella. the result of the culture studies did not influence the recommendation for injection therapy. antibiotics selected for the injected cocktail: based on a literature search we compiled a list of bacteria implicated in prostatitis and selected antibiotics with ample coverage for all that were listed. six compatible antibiotics were mixed in a cocktail to be delivered in one injection. each 10-ml volume of the cocktail contained the following antibiotics: gentamicin, 80 mg, clindamycin, 150 mg, metronidazole, 10 mg, moxifloxacin, 3.2 mg, fluconazole, 2 mg and azithromycin, 50 mg. methylprednisolone, 50 mg was added to this mixture to activate intracellular dormant reticulate bodies of chlamydia trachomatis. the azithromycin and methylprednisolone were reconstituted in 10 ml of 1% lydocaine each. a standard endo-cavitary probe was equipped with a needle guide and a 22-gauge spinal needle was used to deliver 12 ml of the cocktail per injections; 3 ml each to the right and left seminal vesicles and to the right and left lobes of the prostate. one tablet of hydrocodone 5 mg/acetaminophen 300 mg with 800 mg of ibuprofen were sufficient for both sedation and pain management. statistical analysis analysis compared pre-and post-therapy nihcpsi scores and examined whether the magnitude of change in symptom scores after injection therapy related to any of the following: a) duration of prostatitis in months, b) age at first visit c) chlamydia status at first visit d) number of injections received; less than 5 injections, 5-10 injections, more than 10 injections, e) the difference in reported symptom changes in post-therapy intervals: follow-up within 3 months, 3-12 months, 12 months or more. spss v. 20 (8) was used for all descriptive and inferential analyses. a 95% level of significance was set for all inferential tests. inferential tests included paired t-tests, within groups analysis of covariance tests (ancova) and mixed between-within groups analysis of variance tests (anova). chance of benefiting from injection therapy were calculated comparing preand post-therapy dependent variables (outcomes) for the inferential tests. the nihcpsi scores were defined as the assessment measures for “benefiting from the injection therapy (or the extent of benefit)”, and were classified into four outcomes of: pain (scale of 0-22), urinary (scale of 0-10), quality of life (scale of 012), and total score (scale of 0-44). higher numbers in the scores indicated more pain, more urinary problems and less quality of life, resulting in higher total scores. questions to be answered were: does the magnitude of change in symptom scores after injection therapy relate to any of the following categorical variables (table 1): 1. duration of prostatitis (in months), 2. age at first visit (in years), 3. chlamydia status at first visit, 4. number of injections received; less than 5 injections, 5-10 injections, more than 10 injections, 5. the difference in reported symptom changes in post-therapy intervals: follow-up within 3 months, 3-12 months, 12 months or more. results although, most study patients had been previously classified as suffering from “non-bacterial prostatitis”, we recovered a variety of both aerobic and anaerobic bacteria from genital secretions of those who underwent testing. 80% of those tested were positive for chlamydia trachomatis from the urethral swab specimens (table 2). table 3 calculates the measures of central tendency for variables of the study and ranges of the categorical variables before and after intervention. preliminary tests performed a series of paired-sample ttests to compare the pre-and post-intervention nihcpsi scores (n = 77). one ancova was performed for each of the four nihcpsi variables. for all four nih symptom scores the t-test analysis showed significant pre-and post-therapy differences (table 4). the duration of prostatitis (in months) and influence of age at first visit were included as covariates for each of the four ancova tests. there was no significant interaction effect found between the duration of prostatitis or the co-variates of age at first visit and any of the symptom scores or total nihcpsi scores. however, there was a significant main effect for time. the post-therapy nihcpsi scores were significantly lower than the pre-treatment nihcpsi scores for all variables (p < .05), and mirrored the findings of the paired t-test in table 3. although there were significant decreases in all four nihcpsi variable outcomes over time there was no significant effect of age at first visit or the duration of prostatitis. chlamydia status at first visit a series of four two-way (2 x 2) mixed between-within groups analysis of variance (anova) tests were performed to answer question number three. each of the four analyses included one repeated measures (withingroup) independent variable of time with 2 levels (preintervention and post-intervention), and one betweengroup independent variable of chlamydia status at first visit, with two categories (positive vs. negative). again, time was statistically significant for all four nih variable outcomes. all four nihcpsi scores significantly toth_stesura seveso 27/03/18 09:21 pagina 35 archivio italiano di urologia e andrologia 2018; 90, 1 a. toth, f. maria guercini, d. marta feldthouse, j. chao zhang 36 decreased (p < .05) from pre-to post-intervention. however, there was no significant interaction or main effect of chlamydia status at first visit. number of injections received a series of four two-way (3 x 2) mixed between-within groups analysis of variance (anova) tests were performed to address this question. each of the four analyses included one repeated measures (within-group) independent variable of time with 2 levels (pre-intervention and post-intervention), and one between-group independent variable of number of injections received, with three categories of: (a) less than 5 (n = 12), (b) 510 (n = 33), and (c) more than 10 (n = 32). the dependent variables (outcomes) of interest were (a) pain, (b) urinary, (c) quality of life, and (d) total score. nihcpsi pain scores: in group 1 (less than 5 injections) there was no significant interaction effect found between pain and the number of injections received, however, in patients who received between 5 and 10 injections, there was a significant main effect of number of injections received [f (2.74) = 4.351, p = 0.016, partial eta squared = .105]. a post hoc analysis via tukey’s honestly significant difference test (hsd) indicated group 2 (5-10 injections) showed a significantly lower pain score (m = 2.667, se = 1.076) compared to group 1 (less than 5 injections; m = 8.99, se =.649; p = .012). group 3 (more than 10 injections) did not differ significantly from group 2. there was also a significant main effect for the within-groups variable of time. this finding mirrors the findings of the paired t-test for pain from table 4. nihcpsi urinary scores: there was no significant interaction effects or main effects found for the number of injections received on the urinary scores. there was a significant effect for the within-groups variable of time. this finding mirrors the findings of the paired t-test for nih urinary from table 4. nihcpsi quality of life scores: there was a significant interaction of the between-groups variable categories of the number of injections variable and the pre-and postintervention quality of life score. the quality of life score decreased more from pre-to post-intervention for those who received 5-10 injections or more than 10 injections, than for those who received less than 5 injections (f (2.74) = 4.19, p = .019). figure 1 is a graphical representation of the interaction effect. tests of simple effects were performed to investigate the significant interaction effect. a series of three paired-samples t-tests were conducted to look at the difference between quality of life score pre-and post-therapy. one t-test was performed for each of the individual between group levels of (a) less than 5 injections (group 1), (b) 5-10 injections (group 2). and (c) more than 10 injections (group 3). in group 1 (less than 5 injections), there was no statistically significant difference in the quality of life score from preto post-therapy [t (11) = 1.915, p = .082]. for group 2 (5-10 injections) the pre-therapy quality of life score (m = 9.79, sd = 2.233) was significantly higher compared to the post-therapy score [m = 5.18, sd = 3.21; t 32) = 8.22, p < 0.005]. for group 3 (more than 10 injections) the pre-therapy quality of life score was significantly higher (m = 9.94, sd = 1.90) than the post-therapy quality of life score [m = 5.47, sd = 2.95; t (31) = 6.901, p < 0.005]. table 1. frequencies and percentages of the categorical variables of the study (n = 77). categorical variables frequency percent chlamydia status at first visit positive 56 72.7 negative 14 18.2 missing 7 9.1 number of injections received less than 5 12 15.6 5-10 33 42.9 more than 10 32 41.6 post therapy follow-up intervals within 3 months 9 11.7 3-12 months 29 37.7 12 months or more 38 49.4 missing 1 1.3 age at enrolment in the study (in years) mean = 40.51, range 20-67. duration of prostatitis (in months) mean = 83.91, range 2-360. table 2. shows the microbiological findings prior to initiating the injection therapy. a variety of aerobic and anaerobic bacteria were isolated and 80% of those tested showed chlamydia trachomatis elementary bodies in the urethral swab specimen (n=77). variable number % of n number % of % of number % of % of tested (n) positive tested n negative tested n chlamydia 70 91% 56 80% 73% 14 20% 18% mycoplasma 60 78% 4 7% 5% 56 93% 73% aerobes 61 79% 41 67% 53% 20 33% 26% anaerobes 61 79% 52 85% 68% 9 15% 12% figure 1. graph shows significant difference between the number of injections and the preand post-therapy nihcpsi quality of life scores. in groups 2 and 3 the nihcpsi quality of life scores significantly decreased from preto posttherapy. though group 1 also decreased in scores, the decrease however was not significant. toth_stesura seveso 27/03/18 09:21 pagina 36 37archivio italiano di urologia e andrologia 2018; 90, 1 injection therapy for prostatitis in summary, group 2 (5-10 injections) and group 3 (more than 10 injections) showed a significant improvement in the nihcpsi quality of life scores from pre-to post-intervention. however, group 1 (less than 5 injections) did not. nihcpsi total score: a mixedmodel anova was conducted to test the pre-and post-intervention scores for total score, with the between-subjects variable of number of injections received and the within-subjects variable of time. there was a significant main effect for the between-subjects variable, number of injections received [f (2,74) = 6.902, p = 0.002, partial eta squared = .157]. a post hoc analysis via tukey’s hsd indicated that the nihcpsi total scores for group 1 (less than 5 injections; m = 27.708, se = 1.711) were significantly greater than group 2 (5-10 injections; m = 20.424, se = 1.032; p = .001) and group 3 (more than 10 injections; m = 21.391, se = 1.048; p = .007). there was also a significant main effect for the withingroups variable of time. the nihcpsi total scores at post-intervention (m = 15.83, sd = 8.979) were significantly lower than the total pre-intervention nihcpsi total scores [m = 28.09, sd = 6.775; f (1.74) = 87.544, p < 0.0005, partial eta squared = 0.542]. this finding mirrors the findings of the paired t-test for nihcpsi total score from table 4. in conclusion, there were significant decreases in all four nihcpsi variable outcomes from preto post-intervention. additionally, the mean value of total score was significantly higher for group 1 than for groups 2 or 3. time to follow up a series of four two-way (3 x 2) mixed between-within groups analysis of variance (anova) tests were performed to the lapse of time until follow up. each of the four analyses included one repeated measures (withingroup) independent variable of time with 2 levels (pretable 3. measures of central tendency for the four nihcpsi variables of the study (n = 77). variable m sd mdn range nih pain pre-test 12.66 4.35 13 0-21 post-test 7.03 4.944 7 0-19 nih urinary pre-test 5.47 2.950 6 1-10 post-test 2.91 2.586 2 1-10 nih quality of life pre-test 9.96 2.029 10 2-12 post-test 5.90 3.267 6 0-12 nih total pre-test 28.09 6.775 28 14-43 post-test 15.83 8.979 15 0-38 m = mean; sd = standard deviation; mdn = median. figure 2. graph shows significant between-groups differences as to the length of time to follow up. nihcpsi improvement in pain score diminished after longer follow up. figure 3. histogram showing the distribution of the percent improvemnet in nihcpsi total scores. 60% of the treated patients reported at least 50% improvement. table 4. descriptive statistics and results of paired samples t-tests for study outcomes (performed for the four nihcpsi scores with highly significant p values for the difference between pre-intervention to post-intervention scores (n = 77). mean se mean variable/time m sd mdn range diff. diff. t p η2 nih pain 5.63 0.59 9.63 < .0005 0.38 pre-test 12.66 4.35 13 0-21 post-test 7.03 4.94 7 0-19 nih urinary 2.56 0.31 8.19 < .0005 0.31 pre 5.47 2.95 6 1-10 post 2.91 2.59 2 1-10 nih quality of life 7.05 0.35 20.02 < .0005 0.73 pre 9.96 2.03 10 2-12 post 5.90 3.26 6 0-12 nih total 12.26 1.09 11.29 < .0005 0.46 pre 28.09 6.78 28 14-43 post 15.83 8.98 15 0-38 toth_stesura seveso 27/03/18 09:21 pagina 37 archivio italiano di urologia e andrologia 2018; 90, 1 a. toth, f. maria guercini, d. marta feldthouse, j. chao zhang 38 intervention and post-intervention), and one betweengroup independent variable of number of injections received, with three categories of: (a) less than 3 months (n = 9), (b) 3-11 months (n = 29), and (c) 12 or more months (n = 38). the dependent variables (outcomes) of interest were (a) pain, (b) urinary, (c) quality of life, and (d) total. nihcps pain scores: there was a significant interaction of the between-groups variable categories of the time to follow up variable and the preand post-intervention pain score. pain score decreased more for those whose follow up was at the less than 3 months level, than for the other two follow up groups (f (2.73) = 3.43, p = .038) (figure 2). tests of simple effects were performed to investigate the significant interaction effect. a series of three paired-samples t-tests were conducted to look at the difference between pain score pre-and posttherapy intervention. one t-test was performed for each of the individual between group levels of (a) less than 3 months (group 1), (b) 3-11 months (group 2), and (c) 12 or more months (group 3). group 1 (less than 3 months): there was a statistically significant mean difference from the pre-intervention score (m = 13.33, sd = 6.403) to the post-intervention score [m = 3.78, sd = 4.236; t (28) = 7.373, p < 0.0005]. group 2 (3-11 months): there was a statistically significant mean difference from the preintervention score (m = 13.07, sd = 2.963) to the postintervention score [m = 7.31, sd = 4.401, t (37) =5 .415, p < 0.0005]. group 3 (12 or more months): there was a statistically significant mean difference from the preintervention score (m = 11.97, sd = 4.571) to the postintervention scores [m = 4.26, sd = 5.012, t (37) = 5.415, p < 0.005]. all three times to follow-up groups had significant decreases in the mean pain scores, but group 1 indicated a larger decrease from pre-to postintervention. nihcp. si urinary scores: there was no significant interaction effect found between nih urinary from preto postintervention and time to follow up or for the main effect of time to follow-up (p > .05). there was a significant effect for the within-groups variable of time. the total post-test urinary scores were significantly lower than the pre-test nih urinary scores (p < .05). this finding mirrors the findings of the paired t-test from table 4. nihcpsi quality of life: a mixed-model anova was conducted to test the preand post-intervention scores for nih quality of life with the between-subjects variable of time to follow up and the within-subjects variable of time. there was a significant effect for the withingroups variable of time. the total post-therapy nih quality of life scores (p < .05). this finding mirrors the findings of the paired t-test for nih quality of life scores from table 4. nihcpsi total scores; a mixed-model anova was conducted to test the pre-and post-intervention scores for total score with the between-subjects variable of time to follow up and the within-subjects variable of time. there was a significant effect for the within-groups variable of time. the mean post-therapy total scores were significantly lower than the mean pre-therapy scores (p < .05). this finding mirrors the findings of the paired t-test in table 4. discussion until very recently it was a commonly accepted paradigm that chronic bacterial prostatitis is a rare condition, representing 3% to 10% of all cases of chronic prostatitis (9, 10). long term antibiotics therapies are still widely administered, and patients report moderate to marked improvement (11). the use of the polymerase chain reaction (pcr) to diagnose bacterial infections in men with prostatitis (49% for chlamydia) moved a significant % of patient from nonbacterial to bacterial prostatitis (12). in our series of 77 patients, among those tested, finding of chlamydia trachomatis elementary bodies was 80%. this higher isolation rate suggests that in chronic infections the yield for extracellular chlamydia forms diminishes in commonly tested genital fluid samples (urine, semen or eps) and epithelial tissue samples (urethral swab, prostate biopsy) will help identify slow growing intracellular forms more readily (13). in addition to chlamydia we found a variety of aerobic and anaerobic bacteria in semen or eps samples suspected of contributing to both local immune responses and to tissue damage associated with chlamydia infection (14). though a subgroup analysis did not show influence of the chlamydia isolation rate and the chance of benefiting from the injection therapy, it is tempting to speculate that the frequently noted exacerbation of symptoms during prostatitis is best understood by following the intra and extra-cellular phases of the chlamydia life cycle. the frustration with repeatedly failed single antibiotic courses could best be explained by the development of resistant chlamydia strains to the single antibiotic. we propose that the frequently seen hyaline containing scarred, and later calcified nodules, often seen in chronic prostatitis, represent local tissue reaction to chlamydia antigens with simultaneous entrapment of chlamydia and other bacteria. a reduced blood supply to these areas makes it difficult to achieve therapeutic concentration of antibiotics in such areas (15). even if some antibiotics penetrate the cell wall they will have little effect on the viral, reticulate form of chlamydia. the rationale behind adding steroids to the antibiotic cocktail is the ability of steroids to enter the cell and activate dormant, altered forms (spore forms) of chlamydia. by keeping antibiotics in the extracellular space long enough, a gradual depletion of the chlamydia bacterium can be accomplished. this could explain, at least in part, the inferior response in quality of life scores of patients with five or less injections compared to the other two groups, between 5 and 10, or more than 10 injections groups. histology of the chronically infected prostate showing scarring, calcification, and sealed off bacteria supports injection therapy (16). in some cases, as late as six months to a year following injection therapy we have seen a recurrence of symptoms and offered booster injections that were successful in such cases. residual, recurring, or re-infection could be the explanation for reduced symptom improvement that was reported after the longer follow ups. orally given multi-drug regimens are poorly tolerated. by mixing six compatible antibiotics in one cocktail and injecting them trans rectally, one can safely reach thousand-fold the tissue concentration than the one reached toth_stesura seveso 27/03/18 09:21 pagina 38 39archivio italiano di urologia e andrologia 2018; 90, 1 injection therapy for prostatitis by a single orally administered antibiotic. in our experience, injection therapy is safe, well tolerated and all complications are minor including the physical discomfort, pain on injection, minimal bleeding in the semen, urine or stool. no local infection, abscess formation or trauma complicated any of several hundreds of injections administered by our clinic. this study is retrospective, and we recognize the limitations. we believe however that the information contained in this study is significant enough to encourage the urology community to adopt injection therapy as a viable therapy for chronic prostatitis. acknowledgements the authors wish to thank ms. elaine eisenbeisz (statistician, omega statistics, 40960 california oaks road, suite 215, murrieta, ca 92562 http://www.omegastatistics.com) for review and analysis of data and dr. yu-xin liu (microbiologist, for the microbiological testing of genital secretions. 40-35 ithaca street apt 5e, elmhurst, ny 11373, yuxinliu89@hotmail.com). references 1. schaeffer aj. chronic prostatitis and the chronic pelvic pain syndrome. n engl j med. 2006; 355:1690. 2. collins m, fowler f, elliott d, et al. diagnosis and treating chronic prostatitis: do urologist use the four-glass test? urology. 2000; 55:403. 3. collins m, stafford r, o’leary m, barry m. how common is prostatitis? a national survey of physician visits. j urol. 1998; 159:1224. 4. wenninger k, heiman j, rothman i, et al. sickness, impact of chronic nonbacterial prostatitis and its correlates. j urol. 1996; 155:965. 5. mcnaughton collins m, pontari ma, o’leary mp, et al. quality of life is impaired in men with chronic prostatitis: chronic prostatitis collaborative research network. j gen inter med. 2001; 16:656. 6. weidner w, krause w, ludwig m. relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. human reprod update. 1999; 5:421. 7. giamarellou h, tympanidis k, bitos na, et al. infertility and chronic prostatitis. andrologia 1984; 16:417. 8. cohen j. statistical power analysis in directions of psychological science, sage publications, inc. 1992; vol. 1, no. 3, p.98-101. 9. lipsky, benjamin a, byren i, byren h, christopher t. treatment of bacterial prostatitis. reviews of anti-infective agents. 2010; 50:1641. 10. orland sm, hanno pm, wein aj. prostatitis, prostatosis and prostatodynia. urology. 1985; 25:439. 11. nickel jc, downey j, johnston b, clark j. predictors of patient response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. j urol. 2001; 165:1544. 12. choi ys, kim ks, choi sw, et al. microbiological etiology of bacterial prostatitis in general hospital and primary care clinic in korea. prostate int. 2013; 1:133. 13. stephens rs. the cellular paradigm of chlamydial pathogenesis. trends microbiol. 2003; 11:44. 14. hu vh, weiss ha, ramadhani am, et al. innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma. infect immune. 2012; 80:121. 15. darville t, hiltke tj. pathogenesis of genital tract disease due to chlamydia trachomatis. j infect dis. 2010; 201(suppl. 2): s114. 16. madsen po, baumueller a, hoyme u. experimental models for determination of antimicrobials in prostatic tissue, interstitial fluid and secretion. scand j infect dis supl. 1978; 14:145. correspondence attila toth, md (corresponding author) tothmd@gmail.com director, macleod laboratory, associate clinical professor, new york presbyterian medical center new york office: 65 east 79th street, new york, ny. 10075 florida office: 3893 military trail, suite 1. jupiter, fl 33458 (surface correspondence) http://www.fertilitysolution.com frederico maria guercini, md professor of urology via della camilluccia 600, 00135 rome, italy guercini@mclink.il dawn marta feldthouse dawn.feldthouse@gmail.com staff nurse, the macleod laboratory jun chao zhang juneczhang17@gmail.com pre-med student, syracuse university, us toth_stesura seveso 27/03/18 09:21 pagina 39 archivio italiano di urologia e andrologia 2017; 89, 2106 original paper safety of transrectal ultrasound-guided prostate biopsy in patients affected by crohn’s disease lucio dell’atti, andrea benedetto galosi department of urology, university hospital “ospedali riuniti”, ancona, italy. purpose: crohn’s disease (cd) is a chronic inflammatory condition of the gastrointestinal tract. it is usually considered a contraindication to transrectal ultrasound-guided prostate biopsy (trusbx). the aim of this study was to investigate the safety of trusbx in a small cohort of patients with cd. methods: we queried our institutional database clinical data of patients with a diagnosis of cd undergoing trusbx, and a retrospective prospective study of 5 patients was planned. all patients enrolled were in the remission phase of cd and asymptomatic. they received the same antibiotic prophylaxis and a povidone-iodine aqueous solution enema before the procedure. a standardized reproducible technique was used with using a ultrasound machine equipped with a 5-9 mhz multifrequency convex probe “end-fire”. the patients were treated under local anaesthesia, and a 14-core biopsy scheme was performed in each patient as first intention. after the procedure each patient was given a verbal numeric pain scale to evaluate tolerability of trusbx. results: trusbx was successfully completed in all patients. the number of biopsy cores was 14 (12-16). of the 5 biopsy procedures performed 40% revealed prostatic carcinoma (pca) with a gleason score 6 (3+3). no patients required catheterization or admission to the hospital for adverse events after the procedure. the most frequent adverse event was hematospermia (60%), while hematuria was present in 20% of patients and a minimal rectal bleeding in 20% of the patients. no patients reported severe or unbearable pain (score ≥ 8). conclusions: this study suggests that cd may not be an absolute contraindication to trusbx for prostate cancer detection, but still requires a careful patients selection. key words: crohn’s disease; inflammatory bowel disease; prostate biopsy; ultrasonography; prostate cancer; complications. submitted 8 march 2017; accepted 23 april 2017 summary no conflict of interest declared. including genetic factors, immune-regulatory defects, microbial exposure and sex hormones such as androgens (3, 4). recent studies reported that androgens may regulate aspects of human immunity and also be associated with a statistically significant increased risk of inflammatory bowel disease (ibd) (5, 6). prostate cancer (pca) is an androgen-dependent pathologic condition whose anatomical location requires careful consideration in patients with cd (7). however, the detection of pca is reliant on prostate biopsy for histological confirmation (8). therefore, approximately 20-30% of men with cd will require a prostate biopsy within their lifetime, and compared with men non affected, they are at increased risk of developing complications following this procedure (7, 8). although cancer detection rates or the complication rates between transrectal (tr) biopsy and transperineal (tp) biopsy are greatly debated (9, 10), in this retrospective study we analysed the use and the safety of transrectal ultrasound-guided prostate biopsy (trusbx) in a small cohort of five patients with cd. materials and methods between august 2007 and january 2017, we performed a retrospective review of 5 patients affected by cd who underwent trusbx for abnormal digital rectal examination (dre), high prostate-specific antigen (psa) levels (≥ 4 ng/ml), or both. patients with a history of biopsy, surgical treatment for prostatic disease and incomplete clinical data were excluded from our study. all patients enrolled in the study were in the remission phase of cd and asymptomatic. all patients signed a consent form for trusbx. none of the patients was receiving anticoagulants or antiplatelet agents before the procedure. all patients received the same antibiotic prophylaxis: 5 days of ciprofloxacin (500 mg twice daily) starting 24 h before the biopsy (11). moreover, all patients received a povidone-iodine aqueous solution enema starting fifteen minutes before the trusbx (12). all procedures were performed in order to empty the bladder, since we believe that even the state of bladder repletion may be an element of discomfort during the performance of mapping biopsy. trusbx was performed with the patient in the left lateral decubitus using a general electric logiq 7 machine equipped with a 5-9mhz multi-frequency convex probe “end-fire”. the patients were treated under doi: 10.4081/aiua.2017.2.106 introduction crohn’s disease (cd) is a chronic inflammatory condition of the gastrointestinal tract characterized by a relapsing-remitting clinical behaviour, which may involve the whole digestive tract from the oral cavity to the anus (1). incidence of cd is highest during last decades in high income countries as united states and europe with rates ranging between 10-20/100.000 (2). the aetiology of this disease remains unknown; however, it is supposed that a number of causes are implicated, dell'atti_stesura seveso 20/06/17 09:32 pagina 106 107archivio italiano di urologia e andrologia 2017; 89, 2 prostate biopsy and crohn’s disease local anaesthesia with lidocaine spray 10 gr/100 ml applied two minutes before the procedure (13). after having images of the prostate and measurement of the volume, sampling was carried out with a 18-gauge tru-cut needle powered by an automatic spring-loaded biopsy disposable gun. a 14-core biopsy scheme was performed in each patient, as first intention, including 2 basal samples (lateral and medial), 2 parasagittal samples (lateral and medial), 2 apical samples (lateral and medial), and 1 transitional zone sample on each side. after the procedure each patient was given a verbal numeric pain scale (vns), which was designed with 0 representing absence of pain and 10 the maximum pain they perceived in life. patients were discharged after a short period of observation (typically 60 minutes) and once urinated. patients were seen for follow-up 2 weeks after the biopsy and a full clinical outcomes of all cases were available. descriptive statistics for variables with a normal distribution, non-normal distribution, and categorical variables were evaluated using mean and interquartile range, according to their distribution. statistical analyses were performed using microsoft excel 2010 platform. a p < 0.05 was considered to indicate statistical significance. results over the study period on 3,470 men underwent trusbx, 5 patients affected by cd in clinical and endoscopic remission were retrospectively enrolled in the study. the mean age of enrolled patients was 63 years (range 56-71), with a prostate volume of 51 ml (range 39-60), initial psa levels of 7.3 ng/ml (range 4.9-10.2). the clinical characteristics of the patients are shown in table 1. trusbx was successfully completed in all patients. the number of biopsy cores was 14 (range 12-16). of the 5 biopsy procedures performed 2 (40%) revealed pca with a gleason score 6 (3 + 3). in the remain 3 patients 2 biopsies showed prostatitis, while 1 reported benign tissue. patients with higher serum psa appeared more likely to have cancer on trusbx (p < 0.001). no patients required catheterization or admission to the hospital for adverse events after the procedure. the most frequent adverse event was hematospermia (60%), which had also the longest duration (24.6 days). hematuria was present in 20% of patients and a minimal rectal bleeding was observed in 20% of the patients after the biopsy (figure 1). there were no serious infectious complications in this study. the mean pain in the visual numerical scale in patients was 3.4 (2-7). no patients reported severe or unbearable pain (score ≥ 8). discussion crohn’s disease is a ibd characterised by recurrent and destructive inflammation of the gastrointestinal tract (2, 3). approximately 35% of ibd are diagnosed with an extra-intestinal manifestation of the disease, including uveitis, erythema nodosum, peripheral arthritis and sclerosing cholangitis (14). inflammation is known to play an important role in carcinogenesis, and there is also a growing evidence that patients with cd have an increased risk for intestinal table 1. demographic and clinicopathologic features of patients with crohn’s disease undergoing transrectal ultrasound prostate biopsy. patients 1 2 3 4 5 age (yrs) 56 62 59 67 71 age at diagnosis (yrs) 29 35 32 44 52 bmi (kg/m2) 27.2 31 28.4 32.5 33 race caucasian caucasian caucasian caucasian caucasian smoking current past yes never past positive family history pca no no yes no no localisation of cd ileum-colon colon ileum-colon colon ileum prior surgery for cd no no no no yes prostate volume (ml) 46 58 39 60 52 psa level (ng/ml) 5.6 4.9 10.2 6.9 8.5 n° biopsy cores 14 14 12 16 14 abnormal dre, (n) no yes yes no no prostate cancer, (n) no no yes no yes biopsy gleason score, (n) ≤ 6 0 0 1 0 1 7 0 0 0 0 0 ≥ 8 0 0 0 0 0 pain in vns 3 2 7 2 3 bmi = body mass index; cd = crohn’s disease; pca = prostate cancer; psa = prostate-specific antigen; dre= digital rectal examination; vns = verbal numeric scale figure 1. the prevalence of adverse events in patients with crohn’s disease undergoing transrectal ultrasound prostate biopsy. dell'atti_stesura seveso 20/06/17 09:32 pagina 107 archivio italiano di urologia e andrologia 2017; 89, 2 l. dell’atti, a.b. galosi 108 cancers secondary to long-standing intestinal inflammation or secondary to immunosuppressive therapies (15, 16). while it is well established that androgens play a role in pca development, there are new evidences that androgens may also regulate aspects of human immunity (6). moreover, klil-dori et al. reported that the suppression of androgens to castration levels in a large population cohort of patients affected by pca was associated with a decreased risk of ibd (7). in line with this study, the androgen deprivation through surgical castration has been shown to protect the intestinal permeability in a porcine model (17) and influence the composition of murine gut microbiota (18). prostate biopsy plays an important role in diagnosing pca, confirming the grade of cancer and stratifying cancer aggressiveness (8). in 2030% of patients with cd, a prostate biopsy will be require within their lifetime, and compared with patients with other benign intestinal conditions, they are at increased risk of developing postoperative complications following prostate biopsy (19). some studies reported several risk factors in patients with cd following intestinal surgery for postoperative morbidities, including the presence of perforating disease, prolonged duration of symptoms, weight loss, anaemia, malnutrition and several acute flares of cd (19-21). patients with rectal disease such as cd represent a population in which the standard technique of trusbx may not be feasible for postoperative morbidities listed above. however, in literature, the comparisons between the tr and tp prostate biopsy approaches showed no significant difference in the overall cancer detection rate and in the incidence of major or minor complications (10, 22). to our knowledge, this is the first study that report the largest series to date of trusbx in patients affected by cd. fergany and angermeier described the technique of tp prostate biopsy using the ultrasound grid and a stabilizing platform employed for prostate brachytherapy in patient with ulcerative colitis and an ileal pouch. in their case study multiple cores of prostatic tissue were successfully obtained without major complications (23). compared with tr biopsy, tp approach may offer a more aseptic method, with fewer infective complications in light of evidence of fluoroquinolone-resistant bacteria in bowel. however, tp biopsy is a more costly alternative, with longer procedural times and higher risks of acute retention postoperatively (9, 10, 22, 24). in our department we usually employ a tr approach using an end-fire probe, because we believe that to perform prostate biopsy in the anterior area of the gland it is the most appropriate technique. the end-fire probe permits biopsy cores to be taken more transversely (oriented along an anterior-posterior axis), has a more oblique-angled trajectory, and more flexibility in manoeuvring the biopsy direction than sidefire probes (25). in this population of patients trusbx provided a good visualization of the gland and facilitated multiple random needle biopsies under local anaesthesia without major complications. the most frequent adverse event was hematospermia (60%), hematuria and a rectal bleeding were observed in 20% of patients after the procedure, respectively. however, in this study several limitations need to be acknowledged such as the use of a retrospective analysis, enrolling a small patient population, and omitting the preoperative evaluation of clinical symptoms. therefore, the present study is not sufficiently powered to assess the impact of improved prostate biopsy technique on outcomes in patients with cd. conclusions in conclusion, our study suggests that that cd may not be an absolute contraindication to trusbx for pca detection, but still requires a careful patients selection. this case series is a unique, highly selected group of patients affected by cd in clinical remission, further studies to elucidate the best biopsy practices and share decision-making are required. references 1. leighton ja, pasha sf. inflammatory disorders of the small bowel. gastrointest endosc clin n am. 2017; 27:63-77. 2. molodecky na, soon is, rabi dm, et al. increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. gastroenterology. 2012; 142:46-54. 3. xavier rj, podolsky dk. unravelling the pathogenesis of inflammatory bowel disease. nature. 2007; 448:427-34. 4. loftus ev jr. clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. gastroenterology. 2004; 126:1504-17. 5. fijak m, meinhardt a. the testis in immune privilege. immunol rev. 2006; 213:66-81. 6. morse md, mcneel dg. prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune responses. hum immunol. 2010; 71:496-504. 7. klil-drori aj, tascilar k, yin h, et al. androgen deprivation therapy and the incidence of inflammatory bowel disease in patients with prostate cancer. am j epidemiol. 2016; 184:15-22. 8. epstein ji, sanderson h, carter hb et al. utility of saturation biopsy to predict insignificant cancer at radical prostatectomy. urology. 2005;66:356-60. 9. scott s, samaratunga h, chabert c, et al. is transperineal prostate biopsy more accurate than transrectal biopsy in determining final gleason score and clinical risk category? a comparative analysis. bju int. 2015; 116:26-30. 10. shen pf, zhu yc, wei wr, et al. the results of transperineal versus transrectal prostate biopsy: a systematic review and metaanalysis. asian j androl. 2012; 14:310-5. 11. wu xw, ji hz, wang fy. meta-analysis of ciprofloxacin in treatment of crohn's disease. biomed rep. 2015; 3:70-4. 12. hay jm, boussougant y, lacaine f, et al. povidone-iodine enema as a preoperative bowel preparation for colorectal surgery. a bacteriologic study. dis colon rectum. 1989; 32:9-13. 13. dell’atti l. lidocaine spray administration in transrectal ultrasound-guided prostate biopsy: five years of experience. arch ital urol androl. 2014; 86:340-3. 14. feuerstein jd, flier sn, yee eu, et al. a rare case series of concomitant inflammatory bowel disease, sporadic adenomas, and serrated polyposis syndrome. j crohns colitis. 2014; 8:1735-9. dell'atti_stesura seveso 20/06/17 09:32 pagina 108 109archivio italiano di urologia e andrologia 2017; 89, 2 prostate biopsy and crohn’s disease 15. axelrad je, lichtiger s, yajnik v. inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. world j gastroenterol. 2016; 22:4794-801. 16. ullman ta, itzkowitz sh. intestinal inflammation and cancer. gastroenterology. 2011; 140:1807-16. 17. deitch ea, senthil m, brown m, et al. rauma-shock-induced gut injury and the production of biologically active intestinal lymph is abrogated by castration in a large animal porcine model. shock. 2008; 30:135-41. 18. markle jg, frank dn, mortin-toth s, et al. sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. science. 2013; 339:1084-8. 19. bernell o, lapidus a, hellers g. risk factors for surgery and recurrence in 907 patients with primary ileocaecal crohn's disease. br j surg. 2000; 87:1697-701. 20. iesalnieks i, kilger a, glass h, et al. intraabdominal septic complications following bowel resection for crohn's disease: detrimental influence on long-term outcome. int j colorectal dis. 2008; 23:1167-74. 21. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 22. shida y, hakariya t, takehara k, et al. comparison between a combined transrectal and transperineal approach and a transrectal approach for prostate rebiopsy. anticancer res. 2016; 36:4685-90. 23. fergany af, angermeier kw. a technique of transrectal ultrasound guided transperineal random prostate biopsy in patients with ulcerative colitis and an ileal pouch. j urol. 2000; 163:205-6. 24. abdollah f, novara g, briganti a, et al. trans-rectal versus trans-perineal saturation rebiopsy of the prostate: is there a difference in cancer detection rate? urology. 2011; 77:921-5. 25. galosi ab, tiroli m, cantoro d, et al. biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. arch ital urol androl. 2010; 82:248-52. correspondence lucio dell’atti, md, phd (correspondant author) dellatti@hotmail.com andrea benedetto galosi, md department of urology marche polytechnic university university hospital “ospedali riuniti” 71 conca street 60126 torrette, ancona, italy dell'atti_stesura seveso 20/06/17 09:32 pagina 109 stesura seveso 233archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. outcomes of various varicocele treatment options are currently lacking, and confounding factors such as the experience of the operators, the age of the patients and the severity of varicocele have a significant impact on skewing the post-treatment results (7, 8). among all treatment options, the subinguinal approach combined with anterograde intraoperative sclerosis of venous vessels (marmar technique modified by colpi) represents a valid surgical treatment of varicocele (9): this approach exploits the advantages of both the marmar (10) and the tauber (11) technique without the need for microscope or fluoroscope, making the operation more simple and less expensive. surgical correction of varicocele is usually performed as a one-day surgery due to the low risk of peri-operative morbidity. in this context, the ability to resume normal activities soon after surgery is an important indicator of a successful perioperative experience and may be largely associated with the type of performed anesthesia and with peri-operative pain management (12). to the best of our knowledge, studies investigating the best type of anesthesia to be performed in patients undergoing varicocele correction are currently lacking. the purpose of this prospective observational study was to evaluate the difference in the timing of discharge and pain control among patients undergoing surgical correction of varicocele with either local or general anesthesia at a single academic center. material and methods this is a prospective, observational investigation trial. the study protocol was approved by the local ethics committee of the institution “ospedale di circolo e fondazione macchi”, varese, italy. afterward, the study protocol was registered on clinical trials.gov (id number nct02401087). inclusion criteria were: male subjects over the age of 18; with asa i-ii scores; with a clinically significant varicocele scheduled for surgical correction. patients with cognitive impairment or mental retardation; habitual use of opioid analgesics; alterations in the normal values of coagulation or coagulopathies; use of non-steroidal anti-inflammatory drugs in the 5 days preobjective: in this study, we compared postoperative outcomes of patients submitted to varicocele correction under general or local anesthesia at a single center. methods: all patients underwent varicocele surgical treatment with the colpi-modified marmar subinguinal technique. they were managed with either general (group a) or local with ileo-inguinal and ileo-hypogastric nerves block (group b) anesthesia. the two groups were compared in terms of timing of discharge and post-operative pain as assessed with the numeric rating scale (nrs) at both rest and movement (nrsm). results: overall, 63 patients were included with a mean (sd) age of 25 years ± 5 yrs. the nrs mean score was significantly lower for group b during the first 4 days after surgery at both rest and movement (all p < 0.05). patients receiving local anesthesia showed a faster time to first urination (210 vs. 240 min; p = 0.02), although the time to discharge was comparable between the two groups (250 vs. 250 min). conclusions: these results suggest that local anetshesia for varicocele surgical treatment is feasible and provide better pain control and faster recovery after surgery. key words: varicocele; local anesthesia; infertility; recovery. submitted 2 july 2020; accepted 15 october 2020 introduction varicocele is defined as dilated and tortuous veins within the pampiniform plexus of the testis (1, 2). it is one of the main cause of male infertility and is commonly associated with semen impairment. the prevalence of varicocele is approximately 15-20% in the general population, 19%-41% in men with primary infertility, and 45%-81% in men with secondary infertility (3). the pathophysiology of varicocele-associated infertility involves different factors including blood stasis, accumulation of reactive oxygen species at the level of the testis, increased scrotal temperature and reduction of intratesticular testosterone levels (4, 5). surgical treatment of varicocele includes percutaneous embolization or surgical correction with different techniques including open retroperitoneal high ligation, laparoscopic ligation or subinguinal microsurgical technique (6). large-scale comparative studies evaluating the feasibility of local anaesthesia for varicocele correction in one-day-surgery setting. a single center experience giovannni saredi 1, fabrizio i. scroppo 1, paolo capogrosso 1, giacomo maria pirola 2, lorenzo capone 2, andrea pacchetti 3, giuseppe gianesini 1, paolo maggio 1, giulio carcano 4, 5, federico dehò 1, 4 1 department of urology and andrology; circolo and fondazione macchi hospital,varese italy; 2 department of urology, usl toscana sud est, san donato hospital, arezzo, italy; 3 department of urology, san martino hospital, university of genova, italy; 4 university of insubria, varese, italy; 5 department of surgery; circolo and fondazione macchi hospital,varese italy. doi: 10.4081/aiua.2021.2.233 summary archivio italiano di urologia e andrologia 2021; 93, 2 g. saredi, f.i. scroppo, p. capogrosso, g.m. pirola, l. capone, a. pacchetti, g. gianesini, p. maggio, g. carcano, f. dehò 234 ceding the intervention; severe liver or kidney failure; lack of informed consent, were excluded. after obtaining the informed consent, 63 patients with fulfilling the inclusion criteria were recruited in a period between june 2017 and july 2018. patients were divided into two groups: patients included in "group a" underwent general anesthesia (32 patients) and patients included in "group b" underwent local blockage of the ileoinguinal-ileohypogastric nerve (31 patients). the type of anesthesiological protocol was based on the preference of the anesthesiologist. all patients received light sedation with midazolam 0.03 mg/kg i.v. before entering the operating room. moreover, they received a fluid load of 10 ml/kg/h during the surgical procedure and another 5-8 ml/kg in the postoperative period. anesthesiological protocol group a: at the discretion of the anesthesiologist in the operating room, the maintenance of general anesthesia was either with the use of a halogenated agent (sevoflurane) or in tiva (propofol + remifentanil). for induction, fentanyl was used as opioid (for general anesthesia conducted with sevoflurane) and fentanyl or remifentanil for anesthesia conducted in tiva. ventilation was achieved with laryngeal mask. all patients received paracetamol 1 g i.v. as intraoperative analgesia; if the patient complained about pain upon awakening, ketorolac 30 mg i.v. was administered. ondansetron 4 mg i.v. was given as an antiemetic before waking up. in addition to the amount of opioid used, the need for additional antiemetics was also reported. group b: after identification by ultrasound of the ileoinguinal and ileo-hypogastric nerves, by means of a plane technique, the aforementioned nerves were blocked with 0.5% chirocaine 20 ml. afterward, each patient recieved a subcutaneous skin infiltration with 2% carbocaine 10 ml and an endovenous administration with paracetamol 1 g and ketorolac 30 mg as rescue therapy. patients of both groups were discharged at home with the following analgesic therapy: tramadol 37.5 mg + paracetamol 325 mg 1 tablet per day for 3 days. if the patient complains about pain stronger than or equal to 4 point of the numeric rating scale (nrs; figure 1), ketorolac 1 tablet (maximum 2 times a day) was administered as a rescue dose. surgical technique the surgical technique used in this study was the colpimodified marmar subinguinal varicocelectomy combined with antegrade intraoperative sclerotherapy of venous vessels (9). the technique is performed with a 2-3 cm subinguinal incision at the level of the superficial inguinal ring. after exposition of the spermatic cord, a vein in the spermatic cord outside the peri-arterial venous plexus is identified and isolated. the proximal and distal parts of the spermatic cord are clamped and the identified vein is cannulated using a 25 g butterfly needle. afterwards, 1.5-3 ml of 3% atoxysclerol plus 0.5 ml of air is injected; a migration of the sclerosing agent into all visible veins of the spermatic plexus is observed as the movement of the air bubbles. the cannulated vein is then ligated to avoid sclerosing agent leakage. the clamping is released about 8 minutes after the injection. the spermatic and superficial layers are then sutured. skin is closed in a resorbable subcuticular fashion. an ice pack on the wound is always left in situ. follow-up all participants were evaluated before surgery, in the first 3 post-operative hours, at 4 days, 1 month and 3 months after the intervention. the following clinical parameters were considered: time elapsed between the induction of anesthesia and the first urination; time elapsed between the induction of anesthesia and the first walking; pain nrs, pain nrs on movement (nrsm), and any occurred complications. patients filled a self-assessment diary to update about pain at rest and in movement twice a day for the first 3 post-operative days and once on the 4th post-operative day. if a patient still complained of nrs pain ≥ 4, a further outpatient re-evaluation was carried out. statistical analysis the main outcomes of this study was to compare the two groups in terms of the time from surgery to discharge and reported post-operative pain according to the nrs. differences between the two groups were tested with the student t-test for data with normal distribution, while the mann-whitney test was applied for non-normal distributed data. all measured parameters are reported as mean ± standard deviation (sd). all analyses were performed with the med-calc software version 12.2.1. results overall, patients had a mean age of 25 years ± 5 and a mean body mass index (bmi) of 21 kg/m2 ± 2. the mean length of surgery was 38 min ± 12 (table 1). the mean time elapsed between the induction of anesthesia and the first urination was 240 min in group a and 210 min in group b (p = 0.02); the time elapsed until the first walking was 230 min in group a and 220 min in group b (p = 0.6). only 5 patients were able to stand up and walk before 120 minutes in group b vs. no one in group a. figure 1. the numeric rating scale for post-operative pain reporting. the time elapsed between the induction of anesthesia and the patient discharge was 260 min in group a and 250 min in group b (p = 0.1). we then assessed the severity of pain in the first 3 postoperative hours at rest and after mobilization with the nrs: both groups reported a score of 1 at rest, while an nrs score of 1 at movement was reported only for the group a (nrsm) (table 2). the nrs scores during the first 4 days after surgery are reported in table 2. mean score for group b were significantly lower at all time-points. none of the patients required rescue therapy and none experienced complications related to the prescribed therapy. no early or late surgical complications or treatment failures were reported. discussion varicocele is highly prevalent in the young male population and frequently associated with male infertility due to semen impairment. (13) for these reason, surgical correction is often required to improve the chance of conception. as there are various approaches for surgical correction, it is evident from current literature that each technique has its strengths and limitations. the marmar technique modified by colpi is a hybrid between two different surgical approaches: it provides a subinguinal access to the spermatic cord, as in the varicocelectomy according to marmar; on the other hand, it implies the embolization of the spermatic plexus vessels through the antegrade injection of a sclerosing agent, as per tauber technique. the original depiction of the technique is performed under general anesthesia and there are no specific trials evaluating the feasibility of a local anesthesia approach (9, 10, 14). this local ansesthesia approach could have numerous advantages in an outpatient surgery setting: it does not require tracheal intubation, it allows the reduction of postoperative pain and leads to a reduction in costs, given the smaller number of drugs and assistance required. finally, postoperative drowsiness is rare after local as compared to general anesthesia, and therefore the patient is usually more oriented and relaxed (15). when comparing the times from surgery to discharge, we did not find any significative difference between the two groups. therefore, our data suggest the non-inferiority of a local approach compared to a general anesthesia approach for this surgery. regarding the pain evaluation in the first 3 post-operative hours, we noticed significantly lower nrs score for patients receiving local anesthesia. this result is correlated to the average duration of chirocaine for nerve blocks (analgesic coverage up to 17 hours), thanks to which patients enjoy excellent analgesia with no need of additional drugs. similarly, lower pain was reported during the first 4 postoperative days with local anesthesia as compared to general. our results are in line with the literature. nordin et al., in 2003, evaluated acceptance, satisfaction, and quality of life in patients performing hernia repair, respectively under genenal, regional and local anestehsia. the authors found that, patients in the local anesthesia group first felt pain significantly later than patients in the other two groups and they also required less analgesics during the first postoperative day (16). in 2012, kadihasanoglu et al. presented a prospective randomized trial evaluating the feasibility of local anesthesia for varicocelectomy in place of spinal anesthesia. sixty men with varicocele were included in the study, and the evaluation of pain during and after surgery was determined using the visual analogue scale. pain scores between the 2 groups did not differ significantly at 2, 4, 6, 8, 12, or 24 hours after surgery. a positive correlation was found between the duration of symptoms and the visual analogue scale score at 24 hours postoperatively. the mean dosage of injected diclofenac was 46.5 ± 23.3 mg and 32 ± 28.15 mg in the spinal and local anesthesia groups, respectively. the spinal group developed more postoperative complications, such as urinary retention, postspinal backache, headache, hypotension, and delayed mobilization. in line with our findings they concluded that local anesthesia is an effective, simple, and safe approach for subinguinal varicocelectomy with lower morbidity and fast recovery (17). likewise, manaf et al. compared local and general anesthesia in patients who had undergone different andrological procedures including varicocelectomy. they concluded that office-based andrological procedures using local approach could be successfully performed without compromising surgical technique and post-operative outcomes while significantly reducing the overall costs for both the patient and the healthcare system (18). the main limitation of this study is the relatively small number of included patients , although we were able to detect a statistically significant difference between groups. moreover, patients were non-randomized to different treatments thus introducing a potential selection bias. further trials are needed to confirm our findings. 235archivio italiano di urologia e andrologia 2021; 93, 2 local vs general anesthesia for varicocele treatment table 1. baseline characteristics of both groups. group a (n = 32) group b (n = 31) p-value age (years) 25 ± 4 25 ± 6 1 bmi (kg/m2) 22 ± 2 21 ± 2 0.051 duration (min) 38 ± 14 39 ± 11 0.7 asa i 25 29 0.2 asa = american society of anesthesiologists; bmi = body mass index. table 2. reported pain score over the first 4 post-operative days. nrs nrs nrsm nrsm p-value group a group b group a group b 3 hrs post-surgery 1 1 1 0 0.1 i day 8 am 7 3 12 8 < 0.05 i day 8 pm 6 3 9 7 < 0.05 ii day 8 am 4 2 9 5 < 0.05 ii day 8 pm 4 2 7 3 < 0.05 iii day 8 am 2 0 4 2 < 0.05 iii day 8 pm 2 0 4 2 < 0.05 iv day 0 0 2 1 < 0.05 nrs = numeric rating scale. archivio italiano di urologia e andrologia 2021; 93, 2 g. saredi, f.i. scroppo, p. capogrosso, g.m. pirola, l. capone, a. pacchetti, g. gianesini, p. maggio, g. carcano, f. dehò 236 conclusions local anesthesia for varicocele repair using a subinguinal approach is feasible and safe, providing a better control of early postoperative pain as compared to general anesthesia. and a faster recovery without experiencing significant complications. further larger studies are needed to confirm our positive findings. references 1. dubin l, amelar rd. etiologic factors in 1294 consecutive cases of male infertility. fertil steril. 1971; 22:469-74. 2. jarow jp. effects of varicocele on male fertility. hum reprod update. 2001; 7:59-64. 3. salonia a, bettocchi c, carvalho j, et al. eau guidelines on sexual and reproductive health 2020. 4. miyaoka r, esteves sc. a critical appraisal on the role of varicocele in male infertility. adv urol. 2012; 2012:597495. 5. dabaja aa, goldstein m. when is a varicocele repair indicated: the dilemma of hypogonadism and erectile dysfunction? asian j androl. 2016; 18:213-6. 6. marmar jl. the evolution and refinements of varicocele surgery. asian j androl. 2016; 18:171-8. 7. ficarra v, crestani a, novara g, mirone v. varicocele repair for infertility: what is the evidence? curr opin urol. 2012; 22:489-94. 8. baazeem a, belzile e, ciampi a, et al. varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. eur urol. 2011; 60:796-808. 9. colpi gm, carmignani l, nerva f, et al. surgical treatment of varicocele by a subinguinal approach combined with antegrade intraoperative sclerotherapy of venous vessels. bju int. 2006; 97:142-5. 10. marmar jl, kim y. subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. j urol. 1994; 152:1127-32. 11. tauber r, johnsen n. antegrade scrotal sclerotherapy for the treatment of varicocele: technique and late results. j urol. 1994; 151:386-90. 12. chazapis m, walker em, rooms ma, et al. measuring quality of recovery-15 after day case surgery. br j anaesth. 2016; 116:241-8. 13. jensen cfs, østergren p, dupree jm, et al. varicocele and male infertility. nat rev urol. 2017; 14:523-533 14. colpi gm, carmignani l, bozzini g, picozzi s. surgical subinguinal approach to varicocele combined with antegrade intraoperative sclerosis of venous vessels. surg innov. 2012; 19:252-7 15. rivat c, bollag l, richebé p. mechanisms of regional anaesthesia protection against hyperalgesia and pain chronicization. curr opin anaesthesiol. 2013; 26:621-5 16. nordin p, hernell h, unosson m, et al. type of anaesthesia and patient acceptance in groin hernia repair: a multicentre randomised trial. hernia. 2004; 8:220-5. 17. kadihasanoglu m, karaguzel e, kacar ck, et al. local or spinal anesthesia in subinguinal varicocelectomy: a prospective randomized trial. urology. 2012; 80:9-14 18. alom m, ziegelmann m, savage j, et al. office-based andrology and male infertility procedures-a cost-effective alternative. transl androl urol. 2017; 6:761-772. correspondence giovannni saredi, md giovanni.saredi@asst-settelaghi.it fabrizio i. scroppo, md paolo capogrosso, md paolo maggio, md giuseppe gianesini, md department of urology and andrology; circolo and fondazione macchi hospital, varese italy giacomo maria pirola, md lorenzo capone, md department of urology, usl toscana sud est, san donato hospital, arezzo, italy andrea pacchetti, md department of urology, san martino hospital, university of genova, italy giulio carcano, md federico dehò, md university of insubria, varese, italy stesura seveso 59archivio italiano di urologia e andrologia 2018; 90, 1 original paper the role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: a pilot study tommaso cai 1, andrea cocci 2, gianmartin cito 2, bruno giammusso 3, alessandro zucchi 4, francesco chiancone 5, maurizio carrino 5, francesco mastroeni 6, francesco comerci 7, giorgio franco 8, alessandro palmieri 9 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology, university of florence, florence, italy; 3 department of andrology, policlinico morgagni, catania, italy; 4 department of urology, university of perugia, perugia, italy; 5 department of urology, cardarelli hospital, naples, italy; 6 department of urology, azienda ospedaliera papardo, messina, italy 7 urologist, bologna, italy; 8 department of urology, sapienza university of rome, rome, italy; 9 department of urology, university of naples, federico ii, naples, italy. objective: to assess the efficacy and safety of an association of diallyl thiosulfinate with nuciferine and diosgenin in the treatment of a group of patients suffering from premature ejaculation (pe), primary or secondary to erectile dysfunction (ed). materials and methods: from july 2015 to october 2016, 143 patients (mean age 25.3; range 18-39) affected by pe completed the study and were finally analyzed in this phase i study. all patients, after clinical assessment and laboratory evaluation were asked to take an association of diallyl thiosulfinate with nuciferine and diosgenin as oral tablet, once a day, on alternate days, for three months. at the baseline and after three months of treatment, each patient was asked to complete the following questionnaires: international index of erectile function (iief-5), premature ejaculation diagnostic tool (pedt), male sexual health questionnaire (mshq). results: a statistical significant improvement in terms of erectile function, comparing the iief-5 value at baseline and follow-up visit was found (respectively iief-5: 8.7 vs 14.01; p < 0.001). moreover, at follow-up visit, 97/143 men (67.8%) referred a subjective improvement of the erection quality and a better control of the ejaculation (pros). the ielt improved too between the baseline evaluation and the follow-up visit (p < 0.001). conclusion: in conclusion, our study, even if supported by preliminary results, showed how diallyl thiosulfinate, nuciferine and diosgenin is able to improve the control of ejaculation in patients suffering from pe, primary or secondary to ed without any significant adverse effects. key words: diosgenin; muciferine; thiosulfinate; plant extracts; premature ejaculation; treatment. submitted 6 december 2017; accepted 12 december 2017 summary no conflict of interest declared. with prevalence rates of 20-30%, probably affecting every man at some point in his life (2, 3). it may result in unsatisfactory sexual intercourse for both partners, decreasing sexual self-confidence and self-esteem and resulting in an overall reduction of quality of life (qol) (4). lifelong pe occurs within 30-60 seconds after vaginal penetration with nearly every coitus, interesting about > 85% of men affected by this dysfunction, whereas about 10-20% of men ejaculate within 1-2 minutes (5). acquired pe is commonly due to sexual performance anxiety (6), psychological or relationship problems (6), erectile dysfunction (ed) (7), occasionally prostatitis (8), hyperthyroidism (9), or during withdrawal/detoxification from prescribed (10) or recreational drugs (11). in addition, men with this dysfunction are usually older, have a higher mean body max index and a greater incidence of comorbid disease and ed associated to lifelong, variable and subjective pe (12, 13). although the pathophysiologic mechanism of lifelong pe is not fully understood, it is shown that psychosocial, as well as organic factors play a key role in the aetiology (14-16). several studies demonstrated that patients with pe have more dorsal penile nerves, increasing glands penile hypersensivity and hyperexcitability (17). moreover, they also usually have other abnormal autonomic reflex pathways for the ejaculatory process, including shorter bulbo-cavernosal latency time and higher bulbo-cavernosal evoked potentials (18, 19). for this reason, pharmacologic therapy that reduce glands penile hypersensivity should be effective for the treatment of pe. medications, counselling and sexual techniques, that may delay ejaculation, can help the patients to improve sexual intercourse. however, a combination of these factors could be the best choice of treatment to improve efficacy and minimize relapse (20). behavioural therapy essentially include the “stop-start program” developed by semans (21), and its modification, the “squeeze” technique, prodoi: 10.4081/aiua.2018.1.59 introduction premature ejaculation (pe) is defined as uncontrolled ejaculation either before or shortly after sexual penetration (1). it is a very common male sexual dysfunction archivio italiano di urologia e andrologia 2018; 90, 1 t. cai, a. cocci, g. cito, b. giammusso, a. zucchi, f. chiancone, m. carrino, f. mastroeni, f. comerci, g. franco, a. palmieri 60 posed by masters and johnson (22). all these approaches need the partner’s cooperation for a long time, resulting often difficult in the long term (23). pharmacological therapy includes: selective serotonin reuptake inhibitors (ssris) antidepressants (24); dapoxetine (25); anaesthetic creams (26) and phosphodiesterase type 5 inhibitors (pde5i) (27). also some natural compounds (i.e. satureja montana, tribulus terrestris, phyllantus emblica) proved to be efficient in improving sexual quality of life in patients with pe (28). the role of nutraceuticals seems, then, interesting in the management of pe. the aim of this study was to assess the efficacy and safety of diallyl thiosulfinate, nuciferine and diosgenin (campedex-5®) in the treatment of patients affecting by pe, primary or secondary to ed. materials and methods study design from july 2015 to october 2016, we enrolled, in a pilot study, a total of 154 patients, affecting by pe, primary or secondary to ed. each patient signed a written fully informed consent statement before being enrolled in the study and accepted the trial voluntarily. after enrolment, all patients were asked to take campedex-5® oral tablet, once a day, on alternate days, for three months (figure 1). after 30 days all contacted by phone in order to be sure about the adherence to study protocol. after 3 months, all patients were evaluated with clinical evaluation and questionnaires in order to test the treatment efficacy and safety. inclusion and exclusion criteria all men had been in stable, monogamous, heterosexual relationship with at least one sexual intercourse a week with a compliant female partner. exclusion criteria were: age < 18 years, history of a psychiatric or neurological disorder, alcohol or drug abuse, previous genitourinary system trauma or surgery, spinal cord injury, previous radiotherapy, thyroid diseases, hypogonadism, currently taking a drug known to affect sexual function, such as hormonal therapy for prostate cancer. baseline evaluation the aetiology of pe was determined, in all cases, by a complete in-depth medical history, physical examination, hormonal evaluation and patient self-administered questionnaires on sexual function, even submitted to the partners. all the patients received a urological visit that considered the development of external genitalia, the presence of phimosis and/or prepuce anomalies. at the baseline, we collected the following hormonal profile from all patients: serum follicle-stimulating hormone (fsh) concentrations, prolactin levels, thyroid stimulating hormone (tsh), luteinizing hormone (lh) and blood total testosterone (tt). each patient was asked to complete the following questionnaires: international index of erectile function (iief-5), premature ejaculation diagnostic tool (pedt) and male sexual health questionnaire (mshq). questionnaires and pe status evaluation the iief-5 scale was used in order to evaluate the erectile function in the last six months considering the severity of ed, classified as follow: severe (iief-5 ≤ 7), moderate (iief-5 between 8 and 11), mild-moderate (iief-5 between 12 and 16), mild (iief-5 17-21), absent (iief5 between 22 and 25). pedt help to identify men who may have a problem with ejaculating too soon during sexual activity, considering the ejaculation as the release of semen after penetration. pedt investigated the severity of pe, classified as follow: absence of pe (pedt ≤ 8), probably pe (pedt 9-10), certainly present pe (pedt ≥ 11) (29). mshq-ejd is an abridged version of the 25item mshq, seen as a validated, self-administered instrument for assessing the primary domains of erection, ejaculation, and sexual satisfaction in aging men. mshq-ejd described three ejaculatory function items, investigating force (“in the past month, how would you rate the strength or force of your ejaculation?”), volume item (“in the past month, how would you rate the amount or volume of semen or fluid when you ejaculate?”), frequency item (“in the past month, how often have you been able to ejaculate or “cum” when having sexual activity?), and one ejaculation bother item (“if you had any ejaculation difficulties or have been unable to ejaculate, have you been bothered by this?”) (30). ejaculatory function score, which is the sum of the ordinal responses to the three items, ranges from 1 to 15, while bother scores ranges from 0 to 5. furthermore, we collected the intravaginal ejaculation latency time (ielt), as the time from vaginal penetration until ejaculation (31). it was timed on a stopwatch by ‘start’ (penetration) to ‘stop’ (ejaculation). ielt was asked figure 1. the figure shows the study schedule. iief-5: international index of erectile function; pedt: premature ejaculation diagnostic tool; mshq-ejd: male sexual health questionnaire; ielt: intravaginal ejaculation latency time; pros: patients-reported outcomes. both to men and their partners, trying to be honest in recording the time and it was calculated as mean from that perceived by the men and that perceived by partners. they were instructed to calculate and record the exact time after ejaculation. follow-up evaluation at 3 months follow-up evaluation, all patients underwent urological examination and the same laboratory and questionnaires evaluation as at the baseline time. in addition, we evaluated the patients-reported outcomes (pros). pros are defined as a report that comes directly from the patient about the status of his health condition without amendment or interpretation of the patient’s response by a clinician or anyone else (32). the “outcomes” in pro were interpreted broadly to reflect a variety of information reported directly by the patient, investigating the presence of a subjective improvement of erection quality and a positive change of the control of pe. also health-related qol, functional status and treatment adherence were collected. outcome measures and statistical analysis all clinical, laboratory and parameters and questionnaires were compared at the baseline (before to begin treatment) and at follow-up visit (after three months of treatment). all statistical analysis was performed using the ibm spss version 20.0 (spss inc, chicago, il, usa). p < 0.05 was considered statistically significant. results of all 154 men enrolled, 143 patients completed the study voluntarily, 11 patients withdrew the study for personal reasons. 81/143 men (56.6%) had a clinical presentation of lifelong pe, while 62/143 men (43.3%) presented a secondary pe, caused by sexual performance anxiety, psychological or relationship problems and occasionally prostatitis. 44/143 patients (30.7%) had ed associated. the mean age was 25.3 years old (range 18-39). at baseline and follow-up visit, all hormonal parameters collected were in the normal range (table 1). how shown in table 2, at the follow-up visit, the patients shown a statistical significant improvement in terms of erectile function, comparing the iief-5 value at baseline and follow-up visit (respectively iief-5: 8.7 vs 14.0; p < 0.001). median total pedt score changed from 15 (baseline) to 10 (follow-up). regarding mshq-ejd, the majority of patients reported, at the end of treatment, a reduction of awkwardness during sexual intercourses (bother score: 5 vs 3) and an improvement of ejaculatory function disorders (ejaculatory function score: 9 vs 12). ielt shown a clean improvement, increasing significantly from 45.5 sec to 123.7 sec, respectively at baseline and follow-up visit (p < 0.001) (figure 2). moreover, at follow-up visit, of all 143 patients, 97/143 men (67.8%) referred a subjective improvement of the erection quality and a better control of the ejaculation (pros). during the study, no treatment emergent adverse events occurred, let alone some patients interrupted the drug assumption for concomitant therapies or co-morbidities. discussion main finding in this study, we demonstrated how the assumption of organic compounds derived from natural substances is able to improve the quality of erections and the control of ejaculation, increasing the mean ejaculation latency time. in particular, we tested the following combination of diallyl thiosulfinate (20 mg), nuciferine (137.5 mg) and diosgenin (45 mg). results in the context of previous studies thiosulfinates are allylsulfide compounds including allicin, diallyldisulfide, diallyltrisulfide, s-allylmercaptocysteine and s-allylcysteine, a class of phytochemical organosulfurs found essentially in garlic and other vegetables from alliumspecies (33). allicin, or diallyl thiosulfinate, is the most important and representative active ingredient of garlic (allium sativus). this substance is formed when the clumps that make up the bulbs are cut, chewed or otherwise crushed. following these mechanical actions, an enzyme, called allinase, releases from the vacuolary juices, acting on an aminoacid, the allyl, transforming it into allicin. diallyl thiosulphinate can increase the concentration of intracellular glutathione, a substance consisting of three amino-acids (cysteine, glutamic acid and glycine). through a series of reactions, cysteine is transformed in hydrogen sulphide (h2s) produced at the arterial level with particular reference to peripheral circulation. h2s acts as a real proerogenous gaseous mediator which, through the opening 61archivio italiano di urologia e andrologia 2018; 90, 1 nutraceuticals and premature ejaculation table 1. clinical and laboratory characteristics of all analyzed patients. demography, clinical and laboratory characteristics at baseline enrolled patients n° 143 age (mean) (range) 25.3 (18-39) clinical presentation primary pe 81 secondary pe 62 associated ed 44 total testosterone (ng/ml) 14.3 fsh (iu/l) 5.3 lh (iu/l) 6.8 tsh (miu/l) 2.3 prolactin (ng/ml) 7.8 table 2. outcome variables before and after treatment. outcomes variable baseline follow-up p iief-5 (mean score) 8.7 14.01 < 0.001 pedt (mean score) 15 10 < 0.1 mhsq-ejd (ejaculatory function mean score) 9 12 < 0.1 mhsq-ejd (bother mean score) 5 3 < 0.1 ielt (mean score) [min] 45.5 123.7 < 0.001 archivio italiano di urologia e andrologia 2018; 90, 1 t. cai, a. cocci, g. cito, b. giammusso, a. zucchi, f. chiancone, m. carrino, f. mastroeni, f. comerci, g. franco, a. palmieri 62 of potassium channel atp, resulting in increased ca+ ion transfer, produces through a precise hyperpolarization mechanism on smooth muscle cells, a relaxation effect on them. the relaxation of the peripheral smooth muscle also causes the recall of blood resulting in an erection phenomenon (34). diosgenine is the most important active principle of dioscorea (dioscorea villosa), also known as wild yam, a plant belonging to the dioscoreacee family. it is therefore an important precursor of steroids, present in nature in the form of diocin glycoside or other heterosides that are then hydrolysed in acidic environments and has therefore always been used by the pharmaceutical industry as a raw material for the production of hormones, such as dhea. small amounts of dhea are also produced by testicles, ovaries and glial cells. dhea circulates bloodstream especially as a sulfate (dhea-s); in the plasma about 80% of this sulphate is bound to albumin, while the remaining 20% is linked to lipoproteins. the amount of dhea contained in the human body is related to the age of the subject. after birth there is a significant decrease in plasma levels of dhea. starting at five years, levels are rising again to reach the peak of the age of twenty-five; from the age of twenty-five, there is a progressive decrease in the concentration of dhea in the body; this decline begins to become rapid from forty years. at eighth decade, the level does not exceed 10% of the maximum reached twenty-five years. because of this decrease in plasma levels with age, many authors have suspected that dhea was heavily involved in aging-regulating processes, so dhea administration was recommended as an anti-aging method. dhea appears to be involved in many biological functions including sexual activity regulation and stimulation, myelin production and activation of the g6pd-h enzyme that helps to reduce fat cells (35). nuciferine is an alkaloid extracted from the plants nymphaea caerulea and nelumbo nucifera. it has a pharmacological profile of action associated with dopamine receptor blockade. specifically, nuciferine is a partial antagonist of d2-like receptor, a subtype of dopamine receptors which activation is associated with ejaculation and micturition stimulus (36). it induces sedation, hypothermia, ptosis, and catalepsy, if present in higher doses; it inhibits spontaneous motor activity, conditioned avoidance response, amphetamine toxicity and stereotypy. a clinical trial on rats showed that nuciferin, at doses ranging from 25 to 50 mg per kg intraperitoneal, is able to produce sedation levels from moderate to marked and ptosis. the authors have therefore concluded that probably nuciferin acts by blocking dopaminergic receptors: in a further study it has been shown that this substance is able to inhibit amphetamine-induced stereotype, which, as is known, is mediated by the stimulation of dopaminergic receptors (36). this present study showed that ielt significantly increased after treatment with campedex-5®. moreover, diallyl thiosulfinate, nuciferine and diosgenin figure 2. the figure shows the results at the follow-up evaluation by using questionnaires before (pre) and after (post) treatment. iief-5: international index of erectile function; pedt: premature ejaculation diagnostic tool; mshq-ejd: male sexual health questionnaire; ielt: intravaginal ejaculation latency time; pros: patients-reported outcomes. proved effective in improving the quality of erections, increasing significantly iief-5. topical agents, for the treatment of pe, can reduce the hypersensivity of the glands penis, but can induce localized irritation, including pain, burning, delayed ejaculation and loss of penile sensation (37). furthermore, in our study, the treatment with campedex-5® was well tolerated by all patients, no showing any side effect reported during the period study. however, the limitation of the study is related to the methodology used, as it was not a case-control study. more studies should be carried out to clarify the precise role of the active ingredients in campedex-5® and their interactions. conclusions our study, though based on results obtained from a pilot study, shown how diallyl thiosulfinate, nuciferine and diosgenin are able to improve the control of ejaculation in patients suffering from pe, primary or secondary to ed, significantly improving iief and ielt rates. the drug had thus proven to be safe and effective in the treatment of pe, without having clinically relevant side effects. references 1. becker jv, stinson jd. premature ejaculation section of human sexuality and sexual dysfunctions. in re hales et al., eds., the american psychiatric publishing textbook of psychiatry, 5th ed., 2008; 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158:451-455. 20. perelman ma. a new combination treatment for premature ejaculation: a sex therapist's perspective. j sex med. 2006; 3:10041012. 21. dinsmore ww, hackett g, goldmeier d, et al. topical eutectic mixture for premature ejaculation (tempe): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. bju int. 2007; 99:369-375. 22. kockott g. human sexual inadequacy--behavior therapy and the masters and johnson technique. adv biosci. 1973; 10:219-224. 23. waldinger md. premature ejaculation: state of the art. urol clin north am. 2007; 34:591-599 24. cooper k, martyn-st james m, kaltenthaler e, et al. interventions to treat premature ejaculation: a systematic review short report.health technol assess. 2015; 19:1-180. 25. premature ejaculation: dapoxetine; nice advice, may 2014. 26. martyn-st james m, cooper k, ren k, et al. topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. sex health. 2015 nov 25. 27. chen j, keren-paz g, bar-yosef y, matzkin h. the role of phosphodiesterase type 5 inhibitors in the management of premature ejaculation: a critical analysis of basic science and clinical data. eur urol. 2007; 52:1331-9 28. sansalone s, russo gi, mondaini n, et al. a combination of tryptophan, satureja montana, tribulus terrestris, phyllanthus emblica extracts is able to improve sexual quality of life in patient with premature ejaculation arch ital urol androl. 2016; 88:171176. 29. huang yp, chen b, ping p, et al. the premature ejaculation diagnostic tool (pedt): linguistic validity of the chinese version. j sex med. 2014; 11:2232-8. 30. rosen rc, catania ja, althof se, et al. development and vali63archivio italiano di urologia e andrologia 2018; 90, 1 nutraceuticals and premature ejaculation archivio italiano di urologia e andrologia 2018; 90, 1 t. cai, a. cocci, g. cito, b. giammusso, a. zucchi, f. chiancone, m. carrino, f. mastroeni, f. comerci, g. franco, a. palmieri 64 dation of four-item version of male sexual health questionnaire to assess ejaculatory dysfunction. urology. 2007; 69:805-9. 31. waldinger md, quinn p, dilleen m, et al. a multinational population survey of intravaginal ejaculation latency time. j sex med. 2005; 2:492-7. 32. u s. food and drug administration. guidance for industry patient reported outcome measures: use in medical product development to support labeling claims. federal register. 2009; 74:65132-3. 33. gu x, zhu yz. therapeutic applications of organosulfur compounds as novel hydrogen sulfide donors and/or mediators. expert rev clin pharmacol. 2011; 4:123-33. 34. das i, khan ns, sooranna sr. potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications. curr med res opin. 1995; 13:257-63. 35. liu k, zhao w, gao x, , et al. diosgenin ameliorates palmitateinduced endothelial dysfunction and insulin resistance via blocking ikkß and irs-1 pathways. atherosclerosis. 2012; 223:350-8. 36. farrell ms, mccorvy jd, huang xp, et al. in vitro and in vivo characterization of the alkaloid nuciferine. plos one. 2016; 11:e0150602. 37. choi hk, jung gw, moon kh, et al. clinical study of ss-cream in patients with lifelong premature ejaculation. urology. 2000; 55:257-261. correspondence tommaso cai, md (corresponding author) ktommy@libero.it department of urology, santa chiara hospital largo medaglie d'oro 9, trento, italy andrea cocci, md gianmartin cito, md department of urology, university of florence, florence, italy bruno giammusso, md department of andrology, policlinico morgagni, catania, italy alessandro zucchi, md department of urology, university of perugia, perugia, italy francesco chiancone, md maurizio carrino, md department of urology, cardarelli hospital, naples, italy francesco mastroeni, md department of urology, azienda ospedaliera papardo, messina, italy francesco comerci, md urologist, bologna, italy giorgio franco, md department of urology, sapienza university of rome, rome, italy alessandro palmieri, md department of urology, university of naples, federico ii, naples, italy stesura seveso 337archivio italiano di urologia e andrologia 2015; 87, 4 case report penile prosthesis implant with bi-triangular excision and graft for surgical therapy of peyronie’s disease: a case report alexandre de freitas miranda 1, bruno lopes cançado machado 2 1 reconstructive urology and andrology section, department of urology, ipanema federal hospital and urogenital research unit, state university of rio de janeiro, uerj, rio de janeiro, brazil; 2 urological private practice, rio de janeiro, brazil. we present a case of a 65-year-old man, who presented with moderate erectile dysfunction and a dorsal penile deviation of 60° caused by peyronie’s disease. the patient underwent bi-triangularshaped plaque excision, followed by grafting and implantation of inflatable penile prosthesis. complete penile straightening, without mechanical or geometric abnormalities, was achieved using bi-triangular excision and grafting. postoperatively, the patient reported high satisfaction with the results and could perform sexual intercourse naturally. this novel technique corrects any degree of penile curvature, permits malleable and semi-rigid penile prosthesis implantation, avoids penile length loss, and eliminates additional incisions. to our knowledge, this case is the first in the literature in which the bi-triangular technique was successfully used for penile prosthesis implantation secondary to peyronie’s disease. this new technique appears to be a good solution to correct penile curvature during penile prosthesis implantation for the treatment of peyronie’s disease associated with erectile dysfunction. key words: peyronie’s disease; surgery; graft; penile prosthesis; erectile dysfunction. submitted 30 june; accepted 30 september summary no conflict of interest declared. may represents a challenging procedure and in some cases require another incision to access distal defects. herein we report the first case of ppi using the bi-triangular excision and graft (2). case report here we present a case of a 65-year-old man, without comorbidities, who presented with moderate ed and required a phosphodiesterase type 5 inhibitor to have sexual intercourse. he had a dorsal penile deviation of 60° caused by pd. the penile plaque had been stable for 1 year. artificial erection was induced with 0.9% of nacl solution injected into the corpora cavernosa, punctured with a 21g butterfly needle. the technique described by austoni et al. was used to deglove the penis and isolate the neurovascular bundle (3). we marked two triangles on the patient’s tunica albuginea. the bases of the triangles were equal to the disparity between the long and short sides of the curvature (w), and the sum of the triangles’ heights was equal to ¾ of the corpora cavernosa circumference (l) (figure 1a). the apexes of the triangles were located at the middle of the curvature on the concave side (figure 1a). after the excision of the triangles and rectification of the penis, the corpora cavernosa defect acquired a rectangular shape, with longitudinal and transversal lengths equal to w and l, respectively (figure 1b). the defect was closed by a bovine pericardium graft 4.5 × 8.25 cm in size (figure 1c). finally the buck’s fascia was closed, and the penis re-gloved (figure 1d). another 2-cm longitudinal incision was made on each cavernous body to perform the ppi. the fluid reservoir was inserted into the retropubic space through an inguinal ring using the scrotal incision made to deglove the penis. the pump was placed on the subcutaneous space of the scrotum. a 14-fr blake drain was inserted into the scrotum for 24 h. the patient reassumed sexual intercourse 6 weeks after surgery. complete penile straightening, without mechanical or geometric abnormalities, was achieved using bitriangular excision and grafting. postoperatively, the patient reported being highly satisfied with the results and could perform sexual intercourse naturally. doi: 10.4081/aiua.2015.4.337 introduction peyronie’s disease (pd) is a connective tissue disorder characterized by tunica albuginea fibrosis that can generate penile deformity with curvature, narrowing, and shortening and, in 41% of cases, is associated with erectile dysfunction (ed). pd is often associated with psychological disturbance and has a male population prevalence of 3-9%. penile prosthesis implantation (ppi) is a treatment for patients with pd and ed non-responsive to oral treatment. during the implantation, the surgeon may need to perform manual modeling, plaque incision if residual curvature after modeling is greater than 30°, and, if the defect created by the incision is greater than 2 cm, placement of a graft. segal et al. reported that 53.6% of patients underwent ppi and modeling required plaque incision with or without a graft (1). the graft insertion archivio italiano di urologia e andrologia 2015; 87, 4 a. de freitas miranda, b. lopes cançado machado 338 references 1. segal rl, cabrini mr, bivalacqua tj, burnett al. penile straightening maneuvers employed during penile prosthesis surgery: technical options and outcomes. int j impot res. 2014; 26:182-5. 2. miranda af, sampaio fj. a geometric model of plaque incision and graft for peyronie's disease with geometric analyses of different techniques. j sex med. 2014; 11:1546-53. 3. austoni e, altieri vm, tenaglia r. trans-scrotal penile degloving, a new procedure for corporoplasties. urologia. 2012; 79:200-10. correspondence alexandre de freitas miranda, md (corresponding author) contato@alexandremiranda.com.br urogenital research unit, state university of rio de janeiro av 28 de setembro, 87, fundos, vila isabel rio de janeiro, rj, brazil, 20551-030 bruno lopes cançado machado, md blc1904@hotmail.com rua visconde de pirajá, 595, sala 1406, ipanema rio de janeiro, rj, brazil, 22410-002 conclusions to our knowledge, this case is the first in the literature in which the previously reported bi-triangular technique was successfully applied for ppi secondary to pd, validating our previous measures and findings. this new technique appears to be a good solution to correct penile curvature during penile prosthesis implantation for the treatment of pd associated with ed. discussion and supplementary re fe rences are posted as supplementary materials on www.aiua.it figures 1a, b, c, d. surgical procedure. a) penile degloving with the two triangles marked. b) defect resulting after bi-triangular excision. c) penile rectification and tunica albuginea defect closed by bovine pericardium graft. d) inflatable penile prosthesis implantation after re-gloving. 15archivio italiano di urologia e andrologia 2018; 90, 1 original paper the impact of ureteral double-j stent insertion following ureterorenoscopy in patients with ureteral stones accompanied by perirenal fat stranding ercan ogreden 1, ural oğuz 1, erhan demirelli 1, erdal benli 2, özkan özen 3 1 giresun university, faculty of medicine, department of urology, giresun, turkey; 2 ordu university, faculty of medicine, department of urology, ordu, turkey; 3 giresun university, faculty of medicine, department of radiology, giresun, turkey. objective: to evaluate the impact of ureteral stent insertion following semirigid ureterorenoscopy (urs) in patients with perirenal fat stranding (pfs) due to ureteral stones. material and methods: data of 600 patients who underwent urs were analyzed retrospectively. seventy-two patients detected to have pfs accompanying ureteral stone were included. patients who did not undergo double j (dj) stent insertion following semirigid urs were classified as group i (n: 52), while those who underwent stent insertion were classified as group ii (n: 20). side distribution; localization of the stones, stone size, presence of fever, urinary tract infection (utis) and urosepsis rates were compared in the two groups. results: the average age of the patients was 44.4 (20-71) years. male/female ratio and side of the stone location showed similar distribution in both groups (p > 0.05). fever occurred in 23 cases (44.2%) in group i and in 15 cases (75%) in group ii (p = 0.038). utis occurred in 15 cases (28.9%) in group i and in 12 cases (60%) in group ii (p = 0.03). urosepsis presented in 3 (5.8%) and 5 (25%) of the patients in group i and ii, respectively (p = 0.033). conclusions: according to our results, ureteral dj stent insertion following urs in patients with pfs due to ureteral stone caused an increase on postoperative infection related complications. key words: perirenal fat stranding; ureteral stents; ureteral stones; ureterorenoscopy. submitted 15 october 2017; 10 december 2017 summary no conflict of interest declared. ureteric stones (3). extracorporeal shock wave lithotripsy (eswl), ureterorenoscopy (urs) and endoscopic lithotripsy are the most common treatment modalities currently used in ureteral stones. the ureteral dj stent insertion indications are the complications that develop secondary to the presence of the stones and the complications that arise during the surgical procedure (4). however, the use of stents can lead to side effects such as pain, urinary infection, and irritable voiding symptoms (5, 6). thus, we aimed to evaluate the correlation between ureteral dj stent and infective complications such as fever, utis and urosepsis in patients with pfs who develop secondary to ureteral stones. material and methods data of 600 patients who underwent urs in two tertiary centers between may 2010 and may 2017 were analyzed retrospectively. routine laboratory, complete urinalysis, urine cultures, blood cultures and ct scan results were obtained by a comprehensive review of medical records. vital signs were also reviewed and presence of any utis, fever and urosepsis were noted. urine cultures were obtained from patients with asymptomatic bacteriuria and appropriate empirical treatment was started. symptomatic urinary infection criteria included fever, costovertebral angle sensitivity, pyuria (≥ 10 white blood cells per high-power field), and positive urine culture (≥ 105 colony-forming units of uropathogen/ml). urosepsis criteria included at least 2 findings of systemic inflammatory response syndrome (sirs) in the presence of infection. sirs criteria included fever > 38 c° or < 36 c°, heart rate > 90 beats/min, respiratory rate > 20/min or paco2 < 32 mmhg, leucocytes > 12.000/mm3 or < 4.000/mm3. patients diagnosed with urosepsis was treated empirically considering antibiotic susceptibility results. of 600 patients, 72 with pfs and hydronephrosis due to ureteral stones were included in the study. pfs defines the appearance of edema of the fat of the perirenal space at ct. presence of pfs, stone size, side distribution and localization of the stones were documented by reviewing the ct scans (figure 1). patients who did not undergo stent insertion following semirigid urs were classified as doi: 10.4081/aiua.2018.1.15 introduction ureteral stones can lead to partial or complete obstruction of ureteral lumen (1). computerized tomography (ct) is the ideal method for detecting obstructing stones. there are primary and secondary findings of ureteral obstruction due to stones on ct. the primary finding is the detection of stone. secondary findings are hydronephrosis, enlarged ureter, perirenal fat stranding (pfs), pararenal facial thickening, perirenal fluid collection (2). pfs is a ct imaging of the perirenal fat tissue. asymmetric or unilateral pfs is an important indicator of renal inflammation or acute obstruction. it is detected especially in the presence of inflammation such as acute pyelonephritis and acute obstruction secondary to ogreden_stesura seveso 27/03/18 09:17 pagina 15 archivio italiano di urologia e andrologia 2018; 90, 1 e. ogreden, u. oğuz, e. demirelli, e. benli, ö. özen 16 group i (n:52), while those who underwent stent insertion were classified as group ii (n:20). side distribution; localization of the stones, stone size, presence of fever, uti and urosepsis rates were compared in the two groups. statistical analysis results are presented as frequency and percentage (%). the abnormal distribution of data from each group was confirmed with the kolmogorov-smirnov test, thus statistical comparisons were performed using mann whitney-u test. chi-square test was used to examine the dependency between the groups. spss 22.0 software for windows (spss inc., chicago, il) was used for analysis of data. a p value less than 0.05 was considered statistically significant. results the mean age of the patients was 44 (2370) years in group i and 45.3 (20-71) years in group ii (p = 0.811) (table 2). female patients were 14 (26.9%) and 2 (10%) in group i and ii, respectively. male patients were 38 (73.1%) and 18 (90%) in group i and ii, respectively (p = 0.205) (table 1). stones were detected in the right ureter in 27(51.9%) patients in group i and 10(50%) patients in group ii. left ureteric stones were detected in 25 (48.1%) patients and 10 (50%) patients in group i and ii, respectively (p = 1.00) (table 1). lower ureteric stones were found in 46 (88.5%) patients in group i and 9 (45%) patients in group ii. mid ureteric stones were found in 9 (11.5%) patients and 6 (30%) patients in group i and group ii, respectively. upper ureteral stones were observed in only 5 (25%) table 1. demographic distribution of infective complications, gender, stone side and localization according to groups. chi square test group i group ii total n % n % n % chi square p gender female 14 26.9 2 10 16 22.2 fisher's exact 0,205 male 38 73.1 18 90 56 77.8 total 52 100 20 100 72 100 side left ureter 25 48.1 10 50 35 48.6 0 1,00 right ureter 27 51.9 10 50 37 51.4 total 52 100 20 100 72 100 localization lower ureter 46 88.5 9 45 55 76.4 * 0,001 middle ureter 6 11.5 6 30 12 16.7 upper ureter 0 0 5 25 5 6.9 total 52 100 20 100 72 100 fever absent 29 55.7 5 25 34 47.2 4,322 0,038 present 23 44.2 15 75 38 52.8 total 52 100 20 100 72 100 utis absent 37 71.2 8 40 45 62.5 4,726 0,03 present 15 28.9 12 60 27 37.5 total 52 100 20 100 72 100 urosepsis absent 49 94.2 15 75 64 88.9 fisher's exact 0,033 present 3 5.8 5 25 8 11.1 total 52 100 20 100 72 100 utis: urinary tract infections. figure 1. unenhanced tomography of a 53-year-old male patient with left lateral and left testicular pain. [1a perirenal fat stranding (shown by the white arrow) image, 1b perirenal lines (shown by the white arrow) and two stones in the lower calyx of left kidney (indicated by a white arrowhead). 1c perirenal streaks (shown by the white arrow) and dilatation of the left ureter (indicated by a white arrowhead), 1d the left distally ureteral stone (shown by the white arrow)]. ogreden_stesura seveso 27/03/18 09:17 pagina 16 patients in group ii (p = 0.001) (table 1). fever was detected in 23 (44.2%) patients and 15 (75%) patients in group i and group ii, respectively (p = 0.038). in 25 of the 38 patients with fever, at least one species of a microorganism was isolated in their urine and/or blood cultures. the most isolated microorganism was e. coli (95%). uti was detected in 15 patients (28.9%) in group i and 12 patients (60%) in group ii (p = 0.03). in 10 of the 27 patients, urine culture was positive. the most frequently isolated bacteria was e. coli (98%). urosepsis was seen in 3 (5.8%) patients in group i and in 5 (25%) patients in group ii (p = 0.033). all of these patients were found to have microorganisms in both urine and blood cultures (table 1). mean size of the stones was 7.2 mm (4-13 mm) in group i and 11.4 mm (4-20 mm) in group ii. mean size of the stones did significantly differ between the groups (p = 0.001) (table 2). preoperative hydronephrosis was seen in all patients in both groups, whereas postoperative hydronephrosis was not seen in any patient. success was defined as the stone free and success rates of the treatment was 100% in both groups. catastrophic ureteral injuries such as avulsion or perforation did not occur in any patient. discussion perirenal fat stranding (pfs) indicates the appearance of edema in the fat of the perirenal space in ct. asymmetric or unilateral pfs is an important indicator of renal inflammation or acute obstruction. ct is the ideal method for detecting obstructing stones. there are primary and secondary findings of ureteral stones that have acute ureteral obstruction in ct. primary findings are the appearance of stone. secondary findings include hydronephrosis, enlarged ureter, pfs, pararenal fascia thickening, perirenal fluid collection. secondary findings have a high positive and negative predictive value for ureteral stone presence or absence (2, 3, 7). semirigid ureterorenoscopy is a rather effective and minimally invasive method of treatment for ureteral stones. until recently, dj stent insertion was performed in all patients who underwent urs in order to decrease the risk of postoperative ureteral edema and obstruction, to avoid the development of ureteral stenosis, to facilitate the spontaneous passage of small stone fragments and to diminish the postoperative risk of pain. however, routine insertion of dj stent has been questioned because redesigned endoscopic equipments cause less urs complications, intracorporeal lithotripsy devices are quite improved and irritative voiding symptoms secondary to dj stent along with side effects such as hematuria, catheter migration, fever and urinary infection may be seen (8). while ureteral dj stent insertion is not recommended in patients who do not have complications, it is still recommended in patients with complications such as mucosal edema, mucosal damage, hemorrhage, ureteral laceration and stone migration, and in patients with solitary kidney (9, 10). boridy et al. (11) found that there was a significant relationship between the degree of pfs and obstruction in the study of patients with acute ureteral obstruction and the degree of obstruction was high in this study when pfs was excessive. in our study, complications related to infection in the postoperative period were found to be high in patients with pfs. pfs, urine leakage due to small tears in the calyx fornixes is seen as a linear increase in perinephric fat tissue density. however, pfs is not a specific finding. pfs is also seen in acute pyelonephritis, pyelonephrosis and renal vein thrombosis (12). it is recommended to perform contrastenhanced ct scan to exclude other possible causes in patients without stone in ct (13). both obstruction and stasis in ureteral lumen caused by ureteral stones and dj catheter insertion following treatment increase the risk of urinary infection. risk of hydronephrosis, risk of pfs, level of thickening in the pararenal fascias and level of unilateral parenchymal thickening are proportional to severity of ureteral obstruction. pfs is more common in ureteral stones complicated by infection (14, 15). stent insertion is an effective method to provide acute drainage of the hydronephrotic or pyonephrotic kidney (16). but in contrast, it may be the source of the infection in the long term period. several studies reported bacterial colonization rates from 44% to 69% on ureteral stents and bacteriuria rates from 21% to 29.9%. mild fever, urinary tract infection, even sepsis can be seen due to bacterial colonization of dj stents (17). in a study conducted with 87 patients who underwent dj stent insertion following emergency intervention (n:34) or elective intervention (n:53), postoperative fever was seen in 22 (25%) patients who did not have preoperative fever. fever was seen in 56% of the patients who underwent stent insertion following emergency intervention, while it was present in only 6% of the patients underwent stent 17archivio italiano di urologia e andrologia 2018; 90, 1 double-j stent and perirenal fat stranding table 2. the differences between groups in terms of age and stone size. mann whitney u test n mean median min max ss rank avg. z p age group i 52 44.0 42 23 70 11.9 36.13 -0.239 0.811 group ii 20 45.3 43 20 71 15.1 37.45 total 72 44.4 43 20 71 12.8 size/mm group i 52 7.2 7 4 13 2.1 29.87 -4.381 0.001 group ii 20 11.4 10 4 20 4.2 53.75 total 72 8.3 8 4 20 3.4 dj stent: double j stent. ogreden_stesura seveso 27/03/18 09:17 pagina 17 archivio italiano di urologia e andrologia 2018; 90, 1 e. ogreden, u. oğuz, e. demirelli, e. benli, ö. özen 18 insertion following elective intervention. hence it was reported that stent insertion following emergency intervention significantly increased risk of fever (18). in another study, dj stent was inserted in 26 of the 48 patients who underwent urs because of distal ureteral stone and 22 patients were followed up without a stent. urosepsis was found in only 1 patient who underwent dj stent insertion and the difference was not significant (19). a similar study reported that presence of fever was not associated with stent insertion (20). ibrahim at al. (21) analyzed 110 patients with stent and 110 without stent in their large series, prospectively. fever developed in 8 (7.3%) patients and utis developed in 5 (4.5%) patients in the stent group, while fever was present in 10 (9.1%) cases and utis were present in 7 (6.4%) cases in not stented group. although there was no significant difference between the groups, presence of fever and infection were slightly higher in not stented group. they did not evaluate the radiological findings such as pfs. at the end of the urs procedures, stent insertion is not recommended in patients with hydronephrosis and pfs caused by ureteral stones. and the effects of the pfs on postoperative complications is still unclear. to the best of our knowledge, this is the first study focus on this topic in the literature. compared with the literature, we found higher rates of infection related complications of urs in our study. thus pfs due to ureteral obstruction can be a predisposing factor for the postoperative complications associated with infection. in addition, stent insertion did not reduce the risk for fever, utis and sepsis. eventually, they were higher in stented patients without a significant difference. prior studies reported that the necessity of dj stent insertion increases in patients with higher stone burden and in male patients (22, 23). in the population of this study, female/male ratio, side and mean operative times did not significantly differ between the groups (p > 0.05). in contrast, mean stone burden and the localization of the stone were significantly higher in stenting patients. the surgeons' decision for inserting ureteral dj stent seems to be affected mainly by the stone burden and the localization of the stone just like in the literature. we acknowledge that there were several limitations of this study. the most important limitation was that the study was designed in a retrospective nature. thus patients were not randomized, and the surgeons might not be aware of the pfs, especially when the radiologist did not report it. in addition real incidences of significant or insignificant mucosal injuries in the study groups are not clear. therefore, we cannot present the real indications for the ureteral dj stent insertion. hence, we believe that our findings need to be confirmed by further randomized prospective studies. despite the shortcomings mentioned above, this is an important study since there is no previous data in the literature about this topic. conclusions compared with the literature, we found higher rates of infection related complications of urs in this study. ureteral dj stent insertion following urs due to ureteral stones did have a significant effect on postoperative infection related complications such as fever, utis and sepsis in patients with pfs. references 1. straub m, strohmaier wl, berg w, et al. diagnosis and metaphylaxis of stone disease. consensus concept of the national working committee on stone disease for the upcoming german urolithiasis guideline. world j urol. 2005; 23:309-23. 2. takahashi n, kawashima a, ernst rd, et al. ureterolithiasis: can clinical outcome be predicted with unenhanced helical ct? radiology. 1998; 208:97-102. 3. stunell h, buckley o, feeney j, et al. imaging of acute pyelonephritis in the adult. eur radiol. 2007; 17:1820-8. 4. nabi g, cook j, n'dow j, mcclinton s. outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. bmj. 2007; 334:572. 5. joshi hb, newns n, stainthorpe a, et al. ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. j urol. 2003; 169:1060-64. 6. keeley jr fx, timoney ag. routine stenting after ureteroscopy: think again. eur urol. 2007; 52:642-44. 7. fielding jr, steele g, fox la, et al. spiral computerized tomography in the evaluation of acute flank pain: a replacement for excretory urography. j urol. 1997; 157:2071-73. 8. hiller n1, berkovitz n, lubashevsky n, et al. the relationship between ureteral stone characteristics and secondary signs in renal colic. clinical imaging. 2012; 36:768-72. 9. kara c, bayındır m, çiçekbilek i, et al. comparison between ureteroscopy and extracorporeal shock wave lithotripsy in the treatment of distal ureteral stones. turkish journal of urology. 2009; 35:28-33. 10. cevik i, dillioglugil o, akdas a, siegel y. is stent placement necessary after uncomplicated ureteroscopy for removal of impacted ureteral stones? j endourol. 2010; 24:1263-67. 11. boridy ic, kawashima a, goldman sm, sandler cm. acute ureterolithiasis: nonenhanced helical ct findings of perinephric edema for prediction of degree of ureteral obstruction. radiology. 1999; 213:663-7. 12. heneghan jp, dalrymple nc, verga m, et al. soft-tissue "rim" sign in the diagnosis of ureteral calculi with use of unenhanced helical ct. radiology. 1997; 202:709-11. 13. chong wk, wysoki m, heller lg, zegel hg. renal carcinoma presenting with flank pain: a potential drawback of unenhanced ct. ajr am j roentgenol. 2000; 174:667-9. 14. smith rc, levine j, rosenfeld at. helical ct of urinary tract stones. radiol clin n am. 1999; 37:911-52. 15. tenke p, jackel m, nagy e. prevention and treatment of catheterassociated infections: myth or reality? eur urol. 2004; 106-15. 16. goldsmith zg, oredein-mccoy o, gerber l, et al. emergent ureteric stent vs percutaneous nephrostomy for obstructive urolithiasis with sepsis: patterns of use and outcomes from a 15-year experience. bju int. 2013; 112:122-8. 17. paick sh, park hk, oh sj, kim hh. characteristics of bacterial colonization and urinary tract infection after indwelling of double-j ureteral stent. urology. 2003; 62:214-17. 18. paz a, amiel ge, pick n, et al. febrile complications followogreden_stesura seveso 27/03/18 09:17 pagina 18 ing insertion of 100 double-j ureteral stents. j endourol. 2005; 19:147-50. 19. srivastava a, gupta r, kumar a, kapoor r, mandhani a. routine stenting after ureteroscopy for distal ureteral calculi is unnecessary: results of a randomized controlled trial. j endourol. 2003; 17:871-74. 20. cevik i, dillioglugil o, akdas a, siegel y. is stent placement necessary after uncomplicated ureteroscopy for removal of impacted ureteral stones? j endourol. 2010; 24:1263-67. 21. ibrahim hm, al-kandari am, shaaban hs, et al. role of ureteral stenting after uncomplicated ureteroscopy for distal ureteral stones: a randomized, controlled trial. j urol. 2008; 180:961-65. 22. matani ys, al-ghazo ma, al-azab rs, et al. emergency double-j stent insertion following uncomplicated ureteroscopy: risk-factor analysis and recommendations. int braz j urol. 2013; 39:203-8. 23. tanriverdi o, yencilek f, koyuncu h, et al. emergent stenting after uncomplicated ureteroscopy: evaluation of 23 patients. urology. 2011; 77:305-08. 19archivio italiano di urologia e andrologia 2018; 90, 1 double-j stent and perirenal fat stranding correspondence ercan ogreden, md (corresponding author) ercanogreden@gmail.com ural oğuz, md uraloguz@yahoo.com erhan demirelli, md erhandemirelli@yahoo.com giresun university, faculty of medicine, department of urology giresun, turkey erdal benli, md drerdalbenli@gmail.com ordu university, faculty of medicine, department of urology ordu, turkey özkan özen, md ozen@doctor.com giresun university, faculty of medicine, department of radiology giresun, turkey ogreden_stesura seveso 27/03/18 09:17 pagina 19 143archivio italiano di urologia e andrologia 2018; 90, 2 case report rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: presentation of a clinical case lucio dell’atti 1, simone scarcella 1, giulio argalia 2, lorenzo montesi 1, gian marco giuseppetti 2, andrea benedetto galosi 1 1 department of urology, polytechnic university of marche region, university hospital “ospedali riuniti”, ancona, italy; 2 department of radiology, polytechnic university of marche region, university hospital “ospedali riuniti”, ancona, italy. penile trauma represents a urological emergency characterized by the breaking of the albuginea tunic. a fast diagnosis and early surgical repair are the best treatments to avoid post-operative sequelae such as curvatures or deformities of the penis. an ultrasound evaluation may not be able to identify the injury in the tunica albuginea due to the edematous swelling of the penis and clots within the tear deteriorate the image contrast and can hide the injury. we here report a case study of successful management via surgical treatment for rupture of the cavernous body diagnosed by contrast-enhanced ultrasound in a young patient with penile trauma. key words: penile fracture; trauma; ultrasound; contrast enhanced ultrasonography. submitted 2 april 2018; accepted 29 april 2018 summary no conflict of interest declared. the penis reported a hypo-anechoic mass on the right cb, highly suspicious for hematoma but without certain interruption of the tunica albuginea (figure 1a, 1b). due to difficulty detecting the cause of acute hematoma, a ceus study was performed through insertion of a 19 gauge butterfly needle in the corpora cavernosa. ceus examination showed a tunica albuginea’s defect in the right cb with a concomitant area characterized by absence of contrast enhancement, described as compatible with hematoma (figure 1c). an emergency explorative surgery was immediately performed. after circumcision and degloving of the penile shaft we evacuated the hematoma and individuated a tear (maximum diameter 8 mm) in the right cb tunica albuginea. a running suture with absorbable 2-0 polydioxanone, was used for tear repair. no postoperative complications occurred and after 3 days the patient was discharged. discussion the use of us in traumas is now accepted in clinical practice as initial diagnostic evaluation of blunt abdominal trauma. however, up to date, ultrasonographic study of parenchymal lesions is characterized by the presence of frequent false negatives (3). penile traumas generally occur in the proximal or mid shaft of the erect penis, and concomitant lesions to the urethra occur in approximately 10-20% of patients (1, 2). penile fractures are urologic emergencies and require as soon as possible surgical repair. the diagnosis of penile fracture is usually established based on its characteristic history and physical findings (1). however, in all cases an ultrasonographic evaluation should be performed to define the localization of the lesion (2, 3). it is important considering that subcutaneous hematoma confined to the buck’s fascia, in absence of a tunica albuginea laceration, requires medical conservative treatment. only if a tunica albuginea tear is suspected or confirmed by us is mandatory to perform surgery within 24 from the traumatic event in order to reduce hospitalization, perioperative penile deviation and erectile dysfunction risk (2). the echo structure of the corpora cavernosa are homogeneous and doi: 10.4081/aiua.2018.2.143 introduction the fracture of the penis represents an urological emergency characterized by the breaking of the tunica albuginea and cavernous body (cb), frequently resulting in direct trauma, vigorous sexual intercourse, falls, forceful manipulation and masturbation (1). the diagnosis is usually delayed because of the patient’s embarrassment. a fast diagnosis and early surgical repair are the best treatments to avoid post-operative sequelae such as curvatures or deformities of the penis (2). we here report a case study of successful management via surgical treatment for rupture of the cb diagnosed by contrast-enhanced ultrasound (ceus) in a patient with penile trauma. case report a 25-years-old male patient presented to our emergency department for severe penile pain and suspicion of penile fracture after trauma during an act of masturbation. on presentation, the penis showed swelling, ecchymosis without deformity and urethrorrhagia. an ultrasonographic evaluation (us), 7-12 mhz multi-frequency linear probe, was performed first on a transversal plane, from the glans to the base of the penile shaft, and then completed with a longitudinal scan. us examination of dell'atti_stesura seveso 28/06/18 16:42 pagina 143 archivio italiano di urologia e andrologia 2018; 90, 2 l. dell’atti, s. scarcella, g. argalia, l. montesi, g.m. giuseppetti, a.b. galosi 144 identified as two hypoechoic circular structures surrounded by a thin hyperechoic line representing the tunica albuginea (4). in case of edematous swelling and massive clots formation close to the tunica defect, an only us in b-mode could be misleading (2). for a better characterization magnetic resonance imaging (mri) or ceus can improve tissue delineation and a better evaluation of the tunica albuginea integrity. mri, however, it is expensive and rarely used in the evaluation of acute penile trauma (1, 4). ceus, using micro-bubbles contrast agents and complementary harmonic pulse sequences can implements the diagnostic performance of the bmode, distinguish the parenchymal perfusion and defects. moreover, it improves patient tolerance, reduces radiation exposure and can be also safely performed in patients with renal impairment (4, 5). guidelines and recommendations on clinical practice of ceus represent current indications for administration of ultrasound contrast enhancement agents in different urogenital pathologies, including penile conditions (6). conservative management of penile trauma lead to increased rate of complications, such as penile curvature or erectile dysfunction, compared to immediate surgical intervention. ceus is noninvasive, widely viable and may help in the process of exact localization of the tear site in the tunica albuginea, especially in complex and atypical cases. references 1. nomura jt, sierzenski pr. ultrasound diagnosis of penile fracture. j emerg med. 2010; 38:362-365. 2. dell'atti l. the role of ultrasonography in the diagnosis and management of penile trauma. j ultrasound. 2016; 19:161-166. 3. topsøe jf, dencker d. investigation of penile conditions by ultrasound and contrast-enhanced ultrasound presentation of three clinical cases. ultrasound int open. 2015; 1:e78-79. 4. cokkinos dd, antypa e, kalogeropoulos i, et al. contrast-enhanced ultrasound performed under urgent conditions. indications, review of the technique, clinical examples and limitations. insights imaging. 2013; 4:185-198. 5. catalano o, aiani l, barozzi l, et al. ceus in abdominal trauma: multi-center study. abdom imaging. 2009; 34:225-234. 6. tranquart f, mercier l, frinking p, et al. perfusion quantification in contrast-enhanced ultrasound (ceus)--ready for research projects and routine clinical use. ultraschall med. 2012; (33 suppl1):s31-8. figure 1. (a): longitudinal and (b): transverse ultrasound image show an injury of the dorsal subtunical venous plexus in the absence of complete tunica disruption (white arrow). (c): late phase transverse ceus dual mode showing the avascular area representing hematoma and the tear of the right cavernous body as an interruption of the thin echogenic line of the tunica albuginea (white arrow). correspondence lucio dell’atti, md, phd dellatti@hotmail.com simone scarcella, md lorenzo montesi, md andrea benedetto galosi, md department of urology, polytechnic university of marche region, university hospital “ospedali riuniti” via conca 71, 60126 ancona, italy giulio argalia, md gian marco giuseppetti, md department of radiology, polytechnic university of marche region, university hospital “ospedali riuniti”, ancona, italy dell'atti_stesura seveso 28/06/18 16:42 pagina 144 323archivio italiano di urologia e andrologia 2017; 89, 4 case report right ectopic intrathoracic kidney: unusual clinical presentation in a young patient affected by scrotal varicocele lucio dell’atti, andrea benedetto galosi department of urology, university hospital “ospedali riuniti”, ancona, italy. intrathoracic kidney is a partial or complete displacement of the kidney above the hemidiaphragm into the mediastinal compartment of the thorax. it is usually seen as an incidental finding discovered on chest radiograph or abdominal ultrasound. however computed tomography consents the correct detection of intrathoracic masses and defines their shape, size, and extent. we here report a case of ectopic thoracic kidney in a 22-year-old man who had a long history of scrotal discomfort associated with right varicocele. frequently, this ectopia does not affect renal function and the stretched ureter provides good drainage. in literature, a small number of cases shows that varicocele is a possible mode of presentation of kidney tumors, but this is the first case of varicocele secondary to intrathoracic kidney ectopia. key words: renal ectopia; intrathoracic kidney; varicocele. submitted 16 august 2017; accepted 21 september 2017 summary no conflict of interest declared. urologist decided to perform a computed tomography (ct) study in order to evaluate the right kidney. ct scan showed the presence of ectopic kidney in the intrathoracic location on the right side with normal contrast excretion and nondilated pelvicalyceal system (figure 1). a magnetic resonance imaging (mri) study was also performed to assess normal functioning of the intrathoracic kidney (figure 2). the patient underwent right varicocelectomy with microsurgical subinguinal approach. after the procedure the patient was discharged without any surgical treatment after one day of safe observation period and followed-up on outpatient basis. discussion the first case of intrathoracic kidney was observed by wolfromm in 1940 using retrograde pyelography (4). since then, very few such cases (~200) have been reported. doi: 10.4081/aiua.2017.4.323 introduction intrathoracic kidney is a partial or complete displacement of the kidney above the hemidiaphragm into the mediastinal compartment of the thorax (1). this kidney ectopia is a rare clinical condition, and represents less than 5% of all renal ectopias (2). it is usually seen as an incidental finding discovered on chest radiograph or abdominal ultrasound (3). we here report an unusual case of ectopic thoracic kidney in a young man who had a long history of scrotal discomfort associated with right varicocele. case report a 22-years-old male patient presented to our department of urology for chronic scrotal pain and discomfort. on the physical examination, we found no signs of lymphadenopathy in the groin region and a grade 3 isolated right-sided varicocele, while abdominal examination revealed no palpable masses. a scrotal ultrasonography study, using a 10mhz linear probe, revealed a right-sided varicocele showing reflux flow confirmed by scrotal doppler ultrasonography. the patient underwent also renal and bladder ultrasonographic study; the right kidney was infeasible to study because of the impossibility to find it. however, the abdominal ultrasound study showed a normal left kidney and an empty bladder. figure 1. axial ct scan at th 8 level shows the right kidney situated in the right posterior inferior thorax (white arrow). figure 2. mri t2 sequence on sagittal plane confirms the presence of ectopic kidney in the intrathoracic location on the right side with nondilated pelvicalyceal system (white arrow). dell'atti.e$s_stesura seveso 03/01/18 09:49 pagina 323 archivio italiano di urologia e andrologia 2017; 89, 4 l. dell’atti, a.b. galosi 324 this ectopia shows male predominance and occurs more commonly on the left than on the right side (5). thoracic kidney has been described in four types: true ectopia, diaphragm eventration, diaphragmatic hernia, and traumatic diaphragm injuries (6). thoracic kidneys are usually asymptomatic and function normally (2, 3). the diagnosis is mostly incidental, which was also seen in our patient (5). the diagnosis is most usually made following a routine chest radiograph in which the affected hemidiaphragm is elevated slightly. historically, the role of excretory urography has been reported for the diagnosis of a thoracic mass, and its use eliminated the need for further investigation and intervention (6). however, this is now largely replaced by the ct, which consents the detection of intrathoracic masses, defines their shape, size, and extent. it can diagnose function, stones and visualize vascular and ureteral anatomy (7). mri has also been used to diagnose it (1). the etiology of a varicocele is undoubtedly multi-factorial and encloses two pathophysiological causes such as absent or incompetent venous valves, and the angle insertion of the left internal spermatic vein into the left renal vein. however, the etiology of a right-sided varicocele may be different. the pathological causes are: a tumor invasion, an extrinsic compression by an intraabdominal tumour, a damage of the venous drainage of the pampiniform plexus by venous thrombosis (8). in clinical practice an extended ultrasound examination is usually made for the reported association between a renal tumour presenting as an acute varicocele (8, 9). in literature, a small number of cases shows that varicocele is a possible mode of presentation of kidney tumors, but this is the first case of varicocele secondary to intrathoracic kidney ectopia (9). frequently, this ectopia does not affect renal function and the stretched ureter provides good drainage; therefore it does not need any further intervention (10). references 1. al-saqladi aw, akares sa. intrathoracic kidney in a child with literature review. saudi j kidney dis transpl. 2015; 26:349-54. 2. donat sm, donat pe. intrathoracic kidney: a case report with a review of the world literature. j urol. 1988; 140:131-33. 3. sözübir s, demir h, ekingen g, güvenç bh. ectopic thoracic kidney in a child with congenital diaphragmatic hernia. eur j pediatr surg. 2005; 15:206-9. 4. wolfromm mg. situation du rein dans l’eventration diaphragmatique droite. mem acad chirur. 1940; 60:41-47. 5. drop a, czekajska-chehab e, maciejewski r, et al. thoracic ectopic kidney in adults. a report of 2 cases. folia morphol. 2003; 62:313-16. 6. sidhu r, gupta r, dabra a, et al. intrathoracic kidney in an adult. urol int. 2001;66:174-5. 7. clarkson lm, potter s. case report. an unusual thoracic mass. br j radiol. 2009; 82:27-8. 8. lorenc t, krupniewski l, palczewski p, et al. the value of ultrasonography in the diagnosis of varicocele. j ultrason. 2016; 16:359-70. 9. el-saeity ns, sidhu ps. "scrotal varicocele, exclude a renal tumour". is this evidence based? clin radiol. 2006; 61:593-99. 10. jefferson kp, persad ra. thoracic kidney: a rare form of renal ectopia. j urol. 2001; 165:504. correspondence lucio dell’atti, md, phd dellatti@hotmail.com department of urology marche polytechnic university university hospital “ospedali riuniti”. via conca 71, 60126 torrette, ancona, italy andrea benedetto galosi, md department of urology, university hospital “ospedali riuniti”, ancona, italy dell'atti.e$s_stesura seveso 03/01/18 09:49 pagina 324 archivio italiano di urologia e andrologia 2016; 88, 3186 original paper testicular prosthesis: patient satisfaction and sexual dysfunctions in testis cancer survivors francesco catanzariti ¹, benedetta polito ², massimo polito ¹ 1 polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery, university hospital, ancona, italy; ² degree in educational and childhood psychology, salesian pontifical university, rome, italy. purpose: we studied patient satisfaction about sexual activity after prosthesis implantation using validated questionnaires with the aim to discover if testicular prosthesis could be responsible of sexual dysfunctions (erectile dysfunction or premature ejaculation). materials and methods: we evaluated a total of 67 men who underwent radical orchiectomy for testicular cancer and a silicon testicular prosthesis implantation from january 2008 to june 2014 at our hospital. these patients completed 5 validated questionnaires the day before orchiectomy and 6 months after surgery: the international index of erectile function 5 (iief5), the premature ejaculation diagnostic tool (pedt), the body exposure during sexual activities questionnaire (besaq), the body-esteem scale and the rosenberg selfesteem scale. we also evaluated 6 months after surgery any defects of the prosthesis complained by the patients. results: the questionnaires completed by patients didn’t show statistically significant changes for erectile dysfunction (p > 0.05) and premature ejaculation (p > 0.05). on the contrary the psychological questionnaires showed statistically significant change for the besaq (p < 0.001) and the body esteem scale (p < 0.001), but not for the rosenberg self-esteem scale (p > 0,05). a total of 15 patients (22.37%) were dissatisfied about the prosthesis: the most frequent complaint (8 patients; 11.94%) was that the prosthesis was firmer than the normal testis. conclusions: testicular prosthesis implantation is a safe surgical procedure that should be always proposed before orchiectomy for cancer of the testis. the defects complained by patients with testicular prosthesis are few, they don’t influence sexual activity and they aren’t able to cause erectile dysfunction or premature ejaculation. key words: testicular cancer; testicular prostheses; sexual dysfunction; patient satisfaction. submitted 26 march 2016; accepted 5 august 2016 summary no conflict of interest declared. most important period of life for sexual activity. the find of being affected by cancer of the testis and the following loss of the testis from the scrotal sac after orchiectomy are both responsible of a great psychological trauma in these young men, as described in literature (3). the implantation of testicular prostheses could be the solution, but even if good aesthetic results can be obtained, the presence of an artificial testis can be cause of shame and loss of self confidence during sexual activity. most of the papers in literature analyse patient satisfaction for testicular prosthesis just about aesthetic side (size, texture, weight, position), in our study, on the contrary, we studied patient satisfaction after prosthesis implantation about sexual activity using validated questionnaires with the aim to discover if testicular prosthesis could be responsible of any sexual dysfunction (erectile dysfunction or premature ejaculation). methods in lieu of a formal ethics committee, the principles of the helsinki declaration were followed. a total of 95 men underwent radical orchiectomy for testicular cancer from january 2008 to june 2014 at our hospital. of these patients, 67 underwent also a silicon testicular prosthesis implantation. this group of patient completed 5 validated questionnaires the day before orchiectomy and 6 months after surgery: the international index of erectile function 5 (iief-5) (4) to evaluate erectile function; the premature ejaculation diagnostic tool (pedt) (5) to assess premature ejaculation; the body exposure during sexual activities questionnaire (besaq) (6) a 28 item scale to measure anxiety during sexual activity and to evaluate desires and attempts to selectively avoid exposing one’s body (or parts of one’s body) to sexual partners; the body-esteem scale (7) and the rosenberg self-esteem scale (8) those are respectively 35 and 10 item scales created to measure self confidence of each patient towards sexuality and other general aspects of life. we also evaluated any defects of the prosthesis complained by the patients within 6 months after surgery: pain, abnormal size of the prosthesis (larger or smaller than the normal testis), prosthesis texture (firmer than the normal testis), sense of coldness of the prosthesis and doi: 10.4081/aiua.2016.3.186 introduction testicular cancer is one of the most frequent carcinoma in young males. in usa about 8000 men discover to be affected by testicular cancer every year and about 400 men of these die for this disease in a year, but fortunately the five-year survival rate of patients with testicular cancer is 95% (1). peak incidence is in the third decade of life for non-seminoma, and in the fourth decade for pure seminoma (2), so that this disease occurs during the catanzariti_stesura seveso 21/09/16 08:48 pagina 186 187archivio italiano di urologia e andrologia 2016; 88, 3 testicular prosthesis: patient satisfaction and sexual dysfunctions in testis cancer survivors abnormal position of the prosthesis in the scrotal sac (higher than the normal testis). surgical technique we used a silicone testicular prosthesis, with a protective suture guard for easy implantation. the size of the prosthesis to use was determined by ultrasound before surgery. all the implants were placed at the initial surgery via the inguinal approach and none was inserted after orchiectomy as a second procedure. the prosthesis was fixed in the scrotum with a non-absorbable suture. statistical methods all the scores of questionnaires before and after surgery and defects of the prosthesis complained by the patients were collected into a database. general descriptive statistics were measured for categorical and continuous variables. we performed student's t-test to compare mean score of all the five questionnaires (iief5, pedt, besaq, body-esteem scale and rosenberg self-esteem scale) before and after surgery. student's t-test was considered significant if < 0.05. statistical analyses were performed with ibm spss statistics base®. results from january 2008 to june 2014 we performed 95 orchiectomy for cancer of the testis and 67 (70.52%) patients of these decided also to undergo a silicone testicular prosthesis implantation. the remaining 28 (29.47%) patients refused testicular prosthesis for different reasons (table 1): 15 (53.57%) patients were afraid of infection and of the need of a second surgery to repair it; 10 (35.71%) patients didn’t care of remaining just with one testis in the scrotal sac; 3 (10.71%) patients didn’t want prosthesis because they couldn’t accept an artificial testis in the scrotal sac for psychological reasons (shame with the partner during sexual activity or bad memories evoked by self-palpation of the testicular prosthesis). age and marital status of patients who accepted testicular prosthesis implantation are described in table 2. between the 67 patients who underwent implantation two (2.98%) had inflammation with scrotal edema that healed in few days with anti-inflammatory and just one (1.49%) had an hematoma resorbed spontaneously without a second surgery. no major complications (extrusion or migration of the prosthesis) have been described (table 3). the questionnaires (table 4) completed by patients before and 6 months after surgery (mean follow up: 49.42 months) didn’t show statistically significant changes in the score for erectile dysfunction (p > 0.05) and premature ejaculation (p > 0.05). on the contrary the psychological questionnaires showed statistically significant change in the score for the besaq (p < 0.001) and the body esteem scale (p < 0.001), but not for the rosenberg self-esteem scale (p > 0.05). we also collected data about dissatisfaction of patients about the prosthesis and defects of the prosthesis complained by the patients within 6 months from surgery (table 5). fifteen patients (22.37%) were dissatisfied about the prosthesis: one (1.49%) patient reported chronic pain, six (8.95%) men reported abnormal size of the prosthesis compared to the normal testis (five patients reported that the prosthesis was larger than the normal testis and one patient reported that the prosthesis was smaller than the normal testis); eight (11.94%) patients reported that the prosthesis was firmer than the normal testis; two (2.98%) patients complained of sense of coldness of the prosthesis and four (5.97%) patients reported that the prosthesis was higher than the normal testis in the scrotal sac. discussion our study is one of the few studies available in the literature about testicular prosthesis satisfaction after orchiectono. (%) fear of infection 15 (53.57%) regardless of remaining with only one testicle 10 (35.71%) psychological reasons (shame with the partner or other) 3 (10.71%) table 1. reasons of refusal of testicular prosthesis implantation. no. (%) inflammation with scrotal edema 2 (2.98%) hematoma 1 (1.49%) table 3. complications of testicular prosthesis implantation. mean age 34.39 median age 33.00 standard deviation of age 11.24 no. marital status at surgery (%): single or divorced 45 (67.16) married or a partner in a steady relationship 22 (32.83) no. marital status 6 months later (%): single or divorced 48 (71.64) married or a partner in a steady relationship 19 (28.35) table 2. age and marital status of patients who accepted testicular prosthesis implantation. mean score ± sd p value change iief-5 tº 22.83 ± 2.46 t1 22.20 ± 2.84 p > 0.05 pedt tº 7.79 ± 5.30 t1 8.39 ± 5.27 p > 0.05 besaq tº 37.59 ± 11.5 t1 46.17 ± 10.91 p < 0.001 body esteem scale tº 85.14 ± 12.14 t1 77.77 ± 10.24 p < 0.001 rosenberg self esteem scale tº 27.30 ± 3.04 t1 26.45 ± 3.26 p > 0.05 table 4. score changes in the 5 questionnaires (iief-5, pedt, besaq, body esteem scale and rosenberg self esteem scale) at testicular prosthesis implantation (tº) and 6 months later (t¹). catanzariti_stesura seveso 21/09/16 08:48 pagina 187 archivio italiano di urologia e andrologia 2016; 88, 3 f. catanzariti, b. polito, m. polito. 188 my for testicular cancer. this is a great and serious lack in andrology if we consider that there is a great number of studies in literature about breast implants satisfaction after mastectomy. moreover most of these few studies (9, 10) analyse just satisfaction about aesthetic factors (size, texture, weight, position) but not about sexual activity after testicular prosthesis implantation. furthermore the few studies (11, 12) who analyse this aspect use simple and generic questions without using validated questionnaires. the only paper in literature analysing sexual activity after testicular prosthesis implantation with validated questionnaires is the study by turek et al. (13). these authors used the same psychological validated questionnaires (besaq, body-esteem scale and rosenberg self-esteem) that we used in our study but they didn’t use ieef-5 and pedt for the analysis of erectile dysfunction and premature ejaculation before and after testicular prosthesis implantation as we did. moreover their study is about testicular prosthesis implantation not only after orchiectomy for cancer of the testis but also for torsion, trauma or agenesis of the didimus so that turek et al. included in their work 73 children and 76 adults. our study demonstrated that testicular prosthesis implantation is a safe surgical procedure with few risks of complications as the other papers cited showed. the dissatisfaction rate is quite low (22.37%). the changes of the mean scores of psychological questionnaires are statistically significant for besaq and body esteem scale (p < 0.001) but not for the rosenberg esteem scale (p > 0.05) and the changes of the mean scores of iief-5 and pedt before and 6 months after orchiectomy are not statistically significant. these results demonstrate that a testicular prosthesis implantation modifies psychological approach towards the partners during sexual activity because some patients with testicular prosthesis feel shame of it and they try to not show the prosthesis during sexual activity. we also showed that testicular prosthesis doesn’t cause sexual dysfunction (erectile dysfunction or premature ejaculation). however our study has some limitations. first the follow up after testicular prosthesis implantation is short (6 months), second we didn’t compare sexual activity satisfaction of our patients with sexual activity satisfaction of patients those refused testicular prosthesis implantation. conclusions this study confirms that testicular prosthesis implantation is a safe surgical procedure that should be always proposed before orchiectomy for cancer of the testis because complications and defects complained by patients with testicular prosthesis are few. we also showed for the first time that implant doesn’t influence sexual activity and it isn’t able to cause erectile dysfunction or premature ejaculation even if further studies with a control group are needed to confirm this. references 1. cancer facts & figures 2014 and the nci surveillance epidemiology and end results (seer) database 1975-2010. 2. bosl gj, motzer rj.testicular germ-cell cancer. n engl j med. 1997; 337:242. 3. skoogh j, steineck g, cavallin-ståhl e, et al. feelings of loss and uneasiness or shame after removal of a testicle by orchidectomy: a population-based long-term follow-up of testicular cancer survivors. int j androl. 2011; 34:183-92. 4. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j of imp res. 1999; 11:319. 5. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565. 6. cash tf, maikkula cl, yamamiya y. baring the body in the bedroom: body image, sexual self-schemas, and sexual functioning among college women and men. electronic journal of human sexuality 2004, http://www.ejhs.org/volume7/bodyimage.html 7. franzoi sl, shields sa. the body-esteem scale. multidimensional structure and sex differences in a college population. j of pers assess. 1984; 48:173. 8. rosenberg m. society and the adolescent self-image. princeton, nj 1965; princeton university press. 9. adshead j, khoubehi b, wood j, rustin g. testicular implants and patient satisfaction: a questionnaire-based study of men after orchidectomy for testicular cancer. bju int. 2001; 88:559-62. 10. xylinas e, martinache g, azancot v, et al. testicular implants, patient's and partner's satisfaction: a questionnaire-based study of men after orchidectomy. prog urol. 2008; 18:1082-6. 11. incrocci l, bosch jl, slob ak. testicular prostheses: body image and sexual functioning. bju int. 1999; 84:1043-5. 12. yossepowitch o, aviv d, wainchwaig l, baniel j. testicular prostheses for testis cancer survivors: patient perspectives and predictors of long-term satisfaction. j urol. 2011; 186:2249-2252. 13. turek pj, master va. testicular prosthesis study group. safety and effectiveness of a new saline filled testicular prosthesis. j urol. 2004; 172:1427-30. no. (%) dissatisfaction of patients about the prosthesis 15 (22.37) defects of the prosthesis complained by the patients chronic pain 1 (1.49) abnormal size of the testicular prosthesis larger than the normal testis 5 (7.46) smaller than the normal testis 1 (1.49) testicular prosthesis firmer than the normal testis 8 (11.94) sense of coldness of the prosthesis 2 (2.98) testicular prosthesis higher than the normal testis in the scrotal sac 4 (5.97) table 5. dissatisfaction of patients about the prosthesis and defects of the prosthesis complained by the patients 6 months after surgery. correspondence francesco catanzariti, md frenzis83@gmail.com massimo polito, md polytechnic university of marche, faculty of medicine, department of odontostomatologic and specialized clinical sciences, urology clinic, department of general and specialized surgery,university hospital, ancona, italy benedetta polito, md educational and chlidhood psychologist, salesian pontifical university, rome, italy catanzariti_stesura seveso 21/09/16 08:48 pagina 188 stesura seveso archivio italiano di urologia e andrologia 2017; 89, 3238 case report distant subcutaneous spreading of fournier’s gangrene: an unusual clinical identification by preoperative ultrasound study lucio dell’atti, daniele cantoro, guevar maselli, andrea benedetto galosi department of urology, university hospital “ospedali riuniti”, ancona, italy. we present here the first case of successful management via preoperative ultrasonographic (us) study to detect a distant spreading of fournier’s gangrene (fg), which was happened in a 75-year-old man. us study showed the necrotizing infection in the periumbilical region distant 22 cm from the genital tract. a target incision of this periumbilical area and debridement of necrotic tissues was made. computed tomography (ct) is superior to ultrasonography to confirm the diagnosis of fg and support in surgical management, but a ct evaluation in patients with fg may be limited by the frequent presence of concurrent acute renal failure or patient hemodynamic instability. ultrasonography is an ideal technique for evaluating patients in bedside settings and can be routinely used in an emergency. key words: fournier’s gangrene; ultrasonography; computed tomography. submitted 6 march 2017; accepted 27 march 2017 summary no conflict of interest declared. body temperature 38°c. his blood count showed: haemoglobin level, 11.3 g/dl, white blood cell count, 17.000/mm3, and platelet count, 185.000/mm3. c-reactive protein level was 13 mg/dl, glucose 280 mg/ dl and creatinine level was 1.4 mg/dl. physical examination showed genital and perineal swelling, with erythema, edema and necrotic tissue over his scrotum with extension to the perineum (figure 1a); subcutaneous crepitation was also present. as part of the initial assessment, the patient received an us study that demonstrated marked thickening of the scrotal fascia with edema and high-amplitude echoes, as well as an area of subcutaneous gas in the periumbilical region was discovered distant 22 cm from the genital tract (figure 1b). however, a contrast-enhanced computed tomography (ct) was performed to differentiate areas of subcutaneous gas in the periumbilical and genital regions (figure 2). these findings were compatible with fournier gangrene. immediate broad spectrum antibiotic administration were initiated. although the initial vital signs were normal, he rapidly developed septic shock and was emergently taken to the operating room for aggressive surgical therapy including target incision on the periumbilical localization of infection and debridement of necrotic tissues until to be able to contain the progression of the gangrene. the patient was discharged after a flap reconstruction over the scrotum and 28 days of hospitalization. the clinical follow-up was 6 months and showed no signs of infectious or ischaemic complications. discussion fg was first described by jean alfred fournier, a french venereologist, in 1883. at that time, it was described as abrupt in onset with rapid progression to gangrene, but without a clear aetiology. the disease was noted to occur most commonly in young males (4). today, fg is most commonly found in middle-aged men (50-60 years) and, to a much lesser extent, in women (2). fg shows vast heterogeneity in clinical presentation, from insidious onset and slow progression to rapid onset and fulminant course. the characteristic of this necrotizing infection is gas production by the bacterial organisms, which can sometimes (but not always) be assessed on physical exam. however, doi: 10.4081/aiua.2017.3.238 introduction fournier’s gangrene (fg) is an acute, rapidly progressive necrotizing soft-tissue infection of the external genitalia and perineum (1). if not recognized and treated early, it is associated with high morbidity and mortality (2). in addition to the physical exam, there are several diagnostic procedures that can be used to evaluate this necrotizing infection. ultrasonographic (us) study allows to evaluate a scrotal pathology or soft tissue collection, and has been shown to identify subcutaneous gas, even prior to the overt development of crepitus on physical exam (3). we here report the first case of successful management via preoperative us study to detect a distant spreading of fg and allow proper surgical debridement. case report a 75-years-old male patient presented to our emergency department for generalized malaise, fever, appearance of edema, scrotal erythema, and pain symptoms in the perianal region not responsive to the most common anti-inflammatory drugs. the patient's medical history was remarkable for a history of hypertension and diabetes mellitus, diagnosed twenty years ago. on admission, his vital signs were as follows: blood pressure 135/80 mmhg; heart rate 98 bpm and dell'atti2_stesura seveso 01/10/17 15:42 pagina 238 239archivio italiano di urologia e andrologia 2017; 89, 3 distant subcutaneous spreading of fournier’s gangrene an early diagnosis is important because immediate surgical debridement and aggressive antibiotic treatment are indicated (1, 3). thorough physical examination and clinical assessment are favourable for a correct diagnosis of fg, but laboratory studies and imaging can be useful for risk stratification and to identify a potential source, respectively. radiological exams, including radiography, ultrasonography, and ct, can be of value to assess the extent of disease. radiography is the least costly option and can, in some cases, show hyperlucency representing soft-tissue gas before the accompanying clinical crepitations (3). traditionally, owing to its low cost, ready availability, us study has been the primary modality for imaging of the scrotum and can be utilized to examine the scrotal contents, and determine testicular involvement. overall, ct is superior to both ultrasonography and radiography to confirm the diagnosis of fg and support in surgical management. mcgillicuddy et al. in a review of ct findings on adult patients undergoing imaging for the evaluation of a soft-tissue infection reported a sensitivity of 86.3% and a specificity of 91.5%, with a negative predictive value of 85.5% (5). however, imaging evaluation in patients with fg may be limited by the frequent presence of concurrent acute renal failure (thus precluding the use of intravenous contrast material) or patient hemodynamic instability making transport to the radiology department unsafe. us study can be readily performed in bedside settings, which is of particular benefit to patients who are hemodynamically unstable but whose physical examination findings are equivocal (6). the characteristic us features of necrotizing infections comprise subcutaneous multiple hyperechoic foci that show reverberation artefacts, causing “dirty” shadowing that represents gas (figure 3) (1, 6). in conclusion we believe that us study constitutes an excellent minimally invasive alternative in such situations, reduces the extension of surgical field allowing a quick recovery and the risk of under treatment, can value alternate pathologies, such as epididymitis and torsion, does not expose patients to radiation, and does not require contrast-enhanced. based on our experience, a preoperative us study may identify easy and precisely distant foci of infection spreading avoiding wide surgical field and provide earlier control of disease. references 1. di serafino m, gullotto c, gregorini c, et al. a clinical case of fournier's gangrene: imaging ultrasound. j ultrasound. 2014; 17:303-6. 2. luján marco s, budía a, di capua c, et al. evaluation of a severity score to predict the prognosis of fournier's gangrene. bju int. 2010; 106:373-6. 3. levenson rb, singh ak, novelline ra. fournier gangrene: role of imaging. radiographics. 2008; 28:519-28. 4. fournier aj. gangrene foundroyante de la verge. semaine med. 1883; 3:344-46. 5. mcgillicuddy ea, lischuk aw, schuster km, et al. development of a computed tomography-based scoring system for necrotizing softtissue infections. j trauma, 2011; 70:894-9. 6. rajan dk, scharer ka. radiology of fournier's gangrene. ajr. 1998; 170:163-8. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com daniele cantoro, md daniele.cantoro@ospedaliriuniti.marche.it guevar maselli, md guevarmaselli@katamail.com andrea benedetto galosi, md galosiab@yahoo.it department of urology marche polytechnic university university hospital “ospedali riuniti” 71 conca street 60126 torrette, ancona, italy figure 1. genital and perineal swelling, with edema and necrotic tissue over the scrotum and perineum secondary to fournier’s gangrene (a). ultrasonographic probe reported an area of subcutaneous gas in the periumbilical region (distant 22 cm from the genital tract, b). figure 2. longitudinal scan of contrastenhanced computed tomography shows a distant subcutaneous spreading of fournier’s gangrene (yellow arrow). figure 3. the characteristic ultrasonographic features of necrotizing infection comprise subcutaneous multiple echoic spots that show reverberation artefacts, causing “dirty” shadowing that represents gas (yellow arrow). dell'atti2_stesura seveso 01/10/17 15:42 pagina 239 107archivio italiano di urologia e andrologia 2018; 90, 2 original paper effect on prostatic specific antigen by a short time treatment with a curcuma extract: a real life experience and implications for prostate biopsy andrea fabiani 1, carolina morosetti 2, alessandra filosa 3, emanuele principi 4, luca lepri 1, valentina maurelli 1, fabrizio fioretti 1, lucilla servi 1 1 unit of urology, surgical department, macerata hospital, area vasta 3, asur marche, italy; 2 clinical pathology, jesi (an), italy; 3 section of pathological anatomy, department of clinical pathology, macerata hospital, area vasta 3, asur marche, italy; 4 resident, urologic clinic, politechnic university of marche region, ancona, italy. introduction and objectives: psa elevation is associated with prostate cancer and it is used in screening programs for its diagnosis. it is one of the most common indications for referral to an urologist. there’s no consensus about what to do in psa elevation management. antibiotics, nutraceuticals or anti-inflammatories are commonly prescribed in daily practice. our objective was to verify the effect on the psa value of a short 30-day trial of a curcuma extract, than to discuss the implications in terms of reducing the number of prostate biopsies performed. patients and methods: we enrolled 50 consecutive patients admitted at our attention for a first psa over the level of 4 ng/ml or for a suspected psa rising defined as psa velocity (psav) > 0.75 ng/ml/years. they received treatment with curcuma extract, 2 tablets per day for 30 day. all patients received a second psa measurement and trus within 6 days from the end of the therapy. in case of psa reduction below 4 ng/ml, patients were reassured and invited to repeat a psa control over the time. when psa level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (trusbx). results: mean age of the patients was 64.56 ± 8.88 (range, 4281 years). prostate volume was 48.34 ± 15,77 ml (range, 18-80 ml). at visit 1, psa value was in mean 6,84 ± 3.79 ng/ml (range 2.93-21ng/ml). consequently, mean psa density value was 0.16 ± 0.16 (range 0.05-1.11). psa free and psa total ratio at baseline was 16.85 ± 3.9% (range 8-26%). at visit 2, the prostate volume did not change. total psa was 4.65 ± 2,67 ng/ml (range 1-16.82 ng/ml). psa free and psa total ratio (psaf/t) after treatment was 19.68 ± 5.35 % (range 7.8-29%). the differences of total psa and psaf/t between visit 1 and visit 2 were < 0.0001 and p < 0.0036, respectively. we performed 26 trusbx. prostate cancer was diagnosed in 6 cases, pin hg in 2 cases and non neoplastic findings in the remnants 18 patients. conclusions: use of the curcuma extract is able to lower the psa value after a 30-day intake period. we are not able to state that the reduction of psa after intake of this curcuma extract may exclude a prostate cancer. we need further studies to evaluate that. key words: prostatic specific antigen; curcuma; prostate biopsy; prostate cancer; nutraceuticals. submitted 31 december 2017; accepted 12 march 2018 summary no conflict of interest declared. introduction prostatic specific antigen (psa) may be raised as a result of prostate cancer, benign prostatic hyperplasia, prostatic infection or inflammation (1). a raised psa, over a value considered as normal (i.e. 4 ng/ml), usually prompts an ultrasound guided prostate biopsy (trusbx) even in absence of an abnormal digital rectal examination (dre). trusbx is a procedure performed in an ambulatory setting but it is characterized by a morbidity and a patient’s discomfort (2). the scientific literature does not define with certainty what should be the attitude to be taken by the urologist when he is managing a psa elevation, without symptoms and without anomalous findings to the dre. although the prescription of antibiotics or nutraceuticals or anti-inflammatories is widespread in daily practice, the guidelines recommend repeating psa over time, but this does not protect against performing biopsies with negative results for neoplasia. our objective was to verify the effect on the psa value of a short 30-day trial of a curcuma extract and if this effect could have an implication in terms of reducing the number of prostate biopsies. patients and methods patients and study design this was a prospective mono-institutional real-life study of 50 patients who were admitted at our attention for a first psa raised over the level of 4 ng/ml or for a suspected psa rising defined as psa velocity (psav) > 0.75 ng/ml/years. the exclusions criteria were any previous surgical prostatic treatment, any prior prostate biopsy, any therapy with 5-alpha-reductase inhibitors (5ari); (finasteride or dutasteride), any abnormalities detected at dre, any alterations in transrectal ultrasound prostate study (trus), any low urinary tract symptoms (luts) suggesting for urinary tract infection (uti) or recognized physiologic or iatrogenic cause of psa rising. patients enrolled received treatment with prostaflog®, 2 tablets per day for 30 day. they received a second psa doi: 10.4081/aiua.2018.2.107 fabiani_stesura seveso 28/06/18 16:36 pagina 107 archivio italiano di urologia e andrologia 2018; 90, 2 a. fabiani, c. morosetti, a. filosa, e. principi, l. lepri, v. maurelli, f. fioretti, l. servi 108 measurement and trus within 6 days from the end of the therapy. in case of psa reduction below 4 ng/ml, patients were reassured and invited to repeat a psa control over the time. when psa level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (trusbx). technical aspect and measurements at first line visit, patients in each group underwent a clinical evaluation with a dre and trus (end fire bk medical probe, 8808). prostate volume (ml) was measured according to the prostatic ellipsoid formula, multiplying the largest anteroposterior, transverse and cephalocaudal prostate diameters by 0.524. psa density (psad) (ng/ml/g) was defined as psa (ng/ml) at the enrolling visit time divided by prostate volume (ml). trus guided prostate biopsy was performed by a single experienced urologist and consisted in 12 cores of tissue targeting the peripheral zone at the apex, mid gland and the base on each side of the gland, whit an end fire needle access route. prostatic cores were evaluated by a single dedicated genitourinary pathologist. herbal product prostaflog® (naturmed srl) is a food supplement based on plant extracts of curcuma, boswellia, nettle and maritime pine, which promote the physiological functions of the prostate. component quantitative are, per dose (2 tablets): curcumin 500 mg, boswellia 300 mg, nettle 240 mg (betasitosterol intake 1 mg), maritime pine 200 mg (betasitosterol intake 150 mg), soy’s lecitine 70 mg. statistical analyses the statistical analysis was performed with med calc ver. 9.0.2.1 demo mode. for quantitative parameters were determined: mean, standard deviation, median. for all quantitative parameters, the normality or less of the distribution was preliminarily verified with d'agostinopearson test. if the normality was accepted, the data analysis was performed with parametric tests. otherwise with non-parametric tests. results as showed in table 1, mean age of the patients was 64.56 ± 8.88 (range, 42-81 years). prostate volume was 48.34 ± 15.77 ml (range, 18-80 ml). at visit 1, psa value was in mean 6.84 ± 3.79 ng/ml (range, 2.93-21 ng/ml). consequently, mean psa density value was 0.16 ± 0.16 (range 0.05-1.11). psa free and psa total ratio at baseline was 16.85 ± 3.9% (range, 8-26%). at visit 2, the prostate volume did not change. total psa was 4.65 ± 2.67 ng/ml (range, 1-16.82 ng/ml). psa free and psa total ratio (psaf/t) after treatment was 19.68 ± 5.35% (range, 7.8-29%). the differences of total psa and psaf/t between visit 1 and visit 2 were calculated. given the non-normal distribution of data, the analysis was performed with wilcoxon tests for paired data. the value of p was < 0.0001 for total psa. for psaf/t, p < 0.0036. the differences, therefore, between “before and after” were statistically significant. the power of the test was equal to 0.979 (used software g*power 3.0.10). total psa reduction was observed in 41 cases (82%). of 50 patients, 26 (52%) underwent trusbx because of persistent total psa elevation (9/50, 18%) or psa reduction but not under the cut off value of 4 ng/ml (17/50, 34%). hystopathologic results showed prostatic adenocarcinoma in 6 cases (6/26, 23%), in 10 (10/26, 38.5%) acute and chronic flogosis, in 8 (8/26, 30.8%) atrophic findings. monofocal pin hg was detected in 7.69% (2/26). gleason score was 3+3 in 67% (4/6), 4+4 in 17% (1/6). in case of positivity for prostatic cancer, psa was table 1. patients characteristics at visit 1 and visit 2. visit 1 visit 2 p (< 0.005) age (mean, years) 64.56 psa (mean, ng/ml) 6.84 4.65 < 0.0001 psa f/t (mean, %) 16.8 19.68 < 0.0036 prostate volume (mean, ml) 48.34 psa d 0.16 table 3. patient’s characteristics according to the prostatic biopsies results. biopsy positive for cancer biopsy negative for cancer biopsy not performed number of patients 6 20 24 mean psa (ng/ml) 6.48 6.19 2.89 mean psa d 0.14 0.17 0.16 mean psa f/t (%) 13.8 20.35 20.75 mean psa variation (ng/ml) 0.664* 2.43** 2.91 * mean value calculated on 5 cases with psa progression; in one case, psa total has been lowered by trial (0.5 ng/ml) ** all variation were negative. table 2. patient’s characteristics according to the psa value after trial *. patients with psa patients withwith psa patientswith psa lowered under 4 ng/ml lowered still over 4 ng/ml augmentation (n. 24) (n. 17) (n. 9) mean age (years) 63.4 65.29 66.2 mean psa variation (ng/ml) 2.91 2.71 0.70 mean prostatic volume (ml) 46.62 53.17 43.7 number positive biopsies 1 5 number negative biopsies 16 4 * not statistically significant differences were found. fabiani_stesura seveso 28/06/18 16:36 pagina 108 in elevation in 5 cases out of 6. only in one positive case, despite the total psa reduction of 0.5 ng/ml (from 9 ng/ml to 8,5 ng/ml), we have diagnosed an adenocarcinoma. this could mean that in 16 case of 17 (94%) who underwent trusbx for psa not sufficiently reduced, trusbx could not be performed based on the finding of psa reduction after the trial with curcuma extract. the mean of reduction was 2,94 ng/ml (range 0.26-16.2 ng/ml). the 44.5% (4/9) of patients in whom psa increased despite the extract intake had a neoplastic biopsy outcome, but in 2/9 biopsy findings was a pin hg. thus, the 67% of these (6/9) with a psa elevation after the trial, had a non benign biopsy result. in table 2 and table 3 we reported mean psa values according to results after trial and biopsies findings (negative or positive for neoplasm). all subjects included in the evaluation tolerated treatments with curcuma extract. no major complications were registered in case of ultrasound guided prostate biopsy. discussion a raised psa is one of the most common indications for referral to an urologist. however, before a psa test is undertaken, it is important that a frank and honest discussion should be had with the patient about the pros and cons of this blood test (3). in effect, psa measurement has marked a new era in the diagnosis of prostate cancer (4). this antigen, produced almost exclusively by the epithelial cells of the prostate, is not a cancer specific but an organ-specific marker (5). therefore, its serum levels may increase in non malignant conditions such as benign prostate hypertrophy, prostatic infection or inflammation, and prostate cancer (1). the histological architecture of the prostate is disturbed in both prostate cancer and prostatitis, causing greater psa leakage from the lumen of the prostatic glands into the circulation, increasing psa levels (6). because elevated serum psa is associated with prostate cancer and is used in screening programs for prostate cancer, patients with benign causes for elevation of serum psa present a challenge, especially when clinical evaluation and dre are unremarkable. twenty-five percent of men with psa levels from 4 to 10 ng/ml have a biopsy-proven prostate cancer, but 75% undergo unnecessary prostate biopsies, potentially leading to anxiety, discomfort and significant additional health care cost (7). in men with an increasing psa without clinical evidence of infection, a common rational is to treat a subclinical prostate infection, in order to reduce the psa value, avoiding unnecessary prostate biopsies (8). several years ago, already, scardino criticized the unjustified use of antibiotics in a group of patients with a psa elevation and no symptoms due to an uti. he emphasized the various inherent disadvantages associated with this approach, such as costs, toxicity, and the promotion of resistant bacterial species development that would have exposed the biopsied patient to more resistant and aggressive sepsis (9). also in 2014, fandella et al., showed no advantages due to an empiric antibiotic therapy (full dose fluoroquinolone for 20 days) to reduce psa values and avoid unnecessary biopsy in patients with psa levels between 4-10 ng/ml and no signs or symptoms of infections. they concluded that empiric use doesn’t seem to be of clinical benefit in absence of a clinical or laboratory evidence of infection and it might paradoxically be harmful. in their opinion, the repetition of a psa test before scheduling a biopsy remains the only acceptable approach (10). however, over the years, we have witnessed the presentation of various therapeutic approaches aimed at the intervention on the increase of psa before resorting to a biopsy. even the current increased recourse to multiparametric magnetic resonance imaging (mpmri) presents some aspects of accuracy and costs that make it impracticable in a first level of investigation (11-12). bozzini et al. recently reported their multicentric observational experience with beclomethasone dipropionate (bdp) rectal suppositories in case of nonbacterial prostatitis. the eightyfour percent of the patients enrolled underwent a 20-day course of therapy with bdp suppositories and serenoa repens (saw palmetto, dose of 320 mg per day). results showed an effect on symptoms related to prostatitis, but not on psa levels. authors declared that, as expected, psa levels remained stable since it is not a specific parameter for lower urinary tract inflammation (13). but, we know from the literature that inflammation of the prostate is an histological finding in almost every set of prostate biopsies, even when there are no signs of clinical prostatitis. as observed in our study population, this subclinical inflammation can cause psa elevation. furthermore, not the extent of inflammation is of importance, but the disruption of epithelial integrity caused by the inflammatory infiltrate. when confronted with a patient with an elevated psa level whose prostate biopsies reveal no malignancy but only inflammation, this concept can help in determining the need for quick repeat biopsies (14). instead, a psa assessment is more and more frequently prescribed also by general practitioners before being sent to the specialist. hence, the increasing interest in and use of complementary and alternative therapies (cam), especially nutraceuticals (15). in italy, 50% of the medications used for benign prostatic hyperplasia are phytotherapies, and in germany and other european countries, phytotherapies are first-line treatment for mild to-moderate benign prostatic hyperplasia (bph)/luts (16). the best-studied cam therapies for prostate disease include dietary modification, the aforementioned serenoa repens (saw palmetto), pygeum africanum, phytosterols, rye pollen extract and others, and vitamins and minerals, such as vitamin e and selenium (17-20). these products may be utilized alone or in association with antibiotics (21, 22) or anti-inflammatory drugs (23) exploiting in particular the rational of serenoa’s anti-inflammatory action (24). nevertheless, many of the studies are small, short, not randomized, and/or not placebo controlled and they are not focused on the effects on the psa. we have focused our study on curcuma for the growing attention that literature is addressing to this substance, given its proven effects on psa (25-26) and the interest of research on the possible use in the treatment of symptomatic prostatitis (27). in particular, we wanted to evaluate the possibility of obtaining an effect on psa in just a few weeks so as to reduce the patient's stress and reassure him about the 109archivio italiano di urologia e andrologia 2018; 90, 2 effect on prostatic specific antigen by a short time treatment with a curcuma extract: a real life experience and implications for prostate biopsy fabiani_stesura seveso 28/06/18 16:36 pagina 109 archivio italiano di urologia e andrologia 2018; 90, 2 a. fabiani, c. morosetti, a. filosa, e. principi, l. lepri, v. maurelli, f. fioretti, l. servi 110 need to deal with a diagnosis of cancer (28). the results obtained allowed us to verify how curcuma extract is able to lower psa. among the biopsies performed, we observed that the positive ones show a psa increasing or however a less marked reduction compared to patients with negative biopsy. as regards the analysis of the data, taking into account the number of biopsies carried out in patients treated with curcuma extract, it can of course be said that the treatment with this curcuma extract has greatly reduced the number of biopsies to be performed, with 26 biopsies performed respect the 50 that would have been made on the basis of the value of the initial psa, with a reduction of biopsy performed of 48%. we are certainly not able to state that the reduction of psa after intake of curcuma extract, in case of psa > 4 ng/ml and negative dre, can be used as “ex adiuvantibus criterion” for not perform unnecessary biopsy. however, considering the verified statistical power of the results obtained in our cohort, it is undeniable that this curcuma extract is able to lower the value of psa. in particular, when psa raise after trial, biopsy results are not benign in 67% of cases. we recognize that our study suffer from several limitations. first. the lack of a control group. in order to define the role of curcuma extract in reducing unnecessary biopsy, we should make a comparison with a placebo control group. second, to confirm our preliminary real life experience, concerning the rapid and significant reduction of psa, this curcuma extract must be employed in a more sized patient’s sample. third. not all 50 patients enrolled were biopsied. it should be recognized that the execution of the biopsy with a reduced psa, after rising, would have been outside the current indications (2). conclusions psa rising is one of the most common indications for urological evaluation. because elevated serum psa is associated with prostate cancer and is used in screening programs, patients with benign causes for elevation of serum psa present a challenge, especially when clinical evaluation and dre are unremarkable. use of curcuma extract is able to lower the value of psa. we are not able to state that the reduction of psa after trial may exclude a prostate cancer. we need further studies to evaluate that. it is desirable that the use of nutraceutical products in the treatment of prostatic pathology is correctly evaluated in appropriate studies so that, in particular, the use of curcuma does not remain a non-evidence-based practice. authors’ contributions all authors participated in the design and conduct of the study. all authors reviewed and approved the final version of the manuscript. references 1. tchetgen mb, oesterling je. the effect of prostatitis, urinary retention, ejaculation and ambulation on the serum prostate-specific antigen concentration. urol clin north am. 1997; 24:283-291. 2. fandella a, scattoni v, galosi a. italian prostate biopsies group: 2016 updated guidelines insights. anticancer res 2017; 37:413424. 3. kirby rs. raised prostate-specific antigen. in gontero p, et al. (eds.) problem based urology. chapter 24, springer-verlag london 2013; pp 185-189. 4. stamey ta, yang n, hay ar, et al. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987; 317:909-916. 5. mottet n, bastian pj, bellmunt j, et al. guidelines on prostate cancer. in: european association of urology guidelines. european association of urology 2014; p. 16 6. ornstein dk, smith ds, rao gs, et al. biological variation of total, free and percent free serum prostate specific antigen levels in screening volunteers. j urol. 1997; 157:2179-2182. 7. catalona wj, smith ds, ratliff tl, et al. measurement of prostate-specific antigen in serum as a screening test for prostate cancer. n engl j med. 1991; 324:1156-1161. 8. lorente ja, arango o, bielsa o, et al. effect of antibiotic treatment on serum psa and percent free psa levels in patients with biochemical criteria for prostate biopsy and previous lower urinary tract infections. int j biol markers. 2002; 17:84-89. 9. scardino pt. the responsible use of antibiotics for an elevated psa level. nat clin pract urol. 2007; 4:1. 10. fandella a, benvenuto s, guidoni e, et al. empiric antibiotics therapy for mildly elevated prostate specific antigen: helpful to avoid unnecessary biopsies? arch ital urol androl. 2014; 86:202204. 11. ahmed hu, bosaily aes, brown lc, et al. diagnostic accuracy of multi-parametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. lancet 2017; 389:815-822. 12. faria r, soares mo, spackman e, et al. optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost effectiveness analysis based on the prostate mr imaging study (promis). eur urol. 2018; 73:23-30. 13. bozzini g, provenzano m, buffi n, et al. an observational study of the use of beclomethasone dipropionate suppositories in the treatment of lower urinary tract inflammation in men. bmc urology; 2016; 16:25-32. 14. schatteman 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66:119-125. fabiani_stesura seveso 28/06/18 16:36 pagina 110 19. tiscione d, gallelli l, tamanini i, et al. daidzein plus isolase associated with zinc improves clinical symptoms and quality of life in patients with luts due to benign prostatic hyperplasia: results from a phase i-ii study. arch ital urol androl. 2017; 89:12-16. 20. pirola gm, puliatti s, bocchialini t, et al. efficacy of pollen extract in association with group b vitamins for pain relief in chronic prostatitis/chronic pelvic pain syndrome: a survey of urologists' knowledge about its clinical application. arch ital urol androl. 2017; 89:22-25. 21. magri v, trinchieri a, montanari e, et al. reduction of psa values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection. arch ital urol androl. 2007; 79:84-92. 22. cai t, tiscione d, gallelli l, et al. serenoa repens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients. arch ital urol androl. 2016; 88:177-182. 23. gallo l. the effect of a pure anti-inflammatory therapy on reducing prostate-specific antigen levels in patients diagnosed with a histologic prostatitis. urology. 2016; 94:198-203. 24. saidi s, stavridis s, stankov o, et al. effects of serenoa repens alcohol extract on benign prostate hyperplasia. pril (makedon akad nauk umet odd med nauki. 2017; 38:123-129. 25. gupta sc, patchva s, aggarwal bb. therapeutic roles of curcumin: lessons learned from clinical trials. aaps j. 2013; 15:195218. 26. ide h, tokiwa s, sakamaki k, et al. combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. prostate. 2010; 70:1127-1133. 27. morgia g, russo ig, urzì d, et al. a phase ii, randomized, single blinded, placebo-controlled clinical trial on the efficacy of curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii. arch ital urol androl. 2017; 89:110-113. 28. evans r, edwards agk, elwyn g. ‘it’s a maybe test’: men’s experiences of prostate specific antigen testing in primary care. brit j gen pract. 2007; 57:303-310. 111archivio italiano di urologia e andrologia 2018; 90, 2 effect on prostatic specific antigen by a short time treatment with a curcuma extract: a real life experience and implications for prostate biopsy correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it luca lepri, md lucalepri3@libero.it valentina maurelli, md valentinamaurelli@hotmail.it fabrizio fioretti, md, phd fa.fioretti@libero.it lucilla servi, md lucilla.servi@sanita.marche.it surgery department, urology unit, macerata hospital, asur marche area vasta 3, macerata, italy carolina morosetti, md carolina.morosetti@gmail.com clinical pathology, jesi, italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology macerata hospital, asur marche area vasta 3, macerata, italy emanuele principi, md principie@gmail.com resident, urologic clinic, politechnic university of marche region, ancona, italy fabiani_stesura seveso 28/06/18 16:36 pagina 111 15archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.15 results published in the first years of this century were obtained in patients treated in a time period spanning from 1995 to 2003, with a median age of 65 to 67 years, and no mention with regards to the presence of co-morbidities is available. in recent years, however, global life expectancy has increased in both sexes causing an expansion of the elderly segment of the population. ageing is one of the reason for increase in cancer incidence worldwide and, with regards specifically to bc, a 1.5-fold rise has been observed in subjects of 70 years of age and beyond (7). in the ageing population systemic diseases are concurrently diagnosed, namely, cardio-vascular, respiratory, metabolic, etc., therefore the need for chronic medications often represents the norm rather than the exception (8-9). the present study was aimed at documenting the association of advanced age together with the presence of co-morbidities on clinical outcomes of rc. materials and methods study design and patient population the study population consisted of 334 patients submitted consecutively to rc from 01/01/2005 to 31/12/2015 at our tertiary care center and teaching institution, the university of genova, italy. all the charts were examined and data were extracted with regards to pre-, intra-, and post-operative parameters. follow-up records and life status were retrieved from the internal follow-up database of our institute, the liguria hospitalization records, the regional mortality registry, and the genova cancer registry. patients who received neo-adjuvant or adjuvant chemotherapy were excluded from analysis, whereas patients who received salvage (post-rc) chemotherapy and/or radiotherapy were included. patients’ characteristics the recorded baseline patients’ characteristics were: age at rc (arc), gender, full medical history, 12 channel serum multiple analysis compound (smac), physical examination, self-reported comorbidities and chronic objective: to assess the joint effect of age and comorbidities on clinical outcomes of radical cystectomy (rc). methods: 334 consecutive patients undergoing open rc for bladder cancer (bc) during the years 2005-2015 were analyzed. pre-, periand post-operative parameters, including age at rc (arc) and charlson comorbidity index (cci), were evaluated. overall and cancer-specific survivals (os, css) were assessed by univariate and multivariate modelling. furthermore, a three-knot restricted cubic spline (rcs) was fitted to survival data to detect dependency between death-rate ratio (hr) and arc. results: median follow-up time was 3.8 years (iqr = 1.3-7.5) while median os was 5.9 years (95%cl = 3.8-9.1). globally, 180 patients died in our cohort (53.8%), 112 of which (62.2%) from bc and 68 patients (37.8%) for unrelated causes. after adjusting for preoperative, pathological and perioperative parameters, patients with cci > 3 showed significantly higher death rates (hr = 1.61; p = 0.022). the highest death rate was recorded in arc = 71-76 years (hr = 2.25; p = 0.034). after fitting an rcs to both os and css rates, two overlapping nonlinear trends, with common highest risk values included in arc = 70-75 years, were observed. conclusions: age over 70 years and cci > 3 were significant factors limiting the survival of rc and should both be considered when comparing current rc outcomes. key words: radical cystectomy; comorbidity; age; frail patient; elderly. submitted 12 november 2020; accepted 7 december 2020 introduction bladder cancer is one of the most common urological neoplasms and often requires multiple surgical treatment, as well as radical and invasive therapies (1-3). surgery in the form of radical cystectomy (rc) represents the mainstay treatment for organ-confined and locally advanced muscle-invasive bc (mibc). reference studies of rc showed long-term survival rates around 60% and 40% at 5 and 10 years, respectively (4-6). such age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients summary massimo maffezzini 1, vincenzo fontana 2, andrea pacchetti 3, federico dotta 3, mattia cerasuolo 3, davide chiappori 3, giovanni guano 3, guglielmo mantica 3, carlo terrone 3 1 department of urology, ospedale nuovo legnano, ospedale fornaroli magenta, milano, italy; 2 clinical epidemiology unit, irccs policlinico san martino, university of genova, genova, italy; 3 department of urology, irccs policlinico san martino, university of genova, genova, italy. archivio italiano di urologia e andrologia 2021; 93, 1 m. maffezzini, v. fontana, a. pacchetti, f. dotta, m. cerasuolo, d. chiappori, g. guano, g. mantica, c. terrone 16 need for medications, ecg and cardiologic assessment, anesthesiology assessment and american society of anesthesiology (asa) score, and clinical stage of disease. in addition, the charlson comorbidity index (cci) score was assigned based on the recorded data. clinical staging was based on the pathology report of staging trans-urethral resection and by chest and abdomen ct scan. additional tests (i.e. bone scans) were requested at the discretion of the treating physician. treatment all patients underwent rc with bilateral pelvic lymphadenectomy with the standard technique (4; 5; 6). briefly, in the male patient the bladder, prostate, and seminal vesicles, and in the female patient the bladder, uterus, ovaries and anterior wall of the vagina, were removed en bloc. pelvic lymphadenectomy included all the tissue overlaying the major pelvic vessels from the crossing of the ureter over the iliac vessels proximally to the internal inguinal ring distally, and from the genito-femoral nerve laterally to the obturator fossa medially. a form of urinary diversion (i.e. orthotopic reservoirs, ileal conduits, and uretero-cutaneostomy) was selected based on disease stage, arc, co-morbidities, and the surgeon’s preferences. additional data searched included pathological stage and grade, post-operative mortality (pom), 90-day post-operative incidence of complications using the claviendindo scale (10), and length of hospitalization. follow-up data comprised evidence of local and/or distant recurrence, need for further treatment, vital status, and cause of death. outcomes two survival outcomes were considered: os when all deceased patients were assumed to die from bc regardless of the certified cause of death, and css when patients died from causes other than bc were considered as censored at the date of death. patients’ characteristics taken into consideration for analysis were: arc, gender, cci score, baseline hemoglobin (hb) and creatinine (cr) levels, tumor size, lymph-node involvement, histotype, type of urinary diversion and complications. statistical analysis patients and disease-related prognostic factors were explored using descriptive statistics. continuous variables were described using median values and ranges of variation (min-max) and categorized according to statistically or clinically meaningful thresholds, namely quintiles for arc and a level of 10.0 g/dl, and 1.2 mg/dl for hb and serum cr, respectively. a cci score of 3 was used as a cut-off in order to separate lower from higher comorbid patients. all categorical factors were finally expressed in terms of absolute and relative frequencies. univariate survival comparisons were carried out using the kaplan-meier method and the statistical significance of each comparison was assessed by the log-rank test. the association of arc and cci score with survival probability was estimated using the cox regression modelling and expressed as death rate ratio (hr) and corresponding 95% confidence limits (95% cl). for each prognostic factor the cox regression allows to obtain an hr value adjusted for the potential confounding effect of other variables entered the same equation. the likelihood ratio test was applied to evaluate the statistical significance of each prognostic variable included in the cox model (11). in order to point out a non-linear dose-response relationship between arc and death rates, potentially blurred by the categorization process, a three-knot restricted cubic spline (rcs) was fitted to survival data with the cox regression equation. rcs is a flexible fitting procedure that allows the observed data to determine a smoothed functional form of dependency between the death rate (i.e., response) and a continuous prognostic variable (i.e., dose) (12). a two-tailed p-value < 0.05 was considered as significant. all analyses were performed using stata (stata corp. statistical software, release 14. statistical software. college station, tx: statacorp lp, 2015). table 1. frequency distribution of patients’ baseline characteristics. patients’ characteristics no. % age (yrs) at radical cystectomy (median, range) 71, 46-87 46-65 66 19.8 66-70 68 20.4 71-76 66 19.8 77-80 67 20.0 81-87 67 20.0 gender male 288 86.2 female 46 13.8 raw charlson comorbidity index ≤ 3 269 80.5 > 3 59 17.7 missing 6 1.8 tumor stage t0-t1 203 60.8 t2-t3 93 27.8 t4 38 11.4 histotype urothelial 263 78.7 non urothelial/rare variant 71 21.3 lymph node involvement n0 227 68.0 n1-n3 73 21.9 nx 34 10.2 preoperative hemoglobin ≤ 10.0 g/dl 10 3.0 > 10.0 g/dl 302 90.4 missing 22 6.6 preoperative creatinine ≤ 1.2 mg/dl 247 74.0 > 1.2 mg/dl 65 19.5 missing 22 6.6 early complications no 289 86.5 yes 45 13.5 late complications no 289 86.5 yes 45 13.5 urinary diversion ureterocutaneostomy/ileal conduit 203 60.8 orthotopic neobladder 131 39.2 days of hospitalization (median, range) 18, 2-80 2-13 88 26.4 14-17 73 21.9 18-23 94 28.1 24-80 79 23.7 whole sample 334 100.0 results baseline patients’ characteristics are listed in table 1. the median follow-up time was 3.8 years (iqr = 1.3-7.5 years). during the study period, a total of 180 patients died (53.8%), 68 (62.2%) from all causes whereas the remaining 112 patients (37.8%) from bc. the median os was 5.9 years (95%cl = 3.98.1 years). 288 (86.2%) patients were male whereas 46 (13.8%) patients were female. table 2 shows the results of univariate os analysis. arc, cci, tumor stage, histotype, preoperative hemoglobin and creatinine levels, and urinary diversion showed a strong association with os. a significant decreasing tendency in os probabilities was found to be associated to an increasing arc (p-value = 0.006). in addition, comorbid patients with cci score > 3 showed a twofold increased death rate (p-value < 0.001) when compared to patients with lower cci score (≤ 3). the cumulative effect on os of arc and cci score was assessed in a multivariate context by modelling data using the cox regression. after adjusting for gender, tumor stage, lymph node involvement, preoperative hb and cr levels, complications, and urinary diversion the significant association of arc and cci score with os was confirmed (table 3, model 1). specifically, patients with cci score > 3 showed a death rate excess of about 60% when compared to patients with cci score ≤ 3 (hr = 1.61; 95%cl 17archivio italiano di urologia e andrologia 2021; 93, 1 age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy... table 2. one-, threeand five-year overall survival probabilities (pr) estimated through the kaplan-meier method according to levels of study prognostic factors. patients’ overall survival characteristics follow-up one-year three-year five-year t d d% med iqr pr 95%cl pr 95%cl pr 95%cl p-value age at radical cystectomy 46-65 66 26 39.4 6.8 2.4-10.0 0.89 0.79-0.94 0.71 0.58-0.80 0.66 0.53-0.76 0.006 66-70 68 34 50.0 4.1 1.6-8.3 0.84 0.72-0.90 0.62 0.48-0.71 0.55 0.41-0.65 71-76 66 38 57.6 3.5 0.9-6.0 0.70 0.57-0.79 0.54 0.41-0.65 0.47 0.34-0.58 77-80 67 40 59.7 3.3 1.0-6.5 0.75 0.62-0.83 0.58 0.45-0.68 0.47 0.34-0.59 81-87 67 42 62.7 2.3 0.9-6.2 0.72 0.59-0.80 0.47 0.34-0.58 0.43 0.30-0.54 gender male 288 155 53.8 3.7 1.3-7.5 0.78 0.72-0.82 0.58 0.51-0.63 0.52 0.46-0.57 0.882 female 46 25 54.3 3.9 1.1-7.2 0.76 0.60-0.85 0.63 0.47-0.75 0.50 0.33-0.63 raw charlson comorbidity index ≤ 3 269 131 48.7 4.4 1.7-8.1 0.82 0.76-0.85 0.63 0.56-0.68 0.57 0.50-0.62 < 0.001 > 3 59 43 72.9 1.6 0.9-5.2 0.66 0.52-0.76 0.44 0.31-0.56 0.33 0.21-0.45 missing 6 6 100.0 0.1 0.0-0.2 0.17 0.00-0.51 0.17 0.00-0.51 0.17 0.00-0.51 tumor stage t0-t1 203 90 44.3 5.2 2.3-8.4 0.85 0.79-0.89 0.72 0.65-0.77 0.65 0.57-0.71 < 0.001 t2-t3 93 63 67.7 1.9 0.9-4.8 0.70 0.59-0.78 0.38 0.28-0.48 0.33 0.23-0.42 t4 38 27 71.1 1.3 0.4-4.2 0.58 0.40-0.71 0.34 0.19-0.48 0.28 0.14-0.42 histotype urothelial 263 137 52.1 4.0 1.5-8.3 0.81 0.75-0.84 0.62 0.55-0.67 0.53 0.46-0.59 0.032 non urothelial/rare variant 71 43 60.6 2.2 0.5-6.3 0.68 0.55-0.77 0.46 0.33-0.57 0.46 0.33-0.57 lymph node involvement n0 227 101 44.5 8.4 2.1-8.4 0.85 0.79-0.89 0.70 0.63-0.75 0.63 0.55-0.68 < 0.001 n1+n2 73 53 72.6 4.7 0.8-4.6 0.64 0.52-0.74 0.35 0.24-0.46 0.29 0.19-0.40 nx 34 26 76.5 5.2 0.4-5.2 0.59 0.40-0.73 0.32 0.17-0.48 0.29 0.15-0.44 preoperative hemoglobin ≤ 10 10 8 80.0 0.4 0.2-1.0 0.40 0.12-0.67 0.20 0.03-0.47 0.20 0.03-0.47 > 10 302 156 51.7 3.9 1.4-7.4 0.80 0.75-0.84 0.61 0.55-0.66 0.54 0.48-0.59 0.002 missing 22 16 72.7 1.5 0.2-8.2 0.59 0.36-0.76 0.41 0.20-0.60 0.32 0.14-0.51 preoperative creatinine ≤ 1.2 247 118 47.8 4.4 1.7-7.9 0.83 0.77-0.87 0.65 0.58-0.70 0.58 0.51-0.63 < 0.001 > 1.2 65 46 70.8 1.9 0.6-5.6 0.65 0.51-0.74 0.40 0.27-0.51 0.36 0.24-0.48 missing 22 16 72.7 1.5 0.2-8.2 0.59 0.36-0.76 0.41 0.20-0.60 0.32 0.14-0.51 early complications no 289 151 52.2 4.0 0.7-0.8 0.81 0.75-0.85 0.61 0.55-0.66 0.54 0.47-0.59 0.009 yes 45 29 64.4 1.7 0.4-0.6 0.58 0.42-0.70 0.42 0.27-0.55 0.40 0.25-0.53 late complications no 312 167 53.5 3.9 1.3-7.5 0.79 0.73-0.82 0.60 0.54-0.64 0.53 0.46-0.58 0.241 yes 22 13 59.1 2.1 0.9-4.5 0.68 0.44-0.83 0.41 0.20-0.60 0.41 0.20-0.60 urinary diversion ureterocutanostomy/ileal conduit 203 124 60.9 2.5 0.9-6.3 0.70 0.64-0.76 0.50 0.43-0.56 0.44 0.37-0.51 < 0.001 orthotopic neobladder 131 56 42.7 5.2 2.2-8.9 0.89 0.83-0.94 0.72 0.64-0.79 0.65 0.56-0.72 whole sample 334 180 53.9 3.8 1.3-7.5 0.78 0.73-0.82 0.58 0.53-0.64 0.52 0.46-0.57 . t: sample size; d/d%: number/percent of deceased patients; med: median of follow-up time (years); iqr: inter-quartile range (min-max); 95%cl: 95% confidence limits for estimated pr; p-value: probability level associated with the log-rank test. table 3. joint effect of age at radical cystectomy (arc) and charlson comorbidity index (cci) on overall and bladder cancerspecific survival estimated through the cox regression model. regression model patients’ characteristics overall survival cancer-specific survival deaths = 164 (52.7%) deaths = 101 (32.5%) hr 95%cl p-value hr 95%cl p-value 1 age at radical cystectomy 0.034 0.750 46-65 1.00 (ref.) 1.00 (ref.) 66-70 1.92 1.06-3.47 1.57 0.77-3.16 71-76 2.25 1.28-3.94 1.41 0.69-2.84 77-80 2.08 1.19-3.64 1.44 0.73-2.84 81-87 2.03 1.16-3.57 1.41 0.70-2.81 charlson comorbidity index 0.022 0.253 ≤ 3 1.00 (ref.) 1.00 (ref.) > 3 1.61 1.07-2.41 1.38 0.80-2.38 2 age at radical cystectomy 0.155 0.431 46-69 1.00 (ref.) 1.00 (ref.) 70-80 1.39 0.97-1.99 1.09 0.70-1.71 81-87 1.04 0.59-1.83 0.68 0.31-1.48 charlson comorbidity index 0.054 0.437 ≤ 3 1.00 (ref.) 1.00 (ref.) > 3 1.50 0.98-2.26 1.26 0.72-2.21 hr: death rate ratio adjusted for gender, tumor size, lymph nodes involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion; 95%cl: 95% confidence limits for hr; ref.: reference category; p-value: probability level associated with the likelihood ratio test. archivio italiano di urologia e andrologia 2021; 93, 1 m. maffezzini, v. fontana, a. pacchetti, f. dotta, m. cerasuolo, d. chiappori, g. guano, g. mantica, c. terrone 18 = 1.07-2.41; p-value = 0.022). an increase in death rates by arc was observed although the estimated doseresponse relationship appeared to be non-linear. in other words, assuming the death rate of the lowest arc category (46-65 years) as a reference (hr = 1.00) the highest rate was estimated in the intermediate category 71-76 years (hr = 2.25, 95%cl = 1.28-3.94). in order to point out better such a non-monotonic tendency, a cox model was fitted to os data after rearranging arc in three categories using 70 and 80 years as threshold values (table 3, model 2; figure 1). in this case, the intermediate category (70-80 years) showed a death rate which was about 40% higher than those in the other two categories (46-69 and 81-87 years), even though a figure 1. joint effect of age at radical cystectomy (arc) and raw charlson comorbidity index (cci) on life expectancy estimated through the cox regression model. overall survival probabilities are adjusted for gender, tumor size, lymph node involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion. figure 2. relationship between overall (os) and cancer specific (css) death rate ratio (hr) and age at radical cystectomy (arc) estimated using the cox regression model adjusted for gender, tumor size, lymph node involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion. smoothed hr point estimates were obtained by fitting three-knot cubic spline functions to os and css data. 19archivio italiano di urologia e andrologia 2021; 93, 1 age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy... loss in statistical power was pointed out (p-value = 0.155). in order to assess the influence of death on the relationship between arc and cci on survival, all previous analyses were repeated using cs mortality as an outcome. after fitting a three-knot rcs (figure 2) to both survival data series, two overlapping non-linear trends with common upmost risk values included in the arc group 70-75 years were pointed out. discussion multiple systemic diseases known as co-morbidities are diagnosed in the ageing men and women whom, in addition, are also exposed to the risk of developing cancer (89). notably, the presence of multiple systemic diseases necessitating chronic treatment can also undermine the results of cancer treatment. the effect of arc on the prognosis has been investigated previously. the conclusion reported so far are heterogeneous probably because, among other reasons, an objective threshold for dichotomizing this risk factor is not clearly identifiable and, accordingly, the issue remains controversial. nevertheless, in several studies increased arc showed an association with poor prognosis and survival (13-16) and although rc is currently performed in advanced age subjects a systematic review of the literature has outlined a decline in both os and css beginning at the age of 70 years (17). the association of comorbidities and survival after rc has also been investigated. the adult co-morbidity evaluation 27 instrument (ace-27) was used retrospectively in some studies (18-19) showing that co-morbidity score and pathologic stage of disease significantly correlated with reduced os. moreover, in the severe comorbidity group the number needed to harm was 6, that is, for every 6 patients dying after rc 1 death occurred due to co-morbidity per se. the cci score was used also and correlated with the outcomes of rc. koppie et al. classified rc patients with the age-adjusted cci (aa-cci) into three groups, namely i) low aa-cci score ≤ 2 , ii) moderate aa-cci score of 3 to 5 , and iii) a high aa-cci score > 5 (20). they found a median os time of 6.3 years, 3.9 years, and 1.7 years in the low, moderate, and high score groups, respectively. mayr et al. compared the asa score, the ace 27 instrument, the ecog scale, and the aa-cci (21). the authors found that none of the comorbidity indices were significant predictors for css, whereas each index was a significant predictor for cancer-independent mortality. importantly, based on arc and comorbidity a weighed prognostic risk model was developed where after 3 years 47% of the patients within the high-risk group died of causes other than bc, compared with 8% of patients within the low-risk group. in a recently published study, d'andrea et al. analysed a cohort of 46 patients with localized mibc who were considered unfit for rc or tt, and therefore sent to rt alone (22). their survival outcomes were compared to an equal number of patients treated with rc. after performing a propensity score analysis css and os of the patients undergoing rt were substantially the same as those who were treated with rc. the main findings of our study can be summarised as follows. first, after adjusting for known prognostic factors (table 1), patients in the age group 70-80 years showed the greater mortality risk. second, after eliminating the competitive risk of death due to causes different from bc, the curves of os and css show a parallel profile, as outlined by the rcs analysis (figure 2). finally, in patients with 70-80 years and cci score > 3 the mortality risk is remarkably higher (hr = 2.09, 95%cl = 1.23-3.53) than all other groups (figure 1). these findings reproduce closely what reported previously by other authors (21). certain limitations of our study are to be acknowledged. firstly, inherent to the retrospective nature of the investigation (study period: 2005-2015), although the comorbidities were listed at the moment of patient enrolment, the cci score was retrospectively assigned. secondly, the cci score has been commonly used to assess survival for various cancers since it offers a general patient evaluation. however, some particular conditions, i.e., hypertension, lung diseases in the absence of chronic obstructive disease, coronary artery disease in the absence of myocardial infarction, etc., are overlooked. thirdly, based on our dataset we were unable to address several concurrent factors that may have had an influence on survival such as a delay from symptoms-onset and diagnosis/treatment, nutritional status, and post-operative hospitalization in intensive care units, among others. on the other hand, the strengths of our study are to be acknowledged as well. two factors known to influence prognosis are addressed jointly, namely age and co-morbidities, and we were able to confirm their cumulative effect on survival after rc, as previously observed by other researchers. moreover, the study cohort consists in series of consecutive subjects treated at a single referral, high volume center, offering a homogeneous treatment to all patients, that is, rc alone (with pelvic lymphadenectomy), and no selection was made to exclude from treatment older and sicker patients. conclusions in conclusion, in the present cohort analysis of bc patients consecutively submitted to rc we were able to identify age 70-80 years and higher cci score (> 3) as significant factors limiting a better prognosis. although in principle we believe that surgery should not be precluded in the presence of advanced age and comorbidities both factors should be attentively considered when comparing outcomes after rc in contemporary series. implementation of ad hoc trials, focusing on these patients, should be encouraged. acknowledgments the authors thank peter de ville, ma, for linguistic revision. references 1. jue js, koru-sengul t, miao f, et al. neoadjuvant vs adjuvant chemotherapy for muscle-invasive bladder cancer: a propensity matched analysis. minerva urol nefrol. 2020 jan 30. archivio italiano di urologia e andrologia 2021; 93, 1 m. maffezzini, v. fontana, a. pacchetti, f. dotta, m. cerasuolo, d. chiappori, g. guano, g. mantica, c. terrone 20 2. capece m, spirito l, la rocca r, et al. hexaminolevulinate blue light cystoscopy (hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (nmibc): a retrospective analysis. arch ital urol androl. 2020; 92:17-20. 3. mantica g, simonato a, du plessis de, et al. the pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection. minerva urol nefrol. 2018; 70:594-597. 4. stein jp, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. j clin oncol. 2001; 19:666-75. 5. madersbacher s, hochreiter w, burkhard f, et al. radical cystectomy for bladder cancer today a homogeneous series without neoadjuvant therapy. j clin oncol. 2003; 21:690-6. 6. hautmann re, gschwend je, de petriconi rc, et al. cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. j urol. 2006; 176:486-92 7. dy gw, gore jl, forouzanfar mh, et al. global burden of urologic cancers, 1990-2013. eur urol. 2017; 71:437-446. 8. valderas jm, starfield b, sibbald b, et al. defining comorbidity: implications for understanding health and health services. ann fam med. 2009; 7:357-63. 9. sgrò p, sansone m, sansone a, et al. physical exercise, nutrition and hormones: three pillars to fight sarcopenia. aging male. 2019; 22:75-88. 10. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 11. marubini e, valsecchi mg. analyzing survival data from clinical trials and observational studies. john wiley and sons, new york, 1995. 12. harrell fe jr. regression modelling strategies. 2nd ed. new york, springer verlag, 2015. 13. clark pe, stein jp, groshen sg, et al. radical cystectomy in the elderly: comparison of clinical outcomes between younger and older patients. cancer. 2005; 104:36-43. 14. nielsen me, shariat sf, karakiewicz pi, et al. advanced age is associated with poorer bladder cancer-specific survival in patients treated with radical cystectomy. eur urol. 2007; 51:699-706. 15. donat sm, siegrist t, cronin a, et al. radical cystectomy in octogenarians--does morbidity outweigh the potential survival benefits? j urol. 2010; 183:2171-7. 16. chromecki tf, mauermann j, cha ek, et al. multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy. world j urol. 2012; 30:753-759. 17. fonteyne v, ost p, bellmunt j, et al. curative treatment for muscle invasive bladder cancer in elderly patients: a systematic review. eur urol. 2018; 73:40-50. 18. megwalu ii, vlahiotis a, radwan m, et al. prognostic impact of comorbidity in patients with bladder cancer. eur urol. 2008; 53:581-9. 19. fairey as, jacobsen ne, chetner mp, et al. associations between comorbidity, and overall survival and bladder cancer specific survival after radical cystectomy: results from the alberta urology institute radical cystectomy database. j urol. 2009; 182:85-92. 20. koppie tm, serio am, vickers aj, et al. age-adjusted charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. cancer. 2008; 112:2384-92. 21. mayr r, may m, martini t, et al. comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. eur urol. 2012; 62:662-70. 22. d'andrea d, soria f, zehetmayer s, et al. comparative effectiveness of radical cystectomy and radiotherapy without chemotherapy in frail patients with bladder cancer (published online ahead of print, scand j urol. 2020; 54:52-57. correspondence massimo maffezzini, md massimo.maffezzini@gmail.com department of urology, ospedale nuovo legnano, ospedale fornaroli magenta via papa giovanni paolo ii, 20025 legnano (italy) vincenzo fontana, md vincenzo.fontana@hsanmartino.it clinical epidemiology unit, irccs policlinico san martino, university of genova largo benzi 10, 16132 genova (italy) andrea pacchetti, md a.pacchetti.90@gmail.com federico dotta, md fededotta@hotmail.it mattia cerasuolo, md mattiacerasuolo@hotmail.it davide chiappori, md chiappori.davide@gmail.com giovanni guano, md giovanni.guano@gmail.com guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com carlo terrone, md carlo.terrone@med.uniupo.it department of urology, irccs policlinico san martino, university of genova largo benzi 10, 16132 genova (italy) archivio italiano di urologia e andrologia 2017; 89, 4282 original paper medical management in locally advanced and metastatic prostate cancer: does changes in treatment policy have any specific effect on psa levels? murat bagcioglu 1, cristian surcel 2, serkan ozcan 3, cristian mirvald 2, mehmet ali karagoz 4, mert ali karadag 1, emre huri 5, kemal sarica 6 1 urology department kafkas university faculty of medicine, kars, turkey; 2 fundeni clinical institute, center of urologic surgery and renal transplantation, bucharest, romania; 3 urology department artvin state hospital, artvin, turkey; 4 urology department ankara research and training hospital, ankara, turkey; 5 urology department hacettepe university, faculty of medicine, ankara, turkey; 6 urology department kartal research and training hospital, istambul, turkey. objective: androgen deprivation therapy (adt) is commonly used as a first-line treatment for locally advanced and metastatic prostatic cancer (pca). there is no consensus about which alternative treatment should be used after the failure of initial adt. we aimed to investigate the effect of changes in treatment on psa and testosterone levels. material and methods: a total of 120 patients with an established diagnosis of either locally advanced or metastatic pca in two different centers. depending on the type of medical and/or surgical management protocol planned at initial presentation, all cases were divided into three main groups as follows. group 1 (n: 80) included the patients who underwent medical management during whole follow-up period in whom the initial management protocol was later on switched to another medical treatment with different agents, group 2 (n: 20) included patients who were initially treated with a medical management protocol and switched to surgical castration during follow-up evaluation and lastly group 3 (n: 20) included the patients undergoing treated surgical castration as initial treatment modality without any further medical management protocol. results: evaluation of our data did clearly demonstrate a statistically significant difference between the initial and final psa as well as testosterone levels in group 1 cases. mean psa and testosterone levels increased significantly in these cases despite a change in hormonal therapy by using another agent for androgen deprivation. cases in group 2 and 3 cases did not show any statistically significant difference with respect to the mean psa as well as testosterone values during the same follow-up period. conclusions: our data clearly indicated that in case of a biochemical progression, switching into another alternative medical treatment was not effective enough in limiting the rising psa levels in a statistically significant manner when compared with the approaches of switching to surgical castration after initial medical treatment or continuing with regular and close follow-up after initial surgical castration alone. key words: prostats cancer; psa; hormonal therapy; treatment changes. submitted 21 october 2017; accepted 20 november 2017 summary no conflict of interest declared. introduction with a 1.1 million new cases being estimated in 2012, prostate cancer (pca) is the second most frequently diagnosed cancer in males and it represents the fifth leading cause of cancer deaths worldwide (1). although surgical and/or medical management principles are well established in all the stages of the disease, treatment options for cases with a life expectancy of less than 10 years remain still controversial. related with this issue, in addition to its successful outcomes as the first-line treatment option in patients with both locally advanced and metastatic pca, androgen deprivation therapy (adt) has also proven to be successful as the second most common treatment after surgery for localized pca (2, 3). however, there is an ongoing controversy regarding the optimal use of adt in these cases where medical [combined androgen blockade (cab), gonadotropin-releasing hormone (gnrh) agonists alone, gnrh antagonists] or surgical (bilateral orchiectomy) options are being applied with different success as well as undesired effect rates. among the above mentioned options, gnrh agonists are generally preferred as adt due to their reduced psychological morbidity and almost equivalent efficacy to surgical castration (2) but these agents have some adverse effects including testosterone surges, bone loss, and metabolic complications. moreover, biochemical progression which may end up with an advanced stage has also been reported in the majority of cases undergoing medical therapy with gnrh agonists. thus, it seems clear that initial adt may result in an unsuccessful outcome and again there is no established approach in such cases with adt failure. last but not least, there is also no consensus regarding the type of the second-line treatment (another gnrh agonist or gnrh antagonist, antiandrogens, estrogens, steroids, or orchiectomy) to be used in these cases. in this study we aimed to investigate the effect of changes in medical treatment on prostate specific antigen (psa) and testosterone levels. doi: 10.4081/aiua.2017.4.282 bagigoglu_stesura seveso 03/01/18 12:19 pagina 282 283archivio italiano di urologia e andrologia 2017; 89, 4 medical management in locally advanced and metastatic prostate cancer: does changes in treatment policy have any specific effect on psa levels? materials and methods a total of 120 patients with an established diagnosis of either locally advanced or metastatic pca in two different centers between 2003 and 2014 were included into the study program. the study protocol was approved by the local ethics committee (number 2680576354-050-99/97), and a written informed consent stating all details of the investigation protocol was obtained from all of patients before including data from the hospital registry files. in addition to the clinical stage of pca according to tnm classification via digital rectal examination, other relevant data were obtained by findings of computed tomography, transrectal ultrasonography, bone x-ray and bone imaging using 99mtc-methylene-diphosphonate from patient registry files. regarding the inclusion criteria for the study protocol, patients with an initial diagnosis of locally advanced prostate cancer who are not planned for radical prostatectomy or patients with metastatic pca were included into the study program. within the framework of inclusion criteria, in addition to the cases undergoing medical androgen deprivation by applying initial treatment protocols with leuprolide acetate 11.25 mg (lucrin depot, abbott laboratories, saint laurent, qc, canada), goserelin 10.8 mg (zoladex, astrazeneca canada, missisauga, on, canada) or leuprolide acetate 22.5 mg (eligard, astellas pharma inc., tokyo, japan) and bicalutamide 50 mg (casodex, astrazeneca canada) as preferred antiandrogen agents, data were also obtained from the cases undergoing surgical castration. all cases had an adequate long-term follow-up data for a reliable interpretation. on the other hand, exclusion criteria included the patients with organ confined prostate cancer without any local extension and/or metastasis and that undergoing simultaneous radiation therapy. all data derived from the patient registry files were carefully searched and recorded for the clinical variables including age at diagnosis and initial treatment of prostate cancer, gleason score values, presence or absence of bone metastasis (single, multiple or no metastasis), timing and other characteristics of medical management with gnrh agonists (primary treatment and secondary treatment) and disease status (assessment of biochemical recurrence, serum psa values, testosterone levels). biochemical recurrence was defined as a psa value of at least 2 ng/ml followed by another two consecutive rises in serum psa. depending on the type of medical and/or surgical management protocol planned at initial presentation, all cases were divided into three main groups as follows. group 1 (n: 80) included the patients who underwent medical management during whole follow-up period in whom the initial management protocol was later on switched to another medical treatment protocol with different agents; group 2 (n: 20) included patients who were initially treated with a medical management protocol and switched to surgical castration during follow-up; group 3 (n: 20) included the patients undergoing surgical castration as the initial treatment modality without any further change of medical management protocol. during the follow-up period, all patients were seen and evaluated regularly at every 3 months. patients in all groups were comparatively evaluated with respect to the age, bone metastasis and gleason score values. the results are presented as mean ± standard deviation (sd). statistical significance analysis was obtained by using the statistical package for the social science (spss, inc., chicago, illinois, usa) version 15.0. mann-whitney u test and wilcoxon tests were used for the statistical analyses. a p value of less than 0.05 was considered to be statistically significant. results of all the 120 patients included and evaluated, the overall mean age value at the time of initial diagnosis was 67.0 ± 1.5 years, and the mean follow-up duration was 51.3 ± 3.1 months (table 1). the overall mean prostate gland volume prior to treatment was 40.21 ± 1.82 ml. while the mean psa value at the time of diagnosis was 136.88 ± 9.66 ng/ml; gleason 7 and ecog 1 were the most frequent scores in our study group. out of 120 patients 24 had locally advanced pca, 36 had bone metastasis, 32 had lymph node metastasis, 16 had visceral metastasis and lastly 12 were with unknown extension (table 2). as stated above, in group 1 medical management was initiated with a certain protocol in 80 patients (66.6%) and the medical management protocol was switched to another medical protocol with different agents after protable 1. patients’ demographics. group 1 group 2 group 3 p value prostate volume 39.31 ± 2.11 41.14 ± 5.48 43.04 ± 5.38 0.831 age (at biopsy) 67.48 ± 1.95 62.80 ± 2.57 69.20 ± 4.22 0.587 psa level (at biopsy) 135.61 ± 12.16 154.22 ± 30.07 124.89 ± 14.63 0.683 psa: prostate specific antigen. table 2. clinical stage of pca, hormonal therapy first and second treatment. clinical stage n° percent locally advanced, m0 24 20.0 m+, bone disease 36 30.0 m+, lymph node disease 32 26.7 m+, visceral disease 16 13.3 m+, unknown extension 12 10.0 total 120 100.0 hormonal therapy first treatment leuprolide 20 16.7 goserelin 48 40.0 triprorelin 32 26.7 surgical castration 20 16.7 total 120 100.0 hormonal therapy second treatment leuprolide 28 23.3 goserelin 20 16.7 triprorelin 20 16.7 histrelin 12 10.0 surgical castration 40 33.3 total 120 100.0 adt: androgen deprivation therapy. bagigoglu_stesura seveso 03/01/18 12:19 pagina 283 archivio italiano di urologia e andrologia 2017; 89, 4 m. bagcioglu, c. surcel, s. ozcan, c. mirvald, m. ali karagoz, m. ali karadag, e. huri, k. sarica 284 gression. in group 2, 20 patients (16.6%) were initially treated with a medical treatment protocol but the management plan was switched to surgical castration after progression during follow-up. last, 20 patients (16.6%) in group 3 were treated with surgical castration and followed up regularly without any further change of treatment protocol. there was no statistically significant difference between the groups with respect to the mean age, mean initial psa levels and gleason score values as well as the mean prostate volume values (p > 0.05). regarding the agents used within the framework of medical management plan in groups 1 and 2, 20 patients received leuprolide acetate as the initial medical agent for androgen deprivation; 48 patients with goserelin and 32 patients with triptorelin (table 2). as stated above, the initial hormonal management plan was changed and continued with another medical agent after assessing progression of the disease status: 28 patients were treated with leuprolide, 20 patients with goserelin, and 20 patients with triptorelin and other 12 patients with histrelin. on the other hand as shown in table 2, a total of 40 patients were treated with surgical castration in group 2, as secondary treatment after assessment of progression, and in group 3, as initial treatment. maximum androgen blockage was applied in 44 patients and antiandrogens were administered only to prevent flare-up phenomenon in other 76 patients (table 3). no adjuvant treatment was administered in 84 patients, whereas zoledronic acid was administered in 28 cases due to bone problems and denosumab was added to the initial treatment in another 8 cases. of all these cases, although 12 patients continued their management with zoledronic acid, management was switched to denasumab in 44 cases (table 3). time intervals of the periods of treatment are shown in table 4 and figure 1. evaluation of our data did clearly demonstrate a statistically significant difference between the initial and final psa as well as testosterone levels in group 1 cases (table 5). mean psa and testosterone levels increased significantly in these cases despite a change in hormonal therapy by using another agent for androgen deprivation. in other words, switching to another medical management protocol with another agent did not affect the rising psa level in these cases. in group 2 and 3 cases mean psa and testosterone values did not show any statistically significant difference during the same follow-up period. discussion an estimated 242 000 men were diagnosed with pca in 2012 only in the united states, and probably 28 000 of table 5. first-last psa levels and first-last testosterone levels for groups. first psa level last psa p value first testosterone last testosterone p value on treatment level level on treatment level group 1 5.16 ± 0.59 9.20 ± 0.97 0.000 27.08 ± 1.45 38.50 ± 1.66 0.000 group 2 7.36 ± 1.00 7.56 ± 1.33 0.686 30.30 ± 4.4x 41.5x ± 3.90 0.223 group 3 6.77 ± 1.45 9.01 ± 1.37 0.138 24.90 ± 1.88 31.30 ± 5.31 0.225 psa: prostate specific antigen. figure 1. timing of treatments. table 4. timing of treatments. from biopsy from first psa from switch of psa at switch to first psa on to switch of treatment to treatment (month) treatment (month) last psa (month) mean mean mean mean statistic std. error statistic std. error statistic std. error statistic std. error group 1 8,20 .691 22.40 1.963 26.65 3.761 7.6600 .75248 group 2 11,00 2.280 25.00 4.301 24.60 5.501 7.8060 1.50512 group 3 7.60 .245 60.40 5.591 table 3. antiandrogen treatment and adjuvant treatment in first and second period of treatment. antiandrogen in first treatment period n° percent flare-up prevention 76 63.3 max. adt 44 36.7 total 120 100.0 antiandrogen in second treatment period no 32 26.7 yes 72 60.0 surgical castration 36 13.3 total 120 100.0 adjuvant treatment in first treatment period none 84 70.0 zolendronic acid 28 23.3 denosumab 8 6.7 total 120 100.0 adjuvant treatment in second treatment period none 64 53.3 switched to denosumab 44 36.7 zolendronic acid 12 10.0 total 30 100.0 adt: androgen deprivation therapy. bagigoglu_stesura seveso 03/01/18 12:19 pagina 284 285archivio italiano di urologia e andrologia 2017; 89, 4 medical management in locally advanced and metastatic prostate cancer: does changes in treatment policy have any specific effect on psa levels? these men will die from the disease (4, 5). for over two decades, bilateral orchiectomy and gnrh analogues have been accepted as equivalent therapeutic options (6). gnrh are largely preferred by urologists and patients for the treatment of advanced and metastatic pca, although they have similar efficacy to a bilateral orchiectomy. although an initial response to medical castration is often reported, resistance to gnrh agonists in some patients with pca has been previously reported (7, 8). after failure of the initial hormonal therapy, the second line therapy has not yet been completely established and there is no consensus on which alternative treatment alternative should be used (e.g., switching to another gnrh agonist or gnrh antagonist or using antiandrogens, estrogens, steroids, or surgical castration). patients with carcinoma of the prostate eventually progress despite castration. continuing maximal testicular androgen suppression is debatable in this situation (9). these data have been argued by 2 studies that established only a survival advantage in patients continuing gnrh analogues during secondand third-line therapies in case of failure (10, 11). the modest potential benefits of a continuing castration outweigh the minimal risk of treatment despite lack of prospective data in the literature. in addition, all treatment options have been conducted in men under androgen-suppression therapy and such therapy should be continued indefinitely in these patients. even though we did not determine the survival benefits in second-line therapy, we noted ongoing psa progression in all three groups. this progression was statistically significant in patients who had been previously treated with medical treatment and switched to another medical alternative. unlike surgically castrated patients, it seemed that switching to another medical castration regime increased the speed of the biochemical progression process. this ongoing biochemical progression in all three groups may be explained by the aggressive tumor biology of the cases. in fact, as noted previously, the initial psas (> 100 ng/ml) and gleason scores of our patients were very high. taking all these facts into account, in this present study including a large group of cases from two different centers we aimed to evaluate the possible effects of changes in treatment policies during follow-up on the prostatespecific antigen (psa) in cases with locally advanced prostate cancer. evaluation of our results clearly revealed that biochemical progression may occur despite a change in treatment policy by switching to another medical treatment modality even in patients undergoing maximal androgen blockade as initial treatment protocol. although a change in the medical therapy protocol by using another antiandrogen agent was not found to prevent the progression and rise in both psa as well as testosterone values in these cases, possible disease progression seemed to be stabilized in patients in group 2 and group 3 who underwent surgical castration initially after failure of initial medical management or directly as initial approach. in other words, we were able to show that after biochemical progression, switching to surgical castration after a certain period of medical treatment or continuing with surgical castration alone stabilized psa progression in comparison with medical castration plus another medical castration regimen. on the other hand, when we evaluated testosterone levels in cases of all study groups, these values were found to be at castrate levels despite rising psa values. the biochemical progression states was found to be independent of androgen receptors in the three groups. regarding the management of metastatic prostate carcinoma after the failure of initial hormonal therapy, the guidelines of european association of urology (eau) have recommended that these patients should not be started a second-line therapy unless their testosterone serum levels are < 50 ng/dl (level of evidence: 4 a, grade of recommendation: a) and psa serum levels are > 2 ng/ml to ensure correct interpretation of therapeutic efficacy (level of evidence: 4 b, grade of recommendation: b). we used both recommendations in our patients when switching to another treatment alternative (2). the eau panel on this issue also claimed that there is no evidence for the treatment of non-metastatic castration resistant prostate cancer outside of a clinical trial (level of evidence: 3, grade of recommendation: a) and that men who are under maximal androgen blockade should stop antiandrogen therapy once progression of psa is occurred (level of evidence: 2a, grade of recommendation: a). there is not any clear-cut recommendation for the use of the most effective drug as the second line treatment (i.e., chemotherapy or hormone therapy) since no reliable predictive factors exist (level of evidence: 3, grade of recommendation a). our choice in continuing with another maximal androgen blockade protocol in group 1 patients without stopping the antiandrogen therapy was based on the lack of clear evidence about this topic in the literature despite a grade a recommendation for cessation of antiandrogen therapy. as stated above, we used sole psa progression in our study in order to evaluate the response of the patients to the given treatment alternatives. even though there is no consensus about the duration as well as the degree of a decline in psa level, many research studies have used psa as a marker of response like in our study. although psa is a rapid screening tool to evaluate the effect of newer molecules, there is an ongoing and conflicting debate about the role of psa as a surrogate marker in initial treatment failures of prostate carcinoma. tricom and sipuleucel-t studies have revealed a statistically significant overall survival without any psa change and raise questions about the value of psa response for noncytotoxic, non-hormonal drugs (12-14). our current study may have some limitations, in particular not including the psa velocity and doubling time and the cancer-specific and disease-specific survival rates of the patients. furthermore, we failed to conduct a cost effectiveness and quality of life analysis in and among the 3 groups. on the other hand, the retrospective nature of our investigation was also another limitation. there should have been be strict follow-up criteria for evaluating these parameters, but we were unable to perform it due to low sociocultural level of the patients in both bagigoglu_stesura seveso 03/01/18 12:19 pagina 285 archivio italiano di urologia e andrologia 2017; 89, 4 m. bagcioglu, c. surcel, s. ozcan, c. mirvald, m. ali karagoz, m. ali karadag, e. huri, k. sarica 286 turkey and romania. in our opinion, if the study was designed as prospective randomized study the power of our investigation would have been much improved. on the other hand this type of study are lacking in the literature about second-line treatments after initial failure of the first treatment of pca. however despite the above mentioned limitations we believe that our study with a reasonably longer follow-up period of approximately 5 years in a relatively large group of cases from two centers of different countries (i.e., turkey and romania) will be contributive enough to the existing data in about this topic. conclusions in the light of our findings and of the so far reported data in the literature, there is an ongoing controversy concerning the assessment and application of the secondline treatment modalities in patients with metastatic and non-metastatic, castration-resistant prostate carcinoma. our data clearly indicated that in case of a biochemical progression, switching into another medical treatment alternative was not effective enough in limiting the rising psa levels in a statistically significant manner when compared with the approaches of switching to surgical castration after initial medical treatment or continuing with regular and close follow-up after an initial surgical castration alone. however we believe that further prospective randomized studies with larger group of cases and additional predictive parameters are certainly required in this specific group of cases to outline a true and effective algorithm. references 1. torre la, bray f, siegel rl, et al. global cancer statistics, 2012. ca cancer j clin. 2015; 65:87-108. 2. mottet n, bellmunt j, patient eb, et al. eau 2015 guidelines. guidelines on prostate cancer. 3. cooperberg mr, grossfeld gd, lubeck dp, carroll pr. national practice patterns and time trends in androgen ablation for localized prostate cancer. j natl cancer inst. 2003; 95:981-989. 4. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin. 2012; 62:10-29. 5. sutcliffe s, colditz ga. prostate cancer: is it time to expand the research focus to early-life exposures? nat rev cancer. 2013;13:208518. 6. zoladex prostate study group.goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. urology. 1995; 46:220-226. 7. eisenberger ma, blumenstein ba, crawford ed, et al. bilateral orchiectomy with or without flutamide for metastatic prostate cancer. n engl j med. 1998; 1339:1036-1042. 8. curry ea, sweeney cj. resistance to luteinizing hormone releasing hormone agonist therapy for metastatic prostate cancer. j urol. 2002; 168:193. 9. manni a, bartholomew m, caplan r, et al. androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. j clin oncol. 1998; 6:1456-1466. 10. hussain m, wolf m, marshall e, et al. effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase ii chemotherapy trials for hormonerefractory prostate cancer: a southwest oncology group report. j clin oncol. 1994; 12:1868-1875. 11. taylor cd, elson p, trump dl. importance of continued testicular suppression in hormone-refractory prostate cancer. j clin oncol. 1993; 11:2167-2172. 12. kantoff pw, schuetz tj, blumenstein baet al. overall survival analysis of a phase ii randomized controlled trial of a poxviralbased psa-targeted immunotherapy in metastatic castration-resistant prostate cancer. j clin oncol. 2010; 28:1099-1105. 13. small ej, schellhammer pf, higano cs, et al. placebo-controlled phase iii trial of immunologic therapy with sipuleucel-t (apc8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. j clin oncol. 2006; 24:3089-3094. 14. bellmunt j, rosenberg je, choueiri tk. recent progress and pitfalls in testing novel agents in castration-resistant prostate cancer. correspondence murat bagcioglu, md dr.muratbagcioglu@hotmail.com mert ali karadag, md urology department kafkas university faculty of medicine, kars, turkey cristian surcel, md drsurcel@gmail.com cristian mirvald, md fundeni clinical institute, center of urologic surgery and renal transplantation country, bucharest, romania serkan ozcan, md urology department artvin state hospital, artvin, turkey mehmet ali karagoz, md urology department ankara research and training hospital, ankara, turkey emre huri, md emrehuri@gmail.com urology department hacettepe university, faculty of medicine, ankara, turkey kemal sarica, md urology department kartal research and training hospital, istambul, turkey bagigoglu_stesura seveso 03/01/18 12:19 pagina 286 143archivio italiano di urologia e andrologia 2017; 89, 2 original paper predictive factors for stone disease in patients with renal colic hakan türk 1, sıtkı ün 2 1 dumlupınar university, evliya celebi training and research hospital, department of urology, kutahya, turkey; 2 sivas state hospital, department of urology, sivas, turkey. introduction: many patients present to urology and emergency departments for acute renal colic complaints. there are many different imaging studies that can be used in patients with a pre-diagnosis of acute renal colic. in this study, we would like to assess the efficacy of using clinical and laboratory results in patients with flank pain complaint as a predictive factor of urinary system stone disease. materials and methods: all patients were assessed using spinal non-contrast complete abdominal computerized tomography and urine analysis. presence of stones and their number and size were recorded. results: 516 patients who were included in the study were divided into 2 groups according to urinary stone presence. group 1 (n = 388) consisted of patients with stones meanwhile patients in group 2 (n = 128) were stone-free. according to these results, male sex, presence of microscopic hematuria, stone history in the family, nausea and emesis in addition to pain and accompanying urinary symptoms were detected as predictive factors in diagnosing urinary stone disease by multivariate analysis. conclusion: from our study results, we can conclude that uroflowmetry is a very useful tool in monitoring lower urinary system complaints. key words: renal colic; urolithiasis; flank pain; hematuria. submitted 15 february 2017; accepted 23 april 2017 summary no conflict of interest declared. materials and methods patients who presented to our clinic between may 2015 and september 2016 with acute renal colic complaint with a possible diagnosis of urinary system stone disease were included in the study. all patients were assessed using spiral non-contrast complete abdominal computerized tomography (ct). the patients’ age varied from 17 to 68 years. ct results and urinalysis results were all reviewed. non-contrast ct imaging was performed using ge lightspeed 16 pro ct machine with a spiral setting. presence of stones and their number and size were recorded. in addition, patient symptoms, family histories, patient histories and visual analogue scale (vas) scores were all reviewed. results 516 patients who were included in the study were divided into 2 groups according to urinary stone presence. group 1 (n = 388) consisted of patients with stones meanwhile patients in group 2 (n = 128) were stonefree. mean age in group 1 was calculated as 38.53 ± 20.8 (17-68) meanwhile in group 2, mean age was 32.3 ± 18.8 (17-65). male/female ratio in group 1 was 248/140 and 64/64 in group 2. other findings are summarized on table 1. according to these results, male sex, presence of microscopic hematuria, stone history in the family, nausea and emesis in addition to pain and accompanying urinary symptoms were detected as predictive factors in diagnosing urinary stone disease by multivariate analysis. discussion urinary stones cause severe colicky pain by the response of smooth muscle and by epithelial biological responses to a partial or complete obstruction and dilation of the urinary tract according to their localization and size. the pain is so severe that it usually requires er admittance (3). acute renal colic is one of the leading causes for er admittance in our country, much like the rest of the world. about 7-9% of all pain-related emergency calls in europe is thought to be renal colic (4). although renal colic can be seen in all ages, it is more frequent in ages between 35-45 (5, 6). a study done by uluocak et al. reported the mean age of patients with doi: 10.4081/aiua.2017.2.143 introduction many patients come to urology and emergency room (er) settings for acute renal colic complaints. urolithiasis is diagnosed in about 3 to 5% of the general population. patients with a history of previous urinary system stones have about a 50% of risk of recurrence in 10-year periods (1, 2). in order to manage the possible long-term side effects, the cases should be treated and followed up using the most efficient and fastest methods using minimal ionizing radiation exposure. proper treatment strategies and appropriate directions in those patients are essential. there are many different imaging studies that can be used in patients with a pre-diagnosis of acute renal colic. moreover, physical examination findings as well as laboratory results can be a guide in diagnosis. in this study, we would like to assess the efficacy of using clinical and laboratory results in patients with flank pain complaint as a predictive factor in urinary system stone disease. turk_stesura seveso 20/06/17 09:57 pagina 143 archivio italiano di urologia e andrologia 2017; 89, 2 h. türk, s. ün 144 acute renal colic to be 41 with no significant difference between the sexes (7). another study done on a 213patient series reported the mean age of the patients as 40.9 (8). in our study, the mean age of the patients was calculated as 35.2, which is similar to previous results found in the literature and there was no significant difference between the sexes. when sexes are compared, there are different results reported in the literature. although the majority of the studies report that males are more susceptible than females, recent studies report no more such difference (6, 7, 9-11). however, in our study the ratio of male patients was significantly higher in the stone patient group (63.9% vs 36.1%). if the kidney stone is obstructive in nature, it causes colic pain. stones located in renal pelvis or calyxes causing a partial obstruction cause a dull pain on lumbar region. renal colic is a result of stones stretching the ureter and collecting system and resulting in hyperperistalsis. kidney capsule stretching causes a dull pain which is not in colicky. about 60-95% of patients with flank pain in acute colic fashion have ureter stones (5, 12). local occurrences such as mucosal irritation, inflammation, edema and hyperperistalsis also cause pain. especially edema formation can cause colicky pain by stretching free nerve endings. there are no studies found in the literature which uses visual analogue scale (vas) as a predictive factor in urinary stone disease. likewise in our study, we did not find a significant difference in terms of pain severity between stone patients and stone-free patients. hematuria can be seen as a result of traumatizing effect of stones in calyx or pelvis mucosa. most patients have microscopic hematuria. macroscopic hematuria can manifest as transient hematuria or “tea-colored” urine (4, 6, 13, 14). however, absence of hematuria does not rule out urinary stone disease. a study reported hematuria occurrence on 72.2% in stone patients (6). in our study, we observed a significantly higher presence of both microscopic and macroscopic hematuria in stone patients compared to stone-free patients. lifetime risk for stone disease is around 10% for every person in the general population and it is reported 2 times more in males compared to females. ten and 20-year recurrence rates for stone disease increase from 50% to 75%. latest studies report a significant increase in prevalence both in females and the general population (15, 16). in our study, previous stone history or previous stone-related surgery were found to be higher in patients with stones, however, they were not found to be statistically significant. we think this is probably due to the low number of patients included in the study. for those with a history of passing kidney stones in the family, the risk of passing kidney stones rises by two folds compared to normal population. this occurs 2-3 folds more frequently in men than women (5, 17). similarly, we also found out that stone detection rates in patients with family history of renal stones were significantly higher. symptoms such as nausea or emesis can accompany acute flank pain. this is thought to be a result of overstimulation of celiac ganglion (4, 5). in our study, patients with nausea and emesis complaints had a significantly higher rate of stones detected. assessment of additional symptoms in patients with flank pain can be helpful in diagnosis. ureter stones show symptoms by placement of the stone into ureter. pain can vary according to the localization of the stone. in proximal ureter stones, intermittent lumbar pain (colic) is usually seen. as the stone passes towards lower pelvis, the pain spreads to abdominal area. in stones located in ureteral end, the pain spreads towards the groin and inguinal area. vesical irritability symptoms can be seen in stones located in ureterovesical junction (2). in our study, patients with voiding symptoms caused by vesical irritability have a significantly higher rate of urinary stone disease diagnosis. even though there are no similar studies found in the literature, our study results showed a significantly higher detection of urinary stone disease in patients who came table 1. demographics data and clinical measurement values. parameters group 1 group 2 univariate multivariate (n = 388) (n = 128) p value p value mean age 38.53 32.3 0.044 sex 0.005 0.015 male (n) (%) 248 (63.9) 64 (50) emale (n) (%) 140 (36.1) 64 (50) pain score (vas) 6.85 6.31 0.003 0.78 1-4 32 24 5-8 312 96 9-10 44 8 need for painkillers 0.104 yes 348 (76.3) 108 (23.7) no 40 (66.6) 20 (33.4) er admittance for severe pain (n) (%) < 0.0001 0.121 yes 352 (77.8) 100 (22.2) no 36 (56.2) 28 (43.8) microscopic hematuria (n) (%) < 0.0001 < 0.0001 yes 344 (79.6) 88 (20.4) no 44 (52.3) 40 (47.7) stone history (n) (%) < 0.0001 0.14 yes 164 (87.2) 24 (12.8) no 224 (68.2) 104 (31.8) stone surgery history (n) (%) 0.001 0.23 yes 52 (92.8) 4 (7.2) no 336 (73) 124 (27) family history of stones (n) (%) 0.001 0.028 yes 200 (81.9) 44 (18.1) no 188 (69.1) 84 (30.9) pain duration (days) 5.28 11.9 < 0.0001 0.051 nausea and emesis (+) 208 80 < 0.0001 < 0.0001 urinary symptoms (+) 210 102 < 0.0001 < 0.0001 er: emergency room, vas: visual analogue scale. turk_stesura seveso 20/06/17 09:57 pagina 144 to er early for pain. this is probably due to the increased severity of stone-related colic pain compared to other colic pain causes. one of the limitations of our study is the low number of patients. however, we still think that our study has a significant value because it takes into account clinical and laboratory results of patients in the assessment of renal colic. we also think that the parameters used in our study can be developed into a scoring system with prospective studies with much larger patient groups. therefore, our study can be a significant foundation stone in this matter. conclusion in renal colic cases, the superiority of non-contrast sequential spiral ct over other imaging methods is clear due to its speed, accuracy and ability to show non-urinary system related intrabdominal pathologies; especially in er settings. presence of stone history in the family, microscopic hematuria detection in urinalysis and presence of voiding symptoms in patient can also indicate ct imaging for diagnosis and treatment assessment. however, stones are not detected in all patients with flank pain complaints. references 1. ahmad na, ather mh, rees j. unenhanced helical computed tomography in the evaluation of acute flank pain. int j urol. 2003; 10:287. 2. portis a, sundaram c. diagnosis and initial management of kidney stones. am fam physican. 2001; 63:1329-38. 3. labrecque m, dostaler lp, rousselle r, et al. efficacy of nonsteroidal anti-inflammatory drugs in the treatment of acute renal colic. a meta-analysis. arch intern med. 1994; 154:1381-7. 4. müslümanoglu ay, tepeler a. renal kolik, tanı ve tedavisi. marmara medical journal. 2008; 21:187-92. 5. walsh pc, retik ab, vaughan ed jr, wein aj (editors). campbell's urology. in: menon m, resnick mi. urinary lithiasis: etiology, diagnosis, and medical management. 8th edition, philadelphia, saunders, 2002, p. 3227-92. 6. duran l, acar e, çelenk y, et al. evaluation of patients presenting with renal colic in emergency department. kocatepe medical journal. 2014; 15:274-8. 7. uluocak n, erdemir f, atılgan d, ve ark. tokat ilinde üriner sistem tas hastalıgı prevalansı. turkish journal of urology. 2010; 36:81-6. 8. temeltas g, asan ç, müezzinoglu t, büyüksu c. an evaluation of the efficacy of lornoxicam in acute renal colic treatment. inönü üniversitesi tıp fakültesi dergisi 2008; 15:1-3. 9. akıncı h. karabük devlet hastanesine basvuran ürolojik acil olguların analizi. uludag üniversitesi tıp fakültesi dergisi 2009; 35:17-20. 10. aktas c, yencilek e, ay d, et al. comparison of computerized spiral tomography with ultrasonography for detection of ureteral calculi. türkiye acil tıp dergisi 2010; 10:12-4. 11. yigit ö, isık s. seasonal distribution of renal colic visits to emergency department. türkiye acil tıp dergisi. 2008; 8:110-3. 12. federle m, fishman e, jeffrey b, anne v. pocket radiolologistabdominal. 2nd ed. salt lake city: amirsys-w.b. saunders, 2003; p. 305-7. 13. tanagho e, mcaninch j. smith genel üroloji. 17.baskı. istanbul: nobel, 2009; p.1-254. 14. eskelinen m, ikonen j, lipponen p. usefulness of history-taking, physical examination and diagnostic scoring in acute renal colic. eur urol. 1998; 34:467-73. 15. pearle ms, calhoun ea, curhan gc. urologic diseases of america project. urologic diseases in america project: urolithiasis. j urol. 2005; 173:848-57. 16. scales cd jr, curtis lh, norris rd, et al. changing gender prevalence of stone disease. j urol. 2007; 177:979-82. 17. atug f, canoruç n. tekrarlayan üriner sistem kalsiyum taslarının metabolik degerlendirmesi ve medikal yaklagımlar. dicle tıp dergisi 2006; 33:48-52. 145archivio italiano di urologia e andrologia 2017; 89, 2 predictive factors for stone disease correspondence hakan türk, md, specialist in urology (corresponding author) hkntrk000@gmail.com dumlupınar university, evliya celebi training and research hospital, department of urology. kutahya, turkey sıtkı ün, md, specialist in urology sitki@doctor.com sivas state hospital, department of urology, sivas, turkey turk_stesura seveso 20/06/17 09:57 pagina 145 stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2162 original paper no conflict of interest declared. providing satisfactory stone-free rates (sfr) even in case of remarkable stone burden. despite its effectiveness, the main drawbacks of this technique are its invasiveness and the significant risk of haemorrhagic complications, requiring a blood transfusion in around 7% (range 0-20%) of the cases (2). the site of the percutaneous renal puncture and the technique employed for the dilation of the access route are the most crucial steps to perform an effective and safe procedure (3-4). in the last decades, the introduction of small calibre instruments contributed to reduce the complications rate (5), making pcnl safer. however, miniaturized techniques added a few limitations, including reduced visibility, scarce instrument choice for lithotripsy and lapaxy, longer operative times and elevated renal pelvic pressures, restricting the applicability of these techniques to smallto-medium sized stones (6). in order to obtain the best outcomes, the percutaneous access size should be tailored to the distinctive characteristics of both the stone and the patient. this principle allows the urologist to minimize the morbidity of the treatment, enhancing at the same time its effectiveness. the minimally invasive pcnl (mip) set, devised by nagele (7), includes various progressive size nephroscopes and access sheaths in a single system. this modular set can be employed to intraoperatively adjust the tract size to the characteristics of the stones and to the anatomy of the collecting system, and to overcome potentially dangerous accessrelated issues. this allows to combine the advantages of miniaturized and standard pcnl: we defined this concept as the “matryoshka technique” (8). the aim of this study is to describe the indications and the procedural steps of the “matryoshka technique” in pcnl and to report the clinical outcomes from our experience with this approach. materials and methods study design the pcnl database of our tertiary referral stone centre was retrospectively reviewed, and all consecutive patients who underwent a matryoshka pcnl from october 2016 to january 2018 were included in this study. all procedures were carried out by a single expert urologist (more than 1000 pcnls performed) in the objective: miniaturized percutaneous nephrolithotomy (pcnl) reduces the risk of haemorrhagic complications, but the limited field of work represents a drawback. to obtain the best outcomes, the percutaneous access size should be intraoperatively tailored. our purpose is to describe the indications and the procedural steps of the matryoshka technique and to report its clinical outcomes. materials and methods: we performed a retrospective analysis of the data from consecutive matryoshka pcnl procedures from october 2016 to january 2018. collected data included patients’ history, stone characteristics, intraand post-operative items, stone clearance and need for retreatment. the main indication to the matryoshka technique is the inability to securely position a guidewire due to an obstruction or narrowness in the pyelocalyceal system. this technique begins by puncturing the calyx hosting the stone and advancing a hydrophilic guidewire through the needle. if the guidewire cannot proceed beyond the stone, the matryoshka technique is employed for tract stabilization. the tract is carefully dilated with small-bore instruments and a cautious lithotripsy is performed to create enough space to introduce the guidewire beyond the stone under visual control. once the access has been stabilized the surgeon can upsize the tract to the optimum to complete the procedure. additionally, the technique can be employed when an intraoperative reassessment induces the surgeon to further dilate the tract to quicken the procedure. results: sixteen patients were included, with a median stone volume of 3.49 cm3. median operative time was 112 minutes. three clavien i-ii (postoperative fever) and one clavien iiib (colon perforation) complications were reported. no blood transfusions were recorded. three patients underwent scheduled retreatment as part of a multistep procedure. out of the remaining 13 patients, 10 (76.9%) obtained a complete stone clearance. conclusions: the matryoshka technique helps the urologist to obtain a secure percutaneous access and makes pcnl flexible and progressive, potentially minimizing the risk of access-related complications. key words: kidney stones; percutaneous nephrolithotomy; minimally invasive surgical procedures; percutaneous nephrostomy. submitted 9 december 2020; accepted 16 january 2021 introduction percutaneous nephrolithotomy (pcnl) is the gold standard for the treatment of kidney stones larger than 20 mm (1), the matryoshka technique in percutaneous nephrolithotomy stefano paolo zanetti 1, matteo fontana 1, elena lievore 1, matteo turetti 1, fabrizio longo 1, elisa de lorenzis 1, 2, giancarlo albo 1, 2, emanuele montanari 1, 2 1 fondazione irccs ca’ granda ospedale maggiore policlinico, department of urology, milan, italy; 2 department of clinical sciences and community health, university of milan, department of urology, milan, italy. doi: 10.4081/aiua.2021.2.162 summary 163archivio italiano di urologia e andrologia 2021; 93, 2 matryoshka technique in pcnl same centre. collected data included patients’ anthropometrics and medical and surgical history, stone characteristics, intraand post-operative items, complications, stone clearance and need for retreatment. comorbidities were graded according to the charlson comorbidity index. all patients underwent a preoperative contrast-enhanced ct scan to evaluate the stone characteristics (laterality, stone number and location, total volume and mean density expressed in hounsfield units) and to plan the surgical approach. the stone volume was measured by means of the ellipsoid formula (a x b x c x π/6) and in case of multiple stones, total stone volume was calculated as the sum of the volumes of the single stones. intraoperative data included the number of percutaneous tracts employed, the successful placement of a safety guidewire, the access sheath size, lithotripsy modality, intraoperative complications, exit strategy and operative time, defined as the time from the kidney puncture to the exit strategy. the matryoshka technique was evaluated both in terms of indication and tract size upscaling. postoperative items included haemoglobin drop, need for blood transfusions, estimated glomerular filtration rate (egfr) change and length of hospital stay. postoperative complications were graded according to the pcnl-adjusted clavien score (9). stone clearance was assessed through follow-up imaging (ct scan or ultrasound) performed 3-6 months after surgery and was defined as the total absence of residual fragments. all methods were carried out in accordance with relevant guidelines and regulations. informed consent was obtained from all patients or from the legal guardians for patients having age less than 18. this study was approved by the local ethics committee (comitato etico milano area 2). data were collected and analysed using the statistical software spss 25.0 (ibm cor., armonk, ny, usa). indications the main indication to the matryoshka technique in pcnl is the inability to safely pass a guidewire into the renal collecting system without risking disrupting the calyx, due to the presence of a stone occupying the punctured calyx (calyceal staghorn) or its infundibulum (stone-engaged infundibulum), possibly causing the calyx to retain urine (stone-engaged hydrocalyx). in each one of these cases, the lack of a securely positioned guidewire could render the access ineffective and could cause several access-related complications. to minimize these risks, a less disruptive, smaller size tract should be initially employed until the setting is carefully evaluated and a safety guidewire is positioned under visual control, so that the access can be stabilized and upsized. the indication to the matryoshka technique may be posed preoperatively if the urographic phase of the ct scan shows a narrow calyceal infundibulum hosting the stone or a calyceal staghorn stone, but more often it becomes clear during the procedure, when, after puncturing the target calyx, the guidewire cannot proceed beyond the stone in the renal pelvis and down the ureter. furthermore, the matryoshka technique can be employed in those situations in which the guidewire has properly passed, but the surgeon prefers to assess the local anatomy and the actual stone load before dilating the tract. armamentarium the armamentarium to perform a matryoshka pcnl doesn’t differ from that of a classic pcnl. what is essential, though, is the availability of two or more different size nephroscopes and access sheaths to perform a progressive access. at least the first scope and sheath should be miniaturized, in order to start the procedure in the least invasive possible way. the availability of different size instruments allows the surgeon to shift from a smaller to a larger access when the local conditions demand and allow it. in our series we used the mip set (karl storz se, tuttlingen, germany). the complete mip set is composed of three nephroscopes (7.5 ch., 12 ch., 19.5 ch.), and by a series of compatible dilators and metallic percutaneous sheaths, categorized in the extra-small (xs, 9,5 ch.), small (s, 12 ch.), medium (m, 16-22 ch.) and large (l, 24-26 ch.) subsets (8). technique as the traditional pcnl, the matryoshka procedure starts by placing a ureteral catheter up to the renal pelvis and by performing a retrograde pyelogram. if the preoperative urographic ct scan or the pyelogram show a staghorn or an infundibular stone, possibly obstructing the calyceal neck, the setting for the matryoshka technique is defined. subsequently, after placing the patient in the supine valdivia position, the calyx hosting the stone is punctured under fluoroscopic and/or ultrasonographic control and an hydrophilic guidewire is advanced through the needle. if the calyceal neck is narrow or obstructed and the guidewire cannot proceed beyond the stone (figure 1a), the matryoshka technique can be employed for tract stabilization. the tract is carefully dilated with small-bore dilators and sheaths (mip xs, s or m subsets), and a compatible nephroscope is introduced. once the stone has figure 1. representation of the matryoshka technique. (a) stone obstructing the calyceal neck, preventing the guidewire from being inserted; (b) cautious lithotripsy through a small access until creating enough space for the guidewire(s) to pass; (c) tract dilation to the needed or allowed size according to the anatomical relation between the calyx and the stone; (d) further tract dilation in order to speed up the procedure in case of very large stones with favourable anatomy. archivio italiano di urologia e andrologia 2021; 93, 2 s.p. zanetti, m. fontana, e. lievore, m. turetti, f. longo, e. de lorenzis, g. albo, e. montanari 164 been visualized, cautious holmium:yag laser lithotripsy is started, creating enough space for the guidewire to pass, under visual control, beyond the stone into the renal pelvis and possibly down the ureter (figure 1b). since it is always possible to accidentally displace or kink the working guidewire during further manoeuvres and progressive tract dilations, the use of a safety guidewire is recommended as it minimizes the risk of losing the tract. when the access has been stabilized and the anatomical relation between the calyx and the stone is assessed, the surgeon can choose the dilation size needed or allowed, taking care not to dilate the tract beside the stone and not to force the calyx to a diameter exceeding its anatomy (figure 1c). this is the key concept of the matryoshka technique. this technique can also be employed in case of a narrow or partially obstructed calyceal neck irrespective of the secure placement of a working guidewire, or when a miniaturized access is initially chosen to limit pcnl morbidity but nephroscopic evaluation after partial lithotripsy reveals enough space to further dilate the tract. in this situation, it is possible to upsize the tract to the largest calibre that is respectful of the pyelocalyceal anatomy to speed up the procedure. after the secondary dilation is performed, lithotripsy can be continued. an upsized tract offers a wider choice of lithotripsy probes, better irrigation, clearer vision and lower intrapyelic pressures. in case of very large stones, the tract diameter can be further upscaled according to intraoperative needs (figure 1d). after lithotripsy, fragments are evacuated through the vacuum cleaner effect, a nitinol basket or endoscopic graspers. at the end of the procedure, a nephrostomy tube is placed, when needed, over the safety guidewire. results the matryoshka technique was applied in 16 out of 74 procedures (21.6%) performed at our institution in the study period. patients’ and stones’ characteristics are described in table 1. in the 75% of the cases, multiple stones were treated. median total stone volume was 3.49 cm3 (iqr 1.81-5.02). intraoperative items and postoperative outcomes are reported in table 2. median operative time was 112 minutes (iqr 91-130). the indication to the matryoshka technique was access stabilization in 14 cases (87.5%), due to the inability to advance the guidewire beyond the stone because of a calyceal staghorn stone (six cases), a stone-engaged calyceal infundibulum (four cases) or a stone-engaged hydrocalyx (four cases). in the remaining two cases (12.5%), intraoperative reassessment induced the surgeon to upsize the access to speed up and complete the procedure. in all the cases, through the matryoshka technique, we managed to position a safety guidewire and obtain a secure access to the collecting system. three patients reported postoperative fever (clavien i-ii) and one experienced a colonic puncture that was managed by temporary loop colostomy (clavien iiib). median hemoglobin drop was -1.6 g/dl (iqr -1.3 -2.2), and none of the patients experienced a hemorrhagic complication or received a blood transfusion. we registered no complications regarding urinary leakage or drainage. concerning stone clearance, the overall stone free rate was 62.5% (10 out of 16 patients). four patients needed a table 1. patients' and stones' characteristics. sex n (%) male 11 (68.7%) female 5 (31.3%) age (years) mean (± sd) 51.4 (13.7) bmi (kg/m2) mean (± sd) 26.0 (3.4) charlson comorbidity index n (%) 0-1 12 (75%) ≥ 2 4 (25%) history of ipsilateral stone treatment n (%) swl 4 (25%) urs 2 (12.5%) pcnl 3 (18.8%) pyelolithotomy 2 (12.5%) any treatment 6 (37.5%) none 10 (62.5%) laterality n (%) right 8 (50%) left 8 (50%) stone number n (%) single 4 (25%) multiple 12 (75%) stone volume (cm3) median (iqr) 3.49 (1.81-5.02) stone mean hu value (hu) median (iqr) 907 (834-1003) bmi: body mass index; sd: standard deviation; swl: shockwave lithotripsy; urs: ureteroscopy; pcnl: percutaneous nephrolithotomy; iqr: interquartile range; hu: hounsfield units. table 2. intraoperative items and postoperative outcomes. operative time (min) median (iqr) 112 (91-130) percutaneous tract number n (%) single 12 (75%) double 4 (25%) matryoshka technique indication n (%) access stabilization 14 (87.5%) calyceal staghorn 6 (37.5%) stone-engaged infundibulum 4 (25%) stone-engaged hydrocalyx 4 (25%) intraoperative reassessment 2 (12.5%) matryoshka technique size n (%) xs → m 2 (12.5%) s → m 8 (50%) m → l 3 (18.8%) s → m → l 3 (18.8%) exit strategy n (%) nephrostomy 10 (62.5%) nephrostomy + double j stent 2 (12.5%) nephrostomy + ureteral splint 2 (12.5%) tubeless/totally tubeless 2 (12.5%) hb change (g/dl) median (iqr) -1.6 (-1.3 – -2.2) egfr change (ml/min) median (iqr) 0.7 (-2.3-6.6) post-operative complications n (%) none 12 (75%) clavien i-ii 3 (18.8%) clavien iii 1 (6.3%) length of stay (days) median (iqr) 5 (4-6) stone clearance n (%) yes 10 (62.5%) no 6 (37.5%) need for retreatment n (%) no 12 (75%) yes (planned) 3 (18.8%) yes (unplanned) 1 (6.3%) iqr: interquartile range; egfr: estimated glomerular filtration rate; xs: extra-small = 9,5 ch.; s: small = 12 ch.; m: medium = 16-22 ch.; l: large = 24-26 ch. 165archivio italiano di urologia e andrologia 2021; 93, 2 matryoshka technique in pcnl retreatment, which was already scheduled as part of a planned multistep procedure for three of them. ten out of the 13 patients scheduled for a single step procedure (76.9%) obtained a complete stone clearance. the single procedures are presented in table 3, with details regarding the stone load, the matryoshka technique indication and the access tracts size. discussion the authors of a recent review on miniaturized pcnl stated that the surgical treatment that each patient should be offered ought to be tailored to the distinctive characteristics of both the patient and the stone (10). the matryoshka technique is the extremization of this concept: the opportunity to intraoperatively individualize the tract diameter to the anatomy of the pyelocalyceal system enables the surgeon to take advantage of the benefits of the different sized scopes and sheaths in every single procedural step. to the best of our knowledge, this is the first report of a series of patients treated with the matryoshka technique. the main benefit of this technique is to provide a more secure percutaneous approach to the pyelocalyceal system in case of several access-related issues that could potentially undermine both the safety and proficiency of the tract creation. in order to safely dilate the access and to position a percutaneous sheath, a guidewire should be firmly set inside the urinary tract: this manoeuvre is crucial to minimize the risk of kinking or slipping of the guidewire itself, that would render the access difficult or ineffective, and to reduce the mobility of the punctured kidney. when the guidewire cannot be securely held in the pyelocalyceal system, it is prudent to establish the smallest possible tract, which can be created with less strain on the guidewire and the kidney, and it is less harmful than a larger one. after the initial nephroscopy and the subsequent individuation of the issue underlying the suboptimal placement of the guidewire, the route for its advancement can be created by means of a prudent lithotripsy. once the guidewires are firmly positioned, the tract can be dilated to the desired calibre. in addition, the initial assessment of the urinary tract through a miniaturized nephroscope allows a precise recognition of anatomical variations, enabling the surgeon to preserve the integrity of the pyelocalyceal system: for instance, the identification of a narrow calyceal infundibulum could compel the urologist to complete the pcnl with small bore instruments, possibly preventing inadvertent disruptions of the urinary tract. flexibility and scalability are two more strengths of this technique, which allows the reassessment of the local conditions during the procedure and the modification of the surgical approach in case of need. with this concept in mind, the chosen instruments can be readjusted on the basis of the characteristics of both the stone and the patient, and a truly tailored approach can be achieved. the results from our initial experience seem to support these concepts. although we treated complex cases, with significant stone loads and a high prevalence of multiple, staghorn stones, none of the patients experienced an haemorrhagic complication or required a blood transfusion; moreover, no cases of postoperative urine extravasation were recorded. additionally, with the employment of the matryoshka technique, all of the gained accesses have been successfully stabilized and exploited, and none was rendered ineffective because of guidewire slipping or kinking. although we registered a colonic perforation, we do not believe that this complication is related to the matryoshka technique in itself, as it generally occurs during the primary tract creation and not during secondary dilations, that are performed on an already established tract. specifically, the perforation we reported occurred during the initial access despite ultrasonographic control, in a paraplegic patient that suffered from severe bowel disfunction and enlargement. regarding our stone free rate, we believe it can be deemed satisfactory considering that the matryoshka technique is table 3. matryoshka procedures. patient stone load percutaneous tract matryoshka indication matryoshka size n.s., ♀, 35 yrs. 18.9 cm3; hu max 1278; hu mean 681 staghorn (pelvis, middle calyx, lower calyx) 2 tracts (lower calyx) calyceal staghorn 17.5 ch. → 22 ch. r.p., ♂, 45 yrs. 0.74 cm3; hu max 835; hu mean 593 multiple (middle calyx, lower calyx) 2 tracts (lower calyx) stone-engaged infundibulum 12 ch. → 16 ch. b.r., ♂, 62 yrs. 1.79 cm3; hu max 1193; hu mean 904 multiple (middle calyx, lower calyx) 1 tract (lower calyx) stone-engaged hydrocalyx 9.5 ch. → 16 ch. u.l., ♂, 38 yrs. 3.80 cm3; hu max 592; hu mean 458 multiple (pelvis, lower calyx) 2 tracts (lower calyx) stone-engaged infundibulum 9.5 ch. → 17.5 ch. o.p., ♀, 54 yrs. 3.18 cm3; hu max 1415; hu mean 775 single (upper calyx) 1 tract (upper calyx) stone-engaged hydrocalyx 12 ch. → 16 ch. c.c., ♂, 54 yrs. 1.44 cm3; hu max 1659; hu mean 997 multiple (middle calyx, lower calyx) 1 tract (lower calyx) stone-engaged hydrocalyx 12 ch. → 16 ch. s.p., ♂, 52 yrs. 0.82 cm3; hu max 1646; hu mean 962 multiple (middle calyx) 1 tract (middle calyx) stone-engaged hydrocalyx 12 ch. → 16 ch. i.a., ♀, 72 yrs. 3.53 cm3; hu max 1145; hu mean 900 staghorn (pelvis, lower calyx) 1 tract (lower calyx) intraoperative reassessment 12 ch. → 16 ch. t.i., ♀, 62 yrs. 3.45 cm3; hu max 1256; hu mean 906 staghorn (pelvis, lower calyx) 1 tract (lower calyx) intraoperative reassessment 12 ch. → 16 ch. s.t., ♂, 56 yrs. 6.83 cm3; hu max 1045 ; hu mean 950 staghorn (pelvis, lower calyx) 1 tract (lower calyx) stone-engaged infundibulum 17.5 ch. → 24 ch. b.s., ♂, 56 yrs. 2.99 cm3; hu max 1380; hu mean 1150 staghorn (pelvis, lower calyx) 2 tracts (lower and middle calyx) calyceal staghorn 12 ch. → 16 ch. p.m., ♂, 14 yrs. 10.42 cm3; hu max 1049; hu mean 853 staghorn (pelvis, middle calyx, lower calyx) 1 tract (lower calyx) calyceal staghorn 12 ch. → 17.5 ch. → 24 ch. c.l., ♀, 56 yrs. 1.82 cm3; hu max 1859; hu mean 1300 multiple (pelvis, middle calyx, lower calyx) 1 tract (lower calyx) stone-engaged infundibulum 12 ch. → 17.5 ch. c.c., ♂, 53 yrs. 4.42 cm3; hu max ; hu mean staghorn (pelvis, middle calyx, lower calyx) 1 tract (middle calyx) calyceal staghorn 12 ch. → 17.5 ch. → 24 ch. c.s., ♂, 65 yrs. 24.02 cm3; hu max 1619; hu mean 1200 staghorn (complete) 1 tract (lower calyx) calyceal staghorn 16 ch. → 24 ch. m.e., ♂, 49 yrs. 3.61 cm3; hu max 1285; hu mean 908 staghorn (pelvis, lower calyx) 1 tract (lower calyx) calyceal staghorn 12 ch. → 17.5 ch. → 24 ch.. archivio italiano di urologia e andrologia 2021; 93, 2 s.p. zanetti, m. fontana, e. lievore, m. turetti, f. longo, e. de lorenzis, g. albo, e. montanari 166 especially useful in complex and challenging cases, usually characterized by less favourable results. our work is not devoid of limitations. first of all, our sample is quite meagre: this is due to the particular indications of the matryoshka technique, that was applied in a limited number of patients in the considered period of time. secondly, even if the results are encouraging, our work lacks a control group, that we believe would be hard to identify because of the unusual characteristics of the cases treated. additionally, randomizing patients would be extremely difficult, as the indication to our technique is frequently defined intraoperatively. conclusions the matryoshka technique appears to be a safe and effective approach to obtain a secure percutaneous access to the kidney in challenging situations. it makes the pcnl procedure flexible and progressive, allowing the surgeon to intraoperatively adjust the tract size according to the local anatomy and stone characteristics. in this way, the less invasive achievable tract is stabilized, tailored to the patient and the stone, potentially minimizing the chances of calyceal tear and the related risk of complications. references 1. türk c, skolarikos a, neisius a, et al. eau guidelines on urolithiasis. 2019. 2. seitz c, desai m, häcker a, et al. incidence, prevention, and management of complications following percutaneous nephrolitholapaxy. eur urol. 2012; 61:146-158. 3. tahra a, sobay r, bindayi a, et al. papillary vs non-papillary access during percutaneous nephrolithotomy: retrospective, matchpaired case-control study. arch ital urol androl. 2020; 92:50-52. 4. sahin a, uruc f. the comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: which one is safer? arch ital urol androl. 2019; 91:171-173. 5. ruhayel y, tepeler a, dabestani s, et al. tract sizes in miniaturized percutaneous nephrolithotomy: a systematic review from the european association of urology urolithiasis guidelines panel. eur urol. 2017; 72:220-235. 6. heinze a, gozen as, rassweiler j. tract sizes in percutaneous nephrolithotomy: does miniaturization improve outcome? curr opin urol. 2019; 29:118-123. 7. nagele u, schilling d, anastasiadis ag, et al. minimally invasive percutaneous nephrolitholapaxy (mip). urol ausgabe a. 2008; 47:1066-1073. 8. zanetti sp, boeri l, gallioli a, et al. minimally invasive pcnl mip. arch esp urol. 2017; 70:226-234. 9. de la rosette jjmch, opondo d, daels fpj, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-255. 10. proietti s, giusti g, desai m, ganpule ap. a critical review of miniaturised percutaneous nephrolithotomy: is smaller better? eur urol focus. 2017; 3:56-61. correspondence stefano paolo zanetti, md (corresponding author) stefano.p.zanetti@gmail.com matteo fontana, md teo.fontana@yahoo.it elena lievore, md elena.lievore01@gmail.com matteo turetti, md matteo.turetti@gmail.com fabrizio longo, md longomd@gmail.com elisa de lorenzis, md elisa.delorenzis@gmail.com giancarlo albo, md albo.giancarlo@gmail.com emanuele montanari, md emanuele.montanari@unimi.it via della commenda 15, 20122, milano, italy 123archivio italiano di urologia e andrologia 2018; 90, 2 original paper utility of uroflowmetry during the follow-up of children affected by balanitis xerotica obliterans (bxo) salvatore arena, tiziana russo, pietro impellizzeri, saveria parisi, patrizia perrone, carmelo romeo department of human pathology in adult and developmental age “gaetano barresi”, unit of paediatric surgery, university of messina, italy. introduction: to evaluate the outcome of circumcised patients with balanitis xerotica obliterans (bxo) using uroflowmetry (uf). methods: between 2011 and 2013, 180 children underwent a circumcision for phimosis. the foreskin was examined on microscopy. patients with an histological diagnosis of bxo were included in the study. patients with bxo underwent uf two weeks after surgery and treatment with clobetasol propionate ointment. patients were re-evaluated at 6, 12, 18 and 24 months postoperatively clinically and using uf. results: 75 of 180 circumcised patients (41.6%) were included. at two weeks, thirtytwo of 75 patients (42.7%) displayed a pathological uf. at six months, 15 patients (20%) had pathological uf and a new cycle of clobetasol was prescribed. at one year, 10 patients (13.3%) displayed patholgocial uf and underwent progressive urethral dilatation or meatoplasty. at 18 months, 71 patients (94.7%) displayed regular uf, 3 underwent a meatoplasty and one a staged urethroplasty for a severe urethral stenosis. at two years, uf was normal in 74 out of 75 (98.7%). conclusions: we recommend to send for hystological examination all foreskins excised after circumcision. we believe that a clinical and uroflowmetric follow-up of pediatric patients with bxo is mandatory for a prompt identification of post-voiding dysfunction. key words: phimosis; balanitis xerotica obliterans; uroflowmetry. submitted 3 april 2018; accepted 29 april 2018 summary no conflict of interest declared. the urethra causing stenosis and, even if it is related to squamosus cell carcinoma in adulthood, no cases of malignant lesion are reported in pediatric age (5, 7, 9). uroflowmetry (uf) has been traditionally used in the follow-up of patients with voiding dysfunction including children, because it is a simple, non invasive and unexpensive diagnostic tool (13, 14). despite the welldescribed complications of bxo in term of obstructive uropathy, uf is not routinely used during post follow-up in patients undergoing circumcision with a histological diagnosis of bxo. aim of the study is to assess the short and long-term outcome of circumcised patients with bxo using uf, in order to identify early obstructive features related to this disease. materials and methods between january 2011 to december 2013, 180 children underwent a circumcision for clinical diagnosis of secondary phimosis at our department. the foreskin was examined on light microscopy by a pathologist. patients with an histological diagnosis of bxo were included in the study. bxo was defined as an epithelial-stromal lesion characterized by squamous atrophy or hyperplasia, band like infiltration, hyalinization of the papillary dermis, hyperkeratosis, pigment incontinence and/or dermal edema. we excluded from the study patients with pre-operative treatment with corticoid ointment or cream and without histologically proven bxo. a chart review was performed, collecting data relating to demographics, clinical presentation, histopathological findings, steroid therapy and follow-up. patients with bxo underwent uf two weeks after surgery and clobetasol propionate 0.05% ointment was applied once daily, at night, for 4 weeks, then on alternate nights for 4 weeks, and then twice weekly for a further 4 weeks, according to pugliese jm et al. (15). uf was carried out in a quiet and private room, with a comfortable environment to prevent any performance failure. an hour before the test, the children drank fluids for a total equal to the expected bladder capacity (age x 30 ml + 30 ml). the test was performed when the children felt the normal sensation of fullness in the bladder or in the presence of urinary urgency. volume of 50 ml or more and between 50% and 100% if the expected doi: 10.4081/aiua.2018.2.123 introduction lichen sclerosus et atrophicus of the foreskin called also balanitis xerotica obliterans (bxo) is one of main causes of acquired phimosis (1, 2), firstly reported in pediatric age by catterall in 1962 (2). it is a chronic inflammatory disease of unclear etiology, which can affect the foreskin, frenulum, glans, meatus and urethra (1-3). it is believed that the real incidence of bxo is underestimated in the general population and bxo is considered uncommon in children (4). significant obstructive complications secondary to phimosis complicated by bxo are described (5-7), among them urethral meatal stenosis is the most frequent one. as regards, recent studies report that 7-19% of boys circumcised for bxo require a subsequent meatal procedure (5, 8-12) and a meatoplasty is required in up to 36% of cases (5). rarely, bxo affects arena_stesura seveso 28/06/18 16:54 pagina 123 archivio italiano di urologia e andrologia 2018; 90, 2 s. arena, t. russo, p. impellizzeri, s. parisi, p, perrone, c. romeo 124 bladder capacity were considered as relevant for interpretation. at least, two tests are usually done since high variability in uf tests could lead to a misleading diagnosis (16). voided volume, qmax (peak flow rate with a duration of at least two seconds) and uroflow curves were considered for interpretation of results. patients were re-evaluated at 6, 12, 18 and 24 months postoperatively clinically and using uf. the qmax was plotted on body surface related flow rate nomograms that correlate the voided volume of urine to the qmax. the upper 95% tolerance limits for the 5th, 10th, 15th, 20th and 25th percentiles of normal population were used for comparison. to interpret uroflow data we used flow rate nomograms proposed by tonguri (17). the flow pattern was classified as bell ring, plateau or intermittent (18, 19). results 75 out of 180 patients (41.6%) with an histological diagnosis of bxo were included in the study. the mean age at diagnosis was 9.2 ± 2.1 years, ranging from 5 to 15 years. at two weeks, uf showed a mean qmax 10.1 ± 3.3 ml/sec; 32 out of 75 patients (42.7%) displayed a significant low qmax (6.7 ± 1.4 ml/sec) and a plateau flow pattern. at six months after surgery, all patients repeated uf, showing a mean qmax 11.9 ml/sec ± 3.3 ml/sec. fifteen (20%) of these patients had a significant low qmax and a plateau curve, with a mean qmax of 5.9 ± 0.7 ml/sec, while 60 (80%) patients had a normal qmax of with a mean of 13.4 ± 1.5 ml/sec with bell ring flow pattern. we prescribed a new cycle of clobetasol topic treatment for 12 weeks in patients with obstructive pattern at uf. at one year after surgery, overall mean qmax in 75 uf was 13.0 ± 2.5 ml/sec and 10 out of 75 patients (13.3%) displayed a significant low qmax and a pleateau flow pattern; 65 out of 75 patients showed normal qmax (13.9 ± 1.2 ml/sec) with a bell ring uf pattern. the 10 patients with pathological uf (7.3 ± 0.6 ml/sec) underwent progressive urethral dilatation (5 patients) and diagnostic cystoscopy (5 patients). in the latter, cistoscopy was negative for urethral pathology and a meatoplasty was performed. at 18 months, 71 out of 75 patients (94.7%) displayed regular qmax according to age and bell ring flow pattern (mean 14.5 ± 1.0 ml/sec). differently, 4 patients, that previously had undergone progressive urethral dilatation, showed low qmax and a plateau flow pattern (mean 7.3 ± 0.9 ml/sec). a cistoscopy was then performed that was negative for urethral obstruction in 3 patients. the latter underwent a meatoplasty. differently, a severe urethral stenosis occurred in a patient and a two stage buccal mucosal graft was started. at two years, qmax was normal (14.8 ± 2.2 ml/sec) with a bell ring uf pattern in 74 out of 75 (98.7%) patients while it was not assessable in patient underwent first stage of buccal mucosal graft procedure. table 1 summarizes the results. discussion reviewing the literature, the incidence of bxo in patients with phimosis ranges from 5 to 50%, with the peak of incidence at 7-8 years age (1).this difference in the studies could be due to various factors, including the different indications for circumcision and the assessment made by different specialists such as pediatricians, dermatologists, urologists and pediatrics surgeons (1-3). usually, the diagnosis of bxo is initially clinical, displaying un-retractable foreskin, white xerotic appearance of glans and foreskin, dysuria and voiding disturbances. however, the final diagnosis needs to be confirmed by histological examination (20). furthermore, clinical diagnosis seems to underestimate the real incidence of histological bxo. as regards, bochove reported that the 50% of patients with bxo would not have been diagnosed if it was not carried out histological examination, and this data is also confirmed from studies in the adult population (10) on a systematic histological study of foreskin of pediatric patients underwent a circumcision for phimosis, it has been documented that 45.1% of congenital phimosis and 62.3% of acquired phimosis had histological features of bxo (9). kiss et al. (21) reported that 40% of children with phimosis treated by circumcision had a bxo, with a higher incidence in patients aged between 9 and 11 years, and a secondary phimosis was found in 90-93% of the boys with bxo (21-22). moreover, bxo was found in 52.6% of patients with phimosis under the age of five years (23). recently, the incidence of the disease seems to be increased, with a peak between 9 and 11 years (5). it is unclear the reason of this increment, but an increased incidence could be linked to the fact that more foreskin samples have been sent for histopathological examination, due to surgeons awareness about this disease and the foreskin examination, that is performed with more suspicious (5). furthermore, it has been reported an alarming increase of incidence of unrecognized diagnosis of bxo that is placed only when it is responsible of complications (4). we agree with some authors' suggestion to performing routinely histological analysis of the foreskin after circumcision, to avoid potential complications related to bxo. in our experience, an histological diagnosis of bxo was done in 41.6% of children undergone circumcision for secondary phimosis, with an average age of 9.2 ± 2.1 years. data of our study confirmed those of literature. circumcision appears as the definitive treatment in 96% of cases in several studies (8, 22-25) and the treatment with topical steroids following circumcision appears decisive for avoiding complications, the most common of which are stenosis of the table 1. qmax values in patients with histological bxo. normal uf patological uf overall 2 weeks 12.6 ± 1.6 ml/sec (43) 6.7 ± 1.4 ml/sec (32) 10.1 ± 3.3 ml/sec 6 months 13.4 ± 1.5 ml/sec (60) 5.9 ± 0.7 ml/sec (15) 11.9 ± 3.3 ml/sec 12 months 13.9 ± 1.2 ml/sec (65) 7.3 ± 0.6 ml/sec (10) 13.0 ± 2.5 ml/sec 18 months 14.5 ± 1.0 ml/sec (71) 7.3 ± 0.9 ml/sec (4) 14,1 ± 1.9 ml/sec 24 months 14.8 ± 2.2 ml/sec (74) n/a 14.8 ± 2.2 ml/sec arena_stesura seveso 28/06/18 16:54 pagina 124 meatus or urethra (15, 25, 26, 28). as regards, kulkarni described 215 adult patients who underwent surgery for hystologically proven bxo involving the foreskin and the anterior urethra (20), christman et al. described six cases of obstructive urinary complication secondary to bxo in children (7). corbett et al. described meatus as abnormal o affected in 23% patients with bxo at time of circumcision (29). in our experience, 8 patients underwent a successful meatoplasty (in 3 after failed cycles of progressive urethral dilatation), one patient healed after progressive urethral dilatation and another required a two stage urethral reconstruction for severe urethral stricture. while rare, the morbidity that can result from progression of this disease can be significant, leading to obstructive disease with impaired bladder and renal function (7, 30). the diagnosis of bxo can be straightforward with earlier diagnosis and we consider as mandatory the surveillance of patients with bxo following circumcision and to perform uf during follow-up for monitoring changes in urinary flow, evaluating response to topical therapy and deciding whether to switch to second-level exams and/or therapeutic management. the uf test has gained wide acceptance, as the initial screening tool to evaluate voiding function in children because it is considered as a reliable test for the diagnosis and for the follow-up of post-voiding abnormality. as regards, it is traditionally used to evaluate the functional results following hypospadias repair to identify asymptomatic obstruction early, being considered the most accurate, physiologic and non invasive method of assessing bladder outflow obstruction (31). in fact, it is well know that in the urethral strictures, qmax is diminished and the flow pattern loses is normal bell shape and becomes flattened (31). uf allowed us to identify 32 patients with voiding dysfunction out of 75 patients with a histological diagnosis of bxo (44%) and to successfully and promptly treat them with medical or mini-invasive management in 31 cases (97%), recording just one serious urethral lesion, requiring a major surgery. conclusions we recommend that all foreskins excised after circumcision have to be sent for hystological examination for and earlier identification of bxo. we believe that a follow-up of pediatric patients with bxo is mandatory for a prompt identification of post-voiding dysfunction and that the non-invasive, well-accepted and reliable nature of the uf makes it a first tool for the diagnosis and evaluation of bxo related meatal and urethral complications. references 1. jasaitiene d, valiukeviciene s, vaitkiene d, et al. lichen sclerosus et atrophicus in pediatric and adult male patients with congenital and acquired phimosis. medicina (kaunas) 2008; 44:460-6. 2. russo t, currò m, barbera a, et al. expression of transglutaminase in foreskin of children with balanitis xerotica obliterans. int j mol sci. 2016;17. pii: e1551. 3. currò m, russo t, ferlazzo n, et al. anti-inflammatory and tissue regenerative effects of topical treatment with ozonated olive oil/vitamin e acetate in balanitis xerotica obliterans. molecules. 2018; 23. pii: e645. 4. catterall rd, oates jk. treatment of balanitis xerotica obliterans with hydrocortisone injections. br j vener dis. 1962; 38:75-7. 5. celis s, reed f, murphy f, et al. balanitis xerotica obliterans in children and adolescents: a literature review and clinical series. j pediatr urol. 2014; 10:34-9. 6. gargollo pc, kozakewich hp, bauer sb, et al. balanitis xerotica obliterans in boys. j urol. 2005; 174:1409-12 7. christman ms, chen jt, holmes nm. obstructive complications of lichen sclerosus. j pediatr urol. 2009; 5:165-9. 8. becker k. lichen sclerosus in boys. dtsch arztzebl int. 2011; 108:53. 9. clouston d, hall a, lawrentschuk n. penile lichen sclerosus (balanitis xerotica obliterans). bju int. 2011; 108:14-9. 10. bochove-overgaauw dm, gelders w, de vylder am. routine biopsies in pediatric circumcision: (non) sense? j pediatr urol. 2009; 5:178-80. 11. holbrook c, tsang t. management of boys with abnormal appearance of meatus at circumcision for balanitis xerotica obliterans. ann r coll surg engl. 2011; 93:482-4. 12. wilkinson dj, lansdale n, everitt lh, et al. foreskin preputioplasty and intralesional triamcinolone: a valid alternative to circumcision for balanitis xerotica obliterans. j pediatr surg. 2012; 47:756-9. 13. alyami f, farhat w, figueroa vh, et al. utility and cost-effectiveness of uroflowmetry in a busy pediatric urology practice. can urol assoc j. 2014; 8:e615-8 14. anwar a, kurokawa y, takahashi m, et al. functional evaluation of one-stage urethroplasty with parameatal foreskin flaps repair of hypospadias using uroflowmetry. int j urol. 2003; 10:297-301. 15. pugliese jm, morey af, peterson ac. lichen sclerosus: review of the literature and current recommendations for management. j urol. 2007; 178:2268-76. 16. chang sj, yang ss. variability, related factors and normal reference value of post-void residual urine in healthy kindergarteners. j urol. 2009; 182:1933-8. 17. toguri ag, uchida t, bee de. pediatric uroflow rate nomograms. j urol. 1982; 127:727-31. 18. siroky mb. interpretation of urinary flow rates. urol clin north am. 1990; 17:537-42. 19. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn. 2016; 35:471-81. 20. kulkarni s, barbagli g, kirpekar d, et al. lichen sclerosus of the male genitalia and urethra: surgical options and results in a multicenter international experience with 215 patients. eur urol. 2009; 55:945-54. 21. edmonds ev, hunt s, hawkins d, et al. clinical parameters in male genital lichen sclerosus: a case series of 329 patients. j eur acad dermatol venereol. 2012; 26:730-7. 125archivio italiano di urologia e andrologia 2018; 90, 2 uroflowmetry in children affected by bxo arena_stesura seveso 28/06/18 16:54 pagina 125 archivio italiano di urologia e andrologia 2018; 90, 2 s. arena, t. russo, p. impellizzeri, s. parisi, p, perrone, c. romeo 126 22. kiss a, király l, kutasy b, et al. high incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. pediatr dermatol. 2005; 22:305-8. 23. meuli m, briner j, hanimann b, et al. lichen sclerosus et atrophicus causing phimosis in boys: a prospective study with 5-year followup after complete circumcision. j urol. 1994; 152:987-9. 24. jayakumar s, antao b, bevington o, et al. balanitis xerotica obliterans in children and its incidence under the age of 5 years. j pediatr urol. 2012; 8:272-5. 25. mattioli g, repetto p, carlini c, et al. lichen sclerosus et atrophicus in children with phimosis and hypospadias. pediatr surg int. 2002; 18:273-5. 26. depasquale i, park aj, bracka a. the treatment of balanitis xerotica obliterans. bju int. 2000; 86:459-65. 27. liatsikos en, perimenis p, dandinis k, et al. lichen sclerosus et atrophicus. findings after complete circumcision. scand j urol nephrol. 1997; 31:453-6. 28. kizer ws, prarie t, morey af. balanitis xerotica obliterans: epidemiologic distribution in an equal access health care system. south med j. 2003; 96:9-11. 29. homer l, buchanan kj, nasr b, et al. meatal stenosis in boys following circumcision for lichen sclerosus (balanitis xerotica obliterans). j urol. 2014; 192:1784-8. 30. sandler g, patrick e, cass d. long standing balanitis xerotica obliterans resulting in renal impairment in a child. pediatr surg int. 2008; 24:961-4. 31. gonzález r, ludwikowski bm. importance of urinary flow studies after hypospadias repair: a systematic review. int j urol. 2011; 18:757-61. correspondence salvatore arena, md (corresponding author) salarena@unime.it; tel +390902213014 tiziana russo, md pietro impellizzeri, md saveria parisi, md patrizia perrone, md carmelo romeo, md department of human pathology in adult and developmental age “gaetano barresi”, university of messina, unit of paediatric surgery auo “gaetano martino”, viale gazzi, 98124 messina, italy arena_stesura seveso 28/06/18 16:54 pagina 126 127archivio italiano di urologia e andrologia 2018; 90, 2 original paper desmopressin 120 mcg, 180 mcg, 240 mcg: the right treatment for the right patient pietro ferrara 1, 2, ester del vescovo 2, francesca ianniello 1, giulia franceschini 2, luciana romaniello 3, alberto verrotti 4 1 institute of pediatrics, catholic university medical school, rome, italy; 2 campus bio-medico university, rome, italy; 3 san carlo hospital, potenza, italy; 4 department of pediatrics, university of l’aquila, l’aquila, italy. background: the first-line drug therapy for patients with nocturnal enuresis (ne) associated with nocturnal polyuria and normal bladder function is desmopressin (ddavp). objective: to evaluate if increasing dose of oral desmopressin lyophilisate (melt) can improve response rates to ddavp and is useful in enuretic children. materials and methods: we enrolled a total of 260 children all diagnosed with ne. enuretic children were treated with increasing melt at a dose of 120, 180 and 240 mcg a day. results. we included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 ± 2.52 years). of the 237 patients enrolled in the study and treated with melt 120 mcg, a full response was achieved in 135 (56.9%). a partial response was achieved in 21 (8.9%) patients, therefore the dose was increased up to 180 mcg, with further improving symptoms (14.3%) or full response (9.5%), and up to 240 mcg, without usefulness. conclusions: melt at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects. key words: desmopressin; nocturnal enuresis. submitted 14 february 2018; accepted 16 march 2018 summary no conflict of interest declared. ated with nocturnal polyuria and normal bladder function is desmopressin (ddavp) for a period of 3 months following by withdrawal. ddavp is associated with a response rate of about 40-60%, however its effect may not be maintained on discontinuing treatment, and symptoms have been found to recur in about 50-80% after stopping treatment (3). the different formulations of ddavp are an intranasal solution, an oral tablet formulation and the recent oral sublingual lyophilisate (melt). the aim of this study is to evaluate if increasing dose of melt (120, 180, 240 mcg/day) can improve response rates to ddavp in enuretic children. materials and methods we enrolled a total of 260 children all diagnosed with ne, between april 2014 and april 2017, at the paediatric service of campus bio-medico hospital in rome. inclusion criteria were: age > 5 years and a diagnosis of primary mne (pmne) without ne treatment in the last 3 months. exclusion criteria were the presence of secondary ne, any provided story of urinary infection, nephrogenic diabetes or congenital genitourinary anomalies. the children and their families were asked to participate in the study. this study was conducted in accordance with the regulatory standards of good clinical practice and the declaration of helsinki. we carefully evaluated each patients with medical history and physical examination, including monitoring blood pressure, possible sign of spinal dysraphism or polythelia, neurological reflexes and genital examination. during the period of treatment, all patients and their parents were asked to keep a ne calendar depicting the wet and the dry nights and in addition, we educated both child and parents with dietary advices (4). during the follow-up, families were called to verify their adherence and responses to the therapy and dietary recommendations. enuretic children were initially treated for a period of 3 weeks with melt (minirin®) at a dose of 120 mcg a day and after this observation period, the responders or full responders continued treatment up to three months, the doi: 10.4081/aiua.2018.2.127 introduction nocturnal enuresis (ne) is a very common pediatric disorder. according to recent international children’s continence society (iccs), ne is defined as intermittent incontinence occurs exclusively during sleeping periods. ne should not be used to refer to daytime incontinence (1). in children without any other lower urinary tract symptoms and without a history of bladder dysfunction is defined as mono-symptomatic ne (mne). ne is a multifactorial disorder. it has 3 main pathophysiological determinants that are nocturnal polyuria, detrusor overactivity and failure to awaken in response to bladder sensations. when organic disease is not suspected and children suffer from mne that causes a significant problem, it should be treated (2). the first-line drug therapy for patients with mne associferrara_stesura seveso 28/06/18 16:38 pagina 127 archivio italiano di urologia e andrologia 2018; 90, 2 p. ferrara, e. del vescovo, f. ianniello, g. franceschini, l. romaniello, a. verrotti 128 partial responders increased melt at a dose of 180 mcg and non responders were excluded. patients who had increased the dose to 180 were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months, the partial responders increased melt at a dose of 240 mcg and non responders were excluded. finally patients treated with melt 240 mcg were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months and non responders were excluded. according to the iccs classification for initial success, the children were classified as non-responders if there was no or less than 50% decrease in wet nights compared to baseline; partial responders if there was 50% or more, but less than 90% decrease in wet nights compared to baseline; responders if there was a 90% or more decrease in wet nights compared to baseline; full responders if there was a 100% decrease or less than 1 symptom occurrence monthly. results we enrolled 260 children with pne. of these, 23 were excluded for the following reasons: 15 had undergone therapy with melt, 5 were lost to the follow up, 3 because of a further period of observation. we included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 ± 2.52 years). of the 237 patients enrolled in the study and treated with melt 120 mcg, a full response was achieved in 135 (56.9%), a partial response was achieved in 21 (8.9%) and 81 (34.2%) had no response in terms of a decreased number of wet nights, reflecting values in the literature. when the 21 partial responders increased melt at a dose of 180 mcg, 16/21 (76.2%) had no further improvement and a mild improved response was achieved in 3/21 (14.3%); in these patients in which melt dosage was increased to 240 mcg/day, a response or full response was achieved only in 2/21 (9.5%). they were evaluated again after 3 weeks of pharmacological therapy combined with dietary advices. of the 3 patients that increased the dosage to 240 mcg/day, no one had response in terms of a decreased number of wet nights. discussion in our study we would like to highlight the importance of appropriate ddavp administration and to clarify best practice in the use of this medication. reported response rates vary, only 41% of patients achieved ≥ 50% reduction in wet nights in the study by lottman et al. (5), but 77% achieved > 90% reduction in the study by onol et al. (6). it depends on the type of patients selected, suboptimal adherence rates, administration methods and doses and formulations used (7). several studies have demonstrated decreased secretion of adh and a reduced response to antidiuretic hormone in children affected. moreover, ne may be present with several comorbidities such as sleep disorders, psychological problems, parasomnias, left-handedness, polythelia, language disorders and testicular pathology (8-10). various formulations of ddavp are available (tablets, nasal spray) and many studies also showed that the dosage for melt is more predictable due to the significantly smaller variance, however there is only limited information on the response to ddavp in children relative to the dose required to produce an antidiuretic effect for the entire night. in a previous dose-ranging study, ddavp tablets of up to 600 mcg at bedtime did not appear to reach a maximum effect (11, 12). in our study only a small percentage of patients who had increased the dose of melt to 180 mcg have further improved symptoms (14.3%) or was full responders (9.5%). no patient treated with 240 mcg had usefulness. it can suggests the importance of selecting the right treatment for the right patients. patients must be properly evaluated and diagnosed, and therapy must be used appropriately for the treatment to be successful. data show that proper patient screening can predict treatment response, as well as failure rates. a recent study, in fact, suggests that also the use of bladder diaries is highly recommended wherever possible (13). therefore, it is essential that the treating physician recognize that ddavp will not work for all patients, and increasing dosage is not helpful if we do not use some tools to predict response. it is important that the most appropriate treatment strategy is selected as quickly as possible in order to minimize distress and difficulty for the patient and family. melt at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects. references 1. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. j urol. 2014; 191:1863-5. 2. harari md. nocturnal enuresis. j paediatr child health. 2013; 49:264-71. 3. ferrara p, romano v, cortina i, et al. oral desmopressin lyphilisate (melt) for monosymptomatic enuresis: structured versus abrupt withdrawal. j ped urol. 2014; 10:52-5. 4. ferrara p, del volgo v, romano v, et al. combined dietary recommendations, desmopressin, and behavioral interventions may be effective first-line treatment in resolution of enuresis. urol j. 2015; 12:2228-32. 5. lottmann h, baydala l, eggert p, et al. long-term desmopressin response in primary nocturnal enuresis: open-label, multinational study. int j clin pract. 2009;63:35-45. 6. onol ff, guzel r, tahra a, et al. comparison of long-term efficacy of desmopressin lyophilisate and enuretic alarm for monosymptomatic enuresis and assessment of predictive factors for success: a randomized prospective trial. j urol. 2015; 193:655-61. 7. ferrara p, marrone g, emmanuele v, et al. homotoxicological remedies versus desmopressin versus placebo in the treatment of ferrara_stesura seveso 28/06/18 16:38 pagina 128 enuresis: a randomised, double-blind, controlled trial. pediatr nephrol. 2008; 23:269-74. 8. ferrara p, de angelis mc, caporale o, et al. possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study. urol j. 2014; 11:1777-82. 9. ferrara p, ianniello f, romani l, et al. five years of experience in nocturnal enuresis and urinary incontinence in children: where we are and where we are going. urol int. 2014; 92:223-9. 10. garcovich s, gatto a, ferrara p, garcovich a. vulvar pyoderma gangrenosum in a child. ped derm. 2009; 26:629-31. 11. wolfish nm, barkin j, gorodzinsky f, schwarz r. the canadian enuresis study and evaluation – shortand long-term safety and efficacy of an oral desmopressin preparation. scand j urol nephrol. 2003; 37:22-7. 12. schulman sl, stokes a, salzman pm. the efficacy and safety of oral desmopressin in children with primary nocturnal enuresis. j urol. 2001; 166:2427-31. 13. vande walle j, rittig s, bauer s, et al. practical consensus guidelines for the management of enuresis. eur j pediatr. 2012; 171:971-83. 129archivio italiano di urologia e andrologia 2018; 90, 2 desmopressin 120 mcg, 180 mcg, 240 mcg: the right treatment for the right patient correspondence pietro ferrara, md pietro.ferrara@unicatt.it p.ferrara@unicampus.it francesca ianniello, md institute of pediatrics, catholic university medical school largo f. vito 8, 00168. rome, italy ester del vescovo, md giulia franceschini, md campus bio-medico university, rome, italy luciana romaniello, md san carlo hospital, potenza, italy alberto verrotti, md department of pediatrics, university of l’aquila, l’aquila, italy ferrara_stesura seveso 28/06/18 16:38 pagina 129 stesura seveso 335archivio italiano di urologia e andrologia 2015; 87, 4 case report accuracy of pelvic multiparametric mri in diagnosing local recurrence following radical prostatectomy. case report and revision of the literature pietro pepe 1, antonio garufi 2, giandomenico priolo 2, michele pennisi 1 1 urology unit, cannizzaro hospital, catania, italy; 2 imaging department, cannizzaro hospital, catania, italy. a caucasian man (73 years old) six years from radical prostatectomy for prostate cancer (pca) showed biochemical recurrence (bcr); the follow up based on psa evaluated every 6 months was negative (0.1 ng/ml) for 5 years, but in the last year psa increased to 0.3 vs 0.5 ng/ml. the patient was asymptomatic and underwent 3.0 tesla mpmri equipped with surface 16 channels phased-array coil placed around the pelvic area; multiplanar turbo spin-echo t2-weighted (t2w), axial diffusion weighted imaging (dwi), axial dynamic contrast enhanced (dce) and spectroscopy were performed. pelvic mpmri demonstrated the presence of a nodular tissue with a diameter of 10 mm. located on the left of the prostatic fossa near the rectum that was higly sospicious for local pca recurrence. the patient underwent salvage rt (64 gy); one year from rt psa was 0.1 ng/ml suggesting that the patient was free from recurrence. in conclusion, mpmri could be combined with psa kinetics in the evaluation of men with brc also in the presence of psa values < 1 ng/ml. key words: mpmri and prostate cancer; mpmri and local pca recurrence; mpmri and psa failure. submitted 16 august; accepted 30 september summary no conflict of interest declared. adequately detect small-sized local recurrence. recently, an increasing number of studies have been published reporting the acceptable diagnostic accuracy of mpmri for detecting pca (4) and local recurrence (5). in this study, a case of local pca recurrence detected by mpmri in a man with very low psa value is reported. case report a caucasian man (73 years old) six years before underwent rp for pca and definitive specimen showed an organ confined cancer (pt2cn0) with focal positive surgical margin at the apex, gleason score 7 (4 + 3) and negative nodes (0/15). follow up based on psa value evaluated every 6 months was negative (0.1 ng/ml) for 5 years; in the last year psa increased to 0.3 ng/ml and three months later to 0.5 ng/ml; digital rectal examination was negative. the patient was asymptomatic and underwent 3.0 tesla mpmri (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in supine position; multiplanar turbo spin-echo t2-weighted (t2w), axial diffusion weighted imaging (dwi), axial dynamic contrast enhanced (dce) after injection of gadobutrol 0.1 ml/kg and spectroscopy were performed (4). pelvic mpmri demonstrated the presence of a nodular tissue with a diameter of 10 millimeters (mm) located on the left of the prostatic fossa near the rectum (figure 1); moreover, the lesion showed enhancement after gadobutrol administration (dce) resulting higly sospicious for pca recurrence. the patient underwent pelvic salvage rt (64 gy) and 3 months following therapy psa was 0.1 ng/ml and no side effects were recorded. after 1 year of follow up psa value is stable and equal to 0.1 ng/ml; moreover, the patient was not submitted to additional imaging procedures or salvage therapy. discussion bcr following rp develops in about 50% and 10% of high and low risk patients within 15 years from surgery. after rp, serum psa value should decrease to an undetectable level (< 0.1 ng/ml) within 30 days and should remain undetectable; according to european association of urology guidelines, bcr after rp is defined by two condoi: 10.4081/aiua.2015.4.335 introduction despite the current stage migration in the landscape of prostate cancer (pca), 10%-53% of patients will have biochemical recurrence (bcr) following radical prostatectomy (rp) as determined by serum prostate-specific antigen (psa) measurement and psa kinetic values (1). since management strategies for bcr vary based on the likelihood of local versus distant recurrence, nomograms have been developed to predict the site of recurrence and likely response to localized therapy (2); given the potential side effects to which patients may be exposed with salvage therapies, such as radiation therapy (rt) (3) accurate prediction of the location of recurrence is important for selection of appropriate candidates and guidance of radiation therapy delivery. in current practice, imaging or pathological evidence of local recurrence is not necessary to initiate local salvage treatment because current imaging techniques cannot secutive values of serum psa > 0.2 ng/ml. once that bcr occurs, the key question remains whether a psa rise is reflective of local or distant disease in order to plan the most appropriate treatment. generally, psa detectable after 1 year and psa doubling time > 10 months are related to higher risk of local relapse; however, in the clinical practice, it is not so easy to identify the origin of the psa relapse and sometimes many risk factors for both local and distant recurrence are present in the same patient. moreover, it should be taken into account that the psa level does not always correlate well with the tumour burden when are poorly differentiated. therefore, in patients with bcr after surgical treatment, a diagnostic imaging procedure (6, 7) is often carried out to distinguish between local cancer recurrence and distant spread of disease. in the absence of systemic metastases salvage external rt could be assumed to be the first line treatment offering a potential chance of cure; in fact, salvage rt should be initiated when psa levels is < 1.0 ng/ml; however, the general feeling is that the lower the psa level at the time of salvage rt, the better the result and some recent reports suggest that results are best when the serum psa level is < 0.5 ng/ml. in the last years, mpmri has proven to be the most useful tool available up to now for the detection and localization of local pca recurrence after rp (6-10); cirillo et al. (8) showed in 72 patients with bcr and psa included between 0.2-8.8 ng/ml that mpmri had a sensitivity, specificity, ppv (positive predictive value), npv (negative predictive value) and accuracy in detecting locoregional relapse equal to 84.1, 89.3, 92.5, 78.1, and 86.1%. panebianco et al. (9) demonstrated that mpmri was provided of an higher accuracy in comparison with 18f-cho pet/ct in identifying local recurrence of small lesions (range: 5-19.4 mm) and low psa values (psa included between 0.2 and 2.5 ng/ml); mpmri vs pet-ct showed a sensitivity, specificity, ppv, npv and accuracy equal to 92, 75, 96, 60 and 89% vs 62, 50, 88, 18 and 60%, respectively. panebianco et al. (10) in order to validate the role of 3.0 t mpmri in the detection of local pca recurrence analyzed 126 patients with low psa archivio italiano di urologia e andrologia 2015; 87, 4 p. pepe, a. garufi, g. priolo, m. pennisi 336 values (range: 0.5-1.7 ng/ml) and a lesion size (range; 4-8 mm); mpmri demonstrated a sensitivity, specificity, ppv, npv and accuracy equal to 98%, 94%, 97%, 96% and 93%, respectively. in our case, the patient had a bcr characterized by low psa level (0.5 ng/ml) and a lesion diameter of 10 mm.; mpmri showed the presence of pca recurrence in the prostatic fossa allowing to perform salvage rt and psa value one year from rt is equal to 0.1 ng/ml suggesting that the patient is free from recurrence. in definitive, mpmri could be combined with psa kinetics in the evaluation of men with brc also in the presence of psa values < 1 ng/ml. references 1. cooperberg mr, broering jm, carroll pr. time trends and local variation in primary treatment of localized prostate cancer. j clin oncol. 2010; 28:1117-1123. 2. pound cr, partin aw, eisenberger ma, et al. natural history of progression after psa elevation following radical prostatectomy. jama. 1999; 281:1591-1597. 3. peterson jl, buskirk sj, heckman mg, et al. late toxicity after postprostatectomy salvage radiation therapy. radiother oncol. 2009; 93:203-206. 4. pepe p, garufi a, priolo g, pennisi m. can 3 tesla pelvic phasedarray mri avoid unnecessary repeat prostate biopsy in patients with psa below 10 ng/ml? clinical genitourinary cancer. 2015; 13:e27-30. 5. wassberg c, akin o, vargas ha, et al. the incremental value of contrast-enhanced mri in the detection of biopsy-proven local recurrence of prostate cancer after radical prostatectomy: effect of reader experience. am j roentgenol. 2012; 199:360-366. 6. garcia jr, romera n, cozar met al. (11)c-choline pet/ct and multiparametric mri in patients with biochemical relapse of prostate cancer. actas urol esp. 2015; 39:259-263. 7. barchetti f, panebianco v. multiparametric mri for recurrent prostate cancer post radical prostatectomy and postradiation therapy. biomed res int. 2014; 2014:316272. 8. cirillo s, petracchini m, scotti l, et al. endorectal magnetic resonance imaging at 1.5 tesla to assess local recurrence following radical prostatectomy using t2-weighted and contrast-enhanced imaging. eur radiol. 2009; 19:761-769. 9. panebianco v, sciarra a, lisi d, et al. prostate cancer: 1hmrsdcemr at 3t versus [(18)f]choline pet/ct in the detection of local prostate cancer recurrence in men with biochemical progression after radical retropubic prostatectomy (rrp). eur j radiol. 2012; 81:700-708. 10. panebianco v, barchetti f, sciarra a, et al. prostate cancer recurrence after radical prostatectomy: the role of 3-t diffusion imaging in multi-parametric magnetic resonance imaging. eur radiol. 2013; 23:1745-1752. figure 1. a man submitted to radical prostatectomy showed six years later a biochemical recurrence (psa value equal to 0.5 ng/ml). multiparametric pelvic mri demonstrated a lesion with a diameter of 10 mm (ring) located on the left of the rectum and provided of enhancement after gadobutrol administration that was highly suspicious for local prostate cancer recurrence. correspondence pietro pepe, md piepepe@hotmail.com michele pennisi, md urology unit, cannizzaro hospital via messina 829, catania, italy antonio garufi, md giandomenico priolo, md imaging department, cannizzaro hospital, catania, italy stesura seveso 115archivio italiano di urologia e andrologia 2019; 91, 2 original paper a “real life” investigation on the prescriptive habits among italian andrologists: the “conser” survey from italian society of andrology (sia) on sildenafil oral film alessandro palmieri 1, mauro silvani 2, bruno giammusso 3, giovanni liguori 4, nicola mondaini 5, fabrizio palumbo 6, stefano pecoraro 7, oreste risi 8, salvatore sansalone 9, fabrizio ildefonso scroppo 10, alessandro zucchi 11, paolo verze 1, marco capece 1, tommaso cai 12 1 department of urology, university of naples, naples, italy; 2 urology unit, hospital "degli infermi", biella, italy; 3 morgagni clinic, catania, italy; 4 department of urology, university of trieste, trieste, italy; 5 urology unit, nuovo san giovanni di dio hospital, florence, italy; 6 urology unit, san giacomo hospital, monopoli, bari, italy; 7 malzoni center, avellino, italy; 8 neuro-urology unit, treviglio, bergamo, italy; 9 department of urology, university of tor vergata, rome, italy; 10 urology unit, ospedale di circolo di varese, varese, italy; 11 department of urology, university of perugia, perugia, italy. 12 department of urology, santa chiara hospital, trento, italy. even if oral type 5 phosphodiesterase inhibitors (pde5i) seem an effective treatment for erectile dysfunction (ed), the drop-out is high among patients. for this reason, pharmaceutical companies are encouraged to develop new administration routes, such as the orally disintegrating film. the aim of this study was to analyse the prescription habit of italian andrologists affiliated to italian society of andrology (sia) in the era of new oro-dispersible formulation of sildenafil. a 12-items dedicated questionnaire has been distributed to 77 urologists andrologists. as a result of the questionnaire, sildenafil is still the preferred drug of italian andrologists as it is considered the safest and the most effective. it combines the speed of action and the discretion of the intake that are very important issues for the adherence to the treatment according to the italian sample. physicians have also reported the positive feedback of the patients taking sildenafil film as they consider the oro-dispersible formulation either comparable or superior to the old tablet. in conclusion this new formulation has given a new life to an old molecule like sildenafil, and italian andrologists considered this new pharmaceutical formulation as a good tool to improve the patient’s adherence to the treatment and quality of life. key words: erectile dysfunction; sildenafil; oro-dispersible; quality of life; survey; andrology. submitted 6 may 2019; accepted 10 may 2019 summary no conflict of interest declared. defining pde5i efficacy in over 80% of cases of ed, the fact remains that only a minority of men with ed currently seek help by consulting an andrologist and 6070% of those who decide to undertake specific medical care stop treatment for a variety of reasons (4-6). so-called "adherence" to therapy is therefore a primary determinant in the success of treatment but unfortunately there are many factors that often cause a drop-out from the treatment: specialists who prescribe pde5is and give inadequate information to the patient often as result of a superficial andrological visit, expectations of a patients who take ineffective drugs, side effects and high costs. despite the enormous amount of data available in the literature, identification of the specific reasons for patients suspending ed pharmacological treatment is extremely difficult, above all because "evidence-based" studies are lacking. so far, no randomized clinical trial (rct) has been published which compares the efficacy and tolerability of sildenafil, vardenafil, tadalafil and avanafil. the reasons for this gap are largely attributable to the different characteristics of pharmacokinetics, bioavailability and methods of administration of these drugs which affect absorption time, duration and onset of action, methods of use, etc., making comparisons impossible. in addition, published subjective assessment studies, based predominantly on patient opinion, have serious design defects such as comparisons between different drug assays and/or short treatment duration (7-11). despite these difficulties some authors have attempted, for the very first time, a meta-analysis "trade off" aimed at identifying what could be the optimal pde5i in the treatment of ed relative to efficacy and incidence of side effects (5). this analysis was performed on 82 studies (47.626 patients) for efficacy evaluations and 72 studies (20.325 patients) on different molecules’ adverse events. analysis of available data allowed for the identification of sildenafil 50 mg as the most effective drug but was burdened by a higher incidence of adverse events compared to competitors. authors conclude that sildenafil, first put on the mardoi: 10.4081/aiua.2019.2.115 introduction over the last 20 years the use of phosphodiesterase type 5 inhibitors (pde5i) has revolutionized classification and treatment of erectile dysfunction (ed) becoming a firstline therapy as recommended by the guidelines of all major scientific societies (1-3). after the marketing of viagra in 1998, the various international drug companies have approved the use of different molecules characterized by identical mechanisms of action but with different pharmacokinetic properties: in chronological order tadalafil, vardenafil and avanafil. although international medical literature is consistent in archivio italiano di urologia e andrologia 2019; 91, 2 a. palmieri, m. silvani, b. giammusso, et al. 116 ket more than 20 years ago, at a dosage of 50 mg can be considered an initial choice in the treatment of ed of patients for whom high drug efficacy is a priority. although sildenafil is the oldest molecule available on the market, it is the first one engineered in oro-dispersible tablets and oro-dispersible film to improve the pharmacokinetics characteristics with the latter being the latest (12). starting from these considerations it is crucial to understand the efficacy of the drugs in relation to the various formulations and how these ones impact on the specialists’ clinical practice. the aim of this work is to add new elements to define how the introduction of a new sildenafil oro-soluble film has changed ed management in a selected group of italian andrologists from italian society of andrology (sia). survey in the period between may 2017 and december 2017, the italian society of andrology (sia) conducted a survey on pde5i involving numerous italian andrologists. the project is named “conser” (“conservare l’erezione”). a 12-items ad-hoc created and dedicated questionnaire has been sent via registered mail to 77 andrologists affiliated to sia and homogenously distributed on the wide italian regions. some remarkable statistical data have been extrapolated from the overall analysis of the answers, which envisages the prescription reality of pde5i, with attention given, not only from the point of view of the andrological specialist, but also regarding the needs of the patient which, if disregarded, are the primary cause of poor therapeutic compliance. the first interesting data resulting from analysis of the survey, is that according to the andrologists only 9% of the patients have been completely satisfied with the pharmacological therapy they had been prescribed. the problems encountered were mainly cost/reimbursement and low efficacy, thus these factors are the major issues involved in either the specialist prescription and in patient’s adherence to the therapy (tables 1, 2). according to the survey, the most important features a pde5i should ensure are the speed of action and the duration of the effect for either the specialist and the patient (figures 1, 2). regarding to the pharmacokinetics, it is commonly believed that the starting dosage depends on the type of pde5i used. almost two thirds of the patients preferred sildenafil as first therapeutic choice (64.3%), followed by tadalafil, vardenafil e avanafil (20.3%, 8.5% and 6.8% respectively). sildenafil is still the preferred drug of italian andrologists as it is considered the safest and the most effective. finally, with regard to the new oro-soluble film formulation of sildenafil, physicians believe that the new administration route combines the advantages of the speed of action and the discretion of the intake. furthermore, it has been reported that patients easily accept this table 1. which of these aspects can represent a limit to your full satisfaction in the therapeutic approach to the patient with erectile deficit? answer number % cost/refund 49 63.6 dosage 5 6.5 side effects 7 9.1 poor efficacy 16 20.8 total 77 100 table 2. which of these aspects related to therapy represent a limit to the patient? answer number % cost/refund 53 68.8 dosage 1 1.3 side effects 12 15.6 poor efficacy 11 14.3 total 77 100 figure 1. what are the pharmacological characteristics of a pde5-i that, according to your clinical practice, are decisive for therapeutic success? figure 2. what do patients ask from a pde 5-i? speed of action long duration of action possibility of intake without liquids possibility of intake with food speed of action long duration of action possibility of intake without liquids possibility of intake with food form of treatment because of its efficacy, that is either comparable or superior to other oral formulations (table 3). the new formulation of oro-dispersible sildenafil film was prescribed by most of the andrologists involved in the survey with extreme confidence both in naïve patients and in the presence of co-morbidities. discussion in the recent years alternative drug-delivery systems have been developed to improve patient compliance and adherence to the therapy. with regards to the drug absorption, the route of administration is the main factor, and the variables influencing it are represented by the pharmaceutical formulation (coefficient of distribution /dissolubility) and the characteristics of the absorbing surface (extension, permeability, vascularization). having stated that, the best results can be obtained with a greater contact surface between the drug and the mucous membranes which are highly vascularized, a good distribution coefficient of the drug (liposolubility/hydrosolubility ratio) and good permeability of the contact surface (e.g. oral mucous membrane). previous studies have evaluated the efficacy of sildenafil and tested its absorption in the oral mucosa. a first study by el-rashidy et al. (13) proposed a sublingual (delitescent) formulation for sildenafil. the formulation involved the use of the drug (sildenafil), an osmotic agent (mannitol), a hydrophilic carrier (microcrystalline cellulose), and a water-soluble polymer (cellulose derivative). these additional components to the drug had the task of facilitating the transmucosal passage of sildenafil by favouring its absorption (carrier). unfortunately there are no data available on the results. a second study proposed by de siati in 2003 (14) conducted in italy proposed an evaluation of the effects of oral intake of sildenafil (the “old” tablets formulation) for 3 months by comparing the data after a further 3 months of therapy in which the patient pulverized the tablet and placed the powder produced under the tongue. the results obtained showed that the time for the drug to be effective was halved: 62.8 min. (whole tablets) vs. 29.3 min. (sublingual). in the same study all patients stated that they preferred the sublingual route for the most rapidity of action of the drug. wang in 2008 (15) pointed out that sildenafil is a lipophilic molecule and therefore can easily be absorbed at the sublingual level however noted that poor solubility in saliva is a limiting factor for absorption at the level of the oral mucosa and this parameter therefore needs to be improved (16). after about 10 years, research and technology have succeeded in developing new formulations, as in the case of sildenafil in delitescent leaflets (siler) which can be absorbed at the level of the oral mucosa. the new formulation in orodispersible film now has all the characteristics to facilitate sublingual absorption as it is composed of sildenafil, a lipophilic molecule easily absorbed by the oral mucosa, maltodestrine which acts as a "filmogenic" and a solubilizing agent. the maltodestrine also works as a carrier that facilitates its absorption through the oral mucosa (17, 18); stimulating salivation agents such as citric acid, which favor its rapid disintegration, modifying the salivary ph towards acidity and in this way improving the absorption of the drug (19, 20). in a recent paper the “old” oral tablets have been compared to the new sildenafil film whose median action time was 20 minutes. the greater rapidity of absorption, attributed to its pre-gastric absorption, ratified its superiority to the traditional tablet (21). despite its twenty years-long history, our survey declares sildenafil the first choice of italian andrologists. our analysis cannot estimate whether these results are related to the marketing of the new formulations or to the patients’ feedback, however both hypothesis are not mutually exclusive. therefore it is likely that both have contributed to the actual italian state of affairs. the analysis also demonstrate that the new formulation of sildenafil is well known to italian andrologists and that they think the patients would prefer the characteristics of the new formulation to the old one. the new administration route, developed by ibsa (lugano, switzerland) and approved in europe at doses of 25, 50, 75, and 100 mg, is considered a safe and effective alternative to the conventional tablets. finally it gives the possibility of chosing a 75 mg dosage that previous formulations did not consider. conclusions in conclusion, in the world of pde5 inhibitors orodispersible film of sildenafil represents a real technological innovation with a product that is easy to ingest, with great rapidity of action and fewer side effects. in particular, we demonstrated that the advantage of the new formulation of sildenafil in oro-dispersible film is represented, not only by the fact that it can be taken discreetly and without water, but above all by the possibility that the drug can be absorbed, at least in part, directly at the level of the oral mucosa, entering immediately into circulation with no first liver passage. references 1. hatzimouratidis k. can we cure erectile dysfunction? eur urol. 2010; 58:249-50. 2. eardley i, donatucci c, corbin j, et al. pharmacotherapy for erectile dysfunction. j sex med. 2010; 7:524-40. 3. porst h, burnett a, brock g, et al. sop conservative (medical and mechanical) treatment of erectile dysfunction. j sex med. 2013; 10:130-71. 4. corona g, mondaini n, ungar a, et al. phosphodiesterase type 5 (pde5) inhibitors in erectile dysfunction: the proper drug for the proper patient. j sex med. 2011; 8:3418-32. 117archivio italiano di urologia e andrologia 2019; 91, 2 sildenafil oral film table 3. how is the oral formulation received by patients? answer number % optimally 21 35.6 very well 36 61 without difference compared to the other formulations 2 3.4 with mistrust 0 0 total 59 100 archivio italiano di urologia e andrologia 2019; 91, 2 a. palmieri, m. silvani, b. giammusso, et al. 118 5. chen l, staubli se, schneider mp, et al. phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. eur urol. 2015; 68:674-80. 6. fagelman e, fagelman a, shabsigh r. efficacy, safety, and use of sildenafil in urologic practice. urology 2001; 57:1141-4. 7. govier f, potempa aj, kaufman j, et al. a multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. clin ther. 2003; 25:2709-23. 8. von keitz a, rajfer j, segal s, et al. a multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil eur urol. 2004; 45:499-507. 9. ströberg p, murphy a, costigan t. switching patients with erectile dysfunction from sildenafil citrate to tadalafil: results of a european multicenter, open-label study of patient preference. clin ther. 2003; 25:2724-37. 10. althof se. quality of life and erectile dysfunction. urology. 2002; 59:803-10. 11. maurice dh, wilson ls, rampersad sn, et al. cyclic nucleotide phosphodiesterases (pdes): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals., biochem soc trans. 2014; 42:250-6. 12. de toni l, de rocco ponce m, franceschinis e, et al. sublingual administration of sildenafil oro-dispersible film: new profiles of drug tolerability and pharmacokinetics for pde5 inhibitors. front pharmacol. 2018; 6; 9:59. 13. el-rashidy r. controlled release of sildenafil delivered by sublingual or buccal administration. wo 00/5477. 2002. 14. de siati m, saugo m, franzolin n. the start of pharmacological activity after sublingual administration of sildenafil citrate in 30 patients affected by erectile dysfunction. arch ital urol androl. 2003; 75:18-20. 15. wang y, chow mss, zuo z. mechanistic analysis of ph-dependent solubility and trans-membrane permeability of amphoteric compounds: application to sildenafil international journal of pharmaceutics. 2008; 352:217-224 16. rathbone mj, ponchel g, ghazali fa. systemic oral mucosal drug delivery and delivery systems. in: rathbone, m.j. (ed.), oral mucosal drug delivery. marcel dekker, inc., new york, 2004. 17. smyth hdc, hickey aj. carriers in drug powder delivery. american journal of drug delivery. 2005; 3:117-132. 18. parikh a, agarwal s, raut k. a review on applications of maltodextrin in pharmaceutical industry. ijpbs 2014; 4:67-74. 19. shweta kalyan, mayank bansal. recent trends in the development of oral dissolving film. international journal of pharm tech research. 2012; 4:725-733. 20. kathpalia h, gupte a. an introduction to fast dissolving oral thin film drug delivery systems: a review. current drug delivery. 2013; 10:667-684. 21. cocci a, capece m, cito g, et al. effectiveness and safety of orodispersible sildenafil in a new film formulation for the treatment of erectile dysfunction: comparison between sildenafil 100-mg filmcoated tablet and 75-mg oro-dispersible film. j sex med. 2017; 14:1606-1611. correspondence alessandro palmieri, md paolo verze, md marco capece, md department of urology, university of naples, naples (italy) mauro silvani, md urology unit, hospital "degli infermi", biella (italy) bruno giammusso, md morgagni clinic, catania (italy) giovanni liguori, md department of urology, university of trieste, trieste (italy) nicola mondaini, md urology unit, nuovo san giovanni di dio hospital, florence (italy) fabrizio palumbo, md urology unit, san giacomo hospital, monopoli, bari (italy) stefano pecoraro, md malzoni center, avellino (italy) oreste risi, md neuro-urology unit, treviglio, bergamo (italy) salvatore sansalone, md department of urology, university of tor vergata, rome (italy) fabrizio ildefonso scroppo, md urology unit, ospedale di circolo di varese, varese (italy) alessandro zucchi, md department of urology, university of perugia, perugia (italy) tommaso cai, md ktommy@libero.it department of urology, santa chiara hospital largo medaglie d'oro 9, trento (italy) stesura seveso 339archivio italiano di urologia e andrologia 2015; 87, 4 case report three-component hydraulic penile prosthesis malfunction due to penile fibrolipoma secondary to augmentative phalloplasty: a case report gabriele antonini 1, patrizio vicini 2, ettore de berardinis 1, arianna pacchiarotti 3, vincenzo gentile 1, paul perito 4 1 department of urology, “sapienza” rome university, rome, italy; 2 department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy; 3 department of obstetric gynecological science, “sapienza” rome university, rome, italy; 4 perito urology, coral gables hospital miami, florida, usa. fibrolipomas are an infrequent type of lipomas. we describe a case of a man suffering from subcutaneous penile fibrolipoma, who twelve months earlier has been submitted to augmentative phalloplasty due to aesthetic dysmorphophobia. the same patient three years earlier has been submitted to threecomponent hydraulic penile prostheses implantation due to erectile dysfunction. after six months from removing of the mass, the penile elongation and penile enlargement were stable, the prostheses were correctly functioning and the patient was satisfied with his sexual intercourse and life. the diagnostics and surgical characteristics of this case are reported. key words: penile fibrolipoma; augmentative phalloplasty; penis size; penile dysmorphophobia; three-component hydraulic penile prosthesis. submitted 22 may; accepted 30 september summary no conflict of interest declared. fibrolipoma in a patient submitted in the previous twelve months to augmentative phalloplasty due to aesthetic dysmorphophobia. the same patient two years earlier has been submitted to three-component hydraulic penile prostheses placement due to erectile dysfunction. case report we describe the case of a 52-years-old man who presented small penis and erectile dysfunction not responding to pde-5 inhibitors or pge1 infusions. after urological consultation he agreed to undergo an three-pieces hydraulic prostheses placement three years before. the surgery was performed with a standard peno-scrotal approach. the same patient agreed to undergo an augmentative phalloplasty twelve months before resulting in penis enlargement. these last procedure was performed on may 2013. under general anaesthesia, the sovrapubic liposuction was performed. fractions of fat were centrifuged, purified of serum and oil, put into 2-ml syringes. incision with a scalpel at the stretched preputium between two forceps was performed. by inserting and pulling back the coleman’s kobra cannula, purified body fat was transferred from the penis root upwards. overall 45 ml of purified fat cells was transferred. at the end of surgery the patient obtained an increase of 3 cm in circumference. before augmentation with autologous fat transfer the circumference of the penis in flaccid state was 8,5 cm, after augmentation with autologous fat transfer the circumference of the penis was 11,5 cm. twelve months later the patient was found to have a subcutaneous dorsal penis lump. this lump caused pain during erection and difficulty during a sexual intercourse because of the limited penile extension during erection. the trapped penis caused prostheses malfunctioning due to mass compression on cylinders and on the connections between cylinders and pump (figure 1). during penile examination, a lump of approximately 5 × 5 × 4 cm was palpated at the basis of penis, at the level of the proximal third and on the dorsal surface of the penis. on palpatory examination, the lump was hard in doi: 10.4081/aiua.2015.4.339 introduction as described in literature, penis length and width are an issue of social relevance (1, 2). some men otherwise considered as normal may require augmentation cosmetic surgery as a result of an abnormal perception of the dimension of the organ (penile dysmorphophobia). dysmorphophobia may be a functional problem (a man with normal penis but unsatisfied with its size during erection) or aesthetic problem (a man whose penis is normal but who is unsatisfied with its dimension in flaccid state) (3-5). most of elongation and enlargement phalloplasty surgeries have a more apparent effect rather than real effect, rising an increase of the penile size that is more evident during flaccid state rather than during erective status and these operations are exclusively performed in case of patients with aesthetic dysmorphophobia (3-6). in these men a simple operative procedure can be used to increase the volume of the penis by autologous fat transfer. at the same time, the penis can be lengthened by incision of the suspensory ligament below the symphysis, so called “augmentative phalloplasty” (7-10). we report a case of subcutaneous archivio italiano di urologia e andrologia 2015; 87, 4 g. antonini, patrizio vicini, e. de berardinis, a. pacchiarotti, v. gentile, p. perito 340 consistency, painless, mobile under the palpating finger. ultrasonography of the mass was performed using b-mode equipment (sonoscape s8, milestone company) and a linear 8.0 mhz transducer (l741, milestone company). ultrasonography showed a structure with a loss of homogenous echogenicity with multiple hyperechoic zones. under general anesthesia a transverse infrapubic incision of 3 cm at the base of penis was performed to remove the lump (figure 2) it was dissected from the lateral subcutaneous tissue easily but it was very difficult to dissect it from the penile neurovascular bundle and from the prostheses cylinders placed laterally respect to dorsal nerves of neurovascular bundle (figure 3). the connections between cylinders and the pump were freed from any fibrotic tissue (figure 4). attempt to activate the functioning of the sysfigure 1. showing lump at the base of the penis. figure 5. evaluate the correct functioning of the system. figure 6. the macroscopic view of lump during removing. figure 7. histologic caracteristics of fibrolipoma; the section shows intensive mature adipocytes mixed with fibrous tissue. figure 2. infrapubic incision. figure 3. dissection of the mass from penile neurovascular bundle and from the prostheses cylinders. figure 4. dissection of the mass from he connections between cylinders and the pump. tem was successful (figure 5). the mass (5 × 5 × 4 cm) had an elastic texture and was enclosed by a smooth, shining, vascular capsule (figure 6). on the cut surface, a large amount of the interior of the mass was milky-white and composed of homogeneous adipose-like tissue. the removed tissue was submitted to histological examination. as standard procedure the tissue samples of the mass were fixed in 10% buffered formalin and processed for paraffin embedding. the sections were deparaffinised, dehydrated and stained with haematoxylin and eosin. microscopic histopathological examination of the mass revealed adipose tissue with diffusely distributed mature adipocytes and septa of fibrous connective tissue with proliferating fibroblast (figure 7). on the basis of these clinical and histologic characteristics, a diagnosis was done of a subcutaneous penile fibrolipoma. there were no post surgery complications. after six months from third surgery, the penis elongation and prostheses functioning were good and stable, finally the patient was satisfied with his sexual intercourse and his sexual life. the satisfaction of surgical outcome was also assessed at 12 months following the surgery directly asking to the patients “are you satisfied with the result of your surgery”? the patient was satisfied with the outcome of operation. at 12 month, during the postoperative follow up visit, the patient reported a normal three-pieces hydraulic prostheses activation an was satisfied with his sexual life. discussion fibrolipoma is a histological variant of lipoma, the aetiology of this condition is not well known, usually in other organs this lesion is an rare benign tumour (11, 12). the consistency of the fibrolipoma can be soft or firm depending on the amount of fibrous tissue and the treatment is usually an surgical excision (13). as described in literature, in patients affected by aesthetic dysmorphophobia, a simple operative procedure can be used to enlarge the volume of the penis by autologous fat transfer. at the same time, the penis can be lengthened by release of the suspension ligament below the symphysis, so defined “augmentative phalloplasty” (7-10). probably bleeding and lymphorrhea after this treatment, together a large amount of fat implanted, could play a role in the aetiology of penis fibrolipoma such as our case. we suggest to use a compressive bandage on the sovrapubic zone for 4-6 weeks and not to exceed with the amount of fat transferred during the surgery. moreover we suggest not to perform the augmentative phalloplasty in patient with previous hydraulic penile prostheses surgery for not damaging the implant. diagnosis of the lesion was achieved by clinical penile palpation and ultrasonography. in addition to that in the patient’s preoperative diagnosis a magnetic resonance imaging (mri) should be useful and performed (14). in our patient, surgical resection of the lump was very difficult because of the near connection with penis neurovascular bundle and the adherences to it. most probably, the mri could have provided us a better understanding of the involvement of these structures. augmentative phalloplasty with autologous fat transfer and section of the suspension ligament below the symphysis is a generally safe and effective procedure. nevertheless complications may occur, even with a meticulous observation of the steps of the surgery. the complete removing of the mass, consisting in surgical excision with capsular dissection, should be performed but it is not always easy, and in patient with previous penile prosthesis may be useful to recovery a normal prostheses activation. mri helps to determine the best surgical approach increasing the accuracy of diagnosis and treatment. references 1. abecassis m. penis augmentation and elongation. ii international symposium in bonn on aesthetic plastic surgery, bonn, germany, april, 25, 1998 2. el-saweiji a. penisvergroßerung in: lemperl (eds) asthetische chirurgie. 9 erg. lfg 6/03, ecomed verlag, landsberg, 2003. 3. woodohuse crj. the sexual and reproductive consequences of congenital genitourinary anomalies. j urol. 1994; 152:645-51. 4. lehman p. running scared: masculinity and the representation of the male body. philadelphia, pa, temple university press, 1993. 5. austoni e, guarneri a, cazaniga a. a new technique for augmentation phalloplasty: surgery with bilateral saphenous grafts – three years of experience: eur urol. 2002; 42:245-253. 6. alei g, letizia p, ricottilli f, et al. original technique for penile girth augmentation through porcine dermal acellular grafts: results in a 69-patient series. j sex med 2012; 9:1945-53. 7. panfilov d: penis enlargement and elongation. power-point presentation, 13th world congress of ipras, sydney, 2003. 8. panfilov de. augmentative phalloplasty. aesth. plast. surg. 2006; 30:183-197. 9. coleman s: long-term results using autologous fat: a new phylosophy. ii international symposium in bonn on aesthetic plastic surgery, bonn (germany), 1998. 10. horton ce, vorstman b, teasley d, winslow b: hidden penis release: adjunctive suprapubic lipectomy. ann plast surg 1987; 19:131-134. 11. kuzaka b, pykało r [fibrolipoma of the testis). patol pol 1989; 40:243-245 (in polish). 12. mitchiner, ph enlargements of the testis and epididymis. ann roy coll surg engl.1948; 3:176-180. 13. manjuntha bs, pateel gs, shah v. oral fibrolipoma-a rare histological entity: report.of 3 cases and review of literature. j dent. 2010; 7:226-231. 14. cappabianca s, colella g, pezzullo mg, et al. lipomatous lesions of the head and neck region: imaging findings in comparison with histological type. radiol med. 2008; 42:758-770. 341archivio italiano di urologia e andrologia 2015; 87, 4 three-component hydraulic penile prosthesis malfunction due to penile fibrolipoma secondary to augmentative phalloplasty: a case report correspondence gabriele antonini, md ettore de berardins, md vincenzo gentile, md department of urology, “sapienza” rome university, rome, italy patrizio vicini, md (corresponding author) patriziovicini@gmail.com department of urology, “i.n.i.” italian neurotraumatologic institute grottaferrata, rome, italy arianna pacchiarotti, md department of obstetric gynecological science, “sapienza” rome university, rome, italy paul perito, md perito urology, coral gables hospital miami, florida (usa) 313archivio italiano di urologia e andrologia 2017; 89, 4 original paper five-year prospective study on cardiovascular events, in patients with erectile dysfunction and hypotestosterone rosanna iacona 1, vito bonomo 1, mariaconcetta di piazza 1, angela sansone 1, manuela usala 2, salvatore novo 1, carlo pavone 3 1 chair and division of cardiology, university hospital “paolo giaccone”, palermo, italy; 2 orthopedic institute rizzoli department of sicily region (drs), bologna, italy; 3 chair and division of urology, university hospital “paolo giaccone”, palermo, italy. objective: testosterone levels play a role in cardiac and vascular pathology. in the present study we investigated the prognostic significance of this hormone for cardiovascular outcome, in a 5-year follow-up. materials and methods: our cohort included 802 adult subjects, from 40 to 80 years. patients were excluded if they had a past history of peripheral or coronary artery disease, and revascularization. a blood sample was drawn to valuate testosterone level, and we considered normal testosterone levels 300 ng/dl. fmd (flow mediated dilatation) of the brachial artery was assessed by measuring the increase of the brachial artery diameter during reactive hyperemia after transient forearm ischemia. b-mode longitudinal images of the brachial artery were obtained at the level of the antecubital fossa. the fmd was defined as the percentage change in the brachial artery diameter 60 s after releasing the ischemic cuff. erectile dysfunction (erd) was assessed by the international index of erectile function-5 (iief-5) score questionnaire. we considered composite end points including the following major adverse cardiovascular events (maces) results: subjects with lower serum testosterone levels (n = 332) had higher prevalence of traditional cardiovascular risk factors, such as hypertension (p = 0.009), diabetes (p = 0.03), dyslipidemia (p < 0.0001), obesity (p = 0.002), and endothelial function score (p < 0.0001). ami, death after ami, major stroke and all clinical events were more frequent (p < 0.001) in patients with testosterone levels < 300 ng/dl. further, by multiple logistic regression analysis we found that only dyslipidemia (p = 0,001), obesity (p = 0,007), testosterone < 300 ng/dl (p < 0,0001) and ed (p < 0,0001) were independent predictors of future events. conclusions: a therapeutic intervention on testosterone may not only have a positive effect on the cardiovascular system but also an important role in preventing new cardiovascular events. key words: erectile dysfunction; cardiovascular events; prevention. submitted 22 august 2017; accepted 23 october 2017 summary no conflict of interest declared. gy (1). in particular, in the present study we investigated the prognostic significance of this hormone for cardiovascular outcome, in a 5-year follow-up. we aimed to assess whether baseline testosterone levels may be predictors of future cardiovascular events in a cohort of intermediate cardiovascular risk patients, according to framingham risk score, and screened for the presence of ed in our centre of early diagnosis of preclinical and multifocal atherosclerosis and for cardiovascular prevention. the follow-up period was 5 years. we therefore aimed to test the hypothesis that measuring levels of this hormone, can provide information not only on the progression of atherosclerosis disease and therefore about ed, helping to define the prognosis, but can also be considered predictive of the risk of developing cardiovascular events, independently from common risk factors. materials and methods our cohort included 802 adult subjects, males from 40 to 80 years (mean age of the whole population was 57.52 ± 13.85 years old). they were intermediate cardiovascular risk patients, according to framingham risk score, all referred between 2009 and 2014 to our department of cardiology. patients were excluded if they had a past history of peripheral artery disease, coronary revascularization, angina pectoris,myocardial infarction, carotid surgery or cerebrovascular event. the adopted procedures were in agreement with the helsinki declaration of 1975 as revised in 1983 and were approved by the local ethic council. all patients gave their informed consent to participate to the study, and at admission answered a questionnaire on personal and medical items, including age, past medical history and use of medications. the main cardiovascular risk factors were considered. a blood sample was drawn in the morning, after 12-14 h overnight fast, to valuate testosterone level, and we considered normal testosterone levels n300 ng/dl (2, 3). flow mediated dilatation (fmd) of the brachial artery was assessed (4) by measuring the increase of the brachial artery diameter during reactive hyperemia after transient forearmischemia. b-mode longitudinal images of the brachial artery were obtained at the level of the antecubital fossa. doi: 10.4081/aiua.2017.4.313 introduction endothelial dysfunction (ed) represents the earliest event in the development of atherosclerotic plaque, and it actually occurs when a structural lesion is still not evident. clinical and experimental evidence suggests that testosterone levels play a role in cardiac and vascular patholoiacona_stesura seveso 03/01/18 09:47 pagina 313 archivio italiano di urologia e andrologia 2017; 89, 4 ro. iacona, v. bonomo, m. di piazza, a. sansone, m. usala, s. novo, c. pavone 314 after marking the optimal position of the transducer, baseline images of the brachial artery were digitally stored. arterial flow to the forearm was interrupted by insufflation of the forearm cuff for 5 min by 200 mmhg or 50 mmhg above systolic blood pressure, whichever was highest. the fmd was defined as the percentage change in the brachial artery diameter 60 s after releasing the ischemic cuff. erectile dysfunction (erd) was assessed by the international index of erectile function-5 (iief-5) score questionnaire, which was preferentially filled in by the patient himself or, if required, by a trained interviewer. the possible score for the iief-5 ranges from 5 to 25, and erd can be classified into five categories based on the score: severe (5-7), moderate (8-11), mild-to-moderate (12-16), mild (17-21), and no erd (22-25) (5). the median follow-up time for major cv events was 5.1 years. except for 13 participants (excluded from the population) who moved abroad, there was no loss to follow-up in the study. we considered composite end points including the following major adverse cardiovascular events (maces): acute myocardial infarction (ami), death for ami, minor stroke, major stroke, and death for stroke. results baseline clinical characteristics, laboratory data and ultrasonography findings in relation to plasma values of testosterone are summarized in table 1. subjects with lower serum testosterone levels (n = 332) had higher prevalence of traditional cardiovascular risk factors, such as hypertension (p = 0.009), diabetes (p = 0.03), dyslipidemia (p < 0.0001), obesity (p = 0.002), and endothelial function score (p < 0.0001). there were no significant differences in age and in the presence of smoking or familiarity. at five years follow-up we had 47 (5.8%) ami and 27 (3.45%) minor or major stroke. 3.98% was the cardiovascular mortality. ami, death after ami, major stroke and all clinical events were more frequent (p < 0.001) in patients with testosterone levels < 300 ng/dl at baseline (figure 1). table 2 shows the baseline clinical characteristics, laboratory data and ultrasonographic findings in relation to the occurrence of all clinical events (n = 90), as registered in the 5-year follow-up. further, by multiple logistic regression analysis we found that, among all evaluated baseline clinical and laboratory variables, only dyslipidemia (p = 0,001), obesity (p = 0,007), testosterone < 300 ng/dl (p < 0,0001) and ed (p < 0,0001) were independent predictors of future events. discussion several studies had stressed the relation between lower serum testosterone levels and erectile dysfunction, which is also a result of ed. ed is therefore the common etiological factor for erectile dysfunction and cardiovascular events. in our study we wanted to define not only the known relation between ed and a worse erectile function in patients with lower levels of testosterone, but we also evaluate if this hormone could have an influence on cardiovascular outcome, beyond traditional risk factors and preclinical atherosclerosis. there is actually increasing evidence that table 1. relations between total serum testosterone, fmd and ed according to iief-5 (n = 802). no ed mild mild to moderate severe ed moderate ed ed ed total serum testosterone model 1 1.02 0.98 0.90 0.85 0.78 or (ci 95%) (0.89 to 1.16) (0.64 to 1.10) (0.78 to 1.02)** (0.72 to 0.97)*** (0.62 to 0.86)*** model 2 1.03 0.95 0.88 0.83 0.80 or (ci 95%) (0.91 to 1.2) (0.63 to 1.12) (0.80 to 1.06)** (0.77 to 0.95)*** (0.58 to 0.86)*** fmd (%) model 1 1.04 0.94 0.81 0.76 0.68 or (ci 95%) (0.96 to 1.18) (0.82 to 1.07)* (0.69 to 0.94)*** (0.63 to 0.83)*** (0.59 to 0.79)*** model 2 1.06 0.96 0.84 0.73 0.70 or (ci 95%) (1.02 to 1.22) (0.87 to 0.98)* (0.70 to 0.93)*** (0.66 to 0.79)*** (0.64 to 0.73)*** fmd: flow-mediated vasodilation; or: odd ratio; ci: confidence inverval; ed: erectile dysfunction; iief-5: international index of erectile function-5; fmd: artery flow-mediated vasodilation. model 1: adjusted for age. model 2: adjusted for age and cardiovasclular risk factors. *p < 0.05. **p < 0.01. ***p < 0.001. table 2. predictors of cardiovascular events at follow up. univariate logistic regression multiple regression odd ration 95% ci p odd ration 95% ci p diabetes 2.37 1.7797 to 3.1623 < 0.0001 hypertension 4.14 3.0584 to 5.6145 < 0.0001 current smoking 1.34 1.0218 to 1.7823 0.03 familiarity 1.38 1.0485 to 1.8294 0.02 dyslipidemia 4.14 3.0584 to 5.6145 < 0.0001 2.21 1.3944 to 3.5325 0.001 obesity 2.70 1.9326 to 3.9880 < 0.0001 2.23 1.2492 to 3.9924 0.007 testosterone ≤ 300 ng/dl 10.10 7.2609 to 14.0694 < 0.0001 4.90 2.9971 to 8.0251 < 0.0001 erectile function (score) 0.75 0.7275 to 0.7890 < 0.0001 0.86 0.8165 to 0.9094 < 0.0001 endothelial function (%) 0.81 0.7891 to 0.8434 < 0.0001 0.87 0.8321 to 0.9201 < 0.0001 iacona_stesura seveso 03/01/18 09:47 pagina 314 low testosterone levels are associated with increased cardiovascular mortality in men (6-9). on the other hand, there was an association of low testosterone levels with decreased fmd independent of major cardiovascular confounders, so low levels of this hormone may be associated with impaired ed as measured by fmd. conclusions given the demonstrated relationship to events at the follow up, a possible therapeutic intervention on testosterone (with attention to the potentially increased risk of prostate cancer that remains a matter of debate), may not only have a positive effect on the cardiovascular system but also an important role in preventing newcardiovascular events, through a more accurate stratification of patients. references 1. novo s, iacona r, bonomo v, et al. erectile dysfunction is associated with low total serum testosterone levels and impaired flowmediated vasodilation in intermediate risk men according to the framingham risk score, atherosclerosis 2015; 238:415-419. 2. haring r, völzke h, steveling a, et al. low serum testosterone levels are associated with increased risk of mortality in a populationbased cohort of men aged 20-79, eur heart j. 2010; 31:1494-1501. 3. laaksonen de, niskanen l, punnonen k, et al. testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men, diabetes care. 2004; 27:1036-1041. 4. corretti mc, anderson tj, benjamin ej, et al. guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force, j am coll cardiol. 2002; 39:257-265. 5. rhoden el, telöken c, sogari pr, vargas souto ca. the use of the simplified international index of erectile function (iief-5) as a diagnostic tool to study the prevalence of erectile dysfunction. int j impot res. 2002; 14:245-250. 6. sharma r, oni oa, gupta k, et al. normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. eur heart j. 2015; 36:2706-2715. 7vlachopoulos c, jackson g, stefanadis c, montorsi p. erectile dysfunction in the cardiovascular patient. eur heart j. 2013; 34:2034-2046. 8. gencer b, mach f. testosterone: a hormone preventing cardiovascular disease or a therapy increasing cardiovascular events? eur heart j 2015. 9. pavone c, curto f, anello g, et al. prospective, randomized, crossover comparison of sublingual apomorphine (3 mg) with oral sildenafil (50 mg) for male erectile dysfunction. j urol. 2008; 179(5 suppl):s92-4. doi: 10.1016/j. juro.2008.03.144. pmid: 18405767. 315archivio italiano di urologia e andrologia 2017; 89, 4 erectile dysfunction and cardiovascular risk figure 1. major adverse cardiovascular events (maces) at mean follow-up of 5.1 years according to testosterone levels. 80 70 60 50 40 30 20 10 0 p < 0.001 p < 0.001 p < 0.001 p < 0.001 ami death after ami minor stroke maior stroke death after stroke all testosterone ≤ 300 ng/dl (n=142) testosterone > 300 ng/dl (n=38) correspondence rosanna iacona, md (corresponding author) rosanna.iacona@virgilio.it vito bonomo, md vito_bonomo@alice.it mariaconcetta di piazza, md mconcettadipiazza@libero.it angela sansone, md angela.sansone2609@gmail.com salvatore novo, md sav.novo@libero.it chair and division of cardiology, university hospital “paolo giaccone” via del vespro 129, 90127 palermo, italy manuela usala, md manuela.usala@ior.it orthopedic institute rizzoli department of sicily region (drs) via giulio cesare pupilli 1, 40136 bologna, italy carlo pavone, md carlo.pavone@unipa.it chair and division of urology, university hospital “paolo giaccone”, via del vespro 129, 90127 palermo, italy iacona_stesura seveso 03/01/18 09:47 pagina 315 253archivio italiano di urologia e andrologia 2017; 89, 4 original paper risk factors for benign prostatic enlargement: the role of lifestyle habits at younger age. the #controllati2017 initiative study group vincenzo mirone 1, giuseppe carrieri 2, giuseppe morgia 3, luca carmignani 4, giuseppe vespasiani 5, fabio parazzini 6, walter artibani 7 1 università degli studi di napoli federico ii, uoc di urologia della a.o.u. federico ii napoli, italy; 2 dipartimento nefro/urologico clinica urologica e centro trapianti di rene, università degli studi di foggia, italy; 3 università degli studi di catania presidio ospedaliero policlinico, catania, italy; 4 università degli studi di milano, divisione universitaria di urologia, irccs policlinico san donato milano, italy; 5 uoc urologia, fondazione ptv policlinico tor vergata, roma, italy; 6 università degli studi di milano dipartimento di scienze cliniche e di comunità, irccs policlinico, milano, italy; 7 azienda ospedaliera universitaria integrata, verona, italy. objective: the risk factors for benign prostatic enlargement (bpe) are not well understood and particularly few data are available from italian population. materials and methods: this was an observational cross sectional study aimed to examine the association between several risk factors and bpe. during the “#controllati2017” initiative, men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counseling about urologic or andrologic conditions. each participating man underwent a physical examination including digital rectal examination (dre). further he was asked about his medical history, urologic symptoms, sexual activity and related problems. diagnosis of bpe was made by the urologist after dre. results: out of the 1902 [mean age 54 years (sd 12, range 18-92)] considered men, a total of 603 subjects (31.7%) had diagnosis of bpe. the diagnosis of bpe increased from 9.3% in men aged < = 50 years, to 34.1% in those aged 51-60 years and to 58.7% among men aged > 60 years. a history of hypertension, diabetes, heart diseases, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased risk of bpe in the total series and, although not always in a statistically significant way, in strata of age. physical activity (pa) was significantly associated with a decreased risk of bpe. we have further analyzed the risk of bpe in men with one or more of the identified risk factors (i.e. hypertension, diabetes, heart disease, hypercholesterolemia, hypertriglyceridemia and low pa): the risk of bpe increased with number of risk factors reported by the subjects. the estimated risk were higher among younger men. conclusion: in our study a history of hypertension, diabetes, heart disease, hypercholesterolemia and hypertriglyceridemia increased the risk and physical activity lowered the risk of bpe. this risk profile was observed also in men aged < 50 years. key words: benign prostatic enlargement (bpe); hypertension; diabetes; hearth disease; hypercholesterolemia; hypertriglyceridemia; physical activity. submitted 29 november 2017; accepted 8 december 2017 summary no conflict of interest declared. introduction despite the high prevalence of the conditions, the risk factors for benign prostatic hyperplasia (bph) or benign prostatic enlargement (bpe) are not well understood. some studies have suggested a role of diabetes or hypertension in the pathogenesis of pbh (1). further, hdl-cholesterol levels were an independent predictors of prostate enlargement (2). other studies have shown that body mass index and waist circumference were positively related with prostate volume (3, 4). all these factors are associated with metabolic syndrome, a condition that increase the risk of cardiovascular diseases (5). further, it has been suggested that regular physical activity (pa) may decreased the risk of bpe (6). these findings suggest that healthy life habits may lower the risk of growth of prostatic volume. available data on the role of these factors are scanty and particularly few data are available from italian population. in june 2017, the italian society of urology conducted the “#controllati2017” preventive initiative. in the framework of this preventive campaign, data have been collected on determinants of the risk of bpe. materials and methods this was an observational cross sectional study aimed to examine the association between several risk factors and bpe. during the “#controllati2017” (1st june-15th july 2017) initiative, males of any age were offered to attend a free of charge visit for counseling about urologic or andrologic conditions in urological centers affiliated to the italian society of urology (società italiana di urologia). a pamphlet inviting men for a free of charge check-up and listing participating centers was left in chemists and general practitioners’ waiting rooms; an advertising campaign was set in the press and broadcast media. each participating man underwent a physical examination including digital rectal examination (dre) and was doi: 10.4081/aiua.2017.4.253 mirone_stesura seveso 03/01/18 12:12 pagina 253 archivio italiano di urologia e andrologia 2017; 89, 4 v. mirone, g. carrieri, g. morgia, l. carmignani, g. vespasiani, f. parazzini, w. artibani 254 asked by the urologist about his medical history, urologic symptoms, sexual activity and related problems. a total of 173 centers participated to the initiative. epidemiological data were collected in 61 centers for a total of 2572 men who filled the questionnaire. data were recorded with a simple questionnaire used by all centers. the first section, about age and life habits was completed by the patient. history of hypertension, diabetes, hearth diseases and other medical conditions, and the findings of the clinical examination were recorded by the urologist. diagnosis of bpe was made by the urologist after dre. erectile dysfunction (ed) was diagnosed according to the definition of the nih consensus development panel (7). the 2002 international continence society definitions were used for frequency, nicturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying (8). the section on pa included questions on self reported intensity of activity at work and in leisure time separately. patients were asked about their pa, which were classified into five categories (scores between 1 and 5) corresponding to ‘very heavy’, ‘heavy’, ‘average’, ‘moderate’ and ‘light’. the scores of the two highest levels of occupational and leisure pa were combined, in order to obtain adequate numbers in the categories. for the purpose of the present paper we compared the characteristics of subjects with and without bpe. mean (standard deviation, sd), median (range) or frequency (percent,%) were computed as appropriate. odds ratios (or), and the corresponding 95% confidence intervals (ci), were derived using unconditional multiple logistic regression, fitted by the method of maximum likelihood, in which the dependent variable was the presence (case) or absence (control) of bpe and the independent ones were the exposures considered in the analysis. we included in the model potential co-variates table 1. distribution of 603 subjects with and 1299 without benign prostatic enlargement according to selected factors and strata of age. ≤ 50 years 51-60 years ≥ 61 years no bpe bpe adj or no bpe bpe adj or no bpe bpe adj or total series n = 681 n = 70 (95% ci) n = 382 n = 198 (95% ci) n = 236 n = 335 (95% ci) or (95% ci) (90.7) (9.3) (65.9) (34.1) (41.3) (58.7) bmi (kg/m2) < 25 340 (50.9)* 35 (50.7) 1 154 (41.1) 61 (31.6) 1 87 (37.3) 116 (35.4) 1 1 ≥ 25 < 30 254 (38.0) 25 (36.2) 1.0 (0.6-1.6) 168 (44.8) 95 (49.2) 1.4 (1.0-2.1) 117 (50.2) 152 (46.3) 1.0 (0.7-1.9) 1.4 (1.1-1.7) ≥ 30 74 (11.1) 9 (10.8) 1.2 (0.5-2.6) 53 (14.1) 37 (19.2) 1.2 (0.6-2.2) 29 (12.4) 60 (18.3) 1.55 (0.9-2.6) 1.9 (1.4-2.5) smoking habits never smokers 391 (58.1) 34 (48.6) 1 195 (51.3) 87 (43.9) 1 102 (43.8) 140 (42.3) 1 1 ever smokers 282 (41.9) 36 (51.4) 1.5 (0.8-2.7) 185 (48.6) 111 (56.1) 1.3 (0.8-2.0) 131 (56.2.) 191 (57.7) 1.1 (0.7-1.7) 1.4 (0-9-1.8) occupational pa no 122 (18.9) 13 (21.0) 1 77 (21.9) 36 (19.6) 1 43 (22.3) 73 (28.2) 1 1 low 203 (31.4) 20 (32.3) 0.9 (0.4-1.9) 112 (31.9) 56 (30.4) 1.1 (0.7-1.8) 54 (28.0) 82 (31.7) 0.9 (0.5-1.9) 0.9 (0.6-1.1) moderate 193 (29.8) 23 (37.1) 1.1 (0.6-2.3) 108 (30.8) 62 (33.7) 1.2 (0.7-2.0) 79 (40.9) 80 (30.9) 0.6 (0.4-1.0) 0.8 (0.7 -1.1) intense 129 (19.9) 6 (9.7) 0.4 (0.2-1.2) 54 (15.4) 30 (16.3) 1.2 (0.7-2.2) 17 (8.8) 24 (9.3) 0.8 (0.4-1.7) 0.6 (0.4-0.9) leisure pa no 61 (9.1) 5 (7.9) 1 40 (11.0) 30 (16.2) 1 27 (12.3) 41 (12.9) 1 1 low 195 (29.2) 20 (31.8) 1.3 (05-3.5) 115 (31.7) 51 (27.6) 0.6 (0.3-1.1) 62 (28.2) 90 (28.4) 1.0 (0.5-1.7) 0.7 (0.5-1.0) moderate 285 (42.6) 29 (46.0) 1.2 (0.5-3.3) 157 (43.2) 70 (37.8) 0.6 (0.3-1.0) 97 (44.1) 152 (48.0) 1.0 (0.6-1.8) 0.8 (0.6-1.1) intense 128 (19.1) 9 (14.3) 0.9 (0.3-2.8) 51 (14.0) 34 (18.4) 0.9 (0.5-1.7) 34 (15.4) 34 (10.7) 0.7 (0.3-1.3) 0.6 (0.4-0.9) hypertension no 595 (90.6) 50 (76.9) 1 256 (70.0) 106 (56.7) 1 118 (51.8) 150 (45.7) 1 1 yes 62 (9.4) 15 (23.1) 2.9 (1.5-5.4) 110 (30.0) 81 (43.3) 1.8( 1.2-2.6) 110 (48.2) 178 (54.3) 1.2 (0.9-1.8) 3.1 (2.5-3.8) diabetes no 652 (99.2) 62 (98.4) 1 341 (95.0) 164 (90.6) 1 198 (89.2) 266 (83.4) 1 1 yes 5 (0.8) 1 (1.6) 2.1 (0.2-18.3) 18 (5.0) 17 (9.4) 2.0 (1.0-3.9) 24 (10.8) 53 (16.6) 1.6 (0.9-2.8) 3.7 (2.5-5.4) hearth disease no 650 (99.1) 61 (96.8) 1 332 (93.3) 164 (91.1) 1 189 (87.5) 245 (79.8) 1 1 yes 6 (0.9) 2 (3.2) 3.6 (0.7-18.0) 24 (6.7) 16 (8.9) 1.2 (0.7-2.6) 27 (12.5) 62 (20.2) 1.8 (1.1-2.9) 3.5 (2.5-5.0) hypertriglyceridaemia no 601 (91.9) 57 (87.7) 1 302 (86.0) 152 (85.4) 1 181 (85.8) 257 (84.3) 1 1 yes 53 (8.1) 8 (12.3) 1.6 (0.7-3.5) 49 (14.0) 26 (14.6) 1.1(0.6-1.8) 30 (14.2) 48 (15.7) 1.1 (0.7-1.9) 1.4 (1.1-1.9) hypercholesterolaemia no 533 (81.0) 49 (74.2) 1 263 (73.9) 122 (67.4) 1 157 (71.7) 212 (68.0) 1 1 yes 125 (19.0) 17 (25.8) 1.5 (0.8-2.7) 93 (26.1) 59 (32.6) 1.4 (0.9-2.0) 62 (28.3) 100 (32.0) 1.2 (0.8-1.7) 1.6 (1.3-2.0) or: odds ratio; ci: confidence interval; *in some cases the sum does not add up the total due to missing values. mirone_stesura seveso 03/01/18 12:12 pagina 254 considered as categorical variables. the terms included in the model were those found statistically significantly associated with the risk of bpe in the crude analysis. further, we computed an overall risk score including all factors found statistically significantly associated with the risk of bpe in the crude analysis of the total series. subjects were classified according the presence of none, 1,2 3 or more factor and corresponding or were computed. results overall, 2572 men were observed in 61 participating centers: the mean number of attending men per center was 42 (median 35, range 4-126). their mean age was 54 years [standard deviation (sd) 12, range 18-92]. after exclusion of men who did not filled the demographic questionnaire and those who underwent previous partial and complete prostatectomy, we analyzed data from 1902 men, aged 54 years (sd 12, range 1892). the reason for the visit was urinary symptoms in 318 (16.7%), sexual problems in 234 (12.3%), renal disease in 37 (2.0%) and prostatic problems in 346 (18.2%). prevention was the only reason for consultation in 1156 subjects (60.8%, each man could indicate one reason or more). out of the 1902 considered men, a total of 603 subjects (31.7%) had diagnosis of bpe. the diagnosis of bpe increased from 9.3% in men aged <=50 years, to 34.1% in those aged 51-60 years and to 58.7% among men aged > 60 years. the general characteristics of study subjects according to the diagnosis of bpe according to class age are shown in table 1. a history of hypertension, diabetes, hearth disease, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased bpe risk in the total series and, although not always in a statistically significant way, in all the three considered strata of age. pa was significantly associated with a decreased risk of bpe. we have further analyzed the risk of bpe in men with one or more of the identified risk factors (i.e. hypertension, diabetes, hearth disease, hypercholesterolemia and hypertriglyceridemia and pa): the risk of bpe increased with number of risk factors reported by the subjects. the estimated or were higher among younger men (table 2). table 3 considers the frequency of urinary symptoms among men with a diagnosis of bpe in strata of age. the frequency of all symptoms increased with age and dysuria was the most common symptoms at all ages. considering subjects for which the information was available, ed was reported in the 39,8% (225/565) of men with bpe and 16.3% (201/1235) of those without bpe (adj chi suare p < 0.05). this difference in the frequency of de was consistent in the three considered strata of age: in particular considering men aged < 50 years the frequency of ed was 17.5% (11/63) among the men with bpe and 9.9% (64/644) among those without bpe (adj chi square = 0.06). discussion the general results of this analysis show that a history of hypertension, diabetes, hearth disease, hypercholesterolemia and hypertriglyceridemia increase the risk of bpe at all ages. a regular pa tended to decrease the risk. interestingly these factors were associated with pbe risk also in men aged 50 years or less, thus underlining the role of a healthy life style among younger men. this suggestion was also confirmed when we have considered the risk bpe among men with one, two or three of the factors found associated with the risk of pbe: the presence of more risk factors was more markedly associ255archivio italiano di urologia e andrologia 2017; 89, 4 risk factors for benign prostatic enlargement table 2. association between benign prostatic enlargement (bpe) and number of risk factors. ≤ 50 years 51-60 years ≥ 61 years total series no bpe bpe adj or no bpe bpe adj or no bpe bpe adj or adj or n = 681 n = 70 (95% ci) n = 382 n = 198 (95% ci) n = 236 n = 335 (95% ci) (95% ci) (90.7) (9.3) (65.9) (34.1) (41.3) (58.7) number of risk factors reported by the subject 0 494 (72.5) 42 (60.0) 1 187 (49.0) 72 (36.4) 1 82 (34.8) 95 (28.4) 1 1 1 134 (19.7) 17 (24.3) 1.8 (0.8-3.3) 122 (31.9) 75 (37.9) 1.7 (1.1-2.6) 81 (34.3) 105 (31.3) 0.9 (0.6-1.6) 1.3 (1.0-1.8) 2 38 (5.6) 7 (10.0) 2.3 (0.8-6.7) 44 (11.5) 31 (15.7) 1.9 (1.0-3.4) 43 (18.2) 78 (23.4) 1.1 (0.6-1.9) 1.5 (1.0-2.2) ≥ 3 15 (2.2) 4 (5.7) 3.5 (1.0-11.6) 29 (7.6) 20 (10.1) 2.0 (1.0-4.1) 30 (12.7) 57 (17.0) 1.9 (1.0-3.7) 2.1 (1.4-3.3) aor: adjusted odds ratio. including terms for bmi and age. table 3. association between benign prostatic enlargement (bpe) and urinary symptoms. ≤ 50 years 51-60 years ≥ 61 years no bpe bpe no bpe bpe no bpe bpe no. (%) no. (%) no. (%) no. (%) no. (%) no. (%) urgency 96 (14.1)* 10 (14.3) 28 (7.3) 32 (16.2) 11 (4.7) 52 (15.5) nicturia 52 (7.6) 17 (24.3) 47 (12.3) 61 (30.8) 33 (14.0) 115 (34.3) dysuria 86 (12.6) 38 (51.4) 92 (24.1) 108 (54.5) 74 (31.4) 212 (63.3) frequency 46 (6.8) 27 (38.6) 48 (12.7) 79 (39.9) 24 (10.2) 131 (39.1) incomplete voiding sensation 70 (10.3) 32 (45.7) 54 (14.1) 80 (40.4) 26 (11.0) 142 (42.4) *in some cases the sum does not add up the total due to missing values. mirone_stesura seveso 03/01/18 12:12 pagina 255 archivio italiano di urologia e andrologia 2017; 89, 4 v. mirone, g. carrieri, g. morgia, l. carmignani, g. vespasiani, f. parazzini, w. artibani 256 ated with the risk of bpe in men aged 50 years or less. the role of modifiable lifestyle factors on the risk of bph has been widely suggested (9). for example, a review of the literature conducted in the late 2000 and including eight studies has shown, compared to the sedentary group, a pooled odds ratios for bph or luts of 0.70 (95% ci 0.44-1.13, p = 0.14), 0.74 (95% ci 0.60-0.92, p = 0.005), and 0.74 (95% ci 0.59-0.92, p = 0.006) for men engaging in light, moderate, and heavy physical activity, respectively (6). we confirm these findings, in particular the protective effects of pa was more evident among younger men. obesity, elevated fasting plasma glucose, diabetes, dyslipidemia, and the metabolic syndrome may all significantly increase the risks of bph and low urinary tract symptoms (10-12). in our study diabetes, hypercholesterolemia, hypertrigliceridemia were associated with an increased risk of bpe. further a history of hypertension and hearth diseases increased the risk. all these findings underline that bpe shares similar risk factor with metabolic syndrome and cardiovascular diseases. the biological link between these risk factors and the prostatic growth is not completely understood. however, for example, it has been shown that lipids (oxidized low-density lipoprotein, ldl) increase in vitro the secretion of growth and pro-inflammatory factors by human stromal bph cells in culture (13). along this line in a clinical perspective, the addition of statins to standard therapy for bhp lowered prostate volume (14). it has been suggested that metabolic syndrome-dependent prostate growth may play a major role among older men (15). an interesting findings of the present study is the observation that the or of bpe associated with the presence of several risk factors such as pa and hyperlipidemia, diabetes and hypertension were higher (although no statistically significantly different) among younger than older men. this findings underline the role of encouraging healthy lifestyle habits among men under the 50 years of age in order to reduce the risk of bph. limits as previously discussed in the paper reporting the results of the #controllati2016 initiative (16), the major flaw of this study is the fact that the study population were men voluntarily presenting to the participating centers and physicians associated to the italian society of urology (siu). along this line the observed frequency of bpe in this population, about 30%, is higher than reported in the literature (17). further, the participating centers were not randomly identified among all members, so they cannot be considered representative of all italian centers. however, they were well distributed over the main areas of the country and there were no marked differences in the results among centers in various large italian areas, giving strong support to the consistency of the general results. likewise, the prevalence of hypertension and diabetes and overweight were largely similar to the general italian population. for example the percentage of hypertensive subjects was largely consistent with that of the italian population (18) and with the results of the #controllati2016 survey (16). in any case, any inference from the present analysis must be made in strictly comparative terms and strictly referred to men attending urologic services. the diagnosis of bpe was based on dre that tends to underestimate the prostatic volume (17). in any case any misclassification of men with or without bpe should lower the observed associations. the strengths of the study included the fact that it provides information from a large series of men identified in all parts of italy. further, the participation rate was very high. along this line, the patients presented themselves voluntarily to the physician, so their answers to all questions should be truthful. conclusions in our study a history of hypertension, diabetes, hearth disease, hypercholesterolemia and hypertriglyceridemia increased the risk and physical activity lower the risks of bpe. these findings are consistent with other studies. the findings suggest that bpe risk is associated with lifestyle habits and modifiable risk factors of cardiovascular disease. cohort studies are needed to evaluate if modification of lifestyle habits may change the natural history of bph. acknowledgement the #controllati2017 initiative was partially supported by an unconditional grant of menarini. references 1. bourke jb, griffin jp. hypertension, diabetes mellitus, and blood groups in benign prostatic hypertrophy. br j urol. 1966; 38:18-23. 2. nandeesha h, koner bc, dorairajan ln, sen sk. hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia. clin chim acta. 2006; 370:89-93. 3. lee s, min hg, choi sh, et al. central obesity as a risk factor for prostatic hyperplasia. obesity (silver spring) 2006; 14:172-9. 4. muller rl, gerber l, moreira dm, et al. obesity is associated with increased prostate growth and attenuated prostate volume reduction by dutasteride. eur urol. 2013; 63:1115-21. 5. ford es. risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. diabetes care. 2005; 28:1769-78. 6. parsons jk, kashefi c. physical activity, benign prostatic hyperplasia, and lower urinary tract symptoms eur urol. 2008; 53:1228-35. 7. nih consensus conference (1993) impotence. consensus development panel on impotence. jama 1993; 270:83-90. 8. abrams p, cardozo l, fall m, et al. the standardization of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-78. 9. raheem oa, parsons jk. associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms. curr opin urol. 2014; 24:10-4. 10. parsons jk, carter hb, partin aw, et al. metabolic factors assomirone_stesura seveso 03/01/18 12:12 pagina 256 ciated with benign prostatic hyperplasia. j clin endocrinol metab. 2006; 91:2562-8. 11. kristal ar, arnold kb, schenk jm, et al. race/ethnicity, obesity, health related behaviors and the risk of symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. j urol. 2007; 177:1395-400. 12. gupta a, gupta s, pavuk m, roehrborn cg. anthropometric and metabolic factors and risk of benign prostatic hyperplasia: a prospective cohort study of air force veterans. urology 2006; 68:1198-205; parsons jk. modifiable risk factors for benign prostatic hyperplasia and lower urinary tract symptoms: new approaches to old problems. j urol. 2007; 178:395-401. 13. vignozzi l, gacci m, cellai i, et al. fatboosts, while androgen receptor activation counteracts, bph-associated prostate inflammation. prostate. 2013; 73:789-800 14. lee sh, park tj, bae mh, et al. impact of treatment with statins on prostate-specific antigen and prostate volume in patients with benign prostatic hyperplasia. korean j urol. 2013; 54:750-5. 15. gacci m, corona g, vignozzi l, et al. metabolic syndrome and benign prostatic enlargement: a systematic reviewand meta-analysis bju int. 2015; 115:24-31. 16. mirone v, carone r, carrieri g, et al. urinary symptoms and sexual dysfunction among italian men: the results of the #controllati survey.arch ital urol androl. 2017; 89:75-80. 17. vuichoud c, loughlin kr. benign prostatic hyperplasia: epidemiology, economics and evaluation. can j urol. 2015; 22 suppl 1:1-6. 18. passi surveillance http://www.epicentro.iss.it/passi/dati/cardiovascolare.asp, last access november 17th 2017. 257archivio italiano di urologia e andrologia 2017; 89, 4 risk factors for benign prostatic enlargement correspondence vincenzo mirone, md università degli studi di napoli federico ii, uoc di urologia della a.o.u. federico ii napoli, italy giuseppe carrieri, md dipartimento nefro/urologico clinica urologica e centro trapianti di rene, università degli studi di foggia, foggia, italy giuseppe morgia, md università degli studi di catania presidio ospedaliero policlinico, catania, italy luca carmignani, md università degli studi di milano, divisione universitaria di urologia, irccs policlinico san donato milano, italy giuseppe vespasiani, md uoc urologia, fondazione ptv policlinico tor vergata, roma, italy fabio parazzini, md (corresponding author) università degli studi di milano dipartimento di scienze cliniche e di comunità, irccs policlinico, milano, italy fabio.parazzini@unimi.it walter artibani, md azienda ospedaliera universitaria integrata verona, italy *the controllati# study group: abano terme, policlinico: a. porreca; acireale, p.o. s. marta e s. venera di acireale azienda sanitaria provinciale di catania: a. ingrassia; acquaviva delle fonti, ente ecclesiastico ospedale generale regionale f. miulli: g.m. ludovico; adria, ospedale di adria, ulss5 polesana: a. meneghini; agrigento, ospedale san giovanni di dio: m. ruppolo; alba, ospedale san lazzaro: g. fasolis; altamura, ospedale della murgia fabio perinei: m. de siati; ancona, ospedali riuniti: a.b. galosi; andria, asl bat p.o. l. bonomo: a. corvasce; arezzo, ospedale san donato: m. de angelis; avellino, azienda ospedaliera s. giuseppe moscati: v. cicalese; avellino, casa di cura villa esther: m. di martino; baggiovara, nuovo ospedale civile sant'agostino estense: a. mofferdin; bari, azienda ospedaliera policlinico di bari u.o. urologia universitaria 1: m. battaglia; bari, azienda ospedaliera policlinico di bari u.o. urologia universitaria 2: p ditonno; bassano del grappa, ospedale civile: a. celia; benevento, ao gaetano rummo: l. salzano; benevento, casa di cura nuova clinica santa rita: m. coscione; bergamo, casa di cura palazzolo, p. belvisi; bologna, azienda ospedaliero universitaria di bologna policlinico s. orsola: e. brunocilla; borgomanero ospedale ss trinità: g. monesi; borgosesia, ospedale s.s. pietro e paolo: g. cipollone; brescia, presidio ospedaliero: c. simeone; brindisi, presidio di summa-perrino: s. brigante; bussolengo, ospedale orlandi di bussolengo uoc urologia aulss 9 veneto: g. pecoraro; cagliari ospedale ss trinità: a. de lisa; campi bisenzio, ambulatori della misericordia: f. lunghi; carpi, ospedale civile ramazzini: m. brausi; casarano,ospedale ferrari: s. raguso; caserta, azienda ospedaliera sant anna e san sebastiano di caserta: s. caggiano; castelfranco veneto, ospedale san giacomo apostolo: l. de zorzi; castellammare di stabia, casa di cura villa stabia:g. scognamiglio; castiglione del lago, ospedale civile: f. balloni; catania, casa di cura gibiino: c. ranno; catania, ospedale garibaldi nesima: p.g. la rosa; catania, ospedale vittorio emanuele ii: m. falsaperla; catania, policlinico gaspare rodolico clinica urologica università di catania: g. morgia catanzaro, azienda ospedaliera universitaria mater domini: r. damiano; cesano boscone, casa di cura ambrosiana: f.catanzaro; chiari, asst franciacorta ospedale m. mellini: l. tralce; chieti, policlinico ss. annunziata: l. schips; chieti, università degli studi gabriele d'annunzio: r. tenaglia; chieti, villa pini d’abruzzo: g. marascia; città di castello, ospedale civile: f. balloni città sant’angelo, villa serena: r. d’andrea; civitanova marche, ospedale civile: e. caraceni; cosenza, ospedale civile p.o. dell'annunziata: f. ventura; cremona, azienda socio-sanitaria territoriale: c. del boca; domodossola, ospedale san biagio: a. rosa; eboli, ospedale maria ss. addolorata: a. tufano; enna, azienda sanitaria provinciale 4 enna p.o. umberto i: m. d’anca; fano, azienda ospedali riuniti marche nord presidio santa croce di fano: v. beatrici; feltre, ospedale s. maria del pratoulss2: d. xausa; firenze, ospedale aou-careggi: m. carini, s. serni; foggia, ospedali riuniti: g. carrieri; foligno, ospedale san giovanni battista: s. parziani; forlì, ospedale g.b. morgagni-pierantoni: r. gunelli; frascati, ospedale san sebastiano: f. carbonaro; gallicoreggio calabria, aslstruttura poliambulatoriale: m. de martin garbagnate milanese, ospedale guido salvini urologia 1: a. gregori; gela, ospedale vittorio emanuele: n. condorelli; genova, clinica urologica dell'azienda ospedaliero universitaria san martino: c. terrone; genova, ente ospedaliero ospedali galliera: c. introini; gravina di catania, casa di cura musumeci gecas: r. leonardi; guastalla, ospedale civile: a. frattini; isola della scala, ospedale civile: g. pecoraro; jesi, ospedale carlo urbani: v. ferrara; l’aquila, ospedale s. salvatore: l. di clemente; lanciano, ospedale floraspe renzetti: l. schips; latina, ospedale icot: a. carbone; lecce, asl vito fazzi: a. filoni lido di camaiore, ospedale versilia-usl 12 toscana nord ovest: m cecchi; mirone_stesura seveso 03/01/18 12:12 pagina 257 archivio italiano di urologia e andrologia 2017; 89, 4 v. mirone, g. carrieri, g. morgia, l. carmignani, g. vespasiani, f. parazzini, w. artibani 258 locri ospedale spoke: a. verbena; lovere ospedale ss capitanio e gerosa: a ranieri; lucca, nuovo ospedale san luca usl nord-ovest: g. santelli; magenta, ospedale civile: s. sandri; mantova, ospedale poma: b. dall’oglio; messina, azienda ospedaliera universitaria policlinico g. martino: v. ficarra; messina, casa di cura s. camillo: s. bruschetta; messina, ospedali riuniti papardo piemonte: f. mastroeni; milano, azienda socio sanitaria santi paolo e carlo: g. dormia; milano, asst grande ospedale metropolitano niguarda: a. bocciardi; milano, fondazione ca' granda i.r.c.c.s. ospedale maggiore policlinico: e. montanari; milano, humanitas-san pio x: l. nava; milano, istituto europeo di oncologia: o. de cobelli; milano, ospedale s. raffaele: f. montorsi; mirabella eclano, casa di cura villa maria: e. morelli; modena, hesperia hospital: g. ferrari; modena, ocsae nuovo ospedale civile sant'agostino estense: g. bianchi; molfetta, ospedale don tonino bello: m. altomare; mondragone, clinica padre pio: g.s. sepe; monopoli, ospedale civile s. giacomo: v. recapito; montepulciano, stabilimento ospedaliero nottola: g. oliva; napoli, azienda ospedaliera universitaria seconda università degli studi: m. de sio; napoli, istituto nazionale tumori irccs fondazione pascale: s. perdonà; napoli, ospedale buon consiglio fatebenefratelli: v. imperatore; napoli, ospedale cardarelli: p. fedelini; napoli, ospedale cardinale ascalesi: a.r. zito; napoli, ospedale vincenzo monaldi: f. uricchio; napoli, policlinico federico ii: v.g. mirone; negrar, ospedale sacro cuore: s. cavalleri; nocera inferiore, p:o: umberto i: r. sanseverino; novara, azienda ospedaliero universitaria maggiore della carità : a. volpe; novi ligure, ospedale san giacomo asl 22: f. montefiore; nuoro, ospedale san francesco: f.m. cossu; orbassano, azienda ospedaliero-universitaria s. luigi gonzaga: f. porpiglia; ottaviano, casa di cura trusso: g. de stefano; padova, azienda ospedaliera: f. zattoni; padova, centro poliambulatorio ai colli: m. dal bianco; palermo, azienda universitaria ospedaliera policlinico paolo giaccone: a. simonato; parma, aou: u.v. maestroni; perugia, ospedale s. maria della misericordia s. andrea delle fratte: e. mearini; pescara, clinica pierangeli: p. pompa; pescara, presidio ospedaliero: r. renzetti; peschiera del garda, casa di cura pederzoli: g. grosso; piacenza, ospedale guglielmo da saliceto: i.m. tavolini; pisa, azienda ospedaliero universitaria pisana stabilimento di cisanello: c. selli; polla, presidio ospedaliero di polla-asl salerno: d. rubino; ponderano, ospedale degli infermi asl biella: s. zaramella; pordenone, aied: s. bucci; pozzuoli, ospedale santa maria delle grazie: g. di lauro; prato, ospedale misericordia e dolce: f. blefari; ragusa, ospedale civile, f. curto; ravenna, ospedale s. maria delle croci: s. voce; reggio calabria, asl 11 struttura nord: m. de martin; rimini, ospedale degli infermi: f. montanari; rocca di neto: f. greco; roma, aurelia hospital: r. cusumano; roma, azienda ospedaliera sant’andrea: a. tubaro; roma, casa di cura nuova villa claudia: r. giulianelli; roma, clinica fabia mater: m. cappa; roma, complesso integrato columbus: a. d’addessi; roma, fondazione ptv policlinico tor vergata: g. vespasiani; roma, ospedale di zona cristo re: l. defidio roma, ospedale s. carlo forlanini: c. anceschi; roma, ospedale s. filippo neri: g. sampalmieri; roma, policlinico a. gemelli: p. bassi; roma, policlinico umberto i: c. de dominicis; roma, policlinico universitario campus bio-medico: g. muto; salerno, aou s. giovanni di dio r. d’aragona: u. greco; san bonifacio; ospedale fracastoro: c.tallarigo; san cataldo, casa di cura regina pacis:c. cammarata; san donà di piave, casa di cura sileno ed anna rizzola: g. loiero; san donato milanese, ospedale clinicizzato s. donato: l.f. carmignani; san giovanni rotondo, ospedale casa sollievo della sofferenza: a. cisternino; santa maria capua vetere, clinica s. maria della salute: m. sorrentino; sarzana, ospedale san bartolomeo: e. conti; sassari, azienda ospedaliero-universitaria: m. madonia; senigallia, ospedale principe di piemonte: a. cavicchi; sestri levante, asl4chiavarese: m. medica; siena,aous ospedale s. maria delle scotte: g. barbanti; siracusa, azienda ospedaliera umberto i: b. lentini; sondrio, ospedale di sondrio azienda ospedaliera di valtellina e valchiavenna: p. piras; taranto ospedale ss annunziata: f beleggia; teramo, ospedale mazzini: c. vicentini; termoli, ospedale san timoteo: g. di monaco; terni, azienda ospedaliera santa maria: e. mearini; tivoli, ospedale s. giovanni evangelista: a. laganà: trento, ospedale santa chiara: g. malossini; treviglio, ospedale di treviglio-caravaggio-asst bg ovest: o. risi; torino, città della salute e della scienza-ospedale molinette: p. gontero; torino, ospedale cottolengo: c.m. scoffone; torino, ospedale san giovanni bosco castelli di torino sc urologia 2: e. castelli; torino, presidio ospedaliero cto unità spinale struttura complessa di neuro urologia: r. carone; udine, aied: s. ciciliato; vallo della lucania, casa di cura luigi cobellis: a. cavaliere; varese, ospedale di circolo fondazione macchi: a.m. marconi; vasto, ospedale san pio da pietrelcina: l.schips; vercelli, ospedale s. andrea: g. cipollone; verona, azienda ospedaliera-universitaria integrata ospedale borgo trento: w. artibani; viterbo, ospedale di belcolle: a. rizzotto; voghera, azienda socio sanitaria territoriale di pavia ospedale civile: m. mensi. mirone_stesura seveso 03/01/18 12:12 pagina 258 archivio italiano di urologia e andrologia 2018; 90, 2224 case report primary melanoma of the bladder: case report and review of the literature francesco barillaro 1, marco camilli 1, paolo dessanti 2, nader gorji 2, fabio chiesa 3, alessandro villa 3, alessandro pastorino 4, carlo aschele 4, enrico conti 1 1 department of urology, asl 5 spezzino. sarzana la spezia, italy; 2 department of pathology, asl 5 spezzino. la spezia, italy; 3 department of radiology, asl 5 spezzino. sarzana la spezia, italy; 4 department of oncology. asl 5 spezzino. la spezia, italy. skin melanoma represents one of the most common and lethal solid tumor. it usually develops on the skin but it can occur in any tissues with melanine-containing-cells (extracutaneous malignant melanoma). only 4-5% of malignant melanomas originate in extracutaneous tissues, and they have an extremely lethal behavior (1). these non-skin malignant melanomas are rare but extremely aggressive. primary melanoma of the genitourinary tract accounts for less than 0.2% of all melanomas. to date only 28 cases of primary bladder melanoma (pmm) are described. we report a rare case of pmm of the bladder in a 72 years old man treated with radical cystectomy and immunotherapy with nivolumab. key words: bladder melanoma. submitted 16 april 2018; accepted 29 april 2018 summary no conflict of interest declared. troscopy,colonscopy and a ophthalmologic exam ruled out the suspicious of a secondary lesion from a primitive malignant melanoma elsewhere. patient’s case was discussed by the institutional multidisciplinary uro-oncologic disease management team that stated a multimodal treatment. a radical cystectomy with a simple urinary diversion (ucs) and immunotherapy protocol were planned. patient underwent surgery and the final histological exam reported a pt4 n0 mx r0 melanoma of the bladder (figure 1). immunoistochemical exam was positive for s-100, and sox-10 and slightly positive for hmb45 while was negative for cytocheratines cam5.2, ae/1/ae3, 7, 20; actine, cd34, desmin,dog-1, ema, gata-3, myogenine, chromoreanine, psa and p63 (figure 1). two months after surgery patient underwent contrast enhancement computed tomography (cect) without showing progression of the chest nodes. three months doi: 10.4081/aiua.2018.3.224 case report a 72 year-old caucasian man presented to the emergency room of our hospital with gross asymptomatic haematuria. a cystoscopy showed a solid mass with red and brown spots in the surface, consequently the diagnosis of solid bladder tumor was posed. after obtaining informed consent, we performed a trans urethral resection of the bladder tumor (turbt) without a radical debulking of the whole mass due to the aspect of extensive muscle invasion. the histological exam confirmed the diagnosis of pmm of the bladder. patient denied an history of nevi-excision or other surgery. a multiparametric magnetic resonance (mpmr) scan confirmed a solid tumor of 7x6 cm. the lesion extended through all the bladder wall with suspicious iliac nodal metastasis. a fluorodeoxyglucose positron emission tomography computed tomography (fdg pet-ct) scan showed hypermetabolic capitation of the right ilar lymph-nodes and of the mesenteric tissue. a single capitation in para-vertebral region of the low portion of left lung was not clearly identified as metastasis. dermatological exam, gasfigure 1. pathological specimens. barillaro_stesura seveso 03/10/18 09:50 pagina 224 225archivio italiano di urologia e andrologia 2018; 90, 2 primary melanoma of the bladder after surgery patient underwent immunotherapy with nivolumab as for skin melanoma. a 14 day course of intravenous injections of 3 mg/kg of nivolumab in 100 ml of saline solution was completed. a new fdg pet-ct scan six months after surgery showed a complete response of the nodal and mesenteric lesions while reported a decrease in size of the pulmonary lesion (17 mm vs 21 mm). thirteen months after surgery, a new fdg pet-ct showed a 4 mm small right inguinal nodal recurrence and a steady situation of the pulmonary lesion. fifteen months after surgery patient is alive with karnofsky score of 90 and ecog 1-2. discussion primary melanoma of the urinary bladder is an extremely rare neoplasm and to date only 28 cases including this case are reported to medical literature (table 1). the diagnosis of primary melanoma of the bladder is not always easy. ainsworth et al. (2) and siroy and maclennan (3) established some diagnostic criteria for primary bladder tumours: (1) absence of any previous skin lesion, or (2) cutaneous malignant melanoma, or (3) primary visceral malignant melanoma, (4) recurrence pattern showing consistency with the primary tumour diagnosis, (5) atypical melanocytes at the tumour margin on microscopic examination. primary melanoma of the urinary bladder usually affects people over fifty and there is a slight prevalence in male sex (60%). our literature review presents few cases over a wide range of time with extremely different treatments and behavior. in addition, the follow up is extremely heterogeneous and only 12/28 patients (42%) were alive at time of the report with different follow-up (3-144 months; median 20.7 months). first choice treatment is surgery. the treatment can be conservative as trans urethral resection of the bladder tumor (turbt) associated or not with endovesical immunotherapy with bacillus of calmette guerin (bcg); partial cystectomy can be considered as alternative conservative treatment. radical cystectomy can be carried out based on the staging of tumor and in patients with better performance status. chemotherapy can be a possibility as unique therapy for patients who are poor surgical candidates and options include platinum-based chemotherapy as cisplatin/carboplatin plus paclitaxel. immunotherapy can be considered optional. interferon and interleukin (il)-2 are used for metastatic melanoma but the high tossicity and the low response rate reported in literature considerably limited the use. table 1. primary malignant melanomas reported in literature. references age (y) sex treatment follow up (months) outcome 1 wheelock 1942 67 f partial cystectomy 36 died 2 su and prince 1962 61 f none 2 died 3 ainsworth et al. 1976 65 f radical cystectomy 17 alive 4 willis et al. 1980 57 f radical cystectomy 36 died 5 anichkov and nikonov 1982 48 m partial cystectomy 12 died 6 anichkov and nikonov 1982 46 m radical cystectomy 3 alive 7 ironside et al. 1985 56 m none 8 died 8 goldschmidt et al. 1988 53 f partial cystectomy 7 died 9 goldschmidt et al. 1988 56 f none 6 alive 10 philippe et al. 1989 77 m turb n.r. n.r. 11 van ahlen et al. 1992 81 m radical cystectomy, radiotherapy, interferon-alpha 24 died 12 lund et al. 1992 81 f local excision, radiotherapy chemotherapy 15 alive 13 kojima et al. 1992 63 f chemotherapy 18 died 14 lange-welker et al. 1993 75 m partial cystectomy 3 died 15 mourad et al. 1993 34 m radical cystectomy 12 alive 16 niederberger and lome 1993 53 m radical cistectomy 18 alive 17 de torres et al. 1995 44 m radical cystectomy 14 died 18 tainio et al. 1999 52 m turb 8 died 19 garcia montes et al. 2000 44 f turb 144 alive 20 khalbuss et al. 2001 82 f radiotherapy + cistectomy 16 died 21 t. hsu and y. hsu 2002 73 m turb + intravesical bcg and returb at 2-7-9 months 16 alive 22 baudet et al. 2005 7 f partial cystectomy 84 alive 23 pacella et al. 2006 82 m turb 9 died 24 sundersingh et al. 2011 56 m radical cystectomy and pelvic excision four months later 10 alive 25 el ammari et al. 2011 71 m turb 5 died 26 truong et al. 2013 84 f turb + ipilimumab n.r n.r. 27 otto et al. 2017 52 m turb + interferon/dacarbazine 18 died 28 barillaro et al. 2018 72 m radical cystectomy + nivolumab 16 alive barillaro_stesura seveso 03/10/18 09:50 pagina 225 archivio italiano di urologia e andrologia 2018; 90, 2 f. barillaro, m. camilli, p. dessanti, n. gorji, f. chiesa, a. villa, a. pastorino, c. aschele, e. conti 226 the fully human igg4 pd-1 immune checkpoint inhibitor antibody nivolumab has received the fdaapproval in march 2015 for squamous lung cancer treatment. in addition, antibodies targeting pd-1 or pd-l1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (nsclc), renal cell carcinoma (rcc), bladder cancer, and hodgkin's lymphoma. nivolumab plus ipilimumab or nivolumab alone, blocking the interaction between the programmed cell death pd1 and his ligand pd-l1 have been reported to be effective in antitumor response in melanoma (4, 5). other treatment as radiation therapy might be only considered for palliative treatment in bladder melanoma. based on our review turbt or other conservative treatments were carried out in 14 patients (50%) with a survival rate of 28.5% (4/14) in an average follow up of 14 months. one patient was treated with conservative treatment (turbt) along with a combination of interferon plus dacarbazine and died after 18 months. in one case treated with turbt and ipilimumab survival was not reported. three cases did not receive any treatment and the reported follow up showed a death in 2 months and 8 months and a survival at 6 months. one case was treated with chemotherapy alone and died after 18 months. radical cystectomy was carried out in 10 patients with median age of 59 y/o; survival rate was 60% (6/10) at a median follow up of 15.5 months. among patients treated with cystectomy, one received also radiotherapy and died 16 months after primary treatment. one patient received a multimodal treatment combined of cystectomy, radiotherapy and immunotherapy with interferon alpha and died 24 months after. in our case, nivolumab was started as first line treatment after surgery based upon the braf, nras and c-kit wild type molecular pattern. at time of this literature review is the only one reported with clinical and metabolic remission 15 months after primary treatment without relevant toxicities. acknowledgments all authors contributed equally to the manuscript drafting. the authors are the only ones responsible for the content and writing of the paper. conclusions the best treatment of primary bladder melanoma is not univocally recognized due to the small number of cases reported in literature. while a bladder resection can be an option for localized small tumors, radical cystectomy may be the treatment of choice for invasive muscle disease. as for metastatic skin melanoma, immunotherapy with nivolumab seems representing a feasible therapy for this rare neoplasm. the role of the surgical treatment versus only immune or chemotherapy is not known. according to literature review, radiation therapy seems not to be the treatment of choice. according to other cases reported, an almost total remission after 15 months after surgery and immunotherapy, can be considered a good therapeutic choice. references 1. hussein mr. extracutaneous malignant melanomas. cancer invest. 2008; 26:516-34. 2. ainsworth am, clark wh, mastrangelo m, conger kb. primary malignant melanoma of the urinary bladder. cancer. 1976; 37:1928-36. 3. siroy ae1, maclennan gt. primary melanoma of the bladder. j urol. 2011; 185:1096-7. 4. mahoney km, freeman gj, mcdermott df. the next immunecheckpoint inhibitors: pd-1/pd-l1 blockade in melanoma. clin ther. 2015; 37:764-82. 5. robert c, long gv, brady b, et al. nivolumab in previously untreated melanoma without braf mutation. n engl j med. 2015; 372:320-30. correspondence francesco barillaro, md francesco.barillaro@asl5.liguria.it marco camilli, md marco.camilli@asl5.liguria.it fabio chiesa, md fabio.chiesa@asl5.liguria.it alessandro villa, md dr.willaav@gmail.com enrico conti, md enrico.conti@asl5.liguria.it osp. s. bartolomeo via cisa, 19038 santa caterina, sarzana (sp), italy paolo dessanti md paolo.dessanti@asl5.liguria.it nader gorji, md nader.gorji@asl5.liguria.it alessandro pastorino, md alessandro.pastorino@asl5.liguria.it carlo aschele, md carlo.aschele@asl5.liguria.it osp. s. andrea via vittorio veneto 197, 19121 la spezia (sp), italy barillaro_stesura seveso 03/10/18 09:50 pagina 226 61archivio italiano di urologia e andrologia 2020; 92, 1 case report be cautious of “complex hydrocele” on ultrasound in young men evangelos n. symeonidis 1, petros sountoulides 1, irene asouhidou 2, chrysovalantis gkekas 3, ioannis tsifountoudis 4, ioanna tsantila 5, asterios symeonidis 3, christos georgiadis 3, apostolos malioris 3, michail papathanasiou 3 1 department of urology, aristotle university of thessaloniki, “g. gennimatas” general hospital, thessaloniki, greece; 2 department of anatomy and surgical anatomy, aristotle university of thessaloniki, thessaloniki, greece; 3 department of urology, 424 general military hospital of thessaloniki, thessaloniki, greece; 4 department of radiology, 424 general military hospital of thessaloniki, thessaloniki, greece; 5 department of pathology, 424 general military hospital of thessaloniki, thessaloniki, greece. hydrocele is the most common benign cause of painless scrotal enlargement and only very rarely can be reactive to an underlying testicular tumor. we present the case of a healthy young man, complaining of mild left scrotal discomfort and swelling. physical examination revealed a non-tender fluctuant left scrotum and serum tumor markers were normal. scrotal ultrasonography (us) showed a normal right hemiscrotum and testicle and a fluid collection among thickened irregular septations in the left hemiscrotum, a finding which was considered as a complex hydrocele. intraoperatively the presumed “complex hydrocele” was in fact a multicystic testicular tumor. we proceeded with orchiectomy through the scrotal incision and pathology revealed a mixed germ cell tumor of the testis consisting of cystic teratoma, in situ germ cell neoplasia unclassified (igcnu) and sertoli cell tumor. this is the first reported case of this type of testis tumor presenting as complex hydrocele. the aim of this case presentation is to underline the need for an accurate preoperative diagnosis in cases of suspected scrotal pathology in young males. key words: hydrocele; testis tumor; scrotal ultrasonography; igcnu; sertoli cell tumor. submitted 30 september 2019; accepted 23 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.61 introduction hydrocele is usually caused by either the presence of a patent processus vaginalis or an imbalance in the secretion and absorption of fluid within the tunica vaginalis. increased fluid secretion may be a result of inflammation, whereas poor absorption commonly results from thickening of the hydrocele sac or impaired lymphatic drainage. so-called reactive hydrocele is present in 10% of testicular tumors. seminoma is the most common type of testicular tumor (40%) while non-seminomatous germ cell tumors are more rare (1). a mixed germ cell tumor consisting of cystic teratoma, sertoli cell tumor and in situ germ cell neoplasia unclassified (igcnu) is very rare. scrotal ultrasound (us) plays a pivotal role in the diagnosis of hydrocele and other scrotal pathology. however, there are cases where scrotal ultrasonography might fail to reveal a hidden testicular pathology (2-5). we present a case of a hydrocele with complex ultrasonographic features which during elective surgery turned out to be an unusual testicular tumor. case presentation a 24-year-old male presented with a complaint of mild left scrotal discomfort of 3 months’ duration. his medical history was unremarkable with no recall of scrotal trauma or other urological symptoms. physical examination revealed a painless, non-tender, moderately enlarged left hemiscrotum and a non-palpable ipsilateral testis. complete blood count and urinalysis were normal. tumor markers were within normal range with alpha-fetoprotein (a-fp) of 0.96 ng/ml and β-human chorionic gonadotropin (β-hcg) < 1.20 miu/ml. scrotal us showed a large amount of fluid collection in the left scrotal sac containing multiple thick echogenic septations, a finding described by the radiologist as a “complex hydrocele” (figure 1). scrotal us also revealed normal size and echogenicity of both testicles. the sonographic findings were consistent with a “complex” hydrocele of the left testis with inflammatory changes in the surrounding scrotal layers. an elective left hydrocelectomy was performed under the presumptive diagnosis of a complex hydrocele. scrotal exploration refuted the presence of a hydrocele, instead it revealed the presence of a multicystic testicular tumor distorting the testicular parenchyma. following intraoperative consensus and informed parental consent we proceeded with orchiectomy via the scrotal incision (figure 2). histopathology revealed the presence of a mixed germ cell tumor consisting of cystic teratoma, sertoli cell tumor and igcnu (figure 3). following multidisciplinary team (mdt) discussion and negative axial tomography staging the patient received prophylactic chemotherapy and is free of recurrence at 6-month follow-up. discussion although in most cases hydrocele presents as a benign painless swelling, rarely a reactive hydrocele could be simoneidis_stesura seveso 01/04/20 19:00 pagina 61 archivio italiano di urologia e andrologia 2020; 92, 1 e.n. symeonidis, p. sountoulides, i. asouhidou, c. gkekas, i. tsifountoudis, i. tsantila, a. symeonidis, c. georgiadis, a. malioris, m. papathanasiou 62 the first and only sign of a testicular tumor (1, 2). our case highlights the diagnostic pitfall of a non-tender scrotal enlargement clinically and radiologically indicative of a complex hydrocele, which proved to be a testicular tumor in the operating room. a “complex” hydrocele on us is characterized by the finding of multiple thick echogenic septations and calcifications surrounded by fluid with layering echogenic debris (3, 5). further imaging might be necessary in cases scrotal us is ambiguous about the diagnosis of hydrocele. magnetic resonance imaging (mri) emerges as a valuable problem-solving imaging modality in cases of inconclusive or suspicious sonographic findings (6, 7). mri can also provide a much more accurate differentiation of testicular lesions (7). mri can reliably demonstrate detailed information on tissue characteristics and improve differential diagnosis among various scrotal pathology (6, 7). misdiagnosis of a testicular cancer as a hydrocele is very rare. harvey et al. described a case of a 63year-old patient initially listed for hydrocele repair. intraoperatively it was difficult to identify viable testicular parenchyma and the presence of a green caseous material led to the decision for orchiectomy. histopathology revealed an epidermoid cyst (8). iqbal et al. reported two cases of testicular cancer which were initially diagnosed as hydroceles and operated via a scrotal approach. both patients underwent hydrocele repair, and concomitant testicular biopsy revealed embryonal cell carcinoma of the testis which led to radical orchiectomy (9). a metastatic to the testis pancreatic adenocarcinoma was also misdiagnosed as complex hydrocele in a 69-yearpatient who presented with painful swelling of the left scrotum and underwent left hydrocelectomy (10). testicular teratomas can sometimes have a predominantly cystic appearance closely resembling a hydrocele. lin et al. presented a case of a 3-year-old boy with a transilluminating scrotal mass initially diagnosed as a communicating hydrocele. due to impalpable testis they proceeded with ultrasonography which depicted a heterogeneous cystic mass with subsequent orchiectomy revealing mature teratoma (11). there was also a recent report of a case of adult germ cell testicular tumor with again sonographic features suggestive of hydrocele (12). recently, trenti et al. cited an infrequent case of mesothelioma of the tunica vaginalis testis, secondarily diagnosed during hydrocele surgery. contrary to our case, the ultrasonographic findings were that of a simple left hydrocele (13). in our case histopathology revealed the presence of a mixed germ cell tumor consisting of cystic teratoma, igcnu and gonadal stromal tumor (sertoli cell). this is the first reported case of misdiagnosis of this type of testis tumor as complex hydrocele. at mdt discussion of the case one of the proposed reasons for the missed diagnosis was the fact that the extended cystic part of the tumor gave a very hypoechoic image on us mimicking figure 1. scrotal ultrasound (us). arrows depict the anechoic fluid inside the thick septations of the scrotal sac. (a, b, c). image (d) shows a normal in size and echogenicity left testis. images (e, g, f, h) demonstrate a right testis with homogeneous echo texture and echogenicity. figure 2. macroscopic appearance of the multicystic mass, depicting the atrophic left testicular parenchyma. it is worth mentioning the absence of hydrocele. figure 3. histological images. (a) hematoxylin eosin stain (x100): sertoli cell tumor composed mostly of solid nests. (b) hematoxylin eosin stain (x100): in situ germ cell neoplasia unclassified (isgnu): proliferation of malignant germ cells resembling primitive gonocytes confined to the basilar aspect of the seminiferous tubules. (c) hematoxylin eosin stain (x40): gastrointestinal type epithelium and endometrial foci in teratoma of the testis. simoneidis_stesura seveso 01/04/20 19:00 pagina 62 the hypoechoic fluid accumulation seen in a typical hydrocele. on the other hand, it was noted that complex hydroceles usually result from previous failed hydrocelectomies or infected hydroceles and very rarely in de novo cases (14). irrespective of the aetiology, misdiagnosis of a testicular tumor as a complex hydrocele has significant implications in surgical planning as a scrotal incision used for hydroceles is contraindicated in cases of suspected testicular malignancy, and also for patient counselling (2, 9, 15). as a result of this misdiagnosis our patient was listed for a non-urgent elective procedure of hydrocele repair, whereas if a testicular tumor was suspected he should have taken priority and have had the procedure done within days of diagnosis. a high level of suspicion should be maintained in any case of presumed hydrocele with discordance between testicular size, morphology and echotexture on scrotal us especially in younger men. it is important to underline the need for preoperative counseling for the risk of orchiectomy if unanticipated pathology is realized during surgery. in cases of ultrasonographic diagnostic dilemmas, further imaging with scrotal mri should be the next diagnostic step in cases of complex scrotal conditions. conclusions what initially appeared to be a complex hydrocele on ultrasound, was finally diagnosed as a testicular tumor. in this setting, we aimed to underline the need for diligent preoperative ultrasound evaluation of the scrotum in young adults. references 1. mostofi fk, davis j, rehm s. tumors of the testis. iarc sci publ. 1994; 111:407-428. 2. albino g, nenna r, inchingolo cd, marucco ec. hydrocele with surprise. case report and review of literature. arch ital urol androl. 2010; 82:287-90. 3. patil v, shetty sm, das s. common and uncommon presentation of fluid within the scrotal spaces. ultrasound int open. 2015; 1:e34-40. 4. smith zl, werntz rp, eggener se. testicular cancer: epidemiology, diagnosis, and management. med clin north am. 2018; 102:251-264. 5. valentino m, bertolotto m, ruggirello m, et al. cystic lesions and scrotal fluid collections in adults: ultrasound findings. j ultrasound. 2011; 14:208-15. 6. tsili ac, bertolotto m, rocher l, et al. sonographically indeterminate scrotal masses: how mri helps in characterization. diagn interv radiol. 2018; 24:225-236. 7. parenti gc, feletti f, carnevale a, et al. imaging of the scrotum: beyond sonography. insights imaging. 2018; 9:137-148. 8. harvey j, noon ap, beck s, cutinha p. epidermoid cyst of the testis misdiagnosed as a hydrocele: a case report. j med cases. 2010; 1:6-7. 9. iqbal sa, usmani f, shamim m. testicular carcinoma misdiagnosed as hydrocele: lesson to learn pak j med sci. 2007; 23:950-952. 10. kim yw, kim jw, kim jh, et al. metastatic testicular tumor presenting as a scrotal hydrocele: an initial manifestation of pancreatic adenocarcinoma. oncol lett. 2014; 7:1793-1795. 11. lin hc, clark jy. testicular teratoma presenting as a transilluminating scrotal mass. urology. 2006; 67:1290.e3-5. 12. vallonthaiel ag, kakkar a, singh a, et al. adult granulosa cell tumor of the testis masquerading as hydrocele. int braz j urol. 2015; 41:1226-31. 13. trenti e, palermo sm, d'elia c,et al. malignant mesothelioma of tunica vaginalis testis: report of a very rare case with review of the literature. arch ital urol androl. 2018; 90:212-214. 14. metcalfe mj, spouge rj, spouge dj, hoag cc. the use of tpa in combination with alcohol in the treatment of the recurrent complex hydrocele. can urol assoc j. 2014; 8:e445-8. 15. dieckmann kp. diagnostic delay in testicular cancer: an analytic chimaera or a worthy goal? eur urol. 2007; 52:1566-8. 63archivio italiano di urologia e andrologia 2020; 92, 1 be cautious of “complex hydrocele” on ultrasound in young men correspondence evangelos n. symeonidis, md evansimeonidis@gmail.com petros sountoulides, md 1st department of urology, aristotle university of thessaloniki, “g. gennimatas” general hospital, thessaloniki (greece) ethnikis aminis 41, 54635 thessaloniki (greece) irene asouhidou, md department of anatomy and surgical anatomy, aristotle university of thessaloniki, thessaloniki (greece) chrysovalantis gkekas, md asterios symeonidis, md christos georgiadis, md apostolos malioris, md michail papathanasiou, md department of urology, 424 general military hospital of thessaloniki, thessaloniki (greece) ioannis tsifountoudis, md department of radiology, 424 general military hospital of thessaloniki, thessaloniki (greece) ioanna tsantila, md department of pathology, 424 general military hospital of thessaloniki, thessaloniki (greece) simoneidis_stesura seveso 01/04/20 19:00 pagina 63 stesura seveso archivio italiano di urologia e andrologia 2019; 91, 2112 original paper ureteral access sheath use in retrograde intrarenal surgery mustafa karaaslan, senol tonyali, mehmet yilmaz, sedat yahsi, sedat tastemur, erkan olcucuoglu university of health sciences, turkiye yuksek ihtisas training and research hospital, clinic of urology, ankara. objective: to determine if there is a difference between postoperative urinary infection rates after retrograde intra-renal surgery (rirs) when ureteral access sheath (uas) was used or not used. materials and methods: we retrospectively analyzed the medical records of all patients who underwent rirs at our institution between january 2016 and october 2018. results: 129 patients were included in the study. the mean age of the patients was 48.8 ± 12.1 years; 94 patients were male and 35 were female. the mean stone size (largest diameter), stone attenuation and stone volume were 15.3 ± 5.8 mm, 1038 ± 368 hu and 1098 ± 1031 mm3, respectively. out of 129 patients, 81 were treated by using uas (group 1) and 48 were treated without use of uas (group 2). there was no statistically significant difference between the two groups in terms of post-operative infection (p = 0.608). however, the operative time of patients with post-operative infection was statistically higher than the other patients; 88.35 ± 22.5 min versus 59.37 ± 22.1 min (p = 0.017). in multivariate regression analysis, operation time (p = 0.02, r = 1.07) was found to be the sole predictor of post-operative infection. conclusions: using uas during rirs might reduce the intrarenal pressure and also has several advantages. however not prolonging the operation time too much could be of higher importance than uas use in terms of preventing post-operative infection after rirs. key words: nephrolithiasis; sepsis; ureteral access sheath; intrarenal pressure. submitted 27 february 2019; accepted 21 march 2019 summary no conflict of interest declared. history of the use of ureteral access sheath (uas) in furs, for the first time takayasu and aso (4) used a teflon tube throughout the ureter in 1974. the use of uas in furs has many advantages and disadvantages. uas allows repeated access to the upper urinary tract, provides better visibility, allows removing small stone fragments without damaging the ureter, and reduces pyelolymphatic and pyelovenous reflux by lowering renal pelvic pressure (5). in addition, it was reported that it was not uncommon to have severe ureter wall damage during uas placement into the ureter (6). in a multi-centre prospective study, it has been shown that using uas in furs might result in a decrease in the incidence of post-operative fever, urinary tract infection, and in particular sepsis (7). in this study, we aimed to determine if there is a difference between postoperative urinary infection rates after furs which uas was used or was not used. materials and methods after obtaining the approval of institutional review board, we retrospectively analysed the medical records of all patients who underwent rirs at our institution between january 2016 and october 2018. the study was conducted in accordance with the latest version of the declaration of helsinki. informed consent form is not required due to the retrospective nature of the study. patients with anatomical abnormalities such as horseshoe kidney, pelvic kidneys, kidneys with multiple collecting system, and patients who underwent surgery under antibiotic supression were excluded from the study. all patients were evaluated with kidney-ureter-bladder (kub) radiography, non-contrast abdominal computed tomography (ct), complete blood count, serum creatinine, bleeding and clotting times, complete urinalysis and urine culture. patients who have bacteria growth in urine culture were treated with adequate antibiotic therapy and control urine culture confirmed no bacterial growth. the longest diameter of renal stone was determined as stone size. the examined parameters included patient’s demographic information, stone characteristics (size, volume, localization and hounsfield unit), duration of operation, use of ureteral access sheath (uas), stone-free rate, postoperative sepsis and urinary tract infection. stone volume was calculated using the formula: stone volume = length x width x height x π x 0.167. the stone localization was defined as lower pole and non-lower pole. the diagnosis of sepsis was made by determining the focus of the infection and by doi: 10.4081/aiua.2019.2.112 introduction nephrolithiasis was historically treated with open surgery, however currently, minimally invasive modalities such as extracorporeal shoch wave lithotripsy (swl), percutaneous nephrolithotripsy (pnl) and retrograde endoscopic interventions [ureteroscopy (urs), retrograde intrarenal surgery (rirs)] and laparoscopic surgeries are frequently being the treatment of choice. rirs is used more frequently by technological advancements of flexible ureterorenoscopes, which was first used by marshall (1) in 1964 (2). pnl is recommended as the first-line treatment for kidney stones larger than 2 cm in the european urology association (eau) guidelines. swl or endoscopic procedures are recommended for renal stones smaller than 2 cm. flexible urs (furs) could be presented as a second treatment option for stones larger than 2 cm with pnl being the first treatment option, and for lower pole stones larger than 1.5 cm where swl activity was limited (3). when we look at the 113archivio italiano di urologia e andrologia 2019; 91, 2 ureteral access sheath use in retrograde intrarenal surgery the presence of two or more sirs findings. the diagnosis of sirs was based on the criteria of the american college of chest physicians/society of critical care medicine (accp/sccm) consensus conference committee as having 2 or more of the following criteria: 1. body temperature less than 36°c or greater than 38°c; 2. heart rate greater than 90 beats/min; 3. respiration rate > 20/min or paco2 < 32 mmhg; 4. white blood cell counts greater than 12.000/mm3 or less than 4.000/mm3 (8). surgical procedure all procedures were performed under general anesthesia by giving 1 gr cefazolin prophylaxy before the procedure and using flexible ureteroscopes 7.5 and 7.8 french (flexx2tm flex scope, karl storz, germany and semi-flex scopetm, maxiflex, usa). patients were placed in the lithotomy position. mobile c-armed fluoroscopy was used in all procedures. a 0.035 or 0.038 inch guidewire was inserted into the pelvis with a rigid ureterorenoscope. then, 12/14f 45 cm (rocamed) uas was placed into the ureter till the ureteropelvic junction (upj) under the guidence of fluoroscopy. alternatively, depending on the surgeon's preference, the operation was performed by reaching the kidney with flexible ureterorenoscope over the guidewire without inserting the uas. continuous irrigation was performed through furs with 3000 ml 0.3% isotonic solution at 50 cm above the patient. a 270 micron holmium yag laser was used for stone fragmentation. the stone fragments were left for spontaneous passage and no basket was used for stone removal. statistical analysis statistical analysis was performed using ibm spss statistical package v.22.0 for windows (ibm spss corp., armonk, ny, usa). quantitative values are shown as mean ± standard deviation for parametric data and as median ± range for nonparametric data. qualitative values are shown in numbers and percentages. the normality test was performed using the shapiro-wilk test. the chi-square test was used to compare post-operative infection in patients with or without uas, and mann-whitney u test was used to compare the duration of operation. multivariate regression analysis was used to evaluate the most important determinant of post-operative infection. the level of statistical significance was accepted as p < 0.05. results a total of 210 patients were reviewed. 129 patients who met the study criteria were included in the study. the mean age of the patients was 48.8 ± 12.1 years; 94 patients were male and 35 were female. the mean stone size (largest diameter), stone attenuation and stone volume were 15.3 ± 5.8 mm, 1038 ± 368 hu and 1098 ± 1031 mm3, respectively. out of 129 patients, 81 were treated using uas patients (group 1) and 48 were treated without uas (group 2). the mean operative time was 60.2 ± 22.8 min. stone free rate (sfr) was 52.7% (68/129). patient, stone and operation characteristics are given in table 1. the mean stone size, stone volume, stone hu and operation time were similar in group 1 and group 2 (p = 0.34, p = 0.26, p: 0.14 and p: 0.33, respectively). lower pole stone localisation rate was significantly higher in group 1 (62% versus 33%, p = 0.002). there was no statistically significant difference between the two groups in terms of post-operative infection (p = 0,608). however, the operative time of patients with post-operative infection was statistically higher than the other patients; 88.35 ± 22.5 min versus 59.37 ± 22.1 min (p = 0.017). in multivariate regression analysis operation time (p = 0.02, r = 1.07) was found to be the sole predictor of post-operative infection whereas age, sex, stone volume, hu, stone location and uas use were not, (p = 0.65, p = 0.20, p = 0.22, p = 0.95, p = 0.35 and p = 0.78, respectively). discussion in 1964, a stone in the ureter was observed by a 26f cystoscope and the first furs use was reported. by the end of the 1980s, the development of furs has gained momentum. in the 1980s and 1990s initial furs series were published (2). the new generation furs allows the management of proximal ureteral and intrarenal pathologies, including complete removal of the ureter and kidney stones, with high success rates. pyelovenous and pyelolymphatic reflux secondary to irrigation is one of the most important limitations of furs (5). flexible urs is the first treatment option in many cases of treatment of kidney stones. it is recommended as the first treatment option in lower calyceal stones, especially between 1.5-2 cm (3). uass were initially developed to facilitate difficult ureteroscopic access (9). studies have shown the advantages and disadvantages of using uas. the use of uas has been shown to provide better view, multiple entries, removal of fragmented stones and, in particular, to reduce intrapelvic pressure (10). the results of studies on the effect of uas use on sfr after rirs differ. in a study conducted by berquet et al. (11) on 280 patients, there was no difference in the sfr between the patients who were treated using uas or not. also in the present study sfr was similar in the two groups. there are uass of different diameters and lengths. in the study by wright et al. conducted with 10/12f and 12/14f uass in cadaveric pig kidney, the mean intrapelvic pressure was < 40 cm h2o. when hand-assisted manual pump table 1. comparison of patient’s characteristics in uas group and non-uas group. variables uas group non-uas group p value mean stone size (mm) 14.9 ± 5.7 15.8 ± 6 0.341 mean stone volume (mm3) 1022 ± 1026 1226 ± 1038 0.261 mean stone attenuation (hu) 1067 ± 383 988 ± 340 0.149 mean operation time (min) 61.75 ± 22.3 57.79 ± 23.5 0.327 stone localization lower pole: 50 (62%) lower pole: 16 (33%) 0.002 non-lower pole: 31 (38%) non-lower pole: 32 (66.7%) post-operative infection 3 (2.7%) 1 (2.1%) 0.608 sepsis 2 1 urinary tract infection 1 archivio italiano di urologia e andrologia 2019; 91, 2 m. karaaslan, s. tonyali, m. yilmaz, s. yahsi, s. tastemur, e. olcucuoglu 114 was used, it was shown that intrapelvic pressure increased up to 129 cm h2o in cases treated with 10/12f uas, and that this remained at low levels when 12/14f uas was used (12). in another study, intrarenal pressure during furs was measured using a pressure transducer inserted from percutaneous nephrostomy in patients who had percutaneous nephrostomy due to obstructive ureteric stones. the mean pressure in the collecting system was 13.6 mmhg (18.4 cm h2o) before the procedure, while the mean intrarenal pressure in the renal pelvis during furs rose to 94.4 mmhg (128.3 cm h2o) in patients without uas and to 40.6 mmhg (55 cm h2o) in patients with uas (5). in a study conducted using human cadaveric kidney with continuous irrigation with a pressure of 200 cm h2o, renal pelvic pressure increased to 59 cm h2o in patients without uas, and intrapelvic pressure was reported to be below 30 cm h2o in patients with uas depending on the diameter and length of the uas (13). in the present study, we used 12f/14f uas in all cases and we did not use manual irrigation pump. we were not able to measure intrarenal pressure in renal pelvis, but, in the light of the aforementioned studies, our clinical practice might be associated with lower intrarenal pressures. in a prospective study conducted with 2239 patients, it was shown that there was a decrease in the incidence of post-operative fever, urinary tract infection, and especially sepsis in patients who were treated by using uas compared to patients who were treated without uas (7). in a systematic review and meta-analysis, the efficacy and safety of uas was evaluated in a total of 3099 patients, and sfr, intra-operative complications, duration of operation and length of hospital stay were found similar between uas group and non-uas group. postoperative complications (bleeding, fever, urinary tract infection, bladder cramps, pulmonary embolism, and sepsis) were higher in patients treated by using uas (14). in our study, no significant difference was found between patients who were treated with uas or not in terms of post-operative infection. in-vitro studies have shown that pyelovenous reflux exists in case of a pelvic pressure > 35 mmhg (15). the use of manual water pumps raises pressures even higher (12). this may increase the risk of postoperative infection by increasing pyelovenous reflux in parallel with the increase in intrapelvic pressure. in our study, high intrapelvic pressures should have been avoided because we did not use a manual pump so explaining the absence of a significant difference in postoperative infection between the group treated with uas and the group treated without uas. in a study by zhong et al., post-operative sirs was detected in 21 (8.1%) patients amomg 260 cases of furs using uas. the duration of operation was not statistically significant, but it was found to be higher in the sirs group (16). in our present study, the operation time of the patients who developed post-operative infection was significantly higher than that of the other patients. conclusions using uas during rirs reduces the intrarenal pressure and has also several advantages. however not prolonging the operation time too much might be of greater importance than the use of uas in terms of preventing postoperative infection after rirs. references 1. marshall vf. fiber optics in urology. j urol. 1964; 91:110-114. 2. van cleynenbreugel b, kilic o, akand m. retrograde intrarenal surgery for renal stones part 1. turk j urol. 2017; 43:112-121. 3. türk c, petfík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-482. 4. takayasu h, aso y. recent development for pyeloureteroscopy: guide tube method for its introduction into the ureter. j urol. 1974; 112:176-178. 5. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33-36. 6. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-584. 7. traxer o, wendt-nordahl g, sodha h, et al. differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: the clinical research office of the endourological society ureteroscopy global study. world j urol. 2015; 33:2137-2144. 8. bone rc, balk ra, cerra fb, et al. definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. the accp/sccm consensus conference committee. american college of chest physicians/society of critical care medicine. chest. 1992; 101:1644-1655. 9. kourambas j, byrne rr, preminger gm. dose a ureteral access sheath facilitate ureteroscopy? j urol. 2001; 165:789-793. 10. breda a, territo a, lópez-martínez jm. benefits and risks of ureteral access sheaths for retrograde renal access. cur opin urol. 2016; 26:70-75. 11. berquet g, prunel p, verhoest g, et al. the use of a ureteral access sheath does not improve stone-free rate after ureteroscopy for upper urinary tract stones. world j urol. 2014; 32:229-232. 12. wright a, williams k, somani b, rukin n. intrarenal pressure and irrigation flow with commonly used ureteric access sheaths and instruments. central european j urol. 2015; 68:434. 13. rehman j, monga m, landman j, et al. characterization of intrapelvic pressure during ureteropyeloscopy with ureteral access sheaths. urology 2003; 61:713-718. 14. huang j, zhao z, alsmadi jk, et al. use of the ureteral access sheath during ureteroscopy: a systematic review and meta-analysis. plos one 2018; 13:e0193600. 15. wang j, zhou dq, he m, et al. effects of renal pelvic high-pressure perfusion on nephrons in a porcine pyonephrosis model. exp ther med. 2013; 5:1389-1392. 16. zhong w, leto g, wang l, zeng g. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015; 29: 25-8. correspondence mustafa karaaslan mustafakaraaslan23@gmail.com senol tonyali, md (corresponding author) senoltonyali@hotmail.com mehmet yilmaz yilmazmehmet88@hotmail.com sedat yahsi sedatyahsi@yahoo.com sedat tastemur sedattastemur@yahoo.com erkan olcucuoglu, md erkanolcucuoglu@gmail.com archivio italiano di urologia e andrologia 2020; 92, 2112 case report thrombosis of the posterior scrotal vein associated with essential thrombocytemia: report of a case andrea solinas department of surgery, unit of urology, ats sardegna assl carbonia, ospedale sirai, carbonia, italy. mondor’s disease is a rare superficial thrombophlebitis of subcutaneous vein and usually occurs in the anterior and lateral chest. penile mondor’s disease is a rare condition characterized by superficial thrombophlebitis of the dorsal vein of the penis. we report a rare case of atypical penile mondor’s disease involved the right posterior scrotal vein, in a patient affected by essential thrombocythemia. a 50-years old man presented with thrombosis of right posterior scrotal vein. he presented with an indurated subcutaneous and painful cord, palpable along the length of the involved vein and located parallel to the urethra in the posterior aspect of the scrotum. it was treated with lowmolecular-weight heparin and resolves without sequelae. the scrotal vein thrombosis is a fairly rare disease. key words: mondor’s disease; superficial thrombophlebitis; tender cord; scrotal vein thrombosis. submitted 3 december 2019; accepted 16 january 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.112 introduction mondor’s disease is a rare superficial thrombophlebitis of subcutaneous vein and was first described by henry mondor in the superficial veins of the chest wall in 1939 (1). in 1955 braunfalco defined dorsal phlebitis of the penis in the context of generalized phlebitis while the first isolated penile mondor’s disease was defined by helm and hodge in 1958 (2). penile mondor’s disease is rarer, arising out of thrombophlebitis of the penile veins. it has been reported after genital trauma such as stretching and torsion of the veins and can cause endothelial necrosis and thrombosis. it typically involves the dorsal vein of the penis and presents with a cord-like indurated lesion with a beaded feel, palpable along the length of the involved vein. the causes of the disease include frequent and prolonged sexual intercourse, prolonged sexual abstinence, infections, thrombophilia, repair of inguinal or umbilical hernia (3), orchiopexy, varicocelectomy, use of intracavernous drugs, use of vacuum, behçet’s disease, body building exercises, cancer in the pelvic region, metastatic pancreas cancer and migratory phlebitis due to paraneoplastic syndromes and tendency to thrombosis (4). thrombosis occur as a consequence of intravascular coagulation due to injury to vessel wall, stasis, and hypercoagulation known as virchow’s triad. though penile mondor’s disease involving the dorsal vein of the penis has been reported by many authors, atypical localization involved the circumflex vein (5) or the superficial scrotal veins (3-6) are also described. we report a rare case, involved the right posterior scrotal vein, in a patient affected by essential thrombocythemia. case report a 50-years old man presented with a thrombosis of right posterior scrotal vein. he had a cord-like indurated lesion, palpable along the length of the involved vein and located parallel to the urethra in the posterior aspect of the scrotum associated with a feeling of heaviness. there was no fever, hematuria, dysuria. he gave a history of essential thrombocythemia for six months treated by interferon. examination of genito-urinary system was normal. standard investigations (blood and urine) requested were normal, while a blood cell count revealed 800 x 103 platelets. diagnosis was confirmed on doppler ultrasonography of the scrotal superficial venous system. it was treated with low-molecular-weight heparin for eight week and subsequently received aspirin (100 mg once daily) for prophylaxis of recurrences. he resolves without sequelae in eight weeks with recanalization of the vein and remained well three years after therapy. discussion mondor’s disease is a rare superficial thrombophlebitis, historically involving the thoracic venous system. however, it can occur all over the skin. in 1955, the first reported case of mondor’s disease (superficial thrombophlebitis) of the penis was published (2). since then there have been described reports of penile mondor’s disease in the literature. most studies suggest neoplasm, sexual trauma, sickle cell anemia, excessive sexual activity or abstinence as the most frequent etiology and diabetes as predisposing factor due to its frequent pelvic problems leading to a potential venous inflammatory trigger. the application of immunohistochemical markers revealed that almost all mondor’s diseases appeared to be thrombophlebitis of the superficial vein. the progression of phlebitis includes some pathophysiological steps in developing mondor’s disease. at the initial stages, thrombotic events occur in the affected veins. as a result the lumen often becomes occluded with fibrin and inflammatory cells (7). subsequently, the connective tissue gathering in the vessel forms a hard, cord-like solinas_stesura seveso 17/06/20 10:14 pagina 112 113archivio italiano di urologia e andrologia 2020; 92, 2 thrombosis of the posterior scrotal vein induration. thereafter, recanalization proceeds for several weeks until establishment. mondor’s disease can occur without a clearly determined aetiology but in our case, thrombocytemia was identified as a main risk factor. diagnosis of mondor’s disease is usually made on clinical findings, thorough taking of the medical history and a correct physical examination are essential for diagnosing. the thrombosed superficial veins should first be detected with doppler ultrasonography. doppler ultrasonography can be also used in follow-up, showing the recanalization of the endoluminal thrombosis vein (8-9). the standard treatment strategy for mondor’s disease has not yet been established because of the paucity of clear evidence. most cases resolve within 4 to 6 week with re-permeabilization. currently treatment is palliative for most patients with anti-inflammatory drugs and local heparin containing creams but in our patient with thrombophilia we preferred anticoagulation with low-molecularweight heparin and subsequently with aspirin to prevent additional thrombosis. however, antibiotic therapy should be administered when cellulitis is suspected and vein stripping may be necessary for severe, persistent cases. in secondary mondor’s disease, treating the underlying disease is of the highest priority because mondor’s disease itself is not life-threatening, while the underlying diseases may lead to a lethal outcome. conclusions mondor’s disease is a rare self-limiting benign process with acute presentation characterized by a cord-like induration in several parts of the body. although its physiopathology is not exactly known, transection of the vessel during surgery or any type of trauma such as external compression may trigger its possible development. the patient usually feel the superficial vein like a hard cord and present with complaint of pain around this hardness. diagnosis is usually easy with medical history and physical examination. color doppler ultrasound examination is important for differential diagnosis. the relationship between mondor’s disease and other sites of superficial thrombophlebitis remains unclear, but such lesions are considered an initial manifestation of generalized thrombophlebitis. some cases of mondor disease may occur secondary to an underlying disease, such us vasculitis, a hypercoagulative state, or malignancy. the prognosis of secondary mondor’s disease therefore depends on the prognosis of the underlying disease. physicians should correctly identify mondor’s disease, evaluate the possible presence of an underlying disease and avoid performing unnecessary invasive tests or treatment. acknowledgments the article is dedicated to my son lorenzo. references 1. nazir ss, khan m. thrombosis of the dorsal vein of the penis (mondor’s disease): a case report and review of the literature. indian j urol. 2010; 26:431-3. 2. helm jd jr, hodge ig. thrombophlebitis of dorsal vein of the penis: report of a case treated by phenylbutazone (butazolidin). j urol. 1958; 79:306-7. 3. mendez rubio s, menéndez sánchez p, et al. idiopathic thrombosis of the superficial scrotal veins (mondor’s disease) during the postoperative period of an umbilical herniorraphy. arch esp urol. 2012; 65:903-7. 4. öztürk h, penile mondor’s disease. basic clin androl 2014; 3:24:5. 5. arora r, sonthalia s, gera t, sarkar r. atypical penile mondor’s disease-involvement of the circumflex vein. int j std aids. 2015; 26:360-3. 6. fujii y, arisawa c, horiuchi s, et al. thrombosis of the posterior scrotal vein: report of two cases. hinyokika kiyo. 1992; 38:1417-19. 7. amano m, shimizu t. mondor’s disease: a review of the literature. intern med. 2018; 57:2607-12. 8. ouattara a, karim parè a, kaborè af, et al. subcutaneous dorsal penile vein thrombosis or penile mondor’s disease: a case report and literature review. case rep urol. 2019; 2019:1297048. 9. dicuio m, pomara g, ales v, et al. doppler ultrasonography in a young patient penile mondor’s disease. arch ital urol androl. 2005; 77:58-9. correspondence andrea solinas, md (corresponding author) sol.andrea@tiscali.it s.c. urologia, ats sardegna -assl carbonia, ospedale sirai via ospedale, 09013 carbonia (italy) solinas_stesura seveso 17/06/20 10:14 pagina 113 stesura seveso archivio italiano di urologia e andrologia 2015; 87, 4332 case report primary testicular lymphoma: two case reports and review of the literature basri cakiroglu 1, seyit erkan eyyupoglu 2, akif nuri dogan 3, umit noseri 4, suleyman hilmi aksoy 5, ahmet bekir ozturk 6 1 department of urology, hisar intercontinental hospital, umraniye, istanbul, turkey; 2 department of urology, sabuncuoglu serafeddin training and research hospital, amasya, turkey; 3 deparment of internal medicine, hisar intercontinental hospital, umraniye, istanbul, turkey; 4 department of nuclear medicine, hisar intercontinental hospital, umraniye, istanbul, turkey; 5 deparment of radiology, hisar intercontinental hospital, umraniye, istanbul, turkey; 6 deparment of oncology, hisar intercontinental hospital, umraniye, istanbul, turkey. primary testicular lymphoma, is a rare testis tumor that accounts for only less than 9% of all testis tumors. in the preoperative period, it is extremely difficult to distinguish this tumor from other testis tumors. its diagnosis is done by histological analysis. most commonly encountered histological type is diffuse large bcell lymphoma. adjuvant radiotheraphy and/or chemotheraphy is given after orchiectomy. prognosis is worse than other testis tumors. non-metastatic tumors indicates good prognosis within one year. ongoing research in patients with primary testicular lymphoma, are on efficacy of adjuvant theraphies and preventive and cure effect on extranodal extension to central nervous system which is the most common site for recurrency. there are conflicting results because of the small number of patient size. here we present two cases with primary testicular lymphoma at the ages 71 and 82. key words: primary testicular lymphoma; orchiectomy; chemotheraphy; radiotheraphy. submitted 18 december 2014; accepted 31 july 2015 summary no conflict of interest declared. at diagnostic with scrotal ultrasonography (usg), there was diffuse enlargement and increased vascularisation of the right testis when compared with the left one. testis parenchyma was reported as isoechoic. there was no peripheric lymphadenopathy (lap) or hepa tosplenomegaly. laboratory examinations showed hemoglobin 13.57 gr/dl (mcv: 86.61 fl, mch: 31 pg, mchc: 36.27 g/dl); blood leucocyte: 4500/mm3 (65% neutrophil, 35% lymphocyte); trombocytes: 210000/mm3; sedimentation rate: 5/h; serum reactive protein: 0,35 ng/ml; ldh: 212 ui/l (100-190); sgot:35; sgpt: 42; ggt: 38 u/l. tumor markers were negative: alpha-fetoprotein (afp) 1,1 u/l and beta human chorionic globulin (hcg) 0.05 mu/ml. he was diagnosed as orchitis and given 2 week antibiotic and antiinflammatory treatment. at his control visit after treatment, acute symptoms as scrotal pain, testicular pain, and erythema were dissappeared. however, testis enlargement persisted and scrotal doppler usg was performed again. there was reactive hydrocele, the right testis was larger than the left one with no vascularization difference and orchiectomy was planned. right high orchiectomy was performed. at histopathological evaluation, the cells had large nucleus and some of them had prominent nucleolus. at immunohistochemistry analysis the neoplastic cells were cd20 and bcl2 positive; bcl6, cd30 and alk negative. ki67 positivity was above 80% in the areas with good fixing. non-hodgkin diffuse large b-cell lymphoma diagnosis was made (figure 1). the abdominopelvic, thorax and cranial ct were normal. he was in stage i and adjuvant chemotheraphy was planned, 6 dose of cyclophosphamid, novantron, oncovin, prednisolone (cnop) chemo-treatment was done. there was no pathology in abdominal and thorax ct, andno other accompanying pathology at 3 year follow up. case 2 an 82 year-old male patient was admitted to the urology outpatient clinic with fatigue for 3 months, back pain, painless swelling in his left testis. on physical examinadoi: 10.4081/aiua.2015.4.332 introduction primary testicular lymphoma (ptl) is an extranodal lymphoma in which primary origin is testis, and it accounts only 1-2% of all non-hodgkin lymphomas (nhl) and 19% of all testis tumors (1, 2). most of the patients are above 60 years (3) and ptl is the most commonly seen neoplasm in this age group (4). here we present two cases with primary testicular lymphoma. case reports case 1 a 70 year-old male patient, was admitted to the urology outpatient clinic with rapid onset painful swelling on his right testis. on physical examination, right scrotal mass palpation with erythematous scrotum, immobile testis, decreased fluctuation and prehn’s sign indicating orchitis were observed. 333archivio italiano di urologia e andrologia 2015; 87, 4 primary testicular lymphoma: two case reports and review of the literature tion, he was in normal general condition, well oriented and cooperative, with good cognitive status. blood pressure was 110/60 mm hg, pulse 76/minute,temperature 36,1 0c, costovertebral angle tenderness (cvat) -/-, suprapubic tenderness was positive and there was no bladder overdistension. the right testis was in the scrotum with normal dimensions, and epididymis also palpated normally. there was a big and hard mass of the left testis. on digital rectal examination a +1 fibroadenoma texture of prostate was found. at diagnostic ultrasound, there was a diffuse enlarged and vascularized left testis when compared with the right side and testis parenchyme was isoechoic. at physical examination there was no peripheric lap or splenomegaly. his laboratory investigation results were as follows: hemoglobin: 11,3 gr/dl (mcv 83,8 fl, mch 27,8 pg, mchc 33,1 g/dl); blood leucocytes: 6760/ mm3 (65% neutrophil, 35% lymphocyte); thrombocytes: 225 000/mm3; sedimentation rate: 81/h; serum reactive protein: 14 ng/ml; ldh: 443 ui/l (135-225), sgot: 21.8; sgpt: 7.07 u/l. tumor markers were negative: alpha-fetoprotein (afp) 2 ng/ml (< 7) and beta human chorionic globulin (hcg) 0,1 mu/ml (< 2). right inguinal orchiectomy was performed. at pathologic examinations there were diffusely scattered, prominently large, pleomorphic nuclei with irregular contour and thin chromatin, some cells with multilobulated and prominent nucleoulus, wide cytoplasmic cell neoplastic lymphoid infiltration in testis tissue and spermatic cord. the epididymis and rete testis tissue showed normal morphologic appearance. at immunohistochemistry the cells forming lesion were found cd20 (+) and cd3 (-). for typization a wide histochemistry analysis was necessary. the neoplastic cells were cd20 and bcl2 positive; bcl6, cd30 and alk were negative; ki67 positivity was above 80% in the areas with good establishment. the patient was diagnosed with non-hodgkin high grade diffuse large b-cell lymphoma. at abdominopelvic tomography (ct) there was a 26 mm diameter mass lesion with irregular contours at left renal hilus level in the retroperitoneal area. the lesion was adherent to the anterior surface of the psoas muscle. the lower segmentary branch of the left renal artery was surrounded by the mass lesion. there were multiple lymphadenopathies in the left paraaortic region with maximum size 23 x 18 mm, edema in the extraperitoneal region, andlymphadenopathies localized at interaortacaval, retrocaval, bilateral common iliac, external and internal iliac chain, with maximum diameter of 12 mm (lymphoproliferative diseases?/metastasis?) (figure 2a). figure 1. diffuse lymphoma infiltration in the interstitial region between seminiferious tubules in the testis (he x 100). figure 2a. 26 mm diameter mass lesion with irregular contours at left renal hilus level in the retroperitoneal area. figure 2b. multiple hypermetabolic metastatic lesions in bilateral cervical lymph node stations, lung parenchymal and mediastinal regions, abnominopelvic organs and lymphatic nodes and skeletal system. figure 2c. complete metabolic/morphologic regression with absence of hypermetabolic lesions in organs and lymphatic nodes. archivio italiano di urologia e andrologia 2015; 87, 4 b. cakiroglu, s. erkan eyyupoglu, a. nuri dogan, u. noseri, s. hilmi aksoy, a. bekir ozturk 334 the thorax and cranial ct were normal. the initial staging fluorodeoxyglucose (fdg) pet examination showed a maximum 34 mm large lap with hypermetabolic activity and increased uptake, pericardial inclusion, lap with hypermetabolic activity at left renal hilus level and at internal and external iliac level. mass lesion with hypermetabolic activity at the left testis of 65 x 33 mm dimension and multiple metastasis lesions at skeletal system were observed (figure 2b). according to those findings, the patient was classified as stage iv and a 6 dose rituximab, cyclofosfamide, epirubicin, vincristine, prednisolone, zoledronic acid with a 2 dose maintenance rituximab therapy was planned. after the 4th dose, fdg pet was performed to evaluate the response. there was total metabolic and morphologic response so the treatment protocol was continiued. there was no pathology at abdominal ct after six doses. at the end of the maintanance therapy, fdg pet was performed again. total metabolic and morphologic response was confirmed (figure 2c). at the second year follow up, there was a right axillary lap at chest ct with a ground glass density nodule near to the pleura of the left lung, a mass lesion of theright surrenal gland and thickening of the left side. written consent was obtained from the patient and their relatives for publication of the study. conclusions in conclusion, as ptl is a rare disease, there is lack of data that can guide the treatment. however with the aid of retrospective data evaluation, better prognosis was obtained for nodal lymphoma. despite the improvements in local and systemic disease central nervous system (cns) relapse remains the worst complication.. strategies that may decrease the risk of ptl patients will end up with better prognosis. introduction, discussion and supplementary re fe rences are posted as supplementary materials on www.aiua.it references 1. freeman c, berg jw, cutler sj. occurrence and prognosis of extra nodal lymphomas. cancer. 1972; 29:252-60. 2. shahab n, doll dc. testicular lymphoma. semin oncol. 1999; 26:259-69. 3. sussman eb, hajdu si, lieberman ph, whitmore wf. malignant lymphoma of the testis: a clinicopathologic study of 37 cases. j urol. 1977; 118:1004-7. 4. zucca e, conconi a, mughal ti, et al. patterns of out come and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group. j clin oncol. 2003; 21:20-7. correspondence basri cakiroglu, md (corresponding author) drbasri@hotmail.com hisar intercontinental hospital department of urology, saraymh. siteyolu cad. no:7, 34768 umraniye, istanbul, turkey seyit erkan eyyupoglu, md seeseesee@hotmail.com sabuncuoglu serafeddin training and research hospital, department of urology kirazli mh. hastane cad. 05200 amasya, turkey akif nuri dogan, md adogan@hisarhospital.com hisar intercontinental hospital deparment of internal medicine 34768 umraniye, istanbul, turkey umit noseri, md unoseri@hisarhospital.com hisar intercontinental hospital department of nuclear medicine, saray mh., siteyolu cad., no.7, 34768 umraniye, istanbul, turkey suleyman hilmi hilmi aksoy, md saksoy@hisarhospital.com hisar intercontinental hospital deparment of radiology 34768 umraniye, istanbul, turkey ahmet bekir ozturk, md hisar intercontinental hospital deparment of oncology 34768 umraniye, istanbul, turkey cop+ed+fisse 2006 169archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. comparison of greenlight 180-w xps laser vaporization versus transurethral resection of the prostate: outcomes of a single regional center nique has complications (5, 6), such as the transurethral resection syndrome secondary to irrigation fluid absorption, which presents risk factors including bleeding, operative times and large prostatic volume (7, 8). laser treatment of the prostate is acquiring a role as a minimally invasive treatment of bph. potassium tytanyl phosphate (ktp) laser for the treatment of bph was first used by watson in 1995 (9). over the years the greenlight laser has evolved starting from a power of 80 w, passing through a system to 120 w (gl-hps) up to the 180 w xps (gl-xps) in 2011. the increase in power has made it is also necessary to introduce new laser fibers for an efficient ablation of prostate tissue (10). the light beam ktp 532 nm is selectively absorbed by oxyhemoglobin, facilitating coagulation and vaporization of tissues. after its introduction, the technique was confirmed as effective and safe in the short and medium term (11, 12). furthermore, it has been shown that the procedure does not require the anticoagulant suspension because the procedure is almost bloodless, making the procedure optimal in high-risk patients (13). in the present study, we report our experience with photoselective vaporization of the prostate (pvp) and turp regarding complications and functional results with a follow up to 1 year. material and methods we analyzed a prospectively-maintained database collecting data on 100 patients undergoing surgical treatment of bph (50 consecutive pvp and 50 consecutive turp) from march 2015 to march 2016 at the department of urology of trento, italy. the clinical, operative, perioperative, variables are shown in table 1. all complications that occurred within 30 days of discharge and within 1 year have been recorded, defined and graduated according to the clavien dindo system (14) (table 2). comorbidities were evaluated according to preoperative risk assessment by the american society of anesthesiologist (asa score). the functional results were summarized in table 3: international prostate symptom score (ipss); max flow rate (qmax) and prostate specific antigen (psa). this data were recorded preoperatively and at 1 year of follow up. informed consent was obtained from all individual participants included in the study. background: to evaluate the intermediate perioperative outcomes, rate of complications and functional data after xps 180-w greenlight photoselective laser vaporization (pvp) compared with transurethral resection of the prostate (turp) in a prospective non-randomized single centre study. methods: we analyzed a prospectively-maintained database collecting data on 100 patients undergoing surgical treatment of bph (50 consecutive pvp and 50 consecutive turp). all complications, recorded and graduated according to the clavien dindo system and the clinical, operative, perioperative variables were compared. the functional outcomes, international prostate symptom score (ipss), max flow rate (qmax) and prostate specific antigen (psa), were recorded preoperatively and at 1 year of follow up. results: age, prostate volume, use of anticoagulants or antiplatelets, asa score and operative time were comparable in the two groups. the reduction in the hemoglobin levels (0.46 vs 1.8 g/dl), the catheterization time (1.2 vs 3.2 days), the hospital stay (1.7 vs 3.8 days) and rate of transfused patients (0 vs 8%), were significantly lower for pvp. transient re-catherization (6 vs 26%) was significantly lower for pvp. the ipss and qmax at 1 year showed no significant difference. the rate of repeat turp/pvp was higher in the turp group (0 vs 10%). reduction of psa, that reflects the major reduction of prostate volume, was statistically greater in pvp group respect turp group (p = 0.001). conclusions: pvp has advantages in terms of perioperative safety and major complications than turp. functional outcomes at 1 year of follow-up were comparable. key words: greenlight; turp; photoselective vaporization; laser; benign prostatic hyperplasia. submitted 22 april 2020; accepted 31 may 2020 daniele mattevi, lorenzo luciani, rosa spina, claudio divan, stefania cicuto, tommaso cai, valentino vattovani, marco puglisi, stefano chiodini, gianni malossini department of urology, santa chiara hospital, trento, italy. introduction benign prostatic hyperplasia (bph) is a very common disease among elderly men. this pathology leads the patient to have symptoms of the lower urinary tract (luts) and lowers the quality of life (1). medical therapy is usually the first-line treatment (2). thus, more invasive treatment options have to be considered as the disease progresses. transurethral resection of the prostate (turp) is still considered the gold standard for the treatment of luts (3), which improves the urinary flow rate and reduces the voiding symptoms (4). however, this techdoi: 10.4081/aiua.2020.3.169 summary 02mattevi_stesura seveso 24/09/20 14:11 pagina 169 archivio italiano di urologia e andrologia 2020; 92, 3 d. mattevi, l. luciani, r. spina, c. divan, s. cicuto, t. cai, v. vattovani, m. puglisi, s. chiodini, g. malossini 170 surgical technique the turp was performed by two urologists and the pvp was performed by two other urologists. turp was performed with a 26-f resectoscope; at the end, a bladder catheter 22 ch was placed with continuous bladder washing. the pvp was performed using the greenlight xps 180-w laser that uses a lithium tribal crystal instead of the ktp crystal, to produce a more collimated and powerful 532 nm laser beam than 80 w. this results in an intervention faster and greater ability to penetrate into prostate tissue (15). from the veru montanum to the bladder neck, the median and lateral lobes were vaporized with a final result similar to a turp. statistical analysis distribution of continuous variables are reported as mean and standard deviation. categorical variables are presented as numbers and percentages. the comparison between subgroups (surgical approach) was performed using student t test or mann-whitney u test for continuous variables. qualitative data were compared by the χ2 test or spearman correlation. p values were considered significant when less than or equal to 0.05. all analyses were performed using the spss software (ibm corp., armonk, ny). results 100 consecutive patients underwent endoscopic surgical treatment of bph from march 2015 to march 2016: 50 in the pvp and 50 in the turp groups. demographic, preoperative, operative and postoperative characteristics are summarized in table 1: age, prostate volume, use of anticoagulants or antiplatelets, and asa score were comparable between groups. also, the mean operative time was comparable in the two groups. compared to preoperative values, there was a significant reduction in the hemoglobin levels at the end of turp procedure as compared to pvp. the average duration of catheterization was 1.2 ± 0.5 days for pvp and 3.1 ± 3.4 days for turp group (p < 0.001) and also the definitive catheter removal was in favor of pvp (1.4 ± 0.8 vs 5.6 ± 6.6; p < 0.001). hospital stay was also statistically shorter in the pvp as compared to turp (2 days less). during pvp no blood transfusions were necessary whereas 4 patients (8%) undergoing turp were transfused due to a significant bleeding (2 intraoperative and 2 postoperative) (p = 0.04). early (< 30 days) and late complications are presented in table 2. transient recatherization was performed for urinary retention at catheter removal in 13 (26%) of patients undergoing turp and in 3 (6%) undergoing pvp (p = 0.01). five patients (10%) with bladder neck sclerosis or prostate tissue regrowth requiring returp were found in the turp group; none were found in the pvp group (p = 0.02). two cases of mild incontinence were found in turp group. the complications were graduated according to the classification of claviendindo and subdivided in minor and major complications. no major complications were found in pvp group, while 7 occurred in turp group (p = 0.01). overall complications were comparable in two groups. efficacy in terms of ipss, qmax and reduction of psa are shown in table 3. at 1 years, the outcome for both procedures was similar and there were no statistically significant differences between the groups for the primary outcome functional parameters except for psa degrees. the 1 year postoperative mean improvement in ipss was 9.3 ± 3 in the pvp group and 8.7 ± 5.1 in the turp group, and was not statistically different between the two groups (p = 0.58) and this reflected in the qmax score. reduction of psa, that reflects the major reduction of prostate volume, was statistically major in vlp group respect turp group (p = 0.001) table 1. preoperative, and early postoperative outcomes in the two study groups. turp (n = 50) pvp(n = 50) p value age (years) 68.8 ± 11.1 71.6 ± 7.4 0.14 prostate volume (cc) 48.1 ± 14.5 53.3 ± 14.7 0.08 anticoagulans/antiplatelet (n) 18 19 0.83 asa score 3 (n) 11 17 0.18 operative time (min) 61.6 ±27.9 63 ± 15.1 0.8 catheterization time (days) 3.1 ± 3.4 1.2 ± 0.5 0.001 definitive catheter removal (days) 5.6 ± 6.6 1.4 ± 0.8 0.001 tranfused patients (n) 4 0 0.04 hospital stay (days) 3.8 ± 2.6 1.7 ± 0.8 0.001 haemoglobin (g/l) preoperative 14.4 ± 1.3 13.7 ± 1.4 first day 12.6 ± 1.9 13 ± 1.9 hemoglobine reduction 1.8 ± 1.2 0.46 ± 0.42 0.01 table 3. functional results and psa at 12 months. turp (n = 50) pvp (n = 50) p value qmax (ml/s) preoperative 7.6 ± 3 8.4 ± 1.7 0.14 1 year 15.6 ± 6.4 17 ± 3 0.15 δ qmax 8.2 ± 7.2 9.7 ± 2.1 0.16 ipss score preoperative 20.1 ± 5.4 22.2 ± 5.8 0.06 1 year 8.7 ± 5.1 9.3 ± 3 0.58 δ ipss 10.7 ± 6.8 12.9 ± 4.1 0.052 psa (ng/ml) preoperative 2.29 ± 2.19 4.41 ± 2.31 0.001 1 year 1.9 ± 2.8 2.97 ± 1.8 0.03 δ psa 0.59 ± 0.6 1.73 ± 1.4 0.001 table 2. early and late postoperative complications. turp (n = 50) pvp(n = 50) p value early postoperative complications (<30 days) clot retention (n) 13 3 0.01 dysuria/urge (n) 8 16 0.06 late postoperative complications redo turp/vlp (n) 5 0 0.02 incontinence (n) 2 0 0.15 complications based on clavien-dindo classification minor complications (n) 13 11 0.7 major complications (n) 7 0 0.01 overall complications (n) 20 11 0.06 02mattevi_stesura seveso 24/09/20 14:11 pagina 170 discussion for many years, turp has been considered the gold standard for the treatment of luts secondary to benign prostatic hyperplasia. very often, however, turp is characterized by numerous post-operative complications. pvp was then introduced to minimize intra and post-operative complications with minimally invasive intent. the ktp 80-w laser is a light wavelength of 532 nm, which is strongly absorbed by hemoglobin. the greenlight xps 180-w laser provides the same wavelength of 532 nm with similar intrinsic absorption characteristics (15). as a result, laser prostate ablation has been developed to minimize the risk of bleeding complications. the reduction of complications then becomes particularly important in the older and fragile population that frequently carries coronary stents or who suffers from atrial fibrillation, coronary artery disease, valvular cardiopathies or deep vein thrombosis. these conditions are mainly managed through use of oral anticoagulants or antithrombotic agents (16). laser light vaporizes the prostatic tissues layer by layer; the thickness of each layer is 1-2 mm. at the same time, capillary vessels are coagulated to stop bleeding. this explains why the occurrence of intraoperative bleeding and blood transfusion is hardly seen in pvp treatment. in our study, the rate of transfusions and the reduction of hemoglobin is statistically lower in the pvp group as well and this is associated with a lower hospital stay and catheterization time (17).the catheterization and hospital time are important factors affecting patient’s quality of life, so this result indicates a major advantage of pvp. considering complications the clot retention was the most frequent early complication in the turp group (26%) and this may occur as a consequence as well as premature termination of procedure, with consequent inadequate relief of obstruction: only 3 patients (6%) experienced a recatheterization after pvp. large non randomised studies have reported a more favorable safety profile for green light than turp regarding major complications (18) accordingly to our results (7 vs 0; p < 0,001). in our study the reintervention rate was higher in the turp group as respect to the pvp group and it was caused by bladder neck sclerosis or prostate tissue regrowth; another cause may be secondary to the reduced amount of tissue resected in patients undergoing turp, which is underlined by the minor reduction of the postoperative psa. one-year functional results showed dramatic improvement in both groups regarding reduction of ipss and improvement of qmax with no significant difference between both groups. only greater urgency in the pvp group should be reported in the immediate postoperative period. this study reveals that pvp offers more advantages than turp in terms of clot retention, blood transfusion and lower incidence rate of major complications. furthermore, compared to the turp group, patients undergoing pvp have a shorter duration of catheterization, less blood loss and shorter hospital stays, which may explain the broad acceptance of pvp surgery from patients with secondary lut to bph, as confirmed by metanalysis (18-20). the benefits of laser-based prostatic surgery are reflected in its increasing use in daily clinical practice. the bpo rate treated with lasers increased from 6% in 2000 to 45% in 2011 (21). since its introduction in 1995, for example, green lasers now account for about 23% of bph surgeries in france (22). also, it is important to point out that there is a growing interest to improve the use of laser in order to preserve the antegrade ejaculation (23). our study has some limitations. first, this is a non-randomized study comparing different surgical approaches. however, many patients are unwilling to be randomly assigned to a particular surgical treatment and are usually attracted by the most modern surgical procedure or chose a procedure based on personal preferences for a specific surgeon. second, our study involved a relatively low number of patients with inherent biases related to data collection. in this case, selection biases were partially limited by the inclusion criteria: the last consecutive 50 interventions for each surgical technique were included. also, indications to surgery, operative techniques and perioperative management, and data collection should be relatively homogeneous in a single center. furthermore, age, prostate volume, used of anticoagulants or antiplatelets, and asa score were comparable between groups. conclusions pvp has advantages in terms of perioperative safety and rate of major complications than turp. functional outcomes at 1 year of follow-up were comparable. references 1. berry sj, coffey ds, walsh pc, ewing ll the development of human benign prostatic hyperplasia with age. j urol. 1984; 132:474-479. 2. michel mc, mehlburger l, bressel hu, et al. tamsulosin treatment of 19,365 patients with lower urinary tract symptoms: does comorbidity alter tolerability? j urol. 1998; 160:784-791. 3. kaplan sa. re: eauguidelines on the treatment and followup of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. j urol. 2014; 192:1167. 4. holtgrewe hl, mebust wk, dowd jb, et al. transurethral prostatectomy: practice aspects of the dominant operation 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two-yr outcomes of the goliath study. eur urol. 2016; 69:94-102. 13. reich o, bachmann a, siebels m, et al. high power (80 w) potassium-titanyl-phosphate laser vaporization of the prostate in 66 high risk patients. j urol. 2005; 173:158-160. 14. dindo d, demartines n, clavien p.a. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:2. 15. malek rs, kang hw, peng ys, et al. photoselective vaporization prostatectomy: experience with a novel 180 w 532 nm lithium triborate laser and fiber delivery system in living dogs. j urol. 2011; 185:712-8. 16. whitlock ep, burda bu, williams sb, et al. bleeding risks with aspirin use for primary prevention in adults: a systematic review for the u.s. preventive services task force. ann intern med. 2016; 164:826. 17. van cleynenbreugel b, srirangam sj, van poppel h. highperformance system greenlight laser: indications and outcomes. curr opin urol. 2009; 19:33-37. 18. teng j, zhang d, li y, et al. photoselective vaporization with the green light laser vs transurethral resection of the prostate for treating benign prostate hyperplasia: a systematic review and metaanalysis. bju int. 2013; 111:312-323. 19. ding h, du w, lu zp, et al. photoselective green-light laser vaporization vs. turp for bph: meta-analysis. asian j androl. 2012; 14:720-5. 20. thangasamy ia, chalasani v, bachmann a, woo hh. photoselective vaporization of the prostate using 80-w and 120-w laser versus transurethral resection of the prostate for benign prostatic hyperplasia: a systematic review with metaanalysis from 2002 to 2012. eur urol. 2012; 62:315-23. 21. chughtai bi, simma-chiang v, lee r,, et al. trends and utilization of laser prostatectomy in ambulatory surgical procedures for the treatment of benign prostatic hyperplasia in new york state (20002011). j endourol. 2015; 29:700-706. 22. peyronnet b, cornu j-n, rouprêt m, et al. trends in the use of the greenlight laser in the surgical management of benign prostatic obstruction in france over the past 10 years. eur urol. 2015; 67:1193-1195. 23. leonardi r. the lest technique: treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. arch ital urol androl. 2019; 91:35-42. correspondence daniele mattevi, md, febu (corresponding author) danielemattevi85@gmail.com lorenzo giuseppe luciani, md lorenzo_luciani@hotmail.com rosa spina, md rosa.spina@apss.tn.it claudio divan, md claudio.divan@apss.tn.it stefania cicuto, md stefania.cicuto@apss.tn.it tommaso cai, md tommaso.cai@apss.tn.it valentino vattovani, md valentino.vattovani@apss.tn.it marco puglisi, md marco.puglisi@apss.tn.it chiodini stefano, md gianni malossini, md gianni.malossini@apss.tn.it department of urology, santa chiara hospital largo medaglie d’oro 9, 38122, trento, italy 02mattevi_stesura seveso 24/09/20 14:11 pagina 172 75archivio italiano di urologia e andrologia 2017; 89, 1 original paper urinary symptoms and sexual dysfunction among italian men: the results of the #controllati survey vincenzo mirone 1, roberto carone 2, giuseppe carrieri 3, elisabetta costantini 4, giuseppe morgia 5, giuseppe mario ludovico 6, donata villari 7, fabio parazzini 8 on behalf of the #controllati study group* 1 università degli studi di napoli federico ii, uoc di urologia della a.o.u. federico ii, napoli, italy; 2 università degli studi di torino, struttura complessa di neuro-urologia a.o.u. città della salute e della scienza, torino, italy; 3 dipartimento nefro/urologico clinica urologica e centro trapianti di rene, università degli studi di foggia, italy; 4 sezione di urologia femminile, funzionale e di chirurgia urologica mini-invasiva. dipartimento di scienze chirurgiche e biomedicali, università di perugia, italy; 5 università degli studi di catania, presidio ospedaliero policlinico, catania, italy; 6 struttura complessa urologia, ospedale “miulli”, acquaviva delle fonti, italy; 7 università degli studi di firenze, sod chirurgia urologica mini-invasiva e dei trapianti, azienda mista universitaria ospedaliera, careggi, italy; 8 dipartimento di scienze cliniche e di comunità, università di milano, irccs policlinico milano, italy. objective: prevention may improve the quality of life and sexual and reproductive health. to improve prevention require a comprehensive research approach that examines the frequency and risk factors for urologic conditions. in june 2016 the italian urologic society coordinated a preventive initiative : the 1st week of male urologic prevention ”#controllati”. material and methods: during the 1st week of male urologic prevention “#controllati”, men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counseling about urologic or andrologic conditions. each participating man underwent a physical examination. further he was asked about his a medical history and about his urologic symptoms, sexual activity and possible related problems. results: data were collected in 81 centers: 2380 men answered the questionnaire. a total of 1226 subjects participating in the study reported one or more urinary symptom [51.5% (ic 95% 48.9%-54.5%)]. the risk of any urinary symptoms increased with age: in comparison with men aged < = 30 years or less the risk of any urinary symptoms was 2.31, 2.92, 5.12, 7.82 and 17.02 respectively in the class age 31-40, 41-50, 51-60, 61-70 and > = 71. overweight/obese men were at increased risk of any urinary symptoms [or1.35 (95% ci 1.12-1.64)]. 27.2% (ic 95% overall 25.2% -29.3%) of the subjects had at least a sexual disorder (erectile dysfunction, premature ejaculation, hypoactive sexual desire). the erectile dysfunction and hypoactive sexual desire increased with age, but premature ejaculation tended to be higher among younger aged men aged 40 years or more. current any urinary symptoms [or 1.85 (ci 1.40-2.43)], hypertension [or 1.66 (95% ci 1.21-2.26) and diabetes (or 2.37 (95% ci 1.45-3.88)] increased the risk of erectile dysfunction. conclusions: this large survey gives a picture of the burden of the more frequent urologic conditions offering useful information in order to focus preventive campaign. key words: risk factors; urinary symptoms; erectile dysfunction; premature ejaculation. submitted 16 march 2017; accepted 21 march 2017 summary no conflict of interest declared. doi: 10.4081/aiua.2017.1.75 introduction urologic diseases are common among men, leading to significant economic, quality of life and public health issues (1). for example, the reported prevalence of lower urinary tract symptoms (luts) is about 50% (2) and of erectile dysfunction 12% (3). among italian men, the lifelong risk of urologic cancer (prostatic bladder and kidney cancer) is about one out of ten (4). the burden of urologic diseases in men will increase as the population ages, and risk factors for luts, including diabetes and obesity, remain highly prevalent (5). adequate prevention, especially in the field of urology, made in young, adult and advanced age, significantly reduces the frequency of cancer (prostate, kidney, bladder and testicle), allowing also an early diagnosis and timely treatment, and benign disease (urolithiasis, benign prostate hyperplasia and prostatitis, male infertility and sexual dysfunction), that can determine, if neglected, a reduction in the quality of life, and sexual and reproductive health damage. otherwise, to improve prevention requires a comprehensive research approach that examines the frequency and risk factors for urologic conditions. in june 2016 the italian urologic society (siu) coordinated a huge preventive initiative: the 1st week of male urologic prevention “#controllati”. in this paper, we present the results of the initiative, with a special focus on luts and sexual dysfunction. methods during the 1st week of male urologic prevention “#control lati” (june 2016), men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counselling about urologic or andrologic conditions. a pamphlet inviting men for a free of charge check-up and listing participating centers was left in chemists and general practitioners’ waiting rooms and parazzini_stesura seveso 04/04/17 09:29 pagina 75 archivio italiano di urologia e andrologia 2017; 89, 1 v. mirone, r. carone, g. carrieri, e. costantini, g. morgia, g.m. ludovico, d. villari, f. parazzini on behalf of the #controllati study group 76 included in two weekly national journals; an advertising campaign was set in the press and broadcast media. each participating man underwent a physical examination. further he was asked about his a medical history and about his urologic symptoms, sexual activity and possible related problems. data were recorded with a simple questionnaire used by all centers. the first section, about age, marital, educational and professional status, weight, height, family history of prostatic cancer was completed by the patient. history of hypertension, diabetes and other medical conditions, and the findings of the clinical examination, were recorded by the physician. erectile function was assessed by asking men about their sexual performance: erectile dysfunction (ed) was diagnosed according to the definition of the nih consensus development panel (6), when a man was consistently unable to attain or maintain a penile erection sufficient for satisfactory sexual performance. a man was diagnosed as suffering from premature ejaculation (pe) if he had “persistent or recurrent ejaculation with minima sexual stimulation before, or shortly after penetration, and before the person wishes” according to the categorization of the american psychiatric association. patients were directly asked about the presence of this disorder during the visit. the 2002 ics definitions were used for frequency, nocturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying (7). a total of 181 centres participate to the initiative, 70 in the north, 45 in the center and 66 in the south of italy. however, epidemiological data were collected in 81 centers for a total of 2380 men who filled the questionnaire [mean number for center 29 (sd 21), median 25 (interquartile range 24-40)]. mean (standard deviation, sd), median (range) or frequency (percent, %) were computed as appropriate. were also calculated where appropriate confidence limits at 95% of the proportions. finally, we ran an analysis on the risk factors for sexual dysfunction (separately for ed and pe) and urinary disorders. odds ratios (or), and the corresponding 95% confidence intervals (ci), were derived using unconditional multiple logistic regression, fitted by the method of maximum likelihood, in which the dependent variable was the presence (case) or absence (control) of the condition and the independent ones were the exposures considered in the analysis. we included in the model potential co-variates considered as categorical variables (8). the terms included in the model are indicated in the footnotes of the tables. results the general characteristics of study subjects are shown in table 1: the mean age was 53.6 years (ds 11.5, median age 53 years, range 18-87). the most frequent class age was 41 to 50 years (31.09%). the mean body mass index (bmi) was 26.0 (ds 3.6) and the median 25.5. most participants were ever married (70.1%). the 13.2% of subjects reported a diagnosis of hypertension and 3.7% of diabetes. a family history of prostatic cancer was reported in 9.8% of subjects. frequency of psa test screening and semen analysis a total of 1291 men (54.2%, 95% ci 51.3% -57.3%) of the study subjects reported psa testing. considering subjects aged 70 years or more, this percentage increased to 84.9% (95% ci 71.9% -99.5%). overall, 325 men reported a least one semen analysis in life (13.7%, 95% ci 12.2-15.1%) (table 2). frequency of and risk factors for urinary symptoms a total of 1226 subjects participating in the study reported one or more urinary symptom (51.5%, ci 95% 48.9%-54.5%). the most commonly reported urinary symptom was nocturia, in age groups 50 or more, whereas in younger age groups frequency was the most reported (table 3). table 1. characteristics of study subjects. n % age (years) ≤ 30 60 2.6 31-40 171 7.5 41-50 740 32,3 51-60 679 29.7 61-70 467 20.4 ≥ 71 172 7.5 marital status never married 497 22.6 married 1668 75.8 divorced/widower 36 1.6 bmi (kg/m2) < 25.0 877 44.1 25.0 -29.9 886 44.6 ≥ 30.0 225 11.3 hystory of hyperthension (yes) 314 13.2 diabetes (yes) 87 3.7 family history of prostatic cancer (yes) 232 9.8 sometimes, the sums do not add up the total due to missing values table 2. subjects reporting one or more psa testing and semen analysis in life in strata of age. > = 1 psa test in life > = 1 semen analysis in life no* yes no yes n % n % n % n % age (years) ≤ 30 58 2 52 8 (no. = 60) 96.7 3.3 86.7 13.3 31-40 158 13 138 33 (no. = 171) 92.4 7.6 80.7 19.3 41-50 508 232 605 135 (no. = 740) 68.7 31.4 81.8 18.2 51-60 211 468 580 99 (no. = 679) 31.1 68.9 85.4 14.6 61-70 84 383 433 34 (no. = 467) 18.0 82.0 92.7 7.3 ≥ 71 26 146 164 8 (no. = 172) 15.1 84.9 95.4 4.7 total 1089 1291 2055 325 no. = 2380 45.8 54.2 86.3 13.7 *sometimes, the sums do not add up the total due to missing values. parazzini_stesura seveso 04/04/17 09:29 pagina 76 we analyzed risk factors for any urinary disorders: the results of the analysis are presented in table 4. the risk of any urinary symptoms increased with age: in comparison with men aged < = 30 years or less the risk of any urinary symptoms was 2.31, 2.92, 5.12, 7.82 and 17.02 respectively in the age classes 31-40, 41-50, 51-60, 6170 and > = 71. overweight/obese men were at increased risk of any urinary symptoms (or 1.35, 95% ci 1.12-1.64). further, any current sexual dysfunction was associated with an increased risk of any urinary symptoms (or1.60. 95% ci 1.29-1.98). analyzing the association of overweight/obesity and any current sexual dysfunction separately for the various urinary symptoms, we observed similar results. frequency and risk factors of sexual dysfunction table 5 shows the distribution of study subjects in strata of age according to the presence of sexual dysfunction (erectile dysfunction, premature ejaculation, hypoactive sexual desire). 27.2% (ic 95% overall 25.2% -29.3%) of the subjects had at least a sexual disorder. the rate was 30.0% (ci 95% 18.3% -46.5%) in 30 or less, then slightly decrease in group 31-50 and increased in older age groups, being 41,9% in the men aged > = 71 years. the erectile dysfunction and hypoactive sexual desire increased with age, but premature ejaculation tended to be higher among younger aged men aged 40 years or more. 11.9%, (44, % 95% ci 8.7% -15.8%) of men reporting erectile dysfunction were currently treated for the condition (data not shown in table). we computed risk factors for sexual dysfunction separately for premature ejaculation and erectile dysfunction. the results of the analysis are presented in table 6. the or of premature ejaculation decreased with age being, in comparison with men aged < = 30 years, 0.16 (95% ci 0.05-0.50) in men aged > 70 years. 77archivio italiano di urologia e andrologia 2017; 89, 1 urinary and sexual disease in italy table 3. frequency of urinary symptoms according to age. nocturia dysuria incomplete urgency frequency any emptying symptom n % n % n % n % n % n % age (years) ≤ 30 1 4 1 3 3 9 (no. = 60) 1.7 6.7 1.7 5.0 5.0 15.0 31-40 16 20 13 12 25 53 (no. = 171) 9.4 11.7 7.6 7.0 14.6 31.0 41-50 101 88 85 78 90 282 (no. = 740) 13.7 11.9 11.5 10.5 12.2 38.1 51-60 174 116 139 111 125 378 (no. = 679) 25.6 17.1 20.5 16.4 18.4 55.7 61-70 189 81 119 94 104 317 (no. = 467) 40.5 17.3 25.5 20.1 22.3 67.9 ≥ 71 89 46 59 47 51 141 (no. = 172) 51.7 26.7 34.3 27.3 29.7 82.0 total 587 375 428 350 409 1226 no. = 2380 24.7 15.8 18.1 14.7 17.2 51.5 sometimes, the sums do not add up the total due to missing values. table 4. odds ratios (and corresponding 95% confidence intervals) of any urinary symptom according to selected factors. any urinary symptoms no yes or (95ci%) n* % n % age (years) ≤ 30 51 9 85.0 15.0 1° 31-40 118 53 69.0 31.0 2.31 (1.03-5.19) 41-50 458 282 61.9 38.1 2.92 (1.39-6.11) 51-60 301 378 44.3 55.7 5.12 (2.44-10.75) 61-70 150 317 32.1 67.9 7.82 (3.68-16.74) ≥ 71 31 141 18.0 82.0 17.02 (7.36-39.33) bmi (kg/m2) < 25.0 491 386 56.0 44.0 1° ≥ 25.0 475 636 42.8 57.3 1.35 (1.12-1.64) marital status never married 306 191 61.6 38.4 1° married 741 927 44.4 55.6 1.12 (0.8-1.44) divorced/vidower 17 19 47.2 52.8 0.80 (0.34-1.89) any sexual dysfuncion no 916 817 52.9 47.1 1° yes 238 409 36.8 63.2 1.60 (1.29-1.98) *sometimes, the sums do not add up the total due to missing values °reference category or: odds ratio; ci: confidence interval. multivariate estimates including terms for the above listed variables. table 5. frequency of sexual dysfunction according to age. erectile premature hypoactive any sexual dysfunction ejaculation sexual desire dysfunction n % n % n % n % age (years) < =30 6 10 2 18 10.0 16.7 3.3 30.0 31-40 15 20 7 30 8.8 11.79 4.1 22.8 41-50 52 55 39 127 7.0 7.4 5.3 17.2 51-60 107 46 61 184 15.8 6.8 9.0 27.1 61-70 122 35 49 181 26.1 7.5 10.5 38.8 > = 71 51 6 19 72 29.7 3.5 11.2 41.9 total 370 178 182 647 15.6 7.5 7.7 27.2 sometimes, the sums do not add up the total due to missing values. parazzini_stesura seveso 04/04/17 09:29 pagina 77 archivio italiano di urologia e andrologia 2017; 89, 1 v. mirone, r. carone, g. carrieri, e. costantini, g. morgia, g.m. ludovico, d. villari, f. parazzini on behalf of the #controllati study group 78 2.43)], hypertension [or 1.66 (95%ci 1,21-2,26)] and diabetes [or 2.37 (95%ci 1.45-3.88)] increased the risk of erectile dysfunction. discussion before discussing the results of this survey, potential limitations should be considered. the major flaw of this study is that the study population were men voluntarily presenting to the participating centers and physicians associated to the italian society of urology (siu). the participating centers were not randomly identified among all members, so they cannot be considered representative of all italian centers. however, they were well distributed over the main areas of the country and there were no marked differences in the results among centers in various large italian areas, giving strong support to the consistency of the general results. further, the prevalence of hypertension and diabetes and overweight were largely similar to the general italian population. for example the percentage of overweight and obese men was largely similar to that of the italian population (9). finally, the participation rate was very high: for example the answers to the questions about sexuality were missing in a few number of men. along this line, the patients presented voluntarily to the physician, so their answers to sensitive questions about sexual dysfunction should be truthful. the strengths of the study included the fact that it provides information from a large series of men identified in all parts of italy. despite the limitations, the results of this large survey gives a general picture of the burden of urological conditions in the italian populations. urinary symptoms first of all in the present study the self reported frequency of most common low urinary tract symptoms (luts) was about 50%, a proportion largely similar to that reported in the italian centers of epic study. in that study nocturia was the most prevalent luts (2). table 6. odds ratios (and corresponding 95% confidence intervals) of premature ejaculation and erectile dysfunction according to selected factors. premature ejaculation erectile dysfunction no yes or (95%ci) no yes or (95%ci) n* % n % n % n % age (years) <=30 50 10 54 6 83.3 16.7 1° 90.0 10.0 1° 31-40 151 20 156 15 88.3 11.7 0.42 (0.16-1.08) 91.2 8.8 1.07 (0.33-3.52) 41-50 685 55 688 52 92.6 7.4 0.40 (0.18-0.88) 93.0 7.0 0.80 (0.282.34) 51-60 633 46 572 107 93.2 6.8 0.34 (0.15-0.76) 84.2 15.8 1.62 (0.56-4.67) 61-70 432 35 345 122 92.5 7.5 0.38 (01.7-0.89) 73.9 26.1 2.56 (0.88-7.42) > = 71 166 6 121 51 96.5 3.5 0.16 (0.05-0.50) 70.4 29.7 3.31 (1.10-9.95) bmi (kg/m2) > = 24.9 806 71 767 110 91.9 8.1 1° 87.5 12.5 1° > = 25.0 1027 84 895 216 92.4 7.6 0.96 (0.68-1.95) 80.6 19.4 1.25 (0.96-1.63) marital status never married 455 42 443 54 91.6 8.5 1° 89.1 10.9 1° married 1541 127 1377 291 92.4 7.6 1.30 (0.82-1.07) 82.6 17.5 0.84 (0.58-1.21) divorced/vidower 32 4 n.d. 26 10 100.0 0.0 76.0 24.0 1.71 (0.62-4.77) urinary symtoms no 1069 85 1041 113 92.6 7.4 1° 90.2 9.8 1° yes 1133 93 969 257 92.4 7.6 1.32 (0.93-1.89) 79.0 21.0 1.85 (1.40-2.43) erectile dysfunction no 1863 147 92.7 7.3 1° yes 339 31 91.6 8.4 1.42 (0.92-2.21) premature ejaculation no 1863 339 84.6 15.4 1° yes 203 279 42.1 58.0 1.45 (0.94-2.23) hypertension no 1909 157 1793 273 92.4 7.6 1° 86.8 13.2 1° yes 293 21 217 97 93.3 6.7 0.88 (0.53-1.49) 69.1 30.9 1.66 (1.21-2.26) diabetes no 2119 174 1960 333 92.4 7.6 1° 85.5 14.5 1° yes 83 4 50 37 95.4 4.6 0.57 (0.20-1.62) 57.5 42.5 2.37 (1.45-3.88) *sometimes, the sums do not add up the total due to missing values °reference category or: odds ratio; ci: confidence interval. multivariate estimates including term for the above listed variables. nd. not determined. the or of erectile dysfunction increased with age being, in comparison with men aged < = 30 years, 3.31 (95% ci1, 10-9.95) in men aged > 70 years. current any urinary symptoms [or 1.85 (ci 1.40parazzini_stesura seveso 04/04/17 09:29 pagina 78 we confirm these findings. the frequency of urinary symptoms increased markedly with age being about 15% among men aged 30 years or less, but 82% among those aged 71 or more. this findings is consistent with other epidemiologic studies of luts conducted in men, which also showed that the prevalence of all symptoms increased linearly with age (10, 11). overweight/obesity increased the risk of urinary symptoms. in particular overweight /obesity increased the risk of urgency. this finding is consistent with data from other populations (12). interestingly concurrent sexual dysfunction increased the risk of urinary symptoms. sexual dysfunction this study also give further data on the frequency of the main sexual dysfunctions in the italian populations. in the present survey the reported frequency of premature ejaculation was lower than previously reported among italian men. for example, the prevalence of premature ejaculation was of about 20% in a large survey of men attending a free andrologic consultation in about 200 italian medical centers, in the 2001 (13). this difference may be partly due to the fact that in the 2001 survey the mean age of participants was lower than in the present study. it has been suggested that diabetes decreased the risk of pe. for example a decreased risk of pe was found in men with treated diabetes (or 0.6, 95% ci 0.5-0.8) in men attending a free andrologic consultation in 186 italian medical centers, in the setting of a project focused on andrologic prevention in italy (13). it is well known that diabetic patients may develop failure of emission, due both to neuropathic changes of the sympathetic fibers innervating the bladder neck and to aperistalsis of the vas deferens (14). these changes act in opposition to the mechanism of pe, so that it seems diabetes gives a protective effect against such condition in our study the estimated or od ep was lower than unity in men reporting diabetes, but the finding was not statistically significant, possibly due to the limited number of diabetics. with regard to erectile dysfunction, the present analysis confirm that ed is a common condition, particularly among older men. the estimated prevalence of the conditions reported in this study is largely consistent with the findings of a population based study conducted in italy in the late ’90 showing a prevalence of ed of about 12% 3. further this study confirms that diabetes, and hyperthension increased the risk of erectile dysfunction. a more interesting findings id the opportunity of analyzing in a large data set the association between urinary symptoms and ed. some recent data have in fact linked ed risk with the presence of luts (15). we recorded if men suffered from several urinary symptoms: an association emerged between these symptoms and ed. finally, another interesting finding emerging from this survey is the fact that about 85% of subjects aged > 70 year reported on or more psa test life. this proportion however lowered to less than 70% among men aged 5160 year. this finding is consistent with that reported in other countries. for example about 60% of us men aged 76 or older with no history of prostate cancer reported having had a psa test in year before 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158:1733-7. 11. engstrom g, walker-engstrom ml, loof l, leppert j. prevalence of three lower urinary tract symptoms in men-a population-based study. fam pract. 2003; 20:7-10. 12. mondul am, giovannucci e, platz ea. a prospective study of obesity, and the incidence and progression of lower urinary tract symptoms. j urol. 2014; 191:715-21. 13. basile fasolo c, mirone v, gentile v, et al. premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001--a study of the italian society of andrology (sia). j sex med. 2005; 2:376-82. 14. sexton wj, jarow jp. effect of diabetes mellitus upon male reproductive function. urology. 1997; 49:508-13. 15. song j, shao q, tian y, chen s. lower urinary tract symptoms, 79archivio italiano di urologia e andrologia 2017; 89, 1 urinary and sexual disease in italy parazzini_stesura seveso 04/04/17 09:29 pagina 79 archivio italiano di urologia e andrologia 2017; 89, 1 v. mirone, r. carone, g. carrieri, e. costantini, g. morgia, g.m. ludovico, d. villari, f. parazzini on behalf of the #controllati study group 80 erectile dysfunction, and their correlation in men aged 50 years and above: a cross-sectional survey in beijing, china. med sci monit. 2014; 20:2806-10. 16. li j, zhao g, pollack la, et al. use of the prostate-specific antigen test among men aged 75 years or older in the united states: 2006 behavioral risk factor surveillance system. prev chronic dis. 2010; 7(4). available at : https://www.cdc.gov/pcd/issues//2010/jul/ pdf/09_0167.pdf. (last access 15 march 2017). 2010. correspondence vincenzo mirone, md università degli studi di napoli federico ii, uoc di urologia della a.o.u. federico ii, napoli, italy roberto carone, md università degli studi di torino, struttura complessa di neuro-urologia a.o.u. città della salute e della scienza, torino, italy giuseppe carrieri, md dipartimento nefro/urologico clinica urologica e centro trapianti di rene, università degli studi di foggia, foggia, italy elisabetta costantini, md sezione di urologia femminile, funzionale e di chirurgia urologica mini-invasiva. dipartimento di scienze chirurgiche e biomedicali università di perugia, perugia, italy giuseppe morgia, md università degli studi di catania presidio ospedaliero policlinico catania, italy giuseppe mario ludovico, md struttura complessa urologia ospedale “miulli”, acquaviva delle fonti, italy donata villari, md università degli studi di firenze, sod chirurgia urologica mini-invasiva e dei trapianti azienda mista universitaria ospedaliera careggi firenze, italy fabio parazzini, md (corresponding author) fabio.parazzini@unimi.it dipartimento di scienze cliniche e di comunità, università di milano, fondazione irccs ca’ granda ospedale maggiore policlinico via commenda 12, 20122 milano, italy *participating centres: abbate f (caltagirone), altomare m (molfetta), amici a (roma), anceschi c (roma), arena g (cuneo), artibani w (verona), avolio a (ascoli piceno), bassi p (roma), battaglia m (bari), beatrici v (pesaro-fano), beleggia f (taranto), bianchi g (modena), boccafoschi c (alessandria), bocciardi am (milano), brausi m (carpi), brigante s (brindisi), bruschetta s (messina), buizza c (busto arsizio), cafarelli a (ancona), caggiano s (caserta), canclini lp (milano), cappa m (roma), caraceni e (civitanova marche), caravetta a (acri), carbone a (latina), carini m (firenze), carluccio g (tricase), catanzaro f (cesano boscone), cavaliere a (lecce), cavalieri s (negrar), cecchi m (lido di camaiore), celia a (bassano del grappa), chincoli s (andria), cicalese v (avellino), cisternino a (s. giovanni rotondo), conti e (sarzana), corrada pl (vizzolo predabissi), cosentino v (catania), cossu fm (nuoro), cusumano r (roma), cuzzocrea de (bologna), dal bianco m (padova), damiano r (catanzaro), d’anca m (enna), d’andrea r (canistro), de antoni (udine), de ceglie g (cerignola), de lisa a(cagliari), del boca c (cremona), de martin m (reggio di calabria), de siati m (altamura), de sio m (napoli), de zorzi l (castelfranco veneto), defidio l (roma), di clemente l (coppito), di clemente l (avezzano), di marco m (roma), di martino m (avellino), di stefano g (ottaviano), ditonno p (bari), di trapani d (palermo), emili e (imola), fasolis g (alba), ferrando u (torino), ferrara v (jesi), ferrari g (modena), ficarra v (udine), fiorentino v (lagonegro), fischetti g (roma), frea b (torino), galli r (bergamo), galosi ab (ancona), gambarella cherubino m (mercogliano), frattini a (guastalla), garbeglio a (pordenone), gentile v (roma), giulianelli r (roma), gontero p (torino), greco f (roca di neto), greco u (salerno), gregori a (garbagnate milanese), grisanti r (sassuolo), grosso g (peschiera del garda), guizzardi f (caltanisetta), imperatore v (napoli), italiano e (palermo), ippolito c (cona), jungano r (napoli), la rocca l (martina franca), laganà a (tivoli), leonardi r (gravina di catania), lotesoriere o (copertino), lovisolo ja (saronno), lusuardi l (bolzano), maccatrozzo l (treviso), madonia m (sassari), maestroni uv (parma), magno c (messina), malossini g (trento), mammana g (macerata), manoni l (pistoia), marascia g (chieti), marchionni l (roma), martorana g (bologna), mastroeni f (messina), mearini e (terni), meneghini a (santorso), mensi m (voghera), merciai m (oliveto citra), merlo f (venezia mestre), minervini ms (sondrio), monesi g (borgosesia) montorsi f (milano), morelli e (mirabella eclano), natali a (firenze), nigro gl (crotone), oliva g (montepulciano), paola q (sciacca), pecoraro g (isola della scala), pennisi m (catania), perdonà s (napoli), pescione e (napoli), pompa p (pescara), ponchietti r (siena), porena m (perugia), porpiglia f (orbassano), porreca a (abano terme), zito ar (napoli), raber m (milano), ranieri a (lovere), ranno s (catania), ricapito vd (monopoli), risi o (treviglio), rizzotto a (viterbo), rosa a (verbano-cusio-ossola), ruggiero g (telese terme), russo g (s. giorgio a cremano), saita a (catania), salvia g (catania), salzano l (benevento), sandri s (magenta), sanseverino r (nocera inferiore), schiavone d (rovigo), scoffone c (torino), scognamiglio g (castellamare di stabia), schips l (chieti), selli c (pisa), sepe g (mondragone), simeone c (brescia), simonato a (palermo), sorrentino m (s. maria caupa vetere), striano s (caserta) tasso m (brà), tasso m (tivoli), tenaglia r (chieti), terrone c (genova), traficante a (carbonara di bari), tralce l (chiari), trombetta c (trieste), tubaro a (roma), tufano a (eboli), tura m (monza), ventura f (cosenza), verbena a (locri), vespasiani g (roma), vicentini c (teramo), vita a (potenza), voce s (ravenna), volpe a (novara), xausa d (feltre), zarrelli g (vercelli), zaramella s (ponderano), zago t (rho), zattoni f (padova), zoccali c (lamezia terme). data analysis: ricci e, esposito g (milano). parazzini_stesura seveso 04/04/17 09:29 pagina 80 stesura seveso 133archivio italiano di urologia e andrologia 2019; 91, 2 case report merkel cell carcinoma with kidney metastasis in a 81-year-old man. a rare case report aikaterini anastasiou 1, napoleon moulavasilis 1, ioannis leotsakos 1, christos e. nerantzis 2, ioannis anastasiou 1 1 1st university urology clinic, laiko hospital, athens greece; 2 forensic medical service of athens, athens, greece. merkel cell carcinoma (mcc) is a primary neuroendocrine carcinoma of the skin. the prognosis of the disease is considered poor. secondary metastasis is common, however a secondary metastasis to kidney from merkel cell is a very rare phenomenon. we report a case of a man with a mcc metastasis to the right kidney. the suggested management is surgery and afterwards a platinum-based chemotherapy. key words: merkel cell carcinoma; metastasis; kidney. submitted 13 march 2019; accepted 21 march 2019 summary no conflict of interest declared. discussion merkel cell carcinoma is a primary neuroendocrine carcinoma of the skin (1). it is a highly aggressive tumor with common metastasis to lymph nodes, liver, lung and bone (1). the clinical presentation is a rapidly expanding, 1-2 cm sized, asymptomatic, red/pink nodule seen on sun-exposed skin (1). thus it usually affects the head, neck and limbs (1). the mean latency from the primary tumor diagnosis to a systemic metastasis is 2.1 years. merkel cell carcinoma can be metastasized to every organ, with liver and lungs being the most commonly affected solid organs. distant dissemination occurs in up to 40-50% of patients that develop visceral metastasis (4). our patient first was presented with a submaxillary gland tumor. the evolution of the mcc in our patient was also rapid and after 3 months he was diagnosed with a cervical gland tumor and lastly after 4 months with a tumor in parotid. one year later an mri showed a metastasis to the right kidney (figure 1). doi: 10.4081/aiua.2019.2.133 introduction merkel cell carcinoma (mcc) is a rare non melanoma cutaneous malignancy with a high recurrence and mortality rates (1, 2). it commonly metastasizes to lymph nodes, liver, lung and bone. it occurs mainly in elderly, and people with immunosuppression due to organ transplantation and hiv infection (1, 2). secondary kidney tumors in patients without evidence of disseminated non-renal malignancy are rarely observed (3). we present a rare case of a 81-year-old man with a mcc metastasis to the right kidney. case presentation a 81-year-old man was presented to our urology department (1st university urology clinic, laiko hospital, athens, greece) after an mri scan revealed a solid lesion to his right kidney. a biopsy was performed and the histology revealed merkel cell carcinoma (mcc) (figure 1). the patient, has been diagnosed from mcc in the left submaxillary gland, which in the previous year metastasized in the cervical and parotid glands. these tumors where managed with surgery, chemotherapy and radiotherapy. mcc is known for its aggressiveness and in our case the kidney was the rare secondary metastasis of the tumor. the oncology board decided that the patient had to be submitted to a platinum based chemotherapy. today, 3 years after the last cycle of the chemotherapy our patient is without recurrence. figure 1. histology of merkel cell carcinoma. archivio italiano di urologia e andrologia 2019; 91, 2 a. anastasiou, n. moulavasilis, i. leotsakos, c.e. nerantzis, i. anastasiou 134 male sex, advanced age, white skin population, vitamin d deficiency, exposure to ultraviolet b and sun are reported to worsen the prognosis. mcc prognosis is also affected by immunosuppression from organ transplant and hiv infection (2). diagnosis is based on histological and immunohistochemical analysis.. histological features include a triad of vesicular nuclei with tiny nucleoli, numerous mitoses and apoptosis, with accompanying lymphovascular invasion (1). the choice of treatment depends on the characteristics of the disease, the stage at the presentation, the regional lymph node involvement, comorbidities and the performance status of the patient. surgery is the primary option for patients with locoregional primary mcc. a combination therapy with adequate surgical removal and selective adjuvant radiotherapy, can reduce the local recurrence rate in a higher percentage (2). however, it is still common for patients with clinically positive lymph nodes to present a high percentage of recurrence in the form of distant disease. finally, mcc is considered to be a chemotherapysensitive tumor especially for the treatment of metastatic mcc (stage iv), and it is mostly indicated to palliate symptoms (2). accordingly our patient for the first 10 months, the tumors of the glands where managed with surgery, chemotherapy (etoposide 100 x 6, and filgastin) and then radiotherapy. when the mri showed a suspected solid lesion to the right kidney we performed a biopsy and two tumors were found. after the surgery the patient was submitted to a chemotherapy (platinum x 8) and 3 years after the operation is without an evidence of a recurrence conclusions mcc is an aggressive neoplasm, which usually affects the head and the neck. the disease has an average age of presentation of 72 years. metastasis are observed in almost half of the patients. the most common are the lungs, liver and bones. a kidney metastasis is very rare in mcc patients, however it is possible to occur. references 1. medhi s, purandare nc, dua sg, gujral s. bilateral renal metastases in a case of merkel cell carcinoma. j cancer res ther. 2010; 6:353-5. 2. schadendorf d, lebbé c, zur hausen a, et al. merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. eur j cancer. 2017; 71:53-69. 3. pollheimer vs, bodo k, pollheimer mj, et al. merkel cell carcinoma metastasizing to the kidney mimicking primary neuroendocrine renal cancer. apmis. 2007; 115:774-7. 4. kouzmina m, koljonen v, leikola j, et al. frequency and locations of systemic metastases in merkel cell carcinoma by imaging. acta radiol open. 2017; 6:1-7. correspondence aikaterini anastasiou, md aikatianast@gmail.com napoleon moulavasilis, md napomoul@hotmail.com ioannis leotsakos, md j_leot@yahoo.gr iohannis anastasiou, md ekati2@otenet.gr 1st university urology clinic, laiko hospital ag.thoma 17, athens 11527 (greece) christos e. nerantzis, md theano9@otenet.gr forensic medical service of athens, athens (greece) archivio italiano di urologia e andrologia 2017; 89, 2146 short communications alprostadil plus vacuum (vitarum) in severe erectile dysfunction (ed) franco mantovani clinica san giovanni, milan, italy. objectives: severe erectile dysfunction (ed) is not uncommon, as can be seen from the epidemiological literature, and there are several possible causes, which are not always known, or leastways evident. having ascertained the ineffectiveness, intolerance to or rejection of pharmacological aids, the option of prosthetic surgery remains, but before this, it may be wise when feasible to use alprostadil cream in association with vacuum device. material and methods: 12 patients, aged between 55 and 65 years, with severe erectile dysfunction without palpable cavernous fibrosis, were instructed to self-insert into the urethral meatus, 3 mg of alprostadil cream, sufficient to make it easy to place the vacuum device over the penis. results: in the cases observed, the preliminary use of alprostadil cream fast produced an erection with enough rigidity to place the vacuum. a sufficient erection was maintained, obviously using an elastic ring at the base of the penis, to achieve penetration. the reproducibility of the use of alprostadil cream with vacuum device was then confirmed at home, to the satisfaction of the patients. key words: erectile dysfunction; alprostadil cream; vacuum device. submitted 14 april 2017; accepted 23 april 2017 summary no conflict of interest declared. materials and methods twelve patients aged between 55 and 65 years, with severe erectile dysfunction scored between 15 and 20 by the international index of erectile function (iief-15) index and an aetiology falling under the categories mentioned above (but excluding palpable cavernosal fibrosis that was a criterium of exclusion for this treatment) (2), were instructed to self-insert into their own urethral meatus, 3 mg of alprostadil, conveyed in a micro solution gel with dodecyl dimethylammonium propionate (vitaros). this patented natural surfactant technology allows for a rapid absorption of the drug, resulting in a penile turgidity, which is initially modest, but adequate to easily place the vacuum device onto the penis avoiding repeated attempts. the vacuum device is a tool of the andrological therapeutic armamentarium for many years. results in the cases observed, the preliminary turgidity obtained with alprostadil cream (vitaros) was soon followed by an erection produced by the vacuum. a sufficient rigidity for penetration was maintained by using an elastic ring at the base of the penis. this arose in a very brief time span, in the absence of any physical discomfort due to the suction, and did not require any persistent mechanical manoeuvres to enhance rigidity, even starting with a completely flaccid penis. the reproducibility of the use of alprostadil cream in association with vacuum was then confirmed at home, to the satisfaction of the patients (3). discussion in severe ed, the simple use of a vacuum device alone can lead to discomfort, not only physically, but also due to the continuous repeated mechanical manoeuvres needed to produce rigidity, when starting from a completely flaccid penis. the preliminary insertion of alprostadil cream in the urethra prepares the penis, to fit, quickly and safely, to the vacuum, thanks to adequate tumescence being produced. doi: 10.4081/aiua.2017.2.146 introduction severe erectile dysfunction (ed) is such a relentless health care problem that often causes an agonising ordeal to the patient and constitutes a challenge for the dedicated specialist who has to deal with it in daily practice. it is well-known that this condition is anything but rare, as is documented in the epidemiological literature, and that there are several causes, although not always well known or even clarifiable (1). in addition to adverse outcomes of radical pelvic surgery, these include excessive smoking, vasculopathies due to uncompensated diabetes, and even undiagnosed psychoses. having ascertained the ineffectiveness, intolerance or rejection of pharmacological treatments, prosthetic surgery remains an option, but it may be wise and certainly feasible, to try the use of alprostadil cream in association with vacuum device (vitarum) first. mantovani1_stesura seveso 20/06/17 09:58 pagina 146 147archivio italiano di urologia e andrologia 2017; 89, 2 alprostadil and vacuum conclusions when left to choose between the possible inadequacy of pharmacologic treatment and the prospect of a surgical prosthesis, treatment with alprostadil cream in association with vacuum (vitarum) may constitute an acceptable bridging treatment, which is feasible with a favourable cost/benefit ratio, on the arduous pathway of treating severe erectile dysfunction, where palpable cavernous fibrosis is absent. references 1. serefoglu ec, saitz tr, douglas lm, et al. the incidence and types of sexual dysfunction among prostate cancer patients. j sex med. 2012; 9(suppl 5):303-335. 2. osorio cabello l, martinez salamanca fi, egui rojo a, et al. penile morphometric changes after radical prostatectomy: impact of a rehabilitation program. j sex med. 2012; 9(suppl 5):320. 3. ljunggren c, stroberg p. a clinical sexologist appears to play an important role in a penile and sexual rehabilitation program may improve the outcome of sexual function one year after prostate cancer surgery. a prospective interventional study. j sex med. 2012; 9(suppl 5):319-320. correspondence franco mantovani, md mantovanifranco@yahoo.it clinica san giovanni via civitali 71, milano, italy mantovani1_stesura seveso 20/06/17 09:58 pagina 147 stesura seveso archivio italiano di urologia e andrologia 2014; 86, 2118 original paper low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center roberto giulianelli, barbara cristina gentile, giorgio vincenti, luca mavilla, luca albanesi, francesco attisani, gabriella mirabile, francesco pisanti, manlio schettini division of urology, nuova villa claudia, rome, italy. aim of the study: to demonstrate how, in a center with a large number of patients, as our center is, it is possible to perform ureterolithotripsy using a limited set of instruments. methods: we evaluated medical charts of our center related to semirigid ureteral ureteroscopy (urs) with ureterolithotripsy using holmium laser performed from july 2004 to july 2011. overall, 658 urs for ureteral stones were performed in 601 patients, of which 204 in proximal ureter (31%), 86 in the mid (13.06%) and 368 (57.76%) in the distal ureter. in 504 patients (76.5%) ureterohydronephrosis (grade ii-iii) was observed. in 57 patients (8.6%), we performed a bilateral approach at the same time, but most patients had a solitary distal ureteral stone. 106 patients (16.1%) had more than one stone in their distal ureter and 96 (14.8%) had a proximal ureteral stone treated in the same surgery as well. results: the overall stone-free rate for ureteral stones was 86.1% (567/658). success rates for proximal, medial and distal ureteral stones were 68.13% (139/204 patients), 84.8% (73/86 patients) and 96.4% (355/368 patients), respectively. one hundred and twenty patients (18.3%) required additional surgical treatment for their stones beyond the initial urs, including a second urs in 97 patients (14.74%) and urs plus retrograde intra-renal surgery (rirs) in 23 patients (3.54%). the overall stonefree rate after the second treatment was 99.3%. intra-operative complications accounted for 5.92% and consisted of ureteral perforations in 16 pts (2.4%), erosions of urothelium leading to significant bleeding in 15 pts (2.27%), severe pain in 4 pts (0.6%), fever in 3 pts (0.45%) and one case of ureteral avulsion (0.15%). conclusions: this study demonstrates that the use of holmium laser lithotripsy is a safe and effective means of treating ureteral stones regardless of sex, age, stone location, or stone size. the instrumentation we used was extremely limited, in order to reduce costs related to the procedure to an absolute minimum whilst maintaining the two quality indicators for the procedure, namely successrate and length of hospitalisation (86.1% and 34 hours). key words: ureteral calculi; ureteroscopy; holmium laser; lithotripsy. submitted 25 february 2014; accepted 19 may 2014 summary no conflict of interest declared. doi: 10.4081/aiua.2014.2.118 introduction urolithiasis is a common and costly disease displaying increasing worldwide prevalence and incidence rates (1). the lifetime risk of urolithiasis is estimat-ed to be between 5% and 12% in europe and usa, afflicting 13% of men and 7% of woman (2). extracorporeal shock wave lithotripsy (eswl) remains the recommended first-line treatment for most stones (3) but for those stones lodged in the ureter, ureteroscopy (urs) has become the most common treatment method (4). urs is the most commonly advocated treatment for patients with ureteral calculi with a stone-free rate higher than 90% after a single treatment. open ureterolithotomy is no longer considered as a valid op-tion in a well equipped endourological center. with the introduction of in situ extracorporeal shock wave lithotripsy and different intracorporeal techniques in urology practice, up to 95% of ureteral stones can be successfully treated with a minimally invasive method (5-10). in 2007 the eau guideline recom-mended that for ureteral stones requiring removal, because up to 98% of ure-teral calculi < 5 mm in diameter are likely to pass spontaneously, both swl and urs are acceptable first-line treatments in healthy non-pregnant adults who have unilateral calculi (2). in this meta-analysis, overall stone-free rates for swl and urs differed, depending on stone size, location, and treatment method. technological progress in the field of semirigid ureteroscope tech-nology, chiefly involving the miniaturization of the scopes and improved durability, and the introduction of the holmium:yag laser, with its precise and powerful thermal decomposition mechanism, its excellent safety profile and the ability of laser energy to be delivered through small flexible fibers, have opened up the path for fragmentation of stones of all composition types (5-10). use of this increasingly highperformance instrumentation (11), along with the use of dedicated devices which promote access to the ureter or prevent ret-ropulsion of the kidney stone (12), have considerably increased the costs of these procedures. the aim of this study was to demonstrate how, in an high volume center, such our center is,it is possible to perform a ureterolithotripsy for ureteral stones using a minimum set of instruments to complete the treat-ment. 119archivio italiano di urologia e andrologia 2014; 86, 2 low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center materials and methods we evaluated medical charts of our centre related to semirigid ureteral ureteroscopy (urs) with ureterolithotripsy using holmium laser performed, from july 2004 to july 2011, by four urologists. of these, two performed more than 200 upper tract endourological procedures, one almost 100, and one less than 50. in total they performed 658 urs in 601 patients, 457 males and 144 females, with an average age of 43.5 years (15-72 years). stones were in the proximal ureter in 204 patients (31%), in the mid ureter in 86 (13.06%) and in the distal ureter in 368 (57.76%). the average stone diameter was 9.1 mm (range 3-22). most patients had a solitary distal ureteral stone, but 106 (16.1%) had multiple stones in the distal ureter and 96 (14.8%) were treated also for proximal ureteral stones whilst undergoing the same surgery. in 57 patients (8.6%) urs was bilaterally performed and in 37 (5.6%) the procedures were performed under emergency conditions due to acute renal failure. urs was offered in cases where the stone failed a trial of passage for up to 10-12 days from the start of expulsive therapy. preoperative work-up consisted of renal ultrasound (rus) in 645 patients (98.02%), plain kidneyureter-bladder x-ray (kub) in 453 patients (68.8%) and computerized tomography (tc) in 67 patients (10.1%). in 504 patients (76.5%) a ureterohydronephrosis was observed (grade ii-iii), in 534 patients (81.5%) drugresistant pain, in 64 patients (9.7%) haematuria, and in 65 patients (9.87%) fever. all patients were hospitalised on the same day on which we carried out the endoscopic procedure, 602 of those (92.4%) were performed under general anaesthesia. only 56 patients (8.5%), due to severe chronic obstructive pulmonary disease (copd), were given an epidural anaesthesia. our technique involved use of a storz semirigid ureteroscope to make an initial inspection of the bladder to rule out the simultaneous presence of other diseases (e.g. malignancies, flat bladder lesions), and to identify the ureteral orifice to be approached. having assessed its characteristics, and in particular its shape, orifice was cannulated using a 4 f open-toe ureteral catheter advanced through the working channel of the ureteroscope up to about 3-4 cm from the orifice, acting as a “working wire”. at this point, using the pressure of the irrigation flow and relying on the catheter, the affected ureter was reached with an initial movement which involved a delicate lifting of the instrument with subsequent abduction. we proceeded with extreme caution along the ureter, minimizing the flow of water washing, to reduce the risk of pushing the stone upwards, thus reaching the stone and then proceeding with the ureterolithotripsy using the holmium laser with an 0.8 to 1j energy pulse and 8 to 10 hz frequency. the stone was then fragmented with the laser until all pieces were approximately 2 mm or smaller. stone fragments were not routinely extracted and the decision to place a ureteral stent upon completion of the procedure was based on preoperative grade of ureterohydronephrosis and intra-operative findings. we positioned a jj stent in all patients with severe ureterohydronephrosis or when other conditions rendered it necessary (i.e., ureteral wall injury, bleeding, severe inflammatory reaction against the ureteral wall). on the other hand, in 214 patients we left in place the ureteral catheter previously used as a guide, fixed by its distal end to a foley catheter, positioned at the end of the procedure for 24 hours. we did not use a basket to prevent the stone from being pushed upwards. fluoroscopy was not requested for treatment of distal ureteral stones, when calculi were positioned below the intersection with the iliac vessels, whatever their diameters. we used fluoroscopy in 18 patients (2.73%) including 14 with stones (2.12%) in the proximal ureter and 5 (0.75%) in the mid ureter. some patients had concomitant renal calculi that were deemed to be clinically insignificant (usually < 3 mm) and were not treated at the time of urs. patients were instructed to strain their urine postoperatively and to bring the retrieved fragments to their next outpatient appointment so they could be sent for analysis. the charts, including operative reports, were reviewed and data concerning patient and stone characteristics, duration of surgery, use of stents and use of secondary procedures were collected. we recorded data concerning body mass index (bmi) and gender. we also reviewed imaging studies of the patients at 30-day postoperative follow up to assess stone-free rates. computed tomography (ct), renal ultrasound (us) and plain abdominal radiography (kub) were used for imaging. we compared preand postoperative imaging to determine whether renal stones seen on postoperative films were consistent with pre-existing, untreated renal stones or with new, proximally migrated fragments of a ureteral stone. data concerning complications was also recorded. statistical analyses were performed using student t test and chisquare analysis. results overall, 658 urs for ureteral stones were performed in 601 patients, of which 204 in proximal ureter (31%), 86 in the mid (13.06%) and 368 (57.76%) in the distal ureter. in 504 patients (76.5%) ureterohydronephrosis (grade ii-iii) was observed. in 57 patients (8.6%), we performed a bilateral approach at the same time, but most patients had a solitary distal ureteral stone. 106 patients (16.1%) had more than one stone in their distal ureter and 96 (14.8%) had a proximal ureteral stone treated in the same surgery as well. the overall stone-free rate for ureteral stones was 86.1% (567/658). success rates for proximal, medial and distal ureteral stones were 68.13% (139/204 patients), 84.8% (73/86 patients) and 96.4% (355/368 patients), respectively. one hundred and twenty patients (18.3%) required additional surgical treatment for their stones beyond the initial urs, including a second urs in 97 patients (14.74%) and urs plus retrograde intra-renal surgery (rirs) in 23 patients (3.54%). the overall stonefree rate after the second treatment was 99.3%. four patients (0.6%) were judged to be failures (i.e. not stonefree) in that they had new renal stones postoperatively, consistent with proximal migration of ureteral stones after fragmentation that did not clear up. these fragments, however, were 2 mm in size in 75% of patients; in one patient, a 5 mm fragment was found in the ureter by postoperative imaging but the patient was subsequently lost archivio italiano di urologia e andrologia 2014; 86, 2 r. giulianelli, b.c. gentile, g. vincenti, l. mavilla, l. albanesi, f. attisani, g. mirabile, f. pisanti, m. schettini 120 in the follow-up, and was therefore classified as a failure. the overall stone-free rate for the treatment of ureteral stones was worse in the obese group than in the nonobese group, but not statistically significant (82% vs 76%, p = ns). the mean operating time was 32 minutes (1252 minutes, depending on stone burden and impaction) and mean hospital stay was 34 hours (26-42 h). two hundred and twelve patients (32.2%) had a ureteral stent placed before their urs. we performed a bilateral approach in 57 patients (8.6%), and of these the procedure was performed under emergency conditions of acute renal failure in 37 patients (5.6%). fifty-three patients (8.05%) had concomitant urinary tract infection, 69 (10.4%) had severe ureterohydronephrosis (iii grade), 11 (1.94%) ureteral wall injury, 9 (1.36%) bleeding and 13 (1.97%) a severe inflammatory response of the ureteral wall. in all other cases we left the 4 or 5 f ureteral catheter used during the procedure after completely removing all of the ureteral fragments over 3 mm, leaving it out of the external urethral meatus where it was attached to the foley catheter. complications were uncommon. intra-operative complications accounted for 5.92% and consisted of ureteral perforations in 16 pts (2.4%), erosions of urothelium leading to significant bleeding in 15 pts (2.27%), severe pain in 4 pts (0.6%), fever in 3 pts (0.45%) and one case of ureteral avulsion (0.15%). conversion to open surgery was carried out in one patient (0.15%) with a distal ureter stone associated with a neoplasm of the upper tract, where the endoscopic ureteral avulsion manoeuvre occurred accidentally. there was no immediate postoperative mortality. fifty-three patients (8.05%) presented a postoperative urinary tract infection, none of whom required hospitalisation. late complications were persistent haematuria in 66 patients (10.03%) and severe dysuria in 146 patients (25.2%). in 87 patients with dysuria (13.25%) long term use of nsaids was required. early stent removal (within 30 days from surgery) was necessary in 116 patients (17.6%) whereas 98 patients (14.8%) presented at the emergency department complaining of pain in the side of the procedure which was related to the stent, but did not require hospitalisation. discussion the management of ureteral stones has seen a change from open surgery to swl and to endoscopic and laparoscopic surgery. intracorporeal lithotripsy devices and urs have made treatment of ureteric stones much more convenient. rigid urs was first applied for the treatment of distal ureteral calculi in the 1980s. although large (> 10f) diameter ureteroscopes were used, success rates of > 90% were achieved (13). with the development of smaller caliber ureteroscopes and the introduction of improved instrumentation, including the holmium:yag laser, ureteroscopy has evolved into a safer and more effective method of treating ureteral stones. in our study, the overall stone-free rate of urs was comparable to other studies, with stone-free rates ranging from 75% to 93% (14). in fact we obtained an 86.1% overall stone-free rates after holmium laser uretero lithotripsy. leijte ja et al. (15) showed in 105 ureteroscopic holmium laser lithotripsies procedures a total success rate of 84.8% and ullah et al. in 88 ureteral stone cases treated with ureteroscopic holmium laser lithotripsy reported an overall success rate with satisfactory fragmentation in 85.15% (16). safwat et al. observed 239 patients (199 males and 40 females) with an average stone burden of 9.8 mm (range 4 to 20 mm) and reported a success rate of 96.3% after a single session which increased to 99% after 2 sessions (17). in our experience, we have obviously observed different results in terms of stone-free rates, according to the site in which the stone was located. in fact, success rates for proximal, mid and distal ureteral stones were 68.13%, 84.8% and 96.4%,respectively. similarly,in a total of 88 stones, 22 (25%) in the upper ureter, 24 (27.27%) in the middle ureter and 42 (47.72%) in the lower ureter, ullah et al. (17) showed success rates of 72.72%, 87.5% and 95.23%, respectively. similar results were also obtained by subhani et al. (18), who carried out ureteroscopic holmium laser lithotripsy in 209 patients with stones in the lower ureter, 266 in the middle ureter and 65 in the upper tract of the ureter, achieving success rates of 94.73%, 95.11% and 44.61%, respectively. use of flexible ureteroscopy for treating stones located in the proximal tract, would have propably improved our results in terms of stone-free rates in line with available data (68.13% vs 93.1%) (19). however, owing to the costs in-volved, use of this method in our center is exclusively limited to the treatment of complex calculi or for the treatment of intrarenal lithiasis > 2 cm. in our experience, one hundred and twenty patients (18.3%) required addi-tional surgical treatment for their stones beyond the initial urs to achieve an overall stonefree rate of 99.3%. these results, including a second urs in 97 pts (14.74%) and urs plus rirs in 23 pts (3.54%). the holmium laser pro-vides the gold standard for intracorporeal lithotripsy (20) and its use proved to be crucial in our experience. holmium laser can effectively fragment any stone regardless of composition or size and can reach the entire urinary tract since it can be deployed on rigid and flexible ureteroscopes. furthermore, compared to other intracorporeal lithotripsy, holmium laser yields the smallest fragment size, with many even smaller than 1 mm (20). according to international experiences, the use of the holmium laser, enabled us to attain complete pulverization of the stones at the end of our procedures (21, 22). this reduced risk of complications to a minimum (none steinstrasse) and reduced the risk of retropulsion of the stone to a minimum, whereas figures are undoubtedly higher when ballistic lithotripsy is used (23). bapat et al. compared the success rates of lithoclast and holmium laser-assisted ureterorenoscopy in 394 patients assessing at 2 weeks fragmentation into fine pieces of stones and their passage. this occurred in 166/193 (86.01%) patients in the lithoclast group and in 195/201 (97.01%) in the laser group (24). in general complications are uncommon. in bapat’s experience, the complications and the need for auxiliary procedures were significantly less for holmium laser-assisted 121archivio italiano di urologia e andrologia 2014; 86, 2 low-cost semirigid ureteroscopy is effective for ureteral stones: experience of a single high volume center ureteroscopy when compared with pneumatic lithotripsy (24). ullah et al. reported an overall complication rate of 17.04%; the main complications included ureteral perforation (n = 2), ureteral avulsion (n = 1), urosepsis (n = 2) and stone migration (n = 10) (17). subhani et al. described an overall complication rate of 11.83%. the main complications included mucosal lacerations (9.25%), perforation (2.40%), ureteric avulsion (0.18%) (18). in our experience, intra-operative complications accounted for 5.92% of our cases and consisted of ureteral perforations in 16 patients (2.4%) and erosions of urothelium leading to significant bleeding in 15 patients (2.27%). in one patient which presented with a distal ureter stone associated with a neoplasm of the upper tract, we had to convert the endoscopic procedure to open surgery (0.15%), because the endoscopic manoeuvre accidentally caused ureteral avulsion. late complications included persistent haematuria in 66 patients (10.03%) and severe dysuria in 146 (25.2%). out of them 87 patients required long term nsaids treatment (13.25%). costs conducting a stone-free holmium laser-assisted urete roscopy is less costly than a swl procedure (higher number of treatments required to obtain stone-free condition with swl, higher risk of steinstrasse after swl) (25). a study reported the cost of stone removal for both the upper and lower ureter using swl significantly higher compared to endoscopic procedures (ureteroscopy with semirigid ureteroscope and the use of pneumatic lithoclast, or ureteroscopy with flexible ureteroscope and the use of holmium yag laser). the median cost for the upper ureter was € 828 vs € 474.50 and € 396 respectively, and for the lower ureter, € 826 vs € 396 and € 271, p < 0.001 (26). esuvaranathan et al. observed, in a prospective consecutive series of 64 patients who underwent transurethral laser uretero lithotripsy using a 7.2 f semirigid ureteroscope, that the 3-year cost-benefit analysis revealed a smaller difference in cost than expected and the 5-year analysis was advantageous for laser lithotripsy because of its higher success rate (27). at present, costs constitute an increasingly important problem and, unfortunately, they have an increasing influence on the treatment choices in the clinical setting. all this has in fact prompted us to gradually reduce our instrumentation to a minimum and to choose the semirigid ureteroscope as a first choice instead of the flexible one. the latter is instead used only for treating complex ureteral calculi. we have gradually developed a technique for accessing the ureter which requires the use of a simple ureteral catheter, avoiding the use of additional guide wires or instruments to dilate the ureteral ostium. we rely on a simple manoeuvre exploiting the pressure of the washing fluid and the presence of the catheter. the affected ureter is reached with an initial movement which involves a delicate lifting of the instrument and its subsequent abduction. the extreme attention and care with which the movement is carried out reduces the risk of lesions to the ureter and/or its intussusception to a minimum. in our experience, intra-operative complications accounted for 5.92% and we performed conversion to open surgery in only one patient (0.15%). needless to say, we are in complete agreement with all those that sustain that the experience of the surgeon is of the utmost importanc (15) and plays a crucial role in determining a reduced rate of method-related complications. we also feel it is important to have procedure-dedicated surgeons who exclusively carry out all these procedures. in our experience, the mean hospital stay was 34 hours (26-42 h), whilst rombi et al. observed a hospital stay for upper ureter cases of 2.48 days, and 2.43 days for lower ureter, respectively (26). conclusions this study demonstrates that the use of holmium laser lithotripsy is a safe and effective means of treating ureteral stones regardless of sex, age, stone location, or stone size. we found that the overall stone-free rates before holmium laser ureterolithotripsy were 86.1% and 99.3% after the first and second treatment, respectively. complications were uncommon. the instrumentation we used was extremely limited, in order to reduce costs related to the procedure to an absolute minimum whilst maintaining the two quality indicators for the procedure, namely success-rate and length of hospitalisation (86.1% and 34 hours), which reflect those obtained with other experiences. references 1. hesse a, brandle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs 2000. eur urol. 2003; 44:709-13. 2. preminger gm, tiselius hg, assimos dg, et al.: guideline for the management of ureteral calculi. j.urol 2007; 178:2418-34. 3. osman mm, alfano y, kamp s, et al. 5-years follow up od patients with clinically insignificant residual fragmenta and after extracorporeal shock wave lithotripsy. eur urol. 2005; 47:860-4. 4. bader mj, eisner b, porpiglia f, et al. contemporary management of ureteral stones. eur urol. 2012; 61:764-771. 5. yinghao s, linhui w, songxi q, et al. swiss lithoclast pneumatic lithotripter: report of 150 cases. j endourol. 2000; 14:281-3. 6. ather mh, paryani j, memon a, sulaiman mn. a 10-year experience of managing ureteric calculi: changing trends towards endourological interven-tion-is there a role of open surgery? bju int. 2001; 88:173-177. 7. dirim a, tekin mi, aytekin c, et al. ureteroscopic treatment of proximal ureter stones with aid of an antegrade occlusion balloon catheter. acta radiol. 2006; 47:103-6. 8. kupeli b, biri h, isen k, et al. treatment of ureteral stones: comparison of extracorporeal shock wave litho-tripsy and endourologic alternatives. eur urol. 1998; 34:474-479. 9. naqui sa, khalogi m, zafar mn, rizwi sa. treatment of ureteric stones. comparison of laser and pneumatic lithotripsy. br j urol. 1994; 74:694-698. 10. maislos sd, volpe m, albert ps, raboy a. efficacy of the stone cone for treatment of proximal ureteral stones. j endourol. 2004; 18:862-4. 11. sofer m, watterson jd, wollin ta, nott et al.: holmium:yag archivio italiano di urologia e andrologia 2014; 86, 2 r. giulianelli, b.c. gentile, g. vincenti, l. mavilla, l. albanesi, f. attisani, g. mirabile, f. pisanti, m. schettini 122 laser lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2003; 44:482-6. 12. kijvikai k, haleblian ge, preminger gm, de la rosette j. shock wave lithotripsy or ureteroscopy for the management of proximal ureteral calculi: an olddiscussion revisite. j urol. 2007; 178:1157-63. 13. tawfiek er, bagley dh.: management of upper urinary tract calculi with ureteroscopic techniques. urology. 1999; 53:25-31. 14. park h, park m, park t. two-year experience with ureteral stones: extracorporeal shockwave lithotripsy v ureteroscopic manipulation. j endourol. 1998; 12:501-504. 15. leijte ja, oddens jr, lock tm. holmium laser lithotripsy for ureteral calculi: predictive factors for complications and success. j endourol. 2008; 22:257-60. 16. ullah i, wazir bg, alam k, et al. evaluation of safe-ty and efficacy of ureteroscopic lithotripsy in managing ureteral calculi. ann pak inst med sci. 2011; 7:119-112. 17. safwat as, bissada nk, kumar u, et al. a multi-institutional study demonstrating the safety and effica-cy of holmium laser ureterolithotripsy. urotoday int j. 2012; 5:349. 18. subhani gm, javed sa, iqbal z, et al. outcome of retrograde ureteroscopy for the management of ureteric calculi: four years experience. a.p.m.c. 2009; 3;8-12. 19. cocuzza m, colombo jrjr, cocuzza al, et al. outcomes of flexible ureteroscopic lithotripsy with holmium laser for upper urinary tract calculi. int braz j urol. 2008; 34:143-9. 20. preminger gm, tiselius hg, assimos dg, et al. guideline for the management of ureteral calculi. j urol 2007; 178:2418-34. 21. jong-hyun lee, seung hyo woo, eun tak kim, dae kyung kim, jinsung park comparison of patient satisfaction with treatment outcomes between ureteroscopy and shock wave lithotripsy for proximal ureteral stones korean j urol. 2010; 51:788-793. 22. wu cf, shee jj, lin wy, et al. comparison between extracorporeal shock wave lithotripsy and semirigid ureterorenoscope with holmium:yag laser lithotripsy for treating large proximal ureteral stones. j urol. 2004; 172:1899. 23. teichman jm1, vassar gj, bishoff jt, bellman gc holmium:yag lithotripsy yields smaller fragments than lithoclast, pulsed dye laser or electrohydraulic lithotripsy. j urol. 1998; 159:17-23. 24. bapat ss, pai kv, purnapatre ss, et al. comparison of holmium laser and pneumatic lithotripsy in managing upper-ureteral stones. j endourol. 2007; 21:1425-7. 25. nabi g, downey p, keeley f, et al. extracorporeal shock wave lithotripsy (eswl) versus ureteroscopic management of ureteric calculi. cochrane database syst rev. 2007; cd006029. 26. rombi t, triantafyllidis a, fotas a, et al. socioeconomic evaluation of the treatment of ureteral lithiasis. hippokratia. 2011; 15:252-7. 27. esuvaranathan k, tan ec, tan pk, tung kh. does transurethral laser ureterolithotripsy justify its cost? j urol. 1992; 148:1091-4. correspondence roberto giulianelli, md (corresponding author) roberto.giulianelli@virgilio.it barbara cristina gentile, md giorgio vincenti, md luca mavilla, md luca albanesi, md francesco attisani, md gabriella mirabile, md francesco pisanti, md manlio schettini, md division of urology, nuova villa claudia via flaminia nuova, 280 rome, italy stesura seveso archivio italiano di urologia e andrologia 2019; 91, 284 original paper could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? a case-series analysis michele zazzara 1, arjan nazaraj 1, ottavio colamonico 1, marcella mastromauro 2, giuseppe cardo 1, giuseppe mario ludovico 1 1 urology department, ospedale generale regionale “f. miulli", acquaviva delle fonti (ba), italy; 2 pathological anatomy department, ospedale generale regionale “f. miulli", acquaviva delle fonti (ba), italy. the aim of the present case-series analysis was to assess the safety and efficacy of pollen extract in association with vitamins in order to reduce the chronic prostatic inflammation in patients with class iv chronic prostatitis (cp). nineteen non-consecutive patients performed a prostate biopsy for a suspect of prostate cancer. the biopsy histopathological examination showed a class iv cp, in presence of mild/moderate/high degree of inflammation, in association with an extensive (multiple biopsy sites, i.e., ≥ 3) high-grade prostatic intraepithelial neoplasia pin (hgpin) and/or atypical small acinar proliferation (asap). according to eau prostate cancer guidelines prostate biopsy was repeated after 6 months, because of the presence of extensive hgpin or asap. oral administration of pollen extract in association with vitamins (two capsules every 24 h) was prescribed until the repeat biopsy. repeat biopsy histopathological examination showed, in 13 patients (68.4%), a lower degree of inflammation (absent/mild/moderate). key words: prostate; phytotherapeutics; benign prostatic hyperplasia. submitted 2 january 2019; accepted 8 february 2019 summary no conflict of interest declared. histopathological examination showed a class iv cp, in presence of mild/moderate/high degree of inflammation (figure 1), in association with an extensive (multiple biopsy sites, i.e., ≥ 3) high-grade prostatic intraepithelial neoplasia pin (hgpin) and/or atypical small acinar proliferation (asap). about degree of inflammation, the biopsy histopathological examination showed in 6 patients (31.6%) a mild degree of inflammation, in 9 patients (47.3%) a moderate degree of inflammation and in 4 patients (21.1%) an high degree of inflammation. according to the classification of the national institutes of health (nih), class iv chronic prostatitis (cp) are the asymptomatic inflammatory prostatitis (histological prostatitis) with no chronic pelvic pain syndrome (cpps) (3). the mean patient age was 61.1 ± 7.33 years and the median ipss score was 8 (6.5-13.5). the median prostate-specific antigen value, at biopsy, was 5.7 ng/ml (4.9-6.8 ng/ml). according to eau prostate cancer guidelines (4), a prostate biopsy was repeated, after 6 months, because of the presence of extensive hgpin or asap. doi: 10.4081/aiua.2019.2.84 introduction chronic prostatic inflammation (cpi) leads to symptomatic or asymptomatic benign prostatic hyperplasia (bph) (1, 2). under the circumstances that cpi leads to bph and, therefore, to lower urinary tract symptoms (luts) due to bph, cpi could be a target for medical treatment, in patients with asymptomatic or symptomatic bph, acting on prostatic enlargement and luts. phytotherapeutics are a value options due to their generally minimal side-effects. the aim of the present caseseries analysis was to assess the safety and efficacy of pollen extract in association with vitamins (deprox 500®) in order to reduce the chronic prostatic inflammation in patients with class iv chronic prostatitis (cp). case presentation nineteen non-consecutive patients performed a prostate biopsy for a suspect of prostate cancer (pca). the biopsy figure 1. microscopic pathological features in hematoxylin and eosin stain: absent (a), mild (b), moderate (c), high (d) degree of inflammation. 85archivio italiano di urologia e andrologia 2019; 91, 2 could pollen extract in association with vitamins be favorable in the reduction of chronic prostatic inflammation? a case-series analysis under the circumstances of the histological prostatitis diagnosed, a medical oral administration of deprox 500® (two capsules every 24 h) was prescripted until the repeat biopsy. the repeat biopsy histopathological examination showed in 6 patients (31.6%) prostate cancer, in 3 patients (15.8%) extensive hgpin or asap and in 10 patients (52.6%) benign prostatic hyperplasia (bph). moreover, the repeat biopsy histopathological examination showed, in 13 patients (68.4%), a lower degree of inflammation (absent/mild/moderate). specifically, 4 patients (30.8%) showed absent instead of mild degree of inflammation, 7 patients (53.8%) showed mild instead of moderate degree of inflammation (figure 2) and 2 patients (15.4%) showed moderate instead of high degree of inflammation (table 1). the median prostate-specific antigen value, at repeat biopsy, was 5.2 ng/ml (4.3-5.8 ng/ml). deprox 500® was generally well tolerated over the full period. discussion chronic prostatic inflammation (cpi) leads to symptomatic or asymptomatic bph (1, 2). cpi has been observed in a large proportion of patients treated surgically for lower urinary tract symptoms (luts) due to bph and in the histological examination of prostatic biopsies performed for suspect of pca (5). moreover, cpi has been associated with higher prostate volume and a more severe international prostate symptom score (ipss) (5, 6). histologically, cpi is characterized by the presence of large confluent inflammatory nodules in prostatic tissue (5, 6). these nodules release multiple inflammatory mediators that have been shown to stimulate prostatic cell growth. nodules also damage the architecture of the gland, resulting in a chain reaction that further sustains the inflammatory response and promotes prostatic cell growth, prostatic enlargement, and bladder outlet obstruction (7). a prostatic inflammation classification, based on a histologic grading related to the extension of inflammatory cells, has been described (8). specifically, histologic grading can be classified as: grade 0 absent, no inflammation; grade 1 mild, scattered inflammatory cell infiltrate without nodules; grade 2 moderate, no confluent lymphoid nodules; and grade 3 high, large inflammatory areas with confluence. under the circumstances that cpi leads to bph and, therefore, to luts due to bph, cpi could be a target for medical treatment, in patients with asymptomatic or symptomatic bph, acting on prostatic enlargement and luts. in fact, it is described the favorable effects of nonsteroidal anti-inflammatory drugs (nsaids) (9), but their side effects related with long-term use mostly limit their prescription in patients with bph-related luts. phytotherapeutics are a value options due to their generally minimal side-effects. in the present case-series analysis was observed that the use of pollen extract in association with vitamins (deprox 500®) is safe and aids to reduce the severity of chronic prostatic inflammation in patients with class iv chronic prostatitis (cp). this effect is possibly due to the association between the pollen extract and vitamins b6 and b12 that improve the antioxidant activity and anti-inflammatory effect of pollen extract. the present case-series analysis had few limitations that should be taken into account: the small number of enrolled patients, a short follow-up period, a selected patient population, the lack of control group and that this was not a blinded study. conclusions the pollen extract in association with vitamins, such as deprox 500®, could have a favorable effect in the reduction of chronic prostatic inflammation. we expect further studies to evaluate its effect in chronic prostatic inflammation in the near future; in fact, more clinical data are needed to support the use of pollen extract in association with vitamins in a context of an evidence-based medicine. currently, the use of this drug should be considered empirical. references 1. ficarra v, rossanese m, zazzara m, et al. the role of inflammation in lower urinary tract symptoms (luts) due to benign prostatic hyperplasia (bph) and its potential impact on medical therapy. curr urol rep. 2014; 15:463. 2. gandaglia g, briganti a, gontero p, et al. the role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (bph). bju int. 2013; 112:432-41. 3. workshop committee of the national institute of diabetes and digestive and kidney disease (niddk). chronic prostatitis workshop, bethesda, md, 7-8 december, 1995. 4. eau-estro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent. table 1. degree of inflammation. degree of inflammation degree of inflammation (before deprox 500®) pts (after deprox 500®) pts mild 6 pts mild 4 pts moderate 9 pts moderate 7 pts high 4 pts high 2 pts figure 2. a) moderate degree of inflammation before the treatment; (b) mild degree of inflammation after the treatment. archivio italiano di urologia e andrologia 2019; 91, 2 m. zazzara, a. nazaraj, o. colamonico, m. mastromauro, g. cardo, g.m. ludovico 86 mottet n, bellmunt j, bolla m, briers e, cumberbatch mg, de santis m, fossati n, gross t, henry am, joniau s, lam tb, mason md, matveev vb, moldovan pc, van den bergh rcn, van den broeck t, van der poel hg, van der kwast th, rouvière o, schoots ig, wiegel t, cornford p. eur urol. 2017; 71:618-629. 5. robert g, descazeaud a, nicolaïew n, et al. inflammation in benign prostatic hyperplasia: a 282 patients’ immunohistochemical analysis. prostate. 2009; 69:1774-80. 6. nickel jc, roehrborn cg, o'leary mp, et al. the relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the reduce trial. eur urol. 2008; 54:1379-84. 7. kramer g, mitteregger d, marberger m. is benign prostatic hyperplasia (bph) an immune inflammatory disease? eur urol. 2007; 51:1202-16. 8. irani j, levillain p, goujon jm, et al. inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. j urol. 1997; 157:1301-3. 9. kahokehr a, vather r, nixon a, hill ag. non-steroidal antiinflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. bju int. 2013; 111:304-11. correspondence michele zazzara, md michele.zazzara@gmail.com arjan nazaraj, md ari.nazaraj@hotmail.it ottavio colamonico, md ottaviocolamonico@gmail.com giuseppe cardo, md giuseppecardo@hotmail.com giuseppe mario ludovico, md giuseppeludovico@hotmail.com urology department, ospedale generale regionale “f. miulli" strada prov. 127 acquaviva santeramo km. 4.100, 70021 acquaviva delle fonti (ba) (italy) marcella mastromauro, md marcella.mastromauro@libero.it pathological anatomy department, ospedale generale regionale “f. miulli" acquaviva delle fonti (ba), italy 21archivio italiano di urologia e andrologia 2020; 92, 1 original paper time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients simone brardi 1, gabriele cevenini 2 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of medical biotechnologies, university of siena, italy. background: the aim of this longitudinal prospective study was to search if even in the absence of total or partial nephrectomy the kidney size can increase as the kidney function improves. methods: we randomly enrolled 80 adult patients with various degrees of chronic renal failure but non-dialysis dependent neither totally or partially nephrectomized nor affected by any of the pathological conditions that can increase kidney size. the patients underwent a first examination comprehensive of a blood sample and renal ultrasonography and then were submitted to a therapeutic intervention aimed at removing all nephrotoxic agents to finally be subjected to a last similar medical examination. results: the statistical analysis displayed a strong positive correlation between the percentage variation of the renal diameters’ average and the time changes of the gfr (r 0.731; p < 0.01) as well as the percentage variation of the gfr and the time changes variations of the right (r 0.487; p < 0.01) and left cortical kidney thickness (r 0.519; p < 0.01) and finally a strong negative correlation between the removal of nephrotoxic agents and the percentage variation of the renal diameters’ average (r 0.293; p < 0.01) and the time changes of the gfr (r 0.429; p < 0.01). conclusions: in patients with chronic kidney disease, even in the absence of total or partial nephrectomy, under the stimulus of the removal of any nephrotoxic agents, there may be a limited increase in renal size according to a model that sees them vary according to the changes in gfr. key words: longitudinal prospective study; renal length variations; gfr time changes; renal ultrasound; ckd patients. submitted 4 october 2019; accepted 13 november 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.21 introduction the best measure of renal size is the volume which correlates well with the glomerular filtration rate (1). however, calculation of volume is prone to significant error because three independent measurements are used (2). therefore, measurement of maximum renal length has become the clinical standard because it is simple, mode accurate and correlates well with renal volume (3, 2). renal length averages about 11 cm in adults (3) so that 10-12 cm is a useful range for normal renal length, the discrepancy in size between the two kidneys is not abnormal provided that the smaller kidney is not less than 37% of the total renal volume. all measured kidney dimensions of patients with chronic kidney disease (ckd) correlate significantly with kidney function while the correlation with anthropometric parameters which is otherwise present in healthy subjects is lost in patients with ckd (4, 5). more in detail the renal length, as renal failure progresses, significantly decreases (6). therefore, the sonographic appearance of chronic renal failure consists of a decrease in renal size, thinning of the parenchyma (particularly the cortex) and increased echogenicity of the cortex. when cortical thickness cannot be determined because the medullary pyramids are not visible thinning of the cortex can still be appreciated as thinning of the entire parenchyma defined by a cutoff of 12 mm (3). the decrease of renal size and cortical thinning are often most noticeable in renovascular disease and hypertensive nephrosclerosis whereas in glomerular disorders particularly diabetic nephropathy the cortical thickness is often preserved even late in the disease (7). instead, a physiological enlargement is known to occur only in solitary kidneys and during pregnancy while compensatory hypertrophy is seen in adults after nephrectomy (7). nowadays therefore it is well known that average value of kidney’s volume shows a linear decrease with the progression of chronic kidney disease (8) and that kidney volume and its surrogate parameter that is the renal length correlate with gfr (4, 5) but we don’t know if this process, in the absence of total or partial nephrectomy, may be reversible, because until now it was never evaluated if the kidney length correlated also with the time changes of gfr, as can be recorded in a longitudinal type study. so, in order to investigate a similar renal regrowth in the absence of total or partial nephrectomy, we conducted this longitudinal prospective study. materials and methods this study was undertaken between june 2015 to september 2019 in the outpatient nephrology clinic of san donato hospital in arezzo. the study population was randomly selected among adult patients with various degrees of chronic renal failure but non-dialysis dependent and affected or not by hypertension but not by diabetes mellitus neither totally or partially nephrectomized and with the exclusion of those with obstructive uropathy, ischemia, pregnancy, polycystic kidney disease, and malignant diseases. after obtaining the respective informed consent from all participating subjects, we enrolled 80 patients (35 females and 45 males, with an average age, at the time of enrollment, of 71.5 ± 11.7 years) almost all hypertensive (except only four). the average glomerular filtration rate (gfr) (calculated by the ckd epi equation) (9) at the time of enrollment, was brardi_stesura seveso 01/04/20 18:54 pagina 21 archivio italiano di urologia e andrologia 2020; 92, 1 s. brardi, g. cevenini 22 49.4 ± 16.8 ml/min/1.73 m2. after the evaluation of medical history including the complete list of medications and every dietetic therapy, we submitted the enrolled patients to an accurate physical examination, comprehensive of the recording of anthropometric parameters (weight and height) and of a measurement of blood pressure that was taken with a mercury sphygmomanometer applied around each patient’s non-dominant arm after the patient had rested for 15 minutes in a sitting position and with his/her arm placed at the level of the heart. two consecutive blood pressure recordings, taken at a 5-minute interval, were averaged to provide clinic systolic and diastolic blood pressure values. blood samples were taken for serum creatinine and sodium and, where possible, 24-hour urine collection for albuminuria was executed. finally, a b-mode and doppler renal ultrasound was performed. all renal ultrasound examinations were carried out by the same nephrologist experienced in ultrasound examination using the same ultrasound device that was a logiq s7 (ge medical systems italy s.p.a. milan, italy) sonographic system equipped with 3 to 5 mhz transducers. any dimensional parameter of each kidney (i.e. length or else diameter in the longitudinal axis and parenchymal thickness) was registered as the average of two single measurements. the diameter in the longitudinal axis was assessed in a section visually estimated to represent the largest diameter. the cortical thickness was registered in the portion closer to the upper pole and the lower pole of the same kidney (4). doppler signals were obtained from the interlobar arteries from the upper, middle and lower third of both kidneys and resistive index was calculated as the average of 6 measurements (3 from each of the 2 kidneys) taken for each patient. the doppler angle was chosen as close to 0° as possible and special care was taken not to compress the kidney and not to have the patient performing valsalva maneuver because both of them can increase the renal resistive index value. then the patients were submitted to a full therapeutic and dietetic intervention to ameliorate the renal impairment by a wide range of actions such as removal of nephrotoxic drugs (i.e. the hydrochlorothiazide diuretics, non-steroidal anti-inflammatory drugs, etc.) as well as any variation of drug therapy in order to reduce proteinuria and improve blood pressure control avoiding both too low blood pressure values and those that are too high (10). eventually, when it was indicated, it was introduced an hypoproteic, hyposodic as well as hypocaloric diet (11). after on average of 2.5 (± 2.2) year interval the same patients were submitted to a second and last medical examination (to evaluate the outcome of the therapeutic and/or dietetic actions undertaken) which was conducted in the same way as the first one. sample descriptive statistics were calculated, including mean and standard deviation for quantitative variables, and frequency counts and percentages for qualitative variables (tables 1-3). a pearson correlation analysis was performed between quantitative variables, particularly between the time changes of gfr and the average of left/right renal diameters. the linear correlation coefficient, r, was computed and its statistical significance was evaluated at a minimum level of 95% (p < 0.05). all the statistical computations were executed using the spss package, version 10. results in order to investigate if the dimensional parameters of the kidney correlate or not with the variations of the gfr, we compared the percentage variation between basal and final examination (table 4), or delta, of each variable with the percentage variation of the renal diameters’ average in the longitudinal axis and the time changes of gfr (figure 1). the statistical analysis so displayed first a strong positive correlation between the delta of the average renal diameter in the longitudinal axis and time changes of gfr (r 0.731; p < 0.01) and then an equally strong positive correlation between the same delta of gfr and table 1. basic and final characteristics of the enrolled population and percentage changes (mean ± standard deviation). parameters basal values follow-up values delta age (years) 71.5 ± 11.7 73.99 ± 11.39 3.72 ± 3.47 weight (kg) 74.3 ± 11.7 72.4 ± 13 -2.37 ± 7.37 body mass index (bmi) (kg/m^2) 28.3 ± 4.7 27.6 ± 4.9 -2.36 ± 7.4 glomerular filtration rate (gfr) (ml/min/1.73 m^2) 49.4 ± 17 50.6 ± 15.2 6.93 ± 32.4 24-hour urinary albumin excretion (gr/24h) 0.2 ± 0.75 0.13 ± 0.6 -7.31 ± 98.5 right kidney diameter in the longitudinal axis (mm) 101.7 ± 9.7 101.91 ± 8.37 0.70 ± 8.5 left kidney diameter in the longitudinal axis (mm) 103.4 ± 10.4 103.43 ± 9.23 0.33 ± 7 renal diameters’ average in the longitudinal axis (mm) 102.6 ± 9.4 102.67 ± 7.84 0.47 ± 6.9 right kidney renal resistive index 0.73 ± 0.1 0.72 ± 0.07 -0.54 ± 10 left kidney renal resistive index 0.73 ± 0.1 0.72 ± 0.08 -0.68 ± 9.7 blood serum natrium (mmol/l) 142 ± 2.2 141.82 ± 2.30 -0.16 ± 2.2 systolic blood pressure (mmhg) 122.6 ± 17.3 117.79 ± 16.9 -2.6 ± 16.7 diastolic blood pressure (mmhg) 75.9 ± 11.7 72.38 ± 12.68 -3.4 ± 19.3 mean arterial pressure (mmhg) 91.4 ± 11 87.51 ± 11.81 -3.3 ± 16.4 table 2. rates of patients having a preserved kidney cortical thickness (≥ 1.2 cm) or a slightly reduced kidney cortical thickness (> 1 <1.2 cm) or a reduced kidney cortical thickness (< 1 cm). number of patients basal values follow-up values delta number of patients having a preserved right kidney cortical thickness 28 (35%) 30 (37.5%) 7.14 number of patients having a preserved left kidney cortical thickness 25 (31.25%) 28 (35%) 12.00 number of patients having a slightly reduced right kidney cortical thickness 19 (23.75%) 22 (27.5%) 15.79 number of patients having a slightly reduced left kidney cortical thickness 23 (28.75%) 24 (30%) 4.35 number of patients having a reduced right kidney cortical thickness 33 (41.25%) 28 (35%) -15.15 number of patients having a reduced left kidney cortical thickness 32 (40%) 28 (35%) -12.50 table 3. rates of patients taking different drugs or being on a specific diet. number of patients (percentage of the total) basal values follow-up values delta number of patients having hypo protein diet 24 (30%) 57 (71.25%) 137.5 number of patients having hyposodic diet 24 (30%) 62 (77.5%) 158.33 number of patients taking ace inhibitors or angiotensin receptor blockers 58 (72.5%) 52 (65%) -10.34 number of patients taking diuretics 36 (45%) 22 (27.5%) -38.89 number of patients taking nephrotoxic drugs 26 (32.5%) 1 (1.25%) -96.15 brardi_stesura seveso 01/04/20 18:54 pagina 22 the percentage variations of the right (r 0.487; p < 0.01) and left (r 0.519; p < 0.01) kidney cortical thickness. as obvious a similarly strong correlation was found between time changes of right (r 0.661; p < 0.01) and left (r 0.637; p < 0.01) kidney diameters in the longitudinal axis and the time changes of the gfr. instead, no statistical correlation was found between time changes of gfr and percentage variations of right or left renal resistive indices as well as body mass index and proteinuria. about the percentage variations of the blood pressure parameters we found a strong positive correlation only between the time changes of systolic blood pressure and the percentage variation of gfr (r 0.370; p < 0.01) and a weaker positive correlation between the same delta of systolic blood pressure and the time changes of renal diameters’ average in the longitudinal axis (r 0.238; p < 0.05), moreover a strong positive correlation was found between the delta of the mean arterial pressure and the delta of gfr (r 0.289; p < 0.01). a weak negative correlation was found between the strong reduction of the diuretics usage and the delta of the renal diameters’ average in the longitudinal axis (r -0.262; p < 0.05) or the delta of gfr (r -0.226; p < 0.05) while a stronger negative correlation was found between the almost complete removal of any nephrotoxic drugs and the delta of the renal diameters’ average in the longitudinal axis (r -0.293; p < 0.01) or the delta of gfr (r -0.429; p < 0.01). a weak positive correlation was found between the introduction of a low-salt diet and the time changes of gfr (r 0.250; p < 0.05) but no statistical correlation was found between the delta of the renal diameters’ average in the longitudinal axis or the delta of gfr and the variations of serum sodium, the introduction of an low protein diet or the usage of ace inhibitors or angiotensin receptor blockers. finally a strong negative correlation was found between the time changes of the age at the moment of the examination and the delta of the renal diameters’ average in the longitudinal axis (r -0.360; p < 0.01) and the time changes of gfr (r0.304; p < 0.01). discussion in this longitudinal prospective observational type study comparing the average of left and right renal diameters and the time changes of gfr we found a strong positive correlation between the two ones as well as a similar strong positive correlation between the time changes of the gfr and percentage variations of the right and left kidney cortical thickness. all the above means that the renal sizes may increase or decrease synchronously with the time changes of gfr even in absence of the classic conditions that promote the compensatory renal hypertrophy (i.e. mainly radical or partial nephrectomy) as well as of any other condition that may increase the renal dimensions such as mainly the diabetes mellitus. now it is well known that after unilateral radical or partial nephrectomy a compensatory renal growth, promoting significant restoration of lost renal function, is observed in the remnant kidney. this compensatory renal growth following nephrectomy is predominantly due to a renal hypertrophy (i.e. an increase in cell size) dominated by tubular cells (since mainly proximal tubules show increase of length, diameter and volume) and produces a gfr increase so can be termed physiologic compensatory renal hypertrophy in contrast to the so-called pathologic renal hypertrophy that, typical of diabetic nephropathy, it is dominated by a glomerular and podocyte hypertrophy and can lead to further nephron damage, interstitial fibrosis and ultimately end-stage kidney disease (12). lastly, it is known that compensatory kidney growth was not only found to occur 23archivio italiano di urologia e andrologia 2020; 92, 1 time changes of renal dimensions and glomerular filtration rate variations in chronic kidney disease patients table 4. statistically significant correlations. variables delta of the renal delta diameters’ average of the gfr delta of the renal diameters’ average r / 0.731 p / < 0.001 n / 80 delta of the gfr r 0.731 / p < 0.001 / n 80 / delta of the age at the moment of the examination r -0.360 -0.304 p 0.001 0.006 n 80 80 delta of the systolic blood pressure r 0.238 0.370 p 0.035 0.001 n 79 79 delta of the mean arterial pressure r 0.190 0.289 p 0.093 0.01 n 79 79 delta of the right kidney diameters r 0.907 0.661 p < 0.001 < 0.001 n 80 80 delta of the left kidney diameters r 0.866 0.637 p < 0.001 < 0.001 n 80 80 delta of the right kidney cortical thickness r 0.506 0.487 p < 0.001 < 0.001 n 80 80 delta of the left kidney cortical thickness r 0.535 0.519 p < 0.001 < 0.001 n 80 80 delta of the number of patients having a hyposodic diet r 0.068 0.250 p 0.546 0.025 n 80 80 delta of the number of patients taking diuretics r -0.262 -0.226 p 0.019 0.044 n 80 80 delta of the number of patients taking nephrotoxic drugs r -0.293 -0.429 p 0.008 < 0.001 n 80 80 figure 1. a graphical representation of the correlation that was found between the percentage variation of the average of the renal diameters and the time changes of the gfr with respect to the values at the time of the enrollment. brardi_stesura seveso 01/04/20 18:54 pagina 23 archivio italiano di urologia e andrologia 2020; 92, 1 s. brardi, g. cevenini 24 after renal mass reduction by partial nephrectomy but also after partial renal parenchymal damage induced by nephrotoxins (13, 14). now in this study we exercised a decise action aimed at removing all nephrotoxic pharmacological agents and the most common ones that we eliminated at the time of the enrollment were thiazide diuretics with the use of which apoptosis has been observed in the distal tubular cells, just those that dominate the physiological renal hypertrophy (15). therefore, it seems probable that the removal of nephrotoxic agents done in this study may be the action that mostly induced compensatory kidney growth. about the strong positive correlation that we found between time changes of systolic blood pressure and percentage variations of the gfr and the weaker positive correlation found between delta of the systolic blood pressure and time changes of renal diameters’ average in longitudinal axis, we suppose that when in ckd, aorta is stiffed, a decrease of systolic blood pressure can limit the renal perfusion that, in this condition, is mostly dependent by stroke volume, causing a decrease of gfr, reversible with the restoration of systolic blood pressure (10). in fact at the time of enrollment, as part of our action to improve kidney function, we accurately corrected not only the high systolic blood pressure values but also those excessively reduced (i.e. next or less than 100 mmhg) which in the population enrolled were relatively frequent. to the characteristics of the population enrolled in terms of systolic blood pressure, can be probably due the correlation that was found between the reduction of diuretics usage (which can significantly contribute to reducing the systolic blood pressure) and the time changes of renal diameters’average in the longitudinal axis or the delta of the gfr. lastly, as known, another parameter that correlates with kidney length is age: in adults there is a gradual reduction in renal length that becomes more precipitous after age 50 years and that is due entirely to loss of parenchyma. (4, 3, 16). this likely can explain the strong negative correlation that was found between percentage variation of age at the moment of the examination and delta of the average of renal diameters in the longitudinal axis and time changes of gfr. it is our opinion therefore that, in the chronic kidney disease patients, also in the absence of total or partial nephrectomy as well as of any other condition that may increase the renal dimensions such as mainly diabetes mellitus, under the stimulus of the removal of any agent that may hamper renal function (such as, mainly, nephrotoxic drugs or excessively reduced values of systolic blood pressure), can be found a limited increase of the renal sizes according to a model that sees the same renal dimensions reduce or increase depending on changes in the gfr. moreover, in the chronic kidney disease patients, repeated accurate ultrasound measurements of the kidney sizes correlate significantly with the variations of kidney function and therefore can be used as a tool to confirm the trend of renal function. authors’ contributions each author declares to have fully participated in the drafting of the work and assumes all public responsibility for the content. references 1. troell s, berg u, johansson b, et al. comparison between renal parenchymal sono graphic volume, renal parenchymal urographic area, glomerular filtration rate and renal plasma flow in children. scan j urol nephrol. 1988; 22:207. 2. emamian sa, nielsen mb, pedersen jt. intraobserver and interobser variations in sonographic measurements of kidney size in adult volunteers. acta radiol. 1995; 36:399. 3. emamian sa, nielsen mb, pedersen jf, et al. kidney dimensions at sonography: correlation with age, sex, and habitus in 665 adult volunteers. ajr 1993; 160:83. 4. jovanovic d, gasic b, pavlovic s, naumovic r. correlation of kidney size with kidney function and anthropometric parameters in healthy subjects and patients with chronic kidney diseases. ren fail. 2013; 35:896-900. 5. sanusi aa, argundade fa, famirewa oc, et al. relationship of ultrasonographically determined kidney volume with measured gfr, calculated creatinine clearance and other parameters in chronic kidney disease (ckd). nephrol dial transplant. 2009; 24:1690-1694. 6. mazzotta l, sateschi lm, carlini a, antonelli a. comparison of renal ultrasonographic and functional biometry in healthy patients and in patients with chronic renal failure. arch ital urol androl. 2002; 74:206-9. 7, o’neill w. c. sonography of the normal kidney. in: o’neill w. c. atlas of renal ultrasonography. wb saunders company , philadelphia, usa: 2001; pp. 10-19. 8. zubovic sv, kristic s, pasic is. relationship between ultrasonographically determined kidney volume and progression of chronic kidney disease. med glas (zenica) 2016; 13:90-94. 9. levey as, stevens la, et al. a new equation to estimate glomerular filtration rate. ann intern med. 2009; 150:604-612. 10. brardi s, cevenini g. low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a nondialysis dependent chronic kidney disease population. arch ital urol androl. 2019; 90:288-292. 11. di iorio b, de santo ng, anastasio p, et al. the giordanogiovannetti diet. j nephrol. 2013; 26(suppl. 22):143-152. 12. rojas-canales dm, li jy, makuei l, gleadle jm. compensatory renal hypertrophy following nephrectomy: when and how? nephrology (carlton). 2019; 24:1225-1232. 13. cleper r. mechanisms of compensatory renal growth. pediatric endocrinology reviews (per) 2012; 10:152-63. 14. wesson lg. compensatory growth and other growth responses of the kidney. nephron. 1989; 51:149-184. 15. reungjui s, pratipanawatr t, johnson rj, nakagawa t. do thiazides worsen metabolic syndrome and renal disease? the pivotal roles for hyperuricemia and hypokalemia. curr opin nephrol hypertens. 2008; 17:470-476. 16. miletic d, fuckar z, sustic a, et al. sonographic measurement of absolute and relative renal length in adults. j clin ultrasound. 1998; 26:185. correspondence simone brardi, md (corresponding author) sibrardi@gmail.com hemodialysis unit, s. donato hospital, arezzo (italy) gabriele cevenini, md department of medical biotechnologies, university of siena (italy) brardi_stesura seveso 01/04/20 18:54 pagina 24 archivio italiano di urologia e andrologia 2018; 90, 3220 case report management of self-inflicted orchiectomy in psychiatric patient. case report and non-systematic review of the literature marco garofalo 1, alessandro colella 1, paolo sadini 1, lorenzo bianchi 1, giacomo saraceni 2, eugenio brunocilla 1, giorgio gentile 3, fulvio colombo 3 1 department of urology, sant’orsola hospital university of bologna, bologna, italy; 2 complex pelvic surgery unit, department of gynecology and urology, sant'orsola-malpighi hospital, bologna, italy; 3 andrology-unit, sant’orsola hospital university of bologna, department of gynecology and urology, bologna, italy. . introduction: self-inflicted orchidectomy and auto-castration, also known as “eshmun complex” is a rare phenomenon. the aim of our study it to present the management of a patient who performed a self orchiectomy and propose a non-systematic review of literature about self-orchiectomy. material and method: a 27-years old male patient with psychiatric disorder was admitted to our ward to have been cutted his scrotum with scissors and cut away his left testicle causing active bleeding from the left spermatic artery. the patient underwent emergency surgery with clamping of the spermatic cord and hemostasis of the wound. results: after surgery the clinical condition of the patient remained good during whole hospitalization. urgent psychiatric evaluation was performed in order to administer proper therapy for acute management. to best of our knowledge, only 11 cases of self-orchidectomy are reported in literature and all of them except 1 case, underwent surgical exploration. conclusions: self-orchidectomy is an extremely rare phenomenon, often associated with psychiatric disorders, compounded by the use of drugs. in our opinion, emergency surgery should be the first choice of treatment, offering diagnostic and hemostatic purpose in a single act, aimed to prevent acute and postacute complications. key words: self orchiectomy; genital mutilation; self castration. submitted 15 may 2018; accepted 26 july 2018 summary no conflict of interest declared. no mental illness history (8, 9). risk factors for gsm include: commanding hallucinations, religious delusions, substance abuse and social isolation (5, 10, 11). it has been reported a correlation between schizophrenia (or its acute state induced/flared by drugs abuse and acute psychotic states induced by recreational drugs consumption) and major self-mutilations (12, 13); sometimes genital mutilation can also be the presenting sign of schizophrenia (14). auto-castration in a setting of drugs abuse alone, especially of a single drug (mainly methamphetamine and cannabinoids) and within absence of a certified mental illness history, has also been described (15-17). the vast majority of reported cases have occurred among single, white males in their 20s and 30s (18). usually, patients report all the common signs in traumatic amputation of the testis (namely, exposed lacerated wound, avulsion, etc). in addition, very few other cases show genital auto-mutilation of one or both testicles without involving the penile shaft. we show a case of unilateral self-orchidectomy performed in a “surgical fashion”, resulting in a closed wound acute scrotum presentation. the aim of our study it to present the management of a patient who performed a self-orchiectomy; we also propose a non-systematic review of literature about self-orchiectomy. materials and methods 21.03.2017. 03:12 p.m. a 27-years old male patient, voluntarily admitted to st. orsola malpighi hospital’s casualty ward, asking for medical assistance for referred “scrotal bleeding and self-orchidectomy”. patient was already admitted before, since he was followed by a psychiatric clinic due to schizophrenia, not properly adherent to fluphenazine prescription. the patient lucidly reported his psychiatric disorder at beginning of medical consultation and he reported that he incised his scrotum with scissors and cut away his left testicle, then he sutured his scrotum by himself. he had no mention of local anesthesia or analgesic usage. genital examination revealed globally swollen and round scrotum (approximately 15 cm). scrotal skin, looking stretched, dehydrated and clean, was involved by a large doi: 10.4081/aiua.2018.2.220 introduction self-inflicted testicular injury is a rare phenomenon, with less than 200 cases reported in literature (1). scrotal traumas are included in a different genital self-mutilation (gsm) setting, with lesions varying from tissues laceration to ablation of the whole external genitals (2). most self-inflicted testicular injuries have been reported in trans-sexual patients who desire emasculation (3) or by psychotic patients with either functional or organic brain disease (4, 5). self-inflicted orchidectomy and auto-castration, also known as “eshmun complex” (6, 7) is a type of major-selfmutilation (msm) common among young individuals affected by psychiatric disorders, especially during acute psychotic state (1). this traumatic injury is less common in delusional and depressed individuals or in subject with garofalo_stesura seveso 03/10/18 09:49 pagina 220 221archivio italiano di urologia e andrologia 2018; 90, 3 management of self-inflicted orchiectomy in psychiatric patient ecchymosis more evident on the lower-left side. indeed, on the left side, at lower-middle third, a cutaneous suturing measuring approximately 1 x 0.5 cm appeared as repaired by suturing stitches made of common cotton thread (figures 1a, 1b). ultrasound evaluation by scrotal eco-color-doppler (ecd) has been performed, according to the casualty ward’s dedicated acute scrotum diagnostic protocol. the ecd showed a normal, despite dislocated, right testicle (figure 2a) and an extensive hematoma of the left scrotum cavity with a modest color-doppler signal within its content, but no evaluable left testicle (figure 2b). blood exams were indicative for acute infection and inflammation (white blood cells: 19.01 x 10^9/l; neutrophils: 16.13 x 10^9/l); toxicological screening found high amounts of plasmatic cannabinoids (69 ng/ml). total hemoglobin was 13.8 g/dl. within normality ranges of hematocrit and red blood cells total amount. basing on this preliminary data, in absence of major bleeding, considering the regular glasgow coma scale (gcs) and mental status, himself showing a calm and cooperative behavior, we aimed firstly to determine the entity of lesion, the extent of active bleeding and the need of acute management by surgical exploration. examination was extended through palpation and manipulation of external genitals, revealing a scrotal fistula covered by uneven wire stitching on the left scrotal sack. by applying progressive non-traumatic digital pressure, the left scrotum was evacuated from an approximate amount of 400 ml of blood clots and serous/hematic material through the un-sutured scrotal breech. this maneuver allowed palpation of scrotal content. therefore, surgical scrotal exploration was planned in emergency, with the consent of the informed patient. antibiotic prophylaxis was administered by endovenous infusion of cefuroxime 2 gr. first, we removed some black cotton double-wired single-suturing stitches overlapping each other in the left scrotum, assumed to be placed with a sewing needle. so, an irregular circular area of excision of 4 cm involving all scrotal wall tissues, appeared. scrotal incision margins presented as neat as a single or few scissor section lines. evacuation of approximately 100 ml of blood clots revealed an empty left hemiscrotum. an active bleeding sprouting was individuated from the left spermatic artery; this revealed the distal portion of the left spermatic chord (figures 3a, 3b), suggesting that the spermatic chord incision has been conducted by the patient above the testicular veins; no testicular or epididimal remnants were found. didymus and epididymis were missing: in fact, the patients referred in follows consultation, that he threw the testis into the toilet. after clamping and dissection of distal amputated spermatic chord, the vessels and the vas deferens were sutured separately with 2-0 vicryl®. after washing the cavity, the hemostasis check showed no further bleeding and no other trauma. a percutaneous suction drainage has been placed in the left scrotal cavity. finally, the scrotum has been repaired by suturing the dartoic plane and the skin in 4-0 safilquick® absorbable single stitches. results after surgery, the clinical condition of the patient remained good during whole hospitalization. intravenous fluids, anti-inflammatory drugs and analgesic have been administered. the day after the surgical intervention, the vital signs were good and stable; hemoglobin values of 11.0 g/dl in the first postoperative day, lined with the blood loss before the hemostasis in the operating theatre (estimating blood loss: 150 cc) and the inflammation signs were considerably reduced (white blood cells 8.92 x 10^9/l). there was no fever, no local or systemic infection and good status of the surgical wound. urgent psychiatric evaluation was performed in order to administer proper therapy for acute management. the patient referred during the psychiatric evaluation that his act was impelled by voices inside his head, and probably this escalated quickly with chronic and acute abuse of cannabinoids. moreover, he said that he felt no pain during the mutilation. since the surgical postoperafigure 1. preoperative picture of the scrotum, with the surgical suture made by the patient. figure 2. ultrasound of scrotum: a) right scrotum with regular right testis b) left scrotum, without the testis. figure 3. intraoperative picture: the cut funiculus. a. b. a. b. a. b. garofalo_stesura seveso 03/10/18 09:49 pagina 221 archivio italiano di urologia e andrologia 2018; 90, 3 m. garofalo, a. colella, p. sadini, l. bianchi, g. saraceni, e. brunocilla, g. gentile, f. colombo 222 tive convalescence elapsed without complication, the patient was transferred to a psychiatric ward. discussion gsm is a rare phenomenon. the most common self-mutilating behavior is cutting one’s own wrist, which is usually committed by adolescents or by the mentally retarded for attention-seeking purposes. rarely, self-mutilation has a serious scenario that leads the patient to attempt to amputate his penis, to castrate himself, to extract his eye or to amputate his hand (19). the instruments that have been used include kitchen knives, blades, scissors, a chainsaw and an axe. most of cases reported in the literature, consist of patients with psychosis or psychiatric disorders with either functional or organic brain disease. such cases have been observed in schizophrenia or depression, and it is sometimes difficult to diagnose these conditions because such a behavior is usually the only presenting symptom of the psychiatric disorder. however, few cases have been described in non-psychotic persons. it has been suggested that there is no difference in the severity of the self-inflicted injuries between psychotic and non-psychotic patients. in our case report, the reason for self-mutilation of the testis was the status of schizophrenia compounded by the use of drugs. as the degree of mutilation varies, so does the treatment, which can be complex and quite challenging; it often consists of a multidisciplinary management between the urologist, psychiatrist, psychologist and primary care physician. early diagnosis and fast treatment can reduce the acute and post-acute complications (blood loss, infections, hemorrhagic shock…). to best of our knowledge, only 11 cases of self-orchidectomy are reported in literature and all of them except 1 case, underwent surgical exploration (table 1). the main goal of surgical treatment includes restoration of the anatomy and function of mutilated organs, as much as possible. a superficial laceration may require no more than simple suturing; a serious injury with selfmutilation of organ or part of it, as we reported in the present case report, needs an emergency intervention. complications resulting from gsm vary according to the severity of the injury inflicted and the extent of surgical repair undertaken. conclusions self-orchidectomy is an extremely rare phenomenon, often associated with psychiatric disorders, compounded by the use of drugs. in our opinion, emergency surgery should be the first choice of treatment, offering diagnostic and hemostatic purpose in a single act, aimed to prevent acute and post-acute complications. however, a multidisciplinary approach is essential and includes a careful psychiatric evaluation to avoid recurrences and to more extensively support these patients through their mental and physical integrity recovery. references 1. veeder ta, leo rj. male genital self-mutilation: a systematic review of psychiatric disorders and psychosocial factors. gen hosp psychiatry. 2017; 44:43-50. 2. stunell h, power re, floyd m, quinlan dm genital self-mutilation. int j urol. 2006; 13:1358-60. 3. simopoulos ef, trinidad ac. two cases of male genital self-mutilation: an examination of liaison dynamics. psychosomatics. 2012; 53:178-80. 4. patel sr, thavaseelan s, handel ln, et al. bilateral manual table 1. review of literature on penile trauma and anterior urethral rupture: characteristic of studies, population and management. authors study years n° patients psychiatric/neurologic drugs management (total) pathology sutchin r. patel et al. case report 2007 1 gerstmann-straüssler-scheinker _ surgery syndrome helen stunell et al. case report 2006 1 paranoid schizophrenia _ surgery ugur lok et al. case report 2014 1 unknown _ surgery a.a. ajape et al. case report 2010 1 depression _ surgery moudif k. et al. case report 2004 1 unknown unknown surgery wade c. myers m.d., et al. case report 2001 1 schizophrenia conserevative/medical eugene f. simopoulos, m.d., et al. case report 2012 1 major depression, lorazepam, ramelteon surgery social anxiety disorder, gender identity disorder, and complex post-traumatic stress disorder abdurakhmanov ra, et al. case report 2016 1 unknown unknown surgery rehan ahmed siddiquee, et al. case report 2007 1 schizophrenia surgery jacek s. anand et al. case report 2014 1 polydrug abuse methamphetamine borderline personality disorder (up to 500 mg per day) surgery mustapha ahsaini case report 2011 1 cannabis abuse cannabinoids surgery total 11 160 garofalo_stesura seveso 03/10/18 09:49 pagina 222 223archivio italiano di urologia e andrologia 2018; 90, 3 management of self-inflicted orchiectomy in psychiatric patient externalization of testis with self-castration in patient with prion disease. urology. 2007; 70:590.e15-6. 5. ozan e, deveci e, oral m, et al. male genital self-mutilation as a psychotic solution. isr j psychiatry relat sci. 2010; 47:297-303. 6. kushner aw. two cases of auto-castration due to religious delusions. br j med psychol. 1967; 40:293-8. 7. eke n. genital self-mutilation: there is no method in this madness. bju int. 2000; 85:295-298. 8. ajape aa, issa ba, buhari oi, et al. genital self-mutilation. ann afr med. 2010; 9:31-4. 9. mareko gm, othieno cj, kuria mw, et al. body dysmorphic disorder: case report. east afr med j. 2007; 84:450-2. 10. rao kn, bharathi g, chate s. genital self-mutilation in depression: a case report. indian j psychiatry. 2002; 44:297-300. 11. charan sh, reddy cm. genital self mutilation in alcohol withdrawal state complicated with delirium. indian j psychol med. 2011; 33:188-90. 12. vender s, bianchi l, callegari c, et al. cannabis use and genital self-mutilation: an update of case reports. riv psichiatr. 2015; 50:148-50. 13. siddiquee ra, deshpande s. a case of genital self-mutilation in a patient with psychosis. ger j psychiatry. 2007; 10:25-8. 14. myers wc, nguyen m. autocastration as a presenting sign of incipient schizophrenia. psychiatr. serv. 2001; 52:685-6. 15. ahsaini m, tazi f, khalouk a, et al. bilateral testicular self-castration due to cannabis abuse: a case report. j med case rep. 2011; 5:404. 16. anand js, habrat b, barwina m, waldman w. repeated self-mutilation of testicles in the context of methamphetamine use e a case report and brief review of literature. j forensic leg med. 2015; 30:1-3. 17. large m, babidge n, andrews d, et al. major self-mutilation in the first episode of psychosis. schizophr bull. 2009; 35:1012-21. 18. lok u, gulacti u, benlioglu c, et al. self mutilation of genitaliausing teeth. j clin diagn res. 2014; 8:179-80. 19. nerli rb, ravish ir, amarkhed ss, manoranjan ud, prabha v, koura a. genital self-mutilation in nonpsychotic heterosexual males: case report of two cases. indian j. psychiatry 2008;50:285–7 correspondence marco garofalo, md marco.garofalo@unibo.it alessandro colella, md alessandro.colella@studio.unibo.it paolo sadini, md sadini@libero.it lorenzo bianchi, md lorenzo.bianchi3@gmail.com eugenio brunocilla, md eugenio.brunocilla@unibo.it department of urology, sant’orsola hospital university of bologna, bologna, italy giacomo saraceni, md giacomo.sareceni@libero.it complex pelvic surgery unit, department of gynecology and urology, sant'orsola-malpighi hospital, bologna, italy giorgio gentile, md (corresponding author) dr.giorgio.gentile@gmail.com fulvio colombo, md fulvio.colombo@aosp.bo.it andrology-unit, sant’orsola hospital university of bologna, department of gynecology and urology, bologna, italy garofalo_stesura seveso 03/10/18 09:49 pagina 223 85archivio italiano di urologia e andrologia 2018; 90, 2 review resistance of uropathogens to antibacterial agents: emerging threats, trends and treatments gianpaolo perletti 1, 2, vittorio magri 3, tommaso cai 4, konstantinos stamatiou 5, alberto trinchieri 6, emanuele montanari 7 1 department of biotechnology and life sciences, section of medical and surgical sciences, università degli studi dell'insubria, varese, italy; 2 faculty of medicine and medical sciences, ghent university, ghent, belgium; 3 urology secondary care clinic, asst-nord, milan, italy; 4 department of urology, santa chiara regional hospital, trento, italy; 5 department of urology, tzaneio general hospital of piraeus, piraeus, greece; 6 urology unit, a. manzoni hospital, lecco, italy; 7 department of urology, university of milan ca' granda foundation ospedale maggiore policlinico, milan, italy. urinary tract infections are among the most common infectious diseases in humans. today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world. it is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. carbapenemase-producing enterobacteriaceae, multidrug-resistant enterococci and fluoroquinolone resistance determinants in both gram-negative and gram-positive uropathogens are among the greatest emergencies. in this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older – but still active – recommended drugs are summarized. key words: urinary tract infections; resistance; antibacterial agents; antibiotics; carbapenemase; carbapenem resistance. submitted 11 april 2018; accepted 11 april 2018 summary no conflict of interest declared. emerging resistance threats in 2013, the centers for disease control and prevention (usa) included carbapenem-resistant enterobacteriaceae (creb) among the three microorganisms posing an urgent threat to public health, due to the extensive resistance shown by these pathogens to a wide array of antibacterial agents, and to the very high mortality rates reported in patients with bloodstream infections caused by organisms like carbapenem-resistant kp. several international programs are now aimed at fostering research, development and awareness about the threat of pathogen resistance. pivotal european trials are for example eureca (european prospective cohort study on enterobacteriaeae showing resistance to carbapenems), and revisit (revisiting serious bacterial infection with innovation), promoted in the frame of the european combacte-care project, an initiative of the combacte.com collaboration. carbapenem resistance for several decades, extended-spectrum beta-lactamases (esbl) of tem and shv lineage, conferring resistance to a variety of penicillins and third-generation cephalosporins, have represented a worrisome problem for physicians treating patients affected by infectious diseases. in these cases, carbapenem therapy was a useful therapeutic resource against esbl-producing pathogens. however, today the usefulness of carbapenems is decreasing rapidly, and the global spread of carbapenemase-producing enterobacteriaceae (the etiological agents of lung, soft tissue and urinary tract infections) has undoubtedly become the most important threat in the field of infectious diseases. the speed of such spread is alarming: for example, whereas in 2009 the spread of the klebsiella pneumoniae carbapenemase (kpc) in the usa was classified as ‘sporadic’ in half of the federal states and ‘less than sporadic’ in the remaining states (1), in 2014 the entire usa territory has been defined as affected by an ‘endemic’ presence of kpc (2). the concern raised by this mounting trend is due to the doi: 10.4081/aiua.2018.2.85 introduction urinary tract infections (utis) are among the most common bacterial-borne diseases in humans. although antibacterial agents have been the mainstay of treatment for utis for decades, today routine antibiotic therapy is seriously threatened by worldwide outbursts of infections involving multidrug-resistant (mdr), extremely drug-resistant (xdr) or even pan drug-resistant pathogens. gramnegative enterobacteriaceae like klebsiella pneumoniae (kp) and escherichia coli (ec), and gram-positive cocci like enterococcus faecalis and enterococcus faecium are at the same time the most common uropathogens and the bacteria carrying the most powerful resistance determinants. on the basis of a general assessment of the major resistance threats, the present review will focus on worldwide susceptibility trends resulting from large international surveillance studies, and will present some available therapeutic options -either novel or old but still effectivefor the management of resistant infections of urological interest. perletti_stesura seveso 28/06/18 16:33 pagina 85 archivio italiano di urologia e andrologia 2018; 90, 2 g. perletti, v. magri, t. cai, k. stamatiou, a. trinchieri, e. montanari 86 fact that the spectrum of enzymatic activity of carbapenemases is not restricted to drugs like imipenem, ertapenem, meropenem or doripenem, but extends to almost all beta-lactams. moreover, resistance to carbapenems and other beta-lactams is in most cases facilitated by horizontal-transfer of genetic elements like transposons and plasmid-borne integrons, invariably containing multiple resistance determinants which often confer multidrugresistant, extensively drug-resistant or even pan drug-resistant properties to pathogens. k. pneumoniae is the most prevalent pathogen among carbapenem-resistant enterobacteriaceae according to a recent surveillance report by the european centre for disease prevention and control (3). infection with carbapenemase-producing kp (cpkp) can double the mortality rate of affected patients (from 21% to 42%, all infections), and can triplicate the mortality of non-intensive care patients with utis from 13% to 43% in intensive care unit (icu) cases (4). the carbapenemases that have been characterized so far belong to all four ambler classes of beta-lactamases (table 1). among the enzymes of concern for urologists, the class-a, plasmid-borne k. pneumoniae serine carbapenemase (kpc) is today the most common transmissible resistance determinant in enterobacteriaceae. kpc includes more than 20 variants (the most prevalent being kpc-2 and -3), who can hydrolyze virtually all beta-lactam agents including carbapenems, penicillins, broad spectrum cephalosporins and mono bactams. kpcs are only weakly inhibited by clavulanate and tazobactam (1, 5), and the encoding blakpc gene, predominantly present in incf plasmids (with fiik replicons, and often associated with a tn4401 trasposon-like structure), is very often coexpressed with cotrimoxazole, fluoroquinolone and aminoglycoside resistance determinants (6). notably, today kpc is no longer exclusively expressed in kp (mainly the st258 strain) or other creb, but is also found in other species such as pseudomonas aeruginosa (7). the sme enzyme also belongs to class-a carbapenemases, but at present is isolated less frequently than kpc, being in almost all cases restricted table 1. carbapenem resistance determinants in pathogens involved in utis. perletti_stesura seveso 28/06/18 16:33 pagina 86 to the serratia marcescens species, a member of the enterobacteriaceae family (8). class b metallo beta-lactamases/carbapenemases (mbls) require zinc for their catalytic activity. these enzymes are expressed in enterobacteriaceae but also in p. aeruginosa, and can hydrolyze carbapenems, penicillins and cephalosporins, but not monobactams. importantly, mbls are not affected by beta-lactamase inhibitors. the most powerful and most diffuse mbls are the new delhi mbl (ndm), the verona-integron-encoded mbl (vim) and the imp imipenemase (9). the blandm gene variants are harbored by a variety of broad-host-range inc plasmids like inca/c, incf, incr, incn, incm, incx, which are in turn expressed within various pathogen isolates, including the highly prevalent st11 kp clone. pathogens harboring the ndm are often residually susceptible to a single last-resort agent like polymixin e, since ndm is very frequently co-expressed with other carbapenemases (oxa-48, vim and/or kpc) and with multiple resistance determinants such as esbl, ampc beta-lactamases, aminoglycoside-modifying enzymes, fluoroquinolone resistance enzymes (e.g., qnr), macrolide esterases, as well as determinants conferring resistance to trimethoprim-sulphametoxazole. among class c beta-lactamases, the cmy enzymes (e.g., act-1, cmy-1, cmy-2, and cmy-4, often transferred via pymg plasmids) were originally expressed in enterobacter spp. but now are being carried by several other enterobacteriaceae, including kp (cmy-10). act-1 and cmy-1 show moderate carbapenemase activity, are not significantly inhibited by clavulanic acid, and highlevel resistance to carbapenems is often the result of combined drug hydrolysis and impaired drug permeability (e.g., involving ompk35/36 porins) (10, 11). class d oxa beta-lactamases can efficiently hydrolyze penicillins like oxacillin. some oxa enzymes, such as oxa-23, oxa-48, oxa-51 and oxa-58, carried mainly by highly transferable incl group plasmids like poxa48a, have a weak carbapenemase activity. nevertheless, in pathogens like st-11 kp, high-mic carbapenem resistance may result from the concomitant activity of efflux pumps or low-permeability porins (12). as far as carbapenem-resistance in gram-positive pathogens is concerned, three mechanisms of reduced beta-lactam susceptibility have been reported in enterococci: (i) beta-lactamase production as well as (ii) overproduction or (iii) inactivation (by point-mutation) of penicillin-binding proteins like pbp4 or pbp5. notably, carbapenem resistance is mainly caused by point-mutations in pbp4. for example, resistance to faropenem in e. faecalis is due to decreased affinity of the drug for pbp4, due to the acquisition of one or two point mutations in the pbp4-encoding gene (13). plasmid-mediated fluoroquinolone resistance plasmid mediated fluoroquinolone resistance (pmqr) is increasing to the point that international guidelines no longer recommend drugs like ciprofloxacin, ofloxacin or levofloxacin as first-choice agents for treatment of urinary tract infections, when resistance is assessed in at least 10% of pathogen isolates (14, 15). fluoroquinolones (fq) inhibit the activity of bacterial gyrase and topoisomerase iv in gram-negative and -positive pathogens. mutations occurring in the quinolone resistance determining regions of genes encoding these type ii topoisomerases (e.g., in gyra, gyrb, parc or pare subunits) are the most common chromosomal determinants of fq resistance (16). for example, in enterococci resistance to fluoroquinolones is mainly caused by mutations in the gyra and parc genes in gyrase and topoisomerase iv, respectively (17). other mechanisms of resistance to fq are the qepa-encoded efflux pumps, the oqxab-encoded efflux pumps -very common in plasmids carried by k. penumoniae-, the qnr-encoded proteins, impeding the interaction of fq with dna gyrase, and a mutant aminoglycosyde acetyl-transferase (aac (6’)-ib-cr) which acetylates the piperazine ring of fq like norfloxacin and ciprofloxacin (18-21). determinants of pmqr are horizontally transferable. for example, qnra1, a3, a6, b2, b4, b6 and b10 are associated with the mobilizing element insertion sequence iscr, whereas qnrb1 and b20 are associated with is26 and orf1005. the aac (6’)-ib-cr enzyme-encoding gene is often found in association with qnrb and blactx in a cassette within an is26 transposon. in addition, qepa and oqxab are also often mobilized by is26 transposons (22). polymyxin resistance polymyxins (polymyxin b and colistin/polymyxin e) are antibiotics produced by the gram-positive species paenibacillus polymyxa. the plasmidic mcr-1 colistin resistance gene, expressed in klebsiella spp. and other enterobacteriaceae, encodes for a phosphatidy lethano lamine transferase enzyme, lessening the affinity of colistin towards the lipid-a on bacterial cell membranes via enzymatic modification (23). this resistance determinant, rapidly spreading worldwide (24), represents a major threat since polymyxins are considered last-resource antibiotics against creb. glycopeptide resistance together with enterobacteriaceae, enterococci are the most common etiological determinants of urinary tract infections. acquired resistance to glycopeptide antibiotics in enterococci is given by five gene clusters: vana, vanb, vand, vane and vang, leading to the expression of peptidoglycal pentapeptide precursors (ppp) characterized by poor affinity for vancomycin and other glycopeptides. interestingly, vana enterococci are resistant to the lastgeneration glycopeptide dalbavancin but are susceptible to oritavancin, possibily due to the unique dual mechanism of action of the latter (25). horizontal transfer of van genes may occur via tn-1546 transposons, which are found in conjugative and non-conjugative plasmids (26). worldwide resistance trends beta-lactam antibiotic resistance information about worldwide trends in pathogen resistance is not frequently published, due to the fact that global epidemiological studies are difficult to perform, and most studies focus on a single nation or region. nevertheless, quality works like for example the 2016 87archivio italiano di urologia e andrologia 2018; 90, 2 uropathogen resistance threats, trends and treatments perletti_stesura seveso 28/06/18 16:33 pagina 87 archivio italiano di urologia e andrologia 2018; 90, 2 g. perletti, v. magri, t. cai, k. stamatiou, a. trinchieri, e. montanari 88 systematic review by lee et al. (27), or some global surveillance studies, which are occasionally performed, give access to evidence concerning global trends of pathogen chemoresistance. the study to monitor antimicrobial resistance trends (smart) is among the largest global surveillance programs aimed at monitoring longitudinal antimicrobial resistance patterns worldwide. over 200,000 clinical samples have been collected since 2002 from patients with complicated intra-abdominal infections, whereas isolates from patients with utis have been acquired since 2009. among other surveillance actions, susceptibility testing to 12 commonly used antibacterial agents has been performed in different regions of the world. one-hundred ninety-four hospital sites in countries located within the macro-regions of asia/pacific, latin america, middle east/africa, north america, and europe have taken part in the project. within the smart program, the eskape group of pathogens (enterococcus spp, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa and enterobacter spp.) is of main interest to urologists and accounts for the vast majority of resistance encountered in nosocomial settings. global trends. data from the smart project provide an excellent overview of global resistance trends for uropathogens. in the frame of smart, the 2009-2010 susceptibility analysis of e. coli isolates from uti specimens of hospitalized patients in countries worldwide showed an overall 17.9% prevalence of extended-spectrum beta lactamase (esbl) resistance determinants (28), whose rate varied depending on the region considered (asia/pacific, 27.7%, latin america, 23.3%, europe, 18.8%, middle east/africa, 16.2%, northern america, 7.4%). only imipenem and ertapenem demonstrated > 90% susceptibility in esbl-positive e. coli at that time (99.7% and 98% isolates susceptible, respectively), whereas susceptibility to amikacin and piperacillin-tazobactam was lower (87.1% and 84.4%, respectively). the least active agents were ampicillin-sulbactam, all cephalosporins except cefoxitin, and the fluoroquinolones (28). in the discussion of their data, hoban et al. emphasized the relevance of intermediate susceptibility in the treatment of utis, as certain antibacterial agents concentrate physiologically in the urine (28). this suggests that in specific infections showing intermediate susceptibility towards certain agents, high-dose treatment may be attempted in the absence of more suitable options. as far as the geographic distribution of carbapenemases is concerned, the overall mortality due to creb reported in studies from northern america, southern america, europe, and asia was 33.2%, 46.7%, 50%, and 44.8%, respectively (all infections) (4). kp carbapenemases (kpc) are endemic in the usa, china, greece, italy, poland, israel, brazil, argentina, colombia and taiwan, whereas sporadic spread of kpc-producing kp has been observed in virtually all asian, european and american countries (summarized in: 27). the new delhi metallo beta-lactamases (ndm) confer resistance to most beta-lactams including carbapenems, as well as co-resistance to aminoglycosides, tetracyclines, fluoroquinolones and other antibacterials, due to the compresence of various resistance determinants within the same mobile genetic elements. ndm are endemic india, pakistan and bangladesh (27). an analysis of the prevalence of ndm in the in the frame of the smart program for years 20082012 – published in 2015 – showed that isolates of nine different species of ndm-expressing enterobacteriaceae were disseminated in india, serbia, the philippines, saudi arabia, guatemala, vietnam and georgia, and that different variants of the ndm gene were compresent with ctx-m cephalosporinases (29). moreover, enterobacteriaceae producing the vim and imp carbapenemases (alone or coexpressed) have been found in greece, italy, spain, the philippines, turkey, australia, mexico, usa and india, with most isolates concomitantly nonsusceptible to one or more agents like ampicillin-sulbactam, ceftriaxone, cefepime, ceftazidime, piperacillin-tazobactam, ciprofloxacin, amikacin, tigecycline and colistin (30). importantly, kp isolates produced imp-26 together with various vim variants (vim-1, 5, 26 or 27), whereas e. coli expressed imp-1 alone (30). class-d oxa carbapenemases are endemic in india, turkey, morocco, libya, egypt and tunisia, and sporadic spreads have been documented throughout europe and the middle-east (summarized in: 27). oxa enzymes have been recently isolated in all continents. asia-pacific. in the asia-pacific region, 60 centers from 31 countries provided susceptibility data, which were collected in years 2010-2013 and published in 2016 (31). uropathogenic e. coli (upec) and kp were the most prevalent isolates. china showed the highest rates of esbl, both in upec and kp (66.4% in 2010 and 59.9% in 2013 for upec; 60% in 2010 and 54.5% in 2013 for kp). besides china, dramatic increases of esbl-expressing upec were observed for example in thailand (54.2% in 2013 vs. 36.8% in 2010) and hong kong (41.7% in 2013 vs. 25% in 2010), while esbl-kp were substantially increased in new zeland (45.5% in 2013 vs. 23.1% in 2010), south korea (55.6% in 2013 vs. 37.5% in 2010) and the philippines (61.3% in 2013 vs. 37.9% in 2010). in the same region, jean et al. reported a significant increase of the annual rates of carbapenemase prevalence between year 2008 (0.07%) and year 2014 (1.1%), with the blandm-1 allele becoming more prevalent than the imp-26 gene (32). latin america. in 11 latin american countries, analysis of resistance trends in years 2013-2015, published in 2017, showed that esbl-positive kp accounted for 46.6% of uti isolates, substantially higher than the values assessed in smart 2003 (14%). esbl-positive rates of kp were higher (52.9%) in isolates from intensive care unit (icu) compared to non-icu patients (44.4%) (33). ertapenem and imipenem showed slightly lower rates of resistance, compared to other beta-lactams (37.4% and 24.1%, respectively, versus, e.g., > 38% for cephalosporins and piperacillin-tazobactam). among other antimicrobials tested, the aminoglycoside amikacin continues to show high rates of susceptibility (92.3%) for isolates of kp (33). northern america. the smart program provided 24655 isolates from europe and north america, obtained from icu (17.8%) and non-icu (82.2%) wards. data from perletti_stesura seveso 28/06/18 16:33 pagina 88 90 hospitals in canada, in the usa and in 18 european countries were collected. by comparing these regions, in 2015 lob and coworkers found that resistance among enterobacteriaceae in europe was largely driven by kp expressing high rates of esbls (41.2% in intensive care units; mostly ctx-m) and carbapenemases (13.2%; mostly kpc and oxa-types). for all enterobacteriaceae combined, only ertapenem and amikacin inhibited > 90% of icu isolates in both regions. in northern america, ertapenem, imipenem and amikacin inhibited > 90% of kp, whereas in europe only amikacin attained such levels, according to lob et al. (34). in 2016, the same research group also focused on susceptibility patterns of esbl in e. coli from utis, representing the 52% of gram-negative pathogens collected. a significant increase in esbl prevalence was seen in the us (from 7.8% in 2010 to 18.3% in 2014, p < 0.0001), whereas in canada an increase from 10.4% to 13.0% was not statistically significant (35). moreover, isolates from hospital-acquired utis increased considerably in the us (9.4% in 2010 to 27.7% in 2014). the steepest increases over the five-year study period were found among us males (from 7.1% to 26.2%) and older us patients (from 8.8% to 26.6%) (34). europe. national surveillance programs worldwide have reported extensive spreads of carbapenemase-producing uropathogens. logan and weinstein have edited maps showing the spread of creb throughout europe and the world (6). according to the 2017 survey published by the european centre for disease prevention and control (ecdc), 25% to 50% isolates of kp are carbapenemresistant in italy, romania and greece, the latter showing rates beyond the upper limit (36). in europe, the diffusion of kpc is ‘endemic’ in greece, poland and italy (1). from a study involving 3324 non-replicate isolates of enterobacteriaceae from italian hospitals, it was found that 4.3% of isolates were non-susceptible to carbapenems, k. pneumoniae being the most prevalent carrier of the blakpc carbapenemase gene (in 25.1% and 7.7% inpatients and outpatients, respectively) (37). a recent ecdc report focusing on italy, pointed to dramatically increasing resistance trends in this country. for example, the proportion of cpkp blood isolates increased from 1.3% in 2006 to 33.5% in 2015, whereas combined resistance to third-generation cephalosporins, fluoroquinolones and aminoglycosides increased from 2.8% in 2005 to 29.7% in 2015. however, in e. coli the proportion of carbapenem-resistant blood isolates remained low: 0.1% in 2007 to 0.2% in 2015, though combined resistance increased from 0.8% in 2002 to 14.6% in 2015 (38). in germany, a very low incidence of carbapenemase-producing isolates has been documented, as a multicenter study published in 2016 demonstrated an incidence of 0.047 cases per 1000 hospital admissions (39). low prevalence has also been reported in belgium, with 3.5% of enterobacteriaceae being carbapenem non-susceptible through expression of oxa-48, oxa-427, kpc and ndm (40). a steep growth of carbapenem resistance has been reported in france. the oxa-48 and ndm resistance determinants increased from 23.1% in 2012 to 36.2% in 2014 (41). non-beta-lactam antibiotic resistance as far as non-beta-lactam antibiotic susceptibility trends are concerned, certain african countries show dramatic prevalences of pan-resistant infections. for example, it has been reported that in nigeria uropathogenic e. coli (upec) is pan-resistant to cotrimoxazole (100% isolates), and highly resistant to ofloxacin (70%), gentamycin (92%) and tetracycline (88%) (42). in various asia-pacific countries, the smart program reported that the rates of susceptibility to levofloxacin among hospital isolates of e. coli ranged from 83% in new zeland, to 39% in singapore, to 15% in india (cited in: 43). the overall prevalence of fluoroquinolone resistance in upec is dramatically increasing worldwide, with increasing trends in brazil (63.53% increase for ciprofloxacin and 66.50% for norfloxacin from 2010 to 2015)(44), and with values up to 17% in italy and 38% in turkey (summarized in: 45), whereas in the us a 10year study reported an increase from 3% to 17% between 2000 and 2010 (46). in europe, the areas showing the highest rates of pmqr are the mediterranean countries. this distribution extends to the whole mediterranean basin, and the affected countries are croatia, slovenia, greece, italy, spain, france, morocco, algeria, tunisia, egypt, and turkey (47, 48). resistance to cotrimoxazole in community-acquired upec is high in southern america (64% in nicaragua and up to 58% in pediatric cases in brazil), turkey (up to 43%) and greece (27.3%) whereas in the usa a percentage of 24.2 has been reported (45). the prevalence of vancomycin-resistant enterococci (vre) causing symptomatic or asymptomatic infections in europe ranges between 1 and 30%, whereas in the usa, vre are about the 30% of all nosocomial isolates (49). encouragingly, toner et al. reported that the proportion of vre has remained stable between 2006 (13.9%) and 2014 (11.5%), whereas a worrisome increase of resistance to nitrofurantoin has been documented in frame of the same study (just above zero in 2005 to over 40% in 2009 to about 20% in 2014). notably, in that study the prevalence of vancomycin resistance was substantially higher in e. faecium (51.2%) compared to e. faecalis (1.6%)(49). despite the data mentioned above, uropathogens worldwide seem to retain sensitivity against agents like nitrofurantoin and fosfomycin. for example, the prevalence of resistance to nitrofurantoin in upec isolates has been reported to be 2.9% in brazil (year 2007, 50), < 2% in europe and 1.6 in the us (45, 49, 50). the figures concerning fosfomycin appear to be as low, with a prevalence in several european countries inferior to 2% (51, 52). as far as infections of urological concern in the pediatric population are concerned, resistance to ciprofloxacin in e. coli utis increased 10-fold between 2002 and 2009 both in young boys and girls, as shown in a study performed in 195 us pediatric hospitals (1% to 10% and 0.6% to 4% of isolates, respectively) (53). available and emerging therapeutic strategies few randomized controlled studies concerning novel or improved therapeutic protocols against drug-resistant 89archivio italiano di urologia e andrologia 2018; 90, 2 uropathogen resistance threats, trends and treatments perletti_stesura seveso 28/06/18 16:33 pagina 89 archivio italiano di urologia e andrologia 2018; 90, 2 g. perletti, v. magri, t. cai, k. stamatiou, a. trinchieri, e. montanari 90 infections have been performed so far. thus, the available evidence is mainly observational and sometimes limited to case reports. in most cases, studies focusing on enterobacteriaceae are based on complicated cases of pneumonia or bacteremia. despite these limitations, this section will focus on selected therapeutic options -novel or old but still efficaciousfor treatment of infections caused by resistant pathogens of concern to urologists. carbapenems it is known that certain carbapenemase enzymes can decrease the susceptibility of pathogens to carbapenems to a limited extent, and pk/pd data suggest that t > mic targets can be met with high probability of attainment with high-dose continuous infusions of carbapenems (e.g. 6 g/day meropenem) when mics are ranging between 4 and 16 mg/l (summarized in: 54). these experimental data are encouraging, though experts suggest that monotherapy with these agents is not advisable, and that combination therapy including a carbapenem (when mics are ≤ 8 mg/l) can result in lower mortality rates (54). importantly, the efficacy of combined therapies including a carbapenem appears to be mic-dependent, as mortality rates in sepsis patients infected with kpcproducing kp were up to 35% for mics > 16 mg/l, but as low as 13.3% if the mics of meropenem (2g, > 3h infusion thrice daily) were below or equal to 4 mg/l (55). interestingly, combination of two carbapenems might become a last-resort regimen for treating pandrug-resistant and colistin-resort kpc-producing kp infections (bacteremia, pneumonia, and utis). the rationale for such approach is based on the fact that kpc appears to have higher affinity for ertapenem compared to other carbapenems. thus, while kpc would be “engaged” by ertapenem, a co-administered different carbapenem could exert its bactericidal activity. although recent quality observational data are encouraging (56-58), additional, adequately powered studies are urgently warranted. moreover, such evidence may ideally foster the development of ertapenem analogues characterized by higher affinity for kpc compared to the founder compound, in order to optimally exploit such “engagement” activity on carbapenemases. aztreonam monobactam therapy may be considered as an option against enterobacteriaceae expressing class b or d carbapenemases when these determinants are not coexpressed with class a enzymes, which are able to efficiently hydrolyze aztreonam (59). in all cases, susceptibility testing is necessary, due to variable monobactamase activity shown by different subclasses of class-b enzymes. avibactam the novel non-beta-lactam beta-lactamase inhibitor avibactam (figure 1) has been approved in 2016 in the european union for treatment of soft tissue infections, pneumonia and urinary tract infections in combination with the third-generation cephalosporin ceftazidime. avibactam inhibits a broad spectrum of beta-lactamases including a-class, c-class and some d-class carbapenemases (60). in vitro assessments performed in the frame of the inform global surveillance study demonstrated that 98% of creb isolates containing kpc or oxa-48 enzymes were susceptible to this combination, even when the isolates expressed esbls or ampc enzymes (61, 62). however, ceftazidime/avibactam was ineffective against carbapenem-hydrolyzing metallo-beta-lactamases like ndm. in vitro activity of this combination was also demonstrated in the frame of a phase 3 trial involving ceftazidime-resistant utis (63). recently, jayol et al. investigated the in vitro activity of ceftazidime/avibactam, alone (for class a and d carbapenemase producers) or in combination with aztreonam (for class-b carbapenemase figure 1. chemical structure of the novel non-beta-lactam beta-lactamase inhibitors avibactam, relebactam and vaborbactam. structures were drawn using the pubchem nih public repository database (93). perletti_stesura seveso 28/06/18 16:33 pagina 90 producers), against a collection of colistin-resistant and carbapenemase-producing kp isolates (64). it was shown that ceftazidime/avibactam was effective against colistin-resistant and kpc-producing or oxa48-producing kp, and was also efficient against kp isolates co-expressing two carbapenemases. interestingly, the combination of ceftazidime/avibactam with aztreonam was synergic against ndm-producing kp. investigators suggested that such synergic activity could be explained by the neutralization of the esbl activity by avibactam, which can in turn restore the susceptibility of kp to aztreonam (64). these data warrant urgent clinical investigation. the clinical efficacy of the ceftazidime/avibactam combination (2g/0.5g, intravenous q8h) was demonstrated by recent phase 3 studies in patients with complicated utis, including acute pyelonephritis (65, 66). further studies are urgently needed to investigate the clinical cure rates of this combination in utis caused by creb. relebactam the smart program provided isolates from the usa, which were used for testing the activity of imipenem combined with the newly developed, renally excreted carbapenemase inhibitor relebactam. relebactam is structurally related to avibactam, differing only by the presence of an amide functional group bound to a piperidine ring (figure 1). for kp, 99% and 96.1% of isolates were susceptible to imipenem-relebactam and imipenem alone, respectively, and 74.1% of imipenem-resistant isolates were rendered susceptible to the carbapenem by addition of relebactam (67). in vitro assays showed that the combination imipenem/relebactam decreased the mics of kpc-producing kp compared to imipenem alone (mic50: 0.25/4 mg/l, mic90: 1/4 mg/l), but was not as effective against pathogens expressing class d enzymes (e.g., oxa-48 in kp) (68). to date, phase ii clinical trials have reported that imipenem/relebactam is as effective as imipenem alone for treatment of complicated utis, including acute pyelonephritis (69). imipenem-relebactam is currently investigated in the frame of phase iii clinical trials for the treatment of imipenem-resistant infections. vaborbactam vaborbactam (vb) is a boronic acid-based non-beta lactam beta-lactamase inhibitor, registered by fda in 2017 for therapy of complicated urinary tract infections, combined with meropenem (2g/2g, intravenous q8h, to be adjusted in patients with renal impairment). its chemical structure is not related to the ones of avibactam or relebactam (figure 1). similar to meropenem, vb is renally excreted, and up to 60% of a dose is found unchanged in the urine within 24 hours. vb inhibits class a beta-lactamases (including kpc) and class c ampc β-lactamases. the meropenem/vb combination decreases the mics of most resistant enterobacteriaceae (2-fold to > 1024-fold decrease), though it appears that the addition of vb does not improve the activity of meropenem against p. aeruginosa (70). meropenem/vb is active against creb isolates and against enterobacteriaceae showing multidrug-resistant and extensively drug-resistant phenotypes (mic50/90: 0.5/32, 0.03/1, and 0.5/32 mg/l, respectively), though this drug combination showed limited activity against isolates expressing metallo-β-lactamases (e.g., ndm-1, vim) and oxacillinases (e.g., oxa-48, oxa-163) detected in asia-pacific and in certain european countries (71). the tango-1 phase iii clinical trial has reported superiority of meropenem/vb over piperacillin/tazobactam for the treatment of complicated utis, including acute pyelonephritis (72). the tango-2 randomized, openlabel phase iii clinical trial of meropenem/vb versus “best available therapy” in patients with complicated urinary tract infections, bacteremia or pneumonia, was stopped early due to a benefit-risk ratio in favor of meropenem/vb (73). polymyxins the polymyxin antibiotics colistin (poliymyxin e) and poliymyxin b have become a mainstay in the treatment of creb infections. the eucast breakpoint for resistance is 2 mg/l. recent studies resulted in the recommendation to prescribe high doses of the antibiotic (up to 10 million international units), divided into twiceor thrice-daily administrations (74). importantly, combination therapy including colistin and rifampin was shown to be effective against colistin-resistant, kpc-producing kp (75). though new polymyxin derivatives with decreased toxicity are under development, nephrotoxicity occurring in about 40% of cases and neurotoxicity are limiting factors to the extensive administration of colistin for treatment of creb-induced infections. a possible limiting factor to the full exploitation of polymyxins for utis may also be the limited renal clearance of these drugs, though pharmacokinetic studies seem to confirm that the urinary recovery of colistin may be sufficient to attain concentrations above the mics shown for example by xdr p. aeruginosa (76). aminoglycosides plazomicin is a novel aminoglycoside ("neoglycoside") antibiotic closely related to sisomicin and structurally recalling gentamicin. its molecular structure was designed to be resistant against aminoglycoside-modifying enzymes, which are often expressed in creb isolates (77). for example, in non-ndm-expressing creb, the mics of plazomicin ranged between > 0.5 and 2 mg/l, compared to 0.25/ > 256 mg/l and 1/128 mg/l for gentamicin and amikacin, respectively (78). three-hundred multidrug resistant esbl-producing and/or carbapenemase-producing enterobacteriaceae isolates from athens, greece (a creb endemic area), most of which were also resistant to previous generation aminoglycosides (e.g., mic50/mic90 to amikacin = 32/ > 32), were tested for sensitivity to plazomicin. this novel aminoglycoside retained activity against all tested isolates of k. pneumoniae, e. coli, and enterobacter spp., with mic50 and mic90 of 1 and 2 μg/ml, respectively, irrespective of their multidrug-resistant phenotype (79). in strains of creb resistant to gentamicin, tobramycin and amikacin, plazomicin exhibited an mic range of 0.12-4 mg/l, with mic50 and mic90 values of 0.25 and 1 mg/l, 91archivio italiano di urologia e andrologia 2018; 90, 2 uropathogen resistance threats, trends and treatments perletti_stesura seveso 28/06/18 16:33 pagina 91 archivio italiano di urologia e andrologia 2018; 90, 2 g. perletti, v. magri, t. cai, k. stamatiou, a. trinchieri, e. montanari 92 respectively. interestingly, in cpkp isolates, synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin, whereas the combination with tigecycline resulted in indifference (80). the safety and efficacy of plazomicin vs. levofloxacin in treating utis was assessed in a phase ii comparative study, which ended in 2012 (81). microbiological eradication in the plazomicin group (15 mg/kg) was achieved in 93.1% of the patients whose baseline urinary pathogens had a plazomicin mic of 4 mg/l. microbiological eradication in the group receiving levofloxacin (750 mg) was achieved in 93.8% (15/16) of patients with levofloxacin-susceptible baseline urinary pathogens (mic = 4 mg/l). the epic and care phase iii trials, investigating the safety and efficacy of plazomicin in patients with complicated utis and other infections caused by gram-negative pathogens including creb, have been concluded but not yet published in the form of journal articles. fosfomycin only case reports are available showing the efficacy of fosfomycin -administered in monotherapy for uncomplicated utis or combined with colistin against urosepsisin infections caused by enterobacteriaceae expressing kpc, oxa-48 and ndm carbapenemases (82, 83). case reports include accounts of successful combination therapy including dual carbapenem plus oral fosfomycin in utis caused by ndm-expressing enterobacteriaceae (57). such approach is preferable, as the rapid development of resistance during therapy is a major problem related to the usage of fosfomycin as single agent (84). intravenous formulations of fosfomycin allow administration of high doses of the drug (e.g., 4g q6h), if necessary (85). a small prospective case series including eleven critically ill icu patients affected by cpkp bacteremia, uti or pneumonia, was based on administration of intravenous fosfomycin (2-4g q6h) for about 14 days, combined with colistin (n = 6), gentamicin (n = 3) or piperacillin/tazobactam (n = 1), based on ascertained susceptibility. all-cause hospital mortality was 18.2%, and no infection relapse was observed in enrolled patients. intravenous therapy with high-dose fosfomycin appeared to be well tolerated, without renal or liver function test abnormalities (86). further large-scale studies are warranted to confirm these encouraging safety and efficacy results. oritavancin oritavancin is a semi-synthetic lipoglycopeptide, characterized by a threefold mechanism of action: (i) inhibition of the transglycosylation pathway in the bacterial wall synthesis, (ii) inhibition of the transpeptidation step by binding to the peptide bridging cell wall segments and (iii) cell wall disruption. a recent in vitro subset study in the frame of a prevalence analysis performed on over 140.000 bloodstream isolates of enterococci from europe and the usa demonstrated that oritavancin was active against vancomycin-resistant e. faecalis (mic50/90, 0.25-0.5 mg/l), and showed mic50, mic90 and mic100 values of 0.03, 0.12 and 0.25 mg/l against vana-positive e. faecium, respectively (87). oritavancin is renally and fecally excreted as unmodified molecule and may represent an interesting agent for treating complicated utis, though such approach would be off-label, as this drug is approved for the moment only for gram-positive skin and skin structure infections. fluoroquinolones chen et al. have examined in detail how the pharmacokinetic-pharmacodynamic properties of fluoroquinolones could be exploited to design treatment strategies in areas with high rates of fluoroquinolone resistance (43). levofloxacin appears to be a better option compared to ciprofloxacin, since the excretion of the former is by 87% renal (ciprofloxacin: 50%), and since efflux pumps like acrab, mdfa and nore are more active on the latter (88). thus, as the bactericidal activity of these agents is concentration-dependent, the achievement of high peak urine concentrations as a result of high-dose treatment with levofloxacin may be the key for eradicating pathogens showing intermediate fq resistance levels. for example, a single 750 mg dose of levofloxacin achieves a mean urinary cmax of 620 mg/l, with prolonged post-antibiotic effect, compared to 340 mg/l attained by a standard 500 mg dose (89). chen et al. also suggested that in areas with resistance uropathogen rates > 20%, high-dose levofloxacin might be considered as an option for utis caused by e. coli isolates showing a mic ≤ 32 mg/l, after taking into consideration the potential adverse effects of such therapy (43). the aac (6')-i gene product (aac) confers to enterobacteriaceae resistance to aminoglycoside antibiotics through acetylation of specific -nh2 residues at the level of specific amino sugars. a mutated variant of aac (aac (6')-ib-cr) confers resistance to certain fluoroquinolones via acetylation of the (= nh) residue within the piperazine ring of drugs like ciprofloxacin or norfloxacin. this decreases by 4-fold the susceptibility of pathogens to such drugs (90) and increases by 16 times the fluoroquinolone mutant prevention concentration in e. coli (0.2 –> 3.2 mg/l), thus facilitating the survival of target site mutants (91). interestingly, fqs like levofloxacin have a methylated piperazine residue which is virtually protected from the action of aac. thus, if resistance rates caused by the aac are present or suspected, levofloxacin, or other "protected" fqs like prulifloxacin or pefloxacin may be temptatively administered. glycylcyclines together with colistin, tigecycline is often the only agent to which cpkp is residually susceptible. however, the use of this agent for treatment of urological infections is significantly associated with subsequent development of resistance, as shown by van duin and coworkers (or, 6.13; 95% ci, 1.15-48.65) (92). conclusions in conclusion, in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. all medical specialties will be affected by such spread, including foremostly urology. perletti_stesura seveso 28/06/18 16:33 pagina 92 as far as urinary tract diseases are concerned, we believe that the old definition of complicated vs uncomplicated infections should be modified, as any uti involving carbapenemase-expressing uropathogens, or mdr/xdr uropathogens, should be considered and managed as complicated conditions. urgent containment measures must be put into effect, with priority given to those areas of the world characterized by climatic conditions favoring the seasonal outburst of infection epidemics, but also by negligent clinical practice, unprofessional pharmaceutical dispensing, as well as by poor patient compliance and education. rigorous antibiotic stewardship and restriction of novel and old last resort agents to the sole hospital setting will also contribute to the containment of “superbug” epidemics. regretfully, major pharmaceutical companies have abandoned research for novel antibacterial agents due to the little financial reward ensured by drugs which can cure diseases in a very short time and at the same time may become rapidly obsolete due to the emerging of pathogen resistance. nevertheless, public or private research mainly aimed at discovering new therapies against gram-negative organisms is of vital importance. only the future will tell us who will prevail in the struggle for survival between humans and bacteria, and ultimately in the war between the immense resources of human ingenuity and the 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"double carbapenem" and oral fosfomycin for the treatment of complicated urinary tract infections caused by bla(ndm) -harboring enterobacteriaceae in kidney transplantation. transpl infect dis. 2018; 20. 59. morrill hj, pogue jm, kaye ks, et al. treatment options for carbapenem-resistant enterobacteriaceae infections. open forum infect dis. 2015; 2:ofv050. 60. lahiri sd, johnstone mr, ross pl, et al. avibactam and class c β-lactamases: mechanism of inhibition, conservation of the binding pocket, and implications for resistance. antimicrob agents chemother. 2014; 58:5704-13. 61. de jonge bl, karlowsky ja, kazmierczak km, et al. in vitro susceptibility to ceftazidime-avibactam of carbapenemnonsusceptible enterobacteriaceae isolates collected during the inform global surveillance study (2012 to 2014). antimicrob agents chemother. 2016; 60:3163-9. 62. karaiskos i, giamarellou h. multidrug-resistant and extensively drug-resistant gram-negative pathogens: current and emerging therapeutic approaches. expert opin pharmacother. 2014; 15:1351-70. 63. stone gg, bradford pa, newell p, et al. in vitro activity of ceftazidime-avibactam against isolates in a phase 3 open-label clinical trial for complicated intra-abdominal and urinary tract infections caused by ceftazidime-nonsusceptible gram-negative pathogens. antimicrob agents chemother. 2017; 61. 64. jayol a, nordmann p, poirel l, et al. ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing klebsiella pneumoniae. j antimicrob chemother. 2018; 73:542-544. 65. wagenlehner fm, sobel jd, newell p, et al. ceftazidimeavibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: recapture, a phase 3 randomized trial program. clin infect dis. 2016; 63:754-762. 66. carmeli y, armstrong j, laud pj, et al. ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant enterobacteriaceae and pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (reprise): a randomised, pathogen-directed, phase 3 study. lancet infect dis. 2016; 16:661-673. 67. lob sh, hackel ma, kazmierczak km, et al. in vitro activity of imipenem-relebactam against gram-negative eskape pathogens isolated by clinical laboratories in the united states in 2015 (results from the smart global surveillance program). antimicrob agents chemother. 2017; 61. 68. lapuebla a, abdallah m, olafisoye o, et al. activity of imipenem with relebactam against gram-negative pathogens from newyork city. antimicrob agents chemother. 2015; 59:5029-31. 69. sims m, mariyanovski v, mcleroth p, et al. prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. j antimicrob chemother. 2017; 72:2616-2626. 70. zhanel gg, lawrence ck, adam h, et al. imipenemrelebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. drugs. 2018; 78:65-98. 71. castanheira m, huband md, mendes re, et al. meropenemvaborbactam tested against contemporary gram-negative isolates collected worldwide during 2014, including carbapenemresistant, kpc-producing, multidrug-resistant, and extensively drug-resistant enterobacteriaceae. antimicrob agents chemother. 2017; 61. 72. walsh tj, bhowmick t, darouiche r, et al. meropenemvaborbactam vs. piperacillin-tazobactam in tango i (a phase 3 randomized, double-blind trial): outcomes by baseline mic in adults with complicated urinary tract infections or acute pyelonephritis. open forum inf dis. 2017; 4:suppl-1:s536. 73. http://www.themedicinescompany.com/investors/news/medicines-company-announces-tango-2-trial-meropenem-vaborbactamformerly-carbavance. 74. tängdén t, giske cg. global dissemination of extensively drugresistant carbapenemase-producing enterobacteriaceae: clinical perspectives on detection, treatment and infection control. j intern med. 2015; 277:501-12. 75. tascini c, tagliaferri e, giani t, et al. synergistic activity of colistin plus rifampin against colistin-resistant kpc-producing klebsiella pneumoniae. antimicrob agents chemother. 2013; 57:3990-3. 76. luque s, escaño c, sorli l, et al. urinary concentrations of colistimethate and formed colistin after intravenous administration in patients with multidrug-resistant gramnegative bacterial infections. antimicrob agents chemother. 2017; 61. 77. zhanel gg, lawson cd, zelenitsky s, et al. comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. expert rev anti infect ther. 2012; 10:459-73. 78. livermore dm, mushtaq s, warner m, et al. activity of aminoglycosides, including achn-490, against carbapenemresistant enterobacteriaceae isolates. j antimicrob chemother. 2011; 66:48-53. 79. galani i, souli m, daikos gl, et al. activity of plazomicin (achn-490) against mdr clinical isolates of klebsiella pneumoniae, escherichia coli, and enterobacter spp. from athens, greece. j chemother. 2012; 24:191-4. 80. rodríguez-avial i, pena i, picazo jj, et al. in vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing enterobacteriaceae strains. int j antimicrob agents. 2015; 46:616-21. 81. connolly le, riddle v, cebrik d, et al. a multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. antimicrob agents chemother. 2018; 62. 82. peirano g, ahmed-bentley j, woodford n, et al. new delhi metallo-beta-lactamase from traveler returning to canada. emerg infect dis. 2011; 17:242-4. 83. navarro-san francisco c, mora-rillo m, romero-gómez mp, et al. bacteraemia due to oxa-48-carbapenemase-producing enterobacteriaceae: a major clinical challenge. clin microbiol infect. 2013; 19:e72-9. 84. karageorgopoulos de, miriagou v, tzouvelekis ls, et al. emergence of resistance to fosfomycin used as adjunct therapy in kpc klebsiella pneumoniae bacteraemia: report of three cases. j antimicrob chemother. 2012; 67:2777-9. 85. perez f, el chakhtoura ng, papp-wallace km, et al. treatment options for infections caused by carbapenem-resistant enterobacteriaceae: can we apply "precision medicine" to 95archivio italiano di urologia e andrologia 2018; 90, 2 uropathogen resistance threats, trends and treatments perletti_stesura seveso 28/06/18 16:33 pagina 95 archivio italiano di urologia e andrologia 2018; 90, 2 g. perletti, v. magri, t. cai, k. stamatiou, a. trinchieri, e. montanari 96 antimicrobial chemotherapy? expert opin pharmacother. 2016; 17:761-81. 86. michalopoulos a, virtzili s, rafailidis p, et al. intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant klebsiella pneumoniae in critically ill patients: a prospective evaluation. clin microbiol infect. 2010; 16:184-6. 87. mendes re, castanheira m, farrell dj, et al. longitudinal (2001-14) analysis of enterococci and vre causing invasive infections in european and us hospitals, including a contemporary (2010-13) analysis of oritavancin in vitro potency. j antimicrob chemother. 2016; 71:3453-3458. 88. yang s, clayton sr, zechiedrich el. relative contributions of the acrab, mdfa and nore efflux pumps to quinolone resistance in escherichia coli. j antimicrob chemother. 2003; 51:545-556. 89. stein ge, schooley sl, nicolau dp. urinary bactericidal activity of single doses (250, 500, 750 and 1000 mg) of levofloxacin against fluoroquinolone-resistant strains of escherichia coli. int j antimicrob agents. 2008; 32:320-5. 90. robicsek a, strahilevitz j, jacoby ga, et al. fluoroquinolonemodifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. nat med. 2006;12:83-8. 91. cattoir, v; nordmann, p. plasmid-mediated quinolone resistance in gram-negative bacterial species: an update. curr med chem. 2009; 16:1028-1046. 92. van duin d, cober ed, richter ss, et al. tigecycline therapy for carbapenem-resistant klebsiella pneumoniae (crkp) bacteriuria leads to tigecycline resistance. clin microbiol infect. 2014; 20:o1117-20. 93. kim s, thiessen pa, bolton ee, et al. pubchem substance and compound databases. nucleic acids res. 2016; 44:d1202-13. correspondence gianpaolo perletti, phd (corresponding author) gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, università degli studi dell’insubria via a. da giussano, 12 21052 busto a., italy vittorio magri, md urology secondary care clinic, asst-nord, milan, italy tommaso cai, md department of urology, santa chiara regional hospital, trento, italy konstantinos stamatiou, md department of urology, tzaneio general hospital of piraeus, piraeus, greece alberto trinchieri, md urology unit, a. manzoni hospital, lecco, italy emanuele montanari, md department of urology, university of milan-ca' granda foundation ospedale maggiore policlinico, milan, italy perletti_stesura seveso 28/06/18 16:33 pagina 96 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4390 case report no conflict of interest declared. doi: 10.4081/aiua.2020.4.390 primitive small cell carcinoma of the prostate. case report and revision of the literature pietro pepe 1, ludovica pepe 1, mara curdman 2, michele pennisi 1, filippo fraggetta 2 1 urology unit cannizzaro hospital, catania, italy; 2 pathology unit cannizzaro hospital, catania, italy. inguinal hernia repair. the patient had not familiarity for prostate cancer (pca) and assumed antihypertensive and alfa-blocker drugs. at admission, the patient referred chronic fatigue and was anuric from two days, serum creatinine and psa values were equal to 9.6 mg/dl and 4.8 ng/ml, respectively; moreover, digital rectal examination was highly suspicious for pca. in emergency, the patient underwent bilateral application of percutaneous renal nephrostomies to restore kidney function. after three day the patient was submitted to ultrasound-guided extended transperineal biopsy (6); the histology showed the presence of a prostatic scc fulfilling the world health organization criteria that involved all the 12 needle cores (figure 1). the immunohistochemical analysis was positive for chromogranin, synaptophysin and focally for thyroid transcriptation factor 1 (ttf-1); ki67 expression was equal to 85% (figure 2), conversely, ck7 and p63 were negative (7). the patient underwent clinical staging including chest and abdominal computed tomography (ct); evaluation and total body scan those did not demonstrated distant metastases and/or others primitive tumors; in addition, cystoscopy and urinary cytology were negative. the patient underwent multidisciplinary evaluation, but he died 20 days from the diagnosis for progressive clinical worsening (physical and cognitive impairments) before beginning oncological treatment. autopsy was not performed. discussion primitive scc of the prostate is a rare entity and has a presentation that is distinct from its adenocarcinoma counterparts (8); unique features include an unresponsiveness to hormonal therapy, rapid progression, increased risk of lytic bone lesions, presence of visceral metastases, and low psa in relation to disease burden. on the other hand, the majority of prostate scc are diagnosed in men with castration-resistant prostate cancer (crpc) and are often characterized by the presence of neuroendocrine (ne) cancer differentiation. the median time to development of scc in patients with a history of prostatic adenocarcinoma is approximately 18-24 months from diagnosis, but ranges widely from few months to several years. primitive prostate scc was first described by wenk et al. (3) and, recently, zhang et al. (4) reported 8 cases of pure scc; autopsy studies of men who have died from crpc a caucasian man 84 years old was admitted to our department for acute renal failure secondary to severe bilateral hydronephrosis; moreover, the patient referred chronic fatigue and was anuric from two days. serum creatinine and psa values were equal to 9.6 mg/dl and 4.8 ng/ml and digital rectal examination was highly suspicious for prostate cancer. in emergency, the patient underwent bilateral application of percutaneous renal nephrostomies to restore kidney function and, after three days, was submitted to ultrasound-guided extended transperineal biopsy; the histology showed the presence of a prostatic small cell carcinoma (scc) fulfilling the world health organization criteria. the patient underwent clinical staging including chest and abdominal computed tomography evaluation and total body scan that did not demonstrated distant metastases and/or others primitive tumors; in addition, cystoscopy and urinary cytology were negative. the patient underwent multidisciplinary evaluation, but he died 20 days from the diagnosis for progressive clinical worsening (physical and cognitive impairments) before beginning oncological treatment. in conclusion, primitive scc represents a very rare cancer provided of poor prognosis; only the execution of prostate biopsy combined with an accurate specimen analysis allow to make the correct diagnosis and therapeutic treatment. key words: prostate cancer; small cell cancer; prostate small cell cancer; neuroendocrine small cell prostate cancer. submitted 17 july 2020; accepted 30 september 2020 introduction primitive small cell carcinoma (scc) of the prostate is a very rare (0.5% of the cases) and aggressive type of prostatic cancer and often is diagnosed at advanced stage due to early metastasis (1-5); most frequently, scc is associated to progressive hormone-refractory prostate cancer. the biology of scc is poorly understood but it is always implicated in the lethal progression secondary to visceral metastases and lytic bones lesions. in this study, a case of primitive prostate scc has been reported. case report a caucasian 84 years old man was admitted to our department for acute renal failure secondary to severe bilateral hydronephrosis; the patient suffered from blood hypertension and was previously submitted to right summary 391archivio italiano di urologia e andrologia 2020; 92, 4 primitive small cell carcinoma of the prostate have reported the presence of scc in up 10-20% of cases. the histological diagnosis of scc is reached based on the presence of morphological features similar to those found in scc of the lung; using immunohistochemical techniques, the small-cell component could be positive for one or more neuroendocrine markers (i.e., neuron-specific enolase, synapthosiphysin, chromogranin, and cd56) in almost 90% of the cases. studies have demonstrated thyroid transcriptation factor 1 (tyf-1) expression in over 50% of sccs of the prostate, 85-90% loss rate of tumor suppressor retinoblastoma protein (rb1), and 50-60% mutation rate of tp53, limiting its utility in distinguishing primary prostate scc from metastases of other small cell cancers. therefore, in the absence of a primary scc at another site (for example, the lung), the finding of scc on prostate biopsy is almost undoubtedly an indication of prostatic origin. in the last years, gene expression in metastatic crpc neuroendocrine scc prostate has been tested confirming similar molecular profile with small cell lung carcinoma (8). in addition, molecular studies have reported an increased expression of gene involved in cellular proliferation, cell cycle, neuroendocrine differentiation and mitosis. metzger et al. (5) reported on 657 men with neuroendocrine scc an overall survival of 12 months. wang et al. (9) on 260 patients selected from surveillance, epidemiology, and end results (seer) database showed an increased incidence of prostate scc over time that was characterized by presence of high stage (stage iv in 77.7%), nodes involvement (49%) and distant metastases (68%) with psa values greater than 10 ng/ml only in 23% of the cases; although patients underwent chemotherapy (58.8%), surgery (25.4%) and, radiotherapy (31.9%) the observed survival rates of 1-year, 2-year, and 5-year were 42.1%, 22.1%, and 12.5%, respectively. although the poor prognosis, it is important to make distinction between primitive prostate scc and ne-crpc because therapeutic strategy changes and should be managed similarly to other non-prostatic scc. rarely prostatectomy or radiotherapy alone have been shown to be curative because the tumor, in the majority of the cases, is metastatic (5), moreover, prostate scc is usually not responsive to androgen deprivation and disease progression is not associated with rises in serum psa values. in definitive, the best treatment remains the multidisciplinary approach by chemotherapy alone or combined with local therapy that could offer local palliation of clinical symptoms (5, 10). in our case, the patient had a primitive prostate scc characterized as locally advanced cancer involving bladder and kidney function in absence of documented distant metastases; therefore, we don’t know if the patient died from prostate scc or from concomitant onset systemic pathologies. in conclusion, although prostate scc could be suspected in men with crpc with clinical progression, primitive scc represents a very rare cancer provided of poor prognosis and only prostate biopsy combined with an accurate specimen analysis allow to make the correct diagnosis and therapeutic treatment. references 1. terada t. small cell neuroendocrine carcinoma of the prostate: incidence and a report of four cases with an examination of kit and pdgfra. prostate. 2012; 72:1150-1156. 2. wang w, epstein ji. small cell carcinoma of the prostate. a morphologic and immunohistocemical study of 95 cases. am j surg pathol. 2008; 32:65-71. 3. wenk re, bhagavan bs, levy r, et al. ectopic acth, prostatic oat cell carcinoma, and marked hypernatremia. cancer. 1977; 40:773-778. 4. zhang y, ouyang w, sun g, et al. pure small cell carcinoma of prostate: a report of 8 cases. urol int. 2018; 101:263-268. 5. metzger al, abel s, wegner re, et al. patterns of care and outcomes in small cell carcinoma of the prostate: a national cancer database analysis. prostate 2019; 79:1457-1461. 6. pepe p, garufi a, priolo gd, et al. is it time to perform only magnetic resonance imaging targeted cores? our experience with 1,032 men who underwent prostate biopsy. j urol. 2018; 200:774-778. 7. pepe p, fraggetta f, candiano g, aragona f. does ki-67 staining improve quantitative histology in preoperative prostate cancer staging? arch ital urol androl. 2012; 84:32-35. 8. salemi m, galia a, fraggetta f, et al. poly (adp-ribose) polymerase 1 protein expression in normal and neoplastic prostatic tissue. eur j histochem. 2013; 57:e13. 9. wang j, liu x, wang y, ren g. current trend of worsening prognosis of prostate small cell carcinoma: a population-based study. cancer med. 2019; 8: 6799-6806. 10. papandreou cn, daliani dd, thall pf, et al. results of a phase ii study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. j clin oncol. 2002; 20:3072-3080. figure 1. tumour was composed of undifferentiated cells with scant cytoplasm, infiltrating fatty tissue. figure 2. neoplastic cells showed a high proliferative fraction as highlighted by ki67. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com michele pennisi, md ludovica pepe urology unit cannizzaro hospital, catania via messina 829, catania (italy) mara curdman, md filippo fraggetta, md pathology unit cannizzaro hospital, catania (italy) stesura seveso 121archivio italiano di urologia e andrologia 2020; 92, 2 original paper the impact of nutrition and lifestyle on male fertility mahmoud benatta 1, 2, redha kettache 1, 3, noor buchholz 1, alberto trinchieri 1 1 u-merge ltd. (urology for emerging countries), london, uk. 2 department of urology, djilali lyabes university hospital, sidi bel abbes, algeria; 3 department of urology, eph bachir bennacer, biskra, algeria. background and aims: male unexplained infertility has long been suspected to result from environmental, lifestyle and nutritional factors. however, the literature on the subject is still scarce, and clinical studies providing robust evidence are even scarcer. in addition, some similar studies come to different conclusions. dietary pattern can influence spermatogenesis by its content of fatty acids and antioxidants. yet, in an age of industrialized mass food production, human bodies become more exposed to the ingestion of xenobiotics, as well as chemicals used for production, preservation, transportation and taste enhancement of foods. we attempted in this paper to collect the available evidence to date on the effect of nutritional components on male fertility. material and methods: a systematic search of the relevant literature published in pubmed, sciencedirect and cochrane central register of controlled trials database was conducted. literature was evaluated according to the newcastle-ottawascale. results: epidemiological observations are concordant in demonstrating an association of low-quality sperm parameters with higher intake of red meat, processed and organ meat and fullfat dairy. on the contrary, better semen parameters were observed in subjects consuming a healthy diet, rich in fruit, vegetables, whole grains and fish. evidences of the negative impact on male fertility of by-products of water disinfection, accumulation in food chain of persistent organochlorine pollutants, pesticides, phthalates from food and water containers and hormones used in breeding cattle have been reported. clinical trials of the effects of micronutrients on semen parameters and outcomes of assisted fertilization are encouraging, although optimal modality of treatment should be established. conclusions: although quality of evidence should be ameliorated, it emerges that environmental factors can influence male fertility. some nutrients may enhance fertility whereas others will worsen it. with diagnostic analysis on a molecular or even sub-molecular level, new interactions with micronutrients or molecular components of our daily ingested foods and leisure drugs may lead to a better understanding of so far suspected but as yet unexplained effects on male spermatogenesis and fertility. key words: male fertility; nutrients; micronutrients; dietary supplements; lifestyle; xenobiotics. submitted 13 april 2020; accepted 20 april 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.121 introduction male infertility is attracting increasing interest due to its worldwide prevalence and the evidence of decline in semen quality of young health men (1). prevalence of reported male infertility ranges from 2.5% to 12% with highest rates in africa and central/eastern europe (2). rates of male infertility in north america, australia, and central and eastern europe varied from 4.5-6%, 9%, and 8-12%, respectively. male infertility is defined as the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse as reported by couples or female partners of a couple. seminal quality is a prognostic factor of fertility which can be considered a proxy of male infertility although fecundity also depends from other couple-based covariates (3). along the last 50 years a progressive decrease of the quality of the seminal parameters has been observed. a recent systematic review of 185 studies involving more than 40.000 men who provided semen analysis in the period 1973-2011 demonstrated a significant decline between 1973 and 2011 (4). this trend may arise from genetic, developmental and lifestyle factors. particularly, involvement of nutritional factors has been highlighted by many studies. cross-sectional population studies or case-control studies using food questionnaires evaluated the association of dietary patterns or quality of foods with seminal parameters (count, concentration, motility, morphology, dna fragmentation) or with testis volume or sex hormone levels. in addition, some studies from fertility clinics considered more robust outcomes such as implantation rate, rate of clinical pregnancy and of live birth. most of studies focused on the content of saturated fats that could have a negative impact on fertility or on the content of antioxidants and folates that could improve fertility. molecular pathways of the effects of these nutrients in male fertility have been studied but they are not yet fully explained (figure 1) (5-7). saturated fats are prevalent in animal-derived foods as red meat, processed meat and full-fat dairy product while fats from vegetable foods and fishes are polyunsaturated. sperm cell are characterized by a high content of polyunsaturated fatty acids, as docosahexaenoic acid (dha). concentrations of dha with respect to saturated or trans fatty acids influence the melting point of plasmatic membrane, regulate the expression of peroxisome proliferatoractivated receptor gamma (pparg), anti-apoptosis and hormone activity. particularly, omega-3 pufas in fish are precursors of eicosanoids, which contribute to sperm archivio italiano di urologia e andrologia 2020; 92, 2 m. benatta, r. kettache, n. buchholz, a.trinchieri 122 structure) and have a positive impact on testicular function. on the contrary, trans saturated fats interfere with the incorporation of long-chain polyunsaturated fatty acids into sperm membranes during epididymal maturation, and have a negative impact on testicular function, with reduction in total and free testosterone. antioxidants molecules, that are abundant in fruits and vegetables, have a positive effect on male fertility and in general on health conditions, by contrasting the activity of reactive oxygen species (ros). ros (reactive oxygen species) show a biphasic effect on sperm cell function, because at physiological concentrations ros from mitochondria have an important role in capacitation by activation of different intracellular mechanisms (high levels of camp, activating the pka pathway, and leading to tyrosine phosphorylation). on the contrary, oxidative stress from excess ros production causes peroxidation of lipids in the plasmatic membrane together with a damage of spermatic dna. ros have a negative effect on sperm motility by damaging plasmatic membrane and mitochondrial function. folates are involved in dna synthesis and in methylation processes connected with protein synthesis. folate deficiency causes instability and fragility of dna by reducing availability of methylic groups that are a protection factor of dna. other micronutrients are involved in the development of male infertility, as divalent cations such selenium, zinc or manganese that have a role in oxidative stress being incorporated in enzymes such as glutathione peroxidase or superoxide dismutase (8). optimal levels are requested for spermiogenesis, whereas both deficiency and excess intake are associated with alterations of seminal parameters and serum testosterone levels. in addition to the effects of nutrients, food intake can be associated to exposure to food-contaminating toxic substances or hormones that can have a relevant impact on male fertility. in an age of progressive industrialization, and moreover industrial mass food production using herbicides, pesticides, antibiotics, hormones, and chemicals to preserve and enhance the taste of heavily processed foods, these components can be absorbed into the human body. evaluation of the effects of toxic contamination of foods is difficult by using dietary questionnaires whereas more reliable results can be obtained by using biological markers to evaluate exposure to toxic substances. the effects of the intake of some foods on seminal parameters can be biased by the concomitant effect of contamination. by example, it is difficult to differentiate the impact of consumption of vegetables from that of pesticides that are used in agriculture or the effect of red meat from that of residual hormones that could have been used in breeding or that of fish consumption by the risk of contamination from sea water pollution. finally, other information can be derived from the evaluation of the effect of the administration of dietary supplements to ameliorate seminal parameters of subfertile men attending fertility centres. in this paper, we tried to review and summarize the available evidence on the topic. our results are subdivided in two chapters describing review of epidemiological observations and clinical studies respectively. methods a systematic search of the relevant literature published in pubmed, sciencedirect and cochrane central register of controlled trials database was conducted. we reviewed separately epidemiological observations as reported in the literature and clinical trials with various nutritional components and their influence on male fertility. for this reason, two separate searches (up to december 2018) were done using a combination of terms as both, medical subject headings (mesh) and keywords. in the first search, male fertility-related keywords (“male fertility” or “male infertility” or “semen quality” or “oligoasthenozoospermia” or “sperm dna fragmentation” or “sperm dna damage” or “sperm aneuploidy” or “y chromosome”) were used in combination with key words relating to food or nutrient (“food” or “diet” or “nutrition” or “meat” or “fish” or “sugar” or “vegetables” or “fruits” or “dairy” or “genetically modified food” or “alcohol” or “pesticides” figure 1. molecular pathways of the effects of fatty acids and antioxidants in sperm cell (negative effect in red, positive in green). figure 2. systematic literature search 1. figure 3. systematic literature search 2. or “hormone food contaminated” or “tobacco” or “cannabis”) and combined with ‘questionnaire’ (limit: human, english). reviews, clinical trials and case reports were excluded (figure 2). in the second search the same male fertility-related keywords were used in combination with key words relating to vitamin or micronutrient or herbal treatments (“selenium” or “vitamin e” or “coenzyme q10” or “zinc” or “lcarnitine” or “folic acid” or “l arginine” or “herbal”). (limit: human, english). only clinical trials were included (figure 3). the first search screened 103 studies, that were reduced to 38 after evaluation by title and abstract; 29 studies were retrieved by references of the selected studies; a total of 67 studies was assessed and 50 were included in the review. in the second search, the number of study screened, selected by title/abstract, retrieved by references, assessed and included were 79, 43, 14, 57 and 19 respectively. information extracted from each study was charted including: first author's last name; year of publication; number of subjects; food or nutrients or dietary pattern studied. literature was evaluated using the newcastleottawa-scale and evaluation forms. a narrative review of the data from the included studies was done. results epidemiological observations nutrition and lifestyle are considered by several authors as main factors in reproduction and fertility (9-11). recent studies indicate that male obesity (12), as well as lifestyle factors as smoking and alcohol intake affect negatively the sperm quality (13). diet plays a key role in the improvement of sperm parameters, particularly the mediterranean diet which is rich in omega 3 fatty acids, antioxidants and vitamins (vitamin e, vitamin c, beta-carotene, lycopene, cryptoxanthin, lutein) that all are associated with better semen 123archivio italiano di urologia e andrologia 2020; 92, 2 male fertility and nutrition table 1. vitamin, mineral and antioxidant intake and sperm quality. archivio italiano di urologia e andrologia 2020; 92, 2 m. benatta, r. kettache, n. buchholz, a.trinchieri 124 quality parameters (table 1) (14-18). a better compliance with mediterranean diet was found to be associated with better semen quality parameters (sperm concentration, count, and motility) (19). similarly, in non-mediterranean countries, the so called “prudent” or “health conscious” diets, involving high intakes of fruits, vegetables, legumes, fish and whole grains, were related to better sperm quality than “western” diet that is rich in red and processed meat, refined grains, high-energy drinks and sweets (table 2) (20-24). higher intakes of seafood, poultry, whole grains, fruits and vegetables have been consistently associated with better semen parameters in a wide range of studies in north america, europe, the middle east and east asia. (table 3) (10, 19-27). a recent review concluded that diets rich in red and processed meats, potatoes, sweets and sweetened beverages were associated with decreased quality of semen parameters whereas higher intakes of fruits and vegetables, whole grains, seafood and poultry had the opposite effect (34). soy foods have been inversely associated with the quality of semen in some studies (35) although soy food intake in men was not related to outcomes of in vitro fertilization in couples undergoing infertility treatment (36). the intake of trans and saturated fats has been related to poor semen quality. trans-saturated fat intake has also been related to other markers of poor testicular function, such as lower testosterone and lower testicular volume (37-40) (table 4). on the contrary, omega-3 polyunsaturated fats were associated with better seminal parameters and testicular volume (37, 40). table 2. dietary patterns and sperm quality. 125archivio italiano di urologia e andrologia 2020; 92, 2 male fertility and nutrition critical appraisal of this evidence highlights some possible limitations. in most cross-sectional studies populations were numerically limited and not always representative of the general population. many studies were performed on volunteers recruited among university students aged 18 to 23 years, whereas other studies considered men from couples who attended fertility clinics. translation of these results to the general population might be questionable. only a few studies have been carried out in numerically consistent populations representing the general population (23, 38). similarly, case-control studies were performed by comparing the dietary intakes of men from couples attending fertility clinics with and without alterations of seminal parameters. alcohol and caffeine alcohol induces testicular atrophy and alterations of leydig and sertoli cells and decrease luteinizing hormone (lh) and follicle-stimulating hormone (fsh) levels (41). daily consumption of alcohol affects sperm quality and decreases ejaculate volume, sperm counts, and sperm motility. comparing the sperms of 66 "alcoholic" men to table 3. foods and sperm quality. archivio italiano di urologia e andrologia 2020; 92, 2 m. benatta, r. kettache, n. buchholz, a.trinchieri 126 those of 30 "non-alcoholic" men, there was a significant decrease in sperm count, progressive mobility, and vitality (42). chronic high consumption of alcohol (more than 60 g per day or 6 glasses of wine) can lead to azoospermia (43). there is a significant inverse relationship between alcohol consumption and sperm concentration, sperm count and percentage of typical spermatozoids. stopping consumption would restore normal spermatogenesis and azoospermia secondary to alcohol (44). a meta-analysis confirmed that alcohol has a detrimental effect on semen parameters although spermatogenesis seemed to be not affected by a moderate consumption (45). another meta-analysis of the effects of alcohol on in vitro fertilization (ivf) showed that live birth rates are significantly reduced when humans consume alcohol even in lower doses in the month or even the week before attempted fertilization. excessive consumption of alcohol must be avoided in humans during the attempted medical assisted fertilization, but a moderate consumption (one or two glasses of wine per day) might also have an opposite effect on the spermatic characteristics and the results of the medical assisted procreation attempt (46). a systematic review of the effects of coffee and caffeine intake on semen parameters found inconsistent evidences and conflicting results, although some studies showed a possible association with sperm dna damage (47). food and water contamination most of the literature on the effect of water and food contaminants on male infertility is derived from experimental table 4. dietary fats and semen quality. table 5. water and food contaminants and male infertility. 127archivio italiano di urologia e andrologia 2020; 92, 2 male fertility and nutrition animal studies or studies of acute occupational exposure. evidence of the effects in the general population of chronic low-dose exposures is limited because of the complexity of the design of the studies. levels of biological markers of exposure have been correlated with seminal and hormone parameters in general population. available data has been reviewed by gabrielsen and tanrikut (8). in table 5 we summarized evidences about water and food contaminants that could affect male fertility. food contaminants often induce endocrine disorders, as in the case of commonly used glyphosate-based herbicides that act as a disruptor of mammalian cytochrome p450 aromatase activity from concentrations 100 times lower than the recommended use in agriculture and can also affect aromatase gene expression (48). endocrine disorders can also be induced by the presence of residual hormones in red meat and processed meat. in some countries anabolic sex steroids are administered to cattle for growth promotion resulting hormone residues in beef. although the possible biological significance of very low levels of estradiol is neglected, residual hormones are one possible explanation of lower semen quality parameters observed in consumers of processed or red meat (49). on the other hand, maternal beef consumption, and possibly xenobiotics in beef may alter testicular development in utero and adversely affect offspring reproductive capacity (50). despite a lack of human studies, a link between infertility and genetically modified foods (gmf) has been postulated although gmf-related infertility seems to affect women more than men (51). tobacco smokers have an unusually high concentration of heavy metals in the seminal fluid, such lead and cadmium that are negatively correlated with sperm concentration, mobility and morphology (52). on the other hand, high levels of trans-3’-hydroxycotinine (3hc), a metabolite of nicotine, in seminal fluid are correlated with a decreased sperm mobility (53). the seminal plasma analysis of smokers shows a significantly higher proportion of inflammatory proteins. in fact, smoking seems associated with an inflammatory state of the accessory glands, which would eventually cause an alteration of the functional quality of spermatozoids, a decrease of acrosome integrity and mitochondrial activity, and an increased dna fragmentation (54). sperm concentration, total motility, and the number of typical spermatozoids is reduced in smokers (55). tobacco also affects the intrinsic quality of spermatozoids. the analysis of the degree of fragmentation of sperm dna showed a significantly higher fragmentation of dna in smokers than in non-smokers (32% against 25.9%) (56). in an in-vitro fertilization trial, smoking among men was significantly and positively correlated with an increased risk of early spontaneous abortion (or = 2.2) (57). paternal smoking can also influence the health of newborns by transmission of dna damaged by oxidative stress. alterations of the methylation of sperm dna in male smokers are compatible with alterations observed in their offspring (58). in addition, de-novo mutations in paternal spermatozoids induced by smoking can be transmitted (59). cannabis after consumption of cannabis, its metabolites are found in the seminal fluid, and spermatozoa are thus exposed during their passage through the epididymis (60). cannabis interferes with spermatogenesis by central and peripheral mechanisms. the stimulation of receptors coupled to g protein inhibits adenylate cyclase levels decreasing camp levels in testicular tissue, spermatozoa, and hypothalamus. cannabis blocks the hypothalamic release of gnrh and the anterior pituitary production of lh. furthermore, it reduces the release of testosterone from leydig cells via specific receptors (61). in a large sample of the general male population of denmark, there was a significant negative correlation between cannabis consumption and sperm concentration, count, and mobility. in case of regular exposure to cannabis (9 to 18 cannabis joints a week) a decrease in sperm concentration was observed with a significant negative correlation between the amount of cannabis consumed and the sperm count. chronic and intensive use of cannabis (more than 10 cannabis joints per week) was also associated with an alteration of leydig cell function resulting in a significant dose-dependent decrease in testosterone serum levels (62). in conclusion, cannabis use should be considered as a potential cause of alteration of spermatogenesis or a co-factor aggravating preexisting spermatogenesis disorders. obesity obesity is related to excessive intake of food and reduced physical activity. oligospermia is more frequent in obese men and in obesity an increase in dna fragmentation was also described (63). multiple interdependent mechanisms contribute to the negative effect of obesity on male fertility (64). obesity is associated to alterations of the hypothalamic-pituitary axis because of various endocrine mechanisms such as production of estrogens by aromatization of testicular and adrenal androgens in excess adipose tissue, leptin resistance at kisspeptin neurons, and excessive production of endogenous opioids, leading to hypogonadotropic hyper-estrogenic hypogonadism. a significant decrease in free and total testosterone levels and a significant increase in estrogen levels are resulting, both contributing to alteration of spermatogenesis. the decrease in serum testosterone concentration is significantly associated with insulin resistance and a lower volume of ejaculate (65). furthermore, obesity may directly alter spermatogenesis by its action on sertoli cells, as suggested by the more severe decrease in inhibin b levels compared with the decrease in fsh. finally, an increase in scrotal temperature caused by excessive testicular warming in the seated position may negatively affect spermatogenesis. clinical trials several interventional studies evaluated the effect of dietary supplementation on semen parameters of subfertile men or outcomes of assisted fertilization. oral supplements include coenzyme q10, l-carnitine, vitamins, zinc and other antioxidants. coenzyme q10 a significant improvement of spermatogenesis was eviarchivio italiano di urologia e andrologia 2020; 92, 2 m. benatta, r. kettache, n. buchholz, a.trinchieri 128 dent with coenzyme q10 therapy. mean sperm concentration, sperm progressive motility, and rate of sperm with normal morphology improved significantly after 12 month of coenzyme q10 therapy (66). a positive correlation was found between duration of q10 treatment duration and sperm count, motility and morphology (67). even the reduced form of coenzyme q10 (ubiquinol) was significantly effective in men with unexplained oligoasthenoteratozoospermia (68). l-carnitine l-carnitine (lc) together with acetyl-l-carnitine (lac) are commonly used because of their ability to improve sperm quality and pregnancy rate in males suffering from asthenoteratozoospermia (69). lc and lac improve the total oxyradical scavenging capacity of the seminal fluid (70) and prevent dna oxidation of human spermatozoa (71). treatment with lc increased the success rate of intracytoplasmic sperm injection (icsi) (72). in a doubleblind randomized controlled trial, a combination of lc and coenzyme q10 increased sperm motility and rate of progressively motile sperm more than lc or coenzyme q10 alone or than in the control group. the percentage of sperm dna fragments was markedly low and the rate of clinical pregnancy was remarkably higher in the combination group than in controls (73). vitamin e levels of vitamin e in seminal plasma are related to sperm motility (74). accordingly, lower levels of vitamin e were observed in the semen of infertile men (75). a prospective, multi-centered, randomized controlled study reported that vitamin e can improve sperm concentration, percentage of progressively motile sperm, and rate of natural pregnancies (76). zinc and folic acid the zinc concentration of seminal plasma is significantly higher in fertile men in comparison to subfertile men (77). in a study, supplementation with zinc sulphate and folic acid did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men (78), whilst in another double-blind, placebo-controlled interventional study the total normal sperm count increased after a combined zinc sulfate and folic acid treatment in both subfertile and fertile men (79). combination treatment a double-blind placebo-controlled study (80) using supplementation of l-carnitine, fumarate, acetyl-l-carnitine, fructose, coq10, vitamin c, zinc, folic acid and vitamin b12 reported an increase of sperm concentration, total motility and pregnancy rate in couples whose males had varicocele or not. no difference of semen volume and not significant improvement of progressive motility were observed. another double-blind, multi-center, randomized controlled trial showed that a combination of antioxidants and vitamins (vitamin c, vitamin d3, vitamin e, folic acid, zinc, selenium, l-carnitine) did not improve semen parameters or dna fragmentation in infertile men (81). an evidence-based review of randomized trials concluded that antioxidant supplements are beneficial in improving semen quality and clinical pregnancy rates for men from couples undergoing infertility treatment (82). more recent meta-analyses confirmed the positive results of the administration of antioxidants in subfertile men, although the poor quality of the studies considered in their analyses was highlighted. a cochrane meta-analysis considered 61 randomized clinical trials (rcts) with a total population of 6000 subfertile men of couples attending a reproductive clinic to evaluate the effect of the oral administration of a wide range of 18 antioxidants on assisted reproductive techniques outcomes pregnancy or live birth rate (83). only few small studies reported on pregnancy or live birth rate. use of antioxidants increased, the chance of clinical pregnancy from an estimated baseline of 7% following placebo or no treatment to a 12% to 26% rate after antioxidants (or = 2.97). live birth rate after antioxidants ranged between 14 and 26% whereas a 12% rate was observed after placebo or no treatment (or = 1.79). most studies were rated as 'low' to 'very low' quality with high heterogeneity and serious risk of bias (poor reporting of methods of randomisation, unclear or high attrition, low event rates and small sample sizes). in another meta-analysis of 7 studies (84) a significant improvement of semen parameters (count, motility, morphology) was shown after administration of selenium (200 µg/day and 100 µg/day), combination of ), l-carnitine (2 g/day) and acetyl-l-carnitine (lac; 1 g/day) and co-enzyme q10 (200 and 300 mg/day). information of the effect on pregnancy rate 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with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. int urol nephrol. 2012; 44:689-700. 67. safarinejad mr. efficacy of coenzyme q10 on semen parameters, sperm function and reproductive hormones in infertile men. j urol. 2009; 182:237-48. 68. safarinejad mr, safarinejad s, shafiei n, safarinejad s. effects of the reduced form of coenzyme q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. j urol. 2012; 188:526-31. 69. wang yx, yang sw, qu cb,, et al. l-carnitine: safe and effective for asthenozoospermia. zhonghua nan ke xue. 2010; 16:420-2. 70. balercia g, regoli f, armeni t, et al. placebo-controlled doubleblind randomized trial on the use of l-carnitine, l-acetylcarnitine, or combined l-carnitine and l-acetylcarnitine in men with idiopathic asthenozoospermia. fertil steril. 2005; 84:662-71. 71. banihani s, agarwal a, sharma r, bayachou m. cryoprotective effect of l-carnitine on motility, vitality and dna oxidation of human spermatozoa. andrologia. 2014; 46:637-41. 72. wu zm, lu x, wang yw, et al. short-term medication of l-carnitine before intracytoplasmic sperm injection for infertile men with oligoasthenozoospermia. zhonghua nan ke xue. 2012; 18:253-6. 73. cheng jb, zhu j, ni f, jiang h. l-carnitine combined with coenzyme q10 for idiopathic oligoasthenozoospermia: a doubleblind randomized controlled trial. zhonghua nan ke xue. 2018; 24:33-38. 74. thérond p, auger j, legrand a, jouannet p. alpha-tocopherol in human spermatozoa and seminal plasma: relationships with motility, antioxidant enzymes and leukocytes. mol hum reprod. 1996; 2:739-44. 75. omu ae, fatinikun t, mannazhath n, abraham s. significance of simultaneous determination of serum and seminal plasma alphatocopherol and retinol in infertile men by high-performance liquid chromatography. andrologia. 1999; 31:347-54. 76. chen xf, li z, ping p, et al. efficacy of natural vitamin e on oligospermia and asthenospermia: a prospective multi-centered randomized controlled study of 106 cases. zhonghua nan ke xue. 2012; 18:428-31. 77. chia se, ong cn, chua lh, et al. comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between fertile and infertile men. j androl. 2000; 21:53-7. 78. raigani m, yaghmaei b, amirjannti n, et al. the micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. andrologia. 2014; 46:956-62. 131archivio italiano di urologia e andrologia 2020; 92, 2 male fertility and nutrition 79. wong wy, merkus hm, thomas cm, et al. effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. fertil steril. 2002; 77:491-8. 80. busetto gm, agarwal a, virmani a, et al. effect of metabolic and antioxidant supplementation on sperm parameters in oligoastheno-teratozoospermia, with and without varicocele: a doubleblind placebo-controlled study. andrologia. 2018; 50. 81. steiner a, hansen k, diamond mp, et al. antioxidants in the treatment of male factor infertility: results from the double blind, multicenter, randomized controlled males, antioxidants, and infertility (moxi) trial. abstract book of 34th annual meeting of the european society of human reproduction and embryology (eshre), 1-4 july 2018 barcelona; human reproduction 2018; 33 (suppl 1):i30. 82. ahmadi s, bashiri r, nadjarzadeh a. antioxidant supplements and semen parameters:an evidence based review int j reprod biomed 2016; 14:629-736. 83. smits rm, mackenzie-proctor r, yazdani a, et al. antioxidants for male subfertility. cochrane database syst rev. 2019; 3:cd007411. 84. buhling k, schumacher a, eulenburg cz, laakmann e. influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review. reprod biomed online. 2019; 39:269-279. 85. hussain sa, hameed a, nasir f, et al. evaluation of the spermatogenic activity of polyherbal formulation in oligospermic males. biomed research international 2018; 2018:2070895. . . correspondence mahmoud benatta benatta.mahmoud@gmail.com dept. of urology, djilali lyabes university hospital, sidi bel abbes/algeria redha kettache kettacher@gmail.com dept. of urology, eph bachir bennacer, biskra/algeria noor buchholz (corresponding author) scientific-office@u-merge.com noor.buchholz@gmail.com u-merge scientific office 21 athens/greece alberto trinchieri alberto.trinchieri@gmail.com u-merge scientific office stesura seveso 191archivio italiano di urologia e andrologia 2019; 91, 3 case report a purely penoscrotal approach: reservoir placement of an inflatable penile prosthesis (ipp) in an orthotopic neobladder patient. case report cumhur yeşildal, ahmet tevfik albayrak, abdullah hizir yavuzsan, musab !lgi, sinan levent kireççi department of urology, şişli hamidiye etfal training and research hospital, university of health science, istanbul, turkey. introduction: the inflatable penile prosthesis (ipp) is the last step in drug-resistant erectile dysfunction treatment. ipp implantation can be challenging, especially following a cystoprostatectomy with an orthotopic neobladder. there is no consensus about surgical techniques for placement of an ipp reservoir in such patients. in this paper, we present a case of an ipp and reservoir placement with a single penoscrotal incision. case: a 55-year-old patient, who underwent radical cystoprostatectomy with an orthotopic neobladder seven years ago, presented with severe erectile dysfunction. his oncologic status was stable, and he was in remission. he also had high blood pressure and took medication for it. he previously used different medical treatments, such as oral phosphodiesterase-5 inhibitors (pde5i), intraurethral prostaglandin e2 (pge2) installations, and trimix injections. as far as we know, he had no benefit from these treatments. a three-piece ipp was recommended. after a discussion of surgical techniques, we chose the penoscrotal approach, and the ectopic reservoir was placed through the inguinal canal, guided by a forefinger. results: the total operative time was 60 minutes, and the estimated blood loss was minimal. there were no perioperative complications. the patient was discharged on postoperative day one. he could start to use the ipp in the first month. his sexual and urinary functions were normal, and there was no abdominal bulging from the ectopic reservoir at the three-month follow-up. conclusions: in conclusion, ectopic placement of the reservoir through a single penoscrotal incision appears to be a safe and acceptable surgical technique for postoperative ed following a radical cystoprostatectomy with an orthotopic neobladder. key words: penile prosthesis; erectile dysfunction; orthotopic neobladder. submitted 9 february 2019; accepted 13 february 2019 summary no conflict of interest declared. no one had attempted to place an ipp reservoir with a penoscrotal approach in a radical cystoprostatectomy patient with a neobladder. we describe a safe placement method for the reservoir of an ipp via a single penoscrotal incision in a neobladder patient who has a secondary erectile dysfunction due to a past radical cystoprostatectomy (figure 1). case a 55-year-old bladder cancer patient, who had undergone radical cystoprostatectomy with an orthotopic studer neobladder seven years ago, presented with severe erectile dysfunction (ed). he had already used medical treatments such as oral phosphodiesterase-5 (pde5i) inhibitors, trimix, and prostaglandin e2 (pge2). he had hypertension and took medication. our clinic recommended a three-piece inflatable penile prosthesis as an end-stage treatment. at that point, surgical techniques were discussed, and we agreed on the penoscrotal approach. the ectopic reservoir was placed from the inguinal canal, guided by a forefinger. then the posterior wall of the inguinal canal was pricked, and the internal obliques and transversal muscles were separated, followed by circumferential sweeping using the forefinger. the cloverleaf reservoir was established, filled with 65 ml doi: 10.4081/aiua.2019.3.191 introduction although the retropubic and perivesical spaces are known to be the best locations for three-piece ipp reservoirs, the use of these locations becomes impossible with an underlying cause of fibrosis due to pelvic surgery, such as radical prostatectomy, cystectomy, or even radiotherapy to the pelvis. as an alternative to these locations, ectopic reservoirs can be placed between the transverse fascia and the abdominal muscles (1-3). however, as far as we know, figure 1. an abdominal cross-section of the 55-year-old patient, showing the orthotopic bladder formed seven years ago. archivio italiano di urologia e andrologia 2019; 91, 3 c. yeşildal, a. tevfik albayrak, a. hizir yavuzsan, m. !lgi, s. levent kireççi 192 saline solution, and then evaluated for back pressure. finally, a narrowing suture was placed at the orifice of the inguinal canal to prevent the reservoir from slipping downward. discussion a surgeon should carefully plan how and where to place the ipp reservoir in ed patients with a neobladder. as we know, after radical cystoprostatectomy with an orthotopic neobladder, a significant part of the peritoneum cannot be closed. therefore, a part of the small intestine can be found in the pelvic cavity. if the surgeon does not consider this possibility and tries to insert a reservoir with classical methods such as scrotal or infrapubic incision, it may damage the neobladder, the intestines, and even the inferior epigastric vessels (2, 3). there is one report that describes an alternative way to place the ipp reservoir (4). jung kwon kim et al. placed the ipp reservoir with a separate longitudinal incision two fingerbreadths to the left and lateral to the umbilicus. although this approach is feasible, it has no advantage against our technique since it is done with a secondary incision. in our procedure, we placed the ipp and its cloverleaf reservoir using a single penoscrotal incision (figure 2). the total operative time was 60 minutes. there were no perioperative complications, nor was there more blood loss than expected. on the fifteenth day after the surgery, we started to train the patient about how to use the ipp. we recommended abstaining from sexual intercourse for the first six weeks. he was able to begin using the ipp in the sixth week. his sexual and urinary functions were normal, and his sexual satisfaction was very high. there was no abdominal bulging from the ectopic reservoir at the three-month follow-up (figure 3). the ectopic placement of a flat reservoir using only a penoscrotal incision appears to be a safe and feasible surgical technique for postoperative ed following radical cystoprostatectomy with orthotopic neobladder. references 1. al-enezi a, al-khadhari s, al-shaiji tf. three-piece inflatable penile prosthesis: surgical techniques and pitfalls j surg tech case rep. 2011; 3:76-83. 2. perito pe, wilson sk. traditional (retroperitoneal) and abdominal wall (ectopic) reservoir placement j sex med. 2011; 8:656-9. 3. morey af, cefalu ca, hudak sj. high submuscular placement of urologic prosthetic balloons and reservoirs via transscrotal approach j sex med. 2013; 10:603-10. 4. kim jk, cho mc, ku ja hyeon, et al. preperitoneal placement of an inflatable penile prosthesis reservoir for postoperative erectile dysfunction after radical cystoprostatectomy with orthotopic neobladder investig clin urol. 2016; 57:364-366. figure 2. postoperative third month. the reservoir can be seen under the external and internal oblique muscles. figure 3. postoperative third month. penoscrotal operation area. single incision. correspondence cumhur yesildal, md c_yesildal@hotmail.com ahmet tevfik albayrak, md atevfikalbayrak@gmail.com abdullah hizir yavuzsan, md hiziryavuzsan@hotmail.com musab ilgi, md ilgimusab@gmail.com sinan levent kirecci, md sinankirecci@yahoo.com.tr university of health and sciences sisli etfal traning and research hospital urology department halaskargazi cad., etfal sk., 34371 şişli/istanbul (turkey) archivio italiano di urologia e andrologia 2019; 91, 3202 case report ureteral realignment with combined access as a treatment of complete ureteral transection jorge panach-navarrete, marcos antonio lloret-durà, maría medina-gonzález, josé maría martínez-jabaloyas department of urology, university clinic hospital of valencia. facultat de medicina i odontologia, universitat de valència, valencia (spain). ureteral realignment using a ureteral stent can be an alternative treatment in cases of complete ureteral transection and may avoid the need for reconstructive surgery. the combined access can help the passage of the guidewire through the injured area and the threading of the urinary system of the patient. we present a case of a 38-year-old man with multiples abdominal surgeries, who underwent a complete ureteral section treated with ureteral realignment with combined access. the subsequent evolution was favourable, with resolution of the ureteral injury at the acute time, and without the presence of long-term obstruction. although we must accept that the standard treatment of the complete ureteral transection is reconstruction and anastomosis, in cases such as the one prsented, with multiple abdominal surgeries and whenever it is technically feasible, ureteral realignment may be a treatment option. key words: ureteral transection; ureteral trauma; endourology; ureteral realignment. submitted 15 april 2019; accepted 29 april 2019 summary no conflict of interest declared. case report a 38-year-old man with a history of perforated acute diverticulitis, having been treated at first with sigmodectomy and reconstruction of intestinal transit. in the postoperative period he presented with a leak of the intestinal anastomosis, requiring an emergency colostomy. during the postoperative period of the second surgery, he required emergency splenectomy for unnoticed splenic injury during the colostomy. at 12 months, during the scheduled colostomy closure, an inadvertent ureteral injury was produced. due to the patient's paralytic ileus, a computed tomography (ct) scan was performed one week later, finding a contrast leak in the middle area of the distal ureter in the excretory phase (figure 1) and a pelvic collection secondary to the leak. percutaneous drainage of the collection and urgent double j stent placement was decided. in the ascending pyelography, complete extravasation of contrast outside the urinary tract was found about 4 cm above the bladder. in addition, it was not possible to raise the guidewire through the ureter. ureterorenoscopy with a 9.5f semirigid instrument (storz®) was decided, checking for a disheveled area and complete solution of continuity of the ureter, without reaching the proximal end of the ureter with any guidewire. at that time, given the history of multiple abdominal surgeries, the most doi: 10.4081/aiua.2019.3.202 introduction within urogenital system injuries, those in the ureter are relatively infrequent, representing around 1-2.5% of urological traumas. the most frequent location is the distal third of the ureter (73% of cases); and the most frequent cause is surgical iatrogenic damage (75%), which can produce avulsion, perforation, ligature or burning (1). along with gynecological surgery, distal ureter injuries happen most frequently in colorectal surgeries, with a reported incidence of unnoticed ureteral injury of between 0.11 and 0.24%. the diagnosis of these complications should be one of suspicion, as there are no specific signs. this fact implies that, sometimes, ureteral injuries are diagnosed in a deferred manner, in the postoperative period of surgeries (2). the clinical guidelines on urological trauma of the european association of urology and the american association of urology agree that small lesions or ureteral fistulas are subsidiary of conservative treatment with the use of a ureteral stent, a procedure that is safe and effective. on the other hand, larger lesions should be treated with surgical reconstruction followed by urinary diversion (1, 3). we present in this work a case of complete ureteral transection successfully treated by ureteral realignment. figure 1. uroct at the time of diagnosis of the ureteral injury. contrast leakage from the left pelvic ureter. navarrete_stesura seveso 30/09/19 18:29 pagina 202 203archivio italiano di urologia e andrologia 2019; 91, 3 ureteral realignment with combined access recent a week before, ureteral realignment with combined access was decided. then, after percutaneous puncture of the kidney, descending pyelography was performed, measuring a distance of about 2 cm between both ureteral ends. an anterograde guide coated with 0.035 "ptfe (coloplast®)” was descended, outside of the urinary tract. using the ureteroscope and with the help of a 0.035 "sensor® guidewire (boston scientific®)”, the area of the injury was reached, visualizing the ptfe guidewire outside of the tract (figure 2). arriving with the ureteroscope to the edge of the distal end, the ptfe guidewire was lowered to the bladder by means of foreign body forceps and then extracted through the urethra. with the patient threaded, a double j 6f-26 cm vortek® stent (coloplast) was placed retrogradely. in a control uro-ct scan performed a week later, no contrast leakage was found. the ureteral stent was removed after two months. a ct scan and renogram four months after the realignment showed minimal evident pathway in the left kidney and absence of obstruction, with a differential function for the affected kidney of 46% (figure 3). discussion the management of ureteral trauma should be initiated with the prevention of injury. the preoperative placement of a double j stent, the correct identification of the ureter and its proper dissection, are basic maneuvers for any surgery that develops in the proximity of the ureteral tract. in the case of injury, the ideal solution is immediate repair, although this action is not possible many times. that is why, sometimes, treatment must be individualized depending on the stability of the patient, the evolution time of the injury, its severity, or its exact location. ureteral reconstruction with an ulterior temporary urinary diversion is the accepted treatment for major ureteral injuries (1, 3). in the case we present, it was decided to perform a realignment in spite of the intraoperative findings due to the patient's background. this procedure has been previously described by different authors in the context of a complete ureteral transection, with different approaches, number of stents used and maintenance period. wang et al. used a retrograde approach, placing two stents for four months, and resolving the urine leak without long-term complications. in this case, the authors highlighted the difficulty of finding the proximal end under direct vision by retrograde ureteroscopy, solved with the combined approach that we carried out (4). on the other hand, liu et al. reported eight cases of complete transection, treating them with combined access through flexible anterograde and rigid retrograde ureteroscope. this group placed three 5 ch stents, solving the ureteral discontinuity in all cases, but with the development of stenosis in three of the eight cases (5). as far as we know, this work is the third one that describes this technique. although we must accept that the treatment of the complete ureteral transection is reconstruction and anastomosis, in cases such as the one we present, with multiple abdominal surgeries and whenever it is technically feasible, ureteral realignment may be a treatment option. references 1. bryk dj, zhao lc. guideline of guidelines: a review of urological trauma guidelines. bju int. 2016; 117:226-34. 2. eswara jr, raup vt, potretzke am, et al. outcomes of iatrogenic genitourinary injuries during colorectal surgery. urology. 2015; 86:1228-33. 3. morey af, brandes s, dugi dd, et al. urotrauma: aua guideline. j urol. 2014; 192:327-35. 4. wang d, wan sp. retrograde endoscopic management of completely transected ureter discovered postoperatively. j endourol case rep. 2018; 4:84-6. 5. liu c, zhang x, xue d, et al. endoscopic realignment in the management of complete transected ureter. int urol nephrol. 2014; 46:335-40. figure 2. intraoperative images obtained during retrograde ureteroscopy. figure 3. ct and renogram four months after the realignment. they showed minimal patent pathway in the left kidney and absence of obstruction, with a differential function for the affected kidney of 46%. correspondence jorge panach-navarrete, md (corresponding author) jorge.panach@uv.es av. blasco ibáñez, nº 17, valencia, cp 46010 (spain) marcos antonio lloret-durà, md marcosant.lloret@gmail.com maría medina-gonzález, md mariamedinagon@gmail.com josé maría martínez-jabaloyas, md phd marjabaloyas@gmail.com department of urology. university clinic hospital of valencia. facultat de medicina i odontologia. universitat de valència, valencia (spain) navarrete_stesura seveso 30/09/19 18:29 pagina 203 archivio italiano di urologia e andrologia 2017; 89, 2166 case report total phallic reconstruction after penile amputation for donkey bite: case report and review of the literature francesco de luca 1, 2, giulio garaffa 3, angela maurizi 1, emy manzi 4, carlo de dominicis 1, david ralph 3 1 department of gynaecological and urological sciences, sapienza university of rome, rome italy; 2 department of urology azienda ospedaliera san camillo forlanini, rome italy; 3 st. peter's andrology and the institute of urology, university college london hospitals, london uk; 4 department of surgery p. stefanini, sapienza university of rome, rome, italy. there are very few reported cases of traumatic amputation of the male genitalia due to animal bite. the management involves thorough washout of the wounds, debridement, antibiotic prophylaxis, tetanus and rabies immunization followed by immediate reconstruction or primary wound closure with delayed reconstruction, when immediate reconstruction is not feasible. when immediate reconstruction is not feasible, long-term good functional and cosmetic results are still possible in the majority of cases by performing total phallic reconstruction. in particular, it is now possible to fashion a cosmetically acceptable sensate phallus with incorporated neourethra, to allow the patient to void while standing and to ejaculate, and with enough bulk to allow the insertion of a penile prosthesis to guarantee the rigidity necessary to engage in penetrative sexual intercourse. key words: penis; animal bite; phalloplasty; male genital trauma. submitted 6 march 2017; accepted 27 march 2017 summary no conflict of interest declared. ured 4 x 17 cm. the lateral skin plate, which was 14 cm long and 13 cm wide, was wrapped around the neo-urethra in a tube-within-a-tube fashion (3). the vascular supply was the disconnected from the forearm and the phallus was transferred to the recipient pubic region. the penile stump was disassembled with preservation of the crura, the neurovascular bundle and urethra. inferior epigastric artery, long saphenous vein, deep dorsal vein of the penis, ilioinguinal nerves and deep dorsal nerve of the penis were carefully isolated and prepared for the subsequent microsurgical anastomosis. the arterial anastomosis was performed between the inferior epigastric artery and the radial artery. venous drainage was guaranteed by the deep dorsal vein of the penis and the long saphenous vein. orgasmic sensation was guaranteed by the anastomosis between one of the flap nerves to the deep dorsal nerve of the penis while cutaneous sensation was ensured by the ilioinguinal nerve anastomosis. the native urethra stump was spatulated and anastomosed primarily to the phallic neo-urethra. an urethral stent and a suprapubic catheter placed in order to protect the urethral anastomosis whilst healing (4). the defect on the donor forearm was covered with a fullthickness skin graft (ftsg) harvested from the patient’s lower buttock creases (5) (figure 2). after 6 months, a neo-glans was sculptured according to the norfolk technique using a ftsg strip harvested from a relatively hairless area of the abdomen. finally, 6 months later, a 18+1 cm long titan touch® inflatable penile prosthesis was inserted into the phallus to guarantee the rigidity necessary to engage in penetrative sexual intercourse. the crura were used to house the rear aspect of the cylinders while a dacron® tip was fashioned to house the tip of the cylinders thus preventing distal erosion (figure 3). after follow-up of 72 months from the last stage of the operation, the patient is fully satisfied with the cosmetic and functional results of surgery. he is able to void while standing and ejaculate from the tip of the phallus. unfortunately his penile implant got infected 3 times, which required explantation and led to phallus shortening. as a consequence, at present, his penile implant is 16 cm long. doi: 10.4081/aiua.2017.2.166 case report a 7-year old boy, living in rural iran, was bitten through his clothing in the genital area by a donkey. the bite resulted in a partial penile amputation leaving a short penile stump while scrotum and testes were intact (figure 1). immediate penile reconstruction was not possible due to the absence of specialist medical facilities. since the residual penile stump was inadequate for penetrative sexual intercourse, at age 23 the patient underwent total penile reconstruction with the use of a radial artery based free flap (raff). total phallic reconstruction was carried out in 3 stages, each one performed at 6 monthly intervals. the first stage involved the formation of the phallus, the second stage the sculpture of the neo-glans and the last stage, the insertion of the components of a 3-pieces inflatable penile prosthesis. preoperatively an allen’s test was performed in to confirm the patency of the palmar arteries. the flap was formed by two sections separated by a 1 cm wide de-epithelialized strip. the medial section, which was tubularised to form the neo-urethra was of rectangular shape and measde luca_stesura seveso 20/06/17 10:06 pagina 166 167archivio italiano di urologia e andrologia 2017; 89, 2 penile amputation due to donkey bite more common in children (60%) than adults (40%). morbidity is directly related to the severity of the injury and to the time elapsed before seeking for medical assistance. treatment includes thorough washing and irrigation with normal saline solution, debridement and broaddiscussion to date, including the present case, there are 57 published cases of animal bites to male genitalia. a search was conducted using the following words: “trauma”, “male genitalia”, “penis”, “testis” and “animal bite” from december 1966 to december 2016. the majority of cases are due to dog 34 (66.6%), followed by snake 4 (7.8%), viper 2 (3.9%), horse 2 (3.9%), monkey 2 (3.9%), donkey 2 (3.9%), mule (1.9%), alligator 1 (1.9%), rat 1 (1.9%), pig 1 (1.9%), parrot fish 1 (1.9%) (table 1 and 2). animal bites cause penetrating genital trauma, and might increase the risk of infection. genital bites are much table 1. cases reported in literature. animal n author injury man/child dog 1 aineskog h. et al. 2016 penile skin avulsion adult parrot fish 1 kobayashi sa, et al. 2015 avulsion of penile foreskin adult snake 1 tamou sambo b, et al. 2015 penoscrotal gangrene adult viper 1 koffi nr, et al. 2015 swelling child viper 1 hussain t, et al. 2015 swelling and hemorrhagic bullae adult dog 1 miodrag a, et al. 2014 penile skin avulsion adult mule 1 lakmichi ma, et al. 2011 complete penile avulsion adult rat 1 haldar p, et al. 2011 transection of the urethra child snake 1 kossoko h, et al. 2011 urethra injury adult dog 3 bothra r, et al. 2011 emasculation, 2 lacerated wound child dog 1 frank m, et al. 2010 genital avulsion adult dog 1 saleh d, et al. 2009 lest testicular rupture adult dog 1 bertozzi m, et al. 2009 damage of the right vas deferens child dog 1 hon kl, et al. 2007 swelling child snake 1 babata al, et al. 2006 scrotum gangrene adult dog 1 leung ak, et al. 2005 skin avulsion child dog 1 ku jh, et al. 2005 amputation penis and testes child dog 1 budhiraja s, et al. 2002 loss of right testis child pig 1 georgiou p, et al. 2001 subtotal avulsion of penile skin adult dog 8 gomes cm, et al. 2000 5 skin loss,2 spermatic cord avulsion, 8 children horse 1 gomes cm ,et al. 2000 1 partial penis avulsion adult donkey 1 gomes cm, et al. 2000 1 complete scrotal avulsion adult dog 7 cummings jm, et al. 2000 skin avulsion 4 adults 3 children monkey 2 singla sl, et al. 1997 dog 1 redman j. f., 1995 complete testes avulsion child alligator 1 katlowitz nm, et al. 1995 testes avulsion dog 2 tuggle dw et al. 1993 external genitalia loss children dog 1 wolf et al. 1993 both testes loss child dog 1 piza-katzer h, et al. 1989 skin damage adult dog 2 donovan jf et al. 1989 penile and scrotal skin avulsion children non specified animals 6 landercasper j, et al. 1988 snake 1 sinha sn, et al. 1975 scrotal skin necrosis horse 1 noto l 1966 elephantiasis table 2. cases reported in literature. animal n % dog 34 66,6 snake 4 7,8 viper 2 3,9 horse 2 3,9 monkey 2 3,9 donkey 2 3,9 mule 1 1,9 alligator 1 1,9 rat 1 1,9 pig 1 1,9 parrot fish 1 1,9 figure 1. penile amputation. figure 2. donor site forearm. figure 3. phalloplasty with penile prosthesis. de luca_stesura seveso 20/06/17 10:06 pagina 167 archivio italiano di urologia e andrologia 2017; 89, 2 f. de luca, g. garaffa, a.a maurizi, e. manzi, c. de dominicis, d. ralph 168 spectrum antibiotics prophylaxis, as the main risk is infection. primary closure is often recommended in most cases delaying reconstructive surgery to a later date. when the victim is a child, or the wound has been caused by an animal, infectious complications are usually minor, as medical treatment is sought reasonably quickly. pasterurella multocida is often present (20-50% of dog bites). cellulitis often results in premature sepsis (within 24 hours). antibiotic treatment should be broad-spectrum beta-lactam with beta-lactamase inhibitors. fluoroquinolones, cotrimoxazole or chloramphenicol are valid alternatives. the duration of treatment should be individualised and last at least 10-14 days. rabies vaccination will depend on local sanitary policy. appropriate tetanus vaccination is required. references 1. lakmichi ma, wakrim b, jarir r, et al. mule bite to male genitaliawith complete penile and anterior urethra amputation: unsual case and review of the literature. isrn urol. 2011; 2011:723154. 2. evgeniou e, markeson d, iyer s, et al. the management of animal bites in the united kingdom. eplasty. 2013; 13:e27. print 2013. 3. garaffa g, raheem aa, christopher na, et al. total phallic reconstruction after penile amputation for carcinoma. bju int. 2009; 104:852-6. 4. massanyi ez, gupta a, goel s, et al. radial forearm free flap phalloplasty for penile inadequacy in patients with extrophy. j urol. 2013; 190(4 suppl):1577-82. 5. doornaert m, hoebeke p, ceulemans p, et al. penile reconstruction with the radial forearm flap: an update. handchir mikrochir plast chir. 2011; 43:208-14. correspondence francesco de luca, md (corresponding author) francescodeluca10@gmail.com angela maurizi, md angmau81@hotmail.com carlo de dominicis, md carlo.dedominicis@uniroma1.it viale dell'università, 31/33, 00161 roma, italy giulio garaffa, md giuliogaraffa@gmail.com david ralph, md dralph@andrology.co.uk 145 harley street london w1g 6bj (uk) emy manzi, md emymanzi@gmail.com viale del policlinico 155, 00161 roma, italy de luca_stesura seveso 20/06/17 10:06 pagina 168 stesura seveso 107archivio italiano di urologia e andrologia 2019; 91, 2 original paper mini-invasive robotic assisted pyelolithotomy: comparison between the transperitoneal and retroperitoneal approach daniele d’agostino 1, paolo corsi 1, marco giampaoli 1, federico mineo bianchi 2, daniele romagnoli 1, simonecrivellaro 3, giacomo saraceni 2, marco garofalo 2, riccardo schiavina 2, eugenio brunocilla 2, walter artibani 1, angelo porreca 1 1 department of robotic urological surgery, abano terme hospital, abano terme, italy; 2 department of urology, university of bologna, bologna, italy; 3 division of urology, department of surgery, university of illinois at chicago, chicago, il, usa. objective: to compare the retroperitoneal with the transperitoneal approach in a series of patients underwent to robotic-assisted pyelolithotomy (rp). materials and methods: from january 2015 to december 2018 we evaluated 20 patients subjected to robotic pyelolithotomy; 11 patients were treated with retroperitoneal approach (rrp) and 9 with transperitoneal approach (trp). for each patient intra and perioperative data were recorded: operative time (ot), blood loss (bl), length of hospital stay (los), stone clearance, post-operative complications and time to remove the drain. the presence of stone fragments < 4 mm was considered as stone free rate. results: the principal stone burden was greater in the trp group than in the rrp group (48 ± 10 mm vs 32 ± 14 mm, p = 0.12). preoperative hydronephrosis was present in 7 (64%) patients in rrp group and a mild hydronephrosis in 3 of trp group (p = 0.04). the average operative time was higher in the rrp group than in the trp group (203 ± 45 min vs 137 ± 31 min, p = 0.002). the average blood loss was 305 ± 175 ml in the rrp group versus 94 ± 104 ml in the trp group (p = 0.005). the stone free rate was similar between the two groups, 36% (4 patients) in the rrp group and 44% (4 patients) in the trp (p = 0.966). conclusions: rp appears to be a safe and effective minimally invasive treatment for some patients with renal staghorn calculi or urinary tract malformations. the trp may give lower operative time and better results in terms of blood loss and length of hospital stay. key words: transperitoneal pyelolithotomy; retroperitoneal pyelolithotomy. submitted 28 february 2019; accepted 21 march 2019 summary no conflict of interest declared. ing system (2). although, the term ‘staghorn’ provides description of stone configuration, it lacks specific volume criteria and information about stone composition (3). pcnl remains the gold-standard for the management of larger and “staghorn” renal stones. robot assisted laparoscopic surgery (rals) may be useful in the management of upper tract (ut) urolithiasis and it has been frequently considered as an alternative procedure in the management of large or complex renal stones to pnl or open surgery. the mayor advantages are: the possibility to remove the stones integrally, the ability to minimize the bleeding, less pain and lower morbidity. the use of robotic surgery has allowed more success rates than reconstructive urinary tract surgery (4). in addition to remove the stones, the advantages of robotic pyelolithotomy are the possibility to perform reconstructive surgery in presence of anatomical anomalies (e.g. pelvic or horseshoe kidney and malrotated kidneys, failed pnl and stones associated with congenital renal anomalies such as ureteropelvic junction obstruction (upjo) (3). as for the robotic surgery of renal neoplasms (5) rp can be performed transperitoneally or retroperitoneally and there is no evidence of which approach is better than the other. aim of the study is to compare the perioperative outcomes and stone free status between the transperitoneal and retroperitoneal approach of robotic pyelolithotomy . material and methods from january 2015 to december 2018 we retrospectively evaluated 20 patients subjected to robotic pyelolithotomy from 3 high volume centers. the indication for robotic surgical treatment of urolithiasis was discussed with all patients when the informed consent was signed, indicating that the percutaneous nephrolithotomy was the gold standard treatment; however the main indications for the robotic surgical treatment were highlighted as extrarenal pelvis, anatomical abnormalities (e.g. pelvic kidney or horseshoe kidney), simultaneous management of coexisting pathologies such pelvic-ureteral junction obstruction or failed endourological procedure. all the patients enrolled presented an extrarenal pelvis to the preoperative ct scan and pyelolitotomy was proposed as doi: 10.4081/aiua.2019.2.107 introduction stone disease is a highly prevalent condition that unites all countries around the world; the incidence of urolithiasis depends on geographical, racial, and socioeconomic factors. there are a lot of variety of therapeutic option for renal stones: extracorporeal shock wave lithotripsy (eswl), ureteroscopy (urs) and percutaneous nephrolithotomy (pnl) (1). surgical management will depend on many factors including availability of different technologies. “staghorn” stones are large branching stones that fill part of all of the renal pelvis and renal calyces and they can be complete or partial depending on the level of occupancy of the collectarchivio italiano di urologia e andrologia 2019; 91, 2 d. d’agostino, p. corsi, m. giampaoli, et al. 108 a treatment for stones even in the absence of reconstructive surgery. the population is divided into 2 groups: 11 patients were treated with retroperitoneal approach (rrp) and 9 with transperitoneal approach (trp). patients with coagulation disorder, cardiorespiratory diseases, musculoskeletal deformities and morbid obesity were excluded from the study. for each patient the preoperative evaluation included renal function tests, urine routine and microscopic examination. the patients with urinary infection received a course of antimicrobial therapy and they underwent the procedure after the urine culture was sterile. a ct-scan (computed tomography) was performed for each patient to obtain information about the stone location, hydronephrosis, the status of contralateral kidney and the presence of anatomical abnormalities such as upjo or malrotated kidney. all patients were operated under general anesthesia; in the presence of concomitant upjo, pyeloplasty was performed according to the anderson-hynes technique. at the end of each procedure a ureteral stent (double j) and an abdominal (intraperitoneal or retroperitoneal) drain were inserted. the double j stent was removed after 2-3 weeks and the abdominal drain was removed when no traces of creatinine were found in it. for each patient intra and perioperative data were recorded: operative time (ot), blood loss (bl), length of hospital stay (los), stone clearance, post-operative complications and time to remove the drain. the presence of stone fragments < 4 mm was considered as stone free rate. surgical technique transperitoneal approach: the patient was placed in lateral decubitus position at 45° angle. a 12-mm camera port was placed lateral and superior to the umbilicus and three 8-mm robotic working ports were placed under direct vision in the ipsilateral upper quadrant, lower quadrant, and lateral abdomen. a 12-mm assistant port is usually placed close to the midline, midway between the camera port and the robotic ports (figure 1). sometimes a fourth robotic arm was used to aid retraction of the kidney and exposure of the renal pelvis and hilum. the line of toldt was incised, the renocolic ligament was incised, and the colon was dissected and reflected medially to provide clear exposure of the ureteropelvic junction. the ureter was identified, recognizing its peristalsis and dissected. the renal pelvis was exposed by releasing adjacent structures with sharp and blunt dissection. a vertical incision was made in the pelvis, until the stone is exposed. a robotic prograsp forcep was then used to carefully dislodge and remove the stone/s; if the stone was too large it was placed in a specimen retrieval bag and removed at the end of the procedure. direct calyceal vision inspection was performed initially with the 30° optic, and the flexible cystoscope was placed through the 10-mm port, if required, to remove possible remaining stones. a ureteral double-j stent was placed, and thepyelotomy was closed in running fashion with absorbable suture. the perirenal fat was then approximated over the renal pelvis. a drain was placed through one of the trocar sites, the fascia and were closed in standard fashion. retroperitonal approach: the patient was positioned on full flank position, the umbilicus on the break point of the of the table, the legs were positioned and a pillow was put in between (the internal leg was flexed at 45°, while the external leg was totally extended) (figure 2). the table was broken until maximum skin extension was reached in order to have as much working space as possible. the technique of applying trocars has been described (6): an oblique 1.5 cm incision was made at the tip of the 12th rib following the direction of the exterfigure 1. position of trocars on transperitoneal approach. figure 3. position of trocars on retroperitoneal approach. figure 2. position of patient on retroperitoneal approach. nal oblique muscle. the muscle fibers were gently dissected without cutting to the internal oblique muscle fibers, the dissection was then extended through the fascia. a minimal incision (2-3 mm) was done on the internal oblique fascia and the space was first blindly created with the finger through trasversalis fascia then with the introduction and subsequent inflation of a glove connected to the end of a nasal-gastric probe. a 12 mm trocar for the camera was positioned under finger guidance on the iliac crest along the mid-axillary line. an 8 mm robotic trocar was then positioned along the psoas muscle below the 12th rib-vertebra angle. a 12 mm laparoscopic trocar was positioned along the psoas muscle behind the iliac crest. then 12 mm hasson trocar was finally positioned and the working space was created by co2 inflation. the second 8 mm robotic trocar was positioned, after the laparoscopic dissection of the anterior peritoneal reflection, on the anterior axillary line on the same axis as the umbilicus (figure 3). using the robotic scissors and grasper the paranephric fat was first dissected then removed by a ring-clip to increase the workspace. after the identification of ureter, the kidney with its fat was isolated first posteriorly along psoas muscle, and, when necessary, anteriorly. the gerota fascia was incised exposing the perinephric fat. the hilum was then identified, renal pelvis was incised longitudinally and the stones should be easily dislodge and remove using the robotic prograsp. if needed, a flexible cystoscope was introduced through the assistant port to inspect the remaining of the renal pelvis and the calices. a stone basket was used to remove small residual stones from within the kidney. as in other robotic procedures the renal pelvis was then closed using a barbed bidirectional 3.0 suture. the choice of the suture depends by the thickness of the incision of renal pelvis. in the presence of upjo, pyeloplasty was performed both in the transperitoneal approach and in the retroperitoneal approach. statistical analysis all data were statistically analyzed using spss v 21 for macintosh. continuous variables were expressed as means ± standard deviation (sd) whereas categorical variables were expressed as frequencies with percentages. the indipendent-samples t-test and chi-square test were used to compare means and frequencies between the two groups, respectively. results the preoperative characteristics of the 2 groups (table 1) were comparable about age, sex, body mass index (bmi) and number and localization of the stones. the principal stone burden was greater in the trp group (transperitoneal approach) than in the rrp group (retroperitoneal approach) (48 ± 10 mm vs 32 ± 14 mm, p = 0.12). preoperative hydronephrosis was present in 7 (64%) patients in rrp group; in three patients in trp group was present a grade i hydronephrosis (p = 0.04); a ureteral stent was placed preoperatively in 1 (9%) patients in rrp group and in 5 (56%) of patients in trp group (p = 0.024). table 2 presents a comparison between the intra and perioperative outcomes between the two groups. the average operative time was higher in the rrp group than in the trp group (203 ± 45 min vs 137 ± 31 min, p = 0.002). the average blood loss was 305 ± 175 ml in the rrp group versus 94 ± 104 ml in the trp group (p = 0.005). the stone free rate was similar between the two groups, 36% (4 patients) in the rrp group and 44% (4 patients) 109archivio italiano di urologia e andrologia 2019; 91, 2 mini-invasive robotic assisted pyelolithotomy: comparison between the transperitoneal and retroperitoneal approach table 1. patients characteristics. retroperitoneal transperitoneal p value approach approach age mean ± sd 56 ± 10 51 ± 11 0.352 gender (%) male 3 (27) 4 (44) 0.33 female 8 (73) 5 (56) bmi mean ± sd 26 ± 4.5 26 ± 3 0.788 stone number (%) 1 5 (46) 6 (67) 0.26 2 2 (18) 2 (22) 3 4 (36) 0 (0) 4 0 (0) 0 (0) 5 0 (0) 1 (1) principal stone location (%) pelvis 7 (64) 3 (33) 0.25 staghorn 4 (36) 6 (67) lower pole 0 (0) 0 (0) principal stone burden (mm) mean ± sd 32 ± 14 48 ± 10 0.12 side (%) left 5 (45) 5 (56) 0.65 right 6 (55) 4 (44) hidronephrosis (%) yes 7 (64) 3 (30) 0.003 no 4 (36) 7 (70) previous stent (%) yes 1 (9) 5 (56) 0.024 no 10 (91) 4 (44) table 2. comparison between trp and rrp. retroperitoneal transperitoneal p value approach (n 11) approach (n 9) operation time (min) mean ± sd 203 ± 45 137 ± 31 0.002 blood loss (ml) mean ± sd 305 ± 175 94 ± 104 0.005 stone free rate (%) yes 4 (36) 4 (44) 0.966 no 7 (64) 5 (56) residual stone burden (mm) 61 ± 19 58 ± 12 0.08 concomitant pieloplasty sec. anderson-hynes (%) yes 1 (9) 3 (33) 0.18 no 10 (91) 6 (67) drain (days) mean ± sd 4.27 ± 2.7 1 ± 2.7 0.013 lenght of hospital stay (days) mean ± sd 5.3 ± 2.7 2 ± 2.7 0.013 follow-up (months) mean ± sd 10.6 ± 13.5 7.2 ± 5.6 0.48 archivio italiano di urologia e andrologia 2019; 91, 2 d. d’agostino, p. corsi, m. giampaoli, et al. 110 in the trp (p = 0.966). the stone burden of any residual kidney stones was reported in table 2; these are fragments < 1 cm migrated to the lower pole of the kidney which did not require further treatment. concomitant pyeloplasty sec. anderson-hynes was performed with retroperitoneal approach in 1 (9%) patient and with transperitoneal approach in 3 (33%) patients, p = 0.18. the drain was on average removed after 4.27 ± 2.7 days in the rrp group and after 1 ± 2.7 days in the trp group (p = 0.013). the length of hospital stay was lower in the trp group compared to the rrp group (2 ± 2.7 days in the trp group vs 5.3 ± 2.7 days in the rrp group, p = 0.013). discussion the role of robotic assisted surgery continues to develop within the field of urological surgery. in literature, the growing evidence demonstrating that the breadth and complexity of surgical procedures performed using the da vinci platform is continually expanding (7, 8, 4). the robotic surgery, whilst maintaining the benefits of standard laparoscopy, provides the surgeon with additional advantages of greater dexterity, a wider range of movement, tremor filtration, three-dimensional vision, and primary surgeon camera control; moreover, we observed significant continuous improvement in terms of bleeding, complications, hospital stay and global quality of life of patients (9-11). in the treatment of urolithiasis laparoscopic and robotic surgery represent valid options in specific cases; in particular the coexistence of upjo and kidney stones is one of the main indications for the laparoscopic treatment (12). robotic surgery has some advantages over laparoscopic surgery, such as three-dimensional (3d) view, wristed instruments and stable camera. although anatomical and stone characteristics play a crucial role in case selection, rp appears to be the technique most widely used, conceivably as parenchymal bleeding and potential nephron loss are avoided. the majority of the existing literature on robotic-assisted renal surgery (in particular partial and radical nephrectomy) describe transperitoneal approach and only few papers are published on retroperitoneal technique. the papers on the transperitoneal approach emphasize the advantages of robotic surgical system including: 3d visualization, increased degrees of freedom of movement, and enhanced-reconstructive capabilities. based on our experience with laparoscopic retroperitoneal approach for renal cancer (5), we recognized that the retroperitoneal approach combines the advantages of robotic technology (3d visualization, increased degrees of freedom of movements) with the advantages of retroperitoneal approach which includes advantages of direct access to the renal hilum and reduced lesion risk to abdominal organs, earlier return of bowel function and shorter length of hospital stay. a recent meta-analysis has shown that there is no difference in terms of complications, blood loss, time of ischemia, conversion and positive surgical margins in the treatment of renal masses between the retroperitoneal and transperitoneal approach, but a reduction of the operation time with the retroperitoneal approach has been highlighted (13). the use of rigid laparoscopic instruments in the small space of retroperitoneum cavity has made the retroperitoneal approach less used than the transperitoneal approach (14). in the literature, the cases describing the robotic pyelolithotomy were performed with a transperitoneal approach; atug et al. (15), described transperitoneal robotic pyelolithotomy in 55 patients with concomitant upjo: the mean operative time was 275.8 minutes, the mean blood loss was 48.6 ml, the mean length of hospital stay was 1.1 days and the stone free rate was 100%. in our series, the mean operative time, blood loss, length of hospital stays and stone free rate with transperitoneal approach were respectively 137 ± 31 min, 94 ± 104, 2 ± 2.7 days and 44%. for our knowledge this is the first study which compares pyelolithotomy with a retroperitoneal and transperitoneal approach for the management of renal stones: the mean operative time, blood loss and length of hospital stay was lower with the transperitoneal approach, but the stone free rate was similar. swearingen et al. (16) in their series evaluated 27 patients treated with robotic pyelolithotomy and nephrolitotomy with transperitoneal or retroperitoneal access: the mean operative time was 182 min, the mean estimated blood loss was 38 ml and the mean length of stay was 1.7 days. in our series the perioperative outcomes are greater than in the retroperitoneal approach, but the retroperitoneal approach can guarantee some advantages: decreased risk of damage of intraperitoneal structures, direct access to the renal hilum, quicker return of bowel function and earlier mobilization of the patient (17). however, this is a study that contains some limitations such as reduced number of cases evaluated retrospectively, and the absence of long-term follow-up data. further prospective studies are necessaries in order to better analyse the differences between the retroperitoneal approach in relation to the transperitoneal. conclusions robotic pyelolithotomy with retroperitoneal or transperitoneal approach appears to be a safe and effective minimally invasive treatment for some patients with renal stones, in particular the case of staghorn calculi or urinary tract malformations such as upjo. the transperitoneal approach may give lower operative time and better results in terms of blood loss and length of hospital stay. references 1. türk c, petfík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis eur urol. 2016; 69:468-474. 2. healy ka, ogan k. pathophysiology and management of infectious staghorn calculi. urol clin north am. 2007; 34:363-374. 3. preminger gm, assimos dg, lingeman je, et al. chapter 1: aua guideline on management of staghorn calculi: diagnosis and treatment recommendations. j urol. 2005; 173:1991-2000. 4. schiavina r, zaramella s, chessa f, et al. laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. j robot surg. 2016; 10:323-330. 5. porreca a, d'agostino d, dente d, et al. retroperitoneal approach for robot-assisted partial nephrectomy: technique and early outcomes. int braz j urol. 2018; 44:63-68. 6. bove p, iacovelli v, sandri m, et al.. entry techniques in laparoscopic radical and partial nephrectomy: a multicenter international survey of contemporary practices. minerva urol nefrol. 2018; 70:414-421. 7. porreca a, chessa f, romagnoli d, et al.robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon’s experience after a modified modular training. minerva urol nefrol. 2018; 70:193-201. 8. porreca a., salvagio a. dandrea m, et al. robotic-assisted radical prostatectomy with the use of barbed sutures. surg technol int. 2017; 30:39-43. 9. noale m, maggi s, artibani w, et al. pros-it cnr: an italian prostate cancer monitoring project. aging clin exp res. 2017; 29:165-172. 10. porreca a, noale m, artibani w, et al. disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the pros-it cnr study. health qual life outcomes. 2018; 16:122. 11. gacci m, noale m, artibani w, et al. quality of life after prostate cancer diagnosis: data from the pros-it cnr. eur urol focus. 2017; 3:321-324. 12. ramakumar s, lancini v, chan dy, et al. laparoscopic pyeloplasty with concomitant pyelolithotomy. j urol 2002; 167:1378-80. 13. xia l, zhang x, wang x, et al.transperitoneal versus retroperitoneal robot-assisted partial nephrectomy: a systematic review and meta-analysis. int j surg. 2016; 30:109-15. 14. ng cs, gill is, ramani ap, et al. transperitoneal versus retroperitoneal laparoscopic partial nephrectomy: patient selection and perioperative outcomes. j urol. 2005; 174:846-9. 15. atug f, castle ep, burgess sv, et al. concomitant management of renal calculi and pelvi-ureteric junction obstruction with robotic laparoscopic surgery. bju int. 2005; 96:1365-1368. 16. swearingen r, sood a, madi r, et al. zero-fragment nephrolithotomy: a multi-center evaluation of robotic pyelolithotomy and nephrolithotomy for treating renal stones. eur urol. 2017; 72:1014-1021. 17. hu jc, treat e, filson cp, et al. technique and outcomes of robot-assisted retroperitoneoscopic partial nephrectomy: a multicenter study. eur urol. 2014; 66:542-9. 111archivio italiano di urologia e andrologia 2019; 91, 2 mini-invasive robotic assisted pyelolithotomy: comparison between the transperitoneal and retroperitoneal approach correspondence daniele d’agostino, md (corresponding author) dott.dagostino@gmail.com paolo corsi, md pcorsi@casacura.it marco giampaoli, md mgiampaoli@casacura.it daniele romagnoli, md dromagnoli@casacura.it walter artibani, md prof.artibani@gmail.com angelo porreca, md angeloporreca@gmail.com department of robotic urological surgery, abano terme hospital piazza cristoforo colombo 1, 35031 abano terme (pd) (italy) federico mineo bianchi, md federico.mineobianchi@gmail.com giacomo saraceni, md giacomo.saraceni@gmail.com marco garofalo, md marco.garofalo@unibo.it riccardo schiavina, md rschiavina@yahoo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it department of urology, university of bologna, bologna (italy) simone crivellaro, md crivellaro76@hotmail.com division of urology, department of surgery, university of illinois at chicago, chicago, il, (usa) archivio italiano di urologia e andrologia 2018; 90, 3218 case report selective arterial embolization for a high-flow priapism following perineal trauma in a young gymnast grazia bianchi 1, camilla sachs 2, irene campo 2, giovanni liguori 1, carlo trombetta 1 1 department of urology, university of trieste, cattinara hospital, trieste, italy; 2 department of radiology, university of trieste, cattinara hospital, trieste, italy. introduction. high-flow priapism is a rare condition in children, usually due to a perineal trauma. materials and methods. we present a case of traumatic highflow priapism investigated by doppler ultrasound and managed by angiography and selective embolization of a branch of the internal pudendal artery. results. a 13-year-old gymnast underwent perineal trauma during training and developed a high-flow priapism. the first ultrasound (immediately after the trauma) showed the presence of an inhomogeneous area of 3 x 2 cm associated with an anechoic vascularized area (pseudoaneurysm) in the right corpus cavernosum. on the left side there was a similar finding, but of smaller size. after 3 weeks the pseudoaneurysm on the left was completely obliterated while the right one was still present. angiography and superselective catheterization of a branch of the left pudendal artery and its embolization with microspheres and with metal microcoils were performed. after the procedure, ultrasound showed that the right pseudoaneurysm was completely obliterated and there were no more branches reaching it. the cavernous arteries were both pervious. conclusions. selective arterial embolization is a safe treatment that can also be used in pediatric patients. key words: high-flow priapism; perineal trauma; embolization. submitted 5 june 2018; accepted 26 july 2018 summary no conflict of interest declared. and his penis was not completely rigid. the first ultrasound (immediately after the trauma) showed, in the right corpus cavernosum, the presence of an inhomogeneous area of 3 x 2 cm, associated with an anechoic vascularized area (pseudoaneurysm) (2). on the left side there was a similar finding, but of lesser magnitude. after 3 weeks, the patient came to our attention and we performed another doppler ultrasound using linear 5-12 and 5-17 mhz transducers. during the exam, a modest degree of erection could be appreciated. in correspondence to the palpatory finding in the crura, a 1.2 x 0.4 cm cavernous pseudoaneurysm was recognized on the right, fed by a small fistula with turbulent flows and with high velocities. no other vascular afferents were recognized. with compression, we could stop the flow in the pseudoaneurysm with immediate resumption of the pathological stream at the end of compression. after 3 weeks, the pseudoaneurysm on the left was completely obliterated. after retrograde guidewire puncture of the left common femoral artery, we proceeded to selective catheterization of the right hypogastric artery and the right pudendal artery, which were found to be pervious. angiography showed the presence of an arteriocavernosal fistula at the root of the penis with an afferent arterial branch originating from the pudendal artery. we proceeded to superselective catheterization of the branch of the right pudendal artery and its embolization with microspheres (embozene 250 μm) and with metal microcoils (striker 2 x 40 mm). the final angiographic check demonstrated the complete occlusion of the embolized arterial branch (figure 1). doi: 10.4081/aiua.2018.3.218 introduction high-flow (non-ischaemic, arterial) priapism is a nonsexual, persistent erection caused by unregulated cavernous arterial inflow. cavernous blood gases are not hypoxic or acidotic. typically the penis is neither fully rigid nor painful. in children this is a rare condition, usually due to a perineal trauma and does not require emergent treatment (1). case report we present the case of a 13-year-old prepubertal gymnast. he was performing an exercise on parallel bars. during a jump he hit a wooden bar with his genitalia, underwent perineal trauma and developed a high flow priapism. he had a scrotal hematoma, but he had no pain figure 1. angiography before and after embolization. bianchi em_stesura seveso 03/10/18 09:49 pagina 218 219archivio italiano di urologia e andrologia 2018; 90, 3 embolization for a high-flow priapism ta d afterwards, selective catheterization of the left hypogastric artery and of the left pudendal artery were performed and the angiography did’t show any arteriocavernosal fistula on this side (3). ultrasound performed after the procedure showed that the right pseudoaneurysm was completely obliterated and there were no more branches reaching it. the cavernous arteries were both pervious. conclusions selective arterial embolization is a safe and painless treatment that can also be used in young patients. references 1. hacker hw, schwoebel mg, szavay po. nonischemic priapism in childhood: a case series and review of literature. eur j pediatr surg. 2018; 28:255-260. 2. vega-vigo c, márquez-moreno aj, rojo-carmona le, castillo gallardo e. high-flow priapism caused by a pseudoaneurysm and an arteriocavernosal fistula: clinical and radiological approach of 3 cases. arch esp urol. 2014; 67:642-5. 3. bertolotto m, quaia e, mucelli fp, et al. color doppler imaging of posttraumatic priapism before and after selective embolization. radiographics 2003; 23:495-503. correspondence grazia bianchi, md (corresponding author) graziuccia88@libero.it giovanni liguori, md gioliguori33@gmail.com carlo trombetta, md trombcar@units.it università degli studi trieste, urology department – cattinara hospital, strada di fiume 447, trieste, italy camilla sachs, md cami_sachs@hotmail.it irene campo, md irenecampo11@gmail.com università degli studi trieste, radiology department – cattinara hospital, trieste, italy bianchi em_stesura seveso 03/10/18 09:49 pagina 219 293archivio italiano di urologia e andrologia 2017; 89, 4 original paper effectiveness on mild stress and mixed urinary incontinence and impact on quality of life of a phytotherapic product containing astragalus, thyme, lavender, hop, equisetum, red clover, cypress and agrimonia at titrated concentrations. results from a monocentric study oreste risi 1, michele manica 1, rocca carmela lisanti 2, antonio manfredi 1, giuseppe romeo tecci 1 1 ssd urodinamica e andrologia, asst bergamo ovest, italy; 2 uo urologia, humanitas cliniche gavazzeni, bergamo, italy. objectives: to assess any beneficial effect on quality of life of a daily treatment with a phytotherapic product containing astragalus, thyme, lavender, hop, equisetum, red clover, cypress and agrimonia at titrated concentrations in a cohort of female patients complaining mild stress urinary incontinence (sui) or mixed urinary incontinence (mui). materials and methods: 42 non-consecutive female out-patients with mild sui or mild mui were assessed with a clinical evaluation, international consultation on incontinence questionnaire short form (iciq-sf) and patients’ perception of intensity of urgency scale (ppius) at baseline the start of the study and after two months of therapy with the phytotherapic product. at the end of the therapy the patients also compiled patient global impression of improvement (pgi-i). results: after the completion of the study there was a trend towards better results in each item of iciq-sf, but without any statistical significance with an average score in iciq-sf-1 of 3.12 ± 0.981 versus 3.21 ± 0.914 (p = 0.556), in iciq-sf-2 of 3.69 ± 1.422 versus 3.79 ± 1.372 (p = 0.68) and in iciq-sf-3 of 5.95 ± 1.618 versus 6.14 ± 1.670 (p = 0.462). the average reduction of ppius was of 0.09 (1.26 ± 1.481 versus 1.357 ± 1.509, p = 0.705). there was a reduction of average consumption of pads/die from 1.69 ± 0.636 to 1.54 ± 0.543 (p = 0.101). in relation to the pgi score, 23/42 patients (54.7%) reported no changes after the completion of the therapy, 13/42 (30.9%) reported a slight improvement, 5/42 (11.9%) were much improved and 1/42 (2.3%) was slightly worsened. only 2/42 (4.7%) patients discontinued the treatment before of the completion of the study. we did not observe any adverse effects during the period of the study. conclusions: the phytotherapic product seems to cause a slight improvement of the symptoms in a good rate of patients. moreover it has a low rate of withdrawal, due to the lack of adverse events. key words: mixed urinary incontinence; stress urinary incontinence; phytoterapy; qol. submitted 7 march 2017; accepted 6 october 2017 summary no conflict of interest declared. sneezing or coughing. mixed urinary incontinence (mui) is defined as the involuntary loss of urine associated with urgency or with effort or physical exertion or on sneezing or coughing (1). in most studies the reported prevalence in females of isolated sui was of 10-39%, accounting for about a half of all the cases of urinary incontinence. mui is the second most common type, with reported prevalence of 7.5-25% in most studies (1). therefore sui and mui represent an important and common problem involving many women with a high social impact (2). nowadays, according to european association of urology guidelines, the first-line treatment for sui is a supervised intensive pelvic floor muscle training (pmft). biofeedback can be considered as an adjunct in these patients (3). duloxetine 80 mg was proposed as oral therapy for sui but there is no evidence suggesting that it can be offered to women who are seeking a definitive cure for their incontinence. furthermore duloxetine had a high withdrawal rate primarily because of the high rate of adverse events (3-6). therefore apart from the surgical treatment we have no other choice for sui treatment after the pmft and eventually the biofeedback. in mui, pmft seems to be less effective than in pure sui (7). both duloxetine and antimuscarinic drugs seem to be effective to treat sui but it is known that most patients stop drugs because of low level of efficacy, onset of adverse events and high costs of therapy (3, 5, 8). incontinenzamev® 1260 mg is a phytotherapic product with antioxidant properties, proposed as natural remedy to induce physiological effects optimizing the functions of the urinary tract: microcirculation, relaxation, connective tissue tropism. the aim of this study is to assess any beneficial effect on the quality of life (qol) of a daily treatment with incontinenzamev® in a cohort of female patients complaining mild sui or mui. materials and methods from june 2015 to june 2016, 42 female non-consecutive out-patients with a median age of 58 years (range doi: 10.4081/aiua.2017.4.293 introduction stress urinary incontinence (sui) is defined as the involuntary loss of urine on effort or physical exertion or on risi_stesura seveso 03/01/18 12:23 pagina 293 archivio italiano di urologia e andrologia 2017; 89, 4 o. risi, m. manica, r.c. lisanti, a. manfredi, g.r. tecci 294 35-72, mean) referring to the department of urodynamics and andrology of the asst bergamo ovest and suffering from mild sui or mild mui were treated with incontinenzamev® and prospectively evaluated. each patient was assessed before therapy (t0) with an accurate medical history, an urogynaecological examination, a comprehensive examination of urine including urine culture, a 3-day voiding diary, an evaluation of number of pads used per day, a 24-hour pad test, and a compilation of the international consultation on incontinence questionnaire short form (iciq-sf). moreover each patient compiled the patients’ perception of intensity of urgency scale (ppius), a patient-reported instrument to measure the intensity of the urgency. inclusion criteria were: mild sui or mild mui defined as a range of urine loss for the 24-hour pad test from 4 to 20 g, incontinence since at least 6 months, a positive stress-test. exclusion criteria were: positive urine culture, moderate and severe sui (urine loss > 20 g for the 24-hour pad test), concomitant complicating factors as previous surgery for incontinence, previous pelvic radiotherapy, grade 3 or symptomatic prolapse, hematuria, pain or pelvic mass. the 42 patients included in the study assumed incontinenzamev® one tablet/daily for two months. incontinenzamev® 1260 mg is a phytotherapic product containing astragalus, thyme, lavender, hop, equisetum, red clover, cypress and agrimonia at titrated concentrations. during the period of the study no other drugs for incontinence were administered. at the end of the therapy (t1) all the patients were interviewed again and compiled again iciq-sf and ppius. furthermore they filled the patient global impression of improvement (pgi-i), a 1-item questionnaire to evaluate the subjective feeling of improvement. the statistical analysis was performed using ibm spss statictics 23. the comparison of the data relative to iciq-sf an ppius before and at the end of the therapy was performed using wilcoxon signed ranks test. the comparison between the used pads was made with student's t-test. we considered statistically significant a p value ≤ 0.05. results eight out of 42 (19%) patients had a mui with relevant urgency incontinence, evaluated by ppius; 34/42 (81%) complained an isolated sui with (17/34) or without (17/34) urgency symptoms. after the completion of the study there was a trend towards better results in each item of iciq-sf, without any statistical significance with an average score in iciqsf-1 of 3.12 ± 0.981 versus 3.21 ± 0.914 (p = 0.556), in iciq-sf-2 of 3.69 ± 1.422 versus 3.79 ± 1.372 (p = 0.68) and in iciq-sf-3 of 5.95 ± 1.618 versus 6.14 ± 1.670 (p = 0.462). five out of 17 patients (29.4%) who reported urgency symptoms before the beginning of the therapy, improved their ppius score, while 1/17 reported a worse value. the average reduction of ppius was of 0.09 (1.26 ± 1.481 versus 1.357 ± 1.509, p = 0.705). none of the 8 patients with a component of urge incontinence (defined as an initial ppius score = 4) changed their initial value. there was a reduction of average consumption of pads/die from 1.69 ± 0.636 to 1.54 ± 0.543 (p = 0.101). these results are showed in table 1. with regard to the pgi score, 23/42 patients (54.7%) reported no changes after the completion of the therapy, 13/42 (30.9%) reported a slight improvement, 5/42 (11.9%) were much improved and 1/42 (2.3%) was slightly worsened. these results are described in figure 1. only 2/42 (4.7%) patient discontinued the treatment before of the completion of the study because of the lack of efficacy of treatment. we did not observe any adverse effects during the period of the study. discussion pharmacological treatment of stress and mixed urinary incontinence is still a hot topic because of the of low efficacy, the adverse events, and the high costs of the of the available drugs (3, 5, 8). approximately 50% of patients in treatment with antimuscarinic drugs discontinue therapy at 3 months, mainly because of the relevant side effects (9). in the last years mirabegron was proposed for the use in overactive bladder with a grade b of recommendation (3). this drug seems to cause less dry mouth than anticholinergic medications, however the incidence of other side effects such as constipation, hypertension and tachycardia is comparable (10). duloxetine was proposed besides pmft as oral therapy for sui with controversial results and high withdrawal rate (5). table 1. results of the iciq-sf, ppius, pads/die at t0 and at t1. t0 t1 δ p iciq-sf 1 3.21 ± 0.914 3.12 ± 0.981 0.09 0.556 iciq-sf 2 3.79 ± 1.372 3.69 ± 1.422 0.10 0.689 iciq-sf 3 6.14 ± 1.670 5.95 ± 1.618 0.19 0.462 ppius 1.357 ± 1.509 1.26 ± 1.481 0.09 0.705 n pads 1.69 ± 0.636 1.54 ± 0.543 0.15 0.101 figure 1. frequency distribution of the answers to pgi-i questionnaire: “check the number that best describes how your post-treatment condition is now, compared with how it was before you had the treatment”. risi_stesura seveso 03/01/18 12:23 pagina 294 in this study we evaluated the effects on mui and sui of a daily therapy with incontinenzamev, a new phytotherapic product. the main limitations of our study are monocentric design, low number of patients and lack of a placebo control group. given these limitations we observed a slight improvement in 30.9% of patients treated with the study product and a more consistent improvement in 5 patients of the series (11.9% of subjects.). these results are inferior respect to a recent study on mirabegron which prospectively evaluated pgi-i in 317 women after 6 weeks of drug therapy: 11% described themselves as “very much better” and a further 23% as “much better”. anyway the target of this study was different because only women with overactive bladder (oab) were selected. moreover there was a higher rate of withdrawal (14.6%) (11). the same considerations are possible for another study which evaluated the pgi scores in a series of 50 women patients treated with duloxetine for a pure sui: 65% showed improvement after a 12 weeks-treatment but the group was more homogeneous than ours. moreover also in this series there was a higher number of dropouts and adverse events (12). in our study all the questionnaires administrated showed a trend towards better scores after the two months of therapy but we had not a statistical significance. the more evident improvement was relative to the qol (iciq-sf-3). conversely an important result is the low rate of withdrawal during all the period of the study, probably due to the lack of adverse effects of this remedy for incontinence. conclusions to our knowledge this is the first study on incon ti nenzamev. with the limits of a small sample of patients and of the lack of a control group this product seems to cause a slight improvement of the symptoms in a good rate of patients. moreover unlike other drugs it has a very low rate of withdrawal. further studies with a control group are warranted to offer a recommendation and to better assess the target of this product. references 1. abrams p, cardozo l, khoury s, wein a. incontinence. 5th edition, icud-eau 2013. 2. cervigni m, gambacciani m. female urinary stress incontinence. climacteric. 2015; 18 suppl 1:30-6. 3. burkhard fc, lucas mg, berghmans jl, et al. eau guidelines on urinary incontinence in adults. european association of urology 2016. 4. shamliyan ta, kane rl, wyman j, wilt tj. systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. ann intern med. 2008; 148:459-73. 5. mariappan p, alhasso a, ballantyne z, et al. duloxetine, a serotonin and noradrenaline reuptake inhibitor (snri) for the treatment of stress urinary incontinence: a systematic review. eur urol. 2007; 51:67-74. 6. ghoniem gm, van leeuwen js, elser dm, et al. a randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence. j urol. 2005; 173:1647-53. 7. lagro-janssen t, van weel c. long-term effect of treatment of female incontinence in general practice. br j gen pract. 1998; 48:1735-8. 8. sears cl, lewis c, noel k, et al. overactive bladder medication adherence when medication is free to patients. j urol. 2010; 183:1077-1081. 9. wagg a, compion g, fahey a, siddiqui e. persistence with prescribed antimuscarinic therapy for overactive bladder: a uk experience. bju int. 2012; 110:1767-74. 10. warren k, burden h, abrams p. mirabegron in overactive bladder patients: efficacy review and update on drug safety ther adv drug saf. 2016; 7:204-6. 11. balachandran a, duckett j. the efficacy and tolerability of mirabegron in a non-trial clinical setting. eur j obstet gynecol reprod biol. 2016; 200:63-7. 12. deepak p, kumar tn, sen tk. evaluation of efficacy of duloxetine in stress urinary incontinence in women. indian j pharmacol. 2011; 43:176-9. 295archivio italiano di urologia e andrologia 2017; 89, 4 effectiveness on mild stress and mixed urinary incontinence and impact on quality of life of a phytotherapic product containing... correspondence oreste risi, md (corresponding author) oreste_risi@asst-bgovest.it michele manica, md, febu manicaxmichele@gmail.com antonio manfredi, md antonio_manfredi@asst-bgovest.it giuseppe romeo tecci, md rom.doc@libero.it ssd urodinamica e andrologia, asst bergamo ovest piazzale ospedale 1, 24047 treviglio (bg), italy rocca carmela lisanti, md rocca.lisanti@gavazzeni.it uo urologia, humanitas cliniche gavazzeni via mauro gavazzeni 21, 24125 bergamo (bg), italy risi_stesura seveso 03/01/18 12:23 pagina 295 archivio italiano di urologia e andrologia 2019; 91, 3174 original paper transurethral endoscopic approach for large bladder diverticula: evaluation of a large series mauro pacella 1, nicolò testino 1, guglielmo mantica 2, matteo valcalda 1, rafaela malinaric 1, carlo terrone 1 1 department of urology, policlinico san martino hospital, university of genova, genova, italy; 2 department of urology, san raffaele turro hospital, san raffaele university, milan, italy. objective: to present the results of the largest series of patients with bladder diverticula > 4 cm managed with an endoscopic approach and give tips about the execution of the procedure. materials and methods: data of male patients undergone the endoscopic approach for an acquired bladder diverticula > 4 cm from december 2004 to august 2018 were prospectively collected and retrospectively analyzed. the description of the monopolar and bipolar techniques are provided. the success of the procedure was defined as the reduction of the diverticula for more of the 80% of its initial diameter documented at the 3months follow-up imaging. continuous variables with nonparametric distribution were compared using the mann-whitney test, while frequencies of categorical variables were compared between groups by fisher’s exact test with significance level set at 0.05. results: thirty-nine patients with a mean (+/sd) age at surgery of 69.4 ± 8.8 years were enrolled, for an equal number of diverticula managed. the mean diverticular size was 75.1 ± 24.5 millimeters. the mean operative time was 65 ± 21.9 minutes including the prostate surgery. twelve patients (30.8%) were managed with bipolar energy, the others with monopolar. the success of the procedure was achieved in 30 patients (76.9% 7 bipolar and 23 monopolar p = 0.66). conclusions: the endoscopic approach might be considered as a useful option for patients with a large bladder diverticulum who are at risk for major or laparoscopic procedures. key words: bladder diverticula; bph; urinary retention; holep; turp. submitted 21 april 2019; accepted 2 may 2019 summary no conflict of interest declared. laparoscopic or robotic approach. the endoscopic approach using the orandi technique is usually reserved, during other endoscopic procedures, to diverticula less than 4 cm diameter, which are less likely to cause symptoms (1-3). recently, some authors have proposed the endoscopic management with good success also for large diverticula (4-6). we aim to present the results of the largest series of patients with bladder diverticula > 4 cm managed with an endoscopic approach and give tips about the execution of the procedure. materials and methods the characteristics, intraand perioperative data, as well as the follow-up of male patients undergone the endoscopic approach for an acquired bladder diverticula from december 2004 to august 2018 were prospectively collected and retrospectively analyzed. the inclusion criteria were the presence of at least a diverticulum with a major diameter > 4 cm in a patient with comorbidities, an american society of anesthesiology score (asa score) ≥ 2 and a charlson comorbidity index ≥ 3. the preoperative assessment included routine blood tests with serum creatinine, urinalysis, trans-rectal ultrasound (trus), and ct scan or conventional cystogram, uroflometry, international prostatic symptoms score (ipss), serum prostate specific antigen (psa), serum creatinine, urinalysis and urine culture. at a 3 months follow-up all patients included in the study underwent a control cystogram or kidney-ureter-bladder (kub) ultrasound. the success of the procedure was defined as the reduction of the diverticula for more of the 80% of its initial diameter. complications were graded using the claviendindo classification (7). surgery is carried out with the patient in lithotomic position. a meticulous cystoscopy is performed and the subsequent step consist in the fulguration of the whole diverticular mucosa with a rollerball electrode using either the monopolar or bipolar energy source, with a coagulation setting respectively of 60-70 w and 70-80 w. the following step is the incision of the diverticular neck in four different cardinal points (12-3-6-9) and then the flattening of the entire diverticular neck circumference with the same rollerball electrode using plasma vaporization doi: 10.4081/aiua.2019.3.174 introduction acquired bladder diverticula are a herniation of the mucosa through the detrusor muscle and are mainly secondary to an outlet obstruction typically caused by benign prostate enlargement, bladder neck contracture and urethral stenosis. for these reasons, acquired bladder diverticula are usually a disease affecting the elderly male population. the surgical management of a bladder diverticulum itself is not always mandatory but often, especially if of big dimensions, they can lead to post void residual urine, lithiasis, urinary tract infections and ureteral compression. mandatory should be the resolution of the obstruction, while the surgical management of the diverticula is mostly carried out through an open, pacella_stesura seveso 30/09/19 18:22 pagina 174 175archivio italiano di urologia e andrologia 2019; 91, 3 endoscopic approach to manage large bladder diverticula (160 w for monopolar, 180 w for bipolar). subsequently the management of the primary obstruction is carried out (either with a turp, tuip, or other endoscopic procedures) and a 3 ways catheter inserted. all cases were performed by a single urologist (m.p.). an antibiotic prophylaxis (cefazolin 1000 mg), or according to the urinalysis, was started 30 min before surgery. antithrombotic prophylaxis with low-molecular weight heparin was administered when needed according to our department protocol. a 3 months follow up included conventional or ct cystography and abdominal, in addition to physical examination, uroflowmetry and ipss. demographic and clinical characteristics and perioperative data were expressed as the mean ± standard deviation (sd), median with interquantile range (iqr) or as count with percentage. continuous variables with nonparametric distribution were compared using the mann-whitney test, while frequencies of categorical variables were compared between groups by fisher’s exact test with significance level set at 0.05. data were analyzed with sofastat tm for windows. results thirty-nine patients with a mean (+/sd) age at surgery of 69.4 ± 8.8 years were enrolled, for an equal number of diverticula managed. the mean diverticular size was 75.1 ± 24.5 millimeters. six patients (15.4%) underwent general anesthesia while 33 (84.6%) spinal anesthesia. eight patients (20.5%) had a tuip while 31 (79.5%) a turp. the mean operative time was 65 ± 21.9 minutes including the prostate surgery. twelve patients (30.8%) were managed with bipolar energy, the others with monopolar. the success of the procedure was achieved in 30 patients (76.9% 7 bipolar and 23 monopolar p = 0.66 groups not significantly different in terms of age, asa, charlson, prostate size, diverticular size, ipss). the tendency of the diverticulum was to progressively decrease in the first 12 weeks after surgery and during following months (figures 1-2). the catheter was removed at a median time of 10 (8-12) days and the median length of stay was 5 (4-6) days. none of the patients required a blood transfusion. no major complications (clavien-dindo > 2) were seen, while 2 patients (5.1%) developed postoperative fever managed with antibiotic therapy. the median ipss change was 62% (-74% to -46%). discussion the genesis of the diverticula in obstructed patients is determined by the high pressures generated into the bladder during the voiding contraction of the detrusor muscle. during this process, the mucosa extrude through the weakest points of the bladder muscular wall leading to the formation of the bladder diverticula. the need for treatment of secondary bladder diverticula is a debated topic. large bladder diverticula may lead to post void residual urine, lithiasis, urinary tract infections and ureteral compression. for these reasons, some authors have proposed several open or mini-invasive laparoscopic and robotic surgical approaches (8-12). these approaches showed to be successful both in terms of disappear of the diverticulum and symptoms improvement despite often very high operative times. obviously, they were associated to endoscopic surgery in order to manage the causing obstruction. on the contrary, other authors do not see the need to intervene surgically for these benign pathologies, and they place surgical attention only on the underlying cause (13). agarwal et al. evaluated the results of patients with bladder diverticula and outlet obstruction undergone holep alone (13). they found a significant improve in the post-void residual, peak flow and symptoms at a 15 months follow-up, and only 6% of patients requiring diverticulectomy. they concluded that most of patient, even with large diverticula, can avoid more invasive surgical approaches whether the outlet obstruction has been relieved. recently, an in vivo study on rats showed how large bladder diverticula can alter bladder storage and emptying and can lead to dysfunctional voiding (14). furthermore, bladder diverticula with a diameter > 5 cm seems to increase the risk of acute urinary retention in figure 1. patient a – progressive reduction of the diverticular diameter. images at 0-6-12 weeks. figure 2. patient b – complete disappearance of a bladder diverticulum at a ct-scan performed 3 years later for other reasons. pacella_stesura seveso 30/09/19 18:22 pagina 175 archivio italiano di urologia e andrologia 2019; 91, 3 m. pacella, n. testino, g. mantica, m. valcalda, r. malinaric, c. terrone 176 benign prostatic hyperplasia (bph) patients (15). these studies suggest that, in some cases, the surgical management of large bladder diverticula may be necessary. several reports in literature have described the use of endoscopic management of bladder diverticula. orandi et al. published the first report on a series of 17 patients who underwent transurethral fulguration: a complete resolution was achieved in five patients and a decrease in volume in nine (1). likewise, clayman et al. managed six patients obtaining a complete disappear of the diverticulum in five of them and a size reduction in the other (3). yamaguchi et al. reported the most recent and largest series of bladder diverticula fulguration in 1992: twentysix out of thirty-one patients showed a complete resolution (16). in all these studies the size of the managed diverticula was heterogeneous. recently, some authors have proposed the endoscopic management with good success also for large diverticula (4-6). the complete disappearance of the diverticulum may take several months and it depends mainly on the initial dimensions of the diverticulum itself. the pathophysiological process behind these results is not completely clear. the effect of the fulguration of the mucosa may involves also the underlying submucosa, causing ischemia of the diverticular wall and leading to a consequent progressive atrophy. this may determine the progressive retraction and the final disappearance of the diverticulum. data from our study shows that it’s effective in terms of symptoms improvement, with low complication rate and a very short operative time. it adds only few minutes to the mandatory management of the causing obstruction (tuip/turp/holep/thulep/etc), it’s safe, cost-effective and if it fails it doesn’t preclude a subsequent further management through a laparoscopic or robotic approach. with the limit of the small samples, it showed similar outcomes whether performed with monopolar or bipolar energy. the fact that is retrospective and the absence of a group of control undergone another procedure are the main limits of the study. however, we believe it has been successful in showing the possible role of this mini-invasive surgical approach. conclusions although the endoscopic management of large bladder diverticula doesn’t guarantee the same successful rate and radicality of other open or minimally-invasive procedures it showed some advantages such a very short operative time and the possibility to be performed under spinal anesthesia (8-10). furthermore, patients in which the procedure fail can still be further managed with a subsequent different and more radical approach. for these reasons we believe it should be considered as a useful option for patients at risk for major or laparoscopic procedures. references 1. orandi a. transurethral fulguration of bladder diverticulum: new procedure. urology. 1977; 10:30-32. 2. vitale pj, woodside jr. management of bladder diverticula by transurethral resection: re-evaluation of an old technique. j urol. 1979; 122:744. 3. clayman rv, shahin s, reddy p, et al. transurethral treatment of bladder diverticula. alternative to open diverticulectomy. urology. 1984; 23:573. 4. pham kn, jeldress c, hefty t, et al. endoscopic management of bladder diverticula. rev urol. 2016; 18:114-117. 5. chandhoke ra, ghoniem gm. transurethral electrovaporization of bladder diverticulum: an alternative to open or laparoscopic bladder diverticulectomy. j endourol case rep. 2015; 1:11-13. 6. pacella m, mantica g, maffezzini m, et al. large bladder diverticula: a comparison between laparoscopic excision and endoscopic fulguration. scand j urol. 2018; 52:134-138. 7. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 8. rifaioglu mm, warman i, rassweiler j, gözen as. robotic-assisted bladder diverticulectomy. cent european j urol. 2016; 69:238. 9. cacciamani g, de luyk n, de marco v, et al. robotic bladder diverticulectomy: step-by-step extravesical posterior approach technique and outcomes. scand j urol. 2018; 52:285-290. 10. altunrende f, autorino r, patel ns, et al. robotic bladder diverticulectomy: technique and surgical outcomes. int j urol. 2011; 18:265-271. 11. tufek i, mourmouris p, argun ob, et al. robot-assisted bladder diverticulectomy with concurrent management of bladder outlet obstruction. urol int. 2016; 96:432-7. 12. porpiglia f, tarabuzzi r, cossu m, et al. is laparoscopic bladder diverticulectomy after transurethral resection of the prostate safe and effective? comparison with open surgery. j endourol 2004; 18:73-76. 13. agarwal dk, krambeck ae. holmium laser enucleation of the prostate is an effective treatment in patients with concomitant bladder diverticula and outlet obstruction. world j urol. 2018; 36:87-90. 14. celebi s, kuzdan ö, özaydın s, et al. the effect of bladder diverticula on bladder function: an experimental study in rabbits. j pediatr surg. 2016; 51:1538-42. 15. iscaife a, dos anjos g, barbosa c neto, et al. the role of bladder diverticula in the prevalence of acute urinary retention in patients with bph who are candidates to surgery. int braz j urol. 2018; 44:765-770. 16. yamaguchi k, kotake t, nishikawa y, et al. transurethral treatment of bladder diverticulum. urol int. 1992; 48:210-212. correspondence guglielmo mantica, md guglielmo.mantica@gmail.com department of urology, san raffaele turro hospital, san raffaele university via stamira d’ancona 20, 20127 milano (italy) mauro pacella mauropacella@virgilio.it nicolò testino nicolo.testino@live.it matteo valcalda matteo.valcalda@gmail.com rafaela malinaric rafaela.malinaric@gmail.com carlo terrone carlo.terrone@med.uniupo.it department of urology, policlinico san martino hospital, university of genova, genova (italy) pacella_stesura seveso 30/09/19 18:22 pagina 176 163archivio italiano di urologia e andrologia 2019; 91, 3 original paper assesment of anogenital distance as a marker in diagnosis of prostate cancer aytac sahin, musab ali kutluhan, tuncay toprak, yasin vural, ahmet ürkmez, serkan akan, ayhan verit urology department, fatih sultan mehmet training and research hospital, istanbul, turkey. objectives: anogenital distance (agd), the distance from the sexual organs to the anus, is a sexually dimorphic feature in mammals. in this study, we investigated the relationship between anogenital distance and prostate cancer (pca). methods: 52 patients diagnosed with pca and 60 patients with benign prostate hyperplasia as a control group were included in the study. agdap (cephalad insertion of the penis to the center of the anus) and agdas (posterior base (first fold) of the scrotum to the center of the anus) measurements of patients were done and noted before biopsy. results: the mean ages of 52 patients diagnosed with pca and 60 patients with benign prostatic hyperplasia (bph) were 67.70 ± 7.74 and 67.03 ± 7.89, respectively. there was no statistically significant difference in terms of age and serum testosterone levels of the patients diagnosed with prostate cancer or bph (p > 0.05). mean psa values of patients diagnosed with prostate cancer wto be statistically higher than patients with bph (p = 0.000). the mean agdap measurements of patients diagnosed with prostate cancer were statistically higher than those diagnosed with bph (p = 0.000) and there was no significant difference in agdas measurements.(p = 0.823; p > 0.05). conclusions: androgen exposure is thought to play a role in the development pca. also agd may be an indicator of prenatal androgen activity. in our study, we found a direct correlation between agdap and pca. in order to reach a definitive conclusion, randomized controlled trials with larger sample number are needed. key words: anogenital distance; prostate cancer; benign prostate hyperplasia; androgens. submitted 12 june 2019; accepted 26 july 2019 summary no conflict of interest declared. chemicals, such as dioxins that exhibit antiandrogenic activity results in shorter agd distances in rat models (7). further exposure to prenatal androgen causes longer agd development. therefore, agd may be an indicator of prenatal androgen activity (8). in human models studies have shown that, exposures to endocrine disruptors, such as dichlorodiphenyltrichloroethane metabolites, phthalates, dioxins and bisphenol a have been related with shorter agd (9-12). additionally, it was founded that children who had cryptorchidism orhypospadias have shorter agd (13). men with prostate cancer also have shorter agd compared to a control group (14). in this study, we investigated the relationship between anogenital distance and prostate cancer. materials and methods the study was conducted in accordance with the helsinki declaration. all participants gave informed consent for participation. the study was approved by the ethics committee of fatih sultan mehmet training and research hospital. patients diagnosed with prostate cancer with transrectal prostate biopsy due to psa elevation (psa > 2.5 ng/dl) in the urology clinic of fatih sultan mehmet training and research hospital were included in the study. the control group consisted of patients with lower urinary tract complaints who were diagnosed with benign prostate hyperplasia with transrectal prostate biopsy due to psa elevation (psa > 2.5 ng/dl). body mass index (bmi) was calculated as weight in kilograms divided by squared height in meters. two agd variants; agdap, (from the center of the anus to the cephalad insertion of the penis) and agdas, (from the center of the anus to the posterior base of the scrotum) were evaluated (15-16). a digital caliper was used for measuring agd variants in lithotomy position with his thighs at a 45° angle to the examination table. agdap and agdas was measured by two separate physicians and each agd variant was measured three times. the average was calculated. adjustment was made for body mass index instead of weight and height. results a total of 112 patients with age ranging 47-86 years of age were included in the study between april 2018 and doi: 10.4081/aiua.2019.3.163 introduction anogenital distance (agd), the distance from the sexual organs to the anus, is a sexually dimorphic feature in mammals (1). the researchers used agd as a measure of genital development and androgen status to measure reproductive toxicity in both experimental animals and humans. agd is androgen dependent and males have longer agd measures than females (2-4). studies showed that agd is determined in utero and persists during adulthood (5). however, it has been shown that in rats agd shows a plasticity that can be mediated by local androgen/estrogen effect (6). in animals, it has been shown that anogenital distance can change with the effect of fetal androgens. exposure to sahin1_stesura seveso 30/09/19 18:20 pagina 163 archivio italiano di urologia e andrologia 2019; 91, 3 a. sahin, m. ali kutluhan, t. toprak, y. vural, a. ürkmez, s. akan, a. verit 164 may 2019. the mean age of 52 patients diagnosed with prostate cancer was 67.70 ± 7.74; the mean age of 60 patients with benign prostate hyperplasia (bph) was 67.03 ± 7.89. there was no statistically significant difference in terms of age of the patients diagnosed with prostate cancer or bph (p > 0.05). mean psa values of patients diagnosed with prostate cancer were found to be statistically higher than patients with bph (p = 0.000) and there was no statistical difference in terms of serum testosterone levels (p > 0.05). the mean agdap measurements of patients diagnosed with prostate cancer was statistically higher than those diagnosed with bph (p = 0.000) whereas there was no significant difference in agdas measurements.(p = 0.823; p > 0.05) (table 1). there was a statistically significant difference between patients with prostate cancer and bph in terms of bmi averages (p = 0.043; p < 0.05). adjusted agdap values obtained by dividing the agdap by bmi values were significantly higher in the prostate cancer group than in the bph group (p = 0.007). on the other hand there was no statistically significant difference in adjusted agdas (agdas/bmi) values (p > 0.05). statistical analysis while evaluating the findings obtained in the study, ibm spss statistics 25 program was used for statistical analysis.the fit of the parameters to normal distribution was evaluated by shapirowilks test. in addition to descriptive statistical methods (mean, standard deviation), student's t-test was used for comparison of quantitative data between two groups of parameters that were normally distributed. significance was determined as p < 0.05. discussion we investigated the relationship between agd, which is a biological marker of prenatal androgen exposure, and pca. anogenital distance is a sexually dimorphic feature, which is longer in males than in females (17). androgens are necessary for normal development of prostate (18, 19). in a study by castano et al., men with prostate cancer showed shorter agd compared to control group (14). maldonado et al. found that patients with longer agdas had higher cancer severity (20). boyle et al. reported that prostate cancer patients were more exposed to prenatal androgens and their findings are consistent with hypothesis suggesting a relationship between testosterone levels and severity of pca (21). studies reported that there was a relationship between agdas and testosterone levels in both men and women (22, 23). a longer agdas is an indicator of more androgenic prenatal hormonal environment. therefore, it may affect the proliferation of leydig cells, which will cause higher androgen levels in adulthood (24). for this reason, having a longer agdas may increase the possibility that testosterone will be higher in adulthood, resulting in a greater risk of developing a more severe prostate cancer. on the other hand a review (25) reported that, there is no obvious indication that endogenous testosterone is positively correlated with prostate cancer and because of that it does not directly correlate with the aggression of the prostate cancer. there are also additional reports that prostate cancer development is independent of endogenous testosterone levels (26). data obtained from the current literature indicate that testosterone replacement therapy (trt) can be given with the condition that close follow-up is applied to symptomatic hypogonadal patients who underwent radical prostatectomy, brachytherapy or external radiotherapy because of prostate cancer (27). in our study there was no statistical significant difference between groups in terms of serum testosterone levels (p > 0.05). also there was no significant difference between groups in terms of agdas measurements (p = 0.823; p > 0.05) and adjusted agdas (agdas/bmi) values. (p > 0.05). in our study, agdap measurements were significantly higher in the prostate cancer group. also according to adjusted agdap (agdap/bmi) values obtained by dividing agdap by bmi, it was found to be statistically higher in pca group compared to bph group (p = 0.007). however, it is difficult to establish a relationship between testosterone and pca because it is difficult to predict the current testosterone levels of an individual in clinical practice. firstly the methods used to measure testosterone are variable. secondly testosterone levels in an individual can be variable at any time of the day. therefore singular measures are not a good indicator of normal testosterone levels. porcaro et al. (28) reported that pca was significantly associated with serum total testosterone. another study from spain reported that longer agd was associated with lower risk of pca (14). hsieh et al. showed that shorter agdas measurements is associated with genital anomalies (cryptorchidism or hypospadias) in men and established a link between normal genital development and agd in humans (29). furthermore, in many studies, agdap measurements have been found to be associated with prenatal exposure and prostate cancer to endocrine disruptors (30-34, 14). agdas measurements were associated with semen quality and other reproductive hormones (15, 22 to 23). table 1. comparison of patients diagnosed with prostate cancer and bph. prostate ca (n = 52) bph (n = 60) p mean ± sd mean ± sd age (years) 67.70 ± 7.74 67.03 ± 7.89 0.498 psa (ng/ml) 13.78 ± 10.44 8.22 ± 3.23 0.000** testosterone (ng/ml) 4.06 ± 117 4.37 ± 1.77 0.292 bmi (kg/m2) 28.23 ± 3.0 27.05 ± 3.04 0.043* agdap (cm) 13.9 ± 1.31 12.58 ± 1.73 0.000** agdas (cm) 4.91 ± 1.20 4.96 ± 0.89 0.823 adjusted agdap (agdap/bmi) 0.49 ± 0.07 0.46 ± 0.04 0.007* adjusted agdas (agdas/bmi) 0.17 ± 0.04 0.18 ± 0.03 0.312 independent student t test *p<0.05 **p<0.001 sahin1_stesura seveso 30/09/19 18:20 pagina 164 as can be seen, many studies have been conducted in different areas related to anogenital distance and there are no clear results yet. therefore, it is not true to hold only androgens responsible for the development of prostate cancer. further experimental studies are needed for relationship between agd (agdap and agdas) and fetal androgen exposure. limitations of the study the main limitation of our study was that although the patients with psa values of 2.5 ng/dl and above were taken in both groups and histologically differentiated as benign prostatic hyperplasia and prostate cancer by transrectal biopsy, the mean psa value of the control group was statistically lower than the prostate cancer group. choosing patients with similar psa values and prostate volumes in both groups could be better in terms of excluding androgen exposure and agd relationship. additionally, the methods used to measure testosterone are variable. testosterone levels in an individual can be variable at any time of the day.therefore, singular estimates are not a good indicator of normal testosterone levels. so, it is difficult to state anything definite about testosterone levels. conclusions there is a scarce number of studies in the literature about the relationship between anogenital distance and prostate cancer. androgen exposure is thought to play a role in the development of pca, but recent studies demonstrated that there is no relationship between androgens and prostate cancer. on the other hand there are different conclusions about relationship between agd and prostate cancer. in our study, we found a direct correlation between agdap and prostate cancer. in order to reach a definitive conclusion, randomized controlled trials with larger sample number are needed. references 1. sathyanarayana s, beard l, zhou c, grady r. measurement and correlates of ano-genital distance in healthy, newborn infants. int j androl. 2010; 33:317-23. 2. salazar-martinez e, romano-riquer p, yanez-marquez e, et al. anogenital distance in human male andfemale newborns: a descriptive, crosssectional study. environ health. 2004; 3:8. 3. scott hm, hutchison gr, jobling ms, et al. relationship between androgen action in the “maleprogramming window”, fetal sertoli cell number, and adult testis sizein the rat. endocrinology. 2008; 149:5280-7. 4. swan sh. environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. environ res. 2008; 108:177-84. 5. hotchkiss ak, parks-saldutti lg, ostby js, et al. a mixture of the ‘anti-androgens’ linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. biol reprod. 2004; 71:1852-61. 6. mitchell rt, mungall w, mckinnell c, et al. anogenital distance plasticity in adulthood: implications for its use as a biomarker of fetal androgen action. endocrinology. 2015; 156:24-31. 7. faqi as, dalsenter pr, merker hj, chahoud i. reproductive toxicity andtissue concentrations of low doses of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin inmale offspring rats exposed throughoutpregnancy and lactation . toxicol appl pharmacol. 1998; 150:38392. 8. gray le jr, wilson vs, stoker t, et al. adverse effects of environmental anti-androgens and androgens on reproductive development in mammals. int j androl. 2006; 29:96-104. 9. suzuki y, yoshinaga j, mizumoto y, et al. foetal exposure to phthalate esters and anogenital distance in malenewborns. int j androl. 2012; 35:236-44. 10. bustamante-montes lp, hernandez-valero ma, florespimentel d, et al. prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. j dev orig health dis. 2013; 4:300-6. 11. bornehag cg, carlstedt f, jonsson ba, et al. prenatal phthalate exposuresand anogenital distance in swedish boys. environ health perspect. 2015; 123:101-7. 12. miao m, yuan w, he y, et al. inutero exposure to bisphenol-a and anogenital distance of maleoffspring. birth defects res a clin mol teratol. 2011; 91:867-72. 13. jain vg, singal ak. shorter anogenital distance correlates with undescended testis: a detailed genital anthropometric analysis in human newborns. hum reprod. 2013; 28:2343-9. 14. castano-vinyals g, carrasco e, lorente ja, et al. anogenital distance and the risk of prostate cancer. bju int. 2012; 110:e70710. 15. mendiola j, stahlhut rw, jørgensen n, et al. shorter anogenital distance predicts poorer semen quality in young men in rochester, new york. environ health perspect. 2011; 119:958-63. 16. parra md, mendiola j, jørgensen n, et al. anogenital distance and reproductive parameters in young men. andrologia. 2016; 48:3-10. 17. kurzrock ea, jegatheesan p, cunha gr, baskin ls. urethral development in the fetal rabbit and induction of hypospadias: a model for human development. j urol. 2000; 164:1786-92. 18. wilson jd. the critical role of androgens in prostate development. endocrinol metab clin n am. 2011; 40:577-90. 19. yassin a, alrumaihi k, alzubaidi r, et al. testosterone, testosterone therapy and prostate cancer. aging male. 2019; 7:1-9. 20. maldonado-cárceles ab, sánchez-rodríguez c, vera-porras em, et al. anogenital distance, a biomarker of prenatal androgen exposure is associated with prostatecancer severity. prostate. 2017; 77:406-11. 21. boyle p, koechlin a, bota m, et al. endogenous and exogenous testosterone and the risk of prostate cancer and increased prostatespecific antigen (psa) level: a meta-analysis. bju int. 2016; 118:731-41. 22. eisenberg ml, jensen tk, walters rc, et al. the relationship between anogenital distance and reproductive hormone levels in adult men. j urol. 2012; 187:594-8. 23. eisenberg ml, hsieh mh, walters rc, et al. the relationship between anogenital distance, fatherhood, and fertility in adult men. plos one 2011; 6:e18973. 24. wilson jean d. role of androgens in prostate development. endocrinol metab clin north am. 2011; 40:577-590. 25. endogenous hormones and prostate cancer collaborative group, roddam aw, allen ne et al: endogenous sex hormones and 165archivio italiano di urologia e andrologia 2019; 91, 3 assesment of anogenital distance as a marker in diagnosis of prostate cancer sahin1_stesura seveso 30/09/19 18:20 pagina 165 archivio italiano di urologia e andrologia 2019; 91, 3 a. sahin, m. ali kutluhan, t. toprak, y. vural, a. ürkmez, s. akan, a. verit 166 prostate cancer: a collaborative analysis of 18 prospective studies. j natl cancer inst 2008; 100: 170 26. xu x, chen x, hu h, et al. current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. bmc cancer. 2015; 15: 806. 27. morgentaler a, conners iii wp. testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. asian j androl. 2015; 17:206-11. 28. porcaro ab, petroziello a, brunelli m, et al. high testosterone preoperative plasma levels independently predict biopsy gleason score upgrading in men with prostate cancer undergoing radical prostatectomy. urol int. 2016; 96:470-8. 29. hsieh mh, eisenberg ml, hittelman ab, et al. caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. hum reprod. 2012; 27:1577-80. 30. swan sh, sathyanarayana s, barrett es, et al. tides study team. first trimester phthalate exposure and anogenital distance in newborns. hum reprod. 2015; 30:963-72. 31. miao m, yuan w, he y, et al. in utero exposure to bisphenol-a and anogenital distance of male offspring. birth defects res a clin mol teratol. 2011; 91:867-72. 32. bustamante-montes lp, hernandez-valero ma, florespimentel d, et al. prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. j dev orig health dis. 2013; 4:300-6. 33. stamatiou k, pierris n. could testosterone have a therapeutic role in prostate cancer? urol j. 2013; 10:747-54. 34. vafeiadi m, agramunt s, papadopoulou e, et al. in utero exposure to dioxins and dioxin-like compounds and anogenital distance in newborns and infants. environ health perspect. 2013; 121:125-30. correspondence aytac sahin, md draytacsahin@gmail.com musab ali kutluhan, md dr.musab151@gmail.com tuncay toprak, md drtuncay55@hotmail.com yasin vural, md yasin_vural@windowslive.com ahmet ürkmez, md ahmeturkmez@hotmail.com serkan akan, md drserkanakan@hotmail.com ayhan verit, md veritayhan@yahoo.com urology department, fatih sultan mehmet training and research hospital, istanbul (turkey) sahin1_stesura seveso 30/09/19 18:20 pagina 166 archivio italiano di urologia e andrologia 2017; 89, 2110 original paper a phase ii, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii giuseppe morgia, giorgio ivan russo, daniele urzì, salvatore privitera, tommaso castelli, vincenzo favilla, sebastiano cimino urology section, department of surgery, university of catania italy. objective: the management of chronic prostatitis/chronic pelvic pain syndrome type iii (cp/cpps) has been always considered complex due to several biopsychological factors underling the disease. in this clinical study, we aimed to evaluate the efficacy of the treatment with curcumin and calendula extract in patients with cp/cpps iii. material and methods: from june 2015 to january 2016 we enrolled 60 consecutive patients affected by cp/cpps iii in our institution. patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total national institutes of health chronic prostatitis symptom index (nih-cpsi) score ≥ 15 point and diagnosed with nih category iii. patients were then allocated to receive placebo (group a) or treatment (group b). treatment consisted of rectal suppositories of curcumin extract 350 mg (95%) and calendula extract 80 mg (1 suppository/die for 1 month). patients of group b received 1 suppository/die for 1 month of placebo. the primary endpoint of the study was the reduction of nih-cpsi. the secondary outcomes were the change of peak flow, iief-5, vas score and of premature ejaculation diagnostic tool (pedt). results: a total of 48 patients concluded the study protocol. the median age of the all cohort was 32.0 years, the median nih-cpsi was 20.5, the median iief-5 was 18.5, the median pedt was 11.0, the median vas score was 7.5 and the median peak flow was 14.0. after 3 months of therapy in group a we observed a significant improvement of nih-cpsi (-5.5; p < 0.01), iief-5 (+ 3.5; p < 0.01), pedt (-6.5; p < 0.01), peak flow (+2.8; p < 0.01) and vas (-6.5; p < 0.01) with significant differences over placebo group (all p-value significant). conclusions: in this phase ii clinical trial we showed the clinical efficacy of the treatment with curcumin and calendula in patients with cp/cpps iii. the benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. these results should be confirmed in further studies with greater sample size. key words: chronic prostatitis; chronic pelvic pain syndrome type iii; pain; prostate; inflammation. submitted 21 november 2016; accepted 11 january 2017 summary no conflict of interest declared. mechanisms is still lacking due the heterogeneous risks factors and associated conditions. moreover, psychological condition and other trigger factors like infection or inflammation may act amplifying the cp/cpps mechanisms. based on this premise, cp/cpss may negatively impact the quality of life (qol) the psychological aspects of the patients. for all these reasons, the treatment strategies are different and may not necessarily determine a clinical efficacy, due the discrepancy in the treatment effects reported in case series and controlled trials that results from a large placebo effect or publication bias (5, 6). among all therapies, phytotherapy has been largely used applying research to the practice of herbal medicine (7). the effect of such therapy is mainly based on the reduction of pain and in improving qol, added to a mild anti-inflammatory effect. in this context, calendula officinalis linn. (asteraceae) has been a subject of several chemical and pharmacological studies and it has been used especially for wound healing, jaundice and as an antispasmodic. previously published results indicated that c. officinalis posses multiple pharmacological activities including antiinflammatory and antioedematous, antioxidant, immunostimulant, wound healing, hepatoprotective, antibacterial and antifungal and antiviral (8). in addition, numerous lines of evidence have indicated curcuma longa (turmeric) ability in modulating multiple cell signaling molecules such as pro-inflammatory cytokines (tumor necrosis factor (tnf)-α, interleukin (il)-1β, il-6), apoptotic proteins, nf-κb, cyclooxygenase (cox)-2, stat3, ikkβ, endothelin-1, malondialdehyde (mda). there are some evidences about rectal therapies with corticosteroids in patients with cp/cpss, showing better drug’s good safety profile and improving main storage symptoms and clinical findings associated with lower urinary tract inflammation in patients treated with beclomethasone di-propionate suppositories (9). materials and methods from june 2015 to january 2016 we enrolled 60 consecutive patients affected by cp/cpps iii in our institution. patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study according doi: 10.4081/aiua.2017.2.110 introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is one of the most common disease of men under 50 and costly medical condition (1-4). unfortunately, the understanding of the underlying morgia_stesura seveso 26/06/17 09:44 pagina 110 111archivio italiano di urologia e andrologia 2017; 89, 2 treatment of chronic prostatitis/chronic pelvic pain syndrome type iii to european association of urology (eau) guidelines, a negative 4-glass test meares-stamey test and a total national institutes of health chronic prostatitis symptom index (nih-cpsi) score ≥ 15 point were included in the study protocol. patients diagnosed with nih category iiia and iiib using the ppmt (preand post-massage test) have been enrolled. category iiia refers to the presence of white blood cells (wbc) after a prostate massage urine specimen (vb3) (wbc in vb3 > 10/hps). category iiib refers to patients with pelvic pain with no evidence of inflammation on vb3. patients with urinary tract infection urethritis, sexually transmitted disease (std), treatment with phytotherapeutic agents, alpha-blockers or antibiotics, urogenital cancer were excluded from the study. at baseline subjects underwent uroflowmetry to evaluate the peak flow and the post void residual (pvr) and they filled out the international index of erectile function questionnaire (iief-5), the premature ejaculation diagnostic tool (pedt) and the visual analogue score (vas). patients were then randomized to receive treatment (group a) or placebo (group b). treatment consisted of rectal suppositories of curcumin extract 350 mg (95%) and calendula extract 80 mg (1 suppository/die for 1 month). patients of group b received 1 suppository/die for 1 month of placebo that exhibited identical characteristics of the treatment. sample-size calculations were based on 80% power to detect a decline of 5 or more points in the nih-cpsi total score between both groups, using a mean of the nihcpsi of 25 and a standard deviation of 5 based on previous publication and requiring 24 subjects per group. the sample size has been set to 60 allowing a 15% of drop-out rate. the study has been approved the local ethic committee of the university of catania. clinical examination and questionnaires were collected after 3 months of therapy. all subjects gave written informed consent before entering the study, which was conducted in accordance with the declaration of helsinki, and the human ethics committee approved the study protocol. statistical analysis the primary endpoint of the study was the reduction of nih-cpsi. the secondary outcomes were the change of peak flow, iief-5, vas and of premature ejaculation diagnostic tool (pedt). sample-size calculations were based on 80% power to detect a decline of 5 or more points in the nih-cpsi total score between both groups, using a mean of the nih-cpsi of 25 and a standard deviation of 5 based on previous publication (nickel et al.) (10) and requiring 24 subjects per group. the sample size has been set to 60 allowing a 15% of drop-out rate. the mann-whitney u test was used for comparisons in the distribution of nonnormal variables between a pair of treatment. the efficacy variables were tested as change from baseline to 12 weeks relative to primary endpoints and secondary endpoints. a two-sided p-value < 0.05 was considered statistically significant in all the tests used. results a total of 60 patients (median age of 32 years, interquartile range (iqr) 26-38) were enrolled in this study. the median of the duration of cp/cpps was 9 months in both groups (iqr: 5-12). the flow chart of this study is presented in figure 1. of the 60 patients, 48 patients, 24 subjects in the group a and 24 patients in the group b respectively, completed the study protocol. table 1 lists table 1. characteristics of the enrolled patients at baseline. n = 24 n = 24 age (years), median (iqr) 32.0 (29.00-38.0) 32.0 (28.75-38-75) nih-cpsi, median (iqr) 20.5 (15.0-24.5) 20.0 (15.0-25.0) iief-5, median (iqr) 18.5 (17.50-21.00) 18.5 (17.5-21.5) pedt, median (iqr) 11.0 (7.5-13.5) 10.0 (7.0-13.0) peak flow (ml/s), median (iqr) 14.0 (10.5-19.5) 14.5 (10.5-19.5) pvr (ml), median (iqr) 15.0 (0.0-25.0) 14.25 (0.0-24.0) vas, median (iqr) 7.5 (6.5-8.5) 7.5 (6.0-9.0) iqr = interquartile range; nih-cpsi = nih-chronic prostatitis symptom index; iief-5 = international index of erectile function; pedt = premature ejaculation diagnostic tool; pvr = post void residual. figure 1. flow chart of the study. morgia_stesura seveso 26/06/17 09:44 pagina 111 archivio italiano di urologia e andrologia 2017; 89, 2 g. morgia, g.i. russo, d. urzì, s. privitera, t. castelli, v. favilla, s. cimino 112 the baseline characteristics of the patients at enrolment. no statistically significant differences emerged between groups at baseline in terms of collected variables. in the group b, the change from baseline to week 12 was significantly different relative to nih-cpsi (median difference: -5.5; p < 0.01), iief-5 (median difference: +3.5; p < 0.01), pedt (median difference: +5.5; p < 0.01), peak flow (median difference: +2.8; p < 0.01) and vas score (mean difference: -4.5; p < 0.01). no significant difference was observed relative to pvr. in the group a we did not observed any changes from baseline to final follow-up relative to primary and secondary endpoints. when considering the comparison between both groups, we observed significant advantages of group b over group a regarding primary endpoint, iief-5, pedt, peak flow and vas (all p < 0.01) while any difference when considering pvr (figure 2) (table 2). all subjects included in the study protocol tolerated treatments, but we observed a rate of adverse events of 5% in the group b, including diarrhoea (80%) and rectal pruritus (20%). discussion cp/cpps represent one the most frequent disease in male under 50 and it is characterized by the heterogeneity of the risk factors and consequent clinical manifestation. in fact, wide variety of therapies including alpha-blockers, antibiotics, anti-inflammatory medications, and other agents (eg, finasteride, phytotherapy, and gabapentinoids) are routinely used. however, the efficacy of these treatments is controversial, partly because many clinical trials testing these therapies have been small, with little statistical power to detect treatment effects (11). herein we showed that the treatment with rectal suppositories based on curcumin extract 350 mg and calendula extract was clinical efficacious in terms of pain relief, voiding symptoms and urinary flow after 1 month of therapy and compared to placebo. the rationale of such therapy could be multiple and mainly related to their anti-inflammatory properties. in this context, among the numerous natural remedies, turmeric has gained considerable attention due to its profound medicinal values (12). this agent possesses antioxidant, anti-inflammatory, anticancer, antigrowth, anti-arthritic, anti-atherosclerotic, antidepressant, antiaging, antidiabetic, antimicrobial, wound healing and memory-enhancing activities (13). curcumin acts against diverse range of molecular targets and signalling pathways. it can interact with a huge number of different proteins such as nuclear factor e2-related factor 2 (nrf2), β-catenin, nf-κb, p38 mapk, dna (cytosine-5)-methyltransferase-1, cox-2, 5-lipoxygenase, pge2, foxo3, inducible nos, ros, cyclin d1, vegf, glutathione, cytosolic pla2, p-tau (p-τ) and tnf-α. for all these reasons its use has gained popularity against several chronic conditions (14). in a recent meta-analysis of eight randomized clinical trials comprising nine treatment arms, curcumin was effective in reducing circulating tnf-α concentrations (wmd: -4.69 p < 0.001) (15). curcumin has been also combined with other compounds like quercetin and prulifloxacin for the treatment of chronic bacterial prostatitis, showing improvement of clinical efficacy of prulifloxacin (16). on the other part, calendula officinalis flower extract possessed significant anti-inflammatory activity. in chronic anti-inflammatory model using formalin, administration of 250 and 500 mg/kg body weight calendula extract produced an inhibition of 32.9 and 62.3% respectively compared to controls. tnf-alpha production by macrophage culture treated with lipopolysaccharide (lps) was found to be significantly inhibited by calendula extract. moreover, increased levels of pro-inflammatory cytokines il1beta, il-6, tnf-alpha and ifn-gamma and acute phase protein, creactive protein (crp) in mice produced by lps injection were inhibited significantly by the extract. lps induced cyclooxygenase-2 (cox-2) levels in mice spleen were also found to be inhibited by extract treatment (17). however, there are not any comparison between these figure 2. clinical characteristics of the patients after treatment. table 2. characteristics of the enrolled patients after treatment. n = 24 n = 24 nih-cpsi, median (sd) 14.5 (2.31) 20.5 (2.2) iief-5, median (sd) 22.0 (1.42) 18.5 (1.5) pedt, median (sd) 4.5 (3.5) 11 (3.0) peak flow (ml/s), median (sd) 17.3 (4.3) 14 (4.2) pvr (ml), median (sd) 10.0 (7.9) 15 (8.0) vas, median (sd) 2.0 (1.9) 7.5 (2.0) iqr = interquartile range; nih-cpsi = nih-chronic prostatitis symptom index; iief-5 = international index of erectile function; pedt = premature ejaculation diagnostic tool; pvr = post void residual. 25 20 15 10 5 0 morgia_stesura seveso 26/06/17 09:44 pagina 112 113archivio italiano di urologia e andrologia 2017; 89, 2 treatment of chronic prostatitis/chronic pelvic pain syndrome type iii compounds and other for the treatment of cp/cpss. in a meta-analysis published on 2011 on three studies comparing phytotherapy with placebo (n = 223), authors demonstrated a reduction of pain score (standard mean difference (smd): -0.5) and in voiding symptoms (smd: -0.4). moreover, phytotherapy ehibited the second highest response rate after alpha-blockers, showing a risk ratio of 1.6 compared with placebo (11). before concluding some limitations should be addressed. first of all, it is a pilot, phase ii study with a small sample size. moreover, we did not investigate marker of inflammation in the cohort. on the contrary, some strengths of the study are the investigation of new compounds for the treatment of cp/cpps and the randomized placebo controlled design. further study with greater sample size should conducted to confirm these data. conclusions in this phase ii, placebo controlled, clinical trial we demonstrated the efficacy of rectal suppositories with curcumin and calendula for the treatment of cp/cpps, in terms of pain and urinary symptoms. references 1. rees j, abrahams m, doble a, cooper a, prostatitis expert reference g. diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. bju int. 2015; 116:509-25. 2. morgia g, cimino s, favilla v, et al. effects of serenoa repens, selenium and lycopene (profluss(r)) on chronic inflammation associated with benign prostatic hyperplasia: results of "flog" (flogosis and profluss in prostatic and genital disease), a multicentre italian study. int braz j urol. 2013; 39:214-21. 3. morgia g, mucciardi g, gali a, et al. treatment of chronic prostatitis/chronic pelvic pain syndrome category iiia with serenoa repens plus selenium and lycopene (profluss) versus s. repens alone: an italian randomized multicenter-controlled study. urol int. 2010; 84:400-6. 4. russo gi, cimino s, fragala e, et al. relationship between nonalcoholic fatty liver disease and benign prostatic hyperplasia/lower urinary tract symptoms: new insights from an italian cross-sectional study. world j urol. 2015; 33:743-51. 5. engeler ds, baranowski ap, dinis-oliveira p, et al. the 2013 eau guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, a philosophy, or a science? 10 years of development. eur urol. 2013; 64:431-9. 6. vanella l, russo gi, cimino s, et al. correlation between lipid profile and heme oxygenase system in patients with benign prostatic hyperplasia. urology. 2014; 83:1444 e7-13. 7. morgia g, russo gi, voce s, et al. serenoa repens, lycopene and selenium versus tamsulosin for the treatment of luts/bph. an italian multicenter double-blinded randomized study between single or combination therapy (procomb trial). prostate. 2014; 74:1471-80. 8. zaki a, ashour a, mira a, et al. biological activities of oleanolic acid derivatives from calendula officinalis seeds. phytother res. 2016; 30:835-41. 9. bozzini g, provenzano m, buffi n, et al. an observational study of the use of beclomethasone dipropionate suppositories in the treatment of lower urinary tract inflammation in men. bmc urol. 2016; 16:25. 10. nickel jc, krieger jn, mcnaughton-collins m, et al. alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome. n engl j med. 2008; 359:2663-73. 11. anothaisintawee t, attia j, nickel jc, et al. management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and network meta-analysis. jama. 2011; 305:78-86. 12. prasad s, gupta sc, tyagi ak, aggarwal bb. curcumin, a component of golden spice: from bedside to bench and back. biotechnol adv. 2014; 32:1053-64. 13. gupta sc, patchva s, aggarwal bb. therapeutic roles of curcumin: lessons learned from clinical trials. aaps j. 2013; 15:195-218. 14. kunnumakkara ab, bordoloi d, padmavathi g, et al. curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. br j pharmacol. 2016 sep 17. doi: 10.1111/bph.13621. (epub ahead of print) 15. sahebkar a, cicero af, simental-mendia le, et al. curcumin downregulates human tumor necrosis factor-alpha levels: a systematic review and meta-analysis ofrandomized controlled trials. pharmacol res. 2016; 107:234-42. 16. cai t, mazzoli s, bechi a, et al. serenoa repens associated with urtica dioica (prostamev) and curcumin and quercitin (flogmev) extracts are able to improve the efficacy of prulifloxacin in bacterial prostatitis patients: results from a prospective randomised study. int j antimicrob agents. 2009; 33:549-53. 17. preethi kc, kuttan g, kuttan r. anti-inflammatory activity of flower extract of calendula officinalis linn. and its possible mechanism of action. indian j exp biol. 2009; 47:113-20. correspondence giuseppe morgia, md giorgio ivan russo, md, phd (corresponding author) giorgioivan@virgilio.it daniele urzì, md salvatore privitera, md tommaso castelli, md vincenzo favilla, md sebastiano cimino, md urology section, department of surgery, university of catania, italy morgia_stesura seveso 26/06/17 09:44 pagina 113 159archivio italiano di urologia e andrologia 2018; 90, 3 original paper do dental calculi predict the presence of renal stones? bulent kati 1, ergin kalkan 2, eyyup sabri pelit 1, ismail yagmur 1, halil çiftçi 1 1 department of urology, harran university faculty of medicine, sanliurfa, turkey; 2 cagri dental hospital, dental clinic, elazig, turkey. objective: pathological calcifications that occur in various parts of the body may cause stone formation over time. the structure of these stones is similar in many regions of the body. we have studied the relationship between dental calculi and kidney stones. material and methods: a total of 183 patients with dental stone complaints or dental calculi were included between april and august 2016 in the cagri dental hospital, elazig, turkey. patients were evaluated with regard to a urinary tract ultrasonography, urinalysis, oral hygiene, and stone and surgical disease history. all information was statistically investigated. results: the age of the patients in the kidney stones group was significantly higher than the non-kidney stone patients (p < 0.05). in the group with kidney stones, the percentage of dental calculus formation was significantly higher than the group without stones (p < 0.05). in the groups with and without kidney stones, dental stone recurrence rates did not differ significantly (p < 0.05). urinary ph was significantly lower in the group with stones than the group without stones (p < 0.05). conclusions: during a physical examination, the formation of a visible stone, such as a dental calculus, may be an indicator of other types of stones, such as kidney stones, and this should be further investigated. key words: renal stone; dental calculi; stone formation; etiology. submitted 16 may 2018; accepted 5 july 2018 summary no conflict of interest declared. ments (such as a periodontal scaler). calculi are composed of both inorganic (mineral) and organic (cellular and extracellular matrix) components. the mineral portion of a calculus ranges from 40-60%, depending on its location in the dentition, and consists primarily of calcium phosphate crystals organized into four principal mineral phases: octacalcium phosphate, hydroxyapatite, whitlockite, and brushite. the organic component of a calculus is approximately 85% cellular and 15% extracellular matrix (3). renal stones, which are part of a multifactorial disease, are some of the most common problems in modern society and may affect 12-15% of the population with observation of an increase in their prevalence. renal stones are more common in males and are categorized into calcareous (calcium containing) stones, which make up 90% of all stones, and non-calcareous stones. most stones (85%) primarily contain calcium oxalate (caox) admixed with calcium phosphate (cap) in the form of apatite or brushite, or occasionally uric acid; however, less commonly they can be composed primarily of cap. although many systemic diseases, such as primary hyperparathyroidism, bowel disease, and renal tubular acidosis, can result in calcium stone formation, the majority of calcium stones are found in people with no systemic illness (4). although many inherited and systemic diseases are associated with calcium renal stones, most stones are idiopathic (5). in this study, we aimed to evaluate the presence of kidney stones in patients with dental calculus. this was performed according to the dental plaque density in patients who were treated at the same time in the urology clinic. we also aimed to uncover any relationships between these conditions. materials and methods the study group was composed of 183 patients (86 females and 97 males) with an age range from 20 to 65 years. we randomly evaluated dental patients who were diagnosed with dental calculus. based on the amount of plaque, patients were divided into three categories. for the purposes of x-ray assessments of the jaw, panoramic, and retroalveolar region, x-rays in suspicious teeth were made. for the realization of the set objective, visual analyses of the x rays were conducted (figure 1). dental calculus amounts that are generally below 25% doi: 10.4081/aiua.2018.3.159 introduction in dentistry, a calculus or tartar is a form of hardened dental plaque. these are caused by the precipitation of minerals from saliva and gingival crevicular fluid in plaque on the teeth. this precipitation process kills the bacterial cells within the dental plaque, but the rough and hardened surface that is formed provides an ideal surface for further plaque formation. this leads to a calculus build up, which compromises the health of the gingiva. a calculus can form both along the gum line (supragingival) and within the narrow sulcus between the teeth and the gingiva (subgingival) (1). calculus formation is associated with a number of factors including sex, age, bad breath, receding gums, and chronically inflamed gingival (2). brushing and flossing can remove the plaque from which a calculus forms. however, once formed, it is too hard and firmly attached to be removed with a toothbrush. calculus buildup can be removed with ultrasonic tools or dental hand instrukati_stesura seveso 04/10/18 11:58 pagina 159 archivio italiano di urologia e andrologia 2018; 90, 3 b. kati, e. kalkan, e. sabri pelit, i. yagmur, h. çiftçi 160 are termed as “low category,” tartar amounts from 2575% as “medium category,” and as “high category” those amounts between 75-100% (figure 2). after the dental examination, all patients were evaluated with a urinary tract ultrasound and urinalysis (figure 3). fasting second morning specimens were collected from all individuals who had been fasting since 9:00 p.m. the preceding evening. the dental brushing habits of the patients were evaluated in terms of oral hygiene, additional disease, and stone story. all information was collected to determine the incidence of dental calculus and kidney stone in patients. statistical analysis mean, standard deviation, median lowest and highest, frequency, and ratio values were used in the descriptive statistics of the data. the distribution of the variables was measured by the kolmogorov-smirnov test. the mannwhitney u test was used in the analysis of quantitative data. the chi-square test was used in the analysis of qualitative data. the spss 22.0 program was used for all statistical analyses. results the data from all patients were evaluated together (table 1). the age of the patients in the kidney stone group was significantly higher than that of the non-kidney stone group (p < 0.05). the proportion of patients with renal stones who were males was significantly higher than the group without kidney stones (p < 0.05). the dental calculus formation was more prevalent in those without renal stones (p < 0.05). in the groups with and without kidney stones, dental stone recurrence rates did not differ significantly (p > 0.05). urinary ph was significantly lower in the group without stones (p < 0.05) (table 2). in the univariate model, there was a significant difference (p < 0.05) in the age, sex, tooth stone percentage, tooth brushing habits, recurrence frequency, presence of additable 1. characteristics of patients being treated for dental calculi. figure 1. x-ray views of dental calculi (arrows). figure 2a, b, c. appearance of dental calculus during a physical examination. figure 3. the appearance of kidney stones and crystals in the kidney ultrasound (arrows). kati_stesura seveso 04/10/18 11:58 pagina 160 tional disease, oral hygiene level, stone story, and urinary ph values. in the multivariate model, significant and independent (p < 0.05) efficacy was observed in the age of the patients, the percentage of tooth stones, and the stone story, suggesting stone formation (table 3). discussion most of the stones in our bodies can be defined as pathological calcifications. in the literature, there are thousands of articles associated with calcifications occurring in the body, however, this amount is less than the number of articles attempting to explain the relationship between them. stones occurring in different organs resemble their structure suggesting a metabolic disorder that underlies the process of their formation (6, 7). the components of stone formation are similar in many organs (8). davidovich e. et al. evaluated the correlation between dental calculus and disturbed mineral metabolism in pediatric patients with chronic kidney disease. they suggested that there is a possible association between the severity of renal dysfunction in young patients and the formation of dental calculus as an additional manifestation of disturbed calcium-phosphate homeostasis. the combination of several components in saliva including calcium, phosphate, uric acid, and magnesium plays an important role in this process (9). looking at the minerals that make up kidney stones, we see the same accumulation in the kidneys and teeth, suggesting similar mechanisms of stone formation (10). 161archivio italiano di urologia e andrologia 2018; 90, 3 dental and renal calculi table 2. statistical comparisons of patient information. table 3. univariate and multivariate analyses of patient information. kati_stesura seveso 04/10/18 11:58 pagina 161 archivio italiano di urologia e andrologia 2018; 90, 3 b. kati, e. kalkan, e. sabri pelit, i. yagmur, h. çiftçi 162 some researchers have found that nephrolithiasis is also accepted as a predisposing factor to pulpal calcification; however, some others could not find any correlation between the presence of pulp stones and kidney stones (11, 12). some researchers have proposed that some of the minerals found in saliva cause the formation of stones in the salivary glands. salivary sialoliths are predominantly composed of crystals comprising calcium and phosphorous, with small amounts of magnesium, sodium, chloride, silicon, iron, and potassium (13). rakesh n. et al. found that, when comparing sialoliths and nephroliths, they found a high degree of elemental similarity between them. thus, they alleged that prescription drugs used for renal stones may be of some use in the conservative management of sialoliths (14). shaimaa et al. evaluated idiopathic calcium renal stones and their relationship to dental calculi. they reported significant correlations between dental calculus accumulations and calcium renal stone formation, and they offered oral health preventive programs for those patients (15). grases et al. found that salivary calcium concentrations of patients with hydroxyapatite calculi were significantly higher than that found in the saliva of healthy in their study. therefore, their results were practically identical to those found in the hydroxyapatite renal calculi (non-infective phosphate renal calculi) (16, 17). we assessed patients based on oral hygiene, renal stone history, teeth brushing habits, dental calculus recurrence, and comorbidities. the dental calculus percentage was significantly higher in patients with kidney stones. this similarity can be seen because of the materials that make up the stone structure tend to accumulate in the body. this may be an indication that kidney stones can form in patients with a high dental calculus density. this condition, which is not related to the recurrence frequency of the dental calculi, is also directly related to oral hygiene status. conclusions there are similar features in terms of the formation of stones in the body and the minerals they contain. the height of dental calculi observed in the mouth is significant and stimulating in terms of kidney stones in patients. during physical examinations, the formation of a visible stone, such as a dental calculus, can be a predictor of stones such as kidney stones, and this relationship should be further investigated. references 1. turesky ss. what is the role of dental calculus in the etiology and progression of periodontal disease? j periodontol. 1970; 41:285-6. 2. beiswanger bb, segreto va, mallatt me, pfeiffer hj. the prevalence and incidence of dental calculus in adults. j clin dent. 1989; 1:55-8. 3. jin y, yip hk. supragingival calculus: formation and control. crit rev oral biol med. 2002; 13:426-41. 4. coe fl, worcester em, evan ap. idiopathic hypercalciuria and formation of calcium renal stones. nat rev nephrol. 2016; 12:519-33. 5. worcester em, coe fl. clinical practice. calcium kidney stones. n engl j med. 2010; 363:954-63. 6. avogaro a, fadini gp mechanisms of ectopic calcification: implications for diabetic vasculopathy. cardiovasc diagn ther. 2015; 5:343-52. 7. valenzuela a, chung l. calcinosis: pathophysiology and management. curr opin rheumatol. 2015; 27:542-8. 8. aguilar-ruiz j, arrabal-polo ma, sierra m, arrabal-martin m. application of mineralogical techniques in the study of human lithiasis. ultrastruct pathol. 2012; 36:367-76. 9. davidovich e, davidovits m, peretz b, et al. the correlation between dental calculus and disturbed mineral metabolism in paediatric patients with chronic kidney disease. nephrol dial transplant. 2009; 24:2439-45. 10. khan sr, pearle ms, robertson wg, et al. kidney stones. nat rev dis primers. 2016; 2:16008. 11. nayak m, kumar j, prasad lk. a radiographic correlation between systemic disorders and pulp stones. indian j dent res. 2010; 21:369-73. 12. tarim ertas e, inci m, demirtas a, et al. a radiographic correlation between renal and pulp stones west indian med j. 2014; 63:620. 13. hiraide f, nomura y. the fine surface structure composition of salivary calculi. laryngoscope 1980; 90:152. 14. rakesh n, bhoomareddy kantharaj yd, agarwal m, agarwal k. ultrastructural and elemental analysis of sialoliths and their comparison with nephroliths. j investig clin dent. 2014; 5:32-7. 15shaimaa ky, mohammed sa. dental calculus in relation to idiopathic calcium renal stone j bagh coll dentistry. 2012; 24(sp. issue 1):140-145. 16. grases f, santiago c, simonet b. sialolithiasis: mechanisim of calculi formation and etiologic factors. clin chim acta. 2003; 334:131-6. 17. grases f, sohnel o, villacampa ai, march jg. phosphates precipitating from artificial urine and fine structure of phosphate renal calculi. clin chim acta. 1996; 244:45-67. correspondence bulent kati, md bulentkati@harran.edu.tr eyyup sabri pelit, md dreyyupsabri@hotmail.com ismail yagmur, md dr_iyagmur@hotmail.com halil çiftçi, md halilciftci63@hotmail.com harran university, favulty of medicine hospital, urology, 63340 sanliurfa, turkey ergin kalkan, md erginkalkan@hotmail.com assistant professor of urology cagri dental hospital, dental clinic, 23100, elazig, turkey kati_stesura seveso 04/10/18 11:58 pagina 162 archivio italiano di urologia e andrologia 2018; 90, 3176 original paper feasibility study for interspecialistic collaboration in active research of urothelial neoplasms of professional origin roberta stopponi 1, enrico caraceni 2, angelo marronaro 2, andrea fabiani 3, stefania massacesi 1, anna rita totò 1, roberto calisti 1 1 servizio prevenzione e sicurezza ambienti di lavoro, asur marche av3, civitanova marche, italy; 2 urologia asur marche av3 ospedale civitanova marche, italy; 3 urologia asur marche av3 ospedale macerata, italy. introduction: in italy only a small fraction of cancer is reported to the supervisory body and recognised as professional by the insurance institution. among the causes of this sub-notification, especially for lowgrade etiologic fractional cancers such as bladder cancers are the lack of knowledge of carcinogenicity in the occupational field and the consequent incomplete medical history collections. objectives: diagnosis of occupational bladder neoplasms and activation of systematic surveillance of tumors of professional origin through an "active research" program. methods: from july 2010 to july 2017, all patients diagnosed with bladder cancer in the departments of urology of area vasta 3 asur marche underwent a first interview and a further anamnestic study in selected cases.when an occupational exposure was recognised, more information for preventive, social security and criminal justice has been acquired. results: the study highlighted 18 cases of bladder tumors due to occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, which are the most important risk factor for bc after tobacco smoking. conclusions: our study confirmed that active research is an useful tool both for the activation of epidemiological surveillance and for the regional registration of professional tumors. in addition active research of occupational exposure allow obtaining information that can be used for preventive purposes, for criminal justice and for the initiation of medico-legal actions and improvement of working conditions aimed at guaranteeing workers' rights. key words: bladder cancer; occupational exposure; epidemiology. submitted 2 july 2018; accepted 19 july 2018 summary no conflict of interest declared. tumor. the first epidemiological study on occupational cancers was conducted in the usa in the 1980s and attributed 4% of all cancers to occupational exposures (8% for men and 1% for women) (1); a more recent finnish epidemiological study (2) considers 8% of neoplasms (14% for men and 2% for women) as of possible professional origin. according to data from airtum 2009 (3), bladder cancer is the 4th most common cancer in italy, accounting for an estimated 17,000 new cases diagnosed each year. it affects men more frequently than women. over the years there has been both a reduction in the incidence and mortality of bladder cancer (5-year cancer specific survival of 70% and 72%, in men and women respectively). cigarette smoking is the primary risk factor for bladder cancer and several epidemiological studies describe the impact of tobacco smoking on its development. in the developed countries cigarette smoking accounts for 60-66% of all new cases of bladder cancer. occupational exposure still remains the second most important risk factor for bladder cancer (4-6). correlation between bladder cancer and work environment it is well known since 50ths. occupational exposure accounts for about 5 to 15% of all cases (7), depending on the criteria adopted and the geographical areas in which the epidemiological studies have been conducted. the most notable occupational agents which act as the main factors for the development of bladder cancer are the aromatic amines, in particular, followed by polycyclic aromatic hydrocarbons (8). this type of occupational exposure occurs mainly in industrial plants which process paints, dyes, metal and petroleum products, as well as in rubber, cosmetic and print industries. some studies have shown an increased bladder cancer risk among footwear manufacturers. despite the clear evidence of correlation between cancer and occupational exposure, the identification of occupational cancer and, consequently, the insurance compensation of workers, are still lacking, in particular in tumors with a low etiologic fraction such as the bladder cancer. this under-reporting is often caused by the confusion between professional exposure and other determinants at the individual level (9). there are many interventions aimed at improving the obligation of notification by doctors. doi: 10.4081/aiua.2018.3.176 introduction the contribution of occupational exposures to cancers has been clearly identified. however, occupational exposures in many cancers still remain under-reported. identification of occupational diseases can result in both a worker’s compensation by insurance companies and a reimburse for medical assistance related to the specific condition. knowledge of both insurance system and occupational cancer are the main factors that contribute to the request of worker’s compensation. prevalence of occupational cancers vary according to studies design and type of marronaro_stesura seveso 04/10/18 11:14 pagina 176 177archivio italiano di urologia e andrologia 2018; 90, 3 professional urothelial neoplasms a publication by cochrane (10) says that there is no single intervention that has proven to be effective in improving notifications of professional tumors. on the contrary authors conclude by saying that it is important to create a network that allows a better knowledge of professional tumors. it is also important that this network helps to raise awareness among doctors in the clinical setting and contributes to active case research, to patient information and care facilities. with the aim of improving notification of professional tumors it is also important their identification by recordlinkage method (11) or the active research of patients affected by professional diseases by questionnaire of occupational history when the patient is admitted to the hospital or after discharge. finally, for the sake of completeness, other risk factors involving in the development of bladder cancer are infection by schistosoma haematobium responsible for a chronic endemic cystitis, frequent use of cyclophosphamide and phenacetine and consumption of water contaminated by arsenic (12, 13), that is well known in some italian regions (14). in the marche region (occam occupational cancer monitoring research 2001-2005), 1629 cases of bladder carcinoma were detected (out of a total of 1,560,785 inhabitants), which is equivalent to 326 cases each year. the professional etiological fraction attributable to the bladder neoplasm is 5-15%, but considering that during the same period (2001-2005) the insurance certification was made only in 13 patients with professional bladder cancer, it is clear that it is sufficient notification of the bladder of the tumor due to occupational exposure. that notification of the bladder tumors due to occupational exposure is not sufficient. for this reason, considering that in the “occupational prevention and safety service” asur marche av3 of civitanova marche, there is the regional registry of tumors with a low etiological fraction (regional resolution of 29 december 2009), we decide to start a research program on the professional origin bladder cancer among patients admitted to two urological departments (civitanova marche and macerata). methods the urologists of the departments involved in the study enrolled urinary bladder cancer patients from august 2010 through a “short” anamnestic questionnaire, preceded by an explanation of the motivation of this "anamnestic supplement". all subjects with bladder neoplasia were included: there were no recruitment restrictions on age, gender, ethnicity or cancer-stage. subsequently the occupational doctors selected the subjects who, on the basis of the medical history, according to a preliminary postexposure attribution, could have been professionally exposed to bladder carcinogens. the occupational doctors validated the questionnaires referring to cases of transitional cell urothelial carcinoma accepting/validating only the cases of bladder carcinoma with histological diagnosis of the most typically urothelial or epidermoid form (representing the latter the expression of a carcinogenic process with "chronic irritative" component associated with dna damage). this selected cases have been subjected to specific occupational anamnesis using a standardised questionnaire called "questionnaire on work, life habits and health" based on the questionnaires used in the the national register of nose-sinus tumors and the national registry of mesotheliomas (renam and renatuns) studies. collaterally, was conducted an informative campaign about the occupational bladder neoplasia, about the presence of an "active research of professional neoplasies" and about the possibility for workers and former workers to ask, directly or through a medical request, specific information. the standardised anamnestic questionnaire was directly submitted to the cases reached through this channel. the diagnoses of occupational disease and the attributions of exposure and cause were based on coherence between the professional history, technological knowledge, epidemiological evidence and, in the absence of other efficient causes, on the etiopathogenetic model. after the medical history, the occupational doctor proceeded in the: • acquisition of company documentation useful for the legal medical investigation • inspection of the work places if still existing • assignment of an exposure matrix based on the work history • expression of a certain, probable or possible judgment on the professionalism or otherwise of the disease • identification of any responsibility on the part of the company. results the cases reported by the departments of urology and assessed with a brief history were 164 (figure 1). a further nine cases came to the service through other channels: five workers, one of whom was advised by his general practitioner, presented directly to the medical department of the psal service, 3 were sent by the judicial authority represented by two other psal services of the asur marche and the judicial authority figure 1. sources of the cases studied. marronaro_stesura seveso 04/10/18 11:14 pagina 177 archivio italiano di urologia e andrologia 2018; 90, 3 r. stopponi, e. caraceni, a. marronaro, a. fabiani, s. massacesi, a.r. totò, r. calisti 178 (through a request for investigation) competent for the territory and one through the national institute for accident insurance at work (inail) channel (through reporting) (figure 1). overall, 173 cases were evaluated: 27 females and 146 males. in two cases the bladder lesions were benign, while one case showed inflammation. the average age at the first diagnosis is 71.09 years (for the female) and 70.2 years (for the man): the youngest patient is 30 years old and the oldest is 93 years old). the 21% of cases are smokers at the time of the questionnaire administration and the 53% claimed to be an ex-smoker. the medical staff of spsal evaluated the professional exposures of all the cases reported based on the analysis of the short questionnaires administered by urologists deciding to contact about a third (50 workers) for a more detailed professional history: of these seven refused further investigations. after an anamnestic study, an exposure to bladder professional carcinogens was confirmed in more than half of the cases of hospital origin (n = 24); exposure has been revealed for all nine cases that have reached the service through the other channels. from the further anamnestic analysis it was possible to diagnose a professional illness with a certain “attribution of exposure and cause” in 19 cases, all of them male. the insurance process was started for 5 footwear workers, 1 cast-iron founder, 1 aluminum production employee, 2 dyers, 2 paint/varnish production workers, 2 hairdressers, 1 steel worker, 1 metalworker, 1 galvanic worker, 1 plastic rubber production assistant, 1 disinfection worker, 1 ceramic production worker (figure 2). the carcinogenic occupational substances for the bladder are predominantly the aromatic amines (12 cases), the polycyclic aromatic hydrocarbon (4 cases), the tetrachlorethylene (1 case) and the arsenic (1 case) (figure 3). the average of exposure to this substances is 23 years. in two workers, other occupational diseases were diagnosed: namely a tumor of the nasal and paranasal sinuses from exposure to leather powder and asbestosis and pleural plaques from exposure to asbestos. only two companies are still active in which the exposure of workers to the bladder carcinogens has reasonably occurred. figure 2. work activities. figure 3. prevalent exposures in cases for which the insurance process has been launched (aromatic amines aa, polycyclic aromatic hydrocarbons pahs, tetrachlorethylene tce and arsenic as). marronaro_stesura seveso 04/10/18 11:14 pagina 178 179archivio italiano di urologia e andrologia 2018; 90, 3 professional urothelial neoplasms discussion in our target group of 173 patients affected by bladder cancer, occupational exposure accounts for about 10% of all cases which is, on average, the worldwide percentage of professional urothelial neoplasms. we expected this result considering the production of local industry. tobacco smoking is not relevant for the certification of occupational disease when carcinogenic occupational exposure has been clearly established. half of the workers for whom a certification request of occupational disease were made to stop smoking (average 36.8 year of smoking) and 20% were still smoking (30.8 years, on average). we couldn’t find any definitive correlation between occupational exposure and multifocality, grading and histology because our data are insufficient on this purpose. there are some evidences on the literature that occupational exposure could influence prognosis of bladder cancer so it is advisable to further analyse this aspect with a larger amount of data (15) . otherwise, the correlation between occupational exposure and prognosis does not influence certification of professional disease and workers’ compensation. only in one patient after the diagnosis of bladder cancer the medical procedure for the certification of professional disease had been started. therefore we made a request for certification of a professional disease in every patient where occupational exposure was identified except for a patient that needed a further investigation from territorial competent service. nowadays, this study confirms that the most important carcinogenic occupational factors for urothelial neoplasm are aromatic amines and polycyclic aromatic hydrocarbons. in particular we found five patients affected by bladder cancer in leather and footwear industries. processing of leather and footwear are well known to be an important cause of professional bladder cancer due to exposure to aromatic amines in painting processes. we also confirm association between bladder cancer and industrial plants which process metal, in particular steel and iron foundries. this association has been found in other studies too but at the moment there is not significant epidemiological evidence in order to certainly establish a higher risk of bladder cancer in this working context. industrial plants which involves aluminium production are also represented. in the literature aluminium industries are associated with the main carcinogens present in the processing and represented by the volatile derivatives of tar pitch. in our study, in addition to cases of bladder cancer in workers of industrial plants which process paint and dye, association between urothelial neoplasms of the bladder and dyes production which involves use of aromatic amines is also represented. exposure to arsenic was the reason why we judged bladder cancer as a professional origin in a disinfestation worker. in fact arsenic was used to produce pesticides in the past (16). we found a case of bladder cancer in a worker in the galvanic sector. in this case bladder neoplasm is not included in the list of disease to be denounced according to the italian legislation. despite this the first certificate of occupational disease was completed because some studies have showed that exposure to tetrachlorethylene is reasonable associated with an increase of risk of bladder cancer (17). we managed to found two companies still existing in which the exposure of workers to professional bladder carcinogens reasonably existed. one was not a local factory and is based outside marche region. for this reason data was sent to the competent territorial office. instead the other factory is located in the marche region so we were able to identify and characterise carcinogens in the work environment and proceed with action aimed at remove them. in addition another target was searching for responsibilities of the company. the assessment of the presence of clusters is underway in a third company (currently not active) in the marche region and in a company outside the region. conclusions active research of professional bladder neoplasms is a valid and simple tool able to identify cases of cancer of professional origin that otherwise would have remained unknown. active research of professional cancer should be based on the careful clinical history of the patient, the knowledge of production cycles and information on risks obtained from the scientific literature. in this contest certification of tumors of professional origin is also important to obtain workers’ compensation, to activate the systematic epidemiological surveillance of professional bladder neoplasms, to start the regional registration of these diseases, to certificate effects of occupational carcinogens useful for implementing data that can be used for preventive purpose and to evaluate effectiveness of preventive measures adopted to reduce incidence of these neoplasms. our experience confirms that it is fundamental to improve knowledge of bladder carcinogenic risks including professional ones and to implement preventive measures linked not only to life habits but to work environment also. apart from competent medicals, it is also important to involve other professional figures like family physicians and specialists pointing out the necessity of collecting a detailed medical history and to report diseases that could be of professional origin because of an exposition to occupational carcinogens in the past. in addition, occupational physicians need to pay attention, promote and control to the establishment of registers of people who have been exposed to occupational carcinogens (ex art 248 d.lgs 81/08 smi). in the same time they have to improve professional prevention by monitoring the application of the legislation regarding the safety of work environment (art 224 e 225 del dlgs 81/08 smi). it is also crucial to promote the demise of artificial rubber extended to aromatic oils, by substitution with materials (paraffinic oils and naphthenic oils) without ipa or with a significantly reduced content of the same. marronaro_stesura seveso 04/10/18 11:14 pagina 179 archivio italiano di urologia e andrologia 2018; 90, 3 r. stopponi, e. caraceni, a. marronaro, a. fabiani, s. massacesi, a.r. totò, r. calisti 180 references 1. doll r, peto r. the causes of cancer: quantitative estimates of avoidable risks of cancer in the united states today. j natl cancer inst 1981; 66:1191-1308 2. nurminen m, karjalainen a. epidemiologic estimate of the proportion of fatalities related to occupational factors in finland. scand j work environ health. 2001; 27:161-213. 3. airtum, associazione italiana registro tumori, “i trend dei tumori negli anni duemila”, 2009, http://www.registritumori.it/ cms/?q=rapp2009indice. 4. letašiová s, medve’ová a, šovcíková a, et al. bladder cancer, a review of the environmental risk factors. environ health 2012; 11(suppl 1):s11. 5. burger m, catto jwf, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013; 63:234-241. 6. miyazaki j, nishiyama h. epidemiology of urothelial carcinoma. int j urol. 2017; 24:730-734. 7. olfert sm, felknor sa, delclos gl. an updated review of the literature: risk factors for bladder cancer with focus on occupational exposures. south med j. 2006; 99:1256-63. 8. cumberbatch mg, cox a, teare d, catto jw. contemporary occupational carcinogen exposure and bladder cancer: a systematic review and meta-analysis. jama oncol. 2015; 1:1282-90. 9. crosignani p, amendola p, audisio r, et al. [confounding and confusion: recognition of causative relation and identification of victims of occupational carcinogens]. g ital med lav ergon. 2008; 30:3925. (article in italian). 10. curti s, sauni r, spreeuwers d, et al. interventions to increase the reporting of occupational diseases by physicians. cochrane database syst rev. 2015;(3):cd010305. doi: 10.1002/14651858. cd010305.pub2. 11. www.occam.it 12. silverman dt, devesa ss, moore le, rothman n. bladder cancer in schottenfeld d, fraumeni jf jr (eds) cancer epidemiology and prevention, 3rd ed, new york, ny 2006, oxford university press, pp 1101-1127. 13. nuckols jr, freeman le, lubin jh, et al. estimating water supply arsenic levels in the new england bladder cancer study. environ health perspect. 2011; 119:1279-85. 14. di lorenzo g, federico p, de placido s, buonerba c. increased risk of bladder cancer in critical areas at high pressure of pollution of the campania region in italy: a systematic review”. crit rev oncol hematol. 2015; 96:534-41. 15. selinski s, bürger h, blaszkewicz m, et al. occupational risk factors for relapse-free survival in bladder cancer patients. j toxicol environ health a. 2016; 79:1136-1143. 16. boulanger m, tual s, lemarchand c, et al. agricultural exposure and risk of bladder cancer in the agriculture and cancer cohort. int arch occup environ health. 2017; 90:169-178.) 17. vlaanderen j, straif k, ruder a, et al. tetrachloroethylene exposure and bladder cancer risk: a meta-analysis of dry-cleaning-worker studies. environ health perspect. 2014; 122:661-6. correspondence stopponi roberta, md (corresponding author) massacesi stefania, md totò anna rita, md calisti roberto. md servizio prevenzione e sicurezza ambienti di lavoro, asur marche av3, civitanova marche, italy caraceni enrico, md marronaro angelo, md ang6marr@yahoo.it urologia asur marche av3 ospedale civitanova marche (italy) fabiani, md urologia asur marche av3 ospedale macerata (italy) marronaro_stesura seveso 04/10/18 11:14 pagina 180 167archivio italiano di urologia e andrologia 2019; 91, 3 original paper role of sterile pyuria in association to elevated psa values in the diagnosis of non-palpable prostate cancer? selamettin demir department of urology, the ministry of health, university of health sciences, van education and research hospital, van, turkey. objectives: although cancer is believed to develop and progress with the involvement of inflammation, it is still unclear what the correlation between inflammation and prostate cancer is. this study based on results of transrectal ultrasound-guided prostate biopsies aimed to determine whether c-reactive protein (crp) and sterile pyuria were clinically useful in the evaluation of patients with suspect of prostate cancer. materials and methods: this study is a cross-sectional prospective study of patients without clinical prostatitis symptoms. characteristics of the 200 consecutive patients recruited were 3-20 ng/ml value of serum prostate-specific antigen (psa), normal digital rectal examination finding, and sterile urine culture result. all patients underwent 12-core prostatic biopsy. 163 of the 200 patients had benign prostatic hyperplasia confirmed through histology, while the residual 37 patients had prostate cancer. patients with pre-treatment urinary leukocyte count ≤ 3/high power field were categorized as non-pyuria, whilst those with pre-treatment urinary leukocyte count > 3/high power field were categorized as pyuria. the serum crp level was also used to differentiate patients before the biopsy. subgroups were compared regarding a number of clinical variables. results: histology revealed that 70% of pyuria patients and 38.5% of non-pyuria patients presented inflammation (p = 0.001). the pyuria group exhibited significantly higher total psa compared to the non-pyuria group (p = 0.044). the two groups did not differ significantly regarding cancer detection rate (p = 0.752). crp groups were similar regarding cancer detection and histologically-detected inflammation rates. conclusion: in patients with no evidence of clinical prostatitis, sterile pyuria should be considered as a cause of increased psa. although sterile pyuria cannot predict non-palpable prostate cancer, it should be taken into account in urological evaluation in order to demonstrate minute prostatic inflammation due to its simplicity, convenience and non-invasiveness. key words: prostate cancer; inflammation; biopsy; c-reactive protein; pyuria. submitted 16 february 2019; accepted 2 april 2019 summary no conflict of interest declared. ularly non-palpable pca has been increasingly identified at an early stage thanks to the common practice of screening for serum prostate-specific antigen (psa). however, some have argued that biopsies should not be performed unnecessarily (4, 5), because, besides pca, non-malignant prostate conditions, such as inflammation, may be associated with high serum psa as well (6, 7). the general assumption is that pca develops and progresses due to inflammatory processes that disrupt the function of oncogenes and tumor inhibitors, thus damaging dna and activating processes that can trigger tumor cells to grow and proliferate (8, 9). therefore, pca risk is considered to be elevated in men with intraprostatic conditions like proliferative inflammatory atrophy, prostatic intraepithelial neoplasia, and prostatitis, which may be induced by acute or chronic inflammation and are believed to be pca precursors (9, 10). abnormal digital rectal examination (dre) results and/or psa higher than 4.0 ng/ml are among the main markers warranting a prostate biopsy. if dre suggests that pca is likely, then biopsy is vital. on the other hand, psa is the sole basis for deciding performance on non-palpable case biopsy, although it frequently yields false positives because its levels are increased by inflammation (11). thus, it is important to prevent performing unnecessary biopsy for non-palpable case, and for this purpose, a number of psa derived parameters have been considered, including free-to-total psa ratio, psa density (psad) and psa velocity (12, 13). this study sought to determine the extent to which the impact of inflammation on detection of cancer in specimens of prostate biopsy could be gauged based on serum c-reactive protein (crp) level and urinary leukocyte count. materials and methods ethics committee approval was received for this study from the hospita ethics committee (number: 218/13). written informed consent was obtained from patients who participated in this study. a number of 200 consecutive patients were recruited for this study. all of them had serum psa levels in the range 3-20 ng/ml, normal dre findings and sterile urine culture results and underwent transrectal ultrasound-guided 12-core prostatic biopsy (trus-bx) beetwen januray 2018 and february 2019. the study did not include patients with clinical signs of doi: 10.4081/aiua.2019.3.167 introduction in the us, prostate cancer (pca) continues to be the cancer with the second highest mortality rate in men, despite the fact that the number of men dying because of it is not as high as the number of those dying with it for other causes (1, 2). pca risk is believed to be heightened by genetic and environmental factors, but the exact etiology remains unclear (3). nevertheless, pca and particdemir_stesura seveso 30/09/19 18:21 pagina 167 archivio italiano di urologia e andrologia 2019; 91, 3 s. demir 168 prostatitis, macroscopic pyuria, bacteria isolated in urine culture or systemic inflammatory conditions with potential impact on serum crp. the medication regimen consisted of 500 mg ciprofloxacin administered orally twice daily over a period of one week, with the first dose being given 24 hours before the procedure. patients with pretreatment urinary leukocyte count ≤ 3/high power field (h.p.f.) were categorized as non-pyuria, whilst those with pre-treatment urinary leukocyte count > 3/h.p.f. were categorized as pyuria. furthermore, a positive group with serum crp of 0.30 mg/dl or higher and a negative group with serum crp of less than 0.30 mg/dl were distinguished as well (25). elecsys psa kit (roche cobas 411, tokyo, japan) was used for measurement of free and total psa values. alongside the blood sample, urine culture and urine samples were also acquired prior to dre. latex crp immunoturbidimetric kit (crp-latex ‘crplx’, roche, germany, and model no. 6000; hitachi, tokyo, japan) permitted measurement of serum crp before treatment, with 0.30 mg/dl cut-off value with 93% specificity (25). furthermore, a centrifugal automatic analyzer and a light microscope (roche miditron® junior ii, germany) was used for urine analysis, while a scanner with a 6.5 mhz transrectal probe enabled performance of prostate transrectal ultrasonography (trus). prostate scanning was performed in both transverse and sagittal planes whilst the patient was lying on his left side. the formula for a prostate ellipsoid (width × length × height × 0.523) helped to calculate the prostate volume and the total psa was divided by the prostate volume to obtain the psad. moreover, an automatic biopsy gun and an 18-gauge needle were employed to conduct the 12-quadrant biopsy under trus guidance. prostate chronic inflammation was considered to be present when inflammatory cells, lymphocytes, plasma cells and/or histiocytes infiltrated prostatic biopsy specimens (14). data were expressed as means ± sd. spss (ibm spss for windows, ver.24) was used for comparison of the variables associated with the different groups via student’s t-test and chisquare test. statistical significance was indicated by p value of less than 0.05. results the characteristics of every recruited patient are shown in table 1. a proportion of 81.5% of patients (n = 163) was histologically confirmed to have benign prostatic hyperplasia (bph), while the other 18.5% of patients (n = 37) had pca. histology also showed inflammation in biopsy specimens of a proportion of 49.5% of patients (n = 99). a comparison of pca and bph patients in terms of clinical variables is provided in table 1. pca patients had a mean age of 65.47 ± 7.84 years, while bph patients had a mean age of 63.12 ± 7.73 years (p = 0.197). pca patients had significantly higher total psa compared to bph patients (p = 0.001), but the two groups were similar in terms of free-to-total psa ratios. furthermore, pca patients had significantly lower mean prostate volumes (p = 0.040), the psad values were significantly higher in the pca than in the bph group (p = 0.001). however, histology did not show a significant difference between the groups regarding inflammation (p = 0.738). a proportion of 35% of patients (n = 70) exhibited pyuria, while the other 65% (n = 130) did not, as revealed by the distribution of the urinary leukocyte count. a comparison of these two groups in terms of clinical variables, cancer detection rates, and histologically-detected inflammation is provided in table 2. the groups were similar regarding age, free-to-total psa ratio, prostate volume, and psad value, although the pyuria group exhibited significantly higher total psa compared to the non-pyuria group (p = 0.044), as well as significantly higher serum crp (p = 0.001). furthermore, the groups were similar in terms of histological cancer detection rate (p = 0.752), but the pyuria group displayed greater histological inflammation (70% vs 38.5%; p = 0.001). table 1. characteristics of recruited patients. bph ( n = 163) pca (n = 37) p age (years) 63.12 ± 7.73 (40-79) 65.47 ± 7.84 (45-80) 0.637 urinary leukocyte count (n°/h.p.f.) 9.44 ± 19.18 (1-80) 10.71 ± 21.25 (1-90) 0.288 crp (mg/dl) 1.23 ± 1.55 (0.10-8.00) 0.85 ± 0.63( 0.10-3.12) 0.520 t-psa (ng/ml) 5.84 ± 2.54 (3.11-14) 8.72 ± 4.48 (3.65-20.00) 0.001* prostate volume (ml) 57.77 ± 34.65 (17-260) 41.2 ± 20.36 (20-120) 0.040* free to total psa ratio (%) 19 ± 7 (5-38) 22 ± 23 (3-58) 0.752 psad 0.12 ± 0.07 (0.03-0.34) 0.25 ± 0.21 (0.07-0.85) 0.001* histologically-detected inflammation rate 49.7% (81/163) 48.6% (18/37) 0.738 †mean ± sd range; ‡bph versus pca. bph: benign prostatic hyperplasia; crp: c-reactive protein; pca: prostate cancer; t-psa: total prostate-specific antigen; psad: psa density. table 2. clinical variables, cancer detection rates and histologically-detected inflammation rates in pyuria and non-pyuria groups. non-pyuria group (n: 130) pyuria group (n: 70) p age (years) 60.45 ± 7.51 (40-80) 64 ± 6.07 (50-78) 0.637 crp (mg/dl) 0.75 ± 0.78 (0.10-3.22) 2.39 ± 2.09 (0.28-8.00) 0.001* t.psa (ng/ml) 6.42 ± 2.41 (3.29-15.07) 7.85 ± 3.88 (3.11-20.00) 0.044* prostate volume(ml) 50.3 ± 34.4 (17-260) 55.4 ± 26.5 (30-130) 0.208 free to total psa ratio (%) 17 ± 9 (3-35) 20 ± 11 (11-58) 0.814 psad 0.14 ± 0.07 (0.04-0.61) 0.15 ± 0.12 (0.03-0.85) 0.288 histologically-detected inflammation rate 38.5% (50/130) 70% (49/70) 0.001* cancer detection rate 17.6% (23/130) 20% (14/70) 0.752 mean ± sd range; ‡non-pyuria, urinary leukocyte count ≤ 3/h.p.f.; pyuria, urinary leukocyte count > 3/h.p.f.; crp: c-reactive protein; h.p.f.: high power field; t-psa: total prostate specific antigen; psad: psa density. demir_stesura seveso 30/09/19 18:21 pagina 168 two groups of positive crp (71.5%, n = 143) and negative crp (28.5%, n = 57) were also distinguished based on the manner in which pre-treatment serum crp levels were distributed. a comparison of these two groups in terms of clinical parameters, cancer detection rates, and histologically-detected inflammation is provided in table 3. it was observed that the groups were similar regarding age, free-to-total psa ratio, prostate volume, cancer detection rates, and histologically-detected inflammation and psad values. discussion since the first isolation of serine protease psa from prostate epithelial cells that was accomplished by wang et al. in 1979, pca began to be diagnosed and treated based primarily on psa measurement (15). there are significant challenges involved in differentiating pca from bph, especially in cases with intermediate levels of psa. furthermore, psa is not associated exclusively with pca but is expressed by malignant as well as normal prostate glands. efforts to make prostate biopsy more efficient directed attention to a number of factors associated with psa, including the free-to-total psa ratio, psad and psa velocity (12, 13). particular focus was put on serum markers like p53 antibody and insulin-like growth factor 1 (igf-1) with the purpose of enhancing positive predictive value (16, 17), which has also benefitted from pca visualisation innovations, including magnetic resonance spectroscopic imaging, dynamic contrastenhanced magnetic resonance imaging, positron emission tomography and transrectal power doppler imaging (18, 19). reduction of negative biopsy rate as much as possible should be a key priority of management since prostate biopsy can entail a great deal of pain and could result in considerable morbidity. besides pca, benign conditions like benign prostatic hyperplasia, prostatic manipulation, and even asymptomatic and chronic prostatitis are associated with elevated levels of serum psa (6, 7). it is well-known that the development and progression of numerous cancers are associated with the risk factor of inflammation (20), with pre-malignant modifications and adenocarcinoma of the prostate having been found to be underpinned by inflammatory processes (21). cytokines stimulating inflammation, especially interleukin 6 (il-6) (22), have a significant influence on systemic inflammation markers like crp (23). however, il-6 is not only involved in the mobilization of inflammatory cells but is also believed to be mitogenic in the case of prostate cells (24). in a retrospective study on 284 patients showing no cancer signs in sextant ultrasound-guided biopsies, morote et al. reported that 23.2% of patients had non-malignant tissue without inflammation, 68.3% displayed chronic prostatitis, and 8.4% displayed acute prostatitis, which implied that bph specimens had a high rate of prostatic inflammation (11). in a different retrospective study, tomonori et al. found that 53.5% of bph patients and 14.1% of pca patients had inflammation (25). in the present study, histology revealed that 49.7% of bph patients and 48.6% of pca patients had inflammation. asymptomatic prostatitis are diagnosed when inflammatory cells are present in histological prostate biopsy specimens according to the national institute of health (nih) (14). it was noted that serum psa was significantly higher in pyuria patients with a urinary leukocyte count exceeding 3/h.p.f. (p = 0.044), but the two groups were similar regarding the cancer detection rate (p = 0.752). histology revealed that pyuria patients had a high inflammation rate, even though clinical symptoms of prostatitis were absent (p = 0.001) (table 2). furthermore, nih-iv prostatitis is often accompanied by prostate hyperplasia (11, 25-27). however, the results obtained in this study did not determine that serum crp was clinically useful in pca screening. pyuria patients had higher levels of serum crp compared with nonpyuria patients (table 3). high levels of both psa and crp may be due to inflammation. meanwhile, crp positive and negative groups did not differ in terms of inflammation rate and cancer detection rate. it was deduced that prostatic inflammation was more reliably signaled by urinary leukocyte count than serum crp and that serum crp and elevated psa were not closely correlated. according to tomonori et al., non-palpable pca and bph might be differentiated based on an inflammatory index like urinary leukocyte count applied in a clinical setting (25). however, the present study did not support this claim, despite observing that minute prostatic inflammation could be reliably identified based on the urinary leukocyte count. meanwhile, in a different study conducted on 61 patients displaying psa in the range 4-10 ng/ml, normal dre outcomes and inflammation in expressed prostate secretion, karazanashvili et al aimed to come up with solutions for making pca screening more accurate (28). to that end, they used psa value modification following treatment with antibiotics as a diagnostic approach. pca was detected in only 6% of patients with reduced psa values, whereas all patients exhibited prostate inflammation. on the other hand, pca was detected in 83% of patients with unaltered or ele169archivio italiano di urologia e andrologia 2019; 91, 3 urinary inflammation and prostate cancer table 3. clinical variables, cancer detection rates and histologically-detected inflammation rates in positiveand negativec-reactive protein groups. crp negative (n: 57) crp positive (n: 143) p age (years) 63.15 ± 7.20 (40-77) 60± 6.37 (43-80) 0.245 t-psa (ng/ml) 6.80 ± 2.45 (3.23-14.58) 7.15 ± 3.63 (3.11-20.00) 0.991 prostate volume(ml) 55.10 ± 37.32 (17-120) 59.88 ± 29.53 (20-260) 0.200 free to total psa ratio (%) 19 ± 7 (3-55) 16 ± 8 (4-58) 0.738 psad 0.15 ± 0.06 (0.03-0.35) 0.17 ± 0.12 (0.04-0.85) 0.490 histologically-detected inflammation rate 49.1% (28/57) 49.6% (71/143) 0.857 cancer detection rate 12.3% (7/57) 20.1% (30/143) 0.248 mean ± sd range; ‡negative, serum crp < 0.30 mg/dl; positive, serum crp ≥ 0.30 mg/dl; crp, c-reactive protein; t-psa, total prostate specific antigen; psad, psa density. demir_stesura seveso 30/09/19 18:21 pagina 169 archivio italiano di urologia e andrologia 2019; 91, 3 s. demir 170 vated psa values and prostate inflammation was observed in 17% of these patients. the authors concluded that pca screening could be made more accurate by evaluating psa value modification following treatment with antibiotics since high psa was determined to a significant extent by chronic prostatitis. conclusions male individuals are at high risk of asymptomatic prostatitis if their levels of psa are high and they present normal dre outcomes. prior to biopsy, antibiotics or antiphlogistics should be given to pyuria patients and it is advisable to measure psa repeatedly as well. in patients without evidence of clinical prostatitis, sterile pyuria should be kept in mind as a cause of increased psa. although urine leukocyte count cannot predict non-palpable prostate cancer, it should be incorporated in routine urological evaluation to demonstrate minute prostatic inflammation due to its simplicity, convenience and non-invasiveness. author contribution selamettin demir: concept, design, supervision, researches and material, data collection, literature search, writing manuscript, critical review, analysis, interperation. references 1. cooperberg mr, broering jm, carroll pr. risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. j natl cancer inst. 2009; 101:878-887. 2. pishgar f, ebrahimi h, saeedi moghaddam s, et al. global, regional and national burden of prostate cancer, 1990 to 2015: results from the global burden of disease study 2015. j urol. 2018; 199:1224-1232. 3. gann ph. risk factors for prostate cancer. rev urol. 2002; 5:3-10. 4. hernandez j, thompson im. prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker. cancer. 2004; 101:894-904. 5. gosselaar c, roobol mj, schröder fh. prevalence and characteristics of screen-detected prostate carcinomas at low prostatespecific antigen levels: aggressive or insignificant? bju int. 2005; 95:231-7. 6. oesterling je. prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. j urol. 1991; 145:907-23. 7. stamey ta, yang n, hay ar, et al. prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. n engl j med. 1987; 317:909-16. 8. marzo am, platz ea, sutcliffe s, et al. inflammation in prostate carcinogenesis. nat rev cancer. 2007; 7:256-69. 9. sfanos ks, hempel ha, de marzo am. the role of inflammation in prostate cancer. adv exp med biol. 2014; 816:153-81. 10. palapattu gs, sutcliffe s, bastian pj, et al. prostate carcinogenesis and inflammation: emerging insights. carcinogenesis. 2005; 26:1170-81. 11. morote j, lopez m, encabo g, de torres im. effect of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen. eur urol. 2000; 37:537-40. 12. catalona wj, southwick pc, slawin km, et al. comparison of percent free psa, psa density, and age-specific psa cutoffs for prostate cancer detection and staging. urology. 2000; 56:255-60. 13. brawer mk, cheli cd, neaman ie, et al. complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. j urol. 2000; 163:1476-80. 14. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama 1999; 282:236-7. 15. wang mc, valenzuela la, murphy gp, chu tm. purification of a human prostate specific antigen. invest urol. 1979; 17:159-63. 16. suzuki h, akakura k, igarashi t, et al. clinical usefulness of serum antip53 antibodies for prostate cancer detection: a comparative study with prostate specific antigen parameters. j urol. 2004; 171:182-6. 17. renehan ag, zwahlen m, minder c, et al. insulin-like growth factor (igf) -i, igf binding protein-3, and cancer risk: systematic review and meta-regression analysis. lancet. 2004; 363:1346-53. 18. hersh mr, knapp el, choi j. newer imaging modalities to assess tumor in the prostate. cancer control. 2004; 11:353-7. 19. inahara m, suzuki h, nakamachi h, et al. clinical evaluation of transrectal power doppler imaging in the detection of prostate cancer. int urol nephrol. 2004; 36:175-80. 20. mantovani a, allavena p, sica a, balkwill f. cancer related inflammation. nature. 2008; 454:436-444. 21. de marzo am, platz ea, sutcliffe s, et al. inflammation in prostate carcinogenesis. nat rev cancer. 2007; 7:256-269. 22. kushner i. the phenomenon of the acute phase response. ann n y acad sci. 1982; 389:39-48. 23. guthrie gj, roxburgh cs, horgan pg, mcmillan dc. does interleukin-6 link explain the link between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer? cancer treat rev. 2013; 39:89-96. 24. malinowska k, neuwirt h, cavarretta it, et al. interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. endocr relat cancer. 2009; 16:155-169. 25. kato t, suzuki h, komiya a, et al. clinical significance of urinary white blood cell count and serum c-reactive protein level for detection of non-palpable prostate cancer. int j urol. 2006; 13:915-919. 26. stancik i, lüftenegger w, klimpfinger m, et al. effect of nih-iv prostatitis on free and free-to-total psa. eur urol. 2004; 46:760-4. 27. irani j, levillain p, goujon jm, et al. inflammation in benign prostatic hyperplasia: correlation with prostate specific antigen value. j urol. 1997; 157:1301-3. 28. karazanashvili g, managadze l. prostate-specific antigen (psa) value change after antibacterial therapy of prostate inflammation, as a diagnostic method for prostate cancer screening in cases of psa value within 4-10 ng/ml and nonsuspicious results of digital rectal examination. eur urol. 2001; 39:538-43. correspondence selamettin demir, md (corresponding author) drselami1978@hotmail.com the ministry of health, university of health sciences, van education and research hospital, van (turkey) demir_stesura seveso 30/09/19 18:21 pagina 170 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 3248 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.248 nephroureterostomy as a treatment of obstructive uropathy: a single center experience muhammad faisal khan 1, maira saeed babar 1, georgios tsampoukas 2, soumya misra 1 1 urology department north devon hospital, barnstaple, uk; 2 urology department princess alexandra hospital, harlow, uk. objective: to report the outcomes of percutaneous nephroureterostomies performed in a single center a period of ten years. materials and methods: we retrospectively collected and analyzed data for 52 nephroureterostomy procedures that were performed from september 2008 to august 2018. we present patient’s demographics, indications for the procedure, type of anesthesia, technical difficulties, length of stay in hospital and complications. results: a total of 52 procedures including 13 bilateral nephroureterostomies were performed on 39 patients. taking into account the need for replacement of nephroureterostomy procedures during the study period, total number of procedures was 168. out of a total 39 patients, 32 (84%) of patients had advanced cancer. all procedures were performed as day cases using sedation and had no immediate or early complications. ten patients or 16% (27 nephroureterostomies out of total 168 procedures) had minor complications. conclusions: to the best of author’s knowledge, this is the largest case series reporting the outcome of percutaneous nephroureterostomies. we can therefore conclude that percutaneous nephroureterostomy is a useful palliative procedure to relieve ureteric obstruction, when other measures are not possible, and it has low incidence of complications. however, further studies are warranted to compare different procedures used to relieve ureteric obstruction. key words: nephroureterostomy; ostructive uropathy; palliation; nephrostomy; jj stent. submitted 2 march 2020; accepted 15 march 2020 summary introduction ureteric obstruction is a well-known urological problem that has an overall incidence of 3.1% rising to 5.1% in people over age of 60 years (1). it can result in urinary tract obstruction and subsequently may lead to more serious consequences including, renal failure, sepsis or even death. the obstruction can be reversible or irreversible. the etiology of ureteric obstruction includes ureteric calculi, renal papillary necrosis, strictures, pregnancy, renal tract tumors or pelvic masses. in cases where it is not possible to reverse the etiology, methods such as permanent stents, nephrostomies, ureteric diversion and re-implantation or reconstruction become necessary. some patients are not fit to undergo extensive surgery. this leaves them with options of either stenting, or external diversion of urine with nephrostomy tubes and urinary bag. stents (double j or jj) and nephrostomies have their advantages and disadvantages. stents are internalized tubes and hence avoid problems associated with external tubes and bags like wound infections, urine bypassing and leakage of urine, tubes falling out and physical/psychological impact of bags hanging out. disadvantages include stent failure rate of 16-58% (2), stent irritation, pain, infections, hematuria, stent encrustations, stone formation and obstruction and blockage of stents. failure rate due to obstruction secondary to primary prostate, bladder and cervical cancer is high with success rates in the range of 15-21% (3). however, success rates are relatively higher at more than 50% (3) in cases of ureteric obstruction secondary to metastatic cancers. another challenge with stents is the requirement for frequent changes, which involves anesthesia (general or regional). to some extent, frequent changes can be avoided by inserting metallic stents. theoretically, metallic stents by virtue of being metallic may help mitigating the need for replacement too frequently, however their complications in terms of stent blockage or stent migration have been reported to be around 18% (4). nephrostomies, on the other hand have low initial complication rate of up to 3% (5), and can potentially avoid the requirement for anesthesia and bladder infection, and other complications encountered with stents. however, these can be difficult for patients to manage in community as these can frequently get blocked, bypass urine and can get easily pulled out or fall off requiring frequent unplanned visits to hospital. new et al. (5) in their systematic review reported that patients spend up to 50% of their remaining time in hospital, though it is not very clear if it is solely due to nephrostomy complications or contributed largely by primary disease and it’s related complications. also for nephrostomy procedures, an experienced interventional radiologist is required which can be a resource issue. nephrostomy is favoured for patients considered high risk american society of anesthesiologist classification (asa) iii + or where stent change is considered difficult. this is true in cases of significant involvement of the bladder by a prostatic or bladder malignancy. this also includes those cases where attempts to identify ureteral orifices fail due to gross haematuria or difficulty in reaching the bladder due to previous surgery or anatomic anomalies (6, 7). nephroureterostomy is a modification of the nephrostomy technique, where the internal drainage tube extends 249archivio italiano di urologia e andrologia 2020; 92, 3 nephroureterostomy for obstructive uropathy from the renal pelvis, down the ureter, into the bladder, therefore, obviating the need for an external bag to collect the urine in most cases. we describe a single center experience of this unique technique in the management of ureteric obstruction. the primary aim was to analyse and report the outcome including complications related to nephroureterostomy in the management of obstructive uropathy. materials and methods all patients who had the percutaneous nephroureterostomy at our hospital for either malignant or benign conditions causing obstructive uropathy from september 2008 till august 2018 were included in the study. we retrospectively reviewed the computerized record of patient’s admission and discharge, clinic letters, radiology reports, laboratory record and radiologist log of the procedure. we recorded patient’s demographics, their disease characteristics and procedural details including indication, technical details, difficulty, and post procedure parameters including length of stay in hospital, and complications requiring unplanned hospital attendances. we counted the initial procedure with follow up change of nephroureterostomy tubes, which brings the total number of procedures done during the above period to 168. selection criteria in patients who were being managed with stents, percutaneous nephroureterostomy was chosen as the final option if they were deemed high risk for general anaesthesia (asa iii and above) or if they had technically difficult stent changes. patients were also considered for a nephroureterostomy as a palliative solution for life, where a nephrostomy had been initially inserted for renal failure or sepsis related to ureteric obstruction. brief overview of the technique in preparation for the procedure, we measured skin to renal pelvis distance from the ct imaging done prior to the procedure. patients had 160 mg gentamicin as prophylaxis. lidocaine 1% 10 mls was used for local infiltration and midazolam 0-5 mg and/or fentanyl 0-50 mg was used for sedation. patients were monitored throughout the procedure. we used accustick™ ii introducer systems (boston scientific) with radiopaque marker for easy detection under image intensifier screening. the procedure is as follows: 1. 21-gauge diagnostic needle with a stylet is inserted into renal pelvis under ultrasound (uss) guidance. stylet reduces tissue trauma and bend of needle. 2. stylet is withdrawn and urine is aspirated from the kidney. 3. this is followed by insertion of a 0.018" kink-resistant nitinol guide wire, which is designed to provide strength. 4. this is followed by a coaxial sheath/dilator assembly with locking stiffening cannula designed for overthe-wire placement. 5. dilator is re mo ved and contrast injected into the renal pelvis to outline anatomy on image intensifier. 6. once operator is satisfied with the positioning of sheath, nitinol guide wire can be exchanged with a working bentson (cook®) 0.35” guide wire, which can be advanced down to the bladder and the length of the ureter is measured. 7. if any doubt exists or it is a challenging case due to body mass index (bmi) of patient or any other reason, a second 0.018” guide wire can be passed alongside the first nitinol wire instead of removing it. 8. the sheath is removed and “cook®” dilators of 6 french (fr) and 8 fr diameter are used to dilate the tract from skin to renal pelvis. 9. this is followed by advancement of cope nephroureterostomy stent (cook®)” 8.5fr, tapered end diameter of 0.038” and ureteric part of stent 22 to 28 cm long. the length of tube is selected as per measurements made with guide wire length needed to approach bladder from renal pelvis. 10. the external end is locked and closed with a stopper after aspiration of urine from the bladder and kidney and position confirmation with of nephroureterostomy with image intensifier. the following techniques were used to overcome particular challenges. pelviureteric junction (puj) obstruction with dilated renal pelvis: • the above is procedure is altered at step 7 by aspirating urine from renal pelvis and thus reducing the space and encouraging the guide wire to pass through more easily into ureter. • if the above step does not work then an tempotm angiographic catheter 4fr, 65 cm long and 0.038” in diameter with tapered and curved end is introduced over the wire to approach the puj and help wire slide through the narrow opening. tortuous ureter secondary to hydroureter: • this is again negotiated with the angiographic catheter. the slippery terumo® angled or straight 0.035” and 150 cm long guide wire is advanced to the bend of ureter. sliding angiographic catheter to the obstruction follows this. the guide wire is then maneuvered around the bend of ureter gradually until it reaches bladder. strictures in ureter: • the slippery terumo® angled or straight 0.035” and 150 cm long guide wire is passed through the stricture. if that is successful then sterling over the wire balloon dilatation cathetertm (boston scientific) is negotiated through the stricture. it is 80 cm long with a balloon 100 mm long and 4 fr (non dilated) to 12 fr (dilated) in diameter. once stretched the nephroureterostomy catheter is advanced into the bladder. this dilatation is not the permanent solution of stricture and hence the need for nephroureterostomy remains. vesicoureter junction stenosis: • if the above measures fail and it is a very tight stenosis, the distal end of nephroureterostomy is cut. the distal part of nephroureterostomy then remains in disarchivio italiano di urologia e andrologia 2020; 92, 3 muhammad faisal khan, maira saeed babar, georgios tsampoukas, soumya misra 250 tal ureter. it serves the purpose of anchor, providing extra length thus making it difficult for tube to be dislodged. the proximal end of tube is kept open and connected to bag for drainage. following the procedure patients are observed in radiology recovery ward for 4 hours and then sent home. change of nephroureterostomy is usually a straightforward procedure mostly without or with minimal sedation. the old tube is removed over a guide wire and a new one inserted over the same wire and position checked with image intensifier. however if tube is blocked than mostly insertion of amplatz super stiff guide wiretm (boston scientific) 0.35” in diameter and 145 cm long, through the tube clears the blockage. if that does not work then the old tube is removed and the procedure is repeated as new. results a total of 52 nephroureterostomy procedures were done in 39 patients, with 13 patients having bilateral nephroureterostomy. the median age at the time of initial procedure were calculated as 74.7 years (range 39 to 86). the male to female ratio was 3.3:1. nephroureterostomy was not used as first line procedure but was reserved after stents or nephrostomy were not longer considered viable options. the aetiologies of the obstructive uropathy were divided into two broad groups: malignant and non-malignant. the vast majority were due to cancer (85%). in the group with cancer, prostate cancer was the most frequent primary cancer site (n = 17) followed by bladder cancer with 12 patients. remaining patients had other pelvic malignancies or metastatic disease in the pelvis. these results are summarised in table 1. the ap renal pelvic diameter varied from 11 mm to 56 mm (median 24.5 mm). the calculated skin renal pelvis distance ranged from 3.6 cm to 20.7 cm (median 9 cm). from the point of view of this study, early complications were defined as ones occurring during or up to 72 hours after the procedure. there were no early complications. all patients were discharged home the same day from the radiology department without the need for transfer to inpatient wards. we recorded as late complications when patients attended hospital for advice or treatment in an unplanned way rather than for regular and planned change of nephroureterostomy. the total number of complications was 10 (16%) if measured per nephrostomy initially inserted. this number stands increases to 27 (19%) if all the follow-up procedures since initial insertion are counted. none of these complications were life threatening or critically significant requiring immediate pharmacological or interventional input. no patients were recorded as having reported pain as the main cause of concern or demanded regular analgesia or removal of nephroureterostomy as a result. there were no infection or sepsis related events. the main complications included pulled/fallen tube, leaked/bypass and blocked tube. one case was an outlier in respect of number of related hospital attendances. he admitted to self-manipulating tubes as a means to seek medical attention. this led to an exceptionally high number of complications and contributing to 50% (6 out of total 12) of pulled/fallen tubes, 40% (3 out of total of 8) of leakage/bypass and 14% (1 out of total of 7) of blocked tube category. once the social issues were sorted, the patient had no further problems or complications during the last three years of he study period. if we exclude the outlier from the analysis, the complication rate comes down to 9.9%. this is summarized in table 2. discussion our centre is one of the very few centres or perhaps the only centre in the uk performing this radiological-guided procedure for the past few years. it has mainly been performed as a palliative procedure for patients with cancer causing ureteric obstruction. however, it has also been used in our centre for benign conditions. by conducting a review of the outcome of the procedure, the authors have not only attempted to measure the clinical effectiveness of the procedure for our local centre but also generated baseline data for future reference. a detailed literature search revealed very few studies that particularly focused on percutaneous nephroureterostomy, and with small numbers, it makes it particularly difficult to compare studies and draw firm conclusions. we have summarized studies that have captured nephroureterostomy, in table 3. this includes case reports (9, 13), insertion techniques (10-12), one short outcome analysis of cost and complications among nephroureterostomy and jj stent (15), case series (16), and one abstract (17). we found one small study in ileal conduits mentioning complication rate of 16% which is comparable to our study (18). monsky et al compared complications for all three types of decompressive procedures but the evaluation was limited to up to 90 days (14) (summarized in table 4). apart from the absence of long term follow up data, studies have also differed in the definition of complicatable 1. a summary of aetiology of ureteric obstruction. reason for obstructive nephropathy total number (percentage) prostate cancer 17 (43.5%) bladder cancer 12 (30.7%) benign ureteric stricture 3 (7.6%) obstructing stone 2 (5.2%) endometrial cancer 1 (2.6%) retroperitoneal mass 1 (2.6%) colon cancer 1 (2.6%) posterior urethral valve 1 (2.6%) metastatic breast cancer 1 (2.6%) table 2. a summary of late complications. total pulled/ leaked/ blocked infection sepsis total procedures fallen bypass complications 168 6 (3.5%) 5 (2.9%) 6 (3.5%) 0 0 17 (9.9%) 251archivio italiano di urologia e andrologia 2020; 92, 3 nephroureterostomy for obstructive uropathy tions. our complication rates compare favourably to those reported by ali and lee (19, 20) and monsky et al. (14) (table 5). our study has some limitations. this is a retrospective study and the sample size is small. we were unable to measure the quality of life, as this was not recorded at the time. however we can indirectly infer from the data, that all the patients were able to tolerate nephroureterostomy. none of the patients requested removal of nephroureterostomy. all the patients undergoing the procedure did not stay in hospital due to pain or discomfort again suggesting good tolerance to the procedure. table 3. a comparative analysis of studies included. study with year of publication type of study type of tube complications gemender et al. 2017 (9) makramalla et al. 2011 (10) taveres et al. 2008 (11) hadley 2009 (12) hatzidakis et al. 2014 (13) monsky et al. 2013 (14) braga l.h.p et al. 2008 (15) spradling et al. 2019 (16) mahajan et al. (17) tal et al. 2003 (18) case report techniques of ureteral catheters/tubes technique of insertion in paediatric pyeloplasty technique of insertion in paediatric pyeloplasty case report for infected obstructed system by hernia quality-of-life assessment after palliative interventions to manage malignant ureteral obstruction outcome analysis and cost comparison between externalized pyeloureteral and standard stents in 470 consecutive open pyeloplasties percutaneous nephroureteral tube: a useful tool for management of intractable hematuria palliative care intervention in oncology: a pictorial review for the interventional radiologist and the palliative care physician external-internal nephro-uretero-ileal stents in patients with an ileal conduit: long-term results neproureterostomy nephrostomy, nephroureterostomy, stent nephroureterostomy nephroureterostomy (kiss catheter or kidney internal splint/stent) nephroureterostomy nephrostomy, nephroureterostomy and jj stent for 90 days. nephroureterostomy and jj stent nephroureterostomy esophageal, duodenal and colonic stenting, gastrostomy and feeding tubes, percutaneous biliary drainage and stenting, tunneled peritoneal catheters, nephrostomy and nephroureterostomy tubes. endobronchial stents, runneled pleural catheters.: venous stenting for thoracic outlet obstruction, vascular access. nephroureterostomy tumour seeding from bladder to skin none discussed none discussed. 10 patients mean 13 days. 2 blocked and flushed, 1 pulled + infection and requiring jj stent 1 infection. none * short-term comparison. 8.3% complications with urinoma 1, prolong drainage 5, infection 1 and recurrent obstruction 12 (comparable to jj stent) treatment of hematuria with nephroureterostomy not responsive to cystoscopy management. (6 patients) none mentioned 1 out of 16 had recurrent blockages, 2 out of 16 recurrent infections, 3 had failed exchange table 4. monsky et al study elaborated further in this table. complications nephrostomy (16) nephroureterostomy (15) stent (15) dislodged 7 1 1 pain 4 2 1 infection 3 1 1 clogged 4 2 0 leak 1 2 0 fistula 0 0 1 total 20 8 4 quality of life (at 90 days) around 3 around 3 around 3 table 5. comparison of different studies complications with our study. complications ali et al. lee et al. monsky et al. our data complications of nephrostomy complications of nephrostomy complications of nephroureterostomy complications of nephroureterostomy (%) (%) (%) (%) dislodged 2.3 4.8% 6.7% 3.5% infection/fever no data 13.6% 6.7%) 0% sepsis 2% 3.6% 0% 0% clogged 5% no data 13.3% 3.5% urinoma/extravasation/leak 0.3% 4.3% 13.3% 2.9% other organs affected (ileus, pneumonia/atelectasis) no data 5.4% 0% 0% bleeding (requiring transfusion) 2.3% 2.4% 0% 0% pain/intolerance not mentioned not mentioned 13.3% 0% total 11.9% 27.7% 53.2% 9.9% archivio italiano di urologia e andrologia 2020; 92, 3 muhammad faisal khan, maira saeed babar, georgios tsampoukas, soumya misra 252 conclusions we have reported results of a large case series of percutaneous nephroureterostomy. this procedure appears safe and well tolerated and can be performed as day case using local anaesthetic/sedation. further studies are needed to clarify the position of nephroureterostomy amongst other procedures, which provide renal collecting system decompression. acknowledgments we acknowledge dr. jennifer macpherson (consultant radiologist) who kindly provided the list of patients who had nephroureterostomy at our hospital. references 1. bell et. renal diseases. 2nd ed. philadelphia: lea & febiger. 1950:122-125. 2. wong lm, cleeve lk, milner ad, pitman ag. malignant ureteral obstruction: outcomes after intervention. have things changed? j urol. 2007; 178:178-83; 3. kouba e, wallen em, pruthi rs. management of ureteral outcomes. j urol. 2008; 180:444-50. 4. agarwal s, brown ct, bellamy ea, kulkarni r. the thermoexpandable metallic ureteric stent: an 11-year follow-up. bju int. 2009; 103:372-6. 5. new f, deverill s, somani bk. role of percutaneous nephrostomy in end of life prostate cancer patients: a systematic review of the literature. cent european j urol. 2018; 71:404-409. 6. danilovic a, antonopoulos im, mesquita jl, lucon am. likelihood of retrograde double-j stenting according to ureteral obstructing pathology. int braz j urol. 2005; 31:431-6. 7. uthappa mc, cowan nc. retrograde or antegrade double-pigtail stent placement for malignant ureteric obstruction? clin radiol. 2005; 60:608-12. 8. north devon district hospital leaflet for “percutaneous insertion of a nephroureterostomy tube”. available from: url: https://www.northdevonhealth.nhs.uk/wpcontent/uploads/2015/05/percutaneous_insertion_nephroureterostomy_tube.pdf. 9. gemender m, rinzler e, werder g, trace a. seeding of a highgrade papillary urothelial carcinoma of the bladder along a nephroureterostomy tract. radiol case rep 2017; 12:542-545. 10. makramalla a, zuckerman d. nephroureteral stents: principles and techniques. semin intervent radiol. 2011; 28:367-379. 11. taveres a, manaboriboon n, lorenzo a, farhat w. insertion of an internal-external nephroureteral stent during pediatric laparoscopic pyeloplasty: description of the technique. urology. 2008; 71:1199-1202. 12. hadley d, wicher c, wallis m. retrograde percutaneous access for kidney internal splint stent catheter placement in pediatric laparoscopic pyeloplasty: avoiding stent removal in the operating room. j endourol. 2009; 23:1991-1994. 13. hatzidakis a, kozana a, glaritis d, mamoulakis c. right-sided bochdalek hernia causing septic ureteric obstruction. percutaneous treatment with placement of a nephroureteral double pigtail. bmj case rep. 2014; 2014:bcr2014207247. 14. monsky w, molloy c, jin b, et al. quality-of-life assessment after palliative interventions to manage malignant ureteral obstruction. cardiovasc intervent radiol. 2013; 36:1355-1363. 15. braga l, lorenzo a, farhat w, et al. outcome analysis and cost comparison between externalized pyeloureteral and standard stents in 470 consecutive open pyeloplasties. j urol. 2008; 180:16931699. 16. spradling k, elliott c, vo h, reese j. percutaneous nephroureteral tube: a useful tool for management of intractable hematuria. urology. 2019; 126:232-235. 17. mahajan a, pugash r, annamalai g, et al. conference abstract only. international symposium on endovascular therapy (iset) 2013. jvir iset abstracts 145.e25-145.e26 18. tal r, bachar g, baniel j, belenky a. external-internal nephrouretero-ileal stents in patients with an ileal conduit: long-term results. urology. 2004; 63:438-441. 19. ali sm, mehmood k, faiq sm, et al. frequency of complications in image guided percutaneous nephrostomy. j pak med assoc. 2013; 63:816-20. 20. lee wj, patel u, patel s, pillari gp. emergency percutaneous nephrostomy: results and complications. j vasc interv radiol. 1994; 5:135-9. correspondence muhammad faisal khan, md drfaisalkhan@gmail.com maira saeed babar soumya misra urology department north devon hospital, barnstaple, uk georgios tsampoukas, md tsampoukasg@gmail.com urology department princess alexandra hospital, harlow, uk 267archivio italiano di urologia e andrologia 2019; 91, 4 case report right open nephrectomy under combined spinal and peridural operative anesthesia and analgesia (cse): a new anesthetic approach in abdominal surgery michele cotugno 1, matteo dallaglio 2, luca cantadori 2, fabio villani 2, daniel martens 1, federico cantoni 1, michele potenzoni 1, salvatore micali 3, m.c. bernardo rocco 3, andrea prati 1 1 dipartimento chirurgico, u.o. di urologia, ospedale di vaio-fidenza, fidenza, italy; 2 dipartimento chirurgico, u.o. di anestesia e rianimazione, ospedale di vaio-fidenza, fidenza, italy; 3 dipartimento di chirurgia generale e specialità chirurgiche, u.o. di urologia, azienda ospedaliero-universitaria di modena, italy. a case of right open nephrectomy performed under combined spinal and epidural anesthesia and analgesia was presented. this new anesthetic technique gives significant advantages to the patient by avoiding endotracheal intubation with mechanical ventilation and curare administration and by reducing the use of opioids. key words: nephrectomy; spinal; epidural; anesthesia. submitted 5 june 2019; accepted 2 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.268 introduction we describe a case of right open nephrectomy with xifopubic incision in a patient undergoing initially thoracic spinal anesthesia that was later converted into peridural anesthesia and analgesia (cse). patients and methods a 57-year-old male patient with negative medical history for major internal and surgical diseases accessed our operative unit for a massive hematuria. abdomen ultrasound showed a right renal mass suspected as heteroplasia. subsequently he performed a computed tomography (ct) of the abdomen with evidence of an inhomogeneous and hyper-vascularized renal neoformation of 10 x 9 cm with central necrotic area and without safe cleavage from the liver. presence of clots in the renal pelvis, numerous mesenteric and retroperitoneal adenopathies and an occasional finding of a thoracic aortic aneurysm of 4.8 cm were also demonstrated (figures 1, 2). it was decided to perform the intervention of right nephrectomy with xifopubic incision given the size of the mass and the unsafe cleavage from neighboring structures. anesthesiologist performed a combined spinal and epidural (cse) anesthesia and analgesia: subarachnoid puncture at t10-t11 level with whiteacre 25g needle with administration of isobaric bupivacaine 0.5% 10 mg + dexamethasone 4 mg + ketamine 20 mg + midazolam 2 mg reaching a complete sensory and motor block up to t3 level. immediately after the spinal puncture, a peridural catheter was placed at t9-t10 level and the right radial artery was cannulated. beginning of the operation was about 15 minutes after the puncture without any surgical or anesthetic problem. after about 70 minutes 15 ml of ropivacaine 0.5% was administered in the peridural catheter in fractions of 5 ml each in a total time of 30 minutes. in the meantime, peridural infusion of ketamine 50 mg + midazolam 5 mg was started at a rate of 2-3 ml/h. the patient was sedated in a light way, awake to the call and reactive to the light stimulus. he maintained sponfigure 1. antegrade pyelography. figure 2. extraperitoneal approach. cotugno_stesura seveso 10/01/20 09:07 pagina 267 archivio italiano di urologia e andrologia 2019; 91, 4 m. cotugno, m. dallaglio, l. cantadori, f. villani, d. martens, f. cantoni, m. potenzoni, s. micali, m.c. bernardo rocco, a. prati 268 taneous breathing with nasal cannulas and low oxygen flow achieving excellent saturation values. the intervention lasted a total of 2 h and 40 minutes with blood losses of about 200 ml. starting from the closure of the surgical wound, ropivacaine 0.2% infusion was initiated in association with midazolam 5 mg at 5 ml/h. patient controlled analgesia (pca) was continued with 1.5 ml boluses with lockout every 20 minutes. results arterial blood gas (abg) at the end of the procedure showed excellent respiratory exchanges with normocapnia, and lactate in the normal range. post-operative course was regular. vital parameters always remained in the normal range, gastrointestinal canalization was recovered the day after the operation, blood count was stable. bladder catheter was removed on the third postoperative day. subhepatic drainage and epidural catheter were removed on the fourth postoperative day. the apyretic and asymptomatic patient was discharged on the seventh postoperative day waiting for result of histological examination. discussion castellani et al. were the first in italy to describe five cases of radical cystectomy performed under continuous spinal anesthesia, a technique that represents the natural evolution of that used by us (1). numerous authors have shown excellent perioperative outcomes in cardio-vascular, orthopedic, pelvic and abdominal surgery (2-4). it is also interesting to note that the entire procedure was conducted in opioid free mode without negative effect on pain during intraand post-operative period. this is the first case described in italy of open nephrectomy performed with this type of anesthesia and the excellent results obtained leads us to think that we can apply it in other future surgical procedures. conclusions our opinion is that this new anesthetic technique gives significant advantages to the patient, in particular by avoiding endotracheal intubation with mechanical ventilation and curare administration and by reducing the use of opioids. the evolution (using a special device) to continuous spinal anesthesia (csa) could lead to a further improvement of the procedure. randomized and controlled clinical trials will be needed to confirm our initial results. references 1. castellani d, starnari r, faloia l, et al. radical cystectomy in frail octogenarians in thoracic continuous spinal anesthesia and analgesia: a pilot study. ther adv urol. 2018; 10:343-349. 2. michaloudis d, petrou a, bakos p, et al. continuous spinal anaesthesia/analgesia for the perioperative management of high-risk patients. eur j anaesthesiol. 2000; 17:239-247. 3. amin sm, and sadek sf. continuous spinal anesthesia for elderly patients with cardiomyopathy undergoing lower abdominal surgeries. egypt j anaesth. 2016; 32:535-540. 4. jaitly vk and kumar cm. continuous spinal anaesthesia for laparotomy. curr anaesth crit care. 2009; 20:60-64. correspondence michele cotugno, md (corresponding author) mikcot88@libero.it daniel martens dmastens@ausl.pr.it federico cantoni fcantoni@ausl.pr.it michele potenzoni mpotenzoni@ausl.pr.it andrea prati aprati@ausl.pr.it dipartimento chirurgico, u.o. di urologia ospedale di vaio-fidenza, fidenza (italy) matteo dallaglio madallaglio@ausl.pr.it luca cantadori lcantadori@ausl.pr.it fabio villani fvillani@ausl.pr.it dipartimento chirurgico, u.o. di anestesia e rianimazione, ospedale di vaio-fidenza, fidenza (italy) salvatore micali smicali@unimore.it maria cesare bernardo rocco bernardo.rocco@gmail.com dipartimento di chirurgia generale e specialità chirurgiche, u.o. di urologia, azienda ospedaliero-universitaria di modena, modena (italy) cotugno_stesura seveso 10/01/20 09:07 pagina 268 cop+ed+fisse 2006 213archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.213 fatal infections in andrology. atypical clinical presentation of a fournier’s disease valerio olivieri 1, gabriele ruggiero 1, 2, danilo abate 2, nicoletta serra 2, valentina fortunati 3, daniele griffa 1, 2, flavio forte 4, emanuele corongiu 4 1 division of urology, ivrea civil hospital (asl to4), ivrea (turin), italy; 2 division of urology, ciriè hospital (aslto4), ciriè (turin), italy; 3 division of pathology, hospital “policlinico of tor vergata”, rome, italy; 4 division of urology, hospital “madre giuseppina vannini”, rome, italy. background: fournier disease (fd) is a worrisome infection of genital area caused by a polimicrobial infection and characterized by a rapid progression to necrosis. scrotum, perineum and lower abdomen represent the primary sites of origin. clinical presentation and laboratory strongly suggest fd, but if not precociously diagnosed, it may quickly evolve into septic syndrome and patient’s death. case report: a 62 years old caucasian male presented for fever and penile gross oedema recently occurred. no history of previous urinary tract infection, hematuria or genital trauma was referred. he did not complain any storage or voiding low urinary tract symptom (luts); no foci of infection in genitoperineal area was observed nor urethral discharge. the ultrasound (us) revealed a disomogeneous broad thickening of subcutaneous tissues with increased vascularity on color-doppler. when the penis was manipulated in order to reduce oedema, retract foreskin and evaluate the glans, clinical parametres rapidly worsened and the patient developed a septic shock with blood pressure falling down, dyspnoea and tachyarrhythmia, and he was fastly sent to intensive care unit where it has been hemodynamically stabilized and subjected to antibiotic therapy. considering the clinical absence of gangrene’s foci, we opted for a conservative treatment by maintaining bladder catheter and drug therapy. key words: andrology; fournier’s disease; atypical clinical presentation; sepsis. submitted 2 march 2020; accepted 15 march 2020 summary introduction fournier’s disease (fd) is a worrisome of genital area caused by a polimicrobial infection and characterized by a rapid progression to necrosis (1). it is a rare clinical condition accounting for 1.6 cases per 100.000 and represent the 0.01% to 0.06% of all the urological emergency (2). elderly and defeated patients are usually involved. scrotum, perineum and lower abdomen represent the primary sites of origin. it is characterized by a high rate of mortality since it quickly evolves into septic shock and patient’s death. hence, whenever misdiagnosed or not promptly treated, it may result in a fatal infection. clinical presentation and laboratory strongly suggest fd. atypical presentation has been also described in literature1: if not precociously diagnosed, it may quickly evolve into septic syndrome and patient’s death. we report the case of an adult male with uncommon clinical presentation. while opportunely describing this case, we also reviewed the literature about atypical fd. case report a 62 years old caucasian male presented for fever and penile gross oedema recently occurred. he was a smoker but familiarity for penile cancer was ruled out on anamnesis. no history of previous urinary tract infection, haematuria or genital trauma was referred. additionally, he denied any sexual intercourse in the last four weeks. he was affected by metabolic syndrome and diabetes mellitus actually on medication with oral hypoglycemic agents. dipstick urine confirmed glycosuria but was negative for urinary infection. blood examinations were not available. he did not complain any storage or voiding low urinary tract symptom (luts); no foci of infection in genitoperineal area was observed nor urethral discharge. on physical examination the patient was febrile. on local examination inguinal lymph nodes were negative; there was no erythema of the scrotum and the testis were normal. rectal exploration was unremarkable too with a soft enlarged painless prostate. however, the penis presented with an asymptomatic massive oedema extended from pubis to foreskin (figure 1); it was also warm but painless and with a normal skin appearance. the ultrasound examination of the abdomen and pelvis was normal while penile fast sonography revealed an inhomogeneous broad thickening of subcutaneous tissues with increased vascularity on color-doppler. hence, as the penis was further manipulated in order to reduce oedema, retract foreskin and evaluate the glans, clinical parameters rapidly worsened and the patient developed a septic shock with blood pressure falling down, dyspnoea and tachyarrhythmia. he was hospitalized and quickly sent to intensive care unit. during hospitalization, the patient presented with severe hypoxia, acute respiratory distress, marked hypotension and septic shock signs: no impairment of neurological function was present. on general examination it showed bluish colour of the skin at the level of the fingers totally according to intense cyanosis as an expression of severe hypoxia and peripheral vasoconstriction. blood gas analysis (bga) both confirmed hypoxia and metabolic acidosis with high lactate levels. severe leucocytosis, high levels of procalcitonin 15corongiu2_stesura seveso 24/09/20 17:19 pagina 213 archivio italiano di urologia e andrologia 2020; 92, 3 v. olivieri, g. ruggiero, d. abate, n. serra, v. fortunati, d. griffa, f. forte, e. corongiu 214 and c-reactive protein were also confirmed on blood examination. urine and blood culture sampling were mandatory. a bladder catheter (bc) was placed in order to check diuresis as a marker of septic evolution. hence, respiratory and haemodynamic support in combination with a broad-spectrum antibiotic therapy were immediately offered according to guidelines for septic shock treatment. concerning of drugs, we opted for a combination of tazobactam/piperacillin and levofloxacin. however, by persisting severe anuria and hypoxia as a sign of poor response to resuscitation therapy, vasoactive drugs (noradrenaline) were mandatory. clinical parameters progressively improved while patient started to show a response to drug therapy. computed tomography (ct) scanning was subsequently performed: it ruled out abscess or any masses altering venous drainage. urine and blood culture were positive for enterobacteriaceae (enterococcus fæcalis). moreover, three days after hospitalization urethral discharge manifested: samples analysis confirmed enterococcus too. in order to better evaluate penile anatomy and disease extent, magnetic resonance (mr) was offered. it revealed an abscess at the right cavernosal body with a secundary fistula in the urethra (figure 2). furthermore, it appeared as dishomogeneous and hypervascularized with a severe thickening of surrounding soft tissues, as it usually happens in extended panniculitis. signs of necrosis at the level of buck´s fascia and gas in both cavernosal body and soft tissues were also reported strongly suggesting an uncommon isolated fournier´s disease of the penis. the combined approach “drug therapy/surgery” actually represents the gold standard and may be also combined with vacuum assisted closure (vac) or hyperbaric oxygen (hbo) therapy. immediate surgical debridement must be performed as the infection is worsening despite drug therapy: it aims to avoid a fast spread of necrotic tissues and the development towards septic shock. it may be feasible as gangrene clinically manifests but becomes harder in early manifestation since no clear foci of infection are surgically treatable. the main procedure performed is the necrosectomy through the extended and radical demolition of necrotic surgery. wound closure is achieved by different strategies: skin grafting, delayed primary closure and healing by secondary intention. vac therapy and hbo may be combined with drugs and surgery since they act as synergic therapies and speed up wound healing. vacuum-assisted closure has been also proposed but the use is controversial (3). reconstructive surgery may be considered once the clinical resolution has been obtained. in our patient, considering the clinical absence of gangrene’s foci, we opted for a conservative treatment: we performed a urinary diversion by a suprapubic cystostomy and we continued with drug therapy. subsequently we sent the patient to a reference center for andrology, where they proceeded to the implantation of penile prosthesis. conclusions fournier’s disease is an aggressive synergistic genitoperineal fasciitis quickly evolving into sepsis and death. polymicrobial infection actually represents the suggested mechanism. elderly and patients with multiple comorbidities are at high risk to develop. clinical presentation may be variable, strongly conditioning diagnosis and treatment: the later diagnosis, the faster evolution, the higher death. uncommon clinical presentation may lead to a missed diagnosis. antibiotics and extensive surgical debridement represent the gold standard. mortality still remains high. fever and leucocytosis associated to atypical penile swelling should be always evaluated for an uncommon form of fournier’s gangrene. references 1. anchi t, tamura k, inoue k, et al. localized fournier’s gangrene of the penis: a case report. hinyokika kiyo 2009; 55. 2. chawla s, gallop c, mydlo j. fournier’s gangrene: an analysis of repeated surgical debridement. eur urol. 2003; 43:572-575. 3. yanaral f, balci c, ozgor f, et al. comparison of conventional dressings and vacuum-assisted closure in the wound therapy of fournier's gangrene. arch ital urol androl. 2017; 89:208-211. figure 2. right cavernosal body involvement and secondary urethral fistula. figure 1. uncommon clinical presentation of fournier’s gangrene of the penis. correspondence valerio olivieri, md valerio.olivieri@uniroma1.it division of urology, ivrea civil hospital (asl to4), ivrea (turin), italy gabriele ruggiero, md daniele griffa, md division of urology, ivrea civil hospital (asl to4), ivrea (turin), italy danilo abate, md nicoletta serra, md division of urology, ciriè hospital (aslto4), ciriè (turin), italy valentina fortunati, md valerio.olivieri@uniroma1.it division of pathology, hospital “policlinico of tor vergata”, rome, italy flavio forte, md flavioforte@hotmail.com emanuele corongiu, md emanuele.corongiu@libero.it division of urology, hospital “madre giuseppina vannini”, rome, italy 15corongiu2_stesura seveso 24/09/20 17:19 pagina 214 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4328 letter to editor no conflict of interest declared. doi: 10.4081/aiua.2020.4.328 observational study on the effects of a topical formulation in patients with premature ejaculation key words: premature ejaculation; clove oil; zanthoxylum buongeanum; aloe; bisabolol; ejaculation. submitted 13 november 2020; accepted 19 november 2020 to the editor premature ejaculation (pe) has been defined as the inability to control or delay ejaculation, resulting in dissatisfaction or distress of the patient (1). although pe is the most frequent sexual dysfunction, it is still underdiagnosed. an accurate clinical history is the best diagnostic approach that, in the majority of cases, is enough to differentiate between primary and acquired pe. nowadays, treatment is not curative but is effective in increasing the intravaginal ejaculatory latency time (ielt), improving the sexual satisfaction of the couple. combination of behavioural techniques with pharmacotherapy is the best way of treatment. major pharmacological treatments of pe include selective serotonin reuptake inhibitors antidepressants (dapoxetine, paroxetine) and topical anesthetics (2). from 2019 it has been introduced in the italian market a new product for the topical natural approach of pe, containing clove oil, zanthoxylum bungeanum fruit extract with aloe and bisabolol. the aim of the present study was to evaluate the efficacy and the tolerability this topical formulation in patients of different age with pe. an observational study was conducted in order to evaluate efficacy and tolerability of the topical formulation endep® spray in patients with premature ejaculation (pe). patients with clinical diagnosis of pe were enrolled in this observational study. all the patients underwent clinical evaluation including administration of premature ejaculation diagnostic tool (pdt) and international index of erectile function (iief-5) questionnaires (3, 4). the patients were assigned to use endep® spray (two puff before the sexual intercourse) for 30 days. the main outcome measure, evaluated by questionnaire, was the pedt score; the secondary outcome was the improvement in the iief-5 score and the product tolerability evaluated along the whole study period. eligible sunjects were ≥ 18 and ≤ 75 years of age with diagnosis of pe according to the european association of urology (eau) guidelines. patients with supposed or recognized intolerance towards one or more components of the product and patients with prostatic or urethral inflammatory and non-inflammatory pathology (prostatitis, urethritis) were excluded from the study. endep® spray contains clove oil, zanthoxylum bungeanum fruit extract, aloe and bisabolol in the formulation of a sprayble hyperfluid emulsion. all patients were asked to apply one or two puff of the product in the penis area, 10 minutes before the sexual intercourse and were asked to massage the area till the product was completely absorbed. twenty-eight patients with diagnosis of pe were enrolled and treated in this observational study. pedt and iief-5 scores were collected before and after the treatment with and data were analysed. the data show non normal distribution, therefore the wilcoxon test was used. at baseline visit (t0) and after 30 days of treatment (t30) patients were evaluated and asked to complete the two selfadministered questionnaires. at follow up examination after 30 days of treatment (t30) pedt score showed a strong significant variation (median decrease -3.5; p = 0.0002). iief showed a significant but marginal variation (median increase +1.5). correlation with patients age and weight were checked by pearson correlation test pedt variation values showed a clear correlation with weight (p = 0.009); if weight was lower, the decrease in the pedt score was greater. iief variation showed no correlation. no correlation was found with the marital status (wilcoxon test). all patients correctly used the product, showing a 100% compliance to the study protocol without any adverse effect. the aim of the present study was to evaluate the efficacy of a sprayable hyperfluid emulsion in patients with premature ejaculation which has been recently marketed in italy. the formula contains clove oil, zanthoxylum bungeanum fruit extract, aloe, bisabolol. zanthoxylum bungeanum maxim is a natural desensitizer; the extract (zanthalene) is obtained from the fruit of sichuan pepper, a chinese spice known for its chemestetic properties. in vitro investigations on a nerve-muscle preparation have shown that zanthalene has a transitory action on the neuromuscolar synaptic transmission. this activation quickquarto letter_stesura seveso 14/12/20 20:40 pagina 328 329archivio italiano di urologia e andrologia 2020; 92, 4 premature ejaculation improvement ly leads to the depletion of the neurotransmitter. the action is mediated by the voltage-dependent na+ channels, by closing them at the suggested dosages and, in this way, by blocking the electric signal. hydroxy-a-sanshool has demonstrated in vivo to show an interesting activity on thermal and tactile sensitivity (5, 6). eugenol is a volatile phenolic constituent of clove essential oil obtained from eugenia caryophyllata buds and leaves. it is a functional ingredient of numerous products which have been used in the pharmaceutical, food and cosmetic industry. the wide range of eugenol activities includes antimicrobial, anti-inflammatory, analgesic and antioxidant (7). eugenol has anaesthetic properties, due to its ability to inhibit movement of sodium ions in peripheral nerves. methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. the antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral na+ channels (8). in the formulation endep® spray, which is a sprayable hyperfluid emulsion, the clove oil and the the zanthoxylum bungeanum fruit extract are associated with aloe and bisabolol with soothing and emollient action . in this observational study we evaluate the efficacy of the topical application of the product in patients with premature ejaculation. we found that the topical application on demand is able to improve pedt score in patients with premature ejaculation aged between 18 and 75 years, without adverse events or reduction of the vaginal sensitivity of the female partner. however, this study shows some limitations related to the lack of a control group and the small number of patients; for this reason it can be considered as a preliminary observation for future studies and evaluations. in conclusion, in this observational study, we found that the topical treatment with endep® spray used before sexual intercourse significantly improves the pedt score in patients with premature ejaculation. endep® spray idi integratori dietetici italiani, italy references 1. parnham a, serefoglu ec. classification and definition of premature ejaculation. transl androl urol. 2016; 5:416-23. 2. hu qb, zhang d, ma l, et al. progresses in pharmaceutical and surgical management of premature ejaculation. chin med j (engl). 2019; 132:2362-2372. 3. althof se. patient reported outcomes in the assessment of premature ejaculation. transl androl urol. 2016; 5:470-4. 4. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-30. 5. bryant bp, mezine i. alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. 1999. 25; 842:45260. 6. lennertz rc, makoto tsunozaki, bautista dm, stucky cl. physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool. j neurosci. 2010; 24; 30:4353-61. 7. nejad sm, özgünes h, basaran n. pharmacological and toxicological properties of eugenol. turk j pharm sci. 2017; 14:201-206. 8. wang zj, tabakoff b, levinson sr, heinbockel t. inhibition of nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions. acta pharmacol sin. 2015; 36:791-9. correspondence giuseppe quarto, md (corresponding author) giuseppe.quarto@gmail.com luigi castaldo, md giovanni grimaldi, md alessandro izzo, md raffaele muscariello, md sisto perdonà, md division of urology, irccs fondazione g.pascale, naples (italy) giuseppe quarto, luigi castaldo, giovanni grimaldi, alessandro izzo, raffaele muscariello, sisto perdonà division of urology, irccs fondazione g. pascale, naples, italy. quarto letter_stesura seveso 14/12/20 20:40 pagina 329 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2146 original paper microorganisms and antibiotic susceptibilities isolated from urine cultures abdullah gul 1, esra gurbuz 2 1 university of health sciences, bursa yuksek ihtisas training and research hospital, department of urology, bursa, turkey; 2 kelkit state hospital, department of infectious diseases and clinical microbiology, gumushane, turkey. objectives: urinary tract infection (uti) is the second most common cause of infection among all infectious diseases at hospitals. antibiogram results are needed to maintain treatment in patients with suspected uti. however, empirical antibiotic treatment is initiated in patients since it takes time to obtain the results of antibiograms. the aim of this study was to evaluate the urine culture and antibiogram results of patients who were admitted to our hospital with suspected uti and compare the results with other studies. methods: urine cultures requested from the hospital information system database between january of 2018 and 2019 were analyzed. microorganism-positive urine samples and antibiogram results were evaluated and included in the study. results: of the patients, 748 (61.8%) were female and 463 (38.2%) were male. the average age of all patients was 44.9 years. escherichia coli was the most frequently isolated microorganisms from urine cultures (n = 828, 68.4%). among all microorganism-positive urine samples, antibiotic resistance against cefalexin, fusidic acid, ampicillin, erythromycin, levofloxacin, cefuroxime axetil, trimethoprim/ sulfamethoxazole, ceftriaxone and ciprofloxacin was 83.9%, 68.4%, 61.8%, 44.7%, 42.7%, 36.4%, 30%, 28.6% and 26.7%, respectively. conclusions: high resistance to cefalexin, ampicillin, cefuroxime, axetil, trimethoprim/ sulfamethoxazole, ceftriaxone and ciprofloxacin, which are often preferred in empirical antibiotic selection, has been found. we believe that empirical antibiotic selection should not be overlooked in cases of uti. our study may help clinicians use appropriate antibiotics for the clinical management of utis. key words: antibiotic resistance; microorganisms; urine culture. submitted 18 november 2019; accepted 19 january 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.146 introduction antibiotic-resistant microorganisms are becoming widespread and the emergence of bacteria causing multidrugresistant (mdr) urinary tract infection (uti) has become a major public health problem (1, 2). utis are the second most common cause of infection among all infectious diseases at hospitals (3). around 150 million new uti cases develop worldwide each year, with an estimated treatment cost of $ 150 billion (4). the urethra is a portal for urine output, but it also allows pathogenic microorganisms to enter the urinary tract. bacteria live in the vicinity of the urethral opening in both men and women and routinely colonize urine, but women are more likely to develop utis resulting from anatomical differences, hormonal effects and behavior (5, 6). antibiograms are used to maintain treatment in patients with suspected utis. however, empirical antibiotic treatment is initiated in patients since it takes time to obtain the results of antibiograms. the causative agent and the selected antibiotic affect the success of the treatment. the choice of drug for empirical antibiotic treatment is very important because of antibiotic resistance. empirical antibiotic selection should be followed at regular intervals for the sensitivity results of the hospital and the region studied (7). because the prevalence of uti pathogens and their resistance to different antibiotics may have changed over the years (8). antimicrobial resistance is increasing worldwide, leading to infections that are difficult to treat and are associated with high mortality, morbidity and cost (9, 10). the aim of this study was to evaluate the urine culture and antibiogram results of patients who were admitted to our hospital with suspected uti and compare the results with other studies. we believe that our study will help physicians select appropriate empirical antibiotics for the clinical management of utis. morever, it may serve as data source for reviews and meta-analysis in future. materials and methods in this study, both urine cultures and antibiogram results of 1211 patients who were admitted to urology outpatients clinic of van regional training and research hospital between 2018-2019 and who were positive for urine culture were analyzed retrospectively. in the microbiology laboratory urine samples obtained for culture from mid stream by sterile urine containers were evaluated as standard with 0.01 milliliter calibrated flasks with 5% sheep blood and eosin methylene blue (emb) agar and incubated at 37˚c for 18-24 hours. isolated bacteria were identified by fully automated identification with antibiogram device (vitek 2 compact biomerieux, france) and antibiotic susceptibility results were determined. antibiogram results were given in three groups as less sensitive, sensitive and resistant. data were expressed as mean ± standard deviation and percentage. results of the patients, 748 (61.8%) were female and 463 (38.2%) were male. the average age of all patients was 44.9 years. 147archivio italiano di urologia e andrologia 2020; 92, 2 epidemiology of urinary tract infections it was 38.2 years in female patients whilst 55.8 years in male patients. escherichia coli (e. coli) was the most frequently isolated microorganisms (n = 828, 68.4%) from urine cultures. isolated microorganisms are shown in table 1 as number and percentage. when all samples were examined, antibiotic resistance against to cefalexin, fusidic acid, ampicillin, erythromycin, netilmicin, levofloxacin was 83.9%, 68.4%, 61.8%, 44.7%, 43.8%, 42.7%, respectively. also, antibiotic resistance to cefuroxime axetil, cefuroxime, cefixime, trimethoprim/sulfamethoxazole, ceftriaxone, ciprofloxacin was found to be 36.4%, 36%, 34.3%, 30%, 28.6% and 26.7%, respectively. no microorganisms were found to be resistant to amphotericin b, chloramphenicol, colistin, flucytosine and rifampicin. however, antibiotic resistance to meropenem, ertapenem, imipenem and amikacin was found to be 0.88%, 1.14%, 1.5% and 1.6%, respectively. the data on the resistance status of antibiotics are given in table 2 as number and percentage. table 1. microorganisms isolated from urine cultures. isolated microorganisms number percent (%) acinetobacter spp 2 0.17 acinetobacter baumannii 7 0.58 alcaligenes faecalis 1 0.08 burkholderia cepacia 1 0.08 candida albicans 15 1.24 candida famata 1 0.08 candida kefyr 2 0.17 candida krusei 1 0.08 candida spherica 3 0.25 candida tropicalis 3 0.25 citrobacter freundii 2 0.17 citrobacter koseri 3 0.25 enterobacter aerogenes 1 0.08 enterobacter cloacae complex 9 0.74 enterococcus spp 4 0.33 enterococcus faecalis 55 4.5 enterococcus faecium 9 0.74 escherichia coli 828 68.4 klebsiella spp 34 2.8 klebsiella oxytoca 6 0.5 klebsiella pneumoniae 87 7.2 morganella morganii 3 0.25 proteus spp. 4 0.33 proteus mirabilis 21 1.73 providencia rettgeri 4 0.33 pseudomonas aeruginosa 24 1.2 salmonella spp 1 0.08 serratia fonticola 2 0.17 serratia liquefaciens group 2 0.17 serratia marcescens 1 0.08 shigella sonnei 1 0.08 staphylococcus aureus 4 0.33 staphylococcus epidermidis 23 1.9 staphylococcus haemolyticus 3 0.25 staphylococcus hominis 1 0.08 staphylococcus saprophyticus 6 0.5 staphylococcus warneri 1 0.08 stteptococcus spp 2 0.17 streptococcus agalactiae 26 2.15 streptococcus constellatus ssp pharyngis 1 0.08 streptococcus dysgalactiae ssp equisimilis 2 0.17 streptococcus mitis 3 0.25 streptococcus salivarius ssp salivarius 1 0.08 streptococcus sanguinis 1 0.08 total 1211 100 table 2. antibiotic resistance rates. antibiotic sensitive low resistant total percent sensitive (%) amikacin 719 178 15 912 1.6 amoxicillin/clavulanic acid 13 1 7 21 33.3 amphotericin b 15 0 0 15 0 ampicillin 362 2 588 952 61.8 ampicillin/sulbactam 69 0 15 84 17.9 aztreonam 5 18 4 27 14.8 benzylpenicillin 29 5 3 37 8.1 caspofungin 17 0 1 15 5.6 cefalexin 5 0 26 31 83.9 cefepime 25 1 3 29 10.3 cefixime 574 0 300 874 34.3 cefotaxime 14 0 1 5 6.7 cefoxitin 24 769 82 875 9.4 ceftazidime 625 68 218 911 23.9 ceftriaxone 609 26 254 889 28.6 cefuroxime 561 0 316 877 36 cefuroxime axetil 557 0 319 876 36.4 chloramphenicol 4 0 0 4 0 ciprofloxacin 698 46 271 1015 26.7 clindamycin 35 0 10 45 22.2 colistin 37 0 0 37 0 daptomycin 53 0 3 56 5.4 ertapenem 865 2 10 877 1.14 erythromycin 21 0 17 38 44.7 fluconazole 17 0 1 18 5.6 flucytosine 17 1 18 36 0 fosfomycin 847 0 59 906 6.5 fusidic acid 12 0 26 38 68.4 gentamicin 835 5 111 951 11.7 imipenem 873 24 14 911 1.5 levofloxacin 46 1 35 82 42.7 linezolid 130 0 2 132 1.5 meropenem 891 14 8 913 0.88 micafungin 17 0 1 18 5.6 moxifloxacin 17 0 4 21 19 netilmicin 18 0 14 32 43.8 nitrofurantoin 798 1 75 874 8.6 oxacillin 23 0 15 38 39.5 piperacillin 15 2 10 27 37 piperacillin/tazobactam 682 96 124 902 13.7 rifampicin 0 4 0 4 0 teicoplanin 92 0 8 100 8 tetracycline 28 0 13 41 31.7 tigecycline 113 4 0 117 0 tobramycin 26 0 16 42 18.8 trimethoprim/sulfamethoxazole 677 35 310 1022 30.3 vancomycin 128 0 4 132 3 vorikonazol 16 0 0 16 0 archivio italiano di urologia e andrologia 2020; 92, 2 a. gul, e. gurbuz 148 discussion bacteria are the most common etiology of utis, accounting for more than 95% of cases. e. coli is the most common causal organism of utis and is responsible for more than 80% of them (11). wright et al. reported that the rate of e. coli in urine cultures was 67% (12). another study conducted by akbas et al. revealed that the rate of e. coli in urine cultures was 35-80% (13). in our study, we found the rate of e. coli to be 68.4% and this rate is consistent with other studies. microorganisms and antibiotic susceptibilities isolated from urine cultures may differ among countries due to usage of different agents and multifactorial causes. in our study, a serious resistance to cefalexin, which is one of the most common antibiotics used for the treatment of utis, is observed. in a study published in 2019, shrestha et al. reported a 60% resistance to cefalexin (14). ganesh and colleagues also reported 94.1% resistance to cefalexin in their study in the same year (15). in our study, antibiotic resistance rate to cefalexin was found to be 83.9%. all three studies point out that the rate of antibiotic resistance to cefalexin is high. zhanel et al. reported a resistance rate of ampicillin to 37.7% in 2006 (16). bryce et al. found the resistance rate to ampicillin as 60.3% in 2016 (17). in our study, the resistance rate to ampicillin was found to be 61.8%. antibiotics prescribed for utis, most of which are caused by e. coli, have a high prevalence of resistance. when we look at the studies conducted worldwide, we found that ampicillin resistance rate is the highest and nitrofurantoin resistance rate is at very low levels. in our study, we found the nitrofurantoin resistance rate to be 8.6%. conclusions empirical antibiotic selection against e. coli, which is the most frequently isolated microorganism in urine cultures of patients with suspected uti, was highly resistant to most of the antibiotics that are frequently preferred. we think that empirical antibiotic selection in cases of uti should not be overlooked and that such studies should be repeated frequently to carry out current antibiotic susceptibilities. references 1. ibrahim me, bilal ne, hamid me. increased multi-drug resistant escherichia coli from hospitals in khartoum state, sudan. afr health sci. 2012; 12:368. 2. tiruneh m, yifru s, gizachew m, et al. changing trends in prevalence and antibiotics resistance of uropathogens in patients attending the gondar university hospital, northwest ethiopia. int j bacteriol. 2014; 2014:629424. 3. saraçoglu kt, fidan v, pekel ö, et al. !drar kültürlerinde izole edilen bakterilerin antibiyotik duyarlılıkları. j of clin and exp inv. 2013; 4:356. 4. kadanalı a. üriner sistem infeksiyonları. eurasian j med. 2006; 38:119. 5. foxman, b. the epidemiology of urinary tract infection. nat rev urol. 2010; 7:653. 6. minardi d, d’anzeo g, cantoro d, et al. urinary tract infections in women: etiology and treatment options. int j gen med. 2011; 4:333. 7. sucu n, aktoz-boz g, bayraktar ö, et al. üropatojen escherichia coli suslarının antibiyotik duyarlılıklarının yıllar içerisindeki degisimi. klimik dergisi. 2004; 17:128. 8. kehinde a, adedapo k, aimakhu c, et al. urinary pathogens and drug susceptibility patterns of urinary tract infections among antenatal clinic attendees in ibadan, nigeria. j obstet gynaecol res. 2012; 38:280. 9. gardiner bj, stewardson aj, abbott ij, peleg ay. nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. aust prescr. 2019; 42:14. 10. perletti g, magri v, cai t, et al. resistance of uropathogens to antibacterial agents: emerging threats, trends and treatments. arch ital urol androl. 2018; 90:85. 11. nachimuthu r, chettipalayam s, velramar b, et al. urinary tract infection and antimicrobial susceptibility pattern of extended spectrum beta lactamase producing clinical isolates. adv biol res. 2008; 2:78. 12. wright sw, wrenn kd, haynes ml. trimethoprim-sulfamethoxazole resistance among urinary coliform isolates. int j gen med. 1999; 14:606. 13. akbas e, zarakolu p, aktepe oc, et al. !drar yolu enfeksiyonu ön tanısı ile basvuran olgularda idrar örneklerinin mikrobiyolojik olarak degerlendirilmesi: !ki yıllık bir çalısma. mikrobiyoloji bülteni. 1997; 31:351. 14. shrestha lb, baral r, poudel p, khanal b. clinical, etiological and antimicrobial susceptibility profile of pediatric urinary tract infections in a tertiary care hospital of nepal. bmc pediatr. 2019; 19:36. 15. ganesh r, shrestha d, bhattachan b, rai g. epidemiology of urinary tract infection and antimicrobial resistance in a pediatric hospital in nepal. bmc infect dis. 2019; 19:420. 16. zhanel gg, hisanaga tl, laing nm, et al. antibiotic resistance in escherichia coli outpatient urinary isolates: final results from the north american urinary tract infection collaborative alliance (nautica). int j antimicrob agents. 2006; 27:468. 17. bryce a, hay ad, lane if, et al. global prevalence of antibiotic resistance in paediatric urinary tract infections caused by escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. bmj. 2016; 352; i939. correspondence abdullah gul, md dr_abdullahgul@hotmail.com bursa training and research hospital floor 2, 16310 bursa (turkey) orcid 0000-0003-4002-4659 esra gurbuz, md dr.inanhazan@gmail.com kelkit state hospital, department of infectious diseases and clinical microbiology, gumushane (turkey) 157archivio italiano di urologia e andrologia 2019; 91, 3 original paper safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses emanuele corongiu 1, pietro grande 2, angelo di santo 1, giorgio pagliarella 1, stefano squillacciotti 1, emanuele liberati 1, alessandra zampelli 1, valerio olivieri 3, michele innocenzi 4, flavio forte 1 1 department of urology, m.g. vannini hospital, rome, italy; 2 sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris, france; 3 department of urology, ivrea hospital, asl to 4, ivrea, italy; 4 department of urology, bambin gesù hospital, rome, italy. objectives: to evaluate oncological feasibility and oncological and functional results of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy (lpn). patients and methods: patients with posterior renal masses with low nephrometry score (renal ≤ 7) treated who underwent retroperitoneal sutureless zero ischemia.in a single center from january 2016 to november 2017. clinical, surgical and pathological data were prospectively collected. complications were reported according to the modified clavien classification. results: retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy was performed on 15 patients. the indication for nephron-sparing surgery was elective in 11 (73%) patients and imperative in 4 (27%). median renal score was 5 (iqr: 5-7), median tumor diameter 25 mm (iqr: 20-35). in 11 cases, the tumor was located polar (85%), and in 2 cases hilar (15%). there were no intraoperative complications. no cases were converted to radical nephrectomy, and in no case parenchyma suture was necessary. median operative time was 90 min (iqr:40-150), in no case clamping of the renal artery was necessary, median hospital stay was 4 days, median estimated blood loss (ebl) was 310 (180-500) ml. pathological analysis showed renal cell carcinoma in 11 patients (85%), 9 (60%) staged t1a and 2 (13%) t1b. in 4 (27%) an oncocytoma was found. there were no positive surgical margins. one patient developed a major postoperative complication (postoperative renal bleeding requiring super-selective embolization). trifecta rate was 93%. conclusions: sutureless retroperitoneal zero ischemia lpn for the treatment of low-complexity posterior renal masses showed to be safe and feasible. longer follow-up and higher numbers of patients are, however, warranted to draw definitive conclusions on functional outcomes. key words: laparoscopy; kidney cancer; oncological surgery; partial nephrectomy; nephron sparing surgery. submitted 12 july 2019; accepted 21 july 2019 summary no conflict of interest declared. made available in the last decades (1). radical nephrectomy (rn) has represented the gold standard approach for years, lately different nephron sparing (ns) approaches (enucleo-resection, wedge resection, pure enucleation etc.) have been proposed to minimize impact on renal function granting optimal oncologic control. multiple retrospective series have demonstrated a comparable cancer specific survival (css) for ns vs. rn for patients with organ-confined rcc of limited size (pt1) (2 4) making this approach the new gold standard for t1 masses. both eau and aua guidelines recognize pn as a valuable option to be performed whenever feasible irrespective of the surgical approach (open or minimally invasive) (1, 5). both transperitoneal and retroperitoneal approaches have shown to provide similar results in terms of oncologic and surgical safety, with the retroperitoneal one being fitter for posterior located masses (6-8). nevertheless, improvements need to be performed to implement post-operative renal function preservation. both ischemia time and parenchyma loss have been demonstrated to contribute to post-operative renal damage (9, 10). along with complete tumor extirpation without complications, the primary goal for an ideal pn is the maximal preservation of renal function (rf) (11). indeed, as suggested by extensive evidence, an impaired postoperative rf increases the risk of cardiovascular disease, use of specialized health care and death (12). with this regard, quantity and quality of preserved renal parenchyma are the most important determinants of functional recovery after surgery, with type and duration of ischemia possibly playing a secondary role (10). considering this, efforts should be done in both reducing (or eliminating, whenever feasible) ischemia time and reducing the amount of healthy parenchyma removed during tumor resection or destroyed with the haemostatic suture. objective of this study is to describe retroperitoneoscopic sutureless zero ischemia partial nephrectomy technique assessing its feasibility and safety, as well as shortterm oncologic and functional outcomes. doi: 10.4081/aiua.2019.3.157 introduction renal cell carcinoma represents 2-3% of all cancers, with the highest incidence in western countries. despite this, its mortality is slightly decreasing due to earlier detection and improved surgical and non-surgical treatments carongiu_stesura seveso 30/09/19 18:19 pagina 157 archivio italiano di urologia e andrologia 2019; 91, 3 e. corongiu, p. grande, a. di santo, g. pagliarella, s. squillacciotti, e. liberati, a. zampelli, v. olivieri, m. innocenzi, f. forte 158 patients and methods study population from january 2016 to november 2017, 40 consecutive patients with localized renal masses were treated by a single experienced surgeon (ff) in a single institution, with zero ischemia tumor enucleation pn. every patient gave written informed consent to be included in our prospectively maintained institutional database, where clinicopathological data as well as follow-up and complication data of every patient were recorded. approval for the study was granted by the hospital ethics committee and the study conformed to the provisions of the declaration of helsinki. comorbidity status was assessed using charson comorbidity index (cci) (13) and the american association of anesthesiologists (asa) scores (14). clinical procedure and patient monitoring fifteen patients with low nephrometry score (renal ≤ 7) renal masses, located on the posterior surface, were treated using retroperitoneal sutureless zero ischemia approach. pre-operative exclusion criteria for sutureless technique was tumor close contact with collecting system at preoperative ct scan. the remaining patients treated at the hospital during the study timeframe underwent both transperitoneal pn according to mass location and, for those, sutures were used only for the more complex neoplasms, or to repair damaged collecting systems. hemoglobin was dosed preoperatively, then 24 hours after intervention to detect potential postoperative bleeding. renal function was assessed using the estimated glomerular filtration rate (egfr), calculated with the modification of diet in renal disease (mdrd) equation (15) preoperatively, at discharge and at 3-mo post-operative visit. study endpoint primary endpoint was to assess feasibility and safety of retroperitoneal zero ischemia sutureless partial nephrectomy, secondary endpoint was renal function preservation and short-term oncologic outcomes. surgical technique patient’s position and access to the retroperitoneum the patient was placed on flank position, angled at ix-x coastal level for the left side and angled at x-xi coastal level for the right side to better expose the triangle of petit (figure 1). the first incision was performed 3 cm above the iliac ridge, on the mid-auxiliary line. a blunt dissection of the anterior component of the lumbar-dorsal fascia with mayo scissors and subsequently digital dissection is performed until the identification of the postero-lateral surface of the psoas muscle and the distal portion of gerota’s fascia. an inflatable space maker balloon is used to develop the retroperitoneal space. the remaining 2 trocars are placed under digital guide: the anterior one (10 mm) 2 cm above the optical trocar, keeping as much distance as possible from the peritoneal reflection. the posterior trocar, 2 cm higher than the optical trocar, on the posterior axillary or in some cases (depending on the body shape) between the angular line of the scapula and the posterior axillary line. as this trocar is placed through the mass of the large dorsal muscle limiting movements in laterality we prefer to use a 5-mm trocar. a 4th trocar, usually placed at the apex of the 12th coast is inserted during the intervention. an intra-abdominal pressure between 12 and 15 mmhg was used during the entire intervention. identification of the mass and resection the peritoneal reflection until the vena cava (right side) or ureter (left side) is identified. subsequently, the surface of the psoas muscle is released, under the gerota capsule, up to its proximal insertion on the diaphragm (figure 2a). laterally, the lateral-conal fascia is freed until the diaphragmatic insertion, to achieve posterior and lateral mobilization of the pre-renal fat. gerota’s fascia is bluntly dissected cranially, along the renal convexity, starting from its lower apex. the dissection of the perinephric fat is continued until the mass is identified (figure 2b). figure 1. flank position, angled at ix-x coastal level for the left side and angled at x-xi coastal level for the right side to better expose the triangle of petit. figure 2. a) surface of the psoas muscle is released; b) dissection of the perinephric fat until the mass is identified; c) identifying the vascular pole of the neoplasm; d) coagulation with bipolar forceps along the enucleation margin. carongiu_stesura seveso 30/09/19 18:19 pagina 158 identification of the vascular supply and hemostasis the resection of the mass is performed with the aim of tumor enucleation whenever possible, using monopolar scissors and suction. this step is performed totally clampless, for this reason, identifying as soon as possible the vascular pole of the neoplasm, who’s generally represented by an arterial branch lying on the resection burden, is crucial. useful for this purpose is the blunt dissection performed with the tip of the suction device or with the bipolar forceps (figure 2c), rising the lesion bottom to top, while the scissor proceeds with mechanical detachment, pandering to the convexity of the lesion. the vascular pole of the renal tumor is usually coagulated with bipolar forceps, except for some cases where the use of a titanium clip is mandatory due to the presence of larger vessels. the margins of the enucleation are not particularly bloody when the neoplasm is located at the lower pole, on the convexity (along the brodel line, at whose level the interlobar vessels are thinner and fold medially towards the renal sinus), or at the upper pole. in these cases, coagulation with bipolar forceps is sufficient along the enucleation margin (figure 2d). conversely, when lesions are located on the posterior surface of the kidney, the risk to have more than one vascular pole is higher. in those cases, clipping of larger arterial branches could be necessary. final remarks at the end of the procedure the pneumoretroperitoneum is lowered until 5 mm hg to check for any residual bleeding. thereafter, fibrin-based glue (floseal baxter, usa) or gauze (tabotamp ethicon, inc., somerville, nj) is applied on the resection area (figure 3). in our experience this practice resulted more useful for lesions on the posterior surface of the kidney, where intra-renal vascular branches are more extensive. surgical specimen is removed using an endo-bag through the anterior trocar: this to avoid further stress, at the margins of the lumbar-dorsal fascia, which would lead to greater risk of hernial failure. no drain is left in place. postoperative measures pathological examination was performed by a dedicated uro-pathologist according to the 2016 world health organization criteria (16) and to the fuhrman classification (17). positive surgical margin was defined as cancer cells at the level of the inked parenchymal excision surface. the severity of complications was reported according to the modified clavien classification (18). the trifecta rate was calculated as the combination of warm ischemia time < 25 min, negative surgical margins and no complications (up to 90-day follow-up)(11). patients were followed in outpatient setting 3 months after surgery and every 6 months for the first two years, then yearly. the follow-up protocol included: clinical visit, physical examination and a metabolic panel at 1, 3 and 6 month, annually thereafter; computed tomography (ct) at 6 and 12 month, annually thereafter. patients were planned to be discharged at 4th post-operative day as per hospital protocol, egfr was assessed at discharge and at 3 months post-operative visit. results the indication for nephron-sparing surgery was elective 159archivio italiano di urologia e andrologia 2019; 91, 3 retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy figure 3. fibrin-based glue is applied on the resection area. table 1. preoperative characteristics. sutureless transperitoneal overall p retroperitoneal (n = 15) (n = 25) (n = 40) value age, years, mean (sd) 64.0 (13.70) 61.4 (11.71) 62.0 (10.94) > 0.05 bmi, kg/m2, mean (sd) 25.03 (2.11) 25.9 (2.14) 26.00 (2.12) > 0.05 sex m/f 8/7 17/8 25/15 > 0.05 asa score, n (%) > 0.05 1 3 (20) 7 (28) 10 (25) 2 11 (73) 16 (64) 27 (67.5) 3 1 (7) 2 (8) 3 (7.5) cci, median (iqr) 4 (3-4) 4 (3-4) 4 (3-4) > 0.05 affected kidney > 0.05 right 5 (33) 14 (56) 19 (47.5) left 10 (67) 11 (44) 21 (52.5) tumor size, mm, median (iqr) 25 (20-35) 28 (2.5-4) 30 (25-35) > 0.05 renal score > 0.05 < 5 3 (20) 2 (8) 5 (12.5) 5-6 8 (53) 11 (44) 19 (47.5) 7 4 (27) 6 (24) 10 (25) > 7 6 (24) 6 (15) tumor location > 0.05 polar 13 (87) 18 (72) 31 (77.5) hilar 2 (13) 7 (28) 9 (22.5) exophitic rate > 0.05 < 50% 5 (33) 7 (28) 12 (30) ≥ 50% 10 (67) 18 (72) 28 (70) pn indication > 0.05 imperative 4 (27) 2 (8) 6 (15) elective 11 (73) 23 (92) 34 (85) carongiu_stesura seveso 30/09/19 18:19 pagina 159 archivio italiano di urologia e andrologia 2019; 91, 3 e. corongiu, p. grande, a. di santo, g. pagliarella, s. squillacciotti, e. liberati, a. zampelli, v. olivieri, m. innocenzi, f. forte 160 in 11 (73%) patients and imperative in 4 (27%), of those 3 presented a solitary kidney and one had impaired renal function. preoperative median (iqr) egfr was 88 (40-135) ml/min/1.73 m2. median renal score was 5 (iqr: 5-7), median tumor diameter 25 mm (iqr: 20-35); 4 (27%) patients presented a mass with a renal score of 7. the tumor was located polar in 13 (87%) cases and hilar in 2 (13%) cases. further patients’ characteristics for the study population compared to the entire cohort of treated patients are listed in table 1. all interventions were successfully completed, with no report of intraoperative complication. no vascular lesions occurred during the procedure; no cases were converted to radical nephrectomy, in no case the use of parenchymal suture was necessary. median (iqr) operative time was 90 (40150) min. all procedures were completed with zero ischemia technique as in no case clamping of the renal artery was necessary. mean (sd) hospital stay was 4.1 (0.4) days. median (iqr) gfr was 79 (37-124) at discharge and 90 (36121) at 3-month post-operative visit. median iqr grf median (iqr) ebl was 310 (180-500) ml. pathological analysis showed renal cell carcinoma in 11 patients (73%), 9 (60%) staged t1a and 2 (13%) t1b. in 4 (27%) an oncocytoma was found. there were no positive surgical margins. one patient (7%) developed a major postoperative complication, post-operative renal bleeding requiring super-selective embolization, while 3 (20%) developed minor complications (clavien i). trifecta was achieved in 93% of the patients treated with sutureless retroperitoneal approach. furthermore, oncologic and functional results were similar when compared to the transperitoneal cohort (table 2). comment the reports on lower incidence of postoperative acute kidney injury and chronic kidney disease (ckd) after off-clamp pn in the solitary kidney model led to an increased use of this approach for all patients, possibly to avoid the detrimental effect of ischemia on rf (19). whereas the functional benefit of the offtable 2. post-operative outcomes. sutureless transperitoneal overall p retroperitoneal (n = 15) (n = 25) (n = 40) value operative time, min, mean (sd) 100 (31.5) 130 (31.4) 115 (33.2) > 0.05 length of stay, d, mean (sd) 4.13 (0.37) 4.7 (0.88) 4.55 (1.45) > 0.05 estimated blood loss, ml, mean (sd) 370 (299) 425 (285) 410 (275) > 0.05 histology, n (%) > 0.05 oncocytoma 4 (26.6) 2 (8) 6 (15) renal cell carcinoma 11 (73.4) 23 (92) 34 (85) positive surgical margin, n (%) 0 (0) 0 0 (0) maximal tumour-kidney margin, 4.1 (0.7) 4.6 (1.2) 4.4 (0.8) > 0.05 mm, mean (sd) pt stage > 0.05 t1a 9 (60) 18 (72) 27 (67.5) t1b 2 (13.3) 3 (12) 5 (12.5) ≥t2 0 (0) 2 (8) 2 (5) fuhrman grade (for rcc), n (%) > 0.05 i 2 (13.3) 3 (12) 5 (12.5) ii 7 (46.7) 18 (72) 25 (62.5) ≥iii 2 (13.3) 2 (8) 4 (10) complications* > 0.05 i 3 (20) 2 (8) 5 (12.5) ii 1 (4) 1 (2.5) ≥iii 1 (6.7) 1 (4) 2 (5) mean (sd) egfr > 0.05 preoperative 85.23 (29.95) 81.34 (24.22) 80.59 (24.28) discharge 74.77 (23.22) 72.34 (21.24) 71.89 (21.31) 3-mo post-op 81.78 (16.77) 79.12 ( 17.10) 69.25 (16.52) *according to clavien-dindo classification. present study simone et al. minervini et al. overall study population, n 15 380 100 overall sutureless procedures, n (%) 15 (100) 101(26.6) 32 (32) transeritoneal 101 (26.6) n.a. retroperitoneal 15 (100) n.a. clampless procedures, n (%) 15 (100) 101 (100) 18 (56.3) renal score <5 3 (20) 94 (93.1) n.a. 5-6 8 (53) 7 (6.9) n.a. 7 4 (27) n.a. tumour size, mm, median (iqr) 25 (20-35) 24 (15-40) 19 (15-21) exophytic rate, n (%) <50% 5 (33) n.a. 5 (17) ≥50% 10(67) n.a. 27 (83) sex m/f 8/7 63/38 n.a. asa score 1 3 (20) 45 (44.6) n.a. 2 11 (73) 30 (29.7) n.a. 3 1 (7) 26 (25.7) n.a. age, years, median (range) 68 (28-70) 59 (45-73) 62 (46-80) bmi, kg/m2, meadian (iqr) 25.0 (24.2-27.6) n.a. 26 (19.5-35) tumour location polar 13 (87) 96 (95.1) 32 (100) hilar 2 (13) 5 (4.9) operative time, min, median (range) 90 (40-150) 60 (45-160) 115 (80-180) scr, mg/dl, median (range) preoperative 0.8 (0.6-1.7) 0.9 (0.6-1.3) n.a. at discharge 0.9 (0.6-1.8) n.a. 3-mo post-op 0.9 (0.6-1.9) 1 (0.6-1.4) n.a. egfr, ml/min, median (range) preoperative 88 (40-135) 96 (60-120) n.a. at discharge 79 (37-124) n.a. 3-mo post-op 90 (36-121) 93 (58-125) n.a. completed sutureless 15 (100) 97 (96) 32 (100) § § supposed, as no clear statement for the authors is available in the manuscript. carongiu_stesura seveso 30/09/19 18:19 pagina 160 clamp technique has been suggested by several authors both for patients with solitary and normal contralateral kidney (20-23), most of the studies do not include data on resection and reconstruction technique thus potentially either underestimate or overrate the actual effect of arterial clamping. pure tumor enucleation, for those reasons, could help in preserving the maximal amount of healthy parenchyma granting comparable oncologic and surgical outcomes of conventional partial nephrectomy in t1 renal cancer, as previously reported (24), facilitating a better recovery of post-operative renal function (25), although no general consensus exists yet. clampless approach, avoids on one side ischemia-related renal damage (26, 27) and on the other side, it permits to avoid any possible vascular damage related to hilum dissection reducing the time of the intervention. additionally, in experienced hands, clampless approach could facilitate the surgeon to identify major arterial branches and seal it during enucleation. renal function was assessed at discharge and at 3months post-op visit as per-hospital protocol, after this period, as previously described, no intervention related variations in rf should occur (28). renal function was not particularly affected as reported in table 2, no de novo ckd grade ≥ 3a occurred. additionally, the only two patients with a gfr in the range of ckd stage 3 did not experience any notable decrease in rf. the transitory decrease in rf evidenced at discharge, and the complete restoration of the original gfr values for most of the patients in our series could be considered a consequence of the off-clamp approach, as well as the enucleative technique. previous experiences with sutureless pn were reported, showing that under certain conditions it is a safe and effective procedure (29, 30) (table 3). this study confirms previous experiences, demonstrating that this technique may also be applicable for masses with a renal score up to 7, without compromising oncologic and functional outcomes. main limitations of this study include small sample size and retrospective nature of the analysis, although data collection was prospective. nonetheless, present study is unique as it represents the first, to our knowledge, description of this technique. furthermore, our series investigates feasibility and safety retroperitoneoscopic clampless sutureless partial nephrectomy, reporting functional outcomes and trifecta rate with a minimum follow-up length of 6 mo. further studies, employing renal scintigraphy may help determine the real impact of the technique on the operated kidney parenchyma especially in case of imperative indication. although not comparable with larger series of pn, due to the very selective nature of the cohort and the short follow up period, our preliminary experience showed feasibility and safety of sutureless retroperitoneal zero ischemia lpn for the treatment of low-complexity (up to renal 7 score) posterior renal masses. longer follow-up and higher numbers of patients are, however, warranted to draw definitive conclusions. references 1. ljungberg b, albiges l, bensalah k, et al. eau guidelines on renal cell carcinoma [internet]. uroweb. 2018 [cited 2018 mar 27]. available from: https://uroweb.org/guideline/renal-cell-carcinoma/ 2. van poppel h, da pozzo l, albrecht w, et al. a prospective, randomised eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2011; 59:543-52. 3. marchioni m, preisser f, bandini m, et al. comparison of partial versus radical nephrectomy effect on other-cause mortality, cancerspecific mortality, and 30-day mortality in patients older than 75 years. eur urol focus. 2018 feb 2. 4. kunath f, schmidt s, krabbe l-m, et al. partial nephrectomy versus radical nephrectomy for clinical localised renal masses. cochrane database syst rev. 2017; 5:cd012045. 5. campbell s, uzzo rg, allaf me, et al. renal mass and localized renal cancer: aua guideline. j urol. 2017; 198:520-9. 6. ren t, liu y, zhao x, et al. transperitoneal approach versus retroperitoneal approach: a meta-analysis of laparoscopic partial nephrectomy for renal cell carcinoma. plos one. 2014; 9:e91978. 7. choo sh, lee sy, sung hh, et al. transperitoneal versus retroperitoneal robotic partial nephrectomy: matched-pair comparisons by nephrometry scores. world j urol. 2014; 32:1523-9. 8. stroup sp, hamilton za, marshall mt, et al. comparison of retroperitoneal and transperitoneal robotic partial nephrectomy for pentafecta perioperative and renal functional outcomes. world j urol. 2017; 35:1721-8. 9. volpe a, blute ml, ficarra v, et al. renal ischemia and function after partial nephrectomy: a collaborative review of the literature. eur urol. 2015; 68:61-74. 10. zabell jr, wu j, suk-ouichai c, campbell sc. renal ischemia and functional outcomes following partial nephrectomy. urol clin north am. 2017; 44:243-55.. 11. hung aj, cai j, simmons mn, gill is. “trifecta” in partial nephrectomy. j urol. 2013; 189:36-42. 12. go as, chertow gm, fan d, et al. chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. n engl j med. 2004; 351:1296-305. 13. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40:373-83. 14. doyle dj, garmon eh. american society of anesthesiologists classification (asa class). in: statpearls [internet]. treasure island (fl): statpearls publishing; 2018 [cited 2018 jun 4]. available from: http://www.ncbi.nlm.nih.gov/books/nbk441940/ 15. levey as, bosch jp, lewis jb, et al. a more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. modification of diet in renal disease study group. ann intern med. 1999; 130:461-70. 16. moch h, cubilla al, humphrey pa, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. eur urol. 2016; 70:93-105. 17. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg pathol. 1982; 6:655-63. 18. dindo d, demartines n, clavien p-a. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 161archivio italiano di urologia e andrologia 2019; 91, 3 retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy carongiu_stesura seveso 30/09/19 18:19 pagina 161 archivio italiano di urologia e andrologia 2019; 91, 3 e. corongiu, p. grande, a. di santo, g. pagliarella, s. squillacciotti, e. liberati, a. zampelli, v. olivieri, m. innocenzi, f. forte 162 19. mir mc, ercole c, takagi t, et al. decline in renal function after partial nephrectomy: etiology and prevention. j urol. 2015; 193:1889-98. 20. lane br, russo p, uzzo rg, et al. comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. j urol. 2011; 185:421-7. 21. thompson rh, lane br, lohse cm, et al. every minute counts when the renal hilum is clamped during partial nephrectomy. eur urol. 2010; 58:340-5. 22. kim eh, tanagho ys, sandhu gs, et al. off-clamp robot-assisted partial nephrectomy for complex renal tumors. j endourol. 2012; 26:1177-82. 23. kaczmarek bf, tanagho ys, hillyer sp, et al. off-clamp robotassisted partial nephrectomy preserves renal function: a multi-institutional propensity score analysis. eur urol. 2013; 64:988-93. 24. cao d-h, liu l-r, fang y, et al. simple tumor enucleation may not decrease oncologic outcomes for t1 renal cell carcinoma: a systematic review and meta-analysis. urol oncol. 2017; 35:661.e15661.e21. 25. dong w, gupta gn, blackwell rh, et al. functional comparison of renal tumor enucleation versus standard partial nephrectomy. eur urol focus. 2017; 3:437-43. 26. porpiglia f, bertolo r, amparore d, et al. evaluation of functional outcomes after laparoscopic partial nephrectomy using renal scintigraphy: clamped vs clampless technique. bju int. 2015; 115:606-12. 27. simone g, gill is, mottrie a, et al. indications, techniques, outcomes, and limitations for minimally ischemic and off-clamp partial nephrectomy: a systematic review of the literature. eur urol. 2015; 68:632-40. 28. porpiglia f, fiori c, bertolo r, et al. long-term functional evaluation of the treated kidney in a prospective series of patients who underwent laparoscopic partial nephrectomy for small renal tumors. eur urol. 2012; 62:130-5. 29. simone g, papalia r, guaglianone s, gallucci m. “zero ischaemia”, sutureless laparoscopic partial nephrectomy for renal tumours with a low nephrometry score. bju int. 2012; 110:124-30. 30. minervini a, siena g, tuccio a, et al. sutureless hemostatic control during laparoscopic nss for the treatment of small renal masses. surg innov. 2014; 21:32-8. correspondence emanuele corongiu, md (corresponding author) emanuele.corongiu@libero.it angelo di santo adisanto1978@gmail.com giorgio pagliarella giorgiopagliarella@hotmail.com stefano squillacciotti stefano.squillacciotti@gmail.com emanuele liberati emanuele.liberati@libero.it alessandra zampelli a.zampelli@libero.it flavio forte flavioforte@hotmail.com department of urology, m.g. vannini hospital via di acqua bullicante 4 00177 rome (italy) pietro grande grandepietro@gmail.com sorbonne université, assistance publique-hôpitaux de paris, pitié salpétière, urology department, paris (france) valerio olivieri valerio.olivieri@uniroma1.it department of urology, ivrea hospital, asl to 4, ivrea (italy) michele innocenzi innocenzi.michele@gmail.com department of urology, bambin gesù hospital, rome (italy) carongiu_stesura seveso 30/09/19 18:19 pagina 162 55archivio italiano di urologia e andrologia 2020; 92, 1 case report not fatal venous air embolism after holmium laser enucleation of the prostate: case report and review of literature daniele romagnoli 1, mobin ghaemian 2, daniele d’agostino 1, paolo corsi 1, marco giampaoli 1, alessandro del rosso 1, matteo cevenini 3, riccardo schiavina 3, eugenio brunocilla 3, giorgio davià 2, walter artibani 1, angelo porreca 1 1 robotic urology and mini invasive urologic surgery unit, abano terme hospital, abano terme (pd), italy; 2 anesthesiology and postoperative intensive care unit, abano terme hospital, abano terme (pd), italy; 3 department of specialistic, experimental and diagnostic medicine, urology, alma mater studiorum-university of bologna, s. orsola hospital, bologna, italy. objective: holmium laser has demonstrated high efficacy in urethral disobstruction. venous air embolism (vae) is a rare complication of prostate surgery. only two cases of venous air embolism (vae) in patients submitted to holep, have been described. in this paper we show a third case of not fatal vae after holep. materials and methods: a case of vae occurred in holmium laser enucleation (holep) due to obstructive lower urinary tract symptoms (luts) in a 70 years old patient. after the procedure, patient’s end tidal carbon dioxide (etco2) levels dramatically decreased at 17 mmhg, with pressure airway (paw)16 mmhg; oxygen saturation level was at 75%, without any loss in the ventilation circuit and with arterial blood pressure of 94/54 mmhg. due to the negativity for other suspicions, the suspect of vae was postulated. result: the immediate switching from laryngeal mask to oro tracheal intubation increased the oxygen level. a cardiac transthoracic ultrasound was negative for air bubbles inside cardiac cavities, without any alteration in the cardiac kinetics. arterial blood sample turned negative for any alteration compatible with vae and catheter continuous vesical irrigation was started to obtain clear washing fluid without blood cloths. the extubated patient showed no neurological defects. conclusions: an invasive monitoring system is the key to rapidly and correctly identify any embolic episode during this kind of surgery. key words: holmium laser enucleation of the prostate; nitrogen embolus; transurethral resection of the prostate; urethral disobstruction; venous embolism. submitted 4 august 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.55 introduction air embolism is a rare but documented complication of prostate surgery. most of the few cases described are reported to have taken place during transurethral resection of the prostate (turp). holmium laser has demonstrated high efficacy in disobstruction, both in cases of bladder neck incision (1) and in a pure enucleative setting. moreover, holmium laser enucleation of the prostate in prostatic adenoma is a technique which provides excellent relief from obstructive symptoms with the advantage of less risk of both bleeding and recurrence. since holep can be also applied for obstructive symptoms relief in patients with prostate cancer (2, 3), it has gained wide popularity. so far, only two cases of venous air embolism (vae) in patients submitted to holep, have been described by kato (4) and zhang (5). in the present paper another case of vae is reported. case report a 70-year-old patient (172 cm height, 80 kg weight) was scheduled to holep at our institution due to obstructive lower urinary tract symptoms (luts). serum prostate specific antigen (psa) was 3.6 ng/ml, digital rectal examination (dre) was negative for suspicious areas and prostate volume was measured with ultrasound (us) and resulted to be 90 ml. post void residual volume (pvr) was found to be 200 ml, and preoperatory uroflowmetry showed a qmax value of 5.1 ml/sec. the patient had been submitted in 2013 to percutaneous coronary angioplasty and coronary stent positioning, and the home therapy consisted of metoprolole, ramipril and cardioaspirin (not preoperatively withdrawn). preoperative electrocardiogram and chest x-ray were normal, and cardiological evaluation was negative for any modification in the drug scheme. no alterations in preoperative exams were recorded. standard oxygen monitor was established, and general anesthesia was performed through superglotty airway mask igel (intersurgical©) number 4 with gastric tube. induction was performed with intravenous propofol (2 mg/kg and sufentanyl 0.2 µg/kg). anesthesia was realized through sevoflurane (2.0%) without myorelaxant drugs. patient was ventilated with mechanical ventilation with tidal volume 7 ml/kg, respiratory rate of 12 rpm, and i:e ratio of 1:1.5. holep was performed using a 120w ho:yag versapulse® power suite™ laser source (lumenis®, santa clara, california), with a 550 µm slimline™ end firing laser fiber. saline (0.9% w/v) irrigation fluid was used. romagnoli_stesura seveso 01/04/20 18:59 pagina 55 archivio italiano di urologia e andrologia 2020; 92, 1 d. romagnoli, m. ghaemian, d. d’agostino, et al. 56 during the procedure patient remained haemodinamically stable without any loss in the ventilation circuit, with a systemic pressure between 110 and 99 mmhg, a heart rate of 67 bpm, oxygen saturation 99%, end tidal carbon dioxide (etco2) 31 mmhg and pressure airway (paw)16 mmhg. the entire procedure lasted 90 minutes, and before morcellation additional hemostasis with a bipolar loop inserted in a storz® 24 f resectoscope was performed, in order to achieve the highest level of hemostasis in a patient under antiaggregant therapy. no capsular lesion was documented, and morcellation was performed in clear fluid vision, without any bleeding from the surgical field. at the end of the procedure, in order to check for any remnant chip in the bladder, the surgeon filled the bladder with about 80 ml of air, from the outer sheet of the nephroscope. this procedure usually allows visualization of any remnant prostatic adenoma down piece on the bladder floor, preventing their flooding on the dome, as it usually happens when filling the bladder with saline. the surgeon found no remnant chips in the surgical field, but immediately after the placement of the urethral catheter, patient’s etco2 levels dramatically decreased at 17 mmhg, with paw 16 and oxygen saturation level decreased at 75%, without any loss in the ventilation circuit and arterial blood pressure of 94/54 mmhg. so laryngeal mask was switched to oro tracheal intubation (oti), in order to increase the oxygen level. correct positioning of the tube was confirmed by auscultation via stethoscope. pulmonary us ruled out the presence of pneumothorax and atelectasia. due to their negativity, the vae was suspected: the patient was put in trendelenburg position and cardiac transthoracic us showed no air bubbles inside cardiac cavities, without any alteration in the cardiac kinesis. arterial blood sample was collected, but was negative for any alteration compatible with vae. after 5 minutes etco2 levels spontaneously returned to 40 mmhg, with fraction of inspired oxygen (fio2) 40% and oxygen saturation of 100%, and arterial blood sample was negative for any significant alterations (fio2 100%, ph 7.29, po2 217 mmhg, pco2 53 mmhg, sat o2 98%, acid-base excess abe-1.9 mmol/l, lactate level 0.9 mmol/l). catheter continuous irrigation was started, and clear washing fluid without blood cloths was so obtained. the patient was extubated and awakened, and no neurological defects were detected. another arterial blood sample resulted free from any significant alteration (fio2 40%, ph 7.39, po2 75.3 mmhg, pco2 40.5 mmhg, sat o2 94.9%, acid-base excess abe-0.1 mmol/l, lactate level 0.9 mmol/l). only a conjunctival capillary rupture was detected in the right eye (a sign of augmented endothoracic pressure), but no visus defects were detected. patient was transferred to the intensive care unit, where a second transthoracic us was performed, together with a serum dosage of myocardial enzymes (troponine): every analysis was negative for any alteration, so the patient was readmitted to the urology ward. catheter was removed in second postoperative day (pod), while patient was discharged in third pod, without any neurological sequelae. discussion the advantage of holep over turp is the excellent hemostatic effect of holmium laser compared to standard electrical energy. vae cases have been described in turp, while, to the present report, only two cases have been described during holep. the first case (4) was due to an incorrect assembly of the morcellator system, with air entry into the endoscopic circuit. the second (5), has left unanswered the source of the gas leading to a fatal massive vae. the basis for vae are the presence of an open venous system and a condition of sub-atmospheric central venous pressure. moreover (6) air can enter the bloodstream due to active filling: a 5 cm h2o pressure gradient is enough to make air enter the opened vessels (7); this condition may occur in holep enucleative phase, when the surgeon opens perforating vessels, arising from the capsule to the adenoma. it is important to underline that the entity of vae is related to the volume of gas entering the venous system. small size emboli generally have no effect on circulation, thus explaining why there was just a small number of fatal vae during prostate surgery (7-9). the estimated lethal volume of intravenous air in human circulation is 3-5 ml/kg (10). there are two possibilities when air enters into the venous bloodstream: if it enters slowly, it can be reabsorbed at the alveolar-capillary interface (11), or, if the air reaches quickly the right heart an acute occlusion of pulmonary artery outflow ensues, leading to fatal vae. considering this pathophysiology, we suppose that, in our case, the episode of vae has been facilitated by air insufflation inside the bladder (“pneumocystoscopy”), to check for any remnant prostatic chip, preventing the flooding of the chips which is caused by suspension in the irrigation fluid. a similar situation had been described when air was inserted through the urinary catheter at the end of the procedure (6) or due to an incorrect assembly of the irrigation system (12) or to an incorrect assembly in the morcellator device (13). in other cases, however, a clear source of air remains either unclear or just postulated: for example, zhang (5) supposed that fatal vae had been caused by air entrance into the bladder due to the high-frequency intermittent extraction and insertion of the scope from the sheat during a long lasting procedure (two hours and forty minutes). chang (14) identified bubbles resulting by water vapor as a possible source of embolism, while zhang (5) underlined that embolism is linked more likely to air embolus, composed of relatively insoluble nitrogen, than to water embolus resulting from laser absorbance by irrigation fluid. it is also important to underline that, in this case, the patient did not suffer any damage relatd to vae and spontaneously fully recovered, while most of the cases of vae related to prostate surgery are characterized by death of the patient due to massive embolism (7). a possible explanation may be both the amount of air entering the bloodstream, not large, and the absence of any cardiac abnormality as a predisposing factor. an effective strategy to treat vae consists of immediate placement of the patient in left lateral decubitus (durant’s manouver) maintaining trendelenburg position, direct aspiration of romagnoli_stesura seveso 01/04/20 18:59 pagina 56 air from the heart via a central catheter and effective cardiopulmonary resuscitation (if required) (5). as a final consideration, the quality of monitoring is crucial to correctly and directly detect. the correct monitoring scheme is the one adopted in case of general anesthesia, with the possibility of rapidly performing, whenever feasible and possible, transesophageal echocardiography, as reported by hong (15), who described an incidence of 80% of vae during retropubic radical prostatectomy. this procedure remains the actual most sensitive method for detection of air in the hearth, and the recommended monitoring item. in our case, if we had performed the procedure under spinal anesthesia, without invasive monitoring scheme, we might have missed to identify and recognize the embolic episode. therefore, care must be taken in order to avoid any air entrance in the bloodstream, either directly or indirectly. an invasive monitoring system is the key to rapidly and correctly identify any embolic episode. references 1. porreca a, mineo bianchi f, d'agostino d, et al. ejaculation sparing bladder neck incision with holmium laser in patients with urinary symptoms and small prostates: short-term functional results. urol int. 2019; 103:102-107. 2. noale m, maggi s, artibani w, et al. pros-it cnr: an italian prostate cancer monitoring project. aging clin exp res. 2017; 29:165-172. 3. grasso a, cozzi g, de lorenzis e, et al. multicenter analysis of pathological outcomes of patients eligible for active surveillance according to prias criteria. minerva urol nefrol. 2016; 68:237-41. 4. kato t, sugimoto m, matsuoka y, et al. case of vascular air embolism during holmium laser enucleation of the prostate. int j urol. 2015; 22:227-9. 5. zhang w, ren m. fatal massive air embolism during holmium laser enucleation of the prostate (holep). int j clin urol. 2017; 6:60-62. 6. vacanti ca, lodhia kl. fatal massive air embolism during transurethral resection of the prostate. anesthesiology. 1991; 74:186-7. 7. tsou my, teng yh, chow lh, et al. fatal gas embolism during transurethral incision of the bladder neck under spinal anesthesia. anesth analg. 2003; 97:1833-4. 8. albin ms, ritter rr, reinhart r, et al. venous air embolism during radical retropubic prostatectomy. anesth analg. 1992; 74:151-3. 9. memtsoudis sg, malhotra v. catastrophic venous air embolus during prostatectomy in the trendelenburg position. can j anaesth. 2003; 50:1084-5. 10. toung tj, rossberg mi, hutchins gm. volume of air in a lethal venous air embolis. anesthesiology. 2001; 94:360-1. 11. presson rg, kirk kr, haselby ka, et al. fate of air emboli in the pulmonary circulation. j appl physiol. 1989; 67:1898-1902. 12. frasco pe, caswell re, novicki d. venous air embolism during transurethral resection of the prostate. anesth analg, 2004; 99:1864-6. 13. kato t, sugimoto m, matsuoka y, et al. case of vascular air embolism during holmium laser enucleation of the prostate. int j urol. 2015; 22:227-9. 14. chang cp, liou cc, yang yl, sun ms. fatal gas embolism during ureteroscopic holmium:yttrium-aluminiium-garnet laser lithotripsy under spinal anesthesiaa casae report. minim invasive ther allied technol. 2008; 17:259-61. 15. hong jy, kim jy, choi yd, et al. incidence of venous gasembolism during robotic-assisted laparoscopic radical prostatectomy is lower than that during radical retropubic prostatectomy. br j anaesth. 2010; 105:777-81. 57archivio italiano di urologia e andrologia 2020; 92, 1 not fatal venous air embolism after holep correspondence romagnoli daniele, md (corresponding author) danieleromagnoli87@gmail.com d’agostino daniele, md daniele.dagostino@casacura.it corsi paolo, md paolo.corsi@casacura.it giampaoli marco, md marco.giampaoli@casacura.it del rosso alessandro, md adelrosso@casacura.it artibani walter, md prof.artibani@gmail.com porreca angelo, md angeloporreca@gmail.com robotic urology and mini invasive urologic surgery unit, abano terme hospital piazza cristoforo colombo, 1, 35031 abano terme (padova) (italy) ghaemian mobin, md mobin.ghaemian@casacura.it davia’ giorgio, md giorgio.davia@casacura.it anesthesiology and postoperative intensive care unit, abano terme hospital piazza cristoforo colombo, 1, 35031 abano terme (padova) (italy) cevenini matteo, md matteoceve@gmail.com schiavina riccardo, md rschiavina@yahoo.it brunocilla eugenio, md eugenio.brunocilla@unibo.it department of specialistic, experimental and diagnostic medicine, urology, alma mater studiorum-university of bologna, s. orsola hospital via pelagio palagi, 9, 40138 bologna, (italy) romagnoli_stesura seveso 01/04/20 18:59 pagina 57 153archivio italiano di urologia e andrologia 2019; 91, 3 original paper green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven hg-pin or asap. concise review and meta-analysis gianpaolo perletti 1, 2, vittorio magri 3, anne vral 2, konstantinos stamatiou 4, alberto trinchieri 5 1 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 2 department of human structure and repair, faculty of medicine and medical sciences, ghent university, ghent, belgium; 3 asst nord milano, milan, italy; 4 department of urology, tzaneio hospital, piraeus, greece; 5 urology unit, manzoni hospital, lecco, italy. a focused, single outcome meta-analysis on the protective role of extracts of green tea catechins against prostate cancer. randomized, placebo-controlled studies enrolling patients with a histologically confirmed diagnosis of high-grade prostate intraepithelial neoplasia or atypical small acinar proliferation but no prostate cancer were included. meta-analysis for binary data was performed using mantel-haenszel statistics, using a random-effects model. heterogeneity was investigated by calculating the i2. four studies matched the inclusion criteria for the review. the pooled population was 223 patients; 114 and 109 patients were randomized to catechin and placebo groups, respectively. nine cases of prstate cancer occurred in the catechin arm (7.9%), and 24 cases were reported in the placebo arm (22%). pooled analysis resulted in a significant reduction of cancer risk in favor of the catechin arm (risk-ratio = 0.41; 95% ci: 0.190.86; i2 = 0). in conclusion, our data suggest that the intake of concentrated green tea catechin preparations may confer a significant protective effect to carriers of early neoplastic lesions in the prostate. the quality of the evidence is moderate, and additional, largescale studies are warranted to substantiate these preliminary findings. key words: green tea; prostate cancer; prostate; polyphenols; catechins; epigallocatechin-3-gallate. submitted 8 july 2019; accepted 22 july 2019 summary no conflict of interest declared. prostatic intraepithelial neoplasia [hg-pin], atypical smallacinar proliferation [asap]) (6). in the same year, guo et al. performed a similar meta-analysis by adding a third updated study to the pooled trials. also in this case, catechins showed a significant protective effect against prostate cancer (5). the aim of this review and metaanalysis was to search for additional phase ii studies published in the literature, and, if possible, to attempt meta-analysis of the global data published so far. materials and methods a search of the pubmed/medline and embase databases of publications in english, indexed up to june 7th, 2019 was performed, using the following terms: prostate, prostate cancer, *carcinoma, green tea, tea, catechin*, *gallate, ecgc. the single outcome for this review was the incidence/prevalence of prostate cancer in included patients. inclusion criteria (i) patients with histologically-proven hg-pin and/or asap of any age, included in randomized, placebo-controlled clinical trials; (ii) the active treatment arm received a concentrated preparation of green tea catechins; (iii) placebo-controlled studies. exclusion criteria (i) non-randomized trials; (ii) a diagnosis of prostate cancer; (iii) any combination therapy (catechins combined with other drugs or supplements, with surgical procedures, with radiotherapy, etc.). risk of bias analysis was performed by two investigators using the cochrane risk of bias tool (7). the metaessentials software was used for publication bias analysis (8). meta-analysis for binary data was performed using mantel-haenszel statistics with the cochrane review manager 5.3 software. we planned to use a random-effects model, and to attempt confirmatory analysis with a fixed-effects model in case of low heterogeneity. heterogeneity was investigated by calculating the i2. doi: 10.4081/aiua.2019.3.153 introduction in vitro, in vivo and epidemiological studies suggest that the high polyphenol content of green tea may confer to this beverage a protective effect against prostate cancer (pca) (1-5). from year 2006, randomized clinical trials have been performed, focusing on the role of green tea catechins (mainly epigallocatechin-3-gallate) on the prevention or retardation of the onset of prostate cancer. in 2017, a meta-analysis by cui et al., based on two randomized, double-blind, placebo-controlled phase ii trials, resulted in a slightly significant protective effect of concentrated green tea catechin preparations, in patients with histologically proven suspicious lesions (high-grade perletti_stesura seveso 30/09/19 18:18 pagina 153 archivio italiano di urologia e andrologia 2019; 91, 3 g. perletti, v. magri, a. vral, k. stamatiou, a. trinchieri 154 results literature database search retrieved 3230 deduplicated records. title and abstract were screened by two investigators, who selected 7 records for further full-text reading, with no disagreements. three articles were agreed to be excluded for the following reasons: (i) catechins not administered as single-agents, but combined with other supplements (9), (ii) a feasibility study, without cancer incidence as an outcome (10), (iii) a study performed before prostatectomy in men diagnosed with pca (11). four articles were finally selected for risk of bias assessment and meta-analysis (12-15). two and three of these studies were included in the metaanalyses of cui et al. (6) and guo et al. (5), respectively. thus, the present meta-analysis updates their results by addition of two or one extra trial(s), respectively. figure 1 shows the forest plot for the present metaanalysis. the total population is 223 patients; 114 and 109 patients were randomized to catechin and placebo groups, respectively. nine cases of pca occurred in the catechin arm (7.9%), and 24 cases were reported in the placebo arm (22%). although 3 out of 4 studies showed non-significant risk-ratios (12, 13, 15), pooled analysis resulted in a significant reduction of pca risk in favor of the catechin arm (rr = 0.41; 95% ci: 0.19-0.86; p = 0.02), thus confirming and supporting the significant data shown by cui et al. (rr = 0.39; 95% ci: 0.16-0.97) and by guo et al. (rr = 0.38; 95% ci: 0.16-0.86) (5, 6). calculation of the odds ratio for the same studies also resulted in a significant associafigure 1. pooled analysis of four randomized, placebo-controlled studies investigating the protective effect of green tea catechins on the incidence of prostate cancer. the number of subjects allocated to treatment arms, the number of cases of pca, the risk-ratios, the 95% confidence intervals, the z value for the overall effect, the significance of the pooled comparisons, and heterogeneity data (chi2, i2), are presented. data to the left of the vertical no-effect line of the forest plot represent decreased risk for prostate cancer. the diamond represents the overall effect size extending to the limits of the 95% confidence interval of the pooled risk-ratio. the risk of bias analysis for each included study, with explanatory footnotes, is also shown. figure 2. funnel plot for publication bias analysis. we found no evidence of publication bias; the combined effect size (ces, green) and the adjusted estimate of the combined effect size (red) are identical, as no imputation of missing studies was made by the "trim-and-fill" method. in this plot the effect size is expressed as the natural logarithm of the odds ratio. perletti_stesura seveso 30/09/19 18:18 pagina 154 tion between catechin consumption and a lesser prevalence of pca (or = 0.34; 95% ci: 0.15-0.80; p = 0.01). since the present meta-analysis was devoid of heterogeneity (i2 = 0), we re-calculated the risk-ratio using a fixed-effect model. the significance of the pooled data was confirmed (rr = 0.36; 95% ci: 0.17-0.74; p = 0.006; i2 = 0). the publication bias was found to be non-significant by both egger's and begg-mazumdar's tests (p = 0.36 and p = 0.17, respectively), and the "trim-and-fill" method applied to funnel plot analysis did not impute missing studies (figure 2). the cochrane risk of bias tool allowed to assign a high risk of attrition bias to the studies by kumar et al. and micali et al. (figure 1, red symbols); this was due to incomplete outcome data owing to 28% and 27% patient dropout rates, respectively. the remaining items of the cochrane tool show low or unclear risk of bias (figure 1, green or yellow symbols respectively). the overall quality of the evidence is "moderate", as shown in the summary of findings table for the present meta-analysis (grade criteria, table 1). conclusions in conclusion, our updated meta-analysis suggests that the intake of concentrated green tea catechin preparations may confer a significant protective effect to carriers of early neoplastic lesions in the prostate (hg-pin, asap). strengths the meta-analysis was devoid of heterogeneity and publication bias; the general quality of the evidence is moderate, according to grade criteria. limitations: the considerable percentage of dropouts in two studies suggests the presence of attrition bias. caveat it is known that lesions like hg-pin may co-exist with frank carcinoma lesions, which may remain undetected in standard bioptic assessments due to their small size or to the low number of cores. this may be a confounder and a source of detection bias in the studies included in this analysis. acknowledgements we thank louise beckers (ghent university, belgium) for assistance in database search and data extraction. references 1. hastak k, agarwal mk, mukhtar h, agarwal ml. ablation of either p21 or bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. faseb j. 2005; 19:789-91. 2. siddiqui ia, malik a, adhami vm, et al. green tea polyphenol egcg sensitizes human prostate carcinoma lncap cells to trailmediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. oncogene. 2008; 27:2055-63. 3. siddiqui ia, shukla y, adhami vm, et al. suppression of nfkappab and its regulated gene products by oral administration of green tea polyphenols in an autochthonous mouse prostate cancer model. pharm res. 2008; 25:2135-42. 4. zheng j, yang b, huang t, et al. green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies. nutr cancer. 2011; 63:663-72. 5. guo y, zhi f, chen p, et al. green tea and the risk of prostate cancer: a systematic review and meta-analysis. medicine (baltimore). 2017; 96:e6426. 6. cui k, li x, du y, et al. chemoprevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (hgpin): a systematic review and adjusted indirect treatment comparison. oncotarget. 2017; 8:36674-36684. 155archivio italiano di urologia e andrologia 2019; 91, 3 green tea catechins and prostate cancer table 1. green tea catechins for the prevention of prostate cancer. patient or population: men with hg-pin and/or asap intervention: green tea catechin preparations comparison: placebo outcomes illustrative comparative risks* relative effect (95% ci) no of participants (studies) quality of the evidence (grade) comments assumed risk corresponding risk (95% ci) placebo catechins prostate cancer 220 per 1000 90 per 1000 risk-ratio: 0.41 223 ⊕⊕⊕⊖ ⊖high risk of attrition occurrence (42 to 189) (0.19 to 0.86) (5 studies) moderate bias in two studies and small number of participants; ⊕low heterogeneity; ⊕low probability of publication bias *the assumed risk is based on the occurrence of cases of prostate cancer in the placebo population. the corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% ci). ci: confidence interval; rr: risk ratio; or: odds ratio grade working group grades of evidence high quality: further research is very unlikely to change our confidence in the estimate of effect. moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. very low quality: we are very uncertain about the estimate. perletti_stesura seveso 30/09/19 18:18 pagina 155 archivio italiano di urologia e andrologia 2019; 91, 3 g. perletti, v. magri, a. vral, k. stamatiou, a. trinchieri 156 7. higgins jp, altman dg, gøtzsche pc, et al. cochrane bias methods group; cochrane statistical methods group. the cochrane collaboration's tool for assessing risk of bias in randomised trials. bmj. 2011; 343:d5928. 8. suurmond r, van rhee h, hak t. introduction, comparison, and validation of meta-essentials: a free and simple tool for metaanalysis. res synth methods. 2017; 8:537-553. 9. gontero p, marra g, soria f, et al. a randomized double-blind placebo controlled phase i-ii study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. chemoprevention or "chemopromotion"? prostate. 2015; 75:1177-86. 10. lane ja, er v, avery knl, et al. a phase ii randomized placebo-controlled trial of green tea catechins and lycopene in men at increased risk of prostate cancer. cancer prev res (phila). 2018; 11:687-696. 11. nguyen mm, ahmann fr, nagle rb, et al. randomized, double-blind, placebo-controlled trial of polyphenon e in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. cancer prev res (phila). 2012; 5:290-8. 12. kumar nb, pow-sang j, egan km, et al. randomized, placebocontrolled trial of green tea catechins for prostate cancer prevention. cancer prev res (phila). 2015; 8:879-87. 13. brausi m, rizzi f, bettuzzi s. chemoprevention of human prostate cancer by green tea catechins: two years later. a follow-up update. eur urol. 2008; 54:472-3. 14. bettuzzi s, brausi m, rizzi f, et al. chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. cancer res. 2006; 66:1234-40. 15. micali s, territo a, pirola gm, et al. effect of green tea catechins in patients with high-grade prostatic intraepithelial neoplasia: results of a short-term double-blind placebo controlled phase ii clinical trial. arch ital urol androl. 2017; 89:197-202. correspondence gianpaolo perletti gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy department of human structure and repair, faculty of medicine and medical sciences, ghent university, ghent, belgium vittorio magri vittorio.magri@virgilio.it asst nord milano, milan, italy anne vral department of human structure and repair, faculty of medicine and medical sciences, ghent university, ghent, belgium konstantinos stamatiou stamatiouk@gmail.com department of urology, tzaneio hospital, piraeus, greece alberto trinchieri alberto.trinchieri@gmail.com urology unit, manzoni hospital, lecco, italy perletti_stesura seveso 30/09/19 18:18 pagina 156 archivio italiano di urologia e andrologia 2018; 90, 3212 case report malignant mesothelioma of tunica vaginalis testis: report of a very rare case with review of the literature emanuela trenti 1, salvatore mario palermo 1, carolina d'elia 1, evi comploj 1, 2, alexander pycha 3, rodolfo carella 4, armin pycha 1, 5 1 general hospital of bolzano, department of urology, bolzano, italy; 2 department of research, college of health care professions claudiana, bolzano, italy; 3 kantons hospital luzern, department of urology, luzern, switzerland; 4 general hospital of bolzano, department of pathology, bolzano, italy; 5 chair of urology, sigmund freud university medical school, vienna, austria. introduction: mesothelioma of the tunica vaginalis testis is a extremely rare tumor and represents 0.3 to 0.5% of all malignant mesotheliomas. exposure to asbestos often precedes illness. because of its low incidence and nonspecific clinical presentation, it is mostly diagnosed accidentally during surgery for other reasons and the prognosis is usually poor. we present a case of a patient with a mesothelioma of tunica vaginalis testis, diagnosed secondarily during hydrocele surgery, with long-term survival after radical surgery. materials and methods: a 40 years old patient was admitted to our department for routine surgery of a left hydrocele. during the operation a frozen section analysis was requested because of the unusual nodular thickening of the tunica vaginalis: the examination revealed a diffuse malignant mesothelioma with epithelioid structure and tubular-papillary proliferation. therefore a left hemi-scrotectomy with left inguinal lymph node dissection was performed. results: the definitive histology confirmed the previous report of diffuse malignant mesothelioma with angio-invasion but normal testicle findings and negative lymph nodes. no metastases were found on the ct-scan. for the first 2 years a ct was repeated every 4 months, for other 3 years every 6 months and then yearly. six years after surgery the patient is classified as no evidence of disease. conclusions: malignant mesothelioma of the tunica vaginalis testis is a rare entity, often initially thought to be a hydrocele or an epididymal cyst. an aggressive approach with hemiscrotectomy with or without inguinal and retroperitoneal lymphadenectomy can reduce the risk of recurrence. key words: mesothelioma; tunica vaginalis testis; asbestos exposure. submitted 11 june 2018; accepted 5 july 2018 summary no conflict of interest declared. tunica vaginalis testis no asbestos exposure can be documented (2-4). it occurs mostly in middle-aged men but the range of age at presentation can be wide. because of its low incidence and nonspecific clinical presentation, it is mostly diagnosed accidentally during surgery and the prognosis is usually poor. we present a case of a patient with a malignant mesothelioma of tunica vaginalis testis, diagnosed secondarily during hydrocele surgery, with long-term survival after radical surgery. case report a 40 years old patient was admitted to our department for routine left hydrocele surgery. the patient reported progressive scrotal enlargement with discomfort in the left testis and strong groin pain after extended periods of sitting. his past medical history was not significant. no cigarette smoking, trauma or infections were reported. the ultrasonography showed a simple left hydrocele with 350 ml in volume and normal testicular parenchyma. the contralateral testis was normal. the patient underwent resection of the hydrocele; the hydrocele fluid was citrine but the surgeon noted a strange fibrotic thickening of the tunica vaginalis and a frozen section was requested. the patient was discharged one day after the operation, waiting for the definitive histology. the histologic examination revealed a diffuse malignant mesothelioma with epithelioid structure and tubularpapillary proliferation. the computed tomography (ct) showed absence of distant metastases with modest enlargement of the left inguinal lymph nodes up to 22 mm. the patient agreed to a left hemiscrotectomy with left inguinal lymph node dissection, which was thereafter performed. the definitive histology confirmed a diffuse malignant mesothelioma with multiple areas of residual tumors in the tunica vaginalis testis with angioinvasion and stromal infiltration (figures 1, 2) but normal testicular findings and negative lymph nodes. the immunohistochemical study was positive for calretinin, cytocheratin 5/6, thrombomodulin, wt1 and d240 while carcinoembryonic antigen and cytocheratin 20 were negative. after consultation with medical and doi: 10.4081/aiua.2018.3.212 introduction mesothelioma of the tunica vaginalis testis is an extremely rare tumor and the most unusual type, representing 0.3% to 5% of all malignant mesotheliomas. to date only a limited number of cases (about 300) have been reported worldwide in the literature (1, 2). exposure to asbestos is a well-known risk factor for development of mesothelioma with a long latency between exposure and diagnosis, however, in most cases of mesothelioma of trenti_stesura seveso 04/10/18 11:19 pagina 212 213archivio italiano di urologia e andrologia 2018; 90, 3 mesothelioma of the testis radiation oncologists and in absence of evidence of residual disease, adjuvant therapy was not indicated in our patient. a ct was repeated every 4 months for the first 2 years and every 6 months for the next 3 years, thereafter annually. six years after surgery the patient shows no signs of recurrent disease. the occupational physician couldn’t demonstrate an exposure to asbestos of this patient. discussion mesothelioma is an extremely rare malignant tumor, which develops from the internal surface of the pleura, pericardium, peritoneum and tunica vaginalis testis. less then 5% of cases of malignant mesothelioma occur in the tunica vaginalis (5). the first case was described by barbera and rubino in 1957 (6). exposure to asbestos is a well-known risk factor for development of pleural and peritoneal mesothelioma with a very long latency between exposure and diagnosis, however, exposure is less frequently associated with pericardium and tunica vaginalis testis. due to its low incidence, it is unknown whether asbestos exposure plays a role in its etiology: less than half of reported mesothelioma of tunica vaginalis testis are associated with asbestos exposure (7). the first case of malignant mesothelioma of the tunica vaginalis testis, associated with asbestos exposure, was reported by fliegel in 1976 (8). in a general review of 223 cases in 2010, bisceglia et al. found an association with asbestos exposure in only 30-40% of the patients (3). nevertheless in the series of spiess et al. (5) the correlation with asbestos was documented in 80% of the cases and in a recent italian study, based on the data from the lombardy mesothelioma registry, mensi found an asbestos exposure in 67% of the patients with mesothelioma of the tunica vaginalis testis: here the author underlines the importance to collect the occupational history, the living habits, the residential history and the hobbies of the patients (9). in our opinion the investigation of the exposure history should be conducted by an experienced occupational physician (2, 3). other suspected causes of this kind of mesothelioma are scrotal trauma, long-term hydrocele, herniorraphy and exposure radiotherapy (2-10-11). the age at presentation varies from 7 to 87 years in different reports (2, 4). because of the lack of characteristic symptoms, these tumors could be confused on clinical assessment with hydrocele or an epididymal cyst and could initially be treated conservatively, delaying the diagnosis. the patient consults his physician usually for scrotal enlargement, scrotal/inguinal mass or scrotal pain and undergoes surgery with preoperative diagnosis of hydrocele, testicular tumors, inguinal hernia or epididymal cyst. preoperative testicular ultrasonography could show a nodular thickening of the tunica vaginalis testis and a dense fluid inside but it is mostly negative. thus, the diagnosis usually occurs secondarily during surgery and the patient needs further surgical treatment: one third of patients, who underwent only hydrocelectomy, experienced local recurrence compared to approximately 11% of patients, who underwent radical orchiectomy (12-13). inguinal orchiectomy or hemiscrotectomy with inguinal and retroperitoneal lymph node dissection in case of lymph node enlargement and appears to be the preferred treatment for these patients. it is associated with better prognosis and should be proposed when possible. radiotherapy and chemotherapy have failed to yield significant results and their role is still controversial; however adjuvant radiotherapy could be considered to prevent local disease recurrence while adjuvant chemotherapy with combination of permetrexed and cisplatin, which have had a proven efficacy in pleural mesothelioma, should be considered in cases with unfavorable prognosis (4). approximately one third of tumors is locally invasive when diagnosed (1) and more than 50% of patients develop local or distant recurrence with more than 60% figure 1. neoplastic cells with epithelioid structure and tubular-papillary proliferation with parietal and stromal infiltration (hematoxillin and eosin staining and cytocheratin 5 staining 4 x magnification). figure 2. mitosis and nuclear polymorphism (hematoxylin and eosin staining 10 x magnification). trenti_stesura seveso 04/10/18 11:19 pagina 213 archivio italiano di urologia e andrologia 2018; 90, 3 e. trenti, s.m. palermo, c. d'elia, e. comploj, a. pycha, r. carella, a. pycha 214 recurrences within the first 2 years (4, 5, 12, 14). the disease specific survival ranges in different studies between 20 and 30 months with 40% of the patients dying from their disease (5, 12, 14) though the last recent series of recabal et al., with a cohort of 15 patients treated with aggressive surgical management, shows better results: after a median follow-up of 42 months the median overall survival has not been reached (4). because of the high rate of recurrence a close follow up for the first 2 years is paramount; however a local recurrence may occur up to 15 years after surgery, which is why also a long-life follow up has to be considered (15). conclusions malignant mesothelioma of the tunica vaginalis testis is a very rare entity, often initially misinterpreted as a hydrocele or an epididymal cyst. our case shows the importance of a correct diagnosis, even if intraoperatively. a mesothelioma of tunica vaginalis testis should always be suspected in patients with asbestos exposure and rapid enlargement of hemiscrotum and must always be considered in case of fibrotic or nodular thickening of the tunica vaginalis or in case of hemorrhagic or yellow hydrocele fluid. an aggressive surgical approach with hemiscrotectomy with or without inguinal and retroperitoneal lymphadenectomy can reduce the risk of recurrence and improve the poor prognosis of these patients. a close and life-long follow up is recommended. references 1. jankovichova t, jankovich m, ondrus, et al. extremely rare tumor – malignant mesothelioma of tunica vaginalis testis. bratisl med j. 2015; 116:574-576. 2. mrinakova b, kajo k, ondrusova m, et al. malignant mesothelioma of the tunica vaginalis testis. a clinicopathologic analysis of two cases with a review of the literature. klin onkol. 2016; 29:369-374. 3. bisceglia m, dor db, carosi i, et al. paratesticular mesothelioma. report of a case with comprehensive review of literature. advances in anatomic pathology 2010; 17:53-70. 4. recabal p, rosenzweig b, bazzi wm, et al. malignant mesothelioma of the tunica vaginalis testis: outcomes following surgical management beyond radical orchiectomy. oncology. 2017; 107:166-170. 5. spiess pe, tomasz t, kassouf w, et al. malignant mesothelioma of the tunica vaginalis. urology. 2005; 66:397-401. 6. barbera v. rubino m. papillary mesothelioma of the tunica vaginalis. cancer. 1957; 10:183-189. 7. alesawi am, levesque j, fradet v. malignant mesothelioma of the tunica vaginalis testis: comprehensive review of literature and case report. j clin urol. 2015; 8:147-152. 8. fliegel z, kaneko m. malignant mesothelioma of the tunica propria testis in a patient with asbestos exposure. a case report. cancer. 1976; 37:1478-1484. 9. mensi c, pellegatta m, sieno c, et al. mesothelioma of tunica vaginalis testis and asbestos exposure. bju int. 2012; 110:533-537. 10. gürdal m, erol a. malignant mesothelioma of tunica vaginalis testis associated with long-lasting hydrocele: could hydrocele be an etiological factor? int urol nephrol. 2001; 32:687-9. 11. peterson jt, greenberg sb, buffier pa. non-asbestos-related malignant mesothelioma. cancer. 1984; 54:951-960. 12. plas e, riedl cr, pflueger h. malignant mesothelioma of the tunica vaginalis: review of the literature and assessment of prognostic parameters. cancer. 1998; 83:2437-2446. 13. esen t, acar o, peker k, et al. malignant mesothelioma of the tunica vaginalis: presenting with intermittent scrotal pain and hydrocele. case rep med. 2012; 2012:189170. 14. jones ma, young rh, scully re. malignant mesothelioma of the tunica vaginalis: a clinicopathologic analysis of 11 cases with review of the literature, am j surg pathol. 1995; 9:815-825. 15. brimo f, illei pb, epstein ji. mesothelioma of the tunica vaginalis: a series of eight cases with uncertain malignant potential, mod path. 2010; 23:1165-1172. correspondence emanuela trenti, md (corresponding author) emanuela.trenti@sabes.it salvatore mario palermo, md salvatore.palermo@sabes.it carolina d'elia, md carolina.delia@sabes.it evi comploj, md evi.comploj@sabes.it rodolfo carella, md rodolfo.carella@sabes.it armin pycha, md armin.pycha@sabes.it ospedale di bolzano, via l. boehler n. 5, 39100, bolzano, italy alexander pycha, md alexander.pycha@sabes.it luzerner kantonsspital, spitalstrasse 6000, luzern 16, switzerland trenti_stesura seveso 04/10/18 11:19 pagina 214 cop+ed+fisse 2006 173archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.173 tamsulosin plus a new complementary and alternative medicine in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results from a retrospective comparative study ferdinando fusco, massimiliano creta, francesco trama, fabio esposito, felice crocetto, achille aveta, francesco mangiapia, ciro imbimbo, marco capece, roberto la rocca, vincenzo mirone, nicola longo department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii. naples, italy. background: we aimed to compare the efficacy of tamsulosin 0.4 mg once a day alone and the combination therapy involving tamsulosin 0.4 mg once a day plus the complementary and alternative medicine consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid l-glutamine bid in patients with lower urinary tract symptoms related to benign prostatic hyperplasia (luts/bph). methods: we performed a retrospective matched paired comparison. the clinical records of luts/bph patients who underwent medical therapy with tamsulosin 0.4 mg/day plus the complementary and alternative medicine consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid l-glutamine bid between january 2019 to september 2019 were reviewed (group 1). these patients were compared in a 1:1 fashion with luts/bph patients who underwent therapy with tamsulosin 0.4 mg/day alone (group 2). total, storage, voiding and quality of life (qol) international prostate symptom (ipss) score, as well as overactive bladder (oab)-v8 score and treatment-related adverse events recorded at 40 days follow-up in both groups were compared. results: at 40 days follow-up mean total, storage, voiding and qol ipss sub-scores as well as oab-v8 score significantly improved in both groups. intergroup comparison showed statistically significant lower mean total ipss score (11.6 vs 12.4, p = 0.04) mean storage ipss sub-score (6.5 vs 7.5, p = 0.01), and mean oab v8 score (16.7 vs 18.8, p = 0.03) in patients in the group 1. conclusions: the combination of tamsulosin 0.4 mg/die plus the complementary and alternative medicine consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid lglutamine bid provides statistically significant advantages in terms of storage luts improvements in patients with luts/bph compared to tamsulosin 0.4 mg/day alone. these findings are preliminary and further prospective studies on a greater number of patients are needed to confirm it. key words: benign prostatic hyperplasia; combination therapy; lower urinary tract symptoms; phytotherapy. submitted 20 february 2020; accepted 13 march 2020 everyday urological practice and their prevalence increases with ageing (1-3). in the epic study, riboli et al. reported an incidence of storage and voiding luts of about 51% and 26% of men evaluated, respectively (3). interestingly, approximately 18% of men reported the coexistence of storage and voiding symptoms (4, 5). the european association of urology (eau) guidelines strongly recommend a1-adrenoceptor antagonists as first-line therapeutic option in patients with moderate to severe symptoms as they significantly improve urinary symptoms and maxim urinary flow (qmax) (6). in men with moderate-to-severe luts who mainly have bladder storage symptoms eau guidelines strongly recommend muscarinic receptor antagonists (strong recommendation) or beta-3 agonists (weak recommendation) (7). however, a number of concerns have been reported with the prescription of these drugs. antimuscarinics might theoretically decrease bladder strength, thus increasing post-void residual volume (pvr) urine and causing urinary retention. moreover, not all antimuscarinics have been evaluated in elderly men, and long-term studies on their efficacy in men of any age with luts are not yet available. furthermore, antimuscarinics are contraindicated in patients with angle-closure glaucoma, gastrointestinal obstruction, paralytic ileus, myasthenia gravis, severe heart disease (8, 9). on the other hand, mirabegron has been evaluated mainly in female patients (8, 9). in recent years the prescription of phytotherapeutic compounds in patients with luts/bph has gained growing interest (10). these agents represent a heterogeneous group and may contain differing concentrations of active ingredients. the complementary and alternative medicine kubiker (naturmed, italy), consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid lglutamine, has been proposed in the treatment of overactive bladder syndrome (oab) (11). we aimed to compare the efficacy of the combination therapy involving tamsulosin 0.4 mg once a day plus kubiker bid and therapy with tamsulosin 0.4 mg alone in patients with luts/bph. materials and methods we performed a retrospective comparative study. the clinical records of luts/bph patients who underwent introduction lower urinary tract symptoms related to benign prostatic hyperplasia (luts/bph) represent a common complaint in summary 03fusco_stesura seveso 24/09/20 14:12 pagina 173 archivio italiano di urologia e andrologia 2020; 92, 3 f. fusco, m. creta, f. trama, f. esposito, f. crocetto, a. aveta, f. mangiapia, c. imbimbo, m. capece, r. la rocca, v. mirone, n. longo 174 medical therapy with tamsulosin 0.4 mg/day plus kubiker bid between january 2019 to september 2019 were reviewed (group 1). these patients were compared in a 1:1 fashion with luts/bph patients who underwent therapy with tamsulosin 0.4 mg/day alone (group 2). the followings were considered exclusion criteria: post-void residual volume (pvr) > 150 ml, prostate specific antigen (psa) > 10 ng/ml, concomitant therapy with 5-alpha reductase inhibitors and/or phosphodiesterase type 5 inhibitors and/or muscarinic receptor antagonists or beta3 agonists, presence of neurological disorders, previous pelvic surgery, diabetes, urinary tract infections, history of acute urinary retention. the matched-pair comparison was based on the following criteria: psa, prostate volume (pv), qmax, pvr, total international prostate symptom score (ipss), and 8-item overactive bladder questionnaire 8 (oab-v8) score. total, storage, voiding and quality of life (qol) ipss scores, as well as oab-v8 score and treatment-related adverse events recorded at 40 days followup in both groups were compared. descriptive data of continuous variables were expressed as mean ± standard deviation (sd) and compared using the student’s t tests. the analyses were considered significant for a p-value < 0.05. all statistical analyses were performed with spss version 16.0 software. the study was performed in accordance with the ethical standards laid down in the declaration of helsinki. verbal informed consent was obtained from subjects. results overall, 36 eligible patients who underwent medical therapy with tamsulosin 0.4 mg/day plus kubiker were identified and compared to 36 patients who underwent therapy with tamsulosin 0.4 mg/day alone. baseline patients’ characteristics in both groups are reported in table 1. at 40 days follow-up mean total, storage, voiding and qol ipss sub-scores significantly improved in both groups (table 2). similarly, a statistically significant improvement in terms of oab v8 score and qmax was observed in both groups (table 2). intergroup comparison showed statistically significant lower mean total ipss score, mean storage ipss sub-score, and mean oab v8 scores in patients in the group 1. not statistically significant differences in terms of voiding ipss sub-score, qmax and pvr emerged from intergroup analysis. not clinically significant treatment-related adverse events were recorded in both groups. discussion benign prostatic obstruction has been reported to cause morpho-functional alterations involving the detrusor muscle. clinically, these alterations can impair bladder contractility and cause detrusor overactivity, decreasing bladder compliance, and onset of storage luts characterized by an altered bladder sensation, increased daytime frequency, nocturia, urgency and urgency incontinence (121). experimental models have shown that bladder outlet obstruction causes detrusor smooth muscle cells hypertrophy and hyperplasia as well as extracellular matrix alterations that may lead, over time, to detrusor overactivity and, later, to reduced bladder contractility (13-15). as reported in the epiluts study, 45.7% of the 14.139 men evaluated had storage luts (16). a1-blockers act by inhibiting the effect of endogenously released noradrenaline on smooth muscle cells in the prostate thus reducing prostate tone and bladder outlet obstruction (17). these drugs can reduce both storage and voiding luts and are considered the first-line drug treatment for male luts due to their good efficacy, and low rate and severity of adverse events. luts/bph patients with mainly bladder storage symptoms represent a difficult to treat subset of patients. indeed, therapy with a1-blockers may be suboptimal. on the other hand, both muscarinic receptor antagonists and beta-3 agonists should be prescribed with cautions and adherence to treatments with these drugs is often inadequate. herbal treatments are an increasingly popular alternative for treating storage luts (18). to the best of our knowledge, we compared, for the first time, the clinical efficacy of the combination of tamsulosin 0.4 mg/day plus kubiker and tamsulosin 0.4 mg/day alone in patients with luts/bph. we found that the combination therapy provided statistically significant advantages in terms of storage luts as demonstrated by lower ipss storage sub-scores as well as lower oab-v8 score. a number of evidences exist about the potential beneficial effects provided by the compounds contained in the food suppletable 1. baseline patients’ characteristics in both groups. group 1 (n = 36) group 2 (n = 36) p age, years, mean (sd) 65.3 (9.6) 63.4 (8.5) 0.32 prostate volume, ml, mean (sd) 44.1 (24.4) 46.1 (22.7) 0.73 psa, ng/ml, mean (sd) 2.9 (0.8) 3.2 (0.4) 0.91 pvr, ml, mean (sd) 37.0 (11.2) 39.0 (10.8) 0.26 qmax, ml/sec, mean (sd) 11.2 (0.7) 12.5 (0.8) 0.18 ipss total, mean (sd) 17.9 (0.9) 18.0 (0.8) 0.59 ipss voiding, mean (sd) 8.5 (2.2) 9.1 (1.3) 0.15 ipss storage, mean (sd) 9.3 (2.0) 8.8 (1.2) 0.18 ipss qol, mean (sd) 2.9 (0.3) 3.2 (0.4) 0.23 oab v8, mean (sd) 19.6 (0.8) 20.1 (0.9) 0.29 ipss: international prostate symptom score; qol: quality of life; oab v8: 8-item overactive bladder questionnaire; psa: prostate specific antigen; pvr: post-void residua volume; qmax: maximum urinary flow; sd: standard deviation. table 2. ipss and oab v8 scores in both groups at 40-day follow-up. group 1 (n = 36) group 2 (n = 36) p ipss total, mean (sd) 11.6 (1.7) * 12.4 (1.5) * 0.04 ipss voiding, mean (sd) 5.1 (2.1) 4.8 (1.1) 0.58 ipss storage, mean (sd) 6.5 (1.9) * 7.5 (1.6) * 0.01 ipss qol, mean (sd) 2.1 (0.8) 2.4 (0.8) 0.20 oab v8, mean (sd) 16.7 (0.5) * 18.8 (0.8) * 0.03 qmax ml/sec, mean (sd) 13.6 (0.8) 14.1 (0.7) 0.20 pvr, ml, mean (sd) 28.0 (10.2) 32.0 (8.8) 0.42 ipss: international prostate symptom score; oab v8: 8-item overactive bladder questionnaire; pvr: post-void residua volume; qmax: maximum urinary flow; qol: quality of life; sd: standard deviation. *: p < 0.05 with respect to baseline. 03fusco_stesura seveso 24/09/20 14:12 pagina 174 ment kubiker. cucurbita maxima, contained in pumpkin seeds, has been reported to provide benefits in both preclinical and clinical models of lower urinary tract dysfunction (19-25). pre-clinical studies have shown that pumpkin seeds have antioxidant and inflammatory properties and inhibit lipid peroxidation (20). pumpkin seeds administered to rats affected by overactive bladder (oab) syndrome showed to cause an increase of the production of nitric oxide (no) via the no/arginine pathway (22). independently of the acetylcholin/adrenaline system, this pathway generated the relaxation of the bladder detrusorial musculature (23). pumpkin seeds were also shown to modulate prostate growth. abdel rahman et al. found that rats fed with high amounts of pumpkin seeds in the diet had smaller prostate sizes as compared to untreated rats (24). furthermore, tsai and co-workers showed that rats receiving subcutaneous testosterone to induce an increase in prostate size and subsequently treated with pumpkin seeds for 14 days, presented a smaller prostate gland compared to the control group treated only with prazosin (25). nishimura et al. observed that the administration of pumpkin seed extract for 12 weeks significantly reduced the symptoms of oab with no side effects (19). polygonum capsicatum has a strong antioxidant activity, which has been observed in vitro (26). capsaicin is the first vanilloid investigated for therapeutic purposes and evidence exists demonstrating its efficacy in the treatment of luts (11). the capsaicin has been used for the treatment of oab syndrome due to its ability to desensitize the transient receptor potential vanilloid 1 receptor (27). evidence exists demonstrating that vitamin c from food and beverages can modulate voiding symptoms (11). however, the knowledge of the exact mechanism of action deserves further investigations. vitamin d is essential for the proper functioning of the pelvic floor. it has been widely reported that a vitamin deficiency can predispose patients to a high risk of developing luts and incontinence (28, 29). to date, the role of glutamine in patients with luts is widely under-investigated and deserves careful investigations. overall, although preliminary, results from the present study have relevant clinical implications and pose the basis for further investigations. the combination of a1-adrenoceptor antagonists and phytotherapeutic agents containing a mixture of compounds that can interfere with the pathophysiology of bladder dysfunction at multiple levels like kubiker may represent a strategy to discuss in patients with prevalent storage luts/bph for which therapy with a1-adrenoceptor antagonists alone is suboptimal and medical treatments with muscarinic receptor antagonists or beta-3 agonists are not recommended or not tolerated. the main limits of the present study are the retrospective design, the small sample size, and the short follow-up. moreover, the specific role of the various components of kubiker could not be assessed. therefore, results from the present study should be considered preliminary and further studied are needed to confirm the efficacy and safety of the combination of tamsulosin and the food supplement kubiker in luts/bph patients and to identify the subset of patients that can benefit most from this approach. the role of kubiker in women with storage luts represents a further area of interest (11, 30). conclusions the combination of tamsulosin 0.4mg/die plus kubiker bid provides statistically significant advantages in terms of storage luts improvements in patients with luts/bph compared to tamsulosin 0.4 mg/day alone. these findings are preliminary and further prospective studies on a greater number of patients are needed to confirm it. references 1. mirone v, carrieri g, morgia g, et al. risk factors for benign prostatic enlargement: the role of lifestyle habits at younger age. the 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growth in rats. urol int. 2006; 77:269-274. 26. kirino a, takasuka y, nishi a, et al. analysis and functionality of major polyphenolic components of polygonum cuspidatum (itadori). j nutr sci vitaminol. (tokyo). 2012; 58:278-286. 27. cruz f. desensitization of bladder sensory fibers by intravesical capsaicin or capsaicin analogs. a new strategy for treatment of urge incontinence in patients with spinal detrusor hyperreflexia or bladder hypersensitivity disorders. int urogynecol j. 1998; 9:214-220. 28. vaughan cp, johnson tm, goode ps, et al. vitamin d and lower urinary tract symptoms among men: results from the 20052006 national health and nutrition examination survey. urology. 2011; 78:1292-1297. 29. lshazly ma, sultan mf, aboutaleb ha, et al. vitamin d deficiency and lower urinary tract symptoms in males above 50 years of age. urol ann. 2017; 9:170-173. 30. xu p, yong q. female urinary incontinence: diagnosis and treatment. journal of genitourinary research and practice. 2019; 1:22-25. correspondence ferdinando fusco, md ferdinando-fusco@libero.it massimiliano creta, md max.creta@gmail.com francesco trama, md (corresponding author) francescotrama@gmail.com fabio esposito, md fabioesposito025@gmail.com felice crocetto, md felice.crocetto@gmail.com achille aveta, md achille-aveta@hotmail.it francesco mangiapia, md mangiapippo@libero.it ciro imbimbo, md imbimbo@unina.it marco capece, md roberto la rocca, md robertolarocca87@gmail.com vincenzo mirone, md mirone@unina.it nicola longo, md department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii via sergio pansini 5, napoli (italy) 03fusco_stesura seveso 24/09/20 14:12 pagina 176 stesura seveso archivio italiano di urologia e andrologia 2019; 91, 122 original paper successful treatment with pollen extract of hematospermia in patients with xanthogranolomatous prostatitis antonio luigi pastore 1, 2, yazan al salhi 1, andrea fuschi 1, alessia martoccia 1, gennaro velotti 1, lorenzo capone 1, giorgio bozzini 3, natale porta 4, vincenzo petrozza 4, ester illiano 5, elisabetta costantini 5, antonio carbone 1, 2 1 sapienza university of rome, faculty of pharmacy and medicine, department of medico-surgical sciences and biotechnologies, urology unit, latina italy; 2 uroresearch, no profit association for research in urology, latina, italy; 3 department of urology mater domini humanitas castellanza (va), italy; 4 sapienza university of rome, faculty of pharmacy and medicine, department of medico-surgical sciences and biotechnologies, pathology unit, latina italy; 5 department of urology and andrology, university of perugia, terni italy. introduction: the aim of this study was to report our experience in the management of hematospermia observed in 16 patients suffering from xanthogranulomatous prostatitis. methods: recurrent episodes of hematospermia were the onset symptom in all patients, and in 25% of patients it was combined with fever. all patients reported psa value elevation and the digital rectal examination (dre) revealed an increase of the gland size and of its consistency in all cases. in all patients, the hematospermia was treated with the oral administration of two tablets of pollen extract in a single (1 g) dose daily for 30 days. results: sixteen patients were observed between 2008 and 2016, referring hematospermia, progressive lower urinary tract symptoms (luts), and serum psa level increase. to exclude the prostate cancer presence all patients were submitted to transperineal trus guided biopsy. in all the patients complete resolution of hematospermia was achieved treatment with pollen extract. all patients were subsequently treated for luts (alpha-adrenergic blockers), but none reported any significant improvement of symptoms. basing on these pieces of evidence, after 90 days of alpha-blockers therapy, all patients underwent bipolar turp. histological examination of resected prostatic tissue revealed in all patients the diagnosis of xanthogranulomatous prostatitis. conclusions: patients with xanthogranulomatous prostatitis especially experience irritative symptoms, sometimes combined with fever or hematospermia. hematospermia as the onset symptom has not been reported so far. the administration of the pollen extract for 30 days was associated with a complete resolution of hematospermia. key words: hematospermia; lower urinary tract symptoms; pollen extract; xanthogranulomatous prostatitis. submitted 6 october 2018; accepted 26 january 2019 summary no conflict of interest declared. ulomatous prostatitis, post-biopsy granuloma, and systemic granulomatous prostatitis. rare forms of granulomatous prostatitis include sarcoidosis and xanthogranulomatous prostatitis (2). this form is histologically similar to granulomatous prostatitis, with the prominence of foamy histiocytes, which constitute the xanthomatous component. non-specific granulomatous prostatitis and xanthogranulomatous prostatitis are likely caused by a blockage of prostatic ducts and stasis of gland secretions. the resulting epithelial disruption leads to the escape of cellular debris, bacterial toxins, prostatic secretions, including corpora amylacea, sperm and semen into the stroma, determining an intense localized inflammatory response. the most reported onset symptom is represented by irritative lower urinary tract symptoms and a raise of serum prostate-specific antigen (psa) (3) that mimics adenocarcinoma (4). in this study we report our experience on xanthogranulomatous prostatitis observed in 16 patients. all patients were complaining hematospermia, progressive lower urinary tract symptoms (luts), and increasing psa levels. aim of the study is to describe our successful therapeutic management of this bothering onset symptom, hematospermia, related to this rare form of prostatitis. patients and methods all patients came to our attention complaining recurrent episodes of hematospermia (associated with fever in 25% of patients), that represented the onset symptom of all cases. all men suffered also from irritative luts, mostly characterized by urinary frequency, burning, hesitancy, and nocturia. all patients provided written informed consent. the study was conducted in accordance with the declaration of helsinki and was approved by the local medical ethical committee (asl lt ce approval n.08/1636/42 urouniv). in all patients, a psa elevation was observed (range: 4.99.7 ng/ml), with a free/total ratio always greater than 20% (range: 22-36%). digital rectal examination (dre) revealed an increase in the gland volume and a consistency change doi: 10.4081/aiua.2019.1.22 introduction granulomatous prostatitis is a non-specific inflammatory process of the prostate gland, characterized by the presence of granuloma as the main histological feature (1). it is classified as: infectious granuloma, nonspecific gran23archivio italiano di urologia e andrologia 2019; 91, 1 pollen extract for hematospermia with an irregular surface in all cases. the palpatory findings (peripheral nodule of hard consistency) and the serum total psa level > 4 ng/ml lead us to suspect malignancy in all cases. all patients underwent an ultrasoundguided transperineal prostatic biopsy (12 cores) to exclude the presence of prostate cancer. all patients were investigated for chlamydia trachomatis (ct), ureaplasma urealyticum, neisseria gonorrhoeae, herpes viruses (hsv 1/2) and human papillomavirus (hpv). in all cases the hematospermia was treated with the oral administration of two tablets of deprox 500® in a single dose daily, in line with previous studies 5,6 and according with the manufacturer’s instructions (idi® integratori dietetici italiani s.r.l, catania, italy). each administration contained 1 g pollen extract (500 mg per tablet), and vitamins b1, b2, b6, b9, b12 and pp. statistical analysis (student t-test for paired samples) was performed to compare the outcomes before and after medical therapy and preand post-operative. the statistical analysis was done using spss software (version 21.0; spss inc., chicago, il). p values < 0.05 were considered as statistically significant. results sixteen patients were observed between 2008 and 2016, referring hematospermia, progressive lower urinary tract symptoms (luts), and serum psa level increase. in all patients the hematospermia was treated with pollen extract (2 tabs 1 g daily) for 30 days with complete resolution of this symptom. the deprox 500® treatment was well tolerated in all the analyzed patients, and no significant drug-related side-effect was reported. in all 16 cases the results of infection tests, and the prostate biopsy to detect cancer resulted negative. the prostatic biopsy did not allow the histological diagnosis of xanthogranulomatous prostatitis due to the poor biopsy material that did not enable the histotyping of prostatitis. thereafter, all patients were treated for luts (alpha-adrenergic blockers), but none reported any significant improvement of symptoms, as revealed by ipss questionnaire and the qmax registered 30 days post treatment. for this reason, all the subjects were evaluated by transrectal ultrasound examination (trus) and urodynamics. trus showed a marked inhomogeneity of prostate tissue, with several hypo-echoic and hyper-vascularized areas and calcifications along the peripheral surface of the adenoma, while pressure/flow studies showed the presence of a severe bladder outlet obstruction (boo). basing on these evidences, after 90 days of alpha blockers therapy, all patients underwent transurethral bipolar endoscopic resection of the prostate (turp). mean catheterization time was 2.8 days (range: 2-4 days); in only one patient acute urinary retention 48 hours after catheter removal due to inflammatory condition (as revealed by dre) occurred. psa levels significantly decreased (below 2.0 ng/ml) in all patients. functional outcomes before and after alpha blockers, pre and post turp were evaluated by ipss, ipss-qol, maximum flow rate (qmax expressed in ml/sec), and post void residual urine volume (ml). all patients achieved normal ipss scores and normal uroflowmetry parameters 5 weeks after surgery. the data are summarized in table 1. all patients submitted to turp reported significant outcomes at the 3 months’ follow-up visit (p < 0.0001). histological examination of resected prostatic tissue revealed in all patients the diagnosis of xanthogranulomatous prostatitis. discussion the histopathological examination of resected prostatic tissue in all our patients revealed xanthogranulomatous prostatitis with no evidence of malignancy. a non-specific granulomatous inflammation was found, the granulomas were composed of multinucleated giant cells and “xanthogranulomatous cells” (diffusely in 13 cases, focally in one patient; figure 1). xanthomatous histiocytes presented a small dark nuclei and abundant clear to foamy cytoplasm due to fat droplets and could be confused with prostate carcinoma. as confirmed by our case series, the final diagnosis of xanthogranulomatous prostatitis can only be achieved by histopathological examination of the prostate (7, 8). the histological feature of xanthogranulomatous prostatitis is the presence of macrophages with foamy cytoplasm “xanthomatous cells” (cd68+) in the mixed inflammatory infiltrate with multinucleated giant cells. major study limitation was the small number of patients, and the absence of a placebo group of treatment. however, the low number of patients to be enrolled was not sufficient to design a placebo controlled study. in the present study the administration of deprox 500® was able to achieve the complete resolution of hematospermia with a disappearance of this onset symptom in all patients within 15 days of treatment assumption, without severe side-effects. to the best of our knowledge this was the first study to evaluate this treatment for this symptom. furthermore, hematospermia as the onset symptom has not been reported so far. hematospermia has been sporadically reported as an accompanying symptom in very few cases (9), but only in our case series it represented the uncommon symptom of the disease onset. in 40% of all cases reporting hematospermia, an infectious condition is revealed. other etiologic factors are inflamtable 1. functional outcomes before and after alpha blocker’s therapy, and preoperative and 3 months after turp. before therapy after therapy p value ipss (sd) 23.65 (0.12) 23.51 (0.11) 0.486 ipss qol (sd) 4.45 (0.04) 4.54 (0.03) 0.115 qmax (sd) 9.81 (0.13) 9.69 (0.12) 0.553 pvr (sd) 112.95 (0.2) 113.09 (0.18) 0.610 preoperative 3 months after turp p value ipss (sd) 23.51 (0.11) 7.41 (0.11) < 0.0001 ipss qol (sd) 4.54 (0.03) 1.54 (0.05) < 0.0001 qmax (sd) 9.69 (0.12) 20.74 (0.11) < 0.0001 pvr (sd) 113.09 (0.18) 21.12 (0.19) < 0.0001 psa (sd) 6.24 (0.33) 1.32 (0.27) < 0.0001 sd: standard deviation; ipss: international prostate symptom score; qol: quality of life; qmax; maximum flow rate (ml/sec); pvr; post-void residual urine volume (ml); psa; prostate specific antigen (ng/ml). archivio italiano di urologia e andrologia 2019; 91, 1 a.l. pastore, y. al salhi, a. fuschi, a. martoccia, g. velotti, l. capone, g. bozzini, n. porta, v. petrozza, e. illiano, e. costantini, a. carbone 24 matory conditions, neoplasms and iatrogenic factors. after confirming the presence of hematospermia, physicians should perform a clinical evaluation, including clinical history and physical examination with dre. several previous studies evaluated the pollen extract early pain relief in patients suffering from chronic prostatitis/chronic pelvic pain syndrome (5, 6). in 2006, elist in a double-blind randomized placebo controlled study, reported the superiority of pollen extract versus placebo in terms of pain score improvement and treatment of luts during six months of therapy (10). additionally, in 2009, wagenlehner et al. showed that pollen extract improved luts, pain and quality of life after 12 weeks of treatment in patients when compared with placebo (11). in our study, 2 weeks of treatment with deprox 500® provided significant results in terms of hematospermia disappearance. this effect is possibly due to the association between the pollen extract and vitamins b6 and b12 that improve the antioxidant activity of pollen extract. in the study by cai et al., deprox 500® resulted able to provide improved results in terms of early pain reduction in patients with non-inflammatory chronic prostatitis/chronic pelvic pain syndrome (6). conclusions the administration of deprox 500® was able to achieve the complete resolution of hematospermia with a disappearance of this onset symptom in all patients within 15 days of treatment assumption, without side-effects. nevertheless, to completely resolve the bothering symptoms of xanthogranulomatous prostatitis surgery was mandatory in all patients. references 1. epstein ji, hutchins gm. granulomatous prostatitis: distinction among allergic, nonspecific, and post-transurethral resection lesions. hum pathol. 1984; 15:818-25. 2. shanggar k, zulkinfli mz, razack ah, et al. granulomatous prostatitis: a reminder to clinicians. med j malaysia. 2010; 65:21-2. 3. speights vo, jr, brawn pn. serum prostatespecific antigen levels in non-specific granulomatous prostatitis. br j urol. 1996; 77:408-10. 4. srigley jr. benign mimickers of prostatic adenocarcinoma. mod pathol 2004; 17:328-33 5. cai t, luciani lg, caola i, et al. effects of pollen extract in association with vitamins (deprox 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. urologia. 2013; 80(suppl 22):5-10. 6. cai t, wagenlehner fm, luciani lg,et al. pollen extract in association with vitamins provides early pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome. exp ther med. 2014; 8:1032-1038. 7. uzoh cc, uff js, okeke aa. granulomatous prostatitis. bju int. 2007; 99:510-2. 8. pastore al, palleschi g, fuschi a, et al. hematospermia and xanthogranulomatous prostatitis: an unusual onset of a rare diagnosis. can urol assoc j. 2013; 7:e820-e822. 9. stillwell tj, engen de, farrow gm. the clinical spectrum of granulomatous prostatitis: a report of 200 cases. j urol. 1987; 138:320-3. 10. wagenlehner fm, schneider h, ludwig m, et al. a pollen extract (cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. eur urol. 2009; 56:544-551. 11. elist j. effects of pollen extract preparation prostat/poltit on lower urinary tract symptoms in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized, double blind, placebo-controlled study. urology. 2006; 67:60-63. figure 1. a. low-power photomicrograph showing intense inflammatory infiltrate composed of lymphocytes, plasma cells, neutrophils and xanthogranulomatous cells in prostatic tissue (magnification 10×); b. high-power photomicrograph showing xanthomatous component of inflammatory infiltrate, composed of histiocytes with small dark nuclei and abundant clear to foamy cytoplasm (magnification 40×); c. cd68 stain showing the presence of xanthomatous histiocytes in the prostatic stroma (magnification 40×). correspondence antonio luigi pastore, md, phd (corresponding author) antopast@hotmail.com yazan al salhi, md andrea fuschi, md alessia martoccia, md gennaro velotti, md lorenzo capone, md antonio carbone, md antonio.carbone@uniroma1.it sapienza university of rome, faculty of pharmacy and medicine, department of medico-surgical scienes and biotechonologies, urology unit, icot, latina (italy) natale porta, md vincenzo petrozza, md sapienza university of rome, faculty of pharmacy and medicine, department of medico-surgical sciences and biotechnologies, pathology unit, latina italy giorgio bozzini, md department of urology mater domini humanitas castellanza (italy) ester illiano, md elisabetta costantini, md department of urology and andrology, university of perugia, terni (italy) a. b. c. archivio italiano di urologia e andrologia 2018; 90, 2130 original paper clinical comparison between conventional and microdissection testicular sperm extraction for non-obstructive azoospermia: understanding which treatment works for which patient elia maglia, luca boeri, matteo fontana, andrea gallioli, elisa de lorenzis, franco palmisano, stefano paolo zanetti, gianluca sampogna, liliana restelli, edgardo somigliana, mariapia serrago, franco gadda, emanuele montanari irccs fondazione ca’ granda, ospedale maggiore policlinico, department of urology, milan, italy. objectives: the superiority of microdissection testicular sperm extraction (mtese) over conventional tese (ctese) for men with non-obstructive azoospermia (noa) is debated. we aimed to compare the sperm retrieval rate (srr) of mtese to ctese and to identify candidates who would most benefit from mtese in a cohort of caucasian-european men with primary couple’s infertility. material and methods: data from 49 mtese and 96 ctese patients were analysed. we collected demographic and clinical data, serum levels of lh, fsh and total testosterone. patients with abnormal karyotyping were excluded from analysis. age was categorized according to the median value of 35 years. fsh values were dichotomized according to multiples of the normal range (n) (n and 1.5 n: 1-18 miu/ml, and > 18 miu/ml). testicular histology was recorded for each patient. descriptive statistics and logistic regression analyses tested the impact of potential predictors on positive srr in both groups. results: no differences were found between groups in terms of clinical and hormonal parameters with the exception of fsh values that were higher in mtese patients (p = 0.004). srr were comparable between mtese and ctese (49.0% vs. 41.7%, p = 0.40). srrs were significantly higher after mtese in patients with sertoli cell-only syndrome (scos) (p = 0.038), in those older than 35 years (p = 0.03) and with fsh > 1.5n (p < 0.001), as compared to men submitted to ctese. multivariable logistic regression analysis showed that mtese was independent predictor of positive sr in patients older than 35 years (p = 0.002) and with fsh > 1.5n (p = 0.018). moreover, increased fsh levels (p = 0.03) and both scos (p = 0.01) and ma histology (p = 0.04) were independent predictors of srr failure. conclusions: microdissection and ctese showed comparable success rates in our cohort of patients with noa. mtese seems beneficial for patients older than 35 years, with high fsh values, or when scos can be predicted. given the high costs associated with the mtese approach, the identification of candidates most likely to benefit from this procedure is a major clinical need. key words: testicular sperm extraction; non-obstructive azoospermia; infertility; risk factors. submitted 17 february 2018; accepted 10 april 2018 summary no conflict of interest declared. introduction in contrast to obstructive azoospermia in which there is an obstruction in the ductal system, non-obstructive azoospermia (noa) refers to the absence of spermatozoa in semen analysis due to minimal or no production of fully developed spermatozoa in the testicles. approximately 1% of all men and 10% of infertile men are affected by testicular failure as a result of noa (1). testicular spermatozoa can be retrieved in some noa men even despite the absence of ejaculated spermatozoa in their semen, from isolated foci of active spermatogenesis. the chance of fatherhood for the noa patient has changed dramatically in recent years following the introduction of surgical sperm retrieval techniques, in particular conventional tese (ctese) and microdissection tese (mtese). until recently, ctese represented the first-line option to retrieve spermatozoa in noa subjects for intracytoplasmic sperm injection (icsi) (2). however, since its introduction in 1999, mtese has continuously been found to be associated with better sperm retrieval rates (srrs) and fewer complications compared to ctese (3). direct vision with the operating microscope in mtese is of great advantage as larger, whitish tubules, presumably containing more germ cells with active spermatogenesis, can be identified. indeed, as reported by various authors, the rate of positive srr differs significantly between the two techniques, ranging from about 63% to 42% in mtese and from 16% to 45% in ctese (4-6). moreover, ctese can be undermined by potential surgical complications, which are virtually absent in the mtese series (7, 8). this should not be ignored given that a significant number of azoospermic patients are typically affected by secondary disturbances, such hypogonadism, for which mtese may allow for better preservation of the testicular tissue. on the contrary, other authors have failed to find a significant superiority of mtese over ctese in terms of srrs (9, 10). moreover, the overall positive srr, lower costs and high reproducibility of ctese represent unique characteristics that should be taken into account when counseling noa infertile couples (10). microdissection tese, indeed, is a technically challengdoi: 10.4081/aiua.2018.2.130 maglia_stesura seveso 28/06/18 16:38 pagina 130 131archivio italiano di urologia e andrologia 2018; 90, 2 personalized treatment for infertile men ing and expensive procedure that requires dedicated equipment and specifically trained surgeons. considering the different characteristic of each surgical technique and the high heterogeneity in the current literature regarding which technique is superior, we believe it to be of paramount importance to define which patients could benefit most from a complex surgery such as microdissectional tese. the aim of the present study is to compare srr by mtese with that obtained by conventional tese in noa patients and to identify the patients who could most benefit from a microsurgical approach by finding the best predictors of positive sperm retrieval in our cohort. materials and methods the analyses of this cross-sectional study were based on a sample of 145 consecutive white-european men assessed at a single academic centre for primary couple’s infertility (non-interracial infertile couples only) between january 2012 and april 2017. the initial cohort included 149 patients, however 4 (2.68%) men were excluded from the final analysis for missing values. according to the world health organisation (who) criteria, infertility was defined as not conceiving a pregnancy after at least 12 months of unprotected intercourse regardless of whether or not a pregnancy ultimately occurred (11). primary infertility is defined as when a couple has never been able to conceive (11). infertile patients were enrolled if they were between 18 and 55 years of age and had only male factor infertility (mfi); mfi was defined after a comprehensive gynecological evaluation of the female partner. all patients were diagnosed with noa on the basis of a complete history, physical examination, endocrine profile, and chromosomal analysis before being scheduled for tese with sperm freezing. all patients underwent chromosomal analysis and those with abnormal karyotyping were excluded from the study cohort. patients underwent at least two consecutive semen analyses, both showing absence of spermatozoa in the ejaculate after centrifugation. semen samples were collected by masturbation and analysed within 2 h according to the who criteria. patients were assessed with a thorough medical history including age and comorbidities. age was categorized according to the median value of 35 yrs. comorbidities were scored with the charlson comorbidity index (cci) (12). we used the international classification of diseases, 9th revision. for the specific purpose of the analysis, cci was categorized as 0 or ≥ 1. all individuals were sexually active, reporting to have intercourse at least four times per month. body mass index (bmi) defined as weight in kilograms by height in square meters, was calculated. bmi was considered using the cut offs proposed by the national institutes of health (nih): normal weight (18.5-24.9), overweight (25.0-29.9), and class ≥ 1 obesity (≥ 30.0). lifestyle factors potentially related with any impairment of semen quality were carefully assessed. colour-doppler ultrasound was used to detect spermatic vein reflux and to classify the grade of varicocele in infertile patients. as a main entry criterion for the study, only patients with complete data collection were included; therefore, patients with incomplete medical history were excluded. venous blood samples were drawn from each infertile patient between 7 am and 11 am after an overnight fast. follicle-stimulating hormone (fsh), luteinising hormone (lh) and prolactin (prl) were measured using a heterogeneous competitive magnetic separation assay (bayer immuno 1 system, bayer corp., tarrytown, ny, usa). total testosterone (tt) levels were measured via a direct chemiluminescence immunoassay (advia centaur; siemens medical solutions diagnostics, deerfield, il, usa). hypogonadism was defined as tt less than 3 ng/ml (13). the same laboratory analyzed all parameters for all patients. fsh values were categorized into two groups according to multiples of the normal range (n) (n and 1.5n: 1-18 miu/ml, and > 18 miu/ml). patients included in the study were scheduled for conventional ctese or mtese based on the availability of the surgical waiting list. informed consent was obtained after a thorough explanation of results in the literature and the invasiveness of the surgical technique. testicular histology was recorded based on the predominant histological pattern, such as hypospermatogenesis (hs), maturation arrest (ma) and sertoli cell-only syndrome (scos). the same pathologist reviewed all the tissue samples. conventional tese was performed, under general or local anesthesia, unilaterally on the larger testis; when testes volume was equal, the right testis was used. through a small horizontal incision in the right-median part of the scrotal, the skin, dartos muscle, and tunica vaginalis were opened to expose the tunica albuginea. the tunica albuginea was incised for about 5 mm at the middle of the testis. multiple testicular specimens were excised and dispersed between two glass slides, and the embryologist observed the samples under the optic microscope. if no sperm were seen in the initial sample, subsequent samples were taken from other locations, in the upper and lower pole of the testis, and subsequently from the contralateral testis (in only 12% of the cases). microdissection tese was performed under general anesthesia according to the procedure reported previously (3). an attempt was made to identify individual seminiferous tubules that were larger, more opaque and whiter than other tubules in the testicular parenchyma, which were considered to likely contain spermatozoa. if all tubules were seen to have an identical morphological appearance, at least three samples (upper, middle, and lower) were obtained. if no sperm were obtained from the initial sample, the same procedure was performed in the contralateral testis (in 20% of the cases). at the same time of testicular intervention in both procedures, a small tissue specimen was placed in bouin’s solution and sent for histopathological examination. data collection was carried out following the principles outlined in the declaration of helsinki; after approval of the irccs fondazione ca’ granda ospedale maggiore policlinico ethical committee, all patients signed an informed consent agreeing to supply their own anonymous data for this and future studies. data are presented as means (sd; ranges). the statistical significance of differences in means and proportions was tested with the one-way analysis of variance (anova) and pearson chi-square test, respectively. a 95% confidence interval was estimated for the association of categorical maglia_stesura seveso 28/06/18 16:39 pagina 131 archivio italiano di urologia e andrologia 2018; 90, 2 e. maglia, l. boeri, m. fontana, a. gallioli, e. de lorenzis, f. palmisano, s.p. zanetti, g. sampogna, l. restelli, e. somigliana, m. serrago, f. gadda, e. montanari 132 parameters. exploratory analyses were initially applied to all variables; variables were retained for analysis when deemed clinically significant to the results. descriptive statistics tested the association between clinical and hormonal variables and the sperm retrieval rate according to the surgical technique. logistic regression univariable analysis (uva) and multivariable analysis (mva) tested the associations between clinical and laboratory predictors and sperm retrieval failure. moreover, logistic regression analyses tested the association between clinical predictors (e.g age, fsh, testicular histology and surgical technique) and positive sperm retrieval in patients older than the median value of 35 years and in those with fsh > 1.5n (18 mui/ml). statistical tests were performed using spss v. 19 (ibm corp., armonk, ny, usa). all tests were two sided, with a significance level set at 0.05. results table 1 lists the characteristics and the descriptive statistics of the entire cohort of individuals. overall, 96 (66.2%) and 49 (33.8%) infertile patients were submitted to ctese and mtese, respectively. the two groups did not differ in terms of age, bmi and cci. there were no differences in terms of lifestyle factors, history of cryptorchidism, presence of varicocele and postoperative complications between groups. histologic reports showed hypospermatogenesis, maturation arrest and sertoli cell-only syndrome in 49 (33.7%), 32 (22%) and 64 (44.1%) patients, respectively, with no difference according to the surgical technique. the success rate of sperm retrieval in patients with noa was comparable between mtese and ctese (49.0% vs. 41.7%, p = 0.40). table 2 depicts the hormonal characteristics of infertile patients according to the surgical technique. no differences were found between groups in terms of hormonal parameters with the exception of fsh values that were higher in mtese patients (20.9 vs. 12.8 mui/ml; p = 0.004). table 3 shows the influence of clinical parameters (age, fsh values and histological reports) on the success rate of sperm retrieval between groups. sperm retrieval rate was positive in 22/61 (36.1%) patients with fsh ≥ 1.5n (18 miu/ml) (18/30 with mtese, 4/31 with ctese) and in 42/84 (50.0%) patients with fsh < 1.5n (6/19 with mtese, 36/65 with ctese). mtese resulted in a higher srr for those with fsh ≥ 1.5n (p = 0.001). age had a significant impact on sperm retrieval rate in the two groups. in patients younger than 35 years, srr was positive in 48.9% and 41.6% of men submitted to ctese and mtese, respectively. however, for those older than 35 years, mtese resulted in a significantly higher srr (56.0% vs. 35.0%, p = 0.03). the influence of histological diagnosis on the success rate of table 1. characteristics and descriptive statistics of patients (no. = 145). overall ctese mtese p value (f)* no. of patients [no. (%)] 145 (100) 96 (66.2) 49 (33.8) age (years) 0.55 (0.34) mean (sd) 35.4 (5.4) 35.6 (5.4) 34.9 (5.5) range 21-54 21-54 23-48 categorized age [no. (%)] 0.82 (χ2, 0.9) 50-60 3 (2.1) 2 (2.6) 1 (2.9) 61-70 73 (50.3) 48 (50.0) 25 (50.0) 71-80 67 (46.2) 44 (44.9) 23 (47.1) ≥ 81 2 (1.4) 2 (2.6) 0 (0.0) bmi (kg/m2) 0.07 (4.09) mean (sd) 26.8 (3.4) 26.2 (3.1) 29.0 (3.7) range 19.0-34.9 19.0-31.1 24.1-34.9 categorized bmi [no. (%)] 0.36 (χ2, 2.00) 18.5-24.9 39 (26.8) 32 (33.3) 7 (14.3) 25-29.9 83 (57.2) 55 (57.1) 28 (57.1) ≥ 30 23 (15.8) 9 (9.5) 14 (28.6) cci [no. (%)] 0.74 (χ2, 0.11) cci 0 110 (75.8) 75 (77.8) 35 (72.7) cci ≥ 1 35 (24.1) 21 (22.2) 14 (27.3) current smokers [no. (%)] 35 (24.1) 21 (22.2) 14 (27.3) 0.72 (χ2, 0.13) varicocele [no. (%)] 52 (35.8) 35 (36.5) 17 (34.6) 0.86 (χ2, 0.31) cryptorchidism [no. (%)] 27 (18.6) 22 (23.2) 5 (9.1) 0.15 (χ2, 2.1) positive srr [no. (%)] 64 (44.1) 40 (41.7) 24 (49.0) 0.40 (χ2, 0.70) histologic reports [no. (%)] 0.30 (χ2, 2.39) hypospermatogenesis 49 (33.7) 28 (28.9) 21 (42.6) maturation arrest 32 (22.0) 23 (23.7) 9 (19.1) sertoli cell-only syndrome 64 (44.1) 45 (47.4) 19 (38.3) postop. complications [no. (%)] 3 (2.0) 2 (2.1) 1 (2.0) 0.43 (χ2, 1.04) bmi = body mass index; cci = charlson comorbidity index; srr = sperm retrieval rate; *p value according to chi-square test or analysis of variance (anova), as indicated. table 2. hormonal characteristics of patients (no. = 145). overall ctese mtese p value (f)* fsh (mui/ml) 0.04 (8.89) mean (sd) 14.8 (11.8) 12.8 (11.1) 20.9 (12.1) range 1.71-59 1.71-52.3 1.81-59 lh (mui/ml) 0.15 (2.12) mean (sd) 5.7 (4.3) 5.3 (4.1) 7.2 (4.9) range 1.91-18.5 1.91-18.5 2.55-17.7 tt (ng/ml) 0.12 (2.36) mean (sd) 5.0 (4.1) 5.4 (4.5) 3.6 (1.7) range 1.17-24.1 1.17-24.1 2.16-7.58 tt < 3 ng/ml [no. (%)] 34 (23.4) 18 (19.2) 16 (33.3) 0.25 (χ2, 1.33) prl (ng/ml) 0.54 (0.36) mean (sd) 26.3 (9.2) 30.1 (10.6) 11.7 (6.44) range 4.6-68.1 4.6-68.1 5.0-26 tt = total testosterone; fsh = follicle-stimulating hormone; lh = luteinising hormone; prl = prolactin. *p value according to chi-square test or analysis of variance (anova), as indicated. maglia_stesura seveso 28/06/18 16:39 pagina 132 133archivio italiano di urologia e andrologia 2018; 90, 2 personalized treatment for infertile men sperm retrieval was also considered. we obtained spermatozoa via ctese in 64.2% and via mtese in 55.0% of men with a histological diagnosis of hypospermatogenesis. in case of ma, we retrieved sperm in 34.7% of patients via ctese and in 33.3% via mtese. for those with scos, mtese produced a significantly higher srr (50.0% vs. 31.1% with ctese, p = 0.03). in order to strengthen the association between mtese and positive sperm retrieval in older men and in those with higher fsh levels we conducted a logistic regression analysis assessing the relationship between clinical predictors (e.g age, fsh, testicular histology and surgical technique) and positive sperm retrieval in the two groups (table 4). in patients older than the median value of 35 years mtese was univariably associated with positive sr (p = 0.04) and emerged as the only independent predictor of positive sr (or 7.22; p = 0.002) after adjusting for fsh values and testicular histology. similarly, in men with fsh > 18 mui/ml, mtese was associated with positive srr (p = 0.001) at uva and showed independent predictor status for positive sr (or 9.52; p = 0.018) at mva, after adjusting for age and testicular histology. table 5 details uva and mva logistic regression models testing the associations between predictors and sperm retrieval failure. uva showed that higher fsh (p = 0.008), a histological report of scos (p = 0.014) and ma (p = 0.04) were associated with negative srr. conversely, age, lh and testosterone values were not. similarly, logistic mva revealed that fsh levels (or 1.3, p = 0.03), histological reports of scos (or 2.17, p = 0.01) and ma (or 1.87, p = 0.04) achieved independent predictor status for sperm retrieval failure. discussion this study was conducted to evaluate potential differences in terms of srrs between mtese and ctese in our cohort of noa men, and to determine which patients could most benefit from each procedure. we found that mtese yields overall greater, albeit not significantly, rates of sperm retrieval than ctese. secondly, we noted that mtese lead to a higher srr than ctese in older patients (> 35 years), in patients with elevated fsh (i.e > 18 mui/ml) and in those with a histological diagnosis of scos. mtese emerged as independent predictor of positive sr in patients older than 35 years and in those with fsh >18 mui/ml. moreover, the most reliable predictors of negative sperm retrieval were elevated fsh and both scos and ma histology. this study was prompted by existing controversies in the scientific literature regarding the role of mtese and ctese as treatment options for azoospermic men. in fact, determining which of the two procedures is more table 3. sperm retrieval rate according to the class of fsh values, age and histologic reports. ctese mtese p value (f)* fsh (mui/ml) < 18 36/65 (55.3%) 6/19 (31.5%) 0.66 (0.18) > 18 4/31 (12.9%) 18/30 (60.0%) 0.001 (7.0) age (years) < 35 23/47 (48.9%) 10/24 (41.6%) 0.67 (0.18) > 35 17/49 (35.0%) 14/25 (56.0%) 0.03 (4.27) histologic reports hypospermatogenesis 18/28 (64.2%) 12/21 (55.0%) 0.77 (0.01) maturation arrest 8/23 (34.7%) 3/9 (33.3%) 0.76 (0.09) sertoli cell-only syndrome 14/45 (31.1%) 9/19 (50.0%) 0.03 (4.29) *p value according to chi-square test analysis. table 4. logistic regression models predicting positive sperm retrieval (or; p value [95%ci]) in patients with age > 35 years and fsh > 18 mui/ml. positive sperm retrieval age > 35 years fsh > 18 mui/ml uva model mva model uva model mva model ctese vs. mtese 13.40; 0.04 7.22; 0.002 12.66; 0.001 9.52; 0.018 (1.41-21.17) (2.01-15.82) (2.49-24.22) (1.96-19.26) age 0.23; 0.76 0.11; 0.18 (0.11-1.15) (0.06-1.89) fsh 0.97; 0.10 0.18; 0.90 (0.88-1.02) (0.05-1.17) histologic report hypospermatogenesis ref. ref. ref. ref. sertoli cell-only syndrome 0.21; 0.12 0.12; 0.24 0.20; 0.11 0.31; 0.78 (0.02-1.52) (0.03-4.31) (0.03-1.43) (0.21-1.63) maturation arrest 0.34; 0.19 0.11; 0.21 0.23; 0.11 0.34; 0.78 (0.06-1.74) (0.05-3.40) (0.04-1.35) (0.20 -1.45) uva = univariate model; mva = multivariate model. table 5. logistic regression models predicting negative sperm retrieval (or; p value [95% ci]) in the whole cohort (n = 145). sperm retrieval failure uva model mva model or (95% ci) p value or (95% ci) p value age 1.04 (0.951.13) 0.38 1.13 (0.83-1.55) 0.41 fsh 1.11 (1.02-1.16) 0.008 1.31 (1.01-1.68) 0.03 lh 0.76 (0.91-1.21) 0.46 0.65 (0.89-1.26) 0.07 testosterone 0.96 (0.92-1.22) 0.40 0.98 (0.79-1.21) 0.87 histologic report hypospermatogenesis ref. ref. sertoli cell-only syndrome 4.21 (1.31-3.32) 0.014 2.17 (1.01-8.87) 0.01 maturation arrest 3.20 (1.16-1.32) 0.04 1.87 (1.02-7.52) 0.04 uva = univariate model; mva = multivariate model. maglia_stesura seveso 28/06/18 16:39 pagina 133 archivio italiano di urologia e andrologia 2018; 90, 2 e. maglia, l. boeri, m. fontana, a. gallioli, e. de lorenzis, f. palmisano, s.p. zanetti, g. sampogna, l. restelli, e. somigliana, m. serrago, f. gadda, e. montanari 134 likely to produce a better outcome remains challenging since, to date, a general consensus is still lacking among the different authors. in terms of srr, the current literature reports quite unanimously a superiority of mtese over conventional tese (46, 9, 14). for instance, okada et al. (4) reported a srr of 16.7% for the ctese group and 44.6% for mtese. more recently ghalayini et al. (6) found that sperm retrieval was successful in 56.9% patients undergoing mtese in comparison with only 38.2% of ctese patients. the present study showed a slight, but not statistically significant, superiority of mtese over ctese in terms of srr (49.0% vs 41.7%). other authors have also shown a superiority of mtese over ctese in terms of overall srr but without a statistically significant difference between groups (15). previous studies found conventional tese to be associated with significantly higher complication rates than mtese (4, 7). acute and chronic ultrasonographic abnormalities such as haematoma, loss of testicular tissue, inflammatory changes and permanent devascularisation may be found after ctese (7). moreover, ctese may be associated with higher rates of wound infection and iatrogenic hypogonadism that mtese (4). we did not find any differences between groups in terms of postoperative complications, probably due to the low rate of adverse events in our cohort (3 patients, 2 with heamtomas and 1 with wound infections). conventional tese could still offer some advantages over mtese. firstly, microsurgical training generally represents a lengthy, expensive and demanding process that likely cannot be sustained in every institution. in fact, ishikawa et al. (15) showed a steeper learning curve for mtese compared with ctese, highlighting a positive correlation between surgical outcomes and turnover of mtese operations. secondly, mtese requires dedicated and expensive equipment (especially an operating microscope) as well as longer operative times. it is therefore difficult to find a compromise that guarantees the best quality at the lowest cost. one way to deal with this issue could be tailor patient treatment based on robust predictive factors for positive srr. to date, many promising candidates for predictors have been proposed, but a general consensus is still lacking. testicular volume is amongst the frequently proposed predictors. however, colpi et al. (14) and ghalayini et al. (6) found contrasting results, with the former showing no correlation and the latter a positive correlation between higher testicular volume and srrs. another factor, advanced age, is generally associated with poorer sperm parameters and reproductive outcomes (16). however, recent studies have shown that age may not adversely affect sperm retrieval in men undergoing tese (10, 17). of clinical importance, we found significantly higher srrs with mtese in patients older than the median value of 35 years when compared to aged-match patients undergoing ctese. moreover, mtese was an independent predictor of positive sr in men older than 35 years after adjusting for fsh values and testicular histology. this finding could provide an easy to obtain and reliable predictor for identifying the best candidates to submit to mtese, especially if they belong to poor prognosis groups. serum hormonal values represent another potentially useful predictor of srrs. colpi et al. (14) and ghalayini et al. (6) reported a higher failure in sperm retrieval among patients with increased fsh levels. conversely, ramasamy et al. (18) observed comparable or better results in men with high fsh in terms of microsurgical retrieval. our study strongly supports the negative association between srr and fsh levels as we found fsh to be an independent predictor of sr failure in the overall cohort of patients and, more importantly, we showed that srr was significantly higher in mtese patients with high fsh when compared with ctese patients with comparable hormonal values. to strengthen this finding we performed a multivariable analysis to predict positive srr in men with higher fsh values and we found that mtese was independent predictor of positive sr after adjusting for age and testicular histology. testicular histological pattern is one of the most promising parameters for providing both the clinician and patient with a reliable and robust predictive tool for sr outcomes. unfortunately, and differently from the other aforementioned factors, it can be provided only through an invasive surgical procedure and is, therefore, mainly evaluated intraoperatively or retrospectively. our data showed that scos patients had significantly higher srrs from mtese compared to ctese. moreover, scos and ma were independent predictors of sr failure. our outcomes are consistent with previous studies showing the superiority of mtese over ctese in sr outcomes for scos men (4, 6). similarly, the significant association between both scos and ma and sperm retrieval failure has been previously reported (6, 19). it can be concluded that progressively worse histological patterns are associated with lower retrieval results. we can therefore speculate that improvements in srr in poor prognosis patients (those with older age, high fsh values and scos) could be achieved performing mtese instead of ctese. our study presents some limitations. first, it is not a randomized controlled study; our patients were assigned to one of the two groups on the basis of the operating theatre waiting list. second, we didn’t consider some variables such as inhibin b, johnsen score and testicular volume, which have been shown to have a relevant albeit controversial predictive value. finally, we were unable evaluate the pregnancy rate associated with icsi procedures following sperm retrievals. clinical pregnancy followed by the delivery of a healthy child is the main goal of all the procedures described, but it requires extensive follow up. nevertheless, our findings offer some positive implications that could be useful to clinicians not only to offer realistic counselling to couples undergoing arts treatments but also to tailor the best treatment to the patient who could most benefit from it. for example, we showed that mtese was associated with a better srr than ctese in older patients. this finding is important in light of the fact that advanced age is associated with decreasing testosterone levels and mtese guarantees better preservation of the testicular tissue. thus, with mtese representing a reduced risk of hypogonadism, the higher sperm retrieval rate would make mtese doubly beneficial for the patient. secondly, we confirmed the high predictive value of histology, espemaglia_stesura seveso 28/06/18 16:39 pagina 134 135archivio italiano di urologia e andrologia 2018; 90, 2 personalized treatment for infertile men cially for cases of poor prognosis (scos and ma), with mtese yielding the best results for scos patients. a preoperative histological diagnosis is however difficult to obtain unless the patient has already undergone a sperm retrieval procedure. a proposed alternative could be a stepwise approach, such as that described by franco et al. (20), which gradually increases surgical complexity only when necessary. it is undeniable, however, that patients with poor prognosis, as defined by histology, would greatly benefit from moving directly to a microsurgical approach and avoiding procedures that are extremely unlikely to produce positive results. conclusions in conclusion, microdissection and conventional tese showed comparable success rates for sperm retrieval in our cohort of patients with noa. mtese seems to be beneficial for patients older than 35 years, in patients with high fsh values, or when scos can be predicted. given the high costs associated with the mtese approach, the identification of candidates most likely to benefit from this procedure is a major clinical need. references 1. su lm, palermo gd, goldstein m, et al. testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia: testicular histology can predict success of sperm retrieval. j urol. 1999; 161:112-116. 2. kahraman s, ozgur s, alatas c, et al. high implantation and pregnancy rates with testicular sperm extraction and intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia. hum reprod. 1996; 11:673-676. 3. schlegel pn. testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. hum reprod. 1999; 14:131-5. 4. okada h, dobashi m, yamazaki t, et al. conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. j urol. 2002; 168:1063-7. 5. ramasamy r, yagan n, schlegel pn. structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. urology 2005; 65:1190-4. 6. ghalayini if, al-ghazo ma, hani ob, et al. clinical comparison of conventional testicular sperm extraction and microdissection techniques for non-obstructive azoospermia. j clin med res. 2011; 3:124131. 7. schlegel pn, su lm. physiological consequences of testicular sperm extraction. hum reprod 1997; 12:1688-92. 8. silber sj. microsurgical tese and the distribution of spermatogenesis in non-obstructive azoospermia. hum reprod. 2000; 15:2278-84. 9. tsujimura a, matsumiya k, miyagawa y, et al. conventional multiple or microdissection testicular sperm extraction: a comparative study. hum reprod. 2002; 17:2924-9. 10. saccà a, pastore al, roscigno m, et al. conventional testicular sperm extraction (tese) and non-obstructive azoospermia: is there still a chance in the era of microdissection tese? results from a single non-academic community hospital. andrology. 2016; 4:425-9. 11. world health organization web chapter on couple’s infertility. http://www.who.int/reproductivehealth/topics/infertility/definitions (accessed september 3rd, 2015). 12. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40:373-83. 13. bhasin s, cunningham gr, hayes fj, et al. testosterone therapy in men with androgen deficieny syndromes: an american society clinical practice guidelines. j clin endocrinol metab. 2010; 95:2536-59. 14. colpi gm, colpi em, piediferro g, et al. microsurgical tese versus conventional tese for icsi in non-obstructive azoospermia: a randomized controlled study. reprod biomed online. 2009; 18:315-9. 15. ishikawa t, nose r, yamaguchi k, et al. learning curves of microdissection testicular sperm extraction for nonobstructive azoospermia. fertil steril. 2010; 94:1008-11. 16. grunewald s, glander hj, paasch u, kratzsch j. age-dependent inhibin b concentration in relation to fsh and semen sample qualities: a study in 2 448 men. reproduction 2013; 145:237-244. 17. ramasamy r, trivedi nn, reifsnyder je, et al. age does not adversely affect sperm retrieval in men undergoing microdissection testicular sperm extraction. fertil steril. 2014; 101: 653-5. 18. ramasamy r, lin k, gosden lv, et al. high serum fsh levels in men with nonobstructive azoo spermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009; 92:590-3. 19. caroppo e, colpi em, gazzano g, et al. testicular histology may predict the successful sperm retrieval in patients with nonobstructive azoospermia undergoing conventional tese: a diagnostic accuracy study. j assist reprod genet. 2017; 34:149-154. 20. franco g, scarselli f, casciani v, et al. a novel stepwise microtese approach in non obstructive azoospermia. bmc urol. 2016; 16, 20. correspondence elia maglia, md elia.maglia@studenti.unimi.it luca boeri, md (corresponding author) dr.lucaboeri@gmail.com matteo fontana, md teo.fontana@me.com andrea gallioli, md andrea.gallioli@gmail.com elisa de lorenzis, md elisa.delorenzis@gmail.com franco palmisano, md franco.palmisano@hotmail.it stefano paolo zanetti, md stefano.p.zanetti@gmail.com gianluca sampogna, md gianluca.sampogna@unimi.it mariapia serrago, md mariapia.serrago@policlinico.mi.it franco gadda, md franco.gadda@policlinico.mi.it emanuele montanari, md iemanuele.montanari@unimi.it rccs fondazione ca’ granda, ospedale maggiore policlinico, department of urology via della commenda 15, 20122 milano, italy liliana restelli, md liliana.restelli@policlinico.mi.it edgardo somigliana, md edgardo.somigliana@policlinico.mi.it irccs fondazione ca’ granda, ospedale maggiore policlinico, u.o.s.d procreazione medicalmente assistita via festa del perdono 12, 20122 milano, italy maglia_stesura seveso 28/06/18 16:39 pagina 135 stesura seveso 297archivio italiano di urologia e andrologia 2020; 92, 4 original paper l. cindolo and g. ferrari do surgical tutorship for ams and received honoraria for their tutorship. doi: 10.4081/aiua.2020.4.297 introduction lower urinary tract symptoms (luts) are strongly associated with ageing (1) and might be the most evident consequence of benign prostatic hyperplasia (luts/bph). luts/bph, when related to bladder outlet obstruction (boo), are often caused by benign prostatic enlargement (bpe) (2). a surgical treatment is often necessary in luts/bph patients who experience low efficacy of pharmacological therapies or want to discontinue these therapies (3). moreover, some patients may have already progressed and/or experienced luts/bph complications, such as bladder diverticula or vesical calculi before surgery (4). furthermore, since patients with luts/bph are usually aged, other conditions such inguinal hernia may require supplementary surgical treatment (4). nowadays, photoselective vaporization of the prostate (pvp) with greenlight xps 180 watt laser (gl-180-w xps) (american medical systems, minnetonka, minnesota, usa) is considered a valid alternative to turp, thanks to its safeness and efficacy (5). moreover, the gl-180-w xps pvp guarantees an early discharge and limits the need for blood transfusion (6-8). currently, little evidence on the safety, efficacy and feasibility of pvp with other concomitant procedures are available. this evidence derived mostly from single center or case series reports (9, 10). the aim of this study is to evaluate the safety and feasibility of gl-180-w xps pvp combined with other surgical procedures. moreover, we aim to test the effect of simultaneous procedures on perioperative outcomes, functional outcomes and complication rates. materials and methods data on patients in whom pvp was performed to relieve luts/bph symptoms were abstracted from a multi-institutional database (2011-2016). patients were stratified into two groups. in the first group, all patients who had pvp with a concomitant procedure during the same surgical session were included as cases. in the second group, objectives: to explore the safety and feasibility of photo-selective vaporization of the prostate (pvp) with greenlight xps 180 watt laser (gl-180w xps) combined with other surgical procedures. material and methods: data on patients in whom gl-180-w xps was performed to relieve lower urinary tract symptoms/ benign prostatic hyperplasia (luts/bph) symptoms were extracted from a multi-institutional database (2011-2016). patients were stratified into two groups. in the first all patients who had gl-180-w xps with a concomitant procedure during the same surgical session were included as cases while those who underwent gl-180-w xps pvp only were included as control. results: a total of 487 patients were included. fifty-eight (11.9%) patients underwent concomitant procedures. multivariable linear regression models failed to find an association between concomitant procedures and longer laser time (p = 0.4). similarly, multivariable linear regression models failed to find an association between concomitant procedures and laser time even when the analyses were repeated and stratified into endoscopic (p = 0.6) and open/laparoscopic (p = 0.4) procedures. multivariable logistic regression models failed to demonstrate any association between concomitant procedures and early complications (or:1.39, ci: 0.379-2.44, p = 0.2), late complications (or:1.84, ci:0.78-3.98; p = 0.1) and acute urinary retention (or:1.84, ci:0.78-3.98; p = 0.1). when the analyses were repeated and the concomitant procedures stratified into endoscopic and open/laparoscopic ones, they yielded virtually the same results. conclusions: gl-180-w xps pvp could be safely performed in concomitant endoscopic or open/laparoscopic surgery. these results should be taken into consideration in the counseling of the patient who might choose to undergo simultaneous procedures. key words: greenlight laser; concomitant procedures; luts/bph; simultaneous surgery. submitted 24 march 2020; accepted 21 august 2020 the safety and feasibility of the simultaneous use of 180-w greenlight laser for prostate vaporization during concomitant surgery summary roberto castellucci 1, michele marchioni 2, giuseppe fasolis 3, francesco varvello 3, pasquale ditonno 4, gaetano di rienzo 4, francesco greco 5, vincenzo maria altieri 5, antonio frattini 6, giovanni ferrari 7, luigi schips 2, luca cindolo 8 1 department of urology asl abruzzo 2 chieti, italy; 2 department of urology, ss annunziata hospital, “g. d’annunzio” university, chieti, italy; 3 department of urology, “s. lazzaro” hospital, alba, italy; 4 department of emergency and organ transplantation, urology and andrology unit ii, university of bari, bari, italy; 5 department of urology, humanitas “gavazzeni”, bergamo, italy; 6 department of urology, “ercole franchini” hospital, montecchio emilia, italy; 7 department of urology, “hesperia” hospital, modena, italy; 8 department of urology, private hospital villa stuart, rome, italy. castellucci_stesura seveso 14/12/20 20:34 pagina 297 archivio italiano di urologia e andrologia 2020; 92, 4 r. castellucci, m. marchioni, g. fasolis, f. varvello, p. ditonno, g. di rienzo, f. greco, v.m. altieri, a. frattini, g. ferrari, l. schips, l. cindolo 298 all patients who underwent only simple pvp were included as controls. pvp procedures were performed according to the techniques previously described by gomez-sancha and following the surgeons’ preferences (11). the characteristics of patients collected at the time of surgery were age, luts/bph drug therapy, antiplatelet/anticoagulant therapy, asa score. moreover, prostate volume, psa levels, international prostate symptom score (ipss), maximum urinary flow (qmax) and indwelling catheter history before surgery were recorded. intraand perioperative data, including anesthesia type, laser time, energy used, catheterization time and postoperative stay were noted. the laser time referred only to the time from the beginning to the end of laser prostate vaporization. all the patients underwent an outpatient clinic visit at least after 3 months and then annually. during the follow-up visit, ipss, qmax, and psa levels were recorded. the patient global impression of improvement (pgi-i) was evaluated with the pgi-i scale (12). complications were collected and classified as early (within 30 post-operative days) or late (after 90 days). early complications were classified according to the clavien-dindo system (13, 14). our study has been reported in line with the stroccs criteria (15). written informed consent was obtained from all subjects and for this study ethical committee approval was given. statistical analysis descriptive statistics relied on median and interquartile ranges for qualitative covariates and on count and percentages (%) for categorical variables. differences between groups were assessed with the chi-square test for categorical variables and the mann-whitney u test for continuous variables. three sets of analyses were performed. first, multivariable linear regression models examined the effect of concomitant procedures on the laser time. second, separate multivariable logistic regression models tested the effect of concomitant procedures on the rates of early complications, late complications and acute urinary retention. third, all the analyses were repeated after using a different coding that stratified the concomitant procedures into endoscopic versus open/laparoscopic ones. all the multivariable models were adjusted for age and prostate volume. all statistical tests were two-sided. the level of significance was set at p < 0.05. analyses were performed using the r software environment for statistical computing and graphics (version 3.4.3; http://www.r-project.org/). results preoperative and post-operative descriptive analyses in total 487 patients were included. out of them 58 (11.9%) underwent a pvp and a concomitant procedure during the same anesthesia. twenty-nine endoscopic and 29 open/laparoscopic concomitant procedures were performed (table 1). patients who underwent concomitant procedures had a more frequent history of an indwelling catheter (36.2 vs. 21.2%, p = 0.02). moreover, patients with concomitant procedure were more frequently treated for luts/bph symptoms (31 vs. 18.4%, p = 0.02) (table 2). patients who underwent pvp in association with overall pvp pvp + concomitant p-value (n = 487) (n = 429) procedures (n = 58) preoperative parameters age, years 70 (64-76) 70 (64-77) 70.5 (65.2-76) 0.8 follow-up duration, months 17 (11-23,5) 18 (11-24.6) 14.5 (8-19.8) < 0.001 prostate volume, ml (missing = 3) 60 (43.8-80) 60 (45-80) 52 (40-74) 0.05 psa, ng/ml (missing = 58) 2.7 (1.3-4.5) 2,7 (1.3-1.4) 2.5 (1-5.1) 0.7 qmax, ml/s (missing = 116) 8 (6-10) 8 (6,1-10) 7.6 (6.3-10) 0.2 ipss (missing = 118) 25 (21-28) 25 (21-28) 26 (20.5-33.5) 0.05 asa score 0.05 1-2 259 (53.2) 220 (51.3) 39 (67.2) 3-4 93 (19.1) 83 (19.3) 10 (17.2) unknown 135 (27.7) 126 (29.4) 9 (15.5) history of catheterization 112 (23) 91 (21.2) 21 (36.2) 0.02 bph therapy 0.02 5-ari 15 (3.1) 12 (2.8) 3 (5.2) alfa-blocker 236 (48.5) 207 (48.3) 29 (50) combination therapy 139 (28.5) 131 (30.5) 8 (13.8) none 97 (19.9) 79 (18.4) 18 (31) table 1. concomitant procedures. table 2. demographic and clinical characteristics of patients before photo-selective vaporization of the prostate stratified according to the surgical procedure (pvp vs pvp + concomitant procedures). quantitative variables are reported as median and interquartile ranges (iqr). qualitative variables are reported as count and percentages (%). concomitant procedure numbers of procedures kind of surgery vescical lithotripsy 13 endoscopic internal urethrotomy 8 endoscopic turb 5 endoscopic vescical botulinum 3 endoscopic inguinal hernia repair 24 laparoscopic/open colecistectomy 2 laparoscopic/open hydrocelectomy 2 laparoscopic/open laparoscopic bladder diverticulectomy 1 laparoscopic/open other endoscopic procedures were more frequently diagnosed with smaller prostate glands (median volume 50.0 vs. 60.0 ml; p = 0.020) and had more frequently an history of indwelling catheter (41.4 vs. 21.2%, p = 0.012 (supplementary table 1). after the surgery, significant statistical differences were found for the indwelling catheter time which was longer in patients who underwent concomitant procedures (2 vs. 1 day, p = 0.006). moreover, the dipss was slightly wider for patients who underwent concomitant procedures (-20 vs. -18, p = 0.03) than in those who underwent simple pvp (table 3). no differences between the two groups were found in terms of an early and late complication rate (p = 0.3 and p = 0.07 respectively) (table 3). acute urinary retention occurred in 8.4 and 15.5 patients after simple pvp and pvp with concomitant procedure, respectively (p = 0.1). dufm was not statistically significant different between two groups (p = 0.4). most of the patients (56.7%) had no complications at all; among patients with complications the wide majority was graded as clavien-dindo i (40.7%) (tables 3, 4). consistently we found no statistically significant differences in terms of castellucci_stesura seveso 14/12/20 20:34 pagina 298 main postoperative outcomes when pvp patients were compared to those who had pvp in association with other endoscopic procedures (supplementary table 2). multivariable linear regression models multivariable linear regression models failed to find an association between concomitant procedures and longer laser time (coefficient 1.59, -1.90 to 5.08; p = 0.4). similarly, multivariable linear regression models failed to find an association between concomitant procedures and 299archivio italiano di urologia e andrologia 2020; 92, 4 green light laser and concomitant surgery table 3. demographic and clinical characteristics of patients during and after photoselective vaporization of the prostate stratified according to the surgical procedure (pvp vs pvp + concomitant procedures). quantitative variables are reported as median and interquartile ranges (iqr). qualitative variables are reported as count and percentages (%). supplementary table 1. demographic and clinical characteristics of patients before photoselective vaporization of the prostate stratified according to the surgical procedure (pvp vs pvp + other endoscopic procedures). quantitative variables are reported as median and interquartile ranges (iqr). qualitative variables are reported as count and percentages (%). pvp pvp + other endoscopic p-value (n = 429) procedures (n = 29) age, years 70.0 (64.0, 77.0) 72.0 (67.0, 76.0) 0.546 prostate volume, ml 60.0 (45.0, 80.0) 50.0 (35.0, 67.2) 0.020 psa, ng/ml 2.7 (1.3, 4.4) 1.4 (1.0, 3.6) 0.133 qmax, ml/s 8.0 (6.1, 10.0) 8.6 (7.0, 11.0) 0.573 ipss 25.0 (21.0, 28.0) 23.0 (20.0, 30.0) 0.954 asa score 0.477 1-2 220 (51.3%) 17 (58.6%) 3-4 83 (19.3%) 3 (10.3%) unknown 126 (29.4%) 9 (31.0%) history of catheterization 91 (21.2%) 12 (41.4%) 0.012 bph therapy 0.163 5-ari 12 (2.8%) 3 (10.3%) alfa-blocker 207 (48.3%) 14 (48.3%) combination therapy 131 (30.5%) 8 (27.6%) none 79 (18.4%) 4 (13.8%) supplementary table 2. demographic and clinical characteristics of patients during and after photoselective vaporization of the prostate stratified according to the surgical procedure (pvp vs pvp + other endoscopic procedures). quantitative variables are reported as median and interquartile ranges (iqr). qualitative variables are reported as count and percentages (%). pvp pvp + other endoscopic procedures p-value (n = 429) (n = 29) laser time (min) 27.0 (18.0, 38.2) 20.5 (17.0, 33.5) 0.250 energy used (kj) 247.1 (157.1, 360.0) 193.0 (148.8, 337.7) 0.442 discharge day 2.0 (1.0, 2.0) 2.0 (1.0, 2.0) 0.838 catheter removal day 1.0 (1.0, 2.0) 2.0 (1.0, 3.0) 0.079 δ psa, ng/ml -1.3 (-2.9, -0.2) -0.7 (-1.8, -0.3) 0.207 δ qmax, ml/s 11.0 (7.0, 14.0) 8.2 (1.8, 12.8) 0.076 δ ipss -18.0 (-23.0, -14.0) -16.0 (-25.0, -13.0) 0.691 acute urinary retention 36 (8.4%) 5 (17.2%) 0.106 late complications 73 (17.0%) 8 (27.6%) 0.149 early complication 182 (42.4%) 12 (41.4%) 0.912 satisfaction 0.617 not satisfied 16 (3.7%) 2 (6.9%) satisfied 388 (90.4%) 26 (89.7%) unknown 25 (5.8%) 1 (3.4%) clavien-dindo classification 0.356 0 247 (57.6%) 17 (58.6%) 1 170 (39.6%) 11 (37.9%) 2 2 (0.5%) 0 (0.0%) 3a 2 (0.5%) 1 (3.4%) 4a 8 (1.9%) 0 (0.0%) overall pvp pvp + concomitant p-value (n = 487) (n = 429) procedures (n = 58) periand post-operative features laser time (min) (missing = 26) 27 (18-37) 27 (18-38.2) 25 (18.4-34.2) 0.6 energy used (kj) (missing = 5) 246.6 247.1 (157.1-360) 242.4 (169.0-336.1) 0.7 discharge day 2 (1-2) 2 (1-2) 2 (1-2) 0.7 catheter removal day 1 (1-2) 1 (1-2) 2 (1-2,8) 0.006 δ psa, ng/ml -1.3 (-3 to -0.3) -1.3 (-2.9 to -0.2) -1.1 (-3.0 to -0.5) 0.5 δ qmax, ml/s 11 (7-14) 11 (7-14) 12.6 (8.6-13.7) 0.4 δ ipss -18 (-24 to -14) -18 (-23 to -24) -20 (-27.5 to -14) 0.03 acute urinary retention 45 (9.2) 36 (8.4) 9 (15.5) 0.1 late complications 89 (18.3) 73 (17) 16 (27.6) 0.07 early complication 211 (43.3) 182 (42.4) 29 (50) 0.3 satisfaction 0.5 not satisfied 20 (4.1) 16 (3.7) 4 (6.9) satisfied 439 (90.1) 388 (90.4) 51 (87.9) unknown 28 (5.7) 25 (5.8) 3 (5.2) clavien-dindo classification 0.4 0 276 (56.7) 247 (57.6) 29 (50) 1 198 (40.7) 170 (39.6) 28 (48.3) 2 2 (0.4) 2 (0.5) 0 (0) 3a 3 (0.6) 2 (0.5) 1 (1.7) 4a 8 (1.6) 8 (1.9) 0 (0) table 4. early and late complications according to the surgical procedure (pvp vs pvp + concomitant procedures). qualitative variables are reported as count and percentages (%). early complications overall pvp pvp + concomitant procedures fever (< 38°c) 13 (2.7) 12 (2.8) 1 (1.7) fever (≥ 38°c) 15 (3.1) 11 (2.6) 4 (6.9) burning urination 74 (15.2) 61 (14.2) 13 (22.4) bladder tenesmus 37 (7.6) 32 (7.5) 5 (8.6) urge 42 (8.6) 36 (8.4) 6 (10.3) urge incontinence 47 (9.7) 37 (8.6) 10 (17.2) stress incontinence 36 (7.4) 30 (7) 6 (10.3) capsule perforation 6 (1.2) 5 (1.2) 1 (1.7) hematuria 16 (3.3) 16 (3.7) 0 (0) acute urinary retention 45 (9.2) 36 (8.4) 9 (15.5) urinary tract infections 7 (1.4) 7 (1.6) 0 (0) blood transfusion 3 (0.6) 3 (0.7) 0 (0) cardiovascular acute event 13 (2.7) 13 (3) 0 (0) minor cardiovascular event 5 (1) 5 (1.2) 0 (0) major acute cardiovascular event 8 (1.6) 8 (1.9) 0 (0) late complications urethral stenosis 14 (2.9) 11 (2.6) 3 (5.2) bladder neck contracture 18 (3.7) 14 (3.3) 4 (6.9) prostatic fossa sclerosis 8 (1.6) 8 (1.9) 0 (0) urinary stress incontinence 27 (5.5) 23 (5.4) 4 (6.9) re-intervention 10 (2.1) 7 (1.6) 3 (5.2) persistent irritative symptoms 28 (5.7) 22 (5.1) 6 (10.3) urethral stenosis 14 (2.9) 11 (2.6) 3 (5.2) bladder neck contracture 18 (3.7) 14 (3.3) 4 (6.9) castellucci_stesura seveso 14/12/20 20:34 pagina 299 archivio italiano di urologia e andrologia 2020; 92, 4 r. castellucci, m. marchioni, g. fasolis, f. varvello, p. ditonno, g. di rienzo, f. greco, v.m. altieri, a. frattini, g. ferrari, l. schips, l. cindolo 300 laser time even when the analyses were repeated and the concomitant procedures stratified into endoscopic (coefficient 1.21, -3.50 to 5.92, p = 0.6) and open/laparoscopic (coefficient 1.99, -2.88 to 6.85, p = 0.4) ones. multivariable logistic regression models multivariable logistic regression models failed to demonstrate any association between concomitant procedures and early complications (or: 1.39, ci: 0.38-2.44, p = 0.2), late complications (or: 1.84, ci: 0.78-3.98; p = 0.1) and acute urinary retention (or: 1.84, ci: 0.78-3.98; p = 0.1). when the analyses were repeated and the concomitant procedures were stratified into endoscopic and open/laparoscopic ones, they yielded virtually the same results (table 5). discussion we hypothesized that pvp combined with other surgical procedures is feasible and safe. to test our hypothesis, we compared functional and surgical outcomes of patients who underwent pvp combined with other surgical procedures, with those who underwent pvp only. data were abstracted from a large multi-institutional database. our analyses showed several important findings. first, the proportion of patients with a history of catheterization was higher in the concomitant procedure group compared to the standard procedure group (36.2 vs. 21.2%). however, the proportion of patients not pharmacologically treated was also higher in the concomitant procedure compared to the standard procedure (31.0 vs. 18.4%). this finding is of interest because suggests that patients undergoing concomitant procedures could be less compliant to chronic treatments or physicians less prone to prescribe medications in those who are candidate to combination surgery with an history of indwelling catheter. it is worth of consideration the fact that in patients with a history of an indwelling catheter, the use of an alpha-blocker reduces the risk of acute retention after catheter removal (16). moreover, the use of combination therapy in luts/bph patients reduces the risk of complications (17). taken together these observations suggest that it might be of importance for more complex patients, such as those candidates for concomitant procedures, to continue or start luts/bph therapy in order to reduce the risk of complications after surgery. unfortunately, the granularity of our dataset do not allow to specifically investigate this hypothesis, thus larger and prospective studies investigating the effect of luts/bph treatment in concomitant procedure candidates are warrant. second, in a multivariable linear regression model no statistically significant differences were found in laser time between the concomitant procedure and standard procedure groups. we relied on this parameter as a surrogate of surgical difficulties that may occur when more than one procedure is performed. indeed, when concomitant procedures are performed before the pvp, especially for endoscopic treatments (i.e. vesical lithotripsy or internal urethrotomy), bleeding or access difficulties are always a possibility. moreover, it is worth of consideration that in our study the two groups (simple pvp and concomitant procedure) had similar prostate size. in consequence, our findings suggest that the most important predictor of laser time is the prostate size. thus, physicians should not worry to perform concomitant procedures, that do not affect the effectiveness of pvp. the latter is confirmed again by our results, which also showed no detrimental effect of concomitant procedures on overall early complications, late complications or acute urinary retention in multivariable logistic regression models. results were virtually the same even when all the multivariable models were adjusted to the different nature of concomitant surgical procedures (standard, endoscopic and laparoscopic/open) in specific analyses. our findings suggest that pvp performance is not affected by other surgical procedures. such evidence is clinically meaningful considering that almost 10% of patients need more than one treatment, according to our series. this finding corroborates those of smaller and/or more historical series. patel et al. in a smaller single institutional series (n = 372, 38 underwent concomitant procedures) also showed no enucleation and morcellation time differences in patients who underwent holep with concomitant procedures (4). similarly, the feasibility of gl-180-w pvp in combination with various other procedures was shown in small series or case reports (9, 10, 18, 19). more specifically, de la torre et al. explored the feasibility of green light laser 80 or 120 w prostate vaporization and bladder lithotripsy with holmium laser in 19 patients. the authors showed that there was a significant improvement in terms of qmax, post-micturition residual volume, and ipss after surgery with no intrao post-operative complications (10). in a similar study hora et al. reported no perior post-operative complications in 8 patients who underwent laparoscopic bladder diverticulectomy and green light laser hps 120 w or xps 180 w vaporization of prostate in one operative session (19). taken together, our study as well as those previously discussed, show the feasibility of laser surgery and more specifically of gl-180-w pvp concomitantly with other procedures (9, 10, 18-20). third, despite the fact that preoperative ipss was similar in a concomitant procedure compared to the standard, ∆ipss was wider in the concomitant procedure compared to the standard procedure (-20 vs. -18). this finding corroborates the results of previous investigators that showed a larger improvement in terms of ipss in patients who underwent table 5. multivariable logistic regression (adjusted for prostate volume and patient age), concomitant procedures endoscopic and other vs. standard. outcomes odds ratio (95% confidence interval) univariable p-value multivariable p-value early complications standard reference reference endoscopic 0.96 (0.44-2.04) 0.9 0.99 (0.45-2.16) 0.9 laparoscopic/open 1.92 (0.90-4.22) 0.09 1.91 (0.89-4.21) 0.09 late complications standard reference reference endoscopic 1.86 (0.75-4.21) 0.15 1.95 (0.77-4.49) 0.1 laparoscopic/open 1.86 (0.75-4.21) 0.15 1.85 (0.75-4.20) 0.2 acute urinary retention standard reference reference endoscopic 2.27 (0.73-5.89) 0.1 1.91 (0.60-5.11) 0.2 laparoscopic/open 1.75 (0.49-4.81) 0.3 1.76 (0.49-4.97) 0.3 castellucci_stesura seveso 14/12/20 20:34 pagina 300 301archivio italiano di urologia e andrologia 2020; 92, 4 green light laser and concomitant surgery a concomitant procedure compared to a standard procedure (4). this finding is a novelty in the field of gl-180w xps pvp. indeed, to the best of our knowledge no previous studies have investigated functional outcomes after gl-180-w xps pvp with concomitant not urological surgical procedures. for example, de la torre et al. related the use of green light laser 80 or 120 w prostate vaporization and bladder lithotripsy with holmium laser, hora et al. green light laser hps 120 w or xps 180 w with bladder diverticulectomy and cindolo et al related the feasibility of gl-180-w xpspvp associated to robotassisted laparoscopic diverticulectomy (9, 10, 19). it might be hypothesized that in patients with concomitant pathological conditions the relief from multiple comorbidities may exert a positive effect also on ipss, which is wider than in patients with luts/bph only. nevertheless, this study has several limitations. the major limitations are related to its retrospective study and the fact that non-randomized design and different surgical experience could not be controlled in the analytic phase. further limitations included the not standardized preand post-operative patient management. similarly, the assessment and management of the complications may vary according to the different centres. conclusions our study underlines how gl-180-w xps pvp could be safely performed in concomitant endoscopic or open surgery. these results should be taken into consideration in the counseling of the patient who might choose to undergo simultaneous procedures. further studies are warranted to confirm our results. references 1. abrams p, chapple c, khoury s, et al. international consultation on new developments in prostate cancer and prostate diseases. evaluation and treatment of lower urinary tract symptoms in older men. j urol 2013;189:s93-s101. https://doi.org10.1016/j.juro. 2012.11.021. 2. abrams p, cardozo l, fall m, et al. the standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society. urology. 2003; 61:37-49. 3. cindolo l, pirozzi l, sountoulides p, et al. patient’s adherence on pharmacological therapy for benign prostatic hyperplasia (bph)-associated lower urinary tract symptoms (luts) is different: is combination therapy better than monotherapy? bmc urol. 2015; 15:96. 4. patel a, nunez r, mmeje co, humphreys mr. safety and feasibility of concomitant surgery during holmium laser enucleation of the prostate (holep). world j urol. 2014; 32:1543-1549. 5. cindolo l, marchioni m, emiliani e, et al. bladder neck contracture after surgery for benign prostatic obstruction. minerva urol nefrol. 2017; 69:133-143. 6. sountoulides p, tsakiris p. the evolution of ktp laser vaporization of the prostate. yonsei med j. 2008; 49:189. 7. ben-zvi t, hueber p-a, liberman d, et al. greenlight xps 180w vs hps 120w laser therapy for benign prostate hyperplasia: a prospective comparative analysis after 200 cases in a single-center study. urology. 2013; 81:853-858. 8. castellan p, castellucci r, schips l, cindolo l. safety, efficacy and reliability of 180-w greenlight laser technology for prostate vaporization: review of the literature. world j urol. 2015; 33:599-607. 9. cindolo l, ingrosso m, marchioni m, et al. robot-assisted laparoscopic bladder diverticulectomy and greenlight laser anatomic vaporization of the prostate. int braz j urol. 2017;43. 10. de la torre g, barusso g, chernobilsky v, et al. outpatient simultaneous treatment of benign prostatic hyperplasia and bladder lithiasis with greenlighttm and holmium laser. j endourol. 2012; 26:164-167. 11. gomez sancha f, rivera vc, georgiev g, et al. common trend: move to enucleation—is there a case for greenlight enucleation? development and description of the technique. world j urol. 2015; 33:539-547. 12. hossack t, woo h. validation of a patient reported outcome questionnaire for assessing success of endoscopic prostatectomy. prostate int. 2014; 2:182-187. 13. mamoulakis c, efthimiou i, kazoulis s, et al. the modified clavien classification system: a standardized platform for reporting complications in transurethral resection of the prostate. world j urol. 2011; 29:205-210. 14. de nunzio c, lombardo r, autorino r, et al. contemporary monopolar and bipolar transurethral resection of the prostate: prospective assessment of complications using the clavien system. int urol nephrol. 2013; 45:951-959. 15. agha ra, borrelli mr, vella-baldacchino m, et al. the strocss statement: strengthening the reporting of cohort studies in surgery. int j surg. 2017; 46:198-202. 16. fisher e, subramonian k, omar mi. the role of alpha blockers prior to removal of urethral catheter for acute urinary retention in men. cochrane database syst rev. 2014:cd006744. 17. roehrborn cg, barkin j, siami p, et al. clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (bph) by baseline characteristics: 4-year results from the randomized, double-blind combination of avodart and tamsulosin (combat) trial bju int. 2011; 107:946-954. 18. tufek i, mourmouris p, argun ob, et al. robot-assisted bladder diverticulectomy with concurrent management of bladder outlet obstruction. urol int. 2016; 96:432-437. 19. hora m, eret v, stránský p, et al. laparoscopic urinary bladder diverticulectomy combined with photoselective vaporisation of the prostate. videosurgery other miniinvasive tech. 2015; 1:62-67. 20. brassetti a, de nunzio c, delongchamps nb, et al. green light vaporization of the prostate: is it an adult technique? minerva urol nefrol. 2017; 69:109-118. correspondence roberto castellucci, md roberto.castellucci@gmail.com via nazionale adriatica nord 99 pescara (italy) michele marchioni, md mic.marchioni@gmail.com luigi schips, md luigischips@hotmail.com via dei vestini 1 chieti, italy giuseppe fasolis, md info@poliambulatoriosanpaolo.it francesco varvello, md segreteria@francescovarvello.it c.so entoria 16 alba, italy pasquale ditonno, md ditonno@urologia.uniba.it c.so v. emanuele ii, bariitaly gaetano di rienzo, md dirienzo@urologia.uniba.it via lucera 4 bari italy francesco greco, md francesco.greco@gavazzeni.it vincenzo maria altieri, md vmaltieri@alice.it via gavazzeni 1 bergamo, italy antonio frattini, md antoniofrattini@gmail.com via donatori di sangue guastalla, italy giovanni ferrari, md gferrari@hesperia.it via arquà 80 modena, italy luca cindolo, md lucacindolo@virgilio.it via trionfale 5952 roma, italy castellucci_stesura seveso 14/12/20 20:34 pagina 301 321archivio italiano di urologia e andrologia 2017; 89, 4 case report seminal vesicle abscess causing unilateral hydroureteronephrosis: a case report vittorio imperatore 1, massimiliano creta 1, sergio di meo 1, roberto buonopane 1, lorenzo spirito 2, vincenzo mirone 2 1 operative unit of urology, buon consiglio hospital fatebenefratelli, naples, italy; 2 urological clinic, federico ii university of naples, naples, italy. seminal vesicle abscess (sva) is a rare urologic entity. it mainly occurs in subjects with predisposing factors and may be associated with other urogenital infections. we describe the case of a diabetic subject with sva associated with funiculitis, epididymitis and obstructive pyelonephritis. treatment consisted of laparotomic surgical drainage of the abscess and ureteral stent placement. key words: diabetes; hydroureteronephrosis; seminal vesicle abscess. submitted 15 august 2017; accepted 21 september 2017 summary no conflict of interest declared. was 0.7 ng/ml. urinalysis showed pyuria, glycosuria and ketonuria. on digital rectal examination, the prostate could not be easily palpated and a bulging of the rectal wall was evident cranially to the prostate. the left spermatic cord and hemiscrotum were swollen. findings from scrotal ultrasound were compatible with left funiculitis associated with epididymitis and the abdominal ultrasound revealed a right hydroureteronephrosis. intravenous empirical broad-spectrum antibiotic treatment with piperacillin/tazobactam was immediately started. a computed tomography (ct) of the abdomen and pelvis revealed the presence of a 6 x 5 cm, multiloculate pelvic abscess involving the recto-prostatic and the recto-vesical spaces (figure 1). the abscess was adjacent to the bladder and to the rectosigmoid colon that appeared irregularly thickened. moreover, a right hydroureteronephrosis and ipsilateral pyelonephritis were evident. a colonoscopy and a watersoluble contrast enema were required. colonoscopy confirmed an irregular thickening of the rectosigmoid junction and excluded malignancy. the enema excluded the presence of fistulous tracts. a sva was suspected based on clinical, biochemical and radiological findings. doi: 10.4081/aiua.2017.4.321 introduction currently, seminal vesicle abscess (sva) is rarely encountered in everyday clinical practice mainly due to the widespread use of broad spectrum antibiotics in subjects with urinary tract infections (1, 2). however, it may occur in the presence of predisposing conditions such as: anatomic abnormalities, compromised immunity, diabetes, prolonged catheterization, urinary tract infections and instrumentation (1, 2). moreover, sva frequently occurs in concomitance with other urogenital infections such as acute prostatitis, prostate abscess, epididymitis, and funiculitis. clinical diagnosis of sva is often challenging due to nonspecific clinical symptoms (1, 2). treatment modalities for sva include conservative management with long-term antimicrobial therapy or drainage (1, 2). sva drainage can be achieved via laparotomic, percutaneous, transrectal or transurethral accesses. however, due to the rarity of the disease, there are no specific guidelines for the management of this urological entity. we describe the case and clinical management of a diabetic patient presenting with a large sva associated with funiculitis, epididymitis, and unilateral obstructive acute pyelonephritis. case report a 58-year-old man presented to the emergency department with a 7-day history of dysuria and fever. his past medical history was relevant for diabetes mellitus with irregular medical control. a complete blood count demonstrated white blood cells of 23.94 x 10^3 /ml with elevated neutrophil count (89.3%). serum urea nitrogen and creatinine concentrations were 106 mg/dl and 1.73 mg/dl, respectively. blood glucose level was 527 mg/dl and hba1c was 16.7%. prostate specific antigen level figure 1. transverse (a, d), sagittal (b) and coronal (c) computed tomography sections of the pelvis showing a 6 x 5 cm, multiloculate abscess (*) involving the recto-vesical and the recto-prostatic spaces. bladder (b) and rectum (r) walls were irregularly thickened. right ureteral dilatation was evident (arrow). imperatore2_stesura seveso 03/01/18 09:49 pagina 321 archivio italiano di urologia e andrologia 2017; 89, 4 v. imperatore, m. creta, s. di meo, r. buonopane, l. spirito, v. mirone 322 due to the inadequate clinical response to conservative treatment, an open surgical drainage was planned via a median sub umbilical laparotomy. an extraperitoneal approach failed to reach the abscess. consequently, the peritoneum was opened and the abscess was reached through the pouch of douglas. the abscess was drained, the seminal vesicles appeared necrotic so they were removed and sent for histological examination. no other pathological findings were evident. a drainage was left in situ for 5 days. a right ureteral stent was endoscopically positioned. there were no intraoperative or post-operative complications. the operative time was 90 minutes. the postoperative course was uneventful and the patient was discharged home on post-operative day 7. histological examination revealed necrotic tissues. discussion sva represents a rare pathological entity with only few cases reported in the international literature (1, 2). the anatomical relationship of seminal vesicles with neighboring organs such as prostate, bladder, ureter, rectum, and peritoneum is responsible for the wide variety of presenting symptoms, the complex diagnostic work-up and the challenging surgical therapy. sva may occur in isolation or, more frequently, in association with other genitourinary infections such as prostatitis, prostate abscess, funiculitis, or epididymitis (1, 2). the symptoms of sva are nonspecific and may include fever, chills, irritative lower urinary tract symptoms, hematuria, scrotal, perineal, or rectal pain (1, 2). on physical examination, a mass can be palpated above the prostate that can be normal. however, due to the anatomic location, sva cannot be palpated in some cases (2). therefore, the diagnosis requires a high index of clinical suspicion. to our knowledge, we have described the first case of sva causing unilateral ureteral obstruction and pyelonephritis. prostate abscesses, cysts and neoplasms should be included into the differential diagnosis (1, 2). transrectal prostate ultrasound, ct and magnetic resonance are useful imaging modalities in patients with pelvic masses and abscess (1-3). however, ct remains the most commonly prescribed diagnostic tool in cases of sva. it allows to identify predisposing factors and to define the borders of the abscess. typical ct findings include: unilateral or bilateral seminal vesicle enlargement with a central irregular low-density zone, inflammation of the surrounding fat, thickening of the adjacent organs (1, 2). although prostate specific antigen level was within the normal range, a concomitant prostate abscess could not be excluded in the present case. if left untreated, both prostate and sva abscesses may burst into perirectal tissues, the perineum, form a fistula, and are associated with a risk of mortality. conservative medical treatment with antibiotics has been reported to be efficacious in selected cases (1, 2). necrotizing complications may potentially occur. as in other biological fields, necrotic tissues may act as inert bodies thus favoring the persistence of infection (4). some patients may not respond to conservative treatment and abscess drainage is required. multiple drainage techniques have been reported such as transperineal, transgluteal, or transrectal need aspiration, transurethral incision, and surgical drainage via laparotomy. both the trans-abdominal and the trans-perineal routes can be utilized to access to the recto-vesical and the recto-prostatic spaces (5). when surgical drainage is planned, image findings allow to choose the more appropriate approach. in cases of multiloculate abscesses, needle drainage may require multiple punctures and a high risk of persistence has been reported. in the present case, we planned the drainage of the abscess due to the extent of the collection and to the unsatisfactory response to conservative medical therapy. a laparotomic approach was adopted due to the multiloculate anatomy of the abscess and its localization that made it not easily reachable via the trans-perineal route. conclusions sva is a rare urological entity that should be suspected in subjects with evidence of pelvic abscesses and predisposing factors. it may occur in the contest of multiple genitourinary infections and may be responsible for upper urinary tract obstruction. open surgical drainage can be required in selected cases. references 1. kang ys, fishman ek, kuhlman je, goldman sm. seminal vesicle abscesses: spectrum of computed tomographic findings. urol radiol. 1989; 11:182-5. 2. saglam m, ugurel s, kilciler m, et al. transrectal ultrasoundguided transperineal and transrectal management of seminal vesicleabscesses. eur j radiol. 2004; 52:329-334. 3. creta m, mirone v, di meo s, et al. a rare case of male pelvic squamous cell carcinoma of unknown primary origin presenting as perineal abscess and urethral stenosis. arch ital urol androl. 2017; 89:154-155. 4. cennamo p, montuori n, trojsi g, et al. biofilms in churches built in grottoes. 2016; 543:727-38. 5. imperatore v, creta m, di meo s, et al. transperineal repair of a persistent rectourethral fistula using a porcine dermal graft. int j surg case rep. 2014; 5:800-2. correspondence vittorio imperatore, md (corresponding author) v.imperatore@alice.it massimiliano creta, md max.creta@gmail.com sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it operative unit of urology, buon consiglio hospital fatebenefratelli, naples, italy via a. manzoni, 220, 80123 napoli lorenzo spirito, md vincenzo mirone, md urological clinic, federico ii university of naples, naples, italy via s.pansini, 5, 80131 napoli imperatore2_stesura seveso 03/01/18 09:49 pagina 322 stesura seveso 143archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. tification of the patients who will not respond to bcg, in order to implement an aggressive therapy, aiming to maximize the clinical benefit, is clinically important (4). endothelin-1 (et-1) is a multifunctional peptide. et-1 and its receptors a/etar and b/etbr consist the endothelin-axis (et axis), which plays a role in cancer biology. et-1 stimulates tumor cell proliferation, facilitates tumor invasion and metastasis and has antiapoptotic and neoangiogenic effects (5). etar associates with tumor-cell proliferation and tumor progression, inhibition of apoptosis, effects on bone matrix, production of vascular endothelial growth factor (vegf) leading to endothelial cell proliferation and vascular permeability, by increasing the levels of hypoxia-inducible factor1a/hif-1a (5). etbr inducts proliferation of endothelial cells and migration (5). our purpose is to conduct a prospective study of the potential prognostic significance of et-1 in a cohort of primary hgnmiubc patients who were treated postoperatively with bcg (induction as well as maintenance). material and methods we prospectively included patients with transurethrally (tur) resected, primary (single or multiple), non-muscle-invasive, high-grade, urothelial carcinoma of the urinary bladder. the follow-up period started on the day of the first postoperative follow-up cystoscopy (at 3 months after the original endoscopic surgery). exclusion criteria were: present or previous upper urinary tract carcinoma and muscle-invasive disease. the patients received a single immediate postoperative intravesical instillation of chemotherapy (epirubicin 50 mg), if there was no contraindication. random biopsies of the bladder were performed, if there was a suspicion of carcinoma in situ (tis). whenever necessary (cases of incomplete resection or biopsy material without muscle fibers), a tur was repeated within 6 weeks. all patients received an induction (6 weekly intravesical bcg instillations) as well as a 3-year maintenance bcg therapy (6). the follow-up was based on the guidelines for “non-muscle-invasive bladder cancer” by the european objective: to conduct a prospective study of the potential prognostic role of endothelin-1 (et-1) in a cohort of primary high-grade non-muscle-invasive urothelial bladder cancer patients, who were treated with adjuvant intravesical bacillus calmette-guérin (bcg). material and methods: patients with primary high-grade nonmuscle-invasive urothelial bladder cancer, who received postoperatively induction and maintenance bcg therapy, were prospectively included. recurrence and progression were histologically proven. immunohistochemical staining for et-1 was assessed. epidemiological, pathological and clinical parameters as well as the expression of et-1 in tumor specimens were statistically analyzed for recurrence, progression, recurrence-free survival (rfs) and progression-free survival (pfs). results: et-1 associates significantly with recurrence (p = 0.000), progression (p = 0.000), rfs (p = 0.000) and pfs (p = 0.000). the patient’s age is also significant for recurrence (p = 0.003, or = 1.273 95% ci: 1.086-1.492) and rfs (p = 0.013). conclusions: et-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant bcg instillations. furthermore, the patient’s age associates with an increased likelihood for recurrence. key words: et-1; high-grade; non-muscle-invasive bladder cancer; prognosis. submitted 17 november 2020; accepted 25 january 2021 introduction in urothelial bladder cancer about 75% of new patients are diagnosed with a non-muscle-invasive tumor. the most effective adjuvant treatment for high-grade nonmuscle-invasive urothelial bladder cancer (hgnmiubc) is the use of intravesical instillations of bacillus calmetteguérin (bcg) (1). unfortunately, recurrence and progression are documented in about 30% and 12% (0-35%) of these patients (2). furthermore, pt1g3 patients have a 5-year disease progression rate of 19.8% and a 5-year disease-specific death rate of 11.3%, which proves a poor prognosis (3). radical cystectomy is the chosen treatment in cases of failure of bcg therapy. therefore, the early idenendothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer lampros mitrakas 1, stavros gravas 1, foteini karasavvidou 2, ioannis zachos 1, anastasios karatzas 1, athanasios oeconomou 1, georgios koukoulis 2, vasilios tzortzis 1, christos papandreou 3 1 department of urology, faculty of medicine-school of health sciences-university of thessaly, university hospital of larissa, greece; 2 department of pathology and cytology, faculty of medicine-school of health sciences-university of thessaly, university hospital of larissa, greece; 3 department of oncology, school of medicine, aristotle university of thessaloniki, “n.papageorgiou” hospital of thessaloniki, ring road of thessaloniki, greece. doi: 10.4081/aiua.2021.2.143 summary archivio italiano di urologia e andrologia 2021; 93, 2 l. mitrakas, s. gravas, f. karasavvidou, i. zachos, a. karatzas, a. oeconomou, g. koukoulis, v. tzortzis, c. papandreou 144 association of urology/eau (geau) (7). histologically proven urothelial carcinoma after transurethral resection of any cystoscopic lesion found during the follow-up period was set as “disease recurrence”. any change from pta to at least pt1 and from pt1 to at least pt2 stage was set as “disease progression”. our further treatment decisions concerning recurrence and progression were based on the recommendations made by the geau (7). group a consists of 40 consecutive patients with disease recurrence ± progression. a patient was allocated in group a as soon as recurrence was initially documented in the follow-up period. apparently, there can be no progression without the event of recurrence, but it is not for sure that every patient with recurrence will end up in having progression. group b includes 20 consecutive patients who had neither recurrence nor progression. taking into account the predefined size of group a, this size of group b is the minimum numerical value allowing a reliable statistical analysis within a prospective framework. all included patients provided their consent. the pathology staging was done according to the 2009 tnm classification approved by the union international contre le cancer (uicc) which was updated in 2017 (8th edition) and grading was estimated according to the 2004 who grading system. a central pathology review was applied for the grading of the immunohistochemical staining (ihc). representative samples of good morphology and antigenicity of the primary tumors were obtained for staining. staining was performed in a single run and by applying mouse monoclonal antibody for et-1 (clone tr.et.48.5, dilution 1:250, novus biologicals, littleton, colorado, usa). staining intensity (si) of et-1 on a highpower field (figure 1) was classified according to an arbitrary four-tiered scale (no staining = 0, mild = 1, moderate = 2, strong = 3) in a manner consistent with previous investigations (5). epidemiological (age, gender, smoking), pathological (stage t, concomitant carcinoma in situ/tis) and clinical parameters (number of tumors, tumor size, patient group), and et-1 expression were statistically analyzed. univariate analysis for recurrence (rec) and progression (pr) was performed using chi-square or fisher’s exact test and multivariate analysis using multiple logistic regression. univariate analysis for recurrence-free survival (rfs) and progression-free survival (pfs) was performed using log-rank test for categorical variables and cox regression for scale variables. multivariate analysis for rfs and pfs was assessed using cox regression analysis after checking the proportional hazards assumption. the level of statistical significance was set as p ≤ 0.05. all analyses were performed with the use of ibm spss statistics version 21 software. the study was approved by the ethics committeescientific board of the university hospital of larissa and it conforms to the provisions of the declaration of helsinki (as revised in tokyo 2008). results we totally included 60 patients, 40 patients in group a and 20 patients in group b. median follow-up was 63.2 months for group a (n = 40) and 87.8 months for group b (n = 20). baseline characteristics for the total number of patients as well as for the patients of groups a and b are shown in table 1. the results of the ihc for both groups are summarized in table 2 and the detailed results of the ihc regarding rec and pr for group a are presented in table 3. in group a, 27 patients had recurrence (27/40, 67.5%) and the median rfs was 11.3 months. moreover, 13 patients had recurrence and progression (13/40, 32.5%) and the median pfs was 38.9 months. the patients of table 1. baseline characteristics of patients in group a and b. patients’ baseline characteristics total (n = 60) group a (n = 40) group b (n = 20) p value median age (years) 67.3 ± 8.4 (38-87) 68.7 ± 7.4 (58-87) 64.3 ± 9.1 (38-77) 0.749 (*) gender (♂/♀) 50/10 (83.3%/16.7%) 34/6 (85%/15%) 16/4 (80%/20%) 0.356 (^) smoker (yes/no/ex) 30/9/21 (50%/15%/35%) 20/5/15 (50%/12.5%/37.5%) 10/4/6 (50%/20%/30%) 0.112 (^) number of tumors (single/multiple) 31/29 (51.7%/48.3%) 20/20 (50%/50%) 11/9 (55%/45%) 0.471 (^) tumor size (> 3 cm/< 3 cm) 30/30 (50%/50%) 21/19 (52.5%/47.5%) 9/11 (45%/55%) 0.355 (^) concomitant carcinoma in situ (yes/no) 12/48 (20%/80%) 8/32 (20%/80%) 4/16 (20%/80%) 0.642 (^) tumor stage t (ta/t1) 15/45 (25%/75%) 11/29 (27.5%/72.5%) 4/16 (20%/80%) 0.490 (^) (^): pearson chi-square test; (*) : t-test, statistical significance was set as p ≤ 0.05. figure 1. high-grade nonmuscle invasive urothelial carcinoma, stage pt1. strong cytoplasmic immunostaining for et-1 (x400). positive marker the vascular endothelium (arrows). table 2. summarized results of the immunohistochemical staining (ihcs) for groups a and b. ihcs grading of ihcs patients’ group 0 1 (mild) 2 (moderate) 3 (strong) et-1 1 (2.5%) 18 (45%) 15 (37.5%) 6 (15%) a (n = 40) et-1 5 (25%) 12 (60%) 2 (10%) 1 (5%) b (n = 20) group b had neither recurrence nor progression. median rfs and median pfs were 87.8 months. recurrence: in univariate analysis, et-1 (p = 0.000) and age (p = 0.001, t-test) were statistically significant. specifically, among the patients of group a who had recurrence (n = 27/40), 26 of them (26/27, 96.3%) showed et-1 expression in the ihc. the multivariate analysis showed significance only for the patient’s age (p = 0.003, or = 1.273, 95% ci: 1.086-1.492). progression: in univariate analysis, et-1 (p = 0.000) was significant. notably, among the patients of group a who had progression (n = 13/40), 13 of them (13/13, 100%) showed et-1 expression in the ihc. no parameter showed significance in multivariate analysis. recurrence-free survival (rfs): in univariate model, et-1 was importantly associated with rfs (p = 0.000), which is illustrated in the kaplan-meier curves (figure 2). age is significant too (p = 0.013, cox regression). the multivariate model provided no significant finding. progression-free survival (pfs): as it is shown by kaplan-meier curves (figure 3), the univariate analysis revealed the significance of et-1 (p = 0.000). no parameter proved to be significant in multivariate analysis. discussion the two major events in the natural history of hgnmiubc are recurrence and progression to muscle-invasiveness, despite the initial high response-rate to postoperative intravesical bcg treatment (8). from a clinical point of view it is difficult and of value to identify on time and correctly those patients who will experience a failure of bcg-therapy and consequently recurrence and/or progression. of course, the heterogeneity of the tumor does not facilitate a safe prognosis. risk tables for predicting recurrence and progression, based on the six most significant clinical and pathological factors, were developed by the european organization for 145archivio italiano di urologia e andrologia 2021; 93, 2 et-1 worsens prognosis in bladder cancer table 3. detailed results of the immunohistochemical (ihc) staining for group a regarding recurrence and progression. figure 3. the expression of et-1 in primary high-grade non-muscle-invasive urothelial bladder cancer (hgnmiubc) significantly associates with progression-free survival/pfs (ihc: immunohistochemical staining). figure 2. the expression of et-1 in primary high-grade non-muscle-invasive urothelial bladder cancer (hgnmiubc) significantly associates with recurrence-free survival/rfs (ihc: immunohistochemical staining). ihc grading of ihc group a p value 0 1 (mild) 2 (moderate) 3 (strong) rec rfs pr pfs et-1 1/1 (100%) 6/18 (33.3%) 14/15 (93.3%) 6/6 (100%) recurrence n = 27/40 (67.5%) 0.000 * 0.000 ^ et-1 0/1 (0%) 2/18 (11.1%) 7/15 (46.7%) 4/6 (66.7%) recurrence & progression n = 13/40 (32.5%) 0.000 * 0.000 ^ *: chi square-fisher’s exact test; ^: log rank test, statistical significance was set as p ≤ 0.05; rec: recurrence; pr: progression; rfs: recurrence-free survival; pfs: progression-free survival. archivio italiano di urologia e andrologia 2021; 93, 2 l. mitrakas, s. gravas, f. karasavvidou, i. zachos, a. karatzas, a. oeconomou, g. koukoulis, v. tzortzis, c. papandreou 146 research and treatment of cancer (eortc) and represent a means whose prognostic value was confirmed by data from other studies (7, 9). the eortc scoring system has not achieved a universal and unanimous acceptance though. one of the main reasons for this fact is that none of the included patients received maintenance therapy with bcg, which is currently recommended for all the high-risk patients (3). another prognostic model was proposed from the club urológico español de tratamiento oncológico (cueto). in this study, patients were stratified according to the risk of recurrence and progression, which also stratified a patient’s risk of recurrence after bcg plus interferon-a therapy (3). the maintenance scheme lasted for 5-6 months, which is considerably shorter than the actually recommended one by the eau (3). except for these two widespread prognostic tools, there are numerous studies, which propose different prognostic factors, including molecular ones, for categorizing patients in terms of clinical course and outcome (4). for example, cambier et al. studied a total of 1812 ta-t1 patients from eortc studies 30962 and 30911 (3). patients were allocated either to 3 years of maintenance bcg or 1 year of maintenance. the prior recurrence rate and the number of tumors were identified by multivariable analyses as statistically significant prognostic factors for recurrence (3). tumor stage and grade were found to be important for progression and death caused by bladder cancer (3). this study had also limitations (no patients with tis were included, routine repeat tur resection was not performed in high-risk patients, there was no central pathology review, upper urinary tract was not investigated upon recurrence or progression, no use of biomarker). furthermore, palou et al. documented that female gender and carcinoma in situ in the prostatic urethra are negative prognostic factors for recurrence (p = 0.0003, hr:2.53), progression (p = 0.001, hr: 359) and disease specific mortality (p = 0.004, hr: 3.53) in pt1g3 bladder cancer patients treated with bcg (10). another interesting study from gontero et al., showed that pt1g3 patients ≥ 70 years old with tumors ≥ 3 cm and concomitant carcinoma in situ should be handled aggressively because of the high risk of progression (11). recently, sahan et al. found in a retrospective cohort of pt1 bladder urothelial carcinoma patients treated postoperatively with intravesical bcg, for at least 1 year, that the tumor invasion to the muscularis mucosaevascular plexus significantly associates with recurrence (12). in closing, no molecule is turned to be a marker until today. the available data regarding the expression of et axis in bladder cancer does not give a clear end result. eltze et al. examined retrospectively the expression of the endothelin axis in 154 patients with primary bladder cancer (pta-pt2). they ascertain that both lack of et-1 and etar have a negative prognostic impact (13). moreover, an ihc study of 157 radical cystectomy samples demonstrated an overexpression of the entire et axis. a survival benefit (disease-free survival, overall survival) was established only for etbr (+) tumors (14). two experimental studies, in which ku-19-19 bladder cancer cells were implanted in mice, showed that the administration of atrasentan, a selective etar antagonist, lead to a diminished tumor-growth rate with an increased necrosis in the tumor tissue, no significant cytoreduction and increased etar expression, implying an escape mechanism to overcome the antiproliferative effect caused by targeting etar (15, 16). in another ihc retrospective study, et-1 and the microvessel density (mvd) seemed to be “good prognostic factors”, cause the et-1 overexpression was importantly associated with increased mvd and organ-confined disease (17). coming to an end, a prospective study of 2015, based on ihc, recorded that the overexpression of et-1 was remarkably correlated with an increased hazard ratio of progression and death (5). in this case, the included patients suffered from non-metastatic muscle-invasive bladder cancer. we found that the expression of et-1 indicates a higher risk for disease recurrence and progression. regarding the relative survival estimations (rfs, pfs), this higher risk remains documented. et-1 could make us alert, in order to recognize the patients with primary hgnmiubc who are at risk for a bad clinical outcome, taking into consideration that we can accurately identify patients who will not progress or die due to bladder cancer (ptag1), but we cannot reliably identify the ones who do progress and die of their disease (3). within this context, we could offer these patients a radical treatment early in the natural course of the disease, aiming to maximize the clinical benefit. finally, only the patient’s age, among all the rest studied parameters, correlates significantly with recurrence and rfs. so, the implementation of a strict follow up for the elderly patients with primary hgnmiubc is a reasonable decision. the prospective nature of our work is an important advantage. another quality which worths to be mentioned is that our patients are the most homogenous group compared to the included patients of the abovementioned researches (different stages, different types of carcinoma). they all are primary hgnmiubc patients treated postoperatively with intravesical bcg instillations (induction and 3-year maintenance). likewise, we study et-1 using ihc staining, which is the most common methodology in current literature. in our opinion, it is also positive the fact that we applied a central pathology review. on the other hand, it remains as a disadvantage the limited sample. regarding this point, we need to mention that there is no other similar study addressing the same issues, meaning a prospective study of a rather homogenous cohort. the standard of care in hgnmiubc does not achieve an ideal clinical result. the prognosis also remains problematic. taking into account, that a molecular marker could be helpful in this field, our study gives an evidence for the usefulness of et-1 in hgnmiubc as an alert marker for disease recurrence as well as progression. conclusions et-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant bcg instillations. furthermore, the patient’s age associates with an increased likelihood for recurrence. further studies are needed in order to clarify the potential role of 147archivio italiano di urologia e andrologia 2021; 93, 2 et-1 worsens prognosis in bladder cancer et-1 in the active molecular mechanism in bladder cancer and confirm or not our promising finding. acknowledgements the corresponding author has been awarded a supporting funding from the hellenic urological association (hua). references 1. sylvester rj, brausi ma, kirkels wj, et al. long-term efficacy results of eortc genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus calmette-guérin, and bacillus calmette-guérin plus isoniazid in patients with intermediateand high-risk stage ta t1 urothelial carcinoma of the bladder. eur urol. 2010; 57:766-773. 2. soloway m, khoury s. bladder cancer. 2nd edition: icud-eau 2012; 254-261. 3. cambier s, sylvester rj, collette l, et al. eortc nomograms and risk groups for predicting recurrence, progression, and diseasespecific and overall survival in non-muscle-invasive stage ta-t1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus calmette-guérin. eur urol. 2016; 69:60-9. 4. mitrakas l, gravas s, papandreou c, et al. primary high-grade non-muscle-invasive bladder cancer: high nf-b expression in tumor specimens distinguishes patients who are at risk for disease progression. pathol oncol res. 2019; 25:225-231. 5. mitrakas l, gravas s, karasavvidou f, et al. endothelin-1 overexpression: a potential biomarker of unfavorable prognosis in nonmetastatic muscle-invasive bladder cancer. tumour biol. 2015; 36:4699-705. erratum in: tumour biol. 2015; 36:3127 6. lamm dl, blumenstein ba, crissman jd, et al. maintenance bacillus calmette-guérin immunotherapy for recurrent ta, t1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized southwest oncology group study. j urol. 2000; 163:1124-1129. 7. babjuk m, böhle a, burger m, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017; 71:447-461. 8. zachos i, tzortzis v, mitrakas l, et al. tumor size and t stage correlate independently with recurrence and progression in high-risk non-muscle-invasive bladder cancer patients treated with adjuvant bcg. tumour biol. 2014; 35:4185-4189. 9. sylvester rj, van der meijden ap, oosterlinck w, et al. predicting recurrence and progression in individual patients with stage ta t1 bladder cancer using eortc risk tables: a combined analysis of 2596 patients from seven eortc trials. eur urol. 2006; 49:466-5. 10. palou j, sylvester rj, faba or, et al. female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in t1g3 bladder cancer patients treated with bacillus calmette-guérin. eur urol. 2012; 62:118-25. 11. gontero p, sylvester r, pisano f, et al. prognostic factors and risk groups in t1g3 non-muscle-invasive bladder cancer patients initially treated with bacillus calmette-guérin: results of a retrospective multicenter study of 2451 patients. eur urol. 2015; 67:74-82. 12. sahan a, gerin f, garayev a, et al. the impact of tumor invasion to muscularis mucosaevascular plexus on patient outcome in pt1 bladder urothelial carcinoma. arch ital urol androl. 2020; 92:239-243. 13. eltze e, wild pj, wülfing c, et al. expression of the endothelin axis in noninvasive and superficially invasive bladder cancer. relation to clinicopathologic and molecular prognostic parameters. eur urol. 2009; 56:837-847. 14. wülfing c, eltze e, yamini j, et al. expression of the endothelin axis in bladder cancer: relationship to clinicopathologic parameters and long-term survival. eur urol. 2005; 47:593-600. 15. wülfing c, tiemann a, persigehl t, et al. in vivo activity of abt627, a selective endothelin-a-receptor antagonist, in bladder cancer xenograft tumors. proc am soc cancer res. 2005; 46:abstract 3039. 16. herrmann e, tiemann a, eltze e, et al. endothelin-a-receptor antagonism with atrasentan exhibits limited activity on the ku-1919 bladder cancer cell line in a mouse model. j cancer res clin oncol. 2009; 135:1455-1462. 17. herrmann e, bögemann m, bierer s, et al. the role of the endothelin axis and microvessel density in bladder cancer correlation with tumor angiogenesis and clinical prognosis. oncol rep. 2007; 18:133-138. correspondence lampros mitrakas, md, phd (corresponding author) lamprosmit@gmail.com roosevelt 61, 41222 larissa (greece) stavros gravas, md, phd sgravas2002@yahoo.com ioannis zachos, md, phd johnbzac@yahoo.gr anastasios karatzas, md, phd adkaratzas@yahoo.gr athanasios oeconomou, md thaoik@hotmail.com vasilios tzortzis, md, phd tzorvas@otenet.gr department of urology, university hospital of larissa, 41110 larissa (greece) foteini karasavvidou, md, phd fotkarasa@yahoo.gr georgios koukoulis, md, phd kougeo@med.uth.gr department of pathology and cytology, university hospital of larissa, 41110 larissa (greece) christos papandreou, md, phd cpapandreou@auth.gr department of oncology, n.papageorgiou hospital of thessaloniki ring road of thessaloniki, 56 403 thessaloniki (greece) stesura seveso 137archivio italiano di urologia e andrologia 2019; 91, 2 case report a rare cause of clitoromegaly: epidermoid cyst selman karaci 1, deniz kulaksiz 2, cagri akin sekerci 3 1 trabzon kanuni research and training hospital, plastic & reconstructive surgery, trabzon, turkey; 2 trabzon kanuni research and training hospital, gynecology & obstetrics, trabzon, turkey; 3 trabzon kanuni research and training hospital, pediatric urology, trabzon, turkey. clitoromegaly due to non-hormonal causes is rare. in this case, we aimed to present an epidermal cyst that caused clitoromegaly after traditional female circumcision. a 22-year-old african female was referred to our clinic with enlarged clitoris. there is a mobile, soft, nonfluctuant mass with a size of 6 cm originating from the clitoral region at physical examination. under spinal anesthesia the clitoral mass was excised totally and labioplasty was performed. histopathologic examination was reported as epidermal cyst. epidermal cyst should be considered after hormonal reasons are excluded in patients with clitoromegaly who have a history of trauma. key words: clitoromegaly; epidermoid cyst; female circumcision. submitted 1 februart 2019; accepted 1 april 2019 summary no conflict of interest declared. within the normal range. bilateral ovaries and uterus were normal by pelvic ultrasonography. no structure for any male genital organ was observed. for this reason, disorders of sex development were excluded. it was reported as a massive cystic structure with no perfusion on pelvic magnetic resonance imaging. under spinal anesthesia the clitoral mass was excised totally and labiaplasty was performed. during surgery, glans and neurovascular bundle of the clitoris were not observed. it can be associated with previous female circumcision. there was no complication at the postoperative period. histopathologic examination was reported as a 5 x 3 x 2.5 cm epidermal cyst filled with keratinous material. discussion clitoral hypertrophy may be congenital or acquired. congenital forms are usually observed at birth and develop due to hormonal disorders. acquired forms can be divided into two forms, hormonal or non-hormonal. hormonal causes include hypertestosteronism, polycystic ovarian syndrome, virilizing tumors of the ovary or adrenal gland, and exogenous androgen exposure (2). non hormonal causes are more and are associated with neoplasms. epidermoid cyst is one of the rare causes of non-hormonal acquired clitoromegaly. the epidermoid cyst may be intradermal or subcutaneously localized and surrounded by the epidermis wall. epidermoid cyst is formed by keratinized squamous epithelium invagination into the dermis or subcutaneous tissue spontaneously or following trauma and filled with lamine keratin (3). epidermal cysts often occupy the vulva or labia major. clitoral epidermoid cyst can often be observed in african girls or women following trauma caused by genital mutilation (1). spontaneous development without trauma is rare (2). anderson-mueller et al. presented a 17year-old african-american girl with a painful clitoral mass. patient had no female circumcision or any genital trauma. after the endocrinological causes were excluded, the neurovascular bundle of clitoris was preserved and the mass was excised. pathology evaluation reported a benign squamous mucosa with submucosal edema, chronic inflammation, fibrosis, and mild vascular congestion (1). in our case, there was no trauma story and only traditional female circumcision for genital mutiliadoi: 10.4081/aiua.2019.2.137 introduction clitoromegaly often occurs with an increase in endogenous androgen release or by exogenous androgens in women. non-hormonal causes of clitoral hypertrophy is rare and usually present with benign neoplasms. fibroma, leiomyoma, angiokeratoma, pseudolymphoma, hemangioma, hemangiopericytoma, granular cell tumor and neurofibroma were reported as bening neoplasm causing clitoromegaly; carcinoma, endodermal sinus tumor, sarcoma, rhabdomyosarcoma, schwannoma, epithelioid hemangioendothelioma and lymphoma as malignant clitoral tumors (1). in this presentation, an asymptomatic clitoral mass due to epidermal cyst developed following female circumcision was reported. case report a 22-year-old african female was referred to our clinic with enlarged clitoris. the enlargement had been present since early adolescence period. she had a story of traditional female circumcision in early childhood. she had no systemic disease, hirsutism and obesity. she menses regularly every 28 days and secondary sex characteristics were normal. there was a mobile, soft, non-fluctuant mass with a size of 6 cm originating from the clitoral region in physical examination. luteinizing hormone, follicle stimulating hormone, serum prolactin, serum cortisol and 17-hydroxyprogesterone were all found archivio italiano di urologia e andrologia 2019; 91, 2 s. karaci, d. kulaksiz, c. akin sekerci 138 tion. glandular structure and neurovascular bundle were not observed during surgery, while the corporal bodies were seen as a stump. al-ojaimi et al. reported a 19-year-old female with a giant epidermoid cyst measuring 8 x 6 cm (4). in this case, redundant skin was excised after cyst removal. in cases with very large cysts, labiaplasty following excision may be required and we performed it in our case. clitoral enlargement during adolescence period is a very rare condition. endocrinological evaluation should be done after carefully physical examination of internal and external genital system. if necessary, adrenal gland imaging should be included. if non-hormonal causes are diagnosed after this evaluation, biopsy and/or complete resection may be performed (1). conclusions when clitoral hypertrophy is encountered, endocrinological causes should be ruled out in the first step. subsequent malignant or benign clitoral lesions should be considered. imaging methods can be applied in suspicious situations. during the surgical excision, the clitoris (vascularization and innervation) should be protected as much as possible. references 1. schmidt a, lang u, kiess w. epidermal cyst of the clitoris: a rare cause of clitoromrgaly. eur j obstet gynecol reprod biol. 1999; 87:163-5. 2. anderson-mueller be, laudenschlager md, hansen ka. epidermoid cyst of the clitoris: an unusual cause of clitoromegaly in a patient without history of previous female circumcision. j pediatr adolesc gynecol. 2009; 22:e130-2. 3. lee hs, joo kb, song ht, et al. relationship between sonographic and pathologic findings in epidermal inclusion cysts. j clin ultrasound. 2001; 29:374-83. 4. al-ojaimi eh, abdulla mm. giant epidermoid inclusion cyst of the clitoris mimicking clitoromegaly. j low genit tract dis. 2013; 17:58-60. figure 1. before and after surgery. figure 2. excised epidermoid cyst and its contents. correspondence selman karaci, md selmankaraci@gmail.com trabzon kanuni research and training hospital, plastic & reconstructive surgery, trabzon (turkey) deniz kulaksiz, md drdenizkulaksiz@hotmail.com trabzon kanuni research and training hospital, gynecology & obstetrics, trabzon (turkey) cagri akin sekerci, md, febu (corresponding author) cagri_sekerci@hotmail.com trabzon kanuni research and training hospital, pediatric urology, trabzon (turkey) stesura seveso 17archivio italiano di urologia e andrologia 2020; 92, 1 original paper hexaminolevulinate blue light cystoscopy (hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (nmibc): a retrospective analysis marco capece 1, lorenzo spirito 2, roberto la rocca 2, luigi napolitano 2, roberto buonopane 1, sergio di meo 1, maurizio sodo 2, umberto bracale 2, nicola longo 2, alessandro palmieri 2, ferdinando fusco 2, paolo verze 2, gianluigi califano 2, felice crocetto 2, ciro imbimbo 2, vincenzo mirone 2, vittorio imperatore 2, massimiliano creta 2 1 madonna del buon consiglio, “fatebenefratelli” hospital, naples; 2 università degli studi di napoli “federico ii”, naples. background: bladder cancer is the eleventh most commonly diagnosed cancer worldwide. the recurrence rate of this cancer can be very high, up to 45%. photodynamic diagnosis (pdd) is more sensitive than standard procedures for the detection of malignant tumours. the aim of the study was to evaluate oncological outcomes in white light turb (wl-turb) and hexaminolevuninate blue light turb (hal-turb). patients and methods: this was a retrospective longitudinal single-center study. in the period between january 2016 and october 2016 wl-turb was the only therapeutic option available. from november 2016 until april 2017 all turbs were fluorescence-guided (hal-turb). kaplan-meier curves have been used to estimate recurrence free survival rates. results: one hundred and eleven patients underwent halturb and 137 underwent wl-turb. recurrence rate after 12 months was 19.8% (22 out of 111 patients) and 37.2% (51 out of 137 patients) in hal-group and wl-group respectively (p < 0.01). the recurrence-free period was longer in hal-group rather than wl-group (8.9 months vs 7.3 months, p < 0.05). moreover, the recurrence rate during the first 6 months was 3.7% in patients who underwent hal-turb and 16% in those who received wl-turb (p < 0.01). conclusion: the results of the study show that recurrence-free survival was longer in patients undergoing hal-turb compared to the patients who received standard wl-turb. key words: bladder cancer; hexaminolevulinate; turb; pdd; fluorescence cystoscopy. submitted 3 june 2019; accepted 19 july 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.17 introduction bladder cancer is the eleventh most commonly diagnosed cancer worldwide, with the highest incidence among men (1). the recurrence rate of this cancer at the first follow-up evaluation can be very high, up to 45% in patients with multiple tumours at the first diagnosis (2). many studies suggest that early second transurethral resection of bladder tumor (re-turb) improves staging and reduces the recurrence as well as progression rates in high-risk bladder cancer patients (3). in fact, considering the stochastic nature of the technique, a re-turb performed 2-6 weeks after the first turb may find residual tumour in up to 76% of patients (4). one of the reasons for the high recurrence risk of non-muscle invasive bladder cancer (nmibc) is likely to be the persistence of residual lesions following initial turb (5). a key goal in the treatment of nmibc is the successful identification and removal of cancerous tumors to prevent either recurrence and progression of the disease in order to improve cancer-free and overall survival. photodynamic diagnosis (pdd) is performed using violet light after intravesical instillation of 5-aminolaevulinic acid (ala) or hexaminolaevulinic acid (hal). it has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for the detection of malignant tumours, particularly for cis (6). moreover hexaminolevulinate-induced fluorescence cystoscopy, by improving the detection of bladder cancer, leads to a more complete resection and significantly better disease-free survival (7). the aim of our study was to analyze the use of hexaminolaevulinate (hal: hexvix®, photocure, norway) during turb in naïve patients and compare it to white light turb (wl-turb) in terms of recurrence rate within 12 months after turb. patients and methods this is a retrospective longitudinal single-center study. naïve patients with a suspicion of ta/t1 bladder tumour had been recruited from the urology outpatient clinic. the suspicion of bladder tumour had been based on positive urine cytology and flexible cystoscopy performed in the outpatient department by two qualified urologists. exclusion criteria were previous diagnosis of bladder or upper urinary tract cancer, history of chronic specific or capece la rocca_stesura seveso 02/04/20 20:18 pagina 17 archivio italiano di urologia e andrologia 2020; 92, 1 m. capece, l. spirito, r. la rocca, et al. 18 aspecific bladder cystitis, known allergy to hal, presence of porphyria. in the period between january 2016 and october 2016 wl-turb was the only therapeutic option available. from november 2016 until march 2017 all turbs were fluorescence-guided (hal-turb). the hal solution was instilled into the bladder by a nelaton catheter and was to be retained for at least 1 h. blue light induction was obtained with d-light c system by karl storz. at a first instance bladder inspection had been carried out under white light source, and the turb had been performed under white light. subsequently the bladder had been inspected under blue light to identify residual neoplastic tissue at the resection sites or additional tumours that had been missed during white light inspection. wl turb was performed using 1588 aim camera system (stryker, san jose, ca) instead. none of the patients received one-shot chemotherapy after turb. the histopathological evaluation and staging were performed in accordance with the tnm 2009 classification. patients were treated and followed-up according to the european association of urology guidelines (6). all patients received the first cystoscopy at three months. if negative, the cystoscopy was repeated every 3 months in high-risk and intermediate-risk patients, while in low-risk patients it was repeated 9 months after. a recurrence was defined as macroscopic tumour with the histopathological confirmation. adverse events were recorded at each follow-up visit. all data have been recorded and analyzed with spss v. 25 (ibm corp., armonk, ny, usa). recurrence free survival rates were estimated according to the kaplan-meier method, and differences were compared by a log-rank test. results the number of patients who underwent hal-turb for a suspicion of bladder cancer was 111, whilst 137 patients underwent wl-turb. only 17 patients were lost at follow-up and were not included in statistical analysis (11 in hal-turb group and 6 in wl-turb group). all turbs were performed by 2 experienced surgeons. demographical and clinical characteristics of the two populations were summarized in table 1. the populations were homogeneous. mean age was 61.7 years (range 39-91) and 60.7 (range 39-81) in hal-turb group and wl-turb group respectively (p = 0.463). of 248 patients with suspicion of bladder cancer 197 had a urothelial carcinoma, 14 concomitant cis and urothelial carcinoma, 9 only cis, 18 other tumors and 10 had no tumor (table 2). only ten patients were diagnosed with t2 or more invasive disease, however 38 patients underwent a cystectomy. no significant differences were found among the populations of the two groups in terms of table 1. demographical and clinical characteristics. p age hal-turb (mean) 111 61.68 0.463 wl-turb (mean) 137 60.7 lesion size (cm) hal-turb (mean) 111 2.194 0.122 wl-turb (mean) 137 1.996 sex men hal-turb (n) 76 45.20% 0.826 wl-turb (n) 92 54.80% women hal-turb (n) 35 43.80% wl-turb (n) 45 56.30% smokers hal-turb (n) 72 29.80% 0.124 wl-turb (n) 106 43.80% positive cytology hal-turb (n) 19 7.70% 0.817 wl-turb (n) 25 10.10% positive ultrasound hal-turb (n) 95 38.30% 0.108 wl-turb (n) 126 50.80% positive cystoscopy hal-turb (n) 99 39.90% 0.233 wl-turb (n) 128 51.60% table 2. hystology of the patients. type of turb hal-turb wl-turb total hystology urothelial count 80 117 197 carcinoma % in hystology 40.6% 59.4% 100.0% % in type of turb 72.1% 85.4% 79.4% other tumours count 11 7 18 % in hystology 61.1% 38.9% 100.0% % in type of turb 9.9% 5.1% 7.3% cis count 5 4 9 % in hystology 55.6% 44.4% 100.0% % in type of turb 4.5% 2.9% 3.6% urothelial carcinoma count 9 5 14 + cis % in hystology 64.3% 35.7% 100.0% % in type of turb 8.1% 3.6% 5.6% no cancer count 6 4 10 % in hystology 60.0% 40.0% 100.0% % in type of turb 5.4% 2.9% 4.0% total count 111 137 248 % in hystology 44.8% 55.2% 100.0% % in type of turb 100.0% 100.0% 100.0% table 3. chemotherapy/immunotherapy after turb. type of turb hal-turb wl-turb total chemotherapy/ immunotherapy after turb mmc count 38 64 102 % in chemotherapy/ immunotherapy after turb 37.3% 62.7% 100.0% % in type of turb 55.9% 66.7% 62.2% bcg count 30 32 62 % in chemotherapy/ immunotherapy after turb 48.4% 51.6% 100.0% % in type of turb 44.1% 33.3% 37.8% total count 68 96 164 % in chemotherapy/ immunotherapy after turb 41.5% 58.5% 100.0% % in type of turb 100.0% 100.0% 100.0% capece la rocca_stesura seveso 02/04/20 20:18 pagina 18 patients’ characteristics, smoking habits, lesion size. furthermore, no difference was detected between the percentages of patients undergoing chemotherapy or immunotherapy after turb (table 3). none of the patients received one-shot chemotherapy after turb. recurrence rate after 12 months was 19.8% (22 out of 111 patients) and 37.2% (51 out of 137 patients) in hal-group and wl-group respectively (p < 0.01) (figure 1). the recurrence-free period was longer in hal-group rather than wl-group (8.9 months vs 7.3 months, p < 0.05). in addition to that, recurrence rate during the first 6 months was 3.7% in patients who underwent hal-turb and 16% in those who received wl-turb (p < 0.01). no adverse events after the administration of hal were recorded in the group who received the instillation. discussion nowadays the use of hexvix on naïve patients with bladder cancer suspicion is not advisable according to eau guidelines (6). a german multicenter study has confirmed that in patients undergoing turb the use of hal has improved by 6.8% the detection of cancerous lesions in comparison to the standard wl-turb (8). in addition to that, a recent meta-analysis has confirmed the effectiuveness of hal-turb in reducing recurrence rate, however further studies have been claimed to reach a change in the clinical management of the disease (9). as shown in the literature it is also possible to evaluate a risk model for prediction of bladder cancer recurrence (10). in another systematic review and meta-analysis the rate of cancerous progression was significantly lower in patients treated with halvs. wlbased turb (11). at the present time there are no long-term results on disease progression and overall survival, however it is desirable that these variables will decrease. meanwhile the use of hal-turb leads to a reduction of further hospitalizations which in turn reduces hospital costs (12). in our study we compared data of two different approaches to naïve patients with suspicion of bladder cancer. our results show that recurrence-free period was longer in patients undergoing hal-turb rather than patients who received the standard wl-turb. interestingly the recurrence rate during the first 6 months was hugely reduced in hal-group than in wl-group (3.6% vs 16% respectively). a reasonable explanation might be better bladder cancer visualization which results in a more precise and complete initial resection. therefore in our study we lay the foundation for a future stratification of the risk based on the use of violet light after intravesical instillation of 5-aminolaevulinic acid during the initial turb. the future goal will be the preoperative identification of a sub-group of patients who can benefit from the halturb at the first resection. clinical practice points many studies have pointed the benefit of performing fluorescence-guided turb in terms of recurrence rate and progression rate. in our study we have demonstrated that in patients undergoing hal-turb the recurrence free survival was dramatically reduced in the first 6 months. this might be helpful in the search of pre-operative selection of the patients who will definitely benefit from this treatment. references 1. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan2012. int j cancer. 2015; 136:e359-86. 2. witjes ja, kiemeney la, oosterhof go, debruyne fm. prognostic factors in superficial bladder cancer. a review. eur urol. 1992; 21:89-97. 3. dobruchj, borówka a, herr hw. clinical value of transurethral second resection of bladder tumor: systematic review. urology. 2014; 84:881-5. 4. creta m, mirone v, di meo s, et al. endoscopic spatulation of the intramural ureter: a technique to prevent stenosis of the ureterovesical junction in patients undergoing resection of the ureteral orifice. j endourol. 2016; 30:913-7. 19archivio italiano di urologia e andrologia 2020; 92, 1 hexaminolevulinate blue light cystoscopy (hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection... figure 1. kaplan-meier curves on rfs. capece la rocca_stesura seveso 02/04/20 20:18 pagina 19 archivio italiano di urologia e andrologia 2020; 92, 1 m. capece, l. spirito, r. la rocca, et al. 20 5. witjes ja, babjuk m, gontero p, et al. clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: evidence review and updated expert recommendations. eur urol. 2014; 66:863-71. 6. babjuk m, burger m, compérat e, et al. non-muscle invasive bladder cancer. european association of urology guidelines 2019. 7. stenzl a, burger m, fradet y, et al. hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. j urol. 2010; 184:1907-13. 8. bach t, bastian pj, blana a, et al. optimised photodynamic diagnosis for transurethral resection of the bladder (turb) in german clinical practice: results of the noninterventional study optic iii. world j urol. 2017; 35:737-744. 9. lee jy, cho ks, kang dh, et al. a network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. bmc cancer. 2015; 15:566. 10. vartolomei md, ferro m, cantiello f, et al. validation of neutrophil-to-lymphocyte ratio in a multi-institutional cohort of patients with t1g3 non–muscle-invasive bladder cancer. clin genitourin cancer. 2018; 16:445-452. 11. gakis g, fahmy o. systematic review and meta-analysis on the impact of hexaminolevulinate versus white-light guided transurethral bladder tumor resection on progression in non-muscle invasive bladder cancer. bladder cancer. 2016; 2:293-300. 12. klaassen z, li k, kassouf w, et al. contemporary cost-consequence analysis of blue light cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. can urol assoc j. 2017; 11:173-181. correspondence marco capece, md drmarcocapece@gmail.com roberto buonopane, md robertobuonopane@libero.it sergio di meo, md sedime72@yahoo.com madonna del buon consiglio, “fatebenefratelli” hospital, naples lorenzo spirito lorenzospirito@msn.com roberto la rocca, md robertolarocca87@gmail.com luigi napolitano, md nluigi89@libero.it maurizio sodo, md maurizio.sodo@unina.it umberto bracale, md umberto.bracale@unina.it nicola longo, md nicolalongo20@yahoo.it alessandro palmieri, md info@alessandropalmieri.it ferdinando fusco, md ferdinando.fusco2@libero.it paolo verze, md pverze@gmail.com gianluigi califano, md gianl.califano2@gmail.com felice crocetto , md felice.crocetto@gmail.com ciro imbimbo, md cimbimbo@unina.it vincenzo mirone, md mirone@unina.it vittorio imperatore, md v.imperatore1@gmail.com massimiliano creta, md max.creta@gmail.com università degli studi di napoli “federico ii”, naples capece la rocca_stesura seveso 02/04/20 20:18 pagina 20 stesura seveso archivio italiano di urologia e andrologia 2018; 90, 120 original paper semirigid ureteroscopy prior retrograde intrarenal surgery (rirs) helps to select the right ureteral access sheath ioannis boulalas, mauro de dominicis, lorenzo defidio department of urology, cristo re hospital, rome; italy. objective: to evaluate ureteral compliance through semirigid ureteroscopy (surs) in order to select the proper ureteral access sheath (uas) size for retrograde intrarenal surgery (rirs). patients and methods: in a prospective study, 100 consecutive patients selected for elective surs or rirs were recruited. each patient, initially underwent 9.5 fr surs with a safety guidewire 3fr, in order to estimate ureteral compliance. if the ureter was compliant, a gently passage of a 12/14fr uas was attempted. if the ureter was not deemed compliant, passage of either a smaller uas or a smaller semirigid 7fr or a flexible 7.5fr or a digital 8.5fr scope with and without safety guidewire, was attempted. age, gender, disease location, prestenting, previous rirs and/or stone elimination, hydronephrosis, ureteral strictures, unsuccessful procedures, and complications, were analyzed as possible correlated factors of ureteral compliance. results: in 77 patients the ureter was deemed compliant ≥ 14fr. of the preoperative factors that were examined, stent placement before rirs (p < 0.002), previous rirs (p = 0.000) and previous stone elimination (p = 0.004), correlated with ureter ≥ 14fr. ureteral lithiasis (p < 0.001), ureteral strictures (p < 0.05), unsuccessful procedures (p < 0.005) and complications (p = 0.01) correlated with ureter < 14fr. the complication rate was 10% (10 patients) with ureteral injuries grade i in 9 patients and grade iii in 1 patient according to the endoscopic grading system. age, gender, hydronephrosis and urothelial carcinoma (uc) had no influence. conclusions: surs performed before rirs allows selection of the right ureteral access sheath (uas) and avoidance of major complications. pre-stenting, previous rirs and stone elimination history are all factors correlating with a compliant ureter. key words: semirigid ureteroscopy; retrograde intrarenal surgery (rirs); ureteral compliance; ureteral access sheath (uas). submitted 8 november 2017; 19 november 2017 summary no conflict of interest declared. nowadays, retrograde intrarenal surgery (rirs) (2, 3) is used in the treatment of urinary lithiasis (4), upper tract urinary tumors (5, 6), as well as in special circumstances such as pregnancy, anatomic malformations, coagulopathy or solitary kidney (7, 8). urinary stones disease poses a significant health care burden in a working-age population. a recent analysis of national health and nutrition examination survey (nhanes) data in the united states from 2007 to 2010 reported that the prevalence had increased to 8.8% (10.6% among men vs 7.1% among women), compared with 5.5% in nhanes iii (1988-1994) (9). upper tract urothelial carcinoma (utuc) constitutes approximately 5-6% of all urothelial malignancies. ureteral tumors represent approximately 25% of utucs (10). in 2013, the european association of urology (eau) for the first time included rirs as a viable treatment option for renal stones, even larger than 2 cm in diameter (11). moreover, the utuc eau guidelines support renal-sparing surgery in imperative cases and low-risk patients (12). the ureteral access sheath (uas) was introduced as a means of passing a flexible uretero-renoscope into the distal ureter. its use also facilitates multiple re-entries into the kidney, improves fluid outflow, thereby reducing the intrarenal pressure, decreases operative time, increases stone clearance, and protects the endoscope from damage (13, 14). however the routine use of a uas is matter of debate (11). limited data is available to predict which patients selected for rirs may have a difficult ureter and in which cases success is most probable. the hypothesis that endoscopic evaluation of ureteral size may help urologists to select the proper uas size for rirs, was prospectively tested and possible correlating factors for success or failure were analyzed. patients and methods this study was carried out at ‘cristo re’ hospital in rome, after institutional review board approval was obtained, by two experienced urologists, who treated a similar number of patients. both surgeons were present during the procedures, thus avoiding any difference in the assessment accuracy. a total of 100 consecutive patients (72 males and 28 females) between march 2016 and september 2016, with urinary lithiasis, upper urinary tract tumors, hematuria and ureteral stenosis planned for elective semidoi: 10.4081/aiua.2018.1.20 introduction the management of intra-renal collecting system pathology has changed radically over the recent decades mainly due to increasing use of flexible uretero-renoscopy (furs), constituting one of the most dynamic fields of endourology. thanks to technologic improvements in the endoscopic armamentarium, flexible uretero-renoscopic approaches to the kidney have evolved from a mere diagnostic tool, to a complex diagnostic and therapeutic procedure in the entire upper tract collecting system (1). 21archivio italiano di urologia e andrologia 2018; 90, 1 semirigid ureteroscopy prior rirs rigid ureterorenoscopy or rirs were included in the study. all patients had a clinical evaluation, urine dipstix analysis with additional culture and sensitivity if a urinary tract infection (uti) was suspected, a measurement of serum creatinine level, abdominal ultrasonography (us) and a plain abdominal xray. additional computed tomography (ct) was used, according to the level of serum creatinine and stone radiolucency. patients were placed in the lithotomy position and received prophylactic parenteral antibiotics before the procedure, which was performed under spinal or general anesthesia. the standard technique was initiated with rigid cystoscopy, followed by ureteral catheterization of the renal unit in question with an end-hole 5fr catheter (pollack cook urological, spencer, in). a retrograde pyelogram was performed to define the anatomy and visualize any filling defect. a hydrophilic tipped guidewire 0.035/150 cm (sensor®, boston scientific, marlborough, ma, usa) was passed via the ureteral catheter, just to the renal pelvis under fluoroscopic guidance, and set aside as a safety wire, and then the cystoscope and the retrograde catheter were removed. a second hydrophilic tipped guidewire was introduced into the ureteral orifice through the 9.5fr storz semirigid ureteroscope’s (27002l karl storz, rietheim-weilheim, germany) working channel that allowed retrograde ureteral access with relative ease. a gentle attempt was made for ureteroscopic access between these two guidewires. this maneuver allowed the optical ureteral dilation, permitting an easier upper tract access as well as inspection for the presence of pathology such as stones, strictures, or tumors, offering the possibility of treatment along all the ureter and, often, also in the kidney. at the same time, ureteral compliance and caliber were assessed in order to select the proper uas size, avoiding ureteral injuries. the ureteroscope was withdraw and the uas 12\14 fr 35 cm (flexor, cook urological, spencer, in) was introduced gently into the ureter under fluoroscopic control, by gliding over the working guidewire. in patients with ureteral stent, a ptfe guidewire 0.035/145 cm (cook urological, spencer, in) was inserted and advanced to the kidney through the distal end of the stent which had been brought to the urethral meatus. finally the inner uas obturator with the guidewire was removed and the 7fr\43 cm storz semirigid, or flexible or digital ureteroscope (27000l, flex-x2 or, flexxc karl storz, rietheim-weilheim, germany) was inserted to complete the operation with a holmium or thulium iaser device (15). we selected 12\14fr as the best uas size because it can accept all the flexible and some semirigid ureteroscopes, while maintaining a good drainage in order to keep low intrarenal pressures. in difficult cases, when the ureter didn’t accept the larger uas, first we tried to remove the safety guide wire with the purpose to get more room. if still the passage of the larger uas was not easy, we used a smaller uas (11\13fr flexor, cook urological, spencer, in). if this attempt was also without success, we then tried to introduce the flexible or digital scope, with or without the safety guidewire, under visual or fluoroscopic control. if again this attempt was encountered with resistance, we stopped the procedure, put a dj stent and tried the week after. if the patient was not planned for rirs, but presented with an impacted ureteral stone with hydronephrosis, we still inserted an access sheath just below the stone and we performed a lasertripsy of the stone with a semirigid scope 9.5fr inside the access sheath with a safety guidewire 3fr aside, in order to have a continuous flow with gravity irrigation and still low retro-pulsion pressures and expulsion of fragments retrieval through the sheath. the primary outcome was the assessment of the ureteral compliance to identify a potential difficult ureter. a compliant ureter was defined as a ureter ≥ 14fr if accepted easily the passage of a semirigid scope 9.5fr with a safety guidewire 3fr aside. patient’s data collected, included age, gender, side, hydronephrosis, stone location (renal, ureteral, renal & ureteral), utuc, presence of ureteral strictures, an indwelling ureteral stent, previous rirs, and previous stone elimination history. statistical analyses the significance of possible factors affecting ureteral compliance was analyzed. statistical analysis was performed with spss 20 adopting the chi-square test for nominal variables and the mann-whitney u test for continuous variables. statistical significance was considered at p < 0.05. results the study group included 100 consecutive patients that were treated at ‘cristo re’ hospital in rome. patient’s data are presented in table 1. 82% and 18% of the patients were submitted to rirs and surs respectively, with or without use of uas. hydronephrosis was present in 56% of the patients while in 29% a dj stent was inserted before (24 patients) and during surgery (5 patients) due to acute obstruction, insistent pain, fever, pus, ureteral injury, ureteral stricture and non compliant ureter. a compliant ureter with a diameter ≥ 14fr was present in 77 patients because a 12/14fr uas was inserted gently with or without a safety guidewire, either a 9.5fr semirigid ureteroscope with a safety guidewire was used (objective evaluation). in 23 patients, the ureter was non table 1. patient demographics. patient, n 100 mean age years (range) 54 (16-89) men 72 women 28 ureteral stone 18 renal stone 45 ureteral & renal stone 12 utuc, hematuria 22 ureteral stricture 23 side right/left 51/49 hydronephrosis (%) 56 indwelling double-j stent, n(%) 29 previous rirs, n(%) 29 previous stone elimination, n(%) 42 archivio italiano di urologia e andrologia 2018; 90, 1 i. boulalas, m. de dominicis, l. defidio 22 compliant with a diameter < 14fr due to insertion of either a 11/13fr uas after removal of the safety guidewire, or of a 7fr semirigid or flexible or digital ureteroscope with or without safety guidewire (table 2). in 7 patients, we had to stop the procedure and a dj stent or nephrostomy tube was introduced. complications were noted in 10 patients. guidewire-induced ureteral damage occurred in 8 patients with grade i lesions, while uasinduced ureteral injuries occurred in 2 patients with grade i lesion in one case and grade iii in the other according to the endoscopic grading system (16) (table 3). different factors that may influence the ureteral compliance were examined. the following parameters correlated statistically with a ureter ≤ 14f: ureteral lithiasis, ureteral stricture, unsuccessful procedures and complications (table 4). discussion over the last decade the advancements in technology and digital optics have led to an increasing role of furs in the treatment of upper urinary tract pathology. a ureteral access sheath is an important tool during rirs, because it lowers intra-renal pressure, facilitates ureteral re-entry, decreases costs, reduces operative time, and improves flexible uretero-renoscope longevity (17). there are different uas’s in the market with different characteristics, sizes and lengths. factors that are important in clinical application include a lubricated outer coating to facilitate entry, a lower friction inner coating for easy uretero-renoscope insertion, and a reinforced wall to decrease sheath kinking and bulking (18). the standard uas has an external diameter of 14fr, which is larger than the median 9fr to 10fr diameter of non stented ureters, as evaluated on imaging studies (19). insertion of a uas depends on the ureter status and on its anatomic variants. failure rates of primary access due to difficult impassable ureter range from 8%-10% (20, 21). lallas et al. in animal models showed that the over distention created by the uas caused a transient decrease in ureteral blood flow which restored at a basal level by the compensatory mechanisms of the ureteral wall and the integrity of the ureter was preserved. however, care must be taken for selecting an appropriate-size sheath and the duration of surgery should not be long because the risk of stricture development has not been clearly put forward (22). viers et al. examined the association between clinic-radiographic features and need for pre-stenting due to inability of the ureter to accommodate the ureteroscope or the uas, and found 17% incidence of primary upper tract access failure. prior ipsilateral ureteral surgery and stenting were protective whereas < 50% ureteral opacification was associated with an increased risk of access failure (23). some authors position the uas under fluoroscopic guidance with the application of reasonable strength on the working guidewire without the performance of semi-rigid ureteroscopy (23) whereas others calibrate the ureter with an 8f/10f coaxial dilator (boston scientific) (24). additional strategies, that are used to go into the ureter, include routine stent placement before rirs which entails two-stage procedure, sequential ureteral dilators or balloon dilation with significant risk of ureteral injury (25). in a prospective study in 248 patients undergoing surs and furs mogilevkin et al. found that in 22% of patients the uas was not easily passed. factors of successful insertion were: older age, presenting and previous same-side ureteroscopy (25). traxer and thomas, in a two center prospective review, collected data on 359 patients who received a 12/14fr uas before a rirs for renal stones. the authors identified and classified any ureteral injuries. uas-induced ureteral lesions occurred in 46.5% of patients, with complete wall perforation in 13.4%. table 4. parameters of compliant ureter. compliant ≥ 14fr non compliant < 14fr p-value 77 pts 23 pts age 57.6 52.1 0.1 sex (males) 53 (69%) 19 (83%) 0.4 ureteral lithiasis 13 (17%) 14 (61%) < 0.001 pre-stenting 28 (36%) 1 (4%) < 0.002 hydronephrosis 39 (51%) 17 (74%) 0.1 first time rirs 47 (61%) 15 (65&) 1 previous rirs 26 (34%) 3 (13%) 0.000 number of patients with 22 (28%) 4 (17%) 0.6 renal stones ≤ 1.5 cm (%) number of patients with 2 (2.6%) 2 (8.6%) 1 ureteral stones ≤ 1 cm (%) utuc 18 (23%) 4 (17%) 0.5 ureteral stricture 1 (1.3%) 22 (95%) < 0.05 previous stone elimination 29 (38%) 11 (49%) 0.004 unsuccessful procedures 0 7 (30%) < 0.005 complications 5 (6.5%) 5 (21%) < 0.01 table 3. complications. patient 10 patients, grade guidewire 8 8 grade i uas 2 1 grade i 1 grade iii table 2. results of ureteral calibration. patients ureter diameter 77 ≥ 14fr gently passage of a 12/14fr uas with or without a safety guidewire 73 ≥ 14fr gently passage of a 9.5 semirigid ureteroscope with a safety guidewire 4 ≥ 14fr patients ureter diameter 23 < 14fr gently passage of a 11/13f uas after removal of the safety guidewire 1 < 14fr gently passage of a 7fr semirigid, flexible or or digital uretero-renoscope with or without a safety guidewire 22 < 14fr 23archivio italiano di urologia e andrologia 2018; 90, 1 semirigid ureteroscopy prior rirs the authors conclude that is imperative to visualize the ureter at the end of the procedure and that pre-stenting can reduce the risk of severe injury to the ureter. risk factors for high grade lesions included age, male gender, and lack of preoperative stent (26). however, in another work on 2239 patients treated with furs from the clinical research office of the endourological society (croes), traxer et al. reported that uas usage did not increase the risk of ureteral wall damage (27). guzelburc et al. in a prospective study investigated ureteral injuries by placing two different uas (9.5/11.5fr-12/14fr) during retrograde intrarenal surgery (rirs) for renal stones. the researchers identified 41,6% ureteral lesions, with deep tear of the mucosal and submucosal layer in 2.97% (puls grade 2) of patients and no injuries of grade 3+. puls grade 2 patients were all males and a dj stent was placed preoperatively in all cases (28, 29). yet, there have been few studies demonstrating significant long-term ureteral damage following the use of a uas. in the past, one ureteropelvic junction stricture (1.4%) was noted to occur during a mean follow-up of 11 months after uas use (30). in our study 77% of the patients had a compliant ureter ≥ 14fr, and 23 a not compliant ureter < 14fr. age, sex, stone size, hydronephrosis, or utuc had no influence on ureteral compliance in this analysis. patients with an indwelling dj stent, previous rirs history and previous stone elimination accommodated easily a 12/14fr uas. the presence of ureteral stone adversely affected compliance due to acute or chronic inflammation. the ureteral stricture caused by impacted stones, recurrences, or conservative treatment of utuc’s were also consistent with a non compliant ureter < 14fr. finally the unsuccessful procedures and the complications were correlated with a not compliant ureter. the overall low incidence of unsuccessful procedures (7%) is due to the adoption of some tricks before interrupting the procedure, such as the removal of safety guidewire or the use of a smaller uas or ureteroscope. only in 8 patients complications were caused by the guidewire and only in 2 by the uas, of which only one had a grade 3 lesion. the low complications rate (10%), most of them of grade i, is probably due to the respect of the two fundamental endourological rules: the first one is to adapt the instrument\device to the ureter and not the ureter to the instrument, and the second one is to never force in the introduction or extraction of instrument or device. in the current study the importance of our technique to perform surs prior to uas insertion during rirs is demonstrated, as it permits ureteral inspection and allows assessment of ureteral compliance. those with a low likelihood for effective 12/14fr uas include patients with ureteral stricture and ureteral stone. however, this study presents some limitations due to the small number of patients. probably the data can be different in a larger cohort of patients. also, we didn’t have a follow-up of patients to report possible postoperative complications. conclusions semirigid ureteroscopy performed prior retrograde intrarenal surgery (rirs) is an outstanding tool for evaluation of ureteral compliance, allowing selection of the correct uas size. a compliant ureter ≥ 14fr was found in 3/4 of the patients. parameters of successful insertion of a 12/14fr uas were an indwelling dj stent, and a history of previous rirs or stone elimination while the presence of a ureteral stone or stricture, unsuccessful procedures and complications significantly predicted a non compliant ureter < 14fr. references 1. oberlin dt, flum as, bachrach l, et al. contemporary surgical trends in the management of upper tract calculi. j urol. 2015; 193:880. 2. patel a, fuchs gj. expanding the horizons of swl through adjunctive use of retrograde intrarenal surgery: new techniques and indications. j endourol. 1997; 11:33. 3. shin r, lipkin m, preminger g. disposable devices for rirs: where do we stand in 2013? what do we need in the future? world j urol. 2015; 33:241. 4. ordon m, urbach d, mamdani m, et al. the surgical management of kidney stone disease: a population based time series analysis. j urol. 2014; 192:1450. 5. cornu jn, rouprêt m, carpentier x, et al. oncological control obtained after exclusive flexible ureteroscopic management of upper urinary tract urothelial carcinoma. world j urol. 2010; 28:151. 6. cutress ml, stewart gd, wells-cole s, et al. long-term endoscopic management of upper tract uothelial carcinoma (utuc): 20years single-centre experience. bju int. 2012; 110:1608. 7. giusti g, proietti s, cindolo l, et al. sky is not the limit for ureteroscopy: extending the indications and special circumstances world j urol. 2015; 33:257. 8. giusti g, proietti s, cindolo l, et al. is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? world j urol. 2015; 33:309. 9. shoag j, tasian ge, goldfarb ds, et al. the new epidemiology of nephrolithiasis. adv chronic kid dis. 2015; 22:273. 10. bader mj, sroka r, gratzke c, et al. laser therapy for upper urinary tract transitional cell carcinoma: indications and management. eur urol. 2009; 56:65. 11. türk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475. 12. rouprêt m, babjuk m, compérat e, et al. european association of urology guidelines on upper urinary tract urothelial cell carcinoma. update eur urol. 2015; 68:868. 13. stern jm, yiee j, park s. safety and efficacy of ureteral access sheaths. j endourol. 2007; 21:119. 14. bach c, nesar s, kumar p, et al. the new digital flexible ureteroscopes: ‘size does matter’increased ureteric access sheath use. urol int. 2012; 89:408. 15. defidio l, de dominicis m, gianfrancesco d, et al. first collaborative experience with thulium laser ablation of localized upper urinary tract urothelial tumors using retrograde intra-renal surgery arch ital urol androl. 2011; 83:147. 16. karakan t, kilinc mf, demirbas a, et al. evaluating ureteral archivio italiano di urologia e andrologia 2018; 90, 1 i. boulalas, m. de dominicis, l. defidio 24 wall injuries with endoscopic grading system and analysis of the predisposing factors. j endourol. 2016; 30:375. 17. defidio l, de dominicis m, di gianfrancesco l, et al. improving flexible ureterorenoscope durability up to 100 procedures. j endourol. 2012; 26:1329. 18. khanna r and monga m. instrumentation in endourology. ther adv urol. 2011; 3:119. 19. zelenko n, coll d, rosenfeld at, et al. normal ureter size on unenhanced helical. ct ajr. 2004; 182:1039. 20. cetti rj, biers s, kcoghane sr. the difficult ureter: what is the incidence of presenting? ann r coll surg engl. 2011; 93:31. 21. bourdoumis a, tanabalan c, goyal a, et al. stent and come back or balloon dilate and proceed with ureteroscopy? what does the evidence say? urology. 2014; 83:1. 22. lallas c, auge b, raj g, et al. laser doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement j endourol. 2002; 16:583. 23. viers b, viers l, hull n, et al. the difficult ureter: clinical and radiographic characteristics associated with upper urinary tract access at the time of ureteroscopic stone treatment. urology. 2015; 86:878. 24. goldberg h, holland r, tal r, et al. the impact of retrograde intrarenal surgery for asymptomatic renal stones in patients undergoing ureteroscopy for a symptomatic ureteral stone j endourol 2013; 27: 970. 25. mogilevkin y, sofer m, margel d, et al. predicting an effective ureteral access sheath insertion: a bicenter prospective study. j endourol. 2014; 28:1414. 26. traxer o. and thomas a.prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580. 27. traxer o, wendt-nordahl g, sodha h, et al. differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: the clinical research office of the endourological society ureteroscopy global study. world j urol. 2015; 33:2137. 28. guzelburc v, guven s, boz my, et al.intraoperative evaluation of ureteral access sheath-related injuries using post-ureteroscopic lesion scale j laparoendosc adv surg tech a. 2016; 26:23. 29. schoenthaler m, buchholz n, farin e, et al. the postureteroscopic lesion scale (puls): a multicenter video-based evaluation of inter-rater reliability. world j urol. 2014; 32:1033. 30. delvecchio fc, auge bk, brizuela rm, et al. assessment of stricture formation with the ureteral access sheath. urology. 2003; 61:518. correspondence boulalas ioannis, md, phd (corresponding author) iboulalas@yahoo.gr de dominicis mauro, md dedominicism@alice.it defidio lorenzo, md defidio@tin.it department of urology cristo re hospital via delle calasanziane 25, 00167 rome, italy 119archivio italiano di urologia e andrologia 2020; 92, 2 case report bilateral subcutaneous pyelovesical bypass in a hautmann neobladder followed by a mononeuropathy multiplex and an underlying polyarteritis nodosa diagnosis konstantina g. yiannopoulou 1, aikaterini i. anastasiou 2, ioannis katafigiotis 2, dimitrios papadopoulos 3, ioannis anastasiou 2 1 neurology department, henry dunant hospital center, athens, greece; 2 1st university urology clinic, laiko hospital, athens greece; 3 athens medical centre-paleo phaliro clinic, athens, greece. subcutaneous pyelovesical bypasses are the best choice for the long-term palliative treatment of ureteral obstructions. in rare cases this obstruction is due to polyarteritis nodosa. we present the only reported patient with a bilateral detour bypass in a hautmann’s neobladder. the patient also suffers from polyarteritis nodosa. key words: bilateral; detour bypass; hautmann neobladder; polyarteritis nodosa. submitted 10 august 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.119 introduction subcutaneous pyelovesical bypasses or detour bypass is the safest and most effective method for the long-term palliative treatment of ureteral obstructions (1). ureteral obstruction can be caused from either benign or malignant disease (1). we present a rare case of bilateral subcutaneous pyelovesical bypass in a hautmann neobladder in a 66-year-old man. to our knowledge this is the first case ever reported. three months after the second bypass, a mononeuropathy multiplex appeared and polyarteritis nodosa (pon) was diagnosed in the same patient. to our knowledge, five cases of bilateral ureteral stenosis and 16 of unilateral ones due to (pon) have been reported in the literature so far (2). none of them has been occurred in a patient with a neobladder. case presentation a 66-year-old man was presented to our urology department (1st university urology clinic, laiko hospital, athens, greece), with a bladder carcinoma. we performed an endoscopic bladder resection and the final histology revealed a pt2 muscle invasive bladder tumour. a radical cyctectomy was performed with hautmann neobladder as diversion. six months later an obstructed uropathy manifested due to left ureter stenosis and thus we placed a nephrostomy for temporary management. the final treatment was achieved with the placement of a left subcutaneous pyelovesical bypass. three years later the patient’s right ureter presented also stenosis. initially we placed a double j stent which however did not achieve a final solution of the obstruction. consequently, we performed a second subcutaneous pyelovesical bypass in the right ureter (figure 1). three months later, the patient was admitted with right foot and left wrist drop, fever and myalgias. a neurophysiologic evaluation revealed a mononeuropathy multiplex affecting peroneal and radial nerves with both motor and sensory deficits. a mild proximal muscle weakness and a severe muscle tenderness were present. the diagnosis of pon was based upon muscle biopsy from right quadriceps which revealed typical necrotizing vasculitis in medium size arteries in conjunction with elevated sedimentation rate (107 mm/h) and rheumatoid factor (73 iu/ml). the patient was managed with oral prednisolone (1mg/kg), which resulted in gradual resolution of his symptoms. discussion bladder cancer is more common in men than in women and usually does not involve the muscle wall. for this reason it is mainly treated by endoscopic transurethral resection of the bladder tumor (turbt). in our male patient the first surgery was a turbt, which demonstrated cancer infiltrating the bladder muscle wall. those patients are at higher risk and therefore are treated with major surgery to remove the bladder. subcutaneous pyelovesical bypasses are considered to be the best choice for ureteric obstruction, in comparison to other methods, such as the j stent. it is not associated with septicemia and irritative bladder symptoms or frequent infections (1). the fact that there is no participation of the impaired ureter is the main difference between pyelovesical bypasses and other methods (1). ureteral obstruction may be caused by benign as well as malignant disease, but is also an important complication of modern surgeries (1, 3). in fact, uretero-ileal anastomotic stricture (uias) in orthotopic ileal neobladder can develop in 4-10% of cases during a follow-up time of 636 months (3). in our case it was caused by fibrosis in the site of the anastomosis of the ureter with the neobladder. other methods, which have been used to treat this complication, are percutaneous nephrostomy anastasiou_stesura seveso 17/06/20 10:15 pagina 119 archivio italiano di urologia e andrologia 2020; 92, 2 k.g. yiannopoulou, a.i. anastasiou, i. katafigiotis, d. papadopoulos, i. anastasiou 120 and double j stents. in our patient both methods where applied before the use of subcutaneous pyelovesical bypasses, however their efficiency was poor and the detour was the final treatment. nevertheless, this is the first case in the literature where a bilateral ureteric obstruction after hautmann neobladder was managed succesfully with a bilateral pyelovesical bypass. several months after the second detour procedure, patient presented with multiple mononeuropathies and symptoms of systemic inflammation. he was finally diagnosed with pon, an entity that did not show previous clinical or laboratory signs of its existence in our patient. however, ureteral obstruction has been described as a manifestation of pon (2). it is supposed to result from vasculitis of periureteral vessels. to our knowledge, five cases of bilateral ureteral stenosis and 16 of unilateral ones due to (pon) have been reported in the literature so far (2), two of them as the first manifestation of the disease (4). we suggest that the vasculitic background in our patient due to his underlying polyarteritis pathology in conjunction with the major surgical procedure in his bladder contributed to the unprecedented occurrence of such a severe bilateral ureteral obstruction after hartmann neobladder surgical construction that only detour intervention could resolve. conclusions although uias in orthotopic ileal neobladder may develop in 4-10% of cases in the follow-up period of 6-36 months, bilateral uias can also occur. subcutaneous pyelovesical bypasses (detour bypass) can be applied bilaterally with safety and long-term efficacy. furthermore, additional underlying causes of the obstructive process, like systematic vasculitis. should be suspected in these extremely rare cases. references 1. wrona aj, zgajewski j, kopeć n, chodor d, kopcza p, klekot s. subcutaneous pyelovesical bypass detour bypass as a solution for ureteric obstruction. cent european j urol. 2017; 70:429-433. 2. bolat d, zumrutbas ae, baser a, tuncay l. spontaneous ureteral rupture in a patient with polyarteritis nodosa. int urol nephrol. 2016; 48:223-4. 3. mohamed wishahi, hossam elganzoury, amr elkhouly. detour technique, dipping technique, or iieal bladder flap technique for surgical correction of uretero-ileal anastomotic stricture in orthotopic ileal neobladder. int braz j urol. 2015; 41:796-803. 4. jois r, gupta a, krishnamurthy s. ureteric vasculitis, an unusual presentation of polyarteritis nodosa: a case report. int j rheum dis. 2015; 18:577-9. figure 1. placement of the second subcutaneous pyelovesical bypass in the right kidney. correspondence konstantina g. yiannopoulou, md k.giannopoulou.14@hotmail.com neurology department, henry dunant hospital center, athens (greece) aikaterini i. anastasiou, md (corresponding author) ekati2@otenet.gr ioannis katafigiotis, md katafigiotis.giannis@gmail.com ioannis anastasiou, md aikatianast@gmail.com 1st university urology clinic, laiko hospital ag.thoma 17, athens 11527 (greece) dimitrios papadopoulos, md dimipapuro@yahoo.gr athens medical centre-paleo phaliro clinic, athens (greece) anastasiou_stesura seveso 17/06/20 10:15 pagina 120 65archivio italiano di urologia e andrologia 2017; 89, 1 original paper the effect of surgical technique on hemodynamics, arterial oxygenation and pulmonary mechanics in radical prostatectomy operations yucel yuce 1, kutlu hakan erkal 1, cemal goktas 2, bilal eryildirim 2, kemal sarica 2 1 dr. lutfi kirdar training and research hospital, anaesthesiology and reanimation department, kartal, istanbul, turkey; 2 dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey. objective: the effects of surgical technique on respiratory mechanics, arterial oxygenation and hemodynamics in radical prostatectomy operation were investigated. methods: the study was planned on asa ii-iii, 40-65 years old, fourty patients scheduled for radical prostatectomy under general anesthesia. they were divided into two groups: perineal and suprapubic (group p, n = 20; group s, n = 20). heart rate, mean arterial blood pressure, arterial oxygen saturation (spo2), partial pressure of end-tidal carbon dioxide (petco2), peak inspiratory pressure (pip), plato pressure (pplato), partial pressure of oxygen in arterial blood (pao2), partial pressure of carbon dioxide in arterial blood (paco2) values were evaluated at 10 minutes after induction. after the position applied for surgery in the 30.60 and 90th minutes, the alveolar-arterial oxygen pressure gradient (p(a-a) o2), the ratio of physiologic dead space over tidal volume (vd/vt), arterial to end tidal co2 gradient (p(a-et) co2), static compliance (cs), dynamic compliance (cd) were assessed. results: in the assessment of groups, there were not statistical differences about mean blood pressure, heart rate, spo2, petco2, pao2, plateau pressure, and p (a-a) values (p > 0.05). peak inspiratory pressure was higher in group p. peak inspiratory pressure and plateau pressure increased with co2 insufflation in group p. paco2 and p(a-et) co2 were higher statistically significantly in group 0. there was no difference in terms of the petco2 values. vd/vt ratios were statistically significantly lower in the group p. conclusions: suprapubic surgery was shown to improve oxygenation and respiratory mechanics without causing any hemodynamic side effect in radical prostatectomy operation. key words: radical prostatectomy; position; respiratory mechanics; oxygenation. submitted 6 december 2016; accepted 11 january 2017 summary no conflict of interest declared. allel to the increase in the incidence of the prostate cancer, the disease can be diagnosed at early stages and thus it is possible to perform some certain surgical procedures giving curative treatment chances where radical prostatectomy has become the golden standard for definitive treatment (3). with the developments in the surgical techniques and increase in anesthesic confidence, the morbidity of the radical prostatectomy has decreased significantly and the surgical mortality is 5% (4, 5). radical prostatectomy could be performed either via suprapubic or perineal approach and based on the method of dissection and the tools used. each of these methods have its own advantages and disadvantages (4-6). related with this subject, radical perineal prostatectomy (rpp) was described in 1905 by young (7). in addition to some surgical advantages of these two techniques one over the other from certain aspects (8), the position the patient during these approaches may also affect the course of the anestheasia a topic that has not been evaluated in detail so far. in these patients; during general anesthesia arterial oxygenation may be disturbed because of several causes like functional instability of anesthesia equipment, endobronchial intubation, hypoventilation, increase in airway resistance, neuromuscular blockage and surgical position. in 53% of elective surgical procedures mild hypoxemic periods and in 20% of them severe hypoxemic periods may be observed (9). it is found that the real causes of the deterioration of arterial oxygenation during anesthesia are atelectasia and ventilation and perfusion (v/q) mismatch (10). in cases with general anesthesia, due to the effects of the anesthesic agents, the surgical position and the anatomic region of the surgery atelectasis may occur in 90% cases and it causes postoperative respiratory complications (11). especially, it was thought that in cases with high risk this postoperative pulmonary complications of atelectasis cause increase in mortality and morbidity in patients without early diagnosis (12). general anesthesia causes a decrease in functional residual capacity (frc) (5). frc decreases in a 20% ratio even in supine position. this decrease may be due to the decrease in inspiratory muscle tonus and also due to the increase in abdominal pressure and changes in doi: 10.4081/aiua.2017.1.65 introduction with the ageing of world population, the burden of prostate cancer is expected to increase. prostate cancer is the most prevalent cancer among men and the second leading cause of cancer-related death in men in western industrialized countries (1). about 1.1 million cases of prostate cancer were diagnosed worldwide in 2012, accounting for 15% of all cancers in men (2). today paryuce_stesura seveso 04/04/17 09:26 pagina 65 archivio italiano di urologia e andrologia 2017; 89, 1 y. yuce, k. hakan erkal, c. goktas, b. eryildirim, k. sarica 66 thoracic blood volume. with induction of the anesthesia this decrease in frc increases 10% (13). thus, general anesthesia may cause atelectasis inevitably. lithotomy position causes important physiologic changes. the decrease of frc may induce the development of atelectasis and hypoxia. upside down position with lithotomy advances these effects. elevation of the legs increases the venous return and exacerbates the congestive heart failure. usually, mean arterial pressure increases but cardiac output does not change significantly. inversely the rapid lifting down of the legs decreases the venous return and may cause hypotension. it is important to remember that the leg elevation redistributes pooled lower limb blood and this may lead to volume overload in susceptible individuals. diaphragmatic movement can be limited severely by the weight of the abdominal viscera; this further reduces frc and increases atelectasis. during surgery; several ventilation techniques can be performed to decrease the intraoperative alveolararterial oxygen gradient (a-a do2) (14). in this study we aimed to investigate the effects of the patient position and the surgical technique on respiratory mechanics, arterial oxygenation and hemodynamics in radical prostatectomy operations. patients and methods following the approval by the local ethics comittee of kartal dr. lutfi kirdar training and research hospital, we performed our study in urology surgery room of hospital with 40 patients who underwent radical prostatectomy operation. volunteer patients with informed consents in asa i and ii groups between 18-65 years of age without known dm and cardiopulmonary disorders were included to the study. the patients in whom complication occured during the surgery, hypotensive patients, the patients with previous raynaud disease, buerger disease, patients who underwent toracic surgery before and patients with negative modified allen test were excluded from the study. all patients were examined physically one day before the surgery and vital and laboratory findings were controlled. the hemoglobin and hematocrit levels, rbc, wbc, thrombocyte counts, coagulation parameters, serum electrolyte levels, liver function tests (sgot, sgpt), bun and creatinine levels, serum glucose levels, total bilirubin levels of all patients were studied. modified allen test was performed in all patients. they were informed about the procedure and written informed consents were taken. the patients were randomised into two groups as perineal (group p) and suprapubic (group s). no premedication was performed to the patients. when the patients were taken into the operation room, the monitorisation of them by ecg, non invasive blood pressure measurement and spo2 was performed. 0.9% nacl infusion at 8 ml/kg/hour rate was initiated after iv canulation with 22 g canula. radial artery canulation with 20 g canula after local anesthesia was performed. initial measurements of heart rates, blood pressures and spo2 were recorded. for preoperative measurement arterial blood gas samples were taken. for balanced anesthesia tiopental 7 mg/kg, fentanyl 2µg/kg and vecuronium 0,1 mg/kg were used. endotracheal intubation by spiral tubes with 7.0-8.5 mm internal diameters were performed and mechanical ventilation with dräger primus ventilator in ippv mode with 50% n2o-o2 at 2 l/min flow rate and with sevoflurane of mac = 1.0 was initiated. during mechanical ventilation frequency of respiration was 12/min, inspiration/expirationratio was 1:2 and tidal volume was 8 ml/kg. second measurements (s1) were performed 10 minutes after induction at supine position. then l1 was taken 15 minutes after lithotomy position, l2 was taken 30 minutes after lithotomy position, l3 was taken 60 minutes after lithotomy position and l4 was taken 90 minutes after lithotomy position. s2 was taken 15 minutes after supine position again. the recorded parameters were heart rate, spo2, invasive blood pressures, pip, pplateau, etco2 and tidal volume. the dynamic and static compliances of the both groups were calculated from the measured data. the arterial blood gas samples were taken simultaneously at the times which respiratory mechanics were recorded. during the operation invasive mean arterial pressures, heart rates and spo2 levels were recorded. when the operation terminated the patients were positioned again as supine and the inhalational anesthetics were also terminated. 100% o2 was started. after initiation of the spontaneous respiration neuromuscular blockage was reversed with 0.01 mg/kg atropine and 0.04 mg/kg neostigmine. after adequte spontaneous respiration extubation was performed. the other medications during the operation and intraoperative complications were also recorded. in randomised grouped patients peep was performed as 0 cm h2o in group s and 10 cmh2o in group p. intraabdominal insuflation pressure was constant as < 15 mm hg. heart rates, blood pressures, petco2, pip, pplateau, pao2, paco2 levels were recorded 5 minutes after induction, 5 minutes after co2 insuflation, 10 and 30 minutes after head up and right side position, 10 minutes after desuflation and at the recovery room. at the same time periods p (a-a)o2, vd/vt, p(aet)co2, cs, cd were calculated. when operation was terminated inhalational agent peep were also terminated. the durations of the operation and the anesthesia were also recorded. statistical analysis for analysis of the data spss 17.0 program was used. during the evaluation of the data frequency ranges, means, standard deviations, percentages and crosstabs were used. for comparison of the groups independent sample t test, for cathegoric comparison pearson chisquare and fisher’s exact tests were used. in multiple comparisons when there was difference between the groups, to find these groups in which there was difference tukey hsd and dunnet test was used. results there was no statistically significant difference between the groups according to age, body mass index (bmi) and the duration of the anesthesia (p > 0.05) (table 1). yuce_stesura seveso 04/04/17 09:26 pagina 66 in group p and s, there was no statisitically significant difference in basal, 10, 20, 30, 60 and 90 minutes after induction paco2 values (p > 0.05) (table 2). in group p basal, 10, 20, 30, 60 and 90 minutes after induction mean paco2 values are statistically significantly different (p = 0.0001). basal paco2 values were lower than the values at 10, 20, 30, 60 and 90 minutes after induction (p < 0.001) (table 2). in group s basal, 10, 20, 30, 60 and 90 minutes after induction mean paco2 values are statistically significantly different (p = 0.0001). basal paco2 values were higher than the values at 10, 20, 30, 60 and 90 minutes after induction (p < 0.001) (table 2). there was no statistically significant difference between groups according to the p(a-et)co2 levels at all times (p > 0.05). in group p, it was found that the increase in p(a-et)co2 at the time before induction in response to the level at 20 minutes after induction was statistically significant (p < 0.01) (table 3). there was no statistically significant difference between two groups according to the mean pip values before induction (p = 0.002) (table 4). in group s 10, 20, 30, 60 and 90 minutes after induction pip values were not statistically significantly different (p = 0.153) (table 4). in group p 10, 20, 30, 60 and 90 minutes after induction pip values were statistically significantly different (p = 0.013). the pip values were significantly lower than 10, 20, 30, 60 and 90 minutes after induction pip values (p < 0.05) (table 4). there was no statistically significant difference between groups according to the before induction cd levels (p > 0.05) (table 5). the difference between cd levels at all times in group p and the cd levels in group s at 10, 20, 30, 60 and 90 minutes and after induction were statistically significant (p < 0.001) (table 5). the mean vd/vt at 20 min after induction in group p was higher than the value of group s and this was statistically significant (p < 0.05). in group p the vd/vt values at 60 and 90 minutes after induction were higher in response to the value at 30 minutes after induction and this was also statistically significant (p < 0.01) (table 6). 67archivio italiano di urologia e andrologia 2017; 89, 1 the effect of surgical technique on hemodynamics in radical prostatectomy operations table 1. demographic data and the duration of the anesthesia (mean ± sd). perineal suprapubic t p age (year) 59.47 ± 8.72 61.47 ± 9.02 0.21 -0.682 weight (kg) 76.78 ± 9.13 77.15 ± 9.923 -0.05 0.185 length (cm) 165.28 ± 7.42 164.25 ± 8.43 -1.16 0.192 bmi (kg/m2) 26.95 ± 2.88 27.05 ± 2.19 0.86 0.430 duration of anesthesia (min) 130.06 ± 40.02 133.06 ± 41.82 -0.33 0.680 table 2. distribution of the paco2 values in two groups (mean ± sd). paco2 group p (n = 20) group s (n = 20) t p before induction 34.60 ± 3.19 34.55 ± 3.30 1.155 0.001 after induction 10. min 35.90 ± 3.19 43.35 ± 6.90 0.366 0.001 20. min 38.50 ± 3.35 35.05 ± 2.95 0.653 0.001 30. min 44.65 ± 6.67 32.72 ± 5.53 0.024 < 0.001 60. min 42.2 ± 16.21 33.35 ± 5.72 1.51 < 0.001 90. min 41.3 ± 44.14 41.76 ± 7.28 0.811 0.001 table 3. distribution of the p(a-et)co2 values in two groups (mean ± sd). p(a-et)co2 group p (n = 20) group s (n = 20) p before induction 9.74 ± 5.32 9.12 ± 3.47 0.023 after induction 10. min 11.45 ± 5.49 11.65 ± 2.23 0.098 20. min 12.55 ± 7.35 9.48 ± 3.09 0.610 30. min 11.61 ± 5.25 10.72 ± 3.62 0.402 60. min 10.32 ± 8.01 9.30 ± 3.43 0.377 90. min 12.75 ± 5.42 11.61 ± 6.75 0.345 table 4. distribution of the pip values in two group (mean ± sd). pip group p (n = 20) group s (n = 20) t p before induction 17.42 ± 4.51 17.80 ± 4.39 -7.28 0.002 after induction 10. min 21.80 ± 3.82 19.80 ± 4.21 -7.70 0.018 20. min 23.23 ± 3.64 18.20 ± 4.01 -8.41 0.048 30. min 21.15 ± 3.71 17.80 ± 3.31 -11.38 0.005 60. min 22.32 ± 3.38 18.80 ± 4.25 -10.07 0.009 90. min 21.44 ± 34.11 16.80 ± 3.71 -11.05 0.008 table 5. distribution of the cd values in two groups (mean ± sd). cd group p (n = 20) group s (n = 20) p before induction 27.42 ± 4.62 26.32 ± 5.50 (p > 0.05) after induction 10. min 23.80 ± 3.83 15.91 ± 4.21 < 0.001 20. min 23.23 ± 3.65 14.24 ± 5.02 < 0.001 30. min 24.15 ± 3.82 13.50 ± 3.41 < 0.001 60. min 22.32 ± 3.49 15.86 ± 4.26 < 0.001 90. min 23.44 ± 34.12 16.78 ± 5.72 < 0.001 table 6. distribution of the vd/vtvalues in two groups (mean ± sd). vd/vt group p (n = 20) group s (n = 20) p before induction 0.25 ± 0.09 0.21 ± 0.10 < 0.001 after induction 10. min 0.26 ± 0.12 0.24 ± 0.10 < 0.001 20. min 0.22 ± 0.100 0.19 ± 0.12 < 0.001 30. min 0.23 ± 0.12 0.12 ± 0.07 < 0.001 60. min 0.29 ± 0.100 0.12± 0.07 0.009* 90. min 0.24 ± 0.09 0.22 ± 0.08 < 0.001 yuce_stesura seveso 04/04/17 09:26 pagina 67 archivio italiano di urologia e andrologia 2017; 89, 1 y. yuce, k. hakan erkal, c. goktas, b. eryildirim, k. sarica 68 discussion we examined the effects on respiratory mechanics and blood gas analysis of the exaggerated lithotomy position for radical perineal prostatectomy. we found that, with the exception of the carbon dioxide tension, all respiratory parameters were significantly affected by the change of position from the supine to the exaggerated lithotomy position. significant changes were found in airway pressures, compliance and airway resistance, the work of breathing and arterial oxygen tension. different patient positions have been used during radical prostatectomy procedures. the primary surgical methods used for prostatectomy include radical retropubic prostatectomy and radical perineal prostatectomy. the advantages of the perineal approach are decreased blood loss due to the dissection of the prostate without ligation of the deep dorsal venous complex of the penis, direct visualisation of the vesicourethral anastomosis, a reduced operative time, minimisation of surgical stress and a smooth recovery after surgery (9). but it may cause the pelvic and abdominal organs to move in a cephalad direction, leading to compression of the diaphragm and lungs and causing a significant decrease in functional residual capacity. during the surgery different positions were performed after anesthesia induction for different surgical procedures. usually anesthesia induction is performed at supine position and for many procedures supine position is the only position during the operation. but sometimes the position of the patient is changed due to the surgical procedure and the status of the patient. radical retropubic prostatectomy is performed with patients in the supine position, whereas in radical perineal prostatectomy, patients are placed in an exaggerated lithotomy position. the exaggerated lithotomy position used in our study differs from these positions. the patients' legs are first elevated, the knee joints are then flexed 90° and the feet and ankles are securely fastened (15). the patient position required for surgery affects the cardiac function and haemodynamic parameters (15). having information about human anatomy and physiology and phyical equlibrium are important for chosing the most proper position for the patient. with the ideal position, the patient’s physiology must not change and no soft tissue and skeletal damages should be observed. these positions should preserve the cardiovascular and respiratory reserves, the airway, venous interventions and the monitorisations of the patients. they should also provide the most proper position for the surgical procedure. the pulmonary perfusion and ventilation are affected by gravity, chest wall mechanics and the movements of the diaphragm. in a conscious patient lower zones of the lung are ventilated good. small changes in pressures can cause larger changes in lung volumes. during the operation in supine, prone and lateral positions lower lung zones are properly perfused. in patients with neuromuscular blockage and mechanical ventilation, tidal volume decreases by the decrease in diaphragmatic movements. pulmonary ventilation decreases and thus ventilation perfusion mismatch occurs. additionally, pressure towards the mediastinum from upper parts and abdominal pressures from the lower parts make the ventilation difficult. frc decreases 40% during anesthesia in supine position. lithotomy position can be combined with upside down position for promoting the surgical procedure. lower extremities should be opened towards both sides symmetrically and the lumbar lordosis should be supported. for protection of the sciatic, obturatory and femoral nerves, flexion of the hips and the knees > 90°. during the duration of the position perfusion pressures must be maintained. according to the surgical position in addition to all body systems arterial blood gas values also change. the developing monitorisation and ventilation with improvement in technology can provide us proper follow up of the patients and rapid interventions to the possible complications can be performed. the primary surgical methods used for prostatectomy include radical retropubic prostatectomy and radical perineal prostatectomy. the advantages of the perineal approach are decreased blood loss due to the dissection of the prostate without ligation of the deep dorsal venous complex of the penis, direct visualisation of the vesicourethral anastomosis, a reduced operative time, minimisation of surgical stress and a smooth recovery after surgery (15). casati et al. studied the effects on physiological dead space to tidal volume ratio after placing patients in different positions. the values reported were 0.36 (0.05), 0.38 (0.06), and 0.40 (0.04) in the supine, trendelenburg (20°), and prone positions, respectively. this ratio was significantly higher in prone (p < 0.01) but not in the trendelenburg (20°) position compared with the supine position (16). radical retropubic prostatectomy is performed with patients in the supine position, whereas in radical perineal prostatectomy, patients are placed in an exaggerated lithotomy position. the standard lithotomy position or combined lithotomy-trendelenburg position are commonly used for rectal and perineal operations (17). several studies have reported the respiratory effects of the prone, lateral decubitus positions, including during laparoscopic procedures utilising a pneumoperitoneum (16, 17). in our study, we report a significant decrease in pao2 (p < 0.0005) but no significant increases in etco2 and paco2. the decrease in expiratory tidal volume (2.4%) and increase in physiological dead space to tidal volume ratio (11.1%), were not sufficient to produce an increase in carbon dioxide tension. rauh et al. reported that measurements taken 10 min following the creation of a pneumoperitoneum (with an intra-abdominal pressure of 15 mm-hg) produced peak inspiratory pressure increases of 35% and dynamic lung compliance decreases of 27%. the results of rauh et al. are comparable to our study in that after patients were placed in an exaggerated lithotomy position, peak inspiratory pressure increased 34.0% and dynamic lung compliance decreased 27.4%. therefore, it is likely that the exaggerated lithotomy position imposes similar effects on airway pressure and lung compliances as the creation of a pneumoperitoneum of 15 mm-hg (17). yuce_stesura seveso 04/04/17 09:26 pagina 68 ryniak et al. reported increases in paco2 and shunt fraction and a decrease in pao2 associated with the exaggerated lithotomy position. changes in hemodinamics and pulmonary mechanics were compared in patients placed in the exaggerated lithotomy position and in the supine position (18). transperineal access of the retropubic area requires the exaggerated lithotomy position, and this position is used most commonly in radical perineal prostatectomy and urethral reconstruction. however, this position exerts considerable stress on the lower back and imposes a significant additional gradient for the perfusion of the lower limbs. complications of this position include compartment syndrome, neuropraxia, lower back strain, venous air embolism and rhabdomyolysis (18). although radical perineal prostatectomy is associated with the advantages of decreased blood loss, minimised surgical stress and smoother postoperative recovery when compared with radical retropubic prostatectomy, the exaggerated lithotomy position clearly could compromise respiratory function. in our study, 50% of patients (12/24) were 65 years of age or older, and no patients developed respiratory complications during the operation. we examined the effects on respiratory mechanics and blood gas analysis of the exaggerated lithotomy position for radical perineal prostatectomy. we found that, with the exception of the carbon dioxide tension, all respiratory parameters were significantly affected by the change of position from the supine to the exaggerated lithotomy position. significant changes were found in airway pressures, compliance and airway resistance, the work of breathing and arterial oxygen tension. the mechanisms underlying these alterations are not fully elucidated. however, the selective elevation of the sacrum and lower lumbar area by folded sheets or a large wedge may cause the pelvic and abdominal organs to move in a cephalad direction, leading to compression of the diaphragm and lungs and causing a significant decrease in functional residual capacity. in the exaggerated lithotomy position (flexed and head down), as compared with the supine position, ryniak et al. reported a significant decrease in pao2 (p < 0.001) and a significant increase in paco2 (p < 0.001) (18). in our study, we report a significant decrease in pao2 (p < 0.0005) but no significant increases in etco2 and paco2. in obese patients, excessive elevation of the perineal area, and⁄or overflexion of the thighs, may produce a restricted space between the abdomen and thighs. this may severely compromise respiratory mechanics, leading to inadequate ventilation or even barotrauma. transperineal access of the retropubic area requires the exaggerated lithotomy position, and this position is used most commonly in radical perineal prostatectomy and urethral reconstruction. however, this position exerts considerable stress on the lower back and imposes a significant additional gradient for the perfusion of the lower limbs (19). although radical perineal prostatectomy is associated with the advantages of decreased blood loss, minimised surgical stress and smoother postoperative recovery when compared with radical retropubic prostatectomy, the exaggerated lithotomy position clearly could compromise respiratory function. in our study, 50% of patients were 65 years of age or older, and no patients developed respiratory complications during the operation. in conclusion, we have found that the exaggerated lithotomy position produces significant changes on respiratory mechanics and blood oxygenation when compared to the supine position. although this position was well tolerated by most patients, careful monitoring of the respiratory variables is required and it is important to be aware of the potential negative respiratory effects. further work is required to evaluate in more detail the effects of this position in obese patients and patients with co-existing lung disease. conclusions in conclusion, patient position during radical prostatectomy directly affects operative time. even though success and complication rates are not related to position, placing the patient in lithotomy position with an extended leg seems to make the surgery easier and faster, specially when operating males. we have found that the exaggerated lithotomy position produces significant changes on respiratory mechanics and blood oxygenation when compared to the supine position. references 1. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and treatment of clinically localized disease. eur urol. 2011; 59:61-71. 2. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and 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perioperative pulmonary complications in high-risk patients. curr opin anaesthesiol. 2012; 25:1-10. 13. hewlett a, hulands g, nunn j, et al. functional residual capacity during anaesthesia iii: artificial ventilation. brit j anaesth. 1974; 46:495-503. 14. blum jm, blank r, rochlen lr. anesthesia for patients requiring advanced ventilatory support. anesthesiol clin. 2010; 28:25-38. 15. anema jg, morey af, mcaninch jw, et al. complications related to the high lithotomy position during urethral reconstruction. j urol. 2000; 164:360-63. 16. casati a, salvo i, torri g, et al. arterial to end-tidal carbon dioxide gradient and physiological dead space monitoring during general anaesthesia: effects of patients' position. min anestesiol. 1997; 63:177-82. 17. rauh r, hemmerling tm, rist m, et al. influence of pneumoperitoneum and patient positioning on respiratory system compliance. j clin anesth. 2001; 13:361-65. 18. ryniak s, brannstedt s, blomqvist h. effects of exaggerated lithotomy position on ventilation and hemodynamics during radical perineal prostatectomy. scand j urol nephrol. 1998; 32:200-03. 19. choi sj, gwak ms, ko js, et al. the effects of the exaggerated lithotomy position for radical perineal prostatectomy on respiratory mechanics. anaesthesia. 2006; 61:439-43. correspondence yucel yuce, md dryyuce@gmail.com kutlu hakan erkal, md hakerkal@yahoo.com dr. lutfi kirdar training and research hospital, anaesthesiology and reanimation department, kartal, istanbul, turkey cemal goktas, md cemalgoktas@yahoo.com bilal eryildirim, md (corresponding author) bilaleryildirim@yahoo.com kemal sarica, md saricakemal@gmail.com dr. lutfi kirdar training and research hospital urology clinic, istanbul, turkey yuce_stesura seveso 04/04/17 09:26 pagina 70 139archivio italiano di urologia e andrologia 2017; 89, 2 original paper outcome of buccal mucosa urethroplasty in the management of urethral strictures basri cakiroglu 1, orhun sinanoglu 2, ersan arda 1 1 hisar intercontinental hospital department of urology, umraniye, istanbul, turkey; 2 maltepe university medical school department of urology, maltepe, istanbul, turkey. objective: the objective of the study is to report the outcome of buccal mucosal urethroplasty. materials and methods: the follow up data of 15 patients undergoing single stage urethroplasty from september 2010 to september 2015 were retropectively reviewed. they received buccal mucosa graft for urethroplasty. the patients were followed for complications and outcome. results: mean age was 53.7 ± 13.6 the stricture length ranged from 3 to 6 cm (mean 4.4 ± 0.8). the success rate for buccal mucosa urethroplasty (bmu) was 67.7% at 12th month. three patients presenting with voiding difficulty in the 3rd month and one in the next 12 months, had urethral restenosis. one patient had fistula formation at 6th month postoperatively. five patients underwent retreatment procedures such as internal urethrotomy, urethroplasty and/or internal urethrotomy. conclusions: the buccal mucosa is easy to obtain and handle, therefore bmu can be safely and effectively managed outside high volume institutions. key words: urethral stricture; buccal mucosa; urethroplasty. submitted 2 march 2017; accepted 15 april 2017 summary no conflict of interest declared. are associated with stricture recurrence (5). among the mucosal grafts, the buccal mucosa has proved to be a versatile and successful urethral substitute. the use of buccal mucosa graft (bmg) for urethral reconstruction was first reported, in 1894 (6). it is relatively easy to obtain and manipulate, is a wet epithelium, and has a excellent immunity. it is less prone to stricture recurrence especially in the presence of lichen sclerosus. today the buccal mucosa is the preferred donor site for urethral stricture repair (7). however, its harvesting may be associated with donor site morbidities, such as perioral numbness, difficulty in opening the mouth and less commonly, dry mouth, and long term complications such as scarring (8). the thick buccal mucosa epithelium with dense submucosa and extensive capillary network assures rapid neovascularisation and early access of nutrients from the wound bed (4, 9, 10). herein we report our experience with dorsal bmu for the primary repair of anterior urethral strictures. materials and methods after ethics committee approval, we reviewed data of 24 patients with anterior urethral stricture undergoing buccal mucosal urethroplasty (bmu) between september 2010-september 2015. after excluding 5 patients, who had follow-up less than 6-months, and 3 patients lost to follow-up, 15 patients, were finally analyzed. patients with short stricture (< 2.5 cm), strictures with caliber >6 mm, complex strictures (strictures associated with abscess, fistula), posterior urethral strictures, history of oral surgery, visible oral mucosal changes, restricted mouth opening, and previous failed urethroplasty were excluded from the study. the retrospective data of patients undergoing bmu were collected. patient characteristics and baseline data were recorded. all patients underwent uroflowmetry (ufm), urine culture/sensitivity, urethrography, and cystourethroscopy. the oral mucosal characteristics were assessed in all patients during the initial workup. single stage dorsolateral onlay graft urethroplasty was applied in all patients. after intubation under general anesthesia, initially perineal dissection was done. following midline perineal incision, bulbospongiosus muscle was dissectdoi: 10.4081/aiua.2017.2.139 introduction anterior urethral stricture is a pathological fibrous tissue development involving the corpus spongiousum. the most common etiology of anterior urethral stricture is trauma, mostly straddle injury. several factors such as etiology of stricture, site, length and density of the fibrous tissue should be taken into consideration for appropriate management (1). a long segment of urethral stricture is the indication for surgical correction. strictures longer than 2 cm that are not suitable for anastomotic repair therefore, require substitution urethroplasty, where a graft is used . whilst substitution urethroplasty is an established and accepted treatment there is currently no clear consensus on the best graft material (2). pedicled and free grafts have been used including split and full-thickness skin grafts (genital and extra-genital), bladder mucosa, colonic mucosa, tunica vaginalis, tissue-engineered grafts, and intra-oral mucosa (buccal or lingual) (3, 4). long-term results of scrotal and extra-genital skin are disappointing as non-hirsute full-thickness skin grafts cakiroglu_stesura seveso 20/06/17 09:56 pagina 139 archivio italiano di urologia e andrologia 2017; 89, 2 b. cakiroglu, o. sinanoglu, e. arda 140 ed. the urethra was mobilized from cavernosa only on one side beyond midline to preserve the vascular supply. the urethra was opened longitudinally on lateral side. the stricture length was measured. graft was harvested 2 cm longer than the measured stricture length, as there is approximate 10% contraction over time, and width of 15-25 mm was taken to provide a lumen of at least 24 fr after tubularization. for bmu, graft taking was started with the submucosal infiltration of xylocaine and adrenaline (1:100,000) under the marked buccal mucosal patch. approximately, 0.5-1.0 cm mucosa from stenson's duct were left to prevent duct injury. all defects were left open to prevent tension, pain, and distortion. after graft harvest, fat removal was done till the graft appeared creamy white. graft and urethral plate were stretched to avoid postoperative diverticula and postvoid dribbling; attached on cavernosal bodies and after that it was sutured to the urethral plate in dorsolateral onlay fashion. finally, the urethra was closed over 16 fr silicone catheter with 4-0 vicryl. all patients were given intravenous antibiotics for 1 days, followed by oral for 5 days. the patient was allowed clear fluids or liquid diet on day 1 and then gradually soft and regular diet in the following days. in the postoperative period patients were asked to outpatient clinic for reporting the complications. the patients were followed at 1, 3, 6 and 12 months after surgery. voiding symptoms, questionnaires, and ufm were done in all as primary screening for stricture recurrence. urethrography and cystourethroscopy were done as a secondary screening only if the patient developed obstructive symptoms or ufm showed qmax < 15 ml after ruling out lower urinary tract infection. the success of urethroplasty was considered as the primary outcome of the study. we defined success as the absence of any obstructive symptoms and no need of subsequent procedures, such as dilatation, cystourethroscopy, and internal urethrotomy. statistical evaluation data were entered in the ms excel and analyzed in spss version 20 software (ibm corp. ibm spss statistics for windows, version 16.0). continuous variables were presented as means ± standard deviation. proportions (percentages) were calculated for discrete variables. results characteristics of patients and in follow up periods are depicted in table 1. mean age was 53.7 ± 13.6 the stricture length ranged from 3 to 6 cm (mean 4.4 ± 0.8 the success rate for bmg was 67.7% at 12th month. three patients presented with voiding difficulty in the 3rd month, one in the next 12 months, had urethral restenosis. one patient had fistula formation at 6th month postoperatively. one patient was reoperated with internal urethrotomy and subsequent internal urethrotomy with urethroplasty, one with urethroplasty and subsequent urethral dilation, one with internal urethrotomy and subsequent urethral dilation, one with fistula closure. early and immediate graft donor site complications were seen in all patients. pain, difficulty in chewing and numbness of donor site was the most common early complication, but these were mild and transient in all patients. salivary flow changes were not seen in any patient. table 1. characteristics of patients undergoing buccal mucosal urethroplasty. age etiology of stricture stricture length cm comorbidity 3rd month 6th month 12th month reoperation dilation 73 infection (fournier) 6.0 dm+ht stricture normal normal + 50 hypospadias repair 4.0 none stricture normal stricture urethroplasty 47 trauma 4.0 none normal normal normal 44 trauma 5.0 none normal normal stricture urethroplasty 39 trauma 4.0 none normal normal normal 64 instrumentation (tur-p) 4.0 ht normal normal stricture internal urethrotomy + 34 trauma 4.0 none normal normal normal 68 infection 5.0 none normal normal normal 38 hipospadias repair 5.0 ht normal fistula fistula fistula closure 63 infection (urethritis) 5.0 dm+ht normal normal normal 56 instrumentation 3.0 dm+ht+cad normal stricture stricture + (urinary catheter insertion) 75 lichen sclerosis 4.0 ht normal normal normal 62 instrumentation turp 5.0 dm+ht normal normal normal 37 hypospadias repair 3.0 none normal normal normal 55 trauma 5.0 dm stricture stricture stricture urethroplasty + dm: diabetes mellitus; ht: hypertension; cad: coronary artery disease. cakiroglu_stesura seveso 20/06/17 09:56 pagina 140 discussion severe and longer urethral strictures require substitution urethroplasty. miscellaneous tissues have been used in the past however, in the last decade, buccal mucosa gained popularity as the best substitute material for urethral reconstruction (11). buccal mucosa is a convenient donor site for augmentation urethroplasty because of its thick epithelium, high content of elastic fibers and rich vascularity due to pan laminar plexus, and good graft uptake (12). it is easy to obtain, readily available, compatible with wet environment, and butress the local immune status with its increased amount of iga, resistant to infection and has better healing features as demonstrated by rapid healing of aphthous ulcers. a systematic review and meta-analysis of urethral reconstruction with buccal mucosa or penile skin graft (psg) revealed a success rate of 85.9% with buccal mucosa and 81.8% with psg (13). a 90% success rate has been reported when using buccal mucosa dorsal onlay free grafts for the management of bulbar urethral strictures. whereas a 87% success rate when using buccal mucosa urethroplasty to treat 24 pendulous strictures. our series is a 5-year retrospective review, of 24 consecutive patients who underwent buccal mucosa urethroplasty. it is not within the scope of this paper to discuss, in detail, the surgery involved as it is well described in previous studies, but rather to report the outcome following its use. in addition, the nuances such as dorsal versus ventral onlay, one versus two-stage techniques, and the choice of surgery/graft depending on whether the stricture is bulbar pendulous or meatal, are not mentioned in this paper. the overall medium to long-term success rate in our small series is 67.7% at 12th month (when stricture recurrence after stage 1 is considered failure). this lower success rate may be explained with high number of strictures due to trauma and previous hipospadias repair. in the present series, pain, difficulty in chewing and numbness of donor site were the most common early complication. no long-term complications, such as sensory nerve deficit, or damage to stenson’s duct occurred. in paralel to this observation, several authors have reported no important oral complications in their respective studies (14-17). however, in a retrospective review of 49 male patients it was found that 15 (26%) had residual perioral numbness after 6 months, with 5 (9%) having persistent restriction in mouth opening. considering the serious complications, mouth tightness due to oral scar development rates ranged from 9% to 32% in some series with a single serious hematoma case on the graft removal site in the buccal mucosa (18-20). in association with follow-up duration, it is known that all urethral grafts tend to shrink over time. one can claim that, a longer follow-up period is likely to produce poorer results. in this present study the mean follow-up period of 12 months may be the limitation of the study. the other limitation of the study is its retrospective nature. neverthless, in the presence of different stricture etiologies and various parameters such as location, length and surgical techniques, a large prospective randomised trial comparing graft materials and/or techniques would be extremely difficult to design. therefore, despite the relatively small number of patients of our study, the present results seem to contribute modestly to the fact that bmu is a suitable method in substitution urethroplasty. conclusions reconstruction of a urethral stricture, not treatable with end-to-end anastomosis, impose a difficult surgical problem. although the sample size is small, our study suggest that anterior urethral strictures up to 6 cm in length may be effectively managed with bmu. the buccal mucosa is easy to obtain and handle, therefore bmu can be safely and effectively managed outside high volume institutions. furthermore, the rate of complications, from both a urological and oropharyngeal perspective is low. references 1. jordan gh, mccammon ka. surgery of the penis and urethra. campbell-walsh urology. 10th ed. philadelphia: elsevier saunders. 2012; p. 956-1000 2. andrich de, mundy ar. what is the best technique for urethroplasty? eur urol. 2008; 54:1031-1041 3. lumen n, oosterlinck w, hoebeke p. urethral reconstruction using buccal mucosa or penile skin grafts: systematic review and meta-analysis. urol int. 2012; 89:387-394. 4. mangera a, chapple c. management of anterior urethral stricture: an evidence-based approach. curr opin urol. 2010; 20:453458. 5. rogers hs, mcnicholas ta, blandy jp. long-term results of onestage scrotal patch urethroplasty. br j urol. 1992; 69:621-628. 6. sievert kd, seibold j, schultheiss d, et al. reconstructive urology in the change, from its beginning to the close future. urologe a. 2006; 4:52-8. 7l bhargava s, chapple cr. buccal mucosal urethroplasty: is it the new gold standard? bju int. 2004; 93:1191-1193 8. wood dn, allen se, andrich de, et al. the morbidity of buccal mucosal graft harvest for urethroplasty and the effect of nonclosure of the graft harvest site on postoperative pain. j urol. 2004; 172:580-3. 9. bhargava s, chapple cr. buccal mucosal urethroplasty: is it the new gold standard? bju int. 2004; 93:1191-1193. 10. dubey d, vijjan v, kapoor r, et al. dorsal onlay buccal mucosa versus penile skin flap urethroplasty for anterior urethral strictures: results from a randomized prospective trial. j urol. 2007; 178:2466-2469. 11. djordjevic ml. graft surgery in extensive urethral stricture disease. curr urol rep. 2014; 15:424. 12. pansadoro v, emiliozzi p, gaffi m, et al. bmu in the treatment of bulbar urethral strictures. urology. 2003; 61:1008-1010. 13. lumen n, oosterlinck w, hoebeke p. urethral reconstruction using buccal mucosa or penile skin grafts: systematic review and meta-analysis. urol int. 2012; 89:387-394. 14. dubey d, kumar a, mandhani a, et al. buccal mucosal ure141archivio italiano di urologia e andrologia 2017; 89, 2 buccal mucosa urethroplasty cakiroglu_stesura seveso 20/06/17 09:56 pagina 141 archivio italiano di urologia e andrologia 2017; 89, 2 b. cakiroglu, o. sinanoglu, e. arda 142 throplasty: a versatile technique for all urethral segments. bju int. 2005; 95:625-629. 15. grady jd, mccammon k, schlossberg sm, et al. buccal mucosal graft for penile urethral strictures. j urol. 1999; 161:375. 16. morey af, mcaninch jw. technique of harvesting buccal mucosa for urethral reconstruction. j urol. 1996; 155:1696-1697. 17. eppley bl, keating m, rink r. a buccal mucosal harvesting technique for urethral reconstruction. j urol. 1997; 157:1268-1270. 18. dublin n, stewart lh. oral complications after buccal mucosal graft harvest for urethroplasty. bju int. 2004; 94:867-869. 19. caldamone aa, edstrom le, koyle ma, et al. buccal mucosal grafts for urethral reconstruction. urology. 1998; 51(5a suppl):15-19. 20. kane cj, tarman gj, summerton dj, et al. multi-institutional experience with buccal mucosa onlay urethroplasty for bulbar urethral reconstruction. j urol. 2002; 167:1314-1317. correspondence basri cakiroglu, md (corresponding author) drbasri@gmail.com ersan arda, md hisar intercontinental hospital, department of urology, saray mh.siteyolu cad. no.7 34768 umraniye, istanbul, turkey orhun sinanoglu, md maltepe university, medical school department of urology, istanbul, turkey cakiroglu_stesura seveso 20/06/17 09:56 pagina 142 archivio italiano di urologia e andrologia 2019; 91, 3182 original paper how much do people know about male sexual problems? a survey in a selected population sample edoardo s. pescatori 1, anna baldini 2, fabio parazzini 3, 4, nicola ghidini 5, giovanni l. briganti 2 1 andrology service, hesperia hospital, modena, italy; 2 cittadinanzattiva, bologna, italy; 3 dipartimento di scienze cliniche e di comunità, università degli studi di milano, italy; 4 fondazione irccs ca’ granda ospedale maggiore policlinico, milano, italy; 5 urology department, hesperia hospital, modena, italy. objectives: our purpose has been to investigate by an ad hoc questionnaire the knowledge of several aspects of male sexual dysfunction in a significant sample of men and women (largely not physicians) attending an international health care exhibition, held in italy. materials and methods: the survey took place during exposanità, 2018 edition, aimed at medical and non-medical professionals. we devised as investigation tool an ad hoc anonymous questionnaire in two versions, one for each sex. object of this report are questions addressing subject’s knowledge of prevalence of erectile dysfunction (ed), ed causes, ed as early sign of coronary heart disease/myocardial infarction, available ed treatments and attitudes towards penile prosthesis, and reimbursement of ed treatments. results: as many as 1094 convention attendees (495 men, 599 women) participated to the survey (about 4% of total attendees). mean sample age was 40.5 years in men and 39.9 years in women. forty-three percent of the sample worked in healthrelated professions, 5.9% being physicians. respondents globally over-estimated the prevalence of ed. both responding men and women rated psychologic and lifestyle factors as the most frequent ed causes. the majority of responders did not regard ed as a possible predictor of cardiovascular events. oral pills resulted the most known ed treatment by both men (77.2%) and women (79.1%). psychotherapy ranked as the second most known treatment approach. other effective ed treatments (intracavernosal injections, vacuum erection device, penile prostheses) were known by a minority of men (22.2-27.9%) and women (19.2-20.2%). roughly half of the sample (50.7% of men and 48.4% of women) were willing to choose (men) or to support (women) the penile prosthesis option in cases of severe ed; majority of both sexes (71.3% of men and 76.3% of women) expressed no resistances to the perspective of penile prosthesis use. vast majority of men (80.3%) and women (80.4%) considered that coverage for ed treatments should be provided by the national health system. conclusions: the outcomes of our survey show both an elevated prevalence of misconceptions on the role of organic factors in the etiology of ed, and ignorance of the implications of ed on cardiovascular health. knowledge of available second level ed treatments resulted scanty. nonetheless, when confronted with the most aggressive treatment, penile prosthesis, majority of both genders responders would undergo/support this surgery, should it be the only way to solve the erectile problem. in this perspective, population appears ready and overall keen to a treatment option that too often is not addressed by majorisummary funding has been provided by a unrestricted grant by boston scientific. introduction male sexual dysfunctions have been significantly acknowledged by the medical community in recent years only: elucidation of male sexual pathophysiology and availability of effective treatments date no more than 3 decades (1, 2). even more recent is the acquisition that erectile dysfunction (ed) can allow early diagnosis, or be a predictor/sentinel event for future cardiovascular events [i.e. ischemic heart disease (ihd), myocardial infarction (mi)] and dysmetabolic conditions (i.e. diabetes) (3, 4). these concepts are well acknowledged by specialists (andrologists, dedicated urologists/endocrinologists), but seldom by the rest of the medical community. the general population appreciates even less all the above, and too often men with sexual problems bypass medical consultations for improper embarrassment, turning to internet for both online information and self-medication. some detrimental consequences of such scenario include: overlooking underlying specific risk factors and/or medical conditions that are consequently not identified and not addressed, and lack of exposure to some second and third line effective treatments (i.e. intracavernosal vasoactive drugs and penile prostheses). the purpose of this survey has been to investigate by an “ad hoc” questionnaire the knowledge of several aspects of male sexual dysfunctions in a significant sample of men and women (largely non physicians) attending an international health care exhibition, held in italy. members of two regional associations for people rights tightly cooperated for the realization of this project: cittadinanzattiva bologna section (www.cittadinanzattivaer.it) (ab, esp, glb) and assertivo (associazione per la salutesessuale e riproduttiva dell’uomo) (esp, ng). doi: 10.4081/aiua.2019.3.182 ty of the medical community when counseling men with severe ed not responsive to conservative approaches. key words: erectile dysfunction; awareness; penile prosthesis; risk factors; impotence. submitted 18 may 2019; accepted 21 may 2019 pescatori_stesura seveso 30/09/19 18:24 pagina 182 183archivio italiano di urologia e andrologia 2019; 91, 3 how much people know about male sexual problems? materials and methods setting the international health care exhibition where the survey took place was exposanità (www.exposanita.it), held in bologna (italy) from 18 to 21 april, 2018. exposanità is the second largest european international health care exhibition in terms of number of exhibitors and product range; it is held in bologna every two years since 1982. it is dedicated to health care and assistance, and it is aimed at all medical and non-medical professionals who operate in various ways in the public and private sectors. the total number of visitors attending the 2018 edition has been 30199. survey tool: the questionnaire an ad hoc anonymous questionnaire has been created (esp, fp) for the purpose of this survey; the questionnaire had two versions, one for each sex. it consisted of a preliminary section with three questions on age, occupation, relational status, and a question for men only if they ever suffered of uro-andrologic conditions. this tool was preliminarly evaluated by experts for its content, and a limited number of questionnaries was administered to non-experts to ascertain questions comprehension. a formal validation was not deemed appropiate as this questionnaire simply investigates the level of knowledge of specific areas. the ensuing 11 core questions addressed the following areas: – subject’s knowledge on frequency, causes, consequences and treatment modalities/reimbursement for ed; attitudes toward penile prosthesis surgery in case of severe ed. these areas will constitute the focus of this report; the respective questions (male version) are reported in appendix (see supplementary materials). – knowledge of frequency of premature ejaculation, risks linked to penile trauma during intercourse, attitudes towards sexual/reproductive screening for female versus male children. such areas will be addressed in future reports. questionnaire administration cittadinanzattiva volunteers handed out the questionnaire to men and women attending exposanità during the first three days of the event; the questionnaire was self-administered. participants were asked to fold the completed questionnaires and place them in dedicated boxes, located in several spots in the convention area. data analysis mean (standard deviation, sd), median (range) or frequency (percent, %) were computed as appropriate. when appropriate confidence limits at 95% of the proportions were computed. differences in proportions were tested using the chi-square test. results out of 30199 exposanità attendees 1094 (495 men and 599 women) filled the questionnaire. table 1 details the characteristics of study participants according to gender. mean sample age was 40.5 years (15.4 sd) in men and 39.9 years (13.4 sd) in women. forty-three percent of the sample worked in health-related professions without a significant difference between men and women; physicians represented 5.9% of the sample. a stable couple relation was present in 51.9% of men and 62.1% of women. a history of uro-andrologic diseases was reported by 24% of men. table 2 shows the answer to questions about knowledge towards ed: 28.1% of men estimated a prevalence of ed in the general population < 10%, and 16.3% responders > 40%. the corresponding figures in women were 24.7% and 22.5% (chi square heterogeneity p = 14.19, p < 0.05). both responding men and women rated psychologic and lifestyle factors as the most frequent causes of ed. the subset of responders that most acknowledged organic conditions and radical pelvic surgery as frequent ed causes is represented by health care professionals. the majority of responders of both sexes and all ages did not regard ed as a possible predictor of ihd. the subset of responders that most acknowledged ed as a predictor of such condition is represented by health care professionals (data not shown in table). oral pills are the most known ed treatment by both men (77.2%) and women (79.1%). psychotherapy is the second most known treatment approach for both sexes: 38.4% in men, and 41.9% in women, respectively. table 1. characteristics of study participants according to gender. women men chi square no. (%)* no. (%) value age (years) mean (sd) 39.9 (13.4) 40.5 (15.4) < 30 184 (30.7) 154 (3.1) 30-<45 185 (30.9) 156 (31.5) 45-<65 207 (34.6) 143 (28.9) 65 or more 23 (3.8) 42 (8.5) occupation medical doctor 25 (4.2) 40 (8.1) nurse 98 (16.4) 47 (9.5) other health professions 135 (22.5) 110 (22.2) other non health professions° 333 (55,6) 294 (59,4) 1.37 (p = ns)°° missing 8 (1.3) 4 (0.8) married/common-low wife/husband yes 372 (62.1) 257 (51.9) no 215 (35.9) 224 (45.3) 0.80; p < 0.01 missing 12 (2.0) 14 (2.8) history of uro andrologic diseases yes --120 (24.2) no ---367 (74.1) missing --7 (1.4) * the sum does not add up the total due to missing values. ° including retired subjects. °° health vs non health professions. sd = standard deviation. pescatori_stesura seveso 30/09/19 18:24 pagina 183 archivio italiano di urologia e andrologia 2019; 91, 3 e.s. pescatori, a. baldini, f. parazzini, n. ghidini, g.l. briganti 184 the other listed effective ed treatments (intracavernosal injections, ved, penile prostheses) are known by a minority of men (22.2-27.9%) and women (19.220.2%). dietary supplements are referred as possible ed treatment by 13.9% of men and by 11.2% of women. no significant differences in terms of answers emerged among different age ranges and different occupations. two questions addressed the perspective of treatment of severe ed by penile prostheses (table 3). the first explored the willingness to choose (men) or to support (women) the penile prosthesis option: roughly half of the sample (50.7% of men and 48.4% of women) was in favor of this choice. the second question investigated possible resistances to the use of penile prostheses, leaving the possibility of a free comment on the reason/s for such resistances. majority of both sexes expressed no resistances (71.3% of men and 76.3% of women). the main reason for resistance was concerns related to the surgical procedure. the majority of both responding men (80.3%) and women (80.4%) considered that coverage for ed treatment should be provided by the national health system. table 2. knowledge/awareness about erectile dysfunction (ed). women men chi square health non health chi square no. (%)* no. (%) value professions professions value how often do you think ed is common? 3 out of 100 men 40 (6.7) 46 (9.3) 38 (8.4) 47 (7.5) 10 out of 100 men 108 (18.0) 93 (18.8) 77 (16.9) 47 (7.5) 20 out of 100 men 132 (22.0) 148 (29.9) 113 (24.8) 163 (26.0) 30 out of 100 men 158 (26.4) 122 (24.6) 128 (28.1) 163 (26.0) 40 out of 100men 97 (16.2) 58 (11.7) 68 (14.9) 86 (13.7) 50 out of 100 men 38 (6.3) 23 (4.6) 14.19, p < 0.05 21 (4.6) (39 (6.2) which do you think are the most frequent causes of ed?** psycological conditions 333 (67.3) 475 (79.3) 20.30, 316 (69.5) 482 (76.9) 7.51 p < 0.01 p < 0.05 hypertension 121 (24.4) 117 (19.5) 3.84, 108 (23.7) 129 (20.6) 1.54 p = 0.05 p0ns diabetes 107 (21.6) 111 (18.5) 1.61, 119 (26.2) 99 (15.8) 17.60 p = ns p < 0.01 vascular diseases 180 (36.4) 182 (30.4) 4.37, 167 (36.7) 193 (30.8) 4.16 p = 0.04 p < 0.05 unhealthy lifestyles 279 (56.4) 373 (62.3) 3.93, 259 (56.9) 388 (61.9) 2.70 p = 0.05 p < ns infectious diseases 63 (12.7) 45 (7.5) 8.28, 59 (13.0) 48 (7.7) 8.35 p < 0.01 p < 0.05 radical pelvic surgery for prostate / bladder cancer 171 (34.5) 210 (35.1) 0.03, 179 (39.3) 196 (31.3) 7.60 p = ns p < 0.05 old age 258 (52.1) 274 (45.7) 4.41, 211 (46.4) 315 (50.29 1.58 p = 0.04 p = ns trauma of the penis 109 (22.0) 157 (26.2) 2.58, 131 (28.8) 135821.5) 7.50 p ns p < 0.05 do you think that the presence of ed can be an “alarm bell” for subsequent development of which of the following diseases?** obesity 110 (18.4) 123 (24.8) 6.79 112 (24.6) 118 (18.8) 5.29 p = 0.01 p = 0.02 kidney diseases 80 (13.4) 53 (10.7) 0.18 59 (13.0) 72 (11.5) 0.55 p = ns p = ns myocardial infarction/coronary hearth diseases 191 (31.9) 177 (35.8) 0.18 172 (37.8) 193 (30.8) 5.81 p = ns p < 0.05 none 270 (45.1) 196 (39.6) 0.07 173 (38.0) 289 (46.1) 7.02 p = ns p < 0.05 what treatments for ed do you know?** supplements 67 (11.2) 69 (13.9) 0.21 64 (14.1) 70 (11.2) 2.74 p = ns p = ns psychotherapy 251 (41.9) 190 (38.4) 0.24 196 (43.1) 244 (38.9) 1.89 p = ns p = ns oral drugs 474 (79.1) 382 (77.2) 0.43 356 (78.2) 491 (78.3) 0.00 p = ns p = ns intracavernosal injections 115 (19.2) 110 (22.2) 0.22 119 (26.2) 105 (16.7) 14.21 p = ns p < 0.05 vacuum erection devices 134 (22.4) 137 (27.7) 0.04 148 (32.5) 122 (19.5) 24.05 p = ns p < 0.01 penile prosthesis 121 (20.2) 138 (27.9) 0.00 143 (31.4) 112 (17.9) 26.97 p = ns p < 0.01 * the sum does not add up the total due to missing values. ++ multiple answers were allowed. pescatori_stesura seveso 30/09/19 18:24 pagina 184 185archivio italiano di urologia e andrologia 2019; 91, 3 how much people know about male sexual problems? discussion male sexual dysfunctions represent a medical area that has been, and is, heavily investigated in many perspectives: dysfunctions prevalence, specific risk factors, impact of distinct dysfunctions on quality of life, treatment modalities and related patient/partner satisfaction and compliance, etc. a recurrent issue among caregivers is the limited access of sufferers to appropriate treatment options, and how to overcome it. surprisingly, minimal attention has been given by the scientific community on what lay people know of male sexual dysfunctions: specific scientific reports are scanty, at best (5, 6). this is a potential significant bias when planning effective strategies to promote male sexual health and better access to effective treatments, as we feel it should be known upfront what people know and what do not know, what people expect, fear, wish, in order to devise targeted interventions. the purpose of our study has been to explore the knowledge of some key aspects of male sexual dysfunctions in a selected population sample expected to have a knowledge of andrologic problems not inferior to the average general population, being professionals working in the health care area, a very minor part only represented by physicians (less than 6%). in order to do so we devised a questionnaire structured in an epidemiologic perspective. a questionnaire investigating the simple knowledge does not require a formal validation, but an expert evaluation and the administration of a few questionnaires to assess the comprehensibility of the questions. this phase was conducted prior to the investigation by the working group. on the other hand, to interview for example the same group of subjects after a period of time with the same questionnaire is biased by the fact that it is possible that many respondents tend to gather information on the topic of the survey after the first administration of the questionnaire. following, we analyze the outcomes of our survey. respondents globally over-estimated the prevalence of ed, in fact about 70% of responders declared that the frequency of ed is 20% or more. published studies refer to an overall ed prevalence in italy of 10% (7, 8). one possible reason for this finding is that sexuality issues draw the attention of lay public, to the extent that they can be perceived more prevalent than their reality. when requested their opinion on the most frequent ed causes, responders incorrectly selected psychological issues, while as many as 80% of them did not regard diabetes and hypertension as leading ed causes. it is of no surprise that the correct answers of organic conditions and radical pelvic surgery have been more frequently selected by health care professionals. similarly, the majority of responders of both sexes and all ages did not regard ed as a possible predictor of ihd; other authors reported similar findings (9, 10). the subset of responders that most acknowledged ed as a predictor of such condition was again represented by health care professionals. oral pills are the most known ed treatment by both men (77.2%) and women (79.1%). psychotherapy is the second most known treatment approach for both sexes: 38.4% of men, and 41.9% of women, respectively. the other listed effective ed treatments (intracavernosal injections, ved, penile prostheses) are known by a minority of men (22.2-27.9%) and women (19.2-20.2%) only. interestingly, the penile prosthesis option as treatment for severe ed is conceptually accepted by half of the sample of both men and women, we can assume largely not directly/indirectly involved in this condition. furthermore, a sharp majority of the sample would not foresee any problem/resistance in having intercourse by means of the penile prosthesis; of the minority that would have concerns with the prosthesis option the main emerging reason is some sort of fear related to the surgical procedure. such outcomes clash with the attitude of the medical community not dedicated to penile surgery that too often negatively depicts the prosthesis option, despite its key role in treating severe ed cases as those resulting from radical prostatectomy, diabetes, peyronie’s disease (11). vast majority of our sample, both men and women, considered that coverage for ed treatment should be provided by the national health system. this suggests that ed is considered as a significant condition that deserves treatment, and that therapies for ed are not perceived as lifestyle issues. study limitations and strengths we upfront elected to investigate a selected sample of professionals, and accordingly we do not aim to extend our findings to the general italian population. a potential limitation of the study is that the interviewed subjects were randomly identified among exhibition participants, but it is possible that subjects who were present all the period of exposanità were more likely interviewed. in any case the distribution of participants was largely similar with the participants to the convention. finally, the participation rate was very high and the missing value very few. the strengths of the study included the fact that it provides information from a large series of men and women, accounting for about 4% of all exposanità attendees. despite the study design limitations, the results of this large survey give a general picture of the opinion about ed in the italian population. table 3. attitude towards the use of penile prosthesis. women men chi square no. (%) no. (%) value if you or your partner had an ed not responding to drugs, what would you choose/recommend? live with the problem 249 (41.6) 222 (44.8) i would like to solve the problem with penile prosthesis 290 (48.4) 251 (50.7) 0.06; p = 0.81 missing 60 (10.0) 22 (4.1) would you have any concern about the use of prosthesis? none 457 (76.3) 353 (71.3) yes 142 (23.7) 142 (28.7) 3.50; p = 0.06 do you think that the costs related to the treatment of ed should be paid by the national health service? yes 481 (80.3) 398(80.4) no 85 (14.2) 84 (17.0) 0.00; p = ns missing 33 (5.5) 13 (2.6) pescatori_stesura seveso 30/09/19 18:24 pagina 185 archivio italiano di urologia e andrologia 2019; 91, 3 e.s. pescatori, a. baldini, f. parazzini, n. ghidini, g.l. briganti 186 conclusions our investigation provides for the first time in italy a view on what a large sample of men and women think of male sexual dysfunctions and related treatments. the population we investigated was represented by professionals involved in the health care area; it can be easily assumed that their knowledge of the questioned topics is at least not inferior of that of the general population. the outcomes of our survey show that also in this more-thanaverage knowledgeable sample there are misconceptions both on the prevalence of organic factors in the etiology of erectile dysfunction and on the implications of ed on ihd. such findings underscore the need of educational programs aimed to promote population awareness on the real ed risk factors, and their tight correlation with cardiovascular conditions: it is expected that ultimately informed men can adopt healthy lifestyles that could promote both sexual and cardiovascular health. when enquiring the knowledge of available treatments for ed it emerged a scanty awareness of second level treatments. nonetheless, when confronted also with the most aggressive treatment, i.e. penile prosthesis, majority of both genders responders would elect to undergo/support this surgery, should it be the only way to solve the erectile problem. in this perspective population appears ready and overall keen to a treatment option that too often is not addressed by the majority of the medical community when counseling men with severe erectile dysfunctions not responsive to conservative treatments. authors’ contributions edoardo s. pescatori: study ideation and study design, manuscript writing; anna baldini: study design, study conduction, manuscript reviewing; fabio parazzini: study design, statistical analysis, manuscript reviewing nicola ghidini: study conduction; giovanni l. briganti: study conduction acknowledgements authors would like to thank stefano piazza (president), and mauro angiolini (secretary) of the association assertivo (associazione per la salute sessuale e riproduttiva del l’uomo), for condivision of the study, support and strategic advices. references 1. kim n, vardi y, padma-nathan h, et al. oxygen tension regulates the nitric oxide pathway. physiological role in penile erection. j clin invest 1993; 91:437-42. 2. virag r. about pharmacologically induced prolonged erection. lancet. 1985; 1:519-20. 3. jackson g. prevention of cardiovascular disease by the early identification of erectile dysfunction. int j impot res. 2008; 20 suppl 2:s9-14. 4. carrillo-larco rm, luza-dueñas ac, urdániga-hung m, et al. diagnosis of erectile dysfunction can be used to improve screening for type 2 diabetes mellitus. diabet med. 2018; 35:1538-1543. 5. laumann eo, nicolosi a, glasser db, et al. sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the global study of sexual attitudes and behaviors. int j impot res. 2005; 17:39-57. 6. low wy, wong yl, zulkifli sn, tan hm. malaysian cultural differences in knowledge, attitudes and practices related to erectile dysfunction: focus group discussions. int j impot res. 2002; 14:440-5. 7. parazzini f, menchini fabris f, bortolotti a, et al. frequency and determinants of erectile dysfunction in italy. eur urol. 2000; 37:43-9. 8. bortolotti a, parazzini f, colli e, landoni m. the epidemiology of erectile dysfunction and its risk factors. int j androl. 1997; 20: 323-34. 9. shabsigh r, kaufman j, magee m, et al. lack of awareness of erectile dysfunction in many men with risk factors for erectile dysfunction. bmc urol. 2010 5; 10:18. 10. kałka d, domagała z, rakowska a, et al. modifiable risk factors for erectile dysfunction: an assessment of the awareness of such factors in patients suffering from ischaemic heart disease. int j impot res. 2016;28:14-9. 11. pescatori e, alei g, antonini g, et al. insist-ed: italian society of andrology registry on penile prosthesis surgery. first data analysis. arch ital urol androl. 2016; 88:122-7. correspondence edoardo s. pescatori, md (corresponding author) info@andrologiapescatori.it andrology service, hesperia hospital via arquà 80/b 41100 modena (italy) anna baldini, mrs a.baldini@cittadinanzattiva-er.it giovanni l. briganti (medical student) giovanni.briganti1990@gmail.com cittadinanzattiva via castiglione, 24 40124 bologna (italy) fabio parazzini, md fabio.parazzini@unimi.it dipartimento di scienze cliniche e di comunità, università degli studi di milano via commenda 9/12 20122 milano (italy) nicola ghidini, md info@nicolaghidini.it urology department, hesperia hospital via arquà 80/b 41100 modena (italy) pescatori_stesura seveso 30/09/19 18:24 pagina 186 archivio italiano di urologia e andrologia 2018; 90, 4260 original paper the role of nutraceutical medications in men with non bacterial chronic prostatitis and chronic pelvic pain syndrome: a prospective non blinded study utilizing flower pollen extracts versus bioflavonoids angela maurizi 1, francesco de luca 1, antonino zanghi 2, emy manzi 3, costantino leonardo 1, michele guidotti 1, f.p. antonaccio 1, valerio olivieri 4, carlo de dominicis 1 1 department of gynaecological and urological sciences, sapienza university of rome, rome, italy; 2 dipartimento di medical and surgical sciences and advanced technologies g.f. ingrassia, university of catania, catania, italy; 3 department of general surgery, santa scolastica hospital, cassino (fr), italy; 4 division of urology, ivrea hospital asl to4, ivrea, turin, italy. introduction: chronic prostatitis (cp)/chronic pelvic pain syndrome (cpps) represents a challenge for the urologist, since the therapeutic efficacy does not always result in a satisfactory quality of life for the patients. often the side effects of the medications used (antiinflammatories, antibiotics, alpha blockers) far outweighs the benefits gained with their admission. the choice of nutraceutical medications is preferred for their effectiveness, that has been accepted and proven by the scientific community, and for the low incidence of side effects. the objective of this study to compare the therapeutic efficacy of the flower pollen extracts (deprox®) versus bioflavonoids in terms of reduction of symptoms, and in the average waiting time of the variation of the national institute of health chronic prostatitis symptom index (nih-cpsi), and to evaluate the quality of life improvement of the patients affected by cp/cpps. methods: among the 68 patients presented with prostatic symptoms to the hospital “umberto i” in rome, italy between march 2016 and june 2016, 54 patients met the clinical diagnosis of cp/cpps (class iiia or iiib according to the nih classification). the patients were assigned to either treatment with deprox® or quercetin based on a randomization scheme previously determined.the nihcpsi, ipss, qol questionnaires were administered. every patient underwent bacterial cultures and trans-rectal ultrasound. results: there was a statistically significant improvement of the nih-cpsi score and qol in the deprox® group (p = < 0.0001 and p = 0.003 respectively). the average waiting time of the variation of the national institute of health chronic prostatitis symptom index (nih-cpsi) was statistically significant (p = 0.0019). in the absence of efficacy of the “conventional” medications, which also carries significant side effects, the dietary supplements may represent a valid alternative. conclusions: deprox® has demonstrated a significant improvement of the symptoms and quality of life of patients diagnosed with by cp/cpps. furthermore, there was a statistical difference in the average waiting time of the variation of the nih-cpsi) score without side effects as compared to the bioflavonoids complex with quercetin. key words: chronic prostatitis; chronic pelvic pain syndrome; prostatic benign diseases; inflammation; pollen extracts.. submitted 3 july 2018; accepted 19 august 2018 summary no conflict of interest declared. introduction in 1995 the national institute of health (nih) proposed a classification of the prostatitis now internationally accepted (1). the overall incidence of prostatitis in italy results to be about 13.8% (2). based on the literature available data, 5% of the prostatitis belongs the categories i and ii. the antibiotics treatment, in general, results in a good response with resolution of symptoms. the majority of the prostatitis, however, is represented by the category iii type. this is a therapeutic challenge for the practitioners. following a first episode of prostatitis, the likelihood of subsequent episodes is very high, ranging from 20% to 50% in proportion to the age of the subject. prior to establish a possible treatment protocol an accurate medical history and physical examination should be carried out. this obviously includes an accurate digital rectal examination. it is also mandatory to administer the nih-cpsi and the international prostate symptom score (i-pss) questionnaires and to perform the meares and stamey test (3), uroflowmetry, urethral swap test, semen culture, total psa and a transrectal ultrasonography. in spite of the fact that type iii prostatitis is by definition non-bacterial, in many cases the antibiotics administration has resulted in a significant improvement of the symptoms. in fact, the literature supports the use of antibiotics in these cases (4, 5). in both cases bacterial and non-bacterial prostatitis alfa blockers can be added to the antibiotics. modern naturopathic doctors however believe that the prescription of antibiotics for chronic pelvic pain syndrome (cpps) can do more harm than good when bacteria has not been identified. however, cpps is linked to a high rate of treatment failure and patient’s frustration due to their unclear etiology and complexity of symptoms. the primary objectives, addressing this condition, are the mitigation of the symptoms, the improvement of the quality of life, minimizing the side effects of the medical treatment. doi: 10.4081/aiua.2018.4.260 maurizi_stesura seveso 10/01/19 16:05 pagina 260 261archivio italiano di urologia e andrologia 2018; 90, 4 efficacy of flower pollen extracts versus bioflavonoids phytotherapeutic agents remains then a suitable choice, especially for their low or absent side effects. however, there are few prospective and controlled studies to support their use (6, 7). several studies demonstrated that a complex of flower pollen extract is able to produce a persistent improvement in symptoms of cpps with a significant reduction of the nih-cpsi index (8, 9). a phase ii study by cai et al. demonstrated that the flower pollen extract, in association with vitamins, improved significantly the symptoms, the pain, and the qol score of patients with non-inflammatory chronic prostatitis (cp)/cpps, without severe side effects (10). additional studies have demonstrated that several other extract might be able to treat cp/cpps. bioflavonoids are a family of polyphenolic molecules, of which the quercetin is a representative. quercetin has a theoretical benefits for patients with an ongoing inflammatory or ischemic process of the prostate, mechanisms, which are recognized to be the basis of cpps. furthermore, the usually suggested diet poor in bioflavonoids (green tea, caffeine, red wine), quercetin in particular, could worsen the symptoms of cp/cpps (11). the administration of bioflavonoids is then indicated in order to improve the quality of life of cp/cpps patients. also, the bioflavonoids have been shown to play a key role in the inhibition of prostatic cancer cells in vitro (19). the objective of this study is to assess the efficacy and tolerability of the pollen extract compared to the quercetin in patients with cp/cpps. the evaluation of the quality of life and the safety of the active principle represent the secondary endpoints of the study. materials and methods we performed a non-sponsored phase i-ii study in a single urological institution. the study was conducted according to good clinical practice guidelines and the ethical principles of the declaration of helsinki. before the beginning of the study, all participants signed a written informed consent. between march 2016 to june 2016, all consecutive patients presenting with clinical diagnosis of cp/cpps (classes iiia or iiib) were recruited in a single urological institution. the study was designed in accordance with the cp/cpps clinical trial guidelines described by chronic prostatitis collaborative research network nih (12). all the eligible patients completed and returned also the base questionnaires (ipss, qol, nih-cpsi). following the guidelines of the european association of urology (eau) every patient underwent an thorough urological examination and meares-stamey test (13). all the patients who qualified for the study were randomized to either receive flower pollen extract (deprox 500® mg 2 capsules once a day), or quercetin (500 mg twice a day) for 4 weeks. the use of bioflavonoids was selected based on the results of shoskes et al. (15). the patients enrolled were blinded to the type of treatment. a telephone follow up was then conducted 10 days after the treatment to ensure the correct compliance, whilst an outpatients follow up was carried out 30 days after the treatment consisting in a new set of questionnaires plus a urological examination and repeat microbiology cultures. inclusion/exclusion criteria inclusion criteria for the enrolment were defined as follows: the presence of persistent pelvic pain for at least 3 months, in the 6 months preceding the study according to the eau guidelines; nih-cpsi pain score greater than 7 and a negative meares-stamey test (14). figure 1. flowchart of the study. diagnosis of cp/cpps n = 68 esclusion criteria – n = 0. age less than 18 years and more than 65 years – n = 0 preexisting serious diseasesdiagnosis of cp/cpps n = 68 – n = 2 known adverse reaction to the active substance – n = 0 positivity to chlamydia trachomatis test, ureaplasma urealyticum, neisseria gonorrhoeae, herpes virus (hsv 1/2) and human papillomavirus (hpv) – n = 5 current antibiotic therapy inclusion criteria – presence of persistent pelvic pain – pain score (nih-cpsi) > 7 – negative meares-stamey test patients enrolled n = 54 control group n = 27 study group n = 27 maurizi_stesura seveso 10/01/19 16:05 pagina 261 archivio italiano di urologia e andrologia 2018; 90, 4 a. maurizi, f. de luca, a. zanghi, e. manzi, c. leonardo, m. guidotti, f.p. antonaccio, v. olivieri, c. de dominicis 262 exclusion criteria were defined as follows: age less than 18 years old and more than 65 years old; anatomical abnormalities of the urinary tract system; additional urologic diseases; post-void residual urine volume (pvr) > 50 cc; known allergy to the active substance; patients who had recently undergone (< 4 weeks) oral or parenteral antibiotics treatment or who were using prophylactic antibiotic treatment (< 4 weeks); positivity to chlamydia trachomatis test, ureaplasma urealyticum, neisseria gonorrhoeae, herpes virus (hsv 1/2) and human papillomavirus (hpv). patients were randomized into two arms: one had flower pollen extract, two tablets in a single daily dose for four weeks in line with the previous study of cai et al. (10). each dose contained 1 g of pollen extract and b1, b6, b2, b 9, b12, and pp vitamins. the remnant patients received quercetin (500 mg) complex twice daily for four weeks, in line with the study conducted by shoskes et al. (15). validated italian versions of nih-cpsi questionnaires (16) and the international prostate symptom (ipss) scores were administered to each patient. the quality of life was evaluated via a translated version of the qol (17). the nih-cpsi was used to determine the effectiveness of clinical therapy (18). in particular, the expected mean difference for nih-cpsi was chosen as the primary endpoint. all the specimen were collected during the urological examination and brought to the laboratory under refrigerated conditions, for cultures, dna extraction and polymerase chain reaction for chlamydia trachomatis, neisseria gonorrhoeae, hsv 1/2, and hpv detection. in addition all the subjects included in the study underwent rectal examination, transrectal ultrasonography, urine and semen cultures, colonies count, and antibiogram if needed (figure 1). statistical analysis the main statistical analysis was performed on the patient population “intent-to-treat”, corresponding to all the randomized patients described in the consort diagram (figure 1), a flowchart including the patients evaluated, randomized, analysed and excluded (for any reason). the baseline patient characteristics are reported as mean, standard deviation (sd), median, interquartile range (iqr), frequency, or relative percentage, depending on the type of variable distribution. for the baseline comparison (t0) in the two arms of the study we utilized the t-test for the independent variables and the comparisons of mean values. the chi-square was instead used for the comparison of proportions. the comparison of the mean values of the nih-cpsi index between baseline (t0) and at 30 days (t1) was done using paired t-test. all the tests were two-tailed and the statistical significant value was determined to be 0.05. the sample size was calculated from a starting average waiting time of the variation of the national institute of health chronic prostatitis symptom index (nih-cpsi) of 13 and a mean observed difference of 11 (sd ± 2.2) (table 1). results of the 68 patients presented at our institution with prostatic like symptoms during the study time, 54 were enrolled and randomized. of the 14 patients excluded, 7 refused the enrolment, 5 were on antibiotic treatment, and 2 reported known allergy to the active substance. the pre-intervention questionnaires had the following scores: nih-cpsi 25.81 ± 1.61; ipss 8.39 ± 1.74; qol 0.55 ± 0.1 (table 2). table 3 summarizes the clinical characteristics and the enrolment data of the samples taken by arm. there was a statistically significant difference in the duration of the symptoms pre-treatment, and a positive trend in the qol. there were no other statistically significant differences. at one month follow up the observed results between patients that had taken the flower pollen extract were as follows: nih-cpsi 12.22 ± 1.84, ipss 7.3 ± 1.54, qol 0.66 ± 0.1. whereas the results for patients that had taken quercetin at the same interval were: nih-cpsi 14.85 ± 1.85, ipss 7.67 ± 1.27, qol 0.59 ± 0.1 (table 4). the improvement of the symptoms after taking flower pollen extract was statistically significant as compared to them taking quercetin (p = < 0.0001). the qol score was also statistically superior in those taking flower pollen extract (p = 0.003). on the other hand, the ipss score was similar among the two groups (p = 0.39). at the follow up all patients had a negative meares-stamey test, and showed similar laboratory values, as compared to the initial parameters. no adverse reactions have been reported from the treatment in either arms. the expected value (∆ nih-cpsi), depicted in chart i and ii, obtained by evaluating the expected mean difference for the two arms of the nih-cpsi pre and post treatment, was of 13.4444 ± 2.55 for the flower pollen extract , and of 11.11 ± 2.69 for the quercetin, being statistically significant (p = 0.0019) (figure 1). discussion the main result of this study is the efficacy of the flower pollen extract in improving the quality of life and table 1. calculation of the sample size. table 2. patients enrolled in the study. alpha level 0.05 power 90% observed average score 11 expected average delta 13 standard deviation 2.2 n 54 (27 per arm) number of patients 54 age 33 ± 5.25 condition duration 18.85 ± 4.17 nih-cpsi t0 25.81 ± 1.61 ipss t0 8.39 ± 1.74 qol t0 0.55 ± 0.1 maurizi_stesura seveso 10/01/19 16:05 pagina 262 263archivio italiano di urologia e andrologia 2018; 90, 4 efficacy of flower pollen extracts versus bioflavonoids reduce pain in patients with cp/cpps in a statistically significant way compared to the bioflavonoids complex with quercetin. this therapeutic improvement holds true for both the type iiia and iiib cp/cpps patients. those results are in line with the current literature showing the reduction of pain after 30 days of use of flower pollen extract compared to quercetin (10). this effect is probably secondary to the association between the pollen extract and the vitamins b6 and b12, which enhances the protective effects of the pollen extract on the nerves. in fact, as demonstrated in animal experiments, the vitamin b complex (including b1, b6, and b12) has analgesic effects in acute and chronic pain secondary to electrical and thermal stimulation, primary and post diabetic neuronal damage (20, 21). several studies have demonstrated that certain vitamin b, b6 and b12 in particular, are capable of protecting the neurons from specific lesions (22, 23). vitamin b1, b6, and b12 are effective in the treatment of painful syndromes such has lumbago, sciatic nerve neuralgia, trigeminal neuralgia, and the chronic pain associated with diabetic polyneuropathy (24). in contrast to previous studies, our results show that there was no difference in either treatment arms between patient with non-inflammatory cp/cpps and inflammatory cp/cpps. both the flower pollen extract and the quercetin were well tolerated for the entire duration of the protocol. the limitations of this study are the small number of patients enrolled, a short follow up period, and the selected nature of the patients enrolled. furthermore, this was not set up as a double blind study. in the absence of a therapeutic efficacy of the “conventional” medications, the therapeutic options with nutritional supplements are a valid alternative. in deciding the therapeutic intervention it is necessary to choose the active principle that determines an improvement of the qol, the reduction of pain, with high safety levels. conclusions considering the above mentioned limitations, the flower pollen extract determined a significant improvement of the symptoms (pain, and quality of life) in the patients with cp/cpps. a statistically significant difference was also noted in the expected value of the national institute of health chronic prostatitis symptom index (∆ nih-cpsi) in the flower pollen extract group as compared to the bioflavonoids complex with quercetin, without side effects. references 1. krieger jn, et al. nih consensus definition and classification of prostatitis. jama. 1999; 282:236-7 2. bartoletti r, et al. italian prostatis study group. prevalence, incidence estimation, risk factors and characterization of chronic prostatitis/ chronic pelvic pain syndrome in urological hospital outpatients in italy: results of a multicenter case-control observational study. j urol. 2007; 178:2411-5 3. stamey ta. prostatitis. j r soc med. 1981; 74:22-40. 4. wagenlehner fm, weidner w, naber kg. therapy for prostatitis, with emphasis on bacterial prostatitis. expert pin pharmacother. 2007; 8:1667-74. 5. nickel jc. treatment of chronic prostatitis/chronic pelvic pain syndrome. int j antimicrob agents. 2008; 31 (suppl 1):s112-6. 6. herati as, moldwin rm. alternative therapies in the management of chronic prostatitis/chronic pelvic pain syndrome. world j urol. 2013; 31:761-766. 7. shoskes da, zeitlin si, shahed a, rajfer j. quercetin in men with category iii chronic prostatitis: a preliminary prospective, doubleblind, placebo-controlled trial. urology. 1999; 54:960-963. 8. rugendorff ew, weidner w, ebeling l, buck ac. results of treatment with pollen extract (cernilton n) in chronic prostatitis and prostatodynia. br j urol. 1993; 71:433-438. 9. kamijo t, sato s, kitamura t. effect of cernitin pollen-extract on experimental nonbacterial prostatitis in rats. prostate. 2001; 49:122-131. 10. cai t, luciani lg, caola i, et al. effects of pollen extract in association with vitamins (deprox 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. urologia. 2013; 80(suppl 22):5-10. deprox 500® quercitina p value group group number of patients 27 27 age 34 ± 5.9 33.7 ± 4.62 0.81 smokers (%) 63% 48% 0.27 condition duration 17.56 ± 3.88 20.15 ± 4.11 0.02 nih-cpsi t0 25.67 ± 1.62 25.96 ± 1.63 0.5 ipss t0 8.3 ± 2.13 8.5 ± 1.3 0.7 qol t0 0.53 ± 0.1 0.58 ± 0.1 0.07 dysuria 11 (40.8%) 12 (44.5%) 0.95 urgency 6 (22.2%) 5 (18.5%) dysuria+frequency 4 (14.8%) 3 (11%) burning sensation 6 (22.2%) 7 (26%) perineal pain 12 (44..5) 7 (26%) 0.54 scrotal pain 5 (18.5) 8 (30%) soprapubic pain 5 (18.5) 6 (22%) lower abdominal pain 5 (18.5) 5 (18%) no pain 1 (4%) erectile dysfunction (ed) 12 (44%) 10 (37%) 0.94 pramture ejaculation pe) 3 (11%) 3(11%) de+pe 4 (15%) 4 (15%) no sexual symptoms 8 (30%) 10 (37%) type iiia 13 (48%) 11 (41%) 0.58 type iiib 14 (52%) 16 (29%) variables deprox 500® quercitina p value (after 30 days of therapy) group group nih-cpsi t1 12.22 ± 1.84 14.85 ± 1.85 < 0.0001 ipss t1 7.3 ± 1.54 7.67 ± 1.27 0.39 qol t1 0.66 ± 0.1 0.59 ± 0.1 0.003 table 3. clinical characteristics and enrollment data of the samples taken by arm. table 4. 1 month follow up. maurizi_stesura seveso 10/01/19 16:05 pagina 263 archivio italiano di urologia e andrologia 2018; 90, 4 a. maurizi, f. de luca, a. zanghi, e. manzi, c. leonardo, m. guidotti, f.p. antonaccio, v. olivieri, c. de dominicis 264 11. shoskes da, nickel jc. quercetin for chronic prostatitis/chronic pelvic pain syndrome. urol clin north am. 2011; 38:279-84. 12. propert kj, alexander rb, nickel jc, et al. chronic prostatitis collaborative research network. design of a multicenter randomized clinical trial for chronic prostatitis/chronic pelvic pain syndrome. urology. 2002; 59:870-876. 13. grabe m, bjerklund-johansen te, botto h, et al. guidelines on urological infections. european association of urology; arnhem, the netherlands: 2012. p. 66. 14. wagenlehner fm, schneider h, ludwig m, et al. a pollen extract (cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. eur urol. 2009; 56:544-551. 15. shoskes da. quercetin in men with category iii chronic prostatitis: a preliminary prospective, double-blind, placebocontrolled trial. urology. 1999; 54:960-963. 16. giubilei g, mondaini n, crisci a, et al. the italian version of the national institutes of health chronic prostatitis symptom index. eur urol. 2005; 47:805-811. 17. kaplan rm, bush jw, berry cc. health status: types of validity and the index of well-being. health serv res. 1976; 11:478-507. 18. nickel jc, downey j, hunter d, clark j. prevalence of prostatitis-like symptoms in a population based study using the national institutes of health chronic prostatitis symptom index. j urol. 2001; 165:842-845. 19. sharma v, et al. sensitization of androgen refractory prostate cancer cells to anti-androgens through reexpression of epigenetically repressed androgen receptor synergistic action of quercetin and curcumin. mol cell endocrinol. 2016; 431:12-2. 20. jolivalt cg, mizisin lm, nelson a, et al. b vitamins alleviate indices of neuropathic pain in diabetic rats. eur j pharmacol. 2009; 612:41-47. 21. yu cz, liu yp, liu s, et al. systematic administration of b vitamins attenuates neuropathic hyperalgesia and reduces spinal neuron injury following temporary spinal cord ischaemia in rats. eur j pain. 2014; 18:76-85. 22. wang zb, gan q, rupert rl, et al. thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. pain. 2005; 114:266-277. 23. hung kl, wang cc, huang cy, wang sj. cyanocobalamin, vitamin b12, depresses glutamate release through inhibition of voltage-dependent ca2+ influx in rat cerebrocortical nerve terminals (synaptosomes) eur j pharmacol. 2009; 602:230-237. 24. mäder r, deutsch h, siebert gk, et al. vitamin status of inpatients with chronic cephalgia and dysfunction pain syndrome and effects of a vitamin supplementation. int j vitam nutr res. 1988; 58:436-441. correspondence angela maurizi, md (corresponding author) angmau81@hotmail.com francesco de luca, md francescodeluca10@gmail.com costantino leonardo, md michele guidotti, md f.p. antonaccio, md carlo de dominicis, md, professor dipartimento di scienze ginecologico-ostetriche e scienze urologiche, università sapienza viale dell'università, 31/33, 00161, roma, italy antonino zanghì, md dipartimento di scienze mediche, chirurgiche e tecnologie avanzate g.f. ingrassia, università di catania, catania, italy emy manzi, md emymanzi@gmail.com via san pasquale, 03043 cassino (fr), italy valerio olivieri, md valerio.olivieri@uniroma1.it piazza credenza 2, 10015 ivrea (to), italy maurizi_stesura seveso 10/01/19 16:05 pagina 264 325archivio italiano di urologia e andrologia 2017; 89, 4 case report an unusual case of pneumatic nail gun scrotal injury and revision of the literature filippo migliorini 1, leonardo bizzotto 1, pierpaolo curti 2, antonio benito porcaro 1, walter artibani 1 1 department of urology, azienda ospedaliera universitaria integrata, verona, italy; 2 department of urology, ospedale “mater salutis”, legnago, verona, italy. pneumatic nail guns are hand-held tools commonly utilized in both industrial and non occupational setting. these devices facilitate production and boost efficiency but also can be a potential cause of serious injuries. nail guns are the most frequent tool associated trauma with hospitalization among construction workers. the most common sites of injuries are the hand or fingers followed by the lower extremities. we report the first case in literature of a work nail gun injury to male external genitalia. key words: pneumatic nail gun; injury; scrotum; epididymis. submitted 24 august 2017; accepted 21 september 2017 summary no conflict of interest declared. inside the head of the left epididymis was detected a nail (figure 1b) which was easily gently removed in a retrograde fashion. the patient was discharged the next day with no sequelae. discussion since 1959, when pneumatically powered nail guns were introduced in the construction industry, there has been an increasing number of accidents involving these devices (3-5). these tools are efficient, readily available, and easy to use, making them common employed in residential construction, wood-production industries and in non occupational setting (6). pneumatic nail guns have a safety device at the end of the gun muzzle that must be depressed before the fastener can be discharged. there are generally two types of trigger systems which then define how the nail gun fires in response to a trigger press: the sequential actuation trigger (sat) requires that each nail can only be discharged when the safety tip is first depressed and, while held depressed, the trigger is squeezed. the other one is the cat which allows the operator to first squeeze the trigger and, while holding the trigger squeezed, repeatedly bump the safety tip on the work piece to shoot multiple nails. traumatic injuries can occur when an operator intentionally discharges a nail using both types of actuation systems. however, a nail gun equipped with a sat system is much less likely to be discharged unintendoi: 10.4081/aiua.2017.4.325 introduction pneumatic nailers increase production rates in many jobs and reduce manufactoring cost. these tools impart a large amount of energy to a small “projectile” that, if not properly aimed, it can be a potential cause of injury ranging from a slight scratch to serious life threatening trauma and death (1-2). numerous cases of nail gun injuries have been documented involving not only the extremities but also brain, eyes, neck, heart, thorax, spinal cord, bowel and liver (3). according to our best knowledge, an external male genitalia pneumatic nail gun penetrating injury has never been described before. case report a 53-year-old right handed caucasian male, furniture maker presented to the local emergency department for a work pneumatic nail gun injury. the patient, while using a pneumatic nail gun equiped with contact actuation trigger (cat) security system, accidentally slipped and involuntarily fired a nail with sudden onset of scrotal pain. physical examination pointed out a puncture wound in the left side of the scrotum, tenderness of the left testicle and epididymis with no signs of bleeding or haematoma. the x-ray rivealed a thin nail of about 20 mm in length in the left side of the scrotum (figure 1a). a scrotal color doppler ultrasound showed regular testicles and the presence of a thin linear hyperechoic foreign body at the head of left epididymis with no signs of haematoma. blood tests were regular. the patient, after been given prophylaxis with human tetanus immunoglobulin and antibiotic, underwent urgent surgical scrotal exploration. almost completely figure 1. a) the nail at x-ray; b) the nail at the head of the left epididymis. migliorini_stesura seveso 03/01/18 09:50 pagina 325 archivio italiano di urologia e andrologia 2017; 89, 4 f. migliorini, l. bizzotto, p. curti, a.b. porcaro, w. artibani 326 tionally, as the trigger must be activated while the safety tip is depressed against the body. unintentional nail discharge using the cat system typically takes place following nail gun recoil (resulting in a “double fire” second unintended shot) or when the operator has their finger on the trigger and the nail gun nose inadvertently contacts an object (1, 7). gun nailers impart a large amount of energy to a small “projectile” witch can reach the velocity of up to 1500 km/h. the amount of energy required to cause serious injury is fairly low: penetrating of the skin occurs with “projectile” velocities of 165 km/h, whereas bony fractures may occur with a velocities of 215 km/h. when a nail penetrates human tissues the kinetic energy transfers from the object to the surrounding tissues. as the shock wave expand, the temporary cavity created causes crush and stretch damage to tissues (8, 9). from 2006 to 2011 in us hospital eds, a total of 151,000 injuries due to nail guns were treated and just over half of these were work-related. puncture wounds and foreign bodies accounted for over 85% injuries, followed by fractures. approximately 90% of the patients were treated and released and 10% were treated and admitted. injuries most commonly involved the hand/fingers in 56% of the cases, followed by the wrist or lower arm (8.3%), foot or toes (6.9%), knee (4.8%), and eye (4.3%) (10). case reports have described injuries to the thorax, heart, abdominal wall, flank, pelvic wall, facial bones, skull. paralytic spinal cord transection, bowel perforation, long bone fracture, liver laceration, hemopneumothorax, blindness, cerebral damage, and even fatal injuries have been reported (11-13). these trauma can also often be complicated by contamination with oil, paper, or glue and the combination of tissue edema, devitalized tissue, and foreign matter provides an ideal environment for local infection (14). the evaluation of patient with a suspect of retained nail begins with a careful history and physical examination followed by an x ray and, in some cases, an ultrasound or computed tomography scan. special attention should be given to the type of nail gun used and the mechanism of injury. status of tetanus immunization must also be determined and antibiotic prophylaxis has to be given. in case of nail embedded or close to vascular/nervous structures a surgical exploration is mandatory (3). our unusual case of work scrotal injury due to a pneumatic nail gun is the first reported in literature and required a surgical treatment. since these tools will likely continue to be used, management can reduce worker exposure to nail-gun hazards by using a combination of engineering controls, administrative controls and personal protective equipment (7). references 1. lipscomb hj, dement jm, nolan j, et al. nail gun injuries in residential carpentry: lessons from active injury surveillance. inj prev. 2003; 9:20-24. 2. schaller bj, kleindienst a, kruschat t, et al. industrial nail gun injury to the anterior skull base: a case report and review of the literature. j trauma. 2008; 64:e29-32. 3. pierpont yn, pappas-politis e, naidu dk, et al. nail-gun injuries to the hand. eplasty. 2008; 8:479-488. 4. edlich rf, silloway ka, rodeheaver gt, et al. industrial nail gun injuries. compr ther. 1986; 12:42-46. 5. absoud em, harrop sn. hand injuries at work. j hand surg br. 1984; 9:211-5. 6. hoffman dr, jebson pj, steyers cm. nail gun injuries of the hand. am fam physician. 1997; 56:1643-6. 7. albers j, lowe b, lipscomb h, et al. revisiting pneumatic nail gun trigger recommendations. prof saf. 2015; 60:30-33. 8. ordog gj, wasserberger j, balasubramaniam s. shotgun wound ballistics. j trauma. 1988; 28:624-31. 9. childs sa. nail gun injury. orthop nurs. 1991; 10:15-8. 10. lipscomb hj, schoenfisch al. nail gun injuries treated in u.s emergency departments, 2006-2011: not just a worker safety issue. am j ind med. 2015; 58:880-885 11. webb dp, ramsey jj, dignan rj, drinkwater dc jr. penetrating injury to the heart requiring cardiopulmonary bypass: a case study. j extra corpor technol. 2001; 33:249-51. 12. jithoo r, govender st, nathoo n. penetrating nail gun injury of the head and chest with incidental pericallosal artery aneurysm. s afr med j. 2001; 91:316-7. 13. wang mj, chen is, tsai sk. nail gun penetrating injury of the left ventricle and descending aorta. circulation. 1999; 100:e18-9. 14. tikka s. the contamination of missile wounds with special reference to early antimicrobial therapy. acta chir scand suppl. 1982; 508:281-7. correspondence filippo migliorini, md (corresponding author) filippo.migliorini@aovr.veneto.it leonardo bizzotto, md antonio benito porcaro, md walter artibani, md department of urology, azienda ospedaliera universitaria integrata piazzale stefani 1, it37126 verona, italy pierpaolo curti, md department of urology, ospedale “mater salutis”, legnago, verona, italy migliorini_stesura seveso 03/01/18 09:50 pagina 326 335archivio italiano di urologia e andrologia 2016; 88, 4 case report intraoperative ultrasound-guided enucleation of testicular nodule riccardo boschian 1, giovanni liguori 1, stefano bucci 1, michele bertolotto 1, carlo trombetta 1 department of urology and radiology, university of trieste, trieste, italy; objective: we report a case of enucleation of a non-palpable right testicular lesion found incidentally at testicular ultrasonography during investigations in a patient with azoospermia. materials and methods: in 2011 bilateral hypoechoic nonpalpable testicular lesions (5 mm and 3 mm to the right, 3 mm to the left) were found in a 28 years old patient, during diagnostic investigations for azoospermia. in march 2016, ultrasonography showed that the diameter of the right major nodule had grown to 12 mm, characterized by increased vascularization and increased texture. blood exams showed serum fsh above normal levels with negative oncologic markers. the patients underwent surgical enucleation of the right nodule under ultrasonography guidance. results: in post operative day 1 a control ultrasonography documented the disappearance of the lesion. hystopathologic examination diagnosed a leydig cell tumor, with negative surgical margins. the patient is in good clinical conditions and is under periodic ultrasonographic follow up. conclusion: organ sparing surgery represent a good therapeutic option for little intraparenchymal lesions, mostly in young patients in which is preferable to preserve fertility. intraoperatory ultrasonography represent an important tool for the localization of the lesion. key words: leydig cell tumor; ultrasonography; testis sparing surgery. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. periodic ultrasonography follow up showed a progressive increase of the 5 mm right nodule. in march 2016, colordoppler ultrasound showed that the diameter of the right nodule had grown to 12 mm, characterized by increased vascularization and increased texture to elastography. blood exams showed serum fsh above normal levels but normal serum lh and testosterone, with negative oncologic markers. surgical technique: after right inguinal incision and access to the inguinal canal, the right spermatic cord was identified and isolated to the external inguinal ring, with subsequent exteriorization of the testicle. the testicular nodule was identified with intraoperative ultrasonography and marked with a needle. after incision of tunica albuginea, the nodule was resected by blunt dissection and the surgical specimen was sent to histopathological examination. the tunica albuginea was closed and after the eversion of the tunica vaginalis, the testicle was repositioned in the scrotum. intraoperative histological examination diagnosed a leydig cell tumor. results the post operative course was regular, without complications and the patient is in good clinical conditions. in post operative day 1 ultrasonography was performed with the evidence of the disappearance of the lesion in absence of intraparenchymal hematoma. histopathologic exam diagnosed a leydig cell tumor with surgical margins free from disease. the tumor was immunopositive for calretinin, alpha-inhibin and melan-a, with a weak positivity for p53. because of the presence of bilateral lesions (of stable dimensions through the years) and the positivity for p53, the patients is actually under periodic ultrasound follow up. discussion leydig cell tumours represent about 1-3% of adult testicular tumours and are most common in the third to sixth decade in adults (1). only 3% of leydig cell tumours are bilateral and it is the benign definitive histology in 80% of the cases (1). frequently its clinical presentation is asymptomatic with typical features as gynaecomastia, infertility or endocrinological disorders doi: 10.4081/aiua.2016.4.335 presented at 20th national congress sieun, sciacca 2016 case report we report a case of resection of a non-palpable right testicular lesion (histopathologic examination revealed a leydig cell tumor) found incidentally at testicular ultrasonography during investigations in a patient with azoospermia. materials and methods a 28 years old patient underwent surgical enucleation under ultrasonography guidance of a 12 mm nodule to the right testicle. in 2011 bilateral hypoechoic non-palpable testicular lesions, respectively of 5 mm and 3 mm to the right and 3 mm to the left, were found in the patient during diagnostic investigations for azoospermia. through the years boschian-intraoperative ultrasound_stesura seveso 09/01/17 10:47 pagina 335 archivio italiano di urologia e andrologia 2016; 88, 4 r. boschian, g. liguori, s. bucci, m. bertolotto, c. trombetta 336 and it is often detected as a collateral finding during radiological investigations (mostly ultrasonography). testis sparing surgery is highly recommended in every small, non palpable, ultrasound-detected nodule, in absence of rete testis invasion and with normal serum lh and testosterone (1, 2). if the histological examination reveals a malignant tumor, it is possible to perform a delayed orchidectomy. conclusions testis sparing surgery represent a good therapeutic option for little intraparenchymal lesions, mostly in young patients in which is preferable to preserve fertility. intraoperative ultrasonography represent an important tool for the precise identification and marking of the lesion, helping guarantee a radical excision as accurate as possible. references 1. albers p, albrecht w, algaba f, et al. eau guidelines on testicular cancer. 2. giannarini g, dieckmann kp, albers p, et al. organ-sparing surgery for adult testicular tumours: a systematic review of the literature. eur urol. 2010; 57:780-90. correspondence riccardo boschian, md (corresponding author) rboschian@gmail.com giovanni liguori, md gioliguori33@gmail.com stefano bucci, md urostef@yahoo.it michele bertolotto, md bertolot@univ.trieste.it carlo trombetta, md trombcar@units.it department of urology, university of trieste, trieste, italy boschian-intraoperative ultrasound_stesura seveso 09/01/17 10:47 pagina 336 archivio italiano di urologia e andrologia 2019; 91, 4212 original paper mri/trus fusion guided biopsy as first approach in ambulatory setting: feasibility and performance of a new fusion device daniele d’agostino 1, federico mineo bianchi 2, daniele romagnoli 1, marco giampaoli 1, paolo corsi 1, alessandro del rosso 1, riccardo schiavina 2, eugenio brunocilla 2, angelo porreca 1 1 department of robotic urological surgery, abano terme hospital, abano terme, italy; 2 department of urology, university of bologna, bologna, italy. purpose: to evaluate the detection rate of magnetic resonance imaging/transrectal ultrasound (mri/trus) fusion biopsy performed in a series of patients with suspicious prostate cancer in an ambulatory setting. materials and methods: between march 2018 and january 2019 a series of 155 patients undergoing mri/trus fusionguided biopsy were prospectively enrolled. all patients presented a suspected diagnosis for prostate cancer because of raised prostate specific antigen (psa) serum level and/or abnormal physical examination (digital rectal examination), and showed at least one suspicious area at the multiparametric magnetic resonance imaging (mpmri). results: of 155 patients, 58 (37.4%) were biopsy-naïve, 97 (62.6%) had at least 1 previous negative trus-guided biopsy. the median age of the patient cohort was 66 years (iqr, 6169); the median prebiopsy psa value was 7.1 ng/ml (iqr, 58.9). overall, the fusion-tb findings were positive in 94 of 155 patients with a detection rate (dr) of 60%; a significantly high dr was obtained in terms of clinically significant prostate cancer (cspca) by fusion-tb (61 pts; 41.9%). the overall dr in the 121 biopsy-naive patients was 60.6%. in the subgroup of the 34 patients with at least 1 previous set of trus-gb, overall dr was 39.3% (35/50). conclusions: the targeted mri/trus fusion-guided biopsy represents a safe and accurate approach for diagnosis of cspca, especially in patient with previous trus guided biopsy negative and suspicious prostate cancer. key words: prostate cancer; magnetic resonance; prostate biopsy. submitted 8 july 2019; accepted 2 august 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.212 introduction prostate cancer (pca) is the most frequent among solid tumors in the male sex, as emerges from the 2016 estimate of the american cancer society (1). currently, diagnosis of pca is one of the most debated topics in the urology literature (2) and is based on the serum dosage of prostate specific antigen (psa) and digital rectal exploration. psa levels can be elevated not only in the case of prostatic carcinoma but also in the case of other pathologies, such as benign prostatic hyperplasia and inflammatory states of different nature (3) with consequent risk of over-diagnosis and over-treatment. although the introduction of psa has radically changed the diagnosis of pca, as amply highlighted by the literature, it is a test that has limits in terms of sensitivity and specificity; for example about 15% of men with psa levels equal to or below 4.0 ng/ml are affected by prostatic carcinoma that in about 15% of cases is of high-grade (4). to date, the conventional diagnosis of prostatic carcinoma is performed by identifying histopathology on systematic ultrasound-guided biopsy specimens with a sensitivity of 45-70% for clinically significant pca (5). the main disadvantages related to this method are the loss of identification of a substantial portion of patients with significant prostatic carcinoma (about 20%) linked to sampling errors, in particular at the level of the anterior prostate area (6) and the possibility of important complications following the procedure, above all related to sampling performed by trans-rectal ultrasound-guided biopsy (7). the actually limited detection rate represents an important concern and the management of patients with persistent suspected diagnosis of pca and previous set of negative biopsies represents a continuing challenge. magnetic resonance imaging (mri) has shown a high sensitivity and specificity in diagnosing clinically significant pca (cspca) (5, 6) and, exploiting the use of functional studies, multiparametric mri (mpmri) improves the identification of pca lesion within the gland (7, 8). a growing body of evidence suggests that mpmri, improving the risk classification of lesions, could reduce false-negative rates and the necessity of repeat biopsies in presence of suspected pca (8, 9); not surprisingly, a mri targeted biopsy should be strongly applied for any patient with a prior negative set of prostate biopsy who has persistent clinical suspected diagnosis for pca as reported by recent aua consensus statement (9); more frequently mri is used in the first diagnostic phase for pca; for this reason the mri-guided approach of prostatic biopsy is increasingly used. approaches for targeted biopsy include visual estimation trus-gb (cognitive technique), software co-registered mri-ultrasound fusion (fusion technique) and in-bore mri-guided biopsy (mri-gb). studies from literature suggest that there was no significant advantage of mri-gb compared with fusion technique concerning overall d'agostino_stesura seveso 10/01/20 09:02 pagina 212 213archivio italiano di urologia e andrologia 2019; 91, 4 mri/trus fusion guided biopsy detection rate and clinical significant neoplasm detection rate (10) even if the main potential limitation of mri-gb consist of impossibility to perform a simultaneous standard trus biopsy, especially in biopsy naive patients, since up to 16% of men with no suspicious mpmri could reveal cscap on systematic biopsy (11). different software for mri/trus fusion-guided biopsy systems are at the present time used: the aim of this study was to evaluate the detection rate of mri trus fusion biopsy performed in a series of patients with suspicious pca in ambulatory setting with a new fusion device. materials and methods patients cohort and methodology between march 2018 and january 2019 a series of 155 patients undergoing mri/trus fusion-guided biopsy were prospectively enrolled. all patients had a suspected diagnosis for pca because of elevated value of prostate specific antigen (psa) serum level and/or abnormal physical examination (digital rectal examination), and showed at least one suspicious area at the mpmri. according to the european society of urogenital radiology (esur) guidelines, the presence of cspca at mpmri was defined equivocal, likely or highly likely basing on the pirads-v2 (prostate imaging reporting and data systemversion 2) score of 3/5, 4/5 or 5/5, respectively; the localization of index lesion are reported in table 2 (12). this study was conducted under the approval of local institutional review board and in the accordance with good clinical practice guidelines and the ethical principles of the declaration of helsinki. primary endpoints of this study were overall detection rates of pca (pca dr), cspca detection rate (cspca dr). secondary endpoints were correlations between mpmri parameters biopsy results, comparison to definitive pathologic results of surgical specimens (when available) and complications rates. multiparametric magnetic resonance imaging and analysis mri examination and analysis. all the mri examinations were performed with a 32 channels 1.5 t whole body scanner (achieva xr; philips medical systems, best, netherlands) with a 32-channels phased-array surface coil without endorectal coil. after local three-plane acquisition, required for the correct positioning of the sequences, the morphological and functional studies were carried out. morphological study of the prostate gland were obtained with turbo spin echo (tse) t2weighted sequences (te 100 msec, tr 4074 msec, slice thickness 3 mm, slice spacing 0.3 mm, field of view fov 180 x 180 mm and matrix size 276 x 205) in the sagittal, axial and coronal planes, including seminal vesicles and the entire prostate gland. for the functional study, dwi, dce-mri and mrs acquisition were performed. the dwi acquisition was carried out in the axial plane, using a single-shot echo-planar imaging (ssepi) sequence, with three b-values (0, 600 and 1500 s/mm2), slice thickness of 3 mm, fov 180 x 180 mm and matrix size 80 x 71. the dce-mri was obtained using threedimensional (3d) t1w high resolution isotropic volume examination (thrive) sequence during the intravenous injection of a contrast bolus of 0.1 mmol per kilogram of body weight of meglumine gadobenate (multihance, bracco diagnostics, milan, italy), at flow rate of 3.5 ml/sec followed by 15 ml of saline solution. conduct of the biopsy the biopsies were performed within three weeks from the first diagnostic mpmri study by a single urologist with a consolidated experience in mri fusion-gb. all patients received oral antibiotic prophylaxis with quinolones (ciprofloxacin 500 mg) twice a day, started the day before the procedure and prolonged for at least 2 days thereafter. prostate biopsy procedures were conducted in an ambulatory setting with patient in lithotomic position. peri-prostatic nerve blockade local anesthesia with lidocaine 2% was administered immediately before biopsy to each patient. biopsies were conducted using a disposable biopsy gun with a 18-gauge needle and an ultrasound platform (bk ultrasound 5000) with a biplanar probe. using the bk ultrasound 5000 mri-trus fusion platform, fusion-tb was performed on the previously identified suspicious area at the mpmri using a real time alignment of the t2-weighted sequence to the trus image. mri-trus images alignment was possible due to a tracking device consisted in a sensor coil on the trus probe paired with a magnetic field generator in order to register the location of the tracking device in the 3d space. at least 3 cores were taken for each lesion and the number of additional cores were based on the diameter of the lesion. the number of cores taken was related to the size of the lesions; the cores were carried out along the long axis of the lesion with a maximum of two biopsies taken for each needle. trus standard biopsy was a typical 12 cores double sextant template from lateral to medial of base, mid and apex. only the trus images, with no mp-mri target data available, were used for the standard biopsy portion of the case. after the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. statistical analysis continuous variables were reported as medians with interquartile ranges (iqr) whereas categorical variables were described as frequencies with percentages. the mann-whitney and pearson chi-square test were used to compare medians and frequencies among patients with positive and negative biopsies, respectively. uniand multivariate logistic regression models with enter method were used to identify which covariates could predict pca, cspca and concordance between mpmri index lesion and bioptic index lesion. an alpha value of 5% was set to be the threshold to determine statistical significance. statistical analyses were conducted using spss® v21 (ibm corp, armonk, ny) for macintosh®. results the clinical, radiologic, and pathologic characteristics of the entire population are listed in table 1. of 155 patients, 58 (37.4%) were biopsy-naïve, 97 (62.6%) had d'agostino_stesura seveso 10/01/20 09:02 pagina 213 archivio italiano di urologia e andrologia 2019; 91, 4 d. d’agostino, f. mineo bianchi, d. romagnoli, m. giampaoli, p. corsi, a. del rosso, r. schiavina, e. brunocilla, a. porreca 214 at least 1 previous negative set of random trus-gb. the median age of the patient population was 66 years (iqr, 61-69) and median prebiopsy psa level was 7.1 ng/ml (iqr, 5-8.9). the median number of targeted biopsies per patient was 4 (iqr, 3-4), and, accordingly, the median total number of biopsies including the standard 12-cores was 14 (iqr,12-15). at the prebiopsy mpmri study, a total of 155 suspected lesions were identified and were scheduled for fusion-tb. the median diameter of the index lesion was 13 mm (iqr, 9-18.1 mm). the univariate logistic regression model showed a crucial role of v2pirads score of index lesion in the prediction of pca and cspca (tables 3, 4). overall, the fusion-tb findings were positive in 94 of 155 patients with a dr of 60%; a significantly high dr was obtained in terms of clinically significant pca (cspca) of fusion-tb (61 pts; 41.9%). the overall dr in the 121 biopsy-naive patients was 60.6%. in the subgroup of the 34 patients with at least 1 previous set of trus-gb, overall dr was 39.3% (35/50). in the series of biopsy naïve patients whose clinically significant pca (cspca) was found, the location of index lesion was anterior in 26.3% (15/57 cases) while we observed a posterior lesion in 73.7% (42/57 cases). in patients with previous negative trus-gb whose cspca was diagnosed the location of index lesion was anterior in 32.4% (12/37 cases) and posterior in 67.5% (25/37 cases). overall, in the patients with a pi-rads-v2 score of 3 of 5, 4 of 5, and 5 of 5, dr for pcaa were 40.2% (29/72), 77.0% (41/53) and 80.0% (24/30), respectively (p < 0.001). in table 5 are reported univariate logistic regrestable 1. design of studies of serenoa repens for bph treatment. overall population biopsy+patients biopsy-patients p-value (n = 155) (n = 94) (n = 61) age median 66 66 65 0.5 iqr 61-69 61-70 61-69 psa (ng/ml) median 7.1 7.2 7 0.9 iqr 5-8.9 5.4-9.3 4.6-8.8 psa density (ng/ml/cm3) median 0.12 0.13 0.11 0.03 iqr 0.09-0.16 0.1-0.17 0.08-0.13 prostate volume (cm3) median 55 50 58 0.2 iqr 43-75 40-60 46-80 previous trus-gb (%) no 121 (78.1) 57 (60.6) 40 (65.6) 0.6 yes 34 (21.9) 37 (39.3) 21 (34.4) index lesion diameter (mm) median 13 11 13 0.9 iqr 9-18.1 8-16 9-16.5 index lesion location (%) anterior 44 (28.4) 27 (28.7) 17 (27.9) 0.7 posterior 111 (71.6) 67 (71.3) 44 (72.1) index lesion site (%) peripheral 107 (69) 65 (69.1) 42 (68.9) 0.1 central 48 (31) 29 (28.7) 19 (31.1) index lesion pirads v2 score (%) 3 72 (46.5) 29 (38.5) 43 (70.5) < 0.001 4 53 (34.2) 41 (38.5) 12 (19.7) 5 30 (19.4) 24 (23.1) 6 (9.8) total cores taken per patient median 14 14 13 0.96 iqr 12-15 12-15 12-15 target biopsy cores taken per patient median 4 4 4 0.9 iqr 3-4 3-5 3-4 isup grade group (%) negative 61 (39.4) 0 (0) 61 (100) 1 29 (18.7) 29 (18.7) 0 (0) 2 26 (16.8) 26 (16.8) 0 (0) 3 28 (18.1) 28 (18.1) 0 (0) 4 11 (7.1) 11 (7.1) 0 (0) 5 0 (0) 0 (0) 0 (0) dre: digito-rectal examination; iqr: interquartile range; psa: prostate specific antigen; trus-gb: trans-rectal ultrasound-guided biopsy; mri-gb: magnetic resonance imaging-guided biopsy. table 2. localization of index lesion at mpmri and bioptic results stratified according to previous biopsy status and bioptic findings. biopsy+patients biopsy-patients p-value (n = 94) (n = 61) biopsy näive patients (n = 97) index lesion location (%) anterior 15 (26.3) 13 (32.5) 0.7 posterior 42 (73.7) 27 (67.5) index lesion site (%) central 17 (29.8) 15 (37.5) 0.3 peripheral 40 (70.2) 32 (62.5) previous negative biopsies (n = 58) index lesion location (%) anterior 12 (32.4) 4 (19) 0.4 posterior 25 (67.6) 17 (81) index lesion site (%) central 12 (32.4) 4 (19) 0.4 peripheral 25 (67.6) 17 (81) table 3. uni-variate logistic regression model predicting pca (n = 94) at fusion biopsy. univariate analysis hr (95% ci) p-value age (yrs) 1.01 (0.97 -1.07) 0.5 psa (ng/ml) 1.08 (0.97-1.19) 0.2 psa density (ng/ml/cm3) < 0.15 ref. 0.9 0.15 0.94 (0.47-1.87) previous trus-gb no ref. 0.5 yes 1.24 (0.63-2.42) index lesion site peripheral ref. 0.97 central 0.99 (0.49-1.98) lesion location posterior ref. 0.9 anterior 0.98 (0.47-1.96) index lesion pirads v2 score 3 ref. 4 5.07 (2.28-11.24) < 0.001 5 5.93 (2.16-16.3) 0.001 index lesion diameter (mm) 1.01 (0.96-1.07) 0.7 n of cores taken 1 (0.86-1.16) 0.99 n of target cores taken 1.07 (0.72-1.58) 0.8 pca: prostate cancer; hr: hazard ratio; ci: confidence interval; psa: prostate specific antigen; trus-gb: trans-rectal ultrasound-guided biopsy. d'agostino_stesura seveso 10/01/20 09:02 pagina 214 215archivio italiano di urologia e andrologia 2019; 91, 4 mri/trus fusion guided biopsy sion model predicting concordance between index lesion at mpmri and highest gleason score in the bioptic cores. discussion several major changes have taken place in the last decade regarding the diagnosis of pca; the introduction of new imaging techniques (traditional radiology, nuclear medicine, etc.) is radically changing the approach to the patient with pca (13-17). in particular the most important innovation was represented by the introduction of multiparametric magnetic resonance imaging (mpmri) in the diagnosis and management of pca (active surveillance, surgery, radiotherapy, etc.) (18, 19). in fact, this examination showed an elevate detection and localization rate of cspca thus making it possible to perform selected targeted biopsies instead of systematic ultrasound guided biopsies. in any case, trus-gb represents the “gold-standard” technique of histological diagnosis of pca although mri-targeted biopsies (cognitive, fusion and “in bore” technique) significantly increased the detection of high risk pca while decreasing the detection of low risk pca compared with standard biopsy; moreover a lower number of cores could be required in men with suspicious mri findings reducing also potential complications related to the procedure and all the consequence on quality of life (20-22). in our experience we have analyzed the impact of one of the targeted biopsy techniques, the mri-us “fusion” prostate biopsy, in the diagnosis of clinically significant pca; in particular the mri-us “fusion” biopsy is simply described as a way to align a pre-registered mri to an intra-procedure us in order to identify and target suspected lesions within the gland through a dedicated hardware platforms targeting areas found during mpmri and not clearly visible during us scan. based on our experience we can affirm that this technique had high sensitivity, accuracy and specificity than trus-gb and no significant difference for treatment zone between combined biopsies and targeted. the advantages are the high reproducibility and the real time feedback though counterbalanced by the high upfront cost of the device; another advantage of the fusion technique is the ability to perform a systematic biopsy during the same session. in our series of patients the mri-us fusion biopsy showed an elevate accuracy for diagnosis of cspca; in particular the overall dr of cspca was 69.1% (65/94 cases); in particular we observed a statistically significant correlation between the pirads v2 score and the presence of cspca (p < 0.001). these results were in line with available studies in literature (23). evaluating the detection rate of different techniques of targeted biopsy, arsov et al. (24) compared the dr between an “in-bore” approach and a fusion approach: in particular they not observed important improvement in dr by fusion approach. in our previous experience we evaluated the role of “in-bore” mri guided biopsy in a series of 70 patients (25); we observed an overall dr of 45.7% and in particular > 75% in cspca. examining this series we observed an important correlation between the location of index lesion and the finding of pca in the sample of biopsy. venderlink et al. highlighted that there are no significant differences between magnetic resonance and fusion-guided biopsy; the only differences were related with an increasing lesion size (26). considering the overall dr, in a nih study of men with previous negative biopsy, a global dr of 37.4% using mri fision biopsy was reported by vourganti et al. (27). other studies highlighted as performing 12 cores table 4. univariate logistic regression model predicting cspca (n = 54) at fusion biopsy. univariate analysis hr (95% ci) p-value age (yrs) 1.02 (0.97-1.07) 0.2 psa (ng/ml) 1.03 (0.96-1.1) 0.4 psa density (ng/ml/cm3) < 0.15 ref. 0.8 ≥ 0.15 1.08 (0.55-2.12) previous trus-gb no ref. 0.2 yes 1.57 (0.82-3.02) index lesion site peripheral ref. 0.3 central 0.67 (0.33-1.33) index lesion pirads v2 score 3 ref. 4 3.42 (1.63-7.22) 0.001 5 4.86 (1.95-12.11) 0.001 index lesion diameter (mm) 1.01 (0.96-1.07) 0.6 n of cores taken 1.03 (0.89-1.19) 0.7 n of target cores taken 1.09 (0.74-1.6) 0.7 cspca: clinically significant prostate cancer; dre: digito-rectal examination; hr: hazard ratio; ci: confidence interval; psa: prostate specific antigen; trus-gb: trans-rectal ultrasound-guided biopsy. table 5. univariate logistic regression model predicting concordance between index lesion at mpmri and highest cgs in the bioptic cores. univariate analysis multivariate analysis hr (95% ci) p-value hr (95% ci) p-value age (yrs) 1.03 (0.96-1.1) 0.5 psa (ng/ml) 1.05 (0.92-1.2) 0.4 psa density (ng/ml/cm3) < 0.15 ref. 0.5 0.15 1.45 (0.51-4.15) previous trus-gb no ref 0.1 yes 2.2 (0.77-6.23) index lesion site peripheral ref. 0.01 ref. 0.02 central 0.29 (0.11-0.77) 0.3 (0.1-0.82) index lesion location posterior ref. 0.8 anterior 0.84 (0.29-2.43) index lesion pirads v2 score 3 ref. ref. 4 0.74 (0.26-2.08) 0.6 0.75 (0.25-2.2) 0.6 5 8.76 (1.01-76.08) 0.05 8.83 (0.99-78.93) 0.05 index lesion diameter (mm) 1.02 (0.95-1.1) 0.6 n of cores taken 1.07 (0.87-1.31) 0.5 n of target cores taken 0.89 (0.49-1.64) 0.7 mpmri: multi-parametric magnetic resonance imaging; cgs: clinical gleason score; hr: hazard ratio; ci: confidence interval; psa: prostate specific antigen; trus-gb: trans-rectal ultrasound-guided biopsy. d'agostino_stesura seveso 10/01/20 09:02 pagina 215 archivio italiano di urologia e andrologia 2019; 91, 4 d. d’agostino, f. mineo bianchi, d. romagnoli, m. giampaoli, p. corsi, a. del rosso, r. schiavina, e. brunocilla, a. porreca 216 random biopsies the dr for cspca is increasing respect to mri fusion biopsy (28-30); in particular radtke et al. reported that systematic transperineal prostate biopsy was more likely to miss gleason > 7 pca compared with mri targeted biopsy (20.9% vs 12.8%) (30). this dates are apparently in contrast with the results of our study; in fact the elevate dr for clinically significant disease depends on the fact that in addition to perform a standard 12-core biopsy we have added cores in areas normally not considered (lesions of the anterior and transitional); these data support the thesis about the essential role of mpmri and mri guided biopsy of suspicious lesions in the algorithm for evaluating men with previous negative trus-gb but with ongoing suspicion for pca. our study has some limitations: the number of patients, exclusive inclusion of patients with positive findings at mpmri, no follow-up data and the lack of control group. conclusions in conclusion, the results from our present study confirm that the mpmri and mri fusion guided biopsy have the purpose to improve detection of clinically significant pca. in particular the targeted mri/trus fusion-guided biopsy represent a safe and accurate approach for diagnosis of cspca, especially in patient with previous trus guided biopsy negative and suspicious pca. given that the experience of radiologist for mpmri and of urologist for mri/trus fusion-guided biopsy are critical, further studies are necessary to confirm these promising results. references 1. american cancer society; 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186: 1281-5. 24. arsov c, rabenalt r, blondin d, et al. prospective randomized trial comparing magnetic resonance imaging (mri)-guided in bore biopsy to mri-ultrasound fusion and transrectal ultrasound guided d'agostino_stesura seveso 10/01/20 09:02 pagina 216 217archivio italiano di urologia e andrologia 2019; 91, 4 mri/trus fusion guided biopsy prostate biopsy in patients with prior negative biopsies. eur urol. 2015; 68:713-20. 25. schiavina r, vagnoni v, d'agostino d, et al. "in-bore" mriguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. clin genitourin cancer. 2017; 15:417-427. 26. venderlink w, van der leest m, van luijtelaar a, et al. retrospective comparison of direct in-bore magnetic resonance imaging (mri)-guided biopsy and fusion guided biopsy in patients with mri lesions which are likely or highly likely to be clinically significant pca. word j urol. 2017; 35:1849-1855. 27. vourganti s, rastinehad a, yerram nk, et al. multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect pca in patients with prior negative transrectal ultrasound biopsies. j urol. 2012; 188: 2152-7. 28. delongchamps nb, peyromaure m, schull a, et al. prebiopsy magnetic resonance imaging and pca detection: comparison of random and targeted biopsies. j urol. 2013; 189: 493-930 29. kuru th, saeb-parsy k, cantiani a, et al. evolution of repeat prostate biopsy strategies incorporating transperineal and mritrus fusion techniques. world j urol. 2014; 32: 945-5031. 30. radtke jp, kuru th, boxler s, et al. comparative analysis of transperineal template-saturation prostate biopsy versus mri-targeted biopsy with mri-us fusion-guidance. j urol. 2015; 193:87-94. correspondence daniele d’agostino, md (corresponding author) dott.dagostino@gmail.com daniele romagnoli, md marco giampaoli, md paolo corsi, md alessandro del rosso, md angelo porreca, md department of robotic urological surgery, abano terme hospital piazza cristoforo colombo 1, 35031 abano terme (pd) (italy) federico mineo bianchi, md riccardo schiavina, md eugenio brunocilla, md department of urology, university of bologna, bologna (italy) d'agostino_stesura seveso 10/01/20 09:02 pagina 217 archivio italiano di urologia e andrologia 2017; 89, 2156 case report vaginal metastasis of bladder urothelial carcinoma: description of a case and revision of literature carmelo a. di franco 1, daniele porru 1, giovanni giliberto 1, alessandra viglio 2, bruno rovereto 1 1 department of urology, university hospital i.r.c.c.s policlinico s. matteo, pavia, italy; 2 department of pathology, university hospital i.r.c.c.s policlinico s. matteo, pavia, italy. vaginal metastases from urothelial cancer are a rare entity and in literature, few cases are described. we report a case of a 68 year-old woman with history of bladder urothelial carcinoma underwent to radical cystectomy who came in our department after 5 months for pelvic pain and vaginal bleeding. objective examination revealed an ulcerative, solid vaginal lesion in the upper vaginal wall. we performed a vaginal biopsy that showed urothelial carcinoma compatible with the primitive bladder cancer. the patient underwent to surgery and was sent to oncological evaluation. key words: bladder cancer; vaginal metastasis; cistectomy. submitted 3 march 2017; accepted 27 march 2017 summary no conflict of interest declared. indolent lesion of anterior vaginal wall on the right side. we performed a cold biopsy of vaginal lesion. bioptic result suggested an urothelial metastasis of vagina. in the suspect of pelvic disease recurrence, we requested total body ct-scan that showed a vaginal mass of upper right vagina wall. we performed a laborious complete excision of vaginal mass as showed in figure 1. definitive pathologic report reported a vaginal white-grey nodular lesion of around 7 x 6 centimetres (figure 2). doi: 10.4081/aiua.2017.2.156 introduction in literature, few cases of vaginal metastases from bladder urothelial carcinoma after radical cystectomy are reported. usually, urothelial metastases of vagina are a rare entity; in fact, some authors propose preservation of female genitalia organs during radical cystectomy. we describe a case of vaginal metastasis in a patient with history of bladder urothelial carcinoma who was submitted some months before to radical cystectomy. case report a 68 years-old woman underwent in june 2016 radical cystectomy with ileal conduit urinary diversion. pathological report described a bladder neoplastic mass of around 8 centimetres; microscopic histologic examination revealed urothelial carcinoma infiltrating posterior bladder wall (pt2b) high grade (who 2004) g2 (who 1973), with aspect of squamous differentiation and signs of necrosis, images of lymphatic permeation and negative surgical margins. vagina specimen was negative for cancer. we performed extended lymphadenectomy (obturator, external and internal iliac, presacral, paraortic and paracaval) with 29 removed lymph nodes all negative for metastases (n0). in november 2016, after five months from cystectomy, the patient accessed in our department for pelvic pain and vaginal bleeding. objective examination revealed an ulcerative, rough and figure 1. surgical specimen of vagina: to note nodular lesion of vaginal wall as it appeared during objective examination. figure 2. on cutting the specimen presents white-grey nodular lesion of around 6-7 centimetres. di franco_stesura seveso 20/06/17 10:01 pagina 156 157archivio italiano di urologia e andrologia 2017; 89, 2 vaginal metastasis of bladder cancer microscopically (figure 3), it was an urothelial metastasis with extensive squamous metaplasia and necrosis. immunohistochemical examination was cytokeratin 34betae12+, p63+, cytokeratin 7-, cytokeratin 20-; lesion was compatible with the first bladder cancer reported in radical cystectomy specimen. discussion metastasis of urothelial carcinoma to vagina is very rare, with only few cases reported in literature. literature reports suggest that the risk of urothelial metastases of genital organs after female cystectomy is low (1). in fact, some author propose gynaecologic organs sparing cystectomy in female patient candidate for ileal orthotopic neobladder because it can ensure better urinary continence (2-3). the incidence of secondary malignant involvement of the gynaecological organs by bladder cancer was as low as 2.6-5% (4). the reported medium time from the diagnosis of bladder urothelial cancer to vaginal metastasis is 4,3 years (5). in 1985, chin et al. described vaginal recurrence after radical cystectomy; they suggested that the risk of vaginal urothelial metastasis could be previous surgery and radiation to the pelvic organs and patients with tumors other than transitional cell carcinoma, especially those located at the bladder neck and urethra (6). our patient had no history of pelvic surgery or radiotherapy, bladder cancer was localized in posterior bladder wall, and all removed lymph nodes were negative for metastasis. in addition, vaginal specimen was negative for cancer infiltration. we think that metastatic mechanism could be associated to lymphatic permeation through which cancer cells could migrate, not only to lymph nodes but also to adjacent tissues, in this case vagina wall. probably, also squamous differentiation, because of unknown mechanism, could favour cell implantation in squamous vaginal epithelium. moreover, the dimension of nodular vaginal lesion (around 6 centimeters) in few months after radical cystectomy, could suggest that neoplastic cells implanted in vagina wall already before radical surgery. we think that vaginal recurrence after radical cystectomy in a patient with bladder-localized cancer (t2, n0) is a negative prognostic sign that could anticipate a rapid progression of disease. references 1. ali-el-dein b, abdel-latif m, mosbah a, et al. secondary malignant involvement of gynecological organs at radical cystectomy specimens in women: is it mandatory to remove these organ routinely? j urol. 2004; 172:885-887. 2. ali-el-dein b1, mosbah a, osman y, et al. preservation of the internal genital organs during radical cystectomy in selected women with bladder cancer: a report on 15 cases with long term follow-up. eur j surg oncol. 2013; 39:358-64. 3. koie t, hatakeyama s, yoneyama t, et al. uterus-, fallopian tube-, ovary-, and vagina-sparing cystectomy followed by u-shaped ileal neobladder construction for female bladder cancer patients: oncological and functional outcomes. urology. 2010; 75:1499-503. 4. chang ss, cole e, smith jr ja, cookson ms. pathological findings of gynaecologic organs obtained at female radical cystectomy. j urol. 2002; 168:147-9. 5. ohgaki k, horiuchi k, oka f, et al. vaginal metastasis of urothelial carcinoma found incidentally during transurethral resection of a bladder tumor. j nippon med sch. 2008; 75:312-5. 6. chin jl, et al. vaginal recurrence after cystectomy for bladder cancer. j urol. 1985; 134:58-61. correspondence carmelo agostino di franco, md (corresponding author) carmelo_difranco@tiscali.it daniele porru, md giovanni giliberto, md bruno rovereto, md department of urology policlinico s. matteo, pavia v.le golgi, 19, 27100 pavia, italy alessandra viglio, md department of pathology, university hospital i.r.c.c.s policlinico s. matteo, pavia, italy figure 3. microscopically, vaginal lesion was compatible with urothelial carcinoma with extensive signs of squamous metaplasia and necrosis. di franco_stesura seveso 20/06/17 10:01 pagina 157 283archivio italiano di urologia e andrologia 2018; 90, 4 original paper penile fracture with urethral injury: our experience in a tertiary care hospital priyatham kasaraneni, prasad mylarappa, ramesh desi gowda, sandeep puvvada, dheeraj kasaraneni department of urology ms ramaiah medical college, bengaluru, india. penile fracture is a rare urological emergency that always requires immediate attention. it may be associated with urethral trauma in 9% to 20% of cases. we present our experience in treating 12 such cases. this is a prospective observational study extending from january 2000 to december 2016. each patient with penile fracture underwent a thorough clinical evaluation and received proper treatment. seventy-five patients with penile fracture, aged 25 to 36 years (mean, 31.5 years) were evaluated in this study. sexual intercourse was the common mechanism of injury in most of the patients. 12 of the patients had associated urethral injury. all the patients were diagnosed on taking proper history and after clinical examination. all patients were subjected emergency surgical exploration. all the patients underwent minimum of 1 year of follow-up, and were evaluated with local examination, uroflowmetry and colour doppler ultrasonography. penile fracture is associated with urethral injury especially in the presence of suggestive history and physical examination like acute urinary retention, bleeding per urethra. immediate primary surgical management of both the penile fracture and urethral injury is a safe and effective option with minimal complications. key words: penile fracture; urethral injury; corpora; tunica; detumescence. submitted 4 october 2018; accepted 15 november 2018 summary no conflict of interest declared. mon cause of penile fracture is self-inflicted injury. the other cause, taqaandan has been described as an intentional, forceful bending of the erect penile shaft as cultural habit to provide relaxation and release tension (5). with an annual incidence of 0.29-1.36 cases per 100,000 people, some additional etiologies were mentioned in the literature which include impaling a penis in a mattress, slamming the penis in a door, placing an erect penis into tight pants, striking a toilet seat, hitting a bedpost, falling from a tree, and masturbating into a cocktail shaker (6-12). most likely, the laceration is unilateral though bilateral rupture accounts for 2% to 10% of cases. associated urethral injury is rare, with reported frequencies in 10% to 38% (13). urethral injury may be suspected if there is hematuria and inability to void. the presenting features are relatively consistent and typically straightforward. the simple clinical diagnosis usually renders adjunct imaging unnecessary. historically, penile fracture management included mostly conservative, nonsurgical measures. in the 1980s, operative intervention became favorable after several studies demonstrated a decrease in long-term morbidity (14-15). nowadays, immediate surgical exploration is the standard of care because of its advantages like lesser complications, decreased hospital stays, improved outcomes, and better patient satisfaction. not many studies were present on case series of penile fracture with urethral injury apart from case reports. this study is based on our experience with 8 cases of penile fracture associated with urethral injury that were treated at a tertiary care hospital. materials and methods we did a prospective observational study. seventy-five cases of penile fracture were presented to the emergency ward from january 2000 to december 2016. out of them, only 12 had associated urethral injury. informed written consent was taken from all the patients. diagnosis was made on patient’s history and clinical examination alone. we didn’t subject the patients to any radiological investigation. when clinical diagnosis was in doubt in cases of no urethral injury, we had done ultrasonography of penis to look for tunical tears. we subjected all cases to emergency surgical exploration (figures 1-4). circumferential sub coronal incision was doi: 10.4081/aiua.2018.4.283 introduction penile fracture is defined as the rupture of the tunica albuginea of the corpus cavernosum caused by blunt trauma to the erect penis (1). there might be associated injuries which include partial or complete transection of urethral or spongiosal tissue (2). the tunica albuginea layer is a tough fibroelastic sheath, which envelops the ventral corpus spongiosum and dorsally paired corpora cavernosa (3). buck’s fascia and the deep perineal tissue plane that surrounds both the cavernosa and penile vessels, merges proximally with the deep urogenital region. the characteristic injury patterns associated with penile fractures depend on the integrity of this tissue plane. upon tunical disruption, cavernosal bleeding can leak into surrounding tissues and remains in the penis by an intact buck’s fascia (4). penile fracture is mostly associated with sexual intercourse and occurs when the rigid penis slips from the vagina striking the partner’s perineum or pubic bone. in middle east countries, a comkasaraneni_stesura seveso 10/01/19 16:18 pagina 283 archivio italiano di urologia e andrologia 2018; 90, 4 p. kasaraneni, p. mylarappa, r. desi gowda, s. puvvada, dheeraj kasaraneni 284 given to deglove the penis for complete evaluation of injuries. corporal tears were closed with non-absorbable suture (vicryl 3-0). urethral injuries were looked for and if present, mobilization of urethra done to get length for tension free anastomosis. urethra was anastomosed after cutting the margins with absorbable suture (4-0 vicryl) for water tight anastomosis. a 16 fr foley catheter was used for urinary catheterization. all patients were discharged on the 2nd postoperative day. to prevent painful erections, estradiol 0.05 mg was given for 3 weeks. the urethral catheter was removed after 3 weeks. all the patients were followed up at 3 months and 1 year with clinical examination, uroflowmetry and color doppler. results twelve patients out of 75 patients with penile fracture had associated urethral injury. the following table 1 shows the demographical values of the study. we suspected urethral injury clinically on the basis of history in all patients as they had either difficulty voiding, retention of urine or bleeding per urethra and rest of typical features like aubergine sign, crackling sound were also looked for (table 2). retrograde urethrogram was not used in our study. history of sexual intercourse with woman on top position was present in 7 patients whereas 1 patient had history of blunt injury and 2 patients had history of rolling over in the bed. seven patients heard crackling sound at the time of injury. eleven patients had bleeding per urethra. three patients table 1. demographics of the study. parameter value incidence of urethral injury 12 out of 75 cases (16%) mean time from the time of injury to the time of presentation to the hospital 4.62 hours mean age 31.5 years age range 25-36 years no of urban population affected 10 (83.33%) no of rural population affected 2 (16.66%) table 2. clinical findings. clinical findings incidence history of sexual intercourse with woman on top position 9 (75%) history of rolling over in the bed 2 (16.66%) history of blunt injury 1 (12.5%) history of crackling sound 7 (58.33%) bleeding per urethra 11 (91.66%) aubergine sign/egg-plant deformity 12 (100%) acute retention of urine 3 (25%) table 3. intraoperative findings. intra operative findings number of cases partial urethral disruption 11 (91.66%) complete urethral disruption 1 (8.33%) location of injury – proximal shaft of penis 6 (50%) location of injury – mid shaft of penis 2 (16.66%) location of injury – distal shaft of penis 4 (33.33%) figure 1. penile fracture with blood at meatus and developing hematoma. figure 2. hematoma in the buck’s fascia at the proximal part. figure 3. intraoperative photo demonstrating bilateral transverse rupture of the corpora and complete urethral transection. figure 4. photo showing primary reanastomosis of urethra. kasaraneni_stesura seveso 10/01/19 16:18 pagina 284 weren’t able to void from the time of injury. aubergine sign was present in all the cases. on examination, diagnosis of penile fracture was straight forward in 11 patients with typical findings. one patient didn’t have bleeding per urethra and was voiding, we found urethral injury intraoperatively. the intraoperative findings are given in the following flow chart (figure 5) and table 3. the postoperative course for all the six patients was uneventful. all the patients were discharged by postoperative day 2. the mean follow-up of patients was 24 months from the day of surgery. all patients voided well and were documented by uroflowmetry. all patients had no problems with erection. one patient developed penile curvature which did not affect his sexual health. another patient developed stricture urethra. two patients developed urinary tract infections (table 4). discussion the literature shows an incidence of 10% to 38% of urethral injury overall (13). we observed 14.03% incidence in our case series of 75 patients. the frequency of urethral involvement was between 0 and 3 per cent in the middle eastern studies (10). the most common cause of penile fracture with urethral injury in our patients was vaginal intercourse with women on top position in 9 out of 12 patients (75%). during intercourse with woman on top position, the angulation of erect penis makes its ventral surface vulnerable to collision with inferior margin of the pubic arch & symphysis pubis of the woman. in a phase of excitement or during a stage when they are unable to keep rhythm, the penis instead of penetrating deep into vagina, becomes entangled at the introitus and collides on its ventral surface with pubic arch of female partner. this phenomenon is exaggerated due to downward thrust of the woman or the upward stroke of man. therefore, the urethra gets sandwiched between erect corpora of the man and pubic arch of the woman causing mucosal tear & bleeding per urethra (16). in our series of 75 patients, patients with urethral injury presented earlier compared to patients with only penile fracture, most likely because they were unable to void. diagnosis of urethral injury associated with penile fracture is based on history in patients if they had either difficulty voiding, retention of urine or bleeding per urethra. urinalysis is not a mandatory component in the diagnosis of suspected urethral injuries, as it can confuse sometimes. in our study, 11 patients had macroscopic hematuria, whereas gedik et al. reported the presence of microscopic hematuria in 6 out of 107 patients, but none of them had a urethral injury on exploration (17). so, presence of microscopic hematuria might not be an indication of urethral injury, so urinalysis test can be omitted. when in doubt retrograde urethrogram(rgu) is helpful in confirming the presence of a urethral injury but, it’s not without false negative results. mydlo and colleagues reported a false negative rate of 28.5% (2/7 patients) in their small series (18), which might be due to overlying hematoma at the site of injury, which masks the defect. hence the test is not recommended in routine practice. we did not perform any retrograde urethrogram in any of our patients, but we did adequate exposure of penis by circumferential sub coronal incision to prevent missing out urethral injury. eleven patients presented with classical features with penile fracture with urethral injury, apart from one patient without bleeding per urethra, we were able to identify urethral injury intraoperatively which signifies the importance of proper degloving of penile skin for complete examination of injuries. all patients were subjected to emergency surgical exploration to prevent complications like urethral stricture, urethra-cavernous fistula and erectile dysfunction (14, 19-21). complete rupture of urethra has been reported in literature (22), we got only one case (8.33%) with complete rupture of urethra. bilateral corporal injury occurs in 4-10% of cases (23-24), we reported one case with an incidence of 8.33%. isolated urethral injury is very rare and might occur with absence of a snapping sound, sharp pain and detumescence (16). most of our patients had partial urethral tears which account to 11 (91.66%). all patients had the site of the urethral trauma near the site of the corporal tear, which made it easy to identify the site of urethral injury. in one patient we weren’t able to identify the location of urethral injury, so we took the help of saline mixed with methylene blue dye and introduction of a guide wire helped in the identification of urethral injury with more ease. shaeer investigated the value of methylene blue in locating urethral tears in fracture penis and found it reliable and safe (25). primary urethral anastomosis and corporal repair can be done after evacuation of hematoma and removing any devitalized tissue under cover of antibiotics. the outcomes of penile fracture with associated urethral injury repair are dependent on the timing of surgical exploration, the need for urethral catheterization, the type of incision and fashion of suture material utilized, and the requirement 285archivio italiano di urologia e andrologia 2018; 90, 4 penile fracture with urethral injury: our experience in a tertiary care hospital table 4. complications. complications number of cases penile curvature 1 (8.33%) stricture urethra 1 (8.33%) urinary tract infections 2 (16.66%) figure 5. flow chart of intraoperative findingsrupture of the corpora and complete urethral transection. kasaraneni_stesura seveso 10/01/19 16:18 pagina 285 archivio italiano di urologia e andrologia 2018; 90, 4 p. kasaraneni, p. mylarappa, r. desi gowda, s. puvvada, dheeraj kasaraneni 286 for prophylactic antibiotics (18). with early repair, adequate exposure, complete hematoma evacuation, adequate rest to urethra for healing by catheterization can lead to favorable outcomes in the management of penile fracture associated with urethral injury. we used estradiol to prevent erections whereas jallu et al. preferred using diazepam along with oxyphenbutzone (26). we advised the patients to refrain from sexual activity for 6 weeks post-surgery but some studies showed sexual intercourse can be resumed 2 weeks after surgery (27-29). different follow-up protocols and strategies have been reported in different published series (28). in this study, the first follow-up was in the third week after the operation, and all patients underwent clinical evaluation. later the patients were followed up at 3 months and 1 year with clinical examination, uroflowmetry and colour doppler. we noted penile curvature in one patient which didn’t affect their sexual activity. one patient developed short segment stricture of the urethra which was managed with endoscopic dilatation. two patients developed urinary tract infections which were treated conservatively with antibiotics based on urine culture and sensitivity. the limitation of our study is limited sample size. the table 5 shows comparison between 2 similar studies. conclusions penile fracture is associated with urethral injury especially in the presence of suggestive history and physical examination like acute urinary retention or bleeding per urethra. immediate primary surgical management of both the penile fracture and urethral injury is a safe and effective option with minimal complications. compliance with ethical standards the approval of ethical committee of our institution was taken before starting the study. funding this study was not funded by anyone. references 1. mcaninch jw, santucci ra. genitourinary trauma. in: walsh p, retik a, vaughan e, wein a, 2. editors. campbell’s urology. 8th ed. philadelphia: saunders. 2002; p. 3707-44. 2. maharaj d, naraynsingh v. fracture of the penis with urethral rupture. injury. 1998; 29:483. 3. hsu gl, hsieh ch, wen hs, et al. penile venous anatomy: an additional description and its clinical implication. j androl. 2003; 24:921-7. 4. sawh sl, o’leary mp, ferreira md, et al. fractured penis: a review. int j impot res. 2008; 20:366-9. 5. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18 year follow-up study of 352 patients from kermanshah. iran j sex med. 2009; 6:1141-50. 6. kalash ss, young jr jd. fracture of penis: controversy of surgical versus conservative treatment. urology. 1984; 24:21-4. 7. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 8. khinev a. penile fracture. khirurgiia (sofiia) 2004; 60:32-41. 9. chung ch, szeto yk, lai kk. ‘fracture’ of the penis: a case series. hong kong med j. 2006; 12:197-200. 10. zargooshi j. penile fracture in kermanshah, iran: the long-term results of surgical treatment. bju int. 2002; 89:890-4. 11. klein fa, smith mj, miller n. penile fracture: diagnosis and management. j trauma. 1985; 25:1090-2. 12. el-taher am, aboul-ella ha, sayed ma, gaafar aa. management of penile fracture. j trauma. 2004; 56:1138-40. 13. sant gr. rupture of the corpus cavernosum of the penis. arch surg. 1981; 116:1176-8. 14. wespes e, libert m, simon j, schulman cc. fracture of the penis: conservative versus surgical treatment. eur urol. 1987; 13:166-8. 15. seaman e, santarosa r, walton g. immediate repair; key to managing the fractured penis. contemp urol. 1993; 5:13. table 5. comparison of different studies. parameter our study derouiche et al. (28) attam et al. (27) no of patients 12 10 8 mean age 31.5 years 30 years 30.4 years age range 25-36 years 19-46 years 23-51 years median time from the time 6 hours 10 hours mean duration of injury to the time of presentation was 2.7 days, to the hospital median not assessed crackling sound 7 (58.33%) 10 (100%) 6 (75%) acute retention of urine 3 (25%) 2 (20%) not mentioned bleeding per urethra 11 (91.66%) 10 (100%) 6 (75%) aubergine sign/egg-plant deformity 12 (100%) 10 (100%) 6 (75%) bladder palpable 3 (25%) 2 (20%) not mentioned urethrogram not done not done not done bilateral corporal involvement 1 (8.33%) 1 (12.5%) unilateral corporal involvement 11 (91.66%) 10 (100%) 7 (87.5%) right corporal involvement 5 (41.66%) 6 (60%) 5 (62.5%) left corporal involvement 6 (50%) 4 (40%) 2 (25%) proximal corpora 6 (50%) 5 (50%) 6 (75%) mid corpora 2 (16.66%) 4 (40%) not mentioned distal corpora 4 (33.33%) 1 (10%) not mentioned median length of laceration 28 mm 24 mm not mentioned partial urethral disruption 11 (91.66%) 10 (100%) 7 (87.5%) complete urethral disruption 1 (8.33%) 1 (12.5%) supra-pubic cystostomy tube not used used not used penrose drain not used used not used medication to prevent erection estradiol diazepam estradiol median duration of transurethral 21 days 13 days 21 days catheterization median hospital stay 2 days 14 days 2 days follow up mean 24 months 18 months 34.3 months kasaraneni_stesura seveso 10/01/19 16:18 pagina 286 16. mohapatra tp. kumar s. reverse coitus. mechanism of urethral injury in male partner. j urol. 1990; 144:1467-83. 17. gedik a, kayan d, yamis s, et al. the diagnosis and treatment of penile fracture: our 19-year experience. ulus travma acil cerrahi derg. 2011; 17:57-60. 18. mydlo jh, hayyeri m, macchia rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical finding. urology. 1998; 51:616-9. 19. touiti d, ameur a, beddouch a, oukheira h. la rupture de l’urethre au cours des fractures de la verge. a propos de 2 observations. prog urol. 2000; 10:465-468. 20. biserte j, nivet j. traumatisme de l’urethre anterieur: diagnosticet traitement. ann urol. 2006; 40:220-232. 21. paparel p, ruffion a. rupture des corps caverneux: aspects techniques de la prise en charge. ann urol. 2006; 40:267-272. 22. heng ct, brooks aj. penile fracture with complete urethral rupture. asian j surg. 2003; 26:126-7. 23. mydlo jh surgeon experience with penile fracture. j urol. 2001; 166:526-528. 24. koifman l, et al. penile fracture experience in 56 cases. int braz j urol. 2003; 29:35-39. 25. shaeer o. methylene blue-guided repair of fractured penis. j sex med. 2006; 3:349-54. http://dx.doi.org/10.1111/j.1743-6109. 2005.00155.x 26. jallu a, wani na, rashid pa. fracture of the penis. j urol. 1980; 123:285-286. 27. masarani m, dinneen m. penile fracture: diagnosis and management. trends in urology gynaecology & sexual health. 2007; 12:20-24. 28. derouiche a, belhaj k, hentati h, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111-114. 29. amit a, arun k, bharat b, et al. penile fracture and associated urethral injury: experience at a tertiary care hospital. can urol assoc j. 2013; 7:e168-e170. 287archivio italiano di urologia e andrologia 2018; 90, 4 penile fracture with urethral injury: our experience in a tertiary care hospital correspondence priyatham kasaraneni, md kasaraneni.priyatham@gmail.com; kpriyatham@yahoo.co.in prasad mylarappa, md prasadmyluro2@gmail.com ramesh desi gowda, md arunacr1@gmail.com sandeep puvvada, md dr.sandeep001@gmail.com dheeraj kasaraneni, md dheerajkasaraneni@gmail.com department of urology ms ramaiah medical college, bengaluru, india kasaraneni_stesura seveso 10/01/19 16:18 pagina 287 stesura seveso 291archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.291 acceptance of this novel technology within the urology community has steadily increased (1). current european association of urology (eau) guidelines strongly recommend prostate mpmri before re-biopsy in patients with persistent suspicion of pca despite a prior negative biopsy and before confirmatory biopsy in pca patients on active surveillance (as) (2). further potential applications of prostate mpmri include detection of pca in biopsy naïve patients, pca staging prior to treatment and suspicion of local pca recurrence (1, 2). the technique has undergone progressive refinements over time regarding acquisition protocol, image interpretation and reporting (3, 4). in 2012, the european society of urogenital radiology established clinical guidelines for the acquisition, interpretation, and reporting of prostate mpmri in order to allow an adequate level of standardization and consistency (5). these recommendations, popularly referred to as prostate imaging reporting and data system (pi-rads), were based on literature evidence and consensus expert opinion (5). in 2014, the pi-rads version 2 was officially launched (6). currently, the standard mpmri protocol combines morphological information derived from high spatial resolution t2-weighted images, and functional data concerning cell density (diffusion weighted imaging [dwi) with apparent diffusion coefficient [adc) maps) and vascularization (dynamic contrast-enhanced imaging) (7). despite the efforts to improve prostate mpmri adoption and quality of reports, the acceptance and the standardization of the procedure in everyday clinical practice still suffer from many limitations. indeed, mpmri is not readily available at all institutions, and facilities’ adherence to technical standards is variable and sometimes suboptimal (8). attitudes and perceptions toward prostate mpmri vary across countries and, to date, these aspects have not been investigated in italy (9-12). the goal of the present survey was to investigate patterns of attitudes and perceptions among practicing italian urologists with regard to the use of mpmri to manage pca as well as mpmri availability and reporting quality. objective: we aimed to assess the attitudes and perceptions towards multiparametric magnetic resonance imaging (mpmri) of the prostate among italian urologists. material and methods: a national, web-based survey was performed. a questionnaire composed of 18 multiple choice questions was e-mailed to 941 currently active urologists, members of the italian society of urology. preserving anonymity, respondents’ demographics were collected (e.g. geographic region, type of workplace, prostate procedures performed) as well as data concerning their attitudes and perceptions towards mpmri (e.g. indications deemed appropriate, degree of confidence in mpmri results). data were expressed as raw numbers and percentages of survey answers. results: in total, 98 responses were received (participation rate = 10.4%). respondents mostly worked in urban areas (96%) and primarily in hospital settings (89%), while 48% of them worked in southern italy. 97% of respondents considered mpmri useful to detect prostate cancer (pca) in patients with prior negative biopsy, 64% in biopsy-naïve patients and 60% for pca pre-operatory staging. about half (42%) of the participants declared that mpmri results frequently lead them to change pca management strategy. standardization of mpmri acquisition and reporting was partially unsatisfactory. reported waiting time for mpmri scans was longer than 4 weeks for 51% of respondents. the major limitation of this survey includes the small number of participants. conclusions: prostate mpmri is used by italian urologists mainly for detection and for pre-operative staging of pca. further improvements in terms of mpmri availability and report standardization are required. key words: multiparametric magnetic resonance imaging; prostate cancer; prostate imaging reporting and data system; prostate biopsy; survey. submitted 5 july 2020; accepted 3 september 2020 introduction multiparametric magnetic resonance imaging (mpmri) of the prostate has emerged as a valuable tool for the detection of clinically significant prostate cancer (pca) and the attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: a national survey among italian urologists summary arnaldo stanzione 1, massimiliano creta 2, massimo imbriaco 1, roberto la rocca 2, marco capece 2, fabio esposito 2, ciro imbimbo 2, ferdinando fusco 3, giuseppe celentano 2, luigi napolitano 2, francesco mangiapia 2, vincenzo mirone 2, nicola longo 2 1 department of advanced biomedical sciences, university of naples “federico ii”, naples, italy; 2 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 3 department of woman child and of general and specialist surgery, university of campania "luigi vanvitelli", naples, italy. stanzione_stesura seveso 14/12/20 20:33 pagina 291 archivio italiano di urologia e andrologia 2020; 92, 4 a. stanzione, m. creta, m. imbriaco, et al. 292 materials and methods questionnaire an online survey consisting of 18 multiple choice questions (formulated in italian with the aim of increasing the response rate) was designed using the google form application included in the google drive office suite (google llc). the questionnaire was composed of two sections: a first one to assess respondents’ demographics and a second one to evaluate their attitudes and perceptions (i.e. prescription attitudes; mpmri availability; reporting quality; sequences considered useful in clinical practice; perceptions toward the usefulness of the procedure; impact of mpmri results on the decision making process; management of pi-rads 3 lesions; type of targeted prostate biopsy performed or recommended). in particular, questions about demographics included: years since completion of residency, type and location of medical practice, execution of prostate biopsies, and number of prostatectomies performed monthly. mpmri availability was addressed by asking about average waiting time for the exam. questions about attitudes toward mpmri indications investigated the following potential settings: biopsy naïve patients, patients with clinical suspicious pca despite a previous negative biopsy, pre-treatment staging, suspicion of local recurrence, as. questions about reporting quality addressed: the description of the sequences used, the adoption of the pi-rads version 2 scoring system, and the presence of a segmentation map with clear identification of the index lesion in the reports received. questions about perceptions toward the clinical utility of prostate mpmri were formulated to assess the perceived reliability of pi-rads v2 in identifying clinically significant pca, and the utility in the evaluation of local stage and recurrences. some questions required a single answer while others gave the respondents the choice to select as many answers as they felt appropriate. data collection invitations to participate in this anonymous survey were emailed on 28 january 2019 to 941 current italian society of urology (siu) members who gave the approval to the use of their e-mail address. all survey participants were practicing urologists in italy. for those who had not completed the survey, four follow-up reminder e-mail invitations were sent over the following 2 weeks. the survey was closed on 28 february 2019. all respondents had to fully complete the questionnaire before submission since all questions were flagged as mandatory. after submission, users could not review neither amend their answers. both personal contact information and data collected were not accessible to third parties. data analysis data were expressed as raw numbers and percentages of survey answers. chi square and fisher’s exact tests were used to assess variability in responses between demographic groups and according to mpmri availability. statistical analyses were two-sided using a significance level of 0.05. all statistical analyses were performed with spss version 17.0 (spss, inc., chicago, il) software. results a total of 98 responses were received from the survey within 30 days of the initial request (participation rate = 10.4%). table 1 shows demographic data of the respondents and information about average waiting time for prostate mpmri. ninety percent of respondents (n = 88) table 1. survey demographics and mpmri of the prostate availability. question n (%) how many years since you completed residency? < 10 years 42 (43) 10-30 years 46 (47) > 30 years 10 (10) what type of practice do you work in primarily? academic hospital 51 (52) community hospital 36 (37) private practice 11 (11) what type of setting do you practice in? urban 94 (96) non urban 4 (4) in which region do you practice in? north 28 (29) center 23 (23) south 47 (48) do you perform prostate biopsy? yes 69 (70) not 29 (30) on average, how many radical prostatectomies are performed monthly in your center? < 10 40 (41) 10-20 32 (33) > 20 26 (26) on average, how long do your patients wait for a mpmri? < 2 weeks 13 (13) 2-4 weeks 35 (36) > 4 weeks 50 (51) mpmri: multiparametric magnetic resonance imaging figure 1. attitudes toward the prescription of mpmri of the prostate in the various clinical settings. stanzione_stesura seveso 14/12/20 20:33 pagina 292 completed residency less than 30 years before the survey. about half of them (48%, n = 47) worked in southern italy, 96% (n = 94) in urban areas, and 89% (n = 87) primarily in a hospital setting. seventy percent of respondents (n = 69) declared to personally perform prostate biopsy and about half of them (51%, n = 50) declared that their patients wait more than 4 weeks for a prostate mpmri. urologists’ attitudes toward prostate mpmri prescription in various clinical scenarios are reported in table 2. the prevalence of indications for prostate mpmri in the settings explored are shown in figure 1. in particular, the following values were found: suspicious pca in patients with prior negative biopsy (97%, n = 95), suspicious pca in biopsy naïve patients (64%, n = 63), pre-operatory staging (60%, n = 59), active surveillance (24%, n = 24), suspicious local recurrence (21%, n = 21). geographic region and number of radical prostatectomies performed per month were significant factors influencing the prescription of prostate mpmri in biopsy-naïve patients while setting of practice was the only factor influencing the prescription of prostate mpmri in the re-biopsy setting (table 3). results from questions investigating the quality of reports received are showed in table 4. most respondents (81%, n = 79) declared to receive reports including a list of the sequences acquired and evaluated. the percentages of respondents declaring to receive often or almost always a report interpreted using pi-rads v2 guidelines and including a prostate segmentation map with the index lesions highlighted were 88% (n = 86) and 78% (n = 76), respectively. mpmri sequences judged as useful are showed in table 2. forty percent of respondents (n = 39) judged useful the combination of high resolution t2-weighted, axial dwi with adc maps, and axial perfusion sequences. the percentages of respondents judging reliable or highly reliable mpmri in identifying clinically significant pca, in local staging and in evaluating of local recur293archivio italiano di urologia e andrologia 2020; 92, 4 italian survey on prostate mpmri table 2. urologists’ attitudes and perceptions toward mpmri of the prostate. question n (%) when do you prescribe or consider useful to prescribe a mpmri of the prostate? biopsy naïve patients 63 (64) before re-biopsy 95 (97) pre-operatory staging 59 (60) suspicion of local recurrence 21 (21) active surveillance 24 (24) which of the following sequences do you consider useful for your clinical practice? high resolution t2-weighted alone 9 (9) axial dwi with adc maps alone 3 (3) axial perfusion alone 3 (3) high resolution t2-weighted + axial dwi with adc maps 24 (25) high resolution t2-weighted + axial perfusion 2 (2) axial dwi with adc maps + axial perfusion 7 (7) high resolution t2-weighted + axial dwi with adc maps + axial perfusion 39 (40) high resolution t2-weighted + axial dwi with adc maps + axial perfusion + spectroscopy 8 (8) axial dwi with adc maps + axial perfusion + spectroscopy 2 (2) high resolution t2-weighted + axial dwi with adc maps + spectroscopy 1 (1) how do you manage pi-rads 3 lesions? no further investigations 1 (1) secondary interpretation in referral centers 25 (26) targeted prostate biopsy as for pi-rads 4 and 5 lesions 25 (26) targeted prostate biopsy only in cases of high clinical suspicious 20 (19) standard biopsy 27 (28) how often results from mpmri change your strategy? almost always 5 (5) often 36 (37) sometimes 52 (53) hardly ever 5 (5) which technique of targeted prostate biopsy do you perform or advise? visual-cognitive 46 (47) software-assisted registration mri-trus 49 (50) mri guidance 3 (3) in your clinical practice, how do you rate the reliability of pi-rads v2 in identifying clinically significant pca? highly reliable 21 (21) reliable 75 (76) unreliable 2 (2) in your clinical practice, how do you rate the reliability of mpmri in local staging of pca? highly reliable 24 (24) reliable 69 (70) unreliable 5 (5) in your clinical practice, how do you rate the reliability of mpmri in the evaluation of local recurrence? highly reliable 11 (11) reliable 68 (69) unreliable 19 (20) adc: apparent diffusion coefficient; dwi: diffusion weighted imaging; mpmri: multiparametric magnetic resonance imaging; pi-rads: prostate imaging reporting and data system. table 3. indications to mpmri according to demographic features and mpmri availability. biopsy before presuspect patients naive repeat operatory local active patients biopsy staging recurrence surveillance (n = 63) (n = 95) (n = 59) (n = 21) (n = 24) years since completition of residency < 10 (n = 42) 28 (66.7%) 41 (97.6%) 26 (61.9%) 8 (19.0%) 11 (26.2%) 10-30 (n = 46) 27 (58.7%) 44 (95.7%) 25 (54.3%) 10 (21.7%) 12 (26.1%) > 30 (n = 10) 8 (80.0%) 10 (100%) 8 (80.0%) 3 (30.0%) 1 (10.0%) p 0.419 1.000 0.316 0.682 0.657 setting of practice academic hospital (n = 51) 33 (64.7%) 50 (98.0%) 30 (58.8%) 14 (27.5%) 14 (27.5%) community hospital (n = 36) 23 (63.9%) 36 (100%) 22 (61.1%) 6 (16.7%) 8 (22.2%) private practice (n = 11) 7 (63.6%) 9 (81.8%) 7 (63.6%) 1 (9.1%) 2 (18.2%) p 0.999 0.032 0.999 0.333 0.792 region north (n = 28) 23 (82.1%) 26 (92.9%) 18 (64.3%) 2 (7.1%) 8 (28.6%) center (n = 23) 10 (43.5%) 23 (100%) 17 (73.9%) 5 (21.7%) 4 (17.4%) south (n = 47) 30 (63.8%) 46 (97.9%) 24 (51.1%) 14 (29.8%) 12 (25.5%) p 0.016 0.438 0.162 0.060 0.652 do you perform biopsy? yes (n = 69) 42 (60.9%) 68 (98.6%) 40 (58.0%) 15 (21.7%) 17 (24.6%) no (n = 29) 21 (72.4%) 27 (93.1%) 19 (65.5%) 6 (20.7%) 7 (24.1%) p 0.276 0.208 0.486 0.907 0.958 radical prostatectyomies performed in the < 10 (n = 40) 19 (47.5%) 39 (97.5%) 24 (60.0%) 11 (27.5%) 8 (20.0%) working center 10-20 (n = 32) 25 (78.1%) 30 (93.8%) 19 (59.4%) 6 (18.8%) 10 (31.3%) per month > 20 (n = 26) 19 (73.1%) 26 (100%) 16 (61.5%) 4 (15.4%) 6 (23.1%) p 0.014 0.483 0.985 0.495 0.533 waiting time for mpmri < 2 weeks (n =13) 8 (61.5%) 12 (92.3%) 5 (38.5%) 4 (30.8%) 6 (46.2%) 2-4 weeks (n = 35) 23 (65.7%) 33 (94.3%) 24 (68.6%) 7 (20.0%) 6 (17.1%) > 4 weeks (n = 50) 32 (64.0%) 50 (100%) 30 (60.0%) 10 (20.0%) 12 (24.0%) p 0.962 0.139 0.166 0.463 0.114 stanzione_stesura seveso 14/12/20 20:33 pagina 293 archivio italiano di urologia e andrologia 2020; 92, 4 a. stanzione, m. creta, m. imbriaco, et al. 294 rences were 97%, 94% and 79%, respectively. overall, 42% of them declared to change often or almost always pca management strategy based on mpmri results. in total, only 26% of respondents declared to prescribe targeted biopsy in cases of pi-rads 3 lesions as for pirads 4 and 5 lesions. the percentages of respondents declaring to perform or advise targeted prostate biopsy with software assisted registration mri-ultrasound, visual cognitive, and mri guidance techniques were 50%, 47%, and 3%, respectively. geographic region and number of radical prostatectomies performed per month were significant factors influencing the adoption of visual cognitive technique (table 5). discussion the adoption of prostate mpmri to detect and characterize prostate lesions and to tailor the management of pca patients has evolved over the last 10 years (11, 1315). currently, however, the availability of this technology, the quality of reporting, and urologists’ perceptions and attitudes toward significantly varies across countries and some authors have stressed the need to integrate prostate mpmri teaching courses into the training of urologists (16). to the best of our knowledge, we performed the first survey examining prostate mpmri availability, quality of reports as well as urologists’ attitudes and perceptions toward this diagnostic modality in italy. the response rate elicited was within the range of surveys on this topic (10, 11, 17). respondents seemed to look favorably upon use of prostate mpmri, as 100% of them declared to prescribe or consider useful to prescribe it in at least one setting. by comparison, the survey published by muthigi and coworkers in 2017 found only 85.7% of urologists declaring to use prostate mpmri in their practice (9). the top settings for the use of prostate mpmri was in patients with persistent pca suspicion despite a prior negative biopsy (97%), followed by pca suspicion in biopsy naïve patients (64%) and pre-operatory staging (60%). accordingly, most of respondents had a positive perception toward the ability of mpmri to identify clinically significant pca and to provide an adequate local staging. the high percentage of respondents declaring to prescribe mpmri in patients with persistent pca suspicion despite a prior negative biopsy confirms the results from previous surveys from other counties (9, 11). indeed, 89.5% of respondents in the survey by muthigi and coworkers declared to prescribe prostate mpmri in this clinical scenario (9). to date, there is strong evidence demonstrating that mpmri-guided biopsy increases the detection rate for clinically significant pca when compared to standard biopsies and current eau guidelines strongly recommend mpmri prior to repeat biopsy (2). interestingly, we found that urologists working in private practice setting were less prone to prescribe mpmri before repeat biopsy. the percentage of respondents prescribing mpmri on biopsy naïve patients was higher if compared with published evidence. indeed, previous surveys reported percentages of utilization of prostate mpmri in this setting ranging from 36.8% to 53% (9, 11). evidences about prostate mpmri in this setting are contradictory and current guidelines provide only weak recommendations for the adoption of mpmri in patients undergoing their first biopsy (2). however, results from the recent randomized multicenter precision trial involving 500 biopsy-naïve patients with suspected pca support the role of pre-biopsy prostate mpmri and recommendations may change in the future (18). mpmri is considered as the imaging modality of choice for local staging (19). sixty percent of table 5. targeted biopsy modality of choice. visual-cognitive software-assisted mri guidance (n = 46) registration mri-trus (n = 3) (n = 49) years since completition of residency < 10 (n = 42) 19 (45.2%) 21 (50.0%) 2 (4.7%) 10-30 (n = 46) 24 (52.1%) 21 (45.6%) 1 (2.1%) > 30 (n = 10) 3 (30.0%) 7 (70.0%) 0 (0%) p 0.429 0.398 0.714 setting of practice academic hospital (n = 51) 28 (54.9%) 23 (45.0%) 0 (0%) community hospital (n = 36) 13 (36.1%) 20 (55.5%) 3 (8.3%) private practice (n = 11) 5 (45.4%) 6 (54.5%) 0 (0%) p 0.225 0.292 0.125 region north (n = 28) 7 (25.0%) 19 (67.8%) 2 (7.1%) center (n = 23) 13 (56.5%) 10 (43.4%) 0 (0%) south (n = 47) 26 (55.3%) 20 (42.5%) 1 (2.1%) p 0.024 0.088 0.436 do you perform biopsy? yes (n = 69) 33 (47.8%) 33(47.8%) 3 (4.3%) no (n = 29) 13 (44.8%) 16 (55.1%) 0 (%) p 0.786 0.506 0.552 rp performed in the working center per month< 10 (n = 40) 22 (55%) 18 (45.0%) 0 (0%) 10-20 (n = 32) 18 (56.2%) 13 (40.6%) 1 (3.1%) > 20 (n = 26) 6 (23.0%) 18 (69.2%) 2 (7.6%) p 0.017 0.071 0.183 waiting time for mpmri < 2 weeks (n = 13) 6 (46.1%) 7 (53.8%) 0 (0%) 2-4 weeks (n = 35) 18 (51.4%) 17 (48.5%) 0 (0%) > 4 weeks (n = 50) 22 (44%) 25 (50.0%) 3 (6.0%) p 0.818 0.999 0.372 table 4. mpmri data reporting. question n (%) do mpmri reports you receive include a list of mri sequences acquired and evaluated? yes 79 (81) not 19 (19) how often the mpmri reports you receive are interpreted (and lesions scored) using the pi-rads v2 guidelines? almost always 62 (63) often 24 (25) sometimes 11 (11) hardly ever 1 (1) how often the mpmri reports you receive include a prostate segmentation map with the index lesions highlighted? almost always 45 (46) often 31 (32) sometimes 14 (14) hardly ever 8 (8) mpmri: multiparametric magnetic resonance imaging; pi-rads: prostate imaging reporting and data system. stanzione_stesura seveso 14/12/20 20:33 pagina 294 295archivio italiano di urologia e andrologia 2020; 92, 4 italian survey on prostate mpmri respondents in the present survey declared to prescribe mpmri for pre-operatory staging. this finding is in line with published evidences as previous surveys from other countries reported percentages of utilization of mpmri in this setting ranging from 38% to 85% (9, 11, 17). only a small percentage of respondents declared to prescribe prostate mpmri in the clinical setting of as (24%) and suspect local recurrence (21%). mpmri has emerged as a valuable diagnostic modality in both patient selection and monitoring for men who undergoing as for pca and its use in this clinical scenario is gradually increasing (20-22). current eau guidelines strongly recommend prostate mpmri in men on as before confirmatory prostate biopsy if not done before the first biopsy (2). however, multiple barriers have been reported to counteract the widespread use of mpmri for as including quality, cost and access to care (20). accordingly, receipt of mpmri among pca patients on as significantly vary across demographic, geographic, and socioeconomic strata (21). the percentage of respondents prescribing mpmri in as setting we reported is lower if compared to data obtained from published surveys. indeed, 85% of french urologists and 66% of urologists working in the united states declared to utilize mpmri in this setting (11, 17). moreover, although published surveys involving urologists working france and in the united states demonstrated that the percentage of urologists prescribing prostate mpmri in patients enrolled in as was significantly higher among those working in academic hospitals, we failed to confirm this finding (11). similar to as setting, the percentage of urologists involved in the present survey that declared to prescribe mpmri in patients with suspicious of local recurrence was lower when compared to those from other surveys. indeed, 51% of french urologists declared to prescribe mpmri with the intent to detect local recurrence following radical treatments (11). urologists prescribing prostate mpmri need to be confident regarding the report they receive, as both their decision-making process and the quality of targeted prostate biopsy they perform mainly depends on the count, location, and radiographic stage of lesions identified by the radiologist (16, 23). interestingly, about 22% of respondents in the present survey declared to receive reports that sometimes or hardly ever include a prostate segmentation map with the index lesions highlighted, 19% declared to receive reports that do not include a list of mri sequences acquired and evaluated, and 12% declared to receive reports that sometimes or hardly ever are interpreted using the pi-rads v2 guidelines. taken together, these results underline the need to further improve in our country the process of standardization of prostate mpmri reporting. we collected evidences about urologists’ point of view concerning mpmri acquisition protocol and relevance of included sequences. the answers collected seem to indicate that the urologists might not be completely aware of the dominant sequence structure of the pi-rads v2 guidelines. indeed, fewer than half responders (40%) correctly identified the currently recommended protocol suggesting that the major revision of the original pirads has not been universally embraced among urologists. furthermore, it should also be noted that a relatively high percentage (25%) of urologists indicated that a protocol without the perfusion sequence could be considered adequate for their patients. this is somewhat in line with a current trend advocating for the need of shorter, cheaper and less invasive mri protocols and reinforces the ongoing debate about the role of perfusion sequences in prostate imaging (24-26). the management of undetermined, pi-rads 3 lesions has represented a controversial issue for many years. accordingly, the attitude of respondents is heterogeneous with only 26% of them recommending targeted biopsies as for pi-rads 4 and 5 lesions and 20% performing targeted biopsies only in cases of high clinical suspicious. more recent eau guidelines, updated in march 2019, consider prostate lesions with a pi-rads score ≥ 3 as positive and strongly recommend performing targeted plus systematic biopsy in biopsy naïve patients and targeted biopsy only in patients with prior negative biopsy (2). the modality with which prostate lesions identified by mpmri are targeted at biopsy vary considerably. visualcognitive and software-assisted registration mritransrectal ultrasound guidance were the most frequently adopted guidance modalities by respondents in the present survey with mri-guidance being adopted by only 3% of interviewed. of note, the adoption of visualcognitive guidance was significantly lower in northern italy and in centers where more than 20 radical prostatectomies are performed monthly. of note, the modality of lesion targeting during prostate biopsy represents a controversial and evolving issue (27-29). beyond technical aspects, tumor multifocality is frequently involved in the discrepancies between findings from mp-mri, prostate biopsy, and surgical specimens (29). although mri-guidance may represent a promising technique of biopsy guidance, it is still considered a time-consuming and expensive procedure and further investigations are needed to identify the ideal candidates (30). the major limitation of this survey includes the small number of participants. however, the response rate is within published ranges. secondly, respondents are not fully representative of the overall community of italian urologists as those working in private practice setting and 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resonance imaging in prostate cancer active surveillance. bju int. 2019; 124:730-737. 21. fam mm, yabes jg, macleod lc, et al. increasing utilization of multiparametric magnetic resonance imaging in prostate cancer active surveillance. urology. 2019; 130:99-105. 22. höffkes f, arthanareeswaran vk, stolzenburg ju, ganzer r. rate of misclassification in patients undergoing radical prostatectomy but fulfilling active surveillance criteria according to the european association of urology guidelines on prostate cancer: a high-volume center experience. minerva urol nefrol. 2018; 70:588-593. 23. puech p, randazzo m, ouzzane a, et al. how are we going to train a generation of radiologists (and urologists) to read prostate mri? curr opin urol. 2015; 25:522-35. 24. stanzione a, cuocolo r, cocozza s, et al. detection of extraprostatic extension of cancer on biparametric mri combining texture analysis and machine learning: preliminary results. acad radiol. 2019; 26:1338-1344. 25. cuocolo r, stanzione a, rusconi g, et al. psa-density does not improve bi-parametric prostate mr detection of prostate cancer in a biopsy naïve patient population. eur j radiol. 2018; 104:64-70. 26. salvaggio g, calamia m, purpura p, et al. role of apparent diffusion coefficient values in prostate diseases characterization on diffusion-weighted magnetic resonance imaging. minerva urol nefrol. 2019; 71:154-160. 27. pepe p, pepe l, panella p, pennisi m. can multiparametric ultrasound improve cognitive mri/trus fusion prostate biopsy. arch ital urol androl. 2020; 92:89-92 28. d'agostino d, mineo bianchi f, romagnoli d, et al. mri/trus fusion guided biopsy as first approach in ambulatory setting: feasibility and performance of a new fusion device. arch ital urol androl. 2020; 91:211-217. 29. lourenço m, pissarra p, e brito dv, et al. lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece. arch ital urol androl. 2020; 91:218-223. 30. d'agostino d, mineo bianchi f, romagnoli d, et al. comparison between "in-bore" mri guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: preliminary results. arch ital urol androl. 2019; 91:87-92. correspondence arnaldo stanzione, md arnaldostanzione@yahoo.it massimo imbriaco, md mimbriaco@hotmail.it department of advanced biomedical sciences, university of naples “federico ii”, via pansini 5, 80131 naples (italy) massimiliano creta, md (corresponding author) max.creta@gmail.com roberto la rocca, md robertolarocca87@gmail.com marco capece, md drmarcocapece@gmail.com fabio esposito, md fabioesposito025@gmail.com ciro imbimbo, md ciro.imbimbo@unina.it giuseppe celentano, md dr.giuseppecelentano@gmail.com luigi napolitano, md nluigi89@libero.it francesco mangiapia, mp mangiapippo@libero.it vincenzo mirone, md mirone@unina.it nicola longo, md nicolalongo20@yahoo.it department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii" via pansini 5, 80131 naples (italy) ferdinando fusco, md ferdinando-fusco@libero.it department of woman child and of general and specialist surgery, university of campania "luigi vanvitelli" 80131 naples (italy) stanzione_stesura seveso 14/12/20 20:33 pagina 296 cop+ed+fisse 2006 211archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.211 primary small-cell neuroendocrine carcinoma of the bladder: case report and literature review valerio olivieri 1, valentina fortunati 2, luca bellei 1, massimo massarelli 1, gabriele ruggiero 3, danilo abate 3, nicoletta serra 3, daniele griffa 1, 3, flavio forte 4, emanuele corongiu 4 1 division of urology, ivrea hospital (asl to4), ivrea (turin), italy; 2 division of pathology, hospital policlinico of tor vergata, rome, italy; 3 division of urology, ciriè hospital (aslto4), ciriè (turin), italy; 4 division of urology, hospital “madre giuseppina vannini”, rome, italy. background: neuroendocrine tumours (net) are extremely rare and aggressive. although they commonly affect intestine, many organs may be involved such as pancreas, lung or urinary tract. bladder is rarely involved. actually, two main forms of bladder net have been described: small-cell and large-cell. the first one is considered highly agressive since it shows poor oncologic outcomes being mainly diagnosed at advanced stage: the second one is extremely rare and equally aggressive. case report: a 78-years-old caucasian male presented to our facility for lower urinary tract symptoms and gross hematuria recently occurred. he was a strong smoker since many years. no familiarity for urothelial cancer was referred nor previous episodes of hematuria until that time. citology was negative; outpatient ultrasound of the bladder revealed a 3 cm bladder thickening highly suspicious for bladder cancer; patient underwent tc scan that confirmed the bladder lesion. a transurethral resection of the bladder (turb) was performed. after 3 months total body tc showed multiple visceral metastases also involving brain and lymph nodes. best supportive care was offered but the patient died 6 months later. results: pathology revealed a mixed bladder tumor: 30% of the specimen resulted as an high-grade urothelial cancer (g3) and 70% as small-cell neuroendocrine variant.microscopic muscle involvement was excluded. conclusions: neuroendocrine tumors are uncommon entities which origin from cells of neuro-endocrine system and may potentially involve all human tissues. neuroendocrine smallcell carcinoma of the bladder is a non-urothelial histotype: it is highly aggressive and diagnosed mainly at advanced stages. whenever considering the high risk of metastatic spread and the poor prognosis, a multimodal approach is highly suggested. turb alone is uneffective in disease control due to its aggressive nature. unless metastatic, radical cystectomy and adjuvant chemotherapy represent the gold standard. key words: neuroendocrine; bladder cancer; uro-oncology; rare tumors; oncology. submitted 2 march 2020; accepted 15 march 2020 summary introduction neuroendocrine tumours (net) are extremely rare (1) and aggressive. it has been valued the annual incidence is approximately 2.5-5.0 per 100.000. they take origin from cells of nervous and endocrine systems differently expressed in human tissues. although they commonly affect intestine, many organs may be involved such as pancreas, lung or urinary tract. bladder is rarely involved (2). to date two main forms of bladder net have been described: small-cell and largecell. the first one is considered highly aggressive since it shows poor oncologic outcomes being mainly diagnosed at advanced stage: the second one is extremely rare and equally aggressive. data in literature are strongly limited. here we report the case of a small-cell neuroendocrine carcinoma of urinary bladder. while opportunely describing this case, we also reviewed the literature on pubmed about this pathological condition. case report a 78-years-old caucasian male presented to our facility for lower urinary tract symptoms and gross hematuria recently occurred. he was a strong smoker since many years. no familiarity for urothelial cancer was referred nor previous episodes of haematuria until that time. on past anamnesis he suffered from myocardial infarction and chronic fibrillation being actually on medication with acetilsalicilate plus edoxaban. multiple coexisting systemic illness were reported such as hypertension, dyslipidemia and mild chronic renal failure. furthermore, he was also on medication with adrenergic a1-antagonist for a benign prostatic hyperplasia (bph) condition: anyway, his last psa was normal and digito-rectal exploration confirmed an enlarged soft gland. general and systemic examination was unremarkable: no asthenia, weight loss, abdominal palpable masses or acute urinary retention were present. blood examination revealed a mild anaemia while renal function and white blood count were unremarkable. urinalysis confirmed haematuria but cytology was negative. ambulatory ultrasound revealed a 3 cm bladder wall thickening highly suspicious for bladder cancer; the patient subsequently underwent to contrastenhanced ct. the examination confirmed the bladder lesion (figure 1) totally excluding bilateral hydronephrosis, visceral metastases or lymph nodes involvement. a trans urethral resection (turb) of the mass was offered. pathology report revealed a mixed bladder tumour: 30% of specimen resulted as an high-grade urothelial cancer (g3) while 70% as small-cell neuroendocrine variant (figure 2). microscopic muscle involvement was excluded. in order to better characterize the neuroendocrine differentiation, further evaluation using immunohistochemistry was mandatory: cytokeratin, synaptophysin and 14corongiu1_stesura seveso 25/09/20 13:12 pagina 211 archivio italiano di urologia e andrologia 2020; 92, 3 v. olivieri, v. fortunati, l. bellei, m. massarelli, g. ruggiero, d. abate, n. serra, d. griffa, f. forte, e. corongiu 212 ki-67 were used as molecular markers. urothelial histotype resulted positive for cytokeratine but negative for synaptophysin while the neuroendocrine variant was positive for both of them. ki-67, a molecular marker as expression of proliferation rate, was 90% totally suggesting an aggressive bladder cancer, in fact net are histologically graded according to mitotic count and markers of cellular proliferation (ki-67 index) rather than cellular polymorphism: a mitotic count > 20 per 10 hpf and a ki-67 index > 20% defines the high-grade. due to its non-urothelial origins, it was also classified as a highest risk tumour. treatments, in these cases, depends on many factors; several issues such as anatomic location, tumour differentiation, staging, metastases, lymph node involvement and symptoms may help to define the best therapeutic approach. the high-grade forms should be managed by active treatment which may be multimodal. unless metastatic, radical cystectomy and chemotherapy (either neoadjuvant or adjuvant) must be offered (3) since turb alone seems to be an inadequate method of disease control. recently, some authors noted molecular abnormalities in small cell neuroendocrine bladder cancer also raising the question of using target therapies: targeting angiogenesis would be the most promising. anyway, to date immunotherapy still remains under debate. in our case, we evaluated the patient in a multidisciplinary tumour board in order to offer the best disease management. according to karnofsky performance status, comorbidities and iatrogenic bleeding risk, adjuvant chemotherapy and radiation were not suggested: radical cystectomy was also offered but patient refused that option. he simply underwent follow up. after 3 months total body tc showed multiple visceral metastases (figures 3-4) also involving brain and lymph nodes: best supportive care was offered but the patient died 6 months later. conclusions neuroendocrine tumours are uncommon entities1 which origin from cells of neuro-endocrine system and may potentially involve all human tissues. gastrointestinal localization is quite common while genitourinary is rare. neuroendocrine small-cell carcinoma of the bladder is a non-urothelial histotype: it is highly aggressive and diagnosed mainly at advanced stages. it’s considered as an aggressive tumor being characterized by poor prognosis and limited life expectancy. small-cell carcinoma is a type of bladder net along with large-cell variant. to date no treatment has shown established efficacy. whenever considering the high risk of metastatic spread and the poor prognosis, a multimodal approach is highly suggested. turb alone is uneffective in disease control due to its aggressive nature. unless metastatic, radical cystectomy and adjuvant chemotherapy represent the gold standard. immuno ther apy has been proposed but still under debate. given its rarity and the absence of randomized trials, the therapeutic management of this tumor remains difficult and finding useful resources for physicians is troublesome yet. references 1. al-ahmadie h, iyer g. updates on the genetics and molecular subtypes of urothelial carcinoma and select variants. surg pathol clin. 2018; 11:713-723. 2. cramer sf, aikawa m, cebelin m. neurosecretory granules in small cell invasive carcinoma of the urinary bladder. cancer. 1981; 47:724-30. 3. siefker-radtke ao, dinney cp, abrahams na, et al. evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the m.d. anderson cancer experience. j urol. 2004; 172:481-484. figure 1. abdominal contrast enhanced ct showing a right wall bladder lesion. figure 2. microscopic finding showing small cell neuroendocrine bladder cancer reacting to synaptophysin (original magnification x 400). figure 3-4. whole body contrast enhanced ct showing brain and liver multiple metastases in small cell neuroendocrine carcinoma of the bladder (sccb). correspondence valerio olivieri, md valerio.olivieri@uniroma1.it luca bellei, md massimo massarelli, md gabriele ruggiero, md division of urology, ivrea civil hospital (asl to4), ivrea (turin) (italy) daniele griffa, md danilo abate, md nicoletta serra, md division of urology, ciriè hospital (aslto4), ciriè (turin) (italy) valentina fortunati, md valerio.olivieri@uniroma1.it division of pathology, hospital “policlinico of tor vergata”, rome (italy) emanuele corongiu, md (corresponding author) emanuele.corongiu@libero.it flavio forte, md flavioforte@hotmail.com division of urology, hospital “madre giuseppina vannini”, rome (italy) 14corongiu1_stesura seveso 25/09/20 13:12 pagina 212 stesura seveso 263archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.263 l-carnitine as primary or adjuvant treatment in infertile patients with varicocele. a systematic review georgios tsampoukas 1, 4, muhammad faisal khan 2, antigoni katsouri 3, waseem akhter 4, mohamad moussa 5, konstantinos deliveliotis 6, athanasios papatsoris 1, 6, noor buchholz 1 1 u-merge ltd. (urology for emerging countries), london, uk*; 2 department of urology, north devon hospital, barnstaple, uk; 3 department of pharmacy, university of patras, patras, greece; 4 department of urology, princess alexandra hospital, harlow, uk; 5 al zahraa hospital, university medical center, lebanese university, beirut, lebanon; 6 2nd department of urology, university hospital of athens, athens, greece. * u-merge ltd. (urology for emerging countries) ) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com background: varicocele has been found to impair the function of the epididymis resulting in subfertility whereas the varicocelectomy can resolve the phenomenon. l-carnitine is regarded as a biomarker for the function of the epididymis and has been found in reduced concentrations in infertile patients of various causes, including infertile men with varicocele. it seems that lcarnitine and varicocele share clinical significance and the area of research looks promising. objective: to identify the role of l-carnitine in the treatment of varicocele. materials and methods: a systematic search was performed in pubmed/medline with the terms (l-carnitine) and (varicocele) and (l-carnitine) and (varicocelectomy). inclusion criteria were studies reported outcomes of l-carnitine administration alone or in duet, as primary or adjuvant treatment to varicocele. exclusion criteria were non-english language and animal studies. studies using l-carnitine as part of a panel of therapeutic agents were avoided. results: only four suitable studies were identified for discussion. in one randomized study, the combination of l-carnitine and cinnoxicam improved semen parameters in patients with non-high-grade varicocele compared to l-carnitine alone and had a favourable effect on pregnancy rates but the effect of grade is unknown. in another study, as an adjuvant treatment to varicocelectomy, l-carnitine showed no clear benefit. finally, in comparison to surgery, the results are inconclusive; two studies showed some benefit might be expected in low-grade or subclinical varicocele, but surgery appears superior. conclusions: the evidence regarding the role of l-carnitine as a primary or adjuvant treatment of varicocele is sparse. the pathophysiological significance of l-carnitine implicates a potential role of the molecule in the management of varicocele, but the evidence so far is controversial for any recommendations. l-carnitine might be taken into consideration in selected cases; however, further search is needed in order the optimal role of l-carnitine in infertile patients with varicocele to be clarified. key words: varicocele; male infertility; l-carnitine; antioxidants; varicocelectomy. submitted 2 march 2020; accepted 15 march 2020 summary introduction background varicocele is considered one of the most common treatable causes of male infertility (1). the interventional or surgical approach is considered the standard of care for the condition in case of infertility due to favourable outcomes regarding improvement in semen parameters and pregnancy rates (2). in modern era, research has also focused on the varicocele-induced oxidative stress and reduction in antioxidant capacity which results in impaired spermatogenesis, broadening new horizons in the treatment of the condition (3, 4). antioxidative treatment is well-established in idiopathic infertility and oligoasthenoteratospermia (oat), albeit the results still conflicting and the optimal agents or combination still lacking (5). among the investigated agents, l-carnitine (lc) has shown effectiveness on ameliorating oxidative stress, improving semen parameters in infertile patients (6-9). additionally, the molecule has a significant physiological role and the measurement of seminal l-carnitine is used as biomarker for the assessment of epididymal function in patients with various fertility issues including varicocele (10, 11). the measurement of l-carnitine in the semen is meaningful and clinical relevant as a positive correlation between seminal carnitine levels and several semen parameters including motility, concentration and dna quality has been shown in infertile patients with varicocele (12). all the above render lc as a potent biomarker during the evaluation of infertile patients with varicocele and as a potential target in the treatment of such patients as well. in this review, we explore the role of lc in the potential management of varicocele. materials and methods we performed an systematic literature search using the advanced search engine in pubmed/medline with the terms (l-carnitine) and (varicocele) and (l-carnitine) and (varicocelectomy). the results were checked for duplicates in mendeley. our search targeted studies reporting conclusions relating to archivio italiano di urologia e andrologia 2020; 92, 3 g. tsampoukas, m. faisal khan, a. katsouri, w. akhter, m. moussa, k. deliveliotis, a. papatsoris, n. buchholz 264 the role of carnitine management of varicocele. only studies using l-carnitine alone or in duet were included and studies reporting results with combination of multiple antioxidants were avoided. animal studies, case reports and articles in non-english language were excluded; reviews were also excluded from the literature search but were screened independently for the identification of other sources. the flowchart of our strategy is presented on figure 1. the risk of bias assessment of the selected studies is illustrated on figure 2. results (table 1) performance of l-carnitine in infertile patients with varicocele as sole treatment one study was identified reporting the benefit of lc administration in semen parameters of infertile patients with varicocele-induced oat. cavallini et al. randomized patients into 3 groups, group 1 given placebo only, group 2 given oral lc (2 g/d)/acetyl-l-carnitine (1 g/d) and placebo suppository and group 3 given oral lc and suppository cinnoxicam 30 mg every 4 days; the medication were given for a total duration of 6 months whereas the varicocele was graded according to the severity of venous reflux into 5 grades, with grades 1-2 corresponding to subclinical varicocele and grades 3-5 corresponding to clinical grades i, ii and iii respectively (13). the authors observed that the combination group had significantly increased sperm parameters at 3 and 6 months compared to other groups in patients with grade 1 to 4 whereas the effect was durable as long as patients were on the medication; on the other hand, no treatment made any difference in grade 5 varicoceles. thus, the authors concluded that the combination of lc and cinnoxicam suppositories proved a reliable treatment for lowgrade varicoceles in terms of semen parameters but not efficient for high grades; notably, the pregnancy rates were also raised in group 3 but there was no special comment regarding the varicocele grade contribution (13). performance of l-carnitine in comparison to varicocelectomy two studies reported outcomes of varicocelectomy compared to administration of lc. in one study, sofimajidpour et al allocated 62 patients with a mean age of 29 years and mean infertility duration of 3.3 years with clinical varicocele grade ii or more into two groups; thirty-one patients were administrated an oral dose of 250 mg lc four times a day for six months and 31 patients underwent varicocelectomy (14). both groups showed significant improvement in semen parameters including sperm count, motility, morphology and semen volume while no difference was observed between groups (14). notably, the study was not randomized and the groups differed significantly in terms of clinical grade (the 87.1% of the participants in the medicinal group had grade ii varicocele in comparison to 25.8% of patients in the figure 1. prisma 2009 flow diagram. figure 2. risk of bias of the selected studies. surgery group); therefore, it seems that lc supplementation might be an alternative to surgery in infertile patients with grade ii varicocele in terms of semen parameters (14). in a retrospective study of 143 infertile patients with left subclinical varicocele, the authors had allocated the participants into 3 groups according to their preference: a surgery group was treated with microsurgical varicocelectomy, a medical group with 3 g of lc orally for at least 6 months and an observation group including patients deciding no treatment (15). the operation increased the sperm count significantly whereas the pregnancy rate raised to 60%; on the contrary, the lc administration did not offer any benefit in terms of semen parameters but the pregnancy rate was 34.5% differing significantly to observation group (18.7%) (15). performance of l-carnitine as adjuvant treatment to varicocelectomy pourmand et al randomized 100 infertile patients with clinical and subclinical varicocele and dyspermia into two groups; the first group underwent varicocelectomy alone whereas patients in the second group were given adjuvant 750-mg oral lc a day for 6 months (16). the study failed to show any benefit of the adjuvant administration of the agent as neither the semen parameter improvement nor dna damage reduction differed significantly in the patients underwent combined treatment in comparison to the surgery alone group; however, the slope of improvement for morphology and motility was better in the combination treatment group (16). discussion we decided to investigate the role of lc in the management of varicocele for two main reasons. firstly, the epididymis is considered the main supply of lc to the semen, providing around the 95% of the total amount and this is why seminal lc has been proposed as a marker for the assessment of the functional capacity of the organ (17, 18). the finding is significant as lc acts as a co-factor for the mitochondrial transport and the subsequent oxidation of fatty acids and phospholipids which are used by the epididymal spermatozoa as a substantial source of energy (19). subsequently, a positive correlation between seminal plasma total carnitine with total sperm count and morphology has been reported, findings suggesting that the determination of seminal carnitine levels may be a useful test in evaluation of male fertility (20), (21). varicocele has been shown to impair the function of the accessory glands including the epididymis resulting in impaired semen quality (22). such observations come in accordance with experimental data showing that the induction of varicocele causes impairment in the epididymal microenvironment resulting in reduced epididymal carnitine levels and subsequent hypoxia, increased apoptosis and possible subsequent infertility (23). moreover, the beneficial effect of varicocelectomy on the epididymal function is reflected as an increase of epididymis-specific proteins such as alphaglucosidase along with the improvement in semen parameters (24). an intriguing point is that seminal lcarnitine has been reported to be reduced in infertile patients with (low-grade) varicocele and normal semen parameters; the observation is meaningful as it shows that varicoceles might impair epididymal function and cause infertility even if this is not profound in conventional spermiogram, whereas lc could be used to unmask the underlying pathology and facilitate management (25). secondly, the recent years the increased use of antioxidants as empirical treatment for several condi265archivio italiano di urologia e andrologia 2020; 92, 3 l-carnitene and varicocele table 1. summarized data of the studies. scope type of clinical trial number of participants main outcome/conclusions comments cavallini et al. (2004) sofimajidpour et al. (2016) jt seo et al. (2008) pourmand et al. (2014) lc: l-carnitine; oat: oligoasthenoazoospermia; vc: varicocele; sv: subclinical varicocele; * varicocele group. placebo vs lc alone vs lc and cinnoxicam on the improvement of semen parameters in infertile patients with idiopathic oat and infertile patients with oat and various grades of vc (including sv) varicocelectomy vs lc alone on the improvement of semen parameters of infertile patients with varicocele of various clinical grades observation vs varicocelectomy vs lc alone on infertile patients with sv varicocelectomy alone vs varicocelectomy plus adjuvant lc on improvement of semen parameters and dna in infertile patients with varicocele prospective/ randomized prospective/ non-randomized (patient preference) retrospective prospective/(block) randomized 195 patients into 3 groups * 62 patients into 2 groups 143 patients into 3 groups 100 patients into 2 groups significant improvement in grades i-iv for drug combination but no treatment was effective in grade v no significant difference between groups varicocelectomy outnumbered lc monotherapy and observation in both semen parameters and pregnancy rates no statistically significant improvement in terms of parameters and dna damage the higher the grade, the lower the benefit of drug therapy; combination group had increased pregnancy rates, but the contribution of grade is unknown imbalance of grade contribution between groups as most patients at medical group had grade ii and most patients at surgical group had grade iii varicocele lc administration was better vs observation in terms of pregnancy rates but inferior to varicocelectomy lower dose than used in other studies; trend in improvement of dna damage; longer follow-up might be required (> 6 months) archivio italiano di urologia e andrologia 2020; 92, 3 g. tsampoukas, m. faisal khan, a. katsouri, w. akhter, m. moussa, k. deliveliotis, a. papatsoris, n. buchholz 266 tions including male infertility has given birth to a phenomenon called “antioxidant paradox”, which is defined as the unresponsiveness of the body despite the administration of large doses of dietary antioxidants (26). this paradoxical phenomenon along with the possibility of increased toxicity due to excessive use of antioxidants and the harming results of reductive stress have raised concerns for more accurate therapies and specific guidelines in patients suffering from infertility (27). therefore, we focused our search on lc alone or in dual combination as the molecule has physiological significance and we reviewed its clinical relevance as therapeutic agent. the performance of lc in infertile patients with varicocele was reported in one randomized study and the authors concluded that the combination of the agent along with cinnoxicam was proven effective for subclinical and lowgrade varicoceles in comparison to lc alone in terms of semen parameters; however, no treatment was efficient for high grades (13). if the varicocele grade affects the outcome of conservative treatment should be a matter of future research as the evidence is sparse. in a doubleblind, placebo-controlled study, the combination of lcarnitine, fumarate, 5 acetyllcarnitine, fructose, coq10, vitamin c, zinc, folic acid and vitamin b12 for 6 months significantly improved the total sperm count and total and progressive motility in varicocele patients irrespective of grade; however, the pregnancy rate was not the end point in the study and cannot be assessed (28). in another study, 20 infertile patients with grade i varicocele were given multivitamins lc, vitamin c, coenzyme q10, vitamin e, vitamin b9, vitamin b12, zinc, selenium and a significant improvement in sperm dna quality and total sperm count was seen but other semen parameters were not affected (29). patients with low-grade varicoceles might gain some benefit from the administration of lc in combination with other agents but future studies should explore the effect of conservative treatment on pregnancy rates especially in correlation with clinical grades. in terms of comparison with standard of care of varicocelectomy, we identified two studies whom the conclusions should be examined carefully; none of the studies were randomized and one study had significant differences between the compared groups (14). nevertheless, in the latter study, treating grade ii varicocele conservatively with lc had similar results with treating grade iii varicocele surgically and the authors concluded that conservative management could be an alternative to surgery in grade ii varicoceles (14). in the study by seo et al, treating subclinical varicocele with lc results in inferior pregnancy rates comparing to surgery but the performance was better than the observation (15). the observation comes is accordance with results from meta-analysis that subclinical varicocelectomy has some benefit in male infertility (30). also, it seems that lc could be an alternative option in infertile patients with non-highgrade varicoceles, but the level of evidence is low. last but not least, if lc is an alternative to surgery in lowgrade disease needs to be clarified in future, prospective, randomized studies. regarding the role of adjuvant lc in patients undergoing varicocelectomy one randomized study was identified which showed no clear benefit; however, there was a trend in favour of adjuvant treatment for motility and morphology (16). similarly, other agents like ascorbic acid have been tested in the same manner with lc showing similar results (31). although not fully relevant to humans, experimental data have shown that adjuvant treatment with lc may show significant benefit. in one study, akdemir et al randomized 42 male rats into 7 groups comparing the effects of different varicocelectomy techniques with or without adjuvant lc on spermatogenesis and histopathological changes in testicular tissue (32). the authors observed that varicocelized rats treated with testicular non-artery sparing varicocelectomy and adjuvant lc administration had significantly increased mrna expression levels of factors inducing the spermatogenesis comparing to other groups; additionally, in this group of patients the germ cells displayed almost total normalization in their cellular organisation (32). the discrepancy between the experimental studies and human cohorts might be associated with the nature of the condition as in experiments the varicocele is an acute phenomenon while in humans the varicocele represents a chronic disease with long-standing effects on the germ epithelium. although this field is still unexplored, an effort to expand the efficacy of the surgery might be beneficial for some patients. a combined approach could help downgrade the indication in less invasive assisted-reproduction techniques, as this is the case with varicocelectomy in both clinical and subclinical forms (33). in that terms, adjuvant antioxidant treatment might be beneficial increasing the fatherhood chances and reducing the cost as well. if lc can act this role, it needs to be clarified with future research. conclusions lc has a significant physiological role in male reproductive system and its usage sounds promising when evaluating infertile patients with varicocele. as a therapeutic agent, it seems that lc might be used in selected patients, but it cannot replace interventions whereas the level of evidence to support the agent as adjuvant treatment or monotherapy in infertile patients with varicocele is low. future, randomized studies should investigate the optimal role of lc in the management of patients with varicocele. references 1. agarwal a, sharma r, harlev a, esteves s. effect of varicocele on semen characteristics according to the new 2010 world health organization criteria: a systematic review and meta-analysis. asian j. androl. 2016; 18:163. 2. wan x, wang h, ji z microsurgical varicocelectomy for clinical varicocele: a review for potential new indications. andrologia 2017; 49 (10) doi:10.1111/and.12827. 3. erfani majd n, sadeghi n, tavalaee m, et al. evaluation of oxidative stress in testis and sperm of rat following jnduced varicocele. urol j. 2019;16:300-306 4. lorian k, kadkhodaee m, kianian f, et al. long-term nahs administration reduces oxidative stress and apoptosis in a rat model of left-side varicocele. andrologia 2020; 52:e13496. 5. omar mi, pal rp, kelly bd, et al. benefits of empiric nutritional 267archivio italiano di urologia e andrologia 2020; 92, 3 l-carnitene and varicocele and medical therapy for semen parameters and pregnancy and live birth rates in couples with idiopathic jnfertility: a systematic review and meta-analysis. eur urol. 2019; 75:615-625. 6. nada ea, el taieb ma, ibrahim hm, al saied ae-ra. efficacy of tamoxifen and l-carnitine on sperm ultrastructure and seminal oxidative stress in patients with idiopathic oligoasthenoteratozoospermia. andrologia. 2015; 47:801-810 7. majzoub a, agarwal a. systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. arab j urol. 2018; 16:113-124 8. mongioi l, et al. the role of carnitine in male infertility. andrology. 2016; 4:800-807 9. banihani s, agarwal a, sharma r, bayachou m. cryoprotective effect of l-carnitine on motility, vitality and dna oxidation of human spermatozoa. andrologia 2014; 46:637-641 10. wetterauer u, heite hj. carnitine in seminal plasma: its significance in diagnostic andrology. arch androl. 1980; 4:137-43. 11. lewin lm, shalev dp, weissenberg r, soffer y. carnitine and acylcarnitines in semen from azoospermic patients. fertil steril. 1981; 36:214-218. 12. de rosa m, boggia b, amalfi b, et al. correlation between seminal carnitine and functional spermatozoal characteristics in men with semen dysfunction of various origins. drugs r d. 2005; 6:1-9. 13. cavallini g, ferraretti ap, gianaroli l, et al. cinnoxicam and l-carnitine/acetyl-l-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia j androl. 2004; 25:761-70. 14. sofimajidpour h, ghaderi e, ganji o. comparison of the effects of varicocelectomy and oral l-carnitine on sperm parameters in infertile men with varicocele. j clin diagn res. 2016; 10: pc07-10. 15. seo jt, kim kt, moon mh, kim wt. the significance of microsurgical varicocelectomy in the treatment of subclinical varicocele,” fertil steril. 2010; 93:1907-10. 16. pourmand g, movahedin m, dehghani s, et al. does l-carnitine therapy add any extra benefit to standard inguinal varicocelectomy in terms of deoxyribonucleic acid damage or sperm quality factor indices: a randomized study. urology. 2014; 84:821-5. 17. wetterauer u, heite hj. carnitine in seminal fluid as parameter for the epididymal function. andrologia 1978; 10:203-210. 18. milingos sd. the epididymal factor--a diagnostic approach. int j androl. 1985;8:417-420. 19. lenzi a, lombardo f, gandini l, dondero f. metabolism and action of l-carnitine: its possible role in sperm tail function. arch ital urol nefrol androl. 1992; 64:187-196. 20. gürbüz b, yalti s, fiçicioglu c, zehir k. relationship between semen quality and seminal plasma total carnitine in infertile men. j obstet gynaecol. 2003; 23:653-656. 21. matalliotakis i, koumantaki y, evageliou a, et al. l-carnitine levels in the seminal plasma of fertile and infertile men: correlation with sperm quality. int j fertil womens med. 2000; 45:236-240. 22. vivas-acevedo g, lozano-hernandez r, camejo mi. markers of accessory sex glands function in men with varicocele, relationship with seminal parameters. can j urol. 2011; 18:5884-5889. 23. zhang k, wang z, wang h, et al. hypoxia-induced apoptosis and mechanism of epididymal dysfunction in rats with left-side varicocele. andrologia. 2016; 48:318-324 24. lehtihet m, arver s, kalin b, et al. left-sided grade 3 varicocele may affect the biological function of the epididymis. scand j urol. 2014; 48:284-289. 25. pajovic b, dimitrovski a, radojevic n, vukovic m. a correlation between selenium and carnitine levels with hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients. eur rev med pharmacol sci. 2016; 20:598-604. 26. henkel r, sandhu is, agarwal a. the excessive use of antioxidant therapy: a possible cause of male infertility? andrologia. 2019; 51:e13162. 27. agarwal a, parekh n, panner selvam mk, et al. male oxidative stress infertility (mosi): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. world j mens health. 2019; 37:296-312. 28. busetto gm, agarwal a, virmani a, et al. effect of metabolic and antioxidant supplementation on sperm parameters in oligoastheno-teratozoospermia, with and without varicocele: a doubleblind placebo-controlled study. andrologia. 2018; 50doi: 10.1111/and.12927. 29. gual-frau j, abad c, amengual mj, et al. oral antioxidant treatment partly improves integrity of human sperm dna in infertile grade i varicocele patients. hum fertil (camb). 2015; 18:225-9 30. kim hj, seo jt, kim kj, et al. clinical significance of subclinical varicocelectomy in male infertility: systematic review and metaanalysis. andrologia. 2016; 48:654-661. 31. cyrus a, kabir a, goodarzi d, moghimi m. the effect of adjuvant vitamin c after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. int braz j urol. 2015; 41:230-238. 32. akdemir s, gurocak s, konac e, et al. different surgical techniques and l-carnitine supplementation in an experimental varicocele model. andrologia. 2014; 46:910-6. 33. thirumavalavan n, scovell jm, balasubramanian a, et al. the impact of microsurgical repair of subclinical and clinical varicoceles on total motile sperm count: is there a difference? urology. 2018; 120:109-113. correspondence georgios tsampoukas, md scientific-office@u-merge.com – tsampoukasg@gmail.com noor buchholz, md noor.buchholz@gmail.com – u-merge scientific office department of urology, princess alexandra hospital, harlow (uk) u-merge scientific office 1, menandrou street, athens 14561(greece) muhammad faisal khan, md drfaisalkhan@gmail.com department of urology, north devon hospital, barnstaple (uk) antigoni katsouri, md a.katsr@gmail.com department of pharmacy, university of patras, patras (greece) waseem akhter, md waseemakhter@nhs.net department of urology, princess alexandra hospital, harlow (uk) mohamad moussa, md mohamad.moussa@zhumc.org.lb al zahraa hospital, university medical center, lebanese university, beirut (lebanon) konstantinos deliveliotis, md chdeliveli@gmail.com athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, university hospital of athens, athens (greece) stesura seveso 87archivio italiano di urologia e andrologia 2019; 91, 2 original paper comparison between “in-bore” mri guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: preliminary results daniele d’agostino 1, federico mineo bianchi 2, daniele romagnoli 1, paolo corsi 1, marco giampaoli 1, riccardo schiavina 2, eugenio brunocilla 2, walter artibani 1, angelo porreca 1 1 department of robotic urological surgery, abano terme hospital, abano terme, italy; 2 department of urology, university of bologna, bologna, italy. objectives: to evaluate the detection rate of prostate cancer (pca) in patients who underwent to “in bore” magnetic resonance imaging -guided prostate (mri-gb) biopsy compared to the standard transrectal ultrasound guided prostate biopsy (trus-gb). materials and methods: between january 2017 and march 2015 a cohort of 39 consecutive patients was prospectively enrolled. all the patients underwent an "in-bore" guided mri prostatic biopsy and subsequently ultrasound-guided standard prostate biopsy. results: median age of patients was 65.5 years (sd ± 6.6), median total psa serum level was 6.6 ng/ml (sd ± 4.1), median prostate total volume was 51.1 cc (sd ± 26.7). thirty of 39 (76.9%) were biopsy-naïve patients while 7/39 (17.9%) had at least one previous negative random trus-gb; 2/39 (5.1%) patients were already diagnosed as pca and were on active surveillance. in 18/39 (53.8%) men pca was diagnosed; as regards the mri-gb results related to the pi-rads score, biopsies of pirads 3 lesions were positive in 5/18 cases (27.8%), while the number of positive cases of pi-rads 4 and 5 lesions was 7/11 (63.6%) and 6/10 (60%)respectively. at the histological examination, 4/39 (10.3%) had a pca isup grade group 1, 11/39 (28.2%) had a isup 2, 6/39(15.4%) had a isup grade group 3 and 2/39 (5.1%) had a isup 4-5. conclusions: mri-gb represents a promising technique that may offer some of advantages compared to standard systematic trusgb. our preliminary experience in mri-gb resulted safe and feasible and represents a viable procedure for the diagnosis and characterization of pca. key words: prostate cancer; mri guided biopsy; ultrasound guided biopsy. submitted 27 march 2019; accepted 29 april 2019 summary no conflict of interest declared. centage of cases (25-30%), pca may arise from the anterior part of the gland (anterior horn of peripheral gland, central/transitional zones and fibromuscular stroma). for these reasons, “random” trus-gb has a false negative rate of up to 40-50% (5, 6) and clinically significant tumors can often be undetected, especially in larger glands. a higher number of cores can improve the rate of tumors identified but, at the same time, increases the risk of diagnosis of indolent diseases: an aggressive management of these overdiagnosed cases will inevitably lead to an overtreatment, thereby negatively affecting the patients' quality of life. magnetic resonance imaging (mri) is a tool of growing importance in pca diagnosis; furthermore, with the introduction of multiparametric mri (mpmri) the accuracy for characterization of prostate lesion is significantly improved. mpmri, performed before the biopsy, can improve the detection of occult tumors in the areas of prostate generally undersampled during random trus-gb. a growing body of evidences suggest that an accurate tumor identification and sampling can improve risk classification and should reduce false-negative rates and the necessity of repeat biopsies both in biopsy-naïve patients and in patients with prior negative-biopsy (710). however, the increasingly widespread use of the mpmri for the detection of clinically significant pca has involved the need for targeted biopsy reducing the sampling in non-suspicious areas. the techniques for targeted biopsy include visual estimation trus-gb, software co-registered mri ultrasound fusion and in-bore mriguided biopsy (mri-gb); the latter provides the great advantage of direct visualization of the targeted lesion with the same system. thus, the aim this study was to evaluate the detection rate of prostate cancer in patients underwent to “in bore” mri-guided prostate biopsy compared to the standard ultrasound guided prostate biopsy; for secondary endpoint we evaluated the morbility and the complications of both procedures. materials and methods study methodology and population between january 2017 and march 2015 a cohort of 39 doi: 10.4081/aiua.2019.2.87 introduction prostate cancer (pca) represents the most common neoplasm diagnosed in men and the second cause of death after lung cancer (1). digital rectal examination, serum psa assay and ultrasound-guided biopsy (trus-gb) are common methods for prostate cancer diagnosis (2) although not devoid of some limitations and questionable validity. in fact, during prostate ultrasound, the yield of cancer detection remains very low, ranging between 20 and 30% for patients with a serum psa value between 2 and 4 ng/ml (3, 4); moreover, in a non-negligible perarchivio italiano di urologia e andrologia 2019; 91, 2 d. d’agostino, f. mineo bianchi, d. romagnoli, p. corsi, m. giampaoli, r. schiavina, e. brunocilla, w. artibani, a. porreca 88 consecutive patients was prospectively enrolled. the study was conducted with the approval of the institutional review board and all the procedures and reporting were in accordance with the helsinki protocol. patients were informed and a subsequent written consent was acquired. all patients had a suspicion for pca – raised prostate specific antigen (psa) serum level and/or abnormal digital rectal examination (dre) – and showed at the mp-mri previously conducted in our institution at least one suspicious area where the presence of a clinically significant pca was defined equivocal/likely/highly likely, corresponding to a pi-rads (prostate imaging reporting and data system) score ≥ 3 according to the european society of urogenital radiology (esur) guidelines (17). patients with any usual contraindications for mri (eg. metallic implants and/or cardiac pacemakers) were excluded from the study. all patients underwent a "in-bore" guided mri prostatic biopsy and subsequently ultrasound-guided standard prostate biopsy; the urologist who performed the ultrasound-guided prostatic biopsy was always the same and was not aware of the result of mpmri. mri examination and analysis all the mri examinations were performed with a 32 channels 1.5 t whole body scanner (achieva xr; philips medical systems, best, netherlands) with a 32-channels phasedarray surface coil without endorectal coil. after local threeplane acquisition, required for the correct positioning of the sequences, the morphological and functional studies were carried out. morphological study of the prostate gland were obtained with turbo spin echo (tse) t2weighted sequences (te 100 msec, tr 4074 msec, slice thickness 3 mm, slice spacing 0.3 mm, field of view – fov 180 x 180 mm and matrix size 276 x 205) in the sagittal, axial and coronal planes, including seminal vesicles and the entire prostate gland. for the functional study, dwi, dce-mri and mrs acquisition were performed. the dwi acquisition was carried out in the axial plane, using a single-shot echo-planar imaging (ssepi) sequence, with three b-values (0, 600 and 1500 s/mm2), slice thickness of 3 mm, fov 180 x 180 mm and matrix size 80 x 71. the dce-mri was obtained using three-dimensional (3d) t1w high resolution isotropic volume examination (thrive) sequence during the intravenous injection of a contrast bolus of 0,1 mmol per kilogram of body weight of meglumine gadobenate (multihance, bracco diagnostics, milan, italy), at flow rate of 3,5 ml/sec followed by 15 ml of saline solution. conduct of the “in-bore” mri-guided biopsy the biopsies were performed on a different day from the diagnostic mpmri study (within 2-4 weeks) by a single urologist. all patients received oral antibiotic prophylactic therapy 2 days before the maneuver; biopsies were performed transrectally with the patient prone on a 1.5 t mr scanner (achieva xr; philips medical systems, best, netherlands) using a 18-g automatic core-needle, a titanium double-shot biopsy gun, a gadolinium-filled needle-guide, a non-magnetic portable biopsy device (dynatrim, invivo, gainesville, fl) and a dedicated software package for device tracking and target localization (dynacad, invivo, gainesville, fl). before biopsy, dre was performed in order to evaluate any potential anatomic or pathologic condition that could hinder transrectal biopsy and to approximate the position of the gland. the needle sleeve is also a marker for software localization; after the sleeve was assembled on the arm of the biopsy device, fixed on the tabletop of the magnet, and inserted into the rectum, the patient was positioned into the scanner. t2w images in the axial and sagittal direction were obtained for visualization of the prostate and identification of the suspicious lesion; simultaneously, the gadolinium-filled needle guide was properly identified and marked for subsequent track calibration: oblique axial t2w images were aligned with the needle guide in order to allow software registration showing three-dimensional adjustments required to align the track of the biopsy needle through the needle guide and the target lesion. after manual calibration adjustments on the arm of the biopsy device attached to the needle guide, sagittal t2w images in parallel with the long axis were obtained in order to confirm the correct position and the proper direction of the needle guide to the target; reconfirmation of the needle track were repeated until proper alignment was obtained. once the patient was taken from the scanner, biopsy was performed with a median of 2 (range 1-2) cores taken from each target lesion. if targeting was not certain, due to lesion size or subjective judgement of the operator, subsequent axial and sagittal t2w images with the needle in place were obtained to detect needle position and be able to make adjustments for the next core. total table time was appreciatively 45 to 70 minutes per patient. after the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. specimens were processed by routine hystopathological fixation with formalin solution and evaluated by a single dedicated uropathologist with 20 years of experience. conduct of ultrasound guided prostate biopsy the standard biopsy was performed by transrectal approach; the examination was tipically 12 cores collected in a sextant template of biopsies from the medial and lateral area of the apical, mid and the base of prostate, on the left and right lobe. during the trus guided biopsy the mpmri data target was not available. total table time was appreciatively 15 to 30 minutes per patient. after the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. antibiotic prophylaxis was continued by patients for seven days after the procedure. specimens were processed by routine hystopathological fixation with formalin solution and evaluated by a single dedicated uro-pathologist with 20 years of experience. statistical analysis simple descriptive statistical techniques were used to analyze data, in particular median with interquartile range (iqr) and mean ± standard deviation (sd) were used to report continuous variables, whereas frequencies with percentages were used to describe categorical ones. oneway anova and kruskal-wallis k-samples were used to compare means and medians between three groups. pearson’s chi-square test and mc-nemar test were used to compare the association between clinical and pathologic variables. two-tailed p values less than 0.05 were considered statistically significant. statistical analyses were conducted using spss® version 21.0 for macintosh® (ibm corp, armonk, ny). results patient characteristics: median age of patients was 65.5 years (sd ± 6.6), median total psa serum level was 6.6 ng/ml (sd ± 4.1), median prostate total volume was 51.1 cc (sd ± 26.7). thirty of 39 (76.9%) were biopsynaïve patients while 7/39 (17.9%) had at least one previous negative random trus-gb; 2/39 (5.1%) patients were already diagnosed pca on active surveillance. clinical, radiological and pathological characteristics of the entire population of the study are listed in table 1. detection rate all patient enrolled in the study have been subjected both the mri-gb and the trus-gb. the majority of suspected lesions identified with mpmri were located in the posterior zone of the prostate (69% of cases). the mean number of bioptic cores taken from patient was 1 in mri-gb series (range 1-2) and 12 in trus-gb (range 12-14).as reported in table 5, about overall detection rate (dr) of patients who underwent “in-bore” mrigb and trus-gb, in 23/39 (59%) men pca was diagnosed; as regards the mrigb results related to the pi-rads score, biopsies of pi-rads 3 lesions were positive in 5/18 cases (27.8%), while the number of positive cases of pi-rads 4 and 5 lesions was 7/11 (63.6%) and 6/10 (60%) respectively. analyzing the results of mri-gb, globally 17/39 (43.5%) patients presented a clinically significant pca (isup group ≥ 2), while the dr for clinically significant pca in trus-gb was 15/39 patients (38.4%). in the series of “biopsy naïve” patient we observed 14/30 (46.7%) cases of pca detected by mri-gb and 13/30 (43.3%) cases in the series of trus-gb. in patients with previous negative biopsies we observed pca in 2/7 (28.6%) cases both in mri-gb and trus-gb. in the “active surveillance” group we detected 2/2 (100%) men with pca in mri-gb series and 1/2 (50%) in trus-gb 89archivio italiano di urologia e andrologia 2019; 91, 2 comparison between “in-bore” mri guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer... table 1. clinical and radiologic features of patients who underwent “in-bore” biopsy. overall biopsy previous active p (n = 39) näive negative biopsy surveillance value (n = 30) (n = 7) (n = 2) age, years 65.5 ± 6.6 65.3 ± 6.8 66.6 ± 7.1 63.5 ± 2.1 0.8 mean ± sd psa, ng/ml 6.6 ± 4.1 11.7 ± 4.9 10.9 ± 7.4 6.2 ± 1 0.007 mean ± sd psa density, ng/ml/cc 0.14 ± 0.09 0.14 ± 0.09 0.15 ± 0.05 0.13 ± 0.04 0.95 mean ± sd prostate volume, cc 51.1 ± 26.7 46.7 ± 22.2 70.4 ± 38.1 52 ± 8.5 0.1 mean ± sd diameter mpmri area, mm 11.9 ± 5.1 11.7 ± 4.9 13.1 ± 6.5 10 ± 5.7 0.7 mean ± sd area location mpmri+, n (%) posterior 27 (69.2) 21 (70) 4 (57.1) 2 (100) 0.5 anterior 12 (30.8) 9 (30) 3 (42.9) 0 (0) pi-rads-v2, n (%) 3/5 18 (46.2) 14 (46.7) 2 (28.6) 2 (100) 0.5 4/5 11 (28.2) 8 (26.7) 3 (42.9) 0 (0) 5/5 10 (25.6) 8 (26.7) 2 (28.6) 0 (0) table 3. “in-bore” biopsy results stratified according to pirads score. overall pirads score pirads score pirads score p 3 4 5 value number of pts, (%) 39 18 (46.2) 11 (28.2) 10 (25.6) detection rate pca, n (%) 18/39 (53.8) 5/18 (27.8) 7/11 (63.6) 6/10 (60) 0.3 detection rate cspca, n (%) 17/39 (43.5) 3/18 (16.7) 5/11 (45.5) 5/10 (50) 0.1 detection rate cspca/pca, % 17/18 (94.4) 3/5 (60) 5/7 (71.4) 5/6 (83.3) 0.7 isup grade group, n (%) negative 21 (53.8) 13 (72.2) 4 (36.4) 4 (40) 0.1 1 1 (2.5) 1 (5.5) 0 (0) 0 (0) 2 10 (25.6) 3 (16.6) 5 (45.4) 2 (20) 3 4 (10.3) 1 (5.5) 1 (9.1) 2 (20) 4-5 3 (7.6) 0 (0) 1 (9.1) 2 (20) table 2. overall and stratified according to clinical status “in-bore” results. overall biopsy previous active p näive negative biopsy surveillance value detection rate pca, n (%) 18/ 39 (53.8) 14/ 30 (46.7) 2/7 (28.6) 2/ 2 (100) 0.2 detection rate cspca, n (%) 17/ 39 (43.5) 14/ 30 (46.6) 2 /7 (28.6) 1/ 2 (50) 0.1 cspca/overall pca rate, % 17/18 (94.4) 14/14 (100) 2 /7 (28.6) 1/ 2 (50) 0.2 isup grade group, n (%) negative 21 (53.8) 16 (53.3) 5 (71.4) 0 (0) 0.1 1 1 (2.5) 0 (0) 0 (0) 1 (50) 2 10 (25.6) 10 (33.3) 0 (0) 0 (0) 3 4 (10.3) 2 (6.6) 1 (14.2) 1 (50) 4-5 3 (7.6) 2 (6.6) 1 (14.2) 0 (0) table 4. number of bioptic cores taken from patients who underwent in-bore and random biopsies. number of cores overall biopsy näive previous negative active surveillance p (n = 39) (n = 30) biopsy (n = 7) (n = 2) value total 13 (13-14) 13 (13-14) 13 (13-15) 13 (13-13) 0.5 in bore biopsy 1 (1-2) 1 (1-2) 1 (1-1) 1 (1-1) 0.5 random biopsy 12 (12-12) 12 (12-12) 12 (12-14) 12 (12-12) 0.5 archivio italiano di urologia e andrologia 2019; 91, 2 d. d’agostino, f. mineo bianchi, d. romagnoli, p. corsi, m. giampaoli, r. schiavina, e. brunocilla, w. artibani, a. porreca 90 series. the details of results are reported in table 2-8. as far as the secondary endpoint is concerned, we have not observed any complications related to procedures. discussion trus-gb represents the “gold-standard” technique of histological diagnosis of prostate cancer. aim of this study was to investigate the real diagnostic accuracy of a novel prostate biopsy technique mri guided compared to the standard trus-guided biopsy (11). during the recent years, there was an increasing use of mpmri in stadiation of prostate cancer e in order to improve quality of surgery during radical prostatectomy (12). other important application of mpmri is the guide to prostate biopsy in order to improve pca diagnosis with the aim to refine pca risk classification (13) and, simultaneously, to overcome the limitations of contemporary standard trus-gb: low-risk patients could be spared from biopsies reducing overdetection of low-risk cancer while a lower number of cores could be required in men with suspicious mri findings reducing also potential complications related to the procedure and all the consequence on quality of life (14-16). targeted mri-gb has become an alternative approach to trus-gb and several mri-gb methods have been proposed for the diagnosis of pca. in the “cognitive” technique, trus-gb is planned on the basis of mr images; in spite of reduced costs, this method has a long learning curve and the sampling of suspicious lesions may not be guaranteed. the mri-us “fusion” biopsy is simply described as a way to align a pre-registered mri to an intraprocedural us in order to identify and target suspected lesions within the gland through a dedicated hardware platform targeting areas found during mpmri and not clearly visible during us scan; the advantages are the high reproducibility and the real time feedback though counterbalanced by the high up-front cost of the device. the “in bore” technique consists in the execution of the biopsies directly inside the mri scanner with dedicate non-magnetic biopsy devices. despite a longer operative time and higher costs, this method has realtime feedback in needle placement, fewer sampled cores and a low likelitable 5. overall “detection rates” and “pathologic results” of patients who underwent “in-bore” biopsies and random biopsies. number of cores overall (n = 39) in-bore biopsy random biopsy p value detection rate pca, n (%) 23/39 (59) 18/39 (53.8) 18/39 (53.8) 0.9 detection rate cspca, n (%) 20/39 (51.3) 17/39 (43.5) 15/39 (38.4) 0.7 cspca/pca detection rate, % 20/23 (87) 17/18 (94.4) 15/18 (83.3) 0.8 isup grade group, n (%) negative 16 (41) 21 (53.8) 21 (53.8) 0.6 1 4 (10.3) 1 (2.5) 5 (12.8) 2 11 (28.2) 10 (25.6) 7 (17.9) 3 6 (15.4) 4 (10.3) 5 (12.8) 4-5 2 (5.1) 3 (7.6) 1 (2.6) table 6. overall “detection rates” and “pathologic results” of biopsy näive patients who underwent “in-bore” biopsies and random biopsies. overall (n = 30) in-bore biopsy random biopsy p value detection rate pca, n (%) 16/30 (75.4%) 14/30 (46.7) 1 /30 (43.3) 0.8 detection rate cspca, n (%) 15/30 (50%) 14/30 (46.6) 13/30 (43.3) 0.8 cspca/pca detection rate, % 15/16 (93.8%) 14/14 (100) 13/13 (100) 0.5 isup grade group, n (%) negative 14 (46.7) 16 (53.3) 17 (56.7) 0.7 1 1 (3.3) 0 (0) 0 (0) 2 9 (30) 10 (33.3) 8 (26.7) 3 5 (16.7) 2 (6.6) 4 (13.3) 4-5 1 (3.3) 2 (6.6) 1 (3.3) table 7. overall “detection rates” and “pathologic results” of patients with previous negative biopsies who underwent “in-bore” biopsies and random biopsies. overall (n = 7) in-bore biopsy random biopsy p value detection rate pca, n (%) 4/7 (57.4) 2/7 (28.6) 2/7 (28.6) 0.3 detection rate cspca, n (%) 2/7 (42.9) 2/7 (28.6) 1/7 (14.2) 0.1 cspca/pca detection rate, % 2/4 (50) 2/7 (28.6) isup grade group, n (%) negative 1 (14.3) 5 (71.4) 5 (71.2) 0.2 1 4 (57.1) 0 (0) 2 (28.6) 2 0 (0) 0 (0) 0 (0) 3 1 (14.3) 1 (14.2) 0 (0) 4-5 1 (14.3) 1 (14.2) 0 (0) table 8. overall “detection rates” and “pathologic results” of patients in active surveillance who underwent “in-bore” biopsies and random biopsies. overall (n = 2) in bore biopsy random biopsy p value detection rate pca, n (%) 2/2 (100 2/ 2 (100) 1/2 (50) 0.5 detection rate cspca, n (%) 2/2 (100) 1/ 2 (50) 1/2 (50) 1 cspca/pca detection rate, % 2/2 (100) 1/ 2 (50) 1 /1 (100) 0.5 isup grade group, n (%) negative 0 (0) 0 (0) 1 (50) 0.3 1 0 (0) 1 (50) 0 (0) 2 1 (50) 0 (0) 1 (50) 3 1 (50)) 1 (50) 0 (0) 4-5 0 (0) 0 (0) 0 (0) hood of missed target. therefore, the use of “in bore” mri-gb has the potential to reduce the sampling error associated with unselective standard biopsy scheme by providing better disease localization; moreover, accurate risk stratification through improved cancer sampling may impact therapeutic decision making (13, 17). in our experience the overall detection rate of mri-gb and trus-gb are similar; in particular, in the series of mrigb, we observed a slightly higher pca diagnosis of clinically significant disease (43.5% vs 33.3%), although this result was not statistically significant. a recent systematic review showed that mri-gb improved significant pca detection compared to standard trus-gb (relative sensitivity 1.26, 95% ci 1.08-1.46) (18). in their preliminary experience with in-bore technique, panebianco et al. (19) showed a dr for the diagnosis of pca of 80% and 90% of pca cases had intermediate grade aggressiveness. whereas there was currently not enough evidence to recommend mpmri before a first set of prostate biopsies (2), the use of targeted biopsy often achieved significantly higher cancer dr in the repeat biopsy setting. in patients with prior negative biopsy, mri-gb showed a median dr of 42%, significantly higher than those reported in repeating systematic biopsy (20). our preliminary experience in mri-gb confirmed the feasibility and the reproducibility of an “in-bore” strategy on a 1.5 t mr scanner using a 32-channel coil. enghelard et al. (21) reported a dr of 38% in 37 consecutive men with elevated psa levels and negative prostate biopsies underwent a mri-gb in a 1.5-t scanner in the supine position; in similar but larger cohorts, roethke et al. (22) and hoeks et al. (10) found a dr of 52% (52/100) and 41% (14/37), respectively. in our cohort, analyzing the series of patients with previous negative biopsies, the overall dr of mri-gb was higher than trus-gb (57.1% vs 28.6%), particularly in the clinically significant disease (28.5% vs 14.2%). our preliminary results highlighted the excellent correlation between the pi-rads score at mpmri and the isup grade groups in mri-gb cores: this data allows us to infer, on one hand, a high capability of the mpmri to predict the biological aggressiveness of neoplastic lesions and, on the other hand, the good performance of the mri-gb procedure. moreover, the mpmri procedure with this setting and patients in the prone position has been well tolerated and feasible to perform. given an initial learning curve, we believe that the time needed for the procedure can be further reduced optimizing the setting and the positioning of the needle guide. finally, jung et al. (23) found that the rate of positive mri-gb resulted as a function of target size and level of suspicious. it could be argued that obvious that larger target with higher level of suspicious were most likely to yield a positive biopsy; however, the authors concluded that this finding could be helpful when deciding whether to perform a mri-gb. engelhard et al. (21) concluded that suspicious lesions with a diameter > 10 mm could be successfully punctured using this device. in spite of reliable feasibility and the preliminary promising results with an acceptable dr, some limitations of the present study have to be kept in mind. first, the number of patients was small and, as a part of study design, the patients analyzed were only men with positive findings at mpmri: this selected patient population from a single institution series may have a positive influence on the number of tumors detected; however, the study was thought as an initial experience to compare the mri-gb technique and standard trus-gb in order to evaluate its feasibility. consequently, the preliminary results are far from being meaningful and have to be interpreted carefully. second, the study lacks follow up data and no prostate specimen histology can confirm the results of a negative mri-gb; further series with radical prostatectomy specimen as reference standards are required in order to corroborate the benefit of a mri-gb procedure. finally, it is important to highlight that initially mri-gb can represent a time-consuming and expensive procedure but, as reported by other authors (24), initial costs could be written off by reducing treatment related costs and improving risk tumor evaluation and quality of life preventing unnecessary radical treatment of insignificant tumors. conclusions mri-gb represents a promising technique that may offer some of these advantages compared to standard systematic trus-gb. our preliminary experience in mri-gb resulted safe and feasible and represents a viable procedure for the diagnosis and characterization of pca especially in a subgroup of patient with clinically significant disease. further investigations are needed in order to identify who should undergone prostate biopsy and the technique that should be used with the aim of detecting significant pca and reducing the burden of biopsies. references 1. siegel r, naishadham d, jemal a. cancer statistics 2012. ca cancer j clin. 2012; 62:10-21. 2. heidenreich a, bastian pj, bellmunt j, et al. eau guidelines on prostate cancer, part 1: screening, diagnosis, and local treatment with curative intent update 2013. eur urol. 2014; 65:124-137. 3. delongchamps nb, de la roza g, chandan v, et al. diagnostic accuracy of extended biopsies for the staging of microfocal prostate cancers in autopsy specimen. prostate cancer prostatic dis. 2009; 12:137-142. 4. roehl ka, antenor ja, catalona wj. serial biopsy results in prostate cancer screening study. j urol. 2002; 167:2435-9. 5. jones js. saturation biopsy for detecting and characterizing prostate cancer. bju int. 2007; 99:1340-1344. 6. lane br, zippe cd, abouassaly r, et al. saturation technique does not decrease cancer detection during follow up after initial prostate biopsy. j urol. 2008; 179:1746-1750. 7. watanabe y, terai a, araki t, et al. detection and localization of prostate cancer with the targeted biopsy strategy based on adc map: a prospective large-scale cohort study. j magn reson imaging. 2012; 35:1414-1421. 8. numao n, yoshida s, komai y, et al. usefulness of pre-biopsy multiparametric magnetic resonance imaging and clinical variables to reduce initial prostate biopsy in men with suspected clinically localized prostate cancer. j urol. 2013; 190:502-508. 10. siddiqui mm, rais-bahrami s, truong h, et al: magnetic reso91archivio italiano di urologia e andrologia 2019; 91, 2 comparison between “in-bore” mri guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer... archivio italiano di urologia e andrologia 2019; 91, 2 d. d’agostino, f. mineo bianchi, d. romagnoli, p. corsi, m. giampaoli, r. schiavina, e. brunocilla, w. artibani, a. porreca 92 nance imaging/ultrasound fusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal ultrasound biopsy. eur urol. 2013; 64:713-719. 11. schiavina r, vagnoni v, d'agostino d, et al. "in-bore" mriguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. clin genitourin cancer. 2017; 15:417-427. 12. schiavina r, bianchi l, borghesi m, et al. mri displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. j endourol. 2018; 32:315321. 13. vagnoni v, bianchi l, borghesi m, et al. adverse features and competing risk mortality in patients with high-risk prostate cancer. clin genitourin cancer. 2017; 15:e239-e248. 14. porreca a, noale m, artibani w, et al. pros-it cnr study group. disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the pros-it cnr study. health qual life outcomes. 2018; 16:122. 15. gacci m, noale m, artibani w, et al. pros-it cnr study group. quality of life after prostate cancer diagnosis: data from the pros-it cnr. eur urol focus. 2017; 3:321-324. 16. noale m, maggi s, artibani w, et al. pros-it cnr study group. pros-it cnr: an italian prostate cancer monitoring project. aging clin exp res. 2017; 29:165-172. 17. grasso aa, cozzi g, de lorenzis e, et al. multicenter analysis of pathological outcomes of patients eligible for active surveillance according to prias criteria. minerva urol nefrol. 2016; 68:237-41. 18. schoots ig, roobol mj, nieboer d. et al. magnetic resonance targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound guided biopsy: a systematic review and metaanalysis. eur urol. 2015; 68:438-450. 19. panebianco v, barchetti f, manenti g, et al. mr imaging-guided prostate biopsy: technical features and preliminary results. radiol med. 2015; 120:571-578. 20. overduin cg, futterer jj, barentsz jo. mri-guided biopsy for prostate cancer detection: a systematic review of current clinical results. curr urol rep. 2013; 14:209-213. 21. engelhard k, hollenbach hp, kiefer b, et al. prostate biopsy in the supine position in a standard 1.5-t scanner under real time mrimaging control using a mrcompatible endorectal biopsy device. eur radiol. 2006; 16:1237-1243. 22. roethke m, anastasiadis ag, lichy m, et al. mri-guided prostate biopsy detects clinically significant cancer: analysis of a cohort of 100 patients after previous negative trus biopsy. world j urol. 2012; 30:213-218. 23. jung aj, westphalen ac, kurhanewicz j, et al. clinical utility of endorectal mri-guided prostate biopsy: preliminary experience. j magn res imag. 2014; 40:314-323. 24. de rooij m, crienen s, witjes ja, et al. cost-effectiveness of magnetic resonance (mr) imaging and mr-guided targeted biopsy versus systematic transrectal ultrasound–guided biopsy in diagnosing prostate cancer: a modelling study from a health care perspective. eur urol. 2014; 66:430-436. correspondence daniele d’agostino, md (corresponding author) dott.dagostino@gmail.com daniele romagnoli, md dromagnoli@casacura.it paolo corsi, md pcorsi@casacura.it marco giampaoli, md mgiampaoli@casacura.it walter artibani, md prof.artibani@gmail.com angelo porreca, md angeloporreca@gmail.com department of robotic urological surgery, abano terme hospital piazza cristoforo colombo 1, 35031 abano terme (pd) (italy) federico mineo bianchi, md federico.mineobianchi@gmail.com riccardo schiavina, md rschiavina@yahoo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it department of urology, university of bologna, bologna (italy) 1archivio italiano di urologia e andrologia 2018; 90, 1 original paper the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy riccardo schiavina 1, 2, marco borghesi 1, 2, hussam dababneh 1, martina sofia rossi 1, cristian vincenzo pultrone 1, 2, valerio vagnoni 1, francesco chessa 1, lorenzo bianchi 1, angelo porreca 3, alexandre mottrie 4, eugenio brunocilla 1, 2 1 university of bologna, s. orsola-malpighi hospital, dept. of urology, bologna, italy; 2 department of experimental, diagnostic and specialty medicine (dimes), cardio-nephro-thoracic sciences doctorate, university of bologna, bologna, italy; 3 policlinico di abano, dept. of urology, abano terme, italy; 4 olv robotic surgery institute, aalst, belgium. aim: the success of robot assisted laparoscopic prostatectomy (ralp) is mainly due to his relatively short learning curve. twenty cases are needed to reach a “4 hours-proficiency”. however, to achieve optimal functional outcomes such as urinary continence and potency recovery may require more experience. we aim to report the perioperative and early functional outcomes of patients undergoing ralp, after a structured modular training program. methods: a surgeon with no previous laparoscopic or robotic experience attained a 3 month modular training including: a) e-learning; b) assistance and training to the operating table; c) dry console training; d) step by step in vivo modular training performing 40 surgical steps in increasing difficulty, under the supervision of an experienced mentor. demographics, intraoperative and postoperative functional outcomes were recorded after his first 120 procedures, considering four groups of 30 cases. results: all procedures were completed successfully without conversion to open approach. overall 19 (15%) post operative complications were observed and 84% were graded as minor (clavien i-ii). overall operative time and console time gradually decreased during the learning curve, with statistical significance in favour of group 4. the overall continence rate at 1 and 3 months was 74% and 87% respectively with a significant improvement in continence rate throughout the four groups (p = 0.04). considering those patients submitted to nerve-sparing procedure we found a significant increase in potency recovery over the four groups (p = 0.04) with the higher potency recovery rate up to 80% in the last 30 cases. conclusions: optimal perioperative and functional outcomes have been attained since early phase of the learning curve after an intensive structured modular training and less than 100 consecutive procedures seem needed in order to achieve optimal urinary continence and erectile function recovery. key words: training; robot assisted radical prostatectomy. submitted 18 september 2017; accepted 23 september 2017 summary no conflict of interest declared. death in men worldwide (1). radical prostatectomy (rp) represents the standard surgical treatment for clinically localized prostate cancer (2). traditionally this procedure was performed with a retropubic open approach retropubic radical prostatectomy (rrp) (3), with the cost of long hospitalization, the need of additional pain medication and significant blood loss. with the aim to reduce morbidity, hospitalization and to improve functional outcomes, minimally invasive approaches including laparoscopic radical prostatectomy (lrp) and robot assisted laparoscopic prostatectomy (ralp) have been increasingly adopted as alternative to open surgery. in the last two decades ralp has gained more popularity and now is a mainstay of treatment for prostate cancer, with functional and oncological outcomes comparable or even better than rrp and lrp (4-6). one of the main reason for the great diffusion of ralp is the short learning curve: contrarily to lrp, where the learning curve is very steep, those surgeons approaching to ralp were able to perform minimally invasive prostatectomy with optimal results even in the early phase of their learning curve, even with limited laparoscopic skills (7). several studies estimated that few cases (25-40) are needed to shorten operative time, reduce the intraoperative blood loss and complications, thus rapidly achieving proficiency in ralp (8, 9). however, to reach adequate functional outcomes and optimal oncological results in terms of negative surgical margins, more and more cases are needed and the learning curve is more steep for these outcomes (10). as previous described by other authors (11,12), ralp can count two different pattern of learning curves. the “basic learning curve” is centered on operative outcomes, in which 25-50 cases are needed to reach an operative time plateau of 200-240 minutes with low complication rate, even in more challenging patients (11). the “advanced learning curve” is centered on patients outcomes, in which 100, 200 and 300 cases are needed to achieve satisfactory outcomes for the surgeon in terms of continence, potency recovery and positive surgical margins rates, respectively (11). doi: 10.4081/aiua.2018.1.1 introduction prostate cancer is the second most common cancer among men, and represents the fifth cause of cancer chessa_stesura seveso 27/03/18 09:15 pagina 1 archivio italiano di urologia e andrologia 2018; 90, 1 r. schiavina, m. borghesi, h. dababneh, m.s. rossi, c.v. pultrone cristian, v. vagnoni, f. chessa, l. bianchi, a. porreca, a. mottrie, e. brunocilla 2 several parameters can influence the learning curve, such as the type of training program attended, the surgeon-related skills and personal experience in other procedures. a multitude of training programs exists in robotic surgery. recently, some structured modular training programs were developed with the aim to simplify the learning curve in robotic surgery (13, 14): these trainings allowed surgeons with no robotic experience to perform rarp independently, safely, and effectively with subsequent improvement over time but the “advanced” end-points were not evaluable (15). the aim of the present study is to report the early perioperative and functional outcomes after the first 120 cases with a structured intensive modular training program applied to single surgeon with no previous laparoscopic or robotic experience. patients and methods between january 2015 and may 2016, 120 consecutive patients underwent ralp for prostate cancer performed by a single surgeon with some experience in rrp (about 50 cases performed as first surgeon) but no laparoscopic skills (no cases of lrp). all the procedures were performed after attending a structured modular training. ralp was performed transperitoneally using the da vinci xi surgical system (intuitive surgical, inc., sunnyvale, ca, usa) as previously described in details (16). routine pelvic lymph node dissection (plnd) at time of ralp was performed in presence of high risk pca and intermediate risk pca with estimated risk for positive lymph nodes > 5% (2). nerve sparing procedure was performed according to the d’amico risk group classification and preoperative multi-parametric magnetic resonance imaging (mpmri) results in patients with preoperative international index of erectile function score (iief) > 21. clinical, perioperative and pathological data were recorded. sexual functional evaluation with iief2 and continence rate was assessed before and after surgery (13 months). postoperative complications were graded according to the clavien dindo classification (17) and grouped as minor (grade 1-2) or major (grade 3-5) complication. postoperative follow-up and data collection the clinical and radiological assessment during follow-up included cystogram before catheter removal when deemed necessary, physical examination and abdominal ultrasound 1 month after surgery in those submitted to plnd. at 1 and 3 months after surgery we evaluated continence recovery, defined as the need for no pad or one safety-pad per day and potency, defined as erection adequate for penetration or postoperative iief score > 21. the study was in line with the local institutional ethical committees (approval code stud-of by the s. orsolamalpighi hospital, irb september 11, 2012). all patients provided informed consent for anonymous publication of data. modular training before performing the first ralp of the study, the surgeon attained a 3 month modular training which including: a) e-learning consisting of theoretical lessons and video sessions concerning the different steps of the procedure; b) dry lab performing procedures on ex-vivo models and wet lab c) assistance at the operating table; d) console training with simulator; e) step-by step in vivo modular training in which the main surgeon, supervised by an expert mentor (a.p.), performing 40 surgical steps in increasing difficulty (14). the training was performed at a training center in belgium (orsi training center) and at a robotic center in the north of italy (abano terme hospital, padua). statistical analysis means and standard deviation, medians and interquartile ranges were reported for continuous variables. frequencies and proportions were reported for categorical variables. the mann-whitney u test and chi-square tests were used to compare the statistical significance of differences in medians and proportions, respectively. primary outcomes where the overall operative time (ot) and console time, positive surgical margins (psm), complication rates, urinary continence recovery and potency recovery during the learning curve. to assess the learning curve, patients were divided into 4 groups of 30 consecutive ralp: group 1 from case 1 to case 30; group 2 from case 31 to case 60; group 3 from case 61 to case 90; and group 4 from case 91 to case 120. kaplan-meier analyses were used to predict early urinary continence and erectile function recovery after surgery. statistical analyses were conducted using spss version 17.0 (ibm corp, armonk, ny). two-tailed p values less than 0.05 were considered statistically significant. results patient’s demographics and preoperative clinical characteristics are summarized in table 1. all procedures were completed successfully without conversion to open approach. overall, 84 (70%) patients were potent (iief score > 21) at time of surgery and median baseline iief-5 score was 21. all patients were continent before surgery. no statistical differences were found between the four groups. table 2 depicts intraoperative and postoperative outcomes stratified according to the four groups: median ot and console time was 275 and 220 min and gradually decreased during the learning curve, with statistical significance in favour of group 4. median estimated blood loss (ebl) was 470 ml, median hospital stay was 3 day; grade 1-2 postoperative complications were 16 (12%) and grade 3-4 postoperative complications were 3 (2%); the four groups were comparable in terms of estimated blood loss, intraoperative complications, psm and days of hospitalization. a detailed report of intraoperative and postoperative complications stratified according to the study groups is reported in table 3. management of intraoperative complications included intra operative repair of bladder injury (2 cases), bowel injury (1 case) and iliac vein injury (1 case). no intraoperative complications occurred in group 4. overall 19 (15%) post operative complications were reported in 19 patients. most of the adverse events (84%) were graded as minor (clavien chessa_stesura seveso 27/03/18 09:15 pagina 2 3archivio italiano di urologia e andrologia 2018; 90, 1 the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy table 1. demographic and clinical characteristics in overall population and after stratifying patients according to four consecutive groups. variables age mean ± sd median (iqr) bmi mean ± sd median (iqr) baseline psa value ng/ml mean ± sd median (iqr) charlson index n (%) 0 ≥ 1 clinical stage n (%) t1 t2 t3 gleason score at biopsy n (%) 6 7 8-10 d’amico risk group n (%) low intermediate high baseline iief-5 score mean ± sd median (iqr) overall (n = 120) 64.5 ± 6.5 65 (60-69) 26.3 ± 4.4 25.8 (23.6-29.4) 7.8 ± 5 6.3 (5.0-8.7) 103 (85.8) 17 (14.2) 45 (37.5) 73 (60.8) 2 (1.7) 18 (15.0) 75 (62.5) 27 (22.5) 20 (16) 67 (56) 33 (28) 19 ± 6 21 (15-23) group 1 (n = 30) 65.2 ± 7.2 67 (60-73) 25.3 ± 5.8 25.7 (22.5-29.4) 8.2 ± 5.5 6.0 (4.9-9.5) 27 (90) 3 (10) 9 (30) 20 (66.7) 1 (3.3) 5 (16.7) 19 (63.3) 6 (20) 6 (20) 16 (53) 8 (27) 19 ± 5.4 217 (14-23) group 2 (n = 30) 63 ± 5.8 65 (57-68) 26 ± 3.2 26.3 (23.9-28.9) 13 ± 5.7 6.6 (5-8.4) 27 (90) 3 (10) 12 (40) 18 (60) 0 4 (13.3) 20 (66.7) 6 (20) 6 (20) 17 (57) 7 (23) 17 ± 7.1 21 (10-22) group 3 (n = 30) 66 ± 5.7 67 (63-71) 27 ± 4.4 27.4 (24.8-30) 7.16 ± 4.8 6.2 (4.9-9.6) 25 (83.3) 5 (16.7) 7 (23.3) 22 (73.3) 1 (3.3) 5 (16.7) 16 (53.3) 9 (30) 5 (17) 13 (45) 12 (38) 19 ± 5.2 22 (18-23) group 4 (n = 30) 62.3 ± 6.8 63 (59-68) 26 ± 3.8 24.7 (23.1-29.1) 7.8 ± 4.1 6.2 (5-8.9) 24 (80) 6 (20) 17 (56.7) 13 (43.3) 0 4 (13.3) 20 (66.7) 6 (20) 3 (10) 21 (70) 6 (20) 19 ± 6 22 (21-23) p 0.3 0.4 0.3 0.6 0.1 0.9 0.3 0.4 table 2. intraoperative and postoperative outcomes in overall population and after stratifying patients according to four consecutive groups. variables operative time (min) mean ± sd median (iqr) console time (min) mean ± sd median (iqr) estimated blood loss (ml) mean ± sd median (iqr) nerve sparing procedure, n (%) not performed monolateral bilateral lymphadenectomy, n (%) performed intraoperative complications, n (%) pathologic stage, n (%) t2 t3a t3b pathologic gleason score, n (%) 6 7 8-10 positive surgical margins (psm), n (%) psm according to pathologic stage, n (%) pt2 (n=83) pt3a (n=32) pt3b (n=5) hospital stay (days) median (iqr) post-operative complications n (%) clavien 1-2 clavien 3-4 post operative iief-5 score** mean ± sd median (iqr) post operative continence recovery continent , n (%) not continent***, n (%) overall (n = 120) 280 ± 99 275 (245-315) 220 ± 47 220 (185-270) 460 (160) 470 (350-600) 38 (32.5) 22 (18.3) 60 (49.2) 70 (58) 5 (5) 83 (68) 32 (27) 5 (5) 14 (11) 76 (63) 30 (26) 24 (20) 8 (10) 13 (40) 3 (60) 3.5 (3-4) 16 (12) 3 (2) 13 (8) 18 (6-21) 103 (86) 17 (14) group 1 (n = 30) 353 ± 167 330 (294-352) 260 ± 46 270 (220-300) 443 (178) 485 (300-600) 14 (47) 5 (16) 11 (37) 17 (56) 2 (7) 18 (60) 12 (40) 3 (10) 19 (63) 8 (27) 8 (26) 3 (16) 5 (41) 3 (3-4) 9 (30) 12 (7) 14 (6-18) 23 (76) 7 (24) group 2 (n = 30) 300 ± 52 304 (253-336) 237 ± 52 237 (253-336) 362 (108) 350 (300-410) 8 (26) 8 (26) 14 (48) 16 (53) 2 (7) 20 (66) 8 (27) 2 (7) 2 (7) 23 (78) 5 (15) 10 (33) 3 (15) 6 (75) 1 (50) 4 (3-4) 2 (3) 2 (10) 11 (8) 14 (4-19) 21 (70) 9 (30) group 3 (n = 30) 243 ± 33 245 (225-270) 200 ± 33 197 (179-225) 450 (146) 430 (365-525) 10 (33) 5 (16) 15 (50) 19 (63) 1 (3) 21 (73) 7 (20) 2 (7) 7 (22) 14 (48) 9 (30) 4 (13) 1 (5) 1 (14) 2 (100) 3 (3-4.5) 2 (6) 0 12 (9) 18 (0-20) 29 (99) 1 (1) group 4 (n = 30) 221 ± 28.6 215 (200-250) 177 ± 28.4 180 (155-200) 534 (160) 500 (437-600) 6 (21) 4 (13) 20 (66) 14 (46) 0/ 23 (77) 6 (20) 1 (3) 2 (7) 20 (66) 8 (27) 2 (6) 1 (4) 1 (16) 0 3 (3-4) 3 (10) 1 (3) 18 (8) 21 (18-25) 30 (100) 0 p < 0.001 0.01 0.2 0.3 0.393 0.4 0.5 0.4 0.3 0.5 0.3 0.6 0.04 < 0.001 * p value is obtained comparing the four groups. ** 3 months after surgery considering patients referred to nerve sparing approach. *** 3 months after surgery, not continent (>1 safety pad per day). chessa_stesura seveso 27/03/18 09:15 pagina 3 archivio italiano di urologia e andrologia 2018; 90, 1 r. schiavina, m. borghesi, h. dababneh, m.s. rossi, c.v. pultrone cristian, v. vagnoni, f. chessa, l. bianchi, a. porreca, a. mottrie, e. brunocilla 4 i-ii) such as anaemia (31%), fever (26%) and lymphocele (21%). no statistical differences were found in terms of complications between the four groups. the overall continence rate at 1 and 3 months was 74% and 87% respectively (table 2). figure 1 depicts the urinary continence recovery rates after stratifying according to the four groups, 1 month and 3 months after surgery. we found a significant improvement in continence rate throughout the four groups (p = 0.04). all patients in the fourth group were continent 3 months after surgery. considering those patients submitted to nerve-sparing procedure, the median iief-5 was 18 and we found a significant increase in potency recovery over the four groups (p = 0.04). figure 2 shows the potency recovery rate after stratifying according to the four groups. the sexual function recovery rate rises gradually during the first three groups, however the last 30 procedures revealed significantly higher potency recovery rate up to 80%, 3 months after surgery as compared to previous cases. table 3. incidence and type of intraoperative and post-operative complications according to dindo-clavien classification in overall population and after stratifying patients according to four consecutive groups. figure 1. time to potency recovery according to the four groups. type ureteral injury bladder injury bowel injury iliac vein injury type adductor muscle deficit fever lymphocele with fever anemia pulmonary embolism myocardial infarction ureteral injury overall, n 5 (%) 1 (0.8) 2 (1.6) 1 (1.6) 1 (1.6) overall, n 19 (%) 1 (1) 5 (4) 4 (3) 6 (5) 1 (1) 1 (1) 1 (1) group 1 1 (3) 1 (3) group 1 1 (3) 4 (13) 1 (3) 3 (10) group 2 1 (3) 1 (3) group 2 1 (3) 1 (3) 1 (3) 1 (3) group 3 1 (3) group 3 1 (3) 1 (3) group 4 group 4 1 (3) 2 (6) 1 (3) intraoperative complications post-operative complications treatment intraoperative ureteral stent placement intraoperative surgical reparation intraoperative surgical reparation intraoperative surgical reparation treatment medical therapy medical therapy medical therapy medical therapy medical therapy medical therapy ureteral reimplantation dindo-clavien grade n.v. n.v. n.v. n.v. dindo-clavien grade 1 2 2 2 4 4 3 chessa_stesura seveso 27/03/18 09:15 pagina 4 discussion the success of ralp is mainly due to the evidence that even inexperienced robotic surgeons could achieve high standards of surgery, with limited operative time, even in the early phase of the learning curve. instead, complete urinary continence and erectile function recovery may require more surgical experience (18). to date, the number of ralp needed to achieve optimal functional outcomes such urinary continence and erectile function recovery is a hotly debated topic. only limited studies show the functional outcomes during the learning curve (9, 12, 19). hence, the present study aimed to evaluate early functional and perioperative outcomes of an inexperienced robotic surgeon, after attending a structured modular training. notably, in our report of the first 120 consecutive ralp, the intraoperative, post-operative and functional results were comparable to those previously reported in literature (10, 20). the overall operative time, the console time, and the psm gradually decreased during the learning curve. after the first 30 cases the mean console time was comparable to those reported in hands of more experienced surgeons (237 min ± 52) (21). ahlering et al showed only 10-20 cases were required to achieve 4-h proficiency (7). however, doumerc et al. demonstrated that at least 50 patients were needed to achieve a plateau of 200 minutes for an experienced “open-surgeon” who starts with robotic program, without attending a specific modular training (22). another surrogate of proficiency in ralp is psm rate, which mainly related to pathological stage and it's invariably higher in non-organ confined disease (≥ pt3a) (23). however, the incidence of psm in organ confined (oc) prostate cancer is directly related to the quality of surgery (24). indeed, in an initial report of 45 ralp, ahlering et al. reported 14% of psm in organ confined disease (7). accordingly, in a recent meta-analysis, novara et al. shows that psm rate ranges from 0% to 20 % and from 0 to 60% in oc and nonorgan confined disease, respectively (19). with regard of psm rate, our findings underlines that a high quality of surgery was achieved even during the early phase of the learning curve. indeed, overall psm rate was 10% and 40% in oc and non-organ confined disease, respectively. moreover, the psm rate of oc disease decreased from 16% among the initial 30 cases, to 4% in the latter 30 cases. furthermore, we found no statistical difference with respect of the pathological stage between our groups, underlining that the decrease of psm rate is mostly due to the improvement in robotic surgical skills. alike surveillance protocols (25), minimally invasive surgery is aimed to reduce the potential sequelae, morbidity and post-operative complications. in this contest, mean post-operative complication rate for ralp is roughly 9% (21). however, complication rates reported during learning curve could be much higher, ranging from 1% to 40 % (19). in the present series overall post-operative complication rate is 16%, most of them (84%) graded as minor complications (clavien 1-2). in our experience the most severe complication was a ureteral injury which required a ureteral reimplantation. notably, complication rates decreased from 30% in the first group to 13% in the last 30 procedures. this data are consistent with previous reported in literature, underlining that 20-30 cases may be need for a surgeon to overcome the “basic” learning curve. lavery et al. identified an “advanced learning curve” in ralp, concerning urinary continence, erectile function recovery and psm rate. they concluded that 100-300 cases are needed to overcome this steeper learning curve (11). this is related to the relatively high level of difficulty in performing the anastomosis and the optimal compromise between neurovascular bundle preservation and the achievement of negative surgical margins. some results of our study are noteworthy. first, despite our limited experience in robotic surgery and the short follow-up (3 months), we report optimal functional outcomes even in the early phase of the learning curve. second, potency recovery raises exponentially throughout the four groups. in the latter group, 80% of patients undergoing nerve sparing procedures, recovered the preoperative erectile function 3 months after surgery. a wide variability of 3-months potency recovery is reported in literature, ranging from 32% to 68% (18, 26). this could be explained by the several clinical predictors of potency recovery such as age, bmi, baseline iief score, nerve sparing technique and cci (26). 5archivio italiano di urologia e andrologia 2018; 90, 1 the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy figure 2. time to continence recovery according to the four groups. chessa_stesura seveso 27/03/18 09:15 pagina 5 archivio italiano di urologia e andrologia 2018; 90, 1 r. schiavina, m. borghesi, h. dababneh, m.s. rossi, c.v. pultrone cristian, v. vagnoni, f. chessa, l. bianchi, a. porreca, a. mottrie, e. brunocilla 6 third, in our series early (3 months) continence recovery rate, increases during the learning curve, particularly after the first 60 cases, reaching 99% and 100% in group 3 and group 4, respectively. similarly to erectile function recovery, also urinary continence recovery, according to the definition of no-pad, is strongly influenced by age at surgery, prostate volume, bmi, and surgical technique (10, 27). as consequence, more controversial is the impact of surgeon experience and learning curve on the prevalence of urinary incontinence after ralp (10). samadi et al. reported a significant increase of the continence rate after 500 cases (28); conversely excellent results were also reported in several clinical series including 100-200 cases (5, 22, 28). notably, no differences were found in terms of age at surgery, baseline iief score, cci, and nerve sparing technique, between the four groups. this underlines that urinary continence and potency recovery are mostly due to improvement in robotic skills and almost 90 cases are needed to master anastomosis and nerve sparing procedure. despite several strengths, our study has several limitations. first, this study only address perioperative outcomes at short term follow up. second, the number of enrolled patients is limited, and could underestimate the main outcomes. third, the great part of patients enrolled revealed low to intermediate risk pca, since represent a learning curve cohort: it could influence our analysis and it could be not representative of learning curve in different population with higher proportion of high risk disease. fourth, the main surgeon is a robotic naive surgeon experienced in open surgery but with limited skills in laparoscopic surgery. indeed, the learning curve could be affected by previous surgical background and our data are not exportable to robot naive surgeons with pure laparoscopic experience. conclusions in the present series, optimal perioperative and functional outcomes have been attained since early phase of the learning curve after an intensive structured modular training and only 90 consecutive procedures seem needed in order to achieve optimal urinary continence and erectile function recovery. our data suggest that an intensive structured modular training within ralp allows robotic naive surgeons to achieve optimal perioperative and functional outcomes since the early phase of the learning curve indeed, after attending a structured modular training, 20-30 cases are sufficient to shorten operative time and lowering the complication rate. references 1. ferlay j, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015; 136:e359. 2. heidenreich a, bellmunt j, bolla m, et al. eau guidelines on prostate cancer. part 1: screening, diagnosis, and treatment of clinically localised disease. eur urol. 2011; 59:61-71. 3. walsh pc, partin aw, epstein ji. cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. j urol. 1994; 152:1831-6. 4. badani kk, kaul s, menon m. evolution of robotic radical prostatectomy: assessment after 2766 procedures. cancer. 2007; 110:1951-8 5. ficarra v, novara g, rosen r, et al. systematic review and metaanalysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012; 62:405-17. 6. ficarra v, novara g, ahlering t, et al. systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. eur urol. 2012; 62:418-30. 7. ahlering te, skarecky d, lee d, clayman rv. successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. j urol. 2003; 170:1738-41. 8. smith jr ja. robotically assisted laparoscopic prostatectomy: an assessment of its contemporary role in the surgical management of localized prostate cancer. am j surg. 2004; 188:63s-67s. 9. patel vr, tully as, holmes r, lindsay j. robotic radical prostatectomy in the community setting—the learning curve and beyond: initial 200 cases. j urol. 2005; 174:269-72. 10. young hwii ko, jeong hyeon ban, seok ho kang. does robotassisted laparoscopic radical prostatectomy enable to obtain adequate oncological and functional outcomes during the learning curve? from the korean experience. aja. 2009; 167-175. 11. hugh j. lavery, david b. samadi, rahul thaly. the advanced learning curve in robotic prostatectomy: a multi-institutional survey. j robotic surg. 2009; 3:165-169. 12. hashimoto t, yoshioka k, gondo t, et al. learning curve and perioperative outcomes of robot-assisted radical prostatectomy in 200 initial japanese cases by a single surgeon. j endourol. 2013; 27:1218-23. 13. volpe a, ahmed k, dasgupta p, et al. pilot validation study of the european association of urology robotic training curriculum. eur urol. 2015; 68:292-9. 14. lovegrove c, novara g, mottrie a, et al. structured and modular training pathway for robot-assisted radical prostatectomy (rarp): validation of the rarp assessment core and learning curve assessment. eur urol. 2016; 69:526-35. 15. sood a, jeong w, ahlawat r, et al. robotic surgical skill acquisition: what one needs to know? j minim access surg. 2015; 11:10-5. 16. mottrie a, van migem p, de naeyer g, et al. robot-assisted laparoscopic radical prostatectomy: oncologic and functional results of 184 cases. eur urol. 2007; 52:746-50 17. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-96. 18. schiavina r, borghesi m, dababneh h, et al. survival, continence and potency (scp) recovery after radical retropubic prostatectomy: a long-term combined evaluation of surgical outcomes. eur j surg oncol. 2014; 40:1716-23. 19. artibani w, fracalanza s, cavalleri s. learning curve and preliminary experience with da vinci-assisted laparoscopic radical prostatectomy urol int. 2008; 80:237-44. 20. novara g, ficarra v, mocellin s. systematic review and metaanalysis of studies reporting oncologic outcome after robot-assisted radical prostatectomy. eur urol. 2012; 62:382-404. chessa_stesura seveso 27/03/18 09:15 pagina 6 21. novara g, ficarra v, rosen rc. systematic review and metaanalysis of perioperative outcomes and complications after robotassisted radical prostatectomy. eur urol. 2012; 62:431-52. 22. doumerc n, yuen c, savdie r, et al. should experienced open prostatic surgeons convert to robotic surgery? the real learning curve for one surgeon over 3 years. bju int. 2010; 106:378-84. 23. schiavina r, borghesi m, fiorentino m, et al. identification of prostate cancer risk categories according to surgical margins status, pathological stage and gleason score. int j urol. 2013; 20:1097-103. 24. heidenreich a. quality control in radical (laparoscopic) prostatectomy. eur urol. 2006; 49:767-768. 25. brunocilla e, borghesi m, schiavina r, et al. small renal masses initially managed using active surveillance: results from a retrospective study with long-term follow-up. clin genitourin cancer. 2014; 12:178-81. 26. eastham ja. robotic-assisted prostatectomy: is there truth in advertising? eur urol. 2008; 54:720-2. 27. brunocilla e, schiavina r, pultrone cv, et al. preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. int j urol. 2014; 21:157-62. 28. samadi db, muntner p, nabizada-pace f. improvements in robot-assisted prostatectomy: the effect of surgeon experience and technical changes on oncologic and functional outcomes. j endourol. 2010; 24:1105-10. 7archivio italiano di urologia e andrologia 2018; 90, 1 the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy correspondence schiavina riccardo, md rschiavina@yahoo.it borghesi marc, md mark.borghesi1@gmail.com dababneh hussam, md drdababneh@gmail.com rossi martina sofia, md martinasofia.rossi@gmail.com pultrone cristian vincenzo, md cristian.pultrone@gmail.com vagnoni valerio, md vagno07@libero.it chessa francesco, md (corresponding author) francesco.chessa2@studio.unibo.it bianchi lorenzo, md lorenzo.bianchi3@studio.unibo.it brunocilla eugenio, md eugenio.brunocilla@unibo.ituniversity of bologna, s. orsola-malpighi hospital, dept. of urology, bologna via palagi 9 40134, bologna, italy porreca angelo, md angeloporreca@gmail.com policlinico di abano, dept. of urology, abano terme, italy mottrie alexandre, md a.mottrie@telenet.be olv robotic surgery institute, aalst, belgium chessa_stesura seveso 27/03/18 09:15 pagina 7 archivio italiano di urologia e andrologia 2018; 90, 3208 original paper adolescence and andrologist: an imperfect couple soraya olana, rossella mazzilli, michele delfino, virginia zamponi, cristina iorio, fernando mazzilli andrology unit, department of clinical and molecular medicine, sant'andrea hospital, university of rome "sapienza", rome, italy. objective: the aims of this research were to study: a) the prevalence of male adolescents, aged between 10 and 19 years of age, referred to our unit for an andrological assessment; b) the reasons (stated and subsequently modified) for referral; c) the prevalence of clinically diagnosed diseases. materials and methods: a total of 2.855 subjects, referred to the andrology unit for a first examination, were retrospectively studied. for each adolescent, a medical history was taken and an andrological physical examination was carried out. results: prevalence was found to be 6.9% (197/2855). subjects were divided into two groups according to age (a: ≤ 14 and b: ≥ 15 years). the original reason stated for their consultation was corrected by 11.7% of the subjects (23/197); this correction concerned almost all the group b subjects (21/23 (91.3%) vs 2/23 (8.7%) of group a; p < 0.01). regarding sexual dysfunctions, a simple explanation of certain conditions reassured the subject in about 15% of the cases. furthermore, the physical examination proved extremely useful, revealing clinical alterations in more than 60% of subjects. conclusions: in conclusion, to date in italy, the prevalence of adolescents among males referred to an andrology unit for assessment is very low. it is important to encourage adolescents to undergo andrological examination to enable identification of reproductive function and psycho-sexual disorders. key words: adolescence; andrological examination; prevention; sexual dysfunctions; varicocele; cryptorchidism; dysmorphophobias. submitted 11 june 2018; accepted 19 august 2018 summary no conflict of interest declared. pubertal and post-pubertal subjects, and a different approach would be needed for each age range. the reports in the literature concerning this period are not numerous and they are mainly regarding single issues (such as varicocele, infections, anatomical anomalies and pubertal delay), or they report the results of campaigns for prevention, rather than spontaneous referrals requesting a medical examination (4-11). the aims of this work were to evaluate: a) the prevalence of adolescent subjects in a large population of men referred to our andrology unit for an andrological assessment; b) the reasons given for first referral (subsequently modified); c) the prevalence of clinically diagnosed diseases. materials and methods a total of 2,855 subjects, referred to our andrology unit (sant'andrea hospital “sapienza” university of rome) from september 2012 to december 2017 for a first examination, were retrospectively studied. for each adolescent aged between 10 and 19 years, the following were carried out: a) a full medical history; b) an andrological physical examination [body mass index, hair distribution, scrotum, testis, varicocele (grade i-iii), epididymis, penis and breast]. the diagnosis of erectile dysfunction and premature ejaculation were evaluated using the international index of erectile function 5 (iief-5) and premature ejaculation diagnostic tool (pedt) questionnaires (total score ≤ 21 and ≥ 11 respectively). the clinical study was conducted according to the hospital ethics committee guidelines. statistical analysis continuous data were described as absolute values, mean ± standard deviation and range. categorical data were described as absolute, percentage frequency, and 95% confidence intervals. student t-test and fisher's exact test were used for continuous and categorical data, respectively. p < 0.05 was considered statistically significant. results the prevalence of male adolescents was found to be 6.9% (197/2855). the distribution, according to age, is shown in figure 1. doi: 10.4081/aiua.2018.3.208 introduction adolescence is understood to be a transitional phase of growth between childhood and adulthood. the world health organization (who) defines an adolescent as being between 10 and 19 years of age (1). in addition, studies show that only 13% of the age group in question are aware of the professional role that andrologists play (2). screening for teenage pathologies should be an important part of general health management. in many countries, this used to be linked to routine physical examinations associated with military service. the abolition of compulsory military service, in italy, has meant that an important screening opportunity has been lost and this has led to a lower level of preventive care and treatment related to male reproductive and sexual diseases (3). undiagnosed pathologies no longer picked up by such routine screening would affect pre-pubertal, olana_stesura seveso 03/10/18 09:46 pagina 208 209archivio italiano di urologia e andrologia 2018; 90, 3 adolescence and andrologists according to the who definition, the subjects were divided into two age groups: – group a (n = 49; age ≥ 10 ≤ 14), which included subjects in pre-pubertal or peri-pubertal period; bmi 21.8 ± 2.0 kg/m2 (range 18.2-26.3). – group b (n = 148; age ≥ 15 ≤ 19), which included subjects generally in the post-pubertal period; bmi 21.7 ± 2.1 kg/m2 (range 18.3-28.1) (p = ns). reported and actual reasons for andrological consultation the most common reasons given for the andrological consultation were: a preventive andrological check-up, suspected varicocele and other organic diseases. a preventive andrological examination regarded mainly group a (36.7%) rather than group b (12.2%); p < 0.05). while giving information for the medical history, 23/197 (11.7%) subjects corrected the original reason stated for the consultation. this correction concerned almost all the group b subjects (21/23, 91.3%) compared with a minority in group a (2/23, 8.7%) (p < 0.01) (table i). in particular, 8/36 subjects, who had come for a preventive check-up, said they actually needed a consultation for sexual dysfunction. likewise, 10/56 subjects who had initially claimed that they were worried about an organic disease, afterwards admitted that they were instead concerned about sexual dysfunction or dysmorphophobia. finally, we found that 5/9 subjects, who were initially referred to us for a suspected infection, were really suffering from dysmorphophobia or sexual dysfunction. clinical evidence in groups and subgroups (table i) 1. andrological examination: clinical alterations were observed in 17/28 subjects who originally attended for a preventive andrological examination. this concerned mainly group a (13/18 subjects: 1/13 varicocele, 5/13 phimosis or sub-phimosis, 3/13 short table 1. referred, effective reasons of the requested of andrological examination and clinical confirmation in total and subgroups a and b. total group a group b n = 197 n = 49/197 (24.9%) n= 148/197 (75.1%) reasons firstly referred effective clinical evidence firstly referred effective clinical evidence firstly referred effective clinical evidence (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) (n, %, 95%ci) andrological examination varicocele pain testis other organic diseases dysmorphophobias infections and contraception sexual dysfunctions other: trauma, testicular torsion, etc group a: age 10-14 years; group b: age 15-19 years. ci: confidence intervals. *p<0.05 vs group b. figure 1. prevalence based on adolescent’s age. group a: age 10-14 years. 36/197 (18.3) 13.5-24.3 39/197 (19.8) 14.8-26.0 11/197 (5.6) 3.0-9.8 56/197 (28.4) 22.6-35.1 17/197 (8.6) 5.4-13.5 9/197 (4.6) 2.3-8.6 24/197 (12.2) 8.3-17.5 5/197 (2.5) 0.9-6.0 28/197 (14.2) 10.0-19.8 39/197 (19.8) 14.8-26.0 11/197 (5.6) 3.0-9.8 46/197 (23.4) 18.0-30.0 33/197 (16.8) 12.2-22.6 4/197 (2.0) 0.6-5.3 31/197 (15.7) 11.3-21.5 5/197 (2.5) 0.9-6.0 17/28 (60.7) 42.4-76.5 37/39 (94.9) 82.2-99.5 10/11 (90.9) 60.1-99.9 42/46 (91.3) 79.1-97.1 5/33 (15.2) 61.7-31.4 4/4 (100) 45.4-100 26/31 (83.9) 66.9-93.4 5/5 (100) 51.1-100 18/49 (36.7)* 24.6-50.8 9/49 (18.4) 9.8-31.6 2/49 (4.1) 0.4-14.5 16/49 (32.7) 21.2-46.7 3/49 (6.1) 1.5-17.5 1/49 (2.0) < 0.1-11.7 18/49 (36.7)* 24.6-50.8 9/49 (18.4) 9.8-31.6 2/49 (4.1) 0.4-14.5 14/49 (28.6) 17.8-42.5 5/49 (10.2) 4.0-22.2 1/49 (2.0) < 0.1-11.7 13/18 (72.2) 48.8-87.8 9/9 (100) 65.5-100 2/2 (100) 29.0-100 12/14 (85.7) 58.8-97.2 1/5 (20.0) 2.0-64.0 1/1 (100) 16.8-100 18/148 (12.2) 7.6-18.5 30/148 (20.3) 14.5-27.5 9/148 (6.1) 3.1-11.3 40/148 (27.0) 20.5-34.7 14/148 (9.5) 5.6-15.4 9/148 (6.1) 3.1-11.3 24/148 (16.2) 11.1-23.1 4/148 (2.7) 0.8-7.0 10/148 (6.8) 3.6-12.1 30/148 (20.3) 14.5-27.5 9/148 (6.1) 3.1-11.3 32/148 (21.6) 15.7-29.0 28/148 (18.9) 13.4-26.0 4/148 (2.7) 0.8-7.0 31/148 (21.0) 15.3-28.2 4/148 (2.7) 0.8-7.0 4/10 (40.0) 16.7-68.8 28/30 (93.3) 77.6-99.2 8/9 (88.9) 54.3-99.9 30/32 (93.8) 78.8-99.3 4/28 (14.3) 5.1-32.1 4/4 (100) 45.4-100 26/31 (83.9) 66.9-93.4 4/4 (100) 45.4-100 group a: age 10-14 years; group b: age 15-19 years. olana_stesura seveso 03/10/18 09:46 pagina 209 archivio italiano di urologia e andrologia 2018; 90, 3 s. olana, r. mazzilli, m. delfino, v. zamponi, c. iorio, f. mazzilli 210 frenulum, 3/13 retractile testis, 1/13 hypospadias) compared with group b (4/10 subjects: 1/4 varicocele, 1/4 sub-phimosis, 2/4 short frenulum). 2. varicocele: 9/49 subjects in group a and 30/148 subjects in group b referred to us for a suspected varicocele. during the andrological examination we observed varicocele in all the group a subjects (6/9 of grade i, 3/9 of grade ii), and in 28/30 group b subjects (9/28 of grade i, 16/28 of grade ii, 3/28 of grade iii). 3. testis pain: this problem was observed in 2/49 subjects in group a and 9/148 subjects in group b. specifically, two subjects in group a showed epididymal hypertrophy; regarding group b, 8/9 subjects had epididymal hypertrophy, while the remaining subject had grade ii varicocele. 4. other organic diseases: in 12/14 group a subjects, we observed clinical evidence of organic disease (4/12 phimosis, 3/12 gynaecomastia, 3/12 retractile testis, 1/12 cryptorchidism and 1/12 pubertal delay). moreover, in 30/32 group b subjects, we observed clinical confirmation of organic disease (6/30 short frenulum, 5/30 sub-phimosis, 3/30 gynaecomastia, 4/30 retractile testis, 2/30 cryptorchidism, 4/30 hypogonadotropic hypogonadism, 2/30 penis recurvatum, 3/30 phimosis and 1/30 adrenogenital syndrome). 5. dysmorphophobias: in group a, only 1/5 subject showed adipomastia. moreover, in group b, only 4/28 subjects showed any clinical evidence of a condition (3/4 penis in peri-pubic fat and 1/4 adipomastia). 6. infections and contraception: these problems only concerned group b. in particular, 1/4 subjects showed gland inflammation, 1/4 secretion in the urethral meatus, 1/4 condylomas; finally, 1/4 subjects needed information about contraception. 7. sexual dysfunction: these problems only concerned group b. the diagnosis was made by using specific questionnaires (iief-5 and pedt). in particular, premature ejaculation was observed in 16/26 subjects, erectile dysfunction in 8/26 subjects and anejaculation and/or anorgasmia in 2/26 subjects. 8. other: in group a we observed a reduced testicular volume (post trauma) in one subject; in group b we observed a reduced testicular volume post testicular torsion (1/4), post orchitis (1/4), post trauma (2/4). all subjects were directed to the appropriate and specific diagnostic/therapeutic pathways. discussion this study considered the prevalence of male adolescents referred to our andrology unit. the subjects of this study were divided into two groups, according to age. of the 6.9% of adolescents found, 5.2% were regarded subjects of post-pubertal age while only 1.7% were regarded subjects of preand peri-pubertal age. according to the literature (6-8), the main reasons that prompt adolescents to carry out this kind of examination are: suspicion of organic diseases (28.4%), varicocele (19.8%) and preventive andrological check-up (18.3%). however, our study found that other important factors may prompt the decision to undergo such an examination. critical analysis of our results showed that 11.9% of all subjects included in this study corrected the stated motivation for their andrological assessment during the anamnestic interview. this concerned mainly group b subjects, aged ≥ 15 years. this is perhaps because parents reported the problems of the younger subjects. we noted that subjects found some difficulties in explaining to the andrologist their worries regarding sexual dysfunctions and dysmorphophobias. these problems were first reported in the context of a preventive andrological examination or organic disease or a suspicion of infection, but it would seem that a different worry could be the real prompt for an examination in many cases. an interesting finding concerned sexual dysfunctions. in fact, in about 15% of the cases, it was necessary only to explain the real definition of a condition to reassure a subject that there was no real problem. for example, some subjects reported premature ejaculation (pe), with sexual intercourse lasting about 10 minutes. instead, pe can be defined as being intravaginal ejaculation latency time (ielt) of less than 1 minute), which is quite different from the subject's perception. furthermore, no problem was observed in 84% of subjects who had reported dysmorphophobia. a very important point to underline is that the andrological check-up showed itself to be extremely useful in detecting clinical alterations (such as phimosis, gynaecomastia, retractile testis, cryptorchidism and pubertal delay) in more than 60% of subjects. it is for this reason that every effort should be made to ensure that adolescent males get a chance to undergo an andrological screening. the limit of the present work is the single-centre retrospectively based form. in conclusion, in italy, the prevalence of adolescents among the males referred to an andrology unit for assessment is very low. this may be due to the fact that here the professional figure of the andrologist is little known among young males and it is therefore essential to promote awareness of andrological examinations through mass media and school campaigns for prevention (2, 5, 12). early diagnosis of andrological diseases is crucial so as to prevent later problems in reproductive function. finally, sexual education during adolescence is also very important because it could help to reduce many psycho-sexual problems. authors’ role fm and rm conceived the study. so and rm analysed the data drafted the manuscript. all authors contributed to the data collection and/or interpretation, and provided a critical revision of the manuscript. references 1. sixty-fourth world health assembly. resolution wha 64.28: youth and health risks. geneva, world health organization, 2011. 2. mondaini n, silvani m, zenico t, et al. genital diseases awareolana_stesura seveso 03/10/18 09:46 pagina 210 211archivio italiano di urologia e andrologia 2018; 90, 3 adolescence and andrologists ness in young male students: is information necessary to protect them? arch ital urol androl. 2013; 85:14-9. 3. campodonico f, michelazzi a, capurro a, carmignani g. andrologic disease detected during army medical visit. arch ital urol androl. 2003; 75:205-7. 4. hadziselimovic f, herzog b. andrological problems in adolescence. ther umsch. 1994; 51:305-13. 5. foresta c, garolla a, et al. anthropometric, penile and testis measures in post-pubertal italian males. j endocrinol invest. 2013; 36:287-92. 6. pereira nm. phimosis, hydrocele and varicocele. 3 frequent pathologies in the male child and adolescent. acta med port. 1999; 12:137-43. 7. serefoglu ec, saitz tr, la nasa ja jr, hellstrom wj. adolescent varicocoele management controversies. andrology. 2013; 1:109-15. 8. fast am, deibert cm, van batavia jp, et al. adolescent varicocelectomy: does artery sparing influence recurrence rate and/or catch-up growth? andrology. 2014; 2:159-64. 9. maggi m, buvat j. standard operating procedures: pubertas tarda/delayed puberty--male. j sex med. 2013; 10:285-93. 10. foresta c, garolla a, zuccarello d, et al. human papillomavirus found in sperm head of young adult males affects the progressive motility. fertil steril. 2010; 93:802-6. 11. delfino m, elia j, imbrogno n, et al. testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics. j ultrasound med. 2012; 31:383-8. 12. valkenburg pm, peter j. online communication among adolescents: an integrated model of its attraction, opportunities, and risks. j adolesc health. 2011; 48:121-7. correspondence soraya olana, md soraya.olana@gmail.com rossella mazzilli, md (corresponding author) rossella.mazzilli@uniroma1.it michele delfino, md micheledelfino@libero.it virginia zamponi, md virginia22.zamponi@gmail.com cristina iorio, md cristina.iorio90@gmail.com fernando mazzilli, md fernando.mazzilli@uniroma1.it sant'andrea hospital, university of rome "sapienza", rome, italy olana_stesura seveso 03/10/18 09:46 pagina 211 archivio italiano di urologia e andrologia 2017; 89, 4310 original paper prevalence of phimosis and foreskin sliding abnormalities in male adolescents and their correlation with later onset of first sexual intercourse giuseppe la pera 1, francesco de luca 1, 2, attilio guerani 3, alessandro palmieri 4, giorgio franco 2 1 department of urology azienda ospedaliera san camillo forlanini, rome, italy; 2 department of gynaecological and urological sciences, sapienza university of rome, rome, italy; 3 general practitioner, rome, italy; 4 department of urology university of naples, naples, italy. introduction and objectives: the aim of the study is to evaluate the prevalence of andrological abnormalities, such as phimosis and foreskin sliding abnormalities among male adolescents, and if these might interfere with sexuality, leading to a later onset of sexual experiences. material and methods: between april and may 2015 a prevention campaign in andrology was conducted in an area surrounding rome, ostia and the ladispoli area, among 15-19 year-old students. the screening consisted of a frontal lesson with the students in order to explain and raise the awareness of the most common andrological abnormalities and diseases. among the routine anamnestic questions, three additional questions were submitted to 18-year-old boys: “have you ever had sexual intercourse?”, “how old were you when you had your first sexual intercourse?” and “have you consulted a health professional about your genitals?” finally a detailed clinical examination was performed and the outcome sent to the family and to the general practitioner (gp). results: a total of 552 high school students were evaluated. out of them 131 (23.7%) were at least 18 years old. among these, 79 (60.3%) said that they had already had full sexual intercourse. the phimosis and foreskin sliding abnormalities had a prevalence of 12.9% within the 18-year-old students, with a significant prevalence among those who hadn’t had any sexual intercourse at all, 21.1% vs 7.5% p = 0.023. the age of the complete first sexual experience in the circumcised young men was the same as those without phimosis; 89% of the boys with phimosis hadn't had an andrological examination in the previous years. conclusions: male adolescents with phimosis or preputial sliding abnormalities tend to have a late onset of sexual experiences compared to same aged boys without phimosis. these data support the urgent need of an andrological consultation for all boys at the beginning of, and during, their adolescent period because genital abnormalities may interfere with sexuality. finally, in order not to confuse effects with causes, we suggest matching a routine genital physical examination in all studies dealing with sexual psychological aspects of male adolescents. key words: phimosis; foreskin sliding abnormalities; male adolescents; first sexual intercourse; tight foreskin. submitted 21 september 2017; accepted 8 october 2017 summary no conflict of interest declared. introduction phimosis is defined as the inability of the prepuce (foreskin) to be retracted behind the glans penis in uncircumcised males. the prepuce is unretractable in almost 100% of infants and less than 7% of children approaching puberty. the prevalence decrease with the age (1). it may occurs mainly in childhood for congenital factors, while in adulthood it is often the result of chronic diseases of the penis or glans and/or recurrent infections that lead to foreskin and glans adhesions (2). little has been written about the presence of phimosis and foreskin sliding disorders during male adolescence (3), especially if this may affect approaching sex. the aim of this study is to evaluate in a population of male adolescents the prevalence of phimosis and other foreskin sliding disorders and to assess whether these conditions could somehow affect a different approach to sex, such as a late onset of first complete sexual intercourse. material and methods between april and may 2015, the italian society of andrology (sia) and italian association for sexual right (aidass) conducted a prevention campaign in andrology. it was carried out in the municipality of ladispoli and in the borough of ostia, 30 kilometres away from rome. all the boys between 15 and 19 years old and living in the municipality of ladispoli were invited to take part in the survey (a total of 1180 boys), while in the borough of ostia all the boys between 15 and 19 years old attending four high schools were invited. first of all we sent a letter to the family to explain the aim of the campaign and to obtain their written consent for a genital examination for adolescents under 18 years old. the screening was carried out in high schools and at general practitioner (gp) practice. it consisted of lessons with the students in order to explain and raise the awareness of the most common andrological diseases and how to prevent it, showing how to perform testicular self-examination for the prevention of testis cancer. all students underwent to a genital examination by at least one urologist in which the definition of phimosis doi: 10.4081/aiua.2017.4.310 la pera_stesura seveso 03/01/18 12:30 pagina 310 311archivio italiano di urologia e andrologia 2017; 89, 4 prevalence of phimosis and foreskin sliding abnormalities in male adolescents and their correlation with later onset of first sexual intercourse and foreskin sliding abnormalities had been defined according to these three situations: 1. the typical phimosis in which the foreskin cannot be pulled back and past the glans; 2. functional phimosis, in which the foreskin cannot be pulled back past the glans only during erection; 3. frenulum brevis is too short to allow complete foreskin retraction. if one of the above conditions was present then the subject was considered to be affected by phimosis or foreskin sliding abnormalities. the chi-square test was used to analyze the difference in prevalence between those who had already had full sexual intercourse and those who had not. for all students older than 18 years, two additional questions were asked: “have you ever had sexual intercourse and how old were you when you first had sexual intercourse?” and “have you consulted a health professional about your genitals?” at the end, another correspondence was sent to the family and to the gp to let them know the final report. the local ethical committee was informed of the noninterventional and observational nature of the study. the primary end point of the study was to evaluate the prevalence of phimosis and foreskin sliding abnormalities among male adolescents. the secondary objectives were: – to correlate genital abnormalities with late onset of sexual experiences; – to teach self examination to all adolescents aged 15-19 years. this latter aspect, and all results regarding other diseases such as varicocele and its prevalence in boys under 18 years old, will be analyzed in a separate paper. results a total of 552 high school students were evaluated; 131 (23.7%) were at least 18 years; among these, 79 (60.3%) stated that they had already had full sexual intercourse. in more detail, 8 students had their first sexual experience at the age of 14, 19 at the age of 15, 18 at the age of 16, 23 at the age of 17 and 11 at the age of 18 (figure 1). phimosis and foreskin sliding abnormalities were found in 17 cases with a prevalence of 12.9% within the 18-yearold students. there was a higher prevalence of phimosis among students who hadn’t had any sexual intercourse at all: 11 subjects (21.1%) versus 7 (7.5%) students who had had complete sexual experiences (figure 2). the chi-square test was 5.105 with p = 0.023. the age of the first sexual experience of the circumcised students was the same as those without phimosis. furthermore, 89% of subjects with phimosis never had a previous genital examination. discussion this study shows that the prevalence of phimosis and foreskin sliding disorders is significantly higher among those who have not had sexual intercourse (21.1%) than among those who have already had sexual intercourse (7.5%). as shown in literature, the mean age of the first sexual experience is at 16 years (4). these observations show that these boys may face two problems, a biological one and a behavioural one. biological because the degree of phimosis may worsen and lead to a urinary tract infection and because of the hypersensitivity of the glans that leads to premature ejaculation and discomfort or pain during masturbation or sexual intercourse. also, phimosis and sexual disorders can interfere with sexuality, triggering behaviours that can lead to avoidance of sexual intercourse. this is shown by the observation that young men with phimosis tend to have less sexual intercourse than those who do not have phimosis. this observation on adolescent behaviour is new compared to other similar studies (4) because, for the first time, it has been observed that the physical handicap could interfere with their approach to sex, such as delaying their first sexual intercourse, and in some cases could be the cause of psychological fragility. the delayed onset of sexual intercourse may be an adaptive behaviour of a physical disease and not the consequence of a primitive psychological fragility that arises subsequently. this adaptive behaviour has already been demonstrated in other sexual diseases, such as sexual dysfunction, which can trigger substance addiction (5, 6) and a similar mechanism can be the basis of the delayed onset of sexual intercourse. many psychological studies on adolescents’ sexuality and behaviour are based only on questionnaires (7, 8), and figure 1. age at first sexual experience. in column number and percentage distribution of students. figure 2. number of subjects with or without phimosis and distribution according to their sexual experiences. p = 0.023 la pera_stesura seveso 03/01/18 12:30 pagina 311 archivio italiano di urologia e andrologia 2017; 89, 4 g. la pera, f. de luca, a. guerani, a. palmieri, g. franco 312 therefore are not complete in our opinion. in this study we completed the questionnaires with a meticulous examination of the male genitals. accordingly, we correlate the behavioural component with the medical one; this is something new, opening a wide window on the adolescents’ behaviour. in our opinion, studies that investigate adolescent behaviour should be matched with extensive genital examination. because, as shown in this study, some effects may be confused with the causes. this study underlines the importance of offering an andrological screening to all the family in order to prevent and treat andrological disease and promote male sexual health. this is also a way to promote and raise awareness of the importance among adolescents of andrological prevention, and to reduce the social embarrassment that late diagnosis can involve, as well as to explain to young men that there is a dedicated place to discuss sexual issues (9). another good point is to create a network between the general practitioner and the specialist consultant. a critical point is that those percentages may be underestimates. in fact this study is completely based on questionnaires, lessons and clinical examinations, mainly performed at school. we know really well that, even though public instruction is compulsory in italy until the age of 16, those adolescents who are at a disadvantage economically and socially may not be reached, as they will quit or have never been to school. these people are the ones who need more social and medical assistance. in our modest opinion, this highlights a relatively new figure of the uro-andrologist, being the counterpart of the gynaecologist. this person should play an important role in society and should be independent from the urologist. we all know that in italy, in our national health system (nhs) the priority is given to general urology (prostate, bladder and kidney diseases) ahead of the andrological conditions. in fact they are seen as minority patients, as it for was urology at the beginning when it was still included in general surgery and the urologist was seen as a minor surgeon. this should happen for andrology, and it should have its own independence, separate from urology, with its own unit and allocated budget (9, 10). conclusions 21.1% of adolescents with phimosis and other foreskin sliding abnormalities haven’t had any sexual experience at the age of 18, compared to the same aged boys without phimosis. 89% of boys with phimosis did not receive any andrological consultation during adolescence. the direct consequence of this observation is evidence of an urgent need of a routine andrological consultation in all boys at the beginning and during the adolescence period, as the genital pathologies are quite frequent. also, the data suggests the hypothesis that physical genital pathologies act as a cause of late onset of sexual experience and could be a trigger point of psychological fragility. although we suggest matching physical andrological examinations in all studies dealing with sexual male adolescents’ behaviour, more studies are needed to demonstrate that psychological fragility is the aftermath of andrological disease such as, but not limited to, phimosis and foreskin sliding disorders during adolescence. financial support the administration of regione lazio and the italian society of andrology partially supported this study. acknowledgment we thank for their participation to the andrological campaign and for the andrological screening: barrese f., bitelli m., boffini a., bordacconi s., buonprisco f., chiriatti a., ciletti m., florio m., fraschetti m., fucito g., gandini a., iannotta l., lauretti s., marianantoni z., misuraca l., rizzo g., tassi b., travaglia s., tronino m., sanpalmieri m., santagata e., santini e., vaggi l. we also thank the following general practitioners from ladispoli and cerveteri: alesiani mr., aureli a., d'amico mn., fanini m., faris r., gentili g., gionangeli sebasti i., paliotta c., spaziani b., valeri m. special thanks to the administration of ladispoli and the mayor paliotta c. and to zaccari c. head of primary care of asl roma f. references 1. yang c, liu x, wei gh. foreskin development in 10 421 chinese boys aged 0-18 years. world j pediatr. 2009; 5:312-5. 2. westwood m, pinzon j. adolescent male health. paediatric child health 2008; 13:31-36. 3. rizzotto a. evidenziazione delle anomalie genital esterne alla visita di leva. giornale italiano di andrologia. 1997; 3:107-111. 4. vasilenko sa, ram n, lefkowitz es. body image and first sexual intercourse in late adolescence. j adolesc. 2011; 34:327-35. 5. la pera g, franco giannotti c, taggi f, macchia t. prevalence of sexual disorders in those young males who later become drug abusers. j sex marital ther. 2003; 29:149-56. 6. a pera g, carderi a, marianantoni z, et al. sexual dysfunction prior to first drug use among former drug addicts and its possible causal meaning on drug addiction: preliminary results. j sex med. 2008; 5:164-72. 7. carpenter lm. the ambiguity of “having sex”: the subjective experience of virginity loss in the united states. j sex res. 2001; 38:127-139. 8. trani f, gnisci f, nobile cg, angelillo if. adolescents and sexually transmitted infections: knowledge and behaviour in italy j paediatr child health. 2005; 41:260-4. 9. mondaini n, silvani m, zenico t, et al. genital diseases awareness in young male students: is information necessary to protect them? arch ital urol androl. 2013; 85:14-9. 10. foresta c, pizzol d. he had always wanted to ask an andrologist but had never done so. world j clin cases. 2014; 2:546-51. correspondence giuseppe la pera, md (corresponding author) dr.giuseppelapera@gmail.com department of urology azienda ospedaliera san camillo forlanini, rome, italy francesco de luca, md francescodeluca10@gmail.com department of gynaecological and urological sciences, sapienza university of rome, rome, italy attilio guerani, md dr.attilioguerani@gmail general practitioner, rome, italy alessandro palmieri, md alessandro.palmieri@unina.it department of urology university of naples, naples, italy giorgio franco, md giorgio.franco@libero.it department of gynecological and urological sciences, sapienza university of rome, rome, italy la pera_stesura seveso 03/01/18 12:30 pagina 312 archivio italiano di urologia e andrologia 2017; 89, 3232 original paper narrow band imaging (nbi) cystoscopy and assisted bipolar turbt: a preliminary experience in a single centre roberto giulianelli, barbara cristina gentile, luca albanesi, paola tariciotti, gabriella mirabile c.ur.a., urology department, nuova villa claudia clinic, rome. objective: the aim of this study was to compare, in order to increase our ability to detect bladder cancer, the predictive power of narrow band imaging (nbi) versus white light cystoscopy (wl). the secondary objective was to evaluate how the preoperative use of nbi cystoscopy can increase the ability to detect bladder lesions in terms of status, multi-focality and dimensions. materials and methods: between june 2010 and april 2012, 797 consecutive patients, 423 male and 374 female, affected by suspected bladder cancer lesions, underwent to wl plus nbi cystoscopy and subsequently to wl bipolar gyrus pk (olympus, tokyo, japan) transurethral resection of bladder tumour (wl-turbt). the average follow-up was 24 (16-38) months. mean age was 67.7 yrs. (range 46-88). all the patients underwent by same surgeon to wl resection (wl-turbt) of the previously identified lesions by same surgeon. all the removed tissue was sent separately for histological evaluation after mapping the areas of resection on a topographic sheet. results: in our study we considered 797 patients that matched our inclusion criteria. through the use of wl cystoscopy, we identified 603 patients (75.53%) with suspicious lesions, instead, with the use of light nbi, we found 786 patients with suspicious lesions (98.49%).the use of nbi cystoscopy increases by approximately 30% the specific ability to detect lesions not otherwise visible with wl cystoscopy (or 21.9 and rr 1.30), in particular for patients with lesions size < 3 cm (or 24.00; rr 1.40), unifocal (or: 22.28; rr 1.47) and recurrent (or 58.4; rr 1.34). pathology demonstrated the presence of cancer in 512 (64.2%) patients, of whom 412 (51.8%) were visible both with wl cystoscopy and nbi cystoscopy. in our experience, only 11 (1.38%) lesions were only positive at wl cystoscopy (negative at nbi cystoscopy) thus 501 (62.8%, or 10.13; rr 1.21) patients showed bladder oncological lesions positive at nbi cystoscopy. in these patients, the use the nbi cystoscopy has better highlighted a recurrence (p < 0.005; or 22.8, rr 1.23; 95% ci-1.13 to 0.24) or a lesion < 3 cm (p < 0.05; or 11.4 , rr 1.30; 95% ci-0.18 to 0.29) or a unifocal lesion (p < 0.005; or 10.38, rr 1.34, ci 0.18 to 0.30). conclusions: the use of nbi cystoscopy, significantly increases by approximately 30% our predictive power to identify neoplastic lesions, especially unifocal or < 3 cm or recurrent lesions. following wlturbt, stage, dimension and focaliity are statistically significant determinants (p < 0.001) of the bladder oncological lesions detected by nbi cystoscopy rather than by wl cystoscopy. key words: bladder cancer; narrow band imaging (nbi); cystoscopy; bipolar turbt. submitted 15 august 2017; accepted 18 august 2017 summary no conflict of interest declared. introduction bladder cancer is a very common malignant genitourinary tumour and transitional cell carcinoma accounts for almost 90% of all primary bladder tumours. the standard method used to diagnose bladder cancer and monitor patients in the follow-up is white light (wl) cystoscopy. unfortunately, this method may not be able to detect small papillary lesions and carcinoma in situ (cis) lesions (1). tumours not detected in the course of turbt will appear later as a relapse, and some of them may become invasive. this calls for the development of better endoscopic methods, namely fluorescence (2-4), and narrow banding imaging (nbi) cystoscopy (5). nbi is a technique for improving optical images. it is designed for endoscopy and its purpose is to increase the contrast between mucosal surfaces and microvascular structures without resorting to dyes. this technique is based on a phenomenon by which the depth of light penetration into the mucosa increases as the wavelength increases. in nbi, the tissue surface is illuminated with narrow band light, with wavelengths in the blue and green light spectra (415 nm and 540 nm respectively) (6). the primary objective of this study was to assess the ability of nbi to increase the detection rate of lesions not visible with wl cystoscopy. the secondary objective was to evaluate how the preoperative use of nbi cystoscopy can increase the ability to detect bladder lesions in terms of status, focality and dimensions after turbt, as opposed to wl cystoscopy. materials and methods from june 2010 to april 2012, 797 consecutive patients (pts.), 423 male and 374 female, affected by primary (461 pts, 57.8%), recurrent (336 pts, 42.1%), unifocal (491 pts., 61.6%), multifocals (306 pts., 38.3%), < 3 cm (570 pts., 71.5%) and > 3 cm (227 pts., 28.4%) suspicious non-muscle invasive bladder tumours, underwent wl plus nbi cystoscopy and wl plus nbi bipolar turbt with a bipolar gyrus pk scalpel in saline (turis). the mean follow-up was 24 (16-38) month. indication of suitability for turbt was provided on the basis of the eau guideline 2010. all patients provided written informed consent prior to the study. all procedures were carried out initially by performing a cystoscopy with white light. the characterization of the sites, including the number, size and appearance of the neoplasms, were recorded on a topographic bladder map. doi: 10.4081/aiua.2017.3.232 giulianelli_stesura seveso 28/09/17 10:28 pagina 232 233archivio italiano di urologia e andrologia 2017; 89, 3 narrow band imaging (nbi) cystoscopy and assisted bipolar turbt: a preliminary experience in a single centre subsequently a cystoscopy with nbi was carried out to confirm what had been seen by white light examination, and to report other suspicious areas at nbi light. these, too, were recorded on the topographic bladder map. all endoscopic resections were performed with an gyrus pk scalpel, bipolar generator (olympus, tokyo, japan), in saline, with optics at 30 degrees. resection of each lesion was carried out with white light by the same surgeon who had performed cystoscopy and all histopathological evaluations were performed by the a single pathologist on the basis of 2004 who classification. in order to evaluate the efficacy of nbi vs wl cystoscopy, we conducted a hypothesis test to determine whether the difference between the two proportions of positive results obtained by wl and by nbi (p_wl and p_nbi) was significant. the two-proportion z-test was administered on the overall sample and, after turbt, on the hystologically positive set of patients. the appropriate test assumes a model for matched pairs (7). the analysis was carried out in relation to status (primitive and recurring), focality and dimension of detected lesions. all z-scores (before and after turbt) were largely below the selected significance level (α = 0.05). the related confidence intervals were also calculated. in addition we estimated odds ratio (or) and relative risk (rr) to quantify how strong is the difference between nbi and wl results. logistic regression was applied to predict which lesions were in fact malignant after nbi cystoscopy. multiple linear regression analyses tested the association between different prognostic variables and their impact on the ability to identify bladder lesions following nbi cystoscopy. results in our study we considered 797 patients that matched our inclusion criteria. wl cystoscopy was used to identify 603 patients (75.5%) with suspicious lesions, while the use of nbi following wl allowed identifying a total of 786 patients (98.49%). a total of 1.571 suspicious lesions were identified in 797 patients, some of whom had multifocal lesions. of these lesions, 496 (50.6%) were single lesions and 1.075 (49.3%) multiple lesions. of these 1,571 lesions, 1.337 (85.11%) were identified by wl cystoscopy alone. the subsequent use of nbi light allowed finding 234 lesions (14.89%), not visible otherwise with wl, reaching a total of 1.571 suspicious lesions. the use of nbi cystoscopy increases by approximately 30% the ability to detect lesions not otherwise visible with wl cystoscopy alone (or 21.9 and rr 1.30), particularly in patients with lesion size < 3 cm (or 24.00; rr 1.40), unifocal (or: 22.28; rr 1.47) and recurrent lesions (or 58.4; rr 1.34) (table 1). all 797 patients were subjected to bipolar turbt with gyrus pk (olympus, tokyo, japan). the final histology results demonstrated the presence of cancer in 512 (64.2%) patients (table 2), of whom 412 (51.8%) were visible both with wl cystoscopy and nbi cystoscopy. in our experience, 501 (62.8%) patients showed bladder oncological lesions positive in nbi cystoscopy thus only 11 (1.38%) lesions were only positive at wl cystoscopy. totally, 1,571 cancer lesions were identified as suspicious, 1,051 lesions (66.85%) were positive for malignancy and 520 (33.14%) negative for malignancy. the histology after wlturbt showed the ability of nbi cystoscopy to identify, in more than 20%, a lesion oncologically significant than was not evident at wl cystoscopy (table 2). table 1. wl and nbi cystoscopy results (before turbt). all cases yes no total odds odds ratio absolute risk relative risk nbi positive 786 11 797 66.14 0.985 wl positive 603 194 797 3.087 21.9 0.755 1.304 primitive nbi positive 452 9 461 45.10 0.978 wl positive 354 107 461 3.26 13.79 0.785 1.27 recurrent nbi positive 334 2 336 167.0 0.994 wl positive 249 87 336 2.86 55.34 0.741 1.341 unifocal nbi positive 481 10 491 43.6 0.978 wl positive 325 166 491 1.95 22.28 0.662 1.47 multifocal nbi positive 305 1 306 305.0 0.997 wl positive 277 29 306 9.55 31.93 0.905 < 3 cm nbi positive 560 10 570 56.0 0.982 wl positive 399 171 570 2.33 24.00 0.700 1.404 > 3 cm nbi positive 226 1 227 22.6 0.991 wl positive 203 24 227 8.45 13.3 0.894 1.108 table 2. wl and nbi cystoscopy results (hystologically positive after turbt). all cases yes no total odds odds ratio absolute risk relative risk nbi positive 501 11 512 41.6 0.977 wl positive 412 100 512 4.12 10.1 0.805 1.21 primitive nbi positive 317 9 326 31.6 0.969 wl positive 263 63 326 4.17 7.57 0.807 1.20 recurrent nbi positive 184 2 186 92.0 0.989 wl positive 149 37 186 4.02 22.84 0.801 1.235 unifocal nbi positive 290 10 300 26.2 0.963 wl positive 215 85 300 2.5 10.38 0.717 1.344 multifocal nbi positive 211 1 212 211.0 0.995 wl positive 197 15 212 13.3 16.06 0.929 1.071 < 3 cm nbi positive 309 10 319 30.9 0.989 wl positive 223 85 319 2.70 11.40 0.730 1.326 giulianelli_stesura seveso 28/09/17 10:28 pagina 233 archivio italiano di urologia e andrologia 2017; 89, 3 r. giulianelli, b.c. gentile, l. albanesi, p. tariciotti, g. mirabile 234 thanks to use of the nbi light we identified 500 patients with lesions nbi positive oncologically significant (62.7%; or 10.13; rr 1.21). in particular, nbi cystoscopy improved bladder neoplasms detection rate of wl cystoscopy in recurrent (or 22.8 vs 7.5; rr 1.23 vs 1.20), < 3 cm (or 11.4 vs 7.4; rr 1.30 vs 1.06) and unifocal tumours (or 10.38 vs 16.06; rr 1.34 vs 1.07). the difference in detection rate is not so high as in recurrences in primitive lesions (rr 1.23 vs 1.20). in 512 patients with tumors detected after wl turbt, the use the nbi cystoscopy has more frequently demonstrated a recurrent injury (p < 0.005; 95% ci-1.13 to 0.24) or a lesion < 3 cm (p > 0.05; 95% ci-0.18 to 0.29) or an unifocal lesion (p < 0.005; ci 0.18 to 0.30). it is clear that with the nbi cystoscopy, compared to wl cystoscopy alone, we could identify a statistically significantly greater number of neoplastic lesions, in relation to pathological stage and grade (p < 0.005, ic-95% 0.130.21 and p < 0.005; 95% ci0.14 to 0.24, respectively). in particular, we highlighted an higher number of cis lesions (p < 0.005, ic-95% from 0.48 to 0.92) and hg lesions (p < 0.005; ci-95%. in our experience we identified in the group of 512 patients with bladder cancer confirmed after wlturbt, 88 patients who had bladder neoplastic lesions detected only through the use of nbi cystoscopy (wl cystoscopy negative) with an adjunctive detection rate (adr) of 11.4%. the overall false positive detection rate was 33.14% (521 lesions) and after nbi cystoscopy this rate was 39.44%. using the logistic model, we observed that the use of nbi cystoscopy significantly increases our predictive power to identify lesions not visible with wl cystoscopy: primitive lesions (95% ci 2.97-1.095; p < 0.02), multifocal (95% ci 0.06-012; p < 0.0001), and < 3 cm (95% ci 0.05-0.13; p < 0.001). it is interesting to note that hg (high-grade) neoplasms (95% ci 0.14-0.24; p < 0.001) tend to reach a value very close to significance compared to papillary urothelial neoplasms of low malignant potential (punmp) (95% ci 0.004-0.04; p < 0.005) and low grade neoplasms (low-grade) (95% ci 0.10-0.21; p < 0.001). using nbi cystoscopy, the likelihood of identifying patients with a primitive tumour, compared to patients with a relapse, reached approximately 80% (point estimate 1.790, 95% ci 1095-2927). in a patient with a unifocal tumour, the likelihood of having a bladder tumour detected by nbi cystoscopy increases by about seven times compared with those a multifocal tumour (point estimate 0.153, 95% ci 0.060-0.390). nbi cystoscopy has also proved to be very useful in cis. by comparing the sensitivity, specificity, positive predictive value and negative predictive value (npv) of nbi versus wl cystoscopy for cis lesions, we noticed that sensitivity and npv were the statistically significant values (100%, 95% ci, p < 005, and 80.62%, 95% ci, 100%, 95% ci, p < 005, and 78.35%, respectively). nbi cystoscopy increases the likelihood of detecting a cis lesion by about one and a half times compared to a patient with a pta lesion (p < 0.001). discussion bladder cancer is considered the most expensive tumour both in terms of costs for patients per year and in terms of operating costs per patient. up to 70% of patients with nmibc will develop a recurrence after turbt (8). photodynamic diagnosis with hexaminolevulinate blue light cystoscopy has made significant advances in terms of rates (9) of diagnostic accuracy and recurrence for the detection of cis lesions (10), as well as pta and pt1 tumours (11). however, some questions have been raised as regards the cost-effectiveness of this approach. numerous studies have demonstrated the ability to display improved images of the surface layers of the various apparatuses using nbi (10, 12-18). nbi is a diagnostic imaging technique that improves the contrast between mucosal surfaces and microvascular structures, based on the wavelength-dependent increase in the depth of light penetration into the mucosa, without additional costs to conventional cystoscopy and without lengthening the operating time. in our experience, using wl and nbi cystoscopy together, we have identified 234 lesions (14.1%) that wl cystoscopy alone would not have otherwise been able to identify. however, the essential result is not so much the number of lesions that can be identified using nbi as opposed to the number of those visible with wl alone, but rather how many of these are neoplasms. of these 234 lesions identified with nbi alone, as many as 127 were bladder tumours (12.17%) in 88 patients (11,4%). comparing our experience with the data available in the literature, we were able to find some interesting data. the experience of bryan et al. (5) showed a greater capacity to identify lesions (∆ = -7.15%) compared to our results, while our technique showed an improvement (∆ = +3.81%) compared to the results of herr et al. (19) in fact, we detected 12.17% of lesions not otherwise detectable, by wl cystoscopy, thus placing our experience between the two aforementioned studies. to better understand the diagnostic efficacy of the nbi compared to wl cystoscopy an analysis of the odds ratio was performed (positive results against the negatives for each type of investigation). the two methods of cystoscopy did not change the state of the patient on which they were performed. therefore 797 cases can be considered as a sample to which two different but non-interacting methods were administered. the odds ratio, measuring the frequency of success of a technique respect to another, in our case highlights the success of nbi. in fact a value greater than 1 indicates greater effectiveness of nbi in the detection of lesions against the non-detection. if we consider all the cases, the calculated value of or = 21.90 (table 1) shows a strong prevalence of nbi identification of lesions. a more intuitive interpretation of the results is made up of the relative risk. in fact, this index relates the absolute risk (ratio of successes and the total number of cases) of the two methods. in this way it is possible to assess with greater immediacy the effectiveness of the method nbi compared to wl. the use of nbi cystoscopy has therefore allowed improving our ability to overall detect lesions not otherwise visible with wl cystoscopy alone (adr= +30%) in terms of focality (unifocals: or 22.28; rr 1.47) as well as dimensions < 3 cm, or 24.00; rr 1.40) and status (recurrences: or 58.4; rr 1.34). giulianelli_stesura seveso 28/09/17 10:28 pagina 234 235archivio italiano di urologia e andrologia 2017; 89, 3 narrow band imaging (nbi) cystoscopy and assisted bipolar turbt: a preliminary experience in a single centre following wl turbt, we observed 500 pts with nbi bladder oncological lesions, with a adr of 20%. the use of nbi cystoscopy, significantly increases our predictive power to identify lesions not visible with wl cystoscopy, especially for unifocal lesions (p < 0.005, ic-95%0.180.30), those < 3 cm (p < 0.005, ic-95% 0.18-0.29) and recurrent lesions (p < 0.005, ic-95% 0.13-0.24). similarly, through the use of nbi light, we observed that, as regards pathologic stage and grade, we registered an overall increase in bladder lesion detection rate (p < 0.005, ic-95% 0.13-0.21 and p < 0.005; ic-95% 0.140.24, respectively). in our experience, the use of nbi cystoscopy significantly increased the ability to detect both cis lesions (p < 0.0001) and hg (p < 0.005) (table c: d-e) compared to wl cystoscopy. the relative risk (rr) to identify a bladder tumour with nbi turbt is 3 times greater in the case of a pta lg lesion and about 8 times greater if the lesion is a cis. in our experience, as well as in herr’s experience (19), the use of nbi cystoscopy in comparison to wl cystoscopy was particularly useful in the identification of cis lesions, showing a sensitivity and npv of 100% vs. 80.62% and 100% vs. 78.35% (p < 0.05) respectively. by contrast, we recorded a non-significant specificity and ppv. in our experience, the overall false positive detection rate was 33.14% (521 lesions) and after nbi cystoscopy this rate amounted to 39.44%. these data overlap with other international experiences. conclusions this is the first study in the literature in which the ability of nbi cystoscopy to increase the ability to detect suspicious bladder lesions was compared with the use of wl cystoscopy alone in the same patient. the use of nbi cystoscopy, significantly increases our predictive power to identify lesions not visible with wl cystoscopy, especially for unifocal lesions, those < 3 cm and recurrent lesions. following wl turbt, status, dimension and focality are statistically significant determinants in order to detect bladder oncological lesions by nbi cystoscopy rather than wl cystoscopy. in conclusion, nbi is an effective method for the identification of bladder lesions and can be useful in supporting wl cystoscopy. references 1. loidl w, schmidbauer j, susani m, et al. flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance? eur urol. 2005; 47:323-6. 2. grossman hb, gomella l, fradet y, et al. a phase iii multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. j urol. 2007; 178:62-7. 3. fradet y, grossman hb, gomella l, et al. a comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase iii, multicenter study. j urol. 2007; 178:68-73. 4. denzinger s, burger m, walter b, et al. clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. urology. 2007; 69:675-9. 5. bryan rt, billingham lj, wallace dma. narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder. bju int. 2007; 101:702-6. 6. kuznetsov k, lambert r, rey jf. narrow-band imaging: potential and limitations. endoscopy 2006; 38:76-81. 7. agresti a an introduction to categorical data analysis, 2nd edn, j.wiley, 2007. 8. allard p, bernard p, fradet y, et al. the early clinical course of primary ta and t1 bladder cancer: a proposed prognostic index. br j urol. 1998; 81:692-8. 9. brausi m, collette l, kurth k, et al. variability in the recurrence rate at first follow-up cystoscopy after tur in stage ta-t1 transitional cell carcinoma of the bladder: a combined analysis of seven eortc studies. eur urol. 2002; 41:543. 10. kockelbergh js. the role of photodynamic diagnosis in the contemporary management of superficial bladder cancer. rc bju int. 2005; 96:17-21. 11. witjes ja, douglass j. the role of hexaminolevulinate fluorescence cystoscopy in bladder cancer. nat clin pract urol. 2007; 4:542-549. 13. jocham d, stepp h, waidelich r. photodynamic diagnosis in urology: state-of-the-art. eur urol. 2008; 53:1138-1148. 14. hamamoto y, endo t, nosho k, et al. usefulness of narrowband imaging endoscopy for diagnosis of barrett’s esophagus. j gastroenterol. 2004;39:14-20. 15. machida h, sano y, hamamoto y, et al. narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study. endoscopy. 2004; 36:1094-1098. 16. nakayoshi t, tajiri h, matsuda k, et al. magnifying endoscopy combined with narrow band imaging system for early gastric cancer: correlation of vascular pattern with histopathology (including video). endoscopy 2004; 36:1080-1084. 17. shibuya k, hoshino h, chiyo m, et al. high magnification bronchovideoscopy combined with narrow band imaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer. thorax. 2003; 58:989-995. 18. yoshida t, inoue h, usui s, et al. narrow-band imaging system with magnifying endoscopy for superficial esophageal lesions. gastrointest endosc. 2004; 59:288-295. 19. herr hw, donat sm. a comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences; bju int. 2008; 102:1111-1114. correspondence roberto giulianelli, md giulianelli0764@gmail.com barbara cristina gentile, md bcgentile@libero.it luca albanesi, md lacalbanesi@hotmail.com paola tariciotti, md (corresponding author) paola.tariciotti@libero.it gabriella mirabile, md gbrmr78@yahoo.com c.ur.a., urology department, nuova villa claudia clinic, rome, italy giulianelli_stesura seveso 28/09/17 10:28 pagina 235 249archivio italiano di urologia e andrologia 2018; 90, 4 original paper vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: technique and results ramazan topaktaş 1, ahmet ürkmez 1, musab ali kutluhan 1, "smail başıbüyük 2, şinasi yavuz önol 3 1 haydarpaşa numune training and research hospital, department of urology, istanbul, turkey; 2 beylikdüzü kolan hospital, department of urology, istanbul, turkey; 3 onol urology center, department of urology, istanbul, turkey. objective: retropubic radical prostatectomy (rrp) is still widely used in clinical practice in localized prostate cancer because of its high oncological success. the aim of this study was to define the continence status in patients where rhabdosphincter was included in the vesicourethral anastomosis. materials and methods: between november 2004 and september 2010, 90 cases who underwent rrp by the same surgeon in our clinic were taken into the study. in all cases vesicourethral anastomosis was performed include the rhabdosphincter. the anastomosis was performed with mean 2.9 (0-7) interrupted no 2-0 vicryl sutures, depending on the angulation of symphysis pubis and pelvic cavity. pad test was performed to all patients at 1, 3, 6 and 12 months postoperatively. we defined patients as ‘continent’ when they no need pad, as ‘mild incontinence’ when they use only one pad daily, as ‘moderate incontinence’ when they use two or three pads daily and as ‘severe incontinence’ when they use more than three pads daily. results: preoperative total psa value was 12.2 ng/ml (range: 2.7-84 ng/ml). preoperative prostate biopsy results were found that gleason scores were 5, 6, 7 and 8 in 7, 53, 21, 9 patients, respectively. mean operation and urethral catheter removal time was 103 minutes (60-200) and 14,6 days (9-28), respectively. mean hospital stay was 4.6 days (2-20). according to results of postoperative pad tests, 38 (42.2%), 48 (53.3%), 55 (61.1%) and 75 (83.3%) patients were defined as continent in first, third, sixth and twelfth months, respectively. conclusions: we think that, our novel technique of vesicourethral anastomosis in standard rrp provides more optimal urethral position during fixation of pelvic floor and urethra, protect caudal retraction, preserve functional urethral length. also strong full thickness stitch on urethra provides better urinary continence by hanging urethra in our patients. although our early continence rate is better, our long term continence rate is similar to literature. key words: retropubic radical prostatectomy; vesicourethral anastomosis; incontinence; rhabdosphincter. submitted 3 june 2018; accepted 19 july 2018 summary no conflict of interest declared. prostate cancer is organ defined in almost 40% of cases and gold standard treatment is radical prostatectomy (rp) if patient has ten-year life expectancy (2). after 1970s this procedure has been standard treatment especially after walsh’s contributions (3). although this surgical procedure has important efficiencies it has also morbidities that should be considered. to get rid of morbidities and increase efficiency some modified techniques have been tried over years. although in recent decades, laparoscopic and robot-assisted laparoscopic rp have been utilized as alternatives to traditional open surgery, rrp is still widely used in clinical practice (4). in all surgical techniques main aim is to get oncologic control and at the same time to maintain erectile function and continence which otherwise affected can decrease patient quality of life. perioperative and post-operative early complications of radical prostatectomy are bleeding, rectal injury, deep venous thrombosis, pulmonary emboli and lymphocele. late complications are urinary incontinence, erectile dysfunction and anastomotic stricture. most important complication that affect quality of life is urinary incontinence. according to studies incidence is between 5%30% (5, 6). although older studies indicate higher incidence of urinary incontinence in recent years with better knowledge about pelvic anatomy this incidence has decreased. vesicoureteral anastomosis is one of the most important step in radical prostatectomy and if it is not done properly it leads urinary leak, urine accumulation in surgical field and prolonged drainage (7). on the other hand, it leads periurethral fibrosis, bladder neck stricture and urinary incontinence (8). recently improvements in techniques of vesicoureteral anastomosis provides decrease in incidence of stricture and incontinence. urinary continence recovery is a fundamental goal for patients rrp and several surgical techniques, mainly based on musculofascial posterior and/or anterior ligaments reconstructions, have been proposed with the aim of improving urinary continence recovery. aim of our study is to evaluate post-operative urinary incontinence in patients who underwent rrp and had vesicoureteral anastomosis that includes rhabdosphincter. doi: 10.4081/aiua.2018.4.249 introduction prostate cancer is common in man and is the second most common cause of death after lung cancer. incidence of prostate cancer incline after 50 years old and change in different countries according to diet, ethnicity, life style and screening protocols (1). topaktas_stesura seveso 10/01/19 16:03 pagina 249 archivio italiano di urologia e andrologia 2018; 90, 4 r. topaktaş, a. ürkmez, m. ali kutluhan, ". başıbüyük, ş. yavuz önol 250 patients and methods ninety patient who underwent rrp because of clinically localized prostate cancer between november 2004 and september 2010 in bezmialem vakıf university medicine faculty hospital urology clinic was included in our study. local ethics committee approval was taken for study and written consent for each patient was also taken. preoperative and postoperative information of all patient was recorded prospectively. exclusion criteria were: previous urethral or prostatic endoscopic procedures, preoperative urinary incontinence and concomitant neurological diseases (e.g. parkinson disease). bone scan was performed for intermediate and high-risk prostate cancer group and also patients who were symptomatic. in some patients mri was used for confirmation of bone scan lesion. one experienced surgeon performed all surgeries and bladder neck preserved as much as possible. when indicated lymph node dissection was performed and in proper patients nerve sparing technique was used 2-0 vicryl suture was used in vesicourethral anastomosis. sutures placed on urethra including rhabdospinchter from out to in and in to out for bladder (figure 1). 22 f foley catheter was placed. a watertight test was performed at the end of the procedure. age, psa levels, prostate volumes and prostate biopsy results of all patients were recorded preoperatively. operation time, urethral catheterization time, retrivel of drenage time, hospital stay, suture number for vesicoureteral anastomosis and perioperative bleeding was recorded for all patient. also, post-operative follow up period, pathological parameters and complications were recorded. for all patients postoperative third-generation cephalosporin, low-molecular-weight heparin, and elasto-compressive stockings were used for prophylaxis of infections and thromboembolic events, respectively. in postoperative period patients were followed up regularly for urinary incontinence. after retrieval of urethral catheter pad test were used for evaluation of urinary incontinence in 1, 3 and 12 months. patients who didn’t use pad in a day described as continent, patients who used one pad a day described as mild incontinent, patients who used 2-3 pad a day described as moderate incontinent and patients who used 4 pad and more described as severe incontinent. results patient number, age, prostate volume, preop psa values, prostate biopsy results, surgical parameters, hospitality and follow up period were summarized in table 1. 48.8% (44) of patient had history of cigarette smoking. mean operative bleeding was 780 ml (150-3500 ml) and 32,2% (29) of patient had blood transfusion. in one patient myocardial infarction occurred in postoperative second day and transferred to coronary intensive care unit. in this patient urethral catheter was taken off at postoperative 28th day. average suture number for vesicourethral anastomosis was 2.9 (0-7) and in two patient there was no suture (figure 2). in three patients (3.3%) acute urinary retention occurred after urinary catheter retrieval and these patients were catheterized with 12f catheter for three more day. in four patients (4.4%) rectal damage occurred in operation and primer reconstruction with two layers without colostomy was performed. in one patient omental flap with pedicul was used for strengthening rectal repair. in one patient during bladder neck dissection ureteral damage occurred and repaired intraoperatively with ureteroneocystostomy. table 1. preoperative clinical features, operative and early postoperative results of patient. mean ± standard deviation (distribution) or number total number of patients 90 age (year) 64.3 ± 6.01 (51-78) prostate volume (ml) 49.2 ± 24.18 (20-160) preoperative serum psa level (ng/ml) 12.2 ± 9.54 (2.7-84) preoperative gleason score 6.3 ± 0.42 (5-8) operation time (minute) 103 ± 52 (60-200) "ntraoperative bleeding (ml) 780 ± 723.25 (150-3500) drainage time (day) 4.3 ± 2.82 (2-19) urethral catheterization time (day) 14.6 ± 4.39 (9-28) hospital stay (day) 4.6 ± 7.89 (2-29) mean follow up (month) 15.3 ± 2.25 (14-25) figure 1. suture that involves the rhabdospinchter. figure 2. suture numbers for vesicourethral anastomosis. sutureless 1-3 suture 4-6 suture 7 suture 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 continent mild incontinence moderate incontinence severe incontinence 1. ay 3. ay 6. ay 12. ay n um be r of p at ie nt s n um be r of p at ie nt s topaktas_stesura seveso 10/01/19 16:04 pagina 250 after catheter retrivel bladder neck stenosis developed in 10 patients (11,1%) after a mean of 4.3 months (range 27 months) and treated with endoscopic incision. according to pathologic reports 13 (14.4%) patient had pt2a, 15 (16.6%) had pt2b, 28 (31.1%) had pt2c, 27 (30%) had pt3a and 7 (7.7%) patient had pt3b. on the other hand, 6 (6.6%) patient had positive surgical margin and 84 (93.3%) patient had negative surgical margin. in 6 patients with surgical margin positivity, 4 positivity was in prostatic apex while 2 positivity was in other regions of the prostate at first year of follow up 75 (83.3%) patient was continent, 7 (7.7%) patient had mild urinary incontinence, 5 (5.5%) patient had moderate urinary incontinence and 3 (3.3%) patient had severe urinary incontinence. the continence status of the patients according to the postoperative month was summarized in figure 3. seven patients with moderate incontinence and three patients with severe incontinence were found to have endoscopic procedures due to bladder neck stenosis after rrp at the first year of follow-up discussion the most important factor that affect patient’s quality of life after rrp is urinary continence status and early recovery of continence increases patient satisfaction (9). although there was high rate of urinary incontinence in first years of radical prostatectomy prevalence has decreased over years with better understanding of pelvic anatomy, increase in experience, technology and surgical techniques. although there are many studies that try to explain which factors like nerve sparing surgery, tabularization of bladder neck, anastomosis suture number and laparoscopic continuous suturing effect post prostatectomy incontinence, we still can’t estimate which patient has urinary incontinence after radical prostatectomy (1012). one of the most important step in radical prostatectomy is vesicourethral anastomosis. general principles for good anastomosis are watertight, non-stretch, anastomoses that provide the best urethral length and mucosa to mucosa anastomosis several surgical techniques have been proposed in the recent years, with the aim of reducing the urinary continence recovery time and/or improving long-term urinary continence rates. some authors indicated that nerve sparing surgery had positive affect on recovery of urinary continence (12). on the other hand, few studies indicated that nerve sparing surgery had no effect on urinary continence (13). in summary nerve sparing surgery has positive contribution on urinary continence. in our study we did not evaluate the nerve-sparing technique variable in our study this deficiency can cause misconceptions. rhabdospinchter is major structure that influence continence anatomically. it extends like ω-shaped from membranous urethra to prostatic apex anterolaterally. in normal conditions, the urethral sphincter is supported anteriorly by puboprostatic and pubourethral suspensory components, laterally by the medial portion of the levatori ani muscle forming a hammock around the urethra, and by the ischioprostatic ligaments. in our study we placed anastomotic sutures deeply unlike the traditional rrp described by walsh especially in anterior urethra where intense rabdosphincter that surrounds urethra exist (3). we suppose that anastomotic suture that includes rhabdosphincter provides almost original urethral length, prevent caudal retraction of urethra and provide better anatomic positioning of urethra and bladder on pelvic floor. in patients with our technique early functional results are better than literature but long-term outcomes are same. proper and well done apical dissection leads to a better appearance of rhabdosphincter by protecting it. in 2005 montorsi et al. demonstrated that well done apical dissection in nerve sparing surgery protects rhabdosphincter and after catheter retrieval 44% of patient was continent (14). in our study apical surgical margin positivity was seen only in four (4.4%) patient. prevalance of apical surgical margin positivity in literature is between 6.5%-38% (15). we think that well done apical dissection for protecting rhabdospincter provides better continence status. rocco et al. stated that restoration of rhabdosphincter posteriorly or in other word placing rocco sutures provides retraction of rhabdospinchter caudally and prevents separation at posterior median raphe (16). in this study 250 patient who underwent posterior rhabdospinchter repair were compared to 50 patient who didn’t. at the third month of follow up incontinence rate was 85.2% in first group who underwent rhabdospincter repair while it was 46% in control group (16). long term incontinence rate was same in both groups (94% vs 90%) and rhabdospinchter repair didn’t cause additional complication. there are conflicts in studies which evaluate the relationship between incontinence and intraoperative hemorrhage. in some studies, there was no relationship between intraoperative hemorrhage and post prostatectomy incontinence. on the other hand, some studies reported that there was significant relationship between intraoperative hemorrhage and post prostatectomy incontinence (13, 17). intraoperative hemorrhage alone is not a predictive factor for post prostatectomy incontinence without evaluation of other surgical factors. in our 251archivio italiano di urologia e andrologia 2018; 90, 4 vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: technique and results figure 3. pad test classification according to months after catheter removal. topaktas_stesura seveso 10/01/19 16:04 pagina 251 archivio italiano di urologia e andrologia 2018; 90, 4 r. topaktaş, a. ürkmez, m. ali kutluhan, ". başıbüyük, ş. yavuz önol 252 study at first year of follow up only 2 patients out of 15 patient who had mild, moderate and severe incontinence had more than 1000 cc intraoperative bleeding. some studies stated that urethral length should be kept as long as possible for the recovery of continence after rrp and too many sutures for anastomosis shortens urethral length (18). additionally, some studies indicated that less suture number for vesicourethral anastomosis had positive effects on urinary continence and bladder neck stenosis (19). in our study mean suture number was 2.9 (0-7). we think that too many sutures for anastomosis has negative effects on urethral length. another topic related to continence is preservation of bladder neck in radical prostatectomy. many authors investigated relationship between urinary continence and preservation of bladder neck. licht et al. reported in their study which includes 206 patients that preservation of bladder neck didn’t have positive affect on urinary continence, but it was related to less bladder neck stenosis (20). another study indicated that 24 patient who had bladder preserving radical prostatectomy had early recovery of urinary incontinence (21). when we look at these studies, the continence effect of preservation of internal sphincter is to passively keep urine above in the storage phase. in our study we didn’t perform bladder neck preserving rrp and widely resected bladder neck with preservation of ureteral orifices. preservation of puboprostatic ligaments is another topic which can be related to urinary incontinence. some authors indicated positive effects of preservation of puboprostatic ligaments on post prostatectomy incontinence. poore et al. preserved puboprostatic ligaments in 18 patients and compared them to control group which includes 25 patients (22). as a conclusion he founded early continence recovery in patients who underwent puboprostatic ligament preservation. in another study patients were divided into three groups. in first group bladder neck preserving surgery was done in second group puboprostatic ligament preserving surgery was done and to last group both bladder neck and puboprostatic preserving surgery was performed (23). there was no significant difference between three groups in long term urinary incontinence. but bladder neck preserving group had earlier urinary continence than ligament preserving group. in another study sling technique was performed by suturing bladder neck to pubic bone and significant earlier continence rates were indicated according to control group (24). in our study we didn’t perform puboprostatic ligament preserving surgery. but we think that wide suturing in anterior urethra provides normal anatomic position of urethra and by this way it can help external sphincter functions by preventing urethral hypermobility. lack of control group, randomization and the small number of patients included in this preliminary analysis could be considered as the main limitations of the present study. conclusions urinary incontinence after radical prostatectomy affects patients’ quality of life and need to be treated early. recovery of urinary continence depends on patient selection, surgical techniques and definition of continence. we think that by modifications in our vesicourethral anastomosis technique; urethra is placed more anatomically on pelvic floor; caudal retraction of urethra is prevented and by this way functional urethral length stays long and especially wide suturing on anterior urethra sling the urethra anteriorly. according to our experience placing vesicourethral anastomotic suture along with rhabdospinchter is easy to perform. we also think that it is safe and shortens operation time and on the same time offers promising functional results. multicentered, randomized controlled wide series is needed for these topics. references 1. jemal a, tiwari rc, murray t, et al. canser statistics. canser j clin. 2004; 54:8-29. 2. siegel r, naishadham d, jemal a. cancer statistics, 2013. ca cancer j clin. 2013; 63:11-30. 3. walsh pc, lepor h, eggleston jc. radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. prostate. 1983; 4:473-85. 4. gandaglia g, sammon jd, chang sl, et al. comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. j clin oncol. 2014; 32:1419-26. 5. kundu sd, roehl ka, eggener se, et al. potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies. j urol. 2004; 172:2227-31. 6. walsh pc, marschke p, ricker d, burnett al. patient-reported urinary continence and sexual function after anatomic radical prostatectomy. urology. 2000; 55:58-61. 7. arslan m, tuncel a, aslan y, kozacioglu z, et al. comparison of the urethrovesical anastomoses with polyglecaprone (monocryl®) and bidirectional barbed (v-loc 180®) running sutures in laparoscopic radical prostatectomy. arch ital urol androl. 2014; 86:90-4. 8. kylmala t, kaipia a, matikainen m. management of prolonged urinary leakage at the urethra-vesical anastomosis. urol int. 2005; 74:298-300. 9. castle ep, andrews pe, itano n, et al. male sling postprostatectomy incontinence: mean follow up 18 months. j urology. 2005; 173:1657-60. 10. sacco e, prayer-galetti t, pinto f, et al. urinary incontinence after radical prostatectomy: incidence by definition, risk factors and temporal trend in a large series with a long-term follow-up. bju int. 2006; 97:1234-41. 11. lee se, byun ss, lee hj, et al. impact of variations in prostatic apex shape on early recovery of urinary continence after radical retropubic prostatectomy. urology. 2006; 68:137-41. 12. burkhard fc, kessler tm, fleischmann a, et al. nerve sparing open radical retropubic prostatectomy--does it have an impact on urinary continence? j urol. 2006; 176:189-95. 13. lepor h, kaci l. the impact of open radical prostatectomy on continence and lower urinary tract symptoms: a prospective assessment using validated self-administered outcome instruments. j urol. 2004; 171:1216-9. 14. montorsi f, salonia a, suardi n, et al. improving the preservation of the urethral sphincter and neurovascular bundles during open radical retropubic prostatectomy. eur urol. 2005; 48:938-45. topaktas_stesura seveso 10/01/19 16:04 pagina 252 15. kim a, kim m, jeong su, et al. level of invasion into fibromuscular band is an independent factor for positive surgical marginand biochemical recurrence in men with organ confined prostate cancer. bmc urol. 2018; 18:7. 16. rocco f, carmignani l, acquati p, et al. early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. eur urol. 2007; 52:376-83. 17. eastham ja, kattan mw, rogers e, et al. risk factors for urinary incontinence after radical prostatectomy. j urol. 1996; 156:1707-13. 18. myers rp. male urethral sphincteric anatomy and radical prostatectomy. urol clin north am. 1991; 18:211-27. 19. mazaris em, chatzidarellis e, varkarakis im, et al. reducing the number of sutures for vesicourethral anastomosis in radical retropubic prostatectomy. int braz j urol. 2009; 35:158-63. 20. licht mr, klein ea, tuason l, levin h. impact of bladder neck preservation during radical prostatectomy on continence and cancer control. urology. 1994; 44:883-7. 21. gaker dl, gaker lb, stewart jf, gillenwater jy. radical prostatectomy with preservation of urinary continence. j urol. 1996; 156:445-9. 22. poore re, mccullough dl, jarow jp. puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy. urology. 1998; 51:67-72. 23. deliveliotis c, protogerou v, alargof e, varkarakis j. radical prostatectomy: bladder neck preservation and puboprostatic ligament sparing-effects on continence and positive margins. urology. 2002; 60:855-8. 24. kojima y, hamakawa t, kubota y, et al. bladder neck sling suspension during robot-assisted radical prostatectomy to improve early return of urinary continence: a comparative analysis. urology. 2014; 83:632-9. 253archivio italiano di urologia e andrologia 2018; 90, 4 vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: technique and results correspondence ramazan topaktaş, md (corresponding author) ramazantopaktas@yahoo.com ahmet ürkmez, md ahmeturkmez@hotmail.com musab ali kutluhan, md dr.musab151@hotmail.com haydarpaşa numune training and research hospital, clinic of urology, "stanbul, turkey tıbbiye street no:23 34668 uskudar/istanbul "smail başıbüyük, md dr.ismailbb@gmail.com beylikdüzü kolan hospital, department of urology, istanbul, turkey şinasi yavuz önol, md onolurology@yahoo.com onol urology center, department of urology, istanbul, turkey topaktas_stesura seveso 10/01/19 16:04 pagina 253 cop+ed+fisse 2006 207archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.207 non-invasive removal of self-locking entrapped nephrostomy tubes fabio campodonico 1, umberto geremia rossi 2, marco ennas 1, alessandro valdata 2, antonia di domenico 1, francesco pinna 2, carlo introini 1 1 urology unit, ospedale galliera, genova, italy; 2 interventional radiology unit, ospedale galliera, genova italy. introduction: the removal of an encrusted nephrostomy tube can be a challenging maneuver. urological literature is very bare in detailing techniques for removal of entrapped percutaneous catheters. we present a simple, safe and non-invasive technique of nephrostomy removal using a vascular introducer sheath, useful to manage complicated situations such as nephrostomies blocked for severe encrustations or disabled in their self-locking system. surgical technique: the nephrostomy tube is cut and the stump is passed with a suture needle. the suture is passed through the inner vascular introducer sheath tip, and the introducer is then removed. the introducer sheath is advanced over the nephrostomy until joining the pigtail segment, under fluoroscopy guidance. thus the suture is pulled out with strenght to contrast the opposite stiffness of the encrusted coil, until the nephrostomy has safely come out. comment: the sheath exchange technique is quick, involves less manipulation through the perirenal fascia and kidney, and is suitable for different conditions of entrapped nephrostomies. key words: nephrostomy tube; encrustation; vascular sheath; percutaneous nephrostomy. submitted 2 march 2020; accepted 15 march 2020 summary introduction nephrostomy tube is a common device used in several urological procedures during urgent or elective surgery. however, a number of complications can occur to patients such as urinary infections, bleeding, nephrostomy malfunction due to displacement or tube encrustation. moreover, the calcified tube disables the release system in case of a self-locking nephrostomy. thus, the removal of an encrusted nephrostomy tube can be a challenging maneuver. urological literature is very bare in detailing techniques for removal entrapped percutaneous catheters (1). we present a simple, non-invasive technique of nephrostomy removal, useful to manage complicated situations. notes of surgical technique when nephrostomy tube substitution is impossible for severe encrustation, firstly a guidewire should be used tapping the tip through the tube, under fluoroscopy guidance. when the tube patency is not achieved, the rigid stump of the guidewire can be used in the same way. however, in case of a self-locking nephrostomy tube, the use of guidewire is worthless and the release system could be enabled by encrustations. in both conditions, a non-invasive technique of nephrostomy removal is possible using a safety technique. as a consequence of an 8 french malfunctioning nephrostomy, a vascular introducer sheath of 9 french diameter and 10 cm long (radifocus® introducer ii, terumo europe, leuven, belgium) is used with the following steps. the stopcock of the tube is cut and the stump is passed with a needle of a 2/0 silk suture (figure 1a). the silk suture is passed through the inner vascular introducer sheath tip (figure 1b), and the introducer is then removed (figure 1c). the introducer sheath is advanced over the nephrostomy by threading the suture through the tube in order to maintain a straight position (figure 1d). the sheath is advanced progressively until joining the pigtail segment (figure 1e), under fluoroscopy guidance, thus the suture is pulled out with strenght to contrast the opposite stiffness of the encrusted coil, until the nephrostomy is removed (figure 1f). once the encrusted nephrostomy is removed, the introducer sheath may be left in place acting as a guide for a new nephrostomy tube. radiologic steps are summarized in figure 2. discussion a few percutaneous techniques have been proposed in non-urological literature. canby-hagino et al. reported the intraluminal pneumatic lithotripsy. the lithotripsy probe is directly inserted through the nephrostomy encrusted lumen, acting like a mini-jackhammer (2). a similar technique was reported by mangera et al. by using a 1-mm lithoclast probe. the lithotripsy is gently carried on by pulling the nephrostomy onto the lithoclast. an intra and extraluminal fragmentation is done along the straight portion of the tube, under radiological control, to avoid a dangerous exit of the lithoclast probe into the kidney (3). baron and mcclennan firstly reported the simple exchange of catheters using an angiographic catheter sheath. they suggest to leave the sheath on the nephrostomy next to the stopcock of the new pigtail catheter (4). pollack reported on two methods to remove an encrusted nephrostomy. the first permits to remove a tube encrusted along the external tract, but patent in transparietal and coiled segments. the second is similar to our technique, based on 12introini-campodonico_stesura seveso 24/09/20 14:23 pagina 207 archivio italiano di urologia e andrologia 2020; 92, 3 f. campodonico, u.g. rossi, m. ennas, a. valdata, a. di domenico, f. pinna, c. introini 208 the use of a vascular sheath (5). farooq et al. depicted in details the technique employing the angiographic catheter sheath, however in an interventional radiology context (6). finally, studies using a similar technique are very few (46), and mainly refer to the expertise of interventional radiologists in materials and techniques they use for percutaneous retrieval of intravascular foreign bodies (7). our report, however, has two points to be highlighted: this is the first description appearing in urological literature and the nephrostomy tubes we used was a self-locking type, thus resulting in a complicated condition. the technique depicted showed to be useful, simple and safe in the most difficult cases of occluded and entrapped nephrostomy tubes. as reported by baron, “the sheath exchange method is quicker and involves less manipulation through the perirenal fascia and kidney, less fluoroscopy time, and ensures preservation on the tract for direct insertion of the new nephrostomy tube”. when non-invasive maneuvers of nephrostomy removal fail, choice of treatments can be extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous or open surgery. the management of nephrostomy tubes is a common urological task. the urologist should be confident with the different problems encountered, and the technique reported could implement the practical expertise. aknowledgement we wish to thank carlo oliveri and lino squillace for technical assistance. references 1. alnadhari i, alwan ma, salah ma, ghilan am. treatment of retained encrusted ureteral double-j stent. arch ital urol androl. 2019; 18; 90:265-269. 2. canby-hagino ed, caballero rd, harmon wj. intraluminal pneumatic lithotripsy for the removal of encrusted urinary catheters. j urol. 1999; 162:2058-60. 3. mangera a, mehta s, hastie kj, et al. lithoclast removal of an encrusted nephrostomy tube . ann r coll surg engl. 2010; 92:353-4. 4. baron rl, mcclennan bl. replacing the occluded percutaneous catheter. radiology. 1981; 141:824. 5. pollack hl, banner mp. replacing blocked or dislodged percutaneous nephrostomy and ureteral stent catheters. radiology. 1982; 145:203-5. 6. farooq a, agarwal s, vaughan j. safe removal of an ecrusted nephrostomy tube using a vascular sheath: a technique revisited. cardiovasc intervent radiol. 2013; 36:820-3. 7. rossi ug, rollandi ga, ierardi am, et al. materials and techniques for percutaneous retrieval of intravascular foreign bodies. j vasc access. 2019; 20:87-94. figure 1. steps of removal of entrapped nephrostomy. a) the stopcock of the tube is cut and the stump is passed with a needle of a 2/0 silk suture; b) the silk suture is passed through the inner vascular introducer sheath tip; c) the introducer is removed; d) the introducer sheath is advanced over the nephrostomy by threading the suture through the tube; e) the sheath is advanced until joining the pigtail segment; f) the suture is pulled out with strenght until the nephrostomy is removed; g) the nephrostomy removed. figure 2. radiological steps. correspondence fabio campodonico, md (corresponding author) fabio.campodonico@galliera.it marco ennas, md marco.ennas@galliera.it antonia di domenico, md antonia.didomenico@galliera.it carlo introini, md carlo.introini@galliera.it urology unit, ospedale galliera via volta 8, 16128 genova (italy) alessandro valdata, md alessandro.valdata@galliera.it umberto geremia rossi, md umberto.rossi@galliera.it francesco pinna, md francesco.pinna@galliera.it interventional radiology unit, ospedale galliera via volta 8, 16128 genova (italy) 12introini-campodonico_stesura seveso 24/09/20 14:23 pagina 208 263archivio italiano di urologia e andrologia 2019; 91, 4 case report renal autotransplantation: a final option to preserve the kidney after an iatrogenic ureteral injury napoleon moulavasilis 1, ioannis katafigiotis 1, dimitris staios 3, christos nikolaidis 2, spyridon vernadakis 2, john bokos 2, ioannis anastasiou 1 1 1st department of urology, national and kapodistrian university of athens, laiko hospital, athens, greece; 2 renal transplant unit, laiko hospital, athens, greece; 3 urologist, laiko hospital, athens, greece. background: ureteral injuries are not very common and can occur after many surgical procedures. kidney salvage is desirable. renal autotransplantation is a final option for some cases. in this case, we report an autotransplantation of the kidney after an iatrogenic injury of the ureter with totally extraperitoneal approach. case report: a 41 years old female underwent left endoscopic ureterolithotomy with holmium laser for ureteral calculi. an iatrogenic ureteral injury, probably ureteral avulsion, occurred. after multiple interventions, she referred to us with a nephrostomy tube. imaging was performed and left renal autotransplantation was chosen as surgical management. the approach was totally extraperitoneal. no alteration of renal function or of urine outflow was observed during the follow up. conclusions: the report supports the safety and efficacy of renal autotransplantation. key words: ureteral injury; iatrogenic; renal autotransplantation; totally extraperitoneal. submitted 7 july 2019; accepted 20 july 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.263 introduction iatrogenic ureteral injuries are not a very common complication of urologic and non urologic surgery, but it can be quite challenging to correct them. salvaging the kidney function and repairing the defect are of paramount importance. treatment depends on the extent of the ureteral trauma and the site of the injury. minor injuries can be treated endoscopically with ureteral stent placement, but can relapse. more serious injuries or relapses of minor injuries may require more complicated interventions such as ureteral reimplantation with psoas hitch or boari flap, or uretero-ureteral anastomosis. even these more advanced techniques cannot treat the proximal ureter defects, due to short length of healthy ureter (1). renal autotransplantation is a suitable option for such cases. the first case was performed by jd hardy in 1963 to repair a ureteral injury, but its implementation is still limited. we present a case of an iatrogenic ureteral injury with failed endoscopic management that resulted in autotransplantation of the kidney. case report/case presentation a 41 year old female was referred to us after a prolonged history of multiple interventions that resulted in the permanent placement of nephrostomy tube for renal drainage. the initial intervention was endoscopic ureterolithotripsy with holmium yag laser for an impacted ureteral calculi. after complete but strenuous stone fragmentation and removal of semirigid ureteroscope, a complete ureteral avulsion was realised. an immediate open intervention was decided and patient underwent ureteral anastomosis and ureteral stent placement. patient’s post op course was uneventful and she was discharged five days later. two months postoperatively the patient returned to the treating physicians because of abdominal pain and high fever of 38.5°c. emergency imaging with a ct scan revealed a retroperitoneal abscess around the left kidney extending further to the psoas muscle. patient underwent open drainage, recovered and was discharged again with a indwelling ureteral stent. eight months later the patient had a relapse of fever and abdominal pain and ct scan again revealed a retroperitoneal urinoma, that was percutaneously drained. patient was discharged again after clinical improvement with an indwelling ureteral stent and a foley catheter for bladder drainage. seven days later, patient complained of abdominal pain, nausea and vomiting. an ultrasound reported fluid around the kidney extending to the psoas muscle. an attempt to replace the double j stent failed, a percutaneous nephrostomy was placed instead and an ureteral catheter was placed retrogradely. thereafter the patient was referred to our hospital. a treatment strategy was planned. firstly, a computer tomography was performed. the report described that the ureteral catheter drained the retroperitoneal fluid. treatment was given for 6 weeks according to antibiogram of fluid culture following antimicrobial treatment guidelines. the exact site of the urinary tract injury and the extent of the ureteral trauma were investigated thereafter with antegrade pyelography and retrograde ureterography (figure 1). an upper ureteral defect more than 15 cm in length was demonstrated. moreover, magnetic resonance imaging (mri) was performed. autotransplantation was chosen as surgical management. it was performed almost 1 year after the initial intervention (endoscopic ureterolithotripsy with holmium laser). in supine position, previous incision was revised and the approach was totally extraperitoneal (figure 2). the kidney was completely mobilized and was harvested with katafigiotis_stesura seveso 10/01/20 08:56 pagina 263 archivio italiano di urologia e andrologia 2019; 91, 4 n. moulavasilis, i. katafigiotis, d. staios, c. nikolaidis, s. vernadakis, j. bokos, i. anastasiou 264 maximal artery and vein length. a healthy segment of the upper ureter was mobilized. the renal vessels were anastomosed to the iliac vessels to reestablish renal perfusion and blood supply to the kidney was recovered within 40 minutes. the segment of the proximal ureter was anastomosed to the bladder. no intraoperative complications occurred. pigtail (double j stent) was left in the urinary tract for 4 weeks in order to provide safe urine flow from the transplanted kidney. fifteen days after the autotransplantation the patient was discharged from our hospital with good state of the autotransplanted kidney and urinary tract function. ultrasound doppler and dtpa were used to confirm good arterial and venous flow of the transplanted kidney (fig ure 3). thirty-two weeks after surgery, no signs of abnormalities of renal function or urine outflow were observed. discussion the management of major ureteral injury is always a challenge (2). it depends on the location and extent of the injury. renal autotransplantation is considered a suitable option for ureteral injuries especially when there is a major loss of ureteral length. early recognition of the injury is very important because it is followed by minimally invasive procedure. delayed recognition of injury requires treatment with extended procedures as well as high experience of the urologists. repair of long defect of the ureter, especially of the proximal ureter, is a particularly difficult surgical challenge. there are no strict recommendations on the treatment of long ureteral lesions. the treatment choice for every case is unique. the decision for renal autotransplantation should be taken based on the extent and location of ureteral injury as well as patient preference and surgeon experience. conclusions iatrogenic ureteral injuries are relatively uncommon and the loss of a kidney is devastating. renal autotransplantation in the setting of severe loss of ureteral length provides an option as it preserves the renal function (3). this report supports the safety and efficacy of renal autotransplantation. compliance with ethical standards informed consent: written informed consent was obtained from the patient for the publication of this case repost/any accompanying images. references 1. azhar b, patel s, chadha p, hakim n. indications for renal autotransplant: an overview. exp clin transplant. 2015; 13:109-14. 2. benson mc, ring ks, olsson ca. ureteral reconstruction and bypass: experience with ileal interposition, the boari flap-psoas hitch and renal autotransplantation. j urol. 1990; 143:20-3. 3. shekarriz b, lu h, duh q, et al. laparoscopic nephrectomy and autotransplantation for severe iatrogenic ureteral injuries. urology. 2001; 58:540-3. figure 1. antegrade pyelography. figure 2. extraperitoneal approach. figure 3. dtpa. correspondence napoleon moulavasilis, md (corresponding author) napomoul@hotmail.com ioannis katafigiotis, md katafigiotis.giannis@gmail.com ioannis anastasiou, md ekati2@otenet.gr 1st department of urology, national and kapodistrian university of athens, laiko hospital agiou thoma str., athens (greece) christos nikolaidis, md chr.nikolaidis@gmail.com spyridon vernadakis, md svernadakis@yahoo.com john bokos, md johnbokos@gmail.com renal transplant unit, laiko hospital, athens (greece) dimitris staios, md dstaios@yahoo.com urologist, laiko hospital, athens (greece) katafigiotis_stesura seveso 10/01/20 08:56 pagina 264 195archivio italiano di urologia e andrologia 2018; 90, 3 original paper intraoperative ultrasound in robot-assisted partial nephrectomy: state of the art giacomo di cosmo, enrica verzotti, tommaso silvestri, andrea lissiani, roberto knez, nicola pavan, michele rizzo, carlo trombetta, giovanni liguori università degli studi trieste, urology department cattinara hospital, strada di fiume 447, trieste, italy. introduction: nephron-sparing surgery (nss) is of one of the most studied fields in urology due to the balancing between renal function preservation and oncological safety of the procedure. aim of this short review is to report the state of the art of intra-operative ultrasound as an operative tool to improve localization of small renal masses partially or completely endophytic during robotassisted partial nephrectomy (rapn). material and methods: we performed a literature review by electronic database on pubmed about the use of intra-operative us in rapn to evaluate the usefulness and the feasibility of this procedure. results: several studies analyzed the use of different us probes during rapn. among them some focused on using contrastenhanced ultra sonography (ceus) for improving the dynamic evaluation of microvascular structure allowing the reduction of ischemia time (it). we reported that nowaday the use of intraoperative us during rapn could be helpful to improve the preservation of renal tissue without compromising oncological safety. moreover, during rapn there is no need for assistant to hand the us probe increasing surgeon autonomy. conclusions: the use of a robotic ultrasound probe during partial nephrectomy allows the surgeon to optimize tumor identification with maximal autonomy, and to benefit from the precision and articulation of the robotic instrument during this key step of the partial nephrectomy procedure. moreover us could be useful to reduce ischemia time (it). the advantages of nephron-sparing surgery over radical nephrectomy is well established with a pool of data providing strong evidence of oncological and survival equivalency. with the progressive growth of robot-assisted partial nephrectomy (rapn) techniques, the use of several tools has been progressively developed to help the surgeon in the identification of masses and its vascular net. in this short review we tried to analyze the current use of intra-operative ultrasound as an operative tool to improve localization of small renal masses partially or completely endophytic during rapn. key words: robotic surgery; nephron-sparing surgery; intraoperative ultrasound; contrast-enhanced ultrasonography . submitted 6 july 2018; accepted 12 july 2018 summary no conflict of interest declared. ing of imaging techniques such as contrast-enhanced ultrasonography (ceus), magnetic resonance imaging (mri) and computed tomography (ct) that are capable to incidentally diagnose small renal masses (srm). in past decades srm have been treated by radical nephrectomy with increased risk of chronic kidney disease (1). for this reason there’s been increasing interest in using nephron-sparing surgery (nss) techniques and nowadays nss is the standard of care for t1a renal masses and several retrospective series as well as one prospective randomized controlled trial (rct) including patients with organ-confined rcc of limited size, low t-stage (pt1a), have demonstrated a comparable cancer specific survival (css) for nss versus radical nephrectomy (rn) (2, 3). several studies focused on the ischemia time as a predictor of renal function reduction. in this context, in recent years we have seen an increasing use of intraoperative ultrasound (ious) probes and contrast-enhanced ultrasonography (ceus). the use of ultrasound in the intraoperative renal surgery is able to provide indications regarding the parenchyma and vascularization of the kidney. in this paper we describe the different operative approaches and we also performed a short review to focus on the actual application of intraoperative ultrasound in robot-assisted partial nephrectomy (rapn). tecnique instrumentation and technical characteristics the frequency normally used for laparoscopy or robotic ultrasound guidance is between 7.5 and 10 mhz. especially probes with 7.5 mhz can surely provide excellent images for distances between 1 and 4 centimeters. in this context ultrasound is able to detect tumors up to 34 mm diameter (4). probe may be linear (with multiple longitudinal transductors) or convex. linear probe is generally more effective to scan organs with large flat surfaces as liver or spleen while convex probes are usually better for curved surfaces as kidney. to obtain better resolution is sometimes useful to irrigate the surface with saline solution (5). during laparoscopic or robot-assisted procedure, both the assistant or the surgeon can control the laparoscopic ultrasound probe. in this second case the laparoscopic doi: 10.4081/aiua.2018.3.195 introduction renal cell carcinoma (rcc) is the seventh most common urological neoplasm with an incidence of approximatively 270.000 new cases diagnosed each year worldwide. the rising incidence of kidney cancer is related to the improvdi cosmo_stesura seveso 04/10/18 11:16 pagina 195 archivio italiano di urologia e andrologia 2018; 90, 3 g. di cosmo, e. verzotti, t. silvestri, a. lissiani, r.knez, n. pavan, m. rizzo, c. trombetta, g. liguori 196 probe might require adjustment of probe positioning with also a robotic instrument to reduce probe slippage from tumor surface (6, 7). there’s also the possibility of using ultrasound probes directly related to the robotic arm through a grooved ridge on its ventral aspect that fits the robotic grasping instrument allowing control by the surgeon himself. in different series of laparoscopic or robot-assisted partial nephrectomy (lapn and rapn) with laparoscopic ultrasonography, it has been described some difficulty during the identification of tumor borders because the transducer may be not perpendicular to the surface of the kidney. the robotic ultrasound probe, instead, can be handled independently by the surgeon, achieving difficult angles while maintaining perpendicular contact of the probe with kidney surface (7). intraoperative ceus ceus plays a key role in the characterization of malignant renal lesions (8). rapn may be carried out by clamping of hilar vessels or by selective clamping of tumor vessels that aloud to reduce ischemia effects on the whole kidney. several techniques have been described to perform partial ischemia by identifying tumor vessels and clamping or ligating those who feed the tumor (9). finally the intraoperative ultrasonography (ious) can be used for surgery of renal neoplasms, associated with the presence of venous thrombus. in case the thrombus extension is not visible or palpable, ultrasounds may be essential to identify the distal portion of the thrombus itself (10). the contrast agent used during the ceus procedure enhances the kidneys for about 2 minutes in real-time post-injection of contrast. in case of chronic kidney disease renal parenchyma could be enhanced for a shorter period and with lower intensity (11). a second-generation contrast agent, sonovue (bracco, milan, italy) is widely used for the ceus procedure. each milliliter of this contrast agent contains stabilized microbubbles of sulfur hexachloride gas (12). the recommended dose for renal imaging using a single intravenous injection of sonovue is 1-2.4 ml. the ultrasound contrast agent can actually be seen to flow into the renal parenchyma usually within 15-20 seconds after an intravenous injection of sonovue. this contrast enhancement of the renal parenchyma starts with the medulla and spreads to the renal cortex as the kidney is perfused with ultrasound contrast agent. intravenous aliquots of sonovue may be repeated as necessary and most importantly, this contrast agent is not nephrotoxic, as it is excreted by the lungs. thus, it can be used safely in patients with compromised renal functions. the intra-operative ceus technique uses two images: a conventional b-mode or 2d mode (brightness mode) image of the tissue using low acoustic power that produces a two-dimensional image on the screen and a contrast-enhanced mode (a contrast-specific) image which displays the reflection made by the spatial distribution of bubbles (figure 1). when an ultrasound wave falls on the microbubbles, they expand to almost double their original size and contract simultaneously, producing an oscillatory movement. this movement further results in the transmission of return signals to the us machine transducer (13), resulting in successful enhancement of the renal microvasculature and accurate tumor marking. a technique, which we are still developing, is sequential occlusion angiography. in this technique we capitalize on the ability to rapidly destroy or “rupture” the sonovue microbubbles by increasing the ultrasound scanning frequency. this effectively clears the renal parenchyma or tissue being scanned of microbubbles and allows a second or subsequent intravenous injection of sonovue to be administered immediately. in our hands, this is the real advantage of ceus, which undoubtedly, seems to offer a better intra-operative imaging in comparison to power doppler and firefly. the combination of ceus and microbubble contrast agents allows a definite enhancement of contrast resolution, and inhibition of signals from stationary tissues. although, sonovue is more widely used for ceus in most countries except the united states, there are a number of other alternative contrast agents available for this purpose. technical procedures and our experience in our center we perform rapn or lapn for tumors sized < 4 cm with average padua score of 7, most of times at lower pole of the kidney. most of times, transperitoneal approach is used. pre-operative staging is completed by chest and abdomen computed tomography (ct) to assess tumor morphology and vascular anatomy of the hilum. after identification and exposure of hilum, the surgeon release the gerota’s fascia (in case of posterior mass and transperitoneal approach, full mobilization of kidney is required). after giving patient 12.5 mg mannitol, warm ischemia is induced by bulldog clamping on the principal arteria. in this moment intraoperative ultrasound helps to localize the mass, the depth of penetrafigure 1. intra-operative contrast-enhanced ultrasonography (ceus) technique: conventional b-mode or 2d mode (brightness mode) image and contrast-enhanced mode image which displays the reflection made by the spatial distribution of bubbles. courtesy of prof. michele bertolotto, trieste. di cosmo_stesura seveso 04/10/18 11:16 pagina 196 tion inside the parenchyma and its relationship with the collecting system. moreover, ious helps in delineation of tumor margins and peritumoral vascularization: especially a contrast-enhanced ultrasound can enhance the visualization of the tumor and its vascularization during rapn or lapn with more precision consequently increasing the diagnostic accuracy of the surgeon and aloud selective clamping. review of studies we performed as well a comprehensive literature search by electronic bibliographic databases in pubmed up to march 2018 using the following keywords: “contrast enhanced ultrasound”, “intra-operative ultrasound”, “nephron-sparing surgery”, “partial nephrectomy” and “robotic-assisted partial nephrectomy”. the list of all electronically identified bibliographies and articles was then reviewed to distinguish potentially relevant studies including experiments, case reports, and reviews and preliminary clinical studies. we selected studies in the field of intra-operative ultrasound in laparoscopic and rapn. discussion rapn is performed with different techniques based on surgeon preferences, tumor characteristics, patient factors and available technology. according to aua and eau guidelines partial nephrectomy should be offered to all patients with organ confined disease, with mass equal or lass than. although several nephrometric scoring system have been developed (14, 15) to help the surgeon in planning surgical best approach and ct or mri clearly show the relationship between the lesion and renal sinus fat and pyelocaliceal system or involvement of renal vessels, ious can provide more detailed real-time guidance in the operating room for selected t1 lesions. moreover, ious helps determine whether the distance between a main or segmental blood vessel and the tumor is greater 3-5 mm (16, 17). therefore, there is a perceived need for ious especially if the tumor is intraparenchymal and complex according to the nephrometry score. first reports of ious to help identify renal cell carcinoma in patients with poorly visualized and non-palpable disease have been described in 1988 (18). ious could also reduce operative time and ischemia time because it increase mass delimitation in those cases with particularly dense perirenal adipose tissue with highly represented fibrous components. assimos et al. reported using of intraoperative ultrasonography for tumor identification to obtain negative surgical margins during partial nephrectomy (19). great attention has also been given to ious use in the identification of extrarenal venous extension, multifocality and associated renal cysts and has also been reported that the use of intraoperative ultrasonography influenced the choice of surgical approach in 13% of cases (20, 21). in recent years, there has been a progressive shift from laparoscopic partial nephrectomy and rapn due to the ability to reduce the warm ischaemia time (wit) and learning curve during nephron-sparing surgery in robotic surgery (22). a prolonged wit has been demonstrated to be potentially dangerous for renal functions post partial nephrectomy, especially in patients with high risk factors, or underlying disorders such as hypertension, diabetes, and small vessel disease (23-25). surgeons are motivated to avoid global ischemia and consequently reduce the wit by ligating or clamping selective arteries that supply blood to the segment of the kidney containing the tumor helps achieve a lower wit. intra-operative ultrasound seems to be highly useful for this purpose, as it can demonstrate real-time imaging of the renal vasculature. ceus is capable of further reducing the wit by aiding the process of selective clamping, since it permits real-time scanning of the macrovasculature and microvasculature of the kidneys without the need for removing the perinephric fat. kaczmarek et al. (7) performed rapn using a robotic us probe for tumor identification in 22 patients. the gerota’s fascia was opened to expose the renal capsule around the tumor, hilar blood vessels were isolated and clamped in preparation for excision of the tumor under warm ischemia and renoraphy was performed by “sliding clip suture” technique (26). the ultrasound probe was introduced through the assistant port to help the recognition of the border between tumor pseudo-capsule and normal renal parenchyma. the location and extent of the tumor were visualized through the medium of real-time images, obtained from intra-operative ultrasound techniques. images were produced and visualized by the surgeon using the tilepro feature of the da vinci surgical system to produce a picture-on-picture image in the console screen to view the images. finally in some studies have been described intra-operative ultrasound scan using a fourth robotic arm with proart robotic drop-in probe (6, 27). conclusions ious has been demonstrated as one of the most important tool to help surgeon in maximize the loss of nephrons and it can be performed both by using assistant port or robotic probe with surgeon directly handling the probe with sensible benefit from the precision and articulation of robotic instrument. intraoperative ceus can further reduce global wit and thus may improve recovery of renal function. by facilitating selective arterial clamping during rpn and avoiding global ischemia it may decrease the risk of permanent loss of nephrons. most importantly, ceus can help us image the renal microvasculature, without affecting renal function. in addition, ceus is capable of dynamic evaluation and quantification of microvasculature blood (capillary perfusion) in real time. when used in conjunction with a robotic ultrasound probe, ceus can facilitate better visualization of renal vasculature and tumor and ultimately improving acumen and precision. references 1. hollenbeck bk, taub da, miller dc, et al. national utilization trends of partial nephrectomy for renal cell carcinoma: a case of underutilization? urology. 2006; 67: 254-9. 197archivio italiano di urologia e andrologia 2018; 90, 3 intraoperative ultrasound di cosmo_stesura seveso 04/10/18 11:16 pagina 197 archivio italiano di urologia e andrologia 2018; 90, 3 g. di cosmo, e. verzotti, t. silvestri, a. lissiani, r.knez, n. pavan, m. rizzo, c. trombetta, g. liguori 198 2. gratzke c, et al. quality of life and perioperative outcomes after retroperitoneoscopic radical nephrectomy (rn), open rn and nephron-sparing surgery in patients with renal cell carcinoma. bju int. 2009; 104:470. 3. van poppel h, et al. a prospective, randomised eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2011; 59:543. 4. polascik tjmf. intraoperative sonographic evaluation of the kidney. aua update series. 1997; 16:137. 5. lirici, et al. laparoscopy ultrasonography: limits and potential of present technologies. endosc surg allied technol. 1994; 2:127-133. 6. rogers cg et al. maximizing console surgeon independence during robot-assisted renal surgery by using the fourth arm and tile pro. j endourol. 2009; 23:115-121. 7. kaczmarek bf, et al robotic ultrasound probe for tumor identification in robotic partial nephrectomy; initial series and outcomes. int j urol, 2013; 20:172-176, 8. bertolotto m, et al. renal masses as characterized by ultrasound contrast. ultrasound clin. 2013; 8:581-592. 9. gill is, eisenberg ms, aron m, et al. zero ischemia partial nephrectomy: novel laparoscopic and robotic technique. eur urol. 2011; 59:128-134. 10. hsu et al. laparoscopic radical nephrectomy incorporating intraoperative ultrasonography for renal cell carcinoma with renal vein tumor thrombus. urology 2003; 61:1246-1248. 11. piscaglia f, et al. the efmbsu guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (ceus): update 2011 on non-hepatic applications. ultraschall med. 2012; 33:33-59. 12. greis c. technology overview: sonovue (bracco, milan) eur radiol. 2004; 14(supp 8):11-15. 13. uhlendorf v, et al acoustic behavior of current ultrasound contrast agents. ultrasonics. 2000; 38:81-86. 14. kutikov, et al. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009; 182:844-853. 15. ficarra, et al. preoperative aspects and dimensions used for an anatomical (padua) classification of renal tumours in patients who are candidates for nephron.sparing surgery. eur urol. 2009; 56:786-793. 16. li ql, et al. significance of margin in nephron sparing surgery for renal cell carcinoma of 4 cm or less. chine med j (engl). 2008; 121:1662-1665. 17. lam, et al. importance of surgical margin in nephron sparing surgery in the management of renal cell carcinoma. nat. clin pract urol. 2008; 5:308-317. 18. gilbert br, et al. intraoperative sonography: application in renal cell carcinoma. j urol. 1988; 139:582-284. 19. assimos d, et al. intraoperative renal ultrasonography: a useful adjunct to partial nephrectomy. j urol 1991; 146:1218-1220, 20. polascik tj, et al. intraoperative sonography for the evaluation and management of renal tumors: experience with 100 patients. j urol 1995; 154:1676-1680. 21. marshall, et al. intraoperative sonography of renal tumor. j urol 1992; 148:1393-1396. 22. mottrie a, de naeyer g, schatteman p, et al. impact of the learning curve on perioperative outcomes in patients who underwent robotic partial nephrectomy for parenchymal renal tumours” eur urol. 2010; 58:127-132. 23. clark ma, et al. chronic kidney disease before and after partial nephrectomy. j urol. 2011; 185:43-48. 24. thompson rh, et al. every minute counts when the renal hilum is clamped during partial nephrectomy. eur urol. 2010; 58:340345. 25. campbell sc, et al. guideline for management of the clinical t1 renal mass. j urol, 2009; 182:1271-1279. 26. benway bm, et al. robotic partial nephrectomy with sliding-clip renorrhaphy: technique and outcomes. eur urol. 2009; 55:592-599. 27. rao ar, gray r, mayer e, et al. occlusion angiography using intraoperative contrast-enhanced ultrasound scan (ceus): a novel technique demonstrating segmental renal blood supply to assist zero-ischaemia robot-assisted partial nephrectomy. eur urol. 2013; 63:913-9. correspondence giacomo di cosmo, md (corresponding author) giacomo.dicosmo@gmail.com enrica verzotti, md enrica.verzotti@gmail.com tommaso silvestri, md tommaso.silve@gmail.com andrea lissiani, md a_lissiani@gotmail.com roberto knez, md r.knez@libero.it nicola pavan, md nicpavan@gmail.com michele rizzo, md mik.rizzo@gmail.com carlo trombetta, md trombcar@units.it giovanni liguori, md gioliguori33@gmail.com università degli studi trieste, urology department cattinara hospital, strada di fiume 447, trieste, italy di cosmo_stesura seveso 04/10/18 11:16 pagina 198 stesura seveso 239archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.239 the impact of tumor invasion to muscularis mucosaevascular plexus on patient outcome in pt1 bladder urothelial carcinoma ahmet sahan 1, fatma gerin 2, asgar garayev 3, emine bozkurtlar 2, alkan cubuk 1, orkunt ozkaptan 1, kasım ertas 4, yıloren tanidir 3, haydar kamil cam 3, ilker tinay 3 1 kartal dr. lutfi kirdar training and research hospital, department of urology, istanbul, turkey; 2 marmara university, department of pathology, istanbul, turkey; 3 marmara university, department of urology, istanbul, turkey; 4 yuzuncu yıl university, department of urology, van, turkey. objectives: t1 bladder cancer has a wide range of tumor behavior and lamina propria invasion depth has a high potential risk of disease progression. to evaluate the patient outcome according to the tumor invasion to the muscularis mucosae-vascular plexus (mm-vp) in pt1 bladder urothelial carcinoma (buc). materials and methods: this study is a retrospective analysis of patients consecutively recorded from 2007 to 2013. a total of 93 patients with a history of primary pt1 buc and complete follow-up were included. we used a pathological substaging system according to the tumor invasion regarding the mm-vp: pt1a (invasion above mm-vp) and pt1b (mm-vp invasion). we evaluated recurrence-free survival (rfs), progression-free survival (pfs), disease-specific-survival (dss) based on this sub-staging system. results: pathological evaluation regarding the mm-vp invasion revealed 53 patients (57%) as pt1a buc and 40 patients (43%) as pt1b buc. the mean follow-up was 78.8 months. during the follow-up period; 60 patients (64.5%) had tumor recurrences, 32 patients (34.4%) had progression to invasive disease, 18 patients (19.4 %) died during follow-up related to the buc. in 29 (54.7%) of pt1a and in 31(77.5%) of pt1b tumors, the recurrent disease was recorded during the followup period (p = 0.023). dss rates at 5 years for pt1a and pt1b were 80.2% and 60.8%, respectively. pfs, rfs, and dss rates were similar for pt1a/pt1b and did not reach statistical significance (p > 0.05). conclusions: sub-staging of pt1 buc according to the mm-vp invasion showed a limited impact on the outcome in our patient cohort. however, the presence of pt1b disease caused a significantly higher rate of recurrence. key words: t1 bladder cancer; survival; sub staging; muscularis mucosae; lamina propria depth. submitted 2 march 2020; accepted 15 march 2020 summary introduction bladder urothelial carcinoma (buc) with pathological t1 stage represents a complex clinical dilemma due to its high rate of recurrence and progression. in fact, t1 buc comprises a wide spectrum of different cases causing a huge clinical variability. at presentation, 75% of cases are non-muscle invasive bladder cancer (nmibc), and approximately 70 % of patients present as pta, 20 % as pt1, and 10 % with carcinoma in situ (cis) lesions (1). in t1 high-grade tumors, 1 and 5 years of disease-progression rates are 11.4% and 19.8%, respectively, and recurrence rates are between 21% to 53% despite intravesical treatments (2-7). this wide range in the recurrence and progression rates indicates the immense clinical variation of pt1 patients. therefore, the overall management of t1 tumors is a challenge for urologists. how to differentiate the clinically aggressive pt1 tumors and how to provide the appropriate treatment strategy i.e. early cystectomy remains a difficult issue. tumor grade, stage, size of the tumor, multiplicity, and presence of cis are known risk factors for recurrence and progression (1). pathologic features like tumor growth pattern (papillary vs solid), tumor invasion pattern (broad vs trabecular vs infiltrative vs nested), and lymphovascular invasion were investigated to identify the variability of tumor behavior (3, 8, 9). factors dependent on surgery i.e. re-tur has shown the benefit of recurrence and progression-free survival (10). however, no strict criteria to predict prognosis in pt1 buc have not been defined. due to a wide range of tumor behavior, there were many studies related to subclassification/sub-staging of t1 buc since 1990 (11). these sub-staging systems were made according to the invasion of the muscularis mucosae-vascular plexus and invasion depth to lamina propria (11-13). sub-staging according to mm-vp has been reported to be more superior than the invasion depth to lamina propria (14). however, the world health organization (who) (2004)/international society of urological pathology (isup) and clinical guidelines do not recommend the sub-staging of t1 bladder cancer for the current daily practice (15, 16). some reports showed that sub-staging is useful and predictive for progression of pt1 buc (2, 12, 17, 18). on the other hand, sub-staging is technically difficult and so far does not yield a clear prognostically significant separation on t1 bladder tumor (19, 20). therefore, new clinical series are required to evaluate the clinical utility of sub-staging in pt1 buc. in the present study, we evaluated the impact of the invasion of the muscularis mucosae-vascular plexus (mmvp) on the clinical outcome of t1 buc. archivio italiano di urologia e andrologia 2020; 92, 3 a. sahan, f. gerin, a. garayev, e. bozkurtlar, a. cubuk, o. ozkaptan, k. ertas, y. tanidir, h. kamil cam, i. tinay 240 patients and methods we evaluated a total of 140 patients, who were referred to our center or diagnosed in our center with primary and pathologically reported pt1 buc between 2007 to 2013. data of the patients were recorded prospectively in our electronic database and reviewed retrospectively for the study. the study protocol was approved by the local ethics committee (number: 27-2014). due to the retrospective nature of the study, only written consent was obtained from the patients. the original pathology slides of all pt1 bladder tumors were re-evaluated by two uropathologists (eb/fg) for stage and grade. we used the world health organization 2004 classifications to review grade. after this re-evaluation, initial pathological staging was confirmed in 82% of patients. we further excluded patients with a history of previous bladder cancer diagnosis, an absence of muscular layer, an absence of a repeated transurethral resection (re-tur) after 3 to 6 weeks, the presence of concomitant cis and with upstaged/downstaged tumors based on this pathological re-evaluation. a total of 14 patients were lost to follow-up and as a result, 93 patients were eligible for final analysis. all patients received intravesical bcg treatment with at least 1 year duration. the follow-up cystoscopies and imaging of the upper urinary tract are planned according to the recommendation of eau 15. recurrences were defined as pta, pt1 and cis tumors and progression was defined as pt2 or higher stage and/or development of metastasis. we used a pathological sub-staging system according to the tumor invasion regarding the mm-vp: t1a (invasion above mm-vp), t1b (mm-vp invasion) bladder cancer 12. whenever muscularis mucosae-vascular plexus were not identified the presence of large blood vessels in the upper one-half of the lamina propria coursing parallel to the mucosa was used as a morphologic landmark of the level of the mm (figure 1) (12). statistical analyses were performed using the spss software version 20. the chi-square test and student t-test were used to compare in two groups. a p value of less than 0.05 was considered to show statistically significant results. for the multivariate analyses, the possible factors identified with univariate analyses were further entered into the logistic regression analyses to determine independent predictor of tumor recurrence. hosmer-lemeshow goodness of fit statistics was used to access model fit. survival rate was analyzed using the kaplan-meier method and compared between the 2 groups with the log-rank test. results in total 73 male and 20 female patients were included in the study. mean age at initial diagnosis was 64.6 (+/-11.3) years and mean follow up time was 78.8 (+/58.4) months. overall, radical cystectomy was performed in 14 patients (15.0%), and a total of 4 patients (4.3%) refused radical cystectomy due to surgical and/or risks of the anesthesia. these patients received radiotherapy plus chemotherapy due to the progression to muscle-invasive disease during this follow-up. mean recurrence time was 15.2 ± 22.5 months and mean protable 1. characteristics of the patients based on the two sub-staging systems. t1a (n: 53) t1b (n: 40) p value gender (m/f) 42/11 31/9 0.839 age (year) 64.8 (10.7) 64.3 (12.1) 0.834 tumor size (< 3 cm/> 3 cm) < 3 cm 40 (75%) 28 (70%) 0.556 > 3 cm 13 (25%) 12 (30%) tumor number solitary 28 (53%) 25 (62%) 0.351 multiple 25 (47%) 15 (37%) grade (low/high) low 32 (60%) 15 (37%) 0.029 high 21 (40%) 25 (62%) follow up time (month) 83.4 (61.7) 72.7 (46.7) 0.359 recurrence (n) 29 (55%) 31 (77%) 0.023 progression (n) 8 (15%) 10 (25%) 0.231 time to recurrence(month) 17.3 (29.1) 13.2 (14.2) 0.491 time to progression(month) 42.9 (49.8) 30.5 (38.4) 0.440 table 2. logistic regression analysis to determine the independent predictors of recurrence. risk factors sig. exp (b) 95% c.i. for exp (b) lower upper tumor number (solitary vs multiple) 0.068 3.117 0.918 10.585 tumor grade (low vs high ) 0.000 12.643 3.680 43.432 substage (t1a vs t1b) 0.026 4.219 1.191 14.947 tumor size (< 3 cm vs > 3 cm) 0.006 7.325 1.758 30.525 figure 1. microscopic apperarnece. gression time was 37.1 ± 44.5 months considering the all pt1 cases. the results of the comparison of the sub-staging system are shown in table 1. there were no statistically significant differences between the two groups according to age, gender, size, multiplicity, follow up time. the mmvp invasion was not detected in 53 tumors (56.9%) and patients were classified as pt1a. the mm-vp invasion was present in 40 patients (43.0%) that we classified as pt1b. 25 (47.1%) for t1a vs. 15(37.5%) for t1b had multiple tumors (p = 0.351) (table-1). 40% and 62% of patients were high grade buc in t1a and t1b, respectively. there was a statistically significant difference between sub-staging according to pt1a/pt1b and the who 2004 grade system (p = 0.003). in 29 (54.7%) of pt1a and in 31(77.5%) of pt1b tumors, the recurrent disease was recorded during the follow-up period. this difference was statistically significant (p = 0.023). in total, 18 patients (19.3%) progressed to further stages, and 12 patients (14%) died of buc. there was no statistically significant difference between the two groups based on progression (p: 0.231). stepwise multivariate regression analysis revealed that the grade of bladder cancer, the pathological sub-staging system according to the tumor invasion regarding the mm-vp, and tumor size were the prominent factors affecting the recurrence of bladder cancer (table 2). mean recurrence and progression time based on pt1a/ pt1b was 17.3 ± 29.1/42.9 ± 49.8 months and 13.25 ± 14.2/30.5 ± 38.4 months, respectively. although mean recurrence time and progression time longer in pt1a group than pt1b group, it did not reach statistically significant differences between groups because of the small sample size (p > 0.05). disease-specific survival (dss) rates at 5 year for pt1a and pt1b were 80.2% and 60.8%, respectively. progression free survival (pfs), recurrence free survival (rfs) and dss rates were similar for pt1a/pt1b and did not reached statistically significance (p > 0.05) (figures 2-3). discussion in this study, sub-staging based on the invasion of mmvp has no effect on progression and recurrence-free survival rates in patients with pt1 buc. however, patients with pt1b have experienced a higher rate of recurrence during follow-up compared to pt1a group. disease-specific survival was relatively longer in t1a however there was no statistically significant difference in kaplan-meier survival estimate analyses. the management of t1 bladder cancer is a great challenge for urologists because of its wide and unpredictable range of clinical behavior. therefore, pt1 disease represents a spectrum of different patients with different tumor behavior. because of that, investigations have been focused on how to classify and predict the prognosis. tumor grade, size, multiplicity, the presence of cis, re-tur, lymphovascular invasion, bcg treatment, age, histotype and histological variants, tumor growth pattern, 3rd-month cystoscopy results, time to relapse are known parameters that affect prognosis (16). according to tnm classification, pt1 tumors recurrence and progression are not homogeneous some of them very aggressive that require early radical cystectomy. remaining cases should need to follow up with cystoscopies after intravesical therapy. in the contrary, some patients who are treated more aggressively, in fact, may receive overtreatment. however, some 241archivio italiano di urologia e andrologia 2020; 92, 3 substaging of t1 bladder cancer figure 2. kaplan-meier estimates of disease spesific survival according to invasion of mm-vp in primary t1 transitional cell carcinoma (tcc) of the bladder. figure 3. kaplan-meier estimates of recurrence-free (a) and progression-free (b) survival according to invasion of mm-vp in primary t1 transitional cell carcinoma (tcc) of the bladder. whereas the recurrence-free interval and progression-free were similar for both groups. archivio italiano di urologia e andrologia 2020; 92, 3 a. sahan, f. gerin, a. garayev, e. bozkurtlar, a. cubuk, o. ozkaptan, k. ertas, y. tanidir, h. kamil cam, i. tinay 242 pt1 cases may progress to the inoperable stage under the conservative approach. so any improvement to the treatment strategy for the management of pt1 buc is significant. this study proposes that invasion of mm-vp (pt1b) may be associated with a higher and earlier recurrence, although a statistical difference was not shown. larger series with longer follow-up may show a remarkable distinction for pt1b sub-staging. different sub-staging systems have been studied in the literature recently (11, 13, 18). who (2004)/isup and clinical guidelines do not recommend the sub-staging of t1 bladder cancer yet (15, 16). invasion of muscularis mucosae-vascular plexus invasion and depth and area to lamina propria invasion were most commonly applied sub-classification (12, 13). orsola et al. substaged according to invasion superficial to, into or beyond the muscularis mucosae (13, 18). holmang et al. substaged based on the absent or presence of mm-vp invasion (t1a/t1b) as in our study (21). van rhijn et al. investigated two substaging systems based on the extent of lamina propria involvement [t1-microinvasive (t1m) versus t1-extensive-invasive (t1e)] and invasion to mm-vp 12. amin et al. commented that the efficacy of the sub-staging of t1 bladder tumors is still controversial since lack of consensus to define the depth of invasion criteria and established clinical significance (22). the main problem may be the detection of mm-vp since it is not a constant layer, 6% to 75% of pathology specimen were not identified (23). main studies of interest of mm invasion in t1 nmibc with staging system and assessment rate were changes between 63% to 100% (22). in our study we planned to reclassify the t1 tumors based on presence or absence of mm-vp invasion and depth invasion to lamina propria: t1a (the tumor does not infiltrate the mmvp) and t1b (the tumor infiltrates and/or invades the [mm-vp]), and t1m (micro-invasivea single focus of lamina propria invasion with a maximum diameter of 0.5 mm) and t1e (extensive-invasive, > 0.5 mm). if the mm-vp was not seen at the invasion front, we classify pt1a or pt1b according to the depth of invasion into the lamina propria by looking at the mm-vp in tumor-free areas in the same or other tur slides (12). we classified as t1a/b all the patients and classification according to lamina propria invasion depth (t1m/e) < 0.5 mm or > 0.5 mm was not feasible result in our study. since only 6 of the patients classified as t1m bca and all the others reported as t1ebca so we could able to analyze only the presence or absence of mm-vp invasion (t1a/t1b). in literature the largest study was reported by rouprêt et al. with 587 patients, that pt1a/b sub-staging based on the mm-vp invasion was very predictive of t1 nmibc behavior as recurrence-free (p = 0.03) progression-free (p < 0.001) and cancer-specific survival (p = 0.02) in 35 months median follow up time (24). in our study, pt1a buc a was a higher recurrence rate of 29(54.7%) than t1b 31(77.5%) (p: 0.023) but there were no statistically significant differences between two groups with kaplan meier analyses (log rank, p-value > 0.05) in 78.8 (58.4) months mean follow-up time. skoup et al. reported that t1 sub-staging was the indepented prognostic factors for tumour progression (p < 0.0001), cancer-specific survival (p = 0.0001) and overall survival (p = 0.0002) (25). de-marko et al. analyzed two sub-staging systems for t1 bladder cancers based on mm-vp invasion (t1a/b/c) and lamina propria invasion depth (t1m/e) two sub-staging system were not reached prognostic significance level for progression-free survival and disease-specific survival after 9.5 years of follow-up 20. van rhijn et al. evaluated mm-vp invasion depth as t1a/t1b/t1c and lamina propria invasion above or below to 0.5 mm (t1m/t1e), which show a higher predictive value for disease progression and disease-specific survival (12). orsola et al. reported that sub-staging using depth of lamina propria invasion was significant for progression (13). in our study, there were no statistically significant differences between disease progression, recurrence and cancer-specific survival between the t1a/b sub-staging systems. patriarca et al. report that 1 mm invasion system predicted progression (p < 0.04) and re-tur increase the survival rate (26). they reclassified 1 mm sub-staging system in 100% of cases, the t1m/e in 100%, and the anatomy-based method (t1 a/b) in 72.3% of cases (26). in our study, we detected only 6 cases with t1m groups based on 0.5 mm threshold, so 1 mm of invasion threshold might be more useful results clinically. finally, although the eortc and cueto risk scores improve risk stratification by quantifying recurrence and progression possibilities, their performance remains imperfect. these scoring systems may further improve with using this sub-staging system (27). our study has some limitations such as reporting the retrospective data of a relatively small patient group. our results could not show statistically significant differences according to disease-specific survival and progressionfree survival because of the small sample size. conclusions based on the findings presented in this study, sub-staging of t1 buc according to the muscularis mucosae–vascular plexus invasion showed a limited impact on the outcome in our patient cohort. however, the presence of pt1b disease was found to be associated with significantly higher of recurrence. references 1. van rhijn bw, burger m, lotan y, et al. recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. eur urol. 2009; 56:430-42. 2. burger m, oosterlinck w, konety b, et al. icud-eau international consultation on bladder cancer 2012: non-muscle-invasive urothelial carcinoma of the bladder. eur urol. 2013; 63:36-44. 3. hall mc, chang ss, dalbagni g, et al. guideline for the management of nonmuscle invasive bladder cancer (stages ta, t1, and tis): 2007 update. j urol. 2007; 178:2314-30. 4. kulkarni gs, hakenberg ow, gschwend je, et al. an updated critical analysis of the treatment strategy for newly diagnosed high-grade t1 (previously t1g3) bladder cancer. eur urol. 2010; 57:60 70. 5. cambier s, sylvester rj, collette l, et al. eortc nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage 243archivio italiano di urologia e andrologia 2020; 92, 3 substaging of t1 bladder cancer ta-t1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus calmette-guerin. eur urol. 2016; 69:60-9. 6. özkaptan o, çubuk a, dinçer e, et al. extraperitoneal antegrade vs transperitoneal open radical cystectomy: single center experiences with 200 cases. bladder cancer 2020; 6:187-194. 7. budak s, yucel c, keskin mz, et al. pathology outcomes in patients with transurethral bladder tumour resection in a turkish population: a retrospective analysis. arch ital urol androl. 2018; 90:8-10. 8. mathieu r, lucca i, roupret m, et al. the prognostic role of lymphovascular invasion in urothelial carcinoma of the bladder. nat rev urol. 2016; 13:471-9. 9. breyer j, bertz s, müller a, et al. new pathological features predicting prognosis of early-invasive urothelial carcinoma: quantitative substaging and tumour invasion pattern should assist who 1973 grading classification in predicting cancer-specific survival of stage pt1 bladder cance. eur urol. suppl 2016;15:e392. 10. naselli a, hurle r, paparella s, et al. role of restaging transurethral resection for t1 non-muscle invasive bladder cancer: a systematic review and meta-analysis. eur urol focus. 2018; 4:558-567. 11. younes m, sussman j, true ld. the usefulness of the level of the muscularis mucosae in the staging of invasive transitional cell carcinoma of the urinary bladder. cancer. 1990; 66:543-8. 12. van rhijn bw, van der kwast th, alkhateeb ss, et al. a new and highly prognostic system to discern t1 bladder cancer substage. eur urol. 2012; 61:378-84. 13. orsola a, trias i, raventos cx, et al. initial high-grade t1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (t1a/b/c) in bcg-treated and bcg-non-treated patients. eur urol. 2005; 48:231-8. 14. turan t, efiloglu o, gunaydin b, et al. comparative differences between t1a/b and t1e/m as substages in t1 urothelial carcinoma of the bladder. int braz j urol. 2018; 44:267-72. 15. babjuk m, bohle a, burger m, et al. eau guidelines on nonmuscle-invasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017; 71:447-61. 16. humphrey pa, moch h, cubilla al, et al. the 2016 who classification of tumours of the urinary system and male genital organspart b: prostate and bladder tumours. eur urol. 2016; 70:106-19. 17. smits g, schaafsma e, kiemeney l, et al. microstaging of pt1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. urology. 1998; 52:1009-13 18. lee jy, joo hj, cho ds, et al. prognostic significance of substaging according to the depth of lamina propria invasion in primary t1 transitional cell carcinoma of the bladder. korean j urol. 2012; 53:317-23. 19. platz ce, cohen mb, jones mp, et al. is microstaging of early invasive cancer of the urinary bladder possible or useful? mod pathol. 1996; 9:1035-9. 20. de marco v, cerruto ma, d'elia c, et al. prognostic role of substaging in t1g3 transitional cell carcinoma of the urinary bladder. mol clin oncol. 2014; 2:575-80. 21. holmang s, hedelin h, anderstrom c, et al. the importance of the depth of invasion in stage t1 bladder carcinoma: a prospective cohort study. j urol. 1997; 157:800-3 22. amin mb, mckenney jk, paner gp, et al. icud-eau international consultation on bladder cancer 2012: pathology. eur urol. 2013; 63:16-35. 23. ro jy, ayala ag, el-naggar a. muscularis mucosa of urinary bladder. importance for staging and treatment. am j surg pathol. 1987; 11:668-73. 24. roupret m, seisen t, comperat e, et al. prognostic interest in discriminating muscularis mucosa invasion (t1a vs t1b) in nonmuscle invasive bladder carcinoma: french national multicenter study with central pathology review. j urol. 2013; 189:2069-76. 25. soukup v, duskova j, pesl m, et al. the prognostic value of t1 bladder cancer substaging: a single institution retrospective study. urol int. 2014; 92:150-6. 26. patriarca c, hurle r, moschini m, et al. usefulness of pt1 substaging in papillary urothelial bladder carcinoma. diagn pathol. 2016; 11:6. 27. gershman b, boorjian sa, hautmann re. management of t1 urothelial carcinoma of the bladder: what do we know and what do we need to know? bladder cancer 2015; 2:1-14. correspondence ahmet sahan, md alkan cubuk, md (corresponding author) alkancubuk@hotmail.com orkunt ozkaptan, md kartal dr. lutfi kirdar training and research hospital, department of urology, cevizli mh şemsi denizer cad. e-5 karayolu cevizli mevkii, 34890 kartal istanbul (turkey) fatma gerin, md emine bozkurtlar, md marmara university, department of pathology, istanbul (turkey) asgar garayev, md yıloren tanidir, md haydar kamil cam, md ilker tinay, md marmara university, department of urology, !stanbul (turkey) kasım ertas, md yuzuncu yıl university, department of urology, van (turkey) stesura seveso 245archivio italiano di urologia e andrologia 2019; 91, 4 original paper effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: results from the 2018 #controllati survey fabio parazzini 1, walter artibani 2, giuseppe carrieri 3, luca carmignani 4, salvatore voce 5 on behalf of the #controllati study group* 1 università degli studi di milano dipartimento di scienze cliniche e di comunità, irccs policlinico, milano, italy; 2 società italiana di urologia (siu), roma, italy; 3 dipartimento nefro/urologico clinica urologica e centro trapianti di rene, università degli studi di foggia, italy; 4 università degli studi di milano, unità operativa complessa, ospedale policlinico san donato, milano, italy; 5 divisione di urologia ospedale santa maria delle croci, ravenna, italy. objective: overweight and low physical activity (pa) increase the risk of prostatic enlargement and erectile dysfunction (ed). less clear is the role of these factors at young age on the lifelong risk. materials and methods: during june 2018 the italian society of urologists organized the month of male urologic prevention “#controllati”. men aged 18 years or more were invited to attend urologic centers for a visit and counselling about urologic/andrologic conditions. each participating man underwent a physical examination and was asked about urologic symptoms, sexual activity and possible related problems. results: we analyzed data from 2786 men, aged 55.1 years (sd 10.9, range 19-97). a total of 710 (25.5%) subjects had a diagnosis of prostatic enlargement and 632 (22.7%) of de. overweight/obese men were at increased risk of prostatic enlargement and ed with corresponding odds ratio (0r) in comparison with normal or underweight men, being respectively 1.18 (95% confidence interval (ci) 1.00-1.44) and 1.69 (95% ci 1.39-2.05). the or of prostatic enlargement in comparison with men reporting at age 25 a bmi < 25.0 was 1.22 (95% ci 1.01-1.51) for men with a bmi at 25 years of age ≥ 25; the corresponding or value for ed was 1.17 (0.921.48). considering total pa at diagnosis, the or of prostatic enlargement in comparison with no or low pa, was 0.69 (95%ci 0.55-0.86) for men reporting moderate pa and 0.75 (95%ci 0.58-0.98) for those reporting intense pa. when we considered pa at 25 years of age, the or of subsequent diagnosis of prostatic enlargement, in comparison with men reporting no/low pa at 25 years of age was 0.81 (95%ci 0.63-1.04) for men reporting moderate pa and 0.70 (95%ci 0.52-0.99) for those reporting intense pa. conclusions: these findings underline the utility of encouraging healthy lifestyle habits among young men in order to reduce the subsequent risk of prostatic enlargement and ed. key words: benign prostatic enlargement; hypertension; diabetes; heart disease; body mass index; physical activity. submitted 10 april 2019; accepted 1 may 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.245 introduction benign prostatic enlargement (bpe) and erectile dysfunction (ed) are the two most common urologic diseases in men, the estimated prevalence of pe being about 10% in the fourth decades increasing up to 50% thereafter and that of ed being 12% (1, 2). among the risk factors for these two conditions, lifestyles play a major role. it is well recognized, for example, that overweight, low physical activity (pa), hypertension, hypercholesterolemia and hypertriglyceridemia increase the risk of these conditions at advanced age (3-6). less clear is the role of these factors on the lifelong risk when they were present at younger age (7). since 2016 the italian urologic society (siu, società italiana di urologia) coordinates a huge preventive initiative: the month of male urologic prevention ”#controllati” (8, 9). in the framework of this preventive campaign data have been collected on determinants of the risk of prostatic enlargement and ed. in this paper we present the results of the 2018 initiative with a special focus on risk factors for prostatic enlargement and ed and on lifelong risk for these condition in relation to lifestyle at younger age. methods during june 2018, men aged 18 year or more were invited to attend the participating urologic centers for a free of charge visit and counselling about urologic or andrologic conditions. a pamphlet inviting men for check-up was distributed in chemists and general practitioners’ waiting rooms. an advertising campaign was also set on media. at visit, general data were recorded using a simple questionnaire. the first section of the questionnaire, including data on age, life habits height and weight, was completed by the patient. the section on pa included questions on self-reported intensity of pa (‘none’, ‘low’, ‘moderate’,‘intense’) at work and in leisure time separately. history of hypertension, diabetes, cardiopathy, hypertriglyceridemia and hypercholesterolemia were checked by the urologist. information was also collected on body mass index (bmi) and total pa at age 25 year among men aged 30 year or more. parazzini_stesura seveso 14/01/20 12:44 pagina 245 archivio italiano di urologia e andrologia 2019; 91, 4 f. parazzini, w. artibani, g. carrieri, l. carmignani, s. voce on behalf of the #controllati study group 246 each participating man underwent a physical examination, including digital rectal examination (dre), and was asked by the urologist about urologic symptoms, sexual activity and possible related problems. diagnosis of prostatic enlargement was made by the urologist by dre. erectile function was assessed by asking men about their sexual performance: ed was diagnosed, according to the definition of the nih consensus development panel (10), when a man was consistently unable to attain or maintain a penile erection sufficient for satisfactory sexual performance. the 2002 ics definitions were used for frequency, nicturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying (11). a man was considered a smoker if he had smoked more than one cigarette/day for at least one year; ex-smoker if he had smoked more than one cigarette/day for at least one year, but had stopped more than one year before the interview, and non-smoker if he had never smoked more than one cigarette/day. total pa was evaluated combining occupational and leisure time pa. frequencies (%) were computed as appropriate. odds ratios (or), and the corresponding 95% confidence intervals (ci), adjusted for age were derived using unconditional multiple logistic regression, fitted by the method of maximum likelihood, in which the dependent variable was the presence (case) or absence (control) of the condition and the independent ones were the exposures considered in the analysis. we included in the model age considered as categorical variable (12). results during the 2018 campaign a total of 3092 men entered the study. after exclusion of men who underwent previous surgery for partial or complete prostatectomy and those who did not answer at least one of two questions about pa, we analyzed data from 2786 men, aged 55.1 years (sd 10.9, range 19-97). the reason for visit was urinary symptoms in 504 (18.1%), sexual problems in 270 (9.7%), renal disease in 68 (2.4%) and prostatic problems in 429 (15.4%) (more than one reason was allowed). prevention was the only reason for consultation in 1776 subjects (63.8%). a total of 710 (25.5%) subjects had a diagnosis of prostatic enlargement and 632 (22.7%) of de. table 1 shows the distribution, and the corresponding or, of study subjects according to the diagnosis of prostatic enlargement, ed and age, smoking habits and bmi. the risk of prostatic enlargement and ed increased with age: in comparison with men aged <=40 years or less, the risk of prostatic enlargement was 2.57, 7.22, 17.97 and 39.1 in the age classes 41-50, 51-60, 61-70 and >=71, respectively. the corresponding values for ed were 1.15, 1.63, 3.06 and 4.87. smoking increased the risk of ed: in comparison with never smokers, ex-smokers had an increased risk of ed of 1.38 (95%ci 1.11-1.69) and current smokers of 1.92 (95%ci 1.49-2.48). overweight/obese men were at increased risk of prostatic enlargement and ed the corresponding 0r, in comparison with normal or underweight men, being respectively 1.18 (95%ci 1.00-1.44) and 1.69 (95%ci 1.39-2.05). we have also considered (among men aged 30 years or more) the role of overweight/obesity at 25 years of age on the subsequent risk of prostatic enlargement and ed. in comparison with men reporting at age 25 a bmi < 25.0, the or of prostatic enlargement was for men with a bmi at 25 years of age ≥ 25, 1.22 (95%ci 1.01-1.51); the corresponding value for ed was 1.17 (95%ci 0.921.48). table 2 considers the relation between prostatic enlargement and de and urinary symptoms, hypertension, diabetes, cardiopathy, hypertriglyceridemia and hypercholesterolemia. table 1. odds ratios (and corresponding 95% confidence intervals) of bpe and erectile dysfunction according to selected factors. benign prostatic enlargement age adj or (95%ci) erectile dysfunction age adj or (95%ci) no yes no yes no.* (%) no.* (%) no.* (%) no.* (%) age (years) ≤ 40 166 7.8 7 0.9 1° 150 6.8 23 3.5 1° 41-50 782 36.8 87 11.5 2.57 (1.17-5.66) 736 33.2 133 20.0 1.15 (0.71-1.85) 51-60 718 33.8 225 29.6 7.22 (3.34-15.63) 752 33.9 191 28.7 1.63 (1.02-2.60) 61-70 339 16.0 269 35.4 17.97 (8.29-38.96) 413 18.6 195 29.3 3.06 (1.91-4.90) ≥ 71 118 5.6 171 22.5 35.10 (15.83-77.86) 165 7.4 124 18.6 4.87 (2.94-8.06) smoking habits never 1131 53.3 342 45.1 1° 1198 54.1 275 41.3 1° ex smokers 624 29.4 303 39.9 1.2 (0.98-1.47) 668 30.1 259 38.9 1.38 (1.12-1.69) current smokers 343 16.2 103 13.6 1.1 (0.84-1.47) 317 14.3 129 19.4 1.92 (1.49-2.48) < 10 cig/day 127 8.5 34 7.5 0.94 (0.58-1.53) 130 8.5 31 7.6 1.49 (0.96-2.29) ≥ 10 cig/day 192 12.9 67 14.8 1.27 (0.90-1.78) 174 11.3 85 21.0 2.25 (1.66-3.06) bmi (kg/m2) < 25.0 891 43.2 253 35.8 1° 949 44.1 195 30.8 1° ≥ 25.0 1172 56.8 453 64.2 118. (1.00-1.44) 1189 55.2 436 69.0 1.69 (1.39-2.05) bmi at 25 years of age < 25.0 1293 62.3 443 62.4 1° 1335 62.0 401 63.4 1° ≥ 25.0 384 18.5 123 17.3 1.22 (1.01-1.51) 381 17.7 126 19.9 1.17 (0.92-1.48) *sometimes, the sums do not add up the total due to missing values; °reference category or: odds ratio; ci: confidence interval. parazzini_stesura seveso 14/01/20 12:44 pagina 246 a history of hypertension, diabetes, cardiopathy, high cholesterol levels were significantly associated to an increased risk of prostatic enlargement in the total series. likewise, hypertension, diabetes, cardiopathy, high triglyceride and cholesterol levels were significantly associated to an increased risk of ed. 247archivio italiano di urologia e andrologia 2019; 91, 4 lifestyle habits and prostatic enlargement table 2. odds ratios (and corresponding 95% confidence intervals) of bpe and erectile dysfunction according to medical history. benign prostatic enlargement adj or (95%ci) erectile dysfunction adj or (95%ci) no yes no yes no.* (%) no.* (%) no.* (%) no.* (%) urinary symptoms** no 987 46.5 101 13.3 1° 924 41.7 164 24.6 1° yes 1136 53.5 658 86.7 5.14 (3.97-6.67) 1292 58.3 502 75.4 1.82 (1.47-2.25) erectile dysfunction no 1698 80.0 518 68.2 1° yes 425 20.0 241 31.8 1.27 (1.03-1.57) benign prostatic enlargement no 1698 76.6 425 63.8 1° yes 518 23.4 241 36.2 1.27 (1.03-1.57) hypertension no 1492 70.3 369 48.6 1° 1524 68.8 337 50.6 1° yes 407 19.2 275 36.2 1.6 (1.30-2.619) 457 20.6 225 33.8 1.60 (1.29-1.99) missing 224 10.6 115 15.2 235 10.6 104 15.6 -diabetes no 1884 88.7 599 78.9 1° 1964 88.6 519 77.9 1° yes 78 3.7 80 10.5 1.57 (1.08-1.85) 82 3.7 76 11.4 2.43 (1.70-3.47) missing 161 7.6 80 10.5 170 7.7 71 10.7 cardiopathy no 1857 87.5 577 76.0 1° 1925 86.9 509 76.4 1° yes 76 3.6 74 9.7 1.30 (1.02-1.67) 80 3.6 70 10.5 2.12 (1.47-3.06) missing 190 8.9 108 14.2 211 9.5 87 13.1 hypertriglyceridemia no 1753 82.6 586 77.2 1° 1830 82.6 509 76.4 1° yes 130 6.1 62 8.2 1.31 (0.92-1.85) 130 5.9 62 9.3 1.59 (1.13-2.22) missing 240 11.3 111 14.6 256 11.6 95 14.3 hypercholesterolemia no 1548 72.9 492 64.8 1° 1613 72.8 427 64.1 1° yes 301 14.2 143 18.8 1.30 (1.02-1.67) 315 14.2 129 19.4 1.42 (1.11-1.81) missing 274 12.9 124 16.3 288 13.0 110 16.5 *sometimes, the sums do not add up the total due to missing values; **one or more of the followings: nocturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying; °reference category; adjor: adjusted odds ratio; ci: confidence interval. table 3. odds ratios (and corresponding 95% confidence intervals) of premature ejaculation and erectile dysfunction according to physical activity. benign prostatic enlargement adj or (95%ci) erectile dysfunction adj or (95%ci) no yes no yes no.* (%) no.* (%) no.* (%) no.* (%) occupational pa none/low 1002 48.3 354 49.9 1° 1035 48.1 321 50.8 1° moderate 631 30.4 198 27.9 0.89 (0,7-1,1) 657 30.5 172 27.2 0.86 (0.69-1.08) intense 283 13.6 80 11.3 0.97 (0.72-1.31) 286 13.3 77 12.2 0.98 (0.73-1.30) missing 160 7.7 78 11.0 176 8.2 62 9.8 leisure pa low 767 36.9 317 44.6 1° 785 36.4 299 47.3 1° moderate 893 43.0 272 38.3 0.67 (0.55-0.83) 926 43.0 239 37.8 0.66 (0.54-0.80) intense 319 15.4 84 11.8 0.64 (0.51-0.91) 342 15.9 61 9.7 0.48 (0.36-0.66) missing 97 4.7 37 5.2 101 4.7 33 5.2 total pa low 537 25.9 228 32.1 1° 544 25.3 221 35.0 1° moderate 960 46.2 308 43.4 0.69 (0.55-0.86) 995 46.2 273 43.2 0.65 (0.53-0.80) intense 515 24.8 144 20.3 0.75 (0.58-0.98) 545 25.3 114 18.0 0.56 (0.43-0.72) missing 64 3.1 30 4.2 70 3.2 24 3.8 pa at 25 years of age low 401 19.3 160 22.5 1° 415 19.3 146 23.1 1° moderate 820 39.5 273 38.5 0.81 (0.63-1.04) 858 39.8 235 37.2 0.78 (0.61-0.99) intense 773 37.2 244 34.4 0.70 (0.52-0.99) 785 36.4 232 36.7 0.74 (0.58-1.10) missing 82 3.9 33 4.6 96 4.5 19 3.0 *sometimes, the sums do not add up the total due to missing values; °reference category; adjor: adjusted odds ratio; ci: confidence interval. parazzini_stesura seveso 14/01/20 12:44 pagina 247 archivio italiano di urologia e andrologia 2019; 91, 4 f. parazzini, w. artibani, g. carrieri, l. carmignani, s. voce on behalf of the #controllati study group 248 pa was significantly associated with a decreased risk of prostatic enlargement: considering the total pa at diagnosis, the or of prostatic enlargement, in comparison with men reporting no or low pa, was 0.69 (95%ci 0.55-0.86) among men reporting moderate pa and 0.75 (95%ci 0.58-0.98) among those reporting intense pa. the or of subsequent diagnosis of prostatic enlargement were, in comparison with men reporting no/low pa at 25 years of age 0.81 (95%ci 0.63-1.04) for men reporting moderate pa and 0.70 (95%ci 0.52-0.99) for those reporting intense pa at 25 years of age. similar findings emerged when we considered ed risk. discussion the general results of this analysis show that low pa, high bmi and a history of hypertension, diabetes, hypercholesterolemia, cardiopathy increase the risk of prostatic enlargement. high bmi and low pa at 25 year of age increase the risk of prostatic enlargement at older ages. similar results emerged also for the risk profile of ed. limitations as already discussed in the papers presenting the results of 2016 and 2017 initiative (8, 9), the major flaw of this study is that the study population were men voluntarily presenting to the participating centers. the participating centers were not randomly identified among all italian urologic centers, so they cannot be considered representative of all italian centers. however, they were well distributed over the main areas of the country. in any case, any inference from the present analysis must be made in strictly comparative terms and strictly referred to men attending urologic services. the diagnosis of pe was based on dre that tends to underestimate the prostatic volume (2). any misclassification of men with or without bpe or should lower the observed associations. with regard to the diagnosis of de, it was reported by the men and checked for standard criteria by the physician. the results of this study confirm data from different populations that have reported that high bmi, low pa and a history of hypertension, diabetes, hypercholesterolemia, increase the risk of bpe at all ages (13, 14). all these findings underline that benign bpe shares similar risk factors with metabolic syndrome and cardiovascular diseases. the etiological mechanisms that links these risk factors and prostatic growth are not completely understood. however, it has been shown that lipids (oxidized lowdensity lipoproteins) increase in vitro the secretion of growth and pro-inflammatory factors by human stromal bpe cells in culture (15). along this line, in a clinical perspective, the addition of statins to standard therapy for benign pe lowered prostate volume (16). further, alteration of sex steroid hormone metabolism caused by both obesity and diabetes could lead to ‘pro-inflammatory’ conditions, causing release of chemokines potentially associated with prostate enlargement (17). regular pa has been consistently reported to decrease the risk of bpe. a meta-analysis has shown that moderate-to-vigorous physical activity was associated with up to a 25% decreased risk of benign prostatic enlargment, with the magnitude of the protective effect increasing with the higher levels of activity (18). an interesting finding from the present study is the observation that the or of bpe and ed associated with none/low pa and high bmi at 25 years were higher than unity. few data have been published on the role of pa at younger ages on the lifetime risk of bpe. a previous italian case control study have reported that moderate/intense recreational physical activity (> 2 hours week) at age 30-39 decrease the risk of benign bpe of about 30%. the authors concluded that avoidance of sedentary lifestyle through a moderate recreational pa at any age may help preventing a sizeable number (e.g., approximately 20%) of bpe cases (7). with regard to erectile dysfunction, the risk profile of ed was largely similar with that observed for prostatic enlargement. in particular, the present analysis confirms that smoking, overweight, low pa and history of diabetes, hypertension, cardiopathy, hypercholesterolemia, hypertriglyceridemia, all increased the risk of ed. all these findings underline the role of encouraging healthy lifestyle habits among young men in order to reduce the subsequent risk of prostatic enlargement and ed. references 1. parazzini f, menchini fabris f, bortolotti a, et al, frequency and determinants of erectile dysfunction in italy. eur urol. 2000; 37:43-9. 2. vuichoud c, loughlin kr. benign prostatic hyperplasia: epidemiology, economics and evaluation. can j urol. 2015; 22 suppl 1:1-6. 3. lee s, min hg, choi sh, et al. central obesity as a risk factor for prostatic hyperplasia. obesity (silver spring) 2006; 14:172-9. 4. muller rl, gerber l, moreira dm, et al. obesity is associated with increased prostate growth and attenuated prostate volume reduction by dutasteride. eur urol. 2013; 63:1115-21. 5. bourke jb, griffin jp. hypertension, diabetes mellitus, and blood groups in benign prostatic hypertrophy. br j urol. 1966; 38:18-23. 6. nandeesha h, koner bc, dorairajan ln, sen sk. hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia. clin chim acta. 2006; 370:89-93. 7. dal maso l, zucchetto a, tavani a, et al. lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia. int j cancer. 2006; 118:2632-2635. 8. mirone v, carone r, carrieri g, et al. urinary symptoms and sexual dysfunction among italian men: the results of the #controllati survey. arch ital urol androl. 2017; 89:75-80. 9. mirone v, carrieri g, morgia g, et al. risk factors for benign prostatic enlargement: the role of lifestyle habits at younger age. the #controllati2017 initiative study group. arch ital urol androl. 2017; 89:253-258. 10. nih consensus conference (1993) impotence. consensus development panel on impotence. jama 1993; 270:83-90. 11. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-78. 12. baker nj, nelder ja. the glim system. release 3. oxford: numerical algorithms group; 1978. parazzini_stesura seveso 14/01/20 12:44 pagina 248 13. raheem oa, parsons jk. associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms. curr opin urol. 2014; 24:10-4. 14. parsons jk, carter hb, partin aw, et al. metabolic factors associated with benign prostatic hyperplasia. j clin endocrinol metab. 2006; 91:2562-8. 15. vignozzi l, gacci m, cellai i, et al. fatboosts, while androgen receptor activation counteracts, bph-associated prostate inflammation. prostate. 2013; 73: 789-800. 16. lee sh, park tj, bae mhm, et al. impact of treatment with statins on prostate-specific antigen and prostate volume in patients with benign prostatic hyperplasia. korean j urol. 2013; 54:750-5. 17. jerde tj, bushman w. il-1 induces igf-dependent epithelial proliferation in prostate development and reactive hyperplasia. sci signal. 2009; 2:ra49. 18. parsons jk, kashefi c. physical activity, benign prostatic hyperplasia, and lower urinary tract symptoms. eur urol. 2008; 53:1228-1235. 249archivio italiano di urologia e andrologia 2019; 91, 4 lifestyle habits and prostatic enlargement *participating centers: a.o.u. città della salute e della scienza ospedale molinette, torino (gontero paolo) arcispedale sant'anna ferrara (ippolito carmelo) asl reggio calabria (de martin michele) p.o. umberto i, nocera inferiore (sanseverino roberto) asl presidio ospedaliero carmagnola, chieri (marino gaetano) asst franciacorta ospedale m. mellini (chiari tralce luigi) ospedale mater salutis legnago (curti pierpaolo) aurelia hospital, roma (cusumano roberto) azienda ospedaliera universitaria di sassari (madonia massimo) azienda ospedaliera "umberto i" siracusa (lentini bartolomeo) azienda ospedaliera universitaria, parma (maestroni umberto vittorio) azienda ospedaliera, padova (zattoni filiberto) azienda ospedaliera gaetano rummo benevento (salzano luigi) azienda ospedaliera ospedali riuniti papardo piemonte, messina (mastroeni francesco) azienda ospedaliera policlinico di bari (ditonno pasquale) azienda ospedaliera policlinico di bari (battaglia michele) azienda ospedaliera pugliese ciaccio catanzaro (pirritano domenico) azienda ospedaliera s. antonio e biagio, alessandria (serao armando) azienda ospedaliera s. bortolo, vicenza (ferrarese paolo) azienda ospedaliera s. giuseppe moscati, avellino (cicalese virgilio) azienda ospedaliera sant’anna e san sebastiano di caserta (caggiano sergio) azienda ospedaliera santa maria terni (elisabetta costantini) azienda ospedaliera-universitaria "l. vanvitelli" napoli (de sio marco) azienda ospedaliera-universitaria integrata verona (artibani walter) azienda ospedaliera-universitaria mater domini di catanzaro (damiano rocco) azienda ospedaliera-universitaria policlinico g. martino messina (ficarra vincenzo) azienda ospedaliero-universitaria "policlinico vittorio emanuele" catania (falsaperla mari) azienda ospedaliero-universitaria careggi, firenze (carini marco) azienda ospedaliero-universitaria s. luigi gonzaga orbassano (porpiglia francesco) azienda ospedaliero-universitaria maggiore della carità, novara (volpe alessandro) azienda ospedaliero-universitaria pisana stabilimento di cisanello (selli cesare) azienda ospedaliero-universitaria sant' andrea, roma (tubaro andrea) ospedale civile di voghera (mensi mario) azienda socio sanitaria territoriale santi paolo e carlo, milano (dormia guido) campus università degli studi "gabriele d'annunzio" chieti (raffaele tenaglia) casa di cura ambrosiana cesano boscone (catanzaro francesco) casa di cura gibiino catania (ranno christian) casa di cura giovanni xxiii, monastier di treviso (morana carmelo) casa di cura guarnieri, roma (di marco massimiliano) casa di cura luigi cobellis vallo della lucania (cavaliere aniello) casa di cura malatesta novello cesena (cuzzocrea diego) casa di cura musumeci gecas gravina di catania (leonardi rosario) casa di cura nuova clinica santa rita benevento (coscione mario) casa di cura nuova villa claudia, roma (giulianelli roberto) casa di cura regina pacis, san cataldo (cammarata carla) casa di cura romolo hospital rocca di neto (cappa manlio) casa di cura s. rita, atripalda de simone elia virginio; casa di cura san camillo messina (bruschetta sebastiano); casa di cura santa lucia san giuseppe vesuviano (casoli eugenio) casa di cura sileno ed anna rizzola, san donà di piave (loiero gaetano) casa di cura trusso, ottaviano (de stefano giacomo) casa di cura villa betania, roma (buscarini maurizio) casa di cura villa dei fiori, mugnano di napoli (jungano renato) casa di cura villa esther, avellino (di martino mario) casa di cura villa fiorita, prato (dami andrea cesare) casa di cura villa igea, ancona (cafarelli angelo) casa di cura villa maria, mirabella eclano (morelli emilio) casa di cura villa stabia castellammare di stabia (scognamiglio giuseppe) centro medico politerapica, seriate (paolo belvisi) clinica athena villa dei pini, piedimonte matese (dalena giuseppe) clinica padre pio, mondragone (sepe giuseppe salvatore) clinica pierangeli, pescara (pompa paolo) clinica villa pia, roma (campagna adriano) casa di cura pederzoli, peschiera del garda (grosso gaetano) ospedale generale regionale f. miulli, acquaviva delle fonti (ludovico giuseppe mario) ospedale galliera, genova (introini carlo); fondazione policlinico irccs, milano (montanari emanuele); fondazione ptv policlinico, tor vergata, roma (vespasiani giuseppe); grande ospedale metropolitano bianchi melacrino morelli, reggio calabria (cozzupoli pietro); hesperia hospital, modena (ferrari giovanni); humanitas gradenigo, torino (muto giovanni); humanitas san pio x, milano (nava luciano); irccs policlinico san donato (carmignani luca); irccs policlinico milano (elena ricci, data analysis); irccs aou san martino ist, genova (terrone carlo); istituti clinici zucchi, monza (stefano casellato); istituto clinico s. anna, brescia (najati alrabi); istituto europeo di oncologia, milano (de cobelli ottavio); istituto nazionale tumori irccs "fondazione pascale" napoli (perdonà sisto); ospedale casa sollievo della sofferenza, san giovanni rotondo (cisternino antonio); ospedale buon consiglio fatebenefratelli, napoli (imperatore vittorio); ospedale cardarelli, napoli (fedelini paolo); ospedale carlo urbani, jesi (ferrara vincenzo); ospedale civico di cristina benfratelli , palermo (gianfranco savoca); ospedale civile di guastalla (frattini antonio); ospedale civile p.o. dell'annunziata, cosenza (emilio de giacomo); ospedale civile ramazzini carpi (barusi maurizio); ospedale civile s. giacomo, monopoli (vito domenico ricapito); ospedale civile san salvatore, l’aquila (di clemente luigi); ospedale cottolengo, torino (scoffone cesare marco); ospedale degli infermi, rimini (montanari francesco); ospedale del mare, napoli (zito aniello rosario) ; ospedale della murgia fabio perinei, altamura (de siati mario); ospedale di bassano del grappa (celia antonio); ospedale di belcolle, viterbo (rizzotto antonio); ospedale di senigallia (vincenzo ferrara); ospedale di sondrio (giumelli pierluigi); ospedale di villafranca di verona (pecoraro giuseppe); ospedale cristo re, roma (lorenzo defidio); ospedale don tonino bello molfetta (altomare mauro); ospedale garibaldi nesima, catania (la rosa pasquale gianfranco); ospedale icot, latina (carbone antonio); ospedale l. bonomo, andria (corvasce antonio); ospedale madonna delle grazie, matera (disabato giuseppe); ospedale maggiore, bologna (emili emilio); parazzini_stesura seveso 14/01/20 12:44 pagina 249 archivio italiano di urologia e andrologia 2019; 91, 4 f. parazzini, w. artibani, g. carrieri, l. carmignani, s. voce on behalf of the #controllati study group 250 ospedale maria ss. addolorata, erboli (tufano antonio); ospedale niguarda ca' granda, milano (bocciardi aldo); ospedale privato accreditato villa regina, bologna (cuzzocrea diego ettore); ospedale villa serena, forlì (zambelli massimo); ospedale s. giacomo di novi ligure (montefiore franco); ospedale s. giovanni in persiceto (emilo emili); ospedale s. maria della misericordia, s. andrea delle fratte perugia (ettore mearini); ospedale s. maria delle croci, ravenna (voce salvatore); ospedale s. raffaele turro, milano (gaboardi franco); ospedale sacro cuore di gesù fatebenefratelli, benevento (ferravante paolo); ospedale sacro cuore don calabria, negrar (cavalleri stefano); ospedale san bartolomeo, sarzana (conti enrico); ospedale san biagio domodossolarosa antonio; ospedale san camillo forlanini, roma (gaffi marco); ospedale san donato, arezzo (de angelis michele); ospedale san giacomo apostolo, castelfranco veneto (luca de zorzi); ospedale san giovanni battista, foligno (mearini luigi); ospedale san giovanni di dio, agrigento (ruoppolo michele); ospedale san pio da pietrelcina, vasto (schips luigi); ospedale san raffaele, milano (montorsi francesco); ospedale san salvatore. pesaro (beatrici valerio); ospedale san tommaso dei battuti, portogruaro (amenta michele); ospedale sant'ottone frangipane, ariano irpino (grasso gerardo); ospedale santa maria misericordia, udine (valotto claudio); ospedale santa maria regina degli angeli, adria (meneghini agostino); ospedale santissima trinità, cagliari (de lisa antonello); ospedale spoke, locri (capocasale francesco); ospedale ss. capitanio e gerosa, lovere (ranieri antonio); ospedale vincenzo monaldi, napoli (uricchio francesco); ospedali riuniti di ancona (galosi andrea benedetto); ospedali riuniti di foggia (carrieri giuseppe), presidio ospedaliero cerignola (annunziata gennaro); p.o. s. marta e s. venera di acireale (ingrassia antonino); p.o. umberto i, enna (d'anca michele); policlinico agostino gemelli, roma (bassi pierfrancesco); policlinico di abano terme (porreca angelo); ospedale civile di baggiovara (bianchi giampaolo); policlinico federico ii, napoli (mirone vincenzo); policlinico s. orsola-malpighi, bologna (brunocilla eugenio); policlinico ss. annunziata, chieti (schips luigi); polo pontino ospedale icot, latina (carbone antonio); presidio ospedaliero "vittorio emanuele", gela (condorelli sebastiano); policlinico “vittorio emanuele”, catania (morgia giuseppe); presidio ospedale s.s. pietro e paolo, borgosesia (cipollone giovanni), presidio ospedaliero carlo poma, mantova (dall'oglio bruno) presidio ospedaliero cto unità spinale struttura di neuro urologia, torino (carone roberto); presidio ospedaliero di brescia (simeone claudio); presidio ospedaliero di busto arsizio (buizza carlo); presidio ospedaliero di pescara (renzetti roberto); presidio ospedaliero mazzini, teramo (vicentini carlo); presidio ospedaliero occidentale, castellaneta (di lena sebastiano); presidio ospedaliero perrino, brindisi (brigante salvatore); presidio ospedaliero s. andrea, vercelli (cipollone giovanni); ospedale s. maria del prato, feltre (xausa daniele); villa pini d'abruzzo, chieti (marascia gabriele). correspondence fabio parazzini, md (corresponding author) fabio.parazzini@unimi.it dipartimento di scienze cliniche e di comunità, università di milano, fondazione irccs ca’ granda ospedale maggiore policlinico via commenda 12, 20122 milano (italy) walter artibani, md segreteria@siu.it società italiana di urologia (siu), roma (italy) giuseppe carrieri, md giuseppe.carrieri@unifg.it dipartimento nefro/urologico clinica urologica e centro trapianti di rene università degli studi di foggia (italy) luca carmignani, md luca.carmignani@unimi.it università degli studi di milano, unità operativa complessa ospedale policlinico san donato, milano (italy) salvatore voce, md salvatore.voce@auslromagna.it divisione di urologia ospedale santa maria delle croci, ravenna (italy) parazzini_stesura seveso 14/01/20 12:44 pagina 250 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4366 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.366 role of total motile sperm count in the evaluation of young men with bilateral subclinical varicocele and asthenospermia georgios tsampoukas 1, 2, 4, athanasios dellis 1, 3, antigoni katsouri 5, dominic brown 2, konstantinos deliveliotis 6, mohamad moussa 7, noor buchholz 1, athanasios papatsoris 1, 6 1 u-merge ltd. (urology for emerging countries), london, uk; 2 department of urology, princess alexandra hospital, harlow, uk; 3 department of urology, aretaieion academic hospital, athens, greece; 4 department of urology, agios andreas hospital, patras, greece; 5 department of pharmacy, university of patras, patras, greece; 6 2nd department of urology, university hospital of athens, athens, greece; 7 al zahraa hospital, university medical center, lebanese university, beirut, lebanon. *u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com introduction a subclinical varicocele (sv) is defined as the radiological finding of a dilatation of the pampiniform plexus and the presence of venous reflux, in the absence of clinical varicocele (cv) on physical examination (1, 2). the condition is regarded as an early stage for the development of a clinical varicocele and activity seems to increase the risk (3, 4). in comparison to its clinical analogue, a unilateral, subclinical varicocele is considered an entity of uncertain significance, and the evidence to support treatment, even in the context of male infertility, is weak (5). observation, surgical treatment, embolization and empirical treatment with clomiphene citrate or bioflavonoids has been proposed as possible management options (6-8). a special subgroup of infertile patients with right-sided subclinical and a simultaneous left-sided clinical varicocele seem to have a greater benefit from bilateral intervention in terms of improvement in semen quality and pregnancy rates in comparison to unilateral correction, implicating that the right subclinical varicocele is significant (9). in a similar clinical context, the presence of bilateral subclinical varicocele (bsv) seems to represent a distinct entity with noteworthy clinical significance. the prevalence of bsv seems to be higher in older men, whereas the condition is associated with deterioration of semen quality, especially sperm motility, during a long follow-up (10, 11). previously, we had concluded that the presence of introduction: in comparison to its clinical analogue, the subclinical varicocele represents a questionable entity and specific guidelines for the optimal management are lacking. in our previous study of patients with subclinical varicocele, we showed that bilateral condition is associated with risk of dyspermia. in the present study, we evaluated the risk of deterioration of semen quality in men with bilateral disease and impaired motility according to who criteria. materials and methods: men with bilateral subclinical varicocele, not desiring fatherhood at the time of presentation, were included in study. during initial evaluation, the number of total motile sperm count (tmsc) was calculated and the patients’ age, total testicular volume (ttv), maximum venous size and mean resistive index (ri) of the intratesticular arteries were recorded. we classified the participants in five classes according to the tmsc reading: class a-: tmsc < 5 x 106, class a: tmsc between 5-10 x 106, class b: tmsc between 10-15 x 106, class c: tmsc between 15-20 x 106, and class d: tmsc > 20 x 106 per ejaculate. the participants were seen after 6 months for a repeat spermiogram and physical examination. if clinical varicocele was diagnosed or a new abnormality in the spermiogram was noted, the participants were excluded from the study. the remaining patients were allocated to two groups according to the repeat tmsc reading: patients sub-classified into a lower class (group 1), and patients remaining at the same class (group 2). a comparative analysis was performed between two groups. results: nineteen men were included. nine patients were subclassified (group 1). three patients moved to aclass (< 5 x 106). ten patients remained in the same class having no deterioration (group 2). comparing the two groups, no statistically significant difference was recognized for age, ttv, maximum venous size on both sides, and mean ri (p > 0.05). however, the initial reading for tmsc was 14.57 x 106 in group 1, and 22.84 x 106 in group 2, respectively. this difference was statistically significant (p < 0.05). additionally, in a paired analysis there was a significant difference in tmsc after 6 months (p < 0.05), too. summary conclusions: young men with bilateral varicocele and asthenospermia seem to be at risk of deterioration in their semen quality after a follow-up of 6 months. the measurement of tmsc can unmask patients at risk, whereas men with the lowest readings seem to be at highest risk for deterioration. the possibility of a worsening sperm quality should be considered in the appropriate clinical context. key words: varicocele; subclinical; total motile sperm count (tmsc); infertility; bilateral. submitted 21 june 2020; accepted 24 august 2020 367archivio italiano di urologia e andrologia 2020; 92, 4 bilateral subclinical varicocele and asthenospermia bsv has been associated with abnormal semen parameters in young men in comparison to unilateral sv (12). in this study, we followed a population of young men with bsv and asthenospermia in their spermiogram who did not desire fatherhood at time of presentation with a planned follow-up of 6 months. in order to evaluate their fertility capacity, we used the total motile sperm count (tmsc) instead of classical who criteria. tmsc is considered a more reliable tool for the estimation of pregnancy when a male infertility factor is implicated (13). our aim was to evaluate the risk of deterioration in semen quality and identify possible predictive factors in those patients. materials and methods inclusion criteria were males with bilateral subclinical varicocele, having asthenospermia alone (< 32% progressive motility) according to who 2010 criteria in their spermiogram and not desiring fatherhood at the time of presentation. the subjects were recruited during a period of 2 years (november 2016 december 2018). exclusion criteria were clinical varicocele, previous fatherhood, history of relevant surgery, present infertility concerns, active or chronic urogenital infections, signs and symptoms of primary hypogonadism, testicular microlithiasis, background of cancer, and history of intake of gonadotoxic medications or steroids. the subclinical varicocele was diagnosed by colour doppler ultrasound (graded as grade i as per hirsch classification) when the clinical examination was negative, but a venous dilatation larger than 2mm of the pampiniform plexus with reflux during valsava manoeuvre was demonstrated (14, 15). testicular volume was measured by the ultrasound unit according to the formula volume = 0.53 × length × width × height, and the mean value was obtained. also, the mean resistive index (ri) of at least 3 intratesticular arteries on both sides, and the maximum vein diameter on each side were recorded. asthenospermia was documented by two spermiograms, whereby the spermiogram with the lowest motility value was used for reference. as an objective tool for the assessment of sperm potential, the total motile sperm count was used: ejaculate volume (v) x sperm concentration (sc) x progressive motility (a + b) divided by 100%. for the subsequent analysis, we allocated patients into five classes according to tmsc readings: • class a-: tmsc < 5 x 106 • class a: tmsc 5-10 x 106 • class b: tmsc 10-15 x 106 • class c: tmsc 15-20 x 106 • class d: tmsc > 20 x 106 the patients were seen again after six months with a repeat spermiogram and physical examination. according to those follow-up results, we then formed two groups: • group 1: patients reclassified into a lower category • group 2: patients without downclassification. patient who developed additional abnormalities (e.g. oligospermia) in the spermiogram, or evidence of clinical varicocele were excluded. the two groups were compared in terms of age, maximal left vein diameter, maximal right vein diameter, total testicular volume, mean ri value, the grade of reflux, initial tmsc, fsh and testosterone. for statistical analysis, the shapiro-wilk test was used to check normality, and subsequently the student’s t-test and mann-whitney u-test were used accordingly for the detection of statistically significant differences between the two groups. statistical significance value was set at a p < 0.05. a wilcoxon matched-pairs signed rank test was used to assess the difference in the tmsc at the first assessment, and at subsequent follow-up. results nineteen patients were included in the study. the participants’ characteristics are listed in table 1. the distribution of patients in classes initially, and at 6 months is depicted in figure 1. nine patients were downgraded into a lower class (group 1). ten patients remained in the same class unchanged (group 2). three patients downgraded from class a to class a(tmsc < 5 x 106). a paired t-test comparing the initial tmsc and the follow-up tmsc readings showed a significant difference after a mean follow-up of 6.7 months (p < 0.05, table 2). when comparing the mean values of all the parameters figure 1. the classification of patients according to tmsc range: a< 5 x 106. a 5-10 x 106, b 10-15 x 106, c 15-20 x 106, d > 20 x 106. table 1. patients’ characteristics. age mvd mvd fu ri testosterone fsh ttv (years) (left, mm) (right, mm) (months) (ng/dl) (mui/ml) (ml) no. 19 19 19 19 19 19 19 19 min. 18 2.1 2.1 6 0.45 401 2 24.2 max. 34 3.2 2.8 8 0.64 762 7.5 37.8 range 16 1.1 0.7 2 0.19 361 5.5 13.6 mean +/sd 26 + 4.22 2.73 + 0.31 2.56 + 0.17 6.79 + 0.79 0.555 + 0.05 525 + 97.7 3.83 + 1.31 29.4 + 4.08 median 26 2.80 2.60 7 0.55 489 3.90 28.1 std. error of mean 0.967 0.072 0.04 0.181 0.012 22.4 0.3 0.936 sd: standard deviation, mvd: maximal vein diameter, fu: follow-up in months, ri: resistive index, fsh: follicle-stimulating hormone, ttv: total testicular volume. archivio italiano di urologia e andrologia 2020; 92, 4 g. tsampoukas, a. dellis, a. katsouri, d. brown, k. deliveliotis, m. moussa, n. buchholz, a. papatsoris 368 in both groups, no significant difference was detected in terms of age, maximal vein diameter on both sides, ri, testosterone, fsh and ttv. the initial tsmc reading was however significantly different between the patients in both groups (p < 0.05) (table 3). discussion we decided to study men with bilateral varicocele as we regard the condition as the full expression of varicocele disease. the prevalence has been reported as up to 80%, and differences in detection rates are the result of differences in diagnostic approach (16, 17). moreover, bilateral varicocelectomy is superior to unilateral in terms of the main outcome of pregnancy rates (9, 18). furthermore, the possible common pathophysiological background (bsv and asthenospermia) and similar expectations (no fertility issues and no desire for fatherhood at that time) formed a homogenous group which gives reproducibility to our results. we used tmsc as a marker of semen quality as it is a superior predictive tool for the main outcomes for male infertility in comparison to standard who criteria. specifically, the well-studied range classification into 3 groups (tmsc < 5 × 106; 5 20 × 106; > 20 × 106 spermatozoa, regarded as normospermia) seems to have a superior predictive value in terms of spontaneous pregnancy rates whereas the same applies for infertile couples with male factor infertility undergoing intracytoplasmic sperm injection cycles (icsi) (19, 20). also, tmsc can be used as a method to assess the clinical outcome of varicocelectomy in patients with clinical varicocele (cv), and predict the need of further assisted reproduction technology treatment (21). additionally, a study found no significant differences in the improvement of tmsc after repair in men with sv comparing to men with cv whereas most of patients in the subclinical group had bsv which is relevant to our study (22). in our cohort, the paired analysis showed a significant difference between the initial and follow-up tmsc readings. this means that this group of men might be at risk of deterioration of sperm motility in the future. also, we observed that those men experiencing deterioration had their readings below the so-called normal cut-off of 20 x 106 (14.57 x 106 vs 22.84 x 106, p < 0.05). moreover, 3 out of 4 patients with an initial tmsc range of 5-10 x 106 were later found with a tmsc range of < 5 x 106 at follow-up. although these readings do not necessarily imply infertility, this range is nevertheless associated with lower chances of spontaneous pregnancy rates. in clinical practice, infertile patients with these readings might have been advised to undergo assisted-reproductive modalities (19). thus, our results imply that patients with bsv and asthenospermia with gray-zone values of tmsc < 20 x 106, and especially those with the lowest readings may be at risk of deterioration of their semen quality. no statistically significant difference was found between the two groups in terms of age and no specific conclusions can be drawn. once again, the results must be linked to the appropriate clinical context, e.g. the perspective of the patients and the possible expectations of the couple. age does not seem to be a decisive factor for dyspermia in patients with sv (23), but it does have importance in patients with low grade varicocele undergoing varicocelectomy in relation to actual venous size (24). also, we examined the role of vein diameter on both sides and there was no significant difference between the groups. these results are in accordance with our previous study where no association was found between maximal vein diameter in men with sv and dyspermia (12). this does not sound surprising, as even in clinical forms, even grade seems to be inferior to reflux in terms of prediction of the results of varicocelectomy (25). in our study, the role of reflux was not exhaustively examined, as all of our participants by definition had grade i varicocele (valsava induced reflux) according to hirsch classification, which is helpful for the diagnosis of the subclinical form but lacks pathophysiological significance in adults (26). in young boys, pattern of grade i reflux helps stratify the risk for hypotrophy and assist the follow-up (27). in our previous study in adult men, the pattern of the reflux (lasting all the duration of the valsava vs short-lasting reflux) had not been linked to dyspermia in adults patients with subclinical varicocele (12). reflux is notetable 3. comparison of parameters between group 1 and group 2. parameter group no. mean t-test u-value p value age (years) group 1 9 25.56 t = 0.08748, df = 17 0.93 group 2 10 25.40 mvd (right, mm) group 1 9 2.622 t = 1.447, df = 17 0.16 group 2 10 2.51 itmsc (1 x 106) group 1 9 14.57 t = 2.930, df = 17 0.0093* group 2 10 22.84 ri group 1 9 0.57 t = 1.116, df = 17 0.27 group 2 10 0.54 testosterone (ng/dl) group 1 9 545.3 t = 0.8542, df = 17 0.40 group 2 10 506.7 fsh (mui/ml) group 1 9 3.22 t = 2.082, df = 17 0.052 group 2 10 4.37 ttv (ml) group 1 9 27.69 38 0.58 group 2 10 29.97 mvd (left, mm) group 1 9 2.8 40.50 0.73 group 2 10 2.85 *p < 0.05, statistically significant difference, mvd: maximal vein diameter, itmsc: initial total motile sperm count, ri: resistive index, fsh: follicle-stimulating hormone, ttv: total testicular volume. table 2. match-up comparison of tmsc after mean follow-up of 6.7 months. itmsc (millions) ftmsc (millions) wilcoxon test no. 19 19 min. 6,32 4,22 max. 28,6 28.2 range 22.2 24 mean +/sd 18.9 + 7.32 16.5 + 8.13 median 20 16.8 std. error of mean 1.68 1.86 p value 0.0002* *difference statistically significant, p < 0.05, number of pairs 19, sum of positive ranks 10.50, sum of negative ranks -179.5, two-tailed, median of differences -3.0, itmsc: initial total motile sperm count, ftmsc: follow-up total motile sperm count. 369archivio italiano di urologia e andrologia 2020; 92, 4 bilateral subclinical varicocele and asthenospermia worthy though, and the shunt-type (continuous) reflux is strongly associated with testicular hypotrophy in adolescents (28), whereas prolonged reflux may also predict the outcome of varicocelectomy in adults (25). in terms of the endocrinological profile in our study participants, there was no difference between groups in testosterone or fsh. additionally, all readings were within normal limits reflecting the normal testicular volume found in both groups. it is doubtful if sv should be expected to have any significant effect on testicular volume, and the reports are conflicting (29-31). furthermore, we examined the role of intratesticular ri at the cut-off of 0.6 which has been highlighted as a marker of dyspermia (32, 33). we did not focus on linked parameters peak systolic velocity (psv) and end diastolic velocity (edv) as ri is not associated with the angle of recording (which is extremely demanding in tiny arteries like intratesticular ones) and, therefore, operator-independent and more reliable for the scope of our study. in our cohort, there was no difference between the two groups in terms of ri, whereas the median value in our sample could be considered as normal. this discrepancy might be reflected by the pathophysiological background. varicocele may provoke damage in various sites in the genital tract apart from the testicle e.g. the epididymis which is vital for the motility potential of the spermatozoa and some agents are under evaluation (34-36). even low-grade varicoceles may undermine epididymal function causing infertility issues which might be apparent even when the spermiogram is normal (37). another intriguing aspect lies on the intercommunication between the pampiniform and the periprostatic plexus (38, 39). in the varicoceleassociated infertility, patients with deteriorated motility undergoing varicocelectomy might not experience improvement if the periprostatic plexus is apparently dilated which implicates the complexity in the pathophysiology of the condition (40). also, the topography of the damage caused by the sv might be the reason why infertile patients with sv have low levels of oxidative stress markers (41). in our study, the participants had normal testicles, normal ri and asthenospermia; it could be assumed that if bsv was responsible for the semen deterioration, it might have caused damage in a site different than the testicles and this is why ri is within normal limits. either way, it is doubtful if ri can assist during the evaluation of men with sv. we appreciate our study has certain limitations. first and foremost, the men involved had no fertility concerns at that time and they must not be considered infertile. also, we did not correlate with pregnancy rates, which is the main outcome measure in the evaluation of infertile patients with varicocele and therefore, our study cannot provide safe conclusions to infertile patients with the condition. the clinical merit of our findings must be set in an appropriate clinical context of men incidentally found with bilateral svs. secondly, we appreciate that our sample is small. however, the presentation and the selection criteria were major limitations because as matter of fact, the participants represented an asymptomatic population who normally do not attend in the hospital. we managed to increase the sample size through screening and by inviting young men to the cohort. conclusions despite our small sample, our results showed that young males with bsv and asthenospermia are likely to experience deterioration in their tmsc over time. importantly, patients with borderline tmsc readings seem to be at higher risk of deterioration, and especially patients with very low readings. thus, these patients might not be ideal candidates for a wait & watch approach although the optimal management is unknown. of note, there was no correlation with pregnancy rates and therefore, our observations must be utilized in the appropriate clinical context. references 1. belay r, huang g, shen j.-c., ko ek. diagnosis of clinical and subclinical varicocele: how has it evolved? asian j androl. 2016; 18:182. 2. patil v, shetty smcc. das s redefining the criteria for grading varicoceles based on reflux times: a clinicoradiological correlation. ultrasound q. 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pinggera gm, mitterberger m, bartsch g, et al. assessment of the intratesticular resistive index by colour doppler ultrasonography measurements as a predictor of spermatogenesis. bju int. 2008; 101:722-6. 33. hillelsohn jh,chuang kw, goldenberg e, gilbert br. spectral doppler sonography: a noninvasive method for predicting dyspermia. j ultrasound med. 2013; 32:1427-1432. 34. akdemir s, gurocak s, konac e, et al. different surgical techniques and l-carnitine supplementation in an experimental varicocele model. andrologia. 2014; 46:910-6. 35. milingos sd. the epidymal factor — a diagnostic approach. int j androl. 1985; 8:417-420. 36. mongioi l, calogero ae, vicari e, et al. the role of carnitine in male infertility. andrology. 2016; 4:800-7. 37. pajovic b, dimitrovski a, radojevic n, vukovic m. a correlation between selenium and carnitine levels with hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients. eur rev med pharmacol sci. 2016; 20:598-604. 38. de caestecker k, lumen n, spinoit af, et al. varicocele: the origin of benign prostatic hypertrophy? testosterone dosages in the periprostatic plexus. acta clin belg. 2016; 71:281-283. 39. gat y, goren m. benign prostatic hyperplasia: long-term follow-up of prostate volume reduction after sclerotherapy of the internal spermatic veins. andrologia. 2018; 50. 40. condorelli ra, calogero ae, mongioi' l, et al. varicocele and concomitant dilation of the periprostatic venous plexus: effects on semen viscosity sperm parameters. j endocrinol invest. 2016; 39:543-7. 41. ni k, steger k, yang h, et al. a comprehensive investigation of sperm dna damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. andrology. 2016; 4:816-24. correspondence georgios tsampoukas, md (corresponding author) tsampoukasg@gmail.com scientific-office@u-merge.com noor buchholz, md noor.buchholz@gmail.com u-merge scientific office 1, menandrou street, athens 14561 (greece) dominic brown, md dominic.brown5@nhs.net department of urology, princess alexandra hospital, harlow (uk) athanasios dellis, md aedellis@gmail.com department of urology, aretaieion academic hospital, athens (greece) antigoni katsouri, md a.katsr@gmail.com department of pharmacy, university of patras, patras (greece) konstantinos deliveliotis, md chdeliveli@gmail.com athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, university hospital of athens, athens (greece) mohamad moussa, md mohamad.moussa@zhumc.org.lb al zahraa hospital, university medical center, lebanese university, beirut (lebanon) archivio italiano di urologia e andrologia 2017; 89, 112 original paper daidzein plus isolase associated with zinc improves clinical symptoms and quality of life in patients with luts due to benign prostatic hyperplasia: results from a phase i-ii study daniele tiscione 1, luca gallelli 2, irene tamanini 1, lorenzo giuseppe luciani 1, paolo verze 3, alessandro palmieri 3, vincenzo mirone 3, riccardo bartoletti 4, gianni malossini 1, tommaso cai 1 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of health science, school of medicine, university of catanzaro, catanzaro, italy; 3 department of urology, university of naples, federico ii, naples, italy; 4 department of urology, university of pisa, pisa, italy. objective: in the last years there is a growing interest in nutraceutical substances that seems able to improve clinical symptoms in patients with lower urinary tract symptoms (luts) due to benign prostatic hyperplasia (bph). in this paper, we evaluated both efficacy and safety of a combination of daidzein with isolase and zinc in patients with luts due to bph. materials and methods: in a phase i-ii study clinical trial we enrolled patients with clinical and instrumental diagnosis of luts associated to bph that received a six-month treatment with a combination of daidzein with isolase and zinc (1 tablet/day). clinical, laboratory and instrumental analyses were carried out at the time of admission (t0) and 6 months after the ending of the treatment (t1). the italian version of international prostatic symptom score (ipss), international index of erectile function (iief-5) and quality of well-being (qol) questionnaires were used. the development of adverse drug reactions (adrs) and drug interactions (ddis) were recorded using the naranjo scale and drug interaction probability scale. student’s t test and anova test were used for statistical analysis, and the threshold of statistical significance was set at p < 0.05. results: we enrolled 71 patients, 62 (87.3%) completed the follow-up and we documented a significant differences between t0 and t1 in terms of ipss [21.5 ± 1.2 vs 16.2 ± 1.5; (-4.8); p < 0.001], cmax [9.7 ± 3.7vs 15.3 ± 2.5; (+5.6); p < 0.001] and qol [0.56 ± 0.15 vs 0.84 ± 0.19; (+0.28); p < 0.001]. in contrast, no significant difference were recorded in terms of iief-5 [p = 0.50] and psa [p = 0.67]. finally, we did not record any significant adrs or ddis during the study. conclusions: in this study, we documented that a combination of daidzein with isolase and zinc, reduces the clinical symptoms of luts and improves the quality of life in patients with bph, without the development of adrs or ddis. key words: bph; zinc; luts; equol; isoflavones; medical treatment. submitted 20 january 2017; accepted 18 february 2017 summary no conflict of interest declared. vant lower urinary tract symptoms (luts) that can reduce the quality of life (qol) leading to serious clinical manifestations, e.g. acute urinary retention, urinary incontinence, recurrent urinary tract infection, obstructive uropathy, up to surgery (2). to date, two main categories of drugs are prescribed to treat patients with symptomatic bph: 1) α1-adrenoreceptor antagonists that improve the dynamic component of urination (activation of bladder smooth muscles) and relieve the symptoms (3); 2) 5-aris that block the conversion of testosterone to dihydrotestosterone, and deprive the prostatic tissue of trophic androgenic influence (3). the guidelines for bph/luts recommend a combination therapy with α-blockers and 5ari in patients with moderate-tosevere luts and enlarged prostates (3). unfortunately, these treatments may be related with the development of adrs that can induce the discontinuation of the current therapy with an impaired of both clinical symptoms and quality of life (4). even if the current therapeutic strategies for the management of patients affected by luts associated to bph are able to both control the progression of the disease and relief the symptoms, their use is related with the development of adverse drug reactions (adrs) particularly on sexual function (5). in a recent meta-analysis liu and co-workers, evaluating the effects of 5α-reductase inhibitors (5aris) on sexual function in men with bph, documented that both dutasteride and finasteride compared with placebo were associated with the development of sexual dysfunction (6). the development of adrs represents a common problem during drug administration and represents the most common cause of low adherence to the treatment (7). in the last years, there is a grow interest for nutraceutical agents in several clinical manifestations for several reasons, e.g. low side-effect and costs, high level of adherence and a low rate of efficacy of standard treatments with subsequent patient disappointment and drop-out (8-9). several nutraceutical products for the management of bph have been commercialised in italy (10) and between these, a new nutraceutical is migar® mg, an association between daidzein, isolase and zinc. the effects of each component have been well-reported in literature. doi: 10.4081/aiua.2017.1.12 introduction benign prostatic hyperplasia (bph) is one of the most common diseases affecting the elderly male and is the most common clinical condition among all urological outpatients (1). bph is characterized by clinically reletiscione_stesura seveso 04/04/17 09:05 pagina 12 13archivio italiano di urologia e andrologia 2017; 89, 1 nutraceuticals for the management of luts related to bph daidzein is a soy isoflavone, after oral intake it crosses the enterocytes, is reduced to s-(-)equol through the intermediate dihydrodaidzein, and then is converted by deoxygenation to yield the bioactive s-(-)equol by intestinal bacteria (11). several bacteria are able to perform this reaction and one of these, lactococcus garvieae, was found in some italian cheeses and has been used to produce the first natural s-(-) equol-containing nutraceutical (12). the bioactivation of daidzein to s-(-)equol is related to gender, race and age and requires: specific equol-producing bacteria and an optimum intraluminal conditions in terms of redox potential for the above described reactions (13). therefore, the aim of this study is to evaluate the efficacy and safety of migar® mg retard in patients affected by luts related to bph. methods study design we performed a non-sponsored phase i-ii study in a single urological institution between january to june 2016. the study was conducted according in line with good clinical practice guidelines and with the ethical principles of the declaration of helsinki. before the beginning of the study, all participants signed the written informed consent. no placebo run-in period was performed. experimental protocol patients with clinical and instrumental diagnosis of moderated-severe luts related to bph were recruited. we considered patients with moderate-severe luts and with an international prostatic symptom score (ipss) score > 8. at the time of admission (t0), the patients underwent selfadministered baseline questionnaire [ipss, international index of erectile function (iief-5) and quality of well-being (qol)], urological examination with history interview, prostate ultrasound and uroflowmetry (cmax) with evaluation of post-voided residual volume (pvr), in accordance with the procedure described in eau guidelines (3). all patients who met the inclusion criteria were enrolled and received 1 tablet/day of a combination of daidzein with isolase and zinc (migar® mg retard). the follow-up was performed 6 months after the end of therapy (t1) when patients underwent ipss, iief-5qol questionnaires and urological examination with laboratory and instrumental examinations. inclusion and exclusion criteria patients male who were > 45 years, sexually active, with a maximal urinary flow rate (cmax) < 15 ml/s and with a post-residual voided volume < 100 cc, with ipss = 8 or greater, with prostate specific antigen (psa) < 4 ng/ml (or higher in presence of negative prostate biopsy) and iief-5 score > 21 were enclosed in this study. on the other hand, patients with diabetes, liver, and/or renal failure, cancer, prostatitis, active urinary tract infection, chronic retention or polycystic kidney disease were excluded from the study. moreover, we also excluded patients with urethral stenosis or anatomical abnormality interfering with the evaluation of voiding function. patients with a history of transurethral resections of the prostate, laser therapy, or thermo therapy or with allergy to one or more compounds of migar® mg retard were also excluded. finally, were also excluded from the study the patients that received a treatment for luts/bph in the last 6 months. questionnaires and urological examinations the validated italian versions of the ipss (14), iief-5 (15) and qol (16) were self-administered to each patient at the arrival to the urological institution. the qol scale was selected because it has been successfully applied to acute illnesses, whereas other quality of life scales, including the short form-36 (sf-36) health survey, are more suitable in chronic cases (17). higher scores on the qol scale reflect a higher quality of life (16). the iief-5 questionnaire was used for exclude all patients with concomitant erectile dysfunction and for evaluating the impact of treatment on sexual function at the end of the follow-up therapy. composition and characterization of the extracts used migar® mg retard each tablet contains daidzein 20 mg, genistein 20 mg, isolase® 40 mg, zinc 10 mg. instrumental, laboratory and urological evaluation at the time of the enrolment (t0) and during the followup (t1), all patients underwent urological examinations with the prostate volume ultrasound evaluation. ultrasound prostate evaluation was performed during the urological examination with a trans-abdominal approach. the trans-abdominal scan was performed with the patient's supine after applying ultrasonic gel to the suprapubic regions (3). moreover, an uroflowmetry (cmax) with ultrasound evaluation of post-voided residual volume was performed by using urodyn® 1000 system (medtronic functional diagnostics a/s.) (3). all patients were asked to do the psa dosage. in order to exclude urinary tract infection, both leukocyte esterase and nitrite levels were measured in urine samples through dipstick assay (bayer multistik pro reagent strips) (3). main outcome measure the main outcome measure was the improvement of quality of life at the end of the whole study period, in terms of changes in ipss, ipss-qol, cmax, pvr, and qol from baseline to the evaluation point, that is, 6 months. as secondary endpoints we considered a change between t0 and t1 in the following parameters: psa values, prostate volume, progression of disease, and surgical treatment. clinical failure was defined as the persistence of symptoms after the treatment or the suspension of therapy for significant reported adrs, in particular on sexual function (3). finally, from the beginning of the study (t0) and up to its ending (t1), the development of adrs or of drug-drug interactions (ddis) were recorded in agreement with our previous paper (18) using the naranjo scale and the drug interaction probability scale, in agreement with the common terminology criteria for adverse events (ctcae) guidelines (19). safety assessments included treatment-emergent adverse events (teaes) and serious aes (saes). the study design is reported in figure 1. tiscione_stesura seveso 04/04/17 09:05 pagina 13 archivio italiano di urologia e andrologia 2017; 89, 1 d. tiscione, l. gallelli, i. tamanini, l.g. luciani, p. verze, a. palmieri, v. mirone, r. bartoletti, g. malossini1, t. cai 14 efficacy outcome the efficacy outcome was identified as a statistically significant difference between clinical data recorded at the time of admission (t0) and those recorded at the end of the study (t1). drug adherence at the end of the study, the adherence to the treatment was calculated using a formula based on the number of tablets consigned at the time of admission and on the number of tablets returned unused at the end of the study. statistical analysis the required sample size for the present study was calculated under the following conditions: difference between t0 and t1, 4 ± 1 score points in the ipss score; α error level, 0.05 two-sided; statistical power, 80%; and anticipated effect size, cohen’s d = 0.5. the calculation yielded 45 individuals. at baseline, the independent sample 2tailed t-test was used to compare variables. for categorical parameters, chisquare test was applied. changes from baseline to end of therapy were analyzed using ranked one-way analysis of variance (anova) with a term for treatment group. all data are expressed as mean ± standard deviation. the threshold of statistical significance was set at p < 0.05. all reported p-values are two-sided. all statistical analyses were performed by using spss 21.0 (ibm corporation, armonk, ny, usa), while g*power (institut für experimentelle psychologie, heinrich heine universität, dusseldorf, germany) was used for power calculation. results during the study period, 71 patients were enrolled. nine patients (12.7%) were lost during the follow-up and excluded from the analysis, while 62 patients (87.3%) completed the study (mean age 65.4 ± 5.6 years). baseline characteristics history, clinical, laboratory, instrumental and questionnaires data at the time of admission are reported in table 1. follow-up examination at t1 we recorded a significant difference in terms of ipss in all patients [21.5 ± 1.2 vs 16.2 ± 1.5; (-4.8); p < 0.001], and cmax [9.7 ± 3.7 vs 15.3 ± 2.5; (+5.6); p < 0.001], post-voiding residual volume [85 ± 20.6 vs 50 ± 18.5; (-35); p < 0.001], qol [0.56 ± 0.15 vs 0.84 ± 0.19; (+0.28); p < 0.001]. we did not record any in terms of psa evaluation [2.47 ± 5.6 vs 2.09 ± 4.3; p = 0.67], prostate volume [41.5 ± 5.8 vs 42.1 ± 7.5 p = 0.61] and iief-5 [22.1 ± 1.8 vs 22.3 ± 1.5 p = 0.50] between t0 and t1 (table 2). figure 1. the figure shows the study schedule. ipss: international prostatic symptom score; iief-5*: international index of erectile function; qol: quality of well-being. v1: visit 1, at the enrolment; v2: visit 2 at the second follow-up (6 months). table 2. questionnaire results at the first follow-up visit (6 months). table 1. clinical, instrumental and laboratory patient’s data at the enrolment time. the table shows the mean change differences from baseline to 6 months relative to main outcome measures. ipss†: international prostatic symptom score; iief-5*: international index of erectile function; qol‡: quality of well-being. the table shows all anamnestic, clinical and questionnaires data at enrolment. sd#: standard deviation; ipss†: international prostatic symptom score; iief-5*: international index of erectile function; qol‡: quality of well-being baseline values follow-up values (sd* or %) (sd* or %) efficacy outcomes ipss† 21.5 ± 1.2 16.2 ± 1.5 treatment difference -4.8 ± 1.1 (p < 0.001) iief-5* 22.1 ± 1.8 22.3 ± 1.5 treatment difference 0.1 ± 0.2 (p = 0.50) qol§ 0.56 ± 0.15 0.84 ± 0.19 treatment difference 0.28 ± 0.02 (p < 0.001) maximal urinary flow rate (ml/sec) 9.7 ± 3.7 15.3 ± 2.5 treatment difference 5.6 ± 0.8 (p < 0.001) post-voiding residual volume (ml) 85 ± 20.6 50 ± 18.5 treatment difference -35 ± 1.9 (p < 0.001) patients (n°) 62 age (mean ± sd#) 65.4 ± 5.6 marital status married 56 (90.3) unmarried 6 (9.7) educational qualification primary school 31 (50) high school 20 (32.2) university 11 (17.8) sexually active (past month) 62 (100) symptoms score at baseline (mean ± sd#) ipss† 21.5 ± 1.2 iief-5* 22.1 ± 1.8 qol‡ 0.56 ± 0.15 charlson comorbidity index 0-1 62 (100) ≥ 2 laboratory serum totale psa (ng/ml) 2.47 ± 5.6 serum creatinine (ng/ml) 1.0 ± 0.6 urine dipstick negative 62 (100) positive ultrasound and uroflowmetry data prostate volume (ml) 41.5 ± 5.8 post-voiding residual volume (ml) 85 ± 20.6 maximal urinary flow rate (ml/sec) 9.7 ± 3.7 v1 clinical, instrumental, laboratory evaluation, ipss, iief-5, qol and enrolment screening (up to 3 months) treatment: 6 months v2 (6 months) clinical, instrumental, laboratory evaluation, ipss, iief-5, qol migar© mg retard 1 tablet q24h tiscione_stesura seveso 04/04/17 09:05 pagina 14 15archivio italiano di urologia e andrologia 2017; 89, 1 nutraceuticals for the management of luts related to bph adrs during the study period, 1 patient (1.6%) developed a mild adrs (nausea) that did not require drug discontinuation or other treatments. moreover, did not document the development of ddis, while we recorded a 100% adherence to the treatment and a 100% compliance to the experimental protocol. discussion in this phase i-ii clinical trial, we evaluated the efficacy and the safety of a new nutraceutical agent named migar® mg containing daizein, isolase and zinc in the treatment of luts related to bph. it has been documented that in italy, about 50% of treatment used in patients with bph are phytotherapies, while in germany and other european countries, these represent the firstline treatment for mild-to-moderate luts in patients with bph. isoflavones show a chemical structure similar to the estrogen which allows them to bind to both alpha and beta estrogen receptors, exerting estrogen-like effects and so also called as phytoestrogens (21). whereas estrogen binds to and transactivates both estrogen receptors, isoflavones preferentially bind to and transactivate estrogen beta receptor exerciting tissue-selective effects (22) that is expressed in prostate epithelial cells and plays a role in cellular homeostasis inducing anti-proliferative, pro-differentiative (23), and pro-apoptotic effects (2324). in this concern, several clinical trials documented that isoflavones are able to suppress psa expression in patients with prostate cancer cells. in a recent metaanalysis, zhang et al., evaluating the effects of isoflavones on prostate cancer risk, analyzed 11.346 cases and 140.177 controls and documented that daidzein, genistein, and glycitein were associated with a reduction of prostate cancer risk with an odds ratio: 0.85, 0.87 and 0.89, respectively (25). in agreement, in an experimental model performed in human prostate cancer cell lines lu et al., recorded that s-equol has significant anti-prostate cancer activities probably related to the activation of the transcription factor forkhead box o3 via an akt-specific pathway and inhibitory effects on mdm2 expression (26). moreover, in an experimental animal model bae et al. reported that genistein and equol are strong inhibitors of testosterone 5α-reductase enzyme, suggesting that isoflavones could be used in the management of patients with luts (27). in fact, wong et al. documented in elderly men that the dietary intake of genistein, glycitein or daidzein was related with a significant decrease of luts (28). in our study, we documented that oral intake of migar® mg reduces luts with an improvement of uroflowmetry parameters, ipss score and qol. probably these improvements could be related to a potentiating of daidzein induced by isolases that seems to be able to improve the action time of equol reducing its catabolism and increasing its clinical efficacy. on the other hand the presence of zinc in this studied formulation could plays synergic effects with daidzein and isolases. in fact, a long period clinical study (4-year) documented that chronic prostate inflammation is related to both severity and progression of bph and luts and zinc has antioxidant and anti-inflammatory activity and changes in prostate zinc concentrations play a role in the improvement of bph (29). take together these published data confirm our results documenting the efficacy of this new nutraceutical formulation in patients with luts. however, nutraceuticals are dietary supplements, and it is not necessary to demonstrate data on efficacy or safety before marketing therefore could be possible the development of adrs or ddis during their use. in the present study, using the naranjo probability scale and the drug interaction probability scale, we failed to report the development of severe adrs or ddis during the treatment with this compound. in particular, we recorded the development of a probable mild adr in 1 patient only but this manifestation did not induce the discontinuation of the treatment, documenting the safety of this nutraceutical. moreover, must be underlined that enrolled patients did not develop sexual dysfunction, and the optimal sexual activity should be considered as one principal aim in the management of patients with luts associated to bph (30). previously, we documented that a better sexual quality of life is correlated with a higher overall quality of life regardless of the urinary function in patients affected by luts due to bph10. finally, in our study we documented a complete adherence (100%) to the treatment and a complete compliance (100%) to the experimental protocol and it may be related to the improvement of qol. the present study has two limitations: first, the lacks of placebo arm, because in italy ethically patients must receive a treatment during a spontaneous study, as ours; second, we evaluated the safety and efficacy of this new compound for a short time that did not allow evaluating its effects for a long time. conclusions in this study, we demonstrated that combination of daidzein plus isolase and zinc (migar® mg retard) reduces the symptoms and improves the quality of life in patients affected by luts due to bph, without the development of adrs. acknowledgements we are grateful to professor john denton (department of modern philology, university of florence) for manuscript language revision. contributions tc, dt, it data collecting and analyzing; tc, dt, pv manuscript writing; gm, rb, ap, lg, vm supervision. references 1. egan kb. the epidemiology of benign prostatic hyperplasia associated with lower urinary tract symptoms: prevalence and incident rates. urol clin north am. 2016; 43:289-97. 2. fitzpatrick jm. the natural history of benign prostatic hyperplasia. bju int. 2006; 97 suppl 2:3-6; discussion 21-2. 3. oelke m, bachmann a, descazeaud a, et al. eau guidelines on the treatment and follow-up of non-neurogenic male lower urinary tiscione_stesura seveso 04/04/17 09:05 pagina 15 archivio italiano di urologia e andrologia 2017; 89, 1 d. tiscione, l. gallelli, i. tamanini, l.g. luciani, p. verze, a. palmieri, v. mirone, r. bartoletti, g. malossini1, t. cai 16 tract symptoms including benign prostatic obstruction. eur urol. 2013; 64:118-40. 4. kaplan sa. side effects of α-blocker use: retrograde ejaculation. rev urol. 2009; 11(suppl 1):s14-s18. 5. nickel jc, sander s, moon td. a meta-analysis of the vascularrelated safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. int j clin pract. 2008; 62:1547-59. 6. liu l, zhao s, li f, et al. effect of 5α-reductase inhibitors on sexual function: a meta-analysis and systematic review of randomized controlled trials. j sex med. 2016; 13:1297-310. 7. cindolo l, pirozzi l, sountoulides p, et al. patient's adherence on pharmacological therapy for benign prostatic hyperplasia (bph)associated lower urinary tract symptoms (luts) is different: is combination therapy better than monotherapy? bmc urol. 2015; 15:96. 8. cai t, tiscione d, gallelli l, et al. serenoarepens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients. arch ital urol androl. 2016; 88:177-182. 9. cai t, gallelli l, meacci f, et al. the efficacy of umbelliferone, arbutin, and n-acetylcysteine to prevent microbial colonization and biofilm development on urinary catheter surface: results from a preliminary study. j pathog. 2016; 2016:1590952. 10. cai t, morgia g, carrieri g, et al. an improvement in sexual function is related to better quality of life, regardless of urinary function improvement: results from the idiprost® gold study. arch ital urol androl. 2013; 85:184-9. 11. tanaka m, fujimoto k, chihara y, et al. isoflavone supplements stimulated the production of serum equol and decreased the serum dihydrotestosterone levels in healthy male volunteers. prostate cancer prostatic dis. 2009; 12:247-52. 12. fortina mg, ricci g, foschino r, et al. phenotypic typing, technological properties and safety aspects of lactococcus garvieae strains from dairy environments. j appl microbiol. 2007; 103:445-53. 13. kenneth d, setchell r, clerici c. equol: history, chemistry, and formation. j nutr. 2010; 140:1355s-1362s. 14. badia x, garcia-losa m, dal-re r. ten-language translation andharmonization of the international prostate symptom score: developinga methodology for multinational clinical trials. eur urol. 1997; 31:129-40. 15. rosen rc, riley a, wagner g, et al. the international index of erectilefunction (iief): a multidimensional scale for assessment of erectiledysfunction. urology. 1997; 49:822-30. 16. kaplan rm, bush jw, berry cc. health status: types of validity and the index of wellbeing. health serv res 1976; 11:478-507. 17. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin epidemiol. 1998; 51:1025-36. 18. gallelli l, colosimo m, tolotta ga, et al. prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis living in nursing homes. eur j clin pharmacol. 2010; 66:137-44. 19. naranjo ca, busto u, sellers em, et al. a method for estimating the probability of adverse drug reactions. clin pharmacol ther. 1981; 30:239-245. 20. kuiper gg, carlsson b, grandien k, et al. comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. endocrinology. 1997; 138:863-870. 21. margeat e, bourdoncle a, margueron r, et al. ligands differentially modulate the protein interactions of the human estrogen receptors alpha and beta. j mol biol. 2003; 326:77-92. 22. zhang w, makela s, andersson lc, et al. a role for estrogen receptor beta in the regulation of growth of the ventral prostate. proc natl acad sci. usa 2001; 98:6330-6335. 23. imamov o, morani a, shim gj, et al. estrogen receptor-beta regulates epithelial cell differentiation in the mouse ventral prostate. proc natl acad sci. usa 2004; 101:9375-9380. 24. mcpherson sj, hussain s, balanathan p, et al. estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and tnfalpha mediated. proc natl acad sci. usa 2010; 107:3123-3128. 25. zhang q, feng h, qluwakemi b, et al. phytoestrogens and risk of prostate cancer: an updated meta-analysis of epidemiologic studies. int j food sci nutr. 2016; 9:1-15. 26. lu z, zhou r, kong y, et al. s-equol, a secondary metabolite of natural anticancer isoflavone daidzein, inhibits prostate cancer growth in vitro and in vivo, though activating the akt/foxo3a pathway. curr cancer drug targets. 2016; 16:455-65. 27. bae m, woo m, kusuma iw, et al. inhibitory effects of isoflavonoids on rat prostate testosterone 5α-reductase.j acupunct meridian stud. 2012; 5:319-22. 28. wong sy, lau ww, leung pc, et al. the association between isoflavone and lower urinary tract symptoms in elderly men. br j nutr. 2007; 98:1237-42. 29. jarosz m, olbert m, wyszogrodzka g, et al. antioxidant and anti-inflammatory effects of zinc. zinc-dependent nf-αb signaling. inflammopharmacology 2017; 25:11-24 30. messina r, mirone v. benign prostatic hyperplasia an economic assessment of fixed combination therapy based on a literature review. arch ital urol androl. 2015; 87:185-9. correspondence daniele tiscione, md irene tamanini, md lorenzo giuseppe luciani, md gianni malossini, md tommaso cai, md ktommy@libero.it department of urology, santa chiara regional hospital largo medaglie d'oro 9 trento, italy luca gallelli, md department of health science, school of medicine, university of catanzaro, catanzaro, italy paolo verze, md alessandro palmieri, md vincenzo mirone, md department of urology, university of naples, federico ii, naples, italy riccardo bartoletti, md department of urology, university of pisa, pisa, italy tiscione_stesura seveso 04/04/17 09:05 pagina 16 archivio italiano di urologia e andrologia 2020; 92, 134 original paper effectiveness of a novel oral combination of d-mannose, pomegranate extract, prebiotics and probiotics in the treatment of acute cystitis in women dario pugliese 1, anna acampora 2, angelo porreca 3, luigi schips 4, cindolo luca 1 1 department of urology “villa stuart” private hospital, rome, italy; 2 institute of public health, catholic university of sacred heart, rome, italy; 3 department of robotic urological surgery, abano terme hospital, abano terme, italy; 4 department of urology, “g. d'annunzio” university, chieti, italy. objective: urinary tract infections (utis) are defined as the symptomatic presence of pathogens in the urinary tract that are typically diagnosed by microscopy and culture of urine samples. over the long-term antibiotic courses, alternative prophylactic methods as probiotics, cranberry juices and d-mannose have been introduced for recurrence prevention. the present study aimed to determine whether a new combination of d-mannose, pomegranate extract, prebiotics and probiotics is effective in modifying symptoms reported by women with acute uncomplicated acute cystitis. material and methods: this is a pilot study, performed between september 2018 and november 2018 at the department of urology of villa stuart private hospital. a dose of a new combination of agents was administered twice daily for 5 days and then once a day for 10 days. together with the compound, forced hydration (> 2 liters/day) has been strongly suggested. antibiotics were permitted only in case of clinical worsening. changes in patients’ symptoms, the therapeutic effects and changes in quality of life (qol) were evaluated clinically and through a validated questionnaire, the acute cystitis symptom score (acss) at the first visit (t0), 15 (t1) and 30 (t2) days later. results: thirty-three patients were enrolled in the study (mean age 38,1 ± 11.2 years) and all completed the treatment protocol. at t1 visit, all symptoms or the majority of symptoms went off in 10 women (30.3%) and at t2 in 30 women (90.9%); some symptoms still remained in 16 women (48.5%) at t1 and in 3 women (9.1%) at t2; the persistence of all symptoms or the worsening of the condition was observed in 7 patients (21.2%) at t1 and in none at t2. the mean score reported at all the acss sub-scales significantly decreased between baseline and t1 and t2. typical symptoms decreased from 11.5 (10.5-12.6) to 4.9 (4.0-5.9) and to 2.7 (2.1-3.3) (p-values < 0.0001); differential symptoms decreased from 3.1 (2.6-3.6) to 0.6 (0.3-0.9) and to 0.3 (0.1-0.5) (p-values 0.009 to < 0.0001); qol mean score also decrease from 7.2 (6.77.7) to 4.0 (3.3-4.6) and to 1.7 (1.2-2.1) (p-values < 0.0001). six patients required antibiotics and no adverse events were recorded. conclusions: our study suggests that the action of the compounds, administered in this new combination, could help in an effective management of symptoms of acute cystitis in women, without antibiotics, in a wide majority of the cases. lack of microbiological assessment is a clear limitation of the study. moreover, lack of a control group is another important limitation. finally, hyperhydration could have been a confounding factor in interpretation of results. key words: urinary tract infection; cystitis; female; fructooligosaccharide; mannose; prebiotics; probiotics; pomegranate; symptom score. submitted 9 august 2019; accepted 22 november 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.34 introduction urinary tract infections (utis) are common in general practice, and their diagnosis relies on a combination of characteristic signs and symptoms, urinalysis and a positive urine culture (1). an acute uncomplicated cystitis corresponds to a subset of utis including new-onset or recurrent cystitis in non-pregnant women, female patients without relevant anatomical or functional abnormalities of the urinary tract, not related to indwelling urinary catheters, and in the absence of relevant comorbidities such as renal diseases, immunocompromising diseases or diabetes (2, 3). nowadays, antibiotic therapy represents the treatment of choice, recommended by eau guidelines, as it is effective towards the rapid symptoms resolution (2). however, antibiotic usage is related to side effects and increases resistance rates and, consequently, leads to high medical costs, prolonged hospital stays, and increased mortality (2, 4-5). thus, alternative therapies are needed to reduce the risk of antimicrobial resistance development. probiotics (6), cranberry products (7) and d-mannose (8) have been introduced and studied as a single component or in several combinations (9). the aim of this pilot study was to investigate whether a new combination of d-mannose, pomegranate extract, prebiotics and probiotics is effective in modifying symptoms reported by women with acute uncomplicated cystitis. material and methods this is an uncontrolled experimental pilot study, performed between september 2018 and november 2018 at the department of urology of villa stuart private hospital. all patients provided written informed consent. the trial was conducted according to the good clinical practice guidelines and the declaration of helsinki (10) and was approved by the local ethics committee. female patients admitted at our institution during the recruitment period, complaining of urinary symptom suggestive of uti were included in the study. patients were excluded if they presented relevant comorbidities. the exclusion criteria were: pregnancy, antibiotic therapy for uti within the last month, genital infection, not pugliese_stesura seveso 01/04/20 18:55 pagina 34 35archivio italiano di urologia e andrologia 2020; 92, 1 non antibiotic treatment of acute cystitis well compensated diabetes mellitus, abnormality of the urinary tract, signs of pyelonephritis (i.e. fever over 38°c, chills, kidney tenderness by palpation), urine incontinence requiring pads. at the time of inclusion (t0), eligible patients completed the acute cystitis symptom score (acss), a validated questionnaire, specifically developed for self-assessment of acute uncomplicated cystitis (auc) assessing typical and differential symptoms, quality of life, and changes after therapy in female patients with auc (11-13). typical symptoms including frequency, urgency, pain or burning with urination, pain in the suprapubic area, feeling of incomplete bladder emptying and gross hematuria were scored from 0 (not at all) to 3 (severe). secondly, differential symptoms, such as low back pain, vaginal discharge, urethral discharge or fever and chills were also scored from 0 (not at all) to 3 (severe). in addition, patients recorded how much they felt bothered by their symptoms and how much symptoms impacted on their work/everyday practice and social activities (impairment score, range 0 to 3). changes from baseline at first and second follow-up collected as dynamics are categorized from 0 to 4 (0: all symptoms have gone away; 1: majority of symptoms has gone away; 2: majority of symptoms is still present; 3: no changes in my symptoms; 4: now i feel worse). a dose of a new combination of agents, (prolactis ivu©, omega pharma, cantù, italy) was administered twice daily for 5 days and then once a day for 10 days. according to the company data, prolactis ivu contains d-mannose 2 g, prebiotics (fructo-oligosaccharide 1g), pomegranate extract 250 mg (with 70% titration of ellagic acid 175 mg) and probiotics (lactobacillus plantarum lp115 ≥ 2 billion colony-forming unit). each component has a peculiar mechanism of action that contributes to contrast bacteria. d-mannose provides anti-adesive properties against bacteria, in particular e. coli (14). pomegranate extract and, in particular ellagic acid, has proven anti flagellar-propelled motility of certain strains of e. coli (15). lactobacillus plantarum improves vaginal colonization of lactobacilli, a natural mechanism of defense against urinary tract infections (16). in particular, lactobacilli can prevent the adherence, growth and colonization of uropathogenic bacteria (17). fructo-oligosaccharides are prebiotics, that stimulate the growth and activity of intestinal bacteria in the large bowel by acting as a substrate for them (18). together with the combination of agents, forced hydration (> 2 liters/day) has been strongly suggested. patients were instructed to contact the department in case of worsening, persistence or recurrence of symptoms. in case a patient returned with ongoing complaints during the study period, further treatments, including antibiotics, were considered depending on the specific case and on physician choice. dynamics changes, changes in total acss and its subscales were assessed at day 15 (t1) via a telephone interview by a certified urologist, and at day 30 (t2), during the end of study in-office visit. response to treatment in terms of complete response, improvement of symptoms, persistence of symptoms or worsening of symptoms were registered as efficacy outcome. incidence of adverse events and numbers of secondary antibiotic treatment were also registered. statistical analysis descriptive statistics were performed calculating mean value and related standard deviation for continues variables as age, and by frequencies and percentages for categorical variables as menopausal status, presence of cystocele, diabetes mellitus, number of episodes per year ≥ 3. data regarding changes in dynamics were also reported as frequencies and percentages at first and second follow-up. mean scores, mean differences between baseline and first and second follow-up along with their 95% confidence interval were also reported. paired t-test comparing mean scores between baseline and first or second follow-up visit was used in order to test the hypothesis that no differences exist after a period of administration of the studied compound in total or subscale scores. a p-value < 0,05 was considered for statistical significance. all the analyses were performed using statistical package stata 13.1 results forty-two female patients were admitted at our institution, complaining of urinary symptom suggestive of uti. nine patients were excluded due to relevant comorbidities, neurologic bladder or grade iv cystocele according to baden-walker classification (19) with high post-void residual urine (> 100 ml). thirty-three patients were, eventually, enrolled (mean age 38 ± 11.2) and completed the treatment protocol. twenty-one percent were postmenopausal, 24% had a clinically significant cystocele, 27% suffered from wellcompensated diabetes. about 79% reported < 3 episodes of uti/year (table 1). at first follow-up (f-up) t1 visit, all symptoms or the table 1. characteristics of the study sample. table 2. dynamics at first and second follow-up visit (n° and %). characteristic study sample (n = 33) age (mean, sd) 38.1 (11.2) bmi (n, %) < 25 21 (63.6) ≥ 25 12 (36.4) menopause (n, %) 7 (21.2) cystocele (n, %) 8 (24.2) diabetes (n, %) 9 (27.3) episodes per year (n, %) < 3 26 (78.8) ≥ 3 7 (21.2) bmi: body mass index. follow-up 1 follow-up 2 0 2 (6.1) 19 (57.6) 1 8 (24.2) 11 (33.3) dynamic 2 16 (48.5) 3 (9.1) 3 6 (18.2) 4 1 (3.0) pugliese_stesura seveso 01/04/20 18:55 pagina 35 archivio italiano di urologia e andrologia 2020; 92, 1 d. pugliese, a. acampora, a. porreca, l. schips, l. cindolo 36 majority of symptoms went off in 10 women (30.3%) (table 2 dynamics at t1) and at second follow-up visit in 30 women (90.9%) (table 3 dynamics at t2); some symptoms still remained in 16 women (48.5%) at t1 and in 3 women (9.1%) at t2. persistence of symptoms or the worsening of the condition were observed in 7 patients (21.2%) at t1 and in none at t2. bmi and premenopausal state were statistically associated with worse symptom score at t1 (p = 0.015 for bmi ≥ 25 and p = 0.01 for pre-menopausal state). this difference was not confirmed at t2 whereas a trend of association was present for patients with cystocele (p = 0.06) (table 2). regarding the mean score at the acss subscales, the analysis showed a significant reduction in all the subscales between baseline visit and both t1 and t2. the reported mean score in typical symptoms at baseline was 11.5 (10-5--12-6), falling to 4.9 (4.0-5.9) at t1 and to 2.7 (2.1-3.3) at t2 (p-values < 0.0001). the mean score in differential symptoms was 3.1 (2.6-3.6) at baseline, falling to 0.6 (0.3-0.9) at t1 and to 0.3 (0.1-0.5) at t2 (p-values 0.009 to < 0.0001). lastly, the qol mean score was 7.2 (6.7-7.7) at baseline, falling to 4.0 (3.3-4.6) at t1 and to 1.7 (1.2-2.1) at t2 (p-values < 0.0001). also difference in mean scores between baseline and t1 and t2 are reported in table 4. six patients required antibiotics, during t1 (2 patients after 5 days and 4 patients after 7 days) due to symptoms persistence or worsening. these patients were included in symptoms analysis too both in t1 and t2. no adverse events were recorded. discussion the aim of this pilot study was to investigate a new combination of d-mannose, pomegranate extract, prebiotics and probiotics as an effective treatment in modifying a specific questionnaire in women with acute uncomplicated cystitis. acss is an 18-item selfreporting questionnaire including six questions about “typical” symptoms of auc, four questions regarding “differential” symptoms suggestive of alternative diagnoses and three questions on quality of life items (11-13, 20). even if antibiotic therapy is currently the treatment of choice due to high efficacy, this must be balanced against the emergence of microorganism resistant to a great variety of antibiotics. thus, the pain and discomfort of the uti must be balanced with the cost and risk of developing resistance when using antimicrobials (4-5, 21-23). thus, even if continuous prophylaxis and self-starting antibiotic treatment are commonly accepted options for prophylaxis, a non-antibiotic management could be effective also in limiting these recurrences (24-28). the results of this pilot study showed that the majority of patients enrolled were safely treated with progressive resolution of symptoms. in particular, after fifteen days all symptoms or the majority of symptoms went off in 10 women (30.3%) and after thirty days this result was obtained in 90.9% of women. thus, our results sustain the hypothesis that uti is a self-limiting disorder in many patients. even without antibiotic treatment, symptomatic infection seems to heal in a substantial number of women (24). there is no table 4. table 3. mean (95% confidence interval) acss scores changes between baseline and first follow-up acss sub-scales baseline first follow-up difference between baseline p-value and first follow-up typical 11.5 (10.5 to 12.6) 4.9 (4.0 to 5.9) 6.6 (5.9 to 7.3) < 0.0001 differential 3.1 (2.6 to 3.6) 0.6 (0.3 to 0.9) 2.5 (2.0 to 2.9) < 0.0001 quality of life 7.2 (6.7 to 7.7) 4.0 (3.3 to 4.6) 3.2 (2.5 to 3.9) < 0.0001 acss scores changes first and second follow-up first follow-up second follow-up difference between first p-value and second follow-up typical 4.9 (4.0 to 5.9) 2.7 (2.1 to 3.3) 2.2 (1.4 to 3.0) < 0.0001 differential 0.6 (0.3 to 0.9) 0.3 (0.1 to 0.5) 0.3 (0.1 to 0.6) 0.009 quality of life 4.0 (3.3 to 4.6) 1.7 (1.2 to 2.1) 2.3 (1.7 to 2.8) < 0.0001 acss scores changes between baseline and second follow-up baseline second follow-up difference between baseline p-value and second follow-up typical 11.5 (10.5 to 12.6) 2.7 (2.1 to 3.3) 8.8 (7.8 to 9.8) < 0.0001 differential 3.1 (2.6 to 3.6) 0.3 (0.1 to 0.5) 2.8 (2.2 to 3.3) < 0.0001 quality of life 7.2 (6.7 to 7.7) 1.7 (1.2 to 2.1) 5.5 (4.9 to 6.1) < 0.0001 total bmi menopause cystocele diabetes episodes/year dynamic at first follow-up n (%) < 25 ≥ 25 yes no yes no yes no < 3 ≥ 3 0 2 (6.1) 2 (9.5) 0 (0) 2 (28.6) 0 (0) 0 (0) 2 (8.0) 1 (11.1) 1 (4.17) 2 (7.7) 0 (0) 1 8 (24.2) 8 (38.1) 0 (0) 0 (0) 8 (30.8) 0 (0) 8 (32.0) 2 (22.2) 6 (25.0) 7 (26.9) 1 (14.3) 2 16 (48.5) 9 (42.9) 7 (58.3) 2 (28.6) 14 (53.9) 5 (62.5) 11 (44.0) 2 (22.2) 14 (58.3) 12 (46.1) 4 (57.1) 3 6 (18.2) 2 (9.5) 4 (33.3) 3 (42.9) 3 (11.5) 3 (37.5) 3 (12.0) 3 (33.3) 3 (12.5) 4 (15.4) 2 (28.6) 4 1 (3.0) 0 (0) 1 (8.3) 0 (0) 1 (3.9) 0 (0) 1 (4.0) 1 (11.1) 0 (0) 1 (3.9) 0 (0) p value 0.015 0.010 0.172 0.123 0.873 dynamic at second follow-up n (%) < 25 ≥ 25 yes no yes no yes no < 3 ≥ 3 0 19 (57.6) 15 (71.4) 4 (33.3) 3 (42.9) 16 (61.5) 18 (72.0) 1 (12.5) 15 (62.5) 4 (44.4) 17 (65.4) 2 (28.6) 1 11 (33.3) 4 (19.1) 7 (58.3) 3 (42.9) 8 (30.8) 5 (20.0) 6 (75.0) 6 (25.0) 5 (55.6) 8 (30.8) 3 (42.9) 2 3 (9.1) 2 (9.5) 1 (8.3) 1 (14.3) 2 (7.7) 2 (8.0) 1 (12.5) 3 (12.5) 0 (0) 1 (3.9) 2 (28.6) 3 4 p value 0.077 0.551 0.006 0.248 0.097 pugliese_stesura seveso 01/04/20 18:55 pagina 36 37archivio italiano di urologia e andrologia 2020; 92, 1 non antibiotic treatment of acute cystitis general consensus in clinical trial results. a trial by christiaens et al. compared clinically suspected uti treated with nitrofurantoin or placebo. in the placebo group, more than half had some symptomatic improvement and the effect of the treatment was not statistically significant (p = 0.08) (29). conversely, ferry et al. compared different pivmecillinam regimens and a placebo in a large uti trial with slightly a clear advantage in favor of any antibiotic regimen in terms of symptoms resolution (30). moreover, another study of ferry et al., which included 288 patients placebo-treated showed slow decline of symptom. after one week, 30% of women were completely symptoms-free, while 75% were free from suprapubic and loin pain, 45% from urgency and dysuria. at end of study (at six weeks) percentage rose up to 90, 70 and 55%, respectively for specific symptoms and to 54% for all symptoms (31). our result at one-month follow-up is quite similar (57.6%) of complete symptom resolution. to our knowledge, this is the first study which analyses in a real life setting whether hyperhydration and a formula of d-mannose, prebiotics, probiotics and pomegranate extract might be effective in modifying a cystitisspecific questionnaire in women with symptoms of acute cystitis. however, none of these studies involved a symptomatic treatment arm. there are some limitations in our study. lack of control arm and microbiological confirmation of uti are the main limitations. however, in common clinical practice it is difficult to perform a urine culture in many situations like in the week-end or in the evening and night. moreover, we included some women who do not fit the definition of uncomplicated uti according to eau guidelines, including also post-menopausal women, diabetic and with pelvic organ prolapse. a strength point could be that we included also a subset of recurrent utis (rutis). in fact rutis that are defined as having greater than two infections in a 6-month period, or three infections over twelve months, are included in uncomplicated uti but are typically excluded in randomized clinical trial dealing with auc. another limitation of the study is the absence of long term follow up to investigate recurrence in the months after the treatment. given the uncontrolled design of the study, it is not possible to verify the amount of contribution of each component of the formula. conclusions our study suggests that the synergistic action of the components of this new combination could help the bacterial washout resulting in an effective management of acute cystitis in women without antibiotics in a wide majority of the cases. this approach was also safe because no women had consequences of non-antibiotic management. however, a larger sample size and longer follow-up are needed to confirm these promising results. references 1. flores-mireles al, walker jn, caparon m, hultgren sj. urinary tract infections: epidemiology, mechanisms of infection and treatment options. nat rev microbiol. 2015; 13:269-84. 2. bonkat g, bartoletti rr, bruyère f, et al. eau guidelines on urological infections. retrieved from:https://uroweb.org/guideline/ urological-infections/access date 05/08/2019. 3. bent s, nallamothu bk, simel dl, et al. does this woman have an acute uncomplicated urinary tract infection? jama. 2002; 287:2701-2710. 4. chen yh, ko w c, hsueh pr. emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. expert opin. pharmacother. 2013; 14:587-596. 5. bader ms, loeb m, brooks aa. an update on the management of urinary tract infections in the era of antimicrobial resistance. postgrad med. 2017; 129:242-258. 6. schwenger em, tejani am, loewen ps. probiotics for 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gilmore bf. clinical relevance of the eskape pathogens. expert rev. anti infect ther. 2013; 11:297308. 22. bauer ka, kullar r, gilchrist m, file tm jr. antibiotics and adverse events: the role of antimicrobial stewardship programs in 'doing no harm'. curr opin infect dis. 2019; 32:553-558. 23. fenwick ea, briggs ah, hawke ci. management of urinary tract infection in general practice: a cost-effectiveness analysis. br j gen pract. 2000; 50:635-9. 24. sihra n, goodman a, zakri r, et al. nonantibiotic prevention and management of recurrent urinary tract infection. nat rev urol. 2018; 15:750-776. 25. bleidorn j, gagyor i, kochen mm, et al. symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? results of a randomized controlled pilot trial. bmc med. 2010; 8:30. 26. wagenlehner fm, vahlensieck w, bauer hw, et al. prevention of recurrent urinary tract infections. minerva urol nefrol. 2013; 65:9. 27. del popolo g, nelli f. recurrent bacterial symptomaticcystitis: a pilot study on a new natural option for treatment. arch ital urol androl. 2018; 90:101-103. 28. vicariotto f. effectiveness of an association of a cranberry dry extract, d-mannose, and the two microorganismslactobacillus plantarum lp01 and lactobacillusparacasei lpc09 in women affected by cystitis: a pilot study. j clin gastroenterol. 2014; 48 suppl 1:s96-101. 29. christiaens tc, de meyere m, verschraegen g, et al. randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. br j gen pract. 2002; 52:729-34. 30. ferry sa, holm se, stenlund h, et al. clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the lutiw project. scand j prim health care. 2007; 25:49-57. 31. ferry sa, holm se, stenlund h, et al. the natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. scand j infect dis. 2004; 36:296-301. correspondence dario pugliese, md (corresponding author) dariopugliese87@gmail.com luca cindolo, md lucacindolo@gmail.com department of urology “villa stuart” private hospital via trionfale, 5952 rome (italy) anna acampora, md anna.acampora@unicatt.it institute of public health, catholic university of sacred heart largo a. gemelli, 8 rome (italy) angelo porreca, md angelo.porreca@casacura.it department of robotic urological surgery, abano terme hospital piazza cristoforo colombo, 1, 35031 abano terme pd (italy) luigi schips, md luigischips@hotmail.com department of urology, “g. d'annunzio” university via s. camillo de lellis, 66054 vasto (ch) (italy) pugliese_stesura seveso 01/04/20 18:55 pagina 38 139archivio italiano di urologia e andrologia 2019; 91, 3 review nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer arrigo f.g. cicero 1, olta allkanjari 2, gian maria busetto 3, tommaso cai 4, gaetano larganà 5, vittorio magri 6, gianpaolo perletti 7, francesco saverio robustelli della cuna 8, giorgio ivan russo 5, kostantinos stamatiou 9, alberto trinchieri 10, annabella vitalone 2 1 dip. di scienze mediche e chirurgiche, alma mater studiorum università di bologna, bologna, italy; 2 dipartimento di farmacologia e fisiologia “v. erspamer”, sapienza, università di roma, roma, italy; 3 department of urology, sapienza università di roma, policlinico umberto i, roma, italy; 4 department of urology, santa chiara regional hospital, trento, italy; 5 urology department, university of catania, catania, italy; 6 ambulatorio territoriale di urologia ed ecografia urologica, asst nord milano, milano, italy; 7 dipartimento di biotecnologie e scienze della vita, sezione di scienze mediche e chirurgiche, università degli studi dell'insubria, varese, italy, and faculty of medicine and medical sciences, ghent university, ghent belgium; 8 department of drugs sciences, university of pavia, pavia, italy; 9 urology department, tzaneion hospital, piraeus, greece; 10 cdc ambrosiana milano, italy. during the last years, pharmaceutical innovations in primary care are dramatically less frequent and will be even more rare in the next future. in this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new “nutraceutical” science. medicinal plants, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. the pharmacological properties searched for the treatment of prostatic diseases are anti-androgenic, anti-estrogenic, antiproliferative, antioxidant and anti-inflammatory. the most studied and used medicinal plants are serenoa repens, pygeum africanum and urtica dioica. other promising plants are cucurbita pepo, epilobium spp, lycopersum esculentum, secale cereale, roystonea regia, vaccinium macrocarpon. in parallel, epidemiological studies demonstrated that diet may play an important role on incidence and development of prostatic diseases. the mediterranean diet is rich of elements with anti-oxidant properties that act as a protective factor for prostatic cancer. similarly, low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for benign prostatic hyperplasia (bph). serenoa repens in the treatment of symptoms of bph has been tested either alone or, more frequently, in combination with other medicinal plants, alpha-blockers and inhibitors of 5alpha reductase (5-ari). recent meta-analyses found the effectiveness of serenoa repens similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate low urinary tract symptoms (luts), nocturia and discomfort. clinical trials showed potential synergistic effect of serenoa repens with other medicinal plants and drugs. in addition to serenoa repens, there are many other medicinal plants for which clinical evidence is still controversial. urtica dioica, pygeum africanum and curcubita pepo can be considered as an adjunct to the common therapies and their use is supported by studies showing improvement of symptoms and flowmetric indices. lycopene and selenium are summary no conflict of interest declared. doi: 10.4081/aiua.2019.3.139 natural products with antioxidant and anti-inflammatory action. the combination of lycopene and selenium with serenoa repens was able to reduce inflammation in histological prostate sections and to further improve symptom scores and urinary flow in patients with bph on tamsulosin treatment. similar effects could be obtained with the use of other carotenoids, such as astaxanthin, and/or zinc. efficacy on symptoms of patients with bph of some polyphenols such as quercitin, equol and curcumin have been demonstrated by clinical studies. pollen extract is a mixture of natural components able to inhibit several cytokines and prostaglandin and leukotriene synthesis resulting in a potent anti-inflammatory effect. pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. beta-sitosterol is a sterol able to improve urinary symptoms and flow measures, but not to reduce the size of the prostate gland. palmitoylethanolamide (pea) is an endogenous fatty acid amide-signaling molecule with anti-inflammatory and neuroprotective effects that can have an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain. finally, several plant-based products have been subjected to preclinical, in vitro and in vivo, investigations for their potential pharmacological activity against prostate cancer. some epidemiological studies or clinical trials evaluated the effects of beverages, extracts or food preparations on the risk of prostate cancer. some plant species deserved more intense investigation, such as camelia sinensis (green or black tea), solanum lycopersicum (common tomato), punica granatum (pomegranate), glycine max (common soy) and linum usitatissimum (linen). key words: medicinal plant; prostate; benign prostatic hyperplasia; prostate cancer; antiproliferative effect; 5α-reductase; serenoa repens; pygeum africanum; urtica dioica; cucurbita pepo; lycopene; selenium; polyphenols; pollen extract; beta-sitosterol; palmitoylethanolamide. submitted 1 july 2019; accepted 25 july 2019 cicero_stesura seveso 30/09/19 18:17 pagina 139 archivio italiano di urologia e andrologia 2019; 91, 3 a.f.g. cicero, o. allkanjari, g.m. busetto, et al. 140 introduction to nutraceutical prescription (arrigo f.g. cicero) during the last years, the pharmaceutical innovation in primary care are dramatically less frequent and will be even more rare in the next future. in this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new nutraceutical science. the term “nutraceutical” has been created by stephen de felice in 1989 from the union of the words “nutrition” and “pharmaceutical”, to include dietary components or (more generically) botanical bioactive compounds with positive effects on well-being and health preservation, but also for the cure of some common health disorders (1). the most part of nutraceuticals has been identified in vegetables (2) such as β-glucans, tocotrienols, plant sterols/stanols, polifenols (anthocyanins, proanthocyanidins, flavonols, stilbens, catechins, epicatechins, cumarins, ellagic acid, isoflavons, lignans, etc.) whose biological activities are numerous and often well-documented. much less numerous are the nutraceuticals of animal origin, even if some of them, as the omega 3 polyunsaturated fatty acids are among the most used nutraceuticals around the world (4). there are a large number of medical areas where nutraceuticals are currently used, among them urology and andrology. to warrant the consumer safety and to help the citizens to correctly choose the most adequate nutraceuticals, current laws state that the marketed products should be safe and adequately labelled. then, the european commission promoted specific rules on the nutritional and healthy properties of dietary supplements that can be disclaimed on nutraceutical boxes (health claims) (december 20th, 2006) (5, 6). the european commission approved health claims are based on the opinions of an external agency, the european food safety authority (efsa), that periodically should organize meeting of expert panels selected to evaluate and re-evaluate health claims based on the available preclinical and clinical scientific data (7, 8). currently, the use of dietary supplements and functional foods for the health maintenance and disease prevention is in continuous increase and the number of available products in the market is growng even more intensively. so, how to navigate (as prescribers, sellers or consumers) among 20-30 products containing similar bioactives, in different combinations, that suggest similar effects but with costs often really different? for some of them we have (almost) complete preclinical and clinical pharmaco-toxicological dossiers, till the availability of metaanalysis of randomized clinical trials. however, in the most part of cases, what is known about single bioactives is transferred to the combined marketed products without any kind of test on the final formulation. the main reasons of this are resumed in table 1. in fact, the companies need to market new (at least apparently) “unique” products in a context where the registration and copyright are easily copied and scarcely protected. the cost of the high quality bioactives and the need to create original products often push the industries to add more and more low-dosed components in a single pill/tablet to make the product more complex (“original”) trying to make up eventual synergies, almost never demonstrated. of course, the use of low-dosed bioactives is a warranty of product safety and tolerability and to avoid the comparison to pharmacological drugs of natural origin, however it reduces the probability to observe a clinical effect. thus, how to recognize a serious product? as regards monocomponent products, it is relatively easy. the proposed nutraceuticals should have an adequate bibliography support that should include (at least): – the description of the mechanism of action, eventually associated with notes on pharmacokinetic (for instance, resveratrol has an oral bioavailability near to zero, being the supplementation of the raw form of the molecule very doubtful); – a therapeutic indication supported by randomized, double-blind, placebo-controlled clinical trials carried out on subjects similar to the ones we need to treat in regard to age, ethnicity, and disease profile; – quality (bioactive titration) and dosage similar to the one shown to be efficacious and safe in clinical trial. as regards nutraceuticals in combination, the requirement are similar if the single components are all supported by scientific evidence of efficacy and safety, and if they are included in the same pill/tablet at the tested doses. if a kind of synergy of components is suggested, this has to be clearly demonstrated with specific trials or, alternatively, it should be never mentioned. of course, the risk of interaction between the components of a combined nutraceutical should also been considered (9). when the informative brochure of the product is complete and correct, this will help the prescriber to adequately select the more adequate product in the market, being also more protected from a legal point of view (10). we have to remember that the final responsibility of the prescriber remains in the knowledge to of the effective dosages of the bioactives (based on the results of adequately designed clinical trials or their meta-analysis), of possible pharmacological interaction and adverse events, and of the adequate length of treatment (in particular, avoiding short cyclic treatment for chronic diseases). preclinical studies on medicinal plants, used in the treatment of prostatic diseases (annabella vitalone, olta allkanjari) phytotherapy could be useful in the treatment and pretable 1. factors limiting the application of available scientific data to the combinations of nutraceutical products available in the market. • no legal need to prove efficacy • no legal possibility to declare efficacy (lack of approved health claim) • incomplete pharmaco-toxicological dossiers • cost of high quality bioactives and/or of pharmaceutical technologies used to make them bioavailable (for instance coenzyme q10, resveratrol, lycopene) • industry need to differentiate their product from the other ones • need to produce absolutely safe products (often limiting the dosage under the efficacy level) cicero_stesura seveso 30/09/19 18:17 pagina 140 vention of mild to moderate prostatic diseases. the etiology of prostatitis, benign prostatic hyperplasia and hypertrophy (bph) can be complex and the intervention is often multi-targeted. the pharmacological properties useful for the treatment of the urinary tract diseases are anti-androgenic, antiestrogenic, anti-proliferative, antioxidant and antiinflammatory. the most studied and used medicinal plants are: serenoa repens, pygeum africanum and urtica dioica. phytosterols and fatty acids are the pharmacologically active phytochemicals usually found in these plants; however, they are more used as a phytocomplex (total extract of the plant) than as isolated compounds. in preclinical research, serenoa is responsible of numerous mechanisms of action, including: inhibition of the dihydrotestosterone binding (dht) to its receptors present in the cytosol of prostatic cells, of 5α-reductase (both isoforms), of cyclooxygenase (cox) and of 5-lipoxygenase (lox); it induces apoptosis of prostatic epithelial cells and it presents antiestrogenic activity, spasmolytic effect due to blockage of calcium channels and β-adrenergic antagonism (11). similar mechanisms have been found for pygeum and nettle, probably due to the presence of β-sitosterol and consisting in the inhibition of 5α-reductase, of prostatic cell proliferation, blockage of the cell cycle in the g2 phase and induction of apoptosis in prostate cancer cells (12, 13). furthermore, atranorin and atraric acid, present in pygeum, inhibit the androgen receptor nuclear translocation, endogenous psa expression, and fibroblast proliferation in human prostate cells. lignans, lectins and polysaccharides contained in nettle extract, seem to exert anti-proliferative and anti-inflammatory activity, and to inhibit the binding of sex hormones to the sex hormone binding globulin. other promising plants are cucurbita pepo, epilobium spp (14), lycopersum esculentum, secale cereale, roystonea regia, vaccinium macrocarpon. they have anti-inflammatory and anti-androgenic properties. in particular, the tomato fruit extract (containing lycopene, polyphenols, etc.) down-regulates 5α-reductase and inhibits cox. the inhibitory properties against 5α-reductase appear also for roystonea regia, probably exerted by the fatty acids. furthermore, in vitro, antiproliferative, antimicrobial, antioxidant and radical scavenger properties seem encouraging for epilobio, tomato, pollen extracts of secale cereale and roystonea regia (15). vaccinium macrocarpon inhibits aromatase and is helpful in the urinary tract infection, because it acidifies the urine and inhibits bacterial adherence to uroepithelial cells (16). the mechanism of action of the plants listed above has to be confirmed in in vivo models. other specific plants and/or substances have still limited scientific evidence. nutritional epidemiological studies and prostate diseases (giorgio ivan russo, gaetano larganà) prostatic diseases, like prostatic cancer (pca) and benign prostatic hyperplasia (bph), are influenced by different factors, like age, hormone profile and genetics. several epidemiologic studies demonstrated how diet may play an important role in prostatic diseases incidence and development. knowledge of the different kind of effects of foods on prostate could help us to understand how better prevent and treat these diseases, exploiting synergic effects of specific drugs. pca represented the most common incident cancer in men in developed countries in 2013 (17). western diet, characterized by high intake of energy, red and processed meats and fat but low intake of fibres has been associated to an increased risk to develop an advanced pca (18, 19). instead, mediterranean diet (medi), that is characterized by use of olive oil and high intake of fibres, fish, fruits, vegetables, legumes and cereals in association with moderate to low intake of dairy products and moderate intake of wine, is a diet rich of components with anti-oxidant proprieties that could protect from pca (20). in fact, countries following medi, particularly southern european countries, have a lower incidence and mortality from pca, compared to other european countries (21, 22). a 2015 review included several papers evaluating the effect of single components of medi on incidence and development of pca: olive oil, an unsaturated fat, was not associated with the risk of advanced pca, that was increased for saturated fat (23-26); in a 2010 metanalysis (27) there was an association between fish consumption and a significant reduction of pca-specific mortality; higher intake of legumes and cereals has been associated with a decreased risk of several cancer (28) , included pca (29, 30); there was a positive association between dairy product consumption and pca (31); a 2010 review showed how a moderate daily intake of alcohol, 3 drinks per day, does not appear to influence pca risk (32); lastly russo et al. showed how consumption of food rich of phenolic acids, like fruits, vegetable, coffee, tea and cacao were associated to a reduced risk of pca development (33). bph is one of the most common medical conditions in older men (34). a study evaluating more than 3500 patients showed that total protein intake (particularly animal protein) is positively associated with the risk of bph, while in men who consumed at least 4 servings per day of fruits and vegetable, there was a lower risk of bph (35-38). lycopene, contained in tomatoes, seems to help to reduce lower urinary tract symptoms (luts) and to inhibits bph progression, as well as epigallocatechin-3gallate, contained in green tea (39, 40). the human prostate gland contains higher level of zinc than other tissues and kristal et al. (38) showed that zinc could have a protective role for bph, although excessive consumption may significantly increase the risk of advanced pca (41-43). like fot pca, high alcohol intake may be associated with bph (44). in conclusion, epidemiologic studies demonstrated that diet habits could help to prevent pca and bph incidence and their development and could be used in a multimodal therapy to prevent and treat these diseases. particularly, medi, a diet rich of elements with anti-oxidant properties related to use of olive oil, high intake of fibres, fish, fruits, vegetables, legumes and cereals, moderate to low intake of dairy products and moderate intake of wine, is a protective factor for pca. similarly, 141archivio italiano di urologia e andrologia 2019; 91, 3 nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer cicero_stesura seveso 30/09/19 18:17 pagina 141 archivio italiano di urologia e andrologia 2019; 91, 3 a.f.g. cicero, o. allkanjari, g.m. busetto, et al. 142 low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for bph. instead, high intake of saturated fats and animal meat, and excessive alcohol consumption could be a risk for both pca and bph development. clinical use of serenoa repens in bph treatment (kostantinos stamatiou) a variety of phytotherapeutic agents are used in traditional and alternative medicine to treat lower urinary tract symptoms. the most commonly used preparations originate from the species saw palmetto. their extract serenoa repens (sr) exhibits marked anti-inflammatory, anti-androgenic and anti-proliferative effects. for this reason, it has been the subject of clinical and experimental research on the treatment of symptoms of benign prostatic hyperplasia. a non-systematic search was performed in electronic libraries for clinical trials, experimental studies and systematic reviews on the topic. main outcomes of the abovementioned studies are displayed in table 2. sr in the treatment of symptoms of bph has been tested either alone or, more frequently, in combination or in comparison with other phytotherapeutics, alpha-blockers and inhibitors of 5-α reductase (5-ari). with regard to studies using sr extract as monotherapy for men with bph an confirmed lower urinary tract symptoms (luts), lopatkin et al. and giulianelli et al. showed significant improvement in symptom scores (ipss ans iief-5) and uroflowmetry at 6-month follow up (45, 46). accordingly, sinescu et al. (47) demonstrated a significant improvement of mild or moderate luts, quality of life (qol), urinary flow, residual urinary volume and erectile function and gerber et al. demonstrated improvement in urinary symptoms compared with placebo (but no measurable effect on urinary flow) (48). on the contrary, the large trial of camus study group found no differences between improvements of urinary symptoms between sr extract and placebo group at 72-week follow-up (49) in accordance to other placebo-controlled trials (50, 51). recently, ye et al. (52) in a double blind, placebo-controlled study found significant improvements in the urinary flow, ipss, male sexual function (msf-4 and iief scores) in the sr extract group. in none of these studies significant side effects of sr were observed. higher doses of sr cannot influence neither the impact on luts nor the quality of sexual performance (53, 54). efficacy of sr was compared to other treatments. alcaraz et al. (55) found equivalent efficacy with respect to alpha-blockers and 5-ari in luts improvement; pytel et al. (56, 57) confirmed similar results as measured by ipss, qol, index of sexual function (msf-4), size of the prostate, urodynamic parameters (but no change of plasma sexual hormones). a prospective multicentre doubleblind randomized study comparing tamsulosin (0.4 mg/24h) with sr (320 mg/24h) found no differences in ipss, urinary flow and psa at 12-month follow up (58). sr was used in combination with other treatment. the addition of dietary supplements or other phytotherapeutic agents improved the effect of sr (59, 60). the combination of sr with alpha-blockers agents (tamsulosin, silodosin) was more effective than monotherapy according to some authors (61, 62) although others were not able to demonstrate no extra benefits by combination therapy (63-68). recent meta-analyses found the effectiveness of sr similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate luts, nocturia and discomfort (69-71). the ability of sr to reduce prostatic size is controversial, although the association with other natural compounds (such as lycopene, other carotenoids and selenium) could enhance the activity of sr alone by augmenting pro-apoptotic effects and suppressing growth factors expression in hyperplastic prostates (72). the evaluation of the results of bph treatment with sr is made difficult by the variability of the composition of products of different brands in relation the concentration of free fatty acids and the method of extract preparation. clinical use of other medicinal plants for bph treatment: urtica dioica, pygeum africanum e cucurbita pepo (gian maria busetto) alongside the traditional 5α-reductase and β-blockers, medical therapy for luts secondary to bph, is based on nutraceuticals and compounds. in addition to serenoa repens, which has been extensively studied, there are many other substances for which scientific evidence is often controversial. urtica dioica has the capability to decrease testosterone conversion to dyhdrotestosterone (dht), interact with sex hormone-binding globulin (shbg) and block the conversion of androgens to estrogens. other studies report even an antiproliferative action on prostate cancer cells. pygeum africanum is rich in phytosterols and antioxidants. an inhibitory effect on prostate growth factors, on androgenic hormones and an effect on the contractility of table 2. design of studies of serenoa repens for bph treatment. placebo sr 5ari alphapinus + sr+ly+ alphaalphablockers crocus +se blocker blocker +sr sr+ly+ sr se dedhia (50) + + bent (51) + + ye (52) + ++ barry (53) + + alcaraz (55) + + + debruyne (58) + + cai (59) + ++ morgia (60) + ++ morgia (61) + + ++ ryu (63) + ++ boeri (62) + + ++ argirovic (64) + + + bertaccini (67) + + gerber (48) + ++ helfand (49) + + glemain (65) + + + hizli & uygur (66) + + + cicero_stesura seveso 30/09/19 18:17 pagina 142 the detrusor musculature of the bladder have been hypothesized. some authors have also reported an improvement in the parameters of the semen, in particular on sperm motility. curcubita pepo mainly contain fatty acids, specific sterols, tocopherol, carotenoids, vitamins and micronutrients. it is mainly the high ∆-7-sterol content that has the therapeutic effect and that has been shown to reduce prostate volume in the main animal models. these treatments can be considered as an adjunct to the common therapies and their effect is supported by improving symptoms, ipss and flowmetric indices (table 3) (73-84). their action on the volume of the prostate gland and on inflammation is more controversial. the literature is lacking data and double-blind placebo-controlled studies able to improve levels of evidence. it is therefore necessary to continue studying these substances, commissioning adequate trials with 143archivio italiano di urologia e andrologia 2019; 91, 3 nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer table 3. symptoms, ipss and flowmetric indices after treatment with urtica dioica, pygeum africanum and cucurbita pepo. author, year study design patients & controls comparator outcomes measured n° and response rate safarinejad 2005 (73) pavone 2010 (74) lopatkin 2005 (75) lopatkin 2007 (76) changping 2016 (77) barlet 1990 (78) barth 1981 (79) wilt & ishani 1998 (80) hong 2009 (81) friederich 2000 (82) vahlensieck 2015 (83) damiano 2016 (84) urtica dioica double-blind placebo-controlled randomized patients with luts secondary to bph serenoa repens 320 mg + urtica dioica 120 mg + pinus pinaster 5 mg for 30-365 days in luts associated to bph (46%) or cp/cpps (43%) or other conditions (11%) 160 mg sabal fruit extract (serenoa) + 120 mg urtica root extract 2 capsule/day rct 24 weeks 160 mg sabal fruit extract (serenoa) + 120 mg urtica root extract 2 x 1 capsule/day open-label extension of rct for 96 weeks metanalysis of 5 papers luts associated with bph pygeum africanum extract (50 mg) or placebo (1 capsule bid) double-blind 60 days 8 centres (germany, france, austria) pygeum africanum pygeum africanum metanalysis of 18 rcts treatment of bph pumpkin seed oil 320 mg day randomized, double-blind, placebo-controlled trial 12 months bph patients pumpkin seed extract multicentric clinical trial bph (stage i to ii according to alken) 12 weeks pumpkin seed 5 gr bid or pumpkin seed extract 500 mg bid randomized partially blinded placebo-controlled parallel-group trial 12 months patients with luts suggestive of bph narrative review 305 (287 evaluable) urtica dioica 315 (271 evaluable) placebo 320 patients (80 evaluable) 129 (127 evaluable) 128 (126 evaluable) 219 subjects 1128 patients 263 patients 215 patients 1562 patients mean study duration was 64 days (range, 30 to 122 days) 47 patients 2245 1431 6 clinical studies placebo placebo placebo placebo placebo placebo saw palmetto oil pumpkin+saw palmetto placebo urtica dioica vs placebo improved luts 81% vs 16% (p < 0.001) ipss 19.8 to 11.8 vs 19.2 to 17.7 (p = 0.002) peak flow rates +8.2 ml/s vs +3.4 ml/s (p < 0.05) pvr 73 to 36 ml vs no change (p < 0.05) psa and testosterone unchanged in both groups prostate volume by trus 40.1 to 36.3 cc vs no change (p < 0.001) no side effects symptom score significant benefit in 85% no change of prostate volume and qmax treated vs placebo ipss -6 points vs -4 points (p = 0.003) excellent tolerability i-pss -53% (p < 0.001) peak and average urinary flow +19% (p < 0.001) pvr -44% (p = 0.03) adverse events 1/1,181 standardized mean difference (smd) ipss 10.47 (95% ci 18.12 to -2.82, p = 0.007) peak urinary flow rate (qmax) 4.37 (95%ci = 1.55 to 7.19, p = 0.002) prostate volume 3.63 (95%ci = -4.67 to -2.57, p＜0.00001) psa 0.08 (95%ci = -0.23 to 0.07, p = 0.31) micturition improvement 66% vs 31% p < 0.001 gastrointestinal side effects in 5 patients improvement nocturia, qmax, pvr effect size of combined outcome of urologic symptoms and flow measures (-0.8 sd [95% ci -1.4 to -0.3) (n = 6 studies) improvement symptoms (rr = 2.1, 95% ci = 1.4 to 3.1) nocturia 19%, residual urine volume 24%, peak urine flow + 23% mild adverse effects ipss & qol reduced after pumpkin, saw palmetto, pumpkin+saw palmetto psa reduced after pumpkin+saw palmetto qmax increased after pumpkin and saw palmetto prostate volume no change ipss decreased by 41.4% life quality improved by 46. 1% no side effects in 96% responders (ipss decrease > = 5 points) pumpkin seed vs placebp 58.5% vs 47.3% no difference between pumpkin seed extract and placebo ipss and uroflowmetry improvement in 6 studies qol improvement in 4 studies cicero_stesura seveso 30/09/19 18:17 pagina 143 archivio italiano di urologia e andrologia 2019; 91, 3 a.f.g. cicero, o. allkanjari, g.m. busetto, et al. 144 high statistical power, strict inclusion and exclusion criteria and with adequate case studies. carotenoids and mineral supplements (vittorio magri) lycopene and selenium are two natural products with antioxidant and anti-inflammatory action. lycopenes are carotenoids, natural pigments widely distributed in the environment that are synthesized both by plants and bacteria, but not by the animals that must take them with the diet. lycopene accumulates in the prostate and is secreted in the seminal fluid. dietary supplementation of rats resulted in accumulation of lycopene in all prostatic lobes, but preferentially in the lateral lobes. lycopene concentrations are gradually increased and interfered with local prostate androgenic signaling, igf-1 expression, and inflammatory mediators (85, 86). selenium has an essential role in some enzymatic activities such as glutathione-peroxidases (87, 88) that can reduce hydrogen peroxide, and lipid and phospholipid hydroperoxides, counteracting free radical damage and oxygen-reactive species (ros). furthermore, selenium is important for maintaining an efficient immune response (89, 90). studies in vitro and on animal models, have shown that serenoa repens-selenium-lycopene (ser-sely) administered in combination, are synergistic and amplify their action both on the inflammatory and proliferative component (91-93). some clinical studies have confirmed the efficacy of the sr-se-ly association in patients with bph. in the flog study the administration of sr-se-ly in patients who had to undergo prostatic rebiopsy due to suspected prostate cancer showed a significant reduction in inflammation and the number of lymphocytes and macrophages in histological sections (94). in the procomb study (61), patients treated with sr-sely + tamsulosin had a greater reduction in the ipss score, an increase in qmax and a reduction in the post-voiding urinary volume, compared to those treated with tamsulosin alone. a randomized double-blind study of patients with bph treated with an herbal mixture that also contains lycopene showed a significant reduction in the total ipss score, pollakiuria and nocturia in treated patients (95). similar effects to those obtained with lycopene and selenium could be obtained with the use of other carotenoids and/or zinc. astaxanthin, at low concentration, was able to inhibit in vitro 5α-reductase by 98% and to decrease growth of cultured prostate cancer cell lines (96). the accumulation of zinc in prostate tissue depends, more than on dietary intake, on the activity of specific transporters (znt4 and zip4) that can be modulated by natural products as diadzein and genistein (97, 98). in patients with symptomatic bph a combination of zinc, daidzein and isolase (a mixture of enzymes that increases the bioavailability of plant polyphenols) improved at 6-month follow up ipss score, peak urinary flow rate and quality of life (99). the close correlation between prostatic inflammation and luts associated to bph, as demonstrated by mtops and reduce clinical studies (100, 101), suggests a new systematic approach to the medical therapy of symptomatic bph based on the association of a drug with anti-inflammatory activity to alpha-blockers and/or 5ari drugs. considering the side effects of non-steroidal anti-inflammatory drugs (nsaid), the use of natural substances with a low risk of complications is attractive. further studies are needed to evaluate the short and long-term efficacy of this approach to validate its use in the daily clinical practice for treatment of benign prostate diseases. polyphenols (alberto trinchieri) polyphenols are a large class of organic chemicals (> 8000) characterized by the presence of large multiples of phenols structural units. they can be differentiated according to the chemical structure of the polyphenol skeleton. flavonoids, lignins, phenolic acids, stilbenes and other polyphenols belong to this class (table 4). polyphenols can act on prostatic hyperplasia with different mechanisms: inhibition of 5α-reductase; decreased expression of growth factors (igf-i and igf-ii); anti-inflammatory action (reduction of interleukin levels il 1-β, il 6, il-i6 and tumor necrosis factor tnf-α, inhibition of cox-2 and 5-lipogenase, increased synthesis of nitric oxide and expression of nitric oxide synthase ); induction of apoptotic activity (increased expression of pro-apoptotic caspase-3 protein, up-regulation of peroxisomal proliferation receptors ppar α and γ, increased expression of g protein estrogen receptor 1 coupled gper); increased antioxidant activity (superoxide dismutase, glutathione peroxidase). experimental evidences based on in vitro studies on homogenates of hyperplastic prostate cells or prostatic cell lines demonstrated prevalent inhibitory effect of 5αreductase type 2 of isoflavones (phytoestrogens), while flavonols and flavones show inhibitory effect of 5α-reductase type 1 but also anti-inflammatory ant antioxidant effects and induction of apoptosis (102, 103). phenolic acids and lignins also have a combined action on 5αreductase and induction of apoptosis (104). in experimental models of bph in rats, the efficacy of cocoa extract, soy-derived isoflavones, quercitin, a mixture of baicalin and catechin (flavocoxid), equol, anthocyanins derived from black soy, flavonoids extracted from garcinia kola (kolaviron), epigallocatechin-3-gallate, secoisolariciresinol and curcumin was demonstrated (105-115). clinical studies in patients with bph have demonstrated the efficacy of quercitin, a flavonol contained in various foods such as onions, citrus fruits, cranberry, spices, tea and red wine (116), of equol (a metabolite of daidzein which is a soy isoflavon) (117), a flaxseed extract containing the lignin secoiso-lariciresinol diglucoside (sdg) (118) and of curcumin, a derivative of the spice curcuma longa (119). conversely, resveratrol has not been shown to be effective in reducing prostate volume and levels of testosterone, didrotestosterone (dht) and psa (120). different types of polyphenols are contained in medicinal plants that have been used in the treatment of ipb, such as epliobium (121) and extract from the bark of french maritime pine (122). pollen extract, beta-sitosterol and palmitoylethanolamide (pea) (tommaso cai) pollen extract is a mixture of natural components, such as amino acids, carbohydrates, lipids, vitamins, phytoscicero_stesura seveso 30/09/19 18:17 pagina 144 terols and minerals (123). the compound of the pollen extract is able to inhibit several cytokines, such as prostaglandin and leukotriene synthesis and this effect is comparable to that of diclofenac and indomethacin and approximately 10 times higher than that of aspirin (124). the pharmacological effects are due to the inhibiting activity of carvacrol, a pollen extract component, on the nf-kb (nuclerar factor kappa light chain enhancer of activated b cells). the inhibition of nf-kb reduce the levels of prostaglandin e2 and increase the production of beta-endorphins with inflammation decrease and pain relief (125). moreover, several authors demonstrated that pollen extract has a possible pro-apoptotic effect on the prostate via the androgen metabolism. in particular, it protects acinar prostate epithelial cells and inhibits stromal proliferation in association with enhanced apoptosis. finally, several in vitro studies demonstrated that pollen extract is able to inhibit the prostate cancer cell growth 145archivio italiano di urologia e andrologia 2019; 91, 3 nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer table 4. classification, sources, biological and clinical activity of polyphenols used for bph treatment. classification name source in vitro 5-ar in vitro other effects animal models clinical studes flavonoids c6–c3–c6 general structural backbone with two c6 units of phenolic nature flavonols flavanons flavan-3-ols flavones anthocyanidins isoflavones (phytoestrogens) stilbens hydroxylated derivatives of stilbene with c6–c2–c6 structure lignans two units of a phenylpropene derivative fenolic acids phenolic ring and an organic carboxylic acid function (c6-c1 skeleton) other polyfenols quercitin mirecitin fisetin gb1 e gb2 kolaflavonone binaringenina (kolaviron) epigallocatechin-gallate baicalin kaempferol antocianin daidzein genistein biocanin a equol resveratrol secoisolarici-resinol diglucoside enterolactone caffeic acid phenethyl ester (cape) curcumin onions citrus cranberry spices tea red wine red wine strawberry apples grapes garcinia kola green tea scutellaria baicalensis and scutellaria lateriflora apples broccoli, onions, tomatoes black soy soy soy fava beans soy peanuts soy grapes red wine flaxseed sesame flaxseed propoli curcuma lunga (spice) 5-ar type 1 inhibition (?) decreased dht by androgen-independent effect shbg 5-ar type 1 inhibition 5-ar type 1 inhibition 5-ar type 1 inhibition 5-ar type 1 inhibition 5-ar type 2 inhibition 5-ar type 2 inhibition 5-ar type 2 inhibition 5-ar type 2 inhibition 5-ar type 2 inhibition 5-ar type 2 inhibition antinflammatory (decrease cytochines, suppressed tnf-alfa and mcp-1 expression by nf-kappa b inhibition) antioxidant proapoptotic (tgf increase) antioxidant antinflammatory (decreased il-iβ, il-i6, and tnfα) antioxidant decreased igf-i e igf-ii proapoptotic ppar-α e ppar-γ up-regulation antinflammatory (inhibition cicloxigenase 2 and 5-lipooxigenase decrease growth factors proapoptotic proapoptotic increased gper expression decreased growth factors (vegf, tgf-ß1, and igf1). decreased prostate volume no no decreased prostate volume decreased prostate volume decreased prostate volume by a mixture of baicalin and catechin (flavocoxid), no decreased prostate volume decreased prostate volume by soy-derived isoflavones decreased prostate volume decreased prostate volume no no decreased prostate volume ipss decreased qmax increased ipss decrease dht decrease no decrease prostate volume no effect on testosterone and dht ipss decrease cicero_stesura seveso 30/09/19 18:17 pagina 145 archivio italiano di urologia e andrologia 2019; 91, 3 a.f.g. cicero, o. allkanjari, g.m. busetto, et al. 146 and this effect is even more pronounced in the hormoneindependent models, suggesting that there might be a place for the pollen extract in the control of abnormal growth in hormone-insensitive cells (126-130). on the clinical point of view, pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. these evidences have been done by a recent systematic review and meta-analysis (131) of 4 rcts, that demonstrated that the use of flower pollen extracts in the management of cp/cpps patients is associated with a high rate of clinical response without any significant adverse events. the table 5 of all pre-clinical and clinical trials about the use of pollen-extract. no side effects are reported in all clinical trials (132-141). beta-sitosterol is a sterol commonly present in the almost all plants, such as rice bran, wheat germ, peanuts, corn oils, soybeans, saw palmetto, rye grass pollen and pygeum. its activity is due to the fact that cannot be converted to testosterone and inhibits aromatase and 5αreductase (142). due to these pharmacological properties, beta-sitosterol is able to improve urinary symptoms and flow measures, as demonstrated by a cochrane review (143). on the other hand, beta-sitosterol is not able to reduce the size of the prostate gland. in general, no adverse effects are reported during therapy, even if gastrointestinal side effects are the most common. however, we need consider that this compound can enhance the cholesterol-lowering effects of antihyperlipidemic medications. palmitoylethanolamide (pea), an endogenous fatty acid amide-signaling molecule has well-known anti-inflammatory and neuroprotective effects. the clinical antiinflammatory effect is due to the downregulation of mediator release from mast cells, monocytes and macrophages. in particular, in recent experience, pea seems to have interesting activities in regulation of neurogenic and neuropathic pain. it has been demonstrated that pea is able to act on trpv1 channels, by indirect activity and desensitization. several authors showed an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain (144-146). medicinal plants for prevention and treatment of prostatic carcinoma (gianpaolo perletti) medicinal plants and herbal products, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. over the past 20 years, dozens of plant-based products table 5. pre-clinical and clinical trials about the use of pollen-extract. author, year study design patients & controls comparator outcomes measured n° and response rate buck ac, 1989 (132) cai t, 2013 (133) cai t, 2014 (134) elist j, 2006 (135) iwamura h, 2015 (136) jodai a, 1988 (137) monden k, 2002 (138) rugendorff ew, 1993 (139) suzuki t, 1992 (140) wagenlehner fm, 2009 (141) prospective trial (phase ii) prospective trial (phase ii) randomized controlled trial randomized controlled trial randomized placebo-controlled trial prospective trial (phase ii) prospective trial (phase ii) prospective trial (phase ii) prospective trial (phase ii) randomized controlled trial 15 (86.6) 20 (90.0) 41 (75.6) 46 (41.3) 30 (73.3) 28 (64.2) 50 (78.1) 50 (88.2) 32 (75.0) 24 (91.6) 90 (62.2) 25 (96.0) 70 (70.6) 69 (49.3) ibuprofen placebo eviprostat (phyto-therapeutic agent) placebo pollen extract effective in the treatment of chronic prostatitis and prostatodynia pollen extract significantly improved total symptoms, pain, and qol in patients with non-inflammatory cp/cpps without severe side effects pollen extract significantly improved quality of life of patients when compared with those treated with ibuprofen (treatment difference in the nih-cpsi pain domain, -2.14 ± 0.51, p < 0.001; qol scores, p = 0.002) pollen extract is superior to placebo in providing symptomatic relief in men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome pollen extract significantly reduced the symptoms of category iii cp/cpps without any adverse events, in terms of nih-cpsi, ipss, and qol pollen extract significantly reduced the symptoms in 75.0% of all treated patients pollen extract significantly reduced the symptoms of chronic prostatitis group pollen extract significantly reduced the symptoms of category iii cp/cpps without any adverse events, in terms of urinary symptoms and qol pollen extract significantly reduced the symptoms of prostatitis patients without any adverse events pollen extract significantly improved total symptoms, pain, and qol in patients with inflammatory cp/cpps without severe side-effects cicero_stesura seveso 30/09/19 18:17 pagina 146 have been subjected to preclinical in vitro and in vivo investigations for their potential pharmacological activity against prostate cancer (pca). less numerous but worthy of special attention are epidemiological studies or clinical trials in which plant species, administered in the form of beverages, extracts or food preparations, have been studied for their effect on prostate cancer. here follows an example of plant species which have been subjected to deeper investigation. camelia sinensis (cs), in the form of unfermented (green) or fermented (black) tea, is rich in polyphenols, the most representative and investigated being epigallocatechin-3gallate (egcg; green tea contains about 10-fold ecgc compared to black tea). a number of epidemiological and clinical studies have attempted to investigate the preventive effect of cs intake on prostate cancer. such studies have been pooled in at least 6 meta-analyses, among which the work of fei et al. (147), including 29 data series, appears to be the most comprehensive. we deemed interesting to integrate such meta-analysis with the more recent studies of lassed et al. (280 patients, risk ratio = 0.51; 95% ci: 0.14-1.82) and sen et al., (142, 196 men, of which 7036 pca cases; risk ratio: 1.06; 95% ci: 0.98-1.14) (148, 149). our metanalysis (figure 1) (150) shows that, in contrast to the significant data of fei and coworkers (147), (risk ratio = 0.84; 95% ci: 0.71-0.98), the addition of the lassed and sen (148, 149) trials results in a non-significant pooled risk ratio (0.89; 95% ci: 0.77-1.02). the publication bias for this pooled analysis is not significant (egger's test: p = 0.542; begg&mazumdar's test: p = 0.311), but the analysis shows substantial heterogeneity (i2 = 0.69). more focused analyses, investigating the effect of high doses of green tea catechins, tested in the frame of randomized-controlled studies, resulted in a significant protective effect against pca. thus, whereas studies about consumption of cs infusions in the general population have given contradictory results – probably also due to uncertain dosage, length of therapy, herb quality, patient compliance, etc. –, rigorous, controlled clinical trials seem to provide encouraging evidence about the antitumor activity of cs catechins. solanum lycopersicum, the common tomato, contains high quantities of lycopene, a carotenoid antioxydant hydrocarbon (c40h56) devoid of vitamin-a activity. lycopene, investigated in the frame of meta-analyses of epidemiological studies, doesn't seem to show a significant pca preventive activity (151, 152). however, single studies suggest that lycopene shows indeed protective activity (153), and can as well lower psa levels in prostate cancer 147archivio italiano di urologia e andrologia 2019; 91, 3 nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer figure 1. forest plot. risk-ratio for the association between the consumption of various preparations of tea (beverage, concentrates, etc.) and prostate cancer, assessed by pooling 23 epidemiological studies (31 data series). the values at the right of the no-effect unit (n = 1) show an increased relative risk for prostate cancer, whereas data plotted on the left show a protective effect of tea intake against prostate cancer. arch ital urol androl, this issue. random effect model, mantelhaenszel statistics, metaessentials software. cicero_stesura seveso 30/09/19 18:17 pagina 147 archivio italiano di urologia e andrologia 2019; 91, 3 a.f.g. cicero, o. allkanjari, g.m. busetto, et al. 148 patients (154). punica granatum, pomegranate (pg), contains a number of active polyphenol compounds (e.g., elagitannins) and fatty acids (punicic acid). promising preclinical results have not been translated so far into sound clinical evidence. whereas in earlier clinical studies pg seemed to significantly prolong the psa doubling time in patients with localized pca (155), recent placebo-controlled trials failed to show increased psa doubling times by pg preparations, compared to placebo (156, 157). glycine max, the common soy, and linum usitatissimum, known as flax or lineseed, contain isoflavones (e.g., genistein) and lignans which are known to act as phytoestrogens. these compounds, which have been hypothesized to be active against pca growth, have been tested in the frame of clinical trials in pca patients. it is not clear whether soy extracts show any effect on pca and psa, as clinical data produced so far didn't show univocal therapeutic effects (158, 159). similarly, single clinical trials and meta-analyses suggest that flax lignans do not seem to have a significant therapeutic activity (160). however, a metanalysis of observational studies by he and coworkers has evidenced a significant association between high serum levels of the lignan metabolite enterolactone and a reduced odds of prostate cancer (or = 0.76, 95% ci: 0.60-0.97) (he et al.). in conclusion, camelia sinensis catechins, solanum lycopersicum lycopene and the flax lignan metabolite enterolactone have shown some chemopreventive or therapeutic activity against pca. the major limitation of the clinical studies and meta-analyses produced so far is the great variability of key elements such as (i) compound quality (poor standardization), (ii) patient compliance (virtually unknown in observational studies), (iii) active drug dosages (extremely diverse according to dietary customs worldwide), and (iv) preparation modalities. randomized controlled trials versus placebo or versus compounds of established efficacy are still scant. to draw any final conclusion concerning the efficacy of medicinal plants and fruits for preventing or treating pca, additional well-designed, adequately powered clinical trials are urgently needed. references 1. sirtori cr, arnoldi a. introduzione. in: borghi c, cicero afg "nutraceutici ed alimenti funzionali in medicina preventiva". bononia university press, bologna, 2011; 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92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.209 expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature michele salemi 1, angela pettinato 2, filippo fraggetta 2, aldo e. calogero 3, michele pennisi 4, ludovica pepe 4, pietro pepe 4 1 oasi research institute-irccs, troina (en), italy; 2 pathology unit, cannizzaro hospital, catania, italy; 3 section of endocrinology, andrology and internal medicine, department of clinical and experimental medicine, university of catania, italy; 4 urology unit, cannizzaro hospital, catania, italy. micrornas (mirnas) are a class of small, non-coding rnas that act as key regulators in various physiological and pathological processes as prostate cancer (pca). in this study we describe molecular evaluation of 132 and 212 mirnas expression, by real-time reverse-transcription pcr (qrt-pcr), in a caucasian man 64-year-old with locally advanced pca (psa 160 ng/ml, gleason score 4+3/isup grade group 3, clinical stage t3nxm0) who underwent radical retropubic prostatectomy plus extended pelvic lymphadenectomy (lad) as first step of a multimodal therapeutic treatment. a normal prostate of a 67-year-old man removed by post mortem autopsy was used as a control in the study. the mrna for this study was conducted on paraffined prostatic sections of: a) index case of pca; b) metastatic lymph node of index case; c) normal prostate. mirna-132, mirna212 and glyceraldehyde 3-phosphate dehydrogenase (as reference gene) assays were obtained. definitive specimen showed a pt3bn1r1 stage: acinar cells adenocarcinoma with involvement of the seminal vesicles, multifocal positive surgical margins, gleason score 8 (4+4/isup grade group 4), metastases in 5/25 iliac lymph nodes. an increased expression of mirna-132 and mirna-212 in index case of prostatic adenocarcinoma compared to normal prostate tissue was found; moreover, a lower expression of mir-132 and mir-212 in metastatic lymph node compared to primitive pca and normal prostate tissue was demonstrated. although a greater number of patients should be evaluated, these data suggest that the biology of the primary pca, in our clinical case, was different from metastatic lymph node. key words: prostate cancer; mir-132; mir-132; qrt-pcr. submitted 2 march 2020; accepted 15 march 2020 summary introduction prostate cancer (pca) is the most frequently tumor diagnosed in men; although the screening protocols have increased the early diagnosis for organ-confined pca, still today, a not negligible number of initial diagnosis is characterized by high risk or metastatic cancer. patients with high-risk pca are at an increased risk of psa failure, need for secondary therapy, metastatic progression and death from pca; nevertheless, not all high-risk pca patients have uniformly poor prognosis after definitive therapy (radical prostatectomy or radiotherapy). although there is no consensus regarding the optimal treatment of men with high-risk or locally-advanced pca, in the last years, the multi-modal therapy has demonstrated a clinical advantage for the patients (1) and new clinical trials are ongoing to evaluate the best clinical therapeutic approach for each patient. therefore, there is the necessity to better understand the prognosis for each high risk pca using new parameters (i.e., histological and molecular genetics patterns) (2, 3); in this respect, the new techniques of proteomics, rna and dna microarrays, have been used to identify and validate accurate diagnostic biomarkers in samples of prostate tissue (4). micrornas (mirnas) were found aberrantly expressed in pca (9); mir-132 has a central role in the processes of cell adhesion, angiogenesis, and tumorigenesis (mim 610016). several studies have described a strong association between levels of mir-132 and high gleason score pca (10). mir-212 and mir-132 belong to the same family and are transcribed from a stable gene intron noncoding for proteins (mim 613487). mir-212 regulates a sub-set of genes involved in tumor progression in several tumor cell types as pca (5). in this study we describe molecular evaluation of 132 and 212 mirnas expression, by real-time reverse-transcription pcr (qrt-pcr), in a men with locally-advanced pca who underwent radical retropubic prostatectomy (rpp) plus extended pelvic lymphadenectomy (lad) as first step of a multimodal therapeutic treatment. case report a caucasian 64-year-old man had a total psa value of 160.0 ng/ml and positive digital rectal examination. transperineal extended prostatic biopsies (13) showed in all the cores (12/12) an adenocarcinoma with a gleason score 7 (4+3/isup grade group 3) (14); the clinical stadiation performed by total body computed tomography and bone scan showed no presence of metastases (clinical stage pt3nxm0). in january 2019 informed consent was obtained from the patient who accepted to undergo rrp plus extended pelvic lad as first step of a multimodal therapeutic treatment. definitive specimen showed a 13salemi-pepe_stesura seveso 24/09/20 14:24 pagina 209 archivio italiano di urologia e andrologia 2020; 92, 3 m. salemi, a. pettinato, f. fraggetta, a.e. calogero, m. pennisi, l. pepe, p. pepe 210 pt3bn1r1 stage: acinar cells adenocarcinoma with involvement of the seminal vesicles, multifocal positive surgical margins, gleason score 8 (4+4/isup grade group 4), bilateral metastases in 5/25 iliac lymph nodes. a normal prostate of a 67-year-old man removed by post mortem autopsy was used as a control in the study. the mrna for this study was conducted on paraffined prostatic sections of: a) index case of pca; b) metastatic lymph node of index case; c) and normal prostate. mir132, mir-212 and glyceraldehyde 3-phosphate dehydrogenase (gapdh) (as reference gene) assays were obtained from applied biosystems (carlsbad, ca). real-time analysis was performed on light cycler 480 (roche diagnostics; mannheim, germany). the amplified transcripts were quantified using the comparative ct method and relative quantification analysis data were played using the comparative ∆∆ct method included in the software version 1.5 supplied with the lightcycler 480. an increased expression of mirna-132 and mirna-212 in index case of prostatic adenocarcinoma compared to normal prostate tissue was found; moreover, a lower expression of mir-132 and 212 in metastatic lymph node compared to primitive pca and normal prostate tissue (figure 1) was demonstrated. finally, the patient had not clinical complications from rpp; the psa value was equal to 2.7 ng/ml 30 days from surgery and the patient underwent adjuvant radiotherapy and hormonal therapy (lhrh agonist). discussion and conclusions micrornas are short non-coding rnas involved in several important biological processes through regulation of genes post-transcriptionally; carcinogenesis is one of the key biological processes where mirnas play important role in the regulation of genes. the mirnas elicit their effects by binding to the 3' untranslated region (3'utr) of their target mrnas, leading to the inhibition of translation or the degradation of the mrna, depending on the degree of complementary base pairing. the mirnas are deregulated in a wide variety of human cancers; in detail, mir-212 and mir-132 regulate a subset of genes involved in pca progression and lymph node metastasis. data obtained in our case report showed an abnormal over-expression of mir-132 and mir-212 in pca compared to normal prostatic tissue; also we found a down-expression of mir132 and mir-212 in metastatic lymph node. although a greater number of patients should be evaluated, these data suggest that the biology of the primary pca, in our clinical case, was different from metastatic lymph node. references 1. malik zi, fenwick jd. radiotherapy to the primary tumour for patients with metastatic prostate cancer: practice-changing results from stampede. clin oncol. (r coll radiol). 2020; pii: s09366555(19)30540-0. 2. d'antonio a, caputo a, fraggetta f, et al. kpna2/erg coexpression is associated with early recurrence in advanced prostate cancers. appl immunohistochem mol morphol. 2020; 28:62-66. 3. pepe p, fraggetta f, candiano g, aragona f. does ki-67 staining improve quantitative histology in preoperative prostate cancer staging? arch ital urol androl. 2012; 84:32-35. 4. hassan o, ahmad a, sethi s, sarkar fh. recent updates on the role of micrornas in prostate cancer. j hematol oncol. 2012; 5:9. 5. formosa a, lena am, markert ek, et al. dna methylation silences mir-132 in prostate cancer. oncogene 2012; 32:127-134. figure 1. relative expression value of mir-132 and mir-212: control 1 and 1 respectively (histogram with double scale); prostate index case 179.7 and 55.5 respectively; metastatic lymph node 0.267 and 0.319 respectively. correspondence michele salemi, md michelesalemi@hotmail.it oasi research institute-irccs, troina (en) (italy) angela pettinato, md angelapettinato@hotmail.com filippo fraggetta, md pathology unit, cannizzaro hospital, catania (italy) filippofra@hormail.com aldo e. calogero, md acalogero@hotmail.com section of endocrinology, andrology and internal medicine, department of clinical and experimental medicine, university of catania, catania (italy) michele pennisi, md michelepennisi2@virgilio.it ludovica pepe, md ludovicapepe@hotmail.com pietro pepe, md (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital via messina 829, catania (italy) 13salemi-pepe_stesura seveso 24/09/20 14:24 pagina 210 stesura seveso 273archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.273 renal myxoma: an unforeseen diagnosis rui miguel bernardino 1, luis severo 1, luis mascarenhas lemos 2, luis campos pinheiro 1 1 urology department, central lisbon hospital center, lisbon, portugal; 2 pathology department, central lisbon hospital center, lisbon portugal. myxomas are rare tumours that can be found in many anatomical locations. there are only 17 cases of renal involvement documented. our case is an 85 year-old man followed in our consultation with recurrent hematuria after a transurethral resection of a bladder tumour. evaluation with ct showed a solid lesion with 23 x 18 mm partially obliterating the left inferior calyx. the patient underwent a left nephroureterectomy. microscopic examination showed a mass within renal parenchyma adjacent to the renal pelvis composed of plump mildly atypical spindle cells distributed in a copious myxoid matrix. immunohistochemical staining for vimentine, pankeratin (ae1/ae3-), cd34, cd31 and smooth muscle actin were negative. with these histopathological and immunohistochemical findings, the case was diagnosed as renal myxoma. key words: kidney; cancer; myxoma. submitted 2 march 2020; accepted 15 march 2020 summary introduction myxomas are rare benign tumours that can be found in many anatomical locations, such as skin, bones and heart. there are only 17 cases of renal involvement documented. we report a case of a renal myxoma in an old man with history of urothelial tumour, presenting the preoperative imaging evaluation as well as the pathological findings. the present article reports the second case of renal myxoma published in english literature, that was associated with extensive haemorrhage and the first case of a renal myxoma in a patient with past history of urothelial tumour, which made the differential diagnosis even more difficult. case presentation we present an 85-year-old man, followed in our institution since january 2017 for bladder tumour. he underwent transurethral resection of a left lateral wall bladder polyp whose anatomy revealed low grade noninvasive papillary urothelial (or transitional cell) carcinoma(pta). after surgery the patient maintained haematuria. follow-up cystoscopy (3 months after the surgery) did not show lesions suggestive of relapse. the patient had an emergency in june 2017 due to massive haematuria with clots and with repercussion in the hemogram, hemoglobin of 6.5 g/dl, receiving two units of erythrocyte concentrate. evaluation with computed tomography (ct) showed a solid lesion with 23 x 18 mm partially obliterating the left inferior calyx (figures 1, 2). at this time, surgery was recommended for this patient not only due to malignant features on ct but also for his past history of urothelial tumour. he underwent a left laparoscopic nephroureterectomy. after one year of follow-up, the patient was well and completely symptom-free and the annually routine ct didn’t show relapse. he died one year and a half after the surgery from myocardial infraction. imaging findings ultrasound: renal ultrasound revealed a solid nodular lesion in the middle third of the left kidney with about 23 x 18 mm. right kidney had no alterations. ct: ct scan confirmed a solid lesion partially obliterating the lower left calyx, suspected of urothelial neoplasia (figures 1, 2). mri was not done in our case, as the patient had a past history of urothelial tumour, and ct was high suspicious for urothelial neoplasia. renogram: he performed renogram showing normal renal function (left kidney 57% and right kidney 43%). pathological findings lesion within renal parenchyma adjacent to the renal pelvis, circumscribed, somewhat lobulated, composed of plump mildly atypical spindle cells distributed in a copious myxoid matrix (figure 3). a subset of these cells had irregular atypical nuclei, although the atypia was more prominent adjacent to the ulcerated surface of the lesion and may therefore be reactive in nature. there is no significant pleomorphism, mitotic activity or necrosis (figure 4). the lesion cells were positive for vimentin, negative for pankeratin, multifocally positive for smooth muscle actin, while were negative for s-100 protein, cd34, cd31 and pancytokeratin. with the above findings, the lesion was labelled as an atypical myxoid spindle cell neoplasm, consistent with renal myxoma. the lesion has expansive growth conditioning extension and erosion of the adjacent pyelocalyceal structures and no extracapsular extension was documented. discussion there is no reports of specific clinical presentation for renal myxoma and, due to its rarity, renal myxoma is often mislead with other malignant lesions (1). when there were clinical manifestations, flank pain was the most common presenting symptom reported in the 17 cases (2). it is known so far that there is no invasion, metastasis or tumour recurrence (3). in our renal myxoma case, the patient had concomitant past history of archivio italiano di urologia e andrologia 2020; 92, 3 r. miguel bernardino, l.severo, l. mascarenhas lemos, l.campos pinheiro 274 urothelial bladder tumour, which made the differential diagnosis with a urothelial neoplasia even more difficult. the origin of renal myxoma from the renal capsule is less common than parenchymal renal myxoma (1). fibroblast is the originary cell of myxoma. macroscopically, this tumour shows a gelatinous gross appearance due to production of glycosaminoglycan and it is well-defined (3). microscopically, the spindle-shaped cell can be seen in the myxoid stroma, and no mitotic activity is seen. in all reported cases, the tumour cells stained positive for vimentin and in most cases negative for s-100 protein, pancytokeratin and cd34. renal myxoma is a large heterogeneous mass in imaging exams, predominantly hyperechoic in ultrasonography (us) and hypodense in ct. myxomas characteristics in imaging is a relatively regular, multilobulated and welldefined mass, only displacing the adjacent structures without invading them. therefore, pre-operative imaging cannot confidently distinguish myxoma from other renal masses and therefore histopathological confirmation is the only reliable way of doing so. in this context, what is the role of percutaneous biopsy? in general, a biopsy should be performed only to avoid unnecessary or incorrect treatment. appropriate laboratory and diagnostic imaging tests should be exhausted first. only when these steps prove to be inconclusive should a patient be subjected to the risks, discomfort, and expense of a biopsy (4). in our case, as the patient had a history of urothelial bladder tumour, and the ct was high suspicious for urothelial neoplasia, a percutaneous biopsy was not indicated. as the radiological characteristics are very close to those of malignancy, they must be treated as malignant tumors, with the patient being surgically treated. for most cases reported, nephrectomy was the treatment of choice due to suspicion to malignancy. although imaging is required to differential diagnosis, pathological evaluation is needed to differentiate a myxoma from malignancy. advanced imaging models such as ct guided biopsy can help us to get closer to the diagnosis, but for definitive diagnosis, we need immunohistochemistry evaluation (5). tumour enucleation of the myxoma would be enough not only for diagnosis but also for treatment, and overall prognosis of this disease is good (1). conclusions • renal myxomas are extremely rare mesenchymal tumours of the kidney. • the radiological characteristics are very close to thoseof malignancy, therefore they must be treated as malignant tumors. • pathological evaluation is needed to differentiate a myxoma from malignancy. • if the diagnosis of the lesion before surgery is renal myxoma for sure, the best treatment option would be, tumour enucleation. references 1. shah a, sun w, cao d. myxoma of the kidney associated with hemorrhage. indian j surg. 2013:75(suppl. 1):s480-3. 2. suthar ks, vanikar av, patel rd, et al. renal myxoma-a rare variety of benign genitourinary tumour. j clin diagn res. 2015; 9:ed11. 3. hakverdi s, görür s, yaldiz m, et al. renal myxoma: case report and review of the literature. turk j urol. 2010; 36:318-21. 4. young m, leslie sw. renal biopsy. (updated 2019 jun 17). in: statpearls (internet). treasure island (fl): statpearls publishing; 2019 jan-.available from: https://www.ncbi.nlm.nih.gov/books/ nbk470275/ 5. salehipour m, geramizadeh b, dastgheib n, makarem a, asadollah poor a, taheri n. renal myxoma, a case report and review of the literature. urol case rep. 2018; 23:21-22. figure 1. ct scan (excretory phase) confirmed a solid lesion partially obliterating the lower left calyx of about 23 x 18 mm, suspected of urothelial neoplasia. figure 2. same lesion as shown in figure 1 but in nephrographic phase. figure 3. (100x) – h&e stain benign mesenchymal lesion, intraparenchymatous, composed of spindle cells, with a slightly eosinophilic cytoplasm and light and focal cytological atypia, arranged around vessels or scattered on a background of myxoid and haemorrhagic stroma. figure 4. (400x) – h&e stain no mitosis or necrosis is documented. correspondence rui miguel bernardino, md (corresponding author) ruimmbernardino@gmail.com luis severo, md luis.severo@sapo.pt luis mascarenhas lemos, md luisalbuquerquermascarenhas@gmail.com luis campos pinheiro, md luiscampospinheiro@gmail.com centro hospital de lisboa central, epe serviço de urologia, alameda de santo antónio dos capuchos, 1169-050 lisboa (portugal) stesura seveso 251archivio italiano di urologia e andrologia 2019; 91, 4 original paper the association of boswellia resin extract and propolis derived polyphenols can improve quality of life in patients affected by prostatitis like symptoms mattia sibona 1, paolo destefanis 1, marco agnello 1, beatrice lillaz 1, mattia giuliano 1, tommaso cai 2, paolo gontero 1 1 department of urology, department of surgical sciences, a.o.u. città della salute e della scienza di torino, molinette hospital, university of turin, turin, italy; 2 department of urology, santa chiara regional hospital, trento, italy. objectives: chronic prostatitis syndrome is a bothering and poorly understood condition. many patients report genitourinary pain and lower urinary tract symptoms as a main complaint. many different pharmacological or behavioural therapies are prescribed in daily clinical practice, but efficacy data are still lacking. the aim of our study was to test the efficacy and safety of a transrectal delivered association of boswellia resin extract and propolis derived polyphenols for the relief of prostatitis like symptoms. materials and methods: patients affected by chronic/recurrent prostatitis like symptoms were prospectively enrolled in our study from december, 2016 to december, 2018. patients were screened at baseline through clinical examination and validated questionnaires administration: chronic prostatitis symptom index (cpsi), international prostate symptom score (ipss), international index of erectile function (iief). inclusion criteria were: age ≥ 18; prostatitis symptoms persisting for at least 3 of the last 6 months; cpsi pain domain score ≥ 5; previous negative meares-stamey test. treatment consisted on the administration of 1 suppository containing boswellia resin extract and propolis derived polyphenols, once a day for 20 days. the primary endpoint of the study was the improvement of quality of life after treatment, defined by a reduction of ≥ 2 points, or ≥ 25%, of mean cpsi pain domain score, compared to baseline. secondary endpoints were the improvement of posttreatment cpsi total score and the analysis of treatment related adverse events. all patients were re-evaluated 1 month after treatment. results: 40 patients were enrolled in our study. median age (inter quartile range iqr) was 51.5 (41.5-63.2) years. mean baseline cpsi scores were: 22.15 (total score), 9.67 (pain domain), 5.15 (micturition domain) and 7.35 (quality of life domain), respectively. no significant adverse events were reported. at 1 month follow-up, cpsi scores appeared modified as follows: 16.40 (total score, p = 0.001); 6.92 (pain domain; p = 0.001; 4.02 (micturition domain, p = 0.09); 5.45 (quality of life domain, p = 0.002). mean cpsi pain domain score reduction was -2.75 points (-28.5%). mean cpsi total score reduction was -5.75 points (-26%). conclusions: the association of boswellia resin extract and propolis derived polyphenols can reduce genitourinary pain and then improve quality of life of men affected by bothersome prostatitis like symptoms. key words: prostatitis; pain; boswellia serrata; propolis; quality of life. submitted 27 june 2019; accepted 2 august 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.251 introduction prostatitis syndrome is characterised by genitourinary pain and lower urinary tract symptoms (luts). according to different studies, the prevalence of prostatitis in the male population ranges between 2.2% and 13.8% (1), and it is estimated that at least 50% of men have suffered from at least one episode of prostatitis in their lifetime (1). moreover, this disease can account for up to 10% of all urological consults (2). the national institute of health (nih) differentiates prostatitis into several etiologic categories. acute bacterial prostatitis (nih type 1) is characterized by fever and acute onset of luts. conversely, asymptomatic inflammatory prostatitis (nih type 4) is characterized by the absence of symptoms and its diagnosis is usually occasional (3). chronic prostatitis is a pathological entity lying between the two categories, and it is basically defined as a clinical syndrome whose manifestations are prolonged over time. the aetiology of chronic prostatitis may be infectious (chronic bacterial prostatitis, cbp, nih type 2), or merely inflammatory (chronic prostatitis/chronic pelvic pain syndrome, cp/cpps, nih type 3). nevertheless, at least from a clinical point of view, the two conditions appear to be largely overlapping (3). chronic prostatitis remains one of the most common urologic disorders. it is often poorly understood in its causative mechanisms and usually complex to manage. due to a lack of standardized therapeutic protocols, it is often treated with empirical pharmacological therapies, including prolonged antibiotic courses. despite a microbiological evidence of infection is often unavailable, in fact, antibiotics are prescribed up to a third of all patients (4). several alternative therapies have been also evaluated over time, including anti-inflammatory medications, neuromodulators, alpha-blockers, physical and cognitive behavioural therapies, and phytotherapy. however, reliable efficacy data are still lacking. bosexil® is a vegetal extract derived from the resin of boswellia serrata, a plant native to india. boswellic acids (bas) already showed anti-inflammatory and antioxidant properties in a variety of inflammatory diseases, including rheumatoid arthritis, osteoarthritis, and asthma (5, 6), whose physio-pathological pathways could be shared with those of chronic prostatitis. on the other sibona okkkkkkk_stesura seveso 20/01/20 11:26 pagina 251 archivio italiano di urologia e andrologia 2019; 91, 4 m. sibona, p. destefanis, m. agnello, b. lillaz. m. giuliano. t. cai, p. gontero 252 hand, fenolmicina p3®, a polyphenolic extract derived from beehive propolis, demonstrated anti-inflammatory, anti-microbial and antioxidant properties in several preclinical reports (7-9). the aim of our study was to test the efficacy and safety of the association of bosexil® and fenolmicina p3® in relieving prostatitis like symptoms in an adult male, prospective cohort. materials and methods study design and sample size definition our study was conceived as a pilot study, characterised by an observational, non-randomized, prospective approach. the required sample size for this study was determined on the basis of the expected variation of mean chronic prostatitis symptom index (cpsi) pain domain score, compared to baseline. a size of 40 patients was needed to detect a 2 points difference, with an 80% power and a 0.05 alpha error level. patients selection male patients, attending our outpatient service for chronic/recurrent prostatitis like symptoms were prospectively evaluated from december 2016 to december, 2018. a key point for the diagnosis of prostatitis was the presence of chronic perineal or genital pain, exacerbated by micturition or ejaculation. according to current european association of urology (eau) guidelines, prostatitis syndrome was suspected when symptoms persisting for 3 months or more were reported (10). moreover, we included in the study patients with both recurrent symptoms and previous negative meares-stamey test. once screened, patients’ general and urological history was investigated, and a complete urological examination, including a digital rectal examination (dre) was carried out for all candidates to enrolment, in order to confirm prostatic pain and exclude synchronous prostatic diseases, like prostate cancer (pca). moreover, they were all administered three validated questionnaires: nih-chronic prostatitis symptom index (nih-cpsi), international prostate symptom score (ipss) and international index of erectile function (iief). validated questionnaires three international validated questionnaires were used to evaluate patients at baseline and at follow-up: • cpsi: it is an international, validated questionnaire proposed by the nih chronic prostatitis collaborative research network in 1999 to objectively assess prostatitis symptoms (3). it has been validated in italian in 2005 (11). it is composed of three parts, or “individual domains”: a) pain domain, assessing the localization and amount of painful urogenital symptoms; b) micturition domain, focused on luts; c) quality of life domain. • ipss: it is an international, validated questionnaire aiming to assess luts. it is composed of 7 questions about luts, plus 1 question about quality of life. symptoms are classified as: mild (0 to 7 points); moderate (8 to 19 points); severe (20 to 35 points) (12). • iief: it is composed of 15 questions about several aspects of sexual function. it is divided into 5 domains: 1) erectile function; 2) orgasmic function; 3) sexual desire; 4) intercourse satisfaction; 5) overall satisfaction. it allows a minimum of 5 points and a maximum of 75 (13). inclusion criteria inclusion criteria were: age >=18; diagnosis of chronic prostatitis-like symptoms, prolonged for >=3 months over the last six (10); cpsi pain domain score >=5; previous negative meares-stamey test. we excluded from the study patients affected by acute bacterial prostatitis, asymptomatic prostatitis, benign prostatic hyperplasia (bph), pca, inflammatory bowel diseases (ibd), previous intra-vesical therapies (mitomycin, bcg), recent (< 1 month) systemic antibiotic therapies or ongoing specific therapies for chronic prostatitis (including phytotherapy). study schedule at baseline, general medical information and baseline characteristics were recorded. moreover, nih-cpsi, ipss and iief questionnaires were administered. subsequently, patients underwent a 20 days therapy with bosexil® and fenolmicina p3® suppositories (mictalase®). standard therapeutic regimen was one suppository, once a day, for 20 days. every administration (2 g suppository) contained: 1. bosexil® boswellia fitosoma® 2. fenolmicina p3® propolis derived polyphenols 3. silicon dioxide, lecithin, cellulose, silica and solid glycerides. all patients were re-evaluated after 30 days. at followup, they were re-administered the cpsi, ipss and iief questionnaires. results were recorded by using a dedicated database. analysis of results analysis of the results was based on the comparison of pre and post-treatment mean scores of the cpsi (total score and pain, micturition and quality of life domain scores), ipss and iief questionnaires. the primary endpoint of the study was the improvement of quality of life, defined by a statistically and clinically significant reduction of symptoms after treatment. a reduction of at least 2 points or ≥ 25% of pain domain cpsi score was considered clinically significant. secondary endpoints were: 1) total cpsi score statistically and clinically significant reduction, defined by at least 5 points or ≥ 25% reduction of the score after treatment. 2) evaluation of treatment’s safety. for this purpose, adverse events of any type were investigated and reported. statistical analysis the t-test was used to compare the distribution of continue variables. the χ2 test was used to compare categorical variables. the statistical significance was obtained when a p < 0.05 value was reached. the statistical analysis was performed with spss version 20.0 (ibm corp, armonk, ny, usa). the study was conducted according to the statements of the helsinki declaration and the good clinical practice guidelines. sibona okkkkkkk_stesura seveso 20/01/20 11:26 pagina 252 results baseline 40 patients were enrolled in the study. the median (iqr) age was 51.5 (41.5-63.2) years. as concerns descriptive statistics, 2 (5%) patients were cigarette smokers; 1 (2.5%) was affected by diabetes mellitus; 8 (20%) were affected by hypertension (table 1). baseline data were collected for all patients through the cpsi, ipss and iief questionnaires administration. mean (sd) cpsi total score was 22.15 (6.02). mean (sd) cpsi pain domain score was 9.67 (2.77). mean (sd) cpsi micturition and quality of life domain scores were 5.15 (3.17) and 7.35 (2.2), respectively. mean (sd) ipss score was 15.55 (8.8). mean (sd) iief score was 62.6 (16.5). adherence to therapy and adverse events all patients underwent a standard therapeutic regimen. we did not register any case of withdrawal from the study. moreover, we did not register any significant, treatment related adverse event. follow-up follow-up was carried out at 1 month. mean (sd) cpsi pain domain score was 6.92 (4.50), p = 0.001. mean (sd) cpsi total score was 16.40 (8.97), p = 0.001. mean (sd) cpsi micturition and quality of life domain scores were 4.02 (2.71), p = 0.09 and 5.45 (3.21), p = 0.002 respectively. mean cpsi pain domain score reduction was -2.75 points (-28.5%). mean cpsi total score reduction was -5.75 points (-26%). mean (sd) post-treatment ipss score was 12.5 (7.97), p = 0.10, while mean (sd) iief score was 63.85 (16.45), p = 0.74 (results are summarized in table 2). discussion chronic prostatitis still remains a poorly understood condition. many of the underlying pathological patterns of this disease are yet to be enlightened. on the other hand, prostatitis prevalence is not negligible and its symptoms can sometimes be very bothering and negatively affecting patients’ quality of life. poor knowledge and limited therapeutic options often make chronic prostatitis a true urological challenge. despite microbiological definition of the disease is often lacking, prolonged antibiotic administration is still considered a gold standard treatment (10). on the other hand, due to the lack of standardized therapeutic protocols, many other pharmacological or non-pharmacological therapies, including phytotherapy, are often considered by physicians as part of a multimodal treatment, even though evidences about effectiveness and safety of these products are limited (1, 14, 15). our study aimed to test the efficacy and safety of a transrectal delivered association of bosexil® and fenolmicina p3® for the treatment of chronic prostatitis symptoms. among a wide range of other products, boswellia serrata derivatives, like bas and, specifically, bosexil®, have been traditionally attributed a therapeutic potential against several chronic inflammatory diseases. more specifically, literature reports show in vitro, preclinical efficacy data concerning the use of boswellia in different contexts as an antioxidant, revealing a positive effect on the reduction of oxidant species and inflammation (5, 6, 16). besides propolis, rich in polyphenols, is the object of several preclinical reports that have confirmed its anti-inflammatory and antioxidant activity. moreover, propolis shows a strong antioxidant effect, generating a synergistic effect when linked to the activity of boswellia (7-9, 17). as concerns systemic bioavailability of this constituents after oral or transrectal administration, we still undoubtfully reckon with inconclusive data. moreover, no comparative data between the oral and transrectal administration of boswellia resin extracts and propolis are available to our knowledge, but the use of the transrectal way, which allows antioxidant substances to be in contact with the mucosa and antagonize oxidant species thus reducing painful symptoms, appears reasonable. data from our study, which is the first, to our knowledge, addressing the therapeutic role of this association of compounds for the treatment of prostatitis like symptoms, showed some significant results. first, we reported a significant post-treatment reduction of prostatitis like symptoms, which we considered an index of quality of life improvement, as demonstrated by a statistically and clinically significant reduction of both the nih-cpsi total score (p = 0.001) and pain domain score (p = 0.001). moreover, we also registered a significant improvement of the cpsi quality of life domain (p = 0.002). on the other hand, we did not appreciate a similar effect against those symptoms more related to bladder outlet obstruction and bph. in fact, the improvement of the cpsi micturition domain did not reach statistical significance (4.02 versus 5.15 p = 0.09). our results, the most interesting of which is the significant improvement of cpsi pain domain score, find confirmation in previously published, high quality studies. 253archivio italiano di urologia e andrologia 2019; 91, 4 boswellia resin extract and propolis for prostatitis symptoms table 2. baseline and post-treatment (1 month) results of validated questionnaires measuring prostatitis like symptoms. baseline 1 month follow-up p value cpsi total score 22.15 (6.02) 16.40 (8.97) 0.001 cpsi pain domain score 9.67 (2.77) 6.92 (4.50) 0.001 cpsi micturition domain score 5.15 (3.17) 4.02 (2.71) 0.09 cpsi quality of life score 7.35 (2.20) 5.45 (3.21) 0.002 ipss 15.55 (8.8) 12.5 (7.97) 0.10 iief 62.60 (16.5) 63.85 (16.45) 0.74 results are expressed as: mean (standard deviation, sd). cpsi: chronic prostatitis symptom index; ipss: international prostate symptom score; iief; international index of erectile function. table 1. baseline characteristics of patients included in the study. age, years, median (iqr) 51.5 (41.5-63.2) cigarette smoke, n (%) 2 (5) diabetes, n (%) 1 (2,5) hypertension, n (%) 8 (20) coronary artery disease, n (%) 0 (0) age is expressed as median and inter quartile range (iqr). total sample number (n) = 40. sibona okkkkkkk_stesura seveso 20/01/20 11:26 pagina 253 archivio italiano di urologia e andrologia 2019; 91, 4 m. sibona, p. destefanis, m. agnello, b. lillaz. m. giuliano. t. cai, p. gontero 254 as a matter of fact, the use of an nih-cpsi based evaluation of the response to treatment is a common finding in chronic prostatitis trials, even though reference levels are not clearly established and can vary highly between different studies. for example, cai and colleagues (18) demonstrated the superiority of flower pollen extract in association with vitamins over ibuprofen, considering a ≥ 25% reduction in the nih-cpsi total score as clinically significant. similarly, wagenlehner (1) and elist (19) showed a significant improvement of the cpsi total score, cpsi “pain” domain score and qol score as indicative of efficacy of another pollen extract, compared to placebo. in most cases, a reduction > 25-50% or > 2-5 points in nih-cpsi total score or pain domain score, was considered significant (20). as a second strength of our study, we particularly focused on the selection of our sample. in fact, we aimed to differentiate patients affected by prostatitis like symptoms from pure bph or mixed patients. considering that the two conditions, despite sometimes overlapping symptoms, can be differentiated on a clinical basis through accurate anamnestic data collection ad clinical examination, we relied on this to segregate the ones from the others, being the prostatitis patients those characterized by prevalent genitourinary pain compared to the ipb ones affected by prevalent unpainful micturition symptoms. moreover, we used the instrument of the validated questionnaires to obtain an even more accurate patient selection, including only cpsi pain domain ≥ 5 subjects. reflecting the good selection of the included patients and meeting our expectations, patients in our sample referred a better response of the painful, inflammatory symptoms than those more typical of noninflammatory bph. finally, treatment with bosexil® and fenolmicina p3® demonstrated completely safe. no major nor minor adverse side effects were registered. moreover, we did not report any case of withdrawal from the study and no patients were lost to follow-up, even though longer follow-up should be advisable. nonetheless, our study is not devoid of limitations, the major of which is the lack of randomisation and a control group. without any doubt, the absence of a control group makes our results, showing a strong positive effect of the treatment against prostatitis symptoms, susceptible to overestimation, due to possible placebo effect. for this reason, we interpreted our data in the light of other previously published, randomized, controlled trials concerning the same issues, particularly those addressing the use of boswellia resin extracts (21). as we found our results consistent with those reported by randomized controlled trials investigating similar compounds, we judged them highly suggestive of a real therapeutic effect. however, since our study was conceived and has to be considered as a preliminary investigation, the need for further studies concerning these compounds is to be underlined. conclusions the association of bosexil® and fenolmicina p3® can reduce genitourinary pain and then improve quality of life of men affected by bothersome prostatitis like symptoms. references 1. wagenlehner fme, schneider h, ludwig m, et al. a pollen extract (cernilton) in patients with inflammatory chronic prostatitis–chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. eur urol. 2009; 56:544-551. 2. quentin clemens j. male chronic pelvic pain syndrome: prevalence, risk factors, treatment patterns, and socioeconomic impact. curr prostate rep. 2008; 6:81-85. 3. litwin ms, mcnaughton-collins m, fowler fj, et al. the national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. chronic prostatitis collaborative research network. j urol. 1999; 162:369-75. 4. taylor bc, noorbaloochi s, mcnaughton-collins m, et al. urologic diseases in america project. excessive antibiotic use in men with prostatitis. am j med. 2008; 121:444-9. 5. poeckel d, werz o. boswellic acids: biological actions and molecular targets. curr med chem. 2006; 13:3359-69. 6. siemoneit u, koeberle a, rossi a, et al. inhibition of microsomal prostaglandin e2 synthase-1 as a molecular basis for the antiinflammatory actions of boswellic acids from frankincense. br j pharmacol. 2011; 162:147-162. 7. silva jc, rodrigues s, feás x, estevinho lm. antimicrobial activity, phenolic profile and role in the inflammation of propolis. food chem toxicol. 2012; 50:1790-5. 8. ristivojevic p, dimkic i, trifkovic j, et al. antimicrobial activity of serbian propolis evaluated by means of mic, hptlc, bioautography and chemometrics. plos one. 2016; 11:e0157097. 9. naito y, yasumuro m, kondou k, ohara n. antiinflammatory effect of topically applied propolis extract in carrageenan-induced rat hind paw edema. phytother res. 2007; 21:452-6. 10. fall m, baranowski ap, elneil s, et al. european association of urology. eau guidelines on chronic pelvic pain. eur urol. 2010; 57:35-48. 11. giubilei g, mondaini n, crisci a, et al. the italian version of the national institutes of health chronic prostatitis symptom index. eur urol. 2005; 47:805-811. 12. badía x, garcía-losa m, dal-ré r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol. 1997; 31:129-40. 13. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-30. 14. cai t, luciani lg, caola i, et al. effects of pollen extract in association with vitamins (deprox 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. urol j. 2013; 80:5-10. 15. shoskes da, nickel jc. quercetin for chronic prostatitis/ chronic pelvic pain syndrome. urol clin north am. 2011; 38:279-284. 16. hartmann rm, martins mim, tieppo j, et al. effect of boswellia serrata on antioxidant status in an experimental model of colitis rats induced by acetic acid. dig dis sci. 2012; 57:2038-2044. 17. galeotti f, maccari f, fachini a, et al. chemical composition and sibona okkkkkkk_stesura seveso 20/01/20 11:26 pagina 254 antioxidant activity of propolis prepared in different forms and in different solvents useful for finished products. foods. 2018; 19; 7(3). 18. cai t, wagenlehner fme, luciani lg, et al. pollen extract in association with vitamins provides early pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome. exp ther med. 2014; 8:1032-1038. 19. elist j. effects of pollen extract preparation prostat/poltit on lower urinary tract symptoms in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized, doubleblind, placebo-controlled study. urology. 2006; 67:60-3. 20. cai t, verze p, la rocca r,et al. the role of flower pollen extract in managing patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials. bmc urol. 2017; 17:32. 21. galeone g, spadavecchia r, balducci mt, pagliarulo v. the role of proxelan in the treatment of chronic prostatitis. results of a randomized trial. minerva urol nefrol. 2012; 64:135-41. 255archivio italiano di urologia e andrologia 2019; 91, 4 boswellia resin extract and propolis for prostatitis symptoms correspondence mattia sibona, md (corresponding author) mattia.sibona@gmail.com paolo destefanis, md p.deste@gmail.com marco agnello, md agnello.marco89@gmail.com beatrice lillaz, md blillaz@cittadellasalute.to.it mattia giuliano, md mattia.giuliano877@edu.unito.it paolo gontero, md paolo.gontero@unito.it department of urology, department of surgical sciences, a.o.u. città della salute e della scienza di torino, molinette hospital, university of turin, italy corso bramante 88-90, 10126 torino, italy tommaso cai, md ktommy@libero.it department of urology, santa chiara regional hospital, trento, italy largo medaglie d’oro 1, 38122 trento, italy sibona okkkkkkk_stesura seveso 20/01/20 11:26 pagina 255 337archivio italiano di urologia e andrologia 2016; 88, 4 case report experience of percutaneous access under ultrasound guidance in renal transplant patients with allograft lithiasis silvano palazzo, ottavio colamonico, saverio forte, matteo matera, giuseppe lucarelli, pasquale ditonno, michele battaglia, pasquale martino department of emergency and organ transplantation, university of bari, italy. objective: urolithiasis of the transplanted kidney has an incidence of 0.2 to 1.7%, it increases the risk of infection in immunosuppressed patients and it can lead to ureteral obstruction that is often associated with deterioration of renal function. urolithiasis of the transplanted kidney has different characteristics compared to the native kidney, due to the absence of innervation, which does not lead to colic pain. percutaneous approach is an optimal choice in transplant patients. material and methods: here we report our experience in two cadaveric transplant patients with urolithiasis. the first case was a patient of 68 years with a 20 mm stone located in the transplanted kidney pelvis and another smaller in a lower calyx. the second case was a patient of 65 years with a 15 mm stone in the distal part of the transplanted ureter. in both cases the patients were asymptomatic, but they had a reduction in urine output associated with worsening of the transplanted kidney function. the diagnosis was performed in both cases with ultrasound study, showing a severe hydronephrosis and it was confirmed by computed tomography scan. in both cases, we performed a percutaneous nephrolithotomy (pcnl). access was made after targeting the stone, through a lower pole puncture under ultrasound guidance. the first case was treated with pneumatic and laser energy, breaking stones through a nephroscope. in the second case we performed a laser lithotripsy of the ureteral stone, using a flexible videoureteroscope. at the end of both procedures a double-j stent and a 14 fr malecot nephrostomy were positioned, that were removed at 6 weeks and 10 days, respectively. results: both patients achieved a resolution of the worsening of renal function, recovering the spontaneous diuresis. the surgical procedure using ultrasound guidance was safe and allowed quick access to the renal pelvis. both patients experienced no bleeding or infection during hospitalization. conclusions: percutaneous nephrolithotomy (pcnl) is an established safe and effective surgical treatment option for larger renal calculi in renal allografts. the ultrasound guided access to the transplanted kidney in percutaneous treatment of urolithiasis is useful and fast, minimizing patient exposure to ionizing radiation. key words: renal transplant; urinary calculi; percutaneous nephrolithotomy. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. planted patients (1). although it represents a rather uncommon complication, it can lead to significant morbidity and to a devastating loss of graft function if obstruction occurs (2). described for the first time in 1970 by rattiazzi and associates (3), the urolithiasis of the transplanted kidney is considered a transplant complication deserving of a minimally invasive surgical approach, such as percutaneous nephrolithotomy (pcnl) (4). in fact pcnl is the technique of choice for removal of stones larger than 1.5 cm in diameter and it has the advantage of potentially removing all stone fragments at one procedure (5). among the 1291 transplants performed in our institution, 10 (0.7%) showed nephrolithiasis in the renal graft, but only 4 have necessitated surgery. in this report, we describe two patients with kidney transplantation and urolithiasis treated with pcnl under ultrasound guidance. case report the first case was a 68 year old male patient that had received a cadaveric kidney transplant, in the right iliac fossa, 16 years previously for end-stage renal disease of unknown etiology. in 2012 he has undergone pyelolithotomy for transplanted kidney stones before ureteral reimplantation according to lich-gregoir technique. the patient was in pharmacological therapy for hypertension and type 2 diabetes. he came to our attention for anuria and acute renal failure secondary to a severe hydrourete ronephrosis of the allograft (documented by an ultrasound scan) in absence of colic pain. therefore the patient was drained with a percutaneous nephrostomy, that was removed after a few days when it was placed an anterograde double-j ureteral stent. then a computed tomography scan revealed a 20 mm stone located in the transplanted kidney pelvis and another smaller in a lower calyx (figures 1a, 1b). subsequently, after refusing endoscopic surgery to remove obstruction, he underwent a single session of eswl that remained unsuccessful. after this failure, the patient decided to undergo pcnl. therefore, pcnl treatment was carried out in the supine position and general anesthesia. at first, a lower pole puncture was performed, under ultrasound guidance, in order to introduce a stiff 0.038” guidewire into the pelvicalyceal system. a skin incision along the guidewire was made and dilation was performed using a balloon dilator. after tract dilation, doi: 10.4081/aiua.2016.4.337 presented at 20th national congress sieun, sciacca 2016 introduction urolithiasis of the transplanted kidney is a rare complication that occurs in 0.4-1% of the population of transpalazzo-experience of percutaneous access_stesura seveso 09/01/17 10:48 pagina 337 archivio italiano di urologia e andrologia 2016; 88, 4 s. palazzo, o. colamonico, s. forte, m. matera, g. lucarelli, p. ditonno, m. battaglia, p. martino 338 the percutaneous sheath was advanced into the pelvicalyceal system. dilation and advancement of the operating sheath was accomplished under x-ray control. a rigid nephroscope was introduced through the operating sheath and an holmium laser lithotripsy using 365 μm laser fibers was performed. during the procedure we also used a pneumatic lithotriptor (stone breaker). both stones were destroyed and the fragments were removed with graspers. finally a temporary percutaneous 14 fr malecot nephrostomy was positioned in the renal pelvis, also leaving the previously positioned ureteral stent. the second case was represented by a 65 year old male patient with a medical history of hypertension and chronic kidney disease secondary to adpkd (autosomal dominant polycystic kidney disease). in 2009 he was subjected to cadaveric kidney transplantation in the right iliac fossa but after few months occurred a ureteral stricture that required ureteral reimplantation according to lich-gregoir technique. this patient was admitted to our department for a progressive loss of the allograft function associated with severe hydroureteronephrosis (diagnosed through an ultrasound scan). before surgery was performed an abdomen computed tomography scan which revealed the presence of a 15 mm stone in the distal part of the transplanted ureter (figures 2a, 2b). therefore, the patient was prepared for pcnl procedure. at first, the patient was positioned supine and we made a lower pole puncture, under ultrasound guidance, in order to introduce a percutaneous nephrostomy into an anterior calyx of the transplanted kidney. then we made an anterograde ureteropyelography, under x-ray control, which confirmed the presence of a partial obstruction located in the distal part of the allograft ureter. after putting the guidewire through the nephrostomy, the nephrostomy was removed and we proceeded to dilate the operating channel in order to introduce the percutaneous sheath (always under x-ray control). so that we performed a holmium laser lithotripsy of the ureteral stone, through a flexible videoureteroscopy. stone fragments were removed with graspers. finally we introduced an anterograde double-j stent in order to prevent ureteral stricture, but also a temporary percutaneous 14 fr malecot nephrostomy. after surgery both patients immediately had an improvement of renal function with a postoperative course uneventful, experimenting minimal pain. in particular they had no bleeding or infection during hospitalization. in both cases percutaneous nephrostomy was removed only after 10 days under x-ray control, after contrast injection by the nephrostomy which confirmed a stone free state. ureteral stents were removed cystoscopically after 6 weeks. figure 1a. coronal computed tomography image showing stone in a lower calyx and the double-j stent in the right iliac fossa renal allograft. figure 1b. axial (transverse) computed tomography image showing 2 stones in the right iliac fossa renal allograft (the first located in the kidney pelvis and another smaller in a lower calyx). figure 2a. axial (transverse) computed tomography image showing stone in the distal part of the transplanted ureter. figure 2b. coronal computed tomography image showing stone in the distal part of the transplanted ureter. palazzo-experience of percutaneous access_stesura seveso 09/01/17 10:48 pagina 338 discussion urinary lithiasis, following renal transplantation, represents a rather uncommon complication (0.4-1% ) (1, 6). more than one-half of the patients with stones in a kidney transplantation don’t show any symptom of pain. the plausible explanation for this observation is denervation of the transplanted graft (7). the most common symptoms are hematuria, oliguria/anuria, fever, elevation of serum creatinine level, and positive findings in bacterial culture of urine (8). therefore urinary stones can be regarded a potential threat due to the risk of obstruction, sepsis, and potential loss of allograft function (9). allograft stones may be already placed in situ, the socalled donor-gifted allograft lithiasis, or may be the result of new stone formation after transplantation. the latter is believed to be a multifactorial phenomenon, related to both metabolic and urodynamic parameters (10). predisposing risk factors for stone formation are present in most renal allograft recipients. metabolic factors predisposing to stone formation are hyperparathyroidism, hypercalciuria, recurrent urinary tract infection, hypocitraturia and gout. less common risk factors include outflow obstruction, foreign bodies such as stents, nephrostomy tubes, suture materials and donor lithiasis (11, 12). harper et al. investigated risk factors for stone formation in five patients and compared them to 41 transplant patients with no stones. they reported that although patients with calculi in transplants passed significantly more concentrated and alkaline urine, there were other factors contributing to stone formation (13). the treatment methods of urolithiasis in renal transplant recipients are similar and equally safe as those used in the general population. the options for management of transplant stones are conservative, eswl, percutaneous nephrolithomy (pcnl), ureteroscopy (urs) or open surgery. in particular percutaneous removal of calculi from transplanted kidneys, since it was first described in 1985 by hulbert et al. (13), is the technique of choice for removal of stones larger than 1.5 cm in diameter and it has the advantage of potentially removing all stone fragments at one procedure (5). furthermore, because of the relative superficial position of transplanted kidneys, percutaneous management is favored. indeed pcnl has the best success rate, but it is an invasive procedure on a single functioning kidney (14). krambeck, who described the largest series of pcnl in transplant kidneys, reported perioperative complications in about ¼ of patients (15). these complications, however, were to be ascribed more to the state of immunosuppression that surgery. after these considerations, we must consider the role of ultrasonography in the management of kidney transplant complications, such as urolithiasis. in fact, ultrasonography appears to be the most useful diagnostic tool to detect stones and determine their location and size. furthermore it is an easily applied bedside examination that can guide our intervention, in order to treat this complication (16, 17). when we perform a pcnl, the allograft is located in the iliac fossa and the access is typically by way of an anterior calyx with the patient in a supine position. intra-operative ultrasound can be used to assess anatomy before access is attempted, because the proximity of bowel loops and iliac blood vessels introduce the possibility of injury to these structures. in addition immunosuppressive therapy can increase the risk of complications particularly impaired wound healing, fistula formation and perinephric urinoma (5). the aim of our report is to stress the importance of ultrasonography in percutaneous treatment of the transplanted kidney lithiasis. ultrasound has a limited application in percutaneous treatment of native kidney stones because we have some anatomical landmarks (the inferior border of the 12th rib, iliac crest, posterior axillary line) that allow to minimize the risk of damage to the abdominal organs and vascular structures. instead, although the transplanted kidney has a more superficial location, there is an increased risk of bowel damage and injury to the iliac vessels. since the transplanted kidney has an extra anatomical location, there are no bone landmarks capable of guiding the operator in the proper approach to the urinary tract. the extra anatomical position of the neo-ureteral meatus, in association with the difficult accessibility to the high urinary tract because of perimeatal and periureteral fibrosis, make complex if not impossible to execute an ascending pyelography, preventing an x-ray guided approach to the transplanted kidney (18). for this reason we believe that ultrasound can speed up the percutaneous access to the kidney transplant for the treatment of urolithiasis, reducing the risk of bowel and vascular damage. in addition ultrasound, reducing surgery time, may decrease the patient's exposure to ionizing radiation. conclusion the formation of urinary stone following renal transplantation is a rare complication. percutaneous nephrolithotomy (pcnl) is an established safe and effective surgical treatment option for larger renal calculi in renal allografts. in our opinion, the ultrasound guided access to the transplanted kidney in percutaneous treatment of urolithiasis is useful and fast, minimizing patient exposure to ionizing radiation. references 1. rhee bk, bretan pn jr, stoller ml. urolithiasis in renal and combined pancreas/renal transplant recipients. j urol. 1999; 161:1458-62. 2. stravodimos kg, adamis s, tyritzis s, et al. renal transplant lithiasis: analysis of our series and review of the literature. j endourol. 2012; 26:38-44. 3. rattiazzi lc, simmons rl, markland c, et al. calculi complicating renal transplantation into ileal conduits. urology. 1975; 5:29-31. 4. challacombe b, dasgupta p, tiptaft r, et al. multimodal management of urolithiasis in renal transplantation. bju int. 2005; 96:385-389. 5. wong ka, olsburgh j. management of stones in renal transplant. curr opin urol. 2013; 23:175-9. 6. mamarelis g, vernadakis s, moris d, et al. lithiasis of the renal allograft, a rare urological complication following renal transplantation: a single-center experience of 2,045 renal transplantations. transplant proc. 2014; 46:3203-5. 339archivio italiano di urologia e andrologia 2016; 88, 4 percutaneous access in renal allograft lithiasis palazzo-experience of percutaneous access_stesura seveso 09/01/17 10:48 pagina 339 archivio italiano di urologia e andrologia 2016; 88, 4 s. palazzo, o. colamonico, s. forte, m. matera, g. lucarelli, p. ditonno, m. battaglia, p. martino 340 7. ferreira cassini m, cologna aj, ferreira andrade m, et al. lithiasis in 1,313 kidney transplants: incidence, diagnosis, and management. transplant proc. 2012; 44:2373-5. 8. li sd, wang qt, chen wg. treatment of urinary lithiasis following kidney transplantation with extracorporeal shock-wave lithotripsy. chin med j (engl) 2011; 124:1431e4. 9. verrier c, bessede t, hajj p, et al. decrease in and management of urolithiasis after kidney transplantation. j urol. 2012; 187:1651e5. 10. crook tj, keoghane sr. renal transplant lithiasis: rare but time-consuming. bju int. 2005; 95:931-933. 11. klingler hc, kramer g, lodde m, marberger m. urolithiasis in allograft kidneys. urology. 2002; 59: 344-8. 12. rubio bj, chechille tg, parada mr, et al. lithiasis in renal transplantation. actas urol esp. 1995; 19:561-565. 13. hulbert jc, reddy p, young at, et al. the percutaneous removal of calculi from transplanted kidneys. j urol. 1985; 134:324-6. 14. markic d, krpina k, ahel j, et al. treatment of kidney stone in a kidney-transplanted patient with mini-percutaneous laser lithotripsy: a case report. case rep nephrol dial. 2016; 6:26-31. 15. krambeck ae, leroy aj, patterson de, gettman mt. percutaneous nephrolithotomy success in the transplant kidney. j urol. 2008; 180:2545-9. 16. hyang k, jhoong s. cheigh, hee won ham. urinary stones following renal transplantation. korean j intern med. 2001; 16:118122. 17. kolofousi c, stefanidis k, cokkinos dd, et al. ultrasonographic features of kidney transplants and their complications: an imaging review. isrn radiol 2013; 2013:480862. 18. lu h, shekarriz b, stoller ml. donor-gifted allograft urolithiasis: early percutaneous management. urology. 2002; 59:25. correspondence silvano palazzo, md ottavio colamonico, md saverio forte, md matteo matera, md giuseppe lucarelli, md pasquale ditonno, md michele battaglia, md pasquale martino, md department of emergency and organ transplantation, university of bari, bari, italy palazzo-experience of percutaneous access_stesura seveso 09/01/17 10:48 pagina 340 215archivio italiano di urologia e andrologia 2018; 90, 3 case report a rare complication of ureteral stenting: case report of a uretero-arterial fistula and revision of the literature alois mahlknecht 1, leonardo bizzotto 1, christoph gamper 1, anton wieser 2 1 department of urology, azienda sanitaria dell’alto adige, merano, italy; 2 department of radiology, azienda sanitaria dell’alto adige, merano, italy. introduction: uretero-arterial fistulas are a rare condition. the most frequent clinical sign is hematuria. since these bleedings occur intermittently, the diagnosis is very difficult. if not discovered, uretero-arterial fistulas involve a very high rate of mortality or even results in loss of kidney function. case report: the clinical case we describe is an unusual one. after a radical hysterectomy and a subsequent radiotherapy, a hydronephrosis caused by ureteral fibrosis occurred on both sides. therefore, the patient received bilateral ureteral stents. during a change of the ureteral stents 18 months later, a massive bleeding appeared in the right ureter. initially, a clear evidence of a fistula was not possible neither through ct scan nor through selective angiography. there were some indicators of a uretero-arterial fistula, so an endoluminal vessel stent was placed. subsequently the fistula probably led to an erosion of the vessel stent. discussion: a fistula between the ureter and the iliac artery (uaf) is a rare complication. the increase in known cases during the last years is linked to the possibility of ureteral stenting since 1978. until now only 140 cases have been described in literature. the mortality rate through uaf has decreased from 69% in 1980 to 7-23% today. its development can be traced through the pulsation of the artery and the pressure on the ureter. the most important clinical symptom is bleeding. diagnosis is generally difficult and represents the real problem. the sensitivity of the standard angiography examination is 2341%; it can be improved to 63% using the “provocative” method, which means mobilizing the ureteral stent during examination. the therapy in course of the angiography consists of a simultaneous endovascular stent and/or a co-embolisation. conclusion: arterial or uretero-arterial fistulas (uaf) are a rare condition; the diagnosis is very difficult and most of the time the treatment requires a multidisciplinary team. key words: ureteral stenting; uretero-arterial fistula. submitted 18 june 2018; accepted 5 july 2018 summary no conflict of interest declared. went a radical hysterectomy, adnexectomy and a lymphadenectomy. histological examination was a pt2b, n1, (2/19 positive lymph nodes), mo, gr i, ro stage. consequently, the patient underwent radiotherapy. during a control visit in september 2009, a fibrosis plate in the lower pelvis had become visible on the ct and mri scans. this plate compressed both ureters and subsequently caused a hydronephrosis on both sides. the hydronephrosis was more evident on the right side and caused a chronic kidney failure. therefore, the kidney was drained. silicon tu-stents of opti-med, 7 ch, 28 cm were used. the hydronephrosis never receded entirely and a recurrent urinary tract infection with fever occurred. furthermore, the patient suffered from several additional pathologies, e.g. diabetes mellitus type ii, a chronic cardiomyopathy and a diffuse vasculopathy. during a programmed change of the ureteral stent in march 2011, a massive bleeding in the right ureter suddenly arose. through the quick change of the stent a spontaneous tamponade was made. after stabilizing the cardiovascular system and correcting the heavy loss of blood, a ct scan followed by a selective intra-arterial angiography in digital technique were carried out. both examinations showed an ureteroarterial fistula between the right common iliac artery and the ureter; however, a clear evidence could not be found. during the examination, the common and the external iliac artery were successfully repaired. additionally, the internal iliac artery was closed. eight months later, an intermittent macrohematuria occurred again and this time, the “provocative” angiography clearly showed a fistula and also the retrograde pyelography also confirmed a contrast medium leakage (figures 1, 2).with high probability, the fistula was caused by the erosion of the ureteral endoluminal stentgraft. a covering through a second stent was made. in may 2012, a definitive, percutaneous nephrostomy was placed on the right side as additional changes of the ureteral stents would surely have increased the risk of new bleedings. four months later, a severe macrohematuria occurred again. therefore, another endografting of the right common iliac artery with a fluency 10x100 covered stent was placed (figure 3). the patient died two months later probably due to pulmonary embolism. doi: 10.4081/aiua.2018.3.215 introduction uretero-arterial fistulas are a rare condition that can be critical in case of bleeding. since these bleedings occur intermittently, the diagnosis is very difficult. if not discovered, uretero-arterial fistula involve a very high rate of mortality or even results in the loss of kidney function. case report in 2004, the patient was 79 years old. because of a welldifferentiated endometrial carcinoma, the patient undermahlnecht okkkkkkkk_stesura seveso 03/10/18 09:48 pagina 215 archivio italiano di urologia e andrologia 2018; 90, 3 a. mahlknecht, l. bizzotto, c. gamper, a. wieser 216 discussion a fistula between the ureter and the iliac artery (uaf) is a rare complication. the first presentation took place in new york in 1908 when moschcowitz presented a case in which a patient underwent a ureterostomy on both sides and postoperatively developed an erosion on both sides in the external iliac artery caused by a ureteral stone. both vessels were ligated above and below the lesions (1). the increase in known cases during the last years is linked to the possibility of ureteral stenting since 1978 (2). however, uretero-arterial fistulas are a rare condition (3). until now only 140 cases have been described in literature. the mortality rate through uaf has decreased from 69% in 1980 to 7-23% today. the uretero-arterial fistula (uaf) arises where the ureter and the common or external iliac artery meet. its development can be traced through the pulsation of the artery and the pressure on the ureter. above, the edema develops into a necrosis to the ureter wall and eventually into a fistula (5, 6). with an intact wall and mucosa a fistula will not develop. there must be predisposal factors and/or risk factors. indeed, inflammatory reactions after surgery to the ureter wall, local fibrosis of the retroperitoneum after radiotherapy or vascular surgery in the pelvic area can lead to adhesions between the ureter and artery, which then will cause the formation of a fistula (7). however, most of the time fistulas arise after the placement of ureteral stents (8). especially when they lie for a long time, fistulas can develop; even the harder polyethylene stents, which are easier to position, seem to cause fistulas more easily. generally, the period between the positioning of a stent and the formation of a fistula can last between 1 up to 8 years (9). additionally, oncological surgeries in the pelvis (cervix, uterus, and bladder), radiotherapy and vascular surgeries are risk factors for the formation of fistulas (10). a rupture of the vasa vasorum and the weakening of the tunica media and the adventitia of the bigger arteries could be probable causes (11). other factors are rare exceptions for example the surgical drainage after an appendectomy or ureterotomy, where the mechanical pressure of the drain creates a simultaneous inflammatory reaction; or the spontaneous rupture of an aneurysm in the ureter (12, 13). several other factors play a significant role, e.g. in the case description of taylor and reinhard, in which a mycotic aneurysm of the common iliac artery ruptured into the ureter which had a ureteral stent lying for 24 days (14). the most important clinical symptom is bleeding. in most cases, it is intermittent bleeding, in which the thrombosis closes the fistula in the meantime. diagnosis is generally difficult and represents the real problem. through sonogram, urography and ct scan the uretero-arterial fistula cannot be shown. the ct scan has low sensitivity and it is not sufficient as the only imaging technique (8). furthermore, the results of the antegrade or retrograde pyelography are questionable. the cystoscopy with retrograde pyelography has a sensitivity of 45-60% (15). only angiography is relatively suitable for diagnosis. the sensitivity of standard angiography examination is 23-41%; it can be improved to 63% using the “provocative” method, which means mobilizing the ureteral stent during examination (16). the angiography shows evidence of fistulas only during the bleeding phase. if a sonogram or urography shows blood coagula in the renal pelvis-calyceal system in a patient with a lying stent, a uretero-arterial fistula could be the cause (17). therefore, the sonography can give first diagnostic indication. first of all, the therapy depends on the quality of the preoperative diagnosis. if not made correctly and carefully, 32% of the patients consequently suffer from the loss of the kidney through nephrectomy or embolisation (16). with certain diagnosis the therapy consists of supplying the arterial lesion. the ureter does not necessarily have to be repaired (5, 6). the surrounding circumstances are decisive for the choice of therapy: stitching over the figure 1. the “provocative” angiography clearly showed a fistula and also the retrograde pyelography also confirmed a contrast medium leakage. figure 2. this image shows the contrast medium leakage even more distinctly. please note the endovascular stent in the right common iliac artery. figure 3. four months later a fluency 10x100 covered stent was placed. mahlnecht okkkkkkkk_stesura seveso 03/10/18 09:48 pagina 216 lesion, embolising or rather ligating the iliac artery with or without bypass, and interpositioning of a vascular prosthesis. when embolising, the danger of inadequate blood supply of the lower extremities has to be kept in mind; therefore, a vascular surgery to create a bypass is absolutely necessary. in some circumstances, fibrotic changes after preceding surgery and/or radiotherapy as well as recurrent tumours can militate against reconstruction. if these factors do not exist, a direct supply of the artery should be favoured. alternatively, the arterial embolisation of the common iliac artery is recommended. since 1996 endovascular methods have been at hand they are less invasive and are nowadays therapeutic standard (18-20). indeed, in the course of angiography a simultaneous endovascular supply of the fistula through implantation of a covered stent and/or co-embolisation should be favoured. its advantages are obvious: interventional application without surgery and a low operative risk with physiological maintenance of the arterial bloodstream. the only disadvantage is the risk of infection. conclusions arterial or uretero-arterial fistulas (uaf) are a rare condition. until now, about 140 cases have been described. through the increase of gynecological, urological and vascular surgeries in the lesser pelvis and, above all, through the introduction of ureteral stents in 1978, an exponential increase of the cases has been recorded. therefore, for stenting it is recommended to use soft stents and stents that are smaller in diameter when stenting (21, 22). the leading symptom is the massive, mostly intermittent hematuria. if untreated, mortality comes up to 100%. a careful anamnesis and diagnosis are preconditions for a successful therapy. uretero-arterial fistulas arise only when predisposal risk factors like ureteral stents and pelvic pre surgeries occur, or after radiation. through selective selective angiography as digital subtraction technique, clear evidence of the cause of the bleeding can be obtained in the majority of the cases. furthermore, in the course of the same examination an endovascular therapy can be made the case of an uretero-arterial fistula after ureteral stenting on the right side has been described above. the fistula had been successfully treated three times. the very high mortality rate of 67% until 1978 decreased to 17% in 1996 through the introduction of endovascular treatment. in view of the good results as well as the patient’s limited life expectancy because of a malign underlying disease, the endovascular treatment should be the therapy of choice. references 1. moschcowitz av. simultanous ligation of both external iliac arteries for secondary hemorrhage following bilateral ureterolithotomy. ann surg. 1908; 48:872. 2. finney rp. experience with new double j ureteral catheter stent. j urol. 1978; 120:678. 3. bettman ma, murray pd, perlmutt lm, et al. uretero-iliacal anastomotic leaks: percutaneous treatment. radiology. 1983; 148:95. 4. batter sj, mcgovern fj, cambria rp. uretroarterial fistula: case report and review of the literature. urology 1996; 48:481. 5. keller fs, barton re, routh wd, gross gm. gross hematuria in two patients with ureteral-ileal conduits and double-j stents. j vasc intervent radiol. 1990; 1:69. 6. toolin e, pollack hm, mc lean gk, et al. uretero-arterial fistula: a case report. j urol. 1984; 132:553. 7. reiner rj, conway gf, threlkeld r ureteroarterial fistula j urol. 1975; 116:111. 8. krambeck ae, dimarco ds, gertman mt, et al. ureteroiliac artery fistula: diagnosis and treatment algorithm. urology. 2005; 66:990. 9. puppo p, perachino m, ricciotti g, et al. ureteroarterial fistula: a case report. j urol. 1992; 148:863. 10. vandersteen dr, saxon rr, fuchs e, et al diagnosis and management of ureteroiliac artery fistula: value of provocative arteriography followed by common iliac artery embolization and extraanatomic arterial bypass grafting. j urol. 1997; 158:748. 11. dervanian p, castaigne d, travagli jp, et al. arterioureteral fistula after extendet resection of pelvic tumors: report of three cases and review of the literature. ann vasc surg. 1992; 6:362. 12. martinez vmb, gomez aem. postappendectomy aretrio-ureteral fistula. actas urol esp. 1980; 4:331. 13. rennick jm, link dp, palmer jm. spontaneous rupture o fan iliac artery aneurysm into an ureter: a case report and review of the literature. j urol. 1976; 116:111. 14. taylor wn, reinhart hl. mycotic aneurysm of common iliac artery with rupture into right ureter: report of a case. j urol. 1939; 42:24. 15. quillin sp, darcy md, picus d. angiographic evaluation and therapy of arterioureteral fistulas. am j roentg 1994; 162:873. 16. vandersteen dr, saxon rr, fuchs e, et al. diagnosis and management of uretroureteral fistula: value of provocative arteriography followed by common iliac artery embolization and extraanatomic arterial bypass grafting. j urol. 1997; 158:748. 17. hausegger von ka, sonnleitner j, uggowitzer m, et al. iliakouretrale fistel, eine seltene komplikation bei ureterschienung. fortschr roentgenstr. 1996; 164:525. 18. bilbao ji, cosin o, bastarrika g, et al. treatment of ureteroarterial fistulae with covered vascular endoprothesis and ureteral occlusion. cardiovasc intervent radiol. 2005; 28:159. 19. araki t, nagata m, et al. endovascular treatment of ureteroarterial fistulas with stent-grafts. radiat med. 2008; 26:372. 20. krenzien j, zimmermann hb, schott h. die iliaco-ureterale fistel und ihre behandlung mit einem stent-graft der chirurg. 1998; 69:977-980. 21. zweers hmm, driel van mf, mensink hjm. iliac arteryureteral fistula associated with an indwelling ureteral stent. urol int. 1991; 46:213. 22. sparwasser c, kugler a, gilbert p, et al. bilaterale uretero-iliakale fisteln in zusammenhang mit radiatio und ureteraler splintung. urologe a. 1994; 33:85. 217archivio italiano di urologia e andrologia 2018; 90, 3 a rare complication of ureteral stenting: case report of a uretero-arterial fistula and revision of the literature. correspondence alois mahlknecht, md alois.mahlknecht@sabes.it leonardo bizzotto, md christoph gamper, md department of urology, azienda sanitaria dell’alto adige, merano, italy anton wieser, md department of radiology, azienda sanitaria dell’alto adige, merano, italy mahlnecht okkkkkkkk_stesura seveso 03/10/18 09:48 pagina 217 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2149 original paper comparison of the efficiency, safety and pain scores of holmium laser devices working with 20 watt and 30 watt using in retrograde intrarenal surgery: one center prospective study sercan sari 1, mehmet çağlar çakici 2, i̇brahim güven kartal 2, volkan selmï 1, harun özdemïr 3, hakkı ugur ozok 4, ahmet nihat karakoyunlu 2, serkan yildiz 5, emre hepşen 6, serra ozbal 7, hamit ersoy 2 1 bozok university, department of urology,yozgat, turkey; 2 university of health sciences, dışkapı yıldırım beyazıt training and research hospital, department of urology, ankara, turkey; 3 university of health sciences, haseki training and research hospital, istanbul, turkey; 4 karabuk unıversity, department of urology, karabuk, turkey; 5 siirt state hospital, department of urology, siirt, turkey; 6 çubuk state hospital,department of urology, ankara,turkey; 7 university of health sciences, dışkapı yıldırım beyazıt training and research hospital, department of radiology, ankara, turkey. objectives: holmium:yttrium aluminum garnet laser lithotripsy is used in retrograde intrarenal surgery. fragmentation is made with a certain value of pulse energy (joule) and frequency (hertz) in holmium laser lithotripsy and the multiplication of these values gives us total power (watt). devices with maximum power of 20 watt and 30 watt are used in clinical practice. we want to compare the efficiency, safety and pain scores of the lithotripsy made below 20 watt and over 30 watt with 30 watt laser device. materials and methods: 60 patients who had 2-3 cm sized kidney stones and operation planned were prospectively divided into three groups. groups were random identified. in the first group, fragmentation was performed below 20 watt power with 20 watt laser device. in the second group, fragmentation was performed below 20 watt power with 30 watt laser device. in the third group, fragmentation was performed over 20 watt power with 30 watt laser device. demographic, stone, intraoperative and postoperative data were recorded. we compared these groups regarding efficiency, safety and pain score. results: for demographic and stone data, there was a statistically significant difference only for stone number. for intraoperative and postoperative data, there was a statistically significant difference only for ureteral access sheath usage between the groups. success was lower than the other groups in group 1. conclusions: success was higher in groups using 30 watt laser device. there was not statistically significantly difference between complications and pain. 30 watt laser device is safe and efficient in retrograde intrarenal surgery. key words: comparison; efficiency; kidney stone; pain; safety; watt. submitted 16 december 2019; accepted 23 decembe 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.149 introduction the increasing incidence of kidney stone disease caused the increasing number of lithotripsy in urology clinics (1). retrograde intrarenal surgery (rirs) is a new method. its usage recently widened with advances of technology (2). holmium:yttrium aluminum garnet (ho:yag) laser lithotripsy is a lithotripsy method used in rirs. ho:yag laser lithotripsy fragments stone with the photothermal mechanism (3). in ho:yag laser lithotripsy fragmentation is made with a certain value of pulse energy (joule/j) and frequency (hertz/hz.). the multiplication of these values gives us total power (watt/w). in clinical practice, the device with the maximum power of 20 w was at first available. recently the device with maximum power of 30 w has been used. in our study, we used these two devices. we want to compare efficiency, safety and pain scores of the lithotripsy made below 20 w and over 30 w with 30 w laser device. materials and methods after receiving local ethical board approval, a randomized prospective study was planned. study was recorded into national clinical trials (nct) and nct code was taken (nct 02443909). sixty patients who had 2-3 cm sized kidney stones and for whom rirs was planned were divided into three groups. groups were random identified. informed consent was obtained from all individual participants included in the study. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. blood count, biochemical tests, coagulation tests, urine analysis, urine culture, kidney ureter bladder xgraphy (kubg), urinary system ultrasonography (us), computerized tomography (ct) were preoperatively performed. patients age, gender, body mass index (bmi), history of shock wave lithotripsy (swl), american society of anesthesiologists (asa) score, previous stone surgery history, preoperative double j stent (jj) history, anticoagulant usage, kidney anomaly, stone laterality, stone number, stone size and stone localization were recorded. 150archivio italiano di urologia e andrologia 2020; 92, 2 comparison of 20 watt 30 watt laser devices preoperative urine culture was sterile patients were taken dexketoprofen trometamol twice a day as the analgesic and anti-inflammatory treatment after the operation. visual analogue scale (vas) was filled at postoperative eighth hours by patients. patients marked the value equal to his/her pain in the vas. the marked value was recorded. intraoperative operation time, scopy time, postoperative jj stent rate, ureteral access sheath (uas) usage, hospitalization time and complications were recorded. complications were evaluated according to modified clavien and dindo classification. the patients who had kidney anomalies, were < 18 years old, had urinary system infections in the preoperative evaluations were excluded from the study. the patients were divided into three groups. in the first group, fragmentation was performed below 20 w power with 20 w laser device. in the second group, fragmentation was performed below 20 w power with 30 w laser device. in the third group, fragmentation was performed over 20 w power with 30 w laser device. we used dusting and fragmentation methods in our study. preoperative antibiotic was administered to all patients. rirs was performed under general anesthesia with 7.5 french (fr) flexible renoscope (flex-x2; karl storz, tutlingen, germany). after general anesthesia in modified supine position, the patient was taken to modified dorsal lithotomy position. semi-rigid ureterorenoscope was applied into the ureter under fluoroscopic control and 0.035/0.038 inch hydrophilic safety wire was placed into the ureter under fluoroscopic control. semi-rigid ureterorenoscopy was performed. in case of semirigid ureterorenoscopy failure due to ureteral stricture, jj stent was placed and the operation ended. after semirigid ureterorenoscopy, 9.5-11.5 fr or 11-13 fr access sheath (elit flex, ankara, turkey) was placed into the ureter up to the ureteropelvic junction under fluoroscopic control. then flexible renoscope was placed through the uas to provide access to the kidney. when access sheath was not placed, flexible renoscope was moved via safety wire to access the kidney. fragmentation was performed via 200 mm: yttrium aluminum garnet laser probe (dornier medilas h20 and hsolvo; medtech, munich, germany) after the stone had been reached. in group 1 and 2, 8-10 hz. frequency and 1.2-1.8 j pulse energy were used. in group 3, 10-12 hz. frequency and 2-3 j pulse energy were used. we used dusting and fragmentation methods. all calices were explored with flexible renoscope at the end of operation under fluoroscopic control. jj stent was placed into the ureter due to intraoperative conditions. jj stent was taken three weeks later with an outpatient procedure. kubg and us were performed on postoperative first day. ct was performed at postoperative third month. patients who were stone free or had clinically insignificant residual fragment (< 2 mm) after intraoperative and postoperative controls, were evaluated as successful. we compared groups regarding efficiency, safety and pain score. statistical analysis analysis was made with spss for windows 16.0 package program. normality of numerical measurement values distributions was at first researched. one-sample kolmogorov-smirnov test was used to determine the distributions of parameters except for age, bmi and operation time. the distributions were not normal (p < 0.05). kruskal wallis test was used to determine whether there was difference between two groups for gender, asa score, stone laterality, stone localization, stone number, stone size, uas usage, postoperative jj stent usage, residual stone, scopy time, previous stone surgery history, swl history, intraoperative and postoperative complications, anticoagulant usage and vas score. in the patients with statistically significant differences in kruskal wallis test, to determine from which group the difference originated in the analyze, mann-whitney u test was used to perform dual comparisons. one-way anova test was performed to determine whether there was a statistical difference between the groups for age, bmi and operation time. p < 0.05 value was accepted as statistically significant for results. results when we look at demographic and stone data, there was no statistically significant difference for the parameters age, gender, bmi, asa, swl history, previous stone surgery history, anticoagulant usage, preoperative jj stent, stone laterality, stone size and stone localization between the groups. there was a statistically significant difference for stone number (p = 0.036) (table 1). when we evaluate intraoperative and postoperative data, there was no statistically significant difference for operation time, scopy time, postoperative jj stent usage and hospitalization time. there was a statistically significant table 1. demographic and stone characteristics. group 1 (n = 20) group 2 (n = 20) group 3 (n = 20) p age (years) ( ± sd) 51.15 ± 12.58 47.75 ± 14.26 54.45 ± 14.45 0.315 gender (m/f) (n) 8/12 14/6 12/8 0.154 bmi (kg/m2) ( ± sd) 28.57 ± 4.43 28.12 ± 4.60 26.42 ± 3.97 0.265 asa mean (n) 1.551 1.3525 1.671 0.409 swl history (n, %) 5 (25) 2 (10) 3 (15) 0.438 previous surgery history (n, %) 9 (45) 5 (25) 5 (25) 0.298 anticoagulant usage (n, %) 1 (5) 0 0 0.368 preoperative jj stent (n, %) 8 (40) 2 (10) 5 (25) 0.094 stone laterality (r/l) (n) 9/11 7/13 7/13 0.758 stone number (n) ( ± sd) 1.85 ± 0.48 2.20 ± 0.89 1.75 ± 1.41 0.036 stone size (mm) (± sd) 22.30 ± 3.21 22.60 ± 3.33 23.90 ± 4.09 0.56 stone localization (n, %) 0.55 upper calyx (n, %) 1 (5) 1 (5) 1 (5) lower calyx (n, %) 6 (30) 6 (30) 5 (25) mid calyx (n, %) 0 0 2 (10) pelvis (n, %) 2 (10) 3 (15) 8 (40) multicaliceal (n, %) 11 (55) 10 (50) 4 (20) m/f: male/female; bmi: body mass index; asa: american society of anesthesiologists; jj: double j; swl: shock wave lithotripsy. archivio italiano di urologia e andrologia 2020; 92, 2 s. sari, m. çağlar çakici, i̇. güven kartal, v. selmï, h. özdemïr, h. ugur ozok, a. nihat karakoyunlu, s. yildiz, e. hepşen, s. ozbal, h. ersoy 151 difference for uas usage between the groups. there was no statistically insignificant difference between the groups for vas score (table 2). when we look at success, in group 1 seven patients, in group 2 sixteen patients, and in group 3 fifteen patients were stone free. the difference was statistically significant (p = 0.006). in group 1 the operation was unsuccessful in one patient due to malfunctioning of the device, in four patients due to ureteral stricture and in eight patients due to inability to reach the stone. in group 2, the operation was unsuccessful in one patient due to the malfunctioning of the device, in three patients due to inability to reach the stone. in group 3, the operation was unsuccessful due to ureteral stricture in one patient, in two patients due to inability to reach the stone and in two patients due to stone burden. there was not clinically insignificant residual fragment in any group (table 2). complications were seen in five patients for group 1, eight patients for group 2 and four patients for group 3 (p = 0.35). intraoperative complications were seen in three patients for group 1, five patients for group 2 and one patient for group 3 (p = 0.214). postoperative complications were seen in two patients for group 1, six patients for group 2 and three patients for group 3. bleeding was the intraoperative and postoperative associated complication in group 2 (table 2). discussion rirs is a method of increasing use in kidney stone treatment (4). ho:yag laser is used in rirs. a certain value of frequency (hz.) and pulse energy (j) are used in ho:yag laser lithotripsy. the multiplication of these values give us power (w). there are studies to determine optimum power settings in ho:yag laser lithotripsy in the literature (5-7). these are in vitro studies. human stones or stone-like material were used in these studies. in the same power settings, low frequency/high pulse energy and high frequency/low pulse energy were compared in these studies. in the same power settings, the low-frequency high pulse energy is more effective. there are studies that report pulse energy is the major variable affecting fragmentation efficiency (6). total fragmentation increases as pulse energy increase (6). the increase of pulse energy provides fast fragmentation but produces larger fragments (6). retropulsion increases due to the increase of pulse energy (7-10). as retropulsion increases, the distance between fiber tip and stone decreases (7) and the energy applied to the stone decreases (11), so retropulsion decreases fragmentation efficiency (9). also, the high pulse energy is associated with fiber tip malfunctioning and this causes low efficiency (6, 12). when we look at literature, fragmentation speed increases as total power increases. there are studies about low power settings (13). in a study, shorter lithotripsy time was reported by high power settings (2.8 j and 15 hz.), but there was not a comparison (14). in our study, we aimed to compare the efficiency, safety and pain score of the lithotripsy under 20 w and over 20 w power with two different laser devices in the same sized stones. when we look at demographic and stone characteristics, there was no statistically significant difference between the groups except the stone number. when we look at the operation data, there was statistically significant difference between the groups for uas usage rate and success. in group 1, uas usage rate was lower than the other groups, that may explaun the higher number of ureteral stricture observed in group 1. when success was evaluated, it was lower than the other groups in group 1. the inability to reach the stone was seen in 8 patients for group 1, three patients for group 2 and two patients for group 3. the lower caliceal stone rates were similar between the groups. multicaliceal stones rate was higher in group 1 and 2 than group 3. failure due to ureter stricture was higher in group 1 than the other groups. this result can explain the lower success rate in group 1. success was higher in the group in which 30 w laser device was used. the success rate was similar with literature except for group 1. in group 1, due to ureter stricture and multicaliceal stones, success was lower. in our study, first operation success was evaluated. success reached 90-95% after repeating operations in all groups. there was no statistically significant difference between the groups for complications. the increasing pulse energy produces larger fragments (6), so larger residual fragments were seen in group 3. also, steinstrasse was seen in one patient of group 3. operation time was lower in group 3 than group 2 due to increasing pulse energy. operation table 1. !ntraoperative and postoperative data. group 1 (n = 20) group 2 (n = 20) group 3 (n = 20) p average operation time (min.) ( ± sd) 52.40 ± 21.29 61.45 ± 21.60 52 ± 18.23 0.263 average scopy time (sc.) (± sd) 57.05 ± 74.40 35.85 ± 24.13 32.50 ± 21.13 0.57 postoperative jj stent, n (%) 19 (95) 20 (100) 19 (95) 0.368 uretheral access sheath usage, n (%) 14 (70) 20 (100) 19 (95) 0.007 average hospitalisation time (± sd) (day) 1 1 1 1 success, (n) (%) 7 (35) 16 (80) 15 (75) 0.006 stone-free 7 (35) 16 (80) 15 (75) residual fragment (< 3 mm) 0 0 0 residual fragment (≥ 3 mm) 13 (65) 4 (20) 5 (25) vas score (point) (± sd) 3.30 ± 2.15 2.20 ± 1.61 2.60 ± 1.23 0.409 complication rate, n (%) 5 (25) 8 (40) 4 (20) 0.35 intraoperative complication 3 (15) 5 (25) 1 (5) 0.214 mucosal injury, n (%) 1 (5) 1(5) 0 bleeding, n (%) 1 (5) 3 (15) 0 malfunctioning or breakage of instruments, n(%) 1 (5) 1(5) 0 perforation, n (%) 0 0 1 (5) postoperative complication 2 (10) 6 (30) 3 (15) fever (clavien i), n (%) 1 (5) 2 (10) 2 (10) bleeding (clavien i), n (%) 0 3 (15) 0 urinary tract infection (clavien ii), n (%) 1 (5) 1(5) 0 steinstrasse (clavien iiib), n (%) 0 0 1 (5) min: minutes; sec: seconds; jj: double j ; vas: visuel analog scale. 152archivio italiano di urologia e andrologia 2020; 92, 2 comparison of 20 watt 30 watt laser devices time was similar between group 1 and 3. due to the high number of unsuccessful patients in group 1, operation time was lower in group 1. the complication rate is higher in our study when we compared it with literature data. the fewer patient number may explain this result, therefore studies with larger patient number are needed. there was not a statistically significant difference between the groups for vas score. there are few studies evaluating pain in the literature. shoshtari et al. reported the main cause of admission to the hospital was pain (15). singh et al. reported that patients undergoing rirs had more pain than patients undergoing swl at postoperative first and second day (16). oguz et al. reported that female gender, stone size and uas duration time in ureter were statistically significant factors affecting pain (17). in a review researching the effect of female gender on pain scores, tighe et al. observed that postoperative pain scores at first day were higher in females (18). although there are studies that report postoperative jj stent decreases postoperative pain significantly, other studies report that jj stent increases postoperative pain (19). in our study, postoperative jj stent rate was similar between the groups. a limitation of our study was the absence of stone analysis. in a study, comparing ho:yag laser settings, different types stones or stone-like materials were used in vitro (5-7). another limiting factor was the type of laser fiber used. a study reported that fragmentation changed due to use of different laser fiber types (6). the same laser fiber was used in three groups. patient number is another limiting factor because larger patient number studies are needed. conclusions for ho:yag laser lithotripsy in rirs, success was higher in groups using 30 w laser device. there was not statistically significantly difference between complication and pain rates. 30 w laser device is safe and efficient in rirs. references 1. scales cd, smith ac, hanley jm, saigal cs. prevalence of kidney stones in the united states. eur urol. 2012; 62:160-165. 2. wendt ng, mut t, krombach p, et al. do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? urol res. 2011; 39:185-8. 3-vassar gj, chan kf, teichman jmh, et al. holmium:yag lithotripsy:photothermal mechanism. j endourol. 1999; 13:181-190. 4. schoenthaler m, wilhelm k, katzenwadel a, et al. retrograde intrarenal surgery in treatment of nephrolithiasis: is a 100% stonefree rate achievable? j endourol. 2012; 26:489-93. 5. kronenberg p, traxer o. in vitro fragmentation efficiency of holmium: yttrium-aluminum-garnet (yag) laser lithotripsy – a comprehensive study encompassing different frequencies, pulse energies, total power levels and laser fibre diameters. bju int. 2014; 114:261-267. 6. spore ss, teichman jm, corbin ns, et al. holmium:yag lithotripsy:optimal power settings. j endourol. 1999; 13:559.12. 7. sea j, jonat lm, chew bh, et al. optimal power settings for holmium:yag lithotripsy. j urol. 2012; 187:914-9. 8. lee h, ryan rt, teichman jm, et al. stone retropulsion during holmium:yag lithotripsy. j urol. 2003; 169:881. 9. finley ds, petersen j, abdelshehid c, et al. effect of holmium:yag laser pulse width on lithotripsy retropulsion in vitro. j endourol. 2005; 19:1041. 10. kang hw, lee h, teichman jm, et al. dependence of calculus retropulsion on pulse duration during ho:yag laser lithotripsy. lasers surg med. 2006; 38:762. 11. jansen ed, van leeuwen tg, motamedi m, et al. temperature dependency of the absorption coefficient of water for mid-infrared laser irradiation. laser surg med. 1994; 14:258. 12.vassar gj, teichman jmh, glickman rd. holmium:yag lithotripsy efficiency varies with energy density. j urol. 1998; 160:471. 13. razvi ha, densted jd, chun ss, sales sl. intracorporeal lithotripsy with the holmium:yag laser. j urol. 1996; 156:912-914. 14. gould dl. holmium:yag laser and its use in the treatment of urolithiasis: our first 160 cases. j endourol. 1998; 12:23-26. 15. zargar sk, anderson w, rice m. role of emergency ureteroscopy in the management of ureteric stones: analysis of 394 cases. bju int. 2015; 115:946-50. 16. singh bp, prakash j, sankhwar sn, et al. retrograde intrarenal surgery vs extracorporeal shock wave lithotripsy for intermediate size inferior pole calculi: a prospective assessment of objective and subjective outcomes. urology. 2014; 83:1016-22. 17. oguz u, sahin t, senocak ç, et al. factors associated with postoperative pain after retrograde intrarenal surgery for kidney stones.turk j urol. 2017; 43:303-308. 18. tighe pj, riley jl, 3rd, fillingim rb. sex differences in the incidence of severe pain events following surgery: a review of 333,000 pain scores. pain med. 2014; 15:1390-404. 19. mustafa m. the role of stenting in relieving loin pain following ureteroscopic stone therapy for persisting renal colic with hydronephrosis. int urol nephrol. 2007; 39:91-4. correspondence sercan sari, md sercansari92@hotmail.com volkan selmi, md volkanselmi@hotmail.com bozok university, department of urology, yozgat (turkey) mehmet caglar cakici, md mcaglarcakici@hotmail.com !brahim güven kartal, md igk84@hotmail.com ahmet nihat karakoyunlu, md nkarakoyunlu@gmail.com hamit ersoy, md hamitersoy@gmail.com university of health sciences, dışkapı yıldırım beyazıt training and research hospital, department of urology, ankara (turkey) harun özdemir, md dr.harun-17@hotmail.com university of health sciences, haseki training and research hospital, istanbul (turkey) hakkı ugur ozok, md drozok@gmail.com karabuk unıversity, department of urology, karabuk (turkey) serkan yildiz, md s_yildiz55@yahoo.com siirt state hospital, department of urology, siirt (turkey) emre hepsen, md emreepsen@hotmail.com çubuk state hospital,department of urology, ankara (turkey) serra ozbal, md sozbal@gmail.com university of health sciences, dışkapı yıldırım beyazıt training and research hospital, department of radiology, ankara (turkey) stesura seveso 237archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. highest patient and partner satisfaction among all treatment options (3). in the literature, the rate of patient and partner satisfaction varies between 70 and 87% (4).the high satisfaction of the couples also increases the quality of their sexual lives (5). short form (sf) 36 scale is used to measure patient’s quality of life (qol). it has both easy and short applicability. since it is not specific to any disease group, it is recommended to be used in all physical disease groups to determine qol, to reveal the psychosocial aspect of the disease and to determine the change in treatment. (6). ure et al. evaluated patients’ qol with sf 36 scale and observed that it was significantly increased after ppi compared to the preoperative period (7). however, in studies about patient qol who underwent ppi, partner qol was not mentioned much (8). in the current study, patients that did not respond to first-line and second-line treatments, and therefore underwent two-piece ppi were evaluated. the changes in qol with satisfaction levels of patients' and partners' were retrospectively examined. materials and methods the data of 61 patients that underwent ppi due to organic ed between march 2016 and march 2020 were retrospectively reviewed. in total 45 patients and 45 partners agreed to voluntarily participate in the study. inclusion criteria: male patients with placement of two-piece ppi and their female partners, having not received a psychiatric diagnosis and treatment before ppi in their anamnesis, postoperative follow-up period of at least one year. depending on the medical history and socioeconomic status of the patients, the type of prosthesis to be applied was decided. the patients were informed about possible intraoperative and postoperative complications. two-piece prosthesis implantation was performed under spinal anesthesia. in the perioperative period, the penoscrotal region was mechanically cleaned using chlorhexidine alcohol for 10 min. all operations were performed with a penoscrotal incision. dual antibiotics (ciprofloxacin and amoxicillin-clavulanic acid) were continued for two weeks after hospital discharge. the patients were trained to use the prosthesis after one month and were allowed to use the prosthesis after six weeks. objective: the aim of this study is to retrospectively examine patient-partner satisfaction and changes in quality of life due to two-piece penile prosthesis implantation (ppi). there is no data about partner quality of life (qol) related to two-piece ppi in the literature. material and methods: sf 36 scale and modified erectile dysfunction inventory of treatment satisfaction (edits), which were filled before two-piece ppi and at the sixth postoperative month follow-up by male patients (n = 45) and female partners (n = 45), were evaluated. results: we found patient-partner satisfaction rates as 80% and 86% respectively. the changes in all mean scores of sf 36 (mean total score, mean physical health score and mean mental health score) were statistically significant (p < 0.01). again, the differences between all mean scores of sf 36 according to the level of patient-partner satisfaction were statistically significant (p < 0.01). conclusions: two-piece ppi is an important option for ed treatment. it provides significant improvement in patient-partner qol with high treatment satisfaction. key words: two-piece penile prosthesis implantation; patientpartner satisfaction; quality of life. submitted 13 december 2020; accepted 2 january 2021 introduction erectile dysfunciton (ed) is a benign disease and it affects physical and psychosocial health condition. it has an important effect on patient’s and partner’s quality of life. ed treatment consists of three steps. lifestyle modification and risk factor modification should be performed either before or together with ed treatment. oral phosphodiesterase 5 inhibitors (pde5i), vacuum erection device, topical/intraurethralal prostadil, and shock wave therapy are used in the first-line treatment. in the second-line treatment, intracavernosal injection of alprostadil or combination therapy is applied. for the third-line treatment, penile prosthesis implantation (ppi) is available (1). treatment failure is seen in approximately 80% of patients due to their discontinuation with firstline and second-line treatment (2). ppi is therefore an important option for patients that do not comply with or respond to these therapies. in the treatment of ed, ppi is a method that provides does two-piece ppi provide improvement in patient-partner quality of life? engin özbay 1, remzi salar 2, halil ferat öncel 2 1 sbu istanbul kanuni sultan süleyman research and training hospital, department of urology, turkey; 2 sbu sanlıurfa mehmet akif i̇nan research and training hospital, department of urology, turkey. doi: 10.4081/aiua.2021.2.237 summary archivio italiano di urologia e andrologia 2021; 93, 2 e. özbay, r. salar, h.f. öncel 238 sf-36 scale was respectively administered before ppi and at the postoperative sixth month follow-up by face-toface interviews. modified erectile dysfunction inventory of treatment satisfaction (medits) was filled at the postoperative sixth month, too. statistical analysis ibm spss statistics 22.0 program was used for statistical analysis while evaluating the findings obtained in the study. while evaluating the study data, in addition to descriptive statistical methods (mean, standard deviation), paired samples t test was used for the pre-post comparisons of the parameters showing normal distribution. student t test was used for comparisons between the two groups. significance was evaluated at the p < 0.05 level. results the mean age of 45 male patients was 49.7 (± 12) years, and the mean age of their female partners was 42.3 (± 10) years. the mean follow-up period was 40 (± 23) months. diabetes mellitus (%42), radical prostatectomy (%14), penile vascular disease (%38) and peyronie disease (%6) were the etiology of ed. since there was no patient that presented to the hospital with priapism, we did not include it in the table. the american medical service (ams®) two-piece penile prosthesis was implanted in 45 patients. the mean length of hospital stay was three days. in the early postoperative period, one patient developed scrotal hematoma and one developed soft tissue infection due to negligent antibiotic use. in two patients, penoscrotal pain lasted for two months postoperatively. at the fourth postoperative month, mechanical damage was observed in the two-piece penile prosthesis of one patient. the patient-partner satisfaction rates were evaluated using medits at the sixth month. according to the results, 80% of the patients (n = 36) and 86.7% of the partners (n = 39) expressed satisfaction with ppi while 20% of the patients (n = 9) and 13.4% of the partners (n = 6) were dissatisfied with the procedure. sf 36 scale can also be evaluated under two main subscales as “physical health” and “mental health”. table 1 shows the evaluation of sf-36 scores before and after ppi. according to mean total score before ppi, the increase seen in mean total score after ppi was statistically significant (p < 0.01) in patients. and also the increases seen in mean physical health score and mean mental health score after ppi were statistically significant (p < 0.01). according to table 1, the statistical results of the partners were similar to the statistical results of the patients (p < 0.01). table 2 shows the evaluation of sf-36 scores according to satisfaction status. the mean total score of the satisfied group after ppi was significantly higher than the dissatisfied group (p < 0.01). again mean mental health score and mean physical health score of the satisfied group after ppi were significantly higher than the dissatisfied group (p < 0.01). according to table 2, the statistical results of partners showed to be similar to the statistical results of the patients (p < 0.01). discussion two-piece prostheses are preferred in patients who have undergone or are scheduled to undergo organ transplantation in the pelvic region, those with a history of radical pelvic surgery or pelvic radiotherapy, and cases that pose difficulty in terms of reservoir placement in the retzius region (9). other reasons for the preference of two-piece prostheses include their simple application, which makes it easier for the physician to guide the patients in terms of their use and also the full cost coverage of a twopiece penile prosthesis by turkish social security institution (10). lastly, in socioeconomically and socioculturally developed countries, three-piece prostheses are the most preferred type since they can mimic erection as close to nature as possible and have a more cosmetic appearance (11). the disadvantages of three-piece prostheses are that mechanical damage complicates cases and they are more expensive than other types of prosthesis (12). in this study, we used two-piece prostheses for their ease of use and socioeconomic reasons, as well as due to the presence of radical pelvic surgery history in the study population. the most common cause of dissatisfaction after ppi is shortening of the penile length, which is generally 1 to 2 cm (13). in a previous study, the satisfaction rate of patients that underwent prosthesis implantation due to priapism was observed to be 60% due to the complaint of penile shortening (14). patients with peyronie’s disease that undergo ppi may require additional surgical procedures to maintain penile length (15). other reasons for patient dissatisfactions include the development of postoperative infections, mechanical damage, erosion, penile pain, short prosthesis, and soft glans syndrome (13). presence of dm, spinal cord injury, revision surgery, steroid-dependent patients and complicated ppi procedure increase the risk of postop infection. when prosthetable 1. evaluation of sf-36 scores before and after ppi. before ppi after ppi p mean ± sd mean ± sd male patients physical health 63.25 ± 9.35 82.11 ± 16.63 0.001** mental health 58.35 ± 13.65 81.89 ± 18.55 0.001** total scores 60.80 ± 10.69 82.01 ± 17.45 0.001** female partners physical health 62.06 ± 10.43 84.52 ± 15.21 0.001** mental health 55.34 ± 13.92 80.09 ± 19.52 0.001** total scores 58.69 ± 11.69 82.31 ± 17.35 0.001** paired samples t test. **p < 0.01. table 2. evaluation of sf-36 scores according to satisfaction status. unsatisfied satisfied p mean ± sd mean ± sd male patients physical health 52.33 ± 13.47 89.56 ± 4.61 0.001** mental health 46.42 ± 8.23 90.77 ± 3.55 0.001** total scores 49.37 ± 10.67 90.16 ± 3.83 0.001** female partner physical health 49.10 ± 10.63 89.97 ± 4.96 0.001** mental health 35.38 ± 10.17 86.96 ± 7.96 0.001** total scores 42.24 ± 10.39 88.47 ± 6.46 0.001** paired samples t test. **p < 0.01. sis infection develops, all elements of the prosthesis are removed (16). infection treatment is applied. if the new prosthesis is implanted 3-6 months later, the procedure becomes very difficult and the penis becomes shorter. to prevent this complication, salvage procedure can be performed. while removing the prosthesis, mechanical cleaning is applied to the infected tissues with antibiotic solutions in the same session. new ppi is applied in the same session or postponed after 6-8 weeks (17). in our study three patients were dissatisfied with the shortening of their penis length, two patients used oral ciprofloxacin for two months to relieve penile pain. the penile prosthesis of one patient was replaced due to mechanical damage. soft tissue infection was observed in one patient and was suppressed with intravenous antibiotherapy. the unnatural appearance of the prosthesis and the unnatural sensation may also be the cause of dissatisfaction for patient and partner (18). sexual desire disorder, sexual arousal disorders, orgasm and ejeculation problems can also be the cause of dissatisfaction with the patient and partner related to penile prosthesis implantation (19). in the current study three patients were dissatisfied due to ejaculation disorder, two patients and four partners complained of not being fully satisfied with orgasm and one couple was dissatisfied due to the unnatural appearance of the penis. in a study conducted with two-piece prostheses, the patient-partner satisfaction rates were observed to be over 80% (20). çayan et al. conducted a ppi study with 883 patients and reported no statistically significant difference in patient-partner satisfaction rates related to twoand three-piece prostheses, while their satisfaction rates were higher than one-piece prostheses (21). in our study, we calculated the patient and partner satisfaction rates as 80% and 86%, respectively, which is consistent with the literature. ozbay et al. in a study observed that patients with erectile dysfunction due to organic origin disease had sexual dysfunction together with their female partners and the sexual dysfunction of couples improved together after ppi (19). studies have repeatedly shown that ppi positively affects patients’ qol, perceived quality of the couple relationship, partner satisfaction, body image, the relationship with the outside world, and the satisfaction with the implant function (22, 23). in addition, in a study where the patient follow-up period was at least 15 years, it was found that 60% of the patients still used penile prostheses, satisfaction was high, and the qol results were sufficient (8). in this study, patient qol was not at a healthy level before ppi. the significant increase in patients' mean total score, mean physical health score and mean mental health score after ppi indicated an improvement in patient qol. qol of satisfied patients was also at a high level. sexual dysfunction of the female patient negatively affects qol (24). a high rate of sexual dysfunction was observed with the decrease in qol of female patients with organic origin diseases, and it was observed that the same findings were also observed in the male partners of the patients (25-28). successful treatment of female patients' diseases such as hypertension, diabetes, pituitary insufficiency, hypothyroidism and breast cancer improves their sexual dysfunction and qol (29, 30). there are many studies in the literature that evaluate qol of male patients with penile prostheses, but findings evaluating qol of female partners could not be observed in these studies (8, 22, 23). in this study, partners’ qol was not at a healthy level before ppi. the significant increase in partners' mean total score, mean physical health score and mean mental health score after ppi indicated an improvement in partner qol. satisfied partner qol was also at a high level. conclusions high level of patient-partner satisfaction for ed therapy is achieved with the two-piece ppi. in our study, patientpartner qol was not at a healthy level before ppi. but it was observed that patient-partner qol increased similarly after ppi. satisfied patient-partner qol was also at a high level. ethics committee approval harran university faculty of medicine ethical committee approved. consent form and permission was obtained from all patients who participated in the study. references 1. hatzimourotidis k, guiliano f, moncada i, et al. eau guidelines on males sexual dysfunction. 2016; p: 14-22. 2. gümüş bh, albaz ac. erektil disfonksiyon tedavisinde penil protez implantasyonun uzun dönem klinik sonuçları. androl bul. 2017; 19:117-122. 3. efesoy o, özbay e, tek m, et al. longterm outcomes and couple’s satisfaction with three-piece inflatable penile prosthesis surgery in the treatment of erectile dysfunction. türkiye klinikleri j medsci, 2010; 30:1965-70. 4. levine la, estrada cr, morgentaler a. mechanical reliability andsafety of and patient satisfaction with the ambicor inflatable penileprosthesis: results of a 2 center study. j urol. 2001; 166: 932-7. 5. barton gj, carlos ec, lentz ac. sexual quality of life and satisfaction with penile prosthesis. sex med rev. 2019; 7:178-188. 6. newman sp. psychosocial measures in musculoskeletal trials. j rheumatol. 1997; 24:979-84. 7. ure i, ozen a, can c. life quality change after inflatable penile prosthesis implantation. aging male. 2020; 23:362-368. 8. chierigo f, capogrosso p, dehò f, et al. long-term follow-up after penile prosthesis implantation-survival and quality of life outcomes. j sex med. 2019;16:1827-1833. 9. morey af. re: ambicor 2-piece inflatable penile prosthesis: who and how? j urol. 2018; 200:691-692. 10. ozan t, karakeçi a, pirinçci a, et al. iki parçalı sisirilebilir penil protez cerrahisine ait klinik sonuçlar ve hasta memnuniyetinin degerlendirilmesi. f.ü.sag.bil.tıp.derg. 2018; 32:27-30. 11. usta mf. penil protez cerrahisinde yenilikler: 2016 güncelleme. androloji bülteni. 2016; 18 :212-216. 239archivio italiano di urologia e andrologia 2021; 93, 2 does two-piece ppi provide improvement in patient-partner quality of life? archivio italiano di urologia e andrologia 2021; 93, 2 e. özbay, r. salar, h.f. öncel 240 12. esengen s, nalbant i, öztürk u, et al. comparison of penile prosthesis methods: which is more successful? j clin anal med. 2017; 8:421-4. 13. küçük e, bindayı a. penil protez cerrahisi komplikasyonları ve basaçıkma yöntemleri. and bült. 2016; 18:25-29. 14. zacharakis e, garaffa g, raheem a et al. penile prosthes insertion in patients with refractory ischaemic priapism: early vs delayed implantation. bju int 2014; 114:576-581. 15. barrett-harlow b, clavell-hernandez j, wang r. new developments in surgical treatment for penile size preservation in peyronie’s disease. sex med rev. 2019; 7:156-166. 16. mulcahy jj. current approach to the treatment of penile implant infections. ther adv urol. 2010; 2:69-75. 17. mellon mj, broghammer jr, henry gd. the mulcahy salvage: past and present innovations. j sex med. 2015; 12 (suppl 7):432-6. 18. salama n. satisfaction with the malleable penile prosthesis among the couples from the middle eastis it different from that reported elsewhere ? int j impo res. 2004; 16:175-180. 19. özbay e, aydın a, salar r, et al. sexual experiences between partners after penile prosthesis: who is more satisfied? andrologia. 2020; 52:e13461. 20. lux m, reyes-vallejo l, morgentaler a, levine la. outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. j urol. 2007; 177:262-6. 21. çayan s, ascı r, efesoy o, et al. comparison of long-term results and couples’s satisfaction with penile implant types and brands: lessons learned from 883 patients with erectile dysfunction who underwent penile prosthesis implantation. j sex med. 2019; 16:1092-1099. 22. carvalheira a, santana r, pereira nm. why are men satisfied or dissatisfied with penile implants? a mixed method study on satisfaction with penile prosthesis implantation. j sex med. 2015; 12:2474-80. 23. caraceni e, utizi l. questionnaire for the evaluation of quality of life after penile prosthesis implant: quality of life and sexuality with penile prosthesis (qolspp). to what extent does the implant affect the patient’s life? j sex med 2014; 11:1005-1012. 24. buster je. managing female sexual dysfunction. fertil steril. 2013; 100:905-15. 25. tutoglu a, boyaci a, koca i, et al. quality of life, depression, and sexual dysfunction in spouses of female patients with fibromyalgia. rheumatol int. 2014; 34:1079-1084. 26. bilgic d, gokyildiz s, kizilkaya beji n, et al. quality of life and sexual functıon in obese women with pelvic floor dysfunction. women health. 2019; 59:101-113. 27. radoja i, degmecic d. quality of life and female sexual dysfunction in croatian women with stress-, urgencyand mixed urinary incontinence: results of a cross-sectional study. medicina (kaunas). 2019; 55:240. 28. nappi re, cucinella l, martella s, et al. female sexual dysfunction (fsd): prevalence and impact on quality of life (qol). maturitas. 2016; 94:87-91. 29. basson r. female sexual dysfunction in hypopituitarism. lancet. 2007; 70(9589):737. 30. basson r. sexuality in chronic illness: no longer ignored. lancet. 2007; 369(9559):350-2. correspondence özbay engin, md (corresponding author) nozbay63@gmail.com sbu istanbul kanuni sultan süleyman research and training hospital, department of urology, istanbul (turkey) salar remzi, md öncel halil ferat, md sbu sanlıurfa mehmet akif i̇nan research and training hospital, department of urology, sanliurfa (turkey) stesura seveso 79archivio italiano di urologia e andrologia 2019; 91, 2 original paper prostatic calcifications are associated with a more severe symptom burden in men with type ii chronic bacterial prostatitis konstantinos stamatiou 1, vittorio magri 2, gianpaolo perletti 3, alberto trinchieri 4, richard lacroix 1, nektaria rekleiti 1, hippocrates moschouris 1 1 tzaneio hospital, piraeus, greece; 2 asst nord milano, italy; 3 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 4 cdc ambrosiana cesano b, milano, italy. introduction/aim: although prostatic calculi/calcifications are encountered frequently in the urological practice, little is known about the incidence of such lesions, their mechanism of formation, their relationship to other prostate conditions and their clinical significance. the purpose of this study is to describe the characteristics and to investigate the clinical significance of prostatic calcifications (pcs) in patients with chronic bacterial prostatitis (cbp). materials and methods: this study was conducted between 01/02/2013 and 20/02/2018. the patient population for this study included subjects with or without pcs and a confirmed diagnosis of nih category ii chronic bacterial prostatitis (cbp). demographics and clinical history of each assessed patient were reviewed. eligible patients underwent prostatic ultrasound with post-void residual measurement, and the meares-stamey “4-glass” test. symptom severity was measured using the national institutes of health chronic prostatitis symptom index (nih-cpsi) and the international prostatic symptoms score (ipss). antimicrobials were administered to confirmed cases of cbp according to the results of susceptibility tests. after four weeks off-therapy, the nih-cpsi and ipss tests were repeated. variables were compared between patients with and without prostatic calcifications. results: ninety-five cbp patients were included in the study. according to the presence of pcs detected by ultrasound examination, patients were divided into two groups: 41 had pcs (group 1) and 54 didn’t (group 2). no significant between-group baseline differences were found regarding age, marital status, prostate volume, the proportion of common cbp pathogens. concerning highrisk sexual behavior, a significantly higher number of men with pcs practiced anal penetration. moreover, a significantly higher number of men with pcs had a history of chronic prostatitis relapsing episodes. microbiological eradication and the complete resolution of clinical symptoms occurred in similar proportions between the two groups. however, intergroup analysis resulted in significantly higher scores of the nih-cpsi test in group 1, both at the pre-therapy and at the post-therapy time points. conversely, no ipss score differences between groups 1 and 2 were found at both preand post-therapy time points. conclusions: prostatic calcifications do not seem to influence the microbiological outcome of antibacterial treatment. however, the cbp symptoms appear to be more severe in carriers of prostatic calcifications, either before or after antibacterial therapy. key words: prostate; prostatitis; chronic bacterial prostatitis; calcifications; calculi; stones. submitted 20 february 2019; accepted 11 march 2019 summary no conflict of interest declared. introduction the terms prostatic calcifications (pcs), prostatic stones and prostatic calculi are used to describe hyperechoic calcium deposits within the prostate gland. they are a relatively common ultrasound finding whose pathophysiology is partially understood. however, the clinical relevance of these lesions and their association with prostatic diseases remains unclear. traditionally, calcifications are considered to be a random finding of no clinical significance, probably associated with previous infection of the prostate. in fact, are usually found incidentally and are often not associated with a history of prostatitis. while histopathologic investigation showed that most calculi are associated with inflammatory changes, many of the relevant studies haven’t correlated the presence of prostate calcifications with chronic bacterial prostatitis (cbp) (1). nowadays the relation between pcs and cbp remains uncertain and it is still unknown if pcs are clinically insignificant or whether they have the potential to affect the treatment outcome. however, it is deemed important for specialists to become familiar with this entity. in this prospective, observational study, we wished to characterize the clinical features of pcs in men with chronic bacterial prostatitis (nih category ii cbp) and to assess the outcome of therapy in order to better understand their impact on cbp. comparison between cbp patients with or without signs of prostatic calcifications was also attempted. patients and methods this study was conducted between 01/02/2013 and 20/02/2018, after approval by the local ethics committee. participants enrolled for this study were first-referral urological male outpatients presenting with cbp symptoms. group 1 consisted of patients with pcs and confirmed diagnosis of cbp, whereas group 2 included cbp patients without ultrasound evidence of pcs. demographic data and clinical history of each assessed patient were reviewed. inclusion criteria the inclusion criterion for this study was a diagnosis of doi: 10.4081/aiua.2019.2.79 archivio italiano di urologia e andrologia 2019; 91, 2 k. stamatiou, v. magri, g. perletti, a. trinchieri, r. lacroix, n. rekleiti, h. moschouris 80 category ii cbp according to national institutes of health (nih) (2) definition and a microbiological assessment of causative pathogens. exclusion criteria patients suffering from conditions that influence bacterial virulence or host response (eg. immunodeficiency, abnormalities of the urogenital system) and patients who received antibiotics or immunosuppressive treatment within 4 weeks of the recorded visits were excluded from the study. patients diagnosed upon investigation with prostatic diseases other than cbp (category i acute bacterial prostatitis, category iii chronic prostatitis/chronic pelvic pain syndrome, overt symptomatic benign prostatic hyperplasia, neoplasia) as well as patients exhibiting confounding factors (e.g., indwelling catheters, cystostomy, ureterostomy, ureteral stents, previous prostatic surgery or radiotherapy, incomplete compliance to antibacterial therapy assessed by interviewing patients at the end of treatment) were also excluded. patient assessment participants underwent a brief interview in which a complete clinical history was collected. symptom severity was measured using the national institutes of health chronic prostatitis symptom index (nih-cpsi) and the international prostatic symptoms score (ipss) (3). urological visits also included digitorectal examination and urine and/or prostatic secretion sample collection, abdominal ultrasound and post-void residual measurement. calcification evaluation a transrectal ultrasound scan was additionally performed to those who were found with pcs in order to provide both axial and sagittal images, thus improving the evaluation of the number, location, and length of calcifications. trus was performed using an 8.0-mhz rectal probe (ge healthcare, logiq 3). the prostate volume (pv) was measured by trus using the formula for an elliptic volume. besides larger, more echogenic foci that caused acoustic shadowing, also linear calcifications mainly located between transitional and peripheral zone of the glandwere assessed and recorded. calculi were measured instantly at the time when they were detected on trus. a single urologist performed all trus procedures and measured calculi. microbiological evaluation eligible patients underwent the meares-stamey “4-glass” test, based on cultures of first-void (vb1), pre-prostatic massage/midstream (vb2) and post-prostatic massage urine (vb3) specimens, and expressed prostatic secretions (eps) obtained during prostatic massage (4). appropriate antimicrobial agents -accordingly to susceptibility testswere administered to confirmed cases of cbp for a period of 4 weeks. microbiological tests were considered positive when: 1) bacteria grew in the culture of eps and vb3 specimens and did not in vb1 and vb2; 2) bacterial colonies in vb3 were higher in number compared to vb1 and vb2 specimens. given that no standard cutoff levels of the number of bacteria in both urine and prostate secretion samples are defined by consensus for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. cultures, identification and semiquantitative assay for mycoplasma hominis and ureaplasma urealyticum were performed using the mycoplasma ist 2 kit (biomerieux). chlamydia trachomatis was detected by direct immunofluorescence, using monoclonal antibodies against lipopolysaccharide membranes (kallestad). urine samples were cultured undiluted in blood and macconkey agar plates (kallestad lab., tx, usa) and subjected to centrifugation for microscopic examination of the sediment. evaluation of culture results was performed by two specialist microbiologists, who were blinded to patient records. identification of traditional pathogens was performed by conventional methods and the vitek-2 compact system (biomerieux, france), and susceptibility testing was performed by disc diffusion and/or the vitek-2 system. interpretation of susceptibility results was based on clinical and laboratory standards institute (clsi) guidelines. therapy outcome evaluation after four weeks of therapy, the nih-cpsi and ipss tests were repeated. follow-up included also interview, physical examination, transrectal ultrasound and the “4-glass” test. the microbiological response to antibacterial therapy was defined in a manner similar to that of naber et al.: i) eradication: baseline pathogen was eradicated; ii) persistence: baseline pathogen was not eradicated; iii) superinfection: baseline pathogen was eradicated with the appearance of a new pathogen (5). statistical analysis medians and interquartile ranges (iqr) were used to measure the central tendency and data dispersion of questionnaire ordinal scores. for continuous variables, means and standard deviations were calculated. the wilcoxon signed rank test was applied to analyze prevs. post-therapy paired differences in nih-cpsi and ipss scores, whereas the wilcoxon rank sum test was used to calculate the significance of differences between different treatment arms at a given time-point. for continuous variables, paired or unpaired t-tests were used to analyze differences between means. all tests were twotailed if not otherwise indicated, and an alpha error inferior to 5% was set as significance level for each comparison. comparison between proportions of eradicated patients was made using the z-test with the yates’ continuity correction. all inferential calculations were performed using the r open-source software environment. results ninety-five out of 172 eligible patients were assessable at the end of the trial. all patients reported chronic pelvic discomfort and genital pain, with or without lower urinary tract symptoms and sexual dysfunction. the remaining patients, who were not compliant to therapy or who were lost during follow-up were excluded from the study. according to the presence/absence of pcs in ultrasound examination, patients were divided into two groups: 41 individuals had pcs (group 1) and 54 showed no signs of pcs (group 2). the most common symptom in both groups was scrotal/testicular pain (reported by 12 and 17 patients of group 1 and group 2 respectively, p > 0.05, ztest). the most common pathogen in both groups was e. coli (found in 9 and 11 patients of group 1 and group 2 respectively p > 0.05, z-test). data regarding patient demographics, history, clinical symptom presentation and microbiological profiles are listed in tables 1-3. no significant differences were found between groups regarding age, marital status, prostate volume and most sexual behaviors. however, a significantly higher number of men with pcs practiced anal penetration (table 1). incidentally, the vast majority of these subjects showed enterococcal infections (data not shown). a significantly higher number of men with pcs had a history of chronic prostatitis relapsing episodes (table 1). a variety of pathogens were isolated from cbp patients (table 3). in general, patients showing pcs showed a more diverse variety of gram-negative pathogens. however, the intergroup proportions of the most frequently isolated species (e. coli, enterococcus spp., staphylococcus spp.) were not significantly different. in general, patients showing pc showed a more diverse variety of gram-negative pathogens. microbiological eradication occurred in similar proportions between the two groups (table 4). similarly, the resolution of clinical symptoms occurred in equivalent numbers of patients belonging to groups 1 and 2. however, more patients showing no resolution of clinical symptoms belonged to group 1 (n = 18), compared to group 2 (n = 11; p = 0.012; z-test). this difference is likely due to the presence of patients showing uncertain resolution of clinical symptoms in group 2 (n = 6) (table 4). the latter are absent in group 1. the nih-cpsi and the ipss test were used to assess the degree of severity of cbp symptoms in the present study. paired analysis 81archivio italiano di urologia e andrologia 2019; 91, 2 prostatic calcifications are associated with a more severe symptom burden in men with type ii chronic bacterial prostatitis table 1. patient demographic and baseline data. clinical sample study group controls p number of patients 41 54 mean age (years) 46.8 45.1 p > 0.05 chronic prostatitis history (n.) 37 21 p > 0.0001 marital status married (n.) 19 26 p > 0.05 unmarried (n.) 7 9 p > 0.05 divorced (n.) 4 8 p > 0.05 widower (n.) 2 1 p > 0.05 unknown (n.) 9 10 sexual behaviour vaginal penetration (n.) 21 24 p > 0.05 anal penetration (n.) 19 16 p = 0.047a absence of sexual activity (n.) 2 3 p > 0.05 unknown (n.) 6 11 p > 0.05 mean prostate volume 40.1 39.4 p > 0.05 a one-tailed test. table 3. pathogens found in monomicrobial and polymicrobial isolates. isolate group 1 group 2 intergroup significance escherichia coli 13 19 p > 0.05 proteus mirabilis 0 5 na klebsiella pneumoniae 2 0 na morganella morganii 1 0 na haemophilus spp. 1 0 na acinetobacter baumannii 1 1 na enterococcus spp. 8 16 p > 0.05 staphylococcus coagulase-negative 21 21 p > 0.05 streptococcus spp. 2 2 na na = not assessable. table 4. microbiological and clinical outcomes at the end of therapy. outcome group 1 group 2 p pathogen eradicated (%) 26/41 (63%) 41/54 (75%) p > 0.05 pathogen not eradicated 10/41 9/54 p > 0.05 superinfection 5/41 4/54 p > 0.05 clinical resolution 23/41 (56.9%) 37/54 (68.5%) p > 0.05 no clinical resolution 18/41 11/54 p = 0.012 uncertain clinical resolution 6/54 table 2. main and coexisting signs and symptoms in both groups. group 1 group 2 main symptom frequently assessed coexisting symptoms 12 17 scrotal/testicular pain perineal and suprapubic pain, haematuria, frequent urination, nocturia, painful ejaculation, dysuria, penile pain, erectile dysfunction 5 9 perineal pain scrotal pain, dysuria, sexual dysfunction, frequent urination 4 7 dysuria scrotal pain, perineal pain, sexual dysfunction 5 6 feeling of unusual sexual dysfunction, perineal pain heaviness in the scrotum 5 4 frequent urination testicular pain, mild erectile dysfunction, burning, suprapubic pain, scrotal pain 1 haematospermia 2 4 difficult urination frequent urination, scrotal pain, erectile dysfunction 2 5 penile pain dysuria, scrotal pain, dysuria, feeling of burning, frequent urination 3 1 suprapubic pain dysuria 1 feeling of burning across frequent urination, scrotal pain, sexual urethra dysfunction 1 1 local discomfort archivio italiano di urologia e andrologia 2019; 91, 2 k. stamatiou, v. magri, g. perletti, a. trinchieri, r. lacroix, n. rekleiti, h. moschouris 82 showed in both groups highly significant improvements of symptoms, assessed with both tests (table 5). intergroup analysis resulted in significantly higher scores of the nihcpsi test in group 1, both at the pre-therapy and at the post-therapy time points. concerning the ipss test, no differences between groups 1 and 2 were found at both preand post-therapy time points (table 5). discussion while pcs are a common ultrasound finding, their exact prevalence is not known. it has been reported to vary widely, from 7% to 70% with greater incidences occurring in symptomatic conditions (6, 7). differences are mainly due to varieties in the methodology of the studies, as pcs frequency increase with age and in certain conditions, such as prostate hyperplasia and chronic prostatitis. in addition, several studies have strict criteria for prostatic stone definition; thus a large number of cases of prostatic calculi is often overlooked. as mentioned in the methods section, there are two types of echo patterns of calcifications: type i, discrete, multiple small echoes, usually located in the transition and peripheral zones of the prostate or diffusely distributed throughout the gland, and type ii, defining large masses of multiple, coarser echoes (8). some authors consider true stones only those with diameter greater than 3 millimeters (6, 7). in our study the prevalence of pcs among patients with cbp symptoms was about 43%. this finding is similar to that of shoskes et al., who reported a 46.8% incidence in a population of relatively younger patients with pelvic pain syndrome (9). however, contrary to our study, these authors excluded cases with stones smaller than 3 mm. on the contrary, harada et al. defined no limitations on pcs size and found an incidence of 68.8% in a population of patients with benign prostatic hypertrophy with a higher average age (8). according to autopsy studies, the frequency of pcs in the general population is high and has an increasing age distribution rising up to 99% in men over 99 years of age (10). notably, the histological analysis of autopsy material observed histological characteristics of prostatitis in up to 50% of prostates with calcifications -independently to their sizeadditionally questioning on the relation between cbp and pcs (10). in fact, the pathophysiology, the clinical relevance and the association of prostatic calculi with prostatic diseases remain unclear. the exact process of pcs formation is not known. however, it likely involves many factors and according to the origin of the calcification material, pcs may be distinguished in exogenous and endogenous. the basis for the creation of exogenous pcs is urine reflux to the prostatic ducts as a result of urine flow obstruction. in such case, urine components cause local ionic changes and ph elevation, which causes the precipitation of salts and the formation of stones. these calculi are usually larger, situated mainly in the prostatic ducts and their composition is similar to stones found anywhere in the urinary tract (11). the basis for the generation of endogenous pcs is the calcification of amyloid particles (a mixture of protein compound rich in lecithin accumulates and degenerated epithelial cells) within the prostatic ducts. this acts as a foreign body, triggering the deposition of calcium and phosphorus salts by epithelial cells (12). a morphological study showed that most pcs (83%) had bacterial imprints suggesting bacterial colonization and biofilm formation, while another study found dna and proteins from escherichia coli in pc bodies (13, 14). it is well established that other bacteria such as gram-positive enterococcus faecalis and staphylococcus spp., are also biofilm formers. however, in this study escherichia coli, enterococcus faecalis and staphylococcus spp., were found in equivalent proportions in groups 1 and 2 (table 3). of note, cai et al., performed ultrastructural analysis of prostate biopsy cores obtained from radical prostatectomy specimens and they found prostate calcifications in 60%, positive cultures in 30% and a structured microbial biofilm in 10% of the sample (15). as long as biopsy performed for epidemiological purposes provides an instant image of a certain situation, the findings of cai et al., along with our observations suggests that involvement of pathogenic bacteria follows the formation of calcifications. as pcs cause mechanical and chemical corrosive effects on the surrounding tissue, the consequent development of fibrosis and edema results in local narrowing of the prostatic ducts, causing stasis of prostatic fluid and new stone formation in a chronic infection process. in such a condition, larger pcs cause greater obstruction, and in this respect park et al. reported that prostatic inflammatory changes were closely associated with type ii calcifications (16). given that in most cases pcs are detected incidentally during a random ultrasound check, it is believed that the stones themselves do not usually cause symptoms. however, some researchers demonstrated that the presence of calcifications is more frequently observed in patients with chronic bacterial prostatitis and is related to urinary symptoms (17). other researchers found significant correlations between the percentage of pcs and the severity of the nih-cpsi urological symptom subdomain (18). a recent study showed that the presence of pcs may be associated with the severity and worsening of storage symptoms (19), while another recent study showed that pcs plays an important role in sexual dysfunction in middle-aged men with chronic pelvic pain syndrome or chronic prostatitis (20). in the present table 5. scores of nih-cpsi and ipss symptom questionnaires. symptom test questionnaire group 1 group 2 p score score pre-therapy median nhi-cpsi value (iqr) 22 (9) 19 (6) p = 0.036b post-therapy nhi-cpsi value (iqr) 10 (16) 3 (3) p = 0.024b p < 0.0001a p < 0.0001a pre-therapy median ipss value (iqr) 4 (9) 4 (9) p = 0.91b post-therapy median ipss value (iqr) 1 (7) 2 (5) p = 0.84b p < 0.0001a p < 0.0001a a wilcoxon signed rank test (paired); b wilcoxon rank sum test (unpaired intergroup). study, significantly higher total scores of the nih-cpsi test were assessed in group 1, not only before antibacterial treatment, but also after having achieved pathogen eradication (table 5). this suggests that pc are associated with more severe symptoms of chronic prostatitis, at least in the case of chronically occurring infections. such increased severity of symptoms is in agreement with the fact that a significantly higher number of patients belonging to group 1 did not show resolution of clinical symptoms at the end of therapy, compared with men without documented calcifications. in contrast to nihcpsi results, no difference was found between either preor post-therapy scores of the ipss test (table 5). in this respect, one should consider that the ipss test has been tailored for patients with benign prostatic hyperplasia and deals mainly with obstructive voiding symptoms, whereas the nih-cpsi test also includes pain symptoms, pain scales, irritative symptoms, and a specific quality of life domain. thus, this latter test is optimal for assessing prostatitis patients, whereas the former is not, though it is often used to complement the nihcpsi test. our results also suggest that the presence of pcs is associated with a previous history of cbp. in fact, pc may serve as a pathogen niche, acting as a source of recurring infection, also caused by biofilm-embedded pathogens, since after treatment the obstructive stones still remain and the inflammatory process continues. recurrent infection, causing increasing deposition of calcifications, may also occur in patients showing sexual behaviors at high-risk for prostatic infections, like anal sexual intercourse (table 1). references 1. park b, choo sh. the burden of prostatic calculi is more important than the presence. asian j androl. 2017; 19:482-485. 2. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999; 282:236-7. 3. asvestis c, varvadesis t, maravelakis pe. greek version of the national institutes of health chronic prostatitis symptom index (nih-cpsi), its linguistic adaptation and the pilot test of its validity. hellenic urol. 2014; 26:1. 4. stamey ta. prostatitis. j r soc med. 1981; 74:22-40. 5. naber kg. european lomefloxacin prostatitis study group. lomefloxacin versus ciprofloxacin in the treatment of chronic bacterial prostatitis. int j antimicrob agents. 2002; 20:18-27. 6. geramoutsos i, gyftopoulos k, perimenis p, et al. clinical correlation of prostatic lithiasis with chronic pelvic pain syndromes in young adults. eur urol. 2004; 45:333-7. 7. kim wb, doo sw, yang wj, song ys. influence of prostatic calculi on lower urinary tract symptoms in middle-aged men. urology. 2011; 78:447-9. 8. harada k, igari d, tanahashi y. gray scale transrectal ultransonography of the prostate. j clin ultrasound. 1979; 7:45-9. 9. shoskes da, lee ct, murphy d, et al. incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. urology. 2007; 70:235-8. 10. hassler o. calcifications in the prostate gland and adjacent tissues. a combined biophysical and histological study. pathol. microbiol. 1968; 31:97-107. 11. meares em. infection stones of the prostate gland. urology. 1974;4:560-566. 12. magura ce, spector m. scanning electron microscopy of human prostatic corpora amylacea and corpora calculi. scan electron microsc. 1979; 3:713-20. 13. dessombz a, méria p, bazin d, daudon m. prostatic stones: evidence of a specific chemistry related to infection and presence of bacterial imprints. plos one 2012; 7:e51691. 14. sfanos ks, wilson ba, de marzo am, isaacs wb. acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer. proc natl acad sci usa. 2009; 106:3443-8. 15. cai t, tessarolo f, caola i, et al. prostate calcifications: a case series supporting the microbial biofilm theory. investig clin urol. 2018; 59:187-193. 16. park sw, nam jk, lee sd, chung mk. are prostatic calculi independent predictive factors of lower urinary tract symptoms? asian j androl. 2010; 12:221-6. 17. boltri m, magri v, montanari e, et al. computer-assisted quantitative assessment of prostatic calcifications in patients with chronic prostatitis. urol int. 2018; 100:450-455. 18. engelhardt pf, seklehner s, brustmann h, et al. association between asymptomatic inflammatory prostatitis nih category iv and prostatic calcification in patients with obstructive benign prostatic hyperplasia. minerva urol nefrol. 2016; 68:242-9. 19. hyun js. clinical significance of prostatic calculi: a review. world j mens health. 2018; 3615-21. 20. cao jj, huang w, wu hs, et al. prostatic calculi: do they matter? sex med rev. 2018; 6:482-491. 83archivio italiano di urologia e andrologia 2019; 91, 2 prostatic calcifications are associated with a more severe symptom burden in men with type ii chronic bacterial prostatitis correspondence konstantinos stamatiou, md (corresponding author) stamatiouk@gmail.com richard lacroix, md rlacroix@ureach.com nektaria rekleiti, md nekrek@gmail.com hippocrates moschouris, md hipmosch@gmail.com tzaneio hospital, piraeus (greece) vittorio magri, md vittorio.magri@yahoo.it asst nord milano (italy) gianpaolo perletti, md gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, (taly) alberto trinchieri, md alberto.trinchieri@gmail.com cdc ambrosiana cesano b, milano (italy) 243archivio italiano di urologia e andrologia 2017; 89, 3 case report giant primary scrotal lipoma: a case report massimiliano creta 1, giacomo de stefano 2, roberto buonopane 1, ciro barba 2, sergio di meo 1, vittorio imperatore 1, ciro imbimbo 3, vincenzo mirone 3 1 unità operativa di urologia, ospedale buon consiglio fatebenefratelli, napoli, italy; 2 unità operativa di urologia, casa di cura trusso, ottaviano, italy; 3 clinica urologica, università federico ii di napoli, napoli; italy. lipomas are benign mesenchymal tumours that are rarely seen in the scrotum. few cases of primary scrotal lipomas originating from the scrotal wall have been reported in the literature. we describe the case of a giant primary intrascrotal lipoma presenting as scrotal swelling and discomfort. findings from scrotal magnetic resonance imaging were highly suspicious for lipoma. the mass was completely excised and histological examination confirmed the diagnosis of lipoma. key words: magnetic resonance imaging; scrotal lipoma. submitted 22 june 2017; accepted 19 july 2017 summary no conflict of interest declared. formed. the testicles, epididymis and cord structures were intact. a well encapsulated, ovoid yellow-orange mass was found located within the scrotal wall and was easily removed (figure 1). the incision was closed with no drainage and the postoperative course was uneventful. the specimen weighed 600 g. microscopic examination of the tissue revealed the presence of mature adipocytes and the absence of cellular atypia. finally, the diagnosis of primary scrotal lipoma was made. surgery provided a rapid resolution of symptoms. discussion intrascrotal lesions provide a diagnostic challenge for the urologyst due to the multiple anatomic structures found in this confined space (3, 4). while most testicular lesions are malignant, the majority of tumours arising from extratesticular structures are benign (3). despite rare, however, malignant neoplasms may also originate from extratesticular structures and include liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, mesothelioma, and lymphoma. lipomas are the most frequent benign neoplasm of the scrotum. however, they are rarely seen in everyday clinical practice (5). these tumors may develop from the spermatic cord, from herniation of properitoneal fat or may originate from isolated fat cells of the subcutaneous tissues of the scrotal wall. in many cases, the specific site of origin cannot be easily identified. to our knowledge, there are very few cases of primary scrotal lipomas (i.e. lipomas doi: 10.4081/aiua.2017.3.243 introduction lipomas are common benign mesenchymal tumours that may occur in any part of the body. these neoplasms, however, are rarely seen in the scrotum (1). in most cases, scrotal lipomas originate from the adipose tissue of the spermatic cord evolving towards the scrotum or develop in the spermatic cord itself. lipomas that originate from the isolated adipose lobules of the scrotal subcutaneous tissue are uncommon and are called “primary scrotal lipomas” (2-5). we describe the case of a giant primary intrascrotal lipoma presenting as swelling of the scrotum causing discomfort. case report a 54-year-old man was referred to our institution for swelling of the scrotum causing discomfort. his past medical history was unrelevant. on physical examination, an irreducible, elastic, regularly shaped mass was evident on the midline of the scrotum. both testes and spermatic cords were found to be localized in the scrotum and were of normal consistency and size. serum α-feto protein, beta-human chorionic gonadotropin, and lactate dehydrogenase levels were within the normal ranges. ultrasound evaluation showed an heterogeneous, hyperechoic solid mass, not infiltrating the testes. magnetic resonance imaging (mri) was required and revealed an 8 x 10 x 12 cm mass with homogeneous high signal intensity in t1-weighted images. no enhancement was seen after administration of gadolinium contrast material. these findings were highly suspicious for lipoma. surgery was planned. a longitudinal midline scrotal incision was perfigure 1. intra-operative photograph showing a lobulated yellow-orange mass. creta_stesura seveso 28/09/17 10:33 pagina 243 archivio italiano di urologia e andrologia 2017; 89, 3 m. creta, g. de stefano, r.buonopane, c. barba, s. di meo, v. imperatore, c. imbimbo, v. mirone 244 originating from the scrotal wall) published in the scientific literature. symptoms vary with mass size and pressure caused with growing. according to literature data, the size may vary considerably and weight can reach 9 kg (2). ultrasonography and mri play a pivotal role in the evaluation of scrotal masses. ultrasonography is the the first-line imaging modality as it allows to determine whether a lesion is cystic or solid and its localization. lipomas commonly appear as uniformly hyperechoic lesions, without internal flow at color doppler imaging. however, ultrasound findings may be variable and are often nonspecific. mri has the potential to narrow the diagnosic range and can be very helpful in the evaluation of lipomas as it can easily recognize fatty components. indeed, high t1 signal intensity is characteristic of fatcontaining tumors. moreover, lipomas can be differentiated from liposarcomas on mri by the lack of any enhancing soft tissue. however, lesions in this location may have overlapping imaging findings (5). sometimes, well-differentiated liposarcomas may simulate benign lipomas and the differential diagnosis is complicated (2). the present case presented with typical mri findings thus emphasizing the diagnostic role of mri. surgical excision, through scrotal or combined scrotal and inguinal incision, represents the treatment of choice for symptomatic lesions or when a definitive diagnosis cannot be made at imaging (5). surgical excision was requird in the present case in order to manage symptoms. the surgial procedure we described was easy to peform, efficacious and safe. conclusions primary scrotal lipomas are rare, benign tumors that should be take into account in the differential diagnosis of paratesticular scrotal masses. surgical excision provides histopathologic diagnosis and resolution of symptoms. references 1. masciovecchio s, saldutto p, del rosso a, et al. an unusual case of massive funicular lipoma. urologia. 2014; 81:184-6. 2. kaplanoglu v, kaplanoglu h, parlak is, tatar ig. giant intrascrotal lipoma. bmj case rep. 2013; 14:2013. 3. patel ng, rajagopalan a, shrotri ns. scrotal liposarcoma a rare extratesticular tumour. jrsm short rep. 2011; 2:93. 4. montgomery js, bloom da. the diagnosis and management of scrotal masses. med clin north am. 2011; 95:235-44. 5. wolfman dj, marko j, gould cf, et al. mesenchymal extratesticular tumors and tumorlike conditions: from the radiologic pathology archives. radiographics. 2015; 35:1943-54. correspondence massimiliano creta, md max.creta@gmail.com roberto buonopane, md robertobuonopane@libero.it sergio di meo, md s.dimeo72@gmail.com vittorio imperatore, md v.imperatore@alice.it unità operativa di urologia, buon consiglio fatebenefratelli hospital via a. manzoni, 220, 80123, napoli, italy giacomo de stefano, md drgiacomodestefano@gmail.com unità operativa di urologia, casa di cura trusso via san giovanni bosco, 3, 80044 ottaviano na, italy ciro barba, md cirobarba@yahoo.it ciro imbimbo, md max.creta@gmail.com vincenzo mirone, md max.creta@gmail.com clinica urologica, università federico ii di napoli via s.pansini, 5, 80131 napoli, italy creta_stesura seveso 28/09/17 10:33 pagina 244 archivio italiano di urologia e andrologia 2019; 91, 4224 original paper “in-bore” mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation angelo porreca 1, daniele d’agostino 1, mario vigo 2, paolo corsi 1, daniele romagnoli 1, alessandro del rosso 1, riccardo schiavina 3, eugenio brunocilla 3, walter artibani 1, marco giampaoli 1 1 department of urology, abano terme hospital, padua, italy; 2 department of radiology, abano terme hospital, padua, italy; 3 department of urology, university of bologna, bologna, italy. introduction: purpose of our study was to investigate the role of a negative in-bore mri-guided biopsy (mri-gb) in comparison to a negative multiparametric prostate mri (mpmri) and a contextual negative transrectal ultrasound guided biopsy of the prostate with regard to incidental prostate cancer findings in the surgical specimen of men who underwent to holmium laser enucleation of prostate (holep) with a preoperative suspicion of prostate cancer. materials and methods: data of 117 of symptomatic patients for bladder outflow obstruction who subsequently underwent to holep was retrospectively analyzed form a multicentric database. all patients had a raised serum psa and/or an abnormal digital rectal examination (dre) with a pre-interventional mpmri. prostate cancer was excluded either with an en-bore mri-gb (group "in-bore mri-gb" n = 57) in case of a suspect area at the mpmri or with a standard biopsy (group "mpmri + trus-gb" n = 60) in case of a negative mpmri. preoperative characteristic surgical and histological outcomes were analyzed. univariate and multivariate logistic regression model was performed to investigate independent predictors of incidental prostate cancer (ipca). results: both groups presented moderate to severe lower tract urinary symptoms: median ipss was 19 (iqr: 17.0-22.0) in the in-bore mri-gb group and 20 (iqr: 17.5-22.0) in the mpmri + trus-gb (p = 0.71). no statistically significant difference was found between the two groups besides total prostate volume with 68 cc (iqr: 58.0-97.0) in the in-bore mri-gb group and 84 cc (iqr: 70.0-115.0) in the mpmri + tru-gb group (p = 0.01) no differences were registered in surgical time, removed tissue, catheterization time, hospital stay and complications rate. no different rates (p = 0.50) of ipca were found in the in-bore mri-gb group (14%) in comparison with mpmri + trus-gb group (10 %); pt stage and isup grade group in ipca stratification were comparable between the two groups. in multivariate analysis a statistically significant correlation with age as an independent predictive factor of ipca was found (or 1.14; 95% ci: 1.02-1.27; p = 0.02) while no correlations were revealed with psa (or 1.12; 95% ci: 0.99-1.28; p = 0.08) and a negative in-bore mri-gb (or 1.72; 95% ci: 0.51-5.77; p = 0.37). conclusions: including a mpmri and an eventual in-bore mrigb represents a novel clinical approach before surgery in patients with symptomatic obstruction with a concomitant sussummary no conflict of interest declared. doi: 10.4081/aiua.2019.4.224 introduction one of the most common non-malignant disease in aging men is represented by benign prostate enlargement (bpe) (1) which might drives to bladder outlet obstruction (boo) with consequent affected quality of life (qol) leading to the necessity of a surgical procedure. during the preoperative work-up, a prostate cancer (pca) diagnosis might be arise and whenever its presence is suspected, its exclusion is necessary since prostate cancer might represent an heavy burden in quality of life (2) and both an accurate diagnosis and risk stratification are mandatory for an adequate disease management (3, 4). in men with a raised serum prostate specific antigen (psa) and/or abnormal digital rectal examination (dre) the standard of care in order to rule out pca is represented by a 10-12 core ultrasound guided transrectal biopsy of the prostate (trus-gb) (5) which several times leads to either false negative results or non-clinically significant pca (6, 7). during the last years, several new imaging techniques such as magnetic resonance imaging (mri) (8) and positron emission tomography (pet) (9), were introduced in the clinical practice in order to diagnose and stage pca. a multiparametric magnetic resonance imaging (mpmri) of the prostate combines both functional and morphological studies and demonstrated to be a valuable tool for pca diagnosis with high sensitivity and specificity (10). performing a targeted biopsy to mpmri suspect areas might reduce the numbers of necessary biopsies and lower the non-clinically significant pca rates (11). several targeting techniques were proposed: visual estimation trus-gb (cognitive technique), software co-regpicion of pca, leading to low rate of ipca and avoiding unnecessary standard trus-gb biopsies. key words: magnetic resonance imaging; holmium laser enucleation of the prostate; prostate biopsy; prostatic enlargement; prostate cancer. submitted 29 may 2019; accepted 2 august 2019 porreca_stesura seveso 10/01/20 08:49 pagina 224 225archivio italiano di urologia e andrologia 2019; 91, 4 “in-bore” mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients... istered mri-ultrasound fusion (fusion technique) and inbore mri-guided biopsy (mri-gb). in-bore mri-gb has the advantage to provide the greatest probability to sample suspected areas since is performed with a direct and real-time proof of the correct sampling (12) especially in case of high volume prostate. holmium laser enucleation of the prostate (holep) represent an endoscopic surgical technique that allows to obtain patients’ symptoms relief. holep is reported to be applicable to all prostate sizes and to represent a safe, efficient and time-durable surgical solution to patients (13). differently to other laser techniques for the treatment of symptomatic bpe, holep is able to retrieve and adequate enucleated prostatic adenoma tissue, better than transurethral resection of the prostate (turp) and comparable to open simple prostatectomy (14). purpose of our study was to investigate the role of a negative in-bore mrigb in comparison to a negative mpmri and a contextual negative transrectal ultrasound guided biopsy of the prostate with regard to incidental prostate cancer findings in the surgical specimen of men who underwent to holep with a preoperative suspicion of prostate cancer due to a raised psa and/or and abnormal dre. patients and methods population and study design data was retrospectively retrieved from a multicentric database of patients affected by symptomatic boo due to bpe who underwent to holep from january 2017 to december 2018. surgical indication was given in case of persistent bladder outflow obstruction symptoms, international prostatic symptoms score (ipss) higher than 8, peak urinary flow (qmax) ≤ 15 ml/s, non-responsiveness to medical therapies (alfa blockers and/or 5α-reductase inhibitors 5ari), acute and chronic urinary retention or renal function impairment due to boo. all patients selected from the database had exclusively a pre-operative suspicion of pca (total psa > 4 ng/ml and /or abnormal dre) and underwent to a pre-interventional prostate mpmri. multiparametric mri was performed with a 1.5 t whole body scanner (achieva xr; philips medical systems, best, netherlands) with a 32-channels phased-array surface and without an endorectal coil. morphological studies consisted in turbo spin echo (tse) t2-weighted sequences in sagittal, axial and coronal planes while functional studies were obtained through diffusion weighted imaging (dwi) and dynamic contrast enhanced-mri (dce-mri). mpmris were exclusively conducted in one of the two involved centers and images were evaluated by two high experienced uroradiologists according to pi-radsv2, based on esur guidelines for the evaluation and reporting of prostate mpmri (15). patients with a suspicious area at the mpmri (pi-rads v2 score ≥ 3) underwent to in-bore mri-gb (2 cores taken per suspect lesion), resulted negative for pca and then were scheduled for holep. individuals with a negative mpmri (pi-rads -v2 score < 3) underwent to an additional standard random trus-gb (10 or 12 cores were taken based on the prostate volume), resulted negative for pca and then scheduled for holep. pre-operative collected data included age, total psa, dre, prostate and adenoma volume either at mpmri or at transrectal ultrasound, psa density, qmax, ipss, qol, post-voided residual volume (prv), drug assumption, previous acute urinary retention. the following periand post-operative parameters were evaluated: surgical time, removed tissue weight, catheterization time, hospital stay, peri-operative complications, presence of incidental prostate cancer (ipca), pt stage and international society of urological pathology (isup) grade group of each ipca. conduct of the in-bore mri-guided biopsy (mri-gb) biopsies were performed by two urologists with consolidated experience in mri-gb. oral antibiotic prophylaxis was started one day before the procedure prolonged for at least 2 days. peri-prostatic nerve blockade local anesthesia with lidocaine 2% was executed for patients’ pain relief. biopsies were performed transrectally, with patients in a figure 1. the non-magnetic mr-compatible biopsy device fixed on the table top of the magnet. figure 2. the gadolinium-filled needle guide properly identified in a sagittal t2-weighted image (a); the dedicated software (dynacad, invivo, gainesville, fl) shows the 3d adjustments through automatic calculation enabling the proper calibration of the biopsy needle to the target lesion (b). porreca_stesura seveso 10/01/20 08:49 pagina 225 archivio italiano di urologia e andrologia 2019; 91, 4 a. porreca, d. d’agostino, m. vigo, p. corsi, d. romagnoli, a. del rosso, r. schiavina, e. brunocilla, w. artibani, m. giampaoli 226 prone position on the 1.5 t mr scanner, using an 18-g automatic core-needle filled with gadolinium, a non-magnetic portable biopsy device (dynatrim, invivo, gainesville, fl figure 1) and a dedicated software package for device tracking and target localization (dynacad, invivo, gainesville, fl). oblique axial t2w images were aligned with the needle guide in order to allow software registration showing three-dimensional adjustments required to align the track of the biopsy needle through the needle guide and the target lesion (figure 1). after manual calibration adjustments on the arm of the biopsy device attached to the needle guide, sagittal t2w images in parallel with the long axis were obtained in order to confirm the correct position and the proper direction of the needle guide to the target; reconfirmation of the needle track was repeated until proper alignment was obtained. if targeting was not certain, due to lesion size or subjective judgment of the operator, subsequent axial and sagittal t2w images with the needle in place were obtained to detect needle position and be able to make adjustments for the next core (figures 3a, 3b). a maximum of two biopsy cores were taken for each patient. surgical procedure the holep procedure was carried out by four experienced surgeons in either one of the two centers using the lumenis® versa pulse™ holmium laser delivering laser energy with a 550-μm fiber set at 2.0 j and 60 hz (maximum power of 120 w) and a 26fr continuous-flow storz laser resectoscope. a modified gilling's technique (16) was employed and enucleated prostatic lobes were retrieved using lumenis® versacut™ morcellator system. continuous flow irrigation until next morning through a 20f three-way catheter indwelled at the end of the surgery was placed. catheter removal was executed at the second post-operative day in the event of no intercurred complication (e.g. hematuria, fever, acute urinary retention, etc.). statistical analysis overall patients (n = 117) were dived in two groups, “in-bore mri-gb” (n = 57) and “mpmri + trus-gb” (n = 60) respectively based on the presence of a negative in-bore mri-gb or a negative mpmri with a contextual negative trus-gb prior to holep. median values with interquartile ranges (iqr) and frequencies with proportions (%) were reported for continuous and categorical variables respectively. differences between two groups were investigated with mann-whitney u test for continuous data, and chi-square test for categorical values. univariate and multivariate logistic regression model was employed to investigate if any preoperative factors (age, psa, prostate volume, adenoma volume, removed tissue, psa density > 15, negative in-bore mri-gb) could be correlated with ipca in patients who underwent holep with a suspect of pca. ibm spss v.22 with a 2-sided significance level set at p < 0.05, was used for statistical analysis. results a total amount of 117 patients [in-bore mri-gb (n = 57), mpmri + trus-gb (n = 60)] were identified and included in the study. preoperative clinical patients ‘characteristics are listed in table 1. overall median age, psa, prostate volume, adenoma volume and psa density were table 1. general and preoperative clinical characteristics. continuous variables are shown as median (iqr) values while categorical as number (%). statistically significant values are considered as p value < 0.05. psa prostate specific antigen, dre digital rectal examination, qmax maximum peak urinary flow, ipss international prostate symptoms score, qol quality of life, prv post-void volume, 5-ari 5-aromatase receptor inhibitor. mpmri multiparametric magnetic resonance imaging. overall in-bore mri-gb mpmri + trus-gb p value (n = 117) (n = 57) (n = 60) age, years median (iqr) 65.0 (59.5-70.0) 65.0 (60.0-70.0) 65.0 (58.25-69.0) 0.44 psa, ng/ml median (iqr) 6.20 (5.40-9.90) 5.96 (5.26-10.0) 6.00 (4.82-9.87) 0.66 dre, n (%) 0.37 negative 95 (81.2) 44 (77.2) 51 (85.0) positive 22 (18.8) 13 (22.8) 9 (15.0) prostate volume, cc median (iqr) 80.0 (60.0-101.0) 68.0 (58.0-97.0) 84.0 (70.0-115.0) 0.01* adenoma volume, cc median (iqr) 47.0 (35.0-70.0) 47 (35.0-70.0) 50.0 (37.0-73.0) 0.33 psa density, ng/ml/cc median (iqr) 0.08 (0.06-0.13) 0.08 (0.07-0.15) 0.08 (0.06-0.11) 0,41 psa density > 0.15 ng/ml/cc, n (%) 0.06 no 100 (85.5) 45 (78.9) 55 (91.7) yes 17 (14.5) 12 (21.1) 5 (8.3) qmax, ml/sec median (iqr) 9.6 (6.8-9.5) 11.0 (10.2-12.0) 8.7 (8.0-11.0) 0.11 ipss score median (iqr) 20.0 (17.0-22.0) 19.0 (17.0-22.0) 20.0 (17.5-22.0) 0.71 prv, cc median (iqr) 95 (50-150) 80 (52-140) 105 (42-321) 0.32 drug assumption, n (%) 0.65 no 15 (12.2) 6 (10.5) 9 (15.0) alfa blocker 43 (36.8) 24 (42.1) 19 (31.7) 5-ari 12 (10.3) 6 (10.5) 6 (10.0) 5-ari + alfa-blocker 47 (40.2) 21 (36.8) 26 (43.7) previous acute urinary retention, n (%) 0.09 no 105 (89.7) 54 (94.7) 51 (85.0) yes 12 (10.3) 3 (5.3) 9 (15.0) pirads v2 score, n (%) < 3 60 (51.3) 0 (0.0) 60 (100.0) 3 36 (30.8) 36 (63.2) 0 (0.0) 4 18 (15.4) 18 (31.6) 0 (0.0) 5 3 (2.6) 3 (5.3) 0 (0.0) site positive area, n (%) anterior 48 (84.2) 48 (84.2) 0 (0.0) posterior 9 (15.8) 9 (15.8) 0 (0.0) site positive area, n (%) right lobe 31 (54.4) 31 (54.4) 0 (0.0) left lobe 26 (45.6) 26 (45.6) 0 (0.0) porreca_stesura seveso 10/01/20 08:49 pagina 226 227archivio italiano di urologia e andrologia 2019; 91, 4 “in-bore” mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients... 65.0 years (iqr: 59.5-70.0), 6.20 ng/ml (iqr: 5.409.90), 80.0 cc (iqr: 60.0-101.0), 47.0 cc (iqr: 35.070.0) and 0.08 ng/ml/cc (iqr: 0.06-0.13), respectively. a statistically significant difference was found between the two groups in terms of total prostate volume with 68 cc (iqr: 58.0-97.0) in the in-bore mri-gb group and 84 cc (iqr: 70.0-115.0) in the mpmri + tru-gb group (p = 0.01). however no statistically differences were found between the two groups in terms of adenoma volume (47 cc iqr: 35.0-70.0 versus 50 cc iqr: 37.0-73.0; p = 0.33) and the other clinical preoperative characteristics. patients in both groups presented moderate to severe lower tract urinary symptoms with affected quality of life, based on the ipss, and a bladder outflow obstruction with decreased peak urinary flow (qmax). median ipss was 19 (iqr: 17.0-22.0) in the in-bore mri-gb group and 20 (iqr: 17.5-22.0) in the mpmri + trusgb (p = 0.71). no statistically differences were recorded between the two groups in preoperative drug assumption and previous acute urinary retention. the majority of patients with a negative in-bore mri-gb presented either a posterior (84.2%) or a a pi-rads-v2 score 3 area (63.2%). perioperative surgical outcomes, as reported in table 2, were found to be comparable in terms of surgery time, removed issue, catheterization time, hospital stay and perioperative complication. no statistically different rates (p = 0.50) of ipca detected in the resected tissue of in-bore mri-gb group (14%) in comparison with mpmri + trus-gb group (10%) were shown at final pathology examination. comparable pt stage and isup grade group in ipca stratification were found with pt1a stage and isup grade group i (gleason score 3+3) 75.0% versus 66.7% (p = 0.73) and 75.0% versus 63.3% (p = 0.71) respectively in in-bore mri-gb and mpmri + trus-gb group. univariate analysis (table 3) showed that only age (or 1.12; 95% ci: 1.01-1.25; p = 0.03) was correlated with ipca after holep, whereas a preoperative negative in-bore mri-gb wasn’t statistically related to ipca (or 1.46; 95% ci: 0.47-4.53; p = 0.50) such as psa density > 0.15 ng/ml/cc (p = 0.44), psa (p = 0.15), prostate volume (p = 0.41), adenoma volume (p = 0.16), removed tissue (p = 0.93). in a multivariate predictive model a statistically significant correlation with age as an independent predictive factor of ipca was also found (or 1.14; 95% ci: 1.02-1.27; p = 0.02) while no correlations were revealed with psa (or 1.12; 95% ci: 0.99-1.28; p = 0.08) and a negative inbore mri-gb (or 1.72; 95% ci: 0.515.77; p = 0.37) (table 3). discussion holep represents a modern less-invasive treatment of symptomatic bpe with demonstrated safety and effectiveness with long terms results, even in a randomized study (17). respect to other laser bpe surgery, holep leads to a transurethral enucleation which sometimes the retrieval of an ipca in the final pathology. elkoushy et al. (18) conducted a prospective study demonstrating that active surveillance (19, 20) might be a safe clinical option in managing ipca diagnosis after holep, especially because radiotherapy or radical prostatectomy, even if necessary sometimes, often negatively affect quality of life (21). therefore, a different novel clinical approach is necessary when a pca suspicion is present before to schedule surgery for bpe. purpose of our study was to evaluate the role of a negative in-bore mri-gb in comparison to a negative mpmri and a contextual negative transrectal ultrasound guided table 2. perioperative surgical and histological outcomes. continuous variables are shown as median (iqr) values while categorical as number (%). statistically significant values are considered as p value < 0.05. pt stage pathologic t stage, isup international society of urological pathology. mpmri multiparametric magnetic resonance imaging. overall in-bore mri-gb mpmri + trus-gb p value (n = 117) (n = 57) (n = 60) surgery time (min) mean (sd) 70.0 (50.0 -95.0) 70.0 (40.0-80.0) 70.0 (55.0-100.0) 0.85 removed tissue (gr) mean (sd) 30.0 (20.0-55.0) 24.0 (17.0-45.0) 36.0 (24.0-70.0) 0.90 catheterization time (days) median (iqr) 2 (2 – 2) 2 (2-2) 2 (2-2) 0.32 hospital stay (days) median (iqr) 2 (2 – 2) 2 (2-2) 2 (2-2) 0.30 peri-operative complications, n (%) no 109 (93.2) 52 (91.2) 57 (90.5) grade* 1 5 (4.3) 3 (5.3) 2 (6.3) grade* 2 3 (2.5) 2 (3.5) 1 (3.2) 0.36 histopathology (%) negative 103 (88.1) 49 (86.0) 54 (90.0) ipca 14 (12.0) 8 (14.0) 6 (10.0) 0.50 pt stage (%) pt1a 10 (71.4) 6 (75.0) 4 (66.7) pt1b 4 (28.6) 2 (25.0) 2 (33.3) 0.73 isup grade group (%) group i 11 (78.6) 6 (75.0) 5 (83.3) group ii 3 (21.4) 2 (25.0) 1 (16.7) 0.71 table 3. uni and multivariate logistic regression. mri-gb magnetic resonance imaging guided biopsy. statistically significant values are considered as p value < 0.05. or odds ratio, ci confidence interval, psa prostate specific antigen. variables univariate multivariate p value or (95% ci) p value or (95% ci) age [continuous] (years) 0.03* 1.12 (1.01-1.25) 0.02* 1.14 (1.02-1.27) psa [continuous] (ng/ml) 0.15 1.09 (0.96-1.23) 0.08 1.12 (0.99-1.28) prostate volume [continuous] (cc) 0.41 1.01 (0.99-1.02) adenoma volume [continuous] (cc) 0.16 1.02 (0.98-1.04) removed tissue [continuous] (gr) 0.93 1.01 (0.98-1.02) psa density > 15 [yes vs no] (ng/ml/cc) 0.44 1.73 (0.42-6.99) negative in-bore mri-gb (yes vs no) 0.50 1.46 (0.47-4.53) 0.37 1.72 (0.51-5.77) porreca_stesura seveso 10/01/20 08:49 pagina 227 archivio italiano di urologia e andrologia 2019; 91, 4 a. porreca, d. d’agostino, m. vigo, p. corsi, d. romagnoli, a. del rosso, r. schiavina, e. brunocilla, w. artibani, m. giampaoli 228 biopsy of the prostate, before an holep surgery, with regard to incidental prostate cancer findings in individuals with a preoperative suspicion of prostate cancer. all patients of our retrospective multicentric study were symptomatic due boo secondary to bpe, had a raised serum psa and/or an abnormal dre, underwent to a pre-operative mpmri and pca was excluded either with a negative in-bore magnetic resonance imaging guided prostate biopsy (in-bore mri-gb group) or an additional standard prostate biopsy to the negative mpmri (mpmri + trus-gb group). both study groups presented pre-surgery assessments e peri-operative surgical outcomes with no statistically significant differences, besides total prostate volume but not adenoma volume, demonstrating low rates of complications, short hospital stay (median 2 days; iqr 2-2) and catheterization time (median 2 days; iqr 2-2). in the overall selected population of our study, final pathology examination showed a rate of ipca (12%) which is comparable to the interval available in the present literature (8.1-15%) (22-24). the explanation to this range might be found in the various baseline characteristics of the patients, which usually are due to merging individuals with normal psa and dre to patients with suspicion of pca. in fact herlemann et al. (24), in a sub-analysis of their holep study arm, found a 40% ipca rate in a sub-cohort of patients with a preoperative negative trus-gb, highlighting the need of a different preoperative diagnostic approach when a suspect of pca is present before bpe surgery. several preoperative parameters, such as older age, preoperative psa, smaller prostate volume, preoperative trus-gb, were pointed as possible predictor of ipca before bpe surgery. bhojani et al. (23) in their study demonstrated with their regression model that age prior surgery is an independent predictive factor for ipca before holep. in our experience mpmri proved to be a valuable preoperative tool not only, as demonstrated,in planning a precise and safe nerve sparing in patients scheduled for radical prostatectomy (25), but also to exclude pca before holep either with a negative finding or using the same mri in order to guide a precise biopsy in a suspicious area. our reported rate of 12% of ipca after holep in patients with a suspect preoperative pca is lower both than the 40% of the sub cohort of herlemann et al. (24) and the recent 23.1% of 359 patients treated with holep and trus-gb recently reported by kim et al. (26). in our study a negative in-bore mri-gb showed a good reliability in order to safely exclude a pca and didn’t show any statistically difference in percentage of ipca compared to a negative mpmri with a contextual trusgb, 14% versus 10% (p = 0.50), and in pt stage and isup grade group distribution (p = 0.73 and p = 0.71 respectively). both in univariate (or 1.46; 95% ci: 0.474.53; p = 0.50) and multivariate (or 1.72; 95% ci: 0.51-5.77; p = 0.37) regression analysis model a negative in-bore mri-gb wasn’t and independent predictive factor of ipca before holep while at the same regression model age was found to significant either in univariate (or 1.12; 95% ci: 1.01-1.25; p = 0.03) and multivariate (or 1.14; 95% ci: 1.02-1.27; p = 0.02). the retrospective nature of our study and the absence of a randomization are the main limitations and secondly the two groups were not matched. patients’ data with positive in-bore mri-gb or trus-gb were not available thus a prospective randomized data collection is needed in order to confirm our preliminary results. moreover, our data didn’t let a stratification based on an 80cc cut-off prostate volume, and lastly there is both a lack of a long-term oncologic follow-up and the comparison with the histologic gold standard for prostate cancer diagnosis (radical prostatectomy specimen) since the presence of cancer risk in the residual peripheral prostate. despite these important limitations, our study represents a selected cohort of patients due the inclusion of only individuals with serum psa > 4 ng/ml and/or abnormal dre and our data represent one of the first studies available in the clinical use of a prostate mpmri and an inbore mri-gb before holep. however, in order to deeply investigate and confirm our preliminary results randomized trials and further investigations are needed. conclusions our results show that a negative preoperative in-bore mri guided prostate biopsy before holep in patients with raised serum psa and/or 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brunocilla e, bianchi l, et al. state of the art of pet/ct with 11-choline and 18f-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. arch esp urol. 2015; 68:354-70. 10. porpiglia f, manfredi m, mele f, et al. diagnostic pathway with multiparametric magnetic resonance imaging versus standard pathway: results from a randomized prospective study in biopsy-naïve patients with suspected prostate cancer. eur urol. 2017; 72:282-8. 11. schoots ig, roobol mj, nieboer d, et al. magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. eur urol. 2015; 68:438-50. 12. schiavina r, vagnoni v, d’agostino d, et al. “in-bore” mriguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. clin genitourin cancer. 2017; 15:417-27. 13. krambeck ae, handa se, lingeman je. experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. j urol. 2013; 189(1 suppl):s141-145. 14. naspro r, freschi m, salonia a, et al. holmium laser enucleation versus transurethral resection of the prostate. are histological findings comparable? j urol. 2004; 171:1203-6. 15. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016; 69:16-40. 16. gilling pj, kennett k, das ak, et al. holmium laser enucleation of the prostate (holep) combined with transurethral tissue morcellation: an update on the early clinical experience. j endourol. 1998; 12:457-9. 17. lourenco t, pickard r, vale l, et al. alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials. bmj. 2008; 337:a449. 18. elkoushy ma, elshal am, elhilali mm. incidental prostate cancer diagnosis during holmium laser enucleation: assessment of predictors, survival, and disease progression. urology. 2015; 86:552-7. 19. schiavina r, borghesi m, brunocilla e, et al. the biopsy gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy gleason score 3+3: looking for larger selection criteria for active surveillance candidates. prostate cancer prostatic dis. 2015; 18:270-5. 20. grasso aa, cozzi g, de lorenzis e, et al. multicenter analysis of pathological outcomes of patients eligible for active surveillance according to prias criteria. minerva urol nefrol. 2016; 68:237-41. 21. porreca a, noale m, artibani w, et al. disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the pros-it cnr study. health qual life outcomes. 2018; 16:122. 22. nunez r, hurd kj, noble bn, et al. incidental prostate cancer revisited: early outcomes after holmium laser enucleation of the prostate. intern j urol. 2011; 18:543-7. 23. bhojani n, boris rs, monn mf, et al. coexisting prostate cancer found at the time of holmium laser enucleation of the prostate for benign prostatic hyperplasia: predicting its presence and grade in analyzed tissue. j endourol. 2015; 29:41-6. 24. herlemann a, wegner k, roosen a, et al. “finding the needle in a haystack”: oncologic evaluation of patients treated for luts with holmium laser enucleation of the prostate (holep) versus transurethral resection of the prostate (turp). world j urol. 2017; 35:1777-82. 25. schiavina r, bianchi l, borghesi m, et al. mri displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. j endourol. 2018; 32:315-21. 26. kim kh, kim sw, son hs, et al. role of holmium laser enucleation of the prostate to increase cancer detection rate in patients with gray-zone psa level. minerva urol nefrol. 2019; 71:72-8. correspondence porreca angelo, md angeloporreca@gmail.com d’agostino daniele, md daniele.dagostino@casacura.it corsi paolo, md paolo.corsi@casacura.it romagnoli daniele, md danieleromagnoli87@gmail.com del rosso alessandro, md adelrosso@casacura.it artibani walter, md prof.artibani@gmail.com giampaoli marco, md (corresponding author) marco.giampaoli@casacura.it robotic urology and mini invasive urologic surgery unit, abano terme hospital piazza cristoforo colombo, 1, 35031 abano terme (padova) (italy) vigo mario, md department of radiology, abano terme hospital, padua, italy schiavina riccardo, md rschiavina@yahoo.it brunocilla eugenio, md eugenio.brunocilla@unibo.it department of specialistic, experimental and diagnostic medicine, urology, alma mater studiorum-university of bologna, s. orsola hospital via pelagio palagi, 9, 40138 bologna (italy) porreca_stesura seveso 10/01/20 08:49 pagina 229 archivio italiano di urologia e andrologia 2017; 89, 122 original paper efficacy of pollen extract in association with group b vitamins for pain relief in chronic prostatitis/chronic pelvic pain syndrome: a survey of urologists' knowledge about its clinical application giacomo maria pirola, stefano puliatti, tommaso bocchialini, eugenio martorana, salvatore micali, giampaolo bianchi department of urology, university of modena and reggio emilia, modena, italy. introduction and aim of the study: chronic prostatitis/chronic pelvic pain syndrome (cp/cpss) is a pathology of high prevalence in italian male population, difficult to diagnose and to treat and with poor response to conventional therapy. aim of this study was to review the evidence of the literature about the therapeutic effects of a plant product containing flower pollen extracts and group b vitamins on symptoms resolution and amelioration of cp/cpps patients’ quality of life and to investigate the knowledge among practicing urologists about the clinical application of this product. materials and methods: a group of 38 urologists was submitted to an investigational survey of the knowledge of the clinical applications of a plant product containing flower pollen extracts and group b vitamins results: 71% of the urologists interviewed prescribed the plant product for cbp and cp/cpps at least one time in a month and 11% prescribed it more than 5 times; 67% had evidence of clear ameliorations in pain relief and on patient's quality of life and 47% reported that the effectiveness is comparable to nsaids; 39% also reported a significant effect for the improvement of the urinary symptoms of patients. no gastric or general side effects have been noticed during the administration period of this plant product. finally, the cost of the product has always reported to be sustainable for the patients. conclusions: from the results of this investigational survey, we can state that the plant product containing flower pollen extracts and group b vitamins is well-known and demonstrated beneficial effects on symptoms resolution and amelioration of quality of life in patients with chronic prostatitis/chronic pelvic pain syndrome. key words: chronic prostatitis; chronic pelvic pain syndrome; prostatic benign diseases; inflammation; pollen extracts; group b vitamins. submitted 20 january 2017; accepted 15 march 2017 summary no conflict of interest declared. cp/cpps in male population. this disorder, difficult to treat, has multiple consequences on lifestyle and on sexual life. furthermore, cp/cpps is a chronic disease, with unsatisfactory results from conventional therapy. among the multiple therapeutic approaches, long term administration of pollen extracts has been demonstrated to have a precise role in the limitation of flogistic process. bacterial and non-infectious chronic prostatitis could represent inciting factors leading to tissue hyper-proliferation and chronic inflammation, probably by an immuno-modulation mediated by prostatic stromal cells, enabling them to induce and sustain intra-glandular immune responses. group b vitamins have been demonstrated to be capable to interfere with this mechanism, reducing the inflammatory component of cp/cpps. finally, folic acid is well known for its anti-oxidant properties, who join a central role in the reduction of the intracellular reactive oxygen species (ros). several recent studies reported the active role of this vitamin in reducing this component. this factor has a role in the ipb/ inflammatory pathogenesis. commonly cp/cpps requires a prolonged treatment with anti-infiammatory drugs like corticosteroid or nonsteroidal anti-inflammatory drugs (fans) in combination with antibiotics that can lead to gastrolesive and nephrotoxic side effects. about that aspect, really relevant for clinicians who face this pathology, phytotherapeutics are hopeful options of treatment due to their generally minimal side effects. many studies in literature have shown that pollen extract and b vitamins induced a significantly and durable reduction of symptoms in patients with cp/cpps with a relevant improvement in quality of life. the aim of this paper is to review the actual state of art for clinical application of deprox 500® (flower pollen extracts and group b vitamins) in the treatment of cp/cpps. furthermore, we realized an internal survey in our department to investigate the actual knowledge and application of this supplement in current clinical practice in an area of italy. doi: 10.4081/aiua.2017.1.22 introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) has a very high prevalence in italian population, estimated by a recent multicenter observational study to affect about 13.8% of the male population with an age between 25 and 50 years old. several studies in literature evaluate the prevalence of pirola_stesura seveso 04/04/17 09:08 pagina 22 23archivio italiano di urologia e andrologia 2017; 89, 1 efficacy of pollen extract in association with group b vitamins for pain relief in chronic prostatitis/chronic pelvic pain syndrome... materials and methods deprox 500® is a phytotherapeutic composed of flower pollen extract (1000 mg), b1 vitamin (1.4 mg), b2 vitamin (1.6 mg), b6 vitamin (2.0 mg), b12 vitamin (1.0 µg), folic acid (300 µg), pp vitamin (18 mg). it can be used for treatment of prostate chronic inflammatory processes often cause of irritative and obstructive symptoms: bacterial prostatitis, abacterial prostatitis, prostatodynia. its posology is two tablets in a single dose daily and it can be administered for prolonged time for it generally minimal side-effects. clinical use of this phytoterapeutic is based of molecular effect of its components and their synergic effects. in order to understand how this dietary supplement is prescribed, in which patients and with which symptoms, we drafted a rapid and concise survey (table 1). we administered this questionnaire to 10 residents in urology at the university of modena and reggio emilia and to 28 urologists working in the provinces of modena and reggio emilia. the questionnaire was answered by mail or through direct compilation, anonymously. the sample was limited, but representative of the two provinces of modena and reggio emilia, who have a population of about 1.3 million of citizens. results investigational survey on deprox® all the 38 physicians completed the questionnaire in all its parts demonstrating that deprox 500® is a known product in this area, with a wide diffusion between young and senior urologists. by the results (table 2), it is evident that cbp and cp/cpps are common pathological conditions. the 58% of physicians have diagnosed those pathologies in 3-6 patients during a month, and 13% of them in more than 6 patients during the same period of time. 11% of physicians surveyed did not believe in the use of dietary supplements for the treatment of any medical condition and consequently refused the use of deprox 500® whereas 71% prescribed deprox 500® at least one time in a month and 11% prescribed it more than 5 times. the clear majority of physicians who utilized deprox 500® prescribed it correctly for cbp and cp/cpps. 9% of physicians who prescribe deprox 500® haven’t noticed a significant improvement in pain relief and on patient's quality of life suffering from cbp or cp/cpps, while the 67% had evidence of clear ameliorations and 47% reported that the effectiveness is comparable to nsaids. furthermore 39% also reported a significant effect for the improvement of the urinary symptoms of patients. no gastric or general side effects have been noticed during the administration period of deprox 500®. finally, the cost of the integrator has always reported to be sustainable for the patients. table 1. investigational survey on deprox®. • how many times have you diagnosed chronic bacterial prostatitis (cbp) or chronic pelvic pain syndrome/chronic prostatitis (cp/cpps) during the last month? • 0-3 times • 4-6 times • > 6 times • do you trust in alimentary supplement (non pharmacological therapy) for the treatment of urological disorders? • yes • no • how many times have you prescribed deprox® during the last month? • 0 times • 1-5 times • > 5 times • for which urological diseases have you prescribed deprox®? • none • chronic bacterial prostatitis (cbp) in combination with antibiotic therapy chronic prostatitis or chronic pelvic pain syndrome/chronic prostatitis (cp/cpps) • others urologic diseases (specify) • have you noticed an improvement in the quality of life of patients affected of chronic bacterial prostatitis (cbp) or chronic pelvic pain syndrome/chronic prostatitis (cp/cpps) with combination of deprox® + antibiotic therapy? • i do not use deprox® • yes • no • have you noticed an improvement in pain symptoms? • i do not use deprox® • yes • no • have you noticed ameliorations comparable with the results obtained with fans? • i do not use deprox® • yes • no • have you noticed an improvement in urinary symptoms? • i do not use deprox® • yes • no • have patients reported occurrence of gastric side effects after assumption of deprox®? • i do not use deprox® • yes • no • have patients reported occurrence of other side effects after assumption of deprox®? • i do not use deprox® • yes (specify) • no • is the cost of deprox® affordable for the majority of patients? • i do not use deprox® • yes • no pirola_stesura seveso 04/04/17 09:08 pagina 23 archivio italiano di urologia e andrologia 2017; 89, 1 g.m. pirola, s. puliatti, t. bocchialini, e. martorana, s. micali, g. bianchi 24 discussion from the investigational survey on deprox 500®, it can be assumed that it is a dietary supplement widely used by the urologists in our area. the absence of side effects makes it easily and safely administrable for long periods, especially when compared to nsaids, which for many physicians are not considered superior for long-term pain control and expose patients to the risk to of gastric or renal side effects. the number of physicians surveyed is limited, but the data reported on the amount of prescriptions and on patient feedback to their physicians indicate that the product has a positive impact on longlasting diseases as cbp or cp/cpps. flower pollen extracts contained in deprox 500® have an antioxidative action that presents an important role in treatment of many prostate inflammatory diseases. the product is similar to cernilton that was used by rugendorff et al. in their study to evaluate the effect of treatment with pollen extract in chronic prostatitis and prostatodynia. in this research, 56 of 90 (78%) treated patients had a favorable response, in particular 26 (36%) recovered from their symptoms and 30 (42%) showed a functional improvement, with an increase in flow rate and a decrease of microbiological and physical infection related markers in urine and ejaculate (1). another interesting study realized by kamijo t et al. shows the effect of cernitin pollen extracts on experimental sex-hormone induced nonbacterial prostatitis in rats. cernitin pollen extract consist in a preparation composed by eight different pollens, of a water soluble fraction (t-60) and of a fat soluble fraction (gbx). these fractions were administered separately. they observed that pollen extracts protect acinar epithelial cells mainly by gbx and inhibits stromal proliferation in association with enhanced apoptosis mainly by t-60 (2). wagenlehner et al. conducted in 2009 a multicenter, prospective, randomized, double-blind, placebo-controlled phase 3 study comparing the pollen extract (cernilton) to placebo in patients affected by cp/cpps. they demonstrated that, compared to placebo, the pollen extract significantly improved total symptoms, pain, and qol in men with inflammatory cp/cpps without any relevant side-effect. a 12-week administration of pollen extracts resulted in a significantly symptom improvement compared to control group, without any kind of side-effects. the effects of cernilton were also assessed for the treatment of benign prostate hyperplasia, that is a condition often related to chronic prostatitis with a systematic review by macdonald et al. who pointed out that cernilton is well tolerated and modestly improves urological symptoms associated with prostate hyperplasia (3). many studies in literature show an important role of group b vitamins in chronic pain molecular path-ways. mader et al evaluated the vitamin status of inpatients with chronic cephalgia and dysfunction pain syndrome and demonstrated the benefic effects of a vitamin supplementation. they demonstrated that 65% of the patients involved into the study had a subclinical vitamin deficiency and they divided them in two groups treated respectively with a vitamin supplementation and with a placebo. a clear reduction in pain was presented in the active-treatment group and a deterioration of pain was more frequently observed in the placebo group (4). wang et al. investigated the analgesic role of the b vitamins thiamine (b1), pyridoxine (b6) and cyanocobalamin (b12) in rats with neuropathic pain. they assessed that these vitamins at high doses can effectively reduce table 2. survey results. a n (%) b n (%) c n (%) • how many times have you diagnosed chronic bacterial prostatitis (cbp) or chronic pelvic pain syndrome/chronic prostatitis (cp/cpps) during the last month? 11 (29%) 22 (58%) 5 (13%) • do you trust in alimentary supplements (non pharmacological therapy) for the treatment of urological disorders? 34 (89%) 4 (11%) • how many times have you prescribed deprox® during the last month? 7 (18%) 27 (71%) 4 (11%) • for which urological diseases have you prescribed deprox®? 9 (24%) 28 (73%) 1 (3%) • have you noticed an improvement in the quality of life of patients affected of chronic bacterial prostatitis (cbp) or chronic pelvic pain syndrome/chronic prostatitis (cp/cpps) with combination of deprox® + antibiotic therapy? 9 (24%) 26 (67%) 3 (9%) • have you noticed an improvement in pain symptoms? 9 (24%) 26 (67%) 3 (9%) • have you noticed ameliorations comparable with the results obtained with fans? 9 (24%) 18 (47%) 11 (29%) • have you noticed an improvement in urinary symptoms? 9 (24%) 15 (39%) 14 (37%) • have patients reported occurrence of gastric side effects after assumption of deprox®? 9 (24%) 0 (0%) 29 (76%) • have patients reported occurrence of other side effects after assumption of deprox®? 9 (24%) 0 (0%) 29 (76%) • is the cost of deprox® affordable for the majority of patients? 9 (24%) 29 (76%) 0 (0%) pirola_stesura seveso 04/04/17 09:08 pagina 24 25archivio italiano di urologia e andrologia 2017; 89, 1 efficacy of pollen extract in association with group b vitamins for pain relief in chronic prostatitis/chronic pelvic pain syndrome... pain and thermal hyperalgesia caused by peripheral sensory neuron injury. repetitive administration of b vitamins produces a long-term inhibition in both severity and duration of pain and thermal hyperalgesia. this study suggests the clinical utility of the b vitamins in treatment of neuropathic pain due to injury, degeneration or other disorders in the nervous systems (5). deprox 500®, due to its composition, can potentially induce the benefic effects of both components: flower pollen extract and b group vitamins. cai et al. realized a meaningful study to evaluate the efficacy of pollen extract in association with vitamins (deprox 500®) for pain relief in order to improve the quality of life of young patients affected by chronic prostatitis type iiib (cp/cpps). in this study, 20 young men with clinical and instrumental diagnosis of cp/cpps underwent a treatment consisting of 2 tablets of deprox 500® in a single daily dose for 30 days. the main outcome assessment was the improvement of quality of life evaluated by questionnaires about the symptomatology. the treatment significantly improved total symptoms, pain and qol in patients, without relevant side effects. the association with vitamins seemed to improve the antioxidant activity of the pollen extract and the protective effect on the nerves against chronic hyperalgesia (6). the absence of severe side effects is relevant, because cp/cpps requires a prolonged treatment and common antinfiammatory drugs like fans can result in relevant side effects. about that, cai et al. realized a randomized controlled phase iii study, including 87 young patients treated with deprox 500® or ibuprofen to evaluate the effect of pollen extract in associations with vitamins treatment in order to early pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome. of the 87 enrolled patients 41 received deprox 500® and 46 received 600 mg ibuprofen. deprox 500® significantly ameliorated the total symptoms, pain and quality of life compared with ibuprofen without severe side effects (4). these results are encouraging and justify the clinical application of deprox 500® in these pathological conditions. conclusions many studies in literature have shown that pollen extract and b vitamins induced a significantly and durable reduction of symptoms in patients with cp/cpps with a relevant improvement in quality of life. moreover, the absence of several side effects during prolonged treatment is really considerable. our investigational survey about the use of deprox 500® by physicians has showed that the product is recognized and has a proved beneficial effect. acknowledgements "this paper won the prize idipharma 2016 at the 89th congress of the italian society of urology in venice, italy". references 1. rugendorff ew, weidner w, ebeling l and buck ac. results of treatment with pollen extract (cernilton n) in chronic prostatitis and prostatodynia. br j urol. 1993; 71:433-438. 2. kamijo t, sato s, kitamura t. effect of cernitin pollen extract on experimental nonbacterial prostatitis in rats. prostate. 2001; 49:122-131. 3. macdonald r, ishani a, rutks i, wilt tj. a systematic review of cernilton for the treatment of benign prostatic hyperplasia. bju int. 2000; 85:836-41. 4. mäder r, deutsch h, siebert gk, et al. vitamin status of inpa¬tients with chronic cephalgia and dysfunction pain syndrome and effects of a vitamin supplementation. int j vitam nutr res. 1988; 58:436-441. 5. wang zb, gan q, rupert rl, et al. thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. pain. 2005; 114:266-277. 6. cai t, luciani lg, caola i, et al. effects of pollen extract in association with vitamins (deprox 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. urologia. 2013; 80 (suppl 22):5-10. 7. iwamura h, koie t, soma o, et al. eviprostat has an identical effect compared to pollen extract (cernilton) in patients with chronic prostatitis/chronic pelvic pain syndrome: a randomized, prospective study. bmc urol. 2015; 15:120. doi: 10.1186/s12894-0150115-5. 8. wagenlehner fm, bschleipfer t, pilatz a, weidner w. pollen extract for chronic prostatitis-chronic pelvic pain syndrome. urol clin north am. 2011; 38:285-92. doi: 10.1016/j.ucl.2011.04.004. 9. wagenlehner fm, schneider h, ludwig m, et al. a pollen extract (cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. eur urol. 2009; 56:544-51. doi: 10.1016/j.eururo.2009.05.046. correspondence giacomo maria pirola, md gmo.pirola@gmail.com stefano puliatti, md tommaso bocchialini, md eugenio martorana, md salvatore micali, md giampaolo bianchi, md department of urology, university of modena and reggio emilia, modena, italy pirola_stesura seveso 04/04/17 09:08 pagina 25 341archivio italiano di urologia e andrologia 2016; 88, 4 case report the importance of potassium citrate and potassium bicarbonate in the treatment of uric acid renal stones michele barbera 1, andreas tsirgiotis 1, mauro barbera 2, quintino paola 1 1 operative unit of urology, ospedale giovanni paolo ii, sciacca, italy; 2 university of palermo, palermo, italy. uric acid calculi can also be treated without surgery, with simple medical lytic therapy. after appropriate dietary adjustments and add of mineral water, the needed amount of alkali supplementation can increase ph values of the urine in order to dissolve the stones. treatment should be prolonged to prevent stone recurrence. a case of bilateral renal uric acid stones that were successfully treated by alakalizing treatment was presented. key words: potassium citrate; uric acid stones. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. surgery 6 months before and was receiving long-term anticoagulant treatment) was affected by bilateral renal calculi. abdominal computed tomography (ct) without contrast confirmed the presence of bilateral pelvic renal stones measuring 30 x 20 mm in the right kidney and 40 x 30 mm in the left kidney (figure 1). renal stone density was measured according the hounsfield scale (3) that defines as zero hounsfield unit (hu) the radiodensity of water and around 1000 hu the radiodensity of bones. the density of the patient’s stones ranged between 400 and 500 hu, is a typical value of uric acid stones. the patient underwent a therapy with a mixture of potassium citrate (2) and potassium bicarbonate (lithosolv) with the aim to alkalize the urine to achieve ph values between 6.5 and 6.8. the ph of the urines was periodically checked with litmus test and colorimetric comparison table, in order to daily adjust the dose. doi: 10.4081/aiua.2016.4.341 presented at 20th national congress sieun, sciacca 2016 figure 2. ct after 4 months. figure 1. ct pre treatment. introduction the changed dietary habits, related to feeds oriented to excessive intakes of protein or fat, tend to move the body's metabolic balance towards excessive acid load (1). this condition would facilitate, if persisting, the onset of certain diseases, such as osteoporosis and renal calculi (2), which often occur, just in the presence of reduced citrates in the urine and of a urinary acidic ph (5.0-5.5). the maintenance of hyperacidic values of urinary ph more easily induces the precipitation of uric acid in the urine and the consequent formation of uric acid stones. uric acid stones account for about 10% of all urinary stones. the incidence of uric lithiasis increases significantly with age. uric acid is very slightly soluble in an acidic ph, so that the formation of uric acid crystals is practically mandatory when the ph of the urine is persistently below 5.5. predisposing causes: – diabetes mellitus (insulin resistance that characterizes both the metabolic syndrome that type 2 diabetes decreases the urinary ph) (1); – obesity (those with a high body mass index (bmi) have higher urinary excretion of oxalate, urate, sodium and phosphate) bmi has an inverse correlationwith the ph and uric acid urinary supersaturation (not calcium oxalate) is directly related to bmi; – hyperuricosuria and hyperuricemia. case report a 59 year old male patient with diabetes mellitus and heart disease (who underwent coronary heart bypass barbera1-the importance of potassium_stesura seveso 09/01/17 10:49 pagina 341 archivio italiano di urologia e andrologia 2016; 88, 4 m. barbera, a. tsirgiotis, m. barbera, q. paola 342 after 4 months of therapy an abdomen ct without contrast highlighted the disappearance of the stones in the right renal pelvis and the significant reduction of the stones in the left kidney (figure 2). after 7 months of treatment an abdomen ct without contrast was repeated to show total disappearance of the stone in the left kidney (figure 3). discussion the primary goal of the medical treatment of uric acid stones is the reduction of urinary supersaturation for uric acid increasing urinary volume and urinary ph (to 6.57) rather than reducing urinary uric acid excretion. the modification of acidic urinary ph with alkalizing agents would favor the solubilization of urinary uric acid and the dissolution of the stone. a diet rich in fruits and vegetables is the main source of alkalizing substances (3). however, a dietary only approach is not always sufficient, and food supplements may be needed. this occurs mainly in the elderly, in people performing intense physical activity, in postmenopausal women or in those with highly protein diets. the treatment should include: – drinking mineral water in order to achieve an urine output of about 2 liters per day; – a diet limiting foods of animal origin (meat, fish, offal, etc.) and mostly vegetarian should be suggested in order to decrease the load of fixed acids and purines; – food supplementation by potassium alkali salts in order to correct the excessive acid load. the ph measurement can be carried out easily through the use of diagnostic strips. the urinary ph value varies along the day with the most significant drop in the course of the night and in the first morning. for thisreason it is preferable to measure it after awaking.if the ph is below 6, it should be adjusted by taking the alkali supplement in the morning and evening. each dose provides a quantity of potassium in the form of citrate and potassium bicarbonate equal to 1.173 g (30 meq). the total dose may be increased until to 3 administrations a day. the effect of alkalizing action of urine could be verified again by using diagnostic strips. use of allopurinol (150-300 mg, once a day) could be appropriate in presence of hyperuricemia and/or excessive urinary uric acid. references 1. abate n, chandalia m, cabo-chan av jr, et al. the metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. kidney int. 2004; 65:386-392. 2. pak cyc, sakhaee k, fuller c. successful management of uric acid nephrolithiasis with potassium citrate. kidney int. 1986; 30:422-428. 3. welk bk, teichman jm uric acid nephrolithias in the era of noncontrast computed tomography, cuaj. 2008; 2:420-421. correspondence michele barbera, md barbera.mic@gmail.com andreas tsirgiotis, md atsirgiotis@alice.it paola quintino, md q.paola@inwind.it operative unit of urology, ospedale giovanni paolo ii, sciacca, italy mauro barbera, mb barbera.mau@gmail.com university of palermo, palermo, italy figure 3. ct after 7 months. barbera1-the importance of potassium_stesura seveso 09/01/17 10:49 pagina 342 317archivio italiano di urologia e andrologia 2016; 88, 4 case report pseudoaneurysm with arteriovenous fistula of the prostate after pelvic trauma: ultrasound imaging andrea b. galosi, camilla capretti, luca leone, marco tiroli, daniele cantoro, massimo polito institute of urology, department of specialized clinical sciences and odontostomatology, marche polytechnic university, azienda ospedaliero-universitaria, ancona, italy. pseudoaneurysm (pa) associated with an arteriovenous fistula (avf) of the internal pudendal artery branches are very uncommon. we report a case of post-traumatic pa with avf connected to santorini plexus. diagnosis was made with trans-rectal ultrasound (trus) after recurrent hematuria. trus reported a 1.7 × 1.4 × 1.5 cm anechoic area, on anterior prostate apex close to santorini plexus. the use of color doppler in this area revealed high flow velocity that was indicative for avf. the feeding artery was a distal branch of the left pudenda artery. after selective embolization was observed complete occlusion of the feeding branches and disappearance of pa with avf. prostate pa with concomitant symptomatic avf detected with trus has not yet described in literature after pelvic trauma and represents complex diagnostic challenges. this case report suggests that the use of turs and color doppler can provide an important diagnostic and follow-up to address the clinical suspicion of occult vascular injuries using a noninvasive approach. key words: prostate; pseudoaneurysm; arteriovenous fistula; transrectal ultrasonography; pelvic trauma. submitted 15 november 2016; accepted 15 december 2016 summary no conflict of interest declared. detected by trus is secondary to extraperitoneal laparoscopic radical prostatectomy (2). pa, also called false aneurysm, is a perfused sac communicating with an arterial wall disruption. it is delimited by avventitia or media layer or soft-tissue surrounding the artery (3). pa develops from injury or disease (infection or inflammation) of the vessel wall and it may lead to complications such as thrombosis, embolism, rupture or infection (4-5). also avf could be considered a complication of pa. this vascular lesion is slow-growing and clinical manifestations are delayed after causing trauma. therefore complications could be later and diagnosis may be difficult. only angiography or computed tomography (ct) angiography are the best diagnostic imaging (6). ultrasonography (us) with color doppler has high sensibility and specificity in pa (5), however its application in the prostate after pelvic trauma has not been reported yet. trus represents a faster and available method to evaluate prostatic disease. we report a case of massive hematuria due to post-traumatic pesudoaneurysm of the prostate with arteriovenous fistula with santorini plexus. case report a 36-years-old man was referred to emergency department for hematuria after blunt pelvic trauma in a car crash. contrast enhanced abdominal ct and the retrograde urethrogram showed bladder extraperitoneal injury, pelvic bone fracture and bulbar urethral lesion (figure 1a, b, c). doi: 10.4081/aiua.2016.4.317 presented at 20th national congress sieun, sciacca 2016 figure 1. a. contrast computed tomography (ct), axial scan: left obturator internal fossa hematoma compressing and deviating bladder to the right. b. contrast computed tomography (ct), coronal scan: bladder injury in the anterior and left lateral wall. c. retrograde urethrogram: bladder injury in the anterior and left lateral wall. introduction prostate pseudoaneurysms (pa) associated with arteriovenous fistula (avf) are very uncommon (1) and observed after prostatic surgery. to our knowledge there are no cases described of post-traumatic pa with avf detected by trans-rectal ultrasound (trus); in literature, the only case galosi2_pseudoaneurysm with arteriovenous_stesura seveso 09/01/17 10:08 pagina 317 archivio italiano di urologia e andrologia 2016; 88, 4 a.b. galosi, c. capretti, l. leone, m. tiroli, d. cantoro, m. polito 318 in the emergency room a bladder catheter was already placed. patient was treated conservatively and pelvic hematoma disappeared. he underwent neurosurgical procedure for brain hematoma. anti-thrombotic prophylaxis with low molecular weight heparin was prescribed. patient was discharged and transurethral catheter was planned to be removed after 30 days. soon after normal retrograde cystography and urethrogram, a massive urethral bleeding developed. bleeding stopped immediately after transurethral insertion of a new catheter. ct scan and trus showed that the urethral catheter was placed in the bladder, but passing through the santorini plexus instead of the prostatic urethra lumen (figure 2). periprostatic tissue were normal at that time. forty-six days after trauma, open transvesical surgical realignment was performed removing the catheter through the santorini plexus and placing a trans-urethral and suprapubic catheters. the urethral catheter was removed in 15th post-operative day (60 days after trauma), after retrograde urethrogram and recovery of spontaneous urinary stream; 8 hours later, a massive hematuria developed again spontaneously and stopped with placement of a urethral catheter. trus was performed, reporting a 1.7 × 1.4 × 1.5 cm anechoic area, on the left side of prostate apex, located between the urethra (with catheter) and the santorini plexus (figure 3a). the use of color doppler in this area revealed high flow velocity that was suggestive for avf (figure 4a). angiography and ct angiography confirmed a contrastenhanced lesion (about 1 cm) on the left side of prostate base, behind the pubic bone, with early communication with santorini plexus (figures 4b, 5); the feeding artery was a distal branch of the left pudendal artery. embolization of the vascular anomaly was carried out by using minicoils. subsequent angiograms showed an almost complete occlusion of the feeding branches and no persistence of avf. also trus was used for post-embolization control, showing the absence of the anechoic area (figure 3b); the color doppler showed the absence high flux signal, indicating the closure of the communication with santorini plexus. after then, the catheters were removed and the outcome was uneventful. after 8 months of follow-up the patients is doing well. discussion prostate pa with avf detected with trus has not yet described in literature, in particular after a pelvic trauma. other cases described in literature are linked to urological surgery (radical prostatectomy (6-7), transurethral resection of prostate (2), transvesical prostatectomy (1) and holmium laser enucleation (8)). we can observe that false passage of the catheter through the santorini plexus could be considered a iatrogenic cause of the pa. prolonged antithrombotic prophylaxis may have a role to avoid thrombosis in the pa with spontaneous resolution. pa developed 2 months after initial trauma. late hematuria was the first sign of pa in all cases reported by others authors, such as our patient; the persistence of hematuria (after surgical realignment) allowed us to continue diagnostic process. figure 2. urethral catheter passing through the santorini plexus instead than prostatic urethra lumen. figure 3. a. trans-rectal ultrasonography: a 1.7 × 1.4 × 1.5 cm anechogenic area (arrow) on the left side of prostate capsule, adjacent santorini plexus. u: catheter. b. trans-rectal ultrasonography: absence of the anechoic area after embolization (arrow). figure 4. a. trans-rectal ultrasonography with color doppler: high flow velocity that was indicative for avf. b. angiography ct scan: contrast-enhanced lesion (about 1 cm) on the left side of prostate base, behind the pubic bone, with an early communication with santorini plexus. figure 5. ct angiography showing the pseudoaneurysm (arrow). galosi2_pseudoaneurysm with arteriovenous_stesura seveso 09/01/17 10:08 pagina 318 for our experience, trus has been a valuable diagnostic methodic for the first detection; it is readily available, inexpensive and fast (9). in others anatomical sites, us has been reported to have high sensitivity (94%) and high specificity (97%) in the detection of pa (5). gray-scale trus can demonstrate the pa as a hypoechoic cystic. this anechoic lesion should be considered as differential diagnosis with cystic lesion of the prostate. the use of color doppler is helpful for the diagnosis and necessary for a differential diagnosis with prostatic cyst (10). trus can assess size of the pa sac, however the connection of the sac to the artery was not evident in our case. furthermore, any compartments of the pa could be observed (11). doppler presentation of pa with avf is characterized by a typical swirling motion called the “yin-yang sign” within a cystic structure: it indicates bidirectional flow due to swirling of blood (12) as shown in figure 4a. angiography shows a real-time hemodynamic assessment of a selective vascular bed (including identification of collateral vessels); furthermore, angiography has also a therapeutic role. in our experience angiography confirmed the pa with early venous communication, feeding by internal left pudendal artery distal branches. after the embolization we performed a trus with color doppler to confirm the resolution of the pa and the closure of the avf: trus has proved to be an important diagnostic tool also in the follow-up after the treatment of pa with avf. conclusions prostate pseudoaneurysm with concomitant symptomatic arteriovenous fistula detected with trus has not yet described in literature after pelvic trauma. delayed presentation of pseudoaneurysm represents a complex challenges in diagnosis and treatment. this case report supports transrectal ultrasonography with color doppler in differential diagnosis and in the follow-up, using a noninvasive and inexpensive approach. references 1. dell’atti l, galeotti r. pseudoaneurysm secondary to transvesical prostatectomy. indian j urol. 2016; 32: 164165. 2. celtikci p, ergun o, tatar ig, et al. superselective arterial embolization of pseudoaneurysm and arteriovenous fistula caused by transurethral resection of the prostate. pol j radiol. 2014; 79:352-5. 3. schwartz lb, clark et, gewetz bl. anastomotic and other pseudoaneurysms. in: rutherford rb, ed. vascular surger. 5th ed. philadelphia,pa: saunders. 2000; 752-763. 4. la perna l, olin jw, goines d, et al. ultrasound-guided thrombin injection for the treatment of postcatheterization pseudoaneurysms. circulation 2000; 102: 2391-2395. 5. morgan r, belli a. current treatment methods for postcatheterization pseudoaneuryms. j vasc intervent radiol. 2003; 14:697-710. 6. jeong cw, park yh, ku jh, et al. minimally invasive management of postoperative bleeding after radical prostatectomy: transarterial embolization. j endourol. 2010; 24:1529-33. 7. lopes ri, mitre ai, rocha ft, et al. case report: late recurrent hematuria following laparoscopic radical prostatectomy may predict internal pudendal artery pseudoaneurysm and arteriovenous fistula. j endourol. 2009; 23:297-9. 8. asimakopoulus ad, dutto l, preziosi p, et al. holmium laser enucleation of the prostate and iatrogenic arteriovenous fistula treated by superselective arterial embolization. case rep urol. 2016; 2016:4918081. (9. saad ne, saad we, davies mg, et al. pseudoaneurysms and the role of minimally invasive techniques in their management. radiographics. 2005; 25 (suppl 1):s173-89. 10. galosi ab, montironi r, fabiani a, et al. cystic lesions of the prostate gland: an ultrasound classification with pathological correlation. j urol. 2009; 181:647-57. 11. kruger k, zahringer m, sohngen fd, et al. femoral pseudoaneurysms: management with percutaneous thrombin injections-success and effects on systemic coagulation. radiology 2003; 226:452-458. 12. kapoor bs, haddad hl, saddekni s, lockhart me. diagnosis and management of pseudoaneurysms: an update. curr probl diagn radiol. 2009; 38:170-188. 319archivio italiano di urologia e andrologia 2016; 88, 4 pseudoaneurysm with arteriovenous fistula of the prostate correspondence andrea b. galosi, md (corresponding author) galosiab@yahoo.it camilla capretti, md camilla.capretti2@gmail.com marco tiroli, md daniele cantoro, md luca leone, md matteo tallè, md matteo cevenini, md massimo polito, md scuola di specializzazione in urologia università politecnica delle marche clinica urologica, azienda ospedaliero-universitaria ospedali riuniti ancona via conca 71, 61100 torrette di ancona, italy galosi2_pseudoaneurysm with arteriovenous_stesura seveso 09/01/17 10:08 pagina 319 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 3244 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.244 non-invasive evaluation of obstruction after ureteroscopic stone removal: role of renal resistive index assessment bilal eryildirim 1, ahmet sahan 1, özlem türkoğlu 2, murat tuncer 1, övünç kavukoğlu 1, berkan simsek 1, alkan cubuk 1, kemal sarıca 3 1 health sciences university, kartal dr. lutfi kirdar training and research hospital, urology clinic, istanbul, turkey; 2 health sciences university, sultan abdulhamid han training and research hospital, radiology clinic, istanbul, turkey; 3 biruni university, medical school, urology clinic, istanbul, turkey. objectives: the aim of this study is to evaluate prediction of postoperative ureteral obstruction needing ureteral stent insertion by evaluating the resistive index (ri) values and the grade of hydronephrosis. material and methods: a total of 66 adult patients undergoing stentless endoscopic ureteral stone treatment (urs) between january 2018 and january 2019 were included in this prospective study. preoperative patient and stone characteristics were noted. all patients were evaluated with renal doppler ultrasonography study to assess degree of hydronephrosis and ri values. a renal doppler ultrasonography was repeated at postoperative 1st, 3rd and 7th days. changes in both ri and hydronephrosis levels before and after the procedures were noted. on the postoperative 7th day, patients were divided into two groups including obstructive and non-obstructive cases according to ri values assessed where a ri value of 0.7 was accepted as the cut-off for obstruction. the preoperative and perioperative characteristics of both groups were evaluated in a comparative manner. results: the mean patient age was 43.6 ± 1.72 years. significant improvements were noted in ri and grade of hydronephrosis after the operation. the grade of hydronephrosis and ri values were found to improve more significantly on postoperative 3rd day when compared to the postoperative 7th day (p < 0.01 and p < 0.01). a significant correlation was detected between the grade of hydronephrosis (>grade 2) and obstructive ri values (> 0.7) in each postoperative visits (p: 0.001). ri values (> 0.7) at postoperative seventh days were correlated with larger mean stone size, increased ureteral wall thickness, increased diameter of the ureter proximal to the stone, and longer duration of the operation. preoperative high-grade hydronephrosis indicated obstructive ri values at postoperative seventh day (p = 0.001) conclusion: changes in ri values on doppler sonography and the grade of hydronephrosis may be a guiding parameter in assessing postoperative ureteral obstruction. key words: ureteral obstruction; resistive index; renal doppler ultrasonography. submitted 2 march 2020; accepted 15 march 2020 summary introduction urolithiasis is a common disease that affects 5-10% of the general population (1). of all the stones diagnosed ureteral calculi sizing larger than 5 mm may cause obstruction and colic pain requiring immediate management. early intervention on this aspect, not only protects renal morphological and functional integrity but also enables the patient to return to normal life quickly (2, 3). ureteroscopic procedures have an important place not only in the diagnosis but especially in the treatment of ureteral stones. although the procedure is accepted as a minimally invasive approach; some certain complications and procedure-related complaints could be noted in a certain percent of the cases. persistence of the obstruction after ureteroscopic procedures secondary to the edema formation, presence of coagulum, and residual stone fragments is a major problem after this modality. follow-up of the ureteral obstruction in a non-invasive manner constitutes a dilemma both during preoperative and also postoperative periods. renal doppler ultrasonography (usg) may be one of the non-invasive diagnostic methods to help us in evaluating the degree as well as the course of the ureteral obstruction following endoscopic ureteral stone treatment. it has been well shown that changes in the degree of hydronephrosis and resistive index values (δ%) after ureteroscopic stone removal could provide important information regarding the severity (grade) of obstruction (4, 5). insertion of an ureteral stent after ureteroscopic procedures can be a rational option to avoid postoperative obstruction. however, accumulated data so far have clearly shown that despite their protective effects, ureteral stents may certainly have some distressing problems which have been classified as stent-related symptoms (6, 7). due to this fact, the insertion of a stent after these procedures is optional depending on the preference of the surgeon. on the other hand, again, there is no commonly accepted consensus with established certain criteria for the necessity of a ureteral stent after ureteroscopic procedures (8, 9). studies have demonstrated that not all of the dilatation detected in the upper urinary tract after ureteral stone removal will reflect a true obstruction and residual dilation is a commonly observed scenario. taking this fact into account again no reliable criteria with certain parameters have been reported to predict which patients will require ureteral dj stent placement due to ureteral obstruction during follow-up after endoscopic ureteral stone surgery. to fill this gap, in this present prospective study, we aimed to investigate the predict the presence of postoperative ureteral obstruction after ureteral stone removal by evaluating the resistive index values and the grade of hydronephrosis. 245archivio italiano di urologia e andrologia 2020; 92, 3 non-invasive evaluation of obstruction after ureteroscopic stone removal: role of renal resistive index assessment patients and methods a total of 66 adult patients undergoing stentless endoscopic ureteral stone treatment for ureteral stones between january 2018 and january 2019 were included in the study. patients with previous stone surgery including stent placement and auxiliary procedures, congenital anomalies, active urinary tract infection, pregnancy, renovascular disease, or renal insufficiency were all excluded from the program. approval for the study protocol was obtained from our local hospital ethics committee and all cases were well informed about the procedure from all aspects in detail and informed consent was obtained before the intervention (local ethical approval no: 2017/514/115/2). in addition to a detailed medical history; a careful physical examination was done and biochemical examinations including renal functional tests, urine analysis together with urine culture sensitivity tests were performed. although a non-contrast computed tomography (ncct) was performed in all cases during a colic attack; sonography, plain x-ray of the kidney, ureter, and bladder (kub) and excretory urography were done when necessary. in addition to these evaluations, renal color doppler sonography was done preoperatively in all cases in the supine position using 3.5-5mhz transducer of mindray® realtime ultrasound machine model dc-6 (shenzhenmindraybiomedical electronics, nanshan, shenzhen, china). the presence of hydronephrosis was evaluated in each case on bmode and graded as described by piazzese et al. (10). thereafter, the doppler study (color and spectral) of the interlobar arteries was done to calculate the renal resistive index value as [(peak systolic velocity ± end-diastolic velocity)/peak systolic velocity] (11, 12). preoperative stone and patient-related parameters such as stone size and localization, the diameter of the ureter proximal to the stone, the ureteral wall thickness at the site of the ureteral stone (uwt), the grade of hydronephrosis and ri values were all assessed and recorded (3). all ureteroscopic stone removal procedures were performed under general anesthesia by using a semirigid 8 fr ureteroscope (karl storz, tuttlingen, germany). all cases received 1 gr of cephazolin injection for prophylaxis before the procedure. stone fragmentation was accomplished by using the holmium-yag laser. perioperative data including duration of operation, stone-free rate, and hospitalization time were recorded. the interval between initial colic pain and surgery was also recorded. all patients were scheduled for a postoperative follow-up evaluation after 1st day, 3rd day and 7th day following the procedures. a doppler usg was performed at each visit to assess the grade hydronephrosis and ri values. ultrasonography was carried out by the same senior radiologist. changes in both ri and hydronephrosis levels before and after the procedures were given as “percentage of change” (δ%) (difference between a timely measurement with basal level/basal level x100) (10). on the postoperative 7th day, patients were divided into two groups including obstructive and non-obstructive cases according to ri values assessed where a ri value of 0.7 was accepted as the cut-off for obstruction (10). the preoperative and perioperative characteristics of both groups were evaluated in a comparative manner. statistical analysis the ibm spss version 20.0 (ibm co., armonk, ny) was used for statistical analysis. chi-square test was applied to evaluate categorical data and the two-sided p-value was used in inference, and p < 0.05 was accepted as significant. the variables were investigated using visual (histogram) and analytic methods (kolmogorov-smirnow) to determine normal distribution. descriptive analyses were presented using means and standard deviation. the anova was used to compare normally distributed parameters. results of all the 66 patients (40 men and 26 women) evaluated 36 cases had a stone on the right and 30 cases on the left side. the overall mean patient age was 43.6 ± 1.72 years with a mean bmi value of 26.3 ± 0.4 kg/m2. changes in both the ri values and the grade of hydronephrosis before and after the ureterolithotripsy were significantly improved. the grade of hydronephrosis and ri values were found to improve more significantly on postoperative 3rd day when compared to the postoperative 7th day (figures 1, 2). a comparison of hydronephrosis grade and resistive index values in conjunction with the timing of the follow-up period is being shown in table 1. a hydronephrosis grade of 2 and more were detected in 46 of the patients preoperatively. while 30 of these patients were diagnosed as on day 1, 18 patients were on postoperative day 3 and 10 patients on postoperative day 7. a significant correlation was detected between the grade of hydronephrosis (> grade 2) and obstructive ri values (> 0.7) (p: 0.001). according to the resistive index value detected, 42 patients were found to have an obstructive pattern at preoperatively and 26 patients were found to have an obstructive pattern at postoperative day 7. further evaluation of our findings clearly demonstrated that obstructive ri values > 0.7) at postoperative 7 days were well figure 1. delta resistive index changes are shown below during the follow-up. figure 2. delta hydronephrosis grade changes are shown below during the follow-up. archivio italiano di urologia e andrologia 2020; 92, 3246 correlated with larger mean stone size, increased uwt, increased diameter of the ureter proximal to the stone, and longer duration of the operation (table 2). additionally, the presence of preoperative high-grade hydronephrosis seemed to increase the likelihood of postoperative obstruction according to resistive index values assessed at postoperative days 7 (p = 0.001). discussion endourological procedures were introduced to the clinical practice in the 1980s and since then they have been used as widely accepted and reliable methods for ureteral stone treatment with limited complications (14). as a result of the technological improvements, ureterorenoscopes became thinner, and advanced visualization quality resulted in increased success and decreased complication rates. despite a successful ureteroscopic procedure, however, published data have demonstrated that ipsilateral colic pain can be observed due to edema and coagulum formation, residual stone fragments which may cause a temporary urinary obstruction and lead to the symptoms similar to the preoperative period in these patients. in light of these facts, it will be very useful to predict the possibility of postoperative obstruction during the preoperative evaluation period and plan to insert a ureteral stent after successful stone removal. on the other hand, evaluation and follow-up of possible obstructive status after such interventions with minimal or non-invasive means carry considerable importance for the involved cases. renal doppler usg and ri value assessment can be a useful tool in the non-invasive evaluation of upper urinary tract obstruction on this aspect (4, 15). related with this issue, apoku et al reported that renal doppler sonography is highly sensitive and specific for the diagnosis of obstructive uropathy. increased resistive index of the obstructed kidney may be a useful diagnostic tool in situations where intravenous urography cannot be done or is contraindicated. their findings indicated a sensitivity and specificity of 86.7% and 90% respectively following urinary obstruction, an increase in the pressure of the intrarenal collecting system will occur. the result of increased renovascular resistance will eventually cause a reduction in the renal blood flow. an increase in intra-renal vascular resistance diminishes diastolic blood flow velocity in intrarenal arteries which will subsequently cause an increase in the ri values noted (16). similarly, patti et al. have emphasized that ri is a good index of obstruction in children with unilateral hydronephrosis which has been found to be well correlated with the results of diuretic renography in such cases (12). thus, all these findings indicate the possible and effective use of ri value assessment in the follow-up of upper tract obstruction. in our current prospective study, we evaluated the presence and degree of obstruction in the upper urinary system with renal doppler usg (ri values and grade of hydronephrosis) before and after (1, 3, and 7 days) ureterolithotripsy in cases with ureteric stones. we observed a gradual improvement in ri values and grade of hydronephrosis following the removal of ureteral calculi. the change in ri values and grade of hydronephrosis after stone removal (δ%) was found to be statistically significant. furthermore, the improvement in ri values after intervention with significant decrease were well correlated with the decreasing grade of hydronephrotic status during the postoperative follow up period. our current findings implicated that, the ri values and grade of hydronephrosis are convenient and useful parameters in the noninvasive follow-up of obstruction status after ureterolithotripsy. routine ureteral stent insertion is not recommended after an uncomplicated urs, as it both increases the cost and lowers the patients' quality of life. according to eua guidelines, ureteral stents should be inserted in patients with any operative complication (bleeding, perforation, unsuccessful ureterolitotripsy, and ureteral injury) and in all doubtful situations to avoid the possible risk of postoperative complications (8, 9, 17, 18). however finding the answer to outline these “doubtful cases as well as to avoid stressful emergencies” mentioned in the eau urolithiasis guideline, we need to define some predictive parameters to assess such situations. it is a known fact that many patients may refer to the emergency department with colic flank pain after a successful endoscopic ureteral stone surgery. possible causes of partial ureteral obstruction in such cases are edema formation in the ureteral wall or presence of a coagulum in the lumen of the ureter. preoperative prediction of such factors (if possible) is highly important to decide on the placement of a ureteral stent following stone removal. in the light of the ri values obtained, 26 patients (without ant stent in place) had obstructive patterns at postoperative day 7 in our study. of these patients classified as “obstructed” according to the ri values; eight of them had grade 2 hydronephrosis and 18 patients had grade 3 hydronephrosis in the preoperative period. table 1. comparison of hydronephrosis and resistive index values among the days of the surgery. grade of hydronephrosis resistive index values ri 0 ri 1 ri 3 ri 7 0 2 0.680 12 0.611 28 0.583 30 0.562 1 18 0.664 24 0.662 20 0.680* 26 0.695* 2 38 0.729& 28 0.725*, & 18 0.757*, & 10 0.766*, & 3 8 0.840*, &. + 2 0.860*, & 0 0 total 66 0.723 66 0.686 66 0.660 66 0.645 pvalue 0.01 0.01 0.01 0.01 * comparing to 0 p < 0.01; & comparing to 1 p < 0.01; + comparing to 2 p < 0.01. table 2. comparison of obstructive resistive index value based on ri 7th day value to pre-operative parameters. ri < 0.7 (n:40) ri > 0.7 (n:26) p value ureteral stone diameter 6.8(1.6) 8.5(1.4) 0.01 ureteral wall thickness (uwt) 3.3(1.2) 4.9(0.6) 0.01 diameter of theureter 9.2(3.2) 13.6(3.06) 0.01 duration of theoperation 36.2(7.1) 48.0(5.1) 0.01 stone localization (upper/lower) 10/30 10/16 0.245 preoperative grade 0 2 0 of hydronephrosis 1 14 0 0.001 2 24 8 3 0 18 247archivio italiano di urologia e andrologia 2020; 92, 3 non-invasive evaluation of obstruction after ureteroscopic stone removal: role of renal resistive index assessment based on our current findings, we can say that the grade of preoperative hydronephrosis may be associated with the postoperative obstructive pattern and ureteral stent placement might be more beneficial in these patients. additionally, patients with obstructive ri values at postoperative 7 days did also have increased mean stone size, uwt values, the diameter of the ureter proximal to the stone during preoperative evaluations along with longer mean operative duration. these data clearly indicate that postoperative restoration of the obstruction may take some more time if the stone burden, uwt value, the diameter of the ureter proximal to the stone is high and the operation time is longer. our study has certain limitations. first of all the number of cases included in the study program is limited. also, long-term follow-up data are lacking in the groups. however, taking the lack of publications regarding this issue and the first introduction of such parameters to assess the factors affecting postoperative ureteral obstruction; we believe that our current findings will certainly be contributive enough to the existing literature on this critical subject. lastly, it would be interesting to compare cases with high ri > 0.7 and the ones with no or mild upper tract dilatation, to help the urologist to decide to place stent rather than wait for the obstruction to resolve by itself in these cases. however, we were not able to make such a comparison due to the limited number of patients in our groups. conclusions based on our current findings we may state that the changes in ri values on doppler sonography and the grade of hydronephrosis may be a guiding parameter in assessing whether obstruction is removed after endoscopic ureteral stone treatment. if the stone burden is high, operation time is long and the stone is impacted to the ureteric wall, postoperative restoration of obstruction may take longer than anticipated. we believe that in addition to changes in the degree of hydronephrosis outlined, the assessment of renal ri values may provide us further information to differentiate the obstructive pattern after ureteroscopic surgery prior to ureteral catheter placement. references 1. teichman jm. clinical practice. acute renal colic from ureteral calculus. n engl j med. 2004; 350:684-93. 2. joshi hb, obadeyi oo, rao pn. a comparative analysis of nephrostomy, jj stent and urgent in situ extracorporeal shock wave lithotripsy for obstructing ureteric stones. bju int. 1999; 84:264-9. 3. yencilek f, sarica k, erturhan s, et al. treatment of ureteral calculi with semirigid ureteroscopy: where should we stop? urol int. 2010; 84:260-4. 4. apoku in, ayoola oo, salako aa, idowu bm. ultrasound evaluation of obstructive uropathy and its hemodynamic 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et al. the renal resistive index as a predictor of acute hydronephrosis in patients with renal colic. j ultrasound. 2012; 15:239-46. 11. norris cs, pfeiffer js, rittgers se, barnes rw. noninvasive evaluation of renal artery stenosis and renovascular resistance. experimental and clinical studies. j vasc surg. 1984; 1:192-201. 12. patti g, menghini ml, todini ar, et al. the role of the renal resistive index ratio in diagnosing obstruction and in the follow-up of children with unilateral hydronephrosis. bju int. 2000; 85:308-12. 13. tanidir y, sahan a, asutay mk, et al. differentiation of ureteral stones and phleboliths using hounsfield units on computerized tomography: a new method without observer bias. urolithiasis. 2017; 45:323-8. 14. turk c, petrik a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016; 69:468-74. 15. kilic s, altinok mt, ipek d, et al. color doppler sonography examination of partially obstructed kidneys associated with ureteropelvic junction stone before and after percutaneous nephrolithotripsy: preliminary report. int j urol. 2005; 12:429-35. 16. klahr s, pukerson ml. the pathophysiology of obstructive nephropathy: the role of vasoactive compounds in the hemodynamic and structural abnormalities of the obstructed kidney. am j kidney dis. 1994; 23:219-23. 17. seklehner s, sievert kd, lee r, et al. a cost analysis of stenting in uncomplicated semirigid ureteroscopic stone removal. int urol nephrol. 2017; 49:753-61. 18. ogreden e, oguz u, demirelli e, et al. the impact of ureteral double-j stent insertion following ureterorenoscopy in patients with ureteral stones accompanied by perirenal fat stranding. arch ital urol androl. 2018; 90:15-19. correspondence bilal eryildirim, md ahmet sahan, md özlem türkoğlu, md murat tuncer, md berkan simsek, md alkan cubuk, md (corresponding author) alkancubuk@hotmail.com kartal dr. lutfi kirdar training a nd research hospital, department of urology cevizli mh şemsi denizer cad. e-5 karayolu cevizli mevkii, 34890 kartal istanbul (turkey) övünç kavukoğlu, md health sciences university, kartal dr. lutfi kirdar training and research hospital, urology clinic, istanbul (turkey) kemal sarıca, md biruni university, medical school, urology clinic, istanbul (turkey) 89archivio italiano di urologia e andrologia 2020; 92, 2 original paper can multiparametric ultrasound improve cognitive mri/trus fusion prostate biopsy pietro pepe, ludovica pepe, paolo panella, michele pennisi urology unit, cannizzaro hospital, catania, italy. objective: to evaluate the accuracy of multiparametric transrectal ultrasound (contrast-enhanced ultrasound plus elastosonography) in the detection of the suspicious area diagnosed by multiparametric magnetic resonance (mpmri). materials and methods: from june 2018 to june 2019 60 men (median age 63 years) with persistent suspicion of cancer underwent repeat saturation biopsy following pelvic mpmri and the lesions characterized by a pi-rads (prostate imaging reporting and data system) score ≥ 3 were submitted to 4 additional cores by transperineal cognitive fusion biopsy (tpbx). all patients, before prostate biopsy, underwent contrast-enhanced ultrasound (ceus) following intravenous administration of a bolus of sonovue® (2.4 mg of nonpyrogenic suspension of phospholipid/sulphur hexaphloride); in addition, a transrectal elastosonography (tres) was done to evaluate prostate tissue elasticity. the accuracy of multiparametric ultrasound to detect the mpmri lesions was evaluated. results: in 27/60 (45%) of men a t1c prostate cancer (pca) was diagnosed by tpbx and 21 (77.8%) of them were classified as clinically significant cancer (cspca); in detail, 16/21 (76.2%) vs. 5/21 (23.8%) cspca were located in the peripheric and anterior zone of the gland, respectively. median total psa was 10.3 ng/ml (range: 4.9-51 ng/ml). tres and ceus were positive for cspca only in 6/21 (28.5%) and 13/21 (62%) of tpbx showing an increased accuracy directly related with the pi-rads scores conclusions: multiparametric ultrasound using tres and ceus after sonovue® administration did not improve the accuracy of tpbx in diagnosing cspca. key words: prostate cancer; contrast-enhanced ultrasound; multiparametric ultrasound; fusion prostate biopsy. submitted 11 october 2019; accepted 23 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.89 introduction multiparametric magnetic resonance imaging (mpmri) combined with transrectal ultrasound (trus) fusion targeted biopsy has improved the accuracy of standard biopsy schemes in detecting clinically significant prostate cancer (cspca) (1-4). a lot of papers refer about the accuracy of mpmri/trus targeted biopsy in the diagnosis of cancer but there are few data about the standardization of the procedure and/or the optimal technique of targeted biopsy (5-7). although, the in-bore procedure seems to be more accurate to diagnose cspca in comparion with mri/trus fusion biopsy (61 vs. 47%) (8) no clinically significant difference has been reported in multicentric clinical trials comparing cognitive vs. fusion vs. in-bore targeted biopsy (5). in the last years, trus has been enriched by the introduction of tridimensional and computerized images and by the use of contrast media and transrectal elastosonography (tres) (9, 10), which allow better characterization of intraparenchymal microvasculature. the use of microbubble ultrasound contrast agents (uca: sonovue®, definity®, imagent®) improve flow detection in small vessels distinguish the normal from pathological tissue (11-15). in addition, the elastosonography measures the degree of distortion of ultrasound beam under the application of an external force that is displayed and scored over the b-mode image in a colour scale that corresponds to tissue elasticity (16-19). in our series, the accuracy of multiparametric transrectal ultrasound (20) (ceus plus tres) in the detection of the suspicious area diagnosed by mpmri and suitable of targeted transperineal prostate biopsy (tpbx) has been evaluated. material and methods from june 2018 to june 2019 60 caucasians men (median age 63 years; range: 47-75 years) with negative digital rectal examination and previous negative extended biopsy underwent repeat transperineal saturation biopsy (spbx) for the suspicion of cancer (increasing or persistently elevated psa values) (21). after institutional review board and ethical committee approval were granted the informed consent was obtained from all individual participants included in the study. ten days before spbx, all the patients underwent pelvic mpmri. all mpmri examinations were performed using a 3.0 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo t2-weighted, axial diffusion weighted imaging, axial dynamic contrast enhanced mri were performed for each patient. the mpmri lesions characterized by a pi-rads (prostate imaging reporting and data system) version 2 score ≥ 3 were considered suspicious for cancer. two radiologists blinded to pre-imaging clinical parameters evaluated the mpmri data separately and independently. spbx (median of 28 cores; range: 26-30 cores) was perpepe_stesura seveso 17/06/20 10:12 pagina 89 archivio italiano di urologia e andrologia 2020; 92, 2 p. pepe, l. pepe, p. panella, m. pennisi 90 formed transperineally by a hitachi 70 arietta ecograph (chiba, japan) supplied with a bi-planar transrectal probe (5-7.5 mhz) and using a tru-cut 18 gauge needle (bard; covington, ga, usa) under sedation and antibiotic prophylaxis (intravenous administration of 1 gram of cefazolin before prostate biopsy). one urologist with more than 8 years of experience regarding mri/trus fusion targeted biopsy performed the procedure. in the presence of mpmri lesions suggestive of cancer a tpbx (four cores) was added to spbx using the hitachi 70 arietta ecograph (10). the data have been collected following the start criteria (22). all patients, before prostate biopsy, underwent standard trus combined with administration of a bolus of sonovue® (nonpyrogenic suspension of phospholipid/ sulphur hexaphloride) equal to 2.4 mg into a large peripheral vein followed by a flush of saline (10 ml). before scanning with contrast-enhanced ultrasound (ceus), an appropriate setup that included low mechanical index (mi) and a split-screen view to display the contrast and b-mode images at the same time was selected on the logiq e9 echograph (general electric; milwaukee, wi usa) provided of an end-fire transrectal probe. a timer was activated after uca injection and the investigation was performed for 200 seconds (median; range 180-240); at the end of the procedure microbubbles were bursted. post-contrast imaging began as soon as contrast medium was visible on gray scale continuous harmonic imaging (hi); the microbubbles normally were distributed throughout the prostate, that appeared contrastenhanced, and only areas characterized by the sonovue® enhancement (15) were considered suspicious for pca. the tres evaluation was done before the execution of the targeted cognitive biopsy performing a real-time tissue elastosonography of the gland by the shear wave measurament (swm) analysis of the prostate (hitachi 70 arietta ecograph (chiba, japan). after multiparametric ultrasound evaluation the patients were submitted to tpbx plus spbx (1). the clavien-dindo grading system for the classification of biopsy complications was used (23). the detection rate of tpbx in the diagnosis of cspca (gleason score > 6 and/or greatest percentage of cancer > 50% and/or more than two positive cores) was evaluated (24); in addition, the accuracy of multiparametric ultrasound (elastosonography and/or sonovue®) to detect the mri lesions was evaluated. results the overall diagnosis of pca vs. cspca performing spbx was equal to 32/60 (56.7%) vs. 25/60 (41.7%) cases, but the data will refer only to the tpbx detection rate for pca. in 27/60 (45%) of men a t1c pca was diagnosed by targeted fusion biopsy and 21 (77.8%) of them were classified as cspca (table 1); in detail, 16/21 (76.2%) vs. 5/21 (23.8%) cspca were located in the peripheric (figure 1) and anterior zone (figure 2) of the gland, respectively. median total psa was 10.3 ng/ml (range: 4.9-51 ng/ml); the pi-rads scores, sonovue® and tres results are listed in table 1. no side-effects were reported after sonovue® administration; none had significant complications (clavien-dindo grade i) from prostate biopsy that needed hospital admission biopsyrelated; moreover, the mpmri procedure was well tolerated and successfully performed in all cases (men with claustrophobia, cardiac pacemaker and hip replacement were not included in the study). table 1. clinical and histological parameters in 21 patients with clinically significant prostate cancer (cspca) diagnosed by cognitive targeted fusion biopsy. biopsy histology and clinical parameters number of cases gleason score 3 + 4 (gg2) 10 cases pirad-s score (3 vs. 4 vs. 5)* 3 7 0 suspicious tres 1 2 0 suspicious ceus 2 4 0 gleason score 4 + 3 (gg3) 7 cases pirad-s score* 3 3 1 suspicious tres 1 0 1 suspicious ceus 1 2 1 gleason score 4 + 4 (gg4) 3 cases pirad-s score* 0 2 1 suspicious tres 0 0 1 suspicious ceus 0 1 1 gleason score 4 + 5 (gg5) 1 case pirad-s score* 0 0 1 suspicious tres 0 0 0 suspicious ceus 0 0 1 tres: transrectal elastosonography; pi-rads: prostate imaging reporting and data system; ceus: contrast-enhanced ultrasound; gg: grade groups isup (international society of urological pathology). figure 1. sonovue® enhancement in correspondence of the left peripheric zone of the prostate (white arrow). pepe_stesura seveso 17/06/20 10:12 pagina 90 in detail, tres and ceus were positive for cspca only in 6/21 (28.5%) and 13/21 (62%) of cognitive fusion biopsies showing an increased accuracy directly correlated with the pi-rads scores (table 1); in addition, tres analysis did not improve the ceus accuracy. discussion the improvement of diagnostic imaging by mpmri has allowed targeted biopsies of the suspicious area, increasing the diagnosis of cspca (1, 2) and reducing the number of unnecessary systematic biopsies. although mpmri is strongly recommended in men candidate to prostate biopsy (3), still today, systematic biopsy should be always combined with mpmri/trus fusion biopsy due to false negative rate of mpmri (about 20% of the cases) (1) and the variable diagnostic accuracy of the different mpmri/trus fusion biopsy platforms (25). on the other hand, an alternative clinical approach is to begin with mpmri to determine which patients need a targeted biopsy (26). the detection rate of cspca is directly related to the pi-rads score (1, 2) and the results depend on clinical parameters, the number of previous negative biopsies and the quality of tpbx procedures. in the next future it would be good that the artificial intelligence for automatic delineation of the prostate on ultrasound could became reliable and applicable to different scanners to improve, guided prostate biopsies using magnetic resonance imaging-transrectal ultrasound fusion (27). alternatively, the ideal approach to the diagnosis of pca should be to detect significant disease performing a limited number of targeted biopsy cores improving the accuracy of standard trus by multiparametric ultrasound (28); in this respect, a lot of papers have been published on the use of uca as an additional diagnostic tool for improving pca diagnosis (2-4) showing a low detection rate included between 15.5 and 32% (14-20, 29). in addition, in recent years, elastosonography has improved by the introduction of shear wave elastosonography (swe) that is a quantitative method that evaluate local tissue elasticity resulting much less operator dependent; the sensitivity vs. specificity of tres range from 71-82% vs. 60-95% (9) in definitive specimen of men who underwent radical prostatectomy. recently, micro-ultrasound (30) in preliminary studies has demonstrated similar sensitivity to clinically significant prostate cancer as mpmri; unlike mpmri, micro-ultrasound is performed in the office, in real-time during the biopsy procedure, and so is expected to maintain the cost-effectiveness of conventional ultrasound, but larger studies are needed before these results may be applied in a clinical setting. in our series, tres and ceus were positive for cspca only in 6/21 (28.5%) and 13/21 (62%) of cognitive fusion biopsies showing an increased positive results directly related with the pi-rads scores (table 1); in addition, tres analysis did not increased the ceus accuracy. in definitive, the additional use of multiparametric ultrasound did not improve the accuracy of cognitive fusion biopsy in the diagnosis of cspca resulting only in an increased cost of the procedure. regarding our results some consideration should be done. firstly, non-targeted biopsies were performed in ceus or tres suspicious areas, therefore, it is unknown if multiparametric trus would have diagnosed cspca missed by tpbx; secondly, ceus was not performed during the execution of tpbx. third, the false negative rate of mpmri for cspca (4/21 equal to 19% of the cases) has not been correlated to ceus and tres findings. finally, a greater number of cases is needed to confirm the results. conclusions multiparametric ultrasound using tres plus ceus did not improved the accuracy of tpbx in diagnosing cspca. references 1. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? ou experience in 1032 men submitted to prostate biopsy. j urol 2018; 200:774-778. 2. preisser f, theissen l, wenzel m, et al. performance of combined magnetic resonance imaging/ultrasound fusion-guided and systematic biopsy of the prostate in biopsy-naïve patients and patients with prior biopsies. eur urol focus. 2019; pii: s2405-4569(19)30170-1. 3. pepe p, garufi a, priolo g, et al. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol. 2016; 34:1249-1453. 4. pepe p, garufi a, priolo g, et al. transperineal versus transrectal mri/trus fusion targeted biopsy: detection rate of clinically significant prostate cancer. clin genitourin cancer. 2017; 15:e33-e36. 5. wegelin o, exterkate l, van der leest m, et al. the future trial: a multicenter randomised controlled trial on target biopsy techniques based on magnetic resonance imaging in the diagnosis of prostate cancer in patients with prior negative biopsies. eur urol. 2019; 75: 582-590. 6. galosi ab, maselli g, sbrollini g, et al. cognitive zonal fusion biopsy of the prostate: original technique between target and saturation: arch ital urol androl. 2016; 88:292-295. 7. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology. 2019; pii: s0090-4295(19)31022-2. 8. costa dn, goldberg k, leon ad, et al. magnetic resonance imaging-guided in-bore and magnetic resonance imaging-transrectal ultrasound fusion targeted prostate biopsies:an adjusted comparison of clinically significant prostate cancer detection rate. eur urol oncol. 2019; 2:397-404. 9. aboumarzouk om, ogston s, huang z, et al. diagnostic accuracy of transrectal elastosonography (tres) imaging for the diagnosis of prostate cancer: a systematic review and meta-analysis. bju int. 2012; 110:1414-1423. 10. correas jm, drakonakis e, isidori am, et al. update on ultrasound elastography: miscellanea. prostate, testicle, musculo-skeletal. eur j radiol. 2013; 82:1904-1912. 11. mitterberger m, horninger w, pelzer a, et al: a prospective randomized trial comparing contrast-enhanced targeted versus systematic ultrasound guided biopsies: impact on prostate cancer detection. prostate. 2007; 67:1537-1542. 12. colleselli d, bektic j, schaefer g, et al. the influence of prostate volume on prostate cancer detection using a combined approach of 91archivio italiano di urologia e andrologia 2020; 92, 2 multiparametric prostate ultrasound and fusion biopsy pepe_stesura seveso 17/06/20 10:12 pagina 91 archivio italiano di urologia e andrologia 2020; 92, 2 p. pepe, l. pepe, p. panella, m. pennisi 92 contrast-enhanced ultrasonography-targeted and systematic grayscale biopsy. bju int. 2007; 100:1264. 13. linden ra, trabulsi ej, forsberg f, et al. contrast enhanced ultrasound flash replenishment method for directed prostate biopsies. j urol. 2007; 178:2354-2358. 14. taymoorian k, thomas a, slowinski t, et al. transrectal broadband-doppler sonography with intravenous contrast medium administration for prostate imaging and biopsy in men with elevated psa value and previous negative biopsies. anticancer res. 2007; 27:4315-4320. 15. pepe p, candiano g, pennisi m, aragona f. can sonovue targeted biopsy replace extended or saturation biopsy in prostate cancer diagnosis? our experience at primary and repeat biopsy. arch ital urol androl. 2010; 82:155-159. 16. nelson ed, slotoroff cb, gomella lg, halpern ej. targeted biopsy of the prostate: the impact of color doppler imaging and elastography on prostate cancer detection and gleason score. urology. 2007; 70:1136-1140. 17. bercoff j, tanter m, fink m. supersonic shear imaging: a new technique for soft tissue elasticity mapping. ieee trans ultrason ferroelectr freq control. 2004; 51:396-409. 18. nguyen tm, couade m, bercoff j, tanter m: assessment of viscous and elastic properties of sub-wavelength layered soft tissues using shear wave spectroscopy: theoretical framework and in vitro experimental validation. ieee trans ultrason ferroelectr freq control. 2011; 58:2305-2315. 19. tanter m, bercoff j, athanasiou a, et al. quantitative assessment of breast lesion viscoelasticity: initial clinical results using supersonic shear imaging. ultrasound med biol. 2008; 34:1373-1386. 20. mannaerts ck, wildeboer rr, remmers s, et al. multiparametric ultrasound for prostate cancer detection and localization: correlation of b-mode, shearwave elastography and contrast-enhanced ultrasound with radical prostatectomy specimens. j urol. 2019 202:11661173. 21. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 22. moore cm1, kasivisvanathan v, eggener s, , et al. start consortium: standards of reporting for mri-targeted biopsy studies (start) of the prostate: recommendations from an international working group. eur urol. 2013; 64:544-552. 23. dindo d, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of survey. annals of surgery. 2004; 2:205-213. 24. epstein j, walsh p, carmichael m. pathological and clinical findings to predict tumor extent of non palpable (stage t1c) prostate cancer. jama. 1994; 271:368-374. 25. kaufmann s, russo gi, bamberg f, et al. prostate cancer detection in patients with prior negative biopsy undergoing cognitive, robotic or in-bore mri target biopsy. world j urol. 2018; 36:761-768. 26. faria r, soares mo, spackman e, et al. optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate mr imaging study (promis). eur urol. 2018; 73:23-30. 27. van sloun rjg, wildeboer rr, mannaerts ck, et al. deep learning for real-time, automatic, and scanner-adapted prostate (zone) segmentation of transrectal ultrasound, for example, magnetic resonance imaging-transrectal ultrasound fusion prostate biopsy. eur urol focus. 2019; pii: s2405-4569(19)30125-7. 28. grey a, ahmed hu. multiparametric ultrasound in the diagnosis of prostate cancer. curr opin urol. 2016; 26:114-119. 29. delgado oliva f, arlandis guzman s, et al. diagnostic performance of power doppler and ultrasound contrast agents in early imaging-based diagnosis of organ-confined prostate cancer: is it possible to spare cores with contrast-guided biopsy? eur j radiol. 2016; 85:1778-1785. 30. eure g, fanney d, lin j, et al. comparison of conventional transrectal ultrasound, magnetic resonance imaging, and microultrasound for visualizing prostate cancer in an active surveillance population: a feasibility study. can urol assoc j. 2019; 13:e70-e77. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md paolo panella, md michele pennisi, md divisione di urologia, azienda ospedaliera cannizzaro, via messina, 829 95126 catania (italy) pepe_stesura seveso 17/06/20 10:12 pagina 92 archivio italiano di urologia e andrologia 2020; 92, 278 short communication covid-19 pandemic and uro-oncology follow-up: a “virtual” multidisciplinary team strategy and patients’ satisfaction assessment covid-19 pandemic strongly modified the organizations of our clinical practice. strict containment measures have been adopted to limit the disease diffusion. in particular, hospital face-to-face post discharge and follow up visits have been reduced. although cancelling or deferring appointments seems to be a pragmatic approach, this solution may have a devasting long-term impact on health medical care and on patients. in this context, telemedicine and remote consultations may have the potential to provide healthcare minimizing virus exposure. in this paper we describe how multidisciplinary team (mdt) reorganized genitourinary cancer care delivery at our institute (ao ss antonio e biagio e cesare arrigo, alessandria), taking advantage of telematic means. furthermore, we present our preliminary results regarding patients’ satisfaction. key words: covid-19; pandemy; telemedicine. submitted 24 april 2020; accepted 28 april 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.78 in the last few weeks our lives and the organization of our departments have been completely turned upside down by the coronavirus novel sars-cov-2. the virus has rapidly spread all around the world and on the 11th march 2020 the world health organization declared the coronavirus disease 2019 (covid-19) a global pandemic. strict containment measures have been taken by governments worldwide in attempt to curb the virus spread, ranging from school closures, social distancing to complete lockdown. as of the 24th april 2020 there have been 2.626.321 confirmed cases with 181.938 deaths and 213 countries involved (1). covid-19 is, possibly, the greatest challenge healthcare systems around the world have seen for the last years, since drastic health resources reallocations have been necessary to face the pandemic. in this context, routine clinical and surgical activities, including urological practice, have been deeply reorganized prioritizing patients’ safety and well-being. recommendations on the reorganization of urological activities have been provided by different scientific societies (2). in particular, all elective surgeries should be deferred, and surgical intervention should be limited for high grade malignancies and unstable trauma patients. hospital face-to-face post discharge and follow up visits should be reduced implementing telehealth strategies. we believe that oncological communications are by far the most delicate ones to share with the patient and that deserve particular attention. before covid-19 pandemic, weekly multidisciplinary hospital follow-up visits were carried out to patients treated for genitourinary cancers at our institute. our local multidisciplinary team (mdt) involves medical oncologists, radiotherapists, pathologists, clinical nurse specialists and urologists. in order to reduce home-hospital flow, all patients scheduled from march 9th 2020, first day of national lockdown, onwards have been phone called by the clinical nurse specialist and their email collected. they were asked to send the results of their instrumental and biochemical exams’ follow up by mail and to communicate any new clinical onset problem. the patients’ documents and data were collected and then examined by mdt members on weekly videoconference meetings through the use of zoom (zoom video communications, inc. san jose, california, 2011). a clinical report containing oncological outcomes and the corresponding planning, with follow-up exam and visit, were sent to the patients via email accompanied by a telephone call from the urologist. face to face consultations were carried out only in case of disease progression or recurrence, onset of metastasis or severe clinical troubles. the follow-up of 56/60 (93.3%) scheduled patients were successfully managed by the “virtual” mdt, while only 4 patients required a conventional outpatient clinic setting. no complaints, objections or criticisms were recorded, regarding the proposed remote monitoring. at the end of the “virtual” consultations, the patients were asked to reply an anonymous online survey through google forms. with a response rate of 68.3% (41/60) most of the patients showed a high satisfaction (mean: 4.7/5) with no serious complaining about major technical issues. the smartness and convenience of the “virtual” visits were indicated as the most appreciated advantage by 10 francesca ambrosini 1, 2, andrea di stasio 2, guglielmo mantica 1, barbara cavallone 2, armando serao 2 1 department of urology, policlinico san martino hospital, university of genoa, genoa, italy; 2 department of urology, azienda ospedaliera nazionale ss. antonio e biagio e cesare arrigo, alessandria, italy. ambrosini_stesura seveso 17/06/20 10:05 pagina 78 79archivio italiano di urologia e andrologia 2020; 92, 2 follow-up during covid-19 pandemic (24.4%) and 16 (39%) patients, respectively. the lack of clinicians’ physical presence was perceived as the main limit of tele-visit by eleven patients (26.8%). furthermore, 38/41 (92.7%) of the patients felt adequate sensitive data protection and no significant concerns about the privacy and security of remote visits. to date, while telemedicine is gaining popularity and numerous platforms and apps are available, it still poses some technical and practical problems. one of the main limits seems to be absence or unclearness of the legislation that still remains a common stumbling block for providers and patients (3). telemedicine may increase clinical workflow efficiency in the coming years offering several benefits to the health system organization. sars-cov-2 pandemic is now driving the whole word transformation and could provide the decisive push correspondence francesca ambrosini, md (corresponding author) f.ambrosini1@gmail.com department of urology, policlinico san martino hospital, university of genoa largo rosanna benzi, 10, 16132, genoa, italy department of urology, azienda ospedaliera nazionale ss. antonio e biagio e cesare arrigo via venezia 16, 15121, alessandria, italy orcid 0000-0003-2160-763x andrea di stasio, md andrea.distasio@libero.it barbara cavallone, md barbara.cavallone@ospedale.al.it armando serao, md aserao@ospedale.al.it department of urology, azienda ospedaliera nazionale ss. antonio e biagio e cesare arrigo, alessandria (italy) guglielmo mantica, md guglielmo.mantica@gmail.com department of urology, policlinico san martino hospital, university of genoa, genoa, italy to make institutions, clinicians and, above all, patients familiar with telemedicine. references 1. coronavirus [internet]. world health organization. 2020 [cited 24th april 2020]. available from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019. 2. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92(1). https://doi.org/ 10.4081/aiua.2020.2.67. 3. castaneda p, ellimoottil c. current use of telehealth in urology: a review. world j urol. 2019 jul 27. doi: 10.1007/s00345-01902882-9. online ahead of print. ambrosini_stesura seveso 17/06/20 10:05 pagina 79 stesura seveso 93archivio italiano di urologia e andrologia 2019; 91, 2 original paper prostate volume effect on gleason score upgrading in active surveillance appropriate patients emre çamur 1, alper coşkun 2, övünç kavukoğlu 3, utku can 4, önder kara 5, arzu develi çamur 6, kemal sarıca 7, kamil fehmi narter 8 1 amasya university sabuncuoglu serefeddin training and research hospital urology department, amasya, turkey; 2 sanlıurfa training and research hospital urology clinic, sanlıurfa, turkey; 3 gumushane state hospital urology clinic, gumushane, turkey; 4 erzurum training and research hospital urology clinic, erzurum, turkey; 5 kocaeli university medical faculty hospital urology clinic, kocaeli, turkey; 6 suluova state hospital, internal medicine clinic, amasya, turkey; 7 kafkas university training and research hospital urology clinic, kars, turkey; 8 acıbadem mehmet ali aydınlar university hospital urology clinic, istanbul, turkey. introduction: gleason score (gs) upgrading rates in the literature are reported to be around 33-45%. the relationship between prostate volume and gs upgrading should be defined, aiming to reduce upgrading rates in patients with low risk groups who are eligible for active surveillance (as) or minimally invasive treatment, by varying biopsy cores, or lengths of cores according to prostate volumes. in this regard, the aim of our study was to establish the relationship between prostate volume and gs upgrading. materials and methods: we retrospectively analyzed the medical records of 78 patients, who were appropriate for as between 2011-2016 at our hospital. inclusion criteria were patient age under 65 years, psa level under 10 ng/ml, gs (3 + 3) or (3 + 4), and 3 or less positive cores, clinical stages ≤ t2. gs increase in radical prostatectomy specimen was considered as 'upgrading' and in addition, score reported by biopsy as 3 + 4 but in surgical specimen as 4 + 3 were also considered as 'upgrading'. the effect of prostate volume on gleason grade upgrading was examined by calculating upgrading rates separately for patients with prostate volume 30 ml or less, those with 30 to 60 ml, and those over 60 ml. results: as a result of the analysis of the data, upgrading was seen in 35 (44.8%) of 78 patients included in the study. in the cohort mean prostate volume was 49.8 (± 26.3) ml. twenty-two patients (28.2%) had prostate volume 30 ml or less, 34 (43.6%) 30 to 60 ml, and 22 (28.2%) 60 ml or more. the patients were divided into two groups as those with and without gs upgrading. between the groups prostate volume and prostate volume range (0-30/31-60/> 60) were not significantly different (p value > 0.05). conclusions: gleason grade upgrading causes patients to be classified in a lower risk group than they actually are, and may lead to inappropriate treatment. this condition has a direct effect on the decision of active surveillance. therefore, it is important to define the factors that can predict gs upgrading in active surveillance appropriate patients. in this study, we found that prostate volume has no significant effect on upgrading in active surveillance appropriate patients. key words: prostate cancer; gleason score; upgrading; active surveillance. submitted 5 january 2019; accepted 11 march 2019 summary no conflict of interest declared. introduction prostate cancer is the second most common cancer worldwide and the fifth most common cause of cancerrelated deaths. because of this reason, there are lots of studies on prostate cancer (1-2). active surveillance (as) has been defined in the appropriate group of patients for low-risk prostate cancer. gleason score (gs) is the most important criteria for patient selection for as and used in the nomograms. in most studies and nomograms (3+3) gs in the biopsy is used as an inclusion criterium. recently, researchers have included some eligible patients with a biopsy gs 3 + 4 to their studies (3-6). in patients, considered as option, all pathological data, including gs are dependent on prostate needle biopsy. so that, the accuracy of the gs in needle biopsies is very important for this patient groups. however, there may be a significant difference between gss in needle biopsies and radical prostatectomy specimens. if the score in prostatectomy specimen is higher than needle biopsy, that is defined as ‘upgrading’, if it is lower, 'downgrading' is mentioned. upgrading rates in the literature are reported to be around 33-45% (7). because of upgrading, patients who are not actually suitable for as can be recommended with inappropriate treatment options. the reason for this high pathological disruption seems to be that less than 1% of the prostate tissue can be sampled with needle biopsy. assessment in such a small tissue volume can cause tumor tissue to be undetectable or even missed (8-9). this is supported by studies showing that rates of upgrading in needle biopsies of enlarged prostate are lower (10-14). in most of previous studies, an inverse correlation was found between prostate volume and upgrading rates (15-17). kulkarni et al. have not found significant relationship between prostate volume and upgrading rates, in a retrospective study published in 2006 in which they reviewed 369 patients (18). if the relationship between prostate volume and gs upgrading can be assessed, it may be aimed to reduce upgrading rates in patients with low risk groups who are doi: 10.4081/aiua.2019.2.93 archivio italiano di urologia e andrologia 2019; 91, 2 e. çamur, a. coşkun, ö. kavukoğlu, utku can, ö. kara, a. develi çamur, k. sarıca, k. fehmi narter 94 eligible for active follow-up or minimally invasive treatment, by varying biopsy cores, or lengths of cores according to their prostate volumes. in this regard, the aim of our study is to establish the relationship between prostate volume and gs upgrading. materials and methods we retrospectively analyzed the medical records of 78 patients, who are appropriate for as between 2011-2016 at our hospital (dr. lütfi kırdar kartal training and research hospital, istanbul, turkey). age, prostate-specific antigen (psa), prostate volume, total number of cores in the preoperative biopsy, cancer positive core number in the biopsy, gs in the biopsy report, clinical stage, gs in prostatectomy specimen, presence of prostatic intraepithelial neoplasia (pin), extracapsular extension (ece), vascular invasion, surgical margin status, perineural invasion (pni), seminal vesicle involvement (svi) were evaluated. study protocol was approved by ethics committee of dr.lütfi kırdar training and research hospital. inclusion criteria were patient age under 65 years, psa level under 10 ng/ml, gs (3+3) or (3+4), and 3 or less positive cores, clinical stages ≤ t2. prostate volumes were measured transrectally during biopsy, all biopsies were 12 cores and pathologic examination was performed by two experienced uro-pathologists in our hospital. gs, total cores, and cancer positive core numbers were noted in the biopsy specimens that detected adenocarcinoma. the length or percentage of the cancer positive tissue couldn’t found in most reports. gs, pin, surgical marginal status, pni, svi, ece, presence of vascular invasion were registered. biopsy and prostatectomy specimens were evaluated according to 2005 international society of uro-pathologists (isup) modified gleason system. gs increase in radical prostatectomy specimen was assessed as 'upgrading' and in addition also cases in which the score reported by biopsy was 3 + 4 and the score found in the specimen was 4 + 3 were evaluated as 'upgrading'. the effect of prostate volume on gleason grade upgrading was examined. patients initially were divided into gs upgrading or not. these groups were compared in terms of age, psa value, prostate volume, number of total biopsy cores, number of positive cores, clinical stages, surgical margin status, and svi, presence of ece, pin, pni, and vascular invasion. upgrading rates were calculated separately for patients with prostate volume 30 ml or less, those with 30 to 60 ml, and those over 60 ml. in the descriptive statistics of the data, mean, standard deviation, median lowest, highest, frequency and ratio values were used. the distribution of the variables was measured with the kolmogorov simirnov test. mann-whitney u test was used for quantitative independent data analysis. chi-square test was used for the analysis of qualitative independent data and spss 22.0 (statistical package for the social sciences) program was used in the analysis. p value below 0.05 were considered statistically significant (p < 0.05). results as a result of the analysis of the data, upgrading was seen in 35 (44.8%) of 78 patients included in the study. the mean age of patients included in the study was 60.6 (± 4.4) years, and the mean psa was 6.0 (± 2.2) ng/ml. according to needle biopsy reports, 65 patients (83.3%) had a gs of (3 + 3) and 13 patients (16.7%) had (3 + 4). in cohort mean prostate volume was 49.8 (± 26.3) ml. twenty-two patients (28.2%) have prostate volume 30 ml or less, 34 (43.6%) 30 to 60 ml, and 22 (28.2%) 60 ml or more. the demographic and clinico-pathological table 1. demographics and clinico-pathological outcomes of the patients undergoing radical prostatectomy. range median mean+/-sd age 46.0+/-65.0 61.5 60.6+/-4.4 psa 2.3-10.0 5.7 6.0+/2.2 prostate volume 14-135 43.0 49.8+/-26.3 prostate volume 0-30 22 28.2% 31-60 34 43.6% >60 22 28.2% gleason score biopsy 3+3 65 83.3% 3+4 13 16.7% stage t2c 26 33.3% t2 52 16.7% n° positive cores i 31 39.7% ii 17 21.8% iii 30 38.5% gleason score specimen 3+3 38 48.7% 3+4 25 32.1% 4+3 9 11.5% 4+4 5 6.4% 4+5 1 1.3% upgrade (-) 43 44.8% (+) 35 55.1% table 2. comparison of the upgraded and non-upgraded groups. upgrade (-) upgrade (+) p mean median mean median age 59+/-4.8 61 61.4+/-3.8 62 0.183 m psa 5.8+/-2.2 5.4 6.2+/-2.2 5.9 0.529 m prostate volume 53.1+/-28 46 45.8+/-23.9 39 0.303 m prostate volume 0-30 12 27.9% 10 28.6% 0.604 x2 31-60 17 39.5% 17 48.6% > 60 14 32.6% 8 22.9% gs biopsy 3+3 35 81.4% 30 85.7% 0.611 x2 3+4 8 18.6% 5 14.3% n° positive cores i 18 41.9% 13 37.1% 0.747 x2 ii 8 18.6% 9 25.7% iii 17 39.5% 13 37.1% gs specimen 3+4 5 11.6% 20 57.1% 0.000 x2 4+3 0 0 9 25.7% 4+4 0 0 5 14.3% 4+5 0 0 1 2.9% m: mann-whitney u test; x²: chi-square test. outcomes of the patients included in the study are summarized in the table 1. the patients were divided into two groups as those with and without gs upgrading. in the analysis, no significant difference was observed between these groups in terms of age, psa values, biopsy gs, number of positive biopsy cores, clinical stage (p > 0.05). gs (3 + 3) was significantly higher in non-upgrading group (p > 0.05) (table 2). between the groups with different prostate volume (030/31-60/> 60) no significant difference was found (p value > 0.05) (table 2). discussion treatment options in prostate cancer differ according to defined risk groups. low risk patients have better prognosis than middle and high risk group and lower biochemical recurrence rates after radical prostatectomy. in these patients, active follow-up, brachytherapy and focal therapies are used in order to avoid the complications and side effects of radical prostatectomy or radiotherapy (17, 19-20). psa level, clinical stage and gs are used to determine these risk classification (21-22). gs is the most important prognostic factor of prostate cancer risk for classification and choice of treatment options (16, 22-23). accurate determination of patient's risk group and gs at the time of diagnosis is important in order to choose the appropriate treatment options. however, there are significant pathological differences between needle biopsies and radical prostatectomy specimens such as gs upgrading in 33-45%. this high rate led investigators to examine the factors that might be effective to predict upgrading. psa level, number of cores taken, number of positive cores are some of these factors. also there are several studies on the effect of prostate volume on gs upgrading. (10, 15, 24-27). in 2008 turley et al. investigated 586 patients retrospectively. in this study, gs elevation rate was found to be increased as prostate volume decreased (28). in a study that moon et al. reviewed 107 patients retrospectively demonstrating that 12 or less number of cores in the biopsy and prostate volume of 36.5 ml or less were a predictive factor of gs upgrading (15, 29). davies et al. published a retrospective study on prostate volume effect on gs upgrading in 2011. in this large study, medical records of 1.251 low-risk patients were retrospectively investigated and it was found that risk of gs upgrading was more than fifty percent in subjects with prostate volume 36 cm3 compared to those with 58 cm3 (16). similarly, chung et al., in a retrospective study of 247 patients published in 2013, reported that patients with prostate volumes of 25 cm3 or lower had a gs upgrading risk of 2.7 times more than patients with a prostate gland volume of 40 cm3 or more (15). however, in a retrospective study of 369 patients, kulkarni et al. reported no significant relationship between prostate volume and gs upgrading (18). gleason grade elevation is most important in active surveillance. however, a study that examined the effect of prostate volume on gs upgrading in active surveillance appropriate patients has not been previously mentioned in the literature. in this study, 78 patients with active monitoring were included. inclusion criteria were patient age under 65 years, psa level under 10 ng/ml, gs 3+3 or 3+4 and 3 or less positive cores, clinical stage ≤ t2. prostate volume effect on gs upgrading in active surveillance appropriate patients was examined, and patients with prostate volume of 30 ml or less, between 30 ml and 60 ml and greater than 60 ml were compared. according to our results prostate volume found to have no significant effect on gs upgrading in patients who are eligible for active surveillance. retrospective nature and small number size of this study, and the calculation of prostate dimensions by different clinicians were the limitations of our study. conclusions treatment alternatives in prostate cancer may differ according to risk groups. so that it is important to classify patients in the correct risk group. gleason grade upgrading causes patients to be classified in a lower risk group than they actually are, and may lead to inappropriate treatment. this situation has a direct effect on the decision of active surveillance. therefore, it is important to define the factors that can predict gs upgrading in active surveillance appropriate patients. in this study, we found that prostate volume has no significant effect on upgrading in active surveillance appropriate patients. compliance with ethical standards funding: this study was not funded. conflict of interest: all authors declare that they have no conflict of interest. ethical approval: all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent: informed consent was obtained from all individual participants included in the study. references 1. international agency for research on cancer (iarc) cancer fact sheets prostate cancer source globoscan 2018 http://globocan iarc fr/pages/fact_sheets_cancer aspx (20 march 2014, date last accessed). 2014. 2. humphrey p, schuz j. cancers of the male reproductive organs. world cancer report lyon: world health organization. 2014; pp 453-64. 3. thomsen fb, brasso k, klotz lh, et al. active surveillance for clinically localized prostate cancer––a systematic review. j surg oncol. 2014; 109:830-5. 4. loeb s, bruinsma sm, nicholson j, et al. active surveillance for 95archivio italiano di urologia e andrologia 2019; 91, 2 prostate volume and gleason score upgrading archivio italiano di urologia e andrologia 2019; 91, 2 e. çamur, a. coşkun, ö. kavukoğlu, utku can, ö. kara, a. develi çamur, k. sarıca, k. fehmi narter 96 prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. eur urol. 2015; 67:619-26. 5. ploussard g, isbarn h, briganti a, et al. (editors) can we expand active surveillance criteria to include biopsy gleason 3+ 4 prostate cancer? a multi-institutional study of 2,323 patients. urol oncol. 2015; 33:71.e1-9. 6. schiavina r, borghesi m, brunocilla e, et al. the biopsy gleason score 3 + 4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy gleason score 3 + 3: looking for larger selection criteria for active surveillance candidates. prostate cancer prostatic dis. 2015; 18:270-5. 7. bostwick dg, cheng l. urologic surgical pathology. 3 ed: elsevier/saunders; 2014. p. 408-531. 8. partin a. prostat tümörlerinin patolojisi in: yaman ö (ed.) campbell walsh üroloji 10 ed: saunders/günes tıp kitabevleri 2014: pp 2726-34. 9. epstein ji. diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy. mod path. 2004; 17:307-15. 10. freedland sj, kane cj, amling cl, et al. upgrading and downgrading of prostate needle biopsy specimens: risk factors and clinical implications. urology. 2007; 69:495-9 11. pinthus jh, witkos m, fleshner n, et al. prostate cancers scored as gleason 6 on prostate biopsy are frequently gleason 7 tumors at radical prostatectomy: implication on outcome. j urol. 2006; 176:979-84. 12. king cr, mcneal je, gill h, presti jc. extended prostate biopsy scheme improves reliability of gleason grading: implications for radiotherapy patients. int j radiat oncol biol phys. 2004; 59:38691. 13. emiliozzi p, maymone s, paterno a, et al. increased accuracy of biopsy gleason score obtained by extended needle biopsy. j urol. 2004; 172:2224-6. 14. san francisco if, dewolf wc, rosen s, et al. extended prostate needle biopsy improves concordance of gleason grading between prostate needle biopsy and radical prostatectomy. j urol. 2003; 169:136-40. 15. chung ms, lee sh, lee dh, chung bh. is small prostate volume a predictor of gleason score upgrading after radical prostatectomy? yonsei med j. 2013; 54:902-6. 16. davies jd, aghazadeh ma, phillips s, et al. prostate size as a predictor of gleason score upgrading in patients with low risk prostate cancer. j urol. 2011; 186:2221-7. 17. kim kh, lim sk, shin ty, et al. upgrading of gleason score and prostate volume: a clinicopathological analysis. bju int. 2013; 111:1310-6. 18. kulkarni gs, al-azab r, lockwood g, et al. evidence for a biopsy derived grade artifact among larger prostate glands. j urol. 2006; 175:505-9. 19. partin aw, yoo j, carter hb, et al. the use of prostate specific antigen, clinical stage and gleason score to predict pathological stage in men with localized prostate cancer. j urol. 1993; 150:1104. 20. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 21. mottet n, bellmunt j, briers e, et al. diagnostic evaluation. eau-estro-siog guidelines on prostate cancer. eau guidelines office. arnhem, the netherlands, 2016, pp 14-27. 22. d’amico av, moul j, carroll pr, et al. cancer specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. j clin oncol. 2003; 21:2163-72. 23. zincke h, bergstralh ej, blute ml, et al. radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. j clin oncol. 1994; 12:2254-63. 24. kulkarni gs, lockwood g, evans a, et al. clinical predictors of gleason score upgrading. cancer. 2007; 109:2432-8. 25. hong sk, han bk, lee st, et al. prediction of gleason score upgrading in low-risk prostate cancers diagnosed via multi (≥ 12)core prostate biopsy. world j urol. 2009; 27:271-6. 26. miyake h, kurahashi t, takenaka a, et al. improved accuracy for predicting the gleason score of prostate cancer by increasing the number of transrectal biopsy cores. urol int. 2007; 79:302-6. 27. moussa as, li j, soriano m, et al. prostate biopsy clinical and pathological variables that predict significant grading changes in patients with intermediate and high grade prostate cancer. bju int. 2009; 103:438. 28. turley rs, hamilton rj, terris mk, et al. small transrectal ultrasound volume predicts clinically significant gleason score upgrading after radical prostatectomy: results from the search database. j urol. 2008; 179:523-8. 29. moon sj, park sy, lee ty. predictive factors of gleason score upgrading in localized and locally advanced prostate cancer diagnosed by prostate biopsy. korean j urol. 2010; 51:677-82. correspondence emre çamur, md (corresponding author) emre.camur@outlook.com amasya university sabuncuoglu serefeddin training and research hospital urology department, amasya (turkey) alper coşkun, md dr.alper05@gmail.com sanlıurfa training and research hospital urology clinic, sanlıurfa (turkey) övünç kavukoğlu, md ovunckavukoglu@hotmail.com gumushane state hospital urology clinic, gumushane (turkey) utku can, md utkucan99@yahoo.com erzurum training and research hospital urology clinic, erzurum (turkey) önder kara, md onerkara@yahoo.com kocaeli university medical faculty hospital urology clinic, kocaeli (turkey) arzu develi çamur, md develiarzu@hotmail.com suluova state hospital, internal medicine clinic, amasya (turkey) kemal sarıca, md saricakemal@gmail.com kafkas university training and research hospital urology clinic, kars (turkey) kamil fehmi narter, md fehminarter66@gmail.com acıbadem university hospital urology clinic, istanbul (turkey) archivio italiano di urologia e andrologia 2017; 89, 3192 original paper a randomized study to assess the efficacy of herbal product to prevent cisplatin-induced nephrotoxicity in a rat model eyup veli kucuk 1, ahmet bindayi 2, meral mese 3, funda gulcu bulmus 3, ergun parmaksız 3, ali cihangir cetinel 4, zerrin bicik bahcebasi 3, kemal sarica 4 1 umraniye training and research hospital urology clinic, istanbul, turkey; 2 bahcesehir university department of urology, istanbul, turkey; 3 dr. lütfi kirdar training and research hospital nephrology clinic, istanbul, turkey; 4 dr. lütfi kirdar training and research hospital urology clinic, istanbul, turkey. objectives: this study aimed to investigate the protective effect and antioxidant activity of an herbal product that made from multiple plants in a rat model of kidney dysfunction induced by intraperitoneal cisplatin. materials and methods: twenty-four rats were divided into four different groups namely: group 1 control healthy animals without any specific medication, group 2 herbal product only 5 mg/kg, group 3 cisplatin only and group 4 herbal product 5 mg/kg + cisplatin. results: evaluation of our findings demonstrated a significant (p = 0.017) reduction in catalase activities and a significant increase (p = 0.001) in renal tissue malondialdehyde levels in cisplatintreated rats when compared with the control group. also, glutathion and glutathione peroxidase content revealed significant (p = 0.031) reduction in renal tissues of cisplatintreated rats compared with the control group. pre-treatment of rats with the herbal product ameliorated these cisplatininduced changes of the antioxidant enzymes. no statistically significant changes were demonstrated in superoxide dismutase activities in the tissue specimens of any group. conclusions: this potent antioxidant herbal medicine was found to have potential antioxidant activity, which may in turn to be effective in the protection of kidney tissue resulting from cisplatin application. therefore, much attention should be given to the possible role of natural dietary antioxidants for protecting the kidney. key words: animal model; antioxidants; cisplatin; herbal medicine; nephrotoxicity. submitted 30 may 2017; accepted 2 july 2017 summary no conflict of interest declared. ovary (1). of these side effects, nephrotoxicity is the most well-known, established and clinically important toxicity of this drug (2). over the last few decades, different studies were made to investigate the pathophysiological basis of cisplatininduced nephrotoxicity and how to protect kidney from this toxicity. these studies demonstrated number of mechanisms including oxidative stress, dna adducts, inflammation, mitochondrial dysfunction, and direct cytotoxicity to the tubular epithelial cells (2-4). also literature revealed that cisplatin® application might cause renal vasoconstriction that reduces blood flow, causing ischemic damage to the kidney and deteriorate the glomerular filtration rate. these alterations eventually trigger ischemia-induced oxidative stress, a well-known phenomenon that ultimately results in renal tubular cell injury and death. cisplatin® administration in a mice model resulted in marked renal failure characterized by a significant increase in serum urea and creatinine levels due to the formation of oxidative stress as indicated by increased lipid peroxidation and decreased levels of glutathione (gsh), glutathione peroxidase (gshpx), superoxide dismutase (sod) and catalase in renal tissues (5, 6). being aware of the well-known side effects of cisplatin® on the functional and morphological integrity of the kidneys, physicians began to look for protective agents to prevent or at least limit the extent of the renal toxic effects of cisplatin® based chemotherapy. related to this issue, evaluation of literature data demonstrated that asag or tmg, lutein, ascorbic acid and alpha tocopherol may reduce cisplatin-induced renal toxicity either by limiting the extent of renal functional deterioration or increasing the antioxidant capacity of the kidneys (3, 4, 7, 8). on the other hand, in addition to the use of these medical agents, recent data demonstrated that phytotherapy might prevent toxic effects of certain medications causing morphologic as well as functional changes in different organ systems (3, 4, 8-10). in this study, we investigate the potential renoprotective effects of a herbal medication (tutukon®) on cisplatin-induced oxidative stressrelated nephrotoxicity in a rat model. doi: 10.4081/aiua.2017.3.192 introduction despite their well-established curative effects in certain solid organ tumors, chemotherapeutic agents may exhibit dose dependent toxic effects during the course of chemotherapy on certain organ systems, a reality that should inevitably be taken into account by all physicians. cisplatin® (cis-diamminedichloroplatinum ii) is one of the most widely used chemotherapeutic drugs for the treatment of various solid tumors, including those of the breast, head, neck, lung, testis, bladder and kucuk_stesura seveso 28/09/17 10:17 pagina 192 193archivio italiano di urologia e andrologia 2017; 89, 3 prevention of cisplatin nephrotoxicity methods animals this study was made with 24 male wistar white rats, each weighing 250-300 g. ethical committee approval (no: 94-14/2013) was obtained from the animal laboratory of the pendik animal research laboratory (istanbul, turkey) and all procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. all animals were fed standard chow and kept under normal room conditions at a constant temperature (25°c) under a 12 hours light/dark cycle. rats underwent a complete physical examination, biochemical evaluation including blood and urine analyses and stool examination. we estimated that total of 24 subjects would be needed to detect difference among groups with α of 0.05 and a (1-β) of 80%. rats randomly divided into four groups (each with n = 6): group 1 (control group) received only standard rat chow and distilled drinking water without any specific medication. group 2 (tutukon® group) received an herbal product (tutukon®) given via a feeding catheter (20 ml/kg). group 3 (cisplatin group) received cisplatin® only (7.5 mg/kg once i.p.). group 4 (tutukon® + cisplatin® group) received a combined medication (20 ml/kg of tutukon® for seven days + 7.5 mg/kg cisplatin® i.p. after seven days for once). control group animals received only distilled drinking water during all study phases. after two weeks bilateral nephrectomy was performed with bilateral flank incision. all surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering. main chemicals and drugs cisplatin® was used to induce nephrotoxicity in rats according to the method of prabhu et al. (11). applied dose was 7.5 mg/kg rat body weight (intraperitoneal). plant-based herbal medication (tutukon®) fixed-dose combination. dosage form: hydrolate, bottles of 600 ml, 45 ml three times/daily. ingredients: essential oils, flavonoids-quercetin, polysaccharides, rosemarinic acid, boldin, flavonglicozides. composition (per 100 ml of solution): enguisetumarvensis 570 mg, sper gularia rubra 330 mg, peumusboldus 280 mg, opuntiaficusindica 170 mg, sideritisan gu stifolia 170 mg, rozmarinusofficinales 170 mg, cyno dondaktylon 170 mg, melissa officinalis 170 mg. measurement of malondialdehyde (mda) and glutathione levels, superoxide dismutase (sod) and catalase (cat) activities in renal homogenate the homogenization of tissues was carried out in a teflon-glass homogenizer with a buffer containing 1.15% kcl to obtain 1/10 (w/v) whole homogenate. mda levels were directly measured in the homogenates. the homogenates were centrifuged for 30 min at 25000 g at +4°c to determine gsh-px and cat activities. the obtained supernatants were centrifuged again at 25000 g, +4°c for 30 min to determine sod activities. the mda concentrations of tissue homogenates were measured according to a modified method from ohkawa et al. (12) based on the reaction with tba and the results were expressed as nmol/g protein. the gsh-px activities were determined according to the method of beutler, (13) which records the disappearance of nadph at 340 nm, and results were expressed as u/g protein. the cat activities were determined by measuring the decomposition of hydrogen peroxide at 240 nm, according to the method of aebi (14). the results were expressed as k/g protein, where k is the first-order rate constant. sod activities were determined using the method of sun et al. (15) and the results were expressed as u/g protein. tissue gsh concentrations were measured by an assay using the dithionitrobenzoic acid recycling method described by elman (16) and expressed as nmol/mg protein. protein concentrations were measured according to lowry et al. (17). statistical analysis for statistical analysis of the obtained data ncss (number cruncher statistical system) 2007&pass (power analysis and sample size) 2008 statistical software (utah, usa) program was used. the data was expressed in mean +/standard deviation. mann-whitney u and kruskal-wallis tests were used to compare the parameters between two or more groups that don't fit to normal distribution. a p value of < 0.05 was considered as significant. results evaluation of the tissue enzyme levels demonstrated the following findings (figure 1). figure 1. mda, cat, gsh-px and kidney gsh levels according to the groups. kucuk_stesura seveso 28/09/17 10:17 pagina 193 archivio italiano di urologia e andrologia 2017; 89, 3 e. veli kucuk, a. bindayi, m. mese, f. gulcu bulmus, e. parmaksız, a. cihangir cetinel, z. bicik bahcebasi, k. sarica 194 mda: there were statistically significant differences among groups regarding levels of mda (p < 0.001) (table 1). there was a significant increase in renal tissue mda levels in cisplatin-treated rats (cisplatin® only or tutukon® + cisplatin®) compared with the control and tutukon® groups (p < 0.05). there was no statistically significant difference with respect to mda levels between the tutukon® and control groups. lastly, although not statistically significant, renal tissue mda levels of the tutukon + cisplatin® group were found to be comparably lower than the cisplatin® group (p = 0.055) (table 2). sod: there were no statistically significant differences among groups regarding sod activities (p > 0.05) (table 1 and 2). cat: cat activity of the cisplatin-treated rats (cisplatin® only or tutukon® + cisplatin®) was lower than the other groups (figure 1). the combined medication group showed significantly lower cat activity than the control and tutukon® groups (p = 0.025, p = 0.016, respectively). according to comparative studies, cat activity of the cisplatin® group was significantly lower than the control group (p = 0.037). it was also found to be lower but not statistically significant than the tutukon® group (p = 0.055) (table 2). gsh-px: there was statistically significant difference of gsh-px levels among groups (p = 0.031) (table 1). according to dual-comparison of the groups, gshpx levels in the cisplatin® group showed significant reduction compared with tutukon® and combined medication groups (p = 0.037, p = 0.016, respectively) (table 2). gsh: there were statistically significant differences among groups for gsh levels (p = 0.007) (table 1). according to dual comparison results, gsh levels of the cisplatin® group were significantly lower than the tutukon® and combined medication groups (p = 0.010, p = 0.037, respectively) (table 2). discussion cisplatin® is a chemotherapeutic agent widely used for the treatment of various solid cancers. however, nephrotoxicity is one of the major side effects of cisplatin® and published data have shown that an estimated 20% of patients receiving high-dose cisplatin® suffer severe renal dysfunction and approximately one third of patients may experience kidney injury following initial treatment (18, 19). renal tubular injury and cell death are the most prominent pathologic findings originating from reduced blood flow (ischemia) induced oxidative stress in renal tubular cells following the application of this agent. in literature, several mechanisms were documented to be important in renal tubular injury. yonazewa et al. showed that organic cation transporter 2 (oct2) mediates the entry of cisplatin® into the renal tubular cells and stimulate the sensitivity of cisplatin® in these cells. cisplatin® reduces the activity of mitochondrial respiratory complexes, resulting in reactive oxygen species (ros) generation (20). the other mechanism of generation of reactive oxygen species is depletion of endogenous antioxidant, glutathione. cisplatin® may damage the kidney by depletion of critical sulfhydryl centers, including gsh inside the cells, and may provoke damage to the cell by generating a cascade of lipid membrane peroxidation, mitochondrial dysfunction and dna injury which reduces the internal antioxidant storages (21, 22). likewise in our study we found that cisplatin® treatment decreased gsh, gshpx levels, cat activites and increased mda levels. thus, all these findings clearly have shown that cisplatininduced generation of ros, cytokines and chemokines are directly related to its cytotoxicity. ros produce by the xanthine-xanthine oxidase system, mitochondria, and nadph oxidase in cells. following treatment with cisplatin®, ros that produced throughout these systems, are implicated in the pathogenesis of acute renal injury (22). related to this subject, in their original study both maliakel and atasayar et al. showed that administration of asag or tmg markedly reduced the cisplatininduced higher plasma creatinine and urea levels and counteracted the deleterious effects of formed oxidative stress markers by protecting the renal tissue from the cisplatin-induced lipid peroxidation (3, 7). in another study, sindhu and kuttan applied lutein, a non-toxic carotenoid with strong antioxidant activity, to reduce cisplatin-induced renal damage in mice. as shown by the reduction of serum urea and creatinine levels, nephrotoxicity, origitable 1. the evaluation of mda, sod, cat, gsh-px and kidney gsh. mda sod cat gsh-px kidney gsh (nmol/g protein) (u/g protein) (k/g protein) (u/g protein) (nmol/mg protein) mean ± sd mean ± sd mean ± sd mean ± sd mean ± sd control 18.62 ± 2.21 50.87 ± 9.22 30.22 ± 11.3 30.21 ± 8.87 7.76 ± 1.56 tutukon® 19.89 ± 3.73 48.55 ± 10.56 26.90 ± 4.99 32.02 ± 5.79 6.68 ± 1.49 cisplatin® 35.47 ± 7.04 38.75 ± 16.62 14.86 ± 10.63 22.14 ± 7.95 4.19 ± 0.82 tutukon® + cisplatin® 27.10 ± 4.95 47.19 ± 18.59 16.30 ± 4.85 35.45 ± 6.02 5.85 ± 1.41 ap 0.001** 0.667 0.017* 0.031* 0.007** akruskal -wallis test; **p < 0.01; *p < 0.05. table 2. dual comparison of groups. mda sod cat gsh-px kidney gsh group 1 vs group 2b 0.749 0.749 0.522 0.631 0.262 group 1 vs group 3b 0.004** 0.200 0.037* 0.109 0.006** group 1 vs group 4b 0.006** 0.873 0.025* 0.262 0.055 group 2 vs group 3b 0.004** 0.337 0.055 0.037* 0.010* group 2 vs group 4b 0.037* 0.873 0.016* 0.337 0.423 group 3 vs group 4b 0.055 0.522 0.109 0.016* 0.037* bmann whitney u test; **p < 0.01; *p < 0.05. group 1: control; group 2: tutukon®; group 3: cisplatin®; group 4: tutukon® + cisplatin® (combined medication). kucuk_stesura seveso 28/09/17 10:17 pagina 194 195archivio italiano di urologia e andrologia 2017; 89, 3 prevention of cisplatin nephrotoxicity nating from reduced activity of the antioxidant enzymes in the kidney (sod, as well as cat) and increased mda levels, was reduced by lutein treatment (4). the results of this study showed that lutein might effectively protect the kidneys of mice treated with cisplatin®, which was also supported by the histopathologic evaluation of the kidney tissues of the treated animals. last but not least, ajith et al. gave 250 mg/kg or 500 mg/kg vitamins (ascorbic acid and alpha tocopherol) to their subjects to protect from the nephrotoxicty induced by cisplatin® and they found that 500 mg/kg vitamins significantly protected the kidneys. however, the protective effect of vitamins from the cisplatin induced decline of activities of renal antioxidant enzymes such as sod, cat, gshpx noted only in 500 mg/kg dosage group. additionally, authors have observed that both vitamins at dosages of 250 and 500 mg/kg could increase the concentration of reduced gsh and limit the extent of cisplatin-induced lipid peroxidation (8). recent data showed that herbal medicine might prevent some toxic effects of certain medications (3, 4, 8-10). phytotherapy on this aspect may be applied in a complementary fashion to ameliorate these effects. majority of these phytotherapeutic agents have diuretic, anti-inflammatory, antioxidant and vasodilating effects. the active ingredients like essential oils, flavonoids, saponins, xanthine derivatives and glycosides were found responsible of these protective effects (23-25). in a study, administration of plant extract mixtures produced improvements in biochemical, histopathological and cytogenetic parameters (26). other similar studies focused on the possible protective effects of plant extracts with certain ingredients demonstrating the protective effects on both the kidney as well as their specific protective effects on other pathologies in different organ systems (27, 28). antioxidant, diuretic and antidiabetic effects of such agents also might be effective in limiting the toxic effects induced by cisplatin® administration. taking into account the established effects of antioxidants as well as anti-inflammatory agents in the prevention of ischemia-induced injury in renal tubular epithelium, we aimed to evaluate the possible limitation of the extent of oxidative stress resulting from cisplatininduced toxicity by using a potential antioxidant and anti-inflammatory agent (tutukon®) in a rat model. tutukon® (grand medical, spain) is a medication composed of different herbal ingredients demonstrating certain biological effects in tissues. among these effects, the antioxidant potential is one of the most important characteristics of this drug due to its active ingredients. among the eight different ingredients of tutukon®, alkaloids rosmarinic acid, flavonoids, apigenin, luteolin, ekvizetonin saponin, and essential oils are well known for their antioxidant as well as anti-inflammatory effects shown in different studies (23, 25, 29). regarding the mechanism of action, studies showed that these active ingredients may reduce the permeability of kidney capillaries, dilate kidney blood vessels and ureters, restore the tubular epithelial function, induce an osmotic effect, inhibit synthesis and activation of inflammatory mediators and thus prevent inflammatory alterations (24, 30). our current findings clearly showed that pre-treatment with this herbal product also might significant reduction in mda levels and significant elevation of cat activities and gsh levels of the renal tissues in cisplatin-treated rats. evaluation of the antioxidant enzyme (catalase and gshpx) content revealed significant reduction in renal tissues of cisplatin-treated rats compared with the control group as well as in the groups receiving tutukon®. these findings may provide evidence of the antioxidant effect of tutukon® against cisplatin-induced oxidative stress and lipid peroxidation. parallel to the data reported in the literature so far, we found that reduction in the activity of antioxidant enzyme (cat), increased lipid peroxidation (mda) and depletion of gsh in renal tissues were implicated in the pathogenesis of cisplatin® nephrotoxicity. our results also showed that ischemia-induced oxidative stress in renal tubules as well as the inflammatory changes might be the major underlying causes of cisplatin-induced renal functional as well as morphologic deterioration. tutukon® with its potent ingredients may be protective in the limitation of such alterations at least in experimental models. as a conclusion, tutukon® showed an ameliorative effect against cisplatin-induced oxidative stress and renal damage through its antioxidant, anti-inflammatory and antiapoptotic properties. due to the potential antioxidant activity, medicinal plants and natural herbal products like tutukon® may be used as natural dietary antioxidants in protecting the kidney from damage originating from certain chemical agents. however, further studies with larger series of patients under clinical conditions are certainly needed. references 1. miller rp, tadagavadi rk, ramesh g, et al. mechanisms of cisplatin nephrotoxicity. toxins. 2010; 2:2490-518. 2. karasawa t, steyger ps. an integrated view of cisplatin-induced nephrotoxicity and ototoxicity. toxicol lett. 2015; 237:219-27. 3. maliakel dm, kagiya tv, nair ck. prevention of cisplatininduced nephrotoxicity by glucosides of ascorbic acid and alphatocopherol. exp toxicol pathol. 2008; 60:521-7. 4. sindhu er, kuttan r. carotenoid lutein protects the kidney against cisplatin-induced acute renal failure. j environ pathol toxicol oncol. 2013; 32:21-8. 5. kruidering m, van de water b, de heer e, et al. cisplatininduced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes i to iv of the respiratory chain. j pharmacol exp ther. 1997; 280:638-49. 6. malik s, suchal k, gamad n, et al. telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting mapk mediated inflammation and apoptosis. eur j pharmacol. 2015; 748:54-60. 7. atasayar s, gurer-orhan h, orhan h, et al. preventive effect of aminoguanidine compared to vitamin e and c on cisplatin-induced nephrotoxicity in rats. exp toxicol pathol. 2009; 61:23-32. 8. ajith ta, usha s, nivitha v. ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study. clin chim acta. 2007;375:82-6. 9. naqshbandi a, rizwan s, khan mw, et al. dietary flaxseed oil kucuk_stesura seveso 28/09/17 10:17 pagina 195 archivio italiano di urologia e andrologia 2017; 89, 3 e. veli kucuk, a. bindayi, m. mese, f. gulcu bulmus, e. parmaksız, a. cihangir cetinel, z. bicik bahcebasi, k. sarica 196 supplementation ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine. hum exp toxicol. 2013; 32:385-94. 10. razo-rodriguez ac, chirino yi, sanchez-gonzalez dj, et al. garlic powder ameliorates cisplatin-induced nephrotoxicity and oxidative stress. j med food. 2008; 11:582-6. 11. prabhu vv, kannan n, guruvayoorappan c. 1,2-diazole prevents cisplatin-induced nephrotoxicity in experimental rats. pharmacol rep. 2013; 65:980-90. 12. ohkawa h, ohishi n, yagi k. assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. anal biochem. 1979; 95:351-8. 13. beutler e. red cell metabolism: a manual of biochemical methods. 2d ed. new york: grune & stratton; 1975. 14. aebi h. catalase in vitro. methods enzymol. 1984; 105:121-6. 15. sun y, oberley lw, li y. a simple method for clinical assay of superoxide dismutase. clin chem. 1988; 34: 497-500. 16. ellman gl. tissue sulfhydryl groups. arch biochem biophys. 1959; 82:70-7. 17. lowry oh, rosebrough nj, farr al, et al. protein measurement with the folin phenol reagent. j biol chem. 1951; 193:265-75. 18. yang y, liu h, liu f, et al. mitochondrial dysregulation and protection in cisplatin nephrotoxicity. arch toxicol. 2014; 88:1249-56. 19. fukasawa h, furuya r, yasuda h, et al. anti-cancer agentinduced nephrotoxicity. anticancer agents med chem. 2014; 14:921-7. 20. yonezawa a, masuda s, nishihara k, et al. association between tubular toxicity of cisplatin and expression of organic cation transporter roct2 (slc22a2) in the rat. biochem pharmacol. 2005; 70:1823-31. 21. levi j, jacobs c, kalman sm, et al. mechanism of cis-platinum nephrotoxicity: i. effects of sulfhydryl groups in rat kidneys. j pharmacol exp ther. 1980; 213:545-50. 22. arany i, safirstein rl. cisplatin nephrotoxicity. semin nephrol. 2003; 23:460-4. 23. zadra m, piana m, brum tf, et al. antioxidant activity and phytochemical composition of the leaves of solanum guaraniticum a. st.-hil. molecules. 2012; 17:12560-74. 24. calixto jb, santos ar, cechinel filho v, et al. a review of the plants of the genus phyllanthus: their chemistry, pharmacology, and therapeutic potential. medicinal res rev. 1998; 18:225-58. 25. wang h, yang l, zu y, et al. microwave-assisted simultaneous extraction of luteolin and apigenin from tree peony pod and evaluation of its antioxidant activity. scientificworldjournal. 2014; 2014:506971. 26. al-okbi sy, mohamed da, hamed te, et al. prevention of renal dysfunction by nutraceuticals prepared from oil rich plant foods. asian pac j trop biomed. 2014; 4:618-27. 27. conner ta, mcquade c, olp j, et al. effect of intravenous vitamin c on cytokine activation and oxidative stress in end-stage renal disease patients receiving intravenous iron sucrose. biometals. 2012; 25:961-9. 28. mimica-dukic n, simin n, cvejic j, et al. phenolic compounds in field horsetail (equisetum arvense l.) as natural antioxidants. molecules. 2008; 13:1455-64. 29. xi m, hai c, tang h, et al. antioxidant and antiglycation properties of total saponins extracted from traditional chinese medicine used to treat diabetes mellitus. phytother res. 2008; 22:228-37. 30. calixto jb, yunes ra, neto as, et al. antispasmodic effects of an alkaloid extracted from phyllanthus sellowianus: a comparative study with papaverine. braz j med biol res. 1984; 17:313-21. correspondence eyup veli kucuk, md eyupveli@gmail.com umraniye training and research hospital urology clinic, istanbul, turkey ahmet bindayi, md, febu ahmetbindayi@gmail.com bahcesehir university department of urology, istanbul, turkey meral mese, md mesemeral@gmail.com funda gulcu bulmus, md fundagulcu@yahoo.com.tr ergun parmaksız, md drergnprmksz@hotmail.com zerrin bicik bahcebasi, md zerrinbicik@yahoo.com dr. lütfi kirdar training and research hospital nephrology clinic, istanbul, turkey ali cihangir cetinel, md cihangircetinel@gmail.com kemal sarica, md saricakemal@gmail.com dr. lütfi kirdar training and research hospital urology clinic, istanbul, turkey kucuk_stesura seveso 28/09/17 10:17 pagina 196 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper men, bladder cancer accounts for 70.7 cases per 100,000, while women account for 16.3 cases per 100,000 and it accounts for 3.6 per cent of all cancer mortalities (4.9 per cent men and 1.8 per cent women). the main risk factors include age, gender (men are considered to be at higher risk), smoking, exposure to chemicals; certain drugs used in cancer treatment, such as cyclophosphamide; chronic bladder inflammation such as urinary infections or cystitis; family history (4). there are various types of treatment including open, laparoscopic, and robotic surgery, immunotherapy, chemotherapy, and radiotherapy (5). surgery is the primary treatment for bladder cancer. depending on the patient's clinical need, bladder cancer surgery may include removal of the tumour from the bladder wall by cystoscopy (tur-v) or removal of the entire bladder (radical cystectomy). patients undergoing radical cystectomy may be candidates for bladder and urinary tract reconstruction or urinary diversion surgery. patients undergoing radical cystectomy (rc) and ileal conduit must learn to manage an ostomy that requires daily care, manual skills and must cope with the psychosocial impacts that accompany urostomy placement. maintaining patients' good quality of life (qol) depends largely on the caregiver's preparation and management skills (6). in this regard, before and after surgery, nursing and medical staff teach the patient and caregivers how to manage the new physical condition (4). the caregiver's role is of crucial importance; they will be entrusted to follow their relative's assistance at home, throughout the complete clinical and rehabilitation process (7). unfortunately, many caregivers are not adequately prepared to cope with the physical and psychological changes of post-cystectomy life and this leads to worsen the patients' quality of life (8). the aim of this study is to examine caregivers' experiences and training needs after radical cystectomy with urinary diversion for the first three months following the patient's discharge. our study is the first of its kind in italy, and it focuses exclusively on the three-month period at home, following discharge. objective: to examine caregivers' experiences and training needs after radical cystectomy with urinary diversion for the first three months following the patient's discharge. methods: this study applied a phenomenological design approach through open-ended interviews and descriptive analysis. phenomenology applied to empirical research requires researchers to explore the empirical facts narrated by participants. this study followed the consolidated criteria for reporting qualitative research guidelines, a 32 – item checklist for interviews and focus groups. the study population included caregivers of bladder cancer patients, admitted to three italian hospitals. data were collected between march 2020 and march 2022. results: fifty-two caregivers of patients who underwent cystectomy with urinary diversion from three italian hospitals (41 males and 11 females) participated to the study. the data analysis converged in the identification of three themes – with sub-themes – that included various aspects of the caregiver’s lived experiences: 1) living with the burden of being indispensable, for the family member, 2) feeling abandoned by institutions, 3) tiredness and less willingness to look after the relative due to work burden. conclusions: our study demonstrates that the caregiver of a patient with bladder cancer and urostomy in the first three months of hospital discharge is very worried and stressed. despite the training program received in hospital, the caregiver does not recognize the newly acquired skills and has difficulty applying them. further study would be required. key words: bladder cancer; caregiver burden; quality of life; urostomy. submitted 20 november 2022; accepted 22 november 2022 introduction a bladder neoplasia is a malignant tumour that forms in the bladder wall (1). worldwide, it is the ninth most common tumour and the most frequent of the genitourinary tract (2), while it accounts for (3, 4) per cent of all malignancies (america cancer society). it also ranks fourth among all malignant tumours affecting men and eighth among those affecting women (3). according to the italian society cancer registry (airt) every year among management of the patient with urostomy: caregiver needs during the three months after discharge. a qualitative study tatiana bolgeo 1, federico ruta 2, denise gatti 1, francesca gambalunga 3, laura iacorossi 4, roberta di matteo 1, salvatore cotroneo 5, carmelo boccafoschi 6, antonio maconi 1 1 department of research and innovation azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy; 2 general direction, asl bat (health agency), andria, italy; 3 department of biomedicine and prevention, university of rome “tor vergata”, rome, italy; 4 national cancer institute “regina elena”, rome, italy; 5 sc urology, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy; 6 city of alessandria clinic monza polyclinic, alessandria, italy. doi: 10.4081/aiua.2023.11024 summary archivio italiano di urologia e andrologia 2023; 95, 1 t. bolgeo, f. ruta, d. gatti, f. gambalunga, l. iacorossi, r. di matteo, s. cotroneo, c. boccafoschi, a. maconi material and methods design this study applied a phenomenological design approach through open-ended interviews and descriptive analysis (9, 10). according to mortari (10), phenomenology applied to empirical research requires researchers to explore the empirical facts narrated by participants. the research questions focused on caregivers' experiences while caring for a family member with bladder cancer, who underwent radical cystectomy surgery with urostomy, during the 3 months following discharge. the study followed the consolidated criteria for reporting qualitative research (coreq) guidelines, a 32 – item checklist for interviews and focus group (11). this research was approved by the ethical committee of ss antonio e biagio e cesare arrigo hospital, alessandria, italy and data collection took place between march 2020 and march 2022. participants this study employed targeted sampling. the study population included caregivers of bladder cancer patients, who underwent radical cystectomy surgery with the creation of an urostomy in three italian hospitals, willing to share their experiences after their family member's hospital discharge. a minimum of 10 caregivers from each hospital were invited to participate, and recruitment continued until data saturation. caregiver recruitment took place at the hospital during patient discharge to facilitate collection of the caregivers’ experience in the daily management of the disease during the three months following discharge. the inclusion criteria were knowledge of the italian and english language, as well as experience in home care giving. the physicians and nurses in charge and working in the hospital unit made the initial contact with caregivers at least 48 hrs. before researchers, to ensure that the potential participants had enough time to consider their involvement (12). caregivers also received a leaflet, outlining the study's principles and inviting their participation. we agreed on this approach, as it was felt that presence of the patient could jeopardise the participant’s willingness to be open about some of the more negative aspects of caregiving and thus impact on our aim of obtaining in-depth and richly diverse experiences from the caregivers. participants provided written informed consent prior to enrolment, and they provided written informed consent to have their anonymized data presented or published. data collection the study setting was represented by the following hospitals: aou policlinico bari, puglia; azienda ospedaliera alessandria, piedemont; clinica città di alessandria, piedmont. the data was collected through a semi-structured open-ended interview; according to this type of interview the caregivers were able to describe their experiences according to how and what they thought essential to share. the interviews were conducted by rf (male, phd msn, rn), tb (female, phd, msn, rn) and (cb male rn, msn). the interviews were in part face-to-face within the hospital and in part by telephone. each participant chose between the two methods according to their personal needs. for the caregivers who choose face-toface interviews, a room within the hospital facility was available to maintain the confidentiality and the serenity necessary to share their story. the interviews were audiorecorded and verbatim transcribed by the interviewer. a total of 52 interviews were conducted (the time ranged from 30 to 60 minutes) (table 1). data analysis all interviews were transcribed verbatim by nvivo 12 and subsequently reviewed by nurse research scientists tb (rn phd) and fr (rn, phd). interviews were analysed using colaizzi’s (1978) descriptive analysis framework revisited by mortari (2019), which included the following steps: (1) in-depth reading of the transcripts to gain a deeper understanding and meaning of what was being said, by three researchers (tb, fr, cb); (2) extraction of meaningful descriptions provided by participants (tb, fr); (3) re-formulation of meanings into sub-themes and themes (tb, fr); (4) construction of themes’ descriptions of empirical-phenomenological qualities (tb, fr); (5) sharing results with participants for verification (tb, fr); (6) integration of the results into a complete description, i.e. the definition of general statements to summarise the participants' lived experience. the qualitative research data analysis software nvivo (12) was used for data management. table 1. caregiver semi-structured interviews. did the healthcare staff regarding the postoperative management of your family member, provide useful explanations and advice? at discharge, did you have any doubts about the management of the necessary guardianship for your family member? has your life changed from before surgery? could you describe what your typical day is like now? have you ever thought about going to the accident and emergency unit (a&e) in case of difficulty? what are the major difficulties encountered in the three months following discharge? table 2. caregiver socio-demographic characteristics. characteristics caregivers n = 52 age range 27-73 gender male 41 female 11 educational level elementary 28 lower intermediate 15 upper intermediate 7 bachelor’s degree 2 occupation employed full time 26 employed part time 7 unemployed 3 retired 16 relationship with patient spouse 34 daughter 6 son 12 home same 42 different 10 archivio italiano di urologia e andrologia 2023; 95, 1 map-uro results fifty-two caregivers of patients who underwent cystectomy with urinary diversion in three italian hospitals (41 males and 11 females) participated in the study. their socio-demographic characteristics is shown in table 2. the data analysis converged in the identification of three themes – with sub-themes – that include various aspects of the caregiver’s experiences: 1) living with the burden of being indispensable, for the family member, 2) feeling abandoned by institutions, 3) tiredness and less willingness to look after the relative due to work. theme 1: living with the burden of being indispensable to the family member this theme describes the burden the caregiver experiences after discharge. returning home and managing the family member alone, causes insecurity and increases the burden of the caregivers and awareness of their own abilities and limits. disease management involves the development of skills that the caregiver did not previously possess. returning home after discharge involves taking full personal custody of the family member, increasing the burden of responsibility. replacing professional healthcare staff involves the fear of making mistakes and causing harm. two subthemes have been identified, a) "i am not a healthcare professional" and b) "i am afraid of making mistakes." sub-theme 1a: "i am not a healthcare professional" during hospitalization, the patient identified and named his caregiver, who participated in an educational training program that included several meetings with doctors and nurses to plan for possible difficulties to be faced while managing the stoma at home. the caregivers in hospital feel secure and are confident that they are capable of coping with the post-discharge process. at home, however, the situation does not reflect the same feelings: “the problem is that at home i don't have the opportunity to compare myself with someone who understands .... i'm alone” (c6cf), “i am not a nurse and i do not know what to do sometimes ..... i get anxious ... i am afraid of making mistakes” (c2rs) sub-theme 1b: "i am afraid of making mistakes" “in the hospital i felt protected and when i looked after my family member, i had no hesitation. i knew there was someone always ready in case of difficulty” (c9re); “even though i understand what i have to do, the emotional side stops me” (c4as); “it would be enough for me to look at the doctor's eyes and i would have the strength to go on” (c11et); “my family members look at me and monitor me; they think i can make mistakes at any moment” (c8ap). theme 2: feeling abandoned by institutions the second theme describes the condition of feeling abandoned and the stress that the carer feels after hospital discharge. the distancing from healthcare staff causes not only fear but also a sense of strong insecurity. loneliness decreases the awareness of one's own abilities and increases the possibility of making mistakes a subtheme was identified: "the network does not exist". sub-theme: “the network does not exist” at home, the caregiver starts an adaptive phase and tries to implement all the operational instructions they have learnt from the healthcare professionals. in most cases the caregiver changes their habits and moves into the home of the family member they are caring for to avoid leaving them alone. from the interviews it emerged that after a week or so the caregiver tries to contact the family doctor to discuss the hospital discharge letter and new treatments to be administered. "one must remember that the doctor .... if he answers..... does so at set times and first one has to talk to the secretary...... i hope i never get sick after 7 p.m. otherwise i will have to go to the accident and emergency unit" (c21nm); "you must go to the district....there, they will order you the supplies......but i need them now, so how will i manage? (c24op); "the general practitioner told me to be patient......it takes a few days ......then i try phoning the hospital but even there it' s like winning the lottery. the phone rings but nobody answers.... i try again until the switchboard tells me to hold...... again!!!!.......if i can't speak to anyone by tomorrow, i'll go to the hospital." (c26un); "my brother told me don't worry, i'll try to call or go in person and ask what we should do......" (c14lp), theme 3: tiredness and less willingness to look after the relative due to work this theme describes the caregiver's mood and work difficulties during the three months after discharge. they must cope with a new organisation, which in most cases means a lack of free time as they must take care of a family member, in need of assistance. such a situation can be a source of enormous stress for the caregivers, who, in addition to their work, must worry about an equally tiring and demanding subsidiary activity. two sub-themes are identified: a) tiredness and b) sense of responsibility. sub-theme 3a: tiredness the thought of being the only family member caring for the patient causes a sense of fatigue that in the long term impairs daily life. symptoms such as insomnia and asthenia arise, leading to irritability "i hardly sleep at night and i'm nervous during the day... i didn't think taking care of my mum was so demanding... i don't know if i can do it much longer!" (c31tm); "i no longer have time to do anything......my life is centred on my mother's needs and she calls me all the time.....i am tired!" (c36vl) sub-theme 3b: sense of responsibility "every morning i get up with the thought that i have to go to work... i pray that nothing happens at home otherwise how can i manage? i can't leave work and i don't know who to call...." (c2nm); "the problem is that m. doesn't need continuous care but if a tube comes out and i'm not there he gets scared and who knows what happens... it happened once, a few hours passed... and then we had to go to hospital" (c14un). discussion caregivers caring for family members with bladder cancer who have undergone cystectomy and urinary diversion carry a burden.1 many of them are not adequately prepared to cope with post-ostomy life, and they reported that these difficulties often led to a reduced quality of life for the family member as well (8, 13). our study conarchivio italiano di urologia e andrologia 2023; 95, 1 t. bolgeo, f. ruta, d. gatti, f. gambalunga, l. iacorossi, r. di matteo, s. cotroneo, c. boccafoschi, a. maconi ducted in italian hospitals on caregiver experiences, notes some similarities with other studies conducted in other countries. similar difficulties and problems are mentioned such as the need for communication, an increased network, burden and caregiver stress (1, 7). our study reinforces themes highlighted in other studies that cite the importance of good caregiver health education during the family member's hospitalization and identifies a weaker development of community-based services compared to the rest of europe (12). it also reinforces the concept about the sense of duty felt by caregivers and emphasizes the need to obtain some free time for relaxation and leisure to continue caregiving subsequently (8, 14). the originality and strength of this study is to investigate caregivers' difficulties in the first three months after discharge. there are no studies in literature investigating this context. the first months reveal all the doubts and critical issues of caregivers and are the ones most at risk of improper hospital admissions. it emerged from the study themes, that in addition to the training program, an active network and more effective communication with healthcare staff, even after discharge, are crucial. conclusions our study demonstrates that the caregiver of a patient with bladder cancer and urostomy in the first three months after hospital discharge is very worried and stressed. despite the training program received in hospital, the caregiver does not recognize the newly acquired skills and has difficulty applying them. the lack of an active network and effective communication causes insecurity and subsequent hospital re-admissions. there were no substantial differences within the three hospitals for study performance. however, this study has not analysed the different approaches among different informal caregivers and financial status. therefore, further study would be required. references 1. fitch mi, miller d, sharir s, mcandrew a. radical cystectomy for bladder cancer: a qualitative study of patient experiences and implications for practice. can oncol nurs j rev can nurs oncol. 2010; 20:177-187. 2. linee guida carcinoma della vescica. published online 2015. 3. jackson ss, marks ma, katki ha, et al. sex disparities in the incidence of 21 cancer types: quantification of the contribution of risk factors. cancer. 2022; 128:3531-3540. 4. murray ks, prunty m, henderson a, et al. functional status in patients requiring nursing home stay after radical cystectomy. urology. 2018; 121:39-43. 5. gulliford mc, petruckevitch a, burney pg. survival with bladder cancer, evaluation of delay in treatment, type of surgeon, and modality of treatment. bmj. 1991; 303:437-440. 6. masiero m, busacchio d, guiddi p, et al. quality of life and psycho-emotional wellbeing in bladder cancer patients and their caregivers: a comparative analysis between urostomy versus ileal orthotopic neobladder. ecancermedicalscience. 2021; 15:1163. 7. hockman l, bailey j, sanders j, et al. a qualitative assessment of patient satisfaction with radical cystectomy for bladder cancer at a single institution: how can we improve? res rep urol. 2020; 12:447-453. 8. northouse ll, katapodi mc, schafenacker am, weiss d. the impact of caregiving on the psychological well-being of family caregivers and cancer patients. semin oncol nurs. 2012; 28:236-245. 9. colaizzi. existential phenomenological alternatives. accessed august 18, 2022. https://scholar.google.com/scholar_lookup?title=existentialphenomenological+alternatives+for+psychology&author=p.f.+colaizzi &publication_year=1978& 10. mortari l. la fenomenologia empirica in: l.mortari, l. ghirotto. metodi per la ricerca educativa. carocci editore, 2019, pp.41-77 11. tong a, sainsbury p, craig j. consolidated criteria for reporting qualitative research (coreq): a 32-item checklist for interviews and focus groups. int j qual health care j int soc qual health care. 2007; 19:349-357. 12. bagnasco a, rosa f, dasso n, et al. caring for patients at home after acute exacerbation of chronic obstructive pulmonary disease: a phenomenological study of family caregivers’ experiences. j clin nurs. 2021; 30:2246-2257. 13. wulff-burchfield em, potts m, glavin k, mirza m. a qualitative evaluation of a nurse-led pre-operative stoma education program for bladder cancer patients. support care cancer off j multinatl assoc support care cancer. 2021; 29:5711-5719. 14. cianfrocca c, caponnetto v, donati d, et al. the opinions and feelings about their educational needs and role of familial caregivers of parkinson’s disease patients: a qualitative study. acta bio-medica atenei parm. 2020; 91:e2020002. correspondence tatiana bolgeo, rn phd tbolgeo@ospedale.al.it denise gatti, rn dgatti@ospedale.al.it roberta di matteo rn msn1, (corrsponding author) rdimatteo@ospedale.al.it antonio maconi, md amaconi@ospedale.al.it department of research and innovation azienda ospedaliera ss antonio e biagio e cesare arrigo via venezia 16, 15100 alessandria (italy) federico ruta, rn phd federico.ruta@aslbat.it general direction, asl bat (health agency), andria (italy) francesca gambalunga, rn phd francescagambalunga86@gmail.com department of biomedicine and prevention, university of rome “tor vergata”, rome (italy) laura iacorossi, rn phd laura.iacorossi@gmail.com national cancer institute “regina elena”, rome (italy) salvatore cotroneo, rn scotroneo@ospedale.al.it sc urology, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria (italy) carmelo boccafoschi, md cboccafoshi@libero.al.it city of alessandria clinic monza polyclinic, alessandria (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 211archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. symptoms (2). tricyclic antidepressants, cognitive behavior therapy, neuromodulators, and pelvic floor kinesitherapy, stem cells and low-energy shock waves are only some of the proposed managements (3-9). however, the fact that no definite effective treatments for cpp have been identified to date further complicates the scenario and makes most of urologists are not confident with the management of this disease and its available therapies (10). it follows that many patients “jump” from a practitioner to another starting different treatments without a precise therapeutic plan. since cpp is a syndrome caused by many underlying causes and involving different organs, its management might be better lead by the mutual assistance of different healthcare givers. in this light, we recently created in our center a multi-disciplinary team (mdt) and a multi-disciplinary protocol of treatment for cpp patients and we aim to evaluate its effectiveness. materials and methods the data of all consecutive patients referred to our institution for a cpp from november 2016 to february 2019 has been prospectively collected and retrospectively evaluated. according to our institution’s regulation, a formal irb approval is not needed for retrospective studies, since admitted patients are required to sign a consent in order to use their data for scientific purposes. the definition for cpp was that given by the eau guidelines so that “chronic pelvic pain is chronic or persistent pain perceived in structures related to the pelvis of either men or women and must have been continuous or recurrent for at least six months” (11). naïve patients were defined as those not previously managed for these symptoms by a urologist or a gynecologist. only females and male patients with urological pain syndromes are managed in our center and therefore enrolled in the study. patients with non-urological causes of cpp such as irritable bowel syndrome or endometriosis and less than 18 years were excluded. only naïve patients introduction: the aim of the study is to evaluate the effectiveness of a multi-disciplinary team (mdt) and multi-disciplinary approach in the treatment of chronic pelvic pain (cpp). methods: the data of all consecutive patients referred for a cpp from 11/2016 to 2/2019 has been prospectively collected. the sample was divided in two groups: group a, made by patients managed after the institution of our mdt, and group b, made of patients managed before this date. the mdt is composed by three urogynecologists, a psychologist and a physiotherapist. all group a patients underwent a weekly bladder instillation with dimethyl sulfoxide (dmso), kinesiotherapy for trigger points and percutaneous tibial nerve stimulation for 10 consecutive weeks. patients were asked to perform a self-treatment following the stanford protocol and to adhere to a specific diet. all group b patients were managed only with dmso instillations and a strict diet. results: the group a was made of 41 females and 6 males while the group b was made of 38 females and 5 males. the group a patients showed a statistically significant improvement in the pelvic pain urgency frequency, in the frequency times reported at the 6 months voiding diary, and a better patient global impression of improvement. conclusions: our data support the efficacy of the mdt in the management of cpp. the multimodal approach might represent an effective and reproducible non-invasive option to manage successfully cpp. key words: chronic pelvic pain; bladder pain; multi disciplinary team; interstitial cystitis; trigger points. submitted 10 january 2021; accepted 15 february 2021 introduction the chronic pelvic pain (cpp) is a complex and debilitating syndrome that can strongly impact the quality of life, work productivity and health care utilization of both females and males patients (1). this disease is not simply characterized by localized pain but is a syndrome that leads to a systemic worsening of the patient’s health with the appearance of a not irrelevant depression and other the role of the multi-disciplinary team and multi-disciplinary therapeutic protocol in the management of the chronic pelvic pain: there is strenght in numbers! antonella centemero 1*, lorenzo rigatti 1*, donatella giraudo 2, guglielmo mantica 3, davide de marchi 1, elisabetta francesca chiarulli 4, franco gaboardi 1 1 department of urology, san raffaele hospital, milan; 2 service of physiotherapy, san raffaele turro hospital, milan; 3 department of urology, policlinico san martino hospital, university of genoa, genoa; 4 department of urology, asst rhodense, rho, italy. * these authors equally contributed. doi: 10.4081/aiua.2021.2.211 summary archivio italiano di urologia e andrologia 2021; 93, 2 a. centemero, l. rigatti, d. giraudo, g. mantica, d. de marchi, e.f. chiarulli, f. gaboardi 212 who entirely followed the therapeutic plan and follow-up were enrolled. the initial evaluation was made of the collection of a detailed medical history and a physical evaluation, an abdominal ultrasound, routine blood samples and urinalysis with urine culture. psa was tested in males. the sample was divided in two different groups: group a, made by patients managed after the institution of our multi-disciplinary team set in october 2017, and group b, made of patients managed before this date. a multi-disciplinary team core was established at our center, consisting of three urogynecologists, a physiotherapist and a psychologist. the protocol and the modalities of patient discussion were decided by mutual agreement by the core member of the team based on the few similar experiences in the literature (12), their own personal experience (each of the core members > 10 years of experience in the treatment of cpp) and the setting of other mdts for different pathologies. the definition of the protocol and strategy of the mdt took about 3 months before starting. the intent of the mdt is also to continuously update to improve the offer to the patient, every 3 months. eau guidelines (11) on chronic pelvic pain and ics updates were the base for the patients’ management. treating physicians present and discuss the cases with the mdt. the mdt is usually called once a month by the team coordinator, in the first working thursday, and patients are re-discussed by the mdt at 6 months and then when required. the patients with symptoms of anxiety and/or depression were referred also to the psychiatrist. similarly, a neurologist was available “on demand” when required. all patients underwent a complete clinical evaluation with a physical exam and a treatment motivation assessment (1-10 scale). the pelvic pain urgency frequency (puf) questionnaire was administered before the treatment and at 6 months-time. male patients were further assessed with the international prostatic symptoms score (ipss) while all patients were asked to provide a 72hours voiding diary (vd) at the same 0-6 months timing. the patient global impression of improvement (pgi) was assessed at the end of the treatment. all group a patients underwent a weekly bladder instillation with dimethyl sulfoxide (dmso) rimso-50®, a weekly kinesitherapy for trigger points treatment and a weekly percutaneous tibial nerve stimulation (ptns) for 10 consecutive weeks. all patients were asked to perform a self-treatment following the stanford protocol (13) and to adhere strictly to a specific diet for interstitial cystitis. all group b patients were managed only with dmso instillations and the same strict diet. a two-items non-validated questionnaire was administered to all group a patients at the end of the therapeutic management. the questionnaire was anonymous and administered so as to avoid the hawthorne effect. data were entered into a microsoft excel (version 14.0) database and then transferred to sofastat tm 1.4.6 for windows. descriptive statistics were reported as median (first to third quartile). continuous variables with nonparametric distribution were compared using the mannwhitney test, while the frequencies were compared using the t-test calculator and the chi square test of independence. two-tailed tests were used for all comparisons; a p value < 0.05 was considered statistically significant. results according to the inclusion criteria a total number of 90 patients were enrolled in the study. the group a was made of 41 females and 6 males while the group b was made of 38 females and 5 males. the baseline characteristics of the two samples are summarized in table 1. interstitial cystitis, bladder pain syndrome and prostatodynia were the main causes for the referral. all patients had a suprapubic and/or perineal pain accompanied by urinary irritative symptoms (frequency and urgency). the two groups were not statistically different in terms of age, initial puf and ipss score, urgency/frequency times reported at the bladder voiding diary, while were different for marital status. the main results of the two different managements are summarized in the table 2. group a patients showed an improvement in term of puf, in the frequency times reported at the 6 months vd, and a better pgi. no improvement in the ipss was showed in group a patients. four female patients in group a and three in group b were evaluated by the psychiatrist and started on medication for anxiety/ depression. similarly, in group a two female patients were evaluated by the neurologist and started on pregabalin while in group b two females and one male. forty-two (89.4%) of the group a patients felt to be adetable 1. patients’ characteristics. group a group b p age 40 (33-46) 39 (31-45) 0.38 males 6 5 1 females 41 38 1 parities 21 17 0.67 family history of cpp 4 5 0.73 history of sexual abuse 3 4 0.7 anxiety and depression 13 18 0.23 stable partner 25 32 0.049 education 0.41 primary school 2 1 secondary school 22 26 university 23 16 bmi 24.3 (23-25.2) 23.4 (22.1-25) 0.41 smoking 18 15 0.83 prev. perineal surgery 13 17 0.26 self medications at home 36 32 1 type of pain 0.5 suprapubic 43 38 perineal 12 15 main cause for referral 0.84 interstitial cistytis 6 4 bladder pain syndrome 35 34 prostatodynia 6 5 urinary symptoms 0.69 frequency 35 34 urgency 22 18 data are expressed as median. quately followed throughout the therapeutic process, against the 69.8% of the group b (p = 0.02). similarly, 39 (83%) patients of the group a and 35 (81.4%) of the group b felt that different professional figures available has helped/would have helped her/his treatment (p = 0.84). discussion pain is a normal reaction of our body to an external potentially harmful damage. however, for many people pain persists even after the elimination of this cause of damage, sometimes even for weeks and several months, causing a chronic pain syndrome (14). cpp is one of the most debilitating syndromes, also because of the body area interested, which is intimately connected to the psycho-sexual life (15-16). historically, the main recognized causes of "urological" cpp are prostatitis, chronic and interstitial cystitis, nerve damages and previous pelvic urological surgery (11). the multi-disciplinary team is a new concept born a few years ago and that is slowly spreading in medical practice as a therapeutic ideal for many different diseases (17). its introduction and diffusion are mainly linked to oncological pathologies where complex clinical cases are discussed and managed by a heterogeneous team made up of different healthcare givers (surgeons, oncologists, radiologists, pathologists, radiotherapists, etc.). regarding the oncological field, the mdt seem to have a significant impact on patient assessment. however, their impact on clinical and oncological outcomes in cancer patients is supported by little evidence (18). the introduction of multi-disciplinary tasks in the treatment of benign pathologies and complex syndromes is even more recent. in particular, some recent reports have evaluated the role of mdts in the treatment of pain syndromes such as musculoskeletal pain, daily headaches and hip pain, showing how it can facilitate the treatment of refractory patients (19-21). the effectiveness of the mdts in the management of cpp has been evaluated and confirmed by the very few available reports (22-26). gupta et al. (22) reported the experience of the beaumont health system, with the creation of a multi-disciplinary women's urology center, including not only urologists but also gynecologists, experts in pelvic floor physical therapies, colorectal surgeons, integrative medicine practitioners who provide alternative therapies such as acupuncture, and pain psychologists. this model showed to be extremely successful in managing the symptoms of interstitial cystitis and bladder pain syndrome, with a very high patient satisfaction. the women's urology center represents an ideal mdt which might be able to manage all the different types of cpp (not only urological) providing personalized therapeutic patient-based solutions. it is obvious that, for reasons of resources and organization, not all the hospitals may be able to set up a similar team for the treatment of a benign pathology. our study reports the experience of one of the easiest and more simple mdts that can be established, consisting in the addiction of the physiotherapist and the psychologist to the urological management. it is cheap and potentially affordable for every institution and allows a multi-disciplinary management of such difficult patients. the mdt is usually called once a month. the treating physician may present cases directly evaluated or referred in order to plan a multimodal approach targeted on each patient. in our study, the group a patients showed a statistically significant improvement in the puf, in the frequency times reported at the 6 months vd, and a better pgi. on the contrary, the ipss showed no improvement in group a patients but this might be influenced by the very low number of the male sample on which it was evaluated. the questionnaire submitted to the patients showed that most of them considered useful the use of more professional healthcare givers. the availability of multiple different practitioners could not only guaranteeing a more complete therapeutic approach, but also make the patient perceive a better care and less abandonment and frustration. the main limit of the study is that is retrospective, even if data have been collected prospectively over the years. the small size of the cohort, and in particular in the males group, further limit the analysis of the outcomes such as ipss change. however, we believe that it succeeded in evaluating the possible benefit of an integrated approach to cpp. conclusions the multimodal approach might represent an effective and reproducible non-invasive option to manage successfully cpp patients. of fundamental importance is the definition of the various health care givers involved, their role in the diagnostic and therapeutic process, and a strong synergy of the team. further studies on larger samples are needed in order to confirm the effectiveness of the multimodal approach and outline the best treatment protocols. 213archivio italiano di urologia e andrologia 2021; 93, 2 the role of multi-disciplinary team in cpp table 2. outcomes of the two groups. puf at time puf at 6 months puf improvement pgi ipss at time 0 ipss at 6 months ipss improvement vd at time 0 vd at 6 months group a 29 (25-29) 13 (11-17) -16 2 (2-2) 25 (23-29) 17 (11-19) -8 14 (12-16) 7 (7-9) ss 18 ss 8 -10 bs 11 bs 5 -6 group b 27 (25-29) 19 (13-21) -8 3 (2-3) 27 (22-27) 21 (15-22) -7 14 (13-16) 10 (7-11) ss 16 ss 10 -6 bs 11 bs 9 -2 p 0.62 p < 0.05 p < 0.05 p < 0.05 p = 1 p = 0.27 p = 0.31 p = 0.92 p = 0.041 data are expressed as median (1st–3rd quartile); puf = pelvic pain urgency frequency questionnaire; vd = voiding diary; pgi = patient global impression of improvement; ipss = international prostatic symptoms score; ss = symptom score; bs = bother score. archivio italiano di urologia e andrologia 2021; 93, 2 a. centemero, l. rigatti, d. giraudo, g. mantica, d. de marchi, e.f. chiarulli, f. gaboardi 214 references 1. wozniak s. chronic pelvic pain. ann agric environ med. 2016; 23:223-6. 2. gambadauro p, carli v, hadlaczky g. depressive symptoms among women with endometriosis: a systematic review and metaanalysis. am j obstet gynecol. 2019; 220:230-241. 3. polackwich as, shoskes da. chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. prostate cancer prostatic dis. 2016; 19:132-8. 4. stamatiou k, magri v, perletti g, et al. how urologists deal with chronic prostatitis? the preliminary results of a mediterranean survey. arch ital urol androl. 2020; 92:353-356 5. mahran a, baaklini g, hassani d, et al. sacral neuromodulation treating chronic pelvic pain: a meta-analysis and systematic review of the literature. int urogynecol j. 2019; 30:1023-1035. 6. possover m, andersson ke, forman a. neuropelveology: an emerging discipline for the management of chronic pelvic pain. int neurourol j. 2017; 21:243-246. 7. nikkola j, holm a, seppänen m, et al. repetitive transcranial magnetic stimulation for chronic prostatitis/chronic pelvic pain syndrome: a prospective pilot study. int neurourol j. 2020; 24:144149. 8. lin cc, huang yc, lee wc, chuang yc. new frontiers or the treatment of interstitial cystitis/bladder pain syndrome focused on stem cells, platelet-rich plasma, and low-energy shock wave. int neurourol j. 2020; 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25:e34-e39. correspondence antonella centemero, md lorenzo rigatti, md davide de marchi, md franco gaboardi, md department of urology, san raffaele hospital, milan (italy) donatella giraudo, md service of physiotherapy, san raffaele turro hospital, milan (italy) guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com department of urology, policlinico san martino hospital, university of genoa, largo rosanna benzi 10, 16132, genoa (italy) elisabetta francesca chiarulli, md department of urology, asst rhodense, rho (italy) 193archivio italiano di urologia e andrologia 2019; 91, 3 case report priapism induced by use of tamsulosin: a case report and review of the literature marcelo marconi 1, pablo pavez 2, ignacio san francisco 2, paulette narvaez 3 1 andrology unit, department of urology, pontificia universidad católica de chile, santiago, chile; 2 department of urology, pontificia universidad católica de chile, santiago, chile; 3 department of urology, hospital dipreca, santiago, chile. numerous medications have been associated to the development of priapism as an adverse reaction, the most common are intracavernosal vasoactive agents, antipsychotics and antidepressants. alpha blockers, in particular tamsulosin which is widely used in different urological conditions, has been associated to priapism in only few case reports. we present the case of a healthy 45-year-old man who medicated himself with two doses of 0.4 mg of tamsulosin due to a renal colic with spontaneous passage of a 3 mm stone. eight hours after the second tamsulosin dose the patient developed a persistent painful erection not associated to sexual stimulation that lasted for 6 hours. he was admitted to the emergency room, and after history taking and physical evaluation the diagnosis of ischemic priapism was made. the patient denied consumption of any other medication or drug during the last month, blood tests in particular hemogram were normal and no recent history of pelvic trauma was reported. to achieve detumescence, five boluses of 200 mcg of phenylephrine were injected directly in the corpora cavernosa, no further procedures were needed. in the follow-up the patient had no new priapism episodes and he reported no problems with erections in sexual intercourse. tamsulosin is one of most indicated medications in urological general practice; though priapism has been rarely associated to its consumption the risk of this side effect exists, suggesting that patients should be counselled about it. key words: priapism; tamsulosin; adverse effect. submitted 24 april 2019; accepted 6 may 2019 summary no conflict of interest declared. can also develop as a side effect of different medications and drugs, being the most common vasoactive intracavernosal injections, psychotropic medications and recreational drugs (i.e. alcohol, cocaine) (2). alpha-blockers such as prazosin, terazosin and doxazosin have also been reported as an etiology of priapism. tamsulosin, an alpha 1a blocker, has rarely been related to priapism; however, is one of the most indicated medications in general urological practice being the first therapeutic line for the management of benign prostatic hyperplasia (3) and treatment of distal ureteral stones (4). the objective of this case report is to present a case of tamsulosin induced ischemic priapism. case presentation a healthy 45-year-old man with history of one renal colic episode with spontaneous stone elimination 12 months earlier, develops forty-eight hours before consultation a colic left flank pain and lower urinary tract symptoms, in particular urgency and increased urinary frequency, with no fever or macroscopic hematuria. the patient interpreted himself as developing a new renal colic episode so auto-medicated with ketorolac 10 mg three times a day and tamsulosin 0.4 mg once a day. the patient had no history of diabetes, hypertension, neurologic diseases, hematologic disease or any type of drug consumption or abuse. thirty-six hours after the first symptoms and after two doses of tamsulosin the patient spontaneously eliminated a 3 mm stone with no other incidents. the night before consultation approximately eight hours after stone elimination the patient woke up at 6 am with his usual morning erection, he urinated with no difficulties but the erection persisted during the following 5 hours without any sexual stimulation at that time or the night before. the patient tried to achieve detumescence by walking and local ice application with no success at home. he was admitted at noon with already six hours of a constant, painful and unrelated to sexual stimuli erection. at admission, the patient was evaluated by the emergency room physician, who collected a completed medical history excluding consumption of drugs (cocaine, marijuana), antidepressants, antipsychotics, narcotics, intracavernosal injection of vaso-active agents, phosphodiesterase 5 inhibitors, or any other substance associated doi: 10.4081/aiua.2019.3.193 introduction priapism is defined has a prolonged painful erection lasting for more than 4 hours in the absence of sexual stimulation and remaining despite orgasm (1). the three main subtypes are ischemic, non-ischemic and stuttering, being ischemic priapism the most common form, characterized by absence of intracavernous arterial inflow. the incidence of priapism in the general population is low (0.5-0.9 cases per 100,000 person-years); however, it is considered a medical emergency and should be treated promptly to avoid further complications, in particular corporal fibrosis and erectile dysfunction. although a specific etiology cannot be found in up to one-third of the cases of ischemic priapism, defined conditions such as blood dyscrasias and neurological disorders have been associated to its development. priapism marconi_stesura seveso 30/09/19 18:26 pagina 193 archivio italiano di urologia e andrologia 2019; 91, 3 m. marconi, p. pavez, i. san francisco, p. narvaez 194 with priapism risk. the patient had no history of pelvic trauma either major or minor. the only drugs the patient had consumed in the last 48 hours were five 10 mg separated doses of ketorolac and two 0.4 mg doses of tamsulosin. he had a visual analog visual for pain (range 010) of 7 secondary to the painful erection. at admission the physical examination showed: temperature 36,6°c, pulse 84/minute, respiratory rate 18/minute and blood pressure 137/88. heart, lung, abdominal and neurologic examination were normal. genital examination revealed no skin lesions, painless testicular examination with normal volume and a complete painful rigid erection with no tumescence of the glans. a urine analysis revealed microscopic hematuria with no other pathological signs, urine culture developed no bacterial growth 48 hours later, and hemogram was normal with no signs of hematologic disease. after evaluation, a consultation for urologic evaluation was asked. after history taking and physical evaluation, the urologist confirmed the diagnosis of ischemic priapism. to achieve detumescence, after administration of local anesthesia to the base of the penile shaft and while monitoring the heart rate and blood pressure of the patient, boluses of 200 microgram phenylephrine in a two milliliter solution were injected directly in the corpora cavernosa. after five boluses (1000 micrograms) and 20 minutes, detumescence was achieved. no further procedures were needed. the patient was send home with the indication to avoid tamsulosin intake and sexual intercourse for the next seven days. in the follow-up the patient had no new priapism episodes and reported no problems with erections and sexual intercourse. discussion adverse events to different type of medications is one of the most important causes of priapism. the most common drugs involved in priapism development are vasoactive intracavernosal injections, anti-psychotics, antidepressants, cocaine, alcohol (table 1). there are few published reports associating the consumption of alphablockers to the development of priapism, in particular tamsulosin. in a previous systematic review, 13 articles reported a cause-effect relation, among which only three cases were secondary to tamsulosin (5). in one of those cases, tamsulosin was associated to a partial thrombosis of the corpora cavernosa (6), and in a second case the association of tamsulosin to a drug (boceprevir-cyp3a4) that inhibits its degradation triggered a priapism episode (7). when analyzing our case, we were not able to find any other etiology of priapism in our patient. he was healthy, with no hematological or neurologic diseases, and the only two medications he had consumed in the last 48 hours were ketorolac and tamsulosin. there are no reports in the literature associating ketorolac with the development of priapism. as an alpha-blocker tamsulosin would interfere with the detumescence mechanism that is mediated by adrenaline and nor-adrenaline acting on alpha-adrenergic receptors in the corpora cavernosa. considering the previous case-reports and ours, it seems that the development of priapism would be independent of the number tamsulosin doses. even though, tamsulosin related priapism has been rarely reported; the association is relevant considering that this medication is commonly prescribed by urologists to treat benign prostatic hyperplasia, which is an extremely frequent condition in general population. when prescribing tamsulosin, priapism is almost never mentioned as a potential side-effect, questionable our report together with previous ones suggest that patients should be counselled. conclusions tamsulosin is one of most prescribed medications in urological practice, even though priapism has been rarely associated to its consumption, the risk exists, suggesting that patients should be counselled about it. authors contribution mm and fp contributed to the writing of the first draft of the report and the initial discussion. mm was involved in the care and therapy of the patient. isf and pn reviewed the manuscript. mm is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. all authors read and approved the final manuscript. references 1. salonia a, eardley i, giuliano f, et al. european association of urology guidelines on priapism. eur urol. 2014; 65:480-489 2. muneer, a. comparison of eau and uk guidelines on priapism. journal of clinical urology. 2017; 11:127-131. table 1. drugs associated to the development of priapism. intracavernosal vaso-active drugs prostaglandin – papaverine phentolamine antipsychotics clozapine olanzapine risperidone chlorpromazin haloperidol thoridazine antidepressants trazodone imipramine bupropion fluoxetine lithium antianxiety agents hydroxyzine antihypertensives ntiroglicerine hydralazine guanethidine propanolol verapamil alpla-blockers doxazosine prazosine terazosin tamsulosin theophylline vancomycin heparin warfarin erythropoietin alcohol cocaine cannabis marconi_stesura seveso 30/09/19 18:26 pagina 194 3. foster he, barry mj, dahm p, et al. surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline. j urol. 2018; 200:612-619. 4. turk c, neisius ap, seitz c,, et al. (2018) eau guidelines on urolithiasis. https://uroweb.org/guideline/urolithiasis. accessed 04 april 2019 5. spagnul sjt, et al. adrenergic a-blockers: an infrequent and overlooked cause of priapism. international journal of impotence research. 2011; 23:95-98. 6. kilinc m, piskin s, guven r, et al. partial priapism secondary to tamsulosin: a case report and review of the literature. andrologia. 2009; 21:199-201. 7. hammond kp, nielsen c, linnebur sa, et al. priapism induced by boceprevir-cyp3a4 inhibition and α-adrenergic blockade: case report. clin infect dis. 2014; 58:e35-8. 195archivio italiano di urologia e andrologia 2019; 91, 3 priapism and tamsulosin correspondence marcelo marconi, md (corresponding author) mmarconi@andro.cl andrology unit, department of urology, pontificia universidad catolica de chile, cruz del sur 177, santiago (chile) pablo pavez, md info@andro.cl ignacio san francisco, md isanfrancisco@med.puc.cl department of urology, pontificia universidad católica de chile, santiago (chile) paulette narvaez, md kikinarvaez@gmail.com department of urology, hospital dipreca, santiago (chile) marconi_stesura seveso 30/09/19 18:26 pagina 195 archivio italiano di urologia e andrologia 2018; 90, 4288 original paper low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic kidney disease population simone brardi 1, gabriele cevenini 2 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of medical biotechnologies, university of siena, italy. objective: a longitudinal prospective case control study was organized to explore the relationships between glomerular filtration rate (gfr), renal resistive index (rri) and blood pressure values in a non-dialysis dependent adult population affected by chronic kidney disease and exposed to low systolic blood pressure (sbp) values. material and methods: the study sample (54 patients: 31 males and 23 females with an average age of 61.7 ± 19.2 years) was randomly selected from a population of adult non-dialysis dependent patients that scored a sbp < 100 mmhg at the medical examination. the patients were equally divided in two groups defined by the presence and absence of chronic kidney disease, (i.e. a gfr less or greater than 60 ml/min/1.73 m2, respectively). patients were submitted to a full therapeutic and dietetic intervention to correct the hypotension until reaching a steady sbp > 100 mmhg. results: in the group with chronic renal disease, the comparison between the data recorded with sbp < 100 mmhg (t0) and those detected with sbp ≥ 100 mmhg (t1) showed a statistically significant decrease of serum creatinine as well as an increase of gfr (mean serum creatinine t0 – serum creatinine t1: 0.194 ± 0.35, p < 0.01; mean gfr t0 – gfr t1: -4.615 ± 8.8, p < 0.013). there was also a statistically significant reduction of the rri (mean right kidney rri t0 – mean right kidney rri t1: + 0.082 ± 0.03, p < 0; mean left kidney rri t0 – mean left kidney rri t1: 0.076 ± 0.03, p < 0). conclusion: we concluded that, in ckd, when aorta is stiffed, a decrease of sbp can limit the renal perfusion that, in this condition, is mostly dependent by stroke volume, causing an increase of rri and a decrease of gfr that we suppose as reversible with the restoration of sbp. key words: longitudinal prospective case control study; chronic kidney disease; renal doppler ultrasonography; renal resistive index; low systolic blood pressure. submitted 1 november 2018; accepted 15 december 2018 summary no conflict of interest declared. index of renal disease progression) and reduction of systolic blood pressure (sbp) (1). while it is known what should be the normal range for resistance indices (0.47-0.70) (2), the same cannot be said about the ideal thresholds for arterial pressure. in this regard, although there is consensus in setting a target for blood pressure lower than 140/90 mmhg for most individuals, according to some authors the achievement of blood pressure values lower than 130/80 mmhg could guarantee an improvement of the clinical outcome compared to the 140/90 mmhg threshold in adults with chronic kidney disease (3, 4). however, there is no consensus on what may be a minimum threshold for the same blood pressure and this despite it being well known how damage can occur if intensive blood pressure treatment is implemented in patients with chronic renal failure (3). in particular, in a cohort of over 650.000 american veterans suffering from chronic kidney disease, patients who had an "ideal" blood pressure (< 130/80 mmhg) showed an increase in mortality due to the inclusion in this group of individuals with low systolic and/or diastolic arterial values. this association was confirmed both in diabetics and in non diabetics, or in those who had microalbuminuria or not (5). we organized a longitudinal prospective case control study with the intent to explore the relationships between renal function, renal resistive index (rri) (used as a monitoring tool) and blood pressure values in a nondialysis dependent adult population affected by chronic kidney disease and exposed to reduced systolic blood pressure values (sbp < 100 mmhg). materials and methods a longitudinal prospective case control type study was planned. the study sample (54 patients: 31 males and 23 females with an average age of 61.7 ± 19.2 years) was randomly selected from a population of adult non-dialysis dependent patients attending the outpatient nephrology clinic of san donato hospital in arezzo that scored a systolic blood pressure < 100 mmhg at medical examination. the study population was initially affected by hypertendoi: 10.4081/aiua.2018.4.288 introduction recently it has emerged that in a non-dialysis dependent population suffering from chronic kidney disease (ckd) and subjected to conventional therapeutic and dietary treatment there is a statistically significant correlation between reduction of renal resistive index (rri) (which if high, i.e. ≥ 0.7, represent an unfavorable prognostic brardi_stesura seveso 10/01/19 16:19 pagina 288 289archivio italiano di urologia e andrologia 2018; 90, 4 low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic.. sion and/or diabetes mellitus and/or chronic glomerulonephritis with or without chronic kidney disease or albuminuria. patients with obstructive uropathy, acute glomerulonephritis, tubulointerstitial renal diseases, renal artery stenosis and malignant disease were excluded. pregnant women and children were also excluded. the total number of patients was selected to be equally divided in two groups defined by the presence (case) and absence (control) of chronic renal disease, defined by a glomerular filtration rate (gfr) less or greater than 60 ml/min/1.73 m2, respectively. the average gfr (calculated by the ckd epi equation) (6), was 38.5 ± 12.7 ml/min/1.73 m2 for case group and 82.3 ± 17 ml/min/1.73 m2 for control group (table 1). a prevalence of male gender was observed in both study and control groups. the anthropometric parameters (weight, height, age, sex and body mass index) did not differ statistically (at a significance level of 95%) in the two groups (table 1). at the time of enrollment a written informed consent was obtained by all the patients. after the enrollment the patients were submitted to a complete medical examination, comprehensive of the recording of weight and height. a measure of blood pressure was taken with a mercury sphygmomanometer applied around each patient’s non-dominant arm after the patient had rested for 15 minutes in a sitting position and with his/her arm placed at the level of the heart. two consecutives blood pressure recordings, taken at 5 minute interval, were averaged to provide clinic systolic and diastolic blood pressure values. blood and urine samples were obtained for measurement of serum creatinine, glycated hemoglobin and 24-hour urinary albumin excretion. finally, renal doppler ultrasonography examination was carried out by the same nephrologist experienced in ultrasound examination using the same ultrasound device that was a logiq s7 (ge medical systems italy s.p.a. milan, italy) sonographic system equipped with 3 to 5 mhz transducers. doppler signals were obtained from the interlobar arteries from the upper, middle and lower third of both kidneys and resistive index was calculated as the average of 6 measurements (3 from each of the 2 kidneys) taken for each patient. the doppler angle was chosen as close to 0°as possible and special care was taken not to compress the kidney and not to have the patient performing valsalva maneuver because both of them can increase the renal resistive index value. we recorded also the diameters in the longitudinal axis of each kidney and the cortical thickness of each kidney, measured in the portion closer to the upper pole and the lower pole of the same kidney. table 1. baseline characteristics of the population enrolled. gfr group n° mean standard mean (ml/min/1.73 m2) deviation standard error age t0 (years) < 60 26 69.35 18.974 3.721 > 60 25 54.36 16.671 3.334 height (cm) < 60 26 164.038 10.5356 2.0662 > 60 24 167.5 8.3406 1.7025 weight t0 (kg) < 60 26 73.146 12.2153 2.3956 > 60 24 76.817 15.1616 3.0948 body mass index t0 (kg/m2) < 60 26 27.1753 3.6804 0.721794187 > 60 24 27.25421 4.3580 0.88958826 creatinine t0 (mg/dl) < 60 26 1.7892 0.6175 0.12112 > 60 25 0.9456 0.1712 0.03424 gfr t0 (ml/min/1.73 m2) < 60 26 38.615 12.9648 2.5426 > 60 25 82.96 17.3505 3.4701 proteinuria t0 (gr/24h) < 60 25 0.2256 0.3884 0.0776993 > 60 20 0.31645 0.5184 0.1159197 hba1c t0 (%) < 60 6 6.75 0.5089 0.2078 > 60 4 5.975 0.5123 0.2562 sbp t0 (mmhg) < 60 26 90.115 5.2484 1.0293 > 60 25 91.6 4.7697 0.9539 dbp t0 (mmhg) < 60 26 58.192 9.9881 1.9588 > 60 25 66.72 6.9072 1.3814 right kidney rri t0 < 60 25 0.746 0.06212 0.01242 > 60 23 0.6265 0.05407 0.01127 left kidney rri t0 < 60 24 0.7413 0.06306 0.01287 > 60 20 0.63 0.07138 0.01596 right kidney diameter t0 (mm) < 60 26 99.538 12.7349 2.4975 > 60 23 109.478 13.5139 2.8178 left kidney diameter t0 (mm) < 60 24 103.958 12.2065 2.4916 > 60 22 116.045 12.0217 2.563 age t1 (years) < 60 26 68.46 19.59 3.842 > 60 25 53.04 16.352 3.27 weight t1 (kg) < 60 25 74.44 13.4028 2.6806 > 60 23 78.448 15.3239 3.1952 body mass index t1 (kg/m2) < 60 25 27.62463 4.0364 0.807297865 > 60 23 27.65597 4.3396 0.904875025 creatinine t1 (mg/dl) < 60 26 1.5946 0.43552 0.08541 > 60 25 0.978 0.17769 0.03554 gfr t1 (ml/min/1.73 m2) < 60 26 43.231 13.5685 2.661 > 60 25 81.4 21 4.2 proteinuria t1 (gr/24h) < 60 22 0.323682 0.5561 0.118575 > 60 18 0.342389 0.5020 0.1183385 hba1c t1(%) < 60 5 6.34 0.5727 0.2561 > 60 2 6.05 0.2121 0.15 sbp t1 (mmhg) < 60 26 114.654 10.2526 2.0107 > 60 25 109.44 7.6381 1.5276 dbp t1 (mmhg) < 60 26 74.154 13.5135 2.6502 > 60 25 76.84 8.0658 1.6132 right kidney rri t1 < 60 24 0.6638 0.06309 0.01288 > 60 23 0.6348 0.07391 0.01541 left kidney rri t1 < 60 24 0.665 0.06164 0.01258 > 60 22 0.6355 0.07645 0.0163 right kidney diameter t1 (mm) < 60 26 101 13.1088 2.5708 > 60 24 110.417 14.7852 3.018 left kidney diameter t1 (mm) < 60 24 104.458 12.7381 2.6002 > 60 23 116.13 11.8372 2.4682 brardi_stesura seveso 10/01/19 16:19 pagina 289 archivio italiano di urologia e andrologia 2018; 90, 4 s. brardi, g. cevenini 290 we recorded any data about the therapeutic and dietary treatment of the patients with special regard to the use of drugs that may interfere with the rri determinations such as angiotensin ii receptor blockers (arbs) or angiotensin converting enzyme (ace) inhibitors and beta blockers and the use or not of an hyposodic, hypoproteic, hypoglicemic as well as hypocaloric diet. then the patients were submitted to a full therapeutic and dietetic intervention to correct the hypotension by a reduction of dosage or removal of hypotensive drugs. after a variable interval period, depending from the time necessary to recovery a steady systolic blood pressure > 100 mmhg for on average one year, patients were submitted again to a new medical examination comprehensive of the recording of weight and clinic blood pressure values with the same modalities above mentioned. values of serum creatinine, glycated hemoglobin and 24hour urinary albumin excretion were collected again and a new renal doppler ultrasonography was carried out by the above mentioned nephrologist experienced in ultrasound investigation by using the same ultrasound device. all data relating to the therapeutic and dietary treatment used by the patients were recorded again. statistical analysis descriptive statistics included mean and standard deviation for quantitative data, and frequency count and percentage for qualitative data. for quantitative variables, groups were compared with the student t test for unpaired data or the mann-whitney rank test, respectively depending on the normal or non-normal distribution of population data. the normality was assessed by applying the kolmogorov-smirnov test to sample data. comparisons between t0 and t1 were made using the student t test for paired data or the wilcoxon rank test for normal or non-normal data respectively. for dichotomous qualitative variables, frequency counts between groups were compared using the fisher exact test applied to 2 x 2 contingency data. a statistical significance level of 95% was chosen for all statistical analyses (p < 0.05) that were performed using spss software, version 10. results considering the two groups with gfr < 60 and gfr ≥ 60 ml/min/1.73 m2 separately, within the group with gfr < 60 ml/min/1.73 m2, the comparison between the data recorded with systolic blood pressure (sbp) < 100 mmhg (t0) and those detected with sbp ≥ 100 mmhg (t1) showed that, passing from time 0 to time 1, there was a statistically significant increase of body weight (bw) (mean bwt0 bwt1: -1.428 ± 3.2; p < 0. 04), although the clinical significance of this observation was not very relevant as it was about 2%. a statistically and clinically significant decrease of serum creatinine as well as a statistically and clinically significant increase of the glomerular filtrate rate was observed (mean creatinine t0 creatinine t1: 0.194 ± 0.35; p < 0.01; equal to a reduction of approximately 11%; mean gfr t0 gfr t1: 4.615 ± 8.8, p < 0.013, equal to an increase of over 12%). a statistically and clinically significant decrease of the renal resistive index (rri) was also observed (mean right kidney rri t0 – mean right kidney rri t1: + 0.082 ± 0.03, p < 0, equal to a 10.8% reduction. mean left kidney rri t0 – mean left kidney rri t1: 0.076 ± 0.03, p < 0, equal to a reduction of 10.2%). comparison for paired data also identified a statistically significant reduction of the glycated hemoglobin data, to which, however, given the small number of diabetics on the total (6 out of 27 equal to about 22% of the total), it was not possible to attribute a clinical relevance. within the control group (gfr ≥ 60 ml/min /1.73 m2) there was no statistically significant variation between times t0 and t1 except, of course, the increase in the arterial pressure values (systolic and diastolic), a finding that was also found in the cases (gfr < 60 ml/min /1.73 m2) confirming the respect of the working hypothesis. finally considering the two groups together, the comparison for all the variables between time zero and time 1 confirmed a statistically significant increase of body weight as well as a statistically significant decrease in serum creatinine levels and a statistically significant reduction of the intrarenal arterial resistance indices of the right kidney and of the left kidney. in the comparison for paired data a statistically significant reduction of glycated hemoglobin was found for the entire population such as , both for the two groups separately. the comparison of data from the two groups for all the variables, confirmed the quality of the above exposed observations by detecting a significant difference between groups for creatinine at both time intervals, gfr at both time intervals, right kidney rri and left kidney rri at time 0 as well as right kidney diameter and left kidney diameter at both time intervals. discussion a unique feature of the kidney is that it is continually and passively perfused at high volume flow throughout systole and diastole. its vascular resistance is very low so that in comparison to other vascular beds resistance is closer to input and characteristic impedance (7). it is therefore susceptible to upstream influences that may increase fluctuations of pressure and flow, whereas small vessels in other organs are protected by relatively intense vasoconstriction upstream (7). in patients with chronic kidney disease (ckd) and endstage renal disease (esrd) all epidemiological studies have clearly shown that an accelerated arterial and cardiac aging by atherosclerosis is characteristic of these populations. atherosclerosis is a generalized arterial disease of the arterial intima characterized by the presence of plaque and occlusive arterial lesions. the functional consequence of these structural alterations is hardening/sclerosis of vessel walls (arteriosclerosis) and loss of compliance, that is increased stiffness. when the arterial premature aging involves the aorta it stands out for an aortic stiffening and for the disappearance of stiffness/impedance gradients between the central and peripheral arteries. these changes have a double impact: on the heart, upstream, with high systolic and pulse pressures and decreasing diastolic pressure, increased cardiac afterload and arterial circumferential brardi_stesura seveso 10/01/19 16:19 pagina 290 291archivio italiano di urologia e andrologia 2018; 90, 4 low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic.. stress. all these factors promote left ventricular hypertrophy (lvh) which may evolve toward heart failure. downstream, on renal and brain microcirculation, with decrease in glomerular filtration and cognitive functions (8). proof of all this is the fact that strong associations between aortic stiffness and indicators of renal dysfunction (glomerular filtration rate and microalbuminuria) have been described such as with cognitive impairment and dementia besides (as previously mentioned), left ventricular hypertrophy and left ventricular dysfunction (8). physiologically, the higher compliance of the aorta coupled with a progressively lower compliance in peripheral vessels creates a “stiffness gradient” that works as a “hydraulic filter” and acts to buffer pressure pulsations and their transmission to microcirculation and capillary network (principally in the main parenchymal organs such as the kidney and the brain). the more distensible the arterial wall (that is, the lower the stiffness) the smoother the provision of proper flow to peripheral tissues. when the aorta is rigid and cannot be stretched, the entire stroke volume flows through the arterial system and peripheral tissues only during systole with two consequences: intermittent flow and short capillary transit time with reduced metabolic exchanges (9). therefore we believe that, in such a condition, a reduce of the systolic arterial blood pressure, such as a sbp < 100 mmhg, can further and definitely limit the renal perfusion that is already damaged by lacking of a proper aortic buffer. about the doppler renal resistive index (rri) described by pourcelot (10) ((peak sistolic velocity-end diastolic velocity)/peak sistolic velocity) we observe that rri is a traditional index used as a measure of vascular resistance. a value of 0.60 is considered as a normal value for renal rri, whereas 0.70 is usually considered the upper threshold of normal rri in adults. several factors have been described to influence doppler renal arterial waveform and therefore the rri as renal vascular compliance, central hemodynamics (especially arterial stiffness, blood pressure and heart rate), and other factors including age, underlying acute or chronic renal disease and drugs too (11). in this regard it is known that rri decreases with use of renin angiotensin system (ras) inhibitors, due to hemodynamic changes induced by these antihypertensive agents (12) while rri, significantly and independently, increased with use of beta-blockers (13). in the setting of an acute kidney injury the first clinical application of rri was the detection of renal obstruction because renal vasoconstriction is believed to be a key factor in the pathophysiology of acute kidney obstruction. platt et al had proposed that an rri ≥ 0.7 was in favor of an acute renal obstruction and may precede pyelocalicectasis (14). afterwards in 91 patients with acute kidney injury (aki), platt et al. demonstrated that mean rri was significantly higher in patients with persistent aki than in patients with transient aki (15). lastly in a small number of patients with septic shock, deruddre et al. have shown a significant decrease in renal rri when increasing mean arterial pressure (map) with norepinephrine from 65 to 75 mmhg. this study suggests that doppler renal ultrasound may help to determine in each patient the optimal map for renal tissue perfusion and may be a relevant end point to titrate the hemodynamic treatment in septic shock (16). accordingly, we believe that rri may be used as a noninvasive and repeatable tool to assess changes in renal perfusion and it may be useful to determine the optimal therapeutic/preventive modalities for kidney perfusion at the bedside (11). conclusions on the basis of all the above mentioned, we therefore believe that, when in ckd the aorta is stiffed and cannot be stretched, a decrease of the systolic arterial blood pressure, even temporary, can limit the renal perfusion that, in this condition, it is mostly (or entirely) a function of the stroke volume, causing an increase of the rri and a reduction of the glomerular filtration rate as proven by this paper. this scientific work shows that reduced systolic arterial pressure values (i.e. sbp < 100 mmhg) have an effect of worsening of renal function only when there is already a pre-existent significant impairment of the gfr (such as a gfr < 60 ml/min/1.73 m ^ 2) and not when a similar kidney damage is not present. however we believe that, since this decrease in renal function is a function of reduced systolic arterial pressure values, the restoration of the systolic pressure may recover the decrease of renal function that therefore can be considered reversible. these observations appear congruent with what has already been reported by judd et al. and kovesdy et al. (3, 5) who, inspired by the association of low arterial pressure values with an increase in mortality, warns that "lowering sbp to the strict limits recommended by current guidelines (i.e. sbp < 130 mmhg or even lower) in patients with ckd (at the expense of lowering dbp below approximately 70 mmhg) may be deleterious". above all, the data of this study are fully supported by the results of the sprint trial (17) which showed as an intensive blood pressure control (i.e. sbp < 120 mmhg) produces a significant cardiovascular benefit in high-risk patients with hypertension at the price of an higher risk of hypotension, syncope, and accelerated reductions in gfr. in fact in the sprint trial, acute kidney injury or acute renal failure occurred more frequently in the intensively treated group than in the standard-treated group and the authors of this trial believe that the differences in adverse renal outcomes may be related to a reversible intrarenal hemodynamic effect of the greater reduction in blood pressure. furthermore the authors of the sprint trial, as the authors of the present paper, believe that with the currently available data, there is no evidence of substantial permanent kidney injury associated with a treatment with the goal of lower systolic blood-pressure although the possibility of a long-term adverse renal outcome cannot be excluded (17). references 1. brardi s, cevenini g, giovannelli v, romano g. longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients treated brardi_stesura seveso 10/01/19 16:19 pagina 291 archivio italiano di urologia e andrologia 2018; 90, 4 s. brardi, g. cevenini 292 with conventional medical and dietetic therapy. arch ital urol androl. 2017; 89, 4. 2. lubas a, kade g, niemczyk s. renal resistive index as a marker of vascular damage in cardiovascular diseases. int urol nephrol. 2014; 46:395-402. 3. judd e, calhoun da. management of hypertension in ckd: beyond the guidelines. adv chronic kidney dis. 2015; 22:116-122. 4. taler sj, agarwal r, bakris gl et al. kdoqi us commentary on the 2012 kdigo clinical practice guideline for management of blood pressure in ckd. am j kidney dis. 2013; 62:201-213. 5. kovesdy cp, bleyer aj, molnar mz, et al. blood pressure and mortality in us veterans with chronic kidney disease. ann intern med. 2013; 159:233-242. 6. levey as, stevens la, et al. a new equation to estimate glomerular filtration rate. ann intern med. 2009; 150:604-612. 7. o’rourke mf, safar me. relationship between aortic stiffening and microvascular disease in brain and kidney cause and logic of therapy. hypertension. 2005; 46:200-204. 8. london g, covic a. goldsmith d, et al. arterial aging and arterial disease: interplay between central hemodynamics, cardiac work, and organ flow-implications for ckd and cardiovascular disease. kidney int sup. 2011; 1:10-12. 9. briet m, boutouyrie p, laurent s, et al. arterial stiffness and pulse pressure in ckd and esrd. kidney int. 2012; 82:388-400. 10. pourcelot l. applications cliniques de l’examen doppler transcutanè. in peronneau p (ed). velocimetrie ultrasonore doppler. paris. seminare institut national de la santè et de la recherche medicale. 1975; pp 213-40. 11. le dorze m., bouglè a, deruddre s, et al. renal doppler ultrasound: a new tool to assess renal perfusion in critical illness. shock 2012; 37:360-365 12. leoncini g, martinoli c, viazzi f, et al. change in renal resistive index and urinary albumin excretion in hypertensive patients under long-term treatment with lisinopril and nifedipine gits. nephron. 2002; 90:169-173. 13. kuznetsova t, cauwenberghs n, knez j, et al. doppler indexes of left ventricular systolic and diastolic flow and central pulse pressure in relation to renal resistive index. am j hypertens. 2015; 28:535-45. 14. platt jf, rubin jm, ellis jh. acute renal obstruction: evaluation with intrarenal duplex doppler and conventional us. radiology. 1993; 186:685. 15. platt jf, rubin jm, ellis jh. acute renal failure: possible role of duplex doppler us in distinction between acute prerenal failure and acute tubular necrosis. radiology. 1991; 179:419. 16. deruddre s, cheisson g, mazoit jx et al. renal arterial resistance in septic shock: effects of increasing mean arterial pressure with norepinephrine on the renal resistive index assessed with doppler ultrasonography. intensive care med. 2007; 33:1557. 17. the sprint research group. a randomized trial of intensive versus standard blood-pressure control. n engl j med. 2015; 373:2103-2116. correspondence simone brardi, md (corresponding author) hemodialysis unit, s. donato hospital, arezzo, italy gabriele cevenini, md department of medical biotechnologies, university of siena, italy brardi_stesura seveso 10/01/19 16:19 pagina 292 stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11242 1 original paper disease (3). despite a substantial shift to a more favourable stage at presentation of newly diagnosed disease, average age of death from prostate cancer is 77 years of age and has remained stable over the past three decades (3, 4). since huggins reported that surgical castration is an effective treatment for advanced prostate cancer (5), hormonal manipulation with the suppression of gonadal testosterone is a cornerstone for systemic treatment of metastatic prostate cancer (3). however, the disease eventually evolves into mcrpc and death (3). in recent years, the addition of several newly approved combination therapies to androgen deprivation therapy (adt) for treatment in metastatic hormone-sensitive prostate cancer (mhspc), such as abiraterone, docetaxel, apalutamide, enzalutamide or darolutamide, have shown improvements in os and pfs (6-11). despite being extremely effective initially, almost all patients under adt for mhspc eventually develop biochemical and/or clinical evidence of treatment resistance. median os after mcrpc diagnosis is estimated to be between 13.2 to 23.2 months depending on the burden of metastasis at presentation (12). mcrpc is a very heterogeneous disease, representing a vast group of patients with a wide range of characteristics and prognosis. many factors have been pointed out to stratify these patients, such as psa, metastatic burden, age, gleason score and time to castration resistance (13). however, new methods or biomarkers to help clinicians sub-classify and manage these patients are still needed. some inflammation-based and/or nutritional markers have been studied with this goal, such as neutrophil/lymphocyte ratio (14), platelet/lymphocyte ratio (plr) (15), prognostic nutritional index (pni) (16), among others (17-22). serum c-reactive protein (crp), and acute phase reactant, has been used as a surrogate marker of systemic inflammation (17-19). systemic inflammatory response has been shown to be associated with carcinogenesis, tumour progression and metastasis (20). serum albumin (alb) is accepted as a marker of the nutritional status of the body (18). the lower the serum albumin, the more frail the patients tend to be. several recent studies have reported the utility of the car as a prognosis factor in cancer patients (20-22). a higher car corresponds to a status of elevated systemic inflammation and lower nutritional status, suggesting that the patient’s overall condition is poor (18). car value as a prognostic marker has been previously reported in some cancers, such as hepaobjective: to assess the association of c reactive protein/albumin ratio (car) with progression free survival (pfs) and overall survival (os) in castration resistant metastatic prostate cancer (mcrpc) patients. materials and methods: a transversal study was conducted, including all patients diagnosed with mcrpc within a central hospital urological oncology consultation between december 2019 and december 2021 (n = 178) and that were submitted to systemic therapy. crp and albumin results were collected at the beginning of the systemic treatment for mcrpc in 103 patients and, in 75 patients already under treatment at the start of the study, on that occasion (december 2019). all patients were then followed. car was correlated with pfs and os. os and pfs were measured from the day the crp and alb were collected until the event of interest or the final date of follow-up. the sample was divided in two groups according to an optimal cutoff point found in a roc curve. results: the sample showed a median age of 75.76 ± 9.17 years old. using a cut-off point of 0.22, patients with a car ≤ 0.22 (63.2%) showed, compared to car > 0.22, longer pfs (15.92 vs. 9.46 months, r = -0.13, p < 0.05) and os (p = < 0.05, 25,72 vs. 15.79 months, r = -0,24, p < 0.05). better os in patients with car ≤ 0.22 vs > 0.22 was detected on both the group evaluated at the beginning of systemic treatment (26.96 vs 17.63 months, p < 0.05) and the group of patients already under treatment (23.90 vs 11.54 months, p < 0.05). dividing the sample according to the first line treatment chosen, we found os of 26.25 vs 5.9 months (p < 0.05), 27.71 vs 22.57 months (p < 0.05) and 27.36 vs 23.75 months (p = 0.12), for docetaxel, abiraterone and enzalutamide, respectively. conclusions: according to this study, higher values of car are associated with lower pfs and os in mcrpc patients. we found a cut-off value of 0.22 providing the best discrimination for prognosis. car is a good prognosis biomarker, irrespective of the moment of evaluation and chosen treatment option. key words: prostatic cancer; c-reactive protein; albumin; biomarker; prognosis. submitted 6 february 2023; accepteed 25 february 2023 introduction prostate cancer (pca) is the most common non cutaneous malignancy among men (1), and the second leading cause of death from cancer in this population (2). it is estimated that approximately 1 in 8 men (12.9%) will be diagnosed with prostate cancer, and 1 in 40 (2.5%) will die from this c reactive protein/albumin ratio as predictor of prognosis in castration resistant metastatic prostate cancer joão lorigo 1, edgar tavares silva 1, 2, joão pedroso lima 1, 2, vasco quaresma 1, rui pedrosa 1, arnaldo figueiredo 1, 2 1 department of urology, centro hospitalar e universitário de coimbra, coimbra, portugal; 2 university, coimbra, portugal. doi: 10.4081/aiua.2023.11242 summary archivio italiano di urologia e andrologia 2023; 95(3):11242 j. lorigo, e. tavares silva, j. pedroso lima, v. quaresma, r. pedrosa, a. figueiredo 2 tocellular, colorectal, esophageal, pancreatic, small cell lung and cervical neoplasia (14-16, 20-22). however, there is only limited data in prostate cancer patients. the objective of this study was to assess the association of car with pfs and os in a group of mcrpc patients. materials and methods a transversal study was conducted, including all patients diagnosed with mcrpc with a follow-up in a urological oncology consultation at a central hospital in portugal, between december 2019 and december 2021 (n = 178) and that were submitted to systemic therapy (74 abiraterone, 56 enzalutamide and 48 docetaxel). twenty-two patients had received docetaxel before for metastatic hormone-sensitive prostate cancer (mhspc). seventy-five patients were already under treatment and follow-up in december 2019 and this group had the crp and albumin data collected at that date. the remaining 103 patients had the biochemical data collected in the beginning of the systemic treatment (between december 2019 and december 2021). the participants’ characteristics were gathered from the medical records including age, histological grade, disease risk and volume, treatment modality, crp, alb, progression free survival and overall survival. the follow up data were collected until august of 2022. a taxane-based chemotherapy was chosen in the presence of clinical criteria of poor prognosis (short period of response under adt, high metastatic burden, visceral metastasis or poor prognostic genetic mutations) or in patients progressing after novel hormonal agents (nha; abiraterone or enzalutamide). nha were preferred in patients with less aggressive features (asymptomatic, durable response under previous adt, low metastatic burden and no visceral metastases), and as second line therapy in patients that progressed under taxane-based chemotherapy. in the absence of contraindication for either pharmaceutical drugs, patients were sequentially assigned to either enzalutamide or abiraterone group. castration resistance was defined using the european association of urology criteria: 1) three consecutives rises in psa at least one week apart resulting in two 50% increases over the nadir, and a psa > 2 ng/ml, or 2) appearance of new lesions (either two or more new bone lesions or a soft lesion using response evaluation criteria in solid tumours [recist)), or 3) clinical deterioration. os was measured from the day the crp and alb were collected to death from any cause or the final date of followup. pfs was also measured from the day the crp and alb were collected until one of the above-mentioned criteria were met or the final date of follow-up. comparisons between groups were performed using the chi-square test. car was correlated with pfs and os. for that, samples were divided in two groups according to the optimal cutoff point found in a roc curve. os and pfs curves were generated using the kaplan-meier method, and differences between groups were compared using the log-rank test. all data were analysed using a linear regression model and kaplan-meier survival curves. the statistical hypothesis tests with p-value < 0.05 were considered significant. statistical analyses were performed using spss software ver. 25.0 (ibm, armonk, ny, usa). results a total of 200 patients diagnosed with mcrpc were included, median age at inclusion being 75.76 ± 9.17 years old. after a median follow-up of 23 months, 72 patients (36.1%) had died. the most prescribed treatment was abiraterone. table 1 resumes the baseline characteristics of the population. mean crp was 2.30 mg/dl (range from 0.02 to 24.08 mg/dl), mean alb was 3.99 g/dl (range from 1.7 to 5.5 g/dl) and mean car was 0.64. in the present study, the value of 0.22 for car was used as the cut-off value. it provided the maximal youden index values, with an area under the curve (auc) of 0.71 (figure 1). car showed an inverse and significant correlation with table 1. patients’ characteristics and comparison between studied groups. variables total car ≤ 0.22 car > 0.22 p value n % n % n % isup score isup1 6.0% 5.6% 6.7% n.s. isup2 20.2% 24.1% 13.3% n.s. isup3 34.5% 33.3% 36.7% n.s. isup4 17.9% 18.5% 16.7% n.s. isup5 21.4% 18.5% 26.7% n.s. disease burden low volume 49.4% 52.5% 43.3% n.s. high volume 50.6% 47.5% 56.7% n.s. disease risk low risk 64.1% 74.6% 45.5% 0.005 high risk 35.9% 25.4% 54.5% 0.005 local treatment (lt) with lt 67.0% 61.7% 75.7% n.s. without lt 33.0% 38.3% 24.3% n.s. first-line treatment for mcrpc docetaxel 23.5% 15.6% 36.8% 0.015 abiraterone 46.1% 51.6% 36.8% n.s. enzalutamide 30.4% 32.8% 26.3% n.s. figure 1. roc curve. archivio italiano di urologia e andrologia 2023; 95(3):11242 3 car as a prognosis biomarker in mcrpc both pfs and os (r = -0.13 and r = -0.24, p = < 0.05, respectively). correlations shown in figure 2. using a cut-off value of 0.22, patients with a car ≤ 0.22 (63.2%) showed longer pfs (15.92 vs. 9.46 months, p = < 0.05) and os (25.72 vs. 15.79 months, p = < 0.05). survival curves shown in figure 3. when dividing the sample according to when the biochemical parameters were collected, the os of the group evaluated at the beginning of systemic treatment was 26.96 vs 17.63 months, for a car ≤ 0.22 vs > 0.22, respectively (p < 0.05). in the group evaluated during follow-up, the os using the same cut-off point was 23.90 vs 11.54 months, respectively (p < 0.05). survival curves below. dividing the sample according to the first line treatment chosen for mcrpc, it was observed an os of 26.25 vs 5.9 months (p < 0.05), 27.71 vs 22.57 months (p < 0.05) and 27.36 vs 23.75 months (p = n.s.), for docetaxel, abiraterone and enzalutamide, respectively. figure 3. comparing progression free survival (pfs) and overall survival (os) between groups according to car. figure 2,. correlations between car and clinical outcomes. figure 4. comparing overall survival (os) between groups at the start of systemic treatment and during follow-up. archivio italiano di urologia e andrologia 2023; 95(3):11242 j. lorigo, e. tavares silva, j. pedroso lima, v. quaresma, r. pedrosa, a. figueiredo 4 discussion in this study, we analysed the prognostic value of car in 178 mcrpc patients. we found car to be an independent prognostic factor for patients with mcrpc, either at diagnosis and start of systemic treatment and at any point during follow-up. crp production in the liver is up-regulated by proinflammatory cytokines (e.g. interleukin-6 [il-6]) (25). increased crp levels have been reported in many types of malignancies (23). cancer cell proliferation, necrosis, invasion, and hypoxia trigger immune responses in the tumour microenvironment that leads to the generation of various proinflammatory factors (25, 26). two metaanalyses evaluated the role of crp in kidney, bladder and prostate cancers and found a potential prognostic value in all three malignancies (24, 26). despite not being a perfect marker of nutritional status, because of its long half-life and susceptibility to other systemic factors, albumin is well correlated with nutrition status (25). low serum albumin levels are caused by low nutrient intakes and tumour overconsumption (26). protein malnutrition can lead to oedema, impaired organ function and immunosuppression. moreover, hypoalbuminemia is associated with higher mortality in cancer patients (23, 25, 26). recently, several studies have reported the relation between high car and poor prognosis in cancer patients (20-22). accordingly, we found a mean crp and alb, respectively, above (2.30 mg/dl) and below (3.99 g/dl) normal range values. in this study, we used the roc analysis to yield a car 0.22 cut-off value for predicting pfs and os in mcrpc and we were able to find a significant difference between patients with a car ≤ 0.22 or > 0.22. taking advantage of the study design, we tried to find if the ratio was useful at the start of systemic treatment and during follow-up. we found a significant correlation irrespectively of the analysis timing. these findings are in line with previous studies (23, 25, 26). however, all those studies have only evaluated patients in the beginning of systemic treatment. although not surprising, this study proves the usefulness of car predicting outcomes during the oncological follow-up. the number of drugs approved for treatment of mcrpc is vast (27-30). in our study, 27% of the patients received docetaxel, 41.6% abiraterone and 31.5% enzalutamide. we observed a significantly higher proportion of patients with car > 0.22 receiving docetaxel vs nha. this can be due to the higher disease stress associated with the poor risk factors present in these sub-group. because docetaxel was prescribed in patients with more aggressive disease, their os were also lower. however, car was still able to differentiate patients receiving docetaxel according to their prognosis. the groups receiving abiraterone and enzalutamide were more homogenous. when grouping the sample by treatment type, we found longer os for patients with car ≤ 0.22 taking abiraterone, however, patients on enzalutamide didn´t showed a significant difference in os, car (p = 0.12), with patients showing an os of 27.36 and 23.75 months, for a car ≤ 0.22 vs > 0.22, respectively. we attribute this lack of significance to the small sample size. it should be noted that the current study has limitations, including its retrospective nature and a relatively small sample size, which might have caused selection bias. large-scale and prospective studies are further warranted to confirm our preliminary findings. conclusions in conclusion, according to this study, higher values of car are associated with lower pfs and os in mcrpc patients. these results suggest that car is a good prognosis biomarker, irrespective of the moment of evaluation and chosen treatment option. references 1. prostate cancer statistics [internet]. cancer.net. 2012 [cited 2022 nov 12]. available from: https://www.cancer.net/cancertypes/prostate-cancer/statistics. 2. key statistics for prostate cancer | prostate cancer facts [internet]. cancer.org. 2022 [cited 2022 nov 12]. available from: https://www. cancer.org/cancer/prostate-cancer/about/key-statistics.html 3. wein aj, kavoussi lr, partin aw, peters ca. campbell-walsh urology. philadelphia, pa: elsevier; 2016. 4. epstein mm, edgren g, rider jr, et al. temporal trends in cause of death among swedish and us men with prostate cancer. j natl cancer inst. 2012; 104:1335-42. 5. huggins c, hodges cv. studies on prostatic cancer: i. the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. j urol. 2002; 168:9-12. 6. teo my, scher hi. chaarted/getug 12—docetaxel in noncastrate prostate cancers. nat rev clin oncol. 2015; 12:687-8. 7. james n, woods b, sideris e, et al. addition of docetaxel to firstline long-term hormone therapy in prostate cancer (stampede): long-term survival, quality-adjusted survival, and cost-effectiveness analysis. j clin oncol. 2018; 36(6 suppl):162-2. 8. sharma a. a game changing latitude: role of abiraterone plus prednisolone in metastatic hormone-sensitive prostate cancer. indian j urol. 2017; 33:333. 9. davis id, stockler mr, martin a, et al. randomised phase 3 trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: enzamet (anzup 1304). annal oncol. 2014; 25:iv278. 10. chi kn, chowdhury s, radziszewski p, et al. titan: a randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (arn-509) plus androgen deprivation therapy (adt) in metastatic hormone-sensitive prostate cancer (mhspc). annal oncol. 2016; 27:vi265. 11. tombal b, saad f, hussain m, et al. arasens: a phase 3 trial of darolutamide in males with metastatic hormone-sensitive prostate cancer (mhspc). annal oncol. 2017; 28:v291-2. 12. aly m, leval a, schain f, et al. survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in sweden. scand j urol. 2020; 54:115-21. 13. capoun o, mikulová v, jancíková m, et al. prognosis of castration-resistant prostate cancer patients use of the adnatest® system for detection of circulating tumor cells. anticancer research. 2016; 36:2019-26. 14. kasymjanova g, macdonald n, agulnik js, et al. the predictive archivio italiano di urologia e andrologia 2023; 95(3):11242 5 car as a prognosis biomarker in mcrpc value of pre-treatment inflammatory markers in advanced nonsmall-cell lung cancer. cur oncol 2010; 17:52-8. 15. wang d, luo h, qiu m, et al. comparison of the prognostic values of various inflammation based factors in patients with pancreatic cancer. med oncol. 2012; 29:3092-100. 16. buzby gp, mullen jl, matthews dc, et al. prognostic nutritional index in gastrointestinal surgery. am j surg 1980; 139:160-7. 17. sugimoto a, toyokawa t, miki y, et al. preoperative c-reactive protein to albumin ratio predicts anastomotic leakage after esophagectomy for thoracic esophageal cancer: a single-center retrospective cohort study. bmc surg. 2021; 21:348 18. liu z, shi h, chen l. prognostic role of pre-treatment c-reactive protein/albumin ratio in esophageal cancer: a meta-analysis. bmc cancer. 2019; 19:1161. 19. bodner-adler b, kimberger o, schneidinger c, et al. prognostic significance of pre-treatment serum c-reactive protein level in patients with adenocarcinoma of the uterine cervix. anticancer res. 2016; 36:4691-6. 20. he x, li j-p, liu x-h, et al. prognostic value of c-reactive protein/albumin ratio in predicting overall survival of chinese cervical cancer patients overall survival: comparison among various inflammation based factors. j cancer. 2018; 9:1877-84. 21. haruki k, shiba h, horiuchi t, et al. impact of the c-reactive protein to albumin ratio on long-term outcomes after hepatic resection for colorectal liver metastases. am j surg. 2017; 214:752-6. 22. wu m, guo j, guo l, zuo q. the c-reactive protein/albumin ratio predicts overall survival of patients with advanced pancreatic cancer. tumour biol 2016; 37:12525-33. 23. uchimoto t, komura k, fujiwara y, et al. prognostic impact of c-reactive protein-albumin ratio for the lethality in castration-resistant prostate cancer. med oncol. 2019; 37:9. 24. o’brian d, prunty m, hill a, et al. the role of c-reactive protein in kidney, bladder, and prostate cancers. front immunol. 2021; 12:721989. 25. guo s, he x, chen q, et al. the c-reactive protein/albumin ratio, a validated prognostic score, predicts outcome of surgical renal cell carcinoma patients. bmc cancer. 2017; 17:171. 26. wu m, zhou y, chen q, et al. prognostic role of pretreatment creactive protein to albumin ratio in urological cancers: a systematic review and meta-analysis. front oncol. 2022; 12:879803. 27. berthold dr, pond gr, soban f, et al. docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the tax 327 study. j clin oncol. 2008; 26:242-5. 28. beer tm, armstrong aj, rathkopf d, et al. enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 prevail study. eur urol. 2017; 71:151-4. 29. ryan cj, smith mr, fizazi k, et al. abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (cou-aa302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. lancet oncol. 2015; 16:152-60. 30. jarimba rs, eliseu mn, pedroso lima j, et al. novel hormonal agents for metastatic castration-resistant prostate cancer: comparing outcomes. a single-center retrospective study. arch ital urol androl. 2021; 93:393-8. correspondence joão diogo abreu lorigo, md (corresponding author) joaolorigo@gmail.com department urology-centro hospitalar e universitário de coimbra praceta professor mota pinto, 3004-561 coimbra, portugal edgar tavares silva, md edsilvaelv@gmail.com joão pedroso lima, md joaopedrosolima@gmail.com vasco quaresma, md vpdquaresma@gmail.com rui pedrosa, md ruimdp93@gmail.com arnaldo figueiredo, md ajcfigueiredo@gmail.com praceta professor mota pinto, 3004-561 coimbra conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2019; 91, 3198 case report vena cava defect repair using a polytetrafluoroethylene graft after a radical nephrectomy and vena cava resection: a case report volkan izol, mutlu deger, mustafa zuhtu tansug department of urology, faculty of medicine, university of çukurova, adana, turkey. introduction: the gold standard treatment for large renal masses is a radical nephrectomy and the removal of tumor thrombi from the large vessels. here, we discussed the repair of a vena cava defect using a polytetrafluoroethylene (ptfe) graft after a radical nephrectomy and vena cava resection. case: a 69-year-old male patient presented to our clinic with right-sided pain and 10 kg of weight loss over the previous 3 months. the computed tomography showed that the right kidney was 23 x 13 cm in size, with a 7 x 6 x 7 cm contrastenhanced mass at the renal ilum level. the patient underwent a radical nephrectomy, and the vena cava defect was repaired using a ptfe graft. there was also tumor infiltration in the proximal third of the left renal vein. the renal vein defect was also repaired using a ptfe graft, and the end of the graft was sutured to the vena cava graft at a right angle. the histopathological examination showed a fuhrman grade 4 renal cell carcinoma (rcc) with focal sarcomatoid differentiation areas. conclusions: the management of patients with rccs and inferior vena cava (ivc) tumor thrombi should be planned with an experienced team, including a cardiovascular surgeon and liver transplantation team. in these patients, the comorbidities, life expectancy, and imaging methods should be considered for treatment planning in experienced centers. the tumor stage, probability of invasion, and patient’s performance status should also be determined using magnetic resonance imaging during the preoperative period. finally, the needs for a graft or tubular patch, sternotomy, and chemotherapeutic agents after the nephrectomy should be discussed using a multidisciplinary approach. key words: radical nephrectomy; vena cava; renal cell carcinoma; polytetrafluoroethylene; graft. submitted 9 march 2019; accepted 3 april 2019 summary no conflict of interest declared. 10% of the cases at the time of the diagnosis (2-4). evaluating the tumor size, location, inferior vena cava (ivc) thrombus presence, adjacent organ involvement, lymph node involvement, and any distant metastases before performing an intervention is very important for determining the surgical margin and the patient’s survival. nephron sparing surgery or a radical nephrectomy, which is the standard treatment for an organ confined rcc, allows for a high-grade cure. unfortunately, after a radical nephrectomy and tumor thrombus removal in the case of ivc tumors, the 5-year survival rate drops to 3264% (5-8). however, the survival rate in patients who have undergone only radical nephrectomies, without removing any thrombi, declines significantly, and most of these patients die within the first year. despite the significant improvements that have been made in targeted therapy in recent years, the most effective treatment for these patients is still surgery. although large renal masses can be removed safely with the developments that have been made in the preoperative diagnostic methods, anesthesia, and surgical techniques, especially after liver transplantation, morbidity and mortality rates ranging from 2.7-40% have been reported (9). there are three important stages involved in rcc and venous tumor thrombus surgery: renal artery ligation, avena cava tumor thrombectomy, and radical nephrectomy. due to ivc tumor infiltration in certain rare cases, a resection of the infiltrating section of the ivc may also be necessary (10). after the resection and an adequate hepatic vena cava dissection, the vena cava can be anastomosed end to end, or the defect can be repaired with synthetic or homologous grafts. here, we have discussed a vena cava defect repair case in which a polytetrafluoroethylene (ptfe) graft was used after a radical nephrectomy and vena cava resection. case report a 69-year-old male patient presented to our clinic with right-sided pain and 10 kg of weight loss over the previous 3 months. the ultrasonography showed that left kidney was normal, but a mass completely infiltrated the right kidney. the complete blood count and serum biochemistry values were normal, the karnofsky performance scale index was 80%, and the patient's medical history did doi: 10.4081/aiua.2019.3.198 introduction renal cell carcinomas (rccs) account for approximately 3% of all adult solid tumors and approximately 85% of all parenchymal kidney tumors.1 after prostate and bladder tumors, rccs are the third most commonly seen urological tumors, and they exhibit the highest mortality rate of all urological cancers. although an rcc diagnosis can be made during the early stages with the widespread use of imaging modalities, 25% of the patients may have metastatic and venous involvement, extending from the renal vein to the right atrium. this is seen in 4izol_stesura seveso 30/09/19 18:28 pagina 198 199archivio italiano di urologia e andrologia 2019; 91, 3 repair of vena cava defect with polytetrafluoroethylene graft not include any significant features, with the exception of hypertension and smoking 60 packs/years. computed tomography (ct) scan showed that right kidney was 23 x 13 cm in size, with a contrast-enhanced mass at the renal ilum level of 7 x 6 x 7 cm in size. magnetic resonance (mr) imaging was used to determine the relationship between the mass surrounding the renal ilum and the vascular structures. the mr images revealed a 10 cm mass compressing the liver at the right renal ilum level, which extended to the para-aortic midline, filling the renal vein and vena cava, with suspected wall invasion (figure 1). bone scintigraphy and thorax tomography showed no metastases. after patient evaluation, an experienced cardiovascular surgeon and liver transplantation team planned a radical nephrectomy, thrombectomy, and ivc resection and reconstruction. following the necessary preparations, the surgery began with a transperitoneal subcostal incision in right semi-lumbar position under general anesthesia. when the colon was turned over and the retroperitoneal area was reached, a mass extending proximally to the bottom of the liver with the ivc could be seen. there was also tumor infiltration in the proximal third of the left renal vein. the hepatic vena cava was dissected, and vascular clamps were placed on the distal and proximal sections of the vena cava and on the renal vein of the opposite kidney. after controlling the renal arteries, the renal mass was removed to uncover the inferior section of the ivc (figure 2). an approximately 13-cm vena cava defect was repaired using a 16-mm diameter, 13-cm long ptfe graft, achieving continuity of the ivc. the defect in the renal vein was repaired with a 10-mm diameter, 4-cm long ptfe graft, and the end of the graft was sutured to the vena cava graft at a right angle (figure 3). the operation ended after the bleeding was controlled. the operation time was 300 minutes, the estimated blood loss was 5,000 ml, and 14 erythrocyte transfusion units were given. the patient, who was extubated during the postoperative period, was admitted to the service without any problems, and low molecular weight heparin was administered. on the 3rd postoperative day, this patient was started on oral intake; however, he developed acute right-sided pain on the 6th postoperative day, and a hematoma was detected in the operation zone. the hematoma was evacuated under general anesthesia, and no bleeding focus was found. two blood transfusion units were administered, and the procedure was terminated. the preoperative creatinine level was 0.8 mg/dl, the postoperative level increased to 2 mg/dl, and upon discharge, it was 0.7 mg/dl. the patient underwent drainage on the 9th postoperative day, and he was discharged on the 14th postoperative day. the histopathological examination showed a fuhrman grade 4 rcc with focal sarcomatoid differentiation areas. at the 1 month follow-up, the positron emission tomography ct of the operation region showed a large number of mass lesions consistent with metastases extending from the para-aortic region to the pelvic region. there was a recurrent mass in the posteromedial section of the liver, with suspicion of invasion. this patient was referred for a consultation in the medical oncology department, and interferon treatment was started. however, this patient died due to metabolic causes during the 6th postoperative month. discussion the gold standard treatment for large renal masses is a radical nephrectomy and tumor thrombus removal from the large vessels (if there are any). this process was first described by berg in 1913, and since then, it has been applied as a standard treatment method (11, 12). when making surgical decifigure 1. mri revealed a 10 cm mass compressing the liver at the right renal hilum level and extending to the midline paraaortic localization, filling the renal vein, vena cava with suspected wall invasion. figure 2. the renal mass was removed to show the inferior part of the inferior vena cava. figure 3. approximately 13 cm vena cava defect was repaired using a 16 mm diameter x 13 cm long ptfe graft achieving continuity of the inferior vena cava. the defect in the renal vein was repaired with a 10 mm diameter x 4 cm long ptfe graft and the end of the graft was sutured to the vena cava graft at a right angle. izol_stesura seveso 30/09/19 18:28 pagina 199 archivio italiano di urologia e andrologia 2019; 91, 3 v. izol, m. deger, m. zuhtu tansug 200 sions, the metastasis-related symptoms (e.g., ivc syndrome, weight loss, hematuria, edema, and side pain), comorbidities (e.g., hypertension, heart failure, diabetes mellitus, chronic obstructive pulmonary disease, and secondary malignancy), patient's performance status, and patient’s life expectancy must be taken into account. thrombus removal with a radical nephrectomy may reduce the disease-related symptoms. this can lead to a better quality of life for the patient, even though it may not provide a curative treatment (12). additionally, the administration of novel chemotherapeutic agents, such as tyrosine kinase inhibitors (e.g., sunitinib and sorafenib) and mammalian target of rapamycin kinase inhibitors (e.g., temsirolimus and everolimus or rad001), after cytoreductive surgery can also extend the life expectancy of these patients (13). the most important issue when determining the prognosis involving a tumor thrombus is whether the tumor is invasive with regard to the vascular structures. if the tumor has invaded the vascular structures with a thrombus, the prognosis will be worse whether this patient has metastases or not. a good mr imaging examination and transesophageal echocardiography should be performed (during the operation, if necessary) to make this differentiation (14-16). surgery is not difficult for renal tumors with tumor thrombi in the subcortical ivc, and in majority of cases, minimal vena cava invasion can be treated using standard surgical approaches. if the thrombus does not occupy much space in the ivc, a radical nephrectomy alone can be performed, while milking the thrombus to the renal vein. however, more complicated surgical approaches are needed when the thrombus is at a higher level or the right atrium is extended. although various surgical thrombus resection methods have been suggested, a cardiopulmonary bypass, deep hypothermia, and transient circulatory arrest are the ones most commonly used. in addition, various surgical maneuvers, such as hepatic mobilization, the pringle maneuver, or a venovenous bypass, may be required. if vascular invasion is suspected and a surgical decision is made, a partial or total ivc resection and synthetic vascular grafting can be performed. however, these should only be performed in tertiary hospitals using a multidisciplinary approach, including an anesthetist with sufficient experience, a vascular surgeon, a liver transplant team, and a urologist (10-16). when the tumor thrombus partially or totally infiltrates the ivc wall, the wall should be resected until a reliable surgical margin is reached; however, the indications for resection and the reconstructive methods to be used afterwards are not clearly defined. some authors have argued against reconstruction after a suprarenal resection because collateral vessels, such as lumbar, epigastric, and vertebral arteries, may develop. however, other authors have suggested that major venous insufficiency may develop if it is not done. in general, if the ivc wall defect is less than 1/3 of the wall diameter, a direct repair should be performed; if it is excessive, reconstruction should be performed with a ptfe or tubular graft. the ptfe graft was first used by sarti et al. in 1970, and it has been applied safely to patients with malignant tumors since that time (17). the increased laparoscopic renal surgery experience in recent years has brought with it the feasibility of this method for patients with widespread ivc thromboses. in the past, a laparoscopic approach seemed to be relatively contraindicated in cases with a renal vascular tumor thrombosis. nowadays, in some clinics, especially those experienced in laparoscopic surgery, tumor surgeries including level i thromboses and some cases level ii can be performed laparoscopically. in some studies (despite their small number) it has been argued that a handassisted laparoscopic nephrectomy is safe if the thrombus is in the renal vein, and it can even be comparable to an open radical nephrectomy (18, 19). depending on the experience of the clinic, the patient’s risk factors, and the thrombus grade, an open or laparoscopic approach can be used in certain cases. despite the advances that have been made in preoperative imaging methods and the increase in surgical experience, the mortality rates during this operation range between 2.7% and 13%. the most common causes of mortality are massive bleeding and pulmonary emboli (12, 20-22). in one study, 659 patients who underwent thrombectomies at the mayo clinic were evaluated retrospectively, and a 15% complication rate was reported. the subgroup analysis revealed an increase in the complication probability as the thrombus level increased; as a result, the need for a multidisciplinary approach to reduce morbidity was emphasized (23). conclusions the management of patients with rccs that include ivc tumor thrombi should include an experienced team consisting of a cardiovascular surgeon and liver transplantation team in an experienced center. a tumor burden reduction with minimal morbidity to a maximum extent is very important for the patient’s survival. moreover, the tumor stage, invasion probability, patient’s performance status, comorbidities, and life expectancy should be evaluated using imaging methods, such as mr imaging, during the preoperative period. the needs for a graft or tubular patch, sternotomy, and chemotherapeutic agents after the nephrectomy should all be discussed with a multidisciplinary team. the patient should also be informed about the operation and the planned procedures both before and after surgery. references 1. jacqmin d, van poppel h, kirkali z, et al. renal cancer. eur urol. 2001; 39:361-9. 2. janzen nk, kim hl, figlin ra, et al. surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. urol clin north am. 2003; 30:843-52. 3. pagano f, dal bianco m, artibani w, et al. renal cell carcinoma with extension into the inferior vena cava: problems in diagnosis, staging and treatment. eur urol. 1992; 22:200-203. 4. marshall f, dietrick d, baumgartner w, et al. surgical management of renal cell carcinoma with intracaval neoplastic extension above the hepatic veins. j urol. 1988; 139:1166-72. izol_stesura seveso 30/09/19 18:28 pagina 200 201archivio italiano di urologia e andrologia 2019; 91, 3 repair of vena cava defect with polytetrafluoroethylene graft 5. padovan rs, perkov d, smiljanic r, et al. venous spread of renal cell carcinoma. abdom imaging. 2007; 32:530-7. 6. schimmer c, hillig f, riedmiller h, et al. surgical treatment of renal cell carcinoma with intravascular extension. interact cardiovasc thorac surg. 2004; 3:395-7. 7. wotkowicz c, wszolek mf, libertino ja. resection of renal tumors invading the vena cava. urol clin north am. 2008; 35:657-71. 8. kaplan s, ekici s, dogan r, et al. surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. am j surg. 2002; 183:292-9. 9. hallscheidt p, pomer s, roeren t, et al. preoperative staging of renal cell carcinoma with caval thrombus: is staging in mri justified? prospective histopathological correlated study. urologe a. 2000; 39:36-40. 10. duckett jw, lifland jh, peters pc. resection of the inferior vena cava for adjacent malignant diseases. surg gynecol obstet. 1973; 136:711-6. 11. okada y, kumada k, terachi t, et al. long-term followup of patients with tumor thrombi from renal cell carcinoma and total replacement of the inferior vena cava using an expanded polytetrafluoroethylene tubular graft. j urol. 1996; 155:444-7. 12. rigaud j, hetet jf, braud g, et al. surgical care, morbidity, mortality and follow-up after nephrectomy for renal cancer with extension of tumor thrombus into the inferior vena cava: retrospective study since 1990s.eur urol. 2006; 50:302-10. 13. procopio g, verzoni e, de braud f. targeted therapies and survival: what we can learn from studies in advanced renal cell carcinoma. oncology. 2013; 84:39-42. 14. sidana a, goyal j, aggarwal p, et al. determinants of outcomes after resection of renal cell carcinoma with venous involvement. int urol nephrol. 2012; 44:1671-9. 15. boorjian sa, sengupta s, blute m. renal cell carcinoma: vena caval involvement. bju int. 2007; 99:1239-44. 16. kirkali z, van poppel h. a critical analysis of surgery for kidney cancer with vena cava invasion. eur uro.l 2007; 52:658-662. 17. sarti l. total prosthetic transplantation of the inferior vena cava, with venous drainage restoration of the one remaining kidney on the graft, successfully performed on a child with wilms’ tumor. surgery. 1970; 67:851-5. 18. henderson a, murphy d, jaganathan k, et al. rané handassisted laparoscopic nephrectomy for renal cell cancer with renal vein tumor thrombus. urology. 2008; 72:268-72. 19. hoang an, vaporcyian aa, matin sf. laparoscopy-assisted radical nephrectomy with inferior vena caval thrombectomy for level ii to iii tumor thrombus: a single-institution experience and review of the literature. j endourol. 2010; 24:1005-12. 20. steahler g, brkovic d. the role of radical surgery for renal cell carcinoma with extension into vena cava. j urol. 2000; 163:1671-5. 21. skinner dg, pritchett tr, lieskovsky g, et al. vena caval involvement by renal cell carcinoma: surgical resection provides meaningful long-term survival. ann surg. 1989; 210:387-94. 22. nesbitt jc, soltero er, dinney cpn, et al. surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. ann thorac surg. 1997; 63:1592-600. 23. karnes rj, blute ml. surgery insight: management of renal cell carcinoma with associated inferior vena cava thrombus. nat clin pract urol. 2008; 5:329-39 correspondence volkan izol, md mustafa zuhtu tansug, md department of urology, faculty of medicine, university of çukurova adana (turkey) mutlu deger, md, febu (correspondent author) drmutludeger@gmail.com department of urology, faculty of medicine, university of çukurova, adana 01330 (turkey) izol_stesura seveso 30/09/19 18:28 pagina 201 archivio italiano di urologia e andrologia 2018; 90, 3184 original paper diabetes mellitus and prostate cancer metabolism: is there a relationship? hugo pontes antunes 1, ricardo teixo 2, 3, 5, joão andré carvalho 1, miguel eliseu 1, inês marques 2, 3, 5, ana mamede 2, 3, 4, 5, rita neves 2, 3, 5, rui oliveira 3, 6, edgar tavares-da-silva 1, 3, 5, belmiro parada 1, 5, ana margarida abrantes 2, 3, 5, arnaldo figueiredo 1, 5, maria filomena botelho 2, 3, 5 1 urology and transplantation department, coimbra hospital and university centre, coimbra, portugal; 2 cnc.ibili, university of coimbra, coimbra, portugal; 3 institute of biophysics, faculty of medicine, university of coimbra, coimbra, portugal; 4 cics-ubi, health sciences research centre, university of beira interior, covilhã, portugal; 5 institute for clinical and biomedical research (icbr) area of environment genetics and oncobiology (cimago) faculty of medicine university of coimbra, portugal; 6 pathology department, coimbra hospital and university centre, coimbra, portugal. objective: our aim was to evaluate the effects of glucose levels and diabetes mellitus in prostate cancer (pca) biology. materials and methods: two pca cell lines (lncap and pc3) were cultured in rpmi medium with different glucose concentrations [5mm (lg) and 25mm (hg)]. expressions of androgen receptor, her2/neu and glucose transporters (glut1, 3, 5 and 12) were evaluated by flow cytometry. proliferation rate was assessed by colorimetric assay mtt and cellular characterization was performed by haematoxylin and eosin staining. additionally, we performed a cross sectional analysis of 704 patients undergoing radical prostatectomy who were divided into two groups (diabetic and non-diabetic). an analysis of clinical and histological data seeking to identify the differences on tumor aggressiveness between the two groups was performed. results: in lncap cell line, when the glucose concentration in the medium increased, there was an increased in ar expression. regarding expression of her2/neu receptor, medium’s glucose concentration significantly changed the expression of this receptor in both pc3 and lncap cell lines. growth rate was higher on the hg medium for both cell lines. the clinical study of patients undergoing radical prostatectomy revealed no relationship between the presence of diabetes and the development of more aggressive tumours. diabetic patients had significantly higher prostatic volumes, however, no significant difference was found between the relapse risk classification or the isup classification between the two groups. conclusions: our results showed that medium glucose concentration could influence prostate cancer cells growing but not the aggressiveness. key words: diabetes; glucose; prostate cancer; hormonal receptors; 18f-fdg. submitted 20 july 2018; accepted 27 july 2018 summary no conflict of interest declared. this work was supported by strategic projects pest-c/sau/ui3282/ 2013 and feder-compete (poci01-0145-feder-007440). the relationship between the dm and the pca is still not well studied, as with other neoplasms. populational studies have shown conflicting results (6, 7). the reduce study showed no association between the dm and the risk of pca (6). on the other hand, the prostate cancer prevention trial (pcpt) shows an increased risk of pca in diabetic patients (7). reviews from studies of the pre-psa era have shown a negative association between pca and dm (8, 9). latest reviews show that there may be an increased risk for high-grade tumours in diabetic patients, despite a negative association between dm and all forms of pca (10-12). diabetic disease’s parameters as hyperglycaemia (proven by hba1c or by fasting blood glycaemia) show a linear risk association with high-grade tumours (11, 13). pca diagnosis in diabetic patients may be more difficult because diabetics presents lower psa values, lower serum testosterone and higher prostatic volumes (14). finally, some therapies for dm seem to have effect also on pca, as for example metformin, which has been associated with reduction in cancer-specific mortality, as well as less recurrences after curative treatment in pca (15). molecular mechanisms involved in the relationship between dm and neoplasms have been the focus of several works. the main study points were the molecular pathways associated with hyperinsulinemia (16, 17), insulin growth factor-1 (igf-1) and inflammation (18). concerning pca and dm, scientific work at the molecular level is scarce. in addition to the pathways referred above, hyperglycaemia per se seems to have an effect on the androgen receptor (ar) expression (19). the aim of our study was to evaluate the effects of high glucose level, one aspect of the diabetic disease, in pca tumour biology. for this purpose, we evaluated the various molecular expression in pca cell lines, when incubated in different glycaemic environments, simulating normal blood glucose and hyperglycaemia concentrations. to complement the study in cell lines, we performed a revision of our patients’ data subjected to radical prostatedoi: 10.4081/aiua.2018.3.184 introduction diabetes mellitus (dm) and prostate cancer (pca) are two diseases that affect a large number of men in adulthood (1, 2). several studies show how dm can be a risk factor for the development of several neoplasms (1-4) or even to its progression (5). antunes1_stesura seveso 03/10/18 09:42 pagina 184 185archivio italiano di urologia e andrologia 2018; 90, 3 diabetes and prostate cancer metabolism ctomy and compared clinical and histological data of diabetic and non-diabetic patients. materials and methods cell culture prostate cancer cell lines used in this study – lncap (hormone-dependent) and pc3 (hormone-independent) – were obtained in american type culture collection (atcc, usa). cell lines were thawed and propagated in adherent cultures in roswell park memorial institute medium (rpmi), ph 7.4, supplemented with 10% fetal bovine serum (sigma f7524), 1% antibiotic/antimycotic (sigma a5955) and 1% sodium pyruvate (gibco 11360). we used two different formulations of rpmi medium: high glucose (25mm, sigma r4130) or low glucose (5mm). the low glucose (lg) medium resembles normal glycaemia. to obtain 5mm glucose medium, we used a medium without glucose (sigma r1383) to which we added the appropriate amount of glucose (sigma g7528). cells were maintained at 37ºc with 5% co2. expression of androgen receptor (ar) and her2/neu to evaluate the expression of ar and her2/neu, 106 cells were washed with phosphate buffered saline [pbs: 137mm nacl (sigma, s7653), 2.7mm kcl (sigma, p9333), 10mm na2hpo4.2h2o (merck, 6580), 2mm kh2po4 (sigma, p0662), ph=7.4] by centrifugation at 209×g during 5 minutes. cells were stained with anti-ar antibody (abcam ab9474) and with anti-her2/neu-apc (apc, alophycoerythrin) antibody (bd biosystems 340554) for 15 minutes at room temperature in the absence of light. after cells were washed and resuspended in 400μl of pbs. stained cells with anti-ar were washed as described above and stained with a secondary antibody conjugated with phycoerythrin (pe, santa cruz biotechnology sc3818) for 20 minutes at room temperature in the absence of light, and after were washed with pbs by centrifugation at 209×g for 5 minutes and resuspended in 400μl of pbs. the expression of ar and her2/neu were analyzed by flow cytometry. the results obtained are expressed as mean intensity fluorescence (mif). proliferation rate to analyse pca cells growth, 50000 cells/ml were plated in 24 multiwell plates. after 24 and 96 hours, the colorimetric test mtt was performed as described elsewhere 20. the proliferation rate is given by the ratio of the absorbance measured at 96h (ad4) and measured at 24h (ad1). cellular characterization and immunocytochemistry cell lines used in this experiment were morphologically characterized using cytospin centrifugation, on a shandon cytospin ii cytocentrifuge at 471×g for 3min and then stained using haematoxylin and eosin (h&e). the remaining material was then centrifuged at 471×g for 5 min. after, paraffin inclusion of the pellet was performed for immunocytochemistry, on a ventana marker platform bench mark ultra ihc/ish. immunocytochemical analysis was performed using formalin-fixed, paraffin-embedded sections. the avidinbiotin peroxidase complex technique was employed. ki67 antigen (mib-1 clone, 1:50, ultra cc1 antigen retrival, darko) was tested as representative of proliferation index, and evaluated by percentage of expression – it was chosen for each condition a hot spot and counted the percentage of cells with nuclear expression/without expression of ki67 in a high-power field (40x objective – 0.3mm2). the samples were observed under a light microscope – nikon eclipse 50i, and images were obtained using a nikon-digital sight ds-fi1 camera. glucose transporters (gluts) quantification to evaluate the membrane expression of glucose transporters previously referred, 106 cells were washed by centrifugation with pbs at 209×g during 5 minutes. cells were stained with anti-glut1-pe (r&d systems fab1418p), anti-glut3 (r&d systems mab1415), antiglut5 (r&d systems mab1349) and anti-glut12 (santa cruz biotechnology sc-161659) for 15 minutes at room temperature and in the absence of light. after, cells stained with monoclonal antibody anti-glut1-pe were washed with pbs by centrifugation at 209×g during 5 minutes and resuspended in 400μl of pbs. stained cells with the antibodies anti-glut3, anti-glut5 and antiglut12 were washed with pbs by centrifugation at 209×g for 5 minutes and stained with a secondary antibody conjugated with pe (santa cruz biotechnology sc3818) for 20 minutes at room temperature in the absence of light. after incubation, cells were washed with pbs by centrifugation at 209×g during 5 minutes and resuspended in 400μl of pbs. the expression of gluts was analysed by flow cytometry. the results obtained are expressed as mif. 18f-fluorodeoxyglucose (18f-fdg) uptake studies a cell suspension of 2x106 cells/ml was prepared to perform the uptake studies. obtained the suspension, it was left to rest at 37ºc in 25cm2 flasks. after 60 minutes, 25μci/ml of 18f-fdg was added to cell suspension. at 5, 30, 60, 90 and 120 minutes, 200μl of cell suspension were collected for microtubes with iced pbs. the samples were centrifuged at 209×g for 1 minute to separate the pellet from the supernatant, having this been collected to an identified tube. after the separation of pellets and supernatants, the 18f-fdg uptake was determined by counting both fractions in a well counter (capintec crc-15w) in counts per minute (cpm). the uptake studies were performed in normoxia (95% o2 and 5% co2), as well as in hypoxia (93% n2, 2% o2 and 5% co2) conditions. studies in hypoxia were performed in a controlled environment chamber (plaslabs lamsing, mich. 800-866-7527). clinical study a cross sectional analysis of all patients undergoing radical prostatectomy between january 2009 and december 2016 in urology department was performed. we evaluated 704 patients who were divided into two groups (diabetic and non-diabetic). we assessed clinical and histological parameters such as age at pca diagnosis, preantunes1_stesura seveso 03/10/18 09:42 pagina 185 archivio italiano di urologia e andrologia 2018; 90, 3 h. pontes antunes, r. teixo, j. andré carvalho, et al. 186 operative psa, diagnostic biopsy results and surgical specimen pathology. all patients classified as diabetic were already diagnosed prior to radical prostatectomy. the diagnosis was in all cases performed by endocrinologists or general practitioners, with all patients being followed up on a specific diabetes mellitus consultation. all patients underwent open radical prostatectomy. statistical analysis statistical analysis was performed using the ibm® spss® software v. 22.0 (ibm corporation, armonk, new york, usa). the normality distribution of the variables was confirmed through shapiro-wilk. student t-test (parametric) was used in case of normal distribution and homogeneity of variance, otherwise, mann-whitney test (nonparametric) was used. in order to compare cell lines, one-factor analysis of variance (anova) parametric test was used in case of normal distribution and homogeneous variances of the variables, otherwise kruskalwallis nonparametric test was used. multiple comparisons were obtained after games-howell correction. the chi-square test was used to analyse categorical variables. a significant level of 5% was adopted for all comparisons. results expression of ar and her2/neu to characterize both pc3 and lncap cell lines we evaluated hormonal androgen receptor and her2/neu with high and low glucose concentration medium. results are presented in figure 1. according to figure 1a, pc3 cell line does not express androgen receptor in both conditions, as for this receptor, we only consider a positive staining when mif values are higher than 10. on the other hand, lncap cell line (figure 1b) expresses this receptor in both culture conditions but show a significantly higher expression of ar when cultured in high glucose concentration medium (p < 0.05). regarding expression of her2/neu receptor in prostate cancer cell lines, it is possible to observe that glucose concentration in the medium significantly alter the expression of this receptor in both pc3 (figure 1c, p = 0.036) and lncap (figure 1d, p < 0.001) cell lines, with an increased expression in high glucose medium. our results also highlight that androgen-dependent cell line lncap presents a higher expression of this receptor compared to androgen-independent cell line pc3, both in hg (p < 0.001) and in lg (p < 0.01) medium. proliferation rate to evaluate the proliferation rate of pca cell lines, the ratio ad4/ad1 was calculated and is represented in figure 2. results showed that pc3 cell line has a higher growth rate than lncap in both media considered in our work. pc3 cell line presents an ad4/ad1 ratio of 9.2 when cultured in high glucose condition and an ad4/ad1 ratio of 6.1 when cultured in low glucose. thus, it presents a significantly higher proliferative rate in high glucose conditions (p < 0.001). the same observation is valid for lncap cells, presenting an ad4/ad1 ratio of 3.1 when cultured in high glucose condition a significant different value when compared with the ad4/ad1 ratio of 1.5 when cultured in low glucose conditions (p = 0.003). we can also observe that proliferative rate is significantly higher in pc3 cells than in lncap cells, in both glucose conditions, high (p < 0.001) and low (p < 0.001). cellular characterization and immunocytochemistry percentage of positive ki67 cell of prostate cancer cell lines in high and low glucose are, respectively, 38.7% and 9.9% in pc3 cell lines and 11.2% and 3.6% in lncap cell lines. the percentage of ki67 positive cells is significantly higher in cells cultured in high glucose medium, in both lncap and pc3 cell lines. moreover, we observed a higher expression of ki67 in the pc3 cell line in both culture media. glucose transporters (gluts) quantification glucose transporters expression is resumed in figure 3. our results showed that there are differences in the expression of glucose transporters between the two cell lines under study. lncap cell line presented a higher expression of glut12 than pc3 cells when cultured in low glucose condition (p = 0.013). figure 1. expression of androgen receptor in pc3 (a) and lncap (b) in high glucose (hg) and low glucose (lg). expression of her2/neu receptor in pc3 (c) and lncap (d) in high glucose (hg) and low glucose (lg), expressed as mean intensity fluorescence (mif). for each condition, results were obtained with a minimum of eight experiments. graphs represent mean±standard error. statistical significance: *p < 0.05; ***p < 0.001. antunes1_stesura seveso 03/10/18 09:42 pagina 186 187archivio italiano di urologia e andrologia 2018; 90, 3 diabetes and prostate cancer metabolism we also observed that glut1, glut3 and glut5 expression is not different between the two prostate cancer cell lines. moreover, in lncap cells, an increased expression of glut3 were observed when cells were cultured in low glucose medium (p = 0.016). in pc3 cell line, this differential expression due to culture media is observed only for glut1 (p = 0.013). 18f-fluorodeoxyglucose (18f-fdg) uptake studies in our work the uptake profile of 18ffdg was determined in prostate cancer cell lines when cultured in high and low glucose media. our results (figure 4) showed that there are no alterations in 18f-fdg uptake over time when pc3 and lncap cell lines are cultured in high glucose medium. moreover, when cells are culture in low glucose concentration, 18f-fdg uptake significantly increases with time when compared with cells cultured in high glucose concentration. on pc3 cell line, we observed a significantly higher uptake on cells culture on lg compared with hg after 5 minutes (1.46% ± 0.06% vs. 0.76% ± 0.07%, p < 0.001), 30 minutes (5.02% ± 0.58% vs. 1.15% ± 0.07%, p = 0.010), 90 minutes (11.83% ± 2.01% vs. 2.09% ± 0.33%, p = 0.026) and 120 minutes (13.60% ± 1.33% vs. 2.31% ± 0.22%, p = 0.005). on lncap cells, we observed a significantly higher uptake on cells culture on lg compared with hg after 5 minutes (1.92% ± 0.37% vs. 0.51% ± 0.09%, p < 0.045), 30 minutes (4.10% ± 0.10% vs. 0.76% ± 0.02%, p < 0.001), 60 minutes (6.80% ± 0.18% vs. 1.02% ± 0.17%, p < 0.001), 90 minutes (9.46% ± 2.01% vs. 1.28% ± 0.14%, p < 0.001) and 120 minutes (11.78% ± 0.51% vs. 1.41% ± 0.12%, p < 0.001). clinical study demographic and clinicopathological data of patients undergoing radical prostatectomy are shown in table 1. the rate of diabetic patients was 21.2%. diabetic patients had higher prostatic volumes. however, the diagnosis of dm did not show relationship with the development of tumours with more aggressive histology or staging. discussion as mentioned before, the correlation between dm and some neoplasms, like lung, colorectal or breast cancer, is already known (1-3), however, the relationship with pca was not established yet. similarly, populational studies are not clear on establishing an association between this two diseases (68). the diabetic disease has several aspects capable of exerting influence on pca, like hyperinsulinemia (16), igf-1, inflammation and also its treatment (18). in our work, we evaluated another aspect of dm, the hyperglycaemia, and its action on pca behaviour at a molecular level, by using an in vitro model of two pca figure 2. results represent the ratio between the measured absorbance after 96h (day 4, ad4) and after 24h (day 1, ad1) for pc3 (a) and lncap (b). results were obtained with six independent experiments. values represent mean±standard error statistical significance: **p < 0.01; ***p < 0.001. figure 3. expression of gluts in prostate cancer cell line lncap (a) and pc3 (b) in high and low glucose media presented as mean intensity fluorescence. results are expressed as mean±standard error of a minimum of three independent experiments statistical significance: **p < 0.01. figure 4. 18f-fdg uptake in pc3 (a) and lncap (b) prostate cancer cells cultures in high and low glucose media, expressed as percentage of uptake. results are presented as mean±standard error of a minimum of four independent experiments statistical significance: *p < 0.05; **p < 0.01; ***p < 0.001. antunes1_stesura seveso 03/10/18 09:42 pagina 187 archivio italiano di urologia e andrologia 2018; 90, 3 h. pontes antunes, r. teixo, j. andré carvalho, et al. 188 cell lines incubated with different glucose concentrations, resembling a normal glycaemia (lg) and hyperglycaemia (hg). our results showed that pc3 cell line do not significantly express ar, while lncap cell line have a higher expression of this receptor, as was proved by tilley (21) in 1990. for lncap cell line we observed that when medium’s glucose concentration increased, there was an increased in ar expression. this may be explained, in part, by the ar role on the glucose uptake and glycolysis regulation (22). it seems that ar stimulates glycolysis via the metabolic sensor 5′-amp activated protein kinase (ampk) not only for adenosine 5’-triphosphate (atp) production (23, 24) but also for de novo lipid synthesis (25). this is consistent with the typical warburg effect for cancer cells metabolism (26), which is an inefficient way to generate atp in order to acquire nutrients (26). this effect appears to take place in prostate cancer under the ar regulation (22). her2/neu has been indicated as a factor of cancer aggressiveness in other types of cancer (27) and in pca was also related with ar activation in castration resistant prostate cancer (28). our results showed that her2/neu receptor expression was also significantly different with both media glucose concentrations in the two cell lines. there was an increased her2/neu receptor expression with the hg medium. as far as we know, this association was not studied until today in prostate cancer cells, but in breast cancer cells was identified a relationship between her2/neu and the glycolytic phenotype (29). it appears that her2/neu overexpression increases activation of akt, which leads to an up-regulation of glut1 and a down-regulation of m2pk (m2 pyruvate kinase isoenzyme) (29). this down regulation of m2pk leads to an accumulation of glycolytic metabolites, providing substrates for synthetic processes (29). thus, as we mentioned before, pca cells also stimulates glycolysis for a synthetic purpose (25), may the process seen in breast cancer cells also happens with them. 18f-fdg is an analogous of glucose radiolabelled with fluor-18. in the uptake studies we verified that the uptake of the 18f-fdg glucose analogous depends of the medium composition. besides this it is important to have in account the uptake mechanism in which 18f-fdg enters in the cell by facilitated diffusion mediated by membrane glucose transporters, and after it is phosphorylated by hexokinase to fdg-6-phosphate. further the phosphorylation concerning the very strict structural and geometric demands of the reaction, the phosphoglucose isomerase does not recognize fdg-6phosphate and consequently there will be accumulation on the cytoplasm, which means that 18f-fdg-6-p remains inside the cell capable of being detected during the time that remains radioactive. the distribution of radiolabelled fdg reflects not the glycolytic pathway but the exaggerated need of glucose according to the warburg effect (30). the 18f-fdg uptake by the cells was higher with low glucose concentration medium. this can be explained by the absence of competitor in the transporter, which is the glucose present in the medium. since pca cells are metabolically very active, they are greedy to glucose and the lower the content of glucose, the higher is the 18f-fdg uptake. this has clinical relevance because the better the glucose control is, the better will be the images of the pet scan with 18f-fdg. as we determined by the proliferation rate, we verified interesting results, as the pc3 cell line is the one who present a higher growth rate and for both cell lines we saw that the hg medium had the shorter doubling time. moreover, the fact that cells cultured in lg presented a higher 18f-fdg uptake even having a lower proliferation rate highlights the clinical relevance of a good glucose control when a pet scan with 18f-fdg is performed. glut proteins facilitate glucose transport across biological membranes. different expressions of gluts have been related with different kinds of cancer and with cancer specific survival (31-35). gluts 1, 3 and 12 are known for being expressed in pca (31). in our work we observed a similar expression of the investigated glucose transporters in both culture media, exception for glut1 in pc3 cells and glut3 in lncap cells. with the lg medium we observed a significant increase glut1 expression in the pc3 cells and an increase gltu3 expression in the lncap cells. also, in lncap cells, there is a higher expression of glut1, glut3 and glut12 compared with pc3 cells when both cell lines are cultured in hg conditions, showing that maybe these table 1. demographic and clinicopathological features of patients undergoing radical prostatectomy. diabetic group non-diabetic group p value (n = 149) (n = 555) age (years), mean ± sd 64.5 ± 5.6 62.8 ± 6.7 0.003 psa preoperative (ng/ml), mean ± sd 9.2 ± 6.3 9.9 ± 12.0 ns preop. fasting glycaemia (mg/dl), mean ± sd 114.0 ± 25.4 93.9 ± 12.6 0.001 prostatic volume (cc), mean ± sd 54.2 ± 21.3 47.7 ± 18.1 0.001 risk groups, n (%) ns low-risk 50 (33.6%) 208 (37.5%) intermediate-risk 80 (53.5%) 261 (47.0%) high-risk 17 (11.4%) 63 (11.4%) isup of rp specimen, n (%) ns isup grade 1 31 (20.8%) 118 (21.2%) isup grade 2 96 (64.4%) 364 (65.6%) isup grade 3 13 (8.7%) 54 (9.7%) isup grade 4 3 (2.1%) 12 (2.2%) isup grade 5 6 (4.0%) 7 (1.3%) perineural invasion, n (%) 116 (83.5%) 456 (86.4%) ns tnm staging, n (%) ns pt2 85 (57.0%) 328 (59.1%) pt3 64 (43.0%) 227 (40.9%) pn0 93 (62.4%) 357 (64.3%) pn1 12 (8.1%) 37 (6.7%) pnx 44 (29.5%) 161 (29.0%) positive margins, n (%) 41 (27.5%) 138 (24.9%) ns ns = not significant; sd = standard deviation; rp = radical prostatectomy. antunes1_stesura seveso 03/10/18 09:42 pagina 188 189archivio italiano di urologia e andrologia 2018; 90, 3 diabetes and prostate cancer metabolism transporters could be related with the ar (24). despite the results in cell lines, our clinical sample did not show significant differences between tumour development in diabetic and non-diabetic patients. diabetic patients had higher prostatic volumes. in terms of oncologic staging we did not find significant differences, however, we found that the rate of patients with grade 5 of the isup classification is higher in diabetic patients (4.0% vs. 1.3%), although this difference did not reach statistical significance. this result is in agreement with other studies that have reported that dm mainly decreases the risk of low-grade tumors and, to a lesser degree, the risk of high-grade tumors. consequently, it is plausible to assume that dm changes the proportions of pca grades favoring high-grade tumors (7, 11). some series of patients undergoing rp have shown that dm is associated with a higher pca grade (36). however, a previous analysis of the capsure database found no association between dm and pca aggressiveness (37). thus, more studies in this area will be necessary to really clarify the relationship between dm and pca aggressiveness. conclusions our results showed that glucose levels could influence prostate cancer cells behaviour. in the hg medium pca cells had a more aggressive pattern, with higher expression of ar (only for lncap) and her2/neu (for both cell lines) and a higher proliferation rate demonstrated by ki67 staining and ratio ad4/ad1. glut expression had slight variations in both culture conditions, but its expression is significantly higher in lncap cells. thus, incubation of cells in hyperglycaemia-like conditions induced a more aggressive molecular 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prostate cancer recurrence-data from capsure(tm) (united states). cancer causes control. 2005; 16:789-797. correspondence hugo manuel pontes antunes, md (corresponding author) hugoantunes4@gmail.com urology and transplantation dpt, coimbra hospital and university centre rua padre sebastião, nº12 – 2c, 3040-376 coimbra, portugal ricardo teixo, md rcardoteixo@gmail.com joão andré carvalho, md jccarvalho@gmail.com miguel eliseu, md migeliseu3@gmail.com inês marques, md ana mamede,md rita neves, md rui oliveira, md edgar tavares-da-silva, md belmiro parada, md ana margarida abrantes, md arnaldo figueiredo, md maria filomena botelho, md antunes1_stesura seveso 03/10/18 09:42 pagina 190 archivio italiano di urologia e andrologia 2019; 91, 4230 original paper is fast track protocol a safe tool to reduce hospitalization time after radical cystectomy with ileal urinary diversion? initial results from a single high-volume centre daniele romagnoli 1, riccardo schiavina 2, lorenzo bianchi 2, marco borghesi 2, francesco chessa 2, federico mineo bianchi 2, andrea angiolini 2, carlo casablanca 2, marco giampaoli 1, paolo corsi 1, daniele d’agostino 1, eugenio brunocilla 2, angelo porreca 1 1 abano terme hospital, abano terme (pd), italy; 2 st. orsola malpighi universitary urology clinic, bologna (bo), italy. introduction and aim: radical cystectomy (rc) with ileal urinary diversion is one of the most complex urological surgical procedure, and many fast track (ft) protocols have been described to reduce hospitalization, without increasing postoperatory complications. we present the one-year results of a dedicated protocol developed at a high volume centre. materials and methods: the ft protocol was designed after a review of the literature and a multidisciplinary collegiate discussion, and it was applied to patients scheduled to open rc with intestinal urinary diversion. to validate its feasibility, we compared its results with data collected from a 1:1 matched population of patients who had undergone the same surgical procedure, without the implementation of the ft protocol. results: we enrolled in the ft group 11 (55%) patients scheduled to rc with ileal conduit diversion, and 9 patients (45%) scheduled to orthotopic neobladder (studer) substitution, while a numerically equivalent population was enrolled in the control group, matched according to age at surgery, bmi, gender, asa score, cci, preoperative stage and type of urinary diversion. no statistically significant difference was found in terms of pre-operatory and intra-operatory domains. median overall age was 71 years (inter quartile range iqr: 63-76) and mean operatory time was 276 ± 57 minutes. hospitalization time was significantly reduced in the ft group, considering oralization and canalization items we found a significant advantage in the ft group. no statistically significant difference was found in the control of the post-operatory pain. we found no difference, in terms of both early and late complications ratio, among the two populations. complications graded clavien ≥ 3 were found in 4 patients of the control group (20%), while in only one patient (5%) in the fast track group, though this difference was not statistically significant. conclusions: the fast track protocol developed in this study has proven to be effective in significantly reducing hospitalization time in patients submitted to rc with intestinal urinary diversion, without increasing post-operatory complications ratio. key words: radical cystectomy; fast track; enhanced recovery; after surgery. submitted 4 june 2019; accepted 26 june 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.230 introduction bladder cancer (bc) represents the 7th most common cancer in male population and the 11th considering both sexes (1). open rc remains the gold standard for the surgical treatment of localized muscle invasive bladder cancer (mibc) or non-muscle invasive bladder cancer (nmibc) resistant to topic chemoand immunologic therapy (2, 3). rc with urinary diversion is considered one of the most complex urological surgery and is characterized by long hospital stay and high rate of postoperative morbidity and mortality. complication rate could be up to 34.4% (and to 50% in some series) for mildmoderate grade (clavien dindo < 3), and up to 17.5% for severe grade (4, 5) (clavien dindo ≥ 3). even if improvements in surgical procedure have reduced incidence of postoperative complication, it remains important to minimise surgical trauma and optimise perioperative care. the term “fast track” refers to a group of perioperative protocols aimed to standardise perioperative cares, shorten hospital stay, maintain optimal surgical treatment quality without increasing postoperative complication rate (6). they are also commonly known as enhanced recovery after surgery (eras) protocols, as they were firstly described in general surgery. ft schemes are standardised, multimodal and multidisciplinary developed protocols aimed to enhance surgical outcomes referring to perioperative “best clinical practice” (7). the origins of eras protocols date back to the early 90s with the experiences of dahl et al., with bupivacaine intratecal analgesia (8), and kehlet et al. with epidural anaesthesia, high preoperative glucose intake and early mobilization and starting of oral diet, applied on colorectal surgery with a mean reduction of 2 days in terms of hospital stay (9). from the urologist’s point of view, ft protocols can be applied mainly to rc with ileal diversion, considering the complex operation technique, high complication rate and long mean hospital stay. distinctive tract of the ft protocols is that they can be adapted on patient’s needs depending on perioperative management phase. key features of ft protocols are: perioperative diet management, advanced anesthesiological technique, specific antalgic postoperative care (based on non-opioid drugs), early oral diet intake and mobilization (10). we developed a ft protocol with the aim of reducing mean hospitalization time in patients subromagnoli_stesura seveso 10/01/20 08:50 pagina 230 231archivio italiano di urologia e andrologia 2019; 91, 4 fast track protocol after radical cystectomy with ileal urinary diversion mitted to rc with ileal urinary diversion in our centre, without increasing the complications ratio. materials and methods after an extensive review of literature and a multidisciplinary team consult consisting of urologists, anesthesiologists, nurses and nutritionists, we developed an eras protocol (see appendix). to test the effect of this protocol, we designed a pilot observational prospective cohort study, in accordance with the principles and practice of our review board. the protocol focused on the reduction of postoperative nausea and vomiting, early canalization, nasogastric tube (ngt) removal, enteral feeding and mobilization, shorter hospitalization time, without significant worsening in terms of complication rate or pain management. we enrolled 20 consecutive patients candidate to open rc with ileal urinary diversion from january 2016 to april 2017 at a single high volume centre. each operation was performed by surgeons at the end of the learning curve and with extensive experience. the indications for rc included muscle-invasive bladder carcinoma or high-grade non-muscle invasive bladder carcinoma refractory to topic intravesical immunotherapy in fit-for-surgery patients (2, 3). preoperative radiological assessment was realized via a toraco-abdominal computed tomography with urographic reconstructions and contrast enhanced magnetic resonance of the pelvis (we adopted this accessory technique in order to have a precise and detailed study of the pelvis, as previously described) (11). data were prospectively collected from medical records. for each patient of the study population a one-to-one propensity scorematched analysis was performed with a population selected among 64 patients who underwent rc with ileal urinary diversion, without application of the ft protocol. each patient received detailed instructions about ft protocol at preoperative evaluation. adherence to instructions was verified at the time of the hospital admittance. data were prospectively collected for patients in the ft group, while, for patients of the control group, each item was retrospectively collected. preoperative data were collected about age, body mass index (bmi), american society of anesthesiology score (asa score), charlson comorbidity index (cci), smoking habits, clinical stage, grading (defined sec. who 2016 classification) or neoadiuvant therapy. we collected data regarding surgical approach, urinary diversion used, pelvic lymphadenectomy template, number of removed lymph nodes, global operation time (minutes) and intraoperative transfusion rate. postoperative data collection comprehended histological tumor features (such as stage, grading, lymph node status), hospital stay time, ngt removal table 1. preoperative and intraoperative items. overall fast track group control group p value number of patients, n (%) 40 (100%) 20 (50%) 20 (50%) gender, n (%) male 31 (77.5) 16 (80) 15 (75) 0.7 female 49 (22.5) 4 (20) 5 (25) age median (iqr) 71 (63-76) 70 (60-76) 72 (66-75) 0.6 asa score, n (%) 1-2 16 (40) 9 (45) 7 (35) 0.5 3-4 24 (60) 11 (55) 13 (65) cci, n (%) 0 0 (0) 0 (0) 0 (0) 0.8 1-2 7 (17.5) 4 (20) 3 (15) 3-4 15 (37.5) 8 (40) 7 (35) > 4 18 (45) 8 (40) 10 (50) bmi (kg/m2) mean ± sd 28 ± 4.8 28 ± 4.9 28 ± 5 0.9 smoking attitude, n (%) no 16 (40) 11 (55) 5 (25) 0.05 yes 24 (60) 9 (45) 15 (75) clinical stage, n (%) t0 1 (2.5) 0 (0) 1 (5) 0.7 ta-pt1 12 (30) 7 (35) 5 (25) t2 23 (57.5) 11 (55) 12 (60) t3 4 (10) 2 (10) 2 (10) preoperative grade, n (%) g1 1 (2.5) 0 (0) 1 (5) 0.6 g2 5 (5) 1 (5) 1 (5) g3 37 (92.5) 19 (95) 18 (90) neoadjuvant chemotherapy, n (%) no 40 (100) 40 (100) 40 (100) yes 0 (0) 0 (0) 0 (0) surgical approach, n (%) open 39 (97.5) 19 (95) 20 (100) 0.3 laparoscopic 1 (2.5) 1 (5) 0 (0) plnd template, n (%) not performed 2 (5) 1 (5) 1 (5) 0.2 standard 22 (55) 13 (65) 9 (45) extended 14 (35) 4 (20) 10 (50) super-extended 2 (5) 2 (10) 0 (0) lymph node retrieved median (iqr) 14 (10-23) 14 (12-21) 14 (8-24) 0.3 urinary diversion, n (%) ileal conduit 23 (57.5) 11 (55) 12 (60) 0.7 ileal ortotopic neobladder (studer neobladder) 17 (42.5) 9 (45) 8 (40) surgical time (minutes) mean ± sd 276 ± 57 260 ± 56 293 ± 54 0.06 intraoperative transfusion, n (%) no 27 (67.5) 15 (75) 12 (60) 0.3 yes 13 (32.5) 5 (25) 8 (40) pathologic stage, n (%) pt0 2 (5) 1 (5) 1 (5) 0.8 pt1-ptis 9 (22.5) 6 (30) 3 (15) pt2a-pt2b 7 (17.5) 3 (15) 4 (20) pt3a-pt3b 15 (37.5) 6 (30) 9 (45) pt4 7 (17.5) 4 (20) 3 (15) pathologic grade, n (%) g1 2 (5 ) 1 (5) 1 (5) 0.8 g2 2 (5) 1 (5) 1 (5) g3 35 (87.5) 17 (85) 18 (90) g4 1 (2.5) 1 (5) 0 (0) lni, n (%) no 26 (65) 13 (65) 13 (65) 1 yes 14 (35) 7 (35) 7 (35) iqr: inter quartile range; vas: visual analogue scale; asa: american society of anesthesiologists; cci: charlson comorbidity index; bmi: body mass index; sd: standard deviation; plnd: pelvic lymph node dissection; lni: lymph node invasion. romagnoli_stesura seveso 10/01/20 08:50 pagina 231 archivio italiano di urologia e andrologia 2019; 91, 4 d. romagnoli, r. schiavina, l. bianchi, et al. 232 (time and repositioning), pain control (coded by visual analogic scale [vas] standard), time to flatus and time to defecation, lymphorrea amount, time of the start of a light diet and time to drain removal. postoperative complications were stratified as early (before 30 days from surgery) and late complications (between 30 and 90 days from surgery). all complications were graded following the clavien-dindo classication. to compare results between the study population and the control group a one-to-one propensity score-matched analysis was computed by modelling a logistic regression, with the dependent variable as the odds of undergoing fast track protocol and independent variables such as age at surgery, bmi, gender, asa score, cci, preoperative stage and urinary diversion in course of surgery. subsequently, covariate balance between the matched groups was examined. covariates between the two groups were considered equivalent, providing a standardised mean difference ≤ 10%. the primary objective was the evaluation of the eventual reduction in hospitalization ratio, while the secondary objective was the evaluation of any difference in the early (< 30 days) and late (< 90 days) postoperative complication ratio. statistic software r (the r foundation) was used for statistical analysis. chi-square test and t test were used for binomial and continuous variables, respectively. results 11 (55%) patients of ft groups underwent ureteroileocutaneostomy, while 9 (45%) patients underwent urinary diversion with orthotopic neobladder (according to the studer technique), while, in the control group, 12 (60%) patients received ureteroileocutaneostomy and 8 patients (40%) were submitted to orthotopic urinary diversion according to the studer technique. table 1 shows preoperative and intraoperative characteristics of the two study groups. the two groups were statistically homogenous, with no significant difference among them. considering intraoperative parameters, mean operative time was 260 ± 56 min in ft group, while was 293 ± 54 min in the control group, with a difference at the limit of the statistical difference (p = 0.06). table 2 depicts fast track outcomes. ngt was removed earlier in the ft group than in the control group, with a median of 20 hours versus 48 hours, respectively (p < 0.001). just one patient (5%) of the ft group had sng removed after the first 24 hours. no significant difference was noted in ngt repositioning rates between the two groups (15% in ft group and 5% in control group, p = 0.3). table 2. postoperative datas. overall fast track group control group p value number of patients, n (%) 40 (100%) 20 (50%) 20 (50%) ngt removal ( hours) median (iqr) 24 (20-48) 20 (18-20) 48 (48-72) < 0.001 ngt removal after pod 1, n (%) 18 (42.5) 1 (5) 16 (80) < 0.001 ngt repositioning, n (%) 4 (10) 3 (15) 1 (5) 0.3 mobilization (hours postoperatively) mean ± sd 66 ± 43 21 ± 12 106 ± 26 < 0.001 postoperative nausea episodes, n (%) none 25 (62.5) 13 (65) 12 (60) 0.02 1 7 (17.5) 6 (30) 1 (5) > 1 8 (20) 1 (5) 7 (35) postoperative vas score median (iqr) 4 (3-4) 3 (3-4) 4 (3-4) 0.2 time to flatus (pod) median (iqr) 2 (1-3) 1.5 (1-2.75) 3 (2-3.75) 0.004 time to defecation (pod) median (iqr) 5 (3-6) 4 (3-5.75) 6 (4.5-6) 0.02 start of a light diet (pod) median (iqr) 5 (2-8) 2 (2-4.5) 6.5 (6-8) < 0.001 last drain removal (pod) median (iqr) 8 (6-9) 7 (6-9.75) 8.3 (7-9) 0.5 lymphorrea amount (ml) mean ± sd 1720 ± 1534 1776 ± 1710 1665 ± 1380 0.8 hospital stay (days) median (iqr) 12 (9-14) 10 (8-12) 13 (11-14) 0.005 ngt: naso gastric tube; pod: post operatory day; sd: standard deviation; iqr: inter quartile range. table 3. postoperative complications. overall fast track group control group p value number of patients, n (%) 40 (100%) 20 (50%) 20 (50%) overall perioperative (< 30 days) complications, n (%) no 31 (77.5) 14 (70) 17 (85) 0.3 yes 9 (22.5) 6 (30) 3 (15) clavien-dindo classification, n (%) grade 1 6 (66.6) 5 (83.3) 1 (33.3) 0.3 grade 2 2 (22.2) 1 (16.7) 1 (33.3) grade 3 1 (11.1) 0 (0) 1 (33.3) grade 4 0 (0) 0 (0) 0 (0) grade 5 0 (0) 0 (0) 0 (0) type of complication (< 30 days), n (%) dynamic ileus 6 (66.6) 5 (83.3) 1 (33.3) 0.3 anemization 1 (11.1) 1 (16.7) 0 (0) wound infection 1 (11.1) 0 (0) 1 (33.3) deep venous thrombosis 1 (11.1) 0 (0) 1 (33.3) overall postoperative (< 90 days) complications, n (%) no 36 (90) 19 (95) 17 (85) 0.3 yes 4 (10) 1 (5) 3 (15) clavien-dindo classification, n (%) grade 1 0 (0) 0 (0) 0 (0) 0.3 grade 2 0 (0) 0 (0) 0 (0) grade 3 4 (100) 1 (100) 2 (100) grade 4 0 (0) 0 (0) 0 (0) grade 5 0 (0) 0 (0) 0 (0) type of complication (< 90 days), n (%) lymphocele (right iliac fossa) 1 (25) 1 (100) 0 0.2 uretero-ileal anastomosis stricture 2 (50) 0 2 (66.7) laparocele 1 (25) 0 1 (33.3) readmission within 90 days, n (%) 4 (10) 1 (5) 3 (15) 0.3 romagnoli_stesura seveso 10/01/20 08:50 pagina 232 233archivio italiano di urologia e andrologia 2019; 91, 4 fast track protocol after radical cystectomy with ileal urinary diversion mobilization time was significantly shorter in the ft group than in the control group (mean 21 ± 12 hours vs 106 ± 26 hours, respectively, p < 0.001). we observed one (5%) patient in the ft group who had more than one nausea episode postoperatively, while we noted 7 (35%) of such events in the control group (p = 0.02). median time to flatus was 1,5 (iqr 1-3) days in the ft group and 3 (iqr: 2-3.75) days in the control group, with a statistically significant difference (p = 0.004). we also observed a significant shorter time to defecation in the ft group (4 days iqr: 3-5.75) than in the control group (6 days, iqr 4.5-6) with p = 0.02. no statistically significant difference was noted in terms of vas scale, duration and entity of lymphorrea between the two groups. we observed a statistically significant shorter median hospital stay time in the ft group (10 days, iqr: 8-12) than in the control group (13 days, iqr: 11-14, p = 0.005). as depicted in table 3, no statistically significant difference was noted in terms of early and late complication rate among the two groups (p = 0.3 for each type of complication, respectively). considering early complications, only one event graded as clavien 3 was reported (11.1%), and it was a wound infection surgically treated in the control group. considering late complications ratio, 4 events graded as clavien 3 were documented, 1 in the ft group (right iliac fossa lymphocele percutaneously drained), and 3 in the control group (2 cases of uretero-ileal anastomosis stricture surgically corrected, and 1 case of laparocele surgically repaired), though this difference was not statistically significant (p = 0.2). no statistically significant difference was found in terms of readmission rate within 90 days among the two groups (p = 0.3) discussion rc with ileal urinary diversion is a surgery historically affected by a high rate of perioperative morbidity and mortality. with the starting point set in intervention on bowel in general surgery, eras protocols were described in order to improve postoperative outcomes. although a number of eras protocols have been built over the years, all of them found their key features on strategies to improve postoperative recovery rate and reduction of hospital stay time, without worsening postoperative complication rate. after extensive literature review and multidisciplinary meeting between urologists, anaesthetists, nurses and nutritionists, we designed a tailored eras protocol to be adopted at a high volume institution. in order to validate the ft protocol we designed a case-control prospective study, matching patients who underwent rc with ileal urinary diversion and who applied the protocol with patients who underwent the same kind of surgery but without implementation of the protocol. in our cohorts of rc with ileal urinary diversion, the adherence to the ft protocol permitted to obtain a significant shorter hospitalization time, without a significant increase in term of perioperative complications rate. an interesting fact is that no preoperative bowel preparation was adopted, because, as demonstrated by shafii et al., it does not give any significant advantage (12). moreover, the early removal of the ngt tube, in adjunction with a continuous prokinetic stimulus, has proven to be feasible, in accordance to the experience of braga (13), who demonstrated that decompression with ngt in all patients is not necessary ad is associated with an increased incidence of pulmonary complications. an important contribute to this result is represented by the perioperative dietary regimen and by the intraand postoperative pain management. the hypercaloric and hyperglucidic preoperative dietary regimen of the ft protocol allows to create a preoperative supply of proteins and glucose in order to react to the operative stress without significantly compromise the homeostasis and improving the natural healing process. this fact seems to be the possible base for the observation that no wound infections were reported in the ft group. as a matter of fact, wound repair depends on the disponibility of adequate protein and glucose supply, which could be insufficient after a prolonged perioperative fasting period. we observed no statistically significant difference in vas scale evaluation between the two groups, so we might affirm the non-inferiority of an opioid-free pain control regimen (based on fans and continuous infusion via epidural catheter), in comparison with the pain control obtained with opioid drugs. moreover, the absence of opioid administration allows to avoid typical side effects, such as a prolonged intestinal transit, which could hesitate in delayed time to flatus and time to defecation. other aspects of our ft protocol aimed to improve intestinal function, such as administration of prokinetic drugs (metoclopramide) and of chewing-gum, as already been prove successful by kouba et al. (14). we observed a statistically significant reduction of canalization time in ft group compared to control group, either considering median time to flatus (respectively in pod 1,5 vs pod 3, p = 0.004) and median time to defecation (respectively on pod 4 vs pod 6, p = 0.02). moreover we observed that patients of the ft group could tolerate a solid diet regimen on pod 2, significantly sooner in comparison with patients of the control group (median pod 6.5, p < 0.001). these results could be explained by the fact that metoclopramide administration is able to reduce the incidence of nausea and vomiting episodes, and also gastrointestinal complications, as described by pruthi (15). another explanation for this matter could be the fact that faster bowel activity recovery might be reached also with early mobilization and early feeding, as postulated by cerruto et al. (10). internal peristalsis is moreover facilitated by the blocking of visceral afferents and segmental efferences, which is realized by the epidural analgesia (16). the importance of a t11 epidural catheter as a useful tool to increase microvessels perfusion (thus reducing interference with the cardiopulmonary system), has been underlined by friedrich-freksa, who successfully applied this technique to high-risk patients submitted to rc (17). the result of the aforementioned considerations allows patients in the ft group to be discharged 3 days before, in comparison with patients of the control group (mean 10 days vs 13 days, p = 0.005). this result is in line with the literature, though there are discordant experiences, as the one described by cerruto (10), who reported no statistically significant difference in mean hospital stay romagnoli_stesura seveso 10/01/20 08:50 pagina 233 archivio italiano di urologia e andrologia 2019; 91, 4 d. romagnoli, r. schiavina, l. bianchi, et al. 234 time in patients submitted to rc with implementation of a dedicated ft protocol. a promising synergy is represented by ft protocols applied to mini-invasive surgery, a technique which is usually already characterized by a short hospital stay (18). as demonstrated by saar et al. (19), the implementation of a ft protocol in case of robotic approach to rc provides a significant advantage in terms of return to a regular diet and use of postoperative morphine equivalents. the efficacy of ft protocols applied to mini-invasive surgery has led to the recommendation to always adopt them in case of robot assisted radical cystectomy, as written in the paper published by wilson (20). moreover, the use of barbed sutures (21), a typical feature of the robotic approach, might improve the postoperatory continence ratio, as described in case of robotassisted radical prostatectomy (22, 23). another point of interest of ft protocols is the eventual reduction of both postoperative complications ratio and 90-days readmission rates. on a previous publication by cerruto et al. on the effect of a ft protocol in patients candidates to robot-assisted rc with padovana ileal neobladder, the authors reported a lower global rate of postoperative complications (p = 0.004) in patients adherent to the protocol (10). in our study we did not record a statistically significant difference between the two groups in terms of complications or readmission rate. such observation is in partly due to the scarce numerosity of the group of our study. it is important to underline that no major early complication (grade 3 or superior according to the clavien-dindo classification) was observed in the ft group. moreover, of the 4 (10%) major late complications observed, only 1 (5%) was in ft group, while 3 (15%) were in control group. the complication of the ft group was a lymphocele treated with ultrasound-guided percutaneous drainage, which seemed unrelated to ft protocol implementation. on the control group we observed one early and three late complications clavien ≥ 3, consisting of wound infection (early complication), two uretero-ileal anastomotic strictures (a well-documented complication of this kind of surgery) (24) and a laparocele, all of them treated with surgical revision on general anaesthesia. a limitation of the present study is the limited number of patients enrolled, though the scarce numerosity seems to be a common feature in studies concerning ft protocols applied to rc, as confirmed by a recent paper published by freeks et al. (25). conclusions the implementation of the ft protocol to patients submitted to rc with urinary ileal diversion is a safe and effective procedure, which allows to reduce hospitalization time without increasing postoperatory complications ratio. further studies are needed, with larger populations, in order to definitively confirm the superiority of ft protocols over standard protocols in the perioperative management of patients submitted to this surgical procedure. references 1. ferlay j, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries in 2012. eur j cancer. 2013; 49:13741403. 2. babijuk m, et al. eau guidelines: non-muscle-invasive bladder cancer, 2019. 3. witjes ja, et al. eau guidelines: muscle-invasive and metastatic bladder cancer, 2019. 4. schiavina r, et al. perioperative complications and mortality after radical cystectomy when using a standardized reporting methodology. clin genitourin cancer. 2013; 11:189-197. 5. chung y-r, et al. association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. cardiovasc diabetol. 2017; 16:4. 6. geltzeiler cb, et al. prospective study of colorectal enhanced recovery after surgery in a community hospital. jama surg. 2014; 149:955-961. 7. chang ss, et al. analysis of early complications after radical cystectomy: results of a collaborative care pathway, j urol. 2002; 167:2012-6. 8. dahl jb, et al. influence of timing on the effect of continuos extradural analgesia with bupivacaine and morphine after major abdominal surgery, br j anaesth. 1992; 69:4-8. 9. kehlet h, et al. multimodal strategies to improve surgical outcome. am j surg. 2002; 183:630-641. 10. cerruto ma, et al. fast track surgery to reduce short-term complications following radical cystectomy and intestinal urinary diversion with vescica ileale padovana neobladder: proposal for a tailored enhanced recovery protocol and preliminary report from a pilot study. urol int. 2014; 92:41-49. 11. schiavina r, et al. mri displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. j endourol. 2018; 32:315-321. 12. shafii m, et al. is mechanical bowel preparation necessary in patients undergoing cystectomy and urinary diversion? bju int. 2002, 89:879-881. 13. braga m, et al. espen guidelines on parenteral nutrition: surgery. clin nutr. 2009; 28:378-386. 14. kouba ej, wallen em, pruthi rs. gum chewing stimulates bowel motility in patients undergoing radical cystectomy with urinary diversion. urology. 2007; 70:1053-1056. 15. pruthi rs, et al. fast track program in patients undergoing radical cystectomy: results in 362 consecutive patients. j am coll surg. 2010; 210:93-99. 16. white pf, et al. the role of the anesthesiologist in fast track surgery: from multimedial analgesia to perioperative medical care. anesth analg. 2007; 104:1380-1396. 17. friederich-freksa m, et al. cystectomy and urinary diversion in the treatment of bladder cancer without artificial respiration. int braz j urol. 2012; 38:645-651. 18. porreca a, et al. robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon's experience after a modified modular training. minerva urol nefrol. 2018; 70:193-201. 19. saar m, et al. fast-track rehabilitation after robot-assisted laparoscopic cystectomy accelerates postoperative recovery. bju int. 2013; 112:e99-e106. romagnoli_stesura seveso 10/01/20 08:50 pagina 234 235archivio italiano di urologia e andrologia 2019; 91, 4 fast track protocol after radical cystectomy with ileal urinary diversion 20. wilson tg, et al. best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the pasadena consensus panel, eur urol. 2015; 67:363-75. 21. mineo bianchi f, et al. posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: description of the technique and its impact on urinary continence, arch ital urol androl. 2019; 91:5-10. 22. porreca a, et al. robotic-assisted radical prostatectomy with the use of barbed sutures, surg technol int. 2017; 30:39-43. 23. porreca a, et al. bidirectional barbed suture for posterior musappendix enhanced recovery protocol preoperative clinical setting: within 7 days before surgery anestehesiological assessment written dietary recommendations diet with no restrictions preoperative days 24 hours before rc hospital admittance unrestricted clear fluids normal breakfast no bowel preparation perioperative phase day of rc clear fluids allowed up to 2 hours before rc nutritional supply 2 hours before surgery (400 ml/200 calories) elastic compressive stockings ceftriaxone 2 g i.v as prophylaxis for infection intraoperative phase day of rc combined general and epidural anesthesia with intrathecal catheter left in place for the first pods optimized intraoperative intravenous fluid administration ngt insertion preoperatively ad removal at the end of surgery reducing intraoperative blood loss antiemetic prophylaxis infiltration of the surgical wound with local anesthetic postoperative phase day of rc ranitidine 150 mg i.v. metoclopramide 25 mg i.v. every 8 hours intravenous analgesia (paracetamol, ketorolac) epidural analgesia (elastomeric pump loaded with naropine) low molecular weight heparin (lmwh) as prophylaxis for thromboembolic events intravenous hydration (100 ml/h) of 10% glucose solution and electrolyte solution mobilization 6 hours after surgery free clear fluids as tolerated postoperative phase pod 1 female patients: remove vaginal pack active mobilization respiratory rehabilitation exercises 1100 calories diet as tolerated free clear liquids as tolerated analgesia if needed (ropivacaine, paracetamol, ketorolac) metoclopramide 25 mg i.v. every 8 hours ranitidine 150 mg 1 tab/die lmwh as prophilaxys chewing gum (1 piece very 2-4 hours), as tolerated postoperative phase pod 2 1500 calories diet as tolerated free clear fluids active mobilization drain removal (if drained < 50 ml/24 hours) culofascial reconstruction and knotless vesicourethral anastomosis during robot-assisted radical prostatectomy. minerva urol nefrol. 2018; 70:319-325. 24. schiavina r, et al. laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. j robot surg. 2016; 10:323-330. 25. freeks sk, et al. a prospective randomized pilot study evaluating an eras protocol versus a standard protocol for patients treated with radical cystectomy and urinary diversion for bladder cancer, world j urol. 2018; 36:215-220. romagnoli_stesura seveso 10/01/20 08:50 pagina 235 archivio italiano di urologia e andrologia 2019; 91, 4 d. romagnoli, r. schiavina, l. bianchi, et al. 236 epidural catheter removal neobladder flushes 3 trimes a day (every 8 hours) analgesia if required (paracetamol, ketorolac) lmwh as prophylaxis metoclopramide 25 mg i.v. every 8 hours continue ranitidine postoperative phase pod 3 active mobilization 1650 calories diet analgesia if needed (paracetamol, ketorolac) metoclopramide 25 mg i.v. every 8 hours lmwh as prophylaxis continue ranitidine continue neobladder flushing postoperative phase pod 4 active mobilization 2000 calories diet as tolerated analgesia if needed (paracetamol, ketorolac) metoclopramide 25 mg i.v. every 8 hours lmwh as prophylaxis continue ranitidine continue neobladder flushing postoperative phase pods 5 to 7 free diet active mobilization if absence of canalization and oralization after 5 days from surgery, start total parenteral nutrition (tpn) and search for any cause continue neobladder flushing lmwh as prophylaxis continue ranitidine postoperative phase pods 8 and 9 ureteral stents removal clips removal lmwh as prophylaxis postoperative phase pods 10 and 11 schedule for return to home lmwh as prophylaxis (up to 18 days after rc) postoperative phase pod 30 catheter removal (without neocystogram) correspondence daniele romagnoli, md (corresponding author) danieleromagnoli87@gmail.com marco giampaoli, md paolo corsi, md daniele d’agostino, md angelo porreca, md robotic urology and mini invasive urologic surgery unit abano terme hospital, piazza cristoforo colombo 2 abano terme (pd), italy riccardo schiavina, md lorenzo bianchi, md marco borghesi, md federico mineo bianchi, md andrea angiolini, md eugenio brunocilla, md urology unit, s. orsola malpighi university hospital alma mater studiorum via pelagio palagi, 9 bologna (italy) francesco chessa carlo casablanca st. orsola malpighi universitary urology clinic, bologna (bo), italy romagnoli_stesura seveso 10/01/20 08:50 pagina 236 archivio italiano di urologia e andrologia 2019; 91, 4218 original paper lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece mario lourenço 1, pedro pissarra 2, duarte vieira e brito 1, miguel eliseu 3, joao pedro peralta 1, arnaldo figueiredo 3, cristina marques 2 1 urology department portuguese institute of oncology coimbra, coimbra, portugal; 2 radiology department coimbra hospital university centre, coimbra, portugal; 3 urology and kidney transplant department coimbra hospital university centre, coimbra, portugal. introduction: prostatic multiparametric magnetic resonance (mpmri) allows for guided prostate biopsy (pb). objective: to evaluate localization agreement between mpmri lesions and histology obtained by cognitive pb and radical prostatectomy (rp) surgical specimen (ss). methods: out of 115 consecutive cognitive biopsied patients, 37 with positive pb were studied. sample was characterized regarding age, prostatic volume, pi-rads, location of lesion on mpmri, lesion dimension, total number of fragments obtain by pb, number of fragments directed to the lesion, number of fragments with prostatic adenocarcinoma (pca) and isup classification. the relationship between mpmri and ss piece was analysed in 15 patients who underwent rp. results: regarding agreement between mpmri and pb, agreement of location was observed in 26 (70.3%); 7 (18.9%) presented pca positive fragments in the suspected zone plus others in the same lobe; 3 (8.1%) in the suspected zone plus the contralateral lobe and 1 (2.7%) had no pca in the suspected zone but had bilateral pca. the total number of fragments with pca was lower in cases with agreement between mpmri and pb (p < 0.05). regarding agreement between mpmri and ss, 5 cases (33.3%) presented the same location as described by mpmri, 5 (33.3%) showed ipsilateral lesions in other zones of the prostate; 4 (26.7%) presented extensive bilateral lesions on all prostate zones and 1 (6.7%) showed previously unknown contralateral lesions. none of the factors studied related mpmri and rp (p > 0.05). conclusions: localization agreement of mpmri vs pb and mpmri vs ss was present in 26/37 (70.3%) and 5/15 (33.3%), respectively. that suggests the existence of other lesions (multifocality) not identified on mpmri. key words: prostate biopsy; cognitive prostate biopsy; multiparametric magnetic resonance imaging; prostate cancer; localization agreement; multifocality. submitted 4 june 2019; accepted 6 august 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.218 introduction the incidence of prostate cancer (pca) has increased in the last decades, being the most common male malignant disease and a major cause of morbidity and mortality (1-3). this increase is due to the increasing use of screening techniques such as the prostate specific antigen (psa) testing which allows for the detection of lesions at an earlier stage including lesions that may not develop into significant disease (1, 3). pca has high prevalence in the male population (3-4% in northern europe) but low mortality rates (1). currently, the standard method for the diagnosis of pca is digital rectal exam (dre) or psa measurement followed by transrectal ultrasound guided prostate biopsy (pb) in suspected patients although it lacks sensitivity and specificity for lesion detection (1, 2, 4). prostate ultrasound can demonstrate some lesions that appear hypo-echoic when compared to the normal echogenic peripheral zone. however, more than 4050% of cancerous lesions may appear as iso-echoic allowing for many false negatives even when protocols that sample normal prostate are used, such as double sextant biopsy (1, 4, 5). due to this fact, the use of multiparametric magnetic resonance (mpmri), applying the pi-rads scoring system, to complement and in some cases avoid pb has increased (1, 4, 6-10). multiparametric magnetic resonance allows for detection, characterization, staging and assessment of metabolic, morphological and cellular changes of lesions that correlate with tumour aggressiveness; mpmri can also decrease the detection of indolent disease. the combination of mpmri with biopsy (fusion biopsies) increases its value as a diagnostic tool (1, 4, 6, 7, 11-13). the use of mpmri with its ability to detect lesions larger than 0.2 ml, permits in some cases the identification of multiple lesions (multifocality) of localized pca. in fact, prostate can have coexistence of more than one lesion with different gleason score (2, 7, 9, 14). thus, the term index lesion (il) or dominant lesion, has been introduced to define the lesion with the highest gleason score orthe largest lesion in the case of lesions with the same gleason score (6, 7, 14). the multifocality of pca, expressed by the presence of satellite lesions, also underestimates the size and extent of pca. the clinical significance of these factors is still undetermined: in high-risk patients where treatment option is radical prostatectomy (rp) they may not alter prognosis, but they are of high importance when focal treatment is regarded as an option. the use of fusion biopsy may allow for identifilourenco_stesura seveso 10/01/20 11:07 pagina 218 219archivio italiano di urologia e andrologia 2019; 91, 4 mpmri and fusion prostate biopsy cation of more lesions and better planning of treatment (12, 15). it is theorized that the il drives disease progression and that multifocality does not alter prognosis, although a consensus has not been achieved because of divergent results of different studies (6, 15). the use of mpmri to guide biopsies, as a first line diagnostic tool (rather than as second line when pb fails to detect lesions) is increasing, as it is its use to determine the need of prostatic biopsy in some individuals (16). nevertheless, a normal mpmri does not exclude the presence of pca because mpmri can detect lesions with high gleason score and miss lesions with lower gleason and areas deemed non-suspicious can still reveal significant disease with pb (2, 4, 12, 17, 18). correlation between mpmri identified lesions and radical prostatectomy was found to be accurate in lesions equal or superior to 0.2 ml, validating its use for fusion biopsy and possibly guided therapy (12, 17, 19-21). in patients with a negative mpmri, the risk of significant disease (gleason ≥ 7) is still present, although recent studies show a very high negative predictive value. therefore, some studies still recommend pb even with negative mpmri (12, 15, 17, 21). the interobserver variability of prostate mpmri still represents a challenge, as rates are still very variable between studies (8, 11, 13). the aim of this work was to evaluate the correlation between lesions described in mpmri and the histology results obtained by prostate biopsy and rp. methods patients selection a retrospective analysis of 291 consecutive diagnostic mpmri conducted by the same team of radiologists in a tertiary hospital was performed. one hundred fifteen biopsied patients were selected, of whom 56 had a positive biopsy for prostate adenocarcinoma. the data available allowed for the evaluation of agreement between lesion location on mpmri and pb in 37 patients or on mpmri and rp in 15 patients (figure 1). data collection clinical and biochemical data was obtained from consulting patients’ charts. imaging data was obtained from analysis of reports conducted by the same team of radiologists, or by revision of images if insufficient data was present in the reports. anatomopathological data from pb and rp was obtained from consulting reports by the medical team of the pathology department. technical characteristics all mpmri were conducted and described by the same team of radiologists and were revised by a single senior radiologist. of the 291 mpmri, 161 were conducted utilizing the pi-rads v1 classification, while the remaining were evaluated applying the pi rads v2. in this study, being our main endpoint the location of the tumour, no distinction between pi-rads versions was made in order to increase available numbers. exams were performed on a 3t mr scanner. prostate biopsies were conducted by different urologists (non-studied variable) under ultrasound guidance according to cognitive fusion. all patients were submitted to guided biopsy and systematic biopsy (with variable number of cores collected). studied variables the sample obtained was characterized in relation to age, prostate volume, pi-rads score, location of lesion [side (left, right, bilateral, medial), floor (apex, base, medial), zone (peripheral, transition, central, stroma)] and dimension on mpmri. regarding prostate biopsy it was assessed the total number of fragments obtained, the number of fragments directed to the lesion, number of fragments with pca, isup classification and agreement between location of pca in fragments in relation to mpmri. in the 15 patients submitted to rp, the agreement between location of lesion on surgical specimen (ss) and mpmri was evaluated. we included patients with pi-rads score 2 that had any mpmri modification possible to localize (hypointensity lesions in the peripheral zone; circumscribed hypointense or heterogeneous nodules) and had a positive pb. definition of agreement agreement between mpmri/pb and mpmri/ss was defined as agreement of the presence of pca only on the regions identified by mpmri. statistical analysis evaluation of the effect of variables studied on location agreement was conducted utilizing the mann-whitney test (utilizing the statistic program spss v21). the values p < 0.05 were considered statistically significant. results agreement in location mpmri/pb in relation to pb, location was assessed only as side. agreement between mpmri/pb was of about 26 (70.3%), meaning that 11 (29.9%) presented lesions out of the suspected zone. results concerning location of lesions are summarized in table 1. the characterization of studied variables and its effect on agreement are summarized in table 2. of the factors figure 1. patients method selection. lourenco_stesura seveso 10/01/20 11:07 pagina 219 archivio italiano di urologia e andrologia 2019; 91, 4 m. lourenço, p. pissarra, d. vieira e brito, m. eliseu, j.p. peralta, a. figueiredo, c. marques 220 studied, only the total number of fragments with pca was lower in cases with agreement between mpmri and pb (p < 0.05). agreement on location between mpmri/pb for lesions pi-rads 2,3,4 and 5 was 71.4% (n = 5), 100.0% (n = 3), 100% (n = 4) and 60.9% (n = 23), respectively. agreement in location mpmri/pb for lesions isup (pb result) 1,2,3 and 4 was 80% (n = 8), 55.6% (n = 10), 100.0% (n = 3) and 66.7% (n = 2), respectively. agreement in location mpmri/ss agreement on location between mpmri/ss was of 5 (33.3%) (table 1). the characterization and effect of variables on agreement are summarized in table 3, being that no variable had a statistically significant effect. in relation to side, agreement for lesions localized on the right side, left, medial and bilateral was 33.3% (n = 2), 33.3% (n = 2), 0.0% (n = 0) and 50.0% (n = 1), respectively. in relation to the floor, agreement for lesions localized at the base, medium and apex was 33.3% (n = 2), 28.6% (n = 2) and 50.0% (n = 1), respectively. in relation to anatomical zone, agreement for lesions localized in the peripheral zone, transition zone and central zone was 36.4% (n = 4), 33.3% (n = 1) and 0.0% (n = 0), respectively. agreement in location between mpmri/ss for pi-rads lesion score 2,3,4 and 5 was off 0.0% (n = 0), 100% (n = 1), 50.0% (n = 2) and 33.3% (n = 3), respectively. agreement in location for isup 1,2 and 5 (evaluated by ss) was 50.0% (n = 2), 33.3% (n = 4), and 0.0% (n = 0), respectively. in the five exams that showed agreement, all patients presented with an isup ss smaller or similar to the isup obtained by pb (only one patient was reclassified with isup 3 on pb and of isup 2 on ss, having the remaining patients maintained isup classification). table 1. agreement in location between mpmri and lesions objectified in prostatic biopsy and by radical prostatectomy specimen. agreement mpmri vs pb (n = 37) agreement mpmri vs ss (n = 15) agreement 26; 70.3% agreement 5; 33.3% pca in sz + pca in the same lobe 7; 18.9% pca in sz + ipsilateral lesions in other floors 5; 33.3% pca in sz + pca in contralateral lobe 3; 8.1% pca in sz + contralateral lesions 1; 6.7% no pca in sz + bilateral pca 1; 2.7% bilateral lesions in all floors 4; 26.7% pb = prostatic biopsy; pca = prostate cancer; ss = surgical specimen; sz = suspicious zone. table 2. effect of clinical and imaging variables on agreement in location between suspicious lesion of prostate adenocarcinoma on mpmri and prostate biopsy. all patients with agreement p (n = 37) (n = 26) average age (years) 66.6 65.9 ns average psa (ng/ml) 9.1 10.0 ns average volume (cc) 53.5 54.4 ns average number of previous pb 1.3 1.1 ns average diameter of suspicious lesion on mpmri (mm) 24.3 22.9 ns location of lesion in mpmri ns • right 15; 40.5% 10; 38.5% • left 15; 40.5% 11; 42.3% • medial 3; 8.1% 1; 3.8% • bilateral 4; 10.8% 4; 15.4% average total number of fragments 13.0 13.0 ns average number of guided fragments 4.7 4.9 ns pi-rads ns • 2 7; 18.9% 5; 19.2% • 3 3; 8.1% 3; 11.5% • 4 4; 10.8% 4; 15.4% • 5 23; 62.2% 14; 53.8% average number of fragments with pca 3.5 3 statistically significant isup after pb ns • 1 10; 27.0% 8; 30.8% • 2 18; 48.6% 10; 38.5% • 3 5; 13.5% 5; 19.2% • 4 3; 8.1% 2; 7.7% • 5 0; 0.0% 0; 0.0% • unknown 1; 2.7% 1; 3.8% psa = prostatic specific antigen; pb = prostatic biopsy; mpmri = multiparametric magnetic resonance; pca = prostate adenocarcinoma; ns = non significant (p > 0.05); sts = statistically significant (p ≤ 0.05). table 3. effect of clinical and imaging variables on agreement between location of prostate adenocarcinoma suspicious lesion, between mpmri and findings in surgical specimen after radical prostatectomy. all patients with agreement p (n = 15) (n = 5) average age (years) 65.1 63.6 ns average psa (ng/ml) 8.6 10.0 ns average volume (cc) 49.1 53.4 ns average diameter of suspicious lesion on mpmri (mm) 26.4 23.5 ns location of lesion in mpmri ns a) side • right 6; 40.0% 2; 40.0% • left 6; 40.0% 2; 40.0% • medial 1; 6.7% 0; 0.0% • bilateral 2; 13.3% 1; 20.0% b) floor • base 6; 40.0% 2; 40.0% • medial 7; 46.7% 2; 40.0% • apex 2, 13.3% 1; 20.0% c) zone • peripheral 11; 73.3% 4; 80.0% • transition 3; 20.0% 1; 20.0% • central 1; 6.7% 0; 0.0% pi-rads ns • 2 3; 20.0% 0; 0.0% • 3 1; 6.7% 1; 20.0% • 4 2; 13.3% 1; 20.0% • 5 9; 60.0% 3; 60.0% isup ss ns • 1 2; 13.3% 1; 20.0% • 2 12; 80.0% 4; 80.0% • 3 0; 0.0% 4; 80.0% • 4 0; 0.0% 0; 0.0% • 5 1; 6.7% 0; 0.0% psa = prostatic specific antigen; pb = prostatic biopsy; mpmri = multiparametric magnetic resonance; pca = prostate adenocarcinoma; ns = non significant; ss = surgical specimen. lourenco_stesura seveso 10/01/20 11:07 pagina 220 221archivio italiano di urologia e andrologia 2019; 91, 4 mpmri and fusion prostate biopsy in the 10 nonagreeing exams, the isup ss values were superior to the isup bp values in 5 (50.0%) of cases (regarding the five isup 1 patients in pb, four were reclassified as isup 2 in ss and one maintained isup classification). discussion currently the use of “blind” biopsy in the search for pca with the objective of “finding” the neoplasic lesion constitutes an exception when compared to other cancer diagnostic procedures (22). the development of mpmri and the subsequent rise of guided prostate biopsy has been associated with excellent results in detecting significant pca. this has various potential applications of great relevancy, such as reducing the number of unnecessary biopsies, reducing the diagnosis of indolent pca and better planning of focal therapy (2, 19, 23). to make it possible, mpmri has to present high sensitivity and high negative predictive values, which can be evaluated by comparing characteristics of identified lesions on mpmri with findings obtained from prostate biopsy (guided and systematic) and with histopathological result from radical prostatectomy specimens. in this study, agreement between mpmri and pb was 70.3%. in relation to patients without agreement, all presented multifocality. in an interesting way, we observed that all bilateral suspicious lesions on mpmri (n = 4) presented agreement on pb. of all factors studied, only having a small number of positive pb cores for pca, was related to higher agreement between mpmri and pb. this data can be explained by the fact that a higher number of positive cores can be associated to the presence of multifocal lesions not identified by mpmri. the agreement was higher for lesions pi-rads ≤ 3 that for lesions pi-rads > 3 (80.0% vs. 66.7%). agreement between location for mpmri and ss was only 33.3% and multifocality was responsible for the lack of agreement in the 66.7% remaining patients. interestingly, patients with non-agreeing lesions presented with an increased isup classification in relation to pb in 50.0% of cases (vs 0.0% of patients with agreement). none of the factors studied related to agreement (probably by the reduced sample size). the accuracy of mpmri for detecting pca has been widely studied. multiple studies have shown that guided prostate biopsy of the suspected lesion on mpmri detects more clinically significant tumours that systematic biopsy, whereas systematic biopsy detects more nonsignificant tumours. due to this fact, most authors still recommend conducting both techniques at the same time as to increase diagnostic accuracy (2, 3, 5, 22). given that mpmri has a high negative predictive value (between 63 and 98% (24), various authors have defended that mpmri can significantly reduce the number of prostatic biopsies conducted, particularly in patients with previously negative biopsy (3, 4, 21). the accuracy of mpmri is especially high in detecting index lesions, with various recent studies showing values > 85% (7, 14, 19, 20, 25). in our study, the low correlation between lesions identified on mpmri with biopsy and surgical specimen, was related to multifocality, as in our methodology we considered the existence of unidentified multifocal lesions on mpmri as nonagreeing exams. various studies have shown that pca is multifocal in most cases, with a variation of 57 to 91% (26-29). in this context, it is important to assess the characteristics of unidentified lesions on mpmri, being they index or satellite lesions. radtke et al. (19), in a study correlating surgical specimen of radical prostatectomy, objectified that 94% of lesions not identified by mpmri presented with gleason ≤ 3+4. in a study by borkowetz et al. (7), that also related mpmri to ss, mpmri failed to identify 13% of index lesions, that in half of cases presented with a gleason score ≥ 4+3. baco et al. (14) obtained a diagnostic acuity of 95% for il with biopsy guided by mpmri, where the remaining 5% were identified by systematic biopsy. the high sensitivity obtained by combining guided biopsy with systematic biopsy was equally proved in other studies (19, 30). le et al. (6) described the multifocality of pca in 64% of cases, being the mpmri detection rate for all tumours of only 47% (132/283). the sensitivity of mpmri was higher in lesions larger than 1 cm (72%), gleason score ≥ 7 (72%) and for index lesions (80%). in a study conducted by tan et al., mpmri was capable of identifying 46.7% of all tumour foci (31). better results concerning the ability of mpmri in detecting multifocal lesions was described by hegde et al. (12), who described an accuracy of 62.0% in detecting satellite lesions by mpmri ( that in 55.3% presented with gleason score ≥ 3+4). analysing therapeutic applications, particularly focal therapies, it is relevant to highlight that satellite lesions do not necessarily present adjacent to the index lesion, being the average distance of approximately 1 cm (32). the importance of satellite lesions is not totally explained. currently, the most widespread idea supports that potentially metastatic and lethal pca originates from the same aberrant progenitor cell (in other words, with the same monoclonal origin) (33, 34) and that il (correctly identified by mpmri) most likely originates from the same lethal parent cell (35). nevertheless, other studies showed that non-index lesions can be responsible for local invasion (36) and for metastatic pca (37). the identification of pca lesions by mpmri is dependent on multiple factors, namely lesion volume (> 1cc), gleason score (≥ 7), histology, location (inferior to lesion located at the apex ) and of the contrast to normal adjacent tissue (14, 31). currently another matter of debate is the influence of the technique of guided biopsy utilized, namely the difference between cognitive fusion biopsy (utilized in our work), mri-transrectal ultrasound fusion and in-bore mri target biopsy. a recent systematic review showed that in-bore mri target biopsy is superior to cognitive fusion biopsy for the detection of all pca (regardless of gleason score), although it was not superior in detecting significant tumours. the mri-transrectal ultrasound fusion biopsy did not show advantages in relation to cognitive fusion biopsy (38). in this study, all the exams were conducted or revised by the same radiologist, which eliminates the subjective variation in reading mpmri. some studies showed that lourenco_stesura seveso 10/01/20 11:07 pagina 221 archivio italiano di urologia e andrologia 2019; 91, 4 m. lourenço, p. pissarra, d. vieira e brito, m. eliseu, j.p. peralta, a. figueiredo, c. marques 222 for index lesion the interobserver variation is not significant (15, 39), while other studies showed a clear effect of the radiologist´s experience in reading mpmri (13). this work presents with various limitations, namely its retrospective nature and the small number of surgical specimens evaluated. also, histology was assessed by report, which can reduce agreement concerning location (10, 15). another limitation was the inclusion of patients with a pi-rads score of 2, which by definition signifies a negative mpmri (although during pb the areas of the prostate where alterations were present where considered, namely hypointensity lesions in the peripheral zone). lastly, agreement between index lesion and satellite lesion was not evaluated, nor was histopathological characteristics for tumour foci. references 1. boesen l. multiparametric mri in detection and staging of prostate cancer. dan med j. 2017; 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157:223-7. 38. wegelin o, van melick hhe, hooft l, et al. comparing three different techniques for magnetic resonance imaging-targeted prostate biopsies: a systematic review of in-bore versus magnetic resonance imaging-transrectal ultrasound fusion versus cognitive registration. is there a preferred technique? eur urol. 2017; 71:517-31. 39. di campli e, delli pizzi a, seccia b, et al. diagnostic accuracy of biparametric vs multiparametric mri in clinically significant prostate cancer: comparison between readers with different experience. eur j radiol. 2018; 101:17-23. correspondence mario lourenço, md (corresponding author) mariolourenco88@gmail.com duarte vieira e brito, md joao pedro peralta, md urology department portuguese institute of oncology coimbra rua maria bourbon bobone, n57, re/esq, coimbra, 3030-481 portugal pedro pissarra, md cristina marques, md radiology department coimbra hospital university centre, coimbra (portugal) miguel eliseu, md arnaldo figueiredo, md urology and kidney transplant department coimbra hospital university centre, coimbra (portugal) lourenco_stesura seveso 10/01/20 11:07 pagina 223 archivio italiano di urologia e andrologia 2018; 90, 2104 original paper the sufficiency of 6 core sextant prostate biopsy in patients with prostate specific antigen (psa) values over 20 ng/ml cem yücel, salih budak, erdem kısa, orcun celik, zafer kozacıoglu tepecik training and research hospital, urology clinic, izmir, turkey. objective: in this study, we aimed to investigate sufficiency of 6 core prostate biopsy in patients with psa levels elevated above 20 ng/ml. materials and methods: the medical record of the patients who received prostate biopsy at our institution between august 2011 to august 2016 who had serum total psa values above 20 ng/ml, were reviewed retrospectively. in this study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy. a total number of 80 patients were enrolled in this study. patients were divided into two groups, a 6 core biopsy group and a 12 core biopsy group. these groups are compared according to age, total psa, prostate volume and final pathological diagnosis. results: based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had pca in both group 1 and 2. the cancer detection rate in both groups was 95%. although there were higher values of mean age, mean total psa, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in both groups. conclusion: although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with psa values above 20 ng/ml. key words: prostate cancer; biopsy; detection rate; core number. submitted 25 august 2017; accepted 23 october 2017 summary no conflict of interest declared. location of cores (6). six core sextant biopsy is no longer considered adequate. recently, 10 to 12 core biopsies are recommended and biopsies with > 12 cores are not being significantly more conclusive (7). patients with prostate spesific antigen (psa) levels > 20 ng/ml are classified as high risk group for diagnosis of pca (8). this risk increases with age and these patients have higher possibility to have locally advanced or metastatic disease at the time of diagnosis. in the present study, we aimed to investigate sufficiency of 6 core sextant prostate biopsy in patients with psa levels elevated above 20 ng/ml. we hypothesized that there is no significant difference in cancer detection rate between 6 core and 12 core prostate biopsies of men presenting psa values of above 20 ng/ml. materials and methods the medical record of the patients who received prostate biopsy at our institution between august 2011 to august 2016 and had serum total psa values above 20 ng/ml, were reviewed retrospectively. in the present study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy. we excluded the patients who have chronic diseases (diabetes, hyperlipidemia, hypertension, cardiovascular disease), malignancy, psychiatric disorders, acute infections, a history of urinary tract surgery, a prior diagnosis of pca and a history of irradiation. we also excluded patients with psa < 20 ng/ml. after obtaining informed consent from patients, all biopsies were taken transrectally with ultrasonography guidance using a 25 cm 18 gauge, side-notch cutting (tru-cut) needle. the biopsy was applied with patient in lateral decubitus position with periprostatic nerve blockage. a total number of 80 patients were enrolled in this study. the clinic-biological features of patients were recorded. patients were divided into two groups, a 6 core biopsy group (group 1) and a 12 core biopsy group (group 2). these groups were compared according to age, total psa, prostate volume and final pathological diagnosis. we also identified the cancer detection rate and gleason scores of these groups. statistical analysis the conformity of variables to normal distribution was assessed with the shapiro wilk test. descriptive statistics doi: 10.4081/aiua.2018.2.104 introduction prostate cancer (pca) is the most common cancer in men worldwide (1). the diagnosis of pca depends on sufficient tissue sampling of the prostate gland with prostate biopsy (2). the technique of prostate biopsy has evolved through the years with the advent of new technologies. in 1989 hodge et al. first described transrectal ultrasound (trus) guided sextant biopsy method (3). since then, this method has become the worldwide most popular and pca detection has significantly improved. its limitations were soon discovered. many investigator reported falsenegative rates of up to 20-25% for the sextant biopsy (4). this naturally resulted in the development of refinements to the trus-guided sextant biopsy. stamey et al. suggested directing the biopsy more laterally (5). multiple biopsy schemes were subsequently proposed to enhance cancer detection by increasing the number and revising the yucel_stesura seveso 28/06/18 16:35 pagina 104 105archivio italiano di urologia e andrologia 2018; 90, 2 sextant prostate biopsy in high psa for variables with a normal distribution and categorical variables were shown as mean ± standard deviation (sd) and percentage (%), respectively. student’s t-test and chisquare test were used for inter group analyses of continuous variables. more than two independent average compared with anova test and kruskal wallis test. the data analysis was performed using statistical package for the social science (spss inc, chicago, illinois, usa) version 22.0 and a p value of < 0.05 was considered as significant. results a total of 80 patients participated in this study. the mean age of all patients was 72.2±8.4, the mean total psa was 126.0 ± 101.3 ng/ml, the mean prostate volume was 50.4 ± 41.6 ml and overall cancer detection rate was 95.0%. clinical and demographic characteristics of all study patients are listed in table 1. based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had pca in both group 1 and 2. the cancer detection rate in both groups was 95%. the gleason score was found to be 6 in 3 (7.9%), 7 in 14 (36.8%) and ≥ 8 in 21 (55.3%) patients who were diagnosed as pca in group 1 and from the other side 6 in 4 (10.5%), 7 in 11 (28.9%) and ≥ 8 in 23 (60.5%) patients who were diagnosed as pca in group 2. the differances in gleason scores was not determined to be statistically significant (p= 0.783). although there was higher values of mean age, mean total psa, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in group 1 and 2 (table 2). the cancer detection rates of both groups were similar (p = > 0.999). discussion pca is still a major health problem among males all over the world. despite efforts made to identify new serum and biologic markers of disease and refinement of imaging modalities, trus guided biopsy is still most important diagnostic tool. important improvements in the prostate biopsy have evolved though the past century. modern technique of prostate biopsy first began with the study of hodge et al. their method involved taking biopsies from apex, middle and base of each prostate gland para-sagitally. in addition to these six anatomic sites they suggested to take biopsy from hypoechoic regions (3). since then, this method has become the worldwide most popular and pca detection has significantly improved. in 1995, stamey et al. modified the sextant method and directed the biopsy more laterally to peripheral zone where most pca are located. they achieved 20-25% more cancer detection rate than hodges method (5). then many researchers investigated the acceptable number of core biopsies for diagnosis. they make an effort to improve the negative predictive value of prostate biopsy. guichard et al. found the cancer detection rates of 6, 12, 18 and 21 core prostate biopsies were 31.7%, 38.7%, 41.5% and 42.5% respectively (9). similarly to this study, ceylan et al. reported cancer detection rates of 8, 10, 12, 16, and 20 core prostate biopsies as 18.3%, 14.8%, 24%, 22.1%, and 30.3% respectively (10). the logic of these studies is based on increasing the possibility of detecting pca by increasing the sample. six core biopsy is no longer considered adequate. in present study, we found there is no significant difference in cancer detection rate between 6 core and 12 core prostate biopsies of men presenting psa values of above 20 ng/ml. according to current literature, 6 cores biopsy is not recommended but may be sufficient especially in patients with high psa (over 20 ng/ml). prostate cancer risk was summarized using the d'amico classification and psa level is one of three variables on which the risk classification is based (11). according to d'amico scheme, patients with a psa over 20 ng/ml are classified as high risk and these patients have higher possibility to have locally advanced or metastatic disease at the time of diagnosis. stephenson et al. reported that the 15 years prostate cancer specific mortality was 22% in patients with psa of 20.1-50 ng/ml and 4-11% in those with psa < 20 ng/ml and suggested that a psa > 20 ng/ml may indeed be considered a high-risk factor (12). heyns et al. reported that a psa level > 50 ng/ml was associated with a 96% positive predictive value for prostate cancer (13). gerstenbluth et al. reviewed the records of 1,250 patients undergoing trus guided prostate biopsy and identified 187 men (15%) presenting with psa greater than 20 ng/ml. of these 187 men, 157 table 1. clinical and biological characteristics of all patients (n = 80). mean (sd) age (years) 72.2 (± 8.4) psa (ng/ml) 126.0 (± 101.3) prostate volume (ml) 50.4 (± 41.6) pathology (n, %) bph 4 (5.0) pca 76 (95.0) gleason score (n, %) 6 7 (9.2) 7 25 (32.9) ≥ 8 44 (57.9) psa: prostate-specific antigen, bph: benign prostatic hyperplasia; pca: prostate cancer; sd: standard deviation. table 2. comparison of clinical characteristics of 2 groups. group 1 group 2 p value age (years) 74.1 ± 6.8 70.3 ± 8.9 0.072 psa (ng/ml) 139.4 ± 123.0 112.6 ± 72.7 0.265 prostate volume (ml) 54.4 ± 52.5 46.4 ± 26.9 0.358 pathology (n, %) bph 2 (5.0) 2 (5.0) > 0.999 pca 38 (95.0) 38 (95.0) > 0.999 gleason score (n, %) 6 3 (7.9) 4 (10.5) 0.689 7 14 (36.8) 11 (28.9) 0.602 ≥ 8 21 (55.3) 23 (60.5) 0.783 psa: prostate-specific antigen, bph: benign prostatic hyperplasia; pca: prostate cancer. yucel_stesura seveso 28/06/18 16:35 pagina 105 archivio italiano di urologia e andrologia 2018; 90, 2 c. yücel, s. budak, e. kısa, o. celik, z. kozacıoglu 106 (84.0%) were diagnosed with prostate cancer on initial biopsy and 12 patients had repeat biopsy and 6 of these eventually diagnosed pca. overall, 163 of the 187 men (87.2%) were diagnosed with prostate cancer by biopsy. they suggested that carefully selected elderly patients with severe comorbidities may not require biopsy before androgen ablative therapy since psa is highly accurate in diagnosing prostate cancer at levels greater than 50 ng/ml (14). anai et al. recommended that highly select symptomatic men with extremely high serum psa could be started on immediate androgen ablative therapy even without a tissue diagnosis of prostate cancer (15). in the present study, we found 95% cancer detection rate and detected that 90.8% of all patients had high risk pca according to their final pathological diagnosis. the morbidity of prostate biopsy is minimal, reported at < 1% (4). early complications of prostate biopsies include hematospermia (37%), hematuria more than 1 day (14.5%), rectal bleeding more than 2 days (2.2%) and urinary retention that required observation or intervention (1.8%). delayed complications of prostate biopsies are urinary tract obstruction (10.9%), fever (2.9%), sepsis (0.1%) (16). naughton et al. reported similar complication results in a prospective evaluation of 6 and 12 core biopsies (17). contrary to this study, feliciano et al. reported that the increased number of biopsy cores contributed to increased morbidity associated with prostate biopsy (18). we thought that there is not necessary to increase the core number of prostate biopsy if it have not additional contribution to cancer detection. our study has limitations. first limitation of our study is its retrospective nature. not assessing the complications of biopsies was the second limitation of our study. the other limitation of this study is small sample size and this limitation could affect the interpretation of results. a larger series of patients will provide a more accurate picture. conclusions although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with psa values above 20 ng/ml. our results may provide additional information for importance of 6 core biopsy and we believe that a large-scale, multicenter, prospective study will provide a more accurate picture for the clinical significance of 6 core sextant prostate biopsies of men presenting psa values of above 20 ng/ml. as a result, 6 core may be sufficient if prostate biopsy can not be tolerated especially in patients with high psa. references 1. ismail mt, gomella lg. transrectal prostate biopsy. urol clin north am. 2013; 40:457-72. 2. abd tt, goodman m, hall j, et al. comparison of 12-core versus 8-core prostate biopsy: multivariate analysis of large series of us veterans. urology. 2011; 77:541-7. 3. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-4. 4. mariappan p, chong wl, sundram m, mohamed sr. increasing prostate biopsy cores based on volume vs the sextant biopsy: a prospective randomized controlled clinical study on cancer detection rates and morbidity. bju int. 2004; 94:307-10. 5. stamey ta. making the most of six systematic sextant biopsies. urology. 1995; 45:2-12. 6. silletti jp, gordon gj, bueno r, et al. prostate biopsy: past, present, and future. urology. 2007; 69:413-6. 7. kim jw, lee hy, hong sj, chung bh. can a 12 core prostate biopsy increase the detection rate of prostate cancer versus 6 core?: a prospective randomized study in korea. yonsei med j. 2004; 45:671-5. 8. ang m, rajcic b, foreman d, et al. men presenting with prostate specific antigen (psa) values of over 100 ng/ml. bju int. 2016; 117:68-75. 9. guichard g, larre s, gallina a. extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1,000 consecutive patients. eur urol. 2007; 52:430-5. 10. ceylan c, doluoglu og, aglamis e, baytok o. comparison of 8, 10, 12, 16, 20 cores prostate biopsies in determination of prostate cancer and importance of prostate volume. can urol assoc j. 2014; 8:81-5. 11. d’amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 12. stephenson aj, kattan mw, eastham ja, et al. prostate cancerspecific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. j clin oncol. 2009; 27:4300-5. 13. heyns cf, naude am, ahmed g, et al. serum prostate-specific antigen as surrogate for the histological diagnosis of prostate cancer. s afr med j. 2001; 91:685-9. 14. gerstenbluth re, seftel ad, hampel n, et al. the accuracy of the increased prostate specific antigen level (greater than or equal to 20 ng./ml.) in predicting prostate cancer: is biopsy always required? j urol. 2002; 168:1990-3. 15. anai s, west cs, chang m, nakamura k, et al. outcomes of men who present with elevated serum psa (> 20 ng/ml) to an innercity hospital. j natl med assoc. 2007; 99:895. 16. moyer va. u.s. preventive services task force screening for prostate cancer: u.s. preventive services task force recommendation statement. ann intern med 2012; 157:120-34. 17. naughton ck, ornstein dk, smith ds, catalona wj. pain and morbidity of transrectal ultrasound guided biopsy: a prospective randomized trial of 6 versus 12 cores. j urol. 2000; 163:168-71. 18. feliciano j, teper e, ferrandino m, et al. the incidence of fluoroquinolone resistant infections after prostate biopsy are fluoroquinolones still effective prophylaxis? j urol. 2008; 179:952-7. correspondence cem yücel, md meclecuy@hotmail.com salih budak, md (corresponding author) salihbudak1977@gmail.com erdem kısa, md drerdemkisa@hotmail.com orcun celik, md orcuncelik82@hotmail.com zafer kozacıoglu, md associate. prof. zaferkozacioglu@gmail.com tepecik training and research hospital, urology clinic, izmir, turkey 206/26 sok. no:16 d:24 yıldız mah. buca/izmir, türkiye yucel_stesura seveso 28/06/18 16:35 pagina 106 39archivio italiano di urologia e andrologia 2020; 92, 1 original paper comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones ibrahim kartal 1, burhan baylan 1, mehmet caglar cakıcı 1, 2, sercan sarı 1, 3, volkan selmi 1, 3, harun ozdemir 1, 4, fatih yalçınkaya 1 1 department of urology, dıskapı yıldırım beyazıt training and research hospital, health sciences university, ankara, 06110, turkey; 2 department of urology goztepe training and research hospital, faculty of medicine, medeniyet university, istanbul, turkey; 3 department of urology, faculty of medicine, bozok university, yozgat, turkey; 4 department of urology, ministry of health haseki education research hospital, health sciences university, istanbul, turkey. objective: we aimed to retrospectively evaluate the effectiveness and safety of flexible ureteroscopy (f-urs), semirigid ureteroscopy (sr-urs), and shock wave lithotripsy (swl) to treat single 11-20 mm stones in the proximal ureter. materials and methods: patients treated at our clinic for 11-20 mm single stones in the proximal ureter who underwent f-urs, sr-urs or swl as initial lithotripsy methods were compared in terms of their clinical characteristics and treatment outcomes. results: a comparison among 201 patients who had undergone f-urs, 119 patients who had undergone sr-urs, and 162 patients who had undergone swl showed no significant baseline differences in patients’ demographic and stone characteristics. stone-free rates on the 15th day and 3rd month were higher with f-urs (89.6% and 97%, respectively) than with sr-urs (67.2% and 94.1%, respectively) and swl (41.4% and 79.0%, respectively; all p < 0.001). retreatment rates were significantly higher with swl than with the other two modalities (p < 0.001); auxiliary procedure rates were significantly lower with f-urs than with the other two modalities (p < 0.001). treatment-related complication rate at the end of the 3rd month was lower with f-urs than with swl (p = 0.022). furthermore, f-urs was more effective than sr-urs for treating impacted stones. conclusions: we found that f-urs was highly successful as an initial lithotripsy procedure for medium-sized proximal ureteral stones, and it helped achieve early stone-free outcomes with a lower need for retreatment and auxiliary procedures, lower complication rates, and higher effectiveness on the impacted stones compared with sr-urs and swl. key words: lithotripsy; ureter; ureteroscopy. submitted 28 july 2019; accepted 22 november 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.39 introduction urinary tract stones are frequently encountered in urology practice. shock wave lithotripsy (swl), ureteroscopy (urs), percutaneous nephrolithotomy, laparoscopy, and open surgery are available as the treatment modalities for proximal ureteral stones sized > 1 cm (1, 2). european association of urology guidelines recommend urs and swl as primary treatments for stones sized 1.1-2 cm. the american urological association guidelines recommend urs as the optimal treatment but state that patients must be informed about the increased risk of complications and morbidity associated with urs compared with that with other methods (3, 4). the effectiveness and safety of the available methods for treating large proximal ureteral stones have been compared in various recent studies and meta-analyses (1, 5-8). the use of flexible ureteroscopy (f-urs) for stones in the proximal ureter has increased due to advances in technology. flexible urs has been compared with semirigidureterorenoscopy (sr-urs) and sr-urs has been compared with swl; (9, 11) however, comparisons including all three procedures for the treatment of stones in the proximal ureter are not available. this study evaluated the outcomes, safety, effectiveness, and associated complications of f-urs, sr-urs, and swl as the initial lithotripsy treatment for patients with proximal ureteral stones sized 11-20 mm. materials and methods following approval by the local ethics committee, patients treated at our clinic between january 2013 and june 2018 for single stones sized 11-20 mm and located in the proximal ureter were retrospectively evaluated. the proximal ureter was defined as the region between the ureteropelvic junction and the sacroiliac joint (12). patients with multiple stones, history of surgery or anatomical anomalies on the same side, solitary kidneys, concurrent pregnancy, and concomitant intrarenal stones and those aged < 18 years were excluded. detection of stone and evaluation of the treatments were performed using kidney-ureter-bladder x-ray, ultrasound imaging, and/or contrast/non-contrast computed tomography. the procedure was selected after patients were informed in detail about possible re-treatment rates, the possibility of shifting to other treatment, and complications. written informed consents were taken from all patients. in patients for whom urs was chosen, f-urs was prekartal_stesura seveso 01/04/20 18:56 pagina 39 archivio italiano di urologia e andrologia 2020; 92, 1 i. kartal, b. baylan, m. caglar cakıcı, s. sarı, v. selmi, h. ozdemir, f. yalçınkaya 40 ferred mostly for patients with grade 3 and 4 hydroureteronephrosis or with stones closer than 5 cm to the ureteropelvic junction. on the other hand, sr-urs was preferred mostly for patients with stones located more than 5 cm away from the ureteropelvic junction by considering the cost. furthermore, several factors such as the repair process of the device or the intensive use of the f-urs device were effective factors in the device selection in our clinic. to conclude, the device to be used was decided following the joint evaluation of factors such as patient and stone characteristics, socioeconomic reasons, and choice of surgeon. patients with active infections were treated after administering antibiotic therapy and obtaining clean urine cultures. for the analysis, patients were stratified by lithotripsy procedure into f-urs, sr-urs, or swl groups. the patient characteristics included in the analysis were age, sex, side, stone size (recorded as the longest of axial, coronal, or sagittal diameters), body mass index (bmi, kg/m²), operation time (in minutes), stone-free rate (sfr %) on the 15th day and 3rd month, length of hospital stay (in days), complication rate, and need for retreatment and auxiliary procedures. in this study, local inflammation and swelling associated with impacted stones in the sr-urs and f-urs groups was confirmed through endoscopy as previously described (13). the preoperative and postoperative outcomes of the selected ureteroscopy type were assessed. treatment success required achievement of a complete stone-free state or the presence of clinically insignificant residual fragments < 3 mm, which was also considered to be a stone-free state. the 15-day follow-up evaluation included the outcomes of the first session of any procedure. the 3-month follow-up included evaluation of any auxiliary procedures. effectiveness was determined on the basis of the percentage of procedures that resulted in a stone-free state at 3 months. the efficiency quotient was calculated using the formula: = (stone free % × 100)/[100 + retreatment (%) + auxiliary procedures (%)]. perioperative complications were graded based on the modified clavien classification system. swl swl was performed as an outpatient procedure using an electrohydraulic extracorporeal lithotripter (multimed classic, elmed, ankara, turkey). the procedure and its effectiveness have been previously described (7, 14). intramuscular nonsteroidal anti-inflammatory medication was administered prior to the procedure, and fluoroscopy and/or ultrasonography was used as the focusing method, with patients in the prone position. the procedure was concluded after seeing fragmentation on fluoroscopy or after a maximum of 3,000 shock waves. patients without clearance after three sessions were referred for other modalities or follow-up. additional sessions were not scheduled earlier than 15 days. sr-urs the procedures were performed under general anesthesia using a 6/7.5 f sr-urs device (richard wolf, knittlingen, germany or karl storz, tuttlingen, germany). lithotripsy was performed using a medilas h20 holmium laser (dornier med-tech gmbh, wessling, germany). an energy of 0.8-1.5 joules and a frequency of 8-12 hz were preferred. insertion of a 4.8-f, 26-cm ureteral stent was not standard but was performed based on the surgeon’s judgment. ureteral stents were removed after 2-4 weeks. in cases where stones in the proximal ureter were pushed back to the kidney, the procedure was switched to f-urs in the same session. such patients were considered sr-urs failures and were not included in the f-urs group as the intervention was intrarenal. switching from sr-urs to f-urs was accepted as an auxiliary procedure. f-urs the procedures were performed under general anesthesia using a 7.5-f f-urs device (flex x2; karl storz gmbh, tuttlingen, germany). a 0.038-inch floppy guidewire was advanced past the stone through the ureteral orifice following cystourethroscopy. in some cases, a 9.5–11-f access sheath (elit flex, ankara, turkey) was passed over the guidewire. either a 20 watt dornier medilas h-20 or a 30 watt medilas h solvo holmium laser at a wavelength of 2.1 µm (dornier med-tech, wessling, germany) was used. insertion of a 4.8-f, 26-cm ureteral stent was not standard but was performed depending on the surgeon’s choice. the ureteral stent was removed in 2-4 weeks. push-up of the stone was not considered as a complication or failure in the f-urs procedure and lithotripsy was continued in the intrarenal area. statistical analysis statistical analysis was performed using ibm spss statistics 17.0 (ibm corporation, armonk, ny, usa). kolmogorov-smirnov test was used to evaluate whether the distribution of continuous quantitative variables was normal. levene test was used to determine whether the precondition of homogeneity of variances was fulfilled. descriptive statistics were reported as means ± standard deviation for quantitative variables and as numbers and percentages (%) for categorical variables. the significance of differences in quantitative variables that met the assumptions of the parametric test statistics was evaluated using one-way analysis of variance (anova). the significance of differences in the quantitative variables that did not meet the assumptions of the parametric test statistics was evaluated using mann-whitney u test for two independent groups and kruskal-wallis test for more than two independent groups. if the results of the kruskal-wallis test were significant, conover’s test of multiple comparisons was used to determine the reason for the difference. categorical variables were evaluated using pearson’s chi-square, fisher’s exact probability, chi-square with continuity correction, or likelihood ratio tests. a p value of < 0.05 was considered statistically significant. results a total of 482 patients, 119 who underwent sr-urs, 201 who underwent f-urs patients, and 162 who underwent swl for initial lithotripsy, were included in the analysis. the groups did not differ in age, sex, side, american kartal_stesura seveso 01/04/20 18:56 pagina 40 society of anesthesiologists (asa) score, bmi, the presence of hydronephrosis, or stone size (p ≥ 0.05). patients in the swl group exhibited shorter operation time and length of hospital stay than those in either urs group (p < 0.001). the success rate was higher with f-urs than with either sr-urs or swl (p < 0.001) and was higher with sr-urs than with swl (p < 0.001, figure 1). stones were either intraoperatively pushed back into the kidney, or optimal fragmentation was not achieved, in 24 sr-urs procedures; a stone-free state was achieved in 21 of the 24 patients following a switch to f-urs. any extra related complication was not seen in this switch. in 152 (75.6%) of the 201 patients who underwent initial f-urs, the lithotripsy procedure was initiated after insertion of an access sheath. a ureteral stent was inserted for 20 patients to passively dilate the ureter since access could not be achieved. these patients were re-treated at least two weeks later; 6 patients were treated with sr-urs and 14 patients with f-urs. insertion of the ureteral stent may cause bias in evaluations since there were patients who underwent stent insertion before swl for reasons such as renal colic, and there were some groups who prefer stent insertion before ureteroscopy to passively dilate the ureter. therefore, this process should be considered as a part of the procedure and not considered as failure. the patients were included in the groups according to the subsequent procedures. retreatment rates were significantly higher with swl than with the other modalities (p < 0.001). the auxiliary procedure rate was significantly lower with f-urs than with sr-urs or swl (both p < 0.001). auxiliary procedures were performed in 28 sr-urs patients. the high rate resulted from conversion to f-urs in 20.2% of the sr-urs procedures. sfrs were higher with urs than with swl procedures (p < 0.001). the highest efficiency quotient was 0.89, which was achieved in the f-urs group (table 1). a maximum of three sessions were performed for each swl procedure. the mean number of shockwaves and the power decreased at each subsequent session, but the complication rate increased (table 2). hydronephrosis had a negative effect on treatment success in the swl group patients (odds ratio = 40.042, 95% confidence interval: 9.108-176.035; p < 0.001). regarding complication rates, there was no significant difference among the three groups on the 15th day after the initial procedure (p = 0.066); however, a significant difference was observed at the end of the 3rd month (p = 0.022). the mentioned difference was caused by the higher complication rates associated with swl than with f-urs (p = 0.006). however, all three groups showed no differences with regard to the distribution of complications based on the modified clavien classification system (mccs) (p > 0.05). although swl was associated with a higher overall complication rate, the complications were minor as per mccs. sepsis developed in one patient each in the f-urs and srurs groups and required monitoring in the intensive care unit. none of the patients died 41archivio italiano di urologia e andrologia 2020; 92, 1 treatment of proximal ureteral stones table 1. patient characteristics, interventions, and treatment outcomes on 15th day and 3rd month after the initial lithotripsy treatment. sr-urs f-urs swl (n = 119) (n = 201) (n = 162) p-value at the end of the 15th day age 43.9 ± 13.1 44.5 ± 13.1 43.6 ± 12.6 0.774a gender (female/male) 32/87 49/152 35/127 0.586b side (right /left) 59/60 96/105 79/83 0.950b asa score 1.65 ± 0.73 1.73 ± 0.68 1.70 ± 0.70 0.415c anticoagulant use, n (%) 1 (0.8%) 7 (3.5%)e 0 (0.0%)e 0.010d bmi (kg/mm2) 25.1 ± 2.5 25.3 ± 2.7 24.8 ± 2.1 0.186a presence of hydronephrosis, n (%) 102 (85.7%) 178 (88.6%) 129 (79.6%) 0.059b stone size (mm) 13.9 ± 2.6 13.6 ± 2.4 13.4 ± 2.6 0.062c operation time (minutes) 41.6 ± 13.7f,g 50.2 ± 10.9e,f 30.9 ± 3.9e,g < 0.001c complication, n, (%) 22 (18.5%) 24 (11.9%) 15 (9.3%) 0.066b length of hospital stay 1.5 ± 1.6g 1.3 ± 1.1e 0.3 ± 1.1e,g < 0.001c sfr (day 15) 39/80 (67.2%)f 21/180 (89.6%)e,f 95/67 (41.4%)e < 0.001b efficiency quotient 0.51 0.89 0.24 at the end of the 3rd month additional intervention retreatment 8 (6.7%)g 8 (4.0%)e 75 (46.3%)e,g < 0.001b auxiliary procedure 28 (23.5%)f 9 (4.5%)e,f 42 (25.9%)e < 0.001b total complications * 22 + 2 (20.2%) 24 + 3 (13.4%)e 15 + 25 (24.7%)e 0.022b emergency department visit 5 (4.2%)g 4 (2.0%)e 23 (14.2%)e,g < 0.001b total operation time (min) * 44.9 ± 17.8f,g 53.3 ± 17.5f 61.4 ± 33.0g < 0.001c total length of hospital stay(day) * 1.6 ± 1.6g 1.4 ± 1.4e 0.9 ± 1.8e,g 0.001b 3rd month sfr * 7/112 (94.1%)g 6/195 (97.0%)e 34/128 (79.0%)e,g < 0.001b mean number of interventions 1.3± 0.5f,g 1.2 ± 0.4e,f 1.9 ± 1.0e,g < 0.001c *first + additional procedures; a one-way anova; b pearson’s chi-square test; c kruskal–wallis test; d likelihood ratio; e p < 0.05; f-urs vs. swl; f p < 0,01; sr-urs vs. f-urs; g p < 0,01; sr-urs vs. swl. sr-urs = semirigid ureteroscopy; f-urs = flexible ureteroscopy; swl = shock wave lithotripsy; asa = american society of anesthesiologists; bmi = body mass index; sfr = stone-free rate. figure 1. stone-free response achieved on the 15th day and 3rd month after the initial lithotripsy procedure. kartal_stesura seveso 01/04/20 18:56 pagina 41 archivio italiano di urologia e andrologia 2020; 92, 1 i. kartal, b. baylan, m. caglar cakıcı, s. sarı, v. selmi, h. ozdemir, f. yalçınkaya 42 (table 3). the rate of visit to the emergency department for renal colic or other reasons was significantly higher after swl than after the urs procedures (p ≤ 0.001). in addition to the treatments needed to manage the complications occurring after the primary treatment, for temporary relief, four ureteral stents and one percutaneous nephrostomy were needed in sr-urs patients, two ureteral stents and one percutaneous nephrostomy in furs patients, and three ureteral stents and one percutaneous nephrostomy in swl patients. these events were included in the analysis as auxiliary procedures. a sub-analysis was performed to evaluate the difference in outcomes achieved with f-urs and sr-urs in impacted stones. a sfr of 81.3% was achieved with f-urs compared with 51.2% achieved with sr-urs following the first session (p ≤ 0.001). stone size, total sfr, and complication and retreatment rates did not differ significantly with the type of urs (p > 0.05). however, f-urs was associated with longer operation times (p = 0.023), shorter length of hospital stay (p = 0.011), and less need for auxiliary treatments (p = 0.002) compared with sr-urs (table 4). discussion as only about 22% of upper ureteral stones are spontaneously passed, surgical intervention is usually required (15). given the ineffectiveness of medical expulsion therapy, nearly all patients with stones of the size treated in this study require intervention (16). the method chosen to treat upper ureteral stones depends on factors including stone size, pain severity and duration, presence of obstruction, cost, quality of life, surgeon experience, and available resources (17). swl and urs are most commonly used methods; both the procedures have specific advantages and disadvantages and variable outcomes have been reported (8, 18). swl was previously preferred even for stones sized < 10 mm, but the outcomes with swl and urs have been currently reported to be comparable and either can be recommended as the primary treatment (18). urs may provide higher sfrs for stones sized > 10 mm, but it is associated with higher complication rates than swl. this short-term study is consistent with previous reports of higher success and lower complication rates with f-urs compared with srurs and swl. a recent meta-analysis has reported that urs-associated complications have been decreasing without any corresponding decrease in sfr because of improved technology, flexible devices, better tools, and the use of holmium yag lasers (8). a prospective study of over 9600 patients reported increased success rates and decreased complications in the treatment of proximal ureteral stones using flexible devices (19). the risk of pushing a stone into the kidney is increased if it is located near the ureteropelvic junction; this occurred in 22% of the sr-urs procedures in this study. the switch to f-urs involves increased time, effort, and cost. possible hemorrhage and loss of clear vision (10, 20) can make it difficult to switch to f-urs in the same session. however, even if the stone is pushed back with f-urs, intrarenal stones can be accessed, providing the opportunity to complete the treatment without additional interventions as opposed to sr-urs and swl. moreover, the superiority of f-urs is obvious in cases of concomitant upper ureteral and renal stones (21), which were not included in this study.the high rate of intraoperative conversion to f-urs in this study explains the large percentage of auxiliary procedures that were performed in patients initially treated with sr-urs f-urs offers advantages such as being easily maneuvered in the ureter and, in particular, is less affected by a long urethra in males and by the restricted motion in the proximal urethra, unlike sr-urs. besides, a conversion can be made from srurs to f-urs in appropriate cases when the stone is pushed back. in this study, a conversion from sr-urs to f-urs was made in 24 (20.1%) patients, and despite prolonged operation times, stone-free states were achieved in a single session in 21 (87.5%) of the 24 patients. these results suggest that, even if the procedure is initiated with sr-urs, f-urs must be available during the procedure to save patients from undergoing additional sessions. even though swl is less invasive than f-urs, it cannot be used in patients with bleeding diathesis and morbid obesity or in pregnant patients. it is accompanied by high radiation exposure from fluoroscopy, is affected by stone composition, and requires repeated application to table 2. properties of the shock wave lithotripsy sessions. session 1 session 2 session 3 number of patients 162 76 35 presence of hydronephrosis n (%) 129 (79.6%) 75 (98.7%) 34 (97.1%) success n (%) 95 (58.6%) 56 (73.7%) 29 (82.9%) complication n (%) 15 (9.3%) 10 (13.2%) 8 (22.9%) number of shocks 2574.4 ± 332.4 2439.5 ± 315.8 2201.4 ± 373.1 power (kv) 16.6 ± 1.2 16.3 ± 1.2 15.4 ± 0.4 table 3. complications following the initial procedure based on the modified clavien classification system. sr-urs (n = 119) f-urs (n = 201) swl (n = 162) p-value i 12 (10.1%) 11 (5.5%) 9 (5.6%) 0.220a ii 6 (5.0%) 8 (4.0%) 4 (2.5%) 0.517a iii 3 (2.5%) 4 (2.0%) 2 (1.2%) 0.716b iv 1 (0.8%) 1 (0.5%) 0 (0.0%) 0.411b v 0 (0.0%) 0 (0.0%) 0 (0.0%) a pearson’s chi-square test; b likelihood ratio test. sr-urs: semirigid ureteroscopy; f-urs: flexible ureteroscopy; swl: shock wave lithotripsy. table 4. intraoperative and postoperative outcomes of ureteroscopic lithotripsy in the treatment of impacted stones. sr-urs (n = 41) f-urs (n = 91) p-value stone size (mm) 15.4 ± 2.6 14.8 ± 2.5 0.246a operation time (min) 50.1 ± 20.9 59.2 ± 21.3 0.023a 15th day sfr 20/21 (51.2%) 17/74 (81.3%) < 0.001b total sfr 5/36 (87.8%) 5/86 (94.5%) 0.284c total complication n (%) 12 (29.3%) 14 (15.4%) 0.105b length of hospital stay (days) 2.3 ± 2.3 1.6 ± 1.7 0.011a retreatment n (%) 5 (12.2%) 6 (6.6%) 0.316c auxiliary procedure n (%) 13 (31.7%) 8 (8.8%) 0.002b a mann-whitney u test; b chi-square test with continuity correction; c fisher’s exact probability test. sfr: stone-free rate. kartal_stesura seveso 01/04/20 18:56 pagina 42 achieve a stone-free state (22). the use of radiation in f-urs is decreasing, and some reports have described a successful use f-urs with no radiation exposure (23). success rates with a single swl session are low, but stone-free outcomes comparable to those with urs can be achieved with repeated sessions. repetition improved the swl success rate in this study, but it remained lower than that achieved with urs. the stone-free outcome with swl was not lower than that reported in previous studies, but swl was not as effective as f-urs in this patient series because of the quality of the ureteroscopy devices and experience of the surgeons. other investigators have reported fewer complications after swl than urs. in this study, treatment-associated complications were more frequent with swl than with f-urs or srurs because of the occurrence of renal colic in our swl group patients. it was generally of mild severity but often resulted in a visit to the emergency department for outpatient treatment. our results are in line with previous studies reporting renal colic as a frequent complication of swl (24, 25) the low complication rates associated with urs might result from the use of advanced, flexible ureteroscopy devices and the experience of the surgeons at our clinic, who have performed nearly 3,000 f-urs procedures. the occurrence of renal colic was not been monitored in all studies, which would also contribute to a low incidence of complications. the safety of f-urs in elderly patients with comorbidities compared with that of swl and sr-urs may also make it the preferred choice for initial lithotripsy in that population (26). although the cost of f-urs is high, it offers cost benefits because of its high success rate, low complication rate, low need for retreatment, and short recovery time. the treatment of impacted stones is challenging and is associated with decreased success and increased complication rates with both urs and swl (27, 28). endoscopy is the most objective method to identify impacted stones, and we evaluated the effectiveness of urs for treating impacted stones in the proximal ureter. better results were observed with f-urs than with sr-urs, similar to the report of legateme et al. (13). length of hospital stay was greater with sr-urs than with f-urs, which probably reflects the more frequent occurrence of sr-urs complications. when used as the initial treatment, f-urs also provided greater success with fewer auxiliary procedures than sr-urs, and beginning the treatment of impacted stones with f-urs appears to be advantageous overall. the study had some limitations such as not including stone composition in the comparison and not being able to perform a cost analysis. the single-center retrospective design and lack of randomization limit the ability to generalize the findings. other limitations include not considering development of lower urinary tract symptoms and the need for analgesics, which might have influenced treatment selection. finally, late complications such as ureteral obstruction might have been missed because of the short follow-up. conclusions in this patient series, f-urs was found to be more effective than sr-urs and swl for initial lithotripsy of 11-20mm proximal ureteral stones. f-urs helped achieve a better success rate at 15 days with less need for retreatment and auxiliary procedures and better effectiveness for impacted stones compared with sr-urs and swl. these results support the need for a prospective randomized controlled trial to provide sufficient evidence to recommend f-urs as the initial procedure for lithotripsy of proximal ureteral stones. references 1. lopes neto ac, korkes f, silva jl, 2nd, et al. prospective randomized study of treatment of large proximal ureteral stones: extracorporeal shock wave lithotripsy versus ureterolithotripsy versus laparoscopy. j urol. 2012; 187:164-168. 2. rukin nj, siddiqui za, chedgy ecp, somani bk. trends in upper tract stone disease in england: evidence from the hospital episodes statistics database. urol int. 2017; 98:391-396. 3. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-482. 4. assimos d, krambeck a, miller nl, et al. surgical management of stones: american urological association/endourological society guideline, part ii. j urol. 2016; 196:1161-1169. 5. aboutaleb h, omar m, salem s, elshazly m. management of upper ureteral stones exceeding 15 mm in diameter: shock wave lithotripsy versus semirigid ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. sage open med. 2016; 4:2050312116685180. 6. cavildak ik, nalbant i, tuygun c, et al. comparison of flexible ureterorenoscopy and laparoscopic ureterolithotomy methods for proximal ureteric stones greater than 10 mm. urol j. 2016; 13:2484-2489. 7. ozturk md, sener nc, goktug hn, et al. the comparison of laparoscopy, shock wave lithotripsy and retrograde intrarenal surgery for large proximal ureteral stones. can urol assoc j. 2013; 7:e673-676. 8. cui x, ji f, yan h, et al. comparison between extracorporeal shock wave lithotripsy and ureteroscopic lithotripsy for treating large proximal ureteral stones: a meta-analysis. urology. 2015; 85:748-756. 9. karadag ma, demir a, cecen k, et al. flexible ureterorenoscopy versus semirigid ureteroscopy for the treatment of proximal ureteral stones: a retrospective comparative analysis of 124 patients. urol j. 2014; 11:1867-1872. 10. alkan e, saribacak a, ozkanli ao, et al. flexible ureteroscopy can be more efficacious in the treatment of proximal ureteral stones in select patients. adv urol. 2015; 2015:416031. 11. galal em, anwar az, el-bab tk, abdelhamid am. retrospective comparative study of rigid and flexible ureteroscopy for treatment of proximal ureteral stones. int braz j urol. 2016; 42:967-972. 12. frober r. surgical anatomy of the ureter. bju int. 2007; 100:949965. 13. legemate jd, wijnstok nj, matsuda t, et al. characteristics and outcomes of ureteroscopic treatment in 2650 patients with impacted ureteral stones. world j urol. 2017; 35:1497-1506. 14. bas o, bakirtas h, sener nc, et al. comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. urolithiasis. 2014; 42:115-120. 15. turk c, knoll t, seitz c, et al. medical expulsive therapy for 43archivio italiano di urologia e andrologia 2020; 92, 1 treatment of proximal ureteral stones kartal_stesura seveso 01/04/20 18:56 pagina 43 archivio italiano di urologia e andrologia 2020; 92, 1 i. kartal, b. baylan, m. caglar cakıcı, s. sarı, v. selmi, h. ozdemir, f. yalçınkaya 44 ureterolithiasis: the eau recommendations in 2016. eur urol. 2017; 71:504-507. 16. morse rm, resnick mi. ureteral calculi: natural history and treatment in an era of advanced technology. j urol. 1991; 145:263-265. 17. nikoobakht mr, emamzadeh a, abedi ar, et al. transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study. urol j. 2007; 4:207-211. 18. drake t, grivas n, dabestani s, et al. what are the benefits and harms of ureteroscopy compared with shock-wave lithotripsy in the treatment of upper ureteral stones? a systematic review. eur urol. 2017; 72:772-786. 19. perez castro e, osther pj, jinga v, et al. differences in ureteroscopic stone treatment and outcomes for distal, mid-, proximal, or multiple ureteral locations: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014; 66:102-109. 20. liu dy, he hc, wang j, et al. ureteroscopic lithotripsy using holmium laser for 187 patients with proximal ureteral stones. chin med j (engl). may 2012; 125:1542-1546. 21. manikandan r, mittal jk, dorairajan ln, et al. endoscopic combined intrarenal surgery for simultaneous renal and ureteral stones: a retrospective study. j endourol. 2016; 30:1056-1061. 22. turna b, tekin a, yagmur i, nazli o. extracorporeal shock wave lithotripsy in infants less than 12-month old. urolithiasis. 2016; 44:435-440. 23. sarikaya s, senocak c, selvi i, et al. does the use of fluoroscopy really affect the success rate of retrograde intrarenal surgery? arch esp urol. 2018; 71:772-781. 24. salem hk. a prospective randomized study comparing shock wave lithotripsy and semirigid ureteroscopy for the management of proximal ureteral calculi. urology. 2009; 74:1216-1221. 25. lee jh, woo sh, kim et, et al. comparison of patient satisfaction with treatment outcomes between ureteroscopy and shock wave lithotripsy for proximal ureteral stones. korean j urol. 2010; 51:788-793. 26. berardinelli f, de francesco p, marchioni m, et al. rirs in the elderly: is it feasible and safe? int j surg. 2017; 42:147-151. 27. seitz c, tanovic e, kikic z, fajkovic h. impact of stone size, location, composition, impaction, and hydronephrosis on the efficacy of holmium:yag-laser ureterolithotripsy. eur urol. 2007; 52:1751-1757. 28. sarica k, kafkasli a, yazici o, et al. ureteral wall thickness at the impacted ureteral stone site: a critical predictor for success rates after swl. urolithiasis. 2015; 43:83-88. correspondence ibrahim kartal, md ibrahimguvenkartal@gmail.com orcid id (ibrahim kartal): 0000-0002-2313-3522 fatih yalçınkaya, md nykaya2@hotmail.com burhan baylan, md baylanburhan@gmail.com ziraat mahallesi, şehit ömer halis caddesi, 06110, dışekapı-altındağ, ankara, turkey mehmet caglar cakıcı, md mcaglarcakici@hotmail.com eğitim mah. dr. erkin cad. kadıköy/!stanbul 34722, turkey sercan sarı, md sercansari92@hotmail.com çapanoğlu mah. cemil çiçek cad bozok üniversitesi erdoğan akdağ yerleşkesi atatürk yolu 7. km, 66100 azizli/yozgat merkez/yozgat, turkey volkan selmi, md volkanselmi@hotmail.com cemil çiçek cad bozok üniversitesi erdoğan akdağ yerleşkesi atatürk yolu 7. km, 66100 azizli/yozgat merkez/yozgat, turkey harun ozdemir, md dr.harun-17@hotmail.com üniversite neighboord yeni yuva st. num:4 avcılar/!stanbul (by the side of borusan firstschool), turkey kartal_stesura seveso 01/04/20 18:56 pagina 44 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4282 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.282 rapidly spreading worldwide until it reached the pandemic stage declared by who on march 11th (1, 2). after china, italy was initially the country that was hit the hardest across europe. the first case was documented on january 30th, but the emergency started only a few days later. since march 8th 2020 following the decreto del presidente del consiglio (dpcm), the whole country was on lockdown (3). by february 21st, the time when this paper was first drafted, 162.488 cases of covid-19 have been diagnosed causing a total of 21.067 deaths, 28.011 critically ill patients, and 3.186 patients hospitalized in intensive care unit (icu). in the veneto region, whose first cluster was found on february 21st in vo’ euganeo (padua), until today, 14.884 cases and 959 covid-19 deaths have been reported (3). although this pandemic is causing an health emergency unprecedented in the western countries, hospitals started facing the demand to dedicate all medical and logistical resources to the assistance of covid-19 patients and to provide only treatments of urgent procedures or non-deferrable oncological interventions. this has inevitably caused a redistribution of all medical activities that are not directly involved in the management of covid-19 patients. during the covid-19 pandemic, urgent and non-deferrable activities have been kept as such, while non-urgent outpatient visits and surgical activities have been deferred until the end of pandemic (4). however, even those urgent operations have been limited, for instance, non-deferrable oncological operations in high anesthetic risk (asa 3-4) patients became difficult to plan due to a lack of beds in intensive care unit (icu). thus, surgical treatments are reserved mainly to low anesthetic risk patients (asa 1-2) for surgical procedures around renal (tcc), urinary tract urothelial cancer (utuc), bladder and prostate cancer for high risk patients not eligible for radiation, while procedures for any other neoplasms have been postponed. when possible, alternative treatments for prostate cancer were proposed (5, 6). this paper will report the experience of an urology unit (azienda sanitaria 2 marca trevigiana) in treviso, in the veneto region, about urgent inpatient and outpatient activities during covid-19 pandemic. materials and methods for the aim of this observational study, we have considered all outpatients admitted to our unit for urgent visit background: the coronavirus disease (covid-19) is causing a significant health emergency which is overturning dramatically routine activities in hospitals. the outbreak is generating the need to provide assistance to infected patients and in parallel to treat all nondeferrable oncological and urgent benign diseases. a panel of italian urologists agreed on possible strategies for the reorganization of urological routine practices and on a set of recommendations that should facilitate a further planning of both inpatient visits and surgical activities during the covid19 pandemic. according to this only urgent benign and nondeferrable oncological activities have been kept. materials and methods: we have considered urgent outpatient visits requested by emergency department (ed) or by general practitioner (gp) and emergency surgical procedures performed in our urology unit from march 9th to april 14th 2020, during covid-19 pandemic. these figures have been compared to those observed last year from march 9th to april 14th 2019. results: our data show that urgent care visits decreased during cocid-19 pandemic (from 293 to 179). urgent care visits of patients who accessed directly to the ed decreased (from 219 to 107) whereas the number of urgent care visits referred by gp remained unchanged (74 vs 72). consequently, the rate of visits from ed decreased from 75% to 60% and the rate of visit requested by gp increased from 25% to 40% (p = 0.001). particularly, the rate of visits for renal colic, luts and other not precisely defined disorders from ed decreased and the corresponding rates of visits of patients referred by gps increased significantly (p = 0.0001, p = 0.0180 and p = 0.0185, respectively). the rate of visits for acute urinary retention, hematuria, sepsis, acute scrotum, cystitis, prostatitis and genito-urinary trauma from ed and gp remained unchanged. finally, urgency endourology and surgical activities have been stable in relation to the same period last year. conclusions: urological emergency activities during covid19 pandemic are more appropriate since urgent outpatients’ visits required by ed are decreased and emergency surgical and endourological procedures are stable. key words: coronavirus disease 2019 (covid-19); pandemic; emergency; endourology; surgery; urology. submitted 26 may 2020; accepted 12 june 2020 introduction since december 31st 2019 coronavirus disease (covid19) was notified by chinese authorities and has been urological emergency activities during covid-19 pandemic: our experience summary elisa cicerello, mario s mangano, giandavide cova, alessio zordani urology unit, department of surgery, ca’ foncello hospital, treviso, italy. cicerello_stesura seveso 14/12/20 20:30 pagina 282 283archivio italiano di urologia e andrologia 2020; 92, 4 urological emergency during covid-19 pandemic required by emergency department (ed) or by general practitioner (gp) from march 9th to april 14th 2020, which include: renal colic, acute urinary retention, hematuria, urosepsis, genito-urinary trauma, acute scrotum, cystitis, prostatitis, urosepsis, low urinary tract symptoms (luts) and other not precisely defined urinary disorders. emergency endourological procedures for obstruction of upper urinary tract, urosepsis or renal colic refractory to medicaments and surgical operations for acute scrotum or genito-urinary trauma have been analyzed. these figures have been compared to those visited between march 9th and april 14th 2019, a year before the covid-19 outbreak. statistical analysis was carried out by chi-square test as well as student’s test. results these data show that urgent care visits requested by ed reduced during covid-19 pandemic, if compared to those registered in the same time span last year (219 vs 107), while those addressed by gp were stable (74 vs 72). consequently, the rate of visits from ed decreased from 75% to 60% and the rate of visit requested by gp increased from 25% to 40% (p = 0.001) (table 1). a reduction of urgent care visits of patients who accessed the ed for renal colic (-36) , acute urinary retention (-8), hematuria (-12), cystitis (-10) and other not definitely disorders (-11) has been observed in the covid period in comparison to the same period of the last year, while other urgent care visits for urosepsis (=0), prostatitis (+4), genitourinary trauma (-2) and acute scrotum (-2) remained stable. urgent care visits referred by gps, instead, showed no difference for acute urinary retention (+1), hematuria (-3), urosepsis (+2), acute scrotum (-1), prostatitis (-1), genito-urinary trauma (-1) between the pandemic period and the previous year. an increase of visits for renal colic (+7) and a decrease of visits for luts (-6) and cystitis (-8) have been registered. the rate of visits for renal colic, luts and other not precisely defined disorders from ed decreased and the corresponding rates of visits of patients referred by gps increased significantly (p = 0.0001, p = 0.0180 and p = 0.0185, respectively). the rate of visits for acute urinary retention, hematuria, sepsis, acute scrotum, cystitis, prostatitis and genito-urinary trauma from ed and gp remained unchanged. ultimately, there was no difference between the two periods for urgent endourological and surgical procedures (table 2). discussion covid-19 pandemic has revolutionized clinical activities in several urological units. the unfortunate scenario of this pandemic required to address all health medical resources to covid-19 patients. hence, several urological units have been closing and urologists have been asked to support new covid-19 wards that opened across the country. according to urological guidelines (5, 6), in our unit no urgent activities have been drastically cancelled. with regard to undeferrable oncological activities, the need of anesthesiologists, mechanic ventilator and intensive care beds for covid-19 patients, has also delayed oncological operations in high risk patients (asa 3-4). in fact, major surgeries such as radical cystectomy for bladder neoplasm, required in most cases post-operative surveillance in intensive care unit (icu), something that during the covid-19 pandemic is not available. this allowed us to treat low risk anesthetic patients (asa 1-2) and perform only partial (pn) or radical nephrectomy (rn), radical nephroureterectomy (rnu), radical cystectomy (rc) or transurethral resection (turb) for non-muscle invasive high risk bladder cancer and radical prostatectomy (rp) for high risk patients not eligible for radiation. alternative therapies for other patients with prostate cancer have been proposed (radiotherapy or androgenic deprivation). all robotic and laparoscopic procedures have been cancelled according to covid-19 recommendations to avoid virus widespread and to reduce or optimize operating time (7). all inpatient and outpatient procedures for benign diseases have been deferred until the end of the covid-19 emergency, and only urgent activities have been preserved. in our experience, the dramatic decrease of urgent outpatients’ visits addressed by ed during covid-19 pandemic could suggest that those are often non necessary, while those recommended by gp seemed to be table 1. emergency outpatient visits required by emergency department (ed) and general practitioners (gp) before and during covid-19 pandemic. before covid-19 during covid-19 delta sig ed vs gp ed gp tot ed gp tot p urgent inpatient visit 219 (75%) 74 (25%) 293 107 (60%) 72 (40%) 179 -114 0.0010 renal colic 56 (85%) 10 (15%) 66 20 (54%) 17 (46%) 37 -29 < 0.0001 acute urinary retention 32 (78%) 9 (22%) 41 24 (71%) 10 (29%) 34 -7 ns hematuria 32 (67%) 16 (33%) 48 20 (61%) 13 (39%) 33 -15 ns urosepsis 12 (60%) 8 (40%) 20 12 (55%) 10 (45%) 22 +2 ns acute scrotum 11 (65%) 6 (35%) 17 9 (64%) 5 (36%) 14 -3 ns cystitis 11 (55%) 9 (45%) 20 1 (50%) 1 (50%) 2 -18 ns prostatitis 6 (67%) 3 (33%) 9 10 (83%) 2 (17%) 12 +3 ns genitourinary trauma 4 (50%) 4 (50%) 8 2 (40%) 3 (60%) 5 -3 ns luts 38 (76%) 12 (24%) 50 3 (33%) 6 (67%) 9 -41 0.0180 other disorders 17 (94%) 1 (6%) 18 6 (55%) 5 (45%) 11 -7 0.0185 table 2. emergency endourological and surgical procedures performed before and during covid-19 pandemic. nephrostomy catheter catheter testicular genito-urinary abscess tube mono j double j torsion trauma drainage before covid-19 3 3 6 1 1 1 during covid-19 4 4 2 2 1 0 cicerello_stesura seveso 14/12/20 20:30 pagina 283 archivio italiano di urologia e andrologia 2020; 92, 4 e. cicerello, m.s. mangano, g. cova, a. zordani 284 more appropriate since they required emergency procedures. for instance, urgent visits for hematuria were required by gp only in cases of gross hematuria with clot retention and anemia, such as in the case of urological neoplasms or radiotherapy pelvis. hospital admission with a quick correction of anemia and vesical catheter placement, and local irrigation of hemostatic solution are necessary and radiological or urological procedures must be performed in cases those local treatments do not work on the patient. urgent visit for hematuria required by ed decreased, probably because most of the cases were single and asymptomatic episodes: in such cases people’s fear and covid-19 lock down reduced ed admission. this suggests that single and asymptomatic hematuria could be evaluated by sonogram or computerized tomography (ct) at home and urological follow-up should be postponed. thus, unmodified urgent visit for prostatitis by ed have been addressed only for symptomatic prostatitis (strong urgency and frequency, urinary retention, prostate abscess and fever) that need urgent hospitalization: cystostomy, catheter placement and appropriate injecting antibiotic therapy are necessary to avoid urosepsis. urgent visits for prostatitis addressed by gp have been stable probably because gp has continued to treat common and uncomplicated prostatitis at home. besides, urgent inpatient visit for acute scrotum (testicular torsion or scrotal abscess), genito-urinary trauma and urosespsis, required both by gp and ed are unmodified during covid-19 pandemic because they should require urgent endourological or surgical treatments. overall, the decrease of urgent visits for acute urinary retention required by ed has been difficult to understand. a hypothesis could be that strong dysuria is often confused with urinary retention and during covid-19 lock down, when dysuria was not considered urgent problem, patients did not show up to ed at all. on the contrary, urgent outpatient visit addressed by gp for urinary retention before and during pandemic were stable because considered more urgent, which could explain the difference between the two group. furthermore, the decrease of outpatient urgent visit for cystitis required both by gp and ed could suggest that these can be successfully treated with adequate antibiotic therapy and other preventive measures avoiding urological visit. only in case of relapses or fever, non urgent urological evaluation could be performed and radiological follow-up required. the decrease of luts visits, both commissioned by ed and gp could suggest that this is usually a “misnomer”: they are not specific urinary symptoms and cannot imply urgent urological diseases. finally, urgent visit of other non-definite disorders might have been due to variations in code status limitations. the reduction of urgent inpatient visits for renal colic sent by ed suggests that these are not necessary and renal colic could be confused with flank pain of other origin; gp, instead, sent patients mainly showing symptomatic urolithiasis (obstruction of the upper urinary tract, urosepsis or acute pain refractory to medical therapy): almost everyone was admitted to hospital where urgent endourological procedures were required. a percutaneous nephrostomy in local anesthesia was performed in case of severe obstruction of the upper urinary tract and fever. ureteral catheter mono j was used with severe sepsis or in anticoagulant therapy patients, while catheter double j was placed in most of the cases that showed renal colic refractory to medical treatment. when possible, uncomplicated stones located in pelvic ureter were removed, while in all other cases, patients were discharged with ureteral stent double j and the treatment was deferred until the end of covid-19 pandemic. surgical procedures were performed for acute scrotum (testicular torsion, trauma or abscess) or genito-urinary trauma that cannot benefit from conservative treatment or radiological embolization. all these procedures performed during covid-19 pandemic were not different from these required in emergency during the same period last year because urgent urological problems were unaltered. endourological and surgical procedures were performed by expert urologists to minimize time and complications (8). every patient even if asymptomatic underwent covid-19 screening before emergency procedure. enhanced recovery after surgery protocols has been adopted after each treatment and during hospital stay (9-11). we could assert that emergency urological procedures during covid-19 were stable, only urgent outpatient visits were registered and this is probably due to people’s fear of covid-19 as well as to the strict lockdown imposed by dpcm, which order to “stay at home”. additionally, general pratictioners’ activity has not diminished, on the contrary, it continues to take care of patients identifying those who really need hospitalization. this observation suggest that some patients could even be successfully treated at home by gp. conclusions even though urologists are not involved in the first line during the covid-19 pandemic, patients treated with urological emergencies are still present and consistent. urgent urological procedures become necessary especially in episodes of complicated urolithiasis or testicular torsion or genitourinary trauma, in order to prevent obstructive renal failure and urosepsis and the loss of organs, respectively. more specifically, the risk of underestimated patients with complicated urolithiasis seems to be low or absent since symptomatic renal colic have sent to urological unit by gp. in conclusion, covid-19 pandemic has suddenly revolutionized urological activities, but it can also teach how to use ed properly after this pandemic. references 1. soharabi c, et al. world health organization declares global emergency: a review of the 2019 novel coronavirus (covid-19). int j surg. 76:71-76. 2. who. novel coronavirus (covid-199 situation. who https./experience argis.com/experience/685d0ace52164f8a5beeeee 1b9125cd. cicerello_stesura seveso 14/12/20 20:30 pagina 284 285archivio italiano di urologia e andrologia 2020; 92, 4 urological emergency during covid-19 pandemic 3. decreto del presidente del consiglio dei ministri 8 marzo 2020: ulteriori disposizioni del decreto-legge 23 febbraio 2020. n. 6, recante misure urgenti in materia di contenimento e gestione dell’emergenza epidemiologic da covid-19. (20°01522)(guserie generale n.59 del 08-03-2020). 4. italian ministry of health. nuovo coronavirus.www. salute.gov.it/ nuovo coronavirus. 5. ficarra v, novara g, abrate a, et al. urology practice during covid-19 pandemic. minerva urol nephrol. 2020; 72:369-375. 6. european association of urology guidelines. available at https:/uroweb.org/guidelines. 7. zhen mh, boni l, fingerhut a. minimally invasive procedures on the novel coronavirus outbreak: lessons learned in china and italy. ann surg. 2020; 272:e5-e6. 8. porpiglia f, checcucci e, amparore d, et al. slowdown of urology resident’s learning curve during covid-19 emergency. bju int. 2020;,125:e15-e17. 9. enhnanced recovery after surgery society guideline. available at https: /erassociety.org/guidelines/list -of-guidelines/ 10. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72. 11. tafuri a, minervini a, celia a, et al. comment on: hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:80-81. correspondence elisa cicerello, md (corresponding author) elisa.cicerello@tin.it mario s, mangano, md giandavide cova, md alessio zordani, md urology unit, department of surgery, ca’ foncello hospital, treviso, italy. cicerello_stesura seveso 14/12/20 20:30 pagina 285 1archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.1 south america and east asia continue to vaccinate against tb, while other countries rely on targeted vaccination of only high-risk groups (5-7). for more than thirty years; bcg material has also served as the standard intravesical immunotherapy agent in the treatment of non-muscle invasive urinary bladder cancer (nmibc) following transurethral resection (tur) (8, 9). this combined approach to nmibc offers the most successful treatment for bladder cancer to date (8, 10). in the past, the bcg vaccine was examined for its anti-cancer properties, which even until today are not well understood. however, it is speculated that bcg has anti-neoplastic properties through its ability to upregulate immunologic cytokine expression within the urinary bladder and induce a form of trained immunologic memory (11). presently, urinary bladder neoplasms remain in the top 10 most common cancers around the world (12). furthermore, incidence rates of bladder cancer have been increasing over the past twenty years, and the rates of bladder cancer are higher in first world countries (13). in these same countries, tb vaccination programs have ceased or target high-risk individuals, including immigrants from tb endemic areas and a select few indigenous populations living in highly crowded conditions (4-6). the role of bcg in the preventing recurrence of nmibc when combined with tur is well established and standard of care. however, it is presently unknown if the bcg vaccine given in early childhood actually serves as a protective mechanism for the development of bladder cancer in later life and whether or not increased rates of bladder cancer correlate with decreased bcg vaccination in various nations. this scoping literature review serves to summarize what is presently known of the connection between bladder cancer and bcg vaccination, and whether previous bcg immunization has any protective mechanisms for bladder cancer development in later life. results from this review will inform future research endeavors in the area of urinary bladder cancer prevention. methods rationale the rationale of this scoping literature review is to establish whether there is existing literature examining the link background: the bacillus calmette-guerin (bcg) vaccine has long been used for the prevention of tuberculosis (tb) around the world. bcg is also used as an immunotherapy agent for the treatment of non-muscle invasive urinary bladder cancer. this scoping literature review and preliminary data analysis aims to summarize the literature correlating infantile bcg vaccination with the incidence of future bladder cancer. methods: studies were identified by a formal literature search of medline and cochrane central registrar of controlled trials following prisma guidelines. preliminary data analysis was conducted on publicly accessible data summarizing the impact of gender, bcg vaccination, and socio-economic effects on crude and age-standardized rates of bladder cancer. results: as part of our analysis, preliminary regression models demonstrated bcg vaccination status, gender, and socio-economic status to have statistically significant effects on crude and age-standardized rates of bladder cancer incidence. bcg vaccination was associated with a 35-37% lower age-standardized rate of bladder cancer incidence. conclusions: there is very little literature examining the relationship between prior bcg vaccination and rates of bladder cancer incidence. our limited data analysis indicates that a relationship does exist between infantile bcg vaccination and later bladder cancer development, although extensive future investigation is needed in this area. key words: bcg; bladder cancer; bcg vaccine; cancer prevention. submitted 28 december 2020; accepted 29 december 2020 introduction the bacillus calmette-guerin (bcg) vaccine is a live attenuated strain of mycobacterium bovis that has been used for the prevention of tuberculosis (tb) (1). as part of the world health organization global expanded immunization program, since the mid 1900’s, the bcg vaccine has remained as one of the most widely used vaccines around the world (2, 3). implementation of this vaccine has resulted in significantly decreased rates of tb globally (2, 3). in most western countries, immunization campaigns in the early 20th century have led to near eradication of tb and thus discontinuation of bcg vaccination programs (4-6). currently, select countries, primarily in bacillus calmette-guerin vaccine and bladder cancer incidence: scoping literature review and preliminary analysis summary sabrina trigo 1, kaitlin gonzalez 1, livio di matteo 2, asmaa ismail 1, hazem elmansy 1, walid shahrour 1, owen prowse 1, ahmed kotb 1 1 northern ontario school of medicine, thunder bay, on, canada; 2 department of economics, lakehead university, thunder bay, on, canada. archivio italiano di urologia e andrologia 2021; 93, 1 s. trigo, k. gonzalez, l. di matteo, a. ismail, h. elmansy, w. shahrour, o. prowse, a. kotb 2 between the bcg vaccine and rates of bladder cancer. we also aimed to summarize the impact of gender, bcg vaccination, and socio-economic effects on the crude and age-standardized rates of bladder cancer. the relationship between crude and age standardized rates of bladder cancer incidence versus the aforementioned variables and other confounders was examined to investigate if an inverse relationship between current bladder cancer incidence and current use of bcg vaccines is related. retrieval of studies a comprehensive virtual literature search was conducted in medline and the cochrane central registrar of controlled trials using prisma guidelines for scoping literature reviews. a protocol was created for this literature search but was not submitted for publication. this article is a review and consists solely of a literature search and analysis of publicly accessible information. it did not include patient data, thus was exempt from research ethics board approval. the literature search was performed on september 6, 2020. the search was conducted for articles pertaining to the bcg vaccine and bladder cancer published in the english language. search terms used included “bladder cancer” or “urinary bladder neoplasm” and “bcg vaccine” or “bcg” or “mycobacterium bovis”. two reviewers independently reviewed titles, abstracts, full articles, and reference lists of articles selected for full-text review. decision to include an article at any stage of the review was made by consensus, if there was a discrepancy a third reviewer served as a tiebreaker. at each stage of review, all studies were carefully assessed for relevance. inclusion and exclusion criteria in this analysis, we used the following inclusion criteria: (1) original research from randomized controlled trials, cohort studies, case-control studies, observational studies, or correlational studies; (2) patients vaccinated with bcg prior to bladder cancer diagnosis; (3) reported bladder cancer incidence or associated mortality. we did not consider review articles and guidelines or studies that included unvaccinated patients where the outcome of interest was not a bladder neoplasm. external data analysis both linear and log-linear regression analysis was conducted using data obtained from the cancer incidence in five continents, vol. 10, the bcg world atlas, and the international monetary fund (imf) world economic outlook database to describe the impact of bcg vaccination on bladder cancer rates. next, we obtained the age standardized and crude bladder cancer incidence rates for females and males from 70 countries between 2003 and 2007. additional variables of interest were subsequently assigned to these countries, which included the following: if the country has current bacillus-calmetteguerin (bcg) vaccination programs for tb (1 yes, 0 no); whether the national share of 1-year-olds vaccinated for bcg exceeded 80% (1 yes, 0 no); if the country never had a vaccination program or had or discontinued universal bcg vaccination (1 yes, 0 no); the national share of 1-year-olds immunized for bcg in both 1985 and 2015 (%); the median per capita gross domestic product (gdp) from 2003-07; the median unemployment rate from 2003-07; and, the median government spending to gdp (%) from 2003-07. if we accept that current rates of international bcg vaccination are an acceptable proxy for past levels, then the using country having current bcg vaccination for tb (1 yes, 0 no) and national share of 1 y old’s immunized (bcg) (who) in 2015 > 80% can be used as the tb vaccine variables. as well, we can also use another variable defined as country never had or discontinued universal bcg (1 yes, 0 no). this variable may be better at picking up the lagged effects over time of tb vaccine use. results literature search our search resulted in 680 articles. forty-two duplicates were identified and removed. six hundred and thirtyeight articles underwent title screening. subsequently, sixteen abstracts were reviewed, followed by 3 full-text articles and corresponding reference lists. three articles were found to be of relevance to our work, however only one publication examined the relationship between bcg vaccination and bladder cancer. the identified study examined the relationship between childhood bcg vaccination and the subsequent development of lung cancer as the primary outcome of interest and bladder cancer as a secondary outcome. this article found bcg vaccination to not be associated with a decreased rate of bladder cancer (hr, 1.34; 95% ci, 0.22-8.03). the study demonstrated that the rate of lung cancer was significantly lower in those who received the bcg vaccine compared to those who had received the placebo (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% ci, 0.20-0.74; p = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis. no other types of malignant neoplasms were significantly different between the 2 groups; notably, leukemia and lymphoma rates were similar in the bcg group vs placebo group (hr, 0.80; 95% ci, 0.35-1.82). ten individuals had a second malignant neoplasm, including cancers of the skin, breast, uterus, ovary, and pancreas and leukemia. the study was a retrospective review of a clinical trial that had assigned participants to a vaccine group using systematic stratification of participants based on school age, district, and sex. the participants (n = 2963) were subsequently randomized by alternation. the original study occurred at 9 sites in 5 us states in between 1935 and 1998 and involved indigenous and alaskan school children with no prior evidence of tuberculosis infection. one cohort received a single intradermal bcg injection and the other, a saline placebo. the outcome of interest was diagnosis of cancer following bcg vaccination. data exploration age standardized and crude bladder cancer incidence rates for males and females for 70 international geographic units for the period 2003-07 were obtained and additional variables assigned for these national units. these variables include: country has current bcg vaccination for tuberculosis (1 yes, 0 no), country never had or discontinued universal bcg (1 yes, 0 no), national share of 1 y olds immunized (bcg) (who) in 2015 > 80%, bcg immunization coverage among 1-year-olds (who 2017) (%) in 1985, bcg immunization coverage among 1-yearolds (who 2017) (%) in 2015, median per capita gdp 2003-07, median unemployment rate 2003-07 and median government spending to gdp (%) 2003-07. given that bladder cancer is primarily a disease of age and tb vaccination occurs early in life, one can hypothesis that any relationship between rates of vaccination and bladder cancer incidence is a lagged one with current bladder cancer incidence rates a function of rates of vaccination and coverage 30 to 50 years ago. on the other hand, current rates of vaccination may be a suitable proxy for past rates and useful as a determining variable. as well, for some of these variables, it was not possible to assign a value. therefore, while the upper bound size of the dataset is 140 observations, some of the analysis would inevitably be restricted to dataset size of just over half the total number of observations. in any event, the analysis is exploratory and very preliminary. if we accept that current rates of international bcg vaccination are an acceptable proxy for past levels, then using country has current bcg vaccination for tuberculosis (1 yes, 0 no) and national share of 1 y olds immunized (bcg) (who) in 2015 > 80% can be used as the tb vaccine variables. we can look at the relationship between crude and age standardized rates of bladder cancer incidence versus these variables as well as other confounders to see if an inverse relationship between current bladder cancer incidence and current use of tb vaccine. as well, we can also use another variable defined as country never had or discontinued universal bcg (1 yes, 0 no). this variable may be better at picking up the lagged effects over time of tb vaccine use. as well, a variable was generated called national share of 1 y olds immunized (bcg) (who 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country never had or discontinued universal bcg = 1). this exploratory analysis will be confined to those variables for which the most observations are available. in terms of results, locally weighted scatterplot smoothing (lowess) univariate plots of age standardized bladder cancer incidence versus whether there is current universal bcg vaccination [county has current bcg vaccination for tuberculosis (1 yes, 0 no)] is quite negative for males and slightly negative for females (figure 1). plots of the age-standardized incidence rates versus gdp appears to show a hump-shaped relationship for both males and females suggesting rising incidence as gdp rises and then a decline at higher levels of gdp (figure 2). this can be interpreted as rising incidence during rising socio-economic status as captured by per capita gdp but then a leveling off and decline. however, these plots do not control for confounding factors. regression analysis is conducted regressing both crude and age-standardized bladder cancer rates controlling for whether male or female incidence, gdp and gdp squared (to model the potential hump-shaped effect of the economic status variable) and bcg vaccination variables. the regressions are for linear and log-linear models. in the linear models for the determinants of both cruse and age standardized incidence, the first set uses current universal bcg vaccination [county has current bcg vaccination for tuberculosis (1 yes, 0 no)] while the second set uses never or past bcg vaccination [country never had or discontinued universal bcg (1 yes, 0 no)] as the bcg variables. the third set uses whether the percent of 1 year olds vaccinated with bcg in 1985 was greater than 50% [national share of 1 y olds immunized (bcg) (who 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country 3archivio italiano di urologia e andrologia 2021; 93, 1 bacillus calmette-guerin vaccine and bladder cancer incidence figure 1. age standardized bladder cancer incidence rate (2003-07) versus percent of one year old getting bcg vaccination in 1985. a: males (lowess asrw currentbcgvacc if males=1). males that did not receive bcg vaccine had a higher incidence rate of bladder cancer. b: females (lowess asrw currentbcgvacc if males=0). females that did not receive bcg vaccine had a slightly higher incidence rate of bladder cancer. figure 2. age standardized bladder cancer incidence rate (2003-07) versus median per capita gdp (2003-07). a: males (lowess asrw medpercapgdp2003 07 if males=1, bwidth 0.5). there was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining. b: females (lowess asrw medpercapgdp2003 07 if females=1, bwidth 0.5). there was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining archivio italiano di urologia e andrologia 2021; 93, 1 s. trigo, k. gonzalez, l. di matteo, a. ismail, h. elmansy, w. shahrour, o. prowse, a. kotb 4 never had or discontinued universal bcg = 1)]. the loglinear models are for the age-standardized rates only. they are of interest, because being log-linear, the coefficients can be interpreted as percentages and therefore allow for interpretation of magnitudes of the effects. in general, the models suggest that gender, bcg vaccinations and socio-economic effects have statistically significant effects on crude and age-standardized rates of bladder cancer incidence at the 5 and 10 percent level. the log-linear models suggest that all other things given, males have just over 4 times the rate of bladder cancer relative to females while the bcg vaccination variables are associated with a 35-37 percent lower age-standardized rate of bladder cancer incidence after controlling for both gender and gdp. when never having bcg or past bcg tb vaccinations is the included vaccination variable, the results show a 20 percent higher rate of bladder cancer incidence, but the effect is not statistically significant. meanwhile, controlling for gender and bcg vaccination, incidence rises and peaks at approximately $10,000 in per capita gdp (in ppp$) and then begins to decline. there does seem to be some relationship between rates of tb vaccine inoculation and longer-term bladder cancer incidence in the results from this data. these results are interesting but should be interpreted with extreme caution given the relatively small size of the data set as well as the single point in time nature of the data. these are only the 2003-07 incidence rates and the data set could be expanded to include the 2008-12 data. however, the ultimate limitation is the lack of fine granularity that would be provided by a much larger data set consisting of individuals over time – a time series microdata panel – with corresponding data on bcg vaccination and other individual level socio-economic characteristics. whether such a data set exists or could be constructed would be interesting. table 1 illustrate data retrieved from studies countries. country total crude asr m f current never percent bcg percent bcg percent bcg percent bcg medper med medg/gdp cases rate (w) bcg or past 1 yr old 1 yr old 1 yr old 1 yr old cap gdp unemployment 2003-07 vacc bcg 2015 > 80% 1985 1985 > 50% 2015 2003-07 rate 2003-07 males algeria 203 5.60 8.60 1 0 1 0 1 86 1 99 12495.6 15.265 30.765 argentina 1238 15.75 14.93 1 0 1 0 1 90 1 99 15741.187 11.575 24.426 australia 12300 21.38 14.90 1 0 0 1 0 0 40460.543 5.042 34.681 austria 7271 36.40 20.30 1 0 0 1 0 90 1 41363.055 5.225 50.378 bahrain 77 6.60 11.60 1 0 43218.759 5.6 24.923 belarus 4406 19.30 14.40 1 0 1 0 1 0 97 11173.37 1.704 46.515 belgium 12617 61.50 32.00 1 0 0 1 0 0 39592.405 8.267 48.933 brazil 3906 7.38 10.68 1 0 1 0 1 63 1 99 12424.455 11.5 39.239 bulgaria 5237 27.90 15.60 1 0 1 0 1 99 1 97 13086.906 10.177 34.301 canada 24778 31.00 18.90 1 0 0 1 0 0 40588.876 6.758 38.662 chile 267 7.17 8.07 1 0 1 0 1 96 1 93 16958.13 9.3 20.137 china 9172 8.37 6.17 1 0 1 0 1 64 1 99 5669.225 4.2 18.074 columbia 451 4.50 4.85 1 0 1 0 1 76 1 90 9286.189 12.042 28.103 costa rica 486 4.50 5.40 1 0 1 0 1 82 1 83 11110.728 6.495 16.658 croatia 3338 31.20 18.10 1 0 1 0 1 0 98 19252.067 17.583 46.815 cuba 235 14.30 8.30 1 0 1 0 1 98 1 99 cyprus 645 34.30 22.50 1 0 0 0 0 0 35179.581 4.55 39.127 czech rep 8094 32.40 19.80 1 0 0 0 0 0 98 25577.306 7.77 42.273 denmark 6464 48.20 26.20 1 0 0 1 0 80 1 43342.624 4.8 51.242 ecuador 190 3.65 4.55 1 0 0 1 1 99 1 88 8616.508 7.095 21.213 egypt 1231 12.30 19.00 1 0 1 0 1 80 1 96 9132.877 10.917 30.638 estonia 763 24.60 15.70 1 0 1 0 1 90 1 95 22409.357 8.031 33.771 finland 3358 26.10 14.20 1 0 0 1 0 83 1 38798.265 8.475 48.331 france 7627 36.80 19.36 1 0 0 0 0 82 1 37551.869 8.825 52.985 germany 24476 47.88 23.31 1 0 0 0 0 0 38597.366 10.042 46.791 iceland 230 30.50 20.40 1 0 0 0 0 41633.012 2.875 41.303 india 3381 2.10 2.92 1 0 1 0 1 8 0 87 3258.168 26.659 iran 133 5.40 8.50 1 0 1 0 1 79 1 99 16089.323 11.3 19.848 ireland 2009 19.40 14.20 1 0 1 0 0 80 1 77 48034.889 4.775 33.343 israel 5033 30.60 25.40 1 0 0 1 0 68 1 26340.356 11.2 43.685 italy 35154 68.32 32.61 1 0 0 1 0 0 37066.895 7.692 47.144 jamaica 58 3.70 4.10 1 0 1 0 1 51 1 99 8549.17 11.225 31.349 japan 10877 26.78 11.69 1 0 1 0 1 85 1 84 35664.003 4.425 34.598 kuwait 87 3.60 7.70 1 0 1 0 1 0 99 71142.748 1.37 31.914 latvia 1040 24.70 16.30 1 0 1 0 1 0 94 17601.947 10.05 33.478 table 1. details of countries included in our analysis. a table illustrating all retrieved data is included as a supplementary material. 5archivio italiano di urologia e andrologia 2021; 93, 1 bacillus calmette-guerin vaccine and bladder cancer incidence libya 174 7.30 14.90 1 0 1 0 1 87 1 99 36946.588 33.699 lithuania 1930 24.20 16.30 1 0 1 0 1 0 97 18443.757 8.324 33.424 malawi 139 5.90 13.30 1 0 1 0 1 87 1 90 802.359 26.394 malaysia 313 5.45 7.18 1 0 1 0 1 95 1 99 18241.829 3.55 25.884 malta 390 38.90 23.90 1 0 1 0 0 65 1 27147.829 6.942 42.322 new zealand 1617 16.00 9.90 1 0 0 0 0 0 30803.692 3.875 37.066 norway 4467 38.90 21.40 1 0 0 0 0 0 63455.303 4.471 41.485 phillipines 622 2.05 4.45 1 0 1 0 0 76 1 80 4835.821 11.35 19.532 poland 4843 29.40 20.00 1 0 1 0 1 95 1 94 16982.21 17.745 44.395 portugal 174 29.00 21.70 1 0 1 0 0 82 1 32 26384.19 7.582 45.31 qatar 19 3.80 7.60 1 0 1 0 1 76 1 97 124151.906 28.727 korea 11962 9.80 9.60 1 0 1 0 1 47 0 98 26340.46 3.55 19.202 russia 1745 17.00 11.70 1 0 1 0 1 0 96 19374.661 7.15 29.598 saudi arabia 266 2.70 5.60 1 0 1 0 1 89 1 98 45699.25 5.822 29.453 serbia 3997 30.30 16.20 1 0 1 0 1 0 98 11017.344 19.53 41.9 singapore 680 7.90 7.10 1 0 1 0 1 93 1 99 62638.987 3.125 12.379 slovakia 2810 21.50 16.30 1 0 0 0 0 0 90 19940.36 16.358 38.762 slovenia 1457 29.60 18.10 1 0 0 0 0 93 1 26804.884 6.342 41.814 south africa 12 0.50 0.70 1 0 1 0 0 70 1 69 10999.622 24.65 27.175 spain 16120 61.37 33.52 1 0 0 1 0 0 33299.088 9.153 38.315 sweden 8256 36.80 17.50 1 0 0 1 0 16 0 24 41206.175 7.042 51.302 switzerland 4108 38.77 20.38 1 0 0 1 0 0 51299.143 3.691 32.896 thailand 1388 5.07 4.90 1 0 1 0 1 80 1 99 11772.887 1.858 19.331 netherlands 1243 48.00 28.70 1 0 0 1 0 0 44098.7 5.014 42.135 tunisia 883 12.00 12.90 1 0 1 0 1 90 1 97 8802.959 12.819 24.166 turkey 3607 23.58 22.43 1 0 1 0 1 76 1 95 15744.75 9.488 34.31 uganda 31 0.70 2.60 1 0 1 0 1 37 0 93 1559.811 18.776 uk (england) 46707 37.70 19.60 1 0 0 1 0 0 75 37585.365 5 37.943 uk, northern ireland 1250 29.60 18.30 1 0 0 1 0 0 75 37585.365 5 37.943 uk, scotland 5271 42.90 22.50 1 0 0 1 0 0 75 37585.365 5 37.943 uk, wales 3103 43.10 20.50 1 0 0 1 0 0 75 37585.365 5 37.943 ukraine 21497 19.80 13.40 1 0 1 0 0 0 39 7300.773 7.185 43.658 uruguay 1103 23.00 15.80 1 0 1 0 1 92 1 98 12872.245 12.142 29.186 usa 60100 29.50 20.80 1 0 0 1 0 0 49412.962 5.083 33.931 zimbabwe 75 2.60 9.40 1 0 1 0 1 76 1 90 2065.22 8.542 females algeria 6 0.20 0.20 0 1 1 0 1 86 1 99 12495.6 15.265 30.765 argentina 5 0.15 0.23 0 1 1 0 1 90 1 99 15741.187 11.575 24.426 australia 1204 1.87 1.05 0 1 0 1 0 0 40460.543 5.042 34.681 austria 49 0.20 0.10 0 1 0 1 0 90 1 41363.055 5.225 50.378 bahrain 0 0.00 0.00 0 1 43218.759 5.6 24.923 belarus 310 1.20 0.50 0 1 1 0 1 0 97 11173.37 1.704 46.515 belgium 73 0.30 0.10 0 1 0 1 0 0 39592.405 8.267 48.933 brazil 159 0.37 0.45 0 1 1 0 1 63 1 99 12424.455 11.5 39.239 bulgaria 260 1.30 0.50 0 1 1 0 1 99 1 97 13086.906 10.177 34.301 canada 395 0.50 0.20 0 1 0 1 0 0 40588.876 6.758 38.662 chile 1 0.03 0.03 0 1 1 0 1 96 1 93 16958.13 9.3 20.137 china 78 0.09 0.07 0 1 1 0 1 64 1 99 5669.225 4.2 18.074 columbia 14 0.10 0.08 0 1 1 0 1 76 1 90 9286.189 12.042 28.103 costa rica 1 0.00 0.00 0 1 1 0 1 82 1 83 11110.728 6.495 16.658 croatia 133 1.20 0.50 0 1 1 0 1 0 98 19252.067 17.583 46.815 cuba 11 0.70 0.50 0 1 1 0 1 98 1 99 cyprus 4 0.20 0.10 0 1 0 0 0 0 35179.581 4.55 39.127 czech rep 153 0.60 0.20 0 1 0 0 0 0 98 25577.306 7.77 42.273 denmark 87 0.60 0.30 0 1 0 1 0 80 1 43342.624 4.8 51.242 ecuador 5 0.10 0.10 0 1 0 1 1 99 1 88 8616.508 7.095 21.213 egypt 16 0.20 0.30 0 1 1 0 1 80 1 96 9132.877 10.917 30.638 estonia 32 0.90 0.30 0 1 1 0 1 90 1 95 22409.357 8.031 33.771 finland 161 1.20 0.40 0 1 0 1 0 83 1 38798.265 8.475 48.331 france 88 0.46 0.18 0 1 0 0 0 82 1 37551.869 8.825 52.985 archivio italiano di urologia e andrologia 2021; 93, 1 s. trigo, k. gonzalez, l. di matteo, a. ismail, h. elmansy, w. shahrour, o. prowse, a. kotb 6 discussion there was one study we identified in our scoping literature review that discussed the relationship between childhood bcg vaccination and subsequent development of lung cancer and secondarily, bladder cancer development. the study occurred at 9 sites in 5 american states between 1935 and 1998 and involved indigenous schoolchildren with no prior evidence of tb infection. one cohort received a single intradermal bcg injection and the other a saline placebo. bcg vaccination was found not to be associated with a decreased rate of bladder cancer. the authors, however, noted significant limitations to their findings given their small sample size, and therefore this association may be masked (14). findings of our literature search yielding 1 article was expected and indicate that additional studies are required in this area. in support of future studies examining the relationship between bladder cancer development and previous bcg vaccination, we performed a preliminary exploration of data, the results of which were discussed above. racial variation of bladder cancer bladder cancer is the 9th most common malignancy, with five hundred and fifty thousand new cases annually worldwide. geographically, there is significant variation germany 181 0.40 0.13 0 1 0 0 0 ó 0 38597.366 10.042 46.791 iceland 2 0.30 0.10 0 1 0 0 0 41633.012 2.875 41.303 india 186 0.18 0.21 0 1 1 0 1 8 0 87 3258.168 26.659 iran 5 0.20 0.20 0 1 1 0 1 79 1 99 16089.323 11.3 19.848 ireland 19 0.20 0.10 0 1 1 0 0 80 1 77 48034.889 4.775 33.343 israel 32 0.20 0.10 0 1 0 1 0 68 1 26340.356 11.2 43.685 italy 216 0.43 0.13 0 1 0 1 0 0 37066.895 7.692 47.144 jamaica 1 0.10 0.00 0 1 1 0 1 51 1 99 8549.17 11.225 31.349 japan 47 0.11 0.01 0 1 1 0 1 85 1 84 35664.003 4.425 34.598 kuwait 2 0.10 0.20 0 1 1 0 1 0 99 71142.748 1.37 31.914 latvia 26 0.50 0.20 0 1 1 0 1 0 94 17601.947 10.05 33.478 libya 1 0.00 0.10 0 1 1 0 1 87 1 99 36946.588 33.699 lithuania 91 1.00 0.40 0 1 1 0 1 0 97 18443.757 8.324 33.424 malawi 3 0.10 0.20 0 1 1 0 1 87 1 90 802.359 26.394 malaysia 4 0.08 0.05 0 1 1 0 1 95 1 99 18241.829 3.55 25.884 malta 2 0.20 0.10 0 1 1 0 0 65 1 27147.829 6.942 42.322 new zealand 47 0.40 0.30 0 1 0 0 0 0 30803.692 3.875 37.066 norway 139 1.20 0.50 0 1 0 0 0 0 63455.303 4.471 41.485 phillipines 8 0.00 0.05 0 1 1 0 0 76 1 80 4835.821 11.35 19.532 poland 106 0.55 0.25 0 1 1 0 1 95 1 94 16982.21 17.745 44.395 portugal 8 1.30 0.50 0 1 1 0 0 82 1 32 26384.19 7.582 45.31 qatar 0 0.00 0.00 0 1 1 0 1 76 1 97 124151.906 28.727 korea 64 0.10 0.00 0 1 1 0 1 47 0 98 26340.46 3.55 19.202 russia 41 0.30 0.10 0 1 1 0 1 0 96 19374.661 7.15 29.598 saudi arabia 4 0.00 0.10 0 1 1 0 1 89 1 98 45699.25 5.822 29.453 serbia 195 1.40 0.70 0 1 1 0 1 0 98 11017.344 19.53 41.9 singapore 4 0.00 0.00 0 1 1 0 1 93 1 99 62638.987 3.125 12.379 slovakia 100 0.70 0.30 0 1 0 0 0 0 90 19940.36 16.358 38.762 slovenia 51 1.00 0.40 0 1 0 0 0 93 1 26804.884 6.342 41.814 south africa 0 0.00 0.00 0 1 1 0 0 70 1 69 10999.622 24.65 27.175 spain 242 0.88 0.35 0 1 0 1 0 0 33299.088 9.153 38.315 sweden 286 1.30 0.50 0 1 0 1 0 16 0 24 41206.175 7.042 51.302 switzerland 28 0.21 0.11 0 1 0 1 0 0 51299.143 3.691 32.896 thailand 163 0.72 0.63 0 1 1 0 1 80 1 99 11772.887 1.858 19.331 netherlands 325 0.80 0.40 0 1 0 1 0 0 44098.7 5.014 42.135 tunisia 5 0.10 0.10 0 1 1 0 1 90 1 97 8802.959 12.819 24.166 turkey 49 0.33 0.25 0 1 1 0 1 76 1 95 15744.75 9.488 34.31 uganda 0 0.00 0.00 0 1 1 0 1 37 0 93 1559.811 18.776 uk (england) 371 0.30 0.10 0 1 0 1 0 0 75 37585.365 5 37.943 uk, northern ireland 17 0.40 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 uk, scotland 60 0.50 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 uk, wales 26 0.30 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 ukraine 1871 1.50 0.60 0 1 1 0 0 0 39 7300.773 7.185 43.658 uruguay 10 0.20 0.10 0 1 1 0 1 92 1 98 12872.245 12.142 29.186 usa 702 0.30 0.20 0 1 0 1 0 0 49412.962 5.083 33.931 zimbabwe 0 0.00 0.00 0 1 1 0 1 76 1 90 2065.22 8.542 7archivio italiano di urologia e andrologia 2021; 93, 1 bacillus calmette-guerin vaccine and bladder cancer incidence in the incidence of nmibc. asian countries are found to have the lowest incidence of bladder cancer, while north american and western european countries have the highest rates. pursuant to our previous discussion, asian countries have universal bcg vaccination programs, while many western countries do not. the incidence of bladder cancer also tends to increase as gdp increases, before levelling off and declining at higher levels of gdp. there are also racial and ethnic variations in the incidence of bladder cancer where it is twice as likely to occur in white males compared to african american or hispanic men (15). bcg vaccination worldwide in 2010, a database was compiled of immunization protocols; among the 180 countries with available data, 157 countries recommend universal bcg vaccination, while the remaining 23 countries have either stopped bcg vaccination due to a reduction in tb incidence, or never recommended mass bcg immunization and instead favored selective vaccination of “at risk” groups. the united states and canada only recommended bcg immunization for high-risk groups and do not advocate for universal bcg vaccination. in contrast, other countries such as the united kingdom had universal vaccination programs against tb. the m. tuberculosis genome was initially published in 1921, and since this time comparative genomic studies have demonstrated the evolution of bcg vaccine strains. in other words, there are genetic differences in the antigenic proteins utilized in different vaccines over the years, which may translate into variations in efficacy over time. in spite of these differences, we have observed a 35-37% lower age-standardized rate of bladder cancer incidence in countries that vaccinate with the bcg vaccine, even after controlling for both gender and gdp (17). early childhood bcg vaccination and its anti-neoplastic effects although the bcg vaccine is efficacious against childhood tb, its efficacy would be expected to diminish with time and provide variable protection in adulthood. existing literature surrounding bcg immunization and leukemia gives some indication that long-lasting anti-neoplastic properties of the vaccine may exist, despite the waning immunity of the vaccine against tb. specifically, these findings were summarized in a meta-analysis combining multiple studies. the aforementioned review indicated that early life-vaccination is associated with lower rates of childhood leukemia (17). another study demonstrated a reduced incidence of lung adenocarcinoma and squamous cell cancer with infantile bcg vaccination (14). limitations the findings presented in this scoping literature review and preliminary data exploration should be interpreted with extreme caution given the relatively small data set as well as data giving a sole snapshot of statistics. however, the ultimate limitation is the lack of fine granularity that would be provided by a much larger data set consisting of individuals over time, such as with a time series microdata panel. a time series microdata panel, which would ideally have corresponding data on bcg vaccination and other individual level socio-economic characteristics and co-founding variables for bladder carcinogenesis such as smoking. conclusions bladder cancer remains one of the most common malignancies globally. prior work suggests there may be a protective relationship between bcg vaccination and rates of certain cancers. this scoping literature review and preliminary data analysis provides a strong call for future work examining whether prior bcg vaccination correlates with a lower incidence of bladder cancer and whether this vaccine actually has a protective effect on the development of bladder malignancy. references 1. raviglione mc, snider de, kochi a. global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. jama. 1995; 273:220-226. 2. world health organization. immunization, vaccines and biologicals: national programmes and systems. retrieved (2020) from https://www.who.int/immunization/programmes_systems/en/#:~:text= the%20epi%20launched%20at%20that,vaccine)%2c%20measles%2 0and%20poliomyelitis. 3. keja k, chan c, hayden g, henderson rh. expanded programme on immunization. world health stat q. 1988; 41:59-63. 4. world health organization. bcg vaccine: who position paper, february 2018-recommendations. vaccine. 2018; 24:3408-3410. 5. faust l, schreiber y, bocking n. a systematic review of bcg vaccination policies among high-risk groups in low tb-burden countries: implications for vaccination strategy in canadian indigenous communities. bmc public health. 2019; 19:1504. 6. world health organization. expanded programme on immunization (epi) factsheet 2019: south-east asia region. 7. gillini l, cooreman e, wood t, et al. global practices in regard to implementation of preventive measures for leprosy. plos negl trop dis. 2017; 11:e0005399. 8. taylor j, becher e, steinberg g. update on the guideline of guidelines: non muscle-invasive bladder cancer. bjui. 2020; 125:197-205. 9. moss jt, kadmon, d. bcg and the treatment of superficial bladder cancer. dicp. 1991; 25:1355-1367. 10. chen s, zhang n, shao j, wang x. maintenance versus non-maintenance intravesical bacillus calmette-guerin installation for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized clinical trials. intl jos. 2018; 52:248-257. 11. van puffelen jh, keating st, oosterwijk e, et al. trained immunity as a molecular mechanism for bcg immunotherapy in bladder cancer. nature rev uro. 2020; 17:513-525. 12. world cancer research fund. worldwide cancer data: global cancer statistics for the most common cancers. retrieved 82018) from https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancerdata. archivio italiano di urologia e andrologia 2021; 93, 1 s. trigo, k. gonzalez, l. di matteo, a. ismail, h. elmansy, w. shahrour, o. prowse, a. kotb 8 13. richters a, aben kh, kiemeney la. the global burden of urinary bladder cancer: an update. world j urol. 2020; 38:1895-1904 14. usher nt, chang s, howard rs, et al. association of bcg vaccination in childhood with subsequent cancer diagnoses: a 60-year follow-up of a clinical trial. jama netw open. 2019; 2:e1912014. 15. daneshmand, siamak. epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder. retrieved (2020) from: https://www-uptodate-com.proxy.lib.nosm.ca/contents/epidemiologyand-risk-factors-of-urothelial-transitional-cell-carcinoma-of-the-bladder?search=bladder%20cancer%20epidemiology&source=search_resu lt&selectedtitle=1~150&usage_type=default&display_rank=1#h4. 16. zwerling a, behr m, brewer t, et al. the bcg world atlas: a database of global bcg vaccination policies and practises. retrieved (2011) from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc306 2527/ 17. morra me, kien nd, elmaraezy a, et al. early vaccination protects against childhood leukemia: a systematic review and meta-analysis. sci rep. 2017; 7:15986. correspondence sabrina trigo, md strigo@nosm.ca kaitlin gonzalez, md kquinlan@nosm.ca asmaa ismail, md asmaaismail0782@gmail.com hazem elmansy hazemuro100@yahoo.com walid shahrour walid.shahrour@gmail.com owen prowse owenprowse@rogers.ca ahmed kotb, md (corresponding author) drahmedfali@gmail.com assistant professor urology department, northern ontario school of medicine, thunder bay regional health science centre 980 oliver rd, thunder bay, on, canada, p7b 6v4 livio di matteo, phd ldimatte@lakeheadu.ca department of economics, lakehead university, thunder bay, on, canada 51archivio italiano di urologia e andrologia 2019; 91, 1 case report partial cystectomy in young male for a urachal tumor masquerading a bladder leiomyoma maurizio sodo 1, lorenzo spirito 2, roberto la rocca 2, umberto bracale 1, ciro imbimbo 2 1 department of surgery, university of naples federico ii, naples, italy; 2 department of urology, university of naples federico ii, naples, italy. . leiomyoma of the bladder is a very rare disorder that accounts for 0.43% of all bladder neoplasms. although the pathophysiology of the bladder leiomyoma is unknown, there are some theories on it. the patients can be asymptomatic; when present, clinical symptoms (lower urinary tract symptoms and\or hematuria), are associated with tumor size and location. for diagnosis, imaging plays an important role: ultrasound, computed tomography (ct) scan and magnetic resonance imaging (mri) are the examinations most frequently performed. treatment consists of surgical removal of the tumor, and the prognosis is excellent. key words: bladder; leiomyoma; partial cystectomy. submitted 10 september 2018; accepted 27 september 2018 summary no conflict of interest declared. protein s 100 (figure 2a-b). we performed follow up with ultrasonography and ct scan and at 3 and 9 months. ct scans were negative. we evaluated bladder capacity with flowmetry at 3 and 9 months. peak and average flows were 21 ml/min and 10 mil/min. voided volume was 198 ml at 3 months and at 9 months was increased at 296 ml. discussion in our case, ultrasonography showed a well-defined, encapsulated, lobulated mass of the bladder with a homogeneous and solid aspect, findings that were also supported by ct. while ct scans can identify the accudoi: 10.4081/aiua.2019.1.51 case report herein we present a case of leiomyoma of the bladder in young male patient who has been successfully managed with a partial cystectomy using a laparoscopic approach. a 33 year old male with a history of persistent thymus gland was referred to our urology clinic for pelvic pain, urgency and dysuria. no hematuria nor history of weight loss were noticed. his physical examination was unremarkable. blood work and urine test were within normal limits. an ultrasound of the abdomen and pelvis revealed no hydronephrosis nor masses of the upper tract. although only partially filled, the bladder revealed a mass. a computed tomography (ct) scan and magnetic resonance imaging (mri) confirmed the presence of an upper side bladder tumor (60 mm x 58 mm x 47 mm) located along the urachus course without any evidence of distant metastasis but with an increased fat density around the mass (figure 1a-b). the lesion appeared undissociated from the bladder wall. the patient underwent a laparoscopic partial cystectomy and urachus removal with a margin of normal tissue by a 3 trocars technique. the bladder was closed in 2 layers and the peritoneum was then closed. the patient had an uneventful post operative period and a foley’s catheter was left for 7 days. the mass measured grossly 6 × 5 × 4 cm in its greatest dimensions with a smooth surface and hard consistency. a microscopic description revealed typical features of a leiomyoma tumour: positive for actina and negative for cd117 and figure 1. a. large, hard tissue density mass arising from the urachus. the mass is not dissociable by the bladder wall at computed tomography. b. high signal intensity mass on t1 magnetic resonance image. figure 2. a. microscopic description revealed typical features of leiomyoma, positive for actina. b. microscopic description revealed typical features of leiomyoma, negative for cd117 and protein s 100. a. b. a. b. sodo_stesura seveso 26/03/19 09:49 pagina 51 archivio italiano di urologia e andrologia 2019; 91, 1 m. sodo, l. spirito, r. la rocca, u. bracale, c. imbimbo 52 rate location of leiomyoma tumors, they are not adequate to distinguish the solidity of the lesion. therefore, ultrasonography should be performed in indeterminate lesions (as seen in ct) (2). magnetic resonance imaging (mri) can distinguish between mesenchymal and transitional cell tumors (3). leiomyomas have intermediate signal intensity on t1weighted images, while t2weighted images show a low signal intensity (4) but a definitive diagnosis is ultimately made by the histopathological examination. management of leiomyomas is mainly guided by the size and location of the tumor (5). treatment options have ranged from enucleation, partial cystectomy and even, though rarely, radical cystectomy. leiomyomas occur throughout the genitourinary tract, which are most commonly found in the renal capsule. most bladder tumors are derived from urothelial cells, while non-epithelial tumors of the bladder, particularly leiomyomas, are relatively rare, comprising of about 0.43% of all bladder tumors. in their review of 37 patients goluboff et al. reported a preponderance of leiomyoma tumours in women (76%) in their third through sixth decades (59%) with a mean age of 44 years (5). in another series (6) all patients were women, with a mean age of 43.6 years, consistent with the report of guluboff et al. bladder leiomyomas are known to produce symptoms, dependent primarily on their location and secondarily on their size. goluboff et al. demonstrated that patients most commonly presented with obstructive urinary symptoms (49%), irritative symptoms (38%), hematuria (11%) or flank pain (13%), while 19% were asymptomatic. in another large series published by park et al. (6), irritative symptoms occurred most frequently (37.7%), followed by obstructive urinary symptoms (31.1%), hematuria (24.6%) and abdominal bulge or pain (14.8%). bladder leiomyoma are classified into three groups according to the histological location of tumor: endovesical, intramural and extravesical; which account for 63%, 7%, and 30%, respectively (6). traditionally, bladder leiomyomas have been treated by surgical resection. the tumor size, extent, and location and the involvement of the sphincter or ureter determine the route of resection. small endovesical tumors can be managed with transurethral resection (tur) and fulguration. larger endovesical, intramural or extravesical tumors can best be managed with segmental resection or partial cystectomy (7). transvaginal excision and laparoscopic partial cystectomy excision have all been successfully used for bladder leiomyoma removal (8, 9). some investigators have suggested that surgical removal should be reserved for symptomatic tumors. they assert that asymptomatic patients with a high probability of a leiomyoma as detected from the imaging, biopsy and cystoscopy evaluations can be followed up without invasive surgery due to the histologic similarities of bladder and uterine leiomyomas and no reported malignant transformation of bladder leiomyoma. however, bladder leiomyomas often mimic malignant lesions and, depending on the location, can often be diagnosed only after surgical removal. furthermore, surgeons are familiar with performing tur or partial cystectomy and therefore surgical resection is thought to be necessary for both confirmation of the diagnosis and definitive treatment. because the prognosis of patients with a leiomyoma tumor after surgical treatment is excellent and no malignant transformation has been reported to-date, a followup is not considered necessary unless urinary tract symptoms occur. conclusions leiomyoma of the urinary bladder is a rare disorder, comprising of about 0.43% of all bladder tumors. the tumor size, rather than the location, appears to affect the nature of symptoms. successful treatment is up to surgeon, using varying surgical approaches, and the prognosis is good after complete resection. references 1. cornella jl, larson tr, lee ra, et al. leiomyoma of the female urethra and bladder: report of twenty-three patients and review of the literature. am. j. obstet. gynecol. 1997; 176:1278-1285. 2. illescas ff, baker me, weinerth jl bladder leiomyoma: advantages of sonography over computed tomography. urol radiol. 1986; 8:216-218. 3. sundaram cp, rawal a., saltzman b. characteristics of bladder leiomyoma as noted on magnetic resonance imaging. urology. 1998; 52:1142-1143. 4. maya mm, slywotzky c. urinary bladder leiomyoma: magnetic resonance imaging findings. urol radiol. 1992; 14:197-199. 5. goluboff et, o'toole k, sawczuk is. leiomyoma of bladder: report of case and review of literature. urology. 1994; 43:238-41. 6. park jw, jeong bc, seo si, et al. leiomyoma of the urinary bladder: a series of nine cases and review of the literature. urology. 2010; 76:1425-9. 8. kanno k, andou m, yanai s, et al. total laparoscopic treatment with cystotomy for intramural bladder leiomyoma. j minim invasive gynecol. 2018; 25:14-15. 9. yin ff, wang n, wang yl, et al. transvaginal resection of a bladder leiomyoma misdiagnosed with a vaginal mass: a case report and literature review. case rep obstet gynecol. 2015; 2015:981843. correspondence maurizio sodo, md maurizio sodo sodo@unina.it umberto bracale, md bracale@unina.it department of surgery, university of naples federico ii, naples (italy) lorenzo spirito, md (corresponding author) lorenzospirito@msn.com roberto la rocca, mf robertolarocca87@gmail.com ciro imbimbo, md cimbimbo@unina.it department of urology, university of naples federico ii via s. pansini 5, 80131 naples (italy) sodo_stesura seveso 26/03/19 09:49 pagina 52 1archivio italiano di urologia e andrologia 2019; 91, 1 original paper transumbilical laparoendoscopic single-site adrenalectomy: a feasible and safe alternative to standard laparoscopy joão andré carvalho 1, 2, pedro tiago nunes 1, 2, hugo antunes 1, belmiro parada 1, 2, edson retroz 1, edgar tavares-da-silva 1, 2, isabel paiva 3, arnaldo josé figueiredo 1, 2 1 urology and renal transplantation department, coimbra university hospital center, portugal; 2 faculty of medicine, university of coimbra; 3. endocrinology department, coimbra university hospital center, portugal. objectives: standard multi-port laparoscopic adrenalectomy (la) is considered the gold standard for benign adrenal tumors. single-site la has been proposed as a feasible and safe alternative because of lower invasiveness, improved cosmetics, less pain and shorter hospital stay. the objective was to evaluate and compare results of single-site transumbilical laparoendoscopic adrenalectomy with standard la for adrenal tumors. materials and methods: one hundred consecutive adrenalectomies from 93 patients, performed between march 2009 and june 2017, were laparoscopically excised: 59 by standard multi-port la (group 1) and 41 by transumbilical laparoendoscopic single-site adrenalectomy (group 2). data gathered included demographics, comorbidities, preoperative imaging, tumor characteristics, perioperative data, surgical complications, pathology and follow-up. ibm spss statistics 23 software was used and p value < 0.05 was considered significant. results: patients of group 2 were younger (48.7 ± 13.9 versus 59.7 ± 15.1 years; p < 0.001) and had fewer comorbidities (p < 0.05). mean tumor diameter in group 2 was lower than those of group 1 (27.52 ± 14.3 versus 47.9 ± 30.6 mm; p < 0.001). tumor laterality did not influence the choice of technique nor the surgical morbidity. all procedures were successfully completed, although one standard la needed conversion to open surgery. mean operative time, hemorrhagic losses, postoperative opioid analgesic requirement and hospital stay were not statistically different between groups. most patients in group 2 (31 patients, 85.4%) did not require drainage, compared to 14 (25.4%) patients of group 1 (p < 0.001). patients who underwent single-site la resumed normal diet earlier (1.0 ± 0.2 versus 1.6 ± 0.7 days; p < 0.001). there were no reoperations and no perioperative mortality. overall mean follow-up time was 94.9 ± 3.1 months, not statiscally different between groups (p = 0.7). conclusions: our results revealed that transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a feasible and safe alternative to standard laparoscopic adrenalectomy. key words: standard multi-port laparoscopic adrenalectomy; laparoendoscopic single-site surgery: partial adrenalectomy. submitted 26 august 2018; accepted 3 september 2018 summary no conflict of interest declared. standard multiport laparoscopic adrenalectomy (la) involves the use of typically three to five ports, depending on the complexity of the procedure. nowadays, laparo-endoscopic single-site surgery (less) is exciting the scientific community because it offers the opportunity to do major laparoscopic surgery with no visible scars and with potential reduced postoperative pain and hospital stay (2). less has been used for cholecystectomy (3), appendectomy (4) and several urological surgeries (5), but the high degree of difficulty and the longer learning curve tends to make its widespread difficult. less surgery through the umbilicus is the most appealing approach, as it truly avoids any new scar, with the multichannel port being placed through a 1.5 to 2 cmincision at the deep edge of the obliterated embryonic orifice. partial adrenalectomy has been a promising surgical technique mainly in functioning lesion in a solitary adrenal gland or in bilateral hereditary or sporadic tumors with the goal of reducing endocrinopathy. however, it has a relapse risk that we always have to remember (6). here, we present our experience with transumbilical less adrenalectomy comparing with standard multiport laparoscopic multiport, showing our results with partial adrenalectomy too. material and methods between march 2009 and june 2017, 100 adrenal glands from 93 patients underwent transperitoneal laparoscopic adrenalectomy at the urology and renal transplantation department of coimbra university hospital center: 59 (59%) underwent standard multi-port laparoscopy (group 1) and 41 (41%) underwent transumbilical laparo-endoscopic single-site adrenalectomy (group 2). standard multi-port laparoscopy included three to four ports. the multichannel port (triport) and bent laparoscopic instruments were supplied by olympus surgical (keymed house, stock road, united kingdom). the multichannel port was placed through a 2-cm incision at the inner edge of the umbilicus and a bent instrument on the left hand was used to create the operative angle. in 30% of cases, it was needed a forceps with no port to move the liver away from the operative field. all transumbilical laparoendoscopic single-site adrenalecdoi: 10.4081/aiua.2019.1.1 introduction the first laparoscopic adrenalectomy was performed by gagner et al. (1) in 1992 and, since then, it has become the gold standard procedure for most adrenal tumors. carvalho_stesura seveso 25/03/19 17:11 pagina 1 archivio italiano di urologia e andrologia 2019; 91, 1 j.a. carvalho, p. tiago nunes, h. antunes, b. parada, e. retroz, e. tavares-da-silva, i. paiva, a. josé figueiredo 2 tomies were executed by one surgeon while standard la were performed by more than one surgeon. data gathered included demographics, comorbidities, preoperative imaging, tumor characteristics, perioperative data, surgical complications, length of stay, need for analgesia, pathology and follow-up. all patients were evaluated by the endocrinology team with a standard protocol. written informed consent was obtained from all patients and the study was performed according to the declaration of helsinki. data were collected retrospectively and processed with ibm spss statistics 23 software. groups were compared using the chi-square test and t student test for categorical and continuous variables, respectively. survival analysis was done through kaplan-meyer survival curve. statistical significance was set at p value of < 0.05, and all reported p-values are two-sided. results patient demographic data are shown in table 1. patients elected for transumbilical less adrenalectomy were younger and with less comorbidities. preoperative tumor data are shown at table 2. the laterality of the lesion didn’t have any impact in the choice of the surgical technique. 52.5% of the cases submitted to standard multi-port la were incidentally diagnosed nonfunctioning enlarged adrenals. in group 2, arterial hypertension was the main initial symptom and elevated aldosterone was the most common finding. only 24.4% of the tumors submitted to transumbilical less adrenalectomy were non-functioning. perioperative data are shown in table 3. there was no difference between groups concerning operative time and estimated blood loss. 29.3% of transumbilical less surgeries were partial adrenalectomies: no one was done by standard multi-port laparoscopy. seven (7%) patients were submitted to bilateral adrenalectomies, two by multi-port la and five by transumbilical less technique. drainage was placed in a minority of cases submitted to transumbilical less technique while the majority of patients submitted to standard multi-port laparoscopy underwent drainage placement. one case of multi-port la was converted to open surgery due to the table 1. demography and comorbities between groups. group 1: patients submitted to standard multi-port laparoscopy adrenalectomy. group 2: patients submitted to transumbilical approach for laparoendoscopic single-site adrenalectomy. demographic data group 1 group 2 p-value patients (n) 57 (61.3%) 36 (38.7%) number of adrenal glands 59 (59%) 41 (41%) age at surgery (years) 59.7 ± 15.1 48.7 ± 13.9 p < 0.001 sex ns (p: 0.8) male 39.0% 36.6% female 61.0% 63.4% cardiovascular disease 20.3% 2.4% p: 0.013 diabetes mellitus type 2 27.1% 7.3% p: 0.02 ns: non-significant. table 2. preoperative tumour data between groups. group 1: patients submitted to standard multi-port laparoscopy adrenalectomy. group 2: patients submitted to transumbilical approach for laparoendoscopic single-site adrenalectomy. tumor data group 1 group 2 p-value (n = 57) (n = 36) laterality ns (p: 0.6) left 61.0% 61.0% right 39.0% 39.0% presentation p: 0.02 incidental 52.5% 31.7% arterial hypertension 35.6% 39.0% cushing disease 5.1% 24.4% metastasis 0% 2.4% pain 6.8% 2.4% functioning adenoma p: 0.01 yes 50.8% 75.6% no 49.2% 24.4% produced hormone p: 0.002 non-functioning 49.2% 24.4% aldosterone 11.9% 34.1% catecholamines 28.8% 14.6% cortisol 8.5% 26.8% dhea 1.7% 0% mean imaging diameter on ct (mm) 47.9 ± 30.6 27.52 ± 14.3 p < 0.001 mean imaging diameter on ct > 40 mm 56.4% 15.2% p < 0.001 maximum diameter (mm) 120 80 dhea: dehydroepiandrosterone; ns: non-significant. table 3. comparison of perioperative data between groups. group 1: patients submitted to standard multi-port laparoscopy adrenalectomy. group 2: patients submitted to transumbilical approach for laparoendoscopic single-site adrenalectomy. perioperative data group 1 group 2 p-value (n = 57) (n = 36) partial adrenalectomy p < 0.001 yes 0% 29.3% no 100% 70.7% bilateral adrenalectomy ns (p: 0.06) yes 3.6% 14.3% no 96.4% 85.7% operative time (min) unilateral adrenalectomy 93.1 ± 42.1 87.9 ± 46.4 ns (p: 0.9) bilateral adrenlaectomy 82.5 ± 17.6 111 ± 36.8 ns (p: 0.09) estimated blood loss (ml) 34.9 ± 152.6 23.6 ± 87.7 ns (p: 0.4) drainage tube p < 0.001 yes 74.6% 14.6% no 25.4% 85.4% need to convert to open surgery 1.8% 0% ns (p: 0.4) perioperative complications 3 diaphragm 0 ns (p: 0.1) injuries 1 postoperative retroperitoneal hematoma postoperative opioid analgesic requirement ns (p:0.2) yes 44.1% 31.7% np 55.9% 68.3% hospital length of stay (days) 3.2 ± 2.5 2.5 ± 1.4 ns (p: 0.09) time to resume normal diet (days) 1.6 ± 0.7 1.0 ± 0.2 p < 0.001 ns: non-significant; postop: postoperative. carvalho_stesura seveso 25/03/19 17:11 pagina 2 absence of surgical plans in a lesion that revealed to be posteriorly a melanoma metastasis. there were four perioperative complications, all of them during or after a standard multi-port laparoscopic adrenalectomy. there was no difference concerning postoperative opioid analgesic requirement and hospital length of stay. the hospital length of stay was mainly conditioned by medical or hormonal issues more than the surgery itself. however, the time to resume normal diet was lower in group 2. there were neither reoperations nor perioperative mortality and the tumor laterality did not influence surgical morbidity (p > 0.05). transumbilical less technique allowed for a completely hidden scar in all cases, with excellent cosmesis. the final pathology is shown in table 4. the mean pathological diameter was inferior in the group 2 and, in both groups, benign adenoma was the most common diagnosis. in the next table (table 5), there is a brief summary on our experience with partial adrenalectomy. all of them were submitted to transumbilical less technique and all lesions were hormone producing. more than half were bilateral and presented mostly with symptoms of cushing disease and arterial hypertension. the pathological data revealed mainly adenoma and cortical hyperplasia. overall mean follow-up time was 94.9 ± 3.1 months (group 1 = 92.1 ± 5.7 months versus group 2 = 95.6 ± 2.4 months with no statistically difference between groups, p = 0.7), as shown in figure 1. discussion laparoendoscopic single-site adrenalectomy is a minimally invasive surgical technique that is being increasingly used. transumbilical route offers the opportunity to remove the adrenal gland or only the adrenal tumor with only one hidden incision. therefore, the level of patient with the scar cosmetics is expected to be better. 3archivio italiano di urologia e andrologia 2019; 91, 1 transumbilical adrenalectomy table 4. pathological data between groups. group 1: patients submitted to standard multi-port laparoscopy adrenalectomy. group 2: patients submitted to transumbilical approach for laparoendoscopic single-site adrenalectomy. table 5. characteristics of the tumours submitted to transumbilical partial less adrenalectomy. tumor data group 1 group 2 p-value mean pathological diameter (mm) 42.4 ± 27.2 26.50 ± 16.3 p < 0.001 adenoma 41.4% 48.8% p: 0.04 benign pheochromcytoma 20.7% 12.2% malignant pheochromcytoma 6.9% 2.4% intermediate pheochromcytoma 1.7% 2.4% cortical hyperplasia 0% 17.1% carcinoma 10.3% 4.9% myelolipoma 6.9% 0% metastatic lesion ab initio 1.7% 4.9% ganglioneuroma 0% 2.4% cavernous hemangioma 1.7% 0% cyst 3.4% 0% undetermined 5.2% 4.9% tumor data value n 9 laterality left 41.7% right 58.3% bilateral yes 55.6% no 44.4% presentation cushing disease 41.7% arterial hypertension 33.3% incidental 25% functioning adenoma yes 100% no 0% produced hormone cortisol 58.3% aldosterone 41.7% mean imaging diameter on ct (mm) 21.8 ± 10.3 mean imaging diameter on ct > 40 mm 0% pathological data adenoma 50% cortical hyperplasia 41.7% unknown cause 8.3% operative time (minutes) 100.4 ± 31.3 hemorragic losses < 200 cc 100% need of drainage 25% resume to normal diet (days) 1 ± 0.1 hospital length of stay (days) 2.8 ± 1.4 reoperation; perioperative complications; relapse 0 improved or normalized arterial pressure 88.8% postoperative need for replacement medical therapy 16.7% follow-up (months) 17.4 ± 10.6 figure 1. survival curves between groups. group 1: patients submitted to standard multi-port laparoscopy adrenalectomy. group 2: patients submitted to transumbilical approach for laparoendoscopic single-site adrenalectomy. carvalho_stesura seveso 25/03/19 17:11 pagina 3 archivio italiano di urologia e andrologia 2019; 91, 1 j.a. carvalho, p. tiago nunes, h. antunes, b. parada, e. retroz, e. tavares-da-silva, i. paiva, a. josé figueiredo 4 wang et al. (7) concluded that laparoendoscopic single-site adrenalectomy caused less postoperative pain, albeit, requiring a longer surgical time (55-206 minutes). other positive factors in favor of laparoendoscopic single-site adrenalectomy are reduced length of hospital stay and improved postoperative aesthetics (8). jeong et al. (9) compared transumbilical less with standard la to remove a benign adrenal adenoma and concluded that there were no differences concerning operative time, estimated blood loss and hospital stay but the sample was only nine patients. our results showed that transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a feasible and safe alternative to standard laparoscopic adrenalectomy: operative time, hemorrhagic losses, postoperative opioid analgesic requirement and hospital stay were similar, yet normal diet was resumed earlier. more standard la cases were drained, but this difference to transumbilical less may have been promoted by a stronger focus on cosmetics. the coordination between the surgeon and assistant is vital for this procedure to avoid clashing of instruments with the camera: for that reason, bent instruments were used for the left surgeon hand, along with a flexible camera. operative time was the same for the two techniques, but patient selection could be a bias to the analysis: patients submitted to laparoendoscopic single-site adrenalectomy were typically younger, with less comorbidities and with lesions of adrenal gland with a smaller diameter. the rate of perioperative complications and the need for conversion to open surgery was zero in the laparoendoscopic single-site adrenalectomy and only one case of the standard multi-port laparoscopic adrenalectomy need conversion due to absence of surgical safer plans. again, patient selection is extremely important to choose the laparoscopic approach instead of the open approach. the high degree of difficulty and the alleged longer surgical learning curve makes this surgical approach only feasible for experienced laparoscopic surgeons. in our institution, a single urologist performed the transumbilical laparoendoscopic single-site adrenalectomies and standard laparoscopic adrenalectomies were executed by several urologists. the reduced drainage need and the faster recovery of normal diet in transumbilical less adrenalectomies could be biased for that reason. less approach can be implemented in partial adrenalectomy (10). we started to do partial adrenalectomy and all of them were done by transumbilical less technique and all were hormonal active adrenal tumors. during the last years, partial adrenalectomy has been accepted for adrenal tumors in unilateral glands or in patients with hereditary syndromes. our experience is limited, the follow-up is short to see if there is any relapse and only two patients are not corticoid-free of medical therapy. partial adrenalectomy is especially done in conn’s syndrome and in pheochromocytoma. in our series, no pheochromocytoma was submitted to partial adrenalectomy probably because of the multifocal nature of the disease that could explain the relatively high recurrence rate in hereditary pheochromocytoma (10) and for that reason we did not perform partial adrenalectomies in these patients. nagaraja et al. (6) found that the overall recurrence rate was 8% and 85% of the patients were steroid-free. in our series, no relapse was found and 83.3% of patients did not need any substitutive therapeutic after surgery. more experience and more time are needed to evaluate if this technique could be a good alternative to total adrenalectomy. although less partial adrenalectomy may be a well-tolerated and feasible procedure to reduce endocrinopathy, studies proving long-term outcome and controlled trials are missing: earlier publications suggested that only one-third of one gland is sufficient to avoid hormonal deficiency (6). conclusions transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumours could be a good alternative to standard laparoscopic adrenalectomy. our results showed similar perioperative data, less drainage, quicker return to normal diet and with no reoperations or perioperative mortality. references 1. gagner m, lacroix a, bolté e. laparoscopic adrenalectomy in cushing’s syndrome and pheochromocytoma. n engl j med. 1992; 327:1033-1033. 2. miyajima a, hattori s, maeda t, et al. transumbilical approach for laparo-endoscopic single-site adrenalectomy: initial experience and short-term outcome. int j urol. 2012; 19:331-5. 3. piskun g, rajpal s. transumbilical laparoscopic cholecystectomy utilizes no incisions outside the umbilicus. j. laparoendosc. adv surg tech. a 1999; 9:361-4. 4. esposito c. one-trocar appendectomy in pediatric surgery. surg endosc. 1998; 12:177-8. 5. aron m, canes d, desai mm, et al. transumbilical single-port laparoscopic partial nephrectomy. bju int. 2009; 103:516-21. 6. colleselli d, janetschek g. current trends in partial adrenalectomy. curr opin urol. 2015; 25:89-94. 7. wang l, wu z, li m, et al. laproendoscopic single-site adrenalectomy versus conventional lapartoscopic surgery: a systematic review and meta-analysis of observational studies. j endourol. 2013; 27:743-750. 8. lal g, duh qy. laparoscopic adrenalectomy – indications and technique. surg oncol. 2003; 12:105-123. 9. jeong bc, park yh, han dh, et al. laparoendoscopic single-site and conventional laparoscopic adrenalectomy: a matched case-control study. j endourol. 2009; 23:1957-60. 10. ho ch, liao pw, lin vc, et al. laparoendoscopic single-site (less) retroperitoneal partial adrenalectomy using a custom-made single-access platform and standard laparoscopic instruments: technical considerations and surgical outcomes. asian j surg. 2015; 38:6-12. correspondence joão andré carvalho, md (correspondence author) joao.andre.mendes.carvalho@gmail.com rua paulo quintela, lote 6,7ºb, 3030-393 coimbra (portugal) pedro tiago nunes, md ptnunes@gmail.com hugo antunes, md hugoantunes4@gmail.com belmiro parada, md parada.belmiro@gmail.com edson retroz, md edson.retroz@gmail.com edgar tavares-da-silva, md edsilva.elv@gmail.com isabel paiva, md ipaiva@netcabo.pt arnaldo josé figueiredo, md ajcfigueiredo@gmail.com praceta prof. mota pinto 3000-075 coimbra (portugal) carvalho_stesura seveso 25/03/19 17:11 pagina 4 265archivio italiano di urologia e andrologia 2019; 91, 4 case report solitary prostatic cancer metastasis to the testis: a case report and lessons to learn asmaa ismail, hazem elmansy, walid shahrour, owen prowse, ahmed kotb urology department, northern ontario school of medicine, thunder bay, ontario, canada. prostate cancer (pca) is a complex disease. several case series and reports have described the spread of pca to unusual organs, like esophagus, eye and periureteric fat causing ureteropelvic junction obstruction. spread of pca to the testis has been reported in few case reports, however pca was always firstly diagnosed in all published cases and testicular spread of cancer has been diagnosed during follow up of the patients. this case is unique in that, the patient initially presented with a testicular mass and histologic examination after orchiectomy allowed to diagnose prostatic cancer. this patient was 81 years old and he never had psa screening by his family doctor. psa was not even done initially by us considering his age and the presentation with testicular mass. this case may impact clinical practice in several ways: 1) considering pca always in the differential diagnosis of any disease of an adult man, regardless of its presentation because we did not do that at initial patient evaluation and psa was only measured after orchiectomy when pathology demonstrated metastatic pca; 2) suggesting standard orchiectomy with epididemectomy for surgical castration instead of the current surgical technique of subcapsular/subepididymal orchiectomy, because our patient had cancer involving his epididymis as well; 3) suggesting to include psma as a part of preoperative staging for high risk pca patients, in consideration that psma is proving to be a promising new imaging technique that can help diagnosing metastatic pca in unusual locations. key words: prostate cancer; testicular metastasis; psma; orchiectomy. submitted 17 august 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.265 introduction prostate cancer (pca) is a complicated disease that should be considered in the differential diagnosis of any disease in a man over 50 year old, regardless of his initial presentation. pastore et al. (1) recently published a case of pca presented with ocular symptoms turned to be orbital metastasis. mittal et al. (2) described a patient that had bilateral orchiectomy for hormonal control of metastatic pca where histology demonstrated metastatic pca of the testis and epididymis. case report an 81years old man presented to the urology clinic with a left hard and painless testicular mass. tumour markers were normal and ct of chest, abdomen and pelvis was normal. he was counseled and left radical orchiectomy was done. pathology was metastatic adenocarcinoma likely prostatic in origin. the tumour mainly involved epididymis and lower half of the testis. the tumour did show positive immunohistochemical staining to pan-keratin, ema, ck8/18, p53, berep4 and psa, but negative for cd30, ck7, ck20, alpha-fetoprotein, placental alkaline phosphatase, hcg, cea, vimentin, calretinin, ttf-1, and ck 5/6. there was no previous psa testing done. psa was then measured and transrectal ultrasound (trus) guided biopsy was scheduled. psa was 66 ng/ml and trus guided biopsy confirmed pca gleason 4+4 in all cores. bone scan was negative. the patient was counseled about his diagnosis and the absence of other evidence of metastases. external radiotherapy was started with a curative intent. discussion and conclusions almagro et al. (3) had the first pubmed indexed publication describing accidentally discovered pca in the testis during bilateral orchiectomy done for hormonal control. since then; infrequent case reports are being published describing the testicular spread of pca. however, all available case reports included patients known to have pca and had testicular metastasis during follow up course of cancer. table 1 summarizes ways of presentation of testicular metastasis from pca. this case report is unique as it describes a metastatic testicular lesion as a way to diagnose pca. it even leads us to few questions that should be considered during management of this complex disease. is subcapsular/subepididymal orchiectomy a valid option for surgical castration, considering the risk of epididymal silent metastasis? this table 1. some studies of patients with pca presenting with testicular mass. publications presentation janssen et al. (4) during follow up after radical prostatectomy menchini-fabris et al. (5) campara et al. (6) during hormonal treatment of metastatic pca kusaka et al. (7) mittal et al. (2) as a part of initial management of metastatic pca almagro et al. (3) this case report metastatic pca to the testis without previous pca diagnosis ismail_stesura seveso 10/01/20 08:57 pagina 265 archivio italiano di urologia e andrologia 2019; 91, 4 a. ismail, h. elmansy, w. shahrour, o. prowse, a. kotb 266 patient had his cancer involving both the testis and epididymis with no clinical suspicion for epididymal involvement. santos-lopes et al. (8) described a case of pca developing epididymal metastasis during follow up of pca that was discovered because of rising psa. are ct bone scans sufficient for patients presenting with high risk criteria of pca? a recent case series (9) showed that psma was able to detect metastatic pca in unusual sites. another study included 21 patients with high risk pca proved superiority of psma over ct scan, bone scan and mri, with psma changing management of 51% of patients (10). prostate cancer should be always suspected in disease of adult men regardless of their presentation. subcapsular/ subepididymal orchiectomy may not be a safe option for surgical castration. psma scan may be the future single routine investigation for all patients with high risk prostate cancer. references 1. pastore mr, d'aloisio r, cirigliano g, et al. orbital metastasis as presenting symptom from a prostatic adenocarcinoma. eur j ophthalmol. 2019; 1120672119832182. 2. mittal j, dorairajan ln, manikandan r, et al. testicular and epididymal metastasis from prostate carcinoma: a rare manifestation of common disease. j clin diagn res. 2017; 11:pd01pd02. 3. almagro ua. metastatic tumors involving testis. urology. 1988; 32:357-60. 4. janssen s, bernhards j, anastasiadis ag, et al. solitary testicular metastasis from prostate cancer: a rare case of isolated recurrence after radical prostatectomy. anticancer res. 2010; 30:1747-9. 5. menchini-fabris f, giannarini g, pomara g, et al. testicular metastasis as isolated recurrence after radical prostatectomy. a first case. int j impot res. 2007; 19: 108-9. 6. campara z, simic d, aleksic p, et al. metastasis of prostate adenocarcinoma to the testis. med arch. 2016; 70:31820. 7. kusaka a, koie t, yamamoto h, et al. testicular metastasis of prostate cancer: a case report. case rep oncol. 2014; 7:643-7. 8. santos-lopes s, lobo j, henrique r, et al. epididymal metastasis from prostate adenocarcinoma: an unusual and challenging diagnosissuspected in gallium-68 prostate-specific membrane antigen-positron emissiontomography/computed tomography and histologically confirmed. urol ann. 2017; 9:89-91. 9. dureja s, thakral p, pant v, et al. rare sites of metastases in prostate cancer detected on ga-68 psma pet/ct scan. a case series. indian j nucl med. 2017; 32:13-15. 10. hirmas n, al-ibraheem a, herrmann k, et al. [68ga]psma pet/ct improves initial staging and management plan of patients with high-risk prostate cancer. mol imaging biol. 2019; 21:574-581. correspondence asmaa ismail, md asmaaismail@rocketmail.com hazem elmansy, md hazemuro100@yahoo.com walid shahrour, md walid.shahrour@gmail.com owen prowse, md owenprowse@rogers.com ahmed kotb, md drahmedfali@gmail.com urology department, northern ontario school of medicine, thunder bay regional health sciences centre, 980 oliver rd, thunder bay, ontario p7b 6v4 (canada) ismail_stesura seveso 10/01/20 08:57 pagina 266 archivio italiano di urologia e andrologia 2021; 93, 184 letter to editor clinical impact of combined pten and erg rearrangements in localized prostate cancer submitted 30 december 2020; accepted 7 january 2021 no conflict of interest declared. doi: 10.4081/aiua.2021.1.84 to the editor, prostate cancer (pca) is nowadays the second most common malignancy diagnosed among men and is responsible for one of the leading causes of cancer mortality. clinically localized disease may present with a wide variety of clinical behavior including tumors of low clinical significance as well as highly aggressive ones. among patients treated with either radical prostatectomy or radiotherapy there is a risk of biochemical failure (bf). as a result, it is of outmost interest to develop new markers predicting the risk of bf development. several genes and molecular pathways are implicated in the disease development and progression including phosphatase and tensin homolog gene (pten) and ets related gene (erg). pten is a tumor suppressor gene located in chromosome 10q23.3. it encodes the pten protein, a dual lipid phosphatase enzyme, which acts as a negative regulator of the pi3k-akt survival pathway. pten protein dephosphorylates pip3 converting it back to pip2. as a result, the phosphorylation of akt mediated by pip2 conversion to pip3 is inhibited and a g1 cell cycle arrest is induced. in addition, pten may promote oncogenesis in a pip3 independent mechanism involving mapk pathway crosstalk with pten pathway, cell migration, cell adhesion, tumor angiogenesis and dna repair and tumor invasion. erg is an oncogene member of the ets family located in chromosome 21q22.2. the connection between the erg protein and prostate cancer is well documented. erg protein is mostly involved in this process as a fusion protein with transmembrane protease serine 2 (tmprss2), a protein encoded by tmprss2 gene, located in chromosome 21q22.3 (1). although pten loss and erg rearrangement are the most common genomic aberrations in prostate cancer, the relationship between them and how they interfere with cancer recurrence and progression is still unclear. recently, a systematic review and metanalysis was published by liu et al regarding the impact of pten loss and erg rearrangement on recurrence after treatment with radical prostatectomy or brachytherapy. a total of 6744 patients from 17 papers were included in the metanalysis and primary endpoints assessed were biochemical recurrence free (brf) survival and recurrence free survival (rfs). a subgroup analysis was performed according to the degree of pten deletion, erg rearrangement and gleason score. in terms of results, prostate cancer with pten deletion faced a higher risk for recurrence. brf and rfs were lower in a statistically significant way in both groups with heterozygous or homozygous pten loss. the effect was more profound in the homozygous deletion. on the other hand, no correlation was documented regarding the association of erg rearrangement, regardless of pten deletion or not, and the risk for recurrence after radical prostatectomy or brachytherapy. nevertheless, gleason score was proved to be a significant factor predicting recurrence (2). in terms of clinical impact in decision making, there are several clinical trials investigating the use of drugs targeting pten and erg pathways. mapk inhibitors are under investigation as there is a correlation between pten molecular pathway and mapk signaling. pi3k inhibitor ly294002 and pan-akt inhibitor azd5363 deliver promising results in terms of slowing prostate cancer growth. in addition, multikinase inhibitors such as sorafenib, buparlisib and regorafenib also interfere with pi3k/akt/mtor pathway and present as possible treatment options. moreover, ciap-1 antagonist at-iap can sensitize pten deficient tumors to radiotherapy in vitro. moreover, a recent phase ii clinical trial of everolimus, an mtor inhibitor, plus bicalutamide for castration-resistant prostate cancer presented valuable results with 75% of the patients treated with everolimus plus bicalutamide having a decrease in psa of greater than or equal to 50% (1). the prognostic value of pten loss and erg rearrangement was also evaluated by bismar et al. in a study including 463 patients where the pten and erg status was correlated with clinical and pathological features such as gleason score, patients’ outcomes, and possible androgen deprivation therapy. erg expression and pten loss was documented in 85archivio italiano di urologia e andrologia 2021; 93, 1 pten and erg in prostate cancer 28.2% and 38% of patients, respectively. it was quite interesting that among pten negative tumors, 21.8% presented as erg positive. in cases where pten was intact patients presented with better cancer specific survival. on the other hand, patients with decreased pten intensity without erg positivity showed the worst clinical outcome compared to those with no pten loss and no erg expression, where they had best clinical outcome. patients with erg expression with or without pten loss showed intermediate risk in relation to lethal disease (3). the correlation between pten and erg protein expression and prostate cancer is a field of investigation where many mechanisms and pathways are still being discovered in ongoing trials. there is a need of results from new, large clinical trials in order to establish the clinical utility of both pten and erg status in the management of pca patients. references 1. ullman d, dorn d, rais-bahrami s, gordetsky j. clinical utility and biologic implications of phosphatase and tensin homolog (pten) and ets-related gene (erg) in prostate cancer. urology. 2018; 113:59-70. 2. liu r, zhou j, xia s, li t. the impact of pten deletion and erg rearrangement on recurrence after treatment for prostate cancer: a systematic review and meta-analysis. clin transl oncol. 2020; 22:694-702. 3. bismar ta, hegazy s, feng z, et al. clinical utility of assessing pten and erg protein expression in prostate cancer patients: a proposed method for risk stratification. j cancer res clin oncol. 2018; 144:2117-2125. correspondence charalampos fragkoulis, md harisfrag@yahoo.gr ioannis glykas, md konstantinos ntoumas, md urology department, general hospital of athens “g. gennimatas”, athens (greece) athanasios dellis, md 1st department of urology, school of medicine, laiko hospital, national and kapodistrian university of athens, athens (greece) athanasios papatsoris, md 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens (greece) charalampos fragkoulis ¹, ioannis glykas ¹, athanasios dellis 2, konstantinos ntoumas ¹, athanasios papatsoris 3 1 urology department, general hospital of athens “g. gennimatas”, athens, greece. 2 1st department of urology, school of medicine, laiko hospital, national and kapodistrian university of athens, athens, greece. 3 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2020; 92, 3182 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.182 prepuce-sparing corporoplasty as a safe alternative for patients with acquired penile curvature aldo franco de rose 1, francesca ambrosini 1, guglielmo mantica 1, enrico zero 2, riccardo banchero 1, carlo terrone 1 1 department of urology, policlinico san martino hospital, university of genoa, genoa, italy; 2 department of computer science, bioengineering, robotics and systems engineering, university of genoa, genoa, italy. objectives: penile curvature is a rare condition, classified as congenital or acquired (peyronie’s disease) (pd). surgical correction is the standard treatment. it’s common practice to associate circumcision with penile de-gloving to prevent complications. in this paper we evaluate the feasibility of penile surgery avoiding circumcision. materials and methods: patients presenting with penile curvature were treated using a modified nesbit procedure. patients were divided into group a if they opted for a prepuce-sparing surgery and the others into group b. patients were evaluated pre and postoperatively and postoperative complications were assessed. the 5-item international index of erectile function (iief-5) was administered before and 6 months after surgery and we compared the difference of mean value using t-test. results: group a and b were made of 53 and 16 patients respectively. median age was 59 years [interquartile range (iqr) 12] in a and 62 (iqr 9) in b (p = 0.2). median curvature was 40° (iqr 40°) in a and 40 ° (iqr 30°) in b (p = 0.62). mean difference between preand post-operative ieff was 1.9 ± 2 in a and 2.6 ± 2.1 in b (p = 0.36). conclusions: according to our experience, surgical correction of penile curvature without performing circumcision could be a safe and feasible strategy. we recommend performing circumcision only in patients who present with pre-operative phimosis. key words: erectile dysfunction; foreskin; male; phimosis; penile induration. submitted 23 february 2020; accepted 2 april 2020 introduction penile curvature can be considered a relatively uncommon condition, with an incidence of 0,4-0,6%. estimated prevalence is about 0.5% but according to several authors it may reach up to 10% due to misdiagnosis and low awareness of the disease (1, 2). while new promising therapies are developing and spreading (3-4), surgery is still indicated as primary management for many patients with penile curvatures, especially when the curvature does not allow a satisfactory intercourse (5-7). a common feature of the many different techniques of corporoplasty which were proposed over the last decades is to associate circumcision with penile degloving in order to prevent postoperative oedema, phimosis and necrosis of the prepuce (8, 9). however, few recent studies have shown that a prepuce-sparing surgery is feasible with a low rate of local complications (10, 11). we aim to evaluate the feasibility and the safety of prepuce-sparing corporoplasty on a single-institution series. materials and methods data were collected from patients presenting with peyronie’s disease (pd) who underwent to a modified nesbit procedure from january 2014 to january 2019 at a single academic tertiary hospital. our institution’s prospectively updated database that have been retrospectively evaluated. all the procedures were performed by the same experienced surgeon (a.f.d.r.). 1. preoperative assessment and follow-up all patients had a stable disease for at least three months and suffered from pain during erection or during sexual intercourse. all patients underwent a standard clinical assessment, routine blood sample, urinalysis, physical examination during erection (after intracavernous injection of vasoactive drugs or self-photography at orthogonal, frontal, and sagittal planes). curvature degrees were measured using a goniometer. both the prepuce and the degree of penile curvature were assessed before surgery. we considered curvature of more than 30 °. medical and sexual history of patients was taken focusing on any previous penile surgery. the 5-item international index of erectile function (iief-5) was administered before and 6 months after the treatment. degree of angulation was recorded at follow-up with self-photograph at orthogonal, frontal and sagittal planes. 2. sample definition and analysis the patients were divided into two different groups: group a, made by patients who opted for a prepucesparing surgery, and group b made by those who decided to be circumcised. patients’ characteristics, intra-, post-operative and 6 months follow-up data were collected and analysed. post-operative complications were assessed according to clavien-dindo (cd) classification (14). in the two groups, we assessed the difference of mean value of iief-5 score administered before and 6 months after the surgery by using t-test. data were entered into a microsoft excel (version 14.0) database and then transferred to sofastat tm 1.4.6 for windows. descriptive statistics were calculated for all patients’ variables and reported as median (iqr), mean ± stansummary 05de rose-ambrosini_stesura seveso 24/09/20 14:14 pagina 182 183archivio italiano di urologia e andrologia 2020; 92, 3 feasibility of prepuce sparing corporoplasty dard deviation (sd) or as proportion. the homogeneity and data of the two groups were compared using the kolmogorov-smirnov, chi-square, fisher exact and the paired t-test. we set the level of significance to 0.05. 3. surgical procedure and perioperative management in all cases a modified nesbit technique has been performed. the procedure starts with a sub-coronal circumferential incision 1 cm below the coronal sulcus. then the degloving is carried out following the avascular plane between the dartos and the buck’s fascia. we accurately spare the dartos in order not to damage the blood supply to the prepuce. the neurovascular bundle is mobilized from the dorsum of the penis by incising buck’s fascia laterally. five micro-grams of prostaglandin e1 (pge 1) are injected into the corpora cavernosa to obtain an artificial erection. the tunica albuginea can be grasped with an allis clamp or with suspension stitches and then it is excised sharply with a cold scalpel (figure 1). the albuginea continuous solution is closed with interrupted polyglycolic 3/0 suture. the result is assessed by inducing a final hydraulic erection. buck’s fascia is reapproximated with an absorbable monofilament suture. finally, we perform an interrupted 4/0 suture to approximate the skin (figure 2). for patients among group b the surgical procedure was similar to the technique performed for group a except for the final step of the circumcision. the redundant prepuce is pulled upwards, the adhesions to the glans is released, and after skin excision, haemostasis is performed with an electrocautery. we approximate the skin and the mucosal borders with simple interrupted absorbable suture (polyglycolic 3/0). a transurethral catheter is placed during surgery and left for 1-2 days. all patients were premedicated with third generation cephalosporins as prophylactic antibiotic before induction of anaesthesia (12, 13). 4. ethics statement our institution doesn’t require an institutional review board approval for retrospective observational studies. however, every patient at the admission had to give a written consent for the prospective collection and retrospective analysis of data. results group a and b were made of 53 and 16 patients, respectively. the median age was 59 years (iqr 12) in group a and 62 (iqr 9) in group b (p = 0.20). median grade of penile curvature was 40° (iqr 40°) in group a and 40° (iqr 30°) in group b (p = 0.62). the two groups were similar in direction of curvature (table 1). median operating time was 90 minutes (iqr 6) in group a and 100 minutes (iqr 30) in group b (p = 0.03). patients of both two groups had their urethral catheters removed at a median of 1 day (iqr group a 1 and iqr group b 0) after surgery (p = 0.23). median length of stay was 2 day (iqr 1) in group a and 2 day (iqr 0) in group b. twenty-one patients of group a were used to take phosphodiesterase type 5 inhibitor (pde5 inhibitor) before surgery. after the treatment 19 (36%) of them continued to use pde5 inhibitor while two of them started using intracavernous injections of vasoactive medication. figure 1. the electric scalpel delimits the area of corporoplasty subsequently engraved with the cold knife. figure 2. sub-coronal suture with vycril rapid 4/0 stitches without circumcision. table 1. summary table on the population of patients considered in the study. variable group a group b p value number of patients 53 16 0.91 age (y), median (iqr) a 59 (12) 62 (9) 0.20 curvature (°), median (iqr) direction of curvature, n (%) 40° (40°) 40° (30°) 0.62 dorsal 18 (34) 7 (44) 0.74 ventral 16 (30) 5 (31) 0.98 lateral 19 (36) 4 (25) 0.59 ieff-5 score, mean ± sd 19 ± 2 17 ± 2 0.02 a iqr = interquartile range. table 2. summary table on the population of patients considered in the study. variable group a group b p value operating time (minutes), median (iqr) 90 (6) 100 (30) 0.03 duration of catheterization (days), median (iqr) 1 (1) 1 (0) 0.23 hospital stay (d), median (iqr) 1 (1) 1 (0) 0.24 complications cd a grade iii 4 0 cd grade iv 0 0 iief-5 score 6 months after, mean ± sd 21 ± 2 20 ± 2 0.11 iief-5 pre-/post-op. difference 1.9 ± 2 2.6 ± 2.1 0.36 residual curvature at 6 months straight 51 16 < 15° 2 0 a cd = clavien dindo. 05de rose-ambrosini_stesura seveso 24/09/20 14:14 pagina 183 archivio italiano di urologia e andrologia 2020; 92, 3 a.f. de rose, f. ambrosini, g. mantica, e. zero, r. banchero, c. terrone 184 in group b, three patients used pde5 inhibitor before surgery and they continued the same therapy also after the surgery. mean difference between preand postoperative iief was 1.9 ± 2 in group a and 2.6 ± 2.1 in group b (p = 0.36). four patients (7.5%) among group a experienced cd grade iii postoperative complications (secondary circumcision due to post-operative paraphimosis/edema). no cd grade iv complications were reported in both groups. two patients among group a reported recurrent curvature of more than 15 degrees, but in both cases no secondary surgery was required (table 2). discussion penile curvature is a congenital or acquired deformity which results in sexually debilitating condition and significant psychological stress for patients and their partners (15). once medical treatment is excluded or unuseful, surgery becomes the standard of choice (16). both shortening and lengthening procedures are good options for patients. the first technique to correct penile curvature was described by nesbit (17). in the following years various modifications to nesbit’s technique were suggested such as the yachia corporoplasty technique with or without penile degloving. according to the literature the outcomes of the “degloving” and “without degloving” techniques are similar (18). regardless of the procedure performed, penile degloving is generally combined with circumcision to reduce risk of postoperative oedema of the prepuce, with subsequent phimosis and necrosis (19, 20). however, recent studies demonstrate that circumcision is not always necessary, particularly when patients present with no phimosis pre-operatively (10, 11). alei et al. (21) described a new corporoplasty technique named as the ‘doublebreasted’ corporoplasty, with penoscrotal and infrapubic access not requiring circumcision. they reported no major complications nor neurovascular lesions or change in erectile function, low morbidity, low recurrence rate and excellent aesthetic results. garaffa et al. (10) reviewed a series of 251 patients who underwent a lue (86 patients) or a nesbit procedure (162 patients) or a combination of both. they reported very few complications in the group of patients without pre-operatively phimosis that chose not to be circumcised. they could state that circumcision should not be considered as a routine part of penile surgery unless a significant phimosis is present. similarly, pavone et al. (11) reported a series of 147 patients treated with nesbit's corporoplasty without circumcision and no major complication were described. the authors affirmed that circumcision must not be considered a mandatory time in nesbit procedure if the anatomical structures are carefully respected, the number of artificial erections is reduced. in this paper we analysed surgical outcomes of a group of patients treated with modified nesbit procedure without circumcision comparing them with a similar group treated with the same technique but completed with circumcision. pre and post-operative data were similar in both two groups and no major complications were reported. not performing circumcision in penile surgery could be a safe strategy if some precautions are followed. we recommend minimizing trauma of tissues carefully isolating the plane between the dartos and the buck’s fascia to avoid bleeding and ischaemia. in addition, the initial subcoronal circumferential incision 1 cm below the coronal sulcus allows to spare a sufficient prepuce vascularization. in this way the risk of tissue retraction and consequently to phimosis and foreskin necrosis could be reduced. overall, regardless of prepuce sparing surgery, reported success rate with tunica albuginea plication procedures is about 85%, with a good erectile function (iief-5 > 21 in more than 85% of patients) (22). in our analysis surgical correction of penile curvature has a good impact on erectile function (iief score improve in both two groups) and the comparison of the iief difference between the 2 groups didn’t show any statistically significant difference. thus, it seems that if circumcision is not performed sexual outcomes could not be negatively affected. many limitations exist in the current research beginning with the study design because of the retrospective nature of the study and the limited sample. however, the institution’s database has been prospectively updated and the size of the sample, even if small, is comparable to that of other previous studies. furthermore, the enrolment period is quite long. anyway, to the best of our knowledge, the literature on this topic is weak and we couldn’t find any study on this subject with a prospective design. conclusions in conclusion, according to our experience, surgical correction of penile curvature without performing circumcision could be a feasible and safety strategy with low rate of foreskin complications. additional prospective studies with larger patient cohorts are required to draw stronger conclusion. aknowledgments the authors acknowledge the clinical risk management, quality, accreditation and public relation unit of their hospital that actively participated to the development of the research. references 1. yachia d, beyar m, aridogan ia, dascalu s. the incidence of congenital penile curvature. j urol. 1993; 150:1478-9. 2. stuntz m, perlaky a, des vignes f, et al. the prevalence of peyronie's disease in the united states: a population-based study. plos one. 2016; 11:e0150157. 3. liu t, shindel aw, lin g, lue tf. cellular signaling pathways modulated by low-intensity extracorporeal shock wave therapy. int j impot res. 2019; 31:170-176. 4. cocci a, cito g, urzì d, et al. sildenafil 25 mg odt + collagenase clostridium hystoliticum vs collagenase clostridium hystoliticum alone for the management of peyronie's disease: a matched-pair comparison analysis. j sex med. 2018; 15:1472-1477. 05de rose-ambrosini_stesura seveso 24/09/20 14:14 pagina 184 185archivio italiano di urologia e andrologia 2020; 92, 3 feasibility of prepuce sparing corporoplasty 5. garcía-gómez b, gonzález-padilla da, alonso-isa m, et al. plication techniques in peyronie's disease: new developments int j impot res. 2020; 32:30-36. 6. cosentino m, kanashiro a, vives a, et al. surgical treatment of peyronie's disease with small intestinal submucosa graft patch. int j impot res. 2016; 28:106-109. 7. hatzimouratidis k, giuliano f, moncada i, et al. eau guidelines on erectile dysfunction, premature ejaculation, penile curvature and priapism. www.uroweb.org 2019. 8. nyirady p, kelemen z, banfi g, et al. management of congenital penile curvature. j urol. 2008; 179:1495-8. 9. langston jp, carson cc 3rd. peyronie disease: plication or grafting. urol clin north am. 2011; 38:207-16. 10. garaffa g, sacca a, christopher an, ralph dj. circumcision is not mandatory in penile surgery. bju int. 2010; 105:222-4. 11. pavone c, abbadessa d, usala m, et al. circumcision in nesbit corporoplasty: a mandatory time? our experience on 158 patients. urologia. 2012; 79:44-8. 12. van der horst c, martinez portillo fj, seif c, et al. treatment of penile curvature with essed-schroder tunical plication: aspects of quality of life from the patients’ perspective. bju int. 2004; 93:105-8. 13. mantovani f, patelli e, castelnuovo c, nicola m. ‘straighteningreinforcing’ technique for congenital curvature and peyronie’s disease. urol int. 2005; 75:201-3. 14. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-96. 15. de rose af, mantica g, maffezzini m, terrone c. dermal graft surgery for peyronie's disease: long term results at a 15 years follow-up. arch esp urol. 2019; 72:415-421. 16. sokolakis i, schönbauer p, mykoniatis i, et al. long-term results after surgical treatment of congenital penile curvature using a modified nesbit technique world j mens health. 2019; 4 [online ahead of print] 17. nesbit rm. congenital curvature of the phallus: report of three cases with description of corrective operation. j urol. 1965; 171:230-232. 18. dell’atti l, polito m, galosi a. b. is degloving the best method to approach the penile corporoplasty with yachia’s technique? urology. 2019; 126:204-208. 19. kalsi js, christopher n, ralph dj, minhas s. plaque incision and fascia lata grafting in the surgical management of peyronie’s disease. bju int 2006; 98:110-510. 20. adeniyi aa, goorney sr, pryor jp, ralph dj. the lue procedure: an analysis of the outcome in peyronie’s disease. bju int. 2002; 89:404-8. 21. alei g, letizia p, alei l, et al. new surgical technique for ventral penile curvature without circumcision. bju int. 2014; 113:968-74. 22. savoca g, scieri f, pietropaolo f, et al. straightening corporoplasty for peyronie’s disease: a review of 218 patients with median follow-up of 89 months. eur urol. 2004; 46: 610-4. correspondence aldo franco de rose, md aldofdr@libero.it francesca ambrosini, md (corresponding author) f.ambrosini1@gmail.com orcid 0000-0003-2160-763x guglielmo mantica, md guglielmo.mantica@gmail.com riccardo banchero, md riccardo.banchero@hsanmartino.it carlo terrone, md carlo.terrone@med.uniupo.it department of urology, policlinico san martino hospital, university of genoa largo rosanna benzi, 10, 16132, genoa, italy enrico zero, md zero.enrico@gmail.com department of computer science, bioengineering, robotics and systems engineering, university of genoa, genoa, italy 05de rose-ambrosini_stesura seveso 24/09/20 14:14 pagina 185 archivio italiano di urologia e andrologia 2018; 90, 154 original paper how do vegetable oils (hazelnut and canola) affect the reproductive system in male rats? bülent kati 1, fatih oguz 2, ismet yilmaz 3, ender akdemir 4, ramazan altintas 2, nusret akpolat 5, mehmet cagatay taskapan 6 1 harran university, faculty of medicine, urology department, sanliurfa, turkey; 2 inonu university, faculty of medicine, urology department, malatya, turkey; 3 inonu university, faculty of pharmacy, pharmacology department, malatya, turkey; 4 lokman hekim hospital, urology clinic, van, turkey; 5 inonu university, faculty of medicine, pathology department, malatya, turkey; 6 inonu university, faculty of medicine, medical biochemistry department, malatya, turkey. source(s) of support no: this study was supported by inonu university, scientific research projects no: 2011/152 presentation at a meeting: this work is presented in eau 8th south eastern european meeting held in sofia on 26 27 october 2012 objective: vegetable oils have an important place in our daily diet. this study starts from this point to investigate the effects of canola oil and hazelnut oil in the male reproductive system in rats. material and methods: 30 male rats were used in this 16-week study. the animals were divided into three groups: the animals in group i served as the control group, while the animals in group ii and group iii were fed with hazelnut and canola oil, respectively. the testes of all rats were excised for histopathologic evaluation and immunohistochemical (ihc) evaluation with a standard method. blood samples were obtained for determination of serum hormone levels. results: no significant differences were noted with respect to behavior or weight among the three groups. rats in the canola oil group (group iii) had higher luteinizing hormone (lh) and higher testosterone levels than rats in the control group. rats who received hazelnut oil (group ii) exhibited similar findings, with these levels being higher than they were in the control group. no statistical differences were shown for histopathology or ihc testosterone antibody levels across all treatment groups. conclussion: canola oil was shown to have a greater effect on serum lh and testosterone compared to the control group and the group fed with hazelnut oil. further investigation is required into how these oils affect serum hormone and sperm activity. key words: canola oil; hazelnut oil; reproductive system; testosteron. submitted 21 february 2018; 24 february 2018 summary no conflict of interest declared. 2000 bc as a high-erucic acid crop (1). the oil from rapeseed contained > 40% erucic acid, and hesitation existed about this high acid content (as observed in animal studies). high-erucic acid rapeseed oil used to be produced in north america solely in small quantities for industrial, nonfood use (2-3). however, in 1976, canadian scientists were able to improve the quality of previous cultivars of rapeseed by growing the plant traditionally, yielding a conversion that allowed commercial consumption in 1979, canada registered the word “canola” to describe a new seed found to yield an oil; this oil included a smaller amount of erucic acid and glucosinolates. inherently, canola has specific cut-of levels of erucic acid (< 2%) and glucosinolates (< 30 umol/g) for consumption both in humans and in animals (4). in 1985, the united states food and drug administration (fda) accepted canola oil as “generally recognized as safe” (gras) as a dietary component (5). canola has become one of the most important oilseed crops worldwide over the past 40 years; currently, canola oil is the third-largest vegetable oil by volume, after palm and soybean oil (3). hazelnut (corylus avellana l.) is a well-recognized tree nut worldwide. hazelnuts are mainly produced in turkey, italy, spain, the usa, portugal and france. hazelnut oil includes a high amount of both monounsaturated and polyunsaturated fatty acids as well as tocopherols (6). hazelnut oil contains 74.2%-83.1% oleic acid and linoleic acid. therefore, the incorporation of hazelnut oil in meat products may have favourable efects on the health of consumers (7). oils have an important place in the structure of the reproductive hormone system. the main hormones of the male reproductive system are mainly testosterone with follicle stimulating hormone (fsh) and luteinizing hormone (lh). there are very few studies on the effects of these oils on the male reproductive system. because of that; the aim of our study is to investigate the effects of canola oil and hazelnut oil on the male reproductive system, with a focus on evaluating the effects on serum hormone levels and testis histopathology. doi: 10.4081/aiua.2018.1.54 introduction vegetable oils have an important place in our daily diet. commonly used sunflower and olive oil have been widely used since long time. in recent times it has been able to meet our everyday needs in hazelnut oil and canola oil (rapeseed oil), which are increasingly used in areas where they are particularly grown. canola is a plant with bright yellow flowers that belongs to the brassicaceae family. originally from the mediterranean area and northern europe, b. napus is commonly known as rapeseed, and was identified in kati_stesura seveso 27/03/18 09:28 pagina 54 55archivio italiano di urologia e andrologia 2018; 90, 1 canola and nut oils effects on reproductive system materials and methods the selection and preparation of animals in this study, 30 four-month-old sprague-dawley rats were used. inonu university faculty of medicine, experimental animal research and production center provided the rats for study subjects. during the four-month study period, the average weight of the rats was 236.71 ± 19.18 gr. the study was executed according to the rules of the national health institute at inonu university experimental research laboratory, and was performed with the consent of the animals ethics committee of the inonu university faculty of medicine ethics committee (2011/05/18). animals were sheltered in groups of five in standard-sized (40 by 60 cm) cages. the subjects were given 7 days to adapt to their new environment, then separated into 3 groups of 10 rats. specially prepared hazelnut oil (12% concentration) and canola oil (12% concentration also), along with the standard food containing dry pellets and tap water, was used as the diet. indoor lighting was tuned for 12 h of light and 12 h of darkness. heat and moisture were set to 22°c ± 2°c and 50% ± 10%, respectively. preparations for the experiment after the animals were separated into groups, each group was divided into half and sheltered in 2 separate cages. any additional process was applied to the first group (group 1); the second group was fed with the 12% hazelnut oil added to the foodoil (group 2). the third group was fed with food that included 12% canola oil (group 3). external factors often have an impact on testicular functioning. the photoperiod is one of these factors: long photoperiods increase testicular functioning, while short periods reduce it (8). in order to avoid any morphological changes among the groups caused by the various light amounts, all rats were exposed to the rotating 12-h light/12-h dark environment in the lab. reproduction of sperm gradually increases up to the 75th day and the testicular weight increases up to the 100th day. when the first spermatozoa were found at the epididymis tail, about when the rats were 50 days old, they were considered adult (mature) (9). all of the rats used in our experiment were fed for approximately 4 months so that they would become 6-month-old adults and have the highest sperma reproduction. the intent in this design was to eliminate the variance in the sperma reproduction and the epididymal spermatozoa number caused by age. preparation of the food as in the previous studies, the food was prepared considering the daily oil need. pellet food was supplemented with the 12% oil (canola or hazelnut) (8-10). it was used to feed rats after the addition of appropriate fat to the amount of feed and control of homogenous distribution. the total absorption was ensured and, after a checking process, daily food of 18-24 g/rat was placed into the food reservoir. in order to keep the food fresh, a small amount of new food was prepared every week and the drinking water was provided via fresh tapwater adlibitum. biochemical method of analysis the blood taken for the biochemical analysis was put into the tubes and centrifuged at 3500 rpm for 15 minutes. the obtained serum was put into separate tubes and numbered for use with each group. serum samples were evaluated using previously provided elisa kits specific for rats that measured fsh (cusabio biotech co., ltd), lh (cusabio biotech co., ltd), and testosterone (drg international, inc, united states) with the basic radim immunoassay operator (brio) (radim spa, pomezia, italy) device. histopathological and immunohistochemical research method after separation by surgical dissection, the testicles were placed in bouin’s fixative for histopathological evaluation. the testis tissue was chopped with 2-mm apertures using microtome knives; routine tissue observation was practiced by sectioning one slice. five-micron sections were derived from the paraffin-embedded blocks formed from tissue samples. after the process of deparaffinization, the sections were dyed with hematoxylin-eosin (he). in the course of histopathological evaluation, the architectural structure was examined by the help of magnifying method beforehand. subsequently, the size and the number of the seminiferous tubules, the thickness of the tubule basal membranes, the relative share and types of germ cells in the seminiferous germs, the degree of interstitial fibrosis, and the existence of the leydig cells are evaluated in the course of a general examination of the testis cross-section. the evaluation was standardized by using the quantitative clinical scoring method of 1 to 10 for each seminiferous tubule as suggested by johnsen (11). four-micron sections were obtained and placed onto polysine slides forimmunohistochemical dyeing, which was performed automatically using the lecia bond max (leica microsystems inc. u.s.a) device. testosterone primary antibody (genetex, usa) was used as the primary antibody. the strength of the testosterone antibody dyeing was evaluated as a semi-quantitative method; the absence of dye was assigned zero points, while the most powerful dyeing was assigned a score of 3 points. statistical method of analysis spss 15.0 for windows (spss inc., chicago, illinois) was used for statistical analysis. the kolmogorov-smirnov test was used to measure the correspondence of the different parameters and the normal distribution curve. a correspondence was observed between the lh, testosterone, and johnsen scores as well as between the rats’ pre-experimental and post-experimental testicular weights and the normal distribution curve (p > 0.05). on the other hand, no correspondence existed between the fsh hormone distribution and the normal distrubtion curve (p < 0.05). the kruskal-wallis, one-way analysis of variance (anova), and post-hoc tukey tests were used for statistical analyses in the groups that corresponded with the normal distribution curve. p < 0.05 was assumed to be significant for all evaluations. values are given as average ± standard deviation (mean ± sd). results all of the rats were kept alive till the end of the experiment. rats’ pre-experiment and post-experiment (afer 16 kati_stesura seveso 27/03/18 09:28 pagina 55 archivio italiano di urologia e andrologia 2018; 90, 1 b. kati, f. oguz, i. yilmaz, e. akdemir, r. altintas, n. akpolat, m. cagatay taskapan 56 weeks of feeding) average weights are given in table 1. no variance existed between the groups’ inital weights or with these weights during and at the end of the experiment (p > 0.05). the average wet weight of the removed testicles was measured as 1.37 ± 0.80 g for the control group, 1.34 ± 0.13 g for the hazelnut oil group, and 1.48 ± 0.21 g for the canola oil group; there was no significant difference between any 2 of the 3 groups for this parameter (p = 0.103). furthermore, no signficant statistical difference existed in the levels of serum fsh among the groups (p > 0.05) (table 2). the levels of serum lh for rats fed with either hazelnut or canola oil did increase, but this increase was not statistically significant (p > 0.05). when the levels of serum testostosterone of the 3 groups were compared, there was a statistically significant increase in the canola group (p < 0.05). the slight increase in the hazelnut group was not significant (p > 0.05) (table 2). histological examination of the testis the testis were removed for histopathological analysis and preserved within the 10% bouin’s fixative. the testicular parenchyma of the rats (covered by tunica albuginea, leydig cells, and interstital connective tissues) were examined in the seminiferous tubules and interstitial. in the histopathological analysis, 10 cross-cut seminiferous tubules were randomly scored 1 to 10 for each rat testicle according to johnsen scoring criteria. after that, the average value for each rat was calculated, with total group scores and averages obtained (table 3). no significant difference was found among the johnsen score averages (p > 0.05). furthermore, no significant difference existed between the immunohistochemical dyeing strength of total tissue testostosterone antibody of the 3 groups (figure 1). discussion oils are one of the most significant nutrients in that they have essential roles in the human diet and conduct vital activity in the body. the positive or adverse effects of canola and hazelnut oil on the body have not been precisely determined, although their consumption have table 1. increase in the weights of the rats after 16 weeks of feeding. groups→ control group hazelnut group canola group p ao ± ss ao ± ss ao ± ss pre-experiment average weight (g) 247.2 ± 23.10 228.10 ± 34.00 252.50 ± 50.46 0.327 post-experiment average weight (g) 325.0 ± 32.47 316.00 ± 27.39 345.50 ± 43.19 0.177 table 2. average values of serum hormone lh and testosterone * (p = 0.001). figure 1. sample of interstisial painted testosterone antibody group and scores. a) immunohistochemical staning intensity canola oil group 20x (score 3). b) immunohistochemical staning intensity hazelnut oil group 40x (score 2). c) immunohistochemical staning intensity control group 20x (score 1). a. b. c. table 3. johnsen testicle biopsy scores for each group and group averages (p = 0.362). groups↓ hormones→ lh (miu/ml) testosterone (ng/ml) fsh ao ± ss ao ± ss (min-med-max) control 10.86 ± 5.47 1.29 ± 0.45 12.97 26.38 -77.24 hazelnut oil 13.68 ± 3.99 1.88 ± 0.68 21.74 30.90 38.44 canola oil 14.95 ± 4.55 2.53 ± 0.74* 19.06 31.91 9.33 groups johnsen score averages (ao ± ss) control group 9.37 ± 0.27 hazelnut group 9.21 ± 0.31 canola group 9.26 ± 0.20 total 9.28 ± 0.25 kati_stesura seveso 27/03/18 09:28 pagina 56 57archivio italiano di urologia e andrologia 2018; 90, 1 canola and nut oils effects on reproductive system been continuously increasing in people’s diets worldwide. limited and not conclusive scientific evidence would suggest some benefit for canola oil consumption, but results from studies implementing diets containing canola oil in experimental animal models have provided us with conflicting data (10-12). a study by okuyama and colleagues using steroid hormones, canola and soybean oils for a 3-month period in hypertensive rats who were prone to stroke compared various elements in the rats at the end of the 3-month period, although they did not evaluate the impact of the 2 oils on the reproductive system. as a result, while the testostosterone values measured in the testicles of rats in the canola group were found to be low compared to those in the soybean group, corticosteroid and estradiol levels in the tissues demonstrated no significant difference. this difference was assumed to arise from a pathophysiology found in rats with hypertension (13). in our study, serum testosterone level increased while testosterone antibody values measured in the test were similar to the control group. multiple other studies exist on the effects of canola and other oils over periods ranging from 3 to 7 months. infants fed with and without canola oil from the ages of 4 weeks to 7 months did not exhibit significant differences in height and length based on whether they consumed the oil as part of their diets (14). similarly, in our study, weight difference was not shown in rats fed with canola oil and hazelnut oil after 4 months period. de almeida and colleagues evaluated the effects of a diet containing canola oil on the morphology of seminiferous tubules of young rats (15). with evaluation of fsh, lh, and testosterone levels, significant and important information was found in terms of the determination of potential malfunctioning of the reproduction pathophysiology and the conditions of the hypothalamus-hypophyseal axis. in our study, serum testostosterone levels in the groups receiving canola oil were higher compared to the control group (p < 0.05). higher levels were also found in the hazelnut group, although it was not statistically significant compared to the control group (p > 0.05). no significant differences were found among the 3 groups in terms of testicular and body weight (p > 0.05). fsh, prompted by the hypothalamus and released by the anterior pituitary gland, stimulates sertoli cells in the seminiferous tubules, speeding up sperm production of spermatids. furthermore, it was effective in the development and maintenance of fsh sufficent testicular function in men. within our study; no significant difference was found among the fsh values of the 3 groups (p > 0.05). lh, prompted by the hypothalamus (gnrh) and released by the anterior pituitary gland, stimulates the release of testostosterone in the interstitial leydig cells. in our study, lh levels in the hazelnut and canola oil groups were found to be higher compared to the control group, although it was not assumed to be statistically significant (p > 0.05). these results can be attributed to the assumption that these kinds of oils can enhance the stimulation of gnrh via the effects from the hypothalamus or that the oils can generate a slight lh stimulus by directly influencing the anterior pituitary gland. the increased level of testostosterone, especially in the canola group fed with the oils supplied with direct lh, indicates that the results may be explained by the actions of the hypothalamus-hypophyseal axis. new experimental studies are needed to fully understand the effects of the hypothalamus-hypophyseal way. the effects of testosterone on erectile dysfunction and libido indicated that testostosterone has a considerable contribution to maintenance of libido and sexual function (16). the fact that these oils have no significant effect on fsh compared to the control group increases the probability that these hormones are more effective in exerting their effects coming from the hypophysis as opposed to the hypothalamus. there are not many publications examining the effects of these oils on the reproductive system. the effects of hazelnut and canola oil on testicle histopathology were not indicated beforehand. histopathologic examination of the 3 groups’ testicular tissue did not reveal significant differences according to evaluation using johnsen scoring (p > 0.05). thus, no pathological adverse events related to use of these everyday oils in the diet were shown in this study. furthermore, no statistically significant differences between the 3 groups were revealed as a result of the semi-quantitative immunohistochemical evaluation of testicle-tissue dyeing intensity (p > 0.05). conclusion the effects of vegetable oils, which we often use in our daily life, on the reproductive system can be affected by various mechanisms by affecting the hormones. additional studies are needed for the determination of the exact effect of this condition on the tissues and its influence on spermiogenesis. acknowledgments we thank to the biologist fatma ozyalin for his assistance in the care and application of the elisa kits used in this study. references 1. australian government department of health and aging office of the gene technology regulator. the biology of brassica napus l. (canola).version 2: 2008. http://www.ogtr.gov.au/internet/ogtr/publishing.nsf/content/canola3/$file/biologycanola08_2.pdf 2. dupont j, white pj, johnston km, et al. food safety and health effects of canola oil. j am coll nutr. 1989; 8:360-375. 3united states department of agriculture. economic research service – canola. https://www.ers.usda.gov/topics/crops/soybeansoil-crops/canola.aspx 2017. 4. mag t. canola oil processing in canada. j am oil chem soc. 1983; 60:380-384. 5. lin l, allemekinders h, dansby a, et al. evidence of health benefits of canola oil. nutr rev. 2013; 71:370-85. 6. ozdemir m, ackurt f, kaplan m, et al. evaluation of new kati_stesura seveso 27/03/18 09:28 pagina 57 archivio italiano di urologia e andrologia 2018; 90, 1 b. kati, f. oguz, i. yilmaz, e. akdemir, r. altintas, n. akpolat, m. cagatay taskapan 58 turkish hybrid hazelnut (corylus avellana l.) varieties; fatty acid composition, a-tocopherol content, mineral composition and stability. food chem. 2001; 73:411-415. 7. ozdemir, f. akıncı, i. physical and nutritional properties of four major commercial turkish hazelnut varieties. j food eng, 2004; 63:341-347. 8. kus i, songur a, ozogul c, et al. effects of photoperiod on the ultrastructure of leydig cells in rat. arch androl. 2004; 50:193-200. 9. robb gw, amann rp, killian gj. daily sperm production and epididymal sperm reserves of pubertal and adult rats. j reprod fertil. 1978; 54:103-7. 10. cai j, jang jy, kim j, et al. comparative effects of plant oils on the cerebral hemorrhage in stroke-prone spontaneously hypertensive rats. nutr neurosci. 2014; 19:318-326. 11. johnsen sg. testicular biopsy score count-method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. hormones. 1970; 1:2-25. 12. junker r, kratz m, neufeld m, et al. effects of diets containing olive oil, sunflower oil, or rapeseed oil on the hemostatic system. thromb haemost. 2001; 85:280-6. 13. okuyama h, ohara n, tatematsu k, et al.testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat. j toxicol sci. 2010; 35:743-7. 14. rzehak p, koletzko s, koletzko b, et al. gini study group. growth of infants fed formula rich in canola oil (low erucic acid rapeseed oil). clin nutr. 2011; 30:339-45 15. furriel gomes de almeida a, soares da costa ca, gaspar de moura e, et al. effects of soybean or canola oil intake on seminiferous tubules structure in young rats. nutr hosp. 2012; 27:1668-9. 16. isidori am, giannetta e, greco ea, et al. effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a metaanalysis. clin endocrinol (oxf). 2005; 63:280-293. correspondence bülent kati, md, assistant professor of urology bulentkati@harran.edu.tr department of urology, harran university, faculty of urology 63300, sanliurfa, turke fatih oguz, md foguz@hotmail.com inonu university, turgut ozal medical center, urology, malatya 44100 turkey ismet yilmaz, md ismetyilmaz44@hotmail.com inonu university, faculty of pharmacy,, malatya 44100 turkey ender akdemir, md ender_dr@yahoo.com lokman hekim hospital, urology clinic, van, 65100 turkey ramazan altintas, md ramazan449@yahoo.com inonu university, turgut ozal medical center, urology, malatya 44100 turkey nusret akpolat, md nusretakpolat@hotmail.com inonu university, turgut ozal medical center, pathology, malatya 44100 turkey mehmet cagatay taskapan, md mctaskapan@hotmail.com inonu university, turgut ozal medical center, biochemistry malatya 44100 turkey kati_stesura seveso 27/03/18 09:28 pagina 58 stesura seveso 227archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. after the physical exam, varicocele can be confirmed by cdus (1) and cdus may be required in the presence of factors interfering with physical examination. the aim of the current treatment is the ligation of internal and external spermatic vein branches while preserving all arterial structures, lymphatics and the vas deferens. in general, varicocelectomy is performed in patients with poor semen quality, providing improvement in semen parameters in 50-80% of the patients and, in addition, varicocele repair may result in improvements in natural pregnancy rates (2-6). there are studies on the optimal number of veins to be ligated, which varies upon the varicocelectomy technique, while there are not many studies on the parameters effectively predicting this number and on the correlation of surgical success with the number of ligated spermatic veins. in our study, we aimed to evaluate the correlation of pre-varicocelectomy physical examination findings and of cdus measurement results with the number of internal/external spermatic veins ligated during surgery and to analyze whether cdus findings correlate with semen parameters. materials and methods patient population a total of 84 patients diagnosed with grade 3 left varicocele in our clinic between november 15, 2016 and november 15, 2018 were evaluated. patients over 18 years of age who had infertility or abnormal semen parameters or scrotal pain (resistant to medical treatment) with grade 3 left varicocele (visible and palpable spermatic veins without valsalva maneuver at rest) were included in the study. patients who were found to have missing data during data recording, evaluation or analysis, recurrent cases with a history of varicocelectomy, patients with endovascular treatment history for varicose veins and patients under 18 years were excluded from the study. study sesign the study was designed as a retrospective study. no patients underwent any additional tests or assessments background: this study aimed to determine the contribution of color doppler ultrasonography (cdus) performed before varicocelectomy to the success of surgical treatment and to evaluate the correlation between cdus findings and semen parameters. methods: a total of 84 patients diagnosed with grade 3 left varicocele in our clinic between 2016 and 2018 were evaluated. the patients in whom the decision for varicocelectomy was based on only physical examination (pe) findings and abnormal semen analysis (sa) were defined as group 1, while the patients undergoing varicocelectomy based on pe, cdus and sa findings were defined as group 2. the patients diagnosed with varicocele based on pe and cdus findings who were included in a followup protocol due to normal semen parameters were defined as group 3. results: in group 1, there was a total of 28 patients and the mean number of ligated internal spermatic veins was 4.53 (range, 2-10). in group 2, there was a total of 30 patients and the number of ligated internal spermatic veins was 3.76 (range, 1-8). no statistically significant difference was found between group 1 and 2 in terms of the number of internal spermatic veins ligated during varicocelectomy. no statistically significant correlation was found between semen parameters and the number of veins ligated during varicocelectomy in group 1 and 2 and between semen parameters and cdus findings group 2 and 3. conclusions: in patients with primary grade 3 varicocele, diagnosed by physical examination there is no need for additional imaging in primary cases. key words: varicocele; varicocelectomy; color doppler ultrasonography; semen parameters; number of vein ligated. submitted 25 december 2020; accepted 3 february 2021 introduction varicocele is defined as the dilatation of the veins of the pampiniform plexus. diagnostic methods, including physical examination, doppler stethoscope examination, thermography, color doppler ultrasonography (cdus), scintigraphy, and venography are used for the diagnosis of varicocele, although the current view is that physical examination is sufficient and additional imaging methods are not always required for the diagnosis of varicocele. contribution of pre-varicocelectomy color doppler ultrasonography finding to surgery and its correlation with semen parameters caner ediz 1, muhammed cihan temel 1, suna şahin ediz 2, serkan akan 1, serkan yenigürbüz 1, mehmet pehlivanoğlu 1, ömer yılmaz 1 1 department of urology, sultan abdulhamid han education and research hospital, istanbul, turkey; 2 department of radiology, kartal dr. lutfi kirdar city hospital, istanbul, turkey. doi: 10.4081/aiua.2021.2.227 summary archivio italiano di urologia e andrologia 2021; 93, 2 c. ediz, m. cihan temel, s. şahin ediz, s. akan, s. yenigürbüz, m. pehlivanoğlu, ö. yılmaz 228 other than the evaluations performed for the diagnosis of varicocele in routine urologic practice (physical examination, semen analysis and, if required, cdus). all procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. all participating patients gave written informed consent. in all patients, presence and localization of scrotal pain, presence of scrotal swelling, presence of infertility, varicocele grade, semen parameters (total sperm volume, total sperm count, sperm count per milliliter, ratio of forward moving sperms/motile sperms without progressive movement/immotile sperms, ratio of sperms with normal morphology, mean sperm velocity, ejaculate ph, presence of pyospermia) and the number of internal/external spermatic veins ligated during varicocelectomy were recorded. additionally, in accordance with the guideline recommendation, the width of the pampiniform venous plexus was evaluated with cdus and the diameter of the varicose spermatic vein measured during the valsalva maneuver was recorded in required patients. all semen analysis results were evaluated using the reference values defined by world health organization (who) in 2010. the time interval of two semen analysis for each patient was 15 days. the average of two semen analyzes for each patient was taken. sonoscape s40 cdus system (australia) was used in all patients undergoing cdus. a 7.5 mhz-linear probe was used during measurements. first, the testicular structure was examined using grayscale ultrasonography during normal respiration by elevating the chest and head region by 15° while the patients were in supine position. testicular volume was measured by using the “prolate ellipse” formula (w x h x d x 0.52). plexus pampiniformis veins were evaluated by identifying the most dilated vein and then measuring the increase in its diameter during the valsalva maneuver. the presence of reflux was assessed using the color mode during normal respiration and the valsalva maneuver. the patients in whom the decision for varicocelectomy was based on only physical examination (pe) findings and semen analysis (sa) were defined as group 1, while the patients undergoing varicocelectomy based on pe, cdus and sa findings were defined as group 2. the patients diagnosed with varicocele based on pe and cdus findings who were included in the follow-up protocol due to normal semen parameters were defined as group 3. thus, it was planned to compare the contribution of cdus to varicocelectomy (between group 1 and 2) and its correlation in patients with normal or abnormal semen parameters (between group 2 and 3). there were 28, 30 and 26 patients in group 1, 2, and 3, respectively. the patients in group 1 and 2 underwent left subinguinal varicocelectomy (the routine procedure in our clinic) for the diagnosis of grade 3 left varicocele. the patients undergoing varicocelectomy had at least two sperm parameter lower than the sa reference values defined by who or infertility. varicocelectomy was not performed in patients with only scrotal pain and normal sa results. subinguinal varicocelectomy was performed under spinal or general anesthesia. the testis was not routinely delivered from the scrotum and the visible external spermatic vein(s) and internal spermatic veins were ligated by preserving testicular arterial and lymphatic vessels. the patients in group 3 were enrolled into follow-up to control the changes in semen parameters at 6-month intervals. study aim the study had two primary objectives. firstly, we aimed to evaluate the adequacy of physical examination by investigating whether there was a statistically significant difference between group 1 and 2 in terms of the number of internal and external spermatic veins ligated during varicocelectomy and to assess the contribution of radiological imaging to the determination of the optimal number of spermatic veins to be ligated. in addition, we analyzed whether each of the recorded parameters of the patients were in correlation with the number of ligated external and internal spermatic veins. the second aim was to investigate the presence of a correlation between the maximum spermatic vein diameter measured using cdus during the valsalva maneuver and semen parameters in group 2 and 3 patients. we thereby aimed to evaluate the correlation between semen parameters and additional radiological imaging findings in patients with grade 3 varicocele. statistical analysis statistical analyses were performed using spss statistics 22.0 software (spss inc., chicago, il, usa). the normality hypothesis was tested using the kolmogorov-smirnov test during data analysis. descriptive statistics for continuous variables were presented as median and minimum-maximum values. the independent-samples t-test and mann-whitney u-test were used to analyze data not conforming to a normal distribution. pearson and spearman tests were used for correlation analyses. statistical significance was defined as p < 0.05. results the median ages of the patients were 27.5 years (range, 22-39 years) in group 1, 24.5 years (range, 19-39 years) in group 2 and 26 years (range, 18-35 years) in group 3. regarding primary presenting complaints, testicular pain and scrotal swelling were present in 39.28% (11/28) and 39.28% (11/28) of the patients in group 1, respectively; in 53.33% (16/30) and 30% (9/30) of the patients in group 2, respectively; and in 69.23% (18/26) and 30.77% (8/26) of the patients in group 3, respectively. infertility was the presenting complaint in 25% (7/28) and 16.66% (5/30) of the patients in group 1 and 2, respectively. in group 1, there was a total of 28 patients and the total number of ligated internal spermatic veins was 127. the median number of ligated internal spermatic veins was 4 (range, 2-10) in group 1. in group 2, there were a total of 30 patients and the total number of ligated internal spermatic veins was 113. the median number of ligated internal spermatic veins was 4 (range, 1-8) in group 2. no statistically significant difference was found between group 1 and 2 in the number of internal spermatic veins ligated during varicocelectomy (p = 0.114) (table 1). the total number of ligated external veins was 17 and the median number was 0 (range, 0-2) in group 1. a total of 16 external spermatic veins were ligated and the median number of ligated external spermatic veins was 0 (range, 0-2) in group 2. no statistically significant difference was found between group 1 and 2 in terms of the number of external spermatic veins ligated during varicocelectomy (p = 0.845) (table 1). a statistically significant positive correlation was found between the number of internal spermatic veins and the number of external spermatic veins ligated during varicocelectomy in group 1 and 2 (p = 0.023 and p = 0.049). however, a correlation analysis between the numbers of ligated internal and external spermatic veins and semen parameters found no statistically significant correlation in either groups (p > 0.05) (p and r values) (table 2). in group 2, a correlation analysis was conducted to examine the correlation of the maximum spermatic vein diameter measured by cdus during the valsalva maneuver with semen parameters and the number of ligated external and internal spermatic veins. in conclusion, the maximum spermatic vein diameter measured during the valsalva maneuver was not significantly correlated with any of the semen parameters or the numbers of ligated external and internal spermatic veins (p > 0.05) (p and r values) (table 3). in group 3, there was also no statistically significant correlation between semen parameters and the maximum spermatic vein diameter measured during the valsalva maneuver (p > 0.05). discussion varicocele is the most common correctable cause of male infertility (7). approximately 19-41% of the patients presenting with primary infertility are diagnosed with varicocele (8, 9), while this rate ranges from 45% to 81% in patients presenting with secondary infertility (9). the most likely cause of impaired spermatogenesis is testicular hyperthermia associated with varicocele, while increased reactive oxygen products and apoptosis are closely related to the pathophysiology of varicocele (7). varicocele is usually asymptomatic but testicular pain may be the first presenting symptom in 10% of the patients. it is usually unilateral. surgical treatment is extremely successful and relieves pain in 90% of the patients in cases where chronic testicular pain etiologically determined to be caused by varicocele is not relieved by conservative treatment (10). cdus may have a role in the possible differential diagnoses particularly in cases of unexplained scrotal pain. raghavendran et al. (11) reported that severe testicular pain in a patient diag229archivio italiano di urologia e andrologia 2021; 93, 2 varicocele and color doppler ultrasonography table 1. no statistically significant difference was found between group 1 and 2 in the number of internal and external spermatic veins ligated during varicocelectomy (p > 0.05). group 1 (n = 28) group 2 (n = 30) p value median (min-max) median (min-max) internal spermatic vein 4 (2-10) 4 (1-8) 0.114 external spermatic vein 0 (0-2) 0 (0-2) 0.845 table 2. correlation analysis between semen parameter results and the numbers of ligated internal and external spermatic veins in group 1 and 2. no positive correlation was found between any of the parameters evaluated in semen analysis and the number of ligated veins (p > 0.05). semen analysis results p-values for the correlation analysis between semen analysis and the number of ligated internal and external spermatic veins in group 1 and 2 group 1 (n = 28) group 2 (n = 30) group 1 group 1 group 2 group 2 median (min-max) median (min-max) internal spermatic vein external spermatic vein internal spermatic vein external spermatic vein semen volume (ml) 2.3 (1-5) 3 (1-5) 0.59 0.08 0.25 0.54 sperm count (106/ml) 27.45 (0-127) 13.2 (0-89.6) 0.28 0.42 0.98 0.32 total sperm count (x106) 75 (0-345) 46 (0-224) 0.46 0.42 0.78 0.24 forward moving (%) 23 (0-75.4) 23 (0-60) 0.23 0.78 0.85 0.31 motile without progressive movement (%) 17.81 (0-62.3) 21.1 (0-39) 0.74 0.42 0.16 0.66 immotile (%) 49.5 (0-78) 50 (0-95) 0.75 0.5 0.98 0.34 morphology (%) 8 (0-34) 4 (0-20) 0.45 0.181 0.57 0.21 table 3. correlation analysis between semen parameters and spermatic vein diameters measured by cdus in group 2 and 3. no positive correlation was found between any of the parameters evaluated in semen analysis and spermatic vein diameter (p > 0.05). p-values for the correlation analysis between semen analysis results and spermatic vein diameters measured by cdus in group 2 and 3 spermatic vein diameter semen volume sperm count total forward motile without immotile morphology measured by cdus sperm count moving progressive median (mm) (min-max) movement group 2 (n = 30) 3.8 (2.8-7) 0.99 0.96 0.78 0.57 0.055 0.98 0.37 group 3 (n = 26) 2.9 (2.3-4) 0.54 0.56 0.85 0.9 0.4 0.68 0.9 archivio italiano di urologia e andrologia 2021; 93, 2 c. ediz, m. cihan temel, s. şahin ediz, s. akan, s. yenigürbüz, m. pehlivanoğlu, ö. yılmaz 230 nosed with varicocele was due to a thrombus in a varicose vein. presenting complaints may include prominence of testicular vessels and feeling of unilateral scrotal swelling in addition to testicular pain. the dilatation of spermatic veins causes an increase in the temperature in the testicles and scrotum. this increase in temperature may cause a progressive dysfunction in the testicles and epididymis, leading to infertility (12, 13). in our clinical practice, patients with the diagnosis of varicocele without any pathology in semen parameters are offered conservative treatments (use of analgesics or palliative treatment recommendations for pain relief) and follow up at 3-6-month intervals. we perform surgery in cases without relief of testicular pain with conservative treatment. the diagnosis of varicocele is based on physical examination without any need for additional tests. in a study by who, it was demonstrated that 70% of patients were diagnosed with varicocele using venography, while in the same patients this rate was 30-40% with physical examination and physical examination had a false positive rate of 23%. however, the sensitivity and specificity of physical examination in the diagnosis of varicocele were reported to be 71% and 69%, respectively (14-16). we aimed to eliminate this false negativity effect by including patients with grade 3 varicocele in our study group. urology guidelines try to minimize this margin of error by recommending the confirmation by cdus of the diagnosis of varicocele made by physical examination. the benefit of additional diagnostic imaging methods usually does not go beyond supporting the diagnosis, while these methods are still used in the clinical practice of urologists. unfortunately, the contribution of these methods in the evaluation of testicular volume and determination of venous reflux in adult patients is not substantial as in pediatric patients (17). moreover, it contributes to the determination of surgical technique in adolescent varicocelectomy but not in adult varicocelectomy (18). we use cdus in our practice particularly in patients with pathologies interfering with varicocele evaluation (e.g., scrotal edema, cellulitis or prior scrotal surgery), patients with recurrent varicocele and morbid obese patients. however, additional imaging methods revealed no additional result other than supporting the diagnosis and/or establishing differential diagnosis. it should be kept in mind that cdus used in the diagnosis of varicocele is affected by many factors. poor quality of the measuring device causes false-negative diagnoses and excessive mobility of the spermatic cord vessels leads to false-positive diagnoses (19). the employed technique is another influential factor. measurements taken in the standing position are diagnostically more successful compared to the measurements taken in the lying or backward-leaning position (20). the caput of the epididymis is the most suitable region for optimal success of ultrasonographic measurements in varicocele evaluation (21). in analyses evaluating the success of ultrasonography, the sensitivity and specificity of color doppler ultrasonography in the diagnosis of varicocele were 97% and 94%, respectively (22). color doppler examination has a higher sensitivity and specificity and a lower cost compared to thermography and angiography and is a noninvasive evaluation method and the procedure of choice in the diagnosis of venous reflux in varicocele (23). physical examination remains the most valuable method (24, 25), in fact our study found no statistically significant difference between the patients who were diagnosed via physical examination and the patients whose diagnoses were supported by cdus in terms of the numbers of internal and external spermatic veins ligated during varicocelectomy and we concluded that additional imaging had no additional predictive value compared to physical examination in the determination of the number of spermatic veins to be ligated during varicocelectomy in patients with grade 3 varicocele. we therefore do not think that cdus should be used as a routine method. in contrast to the failure in predicting the number of vessels ligated during varicocelectomy, there are studies in the literature reporting that there is a correlation between cdus findings and semen parameters and/or infertility. mahdavi et al. reported that semen volume, sperm count and sperm motility and morphology correlated with cdus findings in patients with varicocele (26). in our study, the maximum spermatic vein diameter measured during the valsalva maneuver by cdus was not significantly correlated with any of the sperm parameters or the numbers of ligated external and internal spermatic veins in group 2. based on the results of our study, cdus performed in addition to physical examination for the diagnosis of varicocele has no contribution to the interpretation of sperm parameters or to the prediction of the number of spermatic veins that should be ligated during the operation. retroperitoneal, laparoscopic, inguinal and subinguinal methods have been described for the treatment of varicocele. in recent years, studies showed that robot-assisted microscopic varicocelectomy is as successful as the conventional methods (27). however, microscopic subinguinal varicocelectomy is the golden standard for the treatment of varicocele (28, 29). this method includes the treatment of venous system by preserving testicular arterial and lymphatic vessels. in conventional varicocelectomy performed without using a microscope or optic magnifier, the most important cause of recurrence after the treatment of varicocele is the inability to ligate the small internal spermatic vein branches due to their invisibility to the naked eye (30). in the literature, it is reported that intraoperative indocyanine green administration is one of the ways of increasing the success of this technique and minimizing testicular artery injuries (29). another method is the use of intraoperative microvascular doppler ultrasonography (10). in a study evaluating 65 patients undergoing microsurgical subinguinal varicocelectomy at variance analysis, only the number of ligated veins 4 mm or more in diameter was higher in grade 3 varicoceles than in grade 1 and 2 varicoceles and the increase in varicocele grade was not related to the total number of ligated veins (31). in a new study, babai et al. was reported that the presence of testicular reflux has no effect on semen analysis parameters, but also does not predict the consequences of varicocelectomy and therefore is not a suitable prognosis factor in varicocele patients (32). also in our study, there was no statistically significant correlation between varicocele grade on physical examination or cdus find231archivio italiano di urologia e andrologia 2021; 93, 2 varicocele and color doppler ultrasonography ings (diameter of the vein or presence of reflux) and the total number of ligated spermatic veins. outcomes of this study are different from those of previous studies of belani et al. (31) and mahdavi et al. (26), but similar to the results of babai et al. (32). based on statistical results, we have not found any radiological data that predict sperm parameters or the number of internal and external spermatic veins ligated during varicocelectomy. therefore, it was demonstrated that inclusion of cdus in the preoperative evaluation in patients with grade 3 varicocele has no effect on surgical decision making or the number of ligated spermatic veins which determines the surgical success index. the present study has several limitations. our study is limited by the small number of patients due to a singlecenter trial. in our operations, we do not use microscopic magnification routinely during surgery and not all the patients were operated on by a single surgeon experienced in the field of andrology. the last limitation of our study was its retrospective evaluation limited to findings of patients with grade 3 varicocele. doppler ultrasound could be useful when varicocele is not visible or palpable. for these reasons, we believe that larger case series will be more effective in the interpretation of our study findings. conclusions the best diagnostic method for grade 3 varicocele is physical examination and there is no need for additional imaging in primary cases. it is obvious that every imaging study will have an additional cost and will cause time and labor loss. imaging studies do not contribute to surgical decision making or the prediction of surgical success. however, it should be kept in mind that physical examination is not sufficient in all cases, yet it can provide useful information particularly for the evaluation of secondary/tertiary varicocele cases and for the diagnosis of additional testicular pathologies. despite of this, semen parameters considered in surgical decision making in patients with grade 3 varicocele do not correlate with physical examination and imaging findings, suggesting that there are more parameters that should be examined for the diagnosis and treatment of grade 3 varicocele. acknowledgments the authors would like to thank the entire staff of the departments of urology and radiology, sultan abdulhamid han education and research hospital. references 1. leslie sw, sajjad h, siref le. varicocele. statpearls. treasure island (fl); 2019. 2. youssef t, abd-elaal e, gaballah g, et al. varicocelectomy in men with nonobstructive azoospermia: is it beneficial? int j surg. 2009; 7:356-360. 3. esteves sc, miyaoka r, roque m, et al. outcome of varicocele repair in men with nonobstructive azoospermia: systematic review and meta-analysis. asian j androl. 2016; 18:246-253. 4. zampieri n, bosaro l, costantini c, et al. relationship between testicular sperm extraction and varicocelectomy in patients with varicocele and nonobstructive azoospermia. urology. 2013; 82:74-77. 5. kizilay f, altay b. evaluation of the effects of antioxidant treatment on sperm parameters and pregnancy rates in infertile patients after varicocelectomy: a randomized controlled trial. int j impot res. 2019; 31:424-431. 6. marmar jl, agarwal a, prabakaran s, et al. reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. fertil steril. 2007; 88:639-648. 7. hassanin am, ahmed hh, kaddah an. a global view of the pathophysiology of varicocele. andrology. 2018; 6:654-661. 8. leslie sw, siref le. varicocele. statpearls. treasure island (fl); 2018. 9. lomboy jr, coward rm. the varicocele: clinical presentation, evaluation, and surgical management. semin intervent radiol. 2016; 33:163-169. 10. owen rc, mccormick bj, figler bd, et al. a review of varicocele repair for pain. transl androl urol. 2017; 6:s20-s29. 11. raghavendran m, venugopal a, kiran kumar g. thrombosed varicocele a rare cause for acute scrotal pain: a case report. bmc urol. 2018; 18:34. 12. shiraishi k, takihara h, naito k. testicular volume, scrotal temperature, and oxidative stress in fertile men with left varicocele. fertil steril. 2009; 91:1388-1391. 13. garolla a, torino m, miola p, et al. twenty-four-hour monitoring of scrotal temperature in obese men and men with a varicocele as a mirror of spermatogenic function. hum reprod. 2015; 30:1006-1013. 14. gat y, bachar gn, zukerman z, et al. physical examination may miss the diagnosis of bilateral varicocele: a comparative study of 4 diagnostic modalities. j urol. 2004; 172:1414-1417. 15. preutthipan s, nicholas oa. comparative study between scrotal physical examination and scrotal ultrasonography in the detection of varicocele in men with infertility. j med assoc thai. 1995; 78:135-139. 16. pryor jl, howards ss. varicocele. urol clin north am. 1987; 14:499-513. 17. macey mr, owen rc, ross ss, et al. best practice in the diagnosis and treatment of varicocele in children and adolescents. ther adv urol. 2018; 10:273-282. 18. cimador m, di pace mr, peritore m, et al. the role of doppler ultrasonography in determining the proper surgical approach to the management of varicocele in children and adolescents. bju int. 2006; 97:1291-1297. 19. tyloch jf, wieczorek ap. standards for scrotal ultrasonography. j ultrason. 2016; 16:391-403. 20. kim ys, kim sk, cho ic, et al. efficacy of scrotal doppler ultrasonography with the valsalva maneuver, standing position, and resting-valsalva ratio for varicocele diagnosis. korean j urol. 2015; 56:144-149. 21. karami m, mazdak h, khanbabapour s, et al. determination of the best position and site for color doppler ultrasonographic evaluation of the testicular vein to define the clinical grades of varicocele ultrasonographically. adv biomed res. 2014; 3:17. 22. bagheri sm, khajehasani f, iraji h, et al. a novel method for investigating the role of reflux pattern in color doppler ultrasound for grading of varicocele. sci rep. 2018; 8:6517. archivio italiano di urologia e andrologia 2021; 93, 2 c. ediz, m. cihan temel, s. şahin ediz, s. akan, s. yenigürbüz, m. pehlivanoğlu, ö. yılmaz 232 23. annoni f, colpi gm, marincola fm, et al. doppler examination in varicocele. a standard method of evaluation. j androl. 1988; 9:248-252. 24. sharlip i, jarow j, bekler a. aua best practice policy. report on varicocele and infertility american urological association inc, baltimore, md, usa 2001. 25. borruto fa, impellizzeri p, antonuccio p, et al. laparoscopic vs open varicocelectomy in children and adolescents: review of the recent literature and meta-analysis. j pediatr surg. 2010; 45:24642469. 26. mahdavi a, heidari r, khezri m, et al. can ultrasound findings be a good predictor of sperm parameters in patients with varicocele? a cross-sectional study. nephrourol mon. 2016; 8:e37103. 27. mccullough a, elebyjian l, ellen j, et al. a retrospective review of single-institution outcomes with robotic-assisted microsurgical varicocelectomy. asian j androl. 2018; 20:189-194. 28. al-kandari am, khudair a, arafa a, et al. microscopic subinguinal varicocelectomy in 100 consecutive cases: spermatic cord vascular anatomy, recurrence and hydrocele outcome analysis. arab j urol. 2018; 16:181-187. 29. cho cl, ho kl, chan wk, et al. use of indocyanine green angiography in microsurgical subinguinal varicocelectomy lessons learned from our initial experience. int braz j urol. 2017; 43:974979. 30. cayan s, kadioglu tc, tefekli a, et al. comparison of results and complications of high ligation surgery and microsurgical high inguinal varicocelectomy in the treatment of varicocele. urology. 2000; 55:750-754. 31. belani js, yan y, naughton ck. does varicocele grade predict vein number and size at microsurgical subinguinal repair? urology. 2004; 64:137-139. 32. babai m, gharibvand mm, momeni m, et al. comparison of preoperative and post-operative (varicocelectomy) sperm parameters in patients suffering varicocle with and without reflux in doppler ultrasonography. j family med prim care. 2019; 8:1730-1734. correspondence caner ediz, assoc. prof. (corresponding author) drcanerediz@gmail.com muhammed temel cihan, md serkan akan, md serkan yenigürbüz, md mehmet pehlivanoğlu, md ömer yılmaz, md department of urology, sultan abdulhamid han education and research hospital tibbiye street. selimiye neighborhood, 34668 uskudar/istanbul (turkey) suna şahin ediz, md department of radiology, kartal dr. lutfi kirdar city hospital, istanbul (turkey) stesura seveso 353archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.353 how urologists deal with chronic prostatitis? the preliminary results of a mediterranean survey konstantinos stamatiou 1, vittorio magri 2, gianpaolo perletti 3, evangelia samara 1, georgios christopoulos 1, alberto trinchieri 4 1 urology department, tzaneion hospital, piraeus, greece; 2 urology secondary care clinic, asst-nord, milan, italy; 3 department of biotechnology and life sciences, university of insubria, varese, italy; faculty of medicine and medical sciences, ghent university, ghent, belgium; 4 manzoni hospital, lecco, italy. being characterized by symptoms of pelvic, genital and suprapubic pain, often associated with lower urinary tract symptoms (luts) and sexual dysfunction. it is an easy to suspect, hard to prove condition. in fact, evaluation and diagnosis of chronic prostatitis (cp) can be confusing and challenging. although the meares-stamey (ms) 4-glass test is the standard method of assessing inflammation and the presence of bacteria in the prostate, it is time consuming and not accurate enough to give a clear diagnosis of bacterial prostatitis. for this reason, it was not universally employed by urologists. however, it is not known to which extent is infrequently used by greek urologists and which diagnostic tests they perform in affected patients alternatively to the ms test. in order to examine greek healthcare professionals' preferences for diagnostic investigation and testing for cp, we performed a questionnaire survey. responses were compared with the ones given by italian counterparts in an attempt to assess similarities or differences in the diagnostic approaches to chronic prostatitis syndromes in southern european mediterranean countries. materials and methods we translated the original italian questionnaire presented by magri and montanari in milan on 26 october 2018 and validated its greek version (1). this 5-item questionnaire explores practice characteristics, attitudes, and diagnostic strategies for the management of chronic prostatitis in italy. after its validation, the questionnaire was uploaded in the internet and greek healthcare professionals were invited by mail to respond, in an attempt to investigate current diagnostic practices for cp in greece. responses were compared with those collected by our italian research partners, reflecting the diagnostic habits of italian urologists, as presented in the study of magri et al. (1). the aim of this study was to assess similarities and differences in clinicians’ attitudes regarding the diagnostic assessment of cp. the local research ethics committee approved the study. results seventy-seven greek urologists were surveyed. responders diagnose chronic prostatitis in a substantial objectives: we performed a questionnaire survey to investigate various issues in the diagnosis of chronic prostatitis (cp) performed by greek urologists and to assess some aspects of prostatitis workup in greece. replies were compared with those of italian clinical research partners in an attempt to clarify the cp diagnostic approaches in southern european mediterranean countries. methods: we translated the original italian questionnaire presented by magri and montanari in the frame of a urological congress held in milan on october 26th, 2018. τhis 5-item questionnaire explores clinical practice characteristics, attitudes, and diagnostic strategies for the management of chronic prostatitis (chronic bacterial prostatitis or chronic prostatitis/chronic pelvic pain syndrome, according to nih criteria). after its validation the questionnaire was uploaded in the internet and greek healthcare professionals were invited by mail to respond. responses were compared with those of italian urologists, in order to determine similarities and differences in attitudes between clinicians regarding the diagnostic assessment of cp. results: there is a wide variation in participants' preferences for diagnostic methods, laboratory tests and clinical examinations both in italy and in greece. in both countries many diagnostic tests performed in affected patients are only geared to exclude other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer), but more suitable methods and tests for the assessment of cp are less frequently used. conclusions: urologists' choices for the diagnostic workup of cp, show a wide international or intra-national variability between greece and italy. although several diagnostic tests are available to differentiate and categorize the types of cp, a large number of urologists use less suitable methods and tests. this fact reflects both the lack of consensual vision in the literature and the difficulties encountered on a daily basis by the physicians. under the light of this evidence, the need of studies establishing consensual guidelines for the optimal diagnosis of cp is becoming imperative. key words: chronic prostatitis; prostate; infection; stamey-meyers. submitted 25 february 2020; accepted 10 march 2020 introduction the term "chronic prostatitis" indicates syndromes which show different aetiologies and variable clinical features summary archivio italiano di urologia e andrologia 2020; 92, 4 k. stamatiou, v. magri, g. perletti, e. samara, g. christopoulos, a. trinchieri. 354 number of men each year (the median number of patients per specialist per month is 11 patients). almost 72% percent of the greek professionals use in their clinical practice the classification of "chronic prostatitis" proposed by the national institutes of health (nih), which identifies two major cp conditions: chronic bacterial prostatitis (cbp) and chronic (abacterial) prostatitis/ chronic pelvic pain syndrome (cp/cpps). there is a wide variation in participants' preferences for diagnostic methods, laboratory tests and clinical examinations both in italy and in greece. in both countries many diagnostic tests performed in affected patients are geared toward excluding other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer) however more suitable methods and tests for the assessment of cp are less frequently used. a comparison between italian and greek survey is presented in the tables 1-4. discussion cp is a common situation affecting relatively young men. its exact frequency is not known. as reported by krieger et al., men in the united states with cp account for 2-5 million ambulatory physician visits per year including 8% of all appointments with a urologist. magri and montanari reported a frequency of 23 patients per urologist per month on average (1). similarly to our study, swiss urologists see a median of 10 patients per month (4). the abovementioned variations could be attributed to differences in health care policies, patients’ preference and urologists’ experience. notably, the average age of responders to our questionnaire was significantly lower than that of the italian study. this fact explains the lower median number of patients per greek specialist and it may also explain the difference in the use of the nih classification of "prostatitis" in the clinical practice between greek and italian specialists (62.7 vs 31.2%). this is likely due to the fact that, compared to older colleagues, the compliance of younger urologists with clinical practice guidelines is higher. however, this might not be the case since a limited use of the nih classification system was also reported in the uk (33%) (5) and in france (35%) (6). large deficits in familiarity with and knowledge of cp, along with a significant uniformity in the medical approach to this condition may explain the above findings (7). as a matter of fact, most urologists acknowledge that chronic prostatitis is the most frustrating and difficult clinical problem to deal within urology (8). this happens likely because the etiopathology of prostatitis is uncertain, several diseases of the urogenital system share common symptoms, the diagnostic work-up of prostatitis is not completely standardized, the microbiological diagnosis is partly inadequate and there are restrictions in the prescription of some clinical and laboratory tests in several countries. as shown in table 1, the preferred diagnostic methods (89.6 and 84.4% of greek and 98.12% and 96.62% of italian urologists) are medical history and physical examination alone or combined with the ipss questionnaire. the greatest part of them (37.6 and 41%) do not use questionnaires routinely. in general, diagnosing cp can table 1. comparison of preferences of diagnostic methods. preferred diagnostic methods italy greece answer choices % % medical history 98.12 89.6 clinical examination (dre) 96.62 84.4 ipss questionnaire 51.13 40.2 nih-cpsi questionnaire 17.29 19.4 shim questionnaire (modified iief questionnaire) 16.17 10.3 iief questionnaire 7.89 1.29 pedt questionnaire 6.39 1.29 upoint questionnaire 1.88 5.19 other questionnaires 0.00 0.00 total respondents 266 77 table 3. comparison of preferences of clinical tests. preferred clinical tests italy greece answer choices % % uroflometry 72.18 81.8 abdominal ultrasound 62.78 92.20 transrectal ultrasound 45.11 10.30 scrotal ultrasound 12.78 6.49 urodynamics 2.63 3.88 urethocystoscopy 3.01 2.59 urethrocystography 2.63 0.00 other diagnostic tests 20.68 10.3 no diagnostic test 0.00 2.59 total respondents 266 77 table 4. comparison of preferences of microbiological tests. preferred microbiological tests italy greece answer choices % % gram+ 83.08 85.6 gram86.84 100 fungi 56.77 20.7 sexually transmitted microbes 77.82 79.4 table 2. comparison of preferences of laboratory tests. preferred laboratory tests italy greece answer choices % % psa 81.20 57.1 midstream urine test 72.18 49.3 urethral swab 39.10 2.59 urethral swab after prostate massage 13.91 1.20 meares & stamey test 20.30 11.6 meares & stamey test with count of the number of leukocytes in vb2 and vb3/eps 16.92 1.20 nickels’ ‘’two glass test’’ 6.39 11.6 semen culture 67.29 74.0 semen culture with count of the number of leukocytes in ejaculate 24.81 2.69 urine cytology 9.02 0.00 spermiogram 13.16 1.20 total respondents 266 77 355archivio italiano di urologia e andrologia 2020; 92, 4 mediterranean urologist and chronic prostatitis be difficult, as the patient history and examination modalities may be quite diverse. in fact, most patients claim genitourinary pain or discomfort, though newly presented sexual dysfunction and new onset of urinary symptoms are also common. less usual presentations include recurrent febrile infections of the urinary tract and the genital system and asymptomatic elevation of serum psa levels (9). the physical examination is usually normal. digital rectal examination findings suggestive of cp (painful and or edematous hardened and tender prostate) may be found in half of the cases (10). other abnormalities that can be found during examination of the prostate, such as calculi and nodules, may impact management decisions. symptom assessment by the nih-cpsi is rarely used in both greece and italy (17.29 and 19.4% of respondents, respectively). an even lower number (12%) was reported by zbrun et al. (4). actually, the nih-cpsi was developed to assess symptoms and quality of life in men with cp/cpps and has demonstrated good reliability and validity (11). it has been long used as the primary outcome variable in multiple trials and studies, though its role as a diagnostic tool is debatable (12). on the other hand, the questions in the nih-cpsi provide a universal clinical assessment of cp, both in terms of initial evaluation and during therapeutic monitoring (13). notably, uk guidelines recommend the nih-cpsi and similar diagnostic tools such as the international prostate symptom score (ipss), the urinary, psychosocial, organspecific, infection, neurological, and tenderness (upoint) algorithm, the international index of erectile function (iief-5) and/or the sexual health inventory for men (shim) scales to assess initial symptom severity and evaluate patient-tailored phenotypic differences (level 3 recommendation) (14). they also suggest psychosocial screening with patient health questionnaire-9 (phq-9) and/or generalised anxiety disorder-7 (gad-7) scales as well (level 5 recommendation) (11). even though the meares and stamey (ms) “4-glass” test is the gold standard test for the cp diagnosis, few italian and greek responders perform it alone (20.3% and 11.6% respectively) or in combination with leukocyte counts (16.92% and 1.2% respectively). time and geographical trends in the use of this test may exist, since the number of italian cp patients not subjected to the ms test was greater in the past 15 years (15). sixty-six per cent of the canadian practitioners’ and 80% of the us counterparts never or rarely perform the ms test in making a diagnosis of prostatitis (16, 17). in contrast, 61% of the british and 51% of the dutch urologists are reported to be using the test (5, 18). kiyota et al. found that only 1.5% of japanese urologists diagnose cp using the ms test, while almost 45% adopt the the “2-glass” preand post-massage test (19). a similar number was reported by swiss urologists (4). the “2-glass” test is rarely used in both italy and greece (6.39 and 11.39% respectively). on the other hand, in our study, semen culture, combined or not with leukocyte counts, was by far the most popular test (76.59 and 92.1% for greek and italian responders respectively) and is known to be the second most used diagnostic test by dutch urologists (18). according to yang et al., the simple culture of expressed prostatic secretion (eps) is the most commonly (43.4%) performed test for the diagnosis of cp in china (20). to our knowledge, current eau guidelines suggest semen culture not to be routinely part of the diagnostic assessment of cp. regarding microbiology tests, both italian and greek responders’ preferences include both gram-negative and gram-positive organisms. some clinicians and microbiologists debate the role of gram-positive other than enterococci (21). currently, gram-positive bacteria tend to be the most frequent isolates in eps and vb3 specimens from cp patients, with coagulase-negative staphylococcal species being the most prevalent isolates in greece (22). in agreement with our findings, most urologist worldwide do not count the number of leukocytes in vb2 or vb3/eps to differentiate between inflammatory and non-inflammatory chronic prostatitis/chronic pelvic pain syndrome. the proportion of urologists following this practice vary significantly worldwide (4, 17, 19). reasons explaining these differences are practically unknown. ku et al., suggest that the personal beliefs and professional characteristics of physicians are the most determinant factors with respect to the urologists’ preferences and routine performance or non-performance of culture tests (23). kiyota et al. found that more than half of japanese urologists felt pessimistic about dealing with cp (19). although many urologists think that chronic non-bacterial prostatitis/chronic pelvic pain syndrome is not an infectious disease, they prescribe antibiotics even when no white blood cells are detected in prostate-specific specimens (4, 23). as shown in our study, a variety of diagnostic tests are performed in patients with a suspected diagnosis of cp, in order to exclude other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer). these include imaging, endoscopy, urodynamics and psa testing. none of them is specifically recommended in the evaluation of patients with prostatitis. however, ultrasonography and uroflowmetry are non-invasive, low cost tests for a rapid study of the anatomy of the urinary system and for a general estimation of the urinary function; hence they could be adopted in cp diagnostic work up (24). conclusions urologists' preferences for diagnostic investigation and testing for cp show considerable worldwide diversity. although several diagnostic tests are available to differentiate and categorize the types of cp, a large number of urologists use less suitable methods and tests. this fact reflects both the lack of consensual vision in the literature and the difficulties encountered on a daily basis by the physicians. under the light of this evidence the need of studies establishing guidelines for its diagnosis is getting imperative. references 1. http://www.amcli.it/wp-content/uploads/2015/08/p20-2018_prostatiti_26_27-ottobre_def_1.pdf 2. https://docs.google.com/forms/d/1n4tnzytksn_ehimebpp9qftok p1tadzqhcoddhbtoow/edit?ts=5dbeb11e archivio italiano di urologia e andrologia 2020; 92, 4 k. stamatiou, v. magri, g. perletti, e. samara, g. christopoulos, a. trinchieri. 356 3. krieger jn, ross so, riley de. chronic prostatitis: epidemiology and role of infection. urology. 2002; 60:8-12. 4. zbrun s, schumacher m, studer ue, hochreiter ww. chronic prostatitis a nationwide survey of all urologists in switzerland. j urol. 2004; 171:27. 5. luzzi ga, bignell c, mandal d, maw rd. chronic prostatitis/chronic pelvic pain syndrome: national survey of genitourinary medicine clinics. int j std aids. 2002; 13:416-419. 6. delavierre d. chronic prostatitis and chronic pelvic pain syndrome: a survey of french urologists. prog urol. 2007; 17:69-76. 7. liu l, yang j. physician's practice patterns for chronic prostatitis. andrologia. 2009; 41:270-6. 8. magri v, boltri m, cai t, et al. multidisciplinary approach to prostatitis. arch ital urol androl. 2019; 90:227-248. 9. stamatiou k, karageorgopoulos d. a prospective observational study of chronic prostatitis with emphasis on epidemiological and microbiological features. urologia. 2013; 10.5301. 10. stamatiou k, moschouris h. a prospective interventional study in chronic prostatitis with emphasis to clinical features. urol j. 2014; 11:1829-33. 11. litwin ms, mcnaughton-collins m, fowler fj jr, et al. the national institutes of health chronic prostatitis symptom index: development and validation of a new outcome measure. j urol. 1999; 162:369-75. 12. roberts ro, jacobson dj, girman cj, et al. low agreement between previous physician diagnosed prostatitis and national institutes of health chronic prostatitis symptom index pain measures j urol. 2004; 171:279-283. 13. wagenlehner fm, van till jw, magri v, et al. national institutes of health chronic prostatitis symptom index (nih-cpsi. symptom evaluation in multinational cohorts of patients with chronic prostatitis/chronic pelvic pain syndrome. eur urol. 2013; 63:953-9. 14. rees j, abrahams m, doble a, cooper a. prostatitis expert reference group (perg). diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. bju int. 2015; 116:509-25. 15. nickel jc, rizzo m, marchetti f, et al. prevalence, characterization, diagnosis and treatment of the prostatitis patient in italy: an opportunity to compare the european prostatitis patient to the north american experience j urol. 2004; 171:27. 16. nickel jc, nigro m, valiquette l, et al. diagnosis and treatment of prostatitis in canada. urology. 1998; 52:797-802. 17. mcnaughton collins m, fowler fj jr, et al. diagnosing and treating chronic prostatitis: do urologists use the four-glass test? urology. 2000; 55:403-7. 18. de la rosette jj, hubregtse mr, karthaus hf, debruyne fm. results of a questionnaire among dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes. eur urol. 1992; 22:14-19. 19. kiyota h, onodera s, ohishi y, et al. questionnaire survey of japanese urologists concerning the diagnosis and treatment of chronic prostatitis and chronic pelvic pain syndrome. int j urol. 2003; 10:636-42. 20. yang j, liu l, xie hw, ginsberg da. chinese urologists’ practice patterns of diagnosing and treating chronic prostatitis: a questionnaire survey. urology. 2008; 72:548-551. 21. krieger jn, ross so, limaye ap, riley de. inconsistent localization of gram-positive bacteria to prostate-specific specimens from patients with chronic prostatitis, urology. 2005; 66:721-725. 22. stamatiou k, magri v, perletti g, et al. chronic prostatic infection: microbiological findings in two mediterranean populations. arch ital urol androl. 2019; 91:177-181. 23. ku jh, paick js, kim sw. factors influencing practices for chronic prostatitis: a nationwide survey of urologists in south korea. int j urol. 2005; 12:976-83. 24. stamatiou k, magri v, perletti g, et al. prostatic calcifications are associated with a more severe symptom burden in men with type ii chronic bacterial prostatitis. arch ital urol androl. 2019; 91:79-83. correspondence konstantinos stamatiou, md stamatiouk@gmail.com evangelia samara, md georgios christopoulos, md urology dpt, tzaneion hospital 2 salepoula str, 18536 piraeus (greece) vittorio magri, md urology secondary care clinic, asst-nord, milan (italy) gianpaolo perletti, phd department of biotechnology and life sciences, university of insubria, varese (italy) alberto trinchieri, md manzoni hospital, lecco (italy) stesura seveso 153archivio italiano di urologia e andrologia 2020; 92, 2 original paper protective effect of chlorogenic acid on renal ischemia/reperfusion injury in rats tuncay toprak 1, cagri akin sekerci 2, hasan riza aydın 3, mehmet akif ramazanoglu 4, fatma demet arslan 5, banu isbilen basok 5, hatice kucuk 6, huseyin kocakgol 3, hamit zafer aksoy 3, seyhan sumeyra asci 7, yılören tanıdır 8 1 fatih sultan mehmet training and research hospital, urology, istanbul; 2 marmara university pendik training and research hospital, pediatric urology, istanbul; 3 kanuni training and research hospital, urology, trabzon; 4 rize state hospital, urology, rize; 5 tepecik training and research hospital, biochemistry, izmir; 6 kanuni training and research hospital, pathology, trabzon; 7 kanuni training and research hospital, anesthesiology and reanimation, trabzon, turkey; 8 marmara university, school of medicine, urology istanbul, turkey. objectives: ischemia/reperfusion (i/r) injury is a common cause of renal injury and to date, many pharmacological agents have been identified to decrease i/r injury. one of the potential compound that can target i/r injury is chlorogenic acid (cga). it has potent antiinflammatory, antibacterial, anti-oxidant, analgesic and antipyretic activities in in vitro experiments and in vivo animal models. the aim of the study was to investigate the protective characteristic of cga on renal i/r injury. material and methods: 24 rats were randomly allocated to three groups (n = 8): sham, i/r+cga and i/r groups. cga was administered intraperitoneally at a dose of 20 mg/kg, 10 min before reperfusion. i/r injury was achieved by clamping the left renal artery for 45 minutes, followed by reperfusion for 4 hours. the left kidneys of the rats were examined for tissue damage by histopathological and biochemical examination. for histological evaluation, egti scoring system was used. for biochemical examination total oxidant status, total antioxidant status and oxidative stress index were used. the power analysis indicated that 8 subjects per group would be required to produce 80% chance of achieving statistical significance at p < 0.05 level. the results are expressed as mean ± sd. mannwhitney u was performed for statistical analysis. results: histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. i-r group had significantly higher histopathological scores than other groups. histopathological improvement was seen after cga treatment. tas, tos and osi values of i-r group were significantly higher than sham group (0.88 vs 0.76 (p: 0.004), 13.8 vs 7.04 (p: 0.021) and 0.15 vs 0.09 (p: 0.034), respectively). in cga treated group tas, tos and osi levels were 0.84, 6.47 and 0.07, respectively. cga treatment resulted in significant improvement in tos and osi parameters. conclusions: cga treatment provided marked improvement in renal histology and suppressed oxidative stress. thus, cga may have a protective effect in renal tissue against i/r injury. key words: renal ischemia; oxidative stress; chlorogenic acid; rat. submitted 29 november 2019; accepted 12 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.153 introduction ischemia/reperfusion (i/r) injury is a common cause of renal injury arising from a variety of clinical circumstances, including partial nephrectomy, renal transplantation, iatrogenic trauma, sepsis and shock (1, 2). it is characterized by restriction of the blood flow, followed by restoring the blood flow and oxygenation. cessation of blood flow causes ischemia and tissue damage. restoration of blood flow during reperfusion period, often leads to exacerbation of these harmful events instead of improving (3). the pathologic processes underlying this injury are complex and include interactions between the endothelium, cell death programs and immune system (4). reactive oxygen radicals (ror), necrosis, apoptosis, and inflammation plays a role in this process but the exact mechanisms remain unclear (5, 6). the production of ror is considered a key reason for oxidative stress during the reperfusion period (6). thus, targeting oxidative stress’ processes is an ideal therapeutic approach. i/r injury in renal transplantation often leads to allograft dysfunction and increased rejection (7). in partial nephrectomy, renal tissue damage may occur due to clamping of renal arteries (8). in the clinical scenario, renal i/r models generated in animals are important to understand the pathophysiology of renal injury and the potential treatment options. to date, many pharmacological agents such as n-acetylcysteine (9), allopurinol (10) or mannitol (11) have been identified to decrease i/r injury after nephron sparing surgery. to prevent the kidney damage due to i/r injury, several anti-inflammatories and antioxidants have been used in experimental studies (12-14). another potential compound that can target i/r injury is chlorogenic acid (cga). it is formed by esterification of quinic and caffeic acids and it is one of the polyphenols abundant in the human diet (15). it has potent anti-inflammatory, antibacterial, anti-oxidant, analgesic and antipyretic activities in in vitro experiments and in vivo animal models (16-18). thus, we investigate protective effects of cga against renal i/r injury in an in vivo rat model which may potentially help us in urological surgeries such as partial nephrectomy and renal transplantation where clamping is required. to examine this, we evaluated histopathological findings and biochemical analyses (including archivio italiano di urologia e andrologia 2020; 92, 2 t. toprak, c. akin sekerci, h. riza aydın, et al. 154 total oxidant (tos) status, total antioxidant (tas) assays). in our knowledge, there have been no studies concerning the protective effect of cga against renal i/r injury. materials and methods the experimental and surgical procedures were conducted according to routine animal care guidelines, and the guide for the care and use of laboratory animals (19). the approval was obtained from institutional animal care and use committee of karadeniz technical university (trabzon, turkey) (approval number/id: 2019/5). 24 male sprague-dawley rats (8 weeks old, weight 230-300 g) were purchased from the karadeniz technical university laboratory animals research centre (trabzon, turkey). all animals were kept in captivity under the same nutritional and environmental conditions. rats were entrained under a 12:12 h dark: light cycle (lights on 6 am-6 pm) with stable temperature (21 ± 2°c) and humidity (60 ± 5%). the rats had sterile water and food available ad libitum. experimental design rats were randomly and equally divided into 3 groups; 1. vehicletreated ischemic (i/r): after sterile conditions were obtained, a midline laparotomy was performed. isotonic saline (1 mg/kg) was applied intraperitoneally 10 min before the beginning of reperfusion. the left kidney pedicle was clamped with an artery clamp for 45 minutes. after 45 minutes of left renal ischemia, the occlusion clamp was removed for reperfusion for 4 hours and the incision was closed. 2. vehicletreated sham (sham): rats underwent the same surgical procedures except unilateral renal occlusion. during the experiment, they were kept under anesthesia with gauze, soaked in saline in the abdominal cavities. 3. cga-treated ischemic (i/r+cga): after sterile conditions were obtained, a midline laparotomy was performed. cga (sigma-aldrich) (20 mg/kg) was applied intraperitoneally 10 min before the beginning of reperfusion. the left kidney pedicle was clamped with an artery clamp for 45 minutes. after 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed. administration of cga cga was dissolved in saline (vehicle) and administered intraperitoneally at a total dose of 20 mg/kg 10 minutes before reperfusion. surgical procedure for anesthetic ketamine hydrochloride (100 mg/kg, ketalar, eczacıbasi, turkey) and xylazine (10 mg/kg) were used intraperitoneally. following fluid replacement with 3 ml·kg-1·h-1 lactated ringer’s solution, the surgical area was prepared for sterilization. then a midline laparotomy incision was performed and the left kidney pedicle was dissected. left renal ischemia was induced by clamping the left renal artery for 45 min for the i/r and i/r-cga groups. for reperfusion the clamp was removed and the pulsation of renal artery was verified visually. after controlling the bleeding, the skin layers were sutured. the rats were sacrificed 4 h after completion of the reperfusion and the left kidneys were removed and stored for biochemical and histopathological examination under favorable conditions. histological analysis removed kidney was fixed with 10% formalin and embedded in paraffin. 5 μm tissue sections obtained for hematoxylin and eosin staining. an experienced, independent pathologist, who was blinded to the groups, analyzed three different tissue sections in each group, using a zeiss axio imager a2 microscope (carl zeiss ag, germany). the histological evaluations of the renal tissue were graded as described in the study of medeiros et al. (20) (table 1). the scores were applied to microscopic changes consistent with tubular necrosis: vacuolization of tubular cells, tubular lumen dilation, intra-tubular cylinders, interstitial fibrosis and tubular cell necrosis. for histological evaluation, egti scoring system, which was developed especially for animal studies in kidney tissues in the context of injury, was also used (21), (table 2). this system consists of histological damage in 4 separate components: endothelial, glomerular, tubular, and interstitial. tas and tos assays the serum tas and tos levels were determined with a table 1. scoring system for renal histopathology. score histopathological pattern 0 normal 0.5 small focal damaged areas 1 < 10% cortical damaged zone 2 10–25% cortical damaged zone 3 25–75% cortical damaged zone 4 > 75% cortical damaged zone table 2. the egti histology scoring system. tissue type damage score tubular no damage 0 loss of brush border (bb) in less than 25% of tubular cells. integrity of basal membrane 1 loss of bb in more than 25% of tubular cells, thickened basal membrane 2 (plus) inflammation, cast formation, necrosis up to 60% of tubular cells 3 (plus) necrosis in more than 60% of tubular cells 4 endothelial no damage 0 endothelial swelling 1 endothelial disruption 2 endothelial loss 3 glomerular no damage 0 thickening of bowman capsule 1 retraction of glomerular tuft 2 glomerular fibrosis 3 tubulo/interstitial no damage 0 inflammation, haemorrhage in less than 25% of tissue 1 (plus) necrosis in less than 25% of tissue 2 necrosis up to 60% 3 necrosis more than 60% 4 novel automatic method, developed by erel (22, 23). the ratio of tas to tos is defined as oxidative stress index (osi), expressed as percentage. statistical analysis ibm spss 22 version (spss ibm, turkey) program was used for analysis. before starting to study, we performed power analysis. the power analysis indicated that 8 subjects per group would be required to produce 80% chance of achieving statistical significance at p < 0.05 level. the kolmogorov-smirnov test was performed to determine the normality of data. the results are expressed as mean ± sd. mann-whitney u was performed for statistical analysis, as appropriate. a p value below 0.05 was considered statistically significant. results cga showed histopathologic improvement in ischemia reperfusion injury as shown in tables 3 and 4. all rats in the sham group had normal histopathological findings. by contrast, as shown in table 3, 4 (50%) rats in the i/r group had small focal damaged areas and 4 (50%) had < 10% cortical damage. in i/r+cga group, 1 (12.5%) rat had normal kidney, 5 (62.5%) had small focal damaged areas and 2 (25%) had < 10% cortical damage. egti scores of the rats in each group are shown in table 4, separately. the pathological figures were shown in figure 1. as shown in table 5, cga improved biochemical values. tas, tos and osi values of the sham group was significantly lower than i/r group (p: 0.004, 0.021, 0.034, respectively). there was no significant difference between the sham and i/r + cga groups in terms of tos and osi values (p: 0.83, 0.52, respectively). tos and osi values of the i/r group were significantly higher than the other groups (p: 0.021, 0.034, respectively for comparison of sham and i/r groups and p: 0.046, 0.040, respectively for comparison of i/r+cga and i/r groups). discussion renal i/r injury is a major reason for renal dysfunction. it induces an inflammatory response and oxidative stress. at the site of inflammation, leukocytes infiltration occurs and results in the secretion of pro-inflammatory cytokines, including tnf-α, hmgb1, il-6, and il-1β (24). ror, produced during reperfusion is considered to play a central role in i/r injury by direct attack on multiple molecule sequences. in living organisms, ror arise as a result of normal biological metabolism and they can distort the structures of dna, fats, proteins and carbohydrates. to ensure i/r experimentally, the left renal artery was occluded for 45 min. it was shown that the 45 min model of ir injury used here provides reproducible and robust assessment of treatment effects against ir injury (25, 26). oxidative stress and antioxidant status can be assessed by several markers and various methods. however, it is both time-consuming and costly to measure these markers separately (27). for this reason, in this study we used tos, tas and osi levels to measure the oxidative stress status. in recent years it has become more common to measure these values (23, 28, 29). in this study tas, tos and osi levels were found to be significantly higher in i/r group compared to sham group and cga alleviated these parameters. the histopathological classification system presented in table 1 was used for histological diagnosis. however, since this system shows only cortical damage. renal ir injury is a complex process which effects the glomerular, tubulo-interstitial and endothelial cells. acute tubular necrosis, loss of endothelial cell integrity, glomerular 155archivio italiano di urologia e andrologia 2020; 92, 2 chlorogenic acid and renal injury table 3. histopathology scoring of cortical damage of the groups. rats sham group i/r group i/r + cga group 1 0 0.5 0.5 2 0 1 0 3 0 1 1 4 0 1 0.5 5 0 0.5 0.5 6 0 0.5 0.5 7 0 1 1 8 0 0.5 0.5 figure 1. histological images of rat renal cortex sections. a; normal renal cortex (sham group), b; tubular necrosis (i/r), c; tubular injury (i/r+cga group. a b c table 5. comparison of groups in terms of biochemical parameters. tas median (min-max) p tos median (min-max) p osi median (min-max) p group 1-2 0.84 (0.76-1)-0.76 (0.66-0.80) 0.021 6.47 (2.1-23.7)-7.04 (4.7-13.9) 0.83 0.07 (0.03-0.26)-0.09 (0.06-0.21) 0.52 group 2-3 0.76 (0.66-0.80)-0.88 (0.75-0.98) 0.0048 7.04 (4.7-13.9)-13.8 (6.4-18.5) 0.021 0.09 (0.06-0.21)-0.15 (0.09-0.19) 0.034 group 1-3 0.84 (0.76-1)-0.88 (0.75-0.98) 0.49 6.47 (2.1-23.7)-13.8 (6.4-18.5) 0.046 0.07 (0.03-0.26)-0.15 (0.09-0.19) 0.040 (1) i-r +cga, (2) sham, (3) i-r. mann whitney u test table 4. comparison of rats in terms of egti scoring. rats sham group i/r group i/r + cga group 1 0 8 5 2 0 7 3 3 0 8 6 4 0 8 3 5 0 5 3 6 0 5 4 7 0 8 7 8 0 4 6 archivio italiano di urologia e andrologia 2020; 92, 2 t. toprak, c. akin sekerci, h. riza aydın, et al. 156 ischemic damage and tubulo-interstitial damage are the hallmarks of renal ir injury which is important for complete and comprehensive documentation. for this reason, egti scoring system was used together with other system. because it is reliable, simple, more informative and more detailed scoring system about the degree of tissue damage of the kidney (21). the histological study showed tubular dilation, tubular necrosis, cellular edema and inflammatory cell infiltration in the tubular interstitium. these lesions were less intense in cga treated rats compared to untreated animals. in order to block inflammatory response and oxidative stress, several drugs have been used to prevent renal i/r injury in several experimental studies (13, 14). however, the new experimental studies will help us to find the most appropriate feasible treatment. in the present study, cga was examined for its potential effects on regulating renal i/r injury. cga is a polyphenol, which is abundantly found in coffee, fruits and vegetables. it has been used as an antioxidant, analgesic and anti-inflammatory. it has a certain number of r-oh radicals that are capable of forming the hydrogen free radical, thereby protecting tissue cells from oxidative damage (30). it has been shown to act as a scavenger of hydroxyl radicals, peroxynitrite and superoxide radicals in a concentrationdependent manner in vitro (31). in the study of yun et al. (32) cga given at 10 mg/kg intraperitoneally, 10 min before ischemia and reperfusion was chosen as the most effective dose for histology evaluation for i/rinduced hepatic injury. in our study, it was administered intraperitoneally at a total dose of 20 mg/kg 10 minutes before reperfusion. previous studies in rat models have shown that cga is protective against hepatic and focal cerebral i/r injury (32, 33). we have observed that cga has a protective effect against renal i/r injury in our study. we considered that cga may serve a protective role in the rat model of renal i/r injury. to the best of our knowledge, there is no data showing the effect of cga on i/r kidney injury and evaluating tas, tos levels and histopathology together. as a limitation of our study, since we did not perform a right nephrectomy, we did not measure plasma creatinine, the most commonly used marker as a measure of renal excretory function (34). conclusions cga treatment provided marked improvement in renal histology and suppressed oxidative stress. thus, cga may have a protective effect in renal tissue against i/r injury. references 1. sagiroglu t, et al. effects of apelin and leptin on renal functions following renal ischemia/reperfusion: an experimental study. exp ther med. 2012; 3: 08-914. 2. snoeijs mg, et al. acute ischemic injury to the renal microvasculature in human kidney transplantation. am j physiol renal physiol. 2010; 299:f1134-40. 3. orvieto ma, et al. ischemia preconditioning does not confer resilience to warm ischemia in a solitary porcine kidney model. urology. 2007; 69:984-987. 4. eltzschig hk. eckle t ischemia and reperfusion—from mechanism to translation. nat med. 2011; 17:1391. 5. zhang j, et al. erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating pi3k/akt signalling. nephrology (carlton). 2015; 20:266-72. 6. wang l, et al. effect of picroside ii on apoptosis induced by renal ischemia/reperfusion injury in rats. exp ther med. 2015; 9:817-822. 7. fadili w, allah mh, laouad i. chronic renal allograft dysfunction: risk factors, immunology and prevention. arab j nephrol transplant. 2013; 6:45-50. 8. martin gl, et al. comparison of total, selective, and nonarterial clamping techniques during laparoscopic and robot-assisted partial nephrectomy. j endourol. 2012; 26:152-156. 9. conesa el, et al. n-acetyl-l-cysteine improves renal medullary hypoperfusion in acute renal failure. am j physiol regul integr comp physiol, 2001; 281: r730-7. 10. rhoden e et al., protective effect of allopurinol in the renal ischemia--reperfusion in uninephrectomized rats. gen pharmacol. 2000; 35:189-93. 11. feitoza cq, et al. cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. int immunopharmacol. 2005; 5:79-84. 12. sahna e, et al. the protective effects of physiological and pharmacological concentrations of melatonin on renal ischemia-reperfusion injury in rats. urol res. 2003; 31:188-193. 13. hosseini f, et al. effect of beta carotene on lipid peroxidation and antioxidant status following renal ischemia/reperfusion injury in rat. scand j clin lab invest. 2010; 70:259-263. 14. kizilgun m, et al. beneficial effects of n-acetylcysteine and ebselen on renal ischemia/reperfusion injury. ren fail. 2011; 33:512-517. 15. suzuki a, et al. chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. j hypertens. 2006; 24:1065-1073. 16. dos santos md, et al. evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. biol pharm bull. 2006; 29:2236-2240. 17. almeida aap, et al. antibacterial activity of coffee extracts and selected coffee chemical compounds against enterobacteria. j agricol food chem. 2006; 54:8738-8743. 18. kono y, et al. iron chelation by chlorogenic acid as a natural antioxidant. biosci biotechnol biochem. 1998; 62:22-27. 19. council nr. guide for the care and use of laboratory animals. 1996, washington, dc: the national academies press. 140. 20. medeiros pjd, et al. effect of sildenafil in renal ischemia/reperfusion injury in rats. acta cir bras. 2010; 25:490-495. 21. chavez r, et al. kidney ischaemia reperfusion injury in the rat: the egti scoring system as a valid and reliable tool for histological assessment. journal of histology and histopathology. 2016; 3. 22. erel o. a novel automated method to measure total antioxidant response against potent free radical reactions. clin biochem. 2004; 37:112-119. 23. erel o. a new automated colorimetric method for measuring total oxidant status. clin biochem. 2005; 38:1103-1111. 24. ysebaert dk, et al. identification and kinetics of leukocytes after 157archivio italiano di urologia e andrologia 2020; 92, 2 chlorogenic acid and renal injury severe ischaemia/reperfusion renal injury. nephrol dial transplant. 2000; 15:1562-74. 25. delbridge m, et al. the effect of body temperature in a rat model of renal ischemia-reperfusion injury. in transplantation proceedings. 2007. elsevier. 26. wystrychowski w, et al. nephroprotective effect of pentoxifylline in renal ischemia–reperfusion in rat depends on the timing of its administration. in transplantation proceedings. 2014. elsevier. 27. tarpey mm, wink da, grisham mb. methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. am j physiol regul integr comp physiol. 2004; 286:r431r444. 28. erel o. a novel automated direct measurement method for total antioxidant capacity using a new generation, more stable abts radical cation. clin biochem. 2004; 37:277-285. 29. harma m, erel o. increased oxidative stress in patients with hydatidiform mole. swiss med wkly. 2003; 133:563-6. 30. zhang j, et al. liquid chromatograph/tandem mass spectrometry assay for the simultaneous determination of chlorogenic acid and cinnamic acid in plasma and its application to a pharmacokinetic study. j pharm biomed anal .2010; 51:685-690. 31. graziani g, et al. apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo. gut. 2005; 54:193-200. 32. yun n, kang j-w, lee s-m. protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. j nutr biochem. 2012; 23:1249-1255. 33. miao m, et al. protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models. saudi pharm j. 2017; 25:556-563. 34. suzuki y, et al. clinical validity of renal function markers including serum cystatin c on chronic kidney disease classification. rinsho byori. 2011; 59:345-351. correspondence tuncay toprak, md (corresponding author) drtuncay55@hotmail.com fatih sultan mehmet training and research hospital, urology, istanbul, turkey e5 karayolu üzeri fatih sultan mehmet hastanesi c blok kat 3 icerenkoy atasehir/istanbul çagrı akın sekerci, md cagri_sekerci@hotmail.com marmara university pendik training and research hospital, pediatric urology, istanbul, turkey hasan riza aydın, assoc. prof. hrizaaydin@gmail.com huseyin kocakgol, md hsynkocakgl@gmail.com hamit zafer aksoy, ass. prof. hamitzaferaksoy@hotmail.com kanuni training and research hospital, urology, trabzon, turkey mehmet akif ramazanoglu, md maramazanoglu@hotmail.com rize state hospital, urology, rize, turkey fatma demet arslan, assoc. prof. fatmademet.arslan@gmail.com tepecik training and research hospital, biochemistry, izmir, turkey banu isbilen basok, assoc. prof. drisbilen@yahoo.com tepecik training and research hospital, biochemistry, izmir, turkey hatice kucuk, ass. prof. dr.hatice.kucuk@hotmail.com kanuni training and research hospital, pathology, trabzon, turkey seyhan sumeyra asci, md seyransumeyra@hotmail.com kanuni training and research hospital, anesthesiology and reanimation, trabzon, turkey yılören tanıdır, assoc. prof. yiloren@yahoo.com marmara university, school of medicine, urology istanbul, turkey stesura seveso 237archivio italiano di urologia e andrologia 2022; 94, 2 review no conflict of interest declared. drugs (cocaine) and perineal trauma leading to presentations of priapism seem to be rising in incidence (2). there are essentially two main types of priapism: high flow and low flow. low flow priapism is more common, and it is associated with a decrease in venous outflow and vascular stasis that, in turn, cause tissue hypoxia and acidosis. high flow priapism is usually due to trauma, although, on rare occasions, it has been idiopathic. the hallmark of this type of priapism is an increase in arterial inflow in the setting of normal venous outflow (3). a general overview of the types of priapism is summarized in table 1. the primary goals of medical therapy for ischemic priapism (ip) are to decompress the corporal bodies and restore arterial blood flow. management of ip should progress in an aggressive and stepwise fashion. management of acute ip starts with the aspiration of blood and the irrigation of the corpora cavernosa, in combination with the use of intracavernous a-agonist injection therapy. phenylephrine is the preferred sympathomimetic agent, but other a-adrenergic agonists may be used, such as ephedrine, epinephrine, norepinephrine, or metaraminol. caution should be taken when using those agents based on the patient’s cardiovascular profile and time used for injection (4). if conservative therapies failed to resolve ip, it is recommended to perform distal shunting first (5). european urology association (eau) guidelines currently recommended that if priapism persists despite the use of first-line treatments including shunting procedures, ed is inevitable. immediate pp insertion is recommended to avoid the corporal fibrosis associated with later insertion (6). it is crucial to prevent future episodes of ip due to its high morbidity. many drugs have been used for this purpose such as oral use of terbutaline, digoxin, baclofen, estrogens, gonadotropin-releasing hormone agonists (gnrh), antiandrogens, and pde5 inhibitors (7). table 2 summarizes the advantages and the disadvantages of each type of therapy used in priapism. it is reasonable to presume that patients diagnosed to have non-ischemic priapism (nip) can undergo observation and conservative management, then pursue embolization if possible with temporary agents (8). angiography with super-selective embolization is the treatment of choice if priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. this disorder can induce irreversible erectile dysfunction. there are three subtypes of priapism: ischemic, non-ischemic, and stuttering priapism. if the patient has ischemic priapism (ip) of less than 24-hours (h) duration, the initial management should be a corporal blood aspiration followed by instillation of phenylephrine into the corpus cavernosum. if sympathomimetic fails or the patient has ip from 24 to 48h, surgical shunts should be performed. it is recommended that distal shunts should be attempted first. if distal shunt failed, proximal, venous shunt, or t-shunt with tunneling could be performed. if the patient had ip for 48 to 72h, proximal and venous shunt or t-shunt with tunneling is indicated, if those therapies failed, a penile prosthesis should be inserted. non-ischemic priapism (nip) is not a medical emergency and many patients will recover spontaneously. if the nip does not resolve spontaneously within six months or the patient requests therapy, selective arterial embolization is indicated. the goal of the management of a patient with stuttering priapism (sp) is the prevention of future episodes. phosphodiesterase type 5 (pde5) inhibitor therapy is considered an effective tool to prevent stuttering episodes but it is not validated yet. the management of priapism should follow the guidelines as the future erectile function is dependent on its quick resolution. this review briefly discusses the types, pathophysiology, and diagnosis of priapism. it will discuss an updated approach to treat each type of priapism. key words: priapism; ischemic priapism; non-ischemic priapism; stuttering priapism. submitted 9 may 2022; accepted 23 may 2022 introduction priapism is defined as a persistent erection due to abnormal mechanisms regulating penile tumescence, rigidity, and flaccidity. the rapid diagnosis and management of priapism are necessary to spare patients ineffective interventions and maintain erectile function outcomes (1). the use of intracavernous injections of papaverine rapidly increases the number of men seeking attention for priapism, a previously rare disease. the use of recreational an update on the management algorithms of priapism during the last decade mohamad moussa 1, mohamad abou chakra 1, athanasios papatsoris 2, athanasios dellis 2, 3, michael peyromaure 4, nicolas barry delongchamps 4, hugo bailly 4, sabine roux 4, ahmad abou yassine 5, igor duquesne 4 1 department of urology, al zahraa hospital, university medical center, lebanese university, beirut, lebanon; 2 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece; 3 department of surgery, school of medicine, aretaieion hospital, national and kapodistrian university of athens, athens, greece; 4 department of urology, cochin hospital, assistance publique-hôpitaux de paris, paris descartes university, paris, france. 5 internal medicine, staten island university hospital, staten island, ny, united states. doi: 10.4081/aiua.2022.2.237 summary archivio italiano di urologia e andrologia 2022; 94, 2 m. moussa, m. abou chakra, a. papatsoris 238 prompt definitive management of nip is desired. cavernosal artery ligation is another option reserved in case of failures of embolization (9). we performed a narrative review to discuss briefly the types, pathophysiology, and diagnosis of priapism. this review will focus on updates in the treatment of each type of priapism. materials and methods we searched electronic databases including pubmed and the scopus database for published studies that analyzed the role of the following medical subject headings (mesh) terms: ‘priapism’ (and) ‘erectile dysfunction’ (or) ‘ischemic priapism’ (and) ‘management’ (or) ‘nonischemic priapism’ (and) ‘management’ (or) ‘stuttering priapism’ (and) ‘management’. this was done in order to ensure the comprehensive inclusion of articles related to the management of priapism. the initial search resulted in 250 articles. after review, we initially excluded papers that were not relevant: 96 articles. at the completion of the review, 154 articles were selected based on their clinical relevance related to the aim. data extraction was performed by all authors. table 3 resumes the research summary. overview of priapism types of priapism there are three different types of priapism: low-flow or ischemic; high-flow or non-ischemic priapism; and recurrent or stuttering priapism (10). stuttering priapism (sp) manifests in recurring episodes of ip incidents of varying duration and should be distinguished from the persistence or rapid recurrence of a single episode of acute priapism. although many of these episodes are self-limited, they can increase in duration and incidence, leading to acute major ip events requiring emergency medical management (11). table 1. overview of each type of priapism. characteristics of each type ischemic priapism non ischemic priapism stuttering priapism etiologies • iatrogenic • traumatic rupture of the cavernous artery • similar to the causes of ischemic priapism • medications or its branches • sickle cell disease is the common cause • intracavernous injection • idiopathic symptoms • penile pain • erection without full rigidity • same as ischemic type • rigid corpora • no pain • multiple recurrent episodes are usually noted • penile trauma corporal blood aspirate • blood is dark • blood is bright red • same as ischemic type • acidity (ph < 7.25) • po2 > 90 • high pco2 (> 60 mmhg) • pco2 < 40 • low po2 (< 30 mmhg) • ph of 7.4 color doppler findings • lack of cavernous artery blood flow • doppler waveforms with peak systolic velocity > 50 cm/s, • low peripheral resistance waveform • very high-resistance flow pattern and end-diastolic velocity that is 0 or negative • elevated, variable cavernosal artery velocity in the cavernous artery table 2. advantages and disadvantages of each type of therapy used in priapism. type of therapy advantages disadvantages penile aspiration and irrigation used in ip • easy to learn • high failure rate • minimally invasive • contraindicated in patients with bleeding disorders or using anticoagulation intracavernosal injections of pharmacological agents used in ip • easy to learn • cardiac side effects • minimally invasive • require cardiovascular monitoring • less than 60% efficacy shunt surgery used in ip • usually, proximal shunt procedures are easy to learn • usually, proximal shunt procedures are difficult to learn • can be used in patients whose intracavernous injections are contraindicated • invasive procedures • duration of priapism affects resolution rates penile prosthesis used in ip • allow recovery of sexual function • increased risk of prosthetic infection • in chronic cases, penile prosthesis surgery is difficult due to fibrosis hormonal therapy used in sp • allow fistula to heal more easily • it may cause erectile dysfunction • multiple side effects such as hot flashes, fatigue, decreased libido selective arterial embolization used in sp cases • minimally invasive • it may cause erectile dysfunction • high failure rate • can cause penile gangrene • can cause perineal abscess ip: ischemic priapism; nip: non ischemic priapism; sp: stuttering priapism 239archivio italiano di urologia e andrologia 2022; 94, 2 an update on the management algorithms of priapism during the last decade epidemiology of priapism epidemiologic studies reported an overall incidence rate of 1.5 per 100,000 man-years. the incidence rate in men 40 years old and older was 2.9 per 100,000 person-years (12). roghmann et al. reported 32,462 visits to the emergency department for priapism between 2006 and 2009 in the united states, which represents a national incidence of 5.34 per 100,000 male subjects per year (13). kulmala et al. reviewed all cases of priapism in finland during the years 1975-90. when cases due to intracorporal injections were excluded, the incidence of priapism was stable and varies from 0.34 to 0.52/100000 males per year. most cases of priapism were seen during the lighter half of the year, between march and august (14). the incidence of priapism among patients with sickle-cell disease (scd) is high (35%). the implications of priapism for erectile and sexual function are significant (15). 30% of males with scd under the age of 20 years reported at least one episode of priapism, whereas frequencies of 30% to 45% are estimated for adult men (16). etiology of priapism numerous etiologies of priapism are considered. the excess release of contractile neurotransmitters, obstruction of draining venules, prolonged relaxation of intracavernosal smooth muscle may lead to an abnormal detumescence (17). various possible etiologies for ip have been described in the literature including hemoglobinopathies (scd), iatrogenic causes like intracavernosal injections, phosphodiesterase 5 (pde5) inhibitors, psychiatric medications (such as risperidone and clozapine), and alpha-1 blockers (18). veno-occlusive crisis can occur in the penis of scd patients, that is often due to stasis and low blood flow rates within the sinusoids of the erectile tissue. in scd patients, there is abnormal signaling of the nitric oxide (no) pathway. this can be the main pathophysiology of priapism in those patients (19). nip is mostly due to the traumatic rupture of the cavernous artery or its branches. most of the time, the venous channels remain open, and the penis is partially erect. nip is usually caused by perineal or penile trauma and can occur after shunt procedures for the management of ip (20). diagnosis of priapism the diagnosis of ip is based on the history and physical examination and may be done by penile blood gas analysis and penile ultrasound (21). a physical examination of the penis should be performed to ascertain whether it is fully erect (as in ip) or partially erect (as in nip) (22). a perineal examination may reveal evidence of trauma in nip cases (8). a recent penile injection site is sometimes found in ip cases examination (23). the diagnosis of ip can be made by a cavernous blood gas analysis to confirm the storage of venous blood within the corpora cavernosa manifesting as a lower partial oxygen pressure (po2 < 30 mmhg), higher partial carbon dioxide pressure (pco2 > 60 mmhg), and a decline of ph (< table 3. search summary used in our review. section of our review number of articles screened number of articles excluded number of articles that were reasons to exclude articles related to the topic from the review process relevant to the review aims from our review priapism definition 10 5 5 not relevant to the aims repetitive content priapism types 15 9 6 not relevant to the aims repetitive content priapism etiologies 9 4 5 not relevant to the aims repetitive content priapism diagnosis 30 14 16 not relevant to the aims repetitive content editorials/comments treatment of ip 70 18 52 not relevant to the aims repetitive content preclinical studies pilot studies editorials/comments same intervention, different outcomes treatment of nip 56 18 38 not relevant to the aims repetitive content preclinical studies no relevant outcomes no comparison group treatment of sp 60 28 32 not relevant to the aims repetitive content preclinical studies no outcomes editorials/comments studies from the same author(s) ip: ischemic priapism; nip: non ischemic priapism; sp: stuttering priapism. archivio italiano di urologia e andrologia 2022; 94, 2 m. moussa, m. abou chakra, a. papatsoris 240 7.25) (24). a penile doppler study is the key radiological tool in the assessment of a patient with priapism. in the ischemic subgroup, cavernosal blood flow typically will be absent, with a high-resistance, low-velocity trace. the diastolic flow will be low or absent. in nip, the doppler study demonstrates normal or elevated cavernosal artery velocities with a high diastolic flow (25). in all patients with priapism, blood count, coagulation tests, sickle cell screen, and hemoglobin electrophoresis with reticulocyte counts should be performed (26). men with sp had a unique baseline doppler ultrasound waveform, with a low peripheral resistance waveform and an elevated, variable cavernosal artery velocity. as proposed by patel et al., this may be the sonographic manifestation of a reduced, fluctuating smooth muscle tone (27). there are two main indications for mri in priapism. in ip, the degree of corporal infarction may influence the decision to intervene. in nip, a fistula can be suspected in the dynamic post-contrast images (28). arteriography may be utilized to precisely localized arterial fistulae in nip; typically this is only undertaken in the context of attempted treatment with super-selective embolization of the affected vessel (29). management of ischemic priapism a duration-directed therapy for ip is crucial. management of ip should progress in a stepwise fashion to achieve resolution as urgent as possible. when the priapism episodes are lasting more than 24 to 36 hours, patients are less likely to respond to corporal blood aspiration and instillation of a-adrenergic agonists because of the presence of irreversible smooth muscle damage. if ip is reversed within 24 hours, there is usually a recovery of erectile function in approximately 50% of patients (30). if based on history, the duration of erection is between 1-2 hours, hypoxic damage to the muscle has been occurred leading to poor muscle response to aadrenergic agonists. previous studies have concluded that priapism episodes of greater than 24 h were associated with a 90% rate of erectile dysfunction (31). cavernous smooth muscle will not respond to alpha-adrenergic agonists if the episodes last more than 48h because of impaired intracavernous circulation and tissue swelling. t-shunt or t-shunt with tunneling should be performed first because doing aspiration and irrigation could delay the therapy (32). a duration-directed therapy for ip is crucial. the treatment algorithm of ip is summarized in figure 1. non surgical options • corporal aspiration the first step in the management of ip is doing corporal aspiration with or without corporal irrigation. this should be performed with a 18 or 19 gauge needle placed at the base of the penis in the 3 o'clock and/or 9 o'clock position. saline solution 0.9% is used for irrigation. an important trick is to continue aspiration till oxygenated blood appeared (33). corporal aspiration and irrigation with 10 degrees c saline for patients with prolonged penile erection were tested. the complete detumescence rate is improved after the cold saline usage (34). an easily constructed priapism task trainer was developed and tested. it is was found that is realistic and useful for resident education. the use of the model in a simulation session can improve resident comfort in performing corpus cavernosa aspiration and phenylephrine injection (35). • intracavernosal injections of pharmacological agents phenylephrine is considered the drug of choice for intracavernosal injection due to its high selectivity for the alpha1-adrenergic receptor, without concomitant beta-mediated inotropic and chronotropic cardiac effects. phenylephrine is injected after adequate dilution in normal saline at a concentration of 100-500 μg/ml. usually, 200 μg is given every three to five minutes directly into the corpora. the maximum dosage is 1 mg within one hour. it is recommended that blood pressure and pulse are monitored every 15 minutes for an hour after phenylephrine injection to monitor any serious cardiovascular side effects (36). according to some studies, patients with ip that fail to respond to conventional doses of an alpha-agonist cannot benefit from continual or high-dose phenylephrine injection, as the cavernosal smooth muscle is damaged and cannot contract (37). wen et al. assessed the efficacy of highdose phenylephrine in treating patients with acute ip. injection of high-dose phenylephrine (1.000 mg q 5 minutes) was given for 17 consecutive cases of iatrogenic ip that occurred after vascular assessment. intracavernosal therapy with high-dose phenylephrine was effective in all cases. phenylephrine at doses higher than previously figure 1. algorithm used for the management of ischemic priapism. 241archivio italiano di urologia e andrologia 2022; 94, 2 an update on the management algorithms of priapism during the last decade reported may be necessary to overcome the effect of acidosis on ligand dissociation from adrenergic receptors (38). sympathomimetic drugs include epinephrine, ephedrine, norepinephrine, and metaraminol. there are no published data that compare the efficacy of these drugs. the summary data developed by the expert panel showed that for all patients with ip, the resolution occurred in 81% of cases treated with epinephrine, 70% with metaraminol, 43% with norepinephrine, and 65% with phenylephrine (39). other options for pharmacologic agents include methylene blue (mb). intracavernosal injection of adrenergic agents can rarely cause systemic toxicity. in rare cases, intracavernosal phenylephrine was associated with subarachnoid hemorrhage and intracavernosal epinephrine injection resulted in severe hypertension and angina pectoris (40). intracavernosal adrenalin was used for patients with ip due to intracavernosal vasoactive agent use. a 2 ml adrenalin (1/100 000) was injected in each cavernosal body. in the patients who did not respond to the first injection, repeated adrenalin injections were performed at 20 min intervals, up to 5 times. intracavernosal adrenalin injection alone had shown to be an effective therapy for the treatment of ip with a short duration of erection (41). etilefrine is an a1-selective agonist that has been used by intracavernous injection for the management of acute priapic episodes showing fewer cardiovascular effects than other drugs (42). mb, a guanylate cyclase inhibitor, is considered a potent inhibitor of endothelial-mediated cavernous relaxation. five ml of mb were injected within the corpora cavernosa and left for 5 minutes. mb is a safe and highly effective treatment agent for short-term pharmacologically induced priapism (43). intracorporal injection of mb is free of complications and as effective as a sympathomimetics treatment for priapism (44). • oral agents terbutaline, a beta-agonist, can be used in the management of priapism. a placebocontrolled study was implemented to study the efficacy of oral medical therapy in the treatment of priapism. a total of 75 patients with pharmacologically induced (prostaglandin e1) prolonged erections were randomized to receive terbutaline, pseudoephedrine, or placebo. detumescence occurred in 36 percent, 28 percent, and 12 percent, respectively. terbutaline was significantly better than placebo (p < 0.05) in achieving detumescence (45). in another study, terbutaline was used in a prolonged erection. the dosage was 5 mg and its effect was observed for 15 min. an additional dosage of 5 mg was given if detumescence did not occur after 15 min and 30 min. results showed that oral terbutaline can be used to treat pharmacologically induced prolonged erection. terbutaline is given cautiously in patients with coronary artery disease, pulmonary edema, and hypokalemia (46). midodrine administered orally is a simple and efficient treatment for the priapism induced by intracavernous injection of prostaglandin e1 in spinal cord injured patients (47). criteria to move to 2nd line therapy for ischemic priapism surgery for ip should be considered only when conservative management options fail. however, there is no experimental evidence detailing the amount of time allowed for first-line treatment before moving on to second-line therapy (36). in the early stages of priapism (< 24-36 hours), conservative measures and aspiration, with or without intracorporeal instillation of a-adrenergic agonists, are usually successful. the shunt surgery is less effective if the duration of priapism is > 48 hours (48). surgical intervention • surgical shunts shunt surgery for priapism diverts blood from the corpus cavernosum into another area such as the corpus spongiosum (glans or urethra) or the venous system (saphenous vein). both the eau and aua guidelines recommend using firstly distal shunts and then proximal shunts in cases where aspiration and instillation of pharmacological agents failed (49). surgical shunts are divided into four anatomical subcategories: percutaneous distal, open distal, open proximal (corporospongiosal) shunts, and vein anastomosis/shunts (50). their types are summarized in figure 2. winter shunt consists of the insertion of a large-bore needle from the glans to the distal side of the corpus cavernosum. the ebbehoj procedure consists of creating a shunt from the glans to the distal corpora using a small incision with the number 10 scalpel (30). t shunt involves passing a number 10 blade vertically through the glans into the corporal bodies bilaterally, rotating the figure 2. surgical shunts used for ischemic priapism. archivio italiano di urologia e andrologia 2022; 94, 2 m. moussa, m. abou chakra, a. papatsoris 242 blade laterally 90° (to avoid urethral injury), and then removing (4). in ip of > 3 days duration and/or when the penis is quite firm after repeated ‘milking’, bilateral tshunts followed by intracavernous tunneling using a straight urethral sound or dilator are indicated. to create tunneling of the corpora cavernosa, a straight 20-24 f straight urethral sound or dilator is inserted through each glans incision and advanced to the penile crura (51). although a t-shaped shunt operation has the advantages of simple operation, and fewer complications, it is not used in case of tumor-induced ip (52). an open distal shunt may be performed if the previous shunt failed to achieve detumescence. the al-ghorab shunt involves a transversal incision that was made on the penile glans, 1 cm distal of the coronal sulcus. two 5-mm circular cone segments of the tunica albuginea create a corporoglandular shunt (53). this shunt procedure can incise the dorsal nerve of the penis and thereby denervate the glans penis. a novel modification to the al-ghorab shunt in which incisions are made on the ventral aspect of the glans in an effort to prevent destruction and preserve the sensations of the glans penis (54). burnett and pierorazio described the corporal "snake" procedure as a modification of the al-ghorab shunt (55). the modified al-ghorab corporoglanular shunt using the burnett snake maneuver is successful in resolving ip, particularly in cases refractory to first-line therapy (56). a shunt cuts a new wound through the collagen-rich tunica albuginea. to prevent the collagen-activated platelets and fibrin phenomena begin to form a clot within minutes to seal off the shun, a perioperative anticoagulant should always be administered in this type of surgery (57). when distal shunts failed, other treatment options included proceeding to open proximal shunts and venous shunts, namely the quackels (unilateral corporospongiosal) or sacher (bilaterally staggered corporospongiosal) shunts (4). the creation of a venous shunt requires microsurgical skills. saphenous vein shunt (greyhack), and dorsal vein graft (barry) has been often used (32). • penile prosthesis more than 90% of patients with priapism lasting > 24 h complain of subsequent erectile dysfunction. the choice of an early penile prosthesis insertion has many advantages. it allows the recovery of sexual function, it may prevent penile shortening, and it is easier to implant a penile prosthesis in the acute setting, with fewer complications (58). early penile prosthesis insertion for acute ip is simple and successful even though distal cylinder can protrude through a defective corpora due to previous shunt surgery. nonabsorbable sling suture of the cylinder to the tunica albuginea is an effective, simple, and safe treatment for this complication (59). immediate insertion of a penile prosthesis for acute refractory ip can treat the acute episode and the erectile dysfunction that will occur with the preservation of penile length (60). no rct assess the use of penile prosthesis in ip. the best type of prosthesis and the timing of its placement is not determined yet. an increased risk of prosthetic infection occurred if a penile prosthesis procedure is performed during the acute phase of priapism. delayed procedure could have technical challenges due to corporal fibrosis (33). the implantation of penile prosthesis in chronic priapism is technically much more challenging and often requires the use of downsized shorter cylinders (61). palmisano et al. used a soft penile prosthesis (spp) for patients with refractory ip in the acute phase. they found that spp insertion can lead to immediate pain relief, preservation of sexual function, and penile size, with a higher surgery reproducibility in an emergency situation (62). the eau recommends that penile prosthesis (either malleable or a three-piece inflatable prosthesis) at the time of presentation could be taken into consideration if ischemia has been presented for more than 36 hours (mainly in sickle cell disease patients), aspiration and sympathomimetic intracavernous injections have failed and distal and proximal shunting have also failed (36). management of non-ischemic priapism nip is not an emergency and will often resolve without treatment. acute conservative treatment, such as ice and site-specific compression to the injury, may be used. however, there are no data that can demonstrate the benefit of those conservative measures (39). super-selective transcatheter embolization of the proximal artery supplying arterial-lacunar fistula should be the present treatment of choice in these cases of high-flow priapism refractory to conservative treatment. autologous clots and gelatine sponge have been used as the embolic agent. more recently, platinum microcoils have been proposed to achieve more precise and selective embolization (63). microcoils are permanent occlusive agents. hence, there are theoretically increased risks of permanent vascular occlusion and subsequent erectile dysfunction with their use (64). temporary materials are initially preferred in most cases of nip. however, cases with arterial embolism using absorbable materials often have a recurrence of priapism, with the recurrence rate reported to be 30% to 40% (24). super-selective transcatheter embolization and transient occlusion of the fistula with an autologous blood clot is an effective therapy for the treatment of nip. numan et al. reviewed their experience with super-selective transcatheter embolization in the treatment of nip. in three (27.2%) of 11 cases, a second embolization was required due to recurrence of priapism. in all patients, erectile function was restored within 6 weeks of the procedure (65). kim et al. reported the effectiveness and safety of super-selective transcatheter embolization in the treatment of nip at nine university hospitals. 27 patients were included in the study. in 24 of 27 patients (89%), a single embolization was sufficient for the complete resolution of priapism. repeat embolization was required in two patients (7%), and in the remaining patient (4%), shunt surgery was performed after embolization (66). using angioembolisation to treat nip, reduced sexual function is the primary adverse effect of interest, with small sample observational studies reporting 19-20% had reduced erection quality after the procedure. preliminary estimates of recurrence rates are between 30 and 40% (67). the type of vessels that are involved in refilling the fistula after embolization is of concern for the outcome of the 243archivio italiano di urologia e andrologia 2022; 94, 2 an update on the management algorithms of priapism during the last decade patients. the fistulas supplied only by cavernosal-spongiosal communications closed spontaneously within 1 month. watchful waiting should be preferred to repeated embolization to avoid the risk of unnecessary procedures (68). color doppler ultrasound allows the confirmation of successful embolization by demonstrating disappearance or size reduction of the fistula (69). surgical treatment consists of selective ligation of the fistula through a transcorporal approach under the guidance of color duplex ultrasound. although surgery has been successful in treating arterial priapism, it is technically challenging and may pose significant risks, mainly erectile dysfunction due to accidental ligation of the cavernous artery instead of the fistula (36). two surgical approaches are used for nip, one extracorporal, and the other transcorporal. despite that transcorporal dissection is a risky procedure, it is appropriate for arterial priapism of prolonged duration, especially if a well-formed vascular pseudocapsule is identified (70). androgen blockade (ab) to suppress nocturnal erections is an alternative treatment for nip. mwamukonda et al. reported the outcomes of 7 patients with nip that were treated with ab. priapism resulted from trauma in three patients and a persistent high-flow state after shunt procedures in four. therapy consisted primarily of 7.5 mg intramuscular monthly leuprolide injections, although bicalutamide and ketoconazole were also utilized as adjunct treatments. therapy duration ranged from 2 months to 6 months. one patient discontinued daily ketoconazole after 1 week because of severe hot flashes. the remaining six patients reported complete resolution of nip (71). the management algorithm of nip is summarized in figure 3. management of stuttering priapism sp is a variant of the ischemic type that is characterized by repetitive, transient, painful, self-limiting episodes of priapism. it is associated with various hematological disorders, including sickle cell disease and pharmacological treatments (72). typically, the priapic events in sp are self-limited, resolving in under 3 h, some lasting for only minutes before spontaneous resolution. it has been reported that 77% of the transitory attacks are sleep-related, 17% are associated with sexual activity (11). if these episodes are not treated, it may evolve into a classic ip and eventually lead to irreversible corporal fibrosis with permanent erectile dysfunction. the goal of the management of a patient with sp is the prevention of future episodes, while the management of each episode should follow the specific treatment recommendations for acute ip (73). hormonal therapy the use of hormonal therapy for the prevention of sp has been a successful medical management option for some patients. caution is strongly advised in using hormonal treatments for prepubertal or adolescent men who have not reached sexual maturation and or in those desiring children, as side effects often result in castrate levels of testosterone creating a contraceptive effect, interfere with closure of the epiphyseal plates and have significant impairments on sexual function (42). hormonal therapy using gonadotropin-releasing hormone analogues (gnrh) has been successful in treating episodes of priapism refractory to classic drugs. it is associated with significant adverse effects, in particular the loss of libido and erectile dysfunction (74). patient with sickle cell disease and recurrent priapism was treated successfully for more than a year with monthly gnrh analogue therapy after failure of standard medical management (75). the use of low-dose estrogen shows is considered an effective and relatively rapid treatment option for some cases of idiopathic sp (76). baker et al. reviewed their 12-year experience with the 5-a reductase inhibitor dutasteride as a potential long-term treatment option for sp. patients were started on a dose of 0.5 mg daily and tapered to a more infrequent dosing schedule, ranging from 0.5 mg every other day to once weekly: 85% of men treated with dutasteride had some degree of improvement, 38% had complete resolution of their symptoms. side effects were minimal and included gynecomastia (8%), decreased libido (8%), and fatigue (8%) (77). rachidfilho et al. demonstrating that the use of finasteride could decrease and control the number of priapism recurrences in patients with sickle cell anemia (78). oral ketoconazole reversibly inhibits testosterone production and has been used to decrease postoperative erections (79). abern et al. used ketoconazole and prednisone with dosing titrated according to figure 3. algorithm used for the management of non-ischemic priapism. archivio italiano di urologia e andrologia 2022; 94, 2 m. moussa, m. abou chakra, a. papatsoris 244 serum testosterone levels to prevent recurrent priapism episodes. eight patients with recurrent ip were treated with ketoconazole and prednisone. patients were seen monthly and therapy was withdrawn after 6 months. one patient had 2 recurrent ip episodes while on ketoconazole and prednisone treatment. another patient had an increase in testosterone from 361 to 432 ng/dl after initiation of therapy, and 3 recurrent ip episodes requiring emergency corporal irrigation. after dose titration testosterone was 184 ng/dl and the patient had no subsequent episodes (80). hoeh et al. reported their experience to prevent recurrent ip using ketoconazole, 16 of 17 patients (94%) had complete resolution of priapism while on ketoconazole. after 6 months, it was recommended to stop the medication (81). the duration of hormonal treatment for effective suppression of recurrent priapic events is still unknown. of the hormonal agents suggested for preventing priapism, gnrh agonists, and anti-androgens appear to be the most efficacious and safe (37). non hormonal therapies baclofen is a centrally acting gamma-amino-butyric acid b (gabab) agonist used to treat spasticity. as baclofen inhibits penile reflex responses. sexual side effects of intrathecal baclofen including the decrease or loss of penile erections (82). oral baclofen, starting with a daily dose of 10 mg that was increased to 30 mg can achieve control of priapism (83). oral baclofen 10 mg, three times a day can be used to treat prolonged erections. after 24 h of therapy, the erection of penis occurred less frequently and each episode lasted for a shorter duration (84). digoxin is a known inhibitor of sodium/potassium adenosine triphosphatase (sodium pump), a plasma membrane enzyme that has a role in the regulation of smooth muscle tone. gupta et al. investigated the effects of digoxin on human corpus cavernosum smooth muscle contractility and overall erectile function. in vitro digoxin caused inhibition of contraction of corporal smooth muscle. in vivo digoxin diminished the penile rigidity during visual sexual stimulation and nocturnal penile tumescence testing compared to placebo without influencing libido or serum testosterone, estrogen, or luteinizing hormone levels (85). oral gabapentin was used to treat refractory idiopathic priapism in three patients. they responded to treatment within 48 h. two men continue not to experience prolonged erections while treated with lower doses of gabapentin for 16 and 24 months, respectively. the third, after successful treatment for 6 months, stopped gabapentin and priapism recurred (86). the rationale for the treatment of priapism with this medication was based on the reported sexual dysfunction possibly caused by gabapentin. although the molecular targets of gabapentin remain unknown, the inhibition of ca2+ efflux from muscle cells in the corpora, with consequent inhibition of smooth muscle relaxation, may explain the effectiveness of gabapentin in the management of refractory priapism (87). also, gabapentin can reduce both testosterone and fsh levels (88). hydroxyurea (hu) has been reported to decrease the number of stuttering priapism episodes in patients who retained erectile function. the beneficial effects may stem from its role as an no donor, as hu has been shown to interact with hemoglobin to form no (89). in a study hu has been used for preventing priapism in patients with sp, hu was introduced at the initial dose of 10 mg/kg, and as the hu dosage increased, the number or length of priapism episodes decreased. the data suggests that hu may prevent priapism attacks in scd (90). phosphodiesterase type 5 (pde5) inhibitors the molecular mechanism of priapism is not clear. champion et al. suggested aberrant downstream signaling of the no pathway based on the finding that mice lacking the gene for endothelial nitric oxide synthase tend to have more a priapic activity (91). dysregulation of the no/cgmp signaling pathway in the penis is thought to be the primary molecular mechanism of recurrent ip. studies identified transcriptional and translational down-regulation of pde5, owing to basally decreased cgmp (92). in a study done by burnett et al. to test the use of pde5 inhibitors to treat recurrent priapism, 13 patients with scd reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily for 8 weeks. priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per-protocol analyses (p = 1.0) (93). in another study, pde5 inhibitors were used as a longterm therapeutic regimen in seven men with recurrent priapism. six men had idiopathic priapism recurrences and one man had sickle cell disease-associated priapism recurrences. tadalafil 5 mg was administered daily. daily long-term oral pde5 inhibitor therapy alleviated priapism recurrences in all patients. five (71.4%) had no episodes of priapism and two (28.6%) referred decrease in their episodes of priapism (94). pde5 inhibitors should be first used under conditions of full detumescence and their efficacy is obtained after 2-4 weeks of use (11). self-injection of intracavernosal sympathomimetics the aua recommends that intracavernosal self-injection of phenylephrine should be considered in patients who either fail or reject the systemic treatment of sp (39). conclusions priapism must be determined as ischemic or nonischemic because the treatments and the 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acad sci u s a. 2005; 102:16611666. 92. anele ua, morrison bf, burnett al. molecular pathophysiology of priapism: emerging targets. curr drug targets. 2015; 16:474483. 93. burnett al, bivalacqua tj, champion hc, musicki b. long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. urology. 2006; 67:1043-1048. 94. nardozza a junior, cabrini mr. daily use of phosphodiesterase type 5 inhibitors as prevention for recurrent priapism. rev assoc med bras (1992). 2017; 63:689-692. correspondence mohamad moussa mohamadamoussa@hotmail.com mohamad abou chakra mohamedabouchakra@hotmail.com department of urology, al zahraa hospital, university medical center, lebanese university, beirut, lebanon athanasios papatsoris agpapatsoris@yahoo.gr athanasios dellis aedellis@gmail.com 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece michael peyromaure michael.peyromaure@aphp.fr nicolas barry delongchamps nicolas.barry-delongchamps@aphp.fr hugo bailly h.bailly.md@gmail.com sabine roux sabine.roux@aphp.fr igor duquesne igor.duquesne@aphp.fr department of urology, cochin hospital, assistance publique-hôpitaux de paris, paris descartes university, paris, france ahmad abou yassine ahmad.a.y.8@gmail.com internal medicine, staten island university hospital, staten island, ny, united states archivio italiano di urologia e andrologia 2020; 92, 158 case report a surgical approach to squamous cell carcinoma of penis that also resolved the psychological dysfunction of the patient napoleon moulavasilis 1, konstantina yiannopoulou 2, marios frangoulis 3, ioannis katafigiotis 1, georgios liapis 4, aikaterini anastasiou 5, ioannis anastasiou 1 1 1st department of urology, national and kapodistrian university of athens, laiko hospital, athens, greece; 2 department of neurology, henry dunant hospital center, athens, greece; 3 plastic surgeon, academic fellowship, national and kapodistrian university of athens, laiko hospital, athens, greece; 4 department of pathology, medical school of athens, national and kapodistrian university of athens, greece; 5 medical school of athens, national and kapodistrian university of athens, greece. in this case study, we present an unusual case with squamous cell carcinoma surrounding the penis involving foreskin and glans of penis. in addition, multiple satellite nodules were noted in the pubis. a 57-year-old circumcised heterosexual male patient presented with a penile lesion existing for 10 years. at the same time, he was referred to an outpatient memory clinic because of persistent subjective memory complaints associated with depression and anxiety. the patient was operated under general anaesthesia. the lesion was resected circumferentially with macroscopic clearance, resulting in complete degloving of the penile shaft. neurovascular bundles were preserved. histopathological analysis of the lesion revealed an invasive and poorly differentiated squamous cell carcinoma, and the surgical margins were free from tumour. the patient was followed for 18 months. he did not have voiding difficulty. pelvic tomographic and physical examination findings did not reveal any episode of recurrence or metastasis. treatment of carcinoma resulted in a simultaneous full recovery of his memory decline and he remained free of depression and anxiety symptoms over time. key words: squamous cell carcinoma; penis; surgical technique. submitted 10 august 2019; accepted 21 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.58 introduction penile carcinoma is an uncommon tumor which is devastating for the patient and therapeutically challenging for the urologist. invasive penile carcinoma accounts for 0.4-0.6% of malignant neoplasms among men (1). carcinoma of the penis usually begins with a small lesion that gradually extends to involve the entire glans, shaft and corpora. patients with cancer of the penis, more than patients with other types of cancer, seem to delay seeking medical attention. explanations include embarrassment, fear, guilt and ignorance (2). the oncologic gold standard for definitive treatment of the penile cancer is surgical amputation of the tumor (3). conservative surgery may be safely performed in well selected patients in order to maintain penile function and length. additionally, penile cancer sufferers can exhibit significant preoperative and postoperative psychological dysfunction (4). however, it appears that by using established reconstructive surgical techniques we are able to achieve significant improvements of anxiety, depression (5) and subjective memory complaints. case report a 57 years old heterosexual male patient presented with a penile lesion existing for 10 years. he has never asked for medical help. as the lesions became aggressive and eventually surrounded the penis, he referred to our department. he suffered from the huge mass, which prevented him from having sex and caused significant voiding diffculty. on physical examination, a tumoural mass resembling a cauliflower measuring nearly 8 x 4 cm encircling the entire penile shaft and satellite nodules in pubis were detected (figure 1). clinically and on pelvic computed-tomography, no inguinal lymphadenopathy was noted. at the same time, he was obviously anxious and he also confessed that he suffered from persistent memory decline and depressive symptoms. consequently, he was referred to an outpatient memory clinic for complete preoperative neuropsychological evaluation. neurological examination and magnetic resonance imaging (mri) of the brain were perfectly normal. nevertheless, the neuropsychological questionnaires revealed a serious depressive and anxiety disorder. he scored 17/21 and 15/21 for anxiety and depression respectively in the hospital anxiety and depression scale (hads) (6) and 11/15 the geriatric depression scale (gds) (7). on the contrary, questionnaires regarding memory difficulties and executive functions (7) were perfectly completed. the patient was operated under general anaesthesia. a complete resection of the glands of penis was performed and the lesion was resected circumferentially with macroscopic clearance, resulting in complete degloving of the penile shaft. neurovascular bundles were detected during the surgical procedure and preserved. the distal urethra sectioned by the circumcision was reconstructed, and the edges were everted, creating a vertical uremoulavasilis_stesura seveso 01/04/20 19:00 pagina 58 59archivio italiano di urologia e andrologia 2020; 92, 1 surgery of squamous cell carcinoma of penis throstomy. the patient’s penis was reconstructed with partial thickness skin graft. a dermotome was employed to achieve a graft, which was placed for immediate reconstruction after the oncologic resection (figure 2). a foley catheter was placed for 7 days. the nodules in pubis were resected with macroscopic clearance as well. the large skin defect that was created as a consequence of this resection forced us to translocate the trunk of the penis in a more convenient location that could be covered by the scrotum (figure 3). according to the pathology report, in gross inspection a tumor of 7.5 x 4 cm in major dimension was noted involving the foreskin and glans of penis. in addition, multiple satellite nodules were noted in pubis. histologically, the tumor was corresponded to a squamous cell carcinoma, exhibiting a solid pattern and minimal keratin production. in a small relatively area, tumor showed “basaloid features” with a solid pattern and peripheral palisading of nuclei, while tumor cells had small size and dark nuclei. chromogranin and synaptophysin immunohistochemical stains were negative, so there was no neuroendocrine differentiation (figures 4, 5). the patient’s post-operative healing was uneventful, and he was discharged after nine days. his hads and gds scores were already improved before discharge and a neuropsychologic reevaluation was scheduled six months later. reevaluation scores in both questionnaires were found within the normal limits, while his subjective memory complaints were totally resolved. after 18 months of follow-up, our patient had not presented any voiding difficulty. pelvic computed tomography and physical examination findings did not reveal any episode of recurrence or metastasis (figure 6). discussion penile amputation remains the standard therapy for patients with deeply invasive or high grade cancers. partial penectomy should be considered in well selected patients exhibiting features for organ preservation strategies. given the fact that the priority is always the cancer treatment, it seems possible that by using established reconstructive surgical techniques, erectile and voiding function, as well as psychological wellbeing of the patients can be preserved (4, 5). furthermore, it has been already demonstrated that penile cancer sufferers can exhibit significant psychological dysfunction. in our patient, subjective memory complaints were additionally present. subjective memory complaints are associated either with sub-syndromal depression and anxiety in healthy cognitively normal adults or with mild cognitive decline (7). therefore, there is a need to identify and assess adequate tools to measure neuropsychological comorbidity in this group of patients (4). conclusions the treatment of the penile cancer has changed dramatically over the recent years. organ-sparing treatments should be the first choice in penile squamous cell carcinoma, whenever this technique is adequately safe and efficient in oncological terms. choosing the right techfigure 1. penile lesion. figure 2. penile graft. figure 3. surgical technique. figure 4. invasive squamous cell carcinoma (h&ex100). figure 6. 18 months later. figure 5. poorly differentiated squamous cell carcinoma with some “basaloid” features and hemorrhage (h&ex100). moulavasilis_stesura seveso 01/04/20 19:00 pagina 59 archivio italiano di urologia e andrologia 2020; 92, 1 n. moulavasilis, k. yiannopoulou, m. frangoulis, i. katafigiotis, g. liapis, a. anastasiou, i. anastasiou 60 nique for the right patient is of paramount importance. surgeon’s experience accompanied with careful selection of patients suffering from this devastating disease but suitable for the safe organ-sparing surgical procedure, allows patients’ access to preserving quality of life treatment options. compliance with ethical standards conflict of interest: authors declare that they have no conflict of interest. informed consent: written informed consent was obtained from the patient for the publication of this case repost/any accompanying images. references 1. vatanasapt v, martin n, sriplung h, chindavijak k, et al. cancer incidence in thailand, 1988-1991. cancer epidemiol biomarkers prev. 1995; 4:475-83. pubmed pmid: 7549802. 2. lynch ht, krush aj. delay factors in detection of cancer of the penis. nebr state med j. 1969; 54:360-7. pubmed pmid: 4238912. 3: horenblas s, van tinteren h, delemarre jf, et al. squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. j urol. 1991; 146:1279-83. pubmed pmid: 1942279. 4. maddineni sb, lau mm, sangar vk. identifying the needs of penile cancer sufferers: a systematic review of the quality of life, psychosexual and psychosocial literature in penile cancer. bmc urol. 2009; 9:8. doi: 10.1186/1471-2490-9-8. 5. rybak j, larsen s, yu m, levine la. single center outcomes after reconstructive surgical correction of adult acquired buried penis: measurements of erectile function, depression, and quality of life. j sex med. 2014; 11:1086-1091. doi: 10.1111/jsm.12417. 6. hartung tj, friedrich m, johansen c, et al. the hospital anxiety and depression scale (hads) and the 9-item patient health questionnaire (phq-9) as screening instruments for depression in patients with cancer. cancer. 2017; 123:4236-4243. doi: 10.1002/cncr.30846. 7. balash y, mordechovich m, shabtai h, et al. subjective memory complaints in elders: depression, anxiety, or cognitive decline? acta neurol scand. 2013; 127:344-50. doi: 10.1111/ane.12038. correspondence moulavasilis napoleon, md napomoul@hotmail.com katafigiotis ioannis, md anastasiou ioannis, md 1st department of urology, national and kapodistrian university of athens, laiko hospital agiou thoma str, athens, 115 27 (greece) yiannopoulou konstantina, md department of neurology, henry dunant hospital center, athens (greece) frangoulis marios, md plastic surgeon, academic fellowship, national and kapodistrian university of athens, laiko hospital, athens (greece) liapis georgios, md department of pathology, medical school of athens, national and kapodistrian university of athens (greece) anastasiou aikaterini, md medical school of athens, national and kapodistrian university of athens (greece) moulavasilis_stesura seveso 01/04/20 19:00 pagina 60 stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11868 1 original paper tion time, expressed in minutes (g/m) (2). efficiency is defined as “the ability to produce something with a minimum amount of effort” (in this context, the best outcome for the patient vs. the minimum operating time) (3). to calculate the resection rate as an efficiency parameter, the surgeon must weight all the resected tissue chips after the operation, or wait for the histopathological findings, when usually the weight of the tissue is recorded (typically, many days later); after that, it is then necessary to calculate the ratio between the amount of resected tissue and the duration of the operation. at present there is not unanimous consensus about the starting point in time of a turp: from the introduction of the cutting device in the urethra or from the first cut chip, and this could lead to variable results in the resection-rate recorded in different centres. materials and methods we enrolled 123 patients with bpe/luts who came to our observation from june 2016 to december 2019. patients were evaluated preoperatively with medical history, symptom questionnaires (ipss and bother score), digital rectal exploration, psa assay, blood tests, serum electrolytes, complete urodynamic examination and transrectal, renal, bladder and prostate ultrasound. all patients underwent turp. patients with bladder stones and/or diverticula, stenosis of the urethra and patients with alterations in coagulation or platelet aggregation were excluded from our study. all patients taking antiplatelet or anticoagulant drugs discontinued therapy according to the guidelines. the procedures were performed under spinal anesthesia, in the lithotomy position, by 5 different operators. turp was performed, in all patients, using a bipolar type resectoscope with a 27 ch diameter liner, continuous flow, and a 'u' shaped cutting loop. the plasmakinetic device had a maximum power of 200 watts, a radiofrequency range of 320 to 450 khz, and a voltage range of 350 to 450 volts. once connected, the generator was programmed for a power of 160 w for shear and 80 w for hemostasis. the bipolar resectoscope used were from two different manufacturers. the main difference between the two types of resectoscopes, as far as the study is concerned, is the different caliber of the irrigation channels of the operating sheaths, which, however, although probably providing different flow rates, do not affect the final recording of the amount of fluid used during the interventions (figure 1). the irriintroduction: transurethral resection of the prostate (turp) is the gold-standard for the treatment of benign prostate enlargement (bpe) associated with lower urinary tract symptoms (luts), after failure of conservative therapy. at present, only resection-rate (grams of prostate resected over time) is regarded as an efficiency parameter to evaluate the skill of the operator and to assess the outcome of the procedure. materials and methods: five surgeons performed turp using a gyrus-type bipolar system in 123 patients with bpe/luts who came to our observation from june 2016 to december 2019. the amount of irrigation fluid used during the procedure was registered and correlated to the operating time, resection-rate, prostate adenoma weight, post-operative bladder irrigation time, intraoperative bleeding and days of catheterization. results: we found an inverse correlation between the amount of irrigation fluid used during turp and the resection-rate recorded for all operators, according to spearman's correlation (r = -0.78, p = 0.002); a direct correlation was also found between the amount of irrigation fluid and the adenoma weight. finally, we also found a direct correlation with intraoperative bleeding and the duration and amount of bladder irrigation during and after turp. conclusions: the amount of irrigation fluid used is proposed as a reliable parameter to estimate the efficiency of the endoscopic procedure as well to assess the skill of the operator and shortterm results. the observed data encourage the possibility of applying this new efficiency indicator to all endoscopic maneuvers. key words: prostate; benign prostatic hyperplasia; obstruction. submitted 23 september 2023; accepted 13 october 2023 introduction transurethral resection of the prostate (turp) is the goldstandard for the treatment of benign prostate enlargement (bpe) associated with lower urinary tract symptoms luts after failure of conservative therapy (1). the choice for the most appropriate surgical therapy depends on the size of the prostate gland and the skills of the operator. the evolution of endoscopic surgical treatments has led to the introduction of bipolar plasma-kinetic energy for trans-urethral resection. in clinical practice, the only parameter used to evaluate the efficiency of a turp is the “resection-rate”, i.e., the ratio between the amount of prostatic tissue resected, expressed in grams, and the resecthe role of irrigation fluid in transurethral resection of the prostate outcomes and surgeon performance federico romantini, daniela biferi, guevar maselli, federico narcisi, maurizio ranieri, luca topazio mazzini hospital, department of urology, asl teramo, teramo, italy. doi: 10.4081/aiua.2023.11868 summary archivio italiano di urologia e andrologia 2023; 95(4):11868 f. romantini, d. biferi, g. maselli, f. narcisi, m. ranieri, l. topazio 2 gation fluid used was 0.9% nacl saline, in three-liter bags connected to a 6-mm-diameter outflow tube attached to the bipolar device. the solution was at room temperature (20°-22°) and placed at a height of 60 cm from the patient's pubic symphysis, at a continuous and constant washing rate. the drained washing fluid flowed into an aspirator (s.ho.w) equipped with a system that allows automatic digital measurement of drained fluid volumes. we measured the amount of irrigation fluid used, the amount of irrigation fluid in the aspirator at the end of the procedure, the surgical time (from insertion of the device into the urethra), and registered the operator. the amount of prostate tissue excised was weighed with a scale at the end of resection; a dufour 20ch catheter was placed in all patients, with continuous and constant irrigation with 9% nacl saline. once clear urine was obtained, bladder irrigation was stopped. in the postoperative period, we evaluated the difference in hemoglobin levels (preoperative vs postoperative), duration of bladder irrigation, and catheter dwell times. statistical analysis all collected data was evaluated as mean (m) ± standard deviation (sd). the correlation between the parameters was calculated using spearman's correlation coefficient. values of p < 0.05 were considered statistically significant. results the median age of the patients was 70.13 years (sd ± 8.74), and the means and relative standard deviations of the preoperative characteristics of the study population are shown in table 1. intraoperative variables such as operation time, volume of irrigation fluid used and resection rate are shown in table 2, with means and their standard deviations. figure 2 shows the inverse correlation between the amount of irrigation fluid used during turp and the resection rate recorded for all operators, according to spearman's correlation (r= -0.78, p = 0.002). figure 3 shows spearman correlation between the amount of irrigation fluid (in liters) and adenoma weight (in grams), stratified by operator. the results for the cumulative data is statistically significant (p = 0.005) (r = 0.61575). table 1. preoperative characteristics of the study population. patients characteristics mean + sd age 70.13 ± 8.74 ipss 17.63 ± 4.58 bs 4.63 ± 1.03 qmax (ml|/s) 7.66 ± 3.38 voided volume (ml) 231.67 ± 101.09 post-void residual volume (pvr) 98.03 ± 113.22 prostate adenoma (g) 38.96 ± 13.56 prostate volume (g) 52.20 ± 16.81 figure 1. details of the different irrigation system of the two bipolar endoscopic resectoscopes used. figure 2. inverse correlation between the amount of fluid used and resection-rate according to spearman's correlation; (r = 0.78, p = 0.002). figure 3. correlation between the amount of irrigation fluid and adenoma weight, stratified by operator. table 2. intraoperative variables recorded during turp. mean + sd operating time (minutes) 71.01 ± 31.52 irrigation fluid (litres) 16.63 ± 5.52 resection-rate (g/m) 0.548 ± 0.18 archivio italiano di urologia e andrologia 2023; 95(4):11868 3 measuring irrigation fluids used during turp figure 4 shows a direct, statistically significant correlation (p = 0.004) between the amount of irrigation fluid used and the duration of bladder irrigation after turp (r = 0.2498). a change in hemoglobin concentration was observed within 48 hours after surgery (p < 0.0001), which was statistically significant, although this was clinically irrelevant in most patients, with no signs or symptoms of severe anemia. the postoperative blood transfusion rate was 0.81%. a direct link was observed between change in hemoglobin concentration and resected tissue weight (p < 0.0001) as well as the amount of irrigation fluid used (figure 5). only one patient was given a blood transfusion on the third postoperative day for anemia. the mean preoperative hemoglobin was 12.4 g/dl and the mean postoperative hemoglobin was 11.5 g/dl. the mean hemoglobin loss was 0.9 g/dl. this result proved not to be clinically relevant. discussion the main purpose of this study was to propose monitoring the amount of irrigation fluid used during a turp procedure as a new parameter of resection efficiency. the efficacy and safety of turp are often discussed in current literature, but there is a lack of quantitatively relevant data on efficiency (4). in clinical practice, resection-rate is described as the only parameter that can evaluate the efficiency of a trans-urethral prostate resection and is often used to compare the skills of different operators or as a benchmark parameter when new techniques or instrument are to be tested. the average resection-rate value during bipolar turp reported in the literature is 0.65 (5). our experience shows an average of 0.55 ± 0.18. higher resection-rate values correspond to a more efficient resection, in terms of time and, most importantly, intraoperative bleeding. the cornerstone of all endoscopic procedures is vision, and an efficient and safe turp requires a clear, blood-free surgical field; the medium through which we look is water, or rather different irrigation fluids containing h2o. during turp, bleeding hampers the procedure and forces the surgeon to use more irrigation fluid, both because resection is slowed and because the operator will increase flow to allow better vision, having to drain more blood from the visual field (6). it is reported in the literature how this type of issue is particularly important during resections with a monopolar instrument, and is less pronounced during resections with a bipolar instrument (6). poorly controlled bleeding not only makes the procedure take longer, but also makes it less accurate, and ultimately, less efficient. our data show a direct correlation between the amount of irrigation fluid used and intraoperative bleeding, which can be quantified as grams of hemoglobin lost during the procedure (difference between preand post-operative values). the correlation was statistically significant. longer operative times are not only related to short-term complications, such as tur syndrome, clot retention, and the need for blood transfusions (7, 8); longer operative time has also been linked to longterm complications, particularly urethral strictures (9). we hypothesized that the amount of irrigation fluid used during bipolar turp could be a valid parameter for estimating the efficiency of resection and predicting the likelihood of shortand long-term complications. indeed, our data show a statistically significant inverse correlation between the resection rate and the amount of irrigation fluid; the correspondence was observed in all operators. a statistically significant direct correlation was observed between the amount of fluid used during surgery and the duration of postoperative bladder irrigation, which in turn is directly dependent on postoperative period hematuria. a smaller amount of irrigation fluid used during turp could be a direct indicator of the likelihood of less hematuria in the postoperative period and the possibility of using slow-flow bladder irrigation after surgery to control bleeding. an inverse correlation was found between irrigation fluid and duration of catheterization after turp; this could allow more accurate prediction of early patient mobilization and shorter hospital stay. follow-up at 40 days showed significant improvement in symptom scores and uroflowmetric parameters, regardless of resection efficiency estimated by resection rate and amount of irrigafigure 4. correlation between the amount of irrigation fluid used and the duration of bladder irrigation after turp, with r: 0.2498 and p = 0.004. figure 5. direct correlation between intraoperative blood loss (difference in pre and post operative hemoglobin concentration) and amount of irrigation fluid used. archivio italiano di urologia e andrologia 2023; 95(4):11868 f. romantini, d. biferi, g. maselli, f. narcisi, m. ranieri, l. topazio 4 tion fluid. aa midand long-term evaluation of patients at 6 and 12 months is needed to better understand the correlation between turp efficiency (expressed by resection rate and irrigation fluid used) and surgery outcomes expressed in ipss questionnaire score. conclusions the present study shows that less irrigation fluid used during transurethral prostatic resection correlates significantly with less intraand postoperative bleeding. thus, a lower amount of fluid used correlates with a better visual field during surgery, which translates into better operating conditions for the operator. postoperatively, this correlation is reflected in shorter catheterization time and hospital stay. the amount of irrigation fluid used is proposed as a reliable parameter for estimating the efficiency of the endoscopic procedure and the skill of the operator; its application may be particularly useful in the evaluation of physicians-in-training, measuring over time any improvement in the operational efficiency of surgeons in their professional training. monitoring and measurement of irrigation fluids could also be used as predictive parameters of the clinical situation in the immediate postoperative period. references 1. eau guidelines. edn. presented at the eau annual congress amsterdam 2022. isbn 978-94-92671-16-5. 2. cury j, coelho rf, bruschini h, srougi m. is the ability to perform transurethral resection of the prostate influenced by the surgeon’s previous experience? clinics. 2008; 63:315-20. 3. the oxford english dictionary, oxford university press, 2019. 4. skolarikos a, rassweiler j, de la rosette jj, et al. safety and efficacy of bipolar versus monopolar transurethral resection of the prostate in patients with large prostates or severe lower urinary tract symptoms: post hoc analysis of a european multicenter randomized controlled trial. j urol. 2016; 195:677-84. 5. kallstrom r, hjertberg h, kjolhede h, et al. use of a virtual reality,real-time, simulation model for the training of urologists in transurethral resection of the prostate. scand j urol nephrol. 2005; 39:313-20. 6. huang x, wang l, wang xh, et al. bipolar transurethral resection of the prostate causes deeper coagulation depth and less bleeding than monopolar transurethral prostatectomy. urology. 2012; 80:1116-1120. 7. mamoulakis c, ubbink dt, de la rosette jj. bipolar versus monopolar transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. eur urol. 2009; 56:798-809. 8. huang x, wang xh, wang hp, et al. comparison of the microvessel diameter of hyperplastic prostate and the coagulation depth achieved with monoand bipolar transurethral resection of the prostate. a pilot study on hemostatic capability. scand j urol nephrol. 2008; 42:265-268. 9. tan gh, shah sa, ali nm, et al. urethral strictures after bipolar transurethral resection of prostate may be linked to slow resection rate. investig clin urol. 2017; 58:186-191. correspondence romantini federico, md (corresponding author) federomantini@gmail.com biferi daniela, md daniela.biferi@aslteramo.it maselli guevar, md gue.maselli@gmail.com narcisi federico, md federico.narcisi@aslteramo.it ranieri maurizio, md maurizio.ranieri@aslteramo.it topazio luca, md luca.topazio@aslteramo.it mazzini hospital, department of urology, asl teramo; teramo, italy conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 215archivio italiano di urologia e andrologia 2020; 92, 3 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.215 management of complications in penile prosthesis reimplantation: a case report camilla capretti 1, antonio avolio 2, alberto florio 2, silvia giovannozzi 2, domenico de carolis 2 1 department of urology, "ospedali riuniti" university hospital and marche polythecnic university, ancona, italy; 2 department of urology, mazzoni hospital, ascoli piceno, italy. a 74-years-old patient, without comorbidity, underwent malleable penile prosthesis (mpp) implantation in 2007. in 2015, after a perineal trauma, he experienced stress urinary incontinence, medial extrusion of the left prosthetic cylinder and an urethrocavernous fistula. the cylinder was removed and an artificial urinary sphincter (aus) implanted, together with a three-component inflatable penile prosthesis (ipp). the left corpus cavernosum (cc) was significantly shorter than the right one due to fibrosis. after 8 months, partial lateral extrusion of the right prosthetic cylinder prompted a replacement with a shorter extensor. six months after, a new diastasis of the ruptured area occurred due to a further cc shortening. the extensor was removed and the cylinder shortened, with a dermal graft applied to the area. long-term patient satisfaction was high. key words: erectile dysfunction; penile prosthesis complications; reimplantation. submitted 2 march 2020; accepted 15 march 2020 summary introduction managing the complications of penile prosthesis reimplantation is one of the biggest challenges in urology. patients can develop corpus cavernosum (cc) scarring, with potential complications and penile shortening. in this study we present a patient with malleable penile prosthesis (mmp) who, after a perineal trauma, underwent inflatable penile prosthesis (ipp) implantation. case report we present the case of a 74-years-old patient with no comorbidities, who underwent radical prostatectomy in 2005. due to an erectile dysfunction not responding to less invasive methods, in 2007 a mpp (subrini) was implanted. in 2015, due to an accident, the patient had a perineal trauma with symphysis pubis diastasis, resulting in stress urinary incontinence and medial extrusion of the left prosthetic cylinder at the level of the navicular fossa. this was due to the thinning and erosion of the tunica albuginea and the creation of an urethrocavernous fistula. thus, the decision was taken to remove the cylinder and wait 6 months for a second surgery, to allow for scar tissue formation. the urethrography before the second surgery revealed a complete spontaneous healing of the fistula (figure 1). consequently, the patient underwent the implantation of an artificial urinary sphincter (aus) (advance) and a three-component ipp (ams 700-cx). during surgery, performed with penoscrotal approach, it occurred that the left cc was significantly shorter (18 cm) than the right one (22 cm), due to scarring and fibrosis. the cylinders were implanted, a pump positioned in the scrotum and a 65 ml reservoir inserted in the retro-pubic space. the prosthesis was activated intraoperatively. after 8 months, due to its partial lateral extrusion, the right prosthetic cylinder (which was 18 + 4 cm long) was extracted. the cc was now 19 cm long, compared to the previous 22 cm. the 4 cm-long extensor was substituted with a 1 cm-long one and the cylinder replaced. the prosthesis was activated intraoperatively, without pressure on the sutured area. after 6 months, a new diastasis of the previous rupture area occurred, with lateral extrusion of the cylinder due to a further cc shortening by 2 cm (17 cm compared to the previous 19 cm). the extensor 1 cm was removed and the cylinder shortened by 1.5 cm and re-positioned, with a total length gain of minus 2.5 cm. since the tunica albuginea was inadequate to cover parts of the cylinder, a graft of bovine dermal collagen (xenform) was applied with semi-continuous 2-0 absorbable monofilament (vicryl) sutures to reinforce the area (figure 2), restoring tunica albuginea continuity. the patient had an uneventful postoperative course with no complications. in 2019, a long-term, telephone-based follow-up showed a iief-5 score of 25 and no need for disposable incontinence products. discussion in this case report, an intense fibrotic reaction occurred after removing the mpp right cylinder, leading to the shortening of the cc. when a mpp is removed and an ipp implanted, a further cc shortening occurs after surgery. while a mpp would always be active, the ipp may not be sufficiently activated by the patient, thus prompting further cc tissue rearrangement. therefore, it is advisable to encourage patients to inflate their prosthesis daily. implementing downsized prosthesis cylinders could also be a possible solution. if patients are uncomfortable with penile shortening, the conversion to standard cylinders (1), is usually possible within 8-12 months. according 16capretti_stesura seveso 24/09/20 17:22 pagina 215 archivio italiano di urologia e andrologia 2020; 92, 3 c. capretti, a. avolio, a. florio, s. giovannozzi, d. de carolis 216 to literature, the combination of aus and ppi does not adversely affect perioperative complications or device survival in relation to the device placement (2). the use of grafts proved to be a safe option, resulting in no infections, rejections or discomfort for the patient. moreover, long-term patient satisfaction proved to be high. in literature, there is no statistically significant difference in patient satisfaction between those undergoing ppi for the first time and those undergoing reimplantation (3). conclusions patients should always be informed of reimplantation risks and complications and encouraged to undergo surgery. the degree of cc fibrosis should always be taken in consideration. graft implementation might be necessary, especially when transitioning from a mpp to an ipp. however, long-term patient satisfaction remains high. references 1. wilson sk. reimplantation of inflatable penile prosthesis into scarred corporeal bodies. int j impot res. 2003; 15(suppl 5):s125-8. 2. boysen wr, cohen aj, kuchta k, et al. combined placement of artificial urinary sphincter and inflatable penile prosthesis does not increase risk of perioperative complications or impact long-term device survival. urology. 2019; 124:264-270. available at: https://doi.org/10.1016/j.urology.2018.10.033. 3. lledó-garcía e, jara-rascón j, moncada iribarren i, et al. penile prosthesis first and replacement surgeries: analysis of patient and partner satisfaction. j sex med. 2015; 12:1646-1653. available at: http://dx.doi.org/10.1111/jsm.12932. a. b. figure 1. a. urethrography performed after the perineal trauma shows the urethrocavernous fistula (yellow circle); b. urethrography repeated before the surgery shows the complete healing of the fistula (green square). figure 2. schematic representation of the graft of bovine dermal collagen (in red) applied to reinforce the tunica albuginea (in blu are represented the prosthetics cylinders). correspondence camilla capretti, md camilla.capretti2@gmail.com department of urology, "ospedali riuniti" university hospital and marche polythecnic university, ancona, (italy) antonio avolio, md antonio.avolio@gmail.com alberto florio, md a.florio1960@gmail.com silvia giovannozzi, md silvia.giovannozzi@alice.it domenico de carolis, md dodecalis@gmail.com department of urology, mazzoni hospital, ascoli piceno (italy) 16capretti_stesura seveso 24/09/20 17:22 pagina 216 archivio italiano di urologia e andrologia 2018; 90, 3166 original paper ultrasound follow up: is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones? grazia bianchi, diego marega, roberto knez, stefano bucci, carlo trombetta department of urology, university of trieste, cattinara hospital, trieste, italy. introduction. after extracorporeal lithotripsy (swl), a spontaneous expulsion of fragments is often reported. the aim of this study is to demonstrate the presence of a stone free status or the presence of clinically insignificant residual fragments (cirfs, defined as “asymptomatic, noninfectious, ≤ 3 mm fragments”) in people with undetected spontaneous expulsion. materials and methods. between may and september 2017, we performed a total of 87 treatments. the device used was a storz medical modulith® slk. all the patients were treated in prone position to reduce respiratory movements and underwent sonography before and four to eight weeks after the treatment. an in line ultrasound targeting was possible with all the stones. people lost to follow up or with ureteral stones were excluded. patients were divided in groups according to gender, previous treatments, stone diameter and position. results. we enrolled 73 patients. 57 patients had a single stone and 16 multiple stones. a mean number of 3044 shock waves was administered with a maximum average energy of 0.68mj/mmq. at follow up, 41 patients (56.2%) were found stone free or with cirfs. the association between undetected expulsion and the presence of cirfs is considered to be not statistically significant (p = 0.89). among patients with cirfs, 25/41 didn’t report expulsion. taking in account the groups our population was divided in, according to gender (p = 0.36), previous treatments (p = 0.44), stone diameter (p = 0.28) and stone position (p = 0.35), the association between undetected spontaneous expulsion and presence of cirfs was never statistically significant. conclusions. an undetected spontaneous expulsion of stone fragments could not be considered a sign of swl treatment failure. the association between undetected expulsion and presence of cirfs is never statistically significant if gender of the patients, previous treatments, stone diameter and stone position are considered. key words: lithotripsy; fragment expulsion; clinically insignificant fragments; swl. submitted 6 june 2018; accepted 19 august 2018 summary no conflict of interest declared. dered if fragment expulsion could be considered a good indicator of a successful treatment. in many patients, reporting that they had not expelled fragments, we actually noticed that insignificant lithiasis was present. the aim of this study is to demonstrate the presence of a stone free status or the presence of clinically insignificant residual fragments (cirfs, defined as “asymptomatic, noninfectious, ≤ 3 mm fragments”) in people with undetected spontaneous expulsion. materials and methods between may and september 2017, we performed a total of 87 treatments. the device used for eswl was storz medical modulith® slk. in this electromagnetic system, the shock waves are generated through a cylindrical coil with a metallic membrane in a water-filled cushion. the magnetic field of the coil causes an expansion of the membrane and the shock wave in water, which is focused by a parabolic reflector. the plastic membrane of the cushion is coupled to the patient by an ultrasound gel. the ultrasound probe is placed in line, allowing continuous monitoring of the treatment. all the patients were treated in prone position to reduce respiratory movements of the stone. they underwent sonography before treatment and four to eight weeks after treatment. no patients had radiographic targeting of stones, because of far better performance of ultrasound targeting in our hands and to avoid x-ray exposure. people lost to follow-up and with ureteral stones were excluded. every patient was given potassium citrate and no one was given expulsive therapy after the treatment. patients were divided into groups according to gender, previous treatments, stone diameter and position. we retrospectively reviewed the data collected and compared the results obtained using chi-square test, with significance considered at p < 0.05. results we enrolled 73 consecutive patients, 53 males and 20 females. 57 patients had a single stone (mean 9,5 ± 3.12 mm) and 16 multiple stones. the mean age was 59 ± 12 years. a mean number of 3044 shock waves was administered with a maximum average energy of 0.68mj/mmq. doi: 10.4081/aiua.2018.3.166 introduction after extracorporeal shock waves lithotripsy (swl), a spontaneous expulsion of fragments is often reported. during the first medical examination after the treatment, the patient is always asked if he had a renal colic or hematuria and fragment expulsions were seen. we wonbianchi ultra_stesura seveso 03/10/18 09:38 pagina 166 167archivio italiano di urologia e andrologia 2018; 90, 3 ultrasound follow up: is an undetected spontaneous expulsion of stone fragments a sign of extracorporeal shock wave treatment failure in kidney stones? table 1 describes the main characteristics, evaluating, for each considered aspect, the presence of reported spontaneous expulsion of fragments and the presence of clinically insignificant residual fragments. at follow up, 41 patients (56.2%) were found stone free or with cirfs. among 73 patients we considered, 28 reported spontaneous expulsion, in particular, among them, 16 were stone free or with cirfs and 12 had stones clinically significant. the association between undetected spontaneous expulsion and the presence of cirfs (primary outcome) is considered to be not statistically significant (p = 0.89). patients without cirfs required further treatments and this is considered a treatment failure (table 2). among 42 patients where cirfs were diagnosed, 25 didn’t report expulsion and were divided into groups according to gender, previous treatments, stone diameter and stone position. according to gender, 19 males and 6 females didn’t report expulsion (p = 0.36). patients who underwent previous treatments (stenting was not considered a treatment because it does not involve fragmentation) were 11 and 14 had no previous treatments or any kind of stone fragmentation (p = 0.44). according to stone diameter, 17 patients with stones ≤ 10 mm and 8 with stones > 10 mm or multiple didn’t report expulsion (p = 0.28) and according to stone position, 8 with stones in lower calyx, 14 in middle and superior calyx, 3 in renal pelvis didn’t report expulsion (p = 0.35). taking in account the groups our population was divided in, according to gender (p = 0.36), previous treatments (p = 0.44), stone diameter (p = 0.28) and stone position (p = 0.35), the association between undetected spontaneous expulsion and presence of cirfs is never statistically significant (table 3). discussion although different definitions (1, 2) of cirfs (clinically insignificant residual fragments) could be found (3) and taking in account that some authors consider cirfs a risk factor for future stone growth (2-4), they are still considered a good indicator of successful eswl fragmentation. the ct scan is believed to be the gold standard for residual fragments detection (5, 6), but we tried to avoid xray exposure, especially in recurrent stone-formers (7). the available studies about residual fragments deal mostly with medical therapy (8, 9), but studies about spontaneous expulsion after eswl could not be found. conclusions an undetected spontaneous expulsion of stone fragments could not be considered a sign of eswl treatment failure. the association between undetected expulsion and presence of cirfs is never statistically significant if gender of the patients, previous treatments, stone diameter and stone position are considered. references 1. sarica k, yuruk e. what should we do with residual fragments. arch esp urol. 2017; 70:245-250. 2. osman mm, alfano y, kamp s, et al. 5-year-follow-up of patients with clinically insignificant residual fragments after extracorporeal shockwave lithotripsy. eur urol. 2005; 47:860-4. 3. chung vy, turney bw. the success of shock wave lithotripsy (swl) in treating moderate-sized (10-20 mm) renal stones. urolithiasis. 2016; 44:441-4. 4. khaitan a, gupta np, hemal ak, et al. post-eswl, clinically table 1. presence of reported spontaneous expulsion of fragments and presence of clinically insignificant residual fragments in relation to different conditions. reported no cirfs no cirfs spontaneous expulsion expulsion males 22 31 33 20 females 6 14 8 12 previous treatments 15 22 20 17 no previous treatments 13 23 21 15 stones ≤ 10 mm 23 34 33 24 stones > 10 mm or multiple 5 11 8 8 lower calyx 13 17 15 15 middle and superior calyx 7 22 20 9 renal pelvis 8 6 6 8 table 2. association between undetected spontaneous expulsion and the presence of cirfs (primary outcome). reported no p spontaneous expulsion expulsion clinically insignificant residual fragments (cirfs) 16 25 0.89 lithiasis that requires further treatments 12 20 table 3. association between undetected spontaneous expulsion and presence of cirfs. reported no p spontaneous expulsion expulsion males 14 19 0.36 females 2 6 previous treatments 9 11 0.44 no previous treatments 7 14 stones ≤ 10 mm 5 8 0.28 stones > 10 mm or multiple 6 14 lower calyx 5 3 0.35 middle and superior calyx 13 17 renal pelvis 3 8 bianchi ultra_stesura seveso 03/10/18 09:39 pagina 167 archivio italiano di urologia e andrologia 2018; 90, 3 g. bianchi, d. marega, r. knez, s. bucci, c. trombetta 168 insignificant residual stones: reality or myth? urology. 2002; 59:20-4. 5. cicerello e, merlo f, maccatrozzo l. management of clinically insignificant residual fragments following shock wave lithotripsy. adv urol. 2012; 2012:320104. 6. skolaris a, papatsoris ag. diagnosis and management of post percutaneous nephrolithotomy residual stone fragments. j endourol. 2009; 23:1751-1755. 7. elkoushy ma, andonian s. lifetime radiation exposure in patients with recurrent nephrolithiasis. curr urol rep. 2017; 18:85. 8. yang tx, liao bh, chen yt, et al. a network meta-analysis on the beneficial effect of medical expulsive therapy after extracorporeal shock wave lithotripsy. sci rep. 2017; 7:14429. 9. janane a, hamdoun a, hajji f, et al. usefulness of adjunctive alpha1-adrenergic antagonists after single extracorporeal shock wave lithotripsy session in ureteral stone expulsion. can urol assoc j. 2014; 8:e8-e11. correspondence grazia bianchi, md (corresponding author) graziuccia88@libero.it diego marega, md roberto knez, md stefano bucci,md carlo trombetta, md trombcar@units.it università degli studi trieste, urology department – cattinara hospital, strada di fiume 447, trieste, italy bianchi ultra_stesura seveso 03/10/18 09:39 pagina 168 archivio italiano di urologia e andrologia 2020; 92, 2114 case report penile verrucous squamous cell carcinoma: a rare case report omer yuksel, emre karabay, osman bilen, çağatay tosun, levent verim haydarpasa numune training and research hospital, university of health sciences, department of urology, uskudar/istanbul turkey. penile cancer is a rare type of urological cancer. predisposing factors include phimosis, poor hygiene, and smoking. circumcision in early childhood has been shown to be protective against penile cancer. about 95% of penile cancers are squamous cell carcinomas, while verrucous type is a rare variant with frequent recurrences, but with a favorable prognosis. the majority of patients are asymptomatic; however, patients may present with pain, discharge, and bad odor depending on the severity of the disease. although hospital admission is often late due to psychosocial factors, cancer is often localized. herein, we report a 61-year-old circumcised patient presenting with painful penile mass who was diagnosed with a penile verrucous squamous cell carcinoma in the light of literature data. key words: penile cancer; verrucous cancer; penectomy. submitted 17 november 2019; accepted 12 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.114 introduction penile cancer is the rarest of urological malignancies in male. its annual incidence is 1/100,000 in the united states (us) and europe. as it is more common in many countries worldwide, it is considered a global health problem (1). according to the american cancer society, 2,080 newly diagnosed penile cancer patients and 410 penile cancer-related death have been estimated in the us in 2019 (2). its incidence is the highest in brazil, uganda, and india and the lowest in the jewish and muslim communities in which male infants and children are mostly circumcised. male circumcision in early childhood has been shown to reduce the risk for penile cancer by three to five-fold, probably as it prevents chronic irritation (3). predisposing factors being uncircumcised, balanoposthitis, balanitis xerotica obliterans (bxo), ultraviolet phototherapy, sexual promiscuity, sexual intercourse in early adolescence, history of condyloma, tobacco smoking, and sexual intercourse with a partner infected with human papillomavirus (hpv) (4). in addition, a high-risk hpv-dna positivity has been associated with reduced survival (5). the most common type of penile cancer is squamous cell carcinoma (scc). penile scc can be divided into several subtypes. the most common subtypes include usual scc (48 to 65%), basaloid carcinoma (4 to 10%), warty carcinoma (7 to 10%), verrucous carcinoma (3 to 8%), papillary carcinoma (5 to 15%), and mixed carcinomas (9 to 10%). verrucous carcinoma is a rare variant of welldifferentiated scc with low malignancy potential. premalignant lesions include penile cutaneous horn, bowenoid papulosis, and bxo, while potential risk factors for the development of penile cancer are penile intraepithelial neoplasms, erythroplasia of queyrat, and bowen disease (3). of these lesions, about 30% result in invasive cancer. penile cancer, which is mostly seen in individuals aged 50 to 70 years, affects glans of penis (48%), prepuce (21%), both glans and prepuce (15%), coronal sulcus (6%), and penile shaft (< 2%). initial physical examination manifestations may widely vary from a small redness to a large ulcer or infiltrative lesion. patients may present with itching, pain, bleeding, discharge, and bad odor depending on the severity of the disease. hospital admission is often late due to psychosocial factors; 15 to 60% of patients seek a medical diagnosis and treatment at least one year after the symptom onset. nonetheless, the disease is localized in 66% of patients. in the initial admission, inguinal lymph nodes must be evaluated. penile cancer metastasizes in a predictable pattern with superficial and deep inguinal lymph nodes occurring first, followed by pelvic and periaortic lymph nodes. distant metastasis is very rare (1 to 10%) and mostly occurs in the late stages of the disease (6). disease staging is based on the american joint committee on cancer tnm staging system depending on the depth of invasion, lymph node invasion, and distant metastases (6, 7). herein, we report a 61-year-old circumcised patient presenting with painful penile mass who was diagnosed with a penile verrucous scc in the light of literature data. case report a 61-year-old male patient who was circumcised at the age of 13 years was admitted to our outpatient clinic with a painful penile mass. although his complaints were present for two years, he did not seek a medical treatment due to psychosocial factors. upon increased penile pain, he applied to our clinic. his medical history revealed no smoking history, except being a social smoker, dysuria, having multiple sexual partners or sexually transmitted disease, or previous surgery. he was on regular medical treatment for hypertension and diabetes mellitus. his familial medical history revealed rectal cancer in his father. physical examination revealed a 2-cm karabay-yuksel_stesura seveso 17/06/20 10:15 pagina 114 115archivio italiano di urologia e andrologia 2020; 92, 2 verrucous carcinoma of penis ulcerative mass with bleeding and itching advancing toward the coronal sulcus from the dorsal layer of the glans without urethral meatus involvement (figure 1). poor penile hygiene was observed. inguinal region examination showed no palpable lymphadenopathy. skin biopsy of the penile ulcer was performed. pathological examination result reported a well-differentiated penile verrucous scc. magnetic resonance imaging and positron emission tomography-computed tomography revealed tanomo clinical stage and partial penectomy was performed (figure 2). partial penectomy pathology was reported t3nxmx. no recurrence or metastasis was observed in the postoperative six months of follow-up. discussion penile cancer is a rare type of cancer which accounts for less than 1% of cancers in men (8). its prevalence is higher in developing countries. it more frequently affects uncircumcised, white men with low income (9). squamous cell carcinoma is the most common type and 33% of sccs originate from premalignant lesions. possible mechanisms which stimulate malignant transformation include chronic irritation, tobacco smoking, and poor penile hygiene which induce chronic inflammation, metaplasia, and differentiation (10). certain types of viral infections such as hpv may also lead to penile cancer through dna damage. in addition, damages in tumor suppressor genes such as p53 disrupt the cell cycle, resulting in dna damage and malignant transformation (4, 5). verrucous scc of the oral cavity was first defined by ackerman in 1948. it accounts for 3 to 8% of penile cancers and 20% of verruciform lesions. it is a rare variant of exophytic, papillomatous, low-grade, and well-differentiated scc. as verrucous sccs mostly present with squamous epithelial hyperplasia and keratinization, misdiagnosis is common, when diagnostic biopsy fails. therefore, biopsy is strongly recommended for definitive diagnosis. its etiology has not been fully understood, yet (11). earlier studies have demonstrated that verrucous sccs are associated with low-risk hpv infection (12). however, later studies using broad-spectrum hpv polymerase chain reaction testing have revealed controversial results. in a study, rubin et al. (12) reported that basaloid and warty sccs were associated with hpv, while the hpv positivity rate was 33.3% and 34.9% for verrucous and usual sccs, respectively. in another study, stankiewicz et al. (13) reported an hpv-dna positivity of 23% and 59% for verrucous and usual sccs, respectively. these findings indicate a low-degree association between penile verrucous scc and hpv. although most of the current data regarding verrucous sccs are based on case reports and case series, surgery is the mainstay of the treatment. the main strategy is wide excision of the mass or partial penectomy. radical penectomy can be performed in rare cases. recurrence of penile verrucous sccs is high; one case with recurrence after 30 years has been reported in the literature (14). in early recurrence, additional resection and even radical penectomy can be performed. distant metastasis is extremely rare and is not seen in almost none of patients with penile verrucous scc. therefore, inguinal lymphadenectomy is reserved for only very few patients. hatzichristou et al. (15) performed inguinal lymphadenectomy in selected patients with penile verrucous scc; however, no specific lesion could be detected. thus, prophylactic inguinal lymphadenectomy is not recommended for this patient population. early diagnosis and prevention are of utmost importance for the management of penile cancer. neonatal circumcision, smoking cessation, and hpv vaccination have been suggested to decrease the incidence of penile cancer. references 1. parkin dm, whelan sl, ferlay j, et al. cancer incidence in five continents. vol. viii. http://www.iarc.fr/en/publicaions/pdfsonline/cancer-epidemiology/iarc-scientific publication-no.155.accessed march 12,2014. 2. american cancer society. cancer facts & figures 2019. atlanta: american cancer society; 2019. 3. barnholtz-sloan js, maldonado jl, pow-sang j, guliano ar. incidence trends in primary malignant penile cancer. urol oncol. 2007; 25:361-367. 4. pizzocaro g, algaba f, horenblas s, et al. eau penile cancer guidelines 2009. eur urol. 2010; 57:1002-1012. 5. bezerra al, lopes a, santiago gh, et al. human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. cancer. 2001; 91:2315-2321. 6. marchionne e, perez c, hui a, khachemoune a. penile squamous cell carcinoma: a review of the literature and case report treated with mohs micrographic surgery. an bras dermatol. 2017; 92:95-99. 7. edge sb, byrd dr, compton cc, et al. ajcc cancer staging manuel. (7th edn), new york, ny: springer. 2010. 8. wilson cn, sathiyasusuman a. associated risk factors of stis figure 1. penile mass on physical examination. figure 2. partial penectomy material. karabay-yuksel_stesura seveso 17/06/20 10:15 pagina 115 archivio italiano di urologia e andrologia 2020; 92, 2 o. yuksel, e. karabay, o. bilen, ç. tosun, l. verim 116 and multipl sexual relationships among youths in malawi. plos one. 2015; 10:e0134286. 9. morrison bf. risk factors and prevalence of penile cancer. west indian medical journal. 2014; 63:559-560. 10. velazquez ef, cubilla al. lichen sclerosus in 68 patients with squmous cell carcinoma of the penis: frequent atypias and correlation with special carcinoma variants suggest a precancerous role. am surg patol. 2003; 27:1448-1453. 11. schwartz ra. verrucous carcinoma of the skin and the mucosa. j am acad dermatol. 1995; 32:1-21. 12. rubin ma, kleter b, zhou m, et al. detection and typing of human papillomavirus dna in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. am j pathol. 2001; 159:1211-1218. 13. stankiewicz e, kudahetti sc, proxse dm, et al. hpv infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. mod pathol. 2009; 22:1160-1168. 14. alouani i, barki a, zizi n, dikhaye s. penile verrucous carcinoma: a new case report in a circumcised man. clin oncol. 2019; 4:1594. 15. hatzichristou dg, apostolidis a, tzortzis v, et al. glansectomy: an alternative surgical treatment for buschke-löwenstein tumors of the penis. urology 2001; 57:966-969. correspondence omer yuksel, md dr_omer_yuksel@hotmail.com emre karabay, md (corresponding author) emrekarabay@gmail.com osman bilen, md osmanbilen1212@gmail.com çağatay tosun, md cagataytosun@hotmail.com levent verim, md leventverim@hotmail.com haydarpasa numune training and research hospital, university of health sciences, dept. urology tibbiye street. no: 23 34668 uskudar/istanbul (turkey) karabay-yuksel_stesura seveso 17/06/20 10:15 pagina 116 265archivio italiano di urologia e andrologia 2018; 90, 4 original paper treatment of retained encrusted ureteral double-j stent ibrahim alnadhari 1, 2, mohammed ahmed alwan 1, morshed ali salah 1, 2, abdulelah m. ghilan 1 1 urology and nephrology center, at al-thawra modern general and teaching hospital, sana’a, yemen; 2 department of urology, al wakra hospital, hamad medical corporation, al wakra, qatar. objectives: we conducted this study to evaluate patients with retained encrusted ureteral stents, identify the predisposing factors and present our experience in the management of such challenging problem. materials and methods: this prospective study was carried out in the period from may 2007 to february 2011 at the urology and nephrology center, al-thawra general hospital, sana’a, yemen. 40 patients with retained encrusted ureteric stents were treated at our center. all patients were initially evaluated with a radiographic imaging for assessment of stent encrustation and stone burden. treatment decisions were based on the site and severity of encrustations in the renal pelvis, ureter and bladder and on our technical situation and availability of instrumentations. multi-modal approaches ranging from extracorporeal shock wave lithotripsy (eswl) to endourological and open urologic procedures were used to achieve stent removal. results: a total of 90 urological procedures were performed to render all 40 patients stent and stone free. the average duration of stent remained indwelling was 24.2 months (range 4 months -16 years). all patients were managed either by minimally or more invasive multi-modal endourological approaches. for upper coil encrustation percutaneous nephrolithotripsy was performed in eight patients, pyelolithotomy in two patients and eswl in three patients. encrustation of the body was treated initially by eswl, followed by retrograde ureteroscopic manipulation in 12 patients. lower coil encrustation was successfully managed by cystolitholapaxy in seven patients and one patient required cystolithotomy. cystolithotomy, pyelolithotomy and ureterolithotomy were carried out in two patients. two patients who had large burden bladder and kidney stones with loss of kidney function underwent nephrectomy and cystolithotomy. conclusions: the retrieval of severely encrusted retained ureteral stent and its associated stone burden poses a real management challenge for urologists due to the need for multimodal procedures and the lack of standardized treatment plan. key words: ureteral stent; double-j stent; encrustation. submitted 25 july 2018; accepted 13 august 2018 summary no conflict of interest declared. relief of obstruction prior to extracorporal shock wave lithotripsy (eswl) and after ureteroscopy (urs) (5, 6). they are also placed after iatrogenic injuries of the ureter and for the purpose of easy identification and protection of the ureter during complex abdominal procedure (7). since zimskind et al. first described the original use of endoscopically inserted indwelling ureteral stent in 1967 (8),various modifications on stent design have been made allowing for easier manipulation (1, 6). modern ureteral stents are generally designed in a double-pigtail or double-j (jj) configuration (3, 9). the ideal stents are those which are easy to insert and remove, radiologically-opaque, having good flow characteristics, biologically inert and chemically stable in urinary tract, and the stent biomaterial should resist encrustation, prevent infection and be widely avail-able at a reasonable cost (3). unfortunately, no stent biomaterial is currently available that meets all of these criteria. a variety of materials including synthetic polymeric compounds (polyurethane/polyethylene) and silicon are available with various biocompatibility and biodurability (3, 6). despite advances in stent deigns and materials, problems related to indwelling ureteral stent use, such as infection, encrustation, stone formation, occlusion, migration and breakage continue to occur (1, 5, 10, 11). retained ureteral stents especially those that are encrusted can be a challenging problem that may lead to serious complications of obstruction, infection and renal impairment if not managed properly (1, 2, 6, 12). the problem of retained stents occurs due to variety of causes. illiteracy and non-compliance of the patient together with poor communication between patients and physicians are the main contributing causes for delay in timely removal of stents (2, 13). we conducted this study to evaluate patients with retained encrusted indwelling ureteral stents, identify the predisposing factors and present our experience in the management of such challenging problem. materials and methods a prospective, observational and cohort study was carried out in the period from may 2007 to february 2011 at the urology and nephrology center, al-thawra general and teaching hospital, the main referral hospital in the country, sana’a, yemen. 40 patients (30 males and 10 females) who were presented with retained encrusted doi: 10.4081/aiua.2018.4.265 introduction the use of indwelling ureteral stents has become an integral part of many urological procedures. they provide free drainage from upper urinary tract to the bladder in cases of renal and ureteral obstruction secondary to a variety of intrinsic or extrinsic factors such as calculi, strictures, congenital anomalies, pelvic malignancies, retro-peritoneal tumors, and fibrosis (1-4). common indications for stent placement include the prevention or alnadhari_stesura seveso 10/01/19 16:06 pagina 265 archivio italiano di urologia e andrologia 2018; 90, 4 i. alnadhari, m. ahmed alwan, m. salah, a.m. ghilan 266 ureteric stents and managed at our hospital during this period. all patients with a retained stent which was defined as “one which could not be removed cystoscopically at the first attempt and required other auxiliary measures or surgical procedure for removal”, were included in the study. patients with no visible encrustation on their stents, in whom the stents were easily removed cystoscopically at first attempt, were excluded from the study, no matter how long was the duration of missing. the indications of initial stent placement, the duration of stent in the urinary system, and the reasons for delayed removal were all reviewed in the history. all patients were initially evaluated with a plain radiography (kub), abdominal ultrasonography and intravenous urography (ivu) for assessment of stent encrustation and associated stone burden. intravenous urography and in some cases, renal isotope scan were also obtained to document the degree of renal function loss. laboratory tests such as complete blood count, urea and creatinine measurements and urine culture and sensitivity tests were routinely performed. treatment decisions were based on the site and severity of encrustations in the renal pelvis, ureter and bladder and on our technical situation and availability of instrumentations. patients were counseled about the benefits, risks and possible complications including sepsis, loss of renal function, injury to surrounding organs and the possible need for further interventions. cystolithotripsy and cystolithotomy were required to treat the distal components of stent. eswl, ureterorenoscopic (urs) manipulations, and ureterolithotomy were used to treat the ureteric part of the stent. eswl, percutaneous nephrolithotripsy (pcnl), and pyelolithotomy were performed to treat the upper coil of the stent, and nephrectomy for removal of non-functioning kidney. all of these procedures were carried out under general anesthesia, except eswl sessions which were performed under parenteral analgesia. post-treatment control kub films and/or ab-domino-pelvic ultrasonography were routinely performed for our patients. results forty patients with retained ureteral stents were managed in our center during the period of the study. patients’ ages ranged from 4 to 70 years (mean 30 years), 30 patients were males and 10 were females. the average duration of stent remained indwelling was 24.2 months (range 4 months16 years). all stents (except two) were placed in the capital sana’a. one of the remaining two was placed in saudi arabia and the other in ibb city. in 22 patients (55%), the stent side was the right while in the remainder 18 (45%), the side was the left. the most common reasons for stent missing, as shown in table 1, were poor compliance of the patients (patients ignored or forgot physicians’ advice regarding its timely removal) and seen in 47.5% of cases, followed by inability to return back to hospital due to financial reasons (30%), and delayed referral after eswl to endourology department for stent replacement or removal in the optimal time (12.5%). in 10% of patients, the reason was poor communication between patients and physicians (the patients did not know about the presence of stent and/or the need for its timely removal). the main initial indications of ureteral stenting and the sites of maximum encrustation are shown in table 1. combinations of eswl, endourologic and open urologic procedures were required to facilitate removal of retained stent and associated stones. a total of 90 urologic procedures were performed to render all 40 patients stent free. averages of 2.25 urologic procedures per patients (range 1-10) were performed during either single or multiple anesthetic sessions as shown in table 1. in 25 out of 40 patients, it was possible to have patients cleared from their retained stents and stone burden in a single anesthetic session. we began by careful evaluation of plain kub for the presence of encrustation on the proximal coil, body and distal coil of the stent. in cases of no visible encrustation, cystoscopy and trial of stent extraction by gentle traction under fluoroscopic control was applied. if it was removed easily, then we did not include the case in our study despite the duration of missing. if we found difficulties in stent extraction, no force was applied to avoid damaging the ureter and the case was considered as a retained stent. eswl was our first choice for cases of retained stent without visible encrustation or with minor encrustation especially on the proximal coil and body. we had three patients with retained stent without clear calcifications in whom eswl to the proximal coil was carried out and then the stent was removed easily. in cases of visible encrustations table 1. baseline characteristic and clinical features of the study population. number of patients n° no (%) 40 sex (male/female) (male/female) 30/10 (75/25%) age mean (range) 30 (4-70) years residency sana’a 13 (32.5%) others 27(67.5%) cause of missing stents poor compliance 19 (47.5%) inability to return back 12 (30%) delay in referral 5 (12.5%) poor communication 4 (10%) indication for initial stent relieve of obstruction 16 (40%) placement intra-operative 15 (37.5%) before eswla 9 (22.5%) site of maximum encrustation kidney (upper coil) 6 (15%) kidney & ureter 4 (10%) ureter (body) 15 (37.5%) bladder (lower coil) 6 (15%) kidney & bladder 4 (10%) totally encrusted 2 (5%) not visible 3 (7.5%) executed therapy eswl 50 (55.5%) ursb 12 (13.3%) cystolitholapaxy 7 (7.7%) pcnlc 8 (8.8%) cystolithotomy 5 (5.5%) pyelolithotomy 4 (4.4%) ureterolithotomy 2 (2.2%) nephrectomy 2 (2.2%) a eswl = extracorporeal shock wave lithotripsy; b urs=ureterorenoscopy; c pcnl = percutaneous nephrolithotomy. alnadhari_stesura seveso 10/01/19 16:06 pagina 266 on plain kub, no attempts at direct removal were done, but we proceeded according to the site and severity of encrustations. if there were linear encrustations on the proximal coil or body, we performed eswl to the site of encrustation and then trial of removal of stent by gentle traction without force. for linear or minor encrustation on the distal coil, we crushed them with forceps or lithotripter to fragment them and remove the fragments. pneumatic lithotripter was used whenever needed. when these less invasive measures failed or if the encrustations were severe, then we manage our patients in retrograde fashion, starting with the bladder component, then the ureter and kidney. cystolithotripsy was our first option for bladder component of encrustations. in children, we did cystolithotomy in two patients to remove bladder encrustations because of large stone burden and to avoid repeated urethral instrumentation and the risk of urethral injury in children, especially males. cystolithotomy was also performed for three adults who had large bulky bladder stone around the distal coil. for ureteral components, we mostly started by preliminary eswl to fragment the encrustations around the stent and then we passed a small (7f) semi-rigid ureteroscope alongside a safety guide-wire under vision and we performed fragmentation of encrustation and removed the fragments. we had one patient with heavy encrustations in the ureteric component and associated cardiac disease that made him unfit for anesthesia, he needed ten sessions of eswl to render him stoneand stent-free. encrustations with large stone burden on the kidney component of the stent were solved by percutaneous nephrolithotripsy (pcnl). solving the bladder and ureteric components, always preceded pcnl. pyelolithotomy was carried out for managing the proximal components in children because we have no pediatric pcnl set in our center and in one adult due to accidental technical problem in our endoscopy unit at that time. we resorted to nephrectomy in two patients who had large bladder and kidney stones burden with loss of kidney function which was demonstrated by radioisotope scanning. cystolithotomy for the bladder component was done during the same session. all procedures were done without intra-operative complications, and there were no significant postoperative complications. two cases with totally encrusted ureteric stent and large stone burden over the entire length of the stent worth detailed reporting as they were managed by cystolithotomy, ureterolithotomy and pyelolithotomy in a single anesthetic session. one of them had a solitary ectopic pelvic kidney. case 1 a five year old boy who had a congenital right solitary ectopic pelvic kidney and presented with a ureteral stent retained for about three years which was inserted as an emergency procedure to relieve upper urinary obstruction. poor compliance was the reason for long indwelling time. his renal functions were normal. kub and ivu radiographs are shown in (figures 1, 2). through a single small oblique incision in the right lower abdomen and in a single anesthetic session, cystolithotomy, then ureterolithotomy and pyelolithotomy were performed for removal of the stent and stone burden. (figures 3, 4). control urinary tract ultrasound showed clearance of stones and the double j stent removed two weeks later. 267archivio italiano di urologia e andrologia 2018; 90, 4 retained encrusted double-j stent treatment figure 1. kub x ray film shows severe encrustations around ureteral stent, renal pelvis and in the bladder. figure 2. intravenous urography shows solitary pelvic kidney with significant hydronephrosis. figure 3. oblique lower abdominal incision and removal of the renal pelvic stone through pyelotomy. figure 4. demonstration of the stones with the extracted retained ureteral stent after their reconfiguration. alnadhari_stesura seveso 10/01/19 16:06 pagina 267 archivio italiano di urologia e andrologia 2018; 90, 4 i. alnadhari, m. ahmed alwan, m. salah, a.m. ghilan 268 case 2 this was a 25-year-old man who had a forgotten encrusted ureteral stent placed as an emergency procedure to relieve a ureteric obstruction two years prior to his presentation to our department. poor compliance was the reason for long indwelling time. his kub radiograph is shown in (figure 5). the vesical and lower ureteric calcifications were managed by cystolithotomy and ureterolithotomy through a lower abdominal incision. the patient was then shifted to flank position where pyelolithotomy and ureterolithotomy for removal of the kidney and upper ureteric encrustations. all of these procedures were performed during a single anesthetic session (figure 6). discussion severely encrusted forgotten ureteral stent is one of the difficult problems in urological practice. major complications associated with retained stents include infection, migration, fragmentation, stone formation, and ureteral obstruction (6, 7, 14-17). these complications, in addition to the potential need for multiple surgical interventions and the lack of defined therapeutic guidelines for treatment represent a real challenge for urologist (3, 15, 16, 18). although the exact etiology of encrustation is unclear, the incidence of encrustation increases with indwelling stent duration. in one study, overall 47.0% of stents were encrusted and the encrustation rate was 26.8% at less than 6 weeks, 56.9% at 6 to 12 weeks and 75.9% at more than 12 weeks (17). risk factors for stent encrustation are poor patient compliance to follow-up, long indwelling time, sepsis, pyelonephritis, recurrent or residual stone formation, lithogenic history, chronic renal failure, pregnancy metabolic and congenital abnormalities (2, 10, 11, 18). the stent indwelling duration in the current series ranged between 4 months to 16 years, with average of 24.2 months, which is comparable with the mean duration time of 22.7 months reported by monga et al. (19). still two other series reported longer average indwelling time of 4.4 years and 4.9 years, with a range of 1-8 years and 1-12 years respectively (4, 7). many times, stents are forgotten either because of illiteracy, non-compliance of the patients who ignore or forget physician advice regarding its timely removal. poor compliance of the patients was the commonest reason for forgotten stents in our study and this can be explained to some extent by the educational level of patients, as many of our patients were either of low educational level or illiterates. all of the retained stents, except two, were inserted in one city (the capital sana’a) due lack of endourologic units in the other cities till the near time. as most of patients lived in areas far from the capital sana’a, they found it difficult to come back for follow-up or removal of their stents. this constitutes another contributing factor for poor compliance and therefore stent missing. the inability of the patient to attend again to hospitals due to financial reasons (poverty) is another considerable cause for retained stent problems in our patients. delayed referral from eswl department to the endoscopy department for removal of the stent within the optimum time is a third reason for stent retention. the last important contributing factor for retained stents in our study was the presence of communication gaps between patient and physician, with failure of the physician to adequately council the patient about the presence of stent, and/or the need for its timely removal. similar to our series, some other series reported poor compliance as the most common reason for retention of these stents (1, 4) while delayed referral by lithotripsy department for stent replacement within the optimal time was reported as the commonest reason by another series (2). multimodal approach is often required for the management of forgotten ureteral stents to achieve successful retrieval of the retained stent and removal of associated stone burden. although there are no standard and specific guidelines for the management of encrusted ureteral stents, many authors have reported their series and proposed their own management algorithms (1, 3, 7, 11). these include multiple urological modalities which may require single or multiple endourological sessions. our treatment options were based upon our technical situations and resources. we utilized an average of 2.25 urologic procedures per patient to render our patients stent and stone free, an average that is comparable with the results of other series which reported average of 2.7 and 2.38 procedures for clearing their patients from retained stents and the associated stones (1, 2). bostanci et al. reported the use of various combinations of endourological techniques in 19 patients with encrusted figure 5. kub x ray film shows severe encrustations and large stone burden around retained ureteric stent. figure 6. shows demonstration of the stones with the extracted retained ureteric stent after their reconfiguration. alnadhari_stesura seveso 10/01/19 16:06 pagina 268 ureteral stents and they were able to render all patients stent and stone free after a single anesthetic session with minimal morbidity and short hospital stay (14). other reports of fewer patients undergoing one-stage removal of encrusted ureteral stents were also published by other authors (2, 15, 20). in 25 out of 40 of our patients, we were able to remove the retained stents and associated stone burden in a single anesthetic session. we were obligated to perform open pyelolithotomy in children due to unavailability of pediatric pcnl set in our center and in one adult due to accidental technical trouble in our endoscopy unit at that time. the advent of modern endourologic technology has enabled the removal of all the retained stents utilizing complete endourologic approach. however, in some cases of sever encrustations, endoscopic manipulations may fail and the options of open or laparoscopic surgery are considered (1, 2 ,7). conclusions the widespread use of indwelling ureteral stent has been translated into documentation of increased number of forgotten stents with their potential complications. stent encrustation and stone formation are among the serious complications of retained ureteral stents. noncompliance of some patients together with poor communication between patients and attending urologists constitute important contributing factors to the missing of ureteral stents. the retrieval of severely encrusted retained ureteral stent and its associated stone burden poses a real management dilemma for urologists due to the need for multimodal procedures and the lack of standardized treatment plan. ideally, the best treatment of these difficult problems is prevention through patients’ education and proper patient-physician communication to conduct clear information to the patient about the presence of the indwelling stent, the risks associated with prolonged indwelling times and the need for its timely removal or replacement. references 1. lam js, gupta m. tips and tricks for the management of retained ureteral stents. j endourol. 2002; 16:733-41. 2. rana am, sabooh a. management strategies and results for severely encrusted retained ureteral stents. j endourol. 2007; 2:62832. 3. acosta-miranda am, milner j, turk tm. the fecal double-j: a simplified approach in the management of encrusted and retained ureteral stents. j endourol. 2009; 23:409-15. 4. rabani sm. combined percutaneous and transurethral lithotripsy for forgotten ureteral stents with giant encrustation. nephrourol mon. 2012; 4:633-5. 5. keane pf, bonner mc, johnston sr, et al. characterization of biofilm and encrustation on ureteric stents in vivo. br j urol. 1994; 73:687-91. 6. mohan-pillai k, keeley fx jr, moussa sa, et al. endourological management of severely encrusted ureteral stents. j endourol. 1999; 13:377-9. 7. murthy kv, reddy sj, prasad dv. endourological management of forgotten encrusted ureteral stents. int braz j urol. 2010; 36:420-9. 8. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. j urol. 1967; 97:840-4. 9. ather mh, talati j, biyabani r. physician responsibility for removal of implants: the case for a computerized program for tracking overdue double-j stents. tech urol. 2000; 6:189-92. 10. borboroglu pg, kane cj. current management of severely encrusted ureteral stents with a large associated stone burden. j urol. 2000; 164:648-50. 11. singh i, gupta np, hemal ak, et al. severely encrusted polyurethane ureteral stents: management and analysis of potential risk factors. urology. 2001; 58:526-31. 12. adanur s1, ozkaya f. challenges in treatment and diagnosis of forgotten/encrusted double-j ureteral stents: the largest single-center experience. ren fail. 2016; 38:920-6. 13. singh v, srinivastava a, kapoor r, kumar a. can the complicated forgotten indwelling ureteric stents be lethal? int urol nephrol. 2005; 37:541-6. 14. bostanci y, ozden e, atac f, et al. single session removal of forgotten encrusted ureteral stents: combined endourological approach. urol res. 2012; 40:523-9. 15. singh d, goel a, ahmed n, singh bp. forgotten stent leading to complex panurinary stone: single-sitting endourologic management. bmj case rep. 2011; 2011:bcr0620103079 16. ecke th, hallmann s, ruttloff j. multimodal stone therapy for two forgotten and encrusted ureteral stents: a case report. cases j. 2009; 2:106. 17. kawahara t, ito h, terao h, et al. ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. j endourol. 2012; 26:178-82. 18. abdelaziz ay, fouda wb, mosharafa aa, et al. forgotten ureteral stents: risk factors, complications and management. afju 2018; 24:28-33. 19. monga m, klein e, castañeda-zúñiga wr, thomas r. the forgotten indwelling ureteral stent: a urological dilemma. j urol. 1995; 153:1817-9. 20. bukkapatnam r, seigne j, helal m. 1-step removal of encrusted retained ureteral stents. j urol. 2003; 170:1111-4. 269archivio italiano di urologia e andrologia 2018; 90, 4 retained encrusted double-j stent treatment correspondence ibrahim ahmed alnadhari, md (corresponding author) ibrahimah1978@yahoo.com morshed ali salah, md morshed.salah@gmail.com urology and nephrology center, at al-thawra modern general and teaching hospital, sana’a, yemen department of urology, al wakra hospital, hamad medical corporation, al wakra, qatar mohammed ahmed alwan, md malwan197200@gmail.com abdulelah m ghilan, md dr_ghilan1@yahoo.com urology and nephrology center, at al-thawra modern general and teaching hospital, sana’a, yemen, alkhamseen street, sana’a, yemen alnadhari_stesura seveso 10/01/19 16:06 pagina 269 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4470 original paper no conflict of interest declared. and surgical fields and increasing medication adherence and self-management of diseases. the world health organization has defined mhealth as “a medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants, and other wireless devices” (8). nowadays, the global usage of smartphones stands at 3.5 billion (9). an increasing number of mobile health applications (mhas) are available for download through the itunes app store and google play store (10). male infertility (mi) is defined as the inability of a male to make a fertile female pregnant, also for a minimum of at least one year of unprotected intercourse. male factor contributes about 50% of all cases of infertility (11, 12). contemporary data suggests that there has been a decline in global fertility rates from 4.7 to 2.4 live births between 1950 and 2017 (13, 14). several reasons were recognized as causes of impaired sperm parameters, among the main ones, varicoceles (15), hypogonadism (16), and genetic disorders (17). treatment can be divided in medical and surgical treatment (lifestyle modifications (18), antioxidant therapy (19, 20), hormone stimulation therapy (21, 22) tese and other surgical approaches (23). mhas development has not regulated, and several apps, currently available (10) in several fields, including andrological, are characterized by poor-quality. the most important evaluation criteria are the number of downloads and the user ratings (24). due to this searching for high-quality information is still more difficult. mobile application rating scale (mars), represents the most widely used and recommended tool providing quantitative, and validated evaluation of mhas (25, 26). several studies reported data about mhas evaluation and adherence to guidelines in different medical and surgical setting (27-30). to the best of our knowledge, no previous studies analyzed the quality of mhas for mi and their adherence to guidelines. our current project aims to provide an overview of mhas, available on the market, developed for mi analyzing quality through the mars and their adherence to european association of urology (eau) guidelines. introduction: male infertility (mi) is one of the most important worrying topics for the fertile age population. nowadays, several mobile health applications (mhas) have been developed to help and assist patients suffering from male infertility (mi), but their quality and adherence to the guidelines is not solved issue yet. materials and methods: on 2nd july 2022, an observational cross-sectional descriptive study of all mhas on male infertility was conducted: a search on both the itunes app store and google play store was performed. our group reviewed all mhas, evaluating the quality, using mobile application rating scale (mars), and the adherence to european association of urology guidelines, with a special tool created for this manuscript. results: in the final analysis we included 10 mhas: 20% (n = 2) from the itunes app store and 80% (n = 8) from the google play store. across the sample, 80% (n = 8) of the apps provided general information on mi, 60% (n = 6) focused on diagnosis and 50% (n = 5) focused on treatment options, respectively. according to mars tool, the mean score was 2.18 (0.78), 3.78 (0.36), 3.0 (0.53), 3.19 (0.45), 2.18 (0.54) for engagement, functionality, aesthetic, information and subjective quality, respectively. according to eau adherence score, the highest score was reported by “infertilità” with 12/15 points while the lowest score was reported by “fertility diet guide”, 0/15 points. conclusions: nowadays, mhas present in the market are not a reliable source of information on mi. an ideal mhas should be based on scientific evidence, user friendly, respecting privacy and security laws, making patients feel capable and confident to change personal behavior or attitudes. key words: keywords: app; male infertility; e-health; mobile phone; mars. submitted 6 september 2022; accepted 24 september 2022 introduction in recent years new technologies, such as internet, social media telemedicine, and mobile health (mhealth) have rapidly grown, particularly during sars cov 2 pandemic outbreak (1-7), supporting patients in several medical male infertility, what mobile health applications “know”: quality analysis and adherence to european association of urology guidelines giovanni maria fusco 1, luigi cirillo 1, marco abate 1, simone morra 1, vincenzo morgera 1, biagio barone 1, felice crocetto 1, gianluigi cacace 1, francesco di bello 1, lorenzo spirito 2, celeste manfredi 2, davide arcaniolo 2, alessandro palmieri 1, ciro imbimbo 1, vincenzo mirone 1, luigi napolitano 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy; 2 urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2022.4.470 summary 471archivio italiano di urologia e andrologia 2022; 94, 4 male infertility and mobile health applications materials and methods search strategy on 2nd july 2022, an observational cross-sectional descriptive study of all mhas on mi was conducted. a search on both the itunes app store and google play store was performed using an iphone 13 and a samsung s10, respectively. “male infertility” and/or “diagnosis”, and/or “treatment” were the keywords used for search tab. these keywords were used according to the search strategy of google play store and itunes app store, which is based on finding keywords in titles, app descriptions and tags. we excluded information available in books, and in other formats. two authors (gc, vm) screened separately in itunes app store and google play store apps during the search by reading the title and description in the app store. one reviewer conducted a search in the itunes app store, and the other in the google play store. reviewers created an excel form to report all mhas and in the second time they were screened according to the exclusion criteria. they included in the present studies all mhas regarding mi, providing a service to patients, in english, and free to download. mhas not specifically focused on mi, not allowing access to all users and those not available in english were excluded. on 4th july 2022 reviewers downloaded and installed the apps on their personal mobile devices. they interacted for thirty minutes with each app to explore its features before completing the mars and then they evaluated adherence to eau guidelines. in case of mhas present in both stores, only the itunes app store version was analyzed. a total of 35 apps were found by our search, 30 (85.7%) of them were from the google play store (android) and 5 (14.3%) of them were from the itunes app store. of all the mhas, 17 were excluded: present in both stores (n=1), not in english (n = 3) and off-topic (n = 13). only 18 mhas were eligible for the final evaluation and were downloaded. finally, 10 mhas were included in the final review after removing 8 mhas that met exclusion criteria after download. the search strategy was performed according to prisma statement (figure 1). mhas characteristics were reported in the table 1. assessment of app quality mobile application rating scale (mars) was used to assess the quality of mhas. mars is a multidimensional instrument of 23 structured questions evaluating different domains: engagement, functionality, esthetics, information, app subjective quality, and app-specific, showing a very acceptable reliability and validity. engagement (interest, customizability, interactivity), functionality (performance, ease of use, navigation), aesthetics (layout, graphics, visual appeal) and information (accuracy of app, credibility, evidence base). subjective (recommendable, worth buying) and 1 category of subjective quality. each category score is the mean of the different items, rated on a 5-point likert-type scale (from 1 = inadequate to 5 = excellent) within its category. the mean of the 4 app quality category scores is used to calculate overall quality score and the final score range from 0 to 5. a score of between 1 and 2/5 is considered as ‘poor’ quality, while 3/5 is ‘acceptable’ and at least 4/5 is ‘good’ quality. if scores differed by a single point, reviewers use the mean of the two ratings, while if scores differed by more than a single point, reviewers solve the discrepancy through discussion and consensus agreement. mean scores were calculated for each domain and an overall quality score was calculated based on the aggregated mean values for each of the four domains. the mean score for subjective quality is calculated. figure 1. archivio italiano di urologia e andrologia 2022; 94, 4 g.m. fusco, l. cirillo, m. abate, et al. 472 assessment of app adherence to eau guidelines based on the eau guidelines 2022 on sexual and reproductive health, an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) according to the sections (9). two independent reviewers (vm, and cf, urologists with high experience in mi) analyzed separately apps for their adherence to eau guidelines. according to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. a score of ‘‘0’’ indicated no adherence to guidelines. a score of ‘‘1’’ indicated a weak adherence. a score of ‘‘2’’ indicated a partial or moderate adherence. a score of ‘‘3’’ indicated strong adherence. where coding scores differed by 1 point, the average of the two ratings was taken. if there was a greater than 1-point discrepancy, a third author reviewed apps and resolved the discrepancy. the possible score on the checklist ranged from 0 to 15 for each app. to facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (11-15). statistical analysis means, standard deviations and range values for each mars domain, as well as the overall quality scores and subjective quality scores, were calculated. means and standard deviations were reported for continuous variables while frequencies and percentages were reported for categorical variables. pearson’s correlations were used to analyze correlations between app downloads and mars ratings. microsoft excel was used for data segregation and analysis. statistical analysis was conducted using ibm spss software (version 25, ibm corp, armonk, ny, usa), considering p < 0.05 as statistically significant. results in the final analysis we included 10 mhas: 20% (n = 2) from the itunes app store and 80% (n = 8) from the google play store. across the sample, 80% (n = 8) of the apps provided general information on mi, 60% (n = 6) focused on diagnosis and 50% (n = 5) focused on treatment options, respectively. risks factors were reported in 50% (n = 5) mhas. information of downloads were available for 80% (n = 8) mhas out of the 10 reviewed. downloads were not reported in mhas downloaded by itunes apple store. all the apps were planned to be used by patients. no information about mhas rating was available. mars scores are represented in table 2. engagement the score in this section was based on a 5-point likert scale in 5 subscales (entertainment, interest, customization, interactivity and target-group). the mean score was 2.18 (0.78). the “yo sperm test wi-fi” app produced by “medical electronic system, llc” received the highest score for the engagement. functionality the score of the functionality section was based on a 5point likert scale in 4 subscales (performance, ease of use, navigation and gestural design). the mean score was 3.78 (0.36). aesthetics the aesthetics section was formed by a 5-point likert scale in 3 subscales (layout, graphics, visual appeal) and the mean score was 3.0 (0.53). “fertility diet guide” protable 1. general characteristics of applications. name of application android/apple/both download producer category focus infertility solutions android 500 dagana apps instruction definition, causes, diagnosis, treatment fertility treatment android 10000 di natale health & fitness definition, diagnosis, treatment sperm count advice android 10000 moreflow health & fitness diet , workouts, lifestyle infertility and its management android 100 fumo medicine definition, causes and risk factors, diagnosis fertility diet guide android 10000 prestige worldwide apps, inc health & fitness diet, lifestyle (male/female) infertility android 1000 nature healthy care entertainment definition, causes, risk factors, diagnosis, treatment how to get pregnant fast android 10000 saleha group entertainment causes, diagnosis, treatment how to get pregnant fast android 5000 dvapps-bsl social causes, diagnosis yo sperm test wi-fi apple n.a. medical electronic system, llc medicine informative, practital (marketing) varicohealth apple n.a. varicocele healing ltd. health & fitness risk factors, causes, lifestyle table 2. mars evaluation. apps name engagement functionality aesthetic information overall mean app subjective (section a) (section b) (section c) (section d) score (sd) quality (section e) yo sperm test wi-fi 4.2 4 3.67 4.17 4.01 (0.24) 3.5 varicohealth 1.8 3.25 2 2.8 2.46 (0.68) 2.5 infertility solutions 2.6 4 2.7 3.7 3.25 (0.70) 2 fertility treatment 2.2 4 3.3 3.25 3.18 (0.74) 1.75 sperm count advice 1.6 4 3.3 3.25 3.04 (1.01) 2.5 infertility and its management 1.6 3.25 2.7 3.25 2.7 (0.78) 1.75 fertility diet guide 2.2 4 3.7 3 3.23 (0.80) 2 infertility 1.6 3.25 2.7 3 2.64 (0.73) 1,75 how to get pregnant fast 2 4 2.7 2.75 2.86 (0.83) 2 how to get pregnant fast 2 4 3.3 2.75 3.01 (0.84) 2 mean (sd) 2.18 (0.78) 3.78 (0.36) 3.0 (0.53) 3.19 (0.45) 3.04 (0.43) 2.18 (0.54) sd = standard deviation. 473archivio italiano di urologia e andrologia 2022; 94, 4 male infertility and mobile health applications duced by “prestige worldwide apps, inc” reached the highest aesthetics score. information the information section was formed by a 5-point likert scale in 7 subscales. the mean score was 3.19 (0.45). the “yo sperm test wi-fi” app produced by “medical electronic system, llc” received the highest score of information. overall mean score the app quality mean score correspond to the mean of the sum of engagement, functionality, aesthetic and information scores. the mean score was 3.04 (0.43). the “yo sperm test wi-fi” app produced by “medical electronic system, llc” received the highest mean score of 4.01 (0.24), while “varicohealth” produced by “varicocele healing ltd”, received the lowest mean score of 2.46 (0.68). subjective quality the subjective quality section consisted of 4 items. the score was 2.18 (0.54). the “yo sperm test wi-fi” app produced by “medical electronic system, llc” received the highest score of subjective quality section of 3.5. eau adherence checklist eau guidelines adherence was evaluated and the eau adherence scores were reported in table 3. the mean definition score was 0.6 (0.84), with 60% (n = 6) apps reporting a score of zero; the mean physiopathology score was 0.7 (1.05) with 60% (n = 6) apps reporting a score of zero; the mean risk factors’ scores was 1.4 (1.17) with 30% (n = 3) apps reporting a score of zero; the mean diagnosis score was 1.2 (1.03) with 30% (n = 3) apps reporting a score of zero; the mean treatment score was 1.1 (0.87) with 30% (n = 3) apps reporting a score of zero.the highest score was reported by “infertilità” produced by “nature healthy care” with an overall eau adherence score of 12 points. the lowest score was reported by “fertility diet guide”, produced by “prestige worldwide apps, inc” with an overall eau adherence score of zero points. variable correlations a pearson correlation coefficient was computed to assess the linear relationship between variables and number of downloads. the only statistically significant correlation was found between the number of download and the section on “risk factors” of the adherence to the eau guidelines scoring system, with r = -0.928, p = 0,001. discussion the aim of the present study was to give an overview of mhas for mi, currently available on the market in order to assess their quality and adherence to eau guidelines. to the best of our knowledge, no previous studies examined this topic, so we addressed this void and identified several noteworthy observations. first, of all 10 apps on mi eligible for the analyses, the majority were present on google play store and 80% reported general information on mi. however, only half of the apps reported information on diagnosis and treatment options. therefore, the developer of apps should improve the quality of the content present in the apps in order to allow a greater understanding of the phenomenon of mi. second, according to mars score criteria, the lowest mean score was reported for the “engagement” section, while the highest mean score was reported for the “functionality” section. these findings are in agreement with o’connor et al. (28) and indicate that the apps were generally better designed in terms of their usability but may have lacked behavioral and design features associated with sustained usage. third, according to eau guidelines adherence scoring system, the lowest mean score was reported in the “definition” section, while the highest score was reported in the “risk factors” section. the overall scores of this tool are very low. these results are corroborated by other published studies highlighting a dramatically low adherence to guidelines. this is due to lack of involvement of healthcare mhas development, representing a great limit, that should be addressed in their future development. on the other side collaboration with healthcare does not meaning high quality. in fact, as reported by dantas et al. in mhas for rheumatic disease, not developed for commercial purposes, but created with a partnership between industry/developers and academic institutions, the quality was still low (29). fourth, according to mars, the best mha currently present on the market is represented by “yo sperm test wifi” developed by “medical electronic system, llc” . this app reported the highest score in every single section of this quality tool. it’s noteworthy that this app reported the highest score in the “engagement” section (4.2), followed by information (4.17), and functionality (4). to the best of our knowledge no previous studies reported this finding in engagement, which generally is the lowest reported score, because mhas are better designed for their usability (efficient and easy to use) and lacked behavioral and design features. this is corroborated by the functionality score which is the highest reported score. yo sperm test wi-fi can make patients feel that they are participating in the management of their disease. the table 3. eau guidelines adherence. name definition physiopathology risk factors diagnosis treatment yo sperm test wi-fi 1 1 2 3 2 varicohealth 0 1 1 0 0 infertility solutions 2 0 2 1 2 fertility treatment 1 0 0 1 2 sperm count advice 0 0 0 0 1 infertility and its management 0 2 3 2 1 fertility diet guide 0 0 0 0 0 infertility 2 3 3 2 2 how to get pregnant fast 0 0 1 2 1 how to get pregnant fast 0 0 2 1 0 mean (sd) 0.6 (0.84) 0.7 (1.05) 1.4 (1.17) 1.2 (1.03) 1.1 (0.87) sd = standard deviation. archivio italiano di urologia e andrologia 2022; 94, 4 g.m. fusco, l. cirillo, m. abate, et al. 474 most reported findings suggest developing mhas with these characteristics. taken together, mhas have a great potential to control the spread of misinformation, raise awareness, helping and informing patients (9). given the rising role of new technologies in the various health-care services, a formal standardization of contents addressed to nonmedical users would be desirable. the majority mhas currently present in the market are not good enough to be used as reliable source of information on mi. however, kruglova et al. developed a mha, infotility xy, to promote men’s reproductive health (31). their study showed evidence of the feasibility of mhas to improve men’s knowledge about fertility, about risks factor. in fact, men involved in the study, identified more risk factors after using the app (m = 17.14, sd = 4.32) compared to before (m = 11.12, sd = 4.53). despite this, nowadays there were a multitude of mhas lacking in quality and correct information. this study has several strengths: this is the first study evaluating the content, the quality, and the adherence to eau guidelines about mi; we performed a rigorous search, screening, and analysis on itunes and google play store; reviewer had experience in mars using. our research is not avoided by some limitation: reproducibility of the research turns out to be complex due to the working method of the app store and google play store (the visibility of apps depends on the device and on the country where the search is performed); the exclusion criteria, which led to the exclusion of paid apps; the guidelines developed for healthcare and not for patients and the constant production of new mhas. conclusions nowadays, mhas present in the market are not a reliable source of information on mi. an improvement by the app developers would be welcome, in order to make the apps good both in terms of content and in terms of compliance with the guidelines. therefore, an ideal mhas should be based on scientific evidence, user friendly, respecting privacy and security laws, making patients feel capable and confident to change personal behavior or attitudes. interesting, it could be the involvement of patients in the development, design, and validation of mhas. references 1. mirone v, creta m, capece m, et al. telementoring for communication between residents and faculty physicians: results from a survey on attitudes and perceptions in an academic tertiary urology referral department in italy. arch ital urol androl. 2021; 93:450-4. 2. vaggers s, puri p, wagenlehner f, somani bk. a content analysis of mobile phone applications for the diagnosis, treatment, and prevention of urinary tract infections, and their compliance with european association of urology guidelines on urological infections. eur urol focus. 2021; 7:198-204. 3. morra s, collà ruvolo c, napolitano l, et al. youtubetm as a source of information on bladder pain syndrome: a contemporary analysis. neurourol urodyn. 2022; 41:237-45. 4. capece m, di giovanni a, cirigliano l, et al. youtube as a source of information on penile prosthesis. andrologia. 2022; 54:e14246. 5. creta m, sagnelli c, celentano g, et al. sars-cov-2 infection affects the lower urinary tract and male genital system: a systematic review. j med virol. 2021; 93:3133-42. 6. turco c, collà ruvolo c, cilio s, et al. looking for cystoscopy on youtube: are videos a reliable information tool for internet users? arch ital urol androl. 2022; 94:57-61. 7. melchionna a, collà ruvolo c, capece m, et al. testicular pain and youtubetm: are uploaded videos a reliable source to get information? int j impot res. 2022 feb 8. doi: 10.1038/s41443-02200536-w. epub ahead of print.. 8. mhealth: new horizons for health through mobile technologies: second global survey on ehealth [internet]. [cited 5 september 2022]. available at https://apps.who.int/iris/handle/10665/44607 9. davalbhakta s, advani s, kumar s, et al. a systematic review of smartphone applications available for corona virus disease 2019 (covid19) and the assessment of their quality using the mobile application rating scale (mars). j med syst. 2020; 44:164. 10. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl 2022;94:211-6. 11. hull mg, glazener cm, kelly nj, conway di, foster pa, hinton ra, et al. population study of causes, treatment, and outcome of infertility. br med j clin res ed. 1985; 291:1693-7. 12. salonia a, bettocchi c, boeri l, et al. european association of urology guidelines on sexual and reproductive health-2021 update: male sexual dysfunction. eur urol 2021; 80:333-57. 13. gbd 2017 population and fertility collaborators. population and fertility by age and sex for 195 countries and territories, 19502017: a systematic analysis for the global burden of disease study 2017. lancet 2018; 392:1995-2051. 14. di bello f, creta m, napolitano l, et al. male sexual dysfunction and infertility in spinal cord injury patients: state-of-the-art and future perspectives. j pers med 2022; 12:873. 15. the influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. world health organization. fertil steril. 1992; 57:1289-93. 16. napolitano l, barone b, morra s, et al. hypogonadism in patients with prader willi syndrome: a narrative review. int j mol sci. 2021; 22:1993. 17. foresta c, garolla a, bartoloni l, et al. genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. j clin endocrinol metab. 2005; 90:152-6. 18. rastrelli g, lotti f, reisman y, et al. metabolically healthy and unhealthy obesity in erectile dysfunction and male infertility. expert rev endocrinol metab. 2019; 14:321-34. 19. creta m, arcaniolo d, celentano g, et al. toxicity of antioxidant supplements in patients with male factor infertility: a systematic review and meta-analysis of randomized controlled yrials. antioxid. 2021; 11:89. 20. bisht s, faiq m, tolahunase m, dada r. oxidative stress and male infertility. nat rev urol. 2017; 14:470-85. 21. reifsnyder je, ramasamy r, husseini j, schlegel pn. role of optimizing testosterone before microdissection testicular sperm extraction in men with nonobstructive azoospermia. j urol. 2012; 188:532-6. 22. fusco f, verze p, capece m, napolitano l. suppression of spermatogenesis by exogenous testosterone. curr pharm des. 2021; 27:2750-3. 475archivio italiano di urologia e andrologia 2022; 94, 4 male infertility and mobile health applications 23. practice committee of the american society for reproductive medicine in collaboration with the society for male reproduction and urology. electronic address: asrm@asrm.org. the management of obstructive azoospermia: a committee opinion. fertil steril. 2019; 111:873-80. 24. amor-garcía má, collado-borrell r, escudero-vilaplana v, et al. assessing apps for patients with genitourinary tumors using the mobile application rating scale (mars): systematic search in app stores and content analysis. jmir mhealth uhealth 2020; 8:e17609. 25. stec ma, arbour mw, hines hf. client-centered mobile health care applications: using the mobile application rating scale instrument for evidence-based evaluation. j midwifery womens health. 2019; 64:324-9. 26. stoyanov sr, hides l, kavanagh dj, et al. mobile app rating scale: a new tool for assessing the quality of health mobile apps. jmir mhealth uhealth. 2015; 3:e27. 27. trecca emc, lonigro a, gelardi m, et al. mobile applications in otolaryngology: a systematic review of the literature, apple app store and the google play store. ann otol rhinol laryngol. 2021; 130:78-91. 28. o’connor sr, kee f, thompson dr, et al. a review of the quality and content of mobile apps to support lifestyle modifications following a transient ischaemic attack or «minor» stroke. digit health. 2021; 7:20552076211065270. 29. dantas lo, carvalho c, santos bl de j, et al. mobile health technologies for the management of urinary incontinence: a systematic review of online stores in brazil. braz j phys ther. 2021; 25:387-95. 30. vega m, mckay er, halani pk. evaluation of mobile applications for patients with fecal incontinence using a modified applications scoring system. int urogynecology j. 2021; 32:2529-36. 31. kruglova k, gelgoot en, chan p, et al. risky business: increasing fertility knowledge of men in the general public using the mobile health application infotility xy. am j mens health. 2021; 15:15579883211049028. correspondence giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md cirilloluigi22@gmail.com marco abate, md marcoabate5@gmail.com simone morra, md (corresponding author) simonemorra93@gmail.com vincenzo morgera, md vincemorgera87@gmail.com biagio barone, md biagio.barone@unina.it felice crocetto, md felice.crocetto@unina.it gianluigi cacace, md cacace.gianlu@gmail.com francesco di bello, md fran.dibello12@gmail.com alessandro palmieri, md info@alessandropalmieri.it vincenzo mirone, md mirone@unina.it ciro imbimbo, md ciro.imbimbo@unina.it luigi napolitano, md luiginap89@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy via sergio pansini n 5, naples (na), campania (italy) lorenzo spirito, md lorenzospirito@msn.com celeste manfredi, md manfredi.celeste@gmail.com davide arcaniolo, md davide.arcaniolo@unicampania.it urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4362 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.362 antioxidant treatment of increased sperm dna fragmentation: complex combinations are not more successful cevahir ozer department of urology, baskent university, adana, turkey. oxidative stress (os) is one of the major causes of dna fragmentation in spermatozoa (8). this makes antioxidants a part of treatment in male infertility. since os can be caused by vastly different oxidants, it is possible to assume that combination therapy will be better than a single agent in antioxidant therapy (9). the purpose of this study was to compare the effectiveness of different antioxidant combinations in infertile men with increased sperm dna fragmentation. materials and methods patients we retrospectively reviewed the records of 637 patients who underwent antioxidant support therapy for increased sperm dna damage between 2014 and 2019. the baseline clinical evaluation for each patient included a comprehensive history and a complete physical examination. semen samples were collected after 2-7 days of sexual abstinence in a specially designated room in our embryology laboratory, with the aid of audiovisual stimulation. conventional semen analysis was performed according to the criteria of world health organization (who). dna fragmentation in spermatozoa was measured using the terminal deoxyribonucleotidyl transferase-mediated dutp nickend labelling (tunel) assay (cell death detection kit, roche biochemicals, mannheim, germany) according to the manufacturer's instructions with minor modifications. all semen tests were repeated at 3 months of treatment. blood samples were taken in the morning to measure follicle-stimulating hormone (fsh), luteinizing hormone (lh) and total testosterone levels at baseline and at the end of 3 months of antioxidant treatment. inclusion and exclusion criteria patients with dna damage of 30% or more were included study. presence of varicocele, leukocytospermia, known genetic abnormality, history of chemotherapy and/or radiotherapy, history of malignancy, history of orchiectomy and/or orchiopexy and patients receiving hormonal therapy were accepted as exclusion criteria. ethical consideration the study was approved by institutional review board (project no: ka19/250). objective: oral antioxidant supplementation is part of the treatment of infertility associated with oxidative stress-related sperm damage. it is possible to assume that the combined use of antioxidants will be better than single agent use. the purpose of this study was to compare the effectiveness of different antioxidant combinations in infertile men with increased sperm dna fragmentation. materials and methods: we retrospectively reviewed the records of 637 patients who underwent antioxidant support therapy for increased sperm dna damage between 2014 and 2019. patients with dna damage of 30% or more were included study. result: a total of 163 patients with follow-up data and who fulfilled the study criteria were included in the study. there were four different treatment groups. no statistically significant differences were found between the groups. after 3 months of antioxidant treatment, there was a statistically significant decrease in sperm dna damage in all treatment groups. however, there was no statistically significant difference between the treatment groups. conclusions: the complexity of the antioxidant combination may not contribute to the success of the treatment or may cause possible side effects, increase the cost of treatment and decrease patient compliance. key words: infertility; oxidative stress; antioxidants. submitted 3 august 2020; accepted 8 september 2020 introduction the conventional semen analysis remains the main diagnostic tool for evaluating male factor infertility (1). however, difficulties resulting from the methodology of the conventional semen analysis significantly reduces the potential diagnostic power of this test. furthermore, the conventional semen analysis cannot clearly identify all cases of male infertility. although conventional semen analysis identifies some features of sperm function, it does not fully assess functional sperm competence (2). the search for a high-diagnostic method that could better predict the etiology and reproductive outcomes of male infertility resulted in a focus on sperm dna integrity and fragmentation (3-5). the level of sperm dna fragmentation seems to correlate negatively with pregnancy and delivery in both natural and assisted conceptions. it is also strongly associated with recurrent spontaneous abortion (6, 7). summary 363archivio italiano di urologia e andrologia 2020; 92, 4 treatment of increased sperm dna fragmentation data interpretation and statistical analysis there were 193 patients who met the study criteria, had follow-up results and used 4 different antioxidant treatment protocols. age, infertility period, history of varicocelectomy, cigarette smoking, alcohol consumption, serum fsh, serum lh and serum testosterone levels, initial conventional semen parameters, and sperm dna damage rate before and after treatment were determined. we used propensity score-matched analysis to balance differences in age, duration of infertility, smoking and alcohol use among antioxidant treatment groups. power value was 76.0% for an effect size value (0.179) that was calculated for sperm dna fragmentation at 3 month of study. with this power value, it was found that the sample size was sufficient. statistical analysis was performed using the statistical package spss software (version 25.0, spss inc., chicago, il, usa). if continuous variables were normal, they were describle as the mean±standard deviation [(p > 0.05 in kolmogorov-smirnov test or shapira-wilk (n < 30)], and if the continuous variables were not normal, they were described as the median. comparisons between groups were made using one way anova for normally distributed data and krukal wallis test were used for the data not normally distributed. since analysis of variance was significant, comparisons were made using the post hoc test or mann-whitney u test. the catagorical variables between the groups was analyzed by using the chi square test. values of p < 0.05 were considered statistically. g-power (version 3.1, department of psychology, university of düsseldorf, germany) was used for post hoc power analysis. results after the treatment groups are homogenized, a total of 163 patients with follow-up data and who fulfilled the study criteria were included in the study. all patients had no known medical problems. the medical history of the patients revealed varicocelectomy in 41 patients. patient characteristics are presented in table 1. no statistically significant differences were found between the groups with regard to age, infertility period, smoking, alcohol consumption, history of varicocelectomy, the initial semen parameters and initial sperm dna damage rate (table 1). there were four different treatment groups that met the criteria. group a received 500 mg daily vitamin c (esterc plus, solgar, usa), 400 iu daily vitamin e (evicap fort, kocak farma, turkey) and 600 mg daily n-acetylcysteine (nac) (assist plus, bilim, turkey). group b received 100 mcg daily selenium (selenium, solgar, usa) and 100 mg daily coenzyme q10 (coq10) (coenzyme q-10, solgar, usa) in addition to vitamin c, vitamin e and nac. group c received commercial multiantioxidant supplement (neofortil m, tani pharma, turkey) in addition to vitamin c, vitamin e and nac. group d received another commercial multiantioxidant supplement (promotil men, centax pharma, turkey) in addition to vitamin c, vitamin e and nac. the multiantioxidant supplement used in group c (neofortil m) contains a daily dose of 600 mg l-carnitine, 250 mg l-arginine, 120 mg vitamin c, 72 mg vitamin e, 15 mg coq10, 60 mcg selenium, 40 mg zinc sulfate and 800 mcg folic acid and the other one used in group d (promotil men) contains a daily dose of 2000 mg l-carnitine, 500 mg l-arginine, 200 mg vitamin c, 120 mg vitamin e, 100 mg coq10, 60 mcg selenium, 60 mg magnesium, 15 mg zinc sulfate, 400 mcg folic acid, 2 mg vitamin b6, 6 mcg vitamin b12, 10 mcg vitamin d, 1 mg vitamin a and 2 mg beta-carotene. table 1. clinical characteristics of patients. group a group b group c group d total p (n: 39) (n: 57) (n: 42) (n: 25) (n: 163) value age (years) 34.91 ± 5.94 36.16 ± 5.01 34.10 ± 4.91 36 ± 5.61 35.31 ± 5.32 0.237 infertility period (years) 5 (1-13) 6 (1-21) 5 (1-5) 7 (1-14) 5 (1-21) 0.211 smoking 15 (44.1) 26 (45.6) 29 (69) 11 (44) 81 (51.3) 0.064 alcohol 0 (0) 4 (7) 3 (7.1) 4 (16) 11 (7) 0.127 varicocelectomy 11 (32.4) 15 (26.3) 8 (19) 7 (28) 41 (25.9) 0.609 semen parameters volume (ml) 3 (1-6) 3 (1-7) 2.5 (1-7) 3 (1-6) 3 (1-7) 0.764 concentration (million/ml) 20 (8-178) 52 (5-282) 63 (3-188) 76 (0-143) 53 (0-282) 0.413 motility (%) 55 (5-75) 55 (0-84) 52.5 (11-79) 55 (0-84) 50 (0-84) 0.983 dna damage (%) 47.72 ± 17.29 50.77 ± 11.26 46.71 ± 10.84 51.12 ± 18.32 49.06 ± 14.03 0.408 table 2. the effect of oral antioxidants on sperm dna damage. initial dna damage (%) 3th month dna damage (%) p group a 47.72 ± 17.29 29.51 ± 12.99 0.0001 group b 50.77 ± 11.26 25.12 ± 13.81 0.0001 group c 46.71 ± 10.84 23.88 ± 16.07 0.0001 group d 51.12 ± 18.32 26.28 ± 18.20 0.0001 total 49.06 ± 14.03 26.03 ± 14.98 0.0001 figure 1. change in dna damage according to treatment groups. archivio italiano di urologia e andrologia 2020; 92, 4 c. ozer 364 after 3 months of antioxidant treatment, there was a statistically significant decrease in sperm dna damage in all treatment groups (table 2 and figure 1). however, there was no statistically significant difference between the treatment groups (p = 0.230). none of the patients had side effects requiring discontinuation of antioxidant support treatment. discussion dna fragmentation of spermatozoa occurs during spermatogenesis and maturation processes. increased sperm dna fragmentation appears to be associated with impaired sperm function. aging, poor lifestyle-related habits (such as smoking, alcohol consumption, environmental radiation and pollution), diseases, drugs, inflammation and infection in the external genital tracts and varicocele may cause an increase in sperm dna fragmentation (8,10-12). all these factors induce sperm dna breaks by three main mechanisms: apoptosis, impairment of sperm chromatin maturation and os (13). os is a condition that is associated with an imbalance between the production and removal of reactive oxygen species (ros) and free radicals (14). antioxidant defense system act as scavengers to neutralize free radicals and overcome the adverse results of os (14, 15). antioxidant system including enzymatic factors (superoxide dismutase, catalase, and glutathione peroxidase), non-enzymatic factors and low-molecular weight compounds (glutathione, nac, vitamin e, vitamin a and c, coq10, carnitines, myo-inositol, lycopene etc.) and nutrients (selenium, zinc, and copper) can protect the body against os (1618). lack of one of these leads to a reduction in the antioxidant capacity of the plasma (17). the rationale behind the use of oral antioxidant therapy is that seminal os is due to increased ros production and/or decreased levels of enzymatic and non-enzymatic seminal antioxidants (19, 20). to date, several studies have shown that exogenous antioxidants have the capacity to counteract oxidative damage or os, improving sperm dna integrity for infertile men with os (18, 21). many oral formulations of antioxidants are readily available in the market and are commonly used to treat men with infertility. the different oral antioxidants available belong to the exogenous antioxidant category and they include vitamin c, vitamin e, coq10, nac, carnitines, trace elements such as zinc, selenium, pentoxifylline, and a combination of these oral antioxidants (20). numerous studies have been conducted to assess the effectiveness of oral antioxidant supplementation for the treatment of infertile men with sperm dna damage. most of the studies showed an improvement in one or more of seminal fluid parameters, whereas some studies reported no positive effect. although there is still no consensus on the type, dosage and duration of antioxidants to be used in the treatment, it appears that in the case of os, doses of antioxidants should be higher than the usual daily dose and because the time required for the development of a mature sperm from spermatogonia is 72 ± 4 days, should be used for at least three months (17, 22, 23). since os may be due to multiple sources, it seems reasonable to assume that a combination of antioxidants targeting the male reproductive system will provide better protection than a single antioxidant (9). however, the complexation of antioxidant therapy may have potential adverse effects including reductive stres (21). furthermore, complex combinations may increase the cost of treatment and may decrease treatment compliance (24). according to our study including 163 patients, complexity of oral antioxidant combination treatment does not appear to contribute to treatment success. the limitation of our study was its retrospective and non-randomized nature. although the small sample size in the groups we compared is another limitation, sample size was found to be sufficient in post hoc power analysis. the variability of the compounds, especially in commercial combinations, is the weakness of our study. since placebo arm ethics is arguable in such studies, we believe that the lack of placebo arm of the study is not a limitation. furthermore, the effect of improvement in sperm dna damage on fertility has not been studied because the female group was not homogenous. conclusions the use of oral antioxidants can help to reduce os and to treat os related sperm dna damage. the use of antioxidant agent combinations is expected to be more successful in the treatment than a single agent. however, it should be noted that the complexation of the combination may not provide an additional contribution to treatment success. therefore, possible side effects, treatment cost and patient compliance should be kept in mind when designing combination protocols. acknowledgements the author would like to thank biostatistics specialist cagla sariturk for her expertise and assistance in statistical analysis. references 1. komiya a, kato t, kawauchi y, et al. clinical factors associated with sperm dna fragmentation in male patients with infertility. scientific world journal. 2014; 2014:868303. 2. santi d, spaggiari g, simoni m. sperm dna fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management meta-analyses. reprod biomed online. 2018; 37:315-326. 3. bungum m. sperm dna integrity assessment: a new tool in diagnosis and treatment of fertility. obstet gynecol int. 2012; 2012:531042. 4. agarwal a, said tm. role of sperm chromatin abnormalities and dna damage in male infertility. hum reprod update. 2003; 9:331345. 5. sakkas d, mariethoz e, manicardi g, et al. origin of dna damage in ejaculated human spermatozoa. rev reprod. 1999; 4:31-37. 6. agarwal a, cho cl, esteves sc. should we evaluate and treat sperm dna fragmentation? curr opin obstet gynecol. 2016; 28:164-171. 7. evgeni e, charalabopoulos k, asimakopoulos b. human sperm 365archivio italiano di urologia e andrologia 2020; 92, 4 treatment of increased sperm dna fragmentation dna fragmentation and its correlation with conventional semen parameters. j reprod infertil. 2014; 15:2-14. 8. wright c, milne s, leeson h. sperm dna damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. reprod biomed online. 2014; 28:684-703. 9. lewis se, john aitken r, conner sj, et al. the impact of sperm dna damage in assisted conception and beyond: recent advances in diagnosis and treatment. reprod biomed online. 2013; 27:325-337. 10. pourmasumi s, sabeti p, rahiminia t, et al. the etiologies of dna abnormalities in male infertility: an assessment and review. int j reprod biomed (yazd) 2017; 15:331-344. 11. cai t, wagenlehner fm, mazzoli s, et al. semen quality in patients with chlamydia trachomatis genital infection treated concurrently with prulifloxacin and a phytotherapeutic agent. j androl. 2012; 33:615-623. 12. alargkof v, kersten l, stanislavov r, et al. relationships between sperm dna integrity and bulk semen parameters in bulgarian patients with varicocele. arch ital urol androl. 2019; 91. 13. moustafa mh, sharma rk, thornton j, et al. relationship between ros production, apoptosis and dna denaturation in spermatozoa from patients examined for infertility. hum reprod. 2004; 19:129-138. 14. pham-huy la, he h, pham-huy c. free radicals, antioxidants in disease and health. int j biomed sci. 2008; 4:89-96. 15. kao sh, chao ht, chen hw, et al. increase of oxidative stress in human sperm with lower motility. fertil steril. 2008; 89:11831190. 16. calogero ae, condorelli ra, russo gi, la vignera s. conservative nonhormonal options for the treatment of male infertility: antibiotics, anti-inflammatory drugs, and antioxidants. biomed res int. 2017; 2017:4650182. 17. walczak-jedrzejowska r, wolski jk, slowikowska-hilczer j. the role of oxidative stress and antioxidants in male fertility. cent european j urol. 2013; 66:60-67. 18. arcaniolo d, favilla v, tiscione d, et al. is there a place for nutritional supplements in the treatment of idiopathic male infertility? arch ital urol androl. 2014; 86:164-170. 19. zini a, al-hathal n. antioxidant therapy in male infertility: fact or fiction? asian j androl. 2011; 13:374-381. 20. alahmar at. role of oxidative stress in male infertility: an updated review. j hum reprod sci. 2019; 12:4-18. 21. gharagozloo p, aitken rj. the role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. hum reprod. 2011; 26:1628-1640. 22. alahmar at. the impact of two doses of coenzyme q10 on semen parameters and antioxidant status in men with idiopathic oligoasthenoteratozoospermia. clin exp reprod med. 2019; 46:112-118. 23. agarwal a, nallella kp, allamaneni ss, said tm. role of antioxidants in treatment of male infertility: an overview of the literature. reprod biomed online. 2004; 8:616-627. 24. mcdonald hp, garg ax, haynes rb. interventions to enhance patient adherence to medication prescriptions: scientific review. jama. 2002; 288:2868-2879. correspondence cevahir ozer, md (corresponding author) cevahirozer@gmail.com dadaloglu mh serinevler 2591 sk no: 4/a, 01250 yuregir, adana (turkey) 203archivio italiano di urologia e andrologia 2018; 90, 3 original paper hibiscus extract, vegetable proteases and commiphora myrrha are useful to prevent symptomatic uti episode in patients affected by recurrent uncomplicated urinary tract infections tommaso cai 1, daniele tiscione 1, andrea cocci 2, marco puglisi 1, gianmartin cito 2, gianni malossini 1, alessandro palmieri 3 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology, university of florence, florence, italy; 3 department of urology, university of naples, federico ii, naples, italy. objective: to evaluate the efficacy of a combination of hibiscus extract, vegetable proteases and commiphora myrrha extract in the prophylaxis of symptomatic episode in women affected by recurrent urinary tract infections (rutis). materials and methods: in this phase ii clinical trial, all patients with history and diagnosis of ruti were enrolled. all patients underwent the following treatment schedule: 1 tablet in the morning and 1 tablet in the evening for 7 days and, then, 1 tablet in the evening for 10 days (1 cycle every each month, for 6 months) of a combination of hibiscus extract, vegetable proteases and commiphora myrrha extract. at the baseline, all patients underwent urologic visit with quality of life (qol) questionnaires and mid-stream urine culture. after 3 and 6 months, all patients underwent urologic visit, urine culture and qol questionnaires evaluation. results: fifty-five women were enrolled (mean age 49.3; range: 28-61). at the enrollment time, the most common pathogen was escherichia coli (63.7%). the median number of uti per 6 months was 5 (iqr: 4-9). at the end of the second follow-up evaluation, 25 women did not reported any symptomatic episode of uti (49%), 18 reported less than 2 episodes (35.3%), while 8 reported more than 2 episodes (15.7%). however, at the first and second follow-up evaluation the clinical statistically significant improvement (qol) was reported by 38/51 (74.5%) (p < 0.001 from baseline) and 43/51 (84.3%) (p < 0.001 from baseline) women, respectively. the median number of uti decreased to 2 (iqr: 0-3). at the end of the follow-up period, 30/51 had sterile urine (58.8%), while 21/51 (41.2%) reported a transition from symptomatic uti to asymptomatic bacteriuria. conclusions: in conclusion, this treatment, in motivated patients, is able to prevent symptomatic uti symptomatic episode and improve patient’s qol. key words: urinary tract infection; ellirose; protelix; serrazimes; myrliq; plant extracts; antibiotic stewardship; treatment. submitted 11 august 2018; accepted 24 august 2018 summary no conflict of interest declared. healthcare costs (1). overall, more than 50% of women report having had at least one uti at some point in their lifetime, and it is estimated that almost 11% of women aged over 18 suffer from a uti each year (2-3). in particular, utis recur approximately in 20-30% of women within 6 months after their first episode (1, 4) and in around 35 to 53% of women within 12 months (5). the management of recurrent uncomplicated utis in women is still object of great discussion. to date, there are not well-established recommendations for a ‘standard’ prophylactic protocol to prevent recurrent uti (6). since the mainstay for the management of recurrent uti still remains a short course of oral antimicrobial therapy, on the other hand the frequent use of antibiotics has led to the spread of multidrug-resistant microorganisms (710). possible side effects, although rare, increasing healthcare costs, and rising bacterial resistance have progressively marked the downfall of classic antibiotic prophylaxis and, over years, paved the way to consider alternative prophylactic methods (4). in this regard nonpharmacological oral supplements, including the phytotherapy and nutraceuticals, seem to be an attractive alternative to antibiotic therapy to ameliorate symptoms related to utis and lower the rate of symptomatic recurrences. these considerations led us to conduct a prospective non-randomized phase ii clinical trial in order to evaluate the efficacy of a combination of ellirose®, protexil®, serrazimes® and myrliq® (aviur® retard) in the prophylaxis of symptomatic episode in women affected by recurrent utis focusing on both the capability to reduce the number of symptomatic recurrences and the efficacy in improving qol. materials and methods study design from september to december 2017, we enrolled in a prospective, non-randomized phase ii study, all women affecting by recurrent uncomplicated uti and attending our centre. written informed consent was obtained doi: 10.4081/aiua.2018.3.203 introduction urinary tract infections (utis) represent the most frequently reported community-acquired infection and carry a significant burden for patients’ quality of life and cai_stesura seveso 04/10/18 11:18 pagina 203 archivio italiano di urologia e andrologia 2018; 90, 3 t. cai, d. tiscione, a. cocci, m. puglisi, g. cito, g. malossini, a. palmieri 204 from all subjects before proceeding with the enrollment. preliminary evaluation was performed by administering qol questionnaires and by performing a preliminary mid-stream urine culture, in line with cai t et al. (11). before enrolment all patients were treated with antibiotics in line with trialist’s choice in order to obtain the infection free condition at baseline. the last isolated bacterial strain before the antibiotic treatment was collected and consider for this analysis. the main outcome measure was, then, the recurrence-free condition at the follow-up visit. all enrolled patients underwent the following treatment schedule: aviur retard® 1 tablet in the morning and 1 tablet in the evening for 7 days and, then, 1 tablet in the evening for 10 days (1 cycle each month, for 6 months). after 30 days from the beginning of the treatment, all patients have been contacted by phone in order to ensure compliance to the treatment. subsequent follow up schedule included urologic visit with qol questionnaires and mid-stream urine culture performed after 3 and 6 months from the beginning of the therapy. in case of acute symptomatic uti episode all patients were treated with antibiotics in line with european association of urology (eau) guidelines on urological infections (12) and in line with the antibiogram. the figure 1 shows the study schedule. clinical and microbiological considerations in accordance with the eau guidelines, the diagnosis of uti was defined according to the following parameters: patient reported symptoms and patient interview, physical examination, bed-side dip-stick urinalysis and urine culture (12). all microbiological and laboratory analyses have been described previously (13). in brief, all cleancatch midstream urine samples collected at room temperature were immediately taken to the laboratory under refrigerated conditions and analyzed. all urine samples were analyzed for common bacteria and yeasts, aliquoted for dna extraction and polymerase chain reaction testing for chlamydia trachomatis, neisseria gonorrhoeae, and urogenital mycoplasma. microbiological culture was performed according to the procedure described by hooton et al. (14). all other microbiological procedures and dna extraction have been performed in line with mazzoli et al. (15). for microbiological diagnosis, a colony count ≥ 105 units/ml was considered the cutoff for significant bacterial growth. inclusion and exclusion criteria we included in this study all patients with recurrent uti, defined as ≥ 2 infections in six months or ≥3 infections in one year. relevant exclusion criteria comprised: evidence of overactive bladder; anatomical abnormalities or previous surgery of the urinary tract; complicated uti; pregnancy; urinary catheterization. moreover, we excluded all patients with active infection by std pathogens. we did not include any other exclusion criteria in order to make the results clinically relevant. composition and characterization of the extracts used all patients who were treated in line with the manufacturer’s instructions (anatek health italia s.r.l. via a. caroncini, 5 20137 milano; www.anatekhealth.com). each administration contained a combination of 200 mg ellirose™, 100 mg protexil®sp750, 100 mg serrazimes®, 60 mg myrliq®pwd. outcome measures and statistical analysis the primary outcome of this study was the rate of recurrence at the end of the study period. a good response to treatment was defined as a significant reduction of recurrences (< 2 in six months). treatment failure was defined as the absence of recurrence reduction at the end of the study period. transition from symptomatic uti to asymptomatic bacteriuria was not considered as treatment failure. in order to obtain significant results to analyze, sample size calculation was based on the following assumptions: difference in terms of recurrence between baseline and follow-up visit: -3 ± 1; α error level, 0.05 two-sided; statistical power, 80%; anticipated effect size, cohen’s d = 0.5. the calculation yielded 43 individuals. taking into account a drop-out rate of 10%, the final sample size has been set to 49 patients in the both groups. statistical analysis was performed by using spss. results fifty-five women were enrolled (mean age 49.3; range: 28-61). at the time of enrollment,the most common isolated pathogen was escherichia coli (63.7%). all patients obtained sterile urine after antibiotic before enrollment. the median number of uti per 6 months was 5 (iqr 49). demographic, microbiological and clinical characteristics at the time of enrollment are reported in table 1. clinical and microbiological data at the first follow-up evaluation (3 months) after 3 months from the beginning of the treatment, 43 out of 51 patients (84.3%) reported a clinical improvement in terms of qol form the baseline (p < 0.001), figure 1. cai_stesura seveso 04/10/18 11:18 pagina 204 while 42 out of 51 patients (82.3%) reported a restore to pre-uti situation. from a microbiological point of view, 40 patients (78.4%) showed sterile urine and 11 (20%) showed a transition from uti to abu (from escherichia coli to enterococcus faecalis). clinical and microbiological data at the second followup evaluation (6 months) at the end of the second follow-up evaluation, 25 women did not reported any acute episode of uti (49%), 18 reported less than 2 episodes (35.3%), while 8 reported more than 2 episodes (15.7%). however, at the first and second follow-up evaluation the clinical statistically significant improvement (qol) was reported by 38/51 (74.5%) (p < 0.001 from baseline) and 43/51 (84.3%) (p < 0.001 from baseline) women, respectively. moreover, the median number of uti decreased to 2 (iqr 0-3). from a microbiological point of view, at the end of the follow-up period, 30/51 sterile urine samples (58.8%) and 21/51 (41.2%) reported a transition from symptomatic uti to abu. the table 2 shows all clinical and microbiological data at the second follow-up evaluation. adherence results and treatment related adverse effects at the end of the study period, the adherence to the therapy was very high. only one patient (1.8%) discontinued the prescribed therapy because of the onset of drug-related adverse effects, nausea in this particular case. discussion the inappropriate use of antibiotics during last years has been paralleled by the growing onset of multidrug-resistant pathogenic strains among community-acquired isolates. the evolution of antimicrobial resistances has resulted into a global public health challenge, with rising costs and greater risk of poorer patient outcomes. nowadays antibiotic stewardship protocols represent a precise imperative need. unfortunately, to date there is not a “gold standard” prophylactic management to prevent recurrent uti. actually, european association of urology guidelines report several non-antibiotic measures for preventing recurrent utis but only a few are based on well-designed randomized clinical trials (13). however it cannot be denied that during last years research in non-antibiotic prophylaxis of recurrent utis has gradually grown. particularly the use of phytotherapy and nutraceuticals might represent a feasible alternative approach for reducing the use of antibiotics and decreasing the rate of symptomatic recurrences (4, 1617). in this light, in this phase ii clinical trial we evaluated the efficacy and safety of a new nutraceutical agent named containing ellirose®, protexil®, serrazimes® and myrliq® in the prophylaxis of symptomatic episodes in women affected by recurrent utis. in our experience aviur® retard was well tolerated, resulting in optimal compliance since only one patient experienced adverse drug related effect which forced the discontinuation of the therapy. moreover a statistically significant improvement in qol was reported in almost 74.5% of patients and in 84% at first and second follow up visit respectively. also from a microbiological point of view aviur® retard showed promising results since almost 60% of patients at the end of the follow-up period showed sterile urine and more than 40% reported a transition from symptomatic uti to abu. to this regard, a significant body of evidence advocated that abu could play a protective role in preventing symptomatic uti recurrences, interfering with the establishment of many enteric pathogens, such as e. coli (8). noteworthy the fact that aviur® retard is able to establish an abu is a tangible proof of the absence of its effects on the normal microbiota. in this sense, the use of non-antibiotic approach should be preferred since it doesn’t interfere with the normal commensal bowel flora. aviur® retard is made of a combination of several nutraceutical agents playing different roles in the prevention of symptomatic uti recurrences. ellirose®, an ibiscus dry extract, is a phytocomplex containing sambubiosides, which seem to have an anti-inflammatory activity by reducing the levels of 205archivio italiano di urologia e andrologia 2018; 90, 3 hibiscus extract, vegetable proteases and commiphora myrrha are useful to prevent symptomatic uti episode table 1. patient’s sociodemographic anamnestic, clinical characteristics at enrolment time. no. of total patients 55 median age (range) 49.3 (28-61) educational level primary school secondary school 25 (45.5) post-secondary education 30 (54.5) sexually active (past month) 48 (87.3) current smoker no 21 (38.2) yes 34 (61.8) number of sex partners 1 49 (89.1) ≥ 1 6 (10.9) number of uti in the past 6 months 2 39 (70.9) ≥ 2 16 (29.1) hormonal status pre-menopausal 35 (63.7) post-menopausal 20 (36.3) isolated strains before abt treatment escherichia coli 35 (63.7) klebsiella spp. 10 (18.2) enterococcus spp. 7 (12.7) others 3 (5.4) table 2. all patient’s sociodemographic anamnestic, clinical characteristics at enrolment time. abt: antibiotic treatment. outcomes variable baseline follow-up p 180 days clinical improvement no episode of uti 0/51 25/51 (49) < 2 episodes of uti 0/51 18/51 (35.3) < 0.001 > 2 episodes of uti 51/51 8/51 (15.7) qol (questionnaire) 91.3 99.0 < 0.001 microbiological improvement sterile urine 0/51 30/51 (58.8) < 0.001 transition to abu from uti 0/51 21/51 (41.2) < 0.001 cai_stesura seveso 04/10/18 11:18 pagina 205 archivio italiano di urologia e andrologia 2018; 90, 3 t. cai, d. tiscione, a. cocci, m. puglisi, g. cito, g. malossini, a. palmieri 206 inflammatory mediators such as inos, no, il-6, mcp1, and tnf-α induced by lps (18). protexil® is a form of concentrated protease derived as an exogenous production from controlled fermentation of maltodextrins through the aspergyllus oryzae. the protease, once absorbed into the blood stream, effectively performs anti-inflammatory and anti-edema functions (19-20). particularly, the proteases from protexil® are bound to alpha 2-macroglobulines, which are thus modified into an activated form. once activated, the alpha-2-macroglobulines bind the citokines tnfalpha (tumor necrosis factor alpha) and tgf-beta (transformative growth factor beta), modulating their activity in an anti-inflammatory way. similarly, serrazimes® is a proteolytic blend composed of enzymes derived from non-pathogenic enterobacteria belonging to genus serratia species e-15. serrazimes® contributes to the maintenance of a balanced immune system response by regulating protein-based immune cell inflammation mediators. it seems that serrazimes® has also an additional analgesic activity due to its capability to block the release of biogenic amines. (19) finally, myrliq® is a commiphora myrrha extract with a standardized content of curzerene, furanoeudesma-1,3-diene, and lindestrene and a high total furanodiene content (20) recent evidence showed that myrrh extract inhibits the production of interluchin-6 (il-6) and interluchin-8 (il-8) in human fibroblast cells. in addition it is involved in the blockage of the proteins involved in the inflammatory process such as cox and also inhibits the formation of no, ros, tnf-α, pge2, nf-kb and mapk (21-22). our results showed that aviur® retard can be taken into consideration as a potential effective prophylactic agent for symptomatic recurrent utis. however, the present study was not devoid of several limitations. possible shortcomings of the study lie in the lack of randomization as well as in the small cohort size. each of these variables might have introduced statistical bias and weaken the overall reliability of the reported findings. acknowledged the limitations, the present study represents the largest series so far evaluating the prophylactic effect of ellirose®, protexil®, serrazimes® and myrliq® in women suffering from recurrent uncomplicated utis. although antimicrobials remain the mainstay of treatment for acute uti, the spread of multidrug resistant microorganisms among community-acquired isolates is worryingly increasing and needs for stronger surveillance and new preventing approaches. only advancing our understandings about alternative treatments, such as phytotherapty and nutraceuticals, will enable us to develop appropriate non-antibiotic approaches and prevention strategies for recurrent utis. to this regard, further phase iii randomized studies and larger series will certainly be needed to confirm and validate our preliminary results. conclusions recurrent urinary tract infections afflict a large number of young women nowadays, with a high impact on patient’s quality of life. currently, several strategies have been purposed and used in order to reduce the number of recurrence and improve qol, without any significant achievement. here, considering the available evidence, the use of phytotherapy seems a feasible antibiotic-sparing approach for reduce the number of recurrence. in our experience, the treatment with aviur retard®, in motivated patients, is able to prevent symptomatic uti episode and improve patient’s qol. moreover, the use of aviur retard® is be able to improve the antibiotic stewardship, reducing the use of antibiotic prophylaxis in these patients. however, further prospective studies are needed to validate our results in larger series. references 1. silverman ja, schreiber hl 4th, hooton tm, hultgren sj. from physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. curr urol rep. 2013; 14:448-56. 2. foxman b, brown p. epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. infect dis clin north am 2003; 17:227-241. 3. jennifer a. silverman, ph.d., henry l. et al. from physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. curr urol rep. 2013; 14:448-56. 4. cai t, tamanini i, kulchavenya e, et al. the role of nutraceuticals and phytotherapy in the management of urinary tract infections: what we need to know? arch ital urol androl. 2017; 89:1. 5. bojana kranjcˇec, dino papesˇ, silvio altarac. d-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. world j urol. 2014; 32:79-84. 6. tandogzu z, wagenlehner fm. global epidemiology of urinary tract infections. curr opin infect dis. 2016; 29:73-79. 7. kostakioti m, hultgren sj, hadjifrangiskou m. molecular blueprint of uropathogenic escherichia coli virulence provides clues toward the development of anti virulence therapeutics. virulence. 2012; 3:592-594. 8. cai t, mazzoli s, mondaini n, et al. the role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? clin infect dis. 2012; 55:771. 9. gupta k, scholes d, stamm we. increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. jama 1999; 281:736-8. 10. naber kg, bergman b, bishop mc, et al. urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau). eau guidelines for the management of urinary and male genital tract infections. eur urol. 2001; 40:576-88. 11. cai t, cocci a, tiscione d, et al. l-methionine associated with hibiscus sabdariffa and boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: focus on antibiotic-sparing approach. arch ital urol androl. 2018; 90:97-100. 12. grabe m, bjerklund-johansen te, botto h et al. antibiotics. in:grabe m, bjerklund-johansen te, botto h, et al. (editors) guidelines on urological infections. arnhem: european association of urology. 2010; p. 69. 13. cai t, nesi g, mazzoli s, et al. asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant cai_stesura seveso 04/10/18 11:18 pagina 206 strains in women with urinary tract infections. clin infect dis. 2015; 61:1655-61. 14. hooton tm, scholes d, gupta k, et al. amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. jama. 2005; 293:949-55. 15. mazzoli s, cai t, rupealta v, et al. interleukin 8 and antichlamydia trachomatis mucosal iga as urogenital immunologic markers in patients with c. trachomatis prostatic infection. eur urol. 2007; 51:1385-93. 16. stange r, schneider b, albrecht u, et al. results of a randomized, prospective, double-dummy, double-blind trial to compare efficacy and safety of a herbal combination containing tropaeoli majoris herba and armoraciae rusticanae radix with cotrimoxazole in patients with acute and uncomplicated cystitis. res rep urol. 2017; 9:43-50. 17. ledda a, belcaro g, dugall m, et al. highly standardized cranberry extract supplementation (anthocran®) as prophylaxis in young healthy subjects with recurrent urinary tract infections. eur rev med pharmacol sci. 2017; 21:389-393. 18. sogo t, terahara n, hisanaga a, et al. anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a hibiscus anthocyanin. biofactors. 2015; 41:58-65. 19. bhagat s, agarwal m, roy v. serratiopeptidase: a systematic review of the existing evidence. int j surg. 2013; 11:209-17. 20. germano a, occhipinti a, barbero f, et al. a pilot study on bioactive constituents and analgesic effects of myrliq®, acommiphora myrrha extract with a high furanodiene content. biomed res int. 2017; 2017:3804356. 21. su s et al. evaluation of the anti-inflammatory and analgesic properties of individual and combined extracts from commiphora myrrha, and boswellia carterii.. j ethnopharmacol. 2012; 139:649-56. 22. bellezza i, et al. furanodien-6-one from commiphora erythraea inhibits the nf-kb signalling and attenuates lps-induced neuroinflammation. mol immunol. 2013; 54:347-54. 207archivio italiano di urologia e andrologia 2018; 90, 3 hibiscus extract, vegetable proteases and commiphora myrrha are useful to prevent symptomatic uti episode correspondence tommaso cai, md ktommy@libero.it daniele tiscione, md marco puglisi, md gianni malossini, md department of urology, santa chiara hospital largo medaglie d'oro 9, trento, italy andrea cocci, md gianmartin cito, md department of urology, university of florence, florence, italy alessandro palmieri, md department of urology, university of naples, federico ii, naples, italy cai_stesura seveso 04/10/18 11:18 pagina 207 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 14 original paper better surgical accuracy. the lack of comparative studies between the different surgical approaches has not allowed for many years to establish which of open, laparoscopic or robotic surgery guarantees better oncological and functional long-term results. today, the most commonly used procedures in various urological centers are laparoscopic and robotic surgery because they are considered minimally invasive techniques but open radical prostatectomy (orp) remains well established and commonly performed in many parts of the world (1). recently alexander haese et al. in a comparative study of robot-assisted and open radical prostatectomy in 10 790 men conclude that: “both surgical approaches, performed in a high volume centre by the same surgeons, achieve excellent, comparable oncological and functional outcomes” (2). we present in this study our experience in traditional open radical prostatectomy surgery performed under spinal anesthesia. materials and methods for analysis in this study, we reviewed the clinical courses of 88 consecutive patients who underwent orp between 05/2016 and 06/2021 at our institution. preoperatively, after diagnostic assessment of prostate cancer with transrectal eco-guided biopsy, an abdominal computerized tomography and bone scintigraphy were performed for staging the disease. pathology results in all patients confirmed adenocarcinoma of the prostate gland. however, some patients with prostate cancer diagnosed elsewhere were also referred to our hospital for further definite treatment. preoperative investigations included a complete blood count, serum coagulation, electrolytes, creatinine, electrocardiogram, and chest x-ray. we have placed the indications for the surgical treatment following the european guidelines 2020, edition 2021. morbidity influenced the choice of the anesthetic regimen. patients with a history of myocardial infarction, previous cerebrovascular accident, transient ischemic attack from the study within a year preoperatively and extensive spinal surgery were considered cases of contraindication for regional anesthesia and the patients were excluded from the study. instead, we considered eligible for the study patients with previous prostate surgery or endoscopic prostate procedures subjected to subsequent open radical prostatectomy. each patient was informed in detail about objective: prostate cancer is one of the most widespread neoplasms affecting the male gender. the most commonly used procedures in various urological centers are laparoscopic and robotic surgery because they are considered minimally invasive techniques. we present our experience in traditional open radical prostatectomy performed under spinal anesthesia. materials and methods: we reviewed the clinical courses of 88 consecutive patients who underwent open radical prostatectomy performed under spinal anesthesia at our institution. results: median age: 67.7 years. median follow up duration: 48 months. median pre-operative psa: 15,9 ng/ml, median prostate weight: 44.5 gr, median surgical time: 96.5 minutes (range 55138). perioperative complications were recorded. the most frequent complication was anemia, 9 cases need blood transfusion after surgery. complications directly related to spinal anesthesia were not observed. most patients were discharged within 5 days from the procedure. after two weeks we observed a quick recovery of total continence in 90% of patients. after 6 months all patients were perfectly continent. erectile dysfunction after 6 months was reported by 48 patients. conclusions: the reasons why the gold standard of radical prostatectomy surgery has been considered general anesthesia are essentially two: the long duration of the surgical procedure and the associated significant blood loss. multiple evidences show that radical retropubic prostatectomy can be safely performed under spinal anaesthesia with various advantages. it is therefore no longer justified to consider general anesthesia as the gold standard for radical prostatectomy with an open technique. key words: prostate cancer; radical prostatectomy; spinal anesthesia. submitted 28 february 2023; accepted 20 march 2023 introduction prostate cancer is one of the most widespread neoplasms affecting the male gender all over the world with variable incidence in relation to the geographical area considered. the gold standard remains in most cases the radical surgical removal of the prostate and district lymph nodes. the anatomical characteristics of the surgical field have made radical prostatectomy the most performed surgical procedure in the world with robotic-assisted laparoscopic technique; this is due to the search for less invasiveness and effectiveness and safety of spinal anesthesia in patients undergoing open radical retropubic prostatectomy salvatore blanco 1, angelica grasso 2, endrit sulmina 3, marco grasso 1 1 department of urology, fondazione irccs san gerardo dei tintori, monza, italy; 2 department of urology, asst santi paolo e carlo, university of milan, milan, italy; 3 department of anesthesia and intensive care medicine, fondazione irccs san gerardo dei tintori, monza, italy. doi: 10.4081/aiua.2023.11281 summary archivio italiano di urologia e andrologia 2023; 95, 2 s. blanco, a. grasso, e. sulmina, m. grasso 15 the advantages and disadvantages of spinal anesthesia and the accompanying risk factors. we have not considered patients’ bmi, although adiposity could influence the outcomes of prostatectomy. we might evaluate this topic in a different work. spinal anesthesia method subarachnoid or spinal anesthesia is a central locoregional anesthesia technique in which the anesthetic, whether or not combined with opiates or alpha agonists, is injected into the subarachnoid space, into the cephalorachid fluid surrounding the spinal cord, reversibly inhibiting sensory and motor nerve conduction. to perform the spinal anesthesia, the patient is positioned seated with knees flexed to 90° and relaxed shoulders, chin touching the chest, trying to bend the lumbar vertebrae outwards, causing the intervertebral space to open allowing the needle to pass through. careful disinfection of the skin with alcoholic solution or iodopovidone is performed. a sterile drape with a central slit is placed and the intervertebral space is searched by palpating the spinous processes of the lumbar vertebrae, then local anesthesia of the skin and the inter spinous and yellow ligaments is applied. for radical prostatectomy the space usually chosen is l2-l3 where hyperbaric bupivacaine is injected at a dosage of 0.12-0.15 mg/kg for a total of 12-14 mg with the addition of an opiate, disufen 2-4 mcgr or morphine 100200 mcg, which prolongs both the duration of anesthesia and postoperative pain control. the drug is injected in a cephalic direction to achieve a level of anesthesia of at least t9-t10, sufficient to cover the skin metameres at the surgical incision site, sub umbilical-pubic. mild or deep sedation is combined for the duration of the operation with benzodiazepines or hypnotics while maintaining spontaneous breathing. the duration of spinal anesthesia is approximately 2-3 hours after which the motor and sensory blockade is slowly resumed, which is prolonged up to 4 hours with the addition of opioids. intraoperative monitoring is done with a 5-lead ecg, with non invasive blood pressure monitoring every 5' and measurement of peripheral saturation. it is useful to place 2 venous accesses of at least 18 g, to perform loading with 500-1000 ml crystalloid and to have blood available as it is an operation with important fluid shift. the side effects of this anesthesia are usually hypotension and bradycardia, easily reversible. time in surgery we defined time of surgery as the period between start of cut on the suprapubic skin and the end of agraffes skin affixing. to reduce variations in surgical skill and experience of the surgeon, all patients in this series of open radical prostatectomies with spinal anesthesia were operated by two surgeons. surgical procedure we describe the technique of open radical prostatectomy developed on the basis of a personal series of more than 1500 procedures. we perform a conventional median surgical incision starting under umbilicus with pelvic space exposure. we performed a bilateral pelvic lymphadenectomy in all patients independently of value gleason grade biopsies or prostate specific antigen (psa) level. the operation was carried out using some variants with respect to the original technique described by walsh (3). our approach results from surgical experience observations collected since 1995 with patients subjected to radical prostatectomy with bladder neck preservation (4) and also using our particular experience in radio guided radical prostatectomy with sentinel lymph node dissection (5). during detachment of the prostate from the bladder, an electro incision was made in the demarcation point between the bladder and the gland, which was highlighted by palpating the balloon of a foley catheter inflated to 10 cc and tautened. following an electro incision extended by about 270° (i.e. from one lateral peduncle to the other in order to spare the ventral area), detachment of the prostatic gland on an anatomic plane was carried out manually by the surgeon. at the end of this operation, urethral and periurethral muscle fibers sectioning were performed by means of scissors. during this stage, particular attention should be paid to the prevention of lesions of the prostatic capsule, or lacerations in the bladder wall, especially in the ventral area. having removed the prostate-vesicular block, bladder neck biopsies were carried out in all quadrants; the urethrovesical anastomosis was performed with the aid of a urethral protractor (6) with 6 single 3/0 monocryl suture. the catheter was removed on the 11th day without the need of any radiological check. patients were discharged usually in the fourth day after surgery. in this study, we focused on findings useful to evaluate if spinal anesthesia could be an efficient and suitable technique for this procedure. particularly we evaluated the abdominal and pelvic muscle relaxation throughout the procedure on a scale of 1 to 4, with 1 indicating poor muscle relaxation and 4 excellent muscle relaxation as already indicated in other experiences of the efficacy of spinal anesthesia on muscle relaxation throughout the operative period (7). we also want to underline the good control of pain in the first postoperative hours which allowed to avoid or reduce the use of opiate drugs. postoperative period postoperatively all patients were monitored in the post anesthesia care unit (pacu). post anesthetic management of the patient included periodic assessment and monitoring of function of the lower urinary tract (urine output, drainage and bleeding), of respiratory function, cardiovascular function, neuromuscular function, temperature, pain (especially the ability of the patient to communicate breakthrough pain or if the feelings of tension is present in the abdominalpubic area), mental status, nausea and vomiting, fluid assessment. postoperative pain management was easily controlled with oral analgesics (fans) since spinal anesthesia demonstrated excellent pain control for at least four to five hours after surgery. therefore, an early mobilization was still guaranteed. hospital stay in order to compare time of hospital stay, minimum and maximum values and median values were calculated. low-weight heparin was administered in the post-operative period (at the end of the hemorrhagic risk) every day of hospitalization, at midnight, and then at home for at least fifteen days. archivio italiano di urologia e andrologia 2023; 95, 2 16 spinal anesthesia for open radical retropubic prostatectomy overall functional follow up the follow-up of the patients monitored the degree of urinary continence achieved during the immediate postoperative period (two weeks after the operation), then at three months, six months and one year after the operation. the degree of continence was assessed during the immediate post-operative period by compilation of a previously validated questionnaire (7), in which patients were invited to annotate actual urine leaks, as well as the need for protective pads. in this study, we defined “dry or continent” patients who did not use pads or just used a safety pad in a day because many patients used a pad as a precautionary measure, despite their sufficient continence. those patients who were completely dry or only subject to a sporadic leakage of drops of urine due to micturition urgency, or on straining or coughing, were defined as continent. finally, we evaluated intraoperative and postoperatively early and late complications of open radical prostatectomy and spinal anesthesia. early complications were defined as those that developed within one month postoperatively, and late ones those observed at least 1 month after operation. results we retrospectively screened 88 patients undergoing open radical prostatectomy for clinically localized prostate cancer (pca). median age was 67.7 years (range from 46 to 81 years) and median follow up duration was 48 months (6 to 54 months). median pre-operative psa was 15.9 ng/ml (range 2.1-80), median prostate weight (as reported by pathologist) was 44.58 g (range 12-86). median preoperative hb was 14.3 mg/dl, at hospital discharge hb was 10.3 mg/dl, and 9 patients have been transfused. median surgical time (calculated by surgical incision until closure of the skin) was 96.5 minutes (range 55-138). clinical-pathological stage were recorded in table 1. the efficacy of spinal anesthesia on muscle relaxation throughout the operative period has been always judged adequate by the surgeon. in all cases the surgery lasted less than two hours and the use of spinal anesthesia was more than sufficient. perioperative complications (intrapostoperatively) were recorded. the most frequent complication was post-operative anemia which was observed in 9 cases out of 88 requiring blood transfusion during stay in hospital and always after surgery. other early complications observed were anastomotic leakage in 2 patients that required prolonged drainage for more than 2 weeks with consequent extension of hospital stay. surgical site infection was observed in 3 patients, in all cases the infections were superficial and did not need specific treatment, surgical drainage being not required in any case. early complications directly related to spinal anesthesia were never observed. late complications were only related to surgical procedure: anastomotic stricture with poor urinary stream (< 10 ml/sec in qmax by uroflowmetry) was observed in 5 patients, requiring an endoscopic incision; more than half of them occurred within 6 months after operation. no case of lymphocele that required specific therapy. anterior urethral stricture was observed in 2 patients. most patients were discharged within 5 days from the procedure (range 3-17). following an anamnestic assessment conducted two weeks after the operation, we observed a quick recovery of total continence in 90% of patients. at six months visit all patients were perfectly continent. erectile dysfunction after 6 months was reported by 48 patients (not considering in this work the pre-operative status, the comorbidities and the correct intake of post-operative pde5 inhibitors). patients’ satisfaction was high; most of them confirmed that they were very happy with this anesthesia. discussion open radical retropubic prostatectomy is an effective treatment for localized prostate cancer but adequate anesthesiologic management is mandatory. spinal anesthesia is a form of regional anesthesia, which indications include lower abdominal and perineal surgery as are many genitourinary surgeries. the use of spinal anesthesia during radical prostatectomy is not usually considered as it is judged not suitable for long-term surgery with significant blood loss (8). in fact, it is generally considered not advisable to employ spinal anesthesia for surgeries lasting for more than 2 hours. on the other hand, time required for the performance of the open radical prostatectomy procedure varies depending on surgeon skill and competence. the advantages of this anesthesia technique for this type of operation are: patient comfort/satisfaction, less sedation score, faster postoperative recovery flatus passing, and mobilization/ambulation and pain control in the first hours postoperatively (8). other advantages are less effective surgical time, less use of amines and fluids, shorter post-anesthesia care unit stay as well as less hospital stay (9) and good muscle relaxation comparable to general anesthesia (10). studies demonstrated that in spinal anesthesia blood loss is less than with general anesthesia (12) although others do not sustain this finding (11). patients with locoregional anesthesia had significantly decreased risk of cardiac arrhythmia, deep vein thrombosis, respiratory depression, intubation risk, atelectasis, pneumonia, ileus, and postoperative nausea and vomiting (4), may have reduced risk of delirium in elderly ages (14) and had better overall survival after radical prostatectomy (14). the disadvantages are the limited duration of anesthesia in case of prolonged interventions, difficulties in the management of hemodynamics in case of significant blood loss as well as the need of conversion to general anesthesia in urgent care with an awake patient. table 1. pt2: 42pts pt3: 46pts n1: 8pts r+: 51pts t2a:5pts, t2b:2pts, t2c:35pts t3a:33pts, t3b:11pts t2an0r0:4pts t3an0r0:9pts t2an0r1:1pt t3an0r1:19pts t2bn0r0:1pt t3an0r2:3pts t2bn0r1:1pt t3an1r1:3pts t2cn0r0:18pts t3bn0r0:3pts t2cn0r1:17pts t3bn0r1:4pts t3bn1r0:1pt t3bn1r1:4pts archivio italiano di urologia e andrologia 2023; 95, 2 s. blanco, a. grasso, e. sulmina, m. grasso 17 spinal anesthesia is not always successful for long surgical procedures and is often associated with undesirable complications (15, 16). in our study the surgery procedure time was brief (median time 95 minutes). advantages of spinal anesthesia were also confirmed in our experience: reduced risk of respiratory complications and quick restoration of bowel function. the combination of the surgeon's experience (17, 18) able to perform the procedures with very limited laparotomies, and the known advantages of spinal anesthesia in terms of better control of postoperative pain, longer control of detrusor contractility, and no impact on the mental state of the patient in addition to the reduction of blood loss and the incidence of thromboembolic events (4), allows, in our opinion, to consider this surgical procedure as a minimally invasive procedure. in fact, these patients, as for other minimally invasive techniques, are characterized by a smooth postoperative time and early discharge, within 4 to 5 days. finally, we consider this procedure to be further advantageous not only in terms of costs for the national health service, but above all in terms of reducing the risk of postoperative delirium and cognitive impairment, given the large number of patients, including elderly ones, who are operated on today. in our opinion, we are recently creating a confused concept of invasiveness that cannot be measured with the length of a cut but with other parameters such as duration of surgery, blood loss, postoperative pain, absence of cognitive disorders, etc. conclusions we want to strongly emphasize that in choosing the type of anesthesia to use, the comparison with the prostatic adenomectomy surgery is crucial. in fact, all over the world and after many evaluations published and validated about 40 years ago, if there are no specific contraindications, prostatic adenomectomy is performed under spinal anesthesia. the reasons why the gold standard of radical prostatectomy surgery has been considered general anesthesia are essentially two: the long duration of the surgical procedure and the associated significant blood loss. it is known that, with the standardization of the surgical technique in highvolume surgical centers like our, the two types of surgery can be equated for bleeding risk and duration. multiple evidences show that radical retropubic prostatectomy can be safely performed under spinal anesthesia with various advantages (19), therefore it is no longer justified to consider general anesthesia as the only gold standard for radical prostatectomy with an open technique. our experience with spinal surgery could, of course, not be transferred to laparoscopic or robotic-assisted surgery where general anesthesia is currently mandatory due to patient’s positioning. references 1. pereira r, joshi a, roberts m, et al. open retropubic radical prostatectomy. transl androl urol. 2020; 9:3025-3035. 2. haese a, knipper s, isbarn h, et al. a comparative study of robotassisted and open radical prostatectomy in 10 790 men treated by highly trained surgeons for both procedures. m. bju int. 2019; 123:1031-1040. 3. walsh pc, retik ab, vaughan ed. anatomic radical retropubic prostatectomy. in: campbell’s urology, 7th ed., philadelphia: w.b. saunders, co., 1998; vol.3, chapt. 86, pp.2565-2588. 4. grasso m, torelli f, lania c, blanco s. the role of bladder neck preservation during radical prostatectomy: clinical and urodynamic study. arch ital urol androl. 2012; 84:1-6. 5. grasso m, blanco s, grasso aac, et al. radio guided radical prostatectomy: evaluation of feasibility, safety and clinical outcomes. minerva urol nefrol. 2016; 68:3-8. 6. fröhlich g, wördehoff a. the urethral protractor. a new instrument for facilitating the anastomosis between urethra and bladder in radical prostatectomy and urethro-intestinal anastomoses following cystectomy. urologe a. 1990; 29:155-7. 7. donovan jl, abrams p, peterset tj. the ics-‘bph’ study: the psychometric validity and reliability of the ics male questionnaire. br j urol. 1996; 77: 554-563. 8. salonia a, crescenti a, suardi n. general versus spinal anesthesia in patients undergoing radical retropubic prostatectomy: results of a prospective, randomized study. urology. 2004; 64:95-100. 9. kofler o, prueckner s, weninger e. anesthesia for open radical retropubic prostatectomy: a comparison between combined spinal epidural anesthesia and combined general epidural anesthesia. prostate cancer. 2019; 2019:4921620. 10. bajwa sj, kulshrestha a. anaesthesia for laparoscopic surgery: general vs regional anaesthesia. j minim access surg. 2016; 12:4-9. 11. wong rp, carter hb, wolfsonet a, et al. use of spinal anesthesia does not reduce intraoperative blood loss. urology. 2007; 70:523-6. 12. pöpping dm, elia n, van aken hk. et al. impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. ann surg. 2014; 259:1056-67. 13. european geriatric medicine, 2013; vol. 4, pp. s17-s18. 14. lee bm, ghotra vs, karam ja, et al. regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. pain manag. 2015; 5:387-395. 15. hartmann b, junger a, klasen j, et al. the incidence and risk factors for hypotension after spinal anesthesia induction: an analysis with automated data collection. anesth analg. 2002; 94:1521-9. 16. bromage pr. neurological complications of subarachnoid and epidural anaesthesia. acta anaesthesiol scand. 1997; 41:439-44. 17. begg cb, riedel er, bachet pb. et al. variations in morbidity after radical prostatectomy. n engl j med. 2002; 346:1138-44. 18. gershman b, meier sk, jeffery mm, et al. redefining and contextualizing the hospital volume-outcome relationship for robotassisted radical prostatectomy: implications for centralization of care. j urol. 2017; 198:92-99. 19. pikramenos k, zachou m, apostolatou e, et al. the effects of method of anaesthesia on the safety and effectiveness of radical retropubic prostatectomy. arch ital urol androl. 2022; 94:396-400. correspondence salvatore blanco, md sblanco_74@yahoo.it marco grasso, md grasso.m@virgilio.it department of urology, fondazione irccs san gerardo dei tintori, monza, italy angelica grasso, md angelicagrasso84@gmail.com department of urology, asst santi paolo e carlo, university of milan, italy endrit sulmina, md e.sulmina@asst-monza.it department of anesthesia and intensive care medicine, fondazione irccs san gerardo dei tintori, monza, italy conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2017; 89, 4296 original paper a randomized, multicenter, controlled study, comparing efficacy and safety of a new complementary and alternative medicine (cam) versus solifenacin succinate in women with overactive bladder syndrome carlo vecchioli-scaldazza 1, carolina morosetti 2, serena maruccia 3, stefano casellato 3, wilma rociola 4, ester illiano 5, francesco garofalo 6 1 uroginecology unit, asur n° 2 jesi (an), italy; 2 clinical laboratory department, asur n° 2 jesi (an), italy; 3 functional urology unit, zucchi clinical institutes, monza, italy; 4 urology unit, asl1, umbria, italy; 5 department of surgical and biomedical sciences, urology and andrology clinic, university of perugia, italy; 6 urology division, villa maria hospital, rimini, italy. introduction: to assess efficacy and tolerability of a new complementary and alternative medicine (cam) consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid l-glutammina, in the treatment of female overactive bladder syndrome (oab). materials and methods: 90 consecutive women with oab symptoms were enrolled in this prospective, randomized, controlled study. women were divided randomly into two groups of 45 patients each. in group a, women received solifenacin succinate (ss), 5 mg. once a day for 12 weeks. in group b, women received cam, 930 mg, twice daily for 12 weeks. women were assessed with 3-day micturition diary, patient perception of intensity of urgency scale (ppius), overactive bladder questionnaire short form (oab-q sf) and patient global impression of improvement questionnaire (pgi-i). results: 8 patients in group a and 1 patient in group b dropped out from therapy because of side effects. a reduction in the number of daily micturitions, nocturia and episodes of urge incontinence was present with both ss and cam with statistically highly significant differences, but cam was significantly more effective than ss. ppius and oab-q sf showed improvements with both ss and cam with a more significant efficacy of cam. pgi-i, demonstrated improvements in the two groups of patients with a greater satisfaction expressed by patients treated with cam. conclusions: the small number of patients does not permit definitive conclusions; however, the results of the research showed the greater effectiveness and tolerability of cam. key words: overactive bladder; solifenacin; capsaicin; cucurbita maxima; capsicum annum; polygonum cuspidatum; vitamin d; vitamin c; glutamine; complementary medicine. submitted 25 september 2017; accepted 3 november 2017 summary no conflict of interest declared. nomic burdens and detrimental effects on the quality of life of patients (2). the prevalence of oab in women increases with age and is present in approximately 30% of women over the age of 65 years (3) and in the general population it is estimated at 11.8% (4). conservative treatment is considered the first line treatment in these patients, but when this therapeutic option is ineffective, antimuscarinic agents represent the therapy of choice. although a long-lasting therapy is required to obtain better control of symptoms, a high percentage of patients undergoing these drugs, discontinue the treatment after a few months especially for side effects (5-6). after failure of a single drug, most practitioners try a different pharmacological treatment and if this second option also fails, more invasive options are considered (7). recently a complementary and alternative medicine (cam) called kubiker (naturmed, montegranaro, fm, italy), consisting of vitamins (c and d), herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and amino acid l-glutammina, has been proposed in the treatment of oab. to assess its efficacy and its tolerability, we performed a randomized, controlled, multicenter study comparing cam with solifenacin succinate, a well-known drug used in the treatment of oab. material and methods from january 2016 to january 2017, 90 consecutive women (mean age 65 years; range 40-75) with symptoms of overactive bladder (urgency, urinary frequency, with or without urge incontinence) were enrolled in this open label, prospective, randomized, controlled study. women were divided randomly into two groups of 45 patients each using online randomization (graph pad quick calcs software: http://www.graphad.com/quickcalcs/ randomize1) by an independent biostatistician who was unaware of treatments performed by patients and was not involved in the study. in group a, women received solifenacin succinate doi: 10.4081/aiua.2017.4.296 introduction overactive bladder syndrome (oab) is a chronic disease characterized by urinary urgency with or without urge incontinence, frequency and nocturia (1) with huge ecovecchioli_stesura seveso 03/01/18 09:46 pagina 296 297archivio italiano di urologia e andrologia 2017; 89, 4 a new complementary and alternative medicine in oab syndrome (ss), 5 mg. once a day for 12 weeks. in group b, women received cam, 930 mg, twice daily for 12 weeks. patients with urinary tract infection, neurological disease, bladder lithiasis, genital prolapse higher than stage ii on pop-q system, uncontrolled narrow angle glaucoma, pelvic tumours, post void residual urine ≥ 100 ml, previously treated with radiation therapy, antimuscarinic agents, antidepressants and antianxiety agents, were excluded. endpoints improvements in oab symptoms, including reduction in number of voids per 24 h, night time frequency, urgency and urge incontinence were considered the primary efficacy end point. the impact of oab symptoms on patients’ quality of life (qol) and the patient impression of improvement were considered the secondary end point. number of voids per 24 h, episodes of nocturia and urge incontinence were evaluated using a 3-day micturition diary. urgency was assessed by the patient perception of intensity of urgency scale (ppius) represented by a 5-point scale from 0 (no urgency) to 4 (urge incontinence). the secondary end point was assessed with the overactive bladder questionnaire short form (oab-q sf). the questionnaire consists of 6 items related to symptoms with 6 possible options ranging from “not at all” (score 1) to “a very great deal” (score 6), and a healthrelated quality of life scale with 13 items, with 6 response options ranging from “none of the time” (score 1) to “all of the time” (score 6). improvement was evaluated with the patient global impression of improvement questionnaire (pgi-i). the pgii is a validated generic tool for assessment of the overall improvement or deterioration that patients experience following the treatment. it is a 7-point scale from “very much improved” (score 1), to “very much worse” (score 7). the micturition diary, oab-q sf and ppius were completed before and after each treatment. pgi-i was performed only at the end of each treatment. the study was conducted in accordance with the ethical principles of the declaration of helsinki and the protocol was approved by the local ethics committee. all patients signed informed consent before starting treatment. the results were assessed by a researcher blinded to treatment performed by patients. statistical analysis statistical analysis was performed using medcalc software (version 12.7.7). data in each group was assessed by d'agostino-pearson test. after having checked the normal distribution, data was processed using parametric tests: paired sample t test or independent sample t test. if normality was rejected, data was processed using non parametric tests: wilcoxon test for paired sample and mannwhitney for independent sample. data was expressed as means ± sd. a p value < 0.05 was considered significant. results of the 50 women initially enrolled in each group, 8 patients in group a suspended therapy because of side effects (dry mouth, constipation), and 1 patient in group b because of allergic reaction. in addition one patient in group b was not evaluable because of incorrect compilation of questionnaires. thus, 42 women in group a (mean age: 66 years, range 42-73) and 48 women in group b (mean age: 64 years, range 40-75) were evaluable for the study. a reduction in the number of daily micturitions was present both with ss and with cam with statistically highly significant differences, but cam was significantly more effective than ss (table 1). a reduction of night micturition was found in group a and in group b with a highly significant statistical difference but cam was statistically more effective than ss. episodes of urge incontinence decreased with highly significant statistical differences in group a and b with more efficacy in the group treated with cam. improvements with highly significant statistical differences were found in the ppius in both ss and cam groups. however cam demonstrated more efficacy than ss with a significant difference. the quality of life of patients evaluated with the oab-q sf, showed highly significant improvements in both ss and cam groups (table 2). however cam was significantly more effective in both items related to symptoms quality of life (table 2). patients’ evaluation of the two different treatments performed at the end of the study assessed with pgi-i, demonstrated improvements in the two groups of patients with a greater satisfaction expressed by patients treated with cam (table 2). table 1. oab symptoms assessed with 3-day micturition diary in patients treated with solifenacin succinate (ss) or cam. 3-day ss (n° 42) cam (n° 48) micturition diary (mean age 66; 42-73) (mean age 64; 40-75) daily micturition before after p value before after p value 11.6 ± 1.2 10.2 ± 1.96 < 0.0001* 11.26 ± 1.02 9.00 ± 1.62 < 0.0001*** ss after vs cam after 0.0046**** nocturia before after p value before after p value 2.7 ± 1.14 2.15 ± 1.42 0.0003* 2.4 ± 0.94 1.45 ± 1.01 < 0,0001*** ss after vs cam after 0,0240**** urge incontinence before after p value before after p value 3.5 ± 1.2 2.55 ± 1.56 < 0.0001*** 3.17 ± 0.93 1.89 ± 1.13 < 0.0001*** ss after vs cam after 0.036** *paired samples t-test; **independent samples t-test; ***wilcoxon test for paired samples; ****mann-whitney test (independent samples). vecchioli_stesura seveso 03/01/18 09:46 pagina 297 archivio italiano di urologia e andrologia 2017; 89, 4 c. vecchioli-scaldazza, c. morosetti, s. maruccia, s. casellato, w. rociola, e. illiano, f. garofalo 298 discussion complementary and alternative medicine (cam) includes various practices, measures and products which are not presently considered to be a part of conventional medicine such as herbal products, vitamins, minerals and amino acids (8). “complementary medicine” does not propose as an alternative to conventional treatment, but rather a supplement to another treatment, while the term “alternative” medicine is also used as a real alternative to conventional medicine (8, 9). more than a third of the population of the united states (us) of america uses some form of cam and different urological conditions and diseases are treated with cam (e.g. luts/bph, cancer, prostatitis, urinary tract infection, urolithiasis, infertility and erectile dysfunction) (8). a 2002 survey of us adults aged ≥ 18 years conducted by the centers for disease control and prevention, indicated that 74.6% of those with oab had used some form of cam and that women were more likely than men to use these treatments (10). cam used in this study, consists of two different vitamins (c and d), three different herbal products (cucurbita maxima, capsicum annum, polygonum capsicatum) and the amino acid l-glutammina. many studies have been carried out in this regard. maserejian et al. in a cross-sectional analysis performed on intakes of vitamins and minerals in relation to urinary complaints in women, found that women who had highdose intake of vitamin c supplements were more likely to report storage symptoms of frequency and urgency, whereas vitamin c from food and beverages were inversely associated with voiding symptoms (11). highly acidic urine, such as that which could result from highdose vitamin c (12), could plausibly affect the urothelium and contribute to lower urinary tract symptoms (luts) (11). a study of the effects of urinary ph on bladder sensitivity in asymptomatic women found that increased urine acidity leads to increased micturition desire (13). ascorbic acid has also been found to activate mast cells, which are present in the urothelium, thereby possibly contributing to luts (14, 15). therefore vitamin c may contribute to luts in dose-dependent and symptom-specific ways and for some women, oab symptoms of frequency and urgency could be ameliorated by the right intake of vitamin c (11). vitamin d has proven to be effective in the treatment of urinary incontinence (16, 17) and its deficiency has been associated with moderate-severe urinary incontinence and with the presence of luts (18, 19). a cross-sectional analysis performed using 2005-2006 national health and nutrition examination survey data about vitamin d and pelvic floor disorders in women, demonstrated how higher vitamin d levels were associated with decreased risk of pelvic floor disorders (20). similar efficacy has been found in vitamin d analogous (elocalcitol) in the therapy of overactive bladder (21). many studies have been performed on cucurbita pepo and cucurbita maxima. the pumpkin seed oil obtained from cucurbita pepo and cucurbita maxima has been proven to be effective in the treatment of oab symptoms with a significant reduction of the symptoms assessed with overactive bladder symptoms score questionnaire (22). furthermore, cucurbita pepo has been effective in improving symptoms and quality of life of patients with bph (23). polygonum cuspidatum has been broadly utilized as a herbal medicine and its components have shown antioxidants activity (24). capsaicin, a chemical used in the therapy of oab syndrome, is present in the fruit of most species of capsicum. capsaicin was the first vanilloid to be used for therapeutic purposes and many studies have been performed on its use in the treatment of luts (25). its intravesical use was effective but its clinical development for treatment of lower urinary tract diseases has been abandoned due to adverse events, reported by > 50% of patients (pelvic pain, facial flush, worsening of incontinence, autonomic dysreflexia, urinary tract infection and haematuria) (25). for this reason there was a preference for the use of resiniferatoxin, a capsaicin analogue, especially for the treatment of intractable luts, particularly those associated with neurogenic detrusor overactivity or idiopathic detrusor overactivity. (26). these two neurotoxins act by desensitizing the transient receptor potential vanilloid type 1 (trpv1), a non-specific ca2+ channel prequestionnaires ss (n° 42) cam (n° 48) (mean age 66; 42-73) (mean age 64; 40-75) oab-q sf 6 before after p value before after p value 26.05 ± 4.04 20.55 ± 7.05 < 0.0001* 24.36 ± 5.92 18.94 ± 5.51 < 0.0001* ss after vs cam after < 0.001** oab-q sf 13 before after p value before after p value 55.35 ± 9.94 44.88 ± 13.13 < 0.0001* 51.81 ± 7.17 38.17 ± 7.29 < 0.0001* ss after vs cam after 0.0062** ppius before after p value before after p value 3.55 ± 0.8 2.65 ± 1.19 < 0.0001*** 3.47 ± 0.71 1.94 ± 0.98 < 0.0001*** ss after vs cam after 0.0039**** pgi-i 2.75 ± 0.99 2.32 ± 0.72 ss vs cam 0.0393**** *paired samples t-test; **independent samples t-test; ***wilcoxon test for paired samples; ****mann-whitney test (independent samples). table 2. improvements assessed with quality of life questionnaire short form (oab-q sf 6 and 13), patient perception of intensity of urgency scale (ppius) and patient global impression of improvement questionnaire (pgi-i) in patients treated with solifenacin succinate (ss) or cam. vecchioli_stesura seveso 03/01/18 09:46 pagina 298 299archivio italiano di urologia e andrologia 2017; 89, 4 a new complementary and alternative medicine in oab syndrome viously known as vanilloid receptor (27). we did not find studies on the use of glutamine in patients with luts. however, even if glutamine is the most abundant amino acid in the bloodstream of mammals and it is classified as a non-essential amino acid, in certain circumstances it may become an essential nutrient (28) as a nutritional supplements in critically ill patients (29). it has an important role in the maintenance of intestinal structure and functions and supplementation with glutamine has proved to be beneficial to the immunological system functions; it improves nitrogen balance and nutritional parameters in the post-operative period and lessens protein loss in severe catabolic states (30). glutamine stimulates synthesis and inhibits the degradation of proteins, it stimulates the synthesis of hepatic glycogen and is an energy source for cell division, for the growth of different cells of rapid replication, such enterocytes, colonocytes and fibroblasts as well as for other cells of the immune system (28). an analysis of the data relating to every constituent component of cam used in this study, appears to confirm that the majority of these components are effective in the treatment of luts. however, in literature there is no product with the same characteristics as this cam. furthermore, the moderate number of patients enrolled in this study, represents a bias that prevents us from drawing definitive conclusions. however the reduction in the number of daily micturitions and episodes of urge incontinence and the improvement in the quality of life in women treated with cam compared to ss, must be underlined, as well as the great adherence to the therapy. patients’ adherence to the therapy represent an important aspect of oab treatment. many studies have shown a high percentage of patients discontinuing therapy prematurely: poor efficacy, side effects (dry mouth, constipation, dry eyes, blurred vision, cognitive impairment) and costs were the most important causes (5, 6). in this study, cam showed a great tolerability with a greater adherence and persistence of patients to therapy with only one woman suspended treatment for allergic reaction. conclusions in this study, this new complementary and alternative medicine recently proposed in the therapy of oab syndrome, was an effective and well tolerated treatment. however, the small number of patients prevent us from drawing definitive conclusions. further studies on a greater number of patients are needed to confirm these findings. references 1. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:167-178. 2. irwin de, milsom i, hunskaar s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of epic study. eur urol. 2006; 50:1306-1314. 3. stewart wf, van rooyen jb, cundiff gw, et al. prevalence and burden of overactive bladder in the united states. world j urol. 2003; 20:327-336. 4. irwin de, abrams p, milsom i, et al. understanding the elements of overactive bladder: questions raised by the epic study. bju int. 2008; 101:1381-1387. 5. anderson ke, chapple cr, cardozo l, et al. pharmacological treatment of overactive bladder: report from the international consultation on incontinence. curr opin urol. 2009; 19:380:394. 6. yu yf, nichol mb, yu ap, ahn j. persistence and adherence of medications for chronic overactive bladder/urinary incontinence in the california medical program. value health. 2005; 4:495-505. 7. bolduc s, katherine m, lebel s, et al. double anticholinergic therapy for refractory overactive bladder. j urol. 2009; 182:2033-2039. 8. dreikorn k. complementary and alternative medicine in urology.bju international. 2005; 96:1177-1184. 9. cohen mh. complementary and integrative medical therapies, the fda, and the nih: definitions and regulation. dermatologic therapy. 2003; 16:77-84. 10. chughtai b, kavaler e, lee r, et al. use of herbal supplements for overactive bladder. rev urol. 2013; 15:93-96. 11. maserejian nn, giovannucci el, mcvary kt, mckinlay jb. intakes of vitamins and minerals in relation to urinary incontinence, voiding, and storage symptoms in women: a cross-sectional analysis from the boston area community health survey. eur urol. 2011; 59:1039-1047. 12. axelrod dr. ascorbic acid and urinary ph. jama. 1985; 254:1310-1311. 13. lavin jm, hosker gl, smith ar. does urinary ph influence micturition desire? neurourol urodin. 1997; 16:396-397. 14. batler ra, sengupta s, forrestal sg, et al. mast cell activation triggers a urothelial inflammatory response mediated by tumornecrosis factor-alpha. j urol. 2002; 168:819-825. 15. dillon pf, root-bernstein rs, lieder cm. ascorbate enhancement of h1 histamine receptor sensitivity coincides with ascorbate oxidation inhibition by histamine receptors. am j physiol cell physiol. 2006; 291:c977-984. 16. oberg j, verelst m, jorde r, et al. high dose vitamin d may improve lower urinary tract symptoms in postmenopausal women. j steroid biochem mol biol. 2017; pii:s0960-0760(17)30078-x. 17. gau jt. urinary incontinence resolved after adequate vitamin d supplementation: a report of two cases. j am geriatric soc. 2010; 58:2438-2439. 18. vaughan cp, johnson tm, goode ps, et al. vitamin d and lower urinary tract symptoms among men: results from the 20052006 national health and nutrition examination survey. urology. 2011; 78:1292-1297. 19. elshazly ma, sultan mf, aboutaleb ha, et al. vitamin d defiency and lower urinary tract symptoms in males above 50 years of age. urol ann. 2017; 9:170-173. 20. badalian ss, rosenbaum pf. vitamin d and pelvic floor disorders in women: results from the national mhealth and nutrition examination survet. obstet gynecol. 2010; 115:795-803. 21. andersson ke. prospective pharmacologic therapies for overactive bladder. ther adv urol. 2009; 1:71-83. 22. nishimura m, ohkawara t, sato h, et al. pumpkin seed oil extracted from cucurbita maxima improves urinary disorders in human overactive bladder. j tradit complement med. 2014; 4:72-4. vecchioli_stesura seveso 03/01/18 09:46 pagina 299 archivio italiano di urologia e andrologia 2017; 89, 4 c. vecchioli-scaldazza, c. morosetti, s. maruccia, s. casellato, w. rociola, e. illiano, f. garofalo 300 23. damiano r, cai t, fornara p, et al. the role of cucurbita pepo in the management of patients affected by lower urinary tract symptoms due to benign prostatic hyperplasia: a narrative review. arch ital urol androl. 2016; 88:136-143. 24. kirino a, takasuka y, nishi a, et al. analysis and functionality of major polyphenolic components of polygonum cuspidatum (itadori). j nutr sci vitaminol. (tokyo). 2012; 58:278-286. 25. cruz f, dinis p. resiniferatoxin and botulinum toxin type a for treatment of lower urinary tract symptoms. neurol urodin. 2007; 26:920-927. 26. apostolidis a, gonzales ge, fowler cj. effect of intravescical resiniferatoxin (rtx) on lower urinary tract symptoms, urodynamic parameters, and quality of life of patients with urodynamic increased bladder sensation. eur urol. 2006; 50:1299-1305. 27. foster he, lake ag. use of vanilloids in urologic disorders. prog drug res. 2014; 68:307-317. 28. fuentes f, velasco dj, recuenco p. metabolic role of glutamine and its importance in nutritional therapy nutr hosp. 1996; 11:215-225. 29. vermeulen ma, van de poll mc, ligthart-melis gc, et al. specific amino acids in the critically ill patient-exogenous glutamine/arginine: a common denominator?. crit care med. 2007; 35(9 suppl):s568-576. 30. campos fg, waitzberg dl, logulo af, et al. the role of glutamine in nutrition in clinical practice. arg gastroenterol. 1996; 33:86-92. correspondence carlo vecchioli-scaldazza, md cascave@alice.it uroginecology unit, asur n° 2 jesi (an) corso cavour 66 62100 macerata, italy carolina morosetti, md cmorose@libero.it clinical laboratory department, asur n° 2 jesi (an) via maiolati 1 60035 jesi (an), italy serena maruccia, md info@serenamaruccia.it stefano casellato, md stcasellato@gmail.com functional urology unit, zucchi clinical institutes, monza via bartolomeo zucchi, 24 20052 monza, italy wilma rociola, md wilmarociola@virgilio.it urology unit, asl1, umbria via luigi angelini 10 06012 città di castello (pg), italy ester illiano, md ester.illiano@inwind.it department of surgical and biomedical sciences, urology and andrology clinic, university of perugia piazzale gambuli 1 06125 perugia, italy francesco garofalo, md fgarofalo3@alice.it urology division, villa maria hospital, rimini viale giacomo matteotti 24 47921 rimini, italy vecchioli_stesura seveso 03/01/18 09:46 pagina 300 stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11869 1 original paper introduction malnutrition is one of the most troublesome comorbidities among hemodialysis patients (hd) (1). factors responsible for malnutrition in hd patients include dialysis factors (e.g. low dialysis adequacy, low quality dialysis membranes and techniques) and dietary factors (e.g. poor appetite and low diet quality) (2). poor nutritional status in hd patients was linked to cognitive impairment (3), cardiac dysfunction (4), hospitalization and mortality (5). assessment of the nutritional status in hd patients is of paramount importance for the sake of better quality of life and clinical outcomes. however, there is a lack of consensus regarding the gold standard indicators (6). fortunately, our understanding of the pathological mechanisms involved in malnutrition and muscle wasting in hd patients has markedly improved over years. one of the significant achievements in this context is identification of myostatin (mstn)/activin system and its transcriptional system (7). mstn, also known as growth development factor-8 (gdf-8) was discovered in 1997. it belongs to the transforming growth factor-ß superfamily. the present study aimed to assess mstn levels in hd patients and its relation to various clinical and biochemical parameters. patients and methods the present case control study was conducted at al-azhar university hospitals, cairo, egypt. the research ethics committee of the faculty of medicine, al-azhar university (fmg-irb). approved the study protocol and written informed consent was obtained from all participants before enrollment in line with helsinki declaration. the study included 60 hd patients who were undergoing hemodialysis for at least rhree years through mature arteriovenous fistula that was fashioned by vascular team in vasbackground and aim: malnutrition is one of the most troublesome comorbidities among hemodialysis patients (hd). myostatin (mstn) belongs to the transforming growth factor-β superfamily. in hd patients, mstn effects are not limited to skeletal muscle growth. the present study aimed to assess mstn levels in hd patients and its relation to various clinical and biochemical parameters. patients and methods: the present case control study included 60 patients on hd for at least three years. in addition, there were age and sex-matched healthy subjects who constitutes the control group. nutritional status was evaluated using the malnutrition inflammation score (mis). muscle wasting in the present study was evaluated using the lean tissue index (lti) as assessed by the body composition monitor (bcm). rectus femoris muscle (rfm) thickness was also measured as indicator for nutritional status of patient. results: the present study included 60 hd patients, and ageand sex-matched healthy controls. patients expressed significantly higher myostatin levels when compared to controls [median (iqr): 221.3 (153.5-688.2) versus 144.8 (97.0-281.7), p < 0.001]. according to mis, patients were classified into those with no/mild malnutrition (n = 22) and others with moderate/severe malnutrition (n = 38). comparison between the two subgroups revealed that the former group had significantly lower myostatin levels [167.7 (150.3-236.3) versus 341.7 (160.9-955.9), p = 0.004]. according to lti, patients were classified into those with muscle wasting (n = 23) and others without muscle wasting (n = 37). comparative analysis showed that patients in the former group had significantly higher myostatin levels [775.1 (325.1-2133.7) versus 161.8 (142.6-302.3), p < 0.001]. conclusions: myostatin seems to be a promising marker for identification of malnutrition and muscle wasting in hd patients. key words: hemodialysis; malnutrition; muscle wasting; myostatin. submitted 23 september 2023; accepted 13 november 2023 relation between myostatin levels and malnutrition and muscle wasting in hemodialysis patients amal h. ibrahim 1, sammar a. kasim 1, alshimaa a. ezzat 2, noha e. ibrahim 3, donia a. hassan 4, amira sh. ibrahim 5, tamer a. abouelgreed 6, ehab m. abdo 7, naglaa m. aboelsoud 2, nermeen m. abdelmonem 8, mohammad thabet alnajem 9, ahmed a. aboomar 10 1 department of internal medicine, nephrology unit, al-azhar university, cairo, egypt; 2 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 3 department of microbial biotechnology, biotechnology research institute, national research centre (nrc), giza, egypt; 4 department of clinical pathology, al-azhar university, cairo, egypt; 5 department of rheumatology and rehabilitation, faculty of medicine for girls, al-azhar university, cairo, egypt; 6 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 7 department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt; 8 department of radiology, thumbay university hospital, ajman, uae; 9 department of radiology, tawam hospital, alain, uae; 10 department of internal medicine, nephrology unit, faculty medicine, tanta university, tanta, egypt. doi: 10.4081/aiua.2023.11869 summary archivio italiano di urologia e andrologia 2023; 95(4):11869 a.h. ibrahim, s.a. kasim, a.a. ezzat, et al. 2 cular department. patients were excluded if they had other neurological, gastrointestinal or endocrinal conditions with direct effect on the nutritional status or if they have associated malignant tumors. a control group was selected from hospital staff. they were age and sex-matched healthy subjects who constitutes the control group. all participants were submitted to sophisticated history taking, thorough clinical assessment and examination of arterio-venous fistula (avf) and standard laboratory investigations. all participants were subjected to ultrasound measurement of rectus femoris muscle thickness by a high frequency linear transducer (l12-4 linear active probe) connected to an ultrasound machine (philips affinity 30, by: singha’s medical system india private limited, new delhi). the ultrasound probe was placed perpendicular to the long axis of the thigh on its anterior surface. the obtained b-mode cross sectional image was adjusted to visualize the rectus femoris muscle, the subcutaneous tissues and the femur. after identifying the muscle tissue, the maximum muscle thickness of the rectus femoris muscle was obtained by scanning the muscle through its length until its insertion into the patella. nutritional status was evaluated using the malnutrition inflammation score (mis) (8). recent studies proved that mis assessment in hd patients is well correlated with biochemical parameters (9) and showed better performance (10) and prognostic value (11). patients were divided into two groups according to their mis values as mild (mis < 6) and moderate/severe malnutrition (mis ≥ 6). muscle wasting in the present study was evaluated using the lean tissue index (lti) as assessed by the body composition monitor (bcm). lti was considered a reliable indicator of skeletal muscle mass (12). in hd patients, low lti was related to poor prognosis (13). patients with lti < 10.0% of the normal reference range were considered to have muscle wasting (14). kt/v was calculated by dialysis machine, and we take the results from the machines screen. control patients had controls had only measurement of myostatin. statistical analysis data obtained from the present study were presented as number and percent, mean and standard deviation (sd) or median and interquartile range (iqr). numerical variables were compared using t test or mann-whitney u t test, as appropriate while categorical variables were compared using chi-square test. spearman’s correlation coefficient was used to correlate numerical variables. binary logistic regression analysis was used to identify predictors of the study outcomes. all statistical procedures were accomplished using spss (version 27, ibm corporation, il, usa). results the present study included 60 hd patients and ageand sex-matched healthy controls. patients expressed signifitable 1. association between ppla score and risk factors for kidney stones or stone recurrence. malnutrition all patients no/mild moderate/severe p value n = 60 n = 22 n = 38 age (years) mean ± sd 54.0 ± 7.9 49.5 ± 6.9 56.5 ± 7.4 0.001 male/female n 29/31 13/9 16/22 0.21 bmi 24.4 ± 3.4 24.6 ± 2.9 24.3 ± 3.7 0.056 comorbidities n (%) dm 23 (38.3) 9 (40.9) 14 (36.8) 0.76 htn 31 (51.7) 13 (59.1) 18 (47.4) 0.38 ihd 17 (28.3) 7 (31.8) 10 (26.3) 0.65 copd 11 (18.3) 4 (18.2) 7 (18.4) 0.98 hcv 9 (15.0) 3 (13.6) 6 (15.8) 0.82 hd duration (months) 47.0 (28.0-76.0) 45.5 (28.8-67.5) 49.5 (21.0-79.8) 0.84 kt/v 1.3 ± 0.1 1.4 ± 0.1 1.3 ± 0.1 0.003 laboratory findings mean ± sd/median (iqr) hb (gm/dl) 9.8 ± 1.3 10.4 ± 0.3 9.5 ± 1.6 < 0.001 wbcs 5.4 ± 2.0 4.7 ± 1.8 5.9 ± 2.0 0.009 platelets 188.0 ± 61.9 167.1 ± 63.1 200.3 ± 58.6 0.015 creatinine (mg/dl) 8.2 ± 2.4 7.9 ± 2.0 8.4 ± 2.6 0.4 urea (mg/dl) 110.0 ± 32.3 97.6 ± 30.1 117.1 ± 31.7 0.047 fbs (mg/dl) 119.6 ± 46.0 117.2 ± 44.2 120.9 ± 47.5 0.54 albumin (gm/dl) 4.0 ± 0.4 4.2 ± 0.2 3.8 ± 0.4 < 0.001 cholesterol (mg/dl) 158.4 ± 44.0 146.3 ± 34.6 165.5 ± 47.6 0.13 triglycerides (mg/dl) 172.3 ± 114.5 131.8 ± 42.7 195.7 ± 135.4 0.026 calcium (mg/dl) 8.9 ± 0.8 8.7 ± 0.8 8.9 ± 0.8 0.41 phosphorus (mg/dl) 4.5 ± 1.5 4.2 ± 1.5 4.6 ± 1.4 0.51 sodium 138.9 ± 4.8 140.1 ± 5.4 138.1 ± 4.3 0.017 potassium 4.9 ± 0.6 4.8 ± 0.6 5.0 ± 0.6 0.033 pth (pg/ml) 407.5 (191.8-895.0) 512.5 (233.0-897.8) 407.5 (187.0-897.8) 0.78 uric acid (mg/dl) 5.8 ± 1.4 5.6 ± 1.7 5.9 ± 1.3 0.56 ferritin (ng/ml) 829.4 (752.4-1689.0) 789.0 (370.8-1689.0) 1408.5 (752.4-1726.3) 0.21 hscrp (mg/l) 111.2 (88.2-121.5) 89.5 (68.6-111.5) 113.9 (100.9-124.0) < 0.001 myostatin 221.3 (153.5-688.2) 167.7 (150.3-236.3) 341.7 (160.9-955.9) 0.004 archivio italiano di urologia e andrologia 2023; 95(4):11869 3 myostatin in hemodialysis cantly higher myostatin levels when compared to controls [median (iqr): 221.3 (153.5-688.2) versus 144.8 (97.0-281.7), p < 0.001]. according to mis, patients were classified into those with no/mild malnutrition (n = 22) and others with moderate/severe malnutrition (n = 38). comparison between both subgroups revealed that subjects in the former group were significantly younger (49.5 ± 6.9 years versus 56.5 ± 7.4, p = 0.001) with higher kt/v (1.4 ± 0.1 versus 1.3 ± 0.1, p = 0.003), higher hemoglobin levels (10.4 ± 0.3 gm/dl versus 9.5 ± 1.6, p < 0.001), higher albumin levels (4.2 ± 0.2 gm/dl versus 3.8 ± 0.4), lower triglycerides levels (131.8 ± 42.7 mg/dl versus 195.7 ± 135.4, p = 0.026), lower hscrp [89.5 (68.6-111.5) mg/dl versus 113.9 (100.9-124.0), p < 0.001] and lower myostatin levels [167.7 (150.3236.3) versus 341.7 (160.9-955.9), p = 0.004] (table 1). according to lti, patients were classified into those with muscle wasting (n = 23) and others without muscle wasting (n = 37). comparative analysis showed that patients in the former group are significantly older (58.3 ± 5.2 years versus 51.2 ± 8.2, p < 0.001) with longer hd duration [71.0 (42.0-101.0) months versus 42.0 (24.0-57.0), p = 0.005], lower kt/v (1.24 ± 0.12 versus 1.37 ± 0.11, p < 0.001), lower hemoglobin (8.7 ± 0.7 gm/dl versus 10.5 ± 1.2, p < 0.001), lower albumin (3.7 ± 0.4 gm/dl versus 4.2 ± 0.3, p < 0.001), higher cholesterol (177.9 ± 51.6 mg/dl versus 146.3 ± 33.9, p = 0.006) and higher triglycerides (226.9 ± 158.5 mg/dl versus 138.4 ± 55.2, p = 0.016). they also showed significantly lower rfm thickness (0.8 +/_ 0.2 versus 1.4 +/0.3 cm p 0.001). and significantly higher hscrp [113.6 (109.1-121.9) mg/dl versus 100.6 (71.5-131.5), p < 0.001] and myostatin 775.1 (325.1-2133.7) versus 161.8 (142.6-302.3), p < 0.001] levels (table 2). comparison between patients with low (< median) and high (≥ median) myostatin levels identified that patients with high myostatin levels were significantly older (57.6 ± 6.4 years versus 50.3 ± 7.8, p < 0.001) with lower albumin levels (3.8 ± 0.4 versus 4.1 ± 0.3 gm/dl, p = 0.003) and higher hscrp levels [113.7 (101.8122.6) mg/dl versus 101.3 (72.0-116.2), p = 0.005] (table 3). correlation analysis recognized significant table 2. comparison between hemodialysis patients with and without muscle wasting regarding clinical and laboratory findings. +ve -ve p value n = 23 n = 37 age (years) mean ± sd 58.3 ± 5.2 51.2 ± 8.2 < 0.001 male/female n 9/14 20/17 0.26 bmi 23.5 ± 3.5 25.5 ± 0.7 0.12 comorbidities n (%) dm 12 (52.2) 11 (29.7) 0.082 htn 13 (56.5) 18 (48.7) 0.55 ihd 7 (30.4) 10 (27.0) 0.78 copd 5 (21.7) 6 (16.2) 0.59 hcv 4 (17.4) 9 (24.3) 0.53 hd duration (months) 71.0 (42.0-101.0) 42.0 (24.0-57.0) 0.005 kt/v 1.24 ± 0.12 1.37 ± 0.11 < 0.001 laboratory findings mean ± sd/median (iqr) hb (gm/dl) 8.7 ± 0.7 10.5 ± 1.2 < 0.001 wbcs 6.5 ± 1.8 4.8 ± 1.9 < 0.001 platelets 220.3 ± 46.2 168.1 ± 62.2 < 0.001 creatinine (mg/dl) 8.0 ± 1.7 8.3 ± 2.8 0.58 urea (mg/dl) 120.7 ± 30.3 103.3 ± 32.1 0.041 fbs 124.3 ± 51.1 116.6 ± 42.9 0.53 albumin (gm/dl) 3.7 ± 0.4 4.2 ± 0.3 <0.001 cholesterol 177.9 ± 51.6 146.3 ± 33.9 0.006 triglycerides 226.9 ± 158.5 138.4 ± 55.2 0.016 calcium (mg/dl) 9.0 ± 0.8 8.8 ± 0.9 0.32 phosphorus (mg/dl) 4.8 ± 1.5 4.3 ± 1.5 0.24 sodium 137.1 ± 3.6 139.9 ± 5.1 0.026 potassium 5.1 ± 0.5 4.8 ± 0.6 0.11 pth (pg/ml) 338.0 (187.0-895.0) 420.0 (262.0-900.5) 0.84 uric acid (mg/dl) 5.9 ± 0.9 5.7 ± 1.7 0.61 ferritin (ng/ml) 825.5 (807.0-1603.0) 833.2 (531.6-1689.0) 0.41 hscrp (mg/l) 113.6 (109.1-121.9) 100.6 (71.5-131.5) < 0.001 myostatin 775.1 (325.1-2133.7) 161.8 (142.6-302.3) < 0.001 table 3. comparison between hemodialysis patients with low and high myostatin levels regarding clinical and laboratory findings. myostatin levels low high p value n = 30 n = 30 age (years) mean ± sd 50.3 ± 7.8 57.6 ± 6.4 < 0.001 male/female n 12/18 17/13 0.2 bmi 23.9 ± 3.0 25.0 ± 3.8 0.22 comorbidities n (%) dm 10 (33.3) 13 (43.3) 0.43 htn 18 (60.0) 13 (43.3) 0.2 ihd 9 (30.0) 8 (26.7) 0.77 copd 7 (23.3) 4 (13.3) 0.32 hcv 6 (20.0) 3 (10.0) 0.28 hd duration (months) kt/v 1.34 ± 0.13 1.3 ± 0.14 0.28 laboratory findings mean ± sd/median (iqr) hb (gm/dl) 10.1 ± 1.3 9.5 ± 1.3 0.059 wbcs 5.2 ± 2.0 5.7 ± 2.0 0.32 platelets 182.1 ± 60.5 194.1 ± 63.7 0.46 creatinine (mg/dl) 8.3 ± 2.1 8.1 ± 2.7 0.87 urea (mg/dl) 110.1 ± 29.5 109.8 ± 35.4 0.97 fbs 126.8 ± 52.0 112.4 ± 38.5 0.23 albumin (gm/dl) 4.1 ± 0.3 3.8 ± 0.4 0.003 cholesterol 155.4 ± 40.2 161.5 ± 47.9 0.59 triglycerides 137.1 ± 55.2 207.5 ± 145.1 0.018 calcium (mg/dl) 8.8 ± 0.9 8.9 ± 0.8 0.59 phosphorus (mg/dl) 4.4 ± 1.5 4.6 ± 1.4 0.51 sodium 138.7 ± 4.8 139.0 ± 4.8 0.79 potassium 5.0 ± 0.7 4.9 ± 0.5 0.58 pth (pg/ml) 311.5 (195.3-897.8) 687.0 (187.0-906.3) 0.32 uric acid (mg/dl) 5.7 ± 1.4 5.9 ± 1.5 0.66 ferritin (ng/ml) 1374.0 (370.8-1835.8) 825.5 (752.4-1689.0) 0.75 hscrp (mg/l) 101.3 (72.0-116.2) 113.7 (101.8-122.6) 0.005 archivio italiano di urologia e andrologia 2023; 95(4):11869 a.h. ibrahim, s.a. kasim, a.a. ezzat, et al. 4 linear correlation between myostatin levels and age (r = 0.47, p < 0.001), hemoglobin (r = -0.29, p = 0.027) albumin (r = -0.37, p = 0.004) and hscrp (r = 0.38, p = 0.003) (table 4). roc curve analysis showed good performance of myostatin levels in identification of moderate/severe malnutrition [auc (95%ci): 0.72 (0.6-0.85)] (figure 1) and muscle wasting [auc (95% ci: 0.83 (0.72-0.94)] (figure 2). discussion patients suffering from chronic kidney disease (ckd), mainly those undergoing hemodialysis (hd), often present malnutrition and muscle wasting, which directly correlate with morbidity and mortality (15). in ckd patients, an up-regulation of myostatin gene expression in skeletal muscle has been found, which was related to il-6 expression, suggesting a link between mstn and microinflammation (16). moreover, it has also been recently described that uremic toxins may accelerate muscle atrophy, by inducing myostatin expression (17). myostatin is secreted by the skeletal myocytes into the bloodstream to act back on the secretory cells limiting their proliferation (18). its actions on the muscular system are mediated through activation of the ubiquitin-proteasome system resulting in inhibition of satellite muscle cell proliferation and differentiation with induction of proteolytic muscle cells (19). in hd patients, mstn effects are not limited to skeletal muscle growth. they are also linked to insulin resistance, inflammation and cardiovascular morbidity (20). however, studies assessing mstn in hd patients are scarce and their results are inconsistent, with some studies (21) showing that patients have mstn levels comparable to healthy controls and others reporting higher levels of mstn in the studied patients (22). the present study detected significantly higher myostatin levels in patients under maintenance hd as compared to healthy controls. in addition, we noted higher myostatin expression in hd patients with moderate/severe malnutrition in contrast to their counterparts with no/mild malnutrition. moreover, those with muscle wasting showed significantly higher myostatin levels in contradiction to their peers without muscle wasting. our conclusions are supported by previous studies. the study of koyun et al. (23), also noted significantly higher myostatin levels in hd patients as compared to controls. in addition, the study of delanaye et al. (24), table 4. correlation between myostatin levels and clinical and laboratory findings in the studied patients. myostatin levels r p age 0.47 <0.001 bmi 0.16 0.22 hd duration -0.03 0.85 kt/v -0.21 0.11 hb -0.29 0.027 wbcs 0.17 0.19 platelets 0.22 0.09 creatinine 0.13 0.3 urea 0.08 0.52 fbs -0.22 0.098 albumin -0.37 0.004 cholesterol 0.14 0.29 triglycerides 0.26 0.041 calcium -0.06 0.66 phosphorus 0.24 0.031 sodium -0.07 0.58 potassium -0.03 0.83 pth 0.24 0.06 uric acid 0.18 0.17 ferritin -0.03 0.84 hscrp 0.38 0.003 k = clearance of a solute (ml/min). t = time (min. or hr.). v = volume of distribution of a solute (ml or liter). figure 1. performance of myostatin levels in identification of moderate/severe malnutrition. figure 2. performance of myostatin levels in identification of muscle wasting. archivio italiano di urologia e andrologia 2023; 95(4):11869 5 myostatin in hemodialysis reported significant association between muscle mass and myostatin levels. they also noted a significant association between myostatin levels and mortality. the present study also identified a significant correlation between myostatin levels and patients age in accordance with the study of han et al. (25). likewise, the study of yasar et al. (26), on renal transplantation, hemodialysis and peritoneal dialysis patients showed that myostatin levels were highest in hd patients. furthermore, they revealed that myostatin was negatively correlated with handgrip strength (hgs, albumin, estimated glomerular filtration rate, and kt/v. however, myostatin had no correlation with inflammatory markers or appendicular skeletal muscle index. moreover, the study of bataille et al. (27), found that myostatin together with activin were increased in patients with ckd without increased production attributing this increase to the impaired renal clearance. similar conclusions were also reported by the study of widajanti et al. (28), on elderly hd patients. in contrast to our findings, the study of lee et al. (29), concluded that lower myostatin levels were associated with lower muscle mass. in addition, esposito et al. (21), found no significant differences between hd patients and healthy controls regarding myostatin levels. they also recognized a positive correlation between myostatin levels and patients’ age and muscle mass. conclusions the results of the present study suggest that myostatin may be a promising marker for identification of malnutrition and muscle wasting in hemodialysis patients. it shows significant association with poor hemodialysis adequacy, anemia and inflammatory marker. references 1. badrasawi m, zidan s, sharif i, et al. prevalence and correlates of malnutrition among hemodialysis patients at hebron governmental hospital, palestine: cross-sectional study. bmc nephrol. 2021; 22:214. 2. sahathevan s, khor bh, ng hm, et al. understanding development of malnutrition in hemodialysis patients: a narrative review. nutrients. 2020; 12:3147. 3. rotondi s, tartaglione l, pasquali m, et al. association between cognitive impairment and malnutrition in hemodialysis patients: two sides of the same coin. nutrients. 2023; 15:813. 4. choi sr, lee yk, cho aj, et al. malnutrition, inflammation, progression of vascular calcification and survival: inter-relationships in hemodialysis patients. plos one. 2019 ; 14: e0216415. 5. sá martins v, adragão t, aguiar l, et al. prognostic value of the malnutrition-inflammation score in hospitalization and mortality on long-term hemodialysis. j ren nutr. 2022; 32:569-577 6. bolasco p. hemodialysis-nutritional flaws in diagnosis and prescriptions. could amino acidlosses be the sharpest “sword of damocles"? nutrients. 2020; 12: 1773. 7. verzola d, barisione c, picciotto d, et al. emerging role of myostatin and its inhibition in the setting of chronic kidney disease. kidney int. 2019; 95:506-517. 8. kalantar-zadeh k, kopple jd, block g, humphreys mh. a malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients. am j kidney dis. 2001; 38:1251-63. 9. bakkal h, dizdar os, erdem s, et al. the relationship between hand grip strength and nutritional status determined by malnutrition inflammation score and biochemical parameters in hemodialysis patients. j ren nutr. 2020; 30:548-555. 10. avesani cm, sabatino a, guerra a, et al. a comparative analysis of nutritional assessment using global leadership initiative on malnutrition versus subjective global assessment and malnutrition inflammation score in maintenance hemodialysis patients. j ren nutr. 2022;32:476-482. 11. brandão da cunha bandeira s, cansanção k, pereira de paula t, peres waf. evaluation of the prognostic significance of the malnutrition inflammation score in hemodialysis patients. clin nutr espen. 2020; 35:109-115. 12. parthasarathy r, oei e, fan sl. clinical value of body composition monitor to evaluate lean and fat tissue mass in peritoneal dialysis. eur j clan nutr. 2019; 73:1520-1528. 13. hwang sd, lee jh, lee sw, et al. risk of overhydration and low lean tissue index as measured using a body composition monitor in patients on hemodialysis: a systemic review and meta-analysis. ren fail 2018; 40:51-59. 14. rosenberger j, kissova v, majernikova m, et al. body composition monitor assessing malnutrition in the hemodialysis population independently predicts mortality. j ren nutr. 2014; 24:172-6. 15. moorthi rn, avin kg. clinical relevance of sarcopenia in chronic kidney disease. curr opin nephrol hypertens. 2017; 26:219-228. 16. verzola d, procopio v, sofia a, et al. apoptosis and myostatin mrna are upregulated in the skeletal muscle of patients with chronic kidney disease. kidney int. 2011; 79:773-782. 17. enoki y, watanabe h, arake r, et al. indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. sci rep. 2016; 6:32084. 18. lee sj. myostatin: a skeletal muscle chalone. annu rev physiol. 2023; 85:269-291. 19. bataille s, chauveau p, fouque d, et al. myostatin and muscle atrophy during chronic kidney disease. nephrol dial transplant. 2021; 36:1986-1993. 20. esposito p, picciotto d, battaglia y, et al. myostatin: basic biology to clinical application. adv clin chem. 2022; 106:181-234. 21. esposito p, battaglia y, la porta e, et al. significance of serum myostatin in hemodialysis patients. bmc nephrol. 2019; 20:462. 22. esposito p, la porta e, calatroni m, et al. modulation of myostatin/hepatocyte growth factor balance by different hemodialysis modalities. biomed res int. 2017; 2017:7635459. 23. koyun d, nergizoglu g, kir km. evaluation of the relationship between muscle mass and serum myostatin levels in chronic hemodialysis patients. saudi j kidney dis transpl. 2018; 29:809-815. 24. delanaye p, bataille s, quinonez k, et al. myostatin and insulinlike growth factor 1 are biomarkers of muscle strength, muscle mass, and mortality in patients on hemodialysis. j ren nutr. 2019; 29:511-520. 25. han ds, chen ym, lin sy, et al. serum myostatin levels and grip strength in normal subjects and patients on maintenance haemodialysis. clin endocrinol. 2011; 75:857-63. 26. yasar e, tek na, tekbudak my, et al. the relationship between myostatin, inflammatory markers, and sarcopenia in patients with chronic kidney disease. j ren nutr. 2022; 32:677-684. archivio italiano di urologia e andrologia 2023; 95(4):11869 a.h. ibrahim, s.a. kasim, a.a. ezzat, et al. 6 27. bataille s, dou l, bartoli m, et al. mechanisms of myostatin and activin a accumulation in chronic kidney disease. nephron dial transplant. 2022; 37:1249-1260. 28. widajanti n, soelistijo s, hadi u, et al. association between sarcopenia and insulin-like growth factor-1, myostatin, and insulin resistance in elderly patients undergoing hemodialysis. j aging res. 2022; 2022:1327332. 29. lee sm, kim se, lee jy, et al. serum myostatin levels are associated with abdominal aortic calcification in dialysis patients. kidney res clin pract. 2019; 38:481-489. correspondence amal h. ibrahim, md mkellany@yahoo.com department of internal medicine, nephrology unit, al-azhar university, cairo, egypt sammar a. kasim, md summerahmed1983@yahoo.com department of internal medicine, nephrology unit, faculty medicine, al-azhar university, cairo, egypt alshimaa a. ezzat, md dr.alshimaa83@gmail.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt noha e. ibrahim, md nohaelsayed855@gmail.com department of microbial biotechnology, biotechnology research institute, national research centre (nrc), giza, egypt donia a. hassan, md dr.donia1@hotmail.com department of clinical pathology, al-azhar university, cairo, egypt amira sh. ibrahim, md amirashahin694@gmail.com department of rheumatology and rehabilitation, faculty of medicine for girls, al-azhar university, cairo, egypt tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt ehab m. abdo, md ehababdo48@yahoo.com department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt naglaa m. aboelsoud, md nglaa.mahmoud@gmail.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt nermeen m. abdelmonem, md neeermeeenmohamed@gmail.com department of radiology, thumbay university hospital, ajman, uae mohammad thabet alnajem, md mtnajem@gmail.com department of radiology, tawam hospital, alain, uae. ahmed a. aboomar, md ahmed_abo_omar12@yahoo.com department of internal medicine, nephrology unit, faculty medicine, tanta university, tanta, egypt conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2021; 93, 1120 case collection no conflict of interest declared. doi: 10.4081/aiua.2021.1.120 case 1. complication management of atypical submucosal ureteral stone localization after multiple endoscopic treatments in a patient with elevated parathyroid hormone levels (erika palagonia, marco tiroli, lucio dell’atti, andrea benedetto galosi) introduction submucosal ureteral stone is a very atypical location and rare condition that can occur after multiple endoscopic procedures. in the literature, there is a complete lack of evidence in the management of this condition. the european association of urology guidelines describe an overall complication rate after retrograde ureterorenoscopy (urs) ranging between 9% and 25% (1). the most frequent complications reported in the literature are: fever and sepsis, steinstrasse and ureteral lesions (2). case report a 24-years-old man was referred to our urology department due to recurrent right flank pain, not amenable with medical therapy, within two weeks from endoscopic lithotripsy with rigid urs for ureteral stone. blood test analysis showed a serum creatinine level of 1.28 mg/dl with an estimated glomerular filtration rate (egfr) of 73 ml/min/1.73m2, white cells count of 13.39 x103/mmc, and remaining indexes within the range of normality. a non-contrast enhanced computed tomography scan of the abdomen described a grade iv hydroureteronephrosis due to a 1.9 cm lumbar ureteral stone with concomitant inflammation and edema of perirenal tissues. a subsequent renal scintigraphy with technetium (99mtc) dimercaptosuccinic acid was performed defining a residual function of 31.6% for the right renal unit. a right urs was attempted without success due to edema and extensive phlogistic reaction of ureteral orifice and a 26 cm 6 ch double j ureteral stent (djs) was placed to drain the renal unit. the patient was discharged the next day and scheduled for a second urs treatment. within 3 months the patient was readmitted due to abdominal right flank pain non-responsive to medical treatment despite the presence of djs. fluoroscopy and retrograde pyelography showed both a proximal calcification of the right djs and the ureteral this collection includes some unusual cases and how they were diagnosed and treated. case 1: a case of a patient with primary hyperthyroidism presenting with a submucosal ureteral stone after endoscopic lithotripsy was described. after multiple endoscopic treatment, the stone was successfully removed by open ureterolithotomy recovering ureteral patency and normal renal function. case 2: a case of burned-out testicular cancer with atypical lymphatic spread (stage ii a) was presented. after right orchiectomy and complete remission of tumor markers, due to atypical metastases location and uncertain histology, the patient was treated with systemic therapy based on bleomycin, etoposide and cisplatin (peb). at re-staging after chemotherapy computed tomography showed reduction of all node metastases and an observation protocol was proposed. case 3: a patient was readmitted to hospital after 12 days from an uneventful robot-assisted radical prostatectomy (rarp) for prostate cancer due to lower abdominal pain plus abdominal distension, nausea and constipation not responsive to medical therapy. computed tomography showed colon and small bowel dilatation without any evidence of anatomical or mechanical obstruction. laparoscopic abdominal exploration confirmed bowel distension without evidence of obstructing lesions. ogilvie’s syndrome or acute colonic pseudo-obstruction (acpo) was diagnosed. the patient fully recovered and was discharged six days after the procedure. case 4: a case of recurrent acute idiopathic scrotal edema (aise) was diagnosed on clinical signs together with the decisive help of pathognomonic ultrasound findings as the “fountain sign”. case 5: small bilateral testicular nodules were diagnosed in a 30-years old patient undergoing scrotal ultrasound in follow up of acute lymphoblastic leukemia. ultrasound guided testis sparing surgery was performed demonstrating leydig cell tumors. key words: submucosal ureteral stone; burened-out testicular cancer; ogilvie’s syndrome; acute colonic pseudo-obstruction (acpo); acute idiopathic scrotal edema (aise); ultrasound guided testis sparing surgery. submitted 9 january 2021; accepted 21 january 2021 unusual clinical scenarios in urology and andrology summary lucio dell’atti 1, andrea fabiani 2, erika palagonia 1, agostini edoardo 1, maria pia pavia 2, simone scarcella 1, valentina maurelli 2, emanuele principi 2, marco tiroli 1, giulio milanese 1, lucilla servi 2, andrea benedetto galosi 1 1 division of urology, university hospital “ospedali riuniti”, school of medicine, department of clinical, special and dental sciences, marche polytechnic university, ancona, italy; 2 urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche, italy. presented at the sieun congress ancona 30 november 1 december 2020 121archivio italiano di urologia e andrologia 2021; 93, 1 unusual clinical scenarios in urology and andrology stone located at lumbar level. in the light of the impossibility of an endoscopic removal of the jj stent, the patient was submitted to an extracorporeal shock wave lithotripsy (eswl) session to fragment the calcified proximal part of the djs with 1600 shocks at maximum power. the djs was then removed and a subsequent urs was performed to complete endoscopically the lithotripsy of residual calcified fragments and to treat the ureteral stone. under direct endoscopic view of the ureter no intraluminal stone was evidenced. however, the radiogram of the abdomen evidenced the presence of a ureteral stone located at the level of the right lumbar ureter. a multidisciplinary meeting was held with nephrologist to decide the appropriate treatment and due to the worsening of renal function and overall clinical conditions an open laparotomy surgery was scheduled. intraoperatively an uretero-lithotomy was necessary to expose the submucosal ureteral stone. a longitudinal incision of the ureter allowed the extraction of the stone and a replacement of the 26 cm x 6 ch djs. the chemical and physical analysis of the stone showed a medium hard stone composed of calcium oxalate and calcium magnesium phosphate. general condition of the patient rapidly improved with both resolution of symptoms and improvement of blood test analysis: serum creatinine level of 1 mg/dl and egfr of 98 ml/min/1,73m2. further laboratory investigations showed a serum calcium level of 11.2 mg/dl and a parathyroid hormone (pth) level of 196 pg/ml (14-85 pg/ml). due to the elevated levels of the pth level an endocrinologist evaluation was requested. the right djs was removed within 20 days from the procedure. retrograde pyelography did not show ureteral strictures or ureteral stone recurrences and absence of hydronephrosis. after 1 year of follow up abdomen ultrasound showed absence of hydronephrosis and the presence of a small 5 mm stone in the lower pole of the right kidney. endocrinological investigation demonstrated a primary hyperparathyroidism; the parathyroid scintigraphy with technetium (99mtc) sestamibi and 99mtc pertechnetate showed a hyper-capturing area in the lower lobe of the right portion of the thyroid lodge, suggestive of a hyperfunctioning parathyroid gland. the patient was scheduled for surgical treatment. conclusions systematic review of literature on this argument showed limited evidence. major complications following endoscopic surgery are potentially numerous and extremely varied, but submucosal ureteral stone localization was not found in any of the studies considered. in our case we believed that the atypical localization of the stone is related to the specific clinical condition of the patient. a condition of primary hyperparathyroidism can lead to an increased risk of calcification in the kidney and ureter, especially in case of concomitant other factors such as infections, changes in urinary ph and the presence of proteins and electrolytes (3). identifying patients at risk of complications after endoscopic treatments is essential to reduce the need of re-intervention. a widely accepted protocol including management of rare complications could represent a topic of great interest for the urological community to guide the best practice. references 1. türk c, petrík a, sarica k, seitz c, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475482. 2. cindolo l, castellan p, primiceri g, et al. life-threatening complications after ureteroscopy for urinary stones: survey and systematic literature review. minerva urol nefrol. 2017; 69:421-431. 3. dell'atti l, papa s. ten-year experience in the management of distal ureteral stones greater than 10 mm in size. g chir. 2016; 37:27-30. case 2. clinical stage iia burned-out testicular cancer with atypical lymphatic spread: a threatening clinical scenario (edoardo agostini, giulio milanese, lucio dell’atti, andrea benedetto galosi) introduction burned out testicular neoplasm is a rare form of cancer accounting 5% of all germ cell tumors (gct). gct clinical stage (cs) iia is defined as any t stage with lymph node metastases less than 2 cm (cn1), with or without stage i tumor markers. depending on main histology and markers level, international guidelines suggest different treatments, ranging from radiotherapy to chemotherapy and retroperitoneal lymph-node dissection (rplnd). optimal management in these patients is still a matter of debate. furthermore, a critical feature in treatment choice is the metastatic pattern to the retroperitoneum lymph-nodes. we report the threatening case of a cs iia burned out right testicular cancer with negativized markers and atypical metastatic spread. case report we report the case of a 44 years-old man referred at our institution for a localized right scrotal pain. ultrasound using a 10mhz linear probe was performed and revealed a 3 cm well-defined highly echogenic lesion with calcified areas in the right testis. preoperative tumor markers were slightly raised: afp 17 ng/ml, hcg 52 mlu/ml, ldh 165. the patient underwent right orchiectomy, and histological specimens revealed regressed gct. chest and abdomen computed tomography (ct) scan performed after surgery showed retroperitoneal pathologically enlarged lymph nodes on the left side of aorta, a little cranially to common iliac arteries origin. the patient repeated tumor markers 10, 15 and 25 days after surgery, showing complete remission since the first analysis. due to atypical metastases location and uncertain histology, we advised for treating patient with systemic therapy based on bleomycin, etoposide and cisplatin (peb). three months after systemic therapy, we re-staged the patient with contrast enhanced chest-abdomen ct scan, showing reduction of all node metastases, now measuring less than 1 cm each. as the largest part of small residual masses after systemic therapy usually contain fibronecrotic tissue, we proposed the patient for observation protocol. archivio italiano di urologia e andrologia 2021; 93, 1 l. dell’atti, a. fabiani, e. palagonia, et al. 122 discussion burned out tumor, also named regressed tumor, is a germ cell tumor that has completely or partially regressed, leaving a scar in the testicular parenchyma with vestiges of gct. it accounts 5% of all gct. pure seminoma is considered the main histology presenting with regressed aspect. the mechanism behind tumor regression is mainly attributed to immunological response by cytotoxic t lymphocytes or ischemic injury. diagnosis is often incidental (ultrasound) or secondary to symptoms of metastatic spread. about primary tumor, a general disorganization of the sound pattern of parenchyma and focal/diffuse hypoechoic lesions are common features, with or without calcifications (1). in 2017 was described a new pattern consisting of welldefined highly echogenic lesion with calcified areas resembling a pearl-oyster (2). in our report, staging by imaging revealed a clinical stage iia with negative markers and with exclusively contralateral metastatic pattern. past elegant studies about retroperitoneum lymphatic supply, showed that right testis drains primarily to the interaortocaval nodes with some drainage to the right paracaval nodes. only in some studies a small but appreciable amount of lymphatic drainage from the right testis was found draining to left para-aortic region. about treatment, clinical stage iia, particularly marker-negative non-seminoma, is actually one of main concern in testicular cancer management. however, national comprehensive cancer network (nccn), american urological association (aua) and european association of urology (eau) guidelines agree in recommending chemotherapy as possible firstline treatment for patients with marker-negative clinical stage iia non seminoma germ cell tumor (nsgct) of the testicle (3). criteria as larger or multiple lymph nodes or metastatic lesions outside the primary landing zone (as in our patient) can be useful in treatment choice. conclusions treatment of cs iia gct with negative markers represents a recurrent impasse for the clinician, with different possible first line effective treatments, depending on primary histopathology and markers. in our case we present this intricate situation, complicated by atypical lymphatic spread and rare histologic specimen (with typical ultrasound pattern). in this threatening setting, we could establish the effectiveness of chemotherapy in this scenario and the usefulness of criteria as metastatic spread pattern for the choice of treatment. references 1. angulo jc, gonzález j, rodríguez n, et al. clinicopathological study of regressed testicular tumors (apparent extragonadal germ cell neoplasms). j urol. 2009; 182:2303-2310. 2. dell'atti l, galosi ab. "pearl oyster": a new ultrasonographic sign of the regressed testicular tumor. j buon. 2017; 22:1610-1611 3. honecker f, aparicio j, berney d, et al. esmo consensus conference on testicular germ cell cancer: diagnosis, treatment and follow-up. ann oncol. 2018; 29:1658-1686. case 3. ogilvie’s syndrome in post robot-assisted radical prostatectomy: the importance of differential diagnosis and surgical treatment (simone scarcella, lucio dell’atti, giulio milanese, andrea benedetto galosi) introduction ogilvie’s syndrome or acute colonic pseudo-obstruction (acpo) is characterized by massive non-toxic acute intestinal distension in the absence of clear anatomical or mechanical obstructions. it was first described by sir william ogilvie in 1948 (1). throughout academic literature, numerous articles regarding acpo have been published describing this rare occurrence after general abdominal surgery, spinal surgery and multiple trauma surgeries in patients with an average onset age of 64-74 years (2). however, reviewing all published articles, only few cases have been reported after genitourinary surgeries (3). certain risk factors have widely been accepted such as a recent major surgery, even in the absence of abdominal involvement, pregnancy, pre-existing medical comorbidities and coexistence of multiple precipitating conditions (systemic illnesses, infections, diabetes or cardiovascular diseases) (4, 5). despite this recognition, there is a substantial lack of a specific etiology and this phenomenon is classified as a disorder of the intestinal motility due to dysfunction of the interstitial cells of the enteric nervous system and concurrent autonomic imbalance. bowel injuries rarely occur in robot-assisted radical prostatectomy during intestinal manipulation or instruments introduction. ogilvie’s syndrome is a sporadic, under-reported diagnosis of exclusion. it can mimic symptoms of intestinal ischemia or perforation but the appropriate treatments of these conditions are different. in this setting, an accurate differential diagnosis is mandatory and atypical cases of colonic obstruction should always raise suspicion. we encountered a case of a patient who developed ogilvie’s syndrome after an uneventful robot-assisted radical prostatectomy (rarp), requiring laparoscopic abdominal explorative surgery. case report a 65 years-old patient with no previous medical history was scheduled at our urological unit for robot-assisted radical prostatectomy (rarp) to treat an organ confined 3+4 = 7 gleason score (grade group 2) prostate cancer. psa was 12 ng/ml and further radiological evaluation through abdominal computed tomography and bones scintigraphy resulted negative for both lymphatic spread and bone metastasis. briganti’s nomogram score for suspected lymphatic invasion resulted 3.5% with no indication to perform lymphadenectomy. a six-port approach with open hasson optical trocar placement was used with instruments insertion completed under direct vision to avoid bowel injuries, as routinely performed by our team during robot assisted and pure laparoscopic surgeries. no intestinal lesion was suspected during the surgery and the procedure was completed uneventfully, with bilateral nerve sparing technique and no lymphadenectomy, by a senior urologist with over twenty years’ experience. within three days the patient was dis123archivio italiano di urologia e andrologia 2021; 93, 1 unusual clinical scenarios in urology and andrology charged with regular intestinal canalization and blood test panel in normal range. after 12 days from rarp he was re-admitted to our institution for lower abdominal pain plus abdominal distension, nausea and constipation not responsive to medical therapy. a full blood test panel showed leukocytosis and elevated acute phase reactants with normal renal function, urea and electrolytes ruling out an electrolyte imbalance and the possibility of a chemical ileus as potential cause for the clinical findings. a consultation of a general surgeon was requested and prompt conservative management was started. presuming a bowel sub-obstruction, the attending general surgeon prescribed bowel rest, nasogastric and rectal drainage associated with the infusion of metoclopramide to treat nausea and for its prokinetic intestinal effect. intravenous empiric antibiotic therapy with co-amoxiclavulanate and metronidazole was started to prevent potential intra-abdominal sepsis. after an initial improvement of symptoms both blood test analysis and clinical condition of the patient worsen and an abdominal computed tomography scan (ct) was planned. it showed a dilated caecum with collapsing descending colon and rectum without any evidence of anatomical or mechanical obstruction. despite the presence of linear pneumatosis within the ascending colon to the hepatic flexure, raising suspect of intestinal ischemia and perforation, no clear evidence of obstructive occlusion was observed (figure 1). the patient clinically deteriorated and accordingly with the radiological findings of suspected visceral rupture and clinical symptoms of peritonitis an emergency laparoscopic explorative abdominal surgery was performed. it confirmed small bowel and colonic distension with a small amount of free fluid in the pelvis, but all intestinal structures resulted viable without evidence of obstructing lesions. only minor adherences were detected and incised within the small bowel. both stool cultures for infective colitis and additional virology blood screening resulted negative. within three days the abdominal drain was removed and the patient was discharged six days from the procedure, after complete recovery. from the combination of radiological, microbiological and clinical data an apco diagnosis was determined, having excluded other causes of both functional and mechanical bowel obstruction (table 1). conclusions with this case report we aim to raise awareness of ogilvie’s syndrome. it remains a sporadic and underreported occurrence of intestinal motility impairment with no defined causes within the urological community. it mimics obstructive symptoms without any definable mechanical obstruction, leading to massive colonic and small bowel intestinal distension. supportive medical management aims to prevent progression to peritonitis and intestinal perforation. in patients failing to respond to conservative approaches urgent surgical intervention is mandatory, to minimize morbidity and mortality. references 1. ogilvie h. large-intestine colic due to sympathetic deprivation; a new clinical syndrome. br med j. 1948; 2:671-673. 2. wegener m, borsh g. acute colonic pseudo-obstruction (ogilvie’s syndrome). presentation of 14 of our own cases and analysis of 1027 cases reported in the literature. surg endosc. 1987; 1:169-174. 3. kevin t.mcvary, daniel p. dalton and michael d.blum. acute intestinal pseudo-obstruction (ogilvie’s syndrome) complicating radical retropubic prostatectomy. j urol. 1989; 141:1210-1212. 4. vanek vw, al-salti m. acute pseudo-obstruction of the colon (ogilvie’s syndrome). an analysis of 400 cases. dis colon rectum. 1986; 29:203-210. 5. galosi ab, dell'atti l, bertaccini a, et al. clinical evaluation of the ixip index to reduce prostate re-biopsies. cancer treat res commun. 2018; 16:59-63. case 4. sonographic finding of “fountain sign” in erythematous scrotum: a case of recurrent acute idiopathic scrotal edema (maria pia pavia, andrea fabiani, emanuele principi, lucilla servi) introduction acute idiopathic scrotal edema (aise) is a self-limiting cause of acute scrotum that mainly affects child population. we present a case of recurrent aise, which diagnosis was made based on clinical signs together with the decisive help of pathognomonic ultrasound findings as the “fountain sign”. case report a nine-year-old patient presented to the emergency department with a 6-hour hystory of bilateral scrotal dyscomfort, swelling and redness. blood test and urinalysis were normal. he was referred to our urology unit. figure 1 case 3. ct of the abdomen showing colonic and small bowel dilatation. table 1 case 3. summary of differential diagnosis between acute colonic pseudo-obstruction (acpo) and bowel obstruction. mechanical dynamic functional adynamic mural (malignant/inflammatory stricture) ileus extramural (congenital bands/adhesions, volvulus) acute mesenteric arterial occlusion intraluminal (colorectal carcinoma) mesenteric vein thrombosis infective colitides inflammatory bowel disease archivio italiano di urologia e andrologia 2021; 93, 1 l. dell’atti, a. fabiani, e. palagonia, et al. 124 the patient was afebrile and asymptomatic. previous medical history was unremarkable. on clinical examination, the scrotum was enlarged but painless and the skin was red and tender at palpation (figure 1). the child underwent scrotal ultrasound (us) scan demonstrating the absence of hydrocele and showing an hyperemic thickened scrotal wall around the testicles in trasverse scan (figure 2). color doppler us showed normal appearance of both testis and epydydimis. diagnosis of aise was made. the patient was discharged with anti-inflammatory therapy improving in a few days. one month later, he returned to the emergency department presenting the same symptoms. clinical and ultrasonographic findings were stackable. the mother reported that he woked up on morning with swollen lips. diagnosis of aise was confirmed. the patient was referred to pediatrics for internal evaluation work-up. aise is defined as a self-limiting condition that mainly affects children between ages 5 to 11 and accounts for > 10% of cases of acute scrotum in childhood. diagnosis of aise made in the original reports was reviewed by santi et al. according to the following criteria: acute onset of redness and swelling of the scrotal sac produced by subcutanous edema, associated with normal testes, after exclusion of further possible cause of acute scrotum (1). the etiology is still unknown and recurrences are reported in approximately 10% of cases. it has been suggested that aise is common among patients with atopic diathesis and it could represent a hypersensitivity reaction related to a angioneurotic edema’s variant. in our case, the patient experienced swelling of the lips which could confirm the correlation with this disease. however, laboratory tests were normal at all. diagnosis is defined as clinically based, but as in our case it may be very difficult to make a certain diagnosis based on clinical findings. reaching an accurate and timely diagnosis is paramount, as it allows to exclude testicular malignancies or diseases requiring urgent care. ultrasonography is the first-line imaging modality to evaluate the acute scrotum. combined with anamnesis and clinical examination, sonographic results become even more helpful when testicular torsion is highly suspected (2). to date, very few papers underlined the role of ultrasonography in the management of the disease. lee et al. stressed the importance of ultrasonography in managing this disorder, describing characteristic us and doppler imaging findings that may help to avoid unnecessary surgical indication (3, 4). the homogeneous thickening and edema of the scrotal wall together with hyperemia of the scrotum were described in previous studies as specific sonographic findings for aise. the “fountain sign” was first described by geiger et al. (5). similarly, in our case we noticed a marked thickening of the scrotal skin characterized by an inhomogeneous us echostructure and an increase in the vascular texture to the color doppler scan (cds); at the transverse cds, the intense blood supply to the interscrotal septum was configured as an increased color doppler signal that resembles a fountain. sonographic finding of “fountain sign” was the only one that allowed us to make a certain diagnosis of aise. in their report, patoulias et al. also highlighted the role of us in the aise diagnosis, stigmatizing the ongoing uncertainty of the diagnosis of exclusion and stressing the need to diagnose the disease based on pathognomic ultrasound signs. conclusions aise is not such a rare condition; the fast and self-limiting resolution underestimates its incidence and limits clarity about its possible etiology. for this reason, the constant use of ultrasonography allows a more rapid and certain clinical diagnosis. however, it has to be proven if the systematic search for the pathognomonic sign can help to define the real spread of the condition and ensure more information about its etiology. it is no longer relevant to define aise as a diagnosis of exclusion. diagnosis can be certainly made through the sonographic finding of “fountain sign”, which is the diagnostic key of the disease. references 1. santi m, lava sag, simonetti gd, et al. acute idiopathic scrotal edema: systematic literature review. eur j pediatr surg. 2018; 28:222-226. 2. martino p, galosi ab, bitelli m, et al. imaging working groupsocieta italiana urologia (siu); società italiana ecografia urologica andrologica nefrologica (sieun). practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. 3. lee a, park sj, lee hk, et al. acute idiopathic scrotal edema: ultrasonographic findings at an emergency unit. eur radiol. 2009; 19:2075-2080. figure 1 case 4. first (left) and recurrent (right) presentation of aise: erythema and redness on the anterior surface of the scrotum. figure 2 case 4. the patognomonic “fountain sign”: hypervascularity of the interscrotal septum was configured as an increased color doppler signal resembling a fountatin at the transverse scan. 125archivio italiano di urologia e andrologia 2021; 93, 1 unusual clinical scenarios in urology and andrology 4. dell’atti l. successful management of an asymptomatic bilateral synchronous testicular carcinoid tumor with a testicular-sparing surgery. asian j androl. 2017; 19:507-508. 5. patoulias d, rafailidis v, feidantsis t, et al. fountain's sign as a diagnostic key in acute idiopathic scrotal edema: case report and review of the literature. acta medica (hradec kralove). 2018; 61:37-39. case 5. ultrasound intraoperative management of bilateral leydig cell tumor in a young patient (andrea fabiani, maria pia pavia, valentina maurelli) introduction testis ultrasound increased detection of small and not palpable testicular lesions. in small nodular lesions, ultrasound guided excision is mandatory. we report a case of a 30-years old patient undergoing an ultrasound guided testis sparing surgery for a small bilateral testicular lesion. case report in april 2015, a young patient underwent a scrotal ultrasound evaluation in follow up of acute lymphoblastic leukemia treated by bone marrow transplantation in 2004. two hypo-echoic small testicular nodules sized 5 mm and 3 mm were diagnosed in left testis mediastinum. in october 2015, at our urologic department, also a diagnosis of a right 5 mm nodular testicular lesion was made. half yearly ultrasound follow up was performed until the evidence of progressive growth of one left nodules (diameter of 1.17 cm from 5 mm) in 2020. male fertility diagnostic work up revealed a non-obstructive azoospermia. the oncologic markers were negative. we decided to perform a bilateral ultrasound guided excisional nodular testicular biopsy (ugent) with an inguinal approach. after scrotum incision, ultrasound was used to identify the lesions. the nodules were marked with a 23-gauge needle (figure 1). after incision of tunica albuginea, the testicular nodule was bluntly dissected and the surgical specimen was sent to frozen section examination. diagnosis of leydig cell tumor for each of three nodules was made. the tunica albuginea was closed. after tunica vaginalis eversion, both testes were replaced in the scrotum (figure 2). testis ultrasound evaluation was performed immediately after nodules excision. ultrasound study of the testis, performed at post-operative day 1, showed the complete disappearance of the lesions without evidence of intra-testicular hematoma. histopathologic exam diagnosed a leydig cell tumor with surgical margins free from disease. conclusions the detection of small and not palpable testicular lesions is increased due to the widespread use of scrotal ultrasound (1). small testicular masses are often benign and do not always require radical orchidectomy. preoperative ultrasound can assess lesion size and the smaller the nodule, the less likely that it is malignant (2). in fact, in selected patients, active ultrasound surveillance may obviate the need for surgical resection. sub centimetric testicular lesions are more likely to be impalpable and are therefore usually detected incidentally on scrotal ultrasound performed for various kind of indications. for hypo-echoic lesions, as in our case, the size is an independent risk factor for malignancy and the risk of the malignancy increase with the lesion size (cut off value: 5 mm) (2). however, nodular size is not always associated with the benign feature. as presented in our previous experience, in a series of 8 small testicular nodules (< 1 cm), we found 37.5% of malignant tumors (4 mm, 6 mm, 8 mm) (3). ultrasound surveillance permits monitoring of lesion size, which may allow more accurate risk stratification. there is no consensus on the appropriate ultrasound surveillance protocol to follow up the small testicular lesions. germ cell tumor doubling time has been reported to be 10 to 30 days based on which some authors recommend a surveillance interval of 3 months, but others applied a 6-month follow up strategy (2). it is also mandatory to underline the importance of intra-operative ultrasound in localization of the lesion, in order to permit the frozen section examination (fse) of the complete excided entire nodule (3). technical aspects of ugent have been extensively illustrated in scientific literature with or without microsurgical approach, independently from use of advanced ultrasound techniques (2). as demonstrated in this case, the simple and low cost needle use (23 gauge) allowed to locate the small nodular lesion and permitted the complete removal. the ugent may be very difficult in case of very small nodules, especially in cases of lesions < 5 mm (3), posing problems both in terms of sending a suffigure 1 case 5. nodules were marked with a 23-gauge needle (white arrow). figure 2 case 5. surgical procedure. archivio italiano di urologia e andrologia 2021; 93, 1 l. dell’atti, a. fabiani, e. palagonia, et al. 126 ficient tissue amount to the fse and for the absence of a sure resection margin. in all cases, also the close collaboration with the pathologist is very useful in reducing diagnostic and therapeutic errors (3). testicular sparing surgery is mandatory in case of benign lesions and also in monorchid. this case highlights the importance of ultrasound testis follow up of small nodules, especially in young patient with infertility risk factors and, mostly, the role of intraoperative ultrasound in testicular sparing approach for small testicular lesions. references 1. galosi ab, fulvi p, fabiani a, et al. testicular sparing surgery in small testis masses: a multinstitutional experience. arch ital urol androl 2016; 4:320-324. 2. dell’atti l. efficacy of ultrasound-guided testicle-sparing surgery for small testicular masses. j ultrasound. 2015; 19:29-33. 3. dell'atti l, fulvi p, galosi ab. are ultrasonographic measurements a reliable parameter to choose non-palpable testicular masses amenable to treatment with sparing surgery? j buon. 2018; 23:439-443. correspondence lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com erika palagonia marco tiroli andrea benedetto galosi division of urology, university hospital “ospedali riuniti”, marche polytechnic university, via conca 71, 60126 ancona (italy) lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com agostini edoardo giulio milanese andrea benedetto galosi division of urology, university hospital “ospedali riuniti”, marche polytechnic university, via conca 71, 60126 ancona (italy) lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com simone scarcella giulio milanese andrea benedetto galosi division of urology, university hospital “ospedali riuniti”, marche polytechnic university, via conca 71, 60126 ancona (italy) maria pia pavia andrea fabiani andreadoc1@libero.it emanuele principi lucilla servi urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche (italy) andrea fabiani andreadoc1@libero.it maria pia pavia valentina maurelli urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche (italy) stesura seveso 5archivio italiano di urologia e andrologia 2019; 91, 1 original paper posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: description of the technique and its impact on urinary continence federico mineo bianchi 1, 2, daniele romagnoli 1, daniele d’agostino 1, antonio salvaggio 1, marco giampaoli 1, paolo corsi 1, lorenzo bianchi 1, marco borghesi 2, riccardo schiavina 2, eugenio brunocilla 2, peterwiklund 3, angelo porreca 1 1 department of urology, policlinic of abano terme (padova), italy; 2 department of urology, s. orsola-malpighi hospital, university of bologna, italy; 3 department of urology, mount sinai institution, icahn school of medicine, usa. objective: the aim of our study is to describe the use of posterior muscle-fascial reconstruction during urethro-ileal anastomosis in bladder cancer (bc) patients submitted to robot-assisted radical cystectomy (rc) with orthotopic neobladder (on) and its role in facilitating dayand night-time continence recovery during a 12-month follow up. materials and methods: we prospectively collected data from 42 consecutive patients who underwent rarc with totally intracorporeal on and extended pelvic lymph node dissection (plnd) at our institution from june 2014 to october 2017. prior to the urethro-neobladder anastomosis we reconstructed the denonvilliers fascia (df) as previously described for radical prostatectomy using a bidirectional barbed suture. day and night-time recovery rates were reported at 3, 6 and 12 months after surgery, with continent patients being those using either no urinary pads or 1 safety pads. results: median age at surgery was 63 yrs, 41 (97.6%) patients were male. 28 (66.7%) patients presented a clinical t2 disease. median operative time and median on reconstruction time were 450 minutes and 180 minutes respectively. 13 (31%) individuals had non-organ confined disease, with 11 (26.2%) patients with positive lymph nodes (median 3 positive lymph nodes) and 2 (4.8%) with non-urothelial cancer at final pathologic examination. median hospital stay and median catheterization time were 7 (iqr 7-8) and 21 (iqr 19-22). during first 30 post-operative days we recorded 7 (16.7%) low-grade clavien and 2 (4.8%) iiia clavien complications, whereas between 30 and 90 postoperative days we recorded 4 (9.5%) low-grade, 4 (9.5) iiia and 1 (2.4%) iiib complications. day-time and night-time continence rates were 61.9% vs 52.4%, 73.8% vs 64.3% and 90.5% vs 73.8% at three, six and twelve months follow up. day-time continence was significantly superior in the younger group (97% vs 57%, p 0.01); night-time continence rates were also superior among < 70 yrs patients, despite not reaching statistical significance (77% vs 57%, p 0.3). conclusions: posterior muscle-fascial reconstruction aids continence recovery in bc patients undergoing rarc with on, with younger and fitter patients most benefitting from on reconstruction. key words: rarc; orthotopic neobladder; posterior musclefascial reconstruction; robotic surgery; radical cystectomy. submitted 8 january 2019; accepted february 2019 summary no conflict of interest declared. introduction radical cystectomy with pelvic lymph node dissection represents the gold standard treatment for muscle-invasive bladder cancer (1). despite ileal conduit (ic) being the most commonly performed type of urinary derivation (ud), orthotopic neobladder (on) reconstruction might lead to a better quality of life, mainly due to a better preservation of patient’s self-image, especially among younger individuals (2). robot-assisted radical cystectomy (rarc) was first described more than 10 years ago and is steadily gaining popularity among tertiary care centers, but most cases of on are performed through a minilaparotomy (3, 4). totally intracorporeal robot-assisted on have been shown to be comparable in terms of urodynamic profiles to open on, as high-volume and lowpressure reservoirs, despite worse continence rates during the first months after surgery (5). continence rate usually improve throughout follow up, as the on requires months to reach its full functional capacity, with 75-95% and 50-85% day-time and night-time continence rates at long term follow-up, respectively (6-8). the aim of our study is to describe our novel technique to perform urethra-neobladder anastomosis and to present its functional results through a 12 months follow-up, with particular regard to day-time and night-time continence rates. materials and methods we prospectively collected data from 42 patients who consecutively underwent rarc with pelvic lymph node dissection (plnd) and totally intracorporeal orthotopic neobladder (on) reconstruction from june 2014 to october 2017 at our institution. every surgical procedure was performed by 2 surgeons (ap and as) with previous experience of urologic robot-assisted surgery. the first procedures were performed after completing a modular training program under a skilled surgeon (pw) (9). surgeons from a second tertiary center participated as table-assistants, after a week of video sessions, as a part of a structured modular training to gradually master doi: 10.4081/aiua.2019.1.5 archivio italiano di urologia e andrologia 2019; 91, 1 f.m. bianchi, d. romagnoli, d. d’agostino, a. salvaggio, m. giampaoli, p. corsi, l. bianchi, m. borghesi, r. schiavina, e. brunocilla, p. wiklund, a. porreca 6 the technique. for each patient we prospectively reported intraand peri-operative data, with complete pathologic data. complications were stratified as early, during first 30 post-operative days, and late, from 30 to 90 postoperative days, and were graded according to claviendindo classification. day-time and night-time continence were evaluated at 3, 6 and 12-month follow up. continence was defined as the need for 1 safety pad or urine loss inferior than 10 g at pad test (10). indications rarc with on was proposed to patients with either muscle-invasive bladder cancer (mibc) or non-muscle-invasive bladder cancer (nmibc) with high risk features, namely high-grade tumour with carcinoma in situ (cis), recurrent high-grade disease after bladder instillations with bacillus calmette-guerin (bcg), multiple and/or large high-grade tumours, recurrent multifocal large low-grade tumours (11, 12). previous abdominal surgery wasn’t considered as an absolute contraindication for robotic surgery, albeit it could lead to sometimes long pre-operative laparoscopic lysis of peritoneal adherences. the presence of tumour of the prostatic urethra leads to a higher chance of urethral lesions, although it is not considered as an absolute contraindication for on reconstruction (13). an intra-operative frozen section was performed to exclude tumour localization of the urethral stump, despite missing 33% of cis at this site (14). as commonly scheduled to prostate cancer patients undergoing radical prostatectomy (rp), pre-operative mpmri was performed to determine the extent of nervesparing (ns) surgical plan in younger and sexually active individuals (15). compromised renal and/or hepatic function were considered as excluding factors for on reconstruction, as well as severe chronic bowel inflammation. age and previous abdominal radiotherapy were not considered as absolute contraindications, although elderly patients share a higher risk of enuresis and nighttime incontinence (8, 16-18). surgical procedure with the patient in steep trendelenburg position we perform trans-peritoneal approach using da vinci xi® surgical system (intuitive surgical, sunnyvale, ca, usa). the ureters are isolated from 4-5 cm below the pelvicureteral junction to the waldeyer’s sheath, where they are clipped using 2 hemo-locks®. the left ureter is transposed through the sigmoid mesocolon. the radical cystoprostatectomy with extended pelvic lymph node dissection is performed as previously described (19, 20). for the only female patient included in our study the uterus and the ovaries were removed along with the anterior wall of the vagina, whose identification was eased by manipulating a sponge in the vagina. after proper examination, no signs of tumour invasion of the vaginal walls were detected, thus allowing us to also preserve the autonomic nerves that run through its lateral walls. the vaginal edges were finally closed using a “clam-shell technique” (20). unior bilateral nerve-sparing was performed whenever oncologically safe, according to pre-operative mpmri results. during the initial part of radical cystectomy, the peritoneum was incised just below the tips of the seminal vesicles to expose the denonvilliers’ fascia (df). in case of nerve-sparing procedures the fascia was then opened and a surgical plane between df and the rectum was developed uni or bi-laterally, as performed during robotic prostatectomy (21). it is essential to spare as much as possible the rhabdosphincter as well as distal urethra, to maintain an adequate closure pressure. after dissection of the prostatic apex, a frozen section of the distal urethra is performed to exclude urethral tumours. each patient also underwent extended plnd, including external as well as internal and common iliac lymph nodes (ln), obturator fossa and pre-sacral area ln. after removal, the cystoprostatectomy specimen and ln are placed in two different impermeable bags to avoid leakage of neoplastic cells. the da vinci xi® is then un-docked, and patient position is flattened to around 10-15° of trendelenburg to proceed with the reconstructive phase. anastomosis technique and totally intracorporeal neobladder reconstruction after further docking of da vinci xi® surgical system, a distal ileal segment is mobilized to reach down the urethral stump. using a 35 or 45 cm bidirectional barbed suture 3/0 (filbloc® assut, europe) as a first step we stitch the denonvilliers fascia (df) with both needles, as performed during urethro-vesical anastomosis of radical prostatectomy (rp) (21-23). using the left needles, the df is gently transposed to the fibrous part of the sphincter with to bites from left to right. the df is then firmly attached to the fibrous sphincter using the right end of the suture. in our opinion, this step is as important during on as for rp. the distribution of tensions will reduce the tractions upon the urethro-ileal anastomosis, limiting urinary leakages and facilitating urinary continence recovery. a 20 f opening is then created on the anti-mesenteric edge of the lower ileal segment using robotic scissors. during the second step, the left end is used to approximate the posterior side of urethral stump to the lower margin of the 20 f opening of the ileal segment using two bites from left to right. with the right end the posterior distal urethra is sutured to the lower margin of the ileal opening. during the third step the urethro-ileal anastomosis is then completed stitching the anastomosis anticlockwise from 5’ to 12’ using the right end and clockwise from 7’ to 12’ using the left end according to van velthoven technique. a 20 f tri-lumen catheter is then placed through the anastomosis. the on is then completed according to the technique described by hosseini using a 50 cm distal ileal segment with a full intracorporeal approach (20). statistical analysis continuous variables were reported as medians with interquartile ranges (iqr) and categorical variables were described as frequencies with percentages. chi-square was used to compare dayand night-time urinary recovery rates among patients aged < 70 yrs and those ≥ 70 yrs, using a one-tailed 95% confidence interval. statistical analysis was performed with statistical package for social science (spss) v 21 for macintosh. results table 1 depicts pre-operative features. 41 out of 42 patients were male, with median age of 63 yrs, median american society of anaesthesiology (asa) score of 2 and median bmi of 26. 28 (66.7%) had mibc with 11 individuals (26.2%) with associated cis; 39 bc patients (92.9%) had a high-grade disease, 15 (35.7%) were submitted to intravesical instillations of bcg and 14 (33.3%) underwent a cycle of adjuvant chemotherapy. median operative time was 450 minutes (table 2), with median cystectomy time of 120 minutes, median plnd time of 90 minutes and median on reconstruction time of 180 minutes. median estimated blood loss (ebl) was 225 ml, 3 (7.1%) patients received intra-operative blood transfusions, 17 (41.5%) and 7 (17.1%) underwent bilateral and unilateral ns preservation, respectively. no patient was converted to laparotomic cystectomy. 2 (4.8%) patients had cis at final pathology, 8 (19%) had t0 disease and 13 (31%) had non-organconfined bc; 9 (21.4%) patients had concomitant cis, 1 (2.4%) had positive bc margins and 2 (4.8%) individuals presented a squamous cell carcinoma (scc). each patient underwent extended plnd, with a median of 31 lymph node (ln) retrieved. 11 patients had positive lymph nodes at final pathology, with a median of 3 (iqr 1-9) ln involved. 17 (41.4%) patients had concomitant prostatic carcinoma (pc), with 12 (29.3%) gleason grade 1 and 5 (12.2 %) grade 2 disease, respectively, and just one case (2.4 %) of positive surgical margins for pc. post-operative data are shown in table 3. median hospital stay was 7 days (iqr 7-8). median catheterization time was 21 days (iqr 19-22). during first 30 postoperative days we recorded 7 (16.7%) low clavien grade complications and 2 (4.8%) grade iiia complications, with 4 (9.5%) individuals who were re-admitted at our institution. between 30 and 90 post-operative days 4 (9.5%) low grade clavien complications were registered, with 4 (9.5%) grade iiia complications and 1 (2.4%) iiib complication (due to urinary leakage from the on), with a total of 7 patients re-admitted at our institution. no patients deceased during first 90 post-operative days. 22 (55.3%) patients reported regular sexual intercourses after 90 post-operative days with oral phosphodiesterase-5 inhibitors (pde 5). 7archivio italiano di urologia e andrologia 2019; 91, 1 posterior muscle-fascial reconstruction before urethro-neobladder anastomosis table 1. patients’ demographic and pre-operative data. table 2. patients’ peri-operative data. number of patients (%)  42 (100) sex (%) male 41 (97.6) female 1 (2.4) age at surgery median 63 iqr (59-68) asa score median 2 iqr 2 2-3 bmi median 26 iqr 23.6-28 pre-operative stage cis 3 (7.1) ta3 (7.1) t1 8 (19) t2 28 (66.7) t3-t4 0 (0) pre-operative grade low grade g1-g2 (%) 3 (7.1) highgrade g3 (%) 39 (92.9) concomitant cis (%) 11 (26.2) previous bcg instillation 15 (35.7) neo-adjuvant cht (%) 14 (33.3) iqr: interquartile range; asa: american society of anesthesiology; bmi: body mass index; cis: carcinoma in situ; bcg: bacillus calmette-guérin; cht: chemotherapy. total operative time (min) median 450 iqr 410-480 cystectomy time (min) median 120 iqr 80-150 plnd time (min) median 90 iqr 80-110 on time (min) median 180 iqr 120-240 estimated blood loss (ml) median 225 iqr 127.5-312.5 intraoperative blood transfusions (%) 3 (7.1) conversion to open surgery (%) 0 (0) ns procedure (%)* no ns 17 (41.5) unilateral ns 7 (17.1) bilateral ns 17 (41.5) pathologic stage (%) cis 2 (4.8) t0 8 (19) t1 9 (21.4) t2 10 (23.8) t3 9 (21.4) t4 4 (9.5) concomitant cis (%) 9 (21.4) positive surgical margins (%) 1 (2.4) hystotype (%) no tumor 8 (19) tcc 32 (76.2) scc 2 (4.8) plnd (%) 42 (100) number of ln retrieved median 31 iqr 24-37 n+ (%) 11 (26.2) number of positive ln # median 3 iqr 1-9 incidental pca (%)* 17 (41.4) gleason grade group* 1 12 (29.3) 2 5 (12.2) 3-5 0 (0.0) positive pca margins (%) ** 1 (6%) iqr: interquartile range; plnd: pelvic lymph node dissection; on: orthotopic neobladder; ns: nerve-sparing; cis: carcinoma in situ; tcc: transitional cell carcinoma; scc: squamous cell carcinoma; ln: lymph node; pca: prostate cancer. * among male patients; ** among male patients with concurrent pca; # patients with positive lymph nodesy. archivio italiano di urologia e andrologia 2019; 91, 1 f.m. bianchi, d. romagnoli, d. d’agostino, a. salvaggio, m. giampaoli, p. corsi, l. bianchi, m. borghesi, r. schiavina, e. brunocilla, p. wiklund, a. porreca 8 continence recovery table 4a depicts overall urinary recovery rate, with 61.9%, 73.8% and 90.5% continent patients during daytime at 3, 6 and 12 months, respectively; night-time continent patients also increased during our 12-month follow-up, with 22 (52.4%), 27 (64.3%) and 31 (73.8%) continent patients at 3, 6 and 12 months as the on gradually reached its full functional capacity. after stratifying 12-month continence rates according to age at surgery (namely < 70 yrs vs ≥ 70 yrs, table 4b) daytime continence was significantly superior in the younger group (97% vs 57%, p 0.01); night-time continence rates were also superior among < 70 yrs patients, despite not reaching statistical significance (77% vs 57%, p 0.3). discussion in the past decade, many surgeons tried to translate different types of on, formerly proposed for open radical cystectomy (orc), for rarc, in order to simplify technique, thus reducing operative times, and to obtain better functional outcomes. the lack of tactile feedback demands a careful manipulation of the bowel down to the deep pelvis, with steep trendelenburg position. no cases of colonic on have been described with robotic surgery; each reported technique describe a refluxing uretero-ileal anastomosis (3). pruthi et al. described a novel technique for robotic neobladder, a u-shaped reservoir without bowel cross-folding and using a stapler device to reduce intraoperative time (24). as evidenced by other authors, also in our series on reconstruction is the most time-consuming step during rarc, with a median time of 180 minutes, compared to 120 minutes for radical cystectomy and 90 minutes for extended plnd. although operative times should lower by gaining more experience with this procedure, this phase is indeed a limiting step for a widespread diffusion of this technique. the lack of cross-folding and the use of a stapler device could however translate in a quicker renal impairment due to higher reservoir pressures and a higher rate of neobladder calculi respectively. as recently evidenced by razor randomized controlled trial, rarc is not related to fewer early and late post-operative complications than orc. despite longer operative times than orc, rarc is related to a lower ebl, lower blood transfusion rate and shorter hospital stay, with comparable oncologic outcomes (25). previously, bochner and al. reported similar outcomes in terms of comorbidities and mortality between orc and rarc with extracorporeal on, with higher costs related to robotic surgery (26). during first 90 post-operative days, we recorded 11 clavien low-grade complications and 7 grade iii complication, of those only one was submitted to a further surgical procedure under general anesthesia to repair a urinary fistula. ureteral strictures represent the most frequent long-term complications after rc with different types of ud, with subsequent loss of renal functions, upper urinary tract infections and need for further invasive procedures. the exact cause for ureteral strictures is unclear but anastomotic ischemia has been proposed as the main factor contributing to their relatively high incidence.(27) in our series 3 (7%) patients developed ureteral strictures during our 3-month follow up, with available literature reports of 5% to 10% of ureteral strictures after rc with uretero-ileal anastomosis; preoperatively dilated ureters are more likely to develop strictures months after surgery (28, 29). the management of ureteral strictures is mostly endoscopic and laparoscopic/robot-assisted among tertiary hospital stay (days) median 7 iqr 7-8 catheterization time (days) median 21 iqr 19-22 < 30-day clavien grade complications 0 33 (78.6) i 5 (11.9) ii 2 (4.8) iiia 2 (4.8) iiib 1 (2.4) iv-v 1 (2.4) < 30-day complications (%) lymphocele 3 (7.1) ureteral stent displacement 1 (2.4) uti 3 (7.1) paralytic ileus 1 (2.4) uretero-ileal anastomosis stricture 1 (2.4) > 30-day re-admission rate (%) 4 (9.5) > 30 and < 90-day clavien grade complications 0 33 (78.6) i 2 (4.8) ii 2 (4.8) iiia 4 (9.5) iiib 1 (2.4) iv-v 0 (0) > 30 and < 90-day complications (%) lymphocele 2 (4.8) uretero-ileal anastomosis stricture 2 (4.8) uti 2 (4.8) acute retention of urine 2 (4.8) urinary leakage 1 (2.4) > 30 and < 90-day re-admission rate (%) 7 (16.7) 90-day mortality (%) 0 (0) potency rate* 22 (53.7) iqr: interquartile range; uti: urinary tract infection; * among male patient. table 3. post-operative and within-90 post operative days features. table 4a. overall dayand night-time continence rate at 3, 6 and 12month follow up. table 4b. dayand night-time continence rates at 12 months stratified according to age at surgery. 3 months 6 months 12 months day-time continence 26 (61.9) 31 (73.8) 38 (90.5) night-time continence 22 (52.4) 27 (64.3) 31 (73.8) < 70 yrs ≥ 70 yrs p-value day-time continence 34 (97.2) 4 (57.1) 0.01 night-time continence 27 (77.1) 4 (57.1) 0.3 care centers, thus reserving laparotomic surgery to a small number of patients (30). all-grade clavien complication rate was 48.9%, which is slightly lower than reported > 60%, with up to 7% of mortality in some series, which could proof a good patient selection for on reconstruction, as further confirmed by a median hospital stay of 7 days. moreover, median ebl and intraoperative transfusion rates were exceptionally lower than those reported by other authors for totally intracorporeal on (31, 32). the choice of on has to be carefully discussed with the patient, with many variables such as age, pre-operative cognitive function, general health, comorbidities, disease stage, post-operative rehabilitation, that are needed to be taken into account when deciding the most suitable type of ud (33, 34). indeed, younger and fitter patients with low tumour burden are the most likely to benefit from on reconstruction, with better continence rates and higher qol scores during follow-up (2). urethro-ileal anastomosis is a crucial step during on reconstruction. a tension-free anastomosis is paramount to prevent strictures and urinary leakages from the urethro-ileal anastomosis. a proper preservation of the external urinary sphincter when dissecting the prostatic apex and the identification of an ileal segment with an adequately long mesentery are crucial to reduce as possible tension when suturing on to the membranous urethra (3). the length of membranous urethra has been itself identified as a very important parameter to predict good continence recovery rates after rp (35). in this context, posterior musculofascial reconstruction with subsequent urethro-on anastomosis using a bidirectional barbed suture, as described for rp, limits tension upon the anastomosis, thus reducing urinary leakages and acute urinary retentions related to strictures (21, 22, 36). in our series, despite a relatively short follow-up, we registered only one case of acute urinary retention and only one urinary leakage, which needed a further surgical procedure to repair the fistula. continence rates at 12 month-follow up were in line with those previously reported for orc of 75-95% and 5085% continence rates during day-time and night-time, respectively (8). after stratifying 12-month recovery rates according to age at surgery, day-time and night-time continence rates were superior for patients aged < 70 yrs, despite night-time continence couldn’t reach statistical significance due to the low number of elderly patients. many authors indicated urinary leakage to be the main culprit of lower qol scores for patients submitted to on versus those with ic (37, 38). a complete recovery of urinary continence after radical cystectomy with on is deeply connected to the full maturation of the newly created reservoir. the estimated time to reach a 300-500 ml is around 8 months. elderly patients are more likely to experience incontinence due to apoptosis of rhabdosphincter cells, with reduced urethral closure pressure, lower sphincter length and progressive denervation of the membranous urethra. furthermore, nerve-sparing techniques have been found to improve continence rates in patients with on (6, 7, 39). according to the epidemiological studies 5% of individuals newly diagnosed with pca declared incontinence prior to any surgical procedure regardless of age, with older individuals with other urinary disturbances reporting even pre-operative higher incontinence rates (40). hence, an accurate assessment of urinary continence in patients undergoing rc with on should be explored, as incontinent patients wouldn’t benefit from an orthotopic reconstruction. at last, potency rates were exceptionally good, as 22 out of 24 male patients who underwent unior bilateral nerve sparing procedures regular sexual intercourses w/o oral medications with pde5-i, which further confirms a proper patient selection for this kind of procedure. the main limitations of this study are the relatively small cohort of patient, the lack of a control group, a relatively short follow-up especially for long-term complications and perhaps the lack of urodynamic studies. conclusions posterior musclefascial reconstruction before performing urethro-ileal anastomosis helps improving urinary continence in patients undergoing rarc with on, with comparable results to orc. a proper patient 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quality of life in men after radical cystectomy with a continent cutaneous diversion or orthotopic bladder substitution: is there a difference? bju int. 2002; 90:386-90. 35. paparel p, akin o, sandhu js, et al. recovery of urinary continence after radical prostatectomy: association with urethral length and urethral fibrosis measured by preoperative and postoperative endorectal magnetic resonance imaging. eur urol. 2009; 55:629-37. 36. porreca a, salvaggio a, dandrea m, et al. robotic-assisted radical prostatectomy with the use of barbed sutures. surg technol int. 2017; 30: p. 39-43. 37. gilbert sm, wood dp, dunn rl, et al. measuring health-related quality of life outcomes in bladder cancer patients using the bladder cancer index (bci). cancer, 2007; 109:1756-62. 38. hedgepeth rc, gilbert sm, he c, et al. body image and bladder cancer specific quality of life in patients with ileal conduit and neobladder urinary diversions. urology. 2010; 76: p. 671-5. 39. gilpin sa, gilpin cj, dixon js, et al. the effect of age on the autonomic innervation of the urinary bladder. br j urol. 1986; 58:378-81. 40. porreca a, noale m, artibani w, et al. pros-it cnr study group. disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the pros-it cnr study. health qual life outcomes, 2018; 16:122. correspondence federico mineo bianchi, md (corresponding author) federico.mineobianchi@gmail.com lorenzo bianchi, md lorenzo.bianchi3@gmail.com marco borghesi, md mark.borghesi1@gmail.com riccardo schiavina, md rschiavina@yahoo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it s. orsola-malpighi hospital, university of bologna, via palagi 9, bologna (italy) daniele romagnoli, md danieleromagnoli87@gmail.com daniele d’agostino, md dott.dagostino@gmail.com antonio salvaggio, md asalvaggio@casacura.it marco giampaoli, md giampaoli.marco85@gmail.com paolo corsi, md pcorsi@casacura.it angelo porreca, md angeloporreca@gmail.com policlinic of abano terme, piazza cristoforo colombo 1, abano terme, padua (italy) peter wiklund, md peter.wiklund@mountsinai.org mount sinai, 625 madison avenue, new york city, new york (usa) archivio italiano di urologia e andrologia 2019; 91, 160 case report late urinary bladder metastasis from breast cancer aldo franco de rose 1, federica balzarini 1, guglielmo mantica 2, carlo toncini 3, carlo terrone 1 1 department of urology, policlinico san martino hospital, university of genoa, italy; 2 department of urology, san raffaele turro hospital, san raffaele university, milan, italy; 3 department of pathology, policlinico san martino hospital, university of genoa, italy. introduction: breast cancer (brc) is the most common non-dermatologic cancer in women. it frequently metastasizes to lung, liver and bone, while the urinary bladder is considered as an unusual site for brc metastases. materials and methods: four years after her first oncologic surgical approach, a known brc patient complained of a left flank pain, dysuria and urgency. computed tomography (ct scan) imaging showed an irregular thickening of the left bladder wall and bilateral hydronephrosis. results: a bladder metastases from brc was diagnosed based on a histological examination of a transurethral resection of the bladder (turb-t) specimen. conclusions: in patients with a history of brc, urinary bladder screening is not needful. however, if low urinary symptoms persist, an evaluation of the bladder should be considered to rule out metastatic involvement. key words: bladder cancer, breast cancer; bladder metastasis; breast cancer metastasis. submitted 5 january 2019; accepted 25 january 2019 summary no conflict of interest declared. of 2013 she presented with painless right breast mass. a mammogram demonstrated a large high dense soft mass lesion in the upper outer quadrant of the right breast (maximum diameter 16 cm). a tru-cut needle biopsy showed 2 foci of invasive ductal carcinoma of 10 and 6 mm (immunohistochemistry was estrogen receptor (er) 95% progesterone receptor (pgr) 40% ki67 40% human epidermal growth factor receptor 2 (her2) negative and er 95% pgr 10% ki67 15% her2 negative, respectively). tumour clinical stage was t1cn1m0. neoadjuvant chemotherapy was started (fec-75 q21 x4 + paclitaxel 80 mg q7x12) and a right mastectomy with ipsilateral axillary lymph node dissection was done in august 2014. pathology revealed invasive ductal carcinoma (idc) with some elements of atypical ductal hyperplasia (adh-din1b) and negative margins. all six removed lymph nodes were involved, one of which presented perineural invasion. tumour pathological stage was pt1c(m)/g2/n2a(6+/6)/m0 luminal b (stage iiia). er and pgr were positive (er 95%, pgr 50%), ki67 1% and her2 were negative. the patient underwent adjuvant radiotherapy from november to december 2014 and hormonal adjuvant treatment with letrozole was administrated from september 2014 to august 2016. she had been on regular follow-up every 6 months until november 2016, when the patient suffered from left subcutaneous inguinal mass. excisional biopsy showed a metastasis from the primary brc with negative margins. immunohistochemistry showed er positive (100%), pgr negative, ki67 40% and her2 negative. in january 2017, a follow-up total-body ct scan displayed left enlarged inguinal lymph nodes. bone scintigraphy was negative. from february 2017, letrozole was substituted with fulvestrant, which was continued until april 2018. at the end of april 2018 a new ct scan showed increasing of lymph node disease (left common iliac lymph nodes, internal obturator lymph nodes and left inguinal lymph nodes). the patient took part in the phase ii trial of the cdk4/6 inhibitor palbociclib as single agent or in combination with the same endocrine therapy (et) received prior to disease progression, in patients with hormone receptor positive (hr+) her2 negative metastatic breast cancer (mbrc) (trend trial). at the end of the first cycle she presented to our attention with left flank pain, dysuria, urge incontinence and doi: 10.4081/aiua.2019.1.60 introduction breast adenocarcinoma is the most frequently diagnosed malignancy in women, with more than 1.6 million new cancer cases diagnosed worldwide (25% of all cancers). brc remains the leading cause of death for cancer in women, despite increased screening programs and advanced therapies, and its mortality is mainly due to metastatic disease. common sites of brc metastasis are lung, liver, bone, lymph nodes and skin while other organs are less frequently involved. bladder metastasis from solid tumours are rare, accounting for up 4.5% of all bladder neoplasms (1). most bladder metastasis are due to direct infiltration from peripheral organs, such as colon and rectum, prostate and cervix. metastasis from distant organs are extremely rare and reported sporadically. the most common are related to stomach and lung tumours as well as melanomas. brc accounts for about 2.4% cases of all bladder metastasis (1). in most instances, bladder metastases from brc are associated with other metastatic involvement of pelvic organ with a very poor survival (2, 3). case report we present the clinical case of a 57 years-old woman with a negative family history regarding brc. at the end de rose_stesura seveso 26/03/19 09:32 pagina 60 61archivio italiano di urologia e andrologia 2019; 91, 1 late bladder metastasis from breast cancer increasing creatinine. abdominal ct scan displayed thickening of the posterior-left bladder wall with bilateral grade i-ii hydronephrosis. cystoscopy showed inflammatory changes and suspicious bladder wall thickening. transurethral resection of bladder tumour (turb-t) was performed. pathology revealed muscular invasive anaplastic cells consistent with the known primary breast adenocarcinoma. microscopically, the bladder layers showed a diffuse infiltration by large size carcinomatous cells displaying round nuclei, distinct nucleoli with a diffuse pattern, without obvious ductal or glandular structure. the urinary transitional epithelium was intact and ulcerated, without dysplastic or neoplastic changes. (figures 1, 2) the muscular layer was deeply involved. neoplastic cells were er and pgr positive, cytocheratin 7 positive, gcdfp 15 positive and mammoglobin positive. ki67 immunostaining was markedly increased. nowadays, the patient is continuing the therapy with palbociclib and fulvestrant. a 3months follow-up cystoscopy and urine cytology didn’t show any bladder recurrence. conclusions bladder metastases from brc are uncommon. however, literature reveals an increase of such occurrence over the last few years, probably due to better imaging techniques. most cases are diagnosed after the diagnosis of primary brc and are usually associated with other metastatic sites. although routine screening of the lower urinary tract is not mandatory for all patients, women presenting with urinary symptoms should be evaluated in order to exclude a bladder metastasis. the imaging should include ultrasound, ct and/or mri scan. once imaging and/or cystoscopy show a bladder neoplasm in a patient with a brc history, a turb-t is mandatory. chemotherapy and/or hormonal therapy, if not already ongoing, should started as soon as a diagnosis is confirmed. generally, the prognosis is poor unless bladder metastases represents the only metastatic site (3). our reported case confirm that bladder metastases may occur late after the diagnosis of the primary tumours. such data support the need for accurate urological follow-up and early intervention if such clinical state is suspected. discussion secondary tumours of the urinary bladder are rare and the majority of them are due to the direct extension of another pelvic neoplasm (4). the minority are metastases originating from lymphoma or from solid tumour such as lung, breast cancers and melanoma. possible mechanisms are through vascular and lymphatic dissemination or direct retroperitoneal invasion (5). to date, approximately 55 cases of urinary bladder metastasis from brc have been reported in literature (3). in the majority of reported cases, the urinary bladder lesions from brc were part of a systemic dissemination and multiple organ involvement. this indicates that bladder metastases are usually late complications of primary disease (6). however, a solitary metastasis to the urinary bladder had also been reported (7, 8). metastases start from the outer layer of bladder wall and advance towards the bladder lumen (9). urinary symptoms correlate with the advancement of this growth. early stages of brc bladder metastases might be asymptomatic, while the most common presenting symptoms are low urinary tract symptoms (luts), flank or abdominal pain, hydronephrosis, and haematuria (9). our patient did not present with macroscopic haematuria. instead, she complained from recurrent dysuria, urge incontinence and progressive renal failure. flank pain was later the major weakening symptom that allowed the investigation through ct scan imaging. diagnostic workshop needs imaging (ultrasound and ct scan), direct visualisation of the bladder mucosa by cystoscopy, and histological confirmation of a specimen obtained by biopsy or turb-t. cystoscopy findings vary and comprehend solid tumour, inflammatory patches, and thickened bladder wall with intact overlying mucosa. in our patient cystoscopy revealed suspicious bladder wall thickening and non-specific inflammatory areas. feldman et al. affirm that assessment should also include further imaging evaluation, citing a case with negative cystoscopy despite strong evidence of bladder wall involvement from the patient’s symptoms, ultrasound and ct scan (10). magnetic resonance imaging the submucosal layer of the urinary bladder is expanded by medium and large size atypical cells, poorly differentiated, that diffusely infiltrate the muscularis propria. the transitional epithelium is intact, without any dysplastic and neoplastic changes or relation/connection to the neoplastic elements. hematoxylin-eosin stain (20x). figure 1. immunohistochemistry staining is diffusely positive for estrogen receptor in neoplastic cells, otherwise the transitional epithelium of urinary bladder is completely negative (20x). figure 2. de rose_stesura seveso 26/03/19 09:32 pagina 61 archivio italiano di urologia e andrologia 2019; 91, 1 a.f. de rose, f. balzarini, g. mantica, c. toncini, c. terrone 62 (mri) scan would help in definitive confirmation of neoplastic bladder infiltration and it would help in precise local cancer staging. pet-ct scan may reveal other metastases. patient assessment should incorporate check of blood serum ca 15-3 level which remains the most sensitive tumour marker in brc follow-up (11). the metastatic pattern of brc may be related to the histologic type of cancer (10). it has been suggested that infiltrating lobular carcinoma (ilc) has a higher bladder metastatic rate in comparison with infiltrating ductal carcinoma (idc) representing approximately 90% of brc (3). some reports have related the likelihood of developing bladder metastases with the presence of positive lymph nodes at first diagnosis of brc or with steroid treatment (11). patients who have been administrated prolonged steroid therapy may develop unusual metastases due to the possible influence of immune-suppressive effects on carcinoma spreading routes. immunohistochemistry is an indispensable adjunct in the correct diagnosis of metastatic tumours in all sites. common markers for suspected breast tumours include the expression of cytokeratin, ck-7, ck-18, ck-19, ck20, gcdfp-15 and er/pgr (8). in the present case, positive ck-7 and cd-138, and negative cd-20 helped the pathologist in confirming the diagnosis of metastatic brc. some authors reported differences in hormonal (er and pgr) and her2 expression between primary and metastatic tissue, with discordance rates ranging from 24 to 39% (6, 12). bladder metastases from brc usually occurs a few months after the initial diagnosis of the primary tumour, but they might also occur years later (3, 10). however, it is possible of bladder metastases being present at the time of first diagnosis of brc, like in the case reported by shah et al. (8), whereby acute renal failure due to the ureteral obstruction was the presenting sign. in our patient the bladder metastasis was identified 4 years after the initial diagnosis of bcr. the standard treatment of urinary bladder metastases from brc involves chemotherapy and hormonal therapy. radiotherapy might be used only to control bladder bleeding. in case of obstructive uropathy, percutaneous drainage or ureteric catheterization should be performed to optimise renal function before starting chemotherapy. references 1. bates aw, baithun si. the significance of secondary neoplasms of the urinary and male genital tract. virchows arch. 2002; 440:640-647. 2. velcheti v, govindan r. metastatic cancer involving bladder: a review. can j urol. 2007; 14:3443-3448. 3. sanguedolce f, landriscina m, ambrosi a, et al. bladder metastases from breast cancer: managing the unexpected. a systematic review. urol int. 2018; 101:125-131. 4. cormio l, sanguedolce f, di fino g, et al. asymptomatic bladder metastasis from breast cancer. case rep urol. 2014; 2014:672591. 5. pontes je, oldford jr. metastatic breast carcinoma to the bladder. j urol. 1970; 104:839-42. 6. zagha rm, hamawy kj. solitary breast cancer metastasis to the bladder: an unusual occurrence. urol oncol. 2007; 25:236-239. 7. ghaida ra, ayoub h, nasr r, et al. bladder metastasis from primary breast cancer: a case report and literature review. cent european j urol. 2013; 66:177-84. 8. shah kg, modi pr, rizvi j. breast carcinoma metastasizing to the urinary bladder and retroperitoneum presenting as acute renal failure. j urol. 2011; 27:135-136. 9. ramsey j, beckman en, winters jc. breast cancer metastatic to the urinary bladder. ochsner journal information. 2008; 8:208212. 10. feldman pa, madeb r, naroditsky i, et al. metastatic breast cancer to the bladder: a diagnostic challenge and review of the literature. urology. 2002; 59:138. 11. łuczyñska e, pawlik t, chwalibóg a, et al. metastatic breast cancer to the bladder case report and review of literature. j radiol case rep. 2010; 4:19-26. 12. lin wc, chen jh. urinary bladder metastasis from breast cancer with heterogeneic expression of estrogen and progesterone receptors. j clin oncol. 2007; 25:4308-4310. correspondence aldo franco de rose, md federica balzarini, md carlo terrone, md department of urology, policlinico san martino hospital, university of genoa, genoa, italy guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com department of urology, san raffaele turro hospital, san raffaele university via stamira d’ancona 20, 20127 milano (italy) carlo toncini, md department of pathology, policlinico san martino hospital, university of genoa, genoa, italy de rose_stesura seveso 26/03/19 09:32 pagina 62 269archivio italiano di urologia e andrologia 2019; 91, 4 case report detection of significant left renal artery stenosis caused by fibromuscular dysplasia with selective angiography ramezan jafari 1, zohreh rostami 2, mohammad nikpoor 2, mohammad javanbakht 2, mohsen sadeghi ghahroudi 3, mahbobeh sadat hosseini 4, behzad einollahi 2 1 department of radiology and chemical injuries research center, baqiyatallah university of medical sciences, tehran, iran; 2 nephrology and urology research center, baqiyatallah university of medical sciences, tehran, iran; 3 atherosclerosis research center, baqiyatallah university of medical sciences, tehran, iran; 4 clinical research development unit, baqiyatallah university of medical sciences, tehran, iran. a 22-year-old female, was referred with a history of a headache and elevated blood pressure without family history of hypertension or familial dyslipidemia. initially, a spiral computed tomographic angiography of the renal arteries was conducted, demonstrating completely abnormal left renal artery at the medial portion of the vessel with suspicious stenosis, which was supposed to be due to fibromuscular dysplasia (fmd). subsequently, the patient underwent selective renal angiography and balloon angioplasty. severe stenosis was observed on the left side and moderate stenosis on the right side in the medial and proximal part of the vessels, respectively. after the diagnosis of fmd, the left side was treated by balloon and finally, the patient was discharged with good control of blood pressure by losartan/amlodipine treatment. key words: fibromuscular dysplasia; computed tomographic angiography; selective renal angiography; balloon. submitted 10 august 2019; accepted 16 october 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.269 introduction fibromuscular dysplasia (fmd) with renovascular hypertension (rvh) is idiopathic with unclear etiology, being a non-inflammatory and non-atherosclerotic vascular disease, which mainly involves the renal arteries leading to rvh. it less commonly affects carotids, vertebral, iliac, subclavian, and visceral arteries (1, 2). fmd is mainly observed in young women and only 10% to 20% of the cases present with renal artery stenosis (ras), causing secondary rvh. the right ra is the prevailing site of fmd although bilateral manifestation is possible in 40% of cases and approximately bilateral fmd is seen in one-third of cases and unilateral fmd of the right ra is three times higher than fmd of the left ra (3, 4). invasive selective renal artery angiography procedure has been considered as the gold standard for the detection and assessment of ras caused by fmd although noninvasive diagnostic techniques such as color doppler ultrasonography and ct angiography can discover ras, especially when localized near to the vascular origin (5, 6). in present study, we report a 22-year-old female with a history of a headache and hypertension due to ras caused by fmd who was successfully treated. case presentation a 22-year-old female patient was referred to our clinic with a history of a headache and elevated blood pressure. after primary examination and relative blood pressure control (from 190/120 to 160/100 mmhg) she was hospitalized for further investigation in the hospital. additionally, she had with no family history of hypertension or familial dyslipidemia and no history of cigarette smoking, alcohol and drug consumption. on physical examination, the patient had normal jugular venous pressure. moreover, in her cardiac exam, there was a systolic murmur (3/6) at the apex. no bruits were heard on her abdomen and carotid regions, and also, the upper and lower extremities pulse was normal and symmetrical. her laboratory results included: wbc: 4.600 neutrophils 71%, hemoglobin: 9.3 g/dl, mcv: 87 fl, mch: 29 pg, platelet: 360000, liver function tests: normal, erythrocyte sedimentation rate: 8 mm/h, c reactive protein: negative, antinuclear antibody: negative, rheumatic factor: negative, anti dsdna antibody: negative, c3: normal, c4: normal, calcium: normal, magnesium: normal, creatinine: 0.8 mg/dl, sodium: 136 meq/dl, potassium: 3.7 meq/dl, 24 hr urine protein: normal, aldosterone: 1230 ng/dl, plasma renin activity: 61.5 ng/ml. at transthoracic echocardiography investigation, she had a mild enlarged left ventricular size and normal function (moderate left ventricular hypertrophy), normal right ventricle size and function, moderate to severe mitral regurgitation, mild to moderate tricuspid regurgitation, moderate aorta insufficiency. renal ultrasonography revealed right and left kidney measuring 107 and 90 mm in length, respectively. color doppler ultrasound indicated that velocity at the origin of the right renal artery was 359 cm/s and at the left was 95 cm/s with a resistive index (ri) of 0.60-0.62 and 0.390.48 at the right and left renal artery, respectively. in consideration of the size difference of the two kidneys and of the reduced ri, plus the elevated serum levels of renin and aldosterone, a supplementary study with computed tomographic angiography (cta) was recommended. a spiral cta of the renal arteries was conducted, revealing unilateral renal fmd. the left renal artery was completely abnormal at the medial portion of the vessel with suspicious stenosis, which was related to fmd at that jafari_stesura seveso 10/01/20 08:59 pagina 269 archivio italiano di urologia e andrologia 2019; 91, 4 r. jafari, z. rostami, m. nikpoor, m. javanbakht, m. sadeghi ghahroudi, m. sadat hosseini, b. einollahi 270 time. a selective renal angiography was performed, demonstrating patent right renal artery without stenosis (figire 1) and mild beading of branches of left renal artery branches. additionally, no accessory or aberrant arterial branch was detected. she underwent selective renal angiography and balloon angioplasty. the most critical stenosis was on the left side (severe) but moderate stenosis was also seen on the right side in the proximal part of the vessel. the left side (more severely affected by fmd) was treated by balloon on the medium part of the vessel. there was a good angiographic outcome after this approach: the stenosis ameliorated notably and there were no spasms or dissections. there were no complications. after angioplasty, she was discharged with good control of blood pressure with losartan/amlodipine therapy. she was asymptomatic and in good overall clinical condition and well-controlled blood pressure was observed after discharge. discussion fmd as an unusual cause of arterial disease, which mainly affects females (aged 15-50 years), and regularly involves the mid or/and distal segments of the renal artery (4, 7). in accordance, our case was a 22-year-old female with a stenosis of the renal artery at the medial portion of the vessel. on the other hand, notwithstanding diverse theories involving genetic, mechanical and hormonal risk factors, cigarette smoking, cardiovascular risk factors and also, intrinsic deficiency of elastic fibers, the pathogenesis of fmd remains undisclosed (8, 9). medical management and pharmacological therapy of hypertension in fmd should pursue the guidelines of the joint national committee on interdiction, inspection, assessment and remedy of high blood pressure (10). the first line therapy when managing patients with symptomatic fmd is the treatment of blood pressure that in patients with ras needs at least one antihypertensive drug (11). furthermore, in young patients, revascularization is an alternative in cases with hypertension refractory to pharmacological therapy (12). balloon angioplasty is beneficial for the remedy of fmd in the principal renal arteries. however, nowadays it is possible to use smaller balloons and better catheter techniques (13, 14). in accordance with the above reported treatment approaches, our patient affected by fmd was treated by balloon on the medium part of the left renal vessel and was discharged with control of blood pressure using losartan/amlodipine. finally, subsequent the angioplasty, the blood pressure in our case returned to normal on antihypertensive drugs. conclusions fmd causing ras and renovascular hypertension is fundamental to be considered in young hypertensives, even in absence of family history of hypertension. moreover, balloon angioplasty as well as selective renal angiography is the 'gold standard' test for ras and must be conducted when renovascular intervention is envisaged. consent informed patient consent was obtained. references 1. geavlete o, calin c, croitoru m, et al. fibromuscular dysplasia a rare cause of renovascular hypertension. case study and overview of the literature data. j med life. 2012; 5:316-20. 2. hundae ay, hebert ca, schussler jm. fibromuscular dysplasia of the renal artery as a cause of secondary hypertension. proc (bayl univ med cent). 2013; 26:405-6. 3. chrysant sg, chrysant gs. treatment of hypertension in patients with renal artery stenosis due to fibromuscular dysplasia of the renal arteries. cardiovasc diagn ther. 2014; 4:36-43. 4. zeina ar, vladimir w, barmeir e. fibromuscular dysplasia in an accessory renal artery causing renovascular hypertension: a case report. j med case rep. 2007; 1:58. 5. colyer wr, eltahawy e, cooper cj. renal artery stenosis: optimizing diagnosis and treatment. prog cardiovasc dis. 2011; 54:29-35. figure 1. axial (a) coronal (b) and volume rendering technique (vrt) of computed tomography (ct) scan images showing beading at mid and distal third of left renal artery with significant stenosis at midportion and sparing of origin which is compatible with fibromuscular dysplasia (fmd). jafari_stesura seveso 10/01/20 08:59 pagina 270 6. radermacher j, chavan a, schäffer j, et al. detection of significant renal artery stenosis with color doppler sonography: combining extrarenal and intrarenal approaches to minimize technical failure. clin nephrol. 2000; 53:333-43. 7. urban ba, ratner le, fishman ek. three-dimensional volumerendered ct angiography of the renal arteries and veins: normal anatomy, variants, and clinical applications. radiographics. 2001; 21:373-386. 8. slovut dp, olin jw. fibromusculardysplasia. n engl j med. 2004; 50:1862-1871. 9. ralapanawa dm, jayawickreme kp, ekanayake em. a case of treatable hypertension: fibromuscular dysplasia of renal arteries. bmc res notes. 2016; 9:6. 10. chobanian av, bakris gl, black hr, et al. the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the jnc 7 report. jama. 2003; 289:2560-2572. 11. weinberg i, gu x, giri j, et al. anti-platelet and anti-hypertension medication use in patients with fibromuscular dysplasia: results from the united states registry for fibromuscular dysplasia. vasc med. 2015; 20:447-453. 12. knorring jv, edgren j, lepäntalo m. long-term results of percutaneous transluminal angioplasty in renovascular hypertension. acta radiologica. 1996; 37:36-40. 13. gumus b, cevik h, vuran c, et al. cutting balloon angioplasty of bilateral renal artery stenosis due to takayasu arteritis in a 5year-old child with midterm follow-up. cardiovasc intervent radiol. 2010; 33:394-7. 14. alhadad a, mattiasson i, ivancev k, et al. revascularisation of renal artery stenosis caused by fibromuscular dysplasia: effects on blood pressure during 7-year follow-up are influenced by duration of hypertension and branch artery stenosis. j hum hypertens. 2005; 19:761-7. 271archivio italiano di urologia e andrologia 2019; 91, 4 left renal artery stenosis correspondence ramezan jafari, md department of radiology and chemical injuries research center, baqiyatallah university of medical sciences, tehran (iran) mohammad javanbakht, md (corresponding author) mhmjvbt81@gmail.com zohreh rostami, md mohammad nikpoor, md behzad einollahi, md nephrology and urology research center, baqiyatallah university of medical sciences, tehran (iran) mohsen sadeghi ghahroudi, md atherosclerosis research center, baqiyatallah university of medical sciences, tehran (iran) mahbobeh sadat hosseini, md clinical research development unit, baqiyatallah university of medical sciences, tehran (iran) jafari_stesura seveso 10/01/20 08:59 pagina 271 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3300 original paper no conflict of interest declared. taking place on a monthly basis. the course is usually supporting 2-3 international trainees per course and includes one day of wet lab training in pigs and one full day of live surgery, where trainees are participating as first and assisting surgeons in the operation of several pcnl cases under the proctoring of a highly skilled surgeon. after the training of more than 90 physicians we conducted an online survey examining whether particular training course and pcnl intensive hands on training courses in general have any impact in the daily surgical practice of attending trainees. materials and methods survey and training physician characteristics: a survey consisting of 26 questions (2x demographic information, 10x pre and 10x post training experience and surgical preferences, 4x overall impressions from the course) was distributed online to a total of 91 trainees that had completed the course. all attending physicians were certified urologists with various previous experience in pcnl. their ethnicity varied from europe (germany:15, france:11, united kingdom:8, austria:8, poland:8, russia:7, bulgaria:5, switzerland:4, greece:4, netherlands:4, cyprus:3, italy:2, slovenia:2, hungary:1, serbia/montenegro:1, spain:1), africa (south africa:2, morocco:1) and middle east (qatar:2, kuwait:1, lebanon:1). a total of 64 trainees responded to our online survey leading to a 70.3% response rate. mean age of responding physicians was 44 years (range: 32-68). self reported experience prior to the course was poor (defined as < 10 cases) in 31.3%, intermediate (defined as > 10 and < 50 cases) in 28.1% and good (defined as > 50 cases) in 40.6% of attending surgeons. hands on wet lab training protocol: a female pig weighting more than 30 kg was anesthetized and placed in the supine position. under cystoscopic and fluoroscopic guidance a 7 fr ureteral catheter was advanced to each kidney. the animal was then placed in prone position and a retrograde pyelography was performed. c-arm was then placed at 30 degrees perpendicular to the long axis of the pig and target calyx or renal pelvis was selected. following a small skin incision an 18g diamond tip needle was advanced towards target in a bull’s eye fashion. after adequate penetration of the needle, the c-arm was rotated to zero degrees and the depth of puncture was objectives: the clinical value and efficiency of hands-on training courses in percutaneous nephrolithotomy (pcnl) remains undocumented. during the last 9 years, a two-day international intensive hands-on training course in fluoroscopic guided prone pcnl is taking place in our department on a monthly basis. course includes wet lab training in the porcine model and live surgery training. in this work we report the outcomes of a survey send to course participants questioning the impact of the course to their clinical practice. materials and methods: a survey consisting of 26 questions was distributed online to a total of 91 trainees that had completed the course. comparison of pre and post course surgical practices was performed using the "n-1" chi-squared test. results: a total of 64 trainees responded to our online survey with 55.6% and 41.3% reporting a modest or major impact to their practice accordingly. notable changes in puncture and dilation technique were evidenced while a uniform reduction in puncture and operative times was documented. 79.4% responded that the course increased the safety of their procedure, 73% that it reduced operating times, 39.7% that increased their stone free rates, 23.8% that reduced their complications and 23.8% that induced to change their instrumentation with respect of that they were using in the past. subgroup analysis including only well experienced surgeons revealed a similar impact to their practice. conclusions: in the proper setting, an intensive hands-on pcnl course can have a significant impact on attending physicians. participation to such events even for experienced surgeons should be encouraged. key words: pcnl; hands-on; wet lab; training; surgical skills. submitted 4 august 2022; accepted 20 august 2022 introduction proper training in percutaneous nephrolithotripsy (pcnl) is of outmost importance to ensure high efficacy of pcnl and reduce its potential morbidity (1). currently, pcnl training is provided by structured residency and fellowship programs worldwide and is further supported by individual theoretical and hands on training courses. nevertheless, the clinical value and efficiency of the latter short-term courses has never been investigated. during the last 9 years, in the university hospital of patras in greece, a two-day international intensive hands on training course in fluoroscopic guided prone pcnl is hands on wet lab and live surgery training in pcnl: any impact to surgical skills of attending surgeons? iason kyriazis 1, panagiotis kallidonis 1, eleni kyrkopoulou 2, theodoros spinos 1, evangelos liatsikos 1 1 department of urology, university of patras, greece; 2 department of economics, athens university of economics and business, greece. doi: 10.4081/aiua.2022.3.300 summary 301archivio italiano di urologia e andrologia 2022; 94, 3 wet lab and live surgery training in pcnl accessed. when needle reached or overpassed the target at zero-degree projection, needle introducer was removed and a 20cc syringe was connected to the needle sheath. under constant aspiration needle sheath was retrieved slowly until urine and contrast was aspirated verifying entrance into the system. a hydrophilic guidewire was then introduced to the system and directed down the ureter. the same process was repeated several times (usually 5-6 punctures per kidney) until all trainees had mastered the technique. a track dilation was then performed over each guidewire using a two-step (16fr and 30fr) amplatz dilation protocol and a 30fr percutaneous access sheath was developed over the last 30fr dilator. each trainee performed at least one track dilation until all attending physicians felt comfortable with the technique. hands on live surgery training: on the next day, all attending physicians participated on the hands-on live surgery course. several cases (mean 7, range 5-10) scheduled to be operated on the regular program of the department of urology of the university hospital of patras in greece underwent pcnl by a leading highly experienced surgeon (e.l.). all patients had provided an informed consent. under close supervision trainees performed the percutaneous punctures and track dilations of all operated cases. each trainee had the chance to assist in 2-3 cases per course. surgical technique our technique has been previously described in details (2, 3). after a retrograde insertion of a ureteral catheter the patient was placed in prone position. puncture target selection and puncture was performed under fluoroscopic guidance with the c-arm at 30 degrees perpendicular to the long axis of the patient. according to the demonstrated technique in the course, the whole pelvicalyceal system including tip of the calyces, infundibulum and joint of calyces to the pelvis could be safely targeted and dilated according to the given stone scenario. needle was advanced parallel to c-arm view in a bull’s eye fashion and its depth of penetration was assessed by rotating carm at zero degrees. ones entrance into the system was achieved a hydrophilic guidewire was inserted and directed down the ureter. special focus on the importance of advancing the wire down the ureter was made. needle was retrieved and an 8fr, 20 cm polyethylene dilator was inserted over the wire reaching the ureter. the hydrophilic guidewire was removed and a super stiff guidewire was introduced inside 8fr dilator until its end coil into the bladder. the short dilator was removed and exchanged over the wire with a 84 cm long polytetrafluoroethylene (ptfe) 8fr catheter above which a two-step amplatz dilation took place by dilating track sequentially to 16fr and 30fr accordingly. a 30fr ptfe sheath was deployed over the last dilator and its proper placement inside the system was verified fluoroscopically. the last, 30fr dilator, was removed leaving the stiff safety guidewire in place passing through the percutaneous sheath. a 26fr rigid nephroscope was introduced and lithotripsy was performed using an ultrasonic lithotriptor. large stone fragments up to 1cm long were grasped and removed in one piece using graspers. flexible nephroscopy was employed if necessary to reach distant calyces from the initial access and verify stone free status. after the procedure an 18-22fr malecot tail stent or a 16fr nephrostomy was placed in the nephrostomy track. statistical analysis: statistical significance of differences between various proportions was tested using the indicated "n-1" chi-squared test (4, 5). results effect of the course on the ability of urologist to establish their own access. prior to the course 12.5% (n = 8) of attending physicians were using a radiologist to establish the access of their cases while none employed radiologist assistance after the course (p < 0.01). effect of the course on track dilation technique: prior to the course, 41.9% of surgeons used alken dilators, 24.2% balloon dilation, 30.6% amplatz dilation and 3.2% other dilation options (eg mini pcnl instrumentation). after the course, the majority of surgeons are using the amplatz dilators (54.1%) followed by alken (26.2%), balloon dilation (16.4%) and others (3.3%). effect of course on track establishment time and overall operation time: a significant change in the pre and post course track establishment times and overall operation times was evident. in the demonstrated technique, mean access establishment time (from skin puncture to initiation of lithotripsy) last regularly less than 10 minutes. prior to the course this was the case for only 15.9% of surgeons while it increased to 47.5% after the course (p < 0.001). in addition, the rate of surgeons requiring more than 20 min to obtain access dropped from 28.6% prior to the course to zero after the course (p<0.001) (figure 1a). similarly, mean overall operative time (from skin puncture to nephrostomy tube placement) in our department is regularly less than an hour (2). prior to the course this was the case for only 12.7% of attending surgeons while rate increased to 36.5% after the course (p < 0.05) and the rate of surgeons reporting more than 1.5 hours for a regular case dropped from 38.1% to 4.8% after the course (p < 0.001) (figure 1b). according to the literature on the learning curve of pcnl, operative times reach a plateau after 40-60 cases (6-8). given that ongoing growing of surgical experience after the course might also contribute to the noted reduction in puncture and operational times to attending surgeons, we separately analyzed time reduction in surgeons reporting good experience (defined as > 50 cases) prior to the course (n = 26). reduction of puncture and operating times in this subgroup of already proficient surgeons was even more prominent than the whole cohort. prior to the course only 30.7% of them could accomplish puncture and dilation in less than 10 min while after the course this rate raised to 65.4% (p < 0.05). similarly, prior to the course 23% required < 1 hour for a regular pcnl case while this rate raised to 50% after the course and 19.2% reported mean operation lasting more than 1.5 hours prior to the course while none reported such times after our training (p < 0.05 and p < 0.01 accordingly). adaptation of tips and tricks: indirect indications of the educational value of this event can be extracted by the adaptation of several technical aspects that were stressed during our training. our department is one of the few archivio italiano di urologia e andrologia 2022; 94, 3 i. kyriazis, p. kallidonis, e. kyrkopoulou, t. spinos, e. liatsikos 302 centers worldwide practicing central (non calyceal) punctures in almost all pcnl cases. the safety of the approach has been previously documented (2, 3). the adaptation of this policy by the attending physicians after the course was notable. prior to the course only 17.5% of attending surgeons were feeling free to exercise non calyceal punctures and 52.4% were performing solely calyceal punctures according to the established gold standard puncture technique. after the course, 75.8% of attending surgeons are practicing non calyceal punctures either rarely (33.9%) or regularly (41.9%) (figure 2). another indirect sign of the educational value of our course was that in the demonstrated technique a guidewire should pass down the ureter in almost every case as a safety measure and orientation tool inside the system. prior to the course 50% of attending physicians had a guidewire down the ureter regularly (defined as > 75% of their cases) which increased to 73% after the course (p < 0.01) (figure 3). overall impressions on the course: 41.3% of attending surgeons considered that the course had a major impact to their daily surgical practice and 55.6% that they gained some tips and tricks to modify their existed technique. only 3.2% (n = 2) reported no impact to their practice. examining what parameters did course change in the established surgical practice of each surgeon, 79.4% responded that it increased the safety of their procedure, 73% that it reduced operating times, 39.7% that increased their stone free rates, 23.8% that reduced their complications and 23.8% that induced to change their instrumentation respect to that they were using in the past (figure 4). interestingly, the impact of the course was not only significant for novice or intermediate skilled surgeons but was similar for experienced surgeons with 46.1% of the 26 experienced surgeons considering that the course had a major impact in their practice. discussion despite the wide applicability of pcnl worldwide, there is a notable lack of data on the evaluation of percutaneous surgery training (9). the vast majority of relevant literature focuses on docufigure 1. gross estimation of mean access (a) and overall operation times (b) before and after the course. h = hours; * = p < 0.001. figure 2. puncture site selection preferences before and after the course. please notice that a subgroup of surgeons in calyceal plus non calyceal puncture group feel free to puncture in every aspect of the kidney based on the given case. * = p < 0.01. 303archivio italiano di urologia e andrologia 2022; 94, 3 wet lab and live surgery training in pcnl menting the learning curve of individual surgeons, the validation of different pcnl simulators and the description of particular modular training programs (6-12). aslam et al. reported global tendencies in endourology training, comparing a significant number of different national systems. they concluded that huge heterogeneity exists in quality of urological training between different countries and continents, underlining the importance of introducing standardization in training worldwide (13). procedure specific courses is a very common tool of surgical training and hands on pcnl courses are widely available in the setting of congresses or expert center initiatives. still their effectiveness in inducing real changes in the clinical practice of attending physicians remain completely undocumented until now. this is the first study reporting the effect of a short intensive hands-on pcnl course on attending surgeons with 96.8% of participants considering to have a direct impact in their practice. basic limitations of the study include the self reporting and retrospective nature of data acquisition and the lack of surrogate markers of outcome improvement (eg. specific operation and fluoroscopy times, blood loss, hospitalization, stone free status and complications for each of their cases). moreover, accumulated experience after the course in addition to other educational activities that trainees potentially followed after this event might have also contributed to their improved outcomes and as a result the examined pcnl course itself cannot be solely responsible for the documented practice changes. another limitation of this current study was, that not all participants responded to our mail. it is thus possible, that non-responders could not be interested to reply because they were less satisfied of the course. finally, this survey has inherited selection bias. some, if not all of participating physicians opted to follow a pcnl course aiming to address limitations faced in their previous practice and as a result they might have been prone and ready to change their technique. still, the large number of responders, the uniform nature of responses documenting a positive impact in various aspects of their surgery and improvements in their operational times and the subgroup analysis demonstrating similar benefits even for those surgeons that had theoretically overpassed pcnl learning curve prior to the course reinforce the conclusions of this study. conclusions literature on the educational value of hands-on pcnl training courses is lacking. in the proper setting, a 2-day intensive hands on pcnl training course can have a significant impact to attending physicians and participation to such events even for experienced surgeons should be encouraged. references 1. kyriazis i, panagopoulos v, kallidonis p, et al. complications in percutaneous nephrolithotomy. world j urol. 2015; 33:1069-77. 2. kyriazis i, kallidonis p, vasilas m, et al. challenging the wisdom figure 4. overall impression (a) and particular effects of the course to clinical practice (b) of participating surgeons. figure 3. percent of cases that a safety guidewire is passed down the ureter before and after the course. * = p < 0.01. archivio italiano di urologia e andrologia 2022; 94, 3 i. kyriazis, p. kallidonis, e. kyrkopoulou, t. spinos, e. liatsikos 304 of puncture at the calyceal fornix in percutaneous nephrolithotripsy: feasibility and safety study with 137 patients operated via a noncalyceal percutaneous track. world j urol. 2017; 35:795-801. 3. kallidonis p, kyriazis i, kotsiris d, et al. papillary vs nonpapillary puncture in percutaneous nephrolithotomy: a prospective randomized trial. j endourol. 2017; 31(s1):s4-s9. 4. campbell i. chi-squared and fisher-irwin tests of two-by-two tables with small sample recommendations. stat med. 2007; 26:3661-75. 5. richardson jt. the analysis of 2 × 2 contingency tables--yet again. stat med. 2011; 30:890. 6. ziawee sam, sichani mm, kashi ah, samzadeh m. evaluation of the learning curve for percutaneous nephrolithotomy. urol j. 2010; 7:226-231. 7. tanriverdi o, boylu u, kendirci m, et al. the learning curve in the training of percutaneous nephrolithotomy. eur urol. 2007; 52:206-212. 8. allen d, o’brien t, tiptaft r. glass j. defining the learning curve for percutaneous nephrolithotomy. j endourol. 2005; 19:279-282. 9. de la rosette jj, laguna mp, rassweiler jj, conort p. training in percutaneous nephrolithotomy--a critical review. eur urol. 2008; 54:994-1001. 10. schilling d, gakis g, walcher u, et al. the learning curve in minimally invasive percutaneous nephrolitholapaxy: a 1-year retrospective evaluation of a novice and an expert. world j urol. 2011; 29:749-753. 11. stern j, zeltser is, pearle ms. percutaneous renal access simulators. j endourol. 2007; 21:270-3. 12. kallidonis p, kyriazis i, vasilas m, et al. modular training for percutaneous nephrolithotripsy: the safe way to go. arab j urol. 2015; 13:270-6. 13. aslam au, philipraj j, jaffrey s, buchholz n. a global snapshot of endourology residency training. arch ital urol androl. 2020; 92:219-229. correspondence iason kyriazis, md, msc, phd, febu (corresponding author) jkyriazis@gmail.com theodoros spinos, md thspinos@otenet.gr panagiotis kallidonis, md, msc, phd, febu pkallidonis@yahoo.com evangelos liatsikos, md, phd liatsikos@yahoo.com department of urology, university of patras, greece rion, patras 26504 eleni kyrkopoulou kyrkopel@aueb.gr department of economics, athens university of economics and business, greece stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4326 letter to editor no conflict of interest declared. doi: 10.4081/aiua.2020.4.326 erectile disfunction medical treatment with phosphodiesterase 5 inhibitors (pde5i) in patients with retinitis pigmentosa and side effects key words: erectile dysfunction; medical treatment; side effects. submitted 29 april 2020; accepted 10 june 2020 to the editor retinitis pigmentosa represents a heterogeneous group of degenerative hereditary pathologies of the retinal photoceptors, some forms mainly affect the cones and others the rods (1). the prevalence of the disease is of 1 case per 30005000 inhabitants (1), in 80-90% of cases these are forms with prevalent involvement of the rods (rcd) and in 10-20% of cases of forms with prevalent involvement of the cones (crd) (2). in 85% of the cases these are isolated forms, while in 15% of syndromic forms (2), the most common syndromic form is usher's syndrome, in which retinitis pigmentosa is associated with neurosensory deafness (3). an extensive search of medline, embase and scopus databases was conducted to retrieve english-language articles published up to 31 dec 2019, assessing side effect of pde5i. the protocol was performed according to the preferred reporting items for systematic reviews and meta-analyses (prisma) statement. all studies have been included. congress meetings, editorial comments and review papers were excluded: further exclusion criteria were full texts not available in english. two reviewers (g.i.r. and a.c.) independently assessed the eligibility of the identified papers and any disagreements were discussed with a third reviewer (g.m.). in the early stages of rcd disease patients show predominantly decreased night and peripheral vision, associated with photophobia. patients with crd complain of photophobia and reduced central vision. in both cases, disease evolution and specific symptoms are difficult to predict and depend on genetic and environmental factors. pde-6 phosphodiesterase 6 is an isoenzyme of pde that is found in the retina and is involved in the transduction of the signal, some forms of retinitis pigmentosa are related to mutations on this enzyme (4). pde5 is the molecular target of several drugs used in the treatment of erectile dysfunction, but some of these drugs have off-target actions on pde6 and may therefore be contraindicated (2). pde5 inhibitors (5-7) phosphodiesterase is an enzyme responsible for the hydrolysis of cgmp, a molecule that allows the erection of the penis thanks to its vasodilatory action on smooth vasal muscle cells. the smooth muscle cells of the corpora cavernosa of the penis express the isoenzyme pde5. inhibitory drugs specific to pde5 are used for the treatment of erectile dysfunction: by inhibiting the enzyme they stop the hydrolysis of cgmp and thus promote vasodilation and erection. off-target action of pde5 inhibitors can result in several adverse reactions. of particular interest are the adverse reactions related to the action on retinal pde6, which may contraindicate treatment in patients with retinitis pigmentosa, where the functioning of the photoceptors is already impaired (tables 1, 2). sildenafil sildenafil is the most used inhibitor of pde5, its action is not entirely specific for pde5 but has a slight affinity for pde6 retinal, in fact 9% of patients report among the adverse reactions, photosensitivity and alterations in color vision (5, 8). the intake of sildenafil may cause transient alterations in the electroretinogram, so it is not recommended for patients with retinitis pigmentosa (4, 5). verdenafil verdenafil is a molecule similar to sildenafil but more potent (7) and more selective than sildenafil, so higher doses are needed for adverse reactions related to the action on pde6 to occur, which are therefore very rare. tadalafil tadalafil has a chemical structure different from that of sildenafil and verdanafil, it has very little action on pde6 so it does not cause adverse reactions for off-target effect on that isoenzyme (9). avanafil avanafil has recently been approved for the treatment of erectile dysfunction, it is a very selective pyrimidine derivative cocci letter_stesura seveso 14/12/20 20:40 pagina 326 327archivio italiano di urologia e andrologia 2020; 92, 4 retinitis pigmentosa and pde5i for pde5, which therefore does not cause adverse reactions related to the action on pde6 (10, 11). following a single 200 mg dose of avanafil, no changes in colour perception were detected, however, the observation was made in a small sample and the data may not be significant. similar results were also obtained in larger studies with larger doses of medication (12). other adverse reactions other side effects were headache, dyspepsia, skin flush for sildenafil (4); headache, dyspepsia, skin flush, rhinitis, lengthening of qt for verdenafil (13, 14); headache, dyspepsia, back pain for tadalafil (5); headache, skin flush, nasal congestion, muscle cramps, postural hypotension for avanafil (10, 11). although there is no evidence in the literature that the administration of pde5i in patients with retinitis pigmentosa may or may not lead to an aggravation of the disease, in the light of the knowledge on the pharmacodynamics of pde5i and on the etiopathogenesis of retinitis pigmentosa, it seems appropriate, as a precaution, to avoid administering to these patients the least selective drugs for pde5 and opt instead for the most selective ones. in case of patient presenting retinitis pigmentosa and organic or post-operative erectile dysfunction, the possibility of pde5i treatment should not be excluded. this kind of patient should be analyzed and should undergo specific genetic tests to assess the presence or absence of mutations in gene coding for pde6 expressed at retinal level. in conclusion the presence of pde6 mutation allows us to avoid oral treatment with pde5i. references 1. pagon ra. retinitis pigmentosa. surv ophthalmol. 1988; 33:137-77. 2. parmeggiani f, sato g, de nadai k, romano mr, binotto a, costagliola c. clinical and rehabilitative management of retinitis pigmentosa: up-to-date. curr genomics. 2011; 12:250-9. 3. boughman ja, vernon m, shaver ka. usher syndrome: definition and estimate of prevalence from two high-risk populations. j chronic dis. 1983; 36:595-603. 4. basu a, ryder rej. new treatment options for erectile dysfunction in patients with diabetes mellitus. drugs. 2004; 64:2667-88. 5. hakky ts, jain l. current use of phosphodiesterase inhibitors in urology. turkish j urol. 2015; 41:88-92. 6. setter sm, iltz jl, fincham je, campbell rk, baker de. phosphodiesterase 5 inhibitors for erectile dysfunction. ann pharmacother. 2005; 39:1286-95. 7. kuthe a. phosphodiesterase 5 inhibitors in male sexual dysfunction. curr opin urol. 2003; 13:405-10. 8. goldstein i, lue tf, padma-nathan h, rosen rc, steers wd, wicker pa. oral sildenafil in the treatment of erectile dysfunction. sildenafil study group. n engl j med. 1998; 338:1397-404. 9. eardley i,cartledge j. tadalafil (cialis) for men with erectile dysfunction. int j clin pract. 2002; 56:300-4. 10. limin m, johnsen n, hellstrom wjg. avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. expert opin investig drugs. 2010; 19:1427-37. 11. alwaal a, al-mannie r, carrier s. future prospects in the treatment of erectile dysfunction: focus on avanafil. drug des devel ther. 2011; 5:435-43. 12. wang r, burnett al, heller wh, omori k, kotera j, kikkawa k. selectivity of avanafil, a pde5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability. j sex med. 2012; 9:2122-9. 13. hellstrom wjg, gittelman m, karlin g, segerson t, thibonnier m, taylor t. vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. j androl. 2002; 23:763-71. 14. carson cc. cardiac safety in clinical trials of phosphodiesterase 5 inhibitors. am j cardiol. 2005; 96:37m-41m. correspondence andrea cocci, md andrea romano, md (corresponding author) romano.andrea7895@gmail.com department of urology, university of florence san luca nuovo padiglione 16/settore c/piano ii largo brambilla 3-50134 firenze (italy) girolamo morelli, md davide frediani, md department of surgery, urology section, university of pisa, pisa (italy) andrea sodi, md department of surgery, ophthalmology section, university of florence, florence (italy) giorgio ivan russo, md department of surgery, urology section, university of catania, catania (italy) andrea cocci 1, andrea romano 1, girolamo morelli 2, davide frediani 2, andrea sodi 3, giorgio ivan russo 4 1 department of surgery, urology section,university of florence, florence, italy; 2 department of surgery, urology section, university of pisa, pisa, italy; 3 department of surgery, ophthalmology section, university of florence, florence, italy; 4 department of surgery, urology section, university of catania, catania, italy. cocci letter_stesura seveso 14/12/20 20:40 pagina 327 stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12245 1 letter to editor key words: erectile dysfunction; nitric oxide; iron. submission 31 december 2023; accepted 17 january 2024 to the editor, erectile dysfunction (ed) is one of the most prevalent conditions affecting men globally, with significant psychological and social consequences (1-2). the prevalence varies across different populations, and it is estimated around 50% in men aged between 40 to 70 (3). the etiology of ed is multifactorial, involving a complex crosstalk between psychological, hormonal, neurogenic, vascular, and structural factors (2, 4, 5) recently, the role of iron homeostasis (ih) is emerging. indeed, it is known that in hereditary hemochromatosis patients, the iron overload accumulated in the penis tissue, resulting in oxidative stress, tissue damages and consequently ed. to date, ih is an essential aspect of human health, and its dysregulation has been historically implicated in neurodegenerative disorders, anemia, or cardiovascular diseases (6). albeit the novel evidence on iron overload consequences on penis tissues, the underlying mechanisms of iron-related-ed remains unknown (7). several hypotheses have been postulated, such as endothelial dysfunction related either to iron overload and deficiency, the anemia, oxidative stress overproduction, and neurogenic dysfunction. first, in hemochromatosis patients the ed could occur due to the storage of iron in penis tissue, endocrine dysfunction as well as decreased serum testosterone level (8). furthermore, also the iron deficiency has been associated with ed. the mechanism underlying the above observations is due to the reduced nitric oxide (no) bioavailability (9). reactive oxygen species (ros) may be involved in the ironrelated-ed. indeed, ros disrupt the oxidative balance, affecting the hypothalamic-pituitary-gonadal axis (hpg) functionality (10). moreover, the reaction of superoxide (o2 •-) with no, resulting in acute impairment of cavernosal relaxation and in long-term penile vasculopathy due to a cellular damage. additionally, iron deficiency can also increase the oxidative stress, compromising antioxidant defense mechanisms (11). indeed, super-oxide dismutase, one of the most antioxidants enzymes, is increased in patients with iron deficiency anemia, due to a compensatory reaction to the oxidative stress. moreover, iron accumulation in the central nervous system can lead to neurodegeneration, and potentially affecting the neural pathways involved in erectile function with reduction of dopamine synthesis (12). in conclusion, ih represents a key role in endothelial and cavernous nerves function. both iron overload and deficiency could impair endothelial function, reducing no bioavailability and vasodilation in the penile vasculature (13). furthermore, the iron storage in the nervous plex could determine nerve injury, leading to ed. the relationship between ih alterations and ed represent a promising research area, with potential implications for the diagnosis and treatment of ed. further research is needed to determine the effective mechanism of neurogenic dysfunction which contributes to ed in the context of ih alterations and whether targeting this mechanism could lead to novel therapeutic interventions. references 1. mirone v, napolitano l, d'emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl. 2021; 93:221-226. 2. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 3. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. iron homeostasis alterations and erectile dysfunction: a new issue in erectile disfunction treatment? claudio marino 1, salvatore iaconis 1, francesco di bello 1,gianluigi cacace 1, giovanni fusco 1, lorenzo romano 1, ernesto di mauro 1, luigi cirillo 1, vincenzo maria altieri 2, 3, francesco mastrangelo 1, luigi napolitano 1, alessandro palmieri 1 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii, naples, italy; 2 department of medicine and health sciences "v. tiberio", university of molise, campobasso, italy; 3 department of urology, humanitas gavazzeni, bergamo, italy. doi: 10.4081/aiua.2024.12245 archivio italiano di urologia e andrologia 2024; 96(1):12245 c. marino, s. iaconis, f. di bello, et al. 2 4. cirillo l, fusco gm, di bello f, et al. sexual dysfunction: time for a multidisciplinary approach? arch ital urol androl. 2023; 95:11236. 5. shamloul r, ghanem h. erectile dysfunction. lancet. 2013; 381:153-65. 6. camaschella c. iron-deficiency anemia. n engl j med. 2015; 372:1832-43. 7. brissot p, ropert m, le lan c, loréal o. non-transferrin bound iron: a key role in iron overload and iron toxicity. biochim biophys acta. 2012; 1820:403-10. 8. barton jc, mcdonnell sm, adams pc, et al. management of hemochromatosis. hemochromatosis management working group. ann intern med. 1998; 129:932-9. 9. choi jw, pai sh, kim sk, et al. iron deficiency anemia increases nitric oxide production in healthy adolescents. ann hematol. 2002; 81:1-6. 10. darbandi m, darbandi s, agarwal a, et al. reactive oxygen species and male reproductive hormones. reprod biol endocrinol. 2018; 16:87. 11, et al. atli g, canli m. response of antioxidant system of freshwater fish oreochromis niloticus to acute and chronic metal (cd, cu, cr, zn, fe) exposures. ecotoxicol environ saf. 2010; 73:1884-9. 12. simonsen u, rodriguez-rodriguez r, dalsgaard t, et al. novel approaches to improving endothelium-dependent nitric oxide-mediated vasodilatation. pharmacol rep. 2009; 61:105-15. 13. he h, qiao y, zhou q, et al. iron overload damages the endothelial mitochondria via the ros/adma/ddahii/enos/no pathway. oxid med cell longev. 2019; 2019:2340392. correspondence claudio marino, md marinoclaudio88@outlook.it salvatore iaconis, md salvatore.iaconis@gmail.com francesco di bello, md fran.dibello12@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com giovanni maria fusco, md giom.fusco@gmail.com lorenzo romano, md lorenzo.romano@unina.it ernesto di mauro, md ernesto.dimauro@unina.it luigi cirillo, md cirilloluigi22@gmail.com francesco mastrangelo, md fmastrangelo91@gmail.com alessandro palmieri, md info@alessandropalmieri.it luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii, naples, 80100, italy vincenzo maria altieri, md vincenzomaria.altieri@gmail.com department of medicine and health sciences "v. tiberio", university of molise, 86100 campobasso, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4286 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.286 vival and function (3). now, the improvements in medical management and the development of novel surgical techniques have improved renal transplantation outcomes in these patients (4, 5). the general strategy, when necessary, is to correct the dysfunction by providing an adequate low-pressure urinary reservoir (bladder augmentation or urinary diversion) with a competent urethral control mechanism to ensure continence and complete bladder evacuation by voiding or clean intermittent catheterization (6). patients with end-stage renal disease and a poorly compliant bladder who did not response satisfactorily to conservative therapy (clean intermittent catheterization and anticholinergics) will require augmentation cystoplasty creating a low-pressure reservoir to protect the future renal transplant. enterocystoplasty using segments of ileum or colon is the most commonly used technique. moreover, if the patient cannot do clean intermittent catheterization through the urethra, a mitrofanoff or monti procedure is necessary to permit adequate bladder empty (7). current knowledge regarding timing of this surgery is based on a small number of studies with small sample sizes. most authors advise performing augmented bladder before renal transplantation to provide the best possible environment for the transplanted kidney (8). unfortunately, only few patients can take early kidney transplantation while most patients require renal replacement therapies and during the waiting period became anuric and do not use the lower urinary tract (9). in order to overcome this problem if augmented bladder is performed before renal transplantation and the patient has anuria, a daily bladder irrigation protocol with saline solutions must be established. the aim of daily bladder irrigation is both to maintain adequate bladder volume and to remove any enteric secretions decreasing the incidence of stones and infections in bladders augmented with the intestine (10). noteworthy many studies have supported that bladder augmentation is a well-established method of treating severe bladder dysfunction in children with esrd who will undergo kidney transplantation. however, there is still some debate about the safety of renal transplantation in the presence of bladder augmentation because of a theoretical increased risk of uti in these immunosuppressed patients, leading to pyelonephritis and graft loss (11, 12). objective: the aim of the study was to assess results and quality of life after kidney transplant in adult patients with previously bladder augmentation or urinary diversion due to significant lower urinary tract dysfunction. materials and methods: this cross-sectional study examines the outcome of 19 renal allografts transplanted in patients with augmented bladder or urinary diversion over a ten years period; moreover we submitted sf36 questionnaire to evaluate quality of life of these patients and compared the results with the general population. result: between january 1, 2005 and 31 december 2015 we performed 19/1093 renal transplantations in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. current post-transplant follow-up was 47 months (range 18-188). no patient developed any episode of acute or chronic rejection. mean serum creatinine after one year from transplant was 102 umol/l. overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. no significant differences emerged between patients undergoing transplant with lower urinary tract dysfunction and patients without, regarding to recurrent urinary tract infection. there was not statistically significant difference for vitality (p = 0.8088) and mental health (p = 0.8668). conclusions: presence of a previously augmented bladder or other lower urinary tract dysfunction treated in kidney transplant patients doesn’t worsen the final outcome. mental health and the vitality of these patients are similar to the general population. key words: kidney transplant; bladder augmentation; urinary diversion; quality of life. submitted 21 august 2020; accepted 2 september 2020 introduction the most common causes of lower urinary tract dysfunction (lutd) are posterior urethral valves, myelomeningocele, sacral agenesis and other congenital genitourinary anomalies. these pathologies are responsible for renal failure in approximately 15% of patients with end-stage renal disease (esdr); this percentage increased to 2030% in pediatric population with esdr (1, 2). for a long time, patients with lutd were considered high-risk recipients because just as lutd may lead to destruction of native kidneys, it also may adversely affect graft suroutcome and quality of life of patients with augmented bladder or urinary diversion after kidney transplantation summary giulia pozza 1, massimo iafrate 2, mariangela mancini 2, cristina silvestre 1, francesca neri 1, lucrezia furian 1, paolo rigotti 1, tommaso prayer galetti 2 1 department of surgery, renal and pancreas transplant unit, university of padua, padua, italy; 2 department of surgery, oncology, and gastroenterology, urology clinic, university of padua, padua, italy. pozza-iafrate_stesura seveso 14/12/20 20:32 pagina 286 287archivio italiano di urologia e andrologia 2020; 92, 4 augmented bladder or urinary diversion after kidney transplantation since 1948, when world health organization defined health as being not only the absence of disease and infirmity, but also the presence of physical, mental and social well-being, the interest in evaluation of quality of life is increased. in case of transplantation, the goal is not only to ensure the survival of patients or preserve physical health but also mental health (13). to our knowledge, in literature there are no reports of quality of life evaluation in this subgroup of transplanted patients. in this cross-sectional study, we examine our experience over a ten years period with renal transplantation in 19 patients with augmented bladder or other urinary diversion to evaluate the quality of life of these patients. material and methods study design this is a cross-sectional study involving all the consecutive patients undergoing kidney transplant and previously submitted to surgery for lower urinary tract dysfunction. all patients gave informed consent before being enrolled in this study. a retrospective review of clinical charts was performed to collect data on the patient kidney function, immunosuppressive therapy and assess the presence of febrile urinary tract infections after renal transplantation or asymptomatic bacteriuria. the primary end-point of the study was to assess the outcome of kidney transplant, in particular evaluating the urinary tract infection (uti). uti was defined as positive urine culture associated with clinical symptoms, indeed asymptomatic bacteriuria was defined as positive urine culture without clinical manifestations. to assess quality of life the sf-36 (short form health survey 36) was selfadministered. questionnaire the sf-36 questionnaire is a non-disease specific questionnaire that has been used to evaluate health-related quality of life for many years. it is self-administered and contains eight scales: physical functioning (pf), functioning-physical role (pr), bodily pain (bp); general health (gh), vitality (vt), social functioning (sf), role functioningemotional (re), and mental health (mh). raw scores range from 0 to 100, with higher scores indicating a better quality of life (qol) (14). the sf-36 has been extensively validated in transplanted patients (15) and in kidney transplant recipients (16). the final scores were compared with those of general italian population controls (17). surgical procedures bladder augmentation was obtained using an intestinal segment (usually ileum) which is opened and sewed into a patch and connected to an opening in the bladder. when necessary, a mitrofanoff technique was applied in order to void the bladder with intermittent catheterization and consist in the creation of a tunnel from the bladder to the cutaneous level using the appendix. all patients underwent kidney transplantation in the right iliac fossa; in most cases an end to side anastomosis was performed from the kidney vessels to the external iliac vessels. when the transplant was performed from a living donor, an end to end anastomosis of the renal artery to the internal iliac artery was used. for uretero-neocystostomy, a lich-gregoire technique was applied after positioning a ureteral stent. ureterocutaneostomy is a simple operative procedure in which the ureter can be easily passed to the cutaneous level and implanted performing a triangular cutaneous flap in order to avoid stenosis. all patients were followed up on our integrated transplant and urologic outpatient clinic and carefully trained by nurses in clean intermittent catheterization (cic). anticholinergic drugs were prescribed as an integration to cic to obtain low urine reservoir pressure. statistical analysis statistical analyses were performed using the spss-2019 software. questionnaire results were shown as mean (standard deviation) while the other continuous variables were shown as media (range). continuous variables were compared using t-test for independent variables. dichotomous variables were compared with chisquare test. a p-value of less than 0.05 was considered to show a statistically significant result. results patients characteristics at transplant a total of 1093 renal transplants in adults were performed at our institution between january 1, 2005 and 31 december 2015, including 19 transplantations (1.7%) performed in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. the patients were 13 man and 6 women, with median age of 35 (23-52) years. all patient had end stage renal failure as a consequence of urological abnormalities. the abnormalities were: neuropathic bladders (5), primary vesicoureteral reflux (3), bladder exstrophy (3), posterior urethral valves (4), others (4) (table 1). in 14 cases an augmentation enterocystoplasty with ileal segment was performed; one patient had a colon conduit; one ureterocutaneostomy; the other three performed bladder recycling of their native bladder through the mitrofanoff or a cystostomy. all patients were anuric before transplant. four of the 19 transplants were from a living donor and 8 of the 19 transplants were retransplanted (second or third). all patients received continuous antibiotic prophylaxis after transplantation with trimethoprimsulfamethoxazole daily until six months post-operatively for prevention of pneumocystis infection. patients follow-up current post-transplant follow-up was 47 months (range 18-188). no patient developed any episode of acute or chronic rejection and the mean serum creatinine after one year from transplant was 102 umol/l. overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. two major complications were registered. in one case graft was lost due to infection in the surgical site that necessitated the removal of the transplanted kidney three days after renal transplantation. latter case was an pozza-iafrate_stesura seveso 14/12/20 20:32 pagina 287 archivio italiano di urologia e andrologia 2020; 92, 4 g. pozza, m. iafrate, m. mancini, c. silvestre, f. neri, l. furiana, p. rigotti, t. prayer galetti 288 ileal obstruction due to abdominal adhesions that necessitated a surgical procedure with intestinal resection. in this case post-operative course was characterized by onset of severe acute pancreatitis and sepsis which causes patient’s death. urinary tract infection occurrence recurrent urinary tract infections (uti) were diagnosed in 4/17 patients (23.5%) during the post-transplant observation period, while in patients undergoing transplant without lower urinary tract dysfunction, during the follow-up uti were diagnosed in 206 patients (p = 0.528). asymptomatic bacteriuria was diagnosed in 9/17 patients (53%). after kidney transplantation, ten patients necessitate intermittent self-catheterization and all these patients were previously treated with an augmentation enterocystoplasty. quality of life outcome thirteen patients fulfilled the sf-36 questionnaire and results are shown in table 2. recipients reported a lower score than italian general population for pf (p < 0,0001), pr (p = 0,0007), bp (p = 0,0046), gh (p < 0,0001), re (p = 0,0462) and sf (p = 0,0200). there was not statistically significant difference for vt (p = 0,8088) and mh (p = 0,8668) as shown in figure 1. discussion treatment of patients with end-stage renal disease due to refractory lower urinary tract dysfunction is certainly not a new issue; nevertheless, it is still a source of dilemma even in transplant units with extensive experience. in our unit, over a ten years period, we performed 1093 kidney transplantation but only in 19 patients (1.7%), the cause of end stage renal disease (esrd) was a lower urinary tract dysfunction (lutd) refractory to medical treatment. in these patients augmentation enterocystoplasty or complete bladder replacement has been shown to be effective in order to achieve a low-pressure reservoir (18, 19) suitable for kidney transplant. before transplantation, all patients with small contracted bladder should be evaluated with a urodynamic functional study for their voiding problems (21, 22) in order to perform a kidney transplant only in patients with low bladder voiding pressure. when a low volume and high-pressure bladder is found out an enterocystoplasty or complete bladder replacement is advised before kidney transplant. in our population, at a median 47 months (range 18188) post-transplant follow-up, no patient developed any episode of acute or chronic rejection and mean serum creatinine after one year from transplant was 102 table 2. the scores on the eight scales of the of the kidney transplantation patients with bladder augmentation who completed 36-item short-form health survey (sf36) questionnaire: physical functioning (pf), role-physical (rp), bodily pain (bp); general health (gh), vitality (vt), social functioning (sf), role-emotional (re), and mental health (mh). figure 1. a comparison of the mean scores of the sf36 questionnaire of the study and control groups. table 1. the characteristics of the 19 kidney recipient patients with urinary tract dysfunctions studied here. patient sex urologic type of age at the age at the abnormalities surgical urologic kidney procedure procedure transplant 1 m primary vescicoureteric reflux ileal cystoplasty 10 35 2 f neuropathic bladder ileal cystoplasty 19 45 3 m bladder extrophy ureterocutaneostomy 26 42 4 f others colon conduit 19 35 5 m neuropathic bladder ileal cystoplasty n.a. 23 6 f others ileal cystoplasty n.a. 52 7 m others ileal cystoplasty 8 32 8 m neuropathic bladder ileal cystoplasty 22 32 9 f bladder extrophy ileal cystoplasty 27 45 10 m primary vescicoureteric reflux mitrofanoff 4 27 11 m posterior urethral valves ileal cystoplasty 10 28 12 m primary vescicoureteric reflux ileal cystoplasty 30 42 13 m posterior urethral valves ileal cystoplasty 26 26 14 f neuropathic bladder ileal cystoplasty 19 36 15 m neuropathic bladder ileal cystoplasty 11 29 16 m posterior urethral valves cystostomy n.a. 41 17 m bladder extrophy ileal cystoplasty 44 49 18 f others ileal cystoplasty 43 60 19 m posterior urethral valves cystostomy 24 27 patient pf rp bp gh vt sf re mh 1 45 0 41 50 55 50 0 56 2 40 25 100 65 100 87.5 100 100 3 50 100 72 22 85 87.5 100 80 4 85 50 74 47 70 87.5 66.7 68 5 90 100 41 92 75 87.5 0 80 6 100 100 100 62 80 62.5 66.7 72 7 70 75 51 85 80 87.5 100 72 8 85 100 72 77 75 75 100 80 9 95 50 51 67 60 75 100 76 10 100 75 84 42 45 50 66.7 40 11 100 100 84 87.15 90 100 100 100 12 100 100 100 50 50 100 100 100 13 90 100 100 52 60 50 0 52 mean 80.8 75 74.6 61.4 71.2 76.9 69.2 75.1 st. dev. 22.1 33.8 22.6 20.3 16.3 18.3 41.8 18.5 pozza-iafrate_stesura seveso 14/12/20 20:32 pagina 288 289archivio italiano di urologia e andrologia 2020; 92, 4 augmented bladder or urinary diversion after kidney transplantation umol/l. overall patients’ survival is 94.8% at the end of follow-up and graft survival is 89.6%. based on our data reservoir recycling seems to have a key role in maintaining, following enterocystoplasty or complete bladder replacement, a low-pressure reservoir with good compliance. moreover after kidney transplant clean intermittent catheterization (cic) is required in patients with augmented bladder to obtain complete voiding (20) to reduce post voiding residual. in our experience all our 10 patients with augmented bladder required cic, except for one woman who is able to void bladder spontaneously and one man who underwent an endoscopic incision of prostate. among our 19 patients with previous lutd symptomatic urinary tract infections were diagnosed in 23.5% of cases during the post-transplant period while uti incidence in our general population of transplanted patients was 18.8% (206 cases). noteworthy asymptomatic bacteriuria was diagnosed in 9/17 patients (53%) and therefore a careful cic prevented symptoms in 29.5% of our patients. despite the need of cic recipients reported according sf-36 questionnaire a lower score than italian general population for physical functioning (pf p < 0.0001), functioningphysical role (pr p = 0,0007), bodily pain (bp p = 0.0046), general health (gh p < 0.0001), role functioning-emotional (re p = 0.0462) and social functioning (sf p = 0.0200). there was not statistically significant difference for vitality vt (p = 0.8088) and mental health (mh p = 0.8668). the observed data are remarkable because sf-36 questionnaire gives an objective evaluation of patients’ quality of life using a tool extensively validated in transplanted patients (15) and in kidney transplant recipients (16). to our knowledge this is the first report in literature on quality of life of transplanted kidney patients with an augmentation enterocystoplasty in adult patients. our data analysis showed that kidney-transplanted patients with previous lower urinary tract dysfunction reported a lower score than italian general population for physical functioning, physical role health problems, bodily pain, general health, emotional role of health problems and social functioning. indeed, there were not statistically significant difference for vitality and mental health. physical quality of life is lower in transplanted patients with bladder augmentation than in general population due to the often complex clinical and surgical history. in our center we try to promote physical activity for all transplanted patients in order to obtain better patients physical well-being. the reason of a worst bodily pain is unclear but could be explained also by the necessity to perform many self-catheterization daily. therefore, a correct education of the patients to the urological maneuver, seems to be important. the good results obtained in the field of vitality and mental health could be explained by a careful selection of the patients and a continuous urological and psychological support after the transplantation. it has to be remarked that these patients before kidney transplantation were often treated with complex surgical procedure to correct lower urinary tract dysfunction and after kidney transplantation need to learn how to void correctly the bladder. despite all these difficulties after a careful preoperative evaluation, detailed information and continuous support, our patient obtained a good quality of life. our study has some limitations. the first limit of our study is the small sample size due to the rarity of the lower urinary tract dysfunction with end-stage renal disease. the second limit is the lack of an adequate control group and for this reason we used the sf-36 norms for italian population as control. for this comparison was necessary to use parametric statistics even if the sample size of the study group was rather low. conclusions this study shows that the presence of a previously augmented bladder or urinary diversion in kidney transplant patients doesn’t worsen the final outcome of kidney transplantation. careful clean intermittent catheterization (cic) markedly reduces symptomatic uti incidence without compromising patients’ quality of life. the sf36 validate quality of life questionnaire demonstrates that mental health and vitality of these patients are similar to the general population. physical status and transplant outcome in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling can be increased through a continuous outpatient support and education programs. references 1. rigamonti w, capizzi a, zacchello g, et al. kidney transplantation into bladder augmentation or urinary diversion. long-term results. transplantation. 2005; 80:1435. 2. mendizabal s, estornell f, zamora i, et al. renal transplantation in children with severe bladder dysfunction. j urol. 2005; 173:226. 3. koo hp, bunchman te, flynn jt, et al. renal transplantation in children with severe lower urinary tract dysfunction. j urol. 1999; 161:240. 4. lopez pereira p, martinez urrutia mj, lobato r, jaureguizar e. renal transplantation in augmented bladders. curr urol rep. 2014; 15:431. 5. ghirardo g, midrio p, zucchetta p, et al. renal transplantation in children weighing < 15 kg: does concomitant lower urinary tract dysfunction influence the outcome? pediatr neprhol. 2015; 30:1337. 6. chun jm, jung go, park jb, et al. renal transplantation in patients with a small bladder. transplantation proceedings. 2008; 40:2333. 7. barry jm. kidney transplantation into patients with abnormal bladders. transplantation. 2004; 77:1120. 8. sullivan me, reynard jm, cranston dw. renal transplantation into the abnormal lower urinary tract. bju int. 2003; 92:510. 9. fontaine e, gagnadoux mf, niaudet p, et al. renal transplantation in children with augmentation cystoplasty: long-term results. j urol. 1988; 140:1129. 10. hatch da, koyle ma, baskin ls, et al. kidney transplantation in children with urinary diversion or bladder augmentation. j urol. 2001; 165:2265. 11. pereira da, barroso u, machado p, et al. effects of urinary tract infection in patients with bladder augmentation and kidney transplantation. j urol. 2008; 180:2607. pozza-iafrate_stesura seveso 14/12/20 20:32 pagina 289 archivio italiano di urologia e andrologia 2020; 92, 4 g. pozza, m. iafrate, m. mancini, c. silvestre, f. neri, l. furiana, p. rigotti, t. prayer galetti 290 12. jesus le, pippi salle jl. pre-transplant management of valve bladder: a critical literature review. j pediatr urol. 2015; 11:5. 13. wright pinson c, feurer i, payne jl, et al. health-related quality of life after different types of solid organ transplantation. ann surg. 2000; 232:597. 14. ware je, snow kk, gandek b. sf-36 health survey. manual and interpretation guide. boston, ma, usa: the health institute, new england medical center, 1993. 15. liem ys, bosch jl, arends lr, et al. quality of life assessed with the medical outcomes study short form 36-item health survey of patients on renal replacement therapy: a sys-tematic review and meta-analysis. value health. 2007; 5:390. 16. weber m, faravardeh a, jackson s, et al. quality of life in elderly kidney transplant recipients. jags. 2014; 62:1877. 17. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin epidemiol. 1998; 51:1025. 18. sheldon ca, gonzalez r, burns mw, et al. renal transplantation into the dysfunctional blad-der: the role of adjunctive bladder reconstruction. j urol. 1994; 152:972. 19. mitchell me, piser ja. intestinocystoplasty and total bladder replacement in children and young adult: follow up in 129 cases. j urol. 1987; 138:579. 20. bianco m, medina j, pamplona m, et al. outcome of renal transplantation in adult patients with augmented bladders. transplant proc. 2009; 41:2382. 21. kashi sh, wynne ks, sadek sa, et al. an evaluation of vesical urodynamics before renal transplantation and its effect on renal allograft function and survival. transplantation 1994; 57:1455. 22. marshall ff, smolev jk, spees ek, et al. the urological evaluation and management of pa-tients with congenital lower urinary tract anomalies prior to renal transplantation. j urol. 1982; 127:1078. correspondence giulia pozza, md mariangela mancini, md cristina silvestre, md francesca neri, md lucrezia furian, md paolo rigotti, md department of surgery, renal and pancreas transplant unit, university of padua, padua (italy) massimo iafrate, md (corresponding author) massimo.iafrate@unipd.it prayer galetti tommaso, md department of surgery, oncology, and gastroenterology urology clinic, university of padua via giustiniani 2 35128 padua (italy) pozza-iafrate_stesura seveso 14/12/20 20:32 pagina 290 cop+ed+fisse 2006 177archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.177 the role of protopine associated with nuciferine in controlling adverse events during hyperthermic intravesical chemotherapy instillations. a nutraceutical approach to control adverse event during intravesical instillations francesco chiancone, maurizio carrino, maurizio fedelini, marco fabiano, francesco persico, clemente meccariello, paolo fedelini department of urology, a. cardarelli hospital, naples, italy. objectives: the aim of this study was to analyse the role of two alkaloid, protopine and nuciferine, in the prevention and the treatment of the low and mild grade adverse events related to the use of hivec® (hyperthermic intravesical chemotherapy) instillations. materials and methods: from september 2017 to september 2019, 100 patients were prospectively randomized into two groups: group a = protopine and nuciferine syrup, 10 ml, once a day, for 8 weeks; group b = placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks. the primary endpoint was the evaluation of the efficacy of the therapy with protopine and nuciferine in controlling of the irritative symptoms. the secondary endpoint was the evaluation of the influences of the treatment on the uroflowmetric parameters. results: the patients of group a showed a better international prostatic symptoms score (ipss) score, a better control of urgency symptoms (ppius) and tolerate well the pain (vas score). the treatment doesn’t modify uroflow-qmax and seems to improve the uroflow-voided volume (ml) without influencing the uroflow-post void residual volume (pvr). moreover, the treatment with protopine and nuciferine has been proven to be effective in the treatment of overactive bladder (oab) symptoms. patients’ evaluation of the two different treatments assessed with patient global impression of improvement questionnaire (pgi-i), demonstrated improvements in the group a, while the group b showed a lower satisfaction. conclusions: protopine and nuciferine can be interesting nutraceutical compounds useful to control irritative and pain related symptoms of intravesical chemo/immunotherapy. key words: complementary medicine; bladder cancer; luts; chemotherapy; overactive bladder; urodynamics. submitted 6 january 2020; accepted 13 march 2020 introduction in recent times, hyperthermic intravesical chemotherapy (hivec®) instillations has been added to the existing regimens as adjuvant and neoadjuvant treatment of bladder cancer (1). most of the side effects were low grade and 97% of patients completed the hivec® protocol (2). in a population of 55 bcg (bacillus calmetteguérin) unresponsive non-muscle invasive bladder cancer (nmibc) patients, 5% of the patients did not complete at least 5 hivec® instillations because of facial swelling, urticaria and urinary tract pain grade 3 according to common terminology criteria for adverse events (ctcae). despite this, 7% of patients reported ctcae grade 1 bladder spams, 11% ctcae grade 1 urinary frequency/urgency, 24% ctcae grade 2 urinary frequency/urgency, 4% ctcae grade 1 urinary tract pain, 9% ctcae grade 2 urinary tract pain and 2% ctcae grade 3 urinary tract pain (3). despite the low number of adverse events, the patients treated with hivec® were significantly more likely to develop urinary frequency, haematuria and bladder spasm than passive mitomycin-c (4). the aim of this study was to analyse the role of two alkaloid, protopine and nuciferinein the prevention and the treatment of the low and mild grade adverse events related to the use of hivec® instillations. materials and methods from september 2017 to september 2019, 100 patients with bacillus of calmette guerin (bcg)-failure (including bcg-refractory tumour, bcg-relapsing tumour and bcg unresponsive tumour) nmibc whose underwent hivec® chemotherapy were prospectively enrolled in this study. the patients (pts) were randomized into two groups using block randomization in order to obtain two groups of equal sample size. in group a, we enrolled 50 patients who received protoves m1® (protopine and nuciferine) syrup, 10 ml, once a day, for 8 weeks. in group b, we enrolled 50 patients who received placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks. they started the therapy two weeks before the beginning of hivec® treatment. inclusion criteria covered all the patients with intermediate-and high-risk nmibc patients who were planned to receive hivec® treatment. patients with uncontrolled underlying diseases (asa iii or iv), post void residual urine ≥ 100 ml, bleeding tendency, drug abuse, chronic pelvic pain, urinary tract infection, neurological disease, bladder lithiasis, renal or liver failure, tachycardia and heart failure were summary 04chiancone_stesura seveso 24/09/20 14:13 pagina 177 archivio italiano di urologia e andrologia 2020; 92, 3 f. chiancone, m. carrino, m. fedelini, m. fabiano, f. persico, c. meccariello, p. fedelini 178 excluded from the study. male patients with lower urinary tract symptoms (luts) and benign prostatic hyperplasia (bph) were not excluded from the study if they had normal values of uroflowmetry and they did not assume any medical treatment for bph. at the baseline, data on demographic and anthropometric features (age, weight, height, bmi [body mass index]), lifestyle characteristics (smoke, alcohol), any comorbidities (hypertension, diabetes mellitus, etc.) were collected. all patients underwent a clinical evaluation (comprised general, genital and urologic examination). before starting the treatment, the following measurements were collected: prostate volume by transrectal ultrasound, prostate specific antigen (psa), uroflowmetry parameters (uroflow-qmax, uroflowvoided volume, uroflow-pvr [post-void residual]), international prostatic symptoms score (ipss) questionnaire, overactive bladder questionnaire-short form (oabqsf) 6 and 13, patient perception of intensity of urgency scale (ppius), and visual analogue scale (vas). psa and ipss were investigated only in male pts. in addition, the patient impression of improvement was assessed. improvement was evaluated with the patient global impression of improvement questionnaire (pgi-i), a validated tool to estimate the improvement or the deterioration associated to the treatment. the primary endpoint was the evaluation of the efficacy of the therapy with protopine and nuciferine in controlling irritative symptoms, including nocturia, urinary frequency, bladder pain, urgency and urge incontinence related to the chemo-hypertermia treatment. the secondary endpoint we evaluated was the influence of the treatment on the uroflowmetric parameters. evaluation was performed after 1 week and after 6 weeks of therapy. statistical analyses were conducted using sas version 9.3 software (sas institute, inc., nc). mean values with standard deviations (± sd) were computed and reported for all items. statistical significance was achieved if p-value was ≤ 0.05 (two-sides). results table 1 depicts patients’ demographics and baseline characteristics. the two groups showed no difference in terms of patients’ demographics as well as tumour characteristics in all variables. of all 100 patients enrolled, 2/50 (4%) of group b withdrew the study for adverse events of hivec treatment. in table 2 and 3 we show a comparison of uroflowmetric parameters and questionnaires from baseline and one and six weeks follow up of treatment in the cases (group a) and in the controls (group b). the uroflow parameters (uroflow-qmax, uroflow-voided volume, uroflow-pvr) did not show statistical significant difference from baseline in the group a and one and six weeks follow-up. otherwise ipss total significantly increase at one week from baseline (p < 0.001), but this difference was not significant at six weeks when ipss total was not significantly worse from baseline (p = 0.09). in group a the quality of life showed a significant worsening from baseline after one week and six weeks of treatment in all parameters and questionnaires analyzed (oab-q sf6, oab-q sf13, ppius, vas scale) but after six weeks of treatment a significanttable 1. demographics and baseline characteristics of the 50 cases and 50 controls. variable value (cases) value (controls) p n° (%) males 40 (80%) 39 (78%) p = 0.8061 females 10 (20%) 11 (22%) p = 0.8061 smokers 12 (24%) 11 (22%) p = 0.8122 non-smokers 38 (76%) 39 (78%) p = 0.8122 diabetes (yes) 5 (10%) 7 (14%) p = 0.5383 diabetes (no) 45 (90%) 43 (86%) p = 0.5383 c.i.s. (yes) 11 (22%) 8 (16%) p = 0.4444 c.i.s. (no) 39 (78%) 42 (84%) p = 0.4444 mean ± sd age at surgery (years) 58.52 ± 5.28 57.64 ± 5.38 p = 0.4138 bmi (kg/m2) 26.754 ± 1.96 26.916 ± 1.91 p = 0.6764 t.u.r.b. (n°) 1.86 ± 1.18 2.08 ± 1.16 p = 0.3495 tumors (last t.u.r.b.) (n°) 3.5 ± 2.44 4.08 ± 2.25 p = 0.2195 psa (ng/ml) 2.33 ± 0.95 2.13 ± 0.95 p = 0.2951 prostate volume (cc) 42.43 ± 13.39 41.38 ± 13.56 p = 0.6977 uroflow-qmax (ml/s) 17.49 ± 2.39 17.39 ± 2.21 p = 0.8285 uroflow-voided volume (ml) 250.6 ± 39.8 242.2 ± 41.2 p = 0.3023 uroflow-pvr (ml) 15.4 ± 10.6 14.9 ± 10.1 p = 0.8097 ipss total 7.05 ± 3.88 7.79 ± 4.55 p = 0.3837 qol score 2.22 ± 1.23 2.34 ± 1.26 p = 0.6310 oab-q sf 6 11.48 ± 5.18 11.92 ± 5.30 p = 0,6755 oab-q sf 13 25.12 ± 11.50 26.02 ± 11.39 p = 0.6950 ppius 0.94 ± 0.79 0.96 ± 0.78 p = 0.8989 vas scale 0.08 ± 0.27 0.18 ± 0.87 p = 0.4395 cis: in situ carcinoma; bmi: body max index; turb: trans urethral bladder resection; psa: prostate specific antigen; pvr: post-void residual; ipss: international prostatic symptoms score; qol: quality of life; oab: overactive bladder; ppius: patient perception of intensity of urgency scale; vas: visual analogue scale. table 2. comparison of uroflowmetry parameters and questionnaires from baseline and between one and six weeks of treatment (cases). variable value (baseline) value (one-week) value (six-weeks) uroflow-qmax (ml/s) 17.49 ± 2.39 16.99 ± 2.55 16.62 ± 2.43 p (from baseline) p = 0.3142 p = 0.0742 variable value (baseline) value (one-week) value (six-weeks) uroflow-voided volume (ml) 250.6 ± 39.8 239.7 ± 40.10 250.9 ± 39.22 p (from baseline) p = 0.1756 p = 0.9698 p (from 1 and 6 weeks) p = 0.1611 uroflow-pvr (ml) 15.4 ± 10.6 18.18 ± 12.46 19.7 ± 12.01 p (from baseline) p = 0.2324 p = 0.0606 p (from 1 and 6 weeks) p = 0.5360 ipss total 7.05 ± 3.88 11.18 ± 4.84 8.35 ± 3.81 p (from baseline) p < 0.001 p = 0.0941 p (from 1 and 6 weeks) p = 0.0016 oab-q sf 6 11.48 ± 5.18 17.16 ± 4.82 14.46 ± 5.60 p (from baseline) p < 0.001 p = 0.0069 p (from 1 and 6 weeks) p = 0.0112 oab-q sf 13 25.12 ± 11.50 36.42 ± 10.67 31.16 ± 11.57 p (from baseline) p < 0.001 p = 0.0102 p (from 1 and 6 weeks) p = 0.0201 ppius 0.94 ± 0.79 2.26 ± 0.88 1.66 ± 0.66 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.0002 pgi-i 4 ± 0 4.2 ± 0.60 2.46 ± 0.86 p (from baseline) p = 0.1161 p < 0.001 p (from 1 and 6 weeks) p < 0.001 vas scale 0.08 ± 0.27 3.38 ± 1.35 2.34 ± 0.96 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p < 0.001 pvr: post-void residual; ipss:international prostatic symptoms score; oab: overactive bladder; ppius: patient perception of intensity of urgency scale; pgi-i: patient global impression of improvement questionnaire; vas: visual analogue scale. 04chiancone_stesura seveso 24/09/20 14:13 pagina 178 ly improvement of quality of life was demonstrated with respect of the values at one week. pgi-1 did not significantly show any change at one week but showed a significant decrease at six weeks follow-up with a greater satisfaction for the treatment. in the group b the uroflow parameters did not show a statistical significant difference from baseline at one and six weeks follow-up except for a significant reduction of uroflow-voided volume (p = 0.0118) at one week. a significant worsening of ipss score was seen at one and six weeks of follow-up (p < 0.001). in this group the quality of life showed a significant worsening after one week and six weeks of treatment from baseline in all parameters and questionnaires analyzed (oab-q sf6, oab-q sf13, ppius, vas scale). at six weeks follow-up a significantly worsening of quality of life was demonstrated from the values at one week. pgi-1 showed a significantly increase from baseline at one and six weeks of follow-up with a worse perception of the response to the therapy. vas scale also showed a significantly increase from baseline at one and six weeks of follow-up. in both cases an increase of values was seen from the one and six weeks of follow-up without reaching a significant difference. table 4 shows a comparison of uroflowmetric parameters and results of questionnaires between cases and controls at one and six weeks. no differences were seen in the uroflow-qmax and in the uroflow-pvr at one (p = 0.8846) and six weeks (0.3951) while the uroflowvoided volume was significantly reduced in the controls at one (p = 0.0234) and six (p = 0.0002) weeks followup. the ipss questionnaire significantly get worse in the group b instead of group a at one (p = 0.0222) and six (p < 0.001) weeks of treatment. group a showed a significantly better oab-q sf 6 and oab-q sf 13 at one and six weeks of follow-up, while the ppius and the vas scale were significantly worse in the group b only at six weeks. pgi-1 showed a worst perception of the condition post-therapy in the group b both after one and six weeks of treatment. no adverse events were reported in both groups. discussion several clinical trials have demonstrated a benefit for chemo-hyperthermia over intravesical chemotherapy alone for treating nmibc (5-6). neoadjuvant hivec consisted of intravesical chemotherapy with mitomycin-c (mmc) combined with bladder hyperthermia, which was achieved in our cases with the bladder recirculation system (brs) system from combat medical. the combat brs device is an external device that heats fluid (mmc in this case) in a sterile disposable bag and recirculates it to the urinary bladder at a constant and controllable temperature and flow rate through a three-way foley catheter. hyperthermia increases drug uptake into the cancer cells, affects drug metabolism, and impairs cellular dna repair mechanisms that normally counteract drug effect (7-9). this treatment might be a feasible option in bcg unresponsive nmibc patients, potentially avoiding or postponing the need for radical surgery in a proportion of these patients (3, 10, 11). nevertheless, this treatment can increase the rate of local adverse events than passive mitomycin-c like urinary frequency, haematuria and bladder spasm (4). protopine has a demonstrated anti179archivio italiano di urologia e andrologia 2020; 92, 3 protopine and nuciferin for hyperthermic intravesical chemotherapy table 3. comparison of uroflowmetry parameters and questionnaires from baseline and between one and six weeks of treatment (controls). variable value (baseline) value (one-week) value (six-weeks) uroflow-qmax (ml/s) 17.39 ± 2.21 17.06 ± 2.25 17.02 ± 2.15 p (from baseline) p = 0.4611 p = 0.3982 p (from 1 and 6 weeks) p = 0.9278 uroflow-voided volume (ml) 242.2 ± 41.22 220.4 ± 43.66 218.8 ± 43.21 p (from baseline) p = 0.0118 p = 0.0067 p (from 1 and 6 weeks) p = 0.8543 uroflow-pvr (ml) 14.9 ± 10.13 13.8 ± 10.08 15.9 ± 9.98 p (from baseline) p = 0.5875 p = 0.6201 p (from 1 and 6 weeks) p = 0.2977 ipss total 7.79 ± 4.55 13.64 ± 5.71 14.62 ± 5.92 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.4016 oab-q sf 6 11.92 ± 5.3 20.58 ± 6.29 24.34 ± 6.3 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.0036 oab-q sf 13 26.02 ± 11.39 43.78 ± 13.02 49.44 ± 12.65 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.0298 ppius 0.96 ± 0.78 2.12 ± 0.69 2.54 ± 0.64 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.0021 pgi-i 4 ± 0 4.82 ± 0.96 5.22 ± 1.02 p (from baseline) p < 0.001 p = 0.0462 p (from 1 and 6 weeks) p = 0.2719 vas scale 0.08 ± 0.27 3.68 ± 1.88 3.92 ± 1.93 p (from baseline) p < 0.001 p < 0.001 p (from 1 and 6 weeks) p = 0.5302 pvr: post-void residual; ipss:international prostatic symptoms score; oab: overactive bladder; ppius: patient perception of intensity of urgency scale; pgi-i: patient global impression of improvement questionnaire; vas: visual analogue scale. table 4. comparison of uroflowmetry parameters and results of questionnaires between cases and controls at one and six weeks. variable value (group a value (group b p value (group a value (group b p 1-week) 1-week) 6-week) 6-week) uroflow-qmax (ml/s) 16.99 ± 2.55 17.06 ± 2.25 0.8846 16.62 ± 2.43 17.02 ± 2.15 0.3951 uroflow-voided volume (ml) 239.7 ± 40.10 220.4 ± 43.66 0.0234 250.9 ± 39.22 218.8 ± 43.21 0.0002 uroflow-pvr (ml) 18.18 ± 12.46 13.8 ± 10.08 0.0562 19.7 ± 12.01 15.9 ± 9.98 0.0611 ipss total 11.18 ± 4.84 13.64 ± 5.71 0.0222 8.35 ± 3.81 14.62 ± 5.92 < 0.001 oab-q sf 6 17.16 ± 4.82 20.58 ± 6.29 0.0029 14.46 ± 5.60 24.34 ± 6.3 < 0.001 oab-q sf 13 36.42 ± 10.67 43.78 ± 13.02 0.0026 31.16 ± 11.57 49.44 ± 12.65 < 0.001 ppius 2.26 ± 0.88 2.12 ± 0.69 0.3782 1.66 ± 0.66 2.54 ± 0.64 < 0.001 pgi-i 4.2 ± 0.60 4.82 ± 0.96 0.0002 2.46 ± 0.86 5.22 ± 1.02 < 0.001 vas scale 3.38 ± 1.35 3.68 ± 1.88 0.3616 2.34 ± 0.96 3.92 ± 1.93 < 0.001 pvr: post-void residual; ipss: international prostatic symptoms score; oab: overactive bladder; ppius: patient perception of intensity of urgency scale; pgi: patient global impression of improvement questionnaire; vas: visual analogue scale. 04chiancone_stesura seveso 24/09/20 14:13 pagina 179 archivio italiano di urologia e andrologia 2020; 92, 3 f. chiancone, m. carrino, m. fedelini, m. fabiano, f. persico, c. meccariello, p. fedelini 180 cholinergicantimuscarinic (11, 12) and gabaergic (1215) action and it is able to influence some neurological systems responsible of bladder functions. moreover, its anti-acetylcholinesterase action give it an antiamnesic property that may hold significant therapeutic value in alleviating certain memory impairments observed in dementia (15, 16). protopine increase the p53-mediated transcriptional activity, resulting in stabilization of p53 protein. it exerts an antiproliferative activity and may have potential effect as a chemopreventive agent for human colon cancer (16, 17). nuciferin is a partial antagonist of d2-like receptor and has a demonstrated regulatory action on the dopaminergic system (responsible of urination onset (17, 18) and seems to reduce states of tension and anxiety on a psychological level (18-20). nuciferine significantly inhibited the lipopolysaccharide (lps)-induced inflammatory cytokine il-6 and tnf-a production in raw 264.7 cells having potential anti-inflammatory activities (20, 21). its use significantly decrease the expression of tlr4 in a dose-dependent manner and potently ameliorates lpsinduced mastitis by inhibition of the tlr4-nf-kb signaling pathway (21, 22). in addiction nuciferine alleviated fructose-induced inflammation by inhibiting tlr4/pi3k/nf-kb signaling and nlrp3 inflammasome activation in rat renal cortex and hk-2 cells, which may contribute to the improvement of renal injury (22, 23). this molecule is an aporphine alkaloid of lotus leaf extract which can induce relaxation in contracted tracheal rings. it induce relaxation in tracheal rings mainly by inhibition of extracellular ca2+ influx through the blockade of voltage-dependent l-type ca2+ channels and/or nonselective cation channels, showing therapeutic effect on respiratory diseases associated with the aberrant contraction of airway smooth muscles and/or bronchospasm (23, 24). in our experience the patients who underwent protopine and nuciferine syrup treatment, showed a better ipss score, a better control of urgency symptoms (ppius) and tolerate well the pain related to the chemo-hyperthermia treatment (vas score) compared to control group. the treatment doesn’t modify uroflow-qmax at 1 and 6 weeks and seems to improve the uroflow-voided volume (ml) withouth influence the uroflow-pvr. moreover protopine and nuciferine syrup treatment has been proven to be effective in the treatment of oab symptoms with a significant reduction of the symptoms assessed with overactive bladder symptoms score questionnaire (oab-q sf6, oab-q sf13) after six weeks of treatment but not after one week of treatment. this underline the need to start the treatment with protopine and nuciferine as soon as possible in order to enhance the effect of the treatment. patients’ evaluation of the two different treatments (protopine and nuciferine vs placebo) assessed with pgi-i, demonstrated improvements in the group of cases with a greater satisfaction expressed by patients at six weeks, while the control group showed a lower satisfaction at one and six weeks. moreover, the treatment with protopine and nuciferine syrup was well tolerated by all patients, none of them showing any side effect during the period study. the study is a double-blind randomized study but is limited by the small number of patients and monocentric nature. conclusions protopine and nuciferine syrup can be an interesting alternative to antinflammatory and antimuscarinic agents to treat irritative and pain related symptoms of intravesical chemo/immunotherapy. more studies should be carried out to clarify the precise role of the active ingredients of protopine and nuciferine syrup and their interactions. references 1. sousa a, inman ba, piñeiro i, et al. a clinical trial of neoadjuvant hyperthermic intravesical chemotherapy (hivec) for treating intermediate and high-risk non-muscle invasive bladder cancer. int j hyperthermia. 2014; 30:166-70. 2. sousa a, piñeiro i, rodríguez s, et al. recirculant hyperthermic intravesical chemotherapy (hivec) in intermediate-high-risk non-muscle-invasive bladder cancer. int j hyperthermia. 2016; 32:374-80. 3. de jong jj, hendricksen k, rosier m, et al. hyperthermic intravesical chemotherapy for bcg unresponsive non-muscle invasive bladder cancer patients. bladder cancer. 2018; 4:35-401. 4. tan ws, palou j , kelly j. safety and tolerability analysis of hyperthermic intravesical mitomycin to mitomycin alone in hivec i and hivec ii: an interim analysis of 307 patients eur urol. 2017; 16;e1150. 5.colombo r, da pozzo lf, lev a, et al. neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer. j urol. 1996; 155:1227-32. 6.lammers rj, witjes ja, inman ba, et al. the role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of nonmuscle-invasive bladder cancer: a systematic review. eur urol. 2011; 60:81-93. 7. ahmed k, zaidi sf. treating cancer with heat: hyperthermia as promising strategy to enhance apoptosis. j pak med assoc. 2013; 63:504-8. 8. kampinga hh. cell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. int j hyperthermia. 2006; 22:191-6. 9. hildebrandt b, wust p, ahlers o, et al. the cellular and molecular basis of hyperthermia. crit rev oncol hematol. 2002; 43:33-56. 10. babjuk m, burger m, compérat e, et al. eau guidelines on non-muscle-invasive bladder cancer, 2019. 11. gözen as, umari p, scheitlin w, et al. effectivity of intravescical thermo-chemotherapy prophylaxis for patients with high recurrence and progression risk for non-muscle invasive bladder cancer. arch ital urol androl. 2017; 89:102-105. 12. ustunes l., laekeman gm, gözler b, et al. in vitro study of the anticholinergic and antihistaminic activities of protopine and some derivatives. j nat prod. 1988; 51:1021-2 13. kardos j, blaskó g, simonyi m. enhancement of gammaaminobutyric acid receptor binding by protopine-type alkaloids. arzneimittelforschung. 1986; 36:939-40. 04chiancone_stesura seveso 24/09/20 14:13 pagina 180 181archivio italiano di urologia e andrologia 2020; 92, 3 protopine and nuciferin for hyperthermic intravesical chemotherapy 14. fedurco mj, gregorová k, šebrlová j, et al. modulatory effects of eschscholzia californica alkaloids on recombinant gabaa receptors. biochem res int. 2015; 2015:617620. 15,häberlein h, tschiersch kp, boonen g, et al. chelidonium majus l.: components with in vitro affinity for the gabaa receptor. positive cooperation of alkaloids. planta med. 1996; 62:227-31. 16. kim sr, hwang sy, jang yp, et al. protopine from corydalis ternata has anticholinesterase and antiamnesic activities. planta med. 1999; 65:218-21. 17. son y, an y, jung j, et al. protopine isolated from nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53. phytother res. 2019; 33:1689-1696. 18. fowler cj, griffiths d, de groat wc. the neural control of micturition. nat rev neurosci. 2008; 9:453-466. 19. kang m, shin d, oh jw, et al. the anti-depressant effect of nelumbinis semen on rats under chronic mild stress induced depression-like symptoms. am j chin med. 2005; 33:205-13. 20. farrel ms, mccorvy jd, huang xp, et al. in vitro and in vivo characterization of the alkaloid nuciferine. plos one. 2016; 11:e0150602. 21. zhang c, deng j, liu d, et al. nuciferine inhibits proinflammatory cytokines via the ppars in lps-induced raw264.7 cells. molecules 2018;23: pii: e2723. 22. chen x, zheng x, zhang m, et al. nuciferine alleviates lpsinduced mastitis in mice via suppressing the tlr4-nf-kb signaling pathway. inflamm res. 2018; 67:903-911. 23. wang mx, zhao xj, chen ty, et al. nuciferine alleviates renal injury by inhibiting inflammatory responses in fructose-fed rats. j agric food chem. 2016; 64:7899-7910. 24. yang x, yu mf, lei j, et al. nuciferine relaxes tracheal rings via the blockade of vdlcc and nscc channels. planta med. 2018; 84:83-90. correspondence francesco chiancone, md (corresponding author) francescok86@gmail.com maurizio carrino, md maurizio fedelini, md marco fabiano, md francesco persico, md clemente meccariello, md paolo fedelini, md urology department, a. cardarelli hospital, via antonio cardarelli 9, 80131 napoli (italy) 04chiancone_stesura seveso 24/09/20 14:13 pagina 181 archivio italiano di urologia e andrologia 2018; 90, 18 original paper pathology outcomes in patients with transurethral bladder tumour resection in a turkish population: a retrospective analysis salih budak 1, cem yücel 1, mehmet zeynel keskin 1, mehmet yoldas 1, erdem kısa 1, ertan can 1, ulku kucuk 2, zafer kozacıoğlu 1 1 tepecik training and research hospital, urology clinic, izmir, turkey; 2 tepecik training and research hospital, pathology department, izmir, turkey. objectives: transurethral bladder tumour resection (turbt) is the common surgical method used in the diagnosis, staging and treatment of patients with bladder tumour. most of the rare tumours other than the urothelial carcinomas of the bladder are in advanced stage on diagnosis and necessitate aggressive treatment. in our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region. materials and methods: we retrospectively evaluated 815 patients who underwent turbt surgery between january 2010 and march 2016 in our clinic with a diagnosis of bladder cancer and at least 1 year follow-up. patients with tumour histopathological examination including histological tumour type, grade and were reported. thirty-nine patients with an unclear pathology report (neighboring organ invasion, cautery artifact, etc) and 17 patients whose data could not be accessed were excluded from the study. the patients who had received chemotherapy or radiotherapy due to any type of malignancy (23) were also excluded from the study. results: the outcomes of 736 patients operated in our clinics due to bladder tumour were evaluated. the mean age was 65.2 ± 8.4; 135 were female and 601 were male. among them 711 patients with urothelial carcinoma were reported (94.2%). according to tnm classification, stage ta was observed in 270 patients (37.9%), stage t1 in 297 (41.7%), and stage t2 in 144 (20.3%). non-urothelial cancers were reported in 25 cases (3.3%). conclusion: the incidence of bladder carcinoma varies between regions. the results of our study are similar to those of the western countries. increased smoking and exposure to environmental carcinogenetic agents may lead to altered incidences and histological types of bladder tumours. revision of regional tumour records may be useful to develop and evaluate future treatment strategies. key words: bladder cancer; transurethral resection; pathology; squamous cell; adenocarcinoma. submitted 14 july 2017; accepted 19 july 2017 summary no conflict of interest declared. sis (2, 3). transurethral bladder tumour resection (turbt) is the basic surgical method used in the diagnosis, staging and treatment of bladder cancer (4). prognosis of urinary bladder tumors is directly connected to histological type and stage of the tumour (5). urothelial carcinomas (uc) constitute 90-95% of bladder cancers (4). the second most common subtype is the squamous cell carcinoma (scc) that has an incidence of less than 5% in western countries (6). adenocarcinomas constitute less than 2% of all bladder cancers (7). most of these rare histologic subtypes are in advanced stage when they are diagnosed and they require more aggressive treatment options (8). in our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region. materials and methods we retrospectively evaluated 815 patients who underwent turbt surgery between january 2010 and march 2016 in our clinic with at least 1 year follow-up. all operations were performed under spinal or general anesthesia. turbt was performed with bipolar energy system using saline irrigation. all obtained materials were placed in containers with 10% formaldehyde and sent to the pathology laboratory. the materials were buried in paraffin blocks after tissue follow-up procedures. sections with 5 micron thickness were prepared from paraffin blocks and stained with hematoxylon-eosin. the cases in which tumours were determined in the histopathological examination were reported by specifying tumour histological subtype, grade and pathological tumour stage. second transurethral resection was performed in cases which had recurrence from clinical and radiologic follow-up, and the highest tumour stage and grade was recorded. thirty-nine cases with unclear pathology (adjacent organ invasion, cautery artifact etc.), 17 cases the data of which could not be accessed, and 23 cases with chemotherapy/radiotherapy due to any malignancy were excluded from the study. results one hundred and eighty five of the 736 patients (25.1%) included in the study were diagnosed as primary bladder doi: 10.4081/aiua.2018.1.8 introduction bladder cancer is the second most common tumour of the genitourinary system (1). global cancer burden continues to increase due to increased age of population, smoking, western diet and exposure to environmental carcinogenebudak_stesura seveso 27/03/18 09:15 pagina 8 9archivio italiano di urologia e andrologia 2018; 90, 1 pathology outcomes in bladder tumor resection cancer and 551 (74.9%) as recurrent after surgery due to bladder tumour. one hundred and thirty five of the patients were female, 601 were male and the mean age was 65.2 ± 8.4. it was determined that incidence of bladder carcinoma is 4.5 times more common in males than females. according to our results of pathological examination, uc was reported at a rate of (94.2%). according to tnm classification, it was determined that 270 patients were in ta stage (38%), 297 patients were in t1 stage (41.8%), and 144 patients were in t2 stage (20.3%) (table 1). twenty five (3.3%) cases were reported as non-urothelial carcinoma. in the pathological evaluation result of these tumours, it was seen that 10 cases were squamous cell carcinoma (1.3%), 9 cases were adenocarcinomas (1.2%), 1 case was neuroendocrine (0.1%), 1 case was small cell carcinoma (0.1%), 2 cases were sarcomatoid carcinoma (0.3%), and 2 cases were bladder leiomyoma (0.3%) (table 2).. discussion currently, the most important prognostic factors in bladder tumours are the pathological stage and the grade of tumour as determined by histopathological examination (5). presence of muscle invasion in bladder carcinomas is very important in terms of foreseeing the prognosis and determining the treatment approach. in the study conducted by horstmann et al., in which 1269 bladder tumours were evaluated, incidence of muscle invasion was reported to be 35.8% (9). in our study, incidence of muscle invasion was determined as 21.9% (161). in western countries, primary scc of bladder is 1.24.5% of all bladder tumours and it is often seen in the seventh decade (10, 11). radical cystectomy is still the most suitable treatment for bladder scc. the 5-year survival rate after cystectomy was reported to be 50% and mean period of survival was 5.4 years (12). almost all squamous cell cancers are already advanced and muscle infiltrative at the time of diagnosis (13). in our study we determined the incidence of scc as 1.3%. adenocarcinomas constitute less than 2% of all bladder cancers (14). adenocarcinoma diagnosis may be considered as originating primarily from the bladder after excluding metastasis or invasion from neighboring organs. due to poor prognosis, standard treatment for adenocarcinomas is radical cystectomy and dissection of the pelvic lymph nodes (15). therefore, early diagnosis is important. in our study we determined the incidence of adenocarcinoma as 1.2%. the benign tumours that are seen in the bladder are myoma, leiomyoma, rhabdomyoma, fibroma, angioma, osteoma and myxoma. the most common benign mesenchymal bladder tumour is leiomyoma (16).the available evidence about most of these rare tumours originate from small retrospective case series (17). in our study, 2 (0.3%) cases of bladder leiomyoma were detected. conclusions there are differences in incidence of bladder carcinoma between regions. the results of our study are similar to those of the western countries. the diagnosis of nonurothelial cancers is usually made in the advanced stage and the most applied treatment is radical surgery. increased smoking and exposure to environmental carcinogenesis may lead to a change in the frequency of histological type of bladder tumours. it may be useful to update regional tumour records to develop and evaluate future treatment strategies. references 1. grossfeld gd, carroll pr. evaluation of asymptomatic microscopic hematuria. urol clin north am. 1998; 25:661-76. 2. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 3. siegel r, naishadham d, jemal a. cancer statistics, 2012. ca cancer j clin. 2012; 62:10-29. 4. richterstetter m, wullich b, amann k, et al. the value of extended transurethral resection of bladder tumour (turbt) in the treatment of bladder cancer. bju int. 2012; 110:76-79. 5. arslan b, bozkurt ih, yonguc t, et al. clinical features and outcomes of nontransitional cell carcinomas of the urinary bladder: analysis of 125 cases. urol ann 2015;7:177-82. 6. shokeir aa. squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. bju international. 2004; 93:216-20. 7. dahm p, gschwend je. malignant non-urothelial neoplasms of the urinary bladder: a review. eur urol. 2003: 44:672-81. 8. manunta a, vincendeau s, kırıkakou g, et al. non-transitional cell bladder carcinomas. bju int. 2005; 95:497-502. 9. horstmann m, witthuhn r, falk m, stenzl a. gender-specific diftable 1. clinical stages of uc cases with tnm classification. stage and grade number of patients (% ) tag1 167 (23.5%) tag2 87 (12.2%) tag3 16 (2.3%) t1g1 92 (12.9%) t1g2 79 (11.1%) t1g3 126 (17.7%) t2 144 (20.3%) total 711 (100%) table 2. distribution of turbt pathologic diagnosis (n = 736). histopathological diagnosis number of patients (% ) urothelial carcinomas 711 (94.2) squamous cell carcinoma 10 (1.3%) adenocarcinoma 9 (1.2%) neuroendocrine 1 (0.1%) leiomyoma 2 (0.3%) small cell carcinoma 1 (0.1%) sarcomatoid carcinoma 2 (0.3%) total 736 (100%) budak_stesura seveso 27/03/18 09:15 pagina 9 archivio italiano di urologia e andrologia 2018; 90, 1 s. budak, c. yücel, mehmet z. keskin, m. yoldas, e. kısa, e. can, u. kucuk, z. kozacıoğlu 10 ferences in bladder cancer: a retrospective analysis. gen med. 2008; 5:385-94. 10. lopez ji, angulo cj, flores cn, toledo jd. squamous cell carcinoma of the urinary bladder. clinico-pathologic study of 7 cases. arch esp urol. 1994; 47:756-60. 11. serretta v, pomara g, piazzo f, gange e. pure squamous cell carcinoma of the bladder in western countries. eur urol. 2000; 37:85-9. 12. ghoneim ma, el mekresh mh, el baz ma, et al. radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1026 cases. j urol. 1997; 158:393-9. 13. el-sayed mi, abdel-rahim am. survival analysis in patients with non-metastatic squamous cell carcinoma of the urinary bladder. middle east j cancer. 2011; 2: 59. 14. dahm p, gschwend je. malignant non-urothelial neoplasms of the urinary bladder: a review. eur urol. 2003; 44:672-81. 15. wilson tg, pritchett tr, lieskovsky g, et al. primary adenocarcinoma of bladder. urology. 1991; 38:223-6. 16. goktug gh, ozturk u, sener nc, et al. transurethral resection of a bladder leiomyoma: a case report. can urol ass j. 2014; 8:111. 17. park jw, jeong bc, seo si, et al. leiomyoma of the urinary bladder: a series of nine cases and review of the literature. urology. 2010; 76:1425-9. correspondence salih budak, md (corresponding author) salihbudak1977@gmail.com tepecik training and research hospital, urology clinic 206/26 sok. no:16 d:24 yıldız mah. buca/izmir, turkey cem yücel, md meclecuy@hotmail.com mehmet zeynel keskin, md zeynel_akd@hotmail.com mehmet yoldas, md yoldas_2297@hotmail.com erdem kısa, md drerdemkisa@hotmail.com ertan can, md drertancan@yahoo.com ulku kucuk, md associate professor kucukulku@hotmail.com zafer kozacıoğlu, md associate professor zaferkozacioglu@gmail.com tepecik training and research hospital, urology clinic tepecik eah, üroloji kliniği, yenişehir, izmir, turkey budak_stesura seveso 27/03/18 09:15 pagina 10 stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3296 original paper no conflict of interest declared. per 100000 men (1). the traditional treatment for suspected tumors is radical orchidectomy and organ-sparing surgery is considered primarily in cases of bilateral tumors or monorchid patients (2). in recent years the widespread use of ultrasound for noncancerous indications has resulted in an increase in incidental, small testicular masses (stms) of questionable significance (3, 4). stms are most efficiently characterized as non-palpable testicular lesions measuring < 25 mm in diameter. however, a specific size cutoff is difficult to define and the exact dimensions are still debated in the literature (5, 6). in this size though, the probability of benign pathology is regarded as significantly high, and thus, a stepwise approach of inguinal surgical exploration, delivery of the organ and frozen section examination is recommended. organ-preserving surgery is preferred if the diagnosis is benign while radical orchidectomy is usually preserved if there is evidence of malignancy (5, 7, 8). the most common scenario on routine ultrasound is the finding of a non-palpable lesion during workup for infertility or scrotal pain, where the majority of these patients have benign lesions and a conservative approach is strongly indicated (9). nevertheless, the management of incidental stms warrants a critical review of the literature as there are no patient selection criteria for an organ-sparing approach, and a strict diagnostic algorithm is lacking. in this review we discuss the significance of stms and the role of organ-sparing approach in the management of the condition. material and methods we performed a non-systematic search in pubmed with the terms ‘small testicular masses’, ‘incidental testicular masses’, ‘testicular sparing approach’ and ‘partial orchidectomy’. only studies in english were included. case reports were excluded and literature reviews were used to identify additional articles. after screening the abstracts, full-text articles were evaluated in an attempt to identify studies engaging with relevant clinical topics. objectives: the widespread use of ultrasonography for the investigation of common urological conditions, such as infertility or pain, has resulted in an increased incidence of incidental non-palpable testicular masses. the majority of these are expected to be benign therefore a conservative approach, either active monitoring or organsparing approach, is recommended. however, there are no clinical or radiological parameters which define the exact nature of such lesions and optimal patient selection criteria are lacking. in this comprehensive review we discuss the significance of incidental, small testicular masses (stms) and the role of organ-sparing approach in the management of these lesions. materials and methods: a non-systematic search was performed using pubmed to identify articles that covered the following topics; clinical implications at diagnosis, role of imaging in identifying the malignant capabilities of a lesion, role of surgery and the final pathology. results: incidental stms are routinely identified following ultrasound examination of infertile men. stms usually measure a few millimeters in size and the majority of these are benign. therefore, strict follow up or an organ-sparing approach, with utilisation of frozen section analysis (fsa), is favored for stms. fsa has a high correlation with final pathology and prevents unnecessary orchidectomies. advances in imaging, namely ultrasound and magnetic resonance imaging may provide enhanced assessment of stms and guidance intraoperatively. conclusions: the optimal approach is not well defined and there is no specific clinical parameter that can predict the nature of stms. the increasing incidence of small, benign testicular masses has resulted in the development of organ-sparing surgery to investigate and manage these lesions. organ-sparing surgery has been shown to be practical and carries excellent oncological outcomes. key words: incidental testicular masses; non-palpable; testissparing surgery; surveillance; ultrasound. submitted 25 february 2021; accepted 5 july 2021 introduction testicular germ-cell tumors (gct) are the most common solid neoplasms in young men with an incidence of 10 incidental testicular masses and the role of organ-sparing approach yash narayan 1, dominic brown 1, stella ivaz 1, krishanu das 2, 3, mohamad moussa 4, georgios tsampoukas 1, 2, athanasios papatsoris 2, 3, noor bucholz 2 1 department of urology, princess alexandra hospital, harlow, uk; 2 u-merge ltd.* (urology for emerging countries), london, uk; 3 consultant urologist, bahrain specialist hospital, bahrain; 4 al zahraa hospital, university medical center, lebanese university, beirut, lebanon. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2021.3.296 summary 297archivio italiano di urologia e andrologia 2021; 93, 3 incidental testicular masses results clinical implications at time of discovery of incidental mass stms can be found at any age, ranging from childhood to adolescence and up to middle aged men (10-12). male infertility presenting as dyspermia or the more severe azoospermia, are amongst the most frequently reported indications for ultrasound examination which results in the diagnosis of an incidental stm (13-19). unspecified testicular or epididymal pain, an acute inflammation in the genital area, scrotal swelling, a history of trauma, varicocele, abdominal pain, hydrocele, suspicion of nephrolithiasis, gynecomastia, and follow up of cryptorchidism are also reported as indications (8, 11, 12, 2025). of note small masses might be discovered during the follow up of patients with previous treatment of gct or other testicular tumors (26-28), and a prior history of cryptorchidism might unmask an undetected testicular mass during follow up (12, 15, 23, 29). in the same vein, extra attention should be given to patients with suspected retroperitoneal, extragonadal gct as stms might indicate a burned out primary testicular tumor (30). role of imaging in the assessment of the malignant potential of the lesion the size of stms on ultrasound usually ranges from 3 mm up to 25 mm (4, 31), and the majority of these lesions will be found to be benign however malignancy cannot be excluded even in the smallest lesions (7, 17). in spite of this, size and risk of malignancy are strongly correlated (5, 32); large lesions seem to carry a greater risk of malignancy and the smaller the nodule, the less likely it is to be malignant (5, 8, 33). using a cutoff of 5 mm in infertile patients with stms, bieniek et al. reported that the majority of these masses did not show significant growth during follow up and could be safely surveilled (19). in such cases toren et al. observed that initial larger size and vascular flow, as identified on ultrasound, were factors associated with intervention during follow up (14). similarly scandura et al. reported that lesions smaller than 5 mm are always benign whereas malignancy can be found in one third of cases in lesions measuring 5-10 mm (29). in another study, gentile and colleagues stated that the malignant probability of stms, measuring less than 10mm, is smaller than 10% whilst the risk increases sevenfold with each millimeter (5). however other authors have advised that inguinal exploration and frozen section analysis (fsa) are essential even in small masses, less than 5 mm, as malignancy cannot be excluded definitely (11). this is because the most common ultrasonographic appearance is of an hypoechoic lesion, a finding which should be regarded as non-specific (33, 34). however dell’atti et al. reported that malignant and benign lesions differ significantly as cancerous lesions were strongly hypoechoic, in appearance, in comparison to benign lesions (89.8% vs 39.3%, p > 0.001) and calcified lesions were strongly associated with benign tumors (25). others have suggested that extra attention should be given to echogenic foci as these might represent burned out tumors and in such cases, the retroperitoneal space should be evaluated (30, 35). the presence of vascularization on color doppler ultrasound is also strongly associated with malignancy whereas small, inflammatory lesions usually do not exhibit any flow (28). contrastenhanced testicular ultrasound, if available, is a costeffective imaging method for the characterization of nonpalpable testicular lesions (36). with the enhancement of diagnostic performance, some authors have reported that the combination of different ultrasonographic techniques in a multiparametric fashion offers excellent sensitivity and specificity in the assessment of stms. the combination of elastography with contrast-enhanced scrotal ultrasound demonstrated a sensitivity of 100%, a specificity of 93%, and a positive likelihood ratio of 14.3 for malignancy (37). magnetic resonance imaging (mri) might also increase the diagnostic accuracy in its ability to distinguish between fat, fluid, fibrosis, cystic and solid lesions; gadolinium contrast enhancement technique may also be able to differentiate between benign and malignant lesions (6, 20). thus, mri can assist the decision making in cases of diagnostic uncertainty favoring a testicular sparing approach in patients with low suspicion of malignancy (6, 38, 39). the operative technique if an intervention is scheduled, the procedure follows the same principles as for radical orchidectomy. the testis is exposed, mobilized and exteriorized through an inguinal incision. the clamping of the spermatic cord is controversial as seeding of malignant cells is mostly related to the nature of the tumor and not with the manipulation alone (40). if cross-clamping is performed before delivery, the testis should be protected from warm ischemia, with an iced pack, as warm ischemia may cause irreversible damage of the testicular parenchyma thus impairing both the endocrine and exocrine functions of the organ (15). there are two possible approaches; one in an avascular plane on the anterior aspect of the organ exposing the whole parenchyma or alternatively a smaller incision directly onto the tumor (40). intraoperatively the use of a linear ultrasound transducer (7.5-15 mhz) can guide the excision and also ensure adequate preservation of testicular parenchyma. some authors perform real-time ultrasonography to facilitate the placement of a stereotaxic hook-shaped needle which can guide the resection (15, 20). either way the tumor is excised and sent for fsa leaving 2-3 mm safe surgical margins (15, 41). frozen-section biopsies should be taken from the borders of the lesion to ensure adequate resection and as a rule, if there is not enough parenchyma for frozen-section biopsies then preservation of the organ is not recommended (40). if the benign nature of a lesion is confirmed or the removal of a malignant tumor is completed, the testicle is placed back into the scrotum otherwise a radical orchidectomy is performed for all other indications (42). significance of frozen section analysis, testis-sparing surgery and random biopsies fsa is regarded as indispensable during organ-sparing surgery in patients with indeterminate stms or if the diagnosis of malignancy is in doubt, regardless of size (8, 43). the correlation of fsa with the final pathology is high, the procedure is dependable, and fsa is not limitarchivio italiano di urologia e andrologia 2021; 93, 3 y. narayan, d. brown, s. ivaz, k. das, m. moussa, g. tsampoukas, a. papatsoris, n. bucholz 298 ed by size (5, 31, 44, 45). it could be stated that fsa prevents unnecessary orchidectomies and enables preservation of the testicular parenchyma (5, 46). therefore, the optimal treatment of stms should include fsa to guide management of the extricated tumour, in the form of testis-sparing surgery (tss) or radical orchidectomy. if a gct is identified on fsa, tss should be considered if imperative indications are met (synchronous bilateral tumours, metachronous tumours in solitary testicle) in order to attempt preservation of fertility and hormonal function (5, 8). in that scenario, field biopsies in a systematic and random manner are also mandatory as in situ germ cell neoplasia may be present elsewhere, even a long distance from the initial tumor. this finding reflects the malignant spread of the tumor and warrants treatment with adjuvant radiotherapy (12, 33). the final pathology in the final specimen, benign lesions are found in most patients and in some studies the incidence is as high as 80% (5, 21, 34, 47). leydig cell tumor is the most frequently reported pathology in non-malignant cases (5, 11, 15, 21, 27, 48). other diagnoses include fibrosis, epidermoid cysts, granulomatous orchitis (25), ectopic nodule of adrenal cortex, adenomatous tumour and fibrous pseudotumor (29). sertoli tumor and hemorrhagic infiltration with no evidence of tumor have also been reported (49). of the malignant lesions, pure seminoma along with the presence of distant carcinoma in situ is the most commonly reported finding (11, 23, 28, 49). leiomyoma, mixed germ cell tumours including embryonal carcinoma, mature teratoma, and liposarcoma have also been reported in the final specimen (27, 50, 51). discussion although there is no specific clinical parameter that can predict the exact nature of stms, those that are non-palpable are usually benign (24). palpability, raised testicular markers, hypoechoicity on ultrasound images, and larger size are considered risk factors for malignancy (52). specific patient groups such as infertile patients seem to enjoy a favorable prognosis thus justifying the avoidance of unnecessary surgery. eifler et al. and lagabrielle et al. found that patients with small, incidental masses identified during work-up for infertility, can usually be monitored with repeat ultrasound and additionally surgical intervention can be performed safely should the clinical need arise (13, 16). in such cases, where intervention is required, the simultaneous performance of tss and microscopic testicular tissue extraction has been proposed by some authors, without causing any significant complication or compromising the remaining testicular volume (15). with regards to the development of secondary hypogonadism, no significant change in plasma testosterone has been reported and secondary hypogonadism should not be expected in patients with bilateral testis undergoing tss for stms (11, 51). however it seems that patients undergoing tss for malignant lesions are at higher risk of secondary hypogonadism as this may be found in up to 15% of cases (42). similarly the effect on endocrine function is comparative even when a radical approach is performed and it increases significantly as the treatment is escalated (53). in this regard, it seems that the approach alone is not entirely responsible, rather it is the relative risk of malignancy that affects the outcome. importantly the oncological prognosis in patients with malignancy is regarded to be excellent (54). therefore, it seems apparent that an organ sparing approach or a surveillance protocol is optimal for patients with incidental testicular masses. some authors have attempted to provide specific recommendations regarding the management of stms such as the diagnostic algorithm proposed by scandura et al. in patients with stms less that 10 mm. they state that if tumor markers are negative an ultrasound should be repeated in 3 months, and if there is no change then the patient can be discharged from further follow up with the recommendation of selfexamination. if there is an increase in size, of less than 20% of the original, an ultrasound is repeated in 3 months and if no change is identified the patient is discharged as previously. alternatively if there is a greater than 20% increase in size then fsa is advised (29). conclusions the increasing incidence of small, non-palpable and benign testicular masses has resulted in the development of organ sparing surgery to investigate and treat these lesions. the optimal approach is not well defined however patients who present for routine investigation of infertility or scrotal pain who have no palpable nodules, negative testicular markers, and lesions only a few millimeters in size are likely to have benign pathology. in such cases options include either an active monitoring program or an organ sparing approach. the latter has been shown to be practicable and reproducible and carries excellent 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baltaci s. should we rely on doppler ultrasound for evaluation of testicular solid lesions? world j urol. 2018; 36:1263-6. 53. jacobs la, vaughn dj. hypogonadism and infertility in testicular cancer survivors. j natl compr canc netw. 2012; 10:558-63. 54. pfister d, paffenholz p, haidl f. testis-sparing surgery in patients with germ cell cancer: indications and clinical outcome. oncol res treat. 2018; 41:356-8. correspondence yash narayan, md y.narayan@nhs.net dominic brown, md dominic.brown5@nhs.net stella ivaz, md stellaivaz@hotmail.com georgios tsampoukas, md tsampoukasg@gmail.com department of urology, princess alexandra hospital, harlow (uk) hamstel road, harlow, united kingdom, cm20 1qx krishanu das, md consultant urologist, bahrain specialist hospital, bahrain mohamad moussa, md mohamad.moussa@zhumc.org.lb al zahraa hospital, university medical center, lebanese university, beirut (lebanon) athanasios papatsoris, md agpapatsoris@yahoo.gr u-merge ltd., london (uk) noor bucholz, md noor.buchholz@gmail.com u-merge ltd., london (uk) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11567 1 original paper in cases of absence of spermatozoa. this would decrease surgical risks, patient discomfort and likely the costs of infertility workup and treatment. in men with non-obstructive azoospermia, spermatozoa may be found in testicular tissue, but their complete absence in testicular biopsy makes the couple unable to conceive (6, 7). although several testicular biopsy techniques are described, the most currently used are testicular sperm aspiration (tesa), open testicular sperm extraction (tese) and microscopic testicular sperm extraction with similar outcomes being reported (4, 6-8). previous studies correlated fsh levels with the rate of success in testicular biopsy but other factors remain to be established of important predictive value, as spermatozoa can still be found in patients with high fsh levels and patients with low volume testicles (7-9). besides, in cases of non-obstructive azoospermia, pregnancies are achieved in 30-50% of couples when spermatozoa are found after sperm harvesting (10). infertile couples usually go through a hard psychological pathway during pregnancy process and predictive factors for positive testicular biopsy may help identifying patients with higher probabilities of successful pregnancy and help to manage expectations (4, 7, 8). therefore, our aim was to identify possible predictive factors for a successful testicular biopsy in men with azoospermia after a diagnostic sperm analysis during infertility evaluation. material and methods patient selection, surgical technique and variables definition all man submitted to testicular biopsy during infertility investigation between january 2015 and december 2021 in centro hospitalar e universitário de coimbra, portugal, were evaluated. a complete medical history and physical examination was performed. testicular volume was evaluated and classified as normal or decreased by physical exam and further confirmed by testicular ultrasonography. serum fsh, lh, total testosterone, free testosterone, and prolactin morning levels for endocrinologic evaluation were assessed and patients had at least two semen analysis confirming azoospermia, according to world health organization guidelines (11). all patients were testicular biopsy naïve. patients with microdelitions and cariotype alterations were excluded. introduction: infertility, the inability to conceive, constitutes a major problem in modern societies. it affects 10 to 15 percent of couples in the united states. evaluation of infertile men is usually complex and often demands a testicular biopsy. materials and methods: we reviewed all azoospermic men submitted to testicular biopsy, in our center, during infertility investigation between january 2015 and december 2021. results: a total of 117 patients with a mean age of 36.5 was considered. biopsy was positive, as defined by the presence of viable spermatozoids by microscopy, in 48.7% of patients (n = 57). patients were divided in two separate groups based on positive (pb) or negative biopsy (nb) and compared. pb-group had normal serum total testosterone levels and higher than nb-group (3.7 ng/ml vs. 2.85 ng/ml, p = 0.021), and normal serum fsh levels and lower than nb-group (6.0 miu/ml vs. 16.0 miu/ml, p < 0.001). the groups were similar concerning serum lh levels (3.9 miu/ml vs. 6.3 miu/ml, p = 0.343. conclusions: predicting outcomes of testicular biopsy is a difficult task. our study found that men with normal testicular volume, normal levels of testosterone and fsh and those with type 1 diabetes mellitus had a higher probability of positive testicular biopsy. key words: male infertility; azoospermia; testicular biopsy; predictive factors. submitted 5 july 2023; accepted 30 july 2023 introduction infertility, the inability to conceive after one year of regular unprotected intercourse, constitutes a major problem in modern societies. it affects 10 to 15 percent of couples in the united states, with male component being the isolated cause in about 20% of cases and representing part of the aetiology in another 30% (1-3). multiple factors contribute for male infertility, from anatomic obstruction and genetic alterations to hormonal disturbances, among many others. evaluation of infertile men is usually complex and requires a careful clinical history, physical exam, semen analysis, hormonal profile and imaging and genetic testing (4). azoospermia, the complete absence of spermatozoa in the ejaculate, is present in 10-20% of all infertile men and can be classified as obstructive or non-obstructive (5). the evaluation of these men often demands a testicular biopsy, with associated morbidity. a non-invasive diagnostic technique predicting the presence of spermatozoa in the testis would be useful to avoid surgical intervention predictive factors for successful testicular biopsy duarte vieira brito, manuel lopes, jose pereira, ana maria ferreira, luis sousa, belmiro parada, arnaldo figueiredo urology and renal transplantation department, coimbra university hospital centre, coimbra, portugal. doi: 10.4081/aiua.2023.11567 summary archivio italiano di urologia e andrologia 2023; 95(3):11567 d. vieira brito, m. lopes, j. pereira, a.m. ferreira, l. sousa, b. parada, a. figueiredo 2 patients were submitted to testicular biopsy under local anaesthesia after spermatic cord blockage as an outpatient procedure. a step-by-step approach is done in our institution, as forward described. percutaneous epididymal sperm aspiration (pesa) is performed as a first procedure in one testicle and then in the contralateral in the case of no spermatozoa retrieval). if no spermatozoa are obtained after pesa, open tese is done. a small scrotal incision is performed without exteriorization of the testicle and testicular parenchyma is excised from at least two different sites. if no spermatozoa are identified the same approach is performed in the contralateral testicle. the extracted tissue is then preserved in sperm preparation substrate and samples are analysed by an experienced biologist. sperm retrieved by pesa or tese was classified as of good quality (sperm concentration > 1/hpf; with mobility in situ > 10%; progressive motility), medium quality (sperm concentration < 1/hpf; with mobility in situ < 10%) or bad quality (rare sperm or spermatid; without mobility). biopsy was considered positive when sperm of good or medium quality sperm was obtained. when no sperm is found a sample is sent for histological confirmation and diagnosis. statistical analysis a demographic analysis of the entire cohort was performed. patients were divided into two groups for comparative analysis: patients who had a positive biopsy (pbgroup) and patients who had a negative biopsy (nbgroup). pearson chi-square and mann-whitney tests were used to compare quantitative and categorical variables across groups. unconditional binary logistic regression was used to evaluate the independent association between possible predictors and detection of spermatozoa in the biopsy. statistical significance in this study was set as p < 0.05. statistical analysis was performed using ibm spss®, version 27.0 for windows. results we had a total of 117 patients with a mean age of 36.5 ± 6.0 years. study sample features are described in table 1. concerning the main conditions that may affect testicular function 22.2% patients (n = 26) presented reduced testicular volume and 20.5% (n = 24) presented with left varicocele. twenty patients (17.1%) had previous history of inguinal or scrotal surgery: four had inguinal hernia correction, eight had radical orchiectomy, four had orchiopexy and four the excision of hydrocele or epididymal cysts. six patients (5%) had been previously treated with systemic chemotherapy. regarding metabolic factors, 32% of patients (n = 37) had overweight or obesity (body mass index > 25 kg/m2), 14.5% (n = 17) had type 1 diabetes mellitus and 36.8% (n = 43) were active smokers. testicular biopsy was positive in 48.7% of patients (n = 57) and these form the pb-group. the remaining 60 patients with negative biopsy constitute nb-group. groups were similar regarding demographic and clinical features, with no difference in age, history of smoking, presence of varicocele and history of inguinal and scrotal surgery (data not shown). on the other hand, the study groups were statistically different in testicular volume (p < 0.001) history of cryptorchidy (p = 0.047) and history of type 1 diabetes mellitus (p = 0.015) with normal testicular volume, no history of cryptorchidy and type 1 diabetes mellitus being predictive factors for successful testicular biopsy. from the 24 patients with imaging diagnosis of varicocele only 8 had a clinical varicocele and these were the patients submitted to repair (varicocele embolization). from those who received varicocele correction, 7 patients (88%) had a positive testicular biopsy (p = 0.059) (table 2). in terms of endocrine evaluation (table 3) pb-group had normal serum total testosterone levels and higher than nb-group (3.7 ng/ml vs. 2.85 ng/ml, p = 0.021), and normal serum fsh levels and lower than nb-group (6.0 miu/ml vs. 16.0 miu/ml, p < 0.001). the groups were similar concerning serum lh levels (3.9 miu/ml vs. 6.3 miu/ml, p = 0.343) and serum prolactin levels (1.5 table 1. patients characteristics. variable frequency (%) decreased testicular volume 26 (22.2) varicocele 24 (20.5) cryptorchidism 4 (3.4) previous systemic chemotherapy 6 (5.1) type 1 diabetes mellitus 17 (14.5) body mass index > 25 kg/m2 37 (31.6) active smoker 43 (36.8) inguinal or scrotal procedures 20 (17.1) radical orchiectomy 8 orchiopexy 4 hydrocele or epididymal cyst correction 4 inguinal hernioplasty 4 positive testicular biopsy 57 (48.7) table 2. potential predictive factors for positive testicular biopsy. variable pb-group a nb-group a p value testicular volume – normal 52 39 < 0.001 cryptorchidism 0 4 0.047 previous systemic chemotherapy 2 4 0.439 type 1 diabetes mellitus 13 4 0.015 body mass index > 25 kg/m2 21 16 0.237 active smoker 19 24 0.455 varicocele embolization 7 1 0.059 a frequency, in absolute number. pb: positive biopsy; nb: negative biopsy. table 3. hormonal differences between positive biopsy (pb) and negative biopsy (nb) groups. hormone pb-group nb-group p value total testosterone (ng/ml) 3.7 2.85 0.021 fsh (miu/ml) 6.0 16.0 < 0.001 lh (miu/ml) 3.9 6.3 0.343 prolactin (ng/ml) 1.5 1.2 0.274 fsh: follicle-stimulating hormone; lh: luteinizing hormone. archivio italiano di urologia e andrologia 2023; 95(3):11567 3 prediction of success of testicular biopsy ng/ml vs. 1.2 ng/ml, p = 0.274). normal fsh serum levels and normal total testosterone levels are predictive factors for positive testicular biopsy. discussion infertility diagnostic work-up and treatment is associated with elevated costs for health systems and has a major impact in individual well-being and couples relationship (2). the development and dissemination of new fertilisation techniques allowed men who were previously defined as infertile to father children, in great part due to testicular biopsy (12, 13). about half of all infertile patients has no identified cause for infertility and determining which men will benefit from a testicular biopsy is still controversial (5). some of the predictive factors for a positive testicular biopsy shown in our analysis are already described in literature but are not strongly established. our cohort is similar to other populations in literature regarding age (minimum 24 years old and maximum 54 years old) and number of positive biopsies (14, 15). an interesting point we found is age: the oldest patient in our population is 54 years old but that was not necessarily associated with lower number of positive biopsies (data no shown) indicating the ability of men to preserve fertility even into older age (16). a total of 8 patients had clinically evident varicocele and were submitted to endovascular embolization. all these patients presented with azoospermia in the spermogram after correction and, despite this, 7 out of 8 had positive biopsy (after correction). some authors advocate the correction of varicocele as beneficial in all patients with infertility, in particular men with semen parameters alterations, even when fertility is still not a concern but as a way to achieve normal testosterone production (16-19). a comparison to patients with untreated varicocele was not done, so a conclusion regarding formal recommendation for varicocele correction in all azoospermic men cannot be made. notwithstanding, the results of successful biopsy after varicocele correction highlights the potential role of the procedure, mainly because in most cases it is a low-risk technique. hormones play a major role in spermatogenesis and so the idea that hormonal levels could predict the success of biopsy has been postulated. in our analysis, patients with a positive biopsy comparing to the ones with negative biopsy had lower (in normal range) fsh levels (6.0 miu/ml vs. 16.0 miu/ml), in line with other studies (9). some studies define a cut-off of 9.9 miu/ml as a predictor for a positive biopsy with > 90% sensitivity, but other levels have been proposed. although it is known that even patients with very high fsh levels can have a positive testicular biopsy, a recent meta-analysis evaluating men with non-obstructive azoospermia reaffirmed fsh levels as a poor predictor for evaluating the success of sperm retrieval (20, 21). this lack of consensus may be due to the fact that fsh levels reflect the amount of testicular germ cells and not mature cells, which does not exclude the presence of mature sperm cells foci (20, 22, 23). in concordance to other studies, our results suggest that normal levels of fsh increase the probability of a positive biopsy but men with increased levels should not be excluded, as sperm may still be found. another testicular function hormone, lh, has been investigated as a possible marker: in our cohort, as in most studies, there was no correlation between serum lh levels and the success of biopsy (20, 24). testosterone, the main hormone produced by the testicular tissue, is hypothesized as a valuable marker of testicular health and fertile capacity (9, 24). our data found that men with negative biopsies had significant lower mean baseline levels of serum testosterone than patients with a positive biopsy (3.7 ng/ml vs. 2.85 ng/ml). most literature did not find a relationship between serum total testosterone level and positive biopsy as our data shows (9, 16). patients with normal testicular volume in our population presented with a higher likelihood of positive biopsy as it is shown by data from other authors (1, 8). the analysis of metabolic factors shows that patients with type 1 diabetes mellitus had higher probability of positive biopsy, while smoking and overweight or obesity did not influence these outcomes. high blood glucose levels are toxic to cellular viability, particularly in testis (25). patients with diabetes in most cases have altered sperm parameters and are more likely to have retrograde ejaculation and atonia of seminal vesicles among other complications (26, 27). data on sperm alterations in diabetic patients is variable: some studies showed spermatozoa with lower motility, altered morphology or decreased sperm production, while others stated that no pathological alterations were found. the prevalence of infertility may also be increased in cases of pre-diabetes (26, 28, 29). men with diabetes mellitus have higher probability of azoospermia and need for fertilization techniques as the disease progresses, and most of them present with normal serum levels of fsh, lh and testosterone (29). our data suggests that type 1 diabetic men benefit from performing testicular biopsy in the presence of azoospermia. a limitation of our analysis was not considering the current drugs used for diabetes treatment as they could affect fertility. overweight and obesity alter fertility, since excessive fatty tissue interferes with hormonal balance and induces sperm parameters alterations: lower sperm motility and total sperm counts and higher risk of azoospermia. however, few studies evaluate the impact of these factors in sperm retrieval from testicular biopsy (30, 31). in general, the higher the body mass index the greater the risk of infertility worsening (30-34). our data found no difference in biopsy success concerning body mass index. besides the potential bias and limitations previously mentioned, sample size is a limitation of our study. strong points are the homogeneity of our sample and the steady team of urologist and biologist performing biopsies and sperm analysis, respectively, ensuring a similar technique. conclusions investigating infertile men and predicting biopsy outcomes is a difficult task. our study found that men with normal testicular volume, normal levels of testosterone and fsh and those with type 1 diabetes mellitus had a higher probability of positive testicular biopsy. more research with larger samples is still needed to ensure more robust data and conclusions. archivio italiano di urologia e andrologia 2023; 95(3):11567 d. vieira brito, m. lopes, j. pereira, a.m. ferreira, l. sousa, b. parada, a. figueiredo 4 references 1. cerilli la, kuang w, rogers d. a practical approach to testicular biopsy interpretation for male infertility. arch pathol lab med. 2010; 134:1197-204. 2. meng mv, greene kl,turek pj. surgery or assisted reproduction? a decision analysis of treatment costs in male infertility. j urol. 2005; 174:1926-31. 3. kim mj et al., molecular and cytogenetic studies of 101 infertile men with microdeletions of y chromosome in 1,306 infertile korean men. j assist reprod genet. 2012; 29:539-46. 4. gudeloglu a and parekattil 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11. björndahl l, kirkman brown j; other editorial board members of the who laboratory manual for the examination and processing of human semen. the sixth edition of the who laboratory manual for the examination and processing of human semen: ensuring quality and standardization in basic examination of human ejaculates. fertil steril. 2022; 117:246-251. 12. schoor ra, et al. the role of testicular biopsy in the modern management of male infertility. j urol 2002; 167:197-200. 13. pesce cm. the testicular biopsy in the evaluation of male infertility. semin diagn pathol. 1987; 4:264-74. 14. jashnani k, et al. fine-needle aspiration cytology of the testes for the classification of azoospermia and its value in the assessment of male infertility. acta cytol. 2020; 64:216-223. 15. chan pt and schlegel pn. diagnostic and therapeutic testis biopsy. curr urol rep. 2000; 1:266-72. 16. kavoussi pk, et al. a comprehensive assessment of predictors of fertility outcomes in men with non-obstructive 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maturation arrest. fertil steril. 1996; 66:110-7. 23. ramasamy r, et al. high serum fsh levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. fertil steril. 2009; 92:590-3. 24. tsujimura a, et al. prediction of successful outcome of microdissection testicular sperm extraction in men with idiopathic nonobstructive azoospermia. j urol. 2004; 172:1944-7. 25. o'neill j, et al. differences in mouse models of diabetes mellitus in studies of male reproduction. int j androl. 2010; 33:709-16. 26. la vignera s, et al. diabetes mellitus and sperm parameters. j androl. 2012; 33:145-53. 27. mallidis c, et al. the influence of diabetes mellitus on male reproductive function: a poorly investigated aspect of male infertility. urologe a. 2011; 50:33-7. 28. boeri l, et al undiagnosed prediabetes is highly prevalent in primary infertile men results from a cross-sectional study. bju int. 2019; 123:1070-1077. 29. liu x, et al. effects of testicular sperm aspiration upon first cycle icsi-et for type 2 diabetic male patients. syst biol reprod med. 2020; 66:355-363. 30. craig jr, et al. obesity, male infertility, and the sperm epigenome. fertil steril. 2017; 107:848-859. 31. leisegang k, et al. obesity and male infertility: mechanisms and management. andrologia. 2021; 53:e13617. 32. leisegang k, henkel r, agarwal a. obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. am j reprod immunol. 2019; 82:e13178. 33. reis lo and dias fg. male fertility, obesity, and bariatric surgery. reprod sci. 2012; 19:778-85. 34. hammoud ao, et al. impact of male obesity on infertility: a critical review of the current literature. fertil steril. 2008; 90:897-904 correspondence duarte vieira brito, md (corresponding author) duartevbrito@hotmail.com manuel lopes, md manuel11070@gmail.com jose pereira, md joseaclpereira@gmail.com ana maria ferreira, md anaferreira6842@gmail.com luis sousa, md luismtbsousa@gmail.com belmiro parada, md parada.belmiro@gmail.com arnaldo figueiredo, md ajcfigueiredo@gmail.com urology and renal transplantation department, coimbra university hospital centre, coimbra, portugal conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 162 original paper no conflict of interest declared. contribute to the etiology of prostate cancer as well as bph. kakegawa et al. showed in a series of repeat prostate biopsies that patients with high serum psa and initial biopsy negative for cancer progressed more frequently to prostate cancer in subsequent biopsies if the initial biopsy was positive for the presence of p. acnes (2, 3). in the present paper we evaluated the potential pathogenic role of p. acnes in the genitourinary tract. for this purpose, we evaluated by real time pcr the presence of p. acnes dna in urine or seminal fluid of patients with recurrent symptoms of urinary infection but negative testing for the most common urinary tract pathogens and sexually transmitted infections (sti) agents as chlamydia trachomatis, mycoplasma genitalium, mycoplasma hominis, ureaplasma parvum and ureaplasma urealyticum. materials and methods patients male patients with recurrent symptoms of urinary tract infection were considered in the present study. patients sought medical attention of the urology specialist due to voiding symptoms (weak stream, straining and hesitancy) or storage problems (urgency, frequency and dysuria) and pain poorly localized in the lower back, hypogastrium, pelvis or genitalia. digital prostate palpation showed tender, swollen and warm prostate or also nodularity. patients with diabetes, spinal cord injury and catheter use were excluded. patients were subjected to urinalysis and urine culture and to semen analysis in case of history of couple infertility. samples were screened for predominant pathogens involved in urinary tract infections (uti) as escherichia coli, klebsiella spp., proteus spp., and enterococcus spp. and for sexually transmitted infection (sti) agents, by molecular methods. patients with negative testing for the most common urinary tract pathogens and sexually transmitted infections (sti) agents were investigated for the presence of dna p. acnes. specimen collection, urinalysis, urine and semen culture urinary and semen specimens were obtained from patient with recurrent symptoms of urinary infection. all the urinary samples were subjected to urinalysis and urine culobjective: propionibacterium acnes has been implicated in the pathogenesis of prostate disease as acute and chronic prostatic inflammation, benign prostatic hyperplasia and prostate cancer although it should still be clarified if propionibacterium acnes (p. acnes) is a commensal or accidental prostate pathogen. aiming to evaluate the pathogenic potential for genitourinary tract of propionibacterium acnes, we investigated the frequency of p. acnes genome in urine or semen samples from men with recurrent symptoms of urinary infection and negative testing for the most common urinary tract pathogens and sexually transmitted infections (sti) agents as chlamydia trachomatis, mycoplasma genitalium, mycoplasma hominis, ureaplasma parvum and ureaplasma urealyticum. materials and methods: the dna extracted from urine and semen samples was analyzed for evaluating the p. acnes genome presence by real-time polymerase chain reaction (pcr). infections were treated with vancomycin and cephalosporins antibiotics and then the search for the p.acnes genome by realtime pcr was repeated. results: the p. acnes qualitative real-time pcr revealed the genome in 73 out of 159 samples examined (108 urine and 51 semen). after antibiotic therapy, p. acnes was never detected. conclusions: these results suggested that p. acnes genome determination should be performed in cases of chronic inflammation in the urinary tract to identify an unknown potential pathogen of genitourinary tract. key words: propionibacterium acnes; prostate hyperplasia; prostate cancer; urinary tract infections. submitted 18 october 2021; accepted 3 december 2021 introduction propionibacterium acnes (p. acnes) is a gram-positive, nonmotile, non-spore forming, anaerobic bacillus. it is ubiquitous and part of the normal flora of the skin. despite it is considered part of our commensal microbiota there are a number of reports correlating p. acnes with several diseases. indeed p. acnes contributes at the pathogenesis of acne vulgaris and was found to be implicated in a widerange of post-operative infectious conditions, such as endocarditis, endophthalmitis and intravascular nervous system infections. p. acnes is also frequently detected in prostate tissue of patients diagnosed with benign prostate hyperplasia (bph) and cancer (1). chronic infection and inflammation have been linked to cancer of several organs suggesting that also prostatic inflammation could propionibacterium acnes in urine and semen samples from men with urinary infection lucrezia manente 1, umberto gargiulo 1, paolo gargiulo 1, giuseppe dovinola 2 1 biodata s.r.l clinical, molecular and genetics laboratory, salerno, italy; 2 specialist urology and andrology clinic, salerno, italy. doi: 10.4081/aiua.2022.1.62 summary 63archivio italiano di urologia e andrologia 2022; 94, 1 propionibacterium acnes genome in the urinary infection ture. midstream urine was collected in a clean vessel and analyzed within 2 h of collection. urinalysis included physical, chemical and microscopic examinations. chemical urinalysis was performed by automated urinalysis system u500 (intermedical diagnostics) detecting blood, protein, glucose, leukocyte esterase and nitrite. microscopic examination was performed to identify cells, bacteria, casts and crystals. physical and chemical findings were: hazy or cloudy appearance, blood presence, glucose > 1000 mg/dl, protein more than trace quantities, leukocyte esterase or nitrite positivity. microscopic findings were: detection of red blood cells (rbc) and/or white blood cells (wbc) ≥ 4 for high power field (hpf) and/or bacteria (data not shown). urine and semen samples for microbiology analysis were collected in sterile vessel. selective and differential solid media (integral system enterobatteri, liofilchem, italy) were used for cultivable microorganisms. lactobacillus species, coagulase-negative staphylococcus and streptococcus were considered normal flora or contaminants and thus urine or semen culture was considered negative. growth and identification of enterobacteriaceae, group b streptococcus, staphylococcus aureus, staphylococcus saprophyticus, enterococcus spp., klebsiella spp., proteus spp., candida spp at > 10000 cfu/ml and 5000 cfu/ml for urine and semen respectively were considered positive culture. dna extraction and sexually transmitted infection (sti) agents detection the urine and semen samples were screened for chlamydia trachomatis and genital mycoplasmas with real time pcr. briefly, the dna extraction was made using prime dna/rna rapid extraction kit (astra biotech, berlin, germany) and the analysis was made by real-time pcr using the kit mycoplasma genitalium/mycoplasma hominis multiplex pcr kit, ureaplasma urealyticum/ureaplasma parvum multiplex kit and chamydia trachomatis pcr kit (astra biotech, berlin, germany) according to the manufacturer’s instructions. propionobacterium acnes identification the dna extracted from urine and semen samples was analyzed for p. acnes genome presence using the p. acnes reca gene (primer design genesig, uk) according to the manufacturer’s instructions. the kit is designed with the broadest possible detection profile to ensure that all clinically relevant strains and subtypes are detected. the analysis was made by realtime pcr and all amplification reactions of the genomic materials were performed with a ariadx real-time pcr system (agilent technologies). antibiotic therapy the treatment of p. acnes infections can be made using antibiotics such as cephalosporine, vancomycin, penicillin, tetracyclines, rifampicin and erythromycin. in our study all the patients with p. acnes infections were treated, initially, with cephalosporins for three months. after cephalosporins therapy if the urine or semen samples were still positive for p. acnes an alternative antibiotic regimen with vancomycin for three months was proposed. results dna p. acnes detection from urine and semen sample out of the 159 samples examined (108 urine and 51 semen samples) the genome of p. acnes was identified in 56 urine and 17 semen samples (tables 1, 2). p. acnes positive patients were treated with cephalosporins therapy. after cephalosporins therapy, p. acnes real time was repeated in 56 urine and 17 semen samples and p. acnes genome was not detected in 51 urine and in 16 semen sample whereas 6 samples (5 urine and 1 semen) were still positive for p. acnes. these patients were treated with vancomycin, an alternative antibiotic therapy, and then were re-evaluated for presence of p. acnes genome. at the end of the vancomycin therapy, p. acnes real time testing was negative per p. acnes genome. discussion uti is the most common urological infection with annual incidence increasing with age in men (4, 5). the presence of localized genitourinary symptoms and signs of urinary tract inflammations and a urine culture with an identified urinary pathogen are suggestive of uti and antibiotic therapy is necessary for the treatment of the infection. any microorganism, ascending the urethra or by reflux of urine into prostatic duct, can infect prostate gland and to cause chronic inflammation in connection with benign prostatic hyperplasia (bph), chronic prostatitis (cp) and prostate cancer (6). in addition to bacterial infections, other factors such as hormone imbalances, dietary carcinogens and environmental factors promote prostate chronic inflammation and lead to injury of the prostate (7). several studies showed that the p. acnes identification was associated with acute and chronic inflammation and, moreover, a high prevalence rates of this bacterium in prostate tissue samples from men with prostate cancer has been demonstrated (8, 9). p. acnes is a common skin anaerobic organism that is capable to resist to phagocytosis through complex cell wall structure, to persist intracellularly within macrophages and to produce exocellular enzymes that can damage the host tissue and induce pro inflammatory cytokines (10). in this study we analyzed, with molecular biology techniques, the urine and semen sample of patients with recurrent symptoms of urological table 1. total samples examined. tot. n. samples 159 urine 108 semen 51 table 2. presence of p.acnes genome in urine and semen samples. samples in which the p. acnes genome was identified urine 56 semen 17 archivio italiano di urologia e andrologia 2022; 94, 1 l. manente, u. gargiulo, p. gargiulo, g. dovinola 64 infections, that were negative for more common genitourinary pathogen and sti agents (11, 12). patients with samples positive for p. acnes were treated with specific antibiotic therapy and showed a positive response in terms of improved clinical condition. a limitation of the present study is the lack of comparative date between urine and semen samples from the same patient, although it is conceivable that the pathogen could be detectable indifferently in both samples. a further objective of our work will be to assess the correlation between p. acnes infection and couple infertility. in fact, our preliminary experience has shown that three patients with a history of couple infertility were able to obtain the pregnancy after antibiotic therapy to eradicate the p. acnes infection. this finding should be confirmed by larger controlled series. conclusions our results show that real time pcr genome screening for p. acnes could be a useful diagnostic tool for utis. p. acnes infection could start a pathogenic cascade causing, in the long term, an inflammatory process of the prostate. indeed, an amount of evidence suggests that the invasion of prostate epithelial cells by p. acnes contributes at the prostate gland diseases (13). references 1. leheste jr, ruvolo ke, chrostowski je, et al. p. acnes-driven disease pathology: current knowledge and future directions. front cell infect microbiol. 2017; 7:81. 2. kakegawa t, bae y, ito t, et al. frequency of propionibacterium acnes infection in prostate glands with negative biopsy results is an independent risk factor for prostate cancer in patients with increased serum psa titers. plos one. 2017; 12:e0169984 3. shannon ba, cohen rj, garrett kl. the antibody response to propionibacterium acnes is an independent predictor of serum prostate-specific antigen levels in biopsy-negative men. bju int. 2008; 101:429-35. 4. griebling tl. urologic diseases in america project: trends in resource use for urinary tract infections in men. j urol. 2005; 173:1288-94. 5. marques lp, flores jt, de barros o, et al. epidemiological and clinical aspects of urinary tract infection in community-dwelling elderly women. braz j infect dis. 2012; 16:436-41. 6. gandaglia g, zaffuto e, fossati n, et al. the role of prostatic inflammation in the development and progression of benign and malignant diseases. curr opin urol. 2017; 27:99-106. 7. de marzo am, platz ea, sutcliffe s, et al. inflammation in prostate carcinogenesis. nat rev cancer. 2007; 7:256-269. 8. alexeyev o, bergh j, marklund i, et al. association between the presence of bacterial 16s rna in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (sweden). cancer causes control. 2006; 17:1127-1133. 9. fassi fehri l, mak tn, laube b, et al. prevalence of propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells. int j med microbiol. 2011; 301:69-78. 10. perry al, lambert pa. propionibacterium acnes. lett appl microbiol. 2006; 42:185-8. 11. cai t, pisano f, nesi g et al. chlamydia trachomatis versus common uropathogens as a cause of chronic bacterial prostatitis: is there any differences? results of a prospective parallel-cohort study. investig clin urol. 2017; 58:460-467. 12. horner pj, martin dh. mycoplasma genitalium infection in men. j infect dis. 2017; 216:s396-405. 13. davidsson, s, mölling p, rider jr, et al. frequency and typing of propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer. infect. agent cancer. 2016; 11:36. correspondence lucrezia manente, phd (corresponding author) l_manente@yahoo.it umberto gargiulo u.gargiulo@hotmail.it paolo gargiulo info@biodatasalerno.it biodata s.r.l clinical, via diaz 22, salerno (italy) giuseppe dovinola, md dovinolap@libero.it specialist urology and andrology clinic via lungomare trieste 172, salerno (italy) 107archivio italiano di urologia e andrologia 2020; 92, 2 case report no conflict of interest declared. doi: 10.4081/aiua.2020.2.107 case reports a 73-year-old male patient with gross hematuria was admitted to the emergency room. anamnestic evaluation revealed a history of multiple aortocoronary bypass, bilateral inguinal hernioplastic, hypertension treated with antihypertensives and anticoagulants and idiopathic retroperitoneal fibrosis assessed one year earlier for obstructive renal failure. the patient was on treatment with prednisone and bilateral ureteral stents. patient was clinically stable, hemoglobin was 10 mg/dl and other blood chemistry parameters were normal. ct scan showed slight enlargement of the aorta associated with retroperitoneal fibrosis involving the abdominal aorta and the common iliac arteries. blood clots were present in the right pyelocaliceal system, along the right ureter and in the bladder. ureteral stents were in place. cystoscopy and a thorough endoscopic evaluation of the right upper urinary tract revealed no existing disease. the following days new episodes of gross-hematuria with right flank pain requiring blood transfusions occurred. after hemodynamic stabilization the patient was urgently subjected to digital angiography. after removal of the double j stent that was replaced by a guidewire, selective arteriography of the common iliac artery and its branches did not show any fistulous tract with the right ureter. it was therefore decided to place a 10 x 59 mm endovascular prosthesis at the intersection of common iliac artery bifurcation with the right ureter on the basis of previous ct scan evaluation of iliac artery ureteral crossing (figure 1). ureteral 6 x 26 stents were deployed again bilaterally in the upper urinary tract. the procedure was uneventful and the patient was discharged five days later without presenting new episodes of blood loss. one month later duplex sonographic evaluation of common iliac and external arteries showed normal blood flow and normal flowmetric indices. uaf is classified into primary (15%) and secondary (85%) type on the basis of its cause. primary causes are natural disease processes of the arterial system such as aneurysms, vascular malformations, or aberrant vessels that erode into the ureter. secondary causes are pelvic surgery (89%) combined with radiation (43%) and with ureteral stent placement (67%) leading to inflammation and fibrosis that, in turn, result in fixation of the ureter to the adjacent artery. high arterial pressure is transmitureteral iliac artery fistula in idiopathic retroperitoneal fibrosis: a case report eugenio di grazia 1, tiziana la malfa 2, gherardo gasso 3 1 u.o.c. di urologia arnas garibaldi-nesima, catania, italy; 2 laboratorio analisi casa di cura mater dei, catania, italy; 3 u.o.c. di chirurgia vascolare arnas garibaldi-nesima, catania, italy. introduction ureter arterial fistula (uaf) is an uncommon condition and about 150 cases are described in the literature. uaf can develop with aorta, common iliac artery, external iliac artery and hypogastric artery. fistulas between ureter and common or external iliac artery are usually associated with a history of pelvic surgery, pelvic irradiation, chronic ureteral stenting and vascular disease (1, 2). the presentation is usually a lifethreatening massive gross hematuria with acute anemia and the diagnosis is still a challenge for urologist, because of misleading cross-sectional imaging, ureteral contrast-enhanced studies and endoscopy to assess the fistula. digital subtracted angiography and vascular treatment are considered to be the best tools for the ureteric-arterial fistula assessment and management (2). retroperitoneal fibrosis (rpf) is a condition of variable etiology characterized by a highly fibrotic retroperitoneal mass that frequently causes ureteral obstruction. rpf encompasses the idiopathic form (irf) (> 75% of the cases) and secondary forms, which include cases secondary to malignancies, infections, drugs, radiotherapy, or other conditions. to our knowledge we report the first case describing the uaf in a patient with irf. ureter-arterial fistula (uaf) is an uncommon condition. the presentation is usually a life-threatening intermittent massive gross hematuria and the diagnosis is still a challenge for urologist. idiopathic retroperitoneal fibrosis (irf) is a condition of unknown etiology characterized by a highly fibrotic retroperitoneal mass that frequently causes ureteral obstruction. to our knowledge we report the first case describing the uaf in a patient suffering from irf. we hypothesize that inflammation and fibrosis resulted in fixation of the ureter to the adjacent artery causing a fistulous path. uaf was managed by deploying a 10 x 59 mm endo-graft at the intersection of common iliac artery bifurcation with the right ureter. post treatment course was uneventful. key words: idiopathic retroperitoneal fibrosis; stent; ureter; uretero-arterial fistula. submitted 25 august 2019; accepted 21 september 2019 summary di grazia_stesura seveso 17/06/20 10:14 pagina 107 archivio italiano di urologia e andrologia 2020; 92, 2 e. di grazia, t. la malfa, g. gasso 108 ted to the juxtaposed arterial and ureteral walls and supposed to determine pressure necrosis and fistula formation. the pressure head of arterial pulsion on a weakened arterial wall against a scarred and fibrotic stented ureter may facilitate fistula formation. idiopathic rpf is a rare disease, with an estimated incidence of 0.1-1.3 cases/100,000 persons per year, and a prevalence of 1.4 cases/100,000 inhabitants (3). idiopathic rpf disease usually involves the adventitia of the abdominal aorta and the iliac arteries and the surrounding retroperitoneum, and histologically shows a mixture of fibrous tissue and chronic inflammation involving the ureters. the fibrous tissue comprises an extracellular matrix composed of type i collagen fibers organized in thick irregular bundles. plasma cells account for a significant proportion of the inflammatory cells. angiographic findings of uaf can vary from dramatic extravasation or a pseudoaneurysm to a subtle irregularity or intimal defect. in approximately one third of the patients with uaf angiography may not reveal abnormal findings, making uaf challenging to observe. another important issue is that the onset of hematuria is usually spontaneous but can be incited by initiation of anticoagulation or ureteral stent manipulation. multiple options exist to treat uaf using the endovascular approach including stent-graft exclusion of the fistula and coil embolization of the affected artery. if stent-graft placement involves the iliac artery bifurcation, embolization of the ipsilateral internal iliac artery with coils or a vascular plug is considered to prevent retrograde feeding of the fistula. conclusions irf and chronic ureteral stenting may determine a uaf with life-threatning severe bleeding. diagnosis is a challenge for urologist and radiologist. minimally invasive angiographic management is recommended for high success and low complication rates. references 1. pillai ak, anderson me, reddick ma, et al. ureteroarterial fistula: diagnosis and and management. ajr am j roentgenol. 2015; 204:w592-w598. 2. mahlknecht a, bizzotto l, gamper c, wieser a. a rare complication of ureteral stenting: case report of a uretero-arterial fistula and revision of the literature. arch ital urol androl. 2018; 90:215-21. 3. rafiei a, weber ta, kongnyuy m, ordorica r. bilateral ureteraliliac artery fistula in a patient with chronic indwelling ureteral stents: a case report and review. case rep urol. 2015; 826760. 4. vaglio a, maritati f. idiopathic retroperitoneal fibrosis j am soc nephrol. 2016; 27:1880-1889. figure 1. ct scan showing the intersection of common iliac artery bifurcation with the right ureter where the fistula path is supposed to be. digital arteriography showing a guidewire in the ureter crossing the common iliac artery. endovascular prosthesis deployment at the intersection of common iliac artery bifurcation with the right ureter. post endograft deployment evaluation showing the prostheris and the patency of iliac arteries. correspondence eugenio di grazia, md (corresponding author) e.digrazia@ao-garibaldi.ct.it u.o.c. di urologia arnas garibaldi-nesima, catania (italy) tiziana la malfa, md laboratorio analisi casa di cura mater dei, catania (italy) gherardo gasso, md u.o.c. di chirurgia vascolare arnas garibaldi-nesima, catania (italy) di grazia_stesura seveso 17/06/20 10:14 pagina 108 stesura seveso 439archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. stone composition, size, and location, as well as the mechanism and parameters of the shockwave generator (1). several studies have proved that stone attenuation values – measured in hounsfield units (hu) on computed tomography (ct) – can predict the outcome of swl. although the threshold values differ in various studies it has generally been accepted that higher ct attenuation values have poor outcomes in terms of success rates (2-5). however, most of these studies address only the role of ct attenuation values from the success rate standpoint and there is a paucity of literature investigating the association between preoperative stone characteristics and the need for postoperative ancillary procedures. we believe that the challenge is not only to fragment the stone, but also to reduce the risk of subsequent ancillary treatments. ancillary treatments such as ureteroscopy (urs) and hospital readmission for pain or fever are frequently encountered after swl. these ancillary treatments have put an undue burden on urological treatment waiting lists. for small ureteral or renal calculi, swl has a comparable efficacy when compared with retrograde intra-renal surgery (rirs) (6). according to the latest guidelines, swl should be considered as the first treatment option in patients with renal stones less than 20 mm and without unfavorable factors for swl success (1). however, the predictors for ancillary procedures after swl are still under investigated and eagerly awaited. therefore, the aim of the present study was to investigate the predictors for the ancillary treatments after (swl) for renal and upper ureteral stones. materials and methods from january 2014 to january 2017, patients undergoing swl using an electromagnetic lithotripter machine (compact delta; dornier medtech gmbh, wessling, germany) for renal and upper ureteral stones ≤ 20 mm were retrospectively reviewed. all patients included in the analysis underwent ct urography prior to swl. the cohort was subdivided into three groups according to stone attenuation values (hu). group i; hu < 500, group ii; hu 500-1000 and group iii; hu ≥ 1000. the paramobjective: to quantify the predictors for the ancillary treatments after extracorporeal shock wave lithotripsy (swl) for renal and upper ureteral stones. materials and methods: from january 2014 to january 2017, patients undergoing swl using an electromagnetic lithotripter machine (compact delta; dornier medtech gmbh, wessling, germany) for renal and upper ureteral stones ≤ 20 mm were retrospectively reviewed. all patients underwent ct urography prior to swl. the cohort was subdivided into three groups according to stone attenuation values in hounsfield units (hu). group i; hu < 500 (n = 20), group ii; hu 500-1000 (n = 51) and group iii; hu ≥ 1000 (n = 180). the parameters included for multivariate analysis were stone size, location, multiplicity, stone attenuation value, number of shocks and stone clearance rate by 3 months. the ancillary treatments were ureteroscopy (urs), ureteral stenting and hospital readmission for pain or fever. results: a total of 251 patients were included in the study. the overall swl success rate was 92.4%. mean stone size was 10.9 ± 2.1, 11.6 ± 3 and 11.4 ± 3.6 mm and mean stone attenuation values were 364 ± 125, 811 ± 154 and 1285 ± 171 hu for groups i, ii and iii respectively. the stone clearance rates by 3 months were 96%, 92% and 88.4% for groups i, ii and iii respectively. on subgroup analysis, group iii required ancillary treatments in 70% of patients whereas group i, ii, did not require any ancillary treatments. on multivariate analysis, stone multiplicity, stone location (lower calyceal stones) and hu were independent significant predictors for the need for ancillary treatments after swl (p values < 0.05). conclusions: patients with stone attenuation value (hu) > 1000, multiple stones and/or lower calyceal stones have higher risk to necessitate ancillary treatments after swl. these patients would likely benefit from upfront endoscopic lithotripsy for treating symptomatic renal or upper ureteral stones. key words: swl; urolithiasis; fragmentation; ancillary treatment; lower calyceal stone. submitted 19 november 2022; accepted 5 december 2022 introduction the outcome of extracorporeal shockwave lithotripsy (swl) relies on several factors, including stone factors such as can we predict the ancillary treatments after extracorporeal shockwave lithotripsy for renal and upper ureteral stones? ahmed ibrahim 1, adel elatreisy 2, abdulghani khogeer 3, abdulsalam ahmadi 4, shashikant mishra 4, mahmoud faisal 2, ravindra sabnis 4, mélanie aubé-peterkin 1, serge carrier 1, arvind ganpule 4, mahesh desai 4 1 department of surgery, division of urology, mcgill university health center, montreal qc, canada; 2 urology department, al-azhar university, cairo, egypt; 3 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 4 muljhibhai patel urological hospital, nadiad, india. * co-first author. doi: 10.4081/aiua.2022.4.439 summary archivio italiano di urologia e andrologia 2022; 94, 4 a. ibrahim, a. elatreisy, a. khogeer, et al. 440 eters included in the multivariate analysis were stone size, location, multiplicity, stone attenuation value, number of shocks and stone clearance rate by 3 months. ureteroscopy (urs), ureteral stenting and hospital readmission for pain or fever were considered post-swl ancillary procedures. for each stone, the mean attenuation value was calculated from a small, non-overlapping region of interest. the swl procedures were all performed as previously described (3). the treatments were performed under conscious sedation using intravenous fentanyl as the primary anesthetic agent. the stones were located under fluoroscopic and/or ultrasonographic guidance, and the shock impulses were given at a frequency of 60 shocks per minutes in all patients (1 hz). shock impulse energy was started at level 1 (10 kv) and ramped up to 6 level (16 kv). the total number of shocks did not exceed 3000. plain x-ray kidney-ureter-bladder (kub) and ultrasound were performed 6 weeks post swl. success rate was defined as inability to detect stone on ultrasound and kub or a residual fragment measuring less than 4 mm. review of literature a pubmed-medline search was conducted for swl contemporary literature and relevant data regarding swl auxiliary procedures and predictors of failure. several articles based on the same patient cohort and success rate measures were included. statistical analysis statistical analyses were performed using spss (spss inc., chicago, il, usa) version 22. comparison of quantitative variables was done using the paired t test (if normally distributed) or the wilcoxon signed rank test (if not normally distributed) or fisher’s exact test for categorical variable. a multivariate logistic regression analysis was used to assess predictors of postoperative ancillary treatments. two-tailed p-values of less than 0.05 were set for statistical significance. results a total of 251 patients were included in this study, including 20 patients in group i, 51 patients in group 2 and 180 patients in group 3. the overall swl success rate at 3 months was 92.4% including 14 patients (5.5%) who developed post swl steinstrasse. the mean stone size was 10.9 ± 2.1, 11.6 ± 3 and 11.4 ± 3.6 mm and the mean stone attenuation values were 364 ± 125, 811 ± 154 and 1285 ± 171 hu for groups i, ii and iii respectively. stone clearance rates were 96%, 92%, 88.4% for groups i, ii and iii respectively. swl failure was encountered in 26 patients (10.4%), 24 patients of them (6.8%) were stone-free after second session of swl and 2 patients (0.8%) necessitated urs. the three groups were comparable in terms of body mass index, stone size and stone location (table 1). on subgroup analysis, group iii patients required urs and ureteral stenting in 10 cases (5.6%), and hospital readmission for persistent renal colic in 4 cases (2.2%) whereas no patients in groups i and ii required ancillary treatments. univariate analysis revealed that there was a significant correlation between age, stone location, stone multiplicity, hu and the need for ancillary procedures (p < 0.05) whereas no significant correlation could be detected for stone size, and gender (table 2). on multivariate analysis, it was found that stone multiplicity, stone location and hu were independent significant predictors for the treatments after swl (p values < 0.05) (table 2). table 3 summarizes swl contemporary series tracking the required auxiliary procedures after swl and predictors of swl failure (7-20). discussion according to the latest guidelines, swl remains the procedure of choice for most upper urinary tract stones ≤ 20 mm in size because of its minimally invasive nature, shorter operative time, established success rates, and minimal complications with long-term safety (1). however, swl monotherapy is not successful in 9.4% to 26.3% of renal and upper ureteric stones (6, 21). several studies have shown that swl efficacy is significantly lower for stones with higher attenuation values (5-8). nevertheless, there is table 1. patients and stone demographic data. parameter value mean age ± sd (years) 37.79 ± 17.7 gender male 181 female 70 mean bmi (kg/m2) 23.97 ± 3.8 stone side, n (%) right 125 left 126 mean stone size ± sd (mm) 11.46 ± 2.74 multiple stones, n (%) 19 (7.57%) stone location, n (%) upper calyx 21 (8.37%) middle calyx 44 (17.53%) lower calyx 50 (19.92%) renal pelvis 82 (32.67%) upper ureter 54 (21.51%) associated hydronephrosis, n (%) mild 51 (20.32%) moderate 25 (9.96%) mean stone attenuation value (hu) 1115 ± 329.79 overall swl success rate 92.4% swl onset, n (%) primary treatment 243 (96.8%) residual stone post pcnl and rirs 16 (6.4%) table 2. predictors for ancillary treatments using univariable and multivariate regression analysis. variable univariable multivariable or 95%ci p or 95%ci p age, years 1.04 (1.01, 1.07) 0.027 0.97 (0.89-1.71) 0.09 stone size (mm) 0.81 (0.78-1.11) 0.082 stone location 1.18 (0.88-1.01) 0.01 1.1 (0.99–1.78) 0.02 stone multiplicity 2.81(1.26-3.54) < 0.001 1.45 (1.16–2.11) 0.01 number of shocks per session 0.91 (0.54–1.02) 0.306 hu (< 1000 vs. ≥ 1000) 2.75 (1.40-4.99) 0.001 3.01 (1.61-6.71) 0.01 gender, male/female 0.81 (0.51–1.00) 0.351 or = odds ratio; ci = confidence interval; hu = hounsfield unit. 441archivio italiano di urologia e andrologia 2022; 94, 4 ancillary treatments after swl a paucity of literature investigating the association between preoperative stone characteristics and the need of postoperative ancillary procedures. therefore, the aim of the present study was to investigate the predictors for the ancillary treatments after (swl) for renal and upper ureteral stones. it was found that overall swl success rate at 3 months was 92.4%. after 3 months follow-up, the stone-free rates were 96%, 92%, and 88.4% for groups i, ii, and iii respectively. on subgroup analysis, group iii (hu > 1000) required urs and ureteral stenting in 5.6% of patients, and hospital readmission for persistent renal colic in 2.2% whereas groups i and ii did not require any ancillary treatments. these results are consistent with current medical literature, indicating that swl is associated with significantly higher retreatment rates compared with rirs and pcnl (21). on multivariate analysis, it was found that stone multiplicity, stone location and hu > 1000 were independent significant predictors for the treatments after swl (p values < 0.05; table 2). interestingly, when we analyzed stone location cases, we found that most of the lower calyceal stone were associated with swl failure and required ancillary treatments. it was reported that several factors such as obesity, stone density, stone composition and unfavorable lower pole anatomy would also affect stone clearance rates (22). these results may change our clinical practice in the following manner; for those patients with multiple stones, a 1-2 cm lower calcyeal stone or stone attenuation value > 1000 hu and who are anxious about the increased complication rates of rirs and pcnl and do not mind retreatment or multiple procedures, swl could be considered an acceptable first management option. favorable lower pole anatomy [infundibular-pelvic angle (> 30°), short calyx (< 10 mm), and wide infundibulum (> 5 mm)] should also be considered in the treatment algorithm (22). most patients, who fail primary swl treatment, are best suited to be treated with endoscopic treatments (rirs or pcnl) due to its high stone-free rate, significantly lower operative and fluoroscopy time. however, patients with challenging lower pole calyceal anatomy, pcnl would be the first option. our study had some limitations including, first the retrospective nature resulting in some missing data such as stone to skin distance, infundibulo-pelvic angle. however, these variables are sufficiently reported in medical literature. secondly, there exists a selection bias which explains the high heterogeneity between groups. finally, the interpretation of our findings may be affected by these confounders. nevertheless, this is one of the rare studies investigating the predictors for the ancillary treatments after swl. conclusions our study suggests that patients with stone attenuation value (hu) > 1000, multiple stones and/or lower calyceal stones have higher risk to necessitate ancillary treatments after swl. those patients could be offered an endoscoptable 3. contemporary published swl series. series study design n ancillary treatment success rate predictors of failure garrido-abad et al. (7) retrospective 270 n/a 68.8% stone size > 9.3 mm stone volume > 237 sav > 951, ssd 133 mm bmi > 26.9 nakasato et al. (8) retrospective 260 n/a 76.5% hu > 815 stone location massoud et al. (9) prospective 305 stienstrusse in 3.6% bmi > 30 conservative in 2.6% lower calyceal stone urs in 10.8% 83% sav > 956.5 abdelaziz et al. (10) retrospective 89 n/a 68.5% hu > 800 ssd > 11.2 ± 2.6 cm quzaid et al. (11) prospective 50 n/a 52% hu > 970 park et al. (12) retrospective 43 n/a 69.7% ssd > 92.03 ± 14.51 mm olive et al. (13) retrospective 98 cystoscopy + ureteric stents in 40.6% 56.3% obesity bmi > 35 bandi et al. (14) retrospective 94 n/a 62% stone volume > 500 microl. talas et al. (15) retrospective 198 n/a 61% in lower calyceal stones ip angle and infundibular width al-ansari et al. (16) retrospective 427 post-eswl 78% stone size, location and number auxiliary procedures were required in 8.4% radiological renal features and congenital renal anomalies. ghoneim et al. (17) retrospective 205 n/a 68.8% ip angle more than 70 degrees infundibular length of > 50 mm wang et al. (18) prospective 89 n/a 52.5% stone burden > 700 mm3 stone density of > 900 hu abdel-khalek et al. (19) retrospective 2954 static steinstrassae in 4.9%. 86.7% patient age, stone size, location and number auxiliary radiological renal features and congenital renal anomalies procedures in 4% sumino et al. (20) retrospective 63 n/a 54% higher infundibular length-to-diameter ratio diameter and number of minor calices archivio italiano di urologia e andrologia 2022; 94, 4 a. ibrahim, a. elatreisy, a. khogeer, et al. 442 ic lithotripsy as a first line therapy for treating symptomatic renal or upper ureteral stones. future prospective studies are definitely warranted. references 1. türk c, knoll t, petrik a, et al. eau guidelines on urolithiasis. eur urol. 2014; 258-89. 2. jeong us, lee s, kang j, han dh, et al. factors affecting the outcome of extracorporeal shock wave lithotripsy for unilateral urinary stones in children: a 17-year single-institute experience. korean j urol. 2013; 54:460-466. 3. hevia m, garcía á, ancizu fj, et al. predicting the effectiveness of extracorporeal shock wave lithotripsy on urinary stones, risk groups for accurate retreatment. actas urol esp. 2017; 41:451-457. 4. el-nahas ar, ei-assmy am, madbouly k, et al. predictors of clinical significance of residual fragments after extracorporeal shockwave lithotripsy for renal stones. j endourol. 2006; 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8: e567-9. 10. ouzaid i, al-qahtani s, dominique s, et al. a 970 hounsfield units (hu) threshold of kidney stone density on non-contrast computed tomography (ncct) improves patients' selection for extracorporeal shockwave lithotripsy (eswl): evidence from a prospective study. bju int. 2012; 110:e438-42. 11. byung-hun park, hoon choi, jin-bum kim, and young-seop chang. analyzing the effect of distance from skin to stone by computed tomography scan on the extracorporeal shock wave lithotripsy stonefree rate of renal stones. korean j urol. 2012; 53:40-43. 12. olivi b1, védrine n, costilles t, et al. extra corporeal shock wave lithotripsy in patients with body mass index over 35 kg/m2. prog urol. 2011; 21:254-9. 13. bandi g, meiners rj, pickhardt pj, nakada sy. stone measurement by volumetric three-dimensional computed tomography for predicting the outcome after extracorporeal shock wave lithotripsy. bju int. 2009; 103:524-8 14. talas h, kilic o, tangal s, safak m. does lower-pole caliceal anatomy predict stone clearance after shock wave lithotripsy for primary lower-pole nephrolithiasis?. urol int. 2007; 79:129-32. 15. al-ansari a1, as-sadiq k, al-said s, et al. prognostic factors of success of extracorporeal shock wave lithotripsy (eswl) in the treatment of renal stones. int urol nephrol. 2006; 38:63-7. 16. ghoneim ia, ziada am, elkatib se. predictive factors of lower calyceal stone clearance after extracorporeal shockwave lithotripsy (eswl): a focus on the infundibulopelvic anatomy. eur urol. 2005; 48:296-302. 17. wang lj1, wong yc, chuang ck. predictions of outcomes of renal stones after extracorporeal shock wave lithotripsy from stone characteristics determined by unenhanced helical computed tomography: a multivariate analysis. eur radiol. 2005; 15:2238-43. 18. abdel-khalek m, sheir kz, mokhtar aa, et al. prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. scand j urol nephrol. 2004; 38:161-7. 19. sumino y, mimata h, tasaki y, et al. predictors of lower pole renal stone clearance after extracorporeal shock wave lithotripsy. j urol. 2002; 168:1344-7. 20. zhang w, zhou t, wu t, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy versus extracorporeal shockwave lithotripsy for treatment of lower pole renal stones: a meta-analysis and systematic review. j endourol. 2015; 29:745-59 21. junbo l, yugen l, guo j, et al. retrograde intrarenal surgery vs. percutaneous nephrolithotomy vs. extracorporeal shock wave lithotripsy for lower pole renal stones 10-20 mm: a meta-analysis and systematic review. urol j. 2019; 16:97-106. 22. bozzini g, verze p, arcaniolo d, et al. a prospective randomized comparison among swl, pcnl and rirs for lower calyceal stones less than 2 cm: a multicenter experience: a better understanding on the treatment options for lower pole stones. world j urol. 2017; 35:1967-75. correspondence ahmed ibrahim, md ahmed.eldemerdash@muhc.mcgill.ca adel elatreisy, md (corresponding author) dr_adelelatreisy@yahoo.com al-azhar university, faculty of medicine cairo, egypt abdulghani khogeer, md dr-abdulghani@hotmail.com abdulsalam ahmadi, md abdulsalamahmadi@hotmail.com shashikant mishra, md mishra@mpuh.org mahmoud faisal, md drfaysl2012e@yahoo.com ravindra sabnis, md rbsabnis@gmail.com mélanie aubé-peterkin, md melanie.aube-peterkin@mcgill.ca serge carrier, md serge.carrier@mcgill.ca arvind ganpule, md doctorarvind1@gmail.com mahesh desai, md mrdesai@mpuh.org stesura seveso 311archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. and location. in particular, stones larger than 20 mm should be managed with percutaneous nephrolithotomy (pcnl), while, below this threshold, the retrograde intrarenal surgery (rirs) and extracorporeal shock-wave lithotripsy (eswl) are the treatments of choice (2-4). however, the continuous technological development and the use of increasingly powerful and safe instruments and techniques broadened the role of rirs also for stones > 20 mm (5-7). stone free rate (sfr) remains one of the primary outcomes after endoscopic surgery for kidney stones. recently, different scores to predict sfr have been formulated for patients undergoing rirs; such as the r.i.r.s. score, the seoul national university renal stone complexity (s-resc) and the resorlu-unsal stone score (russ) (8-10). this latter score was conceived in 2012, and takes in consideration the stone size, its presence at the level of the lower calyces, the infundibulum-pelvic angle (ipa), the number of stones and anatomical alterations. the goal of our study is to externally validate the applicability of russ in a single-center cohort of patients undergoing rirs for kidney stones. materials and methods we retrospectively reviewed medical data of 79 patients who underwent rirs between january 2020 and december 2021 at single center institution. two expert surgeons, highly experienced in rirs (> 500 procedures) performed the operations in a standardized fashion. all procedures were made with patient in lithotomy position under general anesthesia. preoperative single-dose antibiotic prophylaxis was used for all patients. a ureteral access sheath (uas) (flexor, cook medical, bloomington, usa) was inserted under fluoroscopic control if the ureter was compliant, with its tip always above the ureteralpelvic junction. therefore, the correct irrigating fluid outflow was confirmed and a 7.5 ch flexible ureteroscope was inserted (flex x2s, karl storz, tuttlingen, germany). laser lithotripsy was carried out with a 20w holmiumyag laser (ems laser clast, electro medical systems, nyon, switzerland), using a 200-micron fibre. laser setting was objective: pre-operative assessment of renal stones is essential in selecting treatment options and achieving high success rates for retrograde intrarenal surgery (rirs). several nephrolithometric scoring systems have been developed using pre-operative clinical data and stone characteristics. resorlu-unsal stone score (russ) is composed of four different parameters, and each of them adds 1 point to the final score. one point is added in patients with stone size > 20 mm, lower calyceal stones and infundibulo-pelvic angle < 45°, stone number > 1, and abnormal anatomy, respectively. russ categorizes patients into four distinct groups and aims to predict stone-free rates (sfr) after rirs. we externally validated russ and evaluated its predictive accuracy. materials and methods: we performed a retrospective analysis of patients who underwent rirs for renal stones between january 2020 and december 2021. patient age, pre-operative hydronephrosis, stone size, stone density as hounsfield unit (hu), operative time and russ were investigated as potential preoperative predictive factors for stone-free status. russ was applied to all patients, and the nomogram was externally validated. area under the curve (auc) was used for clinical validity assessment. results: the present study included a total of 79 patients. mean patient age was 55.1 ± 15.4 years with a mean stone size was 14.2 ± 4.4 mm. overall, 62/79 (78.4%) patients were stone free after the initial treatment. after applying russ, 36 (45.6%), 29 (36.7%), 10 (12.6%), and 4 (5.1%) patients had a score of 0, 1, 2, and 3, respectively. on multivariate logistic regression russ (or = 0.220; 95%ci: 0.086-0.567; p = 0.002) was identified as the only predictor of postoperative stone-free status. conclusions: russ is a user-friendly scoring system that may predict postoperative stone-free rate after rirs with great efficacy and accuracy. key words: stone; kidney; endoscopic; rirs; stone free rate. submitted 8 september 2022; accepted 9 september 2022 introduction urolithiasis is a common and worldwide increasing disease in developed countries (1). according to the european association of urology (eau) guidelines, the treatment of kidney stones depends mainly on their size external validation of resorlu-unsal stone score in predicting outcomes after retrograde intrarenal surgery. experience from a single institution antonio tufano 1, marco frisenda 1, antonio rossi 2, pietro viscuso 1, guglielmo mantica 3, pierluigi bove 4, rosario leonardi 5, alessandro calarco 2 1 department of maternal-infant and urological sciences, "sapienza" rome university, policlinico umberto i hospital, rome, italy; 2 “cristo re” hospital, rome, italy; 3 policlinico san martino, genova, italy; 4 san carlo di nancy hospital, roma, italy; 5 casa di cura musumecigecas, gravina di catania (ct), italy. doi: 10.4081/aiua.2022.3.311 summary archivio italiano di urologia e andrologia 2022; 94, 3 a. tufano, m. frisenda, a. rossi, et al. 312 5-12 hz and 0.6-1.2 j, either long or short pulse width. gravity irrigation was always used during lithotripsy and an additional intermittent gentle manual irrigation with a 60 ml syringe was added for a short time in case of reduced visibility. irrigating fluid outflow was checked continuously during the whole procedure. residual fragments were removed using a 2.2 fr-1 cm nitinol basket (n-circle, cook medical, bloomington, usa). at the end of the procedure, a final inspection of the upper urinary tract was performed with the aim to detect any residual fragments or ureteral injuries. our inclusion criteria were: 1) patients > 18 years; 2) preoperative non-contrast computed tomography (ncct) documenting a kidney stone > 10 mm. exclusion criteria were: 1) patients with concurrent ureteral stone or with bilateral renal stones; 2) with prior double j catheter; 3) with ureteral strictures; 4) patients without complete clinical records. clinical data and stones characteristics were collected for each patient. stone burden was interpreted as the twodimensional area determined by multiplying the longest diameter by the perpendicular diameter of the stone. in case of multiple stones, the stone burden was defined as the cumulative size. operation time was intended from the beginning of the cystoscopy to the end of the ureteral placement. a score (between 0 and 4) according to russ was assigned to each patient. this score system is based on four criteria, each having equal weight (1 point); stone size > 20 mm, lower pole stone location with ipa < 45°, number of stones in different calyces (> 1) and presence of abnormal renal anatomy (horseshoe kidney or pelvic kidney). the ipa was measured as the inner angle between the ureteropelvic axis and central axis of the lower pole infundibulum as described by elbahnasy et al. (11). the stone-free status was described as the absence of any residual stone fragment ≥ 5 mm at 1 month after surgery follow-up ncct. complications were recorded according to clavien-dindo classification. statistical analysis was carried out using spss software version 27 (spss inc, chicago, usa). continuous variables are presented as means and standard deviations. categorical variables are described by their absolute number and percent frequency. a multivariable logistic cox regression analysis was used to identify independent predictors of sfr. the auc, calculated by receiver operating characteristics curves (roc) of russ was used to assess predictive accuracy of sfr. all p values were two-tailed, with statistical significance set at 0.05 and confidence intervals at 95 % level. results the patients and stones characteristics are shown in table 1. overall, 79 patients were included. of those, 41 (51.9%) were males. mean patient age was 55.1 ± 15.4 years and mean stone size was 14.2 ± 4.4 mm with a mean stone density of 1014.4 ± 276 hu. left side was the most interested, n= 49 (69.1%). with regards to the intrarenal location, 23 (29.1%), 29 (36.7%) and 27 stones (34.2%) were located in the upper, middle and lower calyx, respectively. a total of 3 patients had ectopic kidney and 1 presented with horseshoe kidney. after applying russ, 36 (45.6%), 29 (36.7%), 10 (12.6%), and 4 (5.1%) patients had a score of 0, 1, 2, and 3, respectively. perioperative and postoperative data are shown in table 2. overall, 62/79 (78.4%) patients were stone free after the initial treatment. the mean operation time was 75.3 (± 26.6) minutes. mean hospital stay was 1.6 ± 0.9 days. a total of 2 urosepsis occurred and were treated with appropriate antibiotic therapy with one of them requiring intensive care unit admission; 5 postoperative fever and 1 migration of the double j catheter were also recorded. after adjusting logistic multivariate cox regression table 1. patients’ demographic and stone characteristics. variable overall n = 79 age at surgery (mean, sd) 55.1 (± 15.4) gender (n, %) male 45 (56.9%) female 34 (43.1%) asa score (n, %) 1-2 71 (89.9%) 3-4 8 (10.1%) hydronephrosis (n,%) 16 (20.3%) laterality (n, %) left 54 (68.4%) rigth 25 (31.6%) stone size, mm2 14.2 (4.4) stone density, hu 1014.4 (276) stones, mean (sd) 1.6 (± 0.9) stone location upper calyx 23 (29.1%), middle calyx 29 (36.7%) lower calyx 27 (34.2%) urinary anomaly (n, %) horseshoe kidney 1 (1.3%) pelvic kidney 3 (3.8%) table 2. perioperative and postoperative outcomes. variable overall n = 79 operative time, min (mean, sd) 75.3 (± 26.6) los, days (mean, sd) 1.6 (0.9) overall complications (n, %) 7 (8.9%) clavien grade (n, %) i 6 (7.6%) ii 1 (1.3%) iii iv 1 (1.3%) v table 3. binary logistic cox regression analysis for predictors for postoperative stone-free status. variable or lower higher p value age 1.006 0.956 1.149 0.766 hydronephrosis 0.724 0.194 2.705 0.331 stone size, mm 0.955 0.859 1.152 0.448 stone density, hu 0.992 0.890 1.047 0.806 operative time 0.982 0.749 1.156 0.499 russ 0.220 0.086 0.567 0.002 313archivio italiano di urologia e andrologia 2022; 94, 3 external validation of resorlu-unsal stone score analysis for age, preoperative hydronephrosis, stone size, stone density, russ and operative time, only russ (or = 0.220; 95%ci: 0.086-0.567; p = 0.002) was identified as a statistically significant predictor of postoperative stonefree status (table 3). finally, accuracy of russ reached an auc of 0.76 (figure 1). discussion according to eau guidelines, pcnl is the standard of treatment for renal stones > 2 cm. whilst, treatment for renal stones < 2 cm should be performed with either rirs or eswl. however, the progressive technological improvements in flexible ureterorenoscopy and new performing lasers have extended the surgical indications for kidney stones reaching a comparable success rate for stones > 2 cm in experienced hands and well selected patients (12, 13). notably, several predictive score systems have been recently incorporated in everyday clinical practice in order to predict outcomes following rirs. our aim was to externally validate the russ score, conceived by resorlu et al. in 2012, on an italian cohort of patients. to the best of our knowledge, the present study is the first external validation of russ performed in an italian center. our analysis brought to several noteworthy findings. first, males and left kidney side were the most interested accounting for 56.9% and 68.4%, respectively. second, when adjusting sfr status on multivariable analysis, neither stone density nor stone size reached statistical significance (or: 0.99; p = 0.80 and or: 0.95; p= 0.44). conversely, russ was identified as the only predictive score for sfr (or: 0.32; p = 0.002). this is in agreement with selmi et al. who in a pooled comparison of different nephrolithometric scores showed that russ was the best predictor of sfr (or: 0.45) (14). third, in the present study overall sfr was 78.4%, this rate being in line with results reported from other studies on rirs series (15-17). fourth, russ registered an auc of 0.76. similarly, sfoungaristos et al. russ externally validated russ estimating an auc of 0.70 (18). interestingly, results from a recent metanalysis comparing the predictive ability of the most used scoring systems for sfr has not revealed any superiority of one scoring tool over another (19). however, the high heterogeneity between studies and variables between the scoring systems make difficult to statistically generalize these findings. taken together, russ is a simple and reliable score to apply during the preoperative evaluation of kidney stones. for sure ipa is the most demanding parameter to calculate for urologists, however after a short learning curve with an expert radiologist we were able to perfectly assess this angle. we acknowledge that the present study has some limitations. first, should be interpreted in the context of its retrospective nature. second, the sample size is relatively small and includes fewer cases with high scores for the scoring system. third, rirs is strongly dependent on operator’s skill and potential risk of bias can occur. however, we only selected cases that were performed by expert surgeons in the rirs field. fourth, the russ score has an intrinsic limitation: horseshoe and ectopic kidneys are relatively rare. therefore, only a restricted number of patients scored 3 points. for this reason, our results may overestimate the diagnostic accuracy of this technique and potentially undermine their reproducibility in clinical practice. further validation studies with larger cohorts are needed to confirm the diagnostic accuracy of russ. conclusions treatment planning of kidney stones relies on several predictive scores. russ represents a user-friendly scoring tool that can be used in the prediction of postoperative sfr after rirs. further external validations in larger cohorts are needed to confirm these results. references 1. qian x, wan j, xu j, et al. epidemiological trends of urolithiasis at the global, regional, and national levels: a population-based study. int j clin pract. 2022; 2022:6807203. 2. zheng c, xiong b, wang h, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones > 2 cm: a meta-analysis. urol int. 2014; 93:417-424. 3. karakoyunlu n, goktug g, sener nc, et al. a comparison of standard pcnl and staged retrograde furs in pelvis stones over 2 cm in diameter: a prospective randomized study. urolithiasis. 2015; 43:283-287. 4. donaldson jf, lardas m, scrimgeour d, et al. systematic review and meta-analysis of the clinical effectiveness of shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy for lower-pole renal stones. eur urol. 2015; 67:612-616. 5. zhao z, sun h, zeng t, et al. an easy risk stratification to recommend the optimal patients with 2-3 cm kidney stones to receive retrograde intrarenal surgery or mini-percutaneous nephrolithotomy. urolithiasis. 2020; 48:167-173. figure 1. predictive accuracy of russ. archivio italiano di urologia e andrologia 2022; 94, 3 a. tufano, m. frisenda, a. rossi, et al. 314 6. breda a, angerri o. retrograde intrarenal surgery for kidney stones larger than 2.5 cm. curr opin urol. 2014; 24:179-183. 7. calarco a, frisenda m, molinaro e, lenci n. the active guidewire technique versus standard technique as different way to approach ureteral endoscopic stone treatment. arch ital urol androl. 2021; 93:431-435. 8. xiao y, li d, chen l, et al. the r.i.r.s. scoring system: an innovative scoring system for predicting stone-free rate following retrograde intrarenal surgery. bmc urol. 2017; 17:105. 9. jung jw, lee bk, park yh, et al. modified seoul national university renal stone complexity score for retrograde intrarenal surgery. urolithiasis. 2014; 42:335-340. 10. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". urology 2012;80:512-518. 11. elbahnasy am, shalhav al, hoenig dm, et al. lower caliceal stone clearance after shock wave lithotripsy or ureteroscopy: the impact of lower pole radiographic anatomy. j urol. 1998; 159:676-82. 12. aboumarzouk om, monga m, kata sg, et al. flexible ureteroscopy and laser lithotripsy for stones > 2 cm: a systematic review and meta-analysis. j endourol. 2012; 26:1257-63. 13. hyams es, munver r, bird vg, et al. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j endourol. 2010; 24:1583-8. 14. selmi v, sari s, oztekin u, et al. external validation and comparison of nephrolithometric scoring systems predicting outcomes of retrograde intrarenal surgery. j endourol. 2021; 35:781-788. 15. molina wr, kim fj, spendlove j, et al. the s.t.o.n.e. score: a new assessment tool to predict stone free rates in ureteroscopy from pre-operative radiological features. int braz j urol. 2014; 40:23-9. 16. park j, kang m, jeong cw, et al. external validation and evaluation of reliability and validity of the modified seoul national university renal stone complexity scoring system to predict stonefree status after retrograde intrarenal surgery. j endourol. 2015; 29:888-93. 17. maugeri o, dalmasso e, peretti d, et al. stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (rirs): our experience in 571 consecutive cases. arch ital urol androl. 2021; 93:313-317. 18. sfoungaristos s, gofrit on, mykoniatis i, et al. external validation of resorlu-unsal stone score as predictor of outcomes after retrograde intrarenal surgery. int urol nephrol. 2016; 48:1247-1252. 19. özman o, akgül hm, basataç c, et al. rirsearch study group. recent scoring systems predicting stone-free status after retrograde intrarenal surgery; a systematic review and meta-analysis. cent european j urol. 2022; 75:72-80. correspondence antonio tufano, md antonio.tufano91@gmail.com marco frisenda, md marco.frisenda@uniroma1.it pietro viscuso, md pietro.viscuso@uniroma1.it via del policlinico 155, 00161, rome, (rm) (italy) antonio rossi, md antonio.rossicz@gmail.com department of urology, “cristo re” hospital, via delle calasanziane 25, 00167 rome (rm) (italy) guglielmo mantica, md gugliemo.mantica@gmail.com largo rosanna benzi, 10, 16132, genova (italy) pierluigi bove, md pierluigi.bove@uniroma2.it via aurelia, 275,00165, rome (rm) (italy) rosario leonardi, md leonardi.r@tiscali.it via dell’autonomia 57, gravina di catania (ct) (italy) alessandro calarco, md alecalarco@gmail.com department of urology, “cristo re” hospital, via delle calasanziane 25, 00167 rome (rm) (italy) stesura seveso 497archivio italiano di urologia e andrologia 2021; 93, 4 letter to editor no conflict of interest declared. to the editor, autologous renal transplantation (art) since firstly described in 1963 by hardy, has been used in various cases (1). there are various reasons for the transplantation such as iatrogenic ureteral damage, chronic kidney pain, unresectable renal tumors or renovascular diseases (2, 3). indications concerning the suitable patients for this kind of procedure are gradually increasing. nevertheless, each case is unique, and the treatment must be personalized. art is a procedure with various complications. these include infections, graft failure, urine leak and renal vein thrombosis (2). however, the kidney preservation is of great clinical significance for the patient. in response to the case of moulavasilis et al., kidney preservation was a decision made by both the patient and the multidisciplinary medical team (4). the patient was 41 years old, still capable of getting pregnant. however, she was in an advanced but not prohibitive age for reproduction with increased possibility of complications. why to operate since there is one more functional kidney? during the second half of pregnancy, the glomerular infiltration is increased more than 40% normally (5). chronic kidney disease or even small renal impairment can facilitate the appearance of pregnancy complications such as preeclampsia, in which albuminuria and arterial hypertension are included (6). furthermore, arterial preeclampsia can accelerate renal damage, by causing podocyte loss, endothelial damage, and acute kidney injury (5). as a result, the preference of the patient for renal preservation, the possible desire for pregnancy as well as her good clinical state rendered surgery the final choice. all the aforementioned complications can also occur in pregnancy after renal transplantation (7). risk factors for complications are immunosuppressive treatment (donor transplantation), maternal proteinuria and hypertension (8). these pregnancies are associated with higher risk of both maternal and fetal complications. acute graft rejection, preeclampsia, cesarian sections and low birth weight of fetus are common problems. it should be noticed that the possibility of graft loss is slightly higher the first 2 years postpartum, and no difference is noticed 10 years postpartum compared to nulliparous controls (7-9). except for renal autotransplantation, other choices also exist in patients with ureteral avulsion. anastomosis between pelvis of the kidney and ileum constitutes the ileal ureter. it is recommended in cases with extensive ureter injuries. however, urinary infections and pain can occur in the post-surgical period (10). furthermore, metabolic and intestinal complications are also a frequent medical entity after this type of surgery (11). even appendix interposition has been reported in the literature (12). buccal mucosa onlay constitutes another choice for management of ureteral injuries. the oral mucosa is easily accessible and wet. grafts are taken from either the inner chick or lip. it is an innovative technique, which is used the last years. it can be performed as an open surgery, laparoscopic or robot assisted. even though the reported success of this surgery is very high, this technique should be used in larger series for final assessment (13). however, no information about the success of this surgery exists in patients who need reconstruction of the ureter more than 11 cm (14). restenosis or stricture recurrence have also occurred in some cases (13, 15). nephrostomy is another alternative for cases of ureteral damage. it is a minimally invasive technique which is easily performed. it is usually conducted in patients, in order to stabilize them, and does not usually constitute a permanent solution. the morbidity is very low, less than 0.04% and comcomment on renal autotransplantation: a final option to preserve the kidney after an iatrogenic ureteral injury christos damaskos 1, 2*, nikolaos garmpis 2, 3*, konstantinos nikolettos 4, alexandros patsouras 2, dimitrios schizas 5, anna garmpi 6, vasiliki e. georgakopoulou 7, athanasios syllaios 5, dimitrios dimitroulis 3 1 renal transplantation unit, laiko general hospital, athens, greece; 2 n.s. christeas laboratory of experimental surgery and surgical research, medical school, national and kapodistrian university of athens, athens, greece; 3 second department of propedeutic surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens, greece; 4 obstetric and gynecologic clinic, medical school, democritus university of thrace, alexandroupolis, greece; 5 first department of surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens, greece; 6 first department of propedeutic internal medicine, laiko general hospital, medical school, national and kapodistrian university of athens, athens, greece; 7 department of pulmonology, laiko general hospital, athens, greece. *equal contribution. submitted 26 may 2021; accepted 12 july 2021 doi: 10.4081/aiua.2021.4.497 archivio italiano di urologia e andrologia 2021; 93, 4 c. damaskos, n. garmpis, k. nikolettos, a. patsouras, d. schizas, a. garmpi, v.e. georgakopoulou, a. syllaios, d. dimitroulis 498 plications include colon perforation or bleeding. antibiotic usage before the implementation of the nephrostomy should be initiated (16). finally, nephrectomy is another choice in patients with extensive ureteral damage. the decision of the patient and the difficulty of a possible ureter reconstruction render laparoscopic nephrectomy a possible choice (17). in addition, this procedure is safer, with less complication especially in patients with other comorbidities. on the other hand, the patient has only one functional kidney. various surgical techniques exist for the management of ureteral avulsion. art is a medical intervention, which can be both beneficial and harmful. medical expertise is required, and its use should be implemented when conventional therapeutic methods have already been considered. the reason, time and type of surgery are very important for the clinical outcome of the patient. thus, all types of management can be considered both right and wrong, depending on the final clinical outcome. art is a challenge. references 1. hardy jd, eraslan s. autotransplantation of the kidney for high ureteral injury. j urol. 1963; 90:563-574. 2. vrakas g, sullivan m. current review of renal autotransplantation in the uk. curr urol rep. 2020; 21:33. 3. liu lh, chen z, xiong yy, et al. clinical application of renal autotransplantation in complex urological disease]. zhonghua yi xue za zhi. 2019; 99:907-911. 4. moulavasilis n, katafigiotis i, staios d, et al. renal autotransplantation: a final option to preserve the kidney after an iatrogenic ureteral injury. arch ital urol androl. 2020; 91:263-264. 5. cornelis t, odutayo a, keunen j, hladunewich m. the kidney in normal pregnancy and preeclampsia. semin nephrol. 2011; 31:4-14. 6. kattah a. preeclampsia and kidney disease: deciphering cause and effect. curr hypertens rep. 2020; 22:91. 7. deshpande na, james nt, kucirka lm, et al. pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis. am j transplant. 2011; 11:2388-2404. 8. van buren mc, schellekens a, groenhof tkj, et al. long-term graft survival and graft function following pregnancy in kidney transplant recipients: a systematic review and meta-analysis. transplantation. 2020; 104:1675-1685. 9. sibanda n, briggs jd, davison jm, et al. pregnancy after organ transplantation: a report from the uk transplant pregnancy registry. transplantation. 2007; 83:1301-1307. 10. sevinc c, balaban m, ozkaptan o, et al. the management of total avulsion of the ureter from both ends: our experience and literature review. arch ital urol androl. 2016; 88:97-100. 11. kocot a, kalogirou c, vergho d, riedmiller h. long-term results of ileal ureteric replacement: a 25-year single-centre experience. bju int. 2017; 120:273-279. 12. dagash h, sen s, chacko j, et al. the appendix as ureteral substitute: a report of 10 cases. j pediatr urol. 2008; 4:14-19. 13. xiong s, wang j, zhu w, et al. onlay repair technique for the management of ureteral strictures: a comprehensive review. biomed res int. 2020; 2020:6178286. 14. zhao lc, yamaguchi y, bryk dj, et al. robot-assisted ureteral reconstruction using buccal mucosa. urology. 2015; 86:634-638. 15. arora s, campbell l, tourojman m, et al. robotic buccal mucosal graft ureteroplasty for complex ureteral stricture. urology. 2017; 110:257-258. 16. zagoria rj, dyer rb. do's and don't's of percutaneous nephrostomy. acad radiol. 1999; 6:370-377. 17. ordon m, schuler td, honey rj. ureteral avulsion during contemporary ureteroscopic stone management: "the scabbard avulsion". j endourol. 2011; 25:1259-1262. correspondence christos damaskos, md, msc, phd (corresponding author) x_damaskos@yahoo.gr renal transplantation unit, laiko general hospital & n.s. christeas laboratory of experimental surgery and surgical research, medical school, national and kapodistrian university of athens; 17 agiou thoma street, athens, 11527 (greece) nikolaos garmpis, md, msc, phd n.s. christeas laboratory of experimental surgery and surgical research, medical school, national and kapodistrian university of athens & second department of propedeutic surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens, (greece) konstantinos nikolettos, md obstetric and gynecologic clinic, medical school, democritus university of thrace, alexandroupolis, (greece) alexandros patsouras, md n.s. christeas laboratory of experimental surgery and surgical research, medical school, national and kapodistrian university of athens, athens (greece) dimitrios schizas, md, phd, assistant professor of surgery first department of surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens (greece) anna garmpi, md first department of propedeutic internal medicine, laiko general hospital, medical school, national and kapodistrian university of athens, athens (greece) vasiliki e. georgakopoulou, md department of pulmonology, laiko general hospital, athens (greece) athanasios syllaios, md first department of surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens (greece) dimitrios dimitroulis, md, msc, phd, professor of surgery second department of propedeutic surgery, laiko general hospital, medical school, national and kapodistrian university of athens, athens (greece) archivio italiano di urologia e andrologia 2021; 93, 158 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.58 groups that were treated early since 1 month after surgery by different drugs: intracorporeal injection (ici), phosphodiesterase inhibitor (pde5i) and a combination of both drugs. the objective of this study was to assess the erectile function (ef) in different subgroups of patients who were treated early postoperatively by comparing the preoperative ‘’international index of erectile function (iief) questionnaire’’ results with postoperative results to test the effect of early rehabilitation strategy on erectile dysfunction. there is no evidence in the current literature regarding sexual function recoverability after rc focusing and, in particular, early rehabilitation strategy of erectile function and its effect on other domains of male sexual function (orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) in the nonnerve and nerve sparing group of patients by passing the early phase of recovery. material and methods study design & participants this study was a randomized, double-blinded, clinical trial that evaluated the role of early pharmacologic therapy for the treatment of erectile dysfunction post rc. between february 2014 and 2019, 160 potent male patients with non-metastatic invasive bladder cancer who were operated with radical cystectomy were included in the study. patients were divided into 4 different groups: group a including 40 patients who received no treatment. group b including 40 patients who were treated by intracorporeal injection (ici) of prostaglandin e1 (pge1) at a dosage of 20 micrograms 2 times per week) after one month of surgery to 1 year. group c including 40 patients who were treated by ici+pde5-i after one month of surgery to 1 year. group d including 40 patients who were treated by pde5i: sildenafil, 50 mg after one month of surgery to 1 year. the patients were randomly allocated to each group based on the type of surgery performed. in each group, 20 patients were operated using the nerve sparing (ns) technique and 20 other patients operated using the nonobjectives: no clinical studies testing erectile function (ef) post radical cystectomy (rc) were done. our objective was to assess the effect of early pharmacologic therapy after rc using intracorporeal injection (ici), phosphodiesterase inhibitor (pde5i) and pde5i+ici. materials and methods: in our randomized, double-blinded study, we prospectively enrolled 160 potent male patients with invasive bladder cancer. patients were operated by rc using the nerve-sparing (ns) or non-nerve sparing (nns) technique. they were treated since 1 month postoperatively by different regimens (pde5i vs. ici vs. ici+pde5i). patients were evaluated using the international index of erectile function questionnaire and were followed up regularly at 1, 3, 6, and 12 months using the same parameters. results: one month after therapy, the mean of ef domain improved in both ns and nns group. in the nns group, in patients treated with ici alone and ici+pde5i, the ef domain at 12 months moved to the moderate and to the mild category respectively. in patients treated by the ns approach, the mean value remained in the mild category with or without therapy. conclusions: early pharmacotherapy since one-month post rc using ici and a combination of ici+pde5i can improve the erectile function of patients operated with a nns approach. key words: erectile dysfunction; early rehabilitation; radical cystectomy; nerve-sparing; non nerve-sparing. submitted 21 september 2020; accepted 27 october 2020 introduction radical cystectomy (rc) remains the standard of therapy for high-grade invasive bladder cancer and some categories of superficial bladder cancer (1). sexual dysfunction after rc may be related to multiple factors including surgical trauma to the neurovascular bundle, psychological stress, and type of urinary diversion. rc with urinary diversion significantly affects sexual functioning. the recovery percentage of the erectile function was 49% at 3 years and 79% at 5 years (2, 3). we performed a prospective study testing the erectile function of 160 potent males operated by rc with nerve-sparing and none-nerve sparing technique, dividing them into erectile dysfunction post radical cystectomy. the role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: a randomized, clinical trial summary mohamad moussa 1, athanasios g. papatsoris 2, mohamed abou chakra 3, athanasios dellis 4 1 urology department, zahraa hospital, university medical center, beirut, lebanon; 2 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece; 3 faculty of medical sciences, department of urology, lebanese university, beirut, lebanon; 4 department of urology/general surgery, areteion hospital, athens, greece. 59archivio italiano di urologia e andrologia 2021; 93, 1 erectile dysfunction post radical cystectomy nerve sparing (nns) technique. all patients included in the study fulfilled the following criteria: potent male, sexually active, tumors muscle invasive t3 or less (t2a, t2b, t1high grade), n0, m0, age 45-69, not receiving neoadjuvant chemotherapy. the patients and treating clinicians were blinded to the treatment allocation. follow up visits were noted by another urologist within the same department. sample size based on previous studies, the difference in the mean change in the iief score between the two groups (ns and nns) was 11.7. we conservatively set this value as 11. when a two-tailed test with a test power of 90% and a significance level of 5% was used, 80 patients are required in each group. for 4 treatment subgroups, the total sample size required for this study was estimated to be 160 patients. study intervention the same urologist performed the rc+ ileal conduit (90 patients) or neobladder (70 patients) with or without nerve sparing technique. rc was done with preservation of the neurovascular bundles as described by walsh (5). three groups of patients were treated since one month post operatively with pde5i, ici, pde5i+ici for a period of 1 year where they were followed. the study was performed at zahraa hospital, university medical center in beirut which is an academic, tertiary care hospital with 300 beds. the urology department contains 22 beds; it is staffed by 8 urologists. the study was approved by our institutional review board. our study adheres to consort guidelines. descriptive tables of means and standard deviations were computed for different combinations. outcome measurements erectile function was assessed by iiefscore before and after surgery at 1, 3, 6, 12 months postoperatively. preoperative ef was tested using the iief questionnaire (4). the degree of the erection was categorized on the basis of the ef domain (six questions regarding ef) of iief questionnaire and classified as mild ed (score 1725), moderate ed (score 11-16), or severe dysfunction (score < 10); patients with score > 26 were considered as not having erectile dysfunction. ethics statement the study was approved by our hospital irb (approval no. 2014.12). informed consent was confirmed by the irb. written informed consent was obtained from each participant. statistical analysis statistical analyses for estimated marginal means were performed using a mixed anova with repeated measures. this test determines the interactions between dependent and independent variables. a mixed anova with repeated measures was run on a sample of 160 patients to examine the effect of the treatment group of 4 levels (no therapy, pde5-i, ici, ici+pde5-i), the type of surgery of 2 levels (ns and nns) and the time points of assessment of 5 levels (preoperatively time, 1 month postoperatively, 3 months postoperatively, 6 months postoperatively, 12 months postoperatively) (3 independent variables) on the erectile function. the normal distribution and the homogeneity of variances assumptions for each combination of the groups were checked using respectively the shapiro-wilk tests of normality and the levene's test of equality of error variances. the data was processed using the statistics software spss (statistical package for social sciences) version 19.0. a p value of 0.05 was considered statistically significant. results table1 summarizes the clinicopathologic characteristics of the patients from which reported data were obtained. median patient age in the ns group was 62 vs. 61 in nns group and both groups had the same comorbidities. orthotopic neobladder was performed for 70 patients (45 patients in the ns group and 25 patients in the nns group). ileal conduit urinary diversion was performed in 90 patients (35 of them in the ns group and 55 others in the nns group). the mean preoperative ef domain in nns group was 20.7 wherein in ns group was 21.4. after 1 month it was 6 in nns group wherein in ns group was 9.8 (severe erectile dysfunction). the mean values of ef domains differed in each subgroup of the 2 major groups (ns vs. nns). after 1 month from surgery, nns groups with no therapy, pde5i, ici and ici+pde5 i showed all the same value of 6. in ns groups with no therapy, pde5i, ici and ici+pde5 i subgroup mean value was 12.5, 10.5, 9 and 7.5 respectively. the mean value of ef domains in nns group remained the same with no therapy and pde5i at 3, 6, 12 months with a value of 6, whereas in the ici subgroup it increased to 13.5 at 4 months remaining constant at 6 and 12 months and in the ici+pde5i association, it increased the mild range of 18 at 12 months. the mean of ef domains in ns group increased to become in all subgroups in the mild range. those results are illustrated in details in table 2. when assessing the difference of means between treatment subgroup, we found only a statistical significance (p < 0.05) when comparing the pde5i subgroup with other treatment subgroups (ici, ici+pde5i), where no statistical significance was found when comparing ici table 1. clinicopathologic characteristics and comorbidities of the ns and nns group. ns nns pt 1 hg 25 31 t2a 21 20 t2b 19 9 t3a 15 20 hypertension 20 33 diabetes 13 10 ns: nerve-sparing; nns: non nerve sparing; hg: high grade. archivio italiano di urologia e andrologia 2021; 93, 1 m. moussa, a.g. papatsoris, m. abou chakra, a. dellis 60 vs. ici+pde5i. those results are illustrated in table 3. overall results demonstrated that means differ significantly according to the type of surgery, with 17.5 in ns to 1.72 in nns group (p < 0.001) . results of the treatment subgroups according to type of surgery are illustrated in figure 1. we also assessed the differences of each treatment subgroup according to the type of surgery. we found statistical differences in the nns group, when we compared no therapy with ici or ici+pde5i whereas no difference was noted when comparing no therapy with pde5i or comparing ici with ici+pde5i. we didn’t find any statistical significance in the ns group when comparing all the subgroups between them; those results are illustrated in table 4. discussion ed occurs frequently in patients operated by rc. walsh et al. demonstrated that injury to the neurovascular bundles may contribute to impotence following radical prostatectomy (rp) (5). based on those findings in 1984, walsh used a surgical technique that preserves the branches of the pelvic plexus for the preservation of potency and this technique was called a nerve-sparing technique (6). different sexual-preserving techniques have been described with a different effect on functional and oncological outcomes. the potency rates of capsule sparing cystectomy vs. nerve-sparing cystectomy were not significantly different (50% vs. 40%) as reported by jacobs et al. (7). a study conducted by colombo et al. evaluating 3 techniques of nerve sparing cystectomy showed a significant difference in sexual function preservation using the capsule sparing and seminal vesicle sparing vs. nerve sparing (91.6% vs. 84.25 vs 28.5%) but this study was limited due to a low number of patients operated (8). however, those techniques might be not oncologically safe with high metastasis rate (9). in addition, around half of the cystectomy specimens may contain urothelial carcinoma; cancer control may be compromised by leaving a part of the prostate in the capsule sparing technique (10). therefore, both nerve-sparing cystectomy and prostate capsule sparing cystectomy appear to offer better urinary and sexual function in properly selected patients. more randomized clinical trials are necessary to use those techniques safely in bladder cancer era. several studies reported that the recovery of erectile function after nerve-sparing radical cystoprostatectomy is around 30% to 80% of cases (2, 3, 11, 12). table 2. mean of erectile function domains in the ns and nns group divided into treatment subgroups. treatment subgroup type of surgery none pde5-i ici ici+pde5-i ef_preop nns 20.7 ± 2.9 22 ± 2.2 19.5 ± 3 20.5 ± 2.9 21 ± 3.5 ns 21.45 ± 2.8 24 ± 1.4 21.3 ± 3.2 21 ± 3.6 19.5 ± 3 1 month postop nns 6 ± 0 6 ± 0 6 ± 0 6 ± 0 6 ± 0 ns 9.8 ± 3.2 12.5 ± 3.3 10.5 ± 3.1 9 ± 3.5 7.5 ± 3 3 months postop nns 10.3 ± 1.4 6 ± 0 6 ± 0 13.5 ± 3 15.8 ± 2.6 ns 10.3 ± 3.3 14.3 ± 2.2 14.5 ± 5.7 18.8 ± 4.9 17.5 ± 0.6 6 months postop nns 10.7 ± 0.9 6 ± 0 6 ± 0 13.5 ± 3 17.3 ± 0.9 ns 19.1 ± 3.6 17 ± 4.9 18.3 ± 4.5 21.8 ± 2.6 19.3 ± 2.5 12 months postop nns 10.8 ± 1.1 6 ± 0 6 ± 0 13.5 ± 3 18 ± 1.6 ns 20.9 ± 2.9 19.5 ± 3.1 19.8 ± 2.9 22 ± 2.7 22.3 ± 2.9 pde5-i: phosphodiesterase inhibitor; ici: intracavernosal injection; ef: erectile function; ns: nerve–sparing; nns: non nerve-sparing; post op: post operative period. table 4. direct erectile function domain comparison between patient’s subgroups according to the type of surgery. type of treatment treatment mean mean mean p-value surgery subgroup 1 (g1) subgroup 2 (g2) g1 g2 difference (g1-g2) nns none pde5-i 9.2 8.7 0.5 1 ici 13.4 -4.2 0.039* ici+pde5-i 15.6 -6.4 0.001* pde5-i ici 8.7 13.4 -4.7 0.016* ici+pde5-i 15.6 -6.9 < 0.0001* ici ici+pde5-i 13.4 15.6 -2.2 0.8 ns none pde5-i 17.45 16.85 0.6 1 ici 18.5 -1.05 1 ici+pde5-i 17.2 0.25 1 pde5-i ici 16.85 18.5 -1.65 1 ici+pde5-i 17.2 -0.35 1 ici ici+pde5-i 18.5 17.2 1.3 1 ns: nerve-sparing; nns: non nerve-sparing; pde5-i: phosphodiesterase inhibitor; ici: intracavernosal injection; none: patients not given any treatment. figure 1. two-way interactions for erectile function domain: treatment subgroups × type of surgery. table 3. mean of erectile function domains compared between treatment subgroups. treatment treatment mean mean mean p-value subgroup 1 (g1) subgroup 2 (g2) g1 g2 difference (g1-g2) none pde5-i 13.325 12.775 0.55 1 ici 15.95 -2.625 0.09 ici+pde5-i 16.4 -3.075 0.03* pde5-i ici 12.775 15.95 -3.175 0.02* ici+pde5-i 16.4 -3.625 0.008* ici ici+pde5-i 15.95 16.4 -0.45 1 pde5-i: phosphodiesterase inhibitor; ici: intracavernosal injection; none: patients not giving any treatment. 61archivio italiano di urologia e andrologia 2021; 93, 1 erectile dysfunction post radical cystectomy there is a clear correlation between the age of the patient when operated and the erectile function recovery following nerve-sparing cystectomy as demonstrated by schoenberg et al., who showed that the recovery rate of sexual function was the lowest in men 70-79 year old after 10 years of experience with nerve-sparing radical cystectomy (13). younger age was associate with better sexual function after radical cystectomy then older patients (14-16). impotence and lack of sexual desire were related to radical radiotherapy for bladder cancer with only 34% male patients sexually active after radiation therapy (17). the type of urinary diversion influence also the sexual activity after surgery where patients with ileal conduit diversion reported more erectile dysfunction (18, 19). due to the lack of studies addressing the best treatment for erectile dysfunction post radical cystectomy, the response to oral therapy was extrapolated from series on post prostatectomy erectile dysfunction management, where sildenafil is considered an effective treatment after radical retropubic prostatectomy when both neurovascular bundles have been preserved with response rate after nerve-sparing approach reaching 80% (20, 21). cavernous smooth muscle apoptosis is one mechanism of impotence as tested in multiple experimental studies. apoptosis of smooth muscle in the rat penis was more significant after bilateral neurectomy vs. unilateral neurectomy (22, 23). prostaglandin e1 and pde5i, if given in the early postoperative period could improve erections by providing intracavernosal oxygenation and limiting fibrosis within the corpora cavernosa (24). pde5i, if used as part of the early penile rehabilitation therapy after rp, could preserve intracorporeal smooth muscle content (25). also, it had been shown that early use of pde5i decreased the numbers of apoptotic cells and prevented apoptotic cell death in the penis following denervation (26). zippe et al. demonstrated that sildenafil citrate cannot improve significantly erectile dysfunction after radical cystectomy: out of 22 patients taking sildenafil citrate post-surgery, only 2 (9%) responded positively (18). a study assessing the optimal time for intracavernous prostaglandin e1 administration after non-sparing rp found that early use of prostaglandin injection since 1 month postoperatively could promote the best response but increased the complication rate (27). montorsi et al. conducted a study evaluating the early intracavernous injections of alprostadil after nerve-sparing rp. they reported that early injections after 6 months of follow up induced a significant improvement of the spontaneous erections where 67% of the group treated by early intracavernous aplrostadil injection recovered sufficient spontaneous erections for sexual intercourse (28). padma-nathan et al. demonstrated that early administration of sildenafil since one month after bilateral nervesparing rp may help in spontaneous erectile function recovery (29). cavernous neurotomy may cause cavernous fibrosis and dysfunction by increasing expression of tgf-b1, and collagen i and iii protein. this may explain why patients operated by nerve-sparing approach may respond partially to pharmacologic therapies for erectile dysfunction. some new techniques using intraoperative cavernous nerve stimulation may help in nerve preservation surgeries although those techniques need more investigations (30). there is widespread usage of vacuum therapy (vt) as part of the penile rehabilitation after rp. the underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections (31). yuan et al. assessed the effects of vt on erectile dysfunction (ed) in a rat model of bilateral cavernous nerve crush (bcnc) demonstrating that ef was improved with vt. vt reduced hypoxia-inducible factor-1a (hif1a) expression and apoptotic indices (ai) significantly compared with control. animals exposed to vt had decreased transforming growth factor beta 1 (tgf-b1) expression, increased smooth muscle/collagen ratios (32). a web-based survey of members of the international society for sexual medicine (issm) and its regional affiliates was performed to assess their practice pattern of post-rp pharmacological penile rehabilitation. as part of the primary rehabilitation strategy post rp, 30% of responders used vacuum device, 95% pde5i and 75% used ici (33). in a pilot study, it was demonstrated that initiating the use of a vt protocol at 1 month after rp improves early sexual function and helps to preserve penile length (34). studies have shown that vacuum erectile device therapy improves erectile function in 8495% of patients and it is suggested that penile rehabilitation with vt should begin early after rp (35). the post-rp ed depends on several factors, including patient age, preoperative potency status (baseline ef) and comorbidities (36). preoperative potency is of utmost importance, since patients who complain of some degree of ed or patients who already use pde5-is prior to surgery are at higher risk of developing severe ed postoperatively, regardless of the surgical technique used (37). the main goals of prostate capsule sparing cystectomy are to improve erectile function. eleven published series of prostate sparing cystectomy report 80% or greater rates of potency preservation, and 6 describe 90% or greater preservation (38). jacobs et al. performed a singleinstitution trial of bladder cancer patients. no significant difference in functional results were found in men randomized to prostate capsule sparing or nerve-sparing cystectomy with neobladder creation. mertens et al. reported a 20-year single-center experience of prostate sparing cystectomy for bladder cancer showing that erectile function was intact in 89.7% of patients (39). back to our results, the mean of ef domain after 1 month of surgery was in the category of severe erectile dysfunction in both group ns and nns, when the treatment was started after 1 month. the mean value improved in both groups to become at 12 months in the moderate and mild categories in patient treated with ici and ici+pde5i in the nns group. in other hands, in patients treated by the ns approach, the mean was in the mild category when they were treated by ici or ici+pde5i or in the group not taking any drug. it is important to note that there was no difference between group not given any drug and pde5i therapy alone in both groups (ns vs. nns). it means that early therapy archivio italiano di urologia e andrologia 2021; 93, 1 m. moussa, a.g. papatsoris, m. abou chakra, a. dellis 62 with pde5i alone may be not effective in the early phase of erectile function recovery. it is also necessary to mention that in the nns group the mean improve to mild category if ici and pde5i were associated together and used early post-surgery. it is critical to note the ns group results, showing that the mean of ef domain improved after 12 months to become in the same category in all subgroups, we cannot conclude if this improvement is due to early postoperative aid or related to neuropraxia phenomenon described previously. in the absence of studies assessing erectile dysfunction post cystectomy in both groups (ns vs. nns), our results were discussed in front of those obtained in radical prostatectomies patients. the current study was limited by the methodology used to assess the erectile dysfunction. in fact, patients were evaluated using the international index of erectile function (iief) score only along a short period of follow up. conclusions erectile dysfunction is common after radical cystectomy surgery; it has a great impact on the quality of life of patients. early rehabilitation plans using pharmacotherapy since one month after surgery with ici and a combination of ici+pde5i can improve erectile function in patients operated with non-nerve sparing approach but not with nerve sparing approach. an early rehabilitative strategy with pharmacotherapy may be offered to patients undergoing a non nerve-sparing procedure in order to enhance the recovery of erectile function and improve all other domains. more studies addressing the early rehabilitative strategy of none nerve-sparing radical cystectomies are needed to confirm our findings. references 1. stein jp, skinner dg. results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. bju int. 2003; 92:12-7. 2. schlegel pn, walsh pc. neuroanatomical approach to radical 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cystectomy in a sexually active population. urology. 2004; 64:682-685. 19. hobisch a, tosun k, kinzl j, et al. quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.world j urol. 2000; 18:338-44. 20. zagaja gp, mhoon da, aikens je, brendler cb. sildenafil in the treatment of erectile dysfunction after radical prostatectomy. urology. 2000; 56: 631-634. 21. zippe cd, jhaveri fm, klein ea, et al. role of viagra after radical prostatectomy. urology. 2000; 55:241-245. 22. user hm, hairston jh, zelner d, et al. penile weight and cell subtype specific changes in a postradical prostatectomy model of erectile dysfunction. j urol. 2003; 169:1175-1179. 23. klein lt, miller mi, buttyan r, et al. apoptosis in the rat penis after penile denervation j urol. 1997; 158:626-630. 24. r. wang. penile rehabilitation after radical prostatectomy: where do we stand and where are we going? j sex med. 2007; 4:1085-97. 25. schwartz ej, wong p, graydon rj. sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. j urol. 2004; 171:771-4. 26. la vignera s, condorelli r, d'agata r, et al. dysfunction of the endothelial-platelet pathway in patients with erectile dysfunction before and after daily treatment with tadalafil. andrologia. 2012; 44:152-156. 63archivio italiano di urologia e andrologia 2021; 93, 1 erectile dysfunction post radical cystectomy 27. gontero p, fontana f, bagnasacco a, et al. is there an optimal timing for intracavernous pge1 rehabilitation following nonnerve sparing radical prostatectomy results from an hemodynamic perspective study j urol. 2003; 169:2166-2169. 28. montorsi f, guazzoni g, strambi lf, et al. recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomised trial. j urol. 1997; 158:1408-1410. 29. padma-nathan e, mc cullough, ar, giuliano f. postoperative nightly administration of sildenafil citrate significantly improves the return of normal spontaneous erectile function after bilateral nervesparing radical prostatectomy. j urol. 2003; 4(suppl):375. 30. klotz l. cavernosal nerve mapping: current data and applications. british journal of urology international. 2004; 93:9-13. 31. yuan j, hoang an, romero ca, et al. vacuum therapy in erectile dysfunction--science and clinical evidence int j impot res. 2010; 22:211-9. 32. yuan j, lin h, li p, et al. molecular mechanisms of vacuum therapy in penile rehabilitation: a novel animal study. eur urol. 2010; 58:773-80. 33. teloken p, mesquita g, montorsi f, mulhall j. post-radical prostatectomy pharmacological penile rehabilitation: practice patterns among the international society for sexual medicine practitioners. j sex med. 2009; 6:2032-8. 34. köhler ts, pedro r, hendlin k, et al. a pilot study on the early use of the vacuum erection device after radical retropubic prostatectomy. bju int. 2007; 100:858-62. 35. lin h, wang r. the science of vacuum erectile device in penile rehabilitation after radical prostatectomy. transl androl urol. 2013; 2:61-66. 36. saleh a, abboudi h, ghazal-aswad m, et al. management of erectile dysfunction post-radical prostatectomy. res rep urol. 2015; 7:19-33. 37. gallina a, salonia a, briganti a, et al. prevention and management of postprostatectomy erectile dysfunction. eur urol supplements. 2009; 8:80-7. 38. klotz l. prostate capsule sparing radical cystectomy: oncologic safety and clinical outcome. ther adv urol. 2009; 1:43-50. 39. mertens ls, meijer rp, de vries rr, et al. prostate sparing cystectomy for bladder cancer: 20-year single center experience. j urol. 2014; 191:1250-5. correspondence mohamad moussa, md mohamadamoussa@hotmail.com urology department, zahraa hospital, university medical center, beirut (lebanon) athanasios g. papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens (greece) mohamed abou chakra, md (corresponding author) mohamedabouchakra@hotmail.com faculty of medical sciences, department of urology, lebanese university, beirut, (lebanon), 1108 athanasios dellis, md aedellis@gmail.com department of urology/general surgery, areteion hospital, athens (greece) stesura seveso 169archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. refractory luts, and transurethral resection of the prostate (turp) is the procedure of choice for the majority of men with bph/luts, especially for prostate volumes between 30 and 80 ml (1). despite all the technological and technical improvements since the initial turp descriptions almost a century ago (3), there is still controversy regarding the need for a complete prostatic tissue resection. although some literature recommends a total removal of the adenomatous tissue (4), a relevant body of research supports the thesis that a complete adenoma resection may not be essential, with similar post-operative results with or without it (6). similarly, a relationship between the amount of resected prostate and the outcomes of the surgery has been pursued, yet no correlation has been found between these two variables, neither in smaller (< 40 g) nor in larger (> 40 g) prostates (6). turp is especially effective when bladder outlet obstruction (boo) due to benign prostatic obstruction (bpo) is the main cause for the patient’s luts. a satisfactory surrogate marker for the severity of boo may however be obtained with urinary flow rate studies, as stated by the sirokyliverpool nomograms, in which maximum flow rate (qmax) and bladder volume are used to predict boo (7). furthermore, a recent randomized controlled trial was not able to prove a benefit in performing urodynamic studies in men with luts, since surgical treatment was necessary in around 37% of patients irrespectively of performing urodynamic studies (8). although considered a safe procedure, sexual side effects after turp are still an important issue, with 60-70% of patients reporting retrograde ejaculation, and up to 6.5% complaining of erectile dysfunction (9). other side effects include early urge-incontinence, even though late stress incontinence is rare (0.5%) (10). in recent years, new approaches to turp have been developed, aiming at the reduction of morbidity while maintaining the benefits of the procedure. in that regard, ejaculation preserving techniques are a promising development, with reports of antegrade ejaculation at 3 months post-op in around 90% of patients undergoing ejaculation preserving turp (epturp), with symptomatic and functional outcomes similar to the classic technique (11, 12). a vaporization technique using laser (lest) has also been described, with antegrade ejaculation maintained in up to 80% of objectives: transurethral resection of the prostate (turp) remains one of the goldstandard surgical treatments for benign prostatic hyperplasia/lower urinary tract symptoms. the usefulness of a complete adenoma resection is questionable, with studies reporting no impact of the amount of resected tissue on surgical outcomes, irrespective of prostate volume. the aim of this study was to assess whether in less obstructed patients a less extensive turp may be considered. materials and methods: retrospective analysis of 185 men undergoing turp in one university hospital. retrieved data included pre-operative prostate volume and qmax, as well as resected prostate weight and post-operative qmax. patients were divided in two groups according to pre-operative qmax < 10ml/s and ≥ 10 ml/s. results: a correlation was found between absolute resected prostate weight and post-operative qmax in the group of patients with pre-operative qmax < 10 ml/s (r2 = 0.038, p = 0.032), independently of the pre-operative prostate volume. this association was neither observed in the group of patients with pre-operative qmax ≥ 10 ml/s (r2 = -0.033, p = 0.796) nor in whole population analysis (r2 = 0.019, p = 0.064). likewise, in the group of patients with pre-operative qmax < 10 ml/s, the improvement in qmax was correlated with absolute resected weight and percentage of prostate resected weight (r2 = 0.036, p = 0.037 and r2 = 0.040, p = 0.029, respectively). none of these correlations was found in the group of patients with pre-operative qmax ≥ 10 ml/s (r2 = 0.009, p = 0.463 and r2 = -0.018, p = 0.294, respectively). conclusions: patients with pre-operative qmax ≥ 10 ml/s may do well with less profound prostate resections, whereas patients with lower pre-operative qmax seem to benefit from a complete adenoma resection. key words: transurethral resection of prostate; prostatic hyperplasia; lower urinary tract symptoms; adenoma; urologic surgical procedures. submitted 12 may 2022; accepted 27 may 2022 introduction benign prostatic hyperplasia (bph) is one of the most common causes of lower urinary tract symptoms (luts) in men. current international guidelines recommend a stepwise approach to the treatment of bph/luts (1). however, surgery remains the gold-standard in severe or prostate resection weight matters in severely obstructed men undergoing transurethral resection of the prostate filipe lopes 1, ricardo pereira e silva 1, 2, miguel fernandes 1, tito palmela leitão 1, 2, josé palma dos reis 1, 2 1 urology department, centro hospitalar universitário lisboa norte, lisbon, portugal; 2 urology university clinic, faculty of medicine, university of lisbon, portugal. doi: 10.4081/aiua.2022.2.169 summary archivio italiano di urologia e andrologia 2022; 94, 2 f. lopes, r. pereira e silva, m. fernandes, t. palmela leitão, j. palma dos reisa 170 patients (13). to our knowledge, no diagnostic feature has been firmly established as a predictor for turp outcomes. however, the results of this procedure are heterogenous, with studies reporting a failure in symptomatic relief in around 12% of patients (14), raising the possibility that such predictors exist, at least for some patients. these may nevertheless be statistically concealed in the published studies, due to the analysis of the studied populations as a whole, irrespective of important factors such as boo severity (5). therefore, the aim of this study is to analyze whether pre-operative boo severity may affect a possible influence of prostate resected weight in turp outcomes. methods we conducted a retrospective analysis of patients submitted to turp in a university hospital between february 2011 and november 2015. exclusion criteria were previous luts surgery, prostate cancer, urethral stricture or voided volumes < 125 ml in uroflowmetry. pre-operative data was retrieved, including clinical history, comorbid conditions, medications, uroflowmetry and prostate volume (determined by transrectal ultrasound). post-operatively, weight of the resected dry specimen and post-operative uroflowmetry values were considered. as a second measure of depth of resection, and in order to evaluate a possible influence of pre-operative prostate size, a ratio between the absolute resected prostate weight and prostate volume measured via ultrasound was calculated, henceforth referred to as “percentage of resected weight”. all patients were diagnosed with bph/luts refractory to medical treatment with alfa-blockers and/or 5-alfa reductase inhibitors (5-ari). surgery was performed by 5 different urologists using monopolar or bipolar standard 26french resectoscopes (karl storz®), depending on surgeon preference. the resected tissue underwent fixation with formalin 10% and was weighted using precision scales in the pathology laboratory before routine histologic analysis. bladder catheters were removed 2 to 3 days after the procedure and the patients discharged following spontaneous micturition. post-operative uroflowmetry was performed 4-6 weeks after surgery. patients were stratified in two groups according to preoperative qmax, following the siroky-liverpool nomograms, which define a cut-off value of 10 ml/s as a very strong predictor of boo (≤ 2 standard deviations of the mean for a voided volume ≥ 125 ml) (7, 15). the first group was comprised of patients with pre-operative qmax < 10 ml/s, and the second included patients with preoperative qmax ≥ 10 ml/s. statistical analysis was performed using non-parametric tests as appropriate (given the non-normality of the distributions as determined by kolmogorov-smirnov tests) with ibm spss® 27.0. since the present study was performed in a retrospective fashion, no informed consent was required. complete anonymity of all patients was, however, ensured. results a total of 185 patients were included, with a mean age of 58.5 (± 7.2) years and a mean preand post-operative qmax of 8.8 ± 3.6 and 14.9 ± 7.2 ml/s, respectively. the mean change in qmax after surgery was 6.2 ± 7.1 ml/s. other demographic and clinical characteristics are displayed in table 1. in the whole sample analysis, no statistically significant correlations were found between absolute resected prostate weight or percentage of resected weight and post-operative qmax (r2 = 0.019, p = 0.063 and r2 = 0.019, p = 0.064, respectively). similarly, the pre/post-operative difference in qmax showed no correlation with the resection weight (r2 = 0.006, p = 0.290) or the percentage of resected prostate weight (r2 = 0.006, p = 0.283). when stratifying patients into two groups according to pre-operative qmax < 10 ml/s (n = 121) and ≥ 10 ml/s (n table 1. patient characteristics. mean ± sem median ± iqr range age (y) 58.5 ± 0.53 59 ± 9 37-77 prostate volume (ml) 51.78 ± 1.13 50 ± 22.5 25.0-103.0 uroflowmetry qmax pre-op (ml/s) 8.78 ± 0.26 8.3 ± 5 2.0-18.0 post-op (ml/s) 14.9 ± 0.53 14 ± 10.3 2.0-45.0 difference (ml/s) 6.2 ± 0.52 5.6 ± 9 -7.2-34.8 resected weight (g) 7.7 ± 0.40 6 ± 5.5 0.4-28.0 prw (%) 15.2 ± 0.74 13 ± 11.5 1.0-54.0 frequency comorbid conditions diabetes mellitus (n %) 16 (8.8) neurologic disease (n %) 8 (4.3) previous aur (n %) 14 (7.7) medications anti-cholinergic (n %) 8 (4.4) alfa-blocker (n %) 170 (92.9) 5-ari (n %) 115 (62.8) sem: standard error of the mean; iqr: interquartile range; prw: percentage of resected weight; aur: acute urinary retention; 5-ari: 5-alfa reductase inhibitor. table 2. group characteristics comparison. pre-operative qmax n = 121 < 10 ml/s ≥ 10 ml/s p-value (n = 121) (n = 64) age (y) mean (sem) 59.0 (2.7) 57.5 (2.6) 0.097† prostate volume (ml) mean (sem) 51.4 (4.0) 52.4 (3.8) 0.540† uroflowmetry qmax pre-op (ml/s) mean (sem) 6.6 (1.4) 12.8 (1.5) 0.000† post-op (ml/s) mean (sem) 14.3 (2.7) 16.2 (2.6) 0.028† difference (ml/s) mean (sem) 7.7 (2.5) 3.4 (2.3) < 0.001† resected weight. g. mean (sem) 7.5 (2.4) 8.0 (2.1) 0.106† prw. %. mean (sem) 14.8 (3.2) 16.0 (3.1) 0.109† comorbid conditions diabetes mellitus (n %) 9 (7.4) 7 (10.9) 0.432‡ neurologic disease (n %) 5 (4.1) 3 (4.7) 0.860‡ previous aur (n %) 9 (7.4) 5 (7.8) 0.928‡ medications anti-cholinergic (n %) 3 (2.5) 5 (7.8) 0.087‡ alfa-blocker (n %) 110 (90.9) 60 (93.8) 0.372‡ 5-ari (n %) 74 (61.2) 41 (64.1) 0.650‡ sem: standard error of the mean; prw: percentage of resected weight; aur: acute urinary retention; 5-ari: 5-alfa reductase inhibitor. †: mann-whitney test; ‡: chi-square test; significant differences are highlighted in bold. 171archivio italiano di urologia e andrologia 2022; 94, 2 turp resection weight matters = 64), no differences in demographic or clinical characteristics were found, with the exception of post-operative qmax and pre/post-operative difference in qmax (table 2). post-operative maximum flow was superior in patients with already higher pre-operative qmax (16.2 ml/s vs 14.3 ml/s, p = 0.028). both groups showed a significant increase in qmax post-operatively when compared to baseline maximum flow, although this increase was higher in the group with pre-operative qmax < 10 ml/s (7.7 ml/s vs 3.4 ml/s, p < 0.001). in the group of patients with pre-operative qmax < 10 ml/s, post-operative qmax was correlated with absolute resected prostate weight (r2 = 0.038, p = 0.032), as well as with percentage of resected prostate weight (r2 = 0.051, p = 0.013). in these patients, the difference in pre/postoperative qmax was also strongly associated with absolute resected prostate weight (r2 = 0.036, p = 0.037) and percentage of resected prostate weight (r2 = 0.040, p = 0.029) (figures 1, 2). neither of the above-mentioned correlations were established in the group of patients with pre-operative qmax ≥ 10 ml/s. absolute resected prostate weight and percentage of resected prostate weight were not associated with post-operative qmax (r2 = -0.033, p = 0.796 and r2 = -0.009, p = 0.458, respectively), nor with peri-operative change in qmax (r2 = 0.009, p = 0.463 and r2 = -0.018, p = 0.294, respectively) (figures 1, 2). discussion although many new techniques have evolved in recent years regarding the surgical management of bph/luts, turp remains as the gold-standard surgical therapy in most men with prostatic volume between 30-80 ml (16). however, the extension of adenoma resection is under debate, since some studies reported similar outcomes between complete and partial adenoma resection (6). the outcome of surgical treatment of bph depends on many factors, both related and unrelated to the surgical procedure itself. recent studies analyzed the applicability of machine learning in predicting these outcomes (17). symptomatic relief achieved following turp is the prifigure 1. post-operative qmax (ml/s) per absolute resected weight in patients with pre-operative qmax < 10 ml/s and ≥ 10 ml/s. figure 2. post-operative qmax (ml/s) per percentage of resected weight in patients with pre-operative qmax < 10 ml/s and ≥ 10 ml/s. archivio italiano di urologia e andrologia 2022; 94, 2 f. lopes, r. pereira e silva, m. fernandes, t. palmela leitão, j. palma dos reisa 172 mary goal of this procedure and is best measured through symptom scores, such as the international prostate symptom score (ipss). ipss was found to be correlated with other clinical parameters, such as qmax (18). preand post-operative improvement in uroflowmetry is therefore commonly used as an objective method for surgical effectiveness assessment (16). in agreement with previous studies, our analysis failed to find an association between the extension of adenoma resection and postoperative outcomes in the whole sample analysis. similarly to the present study, other reports explored the influence of pre-operative prostate volume in this correlation, yet no differences were noted (6). these studies concluded that post-operative clinical and symptomatic improvement was not impacted by the resected volume. the same conclusion was obtained through a different line of investigation. with the intent of avoiding sexual sideeffects of turp, recent surgical techniques have been developed, which include the epturp, in which pre and paracollicular tissue is spared (11). although not formally measured, the preservation of some prostatic tissue results in an expected decrease of resected weight. in the available literature, the outcomes (ipss, qmax, voided volume and post-void residual) of epturp are reported as similar to the classic technique, implying that an incomplete adenoma resection may be a viable option (12). however, further studies are necessary to confirm these results, especially since long-term surgical outcomes of this procedure are scarcely reported, with only one available study reporting favorable results at a follow-up of 60 months (11). although boo diagnosis may only be obtained through pressure/flow studies, maximum flow rate obtained via uroflowmetry is much more frequently used, due to its availability, reduced invasiveness and cost, when compared to urodynamic studies (19). furthermore, the recent upstream trial did not prove an advantage in performing urodynamic tests in men with bph/luts, showing similar surgery rates, as well as clinical outcomes in both arms of the study (8). while of unquestionable usefulness in certain patient groups, pressure/flow studies seem not to add value in the diagnostic process of the majority of non-neurogenic male luts, in which cases uroflowmetry might be enough to diagnose boo. in fact, sirokyliverpool uroflowmetry nomograms predict this condition with great efficacy using bladder volume and maximum flow rate. as stated by the authors, a qmax < 10 ml/s is a strong predictor of a clinically relevant boo for bladder volumes of 125 ml or higher (7). more recent investigations reported that around 90% of men with a severe boo (grade iii-vi schäfer classification (20, 21) had a qmax < 14 ml/s on uroflowmetry, whereas only 6% of all men with a low-grade boo (grade i-ii) had a qmax < 10 ml/s (22). furthermore, a recent study reported that men with qmax < 10 ml/s were more likely to develop an acute urinary retention episode (hazard ratio: 5.6) when compared to men with qmax ≥ 10 ml/s (23). this cut-off value was thus used to dichotomize between patients considered as severely obstructed (qmax < 10 ml/s) and patients with mild to moderate voiding dysfunction (qmax ≥ 10 ml/s). the influence of the extent of prostatic resection in turp outcomes has been the scope of some research. however, to our knowledge this is the first analysis of the influence of pre-operative qmax in this relationship. in fact, none of the above-mentioned studies could certify the presence of boo as a cause for luts, since none report urodynamic tests. therefore, it is possible that some patients in these analyses were actually not suffering from true boo. our analysis suggests that in patients with pre-operative qmax < 10 ml/s, a more thorough resection of the prostate is associated with better surgical outcomes. this association was not present in patients with pre-operative qmax ≥ 10 ml/s, although surgery was beneficial in both groups. as suggested by other authors, prostate initial volume could play a role in this relationship, since a larger amount of tissue may need to be resected in order to treat boo in larger rather than in smaller prostates. however, no such influence seems to exist, as the ratio between resected weight/prostate volume is similarly correlated with postoperative qmax only in the group of patients with preoperative qmax < 10 ml/s. similar findings were previously reported by another study (6). these results suggest that severely obstructed patients may profit from a complete adenoma resection. conversely, men with higher maximum flow rates may be good candidates for techniques with less morbidity, such as epturp. if further studies confirm our results, surgeons should be encouraged to adapt their turp technique to the patients’ pre-operative clinical details and expectations concerning surgical side effects, in a patient-tailored way. the present study has several limitations. first, the retrospective design may be a source of bias. second, we did not consider symptom scales such as ipss in our analysis, mainly due to a high level of missing data. even though previous studies proved a high correlation between maximum flow rate and ipss (18), luts grading and change after surgery would have been of great value in the analysis. another source of relevant information would be urodynamic studies, which in our center are not routinely performed to all men with bph/luts. furthermore, in our study, the resected prostate weight was measured in the pathology laboratory after fixation with formaldehyde, using precision scales. this fixation method results in a considerable reduction in specimen weight, and therefore this parameter, while valid for analysis within our studied group, is not directly comparable to previous studies (24). in conclusion, our analysis suggests that patients with preoperative qmax < 10 ml/s undergoing turp benefit from a complete adenoma resection, since resected prostate weight is directly correlated to post-operative qmax and pre/post-operative difference in qmax. the same does not apply for patients with pre-operative qmax ≥ 10 ml/s, in which post-operative qmax and qmax improvement after surgery are independent of resected prostate weight. our results suggest that men with higher pre-operative qmax may do well with less thorough prostate resections, potentially avoiding important side-effects of turp. references 1. gravas s, cornu jn, gacci m, et al. management of non-neurogenic male luts. in: eau guidelines. eau guidelines office; 2020. 2. parsons jk, dahm p, köhler ts, et al. surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline amendment 2020. j urol. 2020; 204:799-804. 173archivio italiano di urologia e andrologia 2022; 94, 2 turp resection weight matters 3. walker km. per-urethral operations for prostatic obstruction. br med j. 1925; 1:201-204. 4. milonas d, verikaite j, jievaltas m. the 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19. drake mj, doumouchtsis sk, hashim h, gammie a. fundamentals of urodynamic practice, based on international continence society good urodynamic practices recommendations. neurourol urodyn. 2018; 37:s50-s60. 20. schäfer w. analysis of bladder-outlet function with the linearized passive urethral resistance relation, linpurr, and a disease-specific approach for grading obstruction: from complex to simple. world j urol. 1995; 13:47-58. 21. d’ancona c, haylen b, oelke m, et al. the international continence society (ics) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. neurourol urodyn. 2019; 38:433-477. 22. boci r, fall m, waldén m, et al. home uroflowmetry: improved accuracy in outflow assessment. neurourol urodyn. 1999; 18:25-32. 23. chan ck, yip skh, wu iph, et al. evaluation of the clinical value of a simple flowmeter in the management of male lower urinary tract symptoms. bju int. 2012; 109:1690-1696. 24. lukacs s, vale j, mazaris e. difference between actual vs. pathology prostate weight in turp and radical robotic-assisted prostatectomy specimen. int braz j urol. 2014; 4:823-827. correspondence filipe lopes, md (corresponding author) filopes94@gmail.com ricardo pereira e silva, md ricardomanuelsilva7@gmail.com miguel fernandes, md mivafer@gmail.com tito palmela leitão, md titopleitao@gmail.com josé palma dos reis, md jpalmareis@campus.ul.pt serviço de urologia, hospital de santa maria avenida professor egas moniz 1649-035 lisboa, portugal archivio italiano di urologia e andrologia 2017; 89, 3178 original paper single plus one port robotic radical prostatectomy (sporp); initial experience volkan tugcu, abdulmuttalip simsek, ismail evren, kamil gokhan seker, ramazan kocakaya, bugra dogukan torer, arda atar, ali ihsan tasci department of urology, bakirkoy dr. sadi konuk training and research hospital, istanbul, turkey. objective: this article reports on patients with early stage prostate cancer treated with single plus one port robotic radical prostatectomy (sporp). materials and methods: since january 2014, we performed sporp in 8 patients with localized prostate cancer. age of patients, clinical stage, operation time, intraoperative and postoperative complications, blood loss, histopathological evaluation, postoperative continence, serum level of psa were evaluated. results: mean age of the 8 patients was 59.85 years. all operations were completed without conversion to standard robotic procedure or open surgery. no intra operative complications occurred. mean operating time was 143 minutes; prostate excision 123 minutes and urethrovesical anastomosis 20 minutes. mean blood loss was 45 ml. preoperative gleason scores were (3 + 4) in one patient and (3 + 3) in 7 patients. postoperative gleason scores were (3 + 4) in 2 patients, and (3 + 3) in 6 patients. all these 8 cases were in t1c clinical stage. early postoperative complications were drain leakage (n = 1), atelectasis (n = 1), wound infection (n = 1) and fever (n = 1). there was no positive surgical margin. the serum level of psa was less than 0.2 ng/ml and no other complications happened during the 4 to 12 months follow-up period. postoperative continence and cosmetic results were excellent. conclusions: it is relatively easy for urologists who are skilled in traditional laparoscopic and robotic surgeries to master sporp. however long-term outcomes of this surgery need further investigations. key words: single plus one port robotic radical prostatectomy (sporp); prostate cancer; initial experience; radical prostatectomy. submitted 3 june 2017; accepted 7 july 2017 summary no conflict of interest declared. the aim of this procedure is to minimize complications associated with number of ports. the present study was designed to define the single plus one port robotic radical prostatectomy (sporp) technique, and to demonstrate its feasibility and safety. during the past few years, the detection of prostate cancer and the number of operations are dramatically increased with usage of prostate specific antigen (psa). open surgery, laparoscopic surgery and robot-assisted laparoscopic surgery have the same results for trifecta at early stage cancer (5-7). however, urologists throughout the world are searching for more minimally invasive technique. we reported 8 robotic radical prostatectomy performed with single-site port (8.5 mm) plus one 8 mm port. materials and methods patients since january 2014 we performed sporp in 8 patients with prostate cancer. patients with localized prostate cancer were included in the study, and patients with a very high body mass index (bmi) (> 35 kg/m2) were excluded from the study. all cases were verified as prostate cancer preoperatively by trans-rectal ultrasound guided 10-core biopsy. no pharmacotherapy or radiotherapy was administered preoperatively. surgical technique under general anesthesia, patients were placed in trendelenburg position. access was gained using open hasson technique with 3 cm umbilical longitudinal incision. rectus fascia was incised and single-site port was inserted transperitoneally. the pneumo-peritoneum was maintained at 12-14 mmhg pressure. 10 mm assistant port was inserted edge of singlesite port without incising the fascia (figure 1). another 8 mm trocar was placed under direct vision at the mcburney point to ease intra corporeal suturing and drainage extraction (figure 2). the procedures were performed technically same as conventional robotic radical prostatectomy with flexible instruments inserted through single-site port and one standard robotic instrument inserted through extra 8 mm port. both deferens vasa were identified and dissected. the semdoi: 10.4081/aiua.2017.3.178 introduction in recent years, laparoendoscopic single-site surgery (less) becomes the latest point of minimal invasive surgery. reducing the number of ports minimizes the complications. conventional less is not easy to learn and perform. in this point da vinci enhances the intracorporeal maneuvering and makes the procedure easier (1-3). radical prostatectomy is the first treatment of choice for localized prostate cancer. robotic radical prostatectomy is improved to reduce the invasiveness and to facilitate the difficulty of open procedure; in this point single port radical prostatectomy is the latest technique (4, 5). tugcu_stesura seveso 28/09/17 10:10 pagina 178 179archivio italiano di urologia e andrologia 2017; 89, 3 single plus one port robotic radical prostatectomy inal vesicles were dissected inferiorly. the dorsal vein complex was over sewed by using a 2-0-polyglycolic acid absorbable suture. the bladder neck was dissected between the bladder neck and prostate by using monopolar scissors and then the urethra was incised. the posterior aspect of bladder neck was dissected and deferens vasa and seminal vesicles were freed bilaterally. the neurovascular bundle was dissected and freed from prostate base by using hem-o-lock. the dorsal vein complex and urethra at the prostate apex were incised. the prostate was released from the denonvillier fascia. after bleeding control, anastomosis was performed with two fixed 3-0 barbed polyglyconate sutures v-loc (covidien). foley catheter was filled with 20 ml sterile water and the watertight anastomosis was verified by filling bladder with 150 ml saline. the prostate specimen was put into organ bag retrieved through the periumbilical incision. a soft drain was placed through the extra 8 mm port (figure 3). foley catheter was removed 7 days later. results since january 2014 we performed sporp in 8 patients with localized prostate cancer. the mean age was 59.85 years (range 49-71). the mean level of psa was 6.91 ng/ml (range 5.78-8.81). preoperative gleason scores were (3 + 4) in one patient and (3 + 3) in 7 patients. all operations were completed successfully without conversion to standard robotic procedure or open surgery. no intra operative complications occurred. the mean operating time was 143 minutes (range 100-180 minutes): prostate excision time was 123 minutes (range 86-156 minutes) and urethrovesical anastomosis time was 20 minutes (range 14-24 minutes). the mean blood loss was 45 ml (range 30-55 ml). all patients were in t1c clinical stage. postoperative gleason scores were (3 + 4) in 2 patient and (3 + 3) in 6 patients. there was no positive surgical margin. early postoperative complications were drain leakage (n = 1), atelectasis (n = 1), wound infection (n = 1) and fever (n = 1). drain leakage was resolved during follow-up on the postoperative day 3 and the other complications were resolved with medical treatment. postoperative continence was excellent. the first operated 6 patients were completely dry, whereas the last operated 2 patients, in their follow-up of 3th and 4th months, were using security pad. no other complications happened during the 4 to 12 months follow-up period. the serum level of psa was less than 0.2 ng/ml. the cosmetic result was excellent (figure 4). discussion the treatment of localized prostate cancer has evolved over the last few decades from open surgery to laparoscopic, robotic and the newest entity single port robotic radical prostatectomy. an increasing number of centers worldwide have adopted less (8). however, it came with surgical limitations such as lack of triangulation, the instrument clashing, and the unfavorable ergonomics. the curved ports allow the instruments to make triangulation on targeted organ. same-sided hand-eye control of the instruments is maintained by software of the da vinci. it enables the surgeon control instrument on the right side of the screen with right hand and control instrument on the left side of the screen with left hand (figure 5). the use of single-site instrumentation in urology was reported in several studies (9, 10). increasing number of the series has resulted in experience with robot-assisted less radical prostatectomy (11). currently literatures show that robot assisted laparoscopic prostatectomy is a safe and feasible procedure with favorable oncologic and functional outcomes (2, 7, 12). anastomosis is the most challenging part of the sporp. figure 1. port configuration for a sporp and 10 mm assistant port. figure 2. demonstrate use of the 8 mm trocar in the mcburney point. figure 3. drain was placed into the 8 mm trocar. figure 4. semilunar umbilical incision and the cosmetic appearance. tugcu_stesura seveso 28/09/17 10:10 pagina 179 archivio italiano di urologia e andrologia 2017; 89, 3 v. tugcu, a. simsek, i. evren, k. gokhan seker, r. kocakaya, b. dogukan torer, a. atar, a. ihsan tasci 180 arms are not conventionally articulated like standard robotic arms. their range of motion is limited. in this point we prefer to use an extra 8 mm robotic port, which facilitates the suturing and is also used for drain extraction. prostate excision and anastomosis time is even less than single port robotic radical prostatectomy (11). in the literature, additional port was used in 14.6% of cases (13). in addition to this, a 10 mm assistant port was inserted edge of single-site port without incising the fascia for the bedside assistant. this facilitates the challenges pointed in the literature related to bedside assisting during less (14-16). conventional robotic procedure is comfortable for surgeon but port scars and complications due to number of ports like hernia or hemorrhage are main handicaps. in one study, mean blood loss during robotic radical prostatectomy was 135 cc, whereas in the present study mean blood loss was found to be 45 cc (17). these handicaps led to identify the technique of sporp. sporp is more minimally invasive when compared with conventional multiple ports robotic or laparoscopic surgery (18, 19). reducing the number of ports concluded with favorable outcomes, such as pain reduction and better cosmesis with robot-assisted less radical prostatectomy (20). in an analysis of 1163 urologic less cases, the conversion rate was 4% to conventional laparoscopic/robotic surgery and 1.1% to open surgery (13). in the current study, all operations were completed successfully without conversion to standard robotic procedure or open surgery. intraoperative complication rate was 3.3%, whereas no intra operative complications occurred in our study (13). the first operated 6 patients were completely dry, whereas the last operated 2 patients, in their follow-up of 3th and 4th months, were using security pad. unfortunately with such a small sample the continence outcomes seem to be difficult to evaluate when compared with the literature (11). as in our experience, minimally invasive techniques have demonstrated less blood loss and shorter convalescence (6). making small incisions can limit the range of motion and visualization, but flexible robotic instruments have facilitated this difficulty. choice of appropriate material such as hem-o-lok clips for nerve sparing, barbed suture for anastomosis and long laparoscopic aspirator is also important. in the current study, patients were relatively young (median age: 59.85 yrs) and in t1c stage, had a low bmi (median: 27.6 kg/m2), with a median prostate volume of 48 ml and a median psa of 6.91 ng/ml. our study population is close to the literature on less robotic prostatectomy (12). surgical margin results seem better than single port laparoscopic radical prostatectomy (11, 21). the most difficult part of the procedure is that it requires robotic and laparoscopic experience. conclusions in conclusion, sporp does not seem as difficult as presented in the initial reports. it is relatively easy for urologists who are skilled in traditional laparoscopic and robotic surgeries to master sporp. in addition the procedure would be easier if the arms were articulated. trifecta is possible with pain reduction and excellent cosmetic results. however, the long-term outcomes of this surgery need further investigations. references 1. jung jh, kim hw, oh ck, et al. simultaneous robot assisted laparoendoscopic single site partial nephrectomy and standard radical prostatectomy. yonsei med j. 2014; 55:535-8. 2. boncher n, vricella g, greene g, madi r. concurrent robotic renal and prostatic surgery: initial case series and safety data of a new surgical technique. j endourol. 2010; 24:1625-9. 3. jung jh, arkoncel fr, lee jw, et al. initial clinical experience of simultaneous robot assisted bilateral partial nephrectomy and radical prostatectomy. yonsei med j. 2012; 53:236-9. 4. cáceres f, cabrera pm, garcía-tello a, et al. safety study of umbilical single-port laparoscopic radical prostatectomy with a new duorotate system. eur urol. 2012; 62:1143-9. 5. kaouk jh , goel rk, haber gp, et al. single-port laparoscopic radical prostatectomy. urology. 2008; 72:1190-3. 6. parsons jk, bennett jl. outcomes of retropubic, laparoscopic, and robotic-assisted prostatectomy. urology. 2008; 72:412-6. 7. rha kh. robot-assisted laparascopic radical prostatectomy. korean j urol. 2009; 50:97-104. 8. kaouk jh, autorino r, kim fj, et al. laparoendoscopic single-site surgery in urology: worldwide multi-institutional analysis of 1076 cases. eur urol. 2011; 60:998-1005. 9. haber gp, white ma, autorino r, et al. novel robotic da vinci instruments for laparoendoscopic single-site surgery. urology. 2010; 76:1279-82. 10. cestari a, buffi nm, lista g, et al. feasibility and preliminary clinical outcomes of robotic laparoendoscopic single-site (r-less) pyeloplasty using a new single-port platform. eur urol. 2012; 62:175-9. 11. white ma, haber gp, autorino r, et al. robotic laparoendoscopic single-site radical prostatectomy: technique and early outcomes. eur urol. 2010; 58:544-50. 12. kaouk jh, haber gp, autorino r, et al. a novel robotic system for single-port urologic surgery: first clinical investigation. eur urol. 2014; 66:1033-1043. figure 5. surgeon control instrument. tugcu_stesura seveso 28/09/17 10:10 pagina 180 181archivio italiano di urologia e andrologia 2017; 89, 3 single plus one port robotic radical prostatectomy 13. autorino r, kaouk jh, yakoubi r, et al. urological laparoendoscopic single site surgery: multi-institutional analysis of risk factors for conversion and postoperative complications. j urol. 2012; 187:1989-94. 14. white ma, haber gp, autorino r, et al. robotic laparoendoscopic single-site surgery. bju int. 2010; 106:923-7. 15. white ma, autorino r, spana g, et al. robotic laparoendoscopic single site urological surgery: analysis of 50 consecutive cases. j urol. 2012; 187:1696-701. 16. autorino r, kaouk jh, stolzenburg ju, et al. current status and future directions of robotic single-site surgery: a systematic review. eur urol. 2013; 63:266-80. 17. tasci ai, bitkin a, ilbey yo, et al. robot-assisted laparoscopic radical prostatectomy: initial experience with first 112 cases. j robot surg. 2012; 6:283-8. 18. clayman rv, box gn, abraham jb, et al. rapid communication: transvaginal single-port notes nephrectomy: initial laboratory experience. j endourol. 2007; 21:640-4. 19. desai mm, berger ak, brandina r, et al. laparoendoscopic single-site surgery: initial hundred patients. urology. 2009; 74:805 12. 20. autorino r, cadeddu ja, desai mm, et al. laparoendoscopic single site and natural orifice transluminal endoscopic surgery in urology: a critical analysis of the literature. eur urol. 2011; 59:26-45. 21. white wm, haber gp, goel rk, et al. single-port urological surgery: single-center experience with the first 100 cases. urology. 2009; 74:801-4. correspondence volkan tugcu, md abdulmuttalip simsek, md (corresponding author) simsek76@yahoo.com ismail evren, md kamil gokhan seker, md ramazan kocakaya, md bugra dogukan torer, md arda atar, md ali ihsan tasci, md department of urology, bakirkoy dr.sadi konuk education and research hospital tevfik saglam caddesi no:11 zuhuratbaba/bakirkoy, istanbul 34147, turkey tugcu_stesura seveso 28/09/17 10:10 pagina 181 archivio italiano di urologia e andrologia 2021; 93, 148 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.48 who (1). once covid-19 is installed, its severity and prognosis depend on multiple factors, including sex (male), age (over 60 years), and the presence of pre-existing diseases (diabetes, hypertension, and cardiovascular diseases) (2). coronaviruses (cov) belong to the coronaviridae family and are characterized by being positive single-stranded rna type, which encodes for topographically positioned proteins: spicules (s), envelope (e), membrane (m), and nucleocapsid (n). in pathogenicity, s proteins are essential to enter the host cell (3). the biology of the testicle represents an ideal model for the study and evaluation of pathologies, given that events of mitosis, meiosis, and cell differentiation occurring in it, in addition to its endocrine regulation. also, the testicle is highly sensitive to variations in body homeostasis. particularly in the case of sars-cov-2, which uses the angiotensin-converting enzyme 2 (ace2) receptor as an entry route, associated with the transmembrane serine protease protein (tmprss2), makes the testis and particularly spermatogenesis potentially vulnerable, since this tissue has high expression of ace2 receptor (4, 5). methods review of studies and international experience a systematic review of the literature was performed using the electronic databases pubmed, scopus and science direct to assess the effect of sars-cov-2 on male sexual tract and function, and its possible sexual transmission. multiple permutations of the following keywords were used: “covid-19, sars-cov-2, transmission, testis, sperm, spermatogenesis, fertility cryopreservation, hormones, testosterone, sexual health”. the search was focused in original articles published between december 2019 and august 2020. there were also included papers that were found relevant to the research team in previous research. editorials, correspondence, case reports were excluded. the experience in reproductive and testicular biology, spermatogenesis and seminal analysis of the work team was also considered in the making of this narrative review. results across all databases a total of 371 articles were found. after reviewing the title and abstract of these, 46 papers introduction: severe acute respiratory syndrome coronavirus 2, (sars-cov-2) was first identified by the chinese centers for disease control and prevention on january 8, 2020 and was declared as a global pandemic on march 11, 2020 by who. sars-cov-2 uses the angiotensin-converting enzyme 2 (ace2) receptor as an entry route, associated with the transmembrane serine protease protein (tmprss2), which makes the testis and particularly spermatogenesis potentially vulnerable, since this tissue has high expression of ace2. material and methods: we performed a systematic literature review by electronic bibliographic databases in pubmed, scopus and sciencedirect up to august 2020 about the effect of sars-cov-2 on male sexual function and its transmission, to assess possible repercussions on sex organs and the existence of a sexual transmission path. results: although sars-cov-2 presence has not been found in testicle samples, it has been demonstrated that it causes histological changes compatible with orchitis, and sex hormone disturbances. tmprss2 is up-regulated in prostate cancer where it supports tumor progression, thus these patients may have a higher risk of sars-cov-2 infection. tmprss2 inhibitors may be useful for the treatment or prevention of covid-19. no viral material has been found in blood or semen, however it has been proven to be present in stool and saliva. conclusion: the male reproductive system would be highly vulnerable and susceptible to infection by sars-cov-2 given the expression of the ace2 receptor in somatic and germ cells. the seminal fluid would remain free of viral presence in patients with covid-19. regardless, non-genital sex could be an important source of viral transmission. in assisted reproduction techniques all necessary tests must be carried out to ensure the donor is free of the virus at the time of collection and handling of the seminal sample. key words: covid-19; andrology; fertility; testis; semen; human. submitted 22 august 2020; accepted 5 october 2020 introduction on january 8, 2020, a new coronavirus was identified at the chinese centers for disease control and prevention. it was named as severe acute respiratory syndrome coronavirus 2, abbreviated as sars-cov-2. the disease that is caused by this virus was denominated coronavirus disease 2019 (covid-19) and declared as notifiable by effects of covid-19 on male sex function and its potential sexual transmission summary héctor rodriguez bustos, gonzalo bravo maturana, felipe cortés-chau, joelle defaur torres, felipe cortés-pino, pablo aguirre, camilo arriaza onel laboratorio de morfología, icbm, facultad de medicina, universidad de chile, santiago, chile. 49archivio italiano di urologia e andrologia 2021; 93, 1 covid-19 on male sexual organs were preliminary selected. the selected papers were critically read, 20 were found to be the most relevant for the purpose of this review. ace2 the ace2 system plays an essential role in protecting cellular homeostasis against viral infection, specifically in covid-19 infection and is widely distributed in the heart, kidney, lung, and testicles (4). ace2 participates as an antagonist of the activation of the classic reninangiotensin system (ras), protecting against cellular damage in hypertension, diabetes and some heart diseases. sars-cov-2 is characterized by occupying the ace2 cell membrane receptor to enter the cell. in the lung, sars-cov-2 invades pneumocytes and macrophages using ace2 receptors (4), although ace2 normally has a protective effect against tissue damage. ace2 is present in non-immune cells, eg, respiratory and digestive tract epithelia, endothelial cells, cells of the simple cubic epithelium of the proximal convoluted tubules of the kidney, and brain neurons, as well as in immune cells such as monocytes and macrophages (3). in other cell types the virus enters its host, but with lower affinity. the expression of ace2 in adult human testis occurs predominantly in spermatogonial cells, sertoli cells of the tubular compartment and leydig cells in the interstitial compartment. these cells are also enriched with intercellular junctions (leydig and sertoli cells) and have low mitochondria concentration. the above described indicates that there are cells in the testicle that can potentially be targeted for infection with the sars-cov-2 virus. it has been described a high expression of ace2 in different types of spermatogenesis cells, such as spermatogonia, early and late spermatocytes, round spermatids, and elongated spermatids (2, 4). it has also been described in somatic endothelial testis cells, leydig cells, and monocytes, thus concluding that the human testis is a potential receptor for sars-cov-2 infection. testicle in patients with the diagnosis of testicular cancer, or being treated for it, medical care should be taken as a priority in-hospital care, although in general, they are at low risk for developing a severe covid-19 infection (6). although sars-cov-2 is the cause of multiple organic alterations, wang et al. (1) states that the male reproductive system may not be immune to alterations. dramatic changes in sex hormones are cited, suggesting a potential impairment of gonadal function (7). in parallel, it is mentioned that in the analysis of testicular biopsies (n = 6) of patients who died of sars, several histopathological processes compatible with orchitis of variable intensity, such as apoptosis in the different types of spermatogenesis cells (cytos i and cytos ii), absence or scarce sperm in the seminiferous tubules, a thickened peritubular compartment, and leukocyte infiltration, specifically citing the basal lamina (8). these findings should be compared with the normal testis morphology, as seen in figure 1. viral presence was not detected through in situ hybridization, but abundant igg precipitates were detected (8). finally, it is suggested that something similar could happen with covid-19 (1). yang et al. (9) analyzed testicular biopsies (n = 11) of patients who died from covid-19. morphological changes suggestive of damage to the seminiferous tubules were reported, such as sertoli cell swelling, vacuolation, cytoplasmic rarefaction, and detachment from tubular basement. interstitial changes consistent with viral orchitis were also described, with edema and mild lymphocytic inflammation, accompanied by a decrease in leydig cell number. although these findings would suggest sarscov-2 may be the causative agent of testicular tissue damage, the effect of hyperthermia, secondary infection, hypoxia, and steroidal therapy cannot be excluded. it is worth mentioning that no evidence of the presence of sars-cov-2 was found in the samples (9). covid-19 effect on sex hormones ma et al. (7) described that in sars-cov-2 infection dramatic changes are developed in sex hormones, testosterone (t) and luteinizing hormone (lh), and in t/lh ratio. in this study, sex-related hormones were compared between reproductive-aged men with sarscov-2 infection and age-matched healthy men (7). it was found that covid-19 patients had significantly figure 1. testicular biopsies. histology of the normal human testis (young and fertile adult male). periodic acid-schiff (pas), hematoxylin (h), and alcian blue staining. a. the tubular compartment includes a simple columnar epithelium formed by sertoli cells with a noticeable basal lamina of collagen iv, plus cytogenic epithelium forming spermatogenesis. human spermatogenesis includes six cell stages, where 4 cycles complete a wave, including processes of mitosis (from dark spermatogonia to spermatocytes i), meiosis (with the most abundant pachytene stage) and cell differentiation (spermatocytes ii, round and elongated spermatids). therefore, there are few tubules in whose lumen sperm are found (< 10%). b. the peritubular compartment that limits the periphery of the seminiferous tubules is composed of 2-5 very thin layers of elongated cells arranged circularly. these cells have fibromuscular contractile characteristics. c. the interstitial compartment is the place where leydig cells are located. leydig cells are abundant and normally distributed in clumps. they have a rounded and central nucleus, and a strongly acidophilic cytoplasm. additionally, c-kit cells, interstitial cells of cajal and fibroblasts can be found in the interstitium. archivio italiano di urologia e andrologia 2021; 93, 1 h. rodriguez bustos, g. bravo maturana, f. cortés-chau, j. defaur torres, f. cortés-pino, p. aguirre, c. arriaza onel 50 higher serum lh and significantly decreased t/lh and fsh/lh ratio. no statistical difference in serum t, e2 or fsh was detected between both groups (7). considering that t levels were similar between both groups, lh levels were dramatically increased in covid-19 group, resulting in decrease in t/lh ratio. this could suggest that sars-cov-2 infection has an effect on the testes similar to what is seen in early stages of primary hypogonadism, in which t levels are maintained by the stimulated production of lh due to the impairment of negative feedback (7). the findings of similar fsh, e2 and t/e2 between both groups could be interpreted as unaltered suppression of fsh by inhibin b secreted by sertoli cells, and conserved peripheral aromatization of androgens. this suggests that sars-cov-2 infection has an important effect on leydig cell function, opposed to what appears to be an unscathed sertoli cell function (7). prostate according to the epidemiological information available on covid-19, the disease is more prevalent in male patients, with a higher incidence compared to female patients. even more in the elderly, where prostate cancer is prevalent (2). montopoli et al. (10), described an action of sars cov-2 through the use of the ace2 receptor and its interaction with the virus protein s by the transmembrane protein tmprss2. tmprss2 inhibition may work to block or decrease the severity of sars-cov-2 infections. interestingly, tmprss2 is an androgen-regulated gene that is up-regulated in prostate cancer where it supports tumor progression and is involved in a frequent genetic translocation with the erg gene. thus, patients with prostate cancer have a higher risk of sars-cov-2 infections compared to patients without cancer. however, prostate cancer patients receiving androgen deprivation therapy appear to be partially protected from sars-cov-2 infections. dana et al. (11) described that tmprss2 is the most common gene involved in primary prostate cancer, indicating that the administration of tmprss2 inhibitors, which are currently used for prostate cancer, may be useful for the treatment or prevention of covid-19. regulators of the expression of tmprss2 protein in the lung may overlap with the risk factors for prostate cancer with tmprss2-erg-positive fusion. explanation of sexspecific difference in the overall incidence of covid-19 should consider possible differences in laboratory tests for sars-cov-2 and the presence and activity of tmprss2 erg associated with prostate cancer, as well as strong tmprss2 regulation. androgen levels could suggest that tmprss2 could partially explain the male prevalence in the covid-19 pandemic. when studying mrna levels, the constitutive expression of tmprss2 in lung tissue does not appear to differ between men and women. it is tempting to speculate that androgen receptor inhibitory therapies could reduce covid-19 susceptibility to lung symptoms and mortality (12). gastrointestinal transmission additionally, zhang et al. (13) described that ace2 is highly expressed in enterocytes, esophageal and colonic epithelium, suggesting possible fecal-oral transmission of sars-cov-2. this hypothesis is sustained by the presence of genetic material of the virus in the faeces during respiratory disease and a few days after recovery (13). detection of sars-cov-2 by saliva has become an alternative option for viral load sampling for diagnosis and follow-up in covid-19 patients, providing a safer and easier alternative for medical personnel to obtain samples, in comparison to nasopharyngeal swabbing (14). viral strains can be found in saliva up to 29 days after infection. therefore covid-19 can be transmitted by saliva directly or indirectly, even among patients without cough or other respiratory symptoms (14). hence, since covid-19 is present and detectable in saliva, this would indicate that it could potentially be transmitted through oral sex. blood transmission chang et al. (15), described that in sars, in some patients, depending on the state of the evolution of the disease, it was possible to find the virus in blood plasma and lymphocytes, although in very low concentrations. transmission of the disease through blood or plasma transfusion has not yet been described. something very similar occurs in cases of mers and covid-19. additionally, others describe that no cases have been reported yet and there is no information on the transmission of the virus through blood transfusion therapies. however, the absence of risk of blood transfusion or its therapeutic by-products cannot be guaranteed. it has been recommended and suggested the use of riboflavin and ultraviolet light, allowing to reduce the viral titers that could be present in whole blood to be used for transfusions. blood products with pathogen reduction may be a safer option for critically ill patients with covid-19, particularly those in high-risk categories (16, 17). cryopreservation of spermatozoids in men who developed infections caused by viruses with viremic phases like zika, ebola and mumps viruses, it is possible to find viral particles in semen for several months after their recovery (18). therefore, when developing sperm cryopreservation processes, it is important to include laboratory protocols that allow ruling out any infection or presence of remains of viral particles. it is necessary to remember that the seminal fluid incorporates the functional and secretory results of several important organs, such as the prostate and seminal glands, and the testicular fluid. yakass et al. (19) indicate that given the structure of the sars-cov-2 virus as enveloped rna viruses, it could still be viable if it is cryopreserved and then heated to be transferred, even in cryopreservation in liquid nitrogen, similar to what is seen in influenza virus infection. therefore, the authors recommend always taking all necessary and sufficient safeguards. although the presence of active viral particles of sarscov-2 has not yet been demonstrated in spermatogenesis or semen, there are warnings and procedures for sperm management obtained from donors for assisted fertilization procedures, suggesting a waiting require51archivio italiano di urologia e andrologia 2021; 93, 1 covid-19 on male sexual organs ment of at least 2 weeks if the donor has recovered from the disease and distancing if it comes from geographic areas with high risk of infection (20). reproductive health in covid-19 pandemic in a state of health emergency such as the covid-19 pandemic, it is necessary to identify the biomedical contributions necessary to assist the population in their reproductive health care, considering both the population in confinement and the patients recovered from the disease. during strict confinement, behavioral adaptations occur inside the household that are generally associated with an overuse of digital technologies (telework and leisure). this implies a great overexposure to blue light (daylight and led light from technological devices) that eventually and sooner rather than later leads to alteration in circadian rhythms, preventing the normal functioning of the pineal gland. this condition has been shown to alter the function of the ovary (21) and the testis (22), in addition to mental disorders. since the pandemic was declared by the who, the most affected countries in europe have been italy and spain. currently, both countries have received the contributions of experts in reproductive health and their association with covid-19. in italy the italian association of andrology (23) and in spain the association for the study of the biology of reproduction and the spanish association of andrology, sexual and reproductive medicine (24) were attentive to the recommendations of the who and new related scientific literature. the complexity of andrology research in pandemic times in south america, the pandemic has been causing health havoc similar to europe, but with a lag of around 2 months. for example, in chile strict quarantine confinement was decreed and implemented from the second week of march to date (august). with the foregoing, only activities classified as essential have been carried out, within which university teaching or research has not been included. most medical services have been targeted or have been converted to covid-19 response mode. therefore, little to no scientific research has been possible to develop in this regard. additionally, the management of the legal aspects regarding the handling of corpses and patient samples in pandemic states means that access to biological material is restricted. conclusions the male reproductive system would be highly vulnerable and susceptible to infection by sars-cov-2 given the expression of the ace2 receptor, both in somatic cells (leydig, peritubular, and sertoli cells), as well as in almost all germ cells in their mitotic, meiotic, and differentiation stages. added to this is the fact that the expression of tmprss2 is regulated by androgens. however, to date, no studies have been published that have found evidence of the virus in the testis, prostate tissue, or semen. therefore, the seminal fluid would still remain free of viral presence in patients with covid-19. regardless, non-genital sex could be an important source of viral transmission in asymptomatic and mild symptomatic patients. it is imperative to rule out that the sperm to be used in assisted reproduction techniques may come from donors who have suffered from covid-19. all necessary tests must be carried out to ensure that the donor is free of the virus at the time of collection of the semen sample, during the procedures and handling of the samples. in case of prostate cancer with indication for radical prostatectomy, if the patient has reproductive intentions, the option of using sperm cryopreservation should be proposed, after studying the absence of active seminal sars-cov-2. considering the difficulty to obtain tissue samples of covid-19 deceased patients, due to the strict protocols and limitation put in order by governmental institutions, mostly all histological research has been done in testis, with almost no studies describing the effects of sarscov-2 in prostate and seminal vesicles, leaving a huge gap in the body of evidence concerning this virus impact on the male reproductive tract. references 1. wang s, zhou x, zhang t, wang z. the need for urogenital tract monitoring in covid-19. nat rev urol. 2020; 17:314-315. 2. cheng h, wang y, wang gq. organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of covid-19. j med virol. 2020; 92:726-730. 3. magrone t, magrone m, jirillo e. focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target a perspective. endocr metab immune disord drug targets 2020; 20:807-811. 4. li my, li l, zhang y, wang xs. expression of the sars-cov-2 cell receptor gene ace2 in a wide variety of human tissues. infect dis poverty. 2020; 9:45. 5. hoffmann m, kleine-weber h, schroeder s, et al. sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. cell. 2020; 181:271-280. 6. secin fp. priorities in testis cancer care during covid-19 pandemic. int braz j urol. 2020; 46:79-85. 7. ma l, xie w, li d, et al. effect of sars-cov-2 infection upon male gonadal function: a single center-based study. medrxiv. 2020. 8. xu j, qi l, chi x, et al. orchitis: a complication of severe acute respiratory syndrome (sars). biol reprod. 2006; 74:410-416. 9. yang m, chen s, huang b, et al. pathological findings in the testes of covid-19 patients: clinical implications. eur urol focus. 2020; 6:1124-1129. 10. montopoli m, zumerle s, vettor r, et al. androgen-deprivation therapies for prostate cancer and risk of infection by sars-cov-2: a population-based study (n = 4532). ann oncol. 2020; 31:10401045. 11. maleki dana p, sadoughi f, hallajzadeh j, et al. an insight into the sex differences in covid-19 patients: what are the possible causes? prehosp disaster med. 2020; 35:438-441. 12. stopsack kh, mucci la, antonarakis es, et al. tmprss2 and covid-19: serendipity or opportunity for intervention? cancer discov. 2020; 10:779-782. archivio italiano di urologia e andrologia 2021; 93, 1 h. rodriguez bustos, g. bravo maturana, f. cortés-chau, j. defaur torres, f. cortés-pino, p. aguirre, c. arriaza onel 52 13. zhang jc, wang s bin, xue yd. fecal specimen diagnosis 2019 novel coronavirus-infected pneumonia. j med virol. 2020; 92:680682. 14. aponte mendez m, rivera marval ek, talebzade toranji m, et al. dental care for patients during the covid-19 outbreak: a literature review. int j sci res dent med sci. 2020; 2:42-45. 15. chang l, yan y, wang l. coronavirus disease 2019: coronaviruses and blood safety. transfus med rev. 2020; 34:75-80. 16. ragan i, hartson l, pidcoke h, et al. pathogen reduction of sars-cov-2 virus in plasma and whole blood using riboflavin and uv light. plos one. 2020; 15:e0233947. 17. keil sd, ragan i, yonemura s, et al. inactivation of severe acute respiratory syndrome coronavirus 2 in plasma and platelet products using a riboflavin and ultraviolet light-based photochemical treatment. vox sang. 2020; 115:495-501. 18. feldmann h. virus in semen and the risk of sexual transmission. n engl j med. 2018; 378:1440-1441. 19. yakass mb, woodward b. covid-19: should we continue to cryopreserve sperm during the pandemic? reprod biomed online. 2020; 40:905. 20. esteves sc, lombardo f, garrido n, et al. sars-cov-2 pandemic and repercussions for male infertility patients: a proposal for the individualized provision of andrological services. andrology. 2021; 9:10-18. 21. espino j, macedo m, lozano g, et al. impact of melatonin supplementation in women with unexplained infertility undergoing fertility treatment. antioxidants (basel). 2019; 8:338. 22. sun t-c, li h-y, li x-y, et al. protective effects of melatonin on male fertility preservation and reproductive system. cryobiology. 2020; 95:1-8. 23. maretti c, privitera s, arcaniolo d, et al. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology. arch ital urol androl. 2020; 92:73-77. 24. josé fg, gonzález jgá, molina jmc, et al. infección por sarscov-2: implicaciones para la salud sexual y reproductiva. rev int androl. 2020; 18:117-23. correspondence héctor rodriguez bustos, mv, msc, dbm, phd (corresponding author) hector3@uchile.cl gonzalo bravo maturana, md gonzalo.bravo.m@ug.uchile.cl felipe cortés-chau, md felipe.cortes.c@ug.uchile.cl joelle defaur torres, md joelle.defaur@ug.uchile.cl felipe cortés-pino, md felipe.cortes.p@ug.uchile.cl pablo aguirre, md pablo.aguirre@ug.uchile.cl camilo arriaza onel, md carriaza@med.uchile.cl laboratorio de morfología, icbm, facultad de medicina. universidad de chile, avda, independencia 1027, santiago (chile) cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 170 original paper no conflict of interest declared. humans and examine their association with such vascular pathologies (3, 4). the role of retinal microvascular diameters has been investigated in many medical vascular diseases, such as cardiovascular, hypertension, diabetes, and kidney diseases (4-7). previous published reports confirmed the strong association of the retinal vasculature changes with predication of cardiovascular risks and nephropathy (6, 7). based on the association of varicocele with medical vascular diseases and its vasculature progressive nature, alterations in retinal vasculature will be assumed to occur in men with varicocele (8, 9). in a previous report, retinal vasculature parameters such as retinal microvascular diameters central retinal venular equivalent (crve), central retinal arteriolar equivalent (crae), and the arteriolar-to-venular ratio (avr) have been emerged to have a clinical correlation with varicocele patients (10). however, the possible relationship between retinal vasculature diameters and fertility was not investigated. in this study, we aimed to detect and evaluate the relationship of retinal vascular calibers with fertility-related parameters, including semen values, and reproductive hormone (serum total testosterone and fsh) in infertile patients with varicocele. patients and methods study population the data of 413 infertile patients who were referred to our andrology department were retrospectively analyzed. from these infertile men, only subjects with varicocele were selected and divided into two groups. group 1 consisted of sixty-eight (68) infertile varicocele patients with abnormal semen parameters (asp). group 2 consisted of sixty-one (61) varicocele normozoospermic subjects. fifty-eight (58) healthy normozoospermic men were enrolled in the study as a control group. none of the subjects in the control group had varicocele or scrotal symptoms. age was similar between the three groups. the study was conducted according to the ethical guidelines of the declaration of helsinki for medical research and all procedures were approved by the institutional review board of the faculty of medicine at jazan university, saudi arabia. all participants gave a signed consent at enrollment. objective: the objective of this study was to assess the relationship between retinal vessel diameters, such as retinal arteriolar diameter, retinal venular diameter, and arteriolar/venular ratio (avr), as clinical parameters of fertility in varicocele patients. materials and methods: sixty-eight (68) infertile varicocele men with abnormal semen parameters and sixty-one (61) varicocele normozoospermic men were included in the study. moreover, fifty-eight (58) healthy normozoospermic men without varicocele were enrolled as a control group. for each participant, retinal vascular diameters were measured from the digital retinal photographs as a central retinal arteriolar equivalent (crae), central retinal venular equivalent (crve), and avr. in addition, hormones (total testosterone and fsh), and semen parameters were assessed and correlated with retinal vessel diameters. results: the mean crae, crve, and avr values were 147.8 ± 15.8 µm, 198.3 ± 39.3 µm, and 0.61 ± 0.01 in infertile varicocele patients, respectively. significant difference of crae, crve, and avr were found when comparing infertile varicocele patients with both varicocele and control normozoospermic male groups (p = 0.01, p = 0.006, and p = 0.007; respectively). larger retinal venular caliber and smaller avr ratio showed a significant inverse correlation with both sperm parameters and hormones (total testosterone and fsh) (p < 0.05). no significant correlations were found between crae with both sperm parameters and hormonal values (total testosterone and fsh) (p > 0.05). conclusions: infertile patients with varicocele showed a significant relationship with the retinal vascular diameter (crve and avr ratio). this finding supports recommendation for regular eye examinations in the varicocele population. key words: infertility; reproductive hormone; retinal vessels; semen parameters; varicocele. submitted 31 august 2021; accepted 21 november 2021 introduction varicocele is a vascular disease affecting approximately 25% of infertile men (1). varicocele is thought to play a crucial role in the pathophysiology of infertility (2). assessment of varicocele pathophysiology effects on fertility requires many non-invasive and efficient procedures. the retinal microcirculation has allowed the physician to visualize the medical vascular diseases noninvasively in retinal vessel diameters: can they predict future risk of infertility in patients with varicocele? mazen a. ghanem 1, 2, essa a. adawi 1, ahmed m. ghanem 3, manal a. safan 4, asaad a. ghanem 5 1 departments of urology, jazan university, ksa and 2 menoufia university, egypt; 3 kasr al-ainy faculty of medicine, cairo university, egypt; 4 medical biochemistry and molecular biology, menoufia university, egypt; 5 ophthalmic mansoura center, mansoura university, egypt. doi: 10.4081/aiua.2022.1.70 summary 71archivio italiano di urologia e andrologia 2022; 94, 1 varicocele and retinal vessels changes selection criteria patients with varicocele and infertility with abnormal semen parameters were assessed according to who guidelines (2010) (11). patients with other urogenital diseases, erectile dysfunction medications, sperm antibodies, and systemic vascular problems affecting the retina (e.g., cardiovascular disease, atherosclerosis, hypertension, and diabetes) were excluded. patients with refractive error within ± 6.0 diopters equivalent sphere and within ± 3.0 diopters astigmatism were excluded. patients with a history of glaucoma, trauma, or previous ocular surgery, and corneal opacity were also excluded. the female partners were also investigated for exclusion of the others causes of infertility, such as ovulatory problems, or tubal obstruction. clinical examination the varicocele diagnosis was confirmed by using 1993 who guidelines (12). subclinical varicocele cases were excluded. subjects of the control group underwent the same evaluation (13). the total testicular volume of all the participants was measured by prader’s orchidometer. all the subjects included in the study underwent detailed ocular examination including slit-lamp anterior segment evaluation (haag-streit, germany), fundus examination with volk 90 diopter, and measurement of intraocular pressure using the goldmann applanation tonometer at 900. the serum concentration of total testosterone, fsh, and glucose and semen parameters were determined by using standardized protocols (14, 15). retinal vessel measurements all the participants had simultaneous stereoscopic color transparency centered on the optic disc (45° fields) with pharmacological mydriasis in the ophthalmic department. most photography sessions coincided with the annual visits. the retinal arterioles and venules caliber were measured by an automatic computed system. by using knudtson et al. formula, the retinal vessel diameters were calculated as central retinal arteriolar equivalent (crae) and central venular equivalent (crve) (16). arteriolar-venular-ratio (avr) was calculated by using both the crae and crve, taking the mean of the results of right and left eye measurements. assessment of the retinal vessels and other retinal diseases was performed by a single trained and certified examiner masked for participant characteristics. data analysis and statistics sample size calculation was based on the outcome of crve as the primary variable of interest. for this calculation, 9 infertile patients with varicocele, 9 normozoospermic patients with varicocele, and 9 healthy normozoospermic subjects without varicocele were enrolled. mean crve values were 197 ± 29.4 μm in the infertile varicocele group, 173 ± 25.6 μm in the varicocele normozoospermic group, and 171 ± 19.2 μm in the control group. based on these numbers and with an alpha = 0.05, it was estimated that 23 subjects per group were necessary to achieve 95% statistical power of the study. furthermore, avr was found 0.62 ± 0.02 in the infertile varicocele group, 0.78 ± 0.01 in the normozoospermic group with varicocele, and 0.79 ± 0.01 in the control group. based on these data and with an alpha = 0.05, 52 subjects per group were necessary to achieve 95% statistical power of the study. therefore, 68 patients with infertile varicocele group, 61 normozoospermic men with varicocele, and 58 healthy normozoospermic subjects (control group) were considered sufficient for the study. the statistical evaluations were performed using ibm spss version 24.0 (armonk, ny). continuous variables were tested for the normality of distribution with the kolmogorov-smirnov test. results were expressed as means ± standard deviation (sd). differences in the means were compared using the student’s t-test and the mannwhitney u-test, when the data were normally and abnormally distributed, respectively. we performed the fisher’s exact test, and chi-square test to determine any statistical difference between the two groups. the correlations between retinal vessel data, seminal parameters, hormonal values, and testicular volume were investigated using the spearman rank correlation. the level of the p-value < 0.05 was considered statistically significant. results descriptive findings the demographic data of the studied groups are shown in table 1. the statistical analysis of the differences of demographic and clinical characteristics among the studied groups demonstrated no significant difference. study of retinal vessel diameters the association between retinal vessel diameters with both seminal parameters and hormonal values are shown in table 2. the mean crae, crve, and avr values were statistically significant different in infertile varicocele patients with abnormal semen values compared to normozoospermic patients with varicocele and control patients (p = 0.01, p = 0.006, and p = 0.007; respectively). in varicocele infertile patients, crve showed a significant inverse correlation with sperm concentration, progressive motility and normal sperm morphology (r = -0.337, p < 0.005; r = -0.289, p < 0.017; r = -0.239, p < 0.049, respectively). in addition, crve had a significant inverse correlation with hormonal values (r = -0.442, p < 0.000 table 1. demographic data and clinical characteristics of the studied groups. parameters varicocele varicocele with control with asp * normozoospermia number of patients 68 61 58 mean age (years) 28.7 ± 2.4 27.9 ± 1.6 29.1 ± 2.1 varicocele grade 0 grade 1 15 (22%) 16 (26%) grade ii 51 (75%) 44 (72%) grade iii 2 (3%) 1 (2%) varicocele laterality 0 left 56 (82%) 52 (87%) right 12 (18%) 8 (13%) *asp: abnormal semen parameters. archivio italiano di urologia e andrologia 2022; 94, 1 m.a. ghanem, e.a. adawi, a.m. ghanem, m.a. safan, a.a. ghanem 72 for total testosterone, and r = -0.338, p < 0.005 for fsh). a significant inverse association was found between avr and sperm and hormonal values (r = -0.360, p < 0.003 for sperm concentration; r = -0.323, p < 0.007 for progressive sperm motility; r = 0.284, p < 0.019 for normal sperm morphology; r = -0.305, p < 0.011 for total testosterone; and r = -0.367, p < 0.002 for fsh). on the contrary, crae did not have any significant correlation with sperm and hormonal values (spearman rank correlation coefficient, p = 0.071 for sperm concentration, p = 0.119 for progressive sperm motility, p = 0.192 for normal sperm morphology, p = 0.137 for total testosterone, and p = 0.060 for fsh) (table 3). retinal vessel diameters (crae, crve, and avr) had no significant correlation with total testicular volume (spearman rank correlation coefficient p > 0.05) (table 3). furthermore, no significant correlation was found between the laterality and grade of varicocele with retinal vasculature diameter (p > 0.05) (data not shown). however, an increase in retinal venular calibration (crve) was prominent in the higher grade of varicocele, although it was not observed in the retinal arteriole. statistically significant differences for seminal values (sperm concentration, progressive sperm motility, and normal sperm morphology), hormonal values (serum total testosterone and fsh), and total testicular volume were observed in both normozoospermic patients with varicocele and controls compared to the infertile patients with varicocele (p < 0.05) (table 2). discussion this study showed a significant association between crve diameter and sperm parameters in infertile varicocele patients. based on this finding, we provide another evidence for the role of medical vascular diseases in the pathophysiology of both varicocele and retinopathy. this finding is consistent with the increased prevalence of peripheral varicose veins, and ectasic changes in the coronary arteries in varicocele patients (17, 1). moreover, the changes of retinal vasculature caliber have been demonstrated and identified as markers in several vascular diseases (4-5, 18). the presence of larger retinal vascular caliber in patients with varicocele is initiated by the effect of hypoxia on retinal blood flow leading to retinal vasodilation. the dilatation of retinal micro-vasculature may also be affected by higher levels of inflammatory biomarkers and by local endothelial nitric oxide (no) synthesis in vascular beds which is a potent vasodilator (19). these primary vascular pathogenetic processes are also involved in the pathogenesis of infertility (2, 9, 20, 21). the vasodilation of the retinal micro-vessels was observed before the onset of microvascular complications of chronic kidney diseases, such as nephropathy (22). similarly, larger venular caliber was related to dyslipidemia, which may reflect a proinflammatory state associated with obesity (23). noteworthy, generalized retinal arteriolar narrowing is shown to be a reflection for future onset of systemic hypertension (18). these previous clinical studies provide evidence that retinal vasculature changes may precede the development of clinical varicocele. consequently, the crve can play a role as an early prediction marker for the severity of varicocele. changes of avr are more predictive than either arteriolar or venular diameter alone. in this study a smaller avr was significantly correlated to sperm parameters. smaller avr values are related mainly to venular dilatation than to arteriolar dilatation. therefore, prominent dilatation was recognized in retinal veins than in retinal artery in varicocele patients (10). however, arteriolar diameters are usually measured against venular ones during ophthalmoscopy clinical examination. this procedure may underestimate the arteriolar caliber and consequently the severity and complications of varicocele. also, smaller avr was associated and affected by the inflammatory mediators (5). despite these previous studies, avr values are more sensitive than crve alone to determine the risk of varicocele (10). in this study, we found a significant association of the caliber of retinal vessels with both total serum testosterone and fsh hormones. the potential role of the hormonal imbalance, induced by varicocele, on the retinal microvascular dilatation was supported in our series (24) showing a negative correlation between retinal vasculature parameters (crve and avr) and the reproductive hormones in infertable 2. changes in retinal vessels diameters, semen parameters, hormonal levels, and testicular volume of the studied groups. parameters varicocele varicocele with control p value * with asp normozoospermia crae (µm) 147.8 ± 15.8 138.7 ± 9.3 136.5 ± 7.5 0.01 crve (µm) 198.3 ± 39.3 171.4 ± 28.4 169.8 ± 24.2 0.006 avr 0.61 ± 0.01 0.77 ± 0.02 0.79 ± 0.02 0.007 semen concentration (million/ml) 12.9 ± 5.7 24.8 ± 13.2 27.5 ± 11.5 0.004 progressive motility (%) 21.7 ± 8.2 36.9 ± 11.3 38.4 ± 13.7 0.005 morphology (% of normal) 14.7 ± 4.9 24.8 ± 13.9 26.6 ± 12.3 0.01 total serum testosterone (ng/ml) 6.3 ± 1.6 13.7 ± 5.7 12.1 ± 8.3 0.04 fsh (miu/ml) 15.1 ± 6.7 5.7 ± 2.6 6.1 ± 2.1 0.001 total testicular volume (ml) 16.2 ± 4.8 28.7 ± 15.4 29.9 ± 18.2 0.002 * p-value (comparison between varicocele group with asp and both varicocele and control normozoospermic groups) values are presented as mean ± sd. asp: abnormal semen parameters; avr: arteriolar-to-venular ratio; crae: central retinal arteriolar equivalent; crve: central retinal venular equivalent. table 3. correlation of infertile varicocele patients’ retinal vessels diameters with semen parameters, hormones levels, and testicular volume. parameters crae (µm) crve (µm) avr r p * r p * r p * sperm concentration (million/ml) -0.221 0.071 -0.337 0.005 -0.360 0.003 progressive motility 0.191 0.119 -0.289 0.017 -0.323 0.007 morphology (% of normal) 0.160 0.192 -0.239 0.049 -0.284 0.019 total serum testosterone (ng/ml) 0.182 0.137 -0.442 0.000 -0.305 0.011 fsh (miu/ml) -0.229 0.060 -0.338 0.005 -0.367 0.002 total testicular volume (ml) -0.135 0.272 -0.145 0.237 -0.213 0.081 r = correlation coefficient. * p-value (by spearman rank correlation). avr: arteriolar-to-venular ratio; crae: central retinal arteriolar equivalent; crve: central retinal venular equivalent. 73archivio italiano di urologia e andrologia 2022; 94, 1 varicocele and retinal vessels changes tile varicocele patients. these retinal vasculature changes may be attributed to the testosterone imbalance associated with testicular insufficiency in men with varicocele. in fact, the severity of these hormonal changes, in this study, may be related to the greater loss of testicular volume in varicocele patients as compared to the normozoospermic healthy subjects. the diminished testicular function is associated with a substantial increase in the fsh and decrease of testosterone levels, resulting in an inverse ratio between serum testosterone and fsh levels. on the other hand, testosterone has a negative direct effect on the vessel vasculature through regulation of the vascular tone and regulation of apoptosis in vascular endothelial cells. on the contrary, it was reported that testosterone did not have any influence on micro-circulation and even that its inhibition improves microvascular dilatation (25). since the vascularity of the testis plays a crucial role in normal testicular function (17), the retinal vessel parameters assessed in this study can be used as a prognostic clinical marker for the gonadal function in varicocele men. our results demonstrated that most varicocele patients with abnormal semen values had higher crve and smaller avr. therefore, high crve and smaller avr could be used as a negative prognostic factor for spermatogenesis quality in varicocele patients and young normal adults. the hemodynamic retinal arteriolar and venular caliber can be determined noninvasively and measured quantitatively, which may allow monitoring of clinical outcomes of varicocele. however, there are some limitations of this study. the number of participants might have been larger. also, this study did not have data about intraocular pressure which may influence retinal vascular caliber measurements. furthermore, photographs were not synchronized with both the fertility and color-doppler ultrasonography (cdus) evaluation because vessel diameter may change because of systemic blood flow changes. our study did not assess the relationship between diameters of the spermatic vessel and the retinal vessels because of the high risk of false-negative and false-positive diagnoses related to cdus performed by different operators. these misinterpretations are related mainly to the mobility of the spermatic cord vessels and to the patient position during measurements (standing or lying). in addition, quantitative data of the scrotal veins (maximum diameter and the presence, velocity, and duration of reflux) were lacking in the reports of sonographic examinations of all participants with clinically diagnosed varicocele (13). moreover, different cutoff considered and controversies about the diagnostic criteria for varicocele in doppler procedures cause difficulty in the evaluation of the results. in consideration of all the previous described influential factors, ediz et al. found that the maximum spermatic vein diameters measured during the valsalva maneuver by cdus were not significantly correlated with any of the sperm parameters (26) although mahdavi et al. reported that sperm parameters correlated with cdus findings in patients with varicocele (27). finally, our results may not be applicable in patients with subclinical varicocele. the strengths of this study include high magnification of digital fundus images with correction for refractive errors and the use of the automatic computed system for quantitative measurement of the retinal vascular parameters. conclusions our results revealed that changes in retinal vascular parameters have a relationship to both seminal parameters and hormonal values. the clinical implication of our results in varicocele patients is that the assessment of retinal arterioles and venules may be a possible prognostic marker for varicocele outcome. however, there is a great need for further experimental investigations with a larger number of patients. acknowledgements the authors would like to thank all employees who agreed to participate in this study and all patients involved in this study for their co-operation. also, we would like to thank manaji m. ba-baeer for his editorial and valuable assistance. references 1. yetkin e, kilic s, acikgoz n, et al. increased prevalence of varicocele in patients with coronary artery ectasia. coron artery dis. 2005; 16:261. 2. nevoux p, mitchell v, chevallier d, et al. varicocele repair: does it still have a role in infertility treatment? curr opin in obstet gynecol. 2011; 23:151. 3. hubbard ld, brothers rj, king wn, et al. methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the atherosclerosis risk in communities study. ophthalmology. 1999; 106:2269. 4. ikram mk, witteman jc, vingerling jr, et al. retinal vessel diameters and risk of hypertension. the rotterdam study. hypertension. 2006; 47:189. 5. klein r, klein be, knudtson m, et al. are inflammatory factors related to retinal vessel caliber? the beaver dam eye study. arch ophthalmology. 2006; 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organization: manual for the standardized investigation and diagnosis of the infertile couple, cambridge university press, cambridge, 1993. archivio italiano di urologia e andrologia 2022; 94, 1 m.a. ghanem, e.a. adawi, a.m. ghanem, m.a. safan, a.a. ghanem 74 13. cina a, minnetti m, pirronti t, et al. sonographic quantitative evaluation of scrotal veins in healthy subjects: normative values and implications for the diagnosis of varicocele. eur urol. 2006; 50:345. 14. ghanem ma, safan ma, ghanem aa, dohle g. the role of varicocele sclerotherapy in men with severe oligo-astheno-teratozoospermia. asian j androl. 2011; 13:867. 15. mitchell v, robin g, boitrelle f, et al. correlation between testicular sperm extraction outcomes and clinical, endocrine and testicular histology parameters in 120 azoospermic men with normal serum fsh levels. int j androl. 2011; 34:299. 16. knudtson md, lee ke, hubbard ld, et al. revised formulas for summarizing retinal vessel diameters. curr eye res. 2003; 27:143. 17. kilic s, aksoy y, sincer i, et al. cardiovascular evaluation of young patients with varicocele. fertil steril. 2007; 88:369. 18. hanssen h, siegrist m, neidig m, et al. retinal vessel diameter, obesity and metabolic risk factors in school children (juventum 3). atherosclerosis. 2012; 221:242. 19. sun c, wang jj, mackey da, wong ty. retinal vascular caliber: systemic, environmental, and genetic associations. surv ophthalmol. 2009; 54:74. 20. barbieri er, hidalgo me, venegas a, et al. varicocele associated decrease in antioxidant defenses. j androl. 1999; 20:713. 21. fraczek m, sanocka d, kamieniczna m, kurpisz m. proinflammatory cytokines as an intermediate factor enhancing lipid sperm membrane peroxidation in in vitro conditions. j androl. 2008; 29:85. 22. kawagishi t, matsuyoshi m, emoto m, et al. impaired endothelium dependent vascular responses of retinal and intrarenal arteries in patients with type 2 diabetes. arterioscler thromb vasc biol. 1999; 19:2509. 23. ouchi n, kihara s, funahashi t, et al. obesity, adiponectin and vascular inflammatory disease. curr opin in lipidol. 2003; 14:561. 24. hsiao w, rosoff js, pale jr, et al. varicocelectomy is associated with increases in serum testosterone independent of clinical grade. urology. 2013; 81:1213. 25. chignalia az, schuldt ez, camargo ll, et al. testosterone induces vascular smooth muscle cell migration by nadph oxidase and c-src-dependent pathways. hypertension. 2012; 59:1263. 26. ediz c, temel mc, sahin ediz s, et al. contribution of pre-varicocelectomy color doppler ultrasonography finding to surgery and its correlation with semen parameters. arch ital urol androl. 2021; 93:227. 27. mahdavi a, heidari r, khezri m, et al. can ultrasound findings be a good predictor of sperm parameters in patients with varicocele? a cross-sectional study. nephrourol mon. 2016; 8:e37103. correspondence mazen a. ghanem, md, phd (corresponding author) mazenghanem99@yahoo.co.uk department of urology, jazan university (ksa) box: 45142, ksa-jazan essa a. adawi, md department of urology, jazan university (ksa) ahmed m. ghanem, md kasr al-ainy faculty of medicine, cairo university, cairo (egypt) manal a. safan, md medical biochemistry and molecular biology, menoufia university (egypt) asaad a. ghanem, md ophthalmic mansoura center, mansoura university (egypt) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12246 1 original paper introduction testicular cancer is associated with a survival rate of over 95% in 5 years, constituting a solid malignancy with a good prognosis. there are many factors leading to this fact including the young age of the patients, the complete surgical excision of the tumor as well as the effective use of chemotherapeutic agents (1). the staging of testicular cancer plays a crucial role in the successful management of the disease including the use of preoperative tumor markers (2). in clinical practice, alpha-fetoprotein (a-fp), beta-human chorionic gonadotropin (b-hcg) and lactate dehydrogenase (ldh) constitute the most common serum markers used in staging stratification. a-fp is a 70kd serum-binding protein that is mainly produced by the yolk sac, liver and intestines. the a-fp levels are peaked between 12-14 weeks of gestation, while they are decreased under 15 ng/ml after the first year of life (3). it has a serum half-life of 5-7 days, while it is considered the most commonly elevated tumor marker in testicular cancer patients (4). hcg is a 38kd protein that is produced by the placental syncytiotrophoblasts and consists of two subunits (a and b). in contrast to subunit a which resembles the pituitary hormones, b-hcg resembles only 70% of luteinizing hormone (lh) and thus is easier to be detected. the b-hcg is characterized by a serum half-life time of 24-36 hours (3, 5). ldh is a 134kd catalytic agent for the interconversion of lactate and pyruvate. ldh is not associated with high specificity for testicular cancer, nevertheless, it may highlight intense enzymatic processes (3). high levels of ldh over 2.000 u/l seem to be associated with an extremely elevated risk for recurrence (6). in recent years, the integration of cellular senescence was remarked as a revolution in the field of biology. interestingly senescence plays a crucial role in tumorigenesis and is considered as hallmark of cancer. it is determined as a special condition of cells and it includes their irreversible growth arrest, metabolism deregulation, purpose: the aim of this experimental study is to investigate the correlation between the presence of senescent cells and the tumor size, the lymphovascular invasion (lvi), the invasion of rete testis (rti), the preoperative tumor markers or pathological stage in patients who underwent orchiectomy for malignant purposes. methods: this experimental study included patients with a history of radical orchiectomy performed from january 2011 to january 2019. the testicular tissue specimens underwent an immunohistopathological process for the detection of the presence of cellular senescence. besides, the tumor size, the histopathological type, the pathological stage of the tumor and the presence of lymphovascular (lvi) or rete testis (rti) invasions were also recorded. additionally, the preoperative serum levels of alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase were recorded. after the completion of immunohistochemical analysis, the rate of senescent cells in each specimen was also recorded. results: the mean senescent cell rate was estimated to be 14.11 ± 11.32% and 15.46 ± 10.58% in patients with presence of lvi or absence of lvi, respectively (p = 0.46). the mean senescent cell rate was calculated at 18.13±12.26% and 12.56 ± 9.38% (p = 0.096) in patients with presence of rti or absence of rti, respectively. the mean senescent cell rate in the pt1 group was calculated at 14.58 ± 9.82%, while in t2 and t3 groups the mean senescent cell rate was estimated to be 15.22 ± 12.03% and 15.35 ± 14.21%, respectively (p = 0.98). a statistically significant correlation was detected between the senescence rate and the tumor size (pearson score 0.40, p = 0.027) and between the rate of senescent cells and the preoperative level of lactate dehydrogenase (ldh) (pearson score -0.53, p = 0.002). conclusions: the presence of cellular senescence was correlated with the extent of the testicular tumor in terms of tumor size as well as the preoperative level of the ldh serum marker. key words: testicular cancer; cellular senescence; preoperative tumor markers; gl13; senescent cells. submitted 31 december 2023; accepted 12 january 2024 cellular senescence in testicular cancer. is there a correlation with the preoperative markers and the extent of the tumor? an experimental study vasileios tatanis 1, dimitris veroutis 2, pavlos pantelis 2, george theocharous 2, helen sarlanis 3, alexandros georgiou 3, angelis peteinaris 1, anastasios natsos 1, napoleon moulavasilis 4, nikolaos kavantzas 3, athanassios kotsinas 2, ioannis adamakis 4 1 department of urology, university of patras, patras, greece; 2 molecular carcinogenesis group, department of histology and embryology, medical school, national kapodistrian university of athens (nkua), athens, greece; 3 department of pathology, medical school, national and kapodistrian university, athens, greece; 4 1st department of urology, national and kapodistrian university of athens, athens, greece. doi: 10.4081/aiua.2024.12246 summary archivio italiano di urologia e andrologia 2024; 96(1):12246 v. tatanis, d. veroutis, p. pantelis, et al. 2 macromolecular damage and a specific secretory phenotype termed senescence associated secretory phenotype (sasp) (7). the cellular senescence could be classified into two types depending on its triggering factors. the first type is widely known as replicative senescence in which the arrest of cellular proliferation is caused by telomere attrition. the second type is stress-induced premature senescence in which stressful stimuli constitute the triggering factors. the role of cellular senescence in the aged skin, in diseases that are determined as age-related and in the procedure of the formation of premalignant lesions is widely studied and presented in the literature. the action of senescence in terms of oncological diseases remains controversial, as it is proven to present both oncosuppressive and oncogenetic characteristics (8). on the one hand, the senescent cells act as tumor-barrier, whereas the accumulation of cells that are vulnerable due to the semi-active metabolic condition may enhance the oncogenesis or the tumor relapses (9). the association of cellular senescence with visceral tumors or major premalignant structures was investigated, although the available literature is restricted. the role of senescent cells has been described in the frame of a plethora of cancer types such as colorectal, pancreatic and hodgkin lymphoma (10). concerning the urogenital region, the presence of cellular senescence in seminomas was detected by savelyeva et al., while majumder et al. evaluated the presence of senescent cells in prostatic intraepithelial neoplasia (pin) and in prostatic cancer (11, 12). to our knowledge, the impact of cellular senescence in different histopathological types and its correlation with the tumor characteristics was not investigated. the aim of this experimental study is to evaluate the correlation of cellular senescence with the extent of the testicular tumor and with the level of preoperative serum markers. materials and methods statement of human rights the ethical committee of the university of athens has approved the conduction of this study in the “laiko” general hospital of athens. informed consent was obtained from all the participants, while the experiments were performed based on the principles of the helsinki declaration. study design this experimental study was conducted retrospectively. the study population included patients with a history of radical orchiectomy performed at the 1st urology department of athens medical school from january 2011 to january 2019. the radical orchiectomy was performed due to testicular cancer in all the patients. patients with secondary testicular tumors, incomplete preand postoperative data, younger than 18 years old, a history of chemotherapy or patients who were lost during the follow-up were excluded. the investigated samples consisted of formalin-fixed paraffin-embedded (ffpe) testicular tissue including tumor, cancerous and premalignant (if available) structures concomitantly and were obtained from the histopathological laboratory. moreover, the samples were sliced into specimens of 4mm thickness and were stained immunohistochemically against lipofuscin with gl13 (sentragor™), p21waf1/cip1 and ki67, to confirm the presence of senescent cells according to the proposed algorithm (13). gl13 is a biotinylated sudan black-b analogue that recognized lipofuscin as a hallmark of senescent cells (8, 14). the p21waf1/cip1 constitutes a protein that is hardly associated with non-cancerous testicular tissue or germ cell neoplasia in situ (gcnis) (14, 15). finally, ki67 is strongly associated with the growth fraction cells, as it identifies their proliferative activity 16. data collection the preoperative variables included the age of the patient and the date of the operation. the testicular dimensions were recorded based on the report of the pathological examination as it is proven to be the most rigorous measurement (17). besides the testicular and tumor sizes, the histopathological type and the pathological stage were recorded. the presence of lymphovascular invasion (lvi) and rete testis invasion (rti) presence was also recorded, based on the pathological report. in the case of mixed tumors, despite the documentation of all the included types and the corresponding rates, the primary histological diagnosis was utilized as the milestone for the patient’s subgrouping. additionally, the preoperative serum levels of a-fp, b-hcg and ldh were recorded. after the completion of immunohistochemical analysis, the total rate of senescent cells in each specimen was also recorded. immunohistochemistry for anti-biotin, p21waf1/cip1 and ki-67 staining the samples were deparaffinized and hydrated while the antigen retrieval was heated mediated using 10 mm of citric acid (ph 6.0) for 15 minutes in a steamer (in the case of sentragor™ staining). in the case of incubation with p21waf1/cip1 and ki67 antibodies, antigen retrieval was completed similarly, but a 25-minute microwave was applied for the heating mediation. normal goat serum was applied for 1 hour at room temperature (dilution 1:40, abcam, ab138478) to achieve the blocking of nonspecific binding of the aforementioned antibodies. the applied primary antibodies included: anti-biotin antibody (dilution 1:300, hyb-8, ab201341, abcam) or antip21waf1/cip1 (dilution 1:200, 12d1, cell signaling) or anti-ki67 (dilution 1:250, sp-6, abcam) and the tissues were incubated overnight at 4°c. the use of the dako real envision detection system kit, (cat.no: k5007) according to the manufacturer’s instructions using dab (brown color), led to the progression of the signal. the specimens were counterstained with hematoxylin to encounter the positive cells. finally, the sections were observed using zeiss axiolab5 optical microscope on the 20x objective (200x magnification, 25μm scale bar) (13). sentragor™ (gl13) staining for senescence detection the sentragor™ staining was performed following the step of blocking non-specific binding sites of primary antibody. the specimens were incubated in 50% ethanol for 5 minutes and then in 70% ethanol for 5 minutes more. sentragor™ was applied in tissues and the speciarchivio italiano di urologia e andrologia 2024; 96(1):12246 3 cellular senescence in testicular cancer mens were covered with glass coverslips, followed by 10minutes incubation at 37°c. afterward, coverslips were gently removed and sections were washed with 50% ethanol for 30 seconds. an extra wash step was performed (3-5 minutes) using triton-x 0.3%/tbs. afterward, the sections were washed with tbs, followed by an overnight application of the anti-biotin antibody (dilution: 1/300, cat.no: k5007) at 4°c (13). statistical analysis continuous variables were presented using the mean value and standard deviation. categorical variables were described as absolute numbers and rates. the comparison of continuous variables was investigated using the two-way t-test, while the correlation between variables was investigated using the pearson correlation coefficient. the differences between multiple groups were evaluated using the one-way anova test. statistical analysis was conducted utilizing the statistical package for the social sciences (spss) software package version 25.0 (ibm corp., armonk, ny). results in this scientific work in order to evaluate the correlation of senescent cells with the pathological tumor stage, preoperative serum tumor markers, lvi and rti in different histological types, specimens from 30 patients were utilized. the mean age of the patients was estimated to be 30.97 ± 8.68 years, while the mean maximum diameter of the testis was recorded to be 6 ± 2.80 cm. tumor size and cellular senescence the mean size of tumors in all groups was estimated to be 4.16 ± 3.25 cm. based on the stratification into groups based on the primary histopathological diagnosis, the larger tumors were identified in the yolk sac groups with a mean maximum diameter of 9.27 ± 4.97 cm, followed by the teratoma group where the mean maximum diameter of the tumor was calculated at 3.83 ± 0.97 cm. the seminomas and embryonal carcinomas were associated with shorter maximum mean diameters (2.9 ± 1.15 cm and 3.46 ± 2.67 cm, respectively). the difference between the groups was statistically significant (p = 0.002). the correlation between cellular senescence and the tumor size overall was statistically significant (pearson score: 0.40, p = 0.027). nevertheless, the correlation in the subgroups did not reach the statistically significant level. more precisely, the pearson score in the seminoma group was estimated at -0.45 (p = 0.13), while in the embryonal tumor group was calculated at 0.05 (p = 0.89). additionally, the pearson scores in the teratomas and yolk sac tumors groups were 0.18 (p = 0.97) and 0.22 (p = 0.86), respectively (table 1). lvi and cellular senescence the lvi was presented in 15/30 (50%) cases, while no lvi was noticed in the remaining 50% of the cases (15/30). more precisely, in 5/13 (38.5%) patients of the seminoma group lvi was detected, while 6/9 (66.7%) patients of the embryonal groups presented with similar pathological characteristics. the lvi was detected in 2/4 (50%) and 2/3 (66.7%) patients in the teratomas and yolk sac tumors, respectively, whereas no lvi was mentioned in the patients with chondrosarcoma. the mean senescent cell rate was estimated to be 14.11 ± 11.32% and 15.46 ± 10.58% in patients with present lvi and absent lvi, respectively. the difference was not statistically significant (p = 0.46). moreover, a statistically significant association between the senescent cell rate and lvi was not observed in seminoma (25.98 ± 8.41% vs 23.96 ± 6.64%, p = 0.66) or embryonal groups (8.92 ± 7.94% vs 4.53 ± 0.93%, p = 0.30) (table 2). rti and cellular senescence the rti was presented in 12/30 (40%) cases, while no rti was noticed in the remaining 60% of the cases (18/30). more precisely, in 6/13 (46.2%) patients of the seminoma group rti was detected, while 4/9 (44.4%) patients of the embryonal groups presented with similar pathological characteristics. the rti was detected in 1/4 (25%) and 1/3 (33.3%) patients in the teratomas and yolk sac tumors, respectively, whereas no rti was mentioned in the patients with chondrosarcoma. the mean senescent cell rate was estimated to be 18.13 ± 12.26% and 12.56 ± 9.38% in patients with present rti or absent rti, respectively. the difference was not statistically significant (p = 0.096). moreover, a statistically significant association between the senescent cell rate and rti was not observed in seminoma (27.58 ± 5.16% vs 22.3 ± 7.97%, p = 0.18) or embryonal groups (9.78 ± 8.16% vs 5.6 ± 1.64%, p = 0.54) (table 3). table 1. evaluation of the senescent cells in relationship to the tumor size. tumor’s maximum senescent cells pearson p-value dameter (mean ± sd) rate (mean ± sd) score overall 4.16 ± 3.25 cm 14.79 ± 10.79% 0.40 0.027* seminoma 2.9 ± 1.15 cm 24.74 ± 7.1% -0.45 0.13 embryonal 3.46 ± 2.67 cm 7.46 ± 6.82% 0.05 0.89 teratoma 3.83 ± 0.97 cm 6.9 ± 1.8% 0.18 0.97 yolk sac 9.27 ± 4.97 cm 6.06 ± 1.79% 0.22 0.86 sd: standard deviation. table 2. evaluation of the senescent cells in the presence or absence of lvi. lvi positive lvi negative p-value overall patients (%) 15 (50%) 15 (50%) senescent cells rate (mean ± sd) 14.11 ± 11.32% 15.46 ± 10.58% 0.46 seminoma patients (%) 5 (38.5%) 8 (61.5%) senescent cells rate (mean ± sd) 25.98 ± 8.41% 23.96 ± 6.64% 0.66 embryonal patients (%) 6 (66.7%) 3 (33.3%) senescent cells rate (mean ± sd) 8.92 ± 7.94% 4.53 ± 0.93% 0.30 lvi: lymphovascular invasion; sd: standard deviation. archivio italiano di urologia e andrologia 2024; 96(1):12246 v. tatanis, d. veroutis, p. pantelis, et al. 4 pathological stage and cellular senescence the association between senescent cell rate and pathological stage of the tumor was also evaluated. in eleven (36.7%), seventeen (56.7%) and two (6.6%) patients the pathological stage was t1, t2 and t3, respectively. the mean senescent cell rate in the t1 group was calculated at 14.58 ± 9.82%, while in the t2 and t3 groups, the mean senescent cell rates were estimated to be 15.22 ± 12.03% and 15.35 ± 14.21%, respectively. the difference did not reach the statistical significance level, as p = 0.98 (table 4). preoperative tumor markers and cellular senescence the correlation between the cellular senescence rate and the preoperative tumor markers constituted another endpoint of the study. in total samples, the correlation between ldh and cellular senescence reached a statistically significant level, as the pearson score was calculated at -0.53 (p = 0.002). on the other hand, no statistically significant correlation between the rate of senescent cells and the a-fp (pearson score: -0.24, p = 0.20) or the bhcg (pearson score: -0.23, p = 0.23) was detected. after the stratification based on the primary histopathological type, ldh was statistically correlated with cellular senescence only in the seminoma subgroup. the pearson scores for ldh were estimated to be 0.56 (p = 0.045), 0.04 (p = 0.92), 0.091 (p = 0.90) and -0.06 (p = 0.96) in seminoma, embryonal, teratoma and yolk sac groups, respectively. the outcomes concerning the pearson scores of a-fp were -0.13, p = 0.66 in the seminoma group; 0.30, p = 0.43 in the embryonal group; 0.39, p = 0.61 in the teratoma group; 0.06, p = 0.96 in the yolk sac group. the correlation between senescent cell rate and the b-hcg did not reach a statistically significant level in any subgroup (pearson score 0.11, p = 0.72 in the seminoma group; pearson score 0.56, p = 0.11 in the embryonal group; pearson score 0.37, p = 0.63 in the teratoma group; pearson score -0.2, p = 0.87 in the yolk sac group) (table 5). discussion the aim of this scientific study was to evaluate the association of the senescent cell detection rate with the tumor size, the preoperative tumor markers, the pathological stage and the presence of lvi and rti. in order to investigate the aforementioned correlation, stains with specific biomarkers showing the state of the examined tissues (proliferation or cellular senescence) were applied. the lipofuscin, which constitutes an established biomarker of senescence, was detected by the gl13 staining (8). the staining pattern in these cells seems to be both perinuclear and cytoplasmic. besides gl13, p2121waf1/cip1 and ki67 stains were utilized to perform a more robust disclosure of the cellular senescence in situ and to elucidate additional elements of the molecular behaviour of the evaluated tissues (18). the outcomes of the study proved that there is a statistical correlation between cellular senescence and the tumor size in overall the sample size, although this correlation was not confirmed in the subgroup analysis. despite being significantly associated with tumor size, cellular senescence does not seem to be strongly correlated with the pathological stage of the tumors. additionally, the presence of lvi or rti does not seem to have a specific association with the senescent cell detection rates. concerning the preoperative tumor markers, no significant association between cellular senescence and the a-fp or b-hcg was detected in either the overall sample size or subgroups. on the other hand, ldh was statistically sigtable 4. evaluation of the senescent cell rate based on the pathological stage. pt1 stage pt2 stage pt3 stage p-value sample size (%) 11 (36.7%) 17 (56.7%) 2 (6.6%) senescent cells rate (mean ± sd) 14.58 ± 9.82% 15.22 ± 12.03% 15.35 ± 14.21% 0.98 sd: standard deviation. table 5. the correlation scores between cellular senescence and the preoperative serum tumor markers. pearson score p-value overall ldh -0.53 0.002* afp -0.24 0.20 b-hcg -0.23 0.23 seminoma ldh 0.56 0.045* a-fp -0.13 0.66 b-hcg 0.11 0.72 embryonal ldh -0.04 0.92 a-fp 0.30 0.43 b-hcg 0.56 0.11 teratoma ldh 0.091 0.90 a-fp 0.39 0.61 b-hcg 0.37 0.63 yolk sac ldh -0.06 0.96 a-fp 0.06 0.96 b-hcg 0.2 0.87 ldh: lactate dehydrogenase; a-fp: alpha-fetoprotein; b-hcg: beta-human chorionic gonadotropin. table 3. evaluation of the senescent cells in the presence or absence of rti. rti positive rti negative p-value overall patients (%) 12 (40%) 18 (60%) senescent cells rate (mean ± sd) 18.13 ± 12.26% 12.56 ± 9.38% 0.096 seminoma patients (%) 6 (46.2%) 7 (53.8%) senescent cells rate (mean ± sd) 27.58 ± 5.16% 22.3 ± 7.97% 0.18 embryonal patients (%) 4 (44.4%) 5 (55.6%) senescent cells rate (mean ± sd) 9.78 ± 8.16% 5.6 ± 1.64% 0.54 rti: rete testis invasion; sd: standard deviation. archivio italiano di urologia e andrologia 2024; 96(1):12246 5 cellular senescence in testicular cancer nificantly correlated with the senescent cell detection rates in the overall sample size and seminoma group, whereas no significant correlation with the embryonal, teratoma and yolk sac groups. to our knowledge, this is the first study that investigated the correlation of cellular senescence with the extent of the tumor and the preoperative serum tumor markers. the impact of cellular senescence in the carcinogenesis of the genitourinary system was documented in both testicular and prostate cancer. the presence of senescent cells in testicular cancer was described by savelyeva et al. (11). the authors investigated the microenvironment of pure seminomas and they identified that it compromises senescent cells (11). concerning prostate cancer, the role of cellular senescence was investigated by majumder et al. and mourkioti et al. majumder et al. evaluated the presence of senescent cells in both premalignant conditions of pin and prostatic cancer tissues. based on their outcomes, senescent cells were detected in cases of pin or pin and prostatic cancer structures concomitantly, whereas no cellular senescence was identified in prostate cancer-only tissues. in our study, cellular senescence was investigated in terms of correlation to the extent of the disease and to the preoperative tumor serum markers in various histopathological types of testicular cancer (12). moreover, mourkioti et al. proved that the downregulation of cdc6 gene expression may enhance androgen receptor blockadeinduced senescence in metastatic prostate cancer cells highlighting the therapeutic impact of cellular senescence even in advanced cancer stages (19). based on our outcomes, a significant correlation of cellular senescence with the tumor size (pearson score: 0.40, p = 0.027) and ldh (pearson score: -0.53, p = 0.045) was identified. thus, we can confirm the presence of senescent cells in various histological types of testicular cancer, even if the correlation was not statistically significant, as was described by savelyeva et al. (11). additionally, contrary to majumder et al., cellular senescence was detected in all histological types of testicular tissue. a possible explanation for that phenomenon could be the different methodology of senescence detection, as gl13 seems to be the most accurate marker for senescence detection since it detects lipofuscin accumulation as a result of the deregulated metabolism, macromolecular damage and cell cycle arrest, the three out of four hallmarks of senescence (14). moreover, the application of additional senescence markers contributed to an improved evaluation of the tissue structures. the controversial impact of cellular senescence in oncogenesis was widely evaluated in the literature. cellular senescence seems to be a barrier to the triggered oncogenes showing its important tumor-suppressive role (18). the cycle arrest condition that characterizes cellular senescence seems to improve the efficacy of the apoptosis or dna-damage repair processes. on the contrary, senescent cells may accumulate in different types of tissue due to the disturbance of the induction/elimination balance. the aforementioned disturbance leads to the accumulation of senescent cells that are vulnerable to modifications of their genome or sasp. these modifications result in either endothelial-to-mesenchymal transition (emt) or selfrenewal which are characterized by invasive/metastatic or stemness potential, respectively (20). besides the cycle arrest, they seem to escape and re-enter the cell cycle, a phenomenon termed “escape from senescence”. the latter are associated with a different phenotype compared to the primary senescent cells and thus they may be characterized as more aggressive and potentially oncogenetic. sasp has a paracrine function that promotes cellular senescence and its tumor-suppressive role in low-grade preneoplastic cells increasing the interleukin, chemokine, growth factors and regulator, receptor and ligand levels, and altering the function of collagens, laminin and reactive oxygen species (bright side) (21). on the contrary, it encourages the escape from senescence and relapse to the cell cycle in the malignant cells (dark side) (7). the modifications of the sasp profile are considered the cause of the bimodal role of cellular senescence. normally, sasp includes interleukins, chemokines, growth factors and additional soluble factors in equilibrium that enhance its tumor-suppressive role. on the other hand, under the impact of p53 loss or oncogenic ras gain, the sasp is modified compromising abnormally elevated interleukins, chemokines and other inflammatory factors that induce the escape phenomenon. more precisely, in prostate cancer, the secretion of sdf-1α factor in the frame of sasp of senescent fibroblasts seems to enhance the prostate cancer progress, while the hypersecretion of inflammatory factors of senescent cells’ sasp may be associated with higher risk for relapse after chemotherapy (21). the latter proves the negative aspect of cellular senescence that is related to the oncological diseases (9, 22). this phenomenon may explain the negative correlation between cellular senescence and the ldh, which has been proved in our study. senescent cells are normally accumulated in premalignant lesions, as described in prostatic and pancreatic cancer, whereas ldh is elevated in some cases of testicular neoplasia as accompanied by intense enzymatic processes (3, 10, 12). in our study, the negative correlation (pearson score: -0.53) may indicate the decrease of senescent cell detection rate during the transformation of the premalignant to malignant conditions (which are characterized by elevated ldh) highlighting the escape phenomenon as described by zampetidis et al. (9). besides the significant negative correlation between ldh and cellular senescence in overall the sample size, another positive correlation was identified in the seminoma subgroup (pearson score: 0.56, p = 0.045). thus, we can consider that the senescent cell detection rate remains at relatively high levels in the seminoma group, while it is decreased in the other histopathological subgroups. this observation may be explained by the sequence of testicular cancer as proposed by von eyben et al. (23). the authors supported that the seminoma constitutes the first step of the transformation of the premalignant conditions (gcnis) to testicular cancer. afterward, the seminoma may be transformed into embryonal carcinoma, followed by the parallel development of teratoma or yolk sac tumor. consequently, we can consider that a significant rate of senescent cells remains in the seminoma, which may escape from senescence in the latter steps (9). there is detailed documentation in the literature regarding the association between senescent cells and colorectal cancer, lung adenocarcinoma, or classical hodgkin lymphoma (10, 24, 25). moreover, the role of cellular senesarchivio italiano di urologia e andrologia 2024; 96(1):12246 v. tatanis, d. veroutis, p. pantelis, et al. 6 cence is also important in the failure of chemotherapy and the disease relapses. the presence of senescent hodgkin and reed-sternberg cells in high proportions (over 10-15%) seems to be a risk factor for poor prognosis in patients suffering from hodgkin lymphoma, as described by broeckelman et al. (26). in our study, the positive correlation of cellular senescence with ldh in the seminoma groups may indicate the presence of a relatively high proportion of senescent cells in the seminomas. taking into consideration the example of hodgkin lymphoma, we may consider the management of both the tumor and the senescent cells in specific cases. the combination of chemotherapeutic agents with senolytics may improve the efficacy of the treatment, prevent tumor relapses and ameliorate the prognosis and the quality of life of the patients. consequently, novel combined chemotherapeutic strategies aiming at both cancerous and senescent cells may be developed and evaluated. there are limitations in our study. the sample size is relatively small, as it includes tissue specimens of 30 patients. besides the reduced sample size, this is the first study to our knowledge that evaluated the correlation between cellular senescence and the extent of testicular cancer or the preoperative tumor markers. moreover, the outcomes of the immunohistochemical staining are not associated with the clinical presentation and the prognosis of the patients. further studies should be conducted for the correlation of immunohistochemical and clinical outcomes. conclusions the presence of cellular senescence was correlated with the extent of the testicular tumor in terms of tumor maximum diameter, whereas the association was insignificant regarding the pathological stage and the lymphovascular or rete testis invasions. the levels of ldh preoperatively seem to be negatively correlated to the presence of cellular senescence, while an additional positive correlation was detected in patients suffering from seminoma. references 1. biggs ml ss. cancer of the testis. in: ries lag yj, keel ge, eisner mp, lin yd, horner m-j, editor. seer survival monograph: cancer survival among adults: us seer program, 1988-2001, patient and tumor characteristics: national cancer institute. 2007; p. 165-70. 2. urology ea. eau guidelines. edn. presented at the eau annual congress milan 2023 ed. 3. milose jc, filson cp, weizer az, hafez ks, montgomery js. role of biochemical markers in testicular cancer: diagnosis, staging, and surveillance. open access j urol. 2011; 4:1-8. 4. germa-lluch jr, garcia del muro x, maroto p, et al. clinical pattern and therapeutic results achieved in 1490 patients with germ-cell tumours of the testis: the experience of the spanish germ-cell cancer group (gg). eur urol. 2002; 42:553-62. 5. lempiainen a, stenman uh, blomqvist c, hotakainen k. free beta-subunit of human chorionic gonadotropin in serum is a diagnostically sensitive marker of seminomatous testicular cancer. clin chem. 2008; 54:1840-3. 6. carl j, christensen tb, von der maase h. cisplatinum dose dependent response in germ cell cancer evaluated by tumour marker modelling. acta oncol. 1992; 31:749-53. 7. gorgoulis vg, halazonetis td. oncogene-induced senescence: the bright and dark side of the response. curr opin cell biol. 2010; 22:816-27. 8. georgakopoulou ea, tsimaratou k, evangelou k, et al. specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. a method applicable in cryo-preserved and archival tissues. aging (albany ny). 2013; 5:37-50. 9. zampetidis cp, galanos p, angelopoulou a, et al. a recurrent chromosomal inversion suffices for driving escape from oncogeneinduced senescence via subtad reorganization. mol cell. 2021; 81:4907-23 e8. 10. myrianthopoulos v, evangelou k, vasileiou pvs, et al. senescence and senotherapeutics: a new field in cancer therapy. pharmacol ther. 2019; 193:31-49. 11. savelyeva av, medvedev ke. seminoma subtypes differ in the organization and functional state of the immune microenvironment. 3 biotech. 2023; 13:110. 12. majumder pk, grisanzio c, o'connell f, et al. a prostatic intraepithelial neoplasia-dependent p27 kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. cancer cell. 2008; 14:146-55. 13. kohli j, wang b, brandenburg sm, et al. algorithmic assessment of cellular senescence in experimental and clinical specimens. nat protoc. 2021; 16:2471-98. 14. evangelou k, lougiakis n, rizou sv, et al. robust, universal biomarker assay to detect senescent cells in biological specimens. aging cell. 2017; 16:192-7. 15. bartkova j, thullberg m, rajpert-de meyts e, et al. cell cycle regulators in testicular cancer: loss of p18ink4c marks progression from carcinoma in situ to invasive germ cell tumours. int j cancer. 2000; 85:370-5. 16. hilbold e, bergmann m, fietz d, et al. immunolocalization of dmrtb1 in human testis with normal and impaired spermatogenesis. andrology. 2019; 7:428-40. 17. paltiel hj, diamond da, di canzio j, et al. testicular volume: comparison of orchidometer and us measurements in dogs. radiology. 2002; 222:114-9. 18. gorgoulis v, adams pd, alimonti a, et al. cellular senescence: defining a path forward. cell. 2019; 179:813-27. 19. mourkioti i, polyzou a, veroutis d, et al. a gata2-cdc6 axis modulates androgen receptor blockade-induced senescence in prostate cancer. j exp clin cancer res. 2023; 42:187. 20. evangelou k, belogiannis k, papaspyropoulos a, et al. escape from senescence: molecular basis and therapeutic ramifications. j pathol. 2023; 260:649-65. 21. coppe jp, desprez py, krtolica a, campisi j. the senescenceassociated secretory phenotype: the dark side of tumor suppression. annu rev pathol. 2010; 5:99-118. 22. galanos p, pappas g, polyzos a, et al. mutational signatures reveal the role of rad52 in p53-independent p21-driven genomic instability. genome biol. 2018; 19:37. archivio italiano di urologia e andrologia 2024; 96(1):12246 7 cellular senescence in testicular cancer 23. von eyben fe, parraga-alava j. meta-analysis of gene expressions in testicular germ cell tumor histologies. int j mol sci. 2020; 21. 24. haugstetter am, loddenkemper c, lenze d, et al. cellular senescence predicts treatment outcome in metastasised colorectal cancer. br j cancer. 2010; 103:505-9. 25. collado m, gil j, efeyan a, et al. tumour biology: senescence in premalignant tumours. nature. 2005; 436:642. 26. brockelmann pj, angelopoulou mk, vassilakopoulos tp. prognostic factors in hodgkin lymphoma. semin hematol. 2016; 53:155-64. correspondence vasileios tatanis, md (corresponding author) tatanisbas@gmail.com department of urology, university of patras, patras, greece university of patras, rio, patras, 26500, greece angelis peteinaris, md peteinarisaggelis@gmail.com anastasios natsos, md anatsos@gmail.com dimitris veroutis, md dimitrisveroutis1@gmail.com pavlos pantelis, md pavlospantelis7@gmail.com george theocharous, md theocharousgiorgos@gmail.com athanassios kotsinas, md akotsin@gmail.com molecular carcinogenesis group, department of histology and embryology, medical school, national kapodistrian university of athens (nkua), athens, greece helen sarlanis, md elenisarlani@gmail.com alexandros georgiou, md alexandrosge11@gmail.com nikolaos kavantzas,md nkavantz@med.uoa.gr department of pathology, medical school, national and kapodistrian university, athens, greece napoleon moulavasilis, md napomoul@hotmail.com ioannis adamakis, md yianton@hotmail.com 1st department of urology, national and kapodistrian university of athens, athens, greece conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2019; 91, 2102 original paper the impact of potassium citrate therapy in the natural course of medullary sponge kidney with associated nephrolithiasis elisa cicerello, matteo ciaccia, giandavide cova, mario mangano urology unit, department of surgery, ospedale ca’ foncello, treviso, italy. objectives: the present study was carried out to evaluate the effectiveness of medical therapy with potassium citrate in preventing calculosis complicating medullary sponge kidney (msk) without renal acidification defects. materials and methods: in a open, uncontrolled, retrospective analysis, 49 msk patients with nephrolithiasis without renal tubular acidosis, underwent a complete metabolic evaluation and received potassium citrate therapy 4-6 g/day. the course of stone disease before and after citrate therapy was determined in each patient from a combination of clinical history, past records, radiographs and kidney ultrasound. the rate of new stone formation/pt/yr, of endourological and extracorporeal procedures, of urinary tract infection (uti) and number of hospitalization before and after medical treatment were calculated. results: metabolic anomalies (hypercalciuria, hypocitraturia, hyperuricuria and hyperoxaluria) were present in 83% of the patients. follow-up before and after alkali citrate therapy was comparable (4.7+/-1.4 and 4.9+/-1.7 years respectively). medical treatment significantly reduced rates of stone formation from 2.0+/-1.0 to 0.2+/-0.5 pt/yr, ureteroscopy (urs) from 0.9+/0.8 to 0.4+/-0.5 pt/yr, extratracoporeal lithotripsy (eswl) from 1.1+/-0.8 to 0.4+/-0.6 pt/yr, urinary tract infections (utis) from 0.8+/-1.2 to 0.3+/-0.5 pt/yr and hospitalization from 1.1+/-0.6 to 0.2+/-0.3 pt/yr, p < 0.001. this effect was observed also in msk patients without metabolic anomalies. in 35 patients the asymptomatic disappearance of calcium stones was also observed. conclusions: our study documents the effectiveness of potassium citrate therapy in preventing neprolithiasis in msk patients also in the absence of distal tubular acidosis. it suggests that in msk patients alkali citrate may promote calcium stone dissolution by oral administration. key words: medullary sponge kidney (msk); nephrolithiasis; potassium citrate therapy. submitted 6 march 2018; accepted 6 december 2018 summary no conflict of interest declared. according to radiographic criteria that include the characteristic “paint brush” appearance of the dilated tubules draining into flattened calyces (2) which may favour salts crystallization and precipitation with consequently stone formation. nephrolithiasis in msk causes pain and urinary infection and requires radiological and ultrasound exams and urological treatments for stone removal. medical treatment to prevent nephrolithiasis has been known from 30 years and numerous studies suggest the effectiveness of potassium citrate in preventing stone formation in different form of nephrolithiasis with economic advantages (3, 4). previous works have demonstrated in msk a variety of metabolic abnormalities which, together the papillary collecting duct dilatation, could play a role in stone formation, including hypercalciuria, hypocitraturia, hyperuricuria and urinary acidification defects (5-7). also the concurrence of hyperparathyroidism and msk has been reported which suggest that renal hypercalciuria from disordered nephron function may lead to parathyroid hyperplasia and adenoma (8). in the past medical treatment with potassium citrate was performed only in the presence of acidification defects and hypocitraturia was shown to normalize with concorrent reduction in stone formation (9). the present study was carried out to evaluate the effectiveness of medical therapy with potassium citrate in preventing calculosis complicating msk in the absence of acidification defects. patients and methods from january 1994 to june 2013 in the urologic clinic of the treviso general hospital we evaluated 842 patients with recurrent calcium stones. sixty-one (7.2%) had the characteristic features of msk on intravenous pyelograms (2), i.e. radial distribution of calcification around enlarged papillae, flattened calyces and dilated collecting tubules with or without cystic deformities. in 58 patients the defect was bilateral and in all cases tubular ectasia involved three or more papillae. for this study, all radiographs were reviewed by one of us and at least one radiologist unaware of the previous diagnosis and diagnostic conclusion was confirmed in 100% of the cases. doi: 10.4081/aiua.2019.2.102 introduction medullary sponge kidney (msk) is a congenital abnormality of the renal medulla characterized by the presence of multiple small cysts. these changes were described by the italian radiologist leonarduzzi and a decade later cacchi e ricci confirmed these finding histopatologically (1). the condition is diagnosed on excretory urograms 103archivio italiano di urologia e andrologia 2019; 91, 2 the impact of potassium citrate therapy in the natural course of medullary sponge kidney with associated nephrolithiasis starting from 2000, our standard medical treatment for all msk stone formers was potassium citrate (4 to 6 gm. per day orally in 2-3 doses). for the aim of this study, we have retrospectively evaluated patients with at least 2 years of continuos potassium citrate therapy and in whom distal renal tubular acidosis (rta) had been excluded. complete rta is diagnosed when at least 2 of the following conditions are observed: morning urinary ph higher than 5.5 (in sterile urine), systemic acidemia, urinary citrate excretion lower 100 mg /24 h. when only one of the three above is observed, an oral ammonium chloride test (nh4cl load 0.05g/kg/body weight over 3 days) was performed and a fasting urine ph after test higher than 5.6 coincident with systemic acidemia was considered diagnostic of rta. as a whole 49 patients (31 males and 18 females, mean age 37.7+/-16.3 and 30.7+/15.2 yrs. respectively) with adequate follow-up and compliance to medical treatment form the bases of this report; all patients had defect and the fully developed form of the anatomic features. patients had been evaluated before the beginning of potassium citrate therapy with a clinical and metabolic protocol, radiological and ultrasound examinations. three 24-hour urine samples were collected on an outpatient basis, while eating the usual diet. urine was analyzed for levels of oxalate, uric acid, calcium, citrate, creatinine, sodium and potassium. after at least 10 hours fasting, venous blood samples were drawn for calcium, phosphate, uric acid, creatinine, and morning spot urine was collected. idiopathic hypercalciuria was defined as 24 hr urine calcium excretion greater than 300 mg, normocalcemia and exclusion of other hypercalciuric conditions. hyperuricuria was definited as a 24 hr uric acid excretion above 800 mg, hypocitraturia as less than 350 mg and hyperoxaluria as more than 40 mg. mean follow-up before and after treatment was 4.7+/-1.4 and 4.9+/-1.7 yrs. respectivelly. the course of stone disease before and after medical treatment was determined in each patient from clinical history, past records, radiographs (kub xray, pielography) and kidney ultrasounds: namely, the number of passed stones, of not expulsed stones, of urological procedures (intracorporeal or extracorporeal treatments), of urinary tract infections (utis) was registered. uti episodes were defined as episode of chills, fever and flank pain that led to medical care. these patients were monitored during potassium citrate theraphy every 6 months with blood creatinine, sodium and potassium and urine analysis. the compliance to medical treatment was evaluated by urinary ph since potassium citrate alkalinizes the urine. ultrasound was carried out every 6 months and kub x-ray with tomography once year to ascertain the exact number of stones. ct scan was only performed in few cases and was excluded for the aim of this study. a new stone was defined as the radiographic apperance, removal, or passage of a stone not present on a prior radiograph. passed or removed stone were analyzed whenever possible. the rate of new stone formation/year, of endourological and extracorporeal procedures, of uti and number of hospitalization before and after medical treatment were calculated as means +/sd of values from each patient. the statistical analysis was carried out by the student ttest for paired data. results hypercalciuria was present in 21 (43%) patients, hypocitraturia in 23 (47%), hyperuricuria in 14 (28%) and hyperoxaluria in 8 (16%). thirteen patients were hypertable 1. effect of potassium citrate therapy on complications in msk patients with index episodes. pre-treatment post-treatment p value pre-treatment post-treatment p value (all patients) (all patients) (student t-paired test) (patients without (patients without (student t-paired test) metabolic anomalies) metabolic anomalies) stones/pt/yr 2.0 ± 1.0 0.2 ± 0.5 < 0.001 1.6 ± 1.0 0.03 ± 0.07 < 0.005 urs/pt/yr 0.9 ± 0.8 0.4 ± 0.5 < 0.001 0.9 ± 0.6 0.2 ± 0.4 < 0.05 eswl/pt/yr 1.1 ± 0.8 0.4 ± 0.6 < 0.001 1.1 ± 0.9 0.2 ± 0.3 < 0.05 uti/pt/yr 0.8 ± 1.2 0.3 ± 0.5 < 0.001 0.8 ± 07 0.2 ± 0.3 < 0.01 hospitalization/pt/yr 1.1 ± 0.6 0.2 ± 0.3 < 0.001 1.1 ± 0.9 0.2 ± 0.3 < 0.01 table 2. effect of potassium citrate therapy on complications in msk patients without index episodes. pre-treatment post-treatment p value pre-treatment post-treatment p value (all patients) (all patients) (student t-paired test) (patients without (patients without (student t-paired test) metabolic anomalies) metabolic anomalies) stones/pt/yr 1.9 ± 1.0 0.2 ± 0.5 < 0.001 1.5 ± 0.9 0.03 ± 0.07 < 0.005 urs/pt/yr 0.9 ± 0.7 0.4 ± 0.5 < 0.001 0.9 ± 0.6 0.2 ± 0.4 < 0.05 eswl/pt/yr 1.1 ± 0.7 0.4 ± 0.6 < 0.001 1.0 ± 0.8 0.2 ± 0.3 < 0.05 uti/pt/yr 0.8 ± 1.1 0.3 ± 0.5 < 0.001 0.8 ± 07 0.2 ± 0.3 < 0.01 hospitalization/pt/yr 1.0 ± 0.6 0.2 ± 0.3 < 0.001 1.0 ± 0.9 0.2 ± 0.4 < 0.01 archivio italiano di urologia e andrologia 2019; 91, 2 e. cicerello, m. ciaccia, g. cova, m. mangano 104 calciuric and hypocitraturic, 4 hyperuricuric and hypercalciuric and 5 hyperuricuric, hypercalciuric and hypocitraturic). in 9 patients (17%) no metabolic anomaly was found. no patient with msk was hypercalcemic and none had hyperparathyroidism. the chemical analysis of stone removed or passed was calcium oxalate (caox) and /or calcium phosphate (cap) and mixed (caox plus uric acid) in 5 patients. starting from the first control after beginning potassium citrate therapy urinary ph significantly increased (from 5.63+/-0.61 to 6.74+/-0.55 respectively, p < 0.0001) without significant changes in plasma creatinine, calcium, phosphate, uric acid, sodium and potassium. furthermore medical treatment significantly reduced rates of stone formation from 2.0+/-1.0 to 0.2+/-0.5 pt/yr, ureteroscopy (urs) from 0.9+/0.8 to 0.4+/-0.5 pt/yr, extratracoporeal lithotripsy (eswl) from 1.1+/-0.8 to 0.4+/-0.6 pt/yr, urinary tract infections (utis) from 0.8+/-1.2 to 0.3+/-0.5 pt/yr and hospitalization from 1.1+/-0.6 to 0.2+/-0.3 pt/yr, p < 0.001. this effect was observed also in msk patients without metabolic abnormalities (table 1). to rule out that these results were due to a ”regression to the mean” bias, we excluded from the analysis the index episodes bringing patients to our attention. table 2 shows the amended results and confirms the favourable activity of alkali citrate treatment. furthermore, in 35 patients we have observed the disappearance of stones present on previous x-ray (figures 1, 2). discussion the frequency of radiographic features of msk may vary from 2.3 to 21% of patients with calcium stones (5, 8). the incidence of msk in our patients whith recurrent calcium nephrolithiasis was 7.2%; for the aim of this study only those patients with the fully developed form of the anatomic defect, easily recognized on routine intravenous pyelograms, were considered. patients with msk usually come to the attention of physicians because of kidney stones. the frequent occurrence of kidney stones is both dependent on the metabolic and anatomic abnormalities. anatomical abnormalities, which determine stasis of urine and infection, may account for renal stones in 17% of our cases lacking metabolic abnormalities. the fact that not all msk patients have metabolic abnormalities has been already reported (5, 10). therefore, when urinary infection is present, it could be the result rather than the cause of the stones (11). our data show a dramatic reduction in the stone rate figure 1. woman 57 yrs old affected by recurrent calcium nephrolithiasis. a, b, x-ray plus urogram performed before the start of treatment with potassium citrate (6 g per day orally in 3 doses). c, x-ray after 6 yrs continuous therapy. most of the left kidney stones disappeared asymptomatically, while for the right ureteral stone ureteroscopy was required. figure 2. man 39 yrs old admitted to our clinic for right flank pain. a, b, x-ray plus urogram showed bilateral nephrolithiasis, more evident on the right kidney. the patient was given potassium citrate (4 g per day orally in 2 doses). c, x-ray 3 yrs later revealed the asymptomatic disappearance of most of the stones. no urological treatment had been performed. a b b c a c 105archivio italiano di urologia e andrologia 2019; 91, 2 the impact of potassium citrate therapy in the natural course of medullary sponge kidney with associated nephrolithiasis during citrate therapy in msk patients without rta and irrespective of the presence of metabolic stone risk factor. as consequence, also a parallel reduction in urological treatment, uti and hospitalization was observed. such an effect is neither prejudiced by a “regression to the mean” bias (table 2) nor by an ascertainment bias of episodes due to the retrospective nature of the study period before the establishment of potassium citrate therapy. although we cannot rule out some imprecision in counting the number of episodes, particulary the number of stones, we are confident that our conclusion about the clinical actvity of citrate treatment is correct, since the given estimates before the treatment could only be lower than in real ones. it is well known that renal tubular acidosis is a common cause of calcium neprolithiasis and nephrocalcinosis. this defect is associated with high urinary ph and low urinary citrate causing the formation of calcium stones. it has also been reported that potassium citrate can correct the acidosis and ameliorate the hypocitraturia preventing calcium nephrolithiasis (9). citrate is known to reduce the urinary saturation of calcium oxalate by complexing calcium and reducing its ionic concentration; it also inihibits nucleation and crystal growth of calcium, oxalate and phosphate. citrate treatment increases urinary citrate excretion, urinary ph and decreases stone formation also in normocitraturic patients (3). furthermore, it has also been reported that potassium citrate therapy seems to be effective in preventing renal stones in patients with msk and nephrolithiasis (12). thus, citrate therapy modifies the urinary milieu leading to condition less prone to stone formation. however, we also unexpectedly observed by x-ray examination the disappearance of preesisting stones in 35 patients (figures 1, 2). in some patients during the citrate therapy follow-up, we observed at first a fragmentation of the stones (similar to the effect of shock wave lithotripsy), thereafter the disappearance of small fragments, and at last of all fragments. the initial disaggregation of stones suggests that citrate may exert some dissolving effect on the concretions occurring in msk. while the effect of citrate therapy on dissolution of uric acid is known from a long time, the effect of citrate therapy on dissolution of calcium stones is astonishing. however, in a previosus study pak too observed a similar finding, i.e., the dissolution of calcium stones after citrate therapy in 8 patients (13). it is generally assumed that calcium stones cannot be dissolved by systemic therapy. only the local irrigation with different solution, some containing also potassium citrate, is considered to be capable to dissolve calcium stones (14). in this case, the high citrate concentration, the high levels of calcium complexing molecules such as edta and high fluxes used most likely explain the efficacy of local irrigation. it is difficult to speculate on the mechanism explaining the dissolving effect of potassium citrate after oral administration. of course, one has to admit that citrate may enter into the stone, destroyng the binding between calcium and oxalate or phosphate and fragmenting the stone in chippings that later are asymptomatically eliminated with the urine. however, the urinary levels of citrate after oral assumption are much lower than those constituing the irrigation solution and certainly do not have the same strong calcium chelating power. this migh be congruent with the slower dissolution of the stones in our msk patients. furthemore, also the fact that stones in msk, because of the anatomical abnormalities of precaliceal collecting tubules, are immobilized longer than in non-msk stones, might play a role. in fact, a longer immobilization should allow a more intense and prolonged effect of even relatively low concentrations of citrate, so that these might be effective. since the occurrence of mixed calcium and urate stones in msk is not unsual (in our case population was observed in 9% of patients), the alternative hypothesis that citrate therapy dissolve the urate component of stones and in such way disaggregated stone may also be advanced. we have previously reported that citrate therapy improves the clearance of residual stone fragments after eswl and hypothesized that the action may due to the inhibition of growth and aggregation of calcium salts. according to present results we could advance that citrate therapy promotes the dissolution of calcium stones, like for uric and cistinuric stones. if urinary infection is present, adeguate antibiotic therapy could prevent the growth of infection stones, also reported in our previous study (15). msk rarely causes renal failure, but if not treated it could worse the quality of life. however, further studies are necessary to investigate this last issue. references 1. gambaro g, feltrin gp, lupo a, et al. medullary sponge kidney (leonarduzzi-cacchiricci disease): a padua medical school discovery in the 1930s. kidney int 2006; 69:663-670. 2. cameron s. medullary sponge kidney. in: oxford textbook of clincal nephrology, 3rd edn, edited by davidson am, cameron js, grunfeld j-p, ponticelli c, ritz e, winearls cg, van ypersele c. oxford, oxford university press, 2004; pp 2495-2501. 3. pak cyc. citrate and renal calculi: an update. min electrolyte metab. 1994; 20:371-377. 4. m sc morgan, pearle ms. medical management of renal stones. bmj. 2016; 352:i52. 5. o' neill m, breslau na, pak cyc. metabolic evaluation of nephrolithiasis in patients with medullary sponge kidney. jama 1981; 12:1233-1236. 6. yagisawa t, kobayashi c, hayashi t, et al. contributory metabolic factors in the development of nephrolitiasis in patients with medullary sponge kidney. am j kidney dis. 2001; 37:1140-1143. 7. osther pj, mathiasen h, hansen ab, nissen hm. urinary acidification and urinary excretion of calcium and citrate in women with medullary sponge kidney. urol int. 1994; 52:126-130. 8. maschio g, tessitore n, d'angelo a, et al. medullary sponge kidney and hyperparathyroidism-a puzzling association. am j nephrol. 1982; 2:77-84. 9. preminger gm, sakhaee k, skurla c, pak cyc. prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal tubular acidosis. j urol. 1985; 134: 20-23. archivio italiano di urologia e andrologia 2019; 91, 2 e. cicerello, m. ciaccia, g. cova, m. mangano 106 10. yendt er, cohanim m. renal calculi. proc 8th int cong. nephrol 1975, karger basel, p 1175. 11. parks j, coe f, strauss a. calcium nephrolithiasis and medullary sponge kidney. n engl j med. 1982; 306:1088-191. 12. fabris a, lupo a, bernich p,, et al. long-term treatment with potassium citrate and renal stones in medullary sponge kidney. cjasn. 2010; 5:1663-1668. 13. pak cyc, skhaee k, fuller cj. physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. trans ass amer phys. 1983; 96:294-305. 14. nakatsuka s, kinoshita h, ueda h, et al. combined treatment of medullary sponge kidney by edta potassium citrate and extracorporeal shock wave lithotripsy. eur urol. 1988; 14:339-342. 15. cicerello e, merlo f, gambaro g, et al. effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolitiasis patients. j urol. 1994; 151:5-9. correspondence elisa cicerello, md (corresponding author) elisa.cicerello@tin.it matteo ciaccia, md matteo.ciaccia@aulss2.veneto.it giandavide cova, md giandavide.cova@aulss2.veneto.it mario mangano, md mario.mangano@aulss2.veneto.it urology unit, department of surgery, ospedale ca’ foncello, treviso, italy archivio italiano di urologia e andrologia 2017; 89, 2158 case report a case of highly aggressive anaplastic seminoma of the testis presenting as fungating scrotal lesion massimiliano creta 1, vincenzo mirone 2, sergio di meo 1, roberto buonopane 1, nicola longo 2, ferdinando fusco 2, nicola rosario forte 3, vittorio imperatore 1 1 unità operativa di urologia, ospedale buon consiglio fatebenefratelli, napoli, italy; 2 clinica urologica, università federico ii di napoli, napoli, italy; 3 unità operativa di anatomia patologica, ospedale fatebenefratelli, benevento, italy. anaplastic seminoma (as) is an uncommon histological variant of classical seminoma of the testis and account for 5%-15% of cases. it is poorly described in the scientific literature. we present the case of a 50-years-old homeless man presenting with fever, marked left scrotal hardness and a fungating left scrotal lesion. he underwent left orchiopexy 40 years before. a computed tomography with contrast media showed a suspect testis cancer with scrotal involvment, extensive intralesional necrosis and multiple systemic metastases. a wide excision of the left hemiscrotum including the testis was performed in order to prevent severe local and systemic infectious complications. histological examination revealed an as. general conditions showed a rapid deterioration and the patient died on post operative day 10. key words: anaplastic seminoma; cryptorchidism; fungating lesion. submitted 1 may 2017; accepted 15 may 2017 summary no conflict of interest declared. case report a 50-years-old homeless man was referred to emergency department for left scrotal tumescence, pain, fever, and fetid discharge through the scrotal skin. his past surgical history was relevant for left orchidopexy performed at the age of 10. physical examination revealed an enlarged and hard left hemiscrotum with a cutaneous fungatng lesion characterized by purulent discharge and multiple cutaneous nodules on the abdomen and thorax (figu re 1). baseline levels of serum alfa fetoprotein and beta subunit of human chorionic gonadotropin were 2.26 ng/ml and 113.8 mui/ml, respectively. white blood cells count was 15.000/mm3 and c-reactive protein was 202 mg/l. a whole body contrast enhanced computed tomography (ct) showed an enhancing solid mass (10 × doi: 10.4081/aiua.2017.2.158 introduction testis cancer (tc) represents 1% of male neoplasms and 5% of urological tumours in western society (1). the predominant histology is germ cell tumour (gct) and peak incidence is in the third decade of life for non-seminoma, and in the fourth decade for pure seminoma (1). to date, most cases of tc are diagnosed at an early stage, are readily treatable and consequently exhibit an excellent prognosis (1). the anaplastic variant of classical seminoma has overall morphologic features of seminoma but with higher number of mitotic figures per high powered field, cellular irregularity, no fibrovascular septae, few lymphoctes, focal necrosis, and pleomorphic cells with nonclear cytoplasm (2). anaplastic seminoma (as) constitutes 5%-15% of testis seminomas and, to date, there are conflicting reports about the clinical behaviour of this neoplasm (2). due to the low number of cases mentioned in scientific literature it is difficult to determine whether the anaplastic differentiation predicts bad prognosis, like other solid tumors with anaplastic biology. in this report, we describe a case of a metastatic as presenting as a fungating scrotal lesion with infectious complications in a patient with history of previous orchidopexy. figure 1. a) clinical picture showing a fungating cutaneous neoplastic ulcers at the level of the left hemiscrotum and the surgical scar of previous orchidopexy (arrowhead). b) contrast enhanced ct scan showing a large enhancing solid mass (10 × 7 cm) with regional extension to the skin in the left hemiscrotum and a large area of inratumoral coagulative necrosis (asterisk). c) contrast enhanced ct scan showing a cutaneous metastasis at the level of the anterior right abdominal wall. d) contrast enhanced ct scan showing liver, renal, nodal and bone metastases. creta2_stesura seveso 20/06/17 10:02 pagina 158 159archivio italiano di urologia e andrologia 2017; 89, 2 fungating anaplastic seminoma 7 cm) in the left hemiscrotum with regional extension to the skin and characterized by a large area of intralesional coagulative necrosis. multiple cutaneous, liver, lung, adrenal, kidney, nodal and bone metastases were also evident. fever, leukocytosis and elevated c-reactive protein levels persisted despite antimicrobial therapy. surgery was consequently planned and a wide excision of the left hemiscrotum including the testis was carried out in order to avoid the occurrence of a severe necrotizing fasciitis. histopathological examination showed a poorly differentiated testis neoplasm characterized by wide areas of necrosis and hemorrage, as well as by sarcomatoid and squamous features compatible with as invading scrotal skin. patient’s general conditions showed a rapid deterioration and he died on post operative day 10 due to acute respiratory failure. discussion to date, there are very few studies and limited information about as in the scientific literature and the clinical behaviour of this histological variant is a matter of debate (2). herein, we present the case of a patient with as arising in a cryptorchid testis 40 years after orchiopexy and characterized by an highly aggressive clinical behaviour. this patient was a unique case due to multiple features and, to our knowledge, there are no other similar reports in the literature. about 10% of testis gct occur in men with a history of cryptorchidism and the hystologic subtype most commonly associated with cryptorchidism is seminoma. according to some evidences, there is a direct correlation between how long the testis is subjected to a cryptorchid position and the incidence of cancer. consequently, contemporary guidelines recommed surgical correction of cryptorchidism before the age of 12 months or 18 months the latest (3). moreover, a careful surveillance for malignant changes is advocated postorchiopexy (3). to our knowledge, there are very few cases of as arising in a cryptorchid testis submitted to orchidopexy and this case also underlines the importance of long-term follow-up of patients after orchidopexy. skin invasion and cutaneous metastases are uncommon in patients with tc and these features have been associated with a poor prognosis. in the present case, the lack of a careful surveillance and the delayed diagnosis due to the poor socioeconomic status also contributed to the poor prognosis. every patient with a suspected testicular mass must undergo inguinal exploration (1). in cases of life threatening disseminated disease, lifesaving chemotherapy should be given up-front, especially when the clinical picture is very likely tc and/or tumour markers are increased. orchiectomy may be delayed until clinical stabilisation occurs (1). treatment of as should be the same as for classical seminoma, stage for stage (2). necrotic neoplastic tissues, like biologically inhert bodies, may represent a substrate for infection and abscess formation (4). urgent surgery was planned in this case due to the evidence of tumor necrosis, local infectious complications, fever and leukocytosis, a clinical picture that may represent the prelude of a lifethreatening necrotizing fascitis and demands prompt and aggressive treatment. however, in the light of the clinical course of present case, the role of any surgical approach in similar patients should be carefully discussed. conclusions as represents an uncommon variant of testis seminoma that may occur in a cryptorchid testis even many years after orchidopexy and present with highly aggressive clinical features. references 1. albers p, albrecht w, algaba f, et al. european association of urology.guidelines on testicular cancer: 2015 update. eur urol. 201 ; 68:1054-68. 2. stein me, zidan j, charas t, et al. anaplastic variant of classical seminoma of the testis: northern israel oncology center experience and brief review of literature. rambam maimonides med j. 2014; 5:e0006. 3. tekgul s, riedmiller h, dogan hs, et al. guidelines on paediatric urology. arnhem, the netherlands: european association of urology, european society for paediatric urology. 2013. 4. cennamo p, montuori n, trojsi g, et al. biofilms in churches built in grottoes. sci total environ. 2016; 543:727-38. correspondence massimiliano creta, md (corresponding author) max.creta@gmail.com sergio di meo, md s.dimeo72@gmail.com roberto buonopane, md robertobuonopane@libero.it vittorio imperatore, md v.imperatore@alice.it unità operativa di urologia, buon consiglio fatebenefratelli hospital, napoli via a. manzoni, 220 80123 napoli, italy vincenzo mirone, md, professor of urology nicola longo, md ferdinando fusco, md clinica urologica, università federico ii di napoli via s. pansini, 5 80131 napoli, italy nicola rosario forte, md unità operativa di anatomia patologica, ospedale fatebenefratelli, benevento viale principe di napoli, 14 82100 benevento, italy creta2_stesura seveso 20/06/17 10:02 pagina 159 stesura seveso 119archivio italiano di urologia e andrologia 2019; 91, 2 original paper male-to-female (mtof) gender affirming surgery: modified surgical approach for the glans reconfiguration in the neoclitoris (m-shape neoclitorolabioplasty) andrea cocci 1, francesco rosi 2, davide frediani 2, michele rizzo 3, gianmartin cito 1, carlo trombetta 3, francesca vedovo 3, simone grisanti caroassai 1, augusto delle rose 1, valeria matteucci 4, piero buccianti 4, cristina ceccarelli 4, marco carini 1, andrea minervini 1, girolamo morelli 2 1 careggi hospital, department of urology, university of florence, florence, italy; 2 department of urology, university of pisa, pisa, italy; 3 department of urology, university of trieste, trieste, italy; 4 department of general surgery, university of pisa, pisa, italy. purpose: the aim of this article is to describe our modified surgical technique for the reconfiguration of the glans in the clitoris and the labia minora, known as the “m-shape neoclitorolabioplasty”. methods: the glans with all its neurovascular bundle is isolated from the corpora cavernosa, incised in y-shape mode and spread in order to obtain an m-shape glandular flap. the “belly” of the m-shape glans will constitute the triangular neoclitoris meanwhile the lateral flaps will constitute the labia minora. the inferior apex of the neoclitoris is fixed to the superior apex of the previously spatulated urethra. the two glans flaps are incised transversally to increase their length and sutured to the sides of the spatulated urethra forming the labia minora. our technique permits to create an aesthetically pleasing neovagina preserving all the glandular erogenous sensitivity. results: 94 patients have been treated with our modified technique of male-to-female (mtof) gender affirming surgery. at median follow-up of 27.57 months, 81 (86.1%) patients reported vaginal intercourse and 78 (82.9%) patients referred presence of erogenous sensitivity during dilatations, intercourse or masturbations. all the glandular tissue is preserved and reconfigured forming the neoclitoris and the labia minora. the m-shape reconfiguration permit to create an aesthetically pleasant neoclitoris. conclusions: this technique could be applied safely and easily to patients undergoing gender affirming surgery, allowing the creation of a neovagina with the best possible erogenous sensitivity without losing aesthetical results. key words: male to female; gender affirming surgery; transgender/transsexual. submitted 15 january 2019; accepted 26 january 2019 summary no conflict of interest declared. complex and multifactorial. the surgical treatment of gd is the gender affirming surgery. in mtof patients, gender affirming surgery involves the creation of a neovagina (vaginoplasty) and the reconstruction of a sensate neoclitoris (neoclitoroplasty) from the penile glans. during the years we have perfected the neoclitorolabioplasty with the specific goal of preserving as much erogenous tissue as possible in order to achieve best possible functional and aesthetic outcomes. the aim of this paper is to illustrate our gender affirming surgery technique focusing on the m-shape neoclitorolabioplasty and its outcomes. materials and methods indications for procedure transsexual women are sent to mtof gender affirming surgery according to the seventh version of the wpath (3) standard of care. furthermore, according to italian laws, all patients have to obtain a formal court authorization for this specific procedure. preoperative preparation all the patients interrupt progynova® (estradiol valerate) 30 days before gender affirming surgery (for thromboembolic risk) and start it again 15 days after gender affirming surgery. a low-residue diet and bowel preparation are recommended to avoid postoperative contamination of the surgical wound. metronidazole and amoxicillin clavulanate are given routinely as prophylactic antibiotics. patients are placed in lithotomy position and intermittent pneumatic compression is used to prevent deep venous thrombosis. the procedure is performed under general anesthesia. a urethral catheter is placed to locate the urethra during the entire procedure. the surgical area is sterilized with betadine® (povidone-iodine) solution. the standard equipe included two surgical teams each composed by two surgeons who perform this surgery. team a operates between the legs of the patient and team b is positioned at the level of the abdomen. doi: 10.4081/aiua.2019.2.119 introduction gender dysphoria (gd) and gender identity disorder have been defined in the diagnostic and statistical manual of mental disorders, fifth edition (1) and in the international classification of diseases, tenth edition (2). according to the standards of care of the world professional association of transgender health (wpath) (3), the management of patients presenting with male-to-female (mtof) gd is archivio italiano di urologia e andrologia 2019; 91, 2 a. cocci, f. rosi, d. frediani, et al. 120 intraoperative considerations the surgery is divided in three main steps: a) management of the perineal space, performed by team a: 1. castration (orchiectomy) 2. creation of the neovaginal cavity; 3. excision of the crura; 4. reduction of the bulb of penis, preparation of urethral stump and spatulating of it; b) management of the penis, performed by team b: 5. degloving of the penis, dissection of the gland and its neurovascular bundle; 6. dissection of the pendulous urethra and excision of the corpora cavernosa; 7. creation of the neoclitoris and the labia minora (neoclitorolabioplasty); c) management of the reconstruction of the external genitalia, performed by the two teams: 8. creation of the labia majora and preparation of the cutaneous grafts; 9. creation of the vulval vestibule, the clitoral hood and the urethral neo-meatus; 10.creation of the cul-de-sac; 11. introflection of the cul-de-sac and suture of the labia majora. step a) and b) are performed at the same time by the two teams working independently. step c) is performed when the other two steps are completed. a) management of the perineal space, performed by team a 1. castration (orchiectomy) initially, a racket shape marking is drawn for the incision in the perineal foreskin by a dermographic pen. the incision is performed along the medial raphe from the scrotum up to the perineum. the perineal skin flap, thus obtained, is inverted downwards, maintaining subcutaneous fat and preserving its vascularization. the testes and the spermatic cords are ligated and dissected at the level of the external inguinal rings, which are closed with a 2/0 monocryl® continuous suture to prevent postoperative hernia formation. the peri-testicular fat is conserved for the secondary purpose of filling and shaping of the labia majora. 2. creation of the neovaginal cavity undoubtedly this is the most complicated and risky step of the whole gender affirming surgery. injuring of the rectum or the membranous urethra are possible complications. fibers of bulbocavernous muscles are divaricated on the midline line and the bulbar urethra is completely freed. the bulbocavernous muscles are totally removed. the perineum is dissected creating a neo-cavity between the urethra and anus. superficial and deep transverse perineal muscles are divaricated laterally. the inferior fascia of urogenital diaphragm is exposed and cut laterally. after that a bluntly dissection is performed in order to create the neovaginal cavity. the dissection proceeds from the medial part of ischial tuberosity until the ischiorectal fossa through the endopelvic fascia. at the end of these procedure membranous urethra and the apex of prostate are reached. then neovaginal cavity is enlarged detaching tissue between the urethra, the prostate, the urinary bladder anteriorly and the rectum posteriorly, up to the peritoneal reflection of the rectovesical pouch. the obtained depth is measured with a centimetered vaginal stent, which must be at least 12 cm. 3. excision of the crura meanwhile the penile urethra is bluntly dissected from the corpora cavernosa by team b, team a excises both the crura from their respective ischiopubic ramus. remnants of spongiosus tissue are sutured with semicontinuous in monocryl® 3/0. 4. reduction of the bulb of penis, preparation of the urethral stump and spatulating of it the bulb of penis is completely excised in order to increase the space of the vulvar introit. at this point the distal urethra is excised and the residual stump is ventrally spatulated and cut to create a lance-like shape of the urethral plate. the apex is fixed to the anterior portion of pubis with a single monocryl® 3/0 stitch. the spatulated urethral plate are sutured with semicontinuous in monocryl® 3/0 at both sides to the ischial branches. with this urethral reconfiguration the anterior part of the neovagina until the neoclitoris is provided by urethral mucosa. b) management of the penis, performed by team b 5. degloving of the penis, dissection of the glans and its neurovascular bundle team b starts with the degloving of the penis. a circumferential subcoronal incision is made and a cylindrical penile skin flap is created, including the foreskin in uncircumcised patients. the penile skin is bluntly dissected from the albuginea. the degloved penis is passed through the posterior scrotal window to facilitate the disassembly. the penile skin flap will constitute part of the wall of the neovagina. after clamping the penis at its base, the dorsal part of the glans along with its neurovascular bundle is bluntly dissected from the corpora cavernosa. 6. dissection of the pendulous urethra and excision of the corpora cavernosa the corpora cavernosa are bluntly dissected from the pendulous urethra (then cut and spatulated by team a), and excised at the levels of the pubis attachment. 7. creation of the neoclitoris and the labia minora (neoclitorolabioplasty) a y-shape marking is drawn for the incision on the dorsal glans by a dermographic pen. the y-shape incision is performed using the electro-cautery and following the markings. in this way an m-shape glans is obtained when it is spread. the “belly” of the m-shape glans will constitute the triangular neoclitoris meanwhile the lateral flaps will constitute the labia minora (figures 1, 2). during this step the neurovascular bundle is folded up on itself and the reflected side is fixed with three 3/0 monocryl® simple stitches to the soprapubic region thus forming the mons veneris. the inferior apex of the neoclitoris is fixed with a 3/0 monocryl® simple stitch to the superior apex of the spatulated urethra. the two glans flaps are incised transversally so that their length is increased and sutured with 3/0 monocryl® to the sides of the spatulated urethra thus forming the labia minora. c) management of the reconstruction of the external genitalia, performed by the two teams 8. creation of the labia majora and preparation of the cutaneous grafts the peri-testicular fat (previously conserved by team a) is sutured with 2/0 monocryl® to the inferior apex of perineum. the purpose of this action is to give volume and thickness to the labia majora. the latero-inferior portions of the penile skin flap are fixed with 2/0 prolene® simple stitches to the lower sides of the racket shape incision (initially made by team a). in this manner the inferior apex of the labia majora is formed. the redundant skin is drawn by dermographic pen and excised by electro-cautery. it will be used as cutaneous graft. on the surgical bench the two cutaneous grafts are thinned out of the subcutaneous fat and sutured together with 2/0 monocryl®. 9. creation of the vulval vestibule, the clitoral hood and the urethral neo-meatus at this point team b has finished its job and team a completes the surgery. the cylindrical penile skin flap is reversed like a glove finger. then the cutaneous base of it is stretched downwards. in this manner the skin covers sequentially the folded neurovascular bundle (forming the mons veneris), the neoclitoris, the labia minora and the spatulated urethra. the cutaneous base is fixed laterally and internally to the entrance of the neovaginal cavity with 2/0 monocryl® simple stitches. afterwards a longitudinal incision is made with scalpel on the covering skin paying attention not to cut the underlying structures. this action is made in order to evert the neclitoris, the labia minora and the spatulated urethra. the edges of the incision are spread. the anterior apex of the incision is sutured with 2/0 monocryl® to the top of neoclitoris forming the clitoral hood (figure 3). the lateral sides are sutured to the labia minora. the posterior apex is sutured to the overturned urethral mucosa forming the urethral neo-meatus. once these actions are completed, the vulval vestibule is obtained. in this manner the mucosa of the spatuleted urethra is used for the creation of the vulval vestibule so that the sensitive surface is increased. 10. creation of the cul-de-sac the vaginal stent is placed in the neovaginal cavity. the part that comes out of the cavity is used as a model to create the cul-de-sac. the penile skin flap is put on the vaginal stent and sutured with continuous in monocryl® 3/0 to the perineal skin flap and the cutaneous grafts in order to obtain the cul-de-sac (figure 4). 11. introflection of the cul-de-sac and suture of the labia majora the vaginal stent is removed and the cul-de-sac is turned inside out and pulled into the neovaginal cavity to become the wall of the neovagina. the labia majora are closed with 2/0 monocryl® running intradermal suture in order to obtain the best aesthetical outcome (figure 5). 12. dressing once the surgery is completed, five gauzes impregnated with betadine® and gentalyn® are sewed sequentially and inserted in the neovaginal cavity. a tie-over dressing is 121archivio italiano di urologia e andrologia 2019; 91, 2 m-shape neoclitorolabioplasty figures 1, 2. the m-shape glans. figure 3. creation of the clitoral hood and the labia majora. archivio italiano di urologia e andrologia 2019; 91, 2 a. cocci, f. rosi, d. frediani, et al. 122 then performed around the neo-meatal orifice. it is fixed with a nylon skin suture. a customized elastic compressive dressing is applied to prevent bleeding. postoperative management and follow-up during all the postoperative in-stay antibiotic prophylaxis with amoxicillin clavulanate 1 g per 3 days and clexane® (enoxaparin sodium) is given. patients are encouraged to mobilize 24 hours after the surgery. they sit with the help of a donut cushion avoiding pressures on the neovagina. the vaginal intruder, the tie-over dressing, the compressive dressing and the urinary catheter are removed 4 days after the surgery and patients are trained to correctly perform daily vaginal dilatation two times per day for 30 minutes each. they are advised to clean the vagina daily with 1/3 betadine® and 2/3 saline solution through a 60 cc cone-catheter syringe before and after the dilations. at the end of dilation, a dressing with gauzes and gentalyn® is applied above the site of surgery. patients are usually discharged within 1 week. progynova® is restarted 15 days after the intervention. the vaginal dilations prosecute for 2 weeks with the same protocol. then dilations are mandatory 3 times per day increasing gradually the diameter of the dilators according to individual tolerance. dilations are continued at least for 2 months after the operation until the patients have regular sexual intercourse. follow-up visits are scheduled at 15, 30 and 60 days after the intervention, then every 3 months. at each visit, physical examination to assess congruous vaginal length and width, neoclitoris and labia minora sensation, cosmetic appearance of the reconstructed vagina and occurrence of any complication are performed. at 60 days visit postoperative urodynamic studies are also performed. at each visit patients are asked regarding frequency and quality of sexual intercourse, ability to achieve orgasm and regrets about the procedure. a reference e-mail address is left to each patient where they can send any photo, question or doubt regarding the surgery and its follow-up (figures 6, 7). figure 4. creation of the cul-de-sac. figure 5. suture of labia majora. figure 6. 6 months long-term follow-up. figure 7. over 1-year long-term follow-up results from february 2011 to april 2018, 94 transsexual women underwent mtof gender affirming surgery. mean age was 29,5 years (iqr: 24.75-34 months). mean follow-up was 27.57 months (iqr: 25.77-29.45). all patients were taking feminizing hormonal therapy with cyproterone acetate and estradiol for at least 3 years before surgery. complications are reported in table 1. during the 7 postoperative days 4 (4.25%) patients required hematic transfusion. partial necrosis of the labia minora occurred in 5 (5.3%) patients but any of them required surgical revision. vaginal stenosis occurred in 6 (6.38%) patients who did not follow the daily vaginal dilatations program because complained uncomfortable filing during the procedure. urethral meatus stricture occurred in 1 (1.1%) patient. one (1.1%) patient developed a rectovaginal fistula and protective colostomy was necessary. one (1.1%) required 10 days of antibiotic therapy for a postoperative infectious complication. two patients underwent surgical revision for hematoma and edema of the lower limbs. at median follow-up of 27 months, 81 (86.1%) patients reported vaginal intercourse and 78 (82.9%) patients referred presence of erogenous sensitivity during dilatations, intercourse or masturbations. discussion the provision of erogenous and tactile sensitivities of the neoclitoris in gender affirming surgery was first described by brown (4) and wesser (5), and this technique is used by most surgeons (6-12). however, most surgeons give the neoclitoris an oval or a triangular shape by excising a part of the glans and “wasting” erogenous tissue (13). in literature dr. preecha and his team (14) have developed a surgical technique where a good part of the glans is preserved by giving it an m-shape and its lateral flaps are used to form the labia minora. for the incision, they draw an m-shape marking on the dorsal glans by dermographic pen. nevertheless, they excise the tissue included below the m-shape marking. our approach differs from preecha’s because we draw a yshape marking on the dorsal glans. then we incise following the markings. at the end we obtain an m-shape glans spreading it after the incision. the central part of the m-shape glans forms the triangular neoclitoris meanwhile the lateral flaps are incised transversally for elongating themselves and form the labia minora. in this manner we obtain aesthetically pleasing genitalia esterna. with this technique cosmetic outcome and erogenous sensitivity are improved. wagner et al. reported in a prospective trial the outcomes of sexual functions of 50 patients that underwent mtof sex reassignment surgery. in this study 30% patients did not reported presence of clitoral orgasm (15). lawrence et al. analyzed retrospectively 232 patients, he reported that 15% of patients rarely refers presence of orgasm during masturbations while 18% never experienced an orgasm (16). in both studies approximately 30% of patients reported insufficient orgasmic function. our technique of neoclitoridolabioplasty could be considered a value option to reduce the risk of insufficient erogenous sensitivity. some authors should advocate that hypersensitivity represent a commonly reported issue that routinely leads to a secondary surgical procedure to cover the clitoris with a hood flaps in order to protect it from an over stimulation (12). remarkably discomfort due to an excessive sensitivity of the neoclitoris could be easily correct while lack of sensitivity is a not corrigible condition. finally, good erogenous sensitivity may permit more pleasant and comfortable dilatations that are essential to preserve the depth of the neovagina and patients particularly enjoyed the idea to preserve as much erogenous tissue as possible. ethical considerations the present study was designed in accordance with the ethical principles of the declaration of helsinki. considering the retrospective design, the study did not require approval by the local ethics committee and informed consent was not required because all procedures were performed according to the standards of care for the health of transsexual, transgender, and gendernonconforming people, version 7. conclusions many procedures to reconfigure the glans in a neo-clitoris have been proposed and are currently used but any has been proven to be superior in terms of aesthetically and functional outcomes. remarkably in some series up to 30% of patients refer inability to achieve orgasm due to an insufficient neoclitoris sensitivity. m-shape neoclitorolabioplasty represent a feasible alternative to the technique commonly used that permits the preservation of all the glans erogenous sensitivity. references 1. association ap. diagnostic and statistical manual of mental disorders (dsm-5®): american psychiatric publishing; 2013. 2. organization wh. international classification of diseases, tenth edition. 3. coleman e, bockting w, botzer m, et al. standards of care 123archivio italiano di urologia e andrologia 2019; 91, 2 m-shape neoclitorolabioplasty table 1. postoperative complications in the period 2011-2018 (n° tot patients = 94). complication n° (%) bleeding 4 (4.25) asymmetries 3 (3.19) vaginal stenosis 6 (6.38) urethral stenosis 1 (1.06) recto-vagina fistula 1 (1.06) hypoesthesia of lower limb 4 (4.25) hematoma of lower limb 1 (1.06) edema of lower limb 1 (1.06) urethral dolor 1 (1.06) infection 1 (1.06) archivio italiano di urologia e andrologia 2019; 91, 2 a. cocci, f. rosi, d. frediani, et al. 124 for the health of transsexual, transgender, and gendernonconforming people, version 7. international journal of transgenderism. 2012; 13:165-232. 4. brown j. creation of a functional clitoris and aesthetically pleasing introitus in sex conversion. transactions of the sixth international congress of plastic and reconstructive surgery paris: masson; 1976; p. 5. 5. wesser dr. a single stage operative technique for castration, vaginal construction and perineoplasty in transsexuals. arch sex behav. 1978; 7:309-23. 6. selvaggi g, monstrey s, ceulemans p, et al. genital sensitivity after sex reassignment surgery in transsexual patients. ann plas surg. 2007; 58:427-33. 7. fang rh, chen cf, ma s. a new method for clitoroplasty in male-to-female sex reassignment surgery. plast reconstr surg. 1992; 89:679-82. 8. eldh j. construction of a neovagina with preservation of the glans penis as a clitoris in male transsexuals. plast reconstr surg. 1993; 91:895-900. 9. rubin so. sex-reassignment surgery male-to-female. review, own results and report of a new technique using the glans penis as a pseudoclitoris. scand j urol nephrol suppl 1993; 154:1-28. 10. rehman j, melman a. formation of neoclitoris from glans penis by reduction glansplasty with preservation of neurovascular bundle in male-to-female gender surgery: functional and cosmetic outcome. j urol. 1999; 161:200-6. 11. hage jj, karim rb. sensate pedicled neoclitoroplasty for male transsexuals: amsterdam experience in the first 60 patients. annal plas surg. 1996; 36:621-4. 12. sigurjonsson h, mollermark c, rinder j, et al. long-term sensitivity and patient-reported functionality of the neoclitoris after gender reassignment surgery. j sex med. 2017; 14:269-73. 13. trombetta c, liguori g, benvenuto s, et al. [neo-urethroclitoroplasty according to petrovic]. urologia 2011; 78:267-73. 14. wangjiraniran b, selvaggi g, chokrungvaranont p, et al. maleto-female vaginoplasty: preecha's surgical technique. j plast surg hand surg. 2015; 49:153-9. 15. wagner s, greco f, hoda mr, et al. male-to-female transsexualism: technique, results and 3-year follow-up in 50 patients. urol int. 2010; 84:330-3. 16. lawrence aa. patient-reported complications and functional outcomes of male-to-female sex reassignment surgery. arch sex behav. 2006; 35:717-27. correspondence andrea cocci, md, ph.d. (corresponding author) cocci.andrea@gmail.com augusto delle rose, md augustodellerose@libero.it marco carini, md, phd carini@unifi.it andrea minervini, md, phd careggi hospital, department of urology, university of florence largo brambilla, 3 50139, florence (italy) francesco rosi, md francescorosi@gmail.com davide frediani, md davide.frediani@gmail.com girolamo morelli, md girolamomorelli@gmail.com department of urology, university of pisa, pisa (italy) michele rizzo, md mik.rizzo@gmail.com carlo trombetta, mf, phd francesca vedovo, md department of urology, university of trieste, trieste (italy) gianmartin cito, md gianmartin.cito@gmail.com simone caroassai grisanti, md simonecaroassai@libero.it valeria matteucci, md piero buccianti, md cristina ceccarelli, md department of general surgery, university of pisa, pisa (italy) stesura seveso archivio italiano di urologia e andrologia 2020; 92, 3268 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.268 a giant adrenal hemorrhagic pseudocyst mimicking a parapelvic renal cyst: a case report and review of the literature erhan ates 1, arif kol 1, gokce su gokce 2, ahmet emre yildiz 1, haluk erol 1 1 department of urology, aydin adnan menderes university school of medicine, aydin, turkey; 2 department of pathology, aydin adnan menderes university school of medicine, aydin, turkey. adrenal pseudocysts are rare, nonfunctional, asymptomatic cystic masses that originate from the adrenal gland and are usually located in the suprarenal area. they are usually incidentally discovered during imaging, but diagnosis can be challenging because they are similar to benign and malignant cystic lesions of the adrenal gland and adjacent organs. we describe a giant, adrenal hemorrhagic pseudocyst that was atypically located, extending from the middle to the lower poles of the kidney, admixed with a renal cortical cyst. key words: adrenal gland; adrenal hemorrhagic pseudocyst; mimicking; renal cyst. submitted 2 march 2020; accepted 15 march 2020 summary introduction adrenal gland cysts are rare lesions that are frequently noted today because of the widespread use of imaging modalities. the incidence rate is 0.06-0.18% (1). the cysts are divided into four types: parasitic (7%), epithelial (9%), pseudocystic (39%), and endothelial (45%). adrenal pseudocysts are benign nonfunctional masses originating from the cortex or medulla of the adrenal gland. the luminal face is not paved with epithelium, and the walls contain dense fibrous connective tissue and (often) calcified and (sometimes) hyalinized areas (2). the cysts are mostly asymptomatic (being nonfunctional) and thus incidentally recognized (3). the masses are mostly small and located in the suprarenal region, but they may be confused with benign and malignant lesions of the adrenal gland and adjacent organs (4, 5). we describe a huge (19 cm diameter) adrenal hemorrhagic pseudocyst that was atypically located, extending from the middle to the lower poles of the kidney, admixed with a renal cortical cyst. case presentation a 21-year-old female with left flank pain 3 weeks in duration was referred to our clinic with a diagnosis of a giant parapelvic renal cyst. her medical history revealed no additional disease, no anticoagulant medication, and no trauma. on physical examination, a palpable mass was detected on the left side. routine laboratory tests including a complete blood count, biochemistry, and liver function tests were normal; the urine was sterile. ultrasonographic imaging revealed a septate cystic mass in the left kidney. contrast-enhanced abdominal computed tomography (ct) revealed a septate hypodense cystic lesion with a somewhat thickened, well-circumscribed, non-solid component 14×9×19 cm in dimension extending from the middle-lower plate of the left kidney to the pelvic region (figure 1). the attenuation was 16 hounsfield units (hu) without and 17 hu with contrast. the lesion was considered a bosniak type ii renal cyst. decortication was planned and a lumbar incision was created. the gerota fascia was opened and a giant cystic mass was observed in the medial, left inferior region of the renal hilum. when the thick fibrous cyst wall was resected from the anterior wall of the hilum, a thick viscous brown liquid with hemorrhagic characteristics was released. we biopsied a frozen section of the cyst wall. the result was benign; we proceeded with decortication. pathological examination revealed a cystic structure featuring intense bleeding and histiocytes that were richly granulated. cells/cell groups with clear cytoplasm were linearly arranged along the cyst wall (figure 2a). multiple blocks containing cells with clear cytoplasm were negative for cytokeratin, cytokeratin 7, cd68, ema, vimentin, and cd10 (figure 2b). however, melan-a staining was strong to diffuse, and inhibin and calretinin stained positively (figure 3). no sample contained epithelium. the findings were compatible with an adrenal hemorrhagic pseudocyst. discussion the classification of adrenal cysts was modified by foster in 1966; four types were recognized: parasitic (7%), epithelial (9%), pseudocystic (39%), and endothelial (45%) (2). pseudocysts are fibrous walled cysts lacking an epithelium and may develop because of vascular malformation, bleeding of the adrenal gland, or cystic degeneration of a primary adrenal or vascular neoplasm (6). although pseudocysts are the second most common type of adrenal cysts encountered in the clinic, they constitute the largest group (60%) of cysts encountered intraoperatively (7). they are usually asymptomatic and thus incidentally diagnosed (3). pseudocysts are more likely to be symptomatic than other adrenal cysts (8). although the cysts are usually small, large cysts can cause infection, rupture, hemorrhage, and compression 269archivio italiano di urologia e andrologia 2020; 92, 3 adrenal pseudocyst mimicking a renal cyst of surrounding organs (3). the increased use of imaging modalities has increased the detection rate of adrenal cystic lesions (1). computed tomography, which is 100% sensitive in terms of identifying small tumors, is the gold standard diagnostic method for adrenal masses (9). the radiological characteristics of adrenal pseudocysts are typical. in ct, most present as unior multi-locular cystic lesions with a thin but well-confined wall filled with a liquid similar to water. however, unlike simple cysts, they may exhibit intracavitary blood and septa extending into the cystic cavity, and a solid component that may be focally calcified, inviting confusion with adrenal tumors. in most cases, the lower wall of the cyst is concave or straight, following the contour of the top kidney pole. the renal parenchyma is separated from the cyst wall by anywhere from a few centimeters to 20-30 mm. thus, adrenal lesions can be differentiated from renal cysts (which are more common) and cystic tumors of the kidney (10). however, it is not always possible to definitively diagnose adrenal pseudocysts, particularly large lesions, via imaging. the differential diagnosis includes malignant adrenal tumors; cystic pathologies of the spleen, liver, and kidney; cystic neoplasms of the pancreatic tail; retroperitoneal mucinous cystic neoplasms; and mesenteric and urachal cysts (5, 11) there are several reasons why an adrenal pseudocyst may be radiologically diagnosed as a renal cyst. an adrenal cyst may develop from an adrenal tumor. in addition, a cyst developing in an adrenal gland that is heterotopically located in the kidney may be wrongly radiologically diagnosed (5). in addition, an adrenal cyst may originate from congenital, adrenal residual tissue or intrarenal, accessory adrenal tissue (12). surgical excision is recommended for all adrenal lesions larger than 5 cm in diameter and functional adrenal pseudocysts that may be malignant (13). some studies have found that adrenal cysts < 4 cm in diameter may also be malignant (9). ct follow-up of lesional size is recommended after a few months (14). open surgery is preferred because masses larger than 6 cm in diameter may be malignant and open surgery facilitates mass control (15). however, some authors report that a laparoscopic approach is safe in any benign and malignant adrenal mass (16, 17). there are even studies reporting that the transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a viable and safe alternative to standard laparoscopic adrenalectomy (18). upon macroscopic examination of surgically resected cysts, endothelial cysts are thin-walled, multiloculated, and contain yellow serous fluid; as in our case, pseudocysts are usually thick-walled, unilocular, and filled with blood or a yellow-brown amorphous liquid (19). figure 1. cystic mass on the left side in the computed tomography sections. figure 2. 2a. large cells with different sizes of vacuolar cytoplasm and some hyperchromatic cells are observed together; 2b. cells with vacuolar clear cytoplasm were not stained with cd68. figure 3. histiocyte-like cells with vacuolar cytoplasm and melan a positive in these cells. archivio italiano di urologia e andrologia 2020; 92, 3 e. ates, a. kol, g. su gokce, a. emre yildiz, h. erol 270 conclusions adrenal pseudocysts, which are usually asymptomatic and incidentally diagnosed, may become symptomatic because of infection, rupture, haemorrhage, or (when large) compression of surrounding organs. imaging may be misleading in terms of diagnosis. benign and malignant masses of adjacent organs, particularly the adrenal gland and kidney, should be kept in mind during differential diagnosis. a definitive diagnosis requires pathological examination after surgical excision. references 1. sebastino s, zhao x, deng f, et al. cystic lesions of the adrenal gland: our experience over the last 20 years. hum pathol. 2013; 44:1797-1803. 2. foster dg. adrenal cysts: review of the literature and report of a case. arch surg. 1966; 92:131-143. 3. papaziogas b, katsikas b, psaralexis k, et al. adrenal pseudocyst presenting as acute abdomen during pregnancy. acta chir belg. 2006; 106:722-725. 4. yue ct, liao a, huang p, et al. a large adrenal pseudocyst mimicking malignant intraabdominal tumor: a case report. zhonghua yi xue za zhi (taipei). 1997; 60:321-325. 5. fan f, pietrow p, wilson la, et al. adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. ann diagn pathol. 2004; 8:87-90. 6. mohan h, aggarwal r, tahlan a, et al. giant adrenal pseudocyst mimicking a malignant lesion. can j surg. 2003; 46:474. 7. groben pa, roberson ib. immunohistochemical evidence for the vascular origin of primary adrenal pseuodocyts. arch pathol lab med. 1986; 110:121. 8. erickson la, lloyd rv, hartman r, et al. cystic adrenal neoplasms. cancer. 2004; 101:1537-1544. 9. yip l, tublin me, falcone ja, et al. the adrenal mass: correlation of histopathology with imaging. ann surg oncol. 2010; 17:846-852. 10. lockhart me, smith jk, kenney pj. imaging of adrenal masses. eur j radiol. 2002; 41:95-112. 11. marwah s, marwah n, garg s, et al. adrenal pseudocyst mimicking cystic neoplasm of pancreatic tail. clin j gastroenterol. 2011; 4:262-265. 12. mitchell n, angrist a. adrenal rests in the kidney. arch pathol. 1943; 35:46-52 13. wedmid a, palese m. diagnosis and treatment of adrenal cyst. curr urol rep. 2010; 11:44-50. 14. passoni s, regusci l, peloni g, et al. a giant adrenal pseudocyst mimicking an adrenal cancer: case report and review of the literature. urol int. 2013; 91:245-258. 15. stimac g, katusic j, sucic m, et al. a giant hemorrhagic adrenal pseudocyst: case report. med princ pract. 2008; 17:419-421. 16. ramacciato g, mercantini p, la torre m, et al. is laparoscopic adrenalectomy safe and effective for adrenal masses larger than 7 cm? surg endosc. 2008; 22:516-521. 17. abate d, giusti g, caria n, et al. surgical approach to adrenal ganglioneuroma: case report and literature review. arch ital urol androl. 2018; 90:145-146. 18. carvalho ja, nunes pt, antunes h, et al. transumbilical laparoendoscopic single-site adrenalectomy: a feasible and safe alternative to standard laparoscopy. arch ital urol androl. 2019; 91:1-4. 19. carvounis e, marinis a, arkadopoulos n, et al. vascular adrenal cysts: a brief review of the literature. arch pathol lab med. 2006; 130:1722-1724. correspondence erhan ates, md, assistant professor of urology (corresponding author) drerhanates@yahoo.com arif kol, md, assistant professor of urology drarifkol@gmail.com ahmet emre yildiz, md, urology aemreyildiz@gmail.com haluk erol, md, professor of urology halukerol@yahoo.com department of urology, aydin adnan menderes university school of medicine, 09010, aydin (turkey) gokce su gokce, md gkc.gkc@windowslive.com department of pathology, aydin adnan menderes university school of medicine, aydin (turkey) 149archivio italiano di urologia e andrologia 2018; 90, 3 original paper safety and efficacy of pnl vs rirs in the management of stones located in horseshoe kidneys: a critical comparative evaluation bilal eryildirim 1, eyup veli kucuk 2, gokhan atis 3, metin ozturk 4, temucin senkul 5, murat tuncer 1, ahmet tahra 2, turgay turan 3, orhan koca 4, ferhat ates 5, omer yilmaz 5, cenk gurbuz 6, kemal sarica 7 1 health sciences university, dr. lütfi kirdar training and research hospital, urology clinic, istanbul, turkey; 2 health sciences university, umraniye training and research hospital, urology clinic, !stanbul, turkey; 3 istanbul medeniyet university, goztepe training and research hospital, urology clinic, istanbul, turkey; 4 health sciences university, haydarpasa numune training and research hospital, urology clinic, istanbul, turkey; 5 health sciences university, sultan abdulhamid han training and research hospital, urology clinic, istanbul, turkey; 6 medistate hospital, urology department, istanbul, turkey; 7 kafkas university, faculty of medicine, urology department. aim: to assess the efficacy and safety of two different techniques (percutaneous nephrolithotomy (pnl) vs retrograde intrarenal surgery (rirs)) in the management of stones in patients with horseshoe kidneys (hsk). patients and methods: departmental files of 88 cases with radiopaque kidney stones in horseshoe kidneys undergoing two different approaches (pnl vs rirs) were evaluated with respect to the success and complication rates of in a retrospective manner. in addition to the factors related with the procedures (success and complication rates, additional procedures), patient and stone characteristics were all well evaluated. findings obtained in both groups were evaluated in a comparative manner with respect to the statistical significance. results: stone free rates were comparable in both groups after 1-week period (81.6% pnl vs 80% rirs). as well as 3 months evaluation (84.2% pnl and 82.0% rirs). the percentage of the cases with residual fragments (> 4 mm) were similar in both groups and while all pnl procedures were completed in one session, mean number of rirs sessions was higher (1.22 ± 0.05). mean duration of the procedure was slightly higher in rirs group and based on clavien scoring system, despite a higher risk of hb drop noted in patients treated with pnl, all complication rates were found to be similar in both groups. conclusion: our results demonstrate that of the available minimally invasive treatment alternatives, both pnl and rirs could be safe and effective alternatives for renal stone removal in patients with hsk. key words: horseshoe kidney; percutaneous nephrolithotomy; retrograde intrarenal surgery; renal stone; ureteroscopy. submitted 8 march 2018; accepted 29 april 2018 summary no conflict of interest declared. urinary stasis in the collecting system which may result in stone formation (1). the reported incidence of urolithiasis in patients with hsk varies between 20% to 60% in different series (3, 4). on the other hand again, abnormal position of the kidney due to congenital fusion abnormality and unusual course of the ureter over the isthmus bring the management of stones in such kidneys into more challenging position. although open surgery has been performed commonly in the past, currently all available minimal invasive treatment alternatives such as extracorporeal shock wave lithotripsy (swl), retrograde intrarenal surgery (rirs) and percutaneous nephrolithotripsy (pnl) are being performed with varying success rates (4). of these alternatives although swl has been performed as a practical and well tolerated procedure by the majority of cases, success rates in such patients are highly variable and stone free rates (sfr) of 31-100% were reported in the literature (5-8). although adequate fragmentation can be achieved by swl, the anatomic abnormalities may prevent fragment passage in a substantial number of these patients. as a second alternative, pnl has already been found to be efficient in the management of relatively large stones cases with hsk with varying success rates. due to the relatively lower position of the kidneys most upper as well as mid renal calyces are found to be located below the twelfth rib, thereby making the supracostal puncture relatively safe in these patients. however, despite the higher success rates obtained, the invasive nature of this method and higher risk of major complications (complication rates 14.3-29.2%) led the endourologists to look for more feasible and less invasive options. stone clearance rates after pnl in series with relatively limited number of renal units have been reported to be 7587.5% (3, 9, 10). last but not least, retrograde intrarenal surgery by using flexible ureterorenoscope has also been shown to be an effective management option; the success rate and associdoi: 10.4081/aiua.2018.3.149 introduction being observed in approximately 1 in 400 to 1 in 666 births, horseshoe kidney (hsk) is the most common renal fusion anomaly (1, 2). anterior displacement of the renal pelvis and high insertion of the involved ureter cause urinary abnormal drainage with flow hinderance and erildirim_stesura seveso 04/10/18 11:07 pagina 149 archivio italiano di urologia e andrologia 2018; 90, 3 b. eryildirim, e.v. kucuk, g. atis, m. ozturk, t. senkul, m. tuncer, a. tahra, t. turan, o. koca, f. ates, o. yilmaz, c. gurbuz, k. sarica 150 ated complications of this method have not been well documented in such patients. despite acceptable stone free rates reported in some trials with relatively limited number of cases, due to the anatomical abnormality, a second look is usually required to render the patient completely stone free. a recent review article focusing on the management of renal stones in hsk demonstrated that rirs may provide acceptable stone free rates (78%) (11). in this present study we aimed to evaluate the clinical efficacy of two different approaches, rirs combined with holmium laser lithotripter and pnl, in treating renal calculi in horseshoe kidney. patients and methods the medical records of 88 cases with radiopaque renal stones in horseshoe kidneys treated with two different types of procedures (pnl vs rirs) in 7 different centers between 2007 and 2016 were reviewed. study protocol was approved by the ethics committee of the hospital. all steps of the study were planned and applied carefully according to helsinki declaration. depending on the type of the procedure applied, cases with horseshoe kidneys were divided into two different groups; in group 1 (n = 38) cases were treated with pnl and in group 2 (n = 50) cases were treated with rirs. all treatment related parameters (stone free rates, number of sessions, treatment duration, hospitalization time, presence of the residual fragments, complications as well as the need for additional interventions) were noted and evaluated between two groups in a comparative manner. preoperative evaluation prior to the above mentioned procedures, in addition to the preoperative laboratory tests including urinalysis, renal functional parameters, complete blood count and prothrombin concentration, urine culture and sensitivity test was performed in all patients with pyuria. patients with urinary tract infection (uti) were treated before the procedure with an appropriate antibiotic regimen. all patients were given prophylactic antibiotics at the time of anesthesia induction. in addition to kidney-ureter-bladder (kub) and urinary system ultrasonography (usg), a non-contrast abdominopelvic computed tomography (ncct) were performed for radiologic evaluation. ncct was also applied to assess the final stone free rates after 3-months and/or when there is any suspicion for residual fragments. both procedures were performed under general anesthesia, a prone position was used for pnl and rirs procedures were performed in lithotomy position. while the stone disintegration was performed with ho-yag laser during rirs, all stones were fragmented by using pneumatic lithotriptor during pnl. postoperative evaluation success rates in all patients were evaluated one week and 3 months after the last session of pnl and rirs with kub and/or urinary system usg to check the degree of stone fragmentation and the presence of obstruction (hydronephrosis) if present. the ultimate success rates were defined as no stone detectable or the presence of fragments < 4 mm on low dose non-contrast ct imaging for all patients. statistical analysis: the prism 5.0 (graphpad software, san diego, ca) was used for the statistical analysis. data are presented as mean standard error of mean. student’s t test was used for both comparison of descriptive statistical methods and evaluation of quantitative data and chi-square test were used to compare the qualitative data between two groups; p < 0.05 was consider significant. results departmental files of 88 cases with kidney stones in horseshoe kidneys (56 male and 32 female (m/f: 1.75) undergoing two different approaches (pnl vs rirs) were evaluated with respect to the success and complication rates of each procedure in a retrospective manner. while the age of the cases ranged from 19 to 60 years (mean 41.161.25); the overall mean size of the stones were 20.590.75 mm (7-42 mm). patients and stone related factors are summarized in table 1. all pnl procedures were completed in one session, but the mean number the sessions for cases undergoing rirs was 1.220.05 (p = 0.0064). although mean duration of the procedure was slightly longer in rirs group (p = 0.9075), mean radiation exposure time was higher in pnl group when compared cases undergoing rirs (p < 0.0001). on the other hand, while the mean duration of hospital stay was 3.150.24 days (1-10) in patients undergoing pnl procedure; this value was 1.580.20 days (1 to 7) in rirs group (p < 0.0001) (table 2). while a nephrostomy tube (14 f) has been placed in 36 cases (94.7%) after the pnl procedure, a double j stent was inserted in 42 of 50 cases undergoing rirs procedure (84.0%). evaluation of the degree of hydronephrosis revealed a mean value of 2.050.14 dilatation in group 1 and 1.460.16 in group 2, there was a statistically significant difference on this aspect (p = 0.0087). table 1. evaluation of patient and stone characteristics in both groups. overall group 1 (pnl) group 2 (rirs) p* n = 88 n = 38 n = 50 age (year) 41.161.25 42.970.87 39.781.68 0.1434 bmi (kg/m2) 28.270.42 29.150.59 27.600.56 0.0643 stone size (mm) 20.590.75 21.551.14 19.460.56 0.4638 hu (hounsfield unit) 97123.46 95734.29 98226.31 0.5496 degree of hydronephrosis (grade) 1.720.11 2.050.14 1.460.16 0.0087 stone location; n, (%) renal pelvis 30 (34.1) 12 (31.6) 18 (36.0) 0.8208 upper calyx 8 (9.1) 3 (7.9) 5 (10.0) 1.0000 middle calyx 9 (10.2) 3 (7.9) 6 (12.0) 0.7263 lower calyx 22 (25.0) 9 (23.7) 13 (26.0) 1.0000 multiple calyces 19 (21.6) 11 (28.9) 8 (16.0) 0.1923 * comparison between group 1 and group 2. erildirim_stesura seveso 04/10/18 11:07 pagina 150 evaluation of the results obtained with two different techniques revealed following findings. evaluation of the success as well as auxiliary procedure rates the overall percentage of the cases with no stones detectable or demonstrating fragments < 4 mm after one week period was 80.7% and the stone free rates were comparable in both groups after 1-week period (81.6% for pnl group and 80.0% for rirs group, p = 0.7886). this was also true during post-operative 3 months evaluation period where 84.2% of cases treated with pnl were stone free when compared with the cases undergoing rirs procedure (82.0%) (p = 0.7820). evaluation of the residual fragments (rf) sizing > 4 mm demonstrated that 5 cases (13.2%) in pnl group; 7 cases in rirs group (14.0%) had such larger residual fragments during early (1-week) follow-up evaluation. during the 3-months follow-up period while 1 case in pnl group passed these fragments spontaneously, fragments passed into the ureter in the other 3 cases. a jj stent have already been inserted in 2 of these 3 cases due to the severe obstruction. fragments were removed with urs in these 3 cases. 1 case was asmptomatic with rf requiring no intervention. on the other hand, regarding the larger residual fragments ( > 4 mm) in 7 cases of rirs group, although 1 case did pass the fragment spontaneously, fragments passed into the ureter in 3 cases and were removed again with urs during 3-months follow-up period. a double j stent was again inserted in only 1 of these 3 cases prior to urs due to the obstruction induced by ureteral stones. pnl was unsucessful in 2 cases due to the difficulty in accessing the stones (5.3%) and rirs was performed in these cases. on the other hand, rirs was unsuccessful in 3 cases (6.0%) because of the difficulty in accessing to the lower pole. a mini-pnl was performed in all these 3 cases with successful stone removal. all these cases were excluded from the study program and were not included in any of these groups (table 2). evaluation of complication rates all complications observed in both groups were classified by using modified clavien scoring system (12). based on this classification, while 11 cases (28.9%) in pnl group demonstrated grade 1 complications, this number was again 11 (22.0%) in rirs group (p = 0.2274). regarding these complications, although fever after the procedures were noted in a total of 14 cases in both groups (6 in pnl and 8 in rirs group) none of these cases demonstrated sepsis during follow-up. morover, regarding the grade 3 complications while 5 cases in pnl group did show such complications, 4 cases in rirs group had this kind of complications (p = 0.4916) (table 3). although evaluation of the rate of hemoglobin drop in both groups showed a statistically significant difference between two groups in (p < 0.0001); 3 cases in pnl group and 1 case in rirs group required blood transfusion (p = 0.3113) without any significant difference between two groups. no severe (grade iv-v) complication was noted in any case. last but not least stone street formation due to the fragment passage into the ureter has been observed in 1 case undergoing pnl in whom a double j stent placement and ureteroscopic stone removal have been performed. discussion representing the most common congenital renal fusion anomaly; hsk is mainly associated with the abnormal position of the kidney associated with the unusual course of upper ureter over the isthmus (2). published data and clinical experience have clearly shown that these anatomical abnormalities cause impaired renal pelvic drainage due to ureteropelvic junction obstruction and resultant hydronephrosis may cause not only with 151archivio italiano di urologia e andrologia 2018; 90, 3 pnl vs rirs in the management of stones located in horseshoe kidney table 2. evaluation of the outcomes of the procedures in terms of success rates as well as early post-operative follow-up data. overall group 1 (pnl) group 2 (rirs) p* n = 88 n = 38 n = 50 mean duration of the procedure (min) 77.3 42.71 75.8 42.64 80.2 65.13 0.9075 mean number of sessions 1.11 0.03 1.00 0.0 1.22 0.07 0.0064 stone free rate; n, (%) 1. week 71 (80.7) 31 (81.6) 40 (80.0) 0.7886 3. month 73 (82.9) 32 (84.2) 41 (82.0) 0.7820 residual stone > 4 mm n, (%) 12 (13.6) 5 (13.2) 7 (14.0) 0.7559 mean fluoroscopy time (sec.) 30.8 05.40 69.2 49.43 20.6 21.81 < 0.0001 mean drop in hb levels (g/dl) 0.74 0.10 1.55 0.15 0.13 0.07 < 0.0001 mean hospital stay (day) 2.46 0.12 3.15 0.24 1.58 0.20 < 0.0001 auxiliary procedures; n, (%) 6 (6.8) 3 (7.9) 3 (6.0) 1.0000 * comparison between group 1 and group 2. table 3. evaluation of the type and grade of complications according to modified clavien classification in both groups.as early post-operative follow-up data. gradecomplication overall group 1 (pnl) group 2 (rirs) p* n = 88 n = 38 n = 50 1 fever > 38 0c; n, (%) 14 (15.9) 6 (15.8) 8 (16.0) 0.2274 hemorrhage/hematuria not requiring blood transfusion; n, (%) 8 (9.0) 5 (1.8) 3 (3.6) 2 hemorrhage/hematuria requiring blood transfusion; n, (%) 4 (4.5) 3 (7.9) 1 (2.0) 0.3113 3a double j stent placement for 3 (3.4) 2 (5.2) 1 (2.0) ureteral stone; n, (%) 0.4916 3b endoscopic treatment for ureteral stone; n, (%) 6 (6.8) 3 (7.9) 3 (6.0) * comparison between group 1 and group 2. erildirim_stesura seveso 04/10/18 11:07 pagina 151 archivio italiano di urologia e andrologia 2018; 90, 3 b. eryildirim, e.v. kucuk, g. atis, m. ozturk, t. senkul, m. tuncer, a. tahra, t. turan, o. koca, f. ates, o. yilmaz, c. gurbuz, k. sarica 152 stone formation but also makes the stone removal procedures more challenging. concerning the stone management principles in these patients, all available minimally invasive stone removal procedures namely swl, pnl and rirs have been applied as with varying stone-free rates in these patients. although limited, published data so far has demonstrated that while altered pyelocalyceal system anatomy and high ureteropelvic junction position may lead to relatively poor results of swl and rirs; similar to the kidneys with normal anatomy, pnl has been reported as an efficient treatment modality for stones located in hsk (13, 14). related with this issue, as a non-invasive and safe alternative, although swl has been well tolerated by the majority of patients, stone-free rates have been reported to be significantly lower after this procedure. when compared with the patients demonstrating normal kidneys, lower efficiency of this approach could be well explained with some certain factors such as greater skin-to-stone distance (particularly for calyceal stones) value and of more importantly restricted urinary drainage. however, despite the lower stone free rates reported to be changing between 31-100% (5-8), higher risk of complications associated with pnl performed for relatively large stones in hsk (14.3-29.2%) make swl also rirs more feasible and safe options in selected cases (3, 9, 10). on the other hand again, developments in instruments technology and increasing experience in minimally invasive management of stones have changed the treatment concepts of urinary calculi meaningfully over the past two decades. as a result, pnl has become the standard of care for the treatment of large (> 2 cm) stones with its evidently higher stone free rates in a single session (15, 16). however, it is well-known that these higher stonefree rates are being obtained at the expense of some certain severe complications (16). in the light of the evident lower stone free rates after swl due to the certain factors mentioned above however, accumulated data so far clearly demonstrate that pnl may constitute a preferred alternative in cases with hsk in experienced hands (3, 17). related with this issue, clinical experience showed that while access to the upper pole calyces during pnl often requires a supracostal approach with the associated risk of pleural injury in patients with normal renal anatomy, due to the relatively lower level of the upper pole, a supracostal puncture appears to be relatively safe in these kidneys. access through the lower pole are not usually recommended due to the posterior location of these calyces. furthermore, upper-pole access in hsk allows the surgeon to remove all stone burden in one session, as the alignment of the nephroscope with the long axis of the kidney aids manipulation of the scope into the upper calyces, renal pelvis, lower calyces, upj (ureteropelvic junction) and proximal ureter in a practical and safe manner. however, as mentined above despite the higher success rates obtained, the complicated nature of this method and higher risk of major complications led the endourologists to look for more feasible and less invasive options (3, 9, 10). evaluation of the literature with respect to the success as well as complications rates of pnl reported in hsk demonstrated varying rates in studies with limited number of cases. in a single session operation using only one tract without any flexible nephroscope, etemadian m. et al. have reported a stone free rate of 71.4% with a transfusion rate of 4.76% being encountered only in 1 patient (18). in their original study again, el ghoneimy mn et al. treated 21 hsk renal units bearing a single pelvic stone in 52% of the cases and a staghorn calculi in 14% of the cases and 85.7% of the cases were stone free after the procedure with negligible complications (19). in a study of 24 cases with hsk again, raj et al. performed upperpole access in the majority of the cases (63%) and reported only one pneumothorax formation. they were also able to note that the use of flexible nephroscope was usually required for a satisfactory stone clearance rate, given as 87.5% (3). last but not least, in relatively larger series of cases symons sj et al. treated stones in 47 cases with hsk and demonstrated that the number of pnl sessions required for stone free status depended on both the stone configuration and the size as well. pnl was used in 60 renal units of 47 patients with a clearance rate of 77% at one session and while 12 (71%) of the 17 patients demonstrating multiple stones were stone-free in one session; 30 (86%) out of 35 with neither multiple nor staghorn stones were completely stone free (10). an alternative to the percutaneous approaches in these cases is flexible ureteroscopy, also referred to as rirs that has been basically used to treat the lower pole stones resistant to swl (20). as a result of increasing experience, relatively larger renal stones have also been treated with this approach and first serie of rirs in hsk patients was published in 2005 where a stone clearance was achieved in 3 of the 4 patients (21). following this publication, in their original study molimard et al. treated 17 patients with hsk and 15 patients (88.2%) with mean stone size of 16 mm were stone free in one session. the success rate was comparable to pnl and better than swl studies with no major complications and 7 (41.2%) patients required more than one session of rirs (22). in another study, 25 renal stones in 20 patients were treated with rirs and a sfr of 70% was reported. the authors found the success rates comparable with pcnl and better than swl with the advantage of lower complication rates (23). currently rirs and holmium yag laser lithotripsy is being increasingly used in the treatment of stone disease particularly in hsk patients. sfr of rirs in the management of hsk patients were reported to be 70% and 88.2 % in the two recently published studies (22, 23). as mentioned above altered orientation of the calyces and high insertion of the ureter coupled with the increased likelihood of upj obstruction, endourologits may face evident technical difficulties during rirs procedure in these cases. in a relatively higher number of cases with hsk patients (32 stones in 23 patients) undergoing rirs, gokce im et al. reported a sfr of 73.9% with acceptable and comparable complication rates (4 of the 23 patients) with previously published series (24). with the advancement of technology, smaller activelydeflectable flexible ureteroscopy (f-urs), equipped with erildirim_stesura seveso 04/10/18 11:07 pagina 152 holmium laser lithotripter and nitinol baskets or graspers increased the effectiveness of rirs in terms of stone-free rates. in this present study we mainly aimed to assess the efficacy and safety of two different techniques (pnl vs rirs) in the management of renal stones in patients with horseshoe kidneys. to our knowledge our study is the first one comparing the efficacy of two different valuable alternatives in the management of renal stones in hsk cases. evaluation of our results clearly showed that sfr’s were comparable in both groups during 1-week (81.6% vs 80.0%) as well as post-operative 3 months evaluation period. the rate of larger residual fragments (> 4 mm) were again similar in both groups. however, while all pnl procedures were completed in a single session, mean number the sessions for cases undergoing rirs was higher than pcnl group (1.220.05). mean duration of the procedure was slightly longer in rirs group when compared with pnl group. regarding the mean degree of hydronephrosis in both groups, there was a statistically significant difference in favour of cases undergoing pnl and this could be best explained by the preference of the surgeons for pnl in kidneys with relatively higher degree of dilatation. last but not least regarding the complications as evaluated on the basis of modified clavien scoring system although they were similar in both groups; evaluation of mean fluoroscopy time as well as mean hb drop rate in both groups clearly revealed them to be higher in cases undergoing pnl procedure. in the light of our findings and the reported literature data as well, we may say that both pnl and rirs procedures are equally effective treatment alternatives in the management of renal stones in patients with hsk. although majority of the patients were stone free after a single session of pnl, taking the more invasive nature of this approach with certain complications (bleeding, extravasation), we believe that rirs may prove itself a valuable alternative with comparable stone free rates despite possible repeated sessions. morover, higher risk of radiation exposure as demonstrated in our cases may be another disadvantage of pnl. depending on the experience of the surgeon and the availability of these systems, best management plan could be made in an individualized basis by considering the patient as well as stone related factors. the major limitation of the current study may be the retrospective nature of our trial and the lack of randomization. additionally management of the cases by 7 different surgeons with variable level of experience could constitute another drawback. however, taking the limited number of studies in small series of cases available in the literature, we believe that as the first trial on this subject comparing rirs vs pcnl in renal stone cases with hsk into account, our findings will be contributive enough to the existing literature. conclusions management of renal stones could be challenging depending on the anatomy as well as stone related factors. of the available minimally invasive treatment alternatives, in the light of the lower stone free rates with swl reported in the published data; both pnl and rirs could be safe and effective alternatives for renal stone removal in patients with hsk. however, we belive that a proper plan could be instituted by considering the experience of the surgeon and availability of the technical equipment. further studies with larger series of cases focusing on the comparative evaluation of both procedures are certainly needed. references 1. bauer s. anomalies of the upper urinary tract. in: walsh pc, retic ab, vaughan ed, et al. ed. campbell’s urology, 8th ed. philadelphia: elsevier saunders. 2002. 2. weizer az, silverstein ad, auge bk, et al. determining the incidence of horseshoe kidney from radiographic data at a single institution. j urol. 2003; 170:1722-6. 3. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horseshoe kidneys. j urol. 2003; 170:48-51. 4. yohannes p, smith ad. the endourological management of complications associated with horseshoe kidney. j urol. 2002; 168:5-8. 5. demirkesen o, yaycioglu o, onal b, et al. extracorporeal shockwave lithotripsy for stones in abnormal urinary tracts: analysis of results and comparison with normal urinary tracts. j endourol. 2001; 15:681-5. 6. kirkali z, esen aa, mungan mu. effectiveness of extracorporeal shockwave lithotripsy in the management of stone-bearing horseshoe kidneys. j endourol. 1996; 10:13-5. 7. sheir kz, madbouly k, elsobky e, et al. extracorporeal shock wave lithotripsy in anomalous kidneys: 11-year experience with two second-generation lithotripters. urology. 2003; 62:10-5. 8. viola d, anagnostou t, thompson tj, et al. sixteen years of experience with stone management in horseshoe kidneys. urol int. 2007; 78:214-8. 9. miller nl, matlaga br, handa se, et al. the presence of horseshoe kidney does not affect the outcome of percutaneous nephrolithotomy. j endourol. 2008; 22:1219-25. 10. symons sj, ramachandran a, kurien a, et al. urolithiasis in the horseshoe kidney: a single-centre experience. bju int. 2008; 102:1676-80. 11. ishii h, rai b, traxer o, et al. outcome of ureteroscopy for stone disease in patients with horseshoe kidney: review of world literature. urology annals. 2015; 7:470-4. 12. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 13. stening sg, bourne s. supracostal percutaneous nephrolithotomy for upper pole caliceal calculi. j endourol. 1998; 12:359-62. 14. skolarikos a, binbay m, bisas a, et al. percutaneous nephrolithotomy in horseshoe kidneys: factors affecting stonefree rate. j urol. 2011; 186:1894-8. 15. turk c, knoll t, petrik a, et al. guidelines on urolithiasis. european urological association web site. http://www.uroweb. org/gls/pdf/ 22%20urolithiasis_lr.pdf. updated 2014. 16. de la rosette jj, opondo d, daels fpj, et al. categorisation of 153archivio italiano di urologia e andrologia 2018; 90, 3 pnl vs rirs in the management of stones located in horseshoe kidney erildirim_stesura seveso 04/10/18 11:07 pagina 153 archivio italiano di urologia e andrologia 2018; 90, 3 b. eryildirim, e.v. kucuk, g. atis, m. ozturk, t. senkul, m. tuncer, a. tahra, t. turan, o. koca, f. ates, o. yilmaz, c. gurbuz, k. sarica 154 complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 17. al-otaibi k, hosking dh. percutaneous stone removal in horseshoe kidneys. j urol. 1999; 162:674-7. 18. etemadian m, maghsoudi r, abdollahpour v, et al. percutaneous nephrolithotomy in horseshoe kidney: our 5-year experience. urology journal. 2013; 10:856-60. 19. el ghoneimy mn, kodera as, emran am, et al. percutaneous nephrolithotomy in horseshoe kidneys: is rigid nephroscopy sufficient tool for complete clearance? a case series study. bmc urol. 2009; 9:17. 20. grasso m, ficazzola m. retrograde ureteropyeloscopy for lower pole caliceal calculi. j urol. 1999; 162:1904-8. 21. weizer az, springhart wp, ekeruo wo, et al. ureteroscopic management of renal calculi in anomalous kidneys. urology. 2005; 65:265-9. 22. molimard b, al-qahtani s, lakmichi a, et al. flexible ureterorenoscopy with holmium laser in horseshoe kidneys. urology. 2010; 76:1334-7. 23. atis g, resorlu b, gurbuz c, et al. retrograde intrarenal surgery in patients with horseshoe kidneys. urolithiasis. 2013; 41:79-83. 24. gokce im, tokatlı z, suer e, et al. comparison of shock wave lithotripsy (swl) and retrograde intrarenal surgery (rirs) for treatment of stone disease in horseshoe kidney patients. ibju. 2016; 42:96-100. correspondence bilal eryildirim, md associate professor bilaleryildirim@yahoo.com tuncer m, md health sciences university, dr. lütfi kirdar training and research hospital, urology clinic, tecerdagi cad. yakutlar sitesi g/11 kartal/istanbul, turkey kucuk ev, md tahra a, md health sciences university, umraniye training and research hospital, urology clinic, !stanbul, turkey atis g, md turan t, md istanbul medeniyet university, goztepe training and research hospital, urology clinic, istanbul, turkey ozturk m, md koca o, md health sciences university, haydarpasa numune training and research hospital, urology clinic, istanbul, turkey senkul t, md ates f, md yilmaz o, md health sciences university, sultan abdulhamid han training and research hospital, urology clinic, istanbul, turkey gurbuz c, md medistate hospital, urology department, istanbul, turkey sarica k, md kafkas university, faculty of medicine, urology department kafkas, turkey erildirim_stesura seveso 04/10/18 11:07 pagina 154 stesura seveso 307archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. background most data on chemical stone composition have been collected in the western world (1-8). it is well known that stone composition is dependent on lifestyle and diet, which in turn is dependent on country, climate and culture. therefore, it is of interest to establish a more globalised map of chemical stone composition around the globe. u-merge, an association gathering urologists from all over the world, is the ideal platform for this task. for this reason, the scientific office of u-merge launched a study to collect the results of urinary stone analyses among different populations in the countries of its members. materials and methods all members of u-merge were invited to join in the study. data were collected by reviewing charts of adult patients (> 18 years) with renal or ureteral stones observed in each participating center who had chemical analysis of the stone available. gender, age, country and stone composition of each patient were recorded in an excel data base. any method of stone analysis was accepted, but the methodology had to be known and registered. a minimum number of 30 patients per center was required. stones analyzed by wet chemical were classified as calcium oxalate (caox) (unspecified), calcium phosphate (cap) (unspecified), mixed calcium oxalate/calcium phosphate (caox/cap), struvite, uric acid (ua), mixed uric acid/calcium oxalate (ua/caox) and cystine. stones analysed by infrared spectroscopy or x-ray diffractometry were classified as caox dihydrate (> 50%), caox monohydrate (> 50%), cap (> 50%), mixed caox/cap (if cap > 10%), struvite (> 50%), carbonate apatite (50%), ua anhydrous (> 50%), ua dihydrate (> 50%), ammonium objective: to study urinary stone composition patterns in different populations around the world. materials and methods: data were collected by reviewing charts of 1204 adult patients of 10 countries with renal or ureteral stones (> 18 years) in whom a stone analysis was done and available. any method of stone analysis was accepted, but the methodology had to be registered. results: in total, we observed 710 (59%) patients with calcium oxalate, 31 (1%) with calcium phosphate, 161 (13%) with mixed calcium oxalate/calcium phosphate, 15 (1%) with carbapatite, 110 (9%) with uric acid, 7 (< 1%) with urate (ammonium or sodium), 100 (9%) with mixed with uric acid/ calcium oxalate, 56 (5%) with struvite and 14 (1%) with cystine stones. calciumcontaining stones were the most common in all countries ranging from 43 to 91%. oxalate stones were more common than phosphate or mixed phosphate/oxalate stones in most countries except egypt and india. the rate of uric acid containing stones ranged from 4 to 34%, being higher in egypt, india, pakistan, iraq, poland and bulgaria. struvite stones occurred in less than 5% in all countries except india (23%) and pakistan (16%). cystine stones occurred in 1% of cases. conclusions: the frequency of different types of urinary stones varies from country to country. calcium-containing stones are prevalent in all countries. the frequency of uric acid containing stones seems to depend mainly on climatic factors, being higher in countries with desert or tropical climates. dietary patterns can also lead to an increase in the frequency of uric acid containing stones in association with high obesity rates. struvite stones are decreasing in most countries due to improved health conditions. key words: urinary calculi; epidemiology; gender; age; calcium oxalate; calcium phosphate; uric acid; struvite; cystine. submitted 18 august 2021; accepted 25 august 2021 stone composition of renal stone formers from different global regions adam haliński 1, kamran hassan bhatti 2, luca boeri 3, jonathan cloutier 4, kaloyan davidoff 5, ayman elqady 6, goran fryad 7, mohamed gadelmoula 6, hongyi hui 8, kremena petkova 9, elenko popov 5, bapir rawa 10, iliya saltirov 9, francisco r. spivacow 11, belthangady monu zeeshan hameed 12, alberto trinchieri 13, noor buchholz 13 1 private medical center "klinika wisniowa" zielona gora; poland; 2 urology unit, city hospital pakpattan, pakistan; 3 department of urology, irccs ca’ granda ospedale maggiore policlinico, university of milan, milan, italy; 4 chu de québec, laval university, québec city, canada; 5 acibadem city clinic tokuda hospital, sofia, bulgaria; 6 urology department, assiut university, assiut, egypt; 7 shar teaching hospital, sulaymanyah city, iraq; 8 department of urology, renji hospital, shanghai jiaotong university school of medicine, shanghai, china; 9 department of urology and nephrology, military medical academy, sofia, bulgaria; 10 smart health tower, sulaymaniyah, kurdistan region, iraq; 11 instituto de investigaciones metabólicas (idim department of urology), buenos aires, argentina; 12 department of urology, kasturba medical college, manipal, karnataka, india; 13 u-merge ltd (urology for emerging countries), london, uk. doi: 10.4081/aiua.2021.3.307 summary archivio italiano di urologia e andrologia 2021; 93, 3 a. haliński, k. hassan bhatti, l. boeri, et al. 308 urate (> 50%), sodium urate (> 50%), mixed ua/caox, cystine. the statistical package for the social sciences (spss) version 11.5 for windows was used for statistical analysis. comparisons were considered to differ significantly if p < 0.05. results in total, 1204 renal stone formers (rsfs) were considered (776 males, 428 females) from 10 countries (argentina, bulgaria, canada, china, egypt, india, iraq, italy, pakistan and poland). twelve institutions from 10 countries have joined the survey as listed below: department of urology, instituto de investigaciones metabólicas, buenos aires (argentina) acibadem city clinic tokuda hospital, sofia (bulgaria) department of urology and nephrology, military medical academy, sofia (bulgaria) chu de québec, laval university, québec city (canada) dep of urolotgy, renji hospital, shanghai jiaotong university school of medicine, shanghai (china) urology department, assiut university, assiut (egypt) department of urology, kasturba medical college, manipal, karnataka (india) urology department, sulaymaniyah surgical teaching hospital, sulaymaniyah (iraq) shar teaching hospital, sulaymanyah city (iraq) department of urology, irccs ca’ granda ospedale maggiore policlinico, milan (italy) city hospital pakpattan, pakpattan (pakistan) private medical center klinika wisniowa, zielona gora (poland) the average age of patients was 49.3+14.4 and the m/f ratio was 1.81. the number, average age and m/f ratio of rsfs from different countries are shown in table 1. the average age of rsfs in italy and canada was greater than that of the rsfs of argentina (p = 0.000), bulgaria (p = 0.000 and p = 0.001), egypt (p-0.000), iraq (p = 0.000, and pakistan (p = 0.000). the average age of rsfs in italy was higher than that of the rsfs in china (p = 0.011). the lowest average age was observed in egypt, iraq, and pakistan, where the average age of rsfs was lower than those of rsfs in canada (p = 0.000), italy (p = 0.000) and china (p = 0.000, p = 0.000 and p = 0.001). in egypt and iraq, the average age of the rsfs was also lower than in bulgaria (p = 0.001, p = 0.002), poland (p = 0.020, p = 0.007) and india (p = 0.009 and p = 0.004). the frequency of the disease was slightly higher in women in poland (52%), whereas it tended to be higher in men in canada (56%), argentina (59%), italy (63%), china (64%) and bulgaria (67%). highest rates in men were observed in pakistan (86%), egypt (78%), india (74%) and iraq (72%). the spectrum of stone composition by gender and age is shown in table 2. in total, we observed 710 (59%) patients with calcium oxalate, 31 (1%) with calcium phosphate, 161 (13%) with mixed calcium oxalate/calcium phosphate, 15 (1%) with carbapatite, 110 (9%) with uric acid, 7 (< 1 %) with urate (ammonium or sodium), 100 (9%) with mixed with uric acid/ calcium oxalate, 56 (5%) with struvite and 14 (1%) with cystine stones. in the calcium-containing group, calcium oxalate stones accounted for 77% and phosphate or mixed calcium phosphate/calcium oxalate stones for the remaining 23%. the frequency of calcium phosphate or mixed calcium phosphate/calcium oxalate ranged from 9 to 74%. the great variability depends on the different methods of analyzing stones and reporting the results. in 403 patients with calcium oxalate stones analyzed by infrared spectroscopy, calcium oxalate monohydrate stones (com) were more frequent than calcium oxalate dihydrate (cod) stones. frequency of calcium oxalate stones was equal in women and men (58% vs 59%), whereas frequency of uric acid containing stones was lower in women than in men (13% vs 21%) and frequency of calcium phosphate and mixed calcium phosphate/calcium oxalate stones (21% vs 14%) and frequency of struvite stones were higher in women. frequency of com stones tended to be higher in men than in women (78 vs 71%) and to increase with age (1839 =78%, 40-59 = 80%, > 60% = 85%). table 1. average age and m/f ratio of rsfs from different countries. argentina bulgaria canada china egypt india iraq italy pakistan poland n° 300 183 50 90 73 35 36 360 44 33 m 179 (59%) 122 (67%) 28 (56%) 58 (64%) 57 (78%) 26 (74%) 26 (72%) 226 (63%) 38 (86%) 16 (48%) f 121 (41%) 61 (33%) 22 (44%) 32 (36%) 16 (22%) 9 (26%) 10 (28%) 134 (37%) 6 (14%) 17 (52%) age 45+12 48+13 56+14 50+12 40+12 50+12 38+13 56+14 40+8 50+17 age p = 0.000; m/f p = 0.002. table 2. spectrum of stone composition by gender and age. gender age class males females 18-39 40-59 > 60 total caox 461 (59%) 249 (58%) 200 (59%) 318 (57%) 192 (62%) 710 (59%) com 223 105 73 136 119 328 cod 52 23 20 34 21 75 caox/cap 89 (11%) 72 (16%) 46 (13%) 80 (14%) 35 (11%) 161 (13%) cap 18 (2.3%) 13 (3.0%) 12 (3.5%) 14 (2.5%) 5 (1.5%) 31 (3%) carbapatite 4 (0.5%) 11 (2.5%) 5 (1.5%) 8 (1.5%) 2 (0.5%) 15 (1%) ca-containing 572 (74%) 345 (80%) 263 (77%) 420 (76%) 234 (76%) 917 (76%) ua 84 (11%) 26 (6%) 22 (6.4%) 49 (8.8%) 39 (12.6%) 110 (9%) urate 4 (0.5%) 3 (0.7%) 0 (0%) 4 (0.5%) 3 (1%) 7 (0.5%) ua/caox 75 (10%) 25 (6%) 25 (7%) 55 (10%) 20 (6%) 110 (9%) ua-containing 163 (21%) 54 (13%) 47 (14%) 108 (19%) 62 (20%) 217 (18%) struvite 33 (4.2%) 23 (5.4%) 23 (7%) 22 (4%) 11 (3.5%) 56 (5%) cystine 8 (1.1%) 6 (1.4%) 8 (2.5%) 4 (0.5%) 2 (0.5%) 14 (1%) total 776 428 341 554 309 1204 309archivio italiano di urologia e andrologia 2021; 93, 3 worldwide renal stone composition frequency of uric acid stones was higher in males and tended to increase with age. the distribution of the different types of stones in rsfs in different countries is described in table 3. calcium-containing stones were the most common in all countries. among calcium-containing stones, calcium oxalate stones were more frequent in all countries except in egypt and india where the frequency of calcium phosphate or mixed calcium phosphate/calcium oxalate was 74% in egypt and 53% in india, respectively. among calcium oxalate stones, the rate of com stones was 100% in egypt, 83% in italy, 81% in bulgaria, 75% in china, and 69% in iraq. the rate of uric acid containing stones ranged 4 to 34% in most countries with the highest rates observed in egypt, india, poland, and bulgaria. struvite stones were less than 5% in all countries but india (23%) and pakistan (16%). cystine stones were less than 2%. discussion stone composition by age and sex in the present study, calcium-containing stones were the most frequent, followed by uric acid-containing stones, while struvite and cystine are less frequent. in accordance with previous reports (9), uric acid containing stones were more frequent in males and in older ages, whereas phosphate stones were more frequent in women. the average age of rsfs in different countries varies but these differences reflect those that are observable in the general population of their countries, which averaged about 20 years lower (figure 1). m/f ratio is different in countries, being balanced between men and women or slightly in favor of men in the countries of north america, europe, south america and china but heavily weighted in favor of men in egypt, pakistan, india and iraq. this finding confirmed the tendency to an increase of stone formation in women of western countries (9), and more recently of china (10), while in egypt, pakistan, india and iraq the ratio of males to females is still similar to what was observed in western countries forty years ago (11). this trend can be explained by the so-called nutrition transition, that is the change in dietary habits across the world with a convergence towards an increased consumption of unhealthy table 3. spectrum of stone composition in different countries. argentina bulgaria canada china egypt india iraq italy pakistan poland tot caox 239 (80%) 97 (53%) 23 (46%) 65 (72%) 12 (16%) 7 (20%) 16 (44%) 214 (59%) 21 (48%) 16 (49%) 710 (59%) com 79 49 12 11 178 cod 18 16 0 5 36 caox/cap 12 (4%) 17 (9%) 11 (22%) 11 (12%) 34 (47%) 8 (23%) 7 (20%) 57 (16%) 0 (0%) 4 (12%) 161 (13%) cap 7 (2%) 0 (0%) 2 (4%) 6 (7%) 0 (0%) 0 (0%) 0 14 (4%) 2 (4%) 0 31 (3%) carbapatite 0 (0%) 3 (2%) 10 (20%) 0 (0%) 0 (0%) 0 (0%) 2 (5%) 0 (0%) 0 (0%) 0 15 (1%) ca-containing 258 (86%) 117 (64%) 46 (92%) 82 (91%) 46 (63%) 15 (43%) 25 (69%) 285 (79%) 23 52% 20 61% 917 (76%) ox % 92% 85% 50% 79% 26% 46% 64% 72% 91% 80% 77% ua pure 27 (9%) 8 (4.5%) 1 (2%) 5 (5%) 0 (0%) 5 (14%) 8 (22%) 39 (10.5%) 11 (25%) 6 (18%) 110 (9%) ua urate 0 (0%) 6 (3.5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (0.5%) 0 (0%) 0 (0%) 7 (1%) ua/caox 6 (2%) 39 (21%) 1 (2%) 1 (1%) 22 (30%) 7 (20%) 1 (3%) 18 (5%) 0 (0%) 5 (15%) 100 (8%) ua containing 33 (11%) 53 29% 2 (4%) 6 6% 22 (30%) 12 (34%) 9 (25%) 58 (16%) 11 (25%) 11 (33%) 217 (18%) struvite 9 (3%) 10 (5.4%) 1 (2%) 2 (3%) 4 (5.5%) 8 (23%) 1 (3%) 12 (3,5%) 8 (18%) 1 (3%) 56 (5%) cystine 0 (0%) 3 (1.6%) 1 (2%) 0 (0%) 1 (1.5%) 0 (0%) 1 (3%) 5 (1.5%) 2 (5%) 1 (3%) 14 (1%) total 300 183 50 90 73 35 36 360 44 33 1204 figure 1. average age in rsfs and general population. archivio italiano di urologia e andrologia 2021; 93, 3 a. haliński, k. hassan bhatti, l. boeri, et al. 310 foods that is the cause of the increase in non-communicable diseases in almost all regions of the world in both sexes (12). consumption of unhealthy foods is still limited in some regions of north africa and south asia that maintain dietary patterns with a lower risk of urinary stones forming. moreover, in some countries the characteristics of family structure and cultural rules still present a nutritional disadvantage for women (13). stone composition by country the spectrum of composition of urinary stones is quite variable in different countries. differences could be attributable to the different characteristics by age and gender of the populations studied, reflecting the distribution by age and gender in the general population of each country. on the other hand, the modality of stone analysis and reporting in the different centers may be a confounding factor (14). for this reason, the most robust data are those comparing the rates of calcium-containing with those of uric acid containing stones, whereas it is less significant to compare the results of different countries in relation to the specific crystallographic composition, which should be compared between patients whose stones have been analyzed and reported in the same laboratory. calcium-containing stones were the most common in vast majority of countries with a rate ranging from 52 to 91%. the highest rates of calcium-containing stones were observed in north america, south america, china and some european countries. in most countries, calcium oxalate stones (in particular, com stones) were the more frequent calcium-containing stones, although calcium phosphate and mixed calcium oxalate/calcium phosphate stones were more frequent than pure calcium oxalate stones in some countries such as egypt and india. this trend agrees with previous observation in north america where a tendency has been reported of an increase in oxalate stones and a decrease in phosphate stones during the last two decades (4, 5). the highest rates of acid uric containing stones were observed in iraq, pakistan, india, egypt and poland and bulgaria. in general, uric acid-containing stones should be more frequent in older male patients, but surprisingly in our study the highest rates of uric acid-containing stones were observed in two countries with the lowest mean age, namely egypt and iraq. this result can be explained by the finding that the frequency of a type of stone is not a measure of the prevalence of the disease in the population, but is the result of the prevalence of different types of urinary stones. in other words, a high frequency of uric acid stones may be due to an increase in the prevalence of uric acid stones but, alternatively, a lower prevalence of other types of stones in the population studied. on the other hand, the impact of environmental factors could be decisive, considering that high temperatures and high humidity cause a decrease of urinary volumes and urinary ph values resulting in an increase of urinary uric acid saturation and of the incidence of uric acid stones (15, 16). in fact, the highest values of uric acid-containing stones were observed in countries with high mean temperatures (17) and tropic or hot desert climates such as egypt, india, pakistan and iraq (table 4) (figure 2). our data confirm previous evidence in the literature showing a high rate of uric acidcontaining stones in pakistan, egypt, and iraq (18-21). in the present figure 2. rate of uric-acid containing stones and mean temperature. table 4. mean temperature, precipitation fall and climate classification in the countries involved in the study. country town temperature precipitation climate köppen-geiger climate mean fall classification system argentina buenos aires 16.8 °c. 1040 mm warm temperate cfa bulgaria sofia 10.2 °c 581 mm warm temperate cfb canada quebec 4.8 °c. 1101 mm cold temperate dfb china shanghai 16.1 °c. 1066 mm warm temperate cfa egypt asyut 22.6 °c. 2 mm hot desert bwh india karnataka 26.7 °c 4866 mm tropical am pakistan pakpattan 24.8 °c 234 mm hot desert bwh iraq sulaymaniyah 16.2 °c 906 mm. warm temperate csa italy milan 13.1°c 1013 mm warm temperate cfa poland zielona gora 8.8 °c 572 mm warm temperate cfb 311archivio italiano di urologia e andrologia 2021; 93, 3 worldwide renal stone composition study, the prevalence of uric acid containing stones was also high in southern india in accordance with previous reports. in fact, the frequency of uric acid-containing stones was reported low (4.28%) or very low (< 1%) in north western india (22, 23), but higher in southern india (24). this difference can be explained by different regional eating habits: in the northern and western regions, a more traditional vegetarian diet is consumed with exclusive consumption of fruit, vegetables and legumes, whereas in the southern regions the consumption of sweets, snacks and pork meat is common (25). on the other hand, in our study the lowest rate of uric acid containing stones was observed in canada, the country with the lowest mean temperature. intermediate rate values were observed in countries with a temperate climate, such as china and italy. the high frequency of uric acid-containing stones in poland is less easily explained, mainly because it contrasts with previous findings showing lower rates of uric acid stones in a series of stones analyzed by infrared spectroscopy (26). possible explanations are high obesity rate of the population (45%) and unfavorable dietary patterns (27). in fact, the adherence to the traditional polish dietary pattern, characterized by high intake of refined grains, potatoes, sugar and sweets is associated with a higher risk of abdominal obesity and hypertriglyceridemia (28). similarly, in bulgaria the frequency of uric acid-containing stones is associated with obesity rates which are among the highest in europe (46%) (27), and with an unhealthy nutritional pattern characterized by high consumption of fatty meats and meat products, highfat milk and a high alcohol intake (29). the rate of struvite stones is generally lower than described in the past, due to improved health conditions and early diagnosis and treatment of urinary tract infections by urease-producers, although in some countries such as pakistan and india it still accounts for a quarter of cases. cystine stone rates are similar in all countries, with similar rates than those reported in the literature. in conclusion, the frequency of different types of urinary stones varies from country to country. calcium-containing stones are the most frequent in all countries, with frequencies of up to 90%. the frequency of uric acid containing stones seems to depend mainly on climatic factors, being more frequent in warmer countries with desert or tropical climates although dietary patterns can also lead to an increase in the frequency of uric acid containing stones in association with high obesity rates. struvite stones are decreasing in most countries except india and pakistan. references 1. daudon m, donsimoni r, hennequin c, et al. sexand age-related composition of 10 617 calculi analyzed by infrared spectroscopy. urol res. 1995; 23:319-26. 2. trinchieri a, rovera f, nespoli r, currò a. clinical observations on 2086 patients with upper urinary tract stone. arch ital urol androl. 1996; 68:251-62. 3. knoll t, schubert ab, fahlenkamp d, et al. urolithiasis through the ages: data on more than 200,000 urinary stone analyses. j urol. 2011 apr;185(4):1304-11. doi: 10.1016/j.juro.2010.11.073. 4. gault mh, chafe l. relationship of frequency, age, sex, stone weight and composition in 15,624 stones: comparison of resutls for 1980 to 1983 and 1995 to 1998. j urol. 2000; 164:302-7. 5. moses r, pais vm jr, ursiny m, et al. changes in stone composition over two decades: evaluation of over 10,000 stone analyses. urolithiasis. 2015; 43:135-9. 6. singh p, enders ft, vaughan le, et al. stone composition among first-time symptomatic kidney stone formers in the community. mayo clin proc. 2015; 90:1356-65. 7. xu lhr, adams-huet b, poindexter jr, et al. temporal changes in kidney stone composition and in risk factors predisposing to stone formation. j urol. 2017; 197:1465-1471. 8. kittanamongkolchai w, vaughan le, enders ft, et al. the changing incidence and presentation of urinary stones over 3 decades. mayo clin proc. 2018; 93:291-299. 9. lieske jc, rule ad, krambeck ae, et al. stone composition as a function of age and sex. clin j am soc nephrol. 2014; 9:2141-6. doi: 10.2215/cjn.05660614. 10. zeng g, mai z, xia s, et al. prevalence of kidney stones in china: an ultrasonography based cross-sectional study. bju int. 2017; 120:109-116. doi: 10.1111/bju.13828. epub 2017 mar 21. 11. johnson cm, wilson dm, o'fallon wm, et al. renal stone epidemiology: a 25-year study in rochester, minnesota. kidney int. 1979; 16:624-31. 12. imamura f, micha r, khatibzadeh s, et al. global burden of diseases nutrition and chronic diseases expert group (nutricode) dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. lancet glob health. 2015; 3:e132-42. 13. rao t, & pingali p. the role of agriculture in women's nutrition: empirical evidence from india. plos one 2018; 13:e0201115. 14. siener r, buchholz n, daudon m, et al. quality assessment of urinary stone analysis: results of a multicenter study of laboratories in europe. plos one 2016; 11:e0156606. 15. stuart ro 2nd, hill k, poindexter j, pak cy. seasonal variations in urinary risk factors among patients with nephrolithiasis. j lithotr stone dis. 1991; 3:18-27. 16. baker pw, coyle p, bais r, rofe am. influence of season, age, and sex on renal stone formation in south australia. med j aust. 1993; 159:390-2. 17. https://it.climate-data.org/ 18. rafique m, bhutta ra, rauf a, chaudhry ia. chemical composition of upper renal tract calculi in multan. j pak med assoc. 2000; 50:145-8. 19. sheir kz, mansour o, madbouly k, et al. determination of the chemical composition of urinary calculi by noncontrast spiral computerized tomography. urol res. 2005; 33:99-104 20. afaj ah, sultan ma. mineralogical composition of the urinary stones from different provinces in iraq. scientific world journal. 2005; 5:24-38. 21. popov e, almusafer m, belba a, et al. obesity rates in renal stone formers from various countries. arch ital urol androl. 2021; 93:189-194. 22. bhat a, singh v, bhat m, et al. spectrum of urinary stone composition in northwestern rajasthan using fourier transform infrared spectroscopy. indian j urol. 2018; 34:144-148. doi: 10.4103/ iju.iju_363_16. 23. ansari ms, gupta np, hemal ak, et al. spectrum of stone composition: structural analysis of 1050 upper urinary tract calculi from northern india. int j urol. 2005; 12:12-6. archivio italiano di urologia e andrologia 2021; 93, 3 a. haliński, k. hassan bhatti, l. boeri, et al. 312 24. marickar ymf. epidemiology of stone disease in kerala, south india. in talati j, tiselius h-g, albala dm, ye z (eds.) urolithiasis: basic science and clinical practice, springer verlag, london, pp 47-51. 25. green r, milner j, joy ej, et al. dietary patterns in india: a systematic review. br j nutr. 2016; 116:142-8. doi: 10.1017/ s0007114516001598. 26. wrobel a, rokita e, taton g, thor p. chemical composition and morphology of renal stones. folia med cracov. 2013; 53:5-15. 27. kotseva k, wood d, de bacquer d, et al. a european society of cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 european countries. eur j prev cardiol. 2016; 23:636-48. doi: 10.1177/2047487315569401. 28. suliga e, kozieł d, ciesla e, et al. dietary patterns in relation to metabolic syndrome among adults in poland: a cross-sectional study. nutrients. 2017; 9. pii: e1366. doi: 10.3390/nu9121366. 29. ncpha.government.bg/files/hranene-en.pdf correspondence adam haliński, md adamhalinski@gmail.com private medical center "klinika wisniowa" anieli krzywon street 2; 65-001 zielona gora (poland) kamran hassan bhatti, md kamibhatti92@gmail.com city hospital pakpattan (pakistan) luca boeri, md dr.lucaboeri@gmail.com department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy kaloyan davidoff, md shennyp@yahoo.com elenko popov, md shennyp@yahoo.com acibadem city clinic tokuda hospital sofia, bulgaria sofia, bul n. vaptzarov 51 b ayman elqady, md mohamed gadelmoula, md mgad73@aun.edu.eg urology department assiut university assiut (egypt) goran fryad, md goranfryad@yahoo.com shar teaching hospital malik mahmood circle street, sulaimani city (kurdistan region-iraq) po box: baxtyary 36b hongyi hui, md 1095340463@qq.com department of urology, renji hospital, shanghai jiaotong university school of medicine no.160, pujian road, shanghai, 200127, china kremena petkova, md dr_petkova@yahoo.com iliya saltirov, md saltirov@vma.bg department of urology and nephrology, military medical academy 3, georgi sofiiski blvd, 1606 sofia, bulgaria bapir rawa, md dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq francisco r spivacow, md frspivacow@gmail.com instituto de investigaciones metabólicas (idim) libertad 836, 1° piso, ciudad autónoma de buenos aires (argentina) belthangady monu zeeshan hameed, md zeeshanhameedbm@gmail.com kasturba medical college, manipal department of urology, kmc hospital, manipal-576104, karnataka, india alberto trinchieri, md alberto.trinchieri@gmail.com noor buchholz, md (corresponding author) noor.buchholz@gmail.com u-merge ltd. (urology for emerging countries), london, uk stesura seveso 285archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. surgery is strictly related to continence and potency sphere (3). as such, apart from cancer control, functional outcomes have been widely explored in an endeavor to timely predict which patients may experience worse sexual and continence recovery (4-5). in the last few years, obesity has emerged has a clinical factor potentially influencing perioperative features. indeed, several studies have reported evidence for obesity being independently associated with higher complication rates (6), as well as worse oncologic (7) and functional outcomes after surgery (8). however, we are still far from drawing definitive conclusions. to date, current literature on this issue has been critically influenced by several features: 1) most studies have defined body habitus using body mass index (bmi), whilst data on district adiposity parameters such as waist circumference (wc), subcutaneous and abdominal fat were poorly investigated; 2) a significant body of evidence still derives from open rp series. as such, reported findings may be not completely contemporary, being rp increasingly performed nowadays by laparoscopic or robot-assisted approach. to address this unmet need, we designed this longitudinal cohort study with a long-term follow-up period to better understand the impact of abdominal visceral adiposity (va), wc and bmi on the recovery of sexual function and continence in patients with pca treated with laparoscopic rp (lrp). materials and methods patients, dataset and study schedule all patients affected by localized intermediate-risk prostate cancer and treated with laparoscopy radical prostatectomy at our centre between january and december 2012, have been enrolled in this longitudinal cohort study. clinical (including bmi and wc), instrumental, surgical, and objective: a prospective longitudinal cohort study on the impact of anthropometric measures on the sexual function and continence recovery in patients treated with laparoscopic radical prostatectomy (lrp) is presented. material and methods: anthropometric measures, international index of erectile function (iief-5) and international prostatic symptoms score questionnaires, were collected before surgery and at the end of follow-up period. all patients were assigned into the following groups: a) non-obese; b) non-obese with central adiposity; c) obese without central adiposity; d) obese with central adiposity. urinary and sexual functions were the outcome measures. results: at the end of follow-up, in 29 patients with visceral adiposity (va) the median iief-5 was 14 (iqr 7-18) while in 49 non-va patients (62.8%) was 22 (iqr 17-24) (p < 0.001). twenty-three patients (79.3%) with va reported complete continence, while 6 (20.7%) used ≥ 2 pads per day. forty-eight patients (97.9%) without va reported complete continence. va was confirmed as a strong independent predictor for worse continence (hr 3.67; 2.75-4.51 ci95% p = 0.003) and sexual function recovery (hr: 4.51; 3.09-5.63 ci95% p < 0.001). conclusion: we truly believe obese with visceral adiposity patients with prostate cancer should receive detailed preoperative counseling before surgery, including higher risk of suboptimal functional outcomes. key words: prostate cancer; adiposity; metabolic syndrome; body mass index; quality of life. submitted 17 may 2021; accepted 3 july 2021 introduction several treatment options are available for the management of localized prostate cancer (pca). to date, more than 40% of pca patients have radical prostatectomy (rp) for their definitive treatment (1-2). quality of life after visceral adiposity is associated with worse urinary and sexual function recovery after radical prostatectomy: results from a longitudinal cohort study tommaso cai 1, 2, andrea cocci 3, fabrizio di maida 3, stefano chiodini 1, francesco ciarleglio 4, lorenzo giuseppe luciani 1, giovanni pedrotti 5, alessandro palmieri 6, gianni malossini 1, michele rizzo 7, giovanni liguori 7, truls e. bjerklund johansen 2, 8, 9 1 department of urology, santa chiara regional hospital, trento, italy; 2 institute of clinical medicine, university of oslo, oslo, norway; 3 department of urology, university of florence, florence, italy; 4 department of surgery, santa chiara regional hospital, trento, italy; 5 department of anesthesiology, santa maria del carmine hospital, rovereto, italy; 6 department of urology, university federico ii, naples, italy; 7 department of urology, university of trieste, trieste, italy; 8 department of urology, oslo university hospital, oslo, norway; 9 institute of clinical medicine, university of aarhus, denmark. doi: 10.4081/aiua.2021.3.285 summary archivio italiano di urologia e andrologia 2021; 93, 3 t. cai, a. cocci, f. di maida, et al. 286 pathological features were recorded before enrolment. all surgical procedures were performed by a single highly trained laparoscopic surgeon (gm). in brief, all procedures have been performed by using an extraperitoneal 5trocar approach (9). the vesico-urethral anastomosis was made via 2 running sutures with 2-0 monocryl according to the technique described by van velthoven (10). all patients underwent oncological follow-up evaluations, in line with international guidelines, for prostate cancer and with our previous studies (9, 11). after six months, one year after surgery and at each year follow-up evaluation, additionally to the standard biochemical and instrumental evaluations, all patients underwent specific questionnaires about quality of life and sexual function. the figure 1 shows the study schedule. the median follow-up period was 86 months (82-95). the study was conducted in line with the strobe statement (http://www.strobestatement.org) and in line with the good clinical practice guidelines and the ethical principles laid down in the latest version of the declaration of helsinki. inclusion and exclusion criteria we consider all patients affected by localized intermediate-risk prostate cancer, in line with the definition and criteria of d’amico (12), and candidates for laparoscopy radical prostatectomy. we excluded from the study patients who had a history of erectile disfunction, patients on pde-5 or 5a-reductase inhibitors, patients with penile prosthesis implants. patients affected by hypotestosteronemia and with other concomitant major diseases were excluded. finally, all patients who require adjuvant hormonal therapy after surgery were also excluded. body mass index and anthropometric measures at the enrolling time, the following anthropometric measures have been collected: height (cm), weight (kg), and waist circumference (cm) measurement. bmi was calculated as weight in kg divided by squared height in meters (kg/m2). the waist circumference was measured using a standard measurement strip with the patients standing and breathing normally, at the midway between the lowest rib margin and iliac crest. in line with the national cholesterol educational program adult treatment panel iii (ncep: atp iii) (13), a cut-off of 102 cm for the waist circumference and of 30 kg/m2 for the bmi has been considered. in line with de nunzio et al. (14). patients were then categorized in 4 body habitus groups: a) non-obese (bmi < 30 kg/m2 and wc < 102 cm) b) non-obese with central adiposity (bmi < 30 kg/m2 and wc ≥ 102 cm) c) obese without central adiposity (bmi > 30 kg/m2 and < wc 102 cm) d) obese with central adiposity (bmi ≥ 30 kg/m2 and wc ≥ 102 cm) even if some authors stated that visceral adiposity index was shown to be a better surrogate index than these single anthropometric indices to use in clinical practice, we decided to not use it due to the complexity of its calculation (15, 16). in fact, visceral adiposity index is comprised of anthropometric measures like bmi, wc and clinical measures of serum triglycerides and high-density lipoprotein-cholesterol levels (15). data collection and urological evaluations at each follow-up visit at the time of surgery, in addition to all anthropometric measures, the following parameters were recorded: the patient’s and partner’s age, the charlson comorbidity index, preoperative prostate-specific antigen levels, gleason score, clinical prostate cancer stage (through an abdominal computed tomography (ct) scan and skeletal scintigraphy), duration of hospital stay and surgical complications. all patients underwent a standard follow-up schedule (figure 1) depending on individual tumors and characteristics, in line with international guidelines and in line with our everyday clinical practice (1, 17). in brief, clinical evaluation with dre, prostate-specific antigen level and instrumental evaluation. moreover, after six months, one year after surgery and at each year follow-up evaluation all patients underwent the following questionnaires: international index of erectile function (iief-5) (18) and international prostatic symptoms score (ipss) (19) questionnaires, in line with previous study (20). continent patients were defined by use of 0 or 1 safety pad/day (11). outcome measures the main outcome measures were change in questionnaire score, the urinary and sexual function recovery at the end of the follow-up evaluation in each body habitus groups. statistical analysis for statistical purposes, independent variables included all patientand tumor-related data available in our institutional database. first, descriptive statistics were obtained reporting medians and interquartile range (iqr, 25th and 75th percentiles) for continuous variables, and frequencies and proportions for categorical variables, as appropriate. continuous variables were compared using the student t test. categorical variables were tested with the chi-square test. bmi and waist circumference were examined as continuous variables using crude and adjusted logistic regressions to evaluate their association with the recovfigure 1. follow-up schedule. 287archivio italiano di urologia e andrologia 2021; 93, 3 visceral adiposity and functional outcomes ery of sexual function and continence. multivariable cox regression analysis to evaluate clinical and surgical predictors for continence and sexual recovery was performed. statistical analyses were performed using spss v. 24 (ibm spss statistics for mac, armonk, ny, ibm corp). a significance level of p < 0.05 was set for all tests. according to the nature of the study, we consider the following sample size to enroll: all patients attending a single centre in the same period between january and december 2012 represent our patients’ population. results overall, 78 patients were considered for this study. median age was 68 (iqr: 62-77) and median pre-operative psa was 9.9 ng/ml (iqr: 3.2-14.7). nerve sparing rp was performed in 36 (46.1%) patients. at final histopathological examination pt2a, pt2b and pt2c were assessed in 26 (33.3%), 15 (19.2%) and 37 (47.5%) patients, respectively. anthropometric measures and questionnaires results at baseline baseline median bmi was 26.3 (iqr: 20.8-34.3), while median wc was 91.6 cm (iqr: 89.3-105.4). pre-operative ipss and iief-5 were 13 (iqr: 12-14) and 25 (iqr: 24-26), respectively. in line with the ncep: atp iii, 23 patients were included in the group a, 9 in the group b, 26 in the group c and 20 in the group d. no differences among the four groups have been showed in terms of preoperative iief-5, ipss scores or pathological data. all clinical, demographic, instrumental and pathological data have been showed in table 1. operative and peri-operative complications only two patients required conversion to open surgery due to intraoperative bleeding, that, however, did not require other emergent managements or intensive care. in 76 cases (97.4%) no complications occurred that required an emergent return to the operating room. even if an increased blood loss has been observed in group b and d when compared with group a and c, there was not statistically significant difference. no statistically significant difference has been showed among the groups in terms of operative median time or hospital stay. no statistically significant differences have been reported among the groups in terms of peri-operative complications (such as thrombosis, prolonged compression nerve injury or bladder neck disruptions). follow-up data survival outcome at a median follow up of 86 months (82-95), 12 patients reported a biochemical recurrence showing a biochemical-recurrence free survival of 84.7%. the overall survival rate at the end of follow-up period was 96.1%. no difference has been reported among the groups in terms of cancer-specific survival and overall survival, according to the baseline model with adjustments for age and year at cancer diagnosis. the figure 2 shows the kaplan-meier curve analysis on the survival probability of patients with prostate cancer by group. table 1. demographic, clinical and pathological patients’ data at the enrolment time. patients (n°) 78 age (median; iqr*) 68 (62-77) educational qualification primary school 55 (70.5) high school 21 (26.9) university 2 (2.6) pre-operative evaluation psa (median; iqr*) 9.9 (3.2-14.7) clinical stage ct2 74 (94.9) ct3 4 (5.1) prostate volume, ml (median; iqr*) 48 (32–78) dre# positive 19 (24.3) bmi§ (median; iqr*) 26.3 (20.8-34.3) waist circumference, cm 91 (89-105) ipss$ 13 (12-14) iief-5’ 25 (24-26) surgical approach nerve-sparing 36(46.1%) unilateral 21 (58.3) bilateral 15 (41.7) pathological findings pt2a 26 (33.3) pt2b 15 (19.2) pt2c 37 (47.5) gleason score 3+3 10 (12.8) 3+4 35 (44.9) 4+3 33 (42.3) positive margins 15 (19.2) ncep: atp iii” group a 23 (29.4) group b 9 (11.5) group c 26 (33.4) group d 20 (25.7) the table shows all baseline characteristics, clinical and pathological parameters. n°= number; iqr* = interquartile range; dre# = digital rectal examination; bmi§ = body mass index; ipss$ = international prostatic symptoms score; iief-5’ = international index of erectile function; ncep: atp iii” = national cholesterol education program adult treatment panel iii. figure 2. kaplan-meier curve analysis on the survival probability of patients with prostate cancer by body habitus. archivio italiano di urologia e andrologia 2021; 93, 3 t. cai, a. cocci, f. di maida, et al. 288 functional outcomes overall, 71 (91%) patients reported complete continence, while 7 (8.9%) used ≥ 2 pads per day. median postoperative iief-5 was 18 (iqr: 7-24). twelve patients (15.4%) reported spontaneous erection without any pharmacological support. conversely, 38 (48.7%) and 10 (12.8%) reported sexual function recovery with the use of oral support and/or pge1 administration, respectively, while 18 patients (23.1%) reported complete absence of erections. the median iief-5 in 29 patients with va (group b+d) was 14 (iqr 7-18) while was 22 (iqr 17-24) in 49 nonva patients (group a+c) (62.8%), with a statistically significant difference between the two groups (p < 0.001) (figure 3). twenty-three patients (79.3%) with va reported complete continence, while 6 (20.7%) used ≥ 2 pads per day. on the other hand, 48 patients (97.9%) without va reported complete continence. all follow-up data stratified for body habitus groups have been showed in table 2. multivariate analysis findings at multivariable analysis, visceral adiposity was confirmed as a strong independent predictor for worse continence (group b: hr 3.67; 2.75-4.51 ci 95%; p = 0.003; group d: hr 2.03; 1.81-3.14 ci 95%; p = 0.04) and sexual function recovery (group b: hr 4.51; 3.09-5.63 ci 95%; p = 0.001; group d: hr 3.33; 3.04-5.09 ci 95%; p = 0.001) (table 3). discussion main findings it is widely known that functional outcomes have a non-negligible impact on health-related quality of life after rp. the impact of obesity on the outcomes of rp, irrespective of surgical approach, has been extensively investigated but we are still far from drawing definitive conclusions (7). yet there is a strong need for further investigation to explore association between continence and sexual recovery and obesity, assessed not only by bmi but also evaluating district adiposity parameters such as wc, subcutaneous and abdominal fat volume. to address this unmet need, we conducted the current longitudinal, cohort study to further pose a little cornerstone towards an in-depth knowledge of this critical issue. on the basis of this background, we demonstrated that obesity with central adiposity was associated with worse continence and sexual function recovery after laparoscopic rp. figure 3. a) median iief-5 in patients by body habitus at baseline and at the end of the study. b) median iief-5 in patients with and without visceral adiposity at baseline and at the end of the study. table 2. functional findings at the follow-up evaluation according to the body habitus. patients (n°) 78 ncep: atp iii# (body habitus) group a group b group c group d patients (n°) 23 (29.4) 9 (11.5) 26 (33.4) 20 (25.7) urinary continence no pad/die 19 7 20 12 no or 1 pad/die 4 1 5 3 2 or more pads/die 0 1 1 5 iief-5§ (median; iqr*) 22 (18-23) 14 (7-16) 22 (17-24) 14 (8-18) ipss’ 11 (6-14) 12 (7-13) 10 (6-11) 11 (6-13) the table shows all follow up data according to the body habitus. n° = number; ncep: atp iii# = national cholesterol education program adult treatment panel iii; iief-5§ = international index of erectile function; iqr* = interquartile range; ipss’ = international prostatic symptoms score. 289archivio italiano di urologia e andrologia 2021; 93, 3 visceral adiposity and functional outcomes results in the context of previous studies first key point of our study is that visceral obesity was confirmed to be independently associated with worse sexual function recovery. of course, the presence of a greater amount of periprostatic adipose tissue may be associated with a higher risk of injury to the neurovascular bundle. moreover, metabolic syndrome itself is linked with worse potency and higher rates of endothelial disfunction (21). actually, several previous studies showed no impact of obesity on sexual domain after open and/or robotic rp (22-24), while other series reported adverse effects (25) or impact with the metabolic and systemic disease (26, 27). however, we would like to point out that in all the above-mentioned health-related quality of life studies, the definition of potency and its measurement was mostly subjective, meaningfully undermining reliability of reported finding. in our study, we tried to overcome this limit by objectively defining preand postoperative erectile function with iief-5 questionnaire. second, visceral obesity resulted an independent predictor also of delayed continence recovery. consistently with our findings, wiltz et al. (25) published one of the largest series, with 945 patients stratified according to bmi, reporting that obesity was associated with worse continence recovery at 12 and 24 months (25). moreover, a systematic review and metanalysis by xu et al. confirmed that obese patients are at higher risk of experiencing worse functional outcomes after rp (28). of course, obesity might also bring about additional physical strain on the bladder, ultimately resulting in more preoperative urinary problems and a prolonged duration of return to continence. considering these underlying issues unrelated to surgical expertise, suboptimal functional outcomes should be discussed with obese patients during preoperative counseling. strengths and limitations of this study the present study was not devoid of limitations. first, this was a retrospective review of a prospectively collected database. second, the relatively small sample size together might have undermined the evaluation of potential predictors of functional outcomes in our series. even if all cases were performed by a single surgeon with extensive experience in lrp, our findings could not be applicable to all surgeonor center-related scenarios. acknowledged these limitations, our study represents the largest series so far exploring association between continence and sexual recovery and obesity, assessed not only by bmi but also evaluating district adiposity parameters such as wc, subcutaneous and abdominal fat volume. further multi-institutional series are warranted to confirm our preliminary findings. conclusions in our experience, visceral adiposity was associated with worse continence and sexual function recovery after laparoscopic rp, highlighting the need for an accurate pre-surgical evaluation of the body habitus and a detailed preoperative counselling before surgery. references 1. mottet n, van den bergh rcn, briers e, et al. eau-eanmestro-esur-siog guidelines on prostate cancer-2020 update. part 1: screening, diagnosis, and local treatment with curative intent. eur urol. 2021; 79:243-262. 2. perletti g, magri v, vral a, et al. green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven hg-pin or asap. concise review and meta-analysis. arch ital urol androl. 2019; 91:153-156 3. sanda mg, dunn rl, michalski j, et al. quality of life and satisfaction with outcome among prostate-cancer survivors. n engl j med. 2008; 358:1250-61. 4. neumaier mf, segall júnior ch, hisano m, et al. factors affecting urinary continence and sexual potency recovery after roboticassisted radical prostatectomy. int braz j urol. 2019; 45:703-712. 5. briganti a, gallina a, suardi n, et al. predicting erectile function recovery after bilateral nerve sparing radical prostatectomy: a proposal of a novel preoperative risk stratification. j sex med. 2010; 7:2521-31. 6. lindner u, lawrentschuk n, abouassaly r, et al. radical prostatectomy in obese patients: improved surgical outcomes in recent years. int j urol. 2010; 17:727-32. 7. yu yd, byun ss, lee se, et al. impact of body mass index on oncological outcomes of prostate cancer patients after radical prostatectomy. sci rep. 2018; 8:11962. 8. khoder wy, trottmann m, stuber a, et al. early incontinence after radical prostatectomy: a community based retrospective analysis in 911 men and implications for preoperative counseling. urol oncol. 2013; 31:1006-11. 9. luciani lg, mattevi d, mantovani w, et al. retropubic, laparotable 3. multivariate analysis results of factors associated with worse functional outcome (urinary and sexual function). categories (variables) multivariate analysis (p) (hr; 95% ci) urinary function age (< 65, ≥ 65 years) (0.57) (hr 1.01; 0.75-1.34) body mass index (kg/m2, continuous) (0.07) (hr 1.62; 0.91-1.92) waist (cm, continuous) (0.32) (hr 1.13; 0.55-1.87) body habitus non-obese (0.08) (hr 0.95; 0.63-0.99) non-obese with central adiposity (0.04) (hr 2.03; 1.81-3.14) obese without central adiposity (0.09) (hr 1.19; 0.69-1.90) obese with central adiposity (0.003) (hr 3.67; 2.75-4.51) charlson comorbidity index (0-1, > 2) (0.89) (hr 1.12; 0.70-1.56) american society of anesthesiologists score (≤ 2, ≥ 3) (0.09) (hr 1.33; 0.90-1.60) sexual function age (< 65, ≥ 65 years) (0.63) (hr 1.07; 0.43-1.65) body mass index (kg/m2, continuous) (0.11) (hr 1.82; 0.90-1.96) waist (cm, continuous) (0.28) (hr 0.91; 0.34-1.23) body habitus non-obese (0.12) (hr 0.80; 0.58-1.12) non-obese with central adiposity (0.001) (hr 3.33; 3.04-5.09) obese without central adiposity (0.08) (hr 1.20; 0.71-1.87) obese with central adiposity (0.001) (hr 4.51; 3.09-5.63) charlson comorbidity index (0-1, > 2) (0.77) (hr 1.93; 0.77-1.60) american society of anesthesiologists score (≤ 2, ≥ 3) (0.93) (hr 1.42; 0.84-1.79) the table shows the multivariate analysis results of factors associated with worse functional outcome (urinary and sexual function) in all enrolled patients. hr = hazard risk; ci = confidence interval. archivio italiano di urologia e andrologia 2021; 93, 3 t. cai, a. cocci, f. di maida, et al. 290 scopic, and robot-assisted radical prostatectomy: a comparative analysis of the surgical outcomes in a single regional center. curr urol. 2017; 11:36-41. 10. van velthoven rf, ahlering te, skarecky dw, et al. technique for laparoscopic running urethrovesical anastomosis: the single knot method. urology. 2003; 61: 699-702. 11. ludovico gm, dachille g, pagliarulo g, et al. bilateral nerve sparing robotic-assisted radical prostatectomy is associated with faster continence recovery but not with erectile function recovery compared with retropubic open prostatectomy: the need for accurate selection of patients. oncol rep. 2013; 29:2445-50. 12. d'amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama. 1998; 280:969-74. 13. kassi e, pervanidou p, kaltsas g, et al. metabolic syndrome: definitions and controversies. bmc med. 2011; 9:48. 14. de nunzio c, albisinni s, freedland sj, et al. abdominal obesity as risk factor for prostate cancer diagnosis and high grade disease: a prospective multicenter italian cohort study. urol oncol. 2013; 31:9971002. 15. amato mc, giordano c, galia m, et al. visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. diabetes care. 2010; 33:920-2. 16. wei j, liu x, xue h, et al. comparisons of visceral adiposity index, body shape index, body mass index and waist circumference and their associations with diabetes mellitus in adults. nutrients. 2019; 11:1580. 17. cai t, nesi g, tinacci g, et al. clinical importance of lymph node density in predicting outcome of prostate cancer patients. j surg res. 2011; 167:267-72. 18. cappelleri jc, rosen rc, smith md, et al. diagnostic evaluation of the erectile function domain of the international index of erectile function. urology 2009; 54:346-351. 19. badia x, garcia-losa m, dal-re r. ten-language translation and harmonization of the international prostate symptom score: developing a methodology for multinational clinical trials. eur urol. 1997; 31:129-40. 20. palmieri a, arcaniolo d, palumbo f, et al. sia-low intensity shock wave for erectile dysfunction (led) study group. low intensity shockwave therapy in combination with phosphodiesterase-5 inhibitors is an effective and safe treatment option in patients with vasculogenic ed who are pde5i non-responders: a multicenter single-arm clinical trial. int j impot res. 2020 jul 18. doi: 10.1038/s41443-020-0332-7. epub ahead of print. 21. otunctemur a, ozbek e, cakir ss, et al. association of erectile dysfunction and urolithiasis. arch ital urol androl. 2014; 86:215-6. 22. freedland sj, haffner mc, landis pk, et al. obesity does not adversely affect health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy. urology. 2005; 65:1131-6. 23. uffort ee, jensen jc. impact of obesity on early erectile function recovery after robotic radical prostatectomy. jsls. 2011; 15:32-7. 24. garg t, young aj, kost ka, et al. patient-reported quality of life recovery curves after robotic prostatectomy are similar across body mass index categories. investig clin urol. 2017; 58:331-338. 25. wiltz al, shikanov s, eggener se, et al. robotic radical prostatectomy in overweight and obese patients: oncological and validated-functional outcomes. urology. 2009; 73:316-22. 26. antunes hp, teixo r, carvalho ja,, et al. diabetes mellitus and prostate cancer metabolism: is there a relationship? arch ital urol androl. 2018; 90:184-190. 27. parazzini f, artibani w, carrieri g, et al. effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: results from the 2018 #controllati survey. arch ital urol androl. 2020; 91:245-250. 28. xu t, wang x, xia l, et al. robot-assisted prostatectomy in obese patients: how influential is obesity on operative outcomes? j endourol. 2015; 29:198-208. correspondence tommaso cai, md ktommy@libero.it stefano chiodini, md lorenzo giuseppe luciani, md gianni malossini, md department of urology, santa chiara regional hospital largo medaglie d'oro, 9, trento (italy) andrea cocci, md fabrizio di maida, md department of urology, university of florence, florence (italy) francesco ciarleglio, md department of surgery, santa chiara regional hospital, trento, italy giovanni pedrotti, md department of anesthesiology, santa maria del carmine hospital, rovereto (italy) alessandro palmieri, md department of urology, university federico ii, naples (italy) michele rizzo, md giovanni liguori, md department of urology, university of trieste, trieste (italy) truls e. bjerklund johansen, md department of urology, oslo university hospital, oslo (norway) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3318 original paper no conflict of interest declared. the first option in such patients without pre-stenting (2). in recent years, the advent of medical engineering has increased the suitability of surgical instruments used for the urinary system. in general, retrograde intrarenal surgery (rirs) has been performed successfully and safely in patients with kidney stones (3). in patients undergoing rirs, minor and major complications may occur due to the operator’s surgical experience, the patients’ unique situations and technical equipment. complications can be treated palliatively but in patients with solitary kidneys, they should be considered more serious (4-5), although many studies have suggested that this surgery can be performed safely in solitary kidneys (6-7). we collected data to evaluate surgical outcomes and to identify limits of rirs for safe treatment of these patients. materials and methods this study was approved by the local ethics committee at our university. we retrospectively reviewed 52 patients with solitary kidneys who were treated with rirs for renal stones between january 2016 and december 2019 including patients who were older than 18 years of age and were without any additional chronic diseases. the pre-operative urine cultures of all patients were confirmed to be negative. the stone burden was assessed by obtaining the stone’s length, which was calculated according to the european association of urology guidelines. the rirs procedures were performed by the same surgical team using a 9.5 f access sheath and the same flexible ureteroscope (karl storz™ germany). a double j stent was used in patients who were unable to have an access sheath inserted and the surgery was postponed for 3-4 weeks later. the stones were broken using a holmium yag laser device (sphinx xjr™, germany) with a force of 6-18 kw. the anaesthesia type was evaluated in conjunction with the anaesthesiologist who performed high spinal or general anaesthesia according to the condition of the patient. serum creatinine levels were evaluated preoperatively, at one day postoperatively and at one-week follow-up. any surgical complications in the patients were assessed using a modified satava classification system (scs). the stone sizes, duration of operation, duration of fluoroscopy, type of anaesthesia, and degree of surgical complications were evaluated retrospectively. operations performed in less or more than 60 minutes were compared to set a time limit for risk of complication. objective: the management of urolithiasis in patients with a solitary kidney is challenging for urologists. this study aimed to evaluate the safety of retrograde intrarenal surgery (rirs) in the treatment of stones in patients with solitary kidney and to reply to the question if there is any limit for this surgery. methods: between january 2016 and december 2019, we enrolled 52 patients who had a solitary kidney and underwent rirs. we collected data on preoperative patient characteristics, stone dimensions, and postoperative outcomes. stone size, duration of operation, duration of fluoroscopy, type of anesthesia, and degree of surgical complication were evaluated retrospectively. surgeries performed in less and more than 60 minutes and with and without complications were compared. results: a total of 52 patients with a kidney stone and a solitary kidney were evaluated. the mean stone size was 14 ± 0.4 cm and surgical success rate was 87.3%. in our study, 13 patients (24.5%) had grade 1 minor complications, and none required a blood transfusion. the mean operation time was 51.9 ± 17.3 minutes. the postoperative creatinine value increased in 6 patients. the duration of operation in the group with complications was significantly higher than that in the group without complications. in patients who underwent an operation lasting ≥ 60 minutes, stone size, fluoroscopy time, and complication rate were significantly higher than in patients who underwent an operation lasting ≤ 60 minutes. conclusion: our opinion is to be careful in patients with a solitary kidney with a big stone and we recommend assigning these procedure to experienced hands for not exceeding 60 minutes in one session. key words: renal stone; ureteroscopy; retrograde intrarenal surgery; complication; solitary kidney. submitted 3 june 2021; accepted 27 june 2021 introduction due to recent advances in endourology, increases have been made in the success of surgical treatment of kidney stones as well as of the variety of complications that may develop. minimally invasive surgery for kidney stones is particularly important for patients with renal failure or with solitary kidney. extracorporeal shock wave lithotripsy (eswl) treatment is a minimally invasive option that is frequently applicable due to its safety and success rate (1). however, since complications that may develop after eswl in patients with solitary kidney may be more severe and require urgent intervention, eswl is far from being do we have a limit for retrograde intrarenal surgery for solitary kidney stone? bulent kati, eyyup sabri pelit, mehmet demir, ismail yagmur, adem tuncekin, halil ciftci harran university, faculty of medicine, urology department, sanliurfa, turkey. doi: 10.4081/aiua.2021.3.318 summary 319archivio italiano di urologia e andrologia 2021; 93, 3 rirs for solitary kidney stones statistical analysis mean, standard deviation, median, range, frequency and ratio values were used in the descriptive statistics of the data. the distribution of the variables was measured with the kolmogorov-smirnov test. an independent sample ttest and the mann-whitney u test were used to analyse the quantitative independent data. in the analysis of dependent quantitative data, the wilcoxon test was used. a chi-square test was used to analyse the qualitative independent data. for the data analysis, the statistical package for the social sciences (spss), version 22.0, was used. results fifty-two stone patients with solitary kidney were evaluated before and after surgery (table 1). the solitary kidneys were congenital in 15 cases (28.3%), caused by a previous contralateral nephrectomy in 21 cases (39.6%) and caused by a non-functioning contralateral unit in 16 cases (32.1%). the postoperative follow-up period was approximately 3 months. our surgical success rate was 87.3%. residual stones less than 4 mm were considered clinically insignificant and were evaluated by non-contrast computerized tomography (ct) after postoperative double j stent extraction. double j stents were removed after an average of 25 ± 7.3 days in patients without additional intervention. stone location was the lower pole of the kidney in 22 (42.3%) patients, lower pole and pelvis or middle pole in 16 (30%) patients, renal pelvis in 10 patients and upper pole in 4 patients. mean age, sex and kidney side distribution and mean stone size in patients with and without complications did not differ significantly (p > 0.05) (table 2). the duration of surgical time in the group with complications was significantly higher than in the group without complications (p < 0.05). there was no significant difference in the duration of fluoroscopy time in the group with and without complications. there was no significant difference (p > 0.05) of anaesthesia type in the group with and without complications (table 2). the preoperative creatinine value was not significantly different (p > 0.05) in patients with or without any complications. in the group with complications, the postoperative increase of serum creatinine was higher than the value recorded in the group without complications (p < 0.05) (table 2). mean age and sex, anaesthesia type and kidney side distribution of the patients were not significantly different between the groups in terms of operation time (p < 0.05). in the group with operation time ≥ 60 min groups, stone size (figure 1), duration of fluoroscopy time and any complication rate (figure 2) were significantly higher than in the group with operation time was ≤ 60 min (p < 0.05) (table 3). figure 2. relationship between operation time and complications. figure 1. relationship between stone size and operation time. table 1. general characteristics of patients with solitary kidney stones. min-max median mean + s.d./n-% age 3.0 84.0 45.5 45.3 ± 17.9 gender female 22 42.3% male 30 57.7% side right 25 48.1% left 27 51.9% kidney stone size (cm) 0.8 2.2 1.3 1.4 ± 0.4 operation time (min.) 15.0 90.0 50.0 50.1 ± 17.3 anesthesia type < 60 33 63.5% ≥ 60 19 36.5% floroscopy time (sec.) 5.0 95.0 45.0 42.0 21.8 anesthesia type general 15 28.8% spinal 37 71.2% complication (-) 40 76.9% (+) 12 23.1% minor complication (grade 1) 1.1 21.2% major complication (> grade 1) 2 3.8% pre-op serume creatinine (mg/dl) 0.70 ± 3.00 1.20 1.28 ± 0.55 post-op serume creatinine (mg/dl) 0.40 8.20 1.00 1.47 ± 1.54 creatinine difference (mg/dl) -1..50 6.60 -0.10 0.19 ± 1.55 archivio italiano di urologia e andrologia 2021; 93, 3 b. kati, e. sabri pelit, m. demir, i. yagmur, a. tuncekin, h. ciftci 320 discussion flexibility and thinning of endoscopic instrumentation have increased day by day for making more comfortable diagnosis and treatment of the urinary system. innovations in technology allowed improvement of ureteroscope design, surgical technique, and accessory instrumentation (8). although less invasive procedures have been developed for the treatment of kidney stones, the first procedure to be considered for certain types of stones is extracorporeal shock wave lithotripsy (eswl), whose use is controversial in patients with solitary kidneys. in fact, even if it is not invasive, eswl is characterized by the risk of complications that may affect renal function and may be risky in patients with solitary kidneys due to a lack of functional compensation by the contralateral kidney. ureteral obstruction by residual stone fragments (steinstrasse), urinary tract infection and sepsis, asymptomatic renal hematoma, kidney nephron losses, may vary between 610% in total and may be a more important risk for patients with solitary kidneys (9). while percutaneous nephrolithotomy (pcnl) is the first surgical option that can be considered for kidney stones larger than 2 cm, rirs is more preferred in patients with solitary kidney stones to prevent organ loss and greater risk of complications. in recent studies, complications like those of rirs are described for miniaturized pcnl, which can be used instead of standard pcnl (10). rirs is an increasingly common and widely preferred procedure because of its high success rate for 1-3 cm kidney stones and its low complication rates (11-12). however, some minor complications, such as haematuria, hydronephrosis, ureteral obstruction by stone fragments and ureteral double j stent dislocation, might be not significant in a patient with two functional kidneys but could be more important for patients with solitary kidneys requiring urgent intervention. concern about the risk of renal dysfunction and subcapsular hematoma associated with the use of high-pressure irrigation during rirs has been raised (13). animal studies have shown that high-pressure irrigation (> 150 mmhg) during ureterorenoscopy without a renal access sheath can lead to parenchymal damage and focal injury of the kidney (14). therefore, this risk should be taken into consideration especially in patients with solitary kidney and renal access sheath should be used (15). even if the success rate in the operations does not change, the use of urethral sheath is recommended, if possible, because it keeps the intrarenal pressure low during the procedure and reduces the risk of post-operative infection (16). we used a 9.5 f renal access sheath in all patients without pre-stenting. it has been shown that inserting a dj stent before surgery does not affect complication or success (17, 18). performing rirs should be more careful in patients with a solitary kidney stone. the application of access sheaths and use of laser should not harm the kidney or ureter and at the end of the procedure, it should be checked dj stent correct placement (3, 7). in our study surgery in solitary kidney was performed by experienced surgeons. the mean stone size was 14 ± 0.4 cm, surgical success was 87.3% and 4 patients (7.5%) had residual stones of table 3. comparison of rirs cases above and below 60 minutes of operation time. operation time < 60 min. operation time ≥ 60 min. mean ± s.s./n-% median mean ± s.s./n-% median p age 44.8 ± 17.8 41.0 46.2 ± 18.6 52.0 0.798 t gender female 14 42.4% 8 42.1% 0.982 x² male 19 57.6% 11 57.9% side right 18 54.5% 7 36.8% 0.219 x² left 15 45.5% 12 63.2% stone size (cm) 1.2 ± 0.4 1.0 1.6 ± 0.4 1.8 0.003 m fluoroscopy time (min.) 31.4 ± 15.1 30.0 60.4 ± 19.4 60.0 0.000 t anesthesia type general 7 21.2% 8 42.1% 0.109 x² spinal 26 78.8% 11 57.9% complication (-) 29 87.9% 11 57.9% 0.013 x² (+) 4 12.1% 8 42.1% minor complication 3 9.1% 8 42.1% 0.005 x² major complication 1 3.0% 1 5.3% 0.687 x² serum creatinine (mg/dl) pre-op 1.2 ± 0.5 1.2 1.3 ± 0.6 1.3 0.723 m post-op 1.2 ± 1.0 0.9 1.9 ± 2.1 1.0 0.264 m preop-postop difference 0.0 ± 1.2 0.1 -0.5 ± 2.0 0.0 0.381 m in-group difference (p) 0.201 w 0.950 w t: t test; m: mann-whitney u test; x2: chi-square test; w: wilcoxon test table 2. comparison of patients with complications (minor or major) and without complications after rirs. complication (-) complication (+) mean ± s.s./n-% median mean ± s.s./n-% median p age 45.8 ± 18.9 45.5 43.8 ± 14.7 45.5 0.735 t gender female 16 42.4% 6 50.0% 0.539 x² male 24 57.6% 6 50.0% side right 19 54.5% 6 50.0% 0.879 x² left 21 45.5% 6 50.0% stone size (cm) 1.3 ± 0.4 1.1 1.6 ± 0.4 1.5 0.099 m operation time (min.) süresi dk 46.8 ± 15.1 45.0 61.3 ± 19.4 60.0 0.010 t floroscopy time (min.) 39.3 ± 20.8 40.0 51.1 ± 23.4 52.5 0.100 t anesthesia type general 11 27.5% 4 33.3% 0.696 x² spinal 29 72.5% 8 66.7% serum creatinine (mg/dl) pre-op 1.23 ± 0.44 1.20 1.42 ± 0.83 1.15 0.810 m post-op 1.03 ± 0.43 0.90 2.93 ± 2.72 2.05 0.005 m preop-postop difference -0.20 ± 0.61 -0.10 1.52 ± 2.70 0.40 0.014 m in-group difference (p) 0.052 w 0.109 w t: t test; m: mann-whitney u test; x2: chi-square test; w: wilcoxon test 321archivio italiano di urologia e andrologia 2021; 93, 3 rirs for solitary kidney stones more than 4 mm. after all the procedures, dj stents were applied and checked and left for the second session. classification systems have been proposed over time for grading complications that can develop during and after rirs. we assessed complications using a modification of satava classification system (scs) (19). ural et al. reported nearly 32% grade 1 intraoperative complications after rirs according to modified scs. grade 1 complications included minimal haematuria, ureteral mucosal surface damage, and difficulties in reaching the stone (20). kuroda et al. reported a rate of minor complication about 5% in a study comparing rirs performed in solitary kidneys and normal patients (14). atis et al. reported a rate of minor complications of 16.6% with no major complications and no need of blood transfusions (6). in our study, 11 patients (20.5%) had grade 1 minor complications (most of them mild haematuria that was observed in 8 patients) and no one needed for blood transfusion. dj stent migration is especially troublesome in postoperative follow-up of patients with solitary kidney. although dj stents are known to cause post-operative irritating symptoms, they should be applied after rirs especially in patients with solitary kidneys (21). accordingly, we applied dj stents to all patients at the end of the procedure. grade 3-4 complications after rirs can threaten the health of patients. although they are rare in the literature, deficit of post-operative follow-up and patient unconsciousness can increase the importance of these complications (22, 23). two of our patients developed postoperative high serum creatinine and oliguriaanuria after discharge. the first patient did not receive enough post-operative hydration causing a reduced urine output until oliguria developed. on postoperative day 4th, urine output and serum creatinine levels returned to normal with appropriate hydration. the other patient presented with anuria on the 5th postoperative day. he reported that his urine output had decreased and ceased for the last two days. despite appropriate hydration, urine output did not increase, and serum creatinine values increased to around 8.9 mg/dl. the patient was urgently operated: after dj stent removal, ureteroscopy demonstrated a dust of fragments adherent along the ureter, ureter was cleaned, and a new 6 f dj stent was placed. although postoperative urine output increased, serum creatine values did not fall below 4.3 mg/dl. after the consultation of the nephrology department, it was decided to enter in a dialysis program with the diagnosis of chronic renal failure. although major complications after rirs are not common in the literature, poor socioeconomic conditions can affect the post-operative recovery of the patients (3-7). it has been reported that patients with solitary kidney have very low complication rates compared to percutaneous nephrolithotomy (pcnl) (11, 22). rirs has been considered a better alternative to pcnl surgery because of similar surgical success, but less blood loss and hospital stay (24). when we evaluated our patients, we observed that minor and major surgical complications increased significantly after surgery of stone greater than 20 mm and when surgery time was more than 60 minutes. (table 3) although rirs appears to be safe and successful in patients with solitary kidneys, the prolongation of surgery may lead to an increase of postoperative complications. we set the 60-minute limit although this limit can be influenced by the characteristics of the patient, of the stone and of the surgical procedure. patients with solitary kidneys should be well informed and followed up before and after surgery. when evaluating a patient, attention should be paid to the size of the stone and therefore to the risk of increased surgical time. for cases that are thought to exceed one hour, we recommend leaving a dj stent for a second session. references 1. el-assmy a, el-nahas ar, hekal ia, et al. long-term effects of extracorporeal shock wave lithotripsy on renal function: our experience with 156 patients with solitary kidney. j urol. 2008; 179:2229-32. 2. ruiz marcellan fj , ibarz servio l, et al. treatment of lithiasis in the patient with a solitary kidney eur urol. 1988; 15:13-7. 3. bas o, tuygun c, dede o, et al. factors affecting complication rates of retrograde flexible ureterorenoscopy: analysis of 1571 procedures-a single-center experience. world j urol. 2017; 35:819-826. 4. gao x, peng y, shi x, et al. safety and efficacy of retrograde intrarenal surgery for renal stones in patients with a solitary kidney: a single-center experience. j endourol. 2014; 28:1290-4. 5. breda a, oreoluwa o, john t, et al. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones eur urol. 2009; 55:1190-6. 6. atis g, gurbuz c, arikan o, kilic m, et al. retrograde intrarenal surgery for the treatment of renal stones in patients with a solitary kidney. urology. 2013; 82:290-4. 7. giusti g, proietti s, cindolo l, et al. is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? world j urol. 2015; 33:309-14. 8. holden t, pedro rn, hendlin k, et al. evidence-based instrumentation for flexible ureteroscopy: a review j endourol. 2008; 22:1423-6. 9. wagenius m, jakobsson j, stranne j, linder a. complications in extracorporeal shockwave lithotripsy: a cohort study. scand j urol. 2017; 51:407-413. 10. di mauro d, la rosa vl, cimino s, et al. clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study. arch ital urol androl. 2020; 91:256-260. 11. zhang y, wu y, li j, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery for the treatment of lower calyceal calculi of 2-3 cm in patients with solitary kidney. urology. 2018; 115:65-70. 12. aboumarzouk om, monga m, kata sg, et al. flexible ureteroscopy and laser lithotripsy for stones > 2 cm: a systematic review and meta-analysis j endourol. 2012; 26:1257-63. 13. de rose af, di grazia e, magnano san lio v, et al. complications of endourological procedures and their treatment. arch ital urol androl. 2020; 92:321-325. 14. schwalb dm, eshghi m, davidian m, et al. morphological and physiological changes in the urinary tract associated with ureteral dilation and ureteropyeloscopy: an experimental study. j urol. 1993; 149:1576-85. archivio italiano di urologia e andrologia 2021; 93, 3 b. kati, e. sabri pelit, m. demir, i. yagmur, a. tuncekin, h. ciftci 322 15. breda a, territo a, lópez-martínez jm. benefits and risks of ureteral access sheaths for retrograde renal access curr opin urol. 2016; 26:70-5. 16. kuroda s, fujikawa a, tabei t, et al. retrograde intrarenal surgery for urinary stone disease in patients with solitary kidney: a retrospective analysis of the efficacy and safety. int j urol. 2016; 23:69-73. 17. shvero a, herzberg h, zilberman d, et al. is it safe to use a ureteral access sheath in an unstented ureter? bmc urol. 2019;19:80. 18. karaaslan m, tonyali s, yilmaz m, et al. ureteral access sheath use in retrograde intrarenal surgery. arch ital urol androl. 2019; 91:112-114. 19. tepeler a, resorlu b, sahin t, et al. categorization of intraoperative ureteroscopy complications using modified satava classification system world j urol. 2014; 32:131-6. 20. oguz u, resorlu b, ozyuvali e, et al. categorizing intraoperative complications of retrograde intrarenal surgery. urol int. 2014; 92:164-8. 21. somani bk, giusti g, sun y, et al. complications associated with ureterorenoscopy (urs) related to treatment of urolithiasis: the clinical research office of endourological society urs global study world j urol. 2017; 35:675-681. 22. cindolo l, castellan p, primiceri g, et al. life-threatening complications after ureteroscopy for urinary stones: survey and systematic literature review minerva urol nefrol. 2017; 69:421-431. 23. adanur s, aydin hr, mohamed o, et al. retrograde intrarenal surgey versus percutaneous nephrolithotomy in patients with significant comorbidities and solitary kidney urolithiasis. 2015; 43:385-386. 24. lianchao j, bing y, zhe z, ningchen li. comparative efficacy on flexible ureteroscopy lithotripsy and miniaturized percutaneous nephrolithotomy for the treatment of medium-sized lower-pole renal calculi j endourol. 2019; 33:914-919. correspondence bulent kati, md, associate prof. (corresponding author) bulentkati@harran.edu.tr eyyup sabri pelit, md dreyyupsabri@hotmail.com mehmet demir, md drdemir02@gmail.com ismail yagmur, md dr_iyagmur@hotmail.com adem tuncekin, md dr_adem65@hotmail.com halil ciftci, md halilciftci63@hotmail.com harran university, faculty of medicine hospital, urology, 63340 sanliurfa (turkey) osmanbey kampusu urology bolumu 63320 sanliurfa (turkey) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3334 original paper no conflict of interest declared. introduction penile curvature (pc) is an increasingly common disorder consisting of an alteration in the shape of the erect penis which instead of being straight appears curved on one or more planes. it can be congenital or acquired. the curvature can be ventral, dorsal, lateral or mixed and it can be associated with urethral malformations. congenital curvature can be caused by disproportionate development of the tunica albuginea of the corporal bodies (1). penises with congenital curvature are usually good-sized and the young patient notices the anomaly after the onset of puberty. the curvature is often ventral, that is the one causing the greatest problems in coital dynamics. acquired penile curvature can be caused by penile fractures or traumas or mostly by peyronie’s disease also called induratio penis plastica (ipp). in both congenital and acquired curvatures the surgical indication arises when the curvature of the penis does not allow normal sexual intercourse. symptoms are an initial difficulty in penetration with pain for the patient and/or for the partner that can evolve towards the impossibility of penetration when the curvature is severe. several alternatives and improvements have been proposed since the first corporoplasty technique was described by nesbit in 1965 (2), although most techniques require circumcision and total penile degloving. this aggressive approach leads to various problems such as altered sensitivity, unsightly scars and high recurrence rates. in order to balance results in term of erectile and aesthetic function, especially in the patient with peyronie’s disease, it is crucial to seek minimally invasive surgical techniques. we describe a new original plication technique where surgical access is at the base of the penis and the albuginea incision is not performed making the surgery safe, easier and minimally invasive. materials and methods between 2012 and 2018 we treated 134 patients suffering from congenital curvature (33) or curvature acquired from peyronie's disease (101) (figure 1). objective: we describe an original minimally invasive penile plication technique with scrotal or infrapubic access, not requiring circumcision, for penile curvature of different severity and types. this technique can be used to correct both congenital and acquired curvatures, mono or bidirectional deformities. materials and methods: between 2012 and 2018 we treated 134 patients suffering from congenital curvature (33) and acquired curvature from peyronie's disease (101). the average curvature was 62.2° (± 30.4°). preoperative evaluation included prostaglandin e1 injection with photographic documentation and measurement of penile angulation, administration of iief15, vasoactive penile doppler ultrasound, analysis of thermal and vibratory sensitivity with genito-sensory-analyzer (gsa) and assessment of nocturnal penile stiffness with rigiscan, performed twice, for a detailed evaluation of patient’s erectile function. scrotal access was performed in patients with dorsal and/or lateral penile curvature; the infrapubic access was performed in patients with ventral curvature. after preparation and incision of colles’ fascia, penis was partially degloved and an original plication technique called "binary corporoplasty" was performed at the site or sites established at preoperative assessment, with non-resorbable synthetic multifilament (premicron®) suture. results: complete correction of penile curvature was achieved in 96.8 % of patients. no major complications were reported, and no patients suffered worsening in erectile function or in penile sensitivity. the average shortening of convex side was 1.65 cm (± 0.7 cm) and all patients report easy intercourse after correction. the average time of surgery was 46 minutes (± 11 min) and all procedures were performed as a day-hospital or ambulatory settings, with local anesthesia and light sedation. overall satisfaction rate is 96%. conclusions: this is a simple and rapid technique that perfectly corrects even the most severe and complex penile curvatures. in comparison to traditional techniques, such as nesbit procedure, this technique is associated with low morbidity, a very low recurrence rate and a great aesthetic results. aesthetic and functional patients’ satisfaction was excellent. key words: corporoplasty; induratio penis plastica; recurvatum; peyronie’s disease; penile disease. submitted 9 september 2022; accepted 12 september 2022 an original mininvasive corporoplasty technique for penile curvature without circumcision antonio rossi 1, giovanni alei 2, pietro viscuso 3, antonio tufano 3, marco frisenda 3, guglielmo mantica 4, pierluigi bove 5, rosario leonardi 6, mauro de dominicis 1, alessandro calarco 1 1 department of urology, “cristo re” hospital, rome, italy; 2 department of plastic and reconstructive surgery, "sapienza" rome university, policlinico umberto i hospital, rome, italy; 3 department of maternal-infant and urological sciences, "sapienza" rome university, policlinico umberto i hospital, rome, italy; 4 policlinico san martino, genova, italy; 5 san carlo di nancy hospital, roma, italy; 6 casa di cura musumeci-gecas, gravina di catania (ct), italy. doi: 10.4081/aiua.2022.3.334 summary 335archivio italiano di urologia e andrologia 2022; 94, 3 original corporoplasty technique before the procedure patients were carefully evaluated to assess type and severity of curvature and any associated malformations. in particular, initial length of the penis and erectile function were assessed. careful evaluation of all these variables together with the patient is mandatory because this is a functional-aesthetic surgical procedure. accurate measurements were made to plan the site and the number of corporoplasties by simulating the straightening of the penis. photographs and measures were taken to document the potential result. in fact, the patient must be aware of the change in length of his penis which consists of an adaptation of the length of the convex side to that of the other side (figure 2). accurate preoperative measurements of the site and length of corporoplasties is crucial because the procedure is performed during flaccidity and hydraulic erection is only used intraoperatively to confirm the correction. in fact, different from the nesbit’s procedure, sites of surgical corrections cannot be evaluated intraoperatively because circumcision is not performed. after pge1 injection, the penis is straightened using a finger as a lever and placing the other hand in opposition at the point of greater curvature until the ideal point of correction of the curvature is identified. according to the radius of the curvature the site and number of corrections is planned. the distance between this identified point of correction and the external urethral meatus is then measured. photographs are taken to guide the surgeon during the operation and to show the patient the postoperative result in terms of shape and size of the penis. the photographs are shown to the patient, so that he could appreciates the change that will occur in his penis. postoperative photographs are compared to the preoperative photographs. this has great significance from the medico-legal point of view. technique our technique does not involve circumcision or subcoronal incision. the technique consists of a dorsal access at the base of the penis in case of ventral bending (figure 3) or a scrotal access for dorsal and/or lateral bending (figure 4), with no consequences on penile sheaths or alterations in sensitivity. the procedure can be performed under either local anesthesia with a light sedation. to correct a dorsal and/or lateral curvature we perform a small median longitudinal incision on the scrotal raphe whereas for the ventral curvatures we perform a small infrapubic incision. both incisions are about 3 cm in length. we access the colles space with bevel scissors creating a space to make degloving easier. the pre-established sites are identified by means of a sterile ruler starting from the meatus while the assistant completely stretches the penis from the glans. with an allis clamp, the selected site in the colles space is pressed and a selective degloving is performed at this level to expose the albuginea in order to make the “track” corporoplasty (figure 5). figure 1. some of the clinical cases treated. congenital and acquired curvature. figure 2. preoperative identification of the correction point/s. figure 3. dorsal incision at the base of the penis. figure 5. selective degloving through scrotal access and identification with allis clamp of the selected site. figure 4. median scrotal incision, preparation of the colles space and penile degloving. figure 6. schematic drawing of the “binary corporoplasty”. protecting the urethra with babcock's forceps, the first corporoplasty is performed medially and the other two laterally to distribute the forces. archivio italiano di urologia e andrologia 2022; 94, 3 a. rossi, g. alei, p. viscuso, et al. 336 when correcting dorsal curvatures, the site of corporoplasty should be placed as close as possible to the groove of corpus spongioum, whereas for ventral curvature it must be close to the dorsal neurovascular bundle. this maneuver is performed in order to to obtain the maximum correction of the penile curvature with the minimal shortening of the penis. a single 0 non-absorbable synthetic multifilament suture is placed in order to perform a special plication on two parallel lines that is therefore called “track” (figure 6). laterally to the corporoplasty described, two corporoplasties should be performed along the line that goes from the dorsal neurovascular bundle, or the spongiocavernosus groove, to the lateral end of the corpus cavernosus at 30° and 60° on the penile sagittal plane. the two corporoplasties should measure 50% at 30° and 25% at 60°. the suture at 30° is usually performed on a single line going in and out from the tunica albuginea and tying the knot. the corporoplasty at 60° is performed with a single suture. this asymmetry allows a uniform distribution of forces from a mechanical point of view reducing the risk of recurrence with a better aesthetic and palpatory result. when the curvature is only dorsal or ventral same operative steps are performed on the contralateral corpus cavernosus. when the curvature is lateral, the described corporoplasty is performed on a single cavernous body. when the curvature is mixed, however, the corporoplastics on the two cavernous bodies will be asymmetrical. after having carried out the corporoplasties at the planned sites, hydraulic erection is obtained to check the achieved correction of the curvature (figure 7). a photographic documentation of the straightening on different floors is obtained. an important advantage of this technique without incision of the albuginea, is that if during the hydraulic erection we have not obtained the perfect correction, or we have corrected excessively, we can remove the stitches or modify the existing ones. colles’s fascia is rebuilt to ensure that the knots are less palpable and to ensure the correct smoothness of the subcutaneous planes of the penis. the small cutaneous breach is sutured. we used donati’s silk 0 stitches especially on the scrotum, to be removed on the 6th post-operative day (figures 8, 9). the final dressing is carried out with an elastic bandage of the penis which is maintained for 30 days. the function of this bandage is initially to avoid swelling and oedema in the immediate post-operative and to limit spontaneous and nocturnal erections. this expedient reduces the tensions on the corporoplasties and guarantees an important reduction of the relapse rate. it is not necessary to use urethral catheters or drains. the patient is asked to avoid sexual activity for 30 days. results the average age of the patients was 49.3 years, the average length of the penis in erection before surgery was 13.5 cm (± 3.3 cm). the average curvature was 62.2° (± 30.4°). the most common curvature was dorsal (50), then dorsolateral (40), ventral (30) and ventro-lateral (14). the average duration of surgery was 46 minutes (± 11 min). there were no major complications during the interventions. among the minor complications we report ecchymosis (9%) palpable nodules (18%) and mild hyposensitivity (3%). after an average 48 months follow-up complete correction of penile curvature was achieved in 96.8% of patients (figures 10, 11). the subjective patient report of satisfaction of the results of surgery was 92%. the relapse rate, defined as postoperative curvature of at least 15°, was 3.2%. only two patients (1.5%) were dissatisfied with the final length of the penis, although it was consistent with the measurements taken and photographed before the operation, confirming the importance to establish which are the patient's expectafigure 7. intraoperative hydraulic erection to evaluate the correction made. figure 10. lateral bending, pre and postoperative after 30 days. figure 11. dorsal bending, pre and postoperative after 30 days.figure 9. aesthetic outcome of dorsal access after 10 days. figure 8. aesthetic outcome of scrotal access after 10 days. 337archivio italiano di urologia e andrologia 2022; 94, 3 original corporoplasty technique tions before the surgery. all patients were satisfied with the aesthetic outcome related to surgical access. the mean score of iief-15 before surgery was 17.2 and after surgery 18.6. discussion curvature of the penis is an abnormal bend in the penis that occurs during erection. it can be congenital or acquired. congenital penile curvature can be caused by disproportionate development of the tunica albuginea of the corporal bodies. in the majority of cases the curvature is ventral but it can also be lateral but rarely dorsal. acquired curvature is usually secondary to la peyronie’s disease. it presents with an initial acute inflammatory phase, which may be associated with pain at rest or during erection. the following stabilization phase is characterized by the formation of hard palpable plaques, that can be fibrotic or calcified, and by the presence of penile curvature (3). the treatment of the acute phase consists of oral drugs and topical treatments such as ionophoresis (4, 5). the surgical approach is restricted to the phase of stabilization. in this phase the patient can present penile curvature, erectile dysfunction, and penile shortening. these problems can occur singularly or in combination. surgery is indicated only in patients with stable disease for at least 3 or 6 months, without variations in penile curvature (6). attesting the stabilization of the disease is very important in order to avoid relapses due to a still active disease rather than to errors or described complications of the technique used. anyway surgery is indicated in patients with penile curvature that does not allow satisfactory intercourse and which is associated with sexual bother. surgery of congenital curvature is deferred until after puberty and can be performed at any time in adult life. however, it is important to solve the problem as soon as possible because the sexual discomfort related to the penile malformation could lead to a loss of self-esteem and avoidance of sexual activity. nesbit corporoplasty or plication techniques are currently recommended in order to adapt the long convex side to the shorter contralateral side allowing the patient to easily penetrate and reduce the psychological impact caused by the malformation. in the acquired curvature the surgical strategies are varied in relation to the extent of the curvature, the patient's erectile function and the size of the penis. possible surgical techniques are: straightening corporoplasties, in case of sufficiently long penis; plaque surgery, which lengthens the penis but can cause erectile dysfunction and with a high risk of recurrence; straightening corporoplasty in association with penile lengthening, in order to compensate the shortening due to the corporoplasty; penile prosthesis implantation, even in association with fracture of the plaque or plaque surgery in order to lengthen the penis. corporoplasties can either shorten the longer convex side of the penis (nesbit’s procedure and its modifications) or lengthen the shorter concave side (plaque surgery) (7). several surgical techniques for the correction of penile curvature have been described over the last few years. the first operation to correct penile curvature was described by nesbit in 1965 (2), consisting of the removal of tunical ellipses on the convex aspect of the penis at the site of major bending of the corpora cavernosa so as to shorten the convexity and correct the curvature this technique involves circumcision and complete degloving of the penis. the number of ellipses to remove, their size and positions are decided intraoperatively, under hydraulically induced erection, by clamping the tunica albuginea with an allis clamp in order to simulate the effect of the correction the nesbit procedure is affected by a 25-30% recurrence rate due to a loss of tension of the suture and causes a considerable penile shortening, especially in patients with dorsal or ventral bending. other reported complications are circumcision outcomes, postoperative haematoma, skin adhesions, unsightly suture tracks and loss of sensation in the glans due to neurovascular impairment (8). on the other hand, the nesbit technique is extremely simple and easy to perform, as such it is still commonly performed. various modifications to nesbit procedure were proposed along time, all requiring circumcision to expose the corpora. the occurrence of complications, such as recurrence of curvature (15-33%), erectile dysfunction (20-32%), altered local sensation (4-10%), palpable and painful nodules (16-66%), and poor outcomes of circumcision, lead to the development of alternative techniques (9-16). plication procedures are based on the same principle as the nesbit operation but are simpler to perform. the use of non-absorbable sutures reduced recurrence of the curvature. results and satisfaction rates are similar to the nesbit procedure. in the early 90’s, we described a new technique with a different surgical access (at the base of penis rather than distally) and a different type of corporoplasty (doublebreasted corporoplasty) (17). these minimally invasive surgical accesses allow the rapid resumption of sexual activity, have excellent aesthetic results, and allow to avoid circumcision and total penis degloving. they are minimally invasive because of small incisions but also they minimally affect erectile function of patients. in our opinion, when allowed by penis length and functionality conditions, it is important to avoid aggressive procedures such as the nesbit technique or plaque surgery. in fact, the straightening corporoplasty does not aim to improve erection, however reducing the section of the corpora cavernosa it slightly increases the pressure inside them. this always causes an improvement in erection which is very useful in peyronie’s patients who may suffer from a degree of erectile dysfunction. the data on erectile function is very important, the other techniques described can negatively affect the patient's sexual function, although they guarantee an excellent percentage of penile straightening. the patient will never be satisfied if he has a longer penis but a worse functionality than before surgery. conclusions in patients with congenital curvature and in those with acquired curvature and with good size and functionality it is important to perform a minimally invasive surgery. furthermore, in light of the controversial results of medical procedures, it is correct to propose a resolutive approach to archivio italiano di urologia e andrologia 2022; 94, 3 a. rossi, g. alei, p. viscuso, et al. 338 the patients. the present technique is easy to perform and overcomes the limitations of other techniques by reducing penile shortening, sensory and aesthetic alterations. the rate of straightening is excellent as well as the patient's final satisfaction rate which is 92%. this data results from the minimally invasive technique and above all on the absence of worsening of erectile function. the possibility of performing the operation in one-day surgery and under local anaesthesia reassures the patients. references 1. makovey i1, higuchi tt, montague dk, et al. congenital penile curvature: update and management. curr urol rep. 2012; 13:290-7. 2. nesbit rm. congenital curvature of the phallus: report of three cases with description of corrective operation. j urol. 1965; 93: 230-2. 3. levine l, rybak j, corder c, farrel mr. peyronie's disease plaque calcification prevalence, time to identification, and development of a new grading classification. j sex med. 2013; 10:3121-8. 4. riedl cr, plas e, engelhardt p, et al. iontophoresis for treatment of peyronie's disease. j urol. 2000; 163:95-9. 5. bolgeo t, di matteo r, gardalini m, et al. quality of life of patients with la peyronie's disease undergoing local iontophoresis therapy: a longitudinal observational study. arch ital urol androl. 2022; 94:75-79. 6. carson cc1, levine la. outcomes of surgical treatment of peyronie's disease. bju int. 2014; 113:704-13. 7. hatzimouratidis k, eardley i, giuliano f, et al. eau guidelines on penile curvature. eur urol. 2012; 62:543-52. 8. rajmil o, arrús j, fernandez m, et al. sensory changes after surgical correction of penile curvature. int j impot res. 2009; 21:366-71. 9. devine cj jr, horton ce. surgical treatment of peyronie’s disease with a dermal graft. j urol. 1974; 111:44-9. 10. ebbehoj j, metz p. new operation for ‘krummerik’(penile curvature). urology. 1985; 26:76-8. 11. kelâmi a. congenital penile deviation and its treatment with the nesbit-kelâmi technique. br j urol. 1987; 60:261-3. 12. udall da. correction of 3 types of congenital curvatures of the penis, including the first reported case of dorsal curvature. j urol. 1980; 124:50-2. 13. montague dk. correction of chordee. the nesbit procedure. urol clin north am. 1986; 13:167-74. 14. yachia d. modified corporoplasty for the treatment of penile curvature. urol 1990; 143:80-2. 15. garaffa g, sacca a, christopher an, ralph dj. circumcision is not mandatory in penile surgery. bju int. 2010; 105:222-4. 16. de rose af, ambrosini f, mantica g, et al. prepuce-sparing corporoplasty as a safe alternative for patients with acquired penile curvature. arch ital urol androl. 2020; 92:182-185. 17. alei g, letizia p, alei l, et al. new surgical technique for ventral penile curvature without circumcision. bju int. 2014; 113:968-974. correspondence antonio rossi, md antonio.rossicz@gmail.com mauro de dominicis, md dedominicism@alice.it alessandro calarco, md (corresponding author) alecalarco@gmail.com department of urology, “cristo re” hospital, via delle calasanziane 25, 00167 rome (italy) giovanni alei, md giovanni.alei@gmail.com department of general surgery and plastic aesthetic surgery, sapienza university of rome, viale del policlinico 155, 00161 rome (italy) pietro viscuso, md pietro.viscuso@uniroma1.it antonio tufano, md antonio.tufano@uniroma1.it marco frisenda, md marco.frisenda57hu@gmail.com maternal and infantile and urologynaecological sciences department sapienza university of rome, viale del policlinico 155, 00161 rome (italy) guglielmo mantica, md gugliemo.mantica@gmail.com policlinico san martino, largo rosanna benzi, 10, 16132, genova (italy) pierluigi bove, md pierluigi.bove@uniroma2.it san carlo di nancy hospital via aurelia, 275,00165, rome (rm) (italy) rosario leonardi, md leonardi.r@tiscali.it casa di cura musumeci gecas, via dell'autonomia 57, gravina di catania (ct) (italy) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4424 original paper no conflict of interest declared. introduction bladder cancer (bc) represents the seventh most diagnosed cancer in men worldwide, and the tenth one considering both genders. moreover, europe is considered one of the countries with the highest incidence with an age-standardized rate of 20 per 100,000 person/years for men (compared to 9.5 worldwide) and 4.6 for women (compared to 2.4 worldwide) (1). furthermore, it is one of the malignancies with a high economic burden due to its treatments and follow-up (2). hence, a correct diagnosis and staging are of utmost importance for correct treatment. transurethral resection of the bladder (turb) is considered the gold standard to ascertain bc diagnosis, and plan further treatments and can be a curative procedure for early-stage disease (pta/t1 tumours) (3-5). nonetheless, guidelines also recommend performing a second turb in specific clinical scenarios, mainly: after an incomplete first turb, when there are doubts about the completeness of the first resection, in case of the absence of detrusor muscle in the specimen (except for ta lg/g1 tumours and primary cis) and when there is the presence of t1 tumours (6, 7). second turb (returb) has the intent to eradicate all the tumour burden since there is a consistent risk of leaving residual tumours and consequently of recurrence (1, 8, 9). to improve the correct tumour identification and improve staging and treatment, hexaminolevulinate photodynamic diagnostics (pdd)-guided turb has been proposed and demonstrated to be more sensitive than conventional procedures (10-13). for these reasons, european guidelines propose to use methods to improve tumor visualization including pdd (1). the aim of our study was to evaluate the advantage of using pdd at first turb on the rate of residual and evaluate if using this technology, we could safely omit a returb, without compromising oncological outcomes. objective: bladder cancer (bc) is considered one of the malignancies with moderate-high incidence, high rate of recurrence and costly management. diagnosis and staging are thus important for therapeutic purposes. considering the risk of residual tumour and understaging, in specific cases, international guidelines recommend performing a second transurethral resection of the bladder (returb). our study aimed to evaluate the impact of hexaminolevulinate photodynamic diagnostics (pdd) at first turb on the rate of residual tumour. materials and methods: we retrospectively analysed patients undergoing turb in our centre between 2012 and 2020. eightytwo patients had a re-turb after a first complete turb with a delay < 3 months. patients who had an incomplete first resection were excluded. we compared patients who underwent standard white light cystoscopy/turb and then hexaminolevulinate pddguided returb (group a, n = 49) and patients with pdd-cystoscopy/turb at the first procedure then white light cystoscopy/returb (group b, n = 33). the residual tumour rate at returb as well as median recurrence-free survival (rfs) were compared between the two groups. results: residual tumour at returb was detected in 48.8% of cases in our cohort, with a significant difference between the two groups (71.4% in group a versus 12.5% in group b, p < 0.001). after a median follow-up of 22 months, the median rfs was 15 months in group a and 32 months in group b, but this difference was not significant (p = 0.7). conclusions: using pdd at the time of the initial turb had a statistically significant impact on the rate of residual tumour at the returb. nevertheless, the percentage of residual tumour even with the use of pdd does not allow for safely omitting second resection. performing a returb with pdd for patients who did not have it initially, provides the same benefit in terms of recurrence-free survival. key words: bladder cancer; hexvix; turb; second resection; residual tumor. submitted 9 october 2022; accepted 19 november 2022 could we safely omit a repeat transurethral resection of the bladder (re-turb) after hexaminolevulinate photodynamic diagnostics (pdd)-turb? vito lorusso 1, 2, 3, laure doisy 1, antonio maria granata 2, andrea gregori 2, celeste manfredi 4, lorenzo spirito 4, carmine sciorio 5, luca giuseppe maria ciancimino 5, samuele molteni 5, michele morelli 6, luigi cirillo 7, luigi napolitano 7, jochen walz 1, geraldine pignot 1 1 department of urology, institut paoli-calmettes cancer center, marseille, france; 2 department of urology, asst fatebenefratelli-sacco hospital, milan, italy; 3 university of milan, milan, italy; 4 urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy; 5 department of urology, asst lecco, ospedale alessandro manzoni, lecco, italy; 6 department of urology, foundation irccs ca' granda ospedale maggiore policlinico, milan, italy; 7 department of neurosciences, science of reproduction and odontostomatology, university of naples federico ii, naples, italy. doi: 10.4081/aiua.2022.4.424 summary 425archivio italiano di urologia e andrologia 2022; 94, 4 re-turb after pdd-turb materials and methods we retrospectively analysed patients undergoing turb in our centre between 2012 and 2020. eighty-two patients had a returb after a first complete turb with a delay < 3 months. patients who had an incomplete first resection were excluded. we compared patients who underwent standard white light cystoscopy/turb and then hexaminolévulinate pdd-guided returb (group a, n = 49) and patients with pdd-cystoscopy/turb at the first procedure then white light cystoscopy/returb (group b, n = 33). the residual tumour rate at returb as well as median recurrence-free survival were compared. comparisons of the proportions were done by the 𝛘² test. kaplan-meier curves were used to analyze time to recurrence and to compare the two groups. the statistical analysis was done with spss version 25 (spss inc., chicago, il, usa). results no statistically significant differences were observed between the two groups in terms of age, sex, history of bladder cancer, stage, grade, presence of cis, presence of muscle and multifocality (table 1). residual tumour at returb was detected in 48.8% of cases in our cohort, with a significant difference between the two groups (71.4% in group a versus 12.5% in group b, p < 0.001). after a median follow-up of 22 months, the median recurrence-free survival (rfs) was 15 months in group a and 32 months in group b (figure 1), but this difference was not significant (p = 0.7). discussion in this retrospective study, we compared patients who underwent standard white light cystoscopy/turb then pdd-guided returb and patients with pdd-cystoscopy/turb at the first procedure then white light cystoscopy/returb. after the first resection, there was a risk of disease recurrence due to a regrowth of undetected lesions. we found that pdd cystoscopy at the time of the initial turb had a statistically significant impact on the rate of residual tumor at the returb. in fact, we found that residual tumor rates at returb were 71.4% and 12.5% in group a and b respectively. our result corroborated data from previously published studies. since its first use in 1994, the benefits of fluorescent light cystoscopy with hexaminolevulinate (hal) in non-muscleinvasive bladder cancer (nmibc) have been reported in many trials. nowadays pdd is widely used for the diagnosis and treatment of superficial bladder cancer. in nmibc the possible benefits of using pddguided turb were higher detection rates, a higher rate of complete resection, and fewer residual tumors (14). several studies reported an increased tumor detection rate by hal-pdd with a most pronounced benefit for cis lesions (15). riedel et al. found lower residual tumor rates for ta and t1 tumors using pdd, while filbeck et al. found a statistically significant reduction of residual tumors only in ta tumors (16, 17). albarghouth et al. showed that the use of pdd significantly reduces the risk of residual tumors compared with conventional turb. in the same study, they have also shown that pdd can significantly improve 3 and 12-month recurrence-free survival especially in low and intermediate-risk tumors, and 1-year progression-free survival in high-risk tumors (18). burger et al. conducttable 1. baseline characteristic and postoperative variable statistics of patient (n = 82). blue light cystoscopy at first turb p value no-group a (n = 49) yes-group b (n = 33) n % n % age (years), median (sd) 69 (9) 71 (9) 0.7 a sex f 8 47 9 52 0.23 b m 41 63 24 36 stage ta 11 73 4 26 0.23 b t1 38 56 29 43 presence of cis yes 32 64 18 36 0.32 b no 17 53 15 46 presence of muscle yes 9 69 4 30 0.44 b no 40 58 29 42 multifocality yes 29 60 19 39 0.8 b no 20 58 14 41 r+ yes 14 33 28 66.7 < 0.001 b no 35 87 5 12.5 recidive yes 36 61 23 39 0.7 b no 13 56 10 43 rfs 15 32 0.7 c f: female; m: male; cis: carcinoma in situ; r+: residual tumor; rfs: recurrence free survival; a student t test; b chi test; c log-rank test. figure 1. kaplan-meier curves for recurrence-free survival time. archivio italiano di urologia e andrologia 2022; 94, 4 v. lorusso, l. doisy, a.m. granata, et al. 426 ed a meta-analysis confirming that hal-pdd cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 month (19). mariappan et al. found that hal-pdd-assisted turb was associated with a significantly lower risk of early recurrence compared to white light turb. moreover, recurrence rate at the first follow-up cystoscopy in the study cohort was 13.6% and 30.9% in the two settings respectively (20). gakis et al. systematically reviewed literature reporting a significantly lower rate of progression in patients treated with pdd compared to white light turb (21). in a recent meta-analysis sun et al. reported that cystoscopy with aminolevulinic acid (ala) or hal was associated to a reduced residual tumor rate compared with standard cystoscopy in nmibc and rfs was higher in the first case at the 12to 24-month follow-up (22). even if we confirmed that the use of pdd allows reducing residual tumour rate, we did not find a statistically significant difference in terms of rfs. this can be explained by the design of our study which establishes the use of pdd in both groups but at different times. probably the difference in terms of rfs favouring the group who perform pdd initially, which is also marked at the beginning of follow-up, tends to be mitigated later by the delayed use of pdd in the other group as shown by the kaplan-meier curves. we also conceived this study to question if the use of pdd at the initial turb would allow for the omission of a reresection that, meaning a second surgical procedure, can have an impact not only for the patient (psychological, surgical or medical-related complications) but also for the healthcare systems in terms of costs. however, despite the advantages of the pdd technique, considering the biological characteristic of bladder cancer and the percentage of the residual tumour even after pdd cystoscopy we do not consider it safe to spare a second resection. our study is not devoid of limitations: mainly its retrospective nature and the small sample size. concluding, returb even with the aid of pdd technology seems to be necessary. even if all studies showed a reduced risk of residual tumour, none of them suggested to avoid a returb. conclusions the quality of the initial turb, when performed by using pdd, had a statistically significant impact on the rate of residual tumour at the returb. nevertheless, the percentage of residual tumour even after pdd cystoscopy is not negligible and cannot allow to safely avoid a second resection. performing a returb with pdd for patients who did not have it initially, provides the same benefit in terms of recurrence free survival. references 1. babjuk m, burger m, capoun o, et al. european association of urology guidelines on non-muscle-invasive bladder cancer (ta, t1, and carcinoma in situ). eur urol. 2022; 81:75-94. 2. sievert kd, amend b, nagele u, et al. economic aspects of bladder cancer: what are the benefits and costs? world j urol. 2009; 27:295-300. 3. napolitano l, barone b, reccia p, et al. preoperative monocyte-tolymphocyte ratio as a potential predictor of bladder cancer. j basic clin physiol pharmacol. 2022; 33:751-757. 4. creta m, celentano g, napolitano l, et al. inhibition of androgen signalling improves the outcomes of therapies for bladder cancer: results from a systematic review of preclinical and clinical evidence and meta-analysis of clinical studies. diagn basel switz. 2021; 11:351. 5. manfredi c, spirito l, calace fp, et al. oral preparation of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin (ialuril® soft gels) for the prevention of luts after intravesical chemotherapy. pathophysiol off j int soc pathophysiol. 2022; 29:365-73. 6. longo n, celentano g, napolitano l, et al. metastasis-directed radiation therapy with consolidative intent for oligometastatic urothelial carcinoma: a systematic review and meta-analysis. cancers. 2022; 14:2373. 7. ferro m, del giudice f, carrieri g, et al. the impact of sarscov-2 pandemic on time to primary, secondary resection and adjuvant intravesical therapy in patients with high-risk nonmuscle invasive bladder cancer: a retrospective multi-institutional cohort analysis. cancers. 202; 13:5276. 8. imperatore v, creta m, di meo s, et al. intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus calmette-guerininduced chemical cystitis: preliminary experience with one-year follow-up. arch ital urol androl. 2018; 90:11-4. 9. morelli m, baboudjian m, vanacore d, et al. early photodynamic diagnosis cystoscopy after bacillus calmette-guérin (bcg) induction for high-risk nonmuscle invasive bladder cancer significantly increased the detection of bcg refractory tumors. j endourol. 2021; 35:1824-8. 10. kausch i, sommerauer m, montorsi f, et al. photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. eur urol. 2010; 57:595606. 11. mowatt g, n’dow j, vale l, et al. photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. int j technol assess health care. 2011; 27:3-10. 12. turco c, collà ruvolo c, cilio s, et al. looking for cystoscopy on youtube: are videos a reliable information tool for internet users? arch ital urol androl. 2022; 94:57-61. 13. capece m, spirito l, la rocca r, et al. hexaminolevulinate blue light cystoscopy (hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (nmibc): a retrospective analysis. arch ital urol androl. 2020; 92:17-20. 14. konecki t, kutwin p, łowicki r, et al. hexaminolevulinate in the management of nonmuscle invasive bladder cancer: a metaanalysis. photobiomodulation photomed laser surg. 2019; 37:551-8. 15. witjes ja, babjuk m, gontero p, et al. clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: evidence review and updated expert recommendations. eur urol. 2014; 66:863-71. 16. riedl cr, daniltchenko d, koenig f, et al. fluorescence endoscopy with 5-aminolevulinic acid reduces early recurrence rate in superficial bladder cancer. j urol. 2001; 165:1121-3. 17. filbeck t, pichlmeier u, knuechel r, et al. clinically relevant improvement of recurrence-free survival with 5-aminolevulinic acid 427archivio italiano di urologia e andrologia 2022; 94, 4 re-turb after pdd-turb induced fluorescence diagnosis in patients with superficial bladder tumors. j urol. 2002; 168:67-71. 18. albarghouth mh, hamza a. the impact of using intraoperative photodynamic diagnosis on the prognosis of bladder cancer. aktuelle urol. 2022; 53:552-558. 19. burger m, grossman hb, droller m, et al. photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. eur urol. 2013; 64:846-54. 20. mariappan p, rai b, el-mokadem i, et al. real-life experience: early recurrence with hexvix photodynamic diagnosis-assisted transurethral resection of bladder tumour vs good-quality white light turbt in new non-muscle-invasive bladder cancer. urology. 2015; 86:327-31. 21. gakis g, fahmy o. systematic review and meta-analysis on the impact of hexaminolevulinateversus white-light guided transurethral bladder tumor resection on progression in nonmuscle invasive bladder cancer. bladder cancer amst neth. 2016; 2:293-300. 22. sun j, ma x, shen h, liu b. effects of fluorescent light cystoscopy in non-muscle-invasive bladder cancer: a systematic review and meta-analysis. photodiagnosis photodyn ther. 2021; 34:102248. correspondence vito lorusso, md vito.lorusso@unimi.it laure doisy, md doisyl@ipc.unicancer.fr antonio maria granata, md antonio.granata@asst-fbf-sacco.it andrea gregori, md andrea.gregori@asst-fbf-sacco.it celeste manfredi, md manfredi.celeste@gmail.com lorenzo spirito, md lorenzo.spirito@unicampania.it carmine sciorio, md carminesciorio@gmail.com samuele molteni, md sa.molteni@asst-lecco.it luca giuseppe maria ciancimino, md lucaciancimino91@gmail.com michele morelli, md michelemorelli4@gmail.com luigi cirillo, md cirilloluigi22@gmail.com luigi napolitano, md (corresponding author) luiginap89@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy via sergio pansini n 5, naples (na), campania (italy) jochen walz, md walzj@ipc.unicancer.fr geraldine pignot, md pignotg@ipc.unicancer.fr stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 126 letter to editor submitted 14 march 2023; accepted 23 march 2023 to the editor, although postoperative pain associated with robot-assisted radical prostatectomy (rarp) is less than pain following the open technique, it remains a fundamental issue as it can be a significant source of discomfort for the patient and lengthen recovery times after surgery. the optimal management of pain after rarp is far from being fully elucidated and many factors have to be evaluated to choose the best analgesic approach (1). pain management in the postoperative period is classically achieved through the administration of intermittent or continuous intravenous drugs; opioids and non-steroidal anti-inflammatory drugs (nsaids) represent the cornerstones of this approach. these drugs have many potential adverse effects (aes). nsaids can affect renal and platelet function leading to kidney injury and significant bleeding, while opioids can be associated with delayed recovery of gut motility, urinary retention, dizziness, nausea, vomiting, and immunosuppression (2). spinal anesthesia is emerging as an alternative technique to control the postoperative pain or even to avoid general anesthesia not only in urological but also in cardiac, gynecological, and spine laparoscopic and robotic surgery (table 1) (3-6). it allows to reduce the drugs dosage and, consequently, their aes. however, several additional advantages can be identified. spinal anesthesia is performed before the induction of general anesthesia and its analgesic effect covers also the intraoperative period, so lower dosage of intraoperative opioids can be used along with lower minimum alveolar concentration of inhalational anesthetics, thus leading to an important reduction of postoperative nausea and vomiting along with a faster recovery of consciousness after general anesthesia; furthermore, the reduction of analgesic drugs during anesthesia can contribute to the hemodynamic stability. recently, some concerns have been raised about the immunosuppressive effect of opioids and, consequently, the potential risk of promoting metastatic spread of cancer cells; therefore, reducing opioid administration in the perioperative period is even more important (7). pikramenos et al. reported their experience in 60 men, underwent combined spinal/epidural anaesthesia during radical retropubic prostatectomy: they showed that combined spinal/epidural anaesthesia is a safe procedure to perform and is associated with less intraoperative blood loss and potentially reduced risks of postoperative complications (8). the role of spinal anesthesia should also be considered in the management of the bladder spasm and the discomfort due to urethral catheter which can impact on the patient satisfaction and on the ability to early recover autonomous walking, with possible dramatic consequences on the risk of thromboembolism and on the length of hospital stay (9). interestingly, several adjuvants can be added to the solution injected in the subarachnoid space thus increasing the ability to achieve the desired effects with very small amounts of drugs. ketamine, dexmedetomidine, midazolam, and clonidine are some examples of drugs which are commonly used with or without opioids to prolong and/or potentiate the effect of the local anesthetic. many combinations of these drugs for spinal anesthesia have so far been reported in literature and appropriate use of their different pharmacological properties can be employed to manage not only postoperative pain but also intraoperative analgesia, allowing rarp to be performed only with spinal anesthesia and light sedation. no study is currently available on the topic, however, as part of a clinical trial, we have begun performing the first cases of rarp under spinal anesthesia in our center, with encouraging preliminary results demonstrating the feasibility and potential of this novel technique. some authors have expressed concerns regarding the risk-benefit ratio of spinal anesthesia, as this technique can cause severe aes. an accidental puncture of an epidural blood or a spinal nerve can lead to permanent injuries such as motor and sensory loss of the lower limbs, loss of sphincters continence, and typical neuropathic symptoms. these complications are actually very rare; for example, the reported incidence of spinal hematoma is about 1:220,000 cases and a careful medical history along with appropriate management of anti-platelet and anticoagulant drugs can significantly reduce the risk (10). absolute contraindications to spinal anesthesia are patient refusal, injection site infection, increased intracranial pressure (except for pseudotumor cerebri), allergy to the drugs to be injected, and uncorrected hypovolemia (as spinal anesthesia role of spinal anesthesia in robot-assisted radical prostatectomy: gamble or opportunity? lorenzo spirito 1, annachiara marra 2, vincenzo mirone 3, celeste manfredi 1, ferdinando fusco 1, luigi napolitano 3, giuseppe servillo 2, nicola logrieco 2, pasquale buonanno 2 1 urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy; 2 department of neurosciences, reproductive and odontostomatological sciences, university of naples “federico ii”, naples, italy; 3 urology unit, department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples. doi: 10.4081/aiua.2023.11311 archivio italiano di urologia e andrologia 2023; 95, 2 l. spirito, a. marra, v. mirone, c. manfredi, f. fusco, l. napolitano, g. servillo, n. logrieco, p. buonanno 127 causes vasodilation due to sympathetic block). relative contraindications are sepsis, coagulopathy, fixed cardiac output states, aortic stenosis (previously considered an absolute contraindication), indeterminate neurological disease, multiple sclerosis and other demyelinating diseases (as demyelinated nerves seem more susceptible to local anesthetic toxicity (11). in conclusion spinal anesthesia to perform rarp can be a gamble or an opportunity depending on the players who take part to the match: the appropriate assessment and selection of the patient, the correct management of the drugs affecting coagulation and platelet function, and the proper use of adjuvants in the solution to be injected are essential for a successful and safe spinal anesthesia. however, the role of spinal anesthesia in the context of rarp needs to be evaluated in randomized controlled trials with adequate sample size and follow-up. not only the impact on the postoperative pain but also on other sources of possible discomfort for the patient should be investigated. the feasibility and relative advantages and disadvantages of spinal anesthesia when used as a replacement for general anesthesia should be clarified with adequate comparative studies. moreover, future studies should compare the spinal anesthesia with novel techniques of regional analgesia such as erector spinae plane and transversus abdominis plane blocks, which are less invasive and consequently safer than the intrathecal administration of drugs. references 1. joshi gp, jaschinski t, bonnet f, kehlet h. prospect collaboration. optimal pain management for radical prostatectomy surgery: what is the evidence? bmc anesthesiol. 2015; 15:159. 2. koh jc, lee j, kim sy, et al. postoperative pain and intravenous patient-controlled analgesia-related adverse effects in young and elderly patients: a retrospective analysis of 10,575 patients. medicine (baltimore). 2015; 94:e2008. 3. gontero p, oderda m, calleris g, et al. awake da vinci robotic partial nephrectomy: first case report ever in a situation of need. urol case rep. 2022; 42:102008. 4. giampaolino p, della corte l, mercorio a, et al. laparoscopic gynecological surgery under minimally invasive anesthesia: a prospective cohort study. updates surg. 2022; 74:1755-1762. 5. dhawan r, daubenspeck d, wroblewski ke, et al. intrathecal morphine for analgesia in minimally invasive cardiac surgery: a randomized, placebo-controlled, double-blinded clinical trial. anesthesiology. 2021; 135:864-876. table 1. use of spinal anesthesia and analgesia in robotic and laparoscopic surgery (see supplementary material for references). article study design surgery groups duration of intervention outcomes beilstein cm et al, 2022 rct urological/rarp or open general anesthesia associated with: group sss: 282 min [240; 322] no differences in qor; radical prostatectomy subarachnoid analgesia (sss) group tas: 270 min [240; 300] no differences in postoperative pain transversus abdomnis plane block (tap) group sa: 274 min [240; 312] systemic lidocaine (sa) gontero p. et al, 2022 case report urologicalc/robotic partial continuous subarachnoid anesthesia 2h 45 min patient hemodinamically stable; nephrectomy no intraoperative desaturation; optimal postoperative analgesia dhawan r et al, 2021 rct cardiac/robotic totally endoscopic general anesthesia without (groups ga) group ga: 290 (238–346) min group sa showed less postoperative pain, coronary artery bypassor with subarachnoid analgesia (group sa) group sa: 315 (235–366) min less need for postoperative morphine, and less cough shim jw et al, 2021 rct urological/rarp general anesthesia with (group non-itmb) group non-itmb: 120 (108-143)) min group itmb less postoperative pain or without (group itmb) intrathecal group itmb: 120 (115-130 min and opioids consumption morphine and bupivacaine shim jw et al, 2020 prospective urological /ralp general anesthesia with: group iv-pca: 123 (109-145) min group itmb required less intraoperative observational group iv-pca: intravenous group rsb: 123 (100-141) min opioids and showed less postoperative patient-controlled analgesia group itmb: 123 (114-138) min pain with a lower postoperative group rsb: rectus sheath bupivacaine block consumption of opioids, better qor. group itmb: intrathecal morphine and bupivacaine bae j et al, 2017 rct urological/ralp general anesthesia with group itm: group itm: 171 ± 42 min group itm showed less postoperative pain intrathecal morphine+ intravenous group iv-pca: 164 ± 41 min and morphine consumption atient-controlled analgesia group iv-pca: only intravenous patient-controlled analgesia segal d et al, 2014 rct urogynecological/robotic general anesthesia without (group ga) group sa showed less postoperative pain, sacrocervicopexy or with subarachnoid anesthesia (sa) lower postoperative consumption of opioids, and a higher satisfaction of patients and nurses ross sb et al, 2013 rct general surgery/laparo-endoscopic general anesthesia (group ga) group ga: 65.2 ± 25.1 min group ea showed less postoperative pain single-site (less) cholecystectomy vs epidural anesthesia (group ea) group ea: 64.5 ± 21.5 min qor: quality of recovery; ralp: robot-assisted laparoscopic prostatectomy; rct: randomized control trial. archivio italiano di urologia e andrologia 2023; 95, 2 128 spinal anesthesia and robot-assisted radical prostatectomy 6. gao s, wei j, li w, et al. accuracy of robot-assisted percutaneous pedicle screw placement under regional anesthesia: a retrospective cohort study. pain res manag. 2021; 2021:6894001. 7. lee bm, singh ghotra v, karam ja, et al. regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. pain manag. 2015; 5:387-95. 8. pikramenos k, zachou m, apostolatou e, et al. the effects of method of anaesthesia on the safety and effectiveness of radical retropubic prostatectomy. arch ital urol androl 2022; 94:396-400. 9. morgan ms, ozayar a, friedlander ji, et al. an assessment of patient comfort and morbidity after robot-assisted radical prostatectomy with suprapubic tube versus urethral catheter drainage. j endourol. 2016; 30:300-5. 10. moen v, dahlgren n, irestedt l. severe neurological complications after central neuraxial blockades in sweden 1990-1999. anesthesiology 2004; 101:950-9. 11. carpenter rl, caplan ra, brown dl, et al. incidence and risk factors for side effects of spinal anesthesia. anesthesiology 1992; 76:906-16. correspondence lorenzo spirito, md lorenzospirito@msn.com celeste manfredi, md manfredi.celeste@gmail.com ferdinando fusco, md ferdinando-fusco@libero.it urology unit, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples annachiara marra, md dottmarraannachiara@gmail.com giuseppe servillo, md giuseppe.servillo@unina.it nicola logrieco, md nicola.logrieco@unina.it pasquale buonanno, md pasquale.buonanno@unina.it department of neurosciences, reproductive and odontostomatological sciences, university of naples “federico ii”, naples, italy vincenzo mirone, md mirone@unina.it luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology university of naples “federico ii” via pansini 5, 80131 naples, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4406 original paper no conflict of interest declared. introduction currently whole-gland therapy such as radical prostatectomy (rp) and external beam radiotherapy (ebrt) still represent the gold standard treatments for localized prostate cancer (pca). both treatments are effective but they can be burdened with procedure-related side effects such as urinary incontinence and erectile dysfunction (1, 2). nowadays there are well-established studies in support of prostate-sparing procedures in low-risk cancer, but the treatment indications have also expanded to small intermediate-risk and high-risk tumours, which are considered life-threatening (3-5). concerns have arisen about the focal treatment of a disease that has been found to be multifocal in 50-76% of patients (6). a high degree of genomic heterogeneity and a 13-26% gleason score heterogeneity have also been reported, even within the positive cores of prostate biopsy (7, 8). in a therapeutic approach for pca the concept of index lesion is therefore decisive. despite the multifocality and heterogeneous disease pattern inside the same gland, the index lesion represents the largest prostatic tumour with the highest histologic grade within the prostate. this is likely to drive the biology of the patient’s disease. in fact, the same genomic sequence has been found in metastatic lesions and in the index lesion within the prostate (9). interestingly, despite being limited to one case, haffner et al. used the whole-genome sequencing and molecular analyses to characterize the lethal clone in a patient who died of pca. surprisingly, the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumour. these findings highlighted le potential importance of investigate molecular prognostic and/or predictive markers to optimize the pathological evaluation and delineate clonal heterogeneity (10). laser interstitial thermotherapy performed by the diode multichannel laser system echolaser x4 is a transperineal percutaneous procedure named soractelitetm that uses laser light transmitted through optical fibres to produce irreversible thermal damage of target tissue. the echolaser x4 system allows multifibre ablation management and provides planning software for optimization background: the aim of this study was to evaluate the outcomes of patients suffering prostate cancer (pca) treated conservatively using 1064 nm laser energy for focal laser ablation (fla). the patients included in the study were unsuitable for surgery or unwilling to receive external beam radiotherapy because they were afraid of the possible side effects of whole-gland therapies. methods: this study included patients with a diagnosis of nonmetastatic pca who underwent fla using soractelitetm system. tissue ablation was performed at a fixed power of 5 w by the diode multichannel laser system echolaser x4 that uses laser light transmitted through optical fibres causing the target tissue to undergo irreversible thermal damage. functional outcomes were evaluated with the international prostatic symptoms score (ipss) and 5-item version of the international index of erectile function (iief-5) before the treatment and one year later. results: ten patients suffering non-metastatic pca were included. four decided upon a conservative treatment because of reduced performance status and for six patients the procedure was chosen electively. all patients underwent multiparametric magnetic resonance imaging at 3 and 12 months and eight out of ten patients underwent prostate biopsy at 6 months. persistent disease was detected in 3 patients who underwent a second ablation. in these patients at the biopsy following the second ablation none harbored residual disease. at follow-up, no patient suffered urinary incontinence requiring the use of pads. no significant worsening in sexual potency measured with iief-5 (p = 0.356) or prostatic symptoms measured at ipss (p = 0.462) were recorded comparing pre-treatment condition vs one-year follow-up. compared with baseline, prostate-specific antigen was significantly reduced at one-year follow-up (3.7 ± 1.1 vs 7.9 ± 4.1 ng/ml; p = 0.008). conclusions: although whole gland therapies remain the gold standard treatment for pca, our results indicate that the soractelitetm system for focal laser ablation, as a very preliminary step, appears to offer a short-term oncologic control of pca with negligible side effects. key words: focal laser ablation; focal therapy; prostate cancer; prostate magnetic resonance imaging; transperineal treatment. submitted 10 september 2022; accepted 23 october 2022 a single-operator experience using echolaser soractelitetm for focal laser ablation of prostate cancer: one more arrow in the quiver for the conservative management of the disease iacopo meneghetti 1, demostene giardino 2, riccardo morganti 3, vincenzo marino 2, filippo menchini fabris 2, riccardo bartoletti 4, novello pinzi 2 1 urology department, ospedale apuane, massa, italy; 2 surgery unit, casa di cura san rossore, pisa, italy; 3 section of statistics, university of pisa, pisa, italy; 4 urology department, university of pisa, pisa, italy. doi: 10.4081/aiua.2022.4.406 summary 407archivio italiano di urologia e andrologia 2022; 94, 4 echolaser soractelitetm for focal laser ablation of prostate cancer of the ablation strategy. it also supports the surgeon with planning for effective and safe needle positioning with respect to the tumour and critical structures to be spared. here, we present the results obtained from our updated single-surgeon prospective cohort of 10 patients with at least one-year follow-up after the use of 1064 nm laser energy for focal laser ablation (fla) of pca. in this cohort we treated patients with only one lesion so as not to have to decide whether to treat the index lesion or also the other/s considered less aggressive/s. materials and methods population characteristics between october 2019 and october 2020, 10 patients candidate to organ-sparing treatment for pca were selected to undergo fla using the soractelitetm procedure. soractelitetm for fla treatment was offered to patients with no metastatic pca, gleason score ≤ 8, tnm stage t1c-t2cn0m0, prostate-specific antigen (psa) ≤ 20 ng/ml, a single lesion with a concordant multiparametric magnetic resonance imaging (mpmri), a tumour volume ≤ 20 ml and a good life expectancy. all patients included in this study had a prostate volume smaller than 65 ml. the patients included in the study were unsuitable for surgery or unwilling to receive ebrt. it was fully explained to the patients that different focal therapies validated were available, but the patients, due to the trust acquired with our working group, choose the aforementioned approach that was presented as experimental. each case had been previously discussed in a multidisciplinary meeting and extensively with the patient, who received written information on the benefits and risks of the procedure. prior to the start of patient recruitment, the surgeon (np) followed a training program, visiting centres with expertise in fla with soractelitetm technology to achieve proficiency in the main aspects of fla (fibre positioning, energy dose, ablation strategy and ablation margin). finally, a representative from the manufacturer of the device trained the surgeon and operating theatre staff on the use of soractelitetm, and assisted the operator for the first 3 cases. protocol and assessment of data the study was performed in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. the confidentiality of patient data was guaranteed as the patients were entered into a database in the form of a number. following institutional review board commitee approval and registration of the protocol (0014161/2019), patients with localized pca were prospectively recruited. the informed consent was obtained from all patients for the use of their data. pre-operative assessment all the patients we followed had undergone mpmri and transperineal prostate biopsy with systematic sampling of the prostate with 12 samples per side for a total minimum of 24 samples. six out of 10 patients underwent biopsy before the mpmri, in the other 4 mpmri was done before the biopsy. in those patients in whom a mpmri was performed before the biopsy, two more samples were taken, targeted, as cognitive biopsy, in the area identified on mpmri. the inclusion of random samples was fundamental for us to exclude the presence of disease in areas not frankly suspicious on mpmri. we classified these patients as carriers of single lesion disease inasmuch the positive biopsy samples were found only in the area highlighted as suspicious on mpmri. all patients had undergone systematic psa testing prior to diagnostic biopsy. in addition, a questionnaire for the evaluation of urinary symptoms and sexual function were administered to the patients before undertaking the therapeutic treatment. technique soractelitetm for fla consists of ultrasound-guided positioning of up to 4 applicators (depending on the tumour volume and shape) consisting of a 21-gauge chiba needle (introducer, elesta spa, calenzano, italy) in whose lumen is inserted a 272-μm quartz optic fibre (fiber optic for pla, elesta spa, calenzano, italy). the fibre tip protrudes 10 mm from the introducer tip. the optic fibres are connected to a multisource laser system operating at 1064 nm (echolaser x4, elesta spa, calenzano, italy). each treatment is performed at a fixed power of 5 w, with the single illumination dose determined on a caseby-case basis according to the tumour size. additional laser fibres can be placed within the tumour volume at a mutual distance ranging from 5 to 10 mm in order to amplify the volume of necrosis obtained by simultaneous tissue irradiation and summative volumetric necrosis. depending on the tumour size in the longitudinal direction, one or more consecutive illuminations are performed with a ‘pull-back’ technique (retraction of the needle-fibre kit by 5-10 mm) during the same treatment session. for the same duration of illumination and dose of energy administered, the thermoablated area is always reproducible regardless of tissue properties and vascularity. the anatomopathological study of a thermoablated tissue area showed that the necrotic area assumes an ellipsoid shape. the treatment ends when the total planned dose is delivered. a single illumination dose ranges from 1200 j to 1800 j, which corresponds to an illumination time of 4 to 6 minutes. in cases where a ‘pull-back’ maneuver is used, the illumination time doubles. a touch panel device (esi, echolaser smart interface, elesta spa, calenzano, italy) can be connected to the auxiliary video output of a general ultrasound scanner and used for treatment planning. esi has a dedicated planning software that allows the visualization of needles insertion trajectories of the needle guide mounted on the us biplanar probe of the connected ultrasound. this facilitates the insertion of regularly spaced multiple parallel needles simultaneously. the treatment planning is crucial for the outcome of the treatment. the esi superimposes on the ultrasound image a graphical representation, consisting of guidelines for the needle trajectories and the depiction of two concentric closed perimeters, an external one for the size of safety distances and an internal one for the size of the ablation area. the size and position of both of these perimeters depend on the treatment parameters (dose, number of fibres, ‘pullback’) and the surgeon can simulate the best treatment strategy before needle insertion. the planning ends when the archivio italiano di urologia e andrologia 2022; 94, 4 i. meneghetti, d. giardino, r. morganti, v. marino, f. menchini fabris, r. bartoletti, n. pinzi 408 tumour is visualized within the internal closed perimeter and all critical structures (urethra, vascular bundle, sphincters, bladder wall and rectum) are located outside the external perimeter. if required, it is possible to increase the distance from the rectum by injecting a 33% (w/v) glucose solution between the prostate and the rectum. the goal of the planning phase of the procedure is to identify the point where the tip of the needle will be located, with respect to the area that will be ablated. the ultrasound software associated with a directional template for guidance allows the placement of the laser fiber(s) in the index lesion with millimeter precision (figure 1). after an observation period of about one hour, a transrectal contrast enhanced ultrasonography to evaluate the extent of the coagulation zone is performed. patients are discharged the day of the procedure without a catheter. follow-up, functional and oncological outcomes all patients were advised to undergo a 6-monthly biopsy sampling, and mpmri at 3 and 12 months. complete response was defined on the basis of negative imaging study results and negative prostate biopsy at 6 months. persistent disease was defined as the presence of suspected or positive imaging study results and/or positive prostate biopsy performed at 6 months. in case of persistent disease, a second ablation was planned. the international prostatic symptoms score (ipss) and 5-item version of the international index of erectile function (iief-5) were completed by each patient prior to the procedure and at 1-year follow-up without changing the intake of any type of drug. psa was also confronted before treatment and at one-year follow-up. intraoperative and postoperative complications were recorded according to satava (11) and clavien-dindo (12), respectively. statistical analysis categorical data were described by frequency; continuous data were expressed as mean and standard deviation. to compare data (ipss, iief-5 and psa) measured at baseline and after 12 months of follow-up, t-tests for paired data were applied. statistical significance was set at p < 0.05 and all analyses were carried out with spss statistics version 27.0 (ibm corp., armonk, ny). results patient characteristics are summarised in table 1. a total of 10 patients suffering non-metastatic pca were included in the present study. fla for pca was selected as the initial treatment for the following reasons: reduced performance status (4 patients) and patient’s own choice (6 patients). at the diagnostic biopsy four patients suffered pca gleason 6 (3+3), two patients had gleason 7 (3+4) table 1. patient characteristics. patient number age (years) indication for fla dre psa (ng/ml) gs laterality diameter of tumour at mpmri (mm) psa (ng/ml) (12 mo) 1 65 elective + 7.3 6 right 5 3.2 2 73 elective 5.1 6 left 14 3.1 3 60 elective 5.1 6 left 7 3.9 4 67 unfit for surgery + 11 7 (4+3) right 20 1.5 5 75 elective 5.2 8 (4+4) left 9 3.6 6 69 elective + 5.7 7 (3+4) left 10 3.2 7 74 unfit for surgery + 17.8 7 (4+3) right 15 5 8 78 elective + 10.1 7 (3+4) right 15 5.2 9 73 unfit for surgery 6.8 7 (4+3) left 11 4.1 10 70 unfit for surgery + 4.9 6 left 7 3.9 +: suspicious. -: non-suspicious. dre: digital rectal examination. fla: focal laser ablation. gs: gleason score. mpmri: multiparametric magnetic resonance imaging. psa: prostate-specific antigen. figure 1. on the left: echolaser smart interface settings during the planning phase. the ablation area (dotted magenta line) is simulated in order to define the best approach in terms of number of fibres, mutual tip position, ‘pullback’ and energy dose. the external circle (dotted cyan line) represents the safety distance to be assured with respect to critical structures (nerves, rectum). on the right: two introducer needles are positioned in a parallel orientation according to the planning. 409archivio italiano di urologia e andrologia 2022; 94, 4 echolaser soractelitetm for focal laser ablation of prostate cancer and three gleason 7 (4+3). only one patient presented a gleason 8 (4+4) disease. all patients underwent mpmri at 3 and 12 months (figure 2). eight out of ten patients underwent prostate biopsy at 6 months. six patients in which the mpmri did not highlight suspected lesions (pi-rads category < 3) had negative biopsy results according to the scheme (12 samples per side with the addition of sampling in the area previously subjected to fla). these patients were considered to have a complete response to treatment. three patients had a persistent disease according to positive (pirads category ≥ 3) mprmi at 3 months. two of them underwent a prostate biopsy according to the scheme with additional samplings in the suspected area. the pathology report revealed that those two patients still harbored pca. one of them refused to undergo prostate biopsy and agreed to directly receive a second treatment in the area of persistence of disease identified on mpmri (pirads category 5). the diagram in figure 3 summarizes the diagnostic-therapeutic process of the entire cohort of patients in our study. the three aforementioned patients with persistent disease underwent a second ablation and at 12 months, mpmri revealed no lesions with pi-rads category > 3. all three patients underwent a transperineal prostate biopsy at 12 months that was negative for pca. all the patients who required a second ablation had a disease > 10 mm at the first mpmri. two patients were unwilling to repeat the biopsy at 6 months. one of them was the aforementioned patient who received directly a second treatment, the other one underwent a mpmri at 6 and 12 months. in the latter patient, a pi-rads category 2 was found in the ablated area at mpmri, compatible with a necrotic area. no complications related to diagnostic prostate biopsies were reported. no patient developed extracapsular invasion (> ct3) or appearance of bone lesions or lymph node swellings (> 1 cm) in the fields of inclusion on any mpmri pelvic scan performed for primary diagnosis or follow-up at 6 months or 1 year. no intraoperative complications were recorded according to the satava classification system (11). postoperatively four patients required analgesic drugs (clavien-dindo grade i). at 1-year follow-up, no patient suffered urinary incontinence that required the use of pads. compared with baseline, no significant worsening in functional outcomes at 1 year was observed as measured with the iief-5 (p = 0.356) and ipss (p = 0.462) (table 2). table 2. psa (ng/ml), ipss and iief-5 levels at baseline and after 12 months. factor mean (sd) p-value psa pre-treatment 7.9 (4.1) 0.008 psa at 1 year follow-up 3.7 (1.1) ipss pre-treatment 6.9 (3.1) 0.462 ipss at 1 year follow-up 7.3 (4.1) iief-5 pre-treatment 11.1 (5.1) 0.356 iief-5 at 1 year follow-up 10.2 (6.7) iief: international index of erectile function. ipss: international prostate symptoms score. psa: prostate-specific antigen. figure 2. on the left: mpmri t2-weighted sequences on the axial view showing a 7 mm carcinoma located in the left apical portion (arrowhead) in a 53-year-old patient before treatment. on the right: the same patient at 3-month follow-up after transperineal fla. a hypointense area compatible with necrotic-coagulative necrosis (arrowhead) matching the previous tumoural area is visible on the mpmri t2weighted image. figure 3. diagnostic-therapeutic process of the entire cohort of the 10 patients included in our study at follow-up. archivio italiano di urologia e andrologia 2022; 94, 4 i. meneghetti, d. giardino, r. morganti, v. marino, f. menchini fabris, r. bartoletti, n. pinzi 410 at 1 year follow-up, mean ± sd psa was significantly reduced relative to baseline (3.7 ± 1.1 vs 7.9 ± 4.1 ng/ml; p = 0.008) (table 1, table 2 and figure 4). discussion conservative treatments aim to control the disease while minimizing the risk of developing side effects, primarily sexual impotence, urinary incontinence and bowel toxicity. in fact, the possibility to treat only a targeted part of the gland reduces the risk of damage to the neurovascular bundles, external urethral sphincter, bladder neck or rectum. our results regarding lower urinary tract symptoms (luts) and sexual function measured with ipss and iief-5 did not demonstrate a statistically significant change one year after the treatment (p = 0.462 and p = 0.356 vs baseline, respectively). our results are in agreement with eggener et al., who found no worsening of ipss symptoms in fla-treated patients. interestingly, however, these investigators found a worsening of sexual function at 1 month (p = 0.03) and 3 months (p = 0.05), although the difference vs baseline was not significant at 12 months (p = 0.38) (13). also van riel et al. found a worsening of sexual function at 1 week after the procedure, although the difference vs baseline was not significant at 1 month (14). moreover, chao et al. in their experience using fla for localized pca found no adverse impact on luts or sexual function at 1 year (15). the presence of an expert technician for the device alongside the surgeon during the first cases is essential to reduce the initial learning curve and thus to improve safety of the procedure (16). regarding the learning curve in using soractelitetm, we believe that it is comparable to the training required for transperineal prostate biopsy, so that in the hands of an expert urologist, the use of the soractelitetm procedure is quite simple. another strength of our study is the fact that all the procedures were performed by a single operator with extensive experience of the transperineal approach, and without the potential confounder of inter-operator differences. the urologist (np) who performed all the procedures in our study had extensive experience in performing transperineal prostate biopsies. to date, it is far more common to perform prostate biopsies via the transrectal access (17), so for the urologist who approaches the use of soractelitetm for fla it would be advisable to first acquire some biopsy experience with a transperineal access before engaging in ablative treatment. we believe that for the urologist experienced in transperineal access, three procedures are sufficient to complete the learning process and carry out adequate treatments. although our results and the overall literature are too preliminary to determine with adequate accuracy any possible advantage or disadvantage regarding the use of soractelitetm for the treatment of pca, we believe that an extraordinary advantage of the method is the ability to evaluate one hour later the effect on the tissue and to be able, in the same session, to expand the ablation in the desired area if this is not satisfactory (figure 5). figure 4. ladder plot illustrating individual changes in psa from pre-treatment (at baseline) to post-treatment (12 months). figure 5. on the left: transverse ultrasound image during ablation. on the right: longitudinal ultrasound image of the same tumour during ablation phase. coagulated tissue appears as a hypoechoic area overlapped by gas artefacts (arrowhead). 411archivio italiano di urologia e andrologia 2022; 94, 4 echolaser soractelitetm for focal laser ablation of prostate cancer similar to other authors who have approached pca with focal therapy for pca, no patient in our cohort needed pads or complained of urinary incontinence after the treatment (18). this represents an outstanding success, as incontinence is statistically the most bothersome side effect of rp with an incidence that in some series reaches 65% (19). even approaches such as ebrt or brachytherapy, which are considered less invasive, are burdened with considerable rates of worsening of urinary obstruction, irritation and worsened bowel symptoms (2). one year after the procedure, a statistically significant reduction in psa was observed compared with baseline (p = 0.008). although three of the patients who had residual disease at 6 months prostate biopsy underwent a second ablation before 12 months, a reduction in psa was evident for each patient in our cohort (figure 4). in contrast to our results, chao et al., reporting oncological and functional outcomes for 34 men who had undergone fla for pca, found that psa was a poor discriminator of disease recurrence in the ablated zone at two-year follow-up (15). none of our patients had a psa > 20 ng/ml at diagnosis, which, as a single factor for d'amico's criteria, would place the case into a high-risk category. while there is no clear indication on the use of both psa and psa-density as eligibility criteria for fla (20), it is often suggested to consider psa ≤ 15 ng/ml as a limit for a patient's suitability for focal therapy (21). the only patient who presented with gleason score 8 disease was a patient who wished to undergo some kind of treatment but was considered unsuitable for other therapeutic treatments because of age and comorbidities. in three patients, disease was persistent after the first fla procedure and in all three cases the disease was present in the same area at follow-up. this is likely related to inaccuracy in pinpointing the entire lesion during the first procedure. our results suggest that the treatment of lesions > 10 mm could be less accurate and require a second-look. the disadvantage of not achieving complete disease ablation at the first attempt, especially in more aggressive diseases, could potentially give the disease the chance to progress. in a study of ultrasound-guided laser ablation in the thyroid gland of a porcine model, ridouani et al. concluded that 3 w/1800 j was the optimal setting to obtain a coagulated necrotic zone of 10 mm with 2 mm margin when utilizing a single needle (22). in our cohort of patients, the energies used were greater and for a single treatment were not lower than 5 w/3600 j. other clinicians who used the soractelitetm system for benign prostatic hyperplasia used a power of 3w for tissue ablation (23). we chose to use greater ablation power for tumour tissue with the aim of greater certainty in disease ablation. in fact, higher powers reduce the duration of the initial phase of heating which can be affected by local tissue properties, and therefore trigger the ablation phase very quickly. this leads to lower interpatient variability of treatment outcomes. in the case of larger lesions, depending on the tumour shape with respect to the needle insertion direction, a ‘pull-back’ maneuver was carried out (needle retraction and second energy dose delivery) or a second fibre was placed in a parallel way with respect to the first one and simultaneous energy delivery was performed. there are some limitations to our study. firstly, the small number of patients limits the robustness of our results, especially those concerning cancer control. secondly, follow-up in this study was limited to one year. therefore, while our data on functional outcome are interesting, the oncological results still need to be validated with a longer follow-up. finally, our data are not sufficient by themselves to formulate an indication for soractelite fla in pca, especially since this is a non-randomized series without a strict exclusion criterion for class of risk. our study highlights important opportunities for future work. it would be interesting to carry out a comparative study for functional and oncological results, standardizing it with patients in the same class of risk, comparing different conservative approaches for the treatment of pca. furthermore, to evaluate the possibility of adopting this technique on a large scale it would be useful to involve both experienced and novice operators to evaluate the feasibility of this technique in therapeutic practice. conclusions our results confirm that soractelitetm for fla treatment is an interesting emerging technology for the treatment of pca. as is the case for other conservative approaches, it must find its place in the landscape of treated patients. safety profiles and functional and oncological results are promising; however, long-term follow-up results are not yet available. additional prospective, multicenter studies are awaited to confirm our results. references 1. boorjian sa, eastham ja, graefen m, et al. a critical analysis of the long-term impact of radical prostatectomy on cancer control and function outcomes. eur urol. 2012; 61:664-75. 2. chen rc, basak r, meyer am, et al. association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and patient-reported quality of life among men with localized prostate cancer. jama. 2017; 317:1141-1150. 3. prepelica kl, okeke z, murphy a, et al. cryosurgical ablation of the prostate: high risk patient outcomes. cancer. 2005; 103:1625-30. 4. bass r, fleshner n, finelli a, et al. oncologic and functional outcomes of partial gland ablation with high intensity focused ultrasound for localized prostate cancer. j urol. 2019; 201:113-119. 5. guenther e, klein n, zapf s, et al. prostate cancer treatment with irreversible electroporation (ire): safety, efficacy and clinical experience in 471 treatments. plos one. 2019; 14:e0215093. 6. djavan b, susani m, bursa b, et al. predictability and significance of multifocal prostate cancer in the radical 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14:257-61. 12. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 13. eggener se, yousuf a, watson s, et al. phase ii evaluation of magnetic resonance imaging guided focal laser ablation of prostate cancer. j urol. 2016; 196:1670-1675. 14. van riel lamjg, van kollenburg raa, vis an, et al. safety and feasibility of soractelite transperineal focal laser ablation for prostate cancer and short-term quality of life analysis from a multicenter pilot study. eur urol open sci. 2022; 39:48-54. 15.chao b, llukani e, lepor h. two-year outcomes following focal laser ablation of localized prostate cancer. eur urol oncol. 2018; 1:129-133. 16. brunckhorst o, volpe a, van der poel h, et al. training, simulation, the learning curve, and how to reduce complications in urology. eur urol focus. 2016; 2:10-18. 17. tamhankar as, el-taji o, vasdev n, et al. the clinical and financial implications of a decade of prostate biopsies in the nhs: analysis of hospital episode statistics data 2008-2019. bju int. 2020; 126:133-141. 18. lepor h, llukani e, sperling d, et al. complications, recovery, and early functional outcomes and oncologic control following in-bore focal laser ablation of prostate cancer. eur urol. 2015; 68:924-6. 19. alivizatos g, skolarikos a. incontinence and erectile dysfunction following radical prostatectomy: a review. scientificworldjournal. 2005; 5:747-58. 20. van luijtelaar a, greenwood bm, ahmed hu, et al. focal laser ablation as clinical treatment of prostate cancer: report from a delphi consensus project. world j urol. 2019; 37:2147-2153. 21. wenger h, yousuf a, oto a, et al. laser ablation as focal therapy for prostate cancer. curr opin urol. 2014; 24:236-40. 22. ridouani f, tuttle rm, ghosn m, et al. ultrasound-guided percutaneous laser ablation of the thyroid gland in a swine model: comparison of ablation parameters and ablation zone dimensions. cardiovasc intervent radiol. 2021; 44:1798-1806. 23. pacella cm, patelli g, iapicca g, et al. transperineal laser ablation for percutaneous treatment of benign prostatic hyperplasia: a feasibility study. results at 6 and 12 months from a retrospective multi-centric study. prostate cancer prostatic dis. 2020; 23:356-363. correspondence iacopo meneghetti, md (corresponding author) iacopo.meneghetti@tiscali.it urology department, ospedale apuane, massa (italy) demostene giardino, md demosteneg@libero.it vincenzo marino, md vincenzo_mar@tiscali.it filippo menchini fabris, md menchinifabris@andrologia.it novello pinzi, md pinzinovello@gmail.com surgery unit, casa di cura san rossore, pisa (italy) riccardo morganti, md r.morganti@ao-pisa.toscana.it section of statistics, university of pisa, pisa (italy) riccardo bartoletti, md riccardo.bartoletti@unipi.it urology department, university of pisa, pisa (italy) cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 1126 letter to editor no conflict of interest declared. to the editor, world health organization (who) defines infertility as the inability of a sexually active partner to achieve a clinically confirmed pregnancy after at least one year of intercourse without contraceptive protection on fertile days (1). as women are primarily responsible for the conception, childbirth, and postpartum, fertility problems have been related to fertile female capacity. however, men play an essential role, being responsible for about 50% of alterations in fertility due to dysfunctions in the male reproductive tract, including varicocele, hypogonadism, poorly descended testicles, testicular tumors, and even anti-sperm autoantibodies (2-4). however, a high percentage of cases of male infertility is still of idiopathic cause. male infertility has also been associated with aging and unhealthy lifestyles, such as cigarette smoking, recreational drug use, alcohol, sedentary lifestyle, psychological stress, as well as environmental factors such as pollution and heat exposure (5, 6). additionally, there is a relationship between infertility and non-contagious diseases or chronic diseases, including cancer, chronic respiratory diseases, cardiovascular diseases, diabetes mellitus, obesity, and prostatitis (7-10) producing stress and general deterioration of health, including seminal parameters and fertile male capacity. prostatitis and obesity prostatitis is a common urogenital disease with a worldwide prevalence between 2.2 and 9.7% and an average of 8.2% (11), and has been directly related to seminal parameters alteration and male fertility (8). on the other hand, the increasing trend of obesity is associated to the decline of male fertility (20). in fact, it has been reported that men with a high bmi tend to be infertile more often than men with adequate body weight (12). several studies have been reported in which an alteration of seminal quality and male fertility is found, along with an increase in the incidence of obesity. furthermore, in the united states, it has been found that sperm counts decrease by 1.5% annually, and obesity has been considered as a possible etiological agent of infertility and reduced fertility (13). to the best of our knowledge, there is insufficient evidence to link obesity and prostatitis. some studies have tried to relate these two pathologies, as wallner et al. (14), who found that having a high bmi acts as a protective factor for prostatitis. although this finding elucidates the relationship between prostatitis and obesity, future studies are necessary. while the relationship between prostatitis and obesity is still unknown, the latter has been involved with the risk of suffering from other prostate diseases, such as benign prostatic hyperplasia and prostate cancer (15, 16). inflammatory status and antioxidants: a threat to fertility with a therapeutic alternative obesity implies an increase in abdominal or visceral adipose tissue, which leads to rise in hormone levels in addition to a chronic inflammatory process (18), which is precisely due to abundant white adipose tissue in obese men, where increased aromatase activity has been found (13, 17). adipose white tissue is considered an endocrine organ, responsible for producing around 30 biologically active peptides, such as leptin and adiponectin, and can even secrete adipokines (as modulating agents) (13). leptin, a hormone derived from adipose tissue, known as the regulator of food intake and body energy expenditure, is mediated by hypothalamus (18, 19) and is necessary for proper functioning of reproductive system (20). this hormone is generated in excess in obese people, contributing to a decrease in androgens and altering male fertility (20). it should be mentioned that obesity is positively associated with a hyperinsulinemic state, which suppresses the production of androgen transporting proteins, such as sex hormone-binding globulin (shbg) and decreases circulating testosterone levels (21). the main component of adipose tissue are adipocytes, specialized cells that can secrete various adipokines, such as tumor necrosis factor a (tnf-a), interleukin 6 (il-6), and tissue factor (18). some of these adipokines have been linked to infertility, testicular cancer, and chronic inflammatory conditions (22). constant inflammation leads to a release of reactive oxyoverweight and obesity: the allies of prostate inflammation juan sebastián moncada lópez, jenniffer puerta suárez, walter darío cardona maya grupo reproducción, facultad de medicina, universidad de antioquia, medellín, colombia. key words: obesity; prostate; fertility; antioxidants; semen. submitted 14 february 2022; accepted 17 february 2022 doi: 10.4081/aiua.2022.1.126 127archivio italiano di urologia e andrologia 2022; 94, 1 prostate inflammation and overweight gen species (ros) and reactive nitrogen species (rns) (23), which generate direct toxic effects (oxidative stress) on sperm, altering conventional seminal parameters such as concentration, motility, and morphology (24) and increases dna damage to sperm and its membrane (25), composed mostly of polyunsaturated fatty acids, which give it fluidity, but also high susceptibility to oxidative stress, due to production of reactive aldehydes, which react with aminoacids, and can even alter mitochondrial function (26). as therapy against oxidative stress, there are antioxidants, which normalize spermatozoa's functioning altered by ros and rns, becoming used as therapy in cases of chronic prostatitis and male infertility (27, 28). there is scientific evidence that supports the hypothesis that sperm are protected from oxidative stress thanks to antioxidants present in seminal plasma (29). some examples of these therapeutic alternatives are superoxide dismutase, catalase, coenzyme q10, carnitine/l-carnitine, vitamin e, isoflavones and green tea (30). analysis of our data to analyze the relationship between prostatitis, obesity, and oxidative stress, a geometric representation of the information obtained from 40 volunteers with a bmi greater than 25 was made through principal component analysis (pca) using prism 9.0 statistical software (graphpad software, san diego, ca, usa) (figure 1). the group included fourteen men with chronic prostatitis symptoms and twenty-six men asymptomatic for urogenital infections. the variables were the ones related to oxidative stress, including sperm membrane lipid peroxidation, antioxidant capacity in serum and semen, production of reactive oxygen species and body mass index. conclusions this analysis showed that 73.1% of controls were located on the lower side, and 64.3% of the patients were located on the top of the graph. indicating that subjects with chronic prostatitis symptoms present a particular distribution of semen parameters compared to asymptomatic controls, which supports the relationship of oxidative stress with prostatitis. in conclusion, prostatitis and obesity are pathologies that are entirely related to male fertile state, and in cases of infertility they should be considered as etiological factors. both coincide in the production of an inflammatory condition, altering sperm function. this damage can be lessened with antioxidant supplementation, an option that should not be ruled out as a therapeutic alternative. finally, future studies that link prostatitis, obesity, and antioxidants may help developing strategies that could allow us to continue assessing importance of male sexual and reproductive health. acknowledgments jsml and jps were supported by a fellowship from minciencias. references 1. zegers-hochschild f, adamson gd, de mouzon j, et al. the international committee for monitoring assisted reproductive technology (icmart) and the world health organization (who) revised glossary on art terminology, 2009. hum reprod. 2009; 24:2683. 2. jungwirth a, giwercman a, tournaye h, et al. european association of urology guidelines on male infertility: the 2012 update. eur urol. 2012; 62:324. 3. restrepo b, cardona maya w. anticuerpos antiespermatozoides y su asociación con la fertilidad. actas urol esp 2013; 37:571. 4. mayorga-torres bj, camargo m, agarwal a, et al. influence of ejaculation frequency on seminal parameters. reprod biol endocrinol. 2015; 13:47. 5. barazani y, katz bf, nagler hm, stember ds. lifestyle, environment, and male reproductive health. urol clin north am. 2014; 41:55. 6. wise la, cramer dw, hornstein md, et al. physical activity and semen quality among men attending an infertility clinic. fertil steril. 2011; 95:1025. figure 1. principal component analysis. the principal component 1, x-axis in figure 1, is considered as the principal axis, because it presented the highest coefficient of variability within the system, with a value of 32.4%, while the principal component 2, collected 24.2% of the variability of the data. archivio italiano di urologia e andrologia 2022; 94, 1 j.s. moncada lópez, j. puerta suárez, w.d. cardona maya 128 7. carlsen e, giwercman a, keiding n, skakkebaek ne. evidence for decreasing quality of semen during past 50 years. bmj. 1992; 305:609. 8. condorelli ra, russo gi, calogero ae, et al. chronic prostatitis and its detrimental impact on sperm parameters: a systematic review and meta-analysis. j endocrinol invest. 2017; 40:1209. 9. williams dht, karpman e, sander jc, et al. pretreatment semen parameters in men with cancer. j urol. 2009; 181:736. 10. chavarro je, toth tl, wright dl, et al. body mass index in relation to semen quality, sperm dna integrity, and serum reproductive hormone levels among men attending an infertility clinic. fertil steril. 2010; 93:2222. 11. krieger jn, lee sw, jeon j, et al. epidemiology of prostatitis. int j antimicrob agents. 2008; 31 suppl 1:s85. 12. sallmen m, sandler dp, hoppin ja, blair a, baird dd. reduced fertility among overweight and obese men. epidemiology. 2006; 17:520. 13. cabler s, agarwal a, flint m, du plessis ss. obesity: modern man's fertility nemesis. asian j androl. 2010; 12:480. 14. wallner lp, clemens jq, sarma av. prevalence of and risk factors for prostatitis in african american men: the flint men's health study. prostate. 2009; 69:24-32. 15. parikesit d, mochtar ca, umbas r, hamid ar. the impact of obesity towards prostate diseases. prostate int. 2016; 4:1. 16. parazzini f, artibani w, carrieri g, et al. effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: results from the 2018# controllati survey. arch ital urol androl 2019; 91:245. 17. roth my, amory jk, page st. treatment of male infertility secondary to morbid obesity. nat clin pract endocrinol metab. 2008; 4:415. 18. trayhurn p, beattie jh. physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. proc nutr soc. 2001; 60:329. 19. bhat gk, sea tl, olatinwo mo, et al. influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse. j androl. 2006; 27:302. 20. isidori am, caprio m, strollo f, et al. leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. j clin endocrinol metab. 1999; 84:3673. 21. tewari r, rajender s, natu sm, et al. diet, obesity, and prostate health: are we missing the link? j androl. 2012; 33:763. 22. bialas m, fiszer d, rozwadowska n, et al. the role of il-6, il-10, tnf-alpha and its receptors tnfr1 and tnfr2 in the local regulatory system of normal and impaired human spermatogenesis. am j reprod immunol. 2009; 62:51. 23. fraczek m, kurpisz m. inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa. j androl. 2007; 28:325-33. 24. agarwal a, sharma rk, nallella kp, et al. reactive oxygen species as an independent marker of male factor infertility. fertil steril. 2006; 86:878. 25. mayorga-torres bjm, camargo m, cadavid ap, et al. are oxidative stress markers associated with unexplained male infertility? andrologia. 2017; 49. 26. agarwal a, rana m, qiu e, et al. role of oxidative stress, infection and inflammation in male infertility. andrologia. 2018; 50:e13126. 27. ross c, morriss a, khairy m, et al. a systematic review of the effect of oral antioxidants on male infertility. reproductive biomedicine online. 2010; 20:711. 28. benatta m, kettache r, buchholz n, trinchieri a. the impact of nutrition and lifestyle on male fertility. arch ital urol androl 2020; 92:121. 29. agarwal a, saleh ra, bedaiwy ma. role of reactive oxygen species in the pathophysiology of human reproduction. fertil steril. 2003; 79:829. 30. ihsan au, khan fu, khongorzul p, et al. role of oxidative stress in pathology of chronic prostatitis/chronic pelvic pain syndrome and male infertility and antioxidants function in ameliorating oxidative stress. biomed pharmacother. 2018; 106:714. correspondence juan sebastián moncada lópez, microbiol. jsebastian.moncada@udea.edu.co jenniffer puerta suárez, phd jenniffer.puerta@udea.edu.co walter darío cardona maya, phd (corresponding author) wdario.cardona@udea.edu.co grupo reproducción, facultad de medicina, universidad de antioquia, medellin (colombia) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 review patch grafts placement, urinary derivations, positioning of nephrostomies and even nephrectomy (2), other lessinvasive techniques can be offered to these patients. embolization with bypass (3), transurethral occlusion using the gianturco coil (4), and the endovascular treatment represent useful and safe less-invasive techniques that are considered as a valid alternative to the surgery, mostly for patients with important comorbidities and history of previous pelvic surgery (5), although no long term follow up has been published to assess the possible complications arising from this kind of techniques, such as prosthetic infections. on the other hand, to obtain a precise and early diagnosis represents another important factor in terms of reducing mortality of these patients. the clinical presentation of the auf is not always immediately suggestive. it can complicate the history of patients affected by many kinds of pathological conditions (urological, gynecological, vascular, etc.) and present with heterogeneous symptomatology (such as massive or intermittent hematuria, flank pain, hydronephrosis, fever, acute urinary retention, anemia until hypovolemic shock). only 22% of these patients received a correct diagnosis before treatment (6). from a pathogenetic point of view, aufs are classified into primary (15%) and secondary (85%) on the basis of their etiology (15). primary causes are natural diseases of the arterial system such as aneurysms, vascular malformations, or aberrant vessels that may erode into the ureter (7-20). secondary aufs are relatively more frequent developing in patients with specific risk factors, such permanent ureteral stenting with periodic replacements, previous abdominal or pelvic radiotherapy, previous abdominalpelvic and vascular surgery, and changes in the micro circulation of major vessels (8-10). pelvic surgery (89%) combined with radiation (43%) and with ureteral stent placement (67%) leads to inflammation and fibrosis that, in turn, result in fixation of the ureter to the adjacent artery (8). radiation damage of the vasa vasorum of the iliac artery or aorta can cause ischemic injury to the arterial wall, being the severity of the ischemic injury radiation dose dependent (21). in addition, the ureteral stent causes abrasive erosion of the ureteral wall. many of those patients are also taking anticancer biotherapies that impair the normal healing processes (22, 23). high arterial pressure is transmitted by the juxtaposed arterial to the ureteral wall resulting in pressure necrosis and fistula objectives: arterio-ureteralfistula (auf) is an infrequent but potentially life-threatening condition. the aim of this study was reviewing the literature to build a flow-chart useful for an early and effective diagnosis and treatment of this pathology. materials and methods: a literature search in pubmed was conducted. in addition, retrieved articles were cross-referenced. data parameters included oncologic, vascular and urological history, diagnostics, treatment, and follow up were collected using a standard template by 2 independent reviewers. results: a total of 140 cases of auf out of 172 available in the literature at the time of the review, were considered. all patients presented gross hematuria. chronic indwelling ureteral catheter (ciuc); history of pelvic surgery (hps) and history of pelvic radiotherapy (hrt) were present respectively in 81%, 62.1% and 58.6% of the sample. the most predominant location of auf was at the common iliac artery ureteral crossing. angiography with provocative measures had the highest diagnostic sensitivity (50%) and endovascular treatment with stentgraft placement across the fistula is the current state of the art treatment choice. conclusions: failure to diagnose can postpone a potentially lifesaving targeted therapy and lead to complications. the identification of the trifecta hematuria, history of pelvic surgery (hps) and history of pelvic radiotherapy (hpr) would allow the identification of patients at high risk of auf, who may benefit from more sensitive early diagnostic investigations such as ct angiography and provocative angiography. the treatment of choice in case of auf to date consist in endovascular prosthesis placement. key words: hematuria; stents; urinary fistula; arterioureteral fistula; endovascular procedures; angiography. submitted 11 october 2022; accepted 3 november 2022 introduction arterioureteral fistulas (aufs) represent infrequent but potentially life-threatening conditions, due to a pathological communication between artery and the ureter, with consequent hematuria. the first case described in literature dates back to 1908 and was reported by moschowitz, who treated the patient with bilateral ligation of the external iliac arteries (1). nowadays, more advanced therapeutic possibilities are certainly available. beyond the classic “open” approaches, including vascular ligations, early diagnosis and management of arterio-ureteral fistulas: a literature review pier paolo prontera 1, carmine sciorio 2, antonio de cillis 1, evangelista martinelli 1, francesco schiralli 1, marco lattarulo 1, angelo d’elia 1, emanuele utano 1, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto, italy; 2 department of urology, “alessandro manzoni” hospital, lecco, italy. doi: 10.4081/aiua.2023.10928 summary archivio italiano di urologia e andrologia 2023; 95, 1 p.p. prontera, c. sciorio, a. de cillis formation (14, 8). a third condition, pregnancy-associated auf, has been reported in three cases (15) that occurred in pregnant patients with severe urinary tract infection before the era of modern antibiotics (15). most authors recognize chronic indwelling ureteral stents, pelvic surgery, pelvic radiotherapy, iliac artery pseudoaneurism and systemic chemotherapy, as the most important risk factors related to aufs development (1-12). according to this evidence and considering the clinical heterogeneity related to the aufs’ presentation, the early identification of the specific risk factors and the immediate use of the most sensitive and specific diagnostic tools, could allow the clinicians to quickly obtain a correct diagnosis, reducing the high mortality related to this pathology (ranging from 7 to 38% according to some authors) (12, 13) and due to the consequent hemodynamic instability. the end point of the present study is to propose a a diagnostic-therapeutic flowchart based on personal experience and the analyses of the data from literature review from 1978 and 2019, in order to improve the sensibility and specificity of the aufs’ diagnostic evaluation, searching for suggestive clinical and anamnestic elements useful to achieve a correct diagnosis and a consequent specific treatment as timely as possible. materials and methods the research was carried out through pubmed database. authors found 172 articles regarding aufs, published from 1978 to 2019 (supplementary materials), using the following keywords: “fistula”, “ureteroarterial”, “arterioureteral”. both urological and radiological papers were considered. exclusion criteria were: 1) aufs in patients who underwent renal transplantation; 2) aufs in in animals; 3) articles reporting not-extractables data. age, gender, primary disease, previous surgery, risk factors (such as chronic indwelling ureteral stents, pelvic surgery, pelvic radiotherapy, iliac artery pseudo-aneurism and systemic chemotherapy), diagnosis methodology, type of treatment, follow-up data and specific mortality, have been evaluated. the review was performed using microsoft excel worksheet and prism-graphpad software. from the literature review presented with this manuscript, 172 articles have emerged based on title and abstract. of these, 32 were excluded, because they didn’t meet the inclusion criteria. the remaining 140 articles were included in the present study (figure 1) (24). the literature review and data extraction were performed concurrently by 2 investigators in order to reduce bias. figure 1. prisma 2020 flow diagram. archivio italiano di urologia e andrologia 2023; 95, 1 arterio-ureteral fistulas results eighty-two out of 140 (58.6%) patients with auf were females and the remaining 58 (41.4%) were males. mean age of patients was 63 years (range 29-87); mean age in women was 59 and mean age in men was 69. primary disease associated with aufs stratifying the cohort by “primary disease” (table 1) it emerged that gynecological cancer was the most frequent cause of aufs (37.9%), followed by rectum/sigmoid cancer (20.7%), vascular disease (20%), low-urinary tract cancer (13.6%) and, finally, other kind of pelvic surgery (7.8%), including lithotomy for ureteral lithiasis, pelvic exenteration for sarcoma, surgical repair for slipped disc, surgery for melanoma, ileo-colic resection for lymphatic malignancy, left leg amputation for ischemia, left ureteral stenosis, robot assisted nephrectomy for nephrolithiasis, fistula on the ureteral stump after bilateral nephrectomy for chronic pyelonephritis and retro-peritoneal fibrosis. risk factors for aufs among the risk factors, the most relevant is the chronic indwelling ureteral catheter (ciuc) that is present in 81% of patients with auf and hematuria (table 2). the association of the presence of ciuc and auf was observed more frequently in women (64.3%) than in men (35.7%) and in the 70-79 years group (32.1%), followed by the 60-69 years group (23.2%) and the 50-59 years group (22.3%). furthermore, out of 140 patients with auf 82 had an history of pelvic radiotherapy (hpr) and 36 of chemotherapy. hpr was observed more frequently in women (74.4%) than in men (25.6%). the distribution by age group did not show significant difference among different age groups. another risk factor strongly associated to the presence of fistula and hematuria is the history of pelvic surgery (hps) that was observed in 62.1% of the sample of which 64.4% were women and 35.6% men. the association between hps and the presence of auf was observed more frequently in the 70-79 years group (35.6%) followed by the 50-59 years group (24.1%) and the 60-69 years group (19.5%). symptoms all patients presented gross hematuria, and 49 of them (35%) experienced gross hematuria as an emergency. this critical event was associated to the ureteral stent exchange procedure and/or to ureteral maneuvers in 39 case reports (27.8%). only ten patients (7.1%) developed a spontaneous aggravation of the hematuria, 6 (4.3%) of which presented a history of endoprosthesis implantation for vascular disease. hydronephrosis or flank pain without mention of hydronephrosis was observed in 46 cases (32.8%), 22 of them (15.7%) being previously treated with rt; 15 pts. (10.7%) who presented this pathological condition had chronic indwelling ureteral stent. fever and/or urinary tract infections were found in 17 pts. (12.1%), out of them nine (6.4%) had concomitant hydronephrosis (table 3). diagnostic work up after hematuria recognition, urethro-cystoscopy was performed in almost all patients, showing blood clots in bladder and pulsatile bleeding from the ureteral meatus. in 103 patients (73.6%) an abdomen-pelvis ct scan was performed, showing an iliac pseudo aneurism in 25 patients (17.8%). ct scan was a definitive diagnostic tool for aufs in 23 cases (22% of all ct scans performed, and 16.4% of all patients). a total of 94 patients (67.1%) underwent diagnostic angiography which in only 44 cases (46.8% of all angiographies performed, and 31.4% of all patients) recognized an auf. the angiographic study shown an iliac pseudo aneurism in 11 pts out of 140 (7.8%). of the 83 (59.2%) retrograde pyelograms performed, 39 (46.9% of all pyelograms and 27.8% of all patients) were diagnostic. the most sensible examination for the aufs detection was angiography with provocative maneuvers. provocative angiography was described and defined as manipulation of ureteral stent or vascular catheter at the site of suspected auf. in 15 of 30 cases provocative angiography was helpful to confirm the diagnosis of auf, representing the most sensitive diagnostic tool available at the state of art (25). a diagnostic ureteroscopy (urs) was performed in 68 pts. (48.6%), but only in 3 cases (4.4%) it was really diagnostable 1. primary disease associated with aufs. n° % gynecological cancer 53 37.9 rectum/sigmoid cancer 29 20.7 vascular disease 28 20 low-urinary tract cancer 19 13.6 other kind of pelvic surgery 11 7.8 table 2. risk factors for aufs. n° % vascular surgery 36 25.7 pelvic surgery 87 62.1 radiotherapy (rt) 82 58.6 chemotherapy (cht) 36 25.7 chronic indwelling ureteral catheter (ciuc) 114 81.4 pelvic surgery+cht+rt 31 22.1 pelvic surgery+rt+stenting (trifecta) 76 54.3 table 3. symptoms. n° % gross hematuria 140 100 hematuria during stent manipulation 39 27.8 hydronephrosis 28 20 flank pain (with no mention of hydronephrosis) 18 12.8 fever ivu 17 12.1 archivio italiano di urologia e andrologia 2023; 95, 1 p.p. prontera, c. sciorio, a. de cillis tic, because of the poor vision due to the massive intraureteral bleeding (table 4). table 5 and 6 present the number and rate of aufs diagnosed by different diagnostic procedures divided by gender and class ages. location of aufs the distribution of the site of aufs was as follow: 56 cases (40%) involved r-cia (right common iliac artery), 44 cases (31.4%) involved l-cia (left common iliac artery), 11 cases (7.8%) involved r-eia (right external iliac artery), 9 cases (6.4%) involved l-iia (left internal iliac artery), 7 cases (5%) involved r-iia (right internal iliac artery) and 6 cases (4.3%) involved l-eia (left-external iliac artery). in 7 patients (5%) aufs interested other arteries, different from the iliac axis (including mesenteric artery and hypogastric arteries) (figure 2). treatment the most commonly used procedure was the endovascular prosthesis implantation, that was performed in 81 cases (57.1%) (table 7). it was followed, in decreasing order of frequency, by surgical “open” vascular repair in 43 cases (30.7%), open nephrectomy with main renal artery embolization in 23 cases, and coil embolization of vascular segment in 20 cases (14.3%) (table 8). out of them secondary treatments have been performed in 38 cases including 9 patients (6.4%) who underwent “open” nephrectomy after an endovascular treatment and others 3 patients received a coil embolization of the ureteral stump after a nephrectomy (table 9). table 5. auf diagnosed by different diagnostic procedures by gender. gender diagnosis f m total angiography 23.0 21.0 44.0 52.27 47.73 (%) ct scan / angio tc 8.0 15.0 23.0 34.78 65.22 (%) provocatory angiography 11.0 4.0 15.0 73.33 26.67 (%) retrograde pyelogram 28.0 11.0 39.0 71.79 28.21 (%) urs 4.0 1.0 5.0 80.00 20.00 (%) frequency missing = 315 table 6. auf diagnosed by different diagnostic procedures by age. class age diagnosis < 40 40-49 50-59 60-69 70-79 > 80 total angiography 5.0 0.0 12.0 8.0 18.0 1.0 44.0 11.36 0.00 27.27 18.18 40.91 2.27 (%) ct scan/angio tc 1.0 1.0 6.0 2.0 10.0 3.0 23.0 4.35 4.35 26.09 8.70 43.48 13.04 (%) provocatory angiography 1.0 0.0 2.0 5.0 5.0 2.0 15.0 6.67 0.00 13.33 33.33 33.33 13.33 (%) retrograde pyelogram 4.0 4.0 10.0 11.0 7.0 3.0 39.0 10.26 10.26 25.64 28.21 17.95 7.69 (%) urs 0.0 0.0 1.0 3.0 1.0 0.0 5.0 0.00 0.00 20.00 60.00 20.00 0.00 (%) frequency missing = 315 table 4. diagnostic work up. n° tot % auf cases auf cases diagnosed diagnosed n° (%) in the total population ct 103 73.6% 23/103 (22.3%) 16.4% angiography 94 67.1% 44/94 (46.8%) 31.4% provocatory angiography 30 21.4% 15/30 (50%) 10.7% retrograde pyelogram 83 59.2% 39/83 (46.9%) 27.8% urs 68 48.6% 3/68 (4.4%) 2.1% figure 2. location of aufs. r: right; l: left; cia: common iliac artery; eia: external iliac artery; iia: internal iliac artery. table 7. treatment n = 178. n° % open nephrectomy/renal artery embolization 23 16.4 open vascular repair 43 30.7 coil embolization of vascular segments 20 14.3 endoprosthesis 81 57.1 coil embolization of ureteral stump 3 2.1 ablation of residual ureteral stump after nephrectomy 8 5.7 table 8. secondary treatment n = 38. n° % endovascular treatment after “open” nephrectomy as first approach 26 18.6 coil embolization of ureteral stump after “open” nephrectomy as first approach 3 2.1 “open” nephrectomy after an endovascular treatment as first approach 9 6.4 table 9. recurrence. n° % (average time to relapse) 12 (8 months) 8.5 archivio italiano di urologia e andrologia 2023; 95, 1 arterio-ureteral fistulas after treatment, 12 patients (8.5%) experienced a recurrence in the follow up, with mean recurrence-time of 8 months. most of them were treated with a endovascular prosthesis implantation, only in two cases the retreatment was made by an “open” repair (table 10). table 11 and 12 show the different procedures divided by gender and class age. mortality authors found a global mortality of 11.4% (16 pts.). in particular, 7 pts. (43.7% of total deaths) were treated with “open” surgery as first approach, 6 pts. (37.5% of total deaths) were treated with coil embolization of a vascular segment, and just 3 pts. (18,75% of total deaths) were not treated but died for hemodynamic complications. case report a 77-years old woman was followed at our urology unit for chronic indwelling ureteral catheter and periodical substitution due to a right ureteral stenosis. in 2012 she underwent an end-to-end ureteral anastomosis due to a ureteral injury during a retroperitoneal surgery for malignant melanoma. furthermore, she had an aortobilateraliliac bypass graft because of an aortic aneurysm. in january 2020, she was admitted in our unit for periodic replacement of the ureteral jj-stent as usual. this time the ureteral stent was calcified, so uretherolitotripsy had to be done first. no problem was encountered during the procedure. a month later she returned for hematuria. the ureteral stent appeared dislocated. the replacement attempt was unsuccessful; therefore, a nephrostomy was placed (figure 2). a few days later, she came back again in the emergency room and was admitted for the occurrence of anemia and hematuria both from nephrostomy and from bladder catheter. at admission in our department, she was hemodynamically stable, although intermittent hematuria was present. a ct scan revealed the presence of clots in the pelvis and calyces and the bladder, with no active vascular bleeding. at first, a conservative management was considered with the administration of several blood transfusions due to the persistent anemia and the adjustment of the anticoagulant therapy with low molecular weight heparin (lmwh). however, intermittent hematuria persisted, and repeated ct scans remained unremarkable. we decided to examine in depth the cause of bleeding and to perform a right ureteroscopy. during this procedure ureteral bleeding was observed, so we opted for a nephrectomy. during an open nephrectomy was observed that the ureter was imprisoned in a tenacious fibrous tissue at the level of the iliac cross. unfortunately, intermittent hematuria recurred after few days. the ct scan and angiography showed no bleeding sources and there was no indication for a radiotherapy for hemostatic purposes. with the radiologists, we performed a provocative maneuver: a 5 fr ureteral catheter was placed in the residual ureteral stump and a retrograde pyelography was performed; a subsequent selective angiography of the right iliac vessels revealed the presence of a fistula between the right ureter and the right common iliac artery prosthesis. from an ipsilateral femoral access, a flush catheter was positioned proximal to the suspected uaf. a covered 11 mm × 5 mm viabahn vascular stent graft (gore® viabahn endoprosthesis) was placed in the right common and external iliac artery. after a few days, about one month later the last ureteral stent replacement, the patient no longer had hematuria and the hemoglobin was rising, therefore she was discharged. she had no recurrence of hematuria or fistula in follow-up. she is still in good condition today. discussion arterioureteral fistulas (aufs) represent infrequent but potentially life-threatening conditions. in most of cases they have a subtle clinical presentation causing a delayed diagnosis. even if gross hematuria is present in all of cases, only in 35% of these there is an emergency set up. in some table 11. different procedures divided by gender. table of treatment by gender gender diagnosis f m total coil embolization of ureteral stump 3.0 0.0 3.0 100.00 0.00 (%) coil embolization of vascular segment 15.0 5.0 20.0 75.00 25.00 (%) endoprosthesis 49.0 32.0 81.0 60.49 39.51 (%) nephrectomy or renal embolization 13.0 10.0 23.0 56.52 43.48 (%) open repair as first approach 21.0 22.0 43.0 48.84 51.16 (%) residual ureteral stump after nephrectomy 6.0 2.0 8.0 75.00 25.00 (%) frequency missing = 2 table 12. different procedures divided by class age. table of treatment by class age class age treatment < 40 40-49 50-59 60-69 70-79 > 80 total coil embolization of 1.0 0.0 1.0 0.0 1.0 0.0 3.0 ureteral stump 33.33 0.00 33.33 0.00 33.33 0.00 (%) coil embolization of 3.0 3.0 3.0 6.0 4.0 1.0 20.0 vascular segment 15.00 15.00 15.00 30.00 20.00 5.00 (%) endoprosthesis 4.0 3.0 23.0 20.0 27.0 4.0 81.0 4.94 3.70 28.40 24.69 33.33 4.94 (%) nephrectomy or renal 1.0 1.0 2.0 6.0 12.0 1.0 23.0 embolization 4.35 4.35 8.70 26.09 52.17 4.35 (%) open repair as first approach 5.0 4.0 7.0 10.0 12.0 5.0 43.0 11.63 9.30 16.28 23.26 27.91 11.63 (%) residual ureteral stump 2.0 0.0 0.0 3.0 3.0 0.0 8.0 after nephrectomy 25.00 0.00 0.00 37.50 37.50 0.00 (%) frequency missing = 2 table 10. retreatment of the recurrence. n° % open vascular repair 2 1.4 endoprosthesis 7 5 death from hemorrhagic shock at the time of the recurrence 3 2.1 archivio italiano di urologia e andrologia 2023; 95, 1 p.p. prontera, c. sciorio, a. de cillis cases of auf there was not enough time to intervene, and the patients died before treatment (3 of 140 in our review, 2.1%). recognizing more common clinical aspects can be the key to achieve an adequate and timely diagnosis. gross hematuria (100%) or hydronephrosis with or without flank pain (32.8%) arising after ureteral stent substitution (27.8%) in a patient with history of chronic indwelling ureteral stent (81%) for previous pelvic surgery with or without radiotherapy is the most common clinical presentation. most of the patients have a history of gynecological (37.9%) or colorectal (20.7%) or bladder (13.6%) cancer or of vascular surgery for the correction of aneurysm (11.4%). the mean time to onset of hematuria from stent placement is 36 months (25). the etiology of secondary auf is not well understood, although a possible mechanism is linked to the erosion secondary to the stent, post inflammatory reaction, and inflammatory reaction in the point of intersection of the vessels with the ureter and it is also due to the mechanical action of the pulsation of the iliac artery. hematuria is often intermittent; in some patients it occurs spontaneously and in others at stent change. as usual when in front of a gross hematuria, cystoscopy and contrasted ct scan are the first investigations to search the cause of bleeding. other exams reported are angiography, retrograde pyelogram, ureteroscopy and provocative angiography. matsunaga et al. in 2020 proposed an algorithm for diagnostic and therapeutic management of ureteroarterial fistula (uaf) in the setting of ileal conduit urinary diversion (16), however, according to our review of the literature, a universal flow chart of investigations still does not exist. therefore, recurrent negative investigations can delay the diagnosis and lead to inappropriate treatments or even to the exitus. even if ct-scan results negative, an arterial-ureteral fistula must be suspected in patients with gross or intermittent hematuria and presenting specific risk factors, like chronic indwelling urethral catheter (ciuc), history of pelvic surgery (hps) and history of pelvic radiotherapy (hpt). the early recognition of this trifecta, according to the literature, can be helpful for smoother diagnostic orientation and consequent early treatment. an immediate multidisciplinary approach involving the urologist, the interventional radiologist and the vascular surgeon could be the best choice. in fact, the most sensitive test for diagnosis of aufs is the angiography concomitant to a provocative procedure (retrograde pyelogram). clinicians should prepare the patient to undergo to simultaneous retrograde pyelogram and angiography with subsequent endoprosthesis implantation. the common iliac artery is the most frequent localization. an “open” repair attempt and nephrectomy should be avoided, when possible, because they may result very challenging due to the previous pelvic surgery and radiotherapy. furthermore, laparotomic approaches have the highest mortality rate and nephrectomy may not be conclusive because the ureteral stump remains. in this last case, a second procedure is necessary, and coil embolization of the ureteral stump is a good option. management of auf has evolved from open repair to minimally invasive modalities owing to the development of stent-grafts and the higher morbidity and mortality associated with definitive surgical repair in a hostile anatomic environment. accordingly, endovascular and endoureteral treatment modalities compare favorably with surgical approaches in terms of uaf-related mortality (7.1% vs 13.3%) and complication rates (28.6% vs 26.7%). these findings mirror results from smaller previous studies analyzing all the forms of treatment of uaf and suggesting the noninferiority of endovascular treatment compared with surgical approaches (6; 13-15, 26). reinterventions after endovascular and endoureteral procedures were largely secondary to fistula recurrence or hemorrhage or to stent occlusion or infection within the first 6 months. although recurrence or hemorrhage and stent occlusion may be managed with repeat endovascular reintervention, stent infection has historically required explantation and conversion to an extra anatomic bypass to definitively remove the infectious nidus and prevent additional complications. from the review proposed, it is not possible to evaluate adequately the long-term efficacy of the various treatments because of the heterogeneity of follow up adopted by authors. the most frequent treatment performed is the placement of endoprostheses. it was proposed to 81 patients and 56 of these underwent a follow-up (16 months of mean follow-up) with a relapse rate of 12.5% (7/56 patients) and a mean time to relapse of 14 months. coil embolization treatment was performed in 20 patients (14.3% of the sample); of these only 14 underwent follow up (mean follow up 11.6 months) with 2 recorded relapses (relapse rate 14% at an average time of 8 months). the small size of data does not allow a satisfactory statistical analysis although from the sample examined the treatment with coil embolization has a higher relapse rate than the treatment with endoprosthesis. nowadays angiography with provocative measures has the highest diagnostic benefit and endovascular treatment with stent-graft placement across the fistula is the current state of the art choice for treatment (23). the advantage of a correct and fast diagnosis are the preservation of overall renal function (no nephrectomy needed) and the reduction in management costs. a universal diagnostic-therapeutic flowchart could be a useful diagnostic tool in order to offer an early diagnosis and effective treatment (figure 3). the diagnosis of auf must be a diagnosis of exclusion. the first step should be the correct collection of clinical history, physical examination, and performing of abdominal ultrasound. the exclusion of “macroscopic” sources of lower urinary tract bleeding is the first diagnostic goal in case of massive and intermittent hematuria. in patients without hemodynamic instability immediate angio-ct with urogram should be performed. from the analysis of the literature data, we have verified that angio-ct has not a high predictive diagnostic power for auf. in patients with gross or intermittent hematuria and the presence of trifecta the clinical suspicion of auf is strong. in case of negative angio-ct we propose the contextual and immediate execution of a provocative angiography. archivio italiano di urologia e andrologia 2023; 95, 1 arterio-ureteral fistulas in patient with unknown auf the removal of the ureteral stent could trigger massive bleeding and therefore it should be deferred at the time of the placement of the endovascular prosthesis, moreover the presence of a stent and its mobilization could be a diagnostic aid during the provocative angiographic study (figure 4). in presence of a massive hematuria with hemodynamic instability an immediate hemodynamic stabilization and urgent angio-ct, with consequent selective angiography, represent the safest approach. the limitations of the current review include its heterogeneous sample size derived predominantly from retrospective case reports. however, despite these limitations, inferences derived from systematic reviews of case reports and case series are recognized as valid and useful decision-making aid, particularly with uncommon entities such as uaf for which there is an absence of strong evidencedbased recommendations and guidelines (17). conclusions management of aufs may be facilitated by using the aforementioned diagnostic and therapeutic algorithmic approach in a multidisciplinary modality involving interventional radiology, urology, and vascular surgery services. the early recognition of the proposed trifecta (ciuc, hps and hrt) can be helpful for smoother diagnostic orientation and consequent early treatment, performing angio-ct examination and immediate provocative angiography. endovascular and endoureteral modalities afford clinical outcomes comparable with those of surgical approaches but close postprocedural follow-up is required. management of this challenging clinical entity may be facilitated by using a standardized and multidisciplinary diagnostic and therapeutic algorithmic approach. figure 3. flow-chart for early diagnosis and treatment of aufs figure 4. right retrograde ureteropyelography with no spillage (a) in patient with left nephrostomy (b). archivio italiano di urologia e andrologia 2023; 95, 1 p.p. prontera, c. sciorio, a. de cillis references 1. moschcowitz a. simultaneous ligation of both external iliac arteries for secondary hemorrhage following bilateral ureterolithotomy. ann surg. 1908; 48:872-875. 2. quillin sp, darcy md, picus d. angiographic evaluation and therapy of ureteroarterial fistulas. am j roentgenol. 1994; 162:873-8. 3. batter sj, mcgroven fj, cambria rp. ureteroarterial fistula: case report and review of the literature. urology 1996; 48:481-489. 4. inoue t, hioki t, arai y, et al. uretroarterial fistula controlled by intraluminal ureteral occlusion. int j urol. 2002; 9:120-121. 5. titomihelakis g, feghali a, nguyen t, et al. endovascular management and the risk of late failure in the treatment of ureteroaterial fistulas. j vasc surg cases innov tech. 2019; 5:396-401. 6. van den bergh rc, moll fl, de vries jp, lock tm. arterioureterial fistulas: unusual suspects systematic review of 139 cases. urology. 2009; 74:251-255. 7. takahashi y, hirai h, sassari y, et al. successful surgical treatment for rapture of an iliac artery aneurysm into a ureter. ann vasc dis. 2009; 2:58-61. 8. madoff dc, toombs bd, skolkin md, et al. endovascular management of ureteral-iliac artery fistulae with wallgraftendoprostheses. gynecol oncol. 2002; 85:212-217. 9. batter sj, mcgroven fj, cambria rp. ureteroarterial fistula: case report and review of the literature. urology. 1996; 48:481-489. 10. puppo p, perachino m, ricciotti g, et al. ureteroarterial fistula: a case report. j urol. 1992; 148:863-864. 11. subiela jd, balla a, bollo j, et al. endovascular management of ureteroarterial fistula: single institution experience and systematic literature review. vasc endovascular surg. 2018; 52:275-286. 12. das a, lewandoski p, laganosky d, et al. ureteroarterial fistula: a review of the literature. vascular. 2016; 24:203-7. 13. van den bergh rc, moll fl, de vries jp, lock tm. arterioureterial fistulas: unusual suspects systematic review of 139 cases. urology. 2009; 74:251-255. 14. fox ja, krambeck a, mcphail ef, lightner d. ureteroarterial fistula treatment with open surgery versus endovascular management: long-term outcomes. j urol. 2011; 185:945-950. 15. bergqvist d, pärsson h, sherif a. arterio-ureteral fistula: a systematic review. eur j vasc endovasc surg. 2001; 22:191-196. 16. matsunaga f, dambaeva a, ponsky le, et al. systematic review of the management of ureteroarterial fistulas after ileal conduit urinary diversion. ajr am j roentgenol. 2021; 216:1452-1461. 17. murad mh, sultan s, haffar s, bazerbachi f. methodological quality and synthesis of case series and case reports. bmj evid based med. 2018; 23:60-63. 18. bietz g, house a, erickson d, endean ed. diagnosis and treatment of arterial-ureteric fistula. j vasc surg. 2014; 59:1701-1704. 19. takahashi y, hirai h, sasaki y, et al. successful surgical treatment for rupture of an iliac artery aneurysm into a ureter. ann vasc dis. 2009; 2:58-61. 20. giordano g, kyriazi e, mavridis c, et al. oncology and complications. arch ital urol androl. 2021; 93:71-76. 21. himmel pd, hassett jm. radiation-induced chronic arterial injury. semin surg oncol 1986; 2:225-247. 22. krambeck ae, dimarco ds, gettman mt, segura jw. ureteroiliac artery fistula: diagnosis and treatment algorithm. urology. 2005; 66:990-994. 23. tselikas l, pellerin o, di primio m, et al. ureteroiliac fistula: modern treatment via theendo-vascular route. diagn interv imaging. 2013; 94 :311-318. 24. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021; 372:n71. 25. pillai ak, anderson me, reddick ma, sutphin pd, kalva sp. ureteroarterial fistula: diagnosis and management. ajr. 2015; 204:w592-w598. 26. kamphorst k, lock tmtw, van den bergh rcn, et al. arterioureteral fistula: systematic review of 445 patients. j urol. 2022; 207:35-43. correspondence pier paolo prontera, md (corresponding author) pierpaolo.prontera@asl.taranto.it antonio de cillis, md antonio.decillis@asl.taranto.it evangelista martinelli, md francesco schiralli, md marco lattarulo, md marco.lattarulo@asl.taranto.it angelo d.elia, md angelodelia@libero.it emanueleutano, md emanueleutano@libero.it francesco saverio grossi, md phd grossifs@libero.it department of urology, “s.s. annunziata” hospital, taranto (italy) carmine sciorio, md carmine.sciorio@gmail.com department of urology, “alessandro manzoni” hospital, lecco (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3336 original paper no conflict of interest declared. motor disorders such as muscle rigidity, bradykinesia, tremor, many nonmotor symptoms (nms) may occur in these patients such as sleep disturbances, anxiety, depression, sexual and urinary complaints (2, 3). nmss are known to be associated with deterioration of quality of life or the development of major complications such as head trauma and hip fractures. neurogenic lower urinary dysfunction (nlud) is a common disorder in pd patients that seriously affects the patient's daily work (4). in particular, frequent urination, urgency, and incontinence seriously affect the quality of life. it could lead the patient to stay home to get close to the toilet and away from people. it is known that psychiatric problems such as anxiety and depression are more common in parkinson's patients than their healthy peers. the exact cause of psychiatric problems is not known. however, refusal of treatment, deterioration of quality of life, and suicidal thinking can lead to important problems. in our opinion, nlud, which causes significant problems even in healthy people, may be a cause for the development of anxiety and depression in parkinson's patients. the aim of this study was to investigate whether there is a relationship between nlud and psychological problems such as anxiety and depression in pd. materials and methods this study was planned jointly by the neurology and urology clinics of ordu university medical faculty. the files of the patients who were admitted to the movement disorder clinic between 2017 and 2019 with the diagnosis of pd and underwent urological evaluation were evaluated retrospectively. 48 patients who met the study criteria were enrolled in the study. for the diagnosis and severity of parkinson's disease, the uk parkinson's disease society brain bank criteria, the unified parkinson's disease rating scale (updrs) and hoehn-yahr scale (h&y) were used (5, 6). secondary parkinsonism, psychiatric disease or drug use, history of pelvic radiotherapy or prostate, bladder and gynecological surgery, urinary tract infection, drug use related to prostate or bladder in the last 3 months, objectives: parkinson's disease (pd) often presents with movement disorder. however, besides motor complaints, there are many complaints such as anxiety, depression, urinary complaints and constipation. the aim of this study was to investigate whether neurogenic lower urinary dysfunction (nlud), which is frequently seen in pd, has an effect on the development of anxiety and depression in these patients. materials and methods: the study included 32 males (66.6%) and 16 females (33.3%); in total 48 subjects were registered. for the diagnosis and severity of pd, the uk parkinson's disease society brain bank criteria, unified parkinson's disease rating scale (updrs) and the hoehn-yahr scale were used. urological evaluation was performed using history, physical examination, laboratory tests and standard forms such as ipss and oab-v8. results: there was no difference between the genders in terms of duration, severity and nlud (p > 0.05). the incidence of anxiety and depression in pd patients was 62.8% and 72.1%, respectively. the prevalence of nlud was 67.4% and depression and anxiety was found to increase (1.06 and 1.28 times, respectively) in relation to nlud. in particular, there was a relationship between storage lower urinary tract symptoms and anxiety and depression development (p < 0.05). conclusions: as expected, it was found that the incidence of nlud, anxiety and depression was increased in pd. in addition, nlud was found to be a risk factor for the development of anxiety and depression. therefore, it is concluded that nlud, which can potentially cause important complications, as well as motor complaints, should be closely monitored and treated in pd patients. key words: bladder dysfunction; anxiety; depression; parkinson’s disease. submitted 13 may 2021; accepted 25 june 2021 introduction idiopathic parkinson's disease (pd) is a common movement disorder characterized by damage to dopaminergic neurons in the substantia nigra. it is the second most common neurodegenerative disease after alzheimer's disease (1). although the most prominent symptoms of pd are effect of bladder dysfunction on development of depression and anxiety in parkinson’s disease erdal benli 1, fahriye feriha ozer 2, nesrin helvaci yilmaz 3, ozge arici duz 3, ahmet yuce 4, abdullah cirakoglu 1, tuba saziye ozcan 5 1 department of urology, ordu university, faculty of medicine, ordu, turkey; 2 department of neurology, koç university faculty of medicine, istanbul, turkey; 3 department of neurology, istanbul medipol university, faculty of medicine, istanbul, turkey, 4 department of urology, darende hulusi efendi state hospital, malatya, turkey; 5 department of neurology, sancaktepe sehit prof. dr. ilhan varank training and research hospital, istanbul, turkey. doi: 10.4081/aiua.2021.3.336 summary 337archivio italiano di urologia e andrologia 2021; 93, 3 parkinson’s disease and bladder dysfunction patients who could not fill in the questionnaire forms by themselves or with the help of their relatives were excluded. depression and anxiety levels of the patients were determined by hamilton depression (hamd) and hamilton anxiety (hama) scales. the hamd scale consists of 17 questions and the total score is obtained by adding the scores given to each question. the severity of depression is classified according to the total score (0-7 normal, 8-16 moderate depression, > 17 major). the hama scale consists of 14 questions and the total score is obtained by adding scores (0-5 points normal, 6-14 medium, > 14 major) (7). urological evaluation of the patients was performed by a specialist in this field with history, physical examination and necessary laboratory studies. urinary complaints of the patients were evaluated using standard questionnaires such as ipss (international prostate symptom score) and oab-v8 (overactive bladder-v8). ipss is an internationally approved form used to describe the patient's lower urinary tract complaints over the past month. the ipss form evaluates the patient's quality of life (qol) as well as complaints related to storage and voiding. this form consists of 8 questions, 7 related to urinary system complaints and one related to qol. each question is given a score between 0-5. the total ipss score in the range of 0-35 is obtained by summing the answers to 7 questions. according to the total ipss score, luts complaints are classified as mild (07), moderate (8-19), and severe (20-35) (8). the internationally accepted oab-v8 form was used for storage lower urinary tract symptoms. the presence of at least one of the symptoms such as frequent urination, difficulty in urination, urgency and urinary incontinence associated with urgency was considered as oab. this form consists of 8 questions and each question is given a score between 0-5, the total score is obtained by adding these points (9). the study received permission from the local ethics committee (number: 2020/118). statistical analysis statistical analyses were performed using commercial software (excel statistics ver. 20.0). student-t test was used to compare mean values. the effect of urinary symptoms on anxiety and depression scores was evaluated using binary logistic regression test. the relationship between anxiety and depression scores and qol and ipss total scores was evaluated by simple regression and correlation analysis. the p value of < 0.05 was used for statistical significance. results a total of 48 subjects 32 men (66.6%) and 16 women (33.3%) were enrolled in the study. mean age (± std) was 69.84 ± 7.47, mean age by gender was 69.22 ± 7.53 and 71.64 ± 7.13 years for men and women, respectively (not significant difference, p = 0.36). the distribution of disease duration by gender was 5.29 ± 3.76 years for males and 5.64 ± 3.13 years for females (p = 0.78). the distribution of updrs total score by gender was 25.77 ± 15.26 for men and 26.10 ± 9.32 for women (p = 0.95) (table 1). there was no difference between the groups in terms of disease stage (p < 0.05). hamd and hama mean scores were; 22.95 ± 9.79 (1-42) and 8.51 ± 5.12 (1-22) respectively. the prevalence of anxiety and depression in patients with parkinson's disease was 62.8% and 72.1%, respectively. the overall mean score of oab-v8 and ipss was 12.60 ± 7.18 (3-26) and 9.58 ± 6.08 (1-25), respectively. the distribution of hama, hamd, oab-v8, ipss and qol scores by gender is shown in table 2. urinary complaints were present in 67.4% of patients in general and in 68.4% of males and 63.6% of females (p = 0.75). storage lower urinary tract symptoms were found in 61% in general, 62.8% in males and 54.5% in females, respectively (p = 0.72). the prevalence of nocturia was 62.8% in general, 63.5% in women and 62.5% in men (p = 0.94). 83% of the patients had never been evaluated or questioned in terms of urinary complaints before. in general, urinary complaints were correlated with anxiety and depression scores (p < 0.05 for both). the risk of depression and anxiety increased with the presence of urinary complaints (1.06 and 1.28 times, respectively). in subgroup analyses, especially storage lower urinary tract symptoms were associated with anxiety and depression scores (p = 0.04). this complaint increased the anxiety and depression scores by 1.05 and 1.07 times, respectively. the prevalence of nocturia was 62.8%. nocturia was found to be associated with both anxiety and depression (p < 0.05). nocturia increased the risk of anxiety by 1.19 times (table 3). ipss total score was correlated with depression and anxiety (p = 0.03 and p = 0.005, respectively). table 1. demographic distribution of patients. table 2. scores of validated questionnairies of asses depression, anxiety and lower urinary tract symptoms. parameters mean std. dev. p-value hamilton anxiety score men 7.5 4.42 0,06 women 10.72 5.44 hamilton depression score men 22.15 1036 0,42 women 25.10 8.14 ipss total score men 9.78 6.24 0,717 women 9 5.76 q-life skor men 2.41 1.60 0,46 women 2 1.54 oab men 11.94 7.02 0.61 women 13.45 8.75 parameters mean std. dev. p-value average age men 69.22 7.53 0.36 women 71.64 7.13 disease duration men 5.29 3.76 0.78 women 5.64 3.13 age of onset of disease men 63.84 8.85 0.47 women 66 7.62 updr total men 25.77 15.26 0.95 women 26.10 9.32 archivio italiano di urologia e andrologia 2021; 93, 3 e. benli, f. feriha ozer, n. helvaci yilmaz, o. arici duz, a.yuce, a. cirakoglu, t. saziye ozcan 338 total ipss score increased the risk of depression and anxiety 1.1 fold. there was a relationship between quality of life score (qol) and depression and anxiety (p = 0.03 and p = 0.03), which increased the risk of anxiety and depression (0.9 and 1.5 times), respectively. discussion parkinson 's disease is a multi-systemic disease which is associated with autonomic dysfunction (especially gastrointestinal problems such as constipation and sexual problems such as urinary and erectile dysfunction), anxiety, depression, sleep disturbance as well as motor complaints. the risk of developing at least one nms in these patients is close to 100% (10). in our patients, urologic problems, such as urinary complaints, and psychiatric disorders, such as anxiety and depression, were commonly observed. during daily practice, most pd patients are monitored only for motor complaints and they receive treatment in this regard. in other words, urinary problems are neglected. our study results support this view. most of our patients (83%) had never been evaluated for nlud before. patients considered nlud as the natural consequence of this disease. the results of the study conducted by gallagher and colleagues also support our conclusions. in this study, nms incidence and their treatment rates in pd patients were examined. as a result of the study, it was found that one patient had an average of 11 nms and only 5 of them received treatment (11). consequently, it was shown that problems other than motor symptoms are frequently neglected in pd patients. studies have shown that nlud is a more common nonmotor disorder in pd patients than in the control group (12). the reason for this is not known exactly. rate of nlud has been reported in the range of 38-71% in the literatüre (13). in our study, the incidence of nlud was 67.4%. oab which is composed of storage lower urinary tract symptoms such as frequent urination, urgency and incontinence is the most common disorder in this patient group. uchiyama et al. reported the incidence of oab as 64% (14). in our study, this rate was 61%. dopaminergic system and autonomic nerve dysfunction in the substantia nigra which is disrupted in pd may be the cause of this pathology (15). when pd deteriorates, the quality of life is affected due to pd because the patient becomes dependent on other people but also because suffers from urinary dysfunction. problems are amplified by a domino effect. for example, nocturia, urgency and fear of urinary incontinence can cause significant problems in the patient's daily life. the daily activities of the patients must be planned in a way that the patient is always close to an accessible toilet and nocturia can cause insomnia and dizziness and in the elderly the risk of falling at night. thus, the patients start to have problems such as staying at home, loneliness, anger, anxiety, frustration and deterioration of social relations. consequently the quality of life is severely impaired (16, 17). this negative environment may facilitate the development or aggravation of psychiatric problems such as anxiety and depression. in a study on this topic, starkstein et al. examined the relationship between autonomic symptoms and the development of depression. the authors reported that the presence of 3 or more autonomic symptoms is a strong predictor of depression (18). for this reason, the american academy of neurology recommends regular monitoring of nms in adjunct to motor complaints (19). it is known that psychiatric problems such as anxiety and depression in pd are more common (7-80%) than the general population and other chronic neurological diseases such as multiple sclerosis. the exact cause of anxiety and depression in these patients is unknown. it may occur as a part of the neurodegenerative process of pd. nlud, which seriously deteriorates the quality of life, even in normal people, can trigger or worsen psychiatric problems in these patients. according to the result of our study, anxiety and depression rates were 76% and 83%, respectively. in addition, there was a relationship between nlud and anxiety and depression development. these results were consistent with the literature. in a study on this topic, engström et al. examined the relationship between nlud and sadness and joy. the authors reported that patients with urinary complaints felt unhappy and sad about twice as much as the control group (20). in another study, irwin et al. examined the relationship between bladder dysfunction and work life, social environment, and emotional well-being. at the end of the study, they reported that nlud has an effect on social intercourse, productivity in business life and feeling good (21). in another study, brittian et al. examined the relationship between post-stroke depression and bladder complaints. at the end of the study, they reported that urinary complaints increased the risk of depression twice (15% vs. 30%). the authors suggested that nlud should be taken seriously in these patients because of the close relationship between depression and suicide (22). in another study, melvilla et al. reported that the risk of developing depression in women with storage lower urinary tract symptoms increased by 3-4 times (23). in our study, qol was assessed with a question in the ipss questionnaire. there was a correlation between qol and anxiety and depression scores. this result is also important for creating a vicious circle. deteriorating quality of life triggers psychological problems and psychological problems can lead to more deterioration of quality of life. in one study, the relationship between depression and qol was investigated. table 3. changes in anxiety and depression scores with bladder complaints. parameters mean std. dev. p-value mean std. dev. p-value general urinary complaints no 4.55 2.50 0.01 16.11 9.41 0.01 yes 9.50 5.25 25.18 8.93 storage no 6.73 5.67 0.04 18.64 10.41 0.04 yes 10.41 4.96 25.43 8.95 nocturia no 4.69 3.06 < 0.001 18.25 10.83 0.01 yes 10.42 4.90 25.20 8.58 incontinence no 7.33 4.85 0.02 22.73 9.45 0.84 yes 11.16 4.91 23.45 11.03 339archivio italiano di urologia e andrologia 2021; 93, 3 parkinson’s disease and bladder dysfunction the researchers reported that 83% of depression predicted impaired qol (24). in another study by schwarz et al., the relationship between anxiety and depression and hrqol (healthrelated quality of life) was examined. in this study, anxiety and depression were reported as the most important risk factors adversely affecting hrqol (25). when the results of the above study are examined in general, there is an inverse interaction between quality of life and depression and anxiety. therefore, especially in this age group, because of the close relationship between depression and suicide, the causes of depression in pd patients should be investigated and treated. as seen in the results of our study, nlud appears to be an important risk factor for the development of anxiety and depression. in our study, rate of nocturia was found to be 62.8%, and it was also identified as a risk factor for the development of anxiety and depression. sleep disorders may be the basis of the relationship between nocturia and anxiety and depression. in other studies, it was found that sleep disorder frequently develops in pd (19). going to the toilet frequently at night results in a sleep break that may manifest itself with fatigue, dizziness, exhaustion, irritability, and depressive mood. insomnia, which causes significant problems even in normal individuals, can have more serious consequences in pd patients. for this reason, nocturia in these patients should be noticed in a timely manner and necessary precautions should be taken. our study has some limitations. the most important of these is the low number of patients and the retrospective design of the study. in addition, other causes of anxiety and depression were not searched in this study. however, we think that this study is one of the few studies examining the relationship between bladder dysfunction and the development of anxiety and depression in pd. conclusions in conclusion, nms such as neurogenic lower urinary dysfunction, anxiety and depression are common in pd patients. however, in daily practice, clinicians who treat these patients often neglect these symptoms because they are more concerned with motor complaints. according to the results of our study, nlud is a risk factor for the development of anxiety and depression. these patients, whose quality of life is already deteriorated due to pd, should not be exposed to problems related to nlud (such as falling, head trauma due to falls, hip fractures, insomnia, anxiety and depression) and the necessary precautions should be followed closely. patients should not be expected to discuss these complaints, because, as we have seen in our study, these complaints can sometimes be forgotten or considered by patients as a natural part of the disease. references 1. chen jj. parkinson's disease: health-related quality of life, economic cost, and implications of early treatment. am j manag care. 2010; 16:87-93. 2. campos-sousa rn, quagliato em, almeida kj, et al. urinary dysfunction with detrusor hyperactivity in women with parkinson's disease cannot be blamed as a factor of worsening motor performance. arq neuropsiquiatr. 2013; 71:591-595. 3. schrag a, dodel r, spottke a, et al. rate of clinical progression in parkinson's disease. a prospective study. mov disord. 2007; 22:938945. 4. wong sy, hong a, leung j, et al. lower urinary tract symptoms and depressive symptoms in elderly men. j affect disord. 2006; 96:83-88. 5. fahn s, elton rl. unified parkinson’s disease rating scale. in: fahn s, marsden cd, goldsteijn m, calne db, editors. recent developments ın parkinson’s disease. macmillan healthcare information. 1987; 2:153-163. 6. hoehn mm, yahr md. parkinsonism: onset, progression and mortality. neurology. 1967; 17:427-442. 7. maier w, buller r, philipp m, heuser i. the hamilton anxiety scale: reliability, validity and sensitivity to change in anxiety and depressive disorders. j affect disord. 1988; 14:61-68. 8. mcvary kt, roehrborn cg, avins al, et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol. 2011; 185:1793-1803. 9. abrams p, cardozo l, fall m, et al. standardisation sub-committee of the international continence society. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourology and urodynamics. 2002; 21:167-178. 10. moussa m, papatsoris ag, abou chakra m, et al. erectile dysfunction in common neurological conditions: a narrative review. arch ital urol androl. 2020; 92:371-385. 11. gallagher da, lees aj, schrag a. what are the most important nonmotor symptoms in patients with parkinson's disease and are we missing them? mov disord. 2010; 25:2493-2500. 12. benli e, özer ff, kaya y, et al. is there a difference between parkinson disease patients and a control group in terms of urinary symptoms and quality of life? turk j med sci. 2016; 46:1665-1671. 13. sakakibara r, tateno f, nagao t, et al. bladder function of patients with parkinson's disease. int j urol. 2014; 21:638-646. 14. uchiyama t, sakakibara r, yamamoto t, et al. urinary dysfunction in early and untreated parkinson's disease. j neurol neurosurg psychiatry. 2011; 82:1382-1386. 15. yoshimura n, kuno s, chancellor mb, et al. dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-ohda) lesion of the nigrostriatal pathway. br j pharmacol. 2003; 139:1425-1432. 16. campos-sousa rn, quagliato em, almeida kj, et al. urinary dysfunction with detrusor hyperactivity in women with parkinson's disease cannot be blamed as a factor of worsening motor performance. arq neuropsiquiatr. 2013; 71:591-595. 17. brown js, vittinghoff e, wyman jf, et al. urinary incontinence: does it increase risk forfalls and fractures? study of osteoporotic fractures research group. j am geriatr soc 2000; 48:721-725. 18. starkstein se, preziosi tj, forrester aw, robinson rg. specificity of affective and autonomic symptoms of depression in parkinson's disease. j neurol neurosurg psychiatry. 1990; 53:869873. 19. lyons ke, pahwa r. the impact and management of nonmotor symptoms of parkinson's disease. am j manag care. 2011; 12:308314. archivio italiano di urologia e andrologia 2021; 93, 3 e. benli, f. feriha ozer, n. helvaci yilmaz, o. arici duz, a.yuce, a. cirakoglu, t. saziye ozcan 340 20. engström g, henningsohn l, steineck g, leppert j. self-assessed health, sadness and happiness in relation to the total burden of symptoms from the lower urinary tract. bju int. 2005; 95:810-815. 21. irwin de, milsom i, kopp z, et al. impact of overactive bladder symptoms on employment, social interactions and emotional wellbeing in six european countries. bju int. 2006; 97:96-100. 22. brittain kr, castleden cm. suicide in patients with stroke. depression may be caused by symptoms affecting lower urinary tract. bmj. 1998; 317:1016-1067. 23. melville jl, delaney k, newton k, katon w. incontinence severity and major depression in incontinent women. obstet gynecol. 2005; 106:585-592. 24. soh se, morris me, mcginley jl. determinants of health-related quality of life in parkinson's disease: a systematic review. parkinsonism relat disord. 2011; 17:1-9. 25. schwarz j, odin p, buhmann c, et al. depression in parkinson's disease. j neurol. 2011; 258:336-338. correspondence erdal benli, md abdullah cirakoglu, md department of urology, ordu university, faculty of medicine, ordu (turkey) fahriye feriha ozer, md department of neurology, koç university faculty of medicine, istanbul (turkey) nesrin helvaci yilmaz, md ozge arici duz, md department of neurology, istanbul medipol university, faculty of medicine, istanbul (turkey) ahmet yuce, md (corresponding author) ahmetyuce7@gmail.com department of urology, darende hulusi efendi state hospital, malatya, turkey tuba saziye ozcan, md department of neurology, sancaktepe sehit prof.dr. ilhan varank training and research hospital, istanbul (turkey) stesura seveso 285archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. diagnosis: the 5-year survival rate is 100% in patients diagnosed with the earliest stage disease and less than 33% if diagnosed at the latest stage (4-7). screening is the best way for pca early diagnosis and it is recommended to all men with no risk factors over 50 years (8, 9). digital rectal exam (dre) in addition to prostate-specific antigen (psa) blood test is the most used test to screen for pca. according to american urology association (aua), dre has considered a useful tool in men referred for an elevated psa (10). moreover, according to european association of urology (eau) guidelines, in 18% of cases pca is detected by suspect dre alone, irrespective of psa level (11, 12). a suspect dre in patients with a psa level < 2 ng/ml has a positive predictive value (ppv) of 5-30% (13). despite dre usually is not painful and only takes a short time, fear and shame of patients appear as barriers. this is usually due to imagination, beliefs, and fantasies that lead the men to envision the dre as something much more awkward than it is. the lack of knowledge or misinformation could be reversed by more comprehensive information (14, 15). youtubetm is the most well-known online video sharing site with five billion videos watched daily and has such a large and diverse community of users, it could be a media channel for improving public awareness and understanding (16, 17). additionally, over the past 2 years, the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) spread, has made internet consultation a remarkable source of medical information (18-23). several studies have already evaluated the quality of youtube™ videos concerning different medical fields. to the best of our knowledge, no studies on dre were found in the literature. previous studies analyzed youtube™ videos’ quality on urological (20, 21, 24-30) and non-urological topics (31, 32), highlighting a diffuse inaccuracy. no previous investigators evaluated youtube™ videos’ quality on dre as a tool for patients’ information. the current study aimed to assess youtube™ videos’ quality on prostate checks, especially on dre, and to investigate if they can inform patients correctly and eradicate their beliefs and myths. objectives: to assess youtube™ videos’ quality on prostate checks, especially on the digital rectal exam (dre), and to investigate if they can inform patients correctly and eradicate their beliefs and myths. methods: a search using as keywords “digital rectal exam for prostate cancer” was performed on the youtubetm platform. we selected the first 100 videos. to assess video quality content, patient education materials assessment tool for audio-visual content (pemat a/v) and misinformation tool were used. results: seventy-three videos were suitable for the analyses. the median pemat a/v understandability score and pemat a/v actionability score were 46.2% (interquartile range [iqr]: 30.8-76.9) and 50.0% (iqr: 25.0-75.0), respectively. the median pemat a/v understandability and actionability scores were 69.2% (iqr: 46.2-88.5) vs 46.2% (iqr: 30.8-61.5) (p = 0.01) and 100.0% (iqr: 87.5-100.0) vs 25.0% (iqr: 25.0-68.8) (p < 0.001), for healthcare workers vs patients, respectively. according to the misinformation tool, the median misinformation score of the overall videos was 2.2 (iqr:1.7-2.8). according to the target audience, the misinformation score was 2.8 (iqr: 2.4-3.5) vs 2.0 (iqr: 1.5-2.8) (p = 0.02), for healthcare workers vs patients, respectively. conclusions: currently, based on our analyses, youtubetm videos’ quality on dre resulted unsatisfactory according to the pemat a/v score and the misinformation tool. videos targeted to healthcare workers got higher quality scores if compared to videos targeted to patients. therefore, youtubetm videos’ may not be considered a reliable source of information on dre for patients. key words: internet; urology; misinformation; prostate cancer; social media. submitted 13 june 2022; accepted 14 july 2022 introduction prostate cancer (pca) is the most common malignancy among elderly men, with 1 276 000 new diagnoses and 359 000 deaths in 2018 worldwide (1, 2). nowadays, pca burden is expected to grow to almost 2.3 million new cases and 740 000 deaths by 2040 (1, 3). several studies show as survival is closely related to the stage at could youtubetm encourage men on prostate checks? a contemporary analysis simone morra 1, luigi napolitano 1, claudia collà ruvolo 1, giuseppe celentano 1, roberto la rocca 1, marco capece 1, massimiliano creta 1, francesco passaro 1, francesco di bello 1, luigi cirillo 1, carmine turco 1, ernesto di mauro 1, gabriele pezone 1, agostino fraia 1, francesco mangiapia 1, ferdinando fusco 2, vincenzo mirone 1, gianluigi califano 1, nicola longo 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples “federico ii”, naples, italy; 2 urology unit, department of woman, child and general and specialized surgery, university of campania 'luigi vanvitelli', naples, italy. doi: 10.4081/aiua.2022.3.??? summary archivio italiano di urologia e andrologia 2022; 94, 3 s. morra, l. napolitano, c. collà ruvolo, et al. 286 materials and methods search strategy and video selection criteria on april the 14th 2021, from 5.30 p.m to 7.30 p.m (cest), a search using as keywords “digital rectal exam for prostate cancer” was performed on the youtubetm platform. the search was limited to the english language. to avoid research bias, any personal account was logged out and a proxy located in the united states via virtual private network (vpn) software was set. we recorded the first 100 videos displayed by relevance. the following exclusion criteria were applied (figure 1): non-english language videos (n = 5), podcasts (n = 1), commercial purpose videos (n = 3), animal videos (n = 1), videos over 30 minutes (n = 3), off-topic videos (n = 14). if duplicated, only one was considered. we recorded, for all the eligible videos, the following variables: length (seconds), views, persistence on youtubetm (days), thumbs-up (a social media term for like), thumbs-down (a social media term for dislike), number of comments, number of videos with disabled comments, channel subscribers (the people or accounts that are subscribed to the channel), video authors (healthcare workers vs patients vs interviewers), target audience (healthcare workers vs patients), video power index (vpi) estimating video popularity (20). quality and misinformation assessment tools two investigators, a senior (gs) and a junior (sm) urology resident, analysed the quality of the eligible videos, and when in contrast an additional investigator, an associate professor (nl), mediate the disagreement. the quality assessment was performed for the overall eligible videos. patient education materials assessment tool for audio-visual content (pemat a/v) 33 and the misinformation tool were used to assess videos’ quality (16, 20, 24-26). first, the pemat a/v is developed to evaluate how viewers could process the information displayed in the videos and how viewers could use them. it is composed of 17 questions addressing the content understandability (questions 1-13) and actionability (questions 14-17). three answers were permitted (agree = 1, disagree = 0, not available = na). the score of all items is added together, divided by the number of items on which the material was rated, and multiplied by 100 to give a percentage score for understandability and actionability, respectively. there is no set cutoff value for the scores. higher scores detect more understandable and actionable content (31, 33). second, the misinformation tool is a validated tool that explores the grade of video misinformation (16, 20, 24, 26). it consists of 4 questions: “does the video clearly describe the procedure?”, “does the video clearly describe the difference between neoplastic disease and other prostate diseases?”, “does the video give information on the pain during the examination?”, “does the video describe the next steps to be performed after the examination?”. it ranges from 1 (extreme misinformation) to 5 (no misinformation). statistical analyses descriptive statistics were presented as medians and interquartile ranges (iqr) and ranges for continuously coded variables or counts and percentages for categorically coded variables. chi-square and kruskalwallis tested the statistical significance in proportions’ and medians’ differences. potential variables correlations were assessed with pearson's test. in all statistical analyses, the r software (www.rproject.org) environment for statistical computing and graphics (r version 4.0.0) was used. all tests were two-sided with a level of significance set at p < 0.05. results videographic characteristics of all 100 videos, 73 were suitable for the analyses (table 1). the median length was 244 seconds (iqr: 129.0-549.0; range: 38.02541.0). the median number of views was 12954 (iqr: 1780.0-199548.0; range: 31.017141766.0) and the median persistence on youtube™ was 985 days (iqr: 237.02155.0; range: 1.0-4550.0). moreover, across the sample, the median number of thumbsup, thumbs-down, comments and subscribers were 41 (iqr: 6.0-256.0.; range: 0200000.0), 4 (iqr: 1.0-45.0; range: 03673.0), 3 (iqr: 0-35.0; range: 0-12695.0), figure 1. prisma diagram depicting inclusion and exclusion criteria of youtubetm video search. 287archivio italiano di urologia e andrologia 2022; 94, 3 youtubetm and prostate checks 7120 (iqr: 1350.0-38100.0; range:0-1670000.0), respectively. disabled comments were recorded in 5 (6.8%) videos. of all videos, 26.0% (n = 19), 13.7% (n = 10), 2.7% (n = 2), 2.7% (n = 2) and 54.8% (n = 40) were produced by medical doctor, private users, nurse, hospital and other, respectively. finally, 20.5% (n = 15) and 79.5% (n = 58) videos were targeted to healthcare workers vs patients, respectively. video quality assessment the overall median pemat a/v understandability and actionability scores were 46.2% (iqr: 30.8-76.9) and 50.0% (iqr: 25.0-75.0), respectively. according to target audience, the median understandability score was statistically significant higher for videos targeted to healthcare workers, relative to patients (69.2% [iqr: 46.2-88.5] vs 46.2% [iqr: 30.8-61.5], p = 0.01). moreover, also the median actionability score was statistically significant higher for videos targeted to healthcare workers, relative to patients (100.0% [iqr: 87.5-100.0] vs 25.0% [iqr: 25.0-68.6], p < 0.001) (table 2). the overall median misinformation score ranged from 1.0 (iqr: 1.0-4.0) to 2.0 (iqr: 1.0-4.0). according to target audience (healthcare workers vs patients) the median misinformation score ranged from 1.0 (iqr: 1.0-1.5) to 4.0 (iqr: 3.0-5.0) vs 1.0 (iqr: 1.0-3.0) to 2.0 (iqr: 1.0-4.0), respectively. specifically, the largest median misinformation score differences between videos targeted to healthcare workers vs patients were recorded for question 1 (4.0 [iqr:3.0-5.0] vs. 1.0 [iqr:1.0-3.0], p < 0.001) and 2 (4.0 [iqr:1.5-4.5] vs. 2.0 [iqr:1.0-3.0], p = 0.02), defined as “does the video clearly describe the procedure?” and “does the video clearly describe the difference between neoplastic disease and other prostate diseases?”, respectively. moreover, the median total misinformation score was 2.2 (iqr:1.7-2.8). specifically, according to target audience (healthcare workers vs patients), the median total misinformation score was 2.8 (iqr:2.4-3.5) vs 2.0 (iqr:1.5-2.8) (p = 0.02), respectively (table 3). table 2. pemat a/v scores of overall youtubetm videos (n = 73) and according to target audience (healthcare workers vs patients) recorded on april 14th, 2021. pemat a/v overall healthcare workers patients p-value (n = 73) 15 (20.5) 58 (79.5) understandability median (iqr) 46.2 (30.8-76.9) 69.2 (46.2-88.5) 46.2 (30.8-61.5) 0.01 range 0-100.0 30.8-100.0 0-100.0 actionability median (iqr) 50.0 (25.0-75.0) 100.0 (87.5-100.0) 25.0 (25.0-68.8) < 0.001 range 0-100.0 50.0-100.0 0-100.0 iqr: interquartile range. table 3. misinformation scores of overall youtubetm videos (n= 73) and according to target audience (healthcare workers vs patients) recorded on april 14th, 2021. misinformation score overall healthcare workers patients p-value (n = 73) 15 (20.5) 58 (79.5) does the video clearly describe the procedure? median (iqr) 2.0 (1.0-4.0) 4.0 (3.0-5.0) 1.0 (1.0-3.0) < 0.001 range 1.0-5.0 2.0-5.0 1.0-5.0 does the video clearly describe the difference between median (iqr) 2.0 (1.0-4.0) 4.0 (1.5-4.5) 2.0 (1.0-3.0) 0.02 neoplastic disease and other prostate diseases? range 1.0-5.0 1.0-5.0 1.0-5.0 does the video give information on the pain during median (iqr) 2.0 (1.0-4.0) 3.0 (2.0-3.0) 2.0 (1.0-4.0) 0.7 the examination? range 1.0-5.0 1.0-5.0 1.0-5.0 does the video describe the next steps to be median (iqr) 1.0 (1.0-3.0) 1 (1-1.5) 1.0 (1.0-3.0) 0.4 performed after the examination? range 1.0-5.0 1.0-4.0 1.0-5.0 total misinformation score median (iqr) 2.2 (1.7-2.8) 2.8 (2.4-3.5) 2.0 (1.5-2.8) 0.02 range 1.0-4.75 1.5-4.25 1.0-4.75 iqr: interquartile range. table 1. videographic characteristics of overall youtubetm videos (n = 73) and according to target audience (healthcare workers vs patients) recorded on april 14th, 2021. videos characteristics healthcare workers patients p-value 15 (20.5) 58 (79.5) length, n (sec) median (iqr) 244 (129.0-549.0) 586 (412.0-719.0) 219 (120.2-373.2) < 0.05 range 38.0-2541.0 60.0-1380.0 38-2541 views median (iqr) 12954 (1780.0-199548.0) 40905 (5046.5-245701.5) 11412 (1720-131047.8) 0.4 range 31-17141766 31.0-851104.0 68-17141766 persistence on youtubetm, n (day) median (iqr) 985 (237-2155) 386 (48.0-1508.5) 1043 (320.2-2604) 0.1 range 1-4550 1.0-3864.0 2-4550 thumbs-up, n median (iqr) 41 (6.0-256.0) 97 (27.0-248.0) 21.5 (6.2-255.2) 0.4 range 0-200000.0 0-6815.0 0-200000.0 thumbs-down, n median (iqr) 4 (1.0-45.0) 11 (1.0-56.5) 4 (0.2-44.8) 0.7 range 0-3673.0 0-249.0 0-36730 number of comments, n median (iqr) 3 (0-35.0) 11 (1.5-30.0) 2 (0-34.2) 0.3 range 0-12695.0 0-682.0 0-12695.0 disabled comments, n (%) no 68 (93.2) 14 (93.3) 54 (93.1) 0.99 yes 5 (6.8) 1 (6.7) 4 (6.9) vpi, n median (iqr) 23.9(2.1-233.5) 62.8 (12.9-444.6) 14.8 (1.9-206.5) 0.3 range 0-11972.6 0-11972.6 0-8454.4 subscribers, n median (iqr) 7120 (1350.0-38100.0) 4650 (3830.0-31400.0) 9710 (1320.0-159750.0) 0.8 range 0-1670000.0 60.0-63700.0 0-1670000.0 author, n (%) medical doctor 19 (26) 8 (53.3) 11 (19) 0.02 private user 10 (13.7) 3 (20) 7 (12.1) nurse 2 (2.7) 1 (6.7) 1 (1.7) hospital 2 (2.7) 0 (0) 2 (3.4) other 40 (54.8) 3 (20) 37 (63.8) iqr: interquartile range; vpi: video power index. archivio italiano di urologia e andrologia 2022; 94, 3 s. morra, l. napolitano, c. collà ruvolo, et al. 288 variable correlations we recorded a positive statistically significant correlation between video length and pemat a/v actionability (r = 0.26, p = 0.02), video length and misinformation question 1 (r = 0.33, p = 0.005), video length and misinformation question 2 (r = 0.24, p = 0.05). conversely, no correlations were recorded between length and pemat a/v understandability (p = 0.06), length and misinformation question 3 (p = 0.07), and length and misinformation question 4 (p = 0.4). similarly, no correlations were recorded between all the other videographic characteristics and quality videos’ assessment tools (all p > 0.05). discussion the current study aimed to assess youtube™ videos’ quality on prostate checks, especially on dre, and to investigate if they can correctly inform patients and eradicate their beliefs and myths. to the best of our knowledge, no studies on dre were found in the literature. we addressed this void and identified several noteworthy observations. first, of all 73 videos eligible for the analyses a median of about thirteen thousand views was recorded, conversely less than fifty thumbs-up, thumbs-down and comments were registered, highlighting a poor interaction between users and youtubetm videos currently available on dre. this observation may result from non-sufficient high videos quality, in terms of videographic characteristics or content. moreover, we recorded that out of 73 videos, about 80% were targeted to patients and more than 50% were produced by people of no medical field. consequently, most of the videos present on youtubetm on dre aimed to explain dre to people without a medical background. these observations support further the aim of the present study, which was to investigate if youtubetm videos could be used as a reliable tool of correct information prostate checks and especially on dre. second, according to the pemat a/v score, the overall median understandability was 46.2% and the overall median actionability was 50.0%. the understandability reflects how viewers could process the information displayed in the videos, while the actionability reflects how viewers could use them. according to shoemaker et al., a pemat score < 70% is considered poorly understandable or poorly actionable (34). in consequence, we recorded poorly understandable and actionable content based on our results. specifically, the median understandability score of videos targeted to healthcare workers was 69.2% and median actionability score was 100.0%. conversely, the median understandability score of videos targeted to patients was 46.2% and the median actionability score was 25.0%. therefore, based on our results, videos targeted to healthcare workers were actionable and only slightly below the limit of the understandability. furthermore, based on our results, videos targeted to patients were neither understandable nor actionable. unfortunately, no previous investigators examined youtube™ information on dre. however, we compared our results with the ones achieved in other studies dealing with the fairness of youtubetm videos on different medical topics. for example, rubel et al., analyzed 50 youtube™ videos focused on sinusitis, reporting similar understandability and actionability scores (57.5% and 33.3, respectively), relative to our results (35). conversely, morra et al., analyzed the quality of 100 youtubetm videos on bladder pain syndrome, reporting higher understandability and actionability scores (66.7% and 75%, respectively) (20). therefore, the understandability and actionability scores of videos have a noticeable variation related to the topics addressed. it may be useful, for future youtube™ video authors, to create new tools to guarantee a homogenous level of understandability and actionability among all the possible topics. third, according to the misinformation tool, we recorded a high rate of misinformation of youtubetm videos on dre. specifically, the lowest overall median score was recorded for question 4, defined as “does the video describe the next steps to be performed after the examination?”, highlighting the incompleteness of youtubetm information on dre. moreover, we highlight a remarkable statistically significant difference between videos targeted to healthcare workers vs patients in terms of misinformation. specifically, for question 2, defined as “does the video clearly describe the difference between neoplastic disease and other prostate diseases?”, we recorded a median of 4.0 (iqr:1.5-4.5) vs. 2.0 (iqr:1.0-3.0) (p = 0.02), for healthcare workers vs patient, respectively. indeed, despite pca is the most common malignancy among elderly men 1, other non-neoplastic diseases can affect the prostate, such as prostatitis or benign prostatic hyperplasia (36-39). therefore, youtubetm videos on dre should clearly describe all the different possible diagnostic scenarios, to reduce misinformation. fourth, we tested pearson’s correlation between videographic characteristics and quality assessment tools scores. a mild positive statistically significant correlation between the video length and pemat a/v actionability, misinformation question 1, misinformation question 2 was recorded. these findings, were consistent with morra et al., highlighting the importance of sufficient time to correctly describe a medical topic, such as dre, to youtubetm users (20). therefore, video length may not be underestimated during the making video process. taken together, according to our results the quality of the information provided by youtubetm videos on dre is low. moreover, according to our data a poor interaction between videos and youtubetm users, testified by few thumbs-up, thumbs-down, and comments, was recorded. authors of future videos on dre should increase the quality of information and improve the appeal of the videos, to increase interaction with the users. given the rising role of multimedia in the various healthcare services, a formal standardization of media contents addressed to medical and non-medical users would be desirable. indeed, this will potentially decrease the risk of misinformation and will provide homogeneous content in the different paths of the healthcare process useful for the patient and family counseling. our study is not devoid of limitations. first, youtubetm search algorithms show videos based on relevance. however, to ensure the most unbiased results, the research was conducted after logging out from any per289archivio italiano di urologia e andrologia 2022; 94, 3 youtubetm and prostate checks sonal account (incognito status) and changing the location setting a vpn proxy to guarantee that the youtubetm videos displayed were not geared toward healthcare professionals or to any previous research. second, we only consider a sample of 100 videos. however, this sample is based on general population search strategy (40). third, it is important to note that this study is limited by the ever-changing content of the internet, which cannot be captured using a cross-sectional design. in conclusion, based on our analyses, youtubetm videos’ quality on dre resulted unsatisfactory according to the pemat a/v score and the misinformation tool. videos targeted to healthcare workers got higher quality scores if compared to videos targeted to patients. therefore, youtubetm videos’ may not be considered a reliable source of information on dre for patients. references 1. ferlay j, colombet m, soerjomataram i, et al. estimating the global cancer incidence and mortality in 2018: globocan sources and methods. int j cancer. 2019; 144:1941-1953. 2. capece m, creta m, calogero a, et al. does physical activity regulate prostate carcinogenesis and prostate cancer outcomes? a narrative review. int j environ res public health. 2020; 17:1441. 3. stolzenbach lf, rosiello g, deuker m, et al. the impact of race and age on distribution of metastases in patients with prostate cancer. j urol. 2020; 204:962-968. 4. jones d, friend c, dreher a, et al. the diagnostic test accuracy of rectal examination for prostate cancer diagnosis in symptomatic patients: a 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analysis. eur j obstet gynecol reprod biol. 2022; 272:82-87. 31. rubel ke, alwani mm, nwosu oi, et al. understandability and actionability of audiovisual patient education materials on sinusitis. int forum allergy rhinol. 2020; 10:564-571. 32. gerundo g, collà ruvolo c, puzone b, et al. personal protective equipment in covid-19: evidence-based quality and analysis of youtube videos after one year of pandemic. am j infect control.2022; 50:300-305. 33. pemat tool for audiovisual materials (pemat-a/v). accessed march 7, 2021. http://www.ahrq.gov/health-literacy/patient-education/pemat-av.html 34. shoemaker sj, wolf ms, brach c. development of the patient education materials assessment tool (pemat): a new measure of understandability and actionability for print and audiovisual patient information. patient educ couns. 2014; 96:395-403. 35. rubel ke, alwani mm, nwosu oi, et al. understandability and actionability of audiovisual patient education materials on sinusitis. int forum allergy rhinol. 2020; 10:564-571. 36. kogan mi, naboka yl, ismailov rs, et al. bacterial prostatitis: epidemiology and etiology. urologiia. 2018; (6):144-148. 37. califano g, collà ruvolo c, creta m, et al. focus on silodosin: pros and cons of uroselectivity. res rep urol. 2020; 12:669-672. 38. verze p, califano g, sokolakis i, et al. the impact of surgery for lower urinary tract symptoms/benign prostatic enlargement on both erectile and ejaculatory function: a systematic review. int j impot res. 2019; 31:319-327. 39. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl. 2021; 93:221-226. 40. megaly m, khalil c, tadros b, tawadros m. evaluation of educational value of youtube videos for patients with coeliac disease. int j celiac dis. 2016; 4:102-104. correspondence simone morra, md luigi napolitano, md claudia collà ruvolo, md giuseppe celentano, md (corresponding author) dr.giuseppecelentano@gmail.com roberto la rocca, md marco capece, md massimiliano creta, md francesco passaro, md francesco di bello, md luigi cirillo, md carmine turco, md ernesto di mauro, md gabriele pezone, md agostino fraia, md francesco mangiapia, md vincenzo mirone, md gianluigi califano, md nicola longo, md department of neurosciences, reproductive sciences odontostomatology, urology unit, university of naples “federico ii”, italy via pansini 5, 80131 naples (italy) ferdinando fusco, md urology unit, department of woman, child and general and specialized surgery, university of campania 'luigi vanvitelli', naples (italy) 117archivio italiano di urologia e andrologia 2018; 90, 2 original paper tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for < 10 mm distal and proximal ureteral stones serdar celik 1, firat akdeniz 1, muge afsar yildirim 2, ozan bozkurt 3, merve gursoy bulut 2, mehmet levent hacihasanoglu 1, omer demir 3 1 gaziemir nevvar salih isgoren hospital, department of urology, izmir, turkey; 2 gaziemir nevvar salih isgoren hospital, department of radiology, izmir, turkey; 3 dokuz eylul university, school of medicine, department of urology, izmir, turkey. objectives: to evaluate the effect of tadalafil compared with four alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive treatment for ureteral stones in male adults. materials and methods: male adults who were admitted to urology clinic with flank pain and diagnosed with non complicated < 10 mm ureteral stone on non-contrast computed tomography (ncct) between june 2014-september 2015 were retrospectively evaluated. a total of 273 patients with ureteral stone were divided into five groups. alfuzosin 10 mg/daily, doxazosin 8 mg/daily, tamsulosin 0.4 mg/daily, silodosin 8 mg/daily and tadalafil 5 mg/daily for 6 weeks were prescribed respectively. stone localization, diameter, volume and hounsfield units were noted as ncct findings. the patients were divided into the two groups based on their stone localization as distal and mid-proximal stones. these two groups were evaluated separately. expulsion rate were noted at the end of 6 weeks. ncct and treatment findings were compared between five drug groups in distal and mid-proximal stones separately. results: age was higher in tadalafil group in distal stones (p = 0.032). expulsion rate was found 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin, 88.6% for silodosin and 90% for tadalafil in distal (p = 0.44) and 21.7%, 30%, 30%, 30% and 54.5% in mid-proximal stones (p = 0.034) respectively. conclusions: expulsion rate was higher in silodosin and tadalafil for distal ureteral stones but the difference didn’t meet statistical significance. however the expulsion rate was significantly higher in tadalafil than in the other groups for mid-proximal ureteral stones. the result of this study showed that tadalafil may increases ureteric stone expulsion. key words: alpha blockers; medical expulsive theraphy; tadalafil; ureteral stone. submitted 17 march 2018; accepted 4 april 2018 summary no conflict of interest declared. or pneumatic lithotripsy with ureterorenoscopy (urs) (2, 3). but these treatments include some risks such as complications of treatment, failure and high cost. therefore, some predictors were determined on non-contrast computed tomography (ncct) of stone diameter, stone volume, hounsfield units (hu) and hounsfield density (hd) to reduce these risks (4). for ureteral stones, although the watchful waiting approach has been reported to be associated with spontaneous stone expulsion for about 50% of ureteral stones, some complications may occur such as urinary tract infections, hydronephrosis and colic events (3). medical expulsive therapy (met), another method for stone expulsion, has become routine in the treatment of obstructive ureteral calculi in recent years. the use of various drugs as met, which affect the ureter via different mechanisms, can reduce symptoms and facilitate stone expulsion. alpha and beta adrenergic receptors were found in the ureter (5). alpha-1 and particularly subtype alpha-1d are the most commonly observed adrenergic receptor subtypes in the ureteral smooth muscle cells (6). alpha blockade has been proven to decrease peristaltic activity, contraction and intraureteral pressure and to improve spontaneous stone passage and decrease both the time to stone passage and analgesic requirements (7, 8). according to european asso ciation of urology guidelines, alpha-blockers are recommended for met because they should ensure well controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve (9). a phosphodiesterase-5 (pde-5) inhibitor (tadalafil), which acts on the no/cgmp signaling pathway of smooth muscles, causes ureteral relaxation (10). a recent study reported that tadalafil showed a high ureteral stone expulsion rate and significant pain control (11). alpha blockers and tadalafil in met have a proven role to promote stone passage and reduce the need for minimally invasive surgery for distal ureteral stones. however, these findings were not investigated for proximal ureteral stones. in related studies only two of three drugs were compared for met with distal ureteral stones. therefore we wanted to evaluate the possible effect of tadalafil compared with alpha blockers, which are alfuzosin, doxazosin, tamsulosin and silodosin, for met in uncomplicated distal and proximal ureteral stones in male adults. doi: 10.4081/aiua.2018.2.117 introduction urinary tract stone disease is most prevalent between the ages of 20 and 40 years and 3 times more common in men than women (1). twenty percent of all urinary tract stones are found in the ureter and many of these stones should be treated with efficacious treatment modalities such as extracorporeal shock wave lithotripsy (swl) and endoscopic laser celik_stesura seveso 28/06/18 16:54 pagina 117 archivio italiano di urologia e andrologia 2018; 90, 2 s. celika, f. akdeniza, m. afsar yildirimb, o. bozkurtc, m. gursoy bulutb, m. levent hacihasanoglua, o. demirc 118 material and methods after approval obtained from the local ethics committee, we retrospectively reviewed the records of > 18 year old male patients with uncomplicated ureteral stones of < 10 mm diameter on ncct images between june 2014 and september 2015. after the informed consent, only male patients were included in the study to standardize patients and to eliminate the differences in expulsion time depending on anatomical differences between female and male patients. there is also an indication problem for tamsulosin, silodosin and tadalafil treatment for female patients in our country. therefore only male patients were selected for the study. patients who had not previously received any alpha blocker or tadalafil treatment were treated with alpha blockers or pde-5 inhibitor for 6 weeks. patients who had only ureteral stone and were treated with one of four alphablockers (alfuzosin 10 mg/daily (xatral, sanofi aventis), doxazosin 8 mg/daily (cardura, pfizer), tamsulosin 0.4 mg/daily (tamprost, zentiva), silodosin 8 mg/daily (urorec, recordati)) as met were included in the study. patients who had concomitant erectile dysfunction and did not accept the use of alpha blockers were treated with tadalafil 5 mg/daily (cialis, lilly and lifta, abdi ibrahim) for possible effect of ureteral stones expulsion and erectile dysfunction treatment. patients who were diagnosed with nephrolithiasis, > 10 mm ureteral stones, bilateral ureteral stones, ureteral stones requiring drainage or obstructive, grade 3 hydronephrosis, multiple ureteral stones and any anatomical abnormalities on ncct examination were excluded from the study. patients with urinary tract infection, fever and elevated creatinine level were also excluded. all patients who had unsuccessful met underwent shock wave lithotripsy (swl) or ureterorenoscopic (urs) treatment. demographic data of included patients (age, height, weight and body mass index (bmi)) were noted. before met, ncct images using 2 mm sections with the liver's dome as cranial border and pubis joint as caudal border at 100 ma 120 kv (alexion tsx-034a, toshiba®, japan) were taken. the localization of stone, the stone diameter, the stone volume, grade of hydronephrosis, the distance of stone from ureterovesical junction (for distal stones) as described by yuceturk cn et al. (12), the distance of stone from ureteropelvic junction (for proximal stones), hounsfield units (hu) and hounsfield density (hd) of the stone measured by ncct were noted. all measurements were calculated by one radiologist. largest stone diameters were measured on longitudinal, transverse, and axial images and mean stone diameter was calculated as the average of these three values. hu and stone volume were calculated with computed tomography viewer program. hd was calculated as the hu divided by mean stone diameter (13). all patients were divided into five drug groups as alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups. drug groups were subdivided into two groups according to the stone localization on ncct images as distal and mid-proximal ureteral stones and were evaluated separately. for stone localization, the anatomical limit of ureteral parts was defined as the level of the iliac artery crossing the ureter. below this area was defined as distal, while above this area was defined as mid-proximal. time interval follow-up of met was 6 weeks. patients were instructed to take diclofenac 50 mg tablets orally during episodes of pain, and filter their urine to detect stone expulsion. expulsion time was noted when the stone was observed in the filtered urine. suspicious expulsions or unsuccessful expulsion of stone were confirmed with ncct at the end of the 6th week. treatment findings (expulsion success rate and expulsion time) were noted at the end of met. demographic data of patients, ncct findings and treatment findings were compared between drug groups for distal and mid-proximal ureteral stones separately. the primary endpoint expected from the study is the expulsion rate for alpha-blockers and tadalafil groups. the secondary endpoint is expulsion times for the groups. finally an important endpoint is the tadalafil expulsion success for mid-proximal ureteral stones. statistical analysis demographic data of patients were analyzed and compared for all groups. the parameters measured on ncct (the stone diameter, grade of hydronephrosis, the stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, hu and hd) were compared between all 5 groups. the pearson χ2 test and kruskal-wallis test were applied between the groups for nonparametric statistical analysis using commercially available software (statistical package for the social sciences, version 20.0; spss, chicago, iii). the alpha level of statistical significance was set at .05. results male adults who were admitted to the urology clinic with flank pain and diagnosed with uncomplicated ureteral table 1. demographic data, tomography findings and expulsion findings of the study population. variables all patients (n = 273) age, year; mean ± sd (range) 41 ± 11.3 (20.3-80) height, cm; mean ± sd (range) 1.74 ± 6 (161-190) weight, kg; mean ± sd (range) 82.7 ± 13.7 (56-125) bmi, kg/m2; mean ± sd (range) 27.2 ± 4.1 (18.3-39.9) percentage of stone localization distal 61.5 mid-proximal 38.5 mean stone diameter, mm; mean ± sd (range) 4.9 ± 1.7 (1-10) stone volume, mm3; mean ± sd (range) 80.3 ± 83.5 (0.5-502) the distance of distal ureteral stone from ureterovesical junction, mm; mean ± sd (range) 9.7 ± 4.3 (1-22) the distance of mid-proximal ureteral stone from ureteropelvic junction, mm; mean ± sd (range) 84.9 ± 37.7 (29-152) hu; mean ± sd (range) 571.2 ± 307.8 (89-1384) hd, hu/mm; mean ± sd (range) 114.5 ± 40 (41.4-280.5) percentage of hydronephrosis grade none 16.9 grade 1 53.1 grade 2 30 grade 3 0 percentage of expulsion success rate 63 expulsion time, day; mean ± sd (range) 11.3 ± 9.5 (2-39) abbreviations: bmi, body mass index; hu, hounsfield units; hd, hounsfield density. celik_stesura seveso 28/06/18 16:54 pagina 118 stone on ncct between june 2014 and september 2015 were retrospectively evaluated. a total of 273 male adults were included in the study. mean age was 41 ± 11.3 (20.3-80) years and mean bmi was 27.2 ± 4.1 (18.3-39.9) kg/m2 for the whole group. mean age, height, weight, bmi, stone localization, mean stone diameter, stone volume, the distance of stone from ureterovesical junction, the distance of stone from ureteropelvic junction, hu, hd, grade of hydronephrosis, stone expulsion rate and expulsion time are given in table 1 for all patients. considering the stone localization there were 168 patients with distal and 105 patients with mid-proximal ureteral stones. in drug groups; 55 patients were treated with alfuzosin, 57 with doxazosin, 54 with tamsulosin, 55 with silodosin and 52 with tadalafil. in the drug groups 32, 37, 34, 35 and 30 patients had distal, and 23, 20, 20, 20 and 22 patients had mid-proximal ureteral stones, respectively. there was no significant difference in the demographic data (height, weight and bmi) of the five groups for distal and mid-proximal ureteral stones (p > .05) (table 2 and 3). age was higher in the tadalafil group than the other groups for distal ureteral stones (p = .032) (table 2). 119archivio italiano di urologia e andrologia 2018; 90, 2 tadalafil as medical expulsive therapy table 2. comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of met in distal ureteral stones. table 3. comparison of computed tomography findings and expulsion rate and time between alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil groups of met in mid-proximal ureteral stones. distal ureteral stones alfuzosin doxazosin tamsulosin silodosin tadalafil p value (n = 168) (n = 32) (n = 37) (n = 34) (n = 35) (n = 30) variables a age, year; median ± sd 41.7 ± 13.3 38.2 ± 12.8 43.9 ± 11.5 39.2 ± 11 46.3 ± 9.9 .026 height, cm; median ± sd 172.9 ± 5.7 175.1 ± 4.8 175.2 ± 7.4 176.3 ± 5.2 178 ± 1.7 .322 weight, kg; median ± sd 82 ± 14 82.6 ± 11 82.1 ± 12.6 82.3 ± 10.9 85.7 ± 12.2 .663 bmi, kg/m2; median ± sd 27.4 ± 3.9 26.9 ± 3.4 26.6 ± 2.8 27.2 ± 3.7 27.1 ± 4.3 .542 stone diameter, mm; median ± sd 4.9 ± 1.4 4 ± 1.7 4.5 ± 1.8 4.5 ± 1.7 4.7 ± 1.8 .227 stone volume, mm3; median ± sd 75.1 ± 73.1 48.6 ± 56.5 68.9 ± 94.4 66.3 ± 69.7 75.1 ± 84.5 .220 the distance of stone from ureterovesical junction, mm; median ± sd 9.5 ± 4.2 9.6 ± 4.9 9.1 ± 3.8 9.5 ±3. 6 10.9 ± 5.1 .66 hounsfield units, hu; median ± sd 527.2 ± 270.6 442.5 ± 269.3 461.3 ± 291.6 491.8 ± 287.5 494.2 ± 268.4 .471 hounsfield density, hu/mm; median ± sd 103.5 ± 35.9 111.1 ± 36.1 99.8 ± 34.2 104.8 ± 34.7 105.2 ± 35.9 .689 percentage of hydronephrosis grade 2 18.7 21.6 129.4 37.1 33.3 .404 percentage of expulsion rate 78.1 75.7 76.5 88.6 90 .44 expulsion time, day; median ± sd 11.7 ± 5.7 11.6 ± 7.2 9.5 ± 7.6 10.9 ± 10.1 5.7 ± 3.4 .019 bmi, body mass index; hu, hounsfield units. a continuous variables were compared by kruskal-wallis test. mid-proximal ureteral stones alfuzosin doxazosin tamsulosin silodosin tadalafil p value (n = 105) (n = 23) (n = 20) (n = 20) (n = 20) (n = 22) variables a age, year; median ± sd 40.8 ± 10.7 39.6 ± 8.7 39.1 ± 10.4 37.8 ± 13.1 41.2 ± 8.3 .765 height, cm; median ± sd 172 ± 4.9 175.3 ± 4.6 172.5 ± 6.6 173.2 ± 5.6 172.7 ± 5.7 .525 weight, kg; median ± sd 89.6 ± 16.4 91.7 ± 19.7 77.7 ± 13 83.6 ± 15.7 79.2 ± 8.3 .177 bmi, kg/m2; median ± sd 30.3 ± 5.7 29.8 ± 5.8 26.2 ± 4.4 27.8 ± 4.9 26.6 ± 2.3 .147 stone diameter, mm; median ± sd 5.3 ± 1.8 5.2 ± 1.2 5.3 ± 1.6 6 ± 1.2 5.7 ± 1.6 .251 stone volume, mm3; median ± sd 101.8 ± 102.2 79.4 ± 52.7 100.4 ± 115.3 123.5 ± 61.2 119 ± 100.9 .207 the distance of stone from ureteropelvic junction, mm; median ± sd 84.4 ± 37.1 77.6 ±35.2 90.7 ± 36.3 81.2 ± 40.6 90.8 ± 40.8 .889 hounsfield units, hu; median ± sd 672.6 ± 294.2 606.7 ± 241.9 775 ± 259.6 721.7 ± 344 838.7 ± 327.2 .125 hounsfield density, hu/mm; median ± sd 127.5 ± 48.7 116.4 ± 36.9 145.7 ± 38.3 116.6 ± 42.2 143.9 ± 35 .062 percentage of hydronephrosis grade 2 26.1 30 30 40 40.1 .185 percentage of expulsion rate 21.7 30 30 30 54.5 .034 expulsion time, day; median ± sd 26 ± 5.6 18 ± 20.8 10.7 ± 12.4 8.3 ± 6 18.3 ± 14.7 .191 bmi, body mass index; hu, hounsfield units. a continuous variables were compared by kruskal-wallis test. celik_stesura seveso 28/06/18 16:54 pagina 119 archivio italiano di urologia e andrologia 2018; 90, 2 s. celika, f. akdeniza, m. afsar yildirimb, o. bozkurtc, m. gursoy bulutb, m. levent hacihasanoglua, o. demirc 120 ncct findings of the drug groups are given in table 2 and 3. there was no significant difference in stone diameter, stone volume, the distance of stone from uretero vesical junction, the distance of stone from ureteropelvic junction, hu, hd and grade of hydronephrosis between the five groups with distal and mid-proximal ureteral stones (p > .05). expulsion rate was 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin 88.6% for silodosin and 90% for tadalafil for distal ureteral stones and 21.7%, 30%, 30%, 30% and 54.5% for mid-proximal ureteral stones, respectively. median expulsion time was 11.7 days for alfuzosin, 11.6 days for doxazosin, 9.5 days for tamsulosin, 10.9 days for silodosin and 5.7 days for tadalafil for distal and 26, 18, 10.7, 8.3 and 18.3 days for mid-proximal ureteral stones, respectively. expulsion rates for silodosin and tadalafil groups with distal ureteral stones were higher than the other three groups, but this result was not statistically significant (p = .44). expulsion time for the tadalafil group was significantly lower than the other drug groups with distal ureteral stones (p = .019) (table 2). expulsion rate of the tadalafil group was significantly higher than the other groups with mid-proximal ureteral stones (p = .034). however, there was no statistically significant difference between the groups in terms of expulsion time for mid-proximal ureteral stones (table 3). discussion in brief, the expulsion rate was higher in silodosin and tadalafil groups compared to the other groups for distal ureteral stones, but did not reach statistical significance between the groups (expulsion rate was 78.1%, 75.7%, 76.5%, 88.6%, and 90% for alfuzosin, doxazosin, tamsulosin, silodosin and tadalafil, respectively). however, the expulsion rate was significantly higher in the tadalafil group compared to the other groups for mid-proximal ureteral stones (21.7%, 30%, 30%, 30% and 54.5%, respectively). also, age was higher in the tadalafil group than in the other groups for distal ureteral stones. in european association of urology (eau) guidelines, met, swl and urs are recommended in the treatment of ureteral stones (9). in recent studies, some possible and accurate predictors were determined that affect the success of swl and urs (4, 14). these predictors were stone diameter, stone volume, hu, and hd of ureteral stones and grade of hydronephrosis on ncct. therefore, in our study these factors were equivalent in the drug groups to reduce the effect on met. according to previous studies, the expulsion rate of distal ureteral stones during watchful waiting is 25-54% with mean expulsion time > 10 days. to increase the expulsion rate and decrease the analgesic requirements, medical therapy is recommended for distal ureteral stones (15-18). in an aua/eau panel, two medical therapies, which are calcium channel blocker and alphareceptor antagonists, were optionally recommended for distal ureteral stones. the meta-analysis of six studies of alpha blockers (280 patients) yielded an expulsion rate of 81% (19). there are several studies that show no significant difference between expulsion rates of alpha-blockers for distal ureteral stones. alfuzosin expulsion rates were reported as 85.6% in a randomized controlled prospective study (20). in a recent randomized, placebo-controlled trial comparing placebo, tamsulosin and nifedipine as met for distal, middle and proximal ureteral stones, there was no significant difference between the groups (21). in a recent meta-analysis, there was no statistically significant difference in stone expulsion rate and time between alfuzosin and tamsulosin (22). in a study evaluating alfuzosin and doxazosin as met for distal ureteral stones, expulsion rates and time were reported as 52.9% and 7.38 ± 5.55 days with alfuzosin, 62% and 7.85 ± 5.11 days with doxazosin, respectively (23). in a prospective randomized study comparing silodosin with tamsulosin, the efficacy of silodosin (high selective antagonist of alpha-1a receptor) was shown to be superior to tamsulosin (alpha-1d and alpha-1a receptors selective antagonist) (24, 25). tadalafil, which is a smooth muscle relaxant, has recently been approved by the us food and drug administration (fda) for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia and erectile dysfunction (10). gratzke et al. demonstrated the role of the pde-5 inhibitors of vardanafil, sildenafil and tadalafil in relaxation of ureteral muscles (26-29). in a recent study kumar et al. detected significantly higher expulsion rate and lower expulsion time in a silodosin group compared to tamsulosin and tadalafil groups for distal ureteral stones (11). in another recent study which compared the expulsion rate and expulsion time of tamsulosin with the combination of tadalafil and tamsulosin, higher expulsion rate and lower expulsion time were detected in the tamsulosin plus tadalafil group (83.6% and 14.9 ± 4.4 days) compared with the tamsulosin group (65.5% and 16.7 ± 4.8 days) (30). in this study, we divided ureteral stones into two groups according to their localization as distal and midproximal. for distal ureteral stones, the stone expulsion rates with silodosin and tadalafil were higher than alfuzosin, doxazosin and tamsulosin, but the difference did not reach statistical significance. however, expulsion time in the tadalafil group was lower than in alpha blocker groups (alfuzosin, doxazosin, tamsulosin and silodosin) for distal ureteral stones. we found a higher expulsion rate in the tadalafil group compared to alphablockers (alfuzosin, doxazosin, tamsulosin and silodosin) for mid-proximal ureteral stones and that was statistically significant. however, expulsion time was not found to be statistically significant between the groups. alpha-blockers and pde-5 inhibitors have separate mechanisms that increase the stone expulsion compared to watchful waiting. successful combination of tamsulosin and tadalafil used by jayant et al. opened up the potential use of a combination of silodosin with tadalafil (11, 30). the limitations of this study are that it is retrospective, non-randomized and has a limited number of patients in drug groups for ureteral stones. due to the retrospective nature of the study, three major parameters, which were celik_stesura seveso 28/06/18 16:54 pagina 120 quantity of additional analgesic usage, frequency of acute renal colic and emergency visits of patients, could not be evaluated. also, age was higher and expulsion time was lower in the tadalafil group than in the other groups for distal ureteral stones. the explanation of this result may be that stone expulsion was a rapid condition of the tadalafil usage or that elderly patients could expel stones more easily due to possibly more compliant ureters. another limitation is that concomitant erectile dysfunction was only present in the tadalafil group. however, additional drug usage or concomitant diseases were not significantly different between the groups. finally the important result of the study and the difference from the other studies is that 5 mg daily tadalafil usage is associated with high stone expulsion success in patients diagnosed with mid-proximal ureteral stones. conclusions the result of this study indicates that tadalafil showed a significantly lower stone expulsion time compared with alpha-blockers for distal ureteral stones. the most important finding is the higher expulsion rate with tadalafil for mid-proximal ureteral stones compared with alpha-blockers. therefore this situation opens up the potential use of a combination of tadalafil and silodosin for distal and midproximal ureteral stones and this combination of tadalafil in met may reduce the need for swl therapy and minimally invasive procedures. however, there is a need for large prospective randomized studies to clarify these findings. references 1. manglaviti g, tresoldi s, guerrer cs, et al. in vivo evaluation of the chemical composition of urinary stones using dual-energy ct. ajr am j roentgenol. 2011; 197:76. 2. ahmed af, al-sayed ay. tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones: prospective, randomized, comparative study. korean j urol. 2010; 51:193. 3. dellabella m, milanese g, muzzonigro g. randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medicalexpulsive therapy for distal ureteral calculi. j urol. 2005; 174:167. 4. celik s, bozkurt o, kaya fg, et al. evaluation of computed tomography findings for success prediction after extracorporeal shock wave lithotripsy for urinary tract stone disease. int urol nephrol. 2015; 47:69. 5. malin jm jr, deane rf, boyarsky s. characterisation of adrenergic receptors in human ureter. br j urol. 1970; 42:171. 6. küpeli b, irkilata l, gürocak s, et al. does tamsulosin enhance lower ureteral stone clearance with or without shock wavelithotripsy? urology. 2004; 64:1111. 7. yilmaz e, batislam e, basar mm, et al. the comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010. 8. watts hf, tekwani kl, chan cw, et al. the effect of alphablockade in emergency department patients with ureterolithiasis. j emerg med. 2010; 38:368. 9. türk c, knoll t, petrik a, et al. guidelines on urolithiasis european association of urology updated march 2015. 10. oelke m, giuliano f, mirone v, et al. monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. eur urol. 2012; 61:917. 11. kumar s, jayant k, agrawal mm, et al. role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). urology. 2015; 85:59. 12. yuceturk cn, dadali m, bagbanci ms, et al. efficacy of silodosin dose in medical expulsive therapy for distal ureteral stones: a retrospective study. urol j. 2017; 14:2944. 13. nakada sy, hoff dg, attai s, et al. determination of stone composition by noncontrast spiral computed tomography in the clinical setting. urology. 2000; 55:816. 14. ito h, kawahara t, terao h, et al. predictive value of attenuation coefficients measured as hounsfield units on noncontrast computed tomography during flexible ureteroscopy with holmium laser lithotripsy: a single-center experience. j endourol. 2012; 26:1125. 15. bensalah k, pearle m, lotan y. cost effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. eur urol. 2008; 53:411. 16. wolf js jr. treatment selection and outcomes: ureteral calculi. urol clin n am. 2007; 34:421. 17. wang cj, tsai pc, chang ch. efficacy of silodosin in expulsive therapy for distal ureteral stones: a randomized double-blinded controlled trial. urol j. 2016; 13:2666. 18. celik s, akdeniz f, afsar yildirim m, et al. computed tomography findings predicting the success of silodosin for medical expulsive therapy of ureteral stones. kaohsiung j med sci. 2017; 33:290. 19. preminger gm, tiselius hg, assimos dg, et al. management of ureteral calculi: eau/aua nephrolithiasis panel. j urol. 2007; 178:2418. 20. sameer, lal s, charak ks, chakravarti s, kohli s, ahmad s. efficacy of nifedipine and alfuzosin in the management of distal ureteric stones: a randomized, controlled study. indian j urol. 2014; 30:387. 21. pickard r, starr k, maclennan g, et al. medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. lancet. 2015; 386:341. 22. liu c, zeng g, kang r, et al. efficacy and safety of alfuzosin as medical expulsive therapy for ureteral stones: a systematic review and meta-analysis. plos one. 2015; 10:e0134589. 23. gurbuz mc, polat h, canat l, et al. efficacy of three different alpha 1-adrenergic blockers and hyoscine n-butylbromide for distal ureteral stones. int braz j urol. 2011; 37:195. 24. dell'atti l. silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. urologia. 2015; 82:54. 25. wang cj, huang sw, chang ch. efficacy of an alpha1 blocker in expulsive therapy of lower ureteral stones. j endourol. 2008; 22:41. 26. gratzke c, uckert s, reich o, et al. pde5 inhibitors. a new option in the treatment of ureteral colic? urologe a. 2007; 46:1219. 121archivio italiano di urologia e andrologia 2018; 90, 2 tadalafil as medical expulsive therapy celik_stesura seveso 28/06/18 16:54 pagina 121 archivio italiano di urologia e andrologia 2018; 90, 2 s. celika, f. akdeniza, m. afsar yildirimb, o. bozkurtc, m. gursoy bulutb, m. levent hacihasanoglua, o. demirc 122 27. gratzke c, uckert s, kedia g, et al. in vitro effects of pde5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. urol res. 2007; 35:49. 28. taher a, schul-knappe p, meyer m, et al. characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. world j urol. 1994; 12:286. 29. kühn r, uckert s, stief cg, et al. relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotidedependent pathways. urol res. 2000; 28:110. 30. jayant k, agrawal r, agrawal s. tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomized controlled trial. int j urol. 2014; 21:1012. correspondence serdar çelik, md, febu, sphd (corresponding author) serdarcelik84@hotmail.com firat akdeniz, md, febu dr.frt@mynet.com mehmet levent hacihasanoglu, md lhhasan@mynet.com gaziemir nevvar salih isgoren hospital, department of urology, izmir, turkey muge afsar yildirim, md mugeavsar@yahoo.com merve gursoy bulut, md gursoymerve@yahoo.com gaziemir nevvar salih isgoren hospital, department of radiology, izmir, turkey ozan bozkurt, associate professor drozanbozkurt@gmail.com omer demir, md, professor omer.demir@deu.edu.tr dokuz eylul university, school of medicine, department of urology, izmir, turkey celik_stesura seveso 28/06/18 16:54 pagina 122 295archivio italiano di urologia e andrologia 2018; 90, 4 case report isolated corpus spongiosum injury after sexual intercourse ioannis anastasiou, aikaterini anastasiou, ioannis katafigiotis, dimitrios tsavdaris, constantinos constantinides 1st urology department, laiko hospital, university of athens, athens, greece. penile fractures are generally rare and underreported. the mechanism of injury is due to a rupture of the corpora cavernosa following blunt or sexual trauma to the penis when fully erect. penile fractures usually present with a ‘popping’ sound with concomitant sudden swelling and ecchymosis of the penis followed by rapid detumescence. urethral involvement occurs only in a small part of the cases. isolated spongiosal injury after sexual intercourse is also extremely rare. the cardinal sign of urethral injury is blood at the meatus. a small laceration can be repaired by simple closure with absorbable sutures, while a complete rupture requires a more complex anastomotic repair. we report a case of a typically presenting penile fracture that was eventually proven to be an isolated corpus spongiosum injury, with no corpora cavernosa involvement. key words: penile fracture, urethral injury, urological trauma, urethroplasty. submitted 6 march 2018; accepted 7 may 2018 summary no conflict of interest declared. subsequently, he presented at the emergency department 6 hours after the accident. during physical examination he presented with a flaccid edematous penis with ecchymosis and blood at the meatus. there was marked tenderness on palpation of the ventral surface of the penis but no palpable abnormalities were noted (figure 1). the patient was able to void. a complete blood count, serum electrolytes revealed no abnormalities and urine analysis revealed haematuria. our patient was scheduled for surgery in order to repair what obviously appeared as a penile fracture using a degloving incision. during surgical exploration no recognizable trauma of the corpora cavernosa was demonstrated so we decided to create an artificial erection, which confirmed our findings. a hematoma was discovered at the abdominal surface of the shaft that was lying over a tear in the corpus spongiosum at the level of the penile urethra approximately 4cm from the glans. the urethra appeared to be torn with the foley catheter easily shown underneath. (figure 1). the defect was closed primarily with 3-0 absorbable sutures, with the foley catheter in place. the urethral catheter remained for 2 weeks. the patient returned six weeks later fully recovered and able to achieve micturition with no problems whatsoever. doi: 10.4081/aiua.2018.4.295 introduction penile fractures are generally rare and underreported. the mechanism of injury is due to a rupture of the corpora cavernosa following blunt or sexual trauma to the penis when fully erect (1). penile fractures usually present with a ‘popping’ sound with concomitant sudden swelling and ecchymosis of the penis followed by rapid detumescence. urethral involvement happens only at a small percentage of the cases (1). symptoms from the urinary tract include blood at the meatus and subsequently a positive urinalysis for blood and/or acute urinary retention (2). we report a case of a typically presenting penile fracture that was eventually proven to be an isolated corpus spongiosum injury, with no corpora cavernosa involvement. case report a 47-year-old man visited the emergency department of our hospital complaining of severe pain and a swollen penis shortly after sexual intercourse the previous night. his medical and surgical history was unremarkable. he mentioned a sudden pain on his penis followed by prompt detumescence after failing to enter his partner’s vagina and hitting with his partially loose penis on her buttocks. he passed blood-stained urine mainly at the beginning of the stream, but was otherwise able to void. figure 1. isolated corpus spongiosum injury. anastasiou_stesura seveso 10/01/19 16:21 pagina 295 archivio italiano di urologia e andrologia 2018; 90, 4 i. anastasiou, a. anastasiou, i. katafigiotis, d. tsavdaris, c. constantinides 296 discussion our patient showed typical clinical characteristics of blunt cavernosal trauma with concomitant urethral involvement. however, it was eventually discovered surgically that he suffered an isolated injury to the corpus spongiosum. in our patient, the diagnosis of penile fracture was made due to the typical clinical features he presented with. no further imaging was performed because surgical exploration was already indicated and surgical repair was probably required. the typical mechanism of injury is during sexual intercourse when the penis fails to enter the vagina and strikes against the pubic symphisis or perineum of the partner involved. at the time of injury a rupture of the cavernosal tunica albuginea occurs with subsequent subcutaneous hematoma of the shaft and involvement of the corpus spongiosum or urethra in approximately 10-22% of cases (1). isolated spongiosal injury after sexual intercourse is extremely rare. blood at the meatus is the cardinal sign of urethral injury and signifies the necessity for further evaluation. in the case of a complete urethral rupture acute urinary retention is the rule with evidence of a palpable distended bladder (2). other signs and symptoms of urethral trauma include hematuria, pain while urinating, and scrotal, penile or perineal edema and ecchymosis due to urinary extravasation and bleeding which can present spontaneously or with a several hour delay (2). penile fractures require immediate exploration because delayed treatment results in higher rates of erectile dysfunction (3). the surgical technique consists of closing the tear in the cavernosal tunica albuginea as well as the concomitant tear in the urethra (3). a small laceration can be repaired by simple closure with absorbable sutures, while a complete rupture requires a more complex anastomotic repair (3). if a concomitant urethral injury is suspected, the gold standard approach for diagnostic evaluation is a retrograde urethrogram (rug). an alternative and more frequently used examination is the flexible cystoscopy under anesthesia during exploration/ repair. conclusions the common presentation of sexual trauma is penile fracture. the majority of the cases have a typical etiology of a penis collision against the perineum or the symphysis pubis. the urologist that encounters a patient with a sexual trauma usually manages the sexual trauma as a common penile fracture and an isolated spongiosal injury could be easily missed. it is important for the urologist that deals with this emergency situation to be aware of the possibility of urethral injury even though the penis is integral, especially when there is blood at the meatus (cardinal sign) or inability to void. references 1. nicolaisen gs, et al. rupture of the corpus cavernosum: surgical management. j urol. 1983; 130:917. 2. mundy ar, et al. urethral trauma. part i: introduction, history, anatomy, pathology, assessment and emergency management. bju int. 2011; 108:310. 3. derouiche a, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111. correspondence ioannis anastasiou, md ekati2@otenet.gr aikaterini anastasiou, md (corresponding author) aikatianast@gmail.com ioannis katafigiotis, md katafigiotis.giannis@gmail.com dimitrios tsavdaris, md dimtsavdaris@gmail.com constantinos constantinides, md ckonstan@med.uoa.gr laiko hospital, agiou thoma 17, athens 11527, greece anastasiou_stesura seveso 10/01/19 16:21 pagina 296 stesura seveso 29archivio italiano di urologia e andrologia 2018; 90, 1 original paper a new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory simone brardi 1, gabriele cevenini 2, angelo giovanni bonadio 3 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of medical biotechnologies, university of siena, italy; 3 pathological anatomy 1, university of pisa, italy. the percutaneous biopsy of native kidneys according to the classical methodology is performed under real time ultrasound guidance with the needle introduction along a trajectory of about 30°, aimed to the lower pole of the kidney. recently, a variant of the classical technique has been introduced by which a perforated ultrasound probe is used to guide the needle along a perpendicular trajectory to the terminal section of the lower kidney pole where the front and back margins of the cortical kidney tissue join each other without renal sinus interposition so to offer to the needle a 3-4 cm thick cortical tissue front which allows to obtain a cortical tissue sample suitable for histological examination even with a single needle pass, while at the same time limiting the possibility of damaging the smaller kidney calices of the lower group whose lesion causes hematuria. in this paper, we present a large survey (50 patients) to compare to data from the literature obtained by using similar needle gauge and with a similar follow-up period after biopsy. the result of this comparison confirms the efficacy of this variant of the classical technique because in front of a statistically lower number of needle passes, it allowed to obtain 100% of samples suitable for histological analysis, in absence of major complications and with a statistically lower post-biopsy hemoglobin drop in comparison to that observed in a group of 44 patients biopsied with a greater number of needle passes, in the only study of the literature which is directly comparable to our study in relation to needle gauge and duration of monitoring. key words: percutaneous renal biopsy; perforated ultrasound probe; perpendicular needle trajectory; number of needle passes. submitted 30 october 2017; accepted 15 november 2017 summary no conflict of interest declared. the guidelines, with the patient in the prone position, the biopsy needle is driven according to a sagittal ultrasound scan, with an angle of about 30 degrees towards the lower kidney pole. usually two needle passes are carried in order to obtain a sufficient amount of renal parenchyma tissue for optic microscopy, immunofluorescence and electron microscopy analysis when necessary (1). recently, in a limited series (4), a variant of the classical technique has been proposed according which placing the patient in the prone position the biopsy needle is driven by a perforated ultrasound probe with a perpendicular trajectory in order to reach the more lower portion of the lower kidney pole, where the front and back margins of the renal cortical join each other without renal sinus interposition (figure 1). by the use of the perforated probe, the needle advances perpendicularly toward a 3-4 cm thick cortical tissue front, without the renal sinus interposition, allowing to collect a suitable sample of cortical kidney tissue with a single needle pass and, at the same time, limiting the possibility of damage to the smaller kidney calices of the lower group whose lesion causes hematuria (5). the first purpose of this technique is therefore to obtain with only one needle pass (compared to the two or more required according to the classical method) (1) and thus with less kidney parenchyma trauma, a quantity of material sufficient to put an histological diagnosis and at the same time to limit the possibility of damaging the calices doi: 10.4081/aiua.2018.1.29 introduction percutaneous kidney biopsy is an important and often irreplaceable instrument for the diagnosis and treatment of kidney disease although it may be associated with multiple complications, most commonly with bleeding which in rare cases can lead to sometimes fatal retroperitoneal bleeding (1-3). for this reason, the renal biopsy technique has evolved over the years to increase its safety until the introduction of spring-loaded needle biopsy device and of real-time ultrasound guidance which are currently considered the “gold standard” procedure for the percutaneous renal biopsy as they allow to minimize the incidence of associated complications (3). according to the classical methodology, as proposed by figure 1. the path of the needle according to the technique of percutaneous renal biopsy with perforated probe and perpendicular needle trajectory. brardi2_stesura seveso 03/04/18 11:06 pagina 29 archivio italiano di urologia e andrologia 2018; 90, 1 s. brardi, g. cevenini, a.g. bonadio 30 present in the renal sinus and therefore the possibility of bleeding because the biopsy is performed where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition. in the following paper we present therefore a survey carried out in a large population with this technique in order to confirm or not the supposed advantages offered by this technique. subjects and methods compared to the previously published pilot survey that counted only 26 cases (4), for this paper. we retrospectively evaluated 50 consecutive patients submitted to percutaneous renal biopsy by the technique of the perforated ultrasound probe with perpendicular needle trajectory at the nephrology ward of the san donato hospital of arezzo from november 2012 to october 2017. the mean age of the 50 patients (32 males and 18 females) was 52.7 ± 16.7 (mean ± sd, range 18-83) years, with average creatinine values (before the biopsy) of 1.7 ± 1.7 mg/dl. (table 1). the bleeding time, prothrombin time, and platelet counts were within the normal range across all patients. each patient, before the procedure, was subjected to renal ultrasound in order to exclude the presence of any of the known contraindications for the execution of renal biopsy (5) and any platelet anti-aggregant and/or anticoagulant was stopped 7 days before the procedure (6). in the case of arterial hypertension, a sufficient control of arterial pressure values was assured, eventually with the addition to the therapy of a calcium channel blocker. finally an informed consent was obtained from each patient (7). percutaneous kidney biopsies were always performed on native kidneys and always at the lower left kidney pole with the exception of two cases (with solitary kidneys) where the biopsy was performed at the lower right kidney pole. for real-time ultrasound guidance, a hitachi convex 3.5hhz perforated ultrasound probe coupled to a hitachi astro 256 ultrasonograph was used. in all cases, the bard monopty needles (bard biopsy systems, tempe, arizona, usa) were used with needle gauge size and length of 16 gauge x 16 mm. renal biopsy was performed with the patient in the prone position while a pillow was placed under the abdomen of the patient (5). after disinfection of the skin with povidone iodine and local anesthesia (lidocaine 20 mg/ml) under real-time ultrasound guidance, according to longitudinal scan planes on the rear axillary line and tilting the probe towards the spine, the needle was directed to the more lower portion of the kidney lower pole where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition, along a bound path perpendicular to the lower pole by the needle passage of a special adapter for the zero degrees angle previously inserted on the ultrasound perforated probe (figure 2). only one needle pass was carried out; the needle pass was repeated only when the sample was not suitable to a first optical analysis. in particular insufficient sampling happened only in those patients who, at the moment of the firing of the needle mechanism for the core sampling, moved for fear or inability to keep the position set (4). all the patients were then subjected to ultrasound imaging immediately after the biopsy, at a distance of about 6 hours and ultimately after the first 24 hours (1, 4). besides, all the patient, after the biopsy, remained in bed for the first 24 hours as recommended by the italian national guidelines (1, 4). before the procedure a blood sample was drawn for blood count that was repeated six hours after the biopsy, while subsequent blood count collections were dictated by the possible presence of hematomas or by major reductions of the hemoglobin at the six-hour control after the biopsy (1, 4). urination was monitored to exclude macrohaematuria and the blood pressure was measured intensively for the first two hours and then at regular intervals of eight hours (1, 4). results even in the larger survey that we present here, as in the preliminary data (4), the biopsy sampling (examined for the most at the pathological anatomy 1 of the university of pisa) was successful (more than 5 glomeruli per biopsy specimen and/or a validation by the anatomopathologist about the presence of sufficient material to diagnose) (5, 8) in the 100% of the cases. the sample then was obtained at the first and only needle pass in 90% of cases (with a slight increase compared to the 88.5% rate found in the first published survey) (4). table 1. characteristics of the patients enrolled. patients, n. 50 age (years)* 52.72 ± 16.70 range (years) 18-83 male/female, n. 32/18 pre-biopsy creatinine (mg/dl)* 1.66 ± 1.68 * mean ± sd figure 2. the moment of needle drive operation with perpendicular needle trajectory; to note the absence of renal sinus interposed. brardi2_stesura seveso 03/04/18 11:06 pagina 30 as in the pilot casuistry, no major complications of renal biopsy were observed and in particular transient macrohaematuria was found only in a patient and no patient was subjected to blood transfusion or death (table 2). however, we must point out that a female patient was transfused far beyond 24 hours of observation due to the failure to observe the expected period of bed rest, so it was necessary a further bed forced rest period but no embolization was required. however subcapsular hematomas was found in 40% of the patients (with a slight reduction versus the 42% found in the pilot survey) but all hematomas were of a non-significant type (i.e. with a maximum thickness of ≤ 2 cm as by definition of italian guidelines) (1) (table 2). finally, the mean hemoglobin value was reduced from the pre-biopsy value of 12.4 ± 2.1 g/dl to the post-biopsy value of 12.0 ± 2.03 g/dl. however, a decrease in hemoglobin values ≥ 2 g/dl (considered significant or associated with increased risk of complications) (9) was reported only in 4.25% of patients (table 2). discussion since the present series did not include controls, as our preliminary study previously published, in order to assess effectiveness and safety of this variant of the classical biopsy technique we had to make a comparison with literature data homogeneous for needle gauge and length of post-bioptic monitoring period (4). for this comparison homogeneity with regard to needle gauge is important as 18 gauge needles were found to have a greater number of complications (10) (probably due to the greater number of needle passes necessary to obtain adequate material for diagnosis) (11) and fewer biopsy specimens in comparison to the use of 14 or 16 gauge needles (10). furthermore in the meta-analysis of corapi et al. (12) there was an increase in the number of blood transfusions in studies with 14 gauge needles compared to 16 or 18 gauge needles. equally important for comparison is the homogeneity of the patient's monitoring period after kidney biopsy, which must be at least 12 hours and better over 24 hours (1), since 33% of the complications occur after the first eight hours and 91% within 24 hours (1, 13). so we have selected within the largest meta-analysis at the time available in literature, that is corapi et al. (12), the studies comparable to our study for needle gauge and duration of the monitoring with sufficient data to calculate the confidence interval for the number of needle passes per patient and the variations of hemoglobin between the pre and post-biopsy value at a distance of about six hours. we identified three papers from which, for completeness of data, we have been able to extrapolate the 95% confidence interval for the number of needle passes carried out, namely maya and allon's study of 2009 (6), for which it is necessary underline that both needles 16 and 18 gauge were used, lin et al. study of 2006 (14), where 16 gauge needles were used for adult patients and 18 gauge needles for pediatric patients (which number is not specified) and, finally, ori et al. study of 2002 (15) where only 16 gauge needles were used. in all three studies selected for comparison, a histological sample sufficient for diagnosis was obtained for almost all patients, though with a number of needle passes greater than in our study. in maya and allon's paper (6) with a 100% validity of the sample for the histological analysis, 1.6 ± 0.8 needle passages (ic 95%: 1.44-1.76) were performed in the 100 patients enrolled. in the paper of lin et al. (14) with a 100% validity of the sample for the histological analysis, 2.2 ± 0.6 passages were performed in 183 outpatients (ic 95%: 2.11-2.29) and 2.3 ± 0.7 passages were performed in 147 inpatients (ic 95%: 2.19-2.41). in the paper of ori et al. (15) in 44 biopsied patients with an older model of ultrasonograph with a 98% of sample adequacy for histological analysis, 4.7 ± 0.3 passages (ic 95%: 4.61-4.79) were performed, while in 41 biopsied patients with a newer ultrasonograph, with a 95% of sample adequacy for histological analysis, 4 ± 0.1 passages (ic 95%: 3.97-4.03) were performed, that is a statistically significant smaller number of needle passes when compared to the other group of 44 patients (table 3). by comparing these data with those of our larger survey in which with a 100% of sample adequacy for the histological analysis, 1.1 ± 0.30 needle passes (ic 95%: 1.021.18) were performed, it clearly emerges a statistically significant difference already found in our preliminary series (4) (table 3). regarding the complications related to renal biopsy and specifically the hemoglobin variations between the prebiopsy value and the one found after an average interval of 6 hours from the biopsy, we could only compare maya and allon's paper (6 ) and the paper of ori et al. (15) since in the work of lin et al. (14) blood count was not routinely collected in all patients after renal biopsy. then comparing 95% confidence intervals for the pre and post-biopsy variation of hemoglobin, we observed that there was no statistically significant difference with maya and allon work data (as in the pilot survey already published) (6), while there was a statistically significant difference with the subgroup of 44 patients undergoing biopsy with the aid of an older ultrasonograph in the work of ori et al. (15) where the hemoglobin reduction was significantly greater than in our patients. indeed there was no statistically significant difference between our data and those of the second group of 41 31archivio italiano di urologia e andrologia 2018; 90, 1 a new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory table 2. results. patients, n. 50 needle passes, n.* 1.10 ± 0.30 sample adequacy for the histological analysis 100% small non-significant hematomas, n. 20 (40%) large hematomas, n. 0 macrohematuria, n. 1 embolizations, n. 0 blood transfusions, n. 0 death, n. 0 hemoglobin decrease (g/dl) to 6 hours after biopsy* -0.44 ± 0.89 hemoglobin fall ≥ 2 gr/dl after biopsy as percent of the total patients 4.25% * mean ± sd brardi2_stesura seveso 03/04/18 11:06 pagina 31 archivio italiano di urologia e andrologia 2018; 90, 1 s. brardi, g. cevenini, a.g. bonadio 32 patients in the same work by ori et al. (15) that were biopsied with the aid of a newer ultrasonography that, as already mentioned, were subjected to a statistically minor number of needle passes than the other group in the same study (table 4). however, to properly evaluate the outcome of this comparison it is necessary to keep in mind that while in the work of ori et al. (15), as in ours, 16 gauge needles were used and the patient remained in bed for the first 24 hours, 18-gauge needles were used in maya's and allon's work (6), and the observation time was limited to only eight hours. since, as well explained in whittier et al. (13), the clinical recognition of major complications increases proportionally to observation time, it is legitimately possible to assume that an observation time of only eight hours (as in the maya and allon's work) (6) may have lost up to 33% of later post-biopsy complications and this is the reason why the only work that can be compared with ours (for the needle gauge and for the duration of the monitoring period) is that of ori et al. (15). likewise, and for the same reasons, regarding to the major complications of renal biopsy (macrohematuria, blood transfusions or deaths) and the formation of post-biopsy hematomas, the only work comparable with ours remains that of ori et al. (15) where in front of only one patient with gross hematuria, two patients (4.5% of the total) in the group of 44 patients subjected to biopsy with an older ultrasonograph and two patients (4, 9% of the total) of the group of 41 biopsied patients with a newer ultrasonograph were transfused, while in our present larger survey in front of only one patient with gross hematuria no major complication was reported and no patient was transfused except one female that did not comply with post-biopsy bed resting and had to be transfused after 24 hours. in the same work by ori et al. (15) significant hematomas were also reported in 5 patients (equal to 11.4% of the total) of the group of 44 patients subject to biopsy with an older ultrasonograph and in 2 patients (equal to 4.9% of the total) of the group of 41 patients subjected to biopsy with a newer ultrasonograph, while in our larger survey, as well as in the preliminary study (4), only non-significant (i.e. with a maximum thickness of ≤ 2 cm) (1, 2) hematomas were found in 20 patients equal to 40% of the total (table 2). this high number of non-significant hematomas, however, may be related to the fact that while in the work of ori et al. (15) after ultrasound examination performed at the time of biopsy, no further ultrasound tests were performed except in the case of complications, in our protocol, renal ultrasound was repeated at 6 and 24 hours after the biopsy in all patients regardless of any symptomatology. conclusions the data provided by the present larger survey confirm the findings of our preliminary series (4) though the lack of a control group is still a limitation of the strength of our conclusions. on this basis we believe that the percutaneous renal biopsy with perforated ultrasound probe and perpendicular needle trajectory, performed in that portion of kidney lower pole where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition, allows to obtain (in native adult kidneys) samples suitable for histological analysis comparable to those provided by repeated needle passes performed according to the classical technique. the statistically lower number of passages is explained by the abundance of cortical tissue that the needle crosses. performing the needle pass in that portion of the lower pole of the kidney where there is no renal sinus interposition and so avoiding to damage the smaller kidney calices of the lower group whose lesion causes hematuria (5) achieved in this larger survey as in the preliminary smaller sample (4), a post-biopsy reduction of the hemoglobin statistically lower than that observed in a subgroup of 44 biopsied patients with an older ultrasonograph and therefore subjected to a statistically significant greater number of needle passes ori et al. (15). table 3. 95% confidence interval (ci) for the needle passes. author patients, n. needle gauge number 95% ci duration of of needle passes post-biopsy monitoring (years of publication) (mean ± sd) (hours) maya and allon (2009) 100 16 e 18 gauge 1.6 ± 0.8 1.44-1.76 8 (but the 16 gauge was used more frequently) lin et al. (2006) 183 (outpatients) 16 and 18 gauge 2.2 ± 0.6 2.11-2.29 6 (but the 16 gauge was used more frequently) 147 (inpatients) 2.3 ± 0.7 2.19-2.41 ori et al. (2002) 44 (subject to biopsy 16 4.7 ± 0.3 4.61-4.79 24 by an older ultrasonograph) 41 (subjected to biopsy 16 4 ± 0.1 3.97-4.03 by a newer ultrasonograph) brardi s et al. (2017) 50 16 1.10 ± 0.30 1.02-1.18 24 table 4. 95% confidence interval (ci) for the hemoglobin variations after biopsy. author patients, n. hemoglobin 95% ci for the variations hemoglobin variations (years of publication) (g/dl)* (g/dl)* maya and allon (2009) 100 -0.54 ± 0.29 -0.48-0.6 ori et al. (2002) 44 (subjected to -0.86 ± 0.16 -0.91-0.81 biopsy by an older ultrasonograph) 41 (subjected to -0.47 ± 0.10 -0.5-0.44 biopsy by a newer ultrasonograph) brardi s et al. (2017) 50 -0.44 ± 0.89 -0.18-0.69 *mean ± sd brardi2_stesura seveso 03/04/18 11:06 pagina 32 as already pointed out in the study of eiro et al. (7) and also reported by zhu et al. (16) in a recent review of factors that can minimize post-biopsy bleeding, although the frequency of needle passes does not differ significantly between cases with moderate complications and cases with no or only mild complications, the frequency of needle passes however represents an independent risk factor, as evidenced by the multivariate logistics analysis conducted in the work of eiro et al. (7). besides the frequency of the needle passes is amongst all (age > 60 years, marked hypertension with pas > 140 or pad > 90 mmhg and amyloidosis) the only risk factor for bleeding, as highlighted in the work of eiro et al. (7), that can be addressed using a technique such as described here, oriented to minimize the number of the needle passes. to confirm this we can also remember the already mentioned fact that with the use of 18 gauge needles, despite a lower caliber, a greater number of complications were found, probably due to the greater number of needle passes required to obtain valid samples for the histological analysis (10, 11). references 1. commissione sin-siapec. requisiti per la biopsia renale: diagnostica nefropatologica ed esecuzione clinica. release 1. in: best practice; www.nephromeet.com. 12 novembre 2015. 2. parrish ae. complications of percutaneous renale biopsy: a review of 37 years'experience. clin nephrol. 1992; 38:135-41. 3. brachemi s, bollèe g. renal biopsy practice: what is the gold standard? world j nephrol. 2014; 3:287-294. 4. brardi s, et al. una variante della tecnica classica eco guidata della biopsia renale percutanea: l’approccio perpendicolare in scansione longitudinale con sonda forata. gin. 2017; 34:146-156. 5. meola m, barsotti g, cupisti a, et al. free-hand ultrasoundguided renal biopsy: report of 650 consecutive cases. nephron. 1994; 67:425-430. 6. maya id, allon m. percutaneous renal biopsy: outpatient observation without hospitalization is safe. seminars in dialysis. 2009; 22:458-461. 7. eiro m, katoh t, watanabe t. risk factors for bleeding complications in percutaneous renal biopsy. clin exp nephrol. 2005; 9:40-45. 8. geldenhuys l, nicholson p, sinha n, et al. percutaneous native renale biopsy adequacy: a successful interdepartmental quality improvement activity. canadian journal of kidney health and disease 2015; 2:8. 9. visconti l, cernaro v, ricciardi ca, et al. renal biopsy: still a landmark for the nephrologist. world j nephrol. 2016; 5:321-327. 10. tøndel c, vikse be, bostad l, svarstad e. safety and complications of percutaneous kidney biopsies in 715 children and 8573 adults in norway 1988-2010. clin j am soc nephrol. 2012; 7:1591. 11. cagnoli l, fuiano g, imbasciati e, et al. linee guida sulle indicazioni ed esecuzione della biopsia renale percutanea e sulla terapia delle nefropatie glomerulari. linee guida sin revisione 2003. giornale italiano di nefrologia. 2003; 20:s3-s47. 12. corapi km, chen jl, balk em, gordon ce. bleeding complications of native kidney biopsy: a systematic review and meta-analysis. am j kidney dis. 2012; 60:62. 13. whittier w l, korbet s m. timing of complications in percutaneous renal biopsy. j am soc nephrol. 2004; 15:142-147. 14. lin wc, yang y, wen yk, chang cc. outpatient versus inpatient renal biopsy: a retrospective study. clinical nephrology. 2006; 66:17-24. 15. ori y, neuman h, chagnac a, et al. using the automated biopsy gun with real-time ultrasound for native renale biopsy. imaj. 222; 4:698-701. 16. zhu ms, chen jz, xu ap. factors that can minimize bleeding complications after renale biopsy. int urol nephrol. 2014; 46:19691975. 33archivio italiano di urologia e andrologia 2018; 90, 1 a new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory correspondence simone brardi, md sibrardi@gmail.com hemodialysis unit, s. donato hospital, arezzo, italy gabriele cevenini, md department of medical biotechnologies, university of siena, italy angelo giovanni bonadio, md pathological anatomy 1, university of pisa, pisa, italy brardi2_stesura seveso 03/04/18 11:06 pagina 33 97archivio italiano di urologia e andrologia 2018; 90, 2 original paper l-methionine associated with hibiscus sabdariffa and boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: focus on antibiotic-sparing approach tommaso cai 1, andrea cocci 2, daniele tiscione 1, marco puglisi 1, fabrizio di maida 2, gianni malossini 1, paolo verze 3, alessandro palmieri 3, vincenzo mirone 3, truls e. bjerklund johansen 4 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology, university of florence, florence, italy; 3 department of urology, university of naples, federico ii, naples, italy; 4 department of urology, oslo university hospital and institute of clinical medicine, university of oslo, oslo, norway. objective: to evaluate the efficacy of a phytotherapic combination of l-methionine associated with hibiscus sabdariffa and boswellia serrata for treatment of acute episodes of uncomplicated urinary tract infections (uti) in women affected by recurrent utis. materials and methods: in this randomized phase iii clinical trial, adult females with uncomplicated uti were enrolled into one of the following treatment groups: group a: phytotherapic combination 1 tablet in the morning and 1 tablet in the evening for 7 days; group b: short term antibiotic treatment according to international guidelines recommendations. at baseline, all patients were evaluated by a urologist and quality of life (qol) questionnaires and mid-stream urine culture. same clinical and laboratory investigations were repeated at each follow-up visit. results: forty-six patients were enrolled in group a and 47 in group b. at the first follow-up (30 days), both groups showed a statistically significant improvement in quality of life scores as compared with baseline assessment [group a: (qol 94.3 vs 98.5 p < 0.001); group b: (qol 94.5 vs 98.7 p < 0.001)]. an improvement from baseline was also seen at the second followup evaluation after 3 months [group a: (qol 94.3 vs 99.1 p < 0.001); group b: (qol 94.5 vs 98.1 p < 0.001)]. at the second follow-up visit, a statistically significant difference in qol was reported between the two groups (99.1 vs 98.1; p < 0.003) and a transition from uti to asymptomatic bacteriuria (abu) was observed 12 of 46 (26%) patients in group a, while no patients in group b demonstrated abu (p = 0.007). conclusions: here, we demonstrated that this phytotherapic combination is able, in comparison to antibiotic treatment, to improve patients quality of life, reducing symptoms in acute setting and preventing the recurrences. interestingly, a significantly higher proportion of patients in the phytotherapy group had abu after three months. our findings are of great interest in an antibiotic stewardship perspective. key words: urinary tract infection; l-methionine; hibiscus sabdariffa; boswellia serrata; plant extracts; antibiotic stewardship; treatment. submitted 19 march 2018; accepted 25 march 2018 summary no conflict of interest declared. significant impact on patients’ quality of life and public health care costs (1). more than half of women report having had at least one uti during their lifetime, and almost 11% of women suffer from a uti every year (23). in particular, 20-30% of women experience another uti within 6 months after their first episode (1). the most common management of recurrent utis is a short course of oral antimicrobial therapy, with possible alteration of the normal microbial flora of the vagina and/or gastrointestinal tract. moreover, frequent use of antibiotics for treatment and prevention of utis increases healthcare costs and the spread of multidrug-resistant microorganisms (4-7). nowadays, there are no universally accepted recommendations on prophylactic antibiotic management to prevent recurrent uti (3). reduced antibiotic prescription would not only prevent resistance but will also lower public health care costs. in this scenario, the use of phytotherapy for symptom relief and decrease of symptomatic recurrences in uti is an intriguing alternative (3). the aim of the present study was to compare the effectiveness of a combination of l-metionina associated with hibiscus sabdariffa and boswellia serrata (acidif plus®) and standard antibiotic treatment of acute episodes of uncomplicated uti in women affected by recurrent uti, focusing on qol improvement and the capability to reduce antibiotic usage. materials and methods study design this is a single centre, randomized and controlled phase iii study. from january to june 2017, we enrolled all women affected by recurrent uncomplicated uti seen in our referral centre. written informed consent was obtained from all subjects before proceeding with the enrollment. baseline assessment comprised evaluation by urologist, completion of qol questionnaires and a mid-stream urine culture. all patients in the antibiotic arm were treated according to an empirical approach, in line with the doi: 10.4081/aiua.2018.2.97 introduction urinary tract infections (utis) represent one of the most common community-acquired infectious diseases with cai_stesura seveso 28/06/18 16:34 pagina 97 archivio italiano di urologia e andrologia 2018; 90, 2 t. cai, a. cocci, d. tiscione, m. puglisi, f. di maida, g. malossini, p. verze, a. palmieri, v. mirone, truls e. bjerklund johansen 98 european association of urology (eau) guidelines recommendations (8). the results of mid-stream urine culture were used only for confirmation of the diagnosis and not for tailoring the treatment. all selected patients were, then, randomly allocated into one of the two following groups: • group a: one-week therapy of acidif plus®, 1 tablet in the morning and 1 tablet in the evening for 7 days. • group b: short term antibiotic therapy according to the trialist’s choice based on the eau guidelines on urological infections (8). after one week from the start of treatment, all patients were contacted by phone in order to ensure compliance to the treatment in both arms. the follow up schedule included urologic visit after one and three months with qol questionnaires and mid-stream urine cultures. the study schedule is shown in figure 1. composition and characterization of the phytotherapeutic extracts used all patients who were randomized to the acidif plus® group received oral administration of 1 tablet of acidif plus® in the morning and 1 tablet in the evening, in line with the manufacturer’s instructions (biohealth srl, rivoli to), italy (http://www.biohealth.it/it/prodotti/linea-acidif/25-acidif-plus). each dose contained a combination of 400 mg of lmethionine associated with 100 mg of hibiscus sabdariffa and 100 mg of boswellia serrata (l.) roxb. inclusion and exclusion criteria exclusion criteria comprised: evidence of overactive bladder; anatomical abnormalities or previous surgery of the urinary tract; complicated uti; intake of antibiotics within 4 weeks before enrollment; pregnancy; indwelling urinary catheter or stent. microbiological and clinical considerations treatment failure in group a was defined as microbiological colonization of at least 105 colony-forming units per milliliter (cfus/ml) of a single uropathogen in the midstream urine culture associated with the persistence of urinary tract symptoms. transition from symptomatic uti to asymptomatic bacteriuria was not considered as treatment failure, but was registered as an improvement in symptoms. in case of treatment failure in group a, patients underwent a short course of antibiotic therapy according to the antibiogram and guidelines recommendations. outcome measures and statistical analysis the primary endpoint was the rate of responders defined as the demonstration of urinary pathogens < 103 cfu/ml in a mid-stream urine culture on the second and third follow up visit (after one and three months respectively from the beginning of the treatment) as well as improvement in symptoms scores. data about the compliance to treatment, frequency of uti recurrences or transition from symptomatic uti to asymptomatic bacteriuria at subsequent follow up visits were also recorded. in order to obtain valid results for analysis, sample size calculation was based on the following assumptions. difference between the groups, 3 ± 1 score points in the qol questionnaire; α error level, 0.05 twosided; statistical power, 80%; anticipated effect size, cohen’s d = 0.5. the calculation yielded 2×41 individuals per group. taking into account a drop-out rate of 10%, the final sample size was set to 90 patients in both groups. statistical analysis was performed by using spss. results ninety-three female patients with clinical evidence of un complicated uti entered the study. forty-six and fortyseven patients were enrolled in group a (mean age 46.5 range: 23-62) and group b (mean age 47.1 range: 22-63), respectively. demographic and clinical characteristics of the study population are shown in table 1. the most commonly isolated bacterial strain at the time of enrollment was escherichia coli (e. coli) in 86.9% (40/46) of patients in group a and in 82.9% (39/47) in group b, respectively. treatment compliance and treatment related adverse effects after 7 days treatment compliance was complete in group a (100%), while within group b 14.9% (7/47) of patients discontinued the prescribed therapy because of drug-related adverse effects. no side effects occurred in the phytotherapy group. figure 1. the figure shows the study schedule. qol: quality of life evaluation. group a: one-week therapy of acidif plus®, 1 tablet in the morning and 1 tablet in the evening for 7 days. group b: short term antibiotic therapy according to the trialist’s choice and eau guidelines on urological infections. cai_stesura seveso 28/06/18 16:34 pagina 98 first follow-up evaluation (30 days) at one month follow up visit, a statistically significant clinical improvement was reported in 95.7% (44/46) of patients in group a (qol 94.3 vs 98.5 p < 0.001) and 100% (47/47) in group b (qol 94.5 vs 98.7 p < 0.001), respectively. no statistically significant differences emerged when comparing qol results in the two groups. a sterile urine culture was reported in 80.4% (37/46) and in 95.7% (45/47) of patients in group a and group b, respectively. notably, in the remaining 19.6% (9/46) of patients within group a a transition from symptomatic uti to asymptomatic bacteriuria (abu) was observed and also a change in microorganism (from e. coli to enterococcus faecalis). on the contrary, only 4.3% (2/47) of patients among group b showed a transition from uti to abu. no treatment failures were recorded in group a. all findings at the first follow-up are shown in table 2. second follow-up evaluation (90 days) at the 3 month follow up visit, 95.7% (44/46) of patients in group a showed a clinically significant improvement (qol 94.3 vs 99.1 p < 0.001), as well as 95.7% (45/47) patients in group b (qol 94.5 vs 98.1 p < 0.001). a statistically significant difference emerged in terms of qol between the two groups (p < 0.003; 99.1 vs 98.1). in group a, 73.9% (34/46) of patients demonstrated a second sterile mid stream urine culture, while the remaining 26% (12/46) of patients showed a transition from symptomatic uti to abu and a change of microorganism (from e. coli to enterococcus faecalis) (p = 0.007). again, no treatment failures were recorded in group a while 2 patients in group b showed symptomatic uti with microbiological demonstration of escherichia coli. no patients in group b showed transition from uti to abu. table 2 shows all findings at the second follow-up visit. discussion although antimicrobials remain the mainstay of treatment for uti, the spread of multidrug resistant microorganisms among community-acquired isolates is worrying and calls for stronger surveillance and new preventive approaches. today, inappropriate antibiotic use and antimicrobial resistance have become major issues worldwide. unfortunately, there is no “gold standard” prophylactic regimen to prevent recurrent uti. actually, eau guidelines present several non-antibiotic measures for preventing recurrent utis but only few are based on well-designed randomized clinical trials (8). furthermore, many women have signs of utis without evidence of bacterial presence, a clinical condition known as abu. although abu is usually treated in women with recurrent utis there is no clear indication for this treatment. a significant body of recent evidence (6-7, 9) has demonstrated that antibiotic treatment of abu is not only pointless, but could even be harmful. particularly, in a randomized controlled study, cai et al. showed that after a 12-month period of antimicrobial therapy of abu in women affected by recurrent utis, the rate of symptomatic utis was higher in patients treated with antibiotics. there was also a higher prevalence of multidrug-resistant e. coli after antibiotic treatment of abu due to enterococcus faecalis (9). these data suggest that abu could play a protective role in preventing symptomatic recurrences, interfering with the settlement in the urinary tract of many enteric pathogens, such as e. coli. in this sense, a non-antibiotic approach should be preferred because it doesn’t modify the normal commensal bowel flora. as a result, research on non-antibiotic prophylaxis of recurrent utis has gradually grown during recent years. particularly, the use of phytotherapy and neutraceuticals could represent a feasible alternative 99archivio italiano di urologia e andrologia 2018; 90, 2 nutraceuticals and recurrent uti table 1. demographic, clinical and microbiological characteristics of all enrolled and analysed women, at the baseline. group a: one-week therapy of acidif plus ®, 1 tablet in the morning and 1 tablet in the evening for 7 days. group b: short term antibiotic therapy according to the trialist’s choice and eau guidelines on urological infections. demographic and clinical characteristics of the study population at baseline group a group b p enrolled patients 46 47 age (mean) 46.5 47.1 previous uti per year (mean) 4.3 4.7 number of sexual partners 1 44 (95.6) 43 (91.4) > 1 marital status married 31 (67.3) 29 (61.7) single 15 (32.7) 18 (38.3) sexual encounters per week (mean) 2.1 2.0 bacterial strains e. coli 40 (86.9) 39 (82.9) e. faecalis 2 (4.4) 2 (4.3) e. faecium 1 (2.2) 1 (2.2) klebsiella spp. 3 (6.5) 5 (10.6) table 2. outcome variables before and after treatment, in the two groups. group a: one-week therapy of acidif plusn®, 1 tablet in the morning and 1 tablet in the evening for 7 days. group b: short term antibiotic therapy according to the trialist’s choice and eau guidelines on urological infections. abu: asymptomatic bacteriuria; uti: symptomatic urinary tract infection; n.s.: not statistically significant. outcomes variable baseline follow-up follow-up p 30 days 90 days clinical improvement group a 0/46 44/46 (95.5) 44/46 (95.5) < 0.001 group b 0/47 47/47 (100) 45/47 (95.7) < 0.001 p (between the groups) n.s. n.s. qol (questionnaire) group a 94.3 98.5 99.1 < 0.001 group b 94.5 98.7 98.1 < 0.001 p (between the groups) n.s. < 0.003 microbiological improvement sterile urine group a 0/46 37/46 (80.4) 34/46 (73.9) n.s. group b 0/47 45/47 (95.7) 44/47 (93.6) n.s. p (between the groups) n.s. n.s. transition to abu from uti group a 9/46 (19.6) 12/46 (26) n.s. group b 2/47 (4.3) 0/46 n.s. p (between the groups) n.s. 0.007 cai_stesura seveso 28/06/18 16:34 pagina 99 archivio italiano di urologia e andrologia 2018; 90, 2 t. cai, a. cocci, d. tiscione, m. puglisi, f. di maida, g. malossini, p. verze, a. palmieri, v. mirone, truls e. bjerklund johansen 100 approach for reducing the use of antibiotics and decreasing the rate of symptomatic recurrences (3, 10-11). in this light, we wanted to evaluate an oral supplementation of l-methionine combined with hibiscus sabdariffa and boswellia serrata (named acudif plus®). l-methionine is a sulfur donor which is necessary for the biosynthesis of cysteine, a sulfide aminoacid. a physiological ph is obtained by the action of l-methionine which creates unfavorable conditions for bacterial colonization since a large number of gram-negative bacteria are able to alkalize the urine by enzymatic degradation of urea. furthermore, dry extract of hibiscus sabdariffa is a phytocomplex containing sambubiosides, which seems to have an anti-inflammatory activity by lowering the levels of inflammatory mediators including inos, no, il-6, mcp1, and tnf-α induced by lps (12). moreover, several preliminary studies demonstrated that hibiscus sabdariffa is able to prevent recurrent uncomplicated urinary tract infections due to its inhibitory activity against escherichia coli and candida albicans (13). finally, boswellia serrata also seems to inhibit some inflammation mediators, in particular 5-lipoxygenase, with a subsequent decrease in inflammatory response mediated by leukotrienes (14). in our knowledge, this is the first study evaluating the prophylactic effect of l-methionine associated with hibiscus sabdariffa and boswellia serrata extracts in women suffering from recurrent uncomplicated utis. in a recent multicenter observational study passaro et al. (15) had already assessed the effectiveness of acidif plus® in reducing the bacterial load and improving symptoms in pregnant women affected by symptomatic uti. in our experience, acid plus® was well tolerated with optimal compliance and no side effects. as many as 95.7% (44/46) of patients demonstrated relevant clinical improvement with a statistically significant difference compared to women treated with standard antibiotic therapy 3 months after the beginning of treatment. moreover, at first follow up visit almost 20% of patients within group a showed a transition from symptomatic uti to abu with lasting results at 3 months. noteworthy, the fact that acidif plus® was able to establish an abu is a tangible proof of absence of effect on the normal urine microbiota. increased understanding of the action of phytotherapy and nutraceuticals will enable us to develop appropriate non-antibiotic treatment and prevention strategies for recurrent utis (16). larger highquality studies are required to confirm the findings in our study. conclusions urinary tract infections affect a large number of women and many suffer from recurrent utis. actually, current antibiotic treatments select multi-drug resistant microorganism, both in the gut and in the bladder, and this practice is no longer sustainable. use of phytotherapy and nutraceuticals is an intriguing approach to reduce the excessive prescription of antibiotics. in the present study we could demonstrate that acidif plus® was able to improve patients qol, lower symptoms in the acute setting and prevent uti recurrences in women with recurrent utis as compared to antibiotic treatment. further prospective studies are needed to validate our results. references 1. silverman ja, schreiber hl 4th, hooton tm, hultgren sj. from physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. curr urol rep. 2013; 14:448-56. 2. foxman b, barlow r, d'arcy h, et al. urinary tract infection: selfreported incidence and associated costs. ann epidemiol. 2000; 10:509-515. 3. cai t, tamanini i, kulchavenya e, et al. the role of nutraceuticals and phytotherapy in the management of urinary tract infections: what we need to know? arch ital urol androl. 2017; 89:1-6. 4. kostakioti m, hultgren sj, hadjifrangiskou m. molecular blueprint of uropathogenic escherichia coli virulence provides clues toward the development of anti virulence therapeutics. virulence. 2012; 3:592-594. 5. gupta k, scholes d, stamm we. increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. jama 1999; 281:736-8. 6. cai t, mazzoli s, mondaini n, et al. the role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? clin infect dis. 2012; 55:771. 7. cai t, koves b, johansen te. asymptomatic bacteriuria, to screen or not to screen and when to treat? curr opin urol. 2017; 27:107-111. 8. european association of urology guidelines on urological infections. http://uroweb.org/guideline/urological-infections/ 9. cai t, nesi g, mazzoli s, et al. asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. clin infect dis. 2015; 61:1655-61. 10. stange r, schneider b, albrecht u, et al. results of a randomized, prospective, double-dummy, double-blind trial to compare efficacy and safety of a herbal combination containing tropaeoli majoris herba and armoraciae rusticanae radix with cotrimoxazole in patients with acute and uncomplicated cystitis. res rep urol. 2017; 9:43-50. 11. ledda a, belcaro g, dugall m, et al. highly standardized cranberry extract supplementation (anthocran®) as prophylaxis in young healthy subjects with recurrent urinary tract infections. eur rev med pharmacol sci. 2017; 21:389-393. 12. sogo t, terahara n, hisanaga a, et al. anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a hibiscus anthocyanin. biofactors. 2015; 4:58-65. 13. utirose™: a natural answer to urinary tract infections issues. brochure produit, rso -002/1, certifié par bureau veritas. 14. pandey rs, singh bk, tripathi yb. extract of gum resins of boswellia serrata l. inhibits lipopolysaccharide induced nitric oxide production in rat macrophages along with hypolipidemic property. indian j exp biol. 2005; 43:509-16. 15. passaro m, mainini g, ambrosio f, et al. effect of a food supplement containing l-methionine on urinary tract infections in pregnancy: a prospective, multicenter observational study. j altern complement med. 2017; 23:471-478. 16. cai t, mazzoli s, migno s, et al. development and validation of a nomogram predicting recurrence risk in women with symptomatic urinary tract infection. int j urol. 2014; 21:929-34. correspondence tommaso cai, md ktommy@libero.it daniele tiscione, mdmarco puglisi, md gianni malossini, md department of urology, santa chiara hospital largo medaglie d'oro 9, trento, italy andrea cocci, md fabrizio di maida, md department of urology, university of florence, florence, italy paolo verze, md alessandro palmieri, md vincenzo mirone, md department of urology, university of naples, federico ii, naples (italy) truls e. bjerklund johansen, md department of urology, oslo university hospital and institute of clinical medicine, university of oslo, oslo (norway) cai_stesura seveso 28/06/18 16:34 pagina 100 archivio italiano di urologia e andrologia 2019; 91, 130 original paper sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function daniele tiscione 1, tommaso cai 1, lorenzo giuseppe luciani 1, marco puglisi 1, daniele mattevi 1, gabriella nesi 2, mattia barbareschi 3, gianni malossini 1 1 department of urology, santa chiara regional hospital, trento, italy; 2 division of pathological anatomy, university of florence, italy; 3 division of pathological anatomy, santa chiara regional hospital, trento, italy. objectives: we evaluated the efficacy of sutureless laparoscopic partial nephrectomy (lpn), using a fibrin gel in order to minimize renal ischemia time and preserve kidney function. materials and methods: nineteen patients (mean age 58.3 ± 7.1) undergoing sutureless lpn using a fbrin gel were compared with a control group consisting of 21 patients (mean age 57.9 ± 7.5) subjected to lpn with standard suturing. intraand post-operative data for the two groups were compared. the following parameters were recorded: patient demographics, charlson comorbidity index, tumor characteristics according to the renal score, warm ischemia and operative times, estimated blood loss, mean hospital stay, post-operative complications referring to the clavien-dindo classification, renal function parameters pathologic and follow-up data. the main outcome measure was renal ischemia time and maintenance of kidney function. results: median warm ischemia time was 13 minutes (range 11-19) in the group treated with fibrin gel and 19 (range 1729) in the control group, with a statistically significant difference (p < 0.001). the two groups were homogeneous in terms of the charlson comorbidity index (4.6 vs 4.8) and renal score (9.6 vs 9.4). median operative time differed significantly in the two groups, 183 minutes (range 145-218) in the group treated with fibrin gel and 201 (range 197-231) in the control group (p < 0.001). a negative surgical margin was reported in 18 patients (94.7%) in the group treated with fibrin gel and in 21 patients (100%) in the control group. no difference in renal function was found between the two groups. conclusions: sutureless lpn with fibrin gel can reduce warm ischemia and total operative time while preserving kidney function. key words: laparoscopic partial nephrectomy; renal cell carcinoma; haemostatic agent; fibrin sealant; complication. submitted 10 august 2018; accepted 5 november 2018 summary no conflict of interest declared. because of the difficulties in hemostasis and management of collecting-system injuries (4). various techniques, instruments and agents have been proposed to minimize intracorporeal suturing and warm ischemia time, but there is no consensus regarding the best approach when dealing with these issues (5). a wide variety of hemostatic agents (ha) and tissue sealants have been employed, the majority approved for use in urology (6). levinson et al. described the first series of 7 partial nephrectomies with these agents, highlighting the safety of the procedure, its contribution to lowering warm ischemia time and the absence of any reported complications (7). hidas compared changes in renal function after nephron-sparing surgery (nss) using has alone versus standard suturing; and reported renal functional loss of 11% versus 20%, respectively, highlighting how the surgeon should aim for shorter warm ischemia times (8). the present study assessed the efficacy of sutureless lpn using a fibrin gel (tissucol®) in order to minimize renal ischemia time and preserve kidney function, when compared with lpn standard suturing. materials and methods study design data from 19 patients (mean age 58.3 ± 7.1) who had undergone sutureless lpn using tissucol® between october 2008 and july 2009 were compared with those from a control group of 21 patients (mean age 57.9 ± 7.5) subjected to lpn with standard suturing during the same period. all patients underwent standard laboratory examinations and radiologic evaluations before tumour staging and surgical planning. demographic and tumor characteristics following the renal score were recorded and the charlson comorbidity index was calculated. all procedures were carried out by a single dedicated uro-oncologic surgeon (g.m.). the following variables were also recorded: operative time, warm ischemia time, estimated blood loss, intra-operative transfusion and complications (intra-operative data); post-operative complications using the clavien-dindo classification and any subsequent treatment, post-operative hospital stay, renal function, pathologic and follow-up findings (post-operative data). renal function was evaluated through a change in serum creatidoi: 10.4081/aiua.2019.1.30 introduction laparoscopic partial nephrectomy (lpn) is the “first-choice treatment” for patients with small renal masses (≤ 4 cm). oncological outcomes are similar to those observed after a radical procedure, with well demonstrated benefits such as a lower risk of long-term renal insufficiency and consequently better prospects for the quality of life (1-4). however, lpn remains a technically complex procedure tiscione_stesura seveso 25/03/19 17:16 pagina 30 31archivio italiano di urologia e andrologia 2019; 91, 1 sutureless laparascopic partial nephrectomy using fibrin gel nine or estimated glomerular filtration rate (egfr) from the baseline according to gill et al. (9). percent change in serum creatinine and egfr was determined by calculating the difference between pre-operative and follow-up data. follow-up visits were scheduled every 6 months after surgery. here, we present the long-term follow-up (12 months) results of renal function preservation. ethical consideration the retrospective nature of the study did not require the ethical committee approval. the study was, however, conducted in line with good clinical practice guidelines, with ethical principles laid down in the latest version of the declaration of helsinki. inclusion and exclusion criteria requirements for inclusion were the presence of a single, solid, contrast-enhanced parenchymal renal mass (attenuation increase > 15 h on contrast-enhanced ct or > 15% on gadolinium-enhanced mri) consistent with renal cell carcinoma on pre-operative imaging and scheduled for lpn (10). patients with severe medical or psychiatric illness barring adequate informed consent, under 18 or over 85years, with major concomitant diseases precluding surgical treatment or who had had radiation therapy to the retroperitoneum or previous abdominal major surgery, with an asa score ≥ 3, poor performance status (ecog 3-4), known anatomical abnormalities of the uro-genital tract, renal vein involvement, lymphadenopathy, extrarenal tumor extension or preoperative ct scan documenting invasion of the collecting system were all excluded. patients with positive cytologic urine analysis or with a previous history of urothelial carcinoma were also excluded. renal score and charlson comorbidity index the r.e.n.a.l.-nephrometry score (ns) was calculated according to kutikov et al. (11). in brief, standardized points (1-3 points per descriptor) are assigned based on tumour size, endophytic/exophytic properties, proximity to the collecting system and lesion location relative to the polar lines. the charlson comorbidity index was calculated using the specific software available on the institute for algorithmic medicine website (a texas non-profi corporation) (http://www.medal.org/onlinecalculators/ch1/ ch1.13/ch1.13.01.php) (12). surgical technique description (tissucol® group) patients were positioned in strict lateral decubitus and four trocars were routinely inserted. lpn was performed via a transperitoneal approach. no pre-operative ureteral stent was routinely placed. gerota’s fascia was opened, the ureter identified and the renal artery isolated (figure 1). vascular control was achieved by clamping the renal artery before tumour resection (figure 1) (warm ischemia time included tumour resection, evaluation of bleeding and application of sealant). during warm ischemia, resection was performed with an electrocautery device and cold-cut endo-shears (figure 2). the perinephric fat was dissected from the kidney at the level of the renal capsule, leaving only the fat overlying the tumour. in all cases, fibrin glue (tissucol® baxter ag) was used as the sealant (figure 3). no additional methods of hemostasis (including suturing) were applied. fibrin glue was spread on the tumour bed using a specific device that allowed the two major components to be applied simultaneously. we used a dual chamber delivery system, in which fibrinogen and factor xiii contained in one chamber were admixed with thrombin in the other directly at the application site. clot formation required 3 minutes and final elimination by macrophages occurred within 2-4 weeks without inducing fibrosis or foreign body reactions (13). the surgical specimen with the tumour and any detached perinephric fat was immediately placed in an endo-catch® bag which was removed at the end of the procedure through the 12-mm port site, extending the incision if necessary (figure 4). biopsy and frozen sections of the resection bed were only performed when tumour infilfigure 1. the figure shows renal vein (v) and artery (a) isolation (above) and the subsequent renal artery clamping (below). figure 2. the figure shows the renal mass resection with an electrocautery device and cold-cut endosheares. t: tumour. tiscione_stesura seveso 25/03/19 17:16 pagina 31 archivio italiano di urologia e andrologia 2019; 91, 1 d. tiscione, t. cai, l.g. luciani, m. puglisi, d. mattevi, g. nesi, m. barbareschi, g. malossini 32 tration was suspected, as suggested by porpiglia (14). in the case of a positive biopsy, radical nephrectomy or deeper resection depended on the individual case. all patients in the control group underwent standard suturing lpn, as described by porpiglia (14). histological analysis histopathology was reviewed according to the 2004 who classification (15). all renal cell carcinomas were classified according to the tnm staging system (16), while nuclear grade was assigned according to the criteria proposed by fuhrman et al. (17). preoperative complication evaluation perioperative complications were classified according to the clavien-dindo system (18). statistical analyses data were entered into a microsoft excel database and transferred to spss 11.0 for apple-macintosh (spss, inc., chicago, illinois). descriptive analysis was used to evaluate all the variables considered. qualitative analyses were compared using the chi-2 or fisher exact tests where applicable, and quantitative analyses with student’s t-test. data are presented as the mean ± standard deviation (sd) or percentage. correlations were assessed by pearson or spearman test. statistical significance was achieved if p was less than 0.05. all reported p-values were two-sided. results patient characteristics at baseline in the tissucol® group, the mean age-adjusted charlson comorbidity index was 4.6 (range 4-7) and mean renal score 9.6 (range 8-12), and in the control group 4.8 (range 4-7) and 9.4 (range 8-11), respectively. table 1 gives the clinical, laboratory and pathologic characteristics of the enrolled patients. intra-operative and peri-operative data tissucol® group after 2-3 minutes of applying the fibrin glue to the resection site, hemostasis was immediate in all cases. all surgery was performed intracorporeally and without hand assistance. median vascular clamping time was 13 minutes (range 11-19) and median operative time 183 minutes (range 145-218). median blood loss was 300 ml (range 150-600). no open conversions were required. five patients (26.3%) presented low-grade complications (clavien ii). four patients (21%) needed blood transfusions, while one patient showed intraoperative invasion of the collecting system that had not been documented pre-operatively by ct scan. this patient was treated with ureteral stenting for 7 days. control group all surgery was carried out intracorporeally without hand assistance. median vascular clamping time was 19 minutes (range 17-29) and median operative time was 201 minutes (range 197-231). median blood loss was 290 ml (range 150-550). there were no open conversions. eight patients (38%) showed low-grade complications (clavien ii), while five patients (23.8%) required blood transfusions. statistically significant differences were found between the two groups for mean ischemia time (p < 0.001), median operative time (p < 0.001) and mean blood loss (p < 0.02). all intra and peri-operative data are summarized in table 2. histological results in the tissucol® group, 18 cases were classified as conventional rcc and 1 as angiomyolipoma, while in the control group 19 were diagnosed as conventional rcc figure 3. the figure shows the intraoperative tissucol® application on the bed of resection. figure 4. the figure shows the resected tumour (t) with the overlying fat (ptf). t ptf tiscione_stesura seveso 25/03/19 17:16 pagina 32 33archivio italiano di urologia e andrologia 2019; 91, 1 sutureless laparascopic partial nephrectomy using fibrin gel and 2 as oncocytoma. there was no sign of residual tumor on frozen section examination of the resection bed in either group. all pathologic data are detailed in table 1. clinical outcome results post-operative hospitalization times were normal for all patients in the tissucol® group (median 5 days, range 4-7) with no relevant complications as regards wound healing or laboratory analyses. there were no significant short-term bleedings from the draining tubes, which were removed before patient discharge. no adverse events were observed during hospitalization or at long-term follow-up (79.6 ± 8.9 months). as regards post-operative hospitalization times or complications, no significant differences were found between the two groups. kidney function preservation post-operative renal function remained stable in all patients. no statistically significant differences were found between the two groups in terms of egfr results at the follow-up visit. in the tissucol® group mean egfr was 78.3 (range 42-127) and in the control group 79.4 (range 55-130). table 2 shows laboratory data at the time of enrolment and follow-up visit. discussion lpn is increasingly performed all over the world and constitutes a valid procedure for the management of small renal tumours, but some technical aspects still need to be improved. even in expert hands, rates of urine leakage and hemorrhage are not negligible (19). despite the development of adjunctive hemostatic agents, none have proved to offer complete hemostasis by themselves (19). in this paper, we demonstrated that sutureless lpn with tissucol® can reduce warm ischemia and total operative times as well as preserve kidney function, without severe complications when compared with standard suturing lpn. in particular, renal suturing during lpn is a difficult step, which increases operative and warm ischemia time. the use of has may well simplify the hemostatic procedure, providing similar results to those observed after suture renorrhaphy. our results highlight some important points. the mean ischemia time of 13.8 minutes is significantly shorter than that reported by lifshitz et al. (31 min) (20). thus, the mean total operative time (183 minutes) is also significantly shorter than described by other authors (14, 21). these results can be explained by the fact that a sutureless technique reduces both total ischemia and operative times. concerning renal function maintenance, our results are promising when compared with the standard technique, probably due to the shorter mean ischemia time in the tissucol® group. breda et al., in a comprehensive review of the practice patterns of urologists performing lpn and the relevant use of hemostatic agents, underlined that although these agents appear to offer some advantage, they should be limited to controlling minor bleeding and as an adjunct to sutured bolsters (22). in describing an alternative technique of lpn for central tumours, weight et al, concluded that in selected patients with a tumor extending table 1. patient anamnestic and clinical characteristics at enrolment time. table 2. peri-operative parameters, complications and renal function. group tissucol® control p no. of patients 19 21 mean age (years) (± sd*) 58.3 ± 7.1 57.9 ± 7.5 0.86 gender 0.72 male 13 16 female 6 5 mean tumor size at ct scan (cm) (± sd*) 3.1 ± 0.9 2.9 ± 0.8 0.78 charlson ci§ 4.6 4.8 r.e.n.a.l score 9.6 9.4 side of lesion 0.74 r° 6 8 l† 13 13 location of lesion 0.68 superior pole 5 4 inferior pole 7 9 central 7 8 location of lesion in renal parenchyma 0.72 exophytic 13 16 deep 6 5 pathological results renal cell carcinoma 18 19 angiomyolipoma 1 oncocytoma 2 fuhrman grade in malignant tumors 0.80 g1 6 (33.3) 7 (36.9) g2 7 (38.9) 9 (47.4) g3 5 (27.8) 3 (15.7) g4 0 0 stage according to uicc classification in malignant tumour 0.65 pt1b 16 (88.8) 15 (78.9) pt2 2 (11.2) 4 (21.1) group tissucol® control p mean operative time (min) (± sd*) 183 ± 25.9 201 ± 27.8 < 0.001 median ischemia time (min) (± sd*) 13 ± 2.3 19 ± 3.5 < 0.001 mean blood loss (ml) (± sd*) 359 ± 142.8 460 ± 126.7 0.02 rate of intra-operative transfusion (%) 4/19 (21) 5/21 (23.8) conversion to open nephrectomy 0/19 3/21 (14.2) 0.23 mean hospital stay (days) (± sd*) 5.8 ± 1.6 6.0 ± 1.5 post-operative acute hemorrhagic event 0/19 1/21 (4.7) post-operative hematoma with transfusion (%) 1/19 (5.2) 3/21 (14.2) 0.23 post-operative urinary leakage with uretheral stenting 1/19 (5.2) 2/21 (9.5) egfr (ml/min/1.73 m2) pre-operative (± sd*) 80.5 ± 10.9 81.2 ± 9.8 post-operative (± sd*) 78.3 ± 11.3 79.4 ± 13.3 tiscione_stesura seveso 25/03/19 17:16 pagina 33 archivio italiano di urologia e andrologia 2019; 91, 1 d. tiscione, t. cai, l.g. luciani, m. puglisi, d. mattevi, g. nesi, m. barbareschi, g. malossini 34 to the collecting system, the lpn defect can be safely reconstructed with a running intraparenchymal hemostatic suture and thrombin sealant with no bolstered renorrhaphy (23). we observed two post-operative complications (bleeding in one case and urine leak in the other), while no open conversion was necessary. in both cases the renal tumour was described as “deep”. several authors have demonstrated the association between depth of tumour invasion and rate of hemorrhage or urine leakage (21-22, 24). the present study shows some limitations that should be taken into account, such as the small number of patients and the lack of a control group. further prospective studies in larger series are mandatory to validate the role of has during lpn. conclusions in our experience, sutureless lpn using tissucol® can reduce warm ischemia and total operative time whilst preserving kidney function with no severe complications when compared with standard suturing lpn. acknowledgements we are grateful to all members of the department of urology (santa chiara regional hospital) for their help in patient data collection and to professor john denton for manuscript language revision. references 1. porpiglia f, fiori c, piechaud t, et al. laparoscopic partial nephrectomy for large renal masses: results of a european survey. world j urol. 2010; 28:525-29. 2. lee ct, katz j, shi w, thaler ht, et al. surgical management of renal tumors 4 cm or less in a contemporary cohort. j urol. 2000; 163:730-36. 3. uzzo rg, novick ac. nephron-sparing surgery for renal tumors: indications, techniques and outcomes. j. urol 2001; 166:6-18. 4. maclennan s, imamura m, lapitan mc, et al. systematic review of oncological outcomes following surgical management of localised renal cancer. eur urol. 2012; 61:972-93. 5. msezane lp, katz mh, gofrit on, et al. hemostatic agents and instruments in laparoscopic renal surgery. j endourol. 2008; 22:403-8. 6. hong ym, loughlin kr. the use of hemostatic agents and sealants in urology. j urol. 2006; 176:2367-74. 7. levinson ak, swanson da, johnson de, et al. fibrin glue for partial nephrectomy. urology. 1991; 38:314-16. 8. hidas g, lupinsky l, kastin a, et al. functional significance of using tissue adhesive substance in nephron-sparing surgery: assessment by quantitative spect of 99m tc-dimercaptosuccinic acid scintigraphy. eur urol. 2007; 52:785-89. 9. gill is, eisenberg ms, aron m, et al. "zero ischemia" partial nephrectomy: novel laparoscopic and robotic technique. eur urol. 2011; 59:128-34. 10. clark pe, woodruff rd, zagoria rj, hall mc. microwave ablation of renal parenchymal tumors before nephrectomy: phase i study. am j roentgenol. 2007; 188:1212-14. 11. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009; 182:844-53. 12. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40.373-83. 13. dalpiaz o, neururer r, bartsch g, peschel r. hemostatic sealants in nephron-sparing surgery: what surgeons need to know. bju int. 2008; 102:1502-08. 14. porpiglia f, volpe a, billia m, scarpa rm. laparoscopic versus open partial nephrectomy: analysis of the current literature. eur urol. 2008; 53:732-43. 15. eble jn, sauter g, epstein ji, et al. world health organization classification of tumours. pathology and genetics of tumours of the urinary system and male genital organs. lyon, france: iarc, 2004. 16. edge sb, byrd dr, compton cc, et al. ajcc cancer staging manual. springer-verlag ed, new york, 2010. 17. fuhrman sa, lasky lc, limas c. prognostic significance of morphologic parameters in renal cell carcinoma. am j surg. pathol. 1982; 6:655-63. 18. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-96. 19. louie mk, gamboa aj, kaplan ag, et al. bovine serum albumin glutaraldehyde for completely sutureless laparoscopic heminephrectomy in a survival porcine model. j endourol. 2010; 24:451-55. 20. lifshitz da, shikanov sa, deklaj t, et al. laparoscopic partial nephrectomy: a single-center evolving experience. urology. 2010; 75:282-87. 21. ramani ap, desai mm, steinberg ap, et al. complications of laparoscopic partial nephrectomy in 200 cases. j urol. 2005; 173:42-7. 22. breda a, stepanian sv, lam js, et al. use of hemostatic agents and glues during laparoscopic partial nephrectomy: a multi-institutional survey from the united states and europe of 1347 cases. eur urol. 2007; 52:798-803. 23. weight cj, lane br, gill is. laparoscopic partial nephrectomy for selected central tumours: omitting the bolster. bju int. 2007; 100:375-78. 24. venkatesh r, weld k, ames cd, et al. laparoscopic partial nephrectomy for renal masses: effect of tumor location. urology. 2006; 67:1169-74. correspondence daniele tiscione, md tommaso cai, md (corresponding author) ktommy@libero.it lorenzo giuseppe luciani, md marco puglisi, md daniele mattevi, md gianni malossini, md department of urology, santa chiara regional hospital, trento (italy) largo medaglie d'oro 9, trento (italy) gabriella nesi, md department of pathology, university of florence, florence (italy) mattia barbareschi, md department of pathology, santa chiara regional hospital, trento (italy) tiscione_stesura seveso 25/03/19 17:16 pagina 34 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4476 review no conflict of interest declared. was considered the standard of treatment justified by two randomized phase 3 trials (swog 8949, eortc30947) (1, 2). both trials showed an overall survival (os) benefit of cn followed by interferon-alpha (ifn-a) 2b versus interferon alone (1-3). since 2005, systemic therapies (st), such as vascular endothelial growth factor receptors (vegfr)-tyrosine kinase inhibitors (tki) and mammalian target of rapamycin (mtor) inhibitors, replaced cytokines as they have been proven superior to cytokines (4, 5). cn was evaluated, regarding possible advantages on os in mrcc patients treated with st, through multiple retrospective studies. the carmena trial (6) and the surtime trial (7), are the only randomized controlled trials (rct) investigating the role of cn in the st era. these two studies reduced the enthusiasm on upfront cn and opened a discussion about which patients treated with st could benefit more by cn. furthermore, new therapeutic agents such as immune check point inhibitors (ici), presented as superior to tki in recent studies (8-10). these controversial observations prompted us to conduct a systematic review in order to examine the role of cn for synchronous mrcc patients in the st era and beyond regarding the overall survival (os), the optimal sequence between st and cn and prognostic factors. methods the systematic review was conducted in accordance with the prisma guidelines (preferred reporting items for systematic reviews and meta-analysis) (11). bibliographic search was performed in medline (pubmed), clinicaltrials.gov, and cochrane library-cochrane central register of controlled trials (central). studies included were those indexed from 2005 in an attempt to limit those conducted in the cytokine era. the last search date was march 14, 2022. the following medical subject heading terms were used in combination with boolean operators (and, or, not): (“cytoreductive nephrectomy”) and ("targeted therapy" or "systemic therapy" or “immune oncology [io]” or immunotherapy or "immune checkpoint inhibitor*" or “immunooncology”) not (review[publication type]) not (meta-analysis[publication type]) not (systematic review[publication type]). two independent reviewers (k.s, t.l) screened all articles retrieved by the initial search. all disagreements were objective: to assess the role of cytoreductive nephrectomy for synchronous metastatic renal cell carcinoma patients in the systemic therapy era and beyond regarding the overall survival, the optimal sequence between systemic therapy and cytoreductive nephrectomy and prognostic factors. methods: the systematic review was conducted in accordance with the prisma guidelines. bibliographic search was performed in medline (pubmed), clinicaltrials.gov, and cochrane library-cochrane central register of controlled trials (central). studies included were those indexed from 2005 in an attempt to limit those conducted in the cytokine era. risk of bias assessment was performed by two authors (k.s and t.l) using the cochrane collaborative risk of bias tool for randomized trials, the cochrane risk of bias in non-randomized studies of interventions (robins-i) tool for nonrandomized studies. results: cytoreductive nephrectomy was associated with improved overall survival in all but one of the observational studies. while in all of these studies the unvariable analysis showed improved overall survival in favor of the cytoreductive nephrectomy group in some studies the subgroup analysis showed no benefit. regarding the optimal sequence, deferred cytoreductive nephrectomy demonstrated better results in more studies than upfront cytoreductive nephrectomy but a advantage was not clearly certain. in the analysis of possible prognostic factors for overall survival with cytoreductive nephrectomy, most common prognostic factors found were age (in 8 studies), tumor histology (in 7 studies), number of metastasis (in 6 studies), and t stage. conclusions: cytoreductive nephrectomy can still play an important role in wisely selected patients, although the role of cytoreductive nephrectomy in the new immunotherapy era needs to be defined. key words: cytoreductive nephrectomy; metastatic renal cell carcinoma; systemic therapy; immune check point inhibitors. submitted 4 september 2022; accepted 2 october 2022 introduction during the last two decades, the role of cytoreductive nephrectomy (cn) in the treatment of synchronous metastatic renal cell carcinoma (mrcc) has been reevaluated many times according to the newly discovered different oncological therapies. in the cytokine era, due to lack of significant effectiveness of medical therapies, cn cytoreductive nephrectomy for synchronous metastatic renal cell carcinoma. is there enough evidence? stamatios katsimperis, lazaros tzelves, themistoklis bellos, konstantinos pikramenos, ioannis manolitsis, ioannis tsikopoulos, iraklis mitsogiannis department of urology, athens, greece. doi: 10.4081/aiua.2022.4.476 summary 477archivio italiano di urologia e andrologia 2022; 94, 4 nephrectomy for metastatic renal cell carcinoma resolved with discussion, and final decision was reached by consensus with a third reviewer (m.i.). reference lists were systematically searched for relevant articles in a snowball procedure. an ethical approval is not required because this study is a review of the existing international literature. study criteria clinical trials, cohort studies, and case-control studies were considered for inclusion (figure 1). excluded studies met ≥ 1 of the following criteria: (1) irrelevant to the subject studies, (2) studies published in a nonenglish language, (3) case reports, case series including less than 10 patients, systematic reviews and meta-analyses, and (4) editorials, perspectives, and letters to the editors, (5) studies including only drugs from cytokine era (studies excluded are summarized in supplementary table 1). types of participants and exposure patients diagnosed with synchronous mrcc, who underwent cn. studies with patients undergoing partial nephrectomy, ablative procedures or nephrectomy for palliative reasons were not included. primary research question was the effect of cn in the os. secondary questions were the optimal sequence between systemic therapies and cn, and possible prognostic factors. risk of bias assessment risk of bias assessment was performed by two authors (k.s and t.l) using the cochrane collaborative risk of bias tool for randomized trials (12), the cochrane risk of bias in non-randomized studies of interventions (robins-i) tool for nonrandomized studies (13) (table 1). most common reasons for the studies evaluating the relationship between cn and os to be classified as having moderate or serious risk of bias were the unmeasured differences between cn and control groups and the inadequate adjustment for confounding factors. the inability to adjust for differences between groups was also found in the studies assessing the prognostic factors and the role of sequence between st and cn. moreover, the studies assessing the sequence between st and cn also demonstrated selection bias. results cytoreductive nephrectomy and overall survivor thirty studies were included in the analysis of the relafigure 1. prisma 2020 flow diagram for new systematic reviews which included searches of databases and registers only. archivio italiano di urologia e andrologia 2022; 94, 4 s. katsimperis, l. tzelves, t. bellos, k. pikramenos, i. manolitsis, i. tsikopoulos, i. mitsogiannis 478 tionship between cn and os (14-42, 65) (table 2). all of the studies except for one (41), which was a prospective randomized trial, were retrospective cohort studies. ten of them were from the surveillance, epidemiology, and end results (seer) database, 4 from international metastatic rcc database consortium (imdc), two from national cancer database (ncdb) and the rest were single or multi-center studies. most common systemic agent used was sunitinib (table 1), while there were three studies (2, 40, 42) comparing cn with the use of icis. these studies are of great importance, as they are the first retrospective studies on the role of cn in the immunotherapy era and demonstrated an os benefit in patients treated with ici plus cn compared to ici alone (hr 0.23-0.39, table 1. risk of bias assessment for non-randomized studies. first author confounding participant intervention deviation from missing outcome selected overall (year) selection classification inteended treatment data measurement reporrting bias day (2016) moderate moderate low low moderate low low moderate de groot (2016) moderate serious low low moderate low low serious hanna (2016) moderate serious low low moderate low low serious heng (2014) moderate serious low low low low low serious klatte (2018) moderate serious low low low low low serious patel (2017) serious moderate low low moderate moderate low serious tatsugami (2015) moderate moderate low low moderate low low moderate you (2011) moderate moderate low low low low low moderate abern (2014) serious moderate low low low low low serious conti (2014) serious moderate low low low low low serious marchioni (2019) serious moderate low low low low low serious patel (2017) serious moderate low low moderate moderate low serious aizer (2014) serious moderate low low low moderate low serious song (2016) serious serious low low low low low serious abel (2017) moderate moderate low low moderate low low moderate corcoran (2014) moderate moderate low low low low low moderate culp (2010) moderate moderate low low low low low moderate culp (2014) moderate moderate low low low low low moderate kalogirou (2017) serious moderate low low low low low serious sakai (2014) moderate moderate low low low low low moderate sharma (2015) moderate moderate low low moderate low low moderate you (2015) serious moderate low low low low low serious macleod (2017) moderate moderate low low moderate low low moderate stroup (2013) serious moderate low low low low low serious wood (2009) serious moderate low low low low low serious luzaggo (2021) moderate moderate low low low low low moderate singla (2020) moderate moderate low low low low low moderate palumbo (2020) moderate moderate low low low low low moderate choi (2018) moderate serious low low low low low serious janish (2020) moderate serious low low moderate low moderate serious alnimer (2021) moderate moderate low low low low low moderate vaishampayan (2019) serious moderate low low low low low serious graham (2019) moderate serious low low low moderate low serious you (2014) moderate moderate low low low low low moderate zhao (2019) serious moderate low low low low low serious poprach (2020) moderate moderate low low low low low moderate bakouny (2020) serious moderate low low low low low serious dragomir (2021) serious moderate low low low moderate low serious ljungberg (2020) serious serious low low low low low serious mcintosh (2020) moderate moderate low low low low low moderate rosiello (2019) serious serious low low low low low serious teishima (2018) serious moderate low low low low low serious adashek (2021) moderate moderate low low low low low moderate bhindi (2020) moderate moderate low low low low low moderate de bruijn (2020) serious serious low low low low low serious uprety (2018) moderate moderate low low low low low moderate study random allocation blinding of participants blinded outcome incomplete selective other overall sequence generation concealment and personnel assessment outcome data reporting bias risk of bias bex (2017) low low low low low low moderate moderate mejean (2018) low low low low low low moderate moderate risk of bias assessment for randomized studies. 479archivio italiano di urologia e andrologia 2022; 94, 4 nephrectomy for metastatic renal cell carcinoma table 2. studies evaluating the association between cn and os. study number systemic agents cn-systemic therapy median os (cn vs no cn) supplementary info of patients used sequence os hr (95% ci) for the study conti (2014) (14), retrospective cohort, n (total) = 20104 nr nr 15 vs 4, hr 0.41 non–clear cell renal cell carcinoma studied usa (seer) 1993-2010 n (cn) = 6915 (95% ci 0.37–0.55) n (no cn) = 13819 aizer (2014) (15), retrospective cohort, n (total) = 591 nr nr 14 vs 6, hr 0.45 cytokines + st usa (seer) 2000-2009 n (cn) = 384 (95% ci 0.39–0.43) n (no cn) = 207 abern (2014) (16), retrospective cohort, n (total) = 7143 nr nr hr 0.33 median os in months: nr usa (seer) 2005-2009 n (cn) = 2629 (95% ci 0.31–0.36) n (no cn) = 4514 vaishampayan (2019) (17), retrospective cohort, n (total) = 18422 nr nr 18 vs 3, hr 0.39 usa (seer) 2010-2016 n (cn)= 7660 (95% ci 0.30–0.33) n (no cn) =10762 zhao (2019) (18), retrospective cohort, n (total) = 1113 nr nr 26 vs 9, hr 0.40 usa (seer) 2010-2014 n (cn) = 618 (95% ci 0.35–0.47) n (no cn) = 415 marchioni (2019) (19), retrospective cohort, n (total) = 851 nr nr hr 0.38 median os in months: nr usa (seer) 2001-2014 n (cn) = 575 (95% ci 0.30–0.47) non-clear cell renal cell carcinoma studied n (no cn) = 276 palumbo (2020) (20), retrospective cohort, n (total) = 2241 nr nr 28 vs 12, hr 0.49 usa (seer) 2010-2015 n (cn) = 1168 (95% ci 0.41–0.58) n (no cn) = 1073 luzzago (2021) (21), retrospective cohort, n (total) = 1573 nr cn before st no treatment = 3 usa (seer) 2006-2015 n (no-treatment) = 350 st alone = 7 n (st alone) = 387 cn = 9 n (cn) = 396 cn+st = 13 n (cn+st) = 440 hr = nr non–clear cell renal cell carcinoma studied alnimer (2021) (22), retrospective cohort, n (total) = 5483 nr nr 24 vs 6, hr 0.33 usa (seer) 2010-2016 n (cn) = 2991 (95% ci 0.28–0.40) n (no cn) = 2483 hanna (2016) (23), retrospective cohort, n (total) = 15390 nr cn before or after st 17.1 vs 7.7, hr 0.49 usa (ncdb) 2006-2013 n (cn) = 5374 (95% ci 0.46–0.52) n (no cn) = 10016 singla (2020) (24), retrospective cohort, n (total) = 391 upfront cn = 197, no cn = 11.6 median os was not reached in the cn group. usa (ncdb) 2015-2016 n (cn) = 221 st before cn = 24 hr 0.23 (95% ci 0.15–0.37) patients were treated with immune n (no cn) = 170 checkpoint inhibitors choi (2018) (25), retrospective cohort, n (total) = 294 sunitinib (52.4%) st before cn 29 vs 11, hr 0.40 korea (single center) 2005-2015 n (cn) = 109 pazopanib (26.2%) (95% ci 0.28–0.58) n (no cn) = 105 sorafenib (10.9%) temsirolimus (4.4%) janish (2020) (26), retrospective cohort, n (total) = 262 sunitinib (66%) cn before st 27 months for the cn group no difference in os between the two groups germany (single center) 2000-2016 n (cn) = 104 sorafenib (20%) p > 0.05 n (no cn) = 158 pazopanib (10%) you (2011) (27), retrospective cohort, n (total) = 78 sunitinib (81%) cn before st 21.6 vs 13.9, hr 0.53 korea (single center) 2006-2009 n (cn) = 45 sorafenib (19%) (95% ci 0.24–1.15) n (no cn) = 33 graham (2019) (28), retrospective cohort, n (total) = 353 sunitinib (54%) cn before st 16.3 vs 8.6, hr 0.62 metastatic papillary renal cell international (imdc) 2005-2017 n (cn) = 244 temsirolimus (23%) (95% ci 0.45–0.85) carcinoma studied n (no cn) = 109 pazopanib (11%) sorafenib (2.8%) klatte (2017) (29), retrospective cohort, n (total) = 261 sunitinib (60.5%) cn before st unadjusted: uk (single center), 2006-2017 n (cn) = 97 pazopanib (28.4%) 25.6 vs 12.4, hr 0.46 n (no cn) = 164 cabozantinib or (95% ci 0.34–0.62) nivolumab (8.4%) iptw-adjusted: 20.9 vs 12.6, other (34.5%) hr 0.63 (95% ci 0.46–0.84) you (2014) (30), retrospective cohort, n (total) = 171 sunitinib (70%), cn before st 19.9 vs 11.7 korea (single center) 2006-2012 n (cn) = 96 sorafenib(19%), hr: nr n (no cn) = 75 pazopanib (4%), temsirolimus (7%) tatsugami (2015) (31), retrospective cohort, n (total) = 330 nr nr 27.4 vs 10.3, hr 0.40 mixed population of approximately half japan (multicenter) 2001-2015 n (cn) = 254 (95% ci 0.29–0.57) patients receiving cytokines and half n (no cn) = 76 subgroup analysis for patients receiving systemic therapy receiving only st: 30.9 vs 15.5, hr 0.48 (95% ci 0.28–0.90) archivio italiano di urologia e andrologia 2022; 94, 4 s. katsimperis, l. tzelves, t. bellos, k. pikramenos, i. manolitsis, i. tsikopoulos, i. mitsogiannis 480 with 95% ci 0.15-0.37 and 0.19-0.83). regarding the sequence of cn and st, cn was administered before st in 12 studies (21, 26-30, 32, 33, 35-37), before or after in 5 (23, 38, 40-42), after in one study (25) while sequence was not specified in the rest. cn was associated with improved os in all but one of the observational studies (26), with hrs ranging from 0.23 to 1.90 (table 1). in all of these studies (14-25, 27-42) the univariable analysis showed improved os in favor of the cn group although in some studies subgroup analysis day (2016) (32), retrospective cohort, n (total) = 91 sunitinib (74%) cn before st 23 vs 10.9, hr 0.33 australia (multicenter) 2006-2012 n (cn) = 46 pazopanib (4%) (95% ci 0.20–0.55) n (no cn) = 45 everolimus (4%) bevacizumab (2%) interferon (2%) temsirolimus (1%) choueiri (2011) (33), retrospective cohort, n (total) = 314 sunitinib (63%) cn before st 19.8 vs 9.4, hr 0.68 canada and usa (multicenter) 2004-2008 n (cn) = 201 sorafenib (30%) (95% ci 0.46–0.99) n (no cn) = 113 bevacizumab (7%) heng (2014) (34), retrospective cohort, n (total) = 1658 cn; no cn nr 20.6 vs 9.6, hr 0.60 international (imdc), years not specified n (cn) = 982 sunitinib (67%; 79%) (95% ci 0.52–0.69) n (no cn) = 676 sorafenib (20%; 8.6%) axitinib (0.4%; 0.4%) bevacizumab (4%; 1.5%) temsirolimus (3.6%; 6.4%) pazopanib (2.8%; 2.8%) everolimus (1%; 1%) other (0.7%; 0.3%) de groot (2016) (35), retrospective population n (total) = 146 sunitinib cn before st 17.9 vs 8.8, hr 0.61 based matched cohort, the netherlands 2008-2010 n (cn) = 73 (95% ci 0.41–0.92) n (no cn) = 73 poprach (2020) (36), retrospective cohort, n (total) = 730 sunitinib (78.8%) cn before st 27.2 vs 14.2, hr 0.55 czech republic (national registry) 2007-2018 n (cn) = 458 pazopanib (21.2%) (95% ci 0.45–0.68) n (no cn) = 272 song (2016) (37), retrospective cohort, n (total) = 74 sunitinib (44.6%) cn before st 32.2 vs 23 china (single center) 2006-2014 n (cn) = 51 sorafenib (29.7%) hr: nr n (no cn) = 23 famitinib (18.9%) pazopanib (6.7%) bhindi (2020) (38), retrospective cohort, n (total) = 1541 sunitinib cn before or after st cn+sunitinib vs sunitinib comparative analyses of upfront cn+ sunitinib imdc 2006-2018 n (cn+sunitinib) = 805 vs sunitinib+dcn 19 vs 10 vs 46 vs sunitinib+ dcn vs sunitinib n (no cn) = 651 upfront cn+sunitinib vs sunitinib n (sunitinib+dcn) = 85 hr 0.89 (95% ci 0.71–1.1) sunitinib+dcn vs sunitinib hr 0.89 (95% ci 0.71–1.1) sunitinib+dcn vs upfront cn +sunitinib hr 0.52 (95% ci 0.39–0.70) patel (2017) (39), retrospective cohort, n (total) = 1062 nr nr hr 1.90 (95% ci 1.61–2.25) os in months nr australia 2001-2009 n (cn) = 289 includes cytokine era n (no cn) = 773 dragomir (2021) (40), retrospective cohort, n (total) = 788 sunitinib (51.1%) cn before cn+st vs st 36 vs 18, hr 0.65 one of few studies including patients treated canada (multicenter) 2011-2020 n (cn) = 80 pazopanib (16.8%) or after st (95% ci 0.52–0.82) with ici n (cn+st) = 383 ipilimumab/ st+cn vs st 48 vs 18, hr 0.41 n (st+cn) = 73 nivolumab (13.8%) (95% ci 0.28–0.60) n (st only) = 282 other (18.9%) cn (only) vs st (only) 24 vs 18, hr 0.75 (95% ci 0.48–1.17) cn+st vs st+cn 36 vs 48, hr 0.66 (95% ci 0.42–1.04) mejean (2018) (41), prospective randomized trial, n (total) = 450 sunitinib cn before or after st 13.9 vs 18.4, hr 0.89 17% of patients in the sunitinib-only france, norway, england, scotland, n (cn) = 226 (95% ci 0.71–1.1) arm received subsequent cn sweden 2009-2017 n (no cn) = 224 bakouny (2020) (42) retrospective cohort, n (total) = 4054 nr cn before or after st cn+ ici vs ici one of few studies including patients treated international (imdc) 2009-2019 n (tt only) = 1386 53.6 vs 21.4, hr = 0.44 with ici n (cn+tt) = 2470 (95% ci 0.30-0.64) n (cn+ici) = 143 cn+ tt vs tt 26.5 vs 10.3, hr = 0.48 n (ici only) = 282 (95% ci 0.45-0.52) uprety (2018) (65), retrospective cohort, n (total) = 3376 nr nr 18 vs 4 usa (seer) 2006-2012 n (cn) = 1110 n (no cn) = 2266 cn = cytoreductive nephrectomy; dcn = deferred cn; os = overall survival; hr = hazard ratio; st = systemic therapy; nr = not reported; ci = confidence interval; seer = surveillance, epidemiology, and end results; ncdb = national cancer database; imdc = international metastatic renal cell carcinoma database consortium. 481archivio italiano di urologia e andrologia 2022; 94, 4 nephrectomy for metastatic renal cell carcinoma table 3. studies evaluating the sequencing of cn and st. study number of patients comparison findings wood (2009) (43), retrospective cohort, n (total) = 102 cn followed by tt versus tt followed by cn unadjusted km analysis revealed similar median css. usa (single center) 2005-2007 n (cn+tt) = 58 31 vs 27.7 mo, p = 0.697 n (tt+cn) = 44 stroup (2013) (44), retrospective cohort, n (total) = 35 cn followed by sunitinib versus sunitinib followed by cn unadjusted km analysis revealed no difference in os usa (multi center) 2005-2009 n (cn+sunitinib) = 17 p = 0.579 n (sunitinib+ cn) = 18 hanna (2016) (23), retrospective cohort, n (total) = 4223 cn followed by tt versus tt followed by cn unadjusted km analysis revealed, 1-, 2-, and 3-year os rates were: 61.2%, usa (ncdb) 2006-2013 n (cn+tt) = 3733 37.8%, 26.6% for cn+tt patients versus 73.3%, 48.1%, 35.3% n (tt+cn) = 490 for tt+cn patients log-rank p < 0.001 macleod (2017) (45), retrospective cohort, n (total) = 537 cn followed by tt versus tt followed by cn median os of cn+tt vs tt+cn: 17.4 vs 9.2 months usa (seer) 2006-2011 n (cn+tt) = 190 hr 0.50 (95% ci 0.38-0.65) in propensity score matching: 5.8 n (tt+cn) = 347 months advantage for immediate cn bex (2018) (7), prospective rct, n (total) = 99 cn followed by sunitinib versus sunitinib followed by cn in the itt population, no difference in pfr at 28 weeks the netherlands, canada, uk, belgium 2010-2016 n (cn+sunitinib) = 50 (cn+sunit. 42% vs sunit.+cn 43% p = 0.61) n (sunitinib+ cn) = 49 median os of cn+sunit. vs sunit.+cn: 15 vs 32.4 months hr 0.57 (95% ci 0.34-0.95) p = 0.032 in the ppp the os was greater in deferred cn but not statistically significant p = 0.23 bhindi (2018) (46), retrospective cohort, n (total) = 15068 cn followed by tt versus tt followed by cn in iptw analysis, median os of cn+tt vs tt+cn: 16.5 vs 9.2 months usa (ncdb) 2006-2013 n (cn+tt) = 6731 hr 0.61 (95% ci 0.59-0.64) p < 0.001 n (tt+cn) = 8337 bhindi (2020) (38), retrospective cohort, n (total) = 1541 cn followed by sunitinib versus sunitinib followed by cn median os of cn+sunitinib vs sunitinib+deferred cn: 19 vs 46 months usa (imdc) 2006-2018 n (cn+sunitinib) = 805 hr 0.52 (95% ci 0.39–0.70) p < 0.001 n (no cn) = 651 n (sunitinib+dcn) = 85 kapoor (2019) (47), retrospective cohort, n (total) = 54 cn followed by tt versus tt followed by cn median os of cn+tt vs tt+cn: 30.7 vs 36.9 months canada (single center) 2009-2016 n (cn+tt) = 32 when stratified by number of metastatic sites (< 3 vs ≥ 3 sites) n (tt+cn) = 22 median os was significantly longer in the upfront tt group with ≥ 3 metastasis sites: 33 vs. 12.1 months hr 4.65 (95% ci 1.18–18.39) p = 0.03 in intermediate-risk patients, upfront tt group had longer os: 70.5 vs. 30.7 months hr 3.25 (95% ci 1.16–9.08) p = 0.03 de bruijn (2020) (48), retrospective analysis, n (total) = 338 cn followed by tt versus tt followed by cn in unselected for risk group pooled data from prospective trials 2006-2016 n (cn+tt) = 149 median os of cn+tt vs tt+cn: 18.4 vs 24.3 months n (tt+cn) = 189 hr 0.78 (95% ci 0.59–1.04) p = 0.09 in intermediate-risk group median os of cn+tt vs tt+cn: 22.8 vs 33 months hr 0.72 (95% ci 0.52–0.99) p = 0.047 dragomir (2021) (40), retrospective cohort, n (total) = 788 cn followed by st versus st followed by cn median os of cn+st vs st+cn: 36 vs 48 months canada (multicenter) 2011-2020 n (cn) = 80 st includes tt or immune check point inhibitors hr 0.66 (95% ci 0.42–1.04) n (cn+st) = 383 n (st+cn) = 73 n (st only) = 282 cn = cytoreductive nephrectomy; os = overall survival; css = cancer specific survival,; hr = hazard ratio; st = systemic therapy; tt = ttargeted therapy; ci = confidence interval; km = kaplan meier; itt = intention to treat; ppp = per protocol population; seer = surveillance, epidemiology, and end results; ncdb = national cancer database; imdc = international metastatic renal cell carcinoma database consortium. showed no benefit (33, 34). choueiri et al. (33) stratified patients according to the imdc prognostic factors and demonstrated that poor-risk patients had no significant benefit in os (hr 0.67 95% ci 0.44-1.01, p = 0.06). also, heng et al. (34), in a similar subgroup analysis showed absence of os benefit for poor risk patients (os 6 vs 5.4 months, p > 0.1). the carmena trial (41), the only prospective trial in this review, compared sunitinib plus cn versus sunitinib alone in mrcc patients and showed for the first time the non-inferiority of systemic therapy compared to upfront cn plus sunitinib, with os 18.4 months vs 13.9 months (hr 0.89 95% ci 0.71-1.1). results were similar in the intermediate risk (hr 0.92 95% ci 0.68-1.24) and poorrisk (hr 0.86 95% ci 0.62-1.17) patients. however, the study has some serious limitations. in the sunitinib alone arm, 17% of the patients underwent subsequent cn and 7% of patients in the cn plus sunitinib arm did not receive surgery. the study also included only poor-risk memorial sloan kettering cancer center (mskcc) and intermediate-risk mskcc patients that have been shown before not to benefit from cn (33, 34). sequencing of cytoreductive nephrectomy and systemic therapies ten studies were included in the analysis of the sequencing of cn and st (table 3). nine studies were retrospective cohorts (23, 38, 40, 43-48), and one was a prospecarchivio italiano di urologia e andrologia 2022; 94, 4 s. katsimperis, l. tzelves, t. bellos, k. pikramenos, i. manolitsis, i. tsikopoulos, i. mitsogiannis 482 tive randomized controlled trial (rct) (7). out of retrospective studies, two were population based (45, 38), three studies used a national hospital-based database (46, 23, 40), two were from a single institution (43, 47), one study was multicenter (44) and one study pooled data from 4 prospective trials (48). in two studies (45, 46), cn prior to st found to have an advantage in os. macleod et al. (45) showed that median os of immediate cn was 17.4 months vs 9.2 in the deferred cn group, with hr 0.50 (95% ci 0.38-0.65). an advantage of 5.8 months for the immediate cn group was also found in propensity score matching. there was no survival benefit regarding the sequencing of cn and st in three studies (40, 43, 44). unadjusted kaplan meier (km) analyses from both wood et al. and stroup et al. did not reveal a benefit in survival in neither the upfront nor the differed cn group (p = 0.697 and p = 0.579 respectively). in the only prospective rct from bex et al. (7) median os in the deferred cn group was greater than in the immediate one in the intention to treat population (32.4 vs 15 months, hr 0.57; 95% ci 0.34-0.95, p = 0.032) but not in the per protocol population (hr 0.71; 95% ci 0.401.24, p = 0.23). similar results with advantage of deferred cn were reported in four more studies (23, 38, 47, 48). interestingly, bhindi et al. (38, 46), in two studies reported contradictory results for the role of deferred cn. when initial treatment with cn, with or without subsequent targeted therapy (tt) was compared to initial treatment with tt, with or without subsequent cn in a sample population pooled from national cancer data base (ncdb) (46), authors found an os benefit for the first group (hr 0.61; 95% ci 0.59-0.64, p < 0.001). however, in a more recent study (38), a retrospective cohort with data from international mrcc database consortium (imdc), comparison of cn followed by sunitinib versus sunitinib followed by cn, favored the latter (hr 0.52; 95% ci 0.39-0.70, p < 0.001). another study of notable mention comes from dragomir et al. (40), as it is the only one that included in the st arm patients who were also treated with ici. this study also favors deferred than initial cn (hr 0.66; 95% ci 0.42-1.04). prognostic factors for os with cn twenty-four studies were included in the analysis of possible prognostic factors for os with cn. in figure 2 independent prognostic factors are demonstrated with green color, those found not to be independent prognostic factors are demonstrated with red, while those not assessed are the ones in the white cells. most common prognostic factors found in the analysis were age (in 8 studies) (15, 18, 23, 27, 30, 39, 52, 53, 57), tumor histology (in 7 studies) (15, 18, 26, 27, 32, 51-53), number of metastasis (in 6 studies) (18, 30, 45, 51, 55, 60), and t stage (in 6 studies) (18, 31, 51-53, 57, 58). other factors were, sarcomatoid histology, imdc or mskcc classification, systemic symptoms, lymphadenopathy, hemoglobin and albumin level, levels of serum calcium or creatinine or platelets, c-reactive protein (crp) level, absolute neutrophil count and neutrophillymphocyte ratio, bone metastasis, lymph node metastasis, visceral metastasis or liver metastasis, tumor grade, sex, body mass index (bmi), marital status, race, level of thrombus, if existing, and other comorbidities. from the factors mentioned above, those associated with poor overall survival after cn are high t stage and number of metastasis, sarcomatoid histology, bone metastasis, lymph node metastasis, visceral metastasis or liver metastasis, thrombus level above the diaphragm, existing comorbidities, presence of systemic symptoms, poor imdc or mskcc classification, unmarried status, poor figure 2. prognostic factors. 483archivio italiano di urologia e andrologia 2022; 94, 4 nephrectomy for metastatic renal cell carcinoma performance status, hemoglobin level less than the lower limit of normal, ldh level above the upper limit of normal and a neutrophile/lymphocyte ratio ≥ 4. female gender, thrombocytosis, crp level ≥ 1 ng/ml, good performance status, and good/intermediate imdc or mskcc classification were considered having an os benefit. discussion treatment of synchronous mrcc has faced many changes in recent years, due to the ongoing development of new drugs, making the therapeutic choice a complex task. the two well-known rcts that were published regarding the role of cn in mrcc patients, carmena and surtime, changed what we thought to be the standard of care. the role of cn was deeply questioned, and systemic therapies were found to be more effective. results from surtime and carmena (6, 7) demonstrated an absence of benefit in immediate cn, while deferred cn showed an os benefit in intermediate risk patients. however, their results should be interpreted with caution as both carmena and surtime, are found to have certain pitfalls. for instance, in carmena there was a significant crossover with 17% of patients in the sunitinib alone arm undergoing subsequent cn, and 7% of patients in the cn plus sunitinib arm not receiving surgery. surtime on the other hand, suffered from poor accrual, changing the primary endpoint from progression free survival (pfs) to progression free rate (pfr). a discordance was also found, between the intention to treat and per protocol population, os outcome. for that reason, the selection of patients who might benefit from cn is of great importance. in our review, most of the studies evaluating the effect of cn in os showed a benefit of cn (1425, 27-42). although most of these studies are retrospective and observational, their results cannot be overlooked. in three studies that used icis (2, 40, 42), cn demonstrated an os benefit. given the absence of prospective studies with patients treated with icis, these results underline the importance of cn in the mrcc treatment. prognostic factors have been described, with age, tumor histology, number of metastasis and t stage being the most common. there are also two prognostic models allowing patient risk stratification: mskcc and imdc risk scores (34, 63). these models stratify patients in favor, intermediate and poor risk categories, using performance status (ps), time from diagnosis to treatment, hemoglobin concentration, calcium level and lactate dehydrogenase level as criteria. according to current evidence, poor mskcc/imdc risk patients do not seem to benefit from upfront cn (33, 34) while other patients such as those with good risk prognosis and good ps seem to benefit the most from cn. it should be noted however, that mskcc/imdc prognostic scores were originally designed to predict os in patients with mrcc, and not the os benefit associated with cn (65). that shows the need for new validated prognostic models. among patients that were found to benefit from cn, the optimal sequence between cn and tt is not yet well established, as was also documented in our review. deferred cn demonstrated better results, in more studies than upfront cn (7, 23, 38, 47, 48) but a certain advantage was not clear. despite the new insights into the treatment of mrcc patients that carmena and surtime provided, tkis are not anymore considered the standard of care as icis have been established as first-line therapy in mrcc patients. three randomized trials: the checkmate-214 (nivolumab plus ipilimumab vs sunitinib), keynote426 (pembrolizumab plus axitinib vs sunitinib), and javelin renal 101 (avelumab plus axitinib vs sunitinib) demonstrated the superiority of icis in the treatment of mrcc whereas sunitinib and other vegfr-tki monotherapies are reserved for those who cannot tolerate ici combination or have no access to these drugs(9-11). what we already know from carmena and surtime has to be re-evaluated. singla et al. (24) in the first retrospective analysis of the role of cn in the immunotherapy era, demonstrated an os benefit for those patients treated with ici plus cn compared to ici alone (hr 0.23; 95% ci 0.15-0.37). in this regard, further data from high level of evidence studies are required in order to define the role of cn in the modern immune oncology (io) era. currently there are two rcts underway, to guide us to that. the probe trial (nct04510597) will evaluate the combination of cn followed by io or tki+ io compared to no cn. the nordic-sun trial (nct03977571) will evaluate the role of deferred cn in patients receiving combination io. we acknowledge that the present study had several limitations. the major limitations were the retrospective nature of the studies included and the small number of studies having icis as the main agent used. the retrospective nature could have resulted in selection bias in performance of cn. moreover, many studies come from an era when systemic therapies were not well established. conclusions the role of cn on mrcc treatment remains a controversial issue. data from most recent studies have questioned the benefit from cn, shifting the first line treatment from surgical to medical. cn can still play an important role in wisely selected patients, although the role of cn in the new immunotherapy era still needs to be defined. references 1. flanigan rc, salmon se, blumenstein ba, et al. nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. n engl j med. 2001; 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200:528-534. 47. kapoor a, wong ecl, fang w, wong nc. upfront cytoreductive nephrectomy vs. upfront systemic therapy in metastatic kidney cancer. can urol assoc j. 2019; 13:e377-e381. 48. de bruijn r, wimalasingham a, szabados b, et al. deferred cytoreductive nephrectomy following presurgical vascular endothelial growth factor receptor-targeted therapy in patients with primary metastatic clear cell renal cell carcinoma: a pooled analysis of prospective trial data. eur urol oncol. 2020; 3:168-173. 49. abel ej, spiess pe, margulis v, et al. cytoreductive nephrectomy for renal cell carcinoma with venous tumor thrombus. j urol. 2017; 198:281-288. 50. dashek jj, zhang y, skelton wp 4th, et al. dissecting outcomes: should cytoreductive nephrectomy be performed for patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation? front oncol. 2021; 10:627025. 51. corcoran at, kaffenberger sd, clark pe, et al. hypoalbuminaemia is associated with mortality in patients undergoing cytoreductive nephrectomy. bju int. 2015; 116:351-7. 52. culp sh, tannir nm, abel ej, et al. can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? cancer. 2010; 116:3378-88. 53. culp sh, karam ja, wood cg. population-based analysis of factors associated with survival in patients undergoing cytoreductive nephrectomy in the targeted therapy era. urol oncol. 2014; 32:561-8. 54. kalogirou c, mulfinger p, sokolakis i, et al. preoperative creactive protein values as a potential component in outcome prediction models of metastasized renal cell carcinoma patients receiving cytoreductive nephrectomy. urol int. 2017; 99:297-307. 55. kapoor a, wong ecl, fang w, wong nc. upfront cytoreductive nephrectomy vs. upfront systemic therapy in metastatic kidney cancer. can urol assoc j. 2019; 13:e377-e381. 56. klatte t, fife k, welsh sj, et al. prognostic effect of cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: a comparative study using inverse probability of treatment weighting. world j urol. 2018; 36:417-425. 57. ljungberg b, sundqvist p, lindblad p, et al. survival advantage of upfront cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma compared with systemic and palliative treatments in a real-world setting. scand j urol. 2020; 54:487-492. 58. mcintosh ag, umbreit ec, holland lc, et al. optimizing patient selection for cytoreductive nephrectomy based on outcomes in the contemporary era of systemic therapy. cancer. 2020; 126:39503960. 59. rosiello g, knipper s, palumbo c, et al. unmarried status is a barrier for access to treatment in patients with metastatic renal cell carcinoma. int urol nephrol. 2019; 51:2181-2188. 60 sharma p, zargar-shoshtari k, caracciolo jt, et al. sarcopenia as a predictor of overall survival after cytoreductive nephrectomy for metastatic renal cell carcinoma. urol oncol. 2015; 33:339.e17-23. 61. sakai i, miyake h, hinata n, fujisawa m. improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy. int j clin oncol. 2014; 19:674-8. 62. teishima j, ohara s, shinmei s, et al. normalization of c-reactive protein levels following cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors is associated with improved overall survival. urol oncol. 2018; 36:339.e9-339.e15. 63. motzer rj, bacik j, schwartz lh, et al. prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. j clin oncol. 2004; 22:454-63. 64. westerman me, shapiro dd, tannir nm, et al. survival following cytoreductive nephrectomy: a comparison of existing prognostic models. bju int. 2020; 126:745-753. 65. uprety d, bista a, smith al, et al. cytoreductive nephrectomy in elderly patients with metastatic renal cell carcinoma in the targeted therapy era. anticancer res. 2018; 38:3013-3018. correspondence stamatios katsimperis, md stamk1992@gmail.com lazaros tzelves, md lazarostzelves@gmail.com themistoklis bellos, md bellos.themistoklis@yahoo.com konstantinos pikramenos, md k.pikramenos@gmail.com ioannis manolitsis, md giannismanolit@gmail.com ioannis tsikopoulos, md ioannistsikopoulos@yahoo.com iraklis mitsogiannis, md imitsog@med.uoa.gr department of urology, athens, greece stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4318 case report no conflict of interest declared. doi: 10.4081/aiua.2020.4.318 giant hydronephrosis secondary to ureterocele with duplex system in adults: report of a case andrea solinas, luca cau, massimiliano fanari, ignazio flaviani, francesco manca, maurizio melis department of surgery, urology unit, ats sardegna assl carbonia, ospedale sirai, carbonia, italy. decrease in appetite but no urological symptoms or signs or fever. he had no history of hematuria or urinary tract infection. clinical examination showed an asymmetric abdominal palpable mass with a smooth surface. the mass extended from the left lumbar region to the pelvic region crossing the midline. laboratory blood investigations were unremarkable. ultrasound showed fluid-filled mass occupying all left abdominopelvic region and pressing the digestive structures. computerized tomography revealed massive hydronephrosis of the left upper pole moiety, measuring around 28 x 15 x 17 cm, with normally enhancing renal parenchyma at the region of lower pole (figures 1, 2). pelvic section revealed dilated and tortuous upper pole moiety ureter with cystic focal dilatation in its submucosal part as it entered the bladder suggestive of ureterocele (figure 3). radionuclide renal scan showed a hydronephrotic left kidney with decreased global glomerular filtration rate of the left side and overall impaired function of the left kidney (8%). radionuclide renal scan (figure 4) documented a marked reduction in the size of the left kidney and poor parenchymal uptake in the corticomedullary phase, followed by delayed excretion, reflecting a reduced pyelocalyceal function. the left curve was considerably lower than the right and showed marked phase delay. the total glomerular filtration rate was 63.2 ml/min, 58.2 ml/min (92%) in the right kidney and 5 ml/min (8%) in the left. the patient underwent complete endoscopic excision of the ureterocele for decompression of the system. complete endoscopic excision of the ureterocele exposed a wide gaping ureteral meatus. retrograde pyelography was not performed nor was a stent inserted. in line with weigert-meyer rule, another ureteral meatus, draining the lower moiety, was detected superolateral to the first. the next day an abdominal ultrasound scan, performed with the bladder catheter in situ, revealed complete resolution of the hydronephrosis of upper pole moiety and collapse of the ureterocele. the ultrasound scan performed after catheter removal demonstrated that the hydronephrosis had formed again, indicating the presence of ureteral reflux, which was demonstrated by a micturating cystourethrogram in the upper tract but not in the lower moiety or in the right kidney. owing to the poorly functioning left kidney a left laparoscopic nephrectomy was performed about 3 months after ureterocele excision. post-operative suites were simple and the giant hydronephrosis in adults is a rare entity. it is defined as an extensive dilatation of the pyelocaliceal cavities occupying a large part of the abdominal cavity. giant hydronephrosis is usually due to pelvi-ureteric junction obstruction and is usually diagnosed in children and infants. ureterocele, which is a cystic dilatation of the terminal ureter, often drains the upper part of the kidney in patients with a duplex system. massive hydronephrosis in a patient with duplex system and obstructive ureterocele was described by aeron et al. in 2017. a thorough search of the major medical databases disclosed that no other cases have been reported since. we describe a second case of unilateral complete duplex system with ureterocele and massive hydronephrosis of the upper moiety in an adult man with intermittent abdominal pain associated with constipation and a decrease in appetite. the renal function of the left kidney was 8% of total function by radionuclide renal scan. the patient subsequently underwent left laparoscopic nephrectomy. key words: massive hydronephrosis; ureterocele; duplex system; nephrectomy. submitted 29 april 2020; accepted 6 june 2020 introduction ureterocele is a cystic dilatation of submucosal distal ureter. it is rare in adults but presents a higher incidence in infants and young children. ureterocele usually affects the upper moiety in case of complete duplication of the pelviureteric system and presents as abdominal pain and infection (1, 2). massive hydronephrosis in adults is a rare entity and is easy to be misdiagnosed. it is defined as an extensive dilatation of the pyelocaliceal cavities occupying a large part of the abdominal cavity. in 1939 stirling defined massive hydronephrosis as the presence of more than 1000 ml or 1.6% of body weight of fluid in the renal collecting system or the involvement of five vertebral heights. the aim of this paper is to present the second case of a massive hydronephrosis in an adult male affecting the duplex system associated with ureterocele. case report a 63-year-old man with a history of left lumbar pain which had not been investigated was referred to our urology unit with an abdominal palpable mass and pain. he had diffuse abdominal pain, persistent constipation and a summary solinas_stesura seveso 14/12/20 20:37 pagina 318 319archivio italiano di urologia e andrologia 2020; 92, 4 hydronephrosis and ureterocele patient was discharged uneventfully on the 4th postoperative day. after three months the patient is asymptomatic and has normal renal function. histology confirmed hydronephrosis, diffuse compression atrophy of the renal parenchyma and chronic interstitial nephritis. discussion in 1939 stirling defined massive hydronephrosis as the presence of more than 1000 ml or 1.6% of body weight of fluid in the renal collecting system. in 1979 crooks et al. defined radiographic criteria for massive hydronephrosis as the kidney occupying the hemi-abdomen which also meets or crosses the midline and has a height of about 5 vertebral bodies (3). with higher standards of medical care massive hydronephrosis is now a rare urological entity, occurring predominantly in children. the commonest cause is congenital pelvi-ureteric-junction obstruction which occurs in 80% of cases (4) followed by stones. other less common causes include congenital ureteral narrowing, ureteropelvic tumors, trauma, renal ectopia, retroperitoneal fibrosis, obstructive megaureter (5), ureteric atresia, polar or aberrant vessels. more than 600 cases have been reported worldwide to date, most of them in the last 15 years (6). massive hydronephrosis is a slowly progressive disease and a huge abdominal mass or distended abdomen may be the only sign. patients may remain asymptomatic until late phase. its wide differential diagnosis includes intraperitoneal cysts (mesenteric or choledochal), retroperitoneal cysts (renal or adrenal or pancreatic pseudocysts), pseudomixoma, ovarian cysts/tumors, ascites (7). it usually presents with vague symptoms such as fatigue, dyspepsia or nausea, mild diffuse abdominal pain or uncomfortable feeling and persistent constipation, urinary tract infection, renal insufficiency or hematuria after trauma in adults (5). ureterocele is a cystic dilation of the distal ureter. it is a congenital anomaly associated with other anomalies such as a duplicated system and other diseases. most of the ureteroceles are diagnosed in utero or during the postpartum screening for congenital malformations (1) while in adult patients it is rare and usually asymptomatic. ureterocele can be associated with a single or a duplex system, the latter being more common. most adult ureteroceles are in single system, intravesical and located on the trigone of bladder. ureterocele in a duplex system most commonly involves the upper pole moiety and hydronephrosis is usually due to obstruction at the lower end. figure 1. abdominal ct scan in coronal and sagittal view showing giant hydronephrosis of the left upper pole moiety occupying almost the whole abdomen with normal renal parenchyma in the region of lower pole (white arrow) dislocated by hydronephrosis and dilated tortuous upper pole moiety ureter. figure 2. contrast-enhanced abdominal ct scan showing giant hydronephrosis of the left upper pole moiety in axial view with normal renal parenchyma at the region of lower pole (white arrow) dislocated by hydronephrosis. figure 3. contrast-enhanced abdominal ct scan. pelvic section revealing dilated upper moiety ureter with cystic focal dilatation in its submucosal part as it enters the bladder (white arrow). figure 4. radionuclide renal scan depicting a reduced size and a markedly reduced parenchymal uptake in the left kidney. the left nephrographic curve is considerably lower than the contralateral curve and shows marked phase delay. solinas_stesura seveso 14/12/20 20:37 pagina 319 archivio italiano di urologia e andrologia 2020; 92, 4 a. solinas, l. cau, m. fanari, i. flaviani, f. manca, m. melis 320 according to weigert-meyer rule, in patients with a duplex system the upper moiety ureter drains into the bladder more medial and inferior to the lower moiety ureter. this was also the case of our patient. ureterocele causing obstruction in adults is uncommon. even uncommon is the association of the massive hydronephrosis with the duplex system in adults. until now, there is only one case of giant hydronephrosis of upper pole moiety in a duplex system associated with ureterocele reported in the literature (1). the management of ureterocele is controversial, which is related to the type of presentation and postoperative morbidity. endoscopic approach, for short operation time and acceptable outcomes, is considered as the gold standard for intravesical ureterocele. the goals of endoscopic techniques are to decompress the obstructed system minimizing the incidence of postoperative reflux (1). other procedures like upper polar nephrectomy or ureterocele excision and common sheath reimplantation are required on the basis of the renal function of an involved moiety, persistent obstruction or vesico-ureteral reflux of the upper tract and occurrence of new vesico-ureteral reflux post-procedure. in our case, endoscopic ureterocele resection was successful in decompressing the dilated system and ureterocele but in consideration of persistent vesico-ureteral reflux of the upper tract and owing to the poorly functioning left kidney we decided to perform a laparoscopic nephrectomy. the interest of our case lies in the combination of rare adult giant hydronephrosis and two uncommon abnormalities: duplex system and obstructive ureterocele. conclusions the most important aspect of management is early diagnosis with accurate preoperative delineation of anatomy of the affected kidney. it is still not easy to differentially diagnosis. it usually presents with vague symptoms such as fatigue, dyspepsia or nausea, urinary tract infection, renal insufficiency or hematuria after trauma in adults (8). it is not likely to consider a massive hydronephrosis diagnosis firstly. nowadays, diagnostic instruments such us ct scan and ultrasonography have facilitated an accurate diagnosis of hydronephrosis. for this reason, the clinician and radiologist could readily diagnose and provide appropriate therapy. adult obstructing ureterocele is uncommon, while adult massive hydronephrosis combined with a duplex system is highly uncommon. the case of our patient, who exhibited all three abnormalities, deserves to be shared with the scientific community. references 1. aeron r, sokhal ak, kumar m, sankhwar s. giant hydronephrosis in a case of ureterocele with duplex system: an entity yet not reported. bmj case rep. 2017. doi:10.1136/bcr-2017-221379. 2. merlini e,lelli chiesa p. obstructive ureterocele-an ongoing challange. world j urol. 2004; 22:107-14. 3. crooks kk, hendren wh, pfister rc. giant hydronephrosis in children. j pediatr surg. 1979; 14:844-50. 4. yang wt, metreweli c. giant hydronephrosis in adults: the great mimic. early diagnosis with ultrasound. postgrad med f. 1995; 71:409-12. 5. solinas a, pau ac, ayyoub m, frongia m. primary obstructive megaureter in adults: management strategy in a young woman. arch ital urol androl. 2010; 82:192-4. 6. guanghui hu, min luo, yunfei xu. giant hydronephrosis secondary to ureteropelvic junction obstruction in adults: report of a case and review of literature. int j clin exp med. 2015; 8:4715-17. 7. kaura ks, kumar m, sokhal ak et al. giant hydronephrosis: still a reality!. turk j urol. 2017; 43:337-44. 8. kaya c, pirincci n, karaman mi. a rare case of an adult giant hydroureteronephrosis due to ureterovesical stricture presenting as a palpable abdominal mass. int urol nephr. 2005; 37:681-83. correspondence andrea solinas, md (corresponding author) sol.andrea@tiscali.it luca cau, md luca.cau@atssardegna.it massimiliano fanari, md massimiliano.fanari@atssardegna.it ignazio flaviani, md ignazio.flaviani@atssardegna.it francesco manca, md franc.manca@atssardegna.it maurizio melis, md maurizio.melis@atssardegna.it s.c. urologia, ats sardegna assl carbonia ospedale sirai, via ospedale, 09013 carbonia (italy) solinas_stesura seveso 14/12/20 20:37 pagina 320 187archivio italiano di urologia e andrologia 2019; 91, 3 original paper effects of antioxidant treatment on seminal parameters in patients undergoing in vitro fertilization laura gambera 1, anita stendardi 1, camilla ghelardi 1, 2, benedetta fineschi 1, 2, rosamaria aini 1 1 a.g.i. medica center for reproductive medicine, siena, italy; 2 department of molecular and developmental medicine, university of siena, siena, italy. objective: the aim of this non controlled trial was to assess whether a therapy with an antioxidant supplement may improve spermatozoa quality in terms of number, motility, morphology and a higher number of successful conceptions in patients with oligoasthenoteratozoospermia undergoing cycles of medically assisted reproduction by intracytoplasmic sperm injection (icsi). materials and methods: 32 patients registered at a.g.i. medica (siena) medically assisted reproduction centre affected by fertility problems associated with oligoasthenoteratozoospermia were included in the study. semen analysis were evaluated according to world health organization 2010, before and after treatment. moreover, we used colorimetric tests to assess oxidative stress. after evaluating oocyte fertilisation rate and the quality of embryos obtained, data were statistically analysed. result: microscopy examination after the therapy, showed a general improvement in sperm parameters (number of sperms, progressive motility, viability and normal morphology) in both baseline and capacitated; also the levels of oxidative stress was notably lower after the treatment. morever we evaluated the outcome of the ivf treatment, the percentage of fertilization and the number of embryos obtained, all the parameters was significantly higher in the n1 group. conclusions: the outcomes of this trial seem to suggest that the administration of our food supplement improve semen parameters and that the evaluation of oxidative stress levels may become a diagnostic tool to assess male infertility in patients undergoing art cycle. key words: assisted reproduction technology; embryo quality; male infertility; oxidative stress; reactive oxygen species; semen quality. submitted 16 may 2019; accepted 25 july 2019 summary no conflict of interest declared. effects on sperm function (2). on the other hand, high levels of ros may induce lipid peroxidation, damage sperm dna (3) and protein modifications (4). furthermore, significant negative relations between oxidative stress (os) parameters and semen, fertilisation rate, development of embryos and pregnancy rates have been observed (5). approximately 25% of men suffering from infertility show high levels of free radicals in semen (6). increased concentration of free radicals may be due to several factors such as inflammation, cigarette smoke, ultraviolet rays, stress, alcohol, exposition to polluting agents, diets too rich in proteins and animal fats and drugs. human ejaculate contains potential sources of ros including leukocytes, germ cells or abnormal spermatozoa (7, 8). from a clinical point of view, all the aforesaid may result in lower fertilization rates, implantation failure, compromised embryo development, multiple abortions and low success in case of application of assisted reproduction techniques (9, 10). considering the high number of factors that may increase oxidative stress and thus damage spermatogenesis and nemaspermic function, antioxidant oral supplements are widely used in patients affected by infertility. in our investigation, we especially observed the therapeutic effects of a food supplement containing larginine, coenzyme q10, vitamin c and e, inositol and active principles from plants such as ginseng and tribulus terrestris. these substances are known to have positive effects on the motility and mitochondrial function of spermatozoa. our non controlled trial was to assess whether a therapy with antioxidants may lead to actual improvement in the quality of spermatozoa as a result of a reduction in reactive oxygen species and consequently to an increase in the number of successful pregnancies in patients undergoing medically assisted reproduction. materials and methods 32 patients enrolled in this study after 12-18 months of unprotected sexual intercourses without conception. sexual development, medical history, physical examination and serum hormone levels were normal. serological, virological and genetic tests which are necessary to start in vitro fertilization (ivf) cycle were performed. all selected patients underwent microbiological analysis doi: 10.4081/aiua.2019.3.187 introduction human infertility affects 15% of couples in their reproductive age, of which 30% is due to male factors. alterations in spermatogenesis may be related to various clinical conditions such as varicocele, cryptorchidism, infections, nutrient deficiencies, traumas, cancer, smoke or exposure to environmental agents. however, in many cases aetiology is not clear and several studies have proved that such condition, defined as idiopathic, may be caused by oxidative stress (1). reactive oxygen species (ros) are chemically reactive molecules that, in physiological conditions, have positive gambera_stesura seveso 30/09/19 18:25 pagina 187 archivio italiano di urologia e andrologia 2019; 91, 3 l. gambera, a. stendardi, c. ghelardi, b. fineschi, r. aini 188 of seminal fluid to search for common bacteria. azoospermic patients and couples whose sterility was due to female factors were excluded from the study. all the patients were informed by the doctor about the use of supplement and written informed consent was obtained from each patient. selected patients took a sachet a day of a food supplement (argifast, san marino, italy) containing l-arginine (3 g), coenzyme q10 (200 mg), vitamin c (240 mg), vitamin b3 (27 mg), tribulus (tribulus terrestris, 60 mg), ginseng (panax ginseng, 12 mg), inositol (100 mg) and vitamin e (36 mg), for a total of 65 days. semen samples collected by masturbation after 3-4 days of sexual abstinence were examined after liquefaction for 30 minutes at 37°c. volume, ph, concentration, viability and sperm motility were assessed according to parameters of the world health organization (who) manual (11). for each sample were counted one hundred sperm and morphological characteristics of sperm organelles (nucleus, acrosomal and tail) were evaluated using an optical microscope (zeiss, magnification 100x). eosin y staining was used to detect necrotic sperm. semen analysis was performed before (time 0) food supplement treatment. the same tests, except for eosin test, were carried out on semen on the day of oocyte retrieval (time 1) at the end of therapy. swim-up selection was performed before and after therapy to compare sperm recovery in the two steps. a sample of semen was washed in gamete buffer (cook medical®, usa) and then centrifuged for 10 minutes at 161 rcf. supernatant was removed and pellet was layered with a variable volume of medium proportional to the number and motility of the spermatozoa detected in the baseline evaluation. the sample was heated at 37°c for 45 minutes and then we controlled spermatozoa concentration, motility and morphology. oxidative stress test oxidative stress analysis was performed with a colorimetric test (oxisperm®, ab analitica, italy) following the instructions of the manufacturer. the reactive gel (rg) was liquefied in a water bath at 90°c for 5 minutes and then the rg temperature was reduced to 37°c. the rg was mixed with the semen sample in an eppendorf tube in order to have a final sperm concentration of 1 × 106/ml (volume proportion 1:1 semen-rg). the mix was gelified at 4°c for 5 minutes and then incubated for 45 minutes at 37°c. the resulting colour of the mix was compared with the colour scheme and the corresponding os level was estimated. samples were subsequently divided into two groups depending only on the os level detected with oxisperm®: low os samples including levels n1 and n2 and high os samples including levels n3 and n4. n1 and n2 samples have optimal/low levels of ros considered not able to damage cells, whereas n3 and n4 samples have levels of ros so high that may cause pathological effects on sperms such as dna fragmentation. assisted reproduction procedure female partners underwent ovarian stimulation through the administration of gonadotropins, which aimed to trigger the growth of multiples follicles at the same time in order to obtain a higher number of fertilizable oocytes. oocytes were recovered from follicular fluid immediately after follicle aspiration. icsi was performed on mature oocytes as described by palermo et al. (12). eighteen hours after icsi, the presence of two pronuclei and two polar bodies was checked to verify normal fertilization. embryos were cultured until embryo transfer, at day 3, were transferred using a catheter into the uterus in an ultrasound-guided procedure. clinical pregnancy was confirmed by ultrasound, which showed the presence of gestational sac and foetal heart beat at the seventh week before transfer, the embryos were evaluated morphologically and graded in order to compare embryo quality in the two different categories of patients (n1 and n2). we gave them a score (13, 14) according to the number of cells and percentage of fragments (15). statistical analysis we used wilcoxon test (a non-parametric test) to compare the data of both groups before and after treatment. we used mann-whitney test (a non-parametric test) and chi-square test to compare groups with levels of os rated n1 and n2. statistical significance was set at p ≤ 0.05. results we selected 32 couples where the male partner was suffering from oligoasthenoteratozoospermia. microbiological surveys did not detect the presence of common bacteria. none of the patients reported side effects and all experienced physical wellness after the 65-days therapy with antioxidants. sperm analysis was performed before the treatment (t0) and about 65 days after therapy on the day of female oocyte retrieval (t1). mean sperm count, progressive motility, normal sperm morphology and eosin y were below the normal range in all patients (table 1). at time 1, semen parameters highlighted a significant improvement in all the categories observed. light microscopy examination after the therapy, showed a general improvement in sperm parameters (number of sperms, progressive motility, viability and normal morphology). in particular, we observed a higher quantity of spermatozoa with a well-formed nucleus and normal flagella, even though the percentage of spermatozoa with good morphology does not exceed the 25th percentile (15). subsequently we compared the data from the swim-up before and after therapy and it was observed a general improve of all sperm parameters examined (table 1). the significant improvement of parameters after swimup proved to be important in order to undergo assisted reproduction techniques since these will be the spermatozoa selected for the icsi. eosin y test on capacitated spermatozoa was carried out neither at time 0 nor at time 1. a colorimetric test was performed on all the samples collected for this trial to detect the presence of free radicals in the semen before and after the treatment with antioxidants (figure 1). after therapy with antioxidants, it was observed that the levels of os were notably lower and none of examined samples showed high or very high os levels. gambera_stesura seveso 30/09/19 18:25 pagina 188 then we evaluated the outcome of the ivf treatment. the percentage of fertilization and the number of embryos obtained, was significantly higher in the n1 group; our comparison highlighted a significant improvement in the embryo quality in the group showing a lower os level. the pregnancy rate was not significative in the two groups analysed (table 2). conclusions a lower number of free radicals in semen may influence positively the development of embryos. many factors may influence treatment outcome and among them reactive oxygen species (ros) have aroused great interest in the scientific literature of the last years. ros play a fundamental physiologic role during the various phases of reproductive process. the presence of antioxidant systems, enzymatic or not, aims to control the excessive production of reactive oxygen species and the damage they may cause (17). a lack of balance results in a condition called os, which leads to lipid peroxidation of plasm membranes, dna fragmentation and cell apoptosis in spermatozoa (18). the manipulation of gametes in vitro during medically assisted reproduction may be influenced by their exposure to high levels of ros, thus suggesting the importance of using antioxidants to neutralize negative effects of the latter. antioxidant therapy has become quite a common treatment in case of male infertility. number of studies describe general positive effects related to the intake of antioxidants. however, outcomes are highly variable depending on the kind of antioxidant used, its concentration or the synergy of several antioxidants administered together. since oxidative stress seems to play a fundamental role in infertility, if antioxidant defence systems are increased, benefits comparable with those deriving from the use of traditional drugs may be obtained. we assessed the effects of a therapy with antioxidants on semen parameters of 32 patients affected by oligoas189archivio italiano di urologia e andrologia 2019; 91, 3 antioxidant treatment on seminal parameters table 1. sperm parameters assessed in selected patients before and after treatment. baseline baseline capacitated capacitated who t0 t1 spermatozoa t0 spermatozoa t1 2010 no. of spermatozoa (x10⁶/ml) 9.45 ± 3.24 13.39 ± 5.06 3.80 ± 2.80 5.83 ± 4.51 > 15 x10⁶ no. of total spermatozoa(x10⁶) 28.44 ± 13.75 40.61 ± 18.80 3.75 ± 2.84 5.94 ± 4.43 > 39 x10⁶ progressive motility (a+b%) 23.68 ± 10.54 37.65 ±10.06 65.15 ± 20.50 75.87 ± 16.76 > 32% normal morphology (%) 3.43 ± 1.68 4.93 ± 1.96 11.46 ± 5.79 15.12 ± 5.76 > 4% eosin test (%) 68.43 ± 3.83 72.68 ± 3.15 > 58% who: world health organization. table 2. comparison of influence of oxidative stress between group n1 and group n2 (9 patients) on the outcome of icsi treatments. n1 (n = 23) n2 (n = 9) no. of retrieved oocytes 5.17 ± 2.90 4 ± 2.17 % of mature oocytes 82.35 83.33 % of fertilization 92.85* 70* no. of embryos obtained 3.43 ± 2.14* 1.77 ± 1.30* % of cleavage 86.81 76.19 no. of transferred embryos 1.30 ± 0.47 1.33 ± 0.5 embryo score (es) 10.22±1.86* 6.94±1.8* % of pregnancies 26.08 22.22 figure 1. time 0: 5 patients showed no oxidative stress (n1); 12 patients had low levels of oxidative stress (n2); 12 patients had high levels of oxidative stress (n3) and 3 patients showed very high levels (n4). time 1: the value of 23 patients tested after the treatment was nearly zero (n1) while 9 patients proved to have n2 levels. gambera_stesura seveso 30/09/19 18:25 pagina 189 archivio italiano di urologia e andrologia 2019; 91, 3 l. gambera, a. stendardi, c. ghelardi, b. fineschi, r. aini 190 thenoteratozoospermia and oxidative stress. morphology, motility and the number of normal spermatozoa are the parameters that significantly improved after 65 days of treatment, thus suggesting that oxidative stress may induce several alterations in the various parts of spermatozoa. the presence of ros results in the break of plasma membranes and such effect may lead to sperm chromatin fragmentation, thus compromising male’s gene pool. the morphologic analysis of spermatozoa samples at time 0 showed a high number of altered acrosomes, which were often missing or reacted. after the therapy with antioxidants, the nucleus was well formed with normal non-reduced acrosomes, thus suggesting that oxidative stress has negative consequences also at this level. the assessment of semen parameters was performed also after the application of swim up method. increased motility rates and a higher number of spermatozoa with normal morphology was observed also after such test. this improvement proved to be significant for the application of assisted reproductive techniques since these spermatozoa will be selected for icsi. the micro-environment of gametes and embryos during assisted reproduction is very different from physiological one: a higher oxygen concentration, temperature and ph surges, as well as prolonged exposition to light and media may be potential exogenous sources of oxidative stress (9). the lack of balance between antioxidant defence systems and reactive oxygen species may cause a damage that could affect the fertilization rates and embryo quality. the impact of oxidative stress seems to have some effects also on the number of embryos obtained. such number was double in the patients with levels of oxidative stress close to zero (n1) compared to those with low levels of os (n2). from such data we can deduce that oxidative stress may negatively influence both fertilization process and the development of embryos. quality assessment of embryos, which is essential during medically assisted reproduction, confirmed that the best ones develop in an environment with almost no oxidative stress. the embryo score given to evaluate embryo quality made it easy to detect the best ones. this practical, non-invasive method allowed us to select the most suitable embryo to be transferred, which led to an increase in implantation rates and to a reduction in the number of multiple pregnancies and related risks. since the production of ros during assisted reproduction techniques cannot be completely eliminated, suitable strategies should be adopted to minimize their effects on the treatment. the observation of abnormal levels of oxidative stress makes clinical analysis clearer, especially when reduced sperm function is not related to known illnesses. the outcomes of this trial seem to suggest that the administration of our food supplement improve semen parameters and that the evaluation of oxidative stress levels may become a diagnostic tool to assess male infertility in patients undergoing art cycle. references 1. agarwal a, majzoub a. role of antioxidants in assisted reproductive techniques. world j mens health 2017; 35:77-93. 2. agarwal a, nallella kp, allamaneni ss, said tm. role of antioxidants in treatment of male infertility: an overview of the literature. reprod biomed online. 2004; 8:616-27. 3. aktan g, dogru-abbasoglu s, küçükgergin c, et al. mystery of idiopathic male infertility: is oxidative stress an actual risk? fertil steril. 2013; 99:1211-5. 4. piomboni p, stendardi a, gambera l, et al. protein modification as oxidative stress marker in normal and pathological human seminal plasma. redox rep. 2012; 17:227-32. 5. tremellen k. oxidative stress and male infertilitya clinical perspective. hum reprod update. 2008; 14:243-58. 6. zini a, san gabriel m, baazeem a. antioxidants and sperm dna damage: a clinical perspective. j assist reprod genet. 2009; 26:427-32. 7. gambera l, campanella g, piomboni p, et al. ruolo di un’associazione tra antiossidanti e stimolanti immunitari naturali nel trattamento dell’astenoteratospermia con leucocitosi. minerva ginecol. 2007; 59:473-9. 8. piomboni p, gambera l, serafini f, et al. sperm quality improvement after natural anti-oxidant treatment of asthenoteratospermic men with leukocytospermia. asian j androl. 2008; 10:201-206. 9. du plessis ss, makker k, desai nr, agarwal a. impact of oxidative stress on ivf. expert rev obstet gynecol. 2008; 3:539-554. 10. opuwari cs, henkel rr. an update on oxidative damage to spermatozoa and oocytes. biomed res int. 2016; 9540142. 11. who laboratory manual for the examination and processing of human semen. 2010; p.225. 12. palermog, joris h, devroey p, van steirteghem ac. pregnancies after intracytoplasmatica injection of a single spermatozoon into oocyte. lancet. 1992; 340:17-18. 13. lee sh, song h, park ys, et al. poor sperm quality affects clinical outcomes of intracytoplasmatic sperm injection in fresh and subsequent frozen-thawed cycles: potential paternal effects on pregnancy outcomes. fertil steril. 2009; 91:798-804. 14. choi hw, park ys, lee sh, et al. effects of maternal age on embryo quality and pregnancy outcomes using testicular sperm with intracytoplasmatic sperm injection. clin exp reprod med. 2016; 43:221-7. 15. veek ll. an atlas of the human gametes and conceptuses. new york: parthenon publishing group; 1999, pp.46-51. 16. maizoub a, agarwal a. antioxidant therapy idiopathic oligoasthenoteratozoospermia. indian j urol. 2017; 33:207-214. 17. aitken rj, clarkson js, fishel s. generation of reactive oxygen species, lipid peroxidation, and human sperm function. biol reprod. 1989; 41:183-97. 18. agarwal a, majzoub a. role of antioxidants in assisted reproductive techniques. world j mens health. 2017; 35:77-93. correspondence laura gambera lauragambera@agimedica.it anita stendardi anitastendardi@agimedica.it rosamaria aini dr.aini@agimedica.it a.g.i. medica center for reproductive medicine viale toselli 94/f, 53100 siena, italy camilla ghelardi c.ghelardi@agimedica.it benedetta fineschi b.fineschi@agimedica.it department of molecular and developmental medicine, university of siena, siena (italy) gambera_stesura seveso 30/09/19 18:25 pagina 190 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3360 review no conflict of interest declared. breaking dna strands that negatively affecting development and embryo implantation negatively (2). sperm integrity, dna damage and genetic material are reflected by dna fragmentation index (sdf) parameter that is suggested as a crucial biomarker for semen quality (3). the sperm dna fragmentation index (sdf) is a potential parameter for the study of fertility. previous studies hinted the possibility of using dna fragmentation with the clinical limit of 25% (4). men with higher dfi are more susceptible to have reproductive problems. a more recent studies claim surgical repair of varicocele can help improve sperm dna quality. this theory is supported as reviewed by the schauer et al. (5) meta-analysis result, stating that regardless of the chosen surgical technique (high ligation, inguinal or subinguinal approach), improvements can be seen. moreover, microsurgical methods offer adequate simplified anatomic visualization with a lower recurrence and complication rate (6). high sdf coupled with normal sperm parameters has yet to be considered as varicocelectomy indication due to the limited studies regarding the impact of such intervention on sdf (4). studies have shown that varicocele repair can improve sperm quality and pregnancy rates of people with clinical varicocele. varicocelectomy may also result in the development of testicular regrowth and improve the sperm dna integrity in up to 80% of cases. considering the impact of untreated varicocele cases, especially on male fertility, it is important to evaluate and provide physicians with the most updated knowledge. a recent meta-analysis (7) evaluated the effect of varicocelectomy, including microsurgical varicocelectomy, on sperm dna integrity, but other studies were more recently published targeted on specific populations with infertility associated to varicocele and with longer follow-up. therefore, this paper aims to update the review of current literature regarding the effects of microsurgical varicocelectomy on sperm dna fragmentation index and sperm parameters. material and methods eligibility criteria inclusion criteria of the chosen studies were: study written in english, available online in full-text, published background: varicocele is known to have impacts in infertility cases and sperm quality. this review aimed to evaluate the effects of microsurgical varicocelectomy on sperm dna fragmentation index (dfi) and sperm parameters. methods: open full english text articles from january 2017 to october 2021 were searched from online database including pubmed, embase, scopus, cochrane library and google scholar. results: systematic search resulted in 277 potential papers. after throughout paper analysis, 5 studies were included in this review. from all five analyzed studies, microsurgical varicocelectomy was statistically proven to reduce dna fragmentation index by 5.46% (mean difference -5.46; 95% ci: -4.79, -6.13; p < 0.00001). moreover, the procedure also significantly improved other sperm parameters (sperm concentration +8.23%, sperm motility +7.17%, sperm progressive motility +2.77%, sperm morphology +0.64%). conclusion: microsurgical varicocelectomy significantly improves spermatogenesis as reflected by biomarkers of infertile men including semen parameters and sperm dna fragmentation (sdf). key words: microsurgical varicocelectomy; sperm dna fragmentation; dna fragmentation index; progressive sperm motility; sperm concentration; sperm morphology; total sperm motility. submitted 23 may 2022; accepted 14 july 2022 introduction varicocele is an abnormal dilatation of pampiniform plexus veins in the spermatic cord that commonly correlates to infertility and bad sperm quality. its incidence reaches up to 15% among normal population while its prevalence varies from 30-80% in primary and secondary infertile patients (1). the etiopathogenesis of varicocele remains unclear. the common hypothesis believes the condition is caused by the lack of oxygen in the scrotum, small vessel obstruction and imbalance of reactive oxygen species (ros) and antioxidant production. the imbalance in specific leads to lipid, protein and nucleic acids damage of the living sperm cells due to high oxidative stress, hence altering their its motility and ability to fuse with oocyte. ros also impair sperm chromatin structure by microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients: a systematic review and meta-analysis of more recent evidence alwin soetandar, bambang sasongko noegroho, safendra siregar, ricky adriansjah, akhmad mustafa department of urology, hasan sadikin academic medical center, faculty of medicine, universitas padjadjaran bandung, indonesia. doi: 10.4081/aiua.2022.3.360 summary 361archivio italiano di urologia e andrologia 2022; 94, 3 microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients between january 2017 to october 2021, designed as randomized controlled trials (rcts) or cohort prospective studies, reporting dfi and sperm parameters after microsurgical varicocelectomy. exclusion criteria studies were excluded if studies were case reports, reviews and other than microsurgical varicocelectomy therapy was performed. guidelines we used the preferred reporting items for systematic reviews and meta-analysis (prisma) guidelines in reporting this study (8) (figure 1). search strategy literature search was performed on pubmed, embase, scopus, cochrane library, and google scholar following prisma guidelines. the search was conducted on september 23rd, 2021 using the search term (“microsurgical varicocelectomy” or “microscopic varicocelectomy” or “microsurgery of varicocele” or “varicocele repair”) and (“sperm parameter” or “sperm analysis” or “sdf". data extraction and quality assessment one reviewer selected literature and inputted data into an excel database. two independent reviewers screened titles and abstracts to determine their eligibility. then, a full-text review was done to obtain detailed information. risk of bias assessment was done based on prisma guidelines. statistical analysis meta-analysis compared preoperative vs. postoperative sperm parameters and sdf using the review manager 5.4.1 software. the main outcome was the mean difference with 95% ci before and after varicocelectomy. if the p value of heterogeneity chi-squared test was less than 0.10 or i2 > 50%, the random-effect model was used. the fixed-effect model was then used if p ≥ 0.10 or i2 ≤ 50%. results study selection systematic search for studies from all available databases resulted in 277 potential papers. after screening and duplicate exclusion, 68 studies were chosen. after second evaluation regarding topic relevance, 12 studies were evaluated. finally, after throughout paper analysis, 5 studies were included in this review (figure 1). three more studies were retrieved with respect to the previous review of qiu et al. (7). they were specifically targeted on patients with infertility associated to varicocele and one of them reported data at a longer follow up period. study characteristics the general characteristics of reviewed prospective studies are listed in table 1. varicocele repair through microsurgical varicocelectomy was done in 95, 141, 67, 120 and 60 patients, respectively. three out of five studies evaluated sdf after three months from the procedure, whereas the other two did the test after 6 and 12 months of operation. the sdf data by varicocele grade was provided by two studies. sperm parameters such as sperm concentration, total and progressive sperm motility and sperm morphology are listed in table 2. only one study didn’t measure sperm concentration. the rest showed massive improvement in both concentration and morphology after the intervention. other than that, two studies reported total and progressive sperm motility, respectively. in general, all included studies resulted in the improvement of sperm parameters after the surgery. pre-and post-operative sdf the sdf was evaluated preoperatively, 3 months or 6 months postoperatively in all of the included studies. the result of meta-analysis for 5 studies were presented in figure 2. the heterogeneity test was statistically significant (chi-squared = 108.39, df = 4, p < .00001, isquared = 96%), hence the random effect model was used otherwise. on average, sdf percentage among clinical varicocele patients showed 5,61% reduction after the procedure (mean difference -5.61; 95% ci: -6.28, -4.94; p < 0.00001). sperm concentration four studies reported sperm configure 1. prisma flow diagram. archivio italiano di urologia e andrologia 2022; 94, 3 a. soetandar, b. sasongko noegroho, s. siregar, r. adriansjah, a. mustafa 362 centration before and after surgery. it was showed an increase of sperm concentration by 8.23% after surgery (mean difference: 8.23; 95% ci: 6.62, 9.85; p < 0.00001) (figure 3). table 1. study characteristics and sdf findings. reference design patients follow up month sdf assay surgical technique main sdf results after surgery fathi et al. (9) prospective cohort 95 male patients with a 1-year history 12 months scd microsurgical subinguinal sdf% decreased from 34.93% ± 5.56% preoperatively of male subfertility to 25.75% ± 5.15% postoperatively (p < 0.001) kavoussi et al. (10) prospective cohort 141 male patients who underwent 3 months scd microsurgical subinguinal sdf% decreased from 29.7% ± 5.0% preoperatively varicocele repair for infertility to 22% ± 0% postoperatively (p < 0.38) vahidi et al. (1) prospective cohort 67 infertile male patients 3 months tunel test microsurgical subinguinal sdf& decreased from 15.93 ± 4.96% preoperative with varicocele to 10.86 ± 4.44% postoperative (p < 0.001) zaazaa et al. (11) prospective cohort 120 male patients associated with 3 months scd microsurgical subinguinal sdf% decreased from 34.6 ± 4.1% preoperative varicocele grade ii and iii to 28.3 ± 5.2% postoperative (p < 0.05) abdelbaki et al. (12) prospective cohort 60 male patients with varicocele 3-6 months scsa microsurgical subinguinal sdf% decreased from 29.49% preoperative to 18.78% postoperative (p < 0.001) sdf = sperm dna fragmentation; scd = sperm chromatin dispersion; tunel = terminal deoxynucleotidyl transferasemediated dutp nick end-labelling. table 2. sperm parameters. reference sperm concentration total sperm motility progressive sperm motility sperm morphology pregnancy rate fathi et al. (9) increased from 26.1 ± 8.5 millions/ml n/a increased from 33.9 ± 1.6% increased from 4.3 ± 0.5 higher pregnancy rate of preoperative to 32.5 ± 8.6 millions/ml preoperative to 36.1 ± 6.3% preoperative to 5.2 ± 1.8% varicocelectomy group (31.1%) postoperative (p = 0.002) postoperative (p = 0.82) postoperative (p = 0.09) compared to control group (13.3%) (p = 0.10) kavoussi et al. (10) increased from 25.5 ± 32.4 millions/ml increased from 47.5 ± 20.3% increased from 25.8 ± 3.8% n/a n/a preoperative to 36.0 ± 37.0 millions/ml preoperative to 53.4 ± 14.5% preoperative to 30.6 ± 14.3% postoperative (p = 0.25) postoperative (p = 0.25) postoperative (p = 0.38) vahidi et al. (1) n/a n/a n/a increased from 13.86 ± 7.85% n/a preoperative to 18.53 ± 7.36% postoperative (p = 0.016) zaazaa et al. (11) increased from 20.8 ± 18.4 millions/ml increased from 24.3 ± 10.8% n/a increased from 1.5 ± 0.5% n/a preoperative to 28.0 ± 22.9 millions/ml preoperative to 32.1 ± 12.1% preoperative to 2.2 ± 0.9% postoperative (p < 0.05) post operative (p < 0.05) postoperative (p < 0.05) abdelbaki et al. (12) increased from 10.9 ± 2.8 millions/ml increased from 36.4 ± 10.7% increased from 10.8 ± 4.6% increased from 2.3 ± 0.7% n/a preoperative to 21.04 ± 8.9 millions/ml preoperative to 53.6 ± 18.9% preoperative to 19.1 ± 8.1% preoperative to 2.7 ± 0.6% postoperative (p < 0.001) postoperative (p < 0.001) post operative (p < 0.001) postoperative (p < 0.001) figure 2. forest plot of meta-analysis on the efficacy of varicocelectomy for sperm dna fragmentation improvement (random-effect model of 5 studies). figure 3. forest plot of sperm concentration (fixed-effect model). 363archivio italiano di urologia e andrologia 2022; 94, 3 microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients total sperm motility both kavoussi et al. and zaazaa et al. evaluated total sperm motility 3 and 6 months post-varicocelectomy. there was meaningful increase by 7.17% (mean difference: 7.17; 95% ci: 4.80, 9.54; p < 0.00001) (figure 4). progressive sperm motility progressive sperm motility was evaluated in three studies comparing preand post-varicocelectomy results, showing a significant increase by 3.77% (mean difference: 3.77; 95% ci: 2.73, 4.82; p < 0.00001) (figure 5). sperm morphology evaluation of sperm morphology before and after the intervention was done in 4 studies showing an increase of sperm morphology by 0.64% (mean difference: 0.64; 95% ci: 0.50, 0.77; p < 0.00001) (figure 6). risk of bias and summary of findings results of risk of bias assessment and summary of findings are reported in tables 3, 4. discussion varicocele has long been associated to higher sdf index damage (13). newer studies has started to include sdf index as a new indicator for varicocelectomy since a prior study had suggested it as a diagnostic tool for clinical varicocele patients (16). the average value of sdf is 1530% and is regarded as high when detected dfi reaches table 3. risk of bias assessment. author year random allocation blinding incomplete other overall sequence concealment generation outcome data bias risk bias fathi et al. 2021 no no no yes no high kavoussi et al. 2019 no no no yes no high vahidi et al. 2018 unclear no no yes no high zaazaa et al. 2018 yes unclear no yes no moderate abdelbaki et al. 2017 no no no no no high table 4. summary of findings. patient or population: varicocele patients intervention: microsurgical varicocelectomy comparison: standard varicocelectomy outcomes; sperm dna fragmentation index and other sperm parameters with mean differences (95%ci) sdf -5.61 95% ci -6.28 to -4.94 sperm concentration 8.23 95% ci 6.62 to 9.85 total sperm motility 7.17 95% ci 4.8 to 9.54 progressive sperm motility 3.77 95% ci 2.73 to 4.82 sperm morphology 0.64 95% ci 0.5 to 0.77 total participants: 483 infertile males [5 studies] follow up: 3–12 months figure 4. forest plot of total sperm motility (fixed-effect model). figure 5. forest plot of progressive sperm motility (random-effect model). figure 6. forest plot of sperm morphology (random-effect model). archivio italiano di urologia e andrologia 2022; 94, 3 a. soetandar, b. sasongko noegroho, s. siregar, r. adriansjah, a. mustafa 364 more than 30%. majority of men with grade ii and iii varicocele have sdf level of more than 30%. moreover, a group of scientists has claimed lower embryo implantation and pregnancy rate happened if sdf threshold was more than 30% (14). this even more suggests a connection between ros level in spermatozoa and sdf. for more than a century, varicocelectomy has always been the first treatment option for subfertile male with palpable varicocele. this procedure is performed through three surgical approaches such as retroperitoneal, inguinal and subinguinal varicocele repair with or without magnification (15). in general, sperm dna integrity in patients improved after the procedure (7). based on eau guideline, varicocelectomy in infertility cases has been shown to enhance semen parameters including sperm motility, concentration, and morphology (16). it also significantly decreases testosterone levels, natural and assisted pregnancy rates. varicocelectomy in infertility cases with absence of semen parameters abnormality and subclinical varicocele is not recommended (16). sdf from meta-analysis of all the 5 analyzed studies, varicocelectomy decreased dna fragmentation index by 5,61% (mean difference -5.61; 95% ci: -6.28, -4.94; p < 0.00001). this result was confirmed in three studies using different methods of assessment (p < 0.001); from 34.93% ± 5.56% preoperatively to 25.75% ± 5.15% postoperatively using sdf assay of scd9, from 15.93 ± 4.96% preoperatively to 10.86 ± 4.44% postoperatively using tunel test1, and from 29.49% preoperatively to 18.78% postoperatively using scsa (12). moreover, a lower sdf index from 34.6 ± 4.1% preoperatively to 28.3 ± 5.2% postoperatively (p < 0.05) was also seen in 120 grade ii and iii varicocele patients (11). similar results of lower dna fragmentation index from 29.7% ± 5.0% to 22% ± 0% (p < 0.38) after varicocele repair among 141 infertile male patients were also observed (4). prior meta-analysis by qiu et al. observed a reduction of sdf percentage after varicocelectomy of -6.14 [95% ci, 6.90 to -5.37].7 results from birowo et al. and wang et al. also supported this finding (4, 13). both studies had demonstrated the impact of varicocele repair in decreasing sdf index, leading to the halt of varicocele progression by downregulating systemic oxidative stress (os) (2). study by neto et al. added that varicocelectomy improved sdf count in all varicocele condition regardless of its grade without much different in treatment duration (17). furthermore, a review of 20 studies reported great reduction of sdf after varicocelectomy during 3-12 months follow up time (2). the findings in this study has been constant with previous literatures (4, 13, 17) concluding that varicocelectomy does bring improvement in sperm dna characteristics in clinical varicocele patients. the dna damage in varicocele can be one of the causes in lower sdf count after varicocelectomy. dna fragmentation happens during sperm synthesis and maturation (3). during the sperm maturation, histones are replaced by smaller arginineand cysteinerich protamine (hp). the replacement hinders sperm dna ability to repair itself when being exposed to internal and external modifications. the misfolding of dna supercoil structures in the chromosome due to the tension twist by the double stranded dna helix that supposed to restore dna actually caused sdf or abnormalities inside the chromatin structure.18 furthermore, external genital tracts inflammation, venous statis and reflux increase risk of sdf by promoting hypoxia, inducing and increasing reactive oxygen species (ros) within the sperm dna. all those changes lead to worse dna damage and fragmentation (3, 13, 19). other than resolving venous stasis and reflux problem, varicocelectomy also reduce ros synthesis, leading to less dna damage (4). sperm parameters schauer et al. evaluated semen parameters after procedures such as high ligation or inguinal or subinguinal were performed. regardless of the methods, meaningful comparable improvements were observed in sperm concentration and motility (5). furthermore, surgical methods (77.5%) had been perceived to give better results in sperm parameter compared to radiological approach (62.5%) (p = 0.032) (20). the measured parameters showed improvement after 3 months of varicocelectomy (21). sperm dna fragmentation was not linked to sperm concentration, morphology and progressive motility.3 result of this review regarding better sperm parameters were similar with prior studies (4, 5, 20). sperm concentration different results were seen from previous studies. li et al. study showed different sperm concentration between control and varicocele group (22). however, nguyen et al. claimed sperm concentration between two groups were alike (14). sperm concentration was evaluated before and after surgery. an elevation of 8,23% were gained after procedure (mean difference: 8.23; 95% ci: 6.62,9.85; p < 0.00001). comparison between preand post-intervention proved there are meaningful rise in sperm concentration (p = 0.009) (22). further statistical analysis exhibited no significant relationship between sperm dna integrity and sperm concentration (22). total sperm motility result of this review goes in accordance with previous study that assessed various varicocelectomy methods and sperm motility. in that study, sperm motility was higher by 6.80% after suprainguinal approach (95% ci 3.95 to 9.66, p < 0.00001), 9.44% after inguinal approach (95% ci 3.72 to 15.16, p = 0.001) and 12.25% by subinguinal approach (95% ci 4.76 to 19.75, p = 0.001) (5). progressive sperm motility higher progressive sperm motility was observed in current and prior studies. study by kadioglu et al. had showed better progressive sperm motility after six months of microsurgical varicocelectomy when compared to baseline (p < 0.05) (23). this study also had similar result with no association found between progressive motility and sperm sdf (3). sperm morphology most of studies showed improvement of sperm morphology after intervention, including result gained in this 365archivio italiano di urologia e andrologia 2022; 94, 3 microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients study. sperm morphology was 2.73% higher after varicocelectomy (mean difference: 2.73; 95% ci: 0.65, 4.80; p = 0.01) (4). only one study by li et al. that had failed to establish such result (p = 0.028) (22). conclusions microsurgical varicocelectomy is not simply the best therapy approach for varicocele repair. it can also benefit in enhancing fertility by lowering sdf as seen in infertility biomarkers including semen parameters and pregnancy rates. among the evaluated studies, only one paper showed better pregnancy rate after surgical procedure. our data supported the hypothesis of spermatogenesis restoration after varicocelectomy in infertile patients. however, further studies using more related publications is needed to prevent publication bias. in this study, only rct prospective studies were included. references 1. vahidi s, moein m, nabi a, narimani n. effects of microsurgical varicocelectomy on semen analysis and sperm function tests in patients with different grades of varicocele: role of sperm functional tests in evaluation of treatments outcome. andrologia. 2018; 50:1-6. 2. roque m, esteves sc. effect of varicocele repair on sperm dna fragmentation: a review. international urology and nephrology. 2018; 50:583-603. 3. yang h, li g, jin h, et al. the effect of sperm dna fragmentation index on assisted reproductive technology outcomes and its relationship with semen parameters and lifestyle. 2019; 8:356-65. 4. birowo p, rahendra wijaya j, atmoko w, rasyid n. the effects of varicocelectomy on the dna fragmentation index and other sperm parameters: a meta-analysis. basic clin androl. 2020; 30:15. 5. schauer i, madersbacher s, jost r, et al. the impact of varicocelectomy on sperm parameters: a meta-analysis. journal of urology. 2012; 187:1540-7. 6. majzoub a, cho cl, agarwal a, esteves sc. adult varicocele diagnosis and treatment. in: esteves sc, cho cl, majzoub a, agarwal a, editors. varicocele and male infertility [internet]. cham: springer international publishing; 2019 [cited 2022 jul 3]. p. 58193. available from: http://link.springer.com/10.1007/978-3-31979102-9_55 7. qiu d, shi q, pan l. efficacy of varicocelectomy for sperm dna integrity improvement: a meta-analysis. andrologia [internet]. 2021 feb [cited 2022 jul 12]; 53(1). available from: https://onlinelibrary.wiley.com/doi/10.1111/and.13885 8. moher d, liberati a, tetzlaff j, et al. preferred reporting items for systematic reviews and meta-analyses: the prisma statement. 2009; 6. 9. fathi a, mohamed o, mahmoud o, et al. the impact of varicocelectomy on sperm dna fragmentation and pregnancy rate in subfertile men with normal semen parameters: a pilot study. arab journal of urology. 2021; 19:186-90. 10. kavoussi pk, abdullah n, gilkey ms, et al. the impact of ipsilateral testicular atrophy on semen quality and sperm dna fragmentation response to varicocele repair. asian journal of andrology. 2019; 21:1-4. 11. zaazaa a, adel a, fahmy i, et al. effect of varicocelectomy and/or mast cells stabilizer on sperm dna fragmentation in infertile patients with varicocele. andrology. 2018; 6:146-50. 12. abdelbaki sa, sabry jh, al-adl am, sabry hh. the impact of coexisting sperm dna fragmentation and seminal oxidative stress on the outcome of varicocelectomy in infertile patients: a prospective controlled study. arab journal of urology. 2017; 15(2):131-9. 13. wang yj, zhang rq, lin yj, et al. relationship between varicocele and sperm dna damage and the effect of varicocele repair: a meta-analysis. reproductive biomedicine online. 2012; 25:307-14. 14. nguyen tt, sang t, thi t, et al. evaluation of sperm dna fragmentation index, zinc concentration and seminal parameters from infertile men with varicocele. 2018; 1-7. 15. johnson d, sandlow j. treatment of varicoceles: techniques and outcomes. fertility and sterility. 2017; 108:378-84. 16. salonia a, bettocchi c, carvalho j, et al. eau guidelines on sexual and reproductive health. 2020. 17. lira neto ft, roque m, esteves sc. effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: a systematic review and meta-analysis. fertility and sterility. 2021; 116:696-712. 18. sakkas d, alvarez jg. sperm dna fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. fertility and sterility. 2010; 93:1027-36. 19. kimura m, nagao k. role of varicocele repair for male infertility in the era of assisted reproductive technologies. 2014; 185-92. 20. çayan s. systematic review of treatment methods for recurrent varicoceles to compare post-treatment sperm parameters, pregnancy and complication rates. 2019; 1-9. 21. al bakri a, lo k, grober e, et al. time for improvement in semen parameters after varicocelectomy. journal of urology. 2012; 187:227-31. 22. li f, yamaguchi k, okada k, et al. significant improvement of sperm dna quality after microsurgical repair of varicocele. systems biology in reproductive medicine. 2012; 58:274-7. 23. kadioglu tc, aliyev e, celtik m. microscopic varicocelectomy significantly decreases the sperm dna fragmentation index in patients with infertility. biomed research international. 2014; 2014. correspondence alwin soetandar alwin19001@mail.unpad.ac.id bambang sasongko noegroho safendra siregar ricky adriansjah akhmad mustafa department of urology, hasan sadikin academic medical center, faculty of medicine, universitas padjadjaran bandung, indonesia stesura seveso 357archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.357 modeling the contribution of the obesity epidemic to the temporal decline in sperm counts alex kasman 1, francesco del giudice 1, 2, eugene shkolyar 1, angelo porreca 3, gian maria busetto 2, ying lu 4, michael l. eisenberg 1, 4 1 department of urology, stanford university school of medicine, stanford, california; 2 department of maternal-infant and urological sciences, “sapienza” rome university, policlinico umberto i hospital, rome, italy; 3 department of urology, policlinico abano terme, abano terme (pd), italy; 4 department of obstetrics and gynecology, stanford university school of medicine, stanford, california; 5 department of biomedical data science, stanford university school of medicine, stanford, california. over the past 40 years (4). additionally, several other studies in specific populations/countries have identified similar findings (5-10). however, the underlying cause or causes of the decline remains unknown. given the complexity of spermatogenesis, there are likely multiple mechanisms behind declining sperm counts (e.g. environmental effects of chemical exposure, endocrine disruption, etc.) (11-14). over the past four decades, the prevalence of obesity has increased over 50% in the world. as the obesity epidemic continues to worsen, the effect it may have on fertility has been increasingly investigated and several studies have been published on the topic. a systematic review by guo et al., showed that overall for every five unit increase in bmi there was a 2.4% drop in sperm count (15). additionally, a recent large observational study of 3,966 sperm donors showed a significant decrease in sperm count for overweight and obese men (16). however, the overall contribution the obesity epidemic has to falling total sperm counts remains unknown. given the public health implications of falling sperm counts, understanding the potential contributions of varying etiologies may have remains important. in the current study, we sought to model the potential contribution the us obesity epidemic could have to sperm counts over the past four decades. materials and methods this systematic review was conducted according to the systematic review and meta-analysis of observational studies in epidemiology (moose) guidelines (17). the research question was established based on the following pico criteria: what is the contribution of the obesity epidemic to the temporal decline in sperm counts? furthermore, our goal was to explore the weighted influence of the us obesity on total sperm counts over the last four decades. obesity rates across the world were determined for the last four decades starting in 1973 up to 2011 using the world health organization’s (who) global health observatory (gho) data (https://www.who.int/gho/ncd/ risk_factors/overweight/en/). obesity rates were quantified using body mass index (bmi). the dates, 1973-2011, were selected based objective: total sperm count (tsc) has been declining worldwide over the last several decades due to unknown etiologies. our aim was to model the contribution that the obesity epidemic may have on declining tsc. materials and methods: obesity rates were determined since 1973 using the who’s global health observatory data. a literature review was performed to determine the association between tsc and obesity. using the measured obesity rates and published tsc since 1973, a model was created to evaluate the association between temporal trends in obesity/temperature and sperm count. results: since 1973, obesity prevalence in the united states was increased from 41% to 67.9%. a review of the literature showed that body mass index (bmi) categories 2, 3, and 4 were associated with tsc (millions) of 164.27, 155.71, and 142.29, respectively. the contribution to change over time for obesity from 1974 to 2011 was modeled at 1.8%. when the model was changed to represent the most extreme possible contribution to obesity reported, the modeled change over time rose to 7.2%. when stratified according to fertility status, the contribution that bmi had to falling sperm counts for all comers was 1.7%, while those presenting for fertility evaluation was 2.1%. conclusions: while the decline in tsc may be partially due to rising obesity rates, these contributions are minimal which highlights the complexity of this problem. key words: obesity; sperm count; total sperm count; semen analysis. submitted 16 september 2020; accepted 15 october 2020 introduction infertility remains an important public health concern with an estimated 15% of couples unable to conceive after 1 year of trying and therefore are labeled infertile with up to 50% having a male factor etiology (1, 2). a such, semen analysis remains an important component of a couple’s fertility evaluation (3). with this knowledge, the overall decline in sperm count worldwide is worrisome and requires further attention. a large meta-analysis of 185 studies and data from over 42,000 men, demonstrated a 50% decline in sperm concentration and counts summary archivio italiano di urologia e andrologia 2020; 92, 4 a. kasman, f. del giudice, e. shkolyar, a. porreca, g.m. busetto, y. lu, m.l. eisenberg 358 on the real world measured sperm count data from the systematic review done by levine et al. (4). to determine the contribution that obesity has, on average, to total sperm count (tsc) we performed a systematic review of the literature in pubmed, embase, and cochrane from 1973-2011, without language restriction, to identify studies that examined infertility and/or male factor infertility in relation to the risk of mortality. the reference lists of the included studies were also screened for relevant articles. original population-based retrospective cohort studies as well as cross-sectional and case-control cohort studies were included and critically evaluated (level of evidence: iii-2, iii-3). case reports, abstracts and meeting reports were excluded from the analysis. search terms included but were not limited to: primary field: body mass index or bmi, obesity, overweight and, infertility, subfertility, semen parameters, or sperm parameters, sperm count, semen quality, sperm quality; secondary fields: oligospermia, azoospermia, oligozoospermia. a total of 26 studies were identified that examined obesity’s impact on male fertility. six of these studies were excluded as they did not report total sperm count. from the remaining 20 studies, bmi was categorized according to healthy weight (bmi 18.5-24.9), overweight (bmi 2529.9), and obese (bmi > 30) using the center for disease control’s standard definition (https://www.cdc.gov/obesity/adult/defining.html). after categorization, a further 7 studies were eliminated due to overlapping bmi categories (e.g. tsc reported together for categories 3 and 4). from these remaining 14 studies, data was extracted to obtain the average tsc for each bmi category across studies with larger studies having a higher weight (table 1). to assess the risk of bias (rob), all included reports were independently reviewed using the “quality assessment tool for observational cohort and crosssectional studies”, provided by the national institute of health (nih), by assessing the potential risk for selection bias, information bias, measurement bias, or confounding bias (confounding bias includes cointerventions, differences at baseline in patient characteristics, and other issues as shown in supplementary table 1) (18). studies were rated as good, fair, and poor quality, where high risk of bias translated to a rating of poor quality (“−”) and low risk of bias translated to a rating of good quality (“+”). no study was considered to be seriously flawed according to the aforementioned criteria. studies’ risk of performance bias was low overall with absence of attrition bias due to incomplete outcome data across all the studies. annual/decade rates of body mass index categories (i.e. normal, overweight, obese) were obtained from the who for 1973 and 2011. for each year, we used our calculated association between bmi category and sperm count to determine the average sperm count based on annual bmi. bmi category, the tsc was then multiplied by the appropriate obesity rate and a tsc for obesity was obtained for that time period (e.g. 1973 or 2011). the rates between 1973 and 2011 were then compared and a percent change over time was calculated. over all years, we could then evaluate changes in sperm count based on temporal trends in obesity over time. tsc was then categorized according to obesity, most extreme bmi contribution (e.g. the study reporting the strongest association between bmi and tsc), region, and fertility status (unknown fertility versus those presenting for fertility evaluation). regional areas (usa, europe, asia, table 1. studies utilized for obesity effect on sperm count. category n studies obese 11504 belloc (2014), paash (2010), shayeb (2011), aggerholm (2008), duits (2010), xiao (2013), macdonald (2012), chavarro (2010), andersen (2015), hajshafiha (2013), vignera (2012), gutorova (2014), ma (2019) extreme obese 297 hammiche (2012) usa 360 chavarro (2010) europe 8643 belloc (2014), paasch (2010), shayeb (2011), aggerholm (2008), duits (2010), anderson (2015), vignera (2012) asia 1304 gutorova (2014), ma (2019), xiao (2013), new zealand 372 macdonald (2012) all comers 2852 paasch (2010), aggerholm (2008), vignera (2012), gutorova (2014) fertility evaluations 8652 belloc (2014), shayeb (2011), duits (2010), xiao (2013), macdonald (2012), chavarro (2010), andersen (2015), hajshafiha (2013) supplementary table 1. risk assessment of individual studies according to “quality assessment tool for observational cohort and cross-sectional studies”. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 belloc 2014 + + + + + + + + + na na paasch 2010 + na + + + + + + na na shayeb 2011 + + na + + + + + + na na aggerholm 2008 + + + + + + + + + na na duits 2010 + + na + + + + + + na na xiao 2013 + + na + + + + + + na na macdonald 2012 + + + + + + + + + na na chavarro 2010 + + + + + + + + + na na hammiche 2012 + + + + + + + + + na na andersen 2015 + + na + + + + + + na na hajshafiha 2013 + + na + + + + + + na na vignera 2012 + + + + + + + + + na na gutorova 2014 + + na + + + + + + na na ma 2019 + + + + + + + + + na na na: not applicable. criteria 1: was the research question or objective in this paper clearly stated? criteria 2: was the study population clearly specified and defined? criteria 3: was the participation rate of eligible persons at least 50%? criteria 4: were all the subjects selected or recruited from the same or similar populations (including the same time period)? were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? criteria 5: were a sample size justification, power description, or variance and effect estimates provided? criteria 6: for the analyses in this paper, was the exposure(s) of interest measured prior to the outcome(s) being measured? criteria 7: was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? criteria 8: for exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome? criteria 9: were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? criteria 10: was the exposure(s) assessed more than once over time? criteria 11: were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? criteria 12: were the outcome assessors blinded to the exposure status of participants? criteria 13: was loss to follow-up after baseline 20% or less? criteria 14: were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? 359archivio italiano di urologia e andrologia 2020; 92, 4 obesity and sperm count and new zealand) were chosen based on those regions sampled in the 14 studies used. p < 0.05 were considered significant. results the average total sperm count (tsc, millions) for increasing bmi categories 2 (normal), 3 (overweight), 4 (obese) were 164.3, 155.7, and 142.3. the average tsc (millions) for individuals above normal bmi range (e.g. categories 3 and 4) was 149. there was not enough data present in the literature for a tsc to be calculated for bmi category 1 (underweight). obesity has increased in prevalence of the past 40 years. in 1973, 59% of men were normal weight and 41% were obese. in contrast, in 2011 (the most recent year with available data), 32.1% were normal with 67.9% obese. averaged across all studies, bmi categories 2, 3, and 4 were associated with tsc (millions) of 164.27, 155.71, and 142.29, respectively. the most extreme association between bmi and sperm count reported tsc (millions) of 68.6, 49.6, and 45.9 for bmi categories 2, 3, and 4, respectively (19). overall, the contribution to change over time for obesity from 1973 to 2011 was calculated at 1.8% (figure 2a). when the model was changed to represent the most extreme possible contribution to obesity reported in any given study, the modeled change over time rose to 7.2% (figure 2a). when modeled based on regional bmi, the change for usa was 9.9%, europe 3.1%, asia 1.9%, and new zealand -0.4% (figure 2b). when stratified according to fertility status, the contribution that bmi had to falling sperm counts for men with unknown fertility status was 1. 7% while those presenting for fertility evaluation was 2.1% (figure 2c). figure 1. prisma flow diagram. figure 2. model of obesity effect on sperm count stratified by overall obesity effect and largest obesity effect: (a) fertility status known versus unknown; (b) and region; (c) reported decline for all models is based on levine et al. (levine, jørgensen, martino, et al., 2017). archivio italiano di urologia e andrologia 2020; 92, 4 a. kasman, f. del giudice, e. shkolyar, a. porreca, g.m. busetto, y. lu, m.l. eisenberg 360 discussion the current report demonstrates the modest impact increasing rates of obesity may have on reported decline in semen quality. increasing obesity rates were shown to have a small (1-10%), though measurable contribution to the overall decline with the most measured effect, logically, observed at the extreme end of obesity’s contribution. additionally, the countries with higher obesity rates were shown to have a larger (~10%), though still modest, contribution to the reported 50% tsc decline over the past half century. when the obesity group was stratified by fertility status, the effect did decrease in observed men with unknown fertility versus those presenting for fertility evaluation. overall, the contributions of rising obesity rates on declining tsc appear to be individually small and suggest that the etiology for reported declines in semen quality are likely multifactorial. as the obesity epidemic continues to worsen globally, the health effects of each continue to gain importance (2023). additionally, during this time period, global sperm counts have been observed to be declining with unknown mechanisms (4-8). obesity has been postulated to be one of the mechanisms driving this especially given its implications for overall health (24). indeed, a number of primary studies have demonstrated that as an individual’s bmi increases that sperm analysis parameters are affected (25-27). however, it should be noted that not all studies have found an impactful reduction in semen parameters in obese men, including a large systematic review by macdonald, et al. (28, 29). the etiology of this potential relationship is likely multifactorial which may explain the small effect that was measured in the current model. increasing obesity has been associated with altered levels of both sex hormone binding globulin and testosterone as well as an increased estradiol to testosterone ratio (30-33). additionally, there is increased conversion of testosterone to estradiol in the setting of increased adiposity (34). all of these hormonal changes may ultimately lead to a negative effect downstream on spermatogenesis through the hypothalamic-pituitary-gonadal axis. while this may be a potential way in which sperm analysis parameters may be affected by obesity, the underlying mechanism through which increased adiposity could lead to impaired spermatogenesis is unknown. in addition, the additional body mass may insulate the scrotum contributing to rising scrotal temperature and lower sperm production. the current model has several other limitations. the model itself is based on data from literature review and therefore is prone to both the bias of suitable articles for data extraction as well as the bias of the primary study itself. additionally, a number of assumptions for the obesity model were made including that the measured effect of obesity overtime is constant. while other factors have been postulated to lead to declining sperm counts (e.g. chemical exposures), rigorous longitudinal surveillance did not allow modeling. conclusions the current report demonstrates the modest contribution that obesity may have on declining total sperm counts and highlights the complex nature of infertility. further studies are needed to examine the underlying mechanisms behind declining total sperm counts as this has large public health implications. references 1. thoma m, mclain a, louis jf, et al. the prevalence of infertility in the united states as estimated by the current duration approach and a traditional constructed approach. fertil steril. 2014; 99:1324-1331. 2. louis j, thoma m, sorensen d, et al. the prevalence of couple infertility in the united states from a male perspective : evidence from a nationally representative sample. andrology. 2013; 1:741-748. 3. oehninger s, ombelet w. limits of current male fertility testing. fertil steril. 2019; 111:835-841. 4. levine h, jørgensen n, martino-andrade a, et al. temporal trends in sperm count: a systematic review and meta-regression analysis. hum reprod update. 2017; 23:646-659. 5. huang c, li b, xu k, et al. decline in semen quality among 30,636 young chinese men from 2001 to 2015. fertil steril. 2017; 107:83-88.e2. 6. centola gm, blanchard a, demick j, et al. decline in sperm count and motility in young adult men from 2003 to 2013: observations from a u.s. sperm bank. andrology. 2016; 4:270-276. 7. sengupta p, nwagha u, dutta s, et al. evidence for decreasing sperm count in african population from 1965 to 2015. afr health sci. 2017; 17:418-427 8. mishra p, negi mps, srivastava m, et al. decline in seminal quality in indian men over the last 37 years. reprod biol endocrinol. 2018; 16:1-9. 9. craig jr, jenkins tg, carrell dt, hotaling jm. obesity, male infertility, and the sperm epigenome. fertil steril. 2017; 107:848-859. 10. kasman am, del giudice f, eisenberg ml. new insights to guide patient care: the bidirectional relationship between male infertility and male health. fertil steril. 2020; 113:469-477. 11. eisenberg ml, li s, cullen mr, et al. increased risk of incident chronic medical conditions in infertile men : analysis of united states claims data. fertil steril. 2015; 105:629-636. 12. mehrpour o, karrari p, zamani n, et al. occupational exposure to pesticides and consequences on male semen and fertility: a review. toxicol lett. 2014; 230:146-156. 13. skakkebaek ne, rajpert-de meyts e, buck louis gm, et al. male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. physiol rev. 2016; 96:55-97. 14. busetto g, del giudice f, virmani a, et al. body mass index and age correlate with antioxidant supplementation effects on sperm quality: post hoc analyses from a double-blind placebo-controlled trial. andrologia. 2020; 52:e13523. 15. guo d, wu w, tang q, et al. the impact of bmi on sperm parameters and the metabolite changes of seminal plasma concomitantly. oncotarget. 2017; 8:48619-48634. 16. ma j, wu l, zhou y, et al. association between bmi and semen quality: an observational study of 3966 sperm donors. hum reprod. 2019; 34:155-162. 17. group m of os in e (moose). meta-analysis of observational studies in epidemiology: a proposal for reporting. jama. 2000; 283:2008-2012. 361archivio italiano di urologia e andrologia 2020; 92, 4 obesity and sperm count 18. national institute of health and department of health and human services, quality assessment tool for observational cohort and cross-sectional studies. 19. hammiche f, laven jse, twigt jm, et al. body mass index and central adiposity are associated with sperm quality in men of subfertile couples. hum reprod. 2012; 27:2365-2372. 20. afshin a, forouzanfar mh, reitsma mb, et al. health effects of overweight and obesity in 195 countries over 25 years. n engl j med. 2017; 377:13-27. 21. parmesan c, yohe g. a globally coherent fingerprint of climate change. nature. 2003; 421:37-42. 22. del giudice f, kasman a, ferro m, et al. clinical correlation among male infertility and overall male health: a systematic review of the literature. investig clin urol. 2020; 61:355-371. 23. del giudice f, kasman a, de barardinis e, et al. association between male infertility and male-specific malignancies: systematic review and meta-analysis of population-based retrospective cohort studies. fertil steril. 2020; epub ahead. 24. heymsfield sb, wadden ta. mechanisms, pathophysiology, and management of obesity. n engl j med. 2017; 376:254-266. 25. jensen tk, andersson am, jørgensen n, et al. body mass index in relation to semen quality and reproductive hormones among 1,558 danish men. fertil steril. 2004; 82:863-870. 26. belloc s, cohen-bacrie m, amar e, et al. high body mass index has a deleterious effect on semen parameters except morphology: results from a large cohort study. fertil steril. 2014; 102:1268-1273. 27. eisenberg ml, kim s, chen z, et al. the relationship between male bmi and waist circumference on semen quality: data from the life study. hum reprod. 2014; 29:193-200. 28. duits fh, van wely m, van der veen f, gianotten j. healthy overweight male partners of subfertile couples should not worry about their semen quality. fertil steril. 2010; 94:1356-1359. 29. macdonald aa, herbison gp, showell m, farquhar cm. the impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. hum reprod update. 2009; 16:293-311. 30. macdonald aa, stewart aw, farquhar cm. body mass index in relation to semen quality and reproductive hormones in new zealand men: a cross-sectional study in fertility clinics. hum reprod. 2013; 28:3178-3187. 31. chavarro je, toth tl, wright dl, et al. body mass index in relation to semen quality, sperm dna integrity, and serum reproductive hormone levels among men attending an infertility clinic. fertil steril. 2010; 93:2222-2231. 32. ehala-aleksejev k, punab m. the different surrogate measures of adiposity in relation to semen quality and serum reproductive hormone levels among estonian fertile men. andrology. 2015; 3:225-234. 33. keskin m, budak s, aksoy e, et al. investigation of the effect of body mass index (bmi) on semen parameters and male reproductive system hormones. arch ital urol androl. 2017; 89:219-221. 34. michalakis k, mintziori g, kaprara a, et al. the complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. metabolism. 2013; 62:457-478. 35. levine h, jørgensen n, martino a, et al. temporal trends in sperm count: a systematic review and meta-regression analysis. hum reprod update. 2017; 23:646-659. correspondence alex kasman, md, ms eugene shkolyar, md angelo porreca md department of urology, policlinico abano terme, abano terme (pd) (italy) francesco del giudice, md gian maria busetto md, phd department of maternal-infant and urological sciences, “sapienza” rome university, policlinico umberto i hospital, rome (italy) ying lu, phd department of biomedical data science, stanford university school of medicine, stanford (california) michael l. eisenberg, md (corresponding author) eisenberg@stanford.edu department of urology, stanford university school of medicine, 300 pasteur dr., s285, stanford, california 94305-5118 327archivio italiano di urologia e andrologia 2017; 89, 4 case report elderly patient with atypical leiomyoma of the bladder presenting as flank pain: a case report mojtaba ameli, mina rahmandoost gonabad university of medical sciences, gonabad, iran. atypical leiomyoma is a rare tumor of the bladder whose correct diagnosis with imaging techniques and cystoscopy is difficult. this tumor is prevalent in females and more common in middle age. in the present study we report a rare case of atypical leiomyoma presenting as flank pain and history of recurrent urinary tract infections in an elderly female. ultrasound (us) showed that the wall of bladder was thickening and irregular, especially in the lower part of the bladder. us revealed hypoechoic solid mass with dimensions of 37 x 26 mm in the posterior bladder wall protruding into the bladder. computed tomography scan of the patient showed a mass with dimensions of 29 x 38 mm in the posterior wall of the bladder that infiltrated the mesenteric fat and also seemed to be invading the intestinal wall. according to the general condition and age of our patient, we removed all of the mass under spinal anesthesia by transurethral bladder resection (turbt). biopsy results showed atypical leiomyoma. about 6 months after the patient follow-up, no recurrence was observed and symptoms had completely resolved. according to the non-specificity of the imaging, of the age of presentation and of clinical manifestations of atypical leiomyoma differential diagnosis for bladder cancer it is recommended. only with histopathologic findings, the diagnosis can be confirmed. key words: leiomyoma; bladder tumor; elderly. submitted 2 september 2017; accepted 23 september 2017 summary no conflict of interest declared. case report we present the case of a 75 years old woman with left flank pain for a month. she had a colicky pain which was positional and radiated to hypogastric area. the patient complained of frequency and had a history of frequent urinary tract inflammation but denied to have chills, fever and hematuria. there was no history of surgery and hospital admission in the patient’s past medical history but she had a history of hypertension and was taking losartan and triamterene by years. there was a soft and without tenderness abdomen with palpable bladder at abdominal examination with no other important finding. urinary tract inflammation was ruled out by urine analysis. other laboratory findings were blood urea nitrogen (bun) 22 mg/dl, serum creatinine 2 mg/dl, white blood count (wbc) 7800 with 75% neutrophils. at ultrasonography the bladder wall was seen as hypertrophied and irregular especially in the inferior part and a solid hypoechoic mass with 37 x 26 mm size was seen on the posterior wall of the bladder protruding into the bladder. at computed tomography (ct) scan it was demonstrated an image of a 29 x 38 mm mass on the posterior wall of the bladder (figure 1) infiltrating to the mesenteric fat which seemed to invade the intestinal wall whereas no evidence of obstruction or hepatic metastasis was seen. doi: 10.4081/aiua.2017.4.327 introduction the leiomyoma is a rare and benign tumor of the bladder including 0.43% of all the bladder tumors according to a study. however, it is the most common benign tumor of the bladder (1). it is more prevalent in women and is frequently observed in the fourth and the fifth decades of the life. well-known atypical leiomyoma arises in the myometrium and it is identified by pleomorphic nuclei, degenerative chromatin and nucleic inclusion. depending on the tumor size and location it has different symptoms (2). the leiomyoma can occur with urinary obstructive and irritative symptoms (3). the urinary obstructive symptoms are the most common symptoms of leiomyoma (49%) whereas about 38% of the patients have urinary irritative symptoms, 11% have hematuria and about 19% are asymptomatic (4). based on our information an atypical leiomyoma of the bladder in a 75 years old woman complaining of flank pain is a uncommon condition. figure 1. a mass in bladder in ct scan without and with contrast. ameli_stesura seveso 03/01/18 09:50 pagina 327 archivio italiano di urologia e andrologia 2017; 89, 4 m. ameli, m. rahmandoost 328 after necessary pre-operative investigations the patient was taken to the operation room where underwent transurethral resection of the bladder of a 4 cm mass. the histological examination demonstrated stretched and spindle tumor cells with moderately atypical nuclei with sporadic mitosis and no necrosis, therefore atypical leiomyoma was diagnosed (figure 2). discussion leiomyoma was first described by virchow (4) and bladder leiomyoma is the most common benign tumor of the bladder (1). the bladder leiomyoma can be intravesical, intramural or extra vesical at macroscopic view. among these three types, the intravesical form is more frequently the cause of bleeding and of irritative and obstructive symptoms as long as they grow into the bladder lumen (5). in the present study, the case of a 75 years old woman is reported who had an uncommon age for the onset of the bladder leiomyoma and at our knowledge is one of the few cases of bladder leiomyoma reported in patients older than 70. the patient was observed with the uncommon presentation of flank pain that was the unique feature of presentation. the atypical leiomyoma is well known to occur in the myometrium and is characterized by pleomorphic nuclei, degenerative chromatin or nucleic inclusions. based on our knowledge the atypical leiomyoma is reported in a few cases that were mostly in the childbearing age. steroidal hormones may have a main role in the development of bladder leiomyoma similarly to what observed in the uterine leiomyoma. the incidence of an atypical leiomyoma in a 75 years old woman in the menopause age who was not taking any steroidal hormones seems to be controversial and interesting. ultrasonography, ct scan, magnetic resonance imaging (mri) and cystoscopy are high value diagnostic tools which can show the morphology and the anatomical location of the leiomyoma. ultrasound shows leiomyoma as a solid flat hypoechoic tumor with hyperechoic mucosal lining (6). also ct scan and the mri are useful for the assessment of the bladder tumors. at ct scan the typical leiomyoma of the bladder is generally described as a round hypodense mass with defined borders and after contrast demonstrates an homogeneous centripetal hyperdensity (7). the atypical leiomyoma of the bladder may show similar morphology of the bladder cancer and makes difficult the diagnosis with ultrasound, ct, mri and cystoscopy. the final diagnosis of the bladder lesion can be achieved by histopathological assessment of the biopsy (8). in our case the diagnosis remained uncertain in relation to the patient’s age and the tumor aspect at ct scan showing a suspect of intestinal invasion until the definitive diagnosis was made by the histopathological assessment. the treatment and the prognosis is determined by the size and the location of the tumor. small asymptomatic tumors may be treated conservatively till onset of the symptoms. for small symptomatic tumors (< 2 cm), the transurethral resection is the treatment of choice although it presents a minor risk of incomplete surgery with need of a second surgery. in our case there was no tumor recurrence after transurethral surgery and at 6 months followup no recurrence of symptoms. extra vesical and large tumors need open surgery or a partial cystectomy based on their size (9). the rate of recurrence is low and this tumor has a good prognosis. conclusion according to the non-specificity of the imaging, patient's age and clinical manifestations, differential diagnosis of atypical leiomyoma with bladder cancer is recommended. the diagnosis was confirmed only with histopathologic findings. references 1. wong-you-cheong jj, woodward pj, manning ma, sesterhenn ia. from the archives of the afip: neoplasms of the urinary bladder: radiologic-pathologic correlation. radiographics. 2006; 26:553-580. 2. goktug gh, ozturk u, sener nc, et al. transurethral resection of a bladder leiomyoma: a case report. can urol assoc j. 2014; 8:e111-e113. 3. greco a, baima c, piana p. leiomyoma of the bladder. report of a case and review of the literature. minerva urol nefrol. 1999; 51:33-8. 4. kretschmer hl leiomyoma of the bladder with a report of a case and a review of the literature. j urol. 1931; 26:575-90. 5. kalathia j, agrawal s, chipde ss, agrawal r. total endoscopic management of a large bladder leiomyoma. urol ann. 2015; 7:527-9. 6. chatterjee s, baksi a, kumar s. dyspareunia due to leiomyoma of the urinary bladder: an unusual presentation of a rare bladder neoplasm. hellenic j surg. 2014; 86:34-36. 7. cornella jl, larson tr, lee ra, et al. leiomyoma of the female urethra and bladder: report of twenty-three patients and review of the literature. am j obstet gynecol. 1997; 176:1278-1285. 8. wu s. imaging findings of atypical leiomyoma of the urinary bladder simulating bladder cancer: a case report and literature review. med ultrason. 2013, 15:161-163. 9. jeschke k, wakoning j, winzely m, henning k. laparoscopic partial cystectomy for leiomyoma of the bladder wall. j urol. 2002; 165:2115-6. correspondence mojtaba ameli, md (corresponding author) mojtaba.ameli@gmail.com fellowship of endourology iran university of medical science, hasheminejad kidney center valinejad avenue, tehran, 1969714713 iran mina rahmandoost gonabad university of medical sciences, gonabad, iran figure 2. magnified view of an atypical zone. ameli_stesura seveso 03/01/18 09:50 pagina 328 stesura seveso 375archivio italiano di urologia e andrologia 2021; 93, 3 letter to editor no conflict of interest declared. to the editor, radical cystectomy (rc) for bladder cancer is a life-changing surgery, associated with high morbidity and mortality rate. ileal neobladder seems as an attractive way for urine management post cystectomy but would carry the risk of retaining urine in the ileal pouch for a long time, resulting in serum electrolyte changes, that may add to the patients’ morbidity. eau guidelines recommend against ileal neobladder for patients with liver and renal disorders, as well as for patients > 80 years old (1). metabolic complications after rc are well known; including hyperchloremic metabolic acidosis and hyperkalemia. all known information about these changes are available through blood work-up done during follow-up of these patients (2). an interesting recent study compared metabolic complications post-neobladder versus ileal conduit. they could identify that there is no significant difference of the metabolic and electrolyte changes between both procedures (3). the goal of our research was to look for the electrolyte’s changes in ileal urine, as early as 1 hour of exposure, in an in vivo model. twenty consecutive patients with muscle invasive bladder tumor (mibt) undergoing rc and ileal neobladder were included in the study. exclusion criteria were patients with renal and hepatic disorders, presence of hydroureteronephrosis, and patients older than 80-year-old. no bowel preparation was done before surgery. ethical approval was obtained from the ethical committee of alexandria university, egypt. consents were obtained from all patients prior to rc. at the time of rc, we started the surgery through intraperitoneal exposure, dissecting both ureters and cutting them, obtaining 120 ml of urine. we then do the ileal resection anastomosis. we separate 40 cm of ileum 20 cm from the ileocecal junction. we generally use gia 80 stapler covidien. ileal contents are squeezed out, then 100 ml of urine is injected into the isolated ileal segment, and 20 ml are left as a control. rc and extended lymphadenectomy were then completed. urine is withdrawn from the isolated ileal segment after 1 hour and sent for analysis. the study was completed over 8 months. the mean age of the patients was 58 (45-65). the study included 17 men and 3 women. the mean reduction in urine volume was 17.5 + 3.45. the mean increase in urine ph was 1.41 + 0.46. urine sodium, calcium, phosphorus and magnesium were increased while potassium, urea and creatinine were reduced, within the ileal segment. figures 1 and 2 illustrate these changes. the changes were consistent in all patients. the bowel is frequently incorporated into the urinary tract following rc or for augmentation. because the permeability and functional properties of the bowel mucosa are different from those of the bladder epithelium, several metabolic disturbances are expected in these patients, including metabolic acidosis, water and electrolyte changes (2-5). the current knowledge of these metabolic changes comes mainly from studying the final outcome of serum changes in these patients. the exact pathogenesis of the metabolic changes that happen after interposition of the intestine in the urinary system has not been studied properly. this is attributed to the lack of a model that records the transepithelial movements of electrolytes after urinary diversion. in the present study, we constructed a model to investigate the early electrolyte changes following inspissation of urine in the ileal segment. our model provides a direct way to know the exact movement of different electrolyte forms and of the inspissated urine in the ileum, with avoidance of any confounding factors. following urine diversion, sodium (na) is secreted in exchange of hydrogen (h) and bicarbonate (hco3) in the exchange of chloride (cl), resulting in the hyperchloremic metabolic acidosis (6). this was well represented in our model, as there was an increased urine sodium and ph level after retention for an hour in the ileal segment. this may explain cho et al. (3) findings of no significant electrolyte changes identified between the ileal conduit and neobladder, as initiation of electrolyte changes and acid base imbalance need < 1 hour to be initiated. the observed decreased potassium (k) level in urine after one hour can be explained by the greater ability of the ileum to reabsorb potassium passively compared to the colon segments, thereby attenuating the risk of hypokalemia that occurs as a result of chronic metabolic acidosis (7). the absorption of k from urine contrast with the clinical observation of studying the electrolyte changes in ileal urine at the time of radical cystectomy and ileal conduit diversion mohamed adel atta 1, tamer abou youssif 1, ahmed kotb 1, 2 1 urology department, alexandria university, alexandria, egypt; 2 urology department, northern ontario school of medicine, thunder bay, on, canada. submitted 15 may 2021; accepted 6 july 2021 doi: 10.4081/aiua.2021.3.375 archivio italiano di urologia e andrologia 2021; 93, 3 m. adel atta, t. abou youssif, a. kotb 376 hypokalemia in these patients. this, however, can be explained by the loss of potassium in the mucus which is excessively secreted in the neobladder. in our model, there was a decline in urinary urea and creatinine levels. this can be attributed to the passive absorption of urea and creatinine. this would explain why these patients would normally have a decreased estimated glomerular filtration rate (egfr) in the absence of obstructive uropathy or a pathological cause. urine osmolality is an index of the concentration of osmotically active particles, particularly chloride, sodium, urea, and potassium. in our model, there was a decrease in urine osmolality. this can be attributed to decreased potassium and urea levels. polydipsia is one of known complications of ileal diversion (8). we think that the increased osmolality in the interstitium secondary to urea absorption stimulates peripheral osmoreceptors that cause polydipsia, even without the plasma effects that would trigger brain osmoreceptors. in animal models, evidence for the presence of peripheral osmoreceptors in the portal vein and liver was identified (9). humans could be having similar receptors that cause the persistent sense of thirst in these patients, explained by persistent urea and k diffusion through the ileum. the observed decrease in the urine volume after one hour can be explained by water absorption against the osmolarity gradient. this contrasts with the clinical observation of increased urine output in these patients, which can be explained by thirst and subsequent diuresis. in our study, the calcium level is raised after one hour; this can be explained by the paracellular transport of calcium. in vitro studies show that calcium is absorbed only in the duodenum and secreted in the jejunum and ileum (10) and this selective absorption and secretion of calcium was referred to as “anomalous solvent drag effect” (11). ileal diversion is so associated with the inherent loss of calcium that can be even before calcium loss from bone as a compensatory mechanism to metabolic acidosis. figure 1. biochemical changes of ileal urine. 377archivio italiano di urologia e andrologia 2021; 93, 3 ileal urine the length of the ileal segment and the duration of contact of urine to the ileal segment would affect the metabolic outcomes. this study, however; explains why patients with ileal conduit urine diversion would still have some degree of electrolyte imbalance. our study is unique in being a prospective study looking at the pathophysiology of electrolyte changes in a unique model avoiding confounding factors. our study is limited by the relatively small number of patients. in conclusions the present in vivo human model shows that there is an inherent property of the human ileum to absorb water, creatinine, urea and potassium and to secrete sodium, calcium, magnesium and phosphorus. these changes would happen regardless of the type of urine diversion using ileum. early preventive measures to the patients’ post-ileal urine diversion would be then recommended. references 1. alfred witjes j, lebret t, compérat em, et al. updated 2016 eau guidelines on muscle-invasive and metastatic bladder cancer. eur urol. 2017; 71:462-475. 2. tanrikut c, mcdougal ws. acid-base and electrolyte disorders after urinary diversion. world j urol. 2004; 22:168-71. 3. cho a, lee sm, noh jw, et al. acid-base disorders after orthotopic bladder replacement: comparison of an ileal neobladder and an ileal conduit. ren fail. 2017; 39:379-384. 4. mills rd, studer ue. metabolic consequences of continent urinary diversion. j urol. 1999; 161:1057-66. 5. lockhart jl, davies r, persky l, et al. acid base changes following urinary tract reconstruction for continent diversion and orthotopic bladder replacement. j urol. 1994; 152:338-42. 6. gough dc. enterocystoplasty. bju int. 2001; 88:739-43. figure 2. electrolytes changes of ileal urine. archivio italiano di urologia e andrologia 2021; 93, 3 m. adel atta, t. abou youssif, a. kotb 378 7. gilbert sm, hensle tw. metabolic consequences and long-term complications of enterocystoplasty in children: a review. j urol. 2005; 173:1080-6. 8. lee rk, abol-enein h, artibani w, et al. urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. bju int. 2014; 113:11-23. 9. lechner sg, markworth s, poole k, et al. the molecular and cellular identity of peripheral osmoreceptors. neuron. 2011; 69:332-44. 10. karbach u, rummel w. cellular and paracellular calcium transport in the rat ileum and the influence of 1,25dihydroxyvitamin d3 and dexamethasone. naunyn schmiedebergs arch pharmacol. 1987; 336:117-24. 11. nellans hn, kimberg dv. anomalous calcium secretion in rat ileum: role of paracellular pathway. am j physiol. 1979; 236:e473-81. correspondence mohamed adel atta, md, professor tamer abou youssif, md alexandria university, alexandria (egypt) ahmed kotb, md, assistant professor (corresponding author) drahmedfali@gmail.com northern ontario school of medicine 980 oliver rd, thunder bay, p7b 6v4, ontario (canada) stesura seveso 465archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. be ≥ 1.5 ml. the sperm concentration is reported as the number of sperm per ml of semen that should be ≥ 15 million per ml. total sperm number (also known as ‘total sperm count’) is described as the total number of sperm in the ejaculate, calculated by multiplying the semen volume by the sperm that should be ≥ 39 million. sperm progressive motility should be ≥ 32% motile within 60 minutes of ejaculation. sperm vitality should be ≥ 58%. sperm normal morphology is described as the percentage of the total number of sperms that should be ≥ 4% (4). covid-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect (6). coronavirus can directly affect testicular tissue as well as some sperm parameters by altering the expression of the angiotensin-converting enzyme 2 gene pattern (ace-2) (7) because seminiferous cells, spermatogonia, leydig cells and sertoli cells express this enzyme (8). studies have shown that ace-2 is present in the post-acrosomal region, neck and middle part of normal sperm (9). sperm ace binds to the glycosyl-phosphatidyl-inositol (gpi) portion of the oocyte zona pellucida and is therefore involved in fertilization (10). n-acetylcysteine (nac), a derivative of amino acid l-cysteine, is used mainly as an antioxidant (11). nac has free radical scavenging activity (12). in addition, daily treatment with nac results in a significant improvement in sperm motility in comparison to placebo (13). nac improved sperm concentration and acrosome reaction while reducing ros and oxidation of sperm dna (14). this study investigates the effect of nac on abnormal sperm parameters in men with covid 19 infection. materials and methods design this interventional study was conducted from march 2020 to july 2021. all couples whose infertility treatment cycle were canceled due to covid-19 pandemic were included in this study. male patients with abnormal sperm analysis before covid-19 were excluded from the study. in total, 273 male patients were included in this study, 47 patients did not present to the infertility center to continue treatment during the time of this study and male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters as concentration, motility and morphology observed in one or two semen analysis with an interval of 1 and 4 weeks. covid-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect. n-acetyl cysteine (nac) improved sperm concentration and acrosome reaction while reducing reactive oxygen species (ros) and oxidation of sperm dna. this interventional study was conducted on 200 men who were referred to private infertility clinics for female factor (their previous semen analysis was normal) and got covid-19 infection in the last 3 months showing an impairment of the latest semen analysis due to covid. men were placed in two groups of control (n = 100) and intervention (nac consumption). subjects who got covid-19 infection had a significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis evaluated before the covid-19 infection. nac consumption significantly improved sperm total motility, sperm morphology and sperm concentration. covid-19 infection has a negative effect on sperm parameters. nac supplementation may have positive effect on sperm parameters. key words: covid-19; sperm; morphology; infection. submitted 25 september 2021; accepted 12 october 2021 introduction according to the international committee for monitoring assisted reproductive technology of world health organization (who), infertility is a reproductive disorder that prevents clinical pregnancy after 12 months or more of unprotected intercourse (1). studies have shown that nearly 72.4 million couples worldwide are involved in infertility problems (2). male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters of concentration, motility and morphology in one or two semen analysis with an interval of 1 and 4 weeks (3). normal sperm parameters are assessed based on who criteria (4). semen analysis is still a powerful and essential tool with a sensitivity of 89.6% that can identify 9 out of 10 men with infertility problems (5). normal semen volume is the total amount of fluid ejaculated that should the effect of n-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of covid-19 in the last three months bahare rafiee 1, seyed mohammad bagher tabei 2 1 phd student of reproductive biology, department of reproductive biology, school of advanced medical sciences and applied technologies, shiraz, iran; 2 genetics department, school of medicine, shiraz university of medical sciences, shiraz, iran. doi: 10.4081/aiua.2021.4.465 summary archivio italiano di urologia e andrologia 2021; 93, 4 b. rafiee, s.m. bagher tabei 466 26 patients presented to continue the treatment more than two months after positive pcr and were excluded from the study. other exclusion criteria were diabetes, hypertension, mumps history, sexually transmitted diseases, varicocele, and chronic diseases history. all the 200 eligible covid-19 patients were willing to participate in the study and were randomly allocated in two groups of controls and treated subjects. all the cases gave a semen sample after completing written informed consent. subjects having a positive nasopharyngeal swab test for covid-19 (eswab collection kit, copan diagnostics) or positive immunoglobulin (ig) m and igg antibodies were considered positive for covid-19 (15). intervention and assessment the subjects took nac 600 mg/day by oral route for 3 months (16). variables including seminal parameters were measured before and after the intervention. semen sampling method semen samples were collected once, at the beginning of study and at the end of the intervention. sperm samples were taken by masturbation after 3-5 days of sexual abstinence and kept in a plastic container. then the samples were incubated at 37°c for 30 minutes and analyzed after one hour. the sperms were counted by light microscope with a magnification of 400. different characteristics of semen including appearance, volume, ph, color, viscosity, liquefaction time, sperm concentration and sperm motility were investigated. statistical analysis for statistical analysis was used the statistical package for social science (spss inc, chicago, illinois, usa) version 16.0. p value significance was set at 0.05 and confidence interval was at 95%. paired t-test was used to compare the results before and after interventions. independent t test was used to compare between control and intervention group. results the average time between initial normal sperm analysis and covid-19 infection was 2 months (range 1-5 months). average time from covid-19 infection and sperm analysis re-evaluation was 6 weeks (range 3-8 weeks). patients who presented more than 2 months after covid-19 infection were excluded. subjects suffering from covid-19 infection had a statistically significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis before the covid-19 infection (table 1). in table 2, results of sperm analysis after nac treatment were not significantly different from initial results of sperm analysis (before covid). in table 3 the results of sperm analysis during the followup of controls are described. results of the initial sperm analysis (before covid) and the last sperm analysis at 3 month follow-up were significant different for sperm motility (p = 0.04) and sperm concentration (p = 0.03). discussion coronavirus disease 2019 (covid-19) is a highly transmissible infectious disease caused by the severe acute respiratory syndrome coronavirus (sars-cov-2), a singlestrand enveloped rna virus belonging to the family of coronaviridae (17). this virus enters host cells mainly through ace-2 and transmembrane protease serine 2 (tmprss2) (18). recent advances suggest a possible infection of the endocrine system in covid-19 patients (19-21). in the present study, we evaluated semen parameters after acute sars-cov-2 infection. subjects suffering from covid-19 infection had a statistically significant impairment of sperm quality (semen volume, sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis before the covid infection. our findings are in accordance with other studies which are available in the literature (22-24). it is recommended that men with positive history of sars-cov-2 who are interested in fertility should be evaluated by a fertility specialist. n-acetylcysteine (nac) is a thiol-based antioxidant that plays an important role in the protection of cellular contable 1. age, body mass index and semen parameters for individuals before and after covid-19 infection. before covid after covid p value age 36.1 ± 4.1 36.1 ± 4.1 0.96 bmi (kg/m2) 23.12 ± 2.5 21 ± 3.1 0.04* volume (ml) 3.5 ± 0.9 2.9 ± 0.6 0.05* sperm concentration (106) 115.1 ± 35.1 68.7 ± 53.6 0.01* total motility (%) 69.9 ± 32.7 30.1 ± 29.6 0.01* morphology 4 ± 1.2 2 ± 0.9 0.03* table 2. comparison of semen parameters before and after covid and after 3 months treatment with nac. nac consumption significantly improved sperm total motility, sperm morphology and sperm concentration. sperm before after covid after nac p value before vs parameters covid before nac after nac volume (ml) 3.10 ± 0.56 2.3 ± 0.6 4.02 ± 0.18 0.03* total motility (%) 81.1 ± 23.2 35.1 ± 29.6 71.6 ± 25.3 0.01* sperm concentration (106/ml) 115 ± 32.5 61.7 ± 53.6 98.7 ± 44.5 0.04* morphology (%) 4 ± 0.6 2 ± 0.9 4 ± 1.5 0.03* table 3. comparison of semen parameters before and immediately after covid infection and after 3 months of follow-up in the control group. sperm before after after 3 p value after parameters covid covid 3 months covid vs 3 of follow-up months follow-up volume (ml) 4.13 ± 0.61 2.5 ± 0.3 4.44 ± 1.32 0.04* total motility (%) 65.10 ± 19.63 37.5 ± 25.1 43.3 ± 21.43 0.06 sperm concentration (106/ml) 110 ± 21.42 58.8 ± 25.1 63.54 ± 54.21 0.071 morphology (%) 3 ± 0.71 2 ± 2.1 3 ± 0.9 0.06 467archivio italiano di urologia e andrologia 2021; 93, 4 n-acetyl cysteine and abnormal sperm parameters after covid-19 stituents against oxidative damage. the hypothetical action of nac comes from the ability to stimulate and sustain intracellular levels of reduced glutathione and to detoxify ros. nac is one of the oldest and most powerful antioxidants that treat various diseases, including respiratory disorders, heart disease, heavy metal poisoning, overdose with acetaminophen and epilepsy (25). safarinejad et al. also reported significant improvements in all semen parameters in subjects receiving selenium or nac (13). the results of this study showed that sperm parameters (volume, concentration, motility and normal morphology) significantly improved after nac supplementation. nac also improved sperm concentration and morphology. conclusions covid-19 infection has a negative influence on sperm parameters. nac oral supplementation may improve sperm parameters. references 1. zegers-hochschild f, adamson gd, de mouzon j, et al. international committee for monitoring assisted reproductive technology (icmart) and the world health organization (who) revised glossary of art terminology. fertil steril. 2009; 92:1520-4. 2. rutstein so, shah ih. 2004. infecundity, infertility, and childlessness in developing countries. dhs comparative reports no. 9. calverton, maryland, usa: orc macro and the world health organization. 3. lotti f, maggi m. ultrasound of the male genital tract in relation to male reproductive health. hum reprod update. 2015; 21:56-83. 4. world health organization. who laboratory manual for the examination of human semen and semen-cervical mucus interaction, 6th ed., cambridge university press, cambridge 2021, pp. 1-86. 5. butt f, akram n. semen analysis parameters: experiences and insight into male infertility at a tertiary care hospital in punjab. j pak med assoc. 2013; 63:558-62. 6. aitken rj. covid-19 and human spermatozoa-potential risks for infertility and sexual transmission? andrology. 2021; 9:48-52. 7. verma s, saksena s, sadri-ardekani h. ace2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis. biol reprod. 2020; 103:449-451. 8. li lj, zhang fb, liu sy, et al. human sperm devoid of germinal angiotensin-converting enzyme is responsible for total fertilization failure and lower fertilization rates by conventional in vitro fertilization. biol reprod. 2014; 90:125. 9. nikolaeva ma, balyasnikova iv, alexinskaya ma, et al. testicular isoform of angiotensin i-converting enzyme (ace, cd143) on the surface of human spermatozoa: revelation and quantification using monoclonal antibodies. am j reprod immunol. 2006; 55:54-68. 10. foresta c, mioni r, rossato m, et al. evidence for the involvement of sperm angiotensin converting enzyme in fertilization. int j androl. 1991; 14:333-9. 11. zafarullah m, li w, sylvester j, ahmad m. molecular mechanisms of n-acetylcysteine actions. cell mol life sci. 2003; 60:6-20. 12. ciftci h, verit a, savas m, et al. effects of n-acetylcysteine on semen parameters and oxidative/antioxidant status. urology. 2009; 74:73-6. 13. safarinejad mr, safarinejad s. efficacy of selenium and/or nacetylcysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. j urol. 2009; 181:741-51. 14. comhaire f, christophe a, zalata a, et al. the effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. prostaglandins leukot essent fatty acids. 2000; 63:159-65. 15. holtmann n, edimiris p, andree m, et al. assessment of sarscov-2 in human semen-a cohort study. fertil steril. 2020; 114: 233-8. 16. ciftci h, verit a, savas m, et al. effects of n-acetylcysteine on semen parameters and oxidative/antioxidant status. urology. 2009; 74:73-6. 17. gorbalenya ae, baker sc, baric rs, et al. the species severe acute respiratory syndrome-related coronavirus: classifying 2019ncov and naming it sars-cov-2. nat. microbiol. 2020; 5:536-544. 18. hoffmann m, kleine-weber h, schroeder s, et al. sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. cell. 2020; 181:271-280.e8. 19. puig-domingo m, marazuela m, giustina a. covid-19 and endocrine diseases. a statement from the european society of endocrinology. endocrine. 2020; 68:2-5. 20. delle fave rf, polisini g, giglioni g, et al. covid-19 and male fertility: taking stock of one year after the outbreak began. arch ital urol androl. 2021; 93:115-119. 21. rodriguez bustos h, bravo maturana g, cortés-chau f, et al. effects of covid-19 on male sex function and its potential sexual transmission. arch ital urol androl. 2021; 93:48-52. 22. paoli d, pallotti f, colangelo s, et al. study of sars-cov-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. j endocrinol invest. 2020; 43:1819-1822. 23. pan f, xiao x, guo j, et al. no evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. fertil steril. 2020; 113:1135-1139. 24. kayaaslan b, korukluoglu g, hasanoglu i, et al. investigation of sars-cov-2 in semen of patients in the acute stage of covid-19 infection. urol int. 2020; 104:678-683. 25. ciftci h, verit a, savas m, et al. effects of nacetylcysteine on semen parameters and oxidative/antioxidant status. urology. 2009; 74:73-76. correspondence bahare rafiee, phd student of reproductive biology (corresponding author) medicalarticle2020@yahoo.com department of reproductive biology, school of advanced medical sciences and applied technologies, shiraz (iran) seyed mohammad bagher tabei genetics department, school of medicine, shiraz university of medical sciences, shiraz (iran) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3268 original paper no conflict of interest declared. resents a first-line option for the treatment of localized pca (2). open rp is the traditional approach, but it is burdened by higher perioperative morbidity, greater blood loss and longer hospitalization (3). over the last three decades, mini-invasive techniques have increasingly gained popularity owing to their advantages on perioperative outcomes over open rp. at present, about two every three rps are laparoscopic or robotassisted (4, 5). laparoscopic radical prostatectomy (lrp) could be performed in either transperitoneal or extraperitoneal route. both these approaches have pros and cons: the transperitoneal lrp (tlrp) provides a broader surgical space with full exposure of all the anatomical landmarks of the pelvis; on the other hand, the extraperitoneal laparoscopic radical prostatectomy (elrp) resembles more the open retropubic rp (6). it also decreases the risk of anesthetic and surgical complications, since it avoids the exposure of intraperitoneal structures and requires less steep trendelenburg tilt. elrp was first described by raboy in 1997(7). since then, no clear evidence of the superiority of one approach to lrp over the other has been highlighted. nevertheless, data on very large series of elrp with long follow-up are still missing. this work presents a retrospective, long-term follow-up analysis of a single-center experience on a large series of elrp, over an 18-years period. material and methods in this retrospective cohort study, we retrospectively reviewed data of 938 patients who underwent elrp at our institution between january 2001 and december 2019. among these, 168 presented exclusion factors and were removed from the analysis while 113 were excluded because of insufficient follow-up or incomplete dataset available. all the procedures were performed by three different surgeons (fsg, db, and ad), using a standardized technique, as described below. all of them were already skilled in laparoscopic surgery, since they had already performed at least 20 laparoscopic procedures at the starting point of the analysis. exclusion criteria were: clinical t4 stage prostate cancers, history of benign prostatic surgery, patient previously objective: to present a retrospective analysis on the oncological and functional outcomes of a single-center experience on a large series of extraperitoneal laparoscopic radical prostatectomies (elrp) with an extended follow-up. materials and methods: herein we present a retrospective review of patients who underwent elrp. oncological and functional follow-up data were collected by means of outpatient visits and telephone interviews, assessing overall mortality and biochemical recurrence-free survival. patients with clinical t4 stage prostate cancer (pca), previous surgery for benign prostatic hyperplasia (bph), previous androgen deprivation, radiotherapy, concomitant chemotherapy and/or experimental therapies, and with insufficient follow-up data were excluded. preoperative data recorded were age, body mass index, ultrasound prostate volume, preoperative psa and clinical stage of pca. operative data (operative time, nerve sparing technique and any perioperative complication) and pathological findings were obtained by consulting the surgical and pathological reports. oncological and functional follow-up were collected during follow-up visits and telephone interview. results: between january 2001 and december 2019, overall 938 elrp were performed at our institution. the median follow-up was 132 months. 69.7% of the patients had complete dataset. the estimated overall biochemical recurrence (bcr)-free survival was 71.4% at 5 years and 58.9% at 10 years. cancer specific survival was 84,5%. erectile function was preserved in the most of patients as postoperative iief-5 score within 12 months after surgery was > 12 in the 82.1%. about the urinary incontinence, 0.76% of the patients presented severe incontinence (continued and persistent loss of urine) and 7.0% were mildly incontinent (using up to one pad per day). conclusions; elrp has shown oncological and functional results comparable to other minimally invasive techniques and to open radical prostatectomy (orp), with favorable perioperative outcomes than the open technique and a reduced complication rate. key words: prostate cancer; radical prostatectomy; laparoscopic prostatectomy; laparoscopy; extraperitoneal prostatectomy. submitted 27 may 2021; accepted 27 june 2021 introduction prostate cancer (pca) represents the most commonly diagnosed cancer in men (1). radical prostatectomy (rp) reponcological and functional outcomes of extraperitoneal laparoscopic radical prostatectomy: an 18-years, single-center experience francesco saverio grossi, emanuele utano, paolo minafra, pier paolo prontera, francesco schiralli, antonio de cillis, evangelista martinelli, marco lattarulo, meri luka, antonio carrieri, angelo d’elia urology unit, s.s. annunziata hospital, taranto, italy. doi: 10.4081/aiua.2021.3.268 summary 269archivio italiano di urologia e andrologia 2021; 93, 3 results of elrp with long-term follow-up treated with androgen deprivation and/or radiotherapy, previous or concomitant chemotherapy and/or experimental therapies. additionally, men with less than 6months follow-up and with largely incomplete dataset were excluded. preoperative data recorded were age, body mass index (bmi), ultrasound prostate volume, preoperative psa, gleason score, and clinical stage. patients were classified in risk groups by considering preoperative clinical stage. operative data (operative time, nerve sparing technique and any perioperative complication) and pathological findings were obtained by consulting the surgical and pathological reports. oncological and functional followup data were collected by means of outpatient visits and telephone interviews, assessing overall mortality and biochemical recurrence-free survival (brfs). oncological management of patients after rp in most of the cases, men with pt2 or pt3 tumors or men with positive surgical margins followed a “wait and see” strategy with eventual subsequent salvage radiotherapy at psa recurrence. biochemical recurrence (bcr) was defined as two consecutive values of psa ≥ 0.2 ng/ml at least 6 weeks after surgery. this threshold matches the classical eau definition of bcr after rp (8), even though this definition has recently changed (9). patients having persistent psa levels > 0.2 ng/ml were considered as having bcr, as well. neither this group of patients, nor men who received adjuvant radiation therapy for locally advanced disease were excluded from the analysis. functional outcomes urinary incontinence (ui) was evaluated by the number of pads needed per 24 h and stratified as follows: 0 pad (no incontinence), 1 pad (mild incontinence), and ≥ 2 pads (severe incontinence). international index of erectile function-5 (iief-5) questionnaire were administered to evaluate the 12-month erectile function, as well as to assess pre-existing erectile dysfunction (10). statistical analysis statistical analysis was carried out with the software stata mp15 (statacorp llc, college station, tx, usa). baseline data were analyzed using descriptive statistics: frequencies were expressed as percentages while continuous variablse were presented as medians and interquartile ranges. we considered a two-tailed p-value of < 0.05 as statistically significant. we present the following article in accordance with the strobe reporting checklist. surgical technique the elrp technique adopted in our urology department was already presented in another work (11). a laparoscopic radical prostatectomy with bilateral pelvic lymph node dissection was performed with an extraperitoneal laparoscopic approach, regardless gleason score and clinical t-stage. the patient was placed in supine position, the table hyperextended at the pubic symphysis level. a 20° trendelenburg tilt was given. the initial incision was medial, 1 cm below the umbilicus. after rectus fascia identification and incision, a blunt dissection was performed under direct vision with a round shape balloon to develop the extraperitoneal space of retzius. four trocars were then placed under direct control of the surgeon’s index finger: two pararectal 10 mm trocars and two 5 mm trocars, 2 cm cranially and medially from the anterior superior iliac spine. a 10 mm structural balloon trocar served as the optical trocar in the median sub umbilical incision. bilateral extended pelvic lymph node dissection was first performed. the template for lymphadenectomy included common, internal and external iliac and obturator lymph nodes. the bladder was divided from the prostatic base in a bladder neck-sparing fashion whenever it was possible. this step was completed using blunt dissection as much as possible. seminal vesicles and deferent ducts were dissected and freed. the dissection of the posterior surface of the prostate could be made along an intra-, inter-, or extrafascial plane according to risk stratification and preoperative erectile function. when a nerve-sparing procedure was planned, the denonvilliers’ fascia was incised in the midline and the dissection along the intrafascial plane was carried on towards the lateral surface of the prostate, strictly avoiding cautery and limiting stretching of the neurovascular bundles. the prostatic pedicles were controlled using endoscopic hem-o-lok clips and cut. the dorsal venous complex (dvc) was divided using an ultrasonic energy scalpel or a combined bipolar/ultrasonic energy device. this is usually sufficient to control any bleeding from dvc and no stitch was usually required. then the prostate apex was carefully divided from the membranous urethra to obtain the longest possible urethral stump. thereafter, the urethra was cut with cold scissors. the specimen was placed in a laparoscopic bag and removed through the sub umbilical incision. the incision was extended if needed. a classical double-running vlock 3-0 suture was adopted during the vesico-prostatic anastomosis. antibiotics, intravenous fluids, and prophylaxis for deep vein thrombosis were given per institutional protocol. blood parameters, diuresis and drainage were monitored and the drain tube removed as soon as possible. the ambulation was encouraged, and diet was started on the first postoperative day. the urethral catheter was removed after ten days, always after performing cystogram. all patients were followed with standardized protocol. outpatient visits were scheduled every 3-month for the first year. at each visit, a physical examination and psa were routinely performed. the clinical history about continence and erectile function was collected. sexual function was measured using the iief-5 questionnaire. men reporting a daily use of no pad were considered as completely continent, whereas the use of one pad per day was considered as mild incontinence. patients were addressed to continence ad sexual rehabilitation with postoperative pelvic floor muscle training and pde5 inhibitors and/or intracavernous injections with customized protocol. archivio italiano di urologia e andrologia 2021; 93, 3 f.s. grossi, e. utano, p. minafra, p.p. prontera, f. schiralli, a. de cillis, e. martinelli, m. lattarulo, m. luka, a. carrieri, a. d’elia 270 results between 2001 and 2019, 938 patients with median age of 67 years (iqr: 62-73) years underwent elrp at our urology department and were followed with a median follow-up time of 132 months (iqr: 63-173 mo). within the total population, 657 (69.7%) have no exclusion criteria and had complete oncological and functional data. the median bmi of the patients was 28.3 kg/m2 (iqr: 26.7-29.5). the median ultrasound prostate volume was 52.2 cc (iqr: 45.5-61.3). preoperative median psa value was 10.5 ng/ml (iqr: 6.4-14.2). complete demographic and operative features are reported in table 1. the median operative time was 115 minutes (iqr: 85184 minutes), whereas the median length of postoperative hospitalization was 3.5 days (iqr: 2.5-4). the posterolateral dissection of the prostate was carried out using a nerve-sparing technique in 408/657 patients (62.1%), in 37.0% on both sides while in 25.1% monolaterally. the 37.9% of men did not receive a nerve-sparing surgery. overall, 66 perioperative complications occurred in 51 men (7.8%). all complications with clavien-dindo classification are listed in table 2. at definitive histology, pathological stage was t2 in 535 (81.4%), t3 in 117 (17.8%) and t4 in 5 cases (0.8%). lymph nodes invasion was observed in 57 men (8.7%). positive surgical margins (psm) were found in 87 (13.2%). among men with t2 prostate cancer, 52 had psm (9.7%). 156 patients (23.7 %) received immediate adjuvant radiation therapy for locally advanced disease (table 3). during the observation period, a total of 58 patients died. in nine of them, the cause of death was linked to pca. the estimated overall bcr-free survival was 71.4% at 5 years and 58.9% at 10 years. in organ-confined prostate cancer the bcr-free survival was 77.2% at 5 years and 65.2% at 10 years. in pt3 stage the bcr-free survival was 47.9% at 5 years and 32.5% at 10 years (table 3). preoperative iief-5 questionnaire showed a good erectile function or at most a mild-moderate erectile dysfunction in 78.1% of the cases (513/657). all these men were interested in postoperative resumption of sexual activity. among these patients, respectively 56.9% and 28.4% underwent nerve-sparing prostatectomy. postoperative iief-5 score within 12 months after surgery was > 12 in the 82.1% (421/513). as for urinary incontinence, after a minimum of 12 months after the surgery, the great majority of patients experimented a complete recovery of the urinary continence (no needing for pad). on the other hand, 5 patients (0.76%) presented severe incontinence (continued and persistent loss of urine) and 46 (7.0%) were mildly incontinent (using one pad per day) (table 4). table 1. demographic and perioperative characteristics. n = 657 results age (y), median (iqr) 67 (62-73) bmi (kg/m2), median (iqr) 28.3 (26.7-29.5) prostate volume (ml), median (iqr) 52.2 (45.5-61.3) psa (ng/ml), median (iqr) 10.5 (6.4-14.2) preoperative potency (iief-5 > 12), n (%) 513 (78.1) preoperative urinary continence, n (%) 657 (100) operative time (m), median (iqr) 115 (85-184) postoperative los (d), median (iqr) 3.5 (2.5-4) overall ns procedures, n (%) yes 408 (62.1) bilateral 243 (37.0) monolateral 165 (25.1) no 249 (37.9) bmi: body mass; psa: prostate-specific antigen; iief-5: international index of erectile function-5; los: length of stay; ns: nerve-sparing; iqr: interquartile range. table 4. functional outcomes 12 months after surgery. postoperative recovery ef, n (%) 421/513 (82.1) surgical technique *, n (%) bilateral ns 292 (56.9) monolateral ns 146 (28.5) non-ns 75 (14.6) complete continence **, n (%) 606 (92.2) mild incontinence **, n (%) 46 (7) severe incontinence **, n (%) 5 (0.8) bef: erectile function; iief-5: international index of erectile function-5; ns: nerve-sparing technique. * in men with preoperative iief-5 ≥ 12. ** continence: no pad; mild incontinence: 1 pad; severe incontinence ≥ 2 pad. table 2. intraoperative and perioperative complications. n (%) blood transfusion 21 3.2 bladder neck contracture 6 0.9 anastomotic leak 9 1.4 ochiepididimitis 3 0.5 symptomatic lymphocele 12 1.8 rectal injury 3 0.5 ileus 8 1.2 deep vein thrombosis 4 0.6 total adverse events 66 clavien dindo i-ii 53 8.1 clavien dindo iii-iv 10 25 table 3. pathological and oncological outcomes. n = 657 n (%) pt2 535 (81.4) pt3 117 (17.8) pt4 5 (0.8) pn+ 57 (8.7) overall psm 87 (13.2) pt2 52 (9.7) pt3 32 (27.4) pt4 3 (60) immediate adjuvant rt 156 (23.7) overall mortality 58 (8.9) bcr free survival 5 years 10 years overall 71.4 58.9 pt2 77.2 65.2 pt3 47.9 32.5 271archivio italiano di urologia e andrologia 2021; 93, 3 results of elrp with long-term follow-up discussion there is an ongoing debate about the worthiness of elrp versus tlrp. both the approaches share the main advantages of laparoscopy over open surgery, such as a better visualization of the surgical field, lower blood loss, a more precise and watertight anastomosis that allows early catheter removal, and a shorter hospital stay. for this reason, the widespread diffusion of minimally invasive prostatectomy have led to a significant reduction of the surgical burden, while ensuring similar oncological results and complication rates compare to open rp (1214, 34). however, no evidence still exists about the superiority of one laparoscopic approach over the other in terms of perioperative outcomes and incidence of complications (15). the transperitoneal approach offers the best visibility and workspace for pelvic surgery. however, the extraperitoneal route reduces potential complications linked to the peritoneum opening, such as bowel injury, ileus, intraperitoneal bleeding or urinary leakage, and formation of intraperitoneal adhesions. moreover, elrp have gained popularity among urologists, since it seems a more straightforward procedure (16, 17). some authors also suggests that this approach may shorten the learning curve, but this point remains controversial (18). the rapidly increasing application of the mini-invasive techniques makes long-term data essential for a proper counselling of the patients. many studies have been directed to show the results of laparoscopic radical extraperitoneal prostatectomy, some even with very large sample size (19). nevertheless, insufficient data on large series of elrp with long-term follow-up are available. with this study, we filled this gap by presenting the results of a large cohort of extraperitoneal laparoscopic radical prostatectomy with extended follow-up. oncological outcomes the complete resection of the tumor is a primary goal of radical prostatectomy and the presence of psm after rp is predictor of psa recurrence and is considered a negative prognostic factor. in our population, the overall rate of psm was 13.2%, while it was 9.7% in the subgroup of t2 tumors. such findings are consistent with those previously reported. the overall rate of positive surgical margins after laparoscopic prostatectomy varies from 19.2% to 38.6% (20-23). very large series of elrp reported psm rates of 10.8-16.1% and 31.2-34.6% in pt2 and pt3 cancers, respectively (19, 24). however, comparative data between extraperitoneal and intraperitoneal lrp show no differences in terms of psm (25, 26), as well as no significant difference exist between open and laparoscopic rp (27). regardless of the surgical technique, one of the most relevant predictors for psm is tumor stage. however, analyzing data by groups, no difference are shown between open prostatectomy and mini-invasive techniques in psm rate for t2 and t3 tumors (27). another important indicator of the oncological safety of a surgical approach is biochemical recurrence (bcr), which has been associated with increased mortality (28). in the present investigation, the overall bcr-free survival was 71.4% at 5 years and 58.9% at 10 years. stratifying our population by tumor stage, it was 77.2% at 5 years and 65.2% at 10 years for t2 stage and 47.9% at 5 years and 32.5% at 10 years for t3 stage tumors (table 3). of note, these results are slightly below those already presented in other studies. indeed, after orp, the 10years bcr-free survival rate is 80 % for t2 prostate cancer (29) and 54% for pt3 tumors (30); on the other hand, the overall 10-year bcr-free survival was 75.6% after lrp (31). our results probably represent the result of the lack of patient selection and, above all, of the “wait and see” strategy adopted in the majority of cases instead of a more aggressive attitude with early initiation of adjuvant therapies. many papers have directly compared the incidence of bcr between lrp to orp. to date, the oncological data with the largest follow-up (49 months) were provided in the work of martínez-holguín et al. (32). this work did not highlight any difference in the incidence of bcr between the two techniques. no long-term data on bcr exist on te direct comparison between tlrp and elrp. functional outcomes we classified patients in three groups: full continence (no need for diapers), mild incontinence (1 per day) and severe incontinence (more than 2 per day). after a twelve-month postoperative follow-up, 92.2% (n = 606) of 657 patients were completely continent, 7% (n = 46) had mild incontinence, and 0.76% (n = 5) needed more than 2 pads per day. these data are consistent with previously published results for lrp (19, 31, 35). stolzenburg et al. presented continence results for the extraperitoneal approach reporting a 12-months continence rate of 92%. overall, we offered a nerve-sparing elrp to 408 patients (62.1%), while, among patients who presented good preoperative erectile function, the 85.4% underwent nervesparing prostatectomy. in this subgroup, 82.1% of men preserved the erectile function 12 month after surgery. our findings on erectile function recovery are in line with some data reported in other series of nerve-sparing prostatectomy, though potency rates after open nervesparing orp vary considerably across studies, reaching up to 86% at 12 months in selected patients (33). in our work, patients are not the result of meticulous selection, except for the identification of the necessary requirements to indicate a nerve-sparing prostatectomy. however, a similar rate of continence recovery partly depends also on our definition of erection recovery, that includes men with mild-moderate erectile dysfunction (iief-5 score higher than 12). perioperative outcomes in our series, elrp was shown to be a procedure with short operative times, and a reduced incidence of intra and perioperative complications. different comparative cohort studies have reported that the extraperitoneal approach needs shorter times (16, 17), but data of a meta-analysis comparing perioperative results and complications of intraperitoneal and extraperitoneal rp show that elrp and tlrp have similar operative times. moreover, blood loss and rate of transfusion of the two techniques are comparable. no significant differences were observed for the rate of intraoperative archivio italiano di urologia e andrologia 2021; 93, 3 f.s. grossi, e. utano, p. minafra, p.p. prontera, f. schiralli, a. de cillis, e. martinelli, m. lattarulo, m. luka, a. carrieri, a. d’elia 272 complications and the rate of open conversion, whereas a higher rate of postoperative complications was reported in the tlrp group (25). several limitations of the present study have to be addressed: the single-centre retrospective design of the present analysis potentially represents a bias. moreover, this a consecutive series of 657 patients who underwent elrp over a period of 18 years by three different surgeons. in that way, this series reflects the evolution of this technique and of the surgeons’ learning curve along such a long time. moreover, the lack of a standardized protocol for the oncological management and the functional rehabilitation represents a limitation. conclusions extraperitoneal rp brings considerable advantages in terms of perioperative outcomes (short duration of surgery, reduced blood losses, low risk of complications) compared to other laparoscopic techniques and orp. it also presents similar results in the main oncological objectives and with optimal recovery of continence and erectile function. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2020. ca cancer j clin. 2020; 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30:556-66. 20. magheli a, busch j, leva n, et al. comparison of surgical technique (open vs. laparoscopic) on pathological and long term functional outcomes following radical prostatectomy. bmc urol. 2014. 7;14:18. 21. dahl d, barry m, mcgovern f, et al. a prospective study of symptom distress and return to baseline function after open versus laparoscopic radical prostatectomy. j urol. 2009; 182:956-65. 22. jurczok a, zacharias m, wagner s, et al. prospective non-randomized evaluation of four mediators of the systemic response after extraperitoneal laparoscopic and open retropubic radical prostatectomy. bju int. 2007; 99:1461-6. 23. jacobsen n, moore k, estey e, voaklander d. open versus laparoscopic radical prostatectomy: a prospective comparison of postoperative urinary incontinence rates. j urol. 2007; 177:615-9. 24. paul a, ploussard g, nicolaiew n, et al. oncologic outcome after extraperitoneal laparoscopic radical prostatectomy: midterm followup of 1115 procedures. eur urol. 2010; 57:267-72. 25. wang k, zhuang q, xu r, et al. transperitoneal versus extraperitoneal approach in laparoscopic radical prostatectomy: a meta-analysis. medicine (baltimore). 2018; 97:e11176. 26. kallidonis, panagiotis p, rai, bhavan pb, et al. critical appraisal of literature comparing minimally invasive extraperitoneal and transperitoneal radical prostatectomy: a systematic review and meta-analysis. arab j urol. 2017; 15:267-279. 27. cao l, yang z, qi l, chen c. robot-assisted and laparoscopic vs open radical prostatectomy in clinically localized prostate cancer: perioperative, functional, and oncological outcomes: a systematic review and meta-analysis. medicine (baltimore). 2019; 98:e15770. 28. uchio e, aslan m, wells c, et al. impact of biochemical recurrence in prostate cancer among us veterans. arch intern med. 2010; 170:1390-5. 273archivio italiano di urologia e andrologia 2021; 93, 3 results of elrp with long-term follow-up 29. chun f, graefen m, zacharias m, et al. anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer world j urol. 2006; 24:273-80. 30. hruza m, bermejo j, flinspach b, et al. long-term oncological outcomes after laparoscopic radical prostatectomy. bju int. 2013; 111:271-80. 31. busch j, stephan c, herold a, et al. long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience bju int. 2012; 110:e985-90. 32. martínez-holguín e, herranz-amo f, mayor de castro j, et al. comparison between laparoscopic and open prostatectomy: oncological progression analysis. actas urol esp. 2021; 45:139145. 33. walsh. radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate. j urol. 2000; 163:1802-7. 34. abboudi h, doyle p, winkler m. day case laparoscopic radical prostatectomy. arch ital urol androl. 2017 ;89:182-185. 35. gozen as, akin y, ates m, et al. the impact of bladder neck sparing on urinary continence during laparoscopic radical prostatectomy; results from a high volume centre. arch ital urol androl. 2017; 89:186-191. correspondence francesco saverio grossi, md (corresponding author) grossifs@libero.it emanuele utano paolo minafra pier paolo prontera francesco schiralli antonio de cillis evangelista martinelli marco lattarulo meri luka antonio carrieri angelo d’elia department of urology, ss annunziata hospital via francesco bruno 1, 74121, taranto (italy) stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4394 case report no conflict of interest declared. doi: 10.4081/aiua.2020.4.394 renal papillary hypertrophy, a rare cause of recurrent gross hematuria; case report and review of literature ahmad beltagy, mohamed elsaqa, islam koraiem, ahmed abulfotooh eid department of urology, faculty of medicine, alexandria university, alexandria, egypt. urine analysis revealed hematuria (> 100 red blood cells) without pyuria or proteinuria. blood count, renal and liver functions and bleeding profile were normal. urine culture and ultrasound were unremarkable. multiphasic renal computed tomography (ct) showed bilateral enlarged papillae causing concave impressions in the calyces of both kidneys, a picture suspicious of hypertrophied renal papillae (figure 1). diagnostic cystoscopy with barbotage bladder cytology were done; both failed to show any positive finding. diagnostic retrograde intrarenal ureteroscopy was done using 7.5 fr flexible ureteroscopy that revealed hypertrophied renal papillae in the upper and middle calyces of both kidneys with active bleeding in some of these papillae (figure 2). selective cytology of both ureters revealed no suspicious findings. in a later setting, holmium:yag laser ablation of hypertrophied papillae of both kidneys was done using 7.5 fr flexible ureteroscopy and 365 μm fiber at settings of 1200 mj and 12 hz. after 3 months follow up, the patient did not report any attacks of gross hematuria, despite the persistence of microscopic hematuria. she also described significant improvement of bilateral loin pain. patient was consented for further process of data collection and publication. discussion renal papillary hypertrophy is one of the rare causes of hematuria. only few cases have been reported in the literature. in 1956, lauret first reported renal papillary hypertrophy in a 9-month-old female infant after nephrectomy for suspected pelvic tumor by retrograde filling defect (2). in 1961, moonen et al. described two cases of a 25-year-old female with microscopic hematuria and 11-year-old male with loin pain (3). histopathology following nephrectomy in these two reports revealed hyperplasia of renal papillae with normal histology (2, 3). the same pathology was reported later on by only few case reports (4-7). the age of reported cases ranged between 9 months and 30 years old. to our best of knowledge, only 8 cases were reported in the literature, 6 females and 2 males. presentations are usually gross or microscopic hematuria with or without flank pain (2-7). however, although association with use of oral contraceptive pills was seen in 3 reported cases, our case never hematuria is a critical symptom that should properly be investigated. one of the rare causes is renal papillary hypertrophy. literature review revealed only few reported cases. biopsy in reported cases has shown hyperplasia of renal papillae with normal histology. we report a case of bilateral renal papillary hypertrophy in a 32 years old female presented with intermittent gross hematuria. computed tomgraphy urography, cystoscopy and selective cytology did not show any positive findings. retrograde flexible uretero-renoscopy showed enlarged renal papillae protruding into upper and middle calyces of both kidneys with clots and active bleeding in some. holmium:yag laser ablation of hypertrophic papillae showed an effective minimally invasive management of the condition. key words: renal papillary hypertrophy; hematuria; laser ablation; flexible ureteroscopy. submitted 1 may 2020; accepted 6 june 2020 background hematuria, either gross or microscopic, should be carefully investigated. hematuria, specifically in adults, should be regarded as a symptom of urologic malignancy till proved otherwise. all patients with hematuria, except perhaps young females with acute bacterial hemorrhagic cystitis, should be thoroughly evaluated (1). renal papillary hypertrophy or hyperplasia is one of the rare causes of gross or microscopic hematuria of benign origin. few cases were reported in the literature (2-7). in this article, we report this case presented with gross hematuria due to bilateral renal papillary hypertrophy and its minimally invasive management with holmium:yag laser ablation together with literature review of this rare pathology and its management. case report a 32 year old female presented with intermittent total gross hematuria with occasional clots and bilateral loin pain for 6 months. other than history of poliomyelitis affecting her left leg with scoliosis of the spine, the patient has no evident clinical history or abnormal clinical findings. she did not complaint of bleeding elsewhere. also, she did not receive neither anticoagulant nor anti-platelet medications. clinical examination showed normal blood pressure. summary 395archivio italiano di urologia e andrologia 2020; 92, 4 renal papillary hypertrophy, a rare cause of recurrent gross hematuria used oral contraceptive pills (6, 7). histopathology, either after nephrectomy or recently with endoscopic biopsy, showed enlarged hyperplastic papillae (multiple rows of cells) with normal histology associated with dilated thin walled veins at the angles of calyces which may be responsible for bleeding (2, 3). ct urography, retrograde study or intravenous pyelography may show lobulated filling defects. magnetic resonance (mr) urogram in 2 reports showed prominent medullary pyramids with apices protruding into calyces causing enlargement and deformity at the calyceal fornices (5, 6). diagnosis was previously reported after nephrectomy for suspected renal or urothelial tumors caused by filling defect on intravenous pyelography or retrograde study. recently, diagnosis depend on direct visualization of hypertrophied papillae by retrograde flexible ureterorenoscopy. biopsy may be omitted, as in our case, in case of multiple or bilateral lesions, negative cytology and absence of suspicious findings. there are no definite guideline recommendations regarding management of papillary hypertrophy. birk et al. reported the effective use of homium:yag laser for ablation of hypertrophied papillae in 2 cases (6). heißler et al. suggested the use of either holmium-yag or thuliumyag laser for ablation according to their use for ablation of upper tract urothelial tumors (7). in our case, we used 365 μm ho:yag laser fiber for bilateral ablation. conclusions renal papillary hypertrophy is a rare cause of gross or microscopic hematuria of that should be kept in mind as differential diagnosis for recurrent hematuria of benign origin. retrograde intrarenal laser ablation represents the most appropriate management. references 1. gerber g, brendler c. evaluation of the urologic patient: history, physical examination, and urinalysis. in: aj wein, lr kavoussi, aw partin (eds.), et al, campbell-walsh urology, 11th ed vol. 1, saunders, philadelphia (2016), chapt 1, pp. 35-59. 2. lauret g, lamy m, thieffry s, et al. children urology (in french). paris: expansion scientifique française, 1956. 3. moonen wa, de groote f. papillary hypertrophy. acta urol belg. 1961; 29:347-50. 4. whitaker rh, edwards d. congenital hypertrophy of a renal papilla. br j urol. 1969; 41:287-9. 5. türkvatan a, erden a, ölçer t, et al. hypertrophic renal papillae mimicking urothelial tumor. eur j rad extra. 2009; 69:e121-3. 6. birk a, afiadata a, upadhyay j. bilateral renal papillary hypertrophy: a rare cause of benign essential hematuria endoscopic diagnosis and management. int arch urol complic. 2017; 3:031. 7. heißler o, seklehner s, riedl c. renal papillary hyperplasia as a cause of persistent asymptomatic microhematuria. j endourol case rep. 2018; 4:1, 152-4. figure 1. ct urography showing enlarged papillae indenting the minor calyces causing smooth filling defect. figure 2. intra renal flexible ureteroscopy showing hypertrophied renal papillae. correspondence ahmad beltagy, md (corresponding author) a_abdelkhalek11@alexmed.edu.eg mohamed elsaqa, md mohamed.elsaqa@alexmed.edu.eg islam koraiem, md ahmed abulfotooh eid, md drahmedaeid@doctor.com alexandria university, alexandria (egypt) 21archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.21 apy are among the treatments of choice for localized pca. however, between 27% and 53% of all patients develop a rising psa and experience biochemical recurrence (bcr) (2). psa elevation is highly predictive of clinical recurrence but not all patients with bcr after treatment with curative intent have local relapse. therefore, it is very important to distinguish the ones that may benefit from local salvage treatment from those that don’t. bcr is defined as 2 consecutive psa values equal or superior to 0.2 ng/ml after radical prostatectomy, or a psa increase equal or superior to 2 ng/ml above the nadir after radiotherapy (3, 4). however, the indication for further treatments should not be based solely on a pre-determined psa threshold but should be decided on the individualized risk of progression (5). in bcr, conventional imaging, such as computed tomography (ct), magnetic resonance imaging (mri) and bone scintigraphy, has limited accuracy for the detection of recurrence sites (local, regional or systemic), especially at low psa levels, while it is known that the optimal therapeutic window for salvage treatment in bcr is below 0.5-1 ng/ml (6). on the one hand, salvage radiotherapy (srt) is considered the treatment of choice for pca patients with bcr after radical prostatectomy. its efficacy depends on early detection of disease limited to the prostatic fossa. on the other hand, distant metastases require systemic therapies, such as hormonal therapy or chemotherapy (7), whereas local treatment may lead to unnecessary side effects (8). therefore, to achieve the best possible results while avoiding unjustified therapies and side effects, treatment must be individualized for each patient. in this field, molecular imaging techniques offer a great potential. in 2011, the heidelberg group introduced [68ga] ga-psma11 (also known as hbed-cc, glu-urealys(ahx)hbed-cc and psma-hbed-cc) in germany for clinical imaging of pca. prostate specific membrane antigen (psma) is a membrane glycoprotein codified by the psma gene (folh1) located on the short arm of chromosome 11. despite the name “specific”, psma is also expressed in other tissues such as the brain, salivary glands, liver, kidney, small intestine, ganglia and neovasculature of some solid tumors, but in very lower levels. concerning prostate, psma is expressed in normal, benign and malignant prostatic epithelium but its expresobjectives: clinical approach of prostate cancer (pca) biochemical recurrence (bcr) is an ever-changing topic. prostate-specific membrane antigen positron emission tomography ([68ga]ga-psma-11 pet-ctpsma pet-ct) has shown good potential in this field. the aim is to evaluate psma pet-ct detection rate in pca bcr and assess its impact on clinical outcome. material and methods: out of 319 patients with pca who underwent psma pet-ct between october 2015 and june 2019, 70 had developed bcr after treatment with curative intent. two groups were created: one with bcr after surgery (rp group) (n: 48; 68.6%) and other with bcr after radiotherapy (rt group) (n: 22; 31.4%). clinical, analytical, pathological and psma pet-ct results were evaluated. results: initial age was different between groups (p = 0.008). rp patients were mainly at intermediate risk (85.1% vs 42.9%, p = 0.001) while rt patients were at low risk of recurrence (8.5% vs 47.6%, p = 0.001). in rp and rt groups, psma petct detected, respectively, pelvic relapse in 31.3% and 63.6%, and extrapelvic relapse in 18.8% and 31.8%. salvage treatment was performed in 61.9% (n = 26) of rp patients and in 15% (n = 3) of rt patients, p < 0.001. of rp patients submitted to salvage treatment, 59.1% achieved complete remission. concerning these patients, local radiotherapy led to complete remission in 68.4% (n = 13). of rt patients submitted to salvage treatment, two had complete remission and one had partial remission.concerning detection rate, psma pet-ct was positive for pelvic relapse when pre-pet psa ≥ 0.8 ng/ml (rp) or ≥ 2.3 ng/ml (rt) and for extrapelvic relapse when psa ≥ 0.4 ng/ml (rp) or ≥ 3.5 ng/ml (rt), p > 0.05. conclusions: biochemical persistence rate after salvage therapy was similar (30-40%). the cut-off psa values for pelvic relapse detected on psma pet-ct were ≥ 0.8 ng/ml (rp) and ≥ 2.3 ng/ml (rt). key words: biochemical recurrence; psma pet-ct; salvage treatment; prostate cancer. submitted 18 july 2020; accepted 28 july 2020 introduction prostate cancer (pca) is the second most commonly diagnosed cancer in men, with an estimated 1.1 million new cases worldwide in 2012, accounting for 15% of all cancers diagnosed (1). radical prostatectomy and radiother[68ga]ga-psma-11 pet-ct: local preliminary experience in prostate cancer biochemical recurrence patients summary joão carvalho 1, 2, pedro nunes 1, 2, edgar tavares da silva 1, 2, rodolfo silva 2, 3, joão lima 1, 2, vasco quaresma 1, 2, arnaldo figueiredo 1, 2 1 department of urology and renal transplantation, coimbra university hospital center, coimbra, portugal; 2 faculty of medicine, coimbra university, coimbra, portugal; 3 department of nuclear medicine; coimbra university hospital center, coimbra, portugal. archivio italiano di urologia e andrologia 2021; 93, 1 j. carvalho, p. nunes, e. tavares da silva, r. silva, j. lima, v. quaresma, a. figueiredo 22 sion in pca is 100-1000-fold of what is observed in normal cells (9, 10). the localization of the catalytic site of psma in the extracellular domain allows the development of small specific inhibitors that are internalized after ligand binding (11). over the last years, many articles concerning the use of [68ga] ga-psma-11 pet/ct (psma pet-ct) in this scenario have been published and the results appear to be promising (12-17), leading to treatment plan changes in up to 87.1% of patients (6). a meta-analysis revealed detection rates of 48% at psa levels of 0.2 ng/ml, increasing to 56% and 70% at levels of 0.5 and 1.0 ng/ml, respectively. these results were quite superior to those observed with conventional imaging techniques and even [18f] choline pet/ct (18). this study aims to evaluate psma pet-ct detection rate in prostate cancer patients with bcr after treatment with curative intent and assess its impact on clinical outcome. material and methods this study followed the rules of the local ethics committee and were in accordance with the helsinki declaration. it was a preliminary cross-sectional study of prostate cancer patients with bcr after treatment with curative intent at our institution. within a total of 319 pca patients who underwent psma pet-ct between october 2015 and june 2019, 70 developed bcr after treatment with curative intent. [68ga]ga-psma-11 was synthesized locally, at icnas (instituto de ciências nucleares aplicadas à saúde). 68ga-psma-hbedcc (glunh-co-nh-lys-(ahx)-[[68ga]ga(n,n’-bis-[2-hydroxy5 (carboxyethyl)benzyl]ethylenediamine-n,n’-diaceticacid]) (68ga-psma-11) was prepared in a similar procedure as described by eder et al. (19). all patients underwent a whole-body pet-ct acquisition (siemens biograph, siemens healthcare, gemini gxl philips, philips) 60 minutes after intravenous injection of 2 mbq/kg of [68ga]ga-psma-11. psma pet-ct scans were acquired in three-dimensional mode with 4 minutes per bed position. patients were well hydrated and voided immediately before the scan. no adverse effects were reported. psma pet-ct images were independently interpreted by two nuclear medicine physicians. in case of disagreement, the final diagnosis was reached by requesting a third opinion. the main criteria of positivity for psma pet-ct scans were: any area of focal uptake of the radiotracer (single or multiple), higher than the surrounding background, that did not correlate with physiologic tracer uptake. psma pet-ct positive lesions were classified as “pelvic relapse” [prostate/prostate bed relapse and/or pelvic lymph nodes, excluding common iliac nodes (lns)] or “extrapelvic relapse” (inguinal lns and/or above common iliac bifurcation lns and/or bone lesions and/or other visceral lesions). psma pet-ct negative scans were considered false negative by definition. two groups were created: patients submitted to surgery (rp group) (n: 48; 68.6%) and patients treated with radiotherapy (rt group) (n: 22; 31.4%). clinical, analytical, pathological and psma pet-ct results were evaluated. all continuous variables were reported as mean and standard deviation. categorical variables were described according to their frequency and percentage. descriptive analysis of demographic and clinical variables was performed. chi-square test was used for categorical variables. continuous variables were compared using the t student. the detection rate of psma pet-ct was assessed. all tests performed were 2-sided. statistical significance was taken at a p value of less than 0.05. all data were analysed using the statistical package for the social sciences (spss) 23.0 (ibm spsss statistics corp.; armonk, new york, usa). results demographic and clinical data (table 1) showed that rt patients were older than rp patients (66 ± 6.5 vs 69 ± 6.2 years, p = 0.008), but psa was similar between groups (8.7 ± 5.7 vs 7.5 ± 5.8 ng/ml, p = 0.4). patients were divided according to the european association of urology (eau) risk group classification for bcr of localised pca: low-risk were defined by psa < 10 ng/ml and gleason score < 7 (isup grade 1) and ct1-2a; intermediate-risk was defined by psa 10-20 ng/ml or gleason score 7 (isup grade 2/3) or ct2b and high-risk was defined by psa > 20 ng/ml or gleason score > 7 (isup grade 4/5) or ct2c (12). most patients in rp group were in the intermediate-risk category (85.1%), while in the rt group the low-risk cattable 1. demographic and clinical data. data rp group (n: 48) rt group (n: 22) p age at pca diagnosis (years) 66 ± 6.5 69 ± 6.2 0.008 initial psa (ng/ml) 8.7 ± 5.7 7.5 ± 5.8 0.4 eau risk groups for bcr of localised pca 0.001 low-risk 8.5% 47.6% intermediate-risk 85.1% 42.9% high-risk 6.4% 9.5% time between initial treatment and bcr (months) 23.5 ± 42.7 44.5 ± 42.5 0.09 rp group: group previously submitted to surgery; rt group: group previously submitted to radiotherapy; pca: prostate cancer; eau: european association urology; bcr: biochemical recurrence. table 2. relapse pattern between groups. data rp group (n: 48) rt group (n: 22) p pelvic relapse 15 (31.3%) 14 (63.6%) 0.001 extrapelvic relapse 9 (18.8%) 7 (31.8%) no disease 24 (50%) 1 (4.5%) global suvmax 8.4 ± 5.7 [3.3-16.7] 5.6 ± 3.9 [2.7-17.4] 0.3 rp group: group previously submitted to surgery; rt group: group previously submitted to radiotherapy; suvmax: maximum standardized uptake values of [68ga]ga-psma-11. table 3. psa value in pelvic and extrapelvic relapse between groups if positive psma pet-ct. data psa value in pelvic psa value in extrapelvic p relapse (ng/ml) relapse (ng/ml) rp group + positive psma pet-ct 0.99 ± 0.9 1.0 ± 13.2 0.6 rt group + positive psma pet-ct 3.0 ± 2.1 4.5 ± 5.4 0.2 rp group: group previously submitted to surgery; rt group: group previously submitted to radiotherapy. egory was the most prevalent (47.6%), with this difference being statistically significant (p = 0.001). the time interval between initial treatment and bcr was similar between groups (table 1). in rp patients, final pathology revealed pt2a in six (13.4%), pt2c in 16 (33.3%), pt3a in 14 (28.9%) and pt3b in 12 cases (24.4%). n status was n0 in 29 (60.4%), n1 in 13 (27.1%) and nx in six cases (12.5%). r status revealed r0 in 41 (85.4%) and r1 in seven cases (14.6%). in rp and rt groups, psma pet-ct detected pelvic relapse in 31.3% and 63.6% of patients and extrapelvic relapse in 18.8% and 31.8%, respectively. psma pet-ct was negative in 24 (50%) of rp group and in one case (4.5%) of rt group. the maximum standardized uptake value (suvmax) of the lesion with the highest [68ga]ga-psma-11 uptake per patient was also analysed, and no statistical significant difference was found between groups (table 2). in positive psma petct, psa values were not able to distinguish between pelvic and extrapelvic disease in either groups (table 3). salvage treatment was performed in 61.9% (n = 26) of rp group (local radiotherapy in 54.7%, radiotherapy to a single bone metastasis in 2.4% and lymphadenectomy in 4.8%) and in 15% (n = 3) of rt group(radical prostatectomy with bilateral pelvic lymphadenectomy in two and high-dose brachytherapy in one case), p < 0.001. out of all rp patients submitted to salvage treatment, 59.1% achieved complete remission. concerning these patients, local radiotherapy led to complete remission in 13 cases (68.4%). neither extended lymphadenectomy nor radiotherapy to the single bone metastasis led to complete remission. in fact, none of the removed nodes harboured tumour cells. out of the three rt patients submitted to salvage treatment, two had complete remission (both submitted to radical prostatectomy with bilateral pelvic lymphadenectomy) and one had partial remission (targeted high-dose brachytherapy). pathology obtained from salvage radical prostatectomy revealed isup grade 2 pt3bn1m0r0 and isup grade 2 pt3bn0m0r0. in both cases, the initial biopsy specimens firstly done before radiotherapy revealed an isup grade 1. concerning detection rate, psma pet-ct was positive for pelvic relapse when pre-psma pet-ct psa ≥ 0.8 ng/ml (rp) or ≥ 2.3 ng/ml (rt) (tables 4, 5) and for extrapelvic relapse when psa ≥ 0.4 ng/ml (rp) or ≥ 3.5 ng/ml (rt), p > 0.05 (tables 6, 7). discussion this study showed the preliminary experience of psma pet-ct in real-world pca patients that experienced bcr after treatment with curative intention. in bcr patients, 68-ga psma avidity in the pelvic region was higher in the radiotherapy than in prostatectomy cohort (63.6% vs 31.3%), in line with other studies that showed a proportion of 52% vs 22% (14). the negativity of psma petct was almost exclusive of rp patients (50% versus 4.5%). gallium 68-psma, similarly to most other psma based agents, has a significant urinary tracer excretion with high activity often seen in the bladder. this could 23archivio italiano di urologia e andrologia 2021; 93, 1 pet in prostate cancer biochemical recurrence table 4. detection rate of psma pet-ct for pelvic relapse in rp patients. sensibility and specificity of psma pet-ct for pelvic relapse in rp patients psa value (ng/ml) sensibility specificity p 0.2 93.3% 3% 0.06 0.3 80% 18.2% 0.4 73.3% 33.3% 0.5 73.3% 60.6% 0.6 73.3% 63.6% 0.7 73.3% 66.6% 0.8 73.3% 72.7% 0.9 66.7% 78.8% 1.0 46.7% 78.8% rp group: group previously submitted to surgery. table 6. detection rate of psma pet-ct for extrapelvic relapse in rp patients. table 7. detection rate of psma pet-ct for extrapelvic relapse in rt patients. sensibility and specificity of psma pet-ct for extrapelvic relapse in rp patients psa value (ng/ml) sensibility specificity p 0.2 88.9% 2.6% 0.9 0.3 77.8% 17.9% 0.4 66.7% 30.8% 0.5 55.6% 41% 0.6 44.4% 51.3% 0.7 44.4% 53.8% 0.8 44.4% 59% 0.9 44.4% 66.7% 1.0 44.4% 74.4% rp group: group previously submitted to surgery. sensibility and specificity of psma pet-ct for extrapelvic relapse in rt patients psa value (ng/ml) sensibility specificity p 0.9 100% 13.3% 0.2 1.8 85.7% 20% 2.0 85.7% 33.3% 2.3 71.4% 33.3% 3.0 71.4% 53.3% 3.5 71.4% 60% 4.0 57.1% 80% 4.5 42.9% 80% rt: group previously submitted to radiotherapy. table 5. detection rate of psma pet-ct for pelvic relapse in rt patients. sensibility and specificity of psma pet-ct for pelvic relapse in rt patients psa value (ng/ml) sensibility specificity p 0.9 92.9% 12.5% 0.5 1.8 85.7% 25% 2.0 71.4% 25% 2.3 71.4% 37.5% 3.0 50% 37.5% 3.5 42.9% 50% rt: group previously submitted to radiotherapy. archivio italiano di urologia e andrologia 2021; 93, 1 j. carvalho, p. nunes, e. tavares da silva, r. silva, j. lima, v. quaresma, a. figueiredo 24 interfere with the evaluation of the postprostatectomy bed/seminal vesicle bed regions as well as lower pelvic lymph nodes. salvage treatment in patients previously submitted to radiotherapy was done only after re-biopsy and confirmation of tumour persistence. in our limited experience, radical prostatectomy could portend better results than high-dose brachytherapy. the final pathological upgrading compared to the pre-radiotherapy biopsy has to be seen with caution, given the difficulties in evaluating the gleason score after radiotherapy. concerning rp patients, radiotherapy was the only effective salvation treatment. other attempts to reach complete remission were not succeeded, even extended lymphadenectomy did not reveal ganglia metastases. in fact, according to budaus et al., the comparison between preoperative psma pet-ct lymph nodes findings with histologic work-up after radical prostatectomy performed for high risk prostate cancer only detected 33.3% of the patients as being true positive for lymph node metastasis, and 66.7% of the patients as a false negative. our population had a reduced incidence of high-risk patients, so we must presume that our results were following the low sensitivity (33.3%) and high specificity (100%) rate of psma pet-ct for detection of lymph node metastasis in this work (15). the suvmax value in our population was low, in line with the findings of demerci et al. (16). they showed that suv max values correlated significantly with grade groups of primary tumours. the eau risk groups for bcr of localised pca in rp and rt were predominantly intermediate and low-risk respectively. this explained the lower suvmax detected in rt patients compared with rp patients. the optimal cut-off psa values for pelvic relapse detected on psma pet-ct were ≥ 0.8 ng/ml (rp) and ≥ 2.3 ng/ml (rt). the optimal cut-off values for extrapelvic relapse detected on psma pet-ct were ≥ 0.4 ng/ml (rp) and ≥ 3.4 ng/ml (rt). sanli et al concluded that a psa value of 0.83 ng/ml was the optimal cut-off value for distinguishing between positive and negative psma petct in general (17). eau guidelines (5) include a weak recommendation for offering psma pet-ct scan to men with a persistent psa > 0.2 ng/ml to exclude metastatic disease. according to our results, this cut-off seems too low. however, it was a preliminary study with few patients and we hope to increase our experience in this setting to see if this cutoff is applied to our population. it has also been reported that patient’s prognosis was improved when salvage therapy was initiated before the psa level exceeds 0.5 ng/ml (20). in our population, the cut-off of 0.5 ng/ml for rp patients was associated with a sensibility of 73.3% and specificity of 72.7% in pelvic relapse and with a sensibility of 55.6% and specificity of 30.8%. literature showed that these cut-off values can differ from 17.5% to 61.5% (6). in other studies, the detection sensitivity of psma petct is dependent on the psa at the time of imaging, with detection sensitivities in the range of 50-60% when the psa is as low as 0.2 to 0.5 ng/ml (21, 22). however, the cut-off value for psa performing psma pet-ct has yet to be defined, and thus prospective studies are required to recommend psma pet-ct for patients with bcr. with increasing use of psma pet-ct scan, its value must be balanced critically with cost and clinical benefit. given the high costs and limited availability of psma pet-ct scan, choline pet-ct is still widely used in patients with prostate cancer relapse, despite its low sensibility for low psa levels. a meta-analysis by han et al. (23) showed that psma pet-ct altered the management in 54% of patients. they reported that the use of psma pet-ct imaging lead to an increase in the proportion of patients receiving radiotherapy (from 56% to 61%), surgery (from 1% to 7%), focal therapy (from 1% to 2%), and multimodal treatment (from 2% to 6%), and to a decrease in patients receiving systemic treatment (from 26% to 12%) and no treatment (from 14% to 11%). the evidence for introducing management changes as a result of psma pet-ct findings is low, and prospective studies are required. the risk of early treatments causing more harm than good, as well as the long-term effects on progression-free and overall survival rates are still unclear (24). an interesting potential benefit of psma pet-ct could be to select, with higher accuracy, patients to highdose radiotherapy for oligometastatic disease. in our study, there was one patient who underwent radiotherapy to a single bone metastasis, yet no complete remission was achieved. whether this approach improves patient outcomes remains unclear, the impact of potentially avoiding androgen deprivation therapy and its toxicity would definitely be important. some limitations must be also elicited as they could influence results and conclusions. the small number of patients, different size groups and the monocentric nature of the study could limit the applicability of these results. population studied was heterogeneous: patients submitted previously to radiotherapy were fewer, older and belonged to a lower risk group for bcr instead of patients submitted previously to radical prostatectomy were almost the double and belonged to an intermediaterisk group. the lack of psa kinetics and the lack of comparison with standard conventional imaging could introduce a bias: the majority of patients did not have a simultaneous approach with conventional imaging. however, the available literature supports psma pet-ct superiority over conventional imaging in this setting (13). conclusions psma pet-ct has shown good potential for using in patients with bcr, but most studies are limited by their retrospective design. despite the limited information in major guidelines, it could be standard in patients with recurrent pca, mainly with low psa. psa level is associated with the positivity rate of psma pet-ct. the cut-off psa values for pelvic relapse detected on psma pet-ct were ≥ 0.8 ng/ml (rp) and ≥ 2.3 ng/ml (rt). however, psa levels could not discriminate between psma petct positivity for pelvic or extrapelvic relapse. biochemical persistence rate after salvage therapy was similar between groups (30-40%). 25archivio italiano di urologia e andrologia 2021; 93, 1 pet in prostate cancer biochemical recurrence references 1. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015; 136:e359-86. 2. freedland sj, humphreys eb, mangold l, et al. death in patients with recurrent prostate cancer after radical prostatectomy: prostatespecific antigen doubling time subgroups and their associated contributions to all-cause mortality. j clin oncol. 2007; 25:1765-71. 3. toussi a, stewart-merrill sb, boorjian sa, et al. standardizing the definition of biochemical recurrence after radical prostatectomywhat prostate specific antigen cut point best predicts a durable increase and subsequent systemic progression? j urol. 2016; 195:1754-9. 4. roach m, hanks g, thames h jr, et al. defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the rtog-astro phoenix consensus conference int j radiat oncol biol; phys. 2006; 65:965-74. 5. van den broeck, van den bergh r, briers e, et al. biochemical recurrence in prostate cancer: the european association of urology prostate cancer guidelines panel recommendations eur urol focus. 2020; 6:231-234. 6. eissa a, elsherbiny a, coelho rf, et al. the role of 68ga-psma pet/ct scan in biochemical recurrence after primary treatment for prostate cancer: a systematic review of the literature. minerva urol nefrol. 2018; 70:462-478. 7. albisinni s, artigas c, aoun f, et al. clinical impact of 68 gaprostate-specific membrane antigen (psma) positron emission tomography/computed tomography (pet/ct) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach. bju int. 2017; 120:197-203. 8. emmett l, van leeuwen pj, nandurkar r, et al. treatment outcomes from 68ga-psma pet/ct-informed salvage radiation treatment in men with rising psa after radical prostatectomy: prognostic value of a negative psma pet. j nucl med. 2017; 58:1972-6. 9. afshar-oromieh a, holland-letz t, giesel fl, et al. diagnostic performance of 68ga-psma-11 (hbed-cc) pet/ct in patients with recurrent prostate cancer: evaluation in 1007 patients. eur j nucl med mol imaging. 2017; 44:1258-68 10. perera m, papa n, christidis d, et al. sensitivity, specificity, and predictors of positive 68ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis eur urol 2016; 70:926-37. 11. meredith g, wong d, yaxley j, et al. the use of 68 g a-psma pet ct in men with biochemical recurrence after definitive treatment of acinar prostate cancer. bju int. 2016; 118:49-55. 12. mottet n, van den bergh r, briers e, et al. eau eanm estro esur siog guidelines on prostate cancer 2020. 13. aboagye eo, kraeber-bodéré f. highlights lecture eanm 2016: “embracing molecular imaging and multi-modal imaging: a smart move for nuclear medicine towards personalized medicine”. eur j nucl med mol imaging. 2017; 44:1559-1574. 14. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigenavid lesions: a systematic review and meta-analysis. eur urol. 2020; 77:403-417. 15. budaus l, leyh-bannurah sm, salomon g, et al. initial experience of 68ga-psma pet/ct imaging in high risk prostate cancer patients prior to radical prostatectomy. eur urol. 2016; 69:393-6. 16. demirci e, kabasakal l, sahin oe, et al. can suvmax values of ga-68-psma pet/ct scan predict the clinically significant prostate cancer? nucl med commun. 2019; 40:86-91. 17. sanli y, kuyumcu s, sanli o, et al. relationships between serum psa levels, gleason scores and results of 68ga-psmapet/ct in patients with recurrent prostate cancer. ann nucl med. 2017; 31:709-717. 18. perera m, papa n, christidis d, et al. sensitivity, specificity, and predictors of positive (68) ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. eur urol. 2016; 70:926-937. 19. eder m, neels o, müller m, et al. novel preclinical and radiopharmaceutical aspects of [(68)ga]ga-psma-hbed-cc: a new pet tracer for imaging of prostate cancer. pharmaceuticals. 2014; 7:779-96. 20. heidenreich a, bastian pj, bellmunt j, et al. european association of urology. eau guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. eur urol. 2014; 65:124-137. 21. eiber m, maurer t, souvatzoglou m, et al. evaluation of hybrid 68ga-psma ligand pet/ct in 248 patients with biochemical recurrence after radical prostatectomy. j nucl med. 2015; 56:668-74. 22. afshar-oromieh a, holland-letz t, giesel fl, et al. diagnostic performance of (68)ga-psma-11 (hbed-cc) pet/ct in patients with recurrent prostate cancer: evaluation in 1007 patients. eur j nucl med mol imaging. 2017; 44:1258-68. 23. han s, woo s, kim yj, suh ch. impact of 68ga-psma pet on the management of patients with prostate cancer: a systematic review and meta-analysis. eur urol. 2018; 74:179-90. 24. murphy dg, sweeney cj, tombal b.gotta catch ‘em al,” or do we? pokemet approach to metastatic prostate cancer eur urol. 2017; 72:1-3. correspondence joão andré mendes carvalho, md (corresponding author) joao.andre.mendes.carvalho@gmail.com estrada da beira, nº 248, 2º d, 3000-173 coimbra, portugal pedro nunes ptnunes@gmail.com edgar tavares da silva edsilva.elv@gmail.com rodolfo silva rodolfompsilva@gmail.com joão lima joaopedrosolima@gmail.com vasco quaresma vpdquaresma@gmail.com arnaldo figueiredo ajcfigueiredo@gmail.com stesura seveso 339archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. introduction men have always been worried about penis size, which can seriously affect their self-esteem. they have the tendency to seek their identity in the penis with the belief that ‘‘bigger is better’’. the stigmas of a small penis, as well as the increasing media influence on sexual issues, have created an increase demand for penile enhancement (1). the term microphallus or micropenis is referred to a penis that is formed normally but is of a small size (less than 7-8 cm during erection or stretched state) and it is probably associated with abnormal production, or a reduced activity, of lh hormone (2). on the other hand, the altered perception of the organ size is called “dysmorphophobia”. these patients present with a normal-sized penis but are dissatisfied both in a flaccid state and during erection (3, 4). it is mandatory for these patients to undergo a psychosexual counselling and try to avoid surgery. the demand for penile lengthening had a tremendous increase in recent years. according to the published data, majority of men who request penile enhancement surgery usually have a normally sized and normally functioning penis (5). in our experience, the most common request for penile lengthening comes from patients that suffer from the so-called ‘‘locker room syndrome”, i.e. anxiety and embarrassment arising from changing in front of the others. at present, no current consensus guidelines are available for treatment of patients with a normal-sized penis (6). the short penis can be congenital or acquired. the congenital small penis is defined as measurements of < 7-8 cm upon erection. the acquired disorders are caused by peyronie’s disease or outcomes of partial penectomy for penile carcinoma. finally, there are cases of relative short penis due to excess pubic fat. the reported normal length of an adult flaccid penis ranges between 7.6 cm and 10.7 cm, and between 11.4 cm and 14.8 cm in erection (7). the increase in length following surgery that is required to satisfy the patient is not well established and is not adequately emphasized in the medical literature. introduction: we report our long experience in the surgical treatment of patients requesting penile lengthening by suspensory ligament release and placement of a custom-made soft silicone pubo-cavernous spacer. the aim was to show that with this surgical technique the results obtained are maintained over time. it is crucial to achieve postoperative satisfaction of these patients who show fragility and self-esteem problems. methods: from 1999 to 2020, we treated 245 patients with congenital or acquired penile brevity. we carefully analysed the preoperative and postoperative (at 6, 12, 24 and 48 months) penile size of the patients to evaluate whether this technique could allow the long-term maintenance of aesthetic results. we also assessed preoperative erectile function and we focused on the psychological aspects to avoid surgery in patients with dysmorphophobia. this original technique involves the section of the suspensory ligament and the implantation of a silicone spacer between the pubic symphysis and the corpora cavernosa. this spacer is conformed to the patient anatomy and maintains the relationship between the anatomical structures unchanged over time. sexual self-esteem and patient satisfaction were assessed with the appssi questionnaire. results: the mean increase in penile length was about 2.5 cm in flaccid state and 1.9 cm in stretched state. there were no injuries of the neurovascular bundle or urethra, and no erectile dysfunction was noted. these results persisted at 6, 12, 24 and 48 months without significant differences. over 80% of patients stated that they were completely satisfied with the results obtained. this satisfaction remained stable along follow up. conclusion: the section of the suspensory ligament and the implant of the soft silicone spacer provide real penis elongation with satisfactory results that persist over time. this technique avoids the frequent complication of short-term shortening due to the scar adhesions of the edges of the dissected ligament. the high aesthetic satisfaction of patients is stable at controls at 6, 12, 24 and 48 months. key words: penile lenghthening; penile augmentation; penile elongation; pubo-cavernous spacer; small penis; suspensory ligament release. submitted 8 september 2022; accepted 9 september 2022 penile lenghthening original technique using a pubo-cavernous spacer. long term results from a series of over 200 patients antonio rossi 1, giovanni alei 2, marco frisenda 1, antonio tufano 1, pietro viscuso 1, guglielmo mantica 3, pierluigi bove 4, rosario leonardi 5, alessandro calarco 6 1 maternal and infantile and urologynaecological sciences department, sapienza university of rome, rome, italy; 2 department of general surgery and plastic aesthetic surgery, sapienza university of rome, rome, italy; 3 policlinico san martino, genova, italy; 4 san carlo di nancy hospital, rome, italy; 5 casa di cura musumeci-gecas, gravina di catania (ct), italy; 6 department of urology, “cristo re” hospital, rome, italy. doi: 10.4081/aiua.2022.3.339 summary archivio italiano di urologia e andrologia 2022; 94, 3 a. rossi, g. alei, m. frisenda, et al. 340 the gold standard of penile lengthening technique consists in the dissection of the suspensory ligament followed by cutaneous “v to y” or “z” plasties (8-10). in cases where the penile shortening is associated with abundant pubic fat, the dissection of the suspensory ligament is performed along with a suprapubic lipectomy or pubic liposuction (11). this cosmetic surgery is commonly performed by experienced plastic surgeons and results in an aesthetic visual lengthening effect. in the last years, new surgical techniques for penile lengthening have been developed to improve the aesthetic appearance and functional state of the penis, giving rise to much controversy regarding their safety, and efficacy (12-18). we report our approach of penile lengthening using a soft silicone pubo-cavernous spacer after suspensory ligament release. methods this study is a retrospective analysis of patients who underwent penile lengthening by sectioning of penile suspensory ligament and using a soft silicone custommade spacer made between the 1999 and the 2020. we have used this surgical procedure in 245 patients aging between 18 and 67 (average age 35 years). the study population included patients with congenital small penis (172); patients with short penis due to fibrosis caused by either peyronie’s disease or trauma (67); patients with short penis resulting from partial penectomy for penile carcinoma (6). in order to select patients qualified for surgery, every patient underwent a pre-surgical diagnostic screening consisting of: medical history, physical examination, sexual hormone profiles. psychiatric/psychosexual assessment. all patients were interviewed by an andro-sexologist. this was done especially in order to understand the motivations, expectations, self-esteem, and to discourage from surgery patients with dysmorphic disorder. preoperative photographs and measurements of the penis were carried out in flaccid state, stretched state and during maximal erection, after intracavernous injection of alprostadil (prostaglandin e1 pge1: 1-5 mcg). the preoperative measures were taken from the base of the penis to the tip of the glans. penile length during erection was also evaluated from the pubo-penile junction to the tip of the glans in the dorsal surface in order to evaluate the angle between the penis shaft and the pubis. this is important to select patients for procedure; in fact patients with laxity of the suspensory ligament or angle > 30° upon erection, were excluded because in these cases we will not obtain significant improvement in length. average measures were 5.6 cm (from 3.8 to 8.2 cm) in flaccid state (mean initial flaccid length), 10.9 cm (from 6.2 to 13.5 cm) during stretched state (mean initial erect length or spl) and 11.2 (from 6.5 to 14 cm) during erection. each patient underwent a doppler penile ultrasound in the flaccid and erect state after pge1 administration to identify any preexisting condition such as peyronie’s disease and vascular erectile dysfunction. the erectile function was also assessed with the administration of the international index of erectile function questionnaire (iief) and with a nocturnal penile tumescence test (rigiscan plus dacomed corporation, minneapolis, mn, usa). surgical technique skin incision is made with the v-y technique in order to allow simultaneous skin lengthening at the time of suturing. the incision is performed about 2-3 cm at the midpoint of the pubo-penile arch (figure 1). after the incision of the subcutaneous tissue, the scarpa fascia is reached. this is exposed in order to reveal the figure 1. skin incision with v-y technique. each branch is about 2 cm figure 3. suspensory ligament release by scissors along the anterior side of the pubic symphysis. figure 4. conformation of the spacer and its relations with the anatomical structures. passage of the points of 0 prolene. figure 5. 3d reconstruction of the relationships between the spacer and the surrounding anatomical structures. figure 6. final y suture in order to stretch the pubic skin. figure 2. exposure of the penis suspensory ligament. 341archivio italiano di urologia e andrologia 2022; 94, 3 penile lenghthening with a pubo-cavernous spacer fundiform ligament, that is then resected. below it, the suspensory ligament (figure 2) is dissected by scissors along the anterior side of the pubic symphysis in an area which is usually avascular (figure 3). this step is performed while the assistant keeps the patient's penis fully stretch in order to feel the release of the corpora cavernosa. at this point a block of soft silicone (allied biomedical carving blocks) is cut to fit the angle created by the cavernous bodies and the pubic symphysis, taking care to conform with the measurements of the newly formed cavity; the spacer is shaped to come into contact anteriorly with the surface of the corpora cavernosa which is convex, while posteriorly with the anterior wall of the pubic symphysis which is concave (figure 4). four 0 prolene stitches are passed through the spacer, two stiches in the deep part, one on the left and one on the right side, and two stitches in the superficial part. holding back the spacer, the stitches are passed through the periostium of the pubic symphysis into the deep part. the silicon spacer is inserted into the cavity and the first two stitches, previously placed in the deep part, are tied. the other two stitches are secured to the periostium in the uppermost part of the newly formed cavity, taking care not to exert pressure upon the penile structures (figures 4, 5). a drain is placed in the deeper part of the formed cavity, which is usually removed 12 to 24 hours after surgery. the subcutaneous part, in the deep tract, is closed with polyglycolic acid, then the scarpa fascia is sutured using interrupted sutures in polyglycolic acid. a y suture, in polyglycolic acid or silk, is then performed to guarantee lowering of the pubo-penile arch (figure 6). this latter surgical step is of utmost importance in order to avoid impairment of the lengthening procedure. according to the surgeon’s opinion, this can also be integrated with further cutaneous plasty with z elongation. placement of a bladder catheter at the end of surgery depends on the type of anesthesia used. in case a catheter is placed, this must be removed within 12 hours. in our case series, the mean operative time was 78 minutes, ranging from 58 to 116 minutes. postoperative antibiotic therapy consists of a combined therapy with rifampicin 300 mg/die, minocycline 50 mg/die and moxifloxacin 400 mg/die for one week. patients are instructed to refrain from sexual intercourses for 30 days after surgery. no traction or vacuum device was used postoperatively. postoperative follow-up and statistical analysis after the post-operative checks, the patients were evaluated at 6, 12, 24 and 48 months. the objective increase in length was calculated by subtracting the preoperative flaccid length and preoperative spl from the postoperative flaccid length and postoperative spl respectively. the satisfaction of surgical outcome was assessed at 6, 12, 24 and 48 months after surgery by directly asking the patients: “are you satisfied with the result of surgery?” and with the appssi questionnaire at the annual check. the results expressed as mean ± standard deviation (sd) were compared using paired and unpaired student t test, fischer exact probability test and chi-squared test. results good aesthetic results were obtained in all cases. the results relating to the aetiology are shown in table 1. all patients, despite of the aetiology category, showed a significant increase of penile length (figures 7-9). the mean increase in flaccid state was 2.54 ± 0.9 cm (p < 0.005), and in stretched state was 1.91 ± 1.1 cm (p < 0.005). minimal lengthening obtained in flaccid state was 1.6 cm and in stretched state was 0.9 cm. the best result was an elongation of 3.5 cm in the flaccid state and of 3.0 cm in stretched state (figure 10). the psychosexual impact of the operation was favorable in the majority of cases. sexual self-esteem and patient satisfaction were significantly improved, as shown by the results of the augmentation phalloplasty patient selection and satisfaction inventory (appssi) completed 12 months postoperatively (table 2). improved self-esteem was recorded in all but eleven patients (234 out of 245 patients scored 95.9%). two hundred (81.6%) out of 245 patients were completely satisfied with the outcomes of surgery to all follow-up checks. sexual activity was encouraged from the fourth postoperative week. at the 6 and 12-month follow-up visit, all patients reported a normal erectile function. the 6-month iief was comfigure 7. preoperative and postoperative result at 7 days. figure 8. preoperative and postoperative result at 30 days. figure 9. preoperative and postoperative result at 6 months. figure 10. preoperative and postoperative result at 12 months. archivio italiano di urologia e andrologia 2022; 94, 3 a. rossi, g. alei, m. frisenda, et al. 342 pleted, and no substantial difference compared to preoperative was found. no postoperative nighttime rigidometry was necessary. as far as the complications are concerned, the following minor events have been observed: infection of the wound in 6 patients (2.5%), moderate pain which disappeared after four weeks in 43 patients (17.5%), and pain exceeding 2 months in 8 patients (3.2%). no alterations in sensitivity during sexual intercourses were reported. at 12 and 24 months after surgery the penile ultrasound in flaccid state and during erection performed to all patients revealed the correct positioning of space-maintainer. only one patient requested removal of the spacer after 13 years. this patient had an important weight loss (43.5 kg) and the spacer came slightly to the surface without creating problems during intercourse. discussion men with small penis are insecure and question their own sexual value (1). by cutting the suspensory ligament below the symphysis the penis can be elongated. however, the suspensory ligament resection does not guarantee definitive results due to scarring of the tissue along the edges of the resection of the ligament itself (6, 19). in order to maintain the distance between the dorsal side of the cavernous bodies and the pubic symphysis, we have made various attempts (considered several possibilities), at first by using a silicone tip of a penile prosthesis and then a testicular silicone prosthesis as described by other surgeons (10). these materials, both biocompatible and available on the market, were not found to be suitable for this purpose. in this case series, a soft type silicone polymer was used as space maintainer. this material has the following advantages: soft type silicone is available in many shapes and sizes; all carving blocks are made of solid silicone elastomer designed for permanent implantation; implants may be trimmed with a scalpel or scissors to meet the individual patient’s needs; implants may be adaptable with the shape and dimension of every newly formed cavity. all the above-mentioned advantages are not achievable by using a testicular prosthesis or fat flap, because it cannot adapt its shape to the cavity. dermal fat grafts or harvesting fat from remote sites were occasionally used to fill the dead space created by the descent of the corpora off the pubic bone after sectioning the suspensory ligament (20). the extraction of the fat flap, on the other hand, makes the entire procedure extended in time and more invasive, as it is associated with higher morbidity, and bleeding can occur in the donor site. moreover, it does not avoid the fibrotic retraction that is responsible for the reattachment of the penis to the pubis. the adjunctive post-operative stretching with vacuum devices or penile extenders is necessary in order to overcome this condition, with an increase in the final cost. moreover, published data on the resulting change in the penile length, using testicular prosthesis or fat flap, are scarce and controversy (21). advancing of the skin is always necessary. at this level, particularly in close proximity to the pubo-penile junction, the skin is thick, with more or less abundant adipose tissue and, in addition, it is hairy, therefore any insufficient advancement towards the penile shaft of the penis could cause an unsatisfactory result. table 1. results in relation to etiology. patient mean initial mean initial stretched mean increase mean increase in stretched satisfaction n° flaccid length, cm penile length, (spl ± sd), cm in flaccid state, cm penile lenght (spl ± sd), cm % overall 245 5.6 ± 0.8 10.9 ± 1.1 2.54 ± 0.9** 1.91 ± 1.1** 81.6 congenital small penis 113 6.5 ± 0.9 11.4 ± 1.6 2.7 ± 0.8* 1.2 ± 1.2* 93 congenital micropenis 69 3.8 ± 1.1 11.5 ± 2.7 2.2 ± 0.7 1.7 ± 1.3 87 peyronie’s disease 60 4.9 ± 0.9 6.2 ± 1.7 3 ± 0.5 1.8 ± 1.2 80 penile trauma 7 7.7 9.3 2.8 1.8 93 penile carcinoma 6 5.6 6.8 2.5 2 75 spl = stretched penile lenght; sd = standard deviation. student t test. *p < 0.005. student t test. **p < 0.0005. table 2. appssi results. suitability assessment (preoperative) n° outcome evaluation (1 year postoperative) n° slight sexual confidence disturbance and/or weak willingness to undergo surgery) no complaints of penile inadequacy and excited about postoperative result (total score 10-12) 0 (unsuitable candidate) (total score 10-12) 177 patients mild complaints, with surgery appearing as a remote option (total score 7-9) 12 patients mild complaints but satisfied (total score 7-9) 58 patients moderate complaints but skeptical of surgery (total score 4-6) 68 patients moderate complaints, with no improvement or indifferent results (total score 4-6) 10 patients severe complaints, with surgery inevitabile option (total score 0-3) 165 patients severe complaints, condition worse than preoperatively (total score 0-3) 0 patients patients total (n): 245 patients. chi-square test with three degrees of freedom = 134.1. p < 0.00001. fisher exact probability test p < 0.00001. appssi = augmentation phalloplasty patient selection and satisfaction inventory. 343archivio italiano di urologia e andrologia 2022; 94, 3 penile lenghthening with a pubo-cavernous spacer m plasty, which became popular in china, is frequently responsible for hypertrophic scars and even necrosis of tissue at the outer edge of the flaps. the v-y advancement is the most commonly used technique; however, several concerns have been risen about the site and extent of the incision (22). the advantages of a y suture, in our opinion are to guarantee lowering of the pubo-penile arch (figure 5) and to avoid impairment of the lengthening performed. postoperative penile traction was not used, as per our experience, the positioning of the penile extender or vacuum device caused discomfort for the patients, was complicated and risky to manage and has given poor results. our technique on the other hand, which includes inserting the space-maintainer of soft silicone into the new cavity, showed a very low incidence of penile retraction. finally, it is extremely important that the urologist evaluates very carefully the patient’s reasons for requesting this kind of treatment, what does the patient expect from it and, in general terms, his psychological situation. we personally insist that our patients have two or more sessions with an andro-sexologist and we stress that counselling cannot be conducted either by a “psychologist” or by a “sexologist” who do not have a proven specific competence in andrological problems. at the end of the counselling the andro-sexologist will prepare a signed report, which in turn will be signed by the patient as his approval. it is also mandatory that the surgeon is particularly careful in case of patients looking only for cosmetic results, partly because their expectations may be far beyond reality and partly because the best surgical result involves a “normal” organ. patients with dysmorphic disorder, profoundly depressed, psychotic patients or patients with not realistic expectations should not be submitted to this surgical procedure (1). conclusions suspensor ligament release alone does not guarantee definitive results. moreover, in some cases worsen the clinical situation due to scarring of the tissue along the edges of the resection of the ligament itself. the placement of a silicon spacer between the penis and the pubis seems to give the best results, as it prevents reattachment and a possible reshortening. the definitive separation between the two anatomical structures is simple to carry out thanks to this small device. the soft silicone makes it easy to shape the spacer and adapt it to the newly formed anatomical cavity of each patient. it is also easy to fix to the pubis and remains stable over time (unlike the fibrosis resulting by use of other materials such as dermal matrix). in our opinion this technique should finally guarantee excellent long-term aesthetic results and high satisfaction rate preventing local recurrence and the loss of the good initial results obtained. footnote original drawings were made by g. alei. references 1. sharp g, oates j. sociocultural influences on men's penis size perceptions and decisions to undergo penile augmentation: a qualitative study. aesthet surg j. 2019; 39:1253-1259. 2. aaronson ia. micropenis: medical and surgical implications. j urol. 1994; 152:4-14. 3. woodhouse cr. the sexual and reproductive consequences of congenital genitourinary anomalies. j urol. 1994; 152:645-51. 4. veale d, miles s, read j, et al. relationship between self-discrepancy and worries about penis size in men with body dysmorphic disorder. body image. 2016; 17:48-56. 5. mondaini n, ponchietti r, gontero p, et al. penile length is normal in most men seeking penile lengthening procedures. int j impot res. 2002; 14:283-286. 6. spyropoulos e, christoforidis c, borousas d, et al. augmentation phalloplasty surgery for penile dysmorphophobia in young adults: considerations regarding patient selection, outcome evaluation and techniques applied. eur urol. 2005; 48:121-128. 7. veale d, miles s, bramley s, et al. am i normal? a systematic review and construction of nomograms for flaccid and erect penis length and circumference in up to 15,521 men. bju int. 2015; 115:978-986. 8. campbell j, gillis j. a review of penile elongation surgery. transl androl urol. 2017; 6:69-78. 9. hoznek a, rahmouni a, abbou c, et al. the suspensory ligament of the penis: an anatomic and radiologic description. surg radiol anat. 1998; 20:413-417. 10. li cy, kayes o, kell pd, et al. penile suspensory ligament division for penile augmentation: indications and results. eur urol. 2006; 49:729-733. 11. pestana ia, greenfield jm, walsh m, et al. management of "buried" penis in adulthood: an overview. plast reconstr surg. 2009; 124:11861195. 12. protogerou v, anagnostopolou s, venierates d, et al. penis ligaments: their use in "increasing" the size of the penis in penile augmentation procedures. anatomical description in human cadavers and clinical results of a phalloplasty series. ann ital chir. 2010; 81:199-204. 13. alter gj, jordan gh. penile elongation and girth enhancement. aua update series 2007; 26:229-237. 14. srinivas bv, vasan ss, mohammed s. penile lengthening procedure with v-y advancement flap and an interposing silicone sheath: a novel methodology. indian j urol. 2012; 28:340-342 15. perovic sv, djordjevic ml, kekic zk, djakovic ng. penile surgery and reconstruction. curr opin urol. 2002; 12:191-194. 16. goodwin we, scott ww. phalloplasty. j urol. 1952; 68:903-908. 17. long dc. [elongation of the penis]. zhonghua zheng xing shao shang wai ke za zhi = zhonghua zheng xing shao shang waikf [i.e. waike] zazhi = chinese journal of plastic surgery and burns. 1990; 6:17-9. 18. wessells h, lue tf, mcaninch jw. complications of penile lengthening and augmentation seen at 1 referral center. j urol. 1996; 155:1617-1620. 19. shaeer o, shaeer k, el-sebaie a. minimizing the losses in penile lengthening: "v-y half-skin half-fat advancement flap" and "t-closure" combined with severing the suspensory ligament. j sex med. 2006; 3:155-60. 20. vardi y, har-shai y, gil t, gruenwald i. a critical analysis of penile enhancement procedures for patients with normal penile size: archivio italiano di urologia e andrologia 2022; 94, 3 a. rossi, g. alei, m. frisenda, et al. 344 surgical techniques, success, and complications eur urol. 2008; 54:1042-1050. 21. dillon be, chama nb, honig sc. penile size and penile enlargement surgery: a review. int j impot res. 2008; 20:519-529. 22. mertziotis n, kozyrakis d, bogris e. is v-y plasty necessary for penile lengthening? girth enhancement and increased length solely through circumcision: description of a novel technique asian j androl. 2013; 15:819-823. correspondence antonio rossi, md antonio.rossi@uniroma1.it marco frisenda, md marco.frisenda57hu@gmail.com antonio tufano, md antonio.tufano@uniroma1.it pietro viscuso, md pietro.viscuso@uniroma1.it maternal and infantile and urologynaecological sciences department sapienza university of rome, viale del policlinico 155, 00161 rome (italy) giovanni alei, md giovanni.alei@gmail.com department of general surgery and plastic aesthetic surgery, sapienza university of rome, viale del policlinico 155, 00161 rome (italy) mantica guglielmo, md gugliemo.mantica@gmail.com policlinico san martino, largo rosanna benzi, 10, 16132, genova (italy) bove pierluigi, md san carlo di nancy hospital, via aurelia, 275, 00165, rome (italy) pierluigi.bove@uniroma2.it leonardi rosario, md leonardi.r@tiscali.it casa di cura musumeci gecas, via dell'autonomia 57, gravina di catania (ct) (italy) alessandro calarco, md (corresponding author) alecalarco@gmail.com department of urology, “cristo re” hospital, via delle calasanziane 25, 00167 rome (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12437 1 original paper this retracts the article “effect of preoperative ureteral stenting on the surgical outcomes of patients with 1-2 cm renal stones managed by retrograde intrarenal surgery using a ureteral access sheath” (https://doi.org/10.4081/aiua.2023.12102) published on december 28, 2023. –––––––––––––––––––––––––– the undersigned tamer abouelgreed, as corresponding author and on behalf of the co-authors, requests the retraction of the above article because he has found that the wording used to present his original data has excessive similarities with the wording of a previously published article. tamer a. abouelgreed https://doi.org/10.4081/aiua.2024.12437 retraction: effect of preoperative ureteral stenting on the surgical outcomes of patients with 1-2 cm renal stones managed by retrograde intrarenal surgery using a ureteral access sheath tamer a. abouelgreed 1, 2, mohamed a. elhelaly 1, el-sayed i. el-agamy 1, rasha ahmed 1, yasser m. haggag 3, m. abdelwadood 4, salma f. abdelkader 5, sameh s. ali 6, naglaa m. aboelsoud 7, mosab f. alassal 8, gehad a. bashir 9, tarek gharib 10 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 gulf medical university, ajman; 3 department of urology, faculty of medicine, al-azhar university, asyut., egypt; 4 department of urology, faculty of medicine, ain shams university, cairo, egypt; 5 department of radiology, faculty of medicine ain shams university, cairo, egypt; 6 department of radiology, sheikh khalifa general hospital, uaq, uae; 7 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 8 department of vascular surgery, saudi german hospital, ajman, uae; 9 department of urology, sheikh khalifa medical city, abu dhabi, uae; 10 department of urology, faculty of medicine, benha university, benha, egypt. doi: 10.4081/aiua.2024.12437 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper and bladder dysfunction (1). the impact and pathophysiology of diabetes on the urinary bladder could be multifactorial including the osmolarity diuresis effect, metabolic perturbation, microvascular damage, and diabetic neuropathy, consequently resulting in detrusor smooth muscle and urinary bladder urothelial dysfunction (2). historically, luts associated with dm were reported as a triad of symptoms; impaired bladder sensation, increased bladder capacity, and decreased detrusor contractility (3). however, more recently, dm was reported to cause a variety of luts, including detrusor overactivity (do), impaired detrusor contractility and urethral dysfunction (4-6). these symptoms culminate in diabetic cystopathy and asymptomatic bacteriuria, which is reported to be between 25% and 90% in the literature (3). despite the main focus of dm associated luts being referred to as diabetic cystopathy for many years, recent evidence has demonstrated the impact of diabetes on the lower urinary tract to be multifactorial (1, 2, 7). furthermore, the pathogenesis of luts in diabetic patients is under-investigated, remaining elusive. osmolarity diuresis effect, metabolic abnormalities, microvascular damage, and neuropathy of diabetes may result in dysfunctions of smooth muscle, urothelium, and neuronal components of the bladder (6, 8). previous studies have reported several urodynamic findings in diabetic patients (1, 8). however, there is a paucity in the literature addressing the urodynamic changes concerning the duration of dm. therefore, the study aimed to address the pattern of urodynamic findings in diabetic patients presenting with luts, comparing short and long-standing dm. patients and methods study design after obtaining ethical approval, a prospective study was conducted on patients who presented with luts symptoms and had a concurrent diagnosis of type 2 dm between february 2016 and may 2018. all subjects signed informed consent to participate in the study. patients with purpose: to address the pattern of urodynamic findings in diabetic patients with lower urinary tract symptoms (luts), comparing short-standing and long-standing type 2 diabetes mellitus (t2dm). methods: a prospective study was conducted on 50 patients presenting with luts and a concurrent diagnosis of t2dm, between february 2016 and may 2018. patients were classified and evaluated according to the duration of diabetes into two groups: short-standing dm (< 15 years, n = 31), and long-standing dm (≥ 15 years, n = 19) groups. the impact of luts and quality of life were assessed in female patients using iciqfluts and male patients using iciq-mluts. results: a total of 50 patients were included in the study. the mean duration of t2dm was 10 ± 0.7 years. the mean age was 56.3 ± 1.2 years, and the mean hba1c was 7.5 ± 1.2%. urodynamic evaluation detected significantly higher detrusor overactivity (do) and increased bladder sensation with the short-standing dm group (35.5 vs. 15.8%, p = 0.01 and 32.3 vs. 5.3%, p = 0.01, respectively). comparatively, weak, or absent detrusor contractility were more frequent in patients with longstanding dm (52% and 26% respectively p = 0.01). as expected, overflow incontinence and straining during voiding were significantly higher in the long-standing dm group (p = 0.04 and p = 0.03, respectively). surprisingly, there was no significant correlation between patients presenting with urgency in their voiding diary (subjective) and urodynamic detection of do (p = 0.07). conclusions: there are different patterns in urodynamic characterizations of t2dm. patients with short-standing dm present more commonly with storage symptoms and detrusor overactivity on urodynamics. contrastingly, patients with long-standing dm present more frequently with voiding symptoms and detrusor underactivity on urodynamics. thus, screening for an underactive bladder is advisable in patients with long-standing t2dm. key words: urodynamic study; diabetes mellitus; luts; urinary bladder; urinary incontinence; detrusor underactivity; detrusor overactivity. submitted 7 december 2022; accepted 6 january 2023 introduction diabetes mellitus (dm) is a prevalent major health condition associated with lower urinary tract symptoms (luts) evaluation of urodynamic pattern in short and long-standing diabetic patients haytham elsakka 1*, ahmed ibrahim 2*, abdulghani khogeer 2, 3, adel elatreisy 4, rawan elabbady 2, osama shalkamy 4, ayesha khan 1, iman sadri 2, ahmad alshammari 2, ahmad khalifa 2, serge carrier 2, melanie aube-peterkin 2 1 urology department, east lancashire hospitals nhs trust, balckburn, lancashire, uk; 2 department of surgery, division of urology, mcgill university health center, montreal qc, canada; 3 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 4 urology department, faculty of medicine, al-azhar university, cairo, egypt. * contributed equally as co-first author. doi: 10.4081/aiua.2023.11072 summary archivio italiano di urologia e andrologia 2023; 95, 1 h. elsakka, a. ibrahim, a. khogeer, et al. previous pelvic surgery, coexisting neurologic disorders, or any other medical condition that interferes with bladder or sphincter function were excluded from the study. patients were classified and evaluated according to the duration of diabetes into short-standing: > 15 years (group i), and long-standing: ≥ 15 years (group ii). subjects’ evaluation all patients were subjected to entire medical history. the impact of luts and quality of life was assessed in female patients utilizing iciq-fluts (international consultation on incontinence modular questionnaire on female lower urinary tract symptoms) and in male patients using iciq-mluts (international consultation on incontinence modular questionnaire on male lower urinary tract symptoms). these questionnaires provide rigorous validity and reliability, both of which are frequently used worldwide (9, 10). patients underwent a clinical examination (including focused neurological examination), furthermore, all patients underwent routine laboratory investigations, which included: urine analysis, urine culture and sensitivity, hba1c, fasting and postprandial blood sugar, and serum creatinine. imaging studies (kub, abdominopelvic us), and urodynamic evaluation. the urodynamic machine used was the ellipse-4 andromeda (gmbh, wallbergstraße 5. d-82024 taufkirchen/potzham germany). statistical analysis statistical analysis was carried out using spss software package version 28.0. numerical values were presented as means and standard deviation (sd). categorical values were presented as frequency and percentages. comparison between different categorical variables was made using fisher’s exact test. additionally, a student's ttest was used to compare the means of the continuous variables among different groups. two-tailed p values less than 0.05 were considered statistically significant. results a total of 50 patients were included in the study: 40 women (80%) and 10 men (20%). the mean age was 56.28 ± 1.14 years (range 45 to 73 years), the mean hba1c was 7.5 ± 1.2%, and the mean fasting blood sugar (fbs) was 199.88 ± 9.24 mg%. the mean duration of dm was 10 ± 0.77 years (table 1). clinical presentation storage symptoms were the predominant class of luts reported by the participants. in particular, 88% described nocturia (44 subjects) followed by 86% noting daytime frequency (43 subjects), urgency 78% (39 subjects), urge incontinence 54% (27 subjects), and nocturnal enuresis 28% (14 subjects). comparatively, voiding luts were reported less frequently: 40% complained of straining during voiding, 38% reported a weak urine stream and 34% of an interrupted stream. overflow incontinence was the main complaint in 20% of the study cohort (table 1). voiding diary charts were reported as the mean of variable per patient as follows: mean diurnal voids/day was 7.78 ± 0.45 and mean nocturnal voids/night was 3.78 ± 0.29; mean of urgency episodes/day was 4.54 ± 0.48, and mean of urge incontinence episodes/day was 2.17 ± 0.51. finally, the mean voided volume/void was 268.47 ± 14.86 ml (table 1). urodynamic evaluation the free flowmetry of the cohort revealed that the mean voided volume was 235 ± 17.05 ml. the mean maximum flow rate was 15.21 ± 1.12 ml/s and the mean of postvoid residual (pvr) urine was 114.94 ± 22.76 ml. of note, 30% of participants had a pvr greater than 100 ml. bladder sensation was normal in 54% (26 patients), increased in 22% (11 patients), reduced in 12% (6 patients) and absent in 14% (7 patients). the mean first sensation volume (fsv) was 159 ± 10.88 ml. the mean first desire volume (fdv) was 255.97 ± 11.36 ml, and the mean strong desire volume (sdv) was 334.68 ± 11.56 ml (table 2). the mean value of bladder compliance was 81.70 ± 9.84 ml/cm h2o. the latter was normal in 88% (44 subjects), reduced in 10% (5 subjects), and increased in 2% (1 subject). the mean maximum cystometric capacity (mcc) was 383.56 ± 15.7 ml of which, was valid for 74% of subjects. the mcc could not be assessed in 26% (13 subjects) due to either absent sensation, urine leakage, or reduced sensation (table 2). of the subjects whom the mcc was successfully calculated, 58% had a normal mcc; it was reduced in 14% and increased in 2% of the study cohort. amongst the studied participants, 28% (14 subjects) had do. the do was phasic in 20% (10 subjects) and termitable 1. patients demographics, clinical presentation, questionnaires evaluation and voiding diary profile. variable value patients demographics: vmean age (se, range), year 56.28 ± 1.14 (45 to 73) male/female ratio, n (%) 10 (20%)/40 (80%) mean duration of dm (se, range), year 10 ± 0.77 (5 to 29) mean fbs (se, range), mg % 199.88 ± 9.24 (102 to 392) hba1c 7.5 ± 1.2 mean serum creatinine (se, range), mg % 1.09 ± .04 (0.5 to 1.5) clinical presentation: nocturia, n (%) 44 (88%) daytime frequency, n (%) 43(86%) urgency, n (%) 39 (78%) urgency incontinence, n (%) 27 (54%) nocturnal enuresis, n (%) 14 (28%) weak stream, n (%) 19 (38%) interrupted stream, n (%) 17 (34%) straining during voiding, n (%) 20 (40%) continuous drippling of urine, n (%) 10 (20%) questionnaires evaluation: iciq-fluts 28.5 ± 7 iciq-mluts 30.3 ± 5.8 voiding diary profile: diurnal voids/day (se, range) 7.78 + 0.45 (2 to 15) nocturnal voids/night (se, range) 3.78 + 0.29 (0 to 8) urgency episodes/day (se, range) 4.54 + 0.48 (0 to 14) urgency incontinence episodes/day (se, range) 2.17 + 0.51 (0 to 14) voided volume/void (se, range) 268.47 + 14.86 (90 to 500) archivio italiano di urologia e andrologia 2023; 95, 1 urodynamics of diabetic patients nal in 8% (4 subjects) with regards to do; the mean value of wave numbers was 3.64 ± 0.82 waves (range 1 to 12 waves), the mean duration was 45.85 ± 10.75 seconds (range 10 to 149 seconds), the mean amplitude was 41.4 ± 6.02 cm h2o, and the mean value of the first contraction volume (fcv) was 141 ± 26.63. the detrusor contractility was normal in 60 % (30 subjects), weak in 26% (13 subjects), and absent in 14 % (7 subjects) (table 2). with regards to the duration of dm, the cohort was classified into group i (short-standing dm, < 15 years) included 31 patients (62%), and group ii (long-standing dm, ≥ 15 years) included 19 patients (38%). the mean score of iciq-fluts was significantly lower in group i when compared with group ii (24.67 ± 5.4 vs. 34.25 ± 4.9; p < 0.001). likewise, the mean score of iciq-mluts was significantly lower for group i when compared with group ii (28.7 ± 5.9 vs. 34 ± 2.3; p = 0.048) (table 3). do and increased bladder sensation were more common in patients with short-standing dm (35.5% vs. 15.8%, p = 0.01) and (32.3 vs. 5.3%, p = 0.01), respectively. in contrast, weak or absent detrusor contractility was more frequent in patients with long-standing dm (52% and 26% respectively p = 0.01). as expected, overflow incontinence and straining during voiding were significantly higher in the long-standing dm group (p = 0.04 and p = 0.03), respectively (table 4). there was no significant correlation between patients presenting with urgency on voiding diary (subjective) and urodynamic detection of do (p = 0.07). discussion diabetic bladder dysfunction can present with a broad spectrum of luts (10). clinically, luts in diabetic patients range from storage symptoms to voiding symptoms. common storage luts experienced by diabetic patients include nocturia, increased daytime frequency, urgency, and urge incontinence. on the other hand, frequently experienced voiding luts in diabetic patients encompass weak flow of urine, interrupted stream, straining during voiding, and eventually urine retention or overflow incontinence. the pathology shows a diverse and progressive evolution from an overactive bladder to a table 3. comparison between the study groups regarding clinical presentation. luts evaluation short-standing dm long-standing dm p value n = 31 (%) n = 19 (%) day time frequency 28 (90.3%) 15 (78.9%) 0.4 nocturia 28 (90.3%) 16 (84.2) 0.66 urgency 26 (83.9%) 13 (68.4%) 0.29 urgency incontinence 18 (58.1%) 9 (47.4) 0.56 nocturnal enuresis 5 (16.1%) 9 (47.4) 0.25 weak stream 7 (22.6%) 12 (63.2) 0.07 interrupted stream 6 (19.4%) 11 (57.9%) 0.12 overflow incontinence 2 (6.5%) 8 (42.1%) 0.04 straining during voiding 7 (22.6%) 13 (68.4%) 0.03 iciq-fluts 24.67 ± 5.4 34.25 ± 4.9 < 0.001 iciq-mluts 28.7 ± 5.9 34 ± 2.3 0.048 table 4. comparison between the study groups regarding urodynamic findings. bladder sensation short-standing dm long-standing dm p value n (%) n=31 n=19 normal 17 (54.8%) 9 (47.4%) 0.01 increased 10 (32.3%) 1 (5.3%) reduced 1 (3.2%) 5 (26.3%) absent 3 (9.7%) 4 (21.4%) bladder compliance 0.1 normal 26 (83.8%) 9 (47.4%) increased 2 (6.4%) 8 (42.1%) reduced 3 (9.7%) 2 (10.5%) maximum cystometric capacity 0.42 normal 17 (54.8%) 12 (63.2 %) increased 1 (3.2%) 0 reduced 6 (19.4%) 1 (5.3%) cannot be assessed 7 (22.6%) 6 (31.6) parameters of detrusor overactivity 0.01 phasic 9 (29%) 1 (5.3) terminal 2 (6.5%) 2 (10.5%) with leak 6 (19.4%) 2 (10.5%) without leak 5 (16.1%) 1 (5.3%) detrusor contractility 0.01 normal 26 (83.9%) 4 (21.1%) weak 3 (9.7%) 10 (52.6%) absent 2 (6.5%) 5 (26.3%) flowmetry 0.12 non obstructed 28 (90.3%) 14 (73.7%) obstructed 1 (3.2%) 0 could not be assessed 2 (6.5%) 5 (26.3%) table 2. urodynamic evaluation of the study’ cohort. 1. free flowmetry: mean voided volume (se, range), ml 235 ± 17.05 ml. (12 to 468) mean maximum flow rate (se, range), ml/s 15.21 ± 1.12 ml/s. (1 to 40) mean amount of post voiding residual urine (se, range), ml 114.94 ± 22.76 ml. (0 to 500) 2. filling cystometry: a. bladder sensation: absent bladder sensation, n (%) 7 (14%) reduced, increased, normal bladder sensation, n (%) 6 (12%), 11(22%), 26(54%) mean first sensation volume (fsv) (se, range) ml 159 ± 10.88 (31 to 352) mean first desire volume (fdv) (se, range) ml 255.97 ± 11.36 (129 to 430) mean strong desire volume (sdv) (se, range) ml 334.68 ± 11.56 (206 to 474) b. bladder compliance: normal, reduced, increased bladder compliance, n (%) 35 (70%), 5 (10%), 10(20%) mean value of bladder compliance (se, range) ml/cm h2o 81.70 ± 9.84 (5.7 to 455) c. maximum cystometric capacity: normal, increased, reduced n (%) 29 (58%), 7(14%), 1(2%) mean maximum cystometric capacity (se, range) ml 383.56 ± 15.7 ml (225 to 657) d. parameters of detrusor overactivity: detrusor overactivity number (se, range) 3.46 ± 0.82 (1 to 12) detrusor overactivity duration (se, range) 45.85 ± 10.75 (10 to 149) detrusor overactivity amplitude (se, range) 41.4 ± 6.02 (7.4 to 75) first contraction volume (se, range) 141 ± 26.63 (31 to 347) e. parameters of leakage with detrusor overactivity: amount of leakage (se, range) 125.62 ± 28.19 (30-258) first leakage volume (se, range) 172.75 ± 32.78 (73-324) leak detrusor pressure (se, range) 56.34 ± 3.77 (43-75) f. pressure flow study: detrusor contractility: normal, weak, absent n (%) 30 (60%), 13 (26%), 7 (14%) g. flow obstructed, not obstructed, could not be assessed n (%) 1 (2%), 42 (84%), 7 (14%) archivio italiano di urologia e andrologia 2023; 95, 1 h. elsakka, a. ibrahim, a. khogeer, et al. poor non-contractile bladder. diabetic urinary symptoms manifest alongside the progression of diabetes. as such, we evaluated diabetic patients presenting with luts to specifically address the urodynamic pattern in such cohort over the course of the disease. therefore, the study was conducted to characterize the specific urodynamic findings associated with the diabetic population in both short and long disease duration. as previously reported, in the early course of diabetes, the main pathological factor is related to polyuria, causing detrusor muscle remodeling, hypertrophy and overactivity. over time, there is an accumulation of toxic metabolites and oxidative stress leading to a decline in detrusor smooth muscles contractility, and bladder urothelium and neuronal alteration. collectively, this results in significant bladder sensation degradation and altered filling response (12). several reports demonstrate both urodynamic do and poor bladder contractility could be present. among 182 diabetic patients with a mean follow-up period of 5 years, kaplan et al. found that do was the main urodynamic pattern (55%), while detrusor contractility was impaired among 23% of patients (13). furthermore, kebapci et al. found that decreased bladder sensation, weak bladder contractility, and increased bladder capacity with pvr < 100 ml were the most prominent urodynamic findings in diabetic patients (14). in their cohort, the duration of diabetes was less than nine years, and hba1c was less than 7%. additionally, yamaguchi et al. reported trends of increased residual urine in long-standing diabetic patients (duration > 10 years) despite not being statistically significant (15). similarly, malik et al. (16) conducted a prospective comparative study on 288 non-diabetic and 96 diabetic women. they detected delayed first sensation, higher cystometric capacity, and reduced detrusor pressure at maximum flow rate among the diabetic group. those findings were more remarkable in long-standing dm (> 10 years). a significant relation between dm and a non-contractile bladder was not identified in their study. in contrast, in the present report, we included diabetic patients with a longer duration and reported weak detrusor contractility in 26% and 14%, respectively. additionally, we detected a significant difference in detrusor contractility between long and short dm duration. 52% of patients had weak detrusor contractility and 26% had very weak detrusor contractility of long-standing t2dm, compared to 9% and 6 % in short-standing, respectively (p < 0.001). furthermore, shin et al. performed a retrospective review of a urodynamic study for 708 females who clinically presented with stress urinary incontinence, comparing the diabetic and non-diabetic groups. they found that qmax and bladder contractility index is significantly reduced among the diabetic group (17). the distinct finding of the present study recognises diabetes mellitus had a different impact on urinary bladder function; the pattern of dysfunction varies according to the duration of dm. storage symptoms were more common amongst short-standing dm patients compared to long-standing t2dm patients. in particular, nocturia (90.3 vs. 84.2%), daytime frequency (90.3 vs. 78.9%), urgency (83.9 vs. 68.4%), and urge incontinence (58.1 vs. 47.4%). in contrast, voiding symptoms were more frequent in long-standing dm, namely weak stream (63.2 vs. 22.6%), interrupted stream (57.9 vs. 19.4%), overflow incontinence (42.1 vs. 6.5%), and straining during voiding (68.4 vs. 22.6%). furthermore, the current study showed no significant correlation between urgency on voiding diary (subjective) and urodynamic detection of do. we reported do in 35.4% of patients who presented with storage luts. such finding might reinforce the pathogenesis theory of diabetic luts as multifactorial (2). in such cohort, storage luts could be explained by the presence of glycosuria and osmolarity diuresis effect prior to detection of do. conversely, previous studies reported significant urodynamic findings in patients with mild voiding luts, specifically in the late stages of diabetic luts (8, 18). they explain that with the insidious onset of diabetic luts, patients may overlook the symptoms. in addition, health care workers tend not to consider bladder dysfunction complications while screening asymptomatic diabetic patients; they pay more attention to neuropathy, nephropathy, and retinopathy (19). hence diabetic patients are liable to be diagnosed during the late stages of diabetic cystopathy. finally, the study is not without limitations. first, the mcc could not be assessed in 31% patients in the longstanding dm group due to absent bladder sensation. however, the filling was stopped after 600 ml to avoid post-procedural urine retention, which is considered high bladder capacity. likewise, the mcc could not be assessed in 22% of the short-standing dm group primarily due to urine leakage. therefore, the bladder filling was stopped earlier in those patients. second, the relatively small sample size of the present study. nevertheless, the present study is prospective with strict and explicit inclusion and exclusion criteria in an attempt to eliminate any confounding factors which might affect bladder function. additionally, the voiding diary provided a subjective evaluation that could not reflect the objective bladder dysfunction in the urodynamic study. thus, we believe it is crucial to create a newly validated screening test for patients with diabetic cytopathy. further prospective studies are still advisable. conclusions there are different patterns in the urodynamic characterization of type 2 diabetic patients. patients with shortstanding dm often present with storage symptoms and detrusor overactivity on urodynamics. comparatively, patients with long-standing dm present more frequently with voiding symptoms and detrusor underactivity on urodynamics. screening for an underactive bladder is advisable in patients with a long-standing dm. references 1. bansal r, agarwal mm, modi m, et al. urodynamic profile of diabetic patients with lower urinary tract symptoms: association of diabetic cystopathy with autonomic and peripheral neuropathy. urology. 2011; 77:699-705. 2. geerlings se, stolk rp, camps mj, et al. diabetes women asymptomatic bacteriuria utrecht study group. risk factors for symptomatic urinary tract infection in women with diabetes. diabetes care. 2000; 23:1737-41. archivio italiano di urologia e andrologia 2023; 95, 1 urodynamics of diabetic patients 3. lee wc, wu hp, tai ty, et al. effects of diabetes on female voiding behavior. j urol. 2004; 17:989-92. 4. yuan z, tang z, he c, tang w. diabetic cystopathy: a review. j diabetes. 2015; 7:442-7. 5. gomez cs, kanagarajah p, gousse ae. bladder dysfunction in patients with diabetes. curr urol rep. 2011; 12:419-26. 6. chancellor mb. the overactive bladder progression to underactive bladder hypothesis. int urol nephrol. 2014; 46(suppl 1):s23. 7. bolgeo t, maconi a, bertolotti m, et al. physiopathology of the diabetic bladder. arch ital urol androl. 2020; 92:314. 8. majima t, matsukawa y, funahashi y, et al. urodynamic analysis of the impact of diabetes mellitus on bladder function. int j urol. 2019; 26:618-622. 9. jackson s, donovan j, brookes s, et al. the bristol female lower urinary tract symptoms questionnaire: development and psychometric testing. br j urol. 1996; 77:805-12. 10. de ridder d, roumeguère t, kaufman l. urgency and other lower urinary tract symptoms in men aged ≥ 40 years: a belgian epidemiological survey using the iciq-mluts questionnaire. int j clin pract. 2015; 69:358-65. 11. capon g, caremel r, de sèze m, et al. the impact of mellitus diabetes on the lower urinary tract: a review of neuro-urology committee of the french association of urology. prog urol. 2016; 26:245-53. 12. daneshgari f, moore c. diabetic uropathy. semin nephrol. 2006; 26:182-5. 13. kaplan sa, te ae, blaivas jg. urodynamic findings in patients with diabetic cystopathy. j urol. 1995; 153:342-4. 14. kebapci n, yenilmez a, efe b, et al. bladder dysfunction in type 2 diabetic patients. neurourol urodyn. 2007; 26:814-9. 15. yamaguchi c, sakakibara r, uchiyama t, et al. overactive bladder in diabetes: a peripheral or central mechanism? neurourol urodyn. 2007; 26:807-13. 16. malik rd, cohn ja, volsky j, et al. a modern comparison of urodynamic findings in diabetic versus nondiabetic women. female pelvic med reconstr surg. 2020; 26:44-50. 17. shin ys, on jw, kim mk. clinical significance of diabetes mellitus on detrusor functionality on stress urinary incontinent women without bladder outlet obstruction. int urogynecol j. 2016; 27:1557-61. 18. esteghamati a, rashidi a, nikfallah a, yousefizadeh a. the association between urodynamic findings and microvascular complications in patients with long-term type 2 diabetes but without voiding symptoms. diabetes res clin pract. 2007; 78:42-50. 19. hill sr, fayyad am, jones gr. diabetes mellitus and female lower urinary tract symptoms: a review. neurourol. urodyn. 2008; 27:362-7. correspondence haytham elsakka, md haythamurology@gmail.com ayesha khan, md ayesha.khan@elht.nhs.uk urology department, east lancashire hospitals nhs trust, balckburn, lancashire (uk) ahmed ibrahim, md, msc (corresponding author) ahmed.eldemerdash@muhc.mcgill.ca eldemerdash90@gmail.com clinical fellow at mcgill university health centre 1001 boulevard décarie, montreal, qc, canada abdulghani khogeer, md dr-abdulghani@hotmail.com department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah (saudi arabia) adel elatreisy, md adel.elatreisy@azhar.edu.eg osama shalkamy, md dr_shalkamy@azhar.edu.eg urology department, faculty of medicine, al-azhar university, cairo (egypt) rawan elabbady, md rawanelabbady93@hotmail.com iman sadri, md iman.sadri@mail.mcgill.ca ahmad alshammari, md dr.shammar@gmail.com ahmad khalifa, md khalifa.urology@gmail.com serge carrier, md serge.carrier@mcgill.ca melanie aube-peterkin, md melanie.aube-peterkin@mcgill.ca department of surgery, division of urology, mcgill university health center, montreal qc (canada) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 301archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. its infrequency (only 1% of male frequencies in the united states), tgct represents the most common malignancy in young men between 20-39 years old in northern and southern europe (the peak age of incidence is 30 years) (1). the incidence of tgct has been increasing in the developed countries for at least four decades (2-4). rates vary by ethnic group: white men are at a higher risk for tgct, with an annual incidence of 6.6/100,000, compared to 1.4/100.000 in black men and 1.9/100.000 in asians/pacific islanders (5, 6). the pathogenesis of tgct is multifactorial, including both genetic and environmental factors (7-9). a relationship between cryptorchidism and testicular cancer is well known (10). however, the risk factors for testicular cancer are not well characterized. a previous unilateral testicular cancer and a family history of testicular tumor are the only other factors clearly associated with increased risk. so far, studies have estimated an increased risk of tgct 8-10 times fold and 4-6 times fold in brothers and sons respectively (7). nonetheless, mortality rates have dropped significantly over the past 3 decades owing to the development of more effective treatments (2). the aim of this study was to investigate the clinical outcomes of tgct in two different age groups treated with active surveillance (as) or active treatment (at), according to the histopathological findings and the stage of disease. materials and methods we retrospectively analyzed 52 patients who underwent surgery for tgct from january 2009 to december 2014. all the patients were divided into two age groups: the group a included children-adolescents from 18 months to 21 years old, while the group b comprised young adults from 22 to 39 years old. clinical, histopathological, therapeutic and follow-up data were collected. for objective: to investigate and compare the effectiveness of active surveillance versus post-surgical active treatment, in patients with testicular germ cells tumor (tgct). materials and methods: we retrospectively analyzed 52 patients who underwent surgery for tgct from january 2009 to december 2014. all the patients were divided into two age groups: the group a included children-adolescents from 18 months to 21 years old, while the group b comprised young adults from 22 to 39 years old. clinical, histopathological, therapeutic and follow-up data were collected. results: overall, 22 patients (42,3%) were enrolled in the group a and 30 patients (57.7%) were categorized in the group b. inguinal orchiectomy was performed in all patients. retroperitoneal lymphadenectomy was performed in 4 patients (7.7%). post-surgical management differed based on clinical stage, resulting in active surveillance or adjuvant therapy. after an average 7 years follow-up period (range: 3.5-9.0 years), the overall survival rate is 100%. the relapse risk is significantly higher for the patients in the group b, displaying a recurrence free-survival rate of 72% versus 95% (group a); 11 relapses (21.1%) were recorded 2 years after surgery. of these, 3 recurrences (12.0%) occurred in patients undergoing an active surveillance approach, while 8 (29.6%) in patients subjected to an active treatment. conclusions: the excellent prognosis in both age groups confirms the high curability of this neoplasia. the active surveillance could represent an optimal option for low recurrence risk tumors. however, post-surgical treatments should be taken into consideration for tgct with high risk factors, including tumor size, lymphovascular and rete testis invasion. key words: testicular germ cell tumors; surgery; children; young adults; active surveillance. submitted 10 march 2021; accepted 7 may 2021 introduction testicular germ cell tumor (tgct) is a rare form of cancer in childhood, adolescence and young adulthood. despite testicular germ cells tumors in adolescents and young adults: management and outcomes from a single-center experience claudio spinelli 1, gianmartin cito 2, girolamo morelli 3, marco ghionzoli 1, alessia bertocchini 1, beatrice sanna 1, luca galli 4, andrea antonuzzo 5, riccardo morganti 6, silvia strambi 1 1 division of pediatric, adolescents and young adults surgery, department of surgical pathology, medical, molecular and critical area, university of pisa, pisa, italy; 2 department of urology and andrology surgery, careggi hospital, university of florence, florence, italy; 3 department of urology and andrology surgery, university of pisa, pisa, italy; 4 medical oncology ii, university of pisa, department of translational research and new technologies in medicine and surgery, university of pisa, pisa, italy; 5 medical oncology i, national health service department of translational medicine research and new technologies in medicine and surgery, university of pisa, pisa, italy; 6 section of statistics, department of clinical and experimental medicine, university of pisa, pisa, italy. doi: 10.4081/aiua.2021.3.301 summary archivio italiano di urologia e andrologia 2021; 93, 3 c. spinelli, g. cito, g. morelli, m. ghionzoli, a. bertocchini, b. sanna, l. galli, a. antonuzzo, r. morganti, s. strambi 302 the guidance during diagnostic assessment, tumor markers levels were recorded, including human chorionic gonadotropin (hcg), alpha-fetoprotein (afp) and lactate dehydrogenase (ldh). total testosterone, estradiol, follicle-stimulating hormone (fsh) and luteinizing hormone (lh) levels were collected pre-operatively. in order to define the pre-surgical tumor stage, all patients underwent thorax and abdomen imaging scans, including contrast-enhancement computed tomography (ct) or magnetic resonance (mr). we selected the treatments for patients according to the european association of urology (eau) guidelines. as is considered a feasible approach in clinical stage (cs) i seminoma testis patients. the as protocol after surgery has involved the evaluation of tumor marker levels every 2 months in the first two years, every 4 months during the third year, every 6 months during the fourth year, and then yearly from the fifth year onwards. chest radiography or abdominal/pelvic ct/mri, color doppler ultrasonography (us) of testicles, abdomen and pelvis were performed every 6 months for the first 3 years and then, abdominal ct/mri after the fifth year. all the patients gave the oral and written consent on management options. moreover, they have been fully informed about the risk of recurrence during the active surveillance approach. for patients with higher cancer stage at diagnosis, active treatment was preferred. meanwhile, disease relapse was defined as imaging or physical examination evidence of metastases and/or elevated tumor markers. follow-up data of the as protocol or the post-surgical at approach were collected. moreover, the overall survival (os) rate and recurrence free survival (rfs) rate was measured. data analysis the authors confirm the availability of, and access to, all original data reported in this study. categorical data were described by absolute and relative frequency. in order to compare the histologic categories (seminomas, non-seminomas) in the group a and the group b in different stages (is, i, ii, iii), the z-test for two proportions was applied. an rfs analysis was performed using the kaplan-meier method and the log-rank test was used to detect differences between “group a” and “group b” curves. the significance was fixed at < 0.05. all analyses, descriptive and inferential, were carried out by spss v.26. results the group a (children-adolescents) included 22 patients (42.3%) and the group b (young adults) comprised 30 patients (57.7%). the median age in group a was 16.0 years (range: 18.0 months-21.0 years), while the median age in group b was 28.0 years (range: 22.0-39.0 years). in the groups b, 2/30 patients (6.6%) reported a paternal family history of seminoma, and 1/30 patient (3.3%) underwent surgery for cryptorchidism. the most common clinical presentation was a palpable and painless testicular mass in 42/52 cases (80.7%), or testis swelling in 10/52 patients (19.2%). three patients (10.0%) in the group b showed distant metastasis at diagnosis: 1 patient (3.3%) had cervical supraclavicular lymph node metastasis as primary clinical presentation and 2 patients (6.7%) had mediastinal lymph node metastasis associated with respiratory symptoms (wheezing, coughing and chest tightness). all patients reported total testosterone, estradiol, fsh and lh levels, in the normal range. tumor markers were expressed in 14/52 cases (26.9%). in all patients with increased tumor markers, normal levels were reached within 12 months after surgery. the median us tumor size was 20.0 mm in the group a (range: 10.0-70.0 mm size) and 22.4 mm in the group b (range: 10.0-50.0 mm). inguinal orchiectomy was performed in all cases. one patient in the group a underwent a scrotal incision due to high volume tumor mass. rplnd was performed simultaneously with orchiectomy in 4 patients (7.7%), resulting in lymph-node involvement at the final pathological analysis. frozen section examination was performed in 33 patients (63.5%): 14 cases in the group a (63.5%) and 19 cases in the group b (36.5%). a testicular prosthesis was placed in 44 patients (84.6%): 17 in the group a (77.3%) and 27 in the group b (90%). the prosthesis insertion occurred during orchiectomy in 42 cases (95.5%) and after surgery in 2 cases (4.5%). histopathological examination was carried out. in 26 cases (50.0%) typical seminomatous germ cell tumor (sgct) was reported: 7 (31.8%) in the group a and 19 (63.3%) in the group b. twenty-six (50.0%) examinations detected typical non seminomatous germ cell tumor (nsgct): 15 (68.2%) in the group a and 11 (33.7%) in the group b. the histologic distribution of tgct is reported in table 1. our study showed that nsgct are significantly more frequent (p-value = 0.050) in children-adolescents, rather than in adults. a histopathology comparison between the two table 1. histologic distribution of tgct. statistics: frequency (%). histology total group a (n = 22) group b (n = 30) p-value sgct 26 (50) 7 (31.8) 19 (63.3) 0.050 nsgct 26 (50) 15 (68.2) 11 (33.7) embryonal carcinoma 19 (36.5) 11 (50) 8 (26.6) 0.150 yolk sac tumor 4 (7.7) 4 (18.2) 0 (0) 0.057 mixed 3 (5.7) 0 (0) 3 (10) 0.354 table 2. histologic category compared between group a and group b in different stages. statistics: frequency (%). stage group a group b p-value stage is sgct 1 (4.6) 1 (3.3) 0.625 nsgt 0 (0) 0 (0) stage i (a/b) sgct 5 (22.8) 11 (36.7) 0.442 nsgt 13 (59) 5 (16.7) 0.04 stage ii (a/b/c) sgct 1 (4.6) 6 (20) 0.232 nsgt 2 (9) 5 (16.7) 0.630 stage iii (a) sgct 0 (0) 1 (3.3) 0.868 ngct 0 (0) 1 (3.3) 0.868 total 22 30 303archivio italiano di urologia e andrologia 2021; 93, 3 tcgt in adolescents and young adults groups in different stages is reported in table 2. comparison of tumor stages at presentation did not show significant differences among groups. as was performed in 32 patients (61.5%), while at was performed in 20 patients (38.5%). post-surgical management is reported in table 3. after an average follow-up period of 7.0 years (range: 3.59.0 years), 11 relapses (21.1%) were recorded within the first 2 years after orchiectomy. recurrence was higher in group b although we must highlight that initial stage distribution was not homogeneous in the two groups. recurrences occurred respectively in retroperitoneal lymphnodes, in retroperitoneal and retromediastinal lymph nodes, or in retroperitoneal lymph nodes with lung metastasis. each of these cases presented with increased tumor markers. out of them, 1 patient underwent rplnd, while the other ones underwent systemic chemotherapy. overall, 8 recurrences (25.0%) were recorded in the at sample, of which 1 case (5.0%) belonging to the group a was diagnosed as nsgct, involved the retroperitoneal lymph nodes and was treated with rplnd. the group b had 7 cases (35.0%) of recurrence, all of them treated with chemotherapy and radiotherapy: 5 of them were sgct and 2 cases were nsgct. all those 7 patients showed a tumor mass greater than 3 cm, local lymphovascular invasion (lvi) signs and infiltration of the rete testis. the overall survival rate is 100%. furthermore, as shown in figure 1, the relapse risk is significantly higher for the patients in the group b, displaying a recurrence free-survival rate of 72% versus 95% (group a). figure 1. recurrence free-survival analysis between group a (rate 95%) and group b (rate 72%). table 3. post-surgical management of sgct-nsct, comparison between group a and group b (as: active surveillance; rt: radiotherapy; ct: chemotherapy; rplnd: retroperitoneal lymphadenectomy). statistics: frequency (%). group a (22 cases) group b (30 cases) histology stage as rt ct ct+rt rplnd as rt ct ct+rt rplnd sgct is 1 (4.5) 1 (3.3) i 5 (22.7) 7 (23.3) 1 (3.3) 2 (6.7) 1 (3.3) ii 1 (4.5) 5 (16.7) 1 (3.3) iii 1 (3.3) nsgt is i 13 (59.1) 2 (9.1) 5 (16.7) ii 2 (6.7) 3 (10) iii 1 (3.3) archivio italiano di urologia e andrologia 2021; 93, 3 c. spinelli, g. cito, g. morelli, m. ghionzoli, a. bertocchini, b. sanna, l. galli, a. antonuzzo, r. morganti, s. strambi 304 discussion testicular cancer is largely found in young and middle-age men, but around 7% of cases occur in children (11-19). tgcts represent 71% of all testicular neoplasms and they include yolk sac tumors, teratoma, seminoma, choriocarcinoma and embryonal carcinoma (20). gonadal stromal tumors (ntgcts) include leydig cell tumor, sertoli cell tumor, juvenile granulosa cell tumor and gonadoblastoma (21, 22). as reported in literature, testicular tumors may be different, based on age-related range in histopathology, molecular biology, malignant potential, clinical behavior and treatment (12, 22-24). moreover, malignant potential is significantly lower in the pediatric age group compared to the other age groups (25). in our study, the incidence of nsgct is higher in the children’s group than in the young-adults group (p = 0.04). an important role in the diagnosis and follow-up is played by serum tumor markers (23, 26). in our case series, tumor markers were expressed in 26,9% of cases. this was true for both age groups for nsgct, where markers reflect tumor widespread, aggressiveness and constitute a prognostic factor for the cancer itself (18); in the young adults group, markers were expressed only in sgct. after surgical treatment, we reached normal levels of serum tumor markers in absence of metastatic disease. on the other hand, we found tumor markers increasing in patients with relapse, in accordance with data reported the literature (24-26). treatment of the primary tgct is performed by radical orchiectomy. post-surgical treatment was based on histopathologic features and disease stage at surgery (2, 27, 28). management options after surgery included surveillance, adjuvant chemotherapy, radiotherapy and rplnd (2, 30). considering the relatively low risk of relapse in testicular cancer, many guidelines recommend surveillance as the preferred initial treatment for all stage i sgct and low-risk stage i nsgct (31). therefore, active surveillance has also been recently adopted by some cancer centers for high-risk stage nsgct, considering that many patients do not require further therapy and those with relapses can be treated with highly effective salvage therapy (16, 27). regarding sgct, the recent strategic algorithm considers surveillance alone for stage i patients with almost 100% of overall survival. eventual relapses may be cured by radiation or chemotherapy (2). adjuvant treatments have declined in recent decades, as surveillance has been increasingly used to avoid unnecessary treatment and related long-term toxicities (2, 30). indeed, historically active surveillance became an option in the 1980’s when it was demonstrated that cisplatin-based chemotherapy could cure almost all recurrences. today, it is the management option suggested by the guidelines because it has nearly the same overall survival rate of other adjuvant treatments as well as being a safe and non-invasive option in selected cases (3, 30-32). the trend nowadays is a de-escalation of therapy toward as for early stage testicular cancers. the main debate against adjuvant chemotherapy is due to the lack of improved overall survival and the association with long-term side effects, including infertility, secondary malignancies, increased risk for cardiovascular disease, impaired kidney function, hearing impairment and peripheral neuropathy (2, 30, 33, 34). nappi et al. (34) found that active surveillance is highly relevant in avoiding overtreatment in 50-85% of patients, with no long-term side effects in non-relapsing patients and an overall survival of almost 100% even in patients with recurrent disease. a study by nayan et al. (35) conducted on 1239 patients with tgct, treated with active surveillance after orchiectomy for clinical stadium i, showed that the risk percentage of relapse in the first 5 years after orchiectomy was 42.4% for high risk nsgct, 17.3% for low risk nsgct, 20.3% for sgct more than 3 cm wide, and 12.2% for sgct less than 3 cm wide. in a study by albers et al. (16) in patients with stage i nsgct, the tumors had a 30% risk of progression which required treatment. furthermore, it is known that the risk of relapse in stage i nsgct is substantially related to the presence of lympho-vascular invasion (lvi), which implies a 30-50% recurrence risk (25, 36). moreover, as discussed by yilmaz et al. (37) in their study, lvi could be considered a prognosticating indicator for nsgct, thus the status of rete testis and testicular hilum should be taken into consideration when choosing therapies. cohn-cedermark et al. (38) advice chemotherapy for patients with at least two risk factors like tumor size and invasion of the rete testis. high-risk patients can also be managed with initial surveillance to spare the 50% in whom disease will not progress, but other studies recommend precautionary chemotherapy (33-35). recurrences occur most commonly in the retroperitoneum, with the majority diagnosed within 2 years after orchiectomy (39, 40). although recurrence rates are not comparable in the two groups due to different initial staging, in our study we observed relapses in the first 2 years after orchiectomy preeminently in the retroperitoneum, in 32.2% of the patients who underwent at compared to 11.1% of patients submitted to as. in the patients with at, lvi and rete testis signs of infiltration were reported (45.5% nsgct and 27.3% sgct). all the relapses in patients with as were histological samples of nsgct in the group b. all the recurrences in both groups presented a tumor mass greater than 3 cm in size. conclusions as proves to be a feasible option for stage i tgct, whereas post-surgical therapy requires to be performed for higher stage of tgct. the kaplan-meier curve shows a significant difference of rfs for younger patients although they presented with different stage at presentation. considering the overall excellent outcomes of as both in terms of os and rfs, our experience suggests that post-orchiectomy active treatments might be limited to selected patients with well-known relapse risk factors, such as tumor size, lymphovascular and rete testis invasion, while the other patients could benefit from an accurate active surveillance approach. 305archivio italiano di urologia e andrologia 2021; 93, 3 tcgt in adolescents and young adults acknowledgments a special thanks to helen romito from sant’anna school of advanced studies in pisa for her editing work. references 1. hayes-lattin b, bleyer a. “testicular cancer” in cancer in adolescents and young adults. springer publishing 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choriocarcinoma metastatic to the brain: report of 2 cases and review of literature. world neurosurgery. 2017; 106:536-542. 26. murray mj, huddart ra, coleman n. the present and future of serum diagnostic tests for testicular germ cell tumors. nat rev urol. 2016; 13:715-725. 27. romo muñoz mi, núñez cerezo v, dore reyes m, et al. tumores testiculares en la edad pediátrica: indicaciones de la cirugía conservadora [testicular tumours in children: indications for testissparing surgery]. an pediatr (engl ed). 2018; 88:253-258. 28. kamran sc, seisen t, markt sc, et al. contemporary treatment patterns and outcomes for clinical stage is testicular cancer. eur urol. 2018; 73:262-270. 29. ehrlich y, beck sd, foster rs, et al. serum tumor markers in testicular cancer. urol oncol. 2013; 31:17-23. 30. gumus m, bilici a, odabas h, et al. outcomes of surveillance versus adjuvant chemotherapy for patients with stage ia and ib non seminomatous testicular germ cell tumors. world j urol. 2017; 35:1103-1110. 31. alanee s, nicholson a, slaton j. contemporary treatment of low risk stage i non-seminomatous germ cell testicular tumors: a survey of the society of urologic oncology. urol. oncol. 2012; 30:749-51. 32. patel hd, srivastava a, alam r, et al. radiotherapy for stage i and ii testicular seminomas: secondary malignancies and servival. urol oncol. 2017; 35:606.e1e7. 33. leveridge mj, siemens dr, brennan k, et al. temporal trends in management and outcomes of testicular cancer: a population-based study. cancer. 2018; 124:2724-2732. 34. nappi l, nichols cr, kollmannsberger ck. new treatments for stage i testicular cancer. clinical adv hematol oncol. 2017; 15:626631. 35. nayan m, jewett mas, hosni a, et al. conditional risk of relapse in surveillance for clinical stage i testicular cancer. eur urol. 2017; 71:120-127. 36. richie jp. cardiovascular disease mortality after chemotherapy or surgery for testicular non seminoma:a population-based study. j urol. 2016; 196:1448-1449. 37. yilmaz a, cheng t, zhang j, trpkov k. testicular hilum and archivio italiano di urologia e andrologia 2021; 93, 3 c. spinelli, g. cito, g. morelli, m. ghionzoli, a. bertocchini, b. sanna, l. galli, a. antonuzzo, r. morganti, s. strambi 306 vascular invasion predict advanced clinical stage in nonseminomatous germ cell tumors. mod pathol. 2013; 26:579-86. 38. cohn-cedermark g, stahl o, tandstad t. swenoteca. surveillance vs.adjuvant therapyof clinical stage i testicular tumors-a review and the swenoteca experience. andrology. 2015; 3:102-10. 39. smart, lopes, rice s, et al. chemotherapy drugs cyclophosphamide, cisplatin and doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis. sci rep. 2018; 8:1773. 40. chung p, warde p. contemporary management of stage i and ii seminoma. curr urol rep. 2013; 14:525-33. correspondence claudio spinelli, md claudio.spinelli@unipi.it marco ghionzoli, md marcoghionzoli@hotmail.com alessia bertocchini, md villinofibbiani@hotmail.com beatrice sanna, md beatricesanna.md@gmail.com silvia strambi, md sil.strambi@gmail.com division of pediatric, adolescents and young adults surgery, department of surgical pathology, medical, molecular and critical area, university of pisa, pisa (italy) gianmartin cito, md (corresponding author) gianmartin.cito@gmail.com girolamo morelli, md girolamomorelli@gmail.com department of urology and andrology surgery, careggi hospital, university of florence largo brambilla, 3 50134 florence (italy) luca galli, md lgalli@unipi.it medical oncology ii, university of pisa, department of translational research and new technologies in medicine and surgery, university of pisa, pisa (italy) andrea antonuzzo, md aantonuzzo@unipi.it medical oncology i, national health service department of translational medicine research and new technologies in medicine and surgery, university of pisa, pisa (italy) riccardo morganti, md r.morganti@ao-pisa.toscana.it section of statistics, department of clinical and experimental medicine, university of pisa, pisa (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper introduction urinary system stone disease, which is an endemic health issue, at least in some regions of the world, can irreparably harm the kidneys if not treated promptly and appropriately. the most significant feature of this disease is its recurrent nature, which is caused by insufficient metabolic evaluation and a lack of appropriate medical care, especially in individuals in high-risk groups (1, 2). while endourologists have made significant advancements in the minimally invasive therapy of calculi, there has been little progress made in the pharmacological management of urolithiasis. allopurinol, potassium citrate, thiazide diuretics, and other medications have been utilized in medical therapy, with different degrees of claimed efficacy (3). the medical method has some efficacy in preventing recurrences, but there are other significant drawbacks, including some drug-related adverse effects and low patient compliance rates observed during extended therapy follow-up. additionally, existing medical therapy techniques may fail due to the agents' insufficient impact on all fundamental relevant pathologic mechanisms at the kidney level given the very complicated etiology of urinary stone formation, which depends on multiple pathologic phases and/or mechanisms. in other words, the fundamental constraint of medical treatment is the impact through only one established pathogenetic process (after the formation of stones). regarding this, despite the fact that certain models concentrate on the creation of novel medications that may have powerful effects on the various stages of stone formation (nucleation, supersaturation, and crystal growth) (47), such models constitute only a rough imitation of the events taking place in the organism (8). introduction: to analyze the dose-dependent preventive effect of a plant-based herbal product on the new crystal formation in a rat model. materials and methods: a total of 42 rats were divided into 7 groups and zinc discs were placed into the bladder of rats to provide a nidus for the development of new crystal formation: group 1: control, group 2: 0.75 percent ethylene glycol (eg); group 3: 0.75 percent eg plus 0.051 ml of the compound; group 4: 0.75 percent eg plus 0.179 ml of the compound; group 5: 0.75 percent eg plus 0.217 ml of the compound; group 6: 0.75 percent eg plus 0.255 ml of the compound; group 7 0.75 percent eg plus 0.332 of the compound). the analysis and comparison focused on the disc weights, changes in urinary oxalate and calcium levels, urinary ph, and the histopathologic evaluation of the inflammatory changes in the bladder after 14 days. results: according to the evaluation of discs placed in the bladders of the animals, animals receiving the herbal compound on a dose-dependent basis showed a limited increase in the disc weights values after 14 days, despite a considerable increase in animals receiving eg alone (p = 0.001). further evaluation of the increase in disc weights on a dose-dependent basis in different subgroups (from groups 3 to 7) demonstrated that the limitation of crystal deposition began to be more prominent as the dose of herbal compound increased. this effect was more evident particularly in comparisons between group 7 and others, according to lsd multiple comparison tests (p = 0.001). as anticipated, there has been no discernible change in the weight of the discs in the control group. although urinary calcium levels in animals of groups 2, 6, and 7 were significantly higher than the other groups, we were not able to demonstrate a close correlation between urinary oxalate levels and the increasing dose levels. even though mean urine ph levels were statistically considerably higher in group 3, there was no statistically significant correlation between the oxalate and calcium levels between all groups, and no association was seen with the administration of herbal agents. the transitional epithelium between the three groups of animals' bladder samples did not exhibit any appreciable difference according to pathological analysis. dose-dependant preventive effect of a herbal compound on crystal formation in rat model rasim güzel 1, i̇smet bilger erïhan 2, i̇sa özaydin 3, uğur aydin 3, murat bağcioğlu 4, ramazan kocaaslan 5, ümit yildirim 2, kemal sarica 6 1 kavacık medistate hospital, istanbul, turkey; 2 kafkas university, medical school, departments of urology, kars, turkey; 3 kafkas university, veterinary faculty, department of surgery, kars, turkey; 4 bahçeşehir university, medical school, departments of urology, istanbul, turkey; 5 konya training and research hospital, konya, turkey; 6 biruni university, medical school, department of urology, istanbul, turkey. doi: 10.4081/aiua.2023.11114 summary conclusions: in this animal model, the treatment of the compound was successful in lowering the amount of crystal deposition surrounding the zinc discs, most noticeably at a dosage of 0.332 ml, three times per day. key words: herbal compound; rat model; crystal formation. submitted 24 december 2022; accepted 29 january 2023 11114 guzel_stesura seveso 23/03/23 12:24 pagina 1 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. some herbal medications have been effectively used and assessed in terms of their shortor long-term efficacy as well as adverse effects to address the aforementioned challenges in the medical treatment and/or prevention of stone disease (6, 8-15). we used a herbal substance in this work that has been shown to have anti-apoptotic, anti-inflammatory, diuretic, nephroprotective, antioxidant, antibacterial, and spasmolytic activities. in some experimental tests, this substance has been proven to be effective at reducing the formation of stones (16). although calcium and oxalate may play a part in stone formation together, the most important risk factor for calcium oxalate stone disease has been revealed to be the presence of "hyperoxaluria". this condition affects 6070% of people (17, 18). the most widely utilized agent to cause hyperoxaluria in animal models is ethylene glycol (eg), which has also been discovered to be the best agent for evaluating and analyzing an agent's efficacy when employed in such models (19). the formation of nidus for further crystal deposition and stone formation in animal models has been described using a variety of models, including the use of plastic discs, the insertion of suture material parts, the implantation of calcium and oxalate crystals, and the implantation of zinc discs into the bladders of the animals (17). zinc disc implantation inside the bladder of hyperoxaluria-induced rats has been a widely used technique so far among these models. while the majority of animals' final stone composition measured on the zinc disc was calcium oxalate, as shown in several of these investigations, magnesium-ammonium-phosphate crystals (stones) were also shown in some other, more limited, experiments (17-19). in the current work, we sought to assess the potential benefits of the herbal ingredient on the prevention of new urinary stone formation by restricting new crystal deposition on the "zinc discs" in a rat model. materials and methods herbal agent we employed a plant-based herbal supplement composed by a stable mix that included rosmarinic acid, boldin, polysaccharides, the flavonoid quercetin, flavonglicozides, and essential fatty acids. its nephroprotective, diuretic, anti-inflammatory, antioxidant, antimicrobial, and spasmolytic activities have been employed as the basis for resolutivo regium. in 250 ml bottles, the medication is offered in hydrolate form. the dose for adults is 7 ml administered three times per day. the herb sideritis angustifolia, the leaves of melissa officinalis, the flowers of opuntia ficus indica, the leaves of peumus boldus, the rhizomes of cynodon dactylon, and the entire plant of spergularia rubra are all included in the drug's composition. it also contains dried parts of the stem of enguisetum arvensis and an aqueous distillate of those parts, as well as flowers. study design the study protocol was accepted by the ethical committee of kafkas university training and research hospital (june 28, 2022, approval number: kau-haydek2022-120). 42 male sprague dawley rats weighing between 300 and 350 grams were involved and divided into 7 groups. the lighting setup was set up to resemble the natural cycle of day and night. all rats in all groups received the appropriate cages, access to food and water without restriction, and normal (physiological) room temperature. small zinc discs were surgically inserted into the rats' bladders while they were under anesthesia in the first phase of the trial. applications of ethylene glycol and herbal compounds were started daily on the second postoperative day. in an effort to determine the minimal dose necessary for the substance to effectively prevent the growth of stones, the drug has been administered in a dose-dependent manner. regarding the treatment regimen in these subgroups, rats in group 2 received water that had 0.75 percent eg added to it. for each rat in group 3, 0.75 percent eg plus 0.051 ml of the compound was administered three times per day. each rat in group 4, received 0.75 percent eg plus 0.179 ml compound three times per day. each rat in group 5 received 0.75 percent eg plus 0.217 ml compound three times per day. for each rat in group 6, 0.75 percent eg plus 0.255 ml compound was given three times daily. finally, 0.75 percent eg plus 0.332 compound ml was given in group 7. treatment was continued for two weeks. group 1 was the control group, which had the zinc disc, but no eg and no herbal compound. rats were sacrificed at the conclusion of the study, after 14 days of treatment with the aforementioned protocols, and urine samples from the harvested bladders were collected for the evaluation of urine ph as well as the urinary levels of calcium and oxalate. harvested bladders were sent for histopathological analysis after the zinc discs were removed. results of the urine test, histopathological findings, and zinc disc weight values were compared between each group. operative technique ketamine hcl (ketalar, eczacibasi inc., istanbul, turkey) and 10 mg/kg xylazine (rompun, bayer turk inc., istanbul, turkey) were administered intramuscularly to induce anesthesia after a 6-hour fast. we assessed the impairment of the reflex arc reaction to compressing the claws in order to determine the efficacy of anesthesia. the skin was then cleaned with the appropriate antiseptic solutions after the incision site had been shaved with a blunt razor blade (poviodine, istanbul-based dioagnokim inc.) sharp dissection was used to split the abdominal wall muscles after a 2 cm incision in the lower quadrants of the abdomen. after the urinary bladders were separated and exposed, a small incision was made to open the bladder lumen. preparation zinc discs weighing 70 ± 2 mg were then placed inside the bladder lumen, and the existing incisions were sealed with 4/0 absorbable polyglactin (vicryl, ethicon inc., somerville, nj, usa). after the bladder was returned to its original position, the skin and abdominal muscles were stitched together with 2/0 silk and 3/0 absorbable polyglactin (vicryl, ethicaon inc., somerville, nj, usa). the rats were left for recovery after the closed incisions had been cleaned. after 14 days, the rats in each group had their bladders opened using the same surgical procedure as above, and urine samples were taken for 11114 guzel_stesura seveso 23/03/23 12:24 pagina 2 archivio italiano di urologia e andrologia 2023; 95, 1 herbal compound on crystal formation in rat model both microbiological and biochemical analysis. the crystal-covered and coated zinc discs were removed for weighting and stone analysis. the rats' bladder walls were removed and sent to pathology. the urine samples were stored and transported at 4°c while the harvested bladders were fixed in 4% neutral formaldehyde, embedded in paraffin blocks, and cut into 4-6 μm sections, and stained with hematoxylin and eosin. after that, the rats were sacrificed. histopathological evaluation prior to paraffin embedding, 10% formalin was used for the fixation of the bladder tissues. after the procedure, blocks were cut 5-6 μm slices and stained with hematoxylin-eosin. a pathologist expert with animal models analyzed the slices. all samples were examined under the light-microscopy and vascular congestion, level of edema (none, mild, moderate, and severe), level of inflammation, the thickness of the epithelium (in millimeters), changes in the epithelium (dysplasia, calcification, fibrosis, mitosis), and epithelial cell layers were recorded. laboratory analysis urine calcium levels were assessed using the photometric o-cresolphthalein complex method (cobas c501 analyzerroche diagnostics, germany). urine oxalate levels were measured using a rat elisa kit (sunred, china; catalogue no: 201-11-5547). urine ph was assessed using strips for urinalysis (dirui, china; catalogue no: 231011501001). statistical analysis the normality of the distribution of continuous variables was tested by the shapiro-wilk test. one-way anova and lsd multiple comparison tests were applied to investigate the difference between groups in terms of numerical variables and kruskal wallis tests were used to compare non-normal data across groups. statistical analysis was performed with spss for windows version 24.0 and a p-value < 0.05 was accepted as statistically significant. results evaluation of our data obtained in seven groups of animals revealed the following findings: effects of the medication on crystal deposition evaluation of the weights of the zinc disks placed in the bladders of animals receiving eg in addition to normal diet and water in group 2 revealed a significant increase at the end of 14 days when compared with the baseline (group 1) values. (p = 0.001, lsd multiple comparisons) (table 1). on the contrary, however, very little increase in the weight of the disks in the control group (group 1) animals has been noted as expected with mean values of 97.83 ± 2.93 during this evaluation, compared to 70 mg. of the free zinc disc weight (table 1). evaluation of the weight of the disks in animals receiving herbal compounds during the study period (in addition to eg administration) demonstrated a reduced (not significant) increase in these values after a 14-day follow-up (p = 0.001, table 1). evaluation of the increase in disc weights on a dose-dependent basis in different subgroups (from groups 3 to 7) demonstrated that the limitation of crystal deposition began to be more prominent as the dose of herbal compound increased. this effect was more evident particularly in comparisons between group 7 and others, according to lsd multiple comparison tests (p = 0.001) (table 1). effects of herbal compound application on urine parameters the mean urinary oxalate levels within groups 2, 3 to 7 were similar (p = 0.018, table 1) with no statistically significant difference between the groups from 2 to 7. only in group 1, the oxalate levels were lower than in the others. the difference was particularly prominent between groups 1 and 2 (p = 0.001). urinary calcium levels in animals of groups 2, 6, and 7 were significantly higher than the other groups as shown in table 1. we were not able to demonstrate a close correlation between urinary oxalate levels and the increasing dose levels. comparative evaluation of the mean urinary ph levels (table 1) showed that although it was significantly higher in group 3 animals (p = 0.026) during the 14-day evaluation, this finding has been accepted to be an isolated finding with no attributed correlation with herbal agent administration. crystals accumulated on the zinc disks were analyzed at the end of the trial and data revealed them to be composed of calcium oxalate in 17 and magnesium ammonium phosphate in 25 rats. effects of the compound on bladder inflammation following the two weeks of the trial period, the bladders were harvested and evaluated with respect to the possible histopathologic alterations. despite a mild degree increase in vascular congestion and edema formation in the animals of groups 4, 5, and 7, pathological evaluation findings revealed no significant difference regarding the presence as well as the extent of edema formation, vascular table 1. evaluation of laboratory findings. parameters oxalate (ng/l) ph calcium (mg/dl) zinc disc weights (mg) groups mean ± sd mean ± sd mean ± sd mean ± sd 1 (n = 6) control group ** 1111.63 ± 223.41 8.47 ± 0.1 2.57 ± 0.26 97.83 ± 2.93 2 (n = 6) 1533.73 ± 137.15 8.33 ± 0.2 4.17 ± 0.4 161.17 ± 11.86 3 (n = 6) 1401.22 ± 197.88 8.65 ± 0.19 2.72 ± 0.29 124.83 ± 10.3 4 (n = 6) 1293.33 ± 81.96 8.5 ± 0.33 3.08 ± 0.21 107 ± 1.9 5 (n = 6) 1381.73 ± 261.7 8.17 ± 0.49 1.68 ± 0.21 101 ± 2 6 (n = 6) 1348.02 ± 104.73 8.22 ± 0.17 4.88 ± 0.53 101 ± 4.6 7 (n = 6) 1419.82 ± 208.79 8.1 ± 0.37 4.23 ± 0.42 79.17 ± 2.4 p value 0.018 * 0.026 * 0.001 * 0.001 * * p: significant at 0.05 level. ** group 1 (control) is the one that had the zinc disc, but no eg (ethylene glycole) and no herbal compound. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 3 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. congestion, and inflammatory cell infiltration between the groups. additionally, no significant alteration was found to note with respect to the pathological changes in transitional epithelium like calcification, mitosis, fibrosis, dysplasia, or a number of epithelial cell layers. discussion prevention of new stone formation particularly in the risk group cases is the most important aim of the medical management for urolithiasis. despite minimally invasive treatment of urinary calculi with endoscopic/ureteroscopic treatment alternatives has gained more importance with their safe and practical characteristics, highly limited advancements have been achieved in the prevention of urinary stones, regarding the agents used with this aim, currently, potassium citrate, allopurinol, thiazide diuretics, and tiopronin are the most commonly applied ones depending on urinary ph and the chemical composition of the stone(s) treated. however, in addition to the ongoing controversies regarding the efficiency and optimal treatment duration of agents, certain side effects resulting in the discontinuation of the drug administration constituted another important limitation in decreasing the patient compliance rates, particularly during long-term follow-up. based on these facts, physicians began to consider phytotherapeutic agents, in other words, herbal compounds as a valuable option for the effective medical management of urinary stones. regarding the underlying pathogenetic mechanisms of calcium oxalate stone formation, accumulated information has clearly demonstrated that hyperoxaluria is one of the most important and crucial factors in this cascade. for that reason, eg is the most commonly used agent to induce hyperoxaluria status and form calcium oxalate crystals in animal models (17). however, some drawbacks have been stated for the use of this model regarding its detrimental effects like metabolic acidosis, cellular injury, and necrosis in tubular epithelial cells which will compromise interpretation of the real effects of either high oxalate levels or the crystals formed as a result of its application (20). in an attempt to reduce the urinary excretion of stone-forming risk factors as well as to inhibit the accumulation of stone crystals, certain herbal medications have been used in animal studies with a certain level of efficacy. with this aim, some experimental studies have pointed out that such herbal compounds could serve as an encouraging, efficient, and also safe alternative due to the limited toxic side effects observed with their application (21). this also emphasizes that phytotherapy can be used as a complementary or direct approach to decrease the established side effects of the commonly used treatment alternatives. literature-derived data show that these herbal compounds may exhibit anti-oxidant, diuretic, vasodilator, spasmolytic, nephroprotective, antibacterial, and anti-inflammatory effects (22-24). to augment such valuable effects some extra active ingredients like essential oils, flavonoids, saponins, xanthine derivatives, and glycosides are also added to these structural units (16). a variety of herbal agents including rubus idaeus (25), phyllanthus niruri (11), herniaria hirsute (22), alisma orientalis (23), and costus spiralis roscoe (24) have been applied with their proven effects of antiurolithiatic activity. although the precise underlying mechanisms causing these preventive effects have yet to be identified, some researchers have shown that these substances have an impact on the levels of oxalate, calcium, and malondialdehyde in the urine of animals who have stones (25). rubus idaeus (european raspberry) on this aspect was found to prevent renal tubular damage by limiting the formation of hyperoxaluria and also the accumulation of calcium oxalate crystals with reduced malondialdehyde excretion in urine. a tropical plant named phyllanthus niruri is known to limit the development of calcium crystals without changing the urinary magnesium or citrate levels. herniara hirsute, a flowering plant, is probably acting by dissolving the residual crystals deposited in the kidney (22). this plant extract decreases caox crystal binding to the tubular epithelium, without making any important difference in the urinary ph, volume, or chemistry. (26). alisma orientalis is known to inhibit stone formation steps like crystal formation, aggregation, and growth (23). the findings of these studies suggest well that these compounds can be efficiently used to inhibit urinary stone development and stone episodes even if the exact pathophysiology is not fully known. in one of these models, a herbal agent was applied to prevent the ethylene glycol-dependant apoptosis and calcium oxalate crystal accumulation in tubular cells of the kidney and it was found to be enough effective in this aspect (16). however, the administration of the compound in this study did not alter the urinary calcium and oxalate levels indicating that the inhibitory effect on stone development is independent of the urinary concentrations of these ions. in other words, obtained results suggested that factors other than calcium and oxalate may also play a role in the pathogenesis of urolithiasis. on the other hand, in addition to the levels of urinary stone-forming risk factors (calcium, oxalate, uric acid), urinary ph levels are also very important in stone formation. some researchers suggested that urinary ph levels in animal models can be changed between the range of 5.0 to 9.0 depending on dietary alterations (27). related to this issue, measured ph levels in this study varied between 7.5 and 9.0 with slightly increased levels reported in group 3 (table 1). additionally, no significant change was found to note with respect to the ph changes in other groups. in this study, we used a phytotherapeutic compound that was produced from fractions of a few different plant extracts. of these ingredients, extracts of opuntia ficus indica (28), rosmarinus officinales (29), and cynodon dactylon (13) have been found to exhibit potent inhibition of urinary stone growth. we evaluated its potential inhibitory effects on crystal formation in the rat model in a dosedependant-based manner and our results revealed that although animals receiving eg showed a significant increase in crystal formation around the zinc disc placed, no or limited change was noted in animals receiving the compound. in other words application of this agent seemed to be protective enough against new crystal formation. the herbal compound application was more effective at a dosage of 0.332 ml, 3 times a day in reducing the extent of crystal deposition in this animal model. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 4 archivio italiano di urologia e andrologia 2023; 95, 1 herbal compound on crystal formation in rat model although the exact mechanism of this litholytic effect is not clear, the excretion of oxalate and calcium seemed to have no role because no significant correlation was assessed. we believe that the potent antioxidant and antiinflammatory effects of this herbal medication, shown well in other studies, may be responsible for the limitation of crystal formation. lastly, pathological evaluation of the bladder tissue specimens revealed no significant difference regarding the presence of edema formation, vascular congestion, inflammatory cell infiltration, and pathological changes in transitional epithelium between the groups. in light of the published data so far in the literature and our current findings as well, we may claim that the abovementioned effects of the herbal medication could play a role also at the kidney level to limit the formation of crystals in the tubules. our study has certain limitations. first of all, the main disadvantage is gender singularity as the study was performed on male animals. regarding this issue, although relatively smaller-sized stones were formed in female rats than in the male ones in a study with a zinc disc model (19), the efficiency of the herbal treatments were found to be similar in both genders (24). on the other hand, spot urine samples were collected for analysis at the time of sacrification, instead of using a metabolic cage and collection of all excreted urine. however, human clinical studies have clearly shown that spot urine also may be useful enough for metabolic assessment (30). last but not least, after stone formation, a herbal compound application is used to prevent stone growth but not chemical dissolution. in conclusion, our current findings demonstrated evident crystal deposition on the surface of the zinc discs, due to the hyperoxaluria induced by ethylene glycol. the herbal compound administration was effective in reducing the extent of crystal deposition around the zinc discs and this effect was found to be the most prominent at a dosage of 0.332 ml, 3 times a day. although the probable mechanism of this litholytic effect is not clear, it was shown not to be related to the excretion of oxalate and calcium. the potent antioxidant, as well as anti-inflammatory effects of this herbal medication shown in other studies, may be responsible for the limitation of crystal formation. however, we believe that further studies are needed to outline the possible effects of the herbal compound on the limitation of new stone formation in humans. references 1. skolarikos a, straub m, knoll t et al. metabolic evaluation and recurrence prevention for urinary stone patients: eau guidelines. eur urol. 2015; 67:750-63. 2. dhondup t, kittanamongkolchai w, vaughan le et al. risk of esrd and mortality in kidney and bladder stone formers. am j kidney dis. 2018; 72:790-97. 3. zisman al. effectiveness of treatment modalities on kidney stone recurrence. clin j am soc nephrol. 2017; 12:1699-708. 4. mager r, neisius a. current concepts on the pathogenesis of urinary stones. urologe a. 2019; 58:1272-80. 5. shadman a, bastani b. kidney calculi: pathophysiology and as a systemic disorder. iran j kidney dis. 2017; 11:180-91. 6. huang hs, ma mc. high sodium-induced oxidative stress and poor anticrystallization defense aggravate calcium oxalate crystal formation in rat hyperoxaluric kidneys. plos one. 2015; 10. 7. naghii mr, jafari m, mofid m, et al. the efficacy of antioxidant therapy against oxidative stress and androgen rise in ethylene glycol induced nephrolithiasis in wistar rats. hum exp toxicol. 2015; 34:744-54. 8. monti e, trinchieri a, magri v, et al. herbal medicines for urinary stone treatment. a systematic review. arch ital urol androl. 2016; 88:38-46. 9. kasote dm, jagtap sd, thapa d, et al. herbal remedies for urinary stones used in india and china: a review. j ethnopharmacol. 2017; 203:55-68. 10. ardakani movaghati mr, yousefi m, saghebi sa, et al. efficacy of black seed (nigella sativa l.) on kidney stone dissolution: a randomized, double-blind, placebo-controlled, clinical trial. phytother res. 2019; 33:1404-12. 11. pucci nd, marchini gs, mazzucchi e, et al. effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention. int braz j urol. 2018; 44:758-64. 12. yousefi ghale-salimi m, eidi m, et al. antiurolithiatic effect of the taraxasterol on ethylene glycol induced kidney calculi in male rats. urolithiasis. 2018; 46:419-28. 13. golshan a, hayatdavoudi p, hadjzadeh ma-r, et al. kidney stone formation and antioxidant effects of cynodon dactylon decoction in male wistar rats. avicenna j phytomed. 7:180-90. 14. bahmani m, baharvand-ahmadi b, tajeddini p, et al. identification of medicinal plants for the treatment of kidney and urinary stones. j renal inj prev. 2016; 5:129-33. 15. nishihata m, kohjimoto y, hara i. effect of kampo extracts on urinary stone formation: an experimental investigation. int j urol. 2013; 20:1032-36. 16. yuruk e, tuken m, sahin c, et al. the protective effects of an herbal agent tutukon on ethylene glycol and zinc disk induced urolithiasis model in a rat model. urolithiasis. 2016; 44:501-07. 17. joshi s, wang w, khan sr. transcriptional study of hyperoxaluria and calcium oxalate nephrolithiasis in male rats: inflammatory changes are mainly associated with crystal deposition. plos one. 2017; 12. 18. khan sr, hackett rl. urolithogenesis of mixed foreign body stones. j urol. 1987; 138:1321-28. 19. prasad k v, bharathi k, srinivasan kk. evaluation of ammannia baccifera linn. for antiurolithic activity in albino rats. indian j exp biol. 1994; 32:311-13. 20. amoroso l, cocumelli c, bruni g, et al. ethylene glycol toxicity: a retrospective pathological study in cats. vet ital. 2017; 53:251-54. 21. posadzki p, watson lk, ernst e. adverse effects of herbal medicines: an overview of systematic reviews. clin med (lond). 2013; 13:7-12. 22. ammor k, bousta d, jennan s, et al. phytochemical screening, polyphenols content, antioxidant power, and antibacterial activity of herniaria hirsuta from morocco. scientific world journal. 2018; 2018:7470384. 23. zhao zy, zhang q, li yf, et al. optimization of ultrasound extraction of alisma orientalis polysaccharides by response surface methodology and their antioxidant activities. carbohydr polym. 2015; 119:101-09. 24. araújo viel t, diogo domingos c, da silva monteiro ap, et al. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 5 archivio italiano di urologia e andrologia 2023; 95, 1 r. güzel, i̇. bilger erïhan, i̇. özaydin, et al. evaluation of the antiurolithiatic activity of the extract of costus spiralis roscoe in rats. j ethnopharmacol. 1999; 66:193-98. 25. nirumand mc, hajialyani m, rahimi r, et al. dietary plants for the prevention and management of kidney stones: preclinical and clinical evidence and molecular mechanisms. int j mol sci. 2018; 19. 26. atmani f, farell g, lieske jc. extract from herniaria hirsuta coats calcium oxalate monohydrate crystals and blocks their adhesion to renal epithelial cells. j urol. 2004; 172:1510-14. 27. cohen sm. role of urinary physiology and chemistry in bladder carcinogenesis. food and chemical toxicology. 1995; 33:715-30. 28. partovi n, ebadzadeh mr, fatemi sj, khaksari m. effect of fruit extract on renal stone formation and kidney injury in rats. nat prod res. 2018; 32:1180-83. 29. naber kg. efficacy and safety of the phytotherapeutic drug canephron® n in prevention and treatment of urogenital and gestational disease: review of clinical experience in eastern europe and central asia. res rep urol. 2013; 5:39-46. 30. van huysduynen ejch, hulshof pjm, van lee l, et al. evaluation of using spot urine to replace 24 h urine sodium and potassium excretions. public health nutr. 2014; 17:2505-11. correspondence rasim güzel, md (corresponding author) rasimguzel@hotmail.com medistate kavacık hospital, department of urology, istanbul (turkey) i̇smet bilger erïhan, md, assistant professor drbilger@yahoo.com ümit yildirim, md, assistant professor dr.umityildirim87@gmail.com kafkas university, medical faculty, department of urology, 36000, kars (turkey) i̇sa özaydin, professor aras_isa@hotmail.com iozaydin@kafkas.edu.tr uğur aydin, assistant professor uguraydin076@hotmail.com kafkas university, veterinary faculty, department of surgery, 36000, kars (turkey) murat bağcioğlu, md, associate professor dr.muratbagcioglu@gmail.com bahçeşehir university, medical faculty, department of urology, 34100, istanbul (turkey) ramazan kocaaslan, md, associate professor ramizkoca@gmail.com konya training and research hospital, konya (turkey) kemal sarica, md, professor saricakemal@gmail.com biruni university, medical school, department of urology, istanbul (turkey) conflict of interest: the authors declare no potential conflict of interest. 11114 guzel_stesura seveso 23/03/23 12:24 pagina 6 stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12305 1 original paper early stage when they can be treated. however, about 25% of bcs are diagnosed at an advanced stage (2). the prognosis depends on many factors (1). sm survival varies significantly according to stage, in both non-invasive and invasive cases. the percentage of non-invasive cancers is relatively high. stage, age, and histology associated with survival (5). the probability of accumulated survival at the end of 1, 3, 5, and 10 years in patients with bc is 0.8989, 0.7132, 0.5752, and 0.2459, respectively. there are significant differences in survival rates between age groups and types of treatment (6). the stage and extent of the cancer are important factors in determining the best treatment for bc (7). continuity cancer survival is generally lower for residents of more socio-economically disadvantaged areas. socio-economic inequality decreases survival due to certain factors (8). in addition, health insurance is the determinant of patient treatment. the burden of cancer survival also affects healthcare systems and society (9). inhospital mortality can occur in patients with bc. the objective of this study was to determine the relationship between income, health insurance, and employment status as prognostic indicators of bladder cancer. materials and methods study design the largest tertiary referral hospital in east java, indonesia, dr. soetomo general academic hospital, carried out a retrospective observational study for patients with bladder cancer. hospitalized bc patients were the subject of the research, which ran for five years, from january 2019 to december 2023. adult bc patients were included, and patients with missing data met the exclusion criteria. the dr. soetomo general academic hospital's ethical review board granted approval for the research, which was carried out under the declaration of helsinki (approval number: 1527/ loe/ 301. 4. 2/ xi/ 2023). data collection the following socioeconomic data were extracted for analysis: income, employment status, and health insurance. patients were divided by income below 4 million rupiah or more than 4 million rupiah, according to the basic salary in background: bladder cancer (bc) is one of the health problems. socioeconomic status (ses) may correlate with patient treatment, possibly impacting patient prognosis. this study aimed to determine the relationship between income, health insurance, and employment status as prognostic indicators of bc. methods: a retrospective observational study for patients diagnosed with bc in a hospital during the 5-year period between january 2019 and december 2023. kaplan-meier test analysis was used to generate overall survival curves stratified by income, employment status, and health insurance. multivariate cox proportional-hazards regression was used to identify factors associated with worse overall survival. results: the results of the analysis on 219 patients showed no difference in patient survival based on income (p > 0.05), while employment status and health insurance showed significant difference in patient survival (p < 0.05). moreover, there were 99 (45.2%) patients died, with the average patient being 58 years old and dominant in male patients. conclusions: prevention of poor outcomes in patients needs to pay attention to certain characteristics, particularly for the loweconomic patients without appropriate national health insurance coverage. key words: bladder cancer; insurance; outcomes; income; employment. submitted 23 january 2024; accepted 3 february 2024 introduction bladder cancer (bc) is a neoplasm that arises from the bladder and is the most common type of urinary tract neoplasm (1). this cancer is included in one of the 10 most common cancers worldwide and has a high mortality rate (2). bc accounts for 3% of global cancer diagnoses and is particularly common in developed countries. this case is mainly found in people aged 55 years, who are found in as many as 90% of diagnoses, and the disease is four times more common in men than women (3). the incidence rate is twice as high in developing countries than in developed countries (1). treatment of bladder cancer tends to be significant and expensive (4). diagnosis relies mainly on cystoscopy, an invasive and costly procedure. most bcs are diagnosed at an the relationship between income, health insurance, and employment status as prognostic indicators of bladder cancer: a survival analysis wahjoe djatisoesanto 1, 2, yufi aulia azmi 1, 2, 3, ida bagus gde tirta yoga yatindra 1, 2 1 department of urology, faculty of medicine, universitas airlangga; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia; 3 department of health sciences, university of groningen, university medical center groningen, groningen, the netherlands. doi: 10.4081/aiua.2024.12305 summary archivio italiano di urologia e andrologia 2024; 96(1):12305 w. djatisoesanto, y. aulia azmi, i. bagus gde tirta yoga yatindra 2 indonesia. they were divided by type of health insurance as patients with national health insurance (jaminan kesehatan nasional/jkn) or private insurance. mortality in this insurance system was defined as death during the hospital stay. statistical analysis survival analysis was done for patients whose income, work status, and health insurance were known. time in months from diagnosis to death from any cause was the primary outcome. for every variable, descriptive epidemiological and survival statistics were computed. the overall survival curves were stratified by income, job status, and health insurance using kaplan-meier test analysis. log-rank tests were used to analyze survival differences. to find the variables linked to a lower overall survival rate, multivariate cox proportional-hazards regression was used. hazard ratios (hr) and accompanying 95% confidence intervals (ci) were utilized. we also analyzed the regression to predict sepsis and metastases as strata. the criterion for statistical significance was fixed at p < 0.05. the statistical studies were conducted using ibm corp.'s spss 25 program in armonk, ny. results there were 99 (45.2%) patients who died. results show that the average patient is 58 years old with prevalence of male patients. our analysis shows that the characteristics of income below 4 million rupiah and education level have significant impact in mortality rates. sociodemographic characteristics are shown in table 1. the results of the socio-economic status (ses) data assessment show that most patients have an income of more than 4 million rupiahs every month. more than half of the respondents were employed. most have health coverage. ses data are shown in table 2. based on the results of survival analysis using kaplan meier (log-rank), there was no difference in patient survival based on income (p > 0.05) (figure 1), while there was a difference in patient survival based on employment status and health insurance (p < 0.05) (figures 2, 3). table 1. socioeconomic status. component n % p race javanese 164 74.9 0.253 madurese 50 22.8 chinese 5 2.3 income ≥ 4 million rupiah 192 87.7 < 0.001 < 4 million rupiah 27 12.3 employment status yes 113 51.6 0.013 no 106 48.4 farmer yes 21 10.6 0.002 no 198 89.4 location urban 52 23.7 0.812 rural 167 76.3 health insurance national insurance 174 79.5 0.827 private insurance 45 20.5 education educated 177 80.8 < 0.001 non-educated 42 19.2 figure 1. survival analysis of bladder cancer patients with different income. archivio italiano di urologia e andrologia 2024; 96(1):12305 3 prognostic indicators of bladder cancer discussion the results showed that there was no difference in patient survival based on income, while, there were differences in patient survival based on employment status and health insurance. previous research has found relationship between socioeconomic status and survival, although socioeconomic assessments were carried out with different standards (10). other studies have found that cancer survival is often poorer among people from more socioeconomically disadvantaged areas. for tumors of connective/soft tissue, bladder, and unknown primary origin, socioeconomic differences in survival decrease with increasing age at diagnosis (8). in addition, health insurance is the determinant of patient treatment. finally, the burden of cancer survival also affects healthcare systems and society (9). figure 2. survival analysis of bladder cancer patients with different employment status. figure 3. survival analysis of bladder cancer patients within different health insurance. archivio italiano di urologia e andrologia 2024; 96(1):12305 w. djatisoesanto, y. aulia azmi, i. bagus gde tirta yoga yatindra 4 taylor et al. discovered that characteristics related with a greater chance of bladder cancer presenting at an advanced stage compared to early stages were race, ethnicity, gender, insurance status, one or more comorbidities, and a median household income of less than $63,000 (11). other researchs have found that lower ses, medicaid insurance, and no insurance all resulted in a higher tumor stage. regardless of the stage of the tumor, poorer ses, having medicaid insurance, and no insurance linked to worse overall survival (os) and disease specific survival (dss) (12). worse overall survival is related to male gender and significant prognostic factors of overall survival include gender (13). other studies found that women's risk levels were significantly higher than men's for up to two years after a bladder cancer diagnosis, especially for muscleinvasive cancers. the common belief that the prognosis for bladder cancer is poorer in women compared to men must be reconsidered (14). in indonesia, national health insurance (nhi) significantly enhances public health and offers low-income households access to care. nonetheless, nhi coverage below the federal minimum or the government's guidelines may affect health at all phases and developments. the growth and development of stunted children, immunization rates, and the quality of life for those with non-communicable illnesses may all be negatively impacted by low nhi coverage. moreover, health insurance is less common among rural homes. the main criterion for eligibility for indonesia's subsidized and contributory programs is that participants must be employed and live in java or bali. low coverage may also be due to the cost of traveling to the health insurance office (15). this burden should be evenly distributed across stakeholders considered in the evaluation of the cost-effectiveness of new anti-cancer drugs (9). patient survival rates can be enhanced through strategic planning for early detection and screening, as well as proper access to appropriate diagnostic and treatment services, particularly in men, considering the significant influence on disease stage at diagnosis (16). conclusions there is no difference in patient survival based on income, while there are differences in patient survival based on employment status and health insurance. health insurance and employment status, specifically being a farmer, might affect the mortality outcomes significantly. ethical approval the dr. soetomo general academic hospital’s ethical review board grants approval for this research carried out under the declaration of helsinki (approval number: 1527/loe/301. 4. 2/xi/ 2023). references 1. kaseb h, nr. a. bladder cancer. in: statpearls [internet]. treasure island (fl): statpearls publishing. 2023. 2. iarc. bladder cancer. 2023; available from: https://www.iarc.who. int/cancer-type/bladder-cancer/ 3. saginala k, barsouk a, aluru js, et al. epidemiology of bladder cancer. med sci. 2020; 8:15. 4. cumberbatch mgk, noon ap. eau on behalf of the young academic urologistsurothelial cancer working party. epidemiology, aetiology and screening of bladder cancer. transl androl urol 2019; 8:5-11. 5. ripoll j, ramos m, montaño j, et al. cancer-specific survival by stage of bladder cancer and factors collected by mallorca cancer registry associated to survival. bmc cancer 2021; 21:676. 6. rezaianzadeh a, mohammadbeigi a, mobaleghi j, mohammadsalehi n. survival analysis of patients with bladder cancer, life table approach. j midlife health. 2012; 3:88-92. 7. bethesda (md): national cancer institute (us). pdq cancer information summaries: bladder cancer treatment: patient version. 2023; available from: https://www.ncbi.nlm.nih.gov/ books/nbk66044/ 8. afshar n, english dr, blakely t, et al. differences in cancer survival by area-level socio-economic disadvantage: a population-based study using cancer registry data. plos one 2020; 15:e0228551. 9. michaeli jc, boch t, albers s, et al. socio-economic burden of disease: survivorship costs for bladder cancer. j cancer policy 2022; 32:100326. 10. russell b, häggström c, holmberg l, et al. systematic review of the association between socioeconomic status and bladder cancer survival with hospital type, comorbidities, and treatment delay as mediators. bjui compass. 2021; 2:140-58. 11. taylor a, gallegos jm, verplancke k, et al. socioeconomic factors associated with stages of bladder cancer at diagnosis: analysis of the national cancer database. j clin oncol 2022; 40(16_suppl):e16531e16531. 12. nazemi a, ghodoussipour s, pearce s, et al. socioeconomic and insurance status are independent prognostic indicators of higher disease stage and worse prognosis in bladder cancer. urol oncol semin orig investig 2019; 37:784-90. 13. fang w, yang zy, chen ty, et al. ethnicity and survival in bladder cancer: a population-based study based on the seer database. j transl med 2020; 18:145. 14. andreassen bk, grimsrud tk, haug es. bladder cancer survival: women better off in the long run. eur j cancer 2018; 95:52-8. 15. sukartini t, arifin h, kurniawati y, et al. factors associated with national health insurance coverage in indonesia. f1000res. 2021; 10:563. 16. amiri m, heshmatollah s, esmaeilnasab n, et al. survival rate of patients with bladder cancer and its related factors in kurdistan province (2013-2018): a population-based study. bmc urol 2020; 20:1-9. correspondence wahjoe djatisoesanto wahjoe.djatisoesanto@fk.unair.ac.id yufi aulia azmi y.aulia.azmi@umcg.nl, yufiazmi@gmail.com ida bagus gde tirta yoga yatindra tirtayogastudi@gmail.com department of urology, faculty of medicine, airlangga university, soetomo general academic hospital jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 7 original paper introduction bladder cancer is the 13th most common cancer worldwide when both sexes are considered. if only the male population is taken into account, the incidence rises to sixth place with a mortality rate of 3.3 per 100.000 population (1). however, cancer incidence is about four times lower in women than in men (2). nevertheless, female gender is an independent risk factor for the disease, which is associated with a higher stage at diagnosis (3). radical cystectomy with urinary diversion and possibly neoadjuvant chemotherapy is the treatment of choice for patients with muscle-invasive bladder cancer or high-risk non-muscleinvasive bladder cancer. in men, this involves removal of the bladder, prostate, seminal vesicles and loco-regional lymph nodes. in women, it is a true anterior pelvic exenteration with removal of the bladder, urethra, uterus, ovaries, adnexa, anterior wall of the vagina and locoregional lymph nodes (4). this surgery has a detrimental effect on both the quality of life and the psychology of the patient, and many high-volume centers have considered it being less disruptive for female patients, especially in the pre-menopausal phase (5). initially, cystectomy with urethral sparing and urinary diversion was performed, but nowadays selected patients undergo cystectomy with genital sparing, which can preserve fertility and a sexually active life (6). in this article we describe our genital organ preservation technique and examine the oncological and functional results at 56 months of follow-up. materials and methods between january 2014 and january 2018, 14 female patients were admitted to the urology department of the irccs casa sollievo della sofferenza foundation in san giovanni rotondo. all patients underwent radical cystectointroduction and objectives: the aim of the study was to evaluate genital sparing radical cystectomy surgery in female patients from the point of view of both oncologic and functional outcomes (with emphasis on urinary and sexual outcomes) in a single high-volume center for the treatment of muscular invasive bladder cancer. materials and methods: between january 2014 and january 2018, 14 female patients underwent radical cystectomy with preservation of genital organs (the entire vagina, uterus, fallopian tubes, ovaries) and orthotopic urinary neobladder (padua neobladder). inclusion criteria were recurrent t1g3 tumors; refractory tumors after bcg therapy without associated carcinoma in situ (cis); t2 or t3a tumors entirely resected at endoscopic transurethral resection of the bladder and not involving urethra/bladder trigone. exclusion criteria were: t3b or higher bladder cancer, associated cis and involvement of urethra or bladder trigone. oncological and histopathological outcomes (overall survival os, recurrence free survival rfs), urinary outcomes (day and night incontinence, intermittent catheterization use, sandvik score) and sexual outcomes (female sexual function index 19 fsfi-19) were considered. the average follow-up time was 56 months. results: considering oncological outcomes, histologic examination reported urothelial carcinoma in 13/14 patients; 8/13 patients (61.5%) had high grade t1 stage, 3/13 patients (23%) had high grade t2 stage and finally 2/13 patients (15.5%) had high-grade t3 stage. one patient presented with embryonal rhabdomyosarcoma completely excised after surgery (pt2an0m0). no patient developed local or metastatic recurrence (rfs 100%); os was 100%. considering urinary continence outcomes, 12/14 patients retained daytime and nighttime continence (85.5%); 2/14 (14.5%) complained of low stress urinary incontinence daily and nighttime urinary leakage. the sandvik score showed complete continence in 7/14 patients (50%); mild degree incontinence in 6/14 patients without use of incontinence devices (43%); moderate degree of incontinence in one patient (7%). the fsfi administered at 1 year from the surgery showed sexual desire in all patients (100%); subjective arousal, achievement of orgasm and sexual satisfaction in 12/14 patients (85.5%); sufficient lubrication in 11/14 patients (78.5%). only one patient (7%) complained about dyspareunia during sexual intercourse. conclusions: our study aims to demonstrate that genital-sparing radical cystectomy is a safe surgery in terms of oncologic outcomes and, most importantly, that it is beneficial in terms of urinary and sexual function. indeed, patients’ quality of life together with their psychological and emotional health should be put on the same level as oncological safety. however, it is a new concept in urologic surgery: the total extended genital sparing radical cystectomy in women antonio cisternino, lorenzo capone, antonio rosati, costanzo latiano, nicola sebastio, antonio colella, giuseppe cretì department of urology, fondazione irccs casa sollievo della sofferenza, san giovanni rotondo, italy. doi: 10.4081/aiua.2023.11058 summary treatment reserved for selected patients who are strongly motivated to preserve fertility and sexual function and thoroughly informed about the benefits and complications of such a procedure. key words: muscle-invasive bladder cancer; high risk non-muscle invasive bladder cancer; total extended genital sparing; oncologic outcomes; sexual life; post-operative continence; quality of life. submitted 4 december 2022; accepted 20 december 2022 archivio italiano di urologia e andrologia 2023; 95, 2 a. cisternino, l. capone, a. rosati, c. latiano, n. sebastio, a. colella, g. cretì 8 my and bilateral pelvic lymphadenectomy with preservation of genitalia (vagina, uterus, fallopian tubes and ovaries) and orthotopic urinary diversion. prior to surgery, they were carefully counseled about the procedure, possible long-term and short-term complications, and finally signed an informed consent. in accordance with the most recent guidelines, we placed as inclusion criteria for surgery: recurrent high-grade t1 tumors, tumors relapsed after bcg therapy without the presence of concomitant carcinoma in situ (cis), t2 and t3a tumors completely excised at endoscopic transurethral resection of the bladder (turb) and not involving the urethra or bladder trigone. all patients were sexually active and were younger than 65 years of age. before surgery, each patient was evaluated by accurate clinical history (with special attention to urinary and sexual function), physical examination, complete abdominal ultrasound, cystoscopy, and bladder biopsy in order to exclude cis or concomitant dysplasia; they also had gynecological examination to exclude tumors or papilloma of the cervix, uterus, or ovaries. finally, all patients were staged by abdominal and pelvic ct with contrast and sequential bone scintigraphy to exclude extension to the peri-vesical fat (t3b), lymph nodes, and/or adjacent organs (t4). exclusion criteria were bladder cancer t3b or higher, concomitant cis, and urethral and/or trigone involvement. all patients had bowel preparation and antibiotic prophylaxis the day before surgery. surgical open technique patients were placed in the trendelenburg supine position with pelvic hyperextension. an incision was made on the midline from the pubis to the umbilicus, after dividing the muscular-aponeurotic planes, the peritoneal sac was opened. lysis of any bowel-omental adhesions was performed, and the bowel was cranially dislocated to expose the pelvis. the bladder was then mobilized to the lateral walls of the pelvis. the residual urachus was circumscribed – paying attention not to injure the lower epigastric vessels –, to be removed with the entire bladder. a careful and systematic examination was carried out to determine the extent of the disease and the possible presence of metastases or massive retroperitoneal lymphadenopathy. at this point the bowel was mobilized from the ascending colon, which was moved medially to gain access to the right ureter. the mesentery was reversed until the retroperitoneal part of the duodenum was exposed. the left colon and sigmoid were then mobilized to the inferior pole of the left kidney to give access to the left ureter. the ureters were then isolated at their entrance to the bladder, were they were ligated and dissected. to exclude neoplastic involvement, the distal margin was sent for extemporaneous histopathology. the umbilical, uterine, superior, and inferior bladder arteries were carefully dissected bilaterally. the bladder was mobilized and the junction between the cervix and the anterior wall of the vagina was identified along the anterior wall of the uterus. the vaginal wall was then dissected at the level of the anteroventral plane of the vagina, at 2 o'clock and 10 o'clock, as close as possible to the bladder wall, in order to preserve the paravaginal tissues containing the autonomic nerves that reach the proximal sphincter. the superior and inferior bladder arteries were dissected at their origin, at the level of the hypogastric arteries, while the uterine arteries and vaginal branches to the paravaginal tissues were spared. once the retropubic space was created and opened, the endopelvic fascia was incised very close to the bladder neck to reduce the risk of inadvertent injury to the paraurethral neurovascular structures, which are crucial for sexual function and continence (figures 1, 2). the urethra was carefully prepared, exposed and divided, and a specimen was sent for extemporaneous histopathological examination (figure 3). at this time, careful dissection of the retroperitoneal lymph nodes was performed. the margins of the resection were cranially defined by the common iliac artery, figure 1. development of the plane between uterus and bladder. figure 2. genital sparing cystectomy with sparing of the uterus, ovaries, tubes and vagina. archivio italiano di urologia e andrologia 2023; 95, 2 9 total extended genital sparing radical cystectomy in female patients laterally by the genito-femoral nerves, inferiorly by the cooper's ligament, caudally by the obturator canal, medially and laterally by the hypogastric vessels. mini-invasive technique out of the 14 patients who underwent radical cystectomy with genital sparing, 3 underwent removal of the bladder using the robot-assisted laparoscopic technique with the da vinci robot (ab medica). during the procedure, patients were placed in the supine position with abducted lower limbs. a catheter was placed. this was followed by a supraumbilical skin incision to access to the abdomen using the hasson open technique, opening of the peritoneum under direct vision, positioning of the first optical trocar and induction of pneumoperitoneum at 12 mmhg. patients were placed in trendelenburg position (> 25°), and the peritoneal cavity and viscera were inspected to exclude adhesions or metastatic pathology. two additional 8 mm robotic surgical ports were placed approximately 8 cm from the optical trocar, 2 cm lateral to the rectus abdominis muscle, at the level of the inferior border of the umbilicus. two further laparoscopic ports were introduced, one 12 mm, 5 cm above the anterior superior iliac spine, on the right mid-axillary line for the surgical tractions; another 5 mm, approximately 2.5 cm above the right robotic ports for the surgical aspirator. finally, the robot was docked with monopolar curved scissors on the right and bipolar prograsp forceps on the left. the steps for radical cystectomy were the same as for open surgery. at the end of the robotic procedure, a suprapubic pfannenstiel incision was made, the surgical piece previously placed in the endobag was removed and finally the orthotopic urinary diversion was packed. orthotopic neobladder at a distance of 15-20 cm from the ileocecal valve, a 40 cm ileal segment is isolated. intestinal continuity is restored with a latero-lateral anastomosis. mechanical sutures are used. the distal loop (approximately 20 cm in length) is lowered to form a 'u' to reach the membranous urethra. the ileal segment is then opened along the antimesenteric border. a 3/0 v-loc suture is used to tunnel the lower part of the ileal loop posteriorly and anteriorly. the proximal loop is folded medially into an inverted u-shape and the opposite inner edges are then sutured from side to side to form an upper ileal cup. this is then inverted at the edges of the lower ileal pouch to create an oval reservoir. the urethro-intestinal anastomosis is packed with 6 detached stitches of resorbable 3/0 glyconate monofilament suture on a 20-ch 3-way neobladder catheter. the uretero-neovesical anastomosis is then exteriorized at the level of the left iliac fossa using bracci ureteral catheters as a guide. a hydraulic leak test of the neobladder is performed and a 24 c tube drain is placed in the retzius excavation at the level of the right iliac fossa. finally, the abdominal wall is closed in layers (figure 4). post-operative assessment patients were evaluated according to age, body mass index (bmi), american society of anesthesiology (asa) score, preoperatively measured hemoglobin and creatinine. surgical outcomes were operative time, discharge hemoglobin and creatinine, days in hospital and perioperative complications in accordance with the clavien-dindo classification system (7). patients were functionally and oncologically followed by outpatient visits quarterly in the first year and biannually thereafter with a program including blood tests, abdominal ultrasound, urine cytology, abdominal and pelvic ct, urethrocystoscopy and chest x-ray. the study evaluated the following oncological outcomes: recurrence free survival (rfs local or metastatic) figure 3. preparation of the urethra. figure 4. final configuration of the neobladder. archivio italiano di urologia e andrologia 2023; 95, 2 a. cisternino, l. capone, a. rosati, c. latiano, n. sebastio, a. colella, g. cretì 10 and overall survival (os) both measured at more than 56 months of follow-up and finally anatomopathological outcomes. in terms of functional outcomes, sexual function was measured using a standardized questionnaire: the female sexual function index (fsfi-19) (8). this is a quick and effective questionnaire that structures female sexual function into 6 different aspects: desire, subjective arousal, lubrication, orgasm, satisfaction, and pain, with a score ranging from a minimum of 2 to a maximum of 36. we administered it both 3 and 12 months after surgery. urinary function was evaluated by the patient's level of continence (day and night) and the use of urinary incontinence devices; the severity of urinary leakage was calculated using the sandvik score (9). finally, urinary retention requiring intermittent urethral catheterization was assessed. results the mean age of the 14 patients who underwent genital sparing radical cystectomy was 57.6 years (range 30-65). the preoperative clinicopathological characteristics of the patients are shown in table 1. regarding surgical outcomes (table 2), the mean operative time for the entire procedure, including cystectomy, bilateral pelvic lymphadenectomy and neobladder reconstruction, was 260 minutes (range 220-396 minutes) for the open procedure and 318 minutes (range 258-432 minutes) for the robotic one. the mean blood loss during surgery was 400 ml (230-710 ml). patients' mean hospital stay was 18 days (15-24 days), and discharge hemoglobin and serum creatinine were 9.3 g/dl (8.9-14.8 g/dl) and 1.2 mg/dl (0.8-1.6 mg/dl), respectively. perioperative complications such as loss of ileo-ileal anastomotic seal, bleeding, or loss of neobladder seal were not observed in any of the patients. none of the patients had complications requiring surgery (grade ≥ 3 according to the clavien-dindo classification of postoperative complications); only one patient had postoperative acute pancreatitis, which was successfully treated with medical therapy. final histopathological examination revealed urothelial carcinoma in 13 patients, of which 8/13 (61.5%) had low grade t1 stage, 3/13 (23%) had high grade t2 stage and, finally, 2 (15.5%) had high grade t3 stage. botryoid variant embryonal rhabdomyosarcoma localized to the bladder and completely excised after surgery (pt2an0m0) was found in one patient at final histopathological examtable 1. patient characteristics. patient characteristics mean (range) age (years) 57.6 (30-65) body mass index 26.1 (20-30.5) preoperative creatinine (mg/dl) 0.86 (0.72-1.1) preoperative hemoglobine (g/dl) 12.7 (11.2-14.3) no. of patients (%) status married 13 (93) unmarried 1 (7) menopause premenopausal 6 (43) postmenopausal 8 (57) asa score i 8 (57) ii 6 (43) previous abdominal surgery cesarean section 1 (7) appendicectomy open 1 (7) location of the tumor posterior wall 6 (43) anterior wall 1 (7) lateral wall 6 (43) dome of the bladder 1 (7) pathological type urothelial carcinoma 13 (93) other (embryonal rhabdomyosarcoma) 1 (7) grading of the tumor low grade 0 (0) high grade 14 (100) staging tnm t1 n0 m0 8 (57) t2 n0 m0 4 (29) t3 n0 m0 2 (14) table 2. surgical and oncologic outcomes. surgical and oncologic outcomes mean (range) operative time (min) open 260 (220-396) robot-assisted 318 (258-432) mean blood loss (ml) 400 (230-710) hospital stay (days) 18 (15-24) postoperative creatinine (mg/dl) 1.2 (0.8-1.6) postoperative hemoglobine (gr/dl) 9.3 (8.9-14.8) no. of patients (%) complications clavien low grade (0-2) 14 (100) clavien high grade (3-5) 0 (0) cystectomy robotic-assisted cistectomy 3 (21) open cystectomy 11 (79) postoperative pathologic stage ta, tis, t1 8 (57.5) t2an0m0 1 (7) t2bn0m0 3 (21.5) t3an0m0 1 (7) t3bn0m0 1 (7) t4 0 (0) pathologic nodal stage n0 14 (100) n+ 0 (0) tumor grading low grade 0 (0) high grade 14 (100) positive surgical margins 0 (0) follow-up 12 months recurrence-free survival 14 (100) overall survival 14 (100) follow-up 24 months recurrence-free survival 14 (100) overall survival 14 (100) follow-up 36 months recurrence-free survival 14 (100) overall survival 14 (100) archivio italiano di urologia e andrologia 2023; 95, 2 11 total extended genital sparing radical cystectomy in female patients ination. resection margins were free of neoplastic pathology in all patients, and all resected lymph nodes were free of tumor pathology. all patients were followed for at least 56 months. during this period, no patient developed local recurrence (urethral and/or neovesical) or metastatic recurrence (rfs 100%) with a 100 % os. the oncological findings are presented in table 2. out of the 14 patients, 12 (85.5%) maintained complete continence both during the day and at night, 2 (15.5%) complained about urine leakage at night, and only 1 required the use of 1-2 pads. the sandvik score showed a state of complete continence in 7 patients (50%), mild incontinence in 6 patients (43%) without the use of urinary incontinence devices, moderate incontinence in 1 patient (7%) with the use of 1-2 pads during the night. only one patient developed urethral-neovesical stenosis after 6 months, which was treated by endoscopic surgery. during the follow-up period, no patient developed hydronephrosis, urethro-neovesical reflux or deterioration of renal function. of the 14 patients who underwent surgery, 13 (93%) were married, 1 was single (7%) but had a stable partner; 6 women (43%) were fertile at the time of surgery, while the other 8 (57%) were already menopausal; all patients were sexually active. as mentioned above, sexual function was assessed using the fsfi-19. this was administered 3 months and 1 year after surgery. one year postoperatively, fsfi showed sexual desire in all patients (100%); subjective arousal, orgasmic attainment and sexual satisfaction in 12/14 patients (85.5%); sufficient lubrication in 11/14 patients (78.5%). dyspareunia during intercourse was reported by only one patient (7%). one year after surgery, all patients were sexually active. finally, when we compared patients' test scores at 3 months and 12 months postoperatively, we found that all patients had higher final test scores after one year, due to improved sexual comfort. these data were also in line with the findings of the outpatient survey (total fsfi 3 months 18.3, range 15-21; total fsfi 12 months: 29.1, range 25-33). functional outcomes are shown in table 3. discussion for more than half a century, radical cystectomy has globally been the procedure of choice for all male and female patients with muscle-invasive bladder cancer or high-risk non-invasive bladder cancer. however, it is an invasive procedure whose main target was, and still is, oncological radicality, aimed to improve the prognosis of patients, which is already poor (5-year survival rate of 63% in stage ii patients and 48% in stage iii patients) (10). at the same time, an attempt was made to mitigate the clinical and psychological consequences to which a patient undergoing radical cystectomy was subjected by reconstructing the lower urinary tract and in particular by orthotopic urinary diversions. nowadays, there is also an increasing focus on the patient's quality of life, and minimally invasive surgical techniques or the search for organ-sparing techniques are a direct consequence of this (11, 12). female gender is considered a protective factor in the epidemiology of many oncological diseases, but this is not the case for bladder cancer where being female means not only having a higher risk of cancer-specific mortality than men, but it is also considered an independent risk factor for bladder cancer-specific death (13, 14). the causes of this universally accepted statistic have been investigated in the underestimation of hematuria due to a false diagnosis of cystitis rather than bladder cancer, resulting in the absence of more accurate examinations (15). another cause is to be identified in anatomy: in women there is no natural anatomical barrier between the bladder and the uterus capable of preventing extraorgan invasion of the bladder tumor, thus leading to a higher rate of diagnosis of advanced-stage tumors (16). for these reasons, radical cystectomy in women with orthotopic urinary diversion developed later than in men (it was only in the early 2000s that the genital organ-sparing cystectomies were performed in women). numerous studies have been conducted to assess the oncological feasibility of sparing first the urethra, then the vagina and finally the genital organs in toto. ali-el-dein et al. in a 1999 study were among the first to show that sparing the urethra and making a neobladder was oncologically safe (17). he again reviewed 609 cystectomy patients for bladder cancer in 2004 and reported a 2.6% incidence of secondary genital co-invasion and a 0% incidence of primary genital cancer (18). groutz et al. in a 1999 study performed 37 radical cystectomies and found genital organ involvement in only one patient (19). in a more recent study in 2019 huang and colleagues showed out of 112 radical cystectomies the presence of uterine invasion in only 5 patients (4.5%) (20). in our institution, we developed a technique with the aim of respecting oncological radicality and totally sparing the genital organs. the diversion used was the padua neobladder because of its favorable urodynamic characteristics (adequate compliance and low pressures) and the use of a relatively short ileum segment. during genital organ sparing, we took special attention to sparing the neurovascular bundles along the lateral wall of the vagina with the aim of preserving not only the patients' fertility but also their sexual function. on the oncological side, none of our patients had genital organ recurrence or lymph node and/or extra lymph node metastases. in table 3. functional outcomes. functional outcomes no of patients (%) continence day-time 14 (100) night-time 12 (85.5) sandvik score 0 (continent) 7 (50) 1-2 (mild incontinence) 6 (43) 3-6 (moderate incontinence) 1 (7) 8-9 (severe incontinence) 0 (0) 12 (very severe incontinence) 0 (0) neobladder complications uretral stricture 1 (7) female sexual function index (fsfi) at 12 months sexual desire 14 (100) sexual arousal 12 (85.5) lubrication 11 (78.5) orgasm 12 (85.5) satisfaction 12 (85.5) pain 1 (7) archivio italiano di urologia e andrologia 2023; 95, 2 a. cisternino, l. capone, a. rosati, c. latiano, n. sebastio, a. colella, g. cretì 12 terms of continence and sexuality, we have had satisfactory results about daytime and nocturnal continence as well as the fertility and sexuality of the patients. as far as complications, except for a single episode of urethral stenosis resolved by surgery, no patient developed prolapse, fistulas between the neobladder and vagina, or alteration of the upper urinary tract. the results of our study, in line with the literature, show that a total extended genital sparing radical cystectomy with sparing of the neurovascular bundle and the pubo-urethral ligaments strongly reduces the risk of vaginal fistulas, pelvic prolapse, neobladder prolapse secondary to an angulation of the uretero-intestinal anastomosis through the anterior wall of the vagina, and chronic urinary retention (21-23). above all, it allows maintenance of good continence, satisfactory sexual function and not least the maintenance of fertility. in fact, in their papers, both ali-el-dein et al. and niver et al. described a patient who became pregnant after the surgery, one of whom was also able to have a child (24, 25). finally, an interesting 2005 case report by puppo et al. presented a patient with cystocele and stress incontinence secondary to subtotal hysterectomy. the patient underwent radical cystectomy with ileal reservoir followed by reconstruction of pelvic floor integrity by colposacropxy using mesh. the hysterectomy with vaginal sparing and fixation of vaginal wall to adjacent structures or sacropexy may be a valid solution both oncologically and functionally. nevertheless, from our point of view, anatomical support to the neobladder secondary to genital sparing, preservation of the neurovascular bundle, and maintenance of fertility are to be pursued in highly motivated and selected patients (26). conclusions total extended genital sparing cystectomy appears to be a safe treatment for high-risk non-muscle invasive or muscle invasive bladder cancer in terms of oncological radicality and it is also beneficial in terms of urinary continence, fertility and sexual function, quality of life and psychological and emotional health. however, it is a treatment that should be reserved for carefully selected patients who are highly motivated by the preservation of fertility and sexual function and who are fully informed about the advantages and disadvantages of this procedure. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021; 71:209-249. 2. ferlay j, colombet m, soerjomataram i, et al. cancer statistics for the year 2020: an overview. int j cancer. 2021. 3. scosyrev e, noyes k, feng c, messing e. sex and racial differences in bladder cancer presentation and mortality in the us. cancer. 2009; 115:68-74. 4. babjuk m, burger m, compérat e, et al. guidelines on non-muscle-invasive bladder cancer (ta, t1 and cis). eau guidelines office, 2022. european association of urology guidelines office arnhem, the netherlands. 5. varkarakis im, pinggera g, antoniou n, et al. pathological review of internal genitalia after anterior exenteration for bladder cancer in women. evaluating risk factors for female organ involvement. int urol nephrol. 2007; 39:1015-1021. 6. kulkarni jn, rizvi sj, acharya up, et al. gynecologic-tract sparing extra peritoneal retrograde radical cystectomy with neobladder. int braz j uro. 2008; 34:180-7. 7. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 8. rosen r, brown c, heiman j, et al. the female sexual function index (fsfi): a multidimensional self-report instrument for the assessment of female sexual function. j sex marital ther. 2000; 26:191-208. 9. sandvik h, seim a, vanvik a, hunskaar s. a severity index for epidemiological surveys of female urinary incontinence: comparison with 48-hour pad-weighing tests. neurourol urodyn. 2000; 19:137-45. 10. witjes ja, bruins hm, carrión a, et al. eau guidelines on muscle-invasive and metastatic bladder cancer 2022. edn. presented at the 37th eau annual congress amsterdam. european association of urology guidelines office arnhem, the netherlands. 11, tang k, li h, xia d, et al. laparoscopic versus open radical cystectomy in bladder cancer: a systematic review and meta-analysis of comparative studies. plos one. 2014; 9:e95667. 12. kalampokis n, grivas n, ölschläger m, et al. radical cystectomy in female patients improving outcomes. curr urol rep. 2019; 20:83. 13. kluth la, rieken m, xylinas e, et al. gender-specific differences in clinicopathologic outcomes following radical cystectomy: an international multi-institutional study of more than 8000 patients. eur urol. 2014; 66:913-9. 14. messer jc, shariat sf, dinney cp, et al. female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis. urology. 2014; 83:863-7. 15. cohn ja, vekhter b, lyttle c, et al. sex disparities in diagnosis of bladder cancer after initial presentation with hematuria: a nationwide claims-based investigation. cancer. 2014; 120:555-61. 16. weissbart sj, smith al. hysterectomy in the urologist's practice. curr urol rep. 2017; 18:4. 17. ali-el-dein b, el-sobky e, hohenfellner m, ghoneim ma. orthotopic bladder substitution in women: functional evaluation. j urol. 1999; 161:1875-80. 18. ali-el-dein b, abdel-latif m, mosbah a, et al. secondary malignant involvement of gynecological organs at radical cystectomy specimens in women: is it mandatory to remove these organs routinely? j urol. 2004; 172:885-7. 19. groutz a, gillon g, konichezky m, et al. involvement of internal genitalia in female patients undergoing radical cystectomy for bladder cancer: a clinicopathologic study of 37 cases. int j gynecol cancer. 1999; 9:302-306. 20. huang h, yan b, shang m, et al. is hysterectomy beneficial in radical cystectomy for female patient with urothelial carcinoma of bladder? a retrospective analysis of consecutive 112 cases from a single institution. bmc urol. 2019; 19:28. 21. moursy ee, eldahshoursy mz, gamal wm, badawy aa. orthotopic genital sparing radical cystectomy in pre-menopausal women with muscle-invasive bladder carcinoma: a prospective study. indian j urol. 2016; 32:65-70. archivio italiano di urologia e andrologia 2023; 95, 2 13 total extended genital sparing radical cystectomy in female patients 22. roshdy s, senbel a, khater a, et al. genital sparing cystectomy for female bladder cancer and its functional outcome; a seven years' experience with 24 cases. indian j surg oncol. 2016; 7:307-11. 23. borghi c, manservigi m, milandri es, et al. the impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions. arch ital urol androl. 2021; 93:255-261. 24. ali-el-dein b, mosbah a, osman y, et al. preservation of the internal genital organs during radical cystectomy in selected women with bladder cancer: a report on 15 cases with long term follow-up. eur j surg oncol. 2013; 39:358-64. 25. niver be, daneshmand s, satkunasivam r. female reproductive organ-sparing radical cystectomy: contemporary indications, techniques and outcomes. curr opin urol. 2015; 25:105-10. 26. puppo p, introini c, calvi p, naselli a. pelvic floor reconstruction before orthotopic bladder replacement after radical cystectomy for bladder cancer. urology. 2005; 65:174. correspondence antonio cisternino, md (corresponding author) antonio.cisternino@libero.it lorenzo capone, md (corresponding author) lorenzocapone@msn.com antonio rosati, md costanzo latiano, md nicola sebastio, md antonio colella, md giuseppe cretì, md department of urology, fondazione irccs casa sollievo della sofferenza, via dei cappuccini, 71013, san giovanni rotondo (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 295archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. need to restart or continue pharmacological treatment may be needed in some patients (3). risk factors for surgical reintervention are not well defined but some authors showed that higher prostatic volume and history of urinary retention with urethral catheterization could be associated with a higher need for reintervention (4). this study aimed to assess factors associated with the need for surgical reintervention and/or continuation of pharmacological treatment. materials and methods after ethical committee approval (protocol number 339/21) and informed consent of the patients, it was performed a retrospective analysis of all consecutive patients who underwent prostatic surgery for male luts associated with bpo in an academic tertiary hospital between 1 may 2015 and 1 may 2016, with a minimum follow-up of five years. the type of surgery, preoperative, postoperative and follow-up analysis were collected in a database. the following preoperative parameters were evaluated: prostate-specific antigen (psa), prostate volume, post-void residual volume (pvr), the pattern of complaints (predominance of storage or emptying), need for previous catheterization, previous episode of acute bacterial prostatitis, duration of pharmacological treatment before surgery and type of drugs used. prostatic volume was measured by transrectal or suprapubic ultrasound. for those taking 5-a reductase inhibitors (5aris) for more than 6 months, tpsa value was adjusted to double. acute bacterial prostatitis was clinically defined as an episode of febrile luts with swollen and tender prostate on digital rectal examination and positive urine culture. in terms of surgical procedures, patients were classified as being submitted to transurethral resection (turp), open/laparoscopic transvesical prostatectomy (tvp) or open/laparoscopic retropubic prostatectomy (rp) according to the surgical report. patients with the following conditions were excluded: history of chronic prostatitis or chronic pelvic pain, previous surgery in the context of prostatic cancer and patients with post-surgical histology of the specimen showing malignancy. prostatic tissue resected was measured and a ratio (percent of resected tissue) was calcuobjective: surgery is the treatment for male lower urinary tract symptoms (luts) related to benign prostatic obstruction (bpo) refractory to pharmacological treatment or with complications. this study aimed to assess factors associated with the need for surgical reintervention and/or continuation of pharmacological treatment. materials and methods: a retrospective analysis of patients who underwent prostatic surgery for male luts associated with bpo between 1 may 2015 and 1 may 2016, with a minimum follow-up of five years, in an academic tertiary hospital. the type of surgery, preoperative, postoperative and follow-up analysis were collected in a database. results: a total of 212 patients were included with a mean age of 70 ± 8.66 years at five years follow-up. at 5 years, a total of 86.9% of patients do not need pharmacological treatment and 12% required surgical reintervention. of the preoperative parameters, it was found a relationship between prior prostatitis and the need for second surgery with an odds ratio of 4.6. conclusions: patients should be informed of the potential need for pharmacological treatment following surgery, or even of the need for reintervention. history of prostatitis seems to be a risk factor for reintervention. key words: prostatic hyperplasia; quality of life; transurethral resection of prostate; prostatectomy. submitted 4 august 2022; accepted 20 august 2022 introduction male lower urinary tract symptoms, commonly known as male luts, are one of the most frequent reasons for contact with healthcare, namely with the urologist. presence of luts has a negative impact on patients’ quality of life (1). luts have historically been linked to bladder outlet obstruction (boo) and the most frequent cause in males is benign prostatic hyperplasia (bph). this occurs when bph advances from benign prostatic enlargement (bpe) to benign prostatic obstruction (bpo) (2). currently, the treatment is organized on a therapeutic ladder, starting with lifestyle measures, followed by pharmacological treatments. surgical interventions are most often reserved for patients with bothersome luts refractory to medical therapy. although this ladder is effective for the majority of patients, in real-life clinical practice, surgery is not always successful and reintervention or the analysis of benign prostatic obstruction surgery: a long-term evaluation in a real-life context alberto costa silva 1, pedro abreu-mendes 1, 2, 3, afonso morgado 1, paulo dinis 1, 2, carlos martins silva 1, 2, 3 1 urology department, centro hospitalar universitário são joão, porto, portugal; 2 faculty of medicine, university of porto, porto, portugal; 3 i3s institute for research and innovation in health, translational neurourology group, porto, portugal. doi: 10.4081/aiua.2022.3.295 summary archivio italiano di urologia e andrologia 2022; 94, 3 a. costa silva, p. abreu-mendes, a. morgado, p. dinis, c. martins silva 296 lated dividing by the preoperative prostate volume. concerning post-surgery parameters, we considered the medication prescribed when the surgery was not effective, the need for a reintervention and the type of surgical technique used. all medications were verified by accessing the patient's clinical file and by asking the patient himself. we grouped the drugs in alpha-blockers (ab), 5ari, anticholinergic (ac) and b3-agonist (b3a). drugs were prescribed by urologists or primary health care physicians. it was confirmed that the medication was not being taken for other purposes (eg, 5ari for androgenetic alopecia). surgical reintervention was verified by the patient’s clinical file and only surgeries performed in the national health service were considered. overall patients characteristics like age, main comorbidities and renal function were also collected. the need for maintenance of pharmacological treatment as well as the need for surgical re-intervention at 5 years was assessed and its association with preoperative parameters was explored. statistical analyses the data were collected and analysed using spss (v. 27 ibm, usa). the shapiro-wilk test was used to test parameter distribution. continuous variables with normal distribution were expressed as the mean ± the standard deviation, non-normally distributed variables were expressed as the median (25th-75th quartiles), and nominal variables were expressed in relative frequencies. for continuous variables, the differences between the groups were evaluated using the anova test if a normal distribution was assumed; otherwise, the kruskal-wallis test was used. categorical variables were compared using the chi-square test. the p significance was set at < 0.05. results a total of 212 patients were included. the patient's mean age at five years follow-up was 70 ± 8.66 years old. overall patient characteristics and perioperative data are depicted in tables 1, 2. regarding the medication taken before surgery, 33.0% were under ab; 13.7% were taking only 5ari; 34% had a combination of ab and 5ari; 5.7% took another combination (mainly ab plus ac). only 13.7% were not under any medication before surgery. regarding the initial surgery performed, 65.6% underwent turp; 24.1% underwent tvp and 10.4% underwent rp. a total of 86.9% of patients did not need pharmacological treatment 5 years after surgery. of those who required pharmacological treatment after surgery, 24.5% were taking ab, 12.2% were taking 5ari, 20.0% were taking a combination of both, 18.4% were taking ac, 12.2% were taking a combination of ab and ac, and 10% took b3a. twelve per cent required surgical reintervention and it was performed in the first 2 years in 57.7% men and between the second and third years in the 34%. only 8% underwent surgery after more than 3 years. of the patients who underwent initial turp, tvp and rp, 84.9%, 98% and 95.5% did not need a surgical reintervention, respectively. the surgical modality chosen for reintervention was returp in 73,1%, internal urethrotomy in 15.4%, bladderneck resection in 7.7% and tvp in 3.8%. there seems to be a statistical association between the presence of a previous episode of prostatitis and the greater need for surgical reintervention (p = 0.004). the relationship between prior prostatitis and the need for a second surgery has an odds ratio of 4.6 (95%, ci 1,7112,32). of those with a previous episode of prostatitis, 28.6% required surgical reintervention. of all patients who required a surgical reintervention, 36.4% had previous prostatitis. the other data were not statistically related to the need for resume pharmacological treatment or of surgical reintervention (table 3). table 1. demographic characteristics. age 1 70 ± 8.66 serum creatinine 2 0.98 (0.80-1.12) obesity 34% (74) hypertension 27% (57) diabetes 18% (40) depression 12% (25) parkinson disease 2.5% (5) chronic kidney disease 1,8% (4) hypogonadism 0.4% (1) 1 mean ± standard error; 2 median (25th–75th quartile). table 2. perioperative data. psa 1 2.4 ng/dl (1.20-4.53) preoperative prostate volume 1 60.00 cm3 (44.25-85.00) pvr 2 69.00 ml (± 22.12) predominance of symptoms 75% voiding; 25% storage presence of nocturia 53.8% urethral catheter for urinary retention 30% percent of resected tissue 1 22.22% (8.62-35.80) ≤ 30%-68.90% 30-50%-12.76% ≥ 50%-18.34% 1 median (25th–75th quartile); 2 mean ± standard error; psa: prostate-specific antigen; pvr: post-void residual volume. table 3. association between preoperative parameters and medication continuation or surgical reintervention; results shown in p-values. variables medication continuation surgical reintervention symptoms pattern 1 0.785 0.840 prostatitis 1 0.073 0.004 urethral catheter for urinary retention 1 0.611 0.635 prostatic volume 2 0.262 0.069 psa 2 0.444 0.903 pvr 2 0.230 0.113 duration medical treatment 1 0.088 0.022 percent of resected tissue 2 0.643 0.138 1 chi-square test; 2 kruskal-wallis test; psa: prostate-specific antigen; pvr: post-void residual volume. 297archivio italiano di urologia e andrologia 2022; 94, 3 analysis of benign prostatic obstruction surgery: a long-term evaluation in a real-life context discussion between our patients, 68.9% of them have psa > 1.4 ng/ml (median psa of 2.4 ng/dl), corroborating the potential relationship between higher psa and the need for intervention. previous studies, like the pless trial, olmsted county study and mtops, have shown that patients with this cut-off of psa are at higher risk of needing surgical treatment (5-7). thirty percent of our patients were catheterized which is similar to other studies (4, 8). we did not find a relationship between the presence of a catheterization (due to urinary retention), higher prostatic volumes, and the need for surgical reintervention, differently to the findings by other authors (4). concerning baseline pvr values, it is known that has little prognostic value for the risk of surgery in patients on medical treatment (namely, ab) (9). three-quarters of patients took medication for less than a year before being submitted for surgery. the duration of medical treatment had no impact on the need for reintervention or the need to return to medication. the predominance of voiding or storage symptoms before first surgery was not associated with the need for postsurgery medication. this finding diverges from han et al., which showed that storage symptoms and use of antimuscarinics were significantly associated with symptom persistence and the need to continue medical therapy after surgery (10). moreover, this group also showed that any previous luts/bpo medication use was significantly associated with symptom persistency and continuing medical therapy, a fact that was not corroborated by our sample. the epidemiological relationship between prostatitis and benign prostatic hyperplasia was shown in case-control studies and a cohort study (11). however, that association is not broadly accepted. in our study, a history of acute prostatitis is significantly associated with the need for a surgical reintervention, resulting in a 4.6 times higher risk of a second procedure, which means a probability of 82% of needing reintervention. this data gives strength to the finding of sauver et al. with an odds ratio of 1.69 and a probability of 70% (12). the baseline degree of luts, even after surgery, in patients with a history of prostatitis may induce a false sense in the urologist of the need for intervention, lowering the threshold for reintervention. the true benefit and consequences of surgery in these patients remain to be seen, and further studies are needed. in this study, a higher ratio of prostatic tissue resected was not associated with less medical continuation or less surgical reintervention. some studies show that there is a poor correlation between the residual prostate weight and symptoms and these are affected by several other confounding factors (13-18). some authors even claim that resection of less than 30% of prostatic tissue seems to be sufficient to alleviate lower urinary tract symptoms related to benign prostate hyperplasia (13). a recent study shows that less profound prostate resections may be sufficient, depending on maximum flow rate (19). in our study, more than two-thirds of our patients have less than 30% of prostatic tissue resected and it was not associated with poorer outcomes. despite that, this is a controversial subject, and some authors postulate the opposite. although nowadays the choice of surgical interventions includes less invasive techniques, our patients were submitted to the “classic” techniques of turp, tvp and rp. in our study, tvp and rp have shown a low rate of need for re-intervention, while turp, although effective, has a higher risk for reintervention. a total of 25 patients (12%) required surgical reintervention. this number is supported by rassweiler et al., who showed similar values, between 3 to 14.5% (3). the reinterventions are mainly performed in the first 3 years (92,0%). the follow-up of patients after surgical reintervention is not well defined and should be evaluated in further studies. however, given these data, we believe that these patients need to be followed for at least 3 years, although not necessarily by a urologist. in the majority of cases, the modality chosen for reintervention was turp (73% of these 25 patients). in 1.9% and 0.9% of all the 212 patients, the reintervention was an internal urethrotomy for urethral stricture and loop resection of bladder neck for bladder neck contracture (bnc), respectively. both complications are more common after turp (20). all our patients who needed urethrotomy or resection of bnc had previously undergone turp. our urethrotomy incidence is similar to the study of sucki et al. (21) and is within the lower range of the 1.4-19% referred in literature (3, 20). our bnc is relatively lower than the 1.79.7% mentioned in other studies (20, 22, 23). we only considered surgical reintervention made in our centre or another one of the portuguese national health service, therefore, there is a chance that some patients who have had surgical reintervention in private clinical setting could be missed. it would be interesting to compare the rate of reinterventions and complications of both “classic” and modern techniques being performed nowadays in a real-life context as a tertiary hospital where both residents and consultants perform surgeries. twenty-three percent of our patients still needed to use male luts medication after surgery and this factor was independent of the type of surgery. some studies show rates of patients needing medication ranging between 15 and 55%. a previous study with longer follow-up (3 years) showed an estimated rate of use of medication of 22% (24), so data of our cohort is in line with other centres. compared with 86.3% of patients who were medicated for bpo before surgery, we have an important decrease in the relative number of patients who need medication after surgery. lifelong medications are costburden and are associated with consequences given by adverse effects and associated with drug interactions. so, medication discontinuation could be an indicator of the success of the procedure, and is important to include it as an effective measure when comparing surgical options, since a large proportion of patients are motivated to undergo surgery in order to discontinuing medication for male luts (25). despite this, we should keep in mind that sometimes the need for medication does not result from a failure in the surgical technique but rather from the luts physiopathological pleiotropism, namely the coexistence of other causes for bladder outlet obstruction (as an anatomical abnormality), the presence of underactive or overactive bladder and of chronic prostatitis (of any type) (10). archivio italiano di urologia e andrologia 2022; 94, 3 a. costa silva, p. abreu-mendes, a. morgado, p. dinis, c. martins silva 298 only 4.2% and 2.4% of our patients are using ac and b3a, respectively. this is lower than 5.7% and 4.7% of the use of ab and its combination with 5ari. in a study by campbell et al., it was shown that abs are used in about 9%, being the most commonly used drug class (25). because ab’s mechanism of action is mainly on receptors located in the bladder neck and prostatic smooth muscle, ab utility following a thorough surgery should be minimal, these authors stated that use of ab is a indicator of quality of surgery (25). given the bladder remodelling and the prevalence of storage symptoms after surgery, they felt that ac and b3a would be commonly used. also, campbell et al. showed that use of ab, 5aris, ac/b3a within the first 5 years after surgery is roughly 25%, 20%, and 15%, respectively (26). a non-negligible portion of the patients (13%) was submitted to surgery without taking any medication previously but our numbers are inferior to those of some literature, referring values around 50% (24). in our series, these were patients referred by primary care physicians with end-term bpo (most commonly with a urethral catheter) or with contraindications to male luts medication and were quickly scheduled for surgery. these data may indicate that primary health care has a more conservative approach to luts, namely through watchful waiting. these data make us believe that education programs targeted to primary care physicians and medical literacy campaigns for the general population should be encouraged. our study has some limitations. it is a retrospective study with possible selection bias. new surgical techniques are the main hot topic nowadays in male luts treatment, and most of their benefits are very well expressed (2730). during the last years, laser enucleation of prostate, namely with holmium laser (holep), has replaced turp as the gold standard surgical treatment for bph (31). on the other hand our study focused on the outcomes of our centre that did not have other newer surgical modalities of bpo treatment. furthermore, the results are from a single tertiary centre where multiple surgeons performed the procedures, including both residents and graduated urologists. this is a reality present in most university hospitals and it’s one of the reasons for considering this study a reallife-based one. a limited number of patients were enrolled, although it is quite an elevated number for 1 year in a single centre. medication compliance is an identified problem in bpo therapy, and we could not evaluate it. we lack data about the time before the beginning of medical treatment and the first surgery such as ipss, qmax and sexual function, which is why we chose not to use data related to these variables collected in the postoperative period given the impossibility of a comparison. conclusions patients should be informed of the potential need for pharmacological treatment following surgery, or even of the need for reintervention. history of prostatitis seems to be a risk factor for reintervention in patients submitted to prostatic surgery for benign obstruction. references 1. kupelian v, wei jt, o’leary mp, et al. prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the boston area community health (bach) survey. arch intern med. 2006; 166:2381-7. 2. gravas s, cornu jn, gacci m, et al. management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). eur assoc urol guidelines [internet]. 2021; available from: https://uroweb.org/wp-content/uploads/eauguidelines-on-non-neurogenic-male-luts-incl.-bpo-2020.pdf 3. rassweiler j, teber d, kuntz r, hofmann r. complications of transurethral resection of the prostate 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participating institutions evaluating 3,885 patients. j urol. 2002; 167:5-9. 9. mochtar ca, kiemeney lalm, van riemsdijk mm, et al. postvoid residual urine volume is not a good predictor of the need for invasive therapy among patients with benign prostatic hyperplasia. j urol. 2006; 175:213-6. 10. han hh, ko wj, yoo tk, et al. factors associated with continuing medical therapy after transurethral resection of prostate. urology 2014; 84:675-80. 11. zhang l, wang y, qin z, et al. correlation between prostatitis, benign prostatic hyperplasia and prostate cancer: a systematic review and meta-analysis. j cancer. 2020; 11:177-89. 12. sauver jls, jacobson dj, mcgree me, et al. longitudinal association between prostatitis and development of benign prostatic hyperplasia. urology. 2008; 71:475-9. 13. antunes aa, srougi m, coelho rf, et al. transurethral resection of the prostate for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia: how much should be 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and success of laser surgery and transurethral resection of the prostate for benign prostatic hyperplasia. urology. 2015; 86:1115-22. 25. campbell ra, gill bc. medication discontinuation following transurethral prostatectomy: an unrecognized effectiveness measure? curr urol rep. 2020; 21:61 26. campbell j, reid j, ordon m, welk b. the utilization of benign prostatic hyperplasia and bladder-related medications after a transurethral prostatectomy. urology 2019; 130:126-31. 27. pallauf m, kunit t, ramesmayer c, et al. endoscopic enucleation of the prostate (eep). the same but different—a systematic review. world j urol. 2021; 39:2383-96. 28. cho sy, park j, yoo s, et al. one-year surgical outcomes of complete or incomplete enucleation of prostate by monopolar electrocoagulation, photoselective vapoenucleation of 120-w greenlight laser, and holmium laser. urology. 2017; 108:142-8. 29. kuntz rm, lehrich k, ahyai sa. holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. eur urol. 2008; 53:160-8. 30. strope sa, vetter j, elliott s, et al. use of medical therapy and success of laser surgery and transurethral resection of the prostate for benign prostatic hyperplasia. urology. 2015; 86:1115-22. 31. mostafa mm, patil n, khalil m, et al. is holmium laser enucleation of prostate equally effective in management of benign prostatic hyperplasia patients with either voiding or storage lower urinary tract symptoms? a comparative study. arch ital urol androl. 2022; 94:174-9. correspondence alberto costa silva, md (corresonding author) albertocsilva8@gmail.com urology department, centro hospitalar universitário são joão, porto, portugal orcid id: 0000-0001-6753-7206 pedro abreu-mendes, md pamendes@gmail.com author orci id: 0000-0002-4304-7023 afonso morgado, md amorg@gmail.com orcid id: 0000-0002-9647-4360 paulo dinis, md pdinis@gmail.com orci id: 0000-0003-2893-5492 carlos martins silva, md cmslva@gmail.com orci id: 0000-0003-1739-1039 35archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.35 introduction asymptomatic maternal hydronephrosis during pregnancy may be present in more than 90% of pregnant women (1-3). therefore, maternal hydronephrosis due to pregnancy is generally considered a normal -physiologicalphenomenon. however, there are also cases of maternal hydronephrosis that require treatment. therefore, maternal pathological obstructive hydronephrosis cases should be differentiated from maternal physiological dilatations. for this purpose, some authors suggest the use of the term "physiological maternal renal pelvic dilatation" to avoid the pathological connotations of the term maternal hydronephrosis (4). according to the literature, the rate of symptomatic maternal hydronephrosis is 0.2-3% (1, 5-10). untreated cases of symptomatic maternal hydronephrosis can cause fulminant pyelonephritis and urosepsis in the presence of urinary infections (9). therefore, it should not be late in the treatment of symptomatic hydronephrosis cases. otherwise, it may cause urosepsis, which may endanger the life of both mother and fetus (5, 11-13). in addition, acute antepartal pyelonephritis significantly increases preterm birth (13, 14). maternal upper urinary tract dilatations, which are considered physiologically normal, are mostly observed on the right side. it usually develops after the mid-gestation (4, 15-19). urinary dilatation in pregnant women is explained by the effect of progesterone on the smooth muscle of the urinary system and the compression of the expanding uterus into the ureter (2, 4, 18, 20). further observation of dilatations on the right side and twin pregnancies also supports this hypothesis (4). in addition, the crossing of the ureter by the ovarian vein at the pelvic brim on the right while running parallel on the left, dextrorotation of the uterus, and the relative protection of the left ureter provided by the sigmoid colon are also possible factors (2, 4, 18). as a matter of fact, maternal hydronephrosis usually improves spontaneously after delivery because the compression of the uterus is removed after birth (19, 20). and a few weeks after birth completely disappeared (15, 18, 20). the first-line imaging test to diagnose maternal hydronephrosis is ultrasonography (us) (21, 22). purpose: the aim of this study is to determine the proportion of maternal hydronephrosis and symptomatic cases requiring treatment in pregnant women without ureteral stones and the characteristics of these cases. materials and methods: between february 2018 and april 2019, all pregnant women followed for pregnancy in obstetrics and outpatient policlinic were evaluated prospectively. maternal hydronephrosis rate, degree of hydronephrosis and side, symptomatic hydronephrosis rate, maximum renal anteroposterior diameter of renal pelvis and visual analogue scale were detected. symptomatic patients were treated conservatively or surgically. findings in both treatment groups were analyzed by t-test or chi-squared test. pearson or spermean’s tests were used for correlation analyzes. results: a total of 1026 pregnant women aged 18-45 (27.7 ± 5.2 years) were followed prospectively. the rate of maternal hydronephrosis was 28.7% and the rate of symptomatic hydronephrosis was 4.7%. of the patients with symptomatic hydronephrosis, 73.4% (3.5% of total) were treated conservatively and 26.5% (1.3% of total) were treated surgically. there was a positive correlation between hydronephrosis and gestational week (p < 0.001), visual analogue scale (p < 0.001) and hematuria (p < 0.05). there was a negative correlation between hydronephrosis and maternal age (p < 0.05) and number of pregnancies (p < 0,001). the anteroposterior diameter of renal pelvis (p < 0.001), visual analogue scale (p < 0.05) and fetal body weight values (p < 0.05) on the right side were higher in the surgical treatment group than the conservative group. conclusions: the majority of cases with maternal hydronephrosis in pregnant women without ureteral stones are asymptomatic. most symptomatic cases can also be treated conservatively. in cases requiring surgical treatment (1.3%), fetal body weight, visual analogue scale and anteroposterior renal pelvis diameter are higher. key words: hydronephrosis; pregnancy; maternal; symptomatic; treatment. submitted 27 august 2020; accepted 21 october 2020 maternal hydronephrosis in pregnant women without ureteral stones and characteristics of symptomatic cases who need treatment: a single-center prospective study with 1026 pregnant women summary zeki bayraktar 1, şerife tuğba kahraman 2, elif seçkin alaç 2, "rem yengel 2, deniz sarıkaya kalkan 2 1 department of urology, school of medicine, istanbul medipol university, istanbul, turkey; 2 department of obstetrics and gynecology, school of medicine, istanbul medipol university, istanbul, turkey. archivio italiano di urologia e andrologia 2021; 93, 1 zeki bayraktar, ş. tuğba kahraman, e. seçkin alaç, i. yengel, d. sarıkaya kalkan 36 because us is a non-invasive and ionizing radiation-free imaging technique (21). in addition, maternal nephrosonography findings during pregnancy were quantitatively and qualitatively documented years ago (15, 16). ultrasonographic evaluation has been the mainstay of obstetric imaging for many years (4). maternal hydronephrosis can be detected with abdominal us from the beginning of the second trimester of pregnancy (23). us is excellent for the detection of hydronephrosis. however, there may be some problems in distinguishing between pregnancy-dependent physiological hydronephrosis and stone-dependent obstructive hydronephrosis. in fact, according to literature data, the success of conventional gray-scale us in detecting obstruction due to ureteral stones is 77-80%, as it cannot detect stones in the middle ureter usually (24). magnetic resonance imaging (mri) technique may be preferred in these patients (22). but the first step of the imaging method that should be preferred during pregnancy is us (21, 23). for detection of maternal renal dilatations, intrarenal calyceal dilatations or anteroposterior renal pelvis diameter (apd) are measured by us (4, 25, 26). the most common measurement for diagnosis and classification is apd. but it gives limited information in terms of prognostic. because although apd is an objective, non-invasive and easily detectable measurement, it cannot show parenchymal changes and the true degree level of hydronephrosis (26). treatment options for symptomatic maternal hydronephrosis are conservative treatment and surgery (1, 5). conservative treatment includes close monitoring, analgesic, intravenous fluid and, if necessary, antibiotics. surgical treatment includes double pigtail (jj) ureteral stent insertion and percutaneous nephrostomy. and it is usually applied in severe flank pain that does not respond to medical treatment and in the presence of severe hydronephrosis (1, 5). however, it is not yet clear which treatment approach should be chosen for patients with symptomatic maternal hydronephrosis (1). our aim in this study was to determine the proportion of maternal hydronephrosis and symptomatic cases requiring treatment in pregnant women without ureteral stones and the characteristics of these cases. materials and methods a prospective controlled study was designed. the study protocol was approved by the institutional ethics committee of the school of medicine, istanbul medipol university, turkey (15/02/2018-604.01.01-e.5443). between february 2018 and april 2019, maternal renal ultrasonography was performed in all pregnant women followed up in the outpatient clinic of gynecology and obstetrics in our university(at least one ultrasonographic measurement in the first, second and third trimester and 2-3 months after birth). the presence and absence of hydronephrosis, if any, degree and side or it were noted. the maximum renal anteroposterior diameter of renal pelvis (apd) was measured in patients with hydronephrosis. serum glucose, blood urea nitrogen (bun), creatinine, white blood cell count (wbc), c-reactive protein (crp), urine analysis(presence of hematuria and leukocyturia) and urine culture-antibiogram were detected. maternal age (year), gestational age (week), body mass index (bmi), number of pregnancies, number of fetuses, arterial blood pressure, amniotic fluid index (afi), birth week, type of delivery, birth sex, baby weight (fbw) and 5. minutes apgar score was recorded. symptomatic patients were treated conservatively or surgically. findings in both treatment groups were analyzed statistically. all ultrasonographic investigations and renal pelvis measurements were performed by radiologists and registered obstetricians who were trained in ultrasonograpy with experience ranging 7 to 25 years, using a logic p6 pro ultrasonography system with a 3.5 mhz broadband curvey array transducer (ge healthcare, gyeonggi, korea). the visual analogue scale (vas) was used to determine severity of the flank pain (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; 0 and 10 points as no pain and maximum pain, respectively) (28). hydronephrosis was classified according to a common grading system, and definitions followed the guidelines of the european association of urology (grade 0, no renal pelvis dilation; grade 1, mild renal pelvis dilation (anteroposterior diameter less than 10 mm) without dilation of the calyces nor parenchymal atrophy; grade 2, moderate renal pelvis dilation (between 10 and 15 mm), including a few calyces; grade 3, renal pelvis dilation with all calyces uniformly dilated, normal renal parenchyma; grade 4, as grade 3 but with thinning of the renal parenchyma, represents mild parenchymal loss; grade 5, severe parenchymal loss (28). all hydronephrosis cases with flank pain (vas > 2), fever and leukocyturia and/or leukocytosis were considered symptomatic. all symptomatic patients with hydronephrosis were referred to the urology outpatient clinic and treated medically or surgically according to clinical and laboratory findings. first, position, analgesic and intravenous fluid treatment were applied in the medical treatment group. in patients with signs of infection such as fever, leukocytosis and elevation of crp, sefamezin was started if the antibiogram result was negative. if the antibiogram result was positive, antibiotic was determined according to antibiogram. the following cases were defined as the failure of medical treatment; 1) the infection findings do not improve within 48 hours despite antibiotic treatment, 2) distortion of renal functions, 3) increased flank pain, or no decrease in flank pain. the patients with at least one of these findings and all patients with hydronephrosis grade 3 were treated surgically by double-j ureteral stent insertion. for this, 6-8 fr double-j ureteral stent (boston scientific, ma, usa) was inserted under local or general anesthesia with cystoscopic guidance to the side of hydronephrosis. in all cases, the hospitalization course and the complications of surgery were recorded. the stent was monitored ultrasound and it was removed one month after delivery. the data obtained were classified and analyzed statistically. statistical analyses were performed using ncss statistical software (number cruncher statistical system, 37archivio italiano di urologia e andrologia 2021; 93, 1 maternal hydronephrosis 2007, kaysville, utah, usa). descriptive statistics (mean ± sd and percentages) were used to present demographic information of the study participants. discrete data are presented as numbers (n) and percentages (%). anova test, t test and chi square test were used for statistical analysis (when appropriate); p values less than 0.05 were considered statistically significant. this study was carried out with 1.026 pregnant women who met the inclusion criteria. power calculation was performed. all proportional and parametric comparisons in subgroups are at least 95% power. inclusion criteria pregnant women followed in the obstetrics clinic. exclusion criteria renal tract calculi, structural renal parenchymal or collecting system anomalies (single kidney, horseshoe kidney, renal ectopia, duplicated collecting system, ectopic ureter, and extra renal pelvis), previous surgical intervention to the kidneys or ureters, and renal malignancy. renal tract calculi was detected mainly by ultrasonography. however, mri was performed in cases whose ureteral stones could not be completely excluded by ultrasonography, especially in middle ureteral stones. results a total of 1.026 pregnant women aged between 18 and 45 years (27.7 ± 5.2) were followed during the study period. the number of cases with hydronephrosis was 295 (28.7%). the mean age of the patients with hydronephrosis was 27.1 ± 4.6 (18-43 years). hydronephrosis was on the right side in 295 patients (28.7%) and on the left side in 27 patients (2.6%). the number of patients with bilateral hydronephrosis was 27 (2.6%). of the 295 pregnant women with hydronephrosis, 246 (83.3%) were asymptomatic. of the 49 patients (16.6%) with hydronephrosis, 36 (73.4%) were treated conservatively and 13 (26.5%) were treated surgically (table 1). there was a positive correlation between hydronephrosis and gestational week (p < 0.001), vas score (p < 0.001) and hematuria (p < 0.05). there was a negative correlation between hydronephrosis and maternal age (p < 0.05) and number of pregnancies (p < 0.001). there was no positive or negative correlation between maternal hydronephrosis and bmi, number of fetuses, glucose, bun, creatinine, wbc, crp, arterial blood pressure, leukocyturia, afi, birth week, delivery type, fbw and apgar score (p > 0.05) (table 2). while leukocituria was positive in 28 of the symptomatic cases (57.1%), only 17 of these cases were culture positable 2. patient characteristics and clinical data. hydronephrosis n (%), mean ± sd grade 0 grade 1 grade 2 grade 3 age (years) 27.9 ± 5.3 27.2 ± 4.5 26.6 ± 4.7 27.9 ± 5.2 r = -0.070. p = 0.024 bmi 26.7 ± 4.6 27.1 ± 5.1 26.2 ± 3.3 31.9 ± 6.2 r = -0.021. p = 0.507 ga (weeks) 23.3 ± 8.6 26.8 ± 6.8 28.7 ± 5.8 29.7 ± 6.9 r = 0.233. p = 0.000 ga at delivery 38.7 ± 1.2 38.8 ± 0.9 38.9 ± 0.8 39.2 ± 0.9 r = 0.091. p = 0.293 number of pregnancy 1.86 ± 1.1 1.68 ± 1.0 1.43 ± 0.7 1.75 ± 0.8 r = -0.128. p = 0.000 multiple pregnancy 5 (0.68%) 1 (0.54%) 2 (2.1%) 0 (0%) r = 0.016. p = 0.616 glucose 84.3 ± 12.6 85.5 ± 12 82.8 ± 10.3 84.3 ± 11.2 r = 0.068. p = 0.459 serum bun (mg/dl) 9.2 ± 2.2 10.3 ± 2.3 9.7 ± 2.7 10.4 ± 3.2 r = 0.170. p = 0.617 creatinine (mg/dl) 0.46 ± 0.13 0.43 ± 0.2 0.38 ± 0.2 0.42 ± 0.3 r = -0.102. p = 0.408 wbc (x103 µl) 9.2 ± 2.3 9.5 ± 2.0 16.3 ± 9.3 17.4 ± 7.2 r = 0.165. p = 0.055 crp (mg/dl) 5.0 ± 2.3 6.1 ± 2.6 7.4 ± 2.5 9.7 ± 2.9 r = 0.297. p = 0.149 apgar score. 5-min 9.7 ± 0.4 9.7 ± 0.4 9.5 ± 0.6 9.9 ± 0.2 r = 0.095. p = 0.225 fbw (kg) 3.37 ± 0.4 3.27 ± 0.3 3.30 ± 0.2 3.59 ± 0.4 r = -0.028. p = 0.755 vas score 0 3.3 ± 1.7 3.1 ± 1.9 6.2 ± 2.1 r = 0.382. p = 0.000 ta (mm/hg); systolic 107.6 ± 12.4 107.9 ± 10.2 109.9 ± 12.7 107 ± 6.3 r = 0.018. p = 0.581 diastolic 65.2 ± 9.3 64.6 ± 8.2 66.6 ± 9.2 63 ± 8.5 r = 0.007. p = 0.816 primipara 341 (46.6%) 104 (56.8%) 63 (68.4%) 11 (55%) r = 0.016. p = 0.616 hematuria 23 (3.1%) 39 (21.3%) 44 (47.8%) 14 (70%) r = 0.244. p = 0.013 leukocyturia 27 (3.7%) 48 (26.2%) 47 (51%) 13 (65%) r = -0.068. p = 0.570 afi; normal 720 (98.4%) 176 (96.1%) 89 (96.7%) 19 (95%) r = -0.32. p = 0.320 polyhydramnios 12 (1.64%) 7 (3.8%) 2 (2.1%) 1 (5%) oligohydramnios 1 (0.13%) 0 (0%) 1 (1.1%) 0 (0%) trimester; r = 0.213. p = 0.000 1 (< 14th weeks) 101 (13.8%) 7 (3.8%) 0 (0%) 0 (0%) 2 (14th-27 weeks) 356 (48.7%) 83 (45.3%) 46 (50%) 4 (20%) 3 (27th-41 weeks) 274 (37.4%) 93 (50.8%) 46 (50%) 16 (80%) treatment; 0 (0%) 11 (6.0%) 18 (19.5%) 20 (%100) r = 0.133. p = 0.648 conservative 0 (0%) 10 (5.4%) 16 (17.3%) 10 (50%) surgical 0 (0%) 1 (0.5%) 2 (2.1%) 10 (50%) participants 731 (71.2%) 183 (62%) 92 (31.1%) 20 (6.7%) total 731 (71.2%) 295 (28.7%) 1.026 (100%) ga, gestational age; bun, blood urea nitrogen; wbc, white blood cells count; crp, creactive protein; fbw, fetal body weight; vas, visual analogue scala; ta, tension arterial, afi, amniotic fluid index; apd, anteroposterior diameter of renal pelvis. table 1. patient characteristics of 1.026 pregnant women. n mean ± sd % age (years) 27.7 ± 5.2 gestational age (weeks) 24.5 ± 8.5 number of pregnancy 1.7 ± 1.0 number of primipara women 516 50.2% number of multiple pregnancy 8 0.7% hydronephrosis side; right 295 28.7% left 27 2.6% bilateral 27 2.6% trimester; 1 (< 14th weeks) 108 10.5% 2 (14th-27 weeks) 489 47.6% 3 (27th-41 weeks) 429 41.8% hydronephrosis; no (grade 0) 731 71.2% hydronephrosis 295 28.7% grade 1 183 17.8% grade 2 92 8.9% grade 3 20 1.9% treatment; 49 4.7% conservative 36 3.5% surgical 13 1.2% total 1.026 100% archivio italiano di urologia e andrologia 2021; 93, 1 zeki bayraktar, ş. tuğba kahraman, e. seçkin alaç, i. yengel, d. sarıkaya kalkan 38 tive (34.6%). sefamesin was used in 20 of these symptomatic cases, nitrofurantoin in 5 and ceftriaxon in 3 of these patients (according to antibiogram). no infection was observed without clinical response. there was no patient who developed sepsis or who did not respond clinically to these anitibiotic treatments. almost all of the pregnant women with hydronephrosis were in the second and third trimester. in the third trimester, there were 155 (52.5%) hydronephrosis (grade 1; 93 (60%), grade 2; 46 (29.6%) grade 3; 16 (10.3%). in the second trimester, there was 133 (45%) hydronephrosis (grade 1; 83 (62%); grade 2; 46 (34.4%), grade 3; 4 (3%). the number of hydronephrosis in the first trimester was only 7 (2.3%), all of which were grade 1. of the 49 patients treated due to hydronephrosis, 18 (36.7%) were in the second trimester and 31 (63.2%) were in the third trimester. the maximum apd on the right side of the patients in the surgical treatment group was significantly higher than the conservative group (27.9 ± 9.6 mm-15.7 ± 5.1 mm, p < 0.0001). similarly, the vas values were significantly higher in the surgical treatment group (5.2 ± 1.9-3.1 ± 1.9; p = 0.0013). fbw values were also higher in the surgical treatment group than the conservative treatment group (3.61 ± 0.37-3.36 ± 0.32; p = 0.031). there was no significant difference between the two treatment groups in terms of other parameters (table 3). double-j stent was easily inserted in all patients and successful responses were obtained in the surgical treatment group. two of the patients in the surgical group (15.3%) complained of stent discomfort and flank pain. but no infection, stent migration, or fragmentation were observed. no invasive procedure such as percutaneous nephrostomy was required in any patient. the mean duration of stent insertion was 4.7 ± 1.2 months. three months after delivery, no hydronephrosis was observed in any patient. discussion our results in this study partially confirm the literature data. some of our findings contradict the literature. in fact, while the rate of maternal hydronephrosis reported in the literature is up to 80-90% (1-4), the maternal hydronephrosis rate in our study is 28.7%. there may be two possible causes of this discrepancy. first, we used the common grading system for the detection and classification of hydronephrosis (28), not the maximal apd. however, most of the studies in the literature have used the maximal apd for hydronephrosis classification. however, although the apd value seems to be an objective measurement, it cannot show the true grade of hydronephrosis (26). the results also vary according to the criteria for hydronephrosis. as a matter of fact, maternal hydronephrosis rate was 21% according to a study in which apd value of 10 mm and above was accepted as hydronephrosis (29). the second, we have also accepted exclusion criteria for some diseases that may cause urinary obstruction such as renal tract calculi, structural renal parenchymal or collecting system anomalies (single kidney, horseshoe kidney, renal ectopia, duplicated collecting system, ectopic ureter, and extra renal pelvis), previous surgical intervention to the kidneys or ureters. this may have reduced our rates of hydronephrosis. maternal hydronephrosis, which are considered physiologically normal, are mostly observed on the right side and usually develop after mid-gestation (4, 15-19). our findings also confirm these data in the literature. however, while the rate of symptomatic maternal hydronephrosis reported in the literature is 0.2-3% (1, 2, 8-10), the rate of symptomatic hydronephrosis in our study is 4.7%. in other words, this ratio is relatively high compared to the literature average. however, the rate of semptomatic cases that need surgical treatment is 1.2%. this ratio coincides with the literature data. we observed a significant relationship between the degree of hydronephrosis and flank pain/vas score. however, there are different data in the literature. for example, farr et al. (27) evaluated that the association between maternal hydronephrosis and acute flank pain during pregnancy in a prospective pilot-study and reported that there is no clear association between the grade of maternal hydronephrosis and pain intensity, which complicates diagnostic assessment. in addition, watson and brost examined 81 pregnant table 3. patient characteristic and clinical data in treatment groups. conservative surgical p value (n = 36) (n = 13) age (years) 26.8 ± 4.4 28.9 ± 4.5 p = 0.1492 body mass index (bmi) 29.7 ± 5.4 27 ± 4.2 p = 0.1099 gestational age (weeks) 28.2 ± 6.6 30 ± 5.3 p = 0.3813 gestational age at delivery 38.7 ± 0.7 39.4 ± 0.9 p = 0.0063 cesarean section rate 24 (66.6%) 8 (61.5%) p = 0.7432 fetal body weight (kg) 3.36 ± 0.32 3.61 ± 0.37 p = 0.0310 apgar score. 5-min 9.8 ± 0.2 9.9 ± 0.2 p = 0.0923 primipara 25 (69.4%) 7 (53.8%) p = 0.3163 tension arterial (mm/hg); systolic 106 ± 7 107 ± 6 p = 0.6496 diastolic 62 ± 8 66 ± 5 p = 0.0993 visual analogue scala 3.1 ± 1.9 5.2 ± 1.9 p = 0.0013 serum blood urea nitrogen (mg/dl) 11.9 ± 3.3 12.4 ± 3.7 p = 0.6522 creatinine (mg/dl) 0.71 ± 0.3 0.72 ± 0.3 p = 0.9184 white blood cells count (x103µl) 12.2 ± 3.3 13.5 ± 3.4 p = 0.2331 c-reactive protein (mg/dl) 11.7 ± 13 17.3 ± 15 p = 0.2074 hospitalization (day) 4.7 ± 2.6 4.1 ± 3.4 p = 0.5149 culture positive rate 13 (36.6%) 4 (30%) p = 0.6718 anteroposterior diameter of renal pelvis (mm); right 15.7 ± 5.1 27.9 ± 9.6 p<0.0001 left 2.7 ± 1.9 4.3 ± 3.7 p = 0.0526 amniotic fluid index (afi); normal 35 (97.2%) 13 (100%) p = 0.5463 polyhydramnios 1 (1.9%) 0 (0%) p = 0.6203 oligohydramnios 0 0 trimester; 1 (< 14th weeks) 0 0 2 (14th-27 weeks) 15 (41.6%) 3 (23%) p = 0.2378 3 (27th-40 weeks) 21 (58.3%) 10 (77%) p = 0.2354 39archivio italiano di urologia e andrologia 2021; 93, 1 maternal hydronephrosis women and observed that there was no association between flank pain and hydronephrosis (29). another finding that does not coincide with the literature data is the correlation between multiple pregnancies and hydronephrosis. according to the literature, more maternal hydronephrosis is observed in twin pregnancies (4). but we could not confirm this finding. because the number of multiple pregnancies in our study was only 8 (0.7%) and it was not statistically sufficient to determine the positive correlation between maternal hydronephrosis and multiple pregnancies. most of the pregnant women with maternal hydronephrosis in this study were asymptomatic (83.3%). in addition, a large proportion of symptomatic cases (73.4%) were treated conservatively. the number of cases requiring surgical treatment was only 1.2%. our findings are consistent with the literature. because the proportion of patients with symptomatic maternal hydronephrosis, which can be treated conservatively, is approximately 70-80%, some of which are reported as high as 96% (1, 2, 5). symptomatic maternal hydronephrosis during pregnancy can be treated conservatively, especially in the presence of mild hydronephrosis. and also maternal-perinatal results are excellent. however, some cases may be resistant to conservative treatment. surgical treatment should be considered for these cases, especially if severe hydronephrosis is present (1, 2, 5). because symptomatic hydronephrosis may cause premature birth or maternal-fetal death when left untreated (13). treatment method of symptomatic hydronephrosis in pregnancy is still unclear (1). according to the literature, approximately 70-80% of the pregnant women with symptomatic hydronephrosis can be treated with conservative approach. for the remaining 20-30%, additional treatments are required (1, 13). however, one of the high dj stent insertion rate (72%) in the literature was published, and additionally, 4% of patients underwent percutaneous nephrostomy (1, 11). for this reason, the optimal treatment option in pregnant women with symptomatic hydronephrosis is unclear (1, 9). fainaru et al. (2) reported that 73% of patients with maternal hydronephrosis had mild hydronephrosis and that they responded perfectly to conservative treatment in terms of maternal-perinatal outcomes, but that 7.1% of symptomatic patients with moderate or severe hydronephrosis did not respond to conservative treatment. tsai et al. (5) reported 80% of patients with maternal hydronephrosis responding to conservative treatment during pregnancy and 0.27% of moderate to severe symptomatic maternal hydronephrosis. the response to conservative treatment reported in the literature is up to 96% (2, 5, 9). so, the authors reported that they obtained a lower rate of response to conservative treatment than the literature because they excluded patients with mild hydronephrosis from the study and included only patients with moderate to severe hydronephrosis (5). however, this rate reported by them is actually consistent with the literature. because according to the literature, the rate of patients who respond to conservative treatment is about 70-80% (13). on the other hand, there are studies reporting higher rates of surgical treatment. in fact, ercil et al. (1) reported the treatment data of a total of 211 patients with symptomatic maternal hydronephrosis, of which 131 (62%) were conservatively treated and 80 (38%) were treated surgically. according to the authors, the high number of patients treated surgically (ie, double-j stent insertion) was related to the purpose of referring patients to the hospital. because all patients were referred from another center and especially for surgical treatment. in addition to this, the presence of urinary tract infections is quite high due to our patient profile which is composed of patients with low socioeconomic level and poor hygienic conditions. in case a high level of antibiotic resistance due to unconscious antibiotic use is added, conservative approach was failed in these patients and surgical intervention was required (1). double-j ureteral stent insertion is effective in the management of symptomatic hydronephrosis (5, 8, 19). early or late complications of ureteral stents may occur if the stent is left for more than three months. however, the morbidity of pigtail stent insertion is minimal if the stent is left for less than three months (5). but some series reported the early and late complications of double pigtail ureteral stents. early complications include patient discomfort, irritative bladder symptom, bacteriuria with or without urinary tract infection, urosepsis, hematuria, or flank pain, and later complications are upward or downward stent migration, calcification, and fragmentation (5, 12). as a matter of fact, in also this study, double-j stent were successfully inserted and removed in all patients in the surgical treatment group. there was no early or later serious complications in any patient. only two patients (15.3%) complained of stent discomfort and flank pain. but no urosepsis, stent migration, calcification or fragmentation were observed. another issue discussed for the treatment of maternal hydronephrosis is whether there are any parameters that can be used to determine the optimal treatment option. ercil et al. (1) reported that crp, wbc and vas levels were higher in the surgical treatment group, which increased the likelihood of surgical treatment, thus high crp and wbc levels seemed to be a predictor for surgical treatment. in our study, vas scores was higher in the surgical treatment group. but we did not observe such a significant difference between the two groups in terms of crp and wbc levels. there are also literature data supporting our findings. generally, crp levels are used to assess treatment response rather than predicting treatment in patients with symptomatic hydronephrosis (1, 5, 9). in a prospective randomized trial, tsai et al. (5) also found no significant difference in wbc, bun, creatinine levels between the conservative and surgical treatment groups. but, in ercil et al’s study (1), no statistically significant difference was found by researchers between the treatment groups in terms of bun and creatinine levels, whereas wbc level was found to be statistically higher for surgical treatment group than the conservative treatment group in both trimester. as the writers say, the main reasons of this difference may be the number of archivio italiano di urologia e andrologia 2021; 93, 1 zeki bayraktar, ş. tuğba kahraman, e. seçkin alaç, i. yengel, d. sarıkaya kalkan 40 patients or the fact that their study group is composed of more complicated patients, especially the higher number of patients with urinary infection (1). however, in pregnant women with flank or low back pain, the presence of obstruction due to urinary tract infection should also be considered, and if appropriate, these infections should be treated appropriately (1, 10-13, 27). some limitations of this study should be taken into account. although the number of pregnant women who were followed prospectively was adequate, the number of multiple pregnancies which could be correlated with maternal hydronephrosis was low. because risk pregnancies including multiple pregnancies, are mostly followed in the central hospital of our university. however, the pregnant women who were followed in the central hospital of our university were not included in this study. therefore, we could not determine the correlation between maternal hydronephrosis and multiple pregnancies. hence, our cohort might not reflect an overall obstetric population in terms of the number of multiple pregnancies. conclusions most cases of maternal hydronephrosis in pregnant women without ureteral stones are asymptomatic. also, a significant part of symptomatic cases can be treated conservatively. however, some of the cases require surgical treatment(double-j ureteral stent insertion). for this reason, maternal hydronephrosis cannot be described as a completely physiological phenomenon. in cases requiring surgical treatment, fetal body weight, visual analogue scale and anterior-posterior renal pelvis diameter were higher than asymptomatic cases. references 1. ercil h, arslan b, ortoglu f, et al. conservative/surgical treatment predictors of maternal hydronephrosis: results of a single-center retrospective non-randomized non-controlled observational study. int urol nephrol. 2017; 49:1347. 2. fainaru o, amnog b, gamzu r, et al. the management of symptomatic hydronephrosis in pregnancy. br j obstet gynecol. 2002; 109:1385. 3. goldfarb ra, neerhurt gj, lederer e. management of acute hydronephrosis of pregnancy by ureteral stenting: risk of stone formation. j urol. 1989; 141:921. 4. wadasinghe su, metcalf l, metcalf p, perry d. maternal physiologic renal pelvis dilatation in pregnancy: sonographic reference data. j ultrasound med. dec 2016; 35:2659. 5. tsai yl, seow km, yieh ch, et al. comparative study of conservative and surgical management for symptomatic moderate and severe hydronephrosis in pregnancy: a prospective randomized study. acta obstet gynecol scand. 2007; 86:1047. 6. docimo sg, dewolf wc. high failure rate of indwelling ureteral stents in patients with extrinsic obstruction: experience at 2 institutions. j urol. 1989; 142:277. 7. jarrard dj, gerber gs, lyon es. management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. j urol. 1993; 42:263. 8. zwergel t, lindenmeir t, wullich b. management of acute hydronephrosis in pregnancy by ureteral stenting. eur urol. 1996; 29:292. 9. puskar d, balagovic i, filipovic a, et al. symptomatic physiologic hydronephrosis in pregnancy: incidence, complications and treatment. eur urol. 2001; 39:260. 10. jarrard dj, gerber gs, lyon es. management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. j urol 1993; 42:263. 11. hellawell go, cowan nc, holt sj, mutch sj. a radiation perspective for treating loin pain in pregnancy by doublepigtail stents. bju int. 2002; 90:801. 12. ringel a, richter s, shalev m, nissenkorn i. late complications of ureteral stents. eur urol. 2000; 38:41. 13. choi ci, yu yd, park ds. ureteral stent insertion in the management of renal colic during pregnancy. chonnam med j. 2016; 52:123. 14. wing da, fassett mj, getahun d. acute pyelonephritis in pregnancy: an 18-year retrospective analysis. am j obstet gynecol. 2014; 210:219e1. 15. cietak ka, newton jr. serial qualitative maternal nephrosonography in pregnancy. br j radiol. 1985; 58:399. 16. cietak ka, newton jr. serial quantitative maternal nephrosonography in pregnancy. br j radiol. 1985; 58:405. 17. di salvo dn. sonographic imaging of maternal complications of pregnancy. j ultrasound med 2003; 22:69. 18. rasmussen pe, nielsen fr. hydronephrosis during pregnancy: a literature survey. eur j obstet gynecol reprod biol. 1988; 27:249. 19. sadan o, berar m, sagiv r, et al. ureteric stent in severe hydronephrosis of pregnancy. eur j obstet gynecol reprod biol.1994; 56:79. 20. clayton jd, roberts ja. the effect of progesterone on ureteral physiology in a primate model. j urol. 1972; 107:945. 21. dell'atti l. our ultrasonographic experience in the management of symptomatic hydronephrosis during pregnancy. j ultrasound. 2014; 21; 19:1. 22. oto a, ernst rd, ghulmiyyah lm, et al. mr imaging in the triage of pregnant patients with acute abdominal and pelvic pain. abdom imaging. 2009; 34:243. 23. di salvo dn sonographic imaging of maternal complications of pregnancy. j ultrasound med. 2003; 22:69. 24. elgamasy a, elsherif a. use of doppler ultrasonography and rigid ureteroscopy for managing symptomatic ureteric stones during pregnancy. bju international. 2009; 106:262. 25. faúndes a, brícola-filho m, pinto e silva jl. dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. am j obstet gynecol. 1998; 178:1082. 26. kajbafzadeh am, keihani s, kameli sm, hojjat a. maternal urinary carbohydrate antigen 19-9 as a novel biomarker for evaluating fetalhydronephrosis: a pilot study. urology. 2017; 101:90. 41archivio italiano di urologia e andrologia 2021; 93, 1 maternal hydronephrosis 27. farr a, ott j, kueronya v, et al. the association between maternal hydronephrosis and acute flank pain during pregnancy: a prospective pilot-study. j matern fetal neonatal med. 2017; 30:2417. 28. naber kg, bergman b, bishop mc, et al. eau guidelines for the management of urinary and male genital tract infections. urinary tract infection (uti) working group of the health care office (hco) of the european association of urology (eau). eur urol. 2001; 40:576. 29. watson wj, brost bc. maternal hydronephrosis in pregnancy: poor association with symptoms of flank pain. am j perinatol. 2006; 23:463. correspondence zeki bayraktar, md (corresponding author) zbayraktar@medipol.edu.tr department of urology, school of medicine, istanbul medipol university çamlık mah. piri reis cad. dilşad sok. papatya sitesi no: 48, 34890-pendik-istanbul (turkey) şerife tuğba kahraman, md stkahraman@medipol.edu.tr elif seçkin alaç, md esalac@medipol.edu.tr i̇rem yengel, md iyengel@medipol.edu.tr deniz sarıkaya kalkan, md dkalkan@medipol.edu.tr department of obstetrics and gynecology, school of medicine, istanbul medipol university, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4350 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.350 clinical results of shock wave lithotripsy treatment in elderly patients with kidney stones: results of 1433 patients cevahir ozer, mehmet ilteris tekin department of urology, baskent university, adana, turkey. used have been identified, the results regarding the effect of age are contradictory (6-9). the purpose of this study was to evaluate the efficacy and safety of swl treatment in elderly patients with kidney stones. materials and methods data from 3024 consecutive patients who underwent swl treatment for urinary tract stone disease since 2003, in three centers of our university, were evaluated retrospectively. a total of 1433 patients in the adult age group (≥ 18 years old) treated for single kidney stones were included in the study. the swl decision was determined by patient and doctor preference. informed consent was obtained from all patients. before the procedure, all patients were evaluated by routine blood and urine analysis, plain abdominal radiography, renal ultrasonography (us), intravenous urography and/or non-contrast computed tomography (ct). swl was not applied in the presence of pregnancy, aortic aneurysm, morbid obesity (bmi ≥ 40), bleeding diathesis, active urinary infection and non-functional kidney on the side of the stone. lithostar modularis uro-plus (siemens medical systems, erlangen, germany), an electromagnetic lithotripter, was used in all three centers for the swl procedure. the procedure was applied to all patients under sedoanalgesia. after the procedure, oral analgesics were recommended to all patients. the results of the procedure were evaluated using kidneys, ureters and bladder (kub) radiography, us and/or ct performed 3 months after the swl treatment. data interpretation and statistical analysis the patients were divided into 3 groups (18-40 years, 41-64 years and ≥ 65 years) depending on their age. demographic data, stone parameters, stone-free rate (sfr) and cirf rate, number of swl sessions and complication rate were analyzed according to age groups. the presence of stones less than 4 mm was considered as clinically insignificant residual stone (10). the data were analyzed using the statistical package of social science (version 25.0; spss inc., chicago, il, usa). comparisons between groups were applied using oneway anova test. the catagorical variables between the groups was analyzed by using the chi square test. only significant variables were included in the multiple objective: in this study, it was aimed to evaluate the efficacy and safety of swl treatment in elderly patients with kidney stones. materials and methods: data from a total of 3024 patients who underwent swl treatment for urinary tract stone disease in three centers of our university were evaluated retrospectively. a total of 1433 patients in the adult age group treated for single kidney stones were included in the study. the patients were divided into 3 groups (18-40, 41-64 and ≥ 65) years depending on their age. demographic data, stone parameters, stone-free rate (sfr) and clinically insignificant residual fragment (cirf) rate, number of swl sessions and complication rate were analyzed according to the age groups. results: the mean age of the patients was 47.38 ± 13.24 years. stone size was significantly lower in the 18-40 years age group compared to other groups (p = 0.000) and the stones were mostly located on the right side in this age group (p = 0.007). there was no significant relationship between age groups and gender, stone localization, and number of swl sessions. the overall sfr was 66.4%. although the sfr was lower (61.4%) and the rate of multiple sessions (27.2%) was higher in ≥ 65 years group, there was no statistically significant difference between age groups regarding sfr, cirf, need for additional sessions, and complication rates. conclusions: due to its similar clinical results, treatment of swl should not be ignored as a treatment option in the geriatric patient group with kidney stones. key words: kidney stones; shock wave lithotripsy; elderly. submitted 14 september 2020; accepted 27 october 2020 introduction urinary stone disease affects individuals, healthcare systems and society due to its high prevalence, recurrent and unpredictable nature and dominance in workingage adults (1). shock wave lithotripsy (swl), flexible ureterorenoscopy, and percutaneous nephrolithotomy are the treatment options offered by the recent guidelines for the treatment of patients with kidney stones (24). as swl is an effective, non-invasive treatment that can be applied without general anesthesia, it remains a current treatment option (5-7). although many predictive factors of the success of swl, such as urinary tract anatomy, severity of concomitant obstruction, body mass index (bmi), stone size, stone density, stone to skin distance and type of swl device summary 351archivio italiano di urologia e andrologia 2020; 92, 4 shock wave lithotripsy in different age groups regression analysis. values of p less than 0.05 were considered statistically significant. results the mean age of the patients was 47.38 ± 13.24 years. stone size was significantly lower in the 18-40 age group compared to the other groups (p = 0.000) and in this age group, the stones were mostly located on the right side in this age group (p = 0.007). there was no significant difference between the age groups regarding gender, stone localization, and number of swl sessions (table 1). the overall sfr was 66.4%. although sfr was lower (61.4%) and the rate of multiple sessions (27.2%) was higher in the ≥ 65 years group, there was no statistically significant difference between the age groups regarding sfr, cirf, need for additional sessions, and complication rates (table 1). since there was only a significant difference in stone size between the groups, it was evaluated by multiple regression analysis, but no significant regression model was obtained. mortality due to swl procedure was not observed in any patient. steinstrasse was observed in 22 (1.5%) patients. its distribution by age groups was 6 (1.3%) patients in 18-40 years group, 14 (1.7%) in 41-64 years group and 2 (1.3%) in ≥ 65 years group. subcapsular hematoma was seen only in 1 patient in the 41-64 years group. one of the 2 patients whose operation was terminated due to arrhythmia was in the 18-40 years group and the other in the ≥ 65 years group. hospitalization was required due to pain in 1 patient and fever in another patient in the 41-64 years group. in the 18-40 years group, 1 patient developed pancreatitis and 1 patient developed urinoma. there was no statistically significant difference between age groups and complication rates (table 1). discussion swl remains one of the treatment methods for the management of kidney stones. treatment of kidney stones in elderly patients can be complicated by comorbid conditions. this makes swl treatment a good option for elderly patients, since it can be applied in an outpatient setting without general anesthesia. in several previous studies, it has been reported that the success rates of swl treatment decreased in elderly patients (10, 11). in a retrospective study of 472 diseases conducted by gokce et al., no difference was found between age groups and success rates of swl (6). in a study by chen et al., the sfr in elderly patients were found similar to that of non-elderly patients (41.1% vs 46.5%) (12). in our study, both sfr and cirf rate among age groups were similar. the fact that the parameters in the evaluation of treatment success such as different age groups (> 60 years, ≥ 65 years and >/≥ 70 years) definition of success (stone-free, stone-free plus cirf), definition of cirf (≤ 2 mm and ≤ 4 mm), time to evaluate success (1 month, 3 months) and evaluation method of treatment result (one or more of kub graphy, us, ct) are not homogeneous makes it difficult to comment on this issue (6, 8, 10, 12-15). chen et al. found that the rate of retreatment in elderly patients who received swl for kidney stones was similar to that of non-elderly patients (38.6% vs 42.9%, p = 0.485) (12). in our study, this rate was 27.2% and there was no statistically significant difference between the other age groups. the frequency of major complications associated with swl in the elderly population is between 0% and 5.6% (6, 12-14, 16). in our study, this rate is 1.9% and is consistent with the literature. whether the incidence of complications associated with swl in the elderly population is higher than the non-elderly population is controversial. while chen et al. had a higher risk of complications in patients ≥ 65 years, gokce et al. did not find any significant difference (6, 12). in our study, we did not find any difference between age groups in terms of complication rates. we believe that the lack of difference may result from the patient selection bias and swl techniques. as in our study, the use of electromagnetic lithotriptors in the treatment of kidney stones with swl provides better pain management (17). we think that better pain management can increase the success rate and reduce the complication rate by providing a better focus of the stone. the prominent limitations of this study are its retrospective nature and lack of some predictive parameters such as urinary tract anatomy, severity of concomitant obstruction, bmi, stone size due to its retrospective nature. however, the large number of patients is the strength of this study. conclusions our results suggest that there is no relationship between the clinical results of swl treatment and age. due to its similar clinical results, treatment of swl with similar clinical results should not be ignored as a treatment option in the geriatric patient group with kidney stones. table 1. characteristic features and clinical outcomes of patients. total 18-40 years 41-64 years ≥ 65 years p number (%) 1433 (100) 448 (31.3) 827 (57.7) 158 (11.0) gender (n, %) 2.77 male 882 (61.5) 286 (63.8) 506 (61.2) 90 (57.0) female 551 (38.5) 162 (36.2) 321 (38.2) 68 (43.0) stone size (mm) 11.99 ± 5.52 10.88 ± 5.00 12.43 ± 5.66 12.80 ± 5.78 0.000 side (n, %) 0.007 right 693 (48.3) 244 (54.5) 377 (45.5) 72 (45.6) left 740 (51.7) 204 (45.5) 450 (55.5) 86 (55.4) localization (n, %) 0.688 upper pole 171 (11.9) 61 (13.6) 90 (10.9) 20 (12.7) middle calyx 166 (11.6) 50 (11.2) 94 (11.4) 22 (14.0) lower pole 375 (26.2) 110 (24.6) 226 (27.3) 39 (24.8) pelvis 721 (50.3) 227 (50.7) 417 (50.4) 77 (45.5) number of sessions (n, %) 0.065 1 1119 (78.1) 364 (81.3) 640 (77.4) 115 (72.8) ≥ 2 314 (21.9) 84 (18.7) 187 (22.6) 43 (27.2) outcome (n, %) stone-free 951 (66.4) 306 (68.3) 548 (66.3) 97 (61.4) 0.285 cirf 297 (20.7) 92 (20.5) 172 (20.8) 33 (20.9) 0.674 complication (n, %) 29 (2.0) 9 (2.0) 17 (2.1) 3 (1.9) 0.991 archivio italiano di urologia e andrologia 2020; 92, 4 c. ozer, m. ilteris tekin 352 acknowledgements the authors would like to thank cagla sariturk, baskent university, adana dr. turgut noyan medical and research center, biostatistics unit. references 1. morgan ms, pearle ms. medical management of renal stones. bmj. 2016; 352:i52. 2. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-482. 3. assimos d, krambeck a, miller nl, et al. surgical management of stones: american urological association/endourological society guideline, part ii. j urol. 2016; 196:1161-1169. 4. pradere b, doizi s, proietti s, et al. evaluation of guidelines for surgical management of urolithiasis. j urol. 2018; 99:1267-1271. 5. knoll t, buchholz n, wendt-nordahl g. extracorporeal shockwave lithotripsy vs. percutaneous nephrolithotomy vs. flexible ureterorenoscopy for lower-pole stones. arab j urol. 2012; 10:336341. 6. gokce mi, akinci a, akpinar c, et al. comparison of efficacy of shock wave lithotripsy in different age groups. journal of urological surgery. 2017; 4:66-70. 7. kocakgol h, yilmaz ah, yapanoglu t, et al. efficacy and predictive factors of the outcome of extracorporeal shock wave lithotripsy: a review of one-thousand-nine-hundred-ninety-seven patients. journal of urological surgery. 2019; 6:207-212. 8. abdel-khalek m, sheir kz, mokhtar aa, et al. prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. scand j urol nephrol. 2004; 38:161-167. 9. ichiyanagi o, nagaoka a, izumi t, et al. age-related delay in urinary stone clearance in elderly patients with solitary proximal ureteral calculi treated by extracorporeal shock wave lithotripsy. urolithiasis. 2015; 43:419-426. 10. abe t, akakura k, kawaguchi m, et al. outcomes of shockwave lithotripsy for upper urinary-tract stones: a large-scale study at a single institution. j endourol. 2005; 19:768-773. 11. kimura m, sasagawa t. significance of age on prognosis in patients treated by extracorporeal shock wave lithotripsy. nihon hinyokika gakkai zasshi. 2008; 99:571-577. 12. chen yz, lin wr, lee cc, et al. comparison of safety and outcomes of shock wave lithotripsy between elderly and non-elderly patients. clin interv aging. 2017; 12:667-672. 13. philippou p, lamrani d, moraitis k, et al. shock-wave lithotripsy in the elderly: safety, efficacy and special considerations. arab j urol. 2011; 9:29-33. 14. sighinolfi mc, micali s, grande m,et al. extracorporeal shock wave lithotripsy in an elderly population: how to prevent complications and make the treatment safe and effective. j endourol. 2008; 22:2223-2226. 15. ng cf, wong a, tolley d. is extracorporeal shock wave lithotripsy the preferred treatment option for elderly patients with urinary stone? a multivariate analysis of the effect of patient age on treatment outcome. bju int. 2007; 100:392-395. 16. polat f, yesil s, ak e, et al. safety of eswl in elderly: evaluation of independent predictors and comorbidity on stone-free rate and complications. geriatr gerontol int. 2012; 12:413-417. 17. bianchi g, marega d, knez r, et al. comparison of an electromagnetic and an electrohydraulic lithotripter: efficacy, pain and complications. arch ital urol androl. 2018; 90:169-171. correspondence cevahir ozer, md cevahirozer@gmail.com mehmet ilteris tekin, md ilterist@hotmail.com department of urology, baskent university, adana (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12049 1 systematic review hemodialysis, pd has the advantage to be performed in a continuous ambulatory setting, called continuous ambulatory peritoneal dialysis (capd). other advantages are less risk to induce hemodynamic instability due to less pro-inflammatory effect involved with the procedure, providing nutritional support via dextrose in the dialysate, lower cost in long-term treatment due to minimal hospital visits or home-care hemodialysis, especially in a remote or rural setting where long-term dialysis is hardly obtained (24). the mortality risk for patients treated with pd is better than with hemodialysis in the short-term and long-term survival is better (1). even though capd treatment was less common than hemodialysis, capd has recently become the preferred mode of treatment for pediatric patients with esrd (1, 5). despite these facts, capd is related to several mechanical complications related to catheter placement, including catheter obstruction by omentum, clot, or fibrin, and catheter migration out of the pelvis. other complications are hypoalbuminemia, hyperglycemia, and infection, which can lead to peritonitis. all complications can lead to catheter failure, needing catheter removal or reinsertion (2, 6). according to ispd guidelines, the insertion of catheters in pediatric patients had an 18% of complication rate, including peritonitis, block of catheter, and catheter leakage (7). the omentectomy procedure, partial or total, was hypothesized for lowering the complication incidence. however, the role of the omentectomy procedure on capd catheter placement in pediatric patients has been differently evaluated in the literature, with some studies showing improvement while others showing no difference (6, 8-11). our study aims to define the advantages of omentectomy as a prophylactic procedure in pediatric patients. methods the systematic review was conducted following the preferred reporting items for systematic reviews and metaanalysis (prisma) (12). our protocol was registered in the prospero database (crd42023412846). introduction: the role of the omentectomy procedure on continuous ambulatory peritoneal dialysis (capd) catheter placement in pediatric patients has been differently evaluated in the literature, with some studies showing improvement while others showing no difference. our study aims to define the advantages of omentectomy compared to a procedure without omentectomy. methods: the literature searching in online databases (pubmed/medline, cochrane library, embase, scopus, and clinicaltrial.gov) following the preferred reporting items for systematic reviews and meta-analysis (prisma) guidelines, has been registered on prospero (crd42023412846). the protocol was performed through april 2023 and focused on pediatric patients treated with an omentectomy procedure and related complications. the risk of bias in each study was assessed using the risk of bias for the non-randomized control trials (robins-i). the effect estimates were extracted as risk ratios with 95% confidence intervals (ci). the heterogeneity of the studies was considered as high heterogeneity if i2 values above 50% or p < 0.05. results: in the total of 676 articles identified in the database searching for screening, nine studies with 775 patients met the criteria for inclusion. the omentectomy procedure significantly showed a lower incidence of catheter obstruction compared to the control group, (or 0.24 [95% ci, 0.12-0.49], p < 0.0001, i2 = 0%). moreover, omentectomy demonstrated a similar trend in the rate of removal or reinsertion of the catheter with high heterogeneity, or 0.25 [95% ci, 0.12-0.51), p = 0.0002, i2 = 70%). conclusions: the omentectomy procedure showed a lower incidence of catheter obstruction and complications leading to removal or reinsertion of the catheter. key words: continuous ambulatory peritoneal dialysis; omentectomy; omental procedure; pediatric; renal failure; complication. submitted 5 november 2023; accepted 11 november 2023 introduction renal replacement therapy for pediatric patients with endstage renal disease (esrd) can be through both peritoneal dialysis (pd) and hemodialysis modalities (1). compared to the prophylactic omentectomy procedure in reducing the complication rate of continuous ambulatory peritoneal dialysis in pediatric: a systematic review and meta-analysis gedewirya kusuma duarsa 1, ronald sugianto 2, pande made wisnu tirtayasa 3, ni made apriliani saniti 4, komang harsa abhinaya duarsa 5 1 department of urology, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia; 2 medical doctor study program, faculty of medicine, universitas udayana, bali, indonesia; 3 department of urology, faculty of medicine, universitas udayana, universitas udayana teaching hospital, bali, indonesia; 4 department of surgery, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia; 5 undergraduate medical doctor study program, faculty of medicine, universitas udayana, bali, indonesia. doi: 10.4081/aiua.2023.12049 summary archivio italiano di urologia e andrologia 2023; 95(4):12049 g.w. kusuma duarsa, r. sugianto, p.m.w. tirtayasa, et al. 2 search strategy according to the prisma statement, the systematic search was conducted in electronic databases, including pubmed/medline, cochrane library, embase, scopus, and clinicaltrial.gov for studies published until april 2023. the literature search included the following terms: (peritoneal dialysis[mesh terms]) or continuous ambulatory peritoneal dialysis[mesh terms] or (peritoneal dialysis[title/abstract] or continuous ambulatory peritoneal dialysis[title/abstract] or catheter dialysis [title/abstract] or capd[title/abstract]) and (omentum[mesh terms] or bursa, omental[mesh terms] or omentectomy[title/abstract] or omental procedure [title/abstract] or omentum procedure[title/abstract]). eligibility criteria for the systematic review, we included studies reporting about pediatric patients, below 18 years old, diagnosed with the end-stage renal disease treated by capd. the exclusion criteria were studies that did not compare the outcome or report a comparative outcome without any data on omentectomy. review articles, case reports, case series, animal studies, and editorial articles were not eligible for this study. the literature screening was done for the article in english only. study selection two author reviewers, at least one specialized in pediatric urology, independently evaluated the citations and abstracts. each reviewer identified article titles relevant to the topic. the selection processes of the study initiate with assessing the clarity of the eligibility criteria and the consistency of each author's decisions. the literature was screened by two reviewers independently (g.w.k.d. and r.s.) for the study's eligibility. first, the studies were screened by the title and the abstract, then they proceeded to full-text screening. in case of disagreement with the study selection, a third author (p.m.w.t) helped to solve controversies. data extraction one reviewer conducted data extraction, while another double-checked it to tabulate the necessary data for each study. data were extracted by two reviewers (g.w.k.d. and r.s.) from all the included studies, including the first author's name, publication date, place were studies were performed, sample mean age, sex, surgical procedure, complication rate (including catheter malposition, migrating catheter, catheter failure, catheter leakage, bleeding, and peritonitis). catheter failure was defined as the complication of capd that needed the removal or re-insertion of the catheter, while catheter obstruction was defined as the occlusion of the catheter due to omental wrapping or fibrin deposition. risk of bias assessment the risk of bias assessment of included studies was evaluated with the risk of bias in non-randomized studies of interventions (robins-i) tool by two reviewers (13). based on the eligibility of the information, the study was classified as low, moderate, serious, or critical for each domain. in case of discrepancies in the scores, the reviewers discussed to define a mutually accepted score. statistical analysis all dichotomous outcomes of retrospective studies were estimated as odd ratios (or) with 95% confidence intervals (ci). when the heterogeneity of the studies showed a p value < 0.05, the random-effects model will be used for the calculation. the meta-analysis data were presented as a forest plot using the revman version 5.4 application. results a total of 676 articles were identified in the database searching for screening. after duplicate removal and 573 studies were screened by title and abstract. out of them 27 studies were identified as potentially eligible studies and assessed by full-text for eligibility. nine studies (14-22) including 775 patients met the criteria for inclusion, as shown in figure 1. figure 1. literature search and selection flow chart. archivio italiano di urologia e andrologia 2023; 95(4):12049 3 peritoneal dialysis with omentectomy in pediatric patients four studies were conducted in america, three in europe, one in africa, and another in asia. the characteristics of included studies are summarized in table 1. the risk of bias assessment showed that all included studies have a serious bias, as shown in table 2. the funnel plot used to assess the publication bias and heterogeneity table 1. characteristics study and profile patient of the included studies. author location study total age sex operation complication catheter surgery patients (year) (gender, %) technique survival time ahmed, 2012 (14) saudi arabia retrospective 31 3.8 ± 6.5 male, 55 open laparotomy peritonitis n/a review female, 45 catheter occlusion by omentum catheter malposition catheter leakage cribs, 2012 (15) usa retrospective 81 12 male, 56 laparoscopy and catheter occlusion omentum and fibrin plug 177 ± 204 days review female, 44 open approach dialysate leakage perforation ladd, 2011 (16) usa retrospective 163 6.3 ± 5.6 male, 49.1 laparoscopy and catheter occlusion by omental wrapping, 759 days review female, 50.9 open surgery fibrin plug for omentectomy peritonitis 198 days catheter malposition for non-omentectomy dialysate leakage intestinal perforation catheter disruption laplant, 2018 (17) usa retrospective 153 4 ± 5.3 n/a open and catheter leakage 585 days, review laparoscopy surgery infection range 36–2872 days adhesion catheter migration ventral hernia macchini, 2006 (18) italy retrospective 78 6.3 ± 6.1 male, 61.5 open technique infection 80% > 12 months review female, 38.5 inguinal hernia 62% > 24 months catheter dislocation 58% > 48 months catheter obstruction by intestinal organs catheter leakage numanoglu, 2008 (19) south africa prospective 26 8.6 male, 53.8 laparoscopy technique catheter obstruction by fibrinous adhesion, 6.4 ± 6.3 months cohort female, 46.2 fimbria, sigmoid colod, omentum catheter leakage bleeding displacement infection schuh, 2021 (20) usa retrospective 184 7.4 (0.27-14.7) male, 62.5 open and laparoscopy mechanical failure 39 days (17-112) review female, 37.5 technique infection catheter migration catheter leakage pumford, 1994 (21) united kingdom retrospective 21 1-10 (range) male, 47.6 mini-laparotomy catheter obstruction n/a review female, 52.4 lewis, 1995 (22) united kingdom retrospective 38 7.8 n/a mini laparotomy catheter obstruction by omentum n/a review peritonitis appendicitis n/a: not available. data are expressed as mean ± standard deviation or median (min-max interquartile range) or count %, as appropriate. table 2. risk of bias assessment. study design bias bias in selection bias in bias due to bias due bias in bias in overall due to of participants measurement departures from to missing measurement selection of the bias confounding into the study of interventions intended interventions data of outcomes reported result ahmed 2012 retrospective review serious no information serious moderated low moderated moderated serious laplant 2018 retrospective review serious serious serious no information low moderate moderate serious ladd 2011 retrospective review serious serious serious moderated moderated serious serious serious laplant 2018 retrospective review serious serious serious no information low moderate moderate serious manchini 2006 retrospective review serious no information moderate low low moderate moderate serious numanoglu 2008 prospective cohort serious no information serious moderate low moderate serious serious schuh 2021 retrospective review serious moderate moderate moderated moderate moderated moderated serious pumford 1994 retrospective review serious serious serious no information no information serious moderate serious lewis 1995 retrospective review serious serious serious no information no information serious serious serious archivio italiano di urologia e andrologia 2023; 95(4):12049 g.w. kusuma duarsa, r. sugianto, p.m.w. tirtayasa, et al. 4 is presented in figure 2. the meta-analysis was assessed for four comparative outcomes: complications leading to removal or reinsertion, catheter obstruction, infections, and catheter leakage. among 339 patients in four studies, the omentectomy procedure significantly showed a lower incidence of catheter obstruction compared to the control group (or 0.24 [95% ci, 0.12-0.49], p < 0.0001, i2 = 0%) as in the forest plot shown in figure 3a (16, 18, 21, 22). moreover, omentectomy demonstrated a similar trend for removal or reinsertion of the catheter in five studies, including 685 patients, with high heterogeneity (or 0.25 [95% ci, 0.12-0.51), p = 0.0002, i2 = 70%). forest plot is shown in figure 3b (14-17, 19, 20). the complication of peritonitis and catheter leakage were reported only in two studies for each complication (16, 17, 22). in contrast, the analysis of both complications demonstrated insignificant results with no heterogeneity figure 3. forest plot pooled effect estimated showed statistical significance. a) omentectomy showed a lower incidence of complications lead to catheter removal in pediatric patients; b) omentectomy showed a lower incidence of complication specific to catheter obstruction compare than without performing omentectomy. figure 2. funnel plot showing that the analysis of removal or reinsertion and leakage of the catheter has high heterogeneity. archivio italiano di urologia e andrologia 2023; 95(4):12049 5 peritoneal dialysis with omentectomy in pediatric patients found (p-value heterogeneity > 0.05). the omentectomy procedure has a insignificantly lower incidence of infections leading to peritonitis (or 0.61 [95% ci, 0.28-1.34], p = 0.22, i2 = 73%), as shown in forest plot in figure 4a. the omentectomy procedure showed a insignificantly higher incidence of catheter leakage compared to capd without omentectomy (or 1.55 [0.70-3.45], p = 0.28, i2 = 0%), as shown in forest plot in figure 4b. discussion in pediatric renal replacement therapy, capd is the preferred treatment option which can be performed at home by low-trained caregivers without routinely visiting the hospital. to reduce the complication of capd, catheter insertion and the improvement in out-hospital care are essential (23). the catheters used for pd are varied, including rigid catheters, tenckhoff catheters, which consist of straight, swan neck, or coiled, and adapted catheters, either from nasogastric tube, surgical drain, or dialysis catheter. however, the most preferred catheter in capd is a flexible cuffed, single or double cuffed, catheter, which can be placed through laparoscopic surgery, open surgery, or the seldinger technique (a guidewire technique under local anesthesia). the omentectomy procedure can be performed only in surgical insertion, either laparoscopic or open technique (2, 23). despite the catheter variability and differences in insertion methods, the comparison of different types and different techniques did not affect the complication rate of capd (24, 25). the complication of capd catheter may lead to pd failure, which prompts catheter removal/reinsertion or return to hemodialysis. the most common causes of capd failure are catheter-related infection and malfunction (26). however, most infectious complications, catheter-related or peritonitis, resolve with conservative treatment, while the catheter obstruction, due to omental blockage, fibrin blockage, clot blockage, or catheter migration with obstruction, may necessitate removal or replacement (10). even if catheter-related infections and peritonitis can be resolved by medication, peritonitis is the more common cause of catheter revision in the first year of treatment (27). the study by phan et al. demonstrated that nonomentectomy catheter insertion was associated with a high re-operative rate for infection and malfunction (25). therefore, the malfunction of the catheter, related to obstruction and catheter migration, often leads to catheter failure (7). moreover, pediatric patients have thinner abdominal muscle layers compared to adults making it difficult to affix the catheter in place, but it helps prevent catheter tip movement and catheter liquid leakage to the skin. these differences might contribute to the different complication rates in pediatrics (15).the comparative studies demonstrated that omentectomy is a statistically significant protective factor in ages below one year old to lower the incidence of early obstruction. the catheter placement with an omentectomy procedure was postulated as a preventive measure against catheter failure due to fluid entrapment or obstruction (24, 27). in this study, the analysis of odds of catheter failure and catheter obstruction in pediatrics significantly assessed the advantage of omentectomy procedures, which means that omentectomy reduces the risk of catheter failure and catheter obstruction due to omental wrap. the same result was shown in a meta-analysis study by kim et al. in the general population (28). the current guidelines for pd in pediatrics did not discuss in deepl regarding the effect of omentectomy procedures (7, 29, 30). on the contrary, there were several recommendations for successful peritoneal dialysis in infants figure 4. forest plot pooled effect estimated showed an insignificant result. a) omentectomy procedure was compared to non-omentectomy for peritonitis, showing an insignificant different result; b) odds of catheter leakage was insignificantly higher in patients with omentectomy. archivio italiano di urologia e andrologia 2023; 95(4):12049 g.w. kusuma duarsa, r. sugianto, p.m.w. tirtayasa, et al. 6 and children. the most common complication is peritonitis, minimalized by prophylactic antibiotics and a downward or lateral exit site placement, appropriate distance from the ostomy site and double-cuffed peritoneal dialysis catheter. for catheter leakage, prevention depend by subcutaneous tissue. therefore, in infants weighing below 3 kg it is recommended to use a single cuff due to the lack of substantial subcutaneous tissue. the other recommendations are delaying initiation of peritoneal dialysis post-catheter insertion for more than 48 hours, using low fill volumes when initiation is started, and using a tenckhoff catheter (7, 30, 31). our study meta-analysis is an update on omentectomy outcome, with more specific analysis in pediatric patients. the previous study by kim et al. has a similar design, but it analyses omental procedures in the general population (27). the limitation of our study is that all included studies were retrospective studies, which are at high risk of bias. therefore, this study cannot differentiate confounding factors that may affect the outcome, including children’s age, weight, type of catheter, surgical techniques (laparoscopic or open surgical), and out-hospital care. however, the current literature demonstrated that those confounding factors, except the patient’s age, did not statistically affect the results. our meta-analysis study brings conclusive finding for controversial advantages of the prophylactic omentectomy procedure. besides, inclusion studies demonstrated a low heterogeneity, which ascertains the findings of the analysis. the rating of the evidence base of this study according to the grade criteria, classified it as moderate (32). finally, we encourage all academicians to perform further research on the omentectomy procedure, as a mono-factor, to decrease the incidence of capd complications. conclusions our meta-analyses demonstrated that the capd with omentectomy as prophylactic procedure in pediatrics is advantageous. in fact, although the omentectomy procedures might increase the risk of catheter exit leakage (p = 0.28), it significantly showed a lower incidence of catheter obstruction (p < 0.0001, or 0.24) and complications leading to removal or reinsertion of the catheter (p < 0.0001, or 0.25). funding statement our study received funding from universitas udayana in contract no: b/1.683/un14.4.a/pt.01.03/2023 for the cost of research and publication. references 1. himmelfarb j, vanholder r, mehrotra r, tonelli m. the current and future landscape of dialysis. nat rev nephrol. 2020; 16:573-85. 2. de galasso l, picca s, guzzo i. dialysis modalities for the management of pediatric acute kidney injury. pediatr nephrol. 2020; 35:753-65. 3. spector bl, misurac jm. renal replacement therapy in neonates. neoreview. 2019; 20:e697-710. 4. niang a, iyengar a, luyckx va. hemodialysis versus peritoneal dialysis in resource-limited settings: curr opin nephrol hypertens. 2018; 27:463-71. 5. pindi g, kawle v, sunkara rr, et al. continuous ambulatory peritoneal dialysis peritonitis: microbiology and outcomes. indian j med microbiol. 2020; 38:72-7. 6. rasmussen sk. an overview of pediatric peritoneal dialysis and renal replacement therapy in infants: a review for the general pediatric surgeon. semin pediatr surg. 2022; 31:151193. 7. nourse p, cullis b, finkelstein f, et al. ispd guidelines for peritoneal dialysis in acute kidney injury: 2020 update (paediatrics). perit dial int j int soc perit dial. 2021; 41:139-57. 8. aksu n, alparslan c, yavascan o, et al. a single-center experience on percutaneously performed partial omentectomy in pediatric peritoneal dialysis patients. ren fail. 2014; 36:755-9. 9. baksi a, asuri k, vuthaluru s, et al. does laparoscopic omentectomy reduce capd catheter malfunction: a three-arm pilot randomized trial. indian j nephrol. 2022; 32:299. 10. reissman p, lyass s, shiloni e, et al. placement of a peritoneal dialysis catheter with routine omentectomy-does it prevent obstruction of the catheter? eur j surg. 2003; 164:703-7. 11. radtke j, schild r, reismann m, et al. obstruction of peritoneal dialysis catheter is associated with catheter type and independent of omentectomy: a comparative data analysis from a transplant surgical and a pediatric surgical department. j pediatr surg. 2018; 53:640-3. 12. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021; 372:n71. 13. sterne ja, hernán ma, reeves bc, et al. robins-i: a tool for assessing risk of bias in non-randomised studies of interventions. bmj. 2016; 355:i4919. 14. ali ahmed am, safer mm, badughiash as, et al. risk factors for peritoneal dialysis catheter failure in children: ann pediatr surg. 2012; 8:35-8. 15. cribbs rk, greenbaum la, heiss kf. risk factors for early peritoneal dialysis catheter failure in children. j pediatr surg. 2010; 45:585-9. 16. ladd ap, breckler fd, novotny nm. impact of primary omentectomy on longevity of peritoneal dialysis catheters in children. am j surg. 2011; 201:401-5. 17. laplant mb, saltzman da, segura bj, et al. peritoneal dialysis catheter placement, outcomes and complications. pediatr surg int. 2018; 34:1239-44. 18. macchini f, valadè a, ardissino g, et al. chronic peritoneal dialysis in children: catheter related complications. a single centre experience. pediatr surg int. 2006; 22:524-8. 19. numanoglu a, rasche l, roth ma, et al. laparoscopic insertion with tip suturing, omentectomy, and ovariopexy improves lifespan of peritoneal dialysis catheters in children. j laparoendosc adv surg tech. 2008; 18:302-5. 20. schuh mp, nehus e, liu c, et al. omentectomy reduces the need for peritoneal dialysis catheter revision in children: a study from the pediatric nephrology research consortium. pediatr nephrol. 2021; 36:3953-9. 21. pumford n, cassey j, uttley ws. omentectomy with peritoneal catheter placement in acute renal failure. nephron. 1994; 68:327-8. 22. lewis m, webb n, smith t, roberts d. routine omentectomy is not required in children undergoing chronic peritoneal dialysis. adv perit dial. 1995; 11:293-5 23. bieber s, mehrotra r. peritoneal dialysis access associated infections. adv chronic kidney dis. 2019; 26:23-9. archivio italiano di urologia e andrologia 2023; 95(4):12049 7 peritoneal dialysis with omentectomy in pediatric patients 24. lemoine c, keswani m, superina r. factors associated with early peritoneal dialysis catheter malfunction. j pediatr surg. 2019; 54:1069-75. 25. phan j, stanford s, zaritsky jj, deugarte da. risk factors for morbidity and mortality in pediatric patients with peritoneal dialysis catheters. j pediatr surg. 2013; 48:197-02. 26. tiewsoh k, soni a, dawman l, et al. chronic peritoneal dialysis in children with chronic kidney disease: an experience from a north indian teaching institute. j fam med prim care. 2021; 10:3682. 27. kim jk, lolas m, keefe dt, et al. omental procedures during peritoneal dialysis insertion: a systematic review and metaanalysis. world j surg. 2022; 46:1183-95. 28. bakal u, sarac m, tartar t, et al. peritoneal dialysis in children: infectious and mechanical complications: experience of a tertiary hospital in elazıg, turkey. niger j clin pract. 2022; 25:1227. 29. gilbert j, lovibond k, mooney a, dudley j. renal replacement therapy: summary of nice guidance. bmj. 2018; 363:k4303. 30. canadian association of pediatric nephrologists (capn) and peritoneal dialysis working group, white ct, gowrishankar m, feber j, yiu v. clinical practice guidelines for pediatric peritoneal dialysis. pediatr nephrol. 2006; 21:1059-66. 31. sanderson kr, harshman la. renal replacement therapies for infants and children in the icu: curr opin pediatr. 2020; 32:360-6. 32. guyatt g, oxman ad, akl ea, et al. grade guidelines: 1. introduction—grade evidence profiles and summary of findings tables. j clin epidemiol. 2011; 64:383-94. correspondence gede wirya kusuma duarsa (corresponding author) gwkurology@gmail.com department of urology, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, denpasar, bali, indonesia jl. sudirman, denpasar, bali, indonesia, 80113 ronald sugianto rsugianto@student.unud.ac.id medical doctor study program, faculty of medicine, universitas udayana, bali, indonesia pande made wisnu tirtayasa wisnu_tirtayasa@unud.ac.id department of urology, faculty of medicine, universitas udayana, universitas udayana teaching hospital, bali, indonesia ni made apriliani saniti apriliani.saniti@gmail.com department of surgery, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia komang harsa abhinaya duarsa abhinaya.duarsa@gmail.com undergraduate medical doctor study program, faculty of medicine, universitas udayana, bali, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2020; 92, 2158 original paper evaluation of the influence of subinguinal varicocelectomy procedure on seminal parameters, reproductive hormones and testosterone/estradiol ratio ünal öztekin, mehmet caniklioğlu, sercan sarı, volkan selmi, abdullah gürel, mehmet şakir taşpınar, levent işıkay bozok unıversıty faculty of medicine, department of urology, yozgat, turkey. objective: varicocele is the most commonly surgically curable cause of male infertility. however, the mechanisms related to the effect of reducing fertility potential have not been clearly identified. the aim of this study was to investigate the effects of varicocelectomy on semen parameters, reproductive hormones and testosterone / estradiol ratio. matherial and methods: fifty seven patients outcomes were evaluated before and 6 months after subinguinal microsurgical varicocelectomy. semen parameters, reproductice hormones and testosteron/estradiol ratio results of patients were compared retrospectively. results: the mean age was 26.8 years. fifty four (94.7%) patients had grade 3 and 3 (5.3%) patients had grade 2 varicocele. there was a significant increase in semen parameters except semen volume. there was a statistically significant increase in serum testosterone levels, but not on testosterone/ estradiol ratio. conclusions: according to our results, microsurgical subinguinal varicocelectomy can be recommended for both improving semen parameters and hormonal recovery. key words: varicocele; testosterone; testosterone/estradiol ratio; semen parameters; reproductive hormones. submitted 14 september 2019; accepted 23 december 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.158 introduction varicocele is a genital abnormality that disrupts the growth and development of the ipsilateral testis and can also reduce the quality of life due to pain symptoms. it is seen in 11.7% of adult males and 25.4% of whose with abnormal sperm parameters. it is thought to cause hypogonadism and to be associated with male subfertility (1). varicocele is the most commonly surgically curable cause of male infertility (2). pain and feeling of scrotal fullness are also indications for surgical treatment (3). factors such as reflux of kidney and adrenal metabolites, hypoxia, endocrine disorders, increased sperm dna fragmentation, oxidative stress, increased intratesticular apoptosis, and disruption of intratesticular enzymes due to temperature increase have been implicated in the etiology (4). however, the mechanisms related to the effect of reducing fertility potential have not been clearly identified (1). there is also limited evidence of how leyding cells and testosterone production are affected after varicocelectomy and how much it changes testosterone production (5). in the literature, it is generally indicated that leydig cell function is negatively affected in varicocele patients with decreased testosterone production and that also hormone level is improved by varicocelectomy (4, 6, 7). studies on rats have shown pathological changes such as increased apoptosis of leydig and sertoli cells causing decreased viability and testosterone synthesis due to varicocele (8, 9). however, there are studies advocating that varicocelectomy has no effect on serum testosterone levels in human studies (3, 10, 11). local hormonal balance between testicular testosterone and estradiol ratio is effective on spermatogenesis. impairment of this balance in semen and serum can cause infertility by disrupting normal spermatogenesis. varicocelectomy can positively affect the balance between testosterone and testosterone/estradiol ratio (t/e) (4). therefore, evaluating t/e ratio changes may provide more useful information (12). the aim of this study was to investigate the effects of varicocelectomy on sperm parameters, reproductive hormones and t/e ratio. materials and methods data of patients who presented with infertility and/or pain and then underwent microsurgical subinguinal varicocelectomy between november 2017 and july 2019 were evaluated retrospectively. after approval from the local ethics committee, patients aged 18 and over were included in the study and the study was conducted in accordance with the declaration of helsinki. fifty seven patients who met the study criteria were evaluated. all patients were examined while standing and evaluated with valsalva maneuver and then color flow doppler ultrasonography (cfdu) was performed. patients were classified according to clinical grading system. grade 0 (subclinical): cannot be detected by inspection or palpation but can only be detected by cfdu. grade i: only palpable on valsalva maneuver. 159archivio italiano di urologia e andrologia 2020; 92, 2 varicocelectomy and hormones grade ii: palpable without valsalva maneuver. grade iii: visible with no need for palpation. patients with known or detected hormonal pathology (hypo/hypergonadism, hypo/hyperthyroidism, hyperprolactinemia), azoospermia and cryptozoospermia (≤ 1 million/ml), body mass index (bmi) ≥ 30 kg/m2, genital tract infection (orchitis, epididymitis, urethritis) and patients who had used chemotherapeutic drugs were excluded from the study. semen analyses were performed after 3-7 days of abstinence using the 2010 criteria of the world health organization (13). semen volume, sperm concentration, total sperm count, progressive motility and total motility data were recorded as semen parameters before and 6 months after varicocelectomy. age, body mass index, hormone profiles including follicle stimulating hormone (fsh), luteinizing hormone (lh), prolactin (prl), estradiol (e2) and total testosterone (t) results and t/e ratios were recorded. subinguinal incision was performed and microsurgical varicocelectomy procedure was performed by defining spermatic cord from external inguinal ring in all patients. preoperative and postoperative results of patients were compared retrospectively. statistical analysis all statistical tests were performed using the statistics package for social sciences version 25 (ibm spss®, chicago, il). kolmogorovsmirnov test was used to determine the normal distribution of data. paired-sample t-test was used for pre-postoperative comparison of parametric data and wilcoxon signed ranks test was used for pre-postoperative comparison of non-parametric data. a value p < 0.05 was considered statistically significant. results a total of 57 patients aged 18-41 (mean: 26.8) were included in the study. the mean bmi value was 24.77 (18.31-29.41) kg/m2. the varicocele grade was grade 2 in 3 (5.3%) patients who underwent varicocelectomy. fifty four (94.7%) patients had grade 3 varicocele. in 21 (36.8%) of the patients, no increase was observed according to the preoperative testosterone values, while 31 (54.3%) had less than 50% and 5 (8.7%) had more than 50% change (table 1). there was no significant difference between preoperative and postoperative semen volumes. there was a statistically significant improvement in sperm concentration, total sperm count, progressive and total sperm motility compared to preoperative period (p < 0.05) (table 2). there were no significant changes in serum fsh, lh, e2, prl values compared to preoperative values. there was a statistically significant increase in serum testosterone levels 507.63 ± 174.27, 547.01 ± 184.59 ng/dl preoperatively and postoperatively, respectively (p = 0.003). however, t/e ratios (preoperative and postoperative 22.36 ± 9.46, 22.87 ± 11.10, respectively) were not significantly changed (p = 0.978) (table 3). discussion varicocele is an abnormal dilation of the plexus pampiniformis and testicular spermatic veins in the spermatic cord (14). it is often caused by left side veins and is a venous dilatation disorder characterized by increased pressure within the internal spermatic vein (6). it affects male fertility by creating anatomical and functional damage within the testis (15). it has been reported that patients with varicocele have higher degree of sperm dna fragmentation when compared to healthy individuals. also, varicocele patients with abnormal sperm parameters have higher fragmentation levels than those with normal sperm parameters (16). more severe damage to the testicle has been reported as the degree of varicocele increases (17). increased venous pressure in the varicocele, which is a dilated venous disease, can cause venous stasis by delaying vascular washout, resulting in impaired thermal regulation leading to hyperthermia and accumulation of toxins (18). as a result of hyperthermia, it has been suggested that after germ cell apoptosis, inhibition of enzymes involved in spermatogenesis (19) and steroid biosynthesis decreases convertable 1. overall and specific course rating. table 2. comparison of semen parameters before and after varicocelectomy. table 3. comparison of hormonal data before and after varicocelectomy. age (mean) (min-max) 26.8 (18-41) bmi kg/m2 (mean)(min-max) 24.77 (18.31-29.41) testosterone change no increase (n) 21 (36.8%) 0-50% increase (n) 31 (54.3%) 50-100% increase (n) 5 (8.7%) bmi: body mass index. preoperative postoperative p value semen volume, ml (mean ± sd) 3.12 ± 1.39 3.33 ± 1.56 0.105b sperm concentration (mil/ml) (mean ± sd) 35.54 ± 24.76 45.13 ± 23.76 0.001a total sperm count, (mil) (mean ± sd) 113.44 ± 98.54 153.84 ± 115.98 < 0.001b progressive motility (type a) (%) 24.71 ± 10.57 28.95 ± 9.95 0.001a total motility (type a+b) (%) 41.96 ± 16.00 45.14 ± 14.63 0.011b a calculated using paired-sample t-test. b calculated using wilcoxon signed ranks tests. sd: standard deviation. preoperative postoperative p valueb serum fsh, miu/ml (mean ± sd) 3.69 ± 2.69 3.73 ± 2.50 0.689 serum lh, miu/ml (mean ± sd) 3.33 ± 1.51 3.32 ± 1.68 0.161 serum prl, ng/ml (mean ± sd) 10.20 ± 3.96 9.86 ± 3.35 0.609 serum e2, ng/l (mean ± sd) 24.88 ± 8.78 26.48 ± 9.02 0.445 serum t, ng/dl (mean ± sd) 507.63 ± 174.27 547.01 ± 184.59 0.003 t/e2 (mean ± sd) 22.36 ± 9.46 22.87 ± 11.10 0.978 b wilcoxon signed ranks tests. sd: standard deviation. fsh: follicle stimulating hormone. lh: luteinizing hormone. prl: prolactin. e2: estradiol and t: total testosterone t/e2: testosterone/estradiol ratio. archivio italiano di urologia e andrologia 2020; 92, 2 ü. öztekin, m. caniklioğlu, s. sarı, v. selmi, a. gürel, m. şakir taşpınar, l. işıkay 160 sion to intratesticular testosterone and synthesis (20). in support of this theory, studies advocating increased testosterone levels after varicocelectomy are presented. in the study of tanrıkut et al. (6), they reported the results of testosterone before and after varicocelectomy as 416 ng/dl and 469 ng/dl respectively in their series of 325 patients with palpable varicocele. they showed a significant increase in testosterone level in two thirds of patients after varicocelectomy. the results of our study were 507.63 ± 174.27 and 547.01 ± 184.59 ng/dl before and after surgery respectively and there was a significant increase (p = 0.003). similarly, two-thirds of our patients had increased testosterone. in the study by sathya s. et al, testosterone levels increased from 1.77 ± 0.18 ng/ml to 3.01 ± 0.43 ng/ml after varicocelectomy (21). hsiao et al. likewise stressed that there was a significant increase in testosterone level and sperm concentration and total sperm count in all varicocelectomy patients, including the 5th and 6th decade age group (22). in a meta-analysis evaluating 814 patients, it was concluded that surgical treatment of varicocele significantly increased leyding cell function and testosterone production (23). numerous studies have shown that testosterone levels are elevated after varicocelectomy, but there are also studies advocating that it does not cause any changes. in the study by rodriguez et al., there was no relationship between varicocele and low testosterone. it was also argued that there was no improvement in semen profile in treated varicoceles (10). similarly, panach-navarrete et al. showed that there was no correlation between the presence of varicocele and decreased serum testosterone level (11). zheng et al. detected that there is not significant change in testosterone levels compared to preoperative values in 104 infertile patients after left or bilateral varicocelectomy procedure (24). although the prevalence of varicocele is widespread worldwide and associated with low testosterone levels, this relationship has not been clearly demonstrated. in this context, it is considered that t/e ratio evaluation can provide more useful information (12). simorangkir et al. concluded that the t/e2 ratio in pampiniform plexus was significantly lower than in the control group in their study by creating varicocele in a rabbit model (25). although there are limited studies on this subject in the literature, the pre and postoperative t/e ratio was found to be 19 ± 7.7 and 27.5 ± 1.2 in the prospective study conducted by gomaa et al. (4). they emphasized that there was a significant postoperative decrease in e2 level (26.9 ± 3.2 and 22.9 ± 3.1 pg/ml p < 0.001, respectively). in our study, t/e2 ratios were 22.36 ± 9.46 and 22.87 ± 11.10, before and after surgery, respectively (p = 0.978). there was an increase in postoperative serum e2 values but it was not statistically significant (p = 0.445). when we evaluated only 36 patients with increased testosterone levels, the mean preoperative and postoperative e2 levels were 23.85 ± 9.17 and 26.92 ± 9.57 ng/l (p = 0.104), respectively. there was an increase in e2 values with increasing t levels. however, it was not statistically significant. in addition, there was no significant increase in t/e ratios in this patient group (p = 0.470). no significant difference was found between the two groups whose t level increased and showed no change (p = 0.212). therefore, it is suggested that these changes may be in the testicular cells regardless of peripheral aromatase activity. although these results suggest that improvement in leydig cell functions after varicocelectomy may increase estradiol production, further prospective randomized studies with more patients and longterm follow-up are needed. a meta-analysis of 548 patients evaluating seven studies emphasized that varicocelectomy provided significant improvement, particularly on progressive sperm motility (26). in another meta-analysis, the varicocelectomy group was compared to the untreated group in terms of semen parameters in adolescents, but no difference was observed between the two groups (27). in general, it is seen that microsurgical varicocelectomy increases sperm concentration and motility (28). also, there was a significant increase in semen volume, sperm concentration and total number, progressive and total motility after varicocelectomy in our study. retrospective design of our study is a limitation. other limitations include low number of study population and short follow-up, collection of single-centered data, and failure to evaluate pregnancy outcomes. conclusions when the data of our study were evaluated, we concluded that subinguinal varicocelectomy procedure with microsurgical method provided significant improvement on semen parameters and testosterone levels. however, we did not find a significant relationship between t/e2 ratio and surgery. according to our results, microsurgical subinguinal varicocelectomy can be recommended for both improving semen parameters and hormonal recovery. however, multicenter prospective randomized studies are needed to clarify relationship with reproductive hormones and semen parameters, including more patients with long-term follow-up and pregnancy rate evaluation. references 1. jungwirth a, diemer t, kopa z, et al. eau guidelines on male infertility. in: jungwirth a, editor. eau guidelines 2018. arnhem: eau guidelines office. 2018; pp. 734-5. 2. sabanegh e, agarwal a. male infertility. tenth edition. ed. kavoussi l, partin a, novick a, peters c, editors: campbell walsh urology. 2012; pp 617-42. 3. resorlu b, kara c, sahin e, unsal a. the significance of age on success of surgery for patients with varicocele. int urol nephrol. 2010; 42:351-6. 4. gomaa md, motawaa ma, al-nashar am, el-sakka ai. impact of subinguinal varicocelectomy on serum testosterone to estradiol ratio in male patients with infertility. urology. 2018; 117:70-7. 5. tanrikut c, goldstein m. varicocele repair for treatment of androgen deficiency. curr opin urol. 2010; 20:500-2. 6. tanrikut c, goldstein m, rosoff js, et al. varicocele as a risk factor for androgen deficiency and effect of repair. bju int. 2011; 108:1480-4. 7. ando s, giacchetto c, colpi g, et al. physiopathologic aspects of leydig cell function in varicocele patients. j androl. 1984; 5:163-70. 161archivio italiano di urologia e andrologia 2020; 92, 2 varicocelectomy and hormones 8. oh ys, jo nh, park jk, gye mc. changes in inflammatory cytokines accompany deregulation of claudin-11, resulting in intersertoli tight junctions in varicocele rat testes. j urol. 2016; 196:1303-12. 9. luo dy, yang g, liu jj, et al. effects of varicocele on testosterone, apoptosis and expression of star mrna in rat leydig cells. asian j androl. 2011; 13:287-91. 10. rodriguez pena m, alescio l, russell a, et al. predictors of improved seminal parameters and fertility after varicocele repair in young adults. andrologia. 2009; 41:277-81. 11. panach-navarrete j, morales-giraldo a, ferrandis-cortes c, et al. is there a relationship between varicocele and testosterone levels? aging male. 2019:1-7. 12. parekattil sj, agarwal a. male infertility: contemporary clinical approaches, andrology, art & antioxidants. male infertility: springer science & business media. 2012; pp. 247-59. 13. world healt organization: laboratory manual for the examination and processing of human semen, 5th ed. geneva: who press; 2010. 14. lomboy jr, coward rm. the varicocele: clinical presentation, evaluation, and surgical management. semin intervent radiol. 2016; 33:163-9. 15. yildiz o, gul h, ozgok y, et al. increased vasoconstrictor reactivity and decreased endothelial function in high grade varicocele; functional and morphological study. urol res. 2003; 31:323-8. 16. alargkof v, kersten l, stanislavov r, et al. relationships between sperm dna integrity and bulk semen parameters in bulgarian patients with varicocele. arch ital urol androl. 2019; 91:2. 17. steckel j, dicker ap, goldstein m. relationship between varicocele size and response to varicocelectomy. j urol. 1993; 149:769-71. 18. eisenberg ml, lipshultz li. varicocele-induced infertility: newer insights into its pathophysiology. indian j urol. 2011; 27:58-64. 19. wang c, cui yg, wang xh, et al. transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. j clin endocrinol metab. 2007; 92:3292-304. 20. rajfer j, turner tt, rivera f, et al. inhibition of testicular testosterone biosynthesis following experimental varicocele in rats. biol reprod. 1987; 36:933-7. 21. sathya srini v, belur veerachari s. does varicocelectomy improve gonadal function in men with hypogonadism and infertility? analysis of a prospective study. int j endocrinol. 2011; 2011:916380. 22. hsiao w, rosoff js, pale jr, et al. older age is associated with similar improvements in semen parameters and testosterone after subinguinal microsurgical varicocelectomy. j urol. 2011; 185:620-5. 23. li f, yue h, yamaguchi k, et al. effect of surgical repair on testosterone production in infertile men with varicocele: a metaanalysis. int j urol. 2012; 19:149-54. 24. zheng yq, gao x, li zj, et al. efficacy of bilateral and left varicocelectomy in infertile men with left clinical and right subclinical varicoceles: a comparative study. urology. 2009; 73:1236-40. 25. simorangkir l, sihombing at, noegroho bs. estrogen-testosterone ratio in plexus pampiniform of normal rabbits and rabbits with left artificial varicocele. indonesian journal of urology. 2013; 20:1-4. 26. kim hj, seo jt, kim kj, et al. clinical significance of subclinical varicocelectomy in male infertility: systematic review and metaanalysis. andrologia. 2016; 48:654-61. 27. zhou t, zhang w, chen q, et al. effect of varicocelectomy on testis volume and semen parameters in adolescents: a meta-analysis. asian j androl. 2015; 17:1012-6. 28. yuan r, zhuo h, cao d, wei q. efficacy and safety of varicocelectomies: a meta-analysis. syst biol reprod med. 2017; 63:120-9. correspondence ünal öztekin, md (corresponding author) dr_unal@hotmail.com mehmet caniklioğlu, md dr.mehmetcaniklioglu@gmail.com sercan sarı, md sercansari92@hotmail.com volkan selmi, md volkanselmi@hotmail.com abdullah gürel, md abdullahgurel@hotmail.com mehmet şakir taşpınar mehmetsakirtaspinar@hotmail.com levent işıkay, md isikay@gmail.com yozgat bozok university, research and application hospital, urology department, yozgat, turkey stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12248 1 original paper the urethral strictures with balloon dilation (4). the successful effect of the drug requires its distribution to the muscle layer of the urethra where the smooth muscle cells are present (5). these cells are responsible for restenosis through their proliferation and production of inappropriate collagen (6). paclitaxel has been proven to inhibit the proliferation of these cells and reduce the production of collagen (7, 8). thus, the use of paclitaxel-coated balloons for the prevention of restenosis after balloon dilation seems to be a promising approach. the distribution of paclitaxel in the normal rabbit urethra has already been evaluated (9). the aim of this experimental study is to provide evidence about the benefits of the application of dcbs in urethral strictures. the current protocol aims to provide evidence on the distribution of paclitaxel (ptx) in the wall of the strictured urethra of rabbits. the drug should be distributed to the muscle layer of the urethra in order to achieve maximal efficiency. moreover, data regarding the efficacy of this approach on the recurrence of the urethral strictures treated by the paclitaxel-coated balloons will be presented. materials and methods ethical standards the current experimental trial was pre-approved by the veterinary administration of the prefecture of western greece and the animals were treated according to the current veterinary protocols. experimental models eighteen domestic male rabbits weighing between 3-4 kg were included in the conduction of the current experimental study. sedation the rabbits were sedated by intramuscular injection with a combination of ketamine and xylazine. intervention the experimental models were placed in the supine posipurpose: the aim of this study is the evaluation of the distribution of paclitaxel (ptx) released by a coated balloon in the layers of rabbit’s urethra. methods: 18 rabbits were included. a laser device was used for the stricture formation. after two weeks, dilation of the strictured urethra was performed by using advance 35lp pta balloons and advance 18 ptx pta balloons. the experimental models were divided into 3 groups. the group α included two rabbits without any intervention except for the stenosis procedure. group b compromised six rabbits that underwent dilation with advance 35lp pta balloons. group c consisted of 10 rabbits to which dilation with both advance 35lp pta balloons and advance 18 ptx pta balloons was applied. histological evaluation and immunohistochemistry were performed on all specimens. results: inflammation, fibrosis and ruptures were detected in the specimens of the study. in specimens of group c the decrease of inflammation and fibrosis rate was greater. anti-ptx antibody was detected in the epithelium, lamina propria and smooth muscle layer of all specimens of urethras that have been harvested immediately and 1 day after the dilation with advance 18 ptx pta balloon and it was not observed in any layer of the urethral wall of the rest of the examined specimens of group c. conclusions: ptx’s enrichment was detected in the smooth muscle layer of all specimens that have been harvested immediately and 24h after the dilation with advance 18 ptx pta balloons. ptx may play an inhibitive role in the recurrence of the stenosis. key words: urethra; stricture; balloon; dilation; paclitaxel. submitted 31 december 2023; accepted 17 january 2024 introduction urethral strictures constitute a significant urological disease that presents a high incidence in the male population (1). the available minimally invasive approaches are associated with high recurrence rates (2). drug coated balloons (dcbs) that release cytostatic substances have been used for the prevention of vascular stenosis (3). in the same concept, these balloons can be used for the reduction of the recurrence rates after the management of minimal invasive treatment of urethral strictures: an experimental study of the effect of paclitaxel coated balloons in the wall of strictured rabbit’s urethra konstantinos pagonis 1, angelis peteinaris 1, constantinos adamou 1, vasileios tatanis 1, athanasios vagionis 1, anastasios natsos 1, mohammed obaidat 1, solon faitatziadis 1, evangelos liatsikos 1, 2, panagiotis kallidonis 1 1 department of urology, university hospital of rion, patras, greece; 2 medical university of vienna, vienna, austria. doi: 10.4081/aiua.2024.12248 summary archivio italiano di urologia e andrologia 2024; 96(1):12248 k. pagonis, a. peteinaris, c. adamou, et al. 2 tion. a urethroscopy was conducted on each rabbit by using a 7fr pediatric nephroscope (storz 27095aa pediatric nephroscope set, karl storz se & co. kg, tuttlingen, germany) . stricture formation took place by using the thulium fiber laser device (quanta fiber dust, samarate, italy) with a 200-μm fiber and power settings 8w (0.5j x 16hz). strictures were formed in the penile urethra approximately 1-2 cm before the sphincter (figure 1). after 2 weeks, an urethrography and an urethroscopy of each model were held. the presence of a urethral stricture of approximately 1 cm in length in all experimental models was confirmed by these procedures. dilation of the stricture with advance 35lphigh pressure balloon (hpb) (cook medical, cook ireland ltd., limerick, ireland 16, diameter 6 mm/ length 40 mm) and advance 18ptxdcb (cook medical, cook ireland ltd., limerick, ireland – 16, diameter 6 mm/ length 40 mm) depending on the study group was conducted in the same session (figure 2). a 0.035’’ inch hydrophilic guidewire was inserted into each urethral lumen under fluoroscopic guidance. a stiff guidewire exchanged the hydrophilic wire over a 7 fr ureteral catheter (cook medical, cook ireland ltd., limerick, ireland). the balloon dilator was placed over the stiff guidewire and inflated to its maximum pressure of 8 atm for at least 5 minutes and then was emptied and removed. follow-up to 6 weeks with urethrography every 2 weeks depending on the study group took place. study groups the experimental models were divided into 3 main groups (groups a, b, and c). the rabbits were sacrificed on specific time periods and the whole length their urethra was obtained. group a: the control group included 2 experimental models where stricture formation was performed without any other intervention. these specimens were obtained two weeks after the stricture formation. group b: 6 rabbits were included in this group. two weeks after the stricture formation, dilation with hpb took place. the subgroups were divided based on the postoperative duration until the harvesting of the urethras to provide information on the stricture condition after conventional balloon dilation. all subgroups included 2 rabbit’s urethras and were defined as: group b.1: harvested urethras 2 weeks after the dilation procedure. group b.2: harvested urethras 4 weeks after the dilation procedure. group b.3: harvested urethras 6 weeks after the dilation procedure. group c: 10 experimental models were included in this study group. two weeks after the stenosis formation, dilation with hpb, at first, and then with dcb took place at the same time. the subgroups were divided in the same way as in group b. 2 rabbit’s urethras were included in each subgroup. the subgroups of group c were defined as: group c.1: harvested urethras immediately after the dilation procedure with both hpb and dcb. group c.2: harvested urethras 1 day after the dilation procedure with both hpb and dcb. group c.3: harvested urethras 2 weeks after the dilation procedure with both hpb and dcb. group c.4: harvested urethras 4 weeks after the dilation procedure with both hpb and dcb. group c.5: harvested urethras 6 weeks after the dilation procedure with both hpb and dcb. figure 1. endoscopic images before and after the stricture formation a. the laser fiber inside the urethral lumen during urethoscopy. b. the initiation of stricture formation. c. urethral stricture 2 weeks after the initial intervention. figure 2. fluoroscopic images a. antegrade urothrography. recognition of the stricture (blue arrow). b. dilation with advance 18 ptx pta balloon on the previously depicted stricture (orange arrow). a b a b c archivio italiano di urologia e andrologia 2024; 96(1):12248 3 paclitaxel coated balloon for urethral stricture pathology process the specimens of urethras were embedded in formalin and standard fixing process with paraffin was performed. 4μmthick sections were enriched with hematoxylin/eosin and were placed on gelatin-eluting glass slides. histological evaluation of the specimens all glass slides were tested by the same expert uropathologist. this procedure is conducted by using a standard light microscope with an attached camera (nikon eclipse 50i and nikon hd color camera head ds-fi2, nikon gmbh, dusseldorf, germany). slides were received from each urethral specimen for the conduction of histology and immunohistochemistry. morphological alterations (stricture, connective tissue formation) and inflammation were microscopically evaluated. the inflammation rate of the urethral layers was estimated according to nakada classification (10). normal appearance of the urethra after microscopic examination was graded as 0 and severe inflammation was graded as 3. immunohistochemistry (ihc) ihc was performed by using the monoclonal anti-body for ihc (anti-taxol antibody from abcam). this process aimed into elucidating the enrichment of ptx in different layers of urethral wall. the ptx’s presence and the location of the agent in the examined slides was evaluated with ihc (figure 3). results histology ruptures across the urethral wall and inflammation were observed in all specimens. in group a the inflammation grade was 3 (according to nakada classification), fibrosis was observed in all layers (squamous epithelium, submucosa, smooth muscle layer) of the urethra. in groups b.1 and b.2 the inflammation grade was 2 and fibrosis was observed in all layers of the urethral tissue. in group b.3 fibrosis in all layers of the urethral wall and inflammation (grade 1) were observed. as for the group c.1 and c.2, the inflammation grade was 3 in both groups and fibrosis was observed in the epithelium tissue, submucosa and smooth muscle layer. blood clots were found in both groups. in group c.3 and c.4 the inflammation grade of the urethral wall was 2 and 1, respectively. fibrosis was observed only in the squamous epithelium and submucosal layer in both groups. in group c.5 the inflammation grade was 1 and fibrosis was observed only in the epithelium tissue of the urethral wall. these results are presented in table 1. figure 3. histolpathological images from the urethral wall of the experimental models. a. specimen from group c.4 b. specimen from group c.1 table 1. histological findings of the harvested urethral specimens regarding the inflammation grade, fibrotic formation, and the integrity of the urethral lumen. experimental study group inflammation grade fibrosis model (nakada classification) 1 a (stricture formation-no intervention) 3 • squamous epithelium • submucosa • smooth muscle layer 2 a (stricture formation-no intervention) 3 • squamous epithelium • submucosa • smooth muscle layer 3 b.1 (stricture formation-dilation 35lp pta balloon-2 weeks) 2 • squamous epithelium • submucosa • smooth muscle layer 4 b.1 (stricture formation-dilation 35lp pta balloon-2 weeks) 2 • squamous epithelium • submucosa • smooth muscle layer a b archivio italiano di urologia e andrologia 2024; 96(1):12248 k. pagonis, a. peteinaris, c. adamou, et al. 4 ihc the specimens of group c were examined for the presence of the antibody of ptx. in all specimens examined of group c.1 and c.2, the anti-ptx antibody was found in the squamous epithelium, submucosa and smooth muscle layer of rabbit’s urethra. in one specimen of group c.1, the anti-ptx antibody was observed, also, in the corpus cavernosum and the connective tissue of the rabbit’s penis. in the rest examined specimens of group c the antibody wasn’t detected in any layer of the urethral wall. the results of the ihc are summarized in table 2. discussion dcbs contribute to the treatment of atherosclerosis, instent recurrence of stenosis and the reduction of the risk of thrombosis without the placement of a permanent foreign object (11-14). dcb is a standard angioplasty balloon coated with a drug, which is embedded in the matrix coating by using a hydrophilic spacer in order to allow the drug to be released after the expansion of the balloon into the vessel lumen. then, the drug is absorbed in the layers table 2. paclitaxel (ptx) distribution in the layers of the examined specimens of the urethral wall based on the immunohistochemical report. experimental study group squamous submucosal smooth muscle model epithelium tissue layer 9 c.1 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-immediately) + + + 10 c.1 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-immediately) + + + 11 c.2 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon -24h) + + + 12 c.2 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon -24h) + + + 13 c.3 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-2 weeks) 14 c.3 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-2 weeks) 15 c.4 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-4 weeks) 16 c.4 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-4 weeks) 17 c.5 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-6 weeks) 18 c.5 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-6 weeks) 5 b.2 (stricture formation-dilation 35lp pta balloon-4 weeks) 2 • squamous epithelium • submucosa • smooth muscle layer 6 b.2 (stricture formation-dilation 35lp pta balloon-4 weeks) 2 • squamous epithelium • submucosa • smooth muscle layer 7 b.3 (stricture formation-dilation 35lp pta balloon-6 weeks) 1 • squamous epithelium • submucosa • smooth muscle layer 8 b.3 (stricture formation-dilation 35lp pta balloon-6 weeks) 1 • squamous epithelium • submucosa • smooth muscle layer 9 c.1 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-immediately) 3 • squamous epithelium • submucosa • smooth muscle layer 10 c.1 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-immediately) 3 • squamous epithelium • submucosa • smooth muscle layer 11 c.2 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon -24h) 3 • squamous epithelium • submucosa • smooth muscle layer 12 c.2 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-24h) 3 • squamous epithelium • submucosa • smooth muscle layer 13 c.3 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-2 weeks) 2 • squamous epithelium • submucosa 14 c.3 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-2 weeks) 2 • squamous epithelium • submucosa 15 c.4 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-4 weeks) 1 • squamous epithelium • submucosa 16 c.4 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-4 weeks) 1 • squamous epithelium • submucosa 17 c.5 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-6 weeks) 1 • squamous epithelium 18 c.5 (stricture formation-dilation 35lp pta balloon+18 ptx pta balloon-6 weeks) 1 • squamous epithelium archivio italiano di urologia e andrologia 2024; 96(1):12248 5 paclitaxel coated balloon for urethral stricture of the vessel wall and reduces the tissue formation which is the normal effect in cases of either balloon expansion or stent placement in the lumen of a vessel (15). the effect of dcbs is attributed to the cytostatic drugs which are coated onto the balloons (16). the currently drug of choice is ptx. ptx constitutes the most tested anti-proliferative drug for the urinary tract (17). the aim of our study is the distribution of ptx in the different layers of the urethral strictured wall. barbalias et al. evaluated the distribution of ptx in the normal rabbit urethral wall (9). the researchers investigated the distribution of ptx in the layers of normal rabbit’s urethra after the inflation of a ptx-coated balloon. they proved that ptx was detected to the epithelium, submucosal, and muscle layers of the normal rabbit’s urethra immediately after the dilatation procedure by using dcb. also, ptx was found 24 and 48 hours after the dilatation process. nonetheless, there is no evidence in this study if the substance is adequately distributed in the case of strictured urethra or the effectiveness of the approach. another difference between the two studies was the timeline. in our study the experiment was conducted in 8 weeks and the follow up of the experimental models lasted up to 6 weeks. however, both studies proved that the smooth muscle layer was enriched by ptx in both normal and strictured urethras, even 6 weeks after the dilatation with dcbs. fu et al. investigated the impact of docetaxel (ptx’s synthetic analogue) in management of urethral strictures (18). they randomly separated forty rabbits in 2 equal groups of 16 rabbits which received high and low dose of docetaxel respectively and a control group of 8 rabbits. retrograde urethral irrigation was used for the administration of docetaxel, once per day for 28 days. normal saline was administrated in the control group. the urethral diameters and the histological findings were evaluated. the diameter of the urethral lumen was significantly lower and the fibrosis and collagen concentration rate was greater in the control group compared to the other groups. these results are similar to the results of our study. nevertheless, the researchers didn’t use any antibody for testing the exact distribution of docetaxel in the different layers of rabbits’ urethras. wikan et al. tested the role of docetaxel and captopril in rna expression of tgf-β1, mmp-1, ctgf, pai-1. these genes play an important role in the formation of fibrotic tissue. they tested four groups of rabbit’s urethra: a control group, a docetaxel group, a combined docetaxel/captopril group and a captopril group. they proved that, only, single docetaxel could decrease the expression of the 3 out of 4 prereferred genes. consequently, this ptx’s synthetic analogue could, also, contribute to the inhibition of fibrotic formation. ji hoon et al. evaluated the effect of ptx-coated stents in dog’s canine urethra (19). they placed two stents (one ptx-coated stent and one polyurethane-coated stent) in each urethral model, one in the proximal and one in the distal urethra. they separated the dogs in 2 equal groups of 10 individuals. first group’s models were sacrificed 4 weeks after the stent’s placement and second group’s models were sacrificed 8 weeks after the stent’s placement. in the first group, they placed the drug-coated stent and the polyurethane-coated stent in the proximal urethra and the distal urethra respectively in 5 dogs and, also, placed the same stents reversely in the remaining five dogs of the group. retrograde urethrography was performed in each model just before the sacrifice of the models and proved that tissue hyperplasia was significantly less in ptx-coated stenting part of the urethra in both groups. the histological evaluation of their experimental study showed that the granulation formation, the papillary projection and the submucosal inflammatory were significantly less in ptx-stenting specimens in both the 4-week and the 8-week group. even if they tested different parameters in different experimental models, their outcomes strengthen theoretically the results of our study and provide evidence about the efficacy of ptx in the urethral tissue. other experimental studies were, also, conducted in the past for the efficacy of ptx in other parts of the urinary tract. liourdi et al. conducted an experimental study in porcine ureteral wall by using dcbs (20). the aim of this study was the elucidation of the possibility of the clinical use of dcbs in ureteral strictures. as for the results, we concluded that ptx was distributed in the urothelium, submucosal, and smooth muscle layers of porcine ureter. also, the inflammation rate was lower in the ptx groups of the study. this result comes to agreement with the results of our study and proves the efficacy of ptx. nevertheless, it is worth mentioning that the experimental models and the anatomical structures of the urinary tract were different. in addition, in our experimental study the urethral wall was already strictured, in contrast with the normal tissue of the ureter of porcine models in the previous mentioned experiment. liatsikos et al. presented an experimental study for the comparison of the efficacy of standard bare metal stents and ptx-coated metal stents in the ureteral wall of porcine models (21). ten standard stents were placed randomly in the right or left ureter of 10 female pigs and ten ptx-coated stents placed in the other ureter of the same porcine models. after a follow-up period of 21 days all experimental models were sacrificed. after the histological evaluation, they concluded that ptx-coated stents contributed to less inflammation and hyperplasia of the ureteral wall compared to standard stents. another important study about the effect of ptx-coated stents in the ureteral tissue’s hyperplasia was presented by kram et al. (22). they compared the efficacy of uncoated polyurethane stents and ptx-coated stents in a rat ureteral model after the conduction of ureteroureterostomy. their outcomes indicated that ptx contributed to decreasing hyperplastic proliferation and postoperative restenosis rate. consequently, ptx-coated balloons or stents may be a promising approach for the management of strictures even in the upper or in the lower urinary tract. a plethora of drugs has been tested regarding the efficacy in the restenosis formation of the urothelial lumen, such as poly-dl-lactic acid, zotarolimus, captopril, halofuginone, protein nanofilm-controlled drugs, rapamycin, insulin-like growth factors, clostiridium histolyticum and others (23-26). however, only ptx proved its feasibility both in experimental and clinical aspects. virasoro et al. presented a prospective, multi-center, clinical study about the usage of optilume® ptx-coated balloon (laborie medical technologies, mississauga, ontario, canada) for the archivio italiano di urologia e andrologia 2024; 96(1):12248 k. pagonis, a. peteinaris, c. adamou, et al. 6 management of patients with urethral stricture (27). the follow-up of the patients lasted 3 years and included the measurement of ipss score, maximum flow rate, post-void residual urine volume and the evaluation of erectile function. all parameters of the study were improved after the intervention with ptx-coated balloons in most of the participants and there was no influence in the sexual function of the patients. elliott and colleagues prepared a randomized controlled trial where 127 patients separated in 2 groups (28). first group included patients treated by optilume® ptx-coated balloon and second group patients treated by urethral dilation or optical internal urethrotomy. after 6 months they evaluated the anatomic success by a simple passage of a flexible cystoscope. 1 year after the primal intervention they measured the ipss score and the maximum flow rate in all participants. they, also, investigated in which of the participants a repeated intervention was necessary. all results of the study were in favor of optilume® ptx-coated balloon group except of minor complications, such as minor hematuria and dysuria which were observed more frequently in patients treated by ptx-coated balloons. there are some limitations related to our experimental trial which should be mentioned. first of all, human anatomy and tissue differs from the experimental rabbit’s model that was used in the current experimental study. moreover, the follow up period of the models lasted until only six weeks. longer-term outcomes are needed for the evaluation of the distribution of ptx in different layers of the urethral wall. in the current study, we have some clues about the efficacy of dcbs in the treatment of strictured urethral lumen as we evaluated the inflammation and fibrosis of the strictured rabbit‘s urethras. nonetheless, it is not possible to do flow studies to the rabbits to obtain more information on the efficacy of the approach. conclusions ptx-coated balloons seem to be an effective approach for the treatment of urethral stenosis. when ptx was released in the strictured rabbit’s urethra, its distribution included all layers of the urethral wall and most importantly the smooth muscle layer, which related to the fibrosis and the restenosis of the lumen. the results showed reduced inflammation and fibrosis. consequently, dcbs may play an important inhibitive role in the restenosis formation. references 1. jacobs me, de kemp vf, albersen m, et al. the use of local therapy in preventing urethral strictures: a systematic review. plos one 2021; 16:e0258256. 2. pang kh, chapple cr, chatters r, et al. a systematic review and meta-analysis of adjuncts to minimally invasive treatment of urethral stricture in men. eurn urol 2021; 80:467-479. 3. tepe g, brodmann m, micari a, et al. 5-year outcomes of drugcoated balloons for peripheral artery in-stent restenosis, long lesions, and ctos. jacc: cardiovas interv 2023; 16:1065-1078. 4. will ta, polcari aj, garcia jg, et al. paclitaxel inhibits ureteral smooth muscle cell proliferation and collagen production in the absence of cell toxicity. j urol 2011; 185:335-340. 5. lee c-h, hsieh m-j, liu s-c, et al. novel bifurcation stents coated with bioabsorbable nanofibers with extended and controlled release of rosuvastatin and paclitaxel. mater sci eng c mater biol appl. 2018; 88:61-69. 6. liu l, lan x, chen x, et al. multi-functional plant flavonoids regulate pathological microenvironments for vascular stent surface engineering. acta biomater 2023; 157:655-669. 7. chen n, guo d, guo y, et al. paclitaxel inhibits cell proliferation and collagen lattice contraction via tgf-β signaling pathway in human tenon's fibroblasts in vitro. eur j pharmacol 2016; 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29:580-589. 21. liatsikos en, karnabatidis d, kagadis gc, et al. application of archivio italiano di urologia e andrologia 2024; 96(1):12248 7 paclitaxel coated balloon for urethral stricture paclitaxel-eluting metal mesh stents within the pig ureter: an experimental study. eur urol 2007; 51: 217-223. 22. kram w, rebl h, wyrwa r, et al. paclitaxel-coated stents to prevent hyperplastic proliferation of ureteral tissue: from in vitro to in vivo. urolithiasis 2020; 48:47-56. 23. han k, park jh, yang sg, et al. ew-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model. plos one 2018; 13:e0192430. 24. kotsar a, nieminen r, isotalo t, et al. biocompatibility of new drug-eluting biodegradable urethral stent materials. urology 2010; 75:229-234. 25. sangkum p, yafi fa, kim h, et al. collagenase clostridium histolyticum (xiaflex) for the treatment of urethral stricture disease in a rat model of urethral fibrosis. urology 2015; 86:647.e641-646. 26. kallidonis p, kitrou p, karnabatidis d, et al. evaluation of zotarolimus-eluting metal stent in animal ureters. j endourol 2011; 25:1661-1667. 27. virasoro r, delong jm, estrella re, et al. a drug-coated balloon treatment for urethral stricture disease: three-year results from the robust i study. res rep urol 2022; 14:177-183. 28. elliott sp, coutinho k, robertson kj, et al. one-year results for the robust iii randomized controlled trial evaluating the optilume(®) drug-coated balloon for anterior urethral strictures. j urol 2022; 207:866-875. correspondence konstantinos pagonis, md (corresponding author) pagonisk7@gmail.com angelis peteinaris, md peteinarisaggelis@gmail.com constantinos adamou, md constantinos.adamou@live.com vasileios tatanis, md tatanisbas@gmail.com athanasios vagionis, md thanos_vagionis@hotmail.gr anastasios natsos, md a.natsos@gmail.com mohammed obaidat, md kasious.klay@gmail.com solon faitatziadis, md solonasfait@gmail.com panagiotis kallidonis, md pkallidonis@yahoo.com department of urology, university hospital of rion, patras, greece evangelos liatsikos, md liatsikos@yahoo.com department of urology, university hospital of rion, patras, greece medical university of vienna, vienna, austria conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12082 1 original paper formed surgery to correct male factor infertility (1, 2). analysis of the literature demonstrated that among men with primary infertility, the proportion of patients with varicocele is 33-40%, and among those who suffer from secondary infertility it is up to 81% (1). according to data from many authors, in varicocele, the testis suffers from venous overflow and it is supplied with blood poor in oxygen and nutrients, leading to atrophy of its tissue (1, 6). another pathogenetic factor is the increase of testicular temperature to + 37°c due to the overflow of venous blood. most men with varicocele are fertile, but the prevalence of infertility in this group is increased compared with the general population. however, more than 40% of patients with varicocele have reduced sperm quality (1). the relationship between varicocele and semen parameters may be different. microcirculation disorders evolving with varicocele leads to an increase in the testis cells' concentration of reactive oxygen species and oxidative stress. the latter is nowadays considered a leading pathophysiological mechanism of pathozoospermia with varicocele (6). recent randomized controlled trials (rcts) have demonstrated that varicocele repair (varicocelectomy) in patients with clinical varicocele and pathologies of semen analysis leads to a significant increase in pregnancy rates (3) and improvement of semen quality in relation to observation group (control) (4). other authors in rcts revealed low efficiency of varicocelectomy in cases of subclinical varicocele and normal semen parameters (5). persad et al. and cayan et al. referring to a large number of studies indicated that microsurgical (inguinal and subinguinal) ligation of spermatic cord veins is the most appropriate surgery for the treatment of clinical varicocele with infertility (6, 7). fukuda et al. conducted a study of 71 infertile men who underwent microsurgical varicocelectomy. the subjects had their semen analysis taken 3 times (before and after the intervention, at 3 and 12 months). the results showed that the quality of semen analysis at 3 months after surgery was significantly better than that before surgery. no statistically significant differences were detected between semen parameters taken at 3 and 12 months after surgery (8). walsh et al. in their study came to the conclusion that introduction and objectives: varicocele is the most common treatable cause of male infertility. the study aimed to compare varicocelectomy efficacy in men with primary (pi) and secondary infertility (si). patients and methods: medical records of 100 men suffering from pi and si and having varicocelectomy at the republican specialized scientific-practical medical center of urology were retrospectively selected and analyzed. patients were divided into 2 groups. group i included 58 men with pi and group ii 42 men with si. preoperative clinical characteristics and semen parameters before and after varicocelectomy were analyzed and compared between groups. results: analysis revealed that the mean age of patients of group i was significantly lower (p < 0.001) and the duration of infertility was accurately shorter (p < 0.01) than those of group ii. main semen parameters increased significantly in group i (e.g., sperm concentration increased by 50%, from 62.2 ± 8.7 to 93.5 ± 10.0 m/ml, and total motile sperm count increased by 113%, from 76.7 ± 17.1 to 163.4 ± 27.8 m p < 0.05), while in group ii only rate of progressive motile sperm increased significantly (by 107%, from 13.5 ± 2.6 to 28.0 ± 5.2% p < 0.05). we identified a significant difference in varicocelectomy efficacy between group i and group ii in change of total motile sperm count (by 113% vs. 74% respectively, p < 0.01). we also revealed a discrepancy between groups in correlation ratio (r) between initial and post-surgical percent of progressive motile sperm. conclusions: patients with si were older and had longer infertility period. varicocelectomy resulted in significant semen parameters improvement in patients with pi. in patients with si, only percent of progressively motile sperm improved significantly. it indicates that advanced male age and long infertility duration may have a negative impact on varicocelectomy success. key words: varicocele; varicocelectomy; primary infertility; secondary infertility. submitted 23 december 2023; accepted 27 december 2023 introduction currently, research are conducted actively on possible causes of male infertility. varicocele is the most common cause of primary and secondary infertility in men. in this regard, varicocele repair remains the most frequently permicrosurgical varicocelectomy efficacy in treatment of men with primary and secondary infertility (retrospective study) shomarufov azizbek 1, 2 1 urology department of tashkent medical academy, uzbekistan; 2 republican specialized scientific-practical medical center of urology, tashkent city, uzbekistan. doi: 10.4081/aiua.2024.12082 summary archivio italiano di urologia e andrologia 2024; 96(1):12082 s. azizbek 2 men with primary and secondary infertility with varicocele may have different clinical characteristics including semen parameters, i.e. males with secondary infertility had significantly better parameters of the semen (sperm concentration) (9). in this regard, we aimed to assess initial semen parameters and varicocelectomy efficacy in men with primary and secondary infertility dividing them into two separate groups. patients and methods during the study, we evaluated the main semen parameters: semen volume (ml), sperm concentration (million/ml) and total sperm count (million), % of sperm with progressive motility, total sperm motility (%), and total motile sperm count (tmc) according to who 2010 manual (10). the presence of varicocele was determined by visual and palpation methods, as well as using doppler ultrasound of the testis according to the 2000 who classification of varicocele (subclinical varicocele, i, ii, iii) (11). patient selection we used the following inclusion and exclusion criteria for recruiting appropriate patients for our study. inclusion criteria patients had their semen analysis taken before and after varicocelectomy (at 3 12 months); patients with a pathological deviation of at least one of the studied parameters of semen analysis; patients with clinical varicocele (grade i-iii); patients with complaints of pregnancy absence in their partners for 12 months and longer period. exclusion criteria patients with azoospermia and normozoospermia (according to who 2010 manual); patients with other infertility causes. patients according to those criteria we selected for the study and carefully explored the medical cards of 100 men aged from 21 to 46 years, who suffered from infertility and varicocele. patients were divided into 2 groups: 58 men with primary infertility (aged from 21 to 38 years) were included in group i and 42 ones with secondary infertility (aged from 24 to 46 years) were recruited into group ii. ethical approval the collection and the analysis of these data were approved by the republican specialized scientific-practical medical center of urology local ethics committee. surgical procedure all patients underwent microsurgical subinguinal/ inguinal varicocelectomy. procedures were performed by three experienced surgeons following the techniques described below. a 4-5 cm incision was made inferior to the external inguinal ring in the subinguinal technique and over the inguinal canal in the inguinal technique. the spermatic cord was isolated, and the veins were dissected away from the arteries, lymphatics, vas deferens, and ligated under special surgical loupes or microscope. statistical analysis statistical data were analyzed by ms excel 2019 and ibm spss© statistics 21.0 statistical packages. the significance of differences between groups was calculated using student's t test for means; differences were considered significant at p < 0.05. results analysis revealed that the mean age of patients in group i was significantly lower (p < 0.001) and the mean duration of infertility was significantly shorter (p < 0.01) than those of patients of group ii (table 1). most patients had left-sided varicocele (76 patients, 76%) (table 1). bmi of 36 (36%) patients was slightly higher than normal (25.0-30.0), which was evaluated as pre-obese, bmi of 18 (18%) was significantly higher than normal (> 30.0), which was assessed as obesity, and bmi of 46 (46%) patients was within normal range (18.5-25.0) (12). following table 2 shows the main semen parameters of patients of both groups before surgery for statistical comparison. as it is seen from table 2, no statistically significant differences in the initial semen parameters were revealed between groups. table 1. key features of group of patients. groups age anthropometric varicocele * duration of infertility m ± g data (in months) m ± g side grade height weight bmi ** left right bilaterlal i ii iii group i 27.4 ± 0.6 1.7 81.2 26.8 40 2 8 (29) 19 (68) 1 (3) 28.7 ± 4.6 group ii 31.0 ± 0.6 1.7 79.9 26.5 36 2 4 5 (23) 15 (68) 2 (9) 51.8 ± 5.6 р < 0.001 < 0.01 total 76 (76) 2 (2) 6 (12) 8 (20) 34 (68) 3 (6) * data are given in absolute numbers in relation to the group. ** body mass index. archivio italiano di urologia e andrologia 2024; 96(1):12082 3 microsurgical varicocelectomy for infertility preoperative and postoperative semen parameters of patients of both groups are given in table 3 for comparison of varicocelectomy efficacy before and after repair, as well as between groups. in the postoperative period, the following changes were observed in average counts of studied semen parameters in both groups: semen volume in both groups remained unchanged (p > 0.05); sperm concentration increased significantly in group i (by 50% p < 0.05), while in group ii it increased not significantly (by 39% p > 0.05); total sperm count increased by 60% (p < 0.05) in group i, whereas in the second one this parameter increased by 44% (p > 0.05); percent of sperm with progressive motility increased more in group ii (by 107% p < 0.05) than in group i (by 75% p < 0.05) and the difference between groups was significant (p < 0.01); total sperm motility also increased significantly (by 50% p < 0.05) in group i, while in group ii this parameter also increased, but not significantly (by 31% p > 0.05); total motile sperm count in group i increased more significantly (p < 0.01) than in group ii (113% p < 0.05 vs. 74% p > 0.05 respectively). as it was shown above, statistically significant differences were revealed between groups in changes in some postoperative semen parameters. in patients of group i varicocelectomy resulted in significant improvements in all semen parameters. in contrast to group i in group ii, statistically accurate improvement occurred for only percent of sperm with progressive motility, which increased more significantly than in group i. we also revealed a significant discrepancy between groups in correlation ratio (r) between the initial and post-operative % of sperm with progressive motility. in patients of group i there was no correlation (r = -0.02), whereas in patients of group ii correlation was direct and strong (r = 0.71). in general, differences between groups in mean correlation ratios between initial and postsurgical semen parameters were not significant (r = 0.4 for group i and r = 0.5 for group ii). discussions currently, a varicocele is the most common surgically curable cause of male infertility. although the vast majority of research supports the opinion of the beneficial effect of surgical treatment of varicocele on sperm parameters (3, 4, 13), the question of the true effect of surgery on testicular function remains unresolved (1). although the exact relationship between improvements in indicators of semen analysis and surgical treatment of varicocele has not been finally determined, a meta-analysis of rcts conducted by agarwal et al. showed significant improvement in semen parameters after varicocelectomy (13), which corresponds to the results of our research. however, interesting is the fact that greater significant changes occurred in patients with primary infertility and varicocele than those in patients with secondary infertility and varicocele, although in patients with secondary infertility a positive effect of intervention was also determined. there are a number of reports on the association between initial semen parameters and the efficacy of the varicocele repair. these studies assumed that men with higher preoperative semen parameters are more likely to see an improvement in their semen parameters after varicocelectable 2. main parameters of semen analysis in both groups in preoperative period for their comparative estimation. groups semen volume. ml sperm concentration total sperm count sperm with progressive total sperm motility total motile sperm count m±m (m/ml) m±m (m) m±m motility (%) m±m (%) m±m (m) m±m first 3.4 ± 0.3 62.2 ± 8.7 213.6 ± 35.9 11.4 ± 2.3 30.8 ± 3.6 76.7 ± 17.1 second 3.7 ± 0.3 47.2 ± 8.6 171.9 ± 33.5 13.5 ± 2.6 35.1 ± 4.6 76.3 ± 19.2 p > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 > 0.05 table 3. comparative assessment of main semen parameters of both groups in preand post-surgical period. groups semen volume. ml sperm concentration total sperm count sperm with progressive total sperm motility total motile sperm count m±m (m/ml) m±m (m) m±m motility (%) m±m (%) m±m (m) m±m group i 1 3.4 ± 0.3 62.2 ± 8.7 213.6 ± 35.9 11.4 ± 2.3 30.8 ± 3.6 76.7 ± 17.1 group i 2 3.4 ± 0.2 93.5 ± 10.0 341.8 ± 46.6 20.0 ± 3.1 46.1 ± 4.5 163.4 ± 27.8 p 3 > 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 group ii 1 3.7 ± 0.3 47.2 ± 8.6 171.9 ± 33.5 13.5 ± 2.6 35.1 ± 4.6 76.3 ± 19.2 group ii 2 3.9 ± 0.3 65.7 ± 10.2 246.9 ± 40.8 28.0 ± 5.2 46.0 ± 6.0 132.7 ± 31.3 p > 0.05 > 0.05 > 0.05 < 0.05 > 0.05 > 0.05 p 4 > 0.05 > 0.05 > 0.05 < 0.01 > 0.05 < 0.01 1 preoperative period; 2 postoperative period; 3 statistically significant changes; 4 statistically significant differences between groups. archivio italiano di urologia e andrologia 2024; 96(1):12082 s. azizbek 4 tomy (14, 15). our study partially confirmed this statement because the association between initial and postsurgical semen parameters was moderate. according to some authors, varicocele is more common in men with si than in men with pi, but the difference is not so high (+3.5%, p < 0.05) (16). they also noted that patients with pi and si were almost of the same age which finding does not agree with our results. it is also worth noting that according to some authors, the average age of men with secondary infertility is older, which corresponds to our data. however, they also state that there is no significant difference in the duration of infertility, whereas our study revealed a significant difference in this parameter between primarily and secondarily infertile men (9, 17). in addition, the above-mentioned authors claim the presence of differences in initial semen parameters of patients with secondary infertility, although to our knowledge no statistically significant differences were revealed between baseline semen parameters of men with primary and secondary infertility. the main limitation of our study was the small sample size that in turn resulted in the differences between groups in mean patient’s age and infertility duration. conclusions the mean age and duration of infertility in patients with si were higher than those in patients with pi. varicocelectomy resulted in significant improvement of main semen parameters in patients with pi. in patients with si varicocelectomy resulted in significant improvement of only a percent of progressively motile sperm. it indicates that advanced male age and long infertility duration may have a negative impact on varicocelectomy success. further large-scale clinical trials are needed to confirm this statement. acknowledgments the authors want to express their gratitude to the head of the urology department of tashkent medical academy, dsc., prof. akilov f.a., and to the director of republican specialized scientific-practical medical center of urology, dsc., prof. mukhtarov sh.t. for their assistance in the arrangement of this study. references 1. salonia a, bettocchi c, capogrosso p, et al. european association of urology. sexual and reproductive health. arnhem, the netherlands; eau, 2023. available at: uroweb.org/guidelines/sexual-and-reproductive-health. 2. wein aj, kavoussi lr, novick ac, et al. (eds.). campbell-walsh urology. 11th ed. saunders, elsevier, philadelphia. 2016, pp. 636637. 3. abdel-meguid ta, al-sayyad a, et al. does varicocele repair improve male infertility? an evidence-based perspective from a randomized, controlled trial. eur urol. 2011; 59:455-61. 4. baazeem a, belzile e, ciampi a, et al. varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. eur urol. 2011; 60:796-808. 5. ficarra v, cerruto ma, liguori g, et al. treatment of varicocele in subfertile men: the cochrane review—a contrary opinion. eur urol. 2006; 49:258-263. 6. persad e, o'loughlin ca, kaur s, et al. surgical or radiological treatment for varicoceles in subfertile men. cochrane database syst rev. 2021; 23;4:cd000479. 7. çayan s, shavakhabov s, kadioglu a. treatment of palpable varicocele review in infertile men: a meta-analysis to define the best technique. j androl. 2009; 30:33-40. 8. fukuda t, miyake h, enatsu n, et al. assessment of timedependent changes in semen parameters in infertile men after microsurgical varicocelectomy. urology. 2015; 86:48-51. 9. walsh tj, wu ak, croughan ms, turek pj. differences in the clinical characteristics of primarily and secondarily infertile men with varicocele. fertil steril. 2009; 91:826-830. 10. world health organization. who laboratory manual for the examination and processing of human semen. 5th edition. geneva: who press, 2010.. 11. jungwirth a, giwercman a, tournaye h, et al. european association of urology guidelines on male infertility: the 2012 update. eur urol. 2012; 62:324-332. 12. bmi classification. global database on body mass index. world health organization. 2006. 13. argawal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. urology. 2007; 70:532-538. 14. samplaski mk, yu c, kattan mw, et al. nomograms for predicting changes in semen parameters in infertile men after varicocele repair. fertil steril. 2014; 102:68-74. 15. bozhedomov va, shomarufov ab, bozhedomova ge, et al. varicocele and reproductive function: pathozoospermia treatment (a prospective comparative study). urologiia. 2021; 5:62-8. 16. bozhedomov va, shomarufov ab, bozhedomova ge, et al. varicocele and reproductive function: epidemiology and infertility risk (the examination of 3632 patients). urologiia. 2021; 3:122-8. 17. gowri v, venkiteswaran kp, al-zakwani i, et al. comparison of the demographics, semen parameters and hormone profiles in men with primary and secondary infertility. sultan qaboos univ med j. 2010; 10:350-353. correspondence dr. azizbek b. shomarufov, phd (corresponding author) doctor.shomarufov@gmail.com 2, farabi, 100109, tashkent, uzbekistan conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12449 1 original paper numerous unrelated pathogens, including several respiratory infections such as influenza a and rsv (4). interestingly, countries with higher rates of bcg immunization were observed to experience lower mortality rates from covid-19 infections compared to countries with lower rates of immunization during the height of the pandemic (5). bcg therapy also represents an important role in the field of urology. intravesical bcg therapy is the goldstandard adjuvant therapy for non-muscle invasive bladder cancer (nmibc) (6). though its specific mechanism remains elusive, its therapeutic role in nmibc has been attributed to local and systemic immune responses (7). consequently, there was growing interest in a possible role for this therapy in protection against covid-19 infection and symptom burden. some evidence has suggested nmibc patients receiving intravesical bcg therapy had lower covid-19 case-fatality rate than the overall population (8). further research on the role of bcg immunization and intravesical therapy on covid-19 infection has been limited. as such, we sought to determine whether intravesical bcg and/or infantile bcg vaccination in patients with nmibc affected the incidence of covid-19 infection. methods retrospective data collection of patients with high-risk nmibc diagnosed after january 1, 2015, from two canadian centers. data collection included basic demographic (age/sex/race), clinical (smoking history/comorbidities/prior bcg vaccination or tuberculosis infection), pathologic (stage/grade of tumour), treatment (intravesical bcg/chemo) and outcome (recurrence/progression) variables. details on bcg including the number of instillations and duration of treatment were obtained. a simple survey was also sent to patients to record possible signs and symptoms of covid-19, or a documented infection. the severity of covid-19 infection was measured by hospitalization, admission to icu and death. the survey was sent at the end of the pandemic. results in this study, 348 patients who had been diagnosed with high-risk nmibc were included. all patients lived in canada, however, 188 were from ontario and 160 were introduction: the study aimed to correlate the history of intravesical bcg as well as infantile bcg immunization with the incidence and severity of covid-19 infection. methods: retrospective data collection of patients with high-risk non muscle invasive bladder cancer (nmibc) from two canadian centers. data collection included a history of bcg instillation, infantile immunization, and the development of covid-19 infection. admission and/ or mortality because of covid-19 was reported. results: we could include data from 348 patients: including 188 and 160 patients from ontario and british columbia respectively. covid-19 affected 15% of these patients. intravesical bcg was used in 44% of these patients. intravesical bcg and/or infantile bcg immunization did not correlate with the incidence of covid-19 infection. conclusions: previous intravesical bcg and/ or a history of infantile bcg vaccination were not more/ less frequent in patients who had covid-19 infection. key words: bladder cancer; bcg; covid-19. submitted 4 march 2024; accepted 28 march 2024 introduction the covid-19 pandemic represented an unprecedented time in modern society, resulting in mortality and morbidity worldwide, as well as significant strain on healthcare resources and professionals. early in the pandemic, tremendous efforts were put forth to identify a vaccination against the etiologic agent in covid-19 infection, sarscov-2 virus. this infection is associated with deregulation of innate immune responses, ultimately resulting in systemic inflammation and mass virus replication (1). trained immunity (ti) is a non-specific, protective inflammatory response generated from immunization against an unrelated pathogen (2). as such, ti was proposed as a mechanism to tackle infection and spread by creating an early immune response (1). prior to the creation of covid-19 specific immunizations, there was interest in the bacillus calmetteguérin (bcg) vaccine for protection against covid-19. the bcg immunization contains live-attenuated mycobacterium bovis and is used to protect against tuberculosis in countries with high incidence (3). the bcg vaccine has reliably demonstrated ti, protecting against does intravesical bacillus calmette-guérin for bladder cancer protect from covid-19? anastasia macdonald 1, lexia bao 2, vahid mehrnoush 1, asmaa ismail 1, livio di matteo 3, ahmed zakaria 1, hazem elmansy 1, peter black 2, ahmed kotb 1 1 department of urology, northern ontario school of medicine university, thunder bay, on, canada; 2 department of urology, university of british columbia, bc, canada; 3 department of economics, lakehead university, thunder bay, on, canada. doi: 10.4081/aiua.2024.12449 summary archivio italiano di urologia e andrologia 2024; 96(2):12449 a. macdonald, l. bao, v. mehrnoush, a. ismail, et al. 2 from british columbia. the mean age was 74 ± 10. of the 348 participants, 44% (n = 152) had received intravesical bcg therapy. history of bcg immunization could only be obtained from the ontario cohort, with 60% (n = 113) being immunized. it was observed that 24% (n = 45) of the ontario cohort had received both intravesical bcg therapy and had a history of infantile bcg immunization. overall, 15% of participants were infected with covid19. there was no significant difference in the incidence of covid-19 infection between those with and without a history of infantile bcg immunization (p > 0.05) and between those who had and had not received intravesical bcg therapy (p > 0.05). comparison of those with bcg immunization and/or bcg intravesical therapy and those with neither intervention did not identify a significant difference in covid-19 (p > 0.05). additionally, there was no significant difference in covid-19 incidence between those with a combined history of intravesical bcg and bcg immunization with other participants (p > 0.05). table 1 illustrates these findings. the median number of bcg doses administered was the same in patients who had been infected with covid-19 and those who had not (12 vs. 12 doses; p > 0.05). there was one incidence of mortality attributed to covid-19 infection in a patient who did not receive intravesical bcg nor had infantile bcg. three cases required non-icu hospital admission. this included 2 patients who received both infantile and intravesical bcg and one patient who did not receive either. the 3 cases recovered well. discussion given the widespread implications of covid-19 infection, significant efforts have been made to understand the relationships between this infection and well-established medical practices. bcg immunization has reliably demonstrated the ability to confer non-specific protection against various illnesses (4). the ability of intravesical bcg therapy to induce such protection remains unclear, although laboratory investigations have suggested intravesical bcg is capable of ti (9). high-risk nmibc patients who had received intravesical bcg therapy represent a unique group of patients during the pandemic, as they had been treated with an agent hypothesized to confer protection against the sars-cov-2 virus. our study did not identify a relationship between intravesical bcg administration and covid-19 infection. this is perhaps unsurprising as bcg therapy is administered locally to the bladder to prevent the recurrence of bladder cancer. studies have suggested the ability of intravesical bcg to confer ti against some respiratory infections, however, these have not been assessed in human studies9. while these installations are believed to generate both local and systemic inflammatory responses (5), the systemic response may not be strong or broad enough to directly prevent covid-19. this may be supported by a study by gallegos et al. (2021), that identified a higher cumulative incidence of covid-19 infection, but lower overall mortality in patients who completed intravesical bcg therapy for nmibc compared to the general population. these authors theorized that intravesical bcg immunization may confer protective benefits in terms of covid-19 severity, rather than the development of infection (8). interestingly, pichler et al. (2023) assessed the ability of intravesical bcg to induce adaptive and innate immunity. they found that repetitive bcg instillations were able to elicit an innate immune response and thus ti in a laboratory setting. it was theorized that it would require a minimum of 6 weeks to elicit this response (10). in our study, those who developed covid-19 infection and those who did not both received a median number of 12 doses of intravesical bcg, thus spanning a course longer than 6 weeks. despite this, there was no difference in the incidence of covid-19 infection in those receiving bcg immunotherapy. our data also demonstrated no correlation between bcg immunization and covid-19 infection. given the many examples of ti protection from bcg immunization, there was strong speculation about its ability to protect against sars-cov-2 as well. this was supported by the observation that countries with mandatory bcg immunization experienced a lower number of covid-19 cases, in addition to reduced mortality (11). despite this observation, the world health organization (who) declared that there was no evidence that the bcg vaccine can protect against covid-19 (12). before the development of covid-19specific immunizations, several randomized control trials had been started to determine the efficacy of bcg immunization to protect against this infection (13). there were several limitations to our study. while intravesical bcg therapy was assessed at two centers, the history of immunization was only assessed at a single center and thus faced inevitable selection bias. further, our study did not account for the comorbidities of patients, which may have influenced their susceptibility to covid-19 infection. in this study, we only assessed incidence of covid-19 infection. future work may seek to categorize the severity and mortality of these patients. conclusions overall, this study did not identify a relationship between the incidence of covid-19 infection and a history of intravesical bcg therapy or bcg immunization in nmibc patients. the number of intravesical bcg doses received by those who were and were not infected did not vary. based on these results, it can be concluded that neither form of bcg therapy confers protection against this infection. table 1. correlation between bcg vaccination and the development of covid-19 infection. no covid-19 covid-19 p value infantile bcg no 58 17 0.3 yes 79 34 intravesical bcg no 161 35 0.1 yes 135 17 infantile and/ or intravesical bcg no 31 13 0.7 yes 106 38 infantile and intravesical bcg no 105 38 0.8 archivio italiano di urologia e andrologia 2024; 96(2):12449 3 bcg covid-19 references 1. kaur g, singh s, nanda s, et al. fiction and facts about bcg imparting trained immunity against covid-19. vaccines 2022; 10:1006. 2. gong w, aspatwar a, wang s, et al. covid-19 pandemic: sarscov-2 specific vaccines and challenges, protection via bcg trained immunity, and clinical trials. expert rev vaccines 2021; 20:857-880. 3. okafor cn, rewane a, momodu ii. bacillus calmette guerin. 2023 jul 3. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2024. 4. koneru g, batiha ge, algammal am, et al. bcg vaccine-induced trained immunity and covid-19: protective or bystander? infect drug resist. 2021; 14:1169-1184. 5. miyasaka m. is bcg vaccination causally related to reduced covid-19 mortality? embo mol med. 2020; 12:e12661. 6. saginala k, barsouk a, aluru js, et al. epidemiology of bladder cancer. med sci (basel). 2020; 8:15. 7. livak kj, schmittgen td. analysis of relative gene expression data using real-time quantitative pcr and the 2(-delta delta c(t)) method. methods (san diego, calif.), 2001; 25:402-408. 8. gallegos h, rojas pa, sepúlveda f, et al. protective role of intravesical bcg in covid-19 severity. bmc urology, 2021; 21:50. 9. van puffelen jh, novakovic b, van emst l, et al. intravesical bcg in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections. j immunother cancer. 2023; 11:e005518. 10. pichler r, diem g, hackl h, et al. intravesical bcg in bladder cancer induces innate immune responses against sars-cov-2. front. immunol. 2023; 14:1202157. 11. miller a, reandelar mj, fasciglione k, et al. (2020). correlation between universal bcg vaccination policy and reduced mortality for covid-19. medrxiv preprint doi: https://doi.org/10.1101/ 2020.03.24.20042937 12. world health organization (2020). bacille calmette-guérin (bcg) vaccination and covid-19. https://www.who.int/newsroom/commentaries/detail/bacille-calmette-gu%e9rin-(bcg)-vaccination-and-covid-19 13. travassos tc, de oliveira jmi, selegatto ib, reis lo. covid19 impact on bladder cancer-orientations for diagnosing, decision making, and treatment. am j clin exp urol. 2021; 9:132-139. correspondence anastasia macdonald anamacdonald@nosm.ca vahid mehrnoush vahidmehrnoush7@gmail.com asmaa ismail asmaaismail0782@gmail.com ahmed zakaria aszakaria81@yahoo.com hazem elmansy hazem.mansy@rocketmail.com ahmed kotb; md, phd, frcsc, frcs urol, febu associate professor drahmedfali@gmail.com department of urology, nosm u, thunder bay, on, canada lexia bao lexia.bao@ubc.ca peter black peter.black@ubc.ca department of urology, university of british columbia, bc, canada livio di matteo ldimatte@lakeheadu.ca department of economics, lakehead university, thunder bay, on, canada conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2020; 92, 3200 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.200 gelatin sponge (spongostan®) and n-butyl-2-cyanoacrylate: utility on percutaneous treatment of persistent urinary leakage after partial nephrectomy. case report and review of the literature. bernardino de concilio 1, francesca vedovo 1, 2, maria carmen mir 3, tommaso silvestri 1, 2, andrea casarin 4, antonio celia 1 1 department of urology, san bassiano hospital, bassano del grappa, italy; 2 department of urology, azienda sanitaria universitaria integrata di trieste, trieste, italy; 3 fundación instituto valenciano oncologia, valencia, spain; 4 department of radiology, san bassiano hospital, bassano del grappa, italy. introduction: percutaneous treatment of persistent urinary fistula after partial nephrectomy using n-butyl-2-cyanoacrylate and gelatin sponge (spongostan®) is an effective and relatively non-invasive procedure that should be considered when a conservative approach fails. three successful cases of percutaneous embolization by using n-butyl-2-cyanoacrylate have been reported in the literature. to our knowledge, the use of spongostan for the treatment of urinary fistula after partial nephrectomy has not been previously described. case report: we present the case of an 82-year old man who underwent percutaneous closure of a urinary fistula following partial nephrectomy by using gelatin sponge (spongostan®) and n-butyl-2-cyanoacrylate. conclusions: we encourage the use of this technique in selected cases. collaboration amongst urologists and skilled interventional radiologist is strongly recommended. key words: cyanoacrylates; fibrin foam; gelatin sponge; urinary fistula. submitted 18 august 2020; accepted 1 september 2020 summary introduction partial nephrectomy (pn) is gold standard for treatment of small renal masses. pn is not exempt of complications, urinary fistula (uf) is one of the most common. its incidence rates between 2 and 10%, depending on the complexity of the surgery. the vast majority of fistulas are self-limited within short-term. however, a small percent of urinary fistula may require active treatment, either by open repair or by percutaneous approach. in the current case, we report the use of n-butyl-2cyanoacrylate and gelatin sponge (spongostan®) in a persistent urinary fistula. case report an 82-year-old man was assessed for an incidentally detected left renal mass at our institution. a ct scan confirmed the presence of a 46 mm round partially, posterior, upper pole mass. (figure 1) patient’s significant past medical history included hypertension, pace-maker implantation and left hip replacement. a robotic assisted laparoscopic partial nephrectomy was performed. the procedure required intraoperative conversion to open procedure due to sclerolipomatosis. pathology report showed a pt1a fuhrman 1-2 clear cell renal carcinoma with negative surgical margins. patient’s postoperative course showed prove of urinary leakage on post-operative day 1 (pod1). a double-j catheter was inserted to improve urinary drainage. at retrograde pyelography, a leakage on the central calix was observed. patient was discharged on pod10 and readmitted one week after due to fevers and diarrhea. a ct scan revealed a left retroperitoneal urinoma 3 cm in diameter with actual drainage through the chest wall and skin (figure 2). the double-j catheter was exchanged to a single-j 8 ch for better drainage. ten day after the exchange a ct scan showed persistent leakage. fistula consisted in a large cavity opened to the perirenal tissue. a percutaneous approach was used to have a direct way to the fistula. there absorbable gelatin sponge (spongostan®) was applied to the fistulous cavity to reduce the volume. five strips of approximately 5 mm x 50 mm were pushed through the introducer to create a scaffold into the renal breach. then 1 ml of n-butyl-2cyanacrilate (glubran 2®; gem, italy) was located over the leakage orifice above the gelatin sponge. the postprocedure retrograde pyelography showed a substantial reduction on the fistulous tract. a 6 ch drainage pigtail tube outside the kidney in the urinoma as well as a single-j stent were placed at the end of the procedure. (figure 3). patient was discharged home the day after the procedure. follow-up ct scan performed within 30 days of procedure showed a decreased debit and complete reduction in urinoma size. both catheters were removed after the control ct scan, 1 month after the procedure and patient never develop any relapse. discussion and literature review according to aua and eau guidelines, pn is considered the standard treatment for t1a tumors and it 09de concilio_stesura seveso 24/09/20 14:20 pagina 200 201archivio italiano di urologia e andrologia 2020; 92, 3 gelatin sponge (spongostan®) and n-butyl-2-cyanoacrylate should be favored over radical nephrectomy in patients with t1b, whenever feasible. controversial data has been published regarding oncological outcomes of small renal masses in surgical terms. retrospective data by van poppel et al. and eortc group supports the use of pn, however, the only prospective randomized trial comparing both techniques did not show large advantage for pn (1). it is well known that pn is not exempt of complications. tumor size, blood loss, ischemia time and endophytic mass location are factors related to uf formation. several authors have described conservative and nonconservative approaches for uf management. kundu et al. reported a conservative approach perinephric drainage (2). ureteric stent placement is a widely accepted strategy in case of persistent urinary leak and a minimum of 30-45 days might be required for resolution. other authors have used endoscopic fulguration of the fistula for sealing. hemostatic agents and tissue sealants are now being used commonly during laparoscopic and robotic (lpn or rpn). the use of fibrin glues may offer adequate hemostasis in patients undergoing lpn when the collecting system is not opened, but in case of entering, a sutured bolster is recommended. nevertheless, in 2007, porpiglia and coworkers published results to the contrary (3). the use of surgical sealants and biologic agents like thrombin, fibrin and collagen glues can be considered when a persistent leakage is present after pn, and they have been successfully used for over one decade. percutaneous embolization of uf is a relatively novel technique that has been used in the last decade (4). more recently the application of cyanoacrylate glues has been reported in different branches of surgery for endoscopic treatment of refractory bile leaks, gastroenteric fistulae, intracranial vascular malformations and also for the management of urinary fistulas. to our knowledge few cases in literature described the endoscopic utilization of cyanoacrylate in repairing uf after urological maneuvers and until now there are only 4 single cases reports of percutaneous successful utilization of cyanoacrylate glue in repairing uf after pn have been reported till date (5, 6). in addition, two clinical case series: one of 13 cases in 9 years by muto et al that reported the use of cyanoacrylate glue in repairing endoscopic percutaneous and endovaginal urinary fistula of various etiologies with a high success rate and few complications (7). the second by selli et al. described 5 patients presenting uf, but only 3 following pn treated with cyanoacrylate glue endoscopically (8). our case describes the association and combination of spongostan to the already approved n-butyl-2-cyanacrilate (glubran 2®). n-butyl-2-cyanacrilate is composed of n-butyl-2cyanoacrylate monomer and metacryloxysulpholane monomer. this compound presents favorable properties such as a good biocompatibility and progressive reabsorption without causing foreign body granulomas. the property of nearly instantaneous bonding makes cyanoacrylates an effective haemostatic agent and tissue adhesive. its polymerization time is rather fast in a wet environment, specifically with weak bases, such as water and blood. the gluing of the catheter tip is a potential complication of the technique especially in case of no dilution of the cyanoacrylate. moreover, accidental glue injection directly into the collecting system may cause urinary obstruction. a skilled interventional radiologist is required for these procedures. spongostan® is a dry artificial sterile sponge of fibrin prepared by clotting with thrombin a foam or solution of fibrinogen. it is used to provide effective local hemostasis in cases of venous oozing where traditional hemostasis has failed. moreover, spongostan® serves as a scaffold for proteins or cells implanted into defects fulfilling its function as a cell scaffold (9). the combination of sealants in our case was critical to obtain a success of treatment with the purpose of decreasing the defects of parenchyma, filling in the cavity and avoiding a large contact with the urine that could compromise the polymerization of glue. ishii k. et al. in a pn animal model study demonstrated that fibrin figure 1. ct scan confirmed the presence of a 46 mm round partially, posterior, upper pole mass. figure 2. ct scan revealed a left retroperitoneal urinoma 3 cm in diameter with actual drainage through the chest wall and skin. figure 3. the post-procedure retrograde showed a substantial reduction on the fistulous tract. a 6 ch nephrostomy tube as well as a single-j stent were placed at the end of the procedure. 09de concilio_stesura seveso 24/09/20 14:20 pagina 201 archivio italiano di urologia e andrologia 2020; 92, 3 b. de concilio, f. vedovo, m.c. mir, t. silvestri, a. casarin, a. celia 202 sealant plus the collagen or gelatin hemostat have a stronger hemostatic effect than fibrin sealant applied alone (10). the histological investigation showed that the fibrin sealant adhered well to kidney tissue when it was applied with the collagen or gelatin hemostat, showing the advantage of combining these two materials for achieving effective hemostasis and closure effect. in our case spongostan sheets are not only important as a bolster at the site of glue application, but also because a new complex is formed at the fistula site when the two substances are used in combination. finally, one critical factor for success in uf closure using cyanoacrylate is the ratio between the length and the diameter of the fistulous tract. tissue losses greater than 1 cm are unlikely to be completely plugged, and urine may continue to flow around the cast. the fistula diameter to length ratio is the more relevant prognostic factor for success and the combination of two sealants in our cases was the key to obtain a complete resolution. conclusions in conclusion, minimally invasive techniques to solve urinary refractory leakage after pn is a safe option. the application of gelatin sponge (spongostan®) and nbutyl-2-cyanoacrylate improves the outcome resolution, particularly in difficult and high volume uf, without implying increased risk of urinary obstruction. we encourage the use of this technique in selected cases. collaboration amongst urologists and skilled interventional radiologist is strongly recommended. acknowledgments: the authors would like to thank dr. andrea casarin whose expertise made this procedure possible. references 1. van poppel h, da pozzo l, albrecht w, et al. a prospective randomized eortc intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol 2007; 51:1606-15. 2. kundu sd, thompson rh, kallingal gj, et al. urinary fistulae after partial nephrectomy. bju int. 2010; 106:1042-4. 3. porpiglia f, renard j, billia m, et al. biological glues and collagen fleece for hemostasis during laparoscopic partial nephrectomy: technique and results of prospective study. j endourol. 2007; 21:423-8. 4. tekin mi, peskircioglu l, boyvat f, özkardes h. practical approach to terminate urinary extravasation: percutaneous fistula tract embolization with n-butyl cyanoacrylate in a case with partial nephrectomy. tech urol. 2001; 7:67-9. 5. aslan g, men s, gülcü a, et al. percutaneous embolization of persistent urinary fistula after partial nephrectomy using n-butyl-2cyanoacrylate. int j urol. 2005; 12:838-41. 6. aning jj, stott ma, watkinson af. glue ablation of a late-presentation urinary fistula after partial nephrectomy. br j radiol. 2009; 82:e246-8. 7. muto g, d’urso l, castelli e, et al. cyanoacrylic glue: a minimally invasive nonsurgical first line approach for the treatment of some urinary fistulas. j urol. 2005; 174:2239-43. 8. selli c, de maria m, manica m, et al. minimally invasive treatment of urinary fistulas using n-butyl-2-cyanoacrylate: a valid first line option. bmc urol. 2013; 13:55. 9. singh i, saran rn, jain m. does sealing of the tract with absorbable gelatin (spongostan®) facilitate tubeless pcnl? a prospective study. j endourol. 2008; 22:2485-93. 10. ishii k, kawashima h, hayama t, et al. combination of a liquid fibrin sealant with sheet-type hemostatic agents: experimental evaluation in partial nephrectomy animal model. int j urol. 2011; 18:478-82. correspondence bernardino de concilio, md antonio celia, md department of urology, san bassiano hospital, bassano del grappa (italy) francesca vedovo, md (corresponding author) francesca.vedovo@gmail.com tommaso silvestri, md department of urology, azienda sanitaria universitaria integrata di trieste strada di fiume 447, 34149 trieste (italy) department of urology, san bassiano hospital, bassano del grappa (italy) maria carmen mir, md fundación instituto valenciano oncologia, valencia (spain) andrea casarin, md department of radiology, san bassiano hospital, bassano del grappa (italy) 09de concilio_stesura seveso 24/09/20 14:20 pagina 202 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4330 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.330 perineural invasion in prostate needle biopsy: prognostic value on radical prostatectomy and active surveillance nuno ramos, alexandre macedo, joão rosa, miguel carvalho urology department, garcia de orta hospital, almada, portugal. tive treatment options such as radical prostatectomy (rp), external beam radiotherapy and brachytherapy to conservative management strategies including active surveillance (as) (2-5). despite the use of adequate therapy in localized pca, approximately 18% of patients will eventually experience biochemical recurrence (bcr) (1, 6). pathological stage, preoperative prostate-specific antigen (psa) levels and gleason score (gs) are widely used as risk factors for bcr (7). in other hand, as has been increasingly adopted to prevent overtreatment in men with low-risk prostate cancer (8). this strategy pretends to identify patients with clinically indolent tumors and avoid or delay definitive treatment, without compromising survival (9). although the concept of as is well established, there is no consensus regarding the optimal characteristics of patients who should be managed by this strategy. therefore, there is a growing interest in the identification of new clinicopathological features in prostate needle biopsy specimens to improve the evaluation of the likelihood of bcr, as improving the selection of patients to as (2, 4, 10). in this setting, perineural invasion (pni) has been increasingly recognized as prognostic marker (11). pni is a histopathologic finding representing the infiltration of cancer cells in, through and/or around nerves and is present in 7%-43% of prostate needle biopsies with pca (4, 12, 13). pni has been implicated in pca cell proliferation and extraprostatic spread, and the presence of pni has been shown to be associated with adverse oncological outcomes (1416). despite of pni being a potential determinant in pca behaviour, the association between pni and pca progression is still a subject of debate. due to the uncertainty regarding the role of pni, we performed a study to evaluate the association of pni in prostate needle biopsy with adverse pathological findings on rp specimens, as well the impact on bcr. we also pretend to evaluate the role of pni in patients’ selection for as (11). materials and methods we performed a single center retrospective cohort study, on male patients, who underwent rp due to clinically localised pca, from january 2010 to december 2016. all patients underwent a 12-core biopsy prior to rp and presence or absence of pni was assessed. pni was defined as the histopathologic finding of circumferential purpose: the aim of this study was to evaluate the clinical impact of perineural invasion (pni) in prostate biopsy in patients submitted to radical prostatectomy and on active surveillance (as). materials and methods: we performed a single center, retrospective, cohort study on patients diagnosed with clinically localized prostate cancer and submitted to radical prostatectomy between january 2010 and december 2016. we evaluated clinical and anatomopathological characteristics from the biopsy and radical prostatectomy specimen and correlated with biochemical recurrence (bcr) using a survival analysis. we also evaluated the impact of pni in patients with criteria for active surveillance. results: the cohort analyzed consists of 107 patients, with a mean age of 63.1 years and a mean psa prior to biopsy of 7.8 ng/ml. in prostate biopsy, 66.4% of the patients had a gleason score of 6, 30.9% had a gleason score of 7, and 2.7% had a gleason score of 8 or higher, with pni being detected in 57 (53.3%) of the patients. regarding the anatomopathological characteristics of the surgical specimen, invasion of the seminal vesicles was observed in 6.5%, lymph nodes involvement in 9.3% and positive surgical margins in 27.1% of the cases. during follow-up, bcr was recorded in 24.3% of cases. clinicopathological features were stratified according to the presence or absence of pni, with statistical significance in relation to the gleason score (p = 0.001), pathologic t stage (p = 0.001), d’amico risk (p = 0.002) and upstaging of the gleason score (p = 0.045). the survival analysis revealed a relationship between pni and bcr (hazard ratio = 2.98; 95% ci: 1.36-6.58; p = 0.007). regarding the men potentially eligible for as, the presence of pni on the biopsy presented a significant relation with gleason upgrade (p = 0.004) and extraprostatic extension (p = 0.017). conclusions: the presence of pni in prostate biopsy is related to adverse anatomopathological factors, being a potential predictor of bcr and have a possible role in the selection of patients for as. key words: prostate cancer; active surveillance; prostatectomy. submitted 22 july 2020; accepted 3 september 2020 introduction prostate cancer (pca) is the second most commonly diagnosed cancer in men and the third cause of cancer related death (1, 2). the best treatment strategies in clinically localized pca remains unclear and varies from definisummary 331archivio italiano di urologia e andrologia 2020; 92, 4 perineural invasion in prostate needle biopsy or longitudinal tracking of pca cells along a nerve, within the perineural space. pni was not always reported on pathology reports and we excluded patients with unknown pni status to minimize the potential for misclassification bias. clinical and the biopsy parameters were evaluated, including age, psa level prior to surgery, prostate volume, number of positive cores, total percent of core involvement and gs. we also assessed histopathologic finding on rp specimens: gs, margin positivity, stage, seminal vesicle involvement and lymphatic invasion. the primary objective of this study was to report the association between pni in prostate needle biopsy and adverse pathological findings on rp specimen, specifically, the presence of extraprostatic extension, surgical gleason upgrading, positive surgical margin, and lymph node involvement. gleason upgrading was defined as pathologic gs higher than the gs in the prostate biopsy. a sub-analysis was focused on evaluating the role of pni on bcr following rp, defined as two successive postoperative psa values of 0.2 ng/ml or greater. a secondary objective of this study, was to evaluate the impact of pni in prostate needle biopsy on the selection of patients for as. the as cohort was based on the patients who performed rp but could be potentially selected for as, defined according to the epstein criteria (clinical stage ≤ t2a, psa density < 0.15 ng/ml, psa < 10 ng/ml, biopsy gleason score ≤ 6, ≤ 2 positive biopsy cores, and ≤ 50% cancer involvement in any biopsy core). a descriptive analysis on the study population was performed. categorical data were compared using pearson's chisquared test and continuous variables with student t-test. the biochemical recurrence-free survival was calculated through the kaplan-meier analysis. to estimate the prognostic value of pni we used cox proportional hazard regression. a two-sided p value < 0.05 was considered as statistically significant. statistical analysis was performed using spss®, version 23.0 (spss inc., chicago, il, usa). results a total of 107 patients were included in the study, of whom 57 (53.3%) had pni of the biopsy specimens. the demographic and the clinical characteristics of the patients are shown in table 1. patient age ranged from 48 to 73 years (mean, 63.1 years; standard deviation (sd), 5.3 years). preoperative serum psa levels ranged from 1.51 to 21.9 ng/ml (mean, 7.8 ng/ml; sd, 3.9 ng/ml) and the clinical t stage was t1c in 48 (44.9%) of the patients, t2a in 28 (26.2%), t2b in 20 (18.7%) and t2c in 11 (10.3%). according to d’amico risk classification 65 (60,7%) patients were low risk, 29 (27,1%) intermediate risk and 13 (12,2%) high risk. from the prostate biopsy specimens, 71 (66.4%) had a gleason score of 6, 33 (30.9%) had a gleason score of 7, and 3 (2.7%) had a gleason score of 8 or higher. the mean number of cores involved by tumor was 4.83 (sd, 1.5), and the mean percent of core involvement was 25.8% (sd, 20%). pathologic findings at rp are summarized in table 2. regarding the rp specimens, 25 (23.4%) showed extraprostatic extension and 29 (27.1%) had positive margins. the seminal vesicles were invaded in 7 (6.5%) cases and lymph nodes were involved in 10 (9.3%). surgical gs upgrading was observed in 26 (24.2%) patients. the mean follow-up time was 71 months (sd 25.3 months) and, in this period, 26 (24.3%) men experienced bcr. clinical and anatomopathological characteristics from the biopsy and rp specimen were stratified according to the presence or absence of pni. significant differences were found, patients with pni presented higher gs on biopsy and rp specimen (p = 0.036 and p = 0.001), table 1. demographic, clinical and prostate biopsy characterization. pni absence pni presence total p (n = 50, 46.7%) (n = 57, 53.3%) (n = 107) age, mean (years) 62.4 (sd 5.2) 63.7 (sd 5.4) 63.1 (sd 5.38) 0.189 psa level (ng/ml) 7.64 (sd 3.6) 7.94 (sd 4.5) 7.8 (sd 3.9) 0.53 prostate volume(mean, gr) 46.5 (sd 17.5) 45.1 (sd 14.8) 45.8 (sd 16.1) 0.46 gs biopsy 0.036 6 39 (78%) 32 (56.1%) 71 (66.4%) 7 10 (20%) 23 (40.3%) 33 (30.9%) ≥ 8 1 (2%) 2 (3.6%) 3 (2.7%) number of positive cores (mean) 4.56 (sd 2.36) 5.07 (sd 2.77) 4.83 (sd 2.5) 0.31 percent of core involvement (mean) 19.48% (sd 17%) 31.3%(sd 20.95%) 25.8% (sd 20%) 0.04 clinical stage 0.019 t1c 23 (46%) 25 (43.9%) 48 (44.9%) t2a 20 (40%) 8 (14%) 28 (26.2%) t2b 6 (12%) 14 (24.6%) 20 (18.7%) t2c 1 (2%) 10 (17.6%) 11 (10.3%) age, psa level prior surgery, clinical stage and anatomopathological characteristics from biopsy stratified in two groups: patients with pni absence and patients with pni presence in the biopsy. categorical data were compared using pearson's chi-squared test and continuous variables with student t-test. table 2. clinical and histopathologic finding on rp specimens’ characterization. pni absence pni presence total p (n = 50, 46.7%) (n = 57, 53.3%) (n = 107) d’amico risk 0.002 low 38 (76%) 27 (47.4%) 65 (60.7%) intermediate 10 (20%) 19 (33.3%) 29 (27.1%) high 2 (4%) 11 (19.3%) 13 (12.2%) gleason score 0.001 6 34 (68%) 20 (35.1%) 71 (66.4%) 7 16 (32%) 34 (59.6%) 33 (30.9%) ≥ 8 3 (5.3%) 3 (2.7%) pathological stage 0.001 pt2a 8 (16%) 7 (12.3%) 15 (14%) pt2b 5 (10%) 1 (1.8%) 6 (5.6%) pt2c 33 (66%) 27 (47.4%) 60 (56.1%) ≥ pt3 4 (8%) 22 (38.6%) 26 (24.3%) gs upgrading 8 (16%) 18 (31.6%) 26 (24.2%) 0.065 lymphatic invasion 3 (6%) 7 (12.3%) 10 (9.3%) 0.27 sv invasion 1 (2%) 6 (10.5%) 7 (6.5%) 0.11 extraprostatic extension 4 (8%) 21 (36.8%) 25 (23.4%) 0.001 margin positivity 8 (16%) 17 (29.8%) 25 (23.4%) 0.09 bcr 9 (18%) 22 (38.6%) 31 (29%) 0.032 clinical and histopathologic finding on rp specimens stratified in two groups: patients with pni absence and patients with pni presence. categorical data were compared using pearson's chi-squared test and continuous variables with student t-test. sv-seminal vesicle. archivio italiano di urologia e andrologia 2020; 92, 4 n. ramos, a. macedo, j. rosa, m. carvalho 332 higher percent of core involvement (p = 0.04), higher clinical and pathologic t stage (p = 0.019 and p = 0.001), higher d’amico risk (p = 0.002) , extraprostatic extension (p = 0.001), and higher bcr (p = 0.032) comparing with patients without pni. on other hand, no significant differences were identified with respect to age (p = 0.189), preoperative psa (p = 0.53), number of positive cores (p = 0.31), gs upgrading (p = 0.065), surgical margin involvement (p = 0.09), lymph node invasion (p = 0.27) and seminal vesicles involvement (p = 0.11). the kaplan-meier curve (figure 1) revealed a poorer recurrence-free survival in patients with pni (log rank test p = 0.04). on univariate cox analysis (table 3), pni was associated with bcr (hr: 2.98, 95% ci: 1.366.58, p = 0.007), as gs on rp specimen (hr: 3.01, 95% ci: 1.34-6.76, p = 0.008), surgical margin positivity (hr: 3.86, 95% ci: 1.907.94, p = 0.0001) and presence of extraprostatic extension (hr: 4.02, 95% ci: 1.98-8.15 p = 0.0001). however, the prognostic role of pni disappeared in multivariate analysis when adjusted for other predictive factors. in the cohort, a total of 29 men submitted to rp were potentially eligible for as, of whom 13 (44.8%) had biopsy pni. the characteristics of this subgroup are listed in table 4. a significant relation between pni and gs upgrade (p = 0.004) and extraprostatic extension (p = 0.017) was found in the as group. discussion the evaluation of pathological features that may predict oncologic outcomes are important for counselling patients and therapy selection, as treatment options in pca differ according to defined risk groups (17). pni was identified as a possible significant marker of adverse pathologic findings in localized pca, however, the oncological significance and prognostic value is still controversial, with inconsistent results among studies (13). the incidence of pni in biopsy specimens in the present study is similar to that reported by ravery et al. (53,3% vs 47%) (18, 19). although, a wide range of incidences have been reported in the literature due to variation in pathologic definitions and interpretation of pni (16). there are many challenges in looking for pni and a negative result may either indicate that there no nerves identified in the biopsy or that nerves were present without invasion (2). on our study, pni presence on the biopsy cores was associated with adverse parameters in rp specimens, including higher gs, higher pathologic t staging and extraprostatic extension. such associations were also reported in a recent meta-analysis were pni was a significant marker to predict high stage disease (4). despite hypothesized that spread along intraprostatic nerves may facilitating extraprostatic tumoral extension, there are controversial results in studies investigating the correlation between pni and bcr. jeon et al. and kang et al. showed that pni is associated with adverse pathologic findings and is an independent predictor for bcr in pca patients who undergo rp (6, 20). the same results were observed by yu et al. and wong et al. in patients who undergo external beam radiotherapy (21, 22). on the figure 1. kaplan-meier curve and log rank test. biochemical recurrence-free survival in patients with or without pni. table 3. association between disease characteristics and biochemical recurrence-free survival. univariate multivariate hr (95% ic) p value hr (95% ic) p value gs in rp specimen < 7 1 ≥ 7 3.01 (1.34 -6.76) 0.008 1.65 (1.04-2.60) 0.032 extraprostatic extension absence 1 presence 4.02 (1.98-8.15) 0.0001 1.26 (0.48-3.27) 0.64 surgical margin negative 1 positive 3.89 (1.90-7.94) 0.0001 3.51 (1.45-8.52) 0.005 pni absence 1 presence 2.98 (1.36-6.58) 0.007 1.64 (0.7-3.86) 0.25 univariate and multivariate cox models. ci: confidence interval; hr: hazard ratio; gs: gleason score. table 4. clinical and histopathologic finding on active surveillance patients. pni absence pni presence total p (n = 16, 55.2%) (n = 13, 44.8%) (n = 29) age, mean (years) 62.5 (sd 4.9) 63.3 (sd 6.7) 62.86 (52-73) 0.362 psa level (ng/ml) 7.31 (sd 4.9) 7 (sd 4.1) 7.1 (sd 4.2) 0.41 prostate volume (mean, gr) 56.9 (sd 24.5) 48.7 (sd 18.4) 53.3 (sd 22) 0.31 gs upgrading 1 (6.3%) 7 (53.8%) 8 (27.6%) 0.004 extraprostatic extension 4 (30.8%) 4 (13.8%) 0.017 csub-group of patients potentially selected to active surveillance. clinical and histopathologic finding stratified in two groups: patients with pni absence and patients with pni presence in the prostate biopsy. 333archivio italiano di urologia e andrologia 2020; 92, 4 perineural invasion in prostate needle biopsy contrary, reeves et al. and freedland et al. reported that pni is not correlated with bcr in pca after rp (23, 24). in our cohort, we found an association between pni and bcr on univariate but not on multivariate analysis. this questions whether pni is an independent prognostic factor or just a risk factor for bcr, since significance is lost when pni presence is controlled for other biopsy parameters, such as gleason score and extraprostatic extension (25). one possible explanation for these findings is that pni may only be an important prognostic factor in a specific sub-group of patients. d’amico et al. found that biopsy pni showed statistical significance on multivariate analysis only in the low risk group and quinn et al. reported that biopsy pni was a significant prognostic factor on multivariate analysis of patients with psa values more than 10 ng/ml (26, 27). in the same setting, rather than evaluated the presence or absence of pni, quantification could have a better predictive value. maru et al. found that pni diameter > 0.25 mm was an independent prognostic indicator for biochemical recurrence on multivariate analysis (28). moreover, sun et al. demonstrated that multifocal pni, rather than unifocal pni, is correlate to shorter biochemical recurrence-free survival in patients with pca (10). as has been widely accepted as an observational strategy, in the last decade, in response to the over-treatment of men with low-risk pca (16). the selection of patients is based on pathologic findings on needle core biopsy. at present, biopsy pni is not included in the established criteria for as selection, thus, whether pni is potentially associated with worse prognosis and preclude a conservative management is not known. in our analysis, the presence of pni in patients who met criteria for as has been associated with adverse pathologic findings at prostatectomy, including gs upstaging and extraprostatic extension. these finding suggest a potential role for biopsy pni in identifying men at risk for progression on as. this evidence is corroborated by a retrospective review of the reduction by dutasteride of clinical progression events in expectant management (reedem) study, with 302 men on as, who describe that pni is an independent predictor of clinical progression (73% after 2 years) (29). similarly, in a cohort of 165 men on as, cohn et al. reported that biopsy pni remained a significant predictor for as failure after adjustment biopsy parameters such as tumour length (30). while these data suggest that patients with biopsy pni on initial biopsy may not be good candidates for as, future study is required to assess prognostic value of this pathologic finding. several limitations should be acknowledged in this study. first, the small number of cases, similar to other series published, limits the statistical power of the conclusions. second, the study design, as a single-institution retrospective analysis with risk of unmeasured bias, does not allow to generalize the conclusions. third, prostatectomy specimens did not undergo a centralized review, so there may be variability in the reporting of pni. ideally, a multicenter randomized prospective study with a larger sample would answer many questions raised in our study. fourth, we only report pni as a binary variable because quantitative measures of pni were not included in pathology reports. finally, a short follow-up with a mean of 71 months can undervalue the bcr. conclusions in conclusion, despite the limitations listed above, this study recognizes the clinicopathological importance and potential prognostic value of pni in pca. the presence of pni on prostate biopsy cores is an important predictive of aggressive disease in patients submitted to rp with clinically localized pca and an indicator of bcr in univariate analysis. additionally, among men who met criteria for as, biopsy pni is associate with gs upgrade and extraprostatic extension and could have a role in the selection of patients for as. a large prospective study with longer follow-up is needed to confirm these results. references 1. zhang lj, wu b, zha zl, et al. perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. bmc urol. 2018; 18:5. 2. ahmad as, parameshwaran v, beltran l, et al. should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively. oncotarget. 2018; 9:20555-20562. 3. vargas so, jiroutek m, welch wr, et al. perineural invasion in prostate needle biopsy specimens. correlation with extraprostatic extension at resection. am j clin pathol. 1999; 111:223-228. 4. celik s, bozkurt o, demir o, et al. effects of perineural invasion in prostate needle biopsy on tumor grade and biochemical recurrence rates after radical prostatectomy. kaohsiung j med sci. 2018; 34:385-390. 5. erdem s, verep s, bagbudar s, et al. the clinical predictive factors and postoperative histopathological parameters associated with upgrading after radical prostatectomy: a contemporary analysis with grade groups. prostate. 2020; 80:225-234. 6. jeon hg, bae j, yi js, et al. perineural invasion is a prognostic factor for biochemical failure after radical prostatectomy. int j urol. 2009; 16:682-686. 7. barsky ar, kraus rd, carmona r, et al. investigating association of perineural invasion on prostate biopsy with gleason score upgrading at prostatectomy: a multi-institutional analysis. cancer med. 2020; 9:3383-3389. 8. verep s, erdem s, ozluk y, et al. the pathological upgrading after radical prostatectomy in low-risk prostate cancer patients who are eligible for active surveillance: how safe is it to depend on bioptic pathology? prostate. 2019; 79:1523-1529. 9. ediz c, akan s, temel mc, yilmaz o. the importance of psadensity in active surveillance for prostate cancer. arch ital urol androl. 2020; 92:136-141. 10. kraus rd, barsky a, ji l, et al. the perineural invasion paradox: is perineural invasion an independent prognostic indicator of biochemical recurrence risk in patients with pt2n0r0 prostate cancer? a multi-institutional study. adv radiat oncol. 2019; 4:96-102. 11. turner rm, 2nd, yecies ts, yabes jg, et al. biopsy perineural invasion in prostate cancer patients who are candidates for active surveillance by strict and expanded criteria. urology. 2017; 102:173-177. 12. strom p, nordstrom t, delahunt b, et al. prognostic value of perineural invasion in prostate needle biopsies: a population-based study of patients treated by radical prostatectomy. j clin pathol. 2020. archivio italiano di urologia e andrologia 2020; 92, 4 n. ramos, a. macedo, j. rosa, m. carvalho 334 13. zhao j, chen j, zhang m, et al. the clinical significance of perineural invasion in patients with de novo metastatic prostate cancer. andrology. 2019; 7:184-192. 14. zareba p, flavin r, isikbay m, et al. perineural invasion and risk of lethal prostate cancer. cancer epidemiol biomarkers prev. 2017; 26:719-726. 15. kuang ag, nickel jc, andriole gl, et al. both acute and chronic inflammation are associated with less perineural invasion in men with prostate cancer on repeat biopsy. bju int. 2019; 123:91-97. 16. wu s, lin x, lin sx, et al. impact of biopsy perineural invasion on the outcomes of patients who underwent radical prostatectomy: a systematic review and meta-analysis. scand j urol. 2019; 53:287-294. 17. camur e, coskun a, kavukoglu, et al. prostate volume effect on gleason score upgrading in active surveillance appropriate patients. arch ital urol androl. 2019; 91:93-96. 18. ravery v, boccon-gibod la, dauge-geffroy mc, , et al. systematic biopsies accurately predict extracapsular extension of prostate cancer and persistent/recurrent detectable psa after radical prostatectomy. urology. 1994; 44:371-376. 19. peng lc, narang ak, gergis c, et al. effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy. urol oncol. 2018; 36:309 e307-309 e314. 20. kang m, oh jj, lee s, et al. perineural invasion and lymphovascular invasion are associated with increased risk of biochemical recurrence in patients undergoing radical prostatectomy. ann surg oncol. 2016; 23:2699-2706. 21. wong ww, schild se, vora sa, halyard my. association of percent positive prostate biopsies and perineural invasion with biochemical outcome after external beam radiotherapy for localized prostate cancer. int j radiat oncol biol phys. 2004; 60:24-29. 22. yu hh, song dy, tsai yy, et al. perineural invasion affects biochemical recurrence-free survival in patients with prostate cancer treated with definitive external beam radiotherapy. urology. 2007; 70:111-116. 23. reeves f, hovens cm, harewood l, et al. does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer? can urol assoc j. 2015; 9:e252255. 24. freedland sj, csathy gs, dorey f, aronson wj. percent prostate needle biopsy tissue with cancer is more predictive of biochemical failure or adverse pathology after radical prostatectomy than prostate specific antigen or gleason score. j urol. 2002; 167:516-520. 25. trpkov c, yilmaz a, trpkov k. perineural invasion in prostate cancer patients who are potential candidates for active surveillance: validation study. urology. 2014; 84:149-152. 26. d'amico av, wu y, chen mh, et al. perineural invasion as a predictor of biochemical outcome following radical prostatectomy for select men with clinically localized prostate cancer. j urol. 2001; 165:126-129. 27. quinn di, henshall sm, brenner pc, et al. prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion. cancer. 2003; 97:1884-1893. 28. maru n, ohori m, kattan mw, et al. prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. hum pathol. 2001; 32:828-833. 29. moreira dm, fleshner ne, freedland sj. baseline perineural invasion is associated with shorter time to progression in men with prostate cancer undergoing active surveillance: results from the redeem study. j urol. 2015; 194:1258-1263. 30. cohn ja, dangle pp, wang ce, et al. the prognostic significance of perineural invasion and race in men considering active surveillance. bju int. 2014; 114:75-80. correspondence nuno ramos, md (corresponding author) nuno.ramos@hgo.min-saude.pt nunoandre33@gmail.com alexandre macedo, md alex.m.macedo89@gmail.com joão rosa, md jpmrosa@yahoo.com miguel carvalho, md uro.miguelcarvalho@gmail.com urology department, garcia de orta hospital av. torrado da silva, 2801-951, almada (portugal) stesura seveso 321archivio italiano di urologia e andrologia 2020; 92, 4 case collection no conflict of interest declared. doi: 10.4081/aiua.2020.4.321 complications of endourological procedures and their treatment aldo franco de rose 1, eugenio di grazia 2, vincenzo magnano san lio 3, khaled refaai 4, martina beverini 1, alberto caviglia 1, davide di mauro 2, giuseppe giordano 3, islam o. koraiem 4, guglielmo mantica 1, diego meo 3, mohamed ramadan 4, mostafa sakr 4, carlo terrone 1 1 department of urology, policlinico san martino hospital, university of genova, genova, italy; 2 azienda policlinico vittorio emanuele, ospedale s. marco, catania, italy; 3 unit of diagnostic and interventional radiology arnas “garibaldi-nesima”, catania, italy; 4 department of urology, alexandria university, egypt. case 1 misplaced percutaneous nephrostomy tube in the inferior vena cava khaled refaai, mohamed ramadan, islam o. koraiem, mostafa sakr introduction percutaneous nephrostomy (pcn) is a useful tool for temporary drainage of obstructed kidney even with sterile hydronephrosis (1). depending on the image guidance, pcn can be an effective and safe procedure. however, significant morbidity due to the development of complications can still occur. potentially serious complications include severe bleeding, septicemia and injury to adjacent organs as bowel perforation, splenic injury, pleural injury or liver injury (2). major complications rate up to 7% have been reported. intravenous misplacement of a urologic catheter is an uncommon complication of percutaneous renal surgery and improper management of it could lead to serious consequences. different techniques can be used for insertion of pcn. the most commonly used techniques are either seldinger’s technique which include puncture of kidney by a needle then insertion of guide wire and dilatation over this wire to form a wide track enough for passage of nephrostomy catheter or one-stab technique (bonnano technique) using a pigtail teflon catheter mounted on a hollow 18g needle which has a sharp beveled edge to be directly inserted in the pelvicalyceal system (3). pcn insertion can be either under ultrasound (us) guidance or combined us and fluoroscopy guidance. less commonly usage of ct can be used especially in abnormal anatomy, ectopic kidney and transplanted kidney (4) contrast enhanced us can be used in non-dilated kidneys (5). combined use of ultrasound and fluoroscopy is expected to achieve better results in terms of success rate and decrease in the occurrence of major complications of percutaneous nephrostomy insertion (6). us alone can be used safely in pcn insertion in case of marked dilatation of pelvicalyceal system especially in one stab technique and also can be used in puncture and dilatation in cases of pregnancy or hypersensitivity to contrast material but by well experienced surgeons (3). endourological treatment for urinary stones and other obstructive urinary tract diseases is minimally invasive but in some cases it involves serious complications. this collection of cases describes some complications of endourological procedures and how they were treated. case 1: a case of right ultrasound-guided percutaneous nephrostomy found to be misplaced in the inferior vena cava. the case was safely managed, but it showed that ultrasound guidance alone may be insufficient so it is recommended that percutaneous nephrostomy should be always placed under fluoroscopic control, either alone or in combination with ultrasound guidance. case 2: a case of renal subcapsular hematoma occurring on retrograde intrarenal surgery at high perfusion pressure. the hematoma was drained under combined ultrasonic and radiological guidance. post treatment recovery was uneventful. large stone size, severe ipsilateral hydronephrosis, long operation time, higher hydrostatic pressure of the irrigating solution and low ureteral wall compliance are supposed to be risks factors associated with renal subcapsular formation. management strategy should be tailored to patient’s clinical conditions. in hemodynamically stable patients, large hematoma drainage is recommended to prevent further complications and favours early recovery. case 3: a case of double j stent fracture discovered one month after the insertion to relieve obstruction from a 1 cm stone in the right proximal ureter. the distal fragment of the stent was removed by cystoscopy while the proximal fragment was removed by semirigid ureteroscopy in two sessions due to fever and extensive calcification. case 4: a mini-invasive technique for transurethral replacement of completely encrusted urinary stents in female patients. this technique allows the interventional radiologist to replace obstructed urinary stents by avoiding more invasive and traumatic urological procedures with sedation. key words: percutaneous nephrostomy; inferior vena cava (ivc); retrograde intrarenal surgery (rirs); renal subcapsular hematoma; ureters; stents; ureteral calculi; fluoroscopy. submitted 17 july 2020; accepted 30 september 2020 summary case collection1_stesura seveso 14/12/20 20:38 pagina 321 archivio italiano di urologia e andrologia 2020; 92, 4 a.f. de rose, e. di grazia, v. magnano san lio, et al. 322 case report a 30-year-old female patient presented to the outpatient clinic with high grade fever and mild right loin pain. examination revealed mild right loin tenderness. laboratory blood tests results showed serum creatinine level of 1.5 mg/dl and white blood cells count of 13.5 x 103/ml and urine analysis showed pus cells more than 100/hpf. patient was admitted to hospital and subsequent imaging confirmed the presence of stones in the right kidney with moderate hydronephrosis and thickening of renal pelvis wall reflecting inflammatory stricture. decision was made to insert a percutaneous nephrostomy (pcn) tube in the right kidney to drain infected hydronephrosis and to ease the later percutaneous nephrolithotomy procedure. right pcn tube was successfully inserted under ultrasound (us) guidance under cover of broad spectrum antibiotics to be modified after results of urine culture and sensitivity test. seldinger’s technique under us guidance was usually used to insert nephrostomy tube. a 18 gauge 25 cm long chiba needle was used to make puncture under us guidance and teflon dilators starting from 8 to 14 f over guidewire were used for blind dilatation of the track to insert a 12 f amecath nephrostomy tube. few days later, the pcn tube slipped and decision was made to reinsert the tube. the same urologist reinserted the tube under us guidance following the usual recommended steps. however, after insertion continuous flow of venous blood was unexpectedly noticed. the tube was clamped and fixed and as the patient was vitally stable she was directly transferred to undergo a computed tomography (ct) scan that demonstrated the pcn tube passing within the right renal vein through a segmental renal vein to reach the inferior vena cava (ivc) (figure 1). the tube was kept clamped and the patient remained vitally stable and decision was made to remove the tube in the operatory room (or) under vision to be ready for any consequences. exploration was done and pcn was safely removed without any subsequent bleeding, renal stones were extracted through a nephrotomy and double j stent was inserted. on post-operative day 2, patient developed mild respiratory distress. pulmonary embolism was suspected. however, radiology and laboratory workup was negative. patient recovered with conservative management and was discharged safely on postoperative day 5. conclusions percutaneous nephrostomy tube should be inserted by welltrained urologists with combined usage of both us and fluoroscopic guidance. in case of intravenous tube misplacement, simple removal is safe and feasible. however, or team should be ready for any unexpected event. case 2 subcapsular hematoma after rirs eugenio di grazia, davide di mauro introduction retrograde intrarenal surgery (rirs) is usually safe and effective for managing < 2 cm kidney stones. complications rate is generally low and not severe. major complications occur in fewer than 0.1% of cases and among these renal subcapsular hematoma (rsh) is exceedingly rare and reported in few papers in literature (7-9). we believe that, although rare, subcapsular hematoma of the kidney deserves attention from endourologists for its severity. we report on a case of renal rsh occurred in a patient after rirs performed by an experienced endourologist to manage intrarenal kidney stone disease. the presentation, common characteristics, risk factors, management and review of the literature are discussed. case report a 32-year-old patient had a 3-month long-standing stent deployed at emergency unit to relieve left kidney stone obstruction. ct scan before stent placement showed a 1.2 cm pyelic stone causing hydronephrosis and another 7 mm stone located at the lower calyx. the patient was scheduled for rirs. the patient was one pack/day smoker and his body mass index (bmi) was 18.4 kg/m2. preoperative evaluation showed no comorbidities. urine culture was negative, blood testing showed haemoglobin (hb) 15.4 g/dl, white blood count (wbc) 8.520, creatinine 0.78 mg/dl and normal coagulation tests. after removal of the calcified stent, flexible ureteroscopy (fu) was started with cystoscopic insertion of a hydrophilic safety wire. then, using a 7 f semirigid ureteroscope, the ureter was inspected toward the ureteric pelvic junction (upj) showing long-standing stent inflammation and no stones along the ureter. we failed to deploy a 10/12 fr ureteral access sheath (uas) because of low ureteral wall compliance. a 7.5 fr flexible fiberoptic ureteroscope and holmium laser with 200 µm fiber were used for lithotripsy. irrigation was located at 80 cm from the operating table and manual intermittent forced irrigation with a 20cc syringe was used when necessary to ameliorate visibility. after about 30 minutes operating time the procedure was aborted because of scope friction with the ureter not percase 1 figure 1. computed tomography scan demonstrating nephrostomy tube passing within the right renal vein through a segmental renal vein to reach the inferior vena cava. case collection1_stesura seveso 14/12/20 20:38 pagina 322 323archivio italiano di urologia e andrologia 2020; 92, 4 complications in endourology mitting to manage the stone properly. a double j stent was replaced and a mini percutaneous nephrolithotomy (minipcnl) was planned at a later time after appropriate patient counselling. after rirs, the patient experienced persistent low-grade fever between 37.3 and 38 °c and a stepwise increase in wbc count in the following days, despite 5 days carbapenems antibiotics full-therapy, and hb dropped to 12.5 g/dl. other clinical signs such as loin pain or hemodynamic instability were not observed. ct scan showed a 5.6 x 3.1 x 11.4 cm left rsh not supplied by active bleeding (figure 1). clinical symptoms and hemodynamic stability induced to manage the complication by placing an 8 f percutaneous nephrostomy catheter in the urinary system and another drainage in the rsh under ultrasonic and radiological guidance. the previously placed ureteral stent was removed to avoid possible ureteral reflux to the affected kidney during urination. at first the drainage of the rsh drained about 50cc, then drained about 10cc per day. culture test on the aspirate was negative. drainage ceased to be productive in the fifth day post procedure and it was removed. post-treatment recovery was uneventful, hb stabilized within 10 g/dl, fever ceased in the second postoperative day and patient was discharged in the fourth postoperative day. minipcnl was performed 2 months later through the same nephrostomy tract when rsh was completely healed. informed consent was obtained by the patient for the reporting of the case. conclusions after rirs, rsh is an anecdotal complication caused by fornix rupture and bleeding. several factors are supposed to favors the risk of renal rupture when high perfusion pressure of irrigation is used. low pressure irrigation and uas deployment are recommended to prevent this severe complication. management strategy is tailored to patient’s clinical conditions. in hemodynamically stable patients, large hematoma drainage is recommended to prevent further complications and favors early recovery. case 3 retrieval of broken dj ureteric stent a rare endourological nightmare aldo franco de rose, martina beverini, alberto caviglia, guglielmo mantica, carlo terrone introduction double-j ureteral stents are commonly used to manage urinary obstructions and their insertion is one of the basic endourological procedure. even though ureteric stenting is usually a simple and fast maneuver, it is not completely devoid of troubles and complications such as malposition, migration and encrustation. these events require further management that sometimes might be challenging for the endourologist. dj stent fracture is a possible but rare complication that is reported in literature in very few cases (10-13), mostly related to long time before removal. we present a rare case of dj stent fracture discovered one month after the insertion. case presentation in february 2020 a 72-year-old man presented to another hospital with fever and right renal colic. he performed a ct scan of the abdomen that found a 1 cm stone in the right proximal ureter, just under the pyelo-ureteral joint. a ureteral double j (dj) stent was placed. after one month the man was admitted to our first aid with fever and right renal colic. complete blood count, renal function tests, and serum electrolytes measurement were performed and an increase in white blood cells and creatinine was found (wbc 12.40 x 10^9/l, creatinine 2.6 mg/dl, egfr 24 ml/m’/1.73 mq, c-reactive protein 41.2 mg/l). the urine culture was positive for staphylococcus epidermidis and hominis. he resulted negative at the covid-19 swab. the patient underwent another abdominal ct scan which showed a right hydronephrosis in addition to the abovementioned stone. furthermore, the previously positioned dj stent was broken, with the proximal tip of the stent correctly positioned in the right renal pelvis while the distal half was completely migrated in the bladder (figure 1a). despite this, the overall appearance of the right kidney was healthy, with cortical thickness within the limits and presence of moderate perirenal edema. the patient underwent ureterorenoscopy. at the preliminary cystoscopy two fragments of the distal end of the stent were found and were removed with grasping forceps (figure 1b). after that, the right ureteral meatus was identified and a safety guidewire was positioned. a pyelography with a minimal dose of contrast was done and then a ureteral catheter was advanced along the ureter inducing the push up of the stone. purulent urine was drained. the semi rigid ureterorenoscope was introduced up to the renal pelvis and the proximal end of the known stent was found there. the stent was taken with a forceps and the removal procedure started, however at the level of the vascular cross the curl of the stent got stuck. considering the emergency and the septic state of the patient we didn’t proceed to laser lithotripsy of the calcified portion of the stent and therefore a mono j urethral stent was placed. after two weeks of case 2 figure 1. ct scan showing a 5.6 x 3.1 x 11.4 cm left renal subcapsular hematoma not supplied by active bleeding. case 3 figure 1. a. ct scan showing the broken dj stent in situ. b. dj stent after the retrieval. case collection1_stesura seveso 14/12/20 20:38 pagina 323 archivio italiano di urologia e andrologia 2020; 92, 4 a.f. de rose, e. di grazia, v. magnano san lio, et al. 324 antibiotic therapy, once the phlogistic indexes were normalized, the ureterorenoscopy was repeated and the last portion of the stent and the stone were removed after laser lithotripsy. a double j stent was placed. the patient tolerated the procedure very well and there were no complications. on the following day, the patient was discharged home with the indication to continue the antibiotic therapy and remove the new stent outpatiently a week later. conclusions broken dj ureteric stent is a rare endourological complication. it can be safely removed with minimal morbidity and mortality by an experienced endourologist. to minimize further complications, hospitalization and costs it is preferable, when possible, to perform the removal of the broken dj stent in one time. it is advisable to perform the surgery in two times in case of complications such as fever or extensive stent calcification. case 4 a mini-invasive technique for transurethral replacement of encrusted urinary stents in female patient. description of the technique and clinical results vincenzo magnano san lio, diego meo, giuseppe giordano introduction ureteral stent placement is a procedure for maintaining ureteral patency in various benign or malignant conditions (14). it may be a short-term bridge waiting for definitive therapy as in the case of ureteral stones or a long-term stenting for benign or malignant ureteral strictures (15). plastic stents are the mainstay of long-term treatment. these stents are prone to obstruction and fouling by urinary salt precipitation (15). traditionally their replacement has been performed cystoscopically, although an alternative is the replacement of urinary stents with a transurethral approach that is performed in the angiography room whose effectiveness is well described in the literature (16). however, complete stent obstruction makes it impossible its replacement on a metal guidewire or an hydrophilic guide wire. we report the effectiveness of a transurethral recovery technique that allows, while maintaining access to the ureter, to remove the encrusted stent and replace it with an analogue by transurethral technique. technique the material needed to replace an encrusted ureteral stent is: • 0,035 inch x 145 superstiff ptfe coated guidewire (amplatz, boston scientific, ratingen, germany) • 0,035 inch x 180 standard coated hydrophilic guidewire (radifocus guidewire m, terumo, tokyo, japan) • 9 fr peel away introducer sheath 15,5 cm length or 9 fr super flex sheath vascular introducer (cutting his terminal valve) • 3-0 silk thread • 4 fr bern shaped catheter (bern, boston scientific, ratingen, germany; ber, cordis, miami, fl, usa) • lidocaine gel 2,5% • klemmer clamp standard or angled • 8 fr plastic double j ureteral stent, 20-22-24 cm length (percuflex, boston scientific, ratingen, germany) after accurate disinfection, with a lidocaine gel 2,5% soaked klemmer clamp the bladder’s tip of the ureteral stent is recovered (figure 1). the proximal portion of the stent (cutting the tip) is externalized and knotted with a silk thread (figure 2). a metal wire is advanced as far as possible inside the stent until it reaches the obstructed portion and keeping the whole system strained, a coaxial introducer sheath is advanced to reach the ureteral meatus (figure 3). it is important to do this operation in 2 people, one gently advancing the introducer, the other one holding the catheter under tension through the silk thread. the stent is then removed while maintaining case 4 figure 1. the bladder tip of the ureteral stent was recovered by a jelly soaked klemmer clamp. case 4 figure 3. a metal wire was advanced as far as possible inside the stent until it reached the obstructed portion and keeping the whole system strained, a coaxial introducer sheath was advanced to reach the ureteral meatus. the stent was then removed while maintaining access to the ureter. case 4 figure 4. the renal pelvis was reached with an hydrophilic guide and a 4 fr bern catheter. the wire was replaced by a superstiff ptfe coated guidewire. finally, the new ureteral stent was positioned. case 4 figure 2. the proximal portion of the stent (cutting the tip) was externalized and knotted with a silk thread. case collection1_stesura seveso 14/12/20 20:38 pagina 324 325archivio italiano di urologia e andrologia 2020; 92, 4 complications in endourology access to the ureter. the renal pelvis is reached, with a hydrophilic guide and a 4 fr bern catheter, and the wire is replaced by a superstiff ptfe coated guidewire. a metal guidewire is advanced up to the renal pelvis inside the introducer sheath and a new 8 fr stent is positioned (figure 4). we developed a novel recovery technique with silk thread and use of a 9 fr vascular introducer sheath which allowed us to remove the obstructed stents while maintaining access to the ureter. case series from january 2013 to january 2020, 402 urinary stents were replaced with a transurethral approach in 325 women with obstructive urinary disorders (benign and malignant). out of them 363 were recovered with a standard transurethral approach using a metal guidewire, but 39 stents were obstructed by encrustations making impossible to replace them with a standard technique. in 38 cases it was possible to replace the obstructed stents. the technique failed in one patient because we were unable to advance the access sheath through the ureteral orifice. encrusted ureteral stents were replaced in 22 women. the number of procedures performed on each patient, who had an encrusted stent, varied from one to three. technical success was achieved in 97.4% procedures. the mean fluoroscopic time was 3 minutes and 25 seconds (range 2 minutes, 31 seconds 13 minutes, 32 seconds). twenty patients had urinary infection associated with obstruction due to an occluded stent. there were 6 cases of transient minor hematuria that resolved spontaneously within 1-2 days after the procedure. there were no major complications. some patients complained of mild pain in the urethra and lower abdomen region when the stent tip was grasped or the stent was removed, but none of them required pain management other than drugs used as part of the pretreatment. in one case a significant stone incrustation in the bladder portion of the stent did not allow for the execution of this technique, therefore we broke the incrustation with the klemmer clamp once the proximal portion of the stent was externalized and therefore the stent could be replaced. conclusions in conclusion, fluoroscopically guided transurethral replacement of encrusted ureteral stents in women is a feasible and safe alternative to cystoscopy. performing this exchange procedure reduces costs compared to cystoscopic exchange of the ureteral stent in the operating room. this technique allows to replace obstructed urinary stents avoiding more invasive and traumatic urological procedures with sedation. references 1. mittal v, biswas m, lal s. percutaneous nephrostomy or double j stenting, which is better modality for obstructive uropathy-a descriptive study. int j res med sci. 2017; 4:3486-91. 2. dyer rb, assimos dg, regan jd. update on interventional uroradiology. urol clin north am. 1997; 24:623-52. 3. venyo a, fatola c, adegbite d, khan a. nephrostomy in pregnancy a district general hospital experience over five years. journal of biomedical graphics and computin. 2014; 5:10.5430/jbgc.v5n1p1. 4. ghani kr, patel u, anson k. computed tomography for percutaneous renal access. j endourol. 2009; 23:1633-9. 5. liu bx, huang gl, xie xh, et al. radiology. 2017; 285:293-301. 6. bhatt s, verma p, grover ret al. success, effectiveness and safety of combined sonographic and fluoroscopic guided percutaneous nephrostomy in malignant ureteral obstruction. int j radiol radiat ther. 2017; 3:165-70. 7. yahsi s, tonyali s, ceylan c, et al. intraparenchymal hematoma as a late complication of retrograde intrarenal surgery. international braz j urol. 2017; 43:367-370. 8. kozminski ma, kozminski dj, roberts ww, et al. symptomatic subcapsular and perinephric hematoma following ureteroscopic lithotripsy for renal calculi. journal of endourology. 2015; 29:277-282. 9. bai j, li c, wang s, et al. subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. bju international. 2012; 109:1230-1234. 10. chua me, morales ml jr. spontaneous fracture of indwelling polyurethane ureteral stents: a case series and review of literature. can urol assoc j. 2012; 6:386-392. 11. ray rp, mahapatra rs, mondal pp, pal dk. long-term complications of jj stent and its management: a 5 years review. urol ann. 2015; 7:41-45. 12. el-faqih sr, shamsuddin ab, chakrabarti a, et al. (1991) polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol. 146:1487-1491. 13. zisman a, siegel yi, siegmann a, lindner a. spontaneous ureteral stent fragmentation. j urol. 1995; 153(3 pt 1):718-721. 14. park sw, cha ih, hong sj, et al. fluoroscopy-guided transurethral removal and exchange of ureteral stents in female patients: technical notes. j vasc interv radiol. 2007; 18:251-6. 15. mccarthy e, kavanagh j, mckernan s, et al. fluoroscopically guided transurethral removal and/or replacement of ureteric stents in women. acta radiol. 2015; 56:635-40. 16. carrafiello g, coppola a, de marchi g, et al. trans-urethral ureteral stent replacement technique (trust): 10-year experience in 1168 patients. cardiovasc intervent radiol. 2018; 41:610-617. correspondence aldo franco de rose, md aldofrancoderose@libero.it martina beverini, md (corresponding author) martina.beverini@live.it alberto caviglia, md caviglialberto@gmail.com guglielmo mantica, md guglielmo.mantica@gmail.com carlo terrone, md carlo.terrone@med.uniupo.it department of urology, policlinico san martino hospital, university of genova largo rosanna benzi 10, 16132 genova davide di mauro, md (corresponding author) davidedimauro84@virgilio.it eugenio di grazia, md eugeniodigrazia@hotmail.com azienda policlinico vittorio emanuele, ospedale s. marco, catania (italy) magnano san lio vincenzo, md meo diego, md (corresponding author) diegomeo@hotmail.it giordano giuseppe, md unit of diagnostic and interventional radiology arnas “garibaldi-nesima” via palermo 636, 95122 catania (italy) khaled refaai, md javacup16@gmail.com mohamed ramadan, md islam o. koraiem, md (corresponding author) drislamosama@live.com mostafa sakr, md uro-oncology unit, department of genito-urinary surgery, faculty of medicine, alexandria university 74 albert st, smouha, 5359472, alexandria, egypt note: supplementary discussion and references are published online as supplementary materials at https://www.pagepressjournals.org/index.php/aiua/index case collection1_stesura seveso 14/12/20 20:38 pagina 325 stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12415 1 original paper age, luts are common in both females and males with similar incidences. rates of storage, voiding, and postmicturition symptoms in females and males are 51.3% vs 59.2%, 25.7% vs 19.5%, and 16.9% vs 14.2%, respectively (1). these patients admit to clinic suffering from usually more than one symptom. therefore, symptom scores obtained from questionnaires are often used for evaluation of these patients (2). the international prostate symptom score (ipss) has been a well-known and frequently used symptom index for many years. despite its prevalent utilization, there are some drawbacks of the ipss. it was devised for males and does not interrogate symptoms such as incontinence and post-void dribbling. on the other hand, overactive bladder questionnaire v8 (oab-v8), which is also commonly used, inquiries about frequency, urgency, urge or stress incontinence, and nocturia. it was conceived for both males and females, but it covers predominantly storage symptoms and does not question voiding difficulty. as a result, a questionnaire which evaluates both males and females and involves all the important lower urinary tract symptoms will be of benefit for clinicians. “comprehensive assessment of self-reported urinary symptoms (casus)” questionnaire, which consists of 93 questions covering a wider spectrum of symptoms when compared with other questionnaires, was developed to enhance phenotypical analyses of the patients with luts by the lower urinary tract dysfunction research network (lurn) (3). based upon casus, which is impractical in clinical use because of its length, cella and colleagues devised and reported first the lurn symptom index of 29 items (lurn si-29) and thereafter lurn symptom index of 10 items (lurn si-10) by abridging the former (4). in these studies, it is stated that a shorter and successful measure (lurn si-10) in correlation with the clinical presentation is obtained, which is also more comprehensive than present luts questionnaires and applicable to both males and females (5). in this study, we aimed to investigate the validity and reliability of the lurn si-10 questionnaire, which was translated into turkish before, in patients with luts. introduction: to evaluate the validity and reliability of the turkish version of the symptoms of lower urinary tract dysfunction research network symptom index-10 (lurn si-10). materials and methods: in this, single-centre study, patients between 18 and 65 years old, who were suffering from lower urinary tract symptoms (luts) without any known urinary tract disease and on no medication, were enrolled. the control group consisted of participants, who were admitted to our clinic suffering from any complaint except luts and met all of the other inclusion and exclusion criteria. participants’ demographics such as age, sex, and level of education were recorded. the turkish version of the lurn si-10, international prostate symptom score (ipss) and overactive bladder questionnaire (oab-v8) were administered to all participants. construct validity was evaluated by confirmatory factor analysis and concurrent validity was evaluated with correlations to similar measures. internal consistency (cronbach's alpha) was used to establish the scale's internal consistency reliability. results: a total of 164 participants were included in the final analysis. of those, 57% were male. the individuals were identified as being in the “patient group” (n = 86) and a “control group” (n = 78). the mean age was 48.24 ± 14.30 years. the median total lurn si-10 scores of patient group and control group were 12.0 (9-18.25) and 4.0 (2.75-6), respectively. the lurn si-10 questionnaire showed a high correlation with the ipss and the oab-v8 questionnaires (r: 0.761; p: 0.001; r: 0.737; p: 0.001, respectively) in concurrent validity analysis. cronbach’s alpha coefficient of the lurn si-10 was 0.850. conclusions: this promising measurement tool can be used to evaluate luts in turkish women and men. further studies should be conducted to assess the clinical usefulness of this questionnaire. key words: lurn si-10; luts; patient reported outcomes; questionnaires; turkish. submitted 22 february 2024; accepted 28 march 2024 introduction lower urinary tract symptoms (luts), which include storage, voiding, and post-micturition symptoms, are related with lower urinary tract dysfunction. above 40 years of reliability and validity analysis of turkish version of the symptoms of lower urinary tract dysfunction research network symptom index-10 questionnaire serkan akan 1, hasan huseyin tavukcu 2, meftun culpan 3, david cella 4 1 department of urology, university of health sciences, fatih sultan mehmet training and research hospital, istanbul, turkey; 2 department of urology, medipol university camlica hospital, istanbul, turkey; 3 department of urology, faculty of medicine, istanbul medeniyet university, istanbul, turkey; 4 department of medical social sciences, feinberg school of medicine, northwestern university, chicago, illinois, usa. doi: 10.4081/aiua.2024.12415 summary archivio italiano di urologia e andrologia 2024; 96(2):12415 s. akan, h. huseyin tavukcu, m. culpan, d. cella 2 materials and methods we obtained a written approval of the developers of the lurn si-10 index for validating it in turkish language. the local ethics committee endorsed the study with decision number 2022/70 in accordance with the helsinki declaration. a written informed consent was signed by all individuals. patient population we planned to enrol a minimum of 70 patients, who admit to our clinic suffering from luts, and a minimum of 70 participants for control group between september 2022 and october 2023 prospectively. our inclusion criteria were: [1] admission to our clinic with clinically significant luts, [2] age between 18 and 65 years, [3] answering all the questions in each questionnaire, [4] signing the written informed consent. our exclusion criteria were: [1] using medications such as alpha blockers, antimuscarinic agents, beta-mimetics, pain killers or drugs potentially impairing lower urinary tract functions, [2] a history of overactive bladder, bladder cancer, chronic pelvic pain syndrome, chronic prostatitis, prostate cancer, and a neurological disorder potentially causing lower urinary tract dysfunction, [3] presence of temporary or permanent urethral or ureteral catheter, [4] presence of a debilitative disorder, [5] being unable to communicate. the control group consisted of participants, who admitted to our clinic suffering from any complaint expect luts and met all the other inclusion and exclusion criteria. tools for data collection demographic data of the participants such as age, sex, education level were collected. all individuals took the turkish version of the lurn si-10 and validated turkish versions of the ipss and oab-v8 questionnaires (6, 7). they were requested to complete the questionnaires on their own without professional aid at first application. lurn si-10 the lurn si-10, first published in 2020, was conceived as a self-reported outcome questionnaire for clinical use with patients to assess luts 2020 (5). it includes 10 questions about frequency, nocturia, urgency, incontinence, bladder pain, voiding, and post-micturition symptoms as well as an additional question measuring dissatisfaction with luts. each question scores between zero and four according to frequency of the symptom (nineth and tenth questions between zero and three). the total score is calculated as “the total score of ten questions x 10/number of the questions answered” (maximum score 38). last question about dissatisfaction with luts is about quality of life and does not affect the total score. ipss the ipss consists of eight questions and is usually used for screening, diagnosing and treatment planning of benign prostate obstruction (bpo). seven questions investigate incomplete emptying of the bladder, frequency, intermittency, urgency, weak stream, straining, and nocturia. the eighth question is about overall quality of life. a score between zero and seven means mild, between eight and 19 means moderate, and between 20 and 35 means severe symptoms. although ipss is generally used in males with the diagnosis of bpo, it is not specific for males or prostate diseases (8). oab-v8 the overactive bladder questionnaire (oab-q) was developed in 2002 by coyne and colleagues as a questionnaire for oab symptoms and quality of life (9). it can be used in patients with a provisional diagnosis of both wet and dry oab. the oab-v8 consists of the first eight questions of the oab-q and is recommended as a screening and awareness test for oab (10). a score between zero and seven indicates mild symptoms and eight and 40 indicates severe symptoms. tarcan and colleagues validated oab-v8 in turkish language in 2012 (11). linguistic validation we obtained a written approval of the developers of the lurn si-10 index for validating it in turkish language. the turkish lurn si-10 questionnaire, which was not validated in turkish language but developed based upon turkish lurn si-29 questionnaire (12), which was validated in turkish and published in 2021, was sent to the corresponding author by developers of lurn si-10 and used in this study. statistical analysis for statistical analyses, ibm spss statistics 22 and amos 22 computer programs were used. normally distribution of the data was controlled by kolmogorov-smirnov test. findings were represented with descriptive statistical methods (minimum, maximum, mean, standard deviation, median, frequency). in comparison of quantitative data, normally distributed groups were compared by using student t test and non-normally distributed groups were compared by using mann whitney u test. qualitative data were compared by using chi-square test. exploratory factor analysis (efa) was performed to test the construct validity of the lurn si-10. kaiser-meyer-olkin (kmo) test was used to assess the sufficiency of the sample for the factor analysis. bartlett test demonstrated the correlation among variables. for evaluating the construct validity, confirmatory factor analysis (cfa) test was applied. model fit was tested by using the χ2 goodness of fit test (χ2, χ2/degree of freedom [df]), the goodness of fit index (gfi), root mean square error of approximation (rmsea), the comparative fit index (cfi), and the nonnormed fit index (nnfi). cronbach’s alpha coefficient was calculated for reliability of the scale. association between non-normally distributed parameters was controlled by using spearman’s rho correlation test. partial correlation analysis was performed for evaluating the correlation between scores after adjustment for age. a p value less than 0.05 was considered statistically significant. results due to incomplete questionnaires, nine participants were excluded. a total of 164 individuals between the age of 18 and 65 years were enrolled in the study. of those, 71 (43.3%) were female, 93 (56.7%) were male, 86 were in archivio italiano di urologia e andrologia 2024; 96(2):12415 3 turkish version of lurn si-10 questionnaire the patient group, and 78 were in the control group. the ratio of the females in the patient group was significantly higher than that in the control group (55.8% vs 29.5%, p < 0.05). the mean age of all participants was 48.24 ± 14.30 years. in the patient and control groups, the mean ages were 50.95 ± 11.79 and 45.24 ± 16.20 years, respectively. the mean age of the patient group was higher than that of the control group significantly (p < 0.05). the median total lurn si-10 scores were 12.0 (9-18.25) vs 4.0 (2.75-6) in patient group and control group, respectively (p < 0.001). the median total ipss scores were 14.0 (9-21.25) vs 4.5 (2-7) in patient group and control group, respectively (p < 0.001). the median total oab-v8 scores were 20.5 (12-28) vs 7.0 (4.75-9.25) in patient group and control group, respectively (p < 0.001). table 1 and figure 1 demonstrate the lurn si10, ipss and oab-v8 scores and scale graphs of the groups, respectively. the validity of the scale exploratory factor analysis (efa) was performed to test the construct validity of the scale. principal component analysis and varimax rotation were used in the factor analysis. associations of lurn si-10 total score with ipss and oab-v8 were assessed for concurrent validity. the lurn si-10 total score demonstrated a high correlation with those of ipss and oab-v8 (r = 0.761, p < 0.001 and r = 0.737, p < 0.001, respectively). figure 2 shows the correlations of lurn si-10 with ipss and oab-v8. when all individuals were assessed, a high, positive, and statistically significant correlation between both lurn si-10 vs ipss (0.76) and lurn si-10 vs oab-v8 (0.73) were observed (p < 0.001). the correlation analyses in patient and control groups are shown in table 2. in addition, the correlations of the lurn si-10 total score with the ipss and the oab-v8 were investigated in male and female participants separately. in all females, a high, positive, and statistically significant correlation between table 1. comparison of total scores of the lurn si-10, ipss, and oab-v8 between groups. total patient control age mean (sd) 50.95 (12) 45.24 (16) 1 0.012* sex n (%) female 48 (%55.8) 23 (%29.5) 2 0.001* male 38 (%44.2) 55 (%70.5) median (iqr) median (iqr) lurn si-10 12 (9-18.25) 4 (2.75-6) 3 0.001* ipss 14 (9-21.25) 5 (2-7) 3 0.001* oab-v8 21 (12-28) 7 (4.75-9.25) 3 0.001* 1 student t test; 2 ki-kare test; 3 mann whitney u test; * p < 0.05 table 2. correlation of the lurn si-10 with the ipss and oab-v8. total patient control ipss r 0.761 0.628 0.472 p 0.001* 0.001* 0.001* oab-v8 r 0.737 0.597 0.490 p 0.001* 0.001* 0.001* spearman’s correlation; *p < 0.05. figure 1. total scores of the lurn si-10, ipss and oab-v8 in groups. figure 2. correlation of the lurn si-10 with the ipss and oab-v8. archivio italiano di urologia e andrologia 2024; 96(2):12415 s. akan, h. huseyin tavukcu, m. culpan, d. cella 4 both lurn si-10 vs ipss (0.75) and lurn si-10 vs oabv8 (0.79) were observed (p < 0.001). besides, a high, positive, and statistically significant correlation was found between the lurn si-10 total score and both ipss and oab-vs in the female patient group (p < 0.001). in the female control group, a high, positive, and statistically significant correlation was found between lurn si-10 total score and oab-v8 (p < 0.001). in all males, a high, positive, and statistically significant correlation was found between the lurn si-10 total score and both ipss and oab-v8 (78% and 67%, respectively) (p < 0.001). besides, a high, positive, and statistically significant correlation was found between the lurn si-10 total score and both ipss and oab-vs in the male patient group (p < 0.001). in the male control group, a high, positive, and statistically significant correlation was found between lurn si-10 total score and ipss (p < 0.001). in the male control group, a low, positive, and statistically significant correlation was found between the lurn si-10 total score and oab-v8 (p = 0.031) (table 3). the reliability of the scale cronbach’s coefficient of the lurn si-10 for the internal consistency of the scale was 0.850. descriptive data and cronbach’s coefficients of the lurn si-10, ipss and oab-v8 questionnaires are shown in table 4. discussion in this study, the validity and reliability assessment of the lurn si-10 questionnaire in turkish was performed to make it applicable in patients with luts. according to results of our study, version of the lurn si-10 demonstrated good internal consistency reliability and concurrent validity, consistent with the results of the original study conducted by lurn group (5). we hope that our study will contribute to standard reporting of symptoms in turkish-speaking patients and lead to improved evaluation of male and female patients with luts. male patients with luts usually admit to clinic suffering from differing types of involuntary loss of urine, which are not adequately caught by the ipss (13). thus, by using the ipss solely, these symptoms, which substantially impair the quality of life, could be overlooked and the patient could miss the appropriate counselling opportunity. on the other hand, oab-v8 is an excellent questionnaire for evaluating various types of involuntary loss of urine but cannot assess voiding symptoms if used solely. when compared with other questionnaires, lurn si10, which was validated in turkish, has several advantages. first, it can be applied to both male and female patients with luts successfully. in addition, lurn si-10 completely interrogates incontinence and post-void dribbling/pain, which are not included in the ipss, and luts such as voiding difficulty, which are not included in the oab-v8. it can prevent waste of time and effort, for both clinicians and patients, to be able to interrogate all luts by application of this questionnaire of only 10 questions without using other scales. in this study, regarding criterion-related validity was assessed with associations of lurn si-10 with ipss and oab-v8. it was found that lurn si-10 was highly correlated with ipss and oab-v8 questionnaires (r = .761 and r = .737, respectively). in our results, cronbach’s alpha internal consistency coefficients of the lurn si-10, ipss and oab-v8 were consistently high (0.850, 0.847, and 0.921, respectively). however, in the control group, internal consistency coefficients were notably lower (0.529, 0.616, and 0.613, respectively). these tools clearly perform better as single total scores in clinical samples, an important consideration when planning future studies. to the best of our knowledge, this is the first study that assesses the validity and reliability of the lurn si-10 in a non-english language. recently, the validity of the lurn si-10 has been tested by comparing with the ipss and its significant correlation has been reported (14). however, that study included only male patients with luts. in our study, comparisons with the control group were made for both male and female patients and a significant correlation was demonstrated. a statistically significant, positive correlation was found between the lurn si-10 and the ipss in both groups (p: 0.001). in 2021, the lurn si-29 was translated into turkish and its validation was completed by comparing with the ipss and urogenital distress inventory (uditable 3. the correlations of lurn-10 with ipss and oab-vs in females and males. lurn si‐10 total patient control female ipss r 0.754 0.603 0.201 p 0.001* 0.001* 0.358 oab-v8 r 0.789 0.603 0.648 p 0.001* 0.001* 0.001* male ipss r 0.780 0.700 0.572 p 0.001* 0.001* 0.001* oab-v8 r 0.668 0.580 0.291 p 0.001* 0.001* 0.031* spearman’s correlation; *p < 0.05. table 4. descriptive statistics and cronbach’s alpha coefficients of the lurn si-10, ipss and oab-v8. n minimum maximum mean ± sd median cronbach’s alpha total lurn si-10 164 0 29 9.27 ± 6.94 8 0.850 ipss 164 0 31 10.27 ± 7.74 8 0.847 oab-v8 164 0 40 13.93 ± 9.64 11 0.921 patient lurn si-10 86 3 29 13.56 ± 6.80 12 0.782 ipss 86 2 31 14.94 ± 7.43 14 0.780 oab-v8 86 2 40 20.23 ± 0.10 20 0.877 control lurn si-10 78 0 12 4.54 ± 2.80 4 0.529 ipss 78 0 13 5.13 ± 3.83 5 0.616 oab-v8 78 0 14 6.97 ± 3.47 7 0.613 archivio italiano di urologia e andrologia 2024; 96(2):12415 5 turkish version of lurn si-10 questionnaire 6) (12). however, it was developed for use in clinical studies and outcomes research. conversely, the lurn si10 was designed as a concise (single-page) form for simple administration in clinical practice. to the best of our knowledge, there is no study investigating the correlation between the lurn si-10 and oab-v8 in english literature. in this study, we opted for the oab-v8, which covers rather storage symptoms, because it was validated in turkish language in 2012 and has been used for more than ten years in our country. a statistically significant, positive correlation was found between the lurn si-10 and the oab-v8 in both patient and control groups (p: 0.001). there are some limitations of this study. we designed the study as a quality improvement initiative to compare the ipss and oab-v8 with the lurn si-10 and for that reason main clinical data such as comorbidities, race/ethnicity, and body mass index are not included in the present analyses. moreover, we were not able to attain the age and sex similarity between the patient and control group since this was a pilot study. further prospective studies, evaluating test-retest reliability, the effects of comorbidities, and any changes in answers in lurn si-10 questionnaire after medical treatment are needed. conclusions in this study, the validity and reliability of the lurn si10 questionnaire in turkish language and its use in patients with luts were assessed. this promising measurement tool is concise and simple, with initial evidence for reliability and validity in clinical samples and can be used to evaluate luts in turkish women and men. further studies should be conducted to assess the clinical usefulness of this questionnaire. references 1. irwin de, milsom i, hunskaar s, et al. population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the epic study. eur urol. 2006; 50:1306. 2. selekman re, harris cr, filippou p, et al. validation of a visual prostate symptom score in men with lower urinary tract symptoms in a health safety net hospital. urology. 2015; 86:354-8. 3. yang cc, weinfurt kp, merion rm, et al. symptoms of lower urinary tract dysfunction research network. j urol. 2016; 196:146-152. 4. cella d, smith ar, griffith jw, et al. a new outcome measure for luts: symptoms of lower urinary tract dysfunction research network symptom index-29 (lurn si-29) questionnaire. neurourol urodyn. 2019; 38:1751-1759. 5. cella d, smith ar, griffith jw, et al. lurn study group. a new brief clinical assessment of lower urinary tract symptoms for women and men: lurn si-10. j urol. 2020; 203:164-170. 6. bozlu m, doruk e, akbay e, et al. effect of administration mode (patient vs physician) and patient's educational level on the turkish version of the international prostate symptom score. int j urol. 2002; 9:417-421. 7. tarcan t, mangır n, özgür mo, et al. constitution and validation of a new symptom assessment tool for overactive bladder: marmara overactive bladder questionnaire (m-obq). journal of urological surgery 2014; 1:24-27. 8. okamura k, nojiri y, osuga y, tange c. psychometric analysis of international prostate symptom score for female lower urinary tract symptoms. urology. 2009; 73:1199-202. 9. coyne k, revicki d, hunt t, et al. psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the oab-q. qual life res. 2002; 11:563. 10. coyne ks, zyczynski t, margolis mk, et al. validation of an overactive bladder awareness tool for use in primary care settings. adv ther 2005; 22:381-94. 11. tarcan t, mangır n, özgür mö, akbal c. oab-v8 aşırı aktif mesane sorgulama formu validasyon çalışması. üroloji bülteni 2012; 21:113-116. 12. culpan m, acar hc, cella d, et al. turkish validation and reliability of the symptoms of lower urinary tract dysfunction research network symptom index-29 (lurn si-29) questionnaire in patients with lower urinary tract symptoms. neurourol urodyn. 2021; 40:2034-2040. 13. helfand bt, smith ar, lai hh, et. al. prevalence and characteristics of urinary incontinence in a treatment seeking male prospective cohort: results from the lurn study. j urol 2018; 200:397-404. 14. glaser ap, kristof tw, judge c, et al. the 10-item lurn symptom index (lurn si-10) detects additional symptoms and shows convergent validity with the ipss in men presenting with lower urinary tract symptoms. urology. 2023; 171:184-189. correspondence serkan akan, md, associate professor (corresponding author) drserkanakan@hotmail.com department of urology, university of health sciences, fatih sultan mehmet training and research hospital, istanbul, turkey hasan huseyin tavukcu, md, associate professor hhtavukcu@yahoo.com department of urology, medipol university camlica hospital, istanbul, turkey meftun culpan, md, associate professor mculpan@gmail.com department of urology, faculty of medicine, istanbul medeniyet university, istanbul, turkey david cella, phd, professor d-cella@northwestern.edu department of medical social sciences, feinberg school of medicine, northwestern university, chicago, illinois, usa conflict of interest: the authors declare no potential conflict of interest. 173archivio italiano di urologia e andrologia 2017; 89, 3 original paper epidemiologic study of urolithiasis in seven countries of south-eastern europe: s.e.g.u.r. 1 study andreas karagiannis 1, andreas skolarikos 1, emanuel alexandrescu 2, dragoslav basic 3, petrisor geavlete 2, alessandro maletta 4, a.yaser muslumanoglu 5, athanasios papatsoris 1, kremena petkova 6, skender saidi 7, aleksandar skakic 3, iliya saltirov 6, kemal sarica 8, sotir stavridis 7, omer yilmaz 9, alberto trinchieri 4 1 2nd department of urology, university of athens, sismanoglio hospital, greece; 2 urological department, saint john emergency clinical hospital, romania; 3 urological clinic, clinical center nis, serbia; 4 ospedale a.manzoni urology department, lecco, italy; 5 department of urology, bagcilar training and research hospital, istanbul, turkey; 6 department of urology and nephrology, military medical academy, sofia, bulgaria; 7 urology department, university clinical centre "mother theresa" skopje, fyr macedonia; 8 dr. lutfi kirdar kartal research and training hospital, istanbul, turkey; 9 department of urology, gata haydarpasa research and teaching hospital, istanbul, turkey. objective: to investigate some epidemiological aspects of kidney stones in the southeastern european area. materials and methods: from september 2015 to december 2015, 538 consecutive patients were treated and evaluated for reno-ureteral stones in eight departments in bulgaria, greece, italy, fyr macedonia, romania, serbia and turkey. results: the age of onset was lower in turkey and higher in italy. the rate of recurrent patients was higher in romania and serbia, while first renal stone formers were more frequent in italy. the previous history of kidney stones, the characteristics of the stones and the dietary habits of the patients were different in different countries. in bulgaria, greece and romania larger calculi from recurrent patients were more frequent. in italy and turkey smaller calculi from first renal stone formers were more frequent. conclusions: the previous history of kidney stones, the characteristics of the stones and the dietary habits of the patients were different in different countries. a common dietary pattern associated with the formation of kidney stones was not observed, but each country showed different risk factors. key words: urolithiasis; epidemiology; diet. submitted 7 may 2017; accepted 15 july 2017 summary no conflict of interest declared. romania and serbia (5). these prevalence rates are higher than those reported in other regions of europe such as germany (4.7%) (6) and the united kingdom (3.5%) (7) and can be explained by the warmer climate. on the contrary, the south-east european area is characterized by the consumption of the mediterranean diet, that has long been associated with lower incidence of cardiovascular disease and cancer (8, 9). some components of the mediterranean diet as vegetables, fruits, potatoes, legumes and dairy products may be potentially favorable for the prevention of kidney stones. aim of this study was to evaluate several epidemiological features and dietary habits, in patients with renal stones treated in seven countries of the south-eastern europe. materials and methods from september 2015 to december 2015, 538 consecutive patients were treated for reno-ureteral stones in eight urological departments in bulgaria, greece, italy, fyr macedonia, romania, serbia and turkey. the patients were evaluated on the basis of a questionnaire posted on www.segurgroup.eu website. the questionnaire investigated extensively patient characteristics, including age, gender, weight, height, body mass index (bmi), working and sporting activity, bowel habits, urinary volume, presence of urological diseases or medical diseases related to stone formation, previous urinary tract infection, renal function, fluid intake and dietary habits, stone history and stone characteristics (size, location, composition, side and treatment modality). working activity was scored as light, heavy and very heavy and sporting activity as light, intermediate, high and professional; intake of food categories (pasta/rice/pizza, meat/poultry/fish, cheese, vegetables, fruit) as never or rarely, often, daily; milk/yogurt intake as n° cups/day; bread intake n° of loafs/slices/day. working activity and doi: 10.4081/aiua.2017.3.173 introduction the epidemiology of urolithiasis has been frequently correlated with geography, climate and culture (1). the area of south eastern europe is relatively homogeneous in topography, climate and eating habits. in some countries of this area the prevalence of urolithiasis was assessed according to population-based studies. in italy, the prevalence was estimated at 6.8% (males) and 4.9% (females) in 1986 and 10.1% (m) and 5.8% (f) in 1998 (2), in turkey it amounted to 14.8% in 1989 (3) and in greece 15% in 2006 (4). limited information is available about renal stone prevalence in bulgaria, fyr macedonia, karagiannis_stesura seveso 28/09/17 10:09 pagina 173 archivio italiano di urologia e andrologia 2017; 89, 3 karagiannis, skolarikos, alexandrescu, basic, geavlete, maletta, muslumanoglu, papatsoris, petkova, saidi, skakic, saltirov, sarica, stavridis, yilmaz, trinchieri 174 dietary assessment was carried out by the urologist which interviewed the patients by recall method. the results of the questionnaire were compared according to the country of the evaluated subjects. stone analysis was performed on the 360 out of 538 patients (the eswl patients didn’t have stone analysis) and was mainly chemical analysis (82%) whereas the rest by diffractometry. statistical analysis normality was tested using the shapiro-wilk test. normally distributed data were presented as mean (s.d.) as for not normally distributed data median and interquartile range (iqr) were used. comparisons between countries for normally distributed data was conducted using anova. comparisons for not normally distributed data was performed using kruskal-wallis test. fisher’s exact test was applied for comparisons with categorical data. dunn’s multiple comparisons test was applied after a significant kruskal-wallis or fishers exact test. sidak correction was used for multiple comparisons between countries. analysis was conducted using statacorp. 2013. stata statistical software: release 13. college station, tx: statacorp lp. results a total of 538 patients were enrolled of whom 124 from bulgaria, 17 from fyr macedonia, 50 from greece, 65 from italy, 122 from romania, 55 from serbia and 106 from turkey. gender and age in total the male to female ratio (m/f) was 1.07 with a 0.82 in bulgaria, 1.42 in fyr macedonia, 1.77 in greece, 1.5 in italy, 1.03 in romania, 0.62 in serbia and 1.23 in turkey. difference of distribution of the disease by gender for different countries was not significant (p = 0.065). age at stone onset was 39.9+/-16.2 in the total population with significant differences between different countries (p < 0.001). in turkey it was significantly lower than in greece, italy, romania and serbia whereas in bulgaria and fyr macedonia it was significantly lower than in greece and italy (table 1). height, weight and bmi there were no statistically significant differences between patients from different countries for height, weight and bmi (table 1). there was a statistically significant difference by gender for weight (p < 0.001), height (p < 0.001) and bmi (p < 0.001). no statistical significant differences of weight (anova f-test = 0.185) and bmi (anova f-test = 0.185) were observed in women by different countries. height of women by different countries was significantly different (anova f-test < 0.001) with serbian female patients taller than female patients of other countries (anova f-test < 0.05) except patients from fyr macedonia. statistical differences of height, weight and bmi (anova f-test < 0.001) were observed in men from different countries. male turkish patients were shorter than patients from all other countries but male patients from italy (anova f-test < 0.05). male bulgarian patients were significantly heavier than male patients from italy, turkey and romania (anova f-test < 0.05) and showed higher bmi scores than male patients from serbia and romania. also male patients from turkey had higher bmi scores than patients from romania (anova f-test < 0.05). urological and medical diseases urological anomalies were observed in 63/538. the more common were urethral stenosis (5.39%), ureteral stenosis (2.6%), ureteropelvic junction (upj) stenosis (2.33%) and horseshoe kidney (1.49%). medical diseases related to renal stone formation were observed in 118/538. the more frequent were bone disease (6.51%), peptic ulcer (6.13%), gout (3.35%), hyperthyroidism (2.24%), diabetes mellitus (2.23%) hyperparathyroidism (1.35%). statistically significant different rates of urological diseases and of medical diseases related to stone formation were observed for patients from different countries (chi2 test p < 0.001 and p = 0.016) with the highest rate of urological diseases observed in romania (73.7%) and. fyr macedonia (88.2%) and the highest rate of medical diseases in turkey (40%). working and sporting activity statistically significant difference was observed for working and sporting activity between patients from different countries (p = 0.001 and p = 0.005) (table 1). bulgarians patients had heavy working activity (47.6%) with respect to patients from other countries (2032.8%). heavy or intermediate sporting activity was more frequent in patients from bulgaria and serbia (51.8% and 50%) with respect to other countries (14%43.8%). dietary habit intakes of pasta, meat, cheese, vegetables, fruit, milk and bread were significantly different in different countries (anova f-test < 0.001) (table 2). patients from italy tended to consume more pasta products (pasta/rice/pizza) in comparison with patients from all other countries (p < 0.05 in all comparisons) except patients from fyr macedonia. patients from romania tended to consume less pasta products in comparison with patients from greece, fyr macedonia and turkey (p < 0.05 in all comparisons) and patients from bulgaria tended to consume less pasta in comparison with patients from all other countries (p < 0.05). patients from romania tended to consume less vegetables in comparison with patients from all other countries (p < 0.05) and those from serbia more vegetables than those from turkey (p < 0.05). patients from italy and fyr macedonia tended to consume more fruits in comparison with patients from all other countries (p < 0.05). patients from romania tended to consume more bread in comparison with patients from all other countries except patients from fyr macedonia (p < 0.05) and patients karagiannis_stesura seveso 28/09/17 10:09 pagina 174 175archivio italiano di urologia e andrologia 2017; 89, 3 epidemiologic study of urolithiasis in seven countries of south-eastern europe: s.e.g.u.r. 1 study table 2. dietary patterns of patients by different countries. table 1. demographic and clinical data of patients by different countries. bulgaria fyr macedonia greece italy romania serbia turkey overall p value (n = 124) (n = 17) (n = 50) (n = 65) (n = 122) (n = 55) (n = 106) (n = 538) gender† 0.065 female 54.8% 41.2% 36.0% 40.0% 49.2% 61.8% 44.8% 48.3% male 45.2% 58.8% 64.0% 60.0% 50.8% 38.2% 55.2% 51.7% bmi‡ 27.4 (5.52) 25.1 (2.65) 26.9 (3.62) 26.0 (4.31) 26.7 (6.07) 26.7 (8.43) 26.5 (4.93) 26.7 (5.57) 0.022 age‡ 52.5 (13.67) 49.9 (15.93) 57.1 (13.70) 50.3 (15.23) 44.7 (15.23) 50.3 (13.35) 43.3(14.88) 48.8(15.10) 0.593 age onset‡ 37.1 (17.43) 36.1 (12.30) 47.3 (17.82) 44.9 (17.86) 42.5 (16.32) 42.4(10.86) 33.8(12.52) 39.9(16.18) < 0.001 first time former 33.9% (n = 42) 35.3% (n = 6) 34.0% (n = 17) 56.9% (n = 37) 14.7% (n = 104) 1.8% (n = 1) 37.1% (n = 39) 45.7% (n = 246) recurrence£ 0.16 0.17 0.37 0.20 1.0 0.71 0.29 0.37 < 0.001 [0.09-0.40] [0.10-0.40] [0.15-0.60] [0.13-0.48] [0.25-1.0] [0.50-1.0] [0.14-0.60] [0.14-0.84] working activity† 0.001 light 52.4% 76.5% 72.0% 67.2% 75.2% 80.0% 72.6% 68.7% heavy 47.6% 23.5% 28.0% 32.8% 24.8% 20.0% 27.4% 31.3% sports† 0.005 light 48.2% 75.0% 86.0% 58.1% 55.7% 50.0% 66.1% 62.1% intermediate 48.2% 25.0% 12.0% 32.3% 39.3% 39.3% 23.7% 31.9% heavy 3.6% 0.0% 2% 9.7% 4.9% 10.7% 10.2% 6.0% bowel† 0.002 regular 79.0% 52.9% 82.0% 79.0% 69.2% 78.4% 58.0% 72.1% non regular 21.0% 47.1% 18.0% 21.0% 30.8% 21.6% 42.0% 27.9% renal insufficiency† < 0.001 < 1.2 79.0% 70.6% 84.0% 76.7% 52.7% 74.6% 89.6% 74.7% > = 1.2 21.0% 29.4% 16.0% 23.3% 47.3% 25.4% 10.4% 25.3% † fisher’s exact test. ‡ data presented as mean (s.d.). one-way anova conducted for comparisons between nations. £ data presented as median [iqr]. dunn test (median test) conducted for multiple comparisons. *iqr = interquartile range. bulgaria fyr macedonia greece italy romania serbia turkey overall p value pasta/rice/pizza/etc.† < 0.001 never/rarely 81.5% 23.5% 8.0% 8.1% 52.5% 25.4% 30.4% 41.9% often 17.7% 17.7% 68.0% 17.7% 43.4% 58.2% 24.5% 33.8% daily 0.8% 58.8% 24.0% 74.2% 4.1% 16.4% 45.1% 24.3% meat (any type)† < 0.001 never/rarely 13.7% 29.4% 6.0% 3.2% 3.3% 0.0% 19.6% 9.6% often 56.5% 23.5% 72.0% 24.2% 82.6% 80.0% 56.9% 61.6% daily 29.8% 47.1% 22.0% 72.6% 14.1% 20.0% 23.5% 28.8% cheese† < 0.001 never/rarely 11.3% 11.8% 6.1% 29.0% 4.1% 50.9% 18.6% 16.8% often 55.6% 23.5% 53.1% 35.5% 87.6% 47.3% 34.3% 54.3% daily 33.1% 64.7% 40.8% 35.5% 8.3% 1.8% 47.1% 28.9% vegetables† < 0.001 never/rarely 1.6% 0.0% 10.0% 21.0% 0.8% 0.0% 12.0% 6.3% often 44.7% 11.8% 36.0% 19.3% 81.7% 23.6% 32.0% 43.6% daily 53.7% 88.2% 54.0% 59.7% 17.5% 76.4% 56.0% 50.1% fruits† < 0.001 never/rarely 19.4% 5.9% 36.0% 19.4% 16.5% 9.1% 29.4% 20.7% often 55.6% 23.5% 30.0% 3.2% 68.6% 81.8% 34.3% 47.7% daily 25.0% 70.6% 34.0% 77.4% 14.9% 9.1% 36.3% 31.6% milk† < 0.001 never 9.7% 0.0% 68.0% 41.0% 29.7% 0.0% 19.6% 24.0% 1-2/day 80.6% 87.5% 30.0% 59.0% 64.4% 63.0% 51.0% 62.3% 3 or more/day 9.7% 12.5% 2.0% 0.0% 5.9% 37.0% 29.4% 13.7% bread† < 0.001 never 4.0% 0.0% 6.0% 16.1% 0.0% 0.0% 6.9% 4.7% 1-2/day 42.8% 58.8% 50.0% 79.0% 25.4% 63.0% 47.0% 47.1% 3 or more/day 53.2% 41.2% 44.0% 4.9% 74.6% 37.0% 46.1% 48.2% † fisher’s exact test. comment: dunn’s test implemented for multiple comparisons of eating habits between patients from different nations. karagiannis_stesura seveso 28/09/17 10:09 pagina 175 archivio italiano di urologia e andrologia 2017; 89, 3 karagiannis, skolarikos, alexandrescu, basic, geavlete, maletta, muslumanoglu, papatsoris, petkova, saidi, skakic, saltirov, sarica, stavridis, yilmaz, trinchieri 176 from italy less bread in comparison with patients from all other countries (p < 0.05). patients from serbia tended to consume more milk than patients from all other countries except fyr macedonia and turkey (p < 0.05) and patients from bulgaria and turkey tended to consume more milk in comparison with patients from greece, italy and romania (p < 0.05). patients from italy tended to consume more meat products in comparison with patients from all other countries (p < 0.05 in all comparison). patients from serbia tended to consume more cheese product in comparison with patients from all other countries (p < 0.05 in all comparisons) and patients from fyr macedonia to consume more cheese products than those from romania (p < 0.05). discussion several studies have shown that urinary calculi tend to be more frequent in men, although infection stones were often more frequently reported in women (10,11). our study confirmed that nephrolithiasis is more frequent in men, although in bulgaria and serbia we observed more stones in women. this can be explained by the higher rate of infection stones in bulgarian patients with respect to patients from other countries. the rate of infection stones in fyr macedonia was much higher but the number of patients from this country was very low. on the other hand, stones were more frequent in females also in serbia, but information of stone composition from this country was limited. age at stone onset was lower in turkey and bulgaria and higher in italy. stone onset of hereditary stones, such as cystine, tend to be low whereas uric acid stone formation is typical of older patients. in our series, cystine stones were more frequent in fyr macedonia and, at a lesser extent, in turkey and bulgaria and uric acid stones were less frequent in fyr macedonia and turkey than in other countries. a higher rate of hereditary stones together with a lower rate of uric acid stones could be an explanation of the lower age at stone onset in turkey. in italy the higher age at stone onset could be related to the prevalence of first renal stone formers that are characterized by a later onset of stone disease (12). the dietary pattern correlated with renal stone formation is complex, because the risk of renal calcium stone formation may depend on a reduced intake of fluids, an insufficient calcium intake, an increased intake of protein and sodium and a reduced intake of potassium (13). consequently, the formation of calcium stones can be favored by reduced fluid intake, excessive consumption of meat, a low intake of milk and dairy products and insufficient consumption of vegetables. not necessarily all of these factors must coexist simultaneously, as it is the sum of the effects of each of them to determine the risk of kidney stones (14). for this reason, it is not surprising to observe different dietary patterns in patients living in different countries where the diet may be different due to geographical, cultural and socioeconomic factors. our study was not specifically designed to evaluate stone prevalence in different countries or the potential role of diet in renal stone formation because of the absence of control subjects, but it interestingly demonstrated that renal stone patients from different countries show different dietary patterns. in italy, socioeconomic changes of the past 50 years have resulted in a progressive abandonment of the traditional mediterranean diet. today, the daily consumption of pasta and rice remained frequent, but the daily meat consumption increased (1 or more servings per day in 75% of cases), while the consumption of cheese and milk is relatively infrequent (never or rarely in 29 and 41%). the dietary pattern of stone patients in bulgaria, greece and turkey tends to be similar with a moderate consumption of meat (1 or more servings a day only in 29.8%, 22% and 23.5%) and a decent cheese consumption (never or rarely in 11.3%, 6.1% and 18.6%). however, the consumption of vegetables and fruit in these countries is relatively low (1 or more servings of vegetables and fruit per day of 53.7 + 25%, 54 + 34% and 56 + 36.3%, respectively) and milk consumption in greece is low (never or rarely in the 68%). in romania and serbia, the consumption of meat and cheese is high (often in 82.6% + 87.6% and 80% + 47.3%), but the consumption of vegetables and fruits is very low in romania (1 or more servings a day in 17.5 and 14.9%) and that of fruit is low in serbia (1 or more servings per day in 9.1%); also the consumption of milk is reduced in romania (never in 29.7%). conclusions in conclusion different dietary patterns can be observed in renal stone formers by different countries: high meat/low dairy in italy, moderate meat & cheese/low fruit & vegetables in greece, bulgaria and turkey, high meat/low vegetables (or fruit) in romania and serbia. references 1. trinchieri a. epidemiology of urolithiasis. arch ital urol androl. 1996; 68:203-250. 2. trinchieri a, coppi f, montanari e, et al increase in the prevalence of symptomatic urinary tract stones during the last ten years. eur urol. 2000; 37:23-25. 3. akinci m. esen t, tellaloglu s. urinary stone disease in turkey: an updated epidemiological study. eur urol. 1991; 20:200-203. 4. stamatiou kn, karanasiou vi, lacroix re, et al. prevalence of urolithiasis in rural thebes, greece rural and remote health. 2006; 6:610. 5. atanassova ss, panchev pk. kidney stones in a southeast european population from bulgaria clin chem lab med. 2013; 51:e227-229. 6. hesse a, brandle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs 2000. eur urol. 2003; 44:709-713. 7. scott r. prevalence of calcified upper urinary tract stone disease in a random population survey. report of a combined study of general practitioners and hospital staff. br j urol. 1987; 59:111-117. karagiannis_stesura seveso 28/09/17 10:09 pagina 176 8. martínez-gonzález ma, salas-salvadó j, estruch r, et al. predimed investigators. benefits of the mediterranean diet: insights from the predimed study. prog cardiovasc dis. 2015; 58:50-60. 9. schwingshackl l, hoffmann g. does a mediterranean-type diet reduce cancer risk? curr nutr rep. 2016; 5:9-17. 10. scales cd jr, curtis lh, norris rd, et al. changing gender prevalence of stone disease. j urol. 2007; 177:979-82. 11. strope sa, wolf js, jr, hollenbeck bk. changes in gender distribution of urinary stone disease. urology. 2010; 75:543-6. 12. trinchieri a, ostini f, nespoli r, et al. a prospective study of recurrence rate and risk factors for recurrence after a first renal stone. j urol. 1999; 162:27-30. 13. curhan gc, willett wc, rimm eb, stampfer mj. a prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. n engl j med. 1993; 328:833-8. 14. trinchieri a, maletta a, lizzano r, marchesotti f. potential renal acid load and the risk of renal stone formation in a case-control study. eur j clin nutr. 2013; 67:1077-80. 177archivio italiano di urologia e andrologia 2017; 89, 3 epidemiologic study of urolithiasis in seven countries of south-eastern europe: s.e.g.u.r. 1 study correspondence andreas karagiannis, md andreaskaragiannis@gmail.com andreas skolarikos, md  andskol@yahoo.com athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, university of athens, sismanoglio hospital, athens, greece emanuel alexandrescu, md manu_alexandrescu@yahoo.com  petrisor geavlete, md geavlete@gmail.com  urological department, saint john emergency clinical hospital bucharest, romania dragoslav basic, md  basicdr@gmail.com aleksandar skakic, md   saleskaka@hotmail.com urological clinic, clinical center nis, nis, serbia alessandro maletta, md a.maletta@ospedale.lecco.it alberto trinchieri, md a.trinchieri@asst-lecco.it ospedale a.manzoni, urology department, lecco, italy a.yaser muslumanoglu, md  ymuslumanoglu56@hotmail.com chief, department of urology, bagcilar training and research hospital istanbul, turkey kremena petkova, md  dr_petkova@yahoo.com  department of urology and nephrology, military medical academy sofia, bulgaria iliya saltirov, md saltirov@yahoo.com skender saidi, md  skendersaidi@yahoo.com sotir stavridis, md  stavridis.sotir@gmail.com  university clinic for urology, university clinical centre "mother theresa", skopje, fyr macedonia kemal sarica, md  chief, department of urology saricakemal@gmail.com  dr. lutfi kirdar kartal research and training hospital, istanbul, turkey omer yilmaz, md  dr.omeryilmaz@yahoo.com department of urology, gata haydarpasa research and teaching hospital, istanbul, turkey karagiannis_stesura seveso 28/09/17 10:09 pagina 177 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper passage through relaxation of the smooth muscles of the ureter and by reducing peristaltic activity. there are high densities of the three alpha-1 receptor subtypes (alpha 1a, 1b, and 1d) in the distal third of ureteric smooth muscle. alpha blocker therapy suppresses basal smooth muscle tone, together with peristaltic frequency and amplitude, while preserving tonic propulsive contractions, resulting in decreased intra-ureteric pressure and greater fluid transport (3). use of alpha-1 adrenergic receptor blockers thus facilitates stone passage. tamsulosin, which exhibits high uroselectivity for alpha1a and 1d activity, and silodosin, which is a more selective alpha-1a adrenergic receptor antagonist, are widely employed in research and are of proven efficacy in met (4). phosphodiesterase-5 inhibitors (pde-5is) act on the smooth muscle nitric oxide/cyclic guanosine monophosphate signaling pathway and produce ureteral relaxation. the lumen of the ureter is thus dilated, allowing stones to pass spontaneously. some studies showed that the pde5i tadalafil can effectively treat distal ureteral calculi as met (5). although tadalafil has been employed to treat sexual dysfunction and lower urinary tract symptoms, its application in met for the treatment of ureteral stones is highly limited. tamsulosin is the alpha-1 adrenoreceptor antagonist most frequently evaluated for the purpose of met and is of proven effectiveness (6). in recent studies, the administration of pde5-is alone and in combination with tamsulosin has led to acceleration of stone passage or even reduction of stone expulsion time and need for analgesics (7). thus, our main aim of comparing tamsulosin, silodosin and tadalafil, is to determine single best monotherapy as a medical expulsive therapy of distal ureteric stones. patients and methods the study was conducted in the department of urology atal-zahraa university hospital, over a period of 6 months (from jan 2022 to july 2022). part of the used methods followed gnyawali et al. 2020 (8). patients, aged from 20 to 60 years, presented with a single lower ureteric stone from 5 mm to 10 mm in size, diagnosed by ultrasound (usg) abdomen/pelvis or kidneyureter-bladder (kub) x-ray, or computed tomography (ct) scan. patients with the presence of multiple ureteric stones, urinary tract infection or hydronephrosis with complicatobjective: to compare the efficacy of tamsulosin, silodosin and tadalafil as a medical expulsive therapy for treatment of distal ureteral calculi. patients and methods: over a period of 6 months (january 2022 to june 2022) this prospective randomized study was conducted on 170 patients with distal ureteric stone ≤ 10 mm. patients were randomly divided into three groups. patients in group a received tamsulosin 0.4mg, in group b received silodosin, and in group c receive tadalafil 5 mg. therapy was given for a maximum of 4 weeks. the rate and time of stone expulsion, the analgesic use, attacks of colic and hospital visits for pain, and adverse effects of drugs were recorded. results: among 170 patients who were enrolled in study, 20 were lost to follow-up (7, 8, 5 in group a, b, and c respectively). there was a significant higher stone passage rate in group c than group a and b (90% vs. 70% and 76% respectively; p-value = 0.043) and shorter expulsion time in group c (8.7 ± 3.3 days) vs. group a (12.5 ± 5.2 days) and group b (11.3 ± 4.2 days) with (p-value = 0.001)(highly statistically significant with p-value < 0.001) and increased amount of analgesics required in group a (225 ± 115.7 mg) and group b (163 ± 77.5 mg) when compared with group c (120 ± 55.3 mg). conclusion: tadalafil is more effective than tamsulosin and silodosin in treatment of patients with distal ureteric stones ≤ 10 mm as regard stone expulsion rate, expulsion time with decreased number of colicky episodes and side effects. key words: ureteral stone; tamsulosin; tadalafil; ssilodosin; medical expulsive therapy. submitted 7 september 2022; accepted 6 october 2022 introduction medical expulsive therapy (met) is a non-invasive modality used in treatment of ureteral stones aimed at achieving spontaneous stone expulsion through relaxation of the smooth ureteral muscles and reduction of peristaltic activity (1). stone passage is contingent on two principal factors, those involving the stone, and those involving the urinary system. stone-related factors include stone size, number, and location within the urinary system. urinary systemrelated factors include ureteric spasm, mucosal edema or inflammation, and the ureteric anatomy (2). the objective of met is to achieve spontaneous stone comparative study between tamsulosin, silodosin and tadalafil as a medical expulsive therapy for lower ureteral stones mohammad ahmad abdelaal, eman m. el-dydamony department of urology, faculty of medicine, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.10849 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. ahmad abdelaal, e.m. el-dydamony ing factors (e.g. sepsis, uncontrollable pain, deterioration of renal function), pregnancy, history of ureteral surgery or previous endoscopic procedures, with kidney or ureteral abnormalities (e.g. single kidney, ureteral malformation), requiring emergency intervention or having allergies to the medications used were not included in the study. written informed consent was taken from all patients. itemized history, clinical examination, routine urine analysis and/or urine culture, serum creatinine, digital kub x-ray and/or usg abdomen and pelvis, and/or kub ct were carried out in all patients. the stone size was determined using the largest dimension. patients were randomized and divided into three equal groups of 170 as demonstrated in figure 1. patients in group a received tamsulosin 0.4 mg, in group b received silodosin, and in group c received tadalafil 5 mg. therapy was given for a maximum of 4 weeks. all groups received diclofenac (50 mg) on demand. drugs were continued until stone expulsion or for a period of 4 weeks. in fact, there is no strong evidence that a prolonged period of drug administration will augment the expulsion rate and limiting the period of treatment reduced the noxious influence of obstruction on kidney function. patients were commanded to drink plenty of fluids and monitor their urine for stone passage using a net. patients were assessed by physical examination, serum creatinine, and the same imaging modality by which the stone in the lower ureter were initially diagnosed. in particular in those who either could not retrieve the stone in their urine or retrieved a stone that did not match the size and shape of the stone observed at the beginning of the study. in case of uncertainty, ct kub was done despite previous imaging modality to confirm stone expulsion. expulsion of the stone ureter, overall dose of analgesic used, number of colic episodes and emergency room visits, and side effect of drugs were registered. semi rigid ureteroscopy was done to those who did not pass stones after 4 weeks of follow-up for stone passage. ethical approval the protocol of the current trial was approved by the local ethics committee of the faculty of medicine for girls al-azhar university, cairo, egypt (study id 1178). written informed consent was obtained from all participants. all procedures were run in compliance with the standards of the declaration of helsinki. statistics data were analyzed using statistical program for social science (spss) version 24. quantitative data were expressed as mean ± sd. qualitative data were expressed as frequency and percentage. mean (average) was considered as the central value of a discrete set of numbers, specifically the sum of values divided by the number of values. standard deviation (sd) was the measure of dispersion of a set of values. differences were considered significant at a p value less than 0.05. results out of 170 patients, who were randomly assigned into 3 groups. seven patients from group a, eight patients from group b and five patients from group c were lost at follow up for various reasons whereas the remaining 150 patients who met the inclusion criteria completed the study. there were no statistically significant differences in patients’ age, gender, and stone size, type or site (table 1). there is statistically significant (p-value = 0.043) increased stone expulsion rate in group c (45 patients, 90%) when compared with group a (35 patients, 70%) and group b (38 patients, 76%). also, there was a statistically significant (p-value = 0.001) longer stone expulsion time in group a (12.5 ± 5.2 days) and group b (11.3 ± 4.2 days) when compared with group c (8.7 ± 3.3 days) (figure 2). the patients in group c had significantly less episodes of colicky pain than group b (11 patients, 22%) and group a (12 patients, 22%) while in group c (3 patients, 6%) with significantly less number of emergency room visits. additionally, the mean requirement of analgesia (diclofenac) was significantly less in group c (120 ± 55.3 table 1. demographic and results. parameter group a group b group c p value mean age (years) 38.7 41.3 41.9 0.375 no. of patients (male/female) 35/15 32/18 34/16 0.809 mean stone size (mm) 6.7± 1.3 6.9± 1.6 6.9 ± 1.5 0.830 stone type (radioopaque/radiolucent) 37/13 40/10 40/10 0.705 expulsion rate (%) 35/50 38/50 45/50 0.043 mean expulsion time (days) 12.5 ± 5.2 11.3 ± 4.2 8.7 ± 3.3 0.001 mean analgesic use (mg) 225 ± 115.7 163 ± 77.5 120 ± 55.3 < 0.001 percentage of hospital visits for pain (%) 24% 22% 6% 0.033 statistical significance was analyzed by student’s t-test and χ2-test. values are presented as mean ± standard deviation. group a: tamsulosin and group; b: silodosin and group c: tadalafil. figure 1. flow chart of the study design study. archivio italiano di urologia e andrologia 2023; 95, 1 medical expulsive therapy for lower ureteral stones mg) than in group a (225 ± 115.7 mg) or group b (163 ± 77.5 mg). stone was not expelled even after 4 weeks of met in 15, 12 and 5 patients in groups a, b and c, respectively. these patients were subsequently treated with ureteroscopic lithotripsy. as regard drug related adverse effects there is no statistically difference between three groups in occurrence of headache, backache or dizziness but there was an increased rate of orthostatic hypotension in group a (10 patients, 20%) and group b (9 patients, 18%) when compared with group c (2 patients, 4%). also retrograde ejaculation was more reported in group b (12 patients, 24%) and group a (10 patients, 20%) when compared with group c (3 patients, 6%) (table 2) (figure 3). discussion different treatment modalities for lower ureteric stones are available ranging from open surgery to minimally invasive methods. but, all these approaches are associated with complications. so, there has been a paradigm shift in the treatment of lower ureteric stone with a primary focus on medical expulsive therapy (met) which is a ratified approach to increase the chance of stone passage. in both american and european guidelines is supported the role of medical expulsive treatment for distal ureteral calculi < 10 mm. in comparison with invasive surgical treatment for ureteric stones, met has a high safety profile and affordable cost. met includes various drugs such as alpha adrenoreceptor antagonists, calcium channel blockers and prostaglandin inhibitors. phosphodiesterase type 5 inhibitors (pde5-is) were more recently approved in the treatment of urinary tract symptoms (9). however, the most commonly used drugs in met are still alpha-blockers, among which tamsulosin is more suitable. the probable mechanism of action of tamsulosin as a met is the selective relaxation (repose) of ureteral smooth muscle (10). silodosin is a more selective a1a-adrenergic receptor antagonist than tamsulosin and has a better stone expulsion rate than tamsulosin (11). on the other hand, tadalafil (a pde5-is) has been also advocated by many studies for treatment of lower urinary tract symptoms (luts) secondary to benign prostatic hyperplasia (bph) in recent years. tadalafil causes the prostate smooth muscle relaxation via the nitric oxide (no)-cyclic guanosine 3’, 5’-monophosphate (cgmp) pathway and thereupon improves luts and the function of the cavernous muscles in cavernous artery. in recent studies, the administration of pde5-is alone and in combination with tamsulosin has led to acceleration of stone passage or even reduction of stone expulsion time and need for analgesics (12). according to earlier studies, the expulsion rate of distal ureteric stone by watchful waiting is 25-54% with mean expulsion time > 10 days and is associated with high analgesic requirement even for stones < 5 mm. to improve the expulsion rate and reduce analgesic requirement, medical therapy is considered for distal ureteral stones (13, 14). the present study was thus conducted to determine the best drug for medical expulsive therapy of distal ureteric stones by comparing effect of tamsulosin, silodosin and tadalafil as regard stone expulsion rate, expulsion time, analgesics used, and side effects. in our study there is a statistically significant (p-value = 0.043) increase of stone expulsion rate in patients on tadalafil (90%) when compared with cases on tamsulosin (70%) or silodosin (76%). another study conducted by puvvada et al., in 2016, compared efficacy of tadalafil and tamsulosin in expulsion of figure 2. comparisons between studied groups as regard stone expulsion rate. figure 3. comparisons between studied groups as regard side effects. table 2. side effects. variable group a group b group c p value headache 7 14% 6 12% 7 14% 0.944 ns backache 9 18% 9 18% 4 8% 0.264 dizziness 7 14% 7 14% 3 6% 0.346 orthostatic hypotension 10 20% 9 18% 2 4% 0.43 s abnormal ejaculation 10 20% 12 24% 3 6% 0.04 s statistical statistical significance was analyzed by the χ2-test. group a: tamsulosin; group b: silodosin and group c: tadalafil. archivio italiano di urologia e andrologia 2023; 95, 1 m. ahmad abdelaal, e.m. el-dydamony lower third ureteric stone. the stone expulsion rate was 84.0% in patients on tadalafil and 68.0% in patients on tamsulosin, with tadalafil showing a significantly higher stone expulsion rate compared with tamsulosin (p value = 0.0130) (15). in 2019, a similar comparison of tadalafil and tamsulosin was done by abhishek laddha et al. who found that the stone expulsion rate was 58% for the placebo group, 80% for the tadalafil group and 74% for the tamsulosin group. tadalafil was superior to placebo in terms of stone expulsion rate (p-value: 0.017) but comparable to tamsulosin (p: 0.139) (16). another study by bahadur kc et al., compared tamsulosin vs. tadalafil as a medical expulsive therapy for distal ureteral stones demonstrating that expulsion rate was significantly higher in the tadalafil group than in the tamsulosin group (84.1% vs. 61.0%, p = 0.017) (17). a comparative study made by parikh et al. in 2019 showed that mean expulsion time of calculi was significantly shorter in patients managed by tadalafil as compared to tamsulosin (13.1 vs. 16.92 days; p < 0.05). complete expulsion was seen in 86.7% cases on tadalafil as compared to only 63.3% cases on tamsulosin (p < 0.05) (18). rate of expulsion was observed to be significantly shorter with tadalafil in most of the studies (19-24). jayant et al. in their study compared the stone expulsion rate of tamsulosin with the tamsulosin and tadalafil combination. the expulsion rate was 74.2% versus 83.9% (p = 0.349) and 65.5% vs. 83.6% (p = 0.031) (25). similarly, hasan et al. found that tadalafil had an expulsion rate of 93% compared with 67% for a placebo group (26). in our study we noticed a statistically significant (p-value = 0.001) longer stone expulsion time in cases on tamsulosin (12.5 ± 5.2 days) and on silodosin (11.3 ± 4.2 days) when compared with patients on tadalafil (8.7 ± 3.3 days). in their study conducted in 2016, puvvada et al., compared efficacy of tadalafil vs. tamsulosin in expulsion of lower third ureteric stonea. the mean time for stone expulsion in patients on tadalafil was 14.7 ± 3.8 days, and in patients on tamsulosin was 16.8 ± 4.5 days. the time was significantly less in tadalafil than in tamsulosin patients (p value = 0.0021) (15). kumar et al., in 2018, noticed that the mean expulsion time from the starting of met was lower for tamsulosin group (9.38 ± 6.66 days) than for tadalafil group (9.61 ± 7.47 days), but this difference was not significant (p = 0.78) (19). jayant et al., who compared tamsulosin with the combination of tamsulosin and tadalafil, demonstrated a significantly decreased expulsion time (16.7 ± 4.8 vs. 14.9 ± 4.4 days, p = 0.003), significantly fewer colicky pain episodes (1.60 ± 1.0 vs. 0.45 ± 0.68, p = 0.000), and significantly less analgesic use (2.90 ± 0.90 vs. 1.87 ± 0.8, p = 0.000) (25). colicky pain in ureteral stones occurs owing to an increase in intraureteral pressure above the site of ureteral obstruction. kinnman et al. demonstrated that a-blockade relieves ureteric colic by blocking the c-fibers responsible for mediating pain (27). both drugs are thought to decrease the frequency and amplitude of phasic peristaltic contractions that accompany ureteric obstruction and to decrease the need for analgesia. in the present study, patients in tadalafil group showed significantly less episodes of colicky pain (3 patients, 6%) than in silodosin (11 patients, 22%) and tamsulosin (12 patients, 22%) with significantly less number of emergency room visits. hasan et al. reported a significantly lower pain score of 3.9 versus 7.9 (p < 0.01) and a significantly lower analgesic requirement in the tadalafil group than in the placebo group (26). mean number of colicky pain episodes in patients with tamsulosin was higher in the study done by puvvada et al. which corresponds to the findings observed in the present study suggesting that tadalafil is also better in controlling pain with lower number of colic episodes and less use of analgesics (15). however, in 2019, li et al. (28) in a meta-analysis showed that the dosage of analgesia administered in tadalafil patients was significantly higher than in tamsulosin patients and the duration of analgesia use in patients who were treated with tamsulosin plus tadalafil was significantly lower than in those who received tamsulosin alone. the average used analgesic dose was reported to be about 200 mg, being 130 mg in kumar et al. (29) and kc et al. (17) studies. in our study the mean requirement of analgesia (diclofenac) was significantly less in patients on tadalafil (120 ± 55.3 mg) than in patients on tamsulosin (225 ± 115.7 mg) or silodosin (163 ± 77.5 mg). as regard drug related adverse effects there is no statistically difference between three groups in occurrence of headache, backache or dizziness, but there is an increased rate of orthostatic hypotension with tamsulosin (10 patients, 20%) and silodosin (9 patients, 18%) when compared with tadalafil cases (2 patients, 4%). retrograde ejaculation was also more frequent in silodosin (12 patients, 24%) and tamsulosin (10 patients, 20%) when compared with tadalafil (3 patients, 6%). in the study by kc et al. (17), the incidence of side effects was similar in both groups and similar results were demonstrated in other studies (25, 29, 30). conclusions tadalafil is more effective than tamsulosin and sildosin in treatment of patients with distal ureteric stones ≤ 10 mm as regard stone expulsion rate, time with decreased number of colicky episodes and side effects. references 1. somani bk, aboumarzouk o, traxer o, et al. medical expulsive therapy for ureteral stones: where do we go from here? nat rev urol. 2016; 13:608-12. 2. ibrahim ai, shetty sd, awad rm, patel kp. prognostic factors in the conservative treatment of ureteric stones. br j urol 1991; 67:358-61. 3. yilmaz e, batislam e, basar mm, et al. the comparison and efficacy of 3 different a1-adrenergic blockers for distal ureteral stones. j urol. 2005; 173:2010-2. 4. campschroer t, zhu y, duijvesz d, et al. alpha-blockers as medical expulsive therapy for ureteral stones. cochrane database syst rev. 2014; (4):cd008509. 5. liu z, su j, yuan d, et al. efficacy and safety of pde5-is and a1 blockers for treating distal ureteral calculi: a mixed treatment comarchivio italiano di urologia e andrologia 2023; 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178:2418-34. 23. tamm ep, silverman pm, shuman wp. evaluation of the patient with flank pain and possible ureteral calculus. radiology. 2003; 228:319-29. 24. wang cj, huang sw, chang ch. efficacy of an a1 blocker in expulsive therapy of lower ureteral stones. j endourol. 2008; 22:41-6. 25. jayant k, agrawal r, agrawal s. tamsulosin versus tamsulosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomized controlled trial. int j urol. 2014; 21:1012-5. 26. hasan hf, jaffal wn, al-hossona ha. the role of tadalafil in lower ureteric stone expulsion. iraqi postgrad med j. 2011; 10:24-32. 27. kinnman e, nygårds eb, hansson p. peripheral a-adrenoreceptors are involved in the development of capsaicin induced ongoing and stimulus evoked pain in humans. pain. 1997; 69:79-85. 28. li jk, qiu s, jin k, et al. efficacy and safety of phosphodiesterase type 5 inhibitors for the treatment of distal ureteral calculi of 5 to 10 mm in size: a systematic review and network meta-analysis. kaohsiung j med sci. 2019; 35:257-264. 29. kumar s, jayant k, agrawal s, singh sk. comparative efficacy of tamsulosin versus tamsulosin with tadalafil in combination with prednisolone for the medical expulsive therapy of lower ureteric stones: a randomized trial. korean j urol. 2014; 55:196-200. 30. rahman mj, faridi ms, mibang n, singh rs. comparing tamsulosin, silodosin versus silodosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a randomised trial. arab j urol. 2018; 16:245-9. acknowledgments all gratitude and kindness for all the patients who agreed to participate in this study. correspondence mohammad ahmad abdelaal, md (corresponding author) maal_uro@yahoo.com eman m. el-dydamony, md emanmohamed.8@azhar.edu.eg 377j+vhw, greek hospital st, as sarayat, el weili, cairo governorate 4391050 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2019; 91, 274 original paper the variation of selective ungal levels after robot-assisted partial nephrectomy: early results of a prospective single center study ottavio colamonico 1, giuseppe cardo 1, edmondo ceci 2, marcello scarcia 1, michele zazzara 1, mario dassira 3, angelo porreca 4, giuseppe m. ludovico 1 1 urology department, ospedale generale “f. miulli”, acquaviva delle fonti, bari, italy; 2 specialistic clinical biochemistry department, ospedale generale “f. miulli”, acquaviva delle fonti, bari, italy; 3 nuclear medicine department, ospedale generale “f. miulli”, acquaviva delle fonti, bari, italy; 4 urology department, policlinico abano terme, padova, italy. objectives: acute kidney injury (aki) secondary to nephron-sparing surgery represents a significant problem in order to preserve renal function. since serum creatinine alone underestimates the early detection of aki several biomarker have been investigated. neutrophil gelatinase-associated lipocalin (ngal) is considered a good biomarker for aki. materials and methods: we report our experience in 28 patients affected by localized renal cell carcinoma and submitted to robot-assisted partial nephrectomy (rapn). in each patient selective urinary ngal levels were dosed before surgery, then 2 and 48 hours after the procedure, through a ureteral catheter inserted into the excretory axis of the operated kidney. moreover, we evaluated split renal function of the preserved renal parenchyma by a 99mtc-dtpa renal scintigraphy, performed before surgery and three months later. results: aki was diagnosed, according to internationally criteria, in 3 patients (10.7%). the baseline selective urinary ngal level was 20.02 ng/ml. this level significantly increased after surgery with a selective urinary ngal level that reached 56.36 ng/ml (p < 0.0001). moreover, a significant reduction in 99mtc-dtpa clearance of the operated kidneys after three months was detected (p < 0.0001). conclusions: selective urinary ngal assay represent a sensitive biomarker of acute kidney injury after robotic nephron sparing surgery, capable of predicting the functional outcome of the operated kidney. key words: neutrophil gelatinase-associated lipocalin (ngal); acute kidney injury (aki); robot-assisted partial nephrectomy (rapn). submitted 18 january 2019; accepted 25 january 2019 summary no conflict of interest declared. assisted partial nephrectomy (rapn) is generally preferred by several worldwide centers (5-6) which can performed either with or without hilar clamping. however unclamping hilar control techniques seem to be safe and feasible approaches, with potentially superior functional outcomes, and non-inferior oncological outcomes, when compared with main artery clamping (7). the direct surgical injury and nephron loss that occurs during pn are associated with the risk of occurrence of acute kidney injury (aki) and chronic kidney disease (ckd). current criteria for aki diagnosis and classification depend on serum creatinine (scr) changes and urine output. (8) unfortunately, the evaluation of kidney injury by scr alone underestimates the early diagnosis of aki, a serious complication after renal surgery, associated with prolonged hospitalization, high morbidity and mortality. the early phase of aki is accompanied with few symptoms or may be completely asymptomatic (9). several biomarkers have been investigated in order to identify and anticipate the diagnosis of aki. among the others neutrophil gelatinase-associated lipocalin (ngal) was extensively evaluated as biomarker of aki and predictor of ckd (10, 11). ngal is a ubiquitous 25-kda protein which expression increases greatly in the presence of a renal damage after ischemia reperfusion injury and nephrotoxicity (12). nowadays ngal is considered a biomarker for aki that has been extensively evaluated in adult and pediatric cardiopulmonary bypass patients (13), kidney transplant patients (14), and patients in intensive care units (15). production of ngal is upregulated following renal injury, and consequently detectable in serum and urine hours prior to scr increases (16). the aim of this study was to evaluate urinary ngal (ungal) both as a marker for early aki in patients undergoing rapn for a ct1 renal cell carcinoma and as a marker able to predict the loss of function of the operated kidney. materials and methods in this prospective study 28 patients undergoing partial robot-assisted nephrectomy for ct1 renal cell carcinoma doi: 10.4081/aiua.2019.2.74 introduction partial nephrectomy (pn) is the treatment of choice for ct1 (< 7 cm) renal tumors because has demonstrated to offer oncological control equal to that of radical nephrectomy (rn) with superior functional outcomes (1-3). the major goal of the nephron-sparing surgery is maximizing renal function preservation. the three main drivers of post-pn functional recovery, in order of importance, are pre-pn function, remnant vascularized nephron mass, and ischemia time (4) nowadays robot75archivio italiano di urologia e andrologia 2019; 91, 2 the variation of selective ungal levels after robot-assisted partial nephrectomy: early results of a prospective single center study at “francesco miulli” hospital from june 2017 to december 2017 were enrolled. after approval from the institutional review board, we obtained written consent from all patients. the preoperative clinical tumor staging workup included computed tomography (ct) or magnetic resonance imaging (mri) of the abdomen and pelvis and chest radiography. we included patients with a solitary renal cortical tumour of ≤ 7 cm and imaging of a normal contralateral kidney before surgery. the patient’s age, gender, charlson comorbidity index score, preoperative scr, preoperative egfr: estimated glomerular filtration rate (egfr), intra and postoperative data and pathologic features (tumor size, padua score, histologic type, and fuhrman’s nuclear grade) were collected. we evaluated the post-operative onset of aki according to kdigo criteria (8). in each patient was collected serum neutrophil gelatinase-associated lipocalin (sngal) and selective urinary neutrophil gelatinase-associated lipocalin (ungal) before surgery, 2 and 48 hours after nephronsparing surgery. in particular ungal was dosed on the urine collected selectively through a ureteral catheter inserted into the excretory axis of the operated kidney, before surgery. ngal was measured into the serum and urine with a commercially available enzyme-linked immunosorbent assay kit (human ngal elisa kitkit 036 ruobioporto diagnostics). the assay is a sandwich elisa performed in microwells coated with a monoclonal antibody to human ngal. bound ngal is detected with another monoclonal ngal antibody labeled with biotin and the assay is developed with horseradish peroxidase (hrp)-conjugated streptavidin followed by the addition of a color-forming substrate. the enzymatic reaction is stopped chemically, and the color intensity is read at 450 nm. furthermore preoperatively, the split renal function of the operated kidneys was measured by a 99mtc-dtpa renal scan. after 3 months we detected the functional loss of the operated kidneys through a second control 99mtc-dtpa renal scan. sequential kidney scintigraphy is a method of choice for both static and dynamic determination of kidney function separately. statistical analysis: we used one-way anova in order to analyze post-operative dosage variations of ungal and sngal as well as compare functional outcomes after on-clamp or off-clamp robot-assisted partial nephrectomy (rapn). statistical significance was considered at p < 0.05. linear regression was applied to determine the correlation of selective urinary ngal assay 48 hours after surgery with the variation of 99mtc-dtpa clearance three months after surgery. the analysis was performed by using the statistical medcalc software (version 18.2.1, medcalc, inc., belgium). results twenty-eight patients were included, mean age was 62.6 (35-88) years. table 1 resumes baseline characteristics and main intraoperative and perioperative data (table 1). seventeen patients underwent off-clamp rapn while the remaining eleven patients were submitted to on-clamp rapn. the choice of hilar clamping during rapn was performed according to the surgeon's experience and the characteristics of the tumor. in patients who underwent on-clamp rapn, the mean warm ischemia time was 12.6 minutes (table 2). table 1. preand peri-operative characteristics of patients undergoing rapn for ct1 rrc. sex male: 15 (53.5%) female: 13 (46.5%) age 62.6 years (35-88) rcc histotype clear cell rcc: 24 (85.7%) chromophobe rcc: 3 (10.7%) papillary rcc: 1 (3.6%) fuhrman grade i: 15 (53.5%) ii: 13 (46.5%) pt1 a: 22 (78.5%) b: 6 (21.5%) mean tumor diameter (cm) 3,1 (1.2-6.5) padua score 6-7: 15 (53.6%) 8-9: 10 (35.7%) ≥ 10: 3 (10.7%) surgical technique off-clamp rapn: 17 (60.7%) on-clamp rapn: 11 (39.3%) medium warm ischemia time (min) 12,6 (7-22) post-operative aki 3 (10.7%) charlson comorbidity index 2.32 (0-6) preoperative egfr (ml/min/1.73 m2) 87.03 (34-115) preoperative scr (mg/dl) 1.07 (0.63-1.73) preoperative ungal (ng/ml) 20.02 (36.8-4.9) preoperative operated kidney cl 99mtc-dtpa (ml/min) 37.45 (58.7-14.2) rcc = renal cell carcinoma; rapn: robot‐assisted partial nephrectomy; aki = acute kidney injury; egfr = estimated glomerular filtration rate; scr = serum creatinine; ungal = urinary neutrophil gelatinase-associated lipocalin; cl = clearance; 99mtc-dtpa= technetium-99m-diethylenetriaminepentaacetic acid. table 2. preand peri-operative characteristics of patients undergoing off-clamp vs on-clamp rapn. off-clamp rapn on-clamp rapn p no. 17 11 sex male 8 9 female 7 4 age (years) 65.8 (35-86) 57.6 (40-88) 0.097 mean tumor diameter (cm) 2.89 ± 1.56 3.6 ± 1.51 0.832 padua score 7.23 ± 1.67 8.72 ± 1.67 0.070 charlson comorbidity index 2.58 ± 1.66 1.90 ± 2.16 0.136 preoperative scr (mg/dl) 1.08 ± 0.31 0.88 ± 0.24 0.218 preoperative egfr (ml/min/1.73 m2) 72.58 ± 24.40 86.45 ± 26.81 0.880 preoperative ungal (ng/ml) 20.52 ± 15.91 19.25 ± 6.73 0.079 preoperative operated kidney cl 99mtc-dtpa (ml/min) 35.79 ± 14.11 40.00 ± 10.85 0.181 aki 2 (11.7%) 1 (9%) 0.831 rapn: robot-assisted partial nephrectomy; aki = acute kidney injury; egfr = estimated glomerular filtration rate; scr = serum creatinine; ungal = urinary neutrophil gelatinase-associated lipocalin; cl = clearance; 99mtc-dtpa= technetium-99m-diethylenetriaminepentaacetic acid. archivio italiano di urologia e andrologia 2019; 91, 2 o. colamonico, g. cardo, e. ceci, m. scarcia, m. zazzara, m. dassira, a. porreca, g.m. ludovico 76 the sngal baseline level was 169.5 ng/ml and did not change postoperatively (p = 0.13). the selective ungal baseline level was 20.02 ng/ml and showed a not negligible increase at 2 and 48 hours after surgery (figure 1). variation after 48 hours after surgery was statistically significant (p < 0.0001). however no statistically significant differences emerged between patients subjected to onclamp vs off-clamp rapn (66.17 ng/ml vs 50.02 ng/ml; p = 0.242). according to kdigo criteria for aki, we detected postoperative aki in 3 of 28 patients, using scr dosage 48 hours after surgery. comparing the pre-operative creatinine with the 48-hours postoperative one, no statistically significant difference was found (p = 0.0669). before comparing patients undergoing onclamp and off-clamp robot-assisted partial nephrectomy (table 2), we evaluated the homogeneity of the two groups through anova. they were homogeneous for egfr pre-intervention (p = 0,88), preoperative scr (p = 0.218), maximum tumor size (p = 0.83), padua score (p = 0.07), preoperative ungal (p = 0.07), charlson comorbidity index (p = 0.13), age (p = 0.09) and preoperative selective 99mtc-dtpa clearance (p = 0.831). evaluating postoperative functional outcome of the operated kidneys at three months we highlighted a statistically significant reduction in 99mtc-dtpa clearance of the operated kidneys 3 months after surgery (p < 0.0001), with a mean functional loss of the operated kidneys by 8.2% (mean change in 99mtc-dtpa clearance of -3.081 ml/min). stratifying the cohort according to the execution of clamping technique (on-clamp vs off-clamp rapn), there was no statistically significant differences between the two groups (p = 0.414) as far as the variation of 99mtc-dtpa clearance of the operated kidneys. finally, we evaluated the correlation between the variation in 99mtc-dtpa clearance 3 months after surgery with the selective dosage of ungal at 48 hours from surgery (figure 2), finding a statistically significant association between the two variables (r2 = 0.2391, p = 0.0083). this correlation has not been highlighted by comparing the variation in 99mtc-dtpa clearance 3 months after surgery with scr dosage 48 hours postoperatively (r2 = 0.12, p = 0.0669). discussion urological patients represent a population at risk of aki which can affect long-term renal function (17). the risk of occurrence of aki in patients undergoing partial/radical nephrectomy and nephroureterectomy is about 43.1% (18). currently, aki is defined according to kdigo criteria based on scr changes and urine output, which arise after renal damage (8). aki observed in renal surgery patients is largely related to direct renal damage. in particular, after a partial nephrectomy, aki is caused by direct removal of renal parenchyma and damage of the remaining tissue from hyperfiltration or ischemia (19, 20). aki does not act exclusively on the renal parenchyma but also systemically through the release of inflammatory cytokines (21). the post-operative onset of aki leads to an increase in post-surgical complications, a lengthening of hospitalization time, an increase in the postoperative mortality rate and a significant increase in health care expenditure with an additional risk of ckd (9, 22, 23). since traditional definitions of aki seem to be not very sensitive until the healthy nephrons are reduced by 50%, a growing interest towards biomarkers able to evaluate even slight worsening of renal function represents an expanding research area (24, 25). neutrophil gelatinase-associated lipocalin (ngal) represents an acute renal injury marker that the latest acute dialysis quality initiative (adqi) guidelines recommend use in patients with suspected aki (26). baseline reference values of sngal are 86.3 ng/ml in men and 88.9 ng/ml in women while ungal has a reference value of 5.7-17.7 ng/ml, but they may increase > 10-fold in serum and > 100-fold in urine following an acute injury. (27) however, human clinical studies have shown conflicting results on the potential clinical use of this biomarker for the assessment of acute kidney injury. abassi has shown that the severity of acute renal injury after nephron sparing surgery is quantitatively correlated to the urinary dosing of ngal (28). in contrast, sprenkle highlighted that changes in urinary ngal dosage of patients undergoing partial nephrectomy are comparable to those of patients undergoing thoracic surgery (29). figure 1. postoperative selective urinary excretion of ngal (mean values). figure 2. correlation between the variation in 99mtc-dtpa clereance 3 months after surgery with the selective dosage of ungal at 48 hours from surgery. 77archivio italiano di urologia e andrologia 2019; 91, 2 the variation of selective ungal levels after robot-assisted partial nephrectomy: early results of a prospective single center study in addition, kyo chul koo examining 176 patients who underwent partial open and laparoscopic nephrectomy, had not shown that ungal could represent a predictive marker of both postoperative aki and ckd 6 months after surgery (30). to the best of our knowledge the current report represents the first prospective study that evaluates postoperative aki and the functional outcome after 3 months from surgery, adopting selective ungal assay. first of all, we showed a statistically significant increase in the selective dosage of ungal after 48 hours from surgery. this result was not confirmed for the serum ngal assay after 48 hours from surgery. probably sngal dosage is significantly affected by postoperative blood loss (not considered in this study), as well as could be influenced by the patient's hydration status. for this reason, we decided to focus our interest on the ungal. comparing selective ungal assay 48 hours after surgery between patients undergoing on-clamp and off-clamp rapn, we did not find a statistically significant difference. in fact, it seems that hilar clamping does not influence the increase in selective ungal dosage and therefore the severity of the acute post-operative renal injury. on the other hand, the diagnosis of aki using the kdigo criteria allowed to diagnose postoperative aki in only 3 patients, suggesting a lack of sensitivity of the diagnostic criteria worldwide used for aki. later we highlighted a worsening of renal function of the operated kidneys 3 months after surgery, through a sequential renal scintigraphy performed before and 3 months after surgery. this result should be explained not as a failure of nephron sparing surgery but as an effect of the high sensitivity of renal scintigraphy in detecting even small changes in renal function compared to the use of scr. indeed, the curvilinear relationship between serum creatinine and egfr may lead to the lack of detection of early stages of aki or ckd (31). the choice of the third postoperative month for the execution of the control scintigraphy, follows the kdigo recommendations (8). comparing patients undergoing on-clamp and off-clamp rapn, there are no differences in losses of 99mtc-dtpa clearance 3 months after surgery. this result could be due either to the short post-operative follow-up period but also to the limited warm ischemia time of on-clamp procedures (the mean warm ischemia time was 12.6 minutes). as we know, warm ischemia time is an important, modifiable predictor of postoperative renal function. in particular, warm ischemia time should not exceed 25 minutes, to avoid a short and long-term reduction in renal function (32). the statistically significant association between the reduction in 99mtc-dtpa clearance 3 months after surgery with the selective dosage of ungal at 48 hours from surgery, highlighted a direct relationship between these two predictors. the limitations of this report should be acknowledged. first, the small number of patients as well as the short time of postoperative follow-up (3 months) limited the power of the analyses. second, the normalized ungal (the ratio of urine ngal to urine creatinine) was not used in this study; moreover, the postoperative urine collection for ungal was performed selectively through a ureteral catheter inserted into the excretory axis of the operated kidney, unlike previous studies where urine was collected from the urethral catheter (28-30). further studies are needed to understand the clinical use of the ungal although it seems clear the importance of implementing the definition of aki with the introduction of new biomarkers. the importance of reno-protective surgery is not in question in this report but we tried to demonstrate the lack of sensitivity of traditional methods. our findings support the concept that the development of reno-protective techniques can prevent the onset of small changes in postoperative renal function, not detected with the scr dosage, but which may impact on the functional outcome of the operated kidney. conclusions selective ungal assay represent a sensitive biomarker in detecting postoperative aki in patients submitted to rapn for a ct1 renal cell carcinoma. furtheremore, selective ungal assay may be consider a predictive biomarker of ckd after nephron-sparing surgery. in our opinion kdigo criteria for aki should be implemented with the clinical use of biomarkers such as ungal. referenves 1. lee jh, you ch, min ge, et al. comparison of the surgical outcome and renal function between radical and nephron-sparing surgery for renal cell carcinomas. korean j urol. 2007; 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10:e0133675. 31. steubl d, block m, herbst v, et al. plasma uromodulin correlates with kidney function and identifies early stages in chronic kidney disease patients. medicine. 2016, 95, e3011. 32. volpe a, blute ml, ficarra v, et al. renal ischemia and function after partial nephrectomy: a collaborative review of the literature eur urol. 2015; 68:61-74. correspondence ottavio colamonico, md ottaviocolamonico@gmail.com giuseppe cardo marcello scarcia michele zazzara giuseppe m. ludovico urology department, ospedale generale “f. miulli” via enrico toti n. 2 acquaviva delle fonti (ba) (italy) edmondo ceci specialistic clinical biochemistry department, ospedale generale “f. miulli”, acquaviva delle fonti, bari (italy) mario dassira nuclear medicine department, ospedale generale “f. miulli”, acquaviva delle fonti, bari, (italy) angelo porreca urology department, policlinico abano terme, padova (italy) stesura seveso 241archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. shielding. there are a variety of ways to reduce fluoroscopy time during interventional procedures; some are methodological and others involve taking advantages of technical features present in modern equipment such as intermittent fluoroscopy, removal of grid, last image hold, electric collimation, dose spreading, adjustment of beam quality, image magnification, dose level settings, and pulsed fluoroscopy (4). the idea behind pulsed fluoroscopy is that modern gridcontrolled x-ray tubes have a grid placed between the cathode and the anode which allows pulses of fluoroscopy to leave the tube at a rate between 1 and 30 frames per second (fps). thus, radiation no longer enters a patient continuously, but rather in a series of short x-rays flashes. when we use fluoroscopy at 30 fps it is called continuous fluoroscopy; on the other hand, aufrichtig et al. (5) defined pulsed fluoroscopy as 15 fps or less. each fluoroscopy unit could be manually set as pulsed fluoroscopy (pf) with refresh rates of 15, 8, or even 4 fps. using phantom models, pf at rates of 15, 10, 7.5, and 3.75 fps were associated with radiation reduction by 22%, 38%, 49%, and 87%, respectively (6, 7). although using pulsed fluoroscopy appears promising in reducing radiation, it always has a potential penalty of a decrease in image quality. on a real-time fluoroscopic image, low pulse rate makes image becomes more noisy or grainy. moreover, with very slow pulse rates, motion such as swallowing, peristalsis and heart beating becomes jerky (choppy). to overcome this obstacle, manufacturers increase the milliamperage settings to achieve a similar visual appearance (8, 9). during retrograde urethrography, using pulsed fluoroscopy is ideal because there is minimal patient movement and we use the real time imaging to delineate the urethra with better identification of the urethral pathology (10). the primary objective is to identify if the use pulsed fluoroscopy mode during retrograde urethrogram to minimize radiation exposure for both the operator and the patient. the secondary objective is to assess whether using 4 frames per seconds (fps) in pulsed mode is sufficient without the need to increase the number of fps. we will also assess the image quality of the study and the concordance between the image and the intraoperative finding during diagnostic cysto-urethroscopy. objectives: retrograde urethrogram (rug) is one of the corner stones for the reconstructive urologist. with hundreds of rugs being performed yearly in busy reconstructive center, the concern for radiation exposure to the patient and the medical personnel becomes important. we propose the use of pulsed fluoroscopy to decrease the radiation exposure for patient and medical personnel. methods: patients presenting to our center with urethral strictures between march 2016 and march 2019 were included in our study. the fluoroscopy machine was set for pulsed fluoroscopy at a setting of 4 pulses per second. patient information including demographics, pre-operative diagnosis, intra-op findings, and fluoroscopy time were recorded. rug was performed to localize the stricture pre-operatively and post-operatively. results: a total of 185 rug were performed between march 2016 and march 2019. the median age was 63 (14-81). the remaining 154 rug had 77 performed pre-operatively and 77 performed post-operatively. pathology was identified in 77 patients. intra-operative confirmation of pre-operative finding was found in 76 patients (98.7%). median fluoroscopy time was found to be 2.43 seconds (0.5 sec6.5 sec). conclusions: pulsed fluoroscopy reduces the radiation exposure in rug without a reduction in the diagnostic capacity of the test. reduction of fluoroscopy can have beneficial cumulative effect as per the alara principle for patients and medical personnel. further studies with randomized control trials could be of great benefit. key words: urethrogram; pulsed fluoroscopy. submitted 19 march 2021; accepted 21 april 2021 introduction retrograde urethrography (rug) and voiding cystourethrography (vcug) are the modalities of choice for imaging the male urethra. first, rug is performed to visualize the adequately distended anterior urethra, and vcug is then performed to properly evaluate the posterior urethra. urethrography is a dynamic imaging modality that should be done by an expert urologist to assure the accuracy of the technique and the correct interpretation thereafter (1, 2). reducing the fluoroscopic exposure without compromising the image quality was always the first priority for manufacturers as well as the surgeons, hence the invention and implementation of the alara principle "as low as reasonably achievable" in 1990 (3). the alara principle has 3 factors, time, distance, and pulsed fluoroscopy in retrograde urethrograms hazem elmansy 1, waleed shabana 1, radu rozenberg 2, abdulrahman ahmad 1, ahmed kotb 1, amer al aref 2, walid shahrour 1 1 department of urology and 2 radiology, northern ontario school of medicine, thunder bay, on, canada. doi: 10.4081/aiua.2021.2.241 summary archivio italiano di urologia e andrologia 2021; 93, 2 h. elmansy, w. shabana, r. rozenberg, a. ahmad, a. kotb, a. al aref, w. shahrour 242 methods patients presenting to our center with urethral strictures between march 2016 and march 2019 were included in our study. rugs were performed by a single urologist. the fluoroscopy machine was set for pulsed fluoroscopy at a setting of 4 pulses per second. the same technique of rug was used in every test. the urologist controlled the pedal for fluoroscopy. patient information including demographics, pre-operative diagnosis, fluoroscopy time, stricture location and length, intra-op findings, and intraop cystoscopy were recorded. rug was performed to localize the stricture pre-operatively. if there is no identification of a stricture, cystoscopy is performed to confirm the negative findings. it was also performed in select patients post-operatively with cystoscopy to confirm the findings. the data was collected retrospectively after ethics approval. patients that had complex stricture disease requiring fluoroscopic manipulation were excluded. results a total of 185 rug were performed between march 2016 and march 2019. the median age was 63 (14-81). there were 20 rug that did not show a stricture, and this was confirmed by cystoscopy in the same setting. there were 11 patients that were excluded as they had complex stricture disease requiring fluoroscopic manipulation. the remaining 154 rug had 77 performed preoperatively and 77 performed post-operatively. pathology was identified in 77 patients. intra-operative confirmation of pre-operative finding was found in 76 patients (98.7%). there were no recorded complications from the rug. strictures locations and demographics were recorded in table 1. median fluoroscopy time was found to be 2.43 seconds (0.5 sec-6.5 sec). discussion rug is a fundamental test for reconstructive urethral surgery. in the high-volume centers, multiple rugs are being performed on a daily basis. as per the alara principle, we would always strive to decrease the amount of radiation used. this can help the medical personnel that are exposed on daily basis to radiation. in addition, with increased dependence on radiological assessments, we would aim at decreasing the accumulated radiation for patients over the years. in our current study, we noted that the fluoroscopy time has a median of 2.43 seconds. according to the studies on phantom models, this might mean an 87% reduction in the amount of radiation (6, 7). we do not have previous results with continuous fluoroscopy or higher pulse rate as this was adopted from the beginning. the usual extrapolation of the data would be that the amount of fluoroscopy would be more than doubled with the higher pulse rate. the use of the fluoroscopy time is not always the best indicator for the cumulative dose compared to the use of the air kerma area product or dose area product (dap). in our study we used the fluoroscopy time as it is a simple way to convey the result and it is one of the indicators for the reduction in the dose. the exclusion of the complicated cases that required fluoroscopic manipulation was due to the fact that they were not representative of the usual fluoroscopy time used in regular diagnostic procedure. this was not due to the image quality being poorer rather than it would bring the average fluoroscopy time to be higher than usual expected. this should not exclude the use of low pulse fluoroscopy in those cases as it would mean lower radiation dose for patients and personnel specially when maneuvers are needed and longer fluoroscopy would be used. the only case where the rug was not diagnostic entirely because of improper opacification of the distal urethra during the rug and not because of reduction of the image quality. this was identified during surgery where the intra-operative finding showed the stricture to be extending all the way to the distal urethra. the comparison between the intra-operative findings and the rug findings did not show reduction in the diagnostic capacity or the capability of pre-operative planning for the surgery. one of the downsides of the lower pulse rate is the lower quality of the image. the image becomes grainy in appearance and it takes some time to get used to that. this grainy appearance does not affect the image contrast or the ability to diagnose stricture as shown in our study. another downside is the noticeable delay between pressing the pedal and the appearance of the image on the screen. this delay can be a matter of seconds or milli seconds and it does not usually affect the outcomes. this would be apparent when the urologist is performing manipulation under fluoroscopy. since the rug does not require manipulation, this delay is acceptable for the reduction of the radiation exposure. another method to decrease radiation exposure is by having the doctor, residents and fellows taking radiation-safety programs. gendelberg et al. (11) has shown that radiation-safety programs decrease the radiation emission and usage after the program was taken by the residents. while some might argue that they use just one image, it is still using the usual frames of the machine. many machines are set on rates of 15 fps while newer machines are set at 8 fps which would be a lower fps used. the regular continuous fluoroscopy is 30 fps which would mean more than 7 times the number of frames needed for one image. table 1. study population and pulsed urethrogram data. number of patients 77 total number of rgu 185 negative rug (excluded) 20 pre and post-operative rug 154 complex rug (excluded) 11 median age (iqr) years 63 (58-71) median fluoroscopy time seconds 2.43 (0.5-6.5) intra-operative confirmation of structure 76 (98.7%) stricture location: penile n (%) 21 (27.2%) bulbar n (%) 42 (54.5%) pan-urethral n (%) 14 (18.1%) there are methods to decrease the fluoroscopy time and radiation exposure in general that can be used. one can bring the part to be examined (in our case, the urethra) as close as possible to the receiving end of the c-arm or the image intensifier. using the last image option if we require more than one image can also reduce the radiation exposure. our study is a retrospective one with the known limitations of retrospective studies. randomized multi-institutional trial can prove beneficial in such situation. conclusions pulsed fluoroscopy reduces the radiation exposure in rug without a reduction in the diagnostic capacity of the test. reduction of fluoroscopy can have beneficial cumulative effect as per the alara principle for patients and medical personnel. further studies with randomized control trials could be of great benefit. references 1. pavlica p, barozzi l, menchi i. imaging of male urethra. eur radiol 2003; 13:1583-1596. 2. kawashima a, sandler cm, wasserman nf, et. al. imaging of urethral disease: a pictorial review. radiographics 2004; 24(suppl 1): s195-s216. 3. european alara network workshop, "experience and new developments in implementing alara in occupational, patient and public exposures", prague, czech republic, 12-15 september 2006, proceedings available on www.eu-alara.net. 4. vehmas t, et al. hawthorne effect. shortening of fluoroscopy times during radiation measurement studies. br j radiol. 1997; 70:10531055. 5. aufrichtig r, xue p, thomas cw, et al. perceptual comparison of pulsed and continuous fluoroscopy. med phys. 1994; 21:245-256. 6. cohen m. optimizing the use of pulsed fluoroscopy to reduce radiation exposure to children. am coll radiol. 2008; 5:205-209. 7. lederman hm, khademian zp, felice m, et al. dose reduction fluoroscopy in pediatrics. pediatr radiol. 2002; 32:844-848. 8. brown ph, thomas rd, silberberg pj, et al. optimization of a fluoroscopeto reduce radiation exposure in pediatric imaging. pediatr radiol. 2000; 30:229-235. 9. schueler ba, julsrud pr, gray je, et al. radiation exposure and efficacy of exposure-reduction techniques during cardiac catheterization in children. ajr am j roentgenol. 1994; 162:173-7. 10. ward vl, strauss kj, barnewolt ce, et al. pediatric radiation exposure and effective dose reduction during voiding cystourethrography. radiology, 2008; 249:1002-1009. 11. gendelberg d, hennrikus w, slough j et al. a radiation safety training program results in reduced radiation exposure for orthopaedic residents using the mini c-arm. clin orthop relat res. 2016; 474:580-4. 243archivio italiano di urologia e andrologia 2021; 93, 2 pulsed fluoroscopy urethrograms correspondence hazem elmansy, md hazem.mansy@rocketmail.com waleed shabana, md waleed.shabana@gmail.com abdulrahman ahmad, md dr.aaa.186@gmail.com ahmed kotb, md kotba@tbh.net walid shahrour, md walid.shahrour@gmail.com department of urology, northern ontario school of medicine, thunder bay, on (canada) radu rozenberg, md rozenber@tbh.net amer al aref, md alarefa@tbh.net department of radiology, northern ontario school of medicine, 980 oliver road, thunder bay, on (canada) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11502 1 original paper isotretinoin, which is widely used in the treatment of acne, one of the most common and disturbing diseases among young people. isotretinoin is the only drug effective on all pathogenic mechanisms of acne, such as inflammation, increased sebum secretion, overgrowth of bacteria such as propionibacterium acnes, and ductal hypercornification (1). although oral isotretinoin is a very effective treatment, it has a teratogenic effect in pregnant women (2). however, there is controversial information on the effect of isotretinoin in men. while there are several studies on spermatogenesis, we have limited information on the long-term effectiveness of isotretinoin use on testicles and spermatogenesis. in addition, it may not be ethically appropriate to conduct studies for evaluating its histological effects in humans. as there is no clear information about the effects of isotretinoin on spermatogenesis, this situation can be a matter of concern and curiosity in male patients using the drug and physicians recommending this drug. therefore, we planned a rat study to evaluate the long-term efficacy of oral isotretinoin on testicular tissues and spermatogenesis. materials and methods animals the animals were procured from the samsun experimental animals research and ethical application center (earac) after obtaining an ethics committee approval from the animal studies ethical committee at ordu university. this study was performed in accordance to the guiding principles for the care and use of laboratory animals. in our study, we used a total of 24 male wistar-albino rats, 4-8 weeks old, with an initial weight of 250-300 g. the rats were housed in rooms at 22 ± 1°c and 45-55% humidity, ensuring 12-hour light and dark cycles and including a maximum of 3 rats in each cage. the temperature and humidity were measured by thermometer and hygrometer, respectively. the ventilation was provided by a room aspirator. the rats had free access to feed and water. all rats were fed with normal rat chow (nucleon, ankara, turkey). objectives: spermatogenesis, in which cell regeneration continues, can be affected by environmental, chemical, psychological factors or various diseases. there is conflicting information in the literature about the effect of isotretinoin, which is widely used in acne treatment, on testes and spermatogenesis. therefore, we planned a rat study to evaluate the long-term efficacy of oral isotretinoin on testicular tissues and spermatogenesis. materials and methods: the group 1 (n = 6) 7.5 mg/kg/day and the group 2 (n = 6) received isotretinoin at a dose of 30 mg/kg/day dissolved in sunflower oil, the sham group (n = 6) received only sunflower oil by gavage, and the control group (n = 6) received standard feed and water for four weeks. after the 4th week, all animals were fed with standard feed and water and followed for the next four weeks. at the end of the 8th week, all animals were sacrificed under deep anesthesia. seminiferous tubule diameters, epithelial thickness, apoptotic index, sperm number and motility recorded results: sperm count, motility, vitality, diameter of seminiferous tubule and germinal epithelium thickness were decreased and apoptotic index increased in the groups received isotretinoin. there was no significant difference between the groups in terms of testosterone levels. conclusions: we consider that further comprehensive studies, including human clinical trials, should be conducted to examine the negative effects of isotretinoin on spermatogenesis in the long term especially when there is a need using isotretinoin in men for various reasons and to eliminate the contradictions in the literature in this regard. key words: isotretinoin; rat; spermatogenesis; testis. submitted 31 may 2023; accepted 1 june 2023 introduction spermatogenesis is a complex process in which mature sperm cells are formed from spermatogonial stem cells as a result of mitosis, meiosis, and cell differentiation. in this active process, the cell cycle continues in seminiferous tubules, which can make the spermatogenetic process sensitive to various factors such as environmental, chemical, toxic and pharmacological agents. one of them is does isotretinoin affect spermatogenesis in the long term? a rat model abdullah cirakoglu 1, sevda onder 2, hatice hancı 3, erdal benli 1, ahmet yüce 1, yeliz kasko arici 4, orhan bas 5, ismail nalbant 6 1 ordu university, faculty of medicine, urology department, ordu, turkey; 2 ordu university, faculty of medicine, dermatology department, ordu, turkey; 3 ordu university, faculty of medicine, histology and embriyology, ordu, turkey; 4 ordu university, faculty of medicine, biostatistics department, ordu, turkey; 5 samsun university, faculty of medicine, anatomy department, samsun, turkey; 6 lokman hekim university, faculty of medicine, urology department ankara, turkey. doi: 10.4081/aiua.2023.11502 summary archivio italiano di urologia e andrologia 2023; 95(3):11502 a. cirakoglu, s. onder, h. hancı, et al. 2 formation of the groups and experimental design a total of 24 male wistar-albino rats, 4-8 weeks old, were used and randomly divided into 4 groups, including 6 in each group. the group 1 (n = 6) received isotretinoin (roaccutane, roche, basel, swiss) at a dose of 7.5 mg/kg/day dissolved in sunflower oil, the group 2 (n = 6) received isotretinoin at a dose of 30 mg/kg/day dissolved in sunflower oil, the sham group (n = 6) 6) received only sunflower oil by gavage, and the control group (n = 6) received standard feed and water for four weeks. after the 4th week, all animals were fed with standard feed and water and followed for the next four weeks. at the end of the 8th week, all animals were sacrificed by cervical dislocation under deep anesthesia with intraperitoneal of ketamine 90 mg/kg (ketalar; eczacıbaşı, istanbul, türkiye) and xylazine hydrochloride 3 mg/kg (rompun; bayer, leverkusen, germany). their testicles were excised bilaterally and their epididymis and testicular tissues were separated from each other for analysis. biochemical analyses in serum after being kept at room temperature for 30 minutes, the blood specimens placed into gel-containing tubes were centrifuged at 3000 g for 15 minutes. the serum samples separated from the centrifuged blood were stored at -80°c until analysis. their testosterone, fsh and lh levels were measured after the serums were dissolved (cobas 8000 e 602, hitachi, roche autoanalyzer). histological procedure at the end of the experiment, while the animals were under deep anesthesia, a midline incision was made, and their testicular and epididymis tissues were meticulously separated from the surrounding tissues. then their epididymis and testicular tissues were separated from each other for analysis. the epididymis tissues were placed in tris phosphate buffer solutions and the testicular tissues in bouin solutions for fixation after they were divided vertically into two pieces. after the tests were fixed in bouin solution, the entire half tests were kept for 3 days in a dry environment protected from light. the tissues were then subjected to routine histological tissue follow-up procedures on the thermo scientific excelsior™ as (thermo fisher scientific, waltham, ma usa), an automatic tissue tracking device. after the follow-up process, the tissues were blocked by embedding in paraffin in histocore arcadia h and histocore arcadia c (leica biosystems nussloch gmbh, nussloch, germany). then, 5-μm thick sections were taken with a fully automatic microtome (leica rm 2255, tokyo, japan). the sections were mounted on slides and stained with hematoxylin and eosin (h & e, leica autostainer xl, minnesota, usa) for histopathological examination and measurements of seminiferous tubule diameter and epithelial thickness. the seminiferous tubule diameter and epithelial thickness were measured using the olympus dp 71 camera-mounted microscope (olympus, tokyo, japan). the analysis 5 research (olympus soft imaging solution gmbh, münster, germany) program was used for this purpose and the properties of the interstitial space. we used the same microscope to take photographs. epididymal sperm count, and sperm motility and vitality the right epididymis was used to evaluate epididymal sperm count, sperm motility and viability. the epididymis was placed in a petri dish with 2 ml of tris buffer solution and divided into 4 parts. it was incubated at 37°c for 30 min to permit sperm release. sperm count and motility were evaluated using the makler sperm counting chamber (sefi -medical instrument, haifa, israel). five milliliters of sperm fluid were dropped from the homogenate into the center of the chamber, and the glass lid was closed. thus, the sperms were allowed to swim in the area with a depth of 10 μm. the sperm count was performed by a light microscope at x 100 magnification. percentages of the motile sperm were calculated among at least 100 spermatozoa. then, to evaluate sperm viability, 5 μl of sperm sample was placed on slides, a drop of 1% eosin y was added and closed with a coverslip. it was evaluated by counting 100 motile and immotile sperms in different areas at x 200 magnification. orange colored sperms were considered dead, and the unstained ones were considered alive. the percentage of viable sperms was calculated (3). tunel staining and apoptosis apoptosis was examined using tunel staining to detect dna fragmentation in the seminiferous tubule epithelium. tunel staining was performed using the in situ cell death detection kit (roche diagnostics, mannheim, germany). evaluation of the tunel stained sections was performed using the light microscope at x 400 by an experienced histologist blinded to the identity of the specimens. tunel-positive cells with no necrotic areas and a brown nucleus were considered apoptotic. tunelpositive cell numbers in 10 seminiferous epithelium regions and the total number of cells were used to calculate ai (tunel-positive cells/total cells x 100) (4). statistical analysis the data were tested for normality using the shapirowilk test and for homogeneity of variance using the levene's test prior to the analyses. one-way anova followed by tukey as post-test was used to compare the groups. descriptive statistics of the data set were expressed as means, standard deviations, and minimum and maximum values. a p-value less than 0.05 (twosided) was considered statistically significant. all statistical analyses were performed using the spss v25 (ibm inc., chicago, il, usa) statistical software. results as a result of the analysis of variance for sperm motility, the difference between the groups was found to be statistically significant (p < 0.001). as a result of the tukey test performed to determine different averages, the sperm motility rate in group 1 and group 2 was significantly lower than the control and sham groups, but there was no significant difference between the control and sham groups (p > 0.05) (p < 0.05). in addition, the decrease in sperm motility was higher in the group 2 than in the group 1. as a result of the analysis of variance for sperm count, the archivio italiano di urologia e andrologia 2023; 95(3):11502 3 effects of isotretinoin on spermatogenesis difference between the groups was found to be statistically significant (p < 0.0). as a result of the tukey test, the sperm count was significantly lower in the group 2 than in the control group (p < 0.05), but the differences between the other groups were not statistically significant (p > 0.05). as a result of the analysis of variance for sperm vitality, diameter of seminiferous tubule, germinal epithelium thickness, and apoptotic index, the differences between the groups were found to be statistically significant (p < 0.001) (table 1). as a result of the tukey test performed to determine different averages; while there was no significant difference between the control and sham groups (p > 0.05), the groups 1 and 2 had significantly lower sperm vitality, diameter of seminiferous tubule (p < 0.05) and germinal epithelial thickness (p < 0.05) and higher apoptotic index value than the control and sham groups (p < 0.05) (figure 1). as a result of the variance analysis performed to compare the testosterone amounts of the groups, the difference between the group averages was not found to be statistically significant (p > 0.05). for all groups, fsh and lh values were below 0.10 miu/ml, therefore it was not possible to compare their fsh and lh values. there was no statistically significant difference between the groups in terms of testosterone levels. discussion isotretinoin is a synthetic retinoid used in the treatment of severe nodulocystic acne where other treatments have failed (5). retinoids are also used to manage other dermatological conditions, such as rosacea, folliculitis, sarcoidosis, granuloma annulare, seborrheic dermatitis, and a variety of keratinization disorders (6). although isotretinoin has been used for many years, hesitations about its side effects still exist. both human and animal studies have reported that it has serious teratogenic effects, decreasing ovarian reserves after 6 months of use of isotretinoin in women (2, 7, 8). given the wide clinical usage of retinoids, clarification of whether retinoids affect the reproductive system in male patients of childbearing age is urgently needed. in addition, there are conflicting results regarding its side effects on male reproductive system. studies have argued that both deficiency and high levels of vitamin a suppress spermatogenesis (9). some other studies have suggested that vitamin a is necessary for spermatogenesis and its deficiency may cause defects in germ cell and testosterone production (10). some human studies argue that isotretinoin has a positive effect on sperm parameters, however we have reached the opposite results in our study. for example, cinar et al. administered a cumulative dose of isotretinoin to 81 male patients to investigate the effects of systemic figure 1. box-plot of the study variables in the groups. table 1. descriptive statistics and the results of statistical analysis for the study variables. variables group n mean std. dev. min-max p-value sperm motility (%) control 6 71.80a 1.59 69.56-73.68 < 0.001 (f = 51.24) sham 6 71.10a 2.20 68.96-75.00 group 1 5 63.43b 4.92 56.52-68.96 group 2 6 53.85c 2.09 51.72-56.52 number of sperm x106 control 6 31.50a 5.58 23.00-38.00 < 0.05 (f = 3.67) sham 6 28.67ab 5.05 20.00-34.00 group 1 5 25.80ab 3.56 21.00-29.00 group 2 6 22.67b 4.68 16.00-29.00 sperm vitality (%) control 6 75.67a 4.63 70.00-82.00 < 0.001 (f = 10.20) sham 6 76.33a 5.13 70.00-84.00 group 1 5 64.00b 5.83 56.00-72.00 group 2 6 63.67b 5.57 56.00-70.00 diameter of seminiferous tubule control 6 239.31a 9.02 228.42-252.81 < 0.001 (f = 60.75) sham 6 236.32a 6.58 227.63-244.35 group 1 5 196.27b 7.59 187.96-204.48 group 2 6 195.34b 6.44 187.20-203.68 germinal epithelium thickness control 6 87.69a 4.43 82.14-92.64 < 0.001 (f = 75.92) sham 6 83.74a 4.41 78.96-88.93 group 1 5 61.73b 5.20 56.66-69.10 group 2 6 58.58b 1.93 55.87-60.80 apoptotic index (%) control 6 3.41b 0.93 2.25-4.84 < 0.001 (f = 263.47) sham 6 3.49b 0.65 2.91-4.56 group 1 5 29.78a 2.80 25.53-32.45 group 2 6 31.94a 3.66 27.87-37.84 f, one-way anova. according to tukey's test, means that do not share a letter are significantly different (p < 0.05). archivio italiano di urologia e andrologia 2023; 95(3):11502 a. cirakoglu, s. onder, h. hancı, et al. 4 isotretinoin on male fertility. they examined spermiogram parameters (sperm concentration, total progressive motility, total progressively motile sperm, normal morphology and viability) and total testosterone, fsh and lh levels before and after the treatment. they observed no significant change in the hormone profile after the treatment, but found significant positive changes in the spermiogram parameters (11). amory et al. administered isotretinoin to patients between the ages of 21 and 60 years with impaired sperm parameters, and found no significant change in their sperm motility, but observed an increase in their sperm concentrations (12). on the other hand, some other human studies reported that isotretinoin treatment did not affect spermatogenesis and hypothalamicpituitary-gonadal axis (13-15). the reason for the different results in our study and those mentioned above may be due to the difference in molecular doses, various uncontrollable non-standard subjective factors that affect the sperm parameters of people with different physical factors such as environment and diet. the wide age range of participants or the investigation of people with damaged spermatogenesis may be the reason for this difference alone. in addition, due to the nature of the research and ethical restrictions in these human studies, it was tried to have an idea by looking at very limited sperm parameters. apart from this, most of these studies in humans do not have a placebo and control groups. our study is valuable as it provides objective histopathological data with peers raised in controlled environments together with standard environment and environmental factors. so much so that at the end of our study, we found that isotretinoin reduced sperm motility, viability and numbers, decreased germinal epithelial thickness and seminiferous tubule diameters, and impaired spermatogenesis by stimulating apoptotic index in testicles. also, interestingly, despite studies claiming that synthetic retinoids may have beneficial effects on semen parameters, isotretinoin has never been offered as a treatment option in patients with impaired spermiogram parameters (16). sengör et al. examined the effects of another synthetic retinoid, acitretin, on spermatogenesis, reported no significant change in the spermatogenesis evaluation and mean tubular diameter between the acitretin-treated and control groups, and found that acitretin had no effect on spermatogenesis (17). we found the opposite results in our study and reached objective histopathological data showing that retinoids stimulate the apoptotic index. this difference may be due to dose-dependence or because sengör et al. could not control some valuable parameters, including the apoptotic index. apoptosis is a complex event regulated by the balance of inducer and repressor factors. it has a critical role in the elimination of damaged spermatogonial cells to prevent the production of abnormal sperm cells (18). spermatocytes that cannot complete their mitotic division are eliminated by apoptosis (19). apoptosis in germ cells increases in infertile men (20, 21). our study found significantly higher apoptotic index in both the groups 1 and 2 than in the control group. this increase in the apoptotic index may be a natural regulation to protect against possible teratogenicity. in addition, although the exact mechanism of action of retinoids is not known, they stimulate apoptosis in sebaceous glands and disrupt cell cycle arrest (22, 23). spermatogenesis is an active process in testis, including continuous cell cycle. it is a natural result that systemic isotretinoin acts on the seminiferous tubules, where cell division continues, along with the sebaceous glands. we consider that this may be the reason for the deterioration in sperm quality and the increase in apoptotic index in our study. like our study, a study examined the apoptotic index and suggested that isotretinoin had damaging effects on spermatogenesis (24). studies about the relationship between different molecules and spermatogenesis have shown an inverse relationship between apoptotic index and spermatogenesis, and this result is in line with those in our study (25, 26). the apoptotic index has not been examined in any of the studies suggesting that isotretinonin has a positive effect on spermatogenesis. if isotretinoin had a spermatogenesis stimulating effect as claimed, it should have decreased in the apoptosis index. however, such information is not mentioned in the presented studies. in particular, the germinal epithelium in the seminiferous tubules is the testicular component directly related to spermatogenic activity (27). therefore, germinal epithelial thickness is a useful parameter in evaluating sperm production (28). it decreases due to decreased cell division (29). isotretinoin-induced cell cycle arrest may also be responsible for the decrease in germinal epithelial thickness, which is one of the results of our study, and therefore the decrease in sperm counts. in our study, isotretinoin decreased germinal epithelial thickness and seminiferous tubule diameters and sperm concentration in testis. these results suggest that isotretinoin has serious damaging effects on spermatogenesis, which is in line with the histopathological results in the literature indicating impaired spermatogenesis. sperm motility is an absolutely necessary function for male fertility. although it has not been fully explained how the sperm gain this ability while passing through the epididymis, it is known that various signaling pathways are effective in developing this ability (30, 31). to be motile, human sperm need a morphologically complete flagellum, be able to produce energy to power flagellar movement and functional signaling pathways. although our study did not reveal precisely which part of this system isotretinoin affects, it has clearly shown that isotretinoin decreases sperm motility in both groups using drugs. the effect of environmental factors on spermatogenesis is well known. several factors such as environmental toxins, diet, stress, drugs, frequency of ejaculation can affect sperm parameters (32, 33). in human studies, it is practically not possible to ensure that all subjects live under the same conditions. this may be the reason for contradictory results in studies. we consider that our results are more reliable since the feeding and environmental conditions of all animals were standard. we also think that our study is more objective, as it revealed the drug’s negative effects on testicular tissue histologically (figures 2, 3). there are also conflicting results regarding the effects of isotretinoin on pituitary hormones. in their study with 47 patients, karadağ et al. (22). reported that isotretinoin may have an effect on pituitary hormones. cinar et al., on archivio italiano di urologia e andrologia 2023; 95(3):11502 5 effects of isotretinoin on spermatogenesis the other hand, reported no significant change in fsh, lh, and testosterone levels after the use of isotretinoin (12). comparing the control group with the groups using 7.5 mg/kg and 30 mg/kg of isotretinoin, our study found no significant difference between their testosterone levels in the long term, but the fsh and lh levels were below measurable values in all groups. therefore, it was not possible to compare the fsh and lh values. however, our results suggest that the effect of isotretinoin on testicles is due to its direct effect on the tissue rather than hormonal changes. as a result, rat studies about the long-term effect of isotretinoin are limited and include contradictory results. therefore, the inability to reach sufficient studies to be a benchmark for our study may be one of the limitations in our study. however, considering that the results obtained from rats subjected to the same environmental factors and feeding are supported by apoptotic index, parallel objective histopathological results and biochemical values, our study makes a valuable contribution to the literature. conclusions our study concludes that the negative effects of isotretinoin on spermatogenesis may be due to its direct damage to testicular tissues. in addition to the necessity of conducting human studies to evaluate the long-term effects of isotretinoin on testicles, we consider that further comprehensive studies, including human clinical trials, should be conducted to examine the negative effects of isotretinoin on spermatogenesis in the long term especially when there is a need using isotretinoin in men for various reasons, and to eliminate the contradictions in the literature in this regard. references 1. zouboulis cc, bettoli v. management of severe acne. br j dermatol. 2015; 172:27-36. 2. henry d, dormuth c, winquist b, et al. occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. cmaj. 2016; 188:723-730. 3. sankako mk, garcia pc, piffer rc, et al. possible mechanism by which zinc protects the testicular function of rats exposed to cigarette smoke. pharmacol rep. 2012; 64:1537-1546. 4. hancı h, odacı e, kaya h, et al. the effect of prenatal exposure to 900-mhz electromagnetic field on the 21-old-day rat testicle. reprod toxicol. 2013; 42:203209. 5. shahada oo, kurdi as, aljawi af, et al. synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome diagnosis in adolescent and isotretinoin as a possible serious exacerbating factor. cureus. 2022; 14:e22776. 6. motamedi m, chehade a, sanghera r, grewal p. a clinician's guide to topical retinoids. j cutan med surg. 2022; 26:71-78. 7. mehra t, borelli c, burgdorf w, et al. treatment of severe acne with low-dose isotretinoin. acta derm venereol. 2012; 92:247-248. figure 2. histological sections in rat testis stained with hematoxylin and eosin (h‐e, ×400). control group (c), sham group (s), 7.5 mg/kg isotretinoin and 30 mg/kg isotretinoin. figure 3. histological sections in rat testis stained with tunel (×400). control group (c), sham group (s), 7,5 mg/kg isotretinoin and 30 mg/kg isotretinoin. normal cells (right arrow) and apoptotic cells (arrowhead). c: seminiferous tubule (star) with regular germinal epithelium and normal structure observed, spermatozoa in the seminiferous tubule lumen (arrowhead), interstitial area with normal structure and leydig cell (lower arrow); s: seminiferous tubule (star) with regular germinal epithelium and normal structure observed, spermatozoa in the seminiferous tubule lumen (arrowhead), occasional vacuolization around spermatogonium (dashed right arrow) 7.5 mg/kg: loss or reduction of spermatozoa (star), vacuolar degeneration (right arrow), opening between seminiferous tubule basal membrane and germinal epithelium (right bent arrow). 30 mg/kg: opening between seminiferous tubule basal membrane and germinal epithelium (right bent arrow), vacuolar degeneration (right arrow), giant cells with multiple nuclei (upper arrow), disorganization and degenerations of germinal epithelium in the seminiferous tubule (multiplication sign). archivio italiano di urologia e andrologia 2023; 95(3):11502 a. cirakoglu, s. onder, h. hancı, et al. 6 8. aksoy h, cinar l, acmaz g, et al. the effect of isotretinoin on ovarian reserve based on hormonal parameters, ovarian volume, and antral follicle count in women with acne. gynecol obstet invest. 2015; 79:78-82. 9. sadek ia, abdul-mohsen mh. long-term administration of vitamin a and the process of spermatogenesis. east mediterr health j. 1999; 5:123-129. 10. livera g, rouiller-fabre v, pairault c, et al. regulation and perturbation of testicular functions by vitamin a. reproduction. 2002; 124:173-180. 11. çinar l, kartal d, ergin c, et al. the effect of systemic isotretinoin on male fertility. cutan ocul toxicol. 2016; 35:296-299. 12. amory jk, ostrowski ka, gannon jr, et al. isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study. andrology. 2017; 5:1115-1123. 13. parsch em, ruzicka t, przybilla b, schill wb. andrological investigations in men treated with acitretin (ro 10-1670). andrologia. 1990; 22:479-482. 14. török l, kádár l, kása m. spermatological investigations in patients treated with etretinate and isotretinoin. andrologia. 1987; 19:629-633. 15. hui liu, jie li, li yu. effects of acitretin on semen quality and reproductive hormone levels in patients with psoriasis vulgaris. dermatologica sinica. 2017; 35:55-58. 16. onder s, çırakoğlu a, nalbant i, et al. does isotretinoin affect spermatogenesis? a rat study. egypt j dermatol venerol. 2021; 41:75-82. 17. sengör b, bayramgürler d, müezzinoglu b, et al. effects of acitretin on spermatogenesis of rats. j eur acad dermatol venereol. 2006; 20:689-692. 18. cai l, hales bf, robaire b. induction of apoptosis in the germ cells of adult male rats after exposure to cyclophosphamide. biol reprod. 1997; 56:1490-1497. 19. print cg, loveland kl. germ cell suicide: new insights into apoptosis during spermatogenesis. bioessays. 2000; 22:423-430. 20. lin ww, lamb dj, wheeler tm, et al. in situ end-labeling of human testicular tissue demonstrates increased apoptosis in conditions of abnormal spermatogenesis. fertil steril. 1997; 68:1065-1069. 21. høst e, lindenberg s, ernst e, christensen f. dna strand breaks in human spermatozoa: a possible factor, to be considered in couples suffering from unexplained infertility. acta obstet gynecol scand. 1999; 78:622-625. 22. karadag as, ertugrul dt, tutal e, akin ko. isotretinoin influences pituitary hormone levels in acne patients. acta derm venereol. 2011; 91:31-34. 23. altucci l, gronemeyer h. the promise of retinoids to fight against cancer. nat rev cancer. 2001; 1:181-193. 24. gencoglan g, tosun m. effects of isotretinoin on spermatogenesis of rats. cutan ocul toxicol. 2011; 30:55-60. 25. ghasemnezhad r, mohammadghasemi f, faghani m, bahadori mh. oxytocin can decrease germ cells apoptotic index in testis under acute ischemia reperfusion in a rat model. iran j reprod med. 2015; 13:283-290. 26. kandirali e, cayan s, armagan a, et al. does the testicular apoptotic index vary with serum gonadotropins and testicular histopathology in infertile men? urol int. 2009; 83:349-353. 27. wing ty, christensen ak. morphometric studies on rat seminiferous tubules. am j anat. 1982; 165:13-25. 28. udoumoh af, igwebuike um, okoye cn, et al. assessment of age-related morphological changes in the testes of post-hatch light ecotype nigerian indigenous chicken. anat histol embryol. 2021; 50:459-466. 29. mohammadnejad d, abedelahi a, soleimani-rad j, et al. degenerative effect of cisplatin on testicular germinal epithelium. adv pharm bull. 2012; 2:173-177. 30. abou-haila a, tulsiani dr. signal transduction pathways that regulate sperm capacitation and the acrosome reaction. arch biochem biophys. 2009; 485:72-81. 31. visconti pe, westbrook va, chertihin o, et al. novel signaling pathways involved in sperm acquisition of fertilizing capacity. j reprod immunol. 2002; 53:133-150. 32. pelit es, katı b, akın y, yeni e. the impact of environmental stress factors on sperm. androl bul. 2017; 19:61-64. 33. nasr m, abd-allah h, ahmed-farid oah, et al. a comparative study between curcumin and curcumin nanoemulsion on high-fat, high-fructose diet-induced impaired spermatogenesis in rats. j pharm pharmacol. 2022; 74:268-281. correspondence abdullah cirakoglu, md ahmet yüce, md (corresponding author) ahmetyuce7@gmail.com erdal benli, md ordu university, faculty of medicine, urology department, ordu, turkey sevda onder, md ordu university, faculty of medicine, dermatology department, ordu, turkey hatice hancı, md ordu university, faculty of medicine, histology and embriyology, ordu, turkey yeliz kasko arici, md ordu university, faculty of medicine, biostatistics department, ordu, turkey orhan bas, md samsun university, faculty of medicine, anatomy department, samsun, turkey ismail nalbant, md lokman hekim university, faculty of medicine, urology department, ankara, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11580 1 original paper 93% of cases on the left side, while bilateral varicoceles are only found in about 25% of patients (3). majority of the left sided varicocele is related to the anatomic factors of the left testicular vein (4). in 1952, tulloch for the first time reported an azoospermic case which responded very well to bilateral varicocelectomy with not only sperm development in the ejaculate, but also normal pregnancy of the wife (5). since then, many studies reported significant improvement in the sperm parameters of patients following bilateral varicocelectomy (6, 7). one theory that claims varicocele to be a disease of bilaterality is the reflux theory. it depends on the presence of either incompetent or absent gonadal vein valves that allow blood to shunt back into the pampiniform plexus of veins. obviously, this is an anatomical deficit that should theoretically exist on both sides (8). this explains why left varicocele can also affect spermatogenesis of the right side as well. previously, the incidence of coexisting right varicocele in the presence of palpable left varicocele was 21-60% as reported by venographic studies. recently, the incidence of bilateral varicoceles is increasing due to the use of modern diagnostic means besides the physical examination, such as color doppler ultrasound (cdus) which has a sensitivity of 97% and specificity of 94% (9). as cdus is operator dependent, its reliability to diagnose and grade varicocele is still controversial (10). thus, assessment of varicocele bilaterality in infertile men seems to be deficient in the literature. on this basis, this study tried to objectively assess varicocele bilaterality in infertile men aiming to improve treatment outcome in this cohort of patients. patients and methods this is a case series study that was conducted in tanta urology department in egypt between january 2019 and january 2022. the study was conducted in accordance with the declaration of helsinki and it was approved by tanta university, faculty of medicine review board (irb number is 35903/10/22). informed consent was obtained by all subjects when they were enrolled. objectives: varicocele is the most common correctable cause of male infertility that always has been a debatable subject as regards how it affects fertility and the best way to treat it. proper assessment of the disease bilaterality is crucial not to miss one side and not to jeopardize treatment outcome. this study aimed to objectively assess varicocele bilaterality in infertile men aiming to improve treatment outcome in this cohort of patients. methods: this prospective study was conducted between january 2019 and january 2022 including infertile males with varicoceles. assessment of missed concomitant contralateral varicocele done pre-operatively by color doppler ultrasound and intraoperatively by intraoperative doppler device and measurement of maximal vein diameter of contralateral side. results: a total of 329 cases completed the study. a hundred cases (30.4%) were initially referred as unilateral varicoceles and 229 (69.6%) as bilateral varicoceles. after reassessment of the study population, bilaterality of varicocele was found to be as high as 98.5% (324/329). repeat cdus strongly correlated with the intraoperative measured varicocele diameter (r = 0.9, p < 0.001). moreover, sperm parameters showed significant improvement 3 and 6 months post varicocelectomy. normal pregnancy after 1 year of surgery occurred in 118 cases (35.9%). conclusions: varicocele bilaterality in infertile men is underreported. thorough assessment by expert radiologists and andrologists is of paramount importance not to miss significant pathology or hazard treatment outcome. key words: male infertility; varicocele bilaterality; varicocelectomy; semen parameters. submitted 9 july 2023; accepted 28 july 2023 introduction varicocele is the commonest surgical cause of male infertility and is found in 40% of patients with primary and 80% of those with secondary infertility (1). the etiopathogenesis of varicocele-induced infertility and the effect of surgical repair on the fertility potentials has always been a matter of debate (2). as reported in the literature, varicocele is found in 78% bilaterality of varicocele: the overlooked culprit in male infertility. case series study khaled mohamed almekaty 1, ahmed mostafa elsharkawy 2, mohamed hasan zahran 3, maged mostafa ragab 1, ayman sayed rashed 4, mahmoud mohamed soliman 5, khaled abdelaziz salem 1, ahmed fayez ghaith 1 1 urology department, tanta university, tanta, egypt; 2 radiology department, tanta university, tanta, egypt; 3 mansoura urology and nephrology centre, mansoura university, mansoura, egypt; 4 urology department, 6th of october university, cairo, egypt; 5 obstetrics and gynecology department, cairo university, cairo, egypt. doi: 10.4081/aiua.2023.11580 summary archivio italiano di urologia e andrologia 2023; 95(3):11580 k. mohamed almekaty, a. mostafa elsharkawy, m. hasan zahran, et al. 2 infertile men (either primary or secondary infertility) initially assessed or referred as unilateral or bilateral varicocele patients were enrolled. patients with history of orchidectomy, cryptorchidism, azoospermia or concomitant female partner infertility were excluded. all patients were subjected to physical examination including local scrotal examination to evaluate the degree and laterality of varicocele and semen analysis before the operation. a repeat scrotal doppler ultrasonography was done for all patients to confirm diagnosis of varicocele and reassess bilaterality of the disease. this repeat cdus was performed by the same expert uroradiologist who was blinded to the findings of physical examination. all patients underwent microsurgical subinguinal varicocelectomy by expert uroandrologists after taking a written informed consent with explanation of the potential complications of the procedure. patients who were diagnosed with bilateral varicoceles underwent bilateral subinguinal ligation straight away. those who were referred with unilateral varicocele had a repeat cdus for reassessment of missed concomitant contralateral varicocele. their palpable sides were operated on first; then the contralateral side was explored as follows; the spermatic cord was delivered and opened at the level of the external inguinal ring. then, the maximal dilated internal spermatic vein diameter was measured using a micrometer fixed to the surgical microscope. also, the veins of the contralateral side were examined for reflux using an intraoperative doppler device (vti intraoperative doppler system 20 mhz). the sound of venous reflux confirmed varicocele diagnosis. patients were followed up for at least 6 months after surgery to evaluate any complications and assess improvement in semen parameters. the primary outcome measure was to assess disease bilaterality and the secondary outcome measure was to report on improvement in semen 3 and 6 months post varicocelectomy and normal pregnancy rate after 1 year. female partners were evaluated by full history taking and thorough examination to exclude female factor infertility. good ovulation was suggested if the female showed menstrual regularity, premenstrual syndrome (pms), mid cyclic pain or discharge, confirmed by normal follicle-stimulating hormone (fsh), luteinizing hormone (lh), thyroid stimulating hormone (tsh), prolactin, estradiol (e2), and anti-mullerian hormone (amh). transvaginal ultrasound was done to exclude any uterine pathology or mullerian anomalies that may interfere with the occurrence of pregnancy. furthermore, folliculometry was done and the presence of good ovulation was declared and confirmed by mid-luteal phase progesterone. after varicocelectomy, the female partners were followed up for 1 year to assess normal pregnancy rate. statistical analysis statistical analysis was performed using spss 16.0 for windows software (spss, inc., chicago, il). chi-square test is used to determine the significant association between the observed frequencies and the expected frequencies. wilcoxon sign test and simple student t-test were used for continuous variables. the difference was considered statistically significant at < 0.05. results in this study 350 patients were initially enrolled and after exclusion, a total of 329 cases completed the study. figure 1 shows the flowchart of cases. a hundred cases (30.4%) were initially referred as unilateral and 229 (69.6%) as bilateral varicoceles. table 1 shows the baseline data of the study population. bilaterality of the disease was reassessed preoperatively by figure 1. flowchart of study population. archivio italiano di urologia e andrologia 2023; 95(3):11580 3 bilaterality of varicocele: examining its disease status a repeat cdus and intraoperatively by measuring the maximal diameter of the largest vein and detecting venous reflux using operative doppler as mentioned in the methodology section. after reassessment of the study population, bilaterality of varicocele was found to be as high as 98.5% (324/329). this is statistically significantly higher than initial cdus (p < 0.001). repeat cdus showed bilaterality in 95 out of the 100 cases (95%) and all had grade 2 varicoceles with median (range, iqr) diameter of 3.2 (2.5-4.1, 2.8-3.5) mm. the cdus diameter strongly correlated with the intraoperative measured diameter 3.4 (1.5-4, 3-3.6) mm, (r = 0.9, p < 0.001). moreover, seminal parameters showed significant improvement at 3 and 6 months post varicocelectomy as shown in table 2. normal pregnancy after 1 year of surgery occurred in 118 cases (35.9%). discussion the exact relationship between bilateral varicocele and infertility is not fully understood, but since tulloch noticed the positive effect of varicocelectomy on improving male fertility, many studies have been conducted to investigate this. interestingly, the degree of varicocele seems to be unrelated to the degree of testicular function affection or even the improvement after varicocelectomy as even a subclinical varicocele can result in male subfertility (11). the only study that tried to clearly address whether or not varicocele in infertile males is a disease of bilaterality is that of gat et al. (12) they used venography and contact thermography to detect “clinically missed” varicoceles. using these 2 modalities, they detected varicocele in 255 out of 286 infertile males (89.1%); bilaterality was confirmed in 206 (80.8%). in the current study, reassessment of varicocele was done by repeat cdus by an expert uroradiologist and intraoperatively by measuring the diameter of the largest vein at the level of the external inguinal ring and by detecting venous reflux using intraoperative doppler device. out of a total of 329 patients, 229 were referred as bilateral (69.6%) but rate of bilaterality reached 98.5% (324 cases) after the “second look” evaluation. most of the studies in the literature reporting the prevalence of varicocele in infertile men rely on physical examination and scrotal ultrasound. gonda et al. (13) reported 95% sensitivity with a 2-mm cutoff for vein diameters for diagnosis of varicocele. both are subjective, operator dependent with significant interpersonal variability. in the current study, 30.4% of patients were referred as unilateral varicocele cases and after reassessment bilaterality was proven in 98.5% (28.9% was misdiagnosed). reports in the literature looking at the prevalence of varicocele bilaterality are scarce. in 1986, mcclure and hricak used cdus to detect subclinical varicocele and detected bilaterality in 70% of their study population (14). chatel et al., gonzalez et al., cockett et al. and gat y et al. detected bilaterality in 60%, 61%, 57% and 89.1% respectively (15-17, 12). the higher prevalence of the disease bilaterality in the gat et al. and the current study as compared to others can be attributed to the use of table 1. patients’ demographics. total number referred as bilateral varicocele referred as unilateral varicocele p-value (no. = 329) (no. = 229) (no. = 100; 4 right and 96 left) age (years) mean ± sd 29.1 ± 3.7 29.1 ± 3.6 29.3 ± 4.5 0.8 age of the partner (years) mean ± sd 27.1 ± 4.1 26.7 ± 3.6 28.6 ± 5.7 0.7 duration of infertility (years) median (iqr) 3.5 (2-5) 3.5 (2-5) 3.5 (2-4) 0.9 right testicular size (ml) mean ± sd 14.9 ± 2.1 14.9 ± 1.9 15.1 ± 3.2 0.4 left testicular size (ml) mean ± sd 14 ± 1.5 14 ± 1.4 14.3 ± 1.6 0.1 sperm density (million/ml) mean ± sd 4.2 ± 1.5 4.2 ± 1.5 4.1 ± 1.2 0.5 sperm motility (a+b) mean ± sd 18.2 ± 5.7 18.3 ± 5.8 17.5 ± 4.6 0.3 grade of varicoceles g1:109 g1: 25 g2:211 g2: 60 g3:138 g3: 15 table 2. outcomes of varicocelectomy. baseline 3 months after surgery 6 months after surgery p1 p2 sperm density (million/ml) median (range, iqr) 5 (0.15-13, 4-5) 7.5 (0-80, 7-10) 11 (0-60, 10-13) < 0.001 < 0.001 sperm motility (a+b) median (range, iqr) 20 (0-60, 15-20) 25 (0-70, 20-30) 40 (0-60, 35-45) < 0.001 < 0.001 p1: comparison between baseline and 3 months. p2: comparison between baseline and 6 months. archivio italiano di urologia e andrologia 2023; 95(3):11580 k. mohamed almekaty, a. mostafa elsharkawy, m. hasan zahran, et al. 4 objective methods of assessment; venography in the former and intraoperative doppler and measurement of the diameter of largest vein in the latter and to the improvement in the accuracy of the modern cdus devices available nowadays. in the current study, both radiologists and surgeons have extensive experience in this field; so repeat cdus strongly correlated to intraoperative assessment of the disease; (r = 0.9, p < 0.001; pearson correlation coefficient). this means that the experience of the ultrasonographer and the surgeon should play a vital role to avoid misdiagnosed varicoceles. the exact mechanism by which varicocele might lead to infertility is still unclear. the pathogenesis is thought to be multifactorial and complex, with several factors mostly acting together. in this complex etiopathogenesis, oxidative stress seems to have a crucial role, among others. oxidative stress results from increased hydrostatic pressure in the pampiniform plexus of veins which leads to stagnation of toxic metabolites, hypoxia together with increased temperature (18). one of the theories that can explain varicocele bilaterality is that there are venous anastomotic channels between the right and left gonadal veins that were detected in venography studies. another theory is the reflux theory which supposes that damage or absence of valves in the gonadal veins is the etiology behind varicocele development which most probably is a bilateral disease (8). this explains why a unilateral palpable varicocele can affect the global testicular function (right and left) and why unilateral varicocelectomy may fail to improve sperm parameters in some cases. the current study supports these theories as varicocele bilaterality was found in 98.5% of patients. this finding shows that varicocele bilaterality is clearly underestimated in practice and in the literature. our technique of artery preservation varicocelectomy using intraoperative doppler was previously described. preserving testicular arteries during varicocelectomy provide significantly better sperm improvement especially in patients with severe oligozoospermia (19). regarding the indication of varicocelectomy, current evidence suggests a positive effect of varicocelectomy on sperm parameters and pregnancy rates only in couples with male factor infertility with a clinically palpable varicocele and abnormal semen parameters (18). randomized controlled trials looking at the effect of varicocelectomy on sperm parameters and pregnancy outcomes are lacking. consequently, available metaanalyses are negatively affected by wide heterogeneity of available studies. however, the randomized controlled trial by abdel-meguid et al. supports the findings of metaanalyses which suggest a beneficial effect of varicocelectomy on sperm parameters. abdel-meguid et al. in 2011 randomized the patients into subinguinal varicocelectomy (treatment group) and observation (control group). after 1 year of follow up all sperm parameters significantly improved in the treatment group (32.2 ± 10.6 vs 18.1 ± 5.8× 106 sperm/ml, 41.0 ± 10 vs 25.3 ± 12.8%, and 39.0 ± 4.5 vs 31.2 ± 4.1% for sperm concentration, motility and morphology, respectively); while no significant difference found in the control group (20). in the current study sperm density and motility significantly improved after 3 and 6 months and 35.9% of the couples achieved normal pregnancy after 1 year from varicocelectomy (table 2). the points of strength of this study among others is the good sample size, prospective design and using objective tools for varicocele reassessment, while the limitation is the lack of sperm morphology data. to the best of our knowledge, this is one of a very few reports addressing possible underestimation of varicocele bilaterality which must be taken into account during management of male factor infertility. conclusions varicocele bilaterality in infertile patients seems to be underestimated in the literature and in clinical practice. in our experience, varicocele bilaterality exists in 98.5% of infertile men. thorough assessment of varicocele bilaterality in infertile men by expert uroradiologist and andrologists is of utmost importance to avoid disease recurrence and optimize treatment outcomes. references 1. sigman m, jarow jp. male infertility. in: walsh pc, retik ab, vaughn ed, wein aj (eds.), campbell’s urology 8th ed. philadelphia: saunders 2002; 1475-1532. 2. yamaguchi m, sakatoku j, takihara h. the application of intrascrotal deep body temperature measurement for the non-invasive diagnosis of varicoceles. fertil steril. 1989; 52:295-301. 3. masson p, brannigan re. the varicocele. urol clin north am. 2014; 41:129-144. 4. sabanegh e, agarwal a. male infertility, in campbell-walsh urology, a. j. wein, l. r. kavoussi, a. c. novick, and a. w. partin, eds., pp. 636-637, saunders, philadelphia, pa, usa, 10th edition, 2012. 5. tulloch ws. a consideration of sterility factors in the light of subsequent pregnancies. edinburgh med j. 1952; 59:29-34. 6. fujisawa m, ishikawa t, takenaka a. the efficacy of bilateral varicocelectomy in patients with palpable bilateral varicoceles: comparative study with unilateral varicocele. urol res. 2003; 31:407-9. 7. libman j, jarvi k, lo k, zini a. beneficial effect of microsurgical varicocelectomy is superior for men with bilateral versus unilateral repair. j urol. 2006; 176:2602-5. 8. gat y, bachar gn, zukerman z, et al. varicocele: a bilateral disease. fertil steril. 2004; 81:424-9. 9. trum j, gubler f, laan r, van der veen f. the value of palpation, varicoscreen contact thermography and colour doppler ultrasound in the diagnosis of varicocele. hum. rep. 1996; 11:1232-1235. 10. hussein af. the role of color doppler ultrasound in prediction of the outcome of microsurgical subinguinal varicocelectomy. j urol. 2006; 176:2141-2145. 11. paduch d, niedzielski j. repair versus observation in adolescent varicocele: a prospective study. j urol. 1997; 158:1128-32. 12. gat y, bachar gn, zukerman z, et al. varicocele: a bilateral disease. fertil steril. 2004; 81:424-9. 13. gonda rl jr, karo jj, forte ra, o'donnell kt. diagnosis of subclinical varicocele in infertility. ajr am j roentgenol. 1987; 148:7175. archivio italiano di urologia e andrologia 2023; 95(3):11580 5 bilaterality of varicocele: examining its disease status 14. mcclure rd, hricak h. scrotal ultrasound of infertile man: detection of subclinical unilateral and bilateral varicoceles. j urol. 1986; 135:711-15. 15. chatel a, bigot jm, helenon c, et al. interet de la phlebographie spermatique dans le diagnostic des sterilites d'origine circulatoire (varicocele). comparaison avec les donnees cliniques, thermographiques et anatomiques. ann. rad. 1978, 21:565. 16. gonzalez r, reddy p, kaye kw, narayan p. comparison of doppler examination and retrograde spermatic venography in the diagnosis of varicocele. fertil steril. 1983; 40:96-9. 17. cockett atk, harrison rm, comhaire f, dubin l. the varicocele and its effect on fertility. contemp surg 1984; 24:111-14. 18. jensen cfs, østergren p, dupree jm, et al. varicocele and male infertility. nat rev urol. 2017; 14:523-533. 19. almekaty k, zahran mh, zoeir a, et al. the role of artery-preserving varicocelectomy in subfertile men with severe oligozoospermia: a randomized controlled study. andrology. 2019; 7:193-198. 20. abdel-meguid ta, al-sayyad a, tayib a, farsi hm. does varicocele repair improve male infertility? an evidence-based perspective from a randomized, controlled trial. eur urol. 2011; 59:455-461. correspondence khaled mohamed almekaty, md dr.khaledhafez@med.tanta.edu.eg maged mostafa ragab, md mmregy@yahoo.com khaled abdelaziz salem, md khsalemmd@gmail.com ahmed fayez ghaith, md (corresponding author) dr_ahmedfayez@yahoo.com urology department, tanta university, tanta, egypt el-gharbia govenorate, tanta. el-gash st. medical campus, the faculty of medicine ahmed mostafa elsharkawy, md ahmed.elsharkawy84@gmail.com radiology department, tanta university, tanta, egypt mohamed hasan zahran, md ahmed.elsharkawy84@gmail.com mansoura urology and nephrology centre, mansoura university, mansoura, egypt ayman sayed rashed, md aymanrashed@msn.com urology department, 6th of october university, cairo, egypt mahmoud mohamed soliman, md dr_mahmoudsoliman@yahoo.com obstetrics and gynecology department, cairo university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 211archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. nentially in recent years and become a more popular tool to support health behavior and to access health information for patients (11). in the last years numerous mobile health applications (mha) have been developed, including in urological and andrological fields, aimed to simplify and assist the lives of patients (12, 13). nowadays more than thousands mha are available for mobile devices, but assessment of their quality is still a problem (14). instruments for the assessment of the quality and content of mha are highly needed, and one of the most used tools is mobile application rating scale (mars). mars has been used in the evaluation of a variety of health apps including depression, urinary incontinence, menstrual cycle and other (16, 17). several apps have been developed for assessing and management of ed. these represent an important tool for patients. however, despite their potential utility, much effort must be made regarding the quality, the validation, and the adherence to guidelines. to the best of our knowledge, there are no studies reporting the quality of apps for ed and their adherence to guidelines. the aim of this study is to give an overview of apps for ed, currently available on the market to evaluate the quality and the adherence to guidelines. material and methods search strategy on 17 january 2022 we conducted a search in google play store for android phones and apple app store for iphones with the keywords ‘erectile dysfunction’ and ‘impotence’ using the search tab. we used a wide array of keywords because google play store and apple app store search strategy is based on finding keywords in the title, app descriptions and tags. other searches of information provided in books or other formats were excluded. two authors (gmf, lc) screened separately in app store and google play store apps during the search by reading the title and description in the app store. a third author (ma) introduction: nowadays numerous mobile health applications (mha) have been developed to assist and simplify the life of patients affected by erectile dysfunction (ed), however the scientific quality and the adherence to guidelines are not yet addressed and solved. materials and methods: on 17 january 2022, we conducted a search in the apple app store and google play store.we reviewed all mobile apps from itunes app store and google play store for ed and evaluated different aspects as well as their usage in screening, prevention, management, and their adherence to eau guidelines. results: a total of 18 apps were reviewed. all apps are geared towards the patient and provide information about diagnoses and treatment of ed. conclusions: mha represent an integral part of patients’ lives, and apps providing services for male sexual dysfunction are constantly increasing. despite this the overall quality is still low. although many of these devices are useful in ed, the problems of scientific validation, content, and quality are not yet solved. further work is needed to improve the quality of apps and developing new accessible, user designed, and high-quality apps. key words: app; e-health; mobile phone; erectile dysfunction; mars. submitted 17 may 2022; accepted 20 may 2022 introduction erectile dysfunction (ed) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance with high impact on the quality of life (qol) (1). the prevalence ranges from 3% to 76.5%, and increases with age, affecting over 50% of men aged 40-70 years, with a negative effect on qol of affected men and their sexual partners (2). ed is generally related to cardiovascular disease, diabetes mellitus, hyperlipidemia, and hypertension, among other disorders (3-9). many options are currently available for ed treatment: lifestyle changes, medical and surgical treatments or their combination (10). mobile applications (apps) have grown expoerectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction luigi napolitano 1, giovanni maria fusco 1, luigi cirillo 1, marco abate 1, claudia mirone 2, biagio barone 1, giuseppe celentano 1, roberto la rocca 1, vincenzo mirone 1, massimiliano creta 1, marco capece 1 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 2 multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples. doi: 10.4081/aiua.2022.2.211 summary archivio italiano di urologia e andrologia 2022; 94, 2 l. napolitano, g.m. fusco, l. cirillo, et al. 212 resolved any discrepancies. at the beginning all apps were reported in excel form and after they were screened according to the exclusion criteria. a total of 493 apps were found by our search, 467 of them were from the google play store (android) and 26 of them were from the apple app store (ios). of the total, 409 apps were screened after removing duplicates and paid apps. of the total screened apps, 343 apps met excluding criteria and were removed. in total, 66 apps were eligible for the final evaluation and were downloaded. finally, 18 apps were included in the final review after removing 48 apps that met exclusion criteria after download. a flow diagram based on the prisma statement (figure 1) was included for the selected apps. table 1 shows the analyzed apps characteristics. the 18 erectile dysfunction apps were evaluated by four members of the research team on a 5-point likert scale based on mars characteristics. app inclusion criteria we included in the analysis all apps regarding ed providing a service to patients. the apps are geared to patients, in english, and free to download. apps not specifically focused on ed, apps not allowing access to all users and those not available in english were excluded. then all reviewers downloaded and installed the apps on their personal mobile device. they interacted for fifteen minutes with each app to explore its features before completing the mars and evaluated their adherence to eau guidelines. to assess apps, they were downloaded to either an android (huawei p20 lite) or iphone (iphone 13 pro). if apps were available in both app stores, the iphone version was assessed. table 1. app characteristics. name of application android/apple/both download producer category focus e.d. therapy meditation apple n.a. ninja chemist llc health & wellness treatment iief-5 erectile dysfunction apple n.a. putu angga risky raharja medicine test idi erectile dysfunction apple n.a. back2medical medicine diagnosis, informative, test myed impotence iief-5 test apple n.a. prognoix pte ltd medicine test smart saa apple n.a. pergali ltd health & wellness informative, test morning glory tracker apple n.a. roman health medical llc health & wellness diary of morning erection men sexual health android > 10000 gangareboy health & fitness informative erectile dysfunction self-test android 1000 r l fellner health & fitness informative, test erectile dysfunction cure yoga android 10000 dr. zio health & fitness treatment erectile dysfunction treatment android 1000 maftal almafary health & fitness information, treatment erectile dysfunction treatment android 5000 revolxa inc. medicine information, risk factors, treatment erectile dysfunction remedy 2021 android 100 maftal almafary instruction information, risk factors, treatment erectile dysfunction remedies android 5000 statesapps health & fitness treatment home remedies android 100000 cutepad studio medicine treatment erectile dysfunction questionnaire android 1000 funny psychology entertainment test erection test android 1000 dr. kareem zaher health & fitness test iief-5 for erectile dysfunction android 500 imedical apps health & fitness test herbal cure android 100000 novaradix medicine treatment figure 1. prisma. 213archivio italiano di urologia e andrologia 2022; 94, 2 erectile dysfunction and mobile phone applications data extraction we conducted a data extraction using a predefined excel form. on 17 january 2022 reviewers discussed methods of recording data to ensure standardized modality. the following data were extracted from mha: title, language, customers, costs, source (google play store or apple app store), field/disease, rating/feedback from the users, service provided. assessment of app quality apps’ quality was assessed using the mars, which showed a very acceptable reliability and validity (12). mars is a multidimensional instrument of 23 structured questions evaluating engagement, functionality, esthetics, information, app subjective quality, and app-specific (17). the scale is composed of 19 items grouped in four categories of perceived app quality: engagement (five items assessing the extent to which the app engages target users); functionality (four items assessing how easy the app is to navigate and the overall app performance); aesthetics (three items assessing visual appearance and style); information (seven items assessing accuracy, quality, and quantity of the app), and 1 category of subjective quality. each category score is the mean of the different items, rated on a 5-point likert-type scale (from 1 = inadequate to 5 = excellent) within its category. the overall quality score was calculated by taking the mean of the 4 app quality category scores, with a final score ranging from 0 to 5. a score of between 1 and 2/5 is considered as ‘poor’ quality, while 3/5 is ‘acceptable’ and at least 4/5 is ‘good’ quality. if scores differed by a single point, the mean of the two ratings was used, with any scores differing by more than a single point being resolved through discussion and consensus agreement between reviewers. mean scores were calculated for each domain and an overall quality score was calculated based on the aggregated mean values for each of the four domains. the mean score for subjective quality was also calculated (15). assessment of app adherence to eau guidelines we create an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) based on section 5 of the eau guidelines of ed. two independent reviewers coded separately apps for their adherence to eau guidelines. both raters were resident in urology with experience in male sexual dysfunction. according to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. a score of ‘‘0’’ indicated no adherence to guidelines. a score of ‘‘1’’ indicated a weak adherence. a score of ‘‘2’’ indicated a partial or moderate adherence. a score of ‘‘3’’ indicated strong adherence. where coding scores differed by 1 point, the average of the two ratings was taken. if there was a greater than 1-point discrepancy, a third author (a full professor) reviewed apps and resolved the discrepancy. the possible score on the checklist ranged from 0 to 15 for each app. to facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (11-15) (18, 19). results out of the 18 apps included in the final analysis, 6 from the apple store and 12 from the google play store, had limited functionality: 6 of them offered iief-5 tests, the other 12 ones offered information about symptoms, diagnosis and treatment, including tools for nutraceutical treatments. in particular, 8 apps (44.4%) included information about treatment options; 1 of them (5.6%) specifically gave information about diagnosis; 7 (38.9%) were overall informative apps, some of them mentioning risk factors. data about downloads were available for 12 apps out of the 18 reviewed. downloads were not available for mha presented in the apple app store. the most downloaded apps were home remedies (android) and herbal cure (android), of which 100000 downloads were reported. all the apps were planned to be used by patients. no information about mha rating was available. mars scale scores are represented in table 2. engagement the score in this section was based on a 5-point likert scale in 5 subscales (entertainment, interest, customization, interactivity and targettable 2. mars scale scores. name of application engagement functionality aesthetics information mean app subjective quality (section a) (section b) (section c) (section d) (a+b+c+d) (section e) ed test risk calculator of erectile dysfunction 2.6 2.75 3 1.67 2.5 1.5 iief-5 erectile dysfunction 1 2.75 1.67 2.71 2.03 1.75 idi erectile dysfunction 4 3.75 3 2.71 3.36 2.75 myed impotence iief-5 test 2 3.5 2.67 2.8 2.74 2.25 smart saa 3.6 3.75 3 3.6 3.49 2.75 morning glory tracker 1 1.5 1 1.4 1.22 1.25 men sexual health 3 4 3 2 3 2 erectile dysfunction self-test 2 3,75 3,66 3 3,10 2,75 erectile dysfunction cure yoga 2 3,50 3,33 2,86 2,92 2,75 erectile dysfunction treatment 2 3,5 3,33 2,43 2,82 2 erectile dysfunction treatment 3 3,75 3,33 3 3,27 2,25 erectile dysfunction remedy 2021 2 3,5 3,33 2,43 2,82 2 erectile dysfunction remedies 1,2 4,25 1 1,43 1,97 1,25 home remedies 3 3,5 2,66 1,85 2,75 1,75 erectile dysfunction questionnaire 1,4 2,5 2 1,14 1,76 1,25 erection test 1,2 2,5 2,66 1,43 1,95 1,75 iief-5 for erectile dysfunction 1,4 2,5 2 1,43 1,84 1,25 herbal cure 1,2 3,5 1 1,85 2,14 1,75 archivio italiano di urologia e andrologia 2022; 94, 2 l. napolitano, g.m. fusco, l. cirillo, et al. 214 group). the mean score was 2.09. scores ranged from 1 to 4 out of 5. the “idi erectile dysfunction” app (ios) produced by back2medical received the highest score for the engagement. this app contains tips for ed self-diagnosis and management, information and a follow-up form that helps the patient to keep track of his eventual improvements. functionality the score of the functionality section was based on a 5point likert scale in 4 subscales (performance, ease of use, navigation and gestural design) and the mean score was 3.26. scores ranged from 1.5 to 4.25. the “erectile dysfunction remedies” app (android) produced by statesapps achieved the maximum score. this app contains home remedies for ed. aesthetics the aesthetics section was formed by a 5-point likert scale in 3 subscales (layout, graphics, visual appeal) and the average score was 2.54. scores ranged from 1 to 3.66 out of 5. the “erectile dysfunction self-test” app (android) developed by rl fellner and designed to self-screen ed and to give tips and info about ed-risk and prostate enlargement, reached the maximum aesthetics score. information the information section was formed by a 5-point likert scale in 7 subscales and the mean score was 2.21. score ranged from 1.14 to 3.6. the smart saa app (ios) developed by pergali ltd achieved the highest score. this app offers the iief-5 test and other questionnaires, informative tips and advice to manage ed and other sexual conditions. it is produced by the sexual advice association, a charitable organization created to help improve the sexual health and wellbeing of men and women. subjective quality the subjective quality section consisted of 4 items. the mean score was 1.94, with scores ranging from 1.25 to 2.75. the “idi erectile dysfunction”, “smart saa”, “erectile dysfunction self-test”, “erectile dysfunction cure yoga” reached the maximum score. eau adherence checklist we evaluated the eau guidelines adherence in 13 apps. five apps were not analyzed because they represent a iief-5 test, a validated diagnostic tool consisting of five selected items to clearly discriminate between subjects with and without ed. eau adherence scores are represented in table 3. the ed definition was reported in 10 (76.9%) apps, the score ranged from 0 to 3 (mean 1.8); physiopathology was reported in 9 (69.2%) apps, the score ranged from 0 to 2 (mean 1.1); risk factors were reported in 10 (76.9%) apps, the score ranged from 0 to 3 (mean 1.7); diagnosis was reported in 8 (61.5%), the score range from 0 to 2 (mean 0.61); treatment was reported in 11 (84.6%), the score ranged from 0 to 3 (mean 1.2). the overall score ranged from 0 to 12 (mean 4.92). the highest score was reported by “erectile dysfunction treatment” (android) produced by revolxa inc. that mainly contains information about erectile dysfunction risk factors, diagnosis and treatment. the maximum definition score of 3 was only reached by three apps out of thirteen, while none of the apps achieved 3 in physiopathology and diagnosis. finally, only three apps and two apps out of the thirteen evaluated, scored 3 respectively in risk factors and treatment. discussion nowadays many studies focus on the evaluation of medical apps in order to understand whether the developers use a validated scientific approach to their creation (2022). although a standardized evaluation method does not exist, a reasonable way to qualify those apps is to combine different scores. this is the reason why in the present study we decided to pursue such an approach for the evaluation of erectile dysfunction apps. to the best of our knowledge this is the first study reviewing the currently available mha for ed, reporting either an assessment of quality, and the adherence to eau guidelines. the most important findings in our study is that at the present time mha for ed have poor quality and highlight low adherence to eau guidelines. first of all we evaluated the quality of the apps using the mars. the mean scores of the four categories were dramatically low. in particular the “engagement” and the “information” scores were lowest 2.09 and 2.21 respectively. engagement assessed the design and interest of the app and software functionality. information assessed accuracy, quality, credibility of the source and evidence basis of information presented in the apps. on the other hand functionality mean score was table 3. eau adherence checklist scores. name of application definition (0-3) physiopathology (0-3) risk factors (0-3) diagnosis (0-3) treatment (0-3) idi erectile dysfunction 3 1 2 0 3 myed impotence iief-5 test 1 n.a. 2 1 n.a. smart saa 2 0 1 0 1 morning glory tracker 0 0 0 0 0 men sexual health 2 1 1 0 1 erectile dysfunction self-test 2 2 2 2 n.a. erectile dysfunction cure yoga n.a. n.a. n.a. n.a. 1 erectile dysfunction treatment 3 2 3 n.a. 1 erectile dysfunction treatment 2 2 3 2 3 erectile dysfunction remedy 2021 3 2 3 n.a. 1 erectile dysfunction remedies 0 0 0 0 1 home remedies n.a. n.a. n.a. n.a. 1 herbal cure n.a n.a. n.a. n.a. 1 215archivio italiano di urologia e andrologia 2022; 94, 2 erectile dysfunction and mobile phone applications the best performance among all categories (3.26). functionality assessed how easy the app and the overall app performance. the same results were reported by o’ connor et al. which evaluated the quality of mobile apps supporting lifestyle changes following a transitory ischemic attack (tia) or ‘minor’ stroke. this suggested that mha were designed and developed in particular for their usability and not to assist, inform and educate patients. mha were developed only for commercial use, without supporting of healthcare (23). this is due to a lack of scientific validation of mha, indicating the necessity to develop high-quality apps and to improve the existing ones. giunti et al. showed in their paper an evident absence of health professionals in the development of healthcare apps. apps are mostly developed by nonhealth professionals who are creative and skilled in design but lack scientific knowledge (24). our study demonstrates that mha for ed lacked quality and most of all did not report to the patients what eau guidelines suggest. our results confirm and corroborate findings of other studies that analyze mha in different clinical and surgical tools. there is a wide range of products not developed in collaboration with healthcare professionals or according to guidelines. to support this idea, each app underwent a eau guidelines adherence test in order to assess the scientificity of those. interestingly the mean score was 4.92 out of 12. only four (30.7%) apps had medium adherence and only one app (7.69%) high adherence respectively. the highest adherence was reported in ed definition although definition has been adequately reported only in three apps. this is a point highlighting the lack of scientific validation of these products. in fact ed definition is reported in several scientific papers and widely available on the internet. “erectile dysfunction treatment” (android) produced by revolxa inc. is the app with the highest guideline adherence. this is not surprising because revolxa inc. produces many mha in different medical fields. regarding treatment our data were in line with the results of vagger et al. in a study about urinary tract infections apps. as shown mha about treatment of urinary tract infections were deficient in these information. in our study the overall treatment median score according to eau guidelines was 1.2 and only two apps reported a score of 3 points. nowadays treatment regimens available for ed include psychotherapy, sex therapy, oral pharmacological agents, androgen replacement therapy, intraurethral therapy, intracavernosal injections, vacuum devices, and surgery. herbal supplements are widely used, but often lack rigorous scientific evidence of their efficacy. four apps suggest use of natural products in ed treatments but many of these are non common and showed poor scientific evidence (garlic, carrots, promenade juice), while only ginseng reported several scientific evidence. balasubramanian et al. in a recent meta-analysis reported the most popular erectile dysfunction supplements available on online marketplaces. ginseng is the most popular followed by l-arginine, and tongkat ali. none of the supplements reported by apps analyzed are present in this list. furthermore, ginseng and l-arginie as shown by borrelli et al. are the only two supplements as an effective efficacy in ed treatment (25). the search strategy also reported several apps suggesting kegel exercise in ed treatments. published studies reported that these exercises to improve pelvic floor muscle could be useful as first line treatment of ed. contractions of the ischiocavernosus and bulbocavernosus muscles (two muscles which are part of pelvic floor) seem to increase the intracavernous pressure, influencing penile rigidity, and compresses the deep dorsal vein of the penis preventing the outflow of blood from penis (26). although in literature many studies have been published, currently guidelines do not report pelvic floor exercises as treatment in ed management. another important point is that despite the high numbers of downloads any mha has a rating. many factors influenced the download of mha, and no studies have been published about the mechanism that generated the rating (27). strengths of our study include: the first study which examines the content, the quality, and the adherence to eau guidelines; the rigorous approach in search strategy, screening, and analysis; the test among the reviewers regarding mars scale use before initiation of the study. the limitations are related to: the reproducibility by different users due to the working method of app store and google play store (the visibility of apps depends on the device and on the country where the search is performed); the exclusion of paid applications; guidelines are developed for healthcare and not for patients; the high proliferation of mha. our study shows that there are a multitude of inaccurate apps resulting from a search in a store even when using appropriate terminology, so patients searching for health information must choose and discern the quality on their own. an ideal mha must be based on scientific evidence, be simple and intuitive to use. mha should provide correct and simple information abouts disease, make the individual confident to change behavior, inform patients about their progress, and provide adequate information about treatments. conclusions the use of mha for ed is a new and unexplored topic, with much potential for future investigation. mha are now an integral part of patients’ lives, from year to year, the number of apps that provide services for male sexual dysfunction is constantly increasing, but the overall quality is still low. although many of these devices are useful in ed, the problems of scientific validation, content, and quality are not yet solved. further work is needed to improve the quality of apps and developing new accessible, user designed, and high-quality apps. references 1. deng w, bivalacqua tj, hellstrom wjg, kadowitz pj. gene and stem cell therapy for erectile dysfunction. int j impot res. 2005; 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32:2529-36. 23. o’connor sr, kee f, thompson dr, et al. a review of the quality and content of mobile apps to support lifestyle modifications following a transient ischaemic attack or «minor» stroke. digit health. 2021; 7:20552076211065270. 24. giunti g, giunta dh, guisado-fernandez e, et al. a biopsy of breast cancer mobile applications: state of the practice review. int j med inf. 2018; 110:1-9. 25. balasubramanian a, thirumavalavan n, srivatsav a, et al. an analysis of popular online erectile dysfunction supplements. j sex med. 2019; 16:843-52. 26. dorey g, speakman m, feneley r, et al. randomised controlled trial of pelvic floor muscle exercises and manometric biofeedback for erectile dysfunction. br j gen pract j r coll gen pract. 2004; 54:819-25. 27. biswas m, tania mh, kaiser ms, et al. accu3rate: a mobile health application rating scale based on user reviews. plos one. 2021; 16:e0258050. correspondence luigi napolitano, md luiginap89@gmail.com giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md (corresponding author) cirilloluigi22@gmail.com marco abate, md marcoabate5@gmail.com biagio barone, md biagio.barone@unina.it giuseppe celentano, md dr.giuseppecelentano@gmail.com roberto la rocca, md robertolarocca87@gmail.com vincenzo mirone, md mirone@unina.it massimiliano creta, md max.creta@gmail.com marco capece, md drmarcocapece@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii" via sergio pansini n 5, naples (italy) claudia mirone, md claudiamirone@outlook.it multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples (italy) stesura seveso archivio italiano di urologia e andrologia 2019; 91, 2130 original paper klinefelter’s syndrome and taurodontism emilia giambersio 1, vincenzo barile 2, antonio marcello giambersio 1 1 “ambulatorio klinefelter” asp potenza, italy; 2 uoc of radiology “poliambulatorio madre teresa” asp potenza, italy. objective: taurodontism is a dental anomaly characterized by an enlarged pulp chamber and apycal displacement of the pulpar floor. the prevalence of taurodontism in normal population is controversial. it has been reported that taurodontism is frequently observed in klinefelter’s patients. the purpose of this study was to assess the prevalence of taurodontism in a group of italian klinefelter’s patients and in a randomly selected male population of italy and to compare the results with published data. materials and methods: digital panoramic radiographs of 16 klinefelter’s patients and of 100 normal males were retrospectively studied in order to investigate the prevalence of taurodontism in these groups of patients. results: taurodont teeth were observed in 2 of the 16 klinefelter’s patients (12.5%) and in 2 of 100 normal males (2.0%). conclusions: our results confirm the higher prevalence of taurodontism in klinefelter’s patients compared to the normal population (12.5% vs. 2.0%). due to the wide discrepancy of incidence of taurodontism reported in literature (0.04%-48.0% in normal population; 12.5%-88.0% in klinefelter’s patients), we conclude that it is not possible to state which is the prevalence of taurodontism in a normal population nor among klinefelter’s patients. key words: klinefelter’s syndrome; taurodontism; 47,xxy; dental anomaly; digital panoramic radiographs. submitted 30 january 2019; accepted 11 march 2019 summary no conflict of interest declared. patients and methods we retrospectively studied the digital panoramic radiographs of 16 klinefelter’s patients who attended the “ambulatorio klinefelter” in italy in order to investigate the prevalence of taurodontism in this group of patients. orthopantomograms of 100 randomly selected patients of the same male italian population were examined as a control group. dental radiographs were analyzed for the presence of taurodontic molars using the categorization hypo-, meso-, and hypertaurodont based on the degree of apical displacement of the pulp chamber floor. a tooth was considered as taurodont when there was an enlarged pulp chamber that was apically displaced and a lack of constriction at the cementoenamel junction (5). results of the 16 klinefelter’s patients, 2 were found to exhibit taurodontic teeth (1 hypo and 1 meso-taurodont) (12.5%) (figure 1). in the group of 100 normal patients we found 2 patients with taurodontic teeth (2 meso-taurodont) (2.0%). discussion clinically, a taurodont tooth appears as normal: its distinguishing features cannot be recognized clinically, therefore the diagnosis is made from radiographs. several criteria have been proposed to define a taurodont tooth, each of them having pros and cons (1, 5-8). moreover, most authors do not provide an objective analysis of cases presented, preferring a subjective diagnosis (1). it has been stated that the incidence of taurodontism is very low in normal population (8-10), others claim that taurodontism is not a rare trait in the modern man (5). some authors report that taurodontism is the most common dental anomaly observed (11), others even consider taurodontism a simple variation of normal teeth (12). the prevalence of taurodontism has been reported to show a wide range of discrepancy in different populations. it was 0.04% in an italian population (2), 1.4% in children of saudi arabia (13), 2.25% in a german population (14), 2.5% in a finnish population (15), 5.6% in young adult israeli patients (6), 15.06% in a french population of 551 patients (where it was the most common dental anomaly observed) (11), 22.9% in an iranian population (7), 46.4% in a young chinese doi: 10.4081/aiua.2019.2.130 introduction taurodontism is defined as a change in the shape of molar teeth characterized in an enlarged pulp chamber, apical displacement of pulpar floor and no constriction at the level of cementoenamel junction (1). the origin of the word comes from the greek tauros, which means bull and odontos which refers to tooth (“bull-like” teeth). the prevalence of taurodontism in normal population has been reported to range between 0.04% (2) and 48.0% (3). an increased incidence of taurodontism has been observed in klinefelter’s patients with a prevalence of 19.4% (4) to 88.0% (5). the purpose of this study was to assess the incidence of taurodontism in a group of italian klinefelter’s patients and in a randomly selected male population of italy and to compare the results with published data of different normal population groups and of klinefelter’s patients. 131archivio italiano di urologia e andrologia 2019; 91, 2 klinetaurodontism population (16) and 48% in a black senegalese population (3). the prevalence of taurodontism that we have found in our group of 100 normal patients was 2.0%. it has been claimed that the wide discrepancy observed could be due to racial variations (17), but the inconsistency of prevalence observed in studies exploring the same populations (0.4% of 4143 patients (9, 18) and 2.8% of 1000 patients (19) in two north indian populations and 0.26% of 6912 patients (12) and 11.2% of 1200 patients (20) in two turkish populations) seems to indicate that the differences reported can be rather due to different criteria used to define taurodontism rather than ethnic variations. an increased prevalence of taurodontism has been reported in klinefelter’s patients. the prevalence observed was 19.4% of 31 klinefelter’s patients (4), 24% of 25 patients (21), 30% of 30 finnish 47,xxy males (15), 40% of 35 klinefelter’s patients (22), 75% of 24 patients (23), 88% of 9 klinefelter’s patients (5). the prevalence of taurodontism that we have found in our group of 16 klinefelter’s patients (12.5%) appears to be lower than what observed in other klinefelter’s populations. taurodontism seems to be associated with several other syndromes such as down’s syndrome (24), 48,xxyy syndrome (25), prader-labhart-willi syndrome (26), wolfhirschhorn syndrome (27-28), pierre robin syndrome (29); it is also more frequent in familial groups (5, 8), in families with wnt10a defects (30) and it is a typical trait frequently found in neanderthal teeth (17). conclusions our results confirm the higher prevalence of taurodontism in klinefelter’s patients compared with the prevalence observed in a normal population (12.5% vs. 2.0%). the wide discrepancy of incidence of taurodontism reported in literature (0.04%-48.0% in normal population; 12.5%-88.0% in klinefelter’s patients) does not allow to determine which is the prevalence of taurodontism in a normal population nor the prevalence among klinefelter’s patients. references 1. jafarzadeh h, azarpazhooh a, mayhall jt. taurodontism: a review of the condition and endodontic treatment challenges. int endod j. 2008; 41:375-88. 2. laganà g, venza n, borzabadi-farahani a, et al. dental anomalies: prevalence and associations between them in a large sample of non-orthodontic subjects, a cross-sectional study. bmc oral health. 2017; 17:62-8. 3. toure b, kane aw, sarr m, et al. prevalence of taurodontism at the level of the molar in the black senegalese population 15 to 19 years of age. odontostomatol trop. 2000; 23:36-9. 4. komatz y, tomoyoshi t, yoshida o, et al. taurodontism and klinefelter’s syndrome. j med genet. 1978; 15:452-4. 5. jaspers mt, witkop jr cj. taurodontism, an isolated trait associated with syndromes and x-chromosomal aneuploidy. am j hum genet. 1980; 32:396-413. 6. shifman a, chanannel i. prevalence of taurodontism found in radiographic dental examination of 1,200 young adul israeli patients. community dent oral epidemiol. 1978; 6:200-3. 7. jamshidi d, tofangchiha m, pozve nj, et al. prevalence of taurodont molars in a selected iranian adult population. iran endod j. 2017; 12:282-7. 8. panigrahi a, panigrahi rg, srilatha kt, et al. non syndromic familial bilateral decidious taurodontism a first case report. j clin diagn res. 2014; 8:zd01-2. 9. patil s, doni b, kaswan s, rahman f. prevalence of taurodontism in the north indian population. j clin exp dent. 2013; 5:e179-82. 10. jayashankara cm, shivanna ak, sridhara ks, kumar ps. taurodontism: a dental rarity. j oral maxillofac pathol. 2013; 17:478. 11. baron c, houchmand-cuny m, enkel b, lopez-cazaux s. prevalence of dental anomalies in french orthodontic patients: a retrospective study. arch pediatr. 2018: 25:426-30. 12. colak h, tan e, byraktar y, et al. taurodontism in a central anatolian population. dent res j. 2013; 10:260-3. 13. yassin sm. prevalence and distribution of selected dental anomalies among saudi children in abha, saudi arabia. j clin exp dent. 2016; 8:e485-90. 14. burklein s, breuer d, schafer e. prevalence of taurodont and pyramidal molars in a german population. j endod. 2011; 37:158-62. 15. varrela j, alvesalo l. taurodontism in 47,xxy males: an effect of the extra x chromosome on root development. j dent res. 1988; 67:501-2. 16. macdonald-jankowski ds. taurodontism in a young adult chinese population. dentomaxillofac radiol. 1993; 22: 140-4. 17. benazzi s, nguyen hn, kullmer o, hublin j. exploring the biomechanics of taurodontism. j anat. 2015; 226:180-8. 18. patil s, doni b, kaswan s, rahman f. prevalence of dental anomalies in indian population. j clin exp dent. 2013; 5:e183-6. 19. bharti r, chandra a, tikku ap, arya d. prevalence of taurodont molars in a north indian population. indian j dent. 2015; 6:27-31. figure 1. radiograph of a taurodontic molar in a klinefelter's patient with enlarged pulp chamber, apical displacement of the pulpar floor and lack of constriction at the level of the cementoenamel junction. archivio italiano di urologia e andrologia 2019; 91, 2 e. giambersio, v. barile, a.m. giambersio 132 20. bilge nh, yesiltepe k, torenek agirman k, et al. investigation of prevalence of dental anomalies by using digital panoramic radiographs. folia morphol. 2018; 77:323-8. 21. hillebrand u, mohr c, plewa g. taurodontism in patients with sex chromosome anomalies. dtsch z mund kiefer gesichtschir. 1990; 14:187-9. 22. rossiwall b. taurodontism in klinefelter’s syndrome. in: bandmann hj, breit r, editors. klinefelter’s syndrome. berlin: springer-verlag, 1984, p. 80-4. 23. schulman gs, redford-badwal d, poole a, et al. taurodontism and learning disabilities in patients with klinefelter syndrome. pediatr dent. 2005; 27:389-94. 24. alpoz ar, eronat c. taurodontism in children associated with trisomy 21 syndrome. j clin pediatr dent. 1997; 22:37-9. 25. krishnamoorthy s, gopikrishna v. endodontic management of a hypertaurodontic tooth associated with 48,xxyy syndrome: a review and case report. j conserv dent. 2015; 18:265-8. 26. bassarelli v, baccetti t, bassarelli t, franchi l. the dentomaxillofacial characteristics of the prader-labhart-willi syndrome. a clinical case report. min stomatol 1991; 40:811-9. 27. babich sb, banducci c, teplitsky p. dental characteristics of the wolf-hirschhorn syndrome: a case report. spec care dentist. 2004; 24:229-31. 28. johnston nj, franklin dl. dental findings of a child with wolfhirschhorn syndrome. int j paediatr dent. 2006; 16:139-42. 29. mateo-castillo jf, pagin o, marchi carvalho im, et al. novel dental phenotype in non-syndromic pierre robin sequence: a retrospective study. arch oral biol. 2019; 97:170-5. 30. yang j, wang s, choi m, et al. taurodontism, variations in tooth number, and misshapened crowns in wnt10a null mice and human kindreds. molecular genetics & genomic medicine. 2015; 3:40-58. correspondence emilia giambersio, md emilia.giambersio@gmail.com antonio giambersio, mf giambersio@libero.it asp poliambulatorio madre teresa ambulatorio klinefelter viale del gallitello, 85100 potenza (italy) vincenzo barile, md vincenzo.barile@aspbasilicata.it asp poliambulatorio madre teresa uoc of radiology viale del gallitello, 85100 potenza (italy) stesura seveso 399archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. techniques were reported to improve continence (4-6). recently, a new method is the retzius-sparing (rs) rarp applied with the posterior approach, defined by galfano et al. (7). the basic principle of this approach is to prevent interference with anatomical structures that provide continence in the anterior region. in this context, many surgeons may consider revising their method. additionally, it is controversial for a surgeon who has completed the learning curve with the standard approach to change their technique using the rs-rarp approach with regard to functional and oncological results. in this study aimed to appraise the functional and oncological outcomes during the rs-rarp learning curve for a surgeon with previous experience of the s-rarp procedure. materials and methods patient selection and study design after the local institutional review board approval, the rsrarp and s-rarp surgeries applied by a single surgeon with experience in robotic surgery between 01.01.2017 and 01.01.2019 were retrospectively evaluated from a prospectively-collected database. the first 50 cases during the rs-rarp learning curve and 50 cases after the second 100 cases with the standard approach were enrolled in the study. surgeon participated in live surgeries before performing rs-rarp. in addition, in the first 10 cases, patients with low-to-moderate volume prostates (≤ 60cc) without a median lobe were preferred. patients with previous prostate and abdominal surgery, incontinence, and presence of lymph node metastasis were excluded from the study. fifty patients who met the inclusion criteria and underwent rs-rarp were considered group 1, and 50 patients who underwent s-rarp were group 2. evaluated variables preoperative evaluation included age, charlson comorbidity index score (cci), prostate-specific antigen (psa), international index of erectile function-5 (iief-5) score, gleason score at biopsy, clinical t stage, prostate volume, and d’amico risk group. furthermore, perioperative variables and pathologiobjective: to appraise the outcomes on the retzius-sparing robot-assisted radical prostatectomy (rs-rarp) learning curve of a surgeon with previous experience of anterior (standard) rarp. materials and methods: the first 50 cases during the rs-rarp learning curve (group 1) and 50 cases after the second 100 cases with the standard approach (group 2) were comprised in the study. patients who used zero or one safety pads were considered continent. erectile function recuperation was characterized as the competence to achieve penetrative intercourse without receiving any medication. all patients were reevaluated at two weeks, first, third, sixth, and 12th months after surgery using iief-5, psa level, and continence status. results: immediate continence rates following catheter removal were 32/50 (64%) in rs-rarp group and 26/50 (52%) in s-rarp group (p = 0.224). the continence recovery rate was 48/50 (96%) in rs-rarp group and 46/50 (92%) in the s-rarp group at 12 months follow-up (p = 0.400). total nerve-sparing surgery was enforced in 36/50 (72%) patients for group 1 and 35/50 (70%) patients for group 2. potency recovery was 27/43 (62.8%) in rs-rarp and 30/44 (68.2%) for s-rarp at 12 months follow up (p = 0.597). surgical margin positivity was detected in 6/50 (12%) cases in the rs-rarp group and in 4/50 (8%) cases in the s-rarp (p = 0.444). conclusions: functional and oncological results are not negatively affected in the first 50 cases for a surgeon who is experienced in s-rarp before transition to the rs-rarp method. key words: learning curve; radical prostatectomy; retziussparing; robotic surgery; trifecta. submitted 28 august 2021; accepted 19 september 2021 introduction prostate cancer is the most frequently diagnosed type of cancer among men and is the second most common cause of cancer-related death in men (1). radical prostatectomy is the most commonly offered treatment modality in eligible patient groups (2). robot-assisted radical prostatectomy (rarp) has become popular in the last two decades. the method most widely adopted by urologists is standard-rarp with an anterior approach (3). the main issue after rarp is preserving continence and erectile function, in addition to oncologic safety. many does transition from standard to retzius-sparing technique in robot-assisted radical prostatectomy affect the functional and oncological outcomes? hakan anıl 1, kaan karamık 2, ali yıldız 3, murat savaş 4 1 department of urology, adana seyhan state hospital, adana, turkey; 2 department of urology, antalya korkuteli state hospital, antalya, turkey; 3 department of urology, okan university hospital, faculty of medicine, istanbul, turkey; 4 department of urology, antalya memorial hospital, antalya, turkey. doi: 10.4081/aiua.2021.4.399 summary archivio italiano di urologia e andrologia 2021; 93, 4 h. anıl, k. karamık, a. yıldız, m. savaş 400 cal features were noted: operative time, anastomosis duration, nerve-sparing status, intraoperative complications, estimated blood loss, presence of lymph node dissection, length of hospital stay, foley catheter removal time, lymph node positiveness, surgical margin status, and pathological stage. patients were followed for at 12 months for continence and potency recovery. immediate continence evaluation was performed within 1 week after catheter removal. patients who used zero or one safety pads were considered continent. erectile function recovery was evaluated in the first month, initially. erectile function recuperation was characterized as the competence to achieve penetrative intercourse without the use of any medication. all patients were reevaluated at two weeks, first, third, sixth, and 12th month after surgery using iief5, psa level, and continence status. surgical technique all robot-assisted radical prostatectomies were implemented by a single surgeon (m.s) who routinely performed over 100 rarps per year. our surgical principles were close to that defined by galfano et al. (7). after the placement of 4 robot trocars and 1 assistant trocar, a 4 arms da vinci robot system (intuitive surgical, la, usa) was docked. the parietal peritoneum was incised horizontally at the anterior layer of the douglas pouch. seminal vesicle pedicles were identified and ligated by using hem-o-lok clips. also, vas deferens were identified and incised. the avascular zone was found by entering among the denonvillier’s fascia and the posterior prostatic fascia. the intrafascial plan was maintained and the prostate apex was reached with dissection. the bladder neck was identified and incised. at this step, we don't use cardinal stitches to identify the bladder neck, unlike galfano and colleagues (7). the anterior surface of the prostate was separated from the santorini plexus. apex separation was achieved and the urethra identified and cutted. the prostate was placed in the endobag. the urethrabladder anastomosis was performed continuously with 3.0 v-lock sutures from the 12-o’clock position. statistical analysis variables were presented as mean±standard deviation, median and interquartile range (25th-75th, iqr), frequency, and percentage. evaluation of categorical data was done with the chi-square or fisher’s exact test. the conformity of the data to the normal distribution was checked with the shapiro-wilk test. student’s t-test or mann-whitney u test was used for continuous variables according to the distribution. the kaplan meier analysis was applied to determine erectile and continence recovery. a two-way repeated-measures anova was used to compare preoperative and postoperative iief scores between surgical approaches. statistical analysis was conducted with ibm spss statistics for windows, version 22.0 (ibm corp., armonk, ny). a p-value < 0.05 was considered as statistically significant. results group 1 and group 2 comprised 50 patients with a median age of 63.5 (iqr 58-68.5) years, and 50 patients with a median age of 66 (iqr, 62-68.5) years, respectively. there were statistically insignificant differences among the groups regarding preoperative demographics and clinical characteristics (table 1). the median operative time was 162.5 (iqr 137.5-210) mins and 150 (iqr 125-220) mins for groups 1 and 2, respectively (p = 0.865). bilateral nerve-sparing surgery was performed in 36/50 (72%) and 35/50 (70%) patients for group 1 and group 2, respectively. intraoperatively, one patient had table 1. demoghraphics and preoperative features. variable rs-rarp s-rarp p value median (iqr) age, years 63.5 (58-68.5) 66 (62-68.5) 0.151 ͳ median (iqr) cci score 2 (1-3) 2 (1-3) 0.531 ͳ median (iqr) bmi, kg/m2 27.2 (24.3-28.7) 28 (25-29.7) 0.223 ͳ median (iqr) psa, ng/ml 9.7 (7.8-11.2) 8.0 (5-13.4) 0.183 ͳ gleason score at biopsy n (%) 0.797 ӿ ≤ 6 31 (62) 32 (64) 7 13 (26) 14 (28) 8-10 6 (12) 4 (8) clinical t stage n (%) 0.695 ӿ t1a-c 33 (66) 29 (58) t2a-b 15 (30) 19 (38) t2c 2 (4) 2 (4) mean (± sd) prostate volume, ml 60.1 ± 24.2 58.8 ± 22.6 0.782 ¥ d’amico risk classification n (%) 0.516 ӿ low 23 (46) 28 (56) intermediate 15 (30) 14 (28) high 12 (24) 8 (16) sd: standart deviation; iqr: interquartile range; cci: charlson comorbidity index; bmi: body mass index; psa: prostate-specific antigen. ͳ: mannwhitney u test. ¥: student’s t-test. ӿ: chi-sqaure test data are presented as mean (± sd) or median (iqr) and frequency (percantage). table 2. peroperative and postoperative results. variable rs-rarp s-rarp p value median (iqr) operative time, mins 162.5 (137.5-210) 150 (125-220) 0.865 ͳ nerve sparing, n (%) 0.843ӿ bilateral 36 (72) 35 (70) unilateral 7 (14) 9 (18) none 7 (14) 6 (12) lymph node dissection, n (%) 21 (42) 19 (38) 0.683 ӿ median (iqr) anastomosis time, mins 20 (15-20) 20 (15-20) 0.952 ͳ median (iqr) blood loss, ml 150 (100-200) 100 (65-150) 0.120 ͳ median (iqr) hematocrit decrease 4.2 (0.7-1.7) 3.9 (0.7-1.6) 0.668 ͳ median (iqr) discharged time, day 3 (2.7-3) 3 (2-3.5) 0.588 ͳ median (iqr) catheter removal time, day 8 (7-9) 8 (7-9) 0.431 ͳ pt, n (%) t0 0 1 (2) t2 38 (76) 36 (72) t3a 7 (14) 8 (16) t3b-4 5 (10) 5 (10) pn, n (%) n0 20(40) 18 (36) n+ 1(2) 1 (2) positive surgical margin, n (%) 0.444 ӿ yes 6 (12) 4 (8) no 44 (88) 46 (92) ͳ: mannwhitney u test. ¥: student’s t-test. ӿ: chi-sqaure test. data are presented as median (iqr) and frequency (percantage). 401archivio italiano di urologia e andrologia 2021; 93, 4 transition from standard to retzius-sparing complete ureteral injury in the rs-rarp group. one patient in the s-rarp group had external iliac vein injury during lymph node dissection. both complications were managed intracorporeally. as a result of the histopathological examination of radical specimens, surgical margin positivity was detected in 6/50 (12%) cases in the rsrarp group and in 4/50 (8%) cases in the s-rarp (p = 0.444). intra-postoperative clinical and pathological outcomes are summarized in table 2. the median catheter discharge time was 8 days (iqr 7-9) in group 1 and 8 (iqr 7-9) days for group 2, respectively (p = 0.431). immediate continence rates following catheter removal were 32/50 (64%) in the rs-rarp group and 26/50 (52%) in the s-rarp group (p = 0.224). the continence recovery rate was 48/50 (96%) in the rsrarp group and 46/50 (92%) in the s-rarp group at 12month follow-up (p = 0.400). comparison of both groups according to continence recovery using kaplanmeier methods is shown in figure 1a. eighty-seven patients, 43 in group 1 and 44 in group 2, who achieved preoperative sexual intercourse were included in the erectile function evaluation. the mean baseline iief-5 score was 21.6 ± 2.5 and 20.7 ± 2.6 in group 1 and 2, respectively (p = 0.143). no statistically significant difference was found between the surgical approach in terms of iief score reductions at 12-month follow-up (p = 0.260) (figure 1b). potency recovery of patients who underwent bilateral or unilateral nerve-sparing surgery was 27/43 (62.8%) in group 1 and 30/44 (68.2%) in group 2 at 12 months follow up. this difference was not statistically significant (p = 0.597). figure 1c shows the kaplanmeier curve for potency recovery at 12-months follow-up (p = 0.719). biochemical recurrence was observed in 7/50 (14%) patients in group 1, and 6/50 (12%) patients in group 2 at median 33 (iqr 28-40) months follow-up (p = 0.766). biochemical recurrence-free survival analysis according to surgical approaches is shown in figure 1d. discussion one-third of men with localized prostate cancer undergo radical prostatectomy (8). incontinence is an adverse effect faced by patients after radical prostatectomy. rs-rarp recently gained popularity with early continence results. in this article, we questioned the effect of the rs-rarp learning curve on functional and oncological results for a surfigure 1. comparison of functional and oncological outcomes between groups. archivio italiano di urologia e andrologia 2021; 93, 4 h. anıl, k. karamık, a. yıldız, m. savaş 402 geon who was experienced in s-rarp before. this study provided that the rs-rarp learning curve period is not adversely affected by either functional or oncologic results. the number of cases required to achieve competence in radical prostatectomy is uncertain. also, there is no objective parameter to be used in defining the learning curve. a study based on complications showed that the complications were significantly reduced after 150 cases (9). in another study examining the learning curve for robotic radical prostatectomy by an experienced surgeon with the open approach, they reported that self-confidence and comfort similar to open surgery were achieved after performing 250 robotic surgeries (10). in a recent study, islamoglu et al. reported that the surgeon experienced in laparoscopy and open radical prostatectomy should have experience of at least 50 cases to achieve the optimal surgical time. however, they found that the learning curve did not affect positive surgical margin (11). another study reported the requirement of 90 cases after intensive structured modular training to achieve optimal perioperative and functional outcomes (12). in this context, we think that the learning curve for rsrarp is person-based and will vary depending on the surgeon's previous skills in laparoscopy and s-rarp. in 2010, galfano et al. defined rs-rarp for the first time in their study, which they defined as the bocciardi approach (7). the theory of this approach is that it has a positive effect on continence and erectile function by protecting structures such as the santorini plexus, pudendal artery, and pubourethral ligament. recent studies show that rs-rarp is advantageous especially in terms of immediate continence (13). in their series of 200 cases, galfano et al. reported a continence rate of 90% at 1 week and 96% at the end of 1 year (14). in a randomized controlled study comparing rs-rarp with s-rarp, continence rates at 1 week were 71% versus 48% in favor of rs-rarp (p = 0.01) (2). in a series of 256 cases involving surgeons on the learning curve, the immediate continence rate was reported as 82% and 90% at the end of 12 months (15). on the other hand, it was emphasized that the high continence rate seen in the early period with the rs-rarp approach is similar to s-rarp after 12 months (12). in our study, although the continence rates in the first week were higher in the rs-rarp group compared to the s-rarp group, no statistical difference was found. at the end of the first year, results were excellent in both groups. sexual potency evaluation was performed in patients with preoperative penetrative sexual intercourse and patients undergoing bilateral or unilateral nerve-sparing surgery. at the end of 12 months, we found a potency rate of 62.8% in the rs-rarp group and 68.2% in the s-rarp group. olivero and colleagues reported a sexual potency rate of 80.4% in their study with surgeons on the rsrarp learning curve. however, they included young patients with full-nerve-sparing procedures in the analysis in this study (15). in a randomized prospective study including 3rd-month penetrative intercourse rates for 30 anterior and 30 posterior approaches by mennon et al., rates were reported as 36.7% in the anterior group and 43.7% in the posterior group. they emphasized that at the end of the 12th month erection sufficient for penetrative intercourse increased to 69.2% in the anterior group and 89% in the posterior group (16). in our study, the rate of erectile function was found to be lower in the rsrarp group compared to the literature. this may be because we included patients from all age groups and patients who underwent unilateral nerve-sparing surgery. positive surgical margin is a valuable data for evaluating oncological outcomes after radical prostatectomy. galfano et al. found a psm rate of 22% in the first 100 cases in their learning curve and 9% in the second 100 patients (14). sayyid and colleagues reported that psm after rsrarp and s-rarp were similar in accordance to pt stage subgroups (for pt2 stage: 16.7% psm in rs-rarp vs 13.7% psm in s-rarp, p = 0.54; for pt3 stage: 47.1% and 47.8%, respectively, p = 0.95) (17). in another study comparing rs-rarp and s-rarp, the rate of psm was 10% in the s-rarp group and 28.2% in the rs-rarp group, and this difference was statistically significant (p = 0.05). however, when pt stage subgroups were compared, no statistical significance was found (18). also, many studies comparing rs-rarp and s-rarp reported similar psm rate and biochemical recurrence-free survival (8). in our study, in accordance with the literature, there was no significant difference in psm rate between the groups. our study has some limitations. first bias may be due to the retrospective design. second, the study has a relatively small sample size. on the other hand, our data were collected prospectively and all surgical procedures were performed by a single surgeon. conclusions this study reported the outcomes for cases on the rs-rarp learning curve of a surgeon with previous experience of s-rarp. according to the data in our study, when a surgeon who is experienced in s-rarp switches to the rsrarp method, functional and oncological results are not negatively affected in the first 50 cases. although immediate continence was found to be lower than the literature in our study, the results are excellent at the end of 12 months. surgeons previously experienced in the s-rarp approach can safely move to the rs-rarp approach. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2018. ca cancer j clin. 2018; 68:7-30. 2. dalela d, jeong w, prasad ma, et al. a pragmatic randomized controlled trial examining the impact of the retzius-sparing approach on early urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2017; 72:677-685. 3. galfano a, secco s, dell'oglio p, et al. retzius-sparing robotassisted radical prostatectomy: early learning curve experience in three continents. bju int. 2021; 127:412-417. 4. patel vr, coelho rf, palmer kj, rocco b. periurethral suspension stitch during robot-assisted laparoscopic radical prostatectomy: description of the technique and continence outcomes. eur urol. 2009; 56:472-8. 5. ma x, tang k, yang c, et al. bladder neck preservation improves time to continence after radical prostatectomy: a systematic review and meta-analysis. oncotarget. 2016; 7:67463-75. 403archivio italiano di urologia e andrologia 2021; 93, 4 transition from standard to retzius-sparing 6. kojima y, takahashi n, haga n, et al. urinary incontinence after robot-assisted radical prostatectomy: pathophysiology and intraoperative techniques to improve surgical outcome. int j urol. 2013; 20:1052-63. 7. galfano a, ascione a, grimaldi s, et al. a new anatomic approach for robot-assisted laparoscopic prostatectomy: a feasibility study for completely intrafascial surgery. eur urol. 2010; 58:457-61. 8. davis m, egan j, marhamati s, et al. retzius-sparing robotassisted robotic prostatectomy: past, present, and future. urol clin north am. 2021; 48:11-23. 9. ou y-c, yang c-r, wang j, et al. the learning curve for reducing complications of robotic-assisted laparoscopic radical prostatectomy by a single surgeon: complications of ralp. bju int. 2011; 108:420-5. 10. herrell sd, smith ja jr. robotic-assisted laparoscopic prostatectomy: what is the learning curve? urology. 2005; 66(5 suppl):105-7. 11. islamoglu e, karamik k, ozsoy c, et al. the learning curve does not affect positive surgical margin status in robot-assisted laparoscopic prostatectomy. urol j. 2018; 15:333-338. 12. schiavina r, borghesi m, dababneh h, et al. the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy. arch ital urol androl. 2018; 90:1-7. 13. phukan c, mclean a, nambiar a, et al. retzius-sparing robotic assisted radical prostatectomy vs. conventional robotic assisted radical prostatectomy: a systematic review and meta-analysis. world j urol. 2020; 38:1123-1134. 14. galfano a, di trapani d, sozzi f, et al. beyond the learning curve of the retzius-sparing approach for robot-assisted laparoscopic radical prostatectomy: oncologic and functional results of the first 200 patients with ≥ 1 year of follow-up. eur urol. 2013; 64:974-80. 15. olivero a, galfano a, piccinelli m, et al. retzius-sparing robotic radical prostatectomy for surgeons in the learning curve: a propensity score-matching analysis. eur urol focus. 2021; 7:772-778. 16. menon m, dalela d, jamil m, et al. functional recovery, oncologic outcomes and postoperative complications after robot-assisted radical prostatectomy: an evidence-based analysis comparing the retzius-sparing and standard approaches. j urol. 2018; 199:12101217. 17. sayyid rk, simpson wg, lu c, et al. retzius-sparing roboticassisted laparoscopic radical prostatectomy: a safe surgical technique with superior continence outcomes. j endourol. 2017; 31:1244-1250. 18. asimakopoulos ad, topazio l, de angelis m, et al. retzius-sparing versus standard robot-assisted radical prostatectomy: a prospective randomized comparison on immediate continence rates. surg endosc. 2019; 33:2187-2196. correspondence hakan anıl, md (corresponding author) dr.hakananil@gmail.com department of urology, adana seyhan state hospital, adana (turkey) kaan karamık, md department of urology, antalya korkuteli state hospital, antalya (turkey) ali yıldız, asst. prof., md department of urology, okan university hospital, faculty of medicine, istanbul (turkey) murat savaş, prof. dr., md department of urology, antalya memorial hospital, antalya (turkey) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12238 1 original paper high cure and long-term survival rates, the fertility burden on survivors is still a major concern. studies have demonstrated a reduction in semen parameters, notably preorchiectomy sperm concentration and total sperm count, as well as a decrease in fertility among patients with tca compared to their healthy counterparts (4). moreover, patients with tca often need additional treatments which further impair spermatogenesis and fertility. despite advancements in these treatments, the gonadotoxic effects of chemotherapy and radiation, coupled with the potential for impaired ejaculation and subsequent infertility following retroperitoneal lymph node dissection (rplnd), contribute to a consistent decrease in fertility among males undergoing additional therapy postorchiectomy (5). in that regard, there is a need for literature investigating the potential role of tca stage in the fertility potential of these patients. the aim of our study was to evaluate the impact of tca stage and histology on preorchiectomy semen parameters, as a surrogate for fertility. we also analyzed the role of elevated tumor markers on sperm abnormalities. materials and methods patient selection we retrospectively collected data on all patients who consecutively received radical orchiectomy for presumed tca and who underwent semen cryopreservation before orchiectomy, between march 2010 and march 2023. we excluded patients with bilateral tumors, patients without germ cell tumor (gct) on final pathology, patients who did not undergo semen cryopreservation and patients who underwent cryopreservation after orchiectomy. the study was approved by the ethical committee of our center. variables our database included data regarding age at diagnosis, body mass index (bmi), tumor size, tumor histology, clinical stage, serum tumor markers, namely alpha-fetoprotein (a-fp), beta subunit of human chorionic gonadotropin (b-hcg) and lactate dehydrogenase (ldh), and semen purpose: to evaluate the influence of testicular cancer histology and stage on sperm parameters in cryopreserved samples collected prior to orchiectomy. materials and methods: we conducted a retrospective analysis of tumor histology, stage and sperm parameters of patients who underwent pre-orchiectomy sperm cryopreservation for testicular cancer between march 2010 and march 2023. the world health organization (who) 2010 sperm reference values were used to identify patients with subnormal semen parameters and to further categorize patients by sperm alteration. localized disease was classified as stage i, while metastatic disease encompassed stages ii and iii. continuous variables were compared using t-test or mann whitney u test, and categorical variables using chi-square and fisher´s exact test. results: a total of 64 patients was identified, 48 (75%) classified as stage i and 16 (25%) classified as stage ii/iii. no difference was found in semen parameters between patients with seminoma and patients with non-seminoma germ cell tumor (nsgct). patients with stage ii/iii disease had significantly lower percentages of progressive motility (36% vs 53%, p = 0.021) and total motility (60% vs 69%, p = 0.015) than stage i patients. when categorizing by sperm alterations according to who 2010 reference values, patients with stage ii/iii disease had significantly higher proportions of asthenozoospermia (38% vs 15%, p = 0.048) and teratozoospermia (63% vs 31%, p = 0.027) than stage i patients. elevated tumor markers were not associated with sperm abnormalities. conclusions: patients with metastatic testicular cancer present with worse sperm quality than patients with localized disease. sperm cryopreservation should be offered to all patients with testicular cancer, and especially emphasized in patients with metastatic disease. key words: testicular cancer; male infertility; cryopreservation; sperm parameters; orchiectomy. submitted 28 december 2023; accepted 29 december 2023 introduction testicular cancer (tca) is the most common malignant tumor in young adult men aged 15-40 years, and accounts for about 1% of all neoplasms in men (1). the incidence of tca has been steadily increasing in recent years, predominantly in developed countries (2, 3).despite having semen parameters in testicular tumor patients before orchiectomy: what is the impact of testicular tumor stage and histology? gonçalo mendes 1, bernardo teixeira 1, mariana madanelo 1, alexandra rocha 1, sofia mesquita 1, joão vital 2, miguel monteiro 1, avelino fraga 1, nuno louro 1 1 department of urology, santo antónio university hospital center, porto, portugal; 2 department of urology, hospital of funchal, funchal, portugal. doi: 10.4081/aiua.2024.12238 summary archivio italiano di urologia e andrologia 2024; 96(1):12238 g. mendes, b. teixeira, m. madanelo, et al. 2 parameters. serum tumor markers were considered elevated if they were above the upper normal limit provided by the laboratory (a-fp 0-7 µg/l, b-hcg 0-2 u/l, ldh 135-225 u/l). semen parameters reviewed included patient´s semen volume, sperm concentration, progressive motility, total motility and morphology. the world health organization (who) 2010 sperm reference values (6) were used to identify patients with subnormal semen parameters and to further categorize patients by sperm alteration (oligozoospermia was defined as < 15 million spermatozoa/ml, asthenozoospermia as < 32% progressive motile spermatozoa and teratozoospermia as < 4% normal forms). stage i disease was considered localized disease, whereas stage ii/iii disease was considered metastatic disease. statistical analysis continuous variables with normal distribution are presented as mean ± standard deviation and compared by student´s t-test, while continuous variables with non-normal distribution are presented as medians accompanied by interquartile ranges (iqrs) and compared by the mannwhitney-u test. categorical variables are presented as proportions, and comparisons of two categorical variables are performed with the pearson’s chi-square test and fisher exact test. a multivariate regression analysis was performed. statistical analyses were conducted using spss statistics version 27. all tests were two-sided, and statistical significance was set at p < 0.05. results a total of 123 patients were diagnosed with tca at our institution in the studied timeframe. a total of 64 patients (52%) were included (patients who underwent semen cryopreservation before orchiectomy). of these, 48 patients (75%) classified as stage i and 16 patients (25%) classified as stage ii/iii. according to histology, 33 patients (52%) were seminoma and 31 patients (48%) were non-seminoma gct (nsgct). baseline characteristics are presented in table 1. age, bmi and tumor size were similar between groups. there was a significantly bigger proportion of nsgct in stage ii/iii patients as compared to patients in the stage i group (75% vs 40%, p = 0.014). a comparison of sperm parameters between both groups according to histology (seminoma vs nsgct) is presented in table 2. all semen parameters were similar between groups, and therefore no difference was observed between patients with seminoma and patients with nsgct. a comparison of sperm parameters between both groups according to stage (stage i vs stage ii/iii) is presented in table 3. in general, all sperm parameters where lower in the stage ii/iii patients. stage ii/iii patients had significantly lower percentage of progressive motility (35.51% in stage ii/iii vs 53.00% in stage i, p = 0.021) and significantly lower percentage of total motility (59.95% in stage ii/iii vs 69.10% in stage i, p = 0.015). additionally, there was a trend towards lower progressive motility and lower total motility (as absolute numbers) in stage ii/iii patients, as well as a tendency to a lesser percentage of morphologically normal spermatozoids in this group. sperm parameters were further categorized according to the who 2010 sperm reference values, and the groups according to stage (i vs ii/iii) were compared. the results are presented in table 3. stage ii/iii patients had a significantly higher proportion of asthenozoospermia (38% in stage ii/iii vs 15% in stage i, p = 0.048) and a significantly higher proportion of teratozoospermia (63% in stage ii/iii vs 31% in stage i, p = 0.027). despite not reaching statistical significance, patients in stage ii/iii table 1. baseline characteristics of the patients. stage i stage ii/iii p (n = 48) (n = 16) age 31.00 ± 5.88 30.69 ± 12.34 0.923 bmi 24.84 ± 4.33 26.67 ± 4.03 0.506 tumor size 38.85 ± 21.59 42.88 ± 23.07 0.528 histology seminoma 29 (60%) 4 (25%) 0.014 nscgt 19 (40%) 12 (75%) bmi: body mass index; nsgct: non-seminoma germ cell tumor. table 2. comparison of preorchiectomy sperm parameters according to tumor histology. total seminoma nsgct p (n = 64) (n = 33) (n = 31) semen volume (ml) 2.95 ± 1.60 3.09 ± 1.56 2.79 ± 1.66 0.468 sperm concentration (millions/ml) 31.50 (10.48-70.00) 37.00 (15.50-84.50) 28.00 (9.00-66.00) 0.330 progressive motility (millions/ml) 19.21 (3.98-39.31) 22.08 (4.11-42.88) 11.50 (3.38-33.53) 0.295 progressive motility (%) 48.63 ± 22.20 50.61 ± 23.36 46.52 ± 21.07 0.465 total motility (millions/ml) 21.83 (6.35-51.32) 26.91 (7.00-54.20) 16.40 (5.75-43.20) 0.347 total motility (%) 65.55 (52.45-77.75) 67.00 (52.95-79.80) 64.50 (52.30-74.50) 0.444 normal morphology (millions/ml) 1.56 (0.29-4.83) 1.70 (0.52-5.51) 1.55 (0.26-4.20) 0.493 normal morphology (%) 4.00 (2.25-7.00) 5.00 (3.00-7.00) 4.00 (2.00-8.00) 0.866 nsgct: non-seminoma germ cell tumor. table 3. comparison of preorchiectomy sperm parameters according to tumor stage. total stage i stage ii/iii p (n = 64) (n = 48) (n = 16) semen volume (ml) 2.95 ± 1.60 3.01 ± 1.71 2.75 ± 1.28 0.578 sperm concentration (millions/ml) 31.50 (10.48-70.00) 33.50 (15.25-73.00) 23.00 (0.03-47.00) 0.129 progressive motility (millions/ml) 19.21 (3.98-39.31) 20.79 (5.33-42.48) 9.65 (0.01-30.84) 0.077 progressive motility (%) 48.63 ± 22.20 53.00 ± 19.29 35.51 ± 25.67 0.021 total motility (millions/ml) 21.83 (6.35-51.32) 24.43 (8.37-54.06) 12.45 (0.01-36.32) 0.088 total motility (%) 65.55 (52.45-77.75) 69.10 (55.43-79.25) 59.95 (5.00-66.68) 0.015 normal morphology (millions/ml) 1.56 (0.29-4.83) 1.63 (0.50-5.40) 0.80 (0.01-4.15) 0.195 normal morphology (%) 4.00 (2.25-7.00) 5.00 (3.00-7.00) 3.00 (0.00-7.50) 0.102 archivio italiano di urologia e andrologia 2024; 96(1):12238 3 semen parameters in testicular tumor group also had higher percentage of oligozoospermia (44% in stage ii/iii vs 23% in stage i, p = 0.108). the proportion of patients with azoospermia was similar between groups. on multivariate regression analysis, elevated tumor markers (afp, b-hcg and ldh) were not associated with abnormalities in sperm parameters (table 5). three patients (5%) used their cryopreserved semen for assisted reproduction techniques (art); two patients had a seminoma and one patient had a nsgct. two patients had stage i disease and one patient had stage ii/iii disease. non-cryopreserved paternity data was unavailable. discussion testicular cancer can play a major role in infertility. analysis of cryopreservation data demonstrates that normal sperm quality is observed in less than half of men with tca before treatment, and 10-35% suffer from infertility. fertility may be impacted by tca through a multitude of axis, including intrinsic infertility associated with the testicular dysgenesis syndrome, the testicular tumor local effect, and systemic effects of hormones secreted by the tumor (7). there is a paucity of literature on the impact of tumor stage and histology in sperm outcomes of patients with tca, with a previous study failing to demonstrate any relation between these factors (8). to the best of our knowledge, this is the largest series on the impact of tumor stage and histology on sperm quality. in our study, we demonstrated that patients with metastatic disease (stage ii/iii) have worse sperm parameters than patients with localized disease (stage i), namely lower progressive and total motility and a higher proportion of asthenozoospermia and teratozoospermia. tumor histology showed no influence on sperm parameters in individuals with tca and elevated tumor markers were not associated with sperm abnormalities. tca can have local adverse effects on spermatogenesis through local growth of the testicular tumor. the occurrence of spermatogenesis defects is most prominent in the vicinity of malignant tumors (9), a trend not observed in benign tumors (10). larger tumor size is correlated with lower levels of spermatogenesis in the ipsilateral testis (11). in fact, testicular tumors > 4 cm exhibit a significant decrease in spermatogenesis compared to tumors < 4 cm (12). tca can also exert deleterious effects on sperm quality through secreted hormones. elevated serum levels of a-fp or b-hcg can disrupt the physiologic feedback mechanism of the hypothalamic-pituitary-gonadal (hpg) axis, which directly regulates testicular function, and hence spermatogenesis (13). disruptions in the levels of luteinizing hormone (lh), follicle-stimulating hormone (fsh), and testosterone are associated with spermatogenesis and a reduction in sperm concentration (5). it has also been demonstrated that any kind of cancer, including tca, may lead to worse sperm quality, with sperm parameters below the who reference values; causative factors have been hypothesized to be a rise in pro-inflammatory circulating cytokines and interleukins (14). moreover, testicular cancer is associated with elevated oxidative stress and dna fragmentation, both potentially contributing to decreased fertility (15, 16). despite these detrimental effects of testicular tumor on sperm quality, orchiectomy does not result in improvement of spermatogenesis; instead, it further deteriorates sperm quality. petersen et al. (17) demonstrated a reduction in sperm concentration, total sperm count and serum inhibin b levels in patients who underwent radical orchiectomy for tca, as well as de novo azoospermia in 9% of patients. a more recent multicenter study evaluating pre and post orchiectomy semen samples concluded that sperm concentration significantly decreased after orchiectomy (18). these studies highlight the importance of cryopreservation, which should ideally be done before orchiectomy, since there is currently no evidence that expedited radical orchiectomy translates into oncological benefit (19). furthermore, in this setting we might find patients who are amenable to surgical testicular sperm extraction (tese) at the time of orchiectomy (onco-tese) (7). patients with tca may be subject to additional treatments other than radical orchiectomy, and these treatments may further impair the fertility of these patients. chemotherapy in tca is dependent on platinum-based agents (cisplatin and carboplatin), which may be combined with other agents, such as bleomycin and etoposide (7). by penetrating the testis blood barrier and targeting actively dividing cells, chemotherapy significantly impairs spermatogenesis, resulting in oligozoospermia and azoospermia. there is a well-established correlation between the failure to conceive and the cumulative dose of chemotherapy (20, 21). in a study of 1191 tca survivors, higher doses of chemotherapy translated into a significant impairment of spermatogenesis, resulting in only 29% of patients being normozoospermic after 11 table 4. comparison of categories of preorchiectomy sperm alterations according to the who 2010 sperm reference values and to tumor stage. stage i stage ii/iii p (n = 48) (n = 16) oligozoospermia (< 15 millions/ml) n (%) 11 (23%) 7 (44%) 0.108 asthenozoospermia (< 32% progressive motility) n (%) 7 (15%) 6 (38%) 0.048 teratozoospermia (< 4% normal forms) n (%) 15 (31%) 10 (63%) 0.027 azoospermia (complete absence of spermatozoa) 2 (4%) 1 (6%) 1.000 any abnormality n (%) 21 (44%) 10 (63%) 0.194 table 5. multivariate regression analysis for the role of elevated tumor markers as predictors of any abnormality in sperm parameters in patients with testicular cancer. covariate or 95% ci p elevated a-fp 2.859 0.693, 11.787 0.146 elevated β-hcg 0.486 0.125, 1.890 0.297 elevated ldh 2.748 0.895, 8.436 0.097 ci: confidence interval; or: odds ratio. archivio italiano di urologia e andrologia 2024; 96(1):12238 g. mendes, b. teixeira, m. madanelo, et al. 4 years of follow-up (22). there is potential for recovery of spermatogenesis, in a time-dependent manner, with 48% and 80% of patients with normal pretreatment sperm concentrations recovering spermatogenesis by 2 and 5 years, respectively (23). radiation therapy is another modality for treatment of tca. it may be applied to retroperitoneal metastases, in which case the testes are exposed to scatter radiation only, generally at low doses which protect fertility, or directly to the testes, in case of germ cell neoplasia in situ; in the latter case, with radiation doses of 16-20 gy frequently used, there are high rates of irreversible azoospermia (5). finally, rplnd is another modality of additional treatment in tca. rplnd might cause retrograde ejaculation or anejaculation due to damage of lumbar plexus and splenic nerves, which renders the patients infertile. despite the very high rates of ejaculatory function preservation with modern nerve sparing techniques, fibrosis might still make this technique difficult, resulting in substantial rates of anejaculation (7). our study concluded that patients with metastatic disease (stage ii/iii) have significantly worse semen parameters than patients with localized disease (stage i); these findings underscore the need for cryopreservation especially in metastatic patients, and a greater emphasis should be placed on cryopreservation in this subset of patients, given that treatment of these patients with one or more of these modalities of adjuvant treatment is generally the rule. only a few studies have evaluated the potential role of histology and stage on sperm quality (8, 24, 25). fraietta et al. (24) reviewed the data of 100 patients with tca and analyzed the patients’ sperm quality according to histologic type (seminoma vs nsgct) and concluded that patients with seminoma had a higher number of motile and morphologically normal spermatozoids than those with nsgct. a more recent study by badia et al. (8) concluded that histology did not influence semen parameters, as these were similar between patients with seminoma and nsgct. this aligns with the results of our study, where we showcased that patients with distinct histology exhibited comparable semen parameters. as for the role of stage, halstuch et al. (25) demonstrated that severe oligozoospermia (< 5 million/ml) was more common in metastatic than non-metastatic nsgct. the same conclusion could not be drawn for patients with seminoma. badia et al. (8) also evaluated the role of stage on semen parameters, and again concluded that semen parameters were similar in tca patients with localized and metastatic disease. these results are conflicting with the results of our study. we did demonstrate differences between different stages, with metastatic disease showing less progressive and total motility and a higher proportion of asthenozoospermia and teratozoospermia, and this was demonstrated for patients with stage ii/iii irrespective of histology. rates of oligozoospermia were, however, similar between groups, despite a tendency towards less oligozoospermia in localized disease. moreover, despite the previously noted effect of secreted hormones, we did not demonstrate and association between elevated tumor markers and sperm abnormalities. we hypothesize that it is the systemic inflammatory process of metastatic testicular cancer, rather than the hormonal burden of elevated tumor markers, that might be responsible for a detrimental effect on spermatogenesis. semen cryopreservation should be discussed and offered to all patients with tca, ideally before orchiectomy to maximize chances of fertility, and if not done before orchiectomy should be pursued prior to chemotherapy or radiation therapy (26). despite these recommendations, only 24-30% of tca patients undergo sperm cryopreservation (24, 27-29). in our study, 64 patients (52%) out of 123 patients diagnosed with tca underwent semen cryopreservation before orchiectomy, with an additional 12 (10%) patients undergoing semen cryopreservation after orchiectomy and before adjuvant treatments, which translated into a total sperm cryopreservation rate of 62%. the timing of cryopreservation is of importance, as noted by the work of rives et al. (18), in which they demonstrated that mean sperm concentration before orchiectomy was significantly higher than after surgery (32x106/ml vs 24x106/ml). moreover, as previously noted, semen cryopreservation before orchiectomy has the potential for selection of patients for onco-tese, which is another advantage (7). it is also worth noting that despite advancements in art in the last years, sperm cryopreservation remains the most cost-effective strategy for fertility preservation (30). therefore, it is the authors’ opinion that semen cryopreservation should be offered in every patient with tca, if possible before orchiectomy, and in light of the results of our study a heightened emphasis should be placed on patients with metastatic disease, as these display overall worse sperm quality and will most probably be subject to additional treatments. our study has several limitations that deserve acknowledgment. the main shortcomings come from its retrospective nature. we could only analyze the information on the medical records, and as a consequence the success rate of pregnancies from cryopreserved sperm samples could not be evaluated. furthermore, we used decreased semen parameters as a surrogate for decreased fertility, even though a direct relationship between the two hasn’t been established. additionally, despite our institution being a high-volume referral center for tca, the relatively short sample size of 64 patients may limit statistical power. in that sense, further studies, preferably prospective and multicenter, are needed in the future to support our findings. conclusions testicular cancer has the potential for infertility. patients with metastatic testicular cancer (stage ii/iii) have worse sperm quality, namely less progressive and total motility of spermatozoids and a bigger proportion of asthenozoospermia and teratozoospermia than patients with localized testicular cancer (stage i). histology appears to play no major role in sperm quality and elevated tumor markers were not shown to be associated with sperm abnormalities. sperm cryopreservation should be offered to all patients with testicular cancer, ideally before orchiectomy, and this should be further emphasized in patients with metastatic disease. further studies are recommended to validate these findings. archivio italiano di urologia e andrologia 2024; 96(1):12238 5 semen parameters in testicular tumor references 1. park js, kim j, elghiaty a, ham ws. recent global trends in testicular cancer incidence and mortality. medicine. 2018; 97:e12390. 2. nigam m, aschebrook-kilfoy b, shikanov s, eggener s. increasing incidence of testicular cancer in the united states and europe between 1992 and 2009. world j urol. 2015; 33:623-31. 3. gurney jk, florio aa, znaor a, et al. international trends in the incidence of testicular cancer: lessons from 35 years and 41 countries. eur urol. 2019; 76:615-23. 4. djaladat h, burner e, parikh pm, et al. the association between testis cancer and semen abnormalities before orchiectomy: a systematic review. j adolesc young adult oncol. 2014; 3:153-9. 5. parekh n v, lundy sd, vij sc. fertility considerations in men with testicular cancer. transl androl urol. 2020; 9(suppl 1):s14-23. 6. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010; 16:231-45. 7. moody ja, ahmed k, yap t, et al. fertility managment in testicular cancer: the need to establish a standardized and evidence-based patient-centric pathway. bju int. 2019; 123:160-72. 8. badia rr, patel a, chertack n, et al. impact of testicular cancer stage on semen parameters in patients before orchiectomy. urol oncol. 2023; 41:151.e11-151.e15. 9. ho gt, gardner h, dewolf wc, et al. influence of testicular carcinoma on ipsilateral spermatogenesis. j urol. 1992; 148:821-5. 10. ho gt, gardner h, mostofi k, et al. the effect of testicular nongerm cell tumors on local spermatogenesis. fertil steril. 1994; 62:162-6. 11. choy jt, wiser hj, bell sw, et al. predictors of spermatogenesis in orchiectomy specimens. urology. 2013; 81:288-92. 12. shoshany o, shtabholtz y, schreter e, et al. predictors of spermatogenesis in radical orchiectomy specimen and potential implications for patients with testicular cancer. fertil steril. 2016; 106:70-4. 13. coward rm, kovac jr, smith rp, lipshultz li. fertility preservation in young men treated for malignancies: options for precancer treatment. sex med rev. 2013; 1:123-34. 14. peluso g, tisato v, singh av, et al. semen cryopreservation to expand male fertility in cancer patients: intracase evaluation of semen quality. j pers med. 2023; 13:1654. 15. said tm, tellez s, evenson dp, del valle ap. assessment of sperm quality, dna integrity and cryopreservation protocols in men diagnosed with testicular and systemic malignancies. andrologia. 2009; 41:377-82. 16. kumar k, lewis s, vinci s, et al. evaluation of sperm dna quality in men presenting with testicular cancer and lymphoma using alkaline and neutral comet assays. andrology. 2018; 6:230-5. 17. petersen pm, skakkebaek ne, rørth m, giwercman a. semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. j urol. 1999; 161:822-6. 18. rives n, perdrix a, hennebicq s, et al. the semen quality of 1158 men with testicular cancer at the time of cryopreservation: results of the french national cecos network. j androl. 2012; 33:1394-401. 19. emmanuel a, kanthabalan a, alexander c, et al. expedited radical orchidectomy for testicular cancer: compromising fertility outcomes without oncological benefit? eur urol. 2021; 80:766-7. 20. puscheck e, philip pa, jeyendran rs. male fertility preservation and cancer treatment. cancer treat rev. 2004; 30:173-80. 21. brydøy m, fosså sd, klepp o, et al. paternity following treatment for testicular cancer. j natl cancer inst. 2005; 97:1580-8. 22. brydøy m, fosså sd, klepp o, et al. sperm counts and endocrinological markers of spermatogenesis in long-term survivors of testicular cancer. br j cancer. 2012; 107:1833-9. 23. lampe h, horwich a, norman a, et al. fertility after chemotherapy for testicular germ cell cancers. j clin oncol. 1997; 15:239-45. 24. fraietta r, spaine dm, bertolla rp, et al. individual and seminal characteristics of patients with testicular germ cell tumors. fertil steril. 2010; 94:2107-12. 25. halstuch d, shtabholtz y, neufeld s, et al. the absence of spermatogenesis in radical orchiectomy specimen is associated with advanced-stage nonseminomatous testicular cancer. urol oncol. 2021; 39:838.e15-838.e20. 26. patrikidou a, cazzaniga w, berney d, et al. european association of urology guidelines on testicular cancer: 2023 update. eur urol. 2023; 84:289-301. 27. ping p, gu bh, li p, et al. fertility outcome of patients with testicular tumor: before and after treatment. asian j androl. 2014; 16:107-11. 28. sonnenburg dw, brames mj, case-eads s, einhorn lh. utilization of sperm banking and barriers to its use in testicular cancer patients. support care cancer. 2015; 23:2763-8. 29. magelssen h, haugen tb, von düring v, et al. twenty years experience with semen cryopreservation in testicular cancer patients: who needs it? eur urol. 2005; 48:779-85. 30. gilbert k, nangia ak, dupree jm, et al. fertility preservation for men with testicular cancer: is sperm cryopreservation cost effective in the era of assisted reproductive technology? urol oncol. 2018; 36:92.e1-92.e9. correspondence gonçalo mendes, md (corresponding author) goncalo.grilomendes@gmail.com bernardo teixeira, md bernardolat@gmail.com mariana madanelo, md marianacmadanelo@gmail.com alexandra rocha, md marialexandrarocha@gmail.com sofia mesquita, md sofiaoplmesquita@gmail.com miguel monteiro, md mmonteiro.iam@gmail.com avelino fraga, md avfraga@gmail.com nuno louro, md nunorlouro@gmail.com department of urology, santo antónio university hospital center, porto, portugal joão vital, md joaopvital@gmail.com department of urology, hospital of funchal, funchal, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2248 review no conflict of interest declared. on the role of cannabis in different types of cancer have mainly focused on the oral cavity, the lungs, the gastrointestinal tract, and genitourinary system. upon legalization of cannabis in canada in october 2018, social acceptance and prevalence of cannabis use have been rising dramatically in parallel with the concern about the disadvantageous and long-term consequences. considering the direct exposure, bladder can be potentially impacted by cannabis use to a considerable extent, i.e. general bladder health, and bladder cancer occurrence and prognosis (3). however, there is a scarcity of data on the link between cannabis use and bladder cancer. to investigate the link between cannabis use and bladder cancer, we conducted a systematic review. materials and methods study objective study objective was to assess the association between cannabis use and bladder cancer. it is noteworthy that the review method was established prior to the conduct of the review, from which there was no significant deviation. search strategy a systematic literature review was performed using studies published in electronic databases including pubmed, medline, and google scholar. based on the boolean search strategy, a variety of combinations contained the following search terms were applied in different search engines to ensure the comprehensiveness of the result. in addition, the reference lists of the retrieved studies were manually screened. the search terms included “marijuana or marihuana or tetrahydrocannabinol or dronabinol or cannabinoid or cannabis, and bladder cancer or bladder carcinoma or bladder tumor or bladder neoplasm or urothelial carcinoma or transitional cell carcinoma. selection criteria we did not restrict the search with specific design, year of publication or human studies due to existing scarcity of literature on this topic. we just excluded the commentary and letter to editor. we enquired two experts in the fields to avoid missing any published or unpublished papers. objective: to assess the association between cannabis use and bladder cancer. methods: a systematic literature review was performed using studies published in electronic databases including pubmed, medline, and google scholar. due to the scarcity of literature on this topic, the search was not limited to a specific design, year of publication, or human studies. the studies were screened by two reviewers in the following steps; first, the studies were discovered according to the predetermined search strategy; second, the unrelated studies and duplicates were eliminated by screening the abstracts, titles, and keywords; third, the full text of relevant and eligible papers were critically appraised and assessed for the risk of bias using the respective tool. the two review authors independently assessed the risk of bias and outcome levels using the newcastle-ottawa scale for the outcomes in observational studies. any disagreements were settled by a third party. results: the search strategy yielded 39 research articles. after removing 21 duplicates, 18 publications were eligible for title and abstract review. thirteen studies were found to be irrelevant and subsequently excluded. only three full-text articles were evaluated and included in the qualitative synthesis. conclusions: the role of cannabis in bladder cancer has been seldom studied. the small number of studies show contradictory findings; potential carcinogenic versus protective effect. the growing interest in cannabis use after legalization necessitates further investigations with a robust design to assess the long-term effect of cannabis on bladder cancer. key words: bladder cancer; cannabis; cannabinoids; marijuana; legalization. submitted 18 march 2022; accepted 5 april 2022 introduction cannabis (also known as marijuana) is a term used to describe a vast array of products that can be produced from any part of the cannabis sativa, cannabis indica, or cannabis ruderalis plants individually, or in combination. the three most common administration routes for cannabis are smoking, vaporizing, and eating (1). when it comes to elimination, cannabis and its byproducts pass through both the gastrointestinal and urinary tracts that can lead to a direct contact and respective responses in the corresponding organs (2). accordingly, many studies the association of bladder cancer and cannabis: a systematic review vahid mehrnoush 1, stacy grace de lima 2, ahmed kotb 1, matthew eric hyndman 3 1 department of urology, northern ontario school of medicine, thunder bay, ontario, canada; 2 inflammation research network-snyder institute for chronic disease, departments of physiology & pharmacology and medicine, university of calgary cumming school of medicine, calgary, alberta, canada; 3 department of urology, southern alberta institute of urology, calgary, alberta, canada. doi: 10.4081/aiua.2022.2.248 summary 249archivio italiano di urologia e andrologia 2022; 94, 2 bladder cancer and cannabis screening data the studies were screened by two reviewers in the following steps; first, the studies were discovered according to the predetermined search strategy; second, the unrelated studies and duplicates were eliminated by screening the abstracts, titles, and keywords; third, the full text of relevant and eligible papers were critically appraised and assessed for the risk of bias using the respective tool. data extraction the following information was extracted from each selected study: population characteristics, type of study, country, and key relevant findings. as noted, the data extraction was performed in duplicate by the two reviewers. the consensus on what information should be extracted and included was achieved. methodological quality (r isk of bias) the two review authors (vm and sdl) independently assessed the risk of bias and outcome levels using the newcastle-ottawa scale for the outcomes in observational studies (6). any disagreements were settled by a third party (ak and meh). results study selection figure 1 depicts the prisma flowchart of the study selection process. the search strategy yielded 39 research articles. after removing 21 duplicates, 18 publications were eligible for title and abstract review. thirteen studies were found to be irrelevant and subsequently excluded. following full-text evaluation, two papers (one commentary and one letter to the editor) were excluded. only three full-text articles were evaluated and included in the qualitative synthesis. table 1. summary of clinical studies on cannabis and bladder cancer. figure 1. prisma flowchart of the results of the literature search. author study design country population intervention/exposure comparator outcome rob chacko et al. 2006 (4) case control usa 124 patients with use of marijuana age-matched control a history of habitual marijuana use in 88.5% and 69.2% moderate bladder cancer of transitional cell carcinoma patients and age-matched controls, respectively (p = 0.008). the association between marijuana use and tumor stage, grade, and number of recurrences of transitional cell carcinoma. thomas et al. 2015 (5) cohort usa 84170 participants cannabis users not reporting cannabis incident bladder cancer 0.3% among cannabis users versus moderate in a multiethnic use 0.4% among men not reporting cannabis use (p < .001). cohort of men aged cannabis use associated with a 45% reduction 45-69 years in bladder cancer incidence (hr, 0.55; 95% ci, 0.31-1.00). nieder et al. 2006 (11) case report usa 1 case use of marijuana na inhaling up to five marijuana cigarettes per day na with bladder cancer for 30 days as the only risk factor for transitional cell carcinoma. rob: risk of bias. na: not applicable. archivio italiano di urologia e andrologia 2022; 94, 2 v. mehrnoush, s.g. de lima, a. kotb, m.e. hyndman 250 included studies characteristics three studies with moderate risk of bias (mainly due to limited information regarding the average marijuana exposure and inadequate adjustment for key confounders) were included for review. table 1 shows the specific details of each. discussion cannabinoids have been shown in studies to inhibit tumor cell growth and induce apoptosis in a variety of cancer cells (5-7). despite widespread cannabis use and evidence of cannabinoids' antitumor activity, little is known about the carcinogenic effects of cannabis, which has been highlighted after cannabis legalization. the findings on the effect of cannabis on other urinary malignancies vary. the only clinical study on penile cancer and cannabis found no link (7). cannabis use appears to be an independent risk factor for the development of testicular germ cell tumors (9-11). the result of a study on the effect of cannabis on prostate cancer did not find a link between cannabis and prostate cancer risk (8); however, in vitro and animal studies strongly suggest that cannabinoids protect against prostate cancer development (9). the clinical studies on renal cancer merely characterized cannabinoid receptor expression in renal neoplasms (10). two studies yielded contradictory results on cannabis and bladder cancer according to our review. chacko et al. compared 52 men under the age of 60 with transitional cell urothelial carcinoma to 104 age-matched controls. their findings revealed that habitual marijuana use was present in 88.5% of patients with bladder cancer while 69.2% of the control group (p = 0.008), implying that marijuana use is associated with an increased risk of bladder cancer (4). this is consistent with the findings of a case report of 45-year-old man in whom excessive marijuana smoking (up to five marijuana cigarette daily more than 30 years was found to be the only risk factor for developing bladder cancer (11). a recent study by thomas et al., which examined the records of 84170 men aged 45-69 years from the california men's health study and followed them for 11 years, discovered that bladder cancer developed in 0.3% of men who used cannabis and 0.4% of men who did not use cannabis (p = 0.001), leading the authors to conclude that cannabis use was associated with a 45% risk reduction in the bladder cancer incidence (5). however, the studies were limited by insufficient adjustment for confounders. knowing the physiology of the tissue expression of cannabinoid receptors can shed more light on the potential role of cannabis in bladder cancer. tyagi et al. found cb1 and cb2 receptors in the urothelium of human bladder (12). both receptors were present in the bladder urothelium and detrusor muscles, but cb1 expression was found to be significantly higher than cb2. cb1 and cb2 receptor expression was twice as high in urothelium as it was in detrusor muscles (12). cannabis has primarily been studied in terms of regulating inflammation and urgency in the treatment of bladder conditions. cb2 agonists have been shown to reduce the severity of murine bladder inflammation when locally administered after acrolin, an inflammatory agent (13). as part of the cannabinoids in multiple sclerosis (cams) study, freeman et al. investigated the effect of cannabinoids on urge incontinence. they assigned 630 patients with multiple sclerosis to receive either cannabis extract, thc, or a matched placebo via oral administration. urge incontinence was significantly reduced with cannabis (38%), and thc (33%), versus placebo (18%) (14). kavia et al. also found that sativex (thc + cannabidiol) can also a positive impact on overactive bladder symptoms in patients with multiple sclerosis (15). the existing small body of evidence indicates that cannabis has a direct effect on the bladder during elimination where the resulting direct contact with the bladder urothelium can cause change in urine peptides and urothelial expression of cb1 and cb2 receptors. although it is currently difficult to study cannabis's effects on the bladder, legalization may increase this possibility due to the increased openness of the population regarding their use of cannabis. because of the long latency nature of bladder cancer development, more robustly designed studies with long-term follow-up are warranted. given the gaps in current knowledge, the authors pose the following dire questions for future observation and study: will cannabis reduce or increase the incidence of bc? will cannabis influence bc aggression in a positive or negative way? will new pathological types of bc emerge? many questions may arise, but only observation and ongoing research will allow us to begin finding true, conclusive evidence. conclusions the role of cannabis in bladder cancer has been seldom studied. the small number of studies show contradictory findings; potential carcinogenic vs protective effect. the growing interest in cannabis use after legalization necessitates further investigations with a robust design to assess the long-term effect of cannabis on bladder cancer. references 1. russell c, rueda s, room r, et al. routes of administration for cannabis use basic prevalence and related health outcomes: a scoping review and synthesis. int j drug policy. 2018; 52:87-96. 2. felder cc, dickason-chesterfield ak, moore sa. cannabinoid biology: the search for new therapeutic targets. mol interv. 2006; 6:149-61. 3. skeldon sc, goldenberg sl. urological complications of illicit drug use. nat rev urol. 2014; 11:169-77. 4. chacko ja, heiner jg, siu w, et al. association between marijuana use and transitional cell carcinoma. urology. 2006; 67:100-4. 5. thomas aa, wallner lp, quinn vp, et al. association between cannabis use and the risk of bladder cancer: results from the california men’s health study. urology. 2015; 85:388-92. 6. wells g, o’connell d, peterson j. the newcastle-ottawa scale (nos) for assessing the quality of non-randomized studies in metaanalysis | request pdf. 2000; available from: https://www.researchgate.net/publication/261773681_the_newcastle-ottawa_scale_ 251archivio italiano di urologia e andrologia 2022; 94, 2 bladder cancer and cannabis nos_for_assessing_the_quality_of_non-randomized_studies_ in_meta-analysis. 7. maden c, sherman kj, beckmann am, et al. history of circumcision, medical conditions, and sexual activity and risk of penile cancer. j natl cancer inst. 1993; 85:19-24. 8. sidney s, quesenberry cpj, friedman gd, tekawa is. marijuana use and cancer incidence (california, united states). cancer causes control. 1997; 8:722-8. 9. ramos ja, bianco fj. the role of cannabinoids in prostate cancer: basic science perspective and potential clinical applications. indian j urol. 2012; 28:9-14. 10. rajanahally s, raheem o, rogers m, et al. the relationship between cannabis and male infertility, sexual health, and neoplasm: a systematic review. andrology. 2019; 7:139-47. 11. nieder am, lipke mc, madjar s. transitional cell carcinoma associated with marijuana: case report and review of the literature. urology. 2006; 67:200. 12. tyagi v, philips bj, su r, et al. differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. j urol. 2009; 181:1932-8. 13. wang z-y, wang p, bjorling de. activation of cannabinoid receptor 2 inhibits experimental cystitis. am j physiol regul integr comp physiol. 2013; 304:r846-53. 14. freeman rm, adekanmi o, waterfield mr, et al. the effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (cams-luts). int urogynecol j pelvic floor dysfunct. 2006; 17:636-41. 15. kavia rbc, de ridder d, constantinescu cs, et al. randomized controlled trial of sativex to treat detrusor overactivity in multiple sclerosis. mult scler. 2010; 16:1349-59. correspondence vahid mehrnoush, md vahidmehrnoush7@gmail.com department of urology, northern ontario school of medicine thunder bay, ontario (canada) stacy grace de lima, bsc stacy.ggibson@gmail.com inflammation research network-snyder institute for chronic disease, departments of physiology & pharmacology and medicine, university of calgary cumming school of medicine, calgary, alberta (canada) ahmed kotb, md, frcsc (corresponding author) drahmedfali@gmail.com northern ontario school of medicine tbrhdc, 980 oliver road thunder bay, ontario (canada) p7b 6v4 matthew eric hyndman, md, frcsc (corresponding author) erichyndman@shaw.ca southern alberta institute of urology, 7007 14 street sw, calgary, ab, canada. t2v 1p9 stesura seveso 173archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. management (1). for the treatment of the upper tract urinary stones in the pediatric population, extracorporeal shock wave lithotripsy (eswl) is still the first-line management option. however, the unpredictable outcome and lower stone-free rates (sfr) are the main disadvantages of this approach (2). on the other hand, using a retrograde intrarenal surgery (rirs) in children might cause vesicoureteral reflux and ureteral strictures and require a longer general anesthesia duration (2). several studies demonstrated acceptable sfr using mini-pcnl in the pediatric population (2, 3). short hospitalization and decreased incidence of bleeding are the main advantages of the mini-pcnl procedure. in contrast, there are some downsides, including prolonged operation time and the need for miniature-sized instruments. an ideal minipcnl tract size in children is the smallest tract possible, as long as it provides enough space for removing the stone fragments. this decrease in the tract size results in a decreased risk of bleeding (3). when performing access to the pyelocaliceal system (pcs) system, for guidance, the surgeon might choose fluoroscopy or ultrasonography (us), based on his/her experience with these devices, their availability in the operation room, and the patient's calyceal anatomy. advantages of using the us as guidance is decreased exposure to radiation and overall cost, decreased rate of visceral injury due to better visualization of adjacent organs, safety in pregnancy, real-time visualization of the pcs and renal parenchyma, better differentiation of the anterior and posterior calyx, detection of radiolucent stones, and the potential to avoid vascular injury by adding doppler flow imaging (3, 4). critical appraisal of mini-pcnl techniques and evaluation of their outcomes in children remain under-reported. therefore, we evaluated the safety and efficacy of usg versus fg mini-pcnl in children in our center. materials and methods this study was approved by the ethics committees of shiraz university of medical sciences (approval code# background: miniaturization of endoscopic instruments in percutaneous nephrolithotomy (pcnl) allowed less invasive procedures with low complication rates, especially in children. this study was conducted to evaluate the safety and efficacy of ultrasonography-guided (usg) versus fluoroscopy-guided (fg) mini-pcnl in children. materials and methods: this is a retrospective comparative study conducted from june 2015 to june 2020. the sample included 70 children (35 pateints underwent usg mini-pcnl and 35 pateints underwent fg mini-pcnl). they were compared mainly by the patients’ demographic characteristics, procedural information, and post-treatment outcomes. in the usg mini-pcnl group, puncturing was performed using a 3.5 mhz us probe, whereas fluoroscopy was utilized in the fg minipcnl group. results: both groups were comparable in terms of gender, previous history of failed eswl, and hydronephrosis grade. the mean stone burden was 15.94 ± 3.69 mm and 19.20 ± 7.41 mm in usg and fg groups, respectively (p = 0.024). the stonefree rate (sfr) was 97.1% in the usg group and 94.3% in the fg group, which was not statistically significant (p = 0.16). mean operative time in the usg group and fg group was 69.00 ± 13.33 minutes and 63.48 ± 16.90 minutes, respectively. four (11.4%) patients in the fg group required blood transfusions to restore the hemodynamic state (p = 0.039). fever was detected in 4 (11.4%) patients in the usg group and 15 (31.4%) patients in the fg group (p = 0.041). conclusions: in children, mini pcnl under usg is safe and as effective as fluoroscopy. key words: fluoroscopy; minimal invasive; nephrolithotomy; percutaneous; ultrasonography. submitted 28 january 2021; accepted 13 march 2021 introduction epidemiologic studies have confirmed the continually growing rate of urinary stone disease in the pediatric population over the past years. due to stone sizes and higher recurrence rate, while being less common than adults, pediatric urinary tract stones require much more difficult minimal invasive percutaneous nephrolithotomy (mini-pcnl) in children: ultrasound versus fluoroscopic guidance ali eslahi 1, 2, faisal ahmed 3, mohammad mehdi hosseini 4, mohammed reza rezaeimehr 5, nazanin fathi 5, hossein-ali nikbakht 6, mohammad reza askarpour 1, seyed hossein hosseini 1, khalil al-naggar 3 1 department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 2 shiraz geriatric research center, shiraz university of medical sciences, shiraz, iran; 3 urology research center, al-thora general hospital, department of urology, ibb university of medical since, ibb, yemen; 4 shiraz nephrology-urology research center, shiraz university of medical sciences, shiraz, iran; 5 student research committee, shiraz university of medical sciences, shiraz, iran; 6 social determinates of health research center, department of biostatics and epidemiology, faculty of medicine, babol university of medical sciences, babol, iran. doi: 10.4081/aiua.2021.2.173 summary archivio italiano di urologia e andrologia 2021; 93, 2 a. eslahi, f. ahmed, m.m. hosseini, m. reza rezaeimehr, n. fathi, h.-ali nikbakht, m. reza askarpour, s. hossein hosseini, k. al-naggar 174 ir.sums.med.rec.1399.638). all pediatric patients who had undergone ultrasound and fluoroscopy-guided mini-pcnl in our referral centers (namazi teaching hospital and ali-asghar teaching hospital, shiraz, southern iran) from june 2015 to june 2020 were enrolled in our study. we gathered the patients' preoperative data, including age and gender, us finding, previous history of eswl failure, stone characteristics such as radiopacity, location, and size. we also gathered perioperative clinical lab data, including complete blood count (cbc), renal function test [blood urea nitrogen (bun) and creatinine], and urine culture. positive cultures were treated with proper antibiotics and admitted with sterile urine for operation. operation and post-operation data including the length of operation, sfr, and hospitalization period were also gathered. using the modified clavien grading system (5), we classified the post-operative complications into five grades. this grading system describes fever as grade i; blood transfusion need, urine leakage, and urinary tract infection as grade ii; double-j placement for urine leakage, ureteroscopy, and need to an axillary procedure as grade iii; urosepsis and neighboring organ injury as grade iv; and death as grade v. the inclusion criteria were age under 18 years, normal renal function, renal stones more than 10 mm, and/or history of previous eswl failure. the exclusion criteria were all cases with active urinary tract infection (uti), uncorrected coagulopathy, congenital abnormalities, and those patients who had undergone transplant or urinary diversion. surgical procedure all patients were admitted 6 hours before the operation and received parenteral hydration and a single prophylactic antibiotic dose. the procedure was done under general anesthesia. in supine position with abducted thigh position, a ureteral catheter 3 fr or 4 fr was inserted into the kidney and taped to a fixed urethral foley catheter (8-12 fr depending on the patients’ age and size). then, the patient was switched into the prone position. after proper padding of the chest, abdomen, knee, and ankle, the patient was draped with sterile coverage. considering the children's increased risk of hypothermia, the patients were kept warm throughout the procedure. in ultrasound guidance group by performing color-doppler us guidance with a 3.5mhz probe (bk medical), the pcs was visualized. based on the child’s age and degree of hydronephrosis, the optimal tract length was chosen. using a one-shot dilatation technique, we passed an 18-gauge access needle into the target calyx using a curved us probe. afterward, its stylet was removed, and 0.035-inch jtipped guidewire was introduced into the targeted calyx. the skin was incised, and an 8 fr polyurethane dilator first dilated the nephrostomy tract and was then removed. alken was then inserted to guide 18 fr amplatz dilator into the pcs. using the length of the measured tract and amplatz shadow for precise placement, we passed the amplatz sheath into the pcs. after confirmation of the amplatz sheet optimal position, both amplatz dilator and alken were removed, leaving the amplatz sheath and guidewire in place. using a 15 fr rigid nephroscope, we performed the nephroscopy to pinpoint the stones' site and then crush them with a pneumatic lithoclast. all stone particles were removed by forceps. all steps, including sfr status, were monitored under the guidance of the us without using fg. in fluoroscopic guidance group for better visualization of the pcs, the contrast was injected through the ureteral catheter. then, under the fg, an 18-gauge needle was passed into the system. next, a safety guidewire was introduced into the pcs. the rest of the procedure was the same as described in the usg group; yet, it was carried out under fg. the tubeless procedure was only performed in those patients with single tract access, minimal bleeding, no significant perforation injuries or residual stones, and no secondary procedure requirement. post-surgery, after 12 to 24 hours, urethral foley and ureteral stent catheter were removed. nephrostomy tubes were removed on the second day after the operation. a plain abdominal film (kub x-ray) and the us was done on the day after the operation, and residual stones, if presented, were followed at least eight weeks for spontaneous passage of fragments less than 4-5 mm. statistical analysis the mean ± sd, median, and inter-quartile range (iqr) described the quantitative variables, and for qualitative variables, frequency (percent) was used. nonparametric test was used if data distribution was not standard. chi-square test was used to assess the potential statistically significant difference. anova was applied to compare the difference of the means between more than two different levels. a p-value of less than 0.05 was considered statistically significant. all data were analyzed using spss version 20 software. results demographic characteristics of the patients and the stone of the two groups are shown in table 1. the total number of patients in each group was 35 patients. in the usg group, the mean age was 5.68 ± 3.05 years, and in the fg group, it was 7.47 ± 3.75 years (p = 0.032). the mean stone size was 15.94 ± 3.69 mm (range15-40 mm) and 19.20 ± 7.41 mm (range15-40 mm) in the usg and fg groups, respectively (p = 0.024). successful access to the target calyx and collecting system was 100% in both groups. the mean length of the tract was 3.17 ± 0.35 mm in the usg group and 3.19 ± 0.37 mm in the fg group. the mean access time to the pcs in the usg group was 1.60 ± 0.70 minutes, while it was 1.56 ± 0.56 minutes in the fg group. mean operative time in the usg group was 69.00 ± 13.33 minutes, and in the fg group, it was 63.48 ± 16.90 minutes. the initial stone-free rate was 94.3% in the usg group and 94.3% in the fg group. however, the final stone-free rate was 97.1% in the usg group and 94.3% in the fg group. the hospital stay was 45.94 ± 4.58 hours and 46.40 ± 5.15 hours in the usg and fg groups. post-operative nephrostomy insertion was performed in 5 (14.3%) patients in the usg group and 11 (31.4%) patients in the fg group (p = 0.088). according to modified clavien classification, grade 1 complications [fever (axillary temperature more than 38° c)] was 31.4% in the fg group versus 11.4% in the usg group (p = 0.041). all patients were treated with suitable antipyretics and antibiotics. regarding grade 2 complications, 4 (11.4%) patients in the fg group experienced intraoperative bleeding, which required transfusions to restore the hemodynamic state (p = 0.039), while the rate of grade 3 complications (need for additional surgery, eswl) was 5.7% in the fg group versus 2.9% in the usg group. the rate of grade 4 complications (urosepsis) was 2.9% in the fg group. other significant complications were not detected (table 2). discussion we have suggested us-guided mini-pcnl as a harmless choice for managing pediatric renal calculi with excellent outcomes and little complications in the present study. abnormalities in the urinary tract anatomy, metabolic disorders, and infections are the most common causes of urinary tract stone formation, especially in pediatric cases (3). in the upper tract calculi, eswl, pcnl, and rirs are standard treatment options in children. we preferred to treat the stones with the least invasive options since the stone recurrence rate is high. thus, eswl is the preferred option for stones less than 20 mm in diameter. however, eswl lower stone free rate, the possibility of increasing hypertension and diabetes mellitus in the long-term and the possible need for multiple treatment sessions are main limitations of this procedure since complete stone removal is the target (6, 7). the technology of miniaturization of the access sheath has progressed recently, and the miniaturized pcnl has recently been categorized into mini-pcnl (≤ 22fr), chinese mini-pcnl (14-20fr), super-mini-pcnl (1014 fr), ultra-mini-pcnl (11-13fr), micro-pcnl (4.8fr), and mini-micro-pcnl (8 fr) (8). several studies have investigated the outcome and safety of mini-pcnl and reported that mini-pcnl was associated with less bleeding and postoperative pain, similar sfr, and lower complication rates than the standard pcnl (9-11). usg mini-pcnl has many advantages, such as an ongoing monitoring of the surrounding tissues and vessels during the procedure, increased accuracy in access to the stone, less staff exposure to radiation, and no need for contrast injection (12). since the tract to the collecting system is shorter in the pediatric population than adults, the us makes it easier for safer tract dilation and precise placement of the needle to the collecting system (13). it was recommended that when used by experienced hands, usg could be a safe and effective alternative to fluoroscopy as guidance (4, 6). despite all the mentioned benefits of using the us in mini-pcnl, it has one major limitation. as an operator-dependent modality, the experience of a surgeon with the us is a major key factor. an additional limiting factor is the low echogenicity of amplatz dilatator and amplatz sheath (14). with a decent residency training program, we can improve the speed of the learning curve. it is suggested that this method should be initially performed in adult patients with simple calculi and it should be performed in younger children with larger complex stones only when the surgeon is fully experienced (13). tian et al. studied the feasibility and safety of ambulatory mini-pcnl on the upper urinary tract calculi; based on the results, the age and stone size showed no effect on the surgery outcome (15). like our study, the mean age and stone size were not statistically equal between the groups. in our study, the average stone size was 15.9 mm in the usg group and 19.2 mm in the fg group. since managing larger stones requires a well-experienced surgeon in order to avoid the need for a second-lookpcnl, this may explain the tendency in surgeons to choose the standard pcnl technique in patients with larger stones. resorlu et al. studied the effect of previous 175archivio italiano di urologia e andrologia 2021; 93, 2 mini pcnl using ultrasound versus fluoroscopy table 1. demographic and clinical characteristics of the patients. variable fluoroscopic ultrasonographic p value group (35) group (35) age (years) a 7.47 ± 3.75 5.68 ± 3.05 0.032 gender b male 23 (65.7%) 25 (71.4%) 0.607 female 12 (34.3%) 10 (28.6%) size of stone (mm) a 19.20 ± 7.41 15.94 ± 3.69 0.024 history of failed eswl b 8 (22.9%) 11 (31.4%) 0.420 previous pcnl b 10 (28.6%) 9 (25.7%) 0.788 single kidney b 8 (22.9%) 0 (0.0%) 0.003 history of uti b 11 (31.4%) 5 (14.3%) 0.088 stone opacity b radiopaque 26 (74.3%) 35 (100.0%) 0.001 radiolucent 9 (25.7%) 0 (0.0%) hydronephrosis grade b mild 18 (51.4%) 20 (57.1%) 0.855 moderate 13 (37.1%) 12 (34.3%) sever 4 (11.4%) 3 (8.6%) laterality b right 8 (22.9%) 22 (62.9%) 0.001 left 27 (77.1%) 13 (37.1%) p-values of < 0.05 were considered significant. a data was presented as mean ± sd; b data was presented as n (%). eswl = extracorporeal shock wave lithotripsy; pcnl = percutaneous nephrolithotomy; uti = urinary tract infection. table 2. intraoperative and postoperative data. variable fluoroscopic ultrasonographic p value group (35) group (35) fluoroscopy screening time (minutes) a 0.60 ± -0.46 0.0001 length of tract (mm) a 3.19 ± 0.37 3.17 ± 0.35 0.845 access time (minutes) a 1.56 ± 0.56 1.60 ± 0.70 0.780 hemoglobin drop (mg/dl) a 2.21 ± 2.59 0.74 ± 0.29 0.002 residual stone > 5 mm b 2 (5.7%) 1 (2.9%) 1.00 hospital stays (hours) a 46.40 ± 5.15 45.94 ± 4.58 0.696 operation time (minutes) a 63.48 ± 16.90 69.00 ± 13.33 0.134 post op nephrostomy b 11 (31.4%) 5 (14.3%) 0.088 initial success rate b 33 (94.3%) 33 (94.3%) 1.000 final success rate b 33 (94.3%) 34 (97.1%) 0.574 *complications grade 1 fever b 15 (31.4%) 4 (11.4%) 0.041 complications grade 2 blood transfusion b 4 (11.4%) 0 (0.00%) 0.039 complications grade 3 2nd-look eswl b 2 (5.7%) 1 (2.9%) 0.931 p-values of < 0.05 were considered significant. a data was presented as mean ± sd; b data was presented as n (%). *complication rate according to clavien–dindo score and types. eswl = extracorporeal shock wave lithotripsy. archivio italiano di urologia e andrologia 2021; 93, 2 a. eslahi, f. ahmed, m.m. hosseini, m. reza rezaeimehr, n. fathi, h.-ali nikbakht, m. reza askarpour, s. hossein hosseini, k. al-naggar 176 open renal surgery and failed eswl on the outcomes of pcnl and reported no significant increase in the risk of pcnl complication (16). likewise, in our study, a history of failed eswl, previous renal surgery, or pcnl, the grade of hydronephrosis and stone location were not statistically significant between the fg and usg groups. for an ideal pcnl outcome, optimal percutaneous access to the pcs is a must. this is achieved under fluoroscopy, us, or ct guidance with a success rate between 86.7-100% (4, 17). in our study, we have a 100% access success rate in both groups. whether using fg or usg, the success rate was the same for accessing the pcs. in the present study, all stones were opaque in the usg group. at the same time, 74% of the fg group patients had opaque stone (p = 0.001). in previous studies, it has been suggested that the incidence of non-opaque stones is accompanied by longer operative times and increased complications, which was noticed in our article (18). zhu et al. reported sfr according to different stone sizes and complexities. in this study, pcnl sfr of us guidance was similar to pcnl with fluoroscopy guidance when treating simple kidney stones (stone scores of 56), but pcnl with fluoroscopy guidance was more effective when stone complexity was higher (stone scores of 7-8). the final sfr was 69.8% for pcnl with us guidance vs. 89.4% for pcnl with fluoroscopy guidance (19). in a systematic review including 14 studies, minipcnl, and ultra mini-pcnl, the sfr was 80%-100% (3). similar to the others, our study showed a stone-free rate of 94.3% vs. 97.1% in the fg and usg groups, respectively, without any statistically significant difference (p = 0.57). our study showed no significant differences in the operative time (63.48 vs. 69.00) in minutes between us-guided and fluoroscopy-guided groups. in another study, the mean operation time in the usg and fg groups was reported to be 88.92 and 79.28 minutes, respectively (20). in our studies, gaining access to the pcs under us guidance was similar to the fluoroscopic-guided access. the mean access time was 1.56 ± 0.56 minutes in the usg group vs. 1.60 ± 0.70 minutes in the fg group. in another study by falahatkar et al., the duration of access to the target calyx was 14.36 ± 14.84 seconds in the usg group vs.14.78 ± 25.54 seconds in the fg group (14). the mean access time to pcs and mean operative time is similar to other studies with no statistically significant difference (12, 21, 22). additionally, the usg had zero radiation exposure. in a systemic review, less than 1% of the patients had a nephrostomy tube placed (3). in our study, nephrostomy drainage time was higher in the fg group, which defies the result of the previously published article (14). this might be due to better visualization of pcs in the usg group and larger stone size in the fg group. the hospital stay was 45.94 ± 4.58 hours in the usg and 46.40 ± 5.15 hours in the fg group (range 2-4 days) in our study, while other studies reported 2.7 to 4.1 days (4, 23). therefore, there was no significant difference in the hospital stay, similar to previous studies. using the clavien-dindo grading system, we found that the overall operative complication rates were not similar. we noticed a relatively higher postoperative fever rate in the fg group [11.4% versus 31.4%, (p = 0.041)]. a higher positive preoperative urine culture in the fg group, an essential prognostic factor for postoperative infectious complications, more nonopaque stones in the fg groups, and shorter time in usg to access the collecting system could explain this higher rate in the fg groups (19). in the present study, four patients in the fg group experienced intraoperative bleeding, which required blood transfusions with patients' successful recovery. this finding is in the same line with andonian et al.’s findings (24). however, a systematic review revealed no significant difference between usg and fg regarding bleeding (22). our explanation was better visualization of the vital organ in the us group and us ability to provide information on the surrounding viscera and the depth of needle penetration and to provide distinguishing images to identify the posterior and anterior calyces (25). two patients needed an axillary procedure (eswl) in the fg group, while one patient needed it in the usg group. additionally, one patient developed urosepsis in the fg group, which was treated with proper antibiotics. in the study by guven et al., which included 107 children aged less than14 years, ureteroscopy was needed in two patients and second-look pcnl in nine patients (26). in another multicentric study on 1205 children, there was one death case due to septic shock (27). no significant complications such as pneumothorax or hydrothorax, colon damage, or any adjacent injuries occurred in both groups, almost similar to previous articles (3). the retrospective nature of this study and the small sample size was our significant limitations. randomization was not done in our study, and we detected the heterogenicity of the stone size and age between our groups. we performed all mini-pcnls in the prone position, and postprocedure imaging was almost limited to plain xr or us. the prone positioning was performed in all of the patients during the procedures. stone composition analysis data were also unavailable. no specific information was available about the operators' experience or the number of surgeons operating on children. therefore, further investigations of the long-term effects in a large sample size with one endourologist are recommended. conclusions our study supports the results of previous studies, suggesting us-guided mini-pcnl as a harmless choice for managing pediatric renal calculi with excellent outcomes and little complications. acknowledgments the authors would like to thank shiraz university of medical sciences, shiraz, iran and, also the center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. references 1. ward jb, feinstein l, pierce c, et al. pediatric urinary stone disease in the united states: the urologic diseases in america project. urology. 2019; 129:180. 177archivio italiano di urologia e andrologia 2021; 93, 2 mini pcnl using ultrasound versus fluoroscopy 2. srisubat a, potisat s, lojanapiwat b, et al. extracorporeal shock wave lithotripsy (eswl) versus percutaneous nephrolithotomy (pcnl) or retrograde intrarenal surgery (rirs) for kidney stones.cochrane database syst rev. 2014:cd007044. 3. jones p, bennett g, aboumarzouk om, et al. role of minimally invasive percutaneous nephrolithotomy techniques-micro and ultra-mini pcnl (<15f) in the pediatric population: a systematic review. j endourol. 2017; 31:816. 4. basiri a, ziaee sa, nasseh h, et al. totally ultrasonographyguided percutaneous nephrolithotomy in the flank position. j endourol. 2008; 22:1453. 5. tefekli a, karadag ma, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008; 53:184. 6. hong y, ye h, yang b, et al. ultrasound-guided minimally invasive percutaneous nephrolithotomy is effective in the management of pediatric upper ureteral and renal stones. j invest surg. 2020:1. 7. ahmed f, askarpour m-r, eslahi a, et al. the role of ultrasonography in detecting urinary tract calculi compared to ct scan. res rep urol. 2018; 10:199. 8. zeng g, zhu w, lam w. miniaturised percutaneous nephrolithotomy: its role in the treatment of urolithiasis and our experience. asian j urol. 2018; 5:295. 9. haghighi r, zeraati h, ghorban zade m. ultra-mini-percutaneous nephrolithotomy (pcnl) versus standard pcnl: a randomised clinical trial. arab j urol. 2017; 15:294. 10. elsheemy ms, elmarakbi aa, hytham m, et al. mini vs standard percutaneous nephrolithotomy for renal stones: a comparative study. urolithiasis. 2019; 47:207. 11. izol v, satar n, bayazit y, et al. which factors affect the success of pediatric pcnl? single center experience over 20 years. arch ital urol androl. 2020; 92:345-9. 12. agarwal m, agrawal ms, jaiswal a, et al. safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (pcnl). bju int. 2011; 108:1346. 13. desai m. ultrasonography-guided punctures-with and without puncture guide. j endourol. 2009; 23:1641. 14. falahatkar s, allahkhah a, kazemzadeh m, et al. complete supine pcnl: ultrasound vs. fluoroscopic guided: a randomized clinical trial. int braz j urol. 2016; 42:710. 15. tian y, yang x, luo g, et al. initial prospective study of ambulatory mpcnl on upper urinary tract calculi. urol j. 2020; 17:14. 16. resorlu b, kara c, senocak c, et al. effect of previous open renal surgery and failed extracorporeal shockwave lithotripsy on the performance and outcomes of percutaneous nephrolithotomy. j endourol. 2010; 24:13. 17. basiri a, ziaee am, kianian hr, et al. ultrasonographic versus fluoroscopic access for percutaneous nephrolithotomy: a randomized clinical trial. j endourol. 2008; 22:281. 18. maghsoudi r, etemadian m, kashi ah, ranjbaran a. the association of stone opacity in plain radiography with percutaneous nephrolithotomy outcomes and complications. urol j. 2016; 13:2899. 19. zhu w, li j, yuan j, et al. a prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. bju int. 2017; 119:612. 20. osman m, wendt-nordahl g, heger k, et al. percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. bju int. 2005; 96:875. 21. abed sm, alhamdani n. ultrasonographic guidance versus fluoroscopic guidance for renal access in percutaneous nephrolithotomy (pcnl): a comparative study.iraqi j med sci. 2019; 18:335. 22. corrales m, doizi s, barghouthy y, et al. ultrasound or fluoroscopy for percutaneous nephrolithotomy access, is there really a difference? a review of literature. j endourol. 2021; 35:241-248. 23. karami h, rezaei a, mohammadhosseini m, et al. ultrasonography-guided percutaneous nephrolithotomy in the flank position versus fluoroscopy-guided percutaneous nephrolithotomy in the prone position: a comparative study. j endourol. 2010; 24:1357. 24. andonian s, scoffone cm, louie mk, et al. does imaging modality used for percutaneous renal access make a difference? a matched case analysis. j endourol. 2013; 27:24. 25. lojanapiwat b. the ideal puncture approach for pcnl: fluoroscopy, ultrasound or endoscopy?. indian j urol. 2013; 29:208. 26. guven s, frattini a, onal b, et al. percutaneous nephrolithotomy in children in different age groups: data from the clinical research office of the endourological society (croes) percutaneous nephrolithotomy global study. bju int. 2013; 111:148. 27. onal b, dogan hs, satar n, et al. factors affecting complication rates of percutaneous nephrolithotomy in children: results of a multi-institutional retrospective analysis by the turkish pediatric urology society. j urol. 2014; 191:777. correspondence ali eslahi, md alieslahi@yahoo.com mohammad mehdi hosseini, md mmhosseini66@gmail.com mohammed reza rezaeimehr, md maareza2000@gmail.com nazanin fathi, md nazaninfathi1997@gmail.com mohammad reza askarpour, md askarvip2@gmail.com seyed hossein hosseini, md shhosseini_6687@yahoo.com urology office, faghihi hospital, zand blvd., shiraz (iran) faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com khalil al-naggar, md alnajjarkh1234@gmail.com urology office, althora general hospital, alodine street, ibb (yemen) hossein-ali nikbakht, md ep.nikbakht@gmail.com social determinates of health research center, babol university of medical sciences, babol, (iran) stesura seveso 313archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. for larger volume stones, but with few severe complications (4, 5); on the other hand, other studies described also life threatening complications of rirs. in every day practice is rirs a really uncomplicated technique? what are the real risks? the purpose of this study is to report the stone free rate (sfr) and clinical complications in patients submitted to rirs. materials and methods outcomes of 514 (mean age was 55 yrs; range: 24-84) consecutive patients (313 males and 201 females) who underwent rirs for renal stones from january 2014 to february 2020 have been retrospectively analyzed. 213 (41.4%) vs 301 (68.6%) stones were located in the right and left kidney; in detail, 213 (41.3%) vs 101 (19.5%) vs 75 (10.6%) vs 239 stones (46.6%) were located in the lower pole vs the middle pole vs the upper pole vs the renal pelvis, respectively. the median stone size was 1.3 cm (range 0.6-3 cm), in 128/514 (24.9%) cases the stones were multiple; ct stone density (hu) 859 (range 436 1674). preintervention double-j stenting was performed in 208/571 (36.5%) cases. overall sfr was evaluated after 3 months following the procedure by means of a non-contrast computed tomography (n-cct). patients who were not considered stone free at the end of the procedure were rescheduled for second look. success was considered as stone-free status or ≤ 0.4 cm fragments clinically insignificant residual fragments (cirf). the 30 days complication rate was classified according to the clavien-dindo (cd) classification system (6). surgical technique all patients were operated in the standard lithotomy position, under general or spinal anesthesia according to anesthetist-patients counseling. preliminary semirigid ureteroscopy (using a 6.5-7 f. ureterorenoscope) was performed to observe the ureter and obtain a preconditioning ureteral dilation. a ureteral access sheath (uas) was positioned (10/12 or 12/14 f retrace® coloplast; 9.5/11.5 or 10.7/12.7 f flexor® cook urological) depending on the ureteral diamintroduction: the purpose of this study is to report the stone free rate (sfr) and clinical complications in patients submitted to retrograde intrarenal surgery (rirs). materials and methods: a total of 571 procedures of upper urinary stones treated using flexible ureteroscopy and holmium laser lithotripsy from january 2014 to february 2020 have been analyzed. overall sfr was evaluated after 3 months following the procedure by means of a non-contrast computed tomography. success was considered as stone-free status or ≤ 0.4 cm fragments. results: the overall sfr was 92.3% in group 1 (stone size: < 1 cm), 88.3% in group 2 (stone size: > 1 ≤ 2 cm), 56.7% in group 3 (stone size: 2-3 cm) and 69.6% in group 4 (multiple stones). post-operative complications, according to the claviendindo (cd) classification system, were recorded in 32 (5.6%) procedures. the major complications recorded were: one case of subcapsular hematoma (srh) associated with pulmonary embolism two days after the procedure (cd grade iiia) treated conservatively and one case of hemorrhagic shock 2 hour with multiple renal bleedings requiring urgent nephrectomy (cd grade iva). conclusions: the rirs is an effective and safe procedure with a high sfr significantly correlated with the stone size; at the same time, rirs could be characterized by severe clinical complications that require rapid diagnosis and prompt treatment. key words: rirs; complications; stone free rate. submitted 18 march 2021; accepted 7 may 2021 introduction the retrograde intrarenal surgery (rirs) was introduced in 2008 as an alternative to extracorporeal shock wave lithotripsy (eswl) and percutaneous nephrolithotomy (pnl) in patients with eswl-refractory and lower pole stones; today, according to the more recent european guidelines (eau guidelines), rirs represents one of the first line treatments for < 2 cm renal stones (1, 2). in fact, in 2013 eau guidelines rirs has been reported as an effective and definitive therapeutic option for renal stones with higher stone free rate (sfr) and low rate of complications (3). many studies have compared rirs to percutaneous surgery (pnl) with results that seem to be similar even stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (rirs): our experience in 571 consecutive cases orazio maugeri 1, ettore dalmasso 2, dario peretti 2, fabio venzano 2, germano chiapello 2, carlo ambruosi 2, claudio dadone 2, astrid bonaccorsi 1, pietro pepe 1, letterio d’arrigo 1, michele pennisi 1 1 urology unit cannizzaro hospital, catania, italy; 2 urology unit s. croce and carle hospital, cuneo, italy. doi: 10.4081/aiua.2021.3.313 summary archivio italiano di urologia e andrologia 2021; 93, 3 o. maugeri, e. dalmasso, d. peretti 314 eter and compliance. the length of the uas inserted was 35 cm for women, 45 cm for men. fluoroscopy was always performed in all cases for instrumentation and control. a 7.5 f flexible fiberoptic ureteroscope and a 200 or 272 micron fiber were used depending on the type of laser. stone treatment consisted in fragmentation and/or dusting, performed by sphinx® jr 30w ho:yag laser system (lisa laser) (412 cases; 72.1%), or 120-w high-power ho:yag laser system (lumenis® ltd.,) (104 cases; 18.2%) or dornier medilas h solvo 30 watt holmium:yag laser (olympus®) (55 cases; 9.6%), depending on the availability of the different lasers case by case. the most appropriate setting and technique depended on stone size and hardness and on the laser used (table 4). for stone size < 1 cm the treatment of choice was fragmentation and complete extraction of the fragments using a zero tip 1.9 fr nitinol basket. for stone size > 1 or ≤ 3 cm rirs procedure was composed by 3 phases: 1) first phase: stone dusting using low energy, high frequency and long pulse width with a persistent contact between laser fiber and stone. 2) extraction of fragments: the major fragments derived from stone dusting were extracted using a zero tip 1.9 fr nitinol basket. all fragments were conserved for stone analysis. 3) second stage: “popcorn effect”: high energy, high frequency and short pulse duration. continuous irrigation with gravity drainage (40 to 50 cm h2o) and syringe-based systems were gently applied to obtain and sustain a clear the operative field. at the end of the procedure a 4.8-6 fr double j stent was placed in radioscopy, with or without strings depending removal time (cut-off was 7 days). in 48 procedures (9.3%), uas could not be applied and consequently the procedure was performed without access sheath. we used: uas 9.5 fr (n = 33), 10-12 fr (n = 158), 10.712.7 fr (n = 43), 12-14 (n = 195). results rirs was performed in 514 patients for a total of 571 procedures (54 second look and 3 third look); preoperative assessment included physical examination, routine urine culture, and n-cct. rirs was performed on standard antibiotic prophylaxis (according to local guidelines) or on targeted antibiotic therapy in case of preoperative positive urine culture (in this case therapy was started 5 days before surgery and continued for 3 more days). preoperative urine cultures were positive in 103 patients (20%). all the infections were treated by specific antibiotic therapy. mean operative time was 67 minutes (range: 17-172); 351 (61.4%) patients underwent rirs under spinal anesthesia, while 220 (38.5%) patients were operated under general anesthesia. the median period between intervention and jj stent removal was 7 days (interquartile range iqr 1-66). median post-operative stay was 1.8 days (iqr 1-19). at 3 months n-cct, the overall success rate was 82.8% (426/514 cases); after the first rirs 345/514 patients were completely free from urolithiasis (sfr: 67.1%), while 72/514 patients had ≤ 4 mm stone fragments in the same renal localization of previously treated lithiasis (cirf rate: 14%). 54 patients had residual stones requiring second-look and three needed a third-look for significant residual fragments. table 1 shows success rate, stone free rate and cirf after first treatments according to stone volume and number; the stone composition by spectrophotometric analysis is reported in table 2. intraoperative complications were reported in 4 patients: – intraoperative bleeding: one during laser lithotripsy and one after placement of the uas. in both cases bleeding led to poor visibility and abortion of the procedure that was rescheduled. – two ureteral wall injuries secondary to uas placement: a grade 2 lesion according to traxer classification (6) were treated with a double j stent for a long period; a grade 3 lesion required percutaneous draining of the kidney. no subsequent strictures were noted during follow up (13 and 18 months). post-operative complications were recorded in 31 (5.4%) procedures (table 3): table 1. stone free rate in the 514 patients submitted to rirs. number of stone single < 1 cm single 1-2 cm single 2-3 cm multiple number of patients 202 247 37 128 overall success rate, pt (%) 186 (92.3%) 130 (88.3%) 21 (56.7%) 89 (69.6%) overall stone free rate, pt (%) 175/186 (94%) 89/130 (68.4%) 14/21 (66.6%) 67/89 (75.2%) overall cirf rate, pt (%) 11/186 (5.9%) 41/130 (31.5%) 7/21 (33.3%) 22/89 (24.7%) stone free rate after i look pt (%) 158/175 (90.2%) 71/89 (79.7%) 6/14 (42.8%) 44/67 (65.6%) stone free rate after ii look pt (%) 17/175 (9.7%) 18/89 (20.2%) 8/14 (57.1%) 23/67 (34.3%) stone free rate after iii look pt (%) cirf rate after i look pt (%) 11/11 (100%) 35/41 (85.3%) 5/7 (71.4%) 21/22 (95.4%) cirf rate after ii look pt (%) 6/41 (14.6%) cirf rate rate after iii look pt (%) 2/7 (14,2%) 1/22 (4.5%) table 2. stone composition to spectrophotometric analysis. stone composition. no. (%) value calcium oxalate monohydrate 194 (37.7%) calcium oxalate dihydrate 102 (19.8%) uric acid 88 (17.1%) mixed 87 (16.9%) calcium oxalate and phosphate (68) calcium oxalate and uric acid (19) carbapatite 17 (3.3%) brushite 4 (0.7%) urate ammonium 6 (1.1%) cystine 4 (0.7%) struvite 2 (0.3%) various types 10 (1.9%) 315archivio italiano di urologia e andrologia 2021; 93, 3 stone free rate and complications of rirs – one patient (0.1%) had a cerebrospinal fluid leak after spinal anesthesia causing headache (cd grade i) treated with bed rest and paracetamol/caffeine; – eleven patients (1.9%) had post-operative nausea and vomiting requiring specific therapy; – fifteen patients (2.6%), developed urosepsis, defined as clinical signs of bacterial infections with positive blood culture (cd grade ii-iiia). among them, twelve (2.8%) required antibiotic therapy (cd grade ii), while in three (0,5%) double j was replaced due to concomitant hydronephrosis with double j displacement (cd grade iiia); – two patients (0.3%) on antiplatelet therapy had postoperative hematuria which required bladder irrigation and prolonged catheterization (cd grade ii). – two patients had hemorrhagic events (0.3%) at the second look of complex multiple kidney stones: 1) subcapsular hematoma (srh) associated with pulmonary embolism two days after the procedure (cd grade iiia). treatments consisted in two blood unit transfusion and angiography, which did not show any blood spill. inferior vena cava filter was placed and anticoagulant therapy was continued for 6 months. 6 months follow up ct scan shows a complete reabsorption of the hematoma (figure 1). 2) hemorrhagic shock 2 hour after rirs due to massive renal bleeding (cd grade iva) (figure 2). ct scan and angiography showed multiple renal bleedings requiring urgent nephrectomy; – eight patients complained severe pain and/or urinary urgency probably as a double j related side effect. discussion in the last years, rirs has become increasingly popular and probably the more common procedure for kidney stones up to 2 cm (7); the high sfr with minimal invasiveness and the outpatient setting have been pointed out as specific benefits by several authors (8, 9). standard success rates range between 65% and 92%. in our study sfr was 86% with a mean operative time of 72 minutes. figure 1. subcapsular hematoma (srh) of left kidney (a: ct axial evaluation) (b: ct coronal evaluation). figure 2. kidney hematoma with multiple renal bleedings following rirs. a: multiple stones of left kidney (preoperative ct evaluation); b: hematoma of left kidney (ct ev-aluation); c: rupture of left kidney (ct evaluation); d: kidney specimen. table 3. clinical complications following rirs classified according to clavien-dindo grading system. clavien-dindo n° of description treatment grade system patients grade i 12 11 nausea and vomiting anti-emetics and supportive care 1 cefalea grade ii 14 12 urosepsis antibiotic therapy 2 haematuria bladder irrigation and prolonged catheterization grade iii a 4 3 urosepsis with double j displacement antibiotic therapy + double j substitution 1 subcapsular renal haematoma (srh) selective artery embolisation + inferior associated with pulmonary embolism vena cava filter and anticoagulation therapy grade iii b grade iv a 1 multiple subcapsular haematoma urgent left nephrectomy table 4. setting laser. energy (joule) frequency (hertz) pulse width 30w ho:yag laser system sphinx® jr (lisa laser) fragmentation 0,8/1j 10/15 hz short pulse (300 μs) dusting 0,5/0,8 j 18/20 hz long pulse (650 μs) pop corn 0,8/1j 15/18 hz short pulse (450 μs) 120-w high-power ho:yag laser system (lumenis®) fragmentation 1j/1,5 j 25/30 hz long pulse (650 μs) dusting 0,2/0,5 j 50/70 hz long pulse (1000 μs) pop-dusting 0,5 j 80 hz short pulse (300 μs) 30 w ho:yag laser medilas h solvo (dornier, olympus®) fragmentation 0,8/1j 10/15 hz dusting 0,5/0,8 j 18/20 hz pop corn 0,8/1j 15/18 hz a. b. a. b. c. d. archivio italiano di urologia e andrologia 2021; 93, 3 o. maugeri, e. dalmasso, d. peretti 316 these results are comparable to the main previous literature (10-12). even if rirs is generally considered a safe procedure, a wide spectrum of intra and mostly post-operative severe events must be considered. literature is weak about detailed analysis of complications even if some reports deal with serious and life threatening complications. cindolo et al. in 2016 (13) in a multi-institutional study reporting fatal cases after rirs, highlighted how this “safe” procedure hides potentially dramatic and fatal complications and the need of a careful post-operative patient monitoring: four patients died for septic complications, one for a cardiac event and one due to hemorrhagic complication. cindolo et al. (14) evaluated life-threatening complications after ureteroscopy for lithiasis, reporting 12 cases of serious complications requiring urgent treatment and even one fatal case. ureteral injury is the most common intraoperative complication; beneficial effects and convenience of using access sheaths have been debated. uas main purpose is to facilitate reentries into renal collecting system, theoretically reducing possible injuries to ureter and urethra. in recent studies, the routine intraoperative use of uas during rirs was recommended because it decreases duration of the interventions, with a minimal morbidity associated (14, 15). in our series, we used ureteral access sheaths for nearly all patients, recording two significant ureteral damage correlated to uas (16). proper management of such complications is crucial to avoid further shortand longterm complications. the urinary tract infection is the most common event (228% of the cases) (17); in our study, 15 (2.6%) patients experienced these clinical complications; all the cases required specific antibiotic therapy with no need of intensive care support (cd ii and iiia). double j displacement, noted in three patients, could have been the reason of post-operative infection. we suggest to check its position by x ray in case of infection, especially when antibiotic therapies are not effective. bleeding and renal rupture are less frequent but could lead to serious consequences. in our series two patients had serious hemorrhagic complications; subcapsular hematoma after rirs is rarely described in the literature and its etiology is not perfectly known (18). various authors have tried to understand what is the cause of subcapsular renal hematoma: increase intrarenal pressure leading to rupture of the fornix and separation of the capsule from the parenchyma, urinary infection and infiltration of leukocytes into the parenchyma which can be damaged by irrigation, laser and guide wires (1922). the sudden expansion and rupture of renal parenchyma is probably the most likely explanation of our cases. chronic hydronephrosis was present in our two haemorrhagic cases; sudden increase in intrarenal pressure was showed to cause twisting, stretching and /or obstruction of the main intrarenal vessels (23). it is remarkable that retrograde pyelogram performed at the end of the procedure didn’t show any leak or renal absorption of contrast dye; clinical complications were suspected for an uncontrolled renal pain, hypotension and hemoglobin drop. in conclusion, rirs should be considered an effective and safe procedure in the treatment of renal stones, but a wide spectrum of complications must be considered. even if rare, complications could lead to life-threatening conditions requiring quick diagnosis and prompt treatment. intraoperative signs of possible post-operative complications may be missing and a careful monitoring is crucial to recognize these events as early as possible. references 1. tiselius hg, alken p, buck c, et al. guidelines on urolithiasis. arnhem, the netherlands: european association of urology. 2008. 2. türk c, knoll t, petrik a, et al. eau guidelines. urolithiasis. 2013. 3. bas o, bakirtas h, sener nc, et al. comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. urolithiasis. 2014; 42:115-20. 4. knoll t, jessen jp, et al. flexible ureterorenoscopy versus miniaturized pnl for solitary renal calculi of 10-30 mm size world j urol. 2011; 29:755-59. 5. dindo d, demartines n, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of survey. ann surgery. 2004; 2:205-213. 6. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:58084. 7. elbir f, basıbüyük i, topaktas r, et al. flexible ureterorenoscopy results: analysis of 279 cases. turk j urol. 2015; 41:113-18. 8. breda a, angerri o. retrograde intrarenal surgery for kidney stones larger than 2.5 cm. curr opin urol. 2014; 24:179-83. 9. breda a, ogunyemi o, leppert jt, et al. flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. eur urol. 2009; 55:1190-96. 10. riley jm, stearman l, troxel s. retrograde ureteroscopy for renal stones larger than 2.5 cm. j endourol. 2009; 23:1395-8. 11. hyams es, munver r, bird vg, et al. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j endourol. 2010; 24:1583-88. 12. di mauro d, la rosa vl, cimino s, di grazia e. clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study. arch ital urol androl. 2020; 91:256-260. 13. cindolo l, castellan p, scoffone cm, et al. mortality and flexible ureteroscopy: analysis of six cases. world j urol. 2016; 34:30510. 14. kourambas j, byrne rr, preminger gm. does a ureteral access sheath facilitate ureteroscopy? j urol. 2001; 165:789-93. 15. karaaslan m, tonyali s, yilmaz m, et al. ureteral access sheath use in retrograde intrarenal surgery. arch ital urol androl. 2019; 91:112-114. 16. rapoport d, perks ae, teichman jm. ureteral access sheath use and stenting in ureteroscopy: effect on unplanned emergency room visits and cost. j endourol. 2007; 21:993-97. 317archivio italiano di urologia e andrologia 2021; 93, 3 stone free rate and complications of rirs 17. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015; 67:125-37. 18. bai j, li c, wang s, et al. subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. bju int. 2012; 109:1230-41. 19. tao w, cai cj, sun cy, et al. subcapsularrenal hematoma after ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. lasers med sci. 2015; 30:1527-32. 20. hyams es, munver r, bird vg, et al. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burden\s that measure 2 to 3 cm: a multi-institutional experience. j endourol. 2010; 24:1583-88. 21. riley jm, stearman l, troxel s. retrograde ureteroscopy for renal stones larger than 2.5 cm. j endourol. 2009; 23:1395-98. 22. di mauro d, la rosa vl, cimino s, di grazia e. clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study. arch ital urol androl. 2020; 91:256260.   23. nuttall mc, abbaraju j, dickinson ik, et al. a review of studies reporting on complications of upper urinary tract stone ablation using the holmium:yag laser. br j med surg urol. 2010; 3:151-59. correspondence orazio maugeri, md (corresponding author) omaugeri@gmail.com bonaccorsi astrid, md pietro pepe, md piepepe@hotmail.com d’arrigo letterio, md michele pennisi, md urology unit cannizzaro hospital, via messina 829, catania (italy) dalmasso etttore, md peretti dario, md venzano fabio, md chiapello germano, md ambruosi carlo, md dadone claudio, md urology unit s. croce and carle hospital, cuneo, (italy) archivio italiano di urologia e andrologia 2020; 92, 2132 original paper percutaneous nephrolithotomy: three-needle technique on two planes. cury’s technique carlos abib cury 1, analaura de oliveira cury 2, victoria caroline pagelkopf 3, vinicius ramos bezerra de morais 3, vitor de almeida fernandes 4, miguel bonfitto 4 1 professor, urology sector, são josé do rio preto school of medicine (famerp), brazil; 2 medical student, votuporanga university center (unifev), brazil; 3 medical student, são josé do rio preto school of medicine (famerp), brazil; 4 resident in urology, são josé do rio preto base hospital/famerp, brazil. introduction: percutaneous nephrolithotomy is the main type of surgery indicated for kidney stones larger than 2 cm. the present study describes a three-needle technique for percutaneous nephrolithotomy on two planes. surgical technique: the patient is first placed in the lithotomy position for cystoscopy, which guides the ureteral and urethral catheter. next, the patient is placed in ventral decubitus for the three-needle technique. with the aid of the nephroscope, the first needle is positioned in the projection of the renal pelvis, the second needle is placed in the most posterior of the inferior calyces and the third needle is aligned with the other two at the most depressible point determined by the surgeon’s index finger. after alignment in the topography of the third needle, an incision is made with the scalpel 1-2 cm perpendicular to the aponeurosis of the latissimus dorsi muscle. the second needle is replaced with a peridural needle, which is used to confirm the location of the inferior renal calyx and limit the depth of the chiba needle inserted in the topography of the third needle, forming a 90° angle with the peridural needle. the chiba needle enables the passage of the guidewire and subsequent dilatation until the 30f caliber for the passage of the amplatz dilator, initiating the conventional procedure. comments: the technique described has been used at our service for 15 years and has the advantages of less morbidity, fewer complications and less use of the nephrostomy tube. the technique is also easy to learn and highly reproducible. key words: urology; nephrolithiasis; percutaneous nephrolithotomy. submitted 27 august 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.132 introduction lithiasis of the urinary tract is a common cause of urological morbidity, affecting approximately 12% of the population and with recurrences in approximately 50% of cases (1-4). for kidney stones larger than 2 cm in diameter, percutaneous nephrolithotomy had been the main treatment method since the first successful surgery described by fernström and johansson in 1976 (2-4). percutaneous nephrolithotomy replaced open surgery for the treatment of these calculi, as the reduction in morbidity and improvement in the experience of surgeons led to the increased indication for this procedure (5, 6). according to the guidelines of the european association of urology and american urological association, the percutaneous approach is indicated for renal calculi larger than 2 cm in diameter or calculi located in the inferior pole larger than 1.0 cm in diameter (2, 3). this paper describes a novel three-needle technique for percutaneous nephrolithotomy on two planes. surgical technique the patient is first placed in the lithotomy position. cystoscopy is performed, followed by insertion of the ureteral and urethral catheter. the patient is then placed in ventral decubitus with the lower limbs slightly flexed for the onset of the three-needle technique. 1. with the aid of the fluoroscope, the projection of the renal pelvis is determined through cutaneous demarcation with kelly forceps (figures 1, 2) in order to not expose the surgeon’s hand to radiation. 2. the first needle (21 g) is positioned in the projection of the renal pelvis previously demarcated by the kelly forceps (figure 3). 3. next, the inferior calyces are located and reached through the injection of contrast through the ureteral catheter (figure 4). the most posterior calyx is preferable due to its proximity to the puncture site. 4. the second needle is inserted in the calyx located in item 3, obeying the same location steps using the kelly forceps (figure 5). 5. the two needles positioned in the pelvis and inferior calyx will serve as reference for the alignment of the third needle (figure 6). 6. the third needle is positioned in the most depressible point between the 12th rib and superior iliac crest determined by the surgeon’s index finger on the axis of the first two aligned needles. the point is near the lumbar triangle and posterior axillary line (figure 7). 7. in the topography of the 3rd needle, an incision is made 1-2 cm perpendicular to the axis of the needles in the skin until reaching the thoracolumbar aponeurosis of the latissimus dorsi, which is also incised (figure 8). 8. next, the second needle in the projection of the inferior calyx is replaced with a peridural needle until reaching the lumen of the calyx, determined by urinary flow, thereby establishing the distance from the 133archivio italiano di urologia e andrologia 2020; 92, 2 percutaneous nephrolithotomy: three-needle technique on two planes skin to the calyx, enabling the definition of the superficial and deep axes (figure 9). 9. with the incision in the muscular and aponeurotic plane, the kelly forceps are placed in the direction of the inferior pole of the kidney, opening the space in which the puncture and dilation of the percutaneous path will be performed (figure 10). 10. in the opening achieved with the kelly forceps, the surgeon’s index finger verifies the path to toward the inferior pole of the kidney, which is easily moved (figure 11). 11. the definitive puncture is initiated with the chiba needle running the previously established path at an initial angle close to 45° (individualized based on body mass and the orientation given by the surgeon’s index finger). the chiba needle should reach the depth determined by the peridural needle (figure 12). figure 3. (a) first needle positioned. (b) confirmation of site through fluoroscopy. figure 6. (a) x-ray showing alignment guided by needles, establishing axis for puncture of third needle (b). figure 1. x-ray showing location of calculus and catheter. figure 2. (a) x-ray showing kelly forceps in center of calculus with aid of fluoroscopy to demarcate projection of first needle to be inserted. (b) cutaneous demarcation with kelly forceps. figure 4. ascending pyelography showing first needle (arrow). figure 8. incision in topography of third needle. figure 5. (a) x-ray showing demarcation of puncture site for second needle in inferior calyces, opting for posterior calyx (b). figure 7. (a) most depressible point identified by index finger located between 12th rib and upper iliac crest. (b) third needle inserted. (c) x-ray showing three needles and (d) respective alignment. archivio italiano di urologia e andrologia 2020; 92, 2 c. abib cury, a. de oliveira cury, v.caroline pagelkopf, v. ramos bezerra de morais, v. de almeida fernandes, m. bonfitto 134 12.upon reaching the extremity of the peridural needle, the chiba needle is in the interior of the selected calyx, confirmed by the flow of urine (figure 13). 13. accessing the inferior calyx, the procedure is initiated by introducing the guidewire, followed by progressive dilation through a telescopic pathway with rigid instruments or individualized dilation to the 30f caliber, replaced by the amplatz® dilator (figure 14). 14.at this point, the entire procedure follows the conventional standard for percutaneous nephrolithotomy, with the advantage that this slanted puncture enables better navigation of the nephroscope through the pelvis as well as the middle and upper calyces, thereby avoiding multiple punctures. comments this technique have been used and improved over the course of 15 years at our service and has the advantage of a single access throughout the entire calyx system, thereby minimizing trauma to the parenchymatous tissue in comparison to a direct puncture, in which there is substantial parenchymatous injury when attempting to reach a neighboring calyx. in most cases, this technique avoids the use of a nephrostomy tube. the three-needle technique is an alternative to conventional percutaneous nephrolithotomy. it is a novel treatment strategy for kidney stones that enables an approach on two planes in the prone position with the aid of a fluoroscope during the procedure. figure 10. (a) insertion of kelly forceps in direction of inferior renal pole, confirmed by x-ray (b). figure 9. (a) replacement of second needle (21 g) with peridural needle to reach calyx, determining puncture depth. (b) peridural needle positioned. (c) x-ray showing locations of first needle and peridural needle (arrows). figure 13. urine flow through lumen of chiba needle. figure 14. (a) x-ray showing insertion of guidewire in calyx system. (b) dilation of path directed by guideline by telescopic route and initial and subsequent rigid instruments (c). (d) introduction of alken’s rod in dilator sleeve enveloping guidewire, which will be starting point for progressive dilation. (e) x-ray confirming location of alken’s rod. (f) introduction of last dilator with coupled amplatz® 30f dilator. (g) x-ray showing amplatz® dilator positioned for continuity of procedure. figure 11. x-ray showing index finger in direction of inferior renal pole. figure 12. (a) insertion of chiba needle, traveling incision path. (b) x-ray showing chiba needle in inferior extremity of peridural needle. 135archivio italiano di urologia e andrologia 2020; 92, 2 percutaneous nephrolithotomy: three-needle technique on two planes the technique obeys the pythagorean theorem, which states that the sum of the squares of the catheti is equal to the square of the hypothenuse: a² + b² = c². cathetus “a” is the linear distance on the surface of the skin determined by the second needle to the third needle. the hypothenuse “c” is defined by the surface of the third needle to the point of cathetus “b”, determined by the second needle positioned in the inferior calyx. by obeying the theorem, the surgeon has greater control over the depth to which he/she wishes to insert the needle. as kidneys are in an inclined position in relation to the spinal column at an angle of approximately 30°, the puncture in the inferior pole enables access to all calyces and the pelvis of the kidney, enabling the surgeon to navigate with the nephroscope through the renal excretory pathway, thereby avoiding further punctures. access through the inferior pole diminishes the risk of injury to the renal vessels. in summation, the technique described herein diminishes the use of the nephrostomy tube at the end of the procedure, leading to less postoperative pain and a shorter hospital stay. references 1. teichman jm. acute renal colic from ureteral calculus. new england journal of medicine. 2004; 350:684-93. 2. guideline e.s. (2016). american urological association (aua) endourological society guideline surgical management of stones: american urological association/american urological association (aua) endourological society guideline surgical management of stones, (april), 1-50. 3. türk c, skolarikos a, neisius a, et al. guidelines associates: donaldson jf, drake t, grivas n, ruhayel y. eau guidelines on interventional treatment for urolithiasis. eau guidelines. edn. presented at the eau annual congress barcelona 2019. isbn 978-9492671-04-2. 4. fernström i, johansson b. percutaneous pyelolithotomy: a new extraction technique. scandinavian journal of urology and nephrology. 1976; 10:257-9. 5. lee jy, jeh su, kim md, et al. intraoperative and postoperative feasibility and safety of total tubeless, tubeless, small-bore tube, and standard percutaneous nephrolithotomy: a systematic review and network meta-analysis of 16 randomized controlled trials. bmc urology. 2017; 17:48. 6. warmerdam gj, de laet k, wijn rp, wijn pf. treatment options for active removal of renal stones. journal of medical engineering engineering & technology. 2012; 36:147-55. correspondence carlos abib cury professor, urology sector, são josé do rio preto school of medicine (famerp), brazil analaura de oliveira cury medical student, votuporanga university center (unifev), brazil victoria caroline pagelkopf vinicius ramos bezerra de morais medical student, são josé do rio preto school of medicine (famerp), brazil vitor de almeida fernandes miguel bonfitto miguelbonfitto@gmail.com resident in urology, são josé do rio preto base hospital/famerp, brazil stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 85 original paper with or without a video connection (1, 2). telemedicine has been defined as the communication of medical information among users through electronic devices, referring to specific clinical services (2-4). during the covid-19 pandemic, the request for telemedicine activities increased exponentially (4-7). indeed, the world health organization and the centers for disease control and prevention (usa) encouraged the use of telemedicine with the aim of limiting people’s mobility and reducing the chance of infection, without compromising patients’ care (8-10). nowadays, the internet is deeply used for professional networking, medical education, research recruitment, and patient information (11-13). among internet sources, youtube™ is the second most used website and over 2.6 billion people worldwide use it at least once a month (14). the open-access material on this platform, which is not peer-reviewed as scientific materials published on pubmed, might spread misleading information. consequently, a quality information analysis must be required. the aim of the current study was to evaluate the overall quality of youtube™ telemedicine-related videos and how it changed before and after covid-19 pandemic. materials and methods web interest assessment we evaluated the interest of the worldwide web users in telemedicine. we queried google™ trends (15) with the terms “telemedicine” and “telehealth”, using the following search settings: “worldwide”, “period from 01/01/2018 to 01/01/2022”, and “all the categories”. the trends of google™ and youtube™ search were independently recorded: the data was depicted as a 0 to 100 scale. the value 100 indicates the highest search frequency of the term, and 50 indicates half of the searches. a score of 0, on the other hand, indicates that not enough data was found for the term. search strategy, selection criteria, and videographic characteristics we queried youtube™ with 19 keyword combinations (supplementary table 1). the search was performed in objective: to assess the quality content of youtubetm videos on telemedicine during covid-19 pandemic. materials and methods: first, the frequency of worldwide youtube™ and google™ searches for telemedicine was analyzed. second, we queried youtube™ with telemedicine-related terms. third, the patient education materials assessment tool for audiovisual materials (pemat a/v), the global quality score (gqs), and the misinformation tool were used for the quality assessment. results: according to selection criteria, 129 videos were collected for the analysis. from january 2018 to january 2022, the peak relative interest on youtube™ and google™ occurred in march 2020. of all, 27.1 and 72.9% were uploaded before (jan 2018-feb 2020) and after (mar 2020-mar 2022) the covid-19 outbreak, respectively. according to the pemat a/v, the overall median understandability and actionability was 50.0% (33.3 [iqr 0-66.7] vs 50.0 [27.1-75], p = 0.2) and 66.7% (63.6 [iqr 50.0-75.7] vs 67.9 [50.0-79.2],p = 0.6), respectively. according to gqs, 3.9%, 17.8%, 24.0%, 26.4% and 27.9% were classified as excellent, good, medium, generally poor, and poor-quality videos, respectively. the highest rate of poor-quality videos was recorded in videos uploaded before covid-19 pandemic (37.1 vs 24.5%). according to overall misinformation score, a higher score was recorded for the videos uploaded after covid-19 pandemic (1.8 [iqr 1.4-2.3] vs 2.2 [1.8-2.8], p = 0.01). conclusions: the interest in telemedicine showed a significant peak when the covid-19 pandemic was declared. however, the contents provided on youtubetm were not informative enough. in the future, official medical institutions should standardize telemedicine regulation and online content to reduce the widespread of misleading information. key words: telehealth; virtual healthcare; healthcare technology; covid-19; social media. submitted 24 january 2023; accepted 17 february 2023 introduction the terms telehealth and telemedicine are often used interchangeably. telehealth is the provision of health care remotely by means of a variety of telecommunication tools, such as smartphones, and mobile wireless devices, telemedicine and youtube™: video quality analysis before and after covid-19 pandemic vincenzo mirone 1, marco abate 1, giovanni m. fusco 1, luigi cirillo 1, luigi napolitano 1, simone morra 1, francesco di bello 1, gianluigi califano 1, claudia mirone 2, roberto la rocca 1, massimiliano creta 1, giuseppe celentano 1, marco capece 1, francesco mangiapia 1, nicola longo 1, claudia collà ruvolo 1 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples “federico ii”, naples, italy; 2 multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2023.11341 summary archivio italiano di urologia e andrologia 2023; 95, 2 v. mirone, m. abate, g.m. fusco, l. cirillo, et al. 86 incognito status to minimize the search history and the geographically related biases. the first 30 videos were examined for each of the 19 keyword combinations. a total of 570 videos was achieved. the following exclusion criteria were applied: duplicates, non-english language, off topic, video length > 30 minutes, and video with marketing purpose. the videos published after the 1st of january 2018 were included. a total of 129 videos were eligible for the analyses (figure 1). for each of the 129 videos included, the following variables were collected on the 25th of march 2022: length (minutes), views, persistence time on youtube™ (days), view ratio (defined as the ratio between the number of views and the persistence time on youtube™), likes, subscribers, number of videos with or without disabled comments, authoring entity (private users, medical doctor, hospitals [such as academic hospitals and academic institutions, or non-academic hospitals and institutions, health-care centers, private practice hospitals], and others [such as news channels, general communication channel, talks]) and target audience (healthcare workers, patients and other [such as general public]). according to the recent youtube™ rules, dislikes are not visible anymore for general internet users. the youtube™ videos were further stratified according to the date of the upload before and after the covid-19 outbreak (march 2020) (16, 17). strategies and instruments for the assessment of videos content video contents were assessed independently by two medical doctors [l.c. and g.m.f.]. a third investigator, a senior urology resident [c.c.r.], adjudicated any differences, and the consensus was achieved among all reviewers. the reviewers were blinded to each other’s evaluations. the patient education materials assessment tool for audiovisual materials (pemat a/v), the global quality score (gqs), and the misinformation tool were used for the video quality assessment. first, the pemat a/v is a systematic tool designed to be completed by professionals, including healthcare providers, health librarians, and others, who provide high-quality materials to patients or consumers. it consists of 17 items developed to evaluate and compare the understandability (questions 1-13) and actionability (questions 14-17) of patient education materials. three answers were permitted (agree = 1, disagree = 0, not available = na). the total score was presented as a percentage obtained by the sum of all points, divided by the number of the items judged as agree or disagree. higher scores detect more understandable and actionable content (12, 18, 19). second, the gqs is a validated tool assessing the quality, feasibility, and clinical utility of each video. five possible scores from 1 (poor quality, poor flow, most of the information missing, not at all useful) to 5 (excellent quality, excellent flow, completely accurate information, very useful) were assigned (20). third, the misinformation tool consists of 5 questions appositely created for the porpoise of the study, as previously done (21-24). the aim of this tool is to examine relevant aspects not investigated with the other validated tools. the questions are as follows: 1. is the telemedicine definition correctly provided? 2. is the telemedicine aim correctly described? 3. are the instruments used for telemedicine correctly described? 4. the patients’ consent regulation in telemedicine is correctly described? 5. are the limits of telemedicine well explained? the possible scores range from 1 (extreme misinformation) to 5 (no misinformation). figure 1. prisma diagram depicting inclusion and exclusion criteria of youtube™ video search. archivio italiano di urologia e andrologia 2023; 95, 2 87 telemedicine and youtube™ statistical analysis descriptive statistics were presented as medians and interquartile ranges (iqr) for continuously coded variables or counts and percentages for categorically coded variables. kruskal-wallis test, chi-square test, and proportion test examined the statistical significance in medians and proportions differences. in all statistical analyses, the r software (www.rproject.org) environment for statistical computing and graphics (r version 4.0.0) was used. all tests were two-sided with a level of significance set at p < 0.05. results worldwide web interest from january 2018 to january 2022, the relative interest on youtube™ ranged from 5 to 19 and from 13 to 20, using respectively the “telehealth” and “telemedicine” keywords (figure 2). for both keywords, the peak occurred in march 2020 (100 and 63, respectively). from january 2018 to january 2022, the relative interest on googletm ranged from 6 to 22 and from 5 to 9, using respectively the “telehealth” and “telemedicine” keyword. for both keywords, the peak occurred in march 2020 (100 and 47 respectively). videographic characteristics of 129 videos (table 1), 35 (27.1%) and 94 (72.9%) were uploaded before (jan 2018-feb 2020) and after (mar 2020-mar 2022) the covid-19 outbreak, respectively. the overall median length was 4.5 minutes (jan 2018-feb 2020: 3 [iqr 1.5-4.5] vs mar 2020-mar 2022: 5.5 [2.4-10.9], p < 0.001), the overall median number of views was 2428 (jan 2018-feb 2020: 7783 table 1. videographic characteristics of 129 youtube™ telemedicine-related videos, recorded on the 25th of march 2022, stratified according to the covid-19 pandemic declaration date (the 9th of march 2020). overall jan 2018-feb 2020 mar 2020-mar 2022 p-value n = 129 n = 35 (27.1) n = 94 (72.9) length, min < 0.001 median 4.5 3 5.5 iqr 2.2-10.0 1.5-4.5 2.4-10.9 views, n 0.02 median 2428 7783 1576 iqr 375-10022 897.5-21220.5 328.5-6526.2 persistence time on youtube™ < 0.001 median 663 1264 600 iqr 400-853 1055.5-1369.5 321.8-676.5 view ratio 0.7 median 3 5.5 3 iqr 0-12 0-8.5 0-12.5 likes, n 0.7 median 16 19.5 15.5 iqr 3-62.5 1-136 3-48.2 comments, n 0.8 median 0 0 0 iqr 0-4 0-5.5 0-4 subscribers, n 0.2 median 3250 2425 4460 iqr 380.5-29600 107.8-26125 524-30900 disabled comments, n (%) no 110 (85.3) 25 (71.4) 85 (90.4) 0.01 yes 19 (14.7) 10 (28.6) 9 (9.6) 0.01 authoring entity, n (%) private user 31 (24.0) 7 (20.0) 24 (25.5) 0.7 medical doctor 14 (10.9) 5 (14.3) 9 (9.6) 0.6 hospital 4 (3.1) 2 (5.7) 2 (2.1) 0.6 other 80 (62.0) 21 (60.0) 59 (62.8) 0.9 target audience, n (%) healthcare workers 45 (34.9) 13 (37.1) 32 (34.0) 0.9 patients 36 (27.9) 12 (34.3) 24 (25.5) 0.4 other 48 (37.2) 10 (28.6) 38 (40.4) 0.3 figure 2. chart-line plot depicting relative frequency of worldwide search for “telehealth” (red) and “telemedicine” (blue) on both youtube™ and google™ searches, observed between the january 1, 2018 and the january 31, 2022. archivio italiano di urologia e andrologia 2023; 95, 2 v. mirone, m. abate, g.m. fusco, l. cirillo, et al. 88 [iqr 897.5-21220.5] vs mar 2020-mar 2022: 1576 [328.5-6526.2], p = 0.02), the overall median view ratio was 2 (jan 2018-feb 2020: 5.5 [iqr 0-8.5] vs mar 2020mar 2022: 3 [0-12.2], p = 0.7) and the median number of likes was 16 (jan 2018-feb 2020: 19.5 [iqr 1-136] vs mar 2020-mar 2022: 15.5 [3-48.2], p = 0.7). moreover, the median number of comments and subscribers was 0 (jan 2018-feb 2020: 0 [iqr 0-5.5] vs mar 2020-mar 2022: 0 [0-4.4], p = 0.8), and 3250 (jan 2018-feb 2020: 2425 [iqr 107.8-26125] vs mar 2020-mar 2022: 4460 [524-30900], p = 0.2), respectively. of all videos, 24.0% (20.0 vs 25.5%), 10.9% (14.3 vs 9.6%), 3.1% (5.7 vs 2.1%), and 62.0% (60.0 vs 62.8%) were produced by private users, medical doctor, hospitals or other, respectively. additionally, 34.9% (37.1 vs 34.0%), 27.9% (34.3 vs 25.5%) and 37.2% (28.6 vs 40.4%) were targeted to healthcare workers, patients and other, respectively (all p > 0.05). videos content results according to the pemat a/v (table 2a), the overall median understandability was 50.0% (jan 2018-feb 2020: 33.3 [iqr 0-66.7] vs mar 2020-mar 2022: 50.0 [27.1-75], p = 0.2) and the overall median actionability was 66.7% (jan 2018-feb 2020: 63.6 [iqr 50.0-75.7] vs mar 2020-mar 2022: 67.9 [50.0-79.2], p = 0.6). according to gqs (table 2b), of all 3.9% (n=5), 17.8% (n=23), 24.0% (n=31), 26.4% (n=34) and 27.9% (n=36) were classified as excellent, good, medium, generally poor, and poor-quality videos, respectively. according to the uploaded date (jan 2018-feb 2020 vs mar 2020-mar 2022), the highest rate of excellent quality videos was recorded in videos uploaded after covid-19 outbreak (0.0 vs 5.3%, p = 0.4). the highest rate of poor-quality videos was recorded in videos uploaded before covid-19 pandemic (37.1 vs 24.5%, p = 0.2) according to the misinformation tool (table 3), the lowest median score was recorded for the question 1 (defined as “is the telemedicine definition correctly provide?”), question 4 (defined as “the patients’ consent regulation is correctly described?”) and question 5 (defined as “are the limits of telemedicine well explained?”). the highest median score was recorded for questions 2 (defined as “is the telemedicine aim correctly described?”) and 3 (defined as “are the instruments used for telemedicine correctly described?”). according to the mean misinformation score, a statistically significant difference was recorded for question 2 (median: 2 [iqr: 1-30] vs 3 [iqr: 2-4], p = 0.01). according to the overall misinformation score, a higher score was recorded for youtube videos uploaded after the covid-19 pandemic (median 1.8 [iqr 1.4-2.3] vs 2.2 [1.8-2.8], p = 0.01) discussion the current study aimed to evaluate the overall quality of youtube™ telemedicine-related videos and how it changed before and after covid-19 outbreak. to the best of our knowledge, no previous investigators examined this topic. we addressed this void and identified several noteworthy observations. first, as clearly shown by the trend analysis, the web interest in telemedicine impressively increased when the covid-19 pandemic was declared (16, 17). furthermore, the interest is keeping high from the outbreak to date, compared to the past. additionally, we revealed a higher interest on the youtube™, relative to the google™ website. in consequence, most of the users interested in the topic obtained information from videos uploaded on the web. this observation further corroborates the intent of the current study, which consisted of examining the quality content on youtube™ videos in table 2. quality assessment with the patient education materials assessment tool for audiovisual materials (pemat a/v) and global quality score (gqs) in overall videos (n = 129) and stratifying according to the covid-19 pandemic declaration date (the 9th march 2020). overall jan 2018-feb 2020 mar 2020-mar 2022 p-value n = 129 n = 35 (27.1) n = 94 (72.9) a) pemat a/v, % actionability 0.02 median 50 33.3 50 iqr 0-75 0-66.7 27.1-75 understandability 0.06 median 66.7 63.6 67.9 iqr 50-77.6 50.0-75.7 50.0-79.2 b) gqs, n (%) excellent 5 (3.9) 0 (0.0) 5 (5.3) 0.4 good 23 (17.8) 7 (20.0) 16 (17.0) 0.9 medium 31 (24.0) 7 (20.0) 24 (25.5) 0.7 generally poor 34 (26.4) 8 (22.9) 26 (27.7) 0.7 poor 36 (27.9) 13 (37.1) 23 (24.5) 0.2 iqr: interquartile range. table 3. quality assessment with the misinformation tool in overall videos (n = 129) and stratifying according to the covid-19 pandemic declaration date (the 9th march 2020). overall jan 2018-feb 2020 mar 2020-mar 2022 p-value n = 129 n = 35 (27.1) n = 94 (72.9) 1. is the telemedicine definition median 1 1 2 0.1 correctly defined? iqr 1-3 1-2 1-3 2. is the telemedicine aim median 3 2 3 0.01 correctly described? iqr 2-4 1-3 2-4 3. are the instruments used for median 3 2 3 0.1 telemedicine correctly described? iqr 2-4 1-3.5 2-3.8 4. the patients’ consent regulation median 1 1 1 0.6 in telemedicine is correctly described? iqr 1-2 1-2 1-2 5. are the limits of telemedicine median 1 1 1 < 0.01 well explained? iqr 1-2 1-1 1-2.8 misinformation score median 2.2 1.8 2.2 0.01 iqr: interquartile range. archivio italiano di urologia e andrologia 2023; 95, 2 89 telemedicine and youtube™ order to make aware internet users on the dangerous possibility of acquiring misleading information. second, we recorded a higher number of videos uploaded after the covid-19 outbreak (35 vs 94). this data may indicate that the general community is becoming more aware regarding the importance of using the internet, and specifically youtube™, as an instrument for getting and spreading information. however, we did not observe differences in terms of authoring entity or target between videos uploaded before and after the covid-19 outbreak. this observation is against our expectations. indeed, we expected that more videos would be produced by healthcare providers and official entities in order to guarantee good quality information to general community. for example, among the medical fields, neurophysiologists intensively used telemedicine to ensure for neurological disorders care during the pandemic. indeed, stipa et al. published a study in the 2020 providing recommendations for guidelines development in this field (9). this study should represent an example for the other specialties to encourage the development of specific guidelines. third, according to the quality assessment tools used in the current study, poor-quality video content was recorded. specifically, according to the pemat a/v tools, both actionability (50%) and understandability (66.7%) scores were low, regardless the year of upload. the understandability reflects how viewers could process the information displayed in the videos, while the actionability reflects how viewers could use them. according to shoemaker et al., a pemat a/v score < 70% is considered poorly understandable or poorly actionable (25). in consequence, based on our results, we recorded poor quality content. furthermore, according to the gqs tool, more than half of the videos were classified as generally poor or poor quality. the same observation was noticed in the videos uploaded before or after the covid-19 pandemic. in consequence, despite a higher number of videos uploaded after the pandemic outbreak, low-quality content was uploaded. unfortunately, we were the first to examine youtube™ video content related to telemedicine and no comparisons was possible. fourth, interesting results emerged from the misinformation tool, which allowed us to investigate other aspects, not well examined by the other validated quality assessment tools used. thanks to that, we discovered that relevant telemedicine aspects were underestimated during the youtube™ video making. for example, we did not record any video explaining the differences between telecollaboration, tele-treatment, tele-monitoring, or tele-support (26). additionally, scant information was provided on the informed consent that should be obtained by healthcare providers (27). last, but not least, the physicians’ roles and responsibilities were rarely provided (28). however, we recorded an improvement of the misinformation tool items score in the videos uploaded after the pandemic declaration, compared to the ones recorded before. these observations may proof that the community is increasingly using the internet as a spreading information instrument on telemedicine, due to the higher requests and unexperienced needs caused by the pandemic. however, with this tool, we also highlighted that all the possible risks behind the telemedicine use were dangerously hidden. taken together, we observed that the telemedicine interest peak occurred in march 2020 on both google™ and youtube™ websites, concordantly with the first pandemic wave. it confirms how youtube™ was highly used to promptly acquire information on telemedicine. moreover, overall reliability and quality of youtube™ videos on this topic were inadequate, as evidenced by a low pemat a/v score and a high number of poor and generally poor quality videos. additionally, important aspects, such as the limited and fragmented insurance coverage of telemedicine, the lower quality of patientphysician relationships, the legal issues, and the differential access to telecommunication technologies based on social and geographic factors, were underestimated. in the future, considering the essential importance of telemedicine in the modern era, it will be mandatory for the official entity to develop proper guidelines to provide the best information to internet users. the current study is not devoid of limitations. first, some reliable or non-reliable videos might be missed, due to our search terms. however, we used 19 keyword combinations to minimize selection errors. second, only english-language videos were included in the final sample. other language videos could provide different information. third, quality assessment videos were subjectively evaluated. however, three investigators were independently involved to analyse video contents and were each other blinded during the evaluation. fourth, youtube™ is a constantly expanding multimedia platform and the contents may rapidly change significantly with new updates over time. conclusions the interest in telemedicine showed a significant peak when the covid-19 pandemic was declared. despite the importance of telemedicine in the modern era, the 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marco abate, md marcoabate5@gmail.com giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md cirilloluigi22@gmail.com luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com simone morra, md simonemorra93@gmail.com francesco di bello, md fran.dibello12@gmail.com gianluigi califano, md gianl.califano2@gmail.com roberto la rocca, md robertolarocca87@gmail.com massimiliano creta, md max.creta@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com marco capece, md drmarcocapece@gmail.com francesco mangiapia, md mangiapiaf@gmail.com nicola longo, md nicolalongo20@yahoo.it claudia collà ruvolo, md c.collaruvolo@gmail.com department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii, via sergio pansini n°5, 80138 naples claudia mirone, md claudiamirone@outlook.it multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper introduction congenital penile curvature (cpc) is a genetically inherited condition characterized by the presence of penile curvature. this malformation, already present at birth, is evident during erection and manifests in the absence of a demonstrable organic penile pathology. the pathogenesis of cpc is unknown (1, 2). however, it has been proposed that cpc may be caused by local androgen insufficiency determined by fetal androgen deficiency. alternatively, local deficiency of 5-alpha reductase, capable of causing penile malformation, has been proposed (3, 4). an ultrastructural study of the tunica albuginea, performed on tissue samples belonging to the ‘lozenge’ removed during nesbit's corrective surgery at the level of the external curvature (the zone of the concave angle), demonstrated the presence in this area of disruption of the tunica albuginea, associated with a chaotic alignment of collagen fibers, able to interfere with the normal mechanical properties of the same albuginea (darewicz et al., 2001) (5). in the frame of the same study, the authors analyzed microscopically the tissue contralateral to the lesions, at the inner side of the curvature, on the side of the convex angle. normal extension of the fibroblasts and blood vessels was demonstrated. moreover, in the latter tissue collagen fibers were shown to be normal both in quantity and in quality and organization. the authors concluded that the diseased area which causes the curvature is located at the level of the tunica albuginea on the external side, i.e. at the level of the great curvature, whereas the "diseased" albuginea is more yielding and extensible, causing this side of the penis to curve towards the opposite side (5). the prevalence of congenital penile curvature is very low and ranges between 0.04 and 0.6% (6-8) of the total population. the incidence of the various types of curvature shows minor variations among different authors: ventral curvatures occur in about 50% of cases, lateral ones in about 25% of cases (20% left, 5% right), mixed ventral/lateral ones in about 20-23% of cases, whereas dorsal curvatures are found in about 5% of cases (6, 9, 10). the incidence of the different degrees of curvature varies between different studies. according to various – and sometimes diverging – opinions, curvatures between 30 and 60 degrees show incidences ranging between 44 and 74%, whereas curvatures above 60 degrees are found by objective: to investigate a possible relationship between a history of congenital penile curvature (cpc) and peyronie's disease (pd), and to characterize the psychological profile of patients suffering from pd, with or without concomitant cpc. methods: we included 519 patients with peyronie's disease (pd), of which 73 were found to have underlaying cpc. as a comparator population, we selected 2166 patients without pd, referring to our tertiary care clinic. in this population we detected 15 subjects with cpc. all patients completed the gad7 (generalized-anxiety-disorder 7 questions) and the phq-9 (patient-health-questionnaire 9 questions) questionnaires. results: the overall prevalence of cpc in pd-patients was 14.07%, compared to a prevalence of 0.69% in the non-pd control population (p < 0.00001). moderate-to-severe anxiety was found to be present in 89.4% of all pd-patients. significantly higher proportions of patients with cpc associated with pd showed severe anxiety, compared to patients with pd alone (57.5% vs. 36.7%, respectively, p = 0.0008). moderatesevere depression was found to be present in 57.8% of all pdpatients. significantly higher proportions of pd patients with a history of cpc showed severe depression, compared to patients with pd alone (13.6% vs. 3.36%, respectively, p < 0.0002). gad-7 median scores were significantly higher in patients with more severe penile curvatures (> 45°; p = 0.029). we did not detect a statistically significant difference between phq-9 median scores based on the severity of pd (p = 0.53). analysis of phq-9 and gad-7 median scores showed significantly worse depressive and anxious symptoms in younger patients (p < 0.001 and p = 0.0013, respectively). conclusions: the presence of congenital-penile-curvature may represent a risk factor for the subsequent onset of peyronie's disease. moderate/severe anxiety and moderate/severe depression were reported in a high fraction of cases. anxiety was significantly higher in patients with more severe penile-curvatures, and depression was present independently of the degree of penile curvature. depression and anxiety were found to be more severe in younger subjects. key words: congenital penile curvature; peyronie’s disease; risk factors. submitted 5 february 2023; accepted 17 february 2023 congenital penile curvature as a possible risk factor for the onset of peyronie's disease, and psychological consequences of penile curvature gianni paulis 1, andrea paulis 2, gianpaolo perletti 3 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy; 3 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy. doi: 10.4081/aiua.2023.11238 summary archivio italiano di urologia e andrologia 2023; 95, 1 g. paulis, a. paulis, g. perletti some in about 32% of cases. alterations of 90 degrees show incidences of about 25%, whereas curvatures below 30 degrees are found in about 40% of cases (6, 9, 10). cpc (also referred to by some authors as "penile chordee") is often associated with hypospadias, as only 4-10% of cases are not associated with this condition (11). corporoplasty is the surgical treatment indicated for cpc (1). the most frequently used corporoplasty techniques include the nesbit procedure and its modifications, albuginea plication techniques, or techniques exploiting the insertion of grafts, aimed at lengthening the penis (10, 12-17). peyronie’s disease (pd) is an acquired penile curvature consisting of a chronic inflammation of the tunica albuginea of penile corpora cavernosa (18). although a genetic origin of the disease has been demonstrated, there is not unanimous agreement on its pathogenesis. trauma appears to be the triggering cause of the onset of the disease, which finally results in deformation of the penis (curvature, hourglass shape, shortening, etc.). the condition is also associated with penile pain, erectile dysfunction and depression (19-22). the incidence of the disease ranges between 3.2% and 13% (23-25). the pathogenesis of pd occurs in two main phases. initially, an active inflammatory phase takes place, whereby the plaque is formed, subsequently progressing to fibrosis and possible calcification. this stage is characterized by pain and by the progressive worsening of the deformation. in the second stage (the stabilization phase), pain has disappeared, and the deformation has stabilized. during the first phase, conservative medical treatment is indicated, including oral antioxidants, vitamin e, non-steroidal anti-inflammatory drugs, penile injections with various drugs (verapamil, interferon-α2b, cortisone, pentoxifylline, collagenase, hyaluronic acid, etc.), and physical therapies (swt, iontophoresis, vacuum penile and traction devices) (26-28). the surgical treatment is indicated in the second phase of the disease, when the curvature is severe and/or when severe erectile dysfunction occurs. the surgical techniques for pd differ according to the specific clinical condition and consist of corporoplasty (simple or with use of grafts), with or without application of penile prostheses (29-31). psychological consequences of congenital or acquired penile curvature the presence of a deformation of the penis showing different degrees of severity can affect the psychological equilibrium and the psycho-social relationships of the patients, resulting in a negative impact on the quality of life (qol). it has been documented that depression may occur in 48% of cases of peyronie's disease, and in 65% of cases of congenital penile curvature (22, 32). patients with penile deviation may show erectile dysfunction caused by sexual performance anxiety. this may be associated with a loss of personal body image, with reduced self-esteem and with a lack of confidence in the ability to achieve a satisfactory sexual intercourse (32). in this respect, surgical treatments have been shown to drastically improve the psychological state and the qol of patients (2, 32, 33). it is established that a diagnosis of pd is associated with alterations of the psycho-social functioning of affected subjects, who may show an array of conditions linked to each other and able to reinforce each other, including depressive symptoms, social isolation, stigmatization and sexual difficulties (34, 35). considering that pd does not affect all males, but only a fraction of those who are genetically predisposed, it may be hypothesized that congenital penile curvature could represent a risk factor for males genetically predisposed to pd. according to this hypothesis, cpc would favor traumatic events of different degrees of severity during coitus (3638). in fact, repeated intercoital thrusts can cause microtraumas in the context of the tunica albuginea of the corpora cavernosa, thus giving rise to the events underlying the formation of the plaque: delamination of the tunica albuginea, micro-hematoma, accumulation of fibrin, recruitment of macrophages, lymphocytes, platelets and fibroblasts, production of pro-inflammatory cytokines, and production and accumulation of collagen (26, 39). the present study was aimed at studying the relationship between a history of congenital penile curvature and peyronie's disease. the psychological impact of pd, in the presence of absence of concomitant cpc, was also investigated in depth. patients and methods we performed a retrospective analysis of the clinical database of a single andrology clinic. from the database we extracted two separate cohorts of patients referring to a single urology/andrology clinic between january 2013 and december 2022. one cohort included patients diagnosed with peyronie's disease (pd). as a comparator population, we extracted a cohort of urological patients without pd. all data were obtained from the available patient records. this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki (fortaleza, 2013) (40): all study subjects were contacted and gave their informed consent to the study. sensitive data have in any case been anonymized in respect of privacy according to legislative decree 10 august 2018, n. 101 adapted to the gdpr (official gazette of the italian republic, general series n.205, dated 04-09-2018). inclusion criteria for the study were an age between 18 and 75 and the completion of two validated psychometric tests: the generalized anxiety disorder 7 questions (gad-7) and the patient health questionnaire 9 questions (phq-9) (41, 42). a diagnosis of cpc was not an exclusion criterion for the present study. the specific inclusion criterion for the pd cohort was a documented diagnosis of peyronie's disease. the exclusion criteria for the comparator control cohort were a diagnosis of peyronie’s disease or erectile dysfunction (ed). the primary endpoint of the study was the association between a history of cpc and the occurrence of pd in a patient population referring to a single tertiary care andrology center. secondary endpoints were the impact of the degree of penile curvature or of the age on the psychological profile of patients showing pd and/or cpc, assessed with the gad-7 and phq-9 tests. archivio italiano di urologia e andrologia 2023; 95, 1 congenital penile curvature as a risk factor for the onset of peyronie's disease statistical analysis to investigate an association between pd and a history of cpc, we calculated the pearson's chi-squared test with yates' continuity correction. statistical analysis was performed on the ‘r’ software environment for statistical computing and graphics. we performed a post-hoc analysis of the statistical power achieved for the crude odds-ratio calculation using the g*power 3.1 software (43). we investigated by the mann-whitney-wilcoxon test the impact of the degree of the penile curve on the median scores of the gad-7 or phq-9 questionnaires in patients stratified in two groups (group a, curve between 0-45 degrees; group b, curve > 45 degrees). we analyzed by the mann-whitney-wilcoxon test the impact of the age of patients on the median scores of the gad-7 or phq-9 questionnaires in patients stratified in two groups (group a, age up to 40 years; group b, age > 40 years). the significance of differences between prevalences/proportions was analyzed by a z-test. statistical analysis was performed on the ‘r’ software environment for statistical computing and graphics. two-sided crude odds ratios and 95% confidence intervals (95% cis) were calculated using the ‘epitools’ package for ‘r’. all statistical analyses were two-tailed. a 5% threshold for an alpha error was used to define statistical significance (significant p-value < 0.05). results we extracted from our database 519 patients meeting the inclusion criteria for this study, consecutively diagnosed with peyronie's disease (pd) between january 2013 and december 2022. as a comparator population, we extracted 2166 patients without pd and/or ed and meeting our inclusion criteria, referring to our tertiary care clinic for urological diseases. characteristics of congenital penile curvature the characteristics of the of cpc detected in 88 patients with or without pd, the prevalence and the degree of the different types of penile curvature are presented in table 1. the curvature angle was found to vary between 5 and 45 degrees. of the 73 patients with cpc who subsequently developed pd, 32 (43.8%) reported significant penile trauma in the weeks/months preceding the onset of the disease. notably, patients with cpc of the lateral type remember their previous penile trauma more frequently. prevalence of cpc in pd vs. non-pd patients in the cohort of 519 patients diagnosed with pd, 73 had a documented history of cpc (14.07%), whereas in the comparator population (n = 2166) cpc was reported in 15 cases (0.69%). the chi-square value for the comparison between frequencies of cpc in the pd and control cohorts was 201.65 (p < 0.0001). the z ratio was 15.4 (p < 0.001). we generated a contingency table comparing the presence/absence of a history of cpc in patients diagnosed or not with pd. the resulting significant crude odds ratio for cpc was 23.23 (95% ci, 13.57 to 42.51, p < 0.0001). post-hoc analysis showed an achieved power equal to 0.99 for the magnitude of effect (odds ratio) and 95% ci shown above. psychological profile of patients with pd with or without cpc the prevalence of anxiety in pd patients with or without cpc was assessed with the gad-7 test. moderate to severe anxiety (gad-7 score > 9) was reported in 89.4% of total patients (table 2). significantly higher proportions of patients with cpc associated with pd showed severe anxiety, compared to patients with pd alone (57.5% vs. 36.7%, respectively, p = 0.0008). conversely, moderate anxiety was reported more frequently in patients with pd alone than in subjects with cpc associated with pd (52.2% vs 34.2%, respectively; p = 0.004). table 1. typology of congenital penile curves and their characteristics in cpc patients with or without pd. type of congenital number degrees of no. and (%) of cases with penile curvature of cases (%) penile curvature memory of previous penile trauma patients with pd lateral 48 (65.7) 5-40 20 (27.39) left side 35 (47.9) 5-30 13 (17.8) right side 13 (17.8) 5-40 7 (9.58) ventral 11 (15.06) 10-40 5 (6.8) ventral and left side 3 (4.1) 5-10 1 (1.3) dorsal 9 (12.3) 10-45 5 (6.8) dorsal and left side 2 (2.7) 5-10 1 (1.3) total 73 32 (43.8) patients without pd lateral 13 (86.6) 5-45 0 (control cohort) left side 10 (66.6) 10-30 0 right side 3 (20.0) 5-45 0 ventral 1 (6.6) 10 0 ventral and left side dorsal dorsal and left side 1 (6.6) 15 0 total 15 0 table 2. prevalence of anxiety in pd patients with or without cpc, assessed with the gad-7 test. gad-7 no. total no. cases with no. cases with z-ratio score range cases (%) pd and cpc (%) pd alone (%) (p) no anxiety 0 2 (0.38) 2 (2.7) 0 (0) not assessable minimal or mild anxiety 1-9 53 (10.2) 4 (5.4) 49 (10.9) -1.073 (0.28) moderate-severe anxiety 10-21 464 (89.4) 67 (91.7) 397 (85.5) 0.71 (0.47) moderate anxiety 10-14 258 (42.0) 25 (34.2) 233 (52.2) -2.85 (0.004) severe anxiety 15-21 206 (39.6) 42 (57.5) 164 (36.7) 3.36 (0.0008) total 519 73 446 archivio italiano di urologia e andrologia 2023; 95, 1 g. paulis, a. paulis, g. perletti the prevalence of depression in pd patients with or without cpc was assessed with the phq-9 test. moderate to severe depression (phq-9 score > 9) was reported in 57.8% of total patients (table 3). significantly higher proportions of pd patients with a history of cpc showed severe depression, compared to patients with pd alone (13.6% vs. 3.36%, respectively, p < 0.0002). the impact of the severity of the penile curvature on the profile of anxiety or depression of pd patients was further investigated by dividing pd patients (irrespectively of concomitant cpc) in two groups, using 45 degrees as a curve cutoff value (group a, ≤ 45 degrees; group b, > 45 degrees). gad-7 median scores were significantly higher in patients with more severe penile curvatures (p = 0.029, table 4). conversely, we did not detect a statistically significant difference between phq-9 median scores based on the severity of penile curvature (p = 0.53, table 4). these results indicate that in pd patients depression can manifest independently of the degree of penile curvature. in addition, we investigated the impact of age on the median scores of both the gad-7 and phq-9 questionnaires, by dividing pd patients (irrespectively of concomitant cpc) into two main age categories, using 40 years as cutoff value (group a, ≤ 40 years; group b, > 40 years). phq-9 median scores were significantly higher in younger patients (p < 0.001, table 5). despite identical median values of gad-7 scores, a significant intergroup difference was found with the mann-whitney-wilcoxon test (0.0013). most likely, and similarly to the phq-9 analysis, younger patients show a higher degree of anxiety, since gad-7 mean values were higher (16.21 ± 3.99) than the mean values assessed in older individuals (14.66 ± 4.66). these results indicate that younger pd patients may have a more pronounced anxious profile. discussion a large number of studies have demonstrated the existence of several risk factors that can increase the possibility of developing pd. these risk factors include penile trauma, smoking, diabetes mellitus, hypertension, dupuytren's disease, alcohol consumption, erectile dysfunction, obesity, dyslipidemia, psoriasis, psoriatic arthritis, and rheumatoid arthritis (44-49). to our knowledge, this is the first study investigating the association between pd and cpc. our results show that the overall prevalence of cpc in patients with pd was significantly higher (14.07%), compared to the prevalence in a non-pd control population (0.69%). these data suggest that the presence of congenital penile curvature (cpc) may represent a risk factor for the subsequent onset of peyronie's disease (pd). a search in the scientific literature retrieved a single article that approaches on the subject (50). in presenting the results of their study, the authors made no reference to cpc as a possible risk factor for pd. the study included a sample of 60 patients who had already undergone tunica albuginea plication surgery (50). the authors specified that 21 patients reported worsening over time of the original congenital curve. the authors also added that these patients were older (mean age 34 years) and showed signs of peyronie's disease (penile shortening, history of penile trauma, palpable penile plaque, etc). in our study we diagnosed various types of congenital penile curves, although, unlike other authors we detected more frequently lateral congenital curves instead of ventral congenital curves (6, 9, 10). our results revealed that severe or moderate anxiety was present in 89.4% of pd patients. although in the literature there is no precise data regarding the incidence of anxiety symptoms during pd, smith and co-workers reported that 81% of pd patients included in their study reported ‘emotional difficulties’ (51). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cpc, compared to pd alone (57.5 vs. 36.7, respectively). table 3. prevalence of depression in pd patients with or without cpc, assessed with the phq-9 test. phq-9 no. total no. cases with no. cases with z-ratio score range cases (%) pd and cpc (%) pd alone (%) (p) no depression 0 2 (0.38) 2 (2.7) 0 (0) not assessable minimal or mild depression 1-9 217 (41.8) 26 (35.6) 191 (42.8) -1.15 (0.24) moderate-severe depression 10-27 300 (57.8) 45 (61.6) 255 (57.1) 0.71 (0.47) moderate depression 10-14 186 (35.8) 25 (34.2) 161 (36.09) -0.31 (0.75) moderately severe depression 15-19 89 (17.1) 10 (13.6) 79 (17.7) -0.84 (0.39) severe depression 20-27 25 (4.8) 10 (13.6) 15 (3.36) 3.92 (< 0.0002) total 519 73 446 table 4. gad-7 and phq-9 median scores in patients stratified according to penile curvature angles. questionnaires group a (n = 449) group b (n = 70) p-value administered angle of penile curvature ≤ 45 degrees angle of penile curvature > 45 degrees (mann-whitney-wilcoxon) phq-9 10 (8) 12 (6) 0.53 median, iqr (mean ± sd) (10.68 ± 4.99) (11.14 ± 5.09) gad-7 14 (7) 14.5 (8) 0.029 median, iqr (mean ± sd) (14.89 ± 4.49) (15.94 ± 4.86) iqr: interquartile range; sd: standard deviation. table 5. gad-7 and phq-9 median scores in pd patients stratified by age. questionnaires group a (n = 126) group b (n = 393) p-value administered angle of penile curvature ≤ 40 degrees angle of penile curvature > 40 degrees (mann-whitney-wilcoxon) phq-9 12.6 10.8 < 0.0001 median, iqr (mean ± sd) (13 ± 5.04) (10.02 ± 4.78) gad-7 14.7 14.7 0.0013 median, iqr (mean ± sd) (16.21 ± 3.99) (14.66 ± 4.66) iqr: interquartile range; sd: standard deviation. archivio italiano di urologia e andrologia 2023; 95, 1 congenital penile curvature as a risk factor for the onset of peyronie's disease in a study about the chronology of depression and distress in men with peyronie's disease, nelson and coworkers demonstrated that 48% of patients show clinically meaningful depression, assessed with the center for epidemiologic studies depression scale (ces-d) (22). in our study moderate to severe depression was reported in a higher fraction of patients (57.8%). however, a direct comparison is hampered by the different psychometric scales used in the two studies. beside corroborating the available evidence, our study suggests that, if not investigated in patients with pd by means of specific questionnaires, depressive and anxious symptoms may generally be underestimated in terms of severity and prevalence. in addition to the data in the overall pd population, we have also found that severe depression was present in a significantly higher fraction of patients with pd and concomitant cpc (13.6%) compared to patients with pd alone (3.36%). in our study we have shown that patients with more pronounced penile curves (> 45 degrees) show a higher degree of anxiety. conversely, analysis of phq-9 median scores using the 45-degree cutoff showed that pd patients develop various degrees of depression independently of the degree of penile curvature. articles containing similar considerations are present in the literature (34, 52-54). furthermore, when we investigated a possible relationship between the scores of the gad-7 and phq-9 questionnaires and the age of patients (age cutoff, 40 years) we noticed that younger patients show more severe depressive and anxious profiles. since age and the degree of penile curvature are potential factors for the development of psychological difficulties, it is deemed necessary to refine the diagnostic profiling of pd patients; a deeper understanding of these aspects may lead to the improvement of therapy protocols and their outcomes. conclusions the presence of congenital penile curvature may represent a risk factor for the subsequent onset of peyronie's disease. although the present study presents the limitations of a retrospective analysis of a patient database, the magnitude of the effect size, its statistical significance and the achieved power support the relative robustness of our results. nevertheless, further studies are needed to confirm cpc as a risk factor for pd, and also to investigate in depth the psychological effects of penile curvature. patients with pd and cpc showed a significantly higher prevalence of more severe depression and anxiety. patients with more pronounced penile curves show a higher degree of anxiety, compared with subjects showing a less severe curvature. depression and anxiety appear to be age-related, as their severity was shown to be higher in younger subjects. in the uro-andrological clinical practice a multidisciplinary approach with the involvement of psychologists would be desirable, in order to offer pd patients psychological support treatment, which can in turn prevent or attenuate the psychological impact of this disease, which has been defined by some eminent authors a psychologically and physically devastating disorder 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paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis, md andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 review introduction the term chronic prostatitis (cp) refers to a group of syndromes of various etiology characterized by subacute and persistent prostatic inflammation although a large proportion of patients with prostatic inflammation don’t have any symptoms (category iv, asymptomatic inflammatory prostatitis). the remaining patients, affected by category ii chronic bacterial prostatitis (cbp) or by category iii chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) may experience pelvic pain, including suprapubic pain, pain in the penis, testicles or perineum, pain during sexual intercourse or during ejaculation, dysuria (painful urination), nocturia and/or urinary urgency. the duration and severity of pain and discomfort varies among patients. chronic pain may be accompanied by several voiding disturbances mainly urgency and nocturia sexual dysfunction as well (1). however pelvic pain is the most prominent symptom (as compared with patients with bph and those with erectile dysfunction (2). stress and a spectrum of various psychological problems are commonly found in cp patients, but it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances (3). moreover, the exact incidence of individual psychological problems remains unspecified. in this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. introduction/aim: a spectrum of psychological problems is commonly found in cp/cpps patients, though it is not yet clear whether, a priori, psychological dysfunctions are the cause of these pain syndromes, or whether these pain conditions are themselves causing psychological disturbances. in this article we present the current perspective on the impact of psychological problems in chronic prostatitis syndromes and we discuss the implications thereof from a clinical perspective. materials and methods: a database and a manual search were conducted in the medline database of the national library of medicine, embase, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status” and “personality”. two independent reviewers performed data extraction. we included clinical studies with available information on chronic prostatitis and related psychological conditions. we considered full-text written papers. we excluded reviews and case reports. in order to reduce the risk of bias we analyzed only studies including patients with confirmed cbp or cp/cpps. bibliographic information in the selected publications was checked for relevant records not included in the initial search. results: database search allowed us to retrieve 638 studies to which we added to 16 additional studies retrieved by handsearching. after screening, 34 relevant papers were identified for thorough review. most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically confirmed cp/cpps including studies with a microbiologically confirmed diagnosis of cbp. the psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. sample size, study design and diagnostic measures varied among studies. conclusions: despite limitations and variations in sample size, study design and diagnostic measures in all included studies, a relation between chronic prostatitis and psychological problems chronic prostatitis and related psychological problems. which came first: the chicken or the egg? a systematic review konstantinos stamatiou 1, margherita trinchieri 2, martina trinchieri 3, gianpaolo perletti 4, vittorio magri 5 1 department of urology, tzaneio hospital, pireus, greece; 2 psichiatry unit, asst rhodense, g. salvini hospital, garbagnate, milano, italy; 3 società italiana di psicoanalisi della relazione sipre, milano, italy; 4 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 5 urology unit, asst fatebenefratelli sacco, milano, italy. doi: 10.4081/aiua.2023.11300 summary is a consistent finding. the existing evidence does not permit to definitely conclude whether psychological problems are a risk factor for cp/cpps or whether they represent an array of symptoms that are associated with the exacerbation of this disease. key words: prostatitis syndromes; chronic bacterial prostatitis; chronic pelvic pain; psychological issues: depression; anxiety; stress; unhappiness; cognitive status; personality. submitted 21 january 2023; accepted 25 february 2023 archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri materials and methods a database and a manual search were conducted in the medline database of the national library of medicine, embase, and other libraries using the key words “prostatitis syndromes”, “chronic bacterial prostatitis”, “chronic pelvic pain”, “males” in various combinations with the terms “psychological issues”, “depression” “anxiety”, “stress”, “unhappiness”, “cognitive status”, “personality”. two independent reviewers performed data extraction by using identical extraction tables. the search was carried out in accordance with preferred reporting items for systematic reviews and meta-analyses (prisma) methodology (4) and were extended from first records up to 15th december 2022. titles were screened and any duplicates removed before abstracts and finally full-text articles were assessed for relevance (figure 1). reference lists were also checked. relevant studies were evaluated by all authors and included in the narrative data synthesis. we included clinical studies with available information on chronic prostatitis and related psychological problems. we considered full-text written papers. we excluded reviews and case reports. in order to reduce the risk of bias we analyzed only studies including patients with confirmed cbp or cp/cpps. bibliographic information in the selected publications was checked for relevant records not included in the initial search. the methodological quality of included studies was assessed independently by 2 authors. case-control and cohort were evaluated using the newcastle-ottawa scale (nos) as bias assessment tool (5). results the initial search of the databases retrieved 668 studies. title/abstract screening led to select 60 papers after exclusion of 618 papers that were judged as not directly relevant to the research question. out of these 60 papers, 19 duplicates were removed. sixteen additional studies were retrieved by handsearching. review of the abstracts led to exclusion of 23 papers due to several reasons (review papers, papers reporting the same series described in other selected papers, congress reports/abstracts with limited information). finally, 34 relevant papers were identified for systematic review (6-39). specifically, 15 records reported case series, 13 were casecontrol studies and 6 were cross-sectional cohort studies. according to the quality assessment of newcastle-ottawa scale, 11 studies out 19 were characterized by high quality with scores ranging between 7 and 9 (supplementary materials). data synthesis most studies included patients with chronic pelvic pain and prostatitis-like symptoms, whereas a smaller number of studies included patients with methodologically confirmed cp/cpps including studies with a microbiologically confirmed diagnosis of cbp. the psychosocial factors examined in the selected studies include pain, catastrophizing, stress, personality factors and social aspects. comorbid psychiatric disorders evidenced in the studies included depression, anxiety and trauma-related disorders, somatization disorders, and substance abuse. some studies investigated the association of pain with each individual psychological disturbance, while others examined the impact of pain in association with the overall quality of life. sample size, study design and diagnostic measures varied among studies. several studies showed that this disease has a significant negative impact on mental and physical quality of life domains (6-9). men with cp/cpps have significantly more disturbances in their psychological profile compared to both healthy control patients (10-12) and patients with chronic pain of different etiology (13). in cp/cpps patients, pain has an impact in different domains of life (viz., sexual relationships) compared with patients with chronic pain of different etiology (viz., work and professional activity) (13). aubin and coworkers, compared self-report questionnaires measuring demographic, pain, and sexual function of men with cp/cpps with those of men without any pain condition. according to their findings, patients affected by cp/cpps differed from controls in the domains of sexual desire, frequency of sexual intercourse, and in the quality of erectile and orgasm functions (14). erectile dysfunction and decreased libido were reported by 43% and 24% of men with cp/cpps, respectively (15). one key difference between the populations investigated was the presence of depression and anxiety. smith et al. compared (a) the sexual and relationship functioning of 38 male patients with cp/cpps with those of their female partners, and (b) the sexual and relationship functioning of both cp/cpps men and their partners with the same items assessed in 37 control couples. compared to control males, men with cp/cpps reported significantly more sexual dysfunction and symptoms of depression. furthermore, the symptoms of depression mediated the relationship between some aspects of sexual function and male participant status as a patient or control (16). therefore, in cp/cpps subjects, the frequency of sexual activity decreased with increasing depression, the orgasm function decreased with increasing depression, and the quality of erectile function decreased with increasing pain symptoms. in addition, overall sexual satisfaction decreased with increasing pain symptoms (14). thus, from these data it appears that the psychological profile of patients can deteriorate in function of the kind and severity of symptoms of cp/cpps. the severity of erectile dysfunction also correlates significantly with anxiety. moreover, both depression and anxiety are closely correlated with chronic pain and urinary symptoms and contribute to the recurrence, refractoriness, and outcome of the disease (17, 18). the incidences of depression and anxiety in patients with cp/cpps are estimated to be approximately 20-50% and 40-60%, respectively. besides depression and anxiety, a variety of somatic and psychological conditions were detected among cp/cpps patients, including disturbances of several personality traits, mental distress, psychological stress, somatization, obsessive-compulsive disorder and interpersonal sensitivity (12, 19). a large population-based cross-sectional survey demonstrated a significantly high occurrence of mental distress archivio italiano di urologia e andrologia 2023; 95, 1 chronic prostatitis and related psychological problems and psychological stress related to cp/cpps in finnish men: suicidal thinking and fear of undetected prostate cancer or of having a sexually transmitted disease was reported by 17% of partients (15). psychological stress has a major impact on the sexuality of cp/cpps patients. in fact, the frequency of sexual activity decreased with increasing depression, arousal/erectile function decreased with increasing pain symptoms and orgasm function decreased with increasing depression. moreover, sexual satisfaction decreased with increasing pain symptoms, stress appraisal, and decreasing belief of a relationship between emotions and pain (14). male participants of the mapp study (national institute of diabetes and digestive and kidney diseases of the national institutes of health, usa) had a significant rate of non-urological associated somatic syndrome (31%) associated with longstanding disease, more severe urological symptoms and higher rates of depression and anxiety (20). a chinese study compared the demographics, character, leukocyte counts in eps, disease course, nih chronic prostatitis syndrome index (nih-cpsi), self-rating anxiety scale (sas) and self-rating depression scale (sds) of 291 cp/cpps patients and 100 normal controls, in order to establish the psychological factors related with cp/cpps. all patients were treated with the same protocol and followed-up for 6 weeks. according to this study, the rate of introversion was significantly higher while that of extroversion was significantly lower in the cp/cpps group compared to the control group. univariate and multivariate analyses with cox regression revealed that anxiety, depression and disease course were the definite factors that negatively affected the prognosis of cp/cpps, while other factors such as age, nih-cpsi, character and leukocyte counts in eps had no influence (12). a korean study investigated the association of personality traits with the baseline clinical characteristics and treatment outcomes of patients with cp/cpps. according to this study, although extraversion, agreeableness, and conscientiousness can influence the clinical characteristics of patients with cp/cpps, they do not affect the overall symptoms or the treatment response in those patients. in contrast, neuroticism is associated with a significantly poorer treatment response and with higher levels of depression and somatization (21). a small study conducted in the usa measured the perceived stress, pain intensity, and pain-related disability 1, 3, 6, and 12 months after a health care visit resulting in a new diagnosis of nonbacterial prostatitis/pelvic pain. according to this study, greater perceived stress during the 6 months after the health care visit was associated with greater pain intensity and disability at 12 months (22). another chinese study compared anxiety, depression, erectile function and the scores of the nih-cpsi among refractory cpps patients who had never received any psychotherapy and non-refractory cpps patients. no significant differences were observed in the chronic prostatitis symptom scores between the two groups, while anxiety and depression scores were significantly higher and that on erectile function was significantly lower in the refractory than in the non-refractory cpps patient group (23). a study based on the taiwan longitudinal health insurance database, compared 8,088 subjects with cp/cpps with 24,264 randomly matched controls and found that cp/cpps is consistently and significantly associated with prior anxiety disorder in all age groups. in particular, subjects aged 40-59 years had the highest rates of prior anxiety disorder among cases compared to controls (24). these results reflected those of a previous study which found that men who experienced severe stress were 1.2 and 1.5 times more likely to report prostatitis than those whose lives were relatively stress-free (25). similarly, a cross-sectional study from estonia revealed a familial predisposition to cp/cpps that may be associated also with susceptibility to respiratory tract infections (26). discussion chronic prostatitis is a relatively common male chronic pain condition. it is characterized by recurrent symptomatic episodes, or flare-ups. between flare-ups, some patients are asymptomatic, while others complain of mild symptoms. patients usually have a long history of persistent symptoms. it isn’t clear what causes chronic pain in cp/cpps, and the etiology of this disease is still uncertain. various theories have been hypothesized, such as autoimmunity, persistent inflammatory statuses, neuroinflammation oxidative stress, pathogen and host-specific factors, pelvic floor tension myalgia, and differences in systemic pressure sensitivity (40-42). in addition, there is evidence that cp/cpps patients show alterations of the hypothalamic-pituitary adrenal axis function in response to acute stress (9). moreover, it has been suggested that stress is a potent factor in the development of cp/cpps; for this reason the term “stress prostatitis” was proposed as an appropriate label for this condition (43). currently, psychological factors are considered to play an important role in cp/cpps and the possible association between personality disorders and chronic pelvic pain development has garnered increasing attention. for example, the validated upoint diagnostic-therapeutic algorithm, in its original or modified version (i.e. upoints, including a sexual function domain), acknowledges the importance of psychological factors in cp/cpps and includes a domain specifically focusing on the psychosocial functioning of patients (44, 45). in the upoint/upoints system, items such as a history of clinical depression, ongoing antidepressant therapy, a history of abuse, maladaptive coping mechanisms (for example, catastrophizing), anxiety, or a high score of a depression scale such as hads qualifies a patient as having a positive psychosocial phenotype. stress can have a significant impact on cp/cpps, as it can worsen the symptoms and significantly affect the emotional state of patients by causing extreme overwhelming or distress (36). on the other hand, it was shown that the development of stress in cp/cpps is time-dependent and is associated with subsequent pain and disability (23, 25). the severity of stress has been reported to depend on individual perception or subjective interpretation of causative factors rather than on the contents or frequency of factors causing stress (37). in a such a case, pain and disability are causative factors of stress while stress is a potent factor in the prolongation and perpetuation of the symptoms. in fact, psychological stress can lead to the archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri worsening of symptoms, and particularly to pain and discomfort during sexual intercourse, thus making patients more anxious and irritated. in turn, these negative emotions can worsen cp/cpps, thus triggering a vicious circle (14). as a consequence, the quality of life of men with cp/cpps can decrease to levels comparable to patients with severe illnesses (38, 39). existing data suggest that the experience and perception of pain is complex, and is maintained by educational, psychosocial, and behavioral variables (46). for this reason, the rate of introversion is significantly higher than that of extroversion in cp/cpps patients (21), and this evidence may also explain the association of cp/cpps with lower educational levels, poor emotional health and a lack of social support (44). therefore, several patients are more prone to develop persisting diseases, especially in the presence of exaggerated media-reported information, describing chronic prostatitis as a very serious condition. in addition, because of the lack of correct understanding about this disease, many patients can feel anxious and worried, fearing that the sexual function and fertility will be affected by cp/cpps. other patients may fear of having undetected prostate cancer or of having a sexually transmitted disease (15). in certain patients, persistent urinary symptoms may lead to weak masculine identity disorder (47). given that depression and anxiety are closely correlated with chronic pain, urinary symptoms, sexual dysfunction and weak masculine identity (14, 37), it could be assumed that, in addition to stress perception, psychological problems, personality traits, educational and behavioral variables can be considered as factors causing or deteriorating symptoms in patients with cp/cpps. this hypothesis explains the high incidence of anxiety and depression in treatment–resistant chronic bacterial prostatitis (24). given the familial predisposition to cp/cpps, the high incidence of cp/cpps among men who experience severe stress and the fact that cpps is consistently and significantly associated with prior anxiety disorders (24, 26), several researchers suggested cp/cpps patients to be psychologically seriously ill. in fact, studies on quality-of-life outcomes suggest that psychiatric disorders strongly coexist with cp/cpps (48). however, in a study by de la rosette and coworkers, it was shown that differences in scores of personality inventory (nvm), symptom checklist (slc-90), and depression inventory (idd) between cp/cpps patients and controls were not of a great magnitude, and in any case of lesser extent compared with differences in scores from psychiatric patients (10). in addition, fishbain et al. showed that some trait tests and inventories may not be pain state-independent, and therefore may interpret post-pain development personality profiles as being indicative of the true pre-pain personality structure (49). conclusions despite limitations and variations in sample size, study design and diagnostic measures shown by the studies included in this review, the relation between chronic prostatitis and different psychological conditions is a consistent finding. the existing evidence does not permit to definitely conclude whether psychological problems are a risk factor of cp/cpps or whether they represent a complex of symptoms that characterize the exacerbation of this disease. however, it seems logical that patients living with chronic (persistent or long-term) physical conditions such as cbp and cp/cpps are more likely to experience poor mental health, 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184:2339-2345. 45. shoskes da, nickel jc, rackley rr, pontari ma. clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes. prostate cancer prostatic dis. 2009; 12:177-183. 46. lian f, shah a, mueller b, welliver c. psychological perspectives in the patient with chronic orchialgia. review transl androl urol. 2017; 6(suppl 1):s14-s19. archivio italiano di urologia e andrologia 2023; 95, 1 k. stamatiou, m. trinchieri, m. trinchieri, g. perletti, v. magri 47. dunphy c, laor l, te a, et al. relationship between depression and lower urinary tract symptoms secondary to benign prostatic hyperplasia. rev urol. 2015; 17:51-7. 48. ku jh, kim sw, paick js. quality of life and psychological factors in chronic prostatitis/chronic pelvic pain syndrome. urology. 2005; 66:693-701. 49. fishbain da, cole b, cutler rb, et al. chronic pain and the measurement of personality: do states influence traits? pain med. 2006; 7:509-29. correspondence konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio hospital 2 salepoula str., 18536 piraeus, greece margherita trinchieri, md margherita.trinchieri@gmail.com psichiatry unit, asst rhodense, g. salvini hospital, garbagnate, milano, italy martina trinchieri, md martinatrinchieri90@gmail.com società italiana di psicoanalisi della relazione sipre, milano, italy gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy vittorio magri, md vittorio.magri@asst-fbf-sacco.it urology unit, asst fatebenefratelli sacco, milano, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12018 1 systematic review according to nccn guidelines, radical nephrectomy (rn) is the treatment of choice for renal mass in all stages, except for stage i and stage iv which requires patient selectivity. the kidney, perirenal adipose tissue, adrenal glands, and surrounding lymph nodes are all removed during radical nephrectomy. the surgical management of rcc has evolved substantially over the last two decades, from an open approach to minimally invasive surgery using laparoscopy (3). in massive and complex renal mass, extensive neovascularization, and local invasion is still challenging for surgeons who perform rn in these patients. intraoperative bleeding which can be life-threatening is the most common complication during this procedure. intraoperative bleeding in radical nephrectomy can be massive and may require transfusion or in some severe cases, intraoperative death may occur (4, 5). renal artery embolization (rae) is a technique that reduces or stops the flow of blood via the renal arteries. almgard conducted this procedure on humans for the first time in the 1970s. this method can stop spontaneous bleeding from the tumor, primary angiomyolipoma treatment, palliative treatment for unresectable renal masses, and as an adjunctive preoperative treatment prior to radical nephrectomy for primary renal masses (6, 7). local edema surrounding the infarcted kidney occurs in 2-3 days after rae. this event was thought to facilitate dissection by providing cleavage that can alleviate the surgery (8, 9). the necessity of preoperative renal artery embolization (prae) prior to radical nephrectomy has been often debated and its benefit is still questioned. massive and complex renal masses with significant neovascularization and extensive local invasion remain a surgeon's nightmare when doing rn. a systematic review and metaanalysis study conducted by shanmugasundaram et al. about prae prior to partial nephrectomy demonstrated a significant reduction in estimated blood loss with manageable post-embolization syndrome. previous metaanalysis regarding pre-operative rae were performed in patients with partial nephrectomy, whereas there is no meta-analysis that has concluded the role of rae in radical nephrectomy. this study aims to determine the effect of preoperative rae prior to radical nephrectomy for rcc, compared to those without preoperative rae (10). introduction: radical nephrectomy for renal cell carcinoma (rcc) is still the treatment of choice for all stages except for stage i and iv, which need patient selectivity. the purpose of renal artery embolization (rae) pre-operative before radical nephrectomy is to facilitate resection, reduce bleeding, and reduce the time to surgery, but the necessity of this procedure is still debatable. this study investigates the efficacy of pre-operative renal artery embolization (prae) before radical nephrectomy for rcc patients. methods: the systematic searches based on prisma guidelines were conducted in pubmed, scopus, web of science, medrxiv, and sciencedirect databases with pre-defined keywords. both analyses, quantitative and qualitative, were performed to assess blood loss, transfusion rate, surgical time, intensive care unit (icu) stay, and hospital stay. results: a total of 921 patients from 8 eligible studies were included. the blood loss was significantly lower in the prae group compared to the control group (p = < 0.00001; smd -20 ml; 95%ci -0.29, -0.12). there is no statistically significant difference between rae and without rae in the transfusion rate nephrectomy (p = 0.53, or 0.65; 95% ci 0.16, 2.57), mean operative time (p = 0.69; smd 5.91; 95% ci -23.25, 35.07), mean length of hospital stay (p = 0.05; smd 0.56; 95% ci 0.00, 1.12), and mean length of stay in the icu (p = 0.45; smd 11.61; 95% ci -18.35, 41.57) conclusions: prae before radical nephrectomy significantly reduces blood loss in rcc patients but is similar in the surgical time, transfusion rate, and length of hospital stay and icu stay. key words: renal artery embolization; renal cell carcinoma; radical nephrectomy. submitted 21 october 2023; accepted 2 november 2023 introduction renal cell carcinoma (rcc) accounts for 5% and 3% of all malignancies, respectively, and is more prevalent in industrialized nations. it is the sixth most common cancer in men and the eighth most common cancer in women. over 400,000 new cases in 2018 and 175,000 fatalities globally were reported (1). according to estimates, there are 2,4-3 instances of kidney cancer per 100,000 people in indonesia, and the majority of these cases are t2 or above when they first show (2). a systematic review and meta-analysis on the efficacy of preoperative renal artery embolization prior to radical nephrectomy for renal cell carcinoma: is it necessary? gullyawan rooseno 1, 2, lukman hakim 1, 2, tarmono djojodimedjo 1, 2 1 department of urology, faculty of medicine, universitas airlangga; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2023.12018 summary archivio italiano di urologia e andrologia 2023; 95(4):12018 g. rooseno, l. hakim, t. djojodimedjo 2 methods review protocol and search strategy this study followed a predetermined protocol according to the guidelines outlined by the preferred reporting items for systematic reviews and meta-analyses (prisma). the literature searches were conducted using several databases (11), including pubmed, scopus, web of science, medrxiv and sciencedirect. the selected keywords used for the search were described as “renal cell carcinoma”, “rcc”, “renal cancer”, “kidney cancer”, “renal carcinoma”, “artery embolization”, “angioembolization”, “rae”, “total nephrectomy”, and “radical nephrectomy”. the study's protocol was registered with prospero (crd42023450827). eligibility criteria the inclusions criteria for this study were as follows: comparative studies, written in english, having at least two comparison groups, and reporting data on intraoperative blood loss, the number of patients receiving transfusions, the length of icu stay and the length of hospitalization and operation time in radical nephrectomy with or without preoperative renal artery embolization. during the selection process, studies that fell under the following categories were excluded: animal experimental studies, non-english studies, duplicated studies, unpublished articles, and studies without full-text. the full search and selection process was demonstrated using 2020 prisma flow diagram (figure 1). data extraction and risk of bias assessment two independent researchers collected the data using a predefined extraction template. in cases of discrepancies or disagreements during data extraction, a third investigator would be involved to discuss and make the final decision. the extracted information encompassed various aspects, including study details (authors, country, publication date, study design, sample size) and baseline characteristic such as age, embolic agents, histopathology, also qualitative and quantitative outcomes (intraoperative blood loss, transfusion rate, the length of icu stay and the length of hospitalization and operation time). the assessment of potential research bias in non-randomized studies was conducted using the newcastle-ottawa scale (nos), which evaluates parameters related to selection, comparability, and exposure. the results obtained from the nos assessment are categorized into three groups. a score ranging from 0 to 3 implicates a low-quality study, a score from 4 to 6 implicates a medium-quality study, and a score from 7 to 9 implicates a high-quality study. for randomized controlled trial (rct) studies, the assessment of potential research bias was conducted using the cochrane rob tools v2, which evaluates four domains, such as randomization process, deviations from intended intervention, missing outcome data, measurement, and selection of reported outcome (12). data analysis the measured end points included intraoperative blood loss, the number of patients receiving transfusions, the length of icu stay and the length of hospitalization and operation time. for the dichotomous variable, the analysis used a p-value below 0.05 as a significant result and an odds ratio (or) with a 95% confidence interval (ci). the continuous variable was assessed using standardized mean difference (smd). heterogeneity between studies was evaluated using i2, where an i2 value above 50% indicated high heterogeneity and a random-effects model was applied for pooled analysis. the fixed-effects model was designed for i2 was less than 50%. the results were provided in forest plots and descriptive narratives. the statistical analysis was conducted using revman 5.4 in windows. figure 1. prisma flow chart. archivio italiano di urologia e andrologia 2023; 95(4):12018 3 renal artery embolization prior to radical nephrectomy results study search our preliminary search found 1477 results. fifteen fullarticles were retrieved for eligibility. following the assessment of the full-text articles, eight were eliminated for several reasons, including differences in intervention, population, and incomplete data. the remaining eight publications were investigated further, as shown in figure 1. clinical characteristics of the included participants were described in table 1. baseline characteristic of the study this research included a total of 921 patients with a mean age of 66 years, ranging from 59 to 66 years old. these participants comprised various articles published between 1979 and 2021. the embolant agent used was absolute ethanol, baloon occlusion, metal spirals, gelfoam, gianturco-wallace, gianturco-anderson-wallace, gelatin sponge, coil embolization, and dehydrated alcohol with balloon occlusion. the baseline characteristics are presented in table 2. risk of bias assessment the comparative and exposure aspects of the selection table 2. characteristic of cancer. author (year) histopathology clinical staging bakal et al., 1993 (14) jaganjac et al., 2014 (15) renal cell carcinoma may et al., 2009 16 clear cell carcinoma, papillary carcinoma, chromophobe carcinoma, and spindle cell carcinoma (pleomorph) singsaas et al., 1979 (17) tang et al., 2020 (18) clear cell renal cell carcinoma, t3a: 19 t3b: 31 t3c: 4 subramanian et al., 2008 (19) renal cell carcinoma, adrenocortical t2-t3a: 2 carcinoma, leiomyosarcoma, t3b: 156 t3c: 57 t4: 6 cochetti et al., 2019 (20) rcc, oncocytoma, chromophobe, t2b: 23 papillary, solitary fibrous tumour, ks, tcc t3a: 27 t3b: 9 t4: 5 velasco et al., 2021 (21) clear cell carcinoma, chromophobe, t3a: 44 papillary, anaplastic, collecting ducts, t4: 2 squamous cell carcinoma, nephroblastoma table 1. characteristic of the study. author (year) study country intervention n age embolant agent time before clavien-dindo outcome design (mean ± sd) surgery (n) bakal et al., 1993 (13) retrospective america rae 24 63.75 (± 12.25) 98% absolute ethanol 24 hours mean transfusion volume, without rae 69 and baloon occlusion volume tumor jaganjac et al., 2014 (14) retrospective germany rae 50 64 (± 20.75) 96% alcohol or ivalon 24-48 hours pain, transfusion rate, without rae 51 61 (± 12) 150-250 μ particles operative time, hematuria central embolization of supply vessel: metal spirals may et al., 2009 (15) retrospective germany rae 189 60.3 (± 90.4) gelfoam, 1-12 days transfusion rate, without rae 189 gianturco-wallace cancer-specific survival, overall survival, and complication singsaas et al., 1979 (16) retrospective america rae 12 gianturco-anderson-wallace 16 hours blood loss and without rae 12 transfusion volume tang et al., 2020 (17) retrospective china rae 24 59 (± 11.8) gelatin sponge 3 hours icu length of stay, without rae 30 59.3 (± 8.9) blood loss, transfusion rate, complications subramanian et al., 2008 (18) retrospective america rae 135 61.25 (± 4.9) absolute ethanol 24 hours operative time, without rae 90 62.5 (± 4.6) and occlusion baloon total vascular bypass, blood loss, transfusion rate, complications, hospital length of stay, length of icu stay, perioperative mortality cochetti et al., 2019 (19) randomize italy rae 30 64.87 (± 13.26) haemostatic absorbable 24 hours operative time, blood loss, prospective cohort without rae 34 gelatin sponge (spongostan, transfusion rate and length ethicon™, somerville, nj, usa), of hospitalization polyvinyl alcohol (pva) embolization particles (contour, boston scientific ™, marlborough, ma, usa), and metallic spirals velasco et al., 2021 (20) retrospective spain rae 9 66 (± 3.42) grade 0-i (33) transfusion rate without rae 37 grade ii (10) and complication grade iii (1) grade v (2) archivio italiano di urologia e andrologia 2023; 95(4):12018 g. rooseno, l. hakim, t. djojodimedjo 4 were well addressed, with adequate follow-up duration and relatively low dropout rates. based on the final assessment, two studies received a nos score of nine, while the remaining studies received scores ranging from 6 to 8, indicating a low risk of bias (table 3). one study assessed using the cochrane rob tool v2 (figure 2). the bias assessment result revealed that the study has a low risk of bias overall. meta analysis of transfusion rate based on a meta-analysis of the six papers included with random-effects (i2 = 91%; p = < 0.00001), there is no statistically significant difference in the transfusion rate between prae and without prae in patient undergoing radical nephrectomy (p = 0.53, or 0.65; 95%ci 0.16, 2.57) (figure 3). meta analysis of mean blood loss based on a meta-analysis of the four papers included with fixed-effects (i2 = 3%; p = 0.38), there is statistically significant difference in the mean blood loss between prae and without prae in patient undergoing radical nephrectomy, which mean blood loss was lower on prae group (p = < 0.00001; smd -0.20; 95%ci -0.29, -0.12) (figure 4). meta analysis of mean operative time based on a meta-analysis of the four papers included with random-effects (i2 = 76%; p = 0.005), there is no statistically significant difference in mean operative time between rae and without rae in patient undergoing radical nephrectomy (p = 0.69; smd 5.91; 95% ci 23.25, 35.07) (figure 5). table 3. new ottawa scale analysis. author (year) study design selection comparability outcome total bakal et al., 1993 14 retrospective **** ** *** 9 jaganjac et al., 2014 15 retrospective *** * *** 7 may et al., 2009 16 retrospective *** ** *** 8 singsaas et al., 1979 17 retrospective ** ** ** 6 tang et al., 2020 18 retrospective **** ** * 7 subramanian et al., 2008 19 retrospective **** ** *** 9 velasco et al., 2021 21 retrospective *** ** ** 7 figure 2. risk of bias analysis using cochrane rob tool v2. figure 3. forest plot for transfusion rate. figure 4. forest plot for mean blood loss [in liter (l)]. figure 5. forest plot for mean operative time (in minutes). archivio italiano di urologia e andrologia 2023; 95(4):12018 5 renal artery embolization prior to radical nephrectomy meta analysis of mean length of stay based on a meta-analysis of the three papers included with fixed effect (i2 = 34%; p = 0.22), there is no statistically significant difference in mean length of stay between rae and without rae in patient undergoing radical nephrectomy (p = 0.05; smd 0.56; 95% ci 0.00, 1.12) (figure 6). meta analysis of mean length of stay in the icu based on a meta-analysis of the two papers included with random-effect (i2 = 93%; p = 0.0001), there is no statistically significant difference in mean length of stay in the icu between rae and without rae in patient undergoing radical nephrectomy (p = 0.45; smd 11.61; 95% ci -18.35, 41.57) (figure 7). discussion intraoperative bleeding is one of the greatest sources of concern for surgeon who will perform rn which is our primary focus of this investigation. preoperative embolization of advanced renal tumors has also been employed to theoretically facilitate rn completion by reducing intraoperative blood loss, induce edema in the surrounding tissue to facilitate excision, and allowing early renal vein ligation. this study showed that rcc patients in the group that received rae before radical nephrectomy showed less bleeding compared to control group. research by zhang et al., showed that 25% of patients experienced bleeding after radical nephrectomy, with the number of patients requiring blood transfusions around 20% (5). rae is a procedure to reduce or completely stop renal artery blood flow by means of catheterization and arterial embolization. when rae was first developed in the 1970s, increasing technological advances expanded the usefulness of the rae procedure (3, 21). the mechanism of prae is to reduce bleeding by preventing the vascularization to grow and develop from the main branches of the renal arteries. in addition, it reduces blood flow to tumor cells and limits neovascularization, which help operator for better view and enhancing technique (22). although prae can reduce blood loss during operation, prae demonstrated an insignificant difference in lowering the number of patients who need transfusions after radical nephrectomy. for other malignancies, prae can reduce the risk of massive intraoperative blood loss in hypervascular tumors, which makes prae the most common treatment for renal malignancies. however, these results did not align with reducing the risk of blood transfusion (23). another study demonstrated a contrasting result, that the embolization of the renal artery before nephrectomy leads to a significant reduction in intraoperative blood loss in line with the reduction in the units of blood transfused. in specific patients, such as renal insufficiency, and anemia, and those undergoing transplant, the protection in transfusion is greater (24). this finding can be caused by factors that influence the condition of patients' transfusion requirements, such as transfusion policy factors, pre-operative baseline hemoglobin, and complications of the procedures (22). one of the iatrogenic complications of rae, which may explain these results, include bleeding at the puncture site and iatrogenic vascular damage (25). the benefits of prae are locating the abnormal blood vessels and managing without losing normal renal parenchyma. moreover, another advantage of rae is visualizing the renal vasculature, which is helpful for tumor resection procedures (26). despite these advantages, there was no significant difference regarding the length of time for surgery between the preoperative rae group and the control group. it can be concluded that this occurs because the duration of surgery is not directly related to prae but rather to the procedural and technical difficulties during surgery. the main goal of rae is not to reduce tumor size but to reduce bleeding (27). the effect of longer operative time, increasing estimated blood loss, and surgical complications may increase the number of blood transfusions, which certainly also prolong the length of stay in the icu and hospital (28). based on the fact that prae reduce the risk of large intraoperative blood loss and minimized the complication risk for surgical procedure, the other analysis performed in this study is the length of stay in the hospital and icu (5), which showed that the prae group did not affect the length of stay in either hospital or icu. despite these figure 6. forest plot for men length of stay of the hospital (in days). figure 7. forest plot for mean length of stay in the icu (in hours). archivio italiano di urologia e andrologia 2023; 95(4):12018 g. rooseno, l. hakim, t. djojodimedjo 6 facts, the differences in hospitalization policies might have a role in in-hospital duration for every hospital. studies included in this meta-analysis have various delay from rae to the surgery, the earliest was three hour and the longest was twelve days. the optimal delay for performing rae would be: maximizing the benefit of tissue oedema after rae, allowing the surgeon to proceed before formation of collateral vessels, and minimizing the patient's post-infarction syndrome. the optimal delay performing rae is 24-48 hours before the surgery (29). the purpose for delaying nephrectomy for 2-3 days was the development of local oedema, which was supposed to facilitate resection. nephrectomy at intervals greater than 3 days was deemed to become progressively more challenging due to increased collateral vasculature (9). our study is a structured study assessing the effect of rae on patients undergoing radical nephrectomy, which has no consensus and agreement regarding the most optimal time for this procedure. however, the limitation of this study is that most of the included studies performed rae before nephrectomy at different time periods, which could lead to bias in the study data. the authors considered that this study has not analyzed the staging of rcc, average preoperative hemoglobin level, mean hemoglobin level of patients receiving transfusions, histological type, intraoperative events, and treatment constraints that may affect the conclusion of this study. we recommend performing multicenter rct studies with selective criteria aimed to evaluate the effectiveness and safety of prae, which cannot be fully analyzed in this study. conclusions the systematic review and meta-analysis showed that prae prior to radical nephrectomy might have potential to reduce blood loss in rcc patient. radical nephrectomy with prae were comparable for surgical time, transfusion rate, and icu stay. further rct studies are needed, involving multicenters, and taking into account factors that cannot be controlled in this study. acknowledgement we gratefully acknowledge the statistical advice of ida bagus gde tirta yoga yatindra, md. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca: a cancer journal for clinicians. 2019; 69:7-34. 2. umbas r, safriadi f, mochtar ca, et al. urologic cancer in indonesia. jpn j clin oncol. 2015; 45:708-12. 3. motzer 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4:727-31. 14. jaganjac s, schefe l, avdagi e, et al. preoperative kidney tumor embolization as procedure for therapy of advanced kidney cancer. acta inform med. 2014; 22:302. 15. may m, brookman-amissah s, pflanz s, et al. pre-operative renal arterial embolisation does not provide survival benefit in patients with radical nephrectomy for renal cell carcinoma. bjr. 2009; 82:724-31. 16. singsaas mw, chopp rt, mendez r. preoperative renal embolization as adjunct to radical nephrectomy. urology 1979; 14:1-4 17. tang g, chen x, wang j, et al. adjuvant instant preoperative renal artery embolization facilitates the radical nephrectomy and thrombectomy in locally advanced renal cancer with venous thrombus: a retrospective study of 54 cases. world j surg onc. 2020; 18:206. 18. subramanian vs, stephenson aj, goldfarb da, et al. utility of preoperative renal artery embolization for management of renal tumors with inferior vena caval thrombi. urology. 2009; 74:154-9. 19. cochetti g, zingaro md, boni a, et al. renal artery embolization before radical nephrectomy for complex renal tumour: which are the true advantages? open medicine. 2019; 14:797-804. 20. caño velasco j, polanco pujol l, herranz amo f, et al. utility of preoperative vascular embolization of renal tumors with left renal vein tumor thrombus. actas urológicas españolas. 2021; 45:615-22. 21. davis c, boyett t, caridi j. renal artery embolization: application and success in patients with renal cell carcinoma and angiomyolipoma. semin intervent radiol. 2007; 24:111-6. 22. muller a, rouvière o. renal artery embolization—indications, technical approaches and outcomes. nat rev nephrol. 2015; 11:288301. 23. lionberg a, jeffries j, van ha tg. renal artery embolization for neoplastic conditions. semin intervent radiol. 2020; 37:420-5. 24. panarese a, d’anselmi f, de leonardis m, et al. embolization of archivio italiano di urologia e andrologia 2023; 95(4):12018 7 renal artery embolization prior to radical nephrectomy the renal artery before graft nephrectomy: a comparing study to evaluate the possible benefits. updates surg. 2021; 73:2375-80. 25. haochen w, jian w, li s, et al. superselective renal artery embolization for bleeding complications after percutaneous renal biopsy: a single-center experience. j int med res. 2019; 47:1649-59. 26. rochon p, hu j. renal artery embolization for renal biopsy bleed. semin intervent radiol. 2016; 33:342-6. 27. reinhart ha, ghaleb m, davis br. transarterial embolization of renal tumors improves surgical outcomes: a case series. int j surg case rep. 2015; 15:116-8. 28. naito s, kato t, tsuchiya n. surgical and focal treatment for metastatic renal cell carcinoma: a literature review. int j of urology. 2022; 29:494-501. 29. schwartz mj, smith eb, trost dw, vaughan ed. renal artery embolization: clinical indications and experience from over 100 cases. bju int. 2007; 99:881-6. correspondence gullyawan rooseno, md gullyawanrooseno@gmail.com lukman hakim, md lukman-h@fk.unair.ac.id tarmono djojodimedjo, md (corresponding author) tar_urology@yahoo.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general-academic hospital, surabaya, east java, indonesia jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 conflict of interest: the authors declare no potential conflict of interest. 55archivio italiano di urologia e andrologia 2017; 89, 1 original paper a retrospective comparison between transrectal and transperineal prostate biopsy in the detection of prostate cancer carmelo agostino di franco 1, hussein jallous 1, daniele porru 1, giovanni luca giliberto 1, tiziano cebrelli 1, carmine tinelli 2, bruno rovereto 1 1 urology department, irccs policlinico s. matteo, pavia, italy; 2 biometrics and medical statistics service, irccs policlinico s. matteo, pavia, italy. background: the aim of this study was to analyze the differences between trusguided transrectal prostate biopsy (tr) and transperineal prostate biopsy (tp) in the diagnosis of prostate cancer. the two biopsy methods were evaluated in terms of diagnostic sensitivity and of early and late complications. methods: this retrospective study was realized through the review of clinical records of 219 men that received a prostate biopsy between 2004 and 2014. the biopsy was performed because of elevated prostate-specific antigen (psa), abnormal digital rectal examination findings (dre), abnormal transrectal ultrasound (trus) findings and symptoms due to prostate diseases. the cohort study was subdivided in two groups: 108 patients received a transrectal biopsy between 2004 and 2006 and 111 received a transperineal biopsy between 2007 and 2014. in both groups, first biopsy was performed with 12 cores scheme whereas second or third biopsy were performed with 18 cores scheme; in this study we excluded patients who underwent to biopsies with different number cores to reduce the bias. both groups were evaluated on the basis of age, total psa, psa ratio (f/t), dre/trus findings, presence/absence of low urinary tracts symptoms (luts), presence/absence of benign prostatic hyperplasia (bph), histologic findings of biopsy cores and immediate/postoperative complications. then, it was evaluated the overall cancer detection rate and the stratified cancer rate on the basis of the previous reported parameters. finally, we analyzed the early and late complication rate in both groups. u mann-whitney test was used to evaluate the quantitative variables and χ2-test or fisher exact test for qualitative variables. p < 0.05 was considered statistically significant. results: 66 cancers were detected in 219 patients of the study; 29 cancers were detected in the tp group and 37 in the tr group. there were no statistically significant differences in the overall cancer rate detected in both groups (26.13% e 34.26% respectively; p = 0.190). however, tp biopsy detected more cancers at first biopsy than tr biopsy (89.7% vs 78.4% respectively; p = 0.021). moreover, tp biopsy detected more cancers in those patients with low cancer suspect (psa < 4 ng/ml, f/t > 15%, negative trus), instead tr biopsy had more sensitivity in detecting cancer in those patients with high cancer suspect (psa > 10 ng/ml, f/t < 15%, trus with abnormal lesions). the presence of bph did not influence sensitivity in both cases. there were no significant differences in the early complication rate whereas a statistically significant difference was observed in the late complication rate (4% vs 11% in tp and tr biopsy, respectively; p = 0.019). summary no conflict of interest declared. introduction the systematic sextant prostate biopsy, introduced in 1989 by hodge et al. (1), has been for long time the gold standard for the diagnosis of prostate cancer. more recent studies have suggested that standard sextant biopsy may underestimate the incidence of cancer, with reported false negative rates of up to 31% (2). to improve the cancer detection rate it was included increasing the number of specimen cores and sampling extended fields of the prostate, in particular lateral prostate regions where usually cancers grow (3). most of american urologists like to perform transrectal (tr) prostate biopsy, while in asian and european countries some institutions prefer transperineal (tp) prostate biopsy. in our institute, the i.r.c.s.s. policlinico s. matteo of pavia, tr biopsy was performed until 2006 when it was replaced by tp method. today, prostate biopsy has been greatly improved with the introduction of prostatic magnetic resonance and the relative fusion-biopsy. however, magnetic resonance is an expensive exam and it is not yet available in all centers, especially in those minors. we want to underline the need to have a diagnostic procedure to detect prostate cancer in the best way, by using traditional prostate biopsy. in this work we analyze, retrospectively, the differences in term of sensitivity and complications rate between transrectal and transperineal biopsies in prostate cancer diagnosis. doi: 10.4081/aiua.2017.1.55 conclusions: no statistically significant differences in sensitivity were observed between tp and tr biopsy, but tp biopsy detected more cancers at first time biopsy. complications rate was lower in the tp group. therefore, we conclude that the urologist has the final choice in deciding the most appropriate biopsy technique, considering sensitivity and complications. key words: urology; oncology; prostate; biopsy; psa; prostatic cancer; transperineal prostate biopsy; transrectal prostate biopsy; rectal exploration. submitted 1 february 2017; accepted 28 february 2017 di franco_stesura seveso 04/04/17 09:23 pagina 55 archivio italiano di urologia e andrologia 2017; 89, 1 c.a. di franco, h. jallous, d. porru, g.l. giliberto, t. cebrelli, c. tinelli, b. rovereto 56 materials and methods we evaluated a cohort of 219 men, randomly chosen among the patients that received a prostate biopsy between 2004 and 2014. in our department transrectal prostate biopsy was performed until 2006 when it was replaced by transperineal prostate biopsy. the cohort was subdivided in two groups on the basis of the used technique: 111 patients in the transrectal biopsy group (tr) and 108 patients in the transperineal biopsy group (tp). in both groups, first biopsy was performed with 12 cores whereas second or third biopsy was performed with 18 cores; in this study we excluded patients who underwent to different number cores biopsies to reduce the bias. patients charts were evaluated in a completely random way, without any criteria of inclusion/exclusion but the fact that patients received a prostate biopsy. the use of anticoagulant drugs was not evaluated because of reduced documentation about it. the prostatic volume was not evaluated because a very low patients number received a volume measurement before biopsy. patients who received a trus before biopsy, were evaluated only as regards presence/absence of suspect nodules. whenever, in the study, we refer to bph we use the clinic parameter or drugs utilization (such as alpha-lytic). all the procedures were trus-guided. table 1 shows the characteristics of patients assigned to transperineal and transrectal biopsy groups. prostate mapping was performed because of elevated prostate-specific antigen (psa), abnormal digital rectal examination findings (dre), abnormal transrectal ultrasound (trus) findings and symptoms due to prostate diseases. each patient had his clinical and nursing charts, laboratory results and ultrasound and pathology reports. in particular, we focused on patients age, on dre/trus findings (recorded as normal, benign or bph and suspect for cancer), on total prostatic specific antigen (tpsa) and psa ratio, on presence/absence of lower urinary tract symptoms (luts) and on presence/absence of benign prostatic hypertrophy (bph). complications occurred during or immediately after the biopsy were defined immediate whereas they were defined late if occurred during the post-operative observation. all the results were inserted in a microsoft excel database. tr biopsies were performed using a preloaded 18-gauge biopsy needle inserted in a biopsy gun. as regards pain control, tr biopsy was performed without anesthesia in 22 patients, with local anesthesia in 77 patients, with sedation in 9 patients. local anesthesia was given through 2% lidocaine periprostatic injection using chiba needle 22-gauge. overall, among the 108 men of tr group 132 biopsies were performed with 21 men receiving a second repeated biopsy and 3 men a third repeated biopsy. the indication to perform a further biopsy in the same patient was the constant psa increase in spite of a first negative biopsy. all first biopsies were performed using a 12-core scheme biopsy; in second and third biopsies we used a 18-cores scheme. finally, we checked the intra-glandular or rectal bleeding at the end of the procedure. tp biopsies were performed using a preloaded 18-gauge biopsy needle inserted in a biopsy gun. all patients received local perineal and periprostatic anesthesia with 2% lidocaine. among the 111 patients of tp group, 125 biopsies were performed with 14 men receiving a second repeated biopsy. also in this case, first biopsy had a 12-core scheme whereas in second and third biopsies we used an 18-cores scheme. at the end of both procedures, all patients were monitored in order to check the possibility of complications. they were discharged after the first asymptomatic urination. in order to stratify patients we used total psa, psa ratio, dre/trus findings (if available). moreover, we evaluated the cancer detection rate (number of cancers/total patients number) in both procedures. complications were divided in hematuria, dysuria/strangury, acute retention of urine, intra-glandular bleeding, rectal bleeding, vasovagal syncope, severe headache, cardiovascular complications (hypertensive crisis, arrhythmias, extra systoles). the quantitative data were summarized with median and interquartile range because they are not normally distributed. on the other hand, qualitative variables were described as counts and percentages. comparisons of quantitative variables of the two groups were realized by u mann-whitney test, whereas we used χ2-test or fisher exact test to analyze the qualitative variables. all tests are two tailed and the significance level was 5% (p < 0.05). all analysis were performed using stata software (ver.9.stata corporation, college station, 2008, texas, usa). results among 219 patients, 66 (30%) received a prostate cancer diagnosis. in particular transperineal biopsy (tp) detected 29 cancers (26.13%) in 111 patients, whereas table 1. patients’ characteristics in two groups (values p < 0.05 are statistically significant). tp (n. 111) tr (n. 108) p-value median age (iqr) 68 (iqr: 61-73) 66 (iqr: 58.5-70.5) 0.0192 median psa (iqr) 6.9 (iqr: 4.94-10.03) 7.8 (iqr: 5.24-12.3) 0.1038 median f/t (%) (iqr) 14.5 (iqr: 10.9-21) 12.8 (iqr: 10-18.7) 0.0703 negative dre* (%) 21 (21.43%) 38 (36.19%) 0.066 benign dre* (%) 51 (52.04%) 43 (40.95%) suspect dre* (%) 26 (26.53%) 24 (22.86%) normal trus** (%) 4 (10.53%) 9 (17.65%) 0.165 benign trus** (%) 21 (55.26%) 18 (35.29%) suspect trus** (%) 13 (34.21%) 24 (47.06%) present luts (%) 52 (46.85%) 45 (42.06%) 0.477 absent luts(%) 59 (53.15%) 62 (57.94%) present bph*** (%) 52 (47.27%) 42 (40.38%) 0.310 absent bph*** (%) 58 (52.73%) 62 (59.62%) abbreviations: tp: transperineal biopsy; tr: transrectal biopsy; psa: prostate-specific antigen; f/t: free psa/ total psa; dre: digital rectal examination; trus: transrectal ultrasound; luts: low urinary tract symptoms; bph: benign prostatic hyperplasia. *: avaliable in 203 pt; **: avaliable in 89 pt; ***: avaliable in 214 pt. di franco_stesura seveso 04/04/17 09:23 pagina 56 transrectal biopsy (tr) detected 37 cancers (34.26%) in 108 men; however there were no statically significant differences (p = 0.190) between two techniques. there was no evidence of pin/asap in the groups analyzed; usually the most common finding was chronic inflammation but in that context we did not considered this; to perform other biopsies in the groups analyzed we considered only the psa velocity/psa increasing. then we considered the repeated biopsies in the same patient: among 111 patients underwent to tp biopsy, 14 (13%) received a second biopsy; among 108 patients of tr group, 21 (19%) received a second biopsy, 3 (2.8%) received a third biopsy. in table 2 we report the number of cancers detected at first and repeated biopsies in relations to the total number of diagnosed cancers; it shows that overall cancer rate detected at first biopsy, in relation to the total number of diagnosed cancers, is greater in tp group than tr group (89.7% vs 78.4%; p = 0.021); in patients who underwent to further biopsies, overall cancer rate was 10.3% and 21.6% in tp and tr group, respectively. then we stratified patients by psa, psa ratio, dre/trus, luts, presence/absence bph. as reported in table 3, in patients with “low cancer suspect” (psa < 10 ng/ml, f/t > 15%, negative trus), tp biopsy had more sensitivity to detect cancer than tr biopsy. on the other hand, tr technique detected more cancers in that patients with “high cancer suspect” (psa > 10 ng/ml, f/t < 15%, trus with suspect images). in addition, when dre was positive, tp biopsy detected more cancers than tr technique (55% vs 43% respectively). there were no statistically significant differences in bph between two groups, so, in this report, the bph presence did not influence biopsy sensitivity. then we analyzed complication rate in both groups: early or immediate complication number, directly biopsy related, was low and it interested only tr group. considering the limited case number, we did not find any statistically significant difference between two groups (0% vs 4.4%; p = 0.118). as for late complications, tr biopsy was less safe than counterparty transperineal. overall, in 257 biopsies we detected 20 cases with complications (7.8%); 5 in tp group whereas 15 in tr group with a statistically significant difference between two men groups (p = 0.019), as shown in table 4. in all cases we had minor complications without need for further hospitalization and resolved, however, within the same day of biopsy. discussion our retrospective study had the aim to compare sensitivity and early/late complications rates between transrectal (tr) and transperineal (tp) prostate biopsy. since the initial description of the systematic biopsy protocol by hodge et al. (1989), few studies have been conducted on transperineal biopsy. kojima et al. (4) in their retrospective work observed a greater improvement, in terms of diagnostic sensitivity, of systematic transperineal 12-core biopsy compared to the standard 6-core biopsy, with an increase of cancer detection rate amounted to 5.2%, assuming at the same time that the conventional 6-core scheme would miss approximately 13.8% of tumors. in a study published in urology in 2000 (5) they compared transrectal and transperineal sextant biopsies; the study was performed ex vivo on 40 samples of radical prostatectomy already “diagnosed” for cancer who underwent to sextant biopsies in transverse and longitudinal way, simulating, respectively, the transrectal and transperineal approach. there were no statistically significant differences between the two methods, although transperineal protocol had shown more effective in sampling the peripheral zone of gland. emiliozzi et al. (6) in 2003 published their scientific work, in which they compared the 6-core transrectal and transperineal biopsies. overall cancer detection rate was 40% (43/107 patients); tp biopsy detected 38% of cancers while transrectal method only 32%. it was demonstrated for the first time that 6-core transperineal biopsy was more sensitive than transrectal counterpart in diagnosing prostate cancer and, at the same time, it began to light the inadequacy of 57archivio italiano di urologia e andrologia 2017; 89, 1 transrectal and transperineal prostate biopsy table 2. number of revealed cancers/overall number of revealed cancers by number of biopsies. tp tr risultati tp vs tr (%) 1° biopsy 26/29 (89.7) 29/37 (78.4) 89.7 vs 78.4 2° biopsy 3/29 (10.3) 6/37 (16.2) 10.3 vs 16.2 3° biopsy 0 (0) 2/37 (5.4) 0 vs 5.4 table 4. number of late complications/number of biopsies (%) in the two groups. tp (%) tr (%) rectal bleeding 0/125 (0) 4/132 (3) dysuria/painful urination 0/125 (0) 3/132 (2.3) acute ritention of urine 2/125 (1.6) 3/132 (2.3) hematuria 3/125 (2.4) 3/132 (2.3) cardiovascular effects 0/125 (0) 1/132 (0.7) (hypertensive crisis, extrasystoles) table 3. number of cancers/overall number of diagnosed cancers stratified by different parameters. tp (29) tr (37) risults tp vs tr (%) psa < 4 4/29 (14) 0/37 (0) 14 vs 0 psa 4.1-10 15/29 (52) 18/37 (49) 52 vs 49 psa > 10 10/29 (34) 19/37 (51) 34 vs 51 f/t > 15% 13/29 (44) 3/37 (1) 44 vs 1 f/t < 15% 16/29 (55) 30/37 (81) 55 vs 81 dre negative 1/29 (3) 13/37 (35) 3 vs 35 dre (bhp) 8/29 (27) 7/37 (19) 27 vs 19 dre suspected 16/29 (55) 16/37 (43) 55 vs 43 trus negative 2/29 (7) 1/37 (3) 7 vs 3 trus (bhp) 2/29 (7) 4/37 (11) 7 vs 11 trus suspected 5/29 (17) 15/37 (40) 17 vs 40 luts (yes) 13/29 (45) 18/37 (49) 45 vs 49 luts (not) 16/29 (55) 19/37 (51) 55 vs 51 di franco_stesura seveso 04/04/17 09:23 pagina 57 archivio italiano di urologia e andrologia 2017; 89, 1 c.a. di franco, h. jallous, d. porru, g.l. giliberto, t. cebrelli, c. tinelli, b. rovereto 58 the standard transrectal sextant protocol. the first real comparison regarding the diagnostic sensitivity and the complications rate between 12-core systematic transperineal and transrectal biopsy, has been developed in a prospective study of 2008 (7) published in nature. they compared 200 men divided randomly into two groups of 100 subjects each, to underwent to, respectively, 12-core tr and tp prostate biopsy; no statistically significant differences between the two biopsy approaches were detected. however, the transperineal biopsy showed "most appropriate" in detecting cancer in patients with psa levels included in the "gray zone" (4.1-10 ng/ml), with a significantly higher proportion of positive core in transition gland zone, generally poorly sampled by tr approach. in our work we found no substantial differences between the two biopsy approaches although the tp method had greater sensitivity in detecting cancer in patients with “low cancer suspicion”. on the other hand, tr biopsy has been more sensitive in those cases defined as "at risk" for prostate cancer, especially in the case of psa > 10 ng/ml, psa ratio < 15%, trus findings of lesions suspicious for prostate cancer. we also found that a number of cancers detected by tr approach was diagnosed only after repeated biopsy, while the initial biopsy was negative for malignancy. especially among all cancers detected by the two biopsy techniques, the tp technique detected 89.7% of the tumors as early as the first biopsy compared to 78.4% of cancers diagnosed by tr method when biopsy was performed for the first time. similarly, only 10.3% of cancers were detected by tp repeated biopsies compared to 21.6% of cancers diagnosed when the tr biopsy was repeated. so we could say that the tp method is more sensitive than the tr one, allowing for faster cancer diagnosis and at the same time reducing the need to submit the same subject to additional biopsies before to reach the diagnosis of prostate cancer. we also assessed the possible presence of bph among patients of our study; the rate of the disease in our sample was approximately 44%, absolutely hand in hand with the data reported in the literature. according to our evaluations, the presence of disease has any influence on the sensitivity of biopsies. some scientific papers, reported some "difficulties" of tr traditional sextant biopsy in detecting cancer in the presence of bph, as the needle biopsy tended to sample the central zone of the gland, the seat of the elective process of benign proliferation. the transrectal protocol we used, allowed a proper sampling of the peripheral zone, tending to spare the central portion of the prostate, and this was possible by directing the bioptic needle more laterally, as among other things, stamey suggested in his study in 1995 (8). when we compared the percentage of positive cores there were no statistically significant differences between the two methods, even if tr biopsy "sampled" a greater number of cancer positive core (16.7% vs. 23.1% respectively), and this could be due to the fact that with one hand by tp approach is more difficult to sample the base of the gland, while on the other hand the transition zone is better sampled and it is interested by prostate cancer in a relatively limited number of cases (approximately 24% of all prostate cancers). few studies have evaluated the differences in complications between the two biopsy methods; in a paper of 2005 (9), was evaluated retrospectively the complication rate between sextant tr and tp biopsies. in a total of 197 biopsies (81 transperineal and 116 transrectal), no statistically significant differences were recorded between the two approaches, with an overall rate of complications of 22.2% and 19.8% respectively for the tp and tr approach. considering, however, the relatively small sample of patients, it was concluded that both methods were safe. most frequent complication tp biopsy related was gross hematuria without any statistically significant differences with tr method. in literature they report a greater risk of serious complications related to tr biopsy, in particular urosepsy and rectal bleeding. infective complications, today are less frequent thanks to antibiotic prophylaxis and pre-biopsy enema, with a rate of 2.2% in the case of tr approach, whereas this percentage is significantly lower with tp approach. in our study, we evaluated early or immediate complications and late complications arisen during post-biopsy observation. we did not find any statistically significant difference in early complications but in tp group there were no complications (0%) whereas in tr group we found 3 complications (2.2%), in particular 2 cases of vaso-vagal syncope and 1 patient with intra-glandular bleeding. as regard late complications, we found a statistically significant difference between tp and tr methods (4% vs 11%, respectively). hematuria and acute urine retention were most frequent complications in tp group whereas in tr group most frequent complication was rectal bleeding followed by dysuria/strangury, urine acute retention and hematuria. in addition, in tr group we detected two unusual complications: severe headache needing analgesic drugs and one man with cardiac rhythm alterations and hypertensive crisis, quickly resolved after drugs administration. unfortunately, it was not possible to assess any long-term complications due to the lack of documentation. as above described, 12-core tp and tr biopsies showed an equivalent sensitivity in overall prostate cancer diagnosis. in general, transrectal biopsy advantage is simplicity of execution and relative needing of anesthesia, whereas main disadvantage is represented by complications rate still relatively high, in particular infections and rectal bleeding. as regards transperineal biopsy advantage is represented by low complications rate whereas main disadvantages are necessity of anesthesia and complexity of execution; however, today refinement of brachytherapy techniques have made it more "family" relationship with this biopsy approach. conclusions this retrospective comparison between tr and tp biopsy did not show any statistically significant difference in terms of diagnostic sensitivity of prostate cancer. however, tp biopsy detected more prostate cancers at first biopsy than tr biopsy (89.7% vs 78.4% respectively). moreover, tp biopsy showed more diagnostic sensitivity in those patients with “low suspect” for prostate cancer than tr biopsy (psa < 10 ng/ml, f/t > 15%, trus di franco_stesura seveso 04/04/17 09:23 pagina 58 negative for suspected lesions). this latter instead, detected more cancers in those patients with higher suspect for prostate cancer (psa > 10 ng/ml, f/t < 15%, trus with abnormal lesions). today, the urologist has more instruments to study a patient with a suspect prostate cancer, for example rmn multiparametric or fusion biopsy. however, not all centers can enjoy these instruments so we think that is important to optimize diagnosis, mostly in low risk patients who represent the majority of patients who come to our observation. in conclusion, the urologist has the final choice in deciding the most appropriate biopsy technique, especially in a context like the present in which more and more patients, not necessarily affected by cancer, underwent prostate biopsy. therefore, should be desirable the use of a technique that combines an appropriate diagnostic sensitivity to a low complication rate: transperineal biopsy seems to be able to satisfy this “compromise”. references 1. hodge kk, mcneal je, terris mk, stamey ta. random systematic versus directed ultrasound-guided transrectal core biopsies of the prostate. j urol. 1989; 142:71-5. 2. borboroglu pg, comer sw, rffenburgh rh, et al. extensive repeat transrectal ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. j urol. 2002; 60:93-7. 3, durkan gc, sheikh n, johnson p, hildreth aj, greene dr. improving prostate cancer detection with an extended-core transrectal ultrasonography-guided prostate biopsy protocol. bju int. 2002; 89:33. 4. kojima m, hayakawa t, saito t, et al. transperineal 12-core systematic biopsy in the detection of prostate cancer. int j urol. 2001; 8:301-7. 5. vis an, boerma mo, ciatto s, et al. detection of prostate cancer: a comparative study of the diagnostic efficacy of sextant transrectal versus sextant transperineal biopsy. urology. 2000; 56:617-21. 6. emiliozzi p, corsetti a, tassi b, et al. best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. urology. 2003; 61:961-6. 7. takenaka a, hara r, ishimura t, et al a prospective randomized comparison of diagnostic efficacy between transperineal and transrectal 12-core prostate biopsy. nature. 2008; 11:134-138. 8. stamey ta. making the most out of six systematic sextant biopsies. urology. 1995; 45:2-12. 9. miller j, perumalla c, heap g. complications of transrectal versus transperineal prostate biopsy. anz j surg. 2005; 75:48-50. 59archivio italiano di urologia e andrologia 2017; 89, 1 transrectal and transperineal prostate biopsy correspondence carmelo agostino di franco, md carmelo_difranco@tiscali.it hussein jallous, md daniele porru, md giovanni luca giliberto, md tiziano cebrelli, md bruno rovereto, md urology department, irccs policlinico s. matteo, pavia, italy carmine tinelli, md biometrics and medical statistics service, irccs policlinico s.matteo, pavia, italy di franco_stesura seveso 04/04/17 09:23 pagina 59 stesura seveso 167archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. invasive modalities for stone treatment are used in those patients, such as, percutaneous nephrolithotomy (pnl), mini-perc, ultramini-perc, micro-perc, extracorporeal shockwave lithotripsy (swl) and flexible ureterorenoscopy (f-urs) with reported variable stone free rates. other possible available treatment options are laparoscopicassisted pnl and laparoscopic pyelolithotomy (lp) (3). in the present study, we report our single center experience in comparing mini-perc versus f-urs for management of renal stones up to 2 cm in patients with anomalous kidneys. materials and methods we retrospectively reviewed the records of patients with stones in anomalous kidneys treated by miniperc between january 2016 to june 2020 and we compared them to the records of patients with same stone criteria treated by flexible ureterorenoscopy. we excluded patients below 18 years, stones more than 2 cm in maximum diameter or patients with multiple stones and patients with ectopic pelvic kidneys. preoperative radiological investigations included plain x-ray of abdomen and pelvis and non-contrast ct. stone size was calculated by measuring the maximum stone diameter. all procedures were performed by the same surgeon at our institute. mini-perc group all procedures were performed under general anesthesia. insertion of a 6 fr open tip ureteric catheter was performed in the lithotomy position, then the patient was turned prone. all pressure points were padded. the optimal calyx of entry was determined by using both biplanar c-arm fluoroscopy after retrograde injection of the half-diluted contrast and ultrasonography (figure 1). if bowel and/or viscera were found across the chosen access, then it was displaced away by pressure of us probe as was described by desai et al. (4). a tract was gradually dilated with fascial dilators (cook urological, usa) and 16.5/17.5 operating sheath was inserted. a 34-cm long semirigid ureteroscope (9.5 fr) (karl storz; tuttlingen, germany) was used with auriga xl 50w holmium laser machine (boston scientific; usa) and 600 µ laser fiber. after inspection of the pelvicalyceal system, the objectives: to report our single center experience in comparing mini-percutaneous nephrolithotomy versus flexible ureterorenoscopy for management of renal stones up to 2 cm in anomalous kidneys. materials and methods: records of the last 30 patients with stones less than 2 cm in anomalous kidney treated by mini-percutaneous nephrolithotomy were reviewed and compared to last 30 patients treated by flexible ureterorenoscopy. results: mean stone size was significantly higher in the minipercutaneous nephrolithotomy group (17.90 mm) than in flexible ureterorenoscopy group (14.97mm) (p < 0.001). mean operative time (80.33 min vs 56.43 min) and fluoroscopy exposure time (4.49 min vs 0.84 min) were significantly higher in the mini-percutaneous nephrolithotomy group than in the flexible ureterorenoscopy group (p < 0.001). the mean post-operative drop in hemoglobin concentration was significantly higher in the mini-percutaneous nephrolithotomy group (0.47 gm versus 0.2 gm) (p < 0.001). stone free rate after 12 weeks follow up was not statistically significant between the 2 groups (90% in minipercutaneous nephrolithotomy vs 80% in flexible ureterorenoscopy) (fep = 0.472). conclusions: both modalities were found to be safe and effective for treatment of stones less than 2 cm in anomalous kidneys. key words: mini percutaneous nephrolithotomy; flexible ureterorenoscopy; anomalous kidneys. submitted 22 february 2021; accepted 21 april 2021 introduction congenital anomalies of the kidney including anomalies of lie, rotation and fusion are caused by impaired migration of the ureteric bud and metanephric blastema upwards from pelvis to upper abdomen. the renal calyces are normally rotated 30-50 degrees behind the coronal axis so that the calyces point laterally, and the pelvis points antero-medially, when this axis is disturbed, the condition is known as renal malrotation (1). the incidence of urolithiasis in anomalous kidneys is higher than in normal kidney, as these conditions lead to impaired urine drainage and urinary stasis as well as an increased incidence of upper urinary tract infection. the anatomy and location of these kidneys makes the management of urolithiasis challenging (2). the majority of those patients have been historically treated with open surgery. however nowadays various minimally mini percutaneous nephrolithotomy versus retrograde flexible ureterorenoscopy in the treatment of renal calculi in anomalous kidneys hussein m. abdeldaeim, omar el gebaly, mostafa said, abdel rahman zahran, tamer abouyoussif department of urology, alexandria university, alexandria, egypt. doi: 10.4081/aiua.2021.2.167 summary archivio italiano di urologia e andrologia 2021; 93, 2 h.m abdeldaeim, o. el gebaly, m. said, a. rahman zahran, t. abouyoussif 168 stone was dusted using holmium-yag laser with energy of 0.5-0.8 j and frequency of 12-16 hz. most of the small fragments were cleared spontaneously with irrigation fluid coming out around the ureteroscope. larger fragments were retrieved by a 5 fr forceps (karl storz, tuttlingen, germany). if the pelvicalyceal system, under fluoroscopic and nephroscopic inspection, was found to be clear, a 6 fr double-j stent (dj) was placed if needed with or without insertion of 14 fr nephrostomy tube (pcn). f-urs group all procedures were performed under general anesthesia with the patient in the lithotomy position, using a 9.5-fr semi-rigid ureteroscope (karl storz; germany); the ureter was cannulated with a 0.038-inch hydrophilic tip guidewire. the lower ureter was dilated by the semi-rigid ureteroscope (karl storz, germany) over the guidewire. retrograde pyelogram through the ureteroscope was done for better understanding of the pelvi-calyceal anatomy. after dilating the ureteral orifice and lower ureter a second hydrophilic tip guidewire was inserted into the pelvicalyceal system. under fluoroscopic guidance a 7.5 fr f-urs (flex-x2; storz, tuttlingen, germany) was back loaded on one of the guidewires into the kidney (figure 2). a pressurized manual irrigation pump was used to have clear vision. after inspection of the pelvis and calyces and identification of the stone, auriga xl 50w holmium yag laser machine (boston scientific; usa) and 200/312 µ laser fiber, with settings of 0.5-0.8 j/12-16 hz was used for dusting the stone. in some patient when in situ stone dusting was difficult, the stones were relocated into the upper calyx using a zero tipped nitinol basket (boston scientific, usa) basket. a jj stent was placed in all patients after the completion of the procedure under fluoroscopy. intraoperative variables were recorded including operative time, fluoroscopy time, need for blood transfusion, complications, etc. postoperative assessment included hemoglobin level, serum creatinine level, need for auxiliary procedures, complications according to clavian dindo classification, and pain assessment using visual analogue scale (vas) (5). plain x-ray abdomen and pelvis was done on the first postoperative day and at 3 months. non contrast ct was also performed. stone free status (sfr) was defined as the absence of any residual fragments ≥ 3 mm at 3 months in ct. statistical analysis was carried out using spss statistics software version 20. categorical variables were described using frequencies and percentages. chi-square test was used for testing associations between categorical variables. when the assumptions of chi-square test were not met, fisher’s exact p value was selected for 2:2 tables and monte carlo p value was reported for more than 2:2 tables. continuous variables were described using mean and standard deviation. in such case, independent sample ttest was used for comparing two independent groups and paired sample ttest was used for comparing two dependent groups. statistical significance was accepted as p < .05. all applied statistical tests of significance were two-tailed. results both groups were comparable regarding age, sex, body mass index and mean stone density. mean stone size was significantly higher in the mini-perc group than in f-urs group (p < 0.001). patients’ demographic data and stone criteria are listed in table 1. overall, the most common presenting symptom was pain (66.7% of patients in mini-perc group vs 40% in furs group) and the most common stone location was the renal pelvis in both groups. figure 1. (a). plain kub showing right hypochondrial radiopaque shadow (b). axial ct cut showing 1.2 cm stone in right laterally malrotated kidney (c). fluoroscopic image after retrograde pyelogram showing complete lateral renal pelvis malrotation with stone inside (blue arrow). figure 2. (a). axial ct cut showing 1.5 cm stone in the lower calyx of left kidney in patient having horseshoe kidney (b). intraoperative fluoroscopic image showing the f-urs inside the left kidney and the stone (black arrow) (c). fluoroscopic image after retrograde contrast injection into the pelvicalyceal system through the f-urs and showing the stone in the lower calyx (black arrow). a. b. c. a. b. c. for residual fragments and one patient was considered for follow up. in f-urs group, 2 patients required a second session of f-urs for residual fragments, 1 patient underwent swl and 3 patients were considered for follow up. in terms of complications, 4 patients in miniperc group suffered moderate postoperative pain (clavien grade i) despite receiving sodium diclofenac and 2 patients developed fever. in f-urs group, three patients suffered moderate colic pain postoperatively (clavien grade i) and fever developed in 6 patients (20%). mild postoperative hematuria was observed in 15 patients (50%) in each group. discussion stones within the normal pelvicalyceal system are accessed and endoscopically treated based on specific and well-known stone factors such as size and location. guidelines and indications of endoscopic management of stones are well known in orthotopic and orthomorphic renal units. however, in the anomalous renal units, deviation from the standard anatomical structure makes stone access and manipulation more challenging. in this study, we observed our previously managed patients with stones in anomalous kidneys. the purpose of this research wss to compare the outcome of mini-perc and flexible urs in treating stones less than 2 cm in diam169archivio italiano di urologia e andrologia 2021; 93, 2 mini-perc vs flexible ureteroscopy in anomalous kidneys table 1. comparison between the two studied groups according to demographic data and stone criteria. mini perc (n = 30) rirs (n = 30) p no. % no. % sex 0.519 male 25 83.3 23 76.7 female 5 16.7 7 23.3 age (years) 0.594 mean ± sd 42.53 ± 10.47 41.07 ± 10.71 bmi 0.553 mean ± sd 29.30 ± 2.78 28.80 ± 3.64 nature of the renal anomaly mcp = medial malrotation 6 20.0 4 13.3 0.451 ventral malrotation 10 33.3 13 43.3 lateral malrotation 1 3.3 2 6.7 horseshoe kidney 10 33.3 10 33.3 renal duplication 3 10 0 0.0 crossed ectopic kidney 0 0.0 1 3.3 stone side 0.121 right 12 40.0 18 60.0 left 18 60.0 12 40.0 stone site mcp = renal pelvis 25 83.3 17 56.7 0.136 lower calyx 4 13.3 9 30.0 upper calyx 0 0.0 1 3.3 middle calyx 1 3.3 3 10.0 stone size (mm) < 0.001* mean ± sd 17.90 ± 2.43 14.97 ± 3.50 stone density (hu) 0.358 mean ± sd 1148.7 ± 279.6 1087.9 ± 225.3 table 2. comparison between the 2 groups regarding clinical and operative outcomes. mini perc (n = 30) rirs (n = 30) p no. % no. % intraoperative complications fep = yes (red out) 3 10 0 0 0.237 no 27 90 30 100 blood transfusion fep = yes 1 3.3 0 0 1.000 no 29 96.7 30 100.0 operative time (minutes) < 0.001* mean ± sd 80.33 ± 15.42 56.43 ± 18.6 radiation exposure time (minutes) < 0.001* mean ± sd 4.49 ± 0.80 0.84 ± 0.41 sfr (3 months) fep = stone free 27 90 24 80 0.472 significant residual 3 10 6 20 hospital stay (day) 0.704 mean ± sd 1.27 ± 0.64 1.33 ± 0.71 hb drop < 0.001* mean ± sd 0.47 ± 0.34 0.20 ± 0.14 auxiliary procedure fep = yes 2 6.7 3 10 1.000 no 28 93.3 27 90 fever fep = yes 2 6.7 6 20 0.254 no 28 93.3 24 80 hematuria fep = yes (mild) 15 50 15 50 1.000 no 15 50 15 50 (vas) pain mcp = no pain 1 3.3 3 10 0.214 mild 25 83.3 24 80 moderate 4 13.3 3 10 from january 2016 till june 2020. 103 patients with stones in anomalous kidneys were treated in our institution; 25 patients were excluded from the current study as they were not meeting the inclusion criteria; 37 patients were treated with mini-perc and 35 patients were treated with f-urs. after excluding 7 patients in the mini-perc group who were lost to follow up and 5 patients in f-urs group, we evaluated 30 patients in the mini-perc group and 30 in the f-urs group (figure 3). operative time (80.33 min vs 56.43 min) and fluoroscopy exposure time (4.49 min vs 0.84 min) were significantly higher in the mini-perc group than in the f-urs group respectively. also, the post-operative drop in hemoglobin concentration was significantly higher in the mini-perc group than f-urs group (0.47 gm versus 0.2 gm respectively) (p < 0.001). no statistically significant difference between the 2 groups was found regarding hospital stay. blood transfusion was required in only 1 patient in the mini-perc group (clavien grade ii). clinical and operative outcomes are summarized in table 2. middle calyceal puncture was done in 15 patients, upper calyceal puncture in 10 patients, lower calyceal puncture in 4 patients and non-papillary puncture in 1 patient. stone free rate on day 1 postoperative was 76.7% (23/30) in mini-perc group and 40% (12/30) in f-urs group; the difference was statistically significant (p = 0.004). after 3 months there was no statistically significant difference in the sfr between both groups. the clinical and operative outcomes are summarized in table 2. in the mini-perc group, two patients underwent swl archivio italiano di urologia e andrologia 2021; 93, 2 h.m abdeldaeim, o. el gebaly, m. said, a. rahman zahran, t. abouyoussif 170 eter in patients with anomalous kidneys. several variables were studied and correlated to stone free rate and incidence of complications. patients of the two groups were matched in terms of preoperative factors except for stone size, which reflected the surgeon's preference for the miniperc in large stones over f-urs. to our knowledge, there is not much data in the literature comparing mini-perc with f-urs for treatment of small and medium sized stone in anomalous kidneys. although the sfr in the mini-perc group (90%) is higher than the f-urs group the difference is not statistically significant and it is associated with a lower complication rate in the f-urs group. post-operative hb drop was significantly higher in the mini-perc group than the f-urs group. pnl is considered an acceptable intervention for stones in anomalous kidneys with reported high sfr (> 90%) (6, 7). unfortunately, in anomalous kidneys, pnl is challenging and potentially associated with risks of access failure and vascular injuries (7). there are several studies that reported the sfr after pnl in patients having different renal anomalies (6-9). mosavi-bahar et al. (8), initially reported 81% success rate after a first session which increased to 100% after second-look pnl and/or swl in 16 patients with anomalous kidneys. similar data with comparable outcome were reported by gupta et al. (6) and rana et al. (9). in a larger series, osther et al. (7), reported standard-pnl in 202 anomalous-kidneys with sfr of 76.6%. furthermore, mini-perc in anomalous kidneys was prospectively evaluated by sanjay-khadgi et al. (10) who reported a sfr of 89.8% after a single session, which was improved to 93.2% after a 2nd mini-perc session and to 98.3% after auxiliary swl. similarly, in our cohort, despite the retrospective nature and the smaller size, we figure 3. flow chart like diagram of inclusion and exclusion criteria showing number of patients excluded, number of patients enrolled, and number of patients subjected to analysis in each group. 171archivio italiano di urologia e andrologia 2021; 93, 2 mini-perc vs flexible ureteroscopy in anomalous kidneys reported 90% initial sfr. in the current study, significantly longer operative time was reported in the miniperc group that can be a consequence of a selection bias as larger stones were more frequently treated by miniperc while small stones by flexible urs. operative time in the current study in mini-perc group (45.0-110 min) is comparable to what was previously reported with standard pnl (69-100 min) (6-9) and in other mini-perc studies (25-105 min). (10) mean operative time in furs group in the current study was 56.43 ± 18.6 min compared with other series, which showed an operative time of 106 min by weizer et al. (2), 126 min by molimard b et al. (11) and 74 min by gajednra et al. (12). in the current series the targeted calyces were selected according to the site of the stone inside the kidney, although in horseshoe kidney upper calyceal puncture was selected in all patients to facilitate access to renal pelvis and lower calyx and avoid bowel injury. the lower calyceal stones which represented 30.0% of the total stone site in f-urs group were approached by the scope deflection in order to take them by tipless nitinol dormia baskets and to reposition in a more favorable site (upper calyces or renal pelvis) for laser lithotripsy (5 patients) or to dust them in situ (4 patients) which took a longer operative time than stones in the other sites, so explaining the wide variation in operative time in f-urs group. the mean hospital stay in the present series is shorter (1.27 days) than reported in previously mentioned standard pnl studies (3-3.2 days) (6-9) and in a mini-perc study (2.75 days) (10). intraoperative blood loss and consequent blood transfusion was the most alarming adverse event in our miniperc series. this group reported significantly greater hemoglobin drop 0.47 g/dl than in flexible urs group and required blood transfusion in one patient (3.3%). blood loss was comparable to what reported by similar studies, due to the presence of abnormal vasculature (6, 13, 14). however, none of our patients in the mini-perc group required angio-embolization, that was reported in some studies using standard pnl (15). in the current study, no pleura related complications occurred in either group. correspondingly, shokeir et al. (15), and viola et al. (16), did not report pleural injuries after upper pole puncture in patients with horseshoe-kidney. on the other hand, mosavi-bahar et al. reported mild pleural complication in two patients (8). gupta et al. (6), and ozden et al. (17), reported pleural injury which was managed by intercostal tube insertion in one patient. raj et al. reported pneumothorax in 6 % of patients with horseshoe kidneys undergoing pnl (18). acute deflection capability (up to 270°) and clear vision of new generation flexible ureteroscope together with progressively thinning of laser fibers and introduction of nitinol stone baskets have facilitated management of calculi located in lower calyces or difficult accessed calyces, therefore f-urs has the potential ability to overcome the anatomical and technical challenges of stone treatment in renal anomalies, leading to sfr (70 to 88.2%) in up to 1.5 sessions for stones < 3 cm (2, 11). in the current series the sfr after 3 months was 80% after a single session of f-urs and 86.6% after the second session. molimard et al. (11) reported sfr of 53% after the first session, and 88.2 % after the second one. gajendra et al. (12) reported 72% sfr after the first procedure and 88% after the second session. haddad et al. reported stone-free rate of 75% for stones with average diameter of 12.22 mm (19). in the current study we reported the sfr of miniperc and f-urs in patients with horseshoe kidneys; 80% (8 patients) who underwent miniperc were stone free after a single session, while in the f-urs group the sfr was 60% (6 patients) after a single session and 70% after the second session which is comparable to the sfr in study conducted by eryildirim et al. (84.2% with conventional pnl and 82.0% with f-urs) (20). the higher sfr in the miniperc group can be attributed to better fragments drainage during the procedure. the retrospective nature of the study allowed us to witness surgeons’ preference in these cases. it was clear the preference of mini-perc over the flexible urs for large stones. the sfr in the current series might have been increased and the need for second look mini-perc or swl might have been lowered if flexible nephroscope was used in combination with mini-perc. however, the outcome of mini-perc in the current series is comparable to other standard pnl and mini-perc studies, taking into consideration that the smaller size of mini-perc allows maneuverability and the access to more calices which might not be reached by standard pnl. being an observational and retrospective study, we acknowledge limitations such as mismatch between study groups, the non-blinding of the surgeons, small sample size, and the lack of cost analysis. consequently, larger prospective randomized studies are needed to accurately compare f-urs and mini-perc in the management of stone in anomalous kidneys and to acknowledge the specific indications of each modality. conclusions mini-perc and f-urs are both feasible, with considerable safety, in the management of stones in anomalous kidneys. the choice between the available endourological procedures requires wisdom in the decision, good evaluation and planning. references 1. yosypiv iv. congenital anomalies of the kidney and urinary tract: a genetic disorder? int j nephrol. 2012; 2012:909083. 2. weizer az, springhart wp, ekeruo wo, et al. ureteroscopic management of renal calculi in anomalous kidneys. urology 2005; 65:265-9. 3. gupta m, lee mw. treatment of stones associated with complex or anomalous renal anatomy. urol clin north am 2007; 34:431-41. 4. desai m. ultrasonography-guided punctures-with and without puncture guide. j endourol 2009; 23:1641-3. 5. graham b. generic health instruments, visual analog scale, and the measurement of clinical phenomena. j rheumatol 1999; 26:22-3. 6. gupta np, mishra s, seth a, et al. percutaneous nephrolithotomy in abnormal kidneys: single-center experience. urology 2009; 73:710-4. archivio italiano di urologia e andrologia 2021; 93, 2 h.m abdeldaeim, o. el gebaly, m. said, a. rahman zahran, t. abouyoussif 172 7. osther pj, razvi h, liatsikos e, et al. percutaneous nephrolithotomy among patients with renal anomalies: patient characteristics and outcomes; a subgroup analysis of the clinical research office of the endourological society global percutaneous nephrolithotomy study. j endourol 2011; 25:1627-32. 8. mosavi-bahar sh, amirzargar ma, rahnavardi m, et al. percutaneous nephrolithotomy in patients with kidney malformations. j endourol 2007; 21:520-4. 9. rana am, bhojwani jp. percutaneous nephrolithotomy in renal anomalies of fusion, ectopia, rotation, hypoplasia, and pelvicalyceal aberration: uniformity in heterogeneity. j endourol 2009; 23:609-14. 10. khadgi s, shretha b, ibrahim h, et al. mini-percutaneous nephrolithotomy for stones in anomalies-kidneys: a prospective study. urolithiasis 2017; 45:407-14. 11. molimard b, al-qahtani s, lakmichi a, et al. flexible ureterorenoscopy with holmium laser in horseshoe kidneys. urology 2010; 76:1334-7. 12. gajednra a, singh j, sabnis r, et al. role of flexible uretrorenoscopy in management of renal calculi in anomalies kidneys: single-center experience. world j urol 2017; 35:319-24. 13. di mauro d, la rosa vl, cimino s, di grazia e. clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study. arch ital urol androl. 2020; 91:256260. 14. binbay m, istanbulluoglu o, sofikerim m, et al. effect of simple malrotation on percutaneous nephrolithotomy: a matched pair multicenter analysis. j urol 2011; 185:1737-41. 15. shokeir aa, el-nahas ar, shoma am, et al. percutaneous nephrolithotomy in treatment of large stones within horseshoe kidneys. urology 2004; 64:426-9. 16. viola d, anagnostou t, thompson tj, et al. sixteen years of experience with stone management in horseshoe kidneys urol int 2007; 78:214-8. 17. ozden e, bilen cy, mercimek mn, et al. horseshoe kidney does it really have any negative impact on surgical outcomes of percutaneous nephrolithotomy? urology 2010; 75:1049-52. 18. raj gv, auge bk, weizer az, et al. percutaneous management of calculi within horse-shoe kidneys. j urol 2003; 170:48-51. 19. haddad r, freschi g, figueiredo f, et al. flexible ureterorenoscopy in position or fusion anomaly: is it feasible? rev assoc med bras 2017; 63:685-8. 20. eryildirim b, kucuk ev, atis g, et al. safety and efficacy of pnl vs rirs in the management of stones located in horseshoe kidneys: a critical comparative evaluation. arch ital urol androl. 2018; 90:149-154. correspondence hussein m abdeldaeim, md h_abdeldaeim@hotmail.com omar el gebaly, md omarelgebaly@hotmail.com mostafa said, md (corresponding author) mstmst2007@yahoo.com abdel rahman zahran, md abdelrahmanzahran@gmail.com tamer abouyoussif, md tamer.abouyoussif@alexmed.edu.eg urology department, faculty of medicine, sultan hussein street, alexandria (egypt) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4428 original paper no conflict of interest declared. introduction bladder cancer (bca) is the tenth most common cancer among men and women and its mortality varies according to sex, geographic location, race/ethnicity, risk factor exposure, and availability of diagnostic and treatment modalities (1). currently, bca is the eighth cause of cancer specific mortality (csm) in the united states, among both sexes (1). radical cystectomy (rc) with bilateral pelvic lymph node dissection and urinary diversion after chemotherapy is the gold-standard treatment for non-metastatic muscle-invasive bladder cancer (mibc) or recurrent high-risk non-muscleinvasive bladder cancer (nmibc) refractory to previous intravesical therapies (2). bca remains affected by a high rate of local and distant recurrences, which are usually up to 50%, especially in patients with advanced stage and lymph node involvement (3). several markers and nomograms have been proposed for bca survival and recurrence prediction (4-6). however, no tool is strongly recommended by international guidelines in disease assessment (2), and pathological tumor features remain the main predictors of oncological outcomes and actually guide decision making regarding use of secondary treatment or follow up schedule (2). among clinical factors, renal function seems to impact oncological outcomes in nmibc, mibc, as well as upper tract urothelial carcinoma. renal function has a pivotal role in patients’ eligibility to chemotherapy (7-9) or different post-operative approaches choice, and in a more adequate follow-up schedule (10, 11). ab0 blood group is commonly assessed in every patient before rc due to the risk of blood transfusion during and after surgery. the role of ab0 blood group system as a predictor of oncological outcomes has been previously investigated among other malignancies due its implication in cellular dynamics (12). specifically, many authors have already shown the association between ab0 blood groups and survival in pancreatic (13), breast (14), and gastro-intestinal tumors (15). few studies investigated the role of ab0 blood group as a predictor of outcome in objectives: we investigated ab0 blood groups prevalence according to preoperative and pathological tumor characteristics, and their association with oncological outcomes, and renal function decline in a contemporary large cohort of bladder cancer (bca) patients, who underwent radical cystectomy (rc) at a tertiary referral center. materials and methods: we retrospectively evaluated data of patients with histologically confirmed and clinically non metastatic bca, who underwent rc between 2014 and 2021 at our institution. kaplan-meier (km) plots and cox regression (cr) models tested the relationship between ab0 blood groups and local recurrence-, metastasis-, cancer specific mortality-, and overall mortality-free survival. logistic regression (lr) models tested the association between ab0 blood groups and renal function decline, defined as an estimated glomerular filtration rate (egfr) < 60 ml/min, at post-operative day 1, discharge and 6months of follow-up. results: of 301 included patients, 128 (42.5%) had group a, 126 (41.9%) had group 0, 28 (9.3%) had group b, and 19 (6.3%) had group ab. patients with group 0 developed higher rates of muscle-invasive bca (p = 0.028) with high-grade features (p = 0.005) at last bladder resection, and less frequently received preoperative immunotherapy with bacillus of calmette-guerin (p = 0.044), than their non-0 counterparts. additionally, these patients harbored more advanced pathologic tumor stage at rc (p = 0.024). km plots showed no differences among all tested cancer control outcomes between ab0 blood groups (p > 0.05 in all cases). patients with group ab presented the lowest median egfr at each time point. in multivariable lr analyses addressing renal function decline, group ab was independently associated with egfr< 60 ml/min at discharge (odds ratio: 4.28, p = 0.047). conclusions: among ab0 blood groups, patients with group 0 exhibited the most aggressive tumor profile. however, no differences were recorded in recurrence or survival rates. group ab independently predicted renal function decline at discharge. key words: ab0 blood groups; bladder cancer; radical cystectomy; outcomes. submitted 21 september 2022; accepted 2 october 2022 ab0 blood groups and oncological and functional outcomes in bladder cancer patients treated with radical cystectomy alessandro tafuri 1, 2*, andrea panunzio 1,3*, antonio soldano 1*, giovanni mazzucato 1, paola irene ornaghi 1, giacomo di filippo 4, alessandra gozzo 1, nicola de maria 1, francesco cianflone 1, aliasger shakir 5, zhe tian 3, matteo brunelli 6, antonio benito porcaro 1, vincenzo pagliarulo 2, walter artibani 1, pierre i. karakiewicz 3, alessandro antonelli 1, maria angela cerruto 1 1 department of urology, university of verona, azienda ospedaliera universitaria integrata di verona, verona, italy; 2 department of urology, “vito fazzi” hospital, lecce, italy; 3 cancer and prognostics health outcomes unit, division of urology, university of montreal health center, montreal, quebec, canada; 4 department of general and hepatobiliary surgery, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy; 5 usc institute of urology, catherine and joseph aresty department of urology, keck school of medicine, university of southern california (usc), los angeles, ca; 6 department of pathology, university of verona, azienda ospedaliera universitaria integrata di verona, verona, italy. * these authors contributed equally to the manuscript. doi: 10.4081/aiua.2022.4.428 summary 429archivio italiano di urologia e andrologia 2022; 94, 4 ab0 blood groups and bladder cancer bca, revealing controversial results (16-19). the aim of this study is to investigate the prevalence of ab0 blood groups and their distribution according to patients’ characteristics and pathological tumor features, in addition to determining the association between ab0 blood groups and renal function decline and oncological outcomes in a contemporary cohort of bca patients, who underwent rc at a high-volume tertiary center. materials and methods population, data collection and evaluation of parameters data collected from patients with histologically confirmed and clinically non metastatic bca, who were treated with rc at the department of urology at the university of verona between september 2014 and february 2021, were retrospectively evaluated. informed consent was obtained for all subjects. the indication for surgery was given in presence of mibc or history of high-risk nmibc refractory to previous intravesical treatment, according to international guidelines (2). for each patient the ab0 genotype blood group system was assessed preoperatively by the department of transfusion medicine. blood groups were routinely determined on microplates using life reagent and instrumentation (astraformedic, de mori group). additional personal information such as age, body mass index (bmi; kg/m2), smoking history and charlson comorbidity index (cci) were collected. preoperative pathological features as nmibc history, tumor grading and staging after last trans-urethral bladder resection (turb), as well as local immunotherapy administration were reported. tumor staging was assessed according to the tumor, node, metastasis (tnm) classification by the union international contre le cancer (uicc, 8th edition) (20), whereas tumor grading was assessed according to the world health organization (who) 20042016 classification system (21). additionally, estimated glomerular filtration rate (egfr) according to chronic kidney disease epidemiology collaboration (ckd-epi) equation (22), was assessed preoperatively, at post-operative day 1 (pod-1), at discharge and at 6 months of follow up. renal function decline was defined as an egfr < 60 ml/min at each evaluated timepoint. after rc surgical specimens were evaluated for tumor stage, grade, concomitant presence of carcinoma in situ (cis), lymph vascular invasion (lvi), positive surgical margins (psm), number of lymph nodes removed, and number of metastatic lymph nodes, by dedicated uropathologists. pelvic lymph node dissection was performed according to international recommendations and the template used included the external iliac, obturator, cloquet and marcille lymph nodes sites (2). all surgical procedures were performed by five experienced and dedicated surgeons, two of whom were classified as high-volume. statistical analyses descriptive statistics included frequencies and proportions for categorical variables. median and interquartile ranges (iqr) were reported for continuously coded variables. kruskal-wallis rank sum test, fisher’s exact test and pearson’s chi-squared test were used to examine the statistical significance of differences in medians and proportions, respectively. kaplan-meier (km) plots were utilized to depict local recurrence-free survival (lrfs), metastasisfree survival (mfs), csm-free survival (csmfs) and overall mortality-free survival (omfs), according to ab0 blood groups. univariable and multivariable cox proportional hazards regression models tested the relationship between ab0 blood groups and oncological outcomes. covariates consisted of age, sex, pt stage, pn stage, presence of cis, psm and lvi. univariable and multivariable logistic regression models were used to test the association between ab0 blood groups and renal function decline at pod-1, discharge and 6-months follow up. all tests were two-sided with a level of significance set at p < 0.05. table 1. descriptive statistics of 301 bladder cancer patients, who underwent radical cystectomy, according to the ab0-blood group system. variable overall 0 a b ab p-value 2 301 (100) 1 126 (41.9) 1 128 (42.5) 1 28 (9.3) 1 19 (6.3%) 1 age at surgery (years) 70 (62, 77) 70 (63, 77) 70 (60, 77) 69 (60, 74) 72 (68, 77) 0.4 sex 0.1 female 62 (20.6) 31 (24.6) 22 (17.2) 8 (28.6) 1 (5.3) male 239 (79.4) 95 (75.4) 106 (82.8) 20 (71.4) 18 (94.7) body mass index (kg/m2) 25.9 (23.8, 28.6) 25.8 (23.4, 28.6) 25.6 (23.8, 28.1) 26.5 (23.9, 29.0) 26.9 (25.6, 29.5) 0.4 smoking history 226 (75.8) 91 (72.8) 94 (74.6) 24 (85.7) 17 (89.5) 0.3 diabetes mellitus 56 (18.6) 20 (15.9) 25 (19.5) 3 (10.7) 8 (42.1) 0.049 charlson comorbidity index 0.1 ≤ 2 172 (57.1) 76 (60.3) 70 (54.7) 18 (64.3) 8 (42.1) > 2 129 (42.9) 50 (39.7) 58 (45.3) 10 (25.7) 11 (57.9) preoperative bcg administration 88 (29.2) 29 (23) 45 (35.1) 9 (33.1) 5 (26.3) 0.2 clinical tumor stage (turb) 0.1 nmibc 137 (45.5) 48 (38.1) 64 (50) 13 (46.4) 12 (63.1) mibc 164 (54.5) 78 (61.9) 64 (50) 15 (53.6) 7 (36.9) grading (turb) 0.002 low grade 15 (5.2) 1 (0.8) 11 (8.9) 0 (0) 3 (15.8) high grade 273 (94.8) 119 (99.2) 113 (91.1) 25 (100) 16 (84.2) pathologic tumor stage nr* pt0-t1 119 (39.7) 45 (36) 55 (43) 10 (35.7) 9 (47.4) pt2 44 (14.7) 14 (11.2) 20 (15.6) 5 (17.8) 5 (26.3) pt3 83 (27.6) 46 (36.8) 28 (21.9) 6 (21.5) 3 (15.8) pt4 54 (18) 20 (16) 25 (19.5) 7 (25) 2 (10.5) presence of cis at final pathology 84 (28) 35 (28) 37 (28.9) 6 (21.4) 6 (31.6) 0.9 pathologic lymph node involvement 96 (32.2) 45 (36) 36 (28.3) 13 (46.4) 2 (11.1) 0.047 number of lymph nodes removed 22 (15, 30) 22 (15, 28) 21 (14, 30) 26 (20, 30) 21 (14, 30) 0.4 lymph vascular invasion 149 (56) 68 (60.2) 63 (55.3) 12 (46.1) 6 (46.1) 0.5 positive surgical margins 34 (11.3) 15 (11.9) 11 (8.6) 5 (17.8) 3 (15.8) 0.4 1 median (iqr); n (%) 2 kruskal-wallis rank sum test; fisher's exact test; pearson's chi-square test * p-value not estimable. bcg, bacillus calmette guerin; turb, trans urethral bladder resection; nmibc, non-muscle-invasive bladder cancer; mibc, muscle-invasive bladder cancer; cis, carcinoma in situ. archivio italiano di urologia e andrologia 2022; 94, 4 a. tafuri, a. panunzio, a. soldano, et al. 430 r software environment for statistical computing and graphics (version 4.1.2) was used for all analyses (r: the r project for statistical computing. https://www.r-project.org). results study population overall, 301 patients were included of which 128 (42.5%) had group a, 126 (41.9%) had group 0, 28 (9.3%) had group b, and 19 (6.3%) had group ab (table 1). the ab0 blood group antigens were only associated with the presence of diabetes mellitus (p = 0.049), tumor grade at last endoscopic procedure (p = 0.002) and pathologic lymph node involvement (p = 0.047). no other statistically significant differences were recorded among demographic and preoperative patients’ characteristics or pathological tumor stage distribution. subgroup analysis showed that patients with group 0 developed higher rates of mibc (p = 0.028) with concomitant high-grade features (p = 0.005) at last bladder resection, and in consequence received less frequently preoperative immunotherapy with bacillus of calmette-guerin (bcg, p = 0.044), compared with their non-0 counterparts. moreover, these patients harbored more advanced pathological tumor stage (t2-4) at rc compared with non-0 patients (p = 0.024, table 2). impact of ab0 blood groups on oncological outcomes median follow up was 22 months (iqr 9-48). of 248 patients with available follow up data, 43 (17.3%) developed local disease recurrence, 63 (25.4%) experienced metastatic progression, 74 (29.8%) died due to any causes, and 52 (21.0%) died due to bca. km plots illustrated the relationship between ab0 blood groups and lrfs, mfs, csmfs and omfs, respectively (figure 1). no statistically significative difference was recorded between the four groups for all tested cancer control outcomes (p > 0.05). univariable and multivariable cox proportional hazards regression models confirmed that ab0 blood group system was not an independent predictor for all tested oncological outcomes, even after adjustment for all covariates (table 3). table 2. descriptive statistics of 301 bladder cancer patients, who underwent radical cystectomy, according to ab0-blood group system: 0 vs. non-0. variable 0 non-0 (a, b, ab) p-value 2 126 (41.9) 1 175 (58.1) 1 age at surgery (years) 70 (63, 77) 70 (60, 77) 0.4 sex 0.1 female 31 (24.6) 31 (17.7) male 95 (75.4) 144 (82.3) body mass index (kg/m2) 25.8 (23.4, 28.6) 26.1 (23.9, 28.6) 0.4 smoking history 91 (73) 135 (78) 0.3 diabetes mellitus 20 (15.9) 36 (20.6) 0.4 charlson comorbidity index 0.3 ≤ 2 76 (60.3) 96 (54.9) > 2 50 (39.7) 79 (45.1) preoperative bcg administration 29 (23) 59 (34) 0.044 clinical tumor stage (turb) 0.028 nmibc 48 (38.1) 89 (50.9) mibc 78 (61.9) 86 (49.1) grading (turb) 0.005 low grade 1 (0.8) 14 (8.3) high grade 119 (99.2) 154 (91.7) pathologic tumor stage 0.024 pt0-1 45 (36) 74 (42.3) pt2 14 (11.2) 30 (17.1) pt3 46 (36.8) 37 (21.1) pt4 20 (16) 34 (19.5) presence of cis at final pathology 35 (28) 49 (28) 0.9 pathologic lymph node involvement 45 (36) 51 (29) 0.2 number of lymph nodes removed 22 (15, 30) 22 (15, 28) 0.9 lymph vascular invasion 68 (60) 81 (53) 0.2 positive surgical margins 15 (12) 19 (11) 0.8 1 median (iqr); n (%) 2 wilcoxon rank sum test; pearson's chi-square test. bcg, bacillus calmette guerin; turb, trans urethral bladder resection; nmibc, non-muscle-invasive bladder cancer; mibc, muscle-invasive bladder cancer; cis, carcinoma in situ. table 3. multivariable cox proportional hazards regression models predicting local recurrence, metastatic progression, cancer specific mortality and overall mortality, in 248 bladder cancer patients, who underwent radical cystectomy, with available follow-up data. variable local recurrence metastatic progression cancer specific mortality overall mortality hr (95% ci) 1 p-value hr (95% ci) 1 p-value hr (95% ci) 1 p-value hr (95% ci) 1 p-value ab0 blood group a vs. 0 0.9 (0.45, 1.79) 0.8 1.15 (0.66, 2) 0.6 1.05 (0.57, 1.95) 0.9 1.41 (0.83, 2.39) 0.2 b vs. 0 0.38 (0.08, 1.75) 0.2 0.70 (0.23, 2.11) 0.5 0.8 (0.23, 2.78) 0.7 1.19 (0.47, 3) 0.7 ab vs. 0 3.68 (0.98, 13.84) 0.054 0.56 (0.07, 4.21) 0.6 1.13 (0.26, 4.99) 0.9 1.14 (0.34, 3.85) 0.8 age at surgery (years) 0.97 (0.94, 1) 0.08 1.05 (1.02, 1.08) 0.003 1.05 (1.01, 1.08) 0.005 1.06 (1.03, 1.09) < 0.001 sex male vs. female 1.02 (0.45, 2.35) 0.9 0.86 (0.44, 1.66) 0.7 1.06 (0.52, 2.15) 0.9 0.9 (0.5, 1.62) 0.7 pathologic tumor stage pt2 vs. pt0-t1 2.70 (0.61, 12.01) 0.2 0.85 (0.25, 2.9) 0.8 1.24 (0.26, 5.84) 0.8 0.91 (0.3, 2.74) 0.9 pt3 vs. pt0-t1 3.89 (0.89, 17.07) 0.07 1.45 (0.49, 4.3) 0.5 1.74 (0.43, 6.98) 0.4 1.46 (0.56, 3.78) 0.4 pt4 vs. pt0-t1 5.64 (1.15, 27.54) 0.033 2.62 (0.83, 7.25) 0.1 4.04 (0.97, 16.78) 0.055 3.06 (1.12, 8.35) 0.029 presence of cis at final pathology yes vs. no 1.94 (0.99, 3.78) 0.053 0.98 (0.54, 1.77) 0.9 1.55 (0.83, 2.86) 0.2 1.52 (0.91, 2.53) 0.1 pathologic lymph node status pn1-2-3 vs pn0 2.30 (1.13, 4.71) 0.022 2.16 (1.2, 3.88) 0.010 2.31 (1.22, 4.35) 0.010 1.72 (1.01, 2.94) 0.046 surgical margins status positive vs. negative 0.64 (0.22, 1.84) 0.4 1.3 (0.61, 2.76) 0.5 1.05 (0.48, 2.27) 0.9 1.05 (0.53, 2.08) 0.9 lymph vascular invasion yes vs. no 1.69 (0.54, 5.31) 0.4 1.59 (0.66, 3.85) 0.3 2.5 (0.82, 7.67) 0.1 1.41 (0.65, 3.06) 0.4 1 1hr = hazard ratio, ci = confidence interval. 431archivio italiano di urologia e andrologia 2022; 94, 4 ab0 blood groups and bladder cancer association between ab0 blood groups and renal function decline patients with group ab exhibited the lowest median egfr at each specified time point compared to their non-ab counterparts (66.4 vs. 47.8 vs. 57.9 vs. 52.8 ml/min at preoperative evaluation, pod-1, discharge, and 6-months follow up, respectively). conversely, patients with group b exhibited the highest median egfr at the preoperative evaluation (78.6 ml/min), as well as at pod-1 (70.6 ml/min) and at discharge (70.4 ml/min). finally, patients with group 0 exhibited the highest median egfr 6 months after rc (71.2 ml/min). however, a statistically significative difference among median egfr within ab0 blood groups was recorded only at discharge (p = 0.030), as shown in supplementary figure 1. in univariable logistic regression models addressing renal function decline at each specified time point, ab group strongly predicted egfr < 60 ml/min at discharge (odds ratio [or]: 3.27, p = 0.025. supplementary table 1). in multivariable logistic regression models ab group remained an independent predictor of renal function decline at discharge even after adjustment for age, preoperative egfr, cci, urinary derivation type and postoperative complications (or: 4.28, p = 0.047). discussion the role of ab0 blood group system as a predictor of oncological outcomes in bca is not well established. the ab0 gene is located in the long arm of chromosome 9 (9q34) (23), and encodes a specific glycosyl transferase, which catalyzes the addition of a monosaccharide to the h antigen, thereby generating surface antigens a and b (23). ab0 blood group antigens are involved in various biological mechanisms. they are expressed on the erythrocytes’ surface, as well as on the surface of many types of epithelial cells, including urothelial cells (23). interestingly, ab0 antigens are mutated or absent in tumor cells in bca (24). loss of blood group antigens on the cell surface can affect cell adhesion, cell signaling, and immune surveillance, crucial factors in the development and progression of cancer (25). the main evidence for this effect has been studfigure 1. kaplan-meier plots illustrating (a) local recurrence free survival, (b) metastasis free survival, (c) cancer specific mortality free survival, (d) overall mortality free survival, in 248 bladder cancer patients, who underwent radical cystectomy with available follow up data, stratified according to the ab0-blood group system. archivio italiano di urologia e andrologia 2022; 94, 4 a. tafuri, a. panunzio, a. soldano, et al. 432 ied in stomach and pancreatic tumors (13, 15). two large independent prospective studies showed that compared to patients with group 0, the risk of pancreatic cancer is 1.3 to 1.7-fold higher for patients with non-0 blood type (13). among urological malignancies, more than 40 years ago, cazzola et al. showed in a small population that ab0 antigens were present on urothelial cells’ surface and that their concentration decreased in less differenced urothelial tumors (26). joh et al. reported an increased risk of developing renal cell carcinoma (rcc) among female patients with non-0 blood groups. however, no survival differences were recorded between rcc patients according to blood groups (27). in prostate cancer, porcaro et al. found in 1114 patients, who underwent robot-assisted radical prostatectomy that the risk of psm was increased in group 0-patients independent of other standard preoperative factors as an expression of more aggressive disease (28). the association between ab0 blood groups and oncological outcomes in bca was previously studied by other investigators with controversial results. in the current study, we observed that group 0 was associated with a worse pathological tumor stage (p = 0.028) and a higher tumor grade (p = 0.05) at the time of last turb before rc, as well as with more advanced pathological tumor stage at the definitive histological examination after rc (p = 0.024). however, these findings did not affect prognosis and survival, due to no statistically significative differences noted among lrfs, mfs, csmfs and omfs according to ab0 blood groups. a historical report by orihuela et al. showed that ab0 blood group system was not associated with stage at presentation in 494 newly diagnosed bca patients. however, among patients with nmibc, those who had group 0 more frequently harbored higher-grade tumors and experienced progression to advanced disease than their non-0 counterparts (29). similarly, klatte et al. in a retrospective cohort including 931 bca patients, found that individuals with blood group 0 had higher recurrence and progression rates than those with group a or b (all p < 0.05) (30). engel et al. examined a case series of 511 bca patients, who underwent rc between 1996 and 2011 and found no differences in survival between the four ab0 blood groups (17). similarly, in a recent single-institution study, d'andrea et al. analyzed data of 463 bca patients, who underwent rc between 1988 and 2003. these authors observed that ab0 blood group system was not associated with oncological outcomes. rather, rhesus-positive patients had an increased risk of relapse-free survival, as well as of csm and om, when compared to resus-negative patients. however, these associations were not confirmed after multivariable adjustment (19). finally, a large multicenter study involving 7906 bca patients, demonstrated that blood group b was associated with higher mortality when compared with other blood groups (p = 0.026). however, even in this case, statistical significance disappeared in multivariable analysis (16). in contrast, gershman et al. retrospectively evaluated data of 2086 bca patients, who underwent rc between 1980 and 2008, and observed that non-0 groups, and in particular group a, was associated with higher csm (hr: 1.23; p = 0.007) (18). in the current study we also tested the association between ab0 blood group system and renal function decline after surgery. interestingly, we observed that patients with group ab exhibited the lowest median egfr values at pod-1, discharge and after 6 months follow up, compared to a, b, and 0 blood group patients. however, a statistically significant difference was recorded only at discharge (p = 0.030). similarly, in multivariable logistic regression models, where group 0 was the referent, ab was associated with a 4-fold higher risk of renal function decline at discharge (p = 0.047). these results could be partially attributable to a more guarded pre-operative clinical conditions of ab patients. additionally, most ab patients were diabetic (p = 0.049). this study might be in line with studies demonstrated an higher thrombotic risk in abpatients with non-valvular atrial fibrillation (31), as well as a higher incidence of cardiovascular diseases in non-0 patients (32), which may induces renal failure. the present study is not devoid of limitations. first, the current investigation is retrospective and suffers of the bias related to these types of studies. second, despite our data being sourced from a high-volume center for bca treatment, the overall sample size is limited. in consequence, our observations required interpretations that account for marginal sample sizes and comparisons of small subgroups. in this context, the observed number of bca patients with group b and ab was very small. however, the prevalence of ab0 blood groups recorded in the current study corresponded to the general ab0 frequency and distribution reported in previous larger historical analyses. additionally, various surgeons as well as pathologists were involved, and ab0 blood group antigen expression within the tumor as well as rhesus factor were not assessed. in the future, a combined evaluation of the patient's blood group and the degree of ab0 antigen expression within the tumor is needed in higher level studies. conclusions among ab0 blood groups, patients with group 0 exhibited the most aggressive tumor profile. however, no differences were recorded in recurrence or survival rates. patients with group ab presented the lowest median egfr at each specified time point. group ab was independently associated with egfr < 60 ml/min at discharge. references 1. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2021. ca: a cancer journal for clinicians. 2021; 71:7-33. 2. powles t, bellmunt j, comperat e, et al. bladder cancer: esmo clinical practice guideline for diagnosis, treatment and follow-up. ann oncol. 2022; 33:244-258. 3. van hauen mb, maibom sl, thind po, et al. risk of recurrence and long-term mortality following radical cystectomy for bladder cancer. scand j urol. 2022; 56:149-154. 4. zhan x, jiang m, deng w, et al. development and validation of a prognostic nomogram for predicting cancer-specific survival in patients with lymph node positive bladder cancer: a study based on seer database. front oncol. 2022; 12:789028. 5. mir mc, marchioni m, zargar h, et al. nomogram predicting bladder cancer–specific mortality after neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer: results of an international consortium. eur urol focus. 2021; 7:1347-1354. 433archivio italiano di urologia e andrologia 2022; 94, 4 ab0 blood groups and bladder cancer 6. bratu o, marcu d, anghel r, et al. tumoral markers in bladder cancer. exp ther med. 2021; 22:1-8. 7. fujita n, hatakeyama s, okita k, et al. impact of chronic kidney disease on oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who underwent adjuvant bacillus calmette-guérin therapy. urol oncol. 2021; 39:191.e9-191.e16. 8. jiang dm, gupta s, kitchlu a, et al. defining cisplatin eligibility in patients with muscle-invasive bladder cancer. nat rev urol. 2021; 18:104-114. 9. tafuri a, odorizzi k, di filippo g, et al. acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: a single-centre experience. arch ital urol androl. 2021; 93:9-14. 10. leow jj, chong yl, chang sl, et al. neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma: a 2020 systematic review and meta-analysis, and future perspectives on systemic therapy. eur urol. 2021; 79:635-654. 11. tafuri a, smith dd, cacciamani ge, et al. programmed death 1 and programmed death ligand 1 inhibitors in advanced and recurrent urothelial carcinoma: meta-analysis of single-agent studies. clin genitourin cancer. 2020; 18:351-360.e353. 12. idris e, tahir r, amhamed a, aboualkasem s. a study on the relationship between blood group and type of cancer. scientific journal for the faculty of science-sirte university. 2022; 2:23-27. 13. wolpin bm, chan at, hartge p, et al. abo blood group and the risk of pancreatic cancer. j natl cancer inst. 2009; 101:424-431. 14. gates ma, xu m, chen wy, et al. abo blood group and breast cancer incidence and survival. int j cancer. 2012; 130:2129-2137. 15. wang z, liu l, ji j, et al. abo blood group system and gastric cancer: a case-control study and meta-analysis. int j mol sci. 2012; 13:13308-13321. 16. klatte t, xylinas e, rieken m, et al. effect of abo blood type on mortality in patients with urothelial carcinoma of the bladder treated with radical cystectomy. urol oncol. 2014; 32:625-630. 17. engel o, soave a, peine s, et al. the impact of the ab0 and the rhesus blood group system on outcomes in bladder cancer patients treated with radical cystectomy. world j urol. 2015; 33:1769-1776. 18. gershman b, moreira dm, tollefson mk, et al. the association of abo blood type with disease recurrence and mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. urol oncol. 2016; 34:4.e1-9. 19. d'andrea d, moschini m, soria f, et al. abo blood group and rhesus factor are not associated with outcomes after radical cystectomy for non-metastatic urothelial carcinoma of the bladder. anticancer res. 2017; 37:5747-5753. 20. würdemann n, wagner s, sharma sj, et al. prognostic impact of ajcc/uicc 8th edition new staging rules in oropharyngeal squamous cell carcinoma. front oncol. 2017; 7:129. 21. humphrey pa, moch h, cubilla al, et al. the 2016 who classification of tumours of the urinary system and male genital organs— part b: prostate and bladder tumours. eur urol. 2016; 70:106-119. 22. levey as, stevens la, schmid ch, et al. a new equation to estimate glomerular filtration rate. ann int med. 2009; 150:604-612. 23. franchini m, liumbruno gm. abo blood group: old dogma, new perspectives. clin chem lab med. 2013; 51:1545-1553. 24. orntoft tf, meldgaard p, pedersen b, wolf h. the blood group abo gene transcript is down-regulated in human bladder tumors and growthstimulated urothelial cell lines. cancer res. 1996; 56:1031-1036. 25. hakomori s. antigen structure and genetic basis of histo-blood groups a, b and o: their changes associated with human cancer. biochim biophys acta. 1999; 1473:247-266. 26. cazzola p, matturri l, trinchieri a, et al. impiego di una metodica di immunofluorescenza indiretta nella ricerca degli antigeni di superficie ab0 (h) sulle cellule dell'epitelio di transizione. arch it urol nefrol. 1981; 53:297. 27. joh hk, cho e, choueiri tk. abo blood group and risk of renal cell cancer. cancer epidemiol. 2012; 36:528-532. 28. porcaro ab, amigoni n, migliorini f, et al. abo blood group system and risk of positive surgical margins in patients treated with robot-assisted radical prostatectomy: results in 1114 consecutive patients. j robot surg. 2021; 16:507-516 29. orihuela e, shahon rs. influence of blood group type on the natural history of superficial bladder cancer. j urol. 1987; 138:758-759. 30. klatte t, xylinas e, rieken m, et al. impact of abo blood type on outcomes in patients with primary nonmuscle invasive bladder cancer. j urol. 2014; 191:1238-1243. 31. jang ay, seo j, park ym, et al. abo blood type is associated with thrombotic risk in patients with nonvalvular atrial fibrillation. j clin med. 2022; 11:3064. 32. neshat s, rezaei a, farid a, et al. cardiovascular diseases risk predictors: abo blood groups in a different role. cardiol rev. 2022. doi: 10.1097/crd.0000000000000463. correspondence alessandro tafuri, md (corresponding author) tafuri.alessandro@gmail.com vincenzo pagliarulo, md enzopagliarulo@yahoo.com department of urology, “vito fazzi” hospital, lecce piazza filippo muratore, 1, 73100 lecce (italy) andrea panunzio, md panunzioandrea@virgilio.it antonio soldano, md soldanoantonio@libero.it giovanni mazzucato, md gio.mazzucato@gmail.com paola irene ornaghi, md paolairene.ornaghi@gmail.com alessandra gozzo, md la.ale.gozzo@gmail.com nicola de maria, md nicola.demaria02@gmail.com francesco cianflone, md fra1178@gmail.com antonio benito porcaro, md drporcaro@yahoo.com walter artibani, md prof.artibani@gmail.com alessandro antonelli, md alessandro_antonelli@me.com maria angela cerruto, md mariaangela.cerruto@univr.it department of urology, university of verona, azienda ospedaliera universitaria integrata di verona, verona (italy) matteo brunelli, md matteo.brunelli@univr.it department of pathology, university of verona, azienda ospedaliera universitaria integrata di verona, verona (italy) giacomo di filippo, md giacomo.difilippo90@gmail.com department of general and hepatobiliary surgery, university of verona, azienda ospedaliera universitaria integrata verona, verona (italy) aliasger shakir, md usc aliasgershakir@gmail.com institute of urology, catherine and joseph aresty department of urology, keck school of medicine, university of southern california (usc), los angeles, ca, us zhe tian, msc zhe.tian24@gmail.com pierre i. karakiewicz, md pierrekarakiewicz@gmail.com cancer and prognostics health outcomes unit, division of urology, university of montreal health center, montreal, quebec, canada stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4420 original paper no conflict of interest declared. introduction prostate cancer (pca) is the second most common cause of cancer death among men (1). transrectal ultrasound-guided biopsies of the prostate (trus-bx), is a well-known diagnostic tool for prostate cancer, with over 2 million/procedures per year in europe and north america combined (2). despite recent evidence that suggests reduced infection risk with the transperineal route (3), trus-bx is still routinely performed all over the world and is considered a relatively safe procedure with low risk of serious adverse events. nevertheless, minor complication such as transient erectile dysfunction (ed) or ejaculatory dysfunctions (ejd) are rare though possible complication after trusbx with complete recovery after 1-3 mos (4). notably, data on ed following trus-bx are heterogeneous as a consequence of varied patient populations and ed classifications. moreover, mehta et al. (5) showed the lack of outcome measurement through validated questionnaires, with only three studies that included the international index of erectile function-15 (iief-15) and just one the male sexual health questionnaire (mshq-ejd). thus, the aim of our study was to prospectively evaluate, through validated questionnaires, the likelihood of a short-term post-trus-bx erectile and/or ejaculatory dysfunctions in sexually active men. materials and methods study population and data collection the study was conducted in accordance with the declaration of helsinki. we prospectively included all male patients, suspected of prostate cancer, undergoing trus-bx in the department of urology, federico ii university, naples, italy, between may 2021 and january 2022. the indications for biopsy were the following: elevated prostate specific antigen (psa) level, psa between 410 ng/ml with psa density ≥ 0.15 ng/ml/cm3 , psa > 10 ng/ml and/or abnormal digital rectal examination (dre). objective: to evaluate the impact on erectile and ejaculatory function following transrectal ultrasound-guided biopsies of the prostate (trus-bx) in sexually active men. methods: monocentric prospective study from may 2021 to january 2022 of consecutive patients with suspected prostate cancer [elevated prostate specific antigen (psa) level and/or abnormal digital rectal examination] undergoing trus-bx. the 15-item version of the international index of erectile function (iief-15), premature ejaculation diagnostic tool (pdet) and short form of male sexual health questionnaire (mshq-ejd short form) were assessed before, one and three months after trus-bx. the primary endpoint was to evaluate the risk of temporary post-biopsy erectile and/or ejaculatory dysfunctions. the statistical significance was set as p value < 0.05. results: a total of 276 consecutive patients were included in the study. the median age, psa and biopsy cores were 65 years (iqr 59-69), 7 ng/ml (iqr 5-9.7) and 16 (iqr 12-16), respectively. we compared the iief subdomains before trus-bx vs. one or three months: the erectile function (ef) decreased after one month (p<0.001) but recovered after three months (p=0.833); the orgasmic function (of), the sexual desire (sd), the intercourse satisfaction (is), the overall satisfaction (os), and total iief decreased significantly after both one and three months compared to pre-biopsy values (p < 0.05). as for ejaculatory function (ejf), pdet, mshq-ejd short form 1, 2, 3 and mshq-ejd short form 4 scores decreased significantly after one month (p < 0.001), but they returned to pre-biopsy values after 3 months: p = 0.538, p = 0.071 and p = 0.098, respectively. conclusions: our study proved that ef, assessed through iief15, and ejaculatory function, assessed through pdet and mshq-ejd short form, were negatively affected by trus-bx one month after the procedure and recovered after three months. interestingly, the other iief-15 subdomains (of, sd, is, os and total) resulted as significantly reduced also after 3 months: this issue highlights the importance of carefully considering the indication to trus-bx. key words: prostate cancer; prostate needle biopsy; erectile dysfunction; ejaculatory dysfunction. submitted 6 september 2022; accepted 14 october 2022 the impact of prostate biopsy on erectile and ejaculatory function: a prospective study michele morelli 1, 2, gianluca sampogna 2, 3, samuele molteni 1, 2, carmine sciorio 1, vito lorusso 2, lorenzo romano 4, roberto la rocca 4, marco capece 4, assunta zimarra 4, luigi napolitano 4*, paolo verze 5, lorenzo spirito 6 1 urology unit, asst ospedale manzoni, lecco, italy; 2 university of milan, milan, italy; 3 urology unit, niguarda hospital, milan, italy; 4 unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii”, naples, italy; 5 department of medicine and surgery "scuola medica salernitana", university of salerno, fisciano, campania, italy. 6 unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli,", naples, italy. doi: 10.4081/aiua.2022.4.420 summary 421archivio italiano di urologia e andrologia 2022; 94, 4 prostate biopsy and sexual dysfunction the validated questionnaires were administered by the urologist who conducted the study via e-mail. baseline parameters were recorded and included: patients age, body mass index (bmi), charlson score, diabetes, hypertension, anticoagulant therapy, antiaggregant therapy, angiotensin receptor blockers therapy, 5-alpha reductase inhibitors therapy, psa values and number of biopsy cores. sexual function questionnaires the participants were asked to answer the validated questionnaires (translated in italian) via e-mail: 15items iief-15 (6), premature ejaculation diagnostic tool (pdet) (7) and a short form of male sexual health questionnaire (mshq-ejd short form) (8). patients were followed with iief-15, pdet and mshq-ejd short form during the study period divided in before (t1) and at 1 (t2) and 3 (t3) months after trus-bx. only the complete questionnaires were recorded in the analysis. the iief-15 score included 5 categories: erectile function (ef), orgasmic function (of), sexual desire (sd), intercourse satisfaction (is) and overall satisfaction (os). response options ranged from 0 (no sexual intercourse) to 5 (normal sexual activity). a total iief-15 score ranging from 5 to 25 was then calculated. the pdet score was categorized from 0 (no problem at all) to 4 (always), with higher scores indicating difficulty with premature ejaculation. the mshq-ejd short form, comprised the four-item ejaculatory function domain assessing frequency of ejaculation, strength of ejaculation, volume of ejaculation and satisfaction. biopsy procedure antibioprophylaxis was started 1 day before the procedure with ciprofloxacin 500 mg (2 tablets per day). trus-bx was performed by senior urologists (> 100 procedures) under local anesthesia (10 ml of 2% lidocaine), with automated tru-cut 18-gauge needle (bard; covington, ga). we performed sextant biopsies (with six cores each lobe) and additional cores from suspected areas. the primary endpoint was to determine early post trusbx erectile and/or ejaculatory dysfunctions through validated questionnaires in men suspected for pca. data analysis descriptive statistics included frequencies and proportions for categorical variables. mean, medians and interquartile ranges (iqr) were reported for continuously coded variables. the categorical variables between the groups were analyzed using the chi-squared and fisher's exact tests, while the continuous variables between groups were analyzed using the mann-whitney u test. wilcoxon sign rank test for paired sample was used to compare continuous non-parametric variables. in all statistical analyses, statistical package for social science (spss), version 20 (ibm corporation, armonk, ny, usa) was used. all tests were two-sided with a level of significance set at p < 0.05. results study population a total of 276 male patients that underwent trus-bx between may 2021 and january 2022 met the inclusion criteria: elevated prostate specific antigen (psa) level, psa between 4-10 ng/ml with psa density ≥ 0.15 ng/ml/cm3, psa > 10 ng/ml and/or abnormal digital rectal examination (dre). the baseline characteristics are summarized in table 1. in the overall cohort, the median age, bmi and charlson comorbidity score were 65 (iqr 59-69) years, 26 (iqr 24-29) and 4 (iqr 2-6), respectively. the median psa was 7 (iqr 5-9.7) and a median of 16 (iqr 12-16) biopsy cores were taken during the trus-bx procedure. iiief-15 questionnaire from t1 to t2, the iief-ef score decreased significantly (21 (iqr 3.0-25.0) vs 19 (iqr 2.0-22.5), p < 0.001) and from t1 to t3, no statistically significant difference was recorded (p = 0.833) (table 2). finally, in the other subdomains (of, sd, is, os) and total, from t1 to both t2 and t3, the iief score decreased significantly (p < 0.05), the changes of specific domains are shown in table 2. table 1. baseline and patients characteristics. overall cohort (n = 276) median (iqr) age, years 65 (59-69) median (iqr) body mass index 26 (24-29) median (iqr) charlson score 4 (2-6) diabetes, n (%) 37(14.4) hypertension, n (%) 29 (10.5) anticoagulant therapy, n (%) 8 (2.9) antiaggregant therapy, n (%) 39 (14.1) angiotensin receptor blockers therapy, n (%) 72 (26) 5-alpha reductase inhibitors therapy, n (%) 42 (15.2) median (iqr) psa antigen 7 (5 -9.7) median (iqr) biopsy cores 16 (12 -16) iqr: interquartile range; psa: prostate-specific antigen. table 2. international index of erectile function (iief) questionnaire administrated to 276 patients before prostate biopsy (time 1), 1 month after (time 2) and 3 mos after (time 3). wilcoxon sign rank test p-value time 1 time 2 time 3 time 1 vs time 2 time 1 vs time 3 iief-ef median 21 19 21 < 0.001 0.833 iqr 3.0-25.0 2.0-22.5 3.0-25.0 iief-of median 7.5 6.5 7 < 0.015 < 0.001 iqr 0-9.8 0-7.5 0-8.0 iief-sd median 6 5 6 < 0.02 < 0.023 iqr 5.0-7.0 4.5-6 5.0-7.0 iief-is median 10 9 9.5 < 0.015 < 0.001 iqr 0-12.0 0-11.0 0-12.0 iief-os median 7 6 7 < 0.001 < 0.001 iqr 4.0-8.0 2.0-8.0 4.0-8.0 iief-tot median 53 49 51 < 0.001 < 0.001 iqr 12.0-61.0 7.0-58 12.0-60.0 ef: erectile function; is: intercourse satisfaction; of: orgasmic function: os: overall satisfaction; sd: sexual desire. archivio italiano di urologia e andrologia 2022; 94, 4 m. morelli, g. sampogna, s. molteni 422 pdet questionnaire from t1 to t2, the pdet score decreased significantly (2 (iqr 0-4.0) vs 2 (iqr 0-4.0), p < 0.001) and from t1 to t3, no statistically significant difference was observed (p = 0.098) (table 3). mshq-ejd short form questionnaire from t1 to t2, the mshq-ejd short form score (1,2,3) decreased significantly (12 (iqr 5.0-14.0) vs 11 (iqr 6.3-14.0), p < 0.001) and from t1 to t3, no statistically significant difference was observed (p = 0.538) (table 3). similarly, from t1 to t2, the mshq-ejd short form score (4) decreased significantly (5 (iqr 3.0-5.0) vs 4 (iqr 4.0-5.0), p < 0.001) and from t1 to t3, no statistically significant difference was observed (p = 0.071) (table 3). a univariate analysis failed to identify the independent predictive factors of erectile and sexual disfunction (results not shown). discussion the study showed a rapid decrease in erectile and ejaculatory function at one month but a promising return to pre trus-bx values was observed. aetiology of ed after trus-bx is likely multifactorial. as suggested by zisman et al. (9), trauma caused by compression associated with haematoma or oedema in the neurovascular bundle are considered the main reasons. moreover, tuncel et al. (10) described multiple radiological changes in prostate parenchyma and bundle in post biopsy men with ed, indeed this could be explained by the fact that the most common form of analgesia used for this procedure is periprostatic nerve block (ppnb) and it is likely to be responsible for damage in neurovascular bundle area, leading to a possible cause of transient ed (11). despite many studies have been correlating ed and prostate biopsy, only limited and controversial results are shown in literature, ranging from no meaningful effect to significant linking with ed in shortand long-term post trus-bx. chrisofos et al. (12), prospectively evaluated 46 men after trus-bx; post biopsy ed were reported in just 6.5% and 4.3% of patients at one and three months, meaning that trus-bx did not induce ed in a statistically significant manner. on the other hand, kamali et al. (13) showed that trus-bx was linked to ed, and by the passage of time (6 months later); the degree of dysfunction significantly worsened (iief-5 mean scores 1 month after biopsy: 18 (6-25); 3 months after: 17 (5-25); 6 months after: 14.5 (5-25)). herein, we assessed the decrease in ef through iief-ef in sexually active men one month after trus-bx and recovering after three months. notably, the other iief subdomains (of, sd, is, os and total) resulted significantly reduced also after 3 months. there are several explanations to this discrepancy of results. first, despite the use of validated questionnaires, the patients may not have sufficient cognition to understand the different subdomains of iief-15. second, in the multifactorial nature of ed, a prevalent issue on psychological condition in our study was observed (is, of, os, sd). deep effect on increased anxiety in patients who undergo trus-bx may be related to the acute healing phase after the procedure and presence of a potentially lethal cancer specific disease (9, 12, 14). moreover, an important aspect of our study, comparable to the current literature (15, 16) was that ejaculation function, assessed through pdet and mshq-ejd short form, didn’t show any change between pre and post trus-bx values. the limitations of the present study should also be acknowledged. first, the absence of a complete psychologic and mental health assessment in our study population considering that the main statistic differences at 3 months were is, of, os and sd. another limitation was the lack of a control group; we were unable to determine the relative short term erectile and ejaculatory disfunction of trus-bx compared to the transperineal approach. however, our study also has several strengths which lies on his methodology. this study is a longitudinal study in which participants were evaluated before, 1 month after and 3 months after trus-bx to avoid possible memory bias. additionally, all subdomains of the international validated scales for examining sexual functions, such as iief, pdet and mshq-ejd short form, were evaluated. conclusions the discrepancy of results existing in literature and the issue in our study highlights the importance of carefully considering the indication to trus-bx. magnetic resonance imaging and other tools (e.g., psa-density/velocity, biomarkers) are warranted to determine the real need for trus-bx, which may negatively affect important domains of male sexual life. references 1. culp mb et al. recent global patterns in prostate cancer incidence and mortality rates. eur urol. 2020; 77:38. 2. loeb s, vellekoop a, ahmed hu, et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-92 3. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8.500 men. arch ital urol androl. 2022; 94:155-159. 4. fujita k, landis p, mcneil bk, pavlovich cp. serial prostate biopsies are associated with an increased risk of erectile dysfunction in men with prostate cancer on active surveillance. j urol. 2009; 182:2664-2669. table 3. ejaculatory function questionnaires administrated to 276 patients before prostate biopsy (time 1), 1 month after (time 2) and 3 mos after (time 3). wilcoxon sign rank test p-value time 1 time 2 time 3 time 1 vs time 2 time 1 vs time 3 mshq-ejd median 12 11 12 < 0.001 0.538 1, 2, 3 iqr 5.0-14.0 6.3-14.0 5-14.5 mshq-ejd median 5 4 5 < 0.001 0.071 4 iqr 3.0-5.0 4.0-5.0 3.0-5.0 pdet median 2 2 2 < 0.001 0.098 iqr 0-4.0 0-4.0 0-4.0 pedt: premature ejaculation diagnostic tool; mshq-ejd: male sexual health-ejaculatory dysfunction questionnaireejaculatory dysfunction. 423archivio italiano di urologia e andrologia 2022; 94, 4 prostate biopsy and sexual dysfunction 5. mehta a, kim wc, aswad kg, et al. erectile function post prostate biopsy: a systematic review and meta-analysis. urology. 2021; 155:1-8. 6. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-830 7. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-573. 8. rosen rc, catania ja, althof se, et al. development and validation of four-item version of male sexual health questionnaire to assess ejaculatory dysfunction. urology. 2007; 69:805-9. 9. zisman a, leibovici d, kleinmann j, et al. the impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety and erectile dysfunction. j urol. 2001; 165:445-54. 10. tuncel a et al. impact of transrectal prostate needle biopsy on erectile function: results of power doppler ultrasonography of the prostate kaohsiung j med sci. 2014; 30:194-9. 11. glaser ap, novakovic k and helfand bt. the impact of prostate biopsy on urinary symptoms, erectile function, and anxiety curr urol rep. 2012; 13:447-54. 12. chrisofos m, papatsoris ag, dellis a, et al. can prostate biopsies affect erectile function? andrologia. 2006; 38:79-83. 13. kamali k, nabizadeh m, ameli m, et al. impact of prostate needle biopsy on erectile function: a prospective study. urologia. 2019; 86:145-147. 14. korfage ij, essink-bot ml, janssens ac, et al. anxiety and depression after prostate cancer diagnosis and treatment: 5-year follow-up. br j cancer. 2006; 94:1093-8. 15. song ph, lee ks, choi jy, et al. 1012 when does ejaculatory dysfunction recover after transrectal ultrasound guided prostate biopsy? eur urol suppl. 2016; 15:e1012. 16. verze p, la rocca r, spirito l, et al. premature ejaculation patients and their partners: arriving at a clinical profile for a real optimization of the treatment. arch ital urol androl. 2021; 93:42-47. correspondence michele morelli samuele molteni carmine sciorio urology unit, asst ospedale manzoni, lecco, italy gianluca sampogna urology unit, niguarda hospital, milan, italy vito lorusso university of milan, milan, italy lorenzo romano roberto la rocca marco capece assunta zimarra luigi napolitano (corresponding author) dr.luiginapolitano@gmail.com unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii” via sergio pansini 5, 80131 naples, italy paolo verze department of medicine and surgery "scuola medica salernitana", university of salerno, fisciano, campania, italy lorenzo spirito unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli,", naples, italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12523 1 original paper tomography (ncct) is the standard for diagnosing urinary stones. however, utilizing ncct for all patients may pose challenges since it has the inherent property of releasing ionizing radiation even with the usage of low-dose ct protocols with possible undesirable effects on the human body. this directed research efforts towards the utilization of other safe diagnostic tools, such as ultrasonography (us) (1-3). us is now established as the primary diagnostic imaging modality in patients with ureteric colic. it is safe (no radiation risk), reproducible, inexpensive, and widely available. it can identify urinary stones, upper urinary tract (uut) dilatation, as well as other causes of acute abdomen like ovarian problems and appendicitis (4). however, bmode us is deemed lesser than ct in diagnosing ureteral stones. us has a sensitivity of 45% and a specificity of 94%, compared to 93.1% and 96.6% for low-dose ct (1, 5). changes in gain and depth, along with other modes such as angling, s (stone-specific) mode, and color doppler capabilities like twinkling artifact (ta), are key variables enhancing us accuracy for stone detection (6, 7). in this study, we aimed to assess the diagnostic efficacy of integrating b-mode and color doppler capabilities of us to establish a robust standalone diagnostic tool for the diagnosis of ureteric stones as an alternative to ncct. patients and methods this is an interventional prospective study carried out between march 2022 and june 2023, including 140 consecutive patients diagnosed with ureteric stones by ncct. we excluded pregnant women, patient with sonographically detected issues responsible of the pain other than ureteric calculi like appendicitis, oophoritis, ovarian cyst and diverticulitis, and patients with double-j ureteric stents. procedures all studied patients initially underwent systematic examination by ncct then us in b-mode and color doppler. objective: to assess the diagnostic efficacy of integrating b-mode and color doppler capabilities of ultrasound (us) to establish a robust standalone diagnostic tool for the diagnosis of ureteric stones as an alternative to non-contrast-enhanced computed tomography (ncct). methods: a total of 140 consecutive patients diagnosed with ureteric stones using ncct were enrolled. on the same day, us in both b-mode and color doppler was performed by an experienced radiologist who was blinded to the ncct scan results. the diagnostic rate of us for stone detection was recorded. additionally, baseline patient and stone characteristics were analyzed for their association with the accuracy of stone detection using us. results: us exhibited a high sensitivity of 91.43%, detecting 128 out of 140 stone foci. notably, ureteric stones in the proximal and uretero-vesical junction (uvj) segments were readily identifiable compared to those in the pelvic region (p = 0.0003). additionally, hydronephrosis enhanced the us's ability to detect stones (p < 0.0001). conversely, abdominal gases and obesity adversely affected us capabilities (p < 0.0001 and p = 0.009, respectively). stone side, size, and density showed no statistically significant impact (p > 0.05). conclusions: us with its color doppler capabilities could serve as a reliable and safe alternative imaging modality in the diagnostic work up of patients with ureterolithiasis. factors including stone location, hydronephrosis, weight and abdominal gases significantly influenced its accuracy. key words: renal colic; urolithiasis; ultrasonography; twinkling artifact. submitted 28 march 2024; accepted 6 april 2024 introduction urolithiasis is a common health issue, with prevalence rates varying worldwide, ranging from 1% to 20% (1, 2). patients with ureteral stones typically present repeatedly to the emergency room (er) with acute abdominal pain, necessitating prompt evaluation. non-contrast-enhanced computed exploring the potential of combined b-mode features and color doppler ultrasound in the diagnosis of ureteric stone as an alternative to ionizing radiation exposure by computed tomography ahmed m. abdel gawad 1, bahaa-eldin a. moustafa 2, tamer a. abouelgreed 3, esam a. elnady 1, saed khater 1, mohamed rehan 1, mohamed f. elebiary 3, basem a. fathy 3, ahmed shaalan 4, nasser ramadan 5, mohamed hindawy 3, salma f. abdelkader 6 1 department of urology, faculty of medicine, al-azhar university, damietta, egypt; 2 department of radiology, faculty of medicine, al-azhar university, damietta, egypt; 3 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 4 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 5 department of urology, nmc royal hospital, sharjah, uae; 6 department of radiology, faculty of medicine, ain shams university, cairo, egypt. doi: 10.4081/aiua.2024.12523 summary archivio italiano di urologia e andrologia 2024; 96(2):12523 a.m. abdel gawad, b.-e. a. moustafa, t.a. abouelgreed, et al. 2 the examination occurred at al-azhar university hospital, new damietta. ncct technique ct imaging was performed using toshiba aquilion 160 slices scanner, japan, 2015. patients were examined with full urinary bladder in supine position. the coverage area extended from the upper pole of both kidneys to the base of the urinary bladder. tube potential of 100-120 kvp and automatic tube current modulation with ma range of 80500 was frequently used; however, the scan acquisition protocols were tailored to the patient body weight and ct scanner technology. axial sections of 5mm thickness were taken, complimented with 3 mm coronal/sagittal reformatted images. stone size was estimated by measuring largest dimension. measurements were made on the soft tissue window (window width 400 hu and window level 30 hu). us (b-mode & color doppler) technique us imaging was performed using a real-time us machine (accuvix xg, samsung medison co., korea 2018) which was equipped with an abdominal curved probe (c2-8 convex probe 2-8 mhz) and linear probe (11l-d high frequency 2d probe 4-10 mhz). patients were examined with full urinary bladder. after applying us gel on the abdomen, us imaging series were acquired aiming to scan the urinary tract as well as other abdominopelvic organs that may be responsible for the complaint. the size and echogenicity of the renal parenchyma (normal, increased, or decreased) and the presence of any detectable parenchymal calcifications or abnormality were noted. starting with the identification of fluid-filled (an-echoic) calyces and renal pelvis, we went ahead to the ureter tracking it in its anatomical site which is also a fluid-filled tubular structure with absent flow signal in color mapping study. the degree of dilatation of the pelvicalyceal system was graded (mild, moderate, and severe), and the ureters were visualized for dilatation. the gases in the intestine that handicapped the visualization of the ureter were fought by gentle pressure by the probe as well as making the patient lie on the contralateral side. identification of calculi in the ureter was by figure 1. us images from a 45-year-old female patient with distal ureteric stone. (a) b-mode us scan of the right kidney in the longitudinal plane showing moderately dilated pelvi-caliceal system (pcs). (b) b-mode us scan of the urinary bladder and distal ureter (which is an-echoic tubular structure) in the longitudinal oblique plane, showing an echogenic stone with posterior acoustic shadowing inside the distal ureter. (c) color doppler scan on the previous plane exhibiting absent flow signal in the tubular structure (ensuring being ureter) & ta caused by the distal ureteric stone. (d) dual (b & color) modes of the same plane. archivio italiano di urologia e andrologia 2024; 96(2):12523 3 combined b-mode and color doppler ultrasound in the diagnosis of ureteric stone detection of abnormal objects with increased echoes on grayscale us that casts posterior acoustic shadowing. color doppler us came after to detect ta presence utilizing a red-blue color map (figures 1, 2). outcome measures data about patients’ age, sex, bmi and stone characteristics (side, size, location, density and hydroureteronephrosis) were collected. in addition, the diagnostic rate of us (b-mode in combination with color doppler) for stone detection was recorded. sample size and statistical analyses an online statistical calculator “https://statulator.com/ samplesize/ss1p.html” was used to estimate the sample size considering the following factors: assuming that 10% of the subjects in the population suffer from urolithiasis (1, 2), 5% absolute precision, and 95% confidence. allowing for a 10% dropout rate, a total sample size of 139 patients was estimated. data were tabulated and analyzed using the spss package 25 (ibm corp, armonk, ny, usa). univariate analyses of continuous and categorical variables were done using the independent sample t-test and chi-square test, respectively. the sensitivity of us (bmode in combination with color doppler) for stone detection was calculated with 95% ci (confidence interval), with statistical significance considered at p < 0.05. informed consent was obtained from all participants in the study, and the protocol for this research project was approved by our ethical committee under the institutional review board (irb/ 00012367-24-03-007). results this study included 140 consecutive patients diagnosed with ureteric stones using ncct. the patients' age ranged from 14 years to 77 years with a mean of 41 years. the pre-procedural patients’ demographics (age, sex and bmi) and stone characteristics (side, size, location, density and hydroureteronephrosis) are detailed in table 1. when b-mode and color doppler us were employed, the us demonstrated a high sensitivity of 91.43% (95% ci: 85.51% to 95.49%), detecting 128 out of 140 stone foci, which indicates its effectiveness in accurately identifying true positive cases. for further analysis, we assessed all factors potentially influencing us accuracy for stone detection, including baseline patients' and stone characteristics (table 2). interestingly, stone-related variables (side, size, and density) showed no statistically significant impact (p > 0.05). conversely, patient-related variables figure 2. us images from a 38-year-old male patient with mid-ureteric stones. (a) b-mode us scan of the right kidney in the longitudinal plane showing mild hun. (b) b-mode us scan on the mid-ureter (which is an-echoic tubular structure) in the longitudinal oblique plane showing two hyperechoic stones with posterior acoustic shadowing inside it (blue arrows). (c) color doppler scan on the previous plane exhibiting absent flow signal in the tubular structure (ensuring being ureter), ta of the two stones & blood flow color signals in iliac vessels (yellow arrow). archivio italiano di urologia e andrologia 2024; 96(2):12523 a.m. abdel gawad, b.-e. a. moustafa, t.a. abouelgreed, et al. 4 (bmi and gaseous abdomen), stone location, and the degree of hydroureteronephrosis (hun) demonstrated a statistically significant association. ureteral stones in the proximal and uretero-vesical junction (uvj) segments were readily identifiable compared to those in the pelvic region (p = 0.0003). additionally, the presence of hun enhanced the us's ability to detect stones (p < 0.0001). conversely, the presence of gases in the abdomen and obesity negatively impacted on us capabilities (p < 0.0001 and p = 0.009, respectively). discussion it is now a common practice to conduct imaging studies in all patients with suspected renal colic admitted to the emergency room. this trend may stem from concerns about overlooking potentially life-threatening conditions that resemble renal colic, such as a ruptured aortic aneurysm, ovarian torsion, or appendicitis. additionally, there is a necessity for imaging confirmation to determine the underlying cause of symptoms before considering discharge (8, 9). ncct is the official method for diagnosing urinary stones due to its benefits, being unaffected by intestinal gas and posing excellent accuracy in detecting ureteral stones. however, concerns about the over-utilization of ct are growing because of increasing health care costs and, more importantly, exposure to ionizing radiation. a study published in the journal of the american medical association estimated that 1 in 1400 people over the age of 60 who receive ncct may develop cancer or leukemia (10). it is noteworthy that radiation exposure has cumulative effects, raising the risk of future cancers. this cumulative impact builds up over time. consequently, young individuals and pregnant women should minimize exposure to radiation whenever possible (11). currently, there is a growing emphasis on radiation protection when imaging patients with suspected renal colic. this focus has extended beyond the radiological community (12, 13) and emergency physicians (14, 15) to include urologists. in the 2023 guidelines on urolithiasis of the european association of urology, it is stated that us should be the primary diagnostic imaging tool in patients with renal colic, and ncct should be reserved for cases where the diagnosis is doubtful (1). us is a safe, cost-effective, non-invasive, and readily available technique for assessing patients with renal colic. importantly, prioritizing us usage can prevent radiation exposure in approximately 70% of cases and possesses the ability to identify alternative diagnoses mimicking renal colic (9, 16). nevertheless, its application remains a subject of debate as it effectively detects dilatation of the excretory system even in inexperienced hands (14). however, challenges arise in directly visualizing stones, particularly in the pelvic ureters, making it operator-dependent for stone detection and relying on “indirect findings” for diagnosis. additionally, the absence of these “indirect findings” does not rule out ureteral stones (17). the performance of us studies by radiologists and modifications in gain and depth settings, along with the utilization of various modes such as angling, s (stone-specific) mode, and color doppler features like ta, have been reported to enhance the precision of us for stone detection (6-8 & 18-20). the color doppler ta manifests as a rapidly alternating signal in color doppler imaging, resembling turbulent flow. it is table 1. baseline (patient and stone) characteristics. patient, n 140 age, mean ± sd (range), year 41.75 ± 5.34 (14-77) sex, n (%) male 99 (70.71) female 41 (29.29) bmi, mean ± sd (range), kg/m2 27.03 ± 2.01 (22.85-31.35) laterality, n (%) rt. 69 (49.29) lt. 71(50.71) hun, n (%) no 17 (12.14) mild (gr.1) 78 (55.72) mod. (gr. 2) 38 (27.14) sever (gr. 3) 7 (5) stone size, mean ± sd (range), mm 8.5 ± 1.19 (3.74-21.2) stone density, mean ± sd (range), hu 693.17 ± 590.35 (110-1440) location, n (%) lumber 42 (30) pelvic 81 (57.86) uvj 17 (12.14) bmi: body mass index; hu: hounsfield units; hun: hydro-uretero-nephrosis; n: number; sd: standard deviation; uvj: uretero-vesical junction. table 2. categorical variables tested against us accuracy for stone detection. variable us total, n p yes no laterality: right 63 6 69 0.96 left 65 6 71 stone size: < 5 mm 25 4 29 0.52 5-10 mm 65 5 70 > 10 mm 38 3 41 stone location: lumber 54 2 56 0.0003 pelvic 35 10 45 uvj 39 0 39 stone density: < 400 43 4 47 0.98 400-1000 56 5 61 > 1000 29 3 32 hun: no 8 9 17 < 0.0001 mild (gr. 1) 77 1 78 mod. (gr. 2) 37 1 38 severe (gr. 3) 6 1 7 bmi: < 25 39 2 41 0.009 25-30 64 3 67 > 30 25 7 32 gaseous abdomen: yes 7 8 15 < 0.0001 no 121 4 125 bmi: body mass index; hun: hydro-uretero-nephrosis; n: number; uvj: uretero-vesical junction. archivio italiano di urologia e andrologia 2024; 96(2):12523 5 combined b-mode and color doppler ultrasound in the diagnosis of ureteric stone often observed when scanning a stationary object with an irregular surface, such as urinary stones, which reflects the doppler signal. in doppler imaging, this phenomenon presents as a jumbled pattern. the spectral analysis of twinkling may reveal aliasing (7). it is very useful to confirm findings of grey-scale, especially in doubtful cases due to the small size of the stone or when its location is in difficult-to-visualize ureteral portions. however, careful interpretation is essential since the jumbled pattern of twinkling may mimic turbulent flow, which could be confusing and may lead to errors in diagnosis. additionally, the presence of aliasing in the twinkling spectrum could further complicate the interpretation, potentially making it challenging to distinguish between true flow abnormalities and artifacts. therefore, it should be interpreted along with other clinical information and imaging modalities to ensure an accurate diagnosis (17). several studies have highlighted the usefulness of us compared to ncct in the initial diagnosis and management of renal colic patients, without a notable increase in complications, serious adverse events, return emergency department visits, or hospitalizations (18-20). in our study, the sensitivity of us for detection of ureteric stones was about 91.43%, detecting 128 out of 140 stone foci (95% ci: 85.51% to 95.49%) which is in accordance with previous reports (21-23). the role of patient’s and stone-related variables in the us detection of ureteric stones has been extensively evaluated in previous reports. factors such as the presence of hun, vascular calcifications and other artifacts that may also be mistaken for stones, experience and knowledge of the urinary tract anatomy and the presence of bowel gas, which may obscure the ureteral calculi, as well as stone size, location, and density, can affect the detection of ureteric stones. for instance, ahmed et al. reported an overall sensitivity of us of 75.4%. the detection rate of mid and distal ureteral stone was lower than that at proximal locations, and the detection rate increased with stone size and the degree of hun. conversely, us is of limited value, particularly when used by an inexperienced radiologist, and in the case of smaller stone size, increased weight, and low grade of hun (22). another study by sen et al. reported a sensitivity of us of 86.8 %, with better success noted in proximal ureteral stones (95.6 %) (21). goertz and lotterman also found that the increasing degree of hun was associated with an increased likelihood of diagnosing ureteric stones using us (24). in a more recent report on the diagnostic value of us in ureteric stones ≤ 10 mm by krakhotkin et al., while the us demonstrated a sensitivity rate exceeding 90% for stones ≥ 5 mm located in the proximal and distal ends of the ureter, its accuracy was notably restricted, not exceeding 53%, for stones sizing 1-3 mm and those situated in the middle ureter possibly due to bowel interposition (25). our results closely align with previous reports, indicating that the stone location and increasing degree of hun were associated with increasing detection rate of ureteric stone in us (p = 0.0003 and < 0.0001, respectively). on the other hand, the presence of bowel gases negatively impacted us capabilities (p < 0.0001). of note all us assessments in our study were conducted solely by an experienced radiologist. regarding the impact of bmi on the sensitivity of us and color doppler capabilities, some studies have reported that higher bmi values decrease the sensitivity of both modalities (22, 26, 27), consistent with our findings (p = 0.009). however, others have not found any correlation (18, 21, 28), possibly due to the small number of patients with bmi > 30 kg/m². as for the role of stone size, it was evaluated in several studies. winkel et al. (16) and mitterberger et al. (19) found no correlation. however, sen et al. (21), ahmed et al. (22), krakhotkin et al. (25), and sorensen et al. (29) reported that as the stone size increased, the sensitivity of us also increased. in our study, the ureteral stone side, size, and density exhibited no statistically significant impact (p > 0.05). limitations our study possesses certain limitations. firstly, color doppler us relies heavily on the examiner's skill; specific training of healthcare professionals may be required to develop sufficient skills and be aware of its strengths and limitations. also, our study was single-blinded; future double-blinded research investigations may shed more light on the preference of us over ncct. furthermore, future studies examining us outcomes in relation to different operators rather than a single expert, as well as investigating the role of stone composition and surface roughness are warranted. conclusions us with its color doppler capabilities could serve as a promising and safe alternative imaging modality in the diagnostic work up of patients with ureterolithiasis. however, factors such as stone location, hun, weight, and the presence of abdominal gases, along with the examiner’s competence significantly influence its accuracy. references 1. a. skolarikos, h. jung, a. neisius, et al. (2023). eau guidelines on urolithiasis limited update march 2023. european association of urology, arnhem, the netherlands. isbn 978-94-92671-19-6. retrieved from https://uroweb.org/guidelines/urolithiasis/. 2. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017; 35:1301-1320. 3. zou b, zhou y, he z, et al. a critical appraisal of urolithiasis clinical practice guidelines using the agree ii instrument. transl androl urol. 2023; 12:977-988. 4. wang m, ma q, chen y, et al. value of the color doppler imaging mode in improving physicians' diagnostic performance in patients with mid-ureteric stones larger than 5 mm: a retrospective study. urolithiasis. 2021; 49:463-469. 5. xiang h, chan m, brown v, et al. systematic review and metaanalysis of the diagnostic accuracy of low-dose computed tomography of the kidneys, ureters and bladder for urolithiasis. j med imaging radiat oncol. 2017; 61:582-590. 6. dunmire b, lee fc, hsi rs, et al. tools to improve the accuracy of kidney stone sizing with ultrasound. j endourol. 2015; 29:1471452. 7. sternberg km, eisner b, larson t, et al. ultrasonography significantly overestimates stone size when compared to low-dose, non-contrast computed tomography. urology. 2016; 95:67-71. archivio italiano di urologia e andrologia 2024; 96(2):12523 a.m. abdel gawad, b.-e. a. moustafa, t.a. abouelgreed, et al. 6 8. may pc, haider y, dunmire b, et al. stone-mode ultrasound for determining renal stone size. j endourol. 2016; 30:958-62. 9. moore cl, carpenter cr, heilbrun ml, et al. imaging in suspected renal colic: systematic review of the literature and multispecialty consensus. j urol. 2019; 202:475-483. 10. rehab abdel rahman el bakry. prospective comparative study between un-enhanced multi-detectors computed tomography and ultrasonography in evaluation of acute renal colic, alexandria journal of medicine 2017; 53:367-371. 11. schmid e, leeson k, xu kt, et al. ct imaging history for patients presenting to the ed with renal colic--evidence from a multi-hospital database. bmc emerg med. 2019; 19:24. 12. moore cl, scoutt l. sonography first for acute flank pain? j ultrasound med. 2012; 31:1703-11. 13. patatas k, panditaratne n, wah tm, et al. emergency department imaging protocol for suspected acute renal colic: re-evaluating our service. br j radiol. 2012; 85:1118-22. 14. dalziel pj, noble ve. bedside ultrasound and the assessment of renal colic: a review. emerg med j. 2013; 30:3-8. 15. smith-bindman r, aubin c, bailitz j, et al. ultrasonography versus computed tomography for suspected nephrolithiasis. n engl j med. 2014; 371:1100-10. 16. van randen a, laméris w, van es hw, et al. optima study group. a comparison of the accuracy of ultrasound and computed tomography in common diagnoses causing acute abdominal pain. eur radiol. 2011; 21:1535-1545. 17. nicolau c, claudon m, derchi le, et al. imaging patients with renal colic-consider ultrasound first. insights imaging. 2015; 6:441447. 18. winkel rr, kalhauge a, fredfeldt ke. the usefulness of ultrasound colour-doppler twinkling artefact for detecting urolithiasis compared with low dose nonenhanced computerized tomography. ultrasound med biol. 2012; 38:1180-1187. 19. mitterberger m, aigner f, pallwein l, et al. sonographic detection of renal and ureteral stones. value of the twinkling sign. int braz j urol. 2009; 35:532-539 20. ripollés t, martínez-pérez mj, vizuete j, et al. sonographic diagnosis of symptomatic ureteral calculi: usefulness of the twinkling artifact. abdom imaging. 2013; 38:863-869. 21. sen v, imamoglu c, kucukturkmen i, et al. can doppler ultrasonography twinkling artifact be used as an alternative imaging modality to non-contrast-enhanced computed tomography in patients with ureteral stones? a prospective clinical study. urolithiasis. 2017; 45:215-219. 22. ahmed f, askarpour mr, eslahi a, et al. the role of ultrasonography in detecting urinary tract calculi compared to ct scan. res rep urol. 2018; 10:199-203. 23. patlas m, farkas a, fisher d, et al. ultrasound vs ct for the detection of ureteric stones in patients with renal colic. br j radiol. 2001; 74:901-4. 24. goertz jk, lotterman s. can the degree of hydronephrosis on ultrasound predict kidney stone size? am j emerg med. 2010; 28:813-6. 25. krakhotkin dv, chernylovskyi va, sarica k, et al. diagnostic value ultrasound signs of stones less than or equal to 10 mm and clinico-radiological variants of ureteric colic. asian j urol. 2023; 10:3949. 26. asbeutah am, bakir yy, swamy n, et al. subject body mass index affects doppler waveform in celiac artery by duplex ultrasound. open cardiovasc med j. 2013; 7:40-45. 27. pichler r, skradski v, aigner f, et al. in young adults with a low body mass index ultrasonography is sufficient as a diagnostic tool for ureteric stones. bju int. 2012; 109:770-774. 28. kielar az, shabana w, vakili m, rubin j. prospective evaluation of doppler sonography to detect the twinkling artifact versus unenhanced computed tomography for identifying urinary tract calculi. j ultrasound med. 2012; 31:1619-1625. 29. sorensen md, harper jd, hsi rs, et al. b-mode ultrasound versus color doppler twinkling artifact in detecting kidney stones. j endourol. 2013; 27:149-153. correspondence ahmed m. abdel gawad (corresponding author) ahgawad84@gmail.com esam a. elnady esammohsen@gmail.com saed khater dr.saedkhater@gmail.com mohamed rehan mrehan4040@gmail.com department of urology, faculty of medicine, al-azhar university, damietta, egypt bahaa-eldin a. moustafa dr.bhaa@gmail.com department of radiology, faculty of medicine, al-azhar university, damietta, egypt tamer a. abouelgreed dr_tamer_ali@yahoo.com mohamed f. elebiary dr_elebiary@yahoo.com basem a. fathy basemhara@gmail.com mohamed hindawy hindawy78@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt ahmed shaalan dr_ahmedshallan@yahoo.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt nasser ramadan nasseruro99@gmail.com department of urology, nmc royal hospital, sharjah, uae salma f. abdelkader salmafathy4@gmail.com department of radiology, faculty of medicine, ain shams university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12192 1 systematic review otubes (swnts) and multi-walled nanotubes (mwnts). swnts consist of a single cylindrical graphene sheet, whereas mwnts comprise multiple concentric layers of graphene sheets (3). the remarkable physical properties of cnts result from their nanoscale architecture. cnts possess a high aspect ratio and extraordinary tensile strength, granting them unmatched mechanical resilience that exceeds traditional materials like steel and diamond in the strength-toweight ratio (4). additionally, cnts exhibit excellent thermal conductivity, facilitating efficient dissipation of heat. these desirable characteristics, along with their electrical conductivity, make cnts highly attractive for diverse applications, including electronics, energy storage, and biomedical devices (5). in the field of medicine, integrating cnts offers significant potential for revolutionary advancements in healthcare (6). the considerable surface area-to-volume ratio of cnts, coupled with their molecular transport capabilities, positions them as promising candidates for drug delivery systems (7). through the functionalization and loading of therapeutic agents onto cnts, controlled and targeted release of drugs to specific tissues or cells becomes achievable (8). additionally, the electrical properties of cnts enable the development of biosensors and implantable devices for precise diagnostic and therapeutic applications, facilitating real-time monitoring and precise control. however, as the utilization of cnts in medical applications continues to expand, thorough evaluation of their impact on human health becomes paramount (9). the interactions between cnts and biological systems necessitate meticulous examination to ensure the safety and efficacy of these nanomaterials. particularly, investigating the potential effects of cnts on reproductive health assumes significance, as reproduction represents a fundamental process for the survival and perpetuation of the human species. cnts interaction with the male reproductive system raises concerns regarding health and fertility. studies of exposure in animals to multi-walled carbon nanotubes models found alterations on hormone levels, sperm motility, sperm count (10). in humans, some studies found no adverse effects on background: in the medical field, it is increasingly common to observe the use of nanotubes, for example, in the administration of drugs. however, nanotubes raise concerns for male fertility due to potential effects on hormone levels and sperm quality observed in animal studies. in addition, animal exposure to multi-walled carbon nanotube models found alterations in hormone levels, sperm motility, and sperm count. limited evidence in humans suggests no adverse effects, but further research is needed. this study aimed to perform a systematic review to assess the in vitro effects of nanotubes on semen and fertility in humans. methods: we included all published in vitro studies about semen or sperm or male fertility and nanotubes in humans. a search was conducted in lilacs, pubmed, and scopus as of may 2023. the risk of bias was assessed using the quin tool. results: four studies using nanotubes on human sperm were included, nanotubes exposure appears not to affect sperm viability; however, some alterations to motility, velocity and production of reactive oxygen species were reported. limited evidence is provided because of the small quantity of publications. conclusions: nanotubes appear to have no adverse effects on human sperm. key words: nanotubes; semen; fertility; human; nanoparticles; reproduction. submitted 14 december 2023; accepted 23 december 2023 introduction carbon nanotubes (cnts) are nanomaterials that have garnered attention due to their unique properties and potential across various fields, including medicine (1). composed of carbon atoms arranged in a hexagonal lattice, cnts form cylindrical structures, akin to rolled-up graphene sheets. this structural arrangement imparts cnts with remarkable mechanical strength, electrical conductivity, and chemical reactivity (2). cnts exhibit a wide range of dimensions, with typical diameters ranging from a few nanometers to tens of nanometers, and lengths varying from a few micrometers to millimeters. based on their structural characteristics, cnts can be categorized into two types: single-walled naneffects of nanotubes on semen quality and fertility in humans: a systematic review of literature william felipe fernández zapata 1, 2, yamile cardona maya 3, cesar isaza merino 4, walter d. cardona maya 2 1 “symbiosis” research hotbed in human reproduction and gestation, faculty of medicine, university of antioquia, udea, medellín, colombia; 2 reproduction group, department of microbiology and parasitology, faculty of medicine, university of antioquia, udea, medellín, colombia; 3 department of basic foundation, pascual bravo university institution, medellín, colombia; 4 department of mechanical engineering, faculty of engineering, university of antioquia, udea, medellín, colombia. doi: 10.4081/aiua.2024.12192 summary archivio italiano di urologia e andrologia 2024; 96(1):12192 w.f. fernández zapata, y. cardona maya, c. isaza merino, w.d. cardona maya 2 sperm quality (11, 12). further research is needed. therefore, the objective of this study was to perform a systematic review to assess the in vitro effects of the nanotubes on semen and fertility in humans. materials and methods the systematic review was performed following the preferred items for systematic reviews and meta-analysis (prisma) reporting guidelines (13). eligibility criteria all publication original investigation peerreviewed articles in english and spanish languages related to in vitro studies on human sperm in humans until may 2023 were included. exclusion criteria all publications related to animal models investigation were excluded. search methods the following search strategy was used in pubmed (fertility or infertility or semen or sperm*) and nanotubes); in scopus (title-abs-key (nanotubes and "male infertility") or title-abs-key (nanotubes and spermatozoa) or title-abs-key (nanotubes and semen)), and in lilacs ((fertility) or (infertility) or (semen) or (sperm)) and (nanotubes). study records the search results from electronic databases were imported into endnote x8 software, and then duplicates were identified. two independent authors (wffz and wdcm) screened the titles and abstracts of the identified studies to assess their eligibility based on predefined inclusion and exclusion criteria. full-text articles of potentially relevant studies were retrieved for further evaluation. any disagreements between the reviewers were resolved through discussion or consultation with a third reviewer to ensure a consensus-based selection process. the study protocol was registered with the prospero international prospective register of systematic reviews (crd42023435569). during the data collection process, two independent authors (wffz and wdcm) extracted relevant information from the selected studies using a standardized data extraction form. this form captured the main characteristics of the study, the title of the study, the characteristics of the nanotubes, the details of the nanotubes, the outcome measures, and the main characteristics of the study. the data extraction process was conducted meticulously for accurate and consistent data collection. any discrepancies or uncertainties were resolved by consensus or with a third reviewer's opinion (figure 1). risk of bias in studies the risk of bias was assessed using the quin tool (14). the present study conducted a risk of bias assessment, examining potential biases in twelve item criteria which wiere scored, and the scores were used to grade the in vitro study as high, medium or low risk of bias. a traffic light plot summarizing the risk of bias was generated using robvis (15). results literature searches identified 340 documents, and 4 articles (11, 12, 16, 17) were finally included after excluding duplicate studies, irrelevant literature, and review articles adhering strictly to the inclusion and exclusion criteria (figure 1). three of the studies used sperm from healthy male volunteers: aminzadeh et al. (17) obtained samples from 30 nonsmoking males, cardona-maya et al. (12) obtained 12 samples from 24,6 ± 5,7 aged males; jha et al. (16) used sperm from fertile males aged 25 to 40. ashgar et al. (11) used semen vials from a cryobank (as in table 1). these studies (11, 12, 16, 17) were conducted in the us, india, iran and colombia; all of them agreed that sperm viability was not affected by nanotubes, no was not significantly produced compared to control in any of the two studies evaluating it (11, 17). aminzadeh et al. (17) found a correlation between nanotubes concentrations added to sperm and ros production similar to ashgar et al. (11), which found an increase of ros generation sperm. jha et al. (16) proved mwnts can interact with and infiltrate sperm cells without causing cell damage. their research reveals that mwnts, compared to other nanoparticles, has markedly lower interaction rates with nucleic acids. making it less likely to disrupt the cellular functions associated with these biological macromolecules. they also demonstrate the ability of cnts to penetrate cell nuclei. this characteristic, combined with their figure 1. flow diagram of the study selection process. archivio italiano di urologia e andrologia 2024; 96(1):12192 3 nanotubules and semen quality reduced interaction with nucleic acids, makes them an excellent candidate for use as intracellular markers. furthermore, these attributes suggest that mwnts could be a promising tool for targeted drug delivery to the nucleus, opening up an exciting new avenue in nanoparticle-based therapeutics. in conducting our review, we made the decision to exclude the works of fan et al. (18) and eyni et al. (19). although fan et al. (18) provides essential insights into the utilization of nanotubes as part of an immunosensor for the follicle-stimulating hormone, their research unfortunately lacks any direct experimentation with human sperm. this absence limits the relevancy of their findings to our review, primarily focused on direct interactions and impacts of nanotubes on human sperm. similarly, the study of eyni et al. (19) while notable for its use of nanotubes in crafting a scaffold to induce differentiation of human stem cells into spermatogonial sperm cells, falls outside of our current review parameters. this study concentrates more on cellular differentiation and less on the interaction between nanotubes and human sperm. therefore, despite their in the respective fields, these studies did not fit closely enough with the purpose of inclusion in our review. none of the included studies specified the sample size calculation nor outcome assessor details; only one study specified operator details. however, it did not provide valuable details of the operator´s training, and overall, we conclude that the risk of bias in the included studies is low (figure 2). there is no risk of bias standardized tool for in vitro studies in medicine, therefore, we used quin tool for reviewing risk of bias in the selected studies (14) (figure 2). discussion our review aimed to assess the in vitro effects of nanotubes on human semen and fertility; four articles matched the requirements and were analyzed demonstrating that exposure of human sperm to cnt does not significantly affect its viability. we did not find another systematic review addressing the research question. the absence of a previous systematic review in this field may be attributed to various factors, including the emerging nature of the research topic, limited research interest, or the absence of a consolidated body of evidence. our study represents a pioneering effort in systematically reviewing the impact of nanotubes on human sperm and male fertility. this is because most research has identified the effect of carbonaceous materials on other species such as rats and mice (20). additionally, some research has figure 2. risk of bias assessment with corresponding biases (d1 to d2) and risk indicators. table 1. summary of the studies included. study used nanotubes variables methodology conclusion ashgar et al. 2016 (11) swcnt viability, straight linear and curvilinear a solution of swcnt was added to exposing sperm to mwcnt did not lead to notable impacts on sperm velocity, ros generation, no generation. human sperm. viability, no was not significantly produced. nonetheless, there were observable alterations in sperm velocity and oxidative stress caused by ros. jha et al. 2016 (14) mwcnt suitability of drug delivery carrier. mwcnt type 5 was added to human sperm. mwcnt covers and enters sperm cells and produces no cell damage, produces less interaction with nucleic acids compared to other nanoparticles, cnt can penetrate nuclei and can be used as a marker, thus can be a candidate for drug delivery to the nucleus aminzadeh et al. 2016 (15) swcnt-cooh viability, motility ros generation, different concentrations (0, 1-100 µg) of a viability was not altered, motility visible altered after 30 min exposure and mwcnt-cooh no generation. solution of acid-oxidized swcnt and mwcnt and decreased with cnt concentration, concentrations upper to 100 were added to human sperm. μg/ml at any time and exposures longer to 3 hours of swcnt-cooh and mwcnt.cooh could induce ros production and no production similar to control. cardona-maya et al. 2020 (12) mwcnt sperm motility. a solution of 1% mwcnt was added mwcnt does not affect sperm motility. to human sperm. mwcnt: multi-wallerd carmbon nanotubes; ros: reactive oxigen species; no: nitric oxide. archivio italiano di urologia e andrologia 2024; 96(1):12192 w.f. fernández zapata, y. cardona maya, c. isaza merino, w.d. cardona maya 4 found that carbonaceous structures such as graphene, graphene oxide, and reduced graphene oxide have no significant effect on sperm viability. however, there were some significant changes in sperm velocity and oxidative stress due to reactive oxygen species (21). these changes were attributed to the exposure times. likewise, some studies have investigated the viability of human sperm exposed to functionalized carbon nanotubes and have not found a significant effect. however, these studies reported that sperm motility decreased and oxidative stress increased, possibly associated with mitochondrial and dna damage (17). one limitation of our systematic review was omitting grey literature and unpublished works, potentially excluding relevant information. conclusions in conclusion, we recommend that the scientific community advance studies employing human in vitro models to comprehend this phenomenon further. such models can be used to comprehend the phenomenon better, resulting in more precise and valuable conclusions. references 1. he h, pham-huy la, dramou p, et al. carbon nanotubes: applications in pharmacy and medicine. biomed res int. 2013; 2013:578290. 2. popov vn. carbon nanotubes: properties and application. materials science and engineering: r: reports. 2004; 43:61-102. 3. anzar n, hasan r, tyagi m, et al. carbon nanotube-a review on synthesis, properties and plethora of applications in the field of biomedical science. sensors international. 2020; 1:100003. 4. isaza m ca, rudas js, cardona-maya y, et al. interfacial phenomena in multiwalled carbon nanotube-reinforced magnesium nanocomposite synthesized by the sandwich technique. metallography, microstructure, and analysis. 2023:1-9. 5. atiq ur rehman m, chen q, braem a, et al. electrophoretic deposition of carbon nanotubes: recent progress and remaining challenges. international materials reviews. 2021; 66:533-562. 6. sharifi m, pothu r, boddula r, bardajee gr. trends of biofuel cells for smart biomedical devices. international journal of hydrogen energy. 2021; 46:3220-3229. 7. zare h, ahmadi s, ghasemi a, et al. carbon nanotubes: smart drug/gene delivery carriers. int j nanomedicine. 2021:1681-1706. 8. saleemi ma, kong yl, yong pvc, wong eh. an overview of recent development in therapeutic drug carrier system using carbon nanotubes. journal of drug delivery science and technology. 2020; 59:101855. 9. barbarino m, giordano a. assessment of the carcinogenicity of carbon nanotubes in the respiratory system. cancers. 2021; 13:1318. 10. farombi eo, adedara ia, forcados ge, et al. responses of testis, epididymis, and sperm of pubertal rats exposed to functionalized multiwalled carbon nanotubes. environ toxicol 2016; 31:543-551. 11. asghar w, shafiee h, velasco v, et al. toxicology study of single-walled carbon nanotubes and reduced graphene oxide in human sperm. sci rep. 2016; 6:1-11. 12. cardona maya y, isaza merino ca, cardona maya wd. [exposure of multi-walled carbon nanotubes to human sperm]. revista cubana de obstetricia y ginecología. 2020; 46:1-11. 13. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. int j surg. 2021; 88:105906. 14. sheth vh, shah np, jain r, bhanushali n, bhatnagar v. development and validation of a risk-of-bias tool for assessing in vitro studies conducted in dentistry: the quin. j prosthet dent. 2022; s0022-3913(22)00345-6. 15. mcguinness la, higgins jpt. risk-of-bias visualization (robvis): an r package and shiny web app for visualizing risk-of-bias assessments. res synth methods. 2021; 12:55-61. 16. jha r, jha pk, gupta s, et al. probing suitable therapeutic nanoparticles for controlled drug delivery and diagnostic reproductive health biomarker development. mater sci eng c mater biol appl. 2016; 61:235-245. 17. aminzadeh z, jamalan m, chupani l, et al. in vitro reprotoxicity of carboxyl-functionalised singleand multi-walled carbon nanotubes on human spermatozoa. andrologia. 2017; 49:e12741. 18. fan y, guo y, shi s, ma j. an electrochemical immunosensor based on reduced graphene oxide/multiwalled carbon nanotubes/ thionine/gold nanoparticle nanocomposites for the sensitive testing of follicle-stimulating hormone. anal methods. 2021; 13:3821-3828. 19. eyni h, ghorbani s, shirazi r, et al. three-dimensional wetelectrospun poly (lactic acid)/multi-wall carbon nanotubes scaffold induces differentiation of human menstrual blood-derived stem cells into germ-like cells. j biomater appl 2017; 32:373-383. 20. francis ap, devasena t. toxicity of carbon nanotubes: a review. toxicol ind health. 2018; 34:200-210. 21. hadizadeh n, zeidi s, khodabakhsh h, et al. an overview on the reproductive toxicity of graphene derivatives: highlighting the importance. nanotechnology reviews. 2022; 11:1076-1100. correspondence william felipe fernández zapata, md william.fernandezz@udea.edu.co walter d. cardona maya, phd (corresponding author) wdario.cardona@udea.edu.co “symbiosis” research hotbed in human reproduction and gestation; reproduction group, department of microbiology and parasitology, faculty of medicine, university of antioquia, udea, medellín, colombia yamile cardona maya, phd y.cardona5837@pascualbravo.edu.co department of basic foundation, pascual bravo university institution, aa 6564, medellín, colombia cesar isaza merino, phd cesar.isaza@udea.edu.co department of mechanical engineering, faculty of engineering, university of antioquia, aa 6564, medellín, colombia conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2021; 93, 142 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.42 introduction premature ejaculation (pe) is the most frequent male sexual disorder but, despite its high frequency, as a medical disorder it is poorly understood. patients are often unwilling to discuss their symptoms and many physicians are not educated enough on effective treatments. as a result, patients may be misdiagnosed or mistreated (1). the issm committee defines lifelong pe as an ejaculation that always or nearly always occurs prior to, or within about 1 minute of, vaginal penetration from the first sexual encounter, together with the inability to retard ejaculation during vaginal penetration which results in negative personal consequences such as distress, bother, frustration, and/or the avoidance of sexual intimacy (2). based upon this definition, timing, a feeling of loss-ofcontrol and, couple distress are the main aspects to be taken into account when facing a patient with pe. in fact, pe has been associated with significant bother, interpersonal problems and dissatisfaction with sexual intercourse for both males and their partners (3-5). therefore patient’s and their partner’s satisfaction play a crucial role in a pe diagnosis and physiopathology more than in other sexual dysfunction (6) and pe could even be categorized as a partner-oriented and indeed partnergenerated male sexual dysfunction, because the symptoms are strictly related to partner’s sexual physiology and to the female sexual response (7). furthermore, data from previous studies show that all female sexual domains (including desire, arousal, lubrication, orgasm) become significantly impaired when partners of men affected with pe (8, 9). despite some efforts to understand in detail the clinical characteristics of pe patients and their partners, to date it has proven difficult to provide a definitive clinical profile of a pe patient and the impact on their partner. the absence of this clinical information makes the profiling and management of the couple more complex. the primary objective of this study was to extrapolate the clinical features of pe patients and their partners in order to arrive at a profile that can be of assistance to physicians in treating couples, one of whom is an pe patient. the aim of the study is to extrapolate clinical features of premature ejaculation (pe) patients and female partners of men affected with pe, in order to get a profile that can be of assistance for physicians within the dynamics of a couple, one of which is a pe patient. an observational, non-interventional, cross-sectional epidemiological study entitled iper (italian premature ejaculation research) was conducted and included two different cohorts of subjects that were randomly sampled from a patient dataset of selected general practitioners: 1. iper-m sub-cohort (1.104 subjects) was made of male subjects in which they were then distinguished patients with or without pe based on the score of the pedt questionnaire; iper-f sub-cohort (1.109 subjects) was made of female subjects from an independent sample of women (therefore not the partners of the iper-m males) in which they then distinguished those partners of a male subject with pe or not. in addition to an identical general questionnaire to explore demographic aspects and habits, each subcohort was then evaluated using validated questionnaires. no differences were noted between pe+/pepatients in terms of alcohol consumption, smoking habits, physical activity nor stress condition in everyday life, employment, socio-economic class and marital status. while the prevalence of pe proportionally increased with age, excluding the 50-59 and 70-80 years decades, in the iper-m group an overall statistically significant difference for the mean age between the pe+ and pegroups (p = 0.002) was detected, but without reaching any difference amongst the different age classes in the iper-f group. the pe+ patients reported a significantly lower frequency rate of sexual intercourse, worse qol (p = 0.006 and p < 0.0001, respectively), and increased anxiety status (p < 0.0001 for both subgroups). this study shows that, rather than talking with a patient affected by pe it would be advisable to introduce the concept of couple counseling with the person patient and his partner, because it is only through classification of both partners as one couple and a full understanding of their mutual sexual experience that pe treatment can be optimized and its results measured accurately. key words: premature ejaculation; partner; profile; clinical. submitted 4 may 2020; accepted 15 may 2020 premature ejaculation patients and their partners: arriving at a clinical profile for a real optimization of the treatment summary paolo verze 1, roberto la rocca 1, lorenzo spirito 1, gianluigi califano 1, luca venturino 1, luigi napolitano 1, antonio cardi 2, davide arcaniolo 3, claudia rosati 4, alessandro palmieri 1, vincenzo mirone 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology section, university of naples federico ii, naples, italy; 2 department of urology, san giovanni hospital, rome, italy; 3 department of urology, vanvitelli university, naples, italy; 4 department of clinical medicine and surgery, university of naples federico ii, naples, italy. 43archivio italiano di urologia e andrologia 2021; 93, 1 clinical profile of pe patients patients and methods an observational, non-interventional, cross-sectional epidemiological study italian premature ejaculation research (iper) was conducted on a cohort of adult males (iper-m) and females (iper-f) that were randomly sampled from a patient dataset of selected general practitioners (gps) throughout italy, applying the same methodology for both cohorts. main criteria for patient enrollment and study design have been previously described (10, 11). the inclusion criteria were adult men and women between the ages of 18 and 80, sexually active of any ethnicity, even if the subjects were predominantly italian. those who were unable to fill in questionnaires due to cognitive or linguistic problems or with a clear indication of no sexual activity at the time of questionnaire administration were excluded. all participants, after signing an informed consent form, received a series of questionnaires to be returned anonymously to their gps in a sealed envelope that was then opened by an independent staff responsible for processing the data. a general questionnaire was administered for both iperm and iper-f cohorts. the iper-m study population was asked to complete in the following validated selfadministered questionnaires: premature ejaculation diagnostic tool (pedt), international index of erectile function (iief-5), sexual quality of life questionnairemale) (sqol-m), self-rating depression scale (sds) and self-rating anxiety scale (sas). the female patients from the iper-f study cohort were asked to report on their partner’s ejaculation time (selfreported intravaginal ejaculation latency time ielt) and presence of sexual dysfunction (including no interest in sex, lack of or delayed orgasm, pain during ejaculation, anxiety and lubrication problems). patients were also asked to complete the following validated questionnaires: adapted from female sexual distress scale (fsds-r-pe), sexual quality of life questionnaire-female (sqol-f), sds and sas. the study did not involve any treatment or invasive diagnostic procedure. per italian law the survey was conducted in accordance with the privacy act and with the declaration of helsinki in all aspects which were applicable. each subject was informed about the purpose of the investigation and was recruited after signing an informed consent form. statistics a descriptive statistical analysis was applied to present results. when appropriate, intra-group comparisons were performed by !2 tests for categorical variables or by variance analysis (anova) for continuous variables. multiple logistic regression models were used to identify independent risk factors for pe. the statistical significance level (p) was 0.05 or less or all statistical tests. data were normally distributed in line with an asymmetry and kurtosis analysis. data were analyzed using sas software, version 9.2 (sas institute inc., cary, nc, usa). results for the iper-m sub-cohort a total of 2.571 male patients were sampled and 1.104 (43%) were recruited into the study. for the iper-f sub-cohort 3.104 female subjects were sampled and, of those, 1.109 were included in the study. table 1 describes demographics and general characteristics of both iper-m and iper-f sample cohorts. the mean age of the iper-m sample was 45.6 years ± 16.9, with 39.6% of the sample aged less than 45 years old. the mean age of the iper-f cohort was 45.1 years ± 15.4 sd, with 44% of the sample aged less than 45 years old. no differences were noted between the pe+/pepatients in both iper-m and iper-f sub-cohorts in terms of alcohol consumption?, smoking habits, physical activity or stress conditions in everyday life as well as employment status, socio-economic class and marital status. instead a greater amount of pe+ patients with a lower table 1. demographics and general characteristics of the study population. a: iper-m sub-cohort pe+ group (n = 119) pegroup (n = 990) age median (sd) – 45.6 (± 16.9) body mass index (kg/cm^2) p < 0.6522 median (sd) 25.58 (3.72) 25.74 (4.81) smoking habits (cig./day) p = 0.5588 never (n. %) 293 (41.50%) 62 (38.50%) < 10 (n. %)) 108 (15.29%) 20 (12.42%) > 10 (n. %) 136 (19.26%) 36 (22.36%) ex smoker (n. %) 169 (23.93%) 43 (26.70%) alcohol consumption p = 0.1428 never (n. %) 139 (19.85%) 22 (13.75%) occasional (n. %) 437 (62.42%) 103 (64.37%) regular (n. %) 124 (17.71%) 35 (21.87%) physical activity p = 0.2073 never (n. %) 248 (35.42%) 68 (43.03%) low (n. %) 152 (21.71%) 30 (18.98%) moderate (n. %) 223 (31.85%) 49 (31.01%) intense (n. %) 77 (11.00%) 11 (6.96%) stress condition (everyday life) p = 0.3307 never (n. %) 44 (6.24%) 9 (5.59%) low (n. %) 279 (39.57%) 52 (32.29%) moderate (n. %) 314 (44.53%) 83 (51.55%) intense (n. %) 68 (9.64%) 17 (10.55%) marital status p = 0.0978 never married (n. %) 257 (36.35%) 42 (26.25%) married (n. %) 398 (56.29%) 102 (63.75%) divorced (n. %) 43 (6.08%) 13 (8.12%) widower (n. %) 9 (1.27%) 3 (1.87%) kind of cohabitation p = 0.0443 no stable partner (n. %) 147 (21.64%) 33 (21.29%) no cohabitation (n. %) 145 (21.35%) 20 (12.90%) stable cohabitation (n. %) 102 (65.80%) 102 (65.80%) education p = 0.5670 no education (n. %) 1 (0.14%) primary (n. %) 43 (6.09%) 12 (7.50%) secondary (n. %) 178 (25.21%) 47 (29.37%) high (n. %) 367 (51.98%) 72 (45.00%) degree (n. %) 117 (16.57%) 29 (18.12%) economic condition p = 0.3177 insufficient (n. %) 64 (9.10%) 11 (6.91%) quite insufficient (n. %) 180 (25.60%) 41 (25.78%) sufficient (n. %) 432 (61.45%) 96 (60.37%) good (n. %) 27 (3.84%) 11 (6.91%) archivio italiano di urologia e andrologia 2021; 93, 1 p. verze, r. la rocca, l. spirito, g. califano, l.venturino, l. napolitano, a. cardi, d. arcaniolo, c. rosati, a. palmieri, v. mirone 44 bmi (22-25) (median 24.87) and pesubjects with a higher bmi (26-30) (median 25.06) were included in the iper-m, though without reaching a statistically significant difference. on the contrary, a higher bmi (pe+ 25.3 ± 4.17 vs pe23.37 ± 3.99; p < 0.0001) was recorded in the iper-f pe+ sub-cohort. furthermore, a general lower educational level (p < 0.0001) was reported in the pe + group of the iper-f sub-cohort, while no differences were observed in this parameter in patients with or without pe in the iper-m group. table 2 reports the pe prevalence stratification data based on age class in the iper-m and iper-f subcohorts, according to the self-estimated ielt (< 1 minute). it is important to underline that within the iper-m group, with the exception of 50-59 years and 70-80 years, the prevalence of pe proportionally increased with age. for each age class, the pedt score and the self-estimated ielt by the patients showed a similar epidemiological trend increasing with age when the cut-off value for pe diagnosis was considered < 1 minute. it is worth highlighting that the same data is confirmed when women from the iper-f sub-cohort reported the age of their pe partner. on the contrary, within the iper-f group, an overall statistically significant difference for the mean age between the pe+ and pegroups (48.6 ± 14.9 yrs and 45.1 ± 14.1 yrs, respectively; p = 0.002) was detected, but without resulting in any differences amongst the different age classes. table 3 reports data on sexual attitudes in both the iperm and iper-f sub-cohorts. it is interesting to note that pe+ patients from the iper-m sub-cohort reported a significantly lower frequency rate of sexual intercourse than the pepopulation and similar findings were also observed in the iper-f group. moreover, it was also revealed that pe+ categories in both iper-m and iper-f cohorts expressed a more frequent lack of sexual interest, lack of orgasm and pain during intercourse, based upon the questionnaire’s response of “often” and “always”, when compared with the pepopulation. table 4 reports data concerning overall quality of sexual life as evaluated by the sqol questionnaire. the iper-m sub-cohort showed a significantly worse qol in pe+ subjects when compared to pepatients (68.27 pe+ vs 89.90 pe-; p = 0.006, respectively). similar findings were recorded for the pe+ category of iper-f group (74.88 pe+ vs 86.13 pe-; p < 0.0001, respectively). results reported in anxiety and depression scales in both sub-cohorts are presented in table 5 interestingly, within both the iper-m and iper-f cohorts, the pe+ categories presented a statistically significant higher score in the z-sas questionnaire with regards to anxiety status b: iper-f sub-cohort b: iper-f sub-cohort table 2. pe prevalence according to self-estimated ielt (< 1 minute) within iper-m (a) and iper-f (b) study populations. a: iper-m sub-cohort pe+ group (n = 119) pegroup (n = 990) age p = 0.002 overall 45.1 (± 15.4) median (sd) 48.6 (± 14.9) 45.1 (± 14.1) body mass index (kg/cm^2) p < 0.0001 median (sd) 25.3 (± 4.17) 23.37 (± 3.99) smoking habits (cig./day) p = 0.0881 never (n. %) 79 (66.66%) 543 (54.86%) < 10 (n. %) 15 (12.61%) 136 (13.68%) > 1 (n. %) 12 (9.90%) 129 (13.00%) ex smoker (n. %) 13 (10.81%) 182 (18.43%) alcohol consumption p = 0.1185 never (n. %) 62 (52.29%) 460 (46.48%) occasional (n. %) 46 (38.53%) 473 (47.73%) regular (n. %) 11 (9.17%) 57 (5.78%) physical activity p = 0.4138 never (n. %) 71 (60.00%) 515 (51.99%) low (n. %) 17 (14.54%) 151 (15.24%) moderate (n. %) 27 (21.81%) 47 (4.89%) intense (n. %) 4 (3.63%) 277 (27.87%) stress condition (everyday life) p = 0.9916 never (n. %) 5 (4.50%) 40 (4.07%) low (n. %) 37 (31.53%) 312 (31.37%) moderate (n. %) 62 (51.35%) 519 (52.54%) intense (n. %) 15 (12.61%) 119 (12.00%) marital status p = 0.2348 never married (n. %) 19 (16.51%) 209 (21.10%) married (n. %) 92 (76.14%) 671 (67.83%) divorced (n. %) 4 (3.66%) 77 (7.78%) widower (n. %) 4 (3.66%) 33 (3.27%) kind of cohabitation p = 0.0651 no stable partner (n. %) 17 (14.28%) 76 (7.72%) no cohabitation (n. %) 19 (16.32%) 208 (20.98%) stable cohabitation (n. %) 83 (69.38%) 706 (71.29%) education p < 0.0001 no education (n. %) 0 3 (0.33%) primary (n. %) 26 (21.81%) 55 (5.63%) secondary (n. %) 27 (22.72%) 199 (19.95%) high (n. %) 45 (38.18%) 526 (52.87%) degree (n. %) 21 (17.27%) 207 (21.19%) economic condition p = 0.9355 insufficient (n. %) 10 (8.25%) 73 (7.37%) quite insufficient (n. %) 29 (24.77%) 265 (26.78%) sufficient (n. %) 77 (64.22%) 619 (62.42%) good (n. %) 3 (2.75%) 33 (3.40%) pe+ pen 139 641 mean age (sd) 47.9 (15.1) 43.2 (16.2) < 20 (%) 1 (1%) 9 (1.4%) 21-29 (%) 13 (9.5%) 98 (15.3%%) 30-39 (%) 17 (11.9%) 120 (18.7%) 40-49 (%) 31 (22.4%) 126 (19.7%) 50-59 (%) 32 (22.9%) 144 (22.4%) > = 60 (%) 45 (32.4%) 144 (22.4%) pe+ pen 90 789 mean age (sd) 48.6 (14.9) 43.7 (14.1) < 20 (%) 0 7 (0.8%) 21-29 (%) 5 (5.9%) 91 (11.5%) 30-39 (%) 13 (14.8%) 170 (21.6%) 40-49 (%) 22 (24.4%) 210 (26.7%) 50-59 (%) 25 (28.1%) 174 (22.1%) > = 60 (%) 24 (26.7%) 137 (17.3%) 45archivio italiano di urologia e andrologia 2021; 93, 1 clinical profile of pe patients (z-sas score > 45) compared to the pegroup (iper-m: 12.7 pe+ % vs 5,1 pe-, p < 0.0001; iper-f: 30.95% vs 15.34%, respectively; p < 0.0001). on the contrary, with regards to depression status (z-sds score > 50), no statistically significant difference between the pe+ and pegroups in both iper-m and iper-f sub-cohorts was revealed (p = 0.5237 iper-m and p = 0.4967 iper-f, respectively). discussion data from this large observational, non-interventional, cross-sectional, epidemiological study help us to get clinical profiles of patients affected by pe and its impact on their partner, providing important details to treat the couple as a whole in an optimal way. as far as we know, this study has some peculiarities in the selection methodology of the samples that distinguish it from many previous publications. in particular, the sample extraction method guarantees an excellent representation of the real population of patients affected by this disorder. secondly, the female sample of this study is not made up, as in previous publications, of the partners of the male patients analyzed, but rather by an independent sampling of women who reported having a partner with premature ejaculation. this distinction has allowed us to validate certain data (prevalence data, sexual attitudes, etc.) on two cohorts of totally independent subjects. finally, the major strength of this study is that sexuality and neuro-psychic comorbidities have been evaluated by using validated questionnaires which provided a very precise general and sexual profile of the sample. overall, what analysis of the data tells us is that in couples where one patient suffers from pe there is a significant problem of sexual dissatisfaction, which is accomtable 3. sexual attitudes according to pe status. a: iper-m sub-cohort table 4. mean scores at sqol questionnaires a: iper-m sub-cohort iper-m pe+ pefrequency of intercourse n (%) n (%) p < 0.001 no sexual intercourse 64 (18.4%) 102 (11.5%) less than once per month 57 (16.4%) 116 (13.1%) 2 to 3 times per month 111 (31.9%) 256 (28.9%) once per week or more 116 (33.3%) 412 (46.5%) pain during intercourse n (%) n (%) p = 0.021 never 205 (82.0%) 660 (88.6%) sometimes 38(15.2%) 76 (10.2%) often 6 (2.4%) 9 (1.2%) always 1 (0.4%) 0 (0.0%) lack of orgasm n (%) n (%) p = 0.006 never 211 (81.5%) 631 (83.2%) sometimes 27 (10.4%) 103 (13.6%) often 15 (5.8%) 16 (2.1%) always 6 (2.3%) 8 (1.1%) no interest for sex n (%) n (%) p = 0.001 never 197 (62.7%) 592 (71.2%) sometimes 78 (24.8%) 193 (23.2%) often 24 (7.6%) 27 (3.2%) always 15 (4.8%) 19 (2.3%) table 5. anxiety and depression profile according to zsas and zsds questionnaires. a: iper-m sub-cohort pe+ group pegroup anxiety (z-sas questionnaire) p < 0.0001 normal total score < 45 (n. %) 123 (87.2%) 603 (95%) mild total score 45-59 (n. %) 15 (10.6%) 31 (4.9%) moderate total score 60-74 (n. %) 3 (2.1%) 1 (0.2%) depression (z-sds questionnaire) p = 0.5237 normal total score < 45 (n. %) 131 (91.0%) 620 (95.5%) mild total score 45-59 (n. %) 9 (6.3%) 28 (4.3%) moderate total score 60-69 (n. %) 4 (2.8%) 1 (0.2%) pe+ group (n = 119)pegroup (n = 990) anxiety (z-sas questionnaire) p < 0.0001 normal total score < 45 (n. %) 82 (69.04%) 838 (84.65%) mild total score 45-59 (n. %) 32 (27.38%) 140 (14.15%) moderate total score 60-74 (n. %) 5 (3.57%) 12 (1.19%) depression (z-sds questionnaire) p = 0.4967 normal total score < 45 (n. %) 106 (88.75%) 896 (90.43%) mild total score 45-59 (n. %) 10 (8.75%) 84 (8.54%) moderate total score 60-69 (n. %) 3 (2.50%) 10 (1.02%) iper-m pe+ pefrequency of intercourse n(%) n (%) p < 0.001 no sexual intercourse 16 (15.5%) 94 (13,2%) less than once per month 14 (12.4%) 101 (10,9%) 2 to 3 times per month 33 (34.9%) 220 (25.9%) once per week or more 31 (33.3%) 372 (48 .5%) pain during intercourse n (%) n (%) p = 0.0247 never 71 (79.6%) 659 (84.2%) sometimes 17(17.8%) 87 (11.2%) often 6 (2.4%) 26 (4.6%) always 1 (0.0%) 0 (0.0%) lack of orgasm n (%) n (%) p = 0.009 never 75 (82.4%) 660 (85.1%) sometimes 10 (11.6%) 105 (12%) often 3 (3.7%) 15 (1.8%) always 2 (2.3%) 8 (1.1%) no interest for sex n (%) n (%) p = 0.001 never 52 (61.3%) 618 (72.6%) sometimes 21 (24.3%) 212 (25.4%) often 8 (9.5%) 12 (1.2%) always 3 (3.9%) 10 (0.8%) iall subjects pe+ subjects pesubjects n 950 n 150 n 664 mean 85,32 mean 68,27 mean 89,90 st.dev 20,09 st.dev 22,66 st.dev 16,16 all subjects pe+ partner pepartner n 992 n 95 n 897 mean 85,05 mean 74,88 mean 86,13 st.dev 16,42 st.dev 19,15 st.dev 15,73 median 91,7 median 79,6 median 92,6 b: iper-f sub-cohort b: iper-f sub-cohort b: iper-f sub-cohort archivio italiano di urologia e andrologia 2021; 93, 1 p. verze, r. la rocca, l. spirito, g. califano, l.venturino, l. napolitano, a. cardi, d. arcaniolo, c. rosati, a. palmieri, v. mirone 46 panied by a progressive reduction in the frequency of sexual contact as well as the onset of a state of anxiety for both partners. from a general point of view, neither the patient nor the partners in the study present a personal profile or lifestyle that highlights risk factors which correlate with the presence of pe. our study confirms data already reported in the literature, whereby pe is not affected by marital or income status (12). on the contrary, with regards to data concerning lifestyle, some of our data conflicts with previously published studies (13). in particular, in our series, obesity does not seem to characterize the pe patient, including, as well as, lack of physical activity, alcohol consumption and smoking status. instead, a certain correlation with psychological factors such as emotional problems and stress is confirmed (14, 15). what is, instead, very important to highlight from an epidemiological point of view, is that our series reveal, contrary to conclusions in the literature, that there is a certain linear correlation between the prevalence of pe and age, which is confirmed by the two independent samples of the iper-m and iper-f sub-cohorts. we are aware of the novelty of this data, although it was already presented in a recent publication (10) of the pepa survey, to date the most representative epidemiological study, which reported increased pe prevalence with age up to 45-50 years. however beyond this age range no further increase was reported and this result could be explained by the fact that the pepa study had been conducted as an internet survey and perhaps 45-80 years old subjects were not fully representative of the general population (16). data from previous studies show that both men with pe and their partners are more likely to report low satisfaction with their sexual relationship, low satisfaction with sexual intercourse, difficulty relaxing during intercourse, and less frequent intercourse (3, 17). this data is largely confirmed by our study in which first of all, there was a strong reduction in the interest in sexual activity in both the pe patients and partners, as demonstrated by the low weekly frequency of sexual relations. once again the relevance of the data is strengthened by the fact that an identical trend comes from two subcohorts of completely independent subjects, who are not partners in a couple. as clearly demonstrated by the data concerning the sexual attitudes of study populations and by the results of the sqol questionnaire, a couple in which there is a male subject affected by pe has a strongly altered sex life from a qualitative point of view in that there is a high risk of not achieving orgasm for both partners. this data, in our opinion, obviously closely correlates and explains the reduction in the frequency of sexual intercourse found in both sub-cohorts iper-m and iper-f in our study, since it is easy to imagine that a couple who does not have a satisfying sex life tends to reduce the frequency of intercourses. this finding contrasts with data from other authors who showed that sex drive and overall interest in sex do not appear to be affected by pe (18). in our view, what remains extremely difficult to explain is how it is possible that a couple that has a similar difficulty in a sexual relationship and above all a reduced quality of the same, tends not to seek help to solve the problem. in the global study of sexual attitudes and behaviors survey, 78% of men who self-reported a sexual dysfunction sought no professional help or advice for their sexual problems, with men more likely to seek treatment for ed than for pe (19). similarly, in the premature ejaculation prevalence and attitudes survey, only 9% of men with self-reported pe consulted a doctor (20). however, the negative impact of pe extends beyond sexual dysfunction with possible serious impact on the psychological profile of both patient and partner, and most importantly, detrimental consequences on the quality of life of the couple. premature ejaculation can have a detrimental effect on self-confidence and the relationship with the partner, and may sometimes cause mental distress, anxiety, embarrassment and depression (3, 17). this data is amply confirmed by our study, which clearly shows that in a population of males affected by pe and of women partners of men affected by pe, there is a marked anxiety profile, with a significant percentage of subjects presenting a level of mild-to-moderate anxiety. on the contrary, compared to what was verified by other studies previously published, in our population of the iper study there is no profile of a depressive state as demonstrated by the non-statistical significance of the differences in pe+ and pepopulations of both sub-cohorts. in our opinion, our data is reinforced by the use of a validated questionnaire such as the z-sds. furthermore, our results showed a two-fold frequency of female sexual distress when the male partner is affected from pe. it has been widely accepted that pe represents a distressing condition, not only for men who suffer from the condition but also for their female partners and that it could lead to couple breakups and lower relationship satisfaction. in our mind, the most relevant data that emerges from this research is that, rather than talking about a male patient affected by pe it would be advisable to introduce the concept of the person affected by pe as part of a couple, because it is only through the classification of both partners and their sexual experience that the results of the treatment can be optimized. this is important, above all, in order to involve, once the diagnostic profiling phase is complete, involving both partners of the whole couple in the therapeutic process with the aim of optimizing the therapeutic outcome. moreover, some preliminary studies have shown that a combination of dapoxetine and behavioral treatment was more effective than dapoxetine alone in patients with lifelong pe (21). there are some major limitations in the present study that must be acknowledged. firstly, the design of the study (observational and cross-sectional) has allowed us to take a fixed picture of the condition of patients, without offering a dynamic assessment with control over time. secondly, pe in men (iper-m sample) has been defined without using the issm evidence-based definition but only based on the presence of ielt < 1 minute. similarly, as regards to the female counterpart (iper-f sample), the stratification data was based on a non-objective tool provided by the partner’s self-reported ielt. 47archivio italiano di urologia e andrologia 2021; 93, 1 clinical profile of pe patients conclusions data from this large observational, non-interventional, cross-sectional, epidemiological study shows that in m-f couples involving a patient with pe there is a significant problem of sexual dissatisfaction for both partners, which is accompanied by a progressive reduction in the frequency of sexual contact as well as the onset of anxiety. taking this into consideration, a full profile of the quality of a couple’s sex life is essential to optimize the results of the pe therapy of male partner. references 1. hatzimouratidis k, giuliano f, moncada i, et al. eau guidelines on erectile dysfunction, premature ejaculation, penile curvature and priapism http://uroweb.org/guideline/male-sexual-dysfunction/ last update march 2018. 2. althof se, mcmahon cg, waldinger md, et al. an update of the international society of sexual medicine's guidelines for the diagnosis and treatment of premature ejaculation(pe) j sex med. 2014; 2:60-90. 3. symonds t, roblin d, hart k, althof s how does premature ejaculation impact a man’s life? j sex marital ther. 2003; 29:361-70. 4. rust j, golombok s, collier j. marital problems and sexual dysfunction: how are they related? br j psychiatry. 1988; 152:629-31. 5. moore jt, goldstein y. sexual problems among family medicine patients. j fam pract. 1980; 10:243-7. 6. rowland dl, cooper se, schneider m. defining premature ejaculation for experimental and clinical 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51:816-23. 17. rowland d, perelman m, althof s, et al. self-reported premature ejaculation and aspects of sexual functioning and satisfaction. j sex med. 2004; 1:225. 18. capece m, la rocca r, mirone v, et al. a systematic review on ischemic priapism and immediate implantation: do we need more data? sexual medicine reviews. 2019; 7:530-534. 19. laumann eo, nicolosi a, glasser db, et al. sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the global study of sexual attitudes and behaviors. int j impot res. 2005; 17:39. 20. porst h, montorsi f, rosen rc, et al. the premature ejaculation prevalence and attitudes (pepa) survey: prevalence, comorbidities, and professional help-seeking. eur urol. 2007; 51:816. 21. cormio l, massenio p, la rocca r, et al. the combination of dapoxetine and behavioral treatment provides better results than dapoxetine alone in the management of patients with lifelong premature ejaculation. j sex med. 2015; 12:1609. correspondence paolo verze, md pverze@gmail.com roberto la rocca, md (corresponding author) robertolarocca87@gmail.com lorenzo spirito, md lorenzospirito@msn.com gianluigi califano, md gianl.califano2@gmail.com luca venturino, md luca.venturino86@gmail.com luigi napolitano, md nluigi@libero.it alessandro palmieri, md info@alessandropalmieri.it vincenzo mirone, md mirone@unina.it department of neurosciences, reproductive sciences and odontostomatology, urology section, university of naples federico ii via s. pansini, 5 80131 naples (italy) antonio cardi, md acardi@hsangiovanni.roma.it department of urology, san giovanni hospital, rome (italy) davide arcaniolo, md davide.arcaniolo@gmail.com department of urology, vanvitelli university, naples (italy) claudia rosati, md claudia.rosati@unina.it department of clinical medicine and surgery, university of naples federico ii, naples (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12067 1 systematic review which was considered an high rate. the most common complication from dj stent insertion is irritative bladder symptoms with 16.326 occurrences (32.7%), followed by hematuria with 7.436 cases (14.8%) (1). these ureteral stent-related problems are often considered a problem arising from the stent materials. a material that is too firm could cause discomfort which lower the patient’s quality of life. on the other hand, soft material could reduce its drainage ability. hydronephrosis, which is caused by external forces such as tumors, could easily beat the resistance force of the stent. firmness is not the only bulk property that could affect stent-related issues. other properties such as wear resistance, young’s modulus, and tensile strength are also fundamental for dj stent material. problems that arise from dj stent could come from mucosal friction during stent placement, infection due to retained microbes in the stent, and encrustation. nowadays, there are various materials used for dj stents although the use of metal is uncommon. metal is very firm, rigid, and has low brittleness. the inflexibility and rigidity of metal stents are highly likely to cause ureteral injury during their placement. furthermore, metal dj stent replacement could be very challenging and risky. thus, polymer is still considered the best option for dj stent. recently, the technology in additive manufacturing has grown rapidly. therefore, the idea to use coating in dj stent to reduce friction, encrustation occurrences, and infection rate has been researched intensively. the research was not limited only to improve bulk properties, but also the surface properties. silver nanoparticle, as one of the most well-researched nanoparticles, has a very potent antimicrobial properties since its positive ion charge could damage the bacterial cell membrane and bind to bacterial dna, preventing the bacteria to perform their basic function (2). therefore, coating material with silver nanoparticles is quite promising to reduce the infection rate. other than silver nanoparticles, triclosan's ability to prevent biosynthesis of bacterial fatty acid allows it to be one of the surging coating materials (3). in summary, both bulk and surface properties are important to determine the characteristics of a material. there are several criteria for the ideal material for dj stent, which are introduction: ureteral stents require materials that balance bulk and surface properties. achieving both can be challenging, as ideal bulk properties may not align with optimal surface properties. thus, researching coatings and biomanufacturing methods for ideal materials is essential. methods: a systematic review and meta-analysis, following prisma guidelines, involved literature searches across five databases: pubmed, scopus, embase, clinicalkey, and cochrane. from 417 screened articles, eight studies were deemed eligible for qualitative and quantitative analysis. the selected articles underwent bias assessment using rob tools 2. results: the systematic review analyzed 1.356 participants. findings revealed that firm ureteral stents significantly increased risk of infection, hematuria, and lower body pain. on the contrary, soft stents reduced infection (or: 0.62; p = 0.004), hematuria (or: 0.60; p = < 0.001), and lower body pain (or: 0.63; p = 0.0002). however, infection reduction effect was uncertain due to heterogeneity. coated vs. non-coated material analysis found no difference in encrustation (or: 1.26; p = 0.52) or infection (or: 1.67; p = 0.99). stent firmness didn't affect encrustation on double j stent (or: 0.97; p = 0.17). conclusions: softer materials like silicone are preferred for ureteral stents to reduce symptoms like hematuria and lower body pain. coatings like silver nanoparticles and triclosan, while enhancing antimicrobial properties, didn't effectively lower infection risk. key words: double j (dj) stent; bulk properties; surface properties; material coating; polymers. submitted 9 november 2023; accepted 14 november 2023 introduction ureteral stent is one of the medical implants more often used by urologists after urinary catheter. double j stent (dj stent) insertion procedure could be categorized as a routine and simple urology procedure. despite various materials researched to fulfill the demand for ideal ureteral stent, there are still numerous issues to be solved. based on research conducted by geavlete et al. in 2021, there were 41.369 complications from 50.000 procedures (82.7%), role of ureteral stent material and coating to prevent ureteral stent related issue: a systematic review and meta analysis ignatius ivan putrantyo 1, syah mirsya warli 2, 3, ginanda putra siregar 2, fauriski febrian prapiska 2, dhirajaya dharma kadar 2, bungaran sihombing 2 1 department of urology, faculty of medicine, universitas indonesia, depok; haji adam malik general hospital, medan, indonesia; 2 division of urology, department of surgery, faculty of medicine, universitas sumatera utara, haji adam malik general hospital, medan, indonesia; 3 department of urology, universitas sumatera utara hospital, universitas sumatera utara, medan, indonesia. doi: 10.4081/aiua.2024.12067 summary archivio italiano di urologia e andrologia 2024; 96(1):12067 i. ivan putrantyo, s. mirsya warli, g. putra siregar, et al. 2 high poisson ratio, high young’s modulus, and high tensile properties and tear resistance with low brittleness and hardness. furthermore, a material with surface properties such as high wettability and hydrophilicity is preferred for ureteral stents since it will lower the risk of infection and risk of ureteral injury during ureteral stent placement (4). however, a material that has good bulk properties mostly does not have ideal surface properties. therefore, further research to seek an ideal material through coating and biomanufacturing is paramount to solve this issue. methods study objective the study was done to determine the material for dj stent with the least side effects and whether it has a significant role in reducing ureteral stent-related issues. this study also aimed to determine whether the coating material has a role in reducing ureteral stent-related problem. eligibility criteria type of studies this study only included controlled trials which focus on ureteral stentrelated symptoms and comparing stents based on their material and coating. we used the pico (patient, intervention, comparison, outcome) model to answer the clinical question of this study. patient: adults requiring dj stent procedure; intervention: dj stent; comparison: dj stent with various materials, coating, and firmness; outcome: infection (primary), hematuria, encrustation, and pain after dj stent placement. type of participant all participants were adult aged 18 years or above who underwent dj stent procedure. participants who consume immunosuppressant or have autoimmune disease, hematological abnormalities, hiv/aids, malignancy, systemic lupus erythematosus were excluded. study screening and selection the authors made a robust search strategy based on the pico concept recommended by cochrane handbook for systematic reviews of intervention version 5.1.0. statistical analysis statistical analysis was performed with review manager 5. the authors performed six different subgroup analysis. heterogeneity was assessed using the i2 statistics. the significance of the pooled effects was evaluated by a z test, and p < 0.05 was defined as significant. the author prespecified a sensitivity analysis to investigate the effect of excluding studies with a high risk of bias to investigate the robustness of this review. the author also repeated primary meta-analysis in case the range of values for decisions was uncertain by using alternative measures of effect size and statistical model. funnel plot was not performed since there were less than ten included studies. results search results initially, the systematic search yielded 2696 articles. the authors then removed 1133 studies due to duplication and other reasons. the rest 1459 were then screened for its relevance based on title and abstract. this process yielded 38 potentially eligible studies. following the fulltext reading, 30 studies were excluded for various reasons and only eight were eligible and included in this study (512) (figure 1). figure 1. prisma chart flow. archivio italiano di urologia e andrologia 2024; 96(1):12067 3 ureteral stent material and coating included studies eight controlled trials were included and no cluster trial and cross-over trial were included in this review. settings the studies were conducted in canada, usa, egypt, uk, ireland, and romania. all studies were performed in a hospital setting. patients there was a total of 2249 patients which comprised 529 participants from soft dj stent group, 1412 participants from the firm dj stent group, 154 participants from the coated group, and 154 participants from the non-coated group. risk of bias in included studies figure 2 illustrated a summary of the authors’ assessment on eight included controlled trials in this study. in summary, there were two studies which regarded to have a low risk of bias by the other, while the rest had moderate risk. since there was no high-risk bias from the studies included, no study was excluded from the meta-analysis. bulk properties in this review, the authors conducted six subgroup analysis, and half of them tried to find out whether firmness has a significant ureteral stent-related side effect. based on figure 3a, it could be concluded that softer dj stent would lower the risk of urinary infection significantly (or: 0.62; 95% ci: 0.45-0.86; p = 0.004). however, this result should be further investigated since it has high heterogeneity (> 50%). therefore, more studies should be conducted in the future to obtain a better understanding of soft stent effect in reducing urinary tract infection (uti). softness also played a key role in reducing hematuria as illustrated in figure 3c, with the odds of people who had soft dj stent will be 0.6 times compared to their counterparts (or: 0.60; 95% ci: 0.48-0.75; p = < 0.001). besides reducing risk of uti and hematuria, soft dj stent could also lower the risk of experiencing lower body pain as depicted in figure 3e. patient who received a relatively softer dj stent experienced a significantly rate of lower body pain. (or: 0.63; 95% ci: 0.49-0.80; p = 0.0002). however, softness has no impact in reducing encrustation occurrences, as illustrated in figure 3d (or: 0.97; 95% ci: 0.69-1.37; p = 0.17). figure 3. generated forest plot. figure 2. assessment of risk of bias. a. b. archivio italiano di urologia e andrologia 2024; 96(1):12067 i. ivan putrantyo, s. mirsya warli, g. putra siregar, et al. 4 surface properties in this review, the authors also observed the role of surface properties in reducing ureteral stent-related issue. the authors conducted a subgroup analysis on coated and non-coated dj stent. as illustrated in figure 3f, there were two studies included where triclosan-eluted stent was used as coating material. however, it was not effective to reduce encrustation (or: 1.26; 95% ci: 0.354.54; p = 0.52). in another subgroup analysis, three studies were included. one of them used silver as coating material, while the rest used triclosan. the authors found that there is no significant effect of coated materials to reduce the occurrences of uti, as shown in figure 3b (or: 1.67; 95% ci: 0.67-4.17; p = 0.99). heterogeneity in this review, there were three reported imprecision and inconsistency in the results where the heterogeneity of subgroup analysis conducted in figure 3a is higher than 40%, and both the p-values given for chi-square in figure 3b and 3f were less than 0.1. discussion there are numerous ways to categorize dj stent materials. in this review, the authors chose the easiest way, which is based on bulk and surface properties. in terms of bulk properties, the authors would like to observe closely on several items such as firmness, young’s modulus, elasticity, tensile strength, wear resistance, and biocompatibility. however, there were very limited research which focus on those areas and the authors only managed to compare based on firmness alone. firmness and softness are often defined ambiguously. thus, a certain parameter to make a clear line between them is of paramount importance. material with value of 40-64 a is categorized as soft while above 65 a is categorized as firm when measured using durometer (9). c. d. e. f. archivio italiano di urologia e andrologia 2024; 96(1):12067 5 ureteral stent material and coating in this study, we can conclude that softer stents will yield less hematuria and lower body pain. even though softness and elasticity could not be used interchangeably, they are closely related. firm dj stent is predicted to increase difficulty in dj stent placement. this means the force needed to insert dj stent would be higher and ureteral mucosal injury would be unavoidable. therefore, it is expected that occurrences of hematuria will be higher. firm dj stent is also considered to cause a higher rate of lower abdominal pain since it will stretch the ureter and sphincter in the ureter with stronger force compared to its counterparts. as mentioned above, firmness is closely related to inflexibility. the inability of firm dj stent to adapt in various body position would cause discomfort in patients (13). nevertheless, firm dj stent has its advantage since it has stronger coil strength and better shaped memory. when placed successfully, it would be a better option to maintain ureteral shape or return to its original shape. therefore, in some cases such as ureter kinking or malignancy-related hydronephrosis, firm dj stent should be considered as an option. bulk properties of material are indeed important to determine dj stent characteristics. advancement in additive manufacturing pushed researchers to further develop dj stent in an untouched area before, which is to improve its surface properties. most of the polymers are hydrophobic while it is known that dj stent placement would be much easier and less in friction if the material is hydrophilic (4, 14). there are several research which focus on hydrophilic coating material. however, the authors could not provide the analysis in this review since some of those manuscripts were made unavailable. thus, this review only focused on triclosan eluted stent and silver nanoparticle stent. based on the studies included in this review, silver nanoparticles and triclosan have insignificant impact in lowering the occurrences of uti and encrustation. silver nanoparticles coating is considered to have a strong antimicrobial activity due to its ability to punch a hole in bacteria cell membrane due to its positive ion charge on the surface (2, 15). similarly, triclosan is also considered to have a potent antimicrobial property due to the ability to prevent biosynthesis of essential dna of the bacteria (3, 16). the authors hypothesized that the inability of these two materials to reduce uti and encrustation could be due to the hydrophobic nature. hydrophobicity is one of the surface properties that is not very essential for dj stent material as it would increase friction between dj stent and ureteral mucosa which later caused ureteral injury. ureteral injury could make the ureter prone to retainment of bacteria and infection. on the other hand, hydrophilic material could make bacteria adhering to dj stent to be flushed easier. even though hydrophilic surface could preserve the original protein conformation and retain its bioactivity, hydrophilic surface resist protein adsorption stronger compared to its counterpart. therefore, it is hypothesized that hydrophilic characteristics are beneficial in reducing infection and encrustation rate. there are also other surface properties which could play a key role in reducing infection and encrustation rate such as nanopattern on the surface material (17). different nanopattern could yield a different cell behavior. however, it is still yet to be further determined which nanopattern surface is optimal to reduce uti and hematuria. conclusions in conclusion, softness played an important role to reduce ureteral stent-related symptoms such as hematuria, and lower body pain. softer polymers such as silicone is more preferrable as ureteral stent material. additional coating material such as silver nanoparticles and triclosan are not effective to reduce risk of infection even though it could enhance its antimicrobial properties through its positive net ion charge and ability to prevent biosynthesis of bacterial fatty acid. acknowledgements we thank medical faculty of universitas indonesia, medical faculty of universitas sumatera utara and adam malik general hospital for their consistent support for the author during this research. references 1. geavlete p, georgescu d, multescu r, et al. ureteral stent complications experience on 50,000 procedures. j med life. 2021; 14:769-775. 2. yin ix, zhang j, zhao is, et al. the antibacterial mechanism of silver nanoparticles and its application in dentistry. int j nanomedicine. 2020; 15:2555-2562. 3. nudera wj, fayad mi, johnson br, et al. antimicrobial effect of triclosan and triclosan with gantrez on five common endodontic pathogens. j endod. 2007; 33:1239-42. 4. yang l, whiteside s, cadieux pa, denstedt jd. ureteral stent technology: drug-eluting stents and stent coatings. asian j urol. 2015; 2:194-201. 5. el-nahas ar, el-assmy am, shoma am, et al. self-retaining ureteral stents: analysis of factors responsible for patients' discomfort. j endourol. 2006; 20:33-7. 6. cadieux pa, chew bh, nott l, et al. use of triclosan-eluting ureteral stents in patients with long-term stents. j endourol. 2009; 23:1187-94. 7. el-nahas ar, lachine m, elsawy e, et al. a randomized controlled trial comparing antimicrobial (silver sulfadiazine)-coated ureteral stents with non-coated stents. scand j urol. 2018; 52:76-80. 8. gadzhiev n, gorelov d, malkhasyan v, et al. comparison of silicone versus polyurethane ureteral stents: a prospective controlled study. bmc urol. 2020; 20:10. 9. joshi hb, chitale sv, nagarajan m, et al. a prospective randomized single-blind comparison of ureteral stents composed of firm and soft polymer. j urol. 2005; 174:2303-6. 10. lennon gm, thornhill ja, sweeney pa, et al. 'firm' versus 'soft' double pigtail ureteric stents: a randomised blind comparative trial. eur urol. 1995; 28:1-5. 11. mendez-probst ce, goneau lw, macdonald kw, et al. the use of triclosan eluting stents effectively reduces ureteral stent symptoms: a prospective randomized trial. bju int. 2012; 110:749-54. archivio italiano di urologia e andrologia 2024; 96(1):12067 i. ivan putrantyo, s. mirsya warli, g. putra siregar, et al. 6 12. scarneciu i, lupu s, pricop c, scarneciu c. morbidity and impact on quality of life in patients with indwelling ureteral stents: a 10-year clinical experience. pak j med sci. 2015; 31:522-6. 13. boeykens m, keller ex, bosio a, et al. impact of ureteral stent material on stent-related symptoms: a systematic review of the literature. eur urol open sci. 2022; 45:108-117. 14. al-aown a, kyriazis i, kallidonis p, et al. ureteral stents: new ideas, new designs. ther adv urol. 2010; 2:85-92. 15. bruna t, maldonado-bravo f, jara p, caro n. silver nanoparticles and their antibacterial applications. int j mol sci. 2021; 22:7202. 16. alfhili ma, lee mh. triclosan: an update on biochemical and molecular mechanisms. oxid med cell longev. 2019; 2019:1607304. 17. modaresifar k, azizian s, ganjian m, et al. bactericidal effects of nanopatterns: a systematic review. acta biomater. 2019; 83:29-36. correspondence ignatius ivan putrantyo ivan.putrantyo@gmail.com department of urology, faculty of medicine, universitas indonesia haji adam malik general hospital, indonesia syah mirsya warli (corresponding author) warli@usu.ac.id department of urology, universitas sumatera utara hospital universitas sumatera utara, medan 20154, indonesia. ginanda putra siregar ginandaputras@gmail.com fauriski febrian prapiska fauriskifprapiska@gmail.com dhirajaya dharma kadar dhirajayadharmakadar@gmail.com bungaran sihombing bungaranhombing@gmail.com division of urology, department of surgery, faculty of medicine, universitas sumatera utara – haji adam malik general hospital, indonesia conflict of interest: the authors declare no potential conflict of interest. 245archivio italiano di urologia e andrologia 2017; 89, 3 letter to the editors about: a retrospective comparison between transrectal and transperineal prostate biopsy in the detection of prostate cancer arch ital urol androl 2017; 89:55-9. key words: prostate biopsy; transperineal; transrectal; detection rate. the eternal enigma in prostatic biopsy access route no conflict of interest declared. doi: 10.4081/aiua.2017.3.245 dear editors, we read with interest the article by di franco et al. (1). the introduction of prostatic magnetic resonance and the relative fusionbiopsy have not yet allowed the expected improvements in prostate biopsy. to our knowledge, there are no works that demonstrate the superiority of fusion techniques on the remaining ultrasound guided prostate biopsies that are still the widely used in the diagnosis of prostate cancer. furthemore, these technologies are expensive exams and they are not yet available in all centers, especially in those minors. we work at a “minor” center and we always keep in mind that the goal of prostatic biopsy is the diagnosis and the staging of prostatic neoplasms.. however, it remains uncertain which of the two techniques, transperineal (tp) or transrectal (tr), is superior in terms of detection rate during first biopsy setting. several studies have compared the prostate cancer detection rate but tr and tp access route in prostatic gland sampling seems to be equivalent in terms of efficiency and complications, as reported by shen pf et al. (2), despite several methodological limitations recognized in their work. the results reported by di franco ca et al. represent the real life experience of most urologists that perform the pb based on their own training experience and available technical devices. from an historical viewpoint, the tp route has been the first one to be used to reach the prostate, both for diagnostic and therapeutic purposes. to date, because it seems to be more invasive and difficult, the tp route is less used worldwide than the tr one (2). theoretically, the tp approach should detect more prostate cancer than the tr way because the cores of the tp approach are directed longitudinally to the peripheral zone and the anterior part of the prostate (4). the results reported by di franco et al. seems to confirm these considerations. however, our real life experience differ from the conclusions reached in their work. we recently conducted a prospective evaluation of 352 patients who underwent their first prostate biopsy because of a suspicious of prostate cancer (elevated prostate specific antigen (psa) and/or abnormal digital rectal examination and/or abnormal findings on transrectal prostatic ultrasound). patients was randomized as following. a total of 187 patients (group a) underwent a prostatic biopsy with a transperineal approach in a lithotomic position, using a biplane probe (8818 bk medical, denmark) and a fan technique with a single perineal median access (5). the remnants 165 patients (group b) underwent a transrectal ultrasound guided prostate biopsy in a left lateral position, using a end fire probe configuration (8818 bk medical, denmark) and a sagittal technique. the bioptic prostatic mapping was performed with a 12-core scheme sec. gore (3) by a single experienced operator and the histopathologic evaluation was performed by a single dedicated uro-pathologist. statistical evaluations were made with a t student test (p < 0.005). group a and group b was similar in term of mean patient age (67.9 years and 67 years respectively), mean total psa (12.1 ng/ml vs 12 ng/ml) and digital rectal examination positivity (22% vs 29%). the global cancer detection rate was 33,69% (63/187) in the transperineal prostate biopsy group and 48,48 % (80/165) in the transrectal approach (p = 0.0047). no significant statistical differences were found in the complications rates between the two groups. statistical evaluation of site of tumor localization reveal only a trend to statistical significance in apical site tumors diagnosed with the tr approach versus the tp technique. the tr approach had a better diagnostic accuracy than tp technique in case of psa < 4 ng/ml, intermediate prostate volume (30 and 50 ml), normal digital rectal examination without any relationship with the patient age. in our experience, two aspect may explain the difference between the two group in term of global detection rate. first, we usually perform transrectal biopsy with a sagittal technique that simulates the transperineal way of needle incidence with the prostatic gland. the lateral and anterior gland portions may be sampled more accurately. second, our transperineal approach consists in a single perineal median access that can make more difficult the gland sampling between the two lobes. however, there was no significant difference in core positivity rate at the peripheral zone, medium gland, apex or any other site such as reported in many randomized clinical trials (2). unlike the conclusions reported by di franco et al., in our experience we found a statistically significant difference between the tr and tp approach, at the first biopsy setting, in term of global cancer detection rate. no differences were found in terms of complications. moreover, our data suggest that tr approach had a better diagnostic accuracy than tp technique in case of psa < 4 ng/ml, prostate volume 30-50 ml, normal digital rectal examination without any relationship with the patient age. the further step of the statistical evaluation of our data will be the definition of the possibility that the tr biopsy determine a better staging of prostate cancer than tp approach as first procedure. references 1. di franco ca, jallous h, porru d, et al. a retrospective comparison between transrectal and transperineal prostate biopsy in the detection of prostate cancer arch ital urol androl. 2017; 89:55-9. 2. shen fp, zhu yc, wei wr, et al. the results of transperineal vs transrectal prostate biopsy: a systematic review and meta-analysis. asian journal of androl. 2012; 14:310-15. 3. gore jl, shariat sf, miles bj, et al. optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate fabiani letter_stesura seveso 28/09/17 10:34 pagina 245 archivio italiano di urologia e andrologia 2017; 89, 3 letter to the editors 246 cancer. j urol. 2001; 165:1554-59. 4. abdollah f, novara g, briganti a, et al. trasrectal versus transperineal saturation re biopsy of the prostate: is there a difference in cancer detection rate? urology. 2011; 77:921. 5. novella g, ficarra v, galfano a, et al. pain assessment after original hyperlink "https://www.ncbi.nlm.nih.gov/pubmed/ 14550444"transperinealhyperlink "https://www.ncbi.nlm.nih.gov/pubmed/14550444" prostate biopsy using a coaxial needle. urology. 2003; 62:689-92. andrea fabiani 1, emanuele principi 2, alessandra filosa 3, lucilla servi 1 1 surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, italy; 2 urologic clinic, polithecnic university of the marche region, ancona, italy; 3 section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche,macerata hospital, italy. correspondence andrea fabiani, md andreadoc1@libero.it lucilla servi, md lucilla.servi@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3 macerata hospital, italy emanuele principi, md resident principie@tiscali.it urologic clinic, polithecnic university of the marche region, ancona, italy alessandra filosa, md phd alessandrafilosa@yahoo.it section of pathological anatomy, department of clinical pathology, area vasta 3, asur marche, macerata hospital, italy fabiani letter_stesura seveso 28/09/17 10:34 pagina 246 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper hypogonadism, which can lead to sexual dysfunction, affects about 40% of men with ibd (3, 5). hypogonadism in ibd patients is linked to taking certain medications and chronic inflammation. testosterone levels have been linked to the medication of opiates and steroids (3, 4, 6). compared to the general male population, male patients with ibd have a higher incidence of sexual dysfunction, which ranges from 15 to 25% (7). about 64% of men with ibd actively experience sexual dysfunction (8). depression, medication, and hypogonadism are all factors that can affect erectile dysfunction in ibd patients (9). it appears that sexual dysfunction is largely caused by proinflammatory cytokines and reactive oxygen species (4). when compared to men with uc and to general population, men with cd have an increased risk of infertility that ranges from 18 to 50%. a decrease in the number, motility, and morphology of spermatozoa is accompanied by an increase in the amount of tnf-a, which causes spermatozoa to undergo apoptosis and further proliferation and differentiation of b-cells, t-cells, and natural killer cells. the inflammatory process is mediated by interleukin-1a and interleukin 1b causing an increase in reactive oxygen species in sperm and direct damage to spermatozoa. in men with ibd, many other factors play a significant role in the development of infertility, including medication and surgical treatment, disease activity, malnutrition, and psychological factors (2, 4). according to wdowiak a et al., men with ibd had significantly lower levels of the total number, concentration, percentage of normal spermatozoa morphology, viability, and progressive motility than the control group. there was no significant difference with the control group's sperm volume or levels of total testosterone, luteinizing hormone (lh), and follicle-stimulating hormone (fsh) (2). the purpose of this study is to determine whether the severity (rectal bleeding) of ibd (especially in ulcerative colitis type) impacted on semen parameters (volume, concentration, progressive motility, non-progressive motility, count of immotile, leukocytes, and immature spermatozoa cells, and morphology) and sex hormone binding globulin (shbg), estradiol, and free testosterone levels. introduction: hypogonadism and inflammatory bowel disease (ibd) are often associated. this association may influence sexual and reproductive function in ibd, including sperm profile and sex steroid hormones. patients and methods: this study included 59 ibd patients diagnosed with ulcerative colitis type ibd. anamnesis was carried out regarding the history of the disease, along with a history of rectal bleeding. evaluation proceeded with sperm and hormone examination if the patient agreed. results: progressive motility sperm, immotile sperm, and normal sperm were found to be significantly different between the rectal bleeding groups. in grade 3 (more significant bleeding) progressive sperm (24.81 ± 5.85, p < 0.0001) and normal sperm (6.33 ± 12.56, p = 0.0003) rates tended to be lower, while immotile sperm tended to be higher (44.48 ± 11.21, p < 0.0001). testosterone and free testosterone levels were also reported to be significantly different between groups, where grade 3 had lower levels 255.9 ± 30.08, p = 0.014 and 4.645 ± 0.5, p = 0.002 respectively. conclusions: our study shows that the degree of rectal bleeding influences sperm motility and morphology, as well as testosterone and free testosterone levels. these results can concern managing ibd patients to fulfill reproductive health care. key words: inflammatory bowel disease; sperm analysis; testosterone; reproductive healthcare; hypogonadism. submitted 18 december 2022; accepted 31 december 2022 introduction ibd is a non-specific chronic inflammatory disease that is brought on by a combination of factors as immune system, environment, intestinal flora, and genetics. ibd's aetiology and pathogenesis remain poorly understood. ulcerative colitis (uc) and crohn's disease (cd) are the ibd conditions that are most prevalent (1). about 2 million people in north america have ibd, while about 2.3 million people in europe do. all over the world, ibd is a common disease, and developing nations with westernized lifestyles continue to see higher incidence rates. more than half of people with ibd are diagnosed when they are younger than 35 years old (2, 4). semen and sex-steroid parameters among inflammatory bowel disease ulcerative colitis type according to rectal bleeding grade darmadi darmadi 1*, cennikon pakpahan 2, 3*, andri rezano 2, 4, wanly syahrizal pasaribu 2, herwindo ahmad 1, adriansyah lubis 5, supardi supardi 2 1 department of internal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia; 2 andrology study program, faculty of medicine, universitas airlangga, surabaya, indonesia; 3 department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia; 4 department of biomedical sciences, division of cell biology, faculty of medicine, universitas padjadjaran, sumedang, west java, indonesia; 5 department of forensic and medicolegal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia. * contributed equally as co-first author. doi: 10.4081/aiua.2023.11100 summary archivio italiano di urologia e andrologia 2023; 95, 1 d. darmadi, c. pakpahan, a. rezano, w. syahrizal pasaribu, h. ahmad, a. lubis, s. supardi materials and methods we conducted a study on patients who came to the gastroenterology polyclinic at haji adam malik general hospital, medan, indonesia, diagnosed with inflammatory bowel disease. this study was designed as cross-sectional. this study was approved by the ethical commission of the faculty of medicine, universitas sumatera utara/haji adam malik general hospital with number 428/kepk/usu/2022. patients selection patients were assessed by a physician with more than three years of experience in diagnosing this disease. male patients diagnosed with ibd, aged 20-45 years, married, and willing to undergo sperm and hormone analysis, were observed at the gastroenterology polyclinic at haji adam malik general hospital from june to september. inflammatory bowel disease was diagnosed using colonoscopy findings, clinical symptoms (evaluation) or expertise opinion and histopathology. all these assessments were used to determine the type of ibd and to calculate the mayo score of ibd. patient were interviewed regarding ibd complaints and then a physical examination was carried out. patient were advised to have sperm and sex steroids checked. if the patient agreed to be examined, he was explained the sperm analysis procedure. procedure and laboratory test after being examined by an internist (enterologist) and diagnosed with ibd, the patient was directed to participate in the study. patients will get an explanation of the purpose of the study. then the patient who agreed signed an informed consent. researchers interviewed marital history, alcohol consumption, smoking, duration of illness, and medication history. for clinical symptoms of ibd, we only stratified patients based on rectal bleeding by mayo score (10) the division based on these symptoms is simple, easy, and objective. this symptom is also what patients often complain about when they come to the clinic. patient were advised to come another day after fasting for at least 8 hours and abstinence from intercourse for 2-7 days. blood was taken at 07.00-09.00 am. it was processed with an enzyme-linked immunosorbent assay (elisa) kit (roche diagnostics ltd., shanghai, china) for sex steroid examination. then, the patient was directed to masturbate to get a semen sample to be examined according to the 2010 edition of the who sperm analysis method. data analysis data were analysed using graphpad prism 9. univariate analysis was performed for each numerical data, such as mean, median, and mode. the normality test was performed to assess parametric data. normally distributed data are presented as mean±sd, whereas non-parametric data are shown as median (iqr). to see differences in semen and hormone analysis parameters between rectal bleeding groups, a one-way anova test was performed. kruskal wallis was an alternative if the data was nonparametric. results patients profile fifty-nine patients agreed to undergo sperm and sex steroid hormone tests from june to september 2022. based on whole assessment, all patients included in this series were ibd of the ulcerative colitis type. the mean age of the patients was 32.90 ± 4.7 years. some reported smoking (22.03%) and consuming alcohol (10.16%). out of them 55 were married and had children. bleeding degree 3 was mostly reported (35.59%). the majority (88.14%) of them never had treatment for ibd. the results of the overall frequency distribution of sperm analysis and sex steroid hormones are presented in table 1. semen analysis and sex steroid the results of semen and sex steroid analysis by rectal bleeding groups are presented in figures 1, 2. on semen analysis, progressive motility, immotile, and morphology were significantly different. in group 3 (more significant bleeding) rate of progressive motility and normal sperm morphology was lower (24.81 ± 5.85 and 6.33 ± 12.56), while rate of immotile sperm was higher than the other groups (44.48 ± 11.21). in other parameters, no significant difference was found. in the analysis of sex steroid levels, testosterone and free testosterone levels were significantly different. testosterone and free testosterone levels in group 3 were lower (255.9 ± table 1. patients and laboratory profile of 59 ibd. parameters results (n=59) age 32.90 ± 4.7 years bmi (body mass index) 22.68 ± 3.6 kg/m2 semen volume 5.0 (3.6-5.2) ml sperm concentration 43.8 (14.5-54.5) million/ml sperm motility pr (progressive) 36.19 ± 12.78% npr (non-progressive) 31.0 (26.0-34)% im (immotile) 35.26 ± 14.45% sperm morphology 32 (21.0-43.0)% leukocyte 0.4 (0-0.6) million/ml immature germ cells 0.2 (0-0.4) million/ml total testosterone 275 (248-330) ng/dl free testosterone 5 (4.5-5.8) ng/dl oestradiol 4 (3.5-4.3) ug/ml shbg 16.81 (15.58-18.04) nmol/l overall mayo score 7.78 ± 2.85 ibd bleeding grade zero 9 (15.25%) first 16 (27.11%) second 13 (22.03%) third 21 (35.59%) on-treatment yes 7 (11.86%) no 52 (88.14%) duration of treatment 2.57 months drug of choice mesalazin and methylprednisolone 7 (100%) smoking 13 (22.03%) alcohol 5 (10.16%) married and have child 55 (93.22%) archivio italiano di urologia e andrologia 2023; 95, 1 semen and sex-steroid in ibd patients 30.08 and 4.645 ± 0.5), while they were not significantly different for oestradiol and shbg. discussion inflammatory bowel diseases (ibd) have emerged as global diseases.(2) recent evidence indicates that a systemic state of inflammation may exert a negative effect on male fertility (2, 11). then it should be pointed out that male infertility is considered to be more prevalent in ibd patients than in the general population (12). therefore, both sexual health and fertility are serious concerns among many patients with ibd, and adequate knowledge of causative factors is of great importance (2). this study analysis showed significantly different of progressive motility, rate of immotile sperm cells, and morphology on semen analysis among rectal bleeding groups. the more severe the bleeding, the more likely is the decrease of motility and of normal sperm shape decreases and the increase of immotile sperm. previous study explained that inflammatory conditions are considered to lead to infertility such as decreased sperm motility, low sperm count, damage to sperm dna, and/or poor semen quality due to a number of factors like high levels of reactive oxygen species (ros) and oxidative stress. oxidative stress has been figure 1. analysis of semen parameters among rectal bleeding group figure 2. analysis of sex steroid among rectal bleeding group. archivio italiano di urologia e andrologia 2023; 95, 1 d. darmadi, c. pakpahan, a. rezano, w. syahrizal pasaribu, h. ahmad, a. lubis, s. supardi known to affect spermatogenesis in the testis, epididymis and at a seminal level (13). then inflammation is accompanied by high levels of reactive oxygen species and oxidative stress, which may exert a negative effect on semen parameters (12). furthermore, the presence of the pro-inflammatory cytokines like tumor necrosis factor-alpha (tnfalpha), interleukin-1alpha (il-1alpha) and interleukin1beta (il-1beta) in the male uro-genital tract may also increase cytokine-mediated anti-fertility effects (13). immunological factors associated with humoral immunity against sperm also may lead to infertility. the underlying mechanism is the induction of antisperm antibodies (asa) due to the cross-reactivity between antigens of spermatozoa and exogenous antigens, such as bacteria (12). our research study also showed significantly different testosterone and free testosterone levels among our study group. our study analysis also showed that patients with higher degree of bleeding, had significantly lower testosterone and free testosterone compared to other group. this result support previous studies reporting consistently reduced serum androgens and an important role in decreasing androgen receptor protein of tnf (12) which plays a central role in the pathogenesis of inflammatory bowel disease. this study has several limitations, mainly concerning the low number of inflammatory bowel disease cases we can include in this study. therefore, additional studies with larger populations might be helpful to a better understanding of the importance and role of the severity of rectal bleeding in the context of male fertility. we also did not consider other opportunistic infections that might have affected our data study. conclusions our study showed that semen parameters (motility and sperm morphology) are associated with the severity of rectal bleeding among ibd patients. the more severe the bleeding, the more likely the decrease of motility and normal sperm shape and the increase of immotile sperm. this suggests that the severity of rectal bleeding contribute to reduce semen quality. testosterone and free testosterone in patients with a more significant degree of bleeding are significantly lower compared to other patients with less severe bleeding. this suggests that the severity of rectal bleeding also play an important role to control this androgen hormone. the result of this study has shown that low motility level, sperm shape, testosterone and free testosterone are related to the severity of rectal bleeding caused by unregulated inflammation led by tnf. references 1. zhang j, wei s, zeng q, et al. prevalence and risk factors of sexual dysfunction in patients with inflammatory bowel disease: systematic review and meta-analysis. int j colorectal dis. 2021; 36:2027-38. 2. wdowiak a, gujski m, bojar i, et al. chronic inflammation impairs male fertility-a case-control study in ulcerative colitis patients. j clin med. 2021; 10:1460 3. de arce ep, quera r, barros jr, sassaki ly. sexual dysfunction in inflammatory bowel disease: what the specialist should know and ask. int j gen med. 2021; 14:2003-15. 4. allocca m, gilardi d, fiorino g, et al. sexual and reproductive issues and inflammatory bowel disease: a neglected topic in men. eur j gastroenterol hepatol. 2018; 30:316-22. 5. szathmári m, vásárhelyi b, treszl a, et al. association of dehydroepiandrosterone sulfate and testosterone deficiency with bone turnover in men with inflammatory bowel disease. int j colorectal dis. 2002; 17:63-6. 6. o’toole a, winter d, friedman s. review article: the psychosexual impact of inflammatory bowel disease in male patients. aliment pharmacol ther. 2014; 39:1085-94. 7. leenhardt r, rivière p, papazian p, et al. sexual health and fertility for individuals with inflammatory bowel disease. world j gastroenterol. 2019; 25:5423-33. 8. hammami mb, mahadevan u. men with inflammatory bowel disease: sexual function, fertility, medication safety, and prostate cancer. am j gastroenterol. 2020; 115:526-34. 9. friedman s, magnussen b, o’toole a, et al. increased use of medications for erectile dysfunction in men with ulcerative colitis and crohn’s disease compared to men without inflammatory bowel disease: a nationwide cohort study. am j gastroenterol. 2018; 113:1355-62. 10. lewis jd, chuai s, nessel l, et al. use of the noninvasive components of the mayo score to assess clinical response in ulcerative colitis. inflamm bowel dis. 2008; 14:1660-6. 11. bel lg, vollebregt am, van der meulen-de jong ae, et al. sexual dysfunctions in men and women with inflammatory bowel disease: the influence of ibd-related clinical factors and depression on sexual function. j sex med. 2015; 12:1557-67. 12. ballinger ab, savage mo, sanderson ir. delayed puberty associated with inflammatory bowel disease. pediatr res. 2003; 53:205-210. 13. sarkar o, bahrainwala j, chandrasekaran s, et al. impact of inflammation on male fertility. front biosci. 2011; 3:89-95. correspondence darmadi darmadi, md darmadi@usu.ac.id herwindo ahmad, md ahmadherwindo@usu.ac.id department of internal medicine, faculty of medicine, universitas sumatera utara, medan (indonesia) cennikon pakpahan, md cennikon.pakpahan@fk.unair.ac.id andrology study program, department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya (indonesia) department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia andri rezano, md andri.rezano@unpad.ac.id andrology study program, department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya (indonesia) department of biomedical sciences, division of cell biology, faculty of medicine, universitas padjadjaran, sumedang, west java (indonesia) wanly syahrizal pasaribu, md syahrizal_on3ly@yahoo.com supardi supardi, md supardi.unair@gmail.com andrology study program, faculty of medicine, universitas airlangga, surabaya (indonesia) adriansyah lubis, md adriansyah.lubis@usu.ac.id department of forensic and medicolegal medicine, faculty of medicine, universitas sumatera utara, medan (indonesia) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2200 original paper no conflict of interest declared. introduction hemorrhagic cystitis (hc) is a condition defined as the presence of hematuria and lower urinary tract symptoms (luts), irritative voiding symptoms, such as urgency, frequency, nocturia and pain or burning with urination (1). radiotherapy (rt) for pelvic malignancies, including prostate cancer (2, 3), could be associated with the development of hc in up to 6.5% of patients, as result of bladder wall modification and neovascularization (4). however, hc may be a complication of hematological cancer treatment, too. medication toxicity and immunemediated hypersensitivity may lead to luts and bladder mucosae bleeding in 7 to 68% of patients treated with cyclophosphamide (5). in literature there are many possible treatments for hc. first line treatments are the most conservative and include hyperhydration, blood transfusion, transurethral three-way catheterization with continuous bladder irrigation, hyaluronic acid instillation and reversal of anticoagulation. second line treatments also include endo-vesical instillation of several compounds (e.g. aluminum compounds, silver or formalin) as well as transurethral surgery with laser or fulguration. in case of failure, third line options proposed include hyperbaric oxygen (hbo) or arterial embolization. in extreme cases a radical cystectomy with urinary derivation might be indicated (6-10). despite the variety of treatments available there is not a consensus about the best treatment to use in these cases (11). more recently, fg endo-vesical application seems to be a promising therapy for hc (12, 13). however, literature is limited to only two single center experiences (12, 13). thus, we aim to report results about efficacy and safety of fg therapy in patients with hc. materials and methods patients and study population we reviewed prospectively collected data from our instiobjectives: fibrin glue (fg) endo-vesical application seems to be a promising therapy for hemorrhagic cystitis (hc). we aimed to evaluate efficacy and safety of fg instillation in patients with hc. methods: patients with hc not responsive to conventional treatments (bladder irrigation, catheterization, blood transfusions, hyperhydration and endoscopic coagulation) were treated with fg endo-vesical instillation (april 2017december 2018). fg was prepared from 120 ml of patient blood with the vivostat® system. after standard cystoscopy, bladder was insufflated with carbon dioxide (co2) according to bladder compliance and autologous fg was applied to bladder wall and bleeding sites. results: ten patients included with grade 2 or higher hc secondary to bone marrow graft for hematological diseases (30%) or to actinic cystitis caused by prostate cancer radiotherapy (rt) (70%). the median hc onset time after rt was 4.8 (iqr 3.96.3) years and 35 (iqr 27.5-62.5) days after hematopoietic stem cell transplantation (hsct). five patients had a complete response after one treatment, three patients had clinical response (grade < 2 hematuria, amelioration of symptoms), one of them required catheterization and bladder irrigation. one patient required a second instillation of fg achieving a clinical response. no adverse events related to the procedure were recorded, however one patient died for causes not related to the procedure. median interstitial cystitis symptoms index was 13.0 (iqr 11.0-15.0) pre-operatively and 4.0 (iqr 2.0-5.0) post-operatively. conclusions: our study showed that, even in hematological patients, autologous fg instillation maybe a safe, repeatable and effective treatment modality in patients with refractory hc. key words: cystitis; radiation; radiotherapy; hemorrhagic cystitis; hemorrhagic cystitis therapy; fibrin glue therapy; actinic cystitis; hsct induced cystitis; hematuria; allogenic transplant. submitted 18 january 2021; accepted 10 march 2021 efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis: 12-months results. a promising therapy for hemorrhagic cystitis alessandra cassani 1, michele marchioni 1, francesco silletta 1, carlo d’orta 1, giulia primiceri 1, ambra rizzoli 1, patrizia di gregorio 2, sandra verna 2, annalisa natale 3, stella santarone 3, francesco berardinelli 1, luigi schips 1 1 “g. d'annunzio” university of chieti, dept. of medical, oral and biotechnological sciences, “ss. annunziata” hospital, urology unit, chieti, italy; asl abruzzo 2, department of urology, chieti, italy; 2 “ss. annunziata” hospital, chieti, italy; asl abruzzo 2, servizio di medicina trasfusionale ed ematologia aziendale ospedaliero centro emofilia 52, chieti, italy; 3 santo spirito hospital, pescara, department of hematology, bone marrow transplant center, pescara, italy. doi: 10.4081/aiua.2021.2.200 summary 201archivio italiano di urologia e andrologia 2021; 93, 2 efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis tutional dataset about patients with hc treated with fg between april 2017 to december 2018. our analyses included data about patients’ demographic (age, gender), condition that led to the hematuria (rt for prostate cancer, allogenic transplant for acute lymphoblastic leukemia, acute myeloid leukemia, hodgkin's lymphoma), time of hematuria onset (identified as the first episode of hematuria after rt or hematopoietic stem cell transplantation (hsct) after systemic chemotherapy treatment with busulfan 12.8 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2), rt type, treatment characteristics (management of the hematuria before the fg instillation), clinical response and toxicity. before treatment, all patients had urine culture test, bladder ultrasound, urine analysis, blood test and cystoscopy. all patients had hc grade 2 (8) or more no responsive to conventional therapy, namely catheterization with bladder irrigation, blood transfusions, hyperhydration and endoscopic coagulation. hc was classified in 4 stages. the subgroup of patients who developed hc after radiotherapy was also classified with the european organization for research and treatment of cancer/radiation therapy oncology group (rtog/eortc) grading of hematuria events due to radiotherapy (14). main classification are reported in table 1. the bladder capacity was evaluated during pre-operative cystoscopy identifying as maximum capacity the filling volume at which the patient felt pain. all the procedures were performed in operative room under loco-regional anesthesia. patients with positive urine cytology, bladder neoformation identified by imaging or during cystoscopy, with a suspect upper urinary tract tumor or any suspect of urothelial carcinoma in situ were considered not-eligible for the procedure and were not included in the current study. surgical procedure we performed a standard cystoscopy with an iglesias 22 ch cystoscope evaluating the bladder mucosa to rule out eventual bladder tumors and identify mucosal lesions. emptied bladder is then insufflated with carbon dioxide (co2) up to obtain a good distention of bladder wall, approximately 180-240 cc occur, according to bladder compliance. no continuous pressure flow was used, and small adjustment were possible thank to the use of a syringe filled with ambient air. good bladder distention is necessary to allow air spray of the fg, guarantee a good vision and prevent bleeding. under vision, the fg applicator is introduced through the cystoscope and autologous fg is applied to the bladder wall with specific care of bleeding sites. the fg instillation procedure usually last approximately 30 minutes. fibrine glue (fg) was prepared with the vivostat® system (vivolution a/s, birkerod, denmark). vivostat® is automated medical device for production and application of a fibrine sealant, it produces protein components of fibrine gel sealant from patient’ own plasma with no risk of infections related to non-autologous plasma sources. the vivostat® system creates from 120 ml of the patient’ blood a concentrated fibrine i solution. the solution is then applied with a ph 10 neutralizing solution in a 7:1 ratio to produce fibrine sealant. the process takes 30 minutes to obtain a syringe of fibrin i solution at a ph of 4.4. the vivostat® application system is composed by an applicator (the mechanical and electronic working part of the system) and a single-use spraypen®. when activated fibrin i and neutralizing solution are delivered in a stream of compressed air forming a fine low-pressure spray of fibrin sealant (12, 13, 15). outcomes measurement patients response was classified as: complete response (no hematuria and no luts); clinical response (absence or amelioration of dysuria, urgency, and frequency, no further need of analgesic medication, persistent hematuria grade < 2) and no response (no clinical response, persistent hematuria grade ≥ 2). full blood count was performed preoperatively and on day 1 to 3. each patient was investigated with interstitial cystitis symptoms index (icsi) (16) pre and postoperative at follow-up. patients were followed by telephone at 3 and 12 months to assess icsi and their bladder status. statistical analyses descriptive analyses were employed. qualitative variables were reported as absolute and relative frequencies (%). quantitative variables were reported as median and interquartile range (iqr). wilcoxon test for paired data tested the hypothesis that the median icsi was higher before the treatment than after. a level of statistical significance was set at p < 0.05. analyses were performed using the r software environment for statistical computing and graphics (version 3.6.1; http://www.rproject.org/). table 1. classification systems. rtog/eortc hc grading hc grading icsi score grade i slight epithelial atrophy minor telangiectasia (microscopic hematuria) microscopic hematuria mild symptoms 0-6 grade ii moderate frequency generalized telangiectasia intermittent macroscopic hematuria macroscopic hematuria moderate symptoms 7-14 grade iii severe frequency and dysuria severe generalized telangiectasia (often with petechiae) hematuria with clots requiring transfusion support severe symptoms 15-20 frequent hematuria reduction in bladder capacity (< 150 cc) grade iv necrosis/contracted bladder (capacity < 100 cc) severe hemorrhagic cystitis macroscopic hematuria with clots and impaired renal function -grade v death for uncontrolled hematuria --hc: hemorrhagic cystitis; eortc: european organization for research and treatment of cancer/rtog: radiation therapy oncology group grading of hematuria events due to radiotherapy; icsi: interstitial cystitis symptoms index. archivio italiano di urologia e andrologia 2021; 93, 2 a. cassani, m. marchioni, f. silletta, et al. 202 results a total of 10 patients were treated. the 30% (n = 3) had hc secondary to bone marrow graft for hematological diseases after systemic chemotherapy treatment, the remaining 70% (n = 7) were diagnosed with actinic cystitis due to prostate cancer rt. the median age was 70 years (iqr 49.0-81.8). in the hematological patients median age was 45 years (iqr 36.0-45.5), while in the radio therapy patients group the median age was 75 years (iqr 70.0-84.5). the median onset time of hematuria was 4.8 (iqr 3.9-6.3) years after rt and 35 (iqr 27.5-62.5) days after hematological treatment. main preoperative and post-operative laboratory findings are reported in table 2. of all, 5 patients (55%) had a complete response (no hematuria or other symptoms), 3 patients (33%) had only clinical response (improvement or absence of symptoms, grade < 2 hematuria) and one of them required catheterization and bladder irrigation. three patients required blood transfusions. one patient died immediately after the loco-regional anesthesia for complications not related to the procedure. only one patient needed a second fg instillation eleven days after the first one, due to grade 3 hematuria and achieving a clinical response after the second instillation dose. median hospital stay was 3 (iqr 1-6) days. no adverse events related to the procedure were recorded. moreover, we recorded a reduction of the median icsi after treatment. indeed, the median icsi was 13.0 (iqr 11.0-15.0) pre-operatively and 4.0 (iqr 2.05.0) postoperatively (p = 0.02). during the median follow up of 12 months, two patients died due to the progression of their hematological condition. none of the others required additional treatment for hematuria. descriptive features and results of included patients are reported in table 3. discussion hemorrhagic cystitis is a urological condition that can meaningfully affect patients’ quality of life. several thertable 3. descriptive features of included patients treated with endovesical instillation of vivostat®. age grade of rtog/ primary cause time from prior intravesical grade of rtog/ response hospital icsi icsi hc pre eortc pre of hc hc onset management hematuria (post-op) eortc post al stay days pre post 1 58 2 3 pc imrt hyperhydration 0 0 complete 2 9 5 2 86 4 4 pc imrt 1 year bladder irrigation, 0 0 complete 3 11 2 catheterism, blood transfusions 3 75 3 4 pc imrt bladder irrigation, 3 3 clinical 26 --catheterism, 1 after 1 after 2 blood transfusions ii treatment ii treatment instillations 4 85 2 3 pc imrt 11 years catheterism 0 0 complete 3 uc uc 5 27 3 -lla hsct 35 days catheterism, bladder irrigation 1 -clinical 1 19 1 6 45 2 -lh hsct 3 months catheterism 0 -complete 1 --7 84 3 4 pc imrt 5 years catheterism, blood transfusions ----12 --8 46 3 -lma hsct 20 days bladder irrigation, 0 -clinical 1 15 13 hyperhydration 9 65 3 3 pc imrt 5 years catheterism, bladder irrigation 0 0 complete 4 uc uc 10 75 3 3 pc imrt bladder irrigation, 1 1 clinical 4 13 4 catheterism hc: hemorrhagic cystitis; eortc: european organization for research and treatment of cancer/rtog: radiation therapy oncology group grading of hematuria events due to radiotherapy; pc: prostate cancer; all: acute lymphoblastic leukemia; hl: hodgkin’slymphoma; aml: acute myeloid leukemia; imrt: intensity modulated radiation therapy; hstc: hematopoietic stem cell transplantation after chemotherapy treatment with busulfan, thiotepa and fludarabine; complete: complete response (no hematuria or other symptoms); clinical: clinical response (amelioration or absence of symptoms, grade < 2 hematuria); uc: urinary catheter in situ. table 2. preoperative and postoperative (at discharge) patients’ blood count. preoperatively postoperatively red blood cells hemoglobin hematocrit platelets count red blood cells hemoglobin hematocrit platelets count count (*106/mm3) (g/dl) (%) (*103/mm3) count(*106/mm3) (g/dl) (%) (*103/mm3) 1 4.74 13.8 48 201 4.5 13.7 43 150 2 4.04 12.8 44 220 4 12.4 40 200 3 2.97 8.4 28.3 273 2.99 8.6 27.9 254 4 4.53 13.7 41.8 180 3.95 11.4 35.4 229 5 2.91 8.9 24.7 39 2.93 8.9 25.2 56 6 2.76 8.9 24 46 2.85 8.7 24 37 7 3.15 9.8 31.3 273 // // // // 8 2.87 9.1 25.6 25 2.79 7.7 22.1 37 9 4.63 12.7 38.7 476 4.63 12.7 38.7 476 10 4.14 13.2 41 238 3.79 12.1 36.7 237 median 3.59 (iqr2.92-4.43) 9.8 (iqr 8.9-13.2) 35 (iqr 26.3-41.6) 210 (iqr 79.5-264.2) 3.79 (iqr 2.96-3.975) 10.15 (iqr 8.675-12.25) 35.4 (iqr 25.2-38.7) 200 (iqr 56-237) 203archivio italiano di urologia e andrologia 2021; 93, 2 efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis apeutic options are available for hc treatment, however neither aua nor eau defined specific guidelines for the treatment of hc (11, 17). the treatment paradigm includes as first line treatment a noninvasive procedure attempting to reduce hematuria while supporting patients’ general condition, such as hyperhydration, blood transfusion, transurethral three-way catheterization, and continuous bladder irrigation (6). in our study we investigated the results that could be obtained with the use of fg in hc patients’ treatment after that first line treatments have failed. our results showed that a good bleeding control could be achieved with fg endo-vesical instillation with no adverse events, no major complication as ureteral orifice closure and hydronephrosis were recorded in our experience. in case of injection near the ureteral orifice the use of a ureteral open-end catheter is recommended to reduce the risk of iatrogenic ureteral occlusion. moreover, our results suggest that the use of fg endo-vesical instillation is related with a meaningful improvement in quality of life as proven by the improvement in icsi score. moreover, our study showed that the procedure is repeatable and that results are reliable over time as showed by our relative long follow-up of approximately 12 months. the use of fg as a hemostatic agent have been previously studied in urological surgery and the use of the vivostat® system have been proven to be effective and safety when applied to urological surgery, in particular to prevent bleeding in renal surgery and lymphatic leakage in lymphadenectomy (18-21). however, only few studies investigated its use for the treatment of hc. specifically, bove et al. have investigated the effectiveness of fg treatment in patients with actinic cystitis with hematuria refractory to standard treatment. their experience was based on a series of 20 patients who developed hc following rt for different types of pelvic cancer: bladder cancer (30%), prostate cancer (35%) or gynecological cancer (35%) (13). they concluded that the endoscopic application of fg is a safe and effective therapeutic alternative for the treatment of hc refractory to conventional therapy because fg adheres tenaciously to the damaged mucosa, prevents the worsening of the inflammatory process from urine exposure and allows the tissue repair process. the endo-vesical application during cystoscopy allows a better view of the bleeding points and a better adhesion of the glue to the damaged mucosa due to the constant intravesical pressure (13). unfortunately, bove and colleagues included only patients with actinic cystitis, conversely in the current report we also included patients with hc related to hematological conditions. this is of importance since the hc related to allogeneic hematopoietic cell transplantation negatively affects patient’s quality of life with an increased risk of death (22, 23). currently its therapy was studied by tirindelli et al. (12) on 35 patients who developed grade > 2 hc not responsive to conventional therapy. complete remission, defined as a regression of all symptoms and the absence of hematuria, was achieved in 100% of the cases at 7 days and 83 ± 7% at 50 days from the fg's instillation. the 6-month survival rates of patients with hc was 49 ± 8% overall. instead, if we consider only patients with complete clinical remission the 6-month survival rates were 59 ± 9%. the results of this study suggest that the endoscopic application of fg should be considered a safe, non-invasive, easily repeatable, and inexpensive option for the management of hc in fragile and immunocompromised patients. when considering other options, hyperbaric oxygen hbo is a widely used treatment. however, success rates are lower than ours (34-87.5% vs. 88% of our experience) with fg (6). browne et al. in a literature review reported a successful rate without recurrences of 74% after hbo. they also reported that the main complication of this treatment was otalgia, occurred in 33% of patients (7). intravesical instillation of various substances such as formalin, aluminum salts or hyaluronic acid is also reported. for instance, pascoe et al. reported a success rate instillation therapy with formalin of 6090% vs. 88% of our experience. however, authors reported serious side effects related to the use of formalin, including death in 2-4% of the cases. more specifically, browne et al. also demonstrated the danger of formalin by recording adverse events, such as bilateral hydronephrosis with anuria, vesico-vaginal fistula, and death in 30% of patients. the same study showed a success rate with hyaluronic acid instillation of 97% (7). conversely, we reported no adverse events directly related to treatment. the only death reported was due to the general compromitted status of the patient and not to the fg application. aluminum salts were also used. however, its use is considered less effective than other endo-vesical treatment, but it is also affected by side effects: 38% of patients showed bladder spasms, transient delirium, urinary tract infections. the success rate was 60% (only 54% of responders had a durable response). imperatore et al. described the use of hyaluronic acid and chondroitin sulfate endo-vesical instillation treatment in 20 patients with refractory bacillus calmette-guerin (bcg) induced chemical cystitis. the study showed an improvement in terms of bladder pain, urinary urgency, urinary volume per void and urinary frequency. the clinical efficacy described in 19/20 patients had a statistically significative improvement durable in time with a permanence of benefit up to one year after therapy suspension (vas score on bladder pain and urgency significantly decrease from the baseline; mean number of voids/24 hour and mean urinary volume per void significantly improved from the baseline p < 0.05 with respect to baseline in both cases) (24). in a recent study masieri et al. analyzed the use of platelet-rich plasma (prp) in patients with hc after hsct, they showed an alternative endo-vesical autologous instillation therapy to treat hc in hematological patients. they studied 10 patients with hc post hstc related to bk virus infection, all patients underwent prp instillation after electrocoagulation of the bleeding areas. no intraoperative complications were recorded, postoperative complications clavien-dindo grade ii occurred in 6 patients: 3 patients required additional blood transfusion, 3 patients required antibiotic therapy. one patient was readmitted for massive hematuria. 6 patients archivio italiano di urologia e andrologia 2021; 93, 2 a. cassani, m. marchioni, f. silletta, et al. 204 had complete response, 3 partial response and one no response. it seems to be a promising treatment option but related to a higher risk of complication compared to our technique with a similar success rate but in a highly selected group of patients (25). in summary our study showed that the use of fg in hc patients is safe and effective with higher success rates and lower complications than other second line treatments. despite the limited number of patients and the lack of a control group, in our study we point out that fg treatment is a promising treatment option also in the group of hematological patients with hc. the main limitation of our study is the small number of patients included and the absence of a control group. in consequence, we are not able to infer if the use of fg treatment could lead to better result than any other conservative treatment and future prospective multicenter study are warrant. however, the same limitation applies also to other studies that included only few more patients. in addition, due to the small number of patients included we were not able to test the effect of fg treatment on hc in analyses adjusted for possible confounders, such as age or primary cause of hc. it might be possible that the effect of fg might differ based on the baseline characteristics of included patients as a consequence of the compound interaction with the host environment. it is also possible that the coagulation cascade promotion based on fg effect might differ in younger vs. older patients. future studies should investigate also molecular aspects of fg instillation. furthermore, we evaluated patients’ quality of life with icsi score. however, other more specific scores about the quality of life in patients affected by malignancy (such as the epic score) would be more insightful (26). in future studies it should be included and evaluated to better clarify patients’ quality of life. finally, we investigated only the clinical presentation of hc without any molecular or laboratory tests that could shed a light on the pharmacodynamic of fg application in hc cases. indeed, literature is poor of evidence in this field and future studies should focus also on these aspects. conclusions autologous fg may be a safe and effective noninvasive and repeatable treatment modality in patients with refractory hc. our report showed its efficacy also in patients treated after hc related to hematological conditions treatments and was no related to any adverse event. authors’ contribution we would like to thank all the urologists m. marchioni, f. silletta, c. d’orta, g. primiceri, a. rizzoli, f berardinelli, l schips that recruited the urological patients, performed the surgical procedures and followed them during the follow-up. they also helped with the drafting of this manuscript. thanks to the hematologist s. santarone and a. natale that recruited and followed the hematological patients during the follow-up, also for the contribution with the processing of the manuscript regarding the hematological therapies and pathologies. thanks to the laboratory doctors p. di gregorio and s. verna that helped us with the preparation of the fg solution from patients own plasma. all authors read and approved the final version of the manuscript. references 1. hemorrhagic cystitis american urological association. available from: https://www.auanet.org/education/auauniversity/ education-products-and-resources/pathology-for-urologists/urinary-bladder/cystitis/hemorrhagic-cystitis. 2. galla a, maggio a, delmastro e, et al. salvage radiation therapy after radical prostatectomy: survival analysis. minerva urol nefrol. 2019; 71:240. 3. antonelli a, palumbo c, noale m, et al. and the pros-it cnr study group. overview of potential determinants of radical prostatectomy versus radiation therapy in management of clinically localized prostate cancer: results from an italian, prospective, observational study (the pros-it cnr study). minerva urol nefrol. 2020; 72:595-604. 4. corman jm, mcclure d, pritchett r, et al. treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. j. urol. 2003; 169:2200–2202. 5. alesawi am, el-hakim a, zorn kc, et al. radiation-induced hemorrhagic cystitis: curr. opin. support. palliat. care. 2014; 8:235-240. 6. pascoe c, duncan c, lamb bw, et al. current management of radiation cystitis: a review and practical guide to clinical management. bju int. 2019; 123:585-594. 7. browne c, davis nf, mac craith e, et al. a narrative review on the pathophysiology and management for radiation cystitis. adv urol. 2015; 2015:1-7. 8. dautruche a, delouya g. a contemporary review about the management of radiation-induced hemorrhagic cystitis: curr opin support palliat care 2018; 12:344-350. 9. mangano ms, de gobbi a, ciaccia m, et al. actinic cystitis: causes, treatment and experience of a single centre in the last five years. urol j. 2018; 85:25-28. 10) calderone ce, lerner sp, taylor jm. the case for salvage cystectomy after pelvic radiation. minerva urol nefrol. 2016; 68:161-71. 11. update series (2015) lesson 3: management of emergency bleeding, recalcitrant clots and hemorrhagic cystitis | aua university. available from: https://auau.auanet.org/node/4709. 12. tirindelli mc, flammia gp, bove p, et al. fibrin glue therapy for severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. biol. blood marrow transplant. 2014; 20:1612-1617. 13. bove p, iacovelli v, tirindelli mc, et al. endoscopic intravesical fibrin glue application in the treatment of refractory hemorrhagic radiation cystitis: a single cohort pilot study. j endourol. 2019; 33:93-98. 14. cox jd, stetz j, pajak tf. toxicity criteria of the radiation therapy oncology group (rtog) and the european organization for research and treatment of cancer (eortc). int j radiat oncol biol phys. 1995; 31:1341-1346. 15. dodd ra, cornwell r, holm ne, et al. the vivostat application system: a comparison with conventional fibrin sealant application systems. technol health care. 2002; 10:401-11. 16. o’leary mp, sant gr, fowler fj, et al. the interstitial cystitis symptom index and problem index. urology. 1997; 49:58-63. 205archivio italiano di urologia e andrologia 2021; 93, 2 efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis 17. engeler d, baranowski ap, berghmans b, et al. eau guidelines on chronic pelvic pain 2020. in: european association of urology guidelines. 2020 edition. european association of urology guidelines office, 2020, arnhem, the netherlands. 18. schips l, dalpiaz o, cestari a, et al. autologous fibrin glue using the vivostat system for hemostasis in laparoscopic partial nephrectomy. eur urol. 2006; 50:801-805. (19. gidaro s, cindolo l, lipsky k, et al. efficacy and safety of the haemostasis achieved by vivostat system during laparoscopic partial nephrectomy. arch ital. urol androl. 2009; 81:223-227. 20. farouk a, tawfick a, reda m, et al. fibrin glue as a sealant in stentless laparoscopic pyeloplasty: a randomised controlled trial. arab j urol. 2019; 17:228-233. 21. garayev a, aytaç ö, tavukcu hh, et al. effect of autologous fibrin glue on lymphatic drainage and lymphocele formation in extended bilateral pelvic lymphadenectomy in robot-assisted radical prostatectomy. j. endourol. 2019; 33:761-766. 22. seber a, shu x, defor t, et al. risk factors for severe hemorrhagic cystitis following bmt. bone marrow transplant. 1999; 23:35-40. 23. leung a, mak r, lie a, et al. clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. bone marrow transplant. 2002; 29:509-513. 24. imperatore v, creta m, di meo s, et al. intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus calmetteguerin induced chemical cystitis: preliminary experience with oneyear follow-up. arch ital urol androl. 2018; 90:11-14. 25. masieri l, sessa f, mari a, et al. intravesical application of platelet-rich plasma in patients with persistent haemorrhagic cystitis after hematopoietic stem cell transplantation: a single-centre preliminary experience. int urol nephrol. 2019; 51:1715-1720. 26. sosnowski r, kulpa m, kosowicz m, et al. basic methods for the assessment of health-related quality of life in uro-oncological patients. minerva urol nefrol. 2017; 69:409-420. correspondence alessandra cassani, md alessandra.cassani@yahoo.com michele marchioni, md mic.marchioni@gmail.com francesco silletta francescosilletta1@gmail.com carlo d’orta, md dortacarlo.8@gmail.com giulia primiceri giulia.primiceri@gmail.com ambra rizzoli ambrarizzoli@libero.it francesco berardinelli, md berardinelli.francesco@gmail.com luigi schips, md luigischips@hotmail.com “g. d’annunzio” university of chieti, dept. of medical, oral and biotechnological sciences, “ss. annunziata” hospital, urology unit, chieti (italy); asl abruzzo 2, dept. of urology, chieti (italy) patrizia di gregorio, md patrizia.digregorio@aslabruzzo2.it sandra verna, md sandra.verna@aslabruzzo2.it “ss. annunziata” hospital, chieti, italy; asl abruzzo 2, servizio di medicina trasfusionale ed ematologia aziendale ospedaliero centro emofilia 52, chieti (italy) annalisa natale, md annalisa.natale@gmail.com stella santarone, md stella.santarone@virgilio.it santo spirito hospital, pescara, department of hematology, bone marrow transplant center, pescara (italy) cop+ed+fisse 2006 107archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.107 introduction peyronie’s disease (pd) is a benign condition causing penile deformities, shortening, loss of penile flexibility and sexual dysfunctions (1). the diagnoses are increasing in number, even in the younger population, because of the increased knowledge about the topic (2). surgical treatment remains the gold standard and it includes penis plication, grafting, and placement of inflatable prosthesis with the aim to restore coital functions (3). buccal mucosa grafts (bmg) provided excellent shortterm results, suggested by the early recovery of spontaneous erections and the prevention of late shrinkage, which is the main cause of graft failure. it also seems to be safe and reproducible, thus representing a valuable treatment option for pd. clinical series are limited yet but functional and cosmetics results are very promising (4). we analyzed our surgical results with the bmg technique applied to 27 patients focusing on the ultrasonographic follow-up and clinical data. methods from our surgical data base, we evaluated 27 consecutive cases treated with a plaque incision and bmg to correct the secondary penile curvature due to pd. clinical, postsurgical and ultrasound follow up data were evaluated. all patients were no responders to medical treatment or previous surgical procedures. the evaluation period was 72 months. data regarding pre-operative work-up, including iief (iief-5) questionnaire administration, detailed clinical history and penile dynamic ultrasound (pge1-induced erection) features were collected (5, 6). the surgical procedures were done previous penile degloving and using a relaxing incision (double y or h shaped) at the point of maximum curvature on the penis. the albuginea defects were covered using bmg grafting introduction: plaque incision and grafting represent the best surgical approach to the peyronie’s disease (pd). the grafting procedures must be restricted to patients with normal preoperative status, excessive curvature and/or deformities. however, the ideal graft has not been identified yet. buccal mucosa grafts (bmg) provided excellent short-term results, ensuring the fast return of spontaneous erections and preventing shrinkage, which is the main cause of graft failure. another fearsome surgical complication is de novo erectile dysfunction (ed). we report our results with bmg focusing on the analysis of ultrasonographic and clinical data demonstrating buccal mucosa as determinant factor that allow to avoid complications. materials and methods: from 2013 to 2019 we performed at our urology unit 27 corporoplasties with bmg to correct complex penile curvature due to pd. clinical, post-surgical and ultrasound follow up data were evaluated. all patients were no responders to medical treatment or previous surgical procedures. the evaluation period was 72 months. data regarding pre-operative work-up, including iief (iief-5) questionnaire administration, detailed clinical history and penile dynamic ultrasound (pge1-induced erection) were collected. the time of spontaneous erection resumption was recorded for each patient. to improve blood supply to the graft, a low-dose pde5-i was prescribed for all patients for a period of two months, starting immediately after discharge. check-ups were scheduled every 3 months, starting from 1 month after surgery. in each visit, patients underwent a penile ultrasound evaluation of graft features. after 6 and 12 months, all patients underwent a penile dynamic ultrasound for erection hardness score determination, then standard ultrasound and clinical evaluation yearly. our analyses were focused on bmg as a major determinant of the surgical success. results: mean age of 27 patients was 57 years (42-71) with a maximum follow up time of 72 months and minimum of 3. site of penile curvature was dorsal in 18 (67%) patients, ventral in 2 (7%), complex in 7 (26%). the degree of the curvature was < 60° in 11 (41%) patients, > 60° in 16 (59%). straightening of penis was reached in 100% of cases. penile shortening resulted in 7.4% (2/27). de novo ed appeared in 2/27 cases with a post-operative rate of pde5i users increasing from 12 to 14 patients (45% vs 52%). ultrasound aspects of bmg, recorded at every follow up visit, results in a hypoechoic plaque with an iperechoic rim that become isoechoic over the time in all cases. no case of scars or seroma was registered. small intra-graft cystic lesions were highlighted in 3 cases (11%). conclusions: bmg may represent a good choice in grafts probuccal mucosa graft in surgical management of peyronie’s disease: ultrasound features and clinical outcomes summary andrea fabiani 1, fabrizio fioretti 1, maria pia pavia 2, luca lepri 1, emanuele principi 1, lucilla servi 1 1 urology unit, surgical department, asur marche area vasta 3, macerata, italy; 2 resident, division of urology, marche polythecnic university, ancona, italy. presented at the sieun congress ancona 30 november 1 december 2020 cedures for pd surgical management. the functional results obtained by bmg procedures were related to the good anatomical characteristics of the patch and were highlighted in our series by use of penile ultrasound, during the follow up period. key words: peyronie’s disease; buccal mucosa; ultrasound; graft; erectile dysfunction. submitted 13 january 2021; accepted 27 january 2021 archivio italiano di urologia e andrologia 2021; 93, 1 a. fabiani, f. fioretti, m.p. pavia, l. lepri, e. principi, l. servi 108 technique (7, 8). the buccal mucosa grafts were harvested as described by eppley et al. (9). after “defatting”, bmg was apposite to cover the albuginea defect with the submucosa surface in contact with the cavernous tissue in order to obtain a quick blood supply and sutured with a 3/0 adsorbable running sutures (maxontm) in each side (figure 1). artificial erection was repeated to evaluate the curvature and deformity correction, defining the need of complementary tunica albuginea plications (10). buck’s fascia was accurately closed with interrupted adsorbable suture, especially in correspondence with the patch site to avoid patch enlargement. in cases of ventral curvatures, urethra was fixed to corpora cavernosa with a tension-free stitches. a small drainage was placed between the buck’s fascia and the dartos. circumcisional incision was closed and dressed. patients were discharged at third post-operative day after catheter, drainage and dressing removal. the time of spontaneous erection resumption was recorded for each patient. to improve blood supply to the graft, a lowdose pde-5 inhibitor (pde-5i) was prescribed for all patients for a period of two months, starting immediately after discharge. check-ups were scheduled every 3 months, starting from 1 month after surgery. in each visit, they underwent a penile ultrasound evaluation of graft features. after 6 and 12 months, all patients underwent a penile dynamic ultrasound for erection hardness score determination, then standard ultrasound and clinical evaluation yearly. all consecutive cases who underwent bmg in a 72-month period of time were analyzed. we studied the ultrasonographic appearance of the bmg at 1, 3, 6 and 12 months after surgery and yearly cosmetics and functional outcomes. results we performed 27 procedures in men with mean penile curvature of degree 61.9° (range 45°-90°), mean age 57 years (42-71) and after mean follow-up of 28.3 months (min 3 max 72). the degree of the curvature was < 60° in 11 (41%) patients, > 60° in 16 (59%). site of penile curvature (degree 61.9° in mean; range 45°-90°), was dorsal in 18 (67%) patients, ventral in 2 (7%), complex in 7 (26%). pre-operative data and results are summarized in tables 1, 2. the patient medical history was characterized from different comorbidities recognized as erectile dysfunction (ed) risk factors. diabetes mellitus was reported in 4 (14.8%) patients; cardiovascular disease in 2 (7.4%), previous radical prostatectomy in 4 (14.8%), preputial lichen sclerosis in 2 (7.4%) and psoriasis in 1. one patient had a failed plication procedure. pre-operative use of pde-5i was referred by 12 patients (45%). pre-operative iief score was 22.5 in mean (11-24). after a follow up period of 28.3 months (3-72), we reported a functional straightening of penis reached in 100% of cases. penile shortening resulted in 7.4% (2/27). all patients had complete spontaneous erections in a period of 1 to 7 days after surgery, however paraphimosis occurred in three cases (14.2%), requiring surgical revision, and one patient (4.7%) develop skin preputial necrosis managed by topical therapy. post-operative mean iief score, at the last follow up was 23.1 (1524). de novo ed appeared in 2/27 cases. post-operative amount of pde5i users increasing from 12 to 14 patients (45% vs 52%). ultrasound was applied at each follow-up visit. ultrasound features during follow up are showed in table 1. salient pre-operative clinical data. number of patients 27 (100%) age (years) 57 (42-71) penile curvature degree pre-op 61.9°(45-90) duration of pd (months) 16.5 (6-48) iief score pre -operative 22.5 (18-24) curvature side dorsal 18 (67%) ventral 2 (7%) complex 7 (26%) pde5i use pre-op 12 (45%) diabetes mellitus 4 (14.8%) previous pd surgery 1 (3.8%) previous radical prostatectomy 4 (14.8%) dupuytren disease associated 1 (3.7%) psoriasis 1 (3.7%) preputial lichen sclerosus 2 (7.4%) cardiovascular disease 2 (7.4%) table 2. results and complications. results (range; %) mean follow up time (months) 28.3 (3-72) time of spontaneous erections resumption (days) 3.2 (1-7) iief score post operative at last follow up 23.1 (15-24) pde5i post operative use 14 (52%) functional penile straightening 27 (100%) penile shortening 2 (7.4%) complications hemorrage at the donor site 1 (4.7%) penile shaft hematoma 1 (4.7%) glandular erection pain 1 (3.7%) preputial edema 4 (14.8%) skin necrosis 1 (3.7%) cystic intra-graft lesions 3 (11%) penile abscess 1 (3.7%) recurvatum relapse 0 (0%) de novo erectile dysfunction 2 (7.4%) figure 1. surgical steps for bmg procedures in a case of ventral curvature. a. buccal mucosa graft harvesting; b. idraulic erection after penile degloving; c. urethral isolation; d. marked transversal incision (double y) on the plaque; e. buccal mucosa grafting; f. final result. figure 2a, b and figure 3. in all cases, post-operative images consisted in a hypoechoic plaque with hyperechoic rim, observed in the graft area during the first month after surgery. progressively, we described the ultrasound disappearance of graft, which has become isoechoic respect the tunica albuginea and not distinguishable from albuginea rim. no case of scars or seroma was registered. small intragraft cystic lesions highlighted in 3 cases (11%). discussion severe pd (> 60°) is still treated by surgical approach that leads an efficient solution in a relatively short time (11). in spite of this, results are not devoid of complications, the most serious is the development of de-novo ed, which seems to be caused by complete surgical excision of the plaque (12). nowadays, plaque incision surgery with grafting is the preferred therapeutic approach (3, 8). in 2005, buccal mucosa was introduced as free autograft in the surgical treatment of pd (13) and then, during the years, evaluated in several others series (14-19). promising results were reported by shioshvili et al. (13) who observed the complete straightening of penis in 92.3% of 26 patients treated with a residual curvature (< 10°) in 7.7%. the shortening of penis was observed in four patients (15.4%) and in two patients (7.7%) a partial reduction of erectile function. they concluded that buccal mucosa showed high properties of adaptation and revascularization, good anatomical and functional clinical results, demonstrating a stable elasticity without late shrinkage. similarly, liu et al. (14) showed that buccal mucosa remained stable with good elasticity over time. they performed replacing the plaque by free autograft of buccal mucosa on 24 patients and obtained satisfactory results: complete penile straightening was achieved in 21/24, slight residual curvature (< 15 degrees) noted in 3 (12.5%), a little shortening of the penis (< 1 cm) in 2 (8.3%). as advancement in term of prevention of de novo ed, cormio and co-workers (15) introduced important technical modifications consisting in the plaque incision instead of excision. bmg was performed similar than others series. in 15 consecutive surgical procedures they reported a 100% of penile straightening, no curvature recurrence and any de novo ed. these results were confirmed by zucchi et al. (16) in 32 patients treated with plaque incision and bmg between 2006 and 2013: in 28 cases, they reported one curvature relapse after 1 year (3.5%) and an immediate significant improvement of iief scores in half of cases, although after 2 years the trend was in reduction. they concluded that corporoplasty with buccal mucosa represent a good treatment choice for most forms of pd. the complete penis straightening was achieved in 73% of 33 patients by gvasalia et al. (17), however a residual curvature (< 20°) was observed in 27% and de novo ed in 18%, commonly in elderly patients, but with a good response to pde-5i. molina-escudero et al. (18) reported the short-term results (penile length, angle of curvature and erectile function) of 10 patients treated through corporoplasty with oral mucosa graft. the straightening of penis was reached in 100% with a shortening rate of 80% and 10 % of de novo ed. in our previous experience with 17 cases (19), we reported favorable results. in this series, that take account of 10 more patients passing from 17 to 27 cases, we have similar results with a longer follow-up. all the procedures were performed as the main indication the failure or inability to sexual intercourse and psychological impairment due to the penile curvature. patients are variably aging, with a medical general history characterized from different comorbidities as, in example, diabetes mellitus, cardiovascular disease, previous pelvic surgical procedure for prostate cancer (table 1). one patient underwent a previous failed plication procedure. pre-operative use of pde5 inhibitors was referred by 12 patients (45%). recognized that several patients had more risk factors of post-operative ed (baseline sexual function, age, graft size or position) (12), the probability of de novo ed should be higher, than that observed. we obtained a very good functional results with 7.4% of de novo ed and a post-operative increase of pde5i users to 52% from 45%. in literature the rate of de novo ed ranges between 0% to 18%. these results may be explained by the nature of buccal mucosa that is a living 109archivio italiano di urologia e andrologia 2021; 93, 1 buccal mucosa and peyronie’s disease figure 2. a. ultrasound patch (white arrow) appearance 3 months after surgery. b. ultrasound patch (green arrow) appearance after surgery (6 months). figure 3. complete patch disappearance in ultrasound evaluation (star; 6 years after surgery). figure 4. small intra-patch cystic lesion. archivio italiano di urologia e andrologia 2021; 93, 1 a. fabiani, f. fioretti, m.p. pavia, l. lepri, e. principi, l. servi 110 tissue with an elevated binding capacity and revascularization which is immediately supplied with blood from the cavernous tissue. in this way, buccal mucosa tends to heal rapidly, immediately integrating with the surrounding albuginea tissue. this translates into a more rapid resumption of spontaneous erections (mean of 3,26 days in our experience) and sexual activity and into a reduced risk of curvature relapse (20). penile ultrasound validated these results showing the process of mucosal patch integration with tunica albuginea. ultrasound has been showed to be a method of choice because his cost effectiveness, repeatability and low invasiveness, if compared to others methods (ie. magnetic resonance) (21). us is mainly used in diagnosis and staging of pd. there are only few reports regarding the ultrasound usefulness in the follow up after treatment. in relapses or in dilations patch evaluation, ultrasound is still decisive (22). in our series, us showed that bmg appears initially as hypoechoic plaques with hyperechoic rim (figure 2a, b) and then evolved in isoechoic over the time. after six years from surgical procedure, we reported a complete disappearance of the patch aspect, confounded with the albuginea (figure 3). no cases of scars, and consequently, of curvature relapse, or seroma were registered. small intra-graft cystic lesions highlighted in 3 cases (11%) (figure 4). any patch bulging has been reported yet.the perfect seal of bmg and the accurate closure of buck’s fascia are important key-factors to obtain a successful result. the biologic characteristics of buccal mucosa reduced the risk of curvature relapse as demonstrated by the high rate of penile straightening reported in 100% in our series while is 87.5-100% in literature. patch ultrasound evaluation confirm these aspects and it is needed in the surgical management of pd. conclusions the functional results obtained by bmg procedures in pd surgical treatment were related to the great anatomical characteristics of the patch and highlighted in our series by use of penile ultrasound during the follow up period. ultrasound features confirmed the characteristics of buccal mucosa as perfect seal in the tunica albuginea defect, created after fibrotic plaque incision, allowing to reduce the risk of de novo ed. references 1. hatzimouratidis k, et al. eau giudelines on erectile dysfunction, premature ejaculation, penile curvature and priapism. 2018. 2. paulis g., cavallini g., barletta d. et al. clinical and epidemiological characteristics of young patients with peyronie’s disease: a retrospective study. res rep urol. 2015; 7:107-111. 3. hatzimouratidis k, hatzichristou dg. plaque incision and grafting represents the best surgical approach to peyronie’s disease patient: con. current sexual health reports. 2006; 3:56-60. 4. garcia gomez b, ralph d, levine l, et al. grafts for peyronie’s disease: a comprehensive review. andrology. 2017; 6:117-126. 5. martino p, galosi ab, bitelli m, et al. practical 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peyronie's disease. j sex med. 2014; 11(suppl 1):33. 18. molina escudero r, alvarez-ardura m, redon-galvez l, et al. cavernoplastia con injerto de mucosa oral para el tratamiento quirurgico de la enfermedad de la peyronie. actas urologicas espanolas. 2016; 40:328-332. 19. fabiani a, servi l, fioretti f, et al. buccal mucosa is a promising graft in peyronie’s disease surgery. our experience and a brief literature review on autologous grafting materials. arch ital urol androl. 2016; 88:115-121. 20. costantini e, zucchi a. reconstructive surgery in peyronie’s disease: what’s new? world j clin urol. 2015; 4:1-4. 21. dell'atti s, manno s, scarcella, et al. analysis of penile ultrasound in peyronie disease: variability and interpretation of sonographic patterns.european urology supplements. 2018; 17:e2751. 22. rolle l, tamagnone a, bollito e, et al. could plaque excision surgery with sis graft induce a new fibrotic reaction in la peyronie’s disease patient? arch ital urol androl. 2007; 79:167-169. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it fabrizio fioretti, md fa.fioretti@libero.it lepri luca, md luca.lepri@sanita.marche.it emanuele principi, md emanuele.principi@sanita.marche.it lucilla servi, md lucilla.servi@sanita.marche.it urology unit, surgical dpt, asur marche area vasta 3, macerata (italy) maria pia pavia, md mariapia.pavia@gmail.com resident, division of urology, marche polythecnic university, ancona (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper tectomy have long been considered the historical gold standard for bpo with prostate volume less and over 80 ml, respectively. despite the excellent long-term functional results of these procedures, new technologies are being developed to reduce the hospital stay, the catheterization time, the haemorrhagic risk and the complication rate. at present, 3 types of laser technologies [holmium, 180w lbo crystal green light xcelerated performance system (xps), thulium] are considered by treatment guidelines for medically-refractory luts at the same level as turp with comparable shortand mid-term results, but with less morbidity and invasiveness (1). nowadays data about long term results are emerging (2-4). at present, the focus about the different laser technologies is not on functional results. the real questions are about which laser has the best safety profile and which laser for which patients should be used. one of the arguments against the widespread use of the holmium laser in bpo treatment is due to the fact that only enucleation procedures can be performed, which are characterized by a long learning curve (5). differently, greenlight and thulium laser are more versatile allowing a change in surgical technique (pure enucleation versus standard or anatomical vaporization) during the same procedure without modifying the functional outcomes and the complication rates (6, 7). in this study, we analysed the different intra and perioperative events between patients undergoing thulium vs. greenlight procedure for benign prostatic obstruction in two centers. materials and methods in this study, we retrospectively reviewed 100 consecutive cases undergoing greenlight standard photoselective vaporization of the prostate (pvp) and 100 consecutive cases undergoing thulium vapoenucleation of the prostate (thuvep) or thulium laser enucleation of the prostate (thulep) at the beginning of the learning curve of two expert endoscopic surgeons. this study and all related procedures were performed in accordance with the declaration of helsinki. informed consent was obtained from all individual participants included in the study. objective: the major strengths of surgical treatment of benign prostatic hyperplasia with laser are reduced morbidity compared to endoscopic resection. no studies analysed the different risk of intra/peri-operative events between patients undergoing thulium and greenlight procedures. materials and methods: we retrospectively reviewed 100 consecutive cases undergoing greenlight vaporization and thulium procedures performed during the learning curve of two expert endoscopic surgeons. pre-operative data, intra and post-operative events at 90 days were analysed. results: patients on antiplatelet/anticoagulant therapy were predominant in the green group (p < 0.0001). rates of blood transfusion (p < 0.0038), use of resectoscope (p < 0.0086), and transient stress urinary incontinence were statistically higher in the thulium group. on the contrary conversions to turp (p < 0.023) were more frequent in greenlight patients. readmissions were more frequently necessary in greenlight group (24%) vs. thulium group (26.6%). the overall complication rate in greenlight and thulium groups were 31% and 53% respectively; clavien 3b complications were 13% in thulium patients versus 1% in greenlight patients. conclusions: greenlight and thulium treatments show similar safety profiles. randomized controlled trial are needed to better clarify the rate of major complications in thulium group, and the incidence of post-operative storage symptoms in these patients’ populations. key words: benign prostatic hyperplasia; complications; greenlight laser; learning curve; safety; thulium laser. submitted 19 december 2022; accepted 31 december 2022 introduction benign prostatic obstruction (bpo) due to benign prostatic hyperplasia (bph) is the most common disease causing lower urinary tract symptoms (luts) in men. up to 50% of men over the age of 50 report some degree of luts. medical therapies, apart from lifestyle modifications, are the first line choice. in case of medical combination therapies failure, surgical management is the solution. transurethral resection of the prostate (turp) and open prostasafety profile of treatment with greenlight versus thulium laser for benign prostatic hyperplasia davide campobasso 1, 2, antonio barbieri 2, tommaso bocchialini 2, gian luigi pozzoli 1, francesco dinale 2, francesco facchini 1, marco serafino grande 1, jean emmanuel kwe 1, 3, michelangelo larosa 1, giulio guarino 1, 3, davide mezzogori 4, elisa simonetti 1, francesco ziglioli 2, antonio frattini 1, umberto vittorio maestroni 2 1 department of urology, ospedale civile di guastalla and ospedale ercole franchini di montecchio emilia, guastalla, italy; 2 department of urology, university hospital of parma, italy; 3 urological residency school network, department of urology, university hospital of modena and reggio emilia, modena, italy; 4 department of engineering and architecture, university of parma, italy. doi: 10.4081/aiua.2023.11101 summary archivio italiano di urologia e andrologia 2023; 95, 1 d. campobasso, a. barbieri, t. bocchialini, et al. we considered only greenlight procedures performed by a single surgeon (af) at the urology department of ercole franchini hospital in montecchio emilia, ausl-irccs of reggio emilia, from 2014 to 2016, with the 180w lbo crystal green light xcelerated performance system (xps)tm (american medical system-ams, minnetonka, minnesota) and a 532 nm fiber (moxy tm fiber). instead, all the procedures with thulium were performed by an expert endoscopic surgeon (ab) at the urology department of the university hospital of parma, from 2015 to 2018, with the thulium laser (cyber tm 200 w, quanta system spa, varese, italy) and a 1000 micron, reusable, front-firing laser fiber. standard greenlight pvp and thuvep/thulep procedures were performed as previously described (4, 8). examined preand post-operative factors and intraand peri-operative data included age, american society of anesthesiology (asa) score, prostate volume evaluated with trans-rectal ultrasound (trus), use of antiplatelet and anticoagulant medications, history of catheterization or retention, conversion to turp, capsular perforation, use of the resectoscope for haemostasis and other intra-operatively recorded events, catheterization time and length of hospital stay. complications were classified according to clavien-dindo classification (9). complications and postoperative events, such as access to hospital for consultation/readmission, incontinence, and erectile dysfunction were collected and classified as early (within 30 post-operative days) or late (31-90 days). luts such as dysuria, urinary frequency or urgency, and urinary incontinence, of any degree and type (stress or urge incontinence), were considered as post-operative complications when they required additional medical examination or therapy and negatively impacted on patient's quality of life. application of bladder catheter and irrigation or re-intervention or medical examination for haematuria were also reported as a complication. all patients underwent an outpatient clinic evaluation at 1 and 3 months. in all cases, antiplatelet therapies (such as glycoprotein iib/iiia receptor inhibitors or adenosine diphosphate -adpinhibitors), and anticoagulant therapies were stopped before surgery and bridging was done based on medical history. conversely, cox inhibitors (aspirin) were not stopped before surgery. antibiotic and antithrombotic prophylaxis were administered to all patients according to local practice protocols. in all cases, at the end of surgery, a three-way bladder catheter was placed with continuous bladder irrigation for at least 12 hours. statistical analyses the anova test and chi-square tests were used for statistical analysis. a p < 0.05 was considered to assess statistical significance. values were presented as n (%) or mean ± sd. results a standard pvp was performed in all 100 patients in the greenlight group, on the contrary 20 patients underwent thuvep and 80 patients thulep in the thulium group. age, asa score, and prostate volume were similar between the two groups. all data are reported in table 1. patients on antiplatelet/anticoagulant therapy were predominant in the green group (p < 0.0001). a history of indwelling catheter history was more represented in the thulium group (p = 0.002). interestingly, considering intra-operative data, the use of resectoscope for haemostasis was more frequent in patients undergoing thulium procedures (p = 0.008), but patients in the greenlight group had a higher conversion rate to turp (5% versus 0%, p = 0.023). no statistical difference was found in capsular perforation rate between thulium and greenlight (p = 0.13), despite an incidence of 12% versus 4%, respectively. no major differences were observed between the two groups in the following post-operative data: hospital stay, catheterization time, early acute urinary retention (aur), erectile dysfunction, post-operative storage symptoms and de novo urgency. blood transfusion rate (p = 0.003) and stress urinary incontinence (sui) three months post-operatively (p = 0.002) were lower in greenlight group. in particular, none of the patients undergoing greenlight pvp needed blood transfusion against 8% in the thulium group. the overall complication rate in greenlight and thulium groups were 31% versus 53% respectively (p < 0.0001) (table 2). the majority of complications in thulium group were clavien grade ii (22%), whereas in the greenlight group they were grade i (25%). thirteen patients needed a second operation for complications in the thulium series (clavien 3b), 84.6% (11 pts) of these being endoscopic revision for haematuria. in 5 cases endoscopic revision for haematuria was performed during the same admission. one patient of greenlight series required open surgery for bladder perforation with extraperitoneal fluid collection. the patient came to our attention after one month for haematuria and blood clots retention, during endoscopic revision a bladder perforation was discovered. in our series, 25% of patients needed an unplanned outpatient’s evaluations after discharge in the greenlight table 1. characteristics of study population. greenlight thulium p value group group age (years) 70.81 ± 7.56 70.73 ± 7.88 0.9 asa score 2.33 2.09 0.1 prostate volume (ml) 50.25 ± 16.67 68.6 ± 35 0.49 indwelling catheter (%) 12% 29% 0.002 antiplatelet and anticoagulant medications (%) 59% antiplatelet 34% antiplatelet < 0.0001 9% anticoagulant 6% anticoagulant capsular perforation (%) 4% 12% 0.13 conversions to turp 5% 0% 0.023 hemostasis with resectoscope 9% 28% 0.008 hospital stay (days) 2.07 ± 0.6 2.82 ± 1.5 0.6 catheterization time (days) 1.98 ± 1.3 1.95 ± 1.4 0.88 blood transfusion (%) 0% 8% 0.003 early urinary retention – aur (%) 12% 8% 0.75 storage symptoms and de novo urgency (%) 27% (27 pts) 39% (39 pts) 0.07 at 1 months 88.8% (24/27) 38.4% (15/39) at 3 months 66.7% (15/27) 5.1% (2/39) sui at three months (%) 7% 18% 0.0029 erectile disfunction (%) 5% 8% 0.38 aur = acute urinary retention; sui = stress urinary incontinence. archivio italiano di urologia e andrologia 2023; 95, 1 safety of green and thulium laser in bph group with 24% (6 pts) readmissions (one patient for heart failure and one for pulmonary embolism one month post-operatively). similarly, in the thulium group 30% of patients needed re-evaluation with 26.6% (8 pts) readmission. haematuria, requiring endoscopic revision was the most common cause of readmission (75% 6 pts). complications divided by time of onset are reported in table 3. discussion in recent years, with the development of laser technologies, overcoming the well-known complications and morbidity rates, turp procedures have decreased (1, 10). the necessity to find less invasive procedures is linked to two aspects. the prevalence of bph increases with advancing age in a linear fashion, and obesity and metabolic syndrome are two risk factors for this condition. all these aspects are prevalent in western countries. nowadays procedures are required to guarantee good functional results, low complications rates, short hospitalization with fast return to normal activity and safety in high-risk patients or patients under anticoagulant or antiplatelet therapy. in the literature, several papers reported data about safety and good results of thulium and greenlight (1, 11, 16, 17). only two papers compared the results of thulium and greenlight for the treatment of bpo (17-19). in the first (17, 18), the authors compared 116 and 118 patients undergone thulium and 120w high-performance system (hps)™ lithium triborate (lbo) vaporization, respectively. the authors did not find statistically significant differences in term of complications, with readmission, transfusion, and re-operation rates of 2.6 vs 1.7%, 2.6% vs 0% and 1.7 vs 5.1%, respectively. no major details are available on these aspects. in the second paper (19), the authors analysed the results of thuvep performed in one center (158 pts) and standard greenlight pvp in 3 centers (93 pts), with no significant differences in term of complications, only hemoglobin drop was in favor of pvp. in the pvp group, 66.7% developed a complication versus the 15.2% of the thuvep group. on the contrary in our series the greenlight group developed an overall complication rate of 31% versus 55% in the thulium group. however, in the study by castellani and colleagues, clavien grade i was the most common complication grade in pvp and thuvep (95.1 versus 35.1%), in line with our experience (80.6% versus 32.7%). the authors reported a reoperation rate after 30 days of 8.6% and 7% in patients undergoing pvp and thuvep, respectively, but they did not specify the cause table 3. association between ppla score and risk factors for kidney stones or stone recurrence. group complications peri-operative early (30 days) late (31-90 days) greenlight 6 acute urinary retention 4 acute urinary retention 2 acute urinary retention 2 fever 1 endoscopic revision with bladder perforation and open conversion 3 urinary tract infection with signs of bacteremia 1 urinary tract infection without signs of bacteremia 1 pulmonary embolism 4 urinary tract infection without signs of bacteremia 2 hematuria without blood clot retention 4 hematuria without blood clot retention 1 heart failure thulium 5 acute urinary retention 3 acute urinary retention 1 endoscopic revision for bladder neck contracture 1 fever 2 fever 5 urinary tract infection with signs of bacteremia 9 urinary tract infection with signs of bacteremia 8 blood transfusion 4 urinary tract infection without signs of bacteremia 5 endoscopic revision for hematuria 6 endoscopic revision for hematuria 1 stenting for ureteral orifice damage 3 hematuria without blood clot retention table 2. overall complication rate. greenlight thulium complications according to clavien-dindo classification (%) clavien i 25% clavien i 18% 12 aur 8 aur 6 hematuria without blood clot retention 4 urinary tract infection without signs of bacteremia 5 urinary tract infection without signs of bacteremia 3 hematuria without blood clot retention 2 fever 3 fever clavien ii 5% clavien ii 22% 3 urinary tract infection with signs of bacteremia 14 urinary tract infection with signs of bacteremia 1 pulmonary embolism 8 blood transfusion 1 heart failure clavien iiib 1% clavien iiib 13% 1 endoscopic revision with bladder perforation and open conversion 11 endoscopic revision for hematuria 1 endoscopic revision for bladder neck contracture 1 stenting for ureteral orifice damage aur = acute urinary retention. archivio italiano di urologia e andrologia 2023; 95, 1 d. campobasso, a. barbieri, t. bocchialini, et al. of the second procedure (haematuria, urethral/bladder neck stenosis etc). unfortunately, the two papers did not focus on safety profile and complications. the authors did not specify how many surgeons and how experienced performed the procedures, the type of complications and the reasons for readmission and re-operation. our study is based on collection of cases of patients treated by two surgeons at the beginning of their learning curve in greenlight pvp and thuvap/thuvep procedures. in particular, in our thulium series, the 5 cases of re-operation for haematuria in the post-operative period occurred in the first 50 procedures, and in 4 cases a capsular perforation was reported during the first enucleation procedures. these patients had a prostate volume < 80 cc (means 56.6 cc) and they were not on anticoagulant or antiplatelet therapies. also, the case of stenting for superficial ureteral orifice lesion occurred during the first 50 procedures. in the remaining 6 cases of re-operation for haematuria described in the post-discharge period for thulium series, one occurred during the first 50 procedures, the other 5 cases were high-risk patients with asa score 3 and prostate volume > 80 cc (mean 109.8 cc) and/or with antiplatelet or anticoagulant therapies. definitely, the 60% of complications clavien grade iiib occurred in the first 50 procedures with thulium, and these issues must be considered when analysing our data. also, the 8% of transfusion rate, which directly correlates with the endoscopic revision rate in the first 50 procedures, must be correctly interpreted. moreover, despite the conversion to turp being more frequent in the greenlight group, all the cases happened in the first 20 procedures and our rate was in line with other series (3). an additional aspect to consider was the higher number of enucleation procedures in the thulium series (80% vs 0%). in fact, the higher resectoscope use in the thulium group is linked to the need for an optimal endoscopic vision before morcellation. also, the 12% of capsular perforation in thulium group is linked to the enucleation procedures. the re-admission rate at 3 months is comparable between thulium and greenlight group (8% and 6%, respectively), with a higher incidence of further urgent medical examination in the patient undergoing greenlight pvp (25% versus 16%). concerning the urinary symptoms, our data on storage symptoms and de novo urgency are in line with the literature and do not differ between the two groups (p = 0.07) (20, 21). however, some differences are present in the time necessary to resolve these symptoms (table 1). in the thulium group, only two patients described persistence of storage symptoms at 3 months versus 15% in the greenlight group. moreover, in our series patients undergone greenlight pvp needed one further medical evaluation for post-operative luts and storage symptoms more frequently than in the thulium group (16% versus 9%). on the contrary, the incidence of transient postoperative urinary stress incontinence is more frequent in the thulium group (18% vs 7%, p = 0.0029). these data are in line with a recent review of the literature regarding thulep procedures, which reported transient irritative symptoms and incontinence between 6.7% and 18.5% (21). furthermore, the risk of incontinence was higher in enucleation than in resection methods and correlates with the learning curve (4). moreover, our study reported the functional results at 3 months. several papers describe a reduction of stress incontinence at 12 months in thulep series (21). some limitations are present in our study, first of all its retrospective nature and the presence of enucleation procedures in the thulium group compared to pvp greenlight group (80% versus 0%). otherwise, the choice to consider the first 100 thulium procedures by a single surgeon, including his learning curve, and 100 consecutives standard grennlight pvp by a surgeon during his learning curve are strengths of this paper. with careful data analysis we found a higher risk of clavien grade iiib complications and blood transfusion in the peri-operative period in the first 50 procedures of thulep. no patients required blood transfusion in the following 50 thulium procedures, despite the prostate volume and the enucleation procedure had increased. in these sub-groups of patients, the risk of endoscopic revision for haematuria was higher in patients with prostate volume > 80 cc and under antiplatelet/anticoagulant therapies. in our real-life setting with thulium and greenlight lasers, both laser systems were documented to be equally safe for patients affected by bpo, also at the beginning of the learning curve. we could not find any significant difference in terms of complications after the first 50 procedures. future prospective randomized studies are needed to confirm this conclusion on both techniques. conclusions greenlight and thulium treatments show similar safety profiles. the higher rate of transient ius in thulium patients is linked to the use of enucleation technique in contrast to vaporization technique with greenlight. furthermore, the higher use of resectoscope for haemostasis during thulium enucleation is needed to perform a safety morcellation procedure. larger study population reflecting multicentred experience would be necessary to better clarify the rate of major complications in thulium group, and the grade and durability of post-operative storage symptoms in these patients’ populations. references 1. gravas s, cornu jn, gacci m, et al. eau guidelines on management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). edn. presented at the eau annual congress amsterdam 2020. isbn 97894-92671-07-3. eau guidelines office, arnhem, the netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/ 2. fallara g, capogrosso p, schifano n, et al. ten-year follow-up results after holmium laser enucleation of the prostate. eur urol focus. 2021; 7:612-617. 3. campobasso d, marchioni m, de nunzio c, et al. predictors of reintervention after greenlight laser photoselective vaporization of the prostate: multicenter long/mid-term follow-up experience. miniinvasive surgery. 2021; 5:45. 4. castellani d, pirola gm, pacchetti a, et al. state of the art of thulium laser enucleation and vapoenucleation of the prostate: a systematic review. urology. 2020; 136:19-34. 5. enikeev d, morozov a, taratkin m, et al. systematic review of the archivio italiano di urologia e andrologia 2023; 95, 1 safety of green and thulium laser in bph endoscopic enucleation of the prostate learning curve. world j urol. 2021; 39:2427-2438. 6. naspro r, gomez sancha f, manica m, et al. from "gold standard" resection to reproducible "future standard" endoscopic enucleation of the prostate: what we know about anatomical enucleation. minerva urol nefrol. 2017; 69:446-458. 7. campobasso d, ferrari g, frattini a. greenlight laser: a laser for every prostate and every urologist. world j urol. 2022; 40:295-296. 8. cindolo l, ruggera l, destefanis p, et al. vaporize, anatomically vaporize or enucleate the prostate? the flexible use of the greenlight laser. int urol nephrol. 2017; 49:405-411. 9. mamoulakis c, efthimiou i, kazoulis s, et al. the modified clavien classification system: a standardized platform for reporting complications in transurethral resection of the prostate. world j urol. 2011; 29:205-210. 10. leonardo c, lombardo r, cindolo l, et al. what is the standard surgical approach to large volume bpe? systematic review of existing randomized clinical trials. minerva urol nefrol. 2020; 72:22-29. 11. castellani d, di rosa m, gasparri l, et al. thulium laser vapoenucleation of the prostate (thuvep) in men at high cardiovascular risk and on antithrombotic therapy: a singlecenter experience. j clin med. 2020; 9:917. 12. meskawi m, hueber pa, valdivieso r, et al. complications and functional outcomes of high-risk patient with cardiovascular disease on antithrombotic medication treated with the 532-nm-laser photovaporization greenlight xps-180 w for benign prostate hyperplasia. world j urol. 2019; 37:1671-1678. 13. campobasso d, marchioni m, altieri v, et al. greenlight photoselective vaporization of the prostate: one laser for different prostate sizes. j endourol. 2020; 34:54-62. 14. campobasso d, acampora a, de nunzio c, et al. post-operative acute urinary retention after greenlight laser. analysis of risk factors from a multicentric database. urol j. 2021; 18:693-698. 15. mattevi d, luciani l, spina r, et al. comparison of greenlight 180-w xps laser vaporization versus transurethral resection of the prostate: outcomes of a single regional center. arch ital urol androl. 2020; 92:169-172 16. castellucci r, marchioni m, fasolis g, et al. the safety and feasibility of the simultaneous use of 180-w greenlight laser for prostate vaporization during concomitant surgery. arch ital urol androl. 2020; 92:297-301 17. elmansy h, hodhod a, elshafei a, et al. comparative analysis of mosestm technology versus novel thulium fiber laser (tfl) for transurethral enucleation of the prostate: a single-institutional study. arch ital urol androl. 2022; 94:180-185. 18. palmero-martí jl, panach-navarrete j, valls-gonzález l, et al. comparative study between thulium laser (tm: yag) 150w and greenlight laser (lbo:nd-yag) 120w for the treatment of benign prostatic hyperpplasia: short-term efficacy and security. actas urol esp. 2017; 41:188-193. 19. castellani d, cindolo l, de nunzio c, et al. comparison between thulium laser vapoenucleation and greenlight laser photoselective vaporization of the prostate in real-life setting: propensity score analysis. urology. 2018; 121:147-152. 20. cindolo l, de nunzio c, greco f, et al. standard vs. anatomical 180-w greenlight laser photoselective vaporization of the prostate: a propensity score analysis. world j urol. 2018; 36:91-97. 21. kyriazis i, swiniarski pp, jutzi s, et al. transurethral anatomical enucleation of the prostate with tm:yag support (thulep): review of the literature on a novel surgical approach in the management of benign prostatic enlargement. world j urol. 2015; 33:525-30. correspondence davide campobasso, md (corresponding author) d.campobasso@virgilio.it gian luigi pozzoli, md pozzolig@ausl.re.it grancesco facchini, md facchinifrancesco@yahoo.it marco serafino grande, md marcogrande2@yahoo.it jean emmanuel kwe, md jeanemmanuelk@yahoo.fr michelangelo larosa, md larosam@ausl.re.it elisa simonetti, md elisasimonetti88@gmail.com antonio frattini, md antonio.frattini@ausl.re.it urology unit, civil hospital of guastalla, azienda usl-irccs di reggio emilia via donatori di sangue 1, guastalla 42016 (re) (italy) antonio barbieri, md barbio68@icloud.com tommaso bocchialini, md tommaso.bocchialini@libero.it francesco dinale, md ceciodinale@gmail.com giulio guarino, md giulio.guarino3@gmail.com francesco ziglioli, md ziglioli@hotmail.it vittorio maestroni, md umaestroni@ao.pr.it department of urology, university hospital of parma viale antonio gramsci, 14, 43126 parma (italy) davide mezzogori, md davide.mezzogori@unipr.it department of engineering and architecture, university of parma parco area delle scienze, 59, 43124 parma (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2180 original paper no conflict of interest declared. and effective treatment option for patients experiencing symptoms of an enlarged prostate. the holep procedure has comparable results to transurethral resection of the prostate (turp) and op, with a low morbidity rate and shorter hospital stay (2-6). holep also demonstrated an acceptable steep learning curve (7). improvements in outcome parameters following holep are durable, and the late complications and reoperation rates reported are very low, up to 18 years (8). recent evidence suggests that mosestm technology has further revolutionized holep with modulated pulsed energy transmission (9). enhanced energy delivery is believed to increase efficiency during holep and reduce the operative and catheterization times, as well as blood loss (10). holep performed using mosestm technology has been shown to provide faster hemostasis than holep with a standard 100-w holmium laser (9). thulium fiber laser enucleation of the prostate (thuflep) is an emerging technology for endoscopic prostate enucleation. one of the advantages of the thulium fiber laser (tfl) is its wavelength (1940 nm), which has a photothermal effect and a more shallow penetration depth. this allows for precise tissue cutting and reduces the carbonization effects associated with thulium:yag lasers (11-13). recent data demonstrate that thuflep is an effective minimally-invasive technique for the surgical management of benign prostatiec hyperplasia (bph), with treatment outcomes comparable to turp and op (13, 14). the objective of this study was to assess the safety and efficacy of tfl in patients who underwent thuflep compared to those that underwent mosestm holep at our institution. patients and methods after obtaining research ethics board approval, we conducted a retrospective review of prospectively collected data of eighty-two patients who underwent transurethral enucleation of the prostate at our institution from august 2020 to september 2021. patients were dichotomized depending on whether they underwent enucleation of the prostate using a 120-w mosestm (lumenis, yoknaem, introduction: novel laser technologies have been developed for the minimally invasive surgical management of benign prostatic hyperplasia (bph). the objective of this study was to assess the safety and efficacy of mosestm technology versus the thulium fiber laser (tfl) in patients with bph undergoing transurethral enucleation of the prostate. methods: we conducted a retrospective review of prospectively collected data of eighty-two patients who underwent transurethral enucleation of the prostate using mosestm or tfl technologies from august 2020 to september 2021. preoperative and intraoperative parameters, in addition to postoperative outcomes, were collected and analyzed. results: twenty patients underwent transurethral enucleation of the prostate with tfl, while 62 had mosestm holep. no statistically significant difference in preoperative characteristics was observed between the groups. patients in the tfl group had longer median enucleation, hemostasis, and morcellation times (p < 0.001) than those in the mosestm cohort. the longer morcellation time of tfl is mostly related to less visibility. the postoperative outcomes ipss, qol, qmax, and post void residual (pvr), were comparable between the groups at 1, 3 and 6 months. the incidence of urge urinary incontinence (p = 0.79), stress urinary incontinence (p = 0.97), and hospital readmission rates (p = 0.1) were comparable between the two groups. conclusions: a satisfactory safety and efficacy profile with comparable postoperative outcomes was demonstrated for both techniques; though, mosestm technology was superior to tfl in terms of shorter overall operative time. key words: benign prostatic hyperplasia; laser; enucleation. submitted 23 march 2022; accepted 25 april 2022 introduction a wide range of laser technologies have been developed for anatomical endoscopic enucleation of the prostate (aeep), which adopts the principle of open prostatectomy (op). the efficacy and safety of aeep have been widely demonstrated, regardless of the energy source utilized (1). holmium laser enucleation of the prostate (holep) is a safe comparative analysis of mosestm technology versus novel thulium fiber laser (tfl) for transurethral enucleation of the prostate: a single-institutional study hazem elmansy 1, amr hodhod 1, ahmed elshafei 1, yasser a noureldin 1, 2, vahid mehrnoush 1, ahmed s. zakaria 1, ruba abdul hadi 1, moustafa fathy 1, 3, loay abbas 1, ahmed kotb 1, walid shahrour 1 1 urology department, northern ontario school of medicine, thunder bay, ontario, canada; 2 urology department, benha university, benha, egypt; 3 urology department, menoufia university, shebin elkom, egypt. doi: 10.4081/aiua.2022.2.180 summary 181archivio italiano di urologia e andrologia 2022; 94, 2 mosestm vs. tfl enucleation of prostate israel) or tfl (soltive premium, olympus, usa). a 550-μm laser fiber and a 28-f continuous flow resectoscope (karl storz se & co. kg, tuttlingen, germany) were used for both procedures. we included patients with a prostate size > 80 g that presented with severe lower urinary tract obstruction that did not respond to medical treatment, refractory urinary retention, refractory hematuria due to prostate enlargement, and bladder stones secondary to bph. preoperative evaluation included patient demographics, a complete medical history, physical examination including a digital rectal exam (dre), the use of antiplatelets and anticoagulants, history of urinary retention, and previous prostate surgery. symptom assessment was completed using the international prostate symptom score (ipss) and quality of life (qol) questionnaires. patients underwent prostate-specific antigen (psa) testing, uroflowmetry, a post-void residual (pvr) bladder scan, and a transrectal ultrasound for prostate volume estimation. patients with psa values above normal or those with abnormal dre findings underwent a preoperative biopsy to exclude prostate cancer. a preoperative cystoscopy was performed in individuals who previously underwent turp to exclude urethral strictures and bladder neck (bn) contracture. surgical parameters including enucleation time, enucleation efficiency, morcellation time, laser energy, resected weight, intraoperative complications, and the need for blood transfusion were recorded. enucleation efficiency is defined as the weight of enucleated prostatic tissue (grams) divided by the enucleation time (minute). early postoperative complications included clot retention, a failed trial of void (tov) and hospital readmission. preoperative and postoperative hemoglobin levels were measured. late postoperative complications included urge urinary incontinence (uui), stress urinary incontinence (sui), urethral strictures, and bn contraction. sui was evaluated with a detailed history regarding the involuntary passage of urine while coughing or sneezing or the use of pads to avoid wetting. clinical evaluation of sui was conducted by asking the patient, with a full bladder, to cough and by observing the passage of any urine. all patients had postoperative follow-ups at 1, 3, 6 and 12 months. our evaluation included ipss, qol, qmax, and pvr. psa levels were measured at three months postoperative. surgical technique our top-down enucleation techniques using the holmium laser or tfl were reported in previous publications (15, 16). postoperative care until august 2020, we performed standard 100-w holep, and our practice was an overnight hospital admission with a next-day tov (< 24 hours). after acquiring mosestm technology in december 2020, we implemented same-day discharge and same-day tov for patients that underwent mosestm holep. the standard practice for tfl prostate enucleation was an overnight admission and next-day tov (< 24 hours). patients who met predetermined discharge criteria following an assessment by the surgeon were offered same-day catheter removal 3 hours postoperatively. they were informed that our standard practice was an overnight admission or same-day discharge with outpatient catheter removal on postoperative day one (pod1). patients with an unfit medical condition (e.g., uncontrolled cardiovascular disease, cognitive disorder, and anticoagulant or antiplatelet therapy) were excluded from early discharge. those without a caregiver or residing beyond city limits were also excluded. patients were not excluded based on pvr, the presence of an indwelling catheter or other subjective criteria. all patients were counselled regarding the option to decline same-day catheter removal and discharge if they felt uncomfortable. if medically feasible, patients were instructed to temporarily hold their antiplatelet and anticoagulant medications before surgery for 7 and 3 days, respectively. a same-day tov was not offered to patients who could not withhold their antiplatelet or anticoagulant therapy. all patients had a three-way foley catheter (22 f, with 75 ml of sterile water in the balloon) inserted postoperatively and were kept on mild traction with continuous bladder irrigation (cbi). the cases were postoperatively transferred to the post anesthesia care unit (pacu) for observation. for mosestm patients, cbi was continued for 2 hours and was then stopped for an additional hour to evaluate the degree of hematuria. while patients who underwent tfl were admitted overnight with cbi. routine blood testing, including a complete blood count and basic metabolic profile, were conducted in the pacu. voiding trials were performed 3 hours postoperatively for mosestm patients and next day for the tfl group. following tov, all patients were assessed by the urologist for suitability for discharge. a tov was performed by filling the catheter with 300500 ml of saline or until the patient felt the urge to urinate. the urine colour, volume voided, and pvr were assessed to ensure there was no concern for hematuria or possible clot retention. predetermined discharge criteria included: if the patient was deemed medically fit, was not on anticoagulants or antiplatelets, had a caregiver, and met discharge criteria (17). patients with a minimum score of 9 on the modified post anaesthetic discharge scoring system were considered ready for discharge. a score of ≥ 2 was required for vital signs, pain and surgical bleeding criteria, whereas a minimum score of 1 was required for all other criteria. before discharge, patients were also required to have acceptable laboratory results, hematuria scores (without cbi or the presence of clots) (18), tolerate diet, and ambulate independently. a tov was considered successful if the patient had a pvr < 300 and if the residual volume was less than half the voided volume, and there was no concern for hematuria or possible clot retention. statistical analyses data collection and statistical analyses were performed using statistical package for the social sciences (spss®) version 26.0 (chicago, il, usa) and jmp® pro16 software (sas institute inc., cary, nc). continuous data were presented using medians and interquartile ranges (iqr) and compared with the mann-whitney u test. numbers and archivio italiano di urologia e andrologia 2022; 94, 2 h. elmansy, a. hodhod, a. elshafei, et al. 182 percentages were used to describe categorical data, which was compared using the chi-square test. the p-value was considered statistically significant if p < 0.05. results of the 82 patients included in the study, 62 underwent mosestm holep, and 20 had transurethral enucleation of the prostate with tfl. the preoperative characteristics of the two groups are listed in table 1. there was no difference between treatment modalities in terms of compared preoperative parameters. patients who underwent tfl prostate enucleation had longer median enucleation, hemostasis, and morcellation times (p < 0.001) compared to mosestm (table 2). moreover, the enucleation efficiency was significantly higher using mosestm technology (p = 0.006). no intraoperative complications were recorded for both technologies. two patients (10%) in the tfl cohort required hospital readmission compared to one (1.6%) in the mosestm group (p = 0.1). all three cases of hospital readmission were due to hematuria. all patients in our study had their catheters removed postoperatively and were discharged from the hospital within 24 hours; though, patients who underwent mosestm holep had their catheters removed within 3 hours postoperatively with a hospital stay ≤ 6 hours. patients who underwent tfl enucleation of the prostate had their catheters removed within 24 hours and had a hospital stay of ≤ 24 hours. none of the patients in our study required postoperative blood transfusion. following catheter removal, one patient (5%) in the tfl group and 3 individuals (4.8%) in the mosestm group experienced sui (p = 0.97). the incidence of uui post-catheter removal was 10% (2 patients) and 8.1% (5 patients) in the tfl and moses tm groups, respectively (p = 0.79). all cases of sui and uui were resolved at 3-months follow-up. the postoperative functional outcomes were comparable between the two groups including median qmax at 1, 3 and 6 months (p = 0.55, p = 0.32, p = 0.82), respectively and median pvr at 1, 3, and 6 months (p = 0.88, p = 0.92, p = 0.31), respectively. the median ipss at 1, 3 and 6 months (p = 0.6, p = 0.26, p = 0.11), respectively and median qol at 1, 3 and 6 months (p = 0.6, p = 0.32, p = 0.71), respectively were also comparable between the groups (figure 1). at 6-months follow-up (figure 2), there were no differences between the groups in terms of improvement in percentages of ipss (p = 0.38), qol (p = 0.77), qmax (p = 0.84), and pvr (p = 0.33). discussion over the last few years, emerging laser technologies have been introduced for bph management. this study compared two well-known technologies: mosestm and the novel tfl. both modalities demonstrated promising results in the management of primary and recurrent enucleation of bph (19). though moses tm and tfl were individually studied with other modalities in the literature, the two technologies were not previously compared. mosestm technology was associated with a shorter operative time compared to conventional holep. this may be due to the enhanced hemostatic properties of mosestm (9, 10, 20). compared to op, tfl was associated with a shorter hospital stay and earlier return to normal activities (14). moreover, tfl was comparable to conventional monopolar turp in the management of moderate-sized prostates (< 80 cc). at 12-months follow-up, tfl was associated with a greater reduction in psa levels, indicating enhanced removal of the prostatic adenoma (13). in the current study, mosestm holep was associated with significantly less enucleation and hemostasis times than tfl. this could be explained by better hemostasis achieved with mosestm technology than tfl. doizi and colleagues found incision depth and coagulation areas were greater with the holmium laser than tfl. moreover, they noticed that the holmium laser had no carbonization zone while it was constant with the tfl (21). in this study, mosestm technology had better enucleation efficiency than tfl (1.6 vs 1.4 g/min, p = 0.006). our reported tfl enucleation efficiency is comparable to other studies. enikeev et al. had an enucleation efficiency of 1.04 g/min using tfl (14). nevo and colleagues reported a mean enucleation efficiency of 1.7 g/min with mosestm 2.0 technology (10). we found that morcellation time was shorter in the table 1. preoperative characteristics of both groups. mosestm tfl p-value (62 patients) (20 patients) age at surgery (median/iqr) yrs 71.4 (64.5-80.1) 73.8 (66.2-82.6) 0.2 indication urine retention n (%) 12 (19.4) 7 (35) 0.15 luts/hematuria n (%) 50 (80.6) 13 (65) comorbidities n (%) 51 (82.3) 13 (65) 0.1 prostate volume (median/iqr) cc 109 (87-122) 102 (91.5-118.75) 0.97 preoperative ipss (median/iqr) 25 (22-28) 25.5 (23.3-28.5) 0.55 preoperative qol (median/iqr) 5 (4-5.25) 5 (4.25-6) 0.34 preoperative qmax (median/iqr) ml/min 7.7 (5.7-10.6) 7.95 (6.4-11) 0.74 preoperative pvr (median/iqr) ml 223 (130-323) 234 (99.5-440) 0.82 preoperative psa (median/iqr) ng/dl 4.8 (3.6-7.4) 4.8 (4.2-5.5) 0.89 preoperative hemoglobin (median/iqr) g/l 145 (140-151) 139 (131.3-143) 0.052 table 2. operative parameters comparing mosestm to tfl technologies in prostate enucleation. mosestm tfl p-value (62 patients) (20 patients) enucleation time (median/iqr) min 46.5 (40-54) 61.5 (55-68.7) < 0.001 hemostasis time (median/iqr) min 3 (2-4) 5 (5-6.7) < 0.001 morcellation time (median/iqr) min 10 (6.7-12) 15 (10.2-22.7) < 0.001 laser energy (median/iqr) kj 79.7 (65.4-99.7) 78.4 (67.8-95.3) 0.75 prostate enucleated weight (median/iqr) g 70 (60-90) 79 (58.5-90.8) 0.51 hemoglobin drop (median/iqr) g/l 10 (7-14) 10.5 (7.3-14) 0.6 enucleation efficiency (median/iqr) g/min 1.6 (1.3-2) 1.4 (1-1.6) 0.006 readmissions n (%) 1 (1.6) 2 (10) 0.1 183archivio italiano di urologia e andrologia 2022; 94, 2 mosestm vs. tfl enucleation of prostate mosestm group compared to the tfl cohort, 10 vs 15 minutes, respectively (p < 0.001). we observed a higher clarity of vision with mosestm due to better hemostasis that facilitated faster morcellation of the adenoma. our morcellation time is similar to that of large and colleagues (mean time = 10.4 min) (9). the morcellation time following tfl prostate enucleation is not well documented in the literature. we cannot compare tov for mosestm and tfl because we adopted a same-day tov for the mosestm cohort, whereas patients who underwent tfl were kept overnight. similarly, the hospital stay cannot be compared as tfl patients were routinely admitted and discharged the following day. in the current study, same-day tov following mosestm enucleation was successful in about 93.5% of patients. figure 1. functional outcomes comparing mosestm to tfl technologies for prostate enucleation. archivio italiano di urologia e andrologia 2022; 94, 2 h. elmansy, a. hodhod, a. elshafei, et al. 184 this result seems promising if we compare it with the 88% successful same-day tov rate, reported by slade et al., following conventional holep (22). although the intraoperative enucleation parameters were better with mosestm technology, both tfl and mosestm had comparable postoperative outcomes at 6 months follow-up (figures 1, 2). other studies reported similar results for both laser technologies (9, 10, 13, 14). our study has some limitations, including its retrospective nature, though it is a retrospective analysis of prospectively collected data. a second limitation is the small number of patients in the tfl group. a similar number of procedures were used to evaluate laser enucleation of the prostate in other studies (10). moreover, the hospital stay and same-day tov of both technologies could not be compared. our study has a relatively short follow-up period; however, similar follow-up intervals were used in the literature (9, 14). additional studies with larger sample sizes and more extended follow-up periods are warranted. conclusions to the extent of our knowledge, this is the first study comparing mosestm and tfl technologies for transurethral prostate enucleation. a satisfactory safety and efficacy profile with comparable postoperative outcomes was demonstrated for both techniques; though, mosestm technology was superior to tfl in terms of shorter overall operative time. references 1. herrmann tr. enucleation is enucleation is enucleation is enucleation. world j urol 2016; 34:1353-5. 2. kuntz rm, ahyai s, lehrich k, fayad a. transurethral holmium laser enucleation of the prostate versus transurethral electrocautery resection of the prostate: a randomized prospective trial in 200 patients. j urol 2004; 172:1012-6. 3. li s, zeng xt, ruan xl, weng h, liu tz, wang x, et al. holmium laser enucleation versus transurethral resection in patients with benign prostate hyperplasia: an updated systematic review with meta-analysis and trial sequential analysis. plos one 2014; 9:e101615. 4. yin l, teng j, huang cj, zhang x, xu d. holmium laser enucleation of the prostate versus transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. j endourol 2013; 27:604-11. 5. naspro r, suardi n, salonia a, scattoni v, guazzoni g, colombo r, et al. holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24-month follow-up. eur urol 2006; 50:563-8. 6. schiavina r, bianchi l, giampaoli m, borghesi m, dababneh h, chessa f, et al. holmium laser prostatectomy in a tertiary italian center: a prospective cost analysis in comparison with bipolar turp and open prostatectomy. arch ital urol androl 2020; 92:82-88 7. gurlen g, karkin k. does holmium laser enucleation of the prostate (holep) still have a steep learning curve? our experience of 100 consecutive cases from turkey. arch ital urol androl 2021; 93:412-7. 8. ibrahim a, alharbi m, elhilali mm, aube m, carrier s. 18 years figure 2. percentage of improvement in ipss, qol, qmax, and pvr at 6-months follow-up. 185archivio italiano di urologia e andrologia 2022; 94, 2 mosestm vs. tfl enucleation of prostate of holmium laser enucleation of the prostate: a single center experience. j urol 2019; 202:795-800. 9. large t, nottingham c, stoughton c, williams j, jr., krambeck a. comparative study of holmium laser enucleation of the prostate with moses enabled pulsed laser modulation. urology 2020; 136:196-201. 10. nevo a, faraj ks, cheney sm, moore jp, stern kl, borofsky m, et al. holmium laser enucleation of the prostate using moses 2.0 vs non-moses: a randomised controlled trial. bju int 2021; 127:553-9. 11. fried nm, murray ke. high-power thulium fiber laser ablation of urinary tissues at 1.94 microm. j endourol 2005; 19:25-31. 12. enikeev d, glybochko p, rapoport l, gahan j, gazimiev m, spivak l, et al. a randomized trial comparing the learning curve of 3 endoscopic enucleation techniques (holep, thuflep, and mep) for bph using mentoring approach-initial results. urology 2018; 121:51-7. 13. enikeev d, netsch c, rapoport l, gazimiev m, laukhtina e, snurnitsyna o, et al. novel thulium fiber laser for endoscopic enucleation of the prostate: a prospective comparison with conventional transurethral resection of the prostate. int j urol 2019; 26:1138-43. 14. enikeev d, okhunov z, rapoport l, taratkin m, enikeev m, snurnitsyna o, et al. novel thulium fiber laser for enucleation of prostate: a retrospective comparison with open simple prostatectomy. j endourol 2019; 33:16-21. 15. elmansy h, hodhod a, kotb a, prowse o, shahrour w. topdown holmium laser enucleation of the prostate: technical aspects and early outcomes. urology 2019; 126:236. 16. elmansy h, shabana w, waugh m, ahmad a, hadi ra, shahrour w. top-down thulium fiber laser enucleation of the prostate: technical aspects. cent european j urol 2021; 74:271. 17. palumbo p, tellan g, perotti b, pacile ma, vietri f, illuminati g. modified padss (post anaesthetic discharge scoring system) for monitoring outpatients discharge. ann ital chir 2013; 84:661-5. 18. abdul-muhsin h, critchlow w, navaratnam a, gnecco j, tay k, girardo m, et al. feasibility of holmium laser enucleation of the prostate as a 1-day surgery. world j urol 2020; 38:1017-25. 19. becker b, netsch c, glybochko p, rapoport l, taratkin m, enikeev d. a feasibility study utilizing the thulium and holmium laser in patients for the treatment of recurrent benign prostatic hyperplasia after previous prostatic surgery. urol int 2018; 101:212-8. 20. nottingham cu, large t, agarwal dk, rivera me, krambeck ae. comparison of newly optimized moses technology vs standard holmium:yag for endoscopic laser enucleation of the prostate. j endourol 2021; 35:1393-9. 21. doizi s, germain t, panthier f, comperat e, traxer o, berthe l. comparison of holmium:yag and thulium fiber lasers on soft tissue: an ex vivo study. j endourol. 2022; 36:251-258. 22. slade a, agarwal d, large t, sahm e, schmidt j, rivera me. expanded criteria same day catheter removal following holmium laser enucleation of the prostate (holep). j endourol 2022. doi: 10.1089/end.2022.0007. epub ahead of print. correspondence hazem elmansy, md, msc, frcsc hazem.mansy@rocketmail.com associate professor & program director of the minimally invasive urologic surgery fellowship program, northern ontario school of medicine, thunder bay, ontario, canada 146 court street south, thunder bay, on, p7b 2x6 amr hodhod, md ahmed elshafei, md yasser a noureldin, md vahid mehrnoush, md ahmed s zakaria, md ruba abdul hadi, rd moustafa fathy, md loay abbas, md ahmed kotb, md walid shahrour, md urology department, northern ontario school of medicine, thunder bay, ontario (canada) stesura seveso 385archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. tance of as lies in evading unnecessary treatments, and so their potentially detrimental side effects, through careful surveillance at specific intervals to disease progression and need for intervention (1). the rationale justified by the slow and indolent course of low-grade prostate cancer (2, 3). moreover, observational studies revealed no significant advantage in patients that underwent surgery versus active surveillance (4, 5). in particular, the protect trial showed a similar 10-year prostate cancer specific survival in patients with localized low-grade prostate cancer that underwent monitoring, surgery, or radiation therapy (6). our purpose is to evaluate our active surveillance protocol and its outcomes in our middle eastern cohort over a 10year span. to our knowledge, this is the first as outcome data reported outside of north america and europe. methods after obtaining institutional review board approval, we performed a retrospective review of our prostate cancer patients’ data at the american university of beirutmedical center (aubmc), a middle eastern tertiary care center, over a span of 10 years (2008-2018). 43 of them satisfied the inclusion criteria into our institution’s active surveillance protocol. our inclusion criteria included low risk prostate cancer defined by the following parameters: psa less than 10, a negative dre or a localized nodule (t1c/t2a), biopsy gleason group grade 1 or 2 as defined by the who criteria, and unilateral disease involvement on biopsy. magnetic resonance imaging (mri) was done to characterize and guide the localization of prostatic lesions for biopsy. consequently, targeted biopsies were taken from those lesions along with random ones. there was no exclusion criteria based on age. to note, patients that were enrolled into the as protocol were thoroughly counseled about available treatment options including their possible side effects. our follow-up strategy based upon a psa and dre every 4-6 months, an initial prostate biopsy at the time of enrollment, and a second biopsy at 1 year. annual mri was not initially part of the protocol, yet it was introduced in the last few years. furthermore, an additional re-biopsy was done after the first year with evident signs of clinical progression such as a suspicious rise in psa, change in dre, or mri progression which included the appearance of a new lesion, or an increased background: the aim of our study was to evaluate the outcome of active surveillance (as) for prostate cancer for a cohort of patients at our institution. methods: a total of 43 patients with low risk prostate cancer were enrolled in an active surveillance pilot program at our institution between 2008 and 2018. follow up protocols included: periodic prostate specific antigen (psa), digital rectal examination (dre), multiparametric mri, and prostate biopsy at one year. pertinent parameters were collected, and descriptive statistics were reported along with a subset analysis of patients that dropped out of the protocol to receive active treatment for disease progression. results: out of 43 eligible patients, 46.5% had a significant rise in follow up psa. dre was initially suspicious in 27.9% of patients, and none had any change in dre on follow up. initially, prostate mris showed pirads 3, 4, and 5 in 14%, 37.2%, and 11.6% respectively, while 23.2% had a negative initial mri. 14% did not have an mri. upon follow up, 18.6% of patients had progression on mri. initial biopsies revealed that 86% were classified as who group 1, while 14% as who group 2. with regards to the follow up biopsies, 11.6% were upgraded. 20.9% of our patients had active treatment; 44.4% due to upgraded biopsy results, 22.2% due to psa progression, 22.2% due to strong patient preference, and 11.1% due to radiologic progression. conclusions: for selected men with low risk prostate cancer, as is a reasonable alternative. the decision for active treatment should be tailored upon changes in psa, dre, mri, and biopsy results. key words: active surveillance; prostate cancer; men’s health; screening; prostate specific antigen. submitted 14 may 2021; accepted 19 july 2021 introduction active surveillance (as) as a management strategy for low grade prostate cancer is a relatively new approach increasingly utilized by clinicians in the light of better comprehension of low-grade prostate cancer behavior. it is a dynamic surveillance strategy that may shift into a direct curative intervention (1). the main goal is to follow-up patients with clinical parameters such as prostate specific antigen (psa), digital rectal examination (dre), imaging and biopsy according to predetermined protocols. the imporoutcomes of active surveillance for clinically localized prostate cancer in a middle eastern tertiary care center mohammad hout 1, ali merhe 1, nassib abou heidar 1, jose m el-asmar 1, wassim wazzan 1, bassel bachir 1, rola jaafar 2, albert el hajj 1, muhammad bulbul 1 1 department of surgery, division of urology, american university of beirut medical center, beirut, lebanon; 2 department of surgery, american university of beirut medical center, beirut, lebanon. doi: 10.4081/aiua.2021.4.385 summary archivio italiano di urologia e andrologia 2021; 93, 4 m. hout, a. merhe, n. abou heidar, et al. 386 complexity of a previously noted one as defined by the pirads system. descriptive statistics of patients and their above parameters were reported along with a subset analysis of patients that dropped out of the protocol to receive treatment for progression of disease. results our populations’ age ranged between 51-78 with a mean of 63.88. psa values ranged between 1.87-15.9. at presentation, a positive dre was present in 27.9% of included patients, whereas negative in 72.1% of them. initial mri’s harbored a pirads 3 lesions in 14% of patients, pirads 4 in 37.2%, pirads 5 in 11.6%. 23.2% of patients had a negative mri and 14% did not have one. the pathology grade of our patients prostate biopsy revealed a who group 1 in 86% of patients while a who group 2 in 14% of the biopsies (table 1). upon regular follow-up, 46.5% of patients (20/43) had a significant rise in follow-up psa, 46.5% (20/43) had a stable psa throughout, and 7% (3/43) did not have a follow-up psa. out of the prostate mris done, 18.6% (8/43) had imaging progression as per the previously stated criteria, 39.5% (17/43) of lesions were stable, and 41.9% (18/43) did not have a follow-up mri. with regards to the follow-up biopsies, 11.6% (5/43) were upgraded to a higher who group, 46.5% (20/43) were either stable or at a lower group, while 41.9% (18/43) of the repeat biopsies were not done (table 2). a descriptive analysis of the patients that dropped out of active surveillance for intervention was performed. 20.9% (9/43) of patients dropped out. analysis according to changes in clinical parameters was performed and demonstrated the following: of the 20 patients who progressed by psa, only 2 patients (10%) dropped out of active surveillance for intervention. of the 8 patients that progressed on follow-up mri, 3 patients (37.5%) dropped out for intervention. of the 3 patients who were upgraded on followup biopsies, 2 patients (66.7%) dropped out for intervention (figure 1). two patients elected to drop out and seek intervention due to psychological/patient preference. of the patients that dropped out of active surveillance, 44.4% (4/9) underwent radical prostatectomy, 44.4% (4/9) underwent radiation therapy plus adt, and 11.1% (1/9) took adt alone (figure 1). of those who underwent radical prostatectomy, 50% (2/4) were upgraded according to the final pathology, while 50% (2/4) maintained the same grade as the last biopsy result. discussion according to the nccn 2019 guidelines, inclusion criteria for active surveillance for prostate cancer includes patients with very low/low-risk disease or intermediate risk disease with low volume disease and a outcome with a life expectancy of 10 years and beyond (7, 8). follow up criteria vary from one institution to another where most opt for a follow-up psa every 6 months, dre every 12 months, and biopsy every 1-2 years. some protocols have incorporated the use of mri every 12 months or more (nccn) (9). our protocol has been consistent with the above recommendations whilst gradually incorporating mri as a valuable aid in decision making. serum marker psa is the frontline parameter that triggers further workup to rule out clinical progression. this was table 1. mean age, mean psa, rate of positive dre, mri results and pathology grade of our population. figure 1. mode of intervention after dropping out from active surveillance. patient demographics results age 63.88 (51-78) psa 6.26 (1.87-15.9) dre (negative) 72.1% (31/43) dre (positive) 27.9% (12/43) mri (not done) 14% (6/43) mri (negative) 23.2% (10/43) mri (pirads 3) 14% (6/43) mri (pirads 4) 37.2% (16/43) mri (pirads 5) 11.6% (5/43) pathology grade who group 1 86% (37/43) who group 2 14% (6/43) table 2. psa, mri and biopsies at follow-up. clinical parameter progressed stable n/a psa 46.5% (20/43) 46.5% (20/43) 7% (3/43) mri 18.6% (8/43) 39.5% (17/43) 41.9% (18/43) pathology 11.6% (5/43) 46.5% (20/43) 41.9% (18/43) table 3. comparison of our results to various north american cohorts studied in different medical centers. center toronto hopkins ucsf canary pass aubmc (8) (29) (10) (30) no of patients 993 1298 321 905 43 median age 68 66 63 63 65 median follow-up 77 60 43 28 40 overall survival 80% 93% 98% n/a cancer specific survival 98% 99.90% 100% 100% conversion to treatment 36.50% 50% 24% 19% 20.90% (rot) gleason grade change 9.50% 15.10% 38% 11.60% (rot) psa increase 11.70% 26% 4.65% (rot) positive lns 0.40% (rot) personal choice 1.60% 8% 8% 4.65% 387archivio italiano di urologia e andrologia 2021; 93, 4 active surveillance for prostate cancer similarly evident in our cohort whereby almost half (46.5%) of our patients had a significant rise in psa that led to the decision of further investigation that included a rebiopsy +/mri. of those with psa progression, 10% (2/20) had an upgraded pathology on repeat biopsy. one remained eligible for the as group, while the other was reclassified from low to intermediate risk group leading to an intervention. it is prudent to follow-up biannually with psa results; however, it is rarely the sole trigger for intervention. when suspicion arises, further clinical workup is warranted via mri and biopsy (10, 11). with regards to the initial dre, all patients were either negative (72.1%) or suspicious to have a t2a lesion on exam (27.9%). patients with large nodules, bilateral nodules, or involvement of seminal vesicles were excluded from active surveillance (12). abnormal dres are associated with an increased risk of detecting high-grade disease (12). any sign of t3 disease or progression in the clinical stage suggested by a dre would warrant a further investigation/intervention in patients with as (13). nevertheless, none of our patients revealed signs of progression upon dre. the addition of mri evaluation proved to be a resourceful tool in clinical decision making for as patients (14-20). it was similarly essential for our patients. upon follow-up, 18.6% (8/43) of our patients progressed on mri, 37.5% (3/8) of those patients that progressed were dropped from as. one of those (1/3), had a suspicious capsule involvement on mri leading to direct intervention, whereas the other two (2/3) patients had a rebiopsy that revealed upgrading of disease leading to intervention. from the total number of patients, only 13% of them were not imaged with mri despite strong recommendation. imaging for prostate cancer, mri has been integral for decision making in as, as it significantly improved detection rates of suspicious lesions. biopsy without mri has a misclassification rate of 20-30% (14). in addition, berglund et al. showed that an immediate confirmatory biopsy for as patients revealed an upgrade in 27% of cases to gleason 7 and above (15). as such, an mri is deemed a crucial addition in the diagnostics of prostate cancer as it can accurately guide targeting of clinically significant lesions in 2/3 of men eligible for active surveillance (16). in addition, mri has a high negative predictive value 90-100% (17), it also lacks sensitivity to low grade tumors of gleason 6 (3+3). therefore, on initial workup a negative mri may omit the need for biopsy to rule out prostate cancer and may even be an attractive alternative of recurrent biopsies leading to a decreased incidence of diagnosing low grade prostate cancer (18, 19). yet, the use of mri for follow-up on as patients should be subject to better defined radiological parameters (20). biopsy results belonging to who group 1 or 2 is the final determinant of patient inclusion to the as protocol of our study. on follow-up, any suspicious clinical parameter would warrant a repeat biopsy. of those, 11.6% (5/43) were upgraded. of the upgraded biopsies 80% (4/5) lead to an intervention. in addition, biopsy result was the trigger for intervention in 44.4% of patients that dropped out of as. in a 41.9% (20/43) of follow-up, biopsies at one year were not done. this high percentage can be explained by lack of patient commitment to the as protocol mainly due to discomfort from undergoing a repeat biopsy as well as false reassurance from the other noninvasive clinical parameters. to note, none of the patients who underwent radical prostatectomy as the intervention of choice had a high-grade pathology specimen (gleason 8 or above). biopsy is indeed the most solid parameter for decision making. according to the prias study, switch to active treatment should be guided by biopsy upgrading and/or clinical t3 disease (13). we compared our results to various north american cohorts studied in different medical centers. despite our small sample size, our numbers were consistent with their results. fortunately, our os and css revealed no deceased patients. this could be explained by our relatively short median follow-up time of 40 months and our small sample size. moreover, our conversion to treatment rate was 20.9% which was comparable to other cohorts (19-50%) (table 3). truly one of the biggest and main challenges in prostate cancer is differentiating low risk pathology from aggressive ones. gleason pathology is currently the most reliable method. mri has an emerging role in aiding clinicians and is gaining popularity as new studies are in favor of its diagnostic potential. biomarkers appear to be promising but await prospective studies to be fully endorsed (1). pca3 and tmprss2:erg may be able to assess risk of aggressive disease yet fail to reveal an independent predictive value or benefit over psa (21). 4k score has a significant association with reclassification biopsy; however, it showed no additional benefit over psa in guiding follow-up biopsies in as (22). genomic markers include 3 genetic tissue assays that are currently fda approved. the decifer genomic classifier which consists of 22 genes, gives a score 0-1 and classifies patients into 3 risk groups (23). genomic prostate score consists of 17 genes and may potentially aid the initial decision for as enrollment (24). cell cycle progression test may similarly aid the decision-making process (25). none have been validated for use in as; however, they may be incorporated in nomograms especially in deciding on as for intermediate risk patients (26). patients with brca1/2 mutations are not recommended to undergo active surveillance. when present, these mutations are associated with increased risk of nodal and distant metastasis as well as poor survival outcomes (27). our as protocol has some limitations. despite an agreed upon consensus on the active surveillance protocol, there was an inter patient variability driven by patient compliance or financial/insurance coverage. in addition, treating physicians in our region are still reluctant to initiate active surveillance protocol for various reasons (28). moreover, a bigger sample size and longer follow-up period would further solidify our findings and improve our understanding of long-term patient outcomes on active surveillance (29, 30). conclusions in conclusion, active surveillance is a practical and appropriate clinical strategy that should be further employed as part of our patient care arsenal. it is a complex and demanding process for both physician and patient alike as it requires rigorous follow-up with shrewd attention to multiple combined clinical parameters as well as patient commitment and willingness to undergo periodic assessments. psa is an essential clinical marker for active surveillance that may subtly guide decision making. archivio italiano di urologia e andrologia 2021; 93, 4 m. hout, a. merhe, n. abou heidar, et al. 388 mri is a useful clinical parameter in as that may obviate need for re-biopsy or even an initial biopsy for prostate cancer. dre and biopsy are major contributors in halting as and proceeding towards an intervention especially with evident disease progression either by an upgraded gleason score or an upstaging upon exam (ct3). references 1. briganti a, fossati n, catto jwf, et al. active surveillance for lowrisk prostate cancer: the european association of urology position in 2018. eur urol. 2018; 74:357-68. 2. popiolek m, rider jr, andren o, et al. natural history of early, localized prostate cancer: a final report from three decades of follow-up. eur urol. 2013; 63:428-35. 3. albertsen pc, hanley ja, fine j. 20-year outcomes following conservative management of clinically localized prostate cancer. jama. 2005; 293:2095-101. 4. johansson e, steineck g, holmberg l, et al. long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the scandinavian prostate cancer group-4 randomised trial. the lancet oncology. 2011; 12:891-9. 5. grossman dc, curry sj, owens dk, et al. screening for prostate cancer: us preventive services task force recommendation statement. jama. 2018; 319:1901-13. 6. hamdy fc, donovan jl, lane ja, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. new engl j med 2016; 375:1415-24. 7. klotz l. active surveillance in intermediate-risk prostate cancer. bju int. 2020; 125:346-54. 8. klotz l, vesprini d, sethukavalan p, et al. long-term follow-up of a large active surveillance cohort of patients with prostate cancer. j clin oncol. 2015; 33:272-7. 9. carroll pr, parsons jk, andriole g, et al. nccn guidelines insights: prostate cancer early detection, version 2.2016. jnccn. 2016; 14:50919. 10. welty cj, cowan je, nguyen h, et al. extended followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer. j urol 2015; 193:807-11. 11. garisto jd, klotz l. active surveillance for prostate cancer: how to do it ight. oncology (williston park) 2017; 31:333-40. 12. gosselaar c, roobol mj, roemeling s, schroder fh. the role of the digital rectal examination in subsequent screening visits in the european randomized study of screening for prostate cancer (erspc), rotterdam. eur urol. 2008; 54:581-8. 13. bokhorst lp, lepisto i, kakehi y, et al. complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the prostate cancer research international: active surveillance (prias) study. bju int. 2016; 118:366-71. 14. ploussard g, salomon l, xylinas e, et al. pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance--does the risk of misclassification vary according to biopsy criteria? j urol. 2010; 183:539-44. 15. berglund rk, masterson ta, vora kc, et al. pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. j urol 2008; 180:1964-7. 16. de rooij m, hamoen eh, futterer jj, et al. accuracy of multiparametric mri for prostate cancer detection: a meta-analysis. ajr 2014; 202:343-51. 17. gaziev g, wadhwa k, barrett t, et al. defining the learning curve for multiparametric magnetic resonance imaging (mri) of the prostate using mri-transrectal ultrasonography (trus) fusion-guided transperineal prostate biopsies as a validation tool. bju int. 2016; 117:80-6. 18. barentsz jo, richenberg j, clements r, et al. esur prostate mr guidelines 2012. eur radiol. 2012; 22:746-57. 19. dianat ss, carter hb, pienta kj, et al. magnetic resonance-invisible versus magnetic resonance-visible prostate cancer in active surveillance: a preliminary report on disease outcomes. urology. 2015; 85:147-53. 20. schoots ig, petrides n, giganti f, et al. magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. eur urol. 2015; 67:627-36. 21. lin dw, newcomb lf, brown ec, et al. urinary tmprss2:erg and pca3 in an active surveillance cohort: results from a baseline analysis in the canary prostate active surveillance study. clin cancer res 2013; 19:2442-50. 22. lin dw, newcomb lf, brown md, et al. evaluating the four kallikrein panel of the 4kscore for prediction of high-grade prostate cancer in men in the canary prostate active surveillance study. eur urol. 2017; 72:448-54. 23. klein ea, haddad z, yousefi k, et al. decipher genomic classifier measured on prostate biopsy predicts metastasis risk. urology. 2016; 90:148-52. 24. klein ea, cooperberg mr, magi-galluzzi c, et al. a 17-gene assay to predict prostate cancer aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. eur urol. 2014; 66:550-60. 25. shore nd, kella n, moran b, et al. impact of the cell cycle progression test on physician and patient treatment selection for localized prostate cancer. j urol. 2016; 195:612-8. 26. wang sy, cowan je, cary kc, et al. limited ability of existing nomograms to predict outcomes in men undergoing active surveillance for prostate cancer. bju int. 2014; 114:e18-e24. 27. castro e, goh c, olmos d, et al. germline brca mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. j clin oncol. 2013; 31:1748-57. 28. el sebaaly r, mansour m, labban m, et al. survey on the practice of active surveillance for prostate cancer from the middle east. prostate int. 2020; 8:41-8. 29. tosoian jj, mamawala m, epstein ji, et al. intermediate and longerterm outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. j clin oncol. 2015; 33:3379-85. 30. newcomb lf, thompson im, jr., boyer hd, et al. outcomes of active surveillance for clinically localized prostate cancer in the prospective, multi-institutional canary pass cohort. j urol. 2016; 195:313-20. correspondence mohammad hout, md mh21@aub.edu.lb ali merhe, md am134@aub.edu.lb nassib fares heidar, md na192@aub.edu.lb jose m el-asmar, md je56@aub.edu.lb wassim wazzan, md ww04@aub.edu.lb bassel bachir, md bb12@aub.edu.lb albert el-hajj, md ae67@aub.edu.lb muhammad bulbul, md, clinical professor (corresponding author) mb30@aub.edu.lb department of urology, american university of beirut medical center riad el-solh 1107 2020 beirut, lebanon rola jaafar, md rj29@aub.edu.lb department of surgery, american university of beirut medical center, beirut, lebanon stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper major financial healthcare burden, with most recourses directed towards long-term follow-up and treatment of complications (1). epidemiology differs among countries due to differences in lifestyle habits, environmental conditions, and diagnostic patterns (2), with reported incidence ratio in european countries ranging between 4.6 for women and 20 for men (1). one of the most identifiable causes of bladder cancer is use of tobacco, either directly or even through environmental exposure, due to contained polycyclic aromatic hydrocarbons and aromatic amines (3), with nearly one out of two cases being attributed to it (4). the relationship between tobacco use and disease incidence is considered dose-related and increases the risk by three-fivefold (5). workers occupied in industry of painting/dye, metal, petroleum and ship construction are also at increased risk due to occupational exposure to aromatic amines/polycyclic hydrocarbons and chlorinated hydrocarbons, accounting for nearly 10% of diagnoses (2, 3, 6, 7). studies have shown that miners, workers in leather and rubber industry, vehicle drivers, firefighters and hairdressers are more frequently diagnosed when working more than 10 years (8, 9). quantity or arsenic and trihalomethanes in drinking water are potentially implicated according to some reports in bladder cancer pathogenesis as well (2, 7, 10). exposure of pelvis to ionizing radiation and administration of pioglitazone or cyclophosphamide have also revealed a positive correlation with bladder cancer, while chronic mucosal lining irritation either from foreign bodies (long-term indwelling catheter) or infections (schistosoma haematobium) are also considered risk factors (2, 7, 11). obesity is considered a pandemic with reported prevalence ranging between 30-60% across countries (12), while numerous studies have indicated increased body mass index (bmi) as an etiological factor for neoplastic disease (13). kanabrocki et al. were the first who mentioned a positive correlation between bladder cancer and obesity back in 1965 (14), with subsequent cohort studies trying to quantify this risk showing conflicting results. up to date the most comprehensive systematic review of literature including a total cohort of nearly 50 million participants and almost 90000 cases of bladder cancer background: risk factors like smoking, radiation, chronic infections and exposure to occupational chemicals are strongly associated with occurrence of bladder cancer. association between increased body weight and bladder cancer has been controversial. the aim of this casecontrol study is to evaluate association of anthropometric characteristics on bladder cancer incidence in greek population. methods: this case-control study was conducted at a tertiary hospital in greece with cases being patients with bladder cancer diagnosed within the last 2 years and controls patients admitted to hospital for reason other than cancer and not related to common risk factors related to bladder cancer. anthropometric characteristics like weight, height, body mass index, waist and hip circumference were measured. analyses was done with r (vienna, austria). results: comparison between groups showed that patients with bladder cancer had higher weight, bmi and waist circumference compared to controls. however, multivariate, binomial logistic regression showed that only age (or 1.03, 95% ci: 1-1.05, p = 0.02), no use of smoke (or 0.12, 95% ci: 0.07-0.23, p < 0.001) and occupation related to bladder cancer (or 7.45, 95% ci: 2.53-27.93, p < 0.001) significantly predicted the incidence of bladder cancer. conclusions: bladder cancer incidence is strongly linked with specific risk factors such as smoking, occupation with exposure to chemicals and smoke, increasing age, radiation and chronic infections. several studies have shown a weak association between anthropometric characteristics and bladder cancer, although most studies in european populations did not confirm these findings. similarly in our case-control study in a greek population, we found potential relationship between increased weight/bmi and waist circumference with bladder cancer, but the association disappeared in multivariate analysis. key words: bladder cancer; bmi; anthropometric characteristics; epidemiology; weight; height; waist circumference; hip circumference. submitted 19 february 2023; accepted 6 march 2023 introduction carcinoma of urinary bladder represents the tenth most common malignancy worldwide when both genders are considered, but the seventh for men and represents a anthropometric characteristics and relationship with non-muscle invasive bladder cancer in greece: a case-control study lazaros tzelves 1, 2, stamatis katsimperis 2, themistoklis bellos 2, marinos berdempes 2, iraklis mitsogiannis 2, athanasios papatsoris 2, charalampos deliveliotis 2, ioannis varkarakis 2, andreas skolarikos 2 1 department of urology/uro-oncology, university college of london hospitals (uclh), london, united kingdom; 2 2nd department of urology, sismanoglio hospital, medical school, national and kapodistrian university of athens, sismanogliou 37 athens, greece. doi: 10.4081/aiua.2023.11266 summary archivio italiano di urologia e andrologia 2023; 95, 1 l. tzelves, s. katsimperis, t. bellos, et al. showed that increased risk existed in overweight men by 12% but not overweighted women, while both obese men and women shoed increased risk (14). height did not seem to correlate with diagnosis, while data for waist circumference was limited and indicated an increased risk only in men by 18% (14). according to authors, subgroup analysis according to geographical region showed that for european populations all associations disappeared, while persisted for asia, australia, and america, raising the question whether mediterranean diet which is commonly followed in several european countries accounted for these discrepancies (14). the aim of this case-control study is to investigate the effect of increased bmi and anthropometric characteristics such as weight, height, waist, and hip circumference to bladder cancer diagnosis, in a sample of greek patients. methods patients and controls all participants in this case-control study were admitted in urology department of sismanoglio hospital, a tertiary hospital in athens, greece between 2018-2022. cases were defined as patients older than 18 years old, men or women, diagnosed with transitional cell non-muscle invasive bladder cancer within the last two years from their entry in the study, who were admitted for management of their bladder cancer, or a complication related to it. exclusion criteria were age < 18 y/o, denial to participate in the study, extreme weight gain or loss (> 15 kg) during the last 5 years, histological type other than pure urothelial carcinoma, stage ≥ t2, radiation treatment in the past, known history of long-term infection with schistosoma haematobium or history of other type of malignancy in the past. controls were consecutive patients who were admitted at the urology department of the hospital between 2018-2022, did not have a history of bladder cancer or other neoplastic disease in the past and who were managed for a condition not related to smoking or other risk factors known to lead to bladder cancer (smoking, exposure to chemicals related to bladder cancer, radiation, chronic infections of the bladder). such conditions were benign prostatic hyperplasia, urinary tract infections, hydrocele and varicocele. all patients, both cases and controls, were informed about the study and were included only when they provided a written informed consent regarding their participation. study protocol was approved by the sismanoglio hospital institutional review board and all principles of helsinki declaration regarding patients’ rights were followed (15). data collection after their admission all participants were interviewed regarding their baseline characteristics and disease specific history using a structured proforma. age, presence of comorbidities (diabetes mellitus, ischemic heart disease, hypertension, chronic obstructive pulmonary disease), history of smoking, type of occupation and information regarding bladder cancer (tnm, previous treatment) were recorded. smoking was stratified to the following categories: never used smoke, former smokers, current smoking < 20 cigarettes/day or current smoking ≥ 20 cigarettes/day. occupation was categorized as non-related to bladder cancer or related to bladder cancer (working in industry where metal, paint/dye, tobacco, petroleum was manufactured or processed, hairdressers, firefighters, workers in ship construction). body weight and height were measured on the day of admission by hospital staff not aware of the presence or not of bladder cancer, while bmi was measured using the quetelet’s formula (weight divided by squared height kg/m2). waist circumference was measured at the point lying in the middle of the distance between the lower rib and iliac crest, while hip circumference was measured above the buttocks. all measurements were performed with patients wearing only light clothes. sample size calculation in order to calculate the sample size, we took into consideration the incidence of increased bmi in greek population (30%) and we calculated the study sample size to 500 participants in total to test for a difference in bmi of 10% between cases and controls (the difference in risk according to literature) and achieve statistical power of 80%. the proportion of cases to controls was 1:1. statistical analysis continuous variables are described as mean ± standard deviation or median and range, according whether normal distribution was followed or not in each variable. categorical outcomes are described with numbers and proportions. two sample t-test or wilcoxon rank sum test with continuity correction were used to compare groups regarding continuous outcomes, according to whether normal distribution was followed or not, respectively. chi-square test or fisher’s test were used to compare groups regarding categorical outcomes. a univariate, binary, logistic regression analysis was performed to determine which independent variables show an important effect on incidence of bladder cancer, while multivariate, binary, logistic regression analysis was subsequently conducted to assess whether independent variables showing significant effect on univariate regression show effect also on multivariate analysis. odds ratios (ors) and the corresponding 95% confidence intervals (ci) were calculated by univariate and multivariate logistic regression analysis. significance was set at p < 0.05. for all analyses, r statistical software (vienna, austria) was used. results a total of 513 participants were included in this analysis, with 256 being cases and 257 controls. the majority of cases (85%) and controls (87%) were males, while comparison between groups revealed that presence of chronic obstructive pulmonary disease, ischemic heart disease, age, height, and hip circumference were not significantly difference between cases and controls. controls reported more frequently zero use of smoke compared to cases (57% versus 14%, p < 0.001). fewer cases reported residing in urban areas compared to controls (70% versus 85%, p < 0.001) and more cases answered being occupied to a field related to bladder cancer than controls archivio italiano di urologia e andrologia 2023; 95, 1 anthropometric characteristics and non-muscle invasive bladder cancer (10% versus 2%, p < 0.001). both diabetes mellitus (42% versus 24%, p < 0.001) and hypertension (78% versus 60%, p < 0.001) were more frequent in cases than controls. mean weight (87.8 versus 83, p < 0.001) and bmi (29.8 versus 27.9, p < 0.001) were higher in cases than controls, while the same applied for waist circumference although the statistical significance was marginal (105.6 versus 103.6, p = 0.046). waisthip ratio was higher in cases than controls (1.02 versus 1, p = 0.024). all baseline characteristics both for groups and controls are shown in table 1. figures 1 and 2 are mosaic plots showing graphically the effect of smoking and type of occupation/residence on bladder cancer, respectively. in a gender-specific analysis, in women height, waist circumference, hip circumference and waisthip ratio were similar in controls and cases, while weight (74.5 versus 67, p < 0.001) and bmi (29.1 versus 27, p = 0.014) were higher in cases than controls. in men, height and hip circumference were similar. weight (89.4 versus 85, p < 0.001), bmi (29.8 versus 28, p < 0.001), waist circumference (106.4 versus 104.1, p = 0.02) and waist circumference (1.03 versus 1.01, p = 0.005) were higher in cases compared to control. all anthropometric characteristics of cases and controls according to gender-specific analysis are shown in table 2. table 1. baseline characteristics of patients and controls in overall sample population. variable values bladder cancer controls p-value gender males 218 (85%) 224 (87%) females 38 (15%) 33 (13%) smoking no 36 (14%) 146 (57%) < 0.001 former 112 (44%) 59 (23%) < 20 cigarettes/day 49 (19%) 28 (11%) ≥ 20 cigarettes/day 59 (23%) 24 (9%) residence rural area 20 (8%) 9 (4%) < 0.001 suburban area 57 (22%) 28 (11%) urban area 179 (70%) 220 (85%) occupation not related to bca 231 (90%) 253 (98%) < 0.001 related to bca 25 (10%) 4 (2%) diabetes mellitus yes 107 (42%) 62 (24%) < 0.001 no 149 (58%) 195 (76%) hypertension yes 199 (78%) 156 (60%) < 0.001 no 57 (22%) 101 (40%) chronic obstructive yes 24 (9%) 28 (11%) 0.672 pulmonary disease no 232 (91%) 229 (89%) ischemic heart disease yes 44 (17%) 40 (16%) 0.706 no 212 (83%) 217 (84%) age (years) 70.1 (10.1) 70 (9.8) 0.887 weight (kg) 87.8 (15.5) 83 (15) < 0.001 height (cm) 171.6 (7.5) 172.5 (8.4) 0.174 bmi (kg/m2) 29.8 (5) 27.9 (4.7) < 0.001 waist circumference (cm) 105.6 (11.5) 103.6 (10.2) 0.046 hip circumference (cm) 103.4 (5.4) 103 (4.5) 0.451 waist-hip ratio 1.02 (0.08) 1 (0.07) 0.024 bca = bladder cancer; bmi = body mass index. categorical variables are presented as n (%) and continuous variables as and mean (± sd). table 2. anthropometric characteristics of patients and controls in females and males. variable bladder cancer females p-value males p-value weight (kg) yes 74.5 (68-83) < 0.001 89.4 (14.8) < 0.001 no 67 (65-71) 85 (14.6) height (cm) yes 160 (157-164) 0.922 173.4 (6.1) 0.194 no 160 (156-163) 174.2 (7.3) bmi (kg/m2) yes 29.1 (26.3-33.5) 0.014 29.8 (4.9) < 0.001 no 27 (24.7-27.9) 28 (4.8) waist circumference (cm) yes 97 (88-113) 0.944 106.4 (10.7) 0.02 no 105 (88-108) 104.1 (9.7) hip circumference (cm) yes 105 (97-111) 0.835 103.1 (4.8) 0.392 no 104 (103-106) 102.7 (4.1) waist-hip ratio yes 0.95 (0.85-1.02) 0.977 1.03 (0.07) 0.005 no 0.99 (0.85-1.05) 1.01 (0.07) bmi = body mass index; sd = standard deviation. wilcoxon rank sum test with continuity correction was used for comparison of continuous data for females, while welch two sample t-test for comparison of continuous date for males. continuous variables as median (25th-75th percentile) for females and mean (± sd) for males. figure 1. mosaic plot on effect of smoking on bladder cancer incidence. figure 2. mosaic plot on effect of occupation/residence on bladder cancer incidence. archivio italiano di urologia e andrologia 2023; 95, 1 l. tzelves, s. katsimperis, t. bellos, et al. univariate, binomial logistic regression evaluating all continuous (age, bmi, weight, height, waist circumference, hip circumference, waist-hip ratio) and categorical (smoking status, area of residence, occupation) independent variables revealed that significant effect on incidence of bladder cancer had age (or 1.04, 95% ci: 1.011.06, p = 0.002), no use of smoke (or 0.13, 95% ci: 0.07-0.24, p < 0.001) and occupation related to bladder cancer (or 8.05, 95% ci: 2.49-33.45, p < 0.001). similarly, multivariate, binomial logistic regression showed that age (or 1.03, 95% ci: 1-1.05, p = 0.02), no use of smoke (or 0.12, 95% ci: 0.07-0.23, p < 0.001) and occupation related to bladder cancer (or 7.45, 95% ci: 2.53-27.93, p < 0.001) significantly predicted the incidence of bladder cancer. all results of binomial logistic regression are shown in table 3. discussion increased body weight has been associated with several types of cancer. for bladder cancer conflicting data exist showing a potential relationship. in their meta-analysis, qin et al pooled data from 11 cohort studies and showed an increased risk of bladder cancer incidence by 10% in obese people (16), while a more updated analysis showed that the association is stronger in men (12-14%) and in continents other than europe (14). increased height has also been implicated in carcinogenesis with the assumption that increased number of cells in taller people may be accompanied by increased chances for mutagenesis. however, several studies failed to detect such an association for bladder cancer (14). waist circumference is considered an index of central obesity and is not well studies regarding its association with bladder cancer incidence (14). this case-control study is the first one performed in a greek population regarding the effect of anthropometric characteristics on bladder cancer occurrence and showed a potential association between increased weight/bmi, increased waist circumference, use of smoke, occupation related to bladder cancer, hypertension, diabetes mellitus with bladder cancer, while multivariate regression analysis revealed that association exists between increasing age, use of smoke and occupation lying in agreement with existing literature. various pathophysiological mechanisms have been proposed to link obesity with increased risk for bladder cancer. one of the most established is the co-existence of obesity with insulin resistance which lead to overproduction of insulin; insulin induces mitosis and potentially carcinogenesis by increasing insulin-like growth factor (igf-1), which initiates molecular pathways for cell proliferation and blocks programmed cell death (17). link between diabetes mellitus and bladder cancer can be partially explained by this association as well. another mechanism is the excess cholesterol in adipose tissue, with cholesterol serving as a prodrome molecule for testosterone production, which in turn stimulates proliferation of epithelial cells (18). secretion of leptin by adipose tissue may also contribute to increased bladder risk, since leptin is a hormone leading to enhanced angiogenesis and subsequently can nourish tumor cells (19). adipose tissue is considered to lead to impaired mitochondrial function and increased reactive oxygen species, due to reduced clearance, thus further increasing cellular oxidative stress and mutations (20). gender specific differences regarding the association of anthropometric characteristics with bladder cancer incidence are observed both in literature and in our study, since although increased bmi/weight was seen in both male and female cases compared to control, increased waist circumference was seen only in male cases. the potential protective role of estrogens can explain these differences (21). embryological origin of bladder and prostate is the same from urogenital sinus and androgendriven growth of bladder cancer cells can also be a potential mechanism in men (22). continent-specific differences are best explained both by genetic differences on a population level, but also from dietary habits, which are known to play a major role in cancer pathophysiology. in europe associations between increased bmi and bladder cancer were not significant in the updated meta-analysis of nearly 50 million participants (14). in the meta-analysis by xenou et al, authors examined the association between fruit/vegetable consumption and bladder cancer (23). they found that citrus fruit consumption had a protective equipment, although not reaching statistical significance, while all analyses regarding consumption of leafy vegetables, dark green vegetables, berries, vegetable/fruit or overall vegetable and fruit consumption did not show a significant protective effect (23). in our study regarding a sample of greek patients with bladder cancer, we detected a potential implication of weight/bmi and waist circumference in bladder cancer, but this was not confirmed in multivariate regression analysis where only well-established risk factors were significant. height and hip circumference also were not significantly different between the groups. this case-control study suffers from specific limitations table 3. results of binomial logistic regression for bladder cancer occurrence. all variables significant predictors only variable or 95% ci p-value variable or 95% ci p-value age 1.04 1.01-1.06 0.002 age 1.03 1.00-1.05 0.02 bmi 1.14 0.07-1.88 0.6 weight 1.01 0.86-1.19 0.87 height 1.00 0.86-1.18 0.97 waist circumference 1.07 0.59-1.96 0.84 hip circumference 0.85 0.46-1.54 0.60 waist-hip ratio 0.84 0.35-1.35 0.79 smoking ≥20 cigarettes/day 1.24 0.61-2.53 0.55 former smoker 0.9 0.49-1.65 0.74 no smoking 0.13 0.07-0.24 < 0.001 no smoking 0.12 0.07-0.23 < 0.001 suburban area 1.49 0.49-4.42 0.48 urban area 0.79 0.28-2.11 0.64 occupation related to bca 8.05 2.49-33.45 0.001 occupation related to bca 7.45 2.53-27.93 < 0.001 bmi = body mass index; bca = bladder cancer; or = odds ratio; ci = confidence interval. archivio italiano di urologia e andrologia 2023; 95, 1 anthropometric characteristics and non-muscle invasive bladder cancer such as the relatively small sample size and lack of dietary habits assessment. however, it is the first one for studying association between a number of anthropometric characteristics with bladder cancer in the greek population and may serve as a basis for future studies. conclusions bladder cancer incidence is strongly linked with specific risk factors such as smoking, occupation with exposure to chemicals and smoke, increasing age, radiation and chronic infections. several studies have shown a weak association between anthropometric characteristics and bladder cancer, although most studies in european populations did not confirm these findings. similarly in our case-control study in a greek population, we found potential relationship between increased weight/bmi and waist circumference with bladder cancer, but the association disappeared in multivariate analysis. references 1. iarc. cancer today. estimated number of new cases in 2020, worldwide, both sexes, all ages. 2021. 2022. (available from: https://gco.iarc.fr/today/online-analysis-table. 2. babjuk m bm, comperat e, gontero p, et al. eau guidelines on non-muscle invasive bladder cancer (ta and t1). (accessed 10 january 2023) (available from: https://d56bochluxqnz.cloudfront.net/ documents/full-guideline/eau-guidelines-on-non-muscle-invasivebladder-cancer-2022.pdf. 3. teoh jy, huang j, ko wy, et al. global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita. eur urol. 2020; 78:893906. 4. freedman nd, silverman dt, hollenbeck ar, et al. association between smoking and risk of bladder cancer among men and women. jama. 2011; 306:737-45. 5. zeegers mp, tan fe, dorant e, van den brandt pa. the impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. cancer. 2000; 89:630-9. 6. colt js, friesen mc, stewart pa, et al. a case-control study of occupational exposure to metalworking fluids and bladder cancer risk among men. occup environ med. 2014; 71:667-74. 7. burger m, catto jw, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013; 63:234-41. 8. reulen rc, kellen e, buntinx f, et al. a meta-analysis on the association between bladder cancer and occupation. scand j urol nephrol suppl. 2008; (218):64-78. 9. harling m, schablon a, schedlbauer g, et al. bladder cancer among hairdressers: a meta-analysis. occup environ med. 2010; 67:351-8. 10. koutros s, baris d, waddell r, et al. potential effect modifiers of the arsenic-bladder cancer risk relationship. int j cancer. 2018; 143:2640-6. 11. tuccori m, filion kb, yin h, et al. pioglitazone use and risk of bladder cancer: population based cohort study. bmj. 2016; 352:i1541. 12. ng m, fleming t, robinson m, et al. global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the global burden of disease study 2013. lancet. 2014; 384:766-81. 13. renehan ag, tyson m, egger m, et al. body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. lancet. 2008; 371:569-78. 14. tzelves l, xenou d, skolarikos a, et al. association of obesity and other anthropometric characteristics with bladder cancer risk: a systematic review and meta-analysis of longitudinal cohort studies. j buon 2021; 26:1040-55. 15. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-4. 16. qin q, xu x, wang x, zheng x. obesity and risk of bladder cancer: a meta-analysis of cohort studies. asian pacific journal of cancer prevention: apjcp. 2013; 14 5:3117-21. 17. zhao h, grossman hb, spitz mr, et al. plasma levels of insulinlike growth factor-1 and binding protein-3, and their association with bladder cancer risk. j urol. 2003; 169:714-7. 18. montella m, di maso m, crispo a, et al. metabolic syndrome and the risk of urothelial carcinoma of the bladder: a case-control study. bmc cancer. 2015; 15:720. 19. cirillo d, rachiglio am, la montagna r, et al. leptin signaling in breast cancer: an overview. j cell biochem. 2008; 105:956-64. 20. beckman kb, ames bn. oxidative decay of dna. j biol chem. 1997; 272:19633-6. 21. mcgrath m, michaud ds, de vivo i. hormonal and reproductive factors and the risk of bladder cancer in women. am j epidemiol. 2006; 163:236-44. 22. rosenzweig ba, bolina ps, birch l, et al. location and concentration of estrogen, progesterone, and androgen receptors in the bladder and urethra of the rabbit. neurourol urodyn. 1995; 14:87-96. 23. xenou d, tzelves l, terpos e, et al. consumption of fruits, vegetables and bladder cancer risk: a systematic review and meta-analysis of prospective cohort studies. nutr cancer. 2022; 74:2003-16. correspondence lazaros tzelves, md (corresponding author) lazarostzelves@gmail.com stamatis katsimperis, md stamk1992@gmail.com themistoklis bellos, md vbellos.themistoklis@gmail.com marinos berdempes, md marinosberdebes@hotmail.com iraklis mitsogiannis, md imitsog@med.uoa.gr athanasios papatsoris, md agpapatsoris@yahoo.gr charalampos deliveliotis, md chdeliveli@gmail.com author ioannis varkarakis, md medvark3@yahoo.com andreas skolarikos, md andskol@yahoo.com 2nd department of urology, sismanoglio hospital, medical school, national and kapodistrian university of athens, sismanogliou 37 athens (greece) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 501archivio italiano di urologia e andrologia 2021; 93, 4 letter to editor no conflict of interest declared. to the editor, benign prostatic hyperplasia (bph) is one of the main causes of patients seeking urological counselling in western countries. it has been estimated that nearly 70 percent of united states men between the ages of 60 and 69 years, and nearly 80 percent of men ≥ 70 years, have some degree of bph (1). bph is a histologic diagnosis defined as an increase in the total number of stromal and glandular epithelial cells within the transition zone of the prostate gland. bph results in benign prostatic enlargement (bpe) that can, in turn, lead to bladder outlet obstruction (boo). bpe and mostly boo is often associated with lower urinary tract symptoms (luts), which can be subdivided into symptoms of urinary storage (eg, urgency, daytime frequency, nocturia, incontinence, etc.), symptoms of urinary voiding (eg, slow stream, intermittent stream or intermittency, hesitancy, straining to void, terminal dribble, dysuria, etc.) and post-voiding symptoms (eg, sensation of incomplete bladder emptying, post-void urinary dribbling, etc.). all above-mentioned symptoms reported by patients with bph contribute to a significantly reduced quality of life (2, 3). the initial treatment for bladder outlet obstruction (boo) secondary to benign prostatic hyperplasia (bph) is generally pharmacologic, especially in patients with mild to moderate symptoms and no clear indication for surgical intervention. medical therapy consists of alpha-blockers, 5-alpha reductase inhibitors, or a combination of these agents (4). alphablockers are first-line agents used for the treatment of symptomatic bph. these drugs relax the smooth muscle tone at the bladder neck. if associated with 5-alpha reductase inhibitor drugs the use of alpha-blockers agents may result more effective than monotherapy with either drug alone (5). given the above, several data in the literature reported that electromagnetic fields (emf) have many biological activities capable of interfering with the ability to reproduce and differentiate cells, modulating the inflammatory system through the increase of oxide-reductive potential, and increasing microvascular motility, atp production, hormonal secretion, antioxidant enzyme activity, and cellular metabolism (6); moreover emf at high frequency and low intensity allows to obtain significant therapeutic results without unwanted side effects, allowing their use also in a wide spectrum of chronic diseases characterized by functional disorders and pain, such as chronic inflammatory diseases (7). the antiphlogistic and stimulating effects of the tissue repair produced by magnetic fields in humans allows to achieve favorable therapeutic results especially in diseases affecting the osteoskeletal system, such as the fractures and the arthropathies (8). the vibrating systems are equipment capable of generating sinusoidal oscillations at various frequencies and transfer them to the body of the subject to be treated through pressure waves, with specially designed platforms just capable of vibrating at variable frequencies (hertz/sec) (9). the treatment with vibrations exerts a safe myo-relaxant effect with consequent reduction of muscle spasticity and is widely used in the field of neuro-rehabilitation (10). with vibratory frequencies varying between 5 and 30 hz, an increase in cerebral cortisone and serotonin has been demonstrated in the rat; in humans, mono or polysynaptic connections are activated in order to generate reflex contractions (11). the stim-plavim®, a device which is capable of simultaneously generating an intense variable electromagnetic field and vibratory stimulation, was object of an observational perspective study in patients affected by voiding symptoms attributed to bladder outlet obstruction secondary to benign prostatic hyperplasia and already treated by alpha-blocker agents. these preliminary results of a randomized crossover clinical trial comparing a new electromagnetic and vibrating device and alpha-blocker agents in patients affected by bladder outlet obstruction secondary to benign prostatic hyperplasia simone brardi 1, giuseppe romano 2, gabriele cevenini 3 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 urology unit, s. maria della gruccia hospital, montevarchi, italy; 3 department of medical biotechnologies, university of siena, italy. key words: benign prostatic hyperplasia; pulsed electromagnetic fields, alpha-bocker agents; randomized crossover clinical trial. submitted 27 august 2021; accepted 19 september 2021 doi: 10.4081/aiua.2021.4.501 archivio italiano di urologia e andrologia 2021; 93, 4 s. brardi, g. romano, g. cevenini 502 patients without stopping the pharmacologic therapy added the application of the stim-plavim® device at the perineal level every day for 30 minutes for a period of 60 days. the application of the above mentioned device resulted in a rapid improvement of voiding symptoms as confirmed by the statistically significant reduction in the mean score of the international prostatic symptoms score (ipps) (12). however, the above mentioned study was performed in an uncontrolled design hence the need to compare the stim-plavim® with the use of alpha-blocker agents which today represent the cornerstone of the current standard therapy for bladder outlet obstruction secondary to bph (4). we hypothesized that, in the above-mentioned patients the use of stim-plavim® device would be more effective than alpha-blockers in reducing the mean volume of bladder residue after voiding. we further hypothesized that the use of stim-plavim® device would improve secondary parameters tied to bph such as the prostatic volume, the total psa value and the ipss more than conventional alpha-blockers agents therapy. material and methods this study was performed in a monocentric, controlled, randomized, two-periods crossover design. each period included 45 daily applications of stim-plavim® device at the perineal level each lasting 30 minutes without the intake of any alphablocker agent (although 5-alpha reductase inhibitors, mainly dutasteride and secondarily finasteride, were used in 60% of cases) or the daily oral intake of an alpha-blocker agent (60% alfuzosin and tamsulosin for the rest) for a same length of 45 days. when already in use the 5-alpha reductase inhibitors were associated with the alpha-blocker agents too and therefore the use of 5-alpha reductase inhibitors remained unchanged in both periods. at crossover and at the end of the study assessment were done. patients were randomly assigned to start the study with a period of daily stim-plavim® device application or a period of daily oral intake of an alpha-blocker agent using a computer-generated list. masking the treatment allocation for physician and patients was not feasible. ten ambulatory patients (mean age 65 ± 7 years) affected by bladder outlet obstruction secondary to bph were enrolled. all patients provided written informed consent before participating. the inclusion criteria were a clinical, laboratory and ultrasound diagnosis of benign prostatic hyperplasia at least 6 months prior and age between 50 and 80 years. exclusion criteria were a proven diagnosis of prostatic cancer, urinary infections, the permanent or temporary use of bladder catheter, neurological voiding disturbances, alpha-blockers agents intolerance or the presence of medical electrical devices incompatible with the use of electromagnetic fields. the volume of bladder residue after voiding was estimated with a suprapubic ultrasound method as well as the prostatic volume was assessed by a transrectal ultrasound method in both cases using the same ultrasound device logiq s7 (ge medical systems italy s.p.a. milan, italy) sonographic system equipped with 3 to 5 mhz convex transducers for the suprapubic ultrasound and a be9cs (ge medical systems italy s.p.a. milan, italy) biplane intracavity probe with a bandwidth of 4-11 mhz for the transrectal ultrasound. all ultrasonography examinations were carried out by the same nephrologist experienced in ultrasound examination. to characterize the subjective evaluation of the urological symptoms, the international prostatic symptoms score (ipss) was assessed and finally was tested the total psa value. the stim-plavim® device used in our study is a medical device consisting of a polyethylene/erthalite container hand piece, washable and sterilizable, consisting of two cylinders: the larger one contains a low voltage electric motor inside, which is connected by a joint to a shaft in aluminum/stainless steel with a modulating speed motor. the shaft containing the motor has the shape of a cradle able to house the high-quality neodymium magnet which exerts an intense magnetic force between 1000 and 1500 gauss. the housing of the magnet in the cradle is assembled asymmetrically so that the rotation of the motor, with adjustable speed by means of a special dedicated electronic program, allows to simultaneously generate an intense permanent and rotating magnetic field and a vibratory trend with specific frequency (between 80 and 140 hertz). the handpiece, with an ergonomic cylindrical shape, is closed at the two lower and upper ends with two caps with screw closure; the upper part of the device also contains a rechargeable electric accumulator (with a common 220 volt electric socket) (figures 1, 2). statistical analysis quantitative variables, preand post-treatment with stim-plavim® device, were tested for their mean reduction using student's t-test for paired data, before testing for normality with the kolmogorov-smirnov test. a significance level of 95% (p < 0.05) was chosen for all statistical analyses performed with spss software, version 10. figure 1. stim-plavim® device. figure 2. stim-plavim® device application modality. 503archivio italiano di urologia e andrologia 2021; 93, 4 stim-plavim® device in benign prostatic hyperplasia results statistically significant reductions in prostate volume, postvoid residual bladder volume and suprapubic prostatic transverse diameter between preand post-treatment with stim-plavim® device were found while there was no statistically significant reduction in psa and ipss. prostatic volume, postvoid residual bladder volume, suprapubic prostatic transverse diameter, total psa and ipss before and after application of stim-plavim® device are shown in table 1. the statistical results of the comparison between preand post-treatment data with stim-plavim® device are instead shown in table 2. reductions in prostate volume (mean difference of 6.35 ml, p = 0.003), postvoid residual bladder volume (mean difference of 28.8 ml, p = 0.032) and suprapubic prostatic transverse diameter (mean difference of 4 mm, p = 0.001) were significant at 95%, while there was no statistically significant reduction in psa and ipss. no problems related to adverse reactions or intolerance neither with the oral intake of alpha-blocker agents neither with application of stimplavim® device were reported. all patients completed the planned two-periods of the study, and none was excluded because of intolerance or lack of compliance. discussion the main finding of this study is that stim-plavim® device significantly reduced, in bph patients, prostate volume and postvoid bladder volume more than the intake of any alpha-blocker agent as well as the suprapubic prostatic transverse diameter. instead, there was no statistically significant reduction in total psa and ipss. these results are partially consistent with the results of previous studies such as that one of elgohary et al. (13) which demonstrated the effectiveness of pulsed electromagnetic fields alone or in association to exercise therapy in the treatment of benign prostatic hypertrophy in terms of ipss improvement and reduction of bladder residue after voiding and that of tenuta et al. (14) which likewise demonstrated the effectiveness of pulsed electromagnetic fields in terms of prostate volume reduction and ipss enhancement. in neither of the two studies however the pulsed electromagnetic fields were compared with the standard drug therapy for benign prostatic hypertrophy. in the study of giannakopoulos et al. (15) the exposure of bph patients to a pulsed electromagnetic field or an alpha blocker therapy resulted in a statistically significant decrease of prostate volume and bladder residue after voiding, in the pulsed electromagnetic fields group, while the ipss showed a statistically significant decrease before and after treatment both with pulsed electromagnetic fields and with the use of alpha-blockers. all above studies however used pulsed electromagnetic fields devices without the vibratory stimulus that is present in the stim-plavim® device. about lack of improvement in ipss with stim-plavim® device it is necessary to point out that are well known the changes in the ipss obtained with dutasteride, tamsulosin, and combination therapy in men with symptomatic benign prostatic hyperplasia and an enlarged prostate because the combination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among those men and is effective regardless of previous bph medical therapy (16). given the above, the performance of stim-plavim® device about ipss, similarly to what found in the work of giannakopoulos (15), represents an invariance result rather than a failure since this result was obtained in comparison with alpha blockers that are very effective in ameliorating the ipss. besides, the failure to reduce ipss remained within clinically insignificant limits and may be certainly compensated by the advantages in terms of greater safety, since all the adverse effects usually associated with alpha-blockers were excluded and there was no notable adverse effect with the use of stim-plavim® device nor significant contraindications to its use which resulted always well tolerated. furthermore stim-plavim® device proved to be safe and more effective than alpha-blockers with respect to quantitative and objective parameters such as prostate volume and bladder residue after voiding. about the invariance of total psa we must point out that in the our study the daily oral intake of an alpha-blocker agent or the use of stim-plavim® device were associated with a wide use of 5-alpha reductase inhibitors whose use remained therefore unchanged throughout the all duration of the study, so that we believe that the use of 5-alpha reductase inhibitors may be cause of the invariance of the total psa values since those drugs have a deep impact over the total psa values (16). table 1. prostatic volume, postvoid residual bladder volume, suprapubic prostatic transverse diameter, total psa and ipss before and after application of stim-plavim® device. after the daily oral intake after 45 daily of an alpha‐blocker application of agent for 45 days and stim‐plavim® device before any application and without any of stim‐plavim® device alpha‐blocker agent prostatic volume (ml) 44 ± 14 37 ± 11 postvoid residual bladder volume (ml) 56 ± 70 28 ± 45 suprapubic prostatic transverse diameter (mm) 47 ± 5 43 ± 6 total psa (ng/ml) 2 ± 2 2 ± 2 ipss (international prostatic symptoms score) 15 ± 6 13 ± 7 table 2. statistical results of the comparison between preand post-treatment data with stim-plavim® device. variable t p-value mean 95% reduction confidence interval lower bound upper bound prostatic volume (ml) 3.95 0.003 6.35 2.72 9.98 postvoid residual bladder volume (ml) 2.54 0.032 28.8 3.14 54.5 total psa (ng/ml) 1.03 0.328 0.479 -0.57 1.53 ipss 0.77 0.459 1.90 -3.66 7.46 suprapubic prostatic transverse diameter (mm) 4.90 0.001 4.00 2.15 5.85 archivio italiano di urologia e andrologia 2021; 93, 4 s. brardi, g. romano, g. cevenini 504 conclusions the our study, despite the small scale of the sample examined, it is the first pulsed electromagnetic fields study provided in a controlled, randomized and crossover design in patients affected by bladder outlet obstruction secondary to bph where the pulsed electromagnetic fields (with the vibratory stimulus that is present in the stim-plavim® device) were compared with the standard bph drug therapy obtaining a statistically significant decrease of two objective and quantitative parameters as the prostate volume and the postvoid residual bladder volume. this study therefore may open to a clinical use on a larger scale of this device in the same patients affected by bladder outlet obstruction secondary to bph. references 1. mcvary kt. epidemiology and pathophysiology of benign prostatic hyperplasia. in: uptodate, post tw (ed), uptodate, waltham, ma. 2020. 2. mcvary kt. lower urinary tract symptoms in men. in: uptodate, post tw (ed), uptodate, waltham, ma. 2020. 3. fourcade ro, lacoin f, rouprêt m, et al. outcomes and general health-related quality of life among patients medically treated in general daily practice for lower urinary tract symptoms due to benign prostatic hyperplasia. world j urol. 2012; 30:419-426. 4. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015; 67:1099-1109. 5. roehrborn cg, siami p, barkin j, et al. for the combat study group. the effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the combat study. j urol. 2008; 179:616-621. 6. binhiv, savin a. effects of weak magnetic fields on biological systems: physical aspects, phys us pekhi. 2003; 46:259-291. 7. mcfarlane jp, foley sj, de winter p, et al. acute suppression of idiopathic detrusor instability with magnetic stimulation of the sacral nerve roots. br j urol. 1997; 80:734-741. 8. haddad jb, obolensky ag, shinnick p. the biologic effects and the therapeutic mechanism of action of electric and electromagnetic field stimulation on bone and cartilage: new findings and a review of earlier work. j altern complement med. 2007; 13:485-490. 9. bosco c, cardinale m. nuove frontiere dell’allenamento sportivo: le vibrazioni. effetti sul comportamento meccanico del muscolo scheletrico. coaching and sport science journal. 1998; 3:53-59. 10. flieger j, karachalios t, khaldi l, et al. mechanical stimulation in the form of vibration prevents postmenopausal bone loss in ovariectomized rats. calcif tissue int. 1998; 63:510-514. 11. rodrigues mp, paiva ll, ramos jgl, ferla l. vibratory perineal stimulationfor the treatment of female stress urinary incontinence: a systematic review. int urogynecol j. 2018; 4:555-562. 12. brardi s, biandolino p, giovannelli v, et al. possible applications of electromagnetic fields in the treatment of symptoms related to benign prostatic hyperplasia. am j urol res. 2020; 5:006-010. 13. elgoharyhm, tantawy sa. pulsed electromagnetic field with or without exercise theraphy in the treatment of benign prostatic hyperplasia. j phys ther sci. 2017; 29:1305-1310. 14. tenuta m, tarsitano mg, mazzotta p, et al. therapeutic use of pulsed electromagnetic field therapy reduces prostate volume and lower urinary tract symptoms in benign prostatic hyperplasia. andrology. 2020; 8:1076-1085. 15. giannakopoulos xk, giotis c, karkabounas s ch, et al. effects of pulsed electromagnetic fields on benign prostate hyperplasia. int urol nephrol. 2011; 43:955-60. 16. roehrborn cg, siami p, barkin j, et al. the influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the combat study. eur urol. 2009; 55:461-471. correspondence simone brardi, md (corresponding author) sibrardi@gmail.com hemodialysis unit, s. donato hospital, arezzo (italy) giuseppe romano, md giuseppe.romano@uslsudest.toscana.it urology unit, s. maria della gruccia hospital, montevarchi (italy) gabriele cevenini, md gabriele.cevenini@unisi.it department of medical biotechnologies, university of siena (italy) stesura seveso 451archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. 11.8-24.7% of adults in north america and europe, and its prevalence increases with age (3). in addition to age, the risk factors for oab include diabetes, uti, and obesity (4, 5). pharmacotherapy is the main treatment for oab in japan, and anticholinergic drugs are considered to be first-line drugs (6). recently, β3 adrenergic agonists, which have completely different mechanism of action from anticholinergic drugs, have become available and have been shown to be effective. β3 adrenergic agonists were awarded a grade-a recommendation in the japanese oab treatment guidelines. however, no study on the criteria for choosing between anticholinergics and β3 adrenergic agonists has been published. when treating patients with oab, how do clinicians choose among these medications, which both have grade-a recommendations and exhibit comparable therapeutic efficacy? are there any factors that influence the selection of these medications? in the present study, we investigated the factors that influence the selection of anticholinergic drugs or β3 adrenergic agonists for oab in the real world practice. materials and methods this was a retrospective study, which used data extracted from electronic records. seventy-five who were diagnosed with oab at the department of urology, teikyo university chiba medical center (ichihara, japan), between january 2013 and december 2014 were included in this study. the overactive bladder symptoms score (oabss) was calculated for each patient, and all of the patients met the diagnostic criteria for oab. oab was diagnosed based on the oabss or the presence of urinary urgency (6). the oabss is a validated self-assessed questionnaire created by the japanese continence society and consists of four questions about oab symptoms (q1: daytime frequency, q2: nighttime frequency, q3: urgency, and q4: urge incontinence) (6). we retrospectively evaluated various factors, including age, administered treatments, body mass index (bmi), pretreatment total oabss, pretreatment score for each oabss factor, post-voiding residual volume (pvr), smoking habits, presence or absence of hypertension, diabetes mellitus, and dyslipidemia. the post-voiding residual (pvr) urine was measured on a transabdominal ultrasonic echogram in all cases. objective: the reasons why anticholinergic drugs or β3 adrenergic agonists are selected as treatments for overactive bladder (oab) are unclear. the aim of this study was to investigate the background data of female oab patients that were prescribed anticholinergic drugs or β3 adrenergic agonists in a real-world setting. materials and methods: between january 2013 and december 2014, 75 patients who had been diagnosed with oab were included in this study. administered medications, age, the persistence on treatment rate at one-year, medical history, pretreatment total overactive bladder symptom score (oabss), pretreatment score for each oabss factor, body mass index (bmi), and various comorbidities were evaluated retrospectively. since there were many types of anticholinergic drugs and few patients, we grouped the patients into those that were prescribed anticholinergic drugs (group a) and those that were prescribed β3 adrenergic agonists (group b). results: 75 patients (29 in group a and 46 in group b) were included in this study. there were no significant differences in age, bmi, obesity, medical history, pretreatment total oabss, or pretreatment score for each oabss factor. there was a significant difference in the post-voiding residual urine volume (pvr) between the groups (group a: 22 ml, group b: 9 ml; p = 0.0252). the 1-year persistence on treatment rate was 28% in both groups. conclusions: there were no significant differences in clinical characteristics of patients who were prescribed anticholinergics and β3 adrenergic agonists for oab treatment, but a marginal difference of pvr value before treatment. the 1-year persistence rates of anticholinergic drugs and β3 adrenergic agonists were considered to be almost equivalent. key words: overactive bladder; anti-cholinergic drugs; β3 adrenergic agonists; post-voiding residual urine volume. submitted 28 october 2022; accepted 10 november 2022 introduction overactive bladder (oab) is a condition with characteristic symptoms of urinary urgency, usually accompanied by increased urinary frequency and nocturia, with or without urge incontinence, in the absence of a urinary tract infection (uti) or any other obvious pathology (1). it was observed that the prevalence of oab among japanese adults aged ≥ 40 years is 12.4%, and the estimated number of patients with oab is 8.1 million (2). oab affects the choice of therapeutic agent in female overactive bladder patients in real-world practice hiroshi masuda, kosuke mikami, kotaro otsuka, kyokusin hou, takahito suyama, kazuhiro araki, satoko kojima, yukio naya department of urology, teikyo university chiba medical center, 3426-3 anesaki, ichihara, chiba 299-0111, japan. doi: 10.4081/aiua.2022.4.451 summary archivio italiano di urologia e andrologia 2022; 94, 4 h. masuda, k. mikami, k. otsuka, k. hou, t. suyama, k. araki, s. kojima, y. naya 452 regarding the administered medications, since many kinds of anticholinergic drugs were administered in small groups of patients, patients were categorized into two groups as those treated with anticholinergic drugs (group a) and those treated with β3 adrenergic agonists (group b). the patients were allowed to discontinue their medication during the follow-up period, according to their desires and the judgement of the attending physician. we investigated the continuation/discontinuation of anticholinergic drug and β3 adrenergic agonist treatment. although we could not examine the reasons for discontinuation. statistical analysis statistical analyses were carried out to identify clinical parameters that differed significantly between groups a and b. the results are shown as mean ± se or percentage. the mann-whitney u test and chi-squared test were used for the statistical analyses. all analyses were performed with jmp version 10 (sas institute inc., cary, nc, usa). a probability value of < 0.05 was considered statistically significant. ethical approval. the institutional review board of teikyo university approved this study (tuic-coi 21-1218). results table 1 shows the patients’ background characteristics. we evaluated 75 patients (29 in group a and 46 in group b) that were prescribed anticholinergic drugs or β3 adrenergic agonists by our department. there were no significant differences in age, bmi, obesity, medical history, the pretreatment total oabss, or the pretreatment scores for individual oabss factors. the mean pretreatment pvr was significantly greater in group a than in group b (22 ml vs. 9 ml, respectively; p = 0.0252) (table 2). a younger age, a lower pretreatment total oabss score, table 1. patient characteristics. no. of patients n = 75 age (years, mean ± se) 70 ± 1.4 medication anticholinergics (n） 29 propiverine 3 imidafenacin 9 fesoterodine 6 solifenacin 11 β3 adrenergic agonists 46 body mass index (kg/m2, mean ± se) 28.2 ± 0.3 oabss daytime frequency 1.0 ± 0.1 nighttime frequency 2.4 ± 0.1 urgency 2.9 ± 0.2 urge incontinence 1.7 ± 0.2 total score 8.1 ± 0.5 pvr (ml, mean ± se) 14 ± 2.6 smoking positive/negative 7/68 alcohol consumption positive/negative 7/68 hypertension positive/negative 38/37 diabetes mellitus positive/negative 10/65 dyslipidemia positive/negative 24/51 oabss: overactive bladder symptom score; pvr: post-voiding residual urine volume. table 2. comparisons between the groups. variable group a (n = 29) group b (n = 46) p-value age (years, mean ± se) 69 ± 1.4 71 ± 1.7 0.5029 body mass index (kg/m2, mean ± se) 28.2 ± 0.5 28.3 ± 0.3 0.6414 oabss daytime frequency 1.1 ± 0.1 1.0 ± 0.1 0.2736 nighttime frequency 2.5 ± 0.1 2.4 ± 0.1 0.7708 urgency 3.1 ± 0.2 2.8 ± 0.3 0.5017 urge incontinence 2.1 ± 0.2 1.5 ± 0.3 0.1298 total score 8.8 ± 0.7 7.7 ± 0.6 0.1639 pvr (ml, mean ± se) 22 ± 5.8 9.2 ± 2.2 0.0247 0-50 ml/51-100 ml/100 ml< 26/3/0 45/1/0 0.1251 smoking positive/negative 4/25 3/43 0.151 alcohol consumption positive/negative 2/27 5/14 0.3061 hypertension positive/negative 13/16 25/21 0.4219 diabetes mellitus positive/negative 3/26 7/39 0.5455 dyslipidemia positive/negative 7/22 17/29 0.2465 oabss: overactive bladder symptom score; pvr: post-voiding residual urine volume. table 3. assessment of the factors affecting the continuation of medical treatment. variable continuation discontinuation p-value group (n = 21) group (n = 54) age (years, mean ± se) 74 ± 1.4 68 ± 1.7 0.2328 medication 0.9495 anticholinergics 8 21 mirabegron 13 33 body mass index (kg/m2, mean ± se) 28.0 ± 0.5 28.3 ± 0.3 0.5236 oabss daytime frequency 1.2 ± 0.1 1.0 ± 0.1 0.201 nighttime frequency 2.6 ± 0.3 2.4 ± 0.1 0.2912 urgency 2.8 ± 0.4 3.0 ± 0.3 0.5301 urge incontinence 1.9 ± 0.4 1.7 ± 0.3 0.614 total score 8.6 ± 0.9 8.1 ± 0.5 0.8093 pvr (ml, mean ± se) 18 ± 5.6 12 ± 3.0 0.3325 smoking positive/negative 0/21 7/47 0.151 alcohol consumption positive/negative 2/19 5/49 0.3061 hypertension positive/negative 9/12 29/25 0.3989 diabetes mellitus positive/negative 4/17 6/48 0.364 dyslipidemia positive/negative 6/15 18/36 0.6914 oabss: overactive bladder symptom score; pvr: post-voiding residual urine volume. 453archivio italiano di urologia e andrologia 2022; 94, 4 treatment in female oab and a lower pvr were associated with a tendency towards medication discontinuation. however, no potential predictors of discontinuation differed significantly between the groups (table 3). the one-year persistence rate of prescriptions from our department was 28% in both groups. discussion in the japanese guidelines for oab, anticholinergic drugs and β3 adrenergic agonists are given grade-a recommendations as treatments for oab (6). however, while there has been some debate about the usage of different anticholinergic drugs, there was insufficient discussion and there are no clear indicators or guidelines regarding the usage of anticholinergic drugs versus β3 adrenergic agonists. therefore, individual medications are being administered for oab without any particular reason in real-world practice, and it seems that choices between anticholinergic drugs and β3 adrenergic agonists are based on the treating doctor’s preferences and experience. in the present study, we investigated the factors that influence the selection of anticholinergic drugs and β3 adrenergic agonists in the real-world. to the best of our knowledge, this is the first study to investigate this among oab patients. safety safety is the first consideration when selecting a drug, and avoiding adverse events should be prioritized over efficacy. β3 adrenergic agonists cause side effects, such as dry mouth and constipation, less frequently than anticholinergic drugs. this should favor the selection of β3 adrenergic agonists. regarding dry mouth, it has been reported that β3 adrenergic agonists cause this symptom in 33% fewer cases than tolterodine (7). in another study, it was reported that the incidence of dry mouth during β3 adrenergic agonist treatment was similar to that produced by a placebo, and that it was associated in one-fifth of cases with anticholinergic drugs (8). it has been observed that dry mouth is an important factor influencing oral medication discontinuation (9). therefore, there is an advantage in choosing β3 adrenergic agonists over anticholinergic drugs. it has also been reported that β3 adrenergic agonists have higher persistence rates than anticholinergics drugs and should be considered for firstline pharmacological treatment for oab (10). furthermore, it should be considered that elderly patients would be more likely to be prescribed β3 adrenergic agonists than anticholinergics because of their high frequency of abnormal bowel movements. finally, it is likely that medications that involve fewer oral doses should be selected for elderly patients because they may already be taking a large number of medications. post-voiding residual urine in a comparative study of anticholinergic drugs and β3 adrenergic agonists, it was reported that there was no significant difference in the increase in the pvr seen during the study period (0.86 ml for the placebo, 0.80 ml for β3 adrenergic agonists, and 0.44 ml for tolterodine) (11). moreover, stöhrer et al. reported that the pvr increased significantly from 50 ml to 87 ml in patients treated with propiverine (12). also, khullar et al. reported that a pvr exceeding 300 ml was seen in 0.2% of patients treated with β3 adrenergic agonists (7). these studies suggest that the pvr is not a determining criterion during the selection of anticholinergic drugs or β3 adrenergic agonists. regarding the frequency of urinary retention, it has been reported that it was < 1% in patients treated with anticholinergic drugs, while it was almost negligible in patients treated with β3 adrenergic agonists (13). in the present study the pretreatment pvr was significantly higher in patients who were prescribed anticholinergics compared to those who were treated with β3 adrenergic agonists, but this finding seemed to be of limited clinical significance because it was related to only three patients with high pvr taking anticholinergics. compliance to treatment it has been reported that the 1-year persistence rates of anticholinergic drugs and mirabegron ranged from 17% to 35% (14) and 19-38% (9, 15, 16), respectively. the 1-year persistence rates of anticholinergic drugs and β3 adrenergic agonists at our institution were similar. it has been reported that treatment discontinuation is also seen in younger age groups, and our study showed a similar trend (17). we suggest that this could be explained by the fact that the drugs were administered at hospital, and an appointment was required to visit the hospital. however, a recent study suggested that β3 adrenergic agonists have very high 1-year persistence rates of 63% in females and 67% in males (18). it was considered that this was probably because β3 adrenergic agonists are safe and well tolerated. non-medical factors recently, a study reported that when physicians received complimentary meals and hospitality by a pharmaceutical company they increased their prescriptions of drugs marketed by that company (19). although this may have affected our prescription patterns, we do not have any information about this in the present study. this could be an important subject for further study, including other oral medications. limitations our study presented some limitations: 1) it was a retrospective cohort study, which involved the extraction of electronically stored clinical data, and it had a small sample size. thus, it will be necessary to validate the findings of this retrospective analysis in prospective studies, including a randomized study, with larger populations in future. we expect that such studies will provide new perspectives on how decisions regarding the selection of anticholinergic drugs and β3 adrenergic agonists are made. 2) since this study only involved females, the factors influencing the selection of anticholinergic drugs or β3 adrenergic agonists in male oab patients were not evaluated. 3) the patients’ complications and the other types of medications they were taking were not investigated, and hence, more detailed patient background information is needed. 4) the two-year observation period was relatively short, archivio italiano di urologia e andrologia 2022; 94, 4 h. masuda, k. mikami, k. otsuka, k. hou, t. suyama, k. araki, s. kojima, y. naya 454 and hence, it may not have been long enough to allow appropriate evaluations to be performed. 5) patients assuming anticholinergics were analyzed collectively because the small number of patients taking different anticholinergics did not allow to analyze them separately. collection of larger populations taking different anticholinergics could give information about difference of outcomes between them. 6) untreated patients were not investigated. 7) we did not investigate refractory oab separately. conclusions there were no significant differences in clinical characteristics of patients who were prescribed anticholinergics and β3 adrenergic agonists for oab treatment, but a marginal difference of pvr value before treatment. the 1-year persistence rates of anticholinergic drugs and β3 adrenergic agonists were considered to be almost equivalent. references 1. abrams p, cardozo l, fall m paul abrams, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. neurourol urody. 2002; 21:167-178. 2. homma y, yamaguchi o, hayashi k. neurogenic bladder society committee. an epidemiological survey of overactive bladder symptoms in japan. bju int. 2005; 96:1314-1318. 3. eapen rs, radomski sb. review of the epidemiology of overactive bladder. res rep urol. 2016; 8:71-76. 4. brown js, mcghan wf, chokroverty s. comorbidities associated with overactive bladder. am j manag care. 2000; 6:s574-579. 5. subak ll, richter he, hunskaar s. obesity and urinary incontinence: epidemiology and clinical research update. j urol. 2009; 182:s2-7. 6. yamaguchi o, nishizawa o, takeda m, et al. clinical guidelines for overactive bladder. int j urol 2009; 16:126-142. 7. khullar v, amarenco g, angulo j, et al. efficacy and tolerability of mirabegron, a β (3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised european-australian phase 3 trial. eur urol. 2013; 63:283-295. 8. yamaguchi o, marui e, kakizaki h, et al. phase iii, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in japanese patients with overactive bladder. bju int. 2014; 113:951-960. 9. chapple cr, nazir j, hakimi z, et al. persistence and adherence with mirabegron versus antimuscarinic agents in patients with overactive bladder: a retrospective observational study in uk clinical practice. eur urol. 2017; 72:389-399. 10. yeowell g, smith p, nazir j. et al. real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (oab): a systemic literature review. bmj open. 2018; 8:e021889. 11. yamaguchi o, ikeda y, ohkawa s. phase iii study to assess longterm (52-week) safety and efficacy of mirabegron, a β3-adrenoceptor agonist, in japanese patients with overactive bladder. luts. 2017; 9:38-45. 12. stöhrer m, madersbacher h, richter r, et al. efficacy and safety of propiverine in sci-patients suffering from detrusor hyperreflexia-a double-blind, placebo-controlled clinical trial. spinal cord. 1999; 37:196-200. 13. nitti vw, khullar v, van kerrebroeck p, et al. mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, doubleblind, placebo-controlled, phase iii studies. int j clin pract. 2013; 67:619-632. 14. wagg a, compion g, fahey a, siddiqui e. persistence with prescribed antimusucarinic therapy for overactive bladder: a uk experience. buj int. 2012; 110:1767-1774. 15. wagg a, franks b, ramos b, berner t. persistence and adherence with the new beta-3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: early experience in canada. can urol asso j. 2015; 9:343-350. 16. sussman d, yehoshua a, kowalski j, et al. adherence and persistence of mirabegron and anticholinergic therapies in patients with overactive bladder: a real-world claims data analysis. int j clin prac. 2017; 71:e12824. 17. kalder m, pantazis k, dinas k, et al. discontinuation of treatment using anticholinergic medications in patients with urinary incontinence. obstet gynecol. 2014; 124:794-800. 18. wada n, watanabe m, banjo h, et al. long-term persistence with mirabegron in a real-world clinical setting. int j urol. 2018; 25:501-506. 19. dejong c, aguilar t, tseng cw, et al. pharmaceutical industry–sponsored meals and physician prescribing patterns for medicare beneficiaries jama intern med. 2016; 176:1114-1122. correspondence hiroshi masuda, md, phd (corresponding author) hrsmasuda@yahoo.co.jp kosuke mikami, md kotaro otsuka, md kyokusin hou, md takahito suyama, md kazuhiro araki, md satoko kojima, md yukio naya, md department of urology, teikyo university chiba medical center, 3426-3 anesaki, ichihara, chiba, 299-0111, japan cop+ed+fisse 2006 91archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. expanded significantly (2). today, they are almost considered a standard and indispensable urological tool. ureteral obstruction is a complex and heterogeneous clinical condition therefore determining the ideal decompression method can be challenging for urologists. these obstructions may develop owing to malignant or benign aetiologies. malignancy that leads to this type of complex obstruction may originate from organs external to the urinary system as colorectal or gynaecological tumors or from organs internal to urinary system such as bladder and prostate cancers (3) (figure 1). the aetiology of benign ureteral obstructions can be intraureteral or extra-ureteral. intra-ureteral causes are the result of various pathologies such as ureteropelvic junction obstruction, impacted chronic ureteral stones or strictures after recurrent endoscopic interventional procedures. extra-ureteral benign obstructions may be caused by the obstetric causes, uterine leiomyomas or retroperitoneal fibrosis (4). in cases of malignancy that cause severe ureteral obstruction, the benefits of draining the upper urinary system include symptomatic relief, preservation and maintenance of renal function, reduction of hospital stay and minimisation of the negative effects on the patient's quality of life (3-5). however, there is still no clear guideline on ideal methods for how to free urinary flow in the management of ureteral obstructions (6). in patients without lower urogenital system pathologies and active urinary tract infection, retrograde ureteral stenting can be used as an alternative for long-term ureteral obstruction or fistula treatment. the jj stents used in this procedure are normally inserted in a retrograde approach by using a guidewire placed by cytoscopic or ureterorenoscopic method (1). however, in this approach, it is sometimes not possible to advance the guidewire proximally to the site of obstruction due to technical shortcomings, especially in patients with anatomical dislocation of the bladder wall, abnormally localised ureteral orifice by the tumor or in patients with malignant obstruction involving a long ureteral segment. in addition, retrograde ureteral stenting can sometimes be difficult or even unsuccessful in patients with obstrucobjective: the aim of the present study was to examine the results of antegrade jj stent placement in upper urinary tract obstruction in patients where retrograde placement was not possible. methods: in this retrospective study, patients who underwent antegrade jj stent placement for malignant ureteral obstruction in the urology clinic of a university hospital between january 1, 2018 and december 31, 2020 were included in the study. jj stent was placed under local or general anaesthesia guided by ultrasonography and fluoroscopy. age, gender, kidney function values, pathologies causing obstruction, and complications of the patients were examined. results: in this study, 40 patients (16 men, 24 women) who underwent antegrade jj stent placement were included. the mean ages of the women and men included were 51 (31-91) years and 62.5 (26-81) years, respectively. in all, antegrade jj stenting was performed in 61 renal units of these patients. of these, 21 were bilateral, 11 in the right collecting system and 8 in the left collecting systems. clinical and technical success was achieved in 59 of the 61 procedures (96.6%). arteriovenous fistula developed in only one patient, whereas no serious complications such as massive bleeding, resistant hematuria or pseudoaneurysm occurred in the remaining patients. the procedure was completed in a mean time of 15-30 minutes. conclusions: antegrade jj stent placement is a procedure with a high success rate and low risk of complications that can be used in patients with severe ureteral obstruction owing to malignant or benign aetiologies. this method should be applied in centres experienced in malignant ureteral obstruction and on patients where retrograde placement was not possible. furthermore, it should be considered as an alternative treatment option to open surgery as it can be performed under local anaesthesia in patients at a high risk of anaesthesia. key words: malignant ureteral obstruction; obstructive uropathy; genitourinary neoplasms; antegrade jj stenting. submitted 9 march 2022; accepted 16 march 2022 introduction ureteral stents were first developed by zimskind et al. (1) in 1967 and have since been used in the treatment of ureteral obstruction or various urogenital fistulas. over time, indications of the use of ureteral stents have antegrade placement of jj catheter in the treatment of malignant ureteral obstruction: retrospective analysis of a single centre eser ordek 1, mehmet kolu 2, mehmet demir 3, bulent kati 3, eyyup sabri pelit 3, ismail yagmur 3 1 kahta state hospital, urology department, adiyaman/turkey; 2 harran university, faculty of medicine, radiology department, sanliurfa, turkey; 3 harran university, faculty of medicine, urology department, sanliurfa, turkey. doi: 10.4081/aiua.2022.1.91 summary archivio italiano di urologia e andrologia 2022; 94, 1 e. ordek, m. kolu, m. demir, b. kati, e. sabri pelit, i. yagmur 92 tive malignancy in the lower urogenital system, those who undergo urinary diversion surgery with ileal conduit, or patients with anatomical changes due to renal transplantation (7). in addition, retrograde ureteral stenting is usually performed under spinal or general anaesthesia that can be associated to serious complications and may be contraindicated in high-risk comorbid patients. in such cases, the best option is a permanent percutaneous nephrostomy or the placement of an ureteral jj catheter in an antegrade manner with a percutaneous approach (8). percutaneous nephrostomy is a minimally invasive treatment option commonly used in the treatment of acute hydronephrosis, which aims to maintain existing renal function by providing drainage of intra-renal content. although percutaneous nephrostomy is a very useful and feasible method, it has certain disadvantages compared to antegrade jj stenting such as a more negative effect on patient comfort, a high risk of infection and easy dislocation of the catheter (8-9). antegrade jj stenting is a minimally invasive alternative treatment technique (8) that is described by several studies in the literature. the aim of the present study was to provide a retrospective analysis of antegrade jj stenting results in a patient population with malignant ureteral obstruction who could not undergo retrograde jj stenting in a tertiary health centre. materials and methods patient selection ethical approval was obtained from the local ethics committee for the study (decision no: hru/21.11.29). the data were obtained from electronic medical records, diagnostic imaging and laboratory examinations of patients who underwent jj stenting due to malignant ureteral obstruction in the urology clinic of our hospital between january 1, 2018 and december 31, 2020. patients with ureteral obstruction who underwent retrograde jj stenting with conventional technique were excluded from the study. conversely, patients who could not undergo retrograde jj stenting or who previously had percutaneous nephrostomy were included in the study. antegrade jj stenting procedures were performed with the guidance of a specialist interventional radiologist by a urologist with clinical experience. absolute contraindications for antegrade jj stenting included uncorrectable coagulopathy, severe vertebral bone and posture disorders, insufficient cardiopulmonary function, hemodynamic instability, pregnancy and severe uncontrolled hypertension. antegrade jj stenting technique after receiving informed consent from the patient or firstdegree patient relatives, the preoperative preparation process was completed. all patients were given preoperative iv (intravenous) antibiotic prophylaxis. all invasive procedures were performed under local or general anaesthesia by ultrasonography and fluoroscopy. after the patient was prepped, the procedure was usually performed in two stages. percutaneous nephrostomy was first performed on patients who did not have previous nephrostomy. then, in the same session, ureteral jj stent was placed in the renal pelvis and ureter and by antegrade method. the patient was placed in the prone position and surgical area was sterilised. an 18-gauge-15 cm chiba needle was used under the guidance of fluoroscopy and ultrasound, which ensured proper placement from the skin to the renal calyx with seldinger technique (10). the location of renal puncture was determined in accordance with the access indication taking into account anatomical constraints (5-10). punctures were normally performed using the posterolateral oblique approach to the upper collecting system along brödel's avascular plane, through the safest and easiest access to the ureteropelvic system (figure 2). figure 1. 3 × 3 × 4 cm bladder tumour localised to the left lateralbladder base that completely covers the left orifice (indicated by the arrow sign). figure 2. schematic drawing of the kidney avascular plane, also known as the brödel line. a: magnification of the angle of entry of the needle into the right kidney, with the patient in the supine position. b: axial slice obtained with the patient in the prone position, demonstrating the ideal entry point for the percutaneous nephrostomy (reference 5). 93archivio italiano di urologia e andrologia 2022; 94, 1 antegrade placement of jj stents the needle was placed in the renal calyx selected by ultrasonography and a urine sample was collected and sent for urinalysis. after the needle was properly positioned, antegrade pyelography was performed with injection of nonionic iodised contrast agent (350 mg i/ml) diluted with sterile saline in a ratio of 1/2 in order to reveal the collecting system anatomy fluoroscopically (figure 3). all sort of pathologies such as obstruction, stenosis or extravasation in the ureter were verified. (figure 4). according to the seldinger technique, a 6 f introducer was placed towards the ureteropelvic junction. using a hydrophilic 0.035-inch guidewire under serial scopy images, the 5 f diagnostic catheter was advanced by passing the obstruction site in the ureter and placed in the bladder. hydrophilic guidewire was removed and a 0.035-inch j-tip teflon-coated guidewire was inserted into the bladder (figure 5). the 5 f catheter was then removed and replaced with a 6 fr × 45 cm introducer sheath. the jj catheter was advanced with the help of the teflon-coated guidewire or with the help of the sheath dilator feeding on the introducer sheath without the guidewire, until the distal end of the stent entered the bladder. the introducer sheath was then pulled back onto the dilator until the sheath remained only in the renal pelvis. at this point, with the help of the dilator, the proximal (renal) tip of the jj catheter was advanced to the appropriate position within the collecting system. serial scopy images were obtained to confirm that the tip of jj stent was curled in the bladder and renal pelvis (figure 6). then, a 6 f percutaneous nephrostomy catheter was placed in the renal pelvis under the guidance of fluoroscopy and fixed to the skin. abdominal ultrasonography was planned for all patients to exclude possible complications after antegrade jj stenting. on postoperative day 1, dusg (direct urinary system radiography) was done to observe the position of the jj catheter and the excretion of the contrast agent used. the nephrostomy catheter of the patients who did not have major complications and who did not have severe hematuria was removed in the postoperative 1-2 days under the guidance of floroscopy. the correct placement of the ureteral stent and the completion of the interventional procedure without major complications was considered as technical success. clinical success was defined figure 3. right antegrade pyelography. figure 4. right antegrade pyelography, narrow segment in proximal urethra and antegrade advancement of guide (indicated by the arrow sign). figure 5. antegrade placement of the guidewire and curling in the bladder (indicated by the arrow sign). figure 6. jj and nephrostomy catheter placed by left antegrade percutaneous approach. archivio italiano di urologia e andrologia 2022; 94, 1 e. ordek, m. kolu, m. demir, b. kati, e. sabri pelit, i. yagmur 94 as decreased blood creatinine levels to normal values, resolved hydronephrosis and complete recovery or decrease in symptoms in postop follow-ups. results during the study, antegrade jj stenting procedure was performed on 40 patients (16 males, 24 females) who presented to our clinic. the mean age of the patients was 56.7 years. in all, antegrade jj stenting was performed in 61 renal units of these patients. of these, 21 were bilateral, 61 were in the right collecting system and 8 in the left collectinf system. clinical and technical success was achieved in 59 of the 61 procedures (96.6%). severe obstruction was caused by malignant causes (bladder-prostate and colorectal cancers, among others) in 34 (85%) of the patients, whereas 6 (15%) had benign etiologies (c-section and ureteroenoscopic interventions, among others) (table 1). the clinical and technical success rate in the patients was 96.3% and 100% for neoplastic and non-neoplastic groups, respectively. in addition, 14 (35%) of the patients had important comorbidities such as coronary artery disease, cerebrovascular disease, diabetes and hypertension. in 33 patients that include those with high anaesthesia risk, the procedure was performed under local anaesthesia, while general anaesthesia was used in 7 patients. the mean blood creatinine values decreased from a preoperative value of 2.3 mg/dl to 1.1 mg/dl after the procedure. in addition, the preoperative kidney antero-posterior (ap) diameter decreased from an average of 25.15 mm to 14.02 mm during postoperative follow-up. in two of the patients with bladder cancer aetiology, malignant ureteral obstruction could not be corrected due to lack of balloon dilatation material in our hospital and antegrade jj stenting could not be performed. therefore, percutaneous nephrostomy was performed (table 2). when the past clinical records of the patients were examined, it was determined that 14 patients had a history of retrograde jj stenting and 17 had a history of percutaneous nephrostomy (table 3). in the present study, antegrade jj stenting was performed through the existing nephrostomy in only three patients. during the follow-up, 75% of the patients developed clinically insignificant minimal haematuria, while almost all patients had pain at the wound site that resolved with simple analgesic treatment. the percutaneous nephrostomy catheter was fixed to the opening site for an average of 24-48 hours until the haematuria was completely resolved. haematuria recovered spontaneously within a few hours, usually without the need for additional intervention. in one patient with colorectal malignancy, arteriovenous fistula, which can be considered a major complication, developed and the necessary treatment with angioembolisation was performed. no other patient developed serious complications such as bleeding, resistant haematuria, arteriovenous fistula or pseudoaneurism requiring transfusion. control dusg taken on postoperative day 1 was checked to ensure that jj stents were in the correct localisation. jj stents were usually removed and new stents were placed within an average of 3 months. the procedure was performed either cystoscopically or table 1. patient distribution according to benign and malignant etiologies. malignancies 34 patients 85.0% endometrium carcinoma 5 12.5% colorectal carcinoma 8 20.0% bladder cancer 10 25.0% prostate cancer 1 2.5% ovarian carcinoma 1 2.5% cervix carcinoma 4 10.0% soft tissue carcinoma 5 12.5% benign causes 6 patients 15.0% surgical ligation (caesarean section) 3 7.5% ureteral stone (ureterorenoscopy) 3 7.5% total 40 patients 100.0% table 3. history of retrograde jj and percutaneous nephrostomy according to aetiology. retrograde percutaneous jj history nephrostomy history malignancies ! x ! x endometrium carcinoma 0 5 0 5 colorectal carcinoma 3 5 3 5 bladder cancer 4 6 6 4 prostate cancer 2 2 2 2 ovarian carcinoma 1 0 1 0 cervix carcinoma 1 4 2 3 soft tissue carcinoma 0 1 0 1 benign causes ! x ! x surgical ligation (caesarean section) 3 0 0 3 ureteral stone (ureterorenoscopy) 0 3 3 0 table 2. aetiology of malignant urological obstructions, together with the distribution of approaches, technical success, failures and complications. indication patients unilateral bilateral technical technical complications approach approach success failure endometrium carcinoma 5 (12.5%) 2 3 5 __ __ colorectal carcinoma 8 (20.0%) 3 5 8 __ 1 bladder cancer 10 (25.0%) 5 5 8 2 __ prostate cancer 4 (10.0%) 2 2 4 __ __ ovarian carcinoma 1 (2.5%) __ 1 1 __ __ cervix carcinoma 5 (12. 5%) 1 4 5 __ __ soft tissue carcinoma 1 (2.5%) __ 1 1 __ __ surgical ligation (caesarean section) 3 (7.5%) 3 __ 3 __ __ ureteral stone (ureterorenoscopy) 3 (7.5%) 3 __ 3 __ __ 95archivio italiano di urologia e andrologia 2022; 94, 1 antegrade placement of jj stents ureterorenoscopically using a retrograde technique with guide wire. procedures were completed between 15-30 minutes on average. discussion ureteral obstructions may occur due to malignant or benign etiologies. in ureteral obstruction, options such as percutaneous nephrostomy or ureteral stenting are the most commonly used treatment methods (12). in the current retrospective study, we investigated the applicability of percutaneous antegrade ureteral stenting in the treatment of severe ureteral obstructions caused by both malignant and benign causes and we found that antegrade stenting is a safe and effective method in cases where the retrograde approach fails. since both acute and chronic ureteral obstruction can cause impairment of renal function, these conditions may lead to severe morbidities. in addition, there is still no clear consensus in the literature on the treatment of malignant ureteral obstruction regarding the patient's clinical picture, emergency status, current technical equipment, or clinician's experience (6-11). the treatment method to be selected is usually determined depending on the physician's personal clinical experience, capabilities of the institution and patient preference (12). percutaneous nephrostomy has various risks such as wound site and urinary tract infection due to mandatory external drainage bag, and it also negatively affects the daily life and comfort of the patient (9). ureteral jj stents are usually placed under cystoscopy with a retrograde approach in various obstruction cases. however, they have been successfully placed with antegrade approach by many years. both techniques are promising and give similar long-term results, but in recent studies, the failure rates of retrograde ureteral stenting in malignant ureteral obstruction has been reported to range between 18.5% and 42% (1213-14). in addition, numerous studies have investigated the applicability of antegrade ureteral stenting (15-16). in addition to similar long-term results, both techniques have their advantages and disadvantages. using a retrograde appoach, it is possible to simultaneously treat concomitant bladder and ureteral stones with endoscopic laser or pneumatic lithotripter or to take a punch biopsy sample from possible malignancies, or to expand existing strictures and relieve obstruction. retrograde ureteral stenting is a one-step procedure but it has the disadvantage to be performed under general or spinal anaesthesia in operating room conditions (2-17). particularly, general anaesthesia is a problem in patients with serious cardiac reserve or respiratory problems, and it is even contraindicated in some cases. in addition, in severe ureteral obstructions caused by malignant etiologies, factors such as external ureteral pressure or bladder invasion reduce the success rates of retrograde stenting method by up to 50% (7-15). clinical trials and observations have proven that antegrade ureteral stenting has higher success rates in severe ureteral obstructions due to both malignant and benign etiologies. success rates reported in the literature range from 80% to 92% (17-18). in addition, balloon dilatation can be performed during antegrade ureteral stenting, increasing technical success rates significantly. furthermore, antegrade ureteral stenting can be performed successfully even under local anaesthesia, as opposed to retrograde method (18). in the present study, clinical and technical success with the antegrade method was 96.6% and the success rate was consistent with the literature. in only two procedures, percutaneous nephrostomy has to be performed because jj stent could not be inserted by antegrade method. major complications associated with antegrade jj stenting have been reported in the literature, but these occur in only 4-8% of cases (10). these complications include retroperitoneal bleeding, which can be treated with angiographic embolisation, perforation of the pleura or intraabdominal organs (such as intestine, liver, spleen) and urosepsis (8-19). significant respiratory complications such as pneumothorax, hydrothorax and empyema are seen in less than 0.2% of patients (6). minor complications such as the extravasation of urine into the retroperitoneal area, subcapsular hematoma and macroscopic hematoma can develop in 3-15% of cases (20). mild haematuria caused by urothelial irritation is a common finding after ureteral stenting and usually improves spontaneously during follow-up. however, in the presence of severe and resistant haematuria that develops after the placement of ureteral stent, ureteroarterial fistula between the ureter and the major or internal iliac artery should be considered first and necessary interventions should be performed quickly (6). the clinician's mastery of urinary system anatomy and vascularisation is vital in choosing a safe pathway for percutaneous puncture and reducing the risk of complications (8-10-11). in the present study, only 3 (7.5%) of the patients developed minor complications including mild lumbar pain and minimal haematuria (clavien degree i), which usually recovered spontaneously within hours. only one patient developed arteriovenous fistula, which is considered a major complication, and the necessary treatment was performed with angioembolisation. in addition, although parenteral antibiotic prophylaxis is applied to all patients before the procedure, urinary tract infection is also a common finding. however, usually these infections can be successfully treated with basic antibiotics. however, if the current infection does not respond to medical pharmacological treatment, jj stents may need to be removed immediately. in the present study, no symptoms of urinary tract infection that required stent removal was observed in any of the patients. the present study has certain limitations. firstm the study was designed and conducted retrospectively. furthermore, the interventional radiology clinic in our hospital has just become operational, therefore the number of patients was limited. it becomes evident that the most important requirement at this stage is the clinical skill of an expert interventional radiology specialist. conclusions the results of this retrospective study show that percutaneous antegrade jj stenting is possible in ureteral obstruction caused by both malignant and benign causes with archivio italiano di urologia e andrologia 2022; 94, 1 e. ordek, m. kolu, m. demir, b. kati, e. sabri pelit, i. yagmur 96 minimal risk of complications and high technical success rate. in addition, antegrade jj stenting stands out as a good alternative option when conventional retrograde placement fails. to the best of our knowledge, there are no large-scale randomised controlled clinical trials in the literature comparing antegrade ureteral jj stenting with retrograde jj stenting. in addition, there is still no clear consensus in the literature on the treatment of malignant ureteral obstruction regarding the patient's clinical picture, emergency status, current technical equipment, or experience of the interventional radiologist. therefore, in patients with malignant ureteral obstruction, randomised controlled trials with a larger population are needed to gain further information on the optimal approach to ureteral jj stenting. references 1. zimskind pd, fetter tr, wilkerson jl. clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. j urol. 1967; 97:840-4. 2. seymour h, patel u. ureteric stenting: current status. semin intervent radiol. 2000; 17:351-65. 3. nunes tf, tibana tk, santos rft, et al. percutaneous insertion of bilateral double j stent. radiol bras. 2019; 52:104-105. 4. fletcher hm, wharfe g, williams np, et al. renal impairment as a complication of uterine fibroids: a retrospective hospital-based study. j obstet gynaecol. 2013; 33:394-8. 5. meira ms, barbosa pnv, bitencourt agv, et al. análise retrospectiva das nefrostomias percutâneas guiadas por tomografia computadorizada em pacientes oncológicos. radiol bras. 2019; 52:14854. 6. hsu l, li h, pucheril d, et al. use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction. world j nephrol. 2016; 5:172-81. 7. chitale sv, scott-barrett s, ho et, burgess na. the management of ureteric obstruction secondary to malignant pelvic disease. clin radiol. 2002; 57:1118-21. 8. venyo akg, hanley t, barrett m, et al. ante-grade ureteric stenting, retrospective experience in managing 89 patients: indications, complications and outcome. journal of biomedical graphics and computing. 2014; 4:47-56. 9. bahu r, chaftari am, hachem ry, et al. nephrostomy tube related pyelonephritis in patients with cancer: epidemiology, infection rate and risk factors. j urol. 2013; 189:130-5. 10. dyer rb, regan jd, kavanagh pv, et al. percutaneous nephrostomy with extensions of the technique: step by step. radiographics. 2002; 22:503-25. 11. van der meer rw, weltings s, van erkel ar, et al. antegrade ureteral stenting is a good alternative for the retrograde approach. curr urol. 2016; 10:87-91. 12. matsuura h, arase s, hori y. ureteral stents for malignant extrinsic ureteral obstruction: outcomes and factors predicting stent failure. int j clin oncol. 2019; 24:306-312. 13. kamiyama y, matsuura s, kato m, et al. stent failure in the management of malignant extrinsic ureteral obstruction: risk factors. int j urol. 2011; 18:379-82. 14. yu sh, ryu jg, jeong sh, et al. predicting factors for stent failure-free survival in patients with a malignant ureteral obstruction managed with ureteral stents. korean j urol. 2013; 54:316-21. 15. turgut b, bayraktar am, bakdık s, et al. placement of double-j stent in patients with malignant ureteral obstruction: antegrade or retrograde approach? clin radiol. 2019; 74:976.e11-976.e17. 16. kahriman g, özcan n, dogan a, et al. percutaneous antegrade ureteral stent placement: single center experience. diagn interv radiol. 2019; 25:127-133. 17. uthappa mc, cowan nc. retrograde or antegrade double-pigtail stent placement for malignant ureteric obstruction? clin radiol. 2005; 60:608-12. 18. adamo r, saad we, brown db. management of nephrostomy drains and ureteral stents. tech vasc interv radiol. 2009; 12:193204. 19. pabon-ramos wm, dariushnia sr, walker tg, et al. society of interventional radiology standards of practice committee. quality improvement guidelines for percutaneous nephrostomy. j vasc interv radiol. 2016; 27:410-4. 20. ganatra am, loughlin kr. the management of malignant ureteral obstruction treated with ureteral stents. j urol. 2005; 174:2125-8. correspondence eser ordek, md (corresponding author) dr_eseser@hotmail.com kahta state hospital, urology department 02000adiyaman (turkey) mehmet kolu, md drrdylg@gmail.com harran university, faculty of medicine hospital, radiology, 63340 sanliurfa (turkey) mehmet demir, md drdemir02@gmail.com bulent kati, md bulentkati@harran.edu.tr eyyup sabri pelit, md dreyyupsabri@hotmail.com ismail yagmur, md dr_iyagmur@hotmail.com harran university, faculty of medicine hospital, urology, 63340 sanliurfa (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 review and 20-70% of inability to conceive in those areas is attributable to the male gender (4). however, these percentages are not veracious due to an underestimation given by a low number of populations involved, the non-unique clinical definition of infertility and religious and cultural restrictions. furthermore, the effect of covid-19 infection on semen quality still needs to be verified, although mechanisms of testicular damage have been reported (5). this clinical condition depends on different underlying pathologies, which include anorchia (vanishing testis syndrome, swyer syndrome), sperm production dysfunction or obstruction from ejaculatory ducts to seminal colliculi. in particular, spermatozoa dysgenesis could be determined mostly by exogenous factors. indeed, environmental factors seem to influence semen quality aberration. several articles showed the impact of the environment on male infertility (6, 7), with various incidences according to the considered population (8). in a recent review, benatta et al. reported a strict correlation between nutrition and male infertily, especially due to the industrialized mass food production and the subsequent ingestion of xenobiotics (9). although the association between exposure to chemicals, such as pesticides (10), is supported, some doubts remain about the physical ones (11). therefore, this narrative review aims to discuss the main work-related male fertility risk factors. materials and methods search design we conducted a comprehensive literature search on studies discussing physical risk factors for male fertility, between april 4 and may 6, 2022, consulting pubmed and scopus. the following keywords were used: male infertility, male impairment, dna damage, human sperm, semen parameters, and genotoxicity. they were associated with the most discussed risk factors, such as heat, physical exertion, radiation, sedentary work, and psychological stress. identification of studies we considered the observational studies, published after the 2000s, describing the correlation between physical agents’ exposure and male infertility. we evaluated the papers according to the patient intervention comparison outcome studytype (picos) model. p: general population background: a decrease in semen quality is an increasingly widespread pathological condition worldwide. jobs and lifestyles have changed a lot with the advancement of technology in the last few decades, and a new series of risk factors for male infertility have spread. objective: this review aims to summarize the current literature on this relationship, evaluating alterations in semen parameters and hormonal profile. methods: a deep research was performed through medline via pubmed, scopus, and web of science on articles regarding the relationship between physical agents and male fertility over the last twenty years. some physical agents already associated with male infertility, such as heat and radiation, while emerging ones, such as physical exertion, psychological stress and sedentary activities, were newly considered. results: most studies described sperm quality after exposure. overall sperm impairment was shown after radiation and alteration of specific parameters, such as sperm concentration, were observed after psychological stress and sedentary work. in addition, an association was also reported between physical exertion and hormonal profile, especially pituitary hormones and testosterone. conclusions: although the associations between physical agents and male infertility are suggestive, the level of evidence of the studies is not adequate to define their influence, except for physical exertion. therefore, new prospective studies are necessary for the validation of the correlation and the possible safeguarding of the exposed working classes. key words: male fertility; semen parameters; hormonal profile; physical agents. submitted 25 september 2022; accepted 24 october 2022 introduction according to who, infertility is a disease of the reproductive system defined by the inability to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. this dysfunction affects up to 15 % of couples, and the cause of over 1/3 of them is male infertility (1). it affects 60-80 million couples over the world (2), and the decline in semen quality occurred over the past century, concomitant to an increase in genitourinary abnormalities (such as cryptorchidism, testicular carcinoma, and hypospadias) (3). the percentage of male infertility ranges from 2 to 12%, with the highest rates in africa and central/eastern europe the role of physical agents’ exposure in male infertility: a critical review carlo giulioni 1, valentina maurizi 2, andrea benedetto galosi 1 1 department of urology, polytechnic university of marche region, umberto i hospital "ospedali riuniti", ancona, italy; 2 department of clinical and molecular sciences, polytechnic university of marche region, "ospedali riuniti" university hospital, ancona, italy. doi: 10.4081/aiua.2023.10890 summary archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi or workers; i: exposure to heat, physical exertion, radiation, sedentary work, or psychological stress; c: comparison with healthy non-exposed male volunteers; o: semen parameters (ejaculate volume, sperm count, sperm concentration, total sperm motility, and sperm morphology) or sex hormone [follicle-stimulating hormone (fsh), luteinizing hormone (lh) and testosterone hormone (th)] levels or dna fragmentation; s: observational studies. eligibility criteria all published human articles in english have been reviewed. the evidence cited in this review comes only from human selected based on the following criteria: • exposure to the risk factor was occupational or environmental. • assessment of semen quality, histological examination, or sperm cells dna fragmentation. • evaluation of sex hormone profile and hypothalamicpituitary-gonadal (hpg) axis status. articles relating only to epidemiological investigations, sex chromosome ratio or other systems were excluded. the quality of all included studies was estabilished the newcastle-ottawa-scale and evaluation forms. results prisma flow diagram of the study was reported in figure 1. eight hundred and fifty-six (856) studies published were identified. two independent authors screened all retrieved records. seven hundred and seventy six (776) articles were excluded by the title and abstract reviewing. eighty (80) were assessed for full-text eligibility. fourty-four (44) studies were excluded due to the following resons: 38 articles regarded chemical agents’ exposure, and 6 were studies on the sperm sex chromosome ratio. the 36 remaining studies were divided according to the agent considered: • 4 for heat exposure. • 9 for physical exertion. • 12 for radiaton. • 5 for sedentary work. • 6 for psychological stress. heat in case of heating of the testicles, an increased metabolism without a corresponding increase in blood supply may occur, with subsequent local hypoxia and harmful effect on spermatozoa. in addition to idiopathic diseases, exogenous factors, such as lifestyle and work, may contribute to a higher temperature of the testicle (12). this risk factor encompasses many types of jobs in both developing and industrial countries. bakers in saudi arabia, exposed to a wet-bulb globe temperature (wbgt) of 37°c, had an infertility rate of 22.7% compared to 3% of the healthy volunteers (13). in a cohort study of the steel industry (workers undergoing wbgt of 36°c) there was a statistically significant difference in seminal parameters (semen volume, sperm morphology, motility, and count) compared to the a non-exposed group (14). nevertheless, shef et al. reported the reversible toxic effect of hyperthermia on semen quality after cessation of heat exposure (15). however, there is not always a significant reduction in semen quality also for workers exposed to extreme heat (16). all considered studies about heat exposure are summarized in table 1. physical exertion moderate physical activity (pa), in addition to better health and decreased stress, contributes substantially to increasing the chances of couples seeking pregnancy. however, an excessive intensity of the exercises may cause stress with an attached alteration of fertility. experimental human studies confirmed inflammatory pathogenesis. a reactive oxygen species (ros) and seminal cytokines increase during aerobic and nonaerobic isometfigure 1. prisma 2009 flow diagram. archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility ric exercise was reported, as demonstrated by malondialdehyde (a marker of lipid peroxidation), lipid hydroperoxide and carbonyls, regardless of concomitants augmented levels of superoxide dismutase (sod), catalase, and total antioxidant capacity (17-19). besides, semen impairment is associated with an altitude greater than 2000 m and the consequent risk of hypoxia among mountaineers (20, 21). hpg axis is also involved, with the reduction of gonadotropin-releasing hormone (gnrh) and production of inhibin (with consequent decrease of fsh, lh, total and free th and increase of prolactin) (22, 23). it is noteworthy that the complete recovery of fertility occurs at different times according to exposure and age (18). on the other hand, mínguez-alarcón et al. found in their study that there are no significant differences in semen at different intensities of exercise (24). physical effort occurs in various jobs, from professional athletes to manual workers. as for the first category, in the rugby and soccer players, both sod and neutrophil levels were higher after a match and the entire season (25, 26). furthermore, the cyclists have a lower proportion of spermatozoa with normal morphology (27), while there is also an impairment in volume, motility, count and dna fragmentation in contact sports (28). the strenuous work negatively impacts the mean sperm count and concentration more than other work-related risk factors (29). studies are shown in table 2 and reported an unequivocal association between physical effort and male impairment. radiation radiation is one of the most in-depth topics considering pathogenesis and its effects on men, as shown in table 3. the only experimental study was conducted on some prisoners: spermatocytes and spermatids can be damaged, respectively, at 2-3 gy and 4-6 gy, and infertility becomes permanent at 3-5 gy; furthermore, complete recovery can be obtained at 9-18 months if < 1 gy and 5years or more with a dose of 4-6 gy (30). nowadays, only observational studies occur for obvious ethical reasons. human studies can be divided according to whether the exposure was to not ionizing or ionizing radiation. the former includes low-frequency energies on the electromagnetic spectrum, including radiofrequency, microwaves, infrared and ultraviolet radiations. several routinely used sources emit them, such as mobile phones, which have a wide range of sar. in a study examining 371 male volunteers, the proportion of rapid progressive motile sperm was significantly lower in men who used their phone for over 60 minutes/day (31). as well, agarwal et al., dividing men according to their active cell phone use, reported a linear relationship between its use and the decrease in total sperm count, motility, viability, and normal morphology (32). not ionizing radiation exposure occurs in several jobs. telecommunications and sonar/radar operators have an increased risk of infertility (or = 1.72 and or = 2.28, respectively) (33). even men in the royal norwegian navy had a higher risk of infertility due to radiofrequency electromagnetic fields exposure, especially in men closer than 10 m from highfrequency aerials (or = 1.93) (34). ionizing radiation comprehends all high energy waves, including alpha, beta, and gamma rays, and removes electrons from atoms and molecules of materials. wdowiak et al. proved that natural and artificial alfa, beta, and gamma radioactive isotopes do not affect semen volume, count, density, and motility, but viability is negatively related to the gamma isotope, and the percentage of sperm with nortable 1. studies concerning the effects of heat on male fertility. reference type of clinical study examined population, n reproductive effects al-otaibi (12) cross-sectional study 137 bakers infertility rate of 22.7% vs 3% in control group hamerezaee et al. (13) cross-sectional study cohort study 30 steel industry workers exposed to heat; 14 workers not exposed significant reduction in sperm volume, normal morphology, motility, and count shefi et al. (14) cross-sectional study 11 infertile men after known hyperthermic exposure. sperm quality impairment improved after the termination of the exposure eisenberg et al. (15) cross-sectional study cohort study 98 workers exposed to extreme heat, 358 workes exposed work not associated with semen quality table 2. studies concerning the effects of physical exertion on male fertility. reference type of clinical study examined population, n exercise period reproductive effects hajizadeh maleki et al. (16) clinical trial 24 long-distance road cyclists 16 weeks low semen volume,sperm motility, normal morphology, concentration, and count pelliccione et al. (17) clinical trial 7 experienced mountaineers 10 days reduction of sperm concentration, increase in serum testosterone verratti et al. (18) clinical trial 7 mountain climbers 5 days reduction of sperm forward motility, increase in lh safarinejad et al. (19) randomized 143 subjects assigned to high-intensity 60 weeks reduction of sperm count, concentration and motility and lh, fsh and testosterone. controlled trial exercise, 286 to moderate-intensity exercis higher changes in high-intensity exercise than moderate – one. regular parameters after recovery period vaamonde et al. (20) randomized 8 non-professional athletes, 8 controls short-term exhaustive reduction of lh and fsh. changes in volume, sperm concentration, controlled trial endurance exercise, 2 weeks count, type “a” and “d” velocity, and moprhology mínguez-alarcón et al. (21) cross-sectional study 215 healthy young men no significative differences. gebreegziabher et al. (26) cross-sectional study 10 long distance competitive cyclists, reduction of sperm normal morphology 10 volunteers performing minimal or no exercise tartibian et al. (27) cross-sectional study 56 elite athletes, lower semen volume, motility, sperm count and normal morphology. 52 physically active volunteer men higher mda and ros levels and dna fragmentation rate eisenberg et al. (28) cross-sectional study 145 men doing strenous worlk, 311 controls lower semen concentration and total sperm count archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi mal morphology is negatively associated with to beta and gamma ones (35). radiation therapy is also a dangerous risk factor, affecting every age range. over the threshold value of 7.5 gy, adult survivors of childhood tumours have a reduced or almost compromised ability to siring a pregnancy and more chances of becoming oligospermic than those not exposed (36). after 1-year of radiotherapy in adults, all semen parameters are significantly lower (37). even among all georgian soldiers, the exposure to cesium137 caused complete azoospermia or critical alterations of semen morphology and motility (38). in diagnostic radiation systems, sperm motility (p < 0.001), viability (p < 0.05), and normal morphology (p < 0.001) were lower in exposed personnel than in healthy men (39). furthermore, kumar et al. discovered that sperm dna denaturation is significantly higher (p < 0.0001) and associated with higher total seminal plasma glutathione (gsh) (p < 0.01) and total antioxidant concentration (p < 0.001) in seminal plasma always in health workers occupationally exposed to radiation than control (40). an increase in micronuclei (mns) derived from acentric chromosome fragments (or whole chromosomes) was also reported among interventional cardiologists (p = 0.02), with a subsequent higher levels of somatic dna damage (41). nevertheless, in a study on employees of the nuclear industries, there was no evidence of an increase in the incidence of infertility compared to the population, even though the median received radiation dose was 12.3 msv (42). sedentary work sedentary activity (sa) occurs in several occupations, such as doctors, engineers, administrators, car drivers, and office workers studies on men show that this risk factor is negatively related to sperm count and concentration (43) and th (44). as mentioned before, the scrotal temperature is closely associated and increases in these conditions with an average value of 0.7°c higher, even 1.7-2.2°c in car drivers (45), with an attached reduction in sperm count (46). hjollund also discovered that sperm concentration decreased by 40% for every 1°c increase, and inhibin b levels decreased in men with the highest daytime scrotal temperature (47). however, in another study, there are no statistically significant differences in semen parameters, although those who spend more than 50% of the seated work time have a higher dna fragmentation index (dfi) (48). although there is proven evidence of heat stress induced by prolonged sitting in table 4, further investigation is needed to demonstrate sedentary work as a risk factor or whether it requires a sedentary lifestyle. psychological stress the distribution varies according to gender, geography, and technological progress, with greater frequency in women, inhabitants in europe and cities than men, those in asia and rural environments, respectively (49, 50). men were analysed in different contexts, with several stressors. in a cross-sectional study, the stress levels in the general population according to a questionnaire were inversely proportional to the values of the semen parameters, affecting sperm count, volume, and concentration (51). eskiocak et al. evaluated the university students, noting table 3. studies concerning the effects of radiation on male fertility. reference type of clinical study examined population, n radiation type reproductive effects fejes et al. (30) cohort study 371 male volunteers: 59 high transmitters (use over 60 minutes/day), not ionizing high transmitters had a decrease in the proportion of rapid 195 control group 1; 88 humans keeping cell phone in the standby progressive motile sperm and an increase in slow progressive position for more than 20 hours daily, 106 control group 2 motile sperm. no differences in sperm based on duration of standby agarwal et al. (31) cross-sectional study 361 humans divided according to their active cell phone use: not ionizing decrease in sperm count, motility, viability, and normal group a: no use (40); group b: 4 h/day (107); morphology with the increase in daily use of cell phone group c: 2-4 h/day (100) and group d: > 4 h/day (114) møllerløkken et al. (32) cross-sectional study 1.487 norwegian navy personnel not ionizing telecommunications and sonar/radar operators have an or of 1.72 and 2.28 respectively baste et al. (33) cross-sectional study 10.497 currently and formerly employed military men not ionizing nearness to high frequency aerials is positively related to higher risk of infertility. or for low degree is 1.39 and or for high degree is 1.93 wdowiak et al. (34) cross-sectional study 4.250 patients attending at fertility center and spermiogram ionizing sperm viability is negatively associated with the gamma isotope, was rrelated to background radioactivity in the lublin region and normal morphology is negatively related to beta and gamma ones green et al. (35) cross-sectional study 6.224 adult survivors of childhood tumor ionizing reduced or almost compromise ability to siring a pregnancy gandini et al. (36) cross-sectional study 166 patients affected by testicular cancer, ionizing decrease in ejaculate volume, sperm concentration, 95 underwent to radiotherapy, 71 underwent to chemiothgerapy count and normal morphology. greater ricovery in subgroup exposed to < 26 gy for sperm conenctration and count bezold et al. (37) cross-sectional study 7 male soldiers ionizing in 57% complete azoospermia, associated with increase in fsh and lh, and in 14% severe oligozoospermia kumar et al. (38) cross-sectional study 83 workers occupationally exposed to ionizing radiation ionizing decrease in sperm motility, viability, and morphological abnormalities; and 51 non-exposed control increase in dna fragmentation and sperm head vacuoles kumar et al. (39) cross-sectional study 83 workers occupationally exposed to ionizing radiation ionizing higher dna fragmentation in exposed men and 51 non-exposed controls andreassi et al. (40) cross-sectional study 31 interventional cardiologists; 31 clinical cardiologists ionizing increase in micronuclei (mns), derived from acentric chromosome fragments or whole chromosomes, and it positively related to years of work doyle et al. (41) cross-sectional study 5.353 employers in nuclear industry ionizing no evidence of association between exposure to low level ionising radiation among men with primary infertility archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility lower levels of sperm concentration, total and rapid progressive motility, and arginase activity before their exams, associated with increased nitrogen monoxide (no) and superoxide dismutase (sod) (52) in seminal plasma. the most frequently encountered stressor in studies is the visit to infertility clinics: an alteration in sperm concentration and motility (53), normal morphology was reported, with a negative association between the degree of stress and the ability to sire a pregnancy (54). psychological stress also affects the work environment, influencing some of them heavily. consulting responses from the job content questionnaire, reduced sperm concentration and count values were detected (55), and men who experienced two or more stressful life events in the past year had a lower percentage of motile sperm and a lower percentage of morphologically normal sperm (56). cited studies, summarised in table 5, demonstrate the validity of psychological stress as an influencing agent for male impairment. discussion this paper reviewed the literature that investigated the impact of physical agents on male fertility. some agents with a known influence on male fertility have been considered, such as heat and radiation, likewise emerging ones, such as physical exertion and psychological stress. heat an optimal test temperature of 3°c lower than in arterial circulation is necessary for spermatogenesis (57). this process is ensured by a cooling process involving the scrotum, pampiniform plexus, and muscles due to the heat exchange mechanism between incoming arterial blood and outgoing venous blood (58). a correlation between testis heat and spermatogenesis occurs, as demonstrated by the latter improvement in patients undergoing after operation for varicocele (59). the environmental temperature also plays a role in fertility as it is inversely proportional to total sperm number, non-progressive motility, and normal morphology (60). in an extensive literature review from 1998, thonneau et al. reported that sperm morphology was the semen parameter most affected with a concomitant increase in time to pregnancy (61). many experimental studies on animals showed the activation of heat shock protein (hsp) by heat, with consequent dna damage, formation of pyknotic nuclei, autophagy and, at least, apoptosis (62, 63). various types of morphological and functional alterations in high-temperature environments have emerged. an experimental study on broiler breeders was carried out: the sperm quality index (sqi) of subjects with normal semen parameters had been reduced after exposure to constant high temperatures, concomitant with a higher percentage of dead sperm, while the heat stress does not cause further deterioration in cases with poor sqi (64). always karaca et al. showed that the sqi decreases after a mix of control sperm with the seminal plasma (sp) of cases exposed to t of 32°c, while the sperm of the exposed combined with the sp of healthy subjects determined lower levels of calcium (ca), with the consequent decrease in sperm motility, and lower fertility (65). only four papers on heat exposure were recently published. in two of them, alterations of several semen parameters were shown (such as sperm normal morphology, total motility, and count) (14, 15), and a higher rate of infertility was reported among bakers in another study table 4. studies concerning the effects of sedentary work on male fertility. reference type of clinical study examined population, n reproductive effects gaskins et al. (42] cross-sectional study 189 healthy young men sperm concentration and count were inversely related to sedentary activity. or of 5.45 of low sperm concentration in less active men compared to active men priskorn et al. (43] cross-sectional study 1210 healthy young men time spent watching television was associated with lower sperm counts, an increase in follicle-stimulating hormone and decreases in testosterone hjollund et al. (45] cross-sectional study 60 men doing sedentary work elevation in scrotal skin temperature is associated with a substantially reduced sperm concentration hjollund et al. (46] cross-sectional study 99 healthy men decrease in sperm concentration, count, fsh per 1°c increment of median daytime scrotal temperature gill et al. (47] cross-sectional study 152 men who spent ≥ 50% of their time at work no statistically significant differences in semen parameters although who in a sedentary position; 102 men who spent < 50% of their time spend more than 50% of the seated work time have a higher dfi table 5. studies concerning the effects of psychological stress on male fertility. reference type of clinical study examined population, n reproductive effects nordkap et al. [50] cross-sectional study 1215 young men sperm count, volume and concentration inversely related to stress eskiocak et al. [51] cross-sectional study 27 university students sperm concentration, total and rapid progressive motility reduction gollenberg et al. [52] cross-sectional study 744 healthy men men reporting 2 or more recent stressful life events had reduced sperm concentration, motility and morphology than < 2 boivin et al. [53] cohort study 818 males in fertility clinics more marital distress required more treatment cycles to conceive (or = 1,20) zou et al. [54] cross-sectional study 384 adult male workers, 88 with high work stress and 296 with low stress decrease in sperm concentration and or total sperm count in stressed workers janevic et al. [55] cross-sectional study 193 healthy men inverse association between perceived stress score and sperm concentration, motility, and normal morphology archivio italiano di urologia e andrologia 2023; 95, 1 c. giulioni, v. maurizi , a.b. galosi (13). another remarkable element is the reversibility of this effect on semen quality. eisenberg et al. showed that heat exposure in certain occupations, such as welders, is associated with altered semen quality, while other jobs have not demonstrated a detriment to semen production (16). therefore, an adequate temperature and sufficient exposure time are necessary to reach a condition of irreversible semen impairment. physical exertion although physical activity is recommended for a healthy lifestyle. indeed, an improvement of all semen parameters (primarily rapid progressive sperm motility) and a reduction of inflammation and oxidative stress markers occur after 3-6 months of training (66, 67). physical exertion may be related to male infertility, and it may be secondary to the immune system due to the proinflammatory cytokines increasing during heavy exertion (68). these proteins are negatively related to sperm motility and morphology (69), and they increase the activity of lipid peroxidation in the sperm cell membrane and dna damage in both mitochondrial and nuclear genomes (70) through a rise of ros production (71). higher antioxidants enzymes levels in athletes than in sedentary subjects occur (72, 73), although their synthesis in semen occurs mainly along the vas deferens, and, therefore, direct ros damage to the testicles and no compensation for spermatogenesis are conceivable (74). a comparison between triathletes and men who practice regular physical activity showed lower levels of sperm motility, morphology, and count (75); even cycling more than 5-h per week was associated with low sperm concentration (76). in a study on extreme mountain bikers, abnormal findings in the scrotal us were reported in 94% of cases, including the most frequent scrotal calculi, epididymal cyst and epididymal calcifications, compared to 16% of controls (77). furthermore, physically "more active" young men have a higher percentage of immotile sperm than "less active" subjects (78). in endurance-trained males, there is a significant reduction in resting testosterone hormone (th) after 6-months of intense training with attached altered prolactin and lutropin release (79). in the majority of the considered studies, physical exertion was associated with altered semen parameters. the most frequent were sperm motility and concentration, although sperm morphology, count, and semen volume were statistically different in most cases. furthermore, controversies about the effect of physical exertion on the hpg axis have emerged. only in 2 out of 4 studies evaluating the hormonal profile did a reduction in fsh, lh or testosterone occur. nevertheless, considering the period of exercise, it appears that, in the first few days of training, there is an increase in sex hormones and a subsequent decline. the overall evidence level of the included studies is noticeable due to the many clinical trials present. therefore, we can see a strong correlation between physical exertion and male infertility. radiation radiation is one of the most widespread physical agents, given its presence in the environment and the devices used routinely. the testis is one of the organs most sensitive to this risk factor because mature spermatozoa are unable to repair damage by radiofrequency (80), whose mechanism is entrusted to sertoli cells through non-homologous end joining (nhej) (81). bergonié reported that the less differentiated cells with higher reproductive activity are the most susceptible to x-rays (82). the sensitivity of spermatogenesis to radiation depends on the wavelength, the time and duration of the exposure, the higher number of non-differentiated cells, and the water content (the effect is directly proportional to the amount of water) (83). the amount of absorbed radiation depends on several factors, which influence the averaged whole-body specific absorption rate (sar). its threshold level is 1,6 w/kg, as decreed by federal communications commission in the usa, while europe follow international electrotechnical commission guidelines, so it is 2 w/kg (84). the irradiation of the spermatids at 3.5-6 gray can cause damage to the testis and may determine permanent infertility, with a risk of congenital anomalies to the offspring (85). nevertheless, infertility can be transitional with 150 msv (86) or 2-3 gy and 4-6 gy (with recovery times of 10-24 months and up to 10 years, respectively) (87). the long-lasting effect of radiation time depends on the foci of γh2ax formed after exposure (88); the repair occurs in two hours, but this period increases already in spermatocytes with exposure over 1 gy (89). dna damage from electromagnetic fields (emf) is also secondary to ros formation (90). although their small dose can favour capacitation, the acrosomal reaction and the fusion with the oocyte (91, 92), oxidative stress reduces sperm count, motility, and viability, inducing lipid peroxidation, a decrease in sperm motility, dna damage and apoptosis (93). besides, it seems responsible for increased apoptosis and is involved in testicular carcinogenesis (94). in the last in vivo experiments, three categories of topics have emerged: 1.effects on sperm cells: after exposure, count, motility, normal morphology, and viability decreased considerably (95). 2.spermatogonia radiosensitivity: sperm cells are less vulnerable than somatic ones due to the complex of the seminiferous tubules, but the repair mechanism to dna damage is slower or not present (96, 97). nevertheless, these considerations are not very relevant because the chromatin in the gametes of mice is more compact than humans and, therefore, less susceptible (98). 3.involvement of hpg axis: wang et al. found under electron microscopy that leydig cells are more susceptible to radiation damage with reduced serum th (99). the hypothalamic cells producing gnrh also seem to be affected (100), with a reduction in the circulation of fsh, lh and th (101). most included articles showed a correlation between radiation and male infertility, considering several variables, such as semen parameters, dna fragmentation index, and ability to siring a pregnancy. as for not ionizing radiation, both studies evaluating semen quality reported a decrease in sperm motility and viability, confirming a targeted action based on the concentration of superoxide anion in semen (102). almost 15,000 military men were archivio italiano di urologia e andrologia 2023; 95, 1 the impact of physicial agents on male fertility recruited in the other two studies to assess the risks associated with radiofrequency electromagnetic fields. proximity to a source that emits radiation is positively associated with the risk of male infertility, with an odds ratio ranging from 1.4 to 2.3 (33, 34). even ionizing radiation seems to harm semen parameters. among patients with testicular cancer who underwent radiotherapy, male soldiers and workers occupationally exposed to ionizing radiation, an overall semen quality impairment occurs, especially for sperm normal morphology and total count. in the three studies assessing its effect on the cell nucleus, two reported a higher dfi value than controls, whereas the micronuclei frequency was higher among interventional cardiologists in the other one. furthermore, adult survivors of childhood cancer have a reduced or almost compromised ability to siring a pregnancy (36). in summary, a negative impact of ionizing and non-ionizing radiation emerged, also focusing on children. sedentary work in a period of technological development and consequently the use of computers and prolonged sitting, the sedentary occupation has become widespread and more frequently associated with other risk factors that may contribute to infertility, such as physical inactivity and obesity. the etiopathogenesis is related to high scrotal temperature following prolonged sitting, which may imply a reduction in sperm count and concentration (103). although several times they were used as synonyms in literature, physical inactivity (pi) is a different concept compared to a sedentary lifestyle since it means failure to reach the recommended pa threshold value (at least 150 minutes of moderate pa per week) (104). even pi has a higher incidence in infertile men, with a decrease in almost all semen parameters (concentration, viability, motility, and morphology) and hormonal levels (fsh, lh and th) (105, 106). nevertheless, sa and pi frequently coexist and negatively affect male fertility. in two controlled trials, where men had to practice moderate exercise regularly, there were evident reductions in inflammation and oxidative stress with the improvement of all semen parameters, dna integrity, pregnancy rate and th in obese people (107, 108). in four out of the five articles sperm quality was affected and the most frequent were sperm concentration and total count (three out of four). in the two articles evaluating the hormonal profile, a reduction in fsh and th occurred, respectively. however, gill et al. reported no association between sa and semen quality alterations, although a higher dfi occurred in patients who spent ≥ 50% of their time at work in a sedentary position (48). given the low number of papers and their evidence level, no definitive conclusions can be obtained; further studies are necessary to establish a substantial correlation between sedentary work and male infertility. psychological stress in 1936 hans selye defined stress as the non-specific response of the organism to every request. this process consists of three distinct phases: alarm, resistance, and exhaustion. in the first two steps, the subject uses his resources and therefore tries to adapt, while, in the last one, the defences fall, and physical, physiological, and emotional symptoms occur. hypothalamic-pituitary-adrenal (hpa) axis mediates the stress response. the paraventricular nucleus activates the catecholaminergic system and produces the hormone crh, the starting point of the hpa axis, determining the production of glucocorticoids. the latter determines the suppression of the transcription of the gnrh receptor gene (109) and, consequently, of the hpg axis. furthermore, in subcortical structures, crh binds especially with the chr-r2 receptor also present in testicular cells (110), which would explain why, in stress, there are apoptosis and age-related degeneration of leydig cells (111) and inhibition of the conversion of androstenedione to th (112). moreover, romeo et al. have shown that some key enzymes involved in the synthesis of catecholamines are present in leydig cells, which could contribute to the regulation of spermatogenesis in times of stress (113). an experimental study validated the latter concept, showing that its effect on fertility depends on the type of stress and that it is not influenced only by adrenal hormones since the administration of th did not affect the outcomes (114). in recent years, animal studies have confirmed the reduction of hpg axis functionality during stress, with a consequent decrease in gnrh, fsh and lh, and the testicular cells apoptosis occurs (115, 116). one of the most noteworthy discoveries in this area was the b-endorphin (b-ep) effect. it is produced by both hypothalamus and pituitary in the testis (117) and, in a stressful time, it inhibits the secretion of gnrh, with a reduction of lh (118), which in turn stimulates the synthesis of b-ep in the testis, suppressing th and sperm production and inducing leydig cells apoptosis (119). in the included studies, sperm concentration was the most altered parameter, while sperm count, total motility and morphology were affected with reduced frequency. even the temporal proximity between the stressful event and the semen quality impairment was reported. indeed, an inverse relationship was reported between male infertility and perceived stress or several recent stressful life events (53, 56). furthermore, boivin et al. reported a higher number of treatment cycles for conception in women who reported more marital distress (54). in summary, the reported studies are promising, and others with higher evidence levels are desirable to ascertain the effect of psychological stress on male fertility. conclusions fertility is vulnerable to several environmental and occupational agents in men. unlike chemical agents, which are more sectorial, physical ones are present in both wellresourced and developing countries. sedentary work has shown a remarkable capacity to cause male impairment in studies. in addition to germ cells, even the testicular supporting ones are influenced by environmental exposure, such as leydig ones, with alteration of the hormonal profile, including th e and gonadotropins. despite these intriguing findings, a cause-effect relationship is hard to state due to the several confounders such as infections, smoking, previous surgeries and outdoor archivio italiano di urologia e andrologia 2023; 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8:709-12. 116. niederberger c. re: regulation of male fertility by the opioid system. j urol. 2012; 187:238-9. 117. xiong x, zhang l, fan m, et al. b-endorphin induction by psychological stress promotes leydig cell apoptosis through p38 mapk pathway in male rats. cells. 2019; 8:1265 118. hajizadeh maleki b, tartibian b. resistance exercise modulates male factor infertility through anti-inflammatory and antioxidative mechanisms in infertile men: a rct. life sci. 2018; 203:150-160. 119. rosety ma, díaz a, rosety jm, et al. exercise improved semen quality and reproductive hormone levels in sedentary obese adults. nutr hosp 2017; 34:608-612 correspondence carlo giulioni, md carlo.giulioni9@gmail.com andrea benedetto galosi, md galosiab@yahoo.it department of urology, polytechnic university of marche region, umberto i hospital "ospedali riuniti", 71 conca street, 60126, ancona, italy valentina maurizi, md valemauri92@gmail.com department of clinical and molecular sciences, polytechnic university of marche region, "ospedali riuniti" university hospital, ancona, italy conflict of interest: the authors declare no potential conflict of interest. 45archivio italiano di urologia e andrologia 2020; 92, 1 original paper influence of sociodemographic factors on treatment’s choice for localized prostate cancer in portugal mário pereira-lourenço, duarte vieira e brito, joão pedro peralta, ricardo godinho, paulo conceição, mário reis, carlos rabaça, amílcar sismeiro urology department instituto português de oncologia francisco gentil, coimbra, portugal. introduction: patients with localized prostate cancer (pca) are active participants in the choice of treatment. objectives: to access the effects of social and demographic factors in the choice of treatment in cases of localized pca, in a portuguese population. methods: identification of all patients with the diagnosis of localized pca in the last four years in an oncological centre. evaluation of the effects of sociodemographic factors (age, profession, literacy, marital status, district and number of inhabitants of the place of residence) in the choice of treatment. results: 300 patients with localized pca were evaluated: 17.3% (n = 52) opted for radical prostatectomy (rp); 39,3% had (n = 118) external radiotherapy; brachytherapy in 29.3% (n = 88) and other options (active surveillance, cryotherapy and hormonal therapy) in 14.1% (n = 42). in relation to surgical treatment (rp) the following results were obtained: a) > 70 years: 3.9% (n = 5); ≤ 70 years: 27.5% (n = 47), p < 0.001; b) primary sector: 10.3% (n = 3); secondary sector: 16.2% (n = 27); tertiary sector: 24.1% (n = 21); quaternary sector: 8.3% (n = 1), p = 0.296; c) marital status married: 17.9% (n = 47); single: 0% (n = 0); divorced: 25.0% (n = 5); widow: 0% (n = 0), p = 0.734; d) residency in a city: 14.1% (n = 13); city > 4000 habitants: 22.7% (n = 15); city ≤ 4000 habitants: 16.9% (n = 24), p = 0.701. using multinomial regression with age (p = 0.001), district (p = 0.035), marital status (p = 0.027) and profession (0.179), this model explained 17.2%-28.4% of therapeutic choices (p < 0.001). conclusions: the main socioeconomical factor that influence treatment choice was age. unmarried patients over 70 years choose less radical prostatectomy. other sociodemographic factors have minor influence in the choice of the treatment. key words: localized prostate cancer; treatment; sociodemographic factors; portugal. submitted 19 september 2019; accepted 13 november 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.45 introduction prostate cancer (pca) is the second most common male cancer, accounting for 13.5% of all cancers diagnosed in the male population. the incidence is greater in developed countries, mostly due to the generalized use of prostate specific antigen (psa) (1). the use of psa allowed for an increased number of diagnosed pca, mostly increasing diagnosis of early stage pca (localized disease), although the benefit on mortality is small and not altering the global mortality (2). patients with pca, for prognostic and therapeutic effects are classified in low-risk, intermediate-risk and high-risk. this classification utilizes psa value, stage and histological grade by the gleason score or by the international society of urological pathology (isup) classification (3). in low-risk patients, knowing that pca behaves many times as an indolent cancer, therapeutic options are active surveillance (as), radical prostatectomy (rp) or radiotherapy (rt), with focus on brachytherapy (bt) and external beam radiotherapy (ebrt) (3). there are no differences in oncological results between the different options (4). however, high risk patients present with a significant risk of disease progression and death by pca, as such current guidelines recommend active treatment with rp with bilateral lymphadenectomy, ebrt plus 2 or 3 years of androgen deprivation therapy (adt) or bt plus ebrt with or without adt (3). again, oncological results are similar between treatment options (4). treatment of localized pca is paradigm of doctor and patient shared choice. the urologist must discuss with the patient the advantages and disadvantages of each treatment, its side effects and allow for the informed and conscious choice by the patient (3, 5). notwithstanding all this recommendations, the agreement between the physician perception and patient preference is inferior to 40% (6). what motivates these patients with the same disease to choose different treatments? is the patient ready for such a hard choice? this choice may be influenced by the beliefs and knowledge of the own patient (7). patients that choose rp believe that this represents their best chance of cure and longevity, as all tumour is removed. patients that opt for rt believe that it is a less invasive treatment, less painful and with less severe side effects (8-10). literacy in health, defined by the ability to access, understand and use health related information various greatly among patients. patients with lower levels of health literacy have a tendency for greater stress levels during the choice of treatment and receive different therapies (11). it is necessary to understand that various sociodemographic factors influence the choice of treatment for localized pca. various demographic, economic and social factors have been described and influencing factors such as age (7, 12-17), race (15-20), financial status (15, 16, 18, 19, 21), health financing by private insurance (7, 17, 19, 20), educational level (21), marriage status (7, 15, 17), populational density of residence area (15, 16, 22) or hospital where treatment is provided (12, 20). laurenco1_stesura seveso 01/04/20 18:57 pagina 45 archivio italiano di urologia e andrologia 2020; 92, 1 m. pereira-lourenço, d. vieira e brito, j.p. peralta, r. godinho, p. conceição, m. reis, c. rabaça, a. sismeiro 46 in portugal there is a lack of data for the degree of influence that sociodemographic factors have in the choice of treatment for localized pca. this work takes advantage of the fact that it was conducted in an oncological centre that treats patients from all the central region of portugal, and has as main objective to access the sociodemographic factors that influence patient preference for surgical treatment (in detriment of other treatments) and to understand if there is any asymmetry in the access of different treatments from patients residing in rural areas. methods study design and population a retrospective study identified all patients that were submitted to a first prostate biopsy in an oncology reference centre (portuguese institute of oncology of coimbra) between january 2014 and december 2018. patients with the diagnosis of localized pca were selected. the choice of treatment was accessed, particularly the option for surgical treatment. we excluded all the patients that did not receive a treatment with curative purpose. evaluated variables and data collection methodology • choice of treatment: rp (classic or laparoscopic), bt, ebrt and other options (patients clinical process). • clinical variables: initial psa and isup classification in prostate biopsy (patients clinical process) • social variables: age at diagnosis, marital status, education and profession (patients clinical process). regarding profession, we classified into four categories: primary sector (extracting and collecting of natural resources, such as farming, fishing, forestry and mining); secondary sector (processing of raw materials, such as manufacturing and construction industries); tertiary sector (services, such as retail, banking, insurance, transports, restaurants, etc.); quaternary sector (knowledge applicable to some business activity that usually involves the provision of services, such as information gathering, distribution and technology, research and development, vocational education, business consulting and strategic financial services). • demographic variables: number of inhabitants of area of residence (city, ≥ 4000 inhabitants, < 4000 inhabitants, accessed by consulting the demographic data of the census of 2011 by the national institute of statistic). statistical analysis univariate analysis utilizing the mann-whitney test. multivariate analysis with multinomial regression. the patients that choose rp were compared with patients that opted for other therapies (evaluated together). a value of p ≤ 0.05 was considered significative. the program spss v21 was utilized. results population characteristics are summarized in table 1. of the 576 biopsied patients, 300 presented with the diagnosis of localized pca. analysing patient’s treatment choice for localized pca, 39.3% (n = 118) opted for ebrt, 29.3% (n = 88) for bt, 17.3% for rp (n = 52) and 14.0% (n = 42) opted for other treatments (20 patients opted for active surveillance, 9 patients opted for cryosurgery and 13 patients received hormonotherapy). of note 9 of the rp were laparoscopic. the effect of the variables studied (univariate analysis) in the choice of surgical treatment is summarized in table 2. in univariate analysis, only age related with the choice of surgical treatment, as 27.5% of patients aged ≤ 7 0 years opted for rp, in contrast with only 3.9% of patients over 70 years (p < 0.001). to evaluate if sociodemographic influenced the choice of surgical treatment, an analysis was conducted utilizing multinomial regression with all the previously described variables, resulting the following statistical significance for variables: age (p < 0.001), profession (p = 0.044), marital status (p = 0.027). another multimodal regression with only the variables that presented statistical significance [age (p < 0.001), marital status (p = 0.027) and profession (0.179)], produced a model that explains 17.2% to 28.4% of choices of surgical treatment (p < 0.001). discussion treatment of localized pca has been regarded as a model of “treatment sensible to patient choice”, where the patients beliefs and knowledge, together with clinical data provided by the physician lead to a shared decision about therapeutic option, even in the absence of strong scientific evidence (23). data from the most recent study table 1. population characteristics. number of biopsied patients 576 diagnosis of pca 60.0% (n = 347) • localized pca 86.5% (n = 300) number of inhabitants • city 31.3% (n = 181) • > 4000 22.1% (n = 121) • ≤ 4000 46.5% (n = 269 education level • primary school 74.7% (n = 432) • high school 19.2% (n = 111) • college 5.4% (n = 31) • no data 0.7% (n = 4) marital status • married 87.5% (n = 506) • single 2.8% (n = 16) • divorced 6.4% (n = 37) • widow 2.8% (n = 16) • no data 0.5% (n = 3) profession • primary sector 8.1% (n = 47) • secondary sector 54.9% (n = 317) • tertiary sector 30.1% (n = 174) • quaternary sector 5.7% (n = 33) • no data 1.2% (n = 7) psa (median) 8.3 ng/ml • ≤ 10 ng/ml 60.3% (n = 328) • > 10 ng/ml 39.7% (n = 216) laurenco1_stesura seveso 01/04/20 18:57 pagina 46 protect (prostate testing for cancer and treatment), showed that during a median follow-up of 10 years, patients with localized pca treated with active surveillance, rt or rp presented with similar mortality rates. however, surgery and rt presented with a smaller incidence of disease progression and metastasis (4). consequently, most patients are confronted with a choice of similarly effective treatments. the oncological centre where this work was conducted, not only receives patients from a vast geographic area but offers a wide range of treatments for patients with pca, without logistical interference (such as different waiting times between options), allowing for a more accurate evaluation of sociodemographic factors. comparing with other studies, our series presented with a small percentage of patients choosing surgical treatment (17.3%), in contrast with a larger number of patients that choose rt techniques (68.6%) (7, 12, 15-17, 19, 21). this fact can be due to the feeling of some patients that rt is less invasive, less painful nand causing fewer side effects on the short term particularly incontinence (8-10). other factor can be related to the low availability of laparoscopic surgery, in theory less invasive and better accepted by the patient. we also observed a small number of patients choosing active surveillance (as), which is why we decided to group these patients with those who chose cryotherapy or hormonotherapy. poor acceptance of as reflects the low tradition of our institution in applying as protocols. furthermore, the majority of patients want to “get rid of” or “cure” the cancer by undergoing aggressive therapy, even with awareness of the potential for significant side effects. most men seem unaware of the uncertainty/controversies that aggressive treatment may not cure their cancer or improve their survival. limited knowledge about as is common, and few patients think of it as a viable option, rather, many men perceive it as “doing nothing” (24). we observed that 13 patients only received hormonotherapy, corresponding to treatment-indicated patients who refused invasive therapies. such an important choice promoted doubt in most patients. a prospective study with psychological evaluation of patients during choice of treatment for pca, determined that most men presented stress related to the choice and patients that present higher levels of doubt felt more negative about therapeutic choice. however, stress related to treatment choice decreased progressively, independently of treatment chosen (25). in something so subjective and dependent on the individual perception of each patient and communication skills, it is highly likely that sociodemographic factors could influence patient choice and their urologist. gordon et al. (26) showed that > 50% afro-americans and 24% of white american studied, understood their disease as “non aggressive”, even after a diagnosis of high risk disease. in our work, age was the only factor that individually influenced the choice of treatment, as patients over 70 years were virtually not subjected to rp (only 3.9%). the influence of age is in agreement with literature (7, 12-17), although such a small number leaves a doubt if some patients were excluded from a valid treatment because of their age. it must be understood that an individual with a life expectancy superior to 10 years should receive the same treatment as a young patient (3). camargo cancela et al. showed in their work that men over 70 years opted 5 times less for curative treatment (pr or rt), being age the main factor in choice, even after adjusting for other clinical and socioeconomical factors (14). in relation to rp, it is likely that older patients do not have this option discussed as much with their urologist, most likely due to the fear of complication, morbidity and presence of other pathologies (27). in a study about rt modalities, patients residing far 47archivio italiano di urologia e andrologia 2020; 92, 1 influence of sociodemographic factors on treatment’s choice for localized prostate cancer in portugal table 2. the effect of socioeconomical variables in choice of treatment (univariate analysis). *p value obtained in comparison between radical prostatectomy vs other treatments all together. number of inhabitants • city • > 4000 • ≤ 4000 education level • primary school • high school • college • no data marital status • married • single • divorced • widow • no data profession • primary sector • secondary sector • tertiary sector • quaternary sector • no data psa • ≤ 10 ng/ml • > 10 ng/ml • unknown isup • ≤ 3 • > 3 age (median) • ≤ 70 years • > 70 years rp 14.1% (n = 13) 22.7% (n = 15) 16.9% (n = 24) 17.3% (n = 41) 21.7% (n = 10) 8.3% (n = 1) 0.0% (n = 0) 17.9% (n = 47) 0.0% (n = 0) 25.0% (n = 5) 0.0% (n = 0) 10.3% (n = 3) 16.2% (n = 27) 24.1% (n = 21) 8.3% (n = 1) 0.0% (n = 0) 18.6% (n = 31) 9.6% (n = 16) 29.4% (n = 5) 17.2% (n = 45) 18.4% (n = 7) 27.5% (n = 47) 3.9% (n = 5) rt 45.7% (n = 42) 39.4% (n = 26) 35.2% (n = 50) 39.8% (n = 94) 41.3% (n = 19) 25.0% (n = 3) 50.0% (n = 2) 39.5% (n = 104) 0.0% (n = 0) 45.0% (n = 9) 55.6% (n = 5) 48.3% (n = 14) 41.3% (n = 69) 34.5% (n = 30) 25.0% (n = 3) 50.0% (n = 2) 32.3% (n = 54) 35.5% (n = 59) 29.4% (n = 5) 34.9% (n = 91) 68.4% (n = 26) 27.5% (n = 47) 55.0% (n = 71) bt 25.0% (n = 23) 28.8% (n = 19) 32.4% (n = 46) 27.1% (n = 64) 32.6% (n = 15) 50.0% (n = 6) 25.0% (n = 1) 30.0% (n = 79) 50.0% (n = 4) 25.0% (n = 5) 0.0% (n = 0) 24.1% (n = 7) 26.9% (n = 45) 32.2% (n = 28) 50.0% (n = 6) 25.0% (n = 1) 39.5% (n = 66) 40.4% (n = 67) 29.4% (n = 5) 33.3% (n = 87) 2.6% (n = 1) 38.6% (n = 66) 17.1% (n = 22) other 15.2% (n = 14) 9.1% (n = 6) 15.5% (n = 22) 15.7% (n = 37) 4.3% (n = 2) 16.7% (n = 2) 25.0% (n = 1) 12.5% (n = 33) 50.0% (n = 4) 5.0% (n = 1) 44.4% (n = 4) 5.6% (n = 5) 15.6% (n = 26) 9.2% (n = 8) 16.7% (n = 2) 25.0% (n = 1) 9.6% (n = 16) 14.5% (n = 24) 11.8% (n = 2) 14.6% (n = 38) 10.5% (n = 4) 6.4% (n = 11) 24.0% (n = 31) p* 0.071 0.850 0.734 0.296 0.956 0.956 < 0.001 laurenco1_stesura seveso 01/04/20 18:57 pagina 47 archivio italiano di urologia e andrologia 2020; 92, 1 m. pereira-lourenço, d. vieira e brito, j.p. peralta, r. godinho, p. conceição, m. reis, c. rabaça, a. sismeiro 48 away from the hospital opted for faster and more definitive treatments (28), although our study points in another direction. another demographic factor is the assessment of the number of inhabitants in the area of residence. in our work we did not find a significative relation, although schymura et al. described that patients from more urban areas and urban-rural opted more for rp in relation to rural areas (15). in our multinomial model, marital status also influenced treatment choice as surgery was chosen in greater number by married and divorced patients. most studies report that married patients opt more for surgical treatment (7, 15, 17, 29). the effect that the partner has in the decision is uncertain. some studies showed the role of support and gathering of information by wives for their husbands, although the final decision was left for the husband (30-32). the effect of personal relations and opinion of friends was studied in other works. patients with friends that have chosen curative and invasive treatment have a easier time opting for similar options (32). patients from cultures with strong family ties, tend to rely more on the option of family (33). in our final statistical model, we also considered profession, although it did not present with relevance. educational level also did not influence choice of treatment. some previous studies showed that patients residing in areas with higher educational levels chose surgical treatment with greater ease (15, 21). more information concerning the effect of economic capacity in the choice of treatment exists in literature (something that we cannot directly relate from profession and education in portugal). patients with greater economic capacity opt more for surgical treatment (15, 16, 21, 34). assessment of these results should be careful, as access to healthcare in the united states of america is very different from the european and portuguese reality. with this in mind, patients with access to private health insurance tend to choose more surgical treatment or more aggressive treatments (7, 17, 19, 20). however, a british study also noted that patients with higher socioeconomical level (defined by education, profession, income) have a tendency for more aggressive treatments (35). although not the main focus of this work, we also evaluated (univariate analysis) the effect of psa and isup on treatment choice and found no relationship. in theory, by including all risk groups for localized disease in the analysis, we could underestimate surgical treatment, as these patients have several less aggressive treatment options to choose. this data indicates that the patient may not understand the risk stratification and its influence in treatment options (36). in our study we did not evaluate the variable urologist in the choice of treatment. different physicians have different clinical opinion and also communicate differently. in a general way, men that chose surgery tend to refer that their urologists opinion was the most important factor in their decision (16, 17, 37). all this process is complex and multifactorial. younger individuals tend to consult various information sources and different doctors. patients with more aggressive disease usually tend to follow in a more strict manure the clinical opinion of their doctor (5). another important fact, is time allowed to the patient to get a decision. patients with more time to decide felt more involved in their choice, allowing them for advice from other doctors and family and social network (5). this work has some limitations, starting with the retrospective design. some factors that can influence choice of treatment were not studied, such as race (not very relevant in the population studied) (15-20) and presence of comorbidities (12, 15). we also decided to compare surgical treatment in relation to other treatments all together, something that can limit the effect of variables between different types of rt or other options. we did not exclude patients with comorbidities, which can interfere in the surgical indication or represent a contraindication for surgery. other limitation is the lack of information about patient preference, degree of understanding of multiple options, time allowed for decision and degree of satisfaction with the form. conclusions the main socioeconomical factor that influence treatment choice was age. the choice for rp from patients over 70 years is residual. a model including the variables age, profession and marital status helped to explain in a significant way patients’ therapeutic choice. factors such as education and residence in rural areas did not seem to influence choice of treatment. references 1. ferlay j, colombet m, soerjomataram i, et al. estimating the global cancer incidence and mortality in 2018: globocan sources and methods. int j cancer. 2019; 144:1941-53. 2. ilic d, djulbegovic m, jung jh, et al. prostate cancer screening with prostate-specific antigen (psa) test: a systematic review and meta-analysis. bmj. 2018; 362:k3519. 3. mottet n, bellmunt j, bolla m, et al. eau-estro-siog guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent. eur urol. 2017; 71:618-29. 4. hamdy fc, donovan jl, lane ja, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. n engl j med. 2016; 375:1415-24. 5. song l, chen rc, bensen jt, et al. who makes the decision regarding the treatment of 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decision-related adjustment after treatment for localized prostate cancer. urology. 2004; 63:751-6. 26. gordon be, basak r, carpenter wr, et al. factors influencing prostate cancer treatment decisions for african american and white men. cancer. 2019; 125:1693-1700. 27. hosain gm, sanderson m, du xl, et al. racial/ethnic differences in treatment discussed, preferred, and received for prostate cancer in a tri-ethnic population. am j mens health. 2012; 6:24957. 28. mahal ba, chen yw, sethi rv, et al. travel distance and stereotactic body radiotherapy for localized prostate cancer. cancer. 2018; 124:1141-9. 29. tyson md, andrews pe, etzioni da, et al. marital status and prostate cancer outcomes. can j urol. 2013; 20:6702-6. 30. srirangam sj, pearson e, grose c, bet al. partner's influence on patient preference for treatment in early prostate cancer. bju int. 2003; 92:365-9. 31. berry dl, ellis wj, woods nf, et al. treatment decision-making by men with localized prostate cancer: the influence of personal factors. urol oncol. 2003; 21:93-100. 32. davison bj, oliffe jl, pickles t, mroz l. factors influencing men undertaking active surveillance for the management of low-risk prostate cancer. oncol nurs forum. 2009; 36:89-96. 33. drake bf, keane te, mosley cm, et al. prostate cancer disparities in south carolina: early detection, special programs, and descriptive epidemiology. j s c med assoc. 2006; 102:241-9. 34. mettlin c, murphy gp, menck h. trends in treatment of localized prostate cancer by radical prostatectomy: observations from the commission on cancer national cancer database, 1985-1990. urology. 1994; 43:488-92. 35. fairley l, baker m, whiteway j, et al. trends in non-metastatic prostate cancer management in the northern and yorkshire region of england, 2000-2006. br j cancer. 2009; 101:1839-45. 36. liu q, xu z, mao s, et al. perineal lipoblastoma: a case report and review of literature. int j clin exp pathol. 2014; 7:3370-4. 37. scherr ka, fagerlin a, hofer t, et al. physician recommendations trump patient preferences in prostate cancer treatment decisions. med decis making. 2017; 37:56-69. 49archivio italiano di urologia e andrologia 2020; 92, 1 influence of sociodemographic factors on treatment’s choice for localized prostate cancer in portugal correspondence mário pereira-lourenço, md (corresponding author) mariolourenco88@gmail.com duarte vieira e brito, md duartevbrito@hotmail.com juan pedro peralta, md joaopedroperalta@gmail.com ricardo godinho, md ricardogodinhoandrade@gmail.com paulo conceição, md pjcconceicao@hotmail.com mario reis, md reismario58@gmail.com carlos rabaça, md carlosrabaca@gmail.com amilcar sismeiro, md urosc2@ipocoimbra.min-saude.pt urology department instituto português de oncologia francisco gentil, coimbra rua maria bourbon bobone, n57, re/esq, coimbra, 3030-481, portugal laurenco1_stesura seveso 01/04/20 18:57 pagina 49 archivio italiano di urologia e andrologia 2019; 91, 4256 original paper clinical and psychological outcomes of patients undergoing retrograde intrarenal surgery and miniaturised percutaneous nephrolithotomy for kidney stones. a preliminary study davide di mauro 1, valentina lucia la rosa 2, sebastiano cimino 1, eugenio di grazia 3 1 department of urology, university of catania, catania, italy; 2 unit of psychodiagnostics and clinical psychology, university of catania, catania, italy; 3 unit of urology, garibaldi hospital, catania, italy. purpose: to assess disease-specific and health-related qol, anxiety and depression as well as satisfaction regarding retrograde intrarenal surgery (rirs) and miniaturized percutaneous nephrolithotomy (mpcnl) intervention for kidney stones up to 2.5 cm. secondarily, pain as well as perioperative and postoperative patient outcomes were evaluated. methods: 60 consecutive patients with kidney stones of dimensions not exceeding 2.5 cm were enrolled in the study of which 30 underwent rirs and 30 mpcnl. perioperative characteristics (age, gender, body mass index (bmi), stone side and size, previous interventions for kidney stones and duration of hospitalization) and surgical outcomes (hemoglobin drop, stone-free rate, visual analogue scale (vas), stenting time, size of ureteral access sheath (uas) deployment, and postoperative complications) of patients were collected. quality of life and psychological outcomes were evaluated using validated questionnaires. results: no significant differences were found between the two groups in terms of age, gender, bmi, stone side and size (p > 0.05). significant differences between the mpcnl and the rirs groups were found regarding stenting time (p = 0.032) and duration of hospital stay (p < 0.001). the stone-free rates of mpcnl vs rirs were not significantly different between the two groups (73.3% vs 66.7%, p > 0.05). periand postoperative complications were not statistically different between the two groups (p > 0.05). rirs group reported higher anxiety and depression scores compared with the mpcnl group (3 [range 0-15] vs 15 [range 6-24], p < 0.01). we found significant differences between the two groups in social (p < 0.05) and vitality (p < 0.01) scores. vas pain score was significantly lower in the mpcnl group than in the rirs one (p < 0.05). conclusions: these results open new scenarios in the treatment of kidney stones up to 2.5 cm when rirs and mpcnl have interchangeable indications. since in our experience complications and success rate are similar, the surgical choice of switching from rirs to mpcnl in real-time and viceversa may be proposed to the patient in the preoperative counseling. key words: rirs; mpcnl; kidney stones; quality of life; satisfaction. submitted 24 september 2019; accepted 24 october 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2019.4.256 introduction retrograde intrarenal surgery (rirs) is recommended as the standard treatment for small to medium (< 2 cm) renal stones by the european association of urology (eau) guidelines. the reason is that a high stone-free rate of usually more than 90% can be achieved, which is potentially related to fewer complications in comparison with percutaneous nephrolithotomy (pcnl). many studies attempted to treat stones of a size up to 2.5 cm with rirs in order to decrease potential pcnl morbidity. contrariwise, rirs failure rates range from 8% to 10% due to a difficult impassable ureter. additionally, the failure rate to insert a standard ureteral access sheath (uas) is probably higher because in most failed ureteroscopies even smaller ureteroscopes cannot be inserted. in these cases, a stent needs to be placed and the procedure postponed. after the ureteral relaxed, rirs can be repeated. double-staged procedures are frustrating for urologists and for patients. moreover, they increase significantly costs related to additional stone treatments and prolonged hospital stay. a real-time surgical alternative, as morbid and mini-invasive as rirs, is needed to avoid staged-procedures. in the last few years many studies reconsidered miniaturized pcnl (mpcnl) as an alternative, which is a more effective approach compared with rirs reporting a better stone-free rate and a similar complications rate (1). furthermore, patients often undergo for several days postoperative ureteral stenting to prevent from complications related to residual fragments in the ureteral passage, potential ureteral edema or post uas inflammation. postoperative ureteral stenting has impacts on the quality of life (qol) for patients, a fact often not considered in rirs and mpcnl researches. the principles of evidencebased medicine recommend considering both clinicalreported outcome (cro) parameters and patient-reported outcomes (pros) (2). despite the adoption of mpcnl and rirs techniques into clinical practice, comparative clinical data, assessing patient satisfaction, taking perioperative and postoperative morbidities into account, is lacking. the primary aim of our study was to assess disease-specific and health-related qol, anxiety and depression as well as satisfaction regarding rirs and mpcnl intervention for kidney stones up to 2.5 cm. secondarily, pain as well as perioperative and postoperative patient outcomes were evaluated. di mauro_stesura seveso 10/01/20 08:55 pagina 256 257archivio italiano di urologia e andrologia 2019; 91, 4 outcomes of surgery for kidney stonesstones. a preliminary study materials and methods study design and ethical approval the study conducted at a tertiary hospital and was carried out in accordance with the declaration of helsinki and the strobe guidelines. informed consent was obtained from all participants before the study. study variables perioperative characteristics (age, gender, body mass index (bmi), stone side and size, previous interventions for kidney stones and duration of hospitalization) and surgical outcomes (hemoglobin drop, stone-free rate (sfr), visual analogue scale (vas), stenting time, size of uas deployment, and postoperative complications) of patients treated between january 2018 and january 2019 were collected. all pre-operative imaging was accomplished by computed tomography (ct) scans with 3 mm cuts. stone size and volumes were collated using the eau stone volume formula (volume = π/6 å~ length x width x depth) using ct scan measurements. stone-free rate was calculated taking stone fragments less than 4 mm by kub radiographic or sonographic evaluation after 3 months postsurgery into account. health related quality of life (hrqol) was evaluated using the italian adaptation of the wisconsin stone quality of life questionnaire (wisqol)3. it is a 28-item, selfadministered instrument designed to evaluate the effect of kidney stones on patients’ qol. through a 5-point likert scale, it is possible to evaluate the following domains: activity/energy level, sleep patterns, social functioning, therapy compliance, physical symptoms, family life, intimacy, and emotional health. a higher score is associated to better qol (3). anxiety and depression levels were assessed through the hospital anxiety and depression scale (hads) (4). it is a self-report questionnaire designed to detect clinical cases of depression and anxiety. it includes two subscales evaluating anxiety (hads-a) and depression (hads-d), respectively. each subscale consists of 7 items to be rated on a four-point scale (0-3). the subscales have a maximum score of 21 and a score above 11 is considered clinically significant (4). both the questionnaires were administered 6 months after surgery. furthermore, we assessd levels of perceived pain and satisfaction regarding the treatment using a vas 10-point scale (5). finally, the procedures were compared regarding surgical outcomes and stonefree rate. periand postoperative complications of procedures were classified using the modified clavien-dindo classification for pcnl surgery (6). participants assuming two balanced groups, a sample size of 58 patients achieve 80% of power with a significance level of 5% to detect a minimum mean difference of 0.78. 60 patients with kidney stones of dimensions not exceeding 2.5 cm were enrolled in the study of which 30 underwent rirs and 30 mpcnl. exclusion criteria were the age under 18 years, transplantation or urinary derivation, congenital anomalies, renal cancer, pregnancy, cardiovascular or pulmonary comorbidities, coagulation disorders only for pcnl surgery, psychological and/or psychiatric diseases, cognitive and linguistic abilities not sufficient to understand and interpret questionnaires used in the study. surgical techniques mpcnl and rirs were performed under general anesthesia and antibiotic prophylaxis with gentamicine 80 mg when preoperative urine culture was negative. antibiotic therapy was performed according to antibiotic sensibility when urine culture was positive at least 3 days before surgery and continued 3 days afterwards. mpcnl a transurethral 5 f open-ended catheter was positioned in the ureter to inject contrast dye in the upper tract in a galdakao-modified supine valdivia position (7). puncture of the calyceal system was performed under both ultrasound and fluoroscopy guidance. after placing a hydrophilic safety guide wire (bard nicore nitinol guidewire with hydrophilic coating. 0,035” x 150 cm stiff shaft-straight tip), a 10 f dual-lumen angiography catheter (boston scientific) and a second safety guide wire were inserted (sensortmptfenitinol guidewire with hydrophilic tip boston scientific). one-shot tract dilation was accomplished over the sensortm guidewire with metal dilatator (karl storz) and a 15 or 17.5 fr amplatz sheath (karl storz) was placed. a 12 f nephroscope (karl storz) was inserted through the amplatz sheath to fragment kidney stones using dusting settings with a 500 µm fiber (0.3 j × 20-30 hz). residual fragments were washed out with a vacuum cleaner effect. the procedure was finished with the placement of an 8 f nephrostomy (fleximatm-boston scientific) or a double j stent (bardinlay ureteral stent 6 f 24-26-28) with attached strings coming out the urethra (when tubeless mpcnl was performed). the nephrostomy was removed after confirming a free ureter passage by antegrade ureterography (2436 h after the procedure). in tubeless mpcnl, the ureteral stent was removed 3 to 7 days after the intervention pulling on the attached strings. rirs rirs was started with cystoscopic (rigid cystoscope 19 f karl storz) insertion of a safety guide-wire (bard nicore nitinol guidewire with hydrophilic coating, 0,035” x 150 cm stiff shaft-straight tip) in supine lithotomic position. a 7 f semirigid ureteroscope (karl storz) was used to exclude intraureteral lesions, stones or insufficient ureter dilation. a second guide wire was inserted, and a 10/12 fr uas, (retrace® coloplast) was deployed over the hydrophilic guidewire inside the ureter if ureteral walls compliance permitted under fluoroscopic guidance. a 7.5 f flexible fiberoptic ureteroscope (flex x2® karl storz) was used for the complete inspection of the pelvicaliceal system. stones were fragmented using a holmium laser dusting set with a 200 µm fiber (lumenis pulse tm 120h). some removal of fragments was not systematically performed using a nitinol basket (zero-tiptmboston scientific) and postoperative stenting (7-14 days) (bard inlay ureteral stent 6 f 24-26-28), with an di mauro_stesura seveso 10/01/20 08:55 pagina 257 archivio italiano di urologia e andrologia 2019; 91, 4 d. di mauro, v.l. la rosa, s. cimino, e. di grazia 258 attached string were used (to be extracted by pulling on the string). statistical analysis statistical analyses were performed using r package “rcmdr” (version 2.5-1). a p value < 0.05 was considered statistically significant. quantitative variables were expressed as mean ± standard deviation (sd) or as median (interquartile range: iqr), when appropriate. categorical variables were expressed as frequencies (percentages). after testing the non-normality of the distribution of quantitative variables with the shapiro wilk test, nonparametric tests were used for data analysis. chi-squared test was utilized to compare categorical variables and mann-whitney test to underline possible significant differences between mpcnl and rirs for the clinical and psychological outcomes examined in this study. results a total of 30 patients who underwent mpcnl and 30 patients who underwent rirs were enrolled in this study. the mean age of the patients was 55 (range 4459) years in the mpcnl group and 57.50 (range 47-61) years in the rirs group. no significant differences were found between the two groups in terms of age, gender, bmi, stone side and size (p > 0.05). however, the two groups were significantly different in terms of previous interventions for kidney stones (p = 0.002). all the demographic data and stone characteristics of the two groups are summarized in table 1. as shown in table 2, significant differences between the mpcnl and the rirs groups were found regarding stenting time (p = 0.032) and duration of hospital stay (p < 0.001). the stone-free rates of mpcnl vs rirs were not significantly different between the two groups (73.3% vs 66.7%, p > 0.05). periand postoperative complications were not statistically different between the two groups (p > 0.05). we found a significant difference regarding hemoglobin drop values in favor of rirs, even if no patient needed blood transfusions (p < 0.001). table 3 describes psychological and qol outcomes assessed in the two groups. statistically significant differences between the mpcnl and the rirs groups were found in terms of hads scores reporting higher anxiety and depression scores, compared with the mpcnl group (3 [range 0-15] vs 15 [range 6-24], p < 0.01). regarding qol evaluated with the wisqol questionnaire, we found significant differences between the two groups in social (p < 0.05) and vitality (p < 0.01) scores. no significant differences were found between the two groups in terms of satisfaction score (p > 0.05). vas pain score was significantly lower in the mpcnl group than in the rirs one (p < 0.05). discussion endourologic stone management comprises several minimally invasive techniques (pcnl, mpcnl, and rirs) and takes several factors such as success rate, complication rate, comorbidities and technological facilities into account. percutaneous surgery was developed in 1980 using at first large access sheaths (28-30 f) facilitating irrigation, debris drainage and active removing of large stones (8). in the last decade, mpcnl has gained attention because it involves a miniaturized nephroscope and offers a nephrostomy tract size < 20 f with the aim of decreasing complications associated with tract size during conventional pcnl while providing comparable sfr (9, 10). besides, in the last two decades an increasing interest for rirs in the management of kidney stones up to 2 cm with successful treatment of larger stones with fewer complications comtable 1. demographic data and stone characteristics of the sample. mpcnl group rirs group p value (n = 30) (n = 30) gender women 22 (73.3) 14 (46.7) 0.064 men 8 (26.7) 16 (53.3) age (yr) 55.00 [44.00, 59.00] 57.50 [47.00, 61.00] 0.415 bmi (kg/m2) 26.48 [24.02, 27.54] 25.43 [23.72, 32.33] 0.750 previous interventions none 11 (36.7) 21 (70.0) 0.002** eswl 2 (6.7) 4 (13.3) pcnl 7 (23.3) 0 (0.0) rirs 10 (33.3) 4 (13.3) urs 0 (0.0) 1 (3.3) stone side bilateral 2 (6.7) 3 (10.0) 0.737 right 16 (53.3) 13 (43.3) left 12 (40.0) 14 (46.7) stone size (cm) 2.00 [1.62, 2.50] 1.55 [1.20, 2.50] 0.219 data are expressed as median [range] and as frequencies (percentages). *p < .05; **p < .01. table 2. postoperative parameters in study groups. mpcnl group rirs group p value (n = 30) (n = 30) clavien complications (%) grade 0 28 (93.3) 28 (93.3) 1.000 grade i 2 (6.7) 2 (6.7) stone-free rate (%) < 4 mm 22 (73.3) 20 (66.7) 0.779 > 4 mm 8 (26.7) 10 (33.3) hospital stay (d) 6.00 [4.00, 9.00] 2.00 [1.00, 5.00] < 0.001 stenting time (d) 7.00 [0.00, 10.00] 8.00 [5.00, 14.75] 0.032* hemoglobin (hb) drop (mg/dl) 1.15 [0.9, 2.50] 0.5 [0.00, 0.7] < 0.001 data are expressed as median [range] and as frequencies (percentages). * p < .05. table 3. psychological outcomes in study groups. mpcnl group rirs group p value (n = 30) (n = 30) hads (anxiety) 3.00 [0.00, 7.00] 7.00 [4.00, 14.00] 0.006** hads (depression) 0.00 [0.00, 5.00] 8.00 [1.00, 10.75] < 0.001** hads (total) 3.00 [0.00, 15.00] 15.00 [6.00, 24.00] 0.001** qol disease score 87.50 [50.00, 95.33] 65.60 [45.35, 85.15] 0.179 qol emotional score 82.10 [57.10, 96.40] 78.60 [57.10, 92.90] 0.629 qol social score 100.00 [81.30, 100.00] 84.40 [63.30, 96.90] 0.028* qol vitality score 100.00 [66.65, 100.00] 50.00 [33.30, 91.70] 0.004** qol total score 90.20 [67.00, 95.50] 68.75 [56.30, 90.43] 0.166 satisfaction score 10.00 [9.00, 10.00] 10.00 [7.00, 10.00] 0.098 vas score 2.00 [1.00, 5.75] 5.00 [4.00, 7.00] 0.032* data are expressed as median [range]. hads: hospital anxiety and depression scale; qol: quality of life; vas: visual analogue scale. *p < .05; ** p < .01. di mauro_stesura seveso 10/01/20 08:55 pagina 258 259archivio italiano di urologia e andrologia 2019; 91, 4 outcomes of surgery for kidney stonesstones. a preliminary study pared to standard pcnl using single or staged ureteroscopic procedures has been reported 6. despite the evolution of mpcnl and rirs techniques into clinical practice, there is still a lack of comparative clinical data assessing patient satisfaction taking into account perioperative and postoperative morbidity. the principles of evidence-based medicine (ebm) call for the consideration of both clinicalreported outcome (cro) parameters and patient-reported outcomes (pros) and the present analysis was conducted with the aim of identifying and critically comparing the outcomes of mpcnl with those of rirs in the management of kidney stones up to 2,5 cm, focusing both on clinical and psychological outcomes. in our sample, stone-free rate was similar in mpcnl compared to the rirs group (73.3% vs 66.7%, p > 0.05). likely, mpcnl would reach the success rate more precociously than rirs as most of rirs performers use laser lithotripsy between 5 and 15 w, using a dusting technique to reduce fragments to easily passible sandlike pieces. instead, mpcnl may guarantee intraoperative stone clearance either by stone dusting or by fragments washed-out through amplatz sheath (11). validated clavien-dindo evaluation for complications did not reveal any statistically significant difference, while hospital stay was in favor for rirs, as expected. in our experience, the length of stay is longer for the nephrostomy management in patients subjected to mpcnl, as patients remain hospitalized while the nephrostomy is still inserted. instead, in tubeless or a totally tubeless patients hospitalization times are overlapping with those of the rirs. patients subjected to rirs are discharged precociously even if they carry a stent because they do not usually require any specific support until stent removal. stenting time was significantly different between the mpcnl and the rirs group (7 days [range 4-5] vs 8 days [range 514.75], p = 0.032). prolonged stenting time in subjects undergoing rirs is required to eliminate fragments and dust after surgery, which may take an indefinite time an aspect of ongoing debate. a complete fragment clearance with a basket is very time consuming and requires an uas of significant diameter to obtain an intraoperative “stone-free” status. on the other hand, rirs failure rates due to a difficult impassable ureter range from 8% to 10% and the failure rate to insert a standard uas is even higher because, in most failed ureteroscopy cases even the smaller diameter ureteroscopes cannot be insert. in these cases, stent placement is necessary, which postpones the procedure. after ureteral relaxation, rirs can be repeated. the double-staged procedures may be frustrating either for urologists or for patients and increase costs management. differently, in the mpcnl fragment clearance is easily obtainable during surgery, allowing to decide whether to use either a stent or nephrostomy for a few days as a precaution to prevent complications (tubeless mpcnl) or not to use tubes at all (totally tubeless). regarding psychological outcomes, we found significant differences between the two groups regarding qol domains of social functioning (p < 0.05) and vitality (p < 0.01). furthermore, the rirs group showed elevated anxiety and depression scores. correlated to this data, also vas pain scores were significantly lower in the mpcnl group compared with the rirs group (p < 0.05). these data are probably due also to the discomfort related to the postoperative stenting time which was longer in patients undergoing rirs. indeed, it has been demonstrated that stents provoke irritating voiding symptoms, hematuria, stent incrustation and fragmentation, back pain, stent migration, infection, pyelonephritis, and ureteral trauma (12, 13). these complications may significantly affect patients qol and could explain the data in favor of mpcnl regarding psychological outcomes (14). even though several studies demonstrated a significant difference in terms of discomfort and distress of stented and not stented patients, deeper insights are needed. ringel et al. reported that 32.7% of their patients had ureteral stents removed because of complications (15). these observations open new scenarios in the treatment of urinary stones for which rirs and mpcnl have interchangeable indications. since the complications and the success rate are similar, the surgical choice of switching from rirs to mpcnl and viceversa may be proposed to patients during pre-operative counseling. moreover, supine position modified according to galdakao variant allows in the selected cases of kidney stones up to 2.5 cm, an easy, no time-consuming switch from retrograde to anterograde treatment and vice-versa when patients are unfit for one over the other technique. this could potentially prevent a double-staged procedure, not compliant ureter, uas insertion failures, impacted stones, anatomical anomalies, inadequate laser dusting for stone physical characteristics and dilated upper tract system. our study, if corroborated by others on this topic, introduces a new possible paradigm in the treatment of urinary stones up to 2.5 cm, for which the technique (rirs or mpcnl) to be used is not decided in the preoperative setting, but in progress during the surgery. strengths and limitations our study represents an important contribution to the comparison between the surgical procedures most used in the treatment of kidney stones, not only in reference to clinical and surgical outcomes but also to psychological and qol ones. for this reason, it may be a reference with regard to the clinical and multidisciplinary management of these patients. however, this study has some limitations. first of all, the sample is small, and it is therefore necessary to conduct further studies on larger samples to confirm the results of the study. furthermore, some data are based on selfreported questionnaires with consequent risk of bias linked to the patient's social desirability. finally, we did not include a specific questionnaire to assess patients experience of stenting. further studies are needed about this topic in order to better understand the real impact of stenting on qol and psychological wellbeing. conclusions rirs is usually considered less invasive than mpcnl and preferred in stones up to 22.5 cm but in several cases planned rirs is not feasible because of unpredictable difficulties forcing the surgeon to place a ureteral stent or nephrostomy and postpone the surgery. in our study, we reported similar outcomes in terms of di mauro_stesura seveso 10/01/20 08:55 pagina 259 archivio italiano di urologia e andrologia 2019; 91, 4 d. di mauro, v.l. la rosa, s. cimino, e. di grazia 260 success-rate, complications and quality of life in up to 2.5 cm stones comparable groups undergoing rirs and mpcnl. interestingly, the increased stenting time in patients subjected to rirs compared to those subjected to mpcnl significantly impacted on qol. these observations open new scenarios in the treatment of kidney stones when rirs and mpcnl have interchangeable indications. since in our experience complications and success rate are similar, the surgical choice of switching from rirs to mpcnl in real-time and viceversa may be proposed to the patient in the preoperative counseling. references 1. davis nf, quinlan mr, poyet c, et al. miniaturised percutaneous nephrolithotomy versus flexible ureteropyeloscopy: a systematic review and meta-analysis comparing clinical efficacy and safety profile. world j urol. 2018; 36:1127-38. 2. garcia sf, cella d, clauser sb, et al. standardizing patientreported outcomes assessment in cancer clinical trials: a patientreported outcomes measurement information system initiative. j clin oncol. 2007; 25:5106-12. 3. penniston kl, antonelli ja, viprakasit dp, et al. validation and reliability of the wisconsin stone quality of life questionnaire. j urol. 2017; 197:1280-8. 4. zigmond as, snaith rp. the hospital anxiety and depression scale. acta psychiatr scand. 1983; 67:361-70. 5. heller gz, manuguerra m, chow r. how to analyze the visual analogue scale: myths, truths and clinical relevance. scand j pain. 2016; 13:67-75. 6. de la rosette jj, opondo d, daels fp, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55 7. scoffone cm, cracco cm, cossu m, et al. endoscopic combined intrarenal surgery in galdakao-modified supine valdivia position: a new standard for percutaneous nephrolithotomy? eur urol. 2008; 54:1393-403. 8. hyams es, munver r, bird vg, et al. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. j endourol. 2010; 24:1583-8. 9. mariani aj. combined electrohydraulic and holmium:yag laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. j urol. 2007; 177:168-73; discussion73. 10. monga m, oglevie s. minipercutaneous nephrolithotomy. j endourol. 2000; 14:419-21. 11. jackman sv, docimo sg, cadeddu ja, bishoff jt, kavoussi lr, jarrett tw. the "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. world j urol. 1998; 16:371-4. 12. de s, autorino r, kim fj, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. eur urol. 2015; 67:125-37. 13. ucuzal m, serce p. ureteral stents: impact on quality of life. holist nurs pract. 2017; 31:126-32. 14. kelly t, kelly mh. living with ureteric stents: a phenomenological study. br j nurs. 2019; 28:s29-s37. 15. ringel a, richter s, shalev m, nissenkorn i. late complications of ureteral stents. eur urol. 2000; 38:41-4. correspondence davide di mauro, md davidedimauro84@virgilio.it sebastiano cimino, md department of urology, university of catania, catania (italy) valentina lucia la rosa, psy. d. psicolarosa@gmail.com unit of psychodiagnostics and clinical psychology, university of catania, catania (italy) eugenio di grazia, md (corresponding author) unit of urology, garibaldi hospital, catania (italy) di mauro_stesura seveso 10/01/20 08:55 pagina 260 stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11978 1 original paper of infection, particularly in developing countries where there is inadequate control over animal infections. while the prevalence of brucellosis in developed countries is currently minimal, isolated cases do arise within occupational cohorts at risk, such as farmers, veterinarians, and laboratory and slaughterhouse personnel (3). brucellosis is linked to a range of genitourinary infections in males, such as brucellar epididymo-orchitis (beo), cystitis, prostatitis, interstitial nephritis, pyelonephritis, exudative glomerulonephritis, the formation of renal and testicular abscesses, and seminal vesiculitis (3). beo is an infrequent complication of brucellosis, occurring in 5.7% of cases, and it is commonly unilateral. the prevailing symptoms encompass fever, scrotal pain, and swelling, chills or rigors, malaise, generalized discomfort, fatigue, and headache. the incidence and nature of complications are contingent upon the specific strain of the infecting brucella, the patient's age, and the duration of the illness (1, 3, 4). it typically affects young and middle-aged individuals, and failure to prompt diagnosis or inadequate management can lead to various complications, such as testicular abscess, necrotizing orchitis, atrophy, infarction, suppurative necrosis, infertility, tumor, and aspermia (5, 6). furthermore, the disease can mimic testicular tumors and tends to recur more than once, which makes it more challenging (1, 7). despite the higher incidence and morbidities of brucellosis in developing countries, few case series on beo are available in the literature (5, 8-13). the current study is a single-center experience focusing on the clinical manifestations, diagnosis, and treatment outcomes of beo, with a literature review of the published case series. the references have been inspected for credibility based on the most up-to-date criteria (14). methods study design this study was a single-center case series involving conbrucella epididymo-orchitis (beo) is a rare complication of brucellosis. despite the high incidence of brucellosis in developing countries, few case series on beo are available. this study focuses on the clinical presentations, diagnosis, and treatment of beo with a review of the literature. this study included consecutive beo patients diagnosed and treated at smart health tower between 2021 and 2023. the required data were retrospectively collected from patients' profiles. the beo diagnosis was established through scrotal doppler ultrasound in cases with a positive rose bengal test and positive igg and igm results for brucellosis, in addition to scrotal pain and swelling. this study included 11 cases whose ages ranged from 22 to 55 years. most of the cases presented with testicular pain (72.7%), followed by fever (63.6%) and arthralgia (63.6%). the right side (54.5%) was slightly more affected than the left side (45.5%). the major abnormal laboratory finding was an elevated c-reactive protein (82%). the treatment was conservative, in which a combination of gentamicin, doxycycline, and rifampicin was administered to the patients for about 6-8 weeks. one case underwent an orchiectomy due to the abscess formation. all the patients responded well to the treatment, with no recurrence. in the middle east, brucellosis remains a concerning infectious disease. early diagnosis, aimed at preventing abscess formation and other complications, takes first priority to avoid invasive interventions. key words: brucellosis; brucella; orchitis; genitourinary infection; orchiectomy; zoonosis. submitted 14 october 2023; accepted 7 november 2023 introduction brucellosis, known as malta fever, is a zoonotic multiorgan disease caused by infection with brucella species. the major sources of infection are dogs, sheep, cattle, goats, swine, camels, and reindeer. human infection can occur through direct contact, inhalation of the microbe, consumption of contaminated meat, or ingestion of unpasteurized milk (1, 2). millions of people globally are at risk brucella epididymo-orchitis: a single-center experience with a review of the literature rawa bapir 1, 2, 3, ahmed mohammed abdalqadir 2, esmaeel aghaways 4, hemn hussein bayz 5, hiwa o. abdullah 1, 3, shaho f. ahmed 1, berun a. abdalla 1, 3, jihad ibrahim hama 6, bryar othman muhammed 5, karokh fadhil hamahussein 1, 7, farman mohammed faraj 2, fahmi hussein kakamad 1, 3, 4 1 smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq; 2 department of urology, sulaimani surgical teaching hospital, sulaimani, iraq; 3 kscien organization, hamdi street, azadi mall, sulaimani, kurdistan, iraq; 4 college of medicine, university of sulaimani, madam mitterrand street, sulaimani, kurdistan, iraq; 5 smart health tower raparin, rania, sulaimani, kurdistan, iraq; 6 research center, university of halabja, halabja, iraq; 7 kurdistan center for gastroenterology and hepatology, sulaimani, kurdistan, iraq. doi: 10.4081/aiua.2023.11978 summary archivio italiano di urologia e andrologia 2023; 95(4):11978 r. bapir, a.mohammed abdalqadir, e. aghaways, et al. 2 secutive beo patients diagnosed and treated at the urology clinic of smart health tower (sht) between january 2021 and january 2023. patients provided explicit consent to partake and to authorize the publication of any related data in this study. the study was ethically evaluated by the scientific committee of sht. data collection after data de-identification, the required data were retrospectively collected from patients' profiles within the urology clinic's database. the extracted information included patient demographics, occupation, clinical presentations, laboratory findings [erythrocyte sedimentation rate (esr), c-reactive protein (crp), complete blood count, liver function tests, rose bengal test (rbt), antibrucella antibodies (igg and igm) by the enzyme-linked immunosorbent assay (elisa), and urine culture], ultrasound (u/s) examination, strategy and outcome of treatment, and follow-up. diagnosis strategy the diagnosis of brucellosis was established based on clinical symptoms consistent with brucellosis, a positive rbt, and positive anti-brucella antibodies (igg and igm) on the elisa. the beo was diagnosed when patients had pain and swelling of the scrotum with enlarged testicles and/or epididymis during the physical examination. the beo diagnosis was confirmed by scrotal doppler u/s in cases with a positive rbt and positive igg and igm results for brucellosis. the u/s features of beo were testicular vascularity, enlargement, nonhomogenous echotexture, and heterogeneous or hypoechoic echogenicity. eligibility criteria all the confirmed cases of beo who were diagnosed and managed in sht between 2021 and 2023 were enrolled in this study. statistical analysis the arrangement and coding of the data were performed using microsoft excel 2019. for qualitative data analysis (descriptive statistics), the statistical package for the social sciences (spss) version 25 was utilized. the data were presented as means, frequencies, and percentages. literature review overall, 15 studies with 393 cases were reviewed in this series, of which most were conducted in turkey (53.3%), followed by iran (20%) and one study per kuwait, saudi arabia, greece, and spain (3-5, 8-13, 15-20). the raw data of each reviewed study is shown in table 1. the mean age of the cases was 34.5 ± 2.71, and most of them (76.6%) were at risk of infection as they either had close contact with animals or used raw meat and unpasteurized milk products. the right and left sides were affected nearly equally, and bilateral involvement has been reported in 51 cases (13%). the major reported symptoms were fever (79.4%), pain (77.9%) and swelling (70%) of the testicles or scrotum, and sweating (57%) (table 2). the three most commonly reported abnormal laboratory findings were high esr (63%), crp (57.3%), and wbc (29.8%). in all cases, the diagnosis was primarily based on clinical findings, with confirmatory tests including brucella antigen tests (97.5%), doppler u/s (63.6%), and positive blood cultures (23.2%). doppler u/s found 7 cases (1.8%) of testicular abscesses. the majority of cases (95.4%) underwent conservative treatment with antibiotics, while orchiectomy and drainage procedures were conducted in 2.8% and 0.3% of cases, respectively. a good outcome was achieved in 97.7% of patients, whereas nine cases (2.3%) failed to respond to the treatment. table 1. raw data of each reviewed series on beo, or brucella orchitis. author country no. risk factors age major symptoms symptoms duration affected (year) case (mean) (mean/day) site animal contact rmmpi fever chills tss tsp sweating arthralgia dysuria anorexia headache r l both alarbid et al (2023) (8) kuwait 11 8 0 32.5 10 0 0 0 0 0 0 0 0 n/a n/a n/a n/a khodadadi et al (2023) (5) iran 50 11 15 38.1 32 31 30 45 30 17 0 12 3 11.26 10 14 26 gozdas et al (2020) (9) turkey 25 14 15 36 16 0 25 25 12 14 4 12 0 20 n/a n/a 2 naz et al (2016) (15) turkey 21 14 16 44.6 14 0 13 21 7 10 0 2 0 n/a 10 10 1 aydemir et al (2015) (4) turkey 6 2 0 39 3 1 4 5 1 2 2 0 0 22* 3 2 1 savasci et al (2014) (10) turkey 28 n/a n/a 31 9 8 28 28 10 1 8 8 0 n/a 11 16 1 gonen et al (2013) (16) turkey 14 6 11 41 ** 12 0 n/a n/a 10 4 0 0 0 ≤ 30 8 6 0 sofian et al (2013) (17) iran 40 19 20 40 37 0 n/a n/a 36 20 13 0 0 ≤ 30 12 16 12 güneş et al (2010) (18) turkey 15 5 10 27 14 3 15 15 12 8 0 0 0 <14->42 9 5 1 celen et al (2009) (3) turkey 27 2 25 28.2 24 16 21 27 19 20 6 13 10 n/a n/a n/a 2 roushan et al (2009) (13) iran 53 37 4 35.5 43 0 54 54 40 12 0 0 0 29 30 22 1 colmenero et al (2007) (19) spain 48 9 11 36.6 48 42 48 48 40 0 2 0 0 52.5 21 25 2 papatsoris et al (2002) (20) greece 17 17 8 30.1 13 0 0 0 0 0 4 0 0 n/a n/a n/a n/a kadikoylu et al (2002) (11) turkey 12 12 n/a 30 12 0 12 12 6 0 0 3 0 n/a n/a n/a n/a memish et al (2001) (12) saudi arabia 26 n/a 10 n/a 25 14 26 26 1 6 4 3 4 <14->42 15 9 2 rmmpi: raw meat or milk product ingestion; n/a: non-available; tss: testicular or scrotal swelling; tsp: testicular or scrotal pain; r: right; l: left; crp: c-reactive protein; wbc: white blood cell; esr: erythrocyte sedimentation rate, alt: alanine transaminase; ast: aspartate aminotransferase; alp: alkaline phosphatase; u/s: ultrasound; csv: conservative; ot: orchiectomy; unk: unknown. * the duration is for only 4 cases. ** median age. archivio italiano di urologia e andrologia 2023; 95(4):11978 3 brucella epididymo-orchitis during the follow-up periods, which were different for each study, 11 cases (2.8%) of recurrence have been documented (table 2). results this study included 11 cases whose ages ranged from 22 to 55 years, with a median and mean age of 31 and 35.3 ± 12.12, respectively. more than half of the cases were workers (55%), and the remaining were shepherds (27%), a butcher, and a student. the majority of the cases presented with testicular pain (72.7%), followed by fever (63.6%), arthralgia (63.6%), sweating (45.5%), and scrotal swelling (45.5%). regarding the laterality, the right side (54.5%) was slightly more affected than the left side (45.5%). abnormal laboratory findings were elevated crp (82%), anemia (27.3%), elevated wbc (18.2%), low wbc (9%), and elevated alanine transaminase (alt) (9%). in addition, rbt and igg and igm antibodies for brucella were positive in all the cases. the treatment strategy was conservative, in which a combination of gentamicin, doxycycline, and rifampicin was administered to all table 2. summary of the published series on beo, or brucella orchitis. variables frequency/percentage country of studies turkey 8 (53.3%) iran 3 (20%) kuwait 1 (6.7%) saudi arabia 1 (6.7%) greece 1 (6.7%) spain 1 (6.7%) demographic data age (mean of means) ± sd 34.5 ± 2.71 risk factors contact with animal 156 (39.7%) raw meat or milk product ingestion 145 (36.9%) affected site right side 129 (32.8%) left side 125 (31.8%) bilateral 51 (13%) n/a 124 (31.5%) major symptoms * fever 312 (79.4%) testicular or scrotal pain 306 (77.9%) testicular or scrotal swelling 276 (70%) sweating 224 (57%) chills 115 (29.3%) arthralgia 114 (29%) anorexia 53 (13.5) dysuria 43 (11%) headache 17 (4.3%) variables frequency/percentage abnormal laboratory findings * high esr 248 (63%) high crp 225 (57.3%) high wbc 117 (29.8%) positive blood culture 91 (23.2%) high alt 65 (16.5%) high ast 49 (12.5%) high alp 23 (6%) anemia 39 (10%) positive urine culture 1 (0.3%) diagnostic tools brucella antigen tests 383 (97.5%) scrotal doppler ultrasound 250 (63.6%) positive blood culture 91 (23.2%) testicular abscess 7 (1.8%) treatment conservative (antibiotics) 375 (95.4%) orchiectomy 11 (2.8%) drainage 1 (0.3%) unknown 11 (2.8%) outcome good 384 (97.7%) failure 9 (2.3%) follow-up recurrence 11 (2.8%) * other symptoms and laboratory findings have been reported in the reviewed studies, but this study reviewed the most common of them. abnormal laboratory findings diagnosis tools abscess treatment outcome recurrence crp wbc esr alt ast alp anemia blood culture urine culture brucella antigen test positive blood culture u/s csv ot drainage n/a n/a n/a n/a n/a n/a 0 11 n/a 11 11 0 0 unk unk unk all good 0 30 13 30 15 9 16 0 0 1 50 0 50 0 50 0 0 all good 0 22 4 12 12 6 n/a 8 1 n/a 25 1 21 1 25 0 1 all good 0 17 3 11 n/a n/a n/a 6 8 n/a 21 8 18 0 21 1 0 2 failures 2 6 2 3 n/a n/a n/a 0 2 0 6 2 5 0 6 0 0 all good 0 20 18 19 14 11 n/a 1 5 n/a 28 5 28 2 21 7 0 4 failures 0 14 3 13 8 7 n/a 1 4 0 14 4 1 0 14 0 0 all good 1 27 10 29 n/a n/a n/a 22 n/a n/a 40 0 0 1 40 0 0 all good 0 15 6 10 7 8 n/a 1 0 n/a 15 0 0 1 15 1 0 all good 0 26 10 25 9 8 5 0 10 0 27 10 27 0 27 0 0 all good 1 n/a 19 41 n/a n/a n/a n/a 8 0 53 8 53 1 53 2 0 6 failures 1 48 7 30 n/a n/a n/a n/a 27 0 39 27 18 1 48 0 0 1 failure 3 n/a 6 13 n/a n/a n/a n/a 9 0 17 9 17 0 17 0 0 all good 0 n/a 10 4 n/a n/a n/a 0 2 n/a 12 2 12 0 12 0 0 all good 2 n/a 6 8 n/a n/a 2 0 4 0 25 4 0 0 26 0 0 all good 1 archivio italiano di urologia e andrologia 2023; 95(4):11978 r. bapir, a.mohammed abdalqadir, e. aghaways, et al. 4 the cases for about 6-8 weeks (table 3). one case underwent orchiectomy as a secondary treatment due to the abscess formation. all the patients responded well to the treatment. after more than 2 years of follow-up for the first case and one year for the newest case, no recurrence has yet been reported. discussion brucellosis represents an endemic multisystemic infectious disease within specific geographical areas such as the middle east, the arabian peninsula, the mediterranean region, and india. its prevalence is significantly greater in rural environments in comparison to urban settings (1). the disease is commonly reported in developing countries; however, it can also be seen in developed countries due to immigration and travel (19). it has been reported that the preponderance of the cases is affected during the spring and summer, which may be caused by consuming milk products and fresh cheese more commonly in the spring (3). the review of the literature revealed that the majority of the cases were reported in turkey, followed by iran, which supported the previous claim. in addition, two reviewed studies were conducted in developed countries like greece and spain (19, 20). the major risk factors for beo are direct contact with animals, inhalation of infectious aerosols, and ingestion of raw meat or unpasteurized milk products (1, 7). among the 393 reviewed cases, 76.6% were at risk of infection (3-5, 8-13, 15-20). in the present study, three cases were shepherds and one was a butcher, whereas for the remaining seven cases, it was unknown whether they had a risk factor for infection or not. scholars reported a higher susceptibility to infection among young males. savasci et al. conducted a retrospective analysis of 28 cases of beo, revealing that the majority of cases occurred between the second and third decades of life, with an average age of 31 years (10). in accordance with that finding, the mean ages of the reviewed and present cases were 34.5 and 35.3 years, respectively. this raises a noteworthy concern, as brucellosis could potentially exert adverse effects on the reproductive outcomes of sexually active young adults (9). in around 20-40% of cases, brucella orchitis is considered to stem directly from epididymitis (1). a study by baykan et al. found that approximately 67% of 24 male cases showed involvement of both the epididymis and testes (21). while celen et al. reported a bilateral testis involvement rate of less than 10%, baykan et al. recorded a relatively higher rate of 21% (3, 21). the bilateral involvement in the reviewed literature was 13%, which is more compatible with celen et al. than baykan et al. in the present series, there was no bilateral involvement, and epididymo-orchitis was found in about 55% of the cases. in general, beo patients have acute symptoms for about two weeks at the time of presentation (22). the primary manifestations of brucellosis can be fever, chills, sweating, nausea, vomiting, myalgia, arthritis, and osteoarticular involvement. in addition to previous symptoms, scrotal pain and swelling may be indicators of beo (1). among the 15 reviewed studies, the prevalent reported symptoms were fever (79.4%), scrotal pain (77.9%), scrotal swelling (70%), and sweating (57%). in line with the literature, the most common presentations in our cases were testicular pain (72.7%), fever (63.6%), arthralgia (63.6%), sweating (45.5%), and scrotal swelling (45.5%). regarding the incidence of beo in patients with brucellosis, it has been reported to occur in 2% to 20% of the cases (1). in their study, celen et al. documented 27 (18.8%) cases of beo within a cohort of 143 patients with brucellosis. meanwhile, papatsoris et al. identified 25 (2.5%) beo cases among a group of 995 cases with brucellosis (3, 20). to distinguish beo from non-specific epididymo-orchitis, several factors have been reported to be considered, such as animal contact history, consumption of raw milk or cheese, gradual onset, extended duration, distinctive undulant fever, mild local inflammation, and the lack of lower urinary tract symptoms alongside insignificant leukocytosis (22). on the contrary, celen et al. mentioned wbc as an important indicator of beo (3). all the cases in the reviewed studies and in the present study had more than one of the distinguishing factors. variables frequency/percentage demographics age range (median, mean ± sd), years 20-55 (31, 35.3 ± 12.12) occupation worker 6 (55%) shepherd 3 (27%) butcher 1 (9%) student 1 (9%) clinical presentations testicular pain 8 (72.7%) fever 7 (63.6%) arthralgia 7 (63.6%) sweating 5 (45.5%) scrotal swelling 5 (45.5%) right 3 (27.3%) left 2 (18.2%) splenomegaly 4 (36.4%) chills 4 (36.4%) affected site right side 6 (54.5%) left side 5 (45.5%) laboratory findings elevated crp (> 5 mg/dl) 9 (82%) anemia (< 13 g/dl) 3 (27.3%) elevated wbc (> 11000) 2 (18.2%) low wbc (< 4000) 1 (9%) elevated alt (> 50 iu/l) 1 (9%) positive rose bengal test 11 (100%) positive igg and igm for brucella 11 (100%) ultrasonography findings vascularity 10 (91%) testicular enlargement 7 (63.6%) heterogenous texture 6 (54.5%) heterogenous echogenicity 4 (36.4%) unretrieved 1 (9%) diagnosis epididymo-orchitis 6 (54.5%) orchitis 5 (45.5%) treatment therapy (duration) gentamicin + doxycycline + rifampicin (6-8 w) 11 (100%) secondary treatment orchiectomy 1 (9%) table 3. baseline characteristics of the beo patients. archivio italiano di urologia e andrologia 2023; 95(4):11978 5 brucella epididymo-orchitis a high wbc was reported in 29.8% of the reviewed cases and 18.2% of the present cases, which may not support the observation of celen et al. (3). distinguishing between beo and non-specific epididymoorchitis is crucial, as treatment delay raises the chance of contralateral involvement, tissue necrosis, and systemic symptoms. thus, in regions where brucellosis is endemic, having a suspicion alone justifies commencing therapy while waiting for definitive lab test results (8, 21). another challenge in the diagnosis of beo is mimicking the disease as a testicular tumor, epididymitis, trauma, hematocele, or torsion of the testis (1, 4). aydemir et al. reported a case of beo that was diagnosed as a testicular tumor based on a u/s examination and later confirmed to be beo by conducting tumor markers, magnetic resonance imaging (mri), and tube agglutination tests. in another study, bapir et al. (1) reported a misdiagnosed case of beo that appeared as a tumor in both doppler u/s and mri. then, the diagnosis was corrected using tumor markers and an rbt test. the diagnosis of brucella orchitis can be established by considering a combination of serology, ultrasonography, and the existence of typical symptoms such as fever, testicular pain, enlargement, and inflammation (1). the primary diagnostic approach for brucellosis is the serum agglutination test, and a positive result is defined as a titer ratio exceeding 1:160 when accompanied by distinct clinical symptoms. nevertheless, in cases of prolonged brucellosis, agglutination test titers might be absent or below 1:160 (1). in such instances, the disease can be detected better by using other serologic tests like coombs’ anti-brucella test, immunocapture agglutination test, 2-mercaptoethanol agglutination test, or elisa, as the immune response to the infection causes an initial increase in igm antibodies followed by a switch to increasing igg antibodies within a few weeks of infection (19). in total, 97.5% of the cases in the reviewed studies were diagnosed based on the various brucella antigen tests. due to the mentioned drawback of the serum agglutination test, all the cases in the present study were diagnosed by rbt and elisa tests. abnormal blood investigation findings are often mild and not very specific. prolonged infection might cause a slight drop in hemoglobin levels, and a moderate increase in esr is commonly seen. liver function tests may show a mild to moderate elevation in alt and aspartate aminotransferase (ast) levels. a high crp level is a noteworthy finding in most cases (3, 17). colmenero et al. reported a positive blood culture in 65.8% of patients with brucellosis and stated the necessity of the method in diagnosing brucellosis. furthermore, the positivity of blood culture in beo cases has been reported to be 53-69% (22). the most significant laboratory findings in the reviewed studies were positive brucella antigen tests (97.5%), high esr (63%), and crp (57.3%). in contrast to the previous findings, the blood culture was positive in only 23.2% of the 393 reviewed cases. in the present study, an elevated crp was the dominant finding (82%), after positive rbt (100%) and elisa (100%). no blood culture was conducted in this study because the diagnosis of brucellosis was based on rbt and elisa. ultrasonography is usually vital for excluding the suspicion of an abscess or tumor rather than confirming the primary diagnosis. the frequent u/s features of beo are testicular enlargement, hypervascularity, inhomogeneous echotexture, and heterogeneous or hypoechoic echogenicity. these features can also be seen in other etiologies of orchitis. thus, the u/s examination cannot be relied on solely for the diagnosis of beo (1, 9). all these features could be seen in the u/s examination of our cases, of which vascularity was the most prevalent finding (91%). it has been indicated that using medications like rifampicin, streptomycin, tetracycline, ciprofloxacin, doxycycline, and cotrimoxazole for at least six weeks has a significant impact on managing brucellosis (1). a suggested approach involves taking a daily combination of doxycycline (200 mg) and rifampicin (600 mg) for around six weeks. it's worth noting that using a single drug for treatment has a higher likelihood of failure compared to using a combination, so medical treatment should involve the use of two or three antibiotics together (1, 10, 21). the rate of treatment failure and the requirement for orchiectomy have been reported to vary from 0% to 40% and from 0% to 5.1%, respectively. in accordance, the rates of treatment failure, recurrence, and orchiectomy among the reviewed cases were 2.3%, 2.8%, and 2.8% consecutively. all patients in this series were treated with antibiotic combinations. one orchiectomy (9%) was conducted due to abscess formation, and no recurrence was reported during the follow-up period. conclusions in developing countries, especially in the middle east, brucellosis remains a concerning infectious disease. as it is commonly diagnosed in young adults, it may have unfavorable effects on the reproductive activity of this group. an early diagnosis to prevent abscess formation and other complications is the first priority to avoid invasive interventions. rbt and elisa, in addition to clinical presentations, may be sufficient for diagnosis. references 1. bapir r, ahmed sf, tahir sh, et al. brucella orchitis presenting as a testicular mass mimicking a testicular tumor: a rare case report. african journal of urology. 2023; 29:5. 2. nahas rs, alsulami a, lashkar mo, thabit ak. brucella epidydimo-orchitis successfully treated with dual oral drug regimen: a case report with differential diagnoses of malignancy and tuberculosis. radiol case rep. 2022; 17:3485-9. 3. celen mk, ulug m, ayaz c, et al. brucellar epididymo-orchitis in southeastern part of turkey: an 8 year experience. braz j infect dis. 2010; 14:109-15. 4. aydemir h, budak g, budak s, et al. different presentation types of primary brucella epididimo-orchitis. arch ital urol androl. 2015; 87:151-3. 5. khodadadi j, dodangeh m, nasiri m. brucellar epididymo-orchitis: symptoms, diagnosis, treatment and follow-up of 50 patients in iran. idcases. 2023; 32:e01736. 6. zana hm, fenk mm, binaiy nf, et al. cancer publications in one year (2022); a cross-sectional study. barw medical journal. 2023; 1(2). 7. tanyel e, tasdelen-fisgin n, sarikaya-genc h, et al. brucella epididymo-orchitis relapsing three times despite treatment. int j infect dis. 2008; 12:215-7. archivio italiano di urologia e andrologia 2023; 95(4):11978 r. bapir, a.mohammed abdalqadir, e. aghaways, et al. 6 8. alarbid a, salem sm, alenezi t, et al. early predictors of brucella epididymo-orchitis. urol ann. 2023; 15:158-61. 9. gozdas ht, bal t. brucellar epididymo-orchitis: a retrospective study of 25 cases. aging male. 2019; 23:29-32. 10. savasci u, zor m, karakas a, et al. brucellar epididymo-orchitis: a retrospective multicenter study of 28 cases and review of the literature. travel med infect dis. 2014; 12:667-72. 11. kadikoylu g, tuncer g, bolaman z, sina m. brucellar orchitis in innerwest anatolia region of turkey: a report of 12 cases. urol int. 2002; 69:33-5. 12. memish za, venkatesh s. brucellar epididymo-orchitis in saudi arabia: a retrospective study of 26 cases and review of the literature. bju international. 2001; 88:72-6. 13. hasanjani roushan mr, baiani m, javanian m, kasaeian aa. brucellar epididymo-orchitis: review of 53 cases in babol, northern iran. scand j infect dis. 2009; 41:440-4. 14. aso sm, jaafar oa, hiwa ob, et al. kscien’s list; a new strategy to discourage predatory journals and publishers (second version). barw medical journal. 2023; 1:1-3. 15. naz h, korkmaz p, cevik f, aykin n. the clinical and laboratory characteristics, treatments, and outcomes of patients with brucella epididymo-orchitis (beo) compared to those without beo. turk j med sci. 2016; 46:1323-8. 16. gonen i, umul m, sozen h, kaya o. brucellar epididymo-orchitis in southwest anatolia, turkey: a retrospective study of 14 patients. acta medica mediterranea. 2013; 29:509-13. 17. sofian m, aghakhani a, banifazl m, et al. differentiation of brucella-induced epididymo-orchitis from nonspecific epididymoorchitis in an endemic area for brucellosis. journal of medical microbiology and infectious diseases. 2013; 1:8-13. 18. günes m, geçit i, bilici s, demir c, et al. brucellar epididymoorchitis: report of fifteen cases. van medical journal. 2010; 17:131-5. 19. colmenero jd, munoz-roca nl, bermudez p, et al. clinical findings, diagnostic approach, and outcome of brucella melitensis epididymo-orchitis. diagnostic microbiology and infectious disease. 2007; 57:367-72. 20. papatsoris ag, mpadra fa, karamouzis mv, frangides cy. endemic brucellar epididymo-orchitis: a 10-year experience. international journal of infectious diseases. 2002; 6:309-13. 21. baykan ah, sayiner hs, inan i. brucella and non-brucella epididymo-orchitis: comparison of ultrasound fndings. med ultrason. 2019; 21:246-250. 22. al-tawfiq ja. brucella epididymo-orchitis: a consideration in endemic area. international braz j urol. 2006; 32:313-5. correspondence rawa bapir, md dr.rawa@yahoo.com hiwa abdullah, md hiewaom96@gmail.com shaho ahmed, md shahomedi87@gmail.com berun abdalla, md berun.anwer95@gmail.com smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq esmaeel aghaways, md esmaeel.aghaways@gmail.com college of medicine, university of sulaimani, madam mitterrand street, sulaimani, kurdistan, iraq hemn bayz, md hemn.bayz@gmail.com smart health tower raparin, karux str, rania, sulaimani, kurdistan, iraq jihad hama, md jihad.hama@gmail.com bryar muhammed, md bryar.muhammed@gmail.com research center, university of halabja, halabja, iraq karokh hamahussein, md karokh12@gmail.com kurdistan center for gastroenterology and hepatology, sulaimani, kurdistan, iraq farman faraj, md farman.faraj@gmail.com ahmed abdalqadir, md ahmed.abdalqadir@gmail.com department of urology, sulaimani surgical teaching hospital, sulaimani, iraq fahmi hussein kakamad, md (corresponding author) fahmi.hussein@univsul.edu.iq college of medicine, university of sulaimani doctor city, building 11, apartment 50 madam mitterrand street, hc8v+f66, 46000 sulaymaniyah, kurdistan, iraq conflict of interest: the authors declare no potential conflict of interest. stesura seveso 71archivio italiano di urologia e andrologia 2021; 93, 1 case collection no conflict of interest declared. doi: 10.4081/aiua.2021.1.71 case 1 role of interventional radiology in the treatment of uretero-arterial fistulas: two-cases of endovascular treatment (giuseppe giordano, diego meo, vincenzo magnano san lio ) introduction uretero-arterial fistulas (fua) are defined as a pathological connection between the ureter and the iliac artery (1, 2). the known risk factors for this pathology are pelvic or genitourinary surgery, pelvic radiotherapy treatments, vascular pathologies such as iliac aneurysms and being chronic carriers of ureteral stents (3). it represents a rare occurrence that is found today more frequently in relation to the increase in life expectancy of patients with pelvic neoplasms (4). it is difficult to diagnose and it is associated with high rates of morbidity and mortality. different therapeutic approaches are possible, in particular interventional radiology techniques, ranging from the use of balloon catheters to intra-arterial embolization and placement of covered stents, have proven to be a less invasive and faster option, offering excellent results in terms of resolution of the pathology. in this report we describe, in addition to the role of interventional radiology in the treatment of this pathology, two cases successfully treated at our center with an endovascular approach. case report a patient (male, 61 years old) was subjected to left hemicolectomy for neoplasia in 2017 and subsequently to pelvic exenteratio with uretero-cutaneous-ileostomy according to bricker for loco-regional relapse. in january this collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. case 1: a case of uretero-arterial fistula in a patient with long-term ureteral stenting for ureteral oncological stricture and a second case associated to retroperitoneal fibrosis were described. abdominal ct, pyelography, cystoscopy were useful to show the origin of the bleeding. angiography is useful for confirming the diagnosis and for subsequent positioning of an endovascular prosthesis which represents a safe approach with reduced post-procedural complications. case 2: a case of patient who suffered from interstitial pneumonitis during a cycle of intravesical bcg instillations for urothelial cancer. the patient was hospitalized for more than two weeks in a covid ward for a suspected of covid-19 pneumonia, but he did not show any evidence of sars-cov-2 infection during his hospital stay. case 3: a case of a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. case 4: a case of a 61 year old male suffering from muscle invasive bladder cancer who was admitted for a radical cystectomy and on the eighth postoperative day developed microangiopathic hemolytic anemia and thrombocytopenia, which clinically defines thrombotic microangiopathy. key words: ureter-arterial fistula; bcg; pneumonitis; bladder tumors; cystectomy; paraganglioma; thrombotic thrombocytopenic purpura. submitted 26 july 2020; accepted 21 august 2020 oncology and complications summary giuseppe giordano 1, evangelia kyriazi 2, charalampos mavridis 3, francesco persico 4, 5, charalampos fragkoulis 6, piergiorgio gatto 7, george georgiadis 3, irene giagourta 2, ioannis glykas 6, rodolfo hurle 4, massimo lazzeri 4, giovanni lughezzani 4, 8, vincenzo magnano san lio 1, charalampos mamoulakis 3, diego meo 1, helen a. papadaki 9, george piaditis 2, charalampos pontikoglou 9, georgios stathouros 6 1 unit of diagnostic and interventional radiology, arnas “garibaldi-nesima”, catania, italy; 2 endocrinology department, general hospital of athens “g. gennimatas”, athens, italy; 3 department of urology, university general hospital of heraklion, university of crete, medical school, heraklion, crete, greece; 4 humanitas clinical and research center irccs, department of urology, rozzano, milan, italy; 5 university of naples federico ii, department of neurosciences, sciences of reproduction, and odontostomatology, naples, italy; 6 urology department, general hospital of athens “g. gennimatas”, athens, greece; 7 ospedale di sestri levante asl 4 liguria, dipartimento medico ad elevata integrazione territoriale, sestri levante, italy; 8 humanitas university, department of biomedical sciences, rozzano, milan, italy; 9 department of hematology, university general hospital of heraklion, university of crete, medical school, heraklion, crete, greece. archivio italiano di urologia e andrologia 2021; 93, 1 g. giordano, e. kyriazi, c. mavridis, et al. 72 2018 in the presence of bilateral hydroureteronephrosis, due to tightened stenosis at the level of the ileal ureteral anastomosis caused by the appearance of pathological tissue attributable to recurrent disease, nephrostomies were placed with subsequent stenting of the ureters with a 8 fr pig tail stent. one year later (january 2019) repeated episodes of intermittent hematuria occurred. in the same month, during a routine control for replacement of urinary stents, performed in the angiography room, a copious bleeding from the right mono j ureteral catheter was appreciated. pyelography was then performed from the ureteral stent. increasing pressure in the ureter, opacification of the common ipsilateral iliac artery was observed through reflux (figure 1). in the same session, therefore, through right transfemoral approach with a 9 fr introducer, it was positioned at the level of the left common iliac artery, on a 0.035 guide, a metal coated stent 9 mm diameter 60 mm long that was subsequently dilated with a 8 mm diameter 4 cm long balloon catheter (figure 2). at the end of the procedure, complete stop of bleeding was observed, which no longer occurred until to the patient's death after about 6 months due to progression of the neoplastic pathology. a patient (male 63 years old) affected by retroperitoneal fibrosis determining bilateral hydroureteronephrosis was subjected to bilateral ureteral stenting with cystoscopic approach; after repeated episodes of hematuria and severe anemization with need for blood transfusions in may 2019, he performed a ct scan in june 2019 that did not show any signs of active bleeding but showed the presence of clots in the right ureter (figure 3). in relation to the finding, confirmed by a cystoscopic evaluation with direct visualization of clots in the bladder coming from the right ureter, the patient was taken to the angiographic room and, after recovering the bladder end of the right urinary stent with a goose neck catheter, an introducer 7 fr 35 cm long was advanced on a metallic guide via transurethral access to the right ureteral meatus to perform a pyelography which however does not show a fistulous route to the iliac artery. however, due to the numerous episodes of hematuria, the clots inside the right ureter, the absence of other bleeding foci and the contiguity of the right ureter with the right common iliac artery at the passage in the external iliac, it was decided to position a 10 mm diameter 59 mm long modular stent via a right transfemoral approach using an 8 fr introducer and to dilate it in its proximal portion in the common iliac with a 12 mm diameter 40 mm long balloon catheter. the procedure was completed by placing an additional uncoated balloon expandable stent 8 mm diameter 60 mm long in the external iliac artery in the presence of a iatrogenic focal dissection (figure 4). the patient, currently was undergoing follow-up and no longer presented hematuria with resolution of anemia. conclusions despite the paucity of the literature data, due also to the rarity of this pathology, the interventional radiology techniques, compared to surgery, should be considered as first choice, especially in urgency, for treatment of uretero-arterial fistula; in particular the positioning of covered stents at the level of the artery in correspondence with the fistula has proved to be a fast, safe and effective system in resolving the hemorrhagic situation and increasing the survival of these patients. thanks also to technological upgrade of modular coated stents, today it is possible to treat fistulous lesions by more precisely calibrating the dimensions of the prosthesis even in vascular districts with different diameters, obtaining a greater hold of the stent with the vessel walls. references 1. moschowitz a. simultaneous ligation of both external iliac arteries for secondary hemorrhage following bilateral ureterolithotomy. ann surg. 1908; 48:872-5. case 1 figure 1. pyelography at high pressure showing opacification of the common iliac artery. case 1 figure 3. ct scan showing clots in the right ureter. case 1 figure 4. placement of uncoated balloon expandable stent 8 mm diameter 60 mm long in the external iliac artery. case 1 figure 2. pyelography at high pressure showing opacification of the common iliac artery. 2. van den bergh rc, moll fl, de vries jp, et al. arterioureteral fistulas: unusual suspects systematic review of 139 cases. urology. 2009; 74:251-5. 3. krambeck ae, dimarco ds, gettman mt, et al. ureteroiliac artery fistula: diagnosis and treatment algorithm. urology. 2005; 66:990-4. 4. fox ja, krambeck a, mcphail ef, et al. ureteroarterial fistula treatment with open surgery versus endovascular management: long-term outcomes. j urol. 2011; 185:945-50. case 2 the effect of bacillus calmette-guérin (bcg) instillations on the immune system: a case report of hypersensitivity pneumonitis during the covid-19 pandemic (francesco persico, massimo lazzeri, giovanni lughezzani, piergiorgio gatto, rodolfo hurle) introduction bcg is a live attenuated vaccine derived from mycobacterium bovis that was developed against tuberculosis at the beginning of the 20th century at the institut pasteur in paris (1). since then, it has been the most used vaccine in the world, with around 130 million children vaccinated every year. moreover, bcg intravesical instillation is a widely used treatment for high-risk non-muscle invasive bladder cancer (nmibc) (2). although the exact mechanism of bcg on tumor prevention is still unclear, a local immune response is presumed. the bcg-induced activation of the immune system involves cd4(+) and cd8(+) lymphocytes, natural killer cells, macrophages, granulocytes, and dendritic cells. bladder cancer cells are killed through cell-mediated cytotoxicity, by the secretion of soluble factors such as trail (tumour necrosis factor-related apoptosis-inducing ligand), and, to a certain extent, by the direct action of bcg (3). recent studies has also suggested that the trained immunity induced by bcg vaccination is protective against multiple infections (1). in this case report, we presented a peculiar case of a male patient with a medical history of recent bcg instillations for nmibc who suffered from interstitial pneumonitis and did not contract sars-cov-2 infection despite his prolonged hospitalization in a covid ward. case report a 63-year-old man was admitted to the er for the suspect of a sars-cov-2 induced interstitial pneumonia during bcg treatment for high-grade nimbc. he did not have a personal history of direct exposure to individuals with sars-cov-2 infection. the patient’s past medical history included a diagnosis of high-grade nmibc in 2012 followed by a bcg induction cycle (one instillation weekly for 6 weeks) and maintenance (one instillation for 3 weeks on months 3, 6, 12, 18, 24) [swog protocol] in 2012-2013. during follow-up, in july 2017, he underwent a diagnostic ureteroscopy for suspicion of upper tract urothelial neoplasm based on positive urinary cytology and a suspicious computed tomography (ct). biopsies histological examination revealed a carcinoma in situ (cis) of left ureter. consequently, the patient underwent an open left nephroureterectomy for cis of the left ureter in september 2017. after surgery, he resumed bcg instillations and underwent 3 bladder mappings resulted negative for urothelial cancer. during the treatment, the patient developed severe irritative symptoms, suggestive for bcg-induced chemical cystitis, that were treated first conservatively with hyaluronic acid instillations in april 2019. in january 2020, after a negative cystoscopy with suspicious cytology, he underwent right flexible ureterorenoscopy with mapping of renal pelvis (negative for urothelial cancer) and selective urinary cytology of right upper urinary tract (suspicious for malignancy). during the procedure, the surgeon placed a jj ureteral stent 6 french x 28 centimeters to perform upper urinary tract instillations. the patient subsequently received intravesical bacillus calmette-guerin (bcg) instillation at weekly intervals. four doses were administered without relevant problems. after the fourth bcg instillation on 13th of march, the patient developed influenza-like symptoms; fever, anorexia, night sweats, shivering, cough, and chest distress persisted for about three weeks, with the body temperature reaching a maximum of 38.1°c. on march 27st, the ureteral stent was removed for a suspicion of an urinary infection and the patient started an empirical antibiotic therapy with ciprofloxacin and trimetoprim-sulfametoxazole as prescribed by his general practicioner. on march 31st, he came to the emergency department of the hospital of sestri levante for a respiratory distress and a physical examination highlighted fine inspiratory crackles in both lungs. upon admission, the patient‘s body temperature was 38.3°c. haemogasanalysis showed oxygen pressure (po2) and carbon dioxide pressure (pco2) of 43 mmhg and 30 mmhg on room air, respectively, with ph of 7.5. the blood exams showed leukocytosis (16760 cells/mm3) with increased levels of c-reactive protein (6 mg/dl) d-dimer, transaminases, ldh and creatinine (1.54 mg/dl). chest radiography highlighted widespread accentuation of the bronchovascular texture. therefore, he was admitted to a covid ward with the suspicion for covid-19 pneumonia. according to institutional protocols, he began a therapy with clarithromycin, ceftriaxone, hydroxychloroquine, enoxaparin and oxygen therapy. the patient performed on the 1st and on the 11th of april two sars-cov-2 oropharyngeal swabs that resulted negative. serology for sars-cov-2 was negative as well. blood culture and urine culture performed on the april 1st were both negative. on april 8th, a chest ct was performed revealing a bilateral subpleural patchy ground-glass appearance associated to the presence of small centrilobular nodules (figure 1). on april 10th, the patient underwent bronchoscopy with broncho-alveolar lavage (bal) that resulted negative for bcg and sars-cov-2. the clinical status improved gradually with normalization of pcr, ddimer, transaminases, ldh and creatinine. oxygen therapy was suspended on april 13th and the patient was discharged on april 15th with diagnosis of hypersensitivity pneumonitis bcg-induced. medical therapy consisted of omeprazole, enoxaparin, levofloxacin and prednisone for one month. on june 22th the patient underwent uri73archivio italiano di urologia e andrologia 2021; 93, 1 oncology and complications archivio italiano di urologia e andrologia 2021; 93, 1 g. giordano, e. kyriazi, c. mavridis, et al. 74 nary cytology and transurethral cystoscopy that were both negative. he did not report significative respiratory symptoms and abnormal findings on chest ct disappeared. conclusions this case report emphasizes the importance of understanding the real effect of bcg on immune system. further researches are needed to understand the possible protective role of immunotherapy with bcg in presence of covid-19 infection. references 1. arts rjw, et al. bcg vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. cell host microbe. 2018; 23:89100.e5. 2. malmstrom pu, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guerin for nonmuscleinvasive bladder cancer. eur urol. 2009; 56:247. 3. redelman-sidi g, glickman ms, bochner bh. the mechanism of action of bcg therapy for bladder cancer-a current perspective. nat rev urol. 2014; 11:153-162. case 3 paraganglioma of the urinary bladder. a case report and review of the literature (evangelia kyriazi, charalampos fragkoulis, irene giagourta, ioannis glykas, georgios stathouros, george piaditis) tumors arising from the chromaffin cells, derived from the embryonic neural crest, usually originate from the adrenal medulla, are designated as pheochromocytomas. paragangliomas (pgls) are such tumors occurring in extra-adrenal locations and represent 10% of all pheochromocytomas (1). plgs are either functional or non-functional depending in the secretion of catecholamines (2). urinary bladder plgs are rare as they represent 6% of all plgs with most common locations the dome or the trigone. plgs located in other sites of the genitourinary system are less common as bladder is the primary site of such tumors (80%) followed by the urethra (12.7%), pelvis (4.9%) and ureter (3.2%) (3, 4). in the current case-report, we present a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. case report a 38-year-old man experiencing palpitation, headache, diaphoresis, and abdominal painafter micturition was referred to the endocrinology department for evaluation and further investigation. when further enquired, he described an 8 year history of the aforementioned symptoms, accompanied by characteristic facial pallor and high blood pressure ranging from 170/95 mmhg to 190/110 mmhg. apart from the moment of episodes coincided with urination, the patient’s blood pressure was marginally elevated. his physical examination and medical history were otherwise unremarkable. the clinical suspicion of a pheo/pgl was confirmed by a 24h urine collection demonstrating elevated levels of urine metanephrine 3257 (100-800 μg/24h) and normetanephrine 3177 (88-44 μg/24h). subsequently, a ct scanning of the abdomen documented the presence of a multi-lobular, homogenously contrast-enhanced mass (5.5 cm x 3.5 cm) arising from the right posterior wall of the urinary bladder. a ct scanning of his neck and thorax was performed but did not reveal any additional pathological findings. patient was referred to the urology department to surgically remove the mass. preoperative preparation included the administration of phenoxybenzamine (a-adrenergic blocking agent) and fluids (nacl 0.9%) in order to restore arterial blood pressure and intravascular volume and avoid intra-operative hypertensive crisis and postresection hypotension. a sub-umbilical midline incision was performed, bladder was mobilized, right ureter was recognized, and the mass was resected from the bladder wall detrusor muscle. the resection was successfully performed without opening the bladder. a single extraperitoneal drain was placed which was removed on the third postoperative day. blood loss during surgery was minimal (< 100 ml). no complications were recorded postoperatively. patient remained normotensive and was subsequently discharged without receiving any antihypertensive treatment. pathology report confirmed the presence of a pgl embedded in smooth muscle fibers of the urinary bladder detrusor muscle. macroscopically, the tumor was a solid, ovular, brown in color mass (4.5 x 3.5 x 3 cm) which was partially encapsulated. microscopically, the neoplasm had developed among smooth muscle cells, was of moderate to high cellularity and had grown in a typical “zellbalen” pattern. the cells had abundant, amphophilic cytoplasm with moderate to high nuclear pleomorphism. focally located giant multinucleated cells were also observed. mitoses were scarce (0-1/10 high power fields). neither necrosis nor vascular invasion was observed. the tumor cells were positive for cga, syp, nse, focally positive for s-100 and p53 (12%) and negative for ckae1/ae3, p63, her2-neu. case 2 figure 1. chest imaging of the patient. the computed tomography scans taken on the 8th of april 2020 showed multiple patchy ground-glass opacities in bilateral subpleural areas with small nodular formations with centerlobulary localization. the image is published under agreement of the patient. 75archivio italiano di urologia e andrologia 2021; 93, 1 oncology and complications the proliferation index ki67 (mib-1) was estimated > 3% (focally up to 8%). follow-up protocol included a 24h urine collection for metanephrines 3 months after surgery which was normal and a post-operative mri of the abdomen which revealed no pathological findings. our patient had neither clinical features implying a syndrome related to pgl nor a positive family history. nevertheless, taking into consideration his young age and the histopathologically proven presence of pgl, we proceeded to his genetic testing to exclude a germline mutation. no disease-associated sequence changes were identified in sdhb, sdhc, sdhd, sdha and sdhaf2 genes. conclusions paraganglioma of the urinary bladder is a rare tumor which, when secretory, has a typical presentation usually related to micturition. in our case, owing to the tumor’s favorable location, the patient was managed with complete resection of his mass leaving the bladder mucosa intact and without the need of partial cystectomy. our case is an exception to the rule, given that urinary bladder pgls management usually entails more invasive and extensive procedures. genetic testing should always be considered, because it provides with invaluable information which may modify our patients’ surveillance and improve their prognosis. finally, it is worth underscoring that patients with pgls should receive life-long follow-up because of the peculiar biological behavior and the malignant potential of their disease. references 1. leestma je, price eb jr. paraganglioma of the urinary bladder. cancer. 1971; 28:1063-73. 2. al-zahrani aa. recurrent urinary bladder paraganglioma. adv urol. 2010; 2010:912125. 3. peng c, bu s, xiong s, et al. non-functioning paraganglioma occurring in the urinary bladder: a case report and review of the literature. oncol lett. 2015; 10: 321-324. 4. lenders jw, duh qy, eisenhofer g, et al. endocrine society. pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. j clin endocrinol metab. 2014; 99:1915-42. case 4 thrombotic thrombocytopenic purpura as a complication after radical cystectomy (charalampos mavridis, george georgiadis, charalampos pontikoglou, helen a. papadaki, charalampos mamoulakis) introduction thrombotic thrombocytopenic purpura (ttp) is a rare entity associated with microangiopathic hemolytic anemia (maha) and thrombocytopenia (1). acute kidney injury, fever, and neurological symptoms may also be present. ttp is fatal if left untreated. triggering factors usually remain unknown but major surgery-induced stress may result in ttp (1). the aim of the present report is to highlight the importance of close follow-up during the postoperative period following major surgery and to underline the importance of immediate pex treatment. to the best of our knowledge, this is the first ttp case reported after radical cystectomy. case report a 61 year old male with multiple high grade/in situ transitional cell bladder tumor and squamous cell bladder cancer and with a past medical history significant for hypertension and diabetes mellitus was admitted for elective radical cystectomy. abdominal/thorax computed tomography (ct) scans and bone scintigraphy showed no metastases and the preoperative laboratory work-up was insignificant as well. the perioperative course was uneventful; two units of red blood cells (rbc) were intraoperatively transfused. on the 6th post-operative day (pd), there was an increase in serum ldh level and a decrease in plt count. plt count decrease was initially attributed to the low-molecular-weight heparin administration (heparin-induced thrombocytopenia), which was then replaced by fondaparinux. on the 8th pd he developed uncontrolled hyperglycemia, confusion, headache and blurred vision. arterial blood gas levels were normal and brain, abdomen-pelvis ct scans showed no abnormalities. laboratory tests revealed an acute ht and plt count decrease, negative direct coombs test, normal prothrombin/activated partial thromboplastin time, normal fibrinogen level, normal troponin level and mildly elevated ddimers. peripheral blood smear revealed five schistocytes per high power field, thereby defining microangiopathic anemia. the combination of microangiopathic anemiathrombocytopenia suggested thrombotic microangiopathy (tma). a second sample sent for analysis within hours showed further ht and plt count deterioration, acute increase in ldh and acute kidney injury (table 1). in view of these findings and taking into consideration case 4 table 1. laboratory results and pex procedures. crea tbil wbc plt ht ldh schistocytes (mg/dl) (mg/dl) count count (%) (iu/l) (per hpf) (103/μl) (109/l) dos 1.04 1.01 11.7 242 36 360 n.a. pd1 1.07 2.6 12.7 251 35.1 390 n.a. pd2 1.12 2.3 14.5 271 35.2 410 n.a. pd3 1.19 1.29 11.6 333 33 382 n.a. pd4 0.9 0.9 14.2 277 34.1 390 n.a. pd5 1.08 1.4 16.9 228 34.6 380 n.a. pd6 1.06 1.9 15 110 33.6 525 n.a. pd7 1.11 1.8 14 35 30.6 705 n.a. pd8 1.47 2.8 20 8 21 1024 5 pd9 (1st pex) 1.55 3.6 27.1 19 17.2 1246 3 pd10 (2nd pex) 1.39 4.4 22.9 41 23.8 1705 2 pd11 (3rd pex) 1.35 3.2 32.5 59 26 707 n.a. pd12 (4th pex) 1.27 1.85 36.1 88 27 622 1 pd13 (5th pex) 1.25 1.35 34 84 28.9 540 1 pd14 (6th pex) 1.22 1.35 14.5 140 30 440 n.a. pd15 1.09 0.9 23 170 30.1 300 n.a. pd16 1.09 0.8 15.1 204 30.4 175 0 pd33 1.02 0.5 10.9 290 33.2 221 n.a. crea, serum creatinine; dos: day of surgery; hpf: high power field; ht: hematocrit; ldh: lactate dehydrogenase; pd: post-operative day; pex: plasma exchange therapy: plt: platelet; tbil: total bilirubin; wbc: white blood cell. archivio italiano di urologia e andrologia 2021; 93, 1 g. giordano, e. kyriazi, c. mavridis, et al. 76 the neurological symptoms of the patient the presumptive diagnosis of ttp was made and immediate treatment was initiated: prednisolone (25 mg t.i.d.) intravenously plus transfusion of two rbc units and nine units of fresh frozen plasma as a temporary measure since pex therapy, the mainstay treatment of ttp (2), is not readily available in our hospital. the next day (9th pd), pex therapy was initiated. the patient eventually improved and was discharged on the 33st pd in good condition. later the diagnosis was made by adamts13 activity test. conclusions major surgery in a patient with coexisting chronic and severe disorders may trigger ttp due to release of unknown factors that can cause disruption of homeostatic blood mechanisms, thus it is deemed crucial to closely follow-up these patients even beyond the 7th pd. ttp should be considered in the differential diagnosis of mha and thrombocytopenia, associated with renal impairment and neurological manifesta-tions that occurs during the postoperative period, in the absence of another clinically apparent etiology. since ttp is fatal if left untreated, physicians must be aware of this rare postoperative complication and immediate pex therapy should be initiated. acknowledgements the authors would like to thank the special research account of the university of crete for supporting the publication of this study (elke no 3550). references 1. eskazan ae, buyuktas d, soysal t. postoperative thrombotic thrombocytopenic purpura. surg today. 2015; 45:8-16. 2. scully m, goodship t. how i treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. br j haematol. 2014; 164:759-66. correspondence giuseppe giordano, md g.giorda@gmail.com diego meo, md (corresponding author) diegomeo@hotmail.it vincenzo magnano san lio, md v.magnano@alice.it unit of diagnostic and interventional radiology arnas “garibaldi-nesima” via palermo 636, 95122 catania (italy) francesco persico, md (corresponding author) francesco.persico90@gmail.com massimo lazzeri, md lazzeri.maximus@gmail.com giovanni lughezzani, md g.lughezzani@gmail.com piergiorgio gatto, md piergiorgio.gatto@asl4.liguria.it rodolfo hurle, md rodolfo.hurle@humanitas.it humanitas clinical and research center irccs via manzoni 56, 20089 rozzano (mi) (italy) evangelia kyriazi, md kyrevan@windowslive.com charalampos fragkoulis, md harisfrag@yahoo.gr irene giagourta, md irene_giag@yahoo.com ioannis glykas, md (corresponding author) giannis.glykas@gmail.com georgios stathouros, md gstathouros@yahoo.gr george piaditis, md edk-pgna@otenet.gr general hospital of athens g. gennimatas, athens (greece) charalampos mavridis, md ch.mavridis@uoc.gr george georgiadis, md geokosgeo@yahoo.gr charalampos pontikoglou, md xpontik@uoc.gr helen a. papadaki, md e.papadaki@uoc.gr charalampos mamoulakis, md (corresponding author) mamoulak@uoc.gr university general hospital of heraklion, university of crete, medical school, heraklion, crete (greece) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3350 review no conflict of interest declared. it usually occurs in the genitourinary tract [commonly the bladder (40%), renal parenchyma (16%), prostate and rarely the ureter (11%)], but it can affect all body organs (2, 3). bladder malakoplakia can manifest as nodules, plaques, or ulcers with voiding symptoms and it can mimic cystitis or bladder tumor (4). at cystoscopy it appears as a yellow soft tiny plaque or ulcer (1). the exact etiology is unknown, but it seems to be caused by a defect of phagocytic or degradative functions of histiocytes in response to e. coli or proteus infection resulting in a chronic inflammatory process (5). the lesions are characterized by presence of large macrophages; foamy histiocytes (known as von hansemann cells) containing michaelis-gutmann bodies (6). the gold standard for diagnosis and treatment has not yet been decided. only case reports about vesical malakoplakia can be found in the literature, hence there is a lack of a review of this disease. for this reason the aim of our study was to review all the case reports about bladder malacoplakia in order to compare them. materials and methods we searched articles on the pubmed web-literature database with the following keywords: “vesical malakoplakia” and “bladder malakoplakia”. the including criteria for our study were: case report and primary bladder malakoplakia as central topic. in the literature we found 254 articles. of this, we excluded 172 articles because they did not respected the including criteria. so we selected 82 case reports. furthermore 47 articles have been discharged because articles were unavailable or subject of the paper was off topic. at final we have included in our study 35 articles. results from the 35 articles analyzed, we obtained 36 case reports. the major problem was to find all the information considering that many case reports were incomplete or unclear in their writing, in particular regarding follow-up. the main characteristics of the patients and the pathology are shown in table 1. objective: the aim of the study is to make a review of the literature about bladder malakoplakia. material and methods: we searched articles on the pubmed web-literature database with the following keywords: “vesical malakoplakia” and “bladder malakoplakia”. in the literature we found 254 articles. at final we have excluded 219 articles, including in our study only 35 articles. results: the overall average age found was 50.85 years. the average age of men was 43.22 years, while that of women was 53.37 years. 75% of the patient cases were women and 25% were men. regarding comorbidities, in 5.55% of the cases were missing whereas 47.22% of the patients suffered from recurrent urinary tract infection (uti) and 19.44% from immune system disorders. urine culture was positive in 69.44% with e.coli being isolated in 92% of cases. hydroureteronephrosis was present in 44.44% of the cases: left in 6.25% of cases, right in 18.75% and bilateral in 75%. the mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. the most frequent site of the lesion was the vesicoureteral junction (vuj) (42.31%), followed by the trigone (38.46%). 30.56% of patients were treated with antibiotic and surgery (transurethral resection of bladder, partial or radical cystectomy), less frequent options were antibiotics alone and surgery alone. the recurrence rate was 15%. conclusions: malakoplakia is a disorder usually related to other affections, like uti and immunodepression, and it seem to be caused by an abnormal macrophage function. in almost half of the described cases of isolated bladder malakoplakia, hydroureteronephrosis and renal failure were present.treatment is not standardized, but both medical and surgical therapies are effective to avoid recurrence. key words: malakoplakia; rare disorder; urinary tract infection. submitted 9 june 2022; accepted 23 june 2022 introduction malakoplakia is a rare disorder which was described for the first time in 1902 by michaelis and gutmann. it affects both sexes, mostly people over 40 years old, patients with immunosuppression, diabetes mellitus, renal transplantation, long-term therapy with systemic corticosteroids and patients with a prior infection of e. coli (1). malakoplakia of the urinary bladder: a review of the literature giordano polisini 1, rocco francesco delle fave 1, camilla capretti 2, angelo marronaro 2, alessia mariagrazia costa 2, luigi quaresima 2, daniele mazzaferro 2, andrea benedetto galosi 1 1 division of urology, university hospital “ospedali riuniti”, school of medicine, department of clinical, special and dental sciences, marche polytechnic university, ancona, italy; 2 department of urology, civitanova marche hospital, civitanova marche, italy. doi: 10.4081/aiua.2022.3.350 summary 351archivio italiano di urologia e andrologia 2022; 94, 3 malakoplakia of the urinary bladder data considered and collected were: age, sex, comorbidity, serum creatinine, presence of bacteria in urine, hydroureteronephrosis, site of injury, treatment and follow-up. the presence or absence of hydronephrosis was derived from imaging examinations: ultrasound, computerized tomography (ct), intravenous pyelography (ivp), etc. as shown in the table 2, the antibiotics used for the treatment were quinolones, trimethoprim-sulfamethoxazole and b-lactams. as not all the articles reported the antibiotic used, we decided to analyze the data by generally referring to the use of antibiotics or not and the same applies to the type of intervention performed. the overall average age found was 50.85 years. the average age of men was 43.22 years, while that of women was 53.37. 75% of the patient cases were women and 25% were men. regarding comorbidities, in 5.55% of the cases they were missing whereas 47.22% of the patients suffered from recurrent urinary tract infections (uti) and 19.44% from immune system disorders (such as diabetes). urine culture was positive in 69.44%. the infection was sustained in 92% of cases by e. coli. missing or negative culture are reported in 30%. on the other hand corynebacterium was occasionally reported. corynebacterium urealyticum is the cause of encrusting cystitis. it is usually missed in routine urine cultures since it does not grow after an overnight incubation. it grows in special media on longer incubation period in special medias. inaccurate search for it could explain the high rate of negative cultures. of the patients with negative urine culture, 85.71% had no history of recurrent uti. of the patients with positive urine culture, 60% had a history of recurrent uti. table 1. characteristics of the patients and the pathology. article age sex comorbility serum urine presence of site of lesion (years) creatinine culture/ ohydro-nephrosis levels (mg/dl) bacteria at imaging hina s et al. jcpsp 2019 (5) 55 female recurrent uti, diabetes 1.1 e. coli right right vuj rabani s et al. urol j 2019 (6) 1.7 female recurrent uti normal e. coli none right lateral wall sirithanaphol w et al. jecr 2018 (2) 66 female panniculitis, sistemic sclerosis, pulmonar fibrosis normal negative none \ parkin cj et al. bj 2020 (15) 82 female recurrent uti, diabetes, lnh 2.66 e. coli bilateral right and left vuj and the trigone gao p et al. jimr 2021 (4) 48 male diabetes 1.4 e. coli right right lateral wall involving right vuj shah a et al. psi 2005 (8) 11 male recurrent uti, megalo-urethra and puj normal e. coli none postero and left lateral walls ristic-petrovic a et al. vp 2013 (3) 53 female recurrent uti \ e. coli \ trigone, left vuj, posterior wall nabeshima a et al. j uoeh 2012 (16) 65 female no significantpasthistory normal e. coli \ trigone bruce r et al. ur 1990 (17) 86 female recurrent uti, small cell carcinoma \ e. coli none bladder dome stamatiou k et al. num 2014 (1) 72 male recurrent uti, diabetes, cvd 21 positive bilateral trigone, left vuj, posterior wall mukha rp et al. iun 2010 (18) 40 male recurrent uti 2.8 \ bilateral \ jordaan hf et al. clin exp dermatol 1990 (19) 68 female recurrent uti, pemfigo and immunodeficiency \ e. coli normal \ minor l et al. j urol 2013 (9) 16 female \ 3 e. coli bilateral \ patniak r et al. cases j 2009 (11) 18 male no significantpasthistory 1.6 negative bilateral trigone, left vuj, bladder neck berney dm et al. histopathology 1996 (12) first case 72 female no significantpasthistory \ negative \ \ berney dm et al. histopathology 1996 (12) second case 57 male acute renal failure \ \ \ \ pozomengual b et al. actas urol esp 2003 (14) 76 female no urological history normal negative none postero wall and bladder dome sulman a et al. urology 2002 (20) 40 female recurrent uti \ e. coli none bladder neck and left lateral wall billis a. nephron 1994 (21) 27 female cri/esdr \ negative \ trigone nukui m et al. hinyokika kiyo, 1997 (22) 63 female no significant past history 2.9 \ bilateral trigone and bilateral vuj batchelor js. br j urol 1991 (23) 63 female recurrent uti \ \ \ posteriorwall bylund j et al. nat clin pract urol 2008 (24) 51 female recurrent uti, blood hypertension 3.4 e. coli bilateral \ feldman s et al. j urol 1980 (25) 50 female recurrent uti 3.8 e. coli bilateral ureteral orifices were not visualized stanton mj. j urol 1983 (13) 48 female recurrent uti \ e. coli none right hemitrigone, right lateral wall and bladder neck fariña perez la. actas urol esp 1999 (26) 69 male cvd, tbc \ corynebacteriumurealyticum none postero and bilateralwall kohda n hinyokika k et al. 1984 (27) 44 female recurrent uti 0.7 negative none posterior, left and right wall zornox dh et al. j urol. 1979 (28) 69 female no significantpasthistory normal e. coli none right lateralwall kato t et al. hinyokika k 2001(29) 70 female recent pyelonephritis, hcv normal e. coli right trigone, bilteral vuj and neck stripling jr et al. south med j 1979 (30) 38 male no significantpasthistory 15 e. coli bilateral trigoneoblitering the ureteral orifices cavallone b, et al. urologia 2018 (31) 65 female recurrent uti, diabetes, obesity 9.3 e. coli bilateral anterior and left lateral wall tsai r et al. ajr am j roentgenol 2016 (32) 31 female \ \ negative none left wall steele b et al. pediatr radiol 2003 (33) 16 female cri, vur 2.8 e. coli bilateral \ tsung sh. urology 1982 (34) 50 female no significantpasthistory normal e. coli \ \ cowie ag et al. br j surg 1970 (35) 50 female recurrent uti normal e. coli none internal meatus andress mr et al. br j radiol 1968 (36) 36 male dystrophia myotonica \ e. coli bilateral widely distributed, with bilateral involvment of vuj melicow mm. j urol 1957 (37) 64 female cholecystectomy \ e. coli left \ archivio italiano di urologia e andrologia 2022; 94, 3 g. polisini, r.f. delle fave, c. capretti, a. marronaro, a.m. costa, l. quaresima, d. mazzaferro, a.b. galosi 352 hydroureteronephrosis was present in 44.44% of the cases, was absent in 36.11%, and was missing in 19.44%. in the patients with hydroureteronephrosis, 6.25% had left, 18.75% right and 75% bilateral hydroureteronephrosis.. the mean serum creatinine of patients with hydroureteronephrosis was 5.11 (1-21) mg/dl. regarding the site of the lesion, this information was missing in 10 cases (27.78%). in most of the remaining 26 cases the disease occurred in more than one area of the bladder. location, in order of frequency, was vesicoureteral junction (vuj) in 42.31%, trigone in 38.46%, left lateral wall in 30.77%, right lateral wall in 26.92%, posterior wall in 26.92%, bladder neck in 15.38%, bladder floor in 7.69% and anterior wall in 3.85%. with regard to treatment, we excluded from the analysis nephrostomies, urinary shunts without cystectomy and ureteral stent placement aimed at treating hydroureteronephrosis and not bladder pathology. treatment in 2.78% of cases was not reported. 30.56% of patients were treated with antibiotic and surgery (transurethral resection of bladder, partial or radical cystectomy). the remaining were treated as follows: 13.89% with antibiotics alone, 22.22% with surgery alone, 5.56% with antibiotic and bethanechol, 5.56% with antibiotic, bethanechol and ascorbic acid, 5.56% with antibiotic, bethanechol, ascorbic acid and surgery, 8.33% with antibiotic, ascorbic acid and surgery and 5.56% with follow-up only. in total, therefore, the two most frequently used treatments were antibiotic therapy (69.44%) and surgery (66.67%). regarding surgery, 75% of operations were transurethral resection of the bladder (turb), the remaining being partial or radical cystectomy. regarding recurrences, they were missing in 12 case reports (33.33%). out of the remaining 24 case reports, we excluded 2 cases because the patient had had a cystectomy and could not perform bladder follow-up and 2 other articles due to sudden death from other causes within about one month after diagnosis. in the remaining 20 reports, the recurrence rate was 15%. cases treated with medical therapy alone (without surgical removal) that demonstrated a reduction of the bladder mass on foltable 2. treatment and follow up. article treatment follow up hina s et al. jcpsp 2019 (5) antibiotics, ascrorbic acid, turb \ rabani s et al. urol j 2019 (6) partial cystectomy, trimethoprim-sulfamethoxazole no recurrence after 9 years sirithanaphol w et al. jecr 2018 (2) ciprofloxacin, turb no recurrence parkin cj et al. bj 2020 (15) amoxicillin-clavulanic acid, turb no recurrence after 2 months gao p et al. jimr 2021 (4) turb, tazobactam bladder recurrence at 6 months with right idroureteronephrosis shah a et al. psi 2005 (8) antibiotics bladder recurrence 2 and 3 years later ristic-petrovic a et al. vp 2013 (3) turb \ nabeshima a et al. j uoeh 2012 (16) turb \ bruce r et al. ur, 1990 (17) antibiotics \ stamatiou k et al. num 2014 (1) quinolones, turb he died 8 months later after a further worsening of renal failure and complications of the cardiovascular system mukha rp et al. iun, 2010 (18) radical cystectomy \ jordaan hf et al. clin exp dermatol 1990 (19) trimethoprim-sulfamethoxazole, bethanechol, ascorbic acid no recurrence minor l et al. j urol 2013 (9) quinolones, bethanechol no recurrence patniak r et al. cases j 2009 (11) antibiotics no recurrence after 10 years berney dm et al. histopathology 1996 (12) first case antibiotics, radical cystectomy the patient initially improved, but developed renal failure and died 3 months after cystectomy berney dm et al. histopathology 1996 (12) second case radical cystectomy he died a month after radical cystectomy pozomengual b et al. actas urol esp 2003 (14) ciprofloxacin, turb at 15 day the patient developed a sepsis and she died after 48 hours sulman a et al. urology 2002 (20) antibiotics, turb \ billis a. nephron 1994 (21) \ \ nukui m et al. hinyokika kiyo 1997 (22) turb, trimethoprim sulfamethoxazole, bethanecol, ascorbic acid no recurrence after 20 months. batchelor js. br j urol 1991 (23) follow up no recurrence after18 months but the patient developed lhn bylund j et al. nat clin pract urol 2008 (24) ciprofloxacin, ascorbic acid, bethanechol, turb no recurrence after 6-9 months feldman s et al. j urol 1980 (25) follow up bladder recurrence after 2 months. the patient underwent total cystectomy stanton mj. j urol 1983 (13) trimethoprim-sulfamethoxazole, ascorbic acid, bethanechol no recurrence after 18 months fariña perez la. actas urol esp 1999 (26) turb after 30 days, he died for heart failure kohda n hinyokika k et al. 1984 (27) turb \ zornox dh et al. j urol 1979 (28) trimethoprim-sulfamethoxazole, ascorbic acid, turb no recurrence after 12 month kato t et al. hinyokika k 2001(29) turb no recurrence after 7 months stripling jr et al. south med j 1979 (30) cephalosporin, turb no recurrence cavallone b et al. urologia 2018 (31) ciprofloxacin, ascorbic acid, turb \ tsai r et al. ajr am j roentgenol. 2016 (32) bethanechol, rifampicin and trimethoprim-sulfamethoxazole no recurrence after 2 months steele b et al. pediatr radiol 2003 (33) ciprofloxacin no recurrence, decrease in the number and size of lesions tsung sh. urology 1982 (34) antibiotics \ cowie ag et al. br j surg 1970 (35) antibiotics, cystotomy no recurrence, small residual nodule that was fulgurated. no further cystoscopic abnormality has developed andress mr et al. br j radiol 1968 (36) turb, antibiotics \ melicow mm. j urol 1957 (37) cystectomy \ 353archivio italiano di urologia e andrologia 2022; 94, 3 malakoplakia of the urinary bladder low-up imaging were not considered as recurrences. the shortest follow-up was 2 weeks and the longest was 10 years. the recurrence rate of patients treated with antibiotics alone was 1/3 (33.33%). the recurrence rate of patients treated with antibiotic and surgery was 1/7 (14.29%). the recurrence rate of patients treated with follow up was 1/2 (50%). on the other hand, according to the single treatment, the recurrence rate of antibiotic use was 11.76%, of surgery 9.09% and follow-up only 50%. discussion malacoplakia is a rare inflammatory and granulomatous disease. it was first identified by michaelis and gutmann in 1902 and its histological features were described by von hansemann in 1903. the term 'malacoplakia' originates from the greek 'malakos' and 'plakos' and means 'soft plaque' (7). according to recent literature, the age of onset is over 50 years with a prevalence four times higher in women. malacoplakia mainly affects the urinary tract, particularly the bladder, followed by the kidney, the prostate and rarely the ureter (4, 5, 38). however, it may also affect other parts of the body including the conjunctiva, tonsils, adrenal glands, spleen, pancreas, retroperitoneum, mesenteric lymph node, brain, lung, and skin and potentially any organ. in addition, urinary involvement is more frequent in women and extra urinary involvement in men (8). the exact etiology is still unclear. however, a close association has been seen with recurrent urinary infections (especially from e. coli) and immunodepression (diabetes, kidney transplant) (7). in fact, malakoplakia is believed to result from defective phagocytosis [due to reduced intracellular levels of cyclic guanosine monophosphate (cgmp)], resulting in inadequate killing of bacteria. it results in granulomatous reaction caused by an accumulation of bacterial degradation products. partially digested bacteria become calcified and accumulate in macrophages, forming the pathognomonic michaelis-gutmann bodies (9). in addition, the macrophages involved in malacoplakia contain high immunoreactive a1-antitrypsin levels unlike other inflammatory processes (except for tuberculosis and xanthogranulomatous pyelonephritis). thus, immunohistochemical search for a1-antitrypsin can be useful for a differential diagnosis (10). clinically, it presents with irritative lower urinary tract symptoms (luts) such as dysuria, pollakiuria, urinary urgency and haematuria. these symptoms may mimic cystitis and bladder cancer. diagnosis is histological by biopsy of the visible mass on cystoscopy which as mentioned above, it appears as a yellow soft tiny plaque or ulcer (11). it is characterized histologically by von hansemann oval histiocytes which contain basophilic lysosomal inclusion bodies called michaelis gutmann bodies (12). imaging examinations (ultrasonography, ct and ivp) may be useful to identify concomitant hydroureteronephrosis and to identify minus defects of the upper urinary tract, indicating its involvement. currently there are no validated guidelines regarding its treatment (5). antibiotics are generally administered to treat the underlying infection, such as quinolones, trimethoprim and rifampicin, in combination or not with ascorbic acid and/or bethanechol (4). ascorbic acid and bethanechol (cholinergic agent) both seems to increase intracellular cyclic guanine monophosphate levels increasing bactericidal phagocytosis function of macrophages (13). surgical intervention is recommended when medical intervention fails (14). the results listed below are in agreement with the data described in the literature: the average age was found to be around 50 years, the disease is more frequent in women than in men, malacoplakia seems to be associated with recurrent uti and immune system disorders. about 90% of positive urine cultures are sustained by e. coli. in our study of the epidemiology, we found a lower mean age of incidence in men than in women by about 10 years, with a women:men frequency ratio of 3:1, instead of 4:1 as reported in the literature. in our review, we decided to look at the site of the disease and found that the most frequently affected sites were the trigone and ureteral meatuses. for the first time in our analysis, we found that about one third of patients had hydronephrosis (mono or bilateral) and that this correlated with involvement of the trigone and/or vuj. in the cases examined, hydronephrosis almost always led to renal failure with mean serum creatinine values of 5.1 mg/dl (the highest value found in a case of acute renal failure was 21 mg/dl). conclusions nowadays, malakoplakia is a disorder not well know, that seems related to other affections, like uti and immunodepression, and is thought to be the result of abnormal macrophage function. in accordance with the literature, it can present with a very-variable spectrum of symptoms although we have shown that in isolated bladder malakoplakia without ureteral involvement, hydroureteronephrosis and renal failure are very common (in almost half of the cases). treatment is not standardized, but both medical and surgical therapies seem to be effective in curing the condition and avoiding recurrence, although we did not collect sufficient data to perform a statistical analysis. references 1. stamatiou k, chelioti e, tsavari a, et al. renal failure caused by malakoplakia lesions of the urinary bladder. nephro urol mon. 2014; 6:e18522. 2. sirithanaphol w, sangkhamanon s, netwijitpan s, foocharoen c. bladder malakoplakia in systemic sclerosis patient: a case report and review literature. j endourol case reports. 2018; 4.1:91-93. 3. ristic-petrovi a, stojnev s, jankovic-velickovic l, marjanovic g. malakoplakia mimics urinary bladder cancer: a case report. vojnosanit pregl. 2013; 70:606-8. archivio italiano di urologia e andrologia 2022; 94, 3 g. polisini, r.f. delle fave, c. capretti, a. marronaro, a.m. costa, l. quaresima, d. mazzaferro, a.b. galosi 354 4. gao p, hu z, du d. malakoplakia of the bladder near the ureteral orifice: a case report, j intern med res. 2021; 49:1-5. 5. hina s, hasan a, iqbal n, et al. malakoplakia of the urinary bladder and unilateral ureter. j coll physicians surg pak. 2019; 29:582-584. 6. rabani s, rabani s, bladder malakoplakia simulating neoplasm in a young girl: report of a case and review of literature. urol j. 2019; 16:614-615. 7. cooper kl, badalato gm, rutman mp. infection of the urinary tract. in: elsevier (ed), campbell-waslsh-wein urology, 12th ed, 2021; 1129. 8. shah a, chandran h. malakoplakia of bladder in childhood, pediatr surg int. 2005; 21:113-115. 9. minor l, lindgren bw. malacoplakia of the bladder in a 16-yearold girl. j urol. 2003; 170:568-9. 10. callea f, van damme b, desmet vj. alpha-1-antitrypsin in malakoplakia. virchows arch a pathol anat histol. 1982; 395:1-9. 11. patnayak r, reddy mk, subramanian s, et al. an unusual case of bilateral hydroureteronephrosis caused by uretero-vesico malakoplakia in a young male: a case report and review of the literature. cases j. 2009; 2:7527. 12. berney dm, thompson i, baithun si. alkaline encrusted cystitis associated with malakoplakia. histopathology. 1996; 28:253-256. 13. stanton mj, lynch jh, maxted wc, chun bk. malacoplakia of the bladder: a case report of resolution with bethanechol, trimethoprim-sulfamethoxazole and ascorbic acid. j urol. 1983; 130:1174-5. 14. pozo mengual b, burgos revilla fj, briones mardones g, et al. malacoplaquia vesical con afectación ganglionar y curso agresivo [bladder malacoplakia with lymphatic involvement and an aggressive course]. actas urol esp. 2003; 27:159-63. 15. parkin cj, acland g, sulaiman b, et al. malakoplakia, a malignant mimic. bladder. 2020; 7:e44. 16. nabeshima a, yamada s, xin g, et al. a case of malakoplakia of the urinary bladder]. j uoeh. 2012; 34:265-70. 17. baumgartner br, alagappian r. malakoplakia of the ureter and bladder. urol radiol. 1990; 12:157-159. 18. mukha rp, kumar s, ramani mk, kekre ns. isolated malacoplakia of the bladder: a rare case report and review of literature, int urol nephrol. 2010; 42:349-350. 19. jordaan hf, heyns cf, allen fj, schneider j. immunosuppressive therapy for pemphigus vulgaris complicated by malakoplakia of the bladder. clin exp dermatol. 1990; 15:442-445. 20. sulman a, goldman h, malacoplakia presenting as a large bladder mass. urology. 2002; 60:163. 21. billis a, bladder malacoplakia in a patient on chronic hemodialysis waiting for kidney transplantation. nephron. 1994; 67:127-128. 22. nukui m, nakagawa y, uchida m. vesical malacoplakia accompanied with bilateral hydronephrosis: a case report. hinyokika kiyo. 1997; 43:49-52. 23. batchelor js, philp nh, ramsden kl, scott kwm.primary lymphoma of the bladder arising from an area of malakoplakia. br j urol. 1991; 68:550-1. 24. bylund j, pais jm jr. a case of acute renal failure caused by bilateral, multifocal malacoplakia lesions of the bladder and ureters. nat clin pract urol. 2008; 5:516-9. 25. feldman s, levy lb, prinz lm. malacoplakia of the bladder causing bilateral ureteral obstruction. j urol. 1980; 123:588-9. 26. fariña pérez la, menéndez p, astudillo a, et al. cistitis alcalina incrustante y malacoplaquia [encrusted alkaline cystitis and malacoplakia]. actas urol esp. 1999; 23:885-7. 27. kohda n, kamei o, oda h, a case of vesical malacoplakia, hinyokika kiyo. 1984; 30:1835-42. 28. sawamura t, sasagawa i, kubota y, et al. malacoplakia of the bladder: efficacy of enoxacine therapy. intern urol nephrol. 1996; 28:175-179. 29. kato t, suzuki y, sugimura j, et al. a case of ureterovesical malacoplakia that manifested hydronephrosis. hinyokika kiyo. 2001; 47:195-7. 30. stripling jr, tomskey gc, lanasa ja jr, ozog ls. ureteral obstruction caused by malacoplakia of the bladder over the ureteral orifice, south med j. 1979; 72:491-492. 31. cavallone b, serao a, audino p, et al. bilateral hydroureteronephrosis with renal failure caused by malacoplakia, urologia. 2018; 85:36-37. 32. epstein bm, patel v, porteous ph. ct appearance of bladder malakoplakia. j comput assist tomogr. 1983; 7:541-3. 33. steele b, vade a, lim-dunham j. sonographic appearance of bladder malacoplakia, pediatr radiol. 2003; 33:253-255. 34. tsung sh. urinary sediment cytology: potential diagnostic tool for malakoplakia, urology. 1932; 10:546-547. 35. cowie ag, whitaker rh. malakoplakia of the bladder with recurrent passage of pseudo-tumour fragments over eight years. br j surg. 1970; 57:883-5. 36. andress mr, lea thomas m, malakoplakia of the bladder demonstrated by double contrast cystography, br j radiol. 1968; 41:231-232. 37. melicow mm, malacoplakia. report of case, review of literature. j urol. 1957; 78:33-40. 38. scannapieco g, grasso m, crippa s, et al. ultrasonographic, serologic, and clinical characteristics of a case of prostatic malacoplakia. arch ital urol androl 2000; 72:254-6. correspondence giordano polisini, md gio.pol.93@gmail.com (corresponding author) rocco francesco delle fave, md dellefavefrancesco@alice.it andrea benedetto galosi, md a.b.galosi@univpm.it division of urology, university hospital “ospedali riuniti”, school of medicine, department of clinical, special and dental sciences, marche polytechnic university, ancona, italy camilla capretti, md camilla.capretti@sanita.marche.it angelo marronaro, md angelo.marronaro@sanita.marche.it alessia mariagrazia costa, md alessia.costa@sanita.marche.it luigi quaresima, md luigi.quaresima@sanita.marche.it daniele mazzaferro, md daniele.mazzaferro@sanita.marche.it department of urology, civitanova marche hospital, civitanova marche, italy stesura seveso 153archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. incidence has steadily increased, predominantly in more developed countries, up to 1/10.000 person-years (2). in many patients, tc is associated with high psychological and physiological burden (3). risk factors for developing tc are the presence of the other components of the testicular dysgenesis syndrome (tds) – cryptorchidism, hypospadias, and sub-/infertility (4); familial history of tc in first-grade relatives (5); and personal history of a contralateral tc (6). the predominant histology is germ cell tumour (gct) in over 90% of cases (7). the most common cgt are derived from germ cell neoplasia in situ (gcnis), comprising seminoma and non-seminomatous (ns)gct – embryonal carcinoma, teratocarcinoma, post-pubertal teratoma, post-pubertal yolk sac tumour, choriocarcinoma, and mixed gct; gcnis-unrelated gct include pre-pubertal gct and spermatocytic tumours; there is also a minority of non-gct that includes sex cord/stromal tumours (derived from leydig cells, sertoli cells or granulosa cells) and secondary cancers (8). tc typically presents as a painless testicular mass or as an incidental ultrasound (us) finding, albeit a significant minority of patients refer pain, either scrotal or in the flank (9). the diagnostic evaluation of tc, with few exceptions, includes physical examination, imaging [testicular us and computerised tomography (ct) of the thorax, abdomen, and pelvis], serum tumour markers (alphafetoprotein, beta subunit of human chorionic gonadotropin, and lactate dehydrogenase), and radical orchiectomy (1). the anatomical extent of the disease should be documented in appropriate staging and classification systems (1, 10), in order to initiate adequate early treatment thus improving patients’ outcome. in most patients, orchiectomy is curative, therefore the prognosis is good. those with metastatic tc may benefit from cisplatin-based chemotherapy regimens [specifically a combination of bleomycin, etoposide, and cisplatin (bep)], due to generally high gct chemosensitivity – this results in excellent cure rates, overall (11). still, there is a significant minority of patients that need further tailored treatment, such as retroperitoneal lymph node dissection (rplnd)/residual mass excision or salobjectives: to describe our experience on testicular cancer (tc) management, underlining the clinical/pathological scope, administered treatments, outcomes, and challenges. tc incidence is rising globally. the predominant histology is germ cell tumour (gct). in most patients, orchiectomy is curative. still, a significant proportion of patients will need further tailored treatment. specialist reference centres have proven themselves successful in this setting. published data regarding tc in northern portugal is lacking. methods: retrospective review of consecutive tc patients at a specialist tertiary referral academic centre between january 2010 and december 2020. statistical analysis was performed using the stata® version 13.1 software. multivariate logistic and survival analyses were performed. results: 125 patients met the inclusion criteria. the median age is 35 (28-40) years; 19% of patients had risk factors for tc – infertility being the most common (11%); 50% of patients wanted sperm cryopreservation prior to treatment; 68% of patients had stage i gct, 16% stage ii, and 17% stage iii. compared to seminoma, non-seminomatous gct were associated with younger age (p < .001) and higher stages at diagnosis (p = .02); 24% of stage ia/b gct underwent adjuvant chemotherapy; 47% of patients with metastatic gct at presentation had refractory disease, requiring tailored treatment. the median follow-up time is 33 (13-65) months. there was no late relapse. the 5-year os rate is 98.0%. the 5-year survival of metastatic disease is 95.8%. conclusions: despite contemporary excellent cure rates, the challenges of testicular cancer management still endure, especially in advanced stages. therefore, public awareness is recommended, in order to avoid late presentations special attention should be given to those who have known risk factors. the existence of reference centres is of paramount importance in order to achieve the best outcomes possible. key words: testicular cancer; germ cell tumour; reference centre; metastatic disease; relapse; risk-adapted treatment. submitted 9 february 2021; accepted 5 march 2021 introduction testicular cancer (tc) accounts for approximately 1% of all male cancers worldwide (1). over recent decades, its specialist management of testicular cancer: report of the last 10 years at a portuguese tertiary referral academic centre andré marques-pinto 1, ana inês gomes 2, joana febra 3, eugénia rosendo 3, manuel castanheira de oliveira 1, avelino fraga 1, 2, josé lafuente de carvalho 1, 2, nuno louro 1, 2 1 urology department, centro hospitalar universitário do porto, porto, portugal; 2 instituto de ciências biomédicas abel salazar, porto, portugal; 3 medical oncology department, centro hospitalar universitário do porto, porto, portugal. doi: 10.4081/aiua.2021.2.153 summary archivio italiano di urologia e andrologia 2021; 93, 2 a. marques-pinto, a.i. gomes, j. febra, e. rosendo, m. castanheira de oliveira, a. fraga, j. lafuente de carvalho, n. louro 154 vage chemotherapy; in rare cases, high-dose chemotherapy with autologous stem cell support may be needed (12). thus, there is a worldwide trend towards establishing reference centres, which have proven themselves successful by their multidisciplinary approach, meticulous follow-up, and suitable salvage therapies (13). since 2016, the centro hospitalar universitário do porto is an official reference centre in tc management, in collaboration with the instituto português de oncologia do porto, on a national level (despacho n.° 3653/2016). this study aims to describe our experience on tc management, underlining the clinical and pathological scope, administered treatments, outcomes, and challenges. methods a retrospective review was performed, comprising consecutive adult patients who had pathologically confirmed tc at a specialist tertiary referral academic centre, centro hospitalar universitário do porto, between january 2010 and december 2020, after institutional review board approval. all cases were discussed in a multidisciplinary tumour board. exclusion criteria comprised primary extragonadal gct, and incomplete data in any of the key variables. relevant information was collected from medical records regarding age, clinical presentation/referral, risk factors, staging [according to the 2016 tumour, node, metastasis classification of the international union against cancer, respective prognostic groups, and the international germ cell cancer collaborative classification for metastatic testicular cancer (1, 10)], pathology, systemic treatment, follow-up, special management problems and outcome. statistical analysis statistical analysis was performed using the stata® version 13.1 software. results for continuous variables were expressed as mean ± standard deviation or as median (interquartile range) according to its distribution. the chi-square test was applied to compare categorical variables. independent sample student t-test and oneway anova were used to compare continuous variables. univariate and multivariate linear and logistic regression analyses were performed according to the variables and expressed as a coefficient or odds ratio (or) and respective 95% confidence interval (95%ci). a survival analysis was performed in order to calculate the overall survival (os) rate. a p value < .05 was considered statistically significant. results the initial study cohort consisted of 129 patients. those with primary extragonadal gct (n = 1) and incomplete data (n = 3) were excluded to give the final cohort for analysis of 125 patients who met the inclusion criteria. there was a 60% increase in the number of patients with newly diagnosed tc since 2016 (20102015 n = 48 versus 2016-2020 n = 77). the median patient age is 35 (28-40) years. all patients are european caucasians. overall, 24 patients (19%) had a confirmed risk factor for tc – cryptorchidism (n = 5, 4.0%), infertility (n = 14, 11%), family history of tc (n = 2, 1.6%), and personal history of contralateral tc (n = 3, 2.4%). the majority of patients presented with a testicular mass (n = 73, 60%) and/or testicular pain (n = 42, 35%). a significant proportion of patients presented with an incidental us finding (n = 30, 25%), some of them in the workup of a retroperitoneal mass (n = 10, 8.0%) or gynecomastia (n = 5, 4.0%). altogether, there was no difference between the number of patients that presented with left sided tc (n = 63, 50%), versus right sided tc (n = 62, 50%). one patient presented with synchronous bilateral tc. after thorough anamnesis and physical examination, a scrotal us was performed on the same day, if not previously done. a minority of patients (n = 15, 12%) had a scrotal us on the following days. a staging ct was performed upfront preferably, though it did not delay radical orchiectomy, which was performed as quickly as possible, within the reference interval – 7 days after the first contact. the majority (n = 75, 66%) desired for a testicular prosthesis to be implanted in the same procedure, irrespective of age (or = .96, p = .10 95%ci [.92-1.00]). all men were offered sperm cryopreservation prior to starting treatment (with a few exceptions of life-threatening disseminated disease), and a significant proportion chose to do so (n = 59, 50%) – that decision was inversely related to age (or = .90, p < .001 95%ci [.86-.95]). pathological exam reported gct in 87% of patients (table 1) – of those, the most frequent was pure seminoma, followed by nsgct, and mixed seminoma-nsgct. almost half the nsgct consisted of embryonal carcinoma (n = 22, 48%), either pure or as the major component of mixed gct. the median tumour size was 30 (17-50) millimetres. notably, there was a histological scar and no evidence of primary tumour in a significant minority (n = 6, 4.8%) – five patients that were diagnosed with burned-out testis tumour and one patient that underwent chemotherapy before orchiectomy – all these patients had histological confirmation of metastatic gct. two thirds of patients had stage i gct, while roughly one third presented with advanced disease (table 1). compared to seminoma, nsgct were associated with younger age (28.7 ± 5.3 vs. 36.1 ± 7.8, p < .001) and higher stages at diagnosis (22 vs. 13, p = .02). a significant proportion of stage ia/b gct underwent adjuvant chemotherapy (table 2), according to risk factors for metastatic relapse – either carboplatin in seminoma or bep in nsgct. no patient underwent adjuvant radiotherapy. there were a few stage ia/b gct that relapsed (table 2), requiring systemic salvage treatment followed, whenever appropriate, by rplnd – seminoma was found in one case, and fibrosis in another. none of them had had adjuvant chemotherapy. regarding metastatic gct at presentation (that is, stage is and higher), all patients (n = 43) underwent primary bep chemotherapy, according to prognostic based groups – in good prognosis (n = 32, 74%), bepx3 (one patient had cisplatin plus etoposide x4 due to previous pulmonary disease), and in intermediate/poor prognosis (n = 11, 26%), bepx4. chemotherapy started as soon as possible after multidisciplinary discussion. most patients had tumour marker decline and regressive tc radiological features at repeated evaluations. of note, no patient with stage iia/b seminoma underwent primary radiotherapy. almost half the patients with metastatic gct (n = 20, 47%) presented refractory disease (table 2), requiring systemic salvage treatment and/or rplnd. the chosen salvage chemotherapy regimen consisted of cisplatin, ifosfamide, and either paclitaxel (n = 3) or vinblastine (n = 2). there was one cisplatin-refractory nsgct that remitted after second salvage combination of gemcitabine and oxaliplatin. regarding rplnd (table 2), viable gct was found in a significant minority of these patients, while the majority had either teratoma or fibrosis. regarding persistent disease/relapse, a logistic model adjusting for age, histological type and stage was found [chi2 (5) = 46.45, p < .001]: when compared to seminoma, nsgct and mixed seminoma-nsgct were associated with higher chances of disease persistence/relapse (table 3); furthermore, higher stages were associated to higher chances of persistent disease/relapse when comparing with stage i gct. the median follow-up time is 33 (13-65) months (n = 125). there was no record of late relapses. the 5-year os rate is 98.0% – there were two patients that died: one with stage iiic nsgct, and other with malignant leydig cell tumour; the remaining patients are in remission. stratifying by histological type, 5-year os is lower for nsgct (96.8%) than for seminoma (100%). regarding stage, the 5-year survival of metastatic disease is 95.8%. a minority of gct patients was lost to follow-up within the 5-year period after diagnosis (n = 7, 5.6%). discussion in this cohort, the majority of patients was in the third/fourth decade of life, which is in concordance with the available literature (2). since the encompassed population for reference centres in northern portugal is not strictly demarcated, and some patients are treated in private practice, no conclusions can be made regarding regional trends in tc incidence. however, our institution has noticed a much higher referral numbers over the last years, since we became an official reference centre for tc management. the main predictor of tc development appears to be the presence of any component of the tds, which may share genetic and/or environmental triggers (4). in fact, a significant proportion of patients in this cohort consists of patients with tds whose tc might have gone unnoticed for a longer period had they not undergone testicular imaging. a large proportion of tc (up to 25%) seem to be genetically linked (14). however, in this cohort, only a negligible proportion of patients reported familial history of tc in first grade relatives. early detection and referral of tc leads to improved overall survival rates. actually, routine scrotal us in patients with tds, specifically those presenting with a personal history cryptorchidism and sub-/infertility, may detect tc in its earlier stages, for which orchiectomy is curative. on the other hand, while testicular pain may lead to earlier presentation, we did not find any difference in tc stages when stratifying by pain. despite the increasing awareness for tc among young men and their partners, roughly one third of patients presented with metastatic disease. this may arise from ignorance, carelessness, shame, fear, denial, rurality, and reliance in alternative medicine. the definitive reasons cannot be assessed in this cohort. in this cohort, as reported in literature (1), the majority of gct consisted of seminoma, whereas nsgct presented earlier and behaved more aggressively. overall, gct accounted for 87% of cases, which is slightly below what is commonly reported (7). this may be due to a higher proportion of sex cord/stromal tumours, namely 155archivio italiano di urologia e andrologia 2021; 93, 2 testicular cancer management: 10-year report table 1. characteristics of participants at diagnosis by histological type. seminoma nsgct mixed s-nsgct scst ** total *** patients, n (%) 63 (50%) 34 (27%) 12 (9.6%) 14 (11%) 125 age, years* 36.1 ± 7.8 28.7 ± 5.3 36.2 ± 7.2 41.7 ± 12.2 35.1 ± 9.3 stage, n (%) i 50 (79%) 17 (50%) 7 (58%) 75 (68%) ii 7 (11%) 9 (26%) 1 (8.3%) 17 (16%) iii 6 (10%) 8 (24%) 4 (33%) 18 (17%) gct: germ cell tumour; nsgct: non seminomatous gct; s nsgct: seminoma nsgct; scst: sex cord/stromal tumours; sd: standard deviation. estimates were given as mean ± sd* or frequency (percentage). **: all scst were leydig cell tumours; ***includes one case of spermatocytic tumour and one case of testicular lymphoma. table 3. multivariate logistic regression to predict refractory gct. variable or 95%ci p value age (years) 1.1 .99-1.2 .09 histological group seminoma reference – nsgct 12.3 1.9-78.5 < .01 mixed s-nsgct 16.3 2.1-125.2 < .01 stage i reference – ii 4.6 1.0-21.9 .05 iii 28.9 6.2-134.1 < .001 gct: germ cell tumour; nsgct: non seminomatous gct; s nsgct: seminoma nsgct: 95%ci: 95% confidence interval; or: odds ratio. table 2. disease management of gct by histological type. seminoma nsgct mixed s-nsgct total stage ia/b gct 50 (77%) 9 (14%) 6 (9%) 65 adjuvant chemotherapy 11 (22%) 3 (33%) 2 (33%) 16 (25%) salvage chemotherapy 1 (2.0%) 1 (11%) 1 (17%) 3 (4.6%) rplnd 0 1 (11%) 1 (17%) 2 (3.1%) viable gct 1 (100%) 1 (50%) teratoma fibrosis 1 (100%) 1 (50%) persistent/relapsing metastatic gct 4 (20%) 11 (55%) 5 (25%) 20 salvage chemotherapy 2 (50%) 2 (18%) 1 (20%) 5 (25%) rplnd 2 (50%) 11 (100%) 4 (80%) 17 (85%) viable gct 3 (27%) 3 (18%) teratoma 4 (36%) 2 (50%) 6 (35%) fibrosis 2 (100%) 4 (36%) 2 (50%) 7 (41%) gct: germ cell tumour; nsgct: non seminomatous gct; rplnd: retroperitoneal lymph node dissection; s nsgct: seminoma nsgct. estimates were given as frequency (percentage). archivio italiano di urologia e andrologia 2021; 93, 2 a. marques-pinto, a.i. gomes, j. febra, e. rosendo, m. castanheira de oliveira, a. fraga, j. lafuente de carvalho, n. louro 156 leydig cell tumours, which accounted for 11% of cases, which is roughly 5-fold the proportion historically mentioned in literature (15). we could not establish the reasons for this pathological difference. the pivotal step of tc treatment is radical orchiectomy, which is a procedure associated with fairly low morbidity as it allows early control of testicular lymphovascular supply, as well as en bloc removal of the specimen (1). usually, with proper counselling, patients are not reluctant to undergo surgery as the possibilities of sperm cryopreservation and prosthesis implantation are reassuring for both fertility and aesthetics, whenever patients may find those issues relevant. remarkably, the proportion of patients that presented with advanced disease with no histological evidence of a primary tc other than a scar is similar to that of recent reports (16). after orchiectomy, further treatment depends on both clinical staging and the pathology report. in this cohort, the majority of patients underwent chemotherapy at any point (adjuvant, primary or salvage) with good compliance and tolerance, overall. in this cohort, no patient underwent adjuvant/primary radiotherapy. the scrupulous follow-up plan might have led to timely identification of relapses and quick tailored treatment, which could explain the low mortality in this cohort. in fact, the multidisciplinary approach that exists in our centre, among other factors, seems to lead to a 5-year os rate of 98.0% and, in metastatic disease, to a 5-year survival of 95.8%, which is higher than what has been recently reported (7, 17). in this cohort, there seems to exist a stronger association between mixed seminoma-nsgct and disease persistence/relapse than in other histological types, which is in concordance with recent reports that show a seminoma component in mixed gct might be associated with more aggressive disease (18). yet, we could not determine whether it is a true association or not, as it may be confounded by the relative proportion of other nsgct components. the major limitation of this study is its retrospective nature, which may have led to some bias, specifically in what concerns risk factors other than those mentioned. furthermore, the follow-up median is still below 5 years. in addition, genetic studies are not routinely undertaken at our centre, therefore no specific genetic counselling could be offered. overall, according to data, our centre offers state-of-theart treatment for tc. in the future, we hope to help to develop a national database, in order to uniformise medical records and standardise clinical procedures. conclusions despite contemporary excellent cure rates, the challenges of testicular cancer management still endure, especially in what concerns advanced stages. late presentation, regardless of the underlying causes, may correlate to higher stages, and represents a major shortcoming even in more developed countries, such as portugal. therefore, increasing public awareness and education in schools, primary care, and media is recommended – special attention should be given to those who have known risk factors for testicular cancer. furthermore, the inclusion of testicular self examination in school curricula might be considered, seeking to detect testicular cancers at a lower stage. the existence of reference centres is of paramount importance in order to achieve the best outcomes possible. acknowledgments we thank the homologous team of instituto português de oncologia do porto for their cooperation in order to achieve the best results possible for the patients being treated in either institution of our reference centre over the years. ethics approval this retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. the institutional human investigation committee (irb) approved this study. references 1. albers p, albrecht w, algaba f, et al. guidelines on testicular cancer: 2015 update. eur urol. 2015; 68:1054-68. 2. gurney jk, florio aa, znaor a, 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sylvester rj, stenning sp, et al. impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. european organization for research and treatment of cancer genito-urinary tract cancer collaborative group and the medical research council testicular cancer working party. j natl cancer inst. 1999; 91:839-46. 14. de toni l, sabovic i, cosci i, et al. testicular cancer: genes, environment, hormones. front endocrinol (lausanne). 2019; 10:408. 15. kim i, young rh, scully re. leydig cell tumors of the testis. a clinicopathological analysis of 40 cases and review of the literature. am j surg pathol. 1985; 9:177-92. 16. astigueta jc, abad-licham ma, agreda fm, et al. spontaneous testicular tumor regression: case report and historical review. ecancermedicalscience. 2018; 12:888. 17. miller kd, nogueira l, mariotto ab, et al. cancer treatment and survivorship statistics, 2019. ca cancer j clin. 2019; 69:363-85. 18. akan s, ediz c, tavukcu hh, et al. the clinical significance of seminoma component in testicular mixed germ cell tumour. urol int. 2020; 104:489-96. correspondence andré marques-pinto, md (corresponding author) andre.fmpinto@gmail.com manuel castanheira de oliveira, md manuelantonielo@gmail.com avelino fraga, md avfraga@gmail.com josé lafuente de carvalho, md lafuentecarvalho@gmail.com nuno louro, md nunorlouro@gmail.com urology department, centro hospitalar universitário do porto, porto (portugal) ana inês gomes, md anainesmg@gmail.com instituto de ciências biomédicas abel salazar, porto (portugal) joana febra, md joana.febra@gmail.com eugénia rosendo, md eugenia.rosendo@gmail.com medical oncology department, centro hospitalar universitário do porto, porto (portugal) stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12003 1 letter to editor key words: prostatic hyperplasia; minimally invasive surgical procedures; lower urinary tract symptoms; sexual dysfunction; urologic surgical procedures. submitted 19 october 2023; accepted 16 november 2023 to the editor, in recent years, alternative solutions have been proposed to obtain effective results comparable to turp, which is currently considered the gold standard, and laser vapo-enucleation techniques (1, 2), but with the possibility of maintaining sexual functions. in recent years there has been a growing trend towards ejaculation preservation. although the results of turp (3), and most laser enucleation techniques are undoubted in the benign prostatic hyperplasia (bph) and lower urinary tract symptoms (luts) management, they often lack in the preservation of ejaculation. all the alternative recently proposed interventions (rezum, aquabeam, urolift, tpla, i-tind, lest) are procedures considered by some authors to be promising in both managing bpo and preserving sexual functions. however, all these methods are limited by a lack of long-term follow-up that would evaluate the efficacy over time, possible complications related to the method and the correct patient selection for a specific method. the aim of this letter is to summarize the available evidence and provide clinicians with practical recommendations on the use of the brand new minimally invasive techniques for the management of bpo. leonardi ejaculation sparing technique (lest) the lest is an ablative technique fully described in 2019 (4). it is the evolution of a technique described in 2009 (5) that achieved outcomes similar to turp, while expanding the indication to larger prostates and preserving ejaculation. this is a debulking laser technique with the aim of preserving the “genital sphincter” (anatomical structure that include the para-urethral musculature, distinguished in proximal and distal portion, and in part the musculature of the bladder neck). other anatomical landmarks, essential to preserve ejaculation, are the orifices of ejaculatory ducts and the floor of prostatic urethra. the preliminary results showed an ipss improvement of about 59% (p < 0.001) at 3 months followup and 67% (p < 0.001) at 12 months follow-up. similarly, the q max improvement was about +179% (p < 0.001) and +163% (p < 0.001) at 3and 12-months follow-up, respectively (5). the quality of life (qol) was 3.5+/-1.2 at the baseline while 1.3+/-1.2 and 1.2+/-0.4 at 3 and 6 months, respectively. an antegrade ejaculation is maintained in about 80% of cases in patients without a middle lobe, although in the presence of a middle lobe this rate drops to about 50% (5). in the beginning, prostates with a size of no more than 60 grams were included (5). currently, the technique is proposed for any prostate size, with pure vaporization for a small prostate and enucleation for a large prostate (4, 5). no severe new minimally invasive solutions for benign prostatic obstruction (bpo) management: a position paper from the urop (urologi ospedalità gestione privata) rosario leonardi 1, 2, francesca ambrosini 3, rafaela malinaric 3, angelo cafarelli 1, 4, alessandro calarco 1, 5, renzo colombo 1, 6, ottavio de cobelli 1, 7, ferdinando de marco 1, 8, giovanni ferrari 1, 9, giuseppe ludovico 1, 10, stefano pecoraro 1, 11, domenico tuzzolo 1, carlo terrone 3, 12, guglielmo mantica 1, 3, 12 1 urologi ospedalità gestione privata (urop); 2 casa di cura musumeci gecas, gravina di catania, italy; 3 irccs ospedale policlinico san martino, genova, italy; 4 urology unit, villa igea, ancona, italy; 5 villa pia hospital, via folco portinari 5, rome, italy; 6 department of urology, vita e salute san raffaele university, milan, italy; 7 department of urology, ieo european institute of oncology, irccs, milan, italy; 8 i.n.i. grottaferrata, roma, italy; 9 hesperia hospital, modena, italy; 10 ospedale miulli, acquaviva delle fonti, bari, italy; 11 neuromed, avellino, italy; 12 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy. doi: 10.4081/aiua.2023.12003 archivio italiano di urologia e andrologia 2023; 95(4):12003 r. leonardi, f. ambrosini, r. malinaric, et al. 2 complications were described, except for minor bleeding at the beginning of urination, which usually occurs for 40 days after surgery. the reason for this lies in the preservation of mucosal areas of the prostatic urethra, that obviously must not be coagulated, that cover the structure to be preserved and that represent the key points of the technique. the authors are working to a variation of technique for the treatment of prostates with median lobe and the preliminary results show an increasing preservation of anterograde ejaculation compared to the past. aquabeam/aquablation aquablation, first described in 2015, uses a heat-less robotic system called acquabeam (acquabeam®, procept biorobotics, redwood shores, ca, usa), which combines ultrasound-guided waterjet technology with advanced planning software for precise ablation of prostate tissue and real-time monitoring during the procedure (6). the technique is recommended for patients with desires of preservation of sexual function and in case of moderate, to severe luts secondary to benign prostatic enlargement (volume 30-80 gr) and/or obstruction with underlying bph (7). the procedure is performed under loco-regional or general anesthesia and 2-4 days of hospitalization are usually required (7-9). one of the main advantages of aquablation is the short median operative time and resection time [30.5, iqr (24-35) and 4, iqr (3.1-4.9), respectively (10)]. sexual outcomes are promising with de novo ejaculatory dysfunction observed in 26.7% of patients and absence of de novo erectile dysfunction (10). the efficacy of aquablation was demonstrated in the united states (u.s.) cohort of the waterjet ablation therapy for endoscopic resection of prostate tissue (water) study, a double-blinded, multicenter, prospective, randomized controlled trial (rct) comparing turp vs. aquablation in patients with moderate-severe luts and a prostate size of 30-80 ml (8). the hypothesis of non-inferiority of aquablation in improving ipss was demonstrated at 6 months (8) and 1 year (11). the benefits in symptom relief were not at the expense of sexual dysfunction. among sexually active men, patients treated with aquablation experienced statistically significant lower rate of anejaculation (at 6 months: 10% vs 36% in turp, p = 0.0003; at 1 year: 9% versus 45% in turp, p = .0006) (8, 11). symptom reduction and qmax improvement results were maintained at 2 years (12) and 3 years of follow-up (9), with statistically comparable improvements in ipss scores between groups (3-year improvement difference: 0.6 points, 95% ci -3.3-2.2, p = 0.7) (9). the same results were reported in patients with large prostates (80-150 ml) (8) at 1 year and 2 year follow-up (water ii) (13-15). the non-inferior efficacy of aquablation was objectively demonstrated in another rct (aquablation vs. turp), were bladder outlet obstruction was measured at 6-month follow-up by using the urodynamic test (16). bhojani et al. reported an increase in qmax of 14.3 ml/sec and a ipss decrease of 15.6 points (17). enthusiasm for the functional outcomes is tempered by concerns about its effectiveness in achieving hemostasis. after ablation, haemostasis is usually achieved using a foley balloon catheter on traction or diathermy or low-powered laser (18). because of the risk of bleeding, hospitalization for monitoring and bladder irrigation is usually required (19). in the water ii trial, 7.9% of the patients required transfusion and/or reintervention due to postoperative bleeding (15). the 6-month rates of grade 2 and 3 clavien-dindo events account for 13.3% (10). most authors found no significant change in iief-15 at 1 year follow-up (20, 21). in most series 0% to 2% of patients required surgical reintervention (i.e. turp/holep) for unsuccessful therapy (15, 21). according to the eau and aua guidelines (2, 22), aquablation should still be considered under investigation considering the lack of long term follow-up and the uncertainties about bleeding risk. rezūm in the rezūm system, thermal energy obtained with high frequency is released in the form of water vapor when the vapor changes from the gaseous to the liquid phase upon contact with the tissue. after the injections, the steam at 107°c distributes into the interstitial tissue spaces and releases stored thermal energy to the prostate tissue, causing cell necrosis. the procedure can be performed in an out-patient setting, using a local transurethral anesthesia. transrectal prostatic block can be performed, if required (23).the operative time is usually less than 1 hour (23, 24) the efficacy of rezūm has been evaluated in rcts and systematic reviews (24-30). mcvary at al. reported the results of a blinded trial in which patients were randomized 2:1 between rezūm system thermal therapy and control (they received no treatment other than rigid cystoscopy simulating surgery) up to 4 years of follow-up. they found symptom relief at three months followup which was confirmed after 12 months, 2 years and 4 years (25, 26, 28). only the rezum group was followed up. no de novo erectile dysfunctions were recorded at one year while erectile and ejaculatory functions were preserved (25). antegrade ejaculation is maintained between 100% and 96.6% (31, 32). patients with troublesome luts but low prostate volume (< 30 g) also experienced significant relief of luts (33). the rezūm could effectively treat patients with median lobes (25, 34, 35), urinary retention (36, 37) and large prostate volumes (≥ 80 g) (31, 33, 35, 38, 39). nevertheless, the improvement of qmax, ipss and qol was assessed only in an early to intermediate follow-up period (maximum 5 years). the gold standard turp improved ipss, qol, and qmax at 3 months and maintained its effect for at least 10 years (40). medical and surgical retreatment rates for rezūm were reported up to 18.9% at 5 years (26) and 10.8% at 2 years (41), respectively.the rezūm system could be a viable alternative option for the treatment of luts due to bpo leading to an improvement in bph symptoms, preserving sexual function with a 3%-6% risk of developing ejaculatory dysfunction, and being associated with a low surgical recurrence rate over five years (26, 29). nevertheless, the level of evidence is low and impaired by several limitations (27) including the lack of a rct directly comparing the rezūm system with the gold standard, and providing a long-term follow-up. archivio italiano di urologia e andrologia 2023; 95(4):12003 3 new minimally invasive solutions for benign prostatic obstruction trans-perineal laser ablation of the prostate (tpla) tpla is one of the most recent ‘ultra-minimally invasive’ ablative surgical treatment available. it uses a low-power diodelaser as the energy source and a small needle is inserted percutaneously transperineally (usually one needle for each lobe) (42), preserving the urethra as opposed to the more traditional transurethral approaches. according to the studies available in literature, tpla was recommended in case of moderate-severe luts with an ipss above 8 or 12 (43, 43-45) and prostate volume > 30 ml. there is one series which did not include patients with a median lobe (46). the procedure can be performed in an ambulatory surgical center, with a relative short operative time [mean setting time 21.33 ± 7.59 and lasing time 8.43 ± 0.79, respectively (44)]. tpla resulted in statistically significant improvement in ipss and qol scores from baseline in most of the available studies (43, 45-48), with frego et al. observing the greatest reduction in ipps score (δ = −16.0 at 12 months) (48). the longest follow-up reported in literature is 3 years, with a significant improvement in ipss (-37.2%; p < 0.01), qmax (+ 45.8%; p < 0.01) and median mshq-ejd (60%; p < 0.01) (49). a recent series published by minafra et al. reported that tpla results are acceptable even after 3 years (49). the results in terms of ejaculatory function are impressive (43, 47, 48, 50). in particular, in some cases, ejaculatory function assessed by the mshqejd questionnaire was not only preserved but even improved (44, 46, 51). no de novo erectile dysfunction was reported (51) the complication rate is generally low and not severe with a 6-month rates of grade 2 clavien-dindo events of 4.6% (44). a case of prostatic abscess was reported by de rienzo et al. and by manenti et al. (4.8% and 4.9%, respectively) managed with percutaneous drainage and antibiotic therapy (44, 46). bertolo et al. recently reported for the first time the results of the comparison between tpla and the gold standard (turp) (52). they found a preservation of the ejaculatory function in 96% of cases of tpla. both treatments significantly improved the median qmax, but the main advantage was observed for turp (tpla vs turp: 15.2 ml/s vs 26.0 ml/s; p < 0.001) (52). more research is needed to evaluate the rate of pharmacological or surgical re-intervention in the long term after tpla. overall, all available data come mainly from a few pilot studies with short follow-up (maximum 3 years) and a limited number of patients, the strength of evidence for which is low and insufficient to make a recommendation. tpla remains under investigation, but it could be considered for people interested in preserving sexual and ejaculatory function. urolift the prostatic urethral lift (pul, urolift, neotract inc. pleasanton, ca, usa) has passed the test of clinical evaluation within 4 years after introduction and was approved by food and drug administration in the 2013 (2). this tissue retracting, permanent implant has a capsular, external tab made of nitinol connected to the plyethylene terephtalate monofilament and a urethral end piece made of stainless steel (53). during urethroscopy, in the ambulatory setting, the tissue-retracting implants are placed at the 2 and 10-o'clock positions guaranteeing integrity of the neurovascular bundle and dorsal plexus. another advantage that urolift offers is tailoring the implants based on the patients' anatomy, regulating the monofilaments' length and tension (54). ideal candidates are patients with prostatic volume between 20 and 70 cc, with 'kissing' lateral lobes of the prostate, ipss > 12, qmax < 15 ml/s and with less than 350cc of post-void residual volume. to deploy the device, the operator uses a needle that is then anchored, with the internal side in the urethra, and with the outer side on the surface of the prostatic capsule. usually, catheterization is not necessary following this procedure. contraindications are men with prostatic volume over 80-100 gr, voluminous median lobe and history of urinary retention (55). the recent evidences did not show superiority of the urolift when compared to the gold-standard (56-58), turp, but it does, however reduce severity of luts. currently, the largest rct available (the l.i.f.t. study) comparing pul vs. a sham control reported durable improvements in ipss (36%), qol (50%), and qmax (44%) at 5-years (58). also, an increase in maximum urine flow-rate (qmax) from 7.88 to 11.08 was evidenced in the same period. some comparative studies described superiority of the urolift to other minimally invasive techniques when it comes to erectile dysfunction. actually, sexual health inventory for men (shim) scores were greater in the urolift (14.8) versus other groups (9.2) (59). moreover, new generation of the pul, marketed as urolift 2, was launched in march 2022. there are some drawbacks to pul technique, like reported adverse events and high costs. the majority of adverse events were mild, such as transient hematuria, dysuria, pelvic pain, blood clots and incontinence (60), but some authors reported formation of pelvic hematoma (61), one of which needed surgical intervention (62), and another that resulted in acute kidney injury and progression of chronic kidney disease (63). also, the lift trial reported the need for retreatment or surgical intervention in 13.6% of patients (54). on the other hand, at longer follow-up (5 years), there were no adverse event reported related to sexual function (58). currently, the urolift is recommended as an alternative non-ablative technique to men with luts interested in preserving ejaculatory function, with prostates < 70 ml and no middle lobe by the guidelines of the european association of urology (2). temporarily implanted nitinol device (itind) the temporary implantable nitinol device (first generation: tind; second generation: itind) (medi-tate®; medi-tate ltd., or akiva, israel) is a recent promising non ablative minimally invasive solution for the management of luts/bph (64). one of the advantages of the technique is the fact that most cases can only be achieved with the use of local anesthetic, with light intravenous sedation if required (65). similarly, most patients can be managed with a day-surgery hospital access. another advantage, comparing to implantable devices, is that itind is a temporary device which avoids the potential complications associated with a permanent device. the itind seems to be of particular benefit to luts/bph patients archivio italiano di urologia e andrologia 2023; 95(4):12003 r. leonardi, f. ambrosini, r. malinaric, et al. 4 (ipss > 12 points and qmax ≤ 12 ml) seeking a minimally invasive treatment associated with a significant improvement in symptoms with the preservation of sexual function. itind could be also recommended in case of bph and sclerosis of the bladder neck. in most series, prostate size was quite small (less than 60-75 cc). porpiglia et al. showed an ipss and qmax improvement by -45% and +67% respectively, at 12 months follow-up (66). similar results were found in the mt02 study, a single arm multicentric study involving 81 patients (67). other series are published, with good results but with shorter follow-up (68). the device and the procedure appear to be moderately safe, with a low number of complications (mostly urinary retention, utis, device displacement, hematuria) and in particular not high grade according to the clavien-dindo classification. a randomized trial based on 175 patients showed no de novo ejaculatory or erectile dysfunction (69). at two-year follow-up, 4 of 81 patients required subsequent surgery (turp/holep) (70). the longest published follow-up is 36 months (71). currently, the itind is not recommended in the guidelines, even though considered a promising technique, waiting for the results of ongoing randomized controlled trials comparing itind to a reference technique. discussion and conclusions all the new minimally-invasive techniques for the treatments of luts due to bpo were developed because of the necessity to offer a patient-tailored, successful, viable treatment for bph while maintaining sexual and ejaculatory function (4, 6, 42, 58). now more than ever, the patients are well informed about all the possibilities that new technologies can offer and how can we, as urologists, improve their quality of life by maintaining good both functions, urinary and sexual. also, quick recovery period and rare serious adverse effect of these minimally invasive technologies make them even more attractive (24). seemingly, they are a relatively easy choice to make when compared to the gold standard, turp, and maybe should be the first one at some point in well selected candidates, but there are some drawbacks to take in consideration such as, in some cases, higher costs, availability, surgical experience of the operators and higher rates of retreatments (24). these are major reasons why urologists should be very careful when proposing new techniques to the patients, choosing the right candidates for the right procedure, and giving them all the necessary information regarding. some of the most important parameters to consider are patients' general health status, prostate volume, and strong desire to preserve ejaculation (2, 72, 73). the doctor-patient relationship, patient-tailored therapy, shared decision, and correct informed consent are more important than ever. from the national health-care institutions' prospective these treatments, if preformed in ambulatory setting, can be extremely useful as they can alleviate the long waiting lists for surgical treatments that require surgical staff, hospitalization, and post-operative care. for example, rezum, itind and urolift can all be offered to the patients in 'day surgery' regime (36, 55, 69). this can be an important advantages for healthcare systems in the post sars-cov-2 era (74, 75). on the other hand, to be able to offer these kinds of services, urologists preforming them must be adequately prepared and trained, and not only on the procedure itself, but on adverse events and complications. the scarcity of specialized training centers and fairly limited diffusion of these novel techniques pose quite an important obstacle in using them, especially in the smaller, more peripheral hospitals. in addition to that, it should be mentioned that some of these techniques did never undergo randomized trials (i.e. itind), and the outcomes of these studies never systematically evaluated using validated outcome measures, therefore the rate of retreatments is still quite uncertain. furthermore, there is a lack of long-term follow-up results, and for that manner it could be difficult to give the patients precise and complete information. nevertheless, minimally invasive treatments are on the rise, especially urolift in the united states (76). one of the greatest benefits of minimally invasive techniques is the preservation of sexual function. de novo erectile function is anedoctal and ejaculatory dysfunction is generally low (15.4% with lest, 3-6% in rezum, 26.7% in aquablation (24, 30). itind and urolift had no impact on ejaculatory dysfunction. it is worth noting that all minimally invasive techniques are relatively young and have a short follow-up, with the exception of lest (laparoscopic endoscopic single-site surgery), which has a follow-up of up to 12 years (4, 5). this remarkable longevity of follow-up data for lest sets it apart from other procedures and underscores its potential and reliability. in addition, lest provided immediate relief of luts after catheter removal, whereas rezum, urolift, and itind provided good results only after some time (2 weeks to six months). obviously, the incorporation in the guidelines and insurance companies are also important factors to consider when implementing them. moreover, urolift is mentioned as the valid alternative in some guidelines, while others are not mentioned or are discouraged because of higher retreatment rates (73) also, not all guidelines agree on the recommendations [nice vs. aua (72, 73)]. the need for cautious interpretation of current analytical results stems primarily from the everevolving landscape of safety and efficacy data on these innovative techniques. currently, ongoing studies are comparing these procedures not only with transurethral resection of the prostate (turp) (nct05762198, nct05840549) but also with various alternative treatments, including purely medical interventions. pending the results of these ongoing studies, these techniques are very promising and appear to be attractive alternative options for future treatment of the disease in selected patients. in conclusion, we would like to provide our position related to each one of the techniques presented. the lest showed promising results in terms of functional outcomes with significant improvements in ipss and qmax, while preserving sexual function. aquablation shows efficacy in improving ipss and qmax with favorable sexual outcomes. concerns about hemostasis and archivio italiano di urologia e andrologia 2023; 95(4):12003 5 new minimally invasive solutions for benign prostatic obstruction bleeding risk remain, but the short operative time and the possibility of an outpatient setting make it a valuable option for patients seeking both symptom relief and preservation of sexual function. rezūm provides significant relief for luts, with a low risk of ejaculatory dysfunction. nevertheless, the level of evidence remains low, and further long-term studies are needed to prove its efficacy compared to the gold standard turp. tpla shows a remarkable improvement in ipss and qol scores, with impressive results in ejaculatory function preservation. due to the limited short-term data and the small number of patients, tpla should remain under investigation. urolift proves effective in reducing luts severity with durable improvements in ipss and qmax, and shows superiority in preserving erectile function. despite the reported adverse events, its outpatient nature and the easy implantation make urolift an attractive option for selected patients. itind is a promising non-ablative solution, that offers significant improvement in symptoms with minimal impact on sexual function. its temporary nature and low complication rates are the main advantage, especially for patients seeking a minimally invasive treatment approach. in conclusion, all of these minimally invasive techniques offer multiple options for patients with boo, balancing efficacy, preservation of sexual function, and potential benefits to the healthcare system. as ongoing studies continue to validate their long-term outcomes and cost-effectiveness, urologists 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130:142-156. 25. mcvary kt, gange sn, gittelman mc, et al. erectile and ejaculatory function preserved with convective water vapor energy treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: randomized controlled study. j sex med 2016; 13:924-933. 26. roehrborn cg, gange sn, gittelman mc, et al. convective thermal therapy: durable 2-year results of randomized controlled and prospective crossover studies for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. j urol 2017; 197:15071516. 27. kang tw, jung jh, hwang ec, borofsky m, kim mh, dahm p. convective radiofrequency water vapour thermal therapy for lower urinary tract symptoms in men with benign prostatic hyperplasia. cochrane database syst rev. 2020; 3:cd013251. 28. mcvary kt, rogers t, roehrborn cg. rezūm water vapor thermal therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia: 4-year results from randomized controlled study. urology 2019; 126:171-179. 29. miller le, chughtai b, mcvary k, et al. water vapor thermal therapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: systematic review and meta-analysis. medicine (baltimore) 2020; 99:e21365. 30. chung asj, woo hh. update on minimally invasive surgery and benign prostatic hyperplasia. asian j urol 2018; 5:22-27. 31. babar m, loloi j, tang k, et al. emerging outcomes of water vapor thermal therapy (rezum) in a broad range of patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review. luts low urin tract symptoms 2022; 14:140-154. 32. campobasso d, siena g, chiodini p, et al. composite urinary and sexual outcomes after rezum: an analysis of predictive factors from an italian multi-centric study. prostate cancer prostatic dis 2023; 26:410-414. 33. ines m, babar m, singh s, et al. real-world evidence with the rezūm system: a retrospective study and comparative analysis on the efficacy and safety of 12 month outcomes across a broad range of prostate volumes. the prostate 2021; 81:956-970. 34. mcvary kt, gange sn, gittelman mc, et al. minimally invasive prostate convective water vapor energy ablation: a multicenter, randomized, controlled study for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. j urol 2016; 195:1529-1538. 35. bassily d, wong v, phillips jl, et al. rezūm for retention—retrospective review of water vaporization therapy in the management of urinary retention in men with benign prostatic hyperplasia. the prostate 2021; 81:1049-1054. 36. johnston mj, noureldin m, abdelmotagly y, et al. rezum water vapour therapy: promising early outcomes from the first uk series. bju int 2020; 126:557-558. 37. siena g, cindolo l, ferrari g, et al. water vapor therapy (rezūm) for lower urinary tract symptoms related to benign prostatic hyperplasia: early results from the first italian multicentric study. world j urol 2021; 39:3875-3880. 38. bole r, gopalakrishna a, kuang r, et al. comparative postoperative outcomes of rezūm prostate ablation in patients with large versus small glands. j endourol 2020; 34:778-781. 39. garden eb, shukla d, ravivarapu kt, et al. rezum therapy for patients with large prostates (≥ 80 g): initial clinical experience and postoperative outcomes. world j urol 2021; 39:3041-3048. 40. hoekstra rj, van melick hhe, kok et, ruud bosch jlh. a 10-year follow-up after transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with benign prostatic hyperplasia; long-term results of a randomized controlled trial: 10-year follow-up after turp, contact laser prostatectomy and electrovaporization for bph. bju int. 2010; 106:822-826. 41. dixon c, cedano er, pacik d, et al. two-year results after convective radiofrequency water vapor thermal therapy of symptomatic benign prostatic hyperplasia. res rep urol volume 2016; 8:207-216. 42. tafuri a, panunzio a, de carlo f, et al. transperineal laser ablation for benign prostatic enlargement: a systematic review and pooled analysis of pilot studies. j clin med 2023; 12:1860. 43. pacella cm, patelli g, iapicca g, et al. transperineal laser ablation for percutaneous treatment of benign prostatic hyperplasia: a feasibility study. results at 6 and 12 months from a retrospective multi-centric study. prostate cancer prostatic dis 2020; 23:356-363. 44. de rienzo g, lorusso a, minafra p, et al. transperineal interstitial laser ablation of the prostate, a novel option for minimally invasive treatment of benign prostatic obstruction. eur urol 2021; 80:95-103. archivio italiano di urologia e andrologia 2023; 95(4):12003 7 new minimally invasive solutions for benign prostatic obstruction 45. cai h-j, fang j-h, kong f-l, et al. ultrasound-guided transperineal laser ablation for percutaneous treatment of benign prostatic hyperplasia: a new minimally invasive interventional therapy. acta radiol 2022; 63:553-558. 46. manenti g, perretta t, calcagni a, et al. 3-t mri and clinical validation of ultrasound-guided transperineal laser ablation of benign prostatic hyperplasia. eur radiol exp 2021; 5:41. 47. patelli g, ranieri a, paganelli a, et al. transperineal laser ablation for percutaneous treatment of benign prostatic hyperplasia: a feasibility study. cardiovasc intervent radiol 2017; 40:1440-1446. 48. frego n, saita a, casale p, et al. feasibility, safety, and efficacy of ultrasound-guided transperineal laser ablation for the treatment of benign prostatic hyperplasia: a single institutional experience. world j urol 2021; 39:3867-3873. 49. minafra p, de rienzo g, gerbasi s, cindolo l, battaglia m, ditonno p. three years outcomes of transperineal laser ablation of the prostate. minerva urol nephrol. 2023; 75:471-478. 50. rosati d, lombardo r, de nunzio c, et al. transperineal interstitial laser ablation of the prostate, a novel option for minimally invasive treatment of benign prostatic obstruction. eur urol 2021; 80:673-674. 51. sessa f, bisegna c, polverino p, et al. transperineal laser ablation of the prostate (tpla) for selected patients with lower urinary tract symptoms due to benign prostatic obstruction: a step-by-step guide. urol video j 2022; 15:100167. 52. bertolo r, iacovelli v, cipriani c, et al. ejaculatory function following transperineal laser ablation vs turp for benign prostatic obstruction: a randomized trial. bju int 2023; 132:100-108. 53. magistro g, stief cg, woo hh. mini-review: what is new in urolift? eur urol focus 2018; 4:36-39. 54. roehrborn cg, gange sn, shore nd, et al. the prostatic urethral lift for the treatment of lower urinary tract symptoms associated with prostate enlargement due to benign prostatic hyperplasia: the l.i.f.t. study. j urol 2013; 190:2161-2167. 55. jones p, rai bp, aboumarzouk o, somani bk. urolift: a new minimally-invasive treatment for benign prostatic hyperplasia. ther adv urol 2016; 8:372-376. 56. gratzke c, barber n, speakman mj, et al. prostatic urethral lift vs transurethral resection of the prostate: 2-year results of the bph6 prospective, multicentre, randomized study. bju int 2017; 119:767-775. 57. rukstalis d, rashid p, bogache wk, et al. 24-month durability after crossover to the prostatic urethral lift from randomised, blinded sham. bju int 2016; 118:14-22. 58. roehrborn cg, barkin j, gange sn, et al. five year results of the prospective randomized controlled prostatic urethral l.i.f.t. study. can j urol 2017; 24:8802-8813. 59. tutrone rf, schiff w. early patient experience following treatment with the urolift prostatic urethral lift and rezum steam injection. can j urol 2020; 27:10213-10219. 60. cantwell al, bogache wk, richardson sf, et al. multicentre prospective crossover study of the ‘prostatic urethral lift’ for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pul for the treatment of luts. bju int 2014; 113:615-622. 61. pollock gr, bergersen a, chaus fm, gretzer m. pelvic hematoma following urolift procedure for bph. urology 2019; 133:e3-e4. 62. cai py, gaffney c, vanden berg rw, et al . pelvic hematoma following urolift procedure for bph. urology 2020; 137:208. 63. ewing b, alavi-dunn n, hamann h, danforth t. large pelvic hematoma following urolift procedure causing renal failure requiring dialysis. urol case rep 2021; 34:101514. 64. amparore d, de cillis s, volpi g, et al firstand second-generation temporary implantable nitinol devices as minimally invasive treatments for bph-related luts: systematic review of the literature. curr urol rep 2019; 20:47. 65. balakrishnan d, jones p, somani bk. itind: the second-generation temporary implantable nitinol device for minimally invasive treatment of benign prostatic hyperplasia. ther adv urol 2020; 12:1756287220934355. 66. porpiglia f, fiori c, bertolo r, et al. temporary implantable nitinol device (tind): a novel, minimally invasive treatment for relief of lower urinary tract symptoms (luts) related to benign prostatic hyperplasia (bph): feasibility, safety and functional results at 1 year of follow-up. bju int 2015; 116:278-287. 67. porpiglia f, fiori c, amparore d, et al. second-generation of temporary implantable nitinol device for the relief of lower urinary tract symptoms due to benign prostatic hyperplasia: results of a prospective, multicentre study at 1 year of follow-up. bju int 2019; 123:1061-1069. 68. de nunzio c, cantiello f, fiori c, et al. urinary and sexual function after treatment with temporary implantable nitinol device (itind) in men with luts: 6-month interim results of the mt-06-study. world j urol 2021; 39:2037-2042. 69. chughtai b, elterman d, shore n, et al. the itind temporarily implanted nitinol device for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: a multicenter, randomized, controlled trial. urology 2021; 153:270-276. 70. kadner g, valerio m, giannakis i, et al. second generation of temporary implantable nitinol device (itind) in men with luts: 2 year results of the mt-02-study. world j urol 2020; 38:3235-3244. 71. porpiglia f, fiori c, bertolo r, et al. 3-year follow-up of temporary implantable nitinol device implantation for the treatment of benign prostatic obstruction. bju int 2018; 122:106-112. archivio italiano di urologia e andrologia 2023; 95(4):12003 r. leonardi, f. ambrosini, r. malinaric, et al. 8 72. lower urinary tract symptoms in men: management | guidance | nice. accessed november 29, 2021. 73. lerner lb, mcvary kt, barry mj, et al. management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline part i initial work-up and medical management. j urol 2021; 206:806-817. 74. leonardi r, bellinzoni p, broglia l, colombo r, de marchi d, falcone l, giusti g, grasso v, mantica g, passaretti g, proietti s, russo a, saitta g, smelzo s, suardi n, gaboardi f. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67 75. ambrosini f, di stasio a, mantica g, et al covid-19 pandemic and uro-oncology follow-up: a “virtual” multidisciplinary team strategy and patients’ satisfaction assessment. arch ital urol androl 2020; 92:78. 76. dalimov z, hamann h, alavi-dunn n, et al. trends in minimally invasive surgical therapies for benign prostatic hyperplasia: treatment substitution or treatment expansion effect by prostatic urethral lift? j urol 2020; 203(suppl 4s):e621. correspondence rosario leonardi, md leonardi.r@tiscali.it casa di cura musumeci gecas, gravina di catania, italy francesca ambrosini, md (corresponding author) f.ambrosini1@gmail.com rafaela malinaric, md rafaela.malinaric@gmail.com carlo terrone, md carlo.terrone@hsanmartino.it guglielmo mantica, md guglielmo.mantica@gmail.com irccs ospedale policlinico san martino, genova, italy largo rosanna benzi 10, 16132, genova, italia angelo cafarelli, md info@angelocafarelli.it urology unit, villa igea, ancona, italy alessandro calarco, md info@alessandrocalarco.com villa pia hospital, via folco portinari 5, rome, italy renzo colombo, md colombo.renzo@hsr.it ottavio de cobelli, md ottavio.decobelli@unimi.it department of urology, vita e salute san raffaele university, milan, italy ferdinando de marco, md info@clinicavillamargherita.it i.n.i. grottaferrata, roma, italy giovanni ferrari, md visite@giovanniferrariurologo.it hesperia hospital, modena, italy giuseppe ludovico, md g.ludovico@miulli.it ospedale miulli, acquaviva delle fonti, bari, italy stefano pecoraro, md cup@diagnosticamedica.org neuromed, avellino, italy domenico tuzzolo, md info@casadelsole.it urologi ospedalità gestione privata (urop) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3366 letter to editor no conflict of interest declared. to the editor, nocturia is a significantly underestimated medical problem that affects seriously patients' quality of life, work engagement, productivity, and overall life conditions per se. nocturia is a common condition, proven to be the most bothersome for patients with lower urinary tract symptoms (luts) (1). people with two or more events of micturition per night have a significant increase in mortality rate and an increased risk of fall-related fractures if they visit the toilet two or more times per night (1). the pathophysiology behind nocturia falls into five main categories: nocturnal polyuria (np), global polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders. urological causes of nocturia are reduced bladder capacity, detrusor overactivity, and other mixed etiologies. np refers to increased urine production during nighttime. the international continence society defines np as nocturnal urine production above 20% for young patients and 33% for older patients (> 65 yrs) (2). np seems to be the most common cause of nocturia. according to the current and most used definition of nocturia by the international continence society (2), the prevalence of np, in both genders, is 44% in those under 65 years, and 31.3% in those 65 years or older (3). in a recent study, np was present in 77% of those with two or more episodes of nocturia per night (4), and in an older study, > 75% of patients with nocturia had np (5). in a very recent study, 31.5% of men and 38.5% of women had np (6). furthermore, it is worth mentioning that in a longitudinal, community-based study, the estimated prevalence of np in men suffering from nocturia was 80% when the classical definition (np index > 33%) was used, but it was reduced to just 15% when was used the definition of nocturnal urine production of > 90 ml/h (7). moreover, using the nocturnal urine production index, the aforementioned recent study concluded that 23.8% and 18.1% of men and women respectively presented np (6). current definitions of np are critical for estimating the prevalence and diagnosis of this condition. it seems that more research and evidence are needed to reach a consensus about the most accurate definition for use in everyday clinical practice (8). np has a multifactorial pathogenesis. several non-urological causes are known to provoke this dysfunction. such causes are untreated diabetes mellitus or insipidus, sleep disorders as obstructive sleep apnea, cardiovascular diseases (hypertension, heart failure) (9), chronic kidney disease, and primary polydipsia. if there is no obvious disorder provoking np, this is defined as np syndrome (10, 11). the interplay among np and pathological conditions such as hypertension, arteriopathy and arterial stiffness, coronary heart disease, and distribution in the third space of body fluid is thought to be significant and it is a topic of current research (11). this is also the case for the role of brain natriuretic peptide (11). according to a well-established point of view, a key factor in the decision to consult a physician is the patient's bother because of this condition. the use of the word “disorder” rather than “complaint” would support the medical seriousness of nocturia to the patient's health (12). it is well known that two or more nocturnal voids are considered to be the clinically meaningful threshold associated with significant adverse consequences to health and well-being (13). furthermore, a strong relationship between np and nocturia and increased urinary frequency has been demonstrated (14). commonly associated consequences include increased mortality and morbidity, increased risk of falls and hip fractures, traffic and work accidents, and increased risk of cardiovascular diseases, diabetes mellitus, and depression (13, 15). it also provokes immunological problems and dysfunction of memory and perception, overall deteriorating quality of life, and increase health costs (13, 15). still, this condition seems to also affect work performance (16). furthermore, the importance of taking sleep into account should be emphasized when assessing the relationship between nocturia and associated outcomes (16). another critical element to be highlighted is that despite traditionally regarding nocturia as a pronominally male condition, robust data support the evidence that it is just as prevalent in women as in men and especially in postmenopausal women (12, 17). the importance of the 'frequency-volume chart,' a very simple exam, has to be underlined as the main tool to guide diagnosis and identify the appropriate treatment of nocturia. especially for np, a frequency-volume chart is a cornerstone for the diagnosis of this condition (18). the treatment rationale for nocturia is that np, due to inadequate antidiuresis, is a major contributing factor to nocturia. nocturia due to nocturnal polyuria (np). a common disorder anastasios athanasopoulos department of urology, medical school, university of patras, patra, greece. doi: 10.4081/aiua.2022.3.366 submitted 12 may 2022; accepted 23 june 2022 367archivio italiano di urologia e andrologia 2022; 94, 3 nocturnal polyuria before starting any pharmaceutical treatment, it would be first beneficial to try some lifestyle modifications, as these can offer an improvement of np. for example, less caffeine, alcohol, and generally fluids intake a couple of hours before bedtime could be of benefit to the patient (18). furthermore, desmopressin administration offers a significant reduction in nocturia episodes and nocturnal urine production, translating into improvements in sleep and quality of life (19-22). newer formulations of desmopressin are well tolerated. the risk of hyponatremia is relatively low with appropriate dosing escalation and taking into consideration that a lower minimum effective dose in females is needed compared to males (22-24). furthermore, sodium monitoring just before treatment initiation and on the first, third, and seventh day of treatment is essential. research for the treatment of np is ongoing and includes highly selective arginine vasopressin 2 receptor agonists, non-steroid anti-inflammatory drugs, sex hormone replacement treatment, and short-acting diuretics (22). improved knowledge regarding nocturia, which is a basic symptom of luts, provides insight to understanding that nocturia, and especially np, can be a pathological entity per se. further research in the future will shed light concerning the pathophysiology of nocturia. there is evidence that the burden of this symptom is considerable in many aspects, especially for the individual and the society. therefore, np should be given the attention it deserves in the medical field, especially by the urological community. references 1. leslie sw, sajjad h, singh s. nocturia. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2021. 2.van kerrebroeck p, abrams p, chaikin d, et al. the standardization of terminology in nocturia: report from the standardisation sub-committee of the international continence society. neurourol urodyn. 2002; 21:179-183. 3. zumrutbas ae, bozkurt ai, alkis o, et al. the prevalence of nocturia and nocturnal polyuria: can new cutoff values be suggested according to age and sex?. int neurourol j. 2016; 20:304-310. 4. clemens jq, wiseman jb, smith ar, et al. lurn study group. prevalence, subtypes, and correlates of nocturia in the symptoms of lower urinary tract dysfunction research network cohort. neurourol urodyn. 2020; 39:1098-1107. 5. weiss jp, van kerrebroeck pe, klein bm, et al. excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. j urol. 2011; 186:1358-1363. 6. weiss jp, bosch jlhr, chapple cr et al. the prevalence of nocturnal polyuria in the united states: results from the epidemiology of nocturnal polyuria study. eur urol focus. 2022; s2405-4569(21)00324-2. 7. van doorn b, blanker mh, kok et, et al. prevalence, incidence, and resolution of nocturnal polyuria in a longitudinal community-based study in older men: the krimpen study. eur urol. 2013; 63:542-547. 8. olesen tk, denys ma, walle jv, et al. systematic review of proposed definitions of nocturnal polyuria and population-based evidence of their diagnostic accuracy. acta clin belg. 2018; 73:268-274. 9. ohishi m, kubozono t, higuchi k, akasaki y. hypertension, cardiovascular disease, and nocturia: a systematic review of the pathophysiological mechanisms. hypertens res. 2021; 44:733-739. 10. monaghan tf, dmochowski rr, verbalis jg, et al. first voided volume: a novel approach to characterize nocturia. neurourol urodyn. 2021; 40:848-54. 11.weiss jp, monaghan tf,epstein mr, lazar jm. future considerations in nocturia and nocturnal polyuria. urology. 2019; 133:34-42. 12.van kerrebroeck p, andersson ke .terminology, epidemiology, etiology, and pathophysiology of nocturia. neurourol urodyn. 2014; 33(suppl 1):s2-5. 13. tikkinen kao, johnson tm, tammela tlj, et al. nocturia frequency, bother, and quality of life: how often is too often? a population-based study in finland. eur urol. 2010; 57:488-498. 14. rubilotta e, castellani d, gubbiotti m, et al. nocturnal polyuria in men performing uroflowmetry for lower urinary tract symptoms. arch ital urol androl. 2021; 93:445-449. 15. carskadon ma. sleep deprivation: health consequences and societal impact. clin north am. 2004; 88:767-776. 16. torimoto k, uchimura n, roitmann e, et al. a large survey of nocturia related to sleep quality and daytime quality of life in young japanese population: nocturne study. neurourol urodyn. 2021; 40:340-347. 17. pauwaert k, goessaert as, ghijselings l, et al. nocturia through the menopausal transition and beyond: a narrative review. int urogynecol j. 2021; 32:1097-1106. 18.weiss jp, everaert k. management of nocturia and nocturnal polyuria. urology. 2019; 133:24-33. 19. gordon dj, emeruwa cj, weiss jp. management strategies for nocturia. curr urol rep. 2019; 20:75. 20. everaert k, hervé f, bosch r, et al. international continence society consensus on the diagnosis and treatment of nocturia. neurourol urodyn. 2019; 38:478-498. 21. kim so, yu hs, kwon d. efficacy of desmopressin to treat nocturnal polyuria in elderly men: effects on sleep quality. urol int. 2016; 96:438442. archivio italiano di urologia e andrologia 2022; 94, 3 a. athanasopoulos 368 22. monaghan tf, weiss jp, everaert k, wein aj. pharmacologic management of nocturnal polyuria: a contemporary assessment of efficacy, safety, and progress toward individualized treatment. ther adv urol. 2021; 13:1756287220988438. 23. juul kv, klein bm, sandström r, et al. gender difference in antidiuretic response to desmopressin. am j physiol renal physiol. 2011; 300:f1116-1122. 24. juul kv, malmberg a, van der meulen e et al. low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. bju int. 2017; 119:776-784. correspondence athanasopoulos a. md, phd tassos_athan@hotmail.com professor of urology functional urology, head of urodynamic urology unit, university of patras, patra (greece) papadiamantopoulou 38 str, patra, greece, 26225 stesura seveso 401archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. 7%, respectively (1, 2). after the diagnosis, a better staging would allow both clinician and patient a betterinformed choice and a better tailored treatment approach. current recommendations from european association of urology (eau) (3) and national comprehensive cancer network (nccn) (4) are for high-risk and vhr localized pca patients to undergo computed tomography (ct) of abdomen and pelvis and whole-body bone scan (bsc). however, it is commonly known that ct and alternatives such as magnetic resonance imaging (mri) have a modest performance for nodal staging (5). more recent nuclear imaging such as positron emission tomography (pet) with choline or prostate-specific membrane antigen (psma) isotopes have been explored, but their utilization in staging localized pca is not standard (6, 7). pet-psma is currently regarded as the most promising radiotracer, but in most of the world it is more expensive and of more limited availability than petcholine (8). as such, in france, it is frequent that we find patients being staged with pet-choline, exam considered in guidelines as having a role in biochemical recurrence. it has the advantage of being cheaper, easily available and reproducible (8). however, its role in staging of localized pca is disputed, with some papers reporting interesting results in the subset of high risk and vhr patients (9, 10). in this work we explore the role of pet choline realized in community non-centralized centers in node staging, when compared with ct findings and with the gold standard of bilateral extended pelvic lymphadenectomy, in patients with vhr pca. methods our center is a high-ranking hospital in pca care, receiving patients mainly from paris, but also from all france and the rest of the world. we maintain a prospectively updated database with all patients who undergo a radical prostatectomy in our center, including our study population. we explored this database for patients with vhr localized pca who underwent pet choline as a method of pre-operative staging, who were treated with robotic assisted laparoscopic prostatectomy (ralp) and extended pelvic lymph node dissection (eplnd), between 2010 and objectives: localized very high-risk prostate cancer (vhr pca) has long suffered from the inex-istence of good lymph node staging methods other than invasive surgery, as computed tomogra-phy has low sensitivity for nodal disease. with the rising use of positron emission tomography (pet), it is clinically meaningful to know its value for these patients. our goal was to evaluate the real-life diagnostic accuracy of pet choline in nodal staging, comparing it with the gold standard of extended pelvic lymph node dissection (eplnd). materials and methods: we reviewed data from a high-volume center, including patients with vhr pca according to current nccn guidelines who underwent community 18f-fluorocholine pet/ct; followed by ro-botic assisted laparoscopic prostatectomy (ralp) and eplnd between 2010 and 2021. results: we included 44 patients and 88 lymph node regions. among those, 14/44 (31.8%) patients and 20/88 (22.7%) regions had nodal disease present on definitive pathology. in comparison with eplnd, we found a sensitivity of 64.3% (95% ci, 39.2-89.4%), specificity of 83.3% (95% ci, 70.096.7%), ppv of 64.3% (95% ci, 39.2-89.4%), and npv of 83.3% (95% ci, 70.0-96.7%) for nodal disease on a patient-based analysis; and sensitivity of 35.0% (95% ci, 14.1-60.0%), specificity of 88.2% (95% ci, 80.6-95.9%), ppv of 46.7% (95% ci, 21.4-71.9%), and npv of 82.2% (95% ci, 73.4-91.0%) on a region-based analysis. conclusions: in our view 18f-fluorocholine pet/ct doesn’t meet the criteria to be a standard exam for pre-operative staging for patients with vhr pca, mostly due to its low sensitivity. however, other radiotracers should continue to be investigated in this setting. key words: positron-emission tomography; prostatic neoplasms; neoplasm staging. submitted 23 october 2022; accepted 30 october 2022 introduction adequately staging of very high-risk (vhr) localized prostate cancer (pca) is of utmost importance, as staging may alter treatment choice. even when patients are well selected for radical treatment, their biochemical recurrence, metastasis, cancer specific mortality and all-cause mortality at 5 years can be as high as 69%, 20%, 5% and accuracy of pet-choline in nodal staging of localized very high-risk prostate cancer nuno dias 1, 2, gianmarco colandrea 1, 3, francisco botelho 2, 4, lara rodriguez-sanchez 1, yann barbé 1, petr macek 1, xavier cathelineau 1 1 urology department, institut mutualiste montsouris, paris, france; 2 urology department, são joão hospitalar and university center, porto, portugal; 3 unit of urology, division of experimental oncology, uri urological research institute, irccs san raffaele scientific institute, vita-salute san raffaele university, milan, italy; 4 institute for life and health sciences investigation, school of medicine, minho university, braga, portugal. doi: 10.4081/aiua.2022.4.401 summary archivio italiano di urologia e andrologia 2022; 94, 4 n. dias, g. colandrea, f. botelho, l. rodriguez-sanchez, y. barbé, p. macek, x. cathelineau 402 2021. patients who had a previous malignancy or history of prior hormonal therapy were excluded. data collection data was collected from our continuously updated database and patient records. we recorded age at time of surgery, pre-operative total psa, clinical t staging, biopsy results, pet choline results, anatomopathological study of prostatectomy and lymph node dissection specimens. the study has received approval by the institutional ethics’ committee. all research was conducted respecting the latest version of helsinki’s declaration. risk groups patients were included if they fulfilled current nccn guidelines (4) criteria for vhr patients: a) at least 1 of: ct3b-ct4, primary gleason pattern 5, > 4 cores with gleason group 4 or 5; and/or b) at least 2 of: ct3a, gleason group 4 or 5, psa > 20 ng/ml. pet choline pet/ct exams were performed in various local centers in france, with images acquired using 18f-fluorocholine tracer being obtained according to institutional protocols, with images being reported by several different community radiologists. pet choline imaging were acquired alongside a tho-raco-abdominal-pelvic ct scan. images were not centrally reviewed. the diagnosis of pathological lymph nodes was based on the presence of increased uptake on pet images of the radiotracer, with exams being considered as positive if reported by the radiologist as positive or suspicious, irrespective of standardized uptake value (suv). ct adjunctive imaging was used only to locate the anomalies and not as a staging method by itself. surgery ralp + eplnd was performed in our institution by seven different assistants, with long experience in robotic surgery and ralp, with frequent participation of fellows under their direct supervi-sion. ralp was performed transperitoneally, and eplnd was performed as per guidelines standard (including node packets from common iliac distal to the ureteric crossing, external iliac, internal iliac, and obturator origins), with nodes from each side being sent and analyzed separately (3). other nodal regions such as presacral and retroperitoneal would only be removed in select cases where imaging was suspicious of lymph node metastasis in those locations, with no cases present in our population. histology biopsy cores were analyzed in the institution where the biopsy was performed and not reviewed, except in doubtful cases. prostatectomy and lymph node dissection products were fixed in formalin and examined in our center by specialized uropathologists, in accordance with isup guidelines, with left and right templates being observed separately (11). statistics statistical analysis was performed with ibm® spss® v27 software. median and interquartile range are presented for continuous variables; frequencies are reported for categorical variables. characteristics of patients were compared using chi-squared analysis for categorical variables and non-parametric mann-whitney u tests for continuous variables (age). statistically significance in this study was set as p < 0.05. all reported p values are two-sided. test characteristics (sensitivity, specificity, vpp, vpn) were calculated for both patient and region based analysis, with 95% confidence intervals. results we identified 2104 consecutive patients submitted to ralp, with 104 being vhr patients and 45 who had had pet choline as part of their disease staging. one patient meeting the inclusion criteria was excluded for not having all information regarding pet choline examen available. forty-four patients and eighty-eight lymph node regions were included in our analysis. patient characteristics patient characteristics are shown in table 1. median patient age was of 63 years old (iqr 59-68) and median total psa of 15 (iqr 9.8-22.2) ng/ml, with 23 patients having a psa > 15 ng/ml. all 44 patients had vhr pca, table 1. patient characteristics. total n = 44 age, median (p25-p75) 63 (59-68) total psa, ng/ml, median (p25-75) 15 (9.8-22.2) clinical t stage, n (%) t1c 4 (9) t2a 6 (14) t2b 4 (9) t2c 8 (18) t3a 17 (39) t3b 5 (11) biopsy at our institution 15 (34) biopsy isup, n (%) 1 5 (11) 2 6 (14) 3 8 (18) 4 16 (36) 5 9 (21) number positive cores, median (p25-75) 6 (4-7) > 4 cores with isup ≥ 4, n (%) 17 (39) pathological t stage, n (%) t2b 1 (2) t2c 7 (16) t3a 21 (48) t3b 15 (34) prostatectomy isup, n (%) 2 8 (18) 3 22 (50) 4 4 (9) 5 10 (23) nodal disease, n (%) 14 (32) number of positive lymph-nodes, n (%) 0 30 (68) 1 4 (9) 2 1 (2) ≥ 3 9 (20) number removed nodes, median (p25-75) 19 (11-26) 403archivio italiano di urologia e andrologia 2022; 94, 4 pet-choline in nodal staging of prostate cancer with 17 (39%) and 5 (11%) having ct3a and ct3b disease, respectively. overall, 9 (21%) patients had isup of 5, and 17 (39%) had more than 4 biopsy cores with isup ≥ 4. histological results after ralp + eplnd showed most patients locally advanced disease, with 48% presenting with pt3a and 34% with pt3b disease; and 23% of patients had a gleason grade group of 5. with a median 19 (iqr 11-26) nodes removed per patient, 14 out of 44 (32%) of patients had nodal metastasis. four (9%) patients had 1 positive lymph node, 1 (2%) had 2 positive lymph nodes and 9 (20%) had ≥ 3 positive lymph nodes identified. 18f-fluorocholine pet/ct and eplnd table 2 presents the cross results between 18f-fluorocholine pet/ct and anatomopathological findings, in a patient and region base analysis. when compared with eplnd, 18f-fluorocholine pet/ct had a false negative rate of 17% and 18% for patient and region-based analysis, respectively; and a false positive rate of 50% and 53%, respectively. table 3 shows the performance of 18f-fluorocholine pet/ct as a test for nodal staging. on a patient-based analysis (n=44); sensitivity was 64.3% (95% ci, 39.289.4%), specificity 83.3% (95% ci, 70.0-96.7%), ppv 64.3% (95% ci, 39.2-89.4%), and npv 83.3% (95% ci, 70.0-96.7%). on a region-based analysis (n=88); sensitivity was 35.0% (95% ci, 14.1-56.0%), specificity 88.2% (95% ci, 80.6-95.9%), ppv 46.7% (95% ci, 21.471.9%), and npv 82.2% (95% ci, 73.4-91.0%). knowing the correlation between biomarkers uptake and psa, we performed the same analysis for patients with psa > 15ng/ml and on a region basis; sensitivity was 50% (95% ci, 24-76%), with specificity of 84% (95% ci, 72-97%), ppv of 58% (95% ci, 30-86%) and npv of 79% (95% ci, 66-93%). sub-group with ≥ 3 positive lymph nodes nine (20%) patients had at least 3 positive lymph nodes at final pathology, with 6 of them having a positive 18ffluorocholine pet/ct. for this subgroup, on a patientbased analysis (n=9); sensitivity was 66.7% (95% ci, 35.9-97.5%), specificity 77.1% (95% ci, 63.2-91.1%), ppv 42.9% (95% ci, 16.9-68.8%), and npv 90.0% (95% ci, 79.3-100.0%). discussion the importance of a good nodal staging in vhr pca patients is three ways. first, patients with node positive disease should be well identified, since these patients may benefit from adjuvant hormonal therapy and/or radiotherapy after surgery, and because they have worse outcomes in biochemical free survival, metastasis free survival and overall survival (2). second, when discussing treatment options with a patient before deciding on a radical treatment, we should be able to provide him with the best information possible, in order to allow the best individual decision. in vhr patients in particular, the rate of node positive disease has been estimated to be as high as 37% (2). third, when surgery for vhr patients is performed, it entails not only radical prostatectomy but also an eplnd, which increases surgical time and risk of perioperative complications, and has not been shown to lead to better patient outcomes (12). as such, if an accurate enough non-invasive staging method were easily available, it could lead to better identifications of node positive patients before intervention, best individualized information before treatment decisions and eventual nonrealization of a procedure with significant comorbidities but no increased benefit to patients (12). current recommended staging of localized vhr pca is ct and whole-body bone scan (3, 4). ct scan relies mainly on size criteria, location and contrast enhancement to classify lymph nodes as suspicious or not. however, ct scan has been extensively reported as having a poor performance for nodal staging, with sensitivity depending on the prostate cancer risk, but remaining low even for high-risk patients (13). knowing this, previous studies have searched for adequate methods for non-invasive pca staging. those alternatives should be sensitive, specific, clinically useful, easily accessible and reproducible (14). previous studies have explored the role of pet choline and pet psma as staging imaging for localized pca, mostly in a trial setting. van den bergh et al. (9) performed a prospective study with 75 patients with negative ct scans and lymph node extension risk assessed to be between 10-35% with partin tables and compared the performance of pre-operative staging with 11c-choline pet and pelvic mri with super-extended pelvic lymphadenectomy results. they reported a low performance of both pet and mri, maintable 3. test performance on patient and region-based analysis. 18f pet-choline values patient-based analysis patients with positive ln 14/44 (31.8%) sensitivity 64.3% [39.2-89.4%] specificity 83.3% [70.0-96.7%] ppv 64.3% [39.2-89.4%] npv 83.3% [70.0-96.7%] region-based analysis regions with positive ln 20/88 (22.7%) sensitivity 35.0% [14.1-56.0%] specificity 88.2% [80.6-95.9%] ppv 46.7% [21.4-71.9%] npv 82.2% [73.4-91.0%] table 2. two-by-two tables presenting cross-results for nodal disease of eplnd and 18f pet-choline, on patient and region-based analysis. 18f pet-choline positive eplnd negative eplnd patient-based analysis total, n 14 30 positive/suspicious, n (%) 9 (64) 5 (17) negative, n (%) 5 (36) 25 (83) region-based analysis total, n 20 68 positive/suspicious, n (%) 7 (35) 8 (12) negative, n (%) 13 (65) 60 (88) archivio italiano di urologia e andrologia 2022; 94, 4 n. dias, g. colandrea, f. botelho, l. rodriguez-sanchez, y. barbé, p. macek, x. cathelineau 404 ly at the expenses of a low sensitivity (pet: 19% and 8% on patient and region-based analysis; mri: 36% and 10% on patient and region-based analysis), which lead them to suggest the absence of benefit in this patient cohort. schiavina et al. (10) reported their retrospective experience with 11c-choline pet in a cohort of intermediate, high and vhr patients. they report low sensitivities for the detection of nodal disease both on medium and highrisk patients, with 17% and 40% in a region-based analysis, respectively. however, in a subgroup of 28 vhr patients where 50% harbored nodal disease, the test performance was better, with sensitivity, specificity, positive predictive value and negative predictive value of 71%, 93%, 91% and 76%, respectively. in our sub-analysis of 9 patients with ≥ 3 positive lymph nodes on high-quality eplnd, 18f-fluorocholine pet/ct on a patient-based analysis had sensitivity, specificity, ppv and npv of 66.7%, 77.1, 42.9, and 90.0%, respectively. this was similar to our results in the overall vhr pca population, with a high npv pointing to a potential role as means of excluding ≥ 3 positive lymph nodes disease. as the number of patients in this group was low (n=9) it would be interesting to see multicenter results in this subgroup, as the presence of ≥ 3 positive lymph nodes has been suggested as an independent risk factor for both biochemical recurrence and metastatic progression, with these patients benefiting from adjuvant treatment after surgery (15). more recently, some studies have shown promise of good results with psma pet/ct staging in the treatment-naïve high-risk patients. hope et al. (16) performed a trial which enrolled 764 patients with intermediate and high-risk pca being considered for prostatectomy at a single institution, who performed 68ga-psma-11 pet/ct prior to intervention. 277 patients ended up receiving radical prostatectomy with extended lymph node dissection, in which the pet sensitivity, specificity, positive predictive value and negative predictive value were of 40% (95% ci, 34-46%), 95% (95% ci, 92-97%), 75% (95% ci, 7080%) and 81% (95% ci, 76-85%), respectively. hofman et al. (17) published the results of probably the most important study so far, the propsma trial. this was a multicenter randomized controlled trial in 10 australian hospitals. 302 patients with high-risk pca were randomly selected for either usual imaging or 68gapsma-11 pet/ct. psma pet performed better than ct scan, and very well, with an 85% (95% ci, 74-96%) sensitivity and 91% (95% ci, 85-97%) specificity for nodal disease. also, although patients who underwent psma pet as staging method didn’t undergo classical staging previously, the exam results are reported to have changed the clinical preferred options in 28% of patients, with 14% being directed from curative to palliative treatment, 7% with a change in radiotherapy technique and 7% with a change in surgical technique. our work analyzed a real-life experience of a region and country where availability of 68ga-psma-11 pet/ct is scarce and 18f-fluorocholine is widespread. as such, many of our patients don’t have the option for the newest but less accessible radiotracer. for that reason, it was important for us to understand the value caretakers are providing vhr pca patients regarding staging imaging. it comes with the limitations of being a retrospective study, which includes patients operated in a single center, with imaging being performed in many centers. the inclusion of only patients who underwent ralp + eplnd may have selected patients with less advanced localized disease stages, more amenable for radical prostatectomy as a treatment choice; and also excluded metastatic patients and radiotherapy patients who didn’t have surgery. the analysis of 18f-fluorocholine pet/ct accuracy was also only made by patient and side, and using every lymph node region separately, as our current technique of eplnd retrieves all nodes of a side all together in a single packet. reviewing our data is important to understand what real life results we get when using 18f-fluorocholine pet/ct in vhr patients, and we found that even though the exam specificity and npv were > 80%, its low sensitivity both on patient (64.3%) and side (35.0%) based analysis are not enough to consider the exam as a “game changer”, even in the vhr pca group. after the first data on new imaging modalities emerged, some studies started suggesting the wide-spread study of new tracers, such as 177lu-psma (18) and government approval of pet/ct for staging (19), which should facilitate the increasing the availability and decreasing the costs of those exams. as such, efforts to advance the knowledge in the field and maintain low-cost accessibility to exams considered clinically useful should be pursued continuously. conclusions we conclude that 18f-fluorocholine pet/ct as staging for patients with vhr localized pca doesn’t meet the criteria to be a standard exam for pre-operative staging. we therefore believe new radiotracers such as the 68ga-psma-11 should continue to be assessed in this setting. governments and health services should also make efforts to ensure that new meth-ods of imaging with clinical utility have a reasonable financial cost and availability. references 1. sundi d, wang vm, pierorazio pm, et al. very-high-risk localized prostate cancer: definition and outcomes. prostate cancer prostatic dis. 2013; 17:57-63. 2. sundi d, tosoian jj, nyame ya, et al. outcomes of very highrisk prostate cancer after radical prostatectomy: validation study from 3 centers. cancer. 2019; 125:391-397. 3. mottet n, cornford p, van den bergh rcn, et al. eau, eanm, estro, esur, isup, siog: guidelines on prostate cancer. 2022. 4. nccn clinical practice guidelines in oncology: prostate cancer. version 3.2022, consulted 23rd april 2022. available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf 5. hövels am, heesakkers ram, adang em, et al. the diagnostic accuracy of ct and mri in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. clin radiol 2008; 63:387-95. 6. umbehr mh, muntener m, hany t, et al. the role of 11ccholine and 18f-fluorocholine positron emission tomography (pet) and 405archivio italiano di urologia e andrologia 2022; 94, 4 pet-choline in nodal staging of prostate cancer pet/ct in prostate cancer: a systematic review and meta-analysis. eur urol 2013; 64:106-17. 7. evangelista l, guttilla a, zattoni f, et al. utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediateto high-risk prostate cancer: a systematic literature review and meta-analysis. eur urol 2013; 63:1040-8. 8. alberts i, mingels c, zacho hd, et al. comparing the clinical performance and cost efficacy of 68ga-psma-11 and 18f-psma-1007 in the diagnosis of recurrent prostate cancer: a markov chain decision analysis. eur j nucl med mol imaging. 2022; 49:4252-4261. 9. van den bergh l, lerute e, haustermans k, et al. final analysis of a prospective trial on functional imaging for nodal staging in patients with prostate cancer at high risk for lymph node involvement. urol oncol. 2015; 33:109.e23-31. 10. schiavina r, bianchi l, bianchi fm, et al. preoperative staging with 11c-choline pet/ct is adequately accurate in patients with very high-risk prostate cancer. clin genitourin cancer. 2018; 16:305-312.e1. 11. saramatunga h, montironi r, true l, et al. international society of urological pathology (isup) consensus conference on handling and staging of radical prostatectomy specimens. working group 1: specimen handling. mod pathol. 2011; 24:6-15. 12. bianchi l, gandaglia g, fossati n, et al. pelvic lymph node dissection in prostate cancer: indications, extent and tailored approaches. urologia. 2017; 84:9-19. 13. briganti a, abdollah f, nini a, et al. performance characteristics of computed tomography in detecting lymph node metastasis in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. eur urol. 2012; 61:1132-8. 14. balboaca sd. medical diagnostic tests: a review of test anatomy, phases and statistical treatment of data. comput math methods med. 2019; 2019:1891569. 15. stolzenbach lf, knipper s, mandel p, et al. oncological outcomes of pathologically organ-confined, lymph node-positive prostate cancer after radical prostatectomy. urol oncol. 2021; 39:234.e1234.e7. 16. hope t, eiber m, armstrong w, et al. diagnostic accuracy of 68ga-psma-11 pet for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection. jama oncol. 2021; 7:1635-1642. 17. hofman m, lawrentschuk n, francis rj, et al. prostate specific membrane antigen pet-ct in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (propsma): a prospective, randomized, multi-centre study. lancet. 2020; 395:1208-1216. 18. farolfi a, calderoni l, mattana f, et al. current and emerging clinical applications of psma pet diagnostic imaging for prostate cancer. j nucl med. 2021; 62:596-604. 19. afaq a, ell pj, bomanji jb. is it time to fund routine nhs usage of psma pet ct? nucl med commun. 2019; 40:975-979. correspondence nuno dias, md (corresponding author) nunodiasds@gmail.com gianmarco colandrea,md colandrea.gianmarco@hsr.it lara rodriguez-sanchez rodriguezsanchezlara@gmail.com yann barbé yann.barbe@imm.fr petr macek, md petr.macek@imm.fr xavier cathelineau, md, phd xavier.cathelineau@imm.fr urology department, institut mutualiste montsouris, paris (france) 42 bd jourdan; 75014 paris (france) francisco botelho, md, msce francisco.botelho@gmail.com urology department, são joão hospitalar and university center, porto (portugal) archivio italiano di urologia e andrologia 2020; 92, 150 original paper papillary vs non-papillary access during percutaneous nephrolithotomy: retrospective, match-paired case-control study ahmet tahra 1, resul sobay 1, ahmet bindayi 2, ferhat yakup suceken 1, eyup veli kucuk 1 1 department of urology, health sciences university, umraniye teaching hospital, istanbul, turkey; 2 department of urology, burhan nalbantoglu hospital, cyprus. objective: the most crucial steps of percutaneous nephrolithotomy (pcnl) are the percutaneous access and dilation of the access route. recent literature suggests that papillary access to renal calyx is the accepted method. despite this rule, we do not always make papillary puncture and we puncture wherever we can to achieve stone-free status and reduce unnecessary access. in this study, we present our results with papillary vs non-papillary access in patients with a kidney stone. material and methods: two hundred and seven patients with non-papillary access and 69 patients with papillary access who had similar demographics (age, body mass index (bmi), stone size) were selected with pair match analysis (3:1). preoperative and postoperative data were collected from the patient's chart. operative time (from starting surgery to nephrostomy tube), drop-in hematocrit level, transfusion rate, duration of hospital stay, perioperative and postoperative complications (clavien-dindo classification) and stone-free status (no or < 3 mm residual stone) were also evaluated in both groups. results: the mean operative time was similar in between two groups. the mean hematocrit decreases not differ between the two groups (p = 0.56). in papillary group, only 2 patients (3.2%) required transfusion and only one patient (1.4%) in the non-papillary group had a transfusion with no statistically significant difference (p = 0.43). the overall complication rates were 7.1% in the papillary group and 7.2% in the non-papillary group (p = 0.89). postoperative mean creatinine level was similar between the two groups. conclusions: in this study, we found that non-papillary access is a feasible option for pcnl in the terms of stone-free status and complication rates. key words: percutaneous nephrolithotomy; access; papillary; non-papillary. submitted 14 september 2019; accepted 13 november 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.50 introduction percutaneous nephrolithotomy (pcnl) is still the standard therapy for the larger calculi in the kidney (1). the most crucial steps of pcnl are the percutaneous access and dilation of the access route. as accepted by literature, punctures must be done through the papilla of the posterior renal calyx to avoid the major vascular structures of the kidney (2). despite this rule, access through the papilla is not always achievable. in our huge volume percutaneous surgery centre (over 400 cases per year) we do not always make papillary puncture and we puncture wherever we can to achieve stone-free status and reduce unnecessary access. non-calyceal puncture method was recently published and the authors concluded that it is feasible and probably not as dangerous as it was stated (3). in this study, we present our results with papillary vs non-papillary access in patients with kidney stone. material and methods after an ethics committee approval was obtained, a total of 638 patients patient undergoing pcnl between january 2017 and june 2018 were analyzed. two hundred and seven patients with non-papillary access and 69 patients with papillary access who had similar demographics (age, bmi, maximum diameter of the stone) were selected with pair match analysis (3:1). preoperative and postoperative data were collected from the patient's chart. operative time (from starting surgery to nephrostomy tube), drop-in hematocrit level, transfusion rate, duration of hospital stay, perioperative and postoperative complications (clavien-dindo classification) and stone-free status (no or < 3 mm residual stone) were also evaluated in both groups. preoperative and postoperative third-month creatinine level were also recorded and analyzed. followup was made with low dose non-enhanced computerized tomography (nect) three months after surgery. patients with a solitary kidney, history of previous surgery (open or endoscopic) or extracorporeal shock wave lithotripsy (eswl) for the same kidney, congenital anatomical variants (horseshoe kidney, ectopic kidney) were excluded. in surgical technique; after insertion of open-end 4 f ureteral catheter in lithotomy position, patients were set to the prone position. all patients were treated with combined fluoroscopic and ultrasound guided pcnl. in papillary access group, papilla of the calyx was punctured. in the other group, the puncture was made through infundibulum of the calyx. the puncture site was corrected under ultrasound control. after insertion of hydrophilic guidewire all cases were dilated up to 16 f with amplatz dilators and then balloon dilatation was made up to 30 f. rigid nephroscope and pneumatic lithotripter were used to remove calculi. fragments were tahra_stesura seveso 01/04/20 18:58 pagina 50 51archivio italiano di urologia e andrologia 2020; 92, 1 papillary vs non-papillary access in pnl removed using basket catheter and forceps. at the end of the procedure, 14 f nephrostomy catheter was inserted in all cases. statistical analysis was performed with the ibm spss version 20 (ibm corp., armonk, ny, usa). fischer’s exact test, pair-match analysis, mann-whitney u, t-test and were used for the analysis of the data and statistical significance was accepted as p-value < 0.05. results patient age, bmi and stone size were similar (nearly the same) in both groups according to case match analysis (table 1). the mean operative time was also similar. the average of hematocrit decrease was 3.45 ± 2.2 in the papillary group and 3.89 ± 3.3 in the non-papillary group with no difference between the two groups (p = 0.56). in the papillary group, only 7 patients (3.8%) required transfusion and only one patient (1.4%) in the non-papillary group had a transfusion with no statistically significant difference (p = 0.43). the overall complication rates were similar being 7.1% in the papillary group and 7.2% in the non-papillary group (p = 0.89). according to clavien-dindo classification, only one patient in the non-papillary group and three patients in non-papillary group had class iiia (required selective angioembolization because of uncontrolled bleeding) complication (p = 0.87). the mean duration of hospital stay was also similar. postoperative mean creatinine level was similar between the two groups. all statistical analysis are showed in table 2. discussion after fernstrom and johansson reported the first percutaneous nephrolithotomy in 1976 and alken et al. published the first series of percutaneous interventions for removing renal stones, pcnl started to become widely used for renal stones (4, 5). operative technique and endoscopic equipment are still evolving to increase success and decrease morbidity. recent literature suggests that preferred puncture site is papillary access on the avascular line to avoid the risk of bleeding. sampaio et al. were studied to determine the best route to puncture in 1992 and they found that; in infundibular access, upper site was injured in 67.6% (41.1% venous and 26.5% arterial), mid site of kidney in 61.5% (38.4% venous and 23.1% arterial) and lower site in 68.2% (54.6% venous and 13.6% arterial). in the direct puncture of pelvis 33.2% injuries were recorded but in calyceal fornix overall injuries were recorded only 7.7% and they were all venous injuries (6). this study had three major concerns; firstly, it was cadaveric study and renal-related anatomical tissue was not evaluated, secondly renal and cortical system was naïve and anatomical changes due to stone was not considered, thirdly no renal functional evaluation was made, and recovery was not assessed. kallidonis et al. published a prospective randomized trial that compared papillary vs non-papillary access in pcnl, and they found that access to infundibulum is the feasible and safe procedure and it is not associated with higher blood loss and transfusion rate (7). kallidonis et al. evaluated infundibulum of the middle calyx approach technique by 99mtc-dimercaptosuccinic acid spect/ct renal scintigraphies and/or computerized tomographies perfusion (ctp); they found that the punctures to the mid calyceal papilla fornix and infundibulum as well as pelvis have similar angles of approach and that effects on parenchyma involved in the tract dilation are similar (8). they concluded that infundibular puncture can be an option to puncture in the performance of pcnl. in another study kyriazis et al. investigated the feasibility and safety of pcnl with non-calyceal access track; they operated 137 patients consecutively, including 10 cases with anatomical variations, under fluoroscopic guidance (3). stone free status was 89.2% for a single stone, 80.4% with multiple and 66.7% for staghorn stones. the overall complication rate was 10.2% and the major complication rate was 3.6%. the authors concluded that calyceal access is possible and safe with stone-free status and low complications. the length of hospitalization is a new investigation era for pcnl. the technology continues to improve, and postoperative complications are decreasing, ‘’outpatient’’ procedure is an option now for highly selected patients (9). however, we still routinely admitted patients to follow-up. in terms of hospital stay our results are comparable with a recent literature (10). in this study, the overall complication rates were 7.1% for the papillary group and 7.2% for the non-papillary group. transfusion rates were 3.8% and 1.4%. in a study by wiesenthal et al. which compared shockwave lithotripsy, ureteroscopy, and pcnl for renal caltable 1. patient characteristics. papillary non-papillary p value group (n: 207) group (n: 69) age 51.6 ± 13.54 52.2 ± 12.43 0.94 bmi (kg/m2) 28.3 ± 5.2 27.9 ± 3.6 0.93 stone size (max diameter, cm) 2.46 ± 4.6 2.38 ± 5.1 0.85 gender f/m, n 66/141 24/45 location upper 23 9 middle 25 11 pelvis 82 26 lower 77 23 values are presented as mean values ± standard deviation. bmi = body mass index; m = male; f = female. table 2. perioperative and postoperative outcomes and complications. papillary non-papillary p value group (n: 207) group (n: 69) operation time, min 58.3 ± 14.3 56.8 ± 15.3 0.56 drop in hematocrit level 3.45 ± 2.2 3.43 ± 2.7 0.93 length of hospital stay, days 4.45 ± 1.9 4.51 ± 1.8 0.42 stone free status (%) 86.4% 85.5% 0.66 mean change in creatinine, mg/dl 0.06 ± 0.29 0.05 ± 0.41 0.68 overall complications, (%) 7.1 7.2 0.89 ≥ clavien-dindo class iii 1.4 1.4 0.87 transfusion rate (%) 3.8 1.4 0.16 values are presented as mean values ± standard deviation. tahra_stesura seveso 01/04/20 18:58 pagina 51 archivio italiano di urologia e andrologia 2020; 92, 1 a. tahra, r. sobay, a. bindayi, f. yakup suceken, e. veli kucuk 52 culi between 100-300 mm2, they found that overall complication in pcnl was 14% (11). in a recent study comparing retrograde intrarenal surgery versus pcnl, in pcnl group bleeding rate was 6.87% and it was higher than our results (10). this study has several limitations; firstly, the study has a retrospective nature. secondly, control patients were not randomized and selected for analysis. the surgeons (three surgeons) are very experienced – over 300 cases – and that may cause low complication rates. patients are not consecutively enrolled in this study and anatomical variations are not evaluated. multiple access and longterm complications are not also evaluated. low number of patients because of the wide exclusion criteria is another limitation of this study. conclusions in this study, we found that non-papillary access is a feasible option for pcnl in terms of stone-free status and complication rates. more anatomical and radiological, prospective randomized studies involving a great number of patients may be needed to determine the safety and efficacy of non-papillary access. references 1. turk c, petrik a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-482. 2. gupta m. om, shah jb, mcdougall em, smith, a. percutaneous management of the upper urinary tract. campbell-walsh urology. ninth ed. saunders elsevier, philadelphia, pa. 2007. 3. kyriazis i, kallidonis p, vasilas m, et al. challenging the wisdom of puncture at the calyceal fornix in percutaneous nephrolithotripsy: feasibility and safety study with 137 patients operated via a noncalyceal percutaneous track. world j urol. 2017; 35:795-801. 4. fernstrom i, johansson b. percutaneous pyelolithotomy. a new extraction technique. scand j urol nephrol. 1976; 10:257-259. 5. alken p, hutschenreiter g, gunther r, marberger m. percutaneous stone manipulation. j urol. 1981; 125:463-466. 6. sampaio fj, zanier jf, aragao ah, favorito la. intrarenal access: 3-dimensional anatomical study. j urol. 1992; 148:1769-1773. 7. kallidonis p, kyriazis i, kotsiris d, et al. papillary vs nonpapillary puncture in percutaneous nephrolithotomy: a prospective randomized trial. j endourol. 2017; 31:s4s9. 8. kallidonis p, kalogeropoulou c, kyriazis i, et al. percutaneous nephrolithotomy puncture and tract dilation: evidence on the safety of approaches to the infundibulum of the middle renal calyx. urology. 2007; 107:43-48. 9. wei c, zhang y, pokhrel gm et al. research progress of percutaneous nephrolithotomy. int urol nephrol. 2018; 50:807-817. 10. zheng c, xiong b, wang hm et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones > 2 cm: a meta-analysis. urol int. 2014; 93:417-424. 11. wiesenthal jd, ghiculete d, d'a honey rj, pace kt. a comparison of treatment modalities for renal calculi between 100 and 300 mm2: are shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy equivalent? j endourol. 2011; 25:481-485. correspondence ahmet tahra, md (corresponding author) ahmettahra@gmail.com resul sobay, md drresulsobay@gmail.com ferhat yakup suceken, md ykpsckn@gmail.com eyup veli kucuk, md eyupveli@gmail.com department of urology, health sciences university umraniye teaching hospital, istanbul, turkey adem yavuz cad. no: 1 34766 istanbul (turkey) orcid id: 0000-0002-5158-5630 ahmet bindayi, md ahmetbindayi@gmail.com department of urology, burhan nalbantoglu hospital, cyprus tahra_stesura seveso 01/04/20 18:58 pagina 52 stesura seveso 255archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. for the treatment of non-malignant conditions in patients who have failed previous conservative therapies. these benign conditions represent a heterogeneous group of disorders including interstitial cystitis, painful bladder syndrome, neurogenic bladder, hemorrhagic/radiation cystitis, endometriosis and refractory genitourinary fistula. treatment begins with non invasive medical therapies but, in refractory cases, a surgical solution should be considered. after cystectomy, a urinary diversion and reconstructive procedures are needed. over the past decades, orthotopic neobladder became a widely accepted technique for urinary diversion and the preferred method after removal of the bladder. initially, it was limited just to men; women were considered ineligible for this procedure because urethra-sparing orthotopic substitution was thought to be associated with an increased risk of local recurrence and voiding dysfunction. with the improved understanding of the female sphincter mechanism, however, this approach has become technically accepted in selected cases (1). an important issue in the decision-making process, prior to urinary diversion in females, is health related quality of life, including the effects of reconstruction of neobladder on physical, social and mental status. comparing the orthotopic neobladder to the other reconstructive options, this approach allows the restoration of a normal self-image and then it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. however, women undergoing cystectomy for benign bladder conditions can face many disorders that can impact on everyday life, such as voiding dysfunction or sexual activity problems. these symptoms and complications can be temporary or permanent. voiding often has a major impact on quality of life and an improved quality of life after urinary diversion fails to be realized when voiding dysfunction arises (2). voiding dysfunction following the orthotopic neobladder can be divided into failure to store urine, during daytime, nighttime or both, and failure to empty, requiring intermittent self-catheterization (3). this paper reviews the literature on the impact of orthoobjective: to review the literature on the impact on female quality of life and sexual function of orthotopic reconstruction after radical cystectomy for non-malignant bladder conditions. radical cystectomy is commonly required to treat malignant conditions but may also be considered for the treatment of non-malignant diseases. these heterogeneous group of disorders includes interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic/radiation cystitis, endometriosis and refractory genitourinary fistula. treatment begins with non-invasive medical therapies but, in non-responder cases, a surgical solution should be considered. such invasive techniques include urinary diversion and reconstructive procedures that have an impact on healthrelated quality of life, physical, social, and mental status. materials and methods: this narrative review research was done using the pubmed database up until 2020, july. all papers referring to cystectomy for benign indication were considered. results: in comparison to other reconstructive options, orthotopic neobladder allows the restoration of a normal self-image and consequently it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. however, women can face many disorders that impact on everyday life, such as voiding dysfunction or sexual activity problems. conclusions: scant data is available about quality of life, sexual life and self-perception in women treated by cystectomy for benign conditions and most literature is dedicated to those indicators in cancer patients. more research is needed to understand the tolerability and the quality of life results of the female population affected by benign conditions undergoing this kind of surgical approach. key words: orthotopic bladder; cystectomy; quality of life; woman; benign conditions; non malignant conditions; endometriosis; interstitial cystitis; neurological bladder; sexuality; urinary symptoms. submitted 25 january 2021; accepted 23 april 2021 introduction cystectomy is commonly required to treat malignant conditions such as urothelial carcinoma of the bladder. cystectomy with urinary diversion may also be considered the impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions chiara borghi 1, margherita manservigi 1, elena sofia milandri 1, carmelo ippolito 3, pantaleo greco 1, lucio dell’atti 2 1 department of surgical sciences, section of obstetrics and gynecology, azienda ospedaliero-universitaria sant’anna, university of ferrara, cona (ferrara), italy; 2 division of urology, department of clinical, special and dental sciences, university hospital "ospedali riuniti" school of medicine, marche polytechnic university, ancona, italy; 3 department of surgical sciences, section of urology, azienda ospedaliero-universitaria sant’anna, university of ferrara, cona (ferrara), italy. doi: 10.4081/aiua.2021.3.255 summary archivio italiano di urologia e andrologia 2021; 93, 3 c. borghi, m. manservigi, e.s. milandri, c. ippolito, p. greco, l. dell’atti 256 topic reconstruction on female quality of life and sexual function after radical cystectomy for non-malignant bladder conditions. materials and methods research was done using the pubmed database up until 2021, january. all papers referring to cystectomy for benign indication were considered. a combination of medical subject headings (mesh) terms was used. the keywords were: orthotopic bladder, cystectomy, quality of life, sexuality, woman, benign, endometriosis, interstitial cystitis, radiation cystitis and neurogenic bladder. all titles and abstracts published in english were evaluated. each article was evaluated according to the inclusion criteria: studies reporting any surgical intervention to treat benign bladder conditions, orthotopic neobladder for benign condition, quality of life after cystectomy and reconstructive surgery with particular attention to female population. all studies were considered, with the exception of those performed on animals, comments, letters, editorials and case reports. due to the high heterogeneity regarding the indication for surgery, surgical approach, anesthesia procedures and complications, only a non-systematic review of literature and a critical synthesis of clinical experiences was performed. results and discussion the initial search yielded a total of 47 articles. forty articles were excluded after title/abstract screening for not meeting inclusion criteria. a total of seven articles strictly related to our issue were finally evaluated and reviewed by the authors. the selection of papers is reported in figure 1. other papers were included because of the topic relevance. non-malignant indications for cystectomy few benign diseases include cystectomy with urinary diversion among the treatment options. all of them have behavioral and medical first line therapies but, when patients are refractory to these less invasive ones, they can be considered for surgery. these conditions are included in the present review’s purpose and here shortly described. interstitial cystitis/painful bladder syndrome (ic/pbs): a chronic debilitating inflammatory disease of the bladder that mainly affects women, most often in the fourth decade or later. it is defined as an unpleasant sensation characterized by suprapubic pain and lower urinary figure 1. flow chart for paper selection. 257archivio italiano di urologia e andrologia 2021; 93, 3 bladder orthotopic reconstruction in women tract symptoms lasting more than six weeks, in absence of infection or other identifiable causes (4, 5). neurogenic bladder: a condition that can be caused by congenital anomalies such as meningomyelocele and spina bifida or by acquired central nervous system diseases, such as spinal cord injury, multiple sclerosis, stroke, and parkinsonism (6). if left untreated, these pathological conditions can lead to a progression of urinary dysfunction. the diagnosis is based on clinical evaluation. biological, radiological, and urodynamic investigations are indicated to plan the best management (6-8). hemorrhagic cystitis is a condition characterized by hematuria and lower urinary tract symptoms. it can be acute or chronic, caused by trauma, infections, chemotherapy, and radiation (9-11). the diagnosis of hemorrhagic/radiation cystitis is based on past medical history, signs, symptoms, urine tests and cystoscopy (12). genitourinary tuberculosis and schistosomiasis are infectious diseases endemic in developing countries that can cause severe urinary damage such as bladder fibrosis. about 30% of extra-pulmonary tuberculosis interest the genitourinary system. the most common symptoms of bladder tuberculosis are flank pain, dysuria, hematuria and frequency (13). the diagnosis is based on clinics, urine testing with sterile pyuria, histopathological examination and radiological exam (caverns of kidney) (14). all patients are treated with antibiotics, but in case of severe retracted bladder or serious reflux that damages the upper urinary tract, a surgical treatment could be necessary (13, 15). in schistosomiasis, the host immune reaction to the bilharzial eggs results in healing by fibrosis and may progress to mucosal, submucosal, or muscular lesions, up to squamous cell carcinoma (16-18). bladder endometriosis is defined as the infiltration of the endometrial tissue into the detrusor muscle. characteristic symptoms include dysuria, frequency, hematuria, urgency and bladder pain, symptoms that may worsen during menstruation. vaginal and physical examinations allow the identification of palpable nodules. trans-vaginal ultrasonography should be regarded as a first line radiological test for the assessment of bladder endometriosis, while magnetic resonance is considered a second-line technique. cystoscopy is used to assess the interior lining of the urethra and bladder (19). conservative approaches can be used, such as the simple resection of endometriotic nodules, however, in selected cases, partial cystectomy is needed (20). orthotopic neobladder surgical principles orthotopic neobladder is one of the reconstructive urinary diversion procedures after cystectomy. technique of orthotopic bladder aim to build a high capacity and low pressure reservoir and to connect it to the native urethra, proximally to the external striated sphincter. the neobladder reservoir is made of de-tubularized gastric, ileum, ileocolonic or colonic segments. maximal neobladder capacity depends on the choice and configuration of bowel segments harvested. in general, pressures are lower and capacities are greater in ileal segments. this procedure allows the patient to void volitionally through the urethra, restoring a more natural voiding pattern (21). long-term quality of life following cystectomy and urinary diversion with orthotopic bladder in the world health organization (who) concept of health and quality of life (qol), the latter is defined as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations and standards and concerns” (22). health-related quality of life after surgery appears to be an important issue in the decision-making process prior to urinary diversion. although disease or anatomic considerations may limit neobladder use in some patients, orthotopic bladder is commonly suitable to many of those undergoing cystectomy. this procedure is associated with significant changes in urinary and sexual function, relationships, and psychosocial habits (23). all these changes impact patients’ perceived quality of life. several groups analyzed qol after radical cystectomy and reconstruction of neobladder for malignant conditions, comparing it with other types of urinary diversion, to clarify the effects on physical, social, and mental status. some proponents of continent orthotopic diversion have used general quality of life instruments (i.e. 36-item short form sf36) (24) to study patient outcomes and have cited incontinence bother, sexual function, and social comfort as possible reasons to use neobladder diversion (25, 26). most investigators, however, have been unable to demonstrate significant differences in quality of life parameters among diversion groups. for example, hobisch at al. compared subjective morbidity of ileal neobladder versus ileal conduit urinary diversion to elucidate its influence on quality of life. using the european organization for research and treatment of cancer quality of life core questionnaire (eortc-qlqc30 (27) they found that patients with a neobladder needed a shorter period of rehabilitation, 92.8% of them did not feel handicapped at all and 87% had no feelings of sickness or illness. they also demonstrated that urinary leakage, odor, and wet clothing were much more common in patients with the stomal appliance of conduit than in the continent reservoir and neobladder patients (28). on the other hand, hedgepeth at al. studied the body image and quality of life, evaluating urinary, sexual and bowel domains, and they did not find any difference between patients undergoing urostomy and those who had neobladder reconstruction (29). there is a paucity of outcome data regarding quality of life after urinary diversion with orthotopic bladder for benign conditions in literature. in a study about bladder substitution by ileal neobladder in women with ic/pbs, authors found that all patients presented good treatment outcomes and quality of life by using sf36 questionnaire. they showed significant improvement of both physical and mental health (30). moreover, the main factors affecting general health qol (gh-qol) after neobladder substitution were voiding dysfunctions. in fact, patients with daytime incontinence or requiring clean intermittent catheterization (cic), had lower sf36 scores than those without these symptoms (2, 30). however, cody and colleagues, in a cochrane collaboration review, analyzed the different types of urinary diversion and the review did not find any significant evidence archivio italiano di urologia e andrologia 2021; 93, 3 c. borghi, m. manservigi, e.s. milandri, c. ippolito, p. greco, l. dell’atti 258 as to the superiority of continent vs incontinent diversion after cystectomy for malignant as well as non-malignant indications (31). voiding dysfunctions in the orthotopic neobladder voiding dysfunctions following orthotopic neobladder can be divided into urinary incontinence during the daytime, night-time or both, or the inability to empty the bladder (“hyper-continence”) requiring cic (32). voiding disorders are frequent findings in female patients after orthotopic neobladder and can arise both from physiological and anatomical defects. risk factors for the development of the daytime urinary incontinence include advanced age, inadequate storage reservoir and alteration of the sphincteric mechanism (3). nerve sparing cystectomy is another factor believed to provide early continence in female patients, along with the preservation of the trigone with no damage to the autonomic nervous system. however, with the preservation of the trigone, a significant portion of patients develop urinary retention, which worsens over time. the highest rates of urinary retentionists are found where nerve-sparing technique is performed (30, 33). another common effect of neobladder is night-time incontinence. it results from the overdistension of the neobladder and lack of voiding sensation. the patient fails to wake up during the night to empty the bladder, allowing excessive urinary volume to overcome the urethral closure mechanism. the use of cystectomy with a neobladder for treatment of patients with bladder carcinoma has been reported with long term follow up, demonstrating that this operation is safe for female patients (34). however, care must be taken at the time of surgery to prevent future voiding problems. in fact, the post-operative reduction in terms of qol is substantial when voiding dysfunctions occur following the neobladder. patients with daytime incontinence or requiring cic had lower sf36 scores than those without incontinence or cic. however, general healthquality of life (gh-qol) score in patients with enuresis was the same as that without enuresis, regardless of the degree of enuresis and urination qol was not as high as surgeons expected (2). on the other hand, it was found that, even if the patient is incontinent and requires 5 to 6 sanitary pads daily, neobladder was preferable to maintain body image (1). sexual function following cystectomy and urinary diversion with orthotopic bladder during radical cystectomy in women, the neurovascular bundles, placed on the lateral walls of the vagina, are usually removed or damaged by removal of the bladder, urethra, and anterior vaginal wall. therefore, anterior exenteration may result in diminished ability or inability to achieve orgasm, decreased lubrication, decreased sexual desire and dyspareunia (35). sexual dysfunction is a prevalent problem after female radical cystectomy and many of bladder cancer specific questionnaires, such as the bladder cancer index (bci), vanderbilt cystectomy index (vci), functional assessment of cancer therapy – bladder (fact-b) and eortc-qol-b20, include sexual function and dysfunction items. for women, the most commonly used questionnaire is the female sexual function index (fsfi), that analyzes specific domains including the degree of vaginal lubrication, ability to achieve orgasm, degree of pain during intercourse, overall sexual desire and interest, and overall sexual satisfaction. craig et al. conducted a clinical study to address sexual dysfunction in a subset of sexually active women undergoing radical cystectomy (rc) using a modified index of female sexual function questionnaire and strattable 1. studies about orthotopic neobladder for benign conditions, extraction of women population. authors, type disease number type of orthotopic mean age qol luts sexual function year of study of benign cases neobladder (years) (evaluated yes/no (evaluated (evaluated after rc or sc instrument if yes) yes/no) yes/no) gross et al., 2015 (37) observational post-radiation cystitis 4 rc with ileal orthotopic neobladder 61.7 no yes no cohn et al., 2014 (38) observational infection, fistula, 2 rc with ileal orthotopic neobladder 57.8 no yes no bleeding, neurogenic (not clear if bladder or pain men or women) gobeaux et al., 2011 (39) observational neurogenic detrusor 31 sc with ileal orthotopic 34.7 yes yes no overactivity neobladder (modified hautmann) (voiding diary, radiological, laboratory, endoscopic and urodynamic assessment) takenaka et al., 2010 (2) observational contracted bladder 1 rc with ileum or colon 62 yes yes no (not clear if as neobladder reservoirs (sf-36 questionnaire) (only in male) man or woman) kochakarn et al., 2007 (30) observational interstitial cystitis 35 rc with ileal orthotopic 45.9 yes yes yes neobladder (sf-36 questionnaire) (modified sturder) studer et al., 2005 (40) observational not specified 17 rc with ileal orthotopic neobladder 65 no yes no (not clear if (only in male) men or women) shimogaki et al., 1999 (1) observational contracted bladder 2 sc with ileal orthotopic neobladder 45.5 yes yes no (questionnaire about voiding status, continence and qol) qol = quality of life. 259archivio italiano di urologia e andrologia 2021; 93, 3 bladder orthotopic reconstruction in women ifying the sexual response by the type of urinary diversion to determine whether vaginal sparing (as performed in the orthotopic diversion) influenced the sexual response. no statistically significant difference was found between the indiana external diversion stoma and the studer orthotopic in women after rc (35). when performed for benign conditions, cystectomy frequently does not need anterior pelvic exenteration. nevertheless, sexual dysfunction may be related to neural injury and changes in pelvic anatomy. other factors that may impact sexual satisfaction and libido include body alterations associated with urinary diversion, resulting in changes in body images, emotional and psychological responses of both patients and their partners, and the age-related changes in libido and sexual interest. patients with orthotopic neobladder do not undergo the same degree of body alteration as others urinary diversion techniques, but the poor urine control and incontinence can be significant stressors that may limit interest in sexual activity (36). moreover, preservation of normal sexual function in women has not been the main goal in most studies of neobladders in women. in conclusion, orthotopic neobladder technique, used for the treatment of benign diseases, allows the improvement of both physical and mental health. urinary symptoms remain the most frequently reported problems affecting general health and sexual function in operated women. sexual function and quality of life in women after radical cystectomy for non-malignant bladder conditions in table 1 we listed the few articles taking into account the population of interest. gross et al. in 2015 evaluated how hysterectomy and nerve sparing affected functional outcomes after ileal orthotopic bladder substitution in 73 women. four of them underwent cystectomy for postradiation cystitis, the other 69 for invasive urothelial cancer. the results showed a strong correlation between postoperative urinary incontinence and preor perioperative hysterectomy. these findings suggest that voiding disorders are related to the damage of autonomic nerves, which run along the lateral aspect of cervix uteri (37). cohn et al. (2014) investigated perioperative outcomes after cystectomy and urinary diversion for the treatment of refractory benign urological diseases, like infection, fistula, bleeding, incontinence, neurogenic bladder or pain. the study group included 8 males and 18 females; 22 patients underwent ileal conduit, 2 underwent ileal neobladder and 2 underwent indiana pouch diversion. the authors demonstrated that cystectomy and urinary diversion resulted in resolution of urological symptoms in 73% of patients but the procedure was morbid for many, in fact 73% of patients experienced a complication within 30 days of surgery (urinary tract infection, abscess, urine leak etc) (38). gobeaux et al. (2011) evaluated continence status, urodynamic changes and long-term sequelae of hautmann pouch following supratrigonal cystectomy in a population of 61 patients, 30 males and 31 females, with neurogenic detrusor overactivity. they found that this surgical technique achieved complete continence in 75% of cases, reduced rates of infection and dependency on pharmacological agents. all these factors contributed to the improvement of qol (39). takenaka et al. (2010) analyzed the general health qol, urinary qol, and sexual qol in 78 males and 8 females five years after orthotopic neobladder substitution. most of the population had bladder cancer or malignancies of other organs that had invaded the bladder. only one patient, whose gender isn’t specified, had a benign pathology. the authors found that although the general health qol was generally well maintained, the presence of intermittent cic or daytime incontinence impaired the qol. regarding sexual satisfaction and female sexual function, authors didn’t examine these items (2). kochakarn et al. in 2007 reported their experience with cystectomy and ileal neobladder in 35 female patients with interstitial cystitis, in particular they assessed general qol, voiding disorders and sexual life. they showed that qol improved in both physical and mental health components; after 6 months diurnal and nocturnal continence were achieved in 100% of patients, spontaneous voiding was noted in 33 cases, the other 2 cases voided spontaneously with residual urine and used intermittent catheterization. among 30 cases of sexually active patients, 12 had mild degree of dyspareunia during the first year, no patient had problems in sexuality after 1 year (30). studer et al. in 2005 presented long-term results of a large series of patients after ileal orthotopic bladder substitution. the study considered 482 patients including 40 women; cystectomy was performed for cancer in 465 cases and for other reasons in only 17 cases (not clear if males or females). the authors demonstrated that the bladder capacity was increased rapidly after surgery, daytime and nighttime frequency decreased during the first year then remained unchanged for 5 years and urinary infections occurred in 10% of patients, in association with residual urine. the sexual function was considered only in men (40). shimogaki et al. (1999) investigated the long-term outcome of orthotopic neobladders in 8 women, 6 of whom were treated for invasive bladder cancer and 2 for contracted bladder. in particular, they focused on qol and voiding dysfunction. they found that patients’ satisfaction was excellent, daytime and nighttime continence was achieved in 88% of the patients, although half of the women required intermittent catheterization (1). in cases of failure of all conservative treatments, cystectomy with enterocystoplasty is used in many institutions for treating ic/pbs. at the beginning of bladder reconstruction in female patients, supratrigonal cystectomy has been used to avoid urinary incontinence. however, even leaving only vestigial bladder muscle, persistent painful bladder was still present. webster et al. reported complete painful relief after additional removal of the trigone in patients submitted to supratrigonal cystectomy and enterocystoplasty for treating ic/pbs (41-43). in fact, urinary incontinence after a neobladder operation depends on creating adequate storage reservoir and preserving the sphincteric mechanism. sectioning the urethra below bladder neck in female patients can maintain the continence mechanism with better emptying than in the case of bladder neck preservation (44). nerve sparing cystecarchivio italiano di urologia e andrologia 2021; 93, 3 c. borghi, m. manservigi, e.s. milandri, c. ippolito, p. greco, l. dell’atti 260 tomy is another factor believed to provide early continence in women. sparing of autonomic nerve fibers provide beneath the urethra was found to provide early urinary control in derived patients. keeping endopelvic fascia intact not only preserves the nerve but also keeps urethra-pelvic ligament, enhancing urinary control (45). conclusions orthotopic neobladder is a complex surgical technique used for reconstruction of lower urinary tract after cystectomy. such procedure is used for benign conditions only in cases of lack of response to conservative treatments. it allows preservation of normal body perception but, on the other hand, it is related to several possible adverse conditions and complications. scant data is available about quality of daily life, sexual life and self-perception in women treated for benign conditions and most literature is dedicated to qol indicators in cancer patients (46). more research is still needed to better understand the tolerability and the quality of life results in the female population affected by benign conditions undergoing this kind of surgical approach. references 1. shimogaki h, okada h, fujisawa m, et al. long-term experience with orthotopic reconstruction of the lower urinary tract in women. j urol. 1999; 161:573-577. 2. takenaka a, hara i, soga h, et al. assessment of long-term quality of life in patients with orthotopic neobladder followed for more than 5 years. int urol nephrol. 2011; 43:749-754. 3. steers wd. voiding dysfunction in the orthotopic neobladder. world j urol. 2000; 18:324-329. 4. hanno p, dmochowski r. status of international consensus on interstitial cystitis/bladder pain syndrome/painful bladder syndrome: 2008 snapshot. neurourol urodyn. 2009; 28:274-286. 5. hanno pm, burks da, clemens jq, et al. aua guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. j urol. 2011; 185:2162-2170. 6. dorsher pt, mcintosh pm. neurogenic bladder. adv urol. 2012; 2012:816274. 7. amarenco g, sheikh ismaël s, chesnel c, et al. diagnosis and clinical evaluation of neurogenic bladder. eur j phys rehabil med. 2017; 53:975-980. 8. westney ol. the neurogenic bladder and incontinent urinary diversion. urol clin north am. 2010; 37:581-592. 9. numazaki y, kumasaka t, yano n, et al. further study on acute hemorrhagic cystitis due to adenovirus type 11. n engl j med. 1973; 289:344-347. 10. dropulic lk, jones rj. polyomavirus bk infection in blood and marrow transplant recipients. bone marrow transplant. 2008; 41:11-18. 11. stillwell tj, benson rc. cyclophosphamide induced hemorrhagic cystitis: a review of 100 patients. cancer 1988; 61:451-457. 12. okaneya t, kontani k, komiyama i, takezaki t. severe cyclophosphamide-induced hemorrhagic cystitis successfully treated by total cystectomy with ileal neobladder substitution: a case report. j urol. 1993; 150:1909-1910. 13. gokce g, kilicarslan h, ayan s, et al. genitourinary tuberculosis: a review of 174 cases. scand j infect dis. 2002; 34:338-340. 14. kulchavenya e. best practice in the diagnosis and management of urogenital tuberculosis. ther adv urol. 2013; 5:143-151. 15. carl p, stark l. indications for surgical management of genitourinary tuberculosis. world j surg. 1997; 21:505-510. 16. khalaf i, shokeir a, shalaby m. urologic complications of genitourinary schistosomiasis. world j urol. 2012; 30:31-38. 17. gray dj, ross ag, li ys, mcmanus dp. diagnosis and management of schistosomiasis. bmj. 2011; 342:1-12. 18. ghoneim ma, shoukry i. the use of ileum for correction of advanced or complicated bilharzial lesions of the urinary tract. int urol nephrol. 1972; 4:25-33. 19. leone roberti maggiore u, ferrero s, candiani m, et al. bladder endometriosis: a systematic review of pathogenesis, diagnosis, treatment, impact on fertility, and risk of malignant transformation. eur urol. 2017; 71:790-807. 20. nezhat ch, malik s, osias j, et al. laparoscopic management of 15 patients with infiltrating endometriosis of the bladder and a case of primary intravesical endometrioid adenosarcoma. fertil steril; 2002; 78:872-875. 21. gschwend je. bladder substitution. curr opin urol. 2003; 13:477-482. 22. measuring health-a review of quality of life measurement scales. accessed july 31, 2020. https://www.ncbi.nlm.nih.gov/pmc/ articles/pmc1059623/ 23. mânsson a, mânsson w. when the bladder is gone: quality of life following different types of urinary diversion. world j urol. 1999; 17:211-218. 24. stansfeld sa, roberts r, foot sp. assessing the validity of the sf36 general health survey. qual life res. 1997; 6:217-224. 25. bjerre bd, johansen c, steven k. health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. a questionnaire survey. br j urol. 1995; 75:200-205. 26. boyd sd, feinberg sm, skinner dg, et al. quality of life survey of urinary diversion patients: comparison of ileal conduits versus continent kock ileal reservoirs. j urol. 1987; 138:1386-1389. 27. aaronson nk, ahmedzai s, bergman b, et al. the european organization for research and t reatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. j natl cancer inst. 1993; 85:365-376. 28. hobisch a, tosun k, kinzl j, et al. quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. world j urol. 2000; 18:338-344. 29. hedgepeth rc, gilbert sm, he c, et al. body image and bladder cancer specific quality of life in patients with ileal conduit and neobladder urinary diversions. urology. 2010; 76:671-675. 30. kochakarn w, lertsithichai p, pummangura w. bladder substitution by ileal neobladder for women with interstitial cystitis. int braz j urol. 2007; 33:486-492. 31. cody jd, nabi g, dublin n, et al. urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. cochrane database syst rev. 2012; 2012:cd003306 32. park jm, montie je. mechanisms of incontinence and retention after orthotopic neobladder diversion. urology. 1998; 51:601-609. 261archivio italiano di urologia e andrologia 2021; 93, 3 bladder orthotopic reconstruction in women 33. chiang ph, huang ys, wu wj, et al. orthotopic bladder substitution in women using the ileal neobladder. j formos med assoc. 2000; 99:348-351. 34. hautmann re, volkmer bg, schumacher mc, et al. long-term results of standard procedures in urology: the ileal neobladder. world j urol. 2006; 24:305-314. 35. zippe cd, raina r, shah ad, et al. female sexual dysfunction after radical cystectomy: a new outcome measure. urology. 2004; 63:1153-1157. 36. modh ra, mulhall jp, gilbert sm. sexual dysfunction after cystectomy and urinary diversion. nat rev urol. 2014; 11:445-453. 37. gross t, meierhans ruf sd, meissner c, et al. orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. eur urol. 2015; 68:664-671. 38. cohn ja, large mc, richards ka, et al. cystectomy and urinary diversion as management of treatment-refractory benign disease: the impact of preoperative urological conditions on perioperative outcomes. int j urol. 2014; 21:382-386. 39. gobeaux n, yates dr, denys p, et al. supratrigonal cystectomy with hautmann pouch as treatment for neurogenic bladder in spinal cord injury patients: long-term functional results. neurourol urodyn. 2012; 31:672-676. 40. studer ue, burkhard fc, schumacher m, et al. twenty years experience with an ileal orthotopic low pressure bladder substitutelessons to be learned. j urol. 2006; 176:161-166. 41. webster gd, maggio mi. the management of chronic interstitial cystitis by substitution cystoplasty. j urol. 1989; 141:287-91. 42. peeker r, aldenborg f, fall m. the treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. j urol. 1998; 159:1479-82. 43. osman ni, bratt dg, downey ap, et al. a systematic review of surgical interventions for the treatment of bladder pain syndrome/interstitial cystitis. eur urol focus. 2020; s24054569(20)30071-7. 44. venn sn, mundy ar. 'nerve-sparing' cystectomy in women. int urogynecol j pelvic floor dysfunct. 2000; 11:237-40. 45. chiang ph, huang ys, wu wj, chiang cp. orthotopic bladder substitution in women using the ileal neobladder. j formos med assoc. 2000; 99:348-51. 46. chong jt, dolat mt, klausner ap, et al. the role of cystectomy for non-malignant bladder conditions: a review. can j urol. 2014; 21:7433-41. correspondence chiara borghi, md (corresponding author) borghi.chr@gmail.com margherita manservigi, md mnsmgh@unife.it elena sofia milandri, md elenasofia.milandri@gmail.com pantaleo greco, md, prof. pantaleo.greco@unife.it department of surgical sciences, section of obstetrics and gynecology, azienda ospedaliero-universitaria sant' anna, university of ferrara, via aldo moro 8, 44124 cona (ferrara), italy carmelo ippolito, md c.ippolito@ospfe.it department of surgical sciences, section of urology, azienda ospedaliero-universitaria sant' anna, university of ferrara, via aldo moro 8, 44124 cona (ferrara), italy dell’atti, md, phd dellatti@hotmail.com division of urology, department of clinical, special and dental sciences, university hospital "ospedali riuniti" school of medicine, marche polytechnic university via conca 71, 60126 ancona (italy) stesura seveso 199archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. altering dna and the acrosomal reaction, and other factors (8-14). however, these results should be interpreted cautiously because the semen of both fertile and infertile men contains microbiota, mainly bacterial (8). urogenital infections in men are less frequent than in women, although they can trigger chronic inflammatory processes such as prostatitis (15). clinically, prostatitis is classified into four types: i) acute bacterial prostatitis; ii) chronic bacterial prostatitis; iii) chronic pelvic pain syndrome; and iv) asymptomatic inflammatory prostatitis (16-18). chronic bacterial prostatitis is responsible for 5 to 10% of total prostatitis cases, and at least 30% of those involve recurrent urinary infections (18). it is estimated that 5 to 10% of acute genitourinary infectious and inflammatory processes end in chronic prostatitis (16). therefore, this work aimed to evaluate the effect of the presence of microorganisms in the semen on seminal quality and inflammatory markers. materials and methods study participants this project was approved by the bioethics committee for research in humans at the institute of medical research, medical school, university of antioquia (act number 006, april/2018). ten subjects with chronic prostatitis-like symptoms and eleven fertile donors asymptomatic for urogenital infections volunteered to participate to the study. the national institute of health of chronic prostatitis symptoms index (nih-cpsi) (19) translated and validated into spanish (20) was employed to select the volunteers according to the criteria reported by nickel et al. (21). the questionnaire contains 13 items that are scored in three discrete domains: pain, urinary symptoms, and the impact on quality of life. we considered as fertile donors those who had children under two years or their partner in pregnancy at study recruitment. to be included in the study they should have no history of any genitourinary symptoms, instrumentation, or surgery, and nih-cpsi total score lesser than 3. on the other hand, the inclusion criteria for the chronic prostatitis-like group were aged > 18 years and presence of prostatitis-like syndrome longer than three months (pain and/or discomfort in the perineum or on ejaculation) with a score in the pain domain of the nihobjective: chronic genitourinary infections can alter male fertility and even promote carcinogenic processes. this study aimed to evaluate the effect of the presence in the semen of microorganisms on semen quality. materials and methods: clinical symptoms and conventional and functional seminal parameters of eleven fertile donors and ten volunteers with prostatitis-like symptoms were evaluated. nitric oxide, antioxidant capacity, and pro-inflammatory cytokines in semen and seminal plasma samples were also quantified. finally, the expression of the ror-γt, foxp3, and t-bet genes in semen and the presence of dna of microorganisms associated with prostatitis in urine and semen were evaluated. results: when compared with fertile donors, volunteers with chronic prostatitis-like symptoms reported erectile dysfunction (0% vs. 10%, p = 0.2825) and premature ejaculation (0% vs. 40%; p = 0.0190). no statistically significant differences were observed in seminal parameters, cytokine measurement, antioxidant capacity, nitric oxide concentration and ror-γt, foxp3, t-bet. microorganisms responsible for sexually transmitted infections and some bacteria associated with the microbiota and infections in the prostate gland were detected. in the semen from the subjects with prostatitis-like symptoms t. vaginalis dna was detected; in addition, n. gonorrhoeae dna was also detected in semen and urine samples. s. pyogenes was detected in the urine samples from the control group. conclusions: prostatitis-like symptoms are a common finding in young men that affect sexual and reproductive health, but not always the seminal parameters or fertility. the presence of prostatitis-like symptoms does not affect seminal quality. however, it appears to be associated with an increased likelihood of erectile dysfunction and premature ejaculation. thus, affecting the quality of life and sexual and reproductive health. key words: prostatitis; fertility; infection; inflammation; seminal quality; sexual health. submitted 17 february 2022; accepted 7 april 2022 introduction frequent exposure of the prostate to infectious processes can promote chronic inflammation (1), alter fertility (24), and even promote cancer (5-7). the role of infection, microbiota and inflammation on male fertility is still controversial (8). in vitro studies have shown how microorganisms can affect sperm function by altering motility, inducing apoptosis, increasing reactive oxygen species, molecular analysis of microorganisms in the semen and their impact on semen parameters jenniffer puerta suárez 1, juan carlos hernandez 2, walter dario cardona maya 1 1 grupo reproducción, departamento de microbiología y parasitología, facultad de medicina, universidad de antioquia udea, medellín, colombia; 2 infettare, facultad de medicina, universidad cooperativa de colombia, medellín, colombia. doi: 10.4081/aiua.2022.2.199 summary archivio italiano di urologia e andrologia 2022; 94, 2 j. puerta suárez, j.c. hernandez, w.d. cardona maya 200 cpsi greater than 4. after agreeing with their participation in the study, all individuals were required to sign an informed consent. each volunteer gave a semen sample and a urine mid-stream sample. a blood sample was also taken by qualified personnel in a red vacutainer tube (becton dickinson, nj, usa) to obtain the serum. finally, participants also filled out a survey including information on sociodemographic factors, lifestyle, urinary symptoms, and relevant other aspects of sexual and reproductive health that allowed us to identify factors associated with prostatitis symptoms. semen collection and analysis semen samples were collected into a sterile sample cup through masturbation after sexual abstinence for 2 to 5 days. conventional seminal parameters volume, progressive motility, concentration, and sperm morphology were evaluated according to parameters established by the world health organization in the fifth edition of its human semen processing manual (22, 23). the sperm concentration was evaluated using the makler chamber (22, 23). functional seminal parameters sperm mitochondrial membrane potential (24), sperm membrane integrity (25), chromatin structure assay (26), sperm membrane lipoperoxidation (27), and intracellular levels of reactive oxygen species (ros) (24) were evaluated by flow cytometry (fortessa-becton dickinson, nj, usa), according to previously established protocols in our lab (24, 28, 29), and analyzing between 5,000 and 10,000 sperm cells. data were plotted and processed using the flowjo 7.6 (tree star, inc. oregon, usa). seminal plasma total antioxidant capacity evaluation three ml of dpph (2,2-diphenyl-1-picrylhydracil) were mixed with 200μl of the sample. after one hour of incubation, the sample was read in a spectrophotometer (spectronic 20 spectrophotometer®; genesys, rochester, ny, usa) at 515 nm, used ascorbic acid as a positive control (28, 29). nitric oxide determination nitric oxide quantification was performed using the commercial griess reagent kit for nitrite determination (molecular probes, oregon, usa) according to the manufacturer's instructions and after deproteinization of the semen and serum samples according to the serafini method (30) as previously reported (29). cytokine quantification quantification of il-12p70, il-10, il-1a, il-6, il-8, tnf, il-2, il-4, il-17, and ifn-a was performed by bd cytometric bead array (cba) in semen samples (human inflammatory cytokines kit, and human th1/th2/th17 cytokine kit, becton dickinson, nj, usa), and the analysis was carried out in the flowjo 7.6 as previously reported (29). forkhead box p3 transcription factor (foxp3), t-box 2 (t-bet), and retinoid-related orphan receptor gt (rorgt) mrna expression. total rna extraction was performed from 200 µl of semen sample using a commercial kit (qiagen rneasy mini kit, qiagen, hilden, germany). the rna was used to synthesize cdna using the commercial revertaid h minus first strand cdna synthesis kit (thermo fisher scientific, waltham, massachusetts, usa). with the cdna obtained, polymerase chain reactions were performed in real-time for the foxp3 (forward: 5-cagcacattcccagagttcctc-3; reverse: 5-gcgtgtgaaccagtggtagatc-3); ror-gt (forward: 5-ttttccgaggatgagattgc-3; reverse: 5ctttccacatgctggctaca-3), and t-bet (forward: 5-gcctacagaatgccgagattact-3; reverse: 5-ggatgc tggtgtcaacagatg-3) genes. the gene expression levels were normalized using lct with b-actin (31). bacterial detection in semen specimens by pcr assays dna extraction dna extraction was performed using the phenol-chloroform technique using 500 µl of the semen sample and the 10 ml urine pellet. briefly, the semen samples were centrifuged at 200g for 10 minutes, and the urine samples were centrifuged at 22000 g for 10 minutes. for each urine or semen sample, 0.5 ml of lysis solution (1m tris, 0.5m edta, 5m nacl, 10% sds, and 0.1% triton x-100) and 5 μl of proteinase k were added for 12 hours at 54°c. subsequently, 1 ml of phenol-chloroform-isoamyl was added, and it was centrifuged at 5000 g for 10 min. then, 1ml of absolute ethanol (-20°c), 50 µl of 3m sodium acetate was added to the recovered supernatant, and it was left at -20°c overnight to precipitate the dna. finally, it was washed with 1 ml of 70% ethanol; the ethanol was allowed to dry, the dna was diluted in 100 µl of dnase/rnase-free water and quantified in a nanodrop 2000 spectrophotometer (thermo scientific, massachusetts, usa). polymerase chain reaction the final 25μl reaction volume contained 12.5μl of master mix (thermo-scientific, massachusetts, usa), a solution containing 0.025 u/l of taq dna polymerase, 2 mm of mgcl2, and 0.2 mm of each dntp (datp, dctp, dgtp, and dttp), 0.2m of each primer, 2 µl of dna (200 ng), and 9.3 µl of water were added to each reaction. the pcr was carried out in a t3000 thermal cycler (whatman, biometra, goettingen, germany); cycling conditions consisted of an initial denaturation step at 94-95ºc for 5 min, followed by 35-40 cycles of specific conditions as previously, and a final elongation of 5-10 min at 72°c, using primers and following pcr conditions previously described (32) for b-actin (33), chlamydia trachomatis (34), escherichia coli (35), klebsiella pneumnoniae (36), lactobacillus spp (37), mycoplasma genitalium (34), neisseria gonorrhoeae (34), ochrobatrum atrophy (38), pseudomonas aeruginosa (36), staphylococcus aureus (36), staphylococcus epidermidis (39), streptococcus agalactiae (40), streptococcus pneumoniae (41), streptococcus pyogenes (42), treponema pallidum (34), trichomonas vaginalis (34), universal bacteria 27f y 1942r (43), ureaplasma urealyticum (44), herpes simplex virus i (34) and ii (34), and human papillomavirus (34). dna extracted from each bacterial strain or clinical isolates obtained from patients was a positive reaction control. lactobacillus spp. dna 201archivio italiano di urologia e andrologia 2022; 94, 2 prostatitis, semen parameters, and microorganisms was obtained from a woman's vaginal smear on day 14 of her menstrual cycle. serum prostate-specific antigen (psa) quantification according to the manufacturer's instructions, total serum psa quantification was performed using the commercial total psa kit (diametra, perugia, italy). psa values greater than 4 ng/ml were considered positive, as previously reported (29). statistical analysis a chi-square and a mann whitney test were used to compare both groups' dichotomous and numerical variables. the data were analyzed using the statistical program graph pad prism 6.0 (graphpad, san diego, ca, usa), and a value of p < 0.05 was considered significant. results eleven fertile donors (median age of 32 years) and ten chronic volunteers with prostatitis-like symptoms (median age of 39.5 years) (p = 0.5219) were included in the study (table 1). mean body mass index was similar in the two groups (fertile donors 25.7 vs. prostatitis-like subjects 23.4, p = 0.2299). only 40% of the prostatitis-like group were married or living with a partner, compared to 100% of the control group (p = 0.0099). erectile dysfunction (10%) and premature ejaculation (40%) were self-reported by the subjects with prostatitis-like symptoms (p = 0.2825 and p = 0.0190, respectively). in addition, 50% of subjects with prostatitis-like symptoms reported a history of chronic diseases and stress (p = 0.0072 and p = 0.0382), and 70% reported feeling anxiety (p = 0.0166) associated with their symptoms. three subjects with prostatitis-like symptoms were excluded from the seminal quality analysis because they reported being vasectomized. no statistically significant differences were found on other sexual health and reproductive aspects evaluated, nor on conventional or functional seminal parameters evaluation. no differences were found between groups in seminal plasma antioxidant capacity, plasma/serum nitrites concentration, or psa determinations (table 2). the il-12p70, il-10, il-1b, il-6, il-8, tnf, il-2, il-4, il17, ifn-g cytokines concentrations were evaluated in serum and seminal plasma samples without finding differences (table 3). table 1. sociodemographic characteristics. characteristics control group n = 11 prostatitis group n = 10 p-value children 100 40 0.0034 education level 0.1005 high school 9.1 0 technician 0 10 university 18.2 60 postgraduate 72.7 30 marital status 0.0099 unmarried 0 50 married 100 40 divorced 0 10 number of sexual partners 0.5250 none 0 10 one to three 36.4 40 more than three 63.6 50 type of sex masturbation 63.6 70 0.7574 vaginal 100 60 0.0197 oral 63.6 60 0.8639 anal 0.2568 insertive 36.4 40 0.5366 receptive 0 20 0.1189 condom use 0.3580 always 0 10 frequently 18.2 20 rarely 64.6 30 never 18.2 40 chi-square. data indicate percentage. table 2. seminal parameters, nitric oxide concentration and serum psa. parameters control group prostatitis group p-value volume (ml) 2.0 (1.5-4.7) 3.5 (1.5-11.8) 0.4556 progressive motility (%) 49.0 (19.0-81.0) 49.0 (6.0-67.0) 0.7414 concentration/ml 100.0 (40.5-270.0) 182.0 (7.0-254.0) 0.3269 viability (%) 79.0 (76.0-91.0) 82.0 (49.0 -85.0) 0.8485 normal morphology (%) 5.2 (4.2-8.7) 4.6 (4.2-7.0) 0.3874 teratozoospermia index 1.25 (1.10-1.52) 1.18 (1.12-1.37) 0.4091 high mitochondrial membrane potential (%) 61.3 (33.5-73.5) 66.6 (12.3-75.5) 0.3167 plasma membrane integrity (%) 63.9 (37.8-84.4) 63.1 (12.1-70.0) 0.8095 ros production (%) 63.0 (34.8-86.2) 56.9 (17.7-66.8) 0.3612 dna fragmentation index (%) 10.9 (10.4-14.9) 10.6 (10.3-14.3) 0.5795 membrane lipoperoxidation (%) 66.8 (9.1-93.3) 71.1 (44.9-96.9) 0.3269 total antioxidant seminal plasma capacity (%) 61.0 (22.1-81.4) 62.3 (9.5-69.7) > 0.9999 seminal plasma nitric oxide concentration (nitritos µm) 1.25 (0.55-11.7) 0.55 (0.23-2.16) 0.1384 serum nitric oxide concentration (nitritos µm) 4.6 (1.6-13.0) 2.8 (1.2-7.4) 0.1728 serum psa (ng/ml) 0.0 (0.0-18.1) 0.45 (0.0-120.0) 0.3292 mann whitney test. data presented as median and range. ros: reactive oxygen species; psa: prostatic-specific antigen. table 3. detection of cytokines in seminal plasma and serum. cytokine control prostatitis-like p-value pg/ml symptoms seminal plasma il-12p70 0 (0-68.9) 8.5 (0-107.5) 0.5907 il-1β 0 (0-36.8) 2.7 (0-31.53) 0.7260 il-6 8.9 (0-86.9) 7.1 (0-101.9) 0.9159 il-8 1808 (0-4202) 1692 (680.4-4334) > 0.999 tnf 0 (0-83.8) 24.7 (0-127.5) 0.1553 il-2 3.9 (0-23.5) 11.4 (4.3-45.7) 0.2940 il-4 0 (0-13.7) 0 (0-19.3) 0.1454 il-10 0 (0-26.7) 1.3 (0-19.3) 0.9113 il-17 9.3 (0-73.1) 6.6 (0-429.9) 0.8749 ifn-γ 0 (0-5.9) 0 (0-33.5) 0.6084 serum il-12p70 0 (0-304.3) 0 (0-95.1) > 0.9999 il-1β 0 (0-54.3) 0 (0-2.7) 0.3246 il-6 0 (0-15.6) 0 (0-14.9) 0.2479 il-8 23.6 (0-301.3) 9.6 (0-66.1) 0.6668 tnf 0 (0-92.7) 0 (0-30.4) 0.3128 il-2 4.9 (2.1-36.0) 8.2 (4.1-47.3) 0.2439 il-4 0 (0-19.4) 0 (0-27.0) 0.3128 il-10 0 (0-10.5) 0 (0-13.1) 0.5573 il-17 0 (0-182.7) 9.9 (0-85.6) 0.2757 ifn-γ 0.3 (0-12.8) 1.3 (0-6.3) 0.6476 mann whitney. data presented as median and range. archivio italiano di urologia e andrologia 2022; 94, 2 j. puerta suárez, j.c. hernandez, w.d. cardona maya 202 figure 1. ror-gt, foxp3 and t-bet genes expression. figure 2. stis dna detection. figure 3. dna detection from other bacteria associated. 203archivio italiano di urologia e andrologia 2022; 94, 2 prostatitis, semen parameters, and microorganisms we also found no statistical difference in the expression of ror-gt, foxp3, and t-bet genes in semen samples (figure 1). finally, we detected microorganisms responsible for stis (figure 2) and some bacteria associated with the microbiota and infections of the prostate gland (figure 3). t. vaginalis dna was detected in 40% of the semen samples of the subjects with prostatitis-like symptoms (p = 0.0197). furthermore, n. gonorrhoeae dna was detected in in 50% and 40% of semen and urine samples of this group (p = 0.0072 and p = 0.0197). s. pyogenes was detected in 45.5% of the urine samples from the control group volunteers (p = 0.0146). discussion male factor is responsible in 50% of infertility cases, highlighting urogenital infections as the leading causes (8, 45). urinary tract infections are the most common type of infection in humans, with an estimated annual prevalence of 150 million, representing a high financial impact (46). in men, urogenital infections are a risk factor for prostatitis development, a disease that dramatically impacts mental and sexual health and quality of life (19, 47). chronic prostatitis is a common but poorly understood disease that affects men of any age regardless of their geographical origin (15, 21). prostatitis has been associated with detriments in seminal quality and affects male fertility (4). in the present study, the seminal quality of fertile donors asymptomatic for urogenital infections was compared with that of men with symptoms of chronic prostatitis without finding significant differences in the conventional or functional parameters. volunteers with prostatitis-like symptoms had 75 and 82% greater semen volume and concentration than the control group of fertile donors, although the difference did not reach statistical relevance. similar findings were obtained by shang et al. (18). n. gonorrhoeae and t. vaginalis were detected more frequently in volunteers with prostatitis-like symptoms. both were also observed in the semen of infertile men being globally prevalent although easily treatable (48). in addition, the genome of other microorganisms, as propionibacterium acnes, was frequently observed in the semen and urine of patients with recurrent urinary tract infections (49), and the presence of t. vaginalis in the urogenital tract was also associated with an increase of the risk of prostate cancer (50). in fact, there is a close relationship between urogenital infections and prostate cancer. it is estimated that one in five neoplasms could be attributed to microorganisms (1), and prostatitis was considered as a risk factor for cancer development (7, 51). however, microorganisms are not a synonymous of disease, because it has been described that the microbiota modulates the immune system; for example, lactobacillus spp. is a protective factor in prostatitis (52). on the other hand, in chronic pelvic pain syndrome animal models, infiltration of macrophages and cd4+ t cells has been observed, which according to the local microenvironment, can differentiate into th1, th2, th17, or treg (regulatory) cells (7). chronic prostatitis patients show specific th1 and th17 immune responses to prostate antigen associated with chronic inflammation of the male genital tract, which may be the basis for the induction and development of chronic pelvic pain (53). among the t cell subpopulations are treg cells that secrete transforming growth factor b (tgf-b) and il-10 and express the foxp3 transcription factor. th17 lymphocytes secrete il-17 and il-22 and express the transcription factor ror-gt with a critical role in infections and tumors. th1 cells secreting ifn-g cytokines, il-2 and tnf-a express the transcription factor t-bet and are essential in developing autoimmune prostatitis (7). activation of th1 and th17 profiles inhibits treg cells' action, promoting the appearance of chronic pelvic pain (7). therefore, we assessed in semen samples the mrna expression of lineage-specifying transcription factors foxp3, t-bet, and rorg-t. furthermore, although we evaluated several essential aspects of sexual and reproductive health and lifestyle, other variables not evaluated in this study including the impact of ejaculation delayed and intercourse interruptions, were described as risk factors for chronic prostatitis (54). even urinary retention and anxiety are risk factors for chronic prostatitis (7). however, this is an excellent approach to evaluating prostatitis's effect on male fertility and understanding the relationship between the urogenital microbiota, infection, and inflammation. the present study is an interesting approach, as a baseline, to understand the impact on the fertility of chronic prostatitis. although prostatitis does not seem to alter the seminal quality, it seems to impact on fertility by promoting the appearance of other diseases such as erectile dysfunction and premature ejaculation. however, a limitation of the present study is the limited number of subjects included in the study could explain the lack of difference observed in the comparison of microbiology and immune response between controls and subjects with prostatitis-like symptoms. conclusions although chronic prostatitis is a disease that affects the quality of life, it does not appear to affect seminal parameters. however, chronic prostatitis seems to be related to alterations in sexual function, such as premature ejaculation and erectile dysfunction. acknowledgments the authors acknowledge the valuable contributions of the volunteers. puerta-suárez j was supported by a fellowship from minciencias (785-2017). references 1. miyake m, ohnishi k, hori s, et al. mycoplasma genitalium infection and chronic inflammation in human prostate cancer: detection using prostatectomy and needle biopsy specimens. cells. 2019; 8:212. 2. xu c, sun gf, 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androl. 2022; 94:62. 50. aglamis e, ceylan c, akin mm. is there a correlation between the aggressiveness of chronic asymptomatic prostatitis national institutes of health category iv and the gleason score in patients with prostate cancer? can urol assoc j. 2020; 14:e568. 51. perletti g, monti e, magri v, et al. the association between prostatitis and prostate cancer. systematic review and meta-analysis. arch ital urol androl. 2017; 89:259. 52. cai t, gallelli l, cione e, et al. the use of lactobacillus casei dg® prevents symptomatic episodes and reduces the antibiotic use in patients affected by chronic bacterial prostatitis: results from a phase iv study. world j urol. 2021; 39:3433-3440. 53. zhang m, liu y, chen j, et al. single-cell multi-omics analysis presents the landscape of peripheral blood t-cell subsets in human chronic prostatitis/chronic pelvic pain syndrome. j cell mol med. 2020; 24:14099. 54. li hj, kang dy. prevalence of sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome: a meta-analysis. world j urol. 2016; 34:1009. correspondence jenniffer puerta suárez jenniffer.puerta@udea.edu.co grupo reproducción, departamento de microbiología y parasitología, facultad de medicina, universidad de antioquia, medellín (colombia) juan carlos hernandez juankhernandez@gmail.com infettare, facultad de medicina, universidad cooperativa de colombia, medellín (colombia) walter dario cardona maya (corresponding author) wdario.cardona@udea.edu.co grupo reproducción, departamento de microbiología y parasitología, facultad de medicina, universidad de antioquia, medellín (colombia) cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 112 original paper no conflict of interest declared. 60% in some reports (2). increased diagnosis of earlystage, incidental renal tumors in tandem with advances in surgical techniques preventing ischemic renal damage and current oncologic outcomes equivalent to the results of radical nephrectomy (rn) at medium-long term, have increased interest in partial nephrectomy (pn) worldwide. however, the risk of postoperative complications is higher in patients who have undergone pn compared to rn (3). among these, postoperative urine leakage is a clinically important complication, adversely affecting patient recovery, and is reported to occur in 0.8% to 15.2% of the patients (4-7). inadequate repair of a collection system during deep layer renorraphy is the main cause of urine leakage. ureteral catheterization during pn has been applied to obviate this risk and to visualize an opened renal calyx for closure and impact on urinary leakage after pn has been fully established (7-9). for each patient double j stent (djs) ureteral catheterization in our clinic is at the surgeon's own discretion. in this study, the usefulness of djs placement in detecting and preventing urinary leakage during open pn (opn) was assessed retrospectively. materials and methods patients after the ethical committee board approval, we designed a retrospective study for opn patients performed between 2002 and 2020 for localized rcc at our center. due to limited access to the previous hospital patient record system, patients who underwent opn between 1996 and 2001 were excluded. the analysis was done with a total of 182 patients. pathological and clinical variables patient demographics included age, gender, comorbidities (presence of diabetes mellitus and hypertension), estimated glomerular filtration rate (egfr), american society of anesthesiology (asa) score, incidence of solitary kidney, and charlson comorbidity index (cci). to assess tumor complexity renal score was used, which considers the size, location, depth, and exophytic characteristics of the tumor. the renal score is categoobjective: to evaluate the impact of double j stent (djs) insertion during open partial nephrectomy (opn) on postoperative prolonged urinary leakage. materials and methods: a retrospective study was made in consecutive cases of opn performed between 2002 and 2020 for localized kidney tumors at our tertiary center. urinary leakage was defined as drainage > 72 hours after surgery by biochemical analysis consistent with urine or radiographic evidence of urine leakage. the patients were divided into two groups according to intraoperative djs placement, and compared regarding clinicopathologic characteristics, perioperative and postoperative outcomes. univariate and multivariate logistic regression analyses were performed to determine the factors associated with urinary leakage after the operation. results: review of records identified 182 patients who were included in the study. in 73 (40%) patients pn was performed without insertion of a djs. thus, 109 (60%) of patients had a djs inserted. apart from higher preoperative egfr values among patients with djs (96.6 vs. 94.3 ml/min/1.73 m²; p = 0.03), demographic characteristics were similar between groups. the two groups were not different regarding perioperative, postoperative and clinicopathologic outcomes. patients with djs had longer ischemia times (31 vs. 23 min; p = 0.02) and longer length of stay (6 vs. 5 days; p = 0.04). urinary leakage was seen in 7.6% (n = 14) of all patients and it did not differ according to djs placement (djs+ 9.2 vs. djs5.5%; p = 0.41). on multivariate analysis, the tumor nearness to the collecting system was the sole independently significant factor (p = 0.04) predicting postoperative urine leak. conclusions: routine intraoperative djs insertion during opn does not appear to reduce the probability of postoperative urine leak. key words: kidney tumor; double j stent; urine leakage; partial nephrectomy. submitted 5 february 2022; accepted 10 february 2022 introduction kidney tumors are the third most common type of cancer among the urological malignancies and constitute 23% of adult cancers (1). following rapid developments in imaging techniques and their more widespread use, incidental detection of renal tumors has increased to does routine intraoperative double j stent insertion avoid urine leakage after open partial nephrectomy? efe bosnali 1, ozdal dillioglugil 1, kerem teke 1, hasan yilmaz 1, busra yaprak bayrak 2, ali kemal uslubas 1, ibrahim erkut avci 1, omer burak argun 3, onder kara 1 1 kocaeli university, school of medicine, department of urology, kocaeli, turkey; 2 kocaeli university, school of medicine, department of pathology, kocaeli, turkey; 3 acibadem mehmet ali aydinlar university, department of urology, school of medicine, istanbul, turkey. doi: 10.4081/aiua.2022.1.12 summary 13archivio italiano di urologia e andrologia 2022; 94, 1 use of double j stent during partial nephrectomy rized as low score (4-6), moderate score (7-9), and high score (10-12). tumor characteristics considered included tumor size, pathological t stage, histology (including subtype), and fuhrman-isup grade. nuclear tumor grading was performed using fuhrman-isup nuclear grading system and grades were classified as low grade (1-2) and high grade (3-4). all histological specimens were analyzed by our institution’s dedicated urological pathologists. main intraoperative parameters such as insertion of djs, operation time, cold and warm ischemia time (cit, wit), estimated blood loss (ebl), intraoperative blood transfusion and complication rates were recorded. postoperative variables included were 30-day postoperative complication rate, length of hospital stay, and 30-day readmission rate. clavien-dindo classification system (10) was used for grading complications that were characterized as minor complications (clavien 1-2) and major complications (clavien 3-5). preoperative and postoperative functional results were assessed by using serum creatinine, and mdrd formula to calculate egfr (11). egfr preservation was defined as follow-up postoperative egfr divided by preoperative egfr x 100. chronic kidney disease (ckd) was defined as gfr < 60 ml/min/1.73m2. surgical technique in most patients, djs was inserted immediately after induction in the lithotomy position. under the cystoscopy guidance 4.8 french djs placement through guidewire was performed under fluoroscopic guidance. in a small proportion of these patients djs insertion was performed immediately after pn at the surgeon’s discretion. in the remaining patients pn was performed without insertion of djs. we used extraperitoneal flank approach. ice slush was used for parenchymal cooling in almost all cases. in a small proportion of the cases non-ischemic pn was performed without clamping the renal artery. during pn, all renal tumors were excised with sufficient resection margin. the defect was closed with two layers of suture method, one to close the bleeding vessels and collecting system, the other to approximate the parenchyma over reconstructed fat pad (12). a single surgical drain (jackson-pratt drain) was inserted at the operative site. in patients who had intraoperative dj stent placement, urethral catheter was removed at postoperative (po) 5th day. in these patients, the jackson-pratt was removed next day if the drain output was not increased after a day period of ureteral urine reflux within the dj stent during active voiding. this was a kind of dj stent reflux test developed by one of us (od) to make sure that the collecting system was completely closed. in other cases, the jackson-pratt was removed on the 3rd po day, provided that the output was less than 50 cc per 24 hours. outcomes urinary leakage was defined as a biochemical analysis consistent with urine persisting for more than 72 hours and/or a radiology finding suggestive of urine leakage. as a routine procedure, in patients with no complications, djss were removed from the patients on the third week after surgery under local anesthesia. for the purposes of this study, according to intraoperative djs placement, the patients were divided into two groups. perioperative postoperative outcomes, and clinicopathologic characteristics were compared between the two groups (djs+ vs. djs-). furthermore, to determine the variables associated with urinary leakage after opn, univariate and multivariate logistic regression analyses were performed. statistical analysis for variables with normal distribution, the data are expressed as mean ± sd. chi-squared test was used to compare categorical variables. for non-normal distributed variables, we presented the data as median [interquartile range (iqr)] and compared the respective groups with mann-whitney u-test. all analyzes were made within 95% confidence interval and the p < 0.05 value was accepted as significant. for the analysis spss v23 (ibm spss statistics, armonk, ny, usa) was used. results in the analysis, a total of 182 patients were included. opn was technically successful in all cases using a retroperitable 1. patient’s demographics, tumor characteristics, and surgical outcomes. variables total open partial nephrectomy (n = 182) age years; mean (± sd) 54.4 (± 10.8) male; n (%) 79 (43.4) white race; n (%) 182 (100) bmi; mean (± sd) 28.3 (± 5.3) cci; med (iqr) 1 (0-1) asa; med (iqr) 2 (2-2) diabetes; n (%) 51 (28) hypertension; n (%) 90 (49.5) prior abdominal surgery; n (%) 48 (26.4) solitary kidney; n (%) 6 (3.3) pre-op egfr; med (iqr) 96 (82.4-105.9) r.e.n.a.l score; med (iqr) 6 (5-8) tumor size, cm; mean (±sd) 3.1 (± 1.2) surgical approach; n (%) retroperitoneal 180 (98.9) operation time, min; med (iqr) 240 (180-240) double-j stent; n (%) 109 (60) routinely (pre-pn) 95 (52.3) as required (post-pn) 14 (7.7) none 73 (40) ebl, ml.; med (iqr) 400 (300-600) technique of ischemia; n (%) warm 15 (8.2) cold 161 (88.5) zero 6 (3.3) ischemia time, minutes; mean (±sd) 26.1 (± 7.7) intraoperative complication; n (%) 10 (5.5) intraoperative transfusion; n (%) 52 (28.6) urine leak; n (%) 14 (7.6) length of stay, days; med (iqr) 5 (4-7) follow up times, months.; med (iqr) 42 (21.3-84.6) asa: american society of anesthesiologists; bmi: body mass index; cci: charlson comorbidity index; egfr: estimated glomerular filtration rate; ebl: estimated blood loss; iqr: interquartile range; opn: open partial nephrectomy; sd: standard deviation. archivio italiano di urologia e andrologia 2022; 94, 1 e. bosnali, o. dillioglugil, k. teke, et al. 14 toneal approach. of these, 95 (52.3%) had djs insertion immediately after induction of general anesthesia, 14 (7.7%) had djs inserted immediately after performance of the opn while in the other 73 (40%) patients pn was performed without insertion of a djs. thus, 109 (60%) of patients had a djs inserted. table 1 summarizes the main demographical and clinical outcomes for the entire series. apart from higher preoperative egfr values among patients with djs+ compared to the djs(96.6 vs 94.3 ml/min; p = 0.03), demographic variables were similar (table 2). no statistically significant differences were seen in renal nephrometry score (p = 0.26) and tumor size (p = 0.26). tumors in the djs+ group presented with a high l score (p = 0.04). between the two groups estimated blood loss (p = 0.12), intraoperative complication (p = 0.71), and transfusion rates (p = 0.4) were not significantly different (table 3). patients in the djs+ group had significantly longer ischemia times (31 vs. 23 min; p = 0.02). in addition, djs+ group patients had a longer length of stay due to reflux test (6 vs. 5 days; p = 0.04). postoperative (p = 0.74) complication rates were similar between groups (p = 0.74) (table 3). urinary leakage was seen in 7.6% (n = 14) of all patients, and it did not differ according to djs placement (djs+ 9.2 vs. djs5.5%; p = 0.41). on univariate analysis, neither djs stenting rates nor urine leakage rates were associated with distribution of cases by years (supplementary table 1). on univariate analysis, renal nephrometry score (or= 1.39; p = 0.04) and tumor nearness (proximity) to the collecting system (p = 0.04) had a significantly higher probability of experiencing urine leak (table 4) whereas it was observed that intraoperative djs placement did not have significant effect on urine leak (or = 1.74; p = 0.36). on multivariate analysis, the tumor nearness to the collecting system was the sole independently significant factor (p = 0.04) predicting postoperative urine leak. table 2. comparison of patients and tumor characteristics between pre-pn double-j insertion and no insertion populations. djs+ (n = 109) djs(n = 73) p value age, years; mean (± sd) 53.8 (±10.9) 55.3 (±10.8) 0.38 male; n (%) 59 (54.1) 44 (60.3) 0.44 bmi; mean (±sd) 28.1 (±5.8) 28.7 (4.5) 0.54 cci; med (iqr) 1 (0-1) 1 (0-2) 0.09 asa; med (iqr) 2 (2-2) 2 (2-2) 0.8 diabetes; n (%) 33 (30.3) 18 (24.7) 0.5 hypertension; n (%) 55 (50.4) 35 (47.9) 0.8 prior abdominal surgery; n (%) 27 (24.8) 21 (28.8) 0.6 solitary kidney; n (%) 3 (2.8) 3 (4.1) 0.6 pre-op egfr; med (iqr) 96.6 (87.2-107.3) 94.3 (78.8-101) 0.03 tumor size, cm; mean (± sd) 3.2 (±1.1) 3 (±1.3) 0.26 side, right; n (%) 67 (60.5) 43 (58.9) 0.7 cystic lesion; n (%) 30 (33) 16 (33.3) 1 hilar location; n (%) 2 (2.3) 2 (4.5) 0.6 r.e.n.a.l score; med (iqr) 6 (5-8) 5 (5-7) 0.26 r.e.n.a.l complexity; n (%) simple (4-6) 53 (60.2) 28 (65.1) intermediate (7-9) 33 (37.5) 15 (34.9) 0.5 complex (10-12) 2 (2.3) 0 (r)adius, max diameter in cm; n (%) ≤ 4 87 (80.6) 59 (83.1) > 4 but < 7 20 (18.5) 20 (15.5) 0.8 ≥ 7 1 (0.9) 1 (0.6) (e)xophytic/endophytic; n (%) ≥ 50% 42 (47.7) 25 (58.1) < 50% 41 (46.6) 16 (37.2) 0.5 entirely endophytic 5 (5.7) 2 (1.5) (n)earness of the tumor to pelvicalyceal system or renal sinus; mm ≥ 7 41 (46.6) 18 (41.9) > 4 but < 7 26 (29.5) 15 (34.9) 0.8 ≤ 4 21 (23.9) 10 (23.3) (l)ocation relative to the polar lines, points; n (%) 1 45 (51.1) 26 (60.5) 2 21 (23.9) 14 (32.6) 0.04 3 22 (25) 3 (2.3) asa: american society of anesthesiologists; bmi: body mass index; cci: charlson comorbidity index; egfr: estimated glomerular filtration rate; iqr: interquartile range; opn: open partial nephrectomy; sd: standard deviation. table 3. comparison of pre-pn double-j insertion and no insertion populations. djs+ (n = 109) djs(n = 73) p value intraoperative variables operation time, min; med (iqr) 240 (180-240) 220 (180-220) 0.3 ebl, ml.; med (iqr) 400 (300-525) 500 (262-900) 0.12 ischemia time, min; mean (± sd) 31 (± 5.9) 23 (± 7.4) 0.02 use of hemostatic agents; n (%) 11 (10.1) 6 (8.2) 0.79 intraoperative complication; n (%) 7 (3.8) 3 (4.1) 0.71 intraoperative transfusion; n (%) 29 (26.6) 23 (31.5) 0.4 postoperative variables length of stay, days; med (iqr) 6 (5-7) 5 (4-6) 0.04 postoperative transfusion; n (%) 7 (6.4) 7 (9.6) 0.57 es units; med (iqr) 2 (1-3) 2 (1-2) need for post-op angioembolisation, n (%) 1 (0.9) 1 (1.4) 0.64 overall post-op complications; n (%) 31 (28.4) 23 (31.5) 0.74 major (clavien-dindo 3-5) 6 (5.4) 7 (9.4) minor (clavien-dindo 1-2) 25 (23) 16 (22.1) acute kidney injury; n (%) 13 (12) 14 (19.7) 0.16 readmission for urologic reasons; n (%) 7 (6.4) 4 (5.4) 0.81 < 30 days 4 (3.6) 3 (4.1) ≥ 30 days 3 (2.2) 1 (1.3) urine leak; n (%) 10 (9.2) 4 (5.5) 0.41 malignant disease; n (%) 89 (81.7) 56 (80) 0.84 pathological tumor stage; n (%) 0.1 t1a 91 (85) 56 (82.4) t1b 16 (15) 8 (11.8) t2a 0 1 (1.5) t3a 0 3 (4.4) positive surgical margin; n (%) 4 (3.7) 1 (1.4) 0.1 fuhrman/isup grade; n (%) 0.36 low fg (1-2) 68 (80) 47 (87) high fg (3-4) 17 (20) 7 (13) follow up times, months; med (iqr) 27.7 (12.6-53.4) 51 (9.1-113) 0.02 latest egfr; med (iqr) 89 (70.4-102.9) 83.7 (70.7-96) 0.16 latest follow up egfr preservation; % med (iqr) 93.1 (82.2-99.3) 92.3 (80-99.6) 0.94 ebl: estimated blood loss; es: erythrocyte suspension; fg: fuhrman grade; isup: international society of urological pathology; egfr: estimated glomerular filtration rate; iqr: interquartile range; sd: standard deviation.. 15archivio italiano di urologia e andrologia 2022; 94, 1 use of double j stent during partial nephrectomy discussion the rcc incidence has increased in the last four decades; beginning from the mid 90's there has been a more rapid increase in diagnosis (13). pn is the preferred method in the treatment of small renal tumors (1) and the clinical target is to leave as much functional renal parenchyma as possible, without obviating the oncological principles. with increasing surgical experience, larger and deeper infiltrating lesions were also approached, requiring surgical access to the pelvicalyceal system to ensure adequate margins of tumor resection. incomplete repair of the collecting system during renorraphy causes urine leak which most probably results in considerable morbidity (14-17). in this study, we evaluated the impact of intraoperative routine djs placement on urinary leakage after opn. the incidence rate of urine leakage reported after pn varies between institutions. in the current study, urinary leakage occurred in 7.6% of the patients. in early opn series the rate of urine leakage was reported to average 6.5%, ranging from 2.1-17% (18, 19). in the new pn series, the rate of urine leakage is around 1-5% (15, 20, 21). the clinical management of urine leakage after pn varies from patient to patient (22). follow-up with serial imaging options is the most preferred approach. another option, ureteral stent insertion, creates a low-pressure system facilitating urine drainage from the collection system and that promotes healing. patients may need percutaneous drainage or repeat surgical intervention when they have complex urine leaks (23). in addition, minimally invasive techniques are a safe option to resolve urinary leakage after pn. application of gelatin sponge (spongostan®) and n-butyl2 cyanoacrylate improves results without increasing the risk of urinary obstruction, especially in the cases of persistent urine leakage (24). in the present study, preoperative djs placement did not significantly reduce the incidence of urinary leakage after pn. for each patient djs ureteral catheterization in our clinic is at the surgeon's own discretion. as described above, preoperative djs placement was a part of djs reflux test to make sure that the collecting system was completely closed. in patients who had positive djs reflux test (increased drain urine output following foley removal), a new foley catheter was placed again to wait for sufficient time for the self-sealing of the collecting system, during which a number of intervals retrograde testing pyelography were performed. it was observed that use of a djs, which was usually placed as a treatment when a urinary leak developed, did not prevent urinary leakage when applied before surgery. at the same supplementary table 1. distribution of urine leakage and dj stenting by years. variables urine leakage (+) urine leakage (-) p value djs (-) djs (+) p value 14 (7.6%) 168 (92.4%) 73 (40.1%) 109 (59.9%) total cases 0.8 0.1 2002 (n = 1) 0 1 (100) 1 (100) 0 2004 (n = 2) 0 2 (100) 2 (100) 0 2006 (n = 4) 0 4 (100) 4 (100) 0 2007 (n = 3) 0 3 (100) 3 (100) 0 2008 (n = 9) 1 (11.1) 8 (88.9) 3 (33.3) 6 (66.6) 2009 (n = 7) 0 7 (100) 3 (42.8) 4 (57.2) 2010 (n = 6) 0 6 (100) 3 (50) 3 (50) 2011 (n = 9) 1 (11.1) 8 (88.9) 3 (33.3) 6 (66.6) 2012 (n = 13) 1 (7.7) 12 (92.3) 6 (46.2) 7 (53.8) 2013 (n = 8) 2 (25) 6 (75) 3 (37.5) 5 (62.5) 2014 (n = 11) 2 (18.2) 9 (81.8) 4 (36.3) 7 (63.7) 2015 (n = 15) 2 (13.3) 13 (86.7) 5 (33.3) 10 (66.6) 2016 (n = 14) 0 14 (100) 5 (35.8) 9 (64.2) 2017 (n = 18) 1 (5.6) 17 (94.4) 6 (33.3) 12 (66.6) 2018 (n = 28) 2 (7.1) 26 (92.9) 8 (29.6) 20 (71.4) 2019 (n = 30) 2 (6.7) 28 (93.3) 12 (40) 18(60) 2020 (n = 4) 0 4 (100) 2 (50) 2 (50) table 4. logistic regression analysis for predicting urine leakage after partial nephrectomy. univariate multivariate or 95 % ci p value or 95 % ci p value age 1.05 0.97-1.08 0.15 1.02 0.97-1.08 0.34 female ref male 1.02 0.34-3.08 0.96 bmi (continuous variable) 0.93 0.82-1.07 0.35 tumor size (per cm) 1.18 0.80-1.74 0.39 baseline egfr (per ml/min/1.73m2) 0.99 0.97-1.02 0.9 ischemia time (per min) 1.07 0.82-1.39 0.6 pre-op hypertension 1.04 0.38-1.14 0.97 pre-op diabetes mellitus 1.03 0.3-3.4 0.96 cci = 0 ref cci > 0 1 0.33-3 1 r.e.n.a.l score (continuous variable) 1.39 1.00-1.93 0.04 exophytic/endophytic 0.88 ≥ 50% ref < 50% 1.19 0.36-3.9 entirely endophytic 1.69 0.17-16.5 nearness 0.04 0.04 ≥ 7 ref ref > 4 but < 7 9.9 1.14-86.5 0.03 9.8 1.14-85.9 0.03 ≤ 4 13.9 1.5-121.7 0.01 15.7 1.76-140.7 0.01 location, relative to polar lines 1 ref 2 1.39 0.36-5.3 3 1.47 0.34-6.4 double j stent + (vs. -) 1.74 0.52-5.7 0.36 estimated blood loss (continuous variable) 1 0.99-1 0.8 ischemia time, (continuous variable) 1.07 0.82-1.39 0.6 intraoperative transfusion+ 1.98 0.65-6.04 0.2 bmi: body mass index; cci: charlson comorbidity index; egfr: estimated glomerular filtration rate. archivio italiano di urologia e andrologia 2022; 94, 1 e. bosnali, o. dillioglugil, k. teke, et al. 16 time, although not statistically significant, djs inserted patients tended to have more urinary leakage compared to the group that was not inserted although the difference was not significant. it could be suggested that making a preoperative clinical decision to place a djs, based on surgeon preference and tumor complexity, may create a bias in the analysis. however, we believe that there is no such bias because of both groups are comparable in terms of patient and tumor characteristics. during pn routine ureteral catheterization has been used to reduce the risk of urine leakage in open, laparoscopic, and robotic cases (7, 9, 25-27). in these studies, it was reported that ureteral catheterization did not reduce the risk of urinary leakage after pn. common feature for these studies, and the difference between these and our study, was that if there was no evidence of urinary leakage, the ureteral catheter was generally removed within two days postoperatively. as far as we know, we report the first study to evaluate the impact of intraoperatively inserted long term djs on urinary leakage after pn. our results showed that opn patients who had a djs inserted can safely be discharged because the rate of urine leakage is similar in these patients compared to patients who did not have. we found that urine leakage following opn was associated with tumor characteristics, rather than djs insertion, consistent with previous reports (5, 28). in our multivariate analysis, nearness of the tumor to the collecting system was the sole independently significant factor predicting urine leakage. this is intuitively reasonable and is thus not an unexpected result. in a considerable proportion of the operations it is not possible to completely remove these tumors without entering the collecting system; inherently, likelihood of later urine leakage increases in such cases. this relationship has been reported previously (15, 29). our study does have some limitations, including its retrospective, non-randomized, single institution design. in addition, as there was a small number of events, multivariable analysis was limited. therefore, our results need to be verified in a large, prospective, multi-institutional studies. in addition, our findings may have limited applicability to other settings because opn was performed using a single technique. in this context, the effect of surgical technique should also be evaluated in any future study. despite these limitations, and although generally not used routinely and mostly used only for therapeutic purposes in the presence of urinary leak, we think our results answer the question of the association between routine djs application in opn and the risk of urinary leakage. conclusions routine intraoperative djs insertion during pn does not appear to reduce the probability of postoperative urine leak. it causes additional costs and does not eliminate the risk of urine leakage but may provide a reasonable means to test urine leakage (djs reflux test) which allows for safety foley catheter reinsertion before the 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ac, streem sb, et al. complications of nephron sparing surgery for renal tumors. j urol. 1994; 151:1177. 19. steinbach f, stockle m, muller sc, et al. conservative surgery of 17archivio italiano di urologia e andrologia 2022; 94, 1 use of double j stent during partial nephrectomy renal cell tumors in 140 patients: 21 years of experience. j urol. 1992; 148:24. 20. kundu sd, thompson rh, kallingal gj, et al. urinary fistulae after partial nephrectomy. bju int. 2010; 106:1042. 21. minervini a, vittori g, antonelli a, et al. open versus roboticassisted partial nephrectomy: a multicenter comparison study of perioperative results and complications. world j urol. 2014; 32:287. 22. meeks jj, zhao lc, navai n, et al. risk factors and management of urine leaks after partial nephrectomy. j urol. 2008; 180:2375. 23. french db, marcovich r. fibrin sealant for retrograde ureteroscopic closure of urine leak after partial nephrectomy. urology. 2006; 67:1081. 24. de concilio b, vedovo f, mir mc, et al. gelatin sponge (spongostan(r)) and n-butyl-2-cyanoacrylate: utility on percutaneous treatment of persistent urinary leakage after partial nephrectomy. case report and review of the literature. arch ital urol androl. 2020; 92:200 25. haber gp, gill is. laparoscopic partial nephrectomy: contemporary technique and outcomes. eur urol. 2006; 49:660. 26. kaouk jh, hillyer sp, autorino r, et al. 252 robotic partial nephrectomies: evolving renorrhaphy technique and surgical outcomes at a single institution. urology. 2011; 78:1338. 27. gill is, desai mm, kaouk jh, et al. laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. j urol. 2002; 167:469 28. peyronnet b, seisen t, oger e, et al. comparison of 1800 robotic and open partial nephrectomies for renal tumors. ann surg oncol. 2016; 23:4277. 29. ficarra v, bhayani s, porter j, et al. predictors of warm ischemia time and perioperative complications in a multicenter, international series of robot-assisted partial nephrectomy. eur urol. 2012; 61:395. correspondence efe bosnali, md efebosnali415@gmail.com ozdal dillioglugil, md odillioglugil@gmail.com kerem teke, md drtekekerem@gmail.com hasan yilmaz, md hasanyilmazm.d@gmail.com ali kemal uslubas, md ali.kemalu@gmail.com ibrahim erkut avci, md erkutavci@gmail.com onder kara, md (corresponding author) onerkara@yahoo.com kocaeli university, school of medicine, department of urology, kocaeli (turkey) busra yaprak bayrak, md bsr2004_86@hotmail.com kocaeli university, school of medicine, department of pathology, kocaeli (turkey) omer burak argun, md drburakargun@gmail.com acibadem mehmet ali aydinlar university, department of urology, school of medicine, istanbul, (turkey) stesura seveso 393archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. since 1941, when charles huggins and colleagues uncovered the hormonal dependence of metastatic prostate cancer, androgen deprivation therapy has been the therapeutical mainstay for metastatic prostate cancer. after decades of absent novelties, we assisted to the introduction of novel hormonal agents for the treatment of castration-resistant metastatic prostate cancer. abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer and are now widely used. abiraterone is an inhibitor of cyp17a1, an enzyme essential in the process of androgen synthesis. enzalutamide competitively inhibits androgen binding to the androgen receptor (ar), nuclear translocation of the ar, dna binding and coactivator recruitment. both abiraterone and enzalutamide are first line treatments for metastatic castrationresistant prostate cancer (mcrpc), but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. our propose was to evaluate the clinical outcomes of patients submitted to either abiraterone or enzalutamide for castration-resistant metastatic prostate cancer in our center. patients and methods patients eligible for this study had a diagnosis of metastatic castration-resistant prostate cancer defined as castrate serum testosterone < 50 ng/ml and biochemical progression (three consecutives rises in prostatic specific antigen (psa) at least one week apart resulting in two 50% increases over the nadir, and a psa > 2 ng/ml) or radiological progression (appearance of new lesions: either two or more new bone lesions or a soft lesion using response evaluation criteria in solid tumours (recist)) and initiated treatment with either abiraterone or enzalutamide between january 1, 2016 and december 31, 2019. follow-up extended from january 1, 2016 until december 31, 2020. in 2019, we treated 358 patients diagnosed with prostate cancer, representing roughly 5.5% cases nationwide. individual clinical cases were discussed in bi-weekly oncourology meetings. patients with clinical criteria of poor prognosis (symptoms, short period of response under introduction: prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. objective: to evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center. patients and methods: we retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between january 1, 2016 and december 31, 2019. the primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. results: enzalutamide had a higher biochemical response rate than abiraterone in patients with mcrpc (77.1% vs 58.1%, p = 0.016). achieving a biochemical response was associated with a lower risk of biochemical progression (or: 0.248, p = 0.017) and death (or: 0.302, p = 0.038). conclusions: enzalutamide conferred higher biochemical response rate than abiraterone in patients with mcrpc. despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. well-designed prospective studies are needed to elucidate the comparative efficacies of these agents. key words: prostate cancer; abiraterone; enzalutamide; castration-resistant. submitted 7 june 2021; accepted 15 august 2021 introduction prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and being the sixth leading cause of cancer-related deaths amongst men worldwide. metastatic prostatic cancer can be roughly divided in two main clinical stages: hormone-sensitive and castrationresistant prostate cancer. novel hormonal agents for metastatic castration-resistant prostate cancer: comparing outcomes. a single-center retrospective study roberto saldanha jarimba 1, miguel nobre eliseu 1, joão pedroso lima 1, vasco quaresma 1, pedro moreira 1, pedro coelho nunes 1, 2, edgar tavares da silva 1, 2, arnaldo josé figueiredo 1, 2 1 urology and renal transplantation department, centro hospitalar e universitário de coimbra, coimbra, portugal; 2 faculty of medicine, university of coimbra, portugal. doi: 10.4081/aiua.2021.4.393 summary archivio italiano di urologia e andrologia 2021; 93, 4 r. saldanha jarimba, m. nobre eliseu, j. pedroso lima, et al. 394 androgen deprivation therapy (adt), high metastatic burden, visceral metastasis or poor prognostic genetic mutations) were treated with taxane-based chemotherapy. the decision to begin treatment with a novel hormonal agent was taken either as first line therapy in patients with less aggressive features (asymptomatic, durable response under previous adt, low metastatic burden and no visceral metastases) or as second line therapy in patients that progressed under first line therapy with taxane-based chemoterapy. in the absence of contraindication for either pharmaceutical drugs, patients were sequentially assigned to either enzalutamide or abiraterone group. the database used was anonymized and unstructured. data were originally extracted from electronic medical records. demographic and clinicopathological features (international society of urological pathology (isup) score, m1 ab inition or progression after local treatment status, previous period of classical androgen deprivation therapy, psa level, previous treatment of taxane-based chemotherapy and localization of metastasis) were registered at baseline. data reported adverse events (aes) was also available. per local protocol, stable patients with metastatic prostate cancer under novel hormonal agents are followed with clinical and analytical evaluation including psa measurement every 3 months by a staff expert. occurrence of biochemical response (defined as a reduction of ≥ 50% of pretreatment psa level after 12 weeks of treatment), psa progression (three consecutives rises in psa at least one week apart resulting in two 50% increases over the nadir, and a psa > 2 ng/ml), radiological progression (appearance of new lesions: either two or more new bone lesions or a soft lesion using recist) diagnosed either by computed tomography (ct) scan, bone scintigraphy or g68 prostate-specific membrane antigen (psma) positron emission tomography (pet), clinical deterioration and/or death and the time of their occurrence were available. the primary endpoints of this study were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. safety was a secondary endpoint. follow-up was stopped when the drug was suspended due to adverse reactions or disease progression. there was no crossover. statistical analysis descriptive statistics of patient and pathological characteristic were calculated for all patients included in the present study, as well as by administered agent. we used a chi-square univariate analysis to assess the statistical significance of the difference between rate response in the abiraterone and enzalutamide group. further, we used a binary logistic regression, adjusted to clinicopathological features, to quantify this association. a cox-regression was performed to uncover predictive co-variates of biochemical progression, radiological progression and overall survival. a survival analysis using a kaplan-meier method was used to evaluate the risk of biochemical progression, radiological progression and overall survival and a log-rank test applied to test for significant differences. all analyses were conducted using ibm spss statistics version 23. all comparisons were made using 2-sided tests, with p < 0.05 considered statistically significant. results a total of 91 patients who initiated a novel hormonal agent, either abiraterone or enzalutamide, between january 2016 and december 2019 were included in the study. 56 (61.5%) patients were treated with abiraterone and the remaining 35 (38.5%) with enzalutamide. 45 (49.5%) patients were diagnosed with metastatic prostate cancer ab inition. 74.7%, 53.8% and 6.6% had bone, lymphatic, and visceral metastasis, respectively. almost 30% of patients had been previously submitted to taxane-based chemotherapy. mean age of the cohort was 74.4 (± 8.26) years, while the mean pretreatment psa level was 231.51 (± 380.15) ng/ml and previous classical androgen deprivation therapy duration was 74.13 (± 54.87) months. median follow-up time was 18.34 months. all covariates, as age, pretreatment psa level, isup score, m1 ab inition or progression after local treatment status, previous period of classical androgen deprivation therapy, previous treatment of taxane-based chemotherapy and localization of metastasis were similar between the groups. baseline demographic and clinicopathological features are shown in table 1. biochemical response overall, rate of biochemical response was 61.5% in mcrpc patients. it was found to be significantly higher in the enzalutamide group than in the abiraterone group, with a rate response of 77.1% and 58.1%, respectively (p = 0.016). in binary logistic regression adjusted to clinicopathological features, enzalutamide was associated with a higher probatable 1. baseline demographic and clinicopathological characteristics by drug of mcrpc patients. demographic and pathological features total abiraterone enzalutamide p (n = 91) (n = 56) (n = 35) age (years) 74.44 ± 8.26 75.00 ± 7.01 73.54 ± 9.980 0.416 pretreatment psa level (ng/ml) 231.51 ± 380.16 215.40 ± 372.82 257.94 ± 401.65 0.717 previous adt (months) 74.13 ± 54.87 77.53 ± 61.66 68.82 ± 42.50 0.882 follow-up (months) 18.34 ± 9.81 17.16 ± 8.71 20.68 ± 11.20 0.276 isup 0.612 1 9 (10%) 4 (7.3%) 5 (14.3%) 2 18 (20%) 13 (23.6%) 5 (14.3%) 3 25 (27.8%) 16 (29.1%) 9 (25.7%) ≥ 4 19 (21.1%) 12 (21.8%) 7 (20%) n/a 19 (21.1%) 10 (18.2%) 9 (25.7%) status 0.934 m1 ab inition 45 (50.6%) 28 (50.9%) 17 (50%) post local treatment 44 (49.4%) 27 (49.1%) 17 (50%) metastasis bone 68 (74.7%) 39 (69.6%) 29 (82.9%) 0.158 ganglionar 49 (53.8%) 30 (53.6%) 19 (54.3%) 0.947 visceral 6 (6.2%) 4 (6.5%) 2 (5.7%) 0.788 post docetaxel 27 (29.7%) 15 (26.8%) 12 (34.3%) 0.446 adt: androgen deprivation therapy; psa: prostate-specific antigen; n/a: not admitted. 395archivio italiano di urologia e andrologia 2021; 93, 4 novel hormonal agents for metastatic castration-resistant prostate cancer: comparing outcomes bility of biochemical response (or: 3.485, p = 0.021). biochemical response was associated with lower probability of biochemical progression (or: 0.248, p = 0.017) and death (or: 0.302, p = 0.038), adjusted to clinicopathological features. subgroup analyses showed no statistically significant difference between biochemical responses in the docetaxelnaïve patients between abiraterone and enzalutamide (56.1% vs 73.9%, p = 0.158), but enzalutamide had a higher response rate than abiraterone in patients previously submitted to docetaxel (83.3% vs 40%, p = 0.019). in the subgroup of patients with metastatic prostate cancer ab inition, that progressed to mcrpc and were docetaxel-naïve, the period of previous classical hormonal therapy was inversely associated with biochemical response (or: 0.928, p = 0.035). biochemical progression mcrpc patients submitted to treatment with enzalutamide and abiraterone had a biochemical progressionfree survival (bpfs) of 19.2 and 30.2 months, respectively. the difference failed to achieve statistical significance (p = 0.284). the kaplan-meier curves for bpfs are showed in the figure 1. in patients who achieved a biochemical response, the bpfs was similar in both enzalutamide group and abiraterone group (24.0 vs 24.3 months, p = 0.651). no covariate factor was identified as predictor of bpfs in multivariate analysis. figure 1. biochemical progression based on administered drug. figure 2. radiological progression based on administered drug. archivio italiano di urologia e andrologia 2021; 93, 4 r. saldanha jarimba, m. nobre eliseu, j. pedroso lima, et al. 396 radiological progression overall, in the mcrpc group the rpfs in patients submitted to enzalutamide was 41.2 months vs 28.57 months in the abiraterone group, but with no statistical significance (p = 0.363). the kaplan-meier curves for rpfs are showed in the figure 2. among biochemical responders, patients submitted to abiraterone had a rpfs of 32.2 months and patients treated with enzalutamide had a rpfs of 29.34 months. no statistically significant differences was achieved (p = 0.791). no covariate factor was identified as predictor of rpfs in multivariate analysis. overall survival all cause time-to-death, in mcrpc patients, was 37.5 months in enzalutamide group and 26 months in abiraterone group, without achieving a statistically significant difference (p = 0.277). the kaplan-meier curves for overall survival (os) are showed in the figure 3. in patients in whom biochemical response was achieved, the abiraterone group had a os of 31.27 months vs 27.30 months in the enzalutamide group, but without statistically significant difference (p = 0.994). in patients that failed to meet biochemical response criteria, os was 31.15 months and 17.58 months in enzalutamide and abiraterone group, respectively. a statistically significant difference was not achieved (31.18 vs 17.58, p = 0.121). no covariate factor was identified as predictor of os in multivariate analysis. aes associated with treatment with abiraterone or enzalutamide overall, 14 patients (14.4%) experienced drug-related adverse events (aes), 10 (16.1%) in abiraterone group and 4 (11.4%) in enzalutamide group. the common aes that occurred in this series were as follows: fatigue (60%) and diarrhea (20%) in abiraterone group and fatigue (100%) in enzalutamide group. only 2 aes ≥ grade 3 were registered, 1 in each group, causing the suspension of the drug. discussion novel hormonal agents are now a cornerstone in the treatment of castration-resistant prostate cancer. both enzalutamide and abiraterone with prednisolone are approved therapies for men with mcrpc. these two drugs have shown clinical efficacy in multicenter phase iii rcts (1-4), yet there is a lack of evidence regarding comparative outcomes of men submitted to treatment with either of the two drugs. findings from previous retrospective studies suggest survival advantages toward enzalutamide compared with abiraterone and prednisolone in the treatment of men with mcrpc (5), although both drugs were effective, with psa rate response over 50%. our analysis is consistent with prior data for better biochemical response with enzalutamide in men with mcrpc. we found that patients in the enzalutamide group had a significantly higher biochemical response than the abiraterone group, with a rate response of 51.8% and 77.1%, respectively (p = 0.016). this seems particularly relevant in patients previously submitted to taxane-based chemotherapy. in a multivariate analysis, enzalutamide was associated with a higher probability of rate response compared with abiraterone (or: 3.485, p = 0.021). biochemical response was associated with a lower probability of biochemical progression (or: 0.248, p = 0.017) and death (or: 0.302, p = 0.038). this data suggests that the higher rate of biochemical response of enzalutamide is associated with better outcomes. respective to other endpoints (biochemical progression, radiological progression, and overall survival), there was a trend toward advantage of enzalutamide over abiraterone with no statistical significance. data showed that in patients who achieved biochemical response, the apparent advantage of enzalutamide over abiraterone disappears. patients who did not achieve a biochemical response had a trend to longer survival when treated to enzalutamide vs abiraterone, albeit not statistically different. as suggested in previous studies (6, 7), this may support an early change of therapeutical strategy when biochemical response is not achieved with abiraterone. figure 3. overall survival based on administered drug. 397archivio italiano di urologia e andrologia 2021; 93, 4 novel hormonal agents for metastatic castration-resistant prostate cancer: comparing outcomes miyake et al., retrospectively reviewed 280 docetaxelnaïve mcrpc patients. a higher psa response rate for patients treated with enzalutamide when compared with abiraterone (70.7% vs 53.1%) was found, in line with our results. on the other hand, a better bpfs in enzalutamide group was also found, which our study failed to find. in this study, because of the drug choice was at physician discretion, there was a preference of abiraterone over enzalutamide in patients with less favorable clinicopathological features based in the results of cou-aa-302 and prevail trials, respectively (8). heo et al. performed a retrospective study that evaluated the outcomes of patients diagnosed with mcrpc treated with abiraterone and enzalutamide in post-docetaxel setting. 54 patients were evaluated (25 in abiraterone group and 29 in enzalutamide group) and a psa rate response was seen 36% and 52% for abiraterone and enzalutamide, respectively. in our cohort the psa rate response was similar for abiraterone (40%), but enzalutamide had a higher response rate than reported in this study (83.3%) in this subset of patients (9). both drugs were well tolerated, with low incidence of drug-related grade ≥ 3 events. only two patients had their treatment suspended. the type of aes registered were in line with ones reported in cou-aa-302 and prevail trials. norris et al. retrospectively studied 198 mcrpc patients submitted to treatment with abiraterone and enzalutamide. significantly higher psa response rates were observed in the enzalutamide (51%) than abiraterone (36%). in our cohort the overall psa response rate were higher, 51.8% and 77.1% in abiraterone and enzalutamide, respectively. there was no significant difference in os between the groups with median os of 15.3 months in abiraterone group versus 22.2 months in the enzalutamide group. the os survival in our study was also higher for enzalutamide (37.5 months for enzalutamide and 27.30 months for abiraterone). these differences can be partially explained by the proportion of patients that were treated in post-docetaxel setting in each study, being the majority of patients in norris et al. cohort and only 30% in ours. as seen in our cohort, higher psa response rates were seen in the pre-docetaxel group compared to the post-docetaxel (10). garcia et al. performed a retrospective observational study reviewing 48 patients with mcrpc (26 in abiraterone group and 22 in enzalutamide). most patients had been submitted to docetaxel. the primary endpoint was biochemical response. unlike our study, no statistically difference in biochemical response between abiraterone and enzalutamide was observed (53.85% and 58.85% for abiraterone and enzalutamide groups, respectively). a low number of patients treated can impair the statistical power of this study (11). khalaf et al. retrospectively analyzed 210 patients (106 in abiraterone and 104 in enzalutamide groups), older than 80 years who received novel hormonal agents for firstline treatment of mcrpc. as in our cohort, the biochemical response was higher in patients treated with enzalutamide than abiraterone (77.9% vs 43.4%) but no os advantage was observed. in our study the psa response rates of docetaxel-naïve patients were similar with the ones reported in this study (56.1% and 73.9% for abiraterone and enzalutamide, respectively) (12). our study has some strengths: similar groups regarding clinicopathological characteristics and a relatively uniform distribution between abiraterone and enzalutamide groups (61.5% vs 38.5%). a 1:1 proportion between abiraterone and enzalutamide was not achieved due to the numerous contraindications to enzalutamide. the approval of abiraterone for treatment of mcrpc was conceded before enzalutamide by national regulatory agency, contributing to the discrepancy in the number of patients in each group. some limitations of this study must however be noted. as a real-life study, the results can be biased by not randomized allocation of patients to different treatments. adverse events were not systematically evaluated due to retrospective nature of this study, making security performance assessment inaccurate. the threshold and image modality (either ct and bone scintigraphy or ga68 petpsma) used for staging patients in the scenario of biochemical progression was not specified, introducing some bias in radiological progression assessment. mean followup period was relatively short. based on our results, enzalutamide conferred higher biochemical response rate than abiraterone in patients with mcrpc. achieving a biochemical response was associated with a lower risk of biochemical progression and death. other endpoints tended to improve in the enzalutamide group although not significantly. well designed prospective studies are needed to elucidate the comparative efficacies of these agents. references 1. fizazi k, scher hi, molina a, et al. abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the cou-aa-301 randomised, double-blind, placebo-controlled phase 3 study. lancet oncol. 2012; 13:983-92. 2. beer tm, armstrong aj, rathkopf de, et al. enzalutamide in metastatic prostate cancer before chemotherapy. n engl j med. 2014; 371:424-33. 3. scher hi, fizazi k, saad f, et al. increased survival with enzalutamide in prostate cancer after chemotherapy. n engl j med. 2012; 367:1187-97. 4. ryan cj, smith mr, fizazi k, et al. abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (cou-aa-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. lancet oncol. 2015; 16:152-60. 5. wang x, yang h, hu x, et al. comparing the clinical efficacy and safety of abiraterone and enzalutamide in metastatic castrationresistant prostate cancer: a systematic review and meta-analysis. j oncol pharm pract. 2021; 27:614-622. 6. khalaf dj, annala m, taavitsainen s, et al. optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. lancet oncol. 2019; 20:1730-9. 7. hung sc, wang ss, li jr, et al. outcome of patients with metastatic castration-resistant prostate cancer after psa progression with abiraterone acetate. anticancer res. 2018; 38:5429-36. archivio italiano di urologia e andrologia 2021; 93, 4 r. saldanha jarimba, m. nobre eliseu, j. pedroso lima, et al. 398 8. miyake h, hara t, terakawa t, et al. comparative assessment of clinical outcomes between abiraterone acetate and enzalutamide in patients with docetaxel-naive metastatic castration-resistant prostate cancer: experience in real-world clinical practice in japan. clin genitourin cancer. 2017; 15:313-9. 9. heo mh, park sh, kim hk, et al. overall survival beyond firstline docetaxel in patients with metastatic castrate-resistant prostate cancer treated with abiraterone acetate or enzalutamide. j clin oncol. 2017; 35(6_suppl):e570-e570. 10. norris t, walter s, williams a, et al. comparison of toxicity and efficacy outcomes of abiraterone and enzalutamide in 198 patients with metastatic castrate resistant prostate cancer. clin oncol. 2017; 29:e87-8. 11. garcía as, mateos aa, esquerdo ml, et al. 4cps-128 effectiveness of abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer. eur j hosp pharm. 2018; 25(suppl 1):a101-a101. 12. khalaf d, zou k, struss wj, et al. efficacy and tolerability of first-line abiraterone + prednisone (abi) versus enzalutamide (enz) for metastatic castration-resistant prostate cancer (mcrpc) in men ≥ 80 years: a retrospective cohort study. j clin oncol. 2018; 36(15_suppl):5051-5051. correspondence roberto saldanha jarimba robertojarimba@chuc.min-saude.pt serviço de urologia, centro hospitalar e universitário de coimbra rua professor mota pinto 3004-561, coimbra (portugal) miguel nobre eliseu, md joão pedroso lima, md vasco quaresma, md pedro moreira, md urology and renal transplantation department, centro hospitalar e universitário de coimbra, coimbra (portugal) pedro coelho nunes, md edgar tavares da silva, md arnaldo josé figueiredo, md urology and renal transplantation department, centro hospitalar e universitário de coimbra & faculty of medicine, university of coimbra, coimbra (portugal) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3270 original paper no conflict of interest declared. biopsy has been established within 12 months from initial diagnosis, there are no definitive data regarding the number of systematic needle cores (extended or saturation biopsy) and the best procedure to diagnose all the cspca reducing the number of scheduled biopsies. in our study, the reclassification rate for cspca at 8-year scheduled transperineal biopsy has been prospectively evaluated in men enrolled in as protocol. materials and methods from may 2013 to september 2017, 160 patients aged between 52 and 73 years (median age 63) with very low risk pca were enrolled in an as protocol. after institutional review board and ethical committee approval were granted, informed consents were obtained from all participants included in the study. presence of the following criteria defined eligibility: life expectancy greater than 10 years, clinical stage t1c, psa below 10 ng/ml, psa density (psad) ≤ 0.20, ≤ 2 unilateral positive biopsy cores, gleason score 6/international society of urologic pathology (isup) grade groups (gg) 1 (6), maximum core percentage of cancer (gpc) ≤ 50% (7). all the patients six months after the pca diagnosis underwent pelvic mpmri 3.0 tesla evaluation before confirmatory transperineal saturation prostate biopsy (spbx; range: 24-32 cores); the procedure was performed with the use of a ge logiq p6 ecograph (general electric; milwaukee, wi) supplied with a bi-planar trans-rectal probe (5-7.5 mhz) using a tru-cut 18 gauge needle (bard; covington, ga) under sedation and antibiotic prophylaxis (8, 10). all mpmri examinations were performed using a 3.0 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multiplanar turbo spin-echo t2-weighted (t2w), axial diffusion weighted imaging (dwi) and axial dynamic contrast enhanced (dce) were performed for each patient. the mpmri lesions characterized by prostate imaging reporting and data system (pi-rads) version 2 scores ≥ 3 were considered suspicious for cancer and submitted to four targeted cores; two radiologists blinded to pre-imaging clinical parameters evaluated the mpmri data sepaintroduction: the reclassification rate for clinically significant prostate cancer (cspca) in men enrolled in active surveillance (as) as been prospectively evaluated. patients and methods: one hundred patients with very low risk pca underwent after 8 years a scheduled transperineal prostate biopsy (spbx = 20 cores) combined with additional mpmri/trus fusion biopsies (4 cores) of lesions pi-rads scores ≥ 3. all the patients, after initial diagnosis, previously had mpmri evaluation combined with transperineal saturation prostate biopsy (confirmatory and 3-year scheduled biopsy). risk reclassification at repeat biopsy triggering the recommendation for active treatment was defined as over 3 or more than 10% of positive cores, gleason score > 6/isup grade group ≥ 2, greatest percentage of cancer (gpc) > 50%. results: multiparametric mri was suspicious (pi-rads ≥ 3) in 30 of 100 cases (30.0%); 70 (70.0%) vs. 20 (20.0%) vs. 10 (10.0%) patients had a pi-rads score ≤ 2 vs. 3 vs. 4, respectively. two (2.0%) patients with pi-rads score 3 and 4 were upgraded (isup grade group 2); spbx and mri/trus fusion biopsy diagnosed 100% and 0% of cspca, respectively. conclusions: transperineal spbx combined with mpmri at initial confirmatory biopsy allow to select an high number of men at very low risk of reclassification during the as follow up (2.0% of the cases at 8 years from diagnosis); these data could be useful to reduce the number of scheduled repeated prostate biopsy during the as follow up. key words: saturation biopsy; active surveillance; targeted prostate biopsy; confirmatory prostate biopsy. submitted 25 june 2022; accepted 3 july 2022 introduction active surveillance (as) is an alternative (1-3) to radical treatment of low-risk prostate cancer (pca) reducing the risk of overtreatment (50% of the cases) (1) and allowing a strict monitoring over time by scheduled clinical evaluations. multiparametric magnetic resonance imaging (mpmri) and mpmri/trus (transrectal ultrasound) fusion targeted biopsy have improved systematic biopsies in the diagnosis of clinically significant pca (cspca) (4, 5), reducing the reclassification rate during the follow up of men in as. although the timing to perform confirmatory confirmatory transperineal saturation prostate biopsy combined with mpmri decrease the reclassification rate in men enrolled in active surveillance: our experience in 100 men submitted to eight-years scheduled biopsy pietro pepe 1, ludovica pepe 1, michele pennisi 1, filippo fraggetta 2 1 urology unit, cannizzaro hospital, catania, italy; 2 pathology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2022.3.270 summary 271archivio italiano di urologia e andrologia 2022; 94, 3 prostate biopsy and active surveillance rately and independently;i moreover, one urologist with more than 25 years of experience performed the biopsy procedure. the data were collected following the screening tool to alert to right treatment (start) criteria (9). at confirmatory biopsy 43/160 (26.8%) were upgraded; conversely, the 117 patients who met clinical criteria to continue as protocol were submitted every six months to psa, psad and clinical evaluation. at three years from diagnosis of cancer (range: 24-30 months), also in the presence of stable clinical parameters, the remaining 110/117 men enrolled in as (7 men abandoned the protocol) underwent scheduled repeated spbx combined with mpmri/trus fusion guided-biopsies of suspicious lesions with pi-rads ≥ 3 (4 targeted fusion cores) (11) and 5.4% of them were upgraded. the clavien-dindo grading system for the classification of biopsy complications was used (12). during the entire follow up 11/160 (6.8%) men autonomously decided to leave the as protocol (other 4 men abandoned the protocol after 3-years follow up); on the contrary, after 8 years from the initial diagnosis the remaining 100 patients who were not upgraded at previous follow up visits, again underwent scheduled spbx (20 cores) combined with mpmri/trus fusion biopsies (4 cores) in the presence of lesions with pi-rads score ≥ 3. risk reclassification at repeat biopsy, triggering the recommendation for active treatment, was defined as over 3 or more than 10% of positive cores, gleason score > 6/isup grade group ≥ 2, greatest percentage of cancer (gpc) > 50%. patients being reclassified underwent definitive treatment (radical prostatectomy or external radiotherapy). results clinical parameters of the 100 patients included in the as protocol who underwent repeated prostate biopsy are listed in the table 1; median psa value increased 1.3 ng/ml (range: 0-2.2 ng/ml) from time of diagnosis to 8-year scheduled repeat biopsy. two (2.0%) patients had unfavourable biopsy histology and were reclassified based on upgrading (2 cases = gleason score 3 + 4/grade group 2), number of positive cores (5 and 6 needle positive cores) and gpc (50% and 80%). in detail, all cspca were located only in the anterior zone of the gland. of the remaining 98 (98%) patients, 70 (70.0%) were found to have very lowrisk pca and in 28 (28.0%) cancer was absent (normal parenchyma); pca was located in the periphery in 48 (48.0%) cases and in the anterior zone in 22 (22.0%) cases and all the 98 patients continued as. multiparametric mri was suspicious (pi-rads ≥ 3) in 30 of 100 cases (30.0%); 70 (70.0%) vs. 20 (20.0%) vs. 10 (10.0%) patients had a pi-rads score ≤ 2 vs. 3 vs. 4, respectively. in detail, the pirads score in the 2 men reclassified was equal to 3 in one case (50%) and 4 in the other case (50%). high level of concordance in the diagnosis of pi-rads score between the two radiologists was found (cohen’s kappa 0.85). none of the patients had significant complications (only claviendindo grade i) resulting from the prostate biopsy, requiring hospital admission; spbx and mri/trus fusion biopsy diagnosed 100% and 0% of cspca, respectively. finally, all the men reclassified underwent external hypofractionated radiotherapy (13). discussion the estimated treatment-free probability at 5, 10 and 15 years from diagnosis of patients enrolled in as protocol with gg1 pca has been reported equal to 76, 64 and 58%, respectively (14); on the other hand, more than one-third of patients, during follow up, are reclassified (i.e., pca upgrading and/or increase in disease extent or patient preference) and submitted to curative treatment (15). in detail, the confirmatory biopsy within one year from diagnosis upgrade the highest number of patients; in particular, the transperineal template biopsy upgrade about 38.0% of patients (16). a lot of studies reported on criteria of patient selection and follow up policies of men enrolled in as protocol: type and timing of imaging, frequency of repeat prostate biopsies, use of psa density and kinetics, genetics biomarkers, use risk calculators, and frequency of clinical follow-up (17-23). although mpmri is strongly recommended in patients enrolled in as protocols (24), at present, systematic prostate biopsies should be always combined with targeted fusion biopsy due to the false negative rate of mpmri (25-27); moreover, the number of targeted-fusion biopsy (in the presence of pi-rads ≥ 3) that should be obtained in addition to systematic prostate biopsy in men enrolled in as protocols (8) has not been established (28). in fact, an accurate biopsy histology could reduce the risk of reclassification allowing to postpone scheduled prostate biopsies in favour of clinical parameters evaluation reducing, at the same time, the complications rate following repeated biopsies (i.e., risk of sepsis and hospitalization) (29). at the same time, an adequate number of needle cores allows to select patients with high volume gg1 pca at risk of reclassification during follow up (33.4% of the cases) (30). in this respect, the number of systematic and/or targeted biopsy cores is an independent predictor for selection of patients with unfavourable characteristics for as (31-35). on the other hand, a relevant critical point remain the adherence of patients to scheduled as follow up; in fact, the estimated drop out to the execution of repeated prostate biopsy at 1 vs. 4 vs. 7 years from initial diagnosis is equal to 11 vs. 30 vs. 29%, respectively (3); therefore, the european association of urology (eau) guidelines strongly recommend to perform repeat biopsy in the presence of clinical suspicion of pca progression (i,e., psad evaluation, progression on mpmri) instead to table 1. clinical parameters of the 100 men enrolled in the active surveillance protocol who underwent scheduled eight-years prostate biopsy. median psa (range) 6.8 ng/ml (2.1-11.3 ng/ml) median psa d (range) 0.12 (0.07-0.18) dre negative mpmri pi-rads score ≤ 2 = 70 cases; 3 = 20 cases; 4 = 10 cases gleason score 6 (3 + 3) isup grade group gg1 gpc (range) 20% (5-50%) prostate weight (range) 58 grams (30-110 grams) psa: prostate specific antigen; psad: psa density; dre: digital rectal examination; mpmri: multiparametric magnetic image resonance; pi-rads: prostate imaging reporting and data system; gpc: greatest percentage of cancer; isup: international society of urologic pathology. archivio italiano di urologia e andrologia 2022; 94, 3 p. pepe, l. pepe, m. pennisi, f. fraggetta 272 repeat biopsies at scheduled times that, anyway, are suggested every three years (36, 37). finally, pathologic parameters play a critical role in identifying appropriate candidates for as; these findings need to be reproducible and consistently reported by pathologists (38-40). in our series, 2/100 (2.0%) men were reclassified based on upgrading (gleason score 7/ isup grade group 2), number of positive cores (5 and 6 positive cores) and gpc (50% and 80%); spbx and mpmri/trus fusion biopsy detected 100 vs. 0% of cspca. in definitive, the execution of spbx plus mpmri at initial confirmatory biopsy allowed to select an high number of men at a very low risk of reclassification (from gg1 to gg2) during the as follow up (5.4% and 2.0% of the cases at respectively 3 and. 8 years from diagnosis) (11); these data could be useful to reduce the number of scheduled repeated prostate biopsy during the as follow up. regarding our results, some considerations should be made. first, in our series there was not a control arm of men submitted to systematic 12 cores prostate biopsy; therefore, the data obtained have been compared with the literature results. second, the results were evaluated on biopsy specimens and not on the entire prostate gland. third, the negative histology of the 9 patients with pirads score 4 should be evaluated during the follow up. finally, a large number of men including a longer follow up are needed to confirm our results. conclusions transperineal spbx combined with mpmri at initial confirmatory biopsy allow to select an high number of men at very low risk of reclassification during the as follow up (2.0% of the cases at 8 years from diagnosis); these data could be useful to suggest reducing the number of scheduled repeated prostate biopsy during the as follow up. references 1. hugosson j, roobol mj, månsson m, et al. a 16-yr follow-up of the european randomized study of screening for prostate cancer. eur urol. 2019; 76:43-51. 2. klotz l. active surveillance for low-risk prostate cancer. curr urol rep 2015; 16:24. 3. kalapara aa, verbeek jfm, nieboer d, movember foundation’s global action plan prostate cancer active surveillance (gap3) consortium: adherence to active surveillance protocols for low-risk prostate cancer: results of the movember foundation's global action plan prostate cancer active surveillance initiative. eur urol oncol. 2020; 3:80-91. 4. pepe p, garufi a, priolo g, pennisi m. can 3 tesla pelvic phasearray mri avoid unnecessary repeat prostate biopsy in patients with psa below 10 ng/ml? clinical genitourinary cancer. 2015: 13:e27-30. 5. tosoian ji, mamawala m, epstein ji, et al. active surveillance of grade group 1 prostate cancer: long-term outcomes from a large prospective cohort eur urol. 2020; 77:675-682. 6. epstein ji, egevad l, amin mb, and grading committee.the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016; 40:244-252, 7. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol. 2017; 51:260-263. 8. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol. 2018: 200:774-778. 9. moore cm, kasivisvanathan v, scott es, start consortium: standards of reporting for mri-targeted biopsy studies (start) of the prostate: recommendations from an international working group. eur urol. 2013; 64:544-552, 10. pepe p, garufi a, priolo g, pennisi m. transperineal vs transrectal mri/trus fusion biopsy: detection rate of clinically significant prostate cancer. clin genitourin cancer. 2017;15:e33-e36. 11. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. clin genitourin cancer. 2021; 19:305-308. 12. dindo d, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of survey. ann surg. 2004; 240:205-213. 13. pepe p, tamburo m, pennisi m, et al. clinical outcomes of hydrogel spacer injection space oar in men submitted to hypofractionated radiotherapy for prostate cancer. in vivo. 2021; 35:3385-3389. 14. carlsson s, benfante n, alvim r, et al. long-term outcomes of active surveillance for prostate cancer: the memorial sloan kettering cancer center experience. j urol. 2020; 203:1122-1127. 15. bruinsma sm, roobol mj, carroll pr, movember foundation's global action plan prostate cancer active surveillance (gap3) consortium: expert consensus document: semantics in active surveillance for men with localized prostate cancer results of a modified delphi consensus procedure. nat rev urol. 2017; 14:312-322. 16. voss j, pal r, ahmed s, et al. utility of early transperineal template-guided prostate biopsy for risk stratification in men undergoing active surveillance for prostate cancer. bju int. 2018; 121:863-870. 17. giganti f, pecoraro m, stavrinides v,, et al. interobserver reproducibility of the precise scoring system for prostate mri on active surveillance: results from a two-centre pilot study. eur radiol. 2020; 30:2082-2090. 18. pepe p, vatrano s, cannarella r, et al. a study of gene expression by rna-seq in patients with prostate cancer and in patients with parkinson disease: an example of inverse comorbidity. mol biol rep. 2021; 48:7627-7631. 19. roscigno m, stabile a, lughezzani g, et al. the use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. 20. pepe p, dibenedetto g, pepe l, pennisi m. multiparametric mri versus selectmdx accuracy in the diagnosis of clinically significant pca in men enrolled in active surveillance. in vivo. 2020; 34:393-396. 21. lam tbl, maclennan s, willemse pm, et al. eau-eanmestro-esur-siog prostate cancer guideline panel consensus statements for deferred treatment with curative intent for localised prostate cancer from an international collaborative study (detective study). eur urol. 2019; 76:790-813. 22. cooley lf, emeka aa, meyers tj, et al. factors associated with time to conversion from active surveillance to treatment for prostate 273archivio italiano di urologia e andrologia 2022; 94, 3 prostate biopsy and active surveillance cancer in a multi-institutional cohort. multicenter study j urol. 2021; 206:1147-1156. 23. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsy in men enrolled in active sirveillance protocols? j clin med. 2022; 16; 11:3473. 24. shapiro dd, gregg jr, lim ah, et al. comparing confirmatory biopsy outcomes between mri-targeted biopsy and standard systematic biopsy among men being enrolled in prostate cancer active surveillance. bju int. 2021; 127:340-348. 25. ploussard g, beauval jb, lesourd m, et al. impact of mri and targeted biopsies on eligibility and disease reclassification in mripositive candidates for active surveillance on systematic biopsies. urology. 2020; 137:126-132. 26. pepe p, garufi a, priolo g, pennisi m. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol. 2016; 34:1249-1453. 27. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer res. 2022; 42:3011-3015. 15785. 28. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology. 2020; 137:133-137. 29. pepe p, aragona f. morbidity following transperineal prostate biopsy in 3,000 patients submitted to 12 vs. 18 vs. more than 24 needle cores. urology. 2013; 81:1142-1146. 30. müller g, bonkat g, rieken m, et al. potential consequences of low biopsy core number in selection of patients with prostate cancer for current active surveillance protocols. urology. 2013; 81:837-842. 31. lu aj, syed js, ghabili k, et al. role of core number and location in targeted magnetic resonance imaging-ultrasound fusion prostate biopsy. eur urol. 2019; 76:14-17. 32. villa l, salonia a, capitanio u, et al. the number of cores at first biopsy may suggest the need for a confirmatory biopsy in patients eligible for active surveillance-implication for clinical decision making in the real-life setting. urology. 2014; 84:634-41. 33. kaye dr, qi j, morgan tm, and michigan urological surgery improvement collaborative. pathological upgrading at radical prostatectomy for patients with grade group 1 prostate cancer: implications of confirmatory testing for patients considering active surveillance. bju int. 2019; 123:846-853. 34. amin a, scheltema mj, shnier r, et al. the magnetic resonance imaging in active surveillance "mrias" trial: use of baseline multiparametric magnetic resonance imaging and saturation biopsy to reduce the frequency of surveillance prostate biopsies. j urol. 2020; 203:910-917. 35. lacetera v, antezza a, papaveri a, et al. mri/us fusion prostate biopsy in men on active surveillance: our experience. arch ital urol androl. 2021; 93:88-91. 36. mottet n, cornford p, van der bergh rcn, et al. eau oncology guideline: prostate cancer, amsterdam 2022. 37. ediz c, akan s, temel mc, yilmaz o. the importance of psadensity in active surveillance for prostate cancer. arch ital urol androl. 2020; 92:136. 38. rajwa p, sprenkle pc, leapman ms. when and how should active surveillance for prostate cancer be de-escalated? eur urol focus. 2021; 7:297-300. 39. montironi r, santoni m, mazzucchelli r, et al. the role of the uro-pathologist in this series should be emphasized as shown by montironi r, prostate cancer: from gleason scoring to prognostic grade grouping. expert rev anticancer ther. 2016; 16:433-440. 40. fandella a, scattoni v, galosi a, et al. italian prostate biopsies group: 2016 updated guidelines insights. anticancer res. 2017; 37:413-424. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md michele pennisi, md urology unit, cannizzaro hospital, catania (italy) filippo fraggetta, md pathology unit, cannizzaro hospital, catania (italy) stesura seveso 259archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.259 best time to wait for the improvement of the sperm parameter after varicocelectomy: 3 or 6 months? mohammad ali ghaed 1, seyed alireza makkian 2, asaad moradi 1, robab maghsoudi 1, alireza gandomi-mohammadabadi 3 1 urology department, firoozgar hospital, iran university of medical sciences, tehran, iran; 2 iran university of medical sciences, tehran, iran; 3 student research committee, school of medicine, iran university of medical sciences, tehran, iran. objective: to estimate the duration of time required following varicocelectomy to wait for the improvements of semen parameters. therefore, we characterized the changes with the time in sperm parameters in men after varicocelectomy. materials and methods: in this prospective cohort study we included consecutively observed men who underwent varicocelectomy between september 2017 and september 2018 in a referral academic hospital. clinical data of the patients, as well as their semen parameters, were measured before surgery and at 3 and 6 months afterward. results: in this study, a total of 100 men with average age of 29.5 ± 6.2 years were included. mean sperm concentration and sperm motility significantly improved by 3 (p < 0.05), but not by 6 months following varicocelectomy. the semen volume and sperm with normal morphology were the same before and after surgery (p > 0.05). there was no statistically significant difference in the improvement of semen parameters when comparing 6 months to 3 months postoperatively (p > 0.05). conclusions: sperm parameters (concentration and motility) improve by 3 months after varicocelectomy without further improvements. consequently, physicians should decide quickly after 3-month of varicocelectomy if surgery has been not helpful and then plan other therapies, like assisted reproductive technology (art) for managing infertility in couples. key words: varicocelectomy; male infertility; semen parameters; time factors; art. submitted 2 march 2020; accepted 15 march 2020 summary introduction varicocele is the most common but correctable cause of infertility in men and is defined as dilated tortuous veins of the pampiniform plexus in the spermatic cord (1). its prevalence rate is 30% in men with primary infertility, up to 80% in men with secondary infertility and 15% in general adult male population (2). the pathophysiology of varicocele-associated infertility has not been well defined. it is thought to be related to the impairment of spermatogenesis induced by increased testicular blood flow, scrotal hyperthermia, reflux of renal and adrenal metabolites, hypoxia from venous stasis and endocrine dysfunction (3, 4). in current practice, varicocelectomy, drug therapy and assisted reproductive technology (art) including intrauterine insemination (iui), in vitro fertilization (ivf), or intracytoplasmic sperm injection (icsi) are some modalities approved for men with varicocele-associated infertility (2). to date, varicocelectomy is one of the most popular modality. there are various ways to perform varicocele repair, including surgical ligation (with or without microscopic approach), laparoscopic surgery and embolization (5-8). the effectiveness of varicocelectomy on male fertility has remained in doubt (3, 9). numerous studies including systematic reviews on clinical results of varicocelectomy have reported improvements in fertility rates and semen parameters (10-14). however, some studies have reported controversial results, consisting of an unstable improvement in fertility following surgery or even worsened semen parameter (15-17). for both couples and physicians, it is important to know the time needed to wait after varicocelectomy for the best improvement in semen parameters. so they can assess better the changes in semen parameters and the need to plan on other therapies as invasive forms of art (18). according to the report of the practice committee of american society for reproductive medicine in 2014, time to improvement in semen parameters following varicocelectomy is usually 3 to 6 months (19). while this has become a common practice, there are only a few studies that assess the time needed to wait for the improvement of sperm parameters following varicocelectomy. therefore, this study was evaluated the time-dependent changes in semen parameters in men who underwent microsurgical inguinal varicocelectomy and had semen analyses at baseline, and 3 and 6 months following surgery to estimate the duration of time required to wait for improvement of semen parameters. materials and methods this prospective cohort study was conducted in consecutive men who underwent unilateral inguinal varicocelectomy. it was carried out in a referral academic hospital between september 2017 and september 2018 after approval of ethical committee of iran university of medical sciences. all patients filled an informed written consent form. inclusion criteria were infertile men who had a leftsided palpable varicocele (grade i/ii/iii) and were further documented with doppler duplex ultrasound with at least archivio italiano di urologia e andrologia 2020; 92, 3 m. ali ghaed, s. alireza makkian, a. moradi, r. maghsoudi, a. gandomi-mohammadabadi 260 one or more abnormal semen parameter and also adolescents who had left palpable varicocele and objective evidence of reduced ipsilateral testicular size more than 20% is in comparison with the right testis (19). infertility was defined as male partner who was unsuccessful to achieve successful fertility at least after 12 months of regular unprotected sexual intercourse or couples who had been able to get pregnant at least once, but now is unable with female partners normal in fertility re gynecologist. the semen samples from infertile individuals were classified according to the who-2010, and samples with a sperm concentration < 15 million/ml (oligozoospermic) and/or progressive motility (a+b) < 32% (asthenozoospermic) and/or morphologically normal sperm < 4%( teratozoospermic) considered as abnormal. the largest vein diameter and reversal blood flow of pampiniform plexus of veins were measured. diagnosis of clinical varicocele was based on 2 criteria: 1) left-sided venus diameter cut-point values of 2.5 mm in rest or 3 mm during valsalva and 2) presence of retrograde flow (20). exclusion criteria were additional causes of infertility, significant medical diseases, leucocytospermia, azoospermia, patients with a history of probable sexually transmitted diseases and previous history of scrotal or inguinal trauma or surgery. all patients’ information including demographic information (age, marriage, number of children) and smoking habits were obtained and entered into the checklist. then patients underwent microsurgical inguinal varicocelectomy by a single expert urologist. masturbation was used to collect semen samples following 3-day period of sexual abstinence. the samples were analyzed within 1 hour after collection to measure the ejaculation volume, sperm concentration, motility and morphology. to eliminate the effects of different test kits from different laboratories, three-stage trials of patients were conducted in a single laboratory. based on the last guidelines of the world health organization (who) (2010), computer-aided sperm analysis (casa) was used to assess sperm concentration, motility and morphology. we documented any pregnancy that might occur during the study period. semen analyses were obtained before, 3 and 6 months after surgery. we followed the participants for 6 months after the day of surgery. the primary outcome measure was characterizing the time-dependent changes of each semen parameter during. secondary outcomes were determining spontaneous pregnancy rate after intervention during 6 months follow-up. the provided data were analyzed by spss 18 (statistical package for social sciences, chicago, il). continuous variables with normal distribution were described using means ± sem (standard error of mean). paired t-test was used for comparison between the preand post-surgery. wilcoxon signed-ranks test was used for the parameters with a non-normal distribution. p-value less than 0.05 were considered statistically significant. results one-hundred patients (mean age = 29.5 ± 6.2 years; range: 17-46) with various grades of varicocele were enrolled in our study. all patients had a left-sided varicocele; six patients (6%) had grade 1 varicocele, 18 (18%) had grade 2, and 76 (76%) had grade 3. among our patients, 65 patients were married: 39 of them had primary infertility and 26 of them had secondary infertility. the mean of vein dilatation was 3.62 ± 1.2 and the mean of reflux duration in pampiniform plexus of veins was 2.3 ± 1.8 seconds. sperm concentration among 78 patients was under 15 million/ml, progressive motility among 49 patients was under 32% and normal morphology among 7 patients was under 4%. therefore, the 100 individuals with grades i, ii & iii varicocele were sub-grouped to oligoasthenoteratozoospermic (n = 2), oligoteratozoospermic (n = 5), oligoasthenozoospermic (n = 25) oligozoospermic (n = 46) and asthenozoospermic(n =22). other demographic data are listed in table 1. sperm concentration and motilities were significantly increased by 3 months but not by 6 months following surgical therapy compared with preoperative. no further significant improvement was found in sperm concentration or motility after 3 months up to 6 months after surgery. semen volume and the proportion of sperm with normal morphology did not significantly improve during the study. in table 2 we summarized the findings of semen parameters analysis before,3 and 6 months after varicocelectomy. also 24 of the 65 married patients’ wives (37%) table 1. demographic and baseline characteristics of participants. characteristic patients (n = 100) age (y) 29.5 ± 6.2 marriage, n (%) married 65 (65%) single 35 (35%) smoking, n (%) 67 (67%) type of infertility, n (%) primary 39 (39%) secondary 26 (26%) grade of varicocele, n(%) 1 6 (6%) 2 18 (18%) 3 76 (76%) table 2. changes in semen parameters at 3 and 6 months after surgery. timing of semen analysis according to surgery p-value parameters* preoperative 3 months 6 months before vs. 3 mo before vs. 6 mo 3 mo after vs. 6 mo semen volume (ml) 2.91 ± 1.36 2.94 ± 1.22 2.93 ± 1.30 .272 .741 .852 sperm concentration (million/ml) 16.33 ± 20.41 19.36 ± 20.66 17.79 ± 15.36 .012 .120 .903 sperm morphology (% normal): 50.01 ± 21.51 51.40 ± 19.57 49.79 ± 18.80 .229 .657 .192 progressive motile sperm count (%) 42.43 ± 22.04 47.98 ± 19.01 46.48 ± 21.58 .001 .075 .194 * data are expressed as means ± sem (standard error of mean). got pregnant, including 19 (49%) and 5 (19%) in patients with primary and secondary infertility, respectively. discussion the most common diagnosed cause of infertility in men is varicocele, and about 30% of infertile men with primary infertility have varicocele. many factors such as altered venous pressure, hyperthermia, testicular blood flow, oxidative stress, hormonal imbalance, toxic substances, genetic factors, and lifestyle are among factors that are supposed to have a role in varicocele (21). in this study, our patients underwent microsurgical varicocelectomy, which has been regarded as the gold standard in comparison with other surgical techniques and radiological management such as retrograde embolization in terms of the recurrence rate and the pregnancy rate (22, 23). while there are conflicting findings regarding the effects of varicocelectomy on fertility rates in couples with infertility, strong accepted evidence and reports suggest it has a positive effect on male reproduction because it upgrades semen parameters, reduces sperm dna fragmentation, improves art outcomes and increases spontaneous pregnancy rates (24). two meta-analysis by agarwal et al. (3) and marmar et al. (25) in 2007 assessed the effects of varicocelectomy on semen parameters, and concluded that surgical varicocelectomy has a positive effect on all semen parameters in infertile men with a clinical varicocele. in this study, we reported significant increase in sperm concentration and motility at 3 months but not at 6 months after varicocelectomy. however, we did not observe significant improvement in other parameters including sperm morphology and semen volume. revised who manual (2010) has recommended casa system as a selective means to analyze semen samples, that it has not been routinely used before 2010 for semen analysis. in this study, we performed semen analysis by using this new method based on the guidelines of the who (2010) and confirmed the varicocelectomy effect by a more accurate system. ariagno et al. (26) also used casa to assess semen parameters. however, improvement of all semen parameter was insignificant in contrast to our study. this difference in the improvement of sperm parameters between different studies can be related to the type of male factor infertility, heterogeneity of intrasamples, type of surgery, sample sizes, type of semen assessment, etc. in addition, varicocelectomy, a low-risk modality with minimal morbidity, has many advantages over the simple improvement of sperm parameters. it could improve other parameters of sperm quality that we do not assess in standard semen testing, such as sperm deoxyribonucleic acid fragmentation rates. alargkof v, et al. (27), zini et al. (28) and smit et al. (29) found that there is a higher degree of dna fragmentation in patients with varicocele and significantly improvements after varicocelectomy of semen parameters and dna fragmentation rates in men with infertility. previously studies demonstrated varicocelectomy potentially improves semen parameters that lead to applying less invasive and expensive forms of art or even natural pregnancy (30). in past years, several options other than varicocelectomy such as iui and ivf have been introduced to improve couples’ chance of conceiving (31). accordingly, it has become a common concern for couples to know the duration needed to wait for the improvement of semen parameters after varicocelectomy; since it is unacceptable for most couples, especially those with an elderly woman, to wait a long time for the outcome of varicocelectomy to become clear. instead, they prefer to continue directly with iui or ivf, resulting in missing the benefit of varicocelectomy. regarding these findings, in this study we retrospectively investigated the time-dependent changes in the semen parameters results in 100 men following varicocelectomy to estimate the time needed to note improvements in semen parameters. improvements in the semen parameters after 3 months following surgery were not significant in our patients. al bakri et al. (32) and fukuda et al. (24) reported similar findings to our study. these findings suggest that up to 3 months after surgery, improvement in semen parameters could occur, and further improvement after that time in unexpected. therefore, varicocelectomy is an acceptable option for men with clinical varicocele, even for couples with advanced female age; because they could quickly proceed to art if their semen parameters did not improve up to 3 months after the surgery. in this study spontaneous pregnancy was achieved in 37% of couples during a 6-month period after varicocelectomy, and rate of pregnancy was higher in patients with primary infertility (49%) in comparison with secondary infertility (19%). abdel-meguid ta et al. (9) reported a pregnancy rate of 36.4% during a 12-month follow-up in patients who underwent surgery and concluded varicocelectomy increase odds of spontaneous pregnancy within 1 year of follow-up which is consistent with our results. contrary to these findings, nieschlag et al. (33), found no difference in the odds of pregnancy in varicocele-treated patients compared with no treatment, suggesting no benefit for varicocele treatment there are several limitations to this study. initially, it had a relatively small sample size and was a non-randomized study without a control group. therefore, the findings of this study need to be confirmed with a larger group to determine definite results. in addition, we followed our patients up to 6 months after surgery. as pregnancy is the ultimate goal for infertility due to this short duration of observation in patients, for efficient evaluation of pregnancy rate, we should consider at least 1-year follow-up, and compare results of intervention group with a control group. finally, it is better to investigate the characteristics data of the female partner, as her age because of its impact on the decision-making process in couples. conclusions sperm parameters (concentration and motility) improve by 3 months following varicocelectomy and then do not improve further by 6 months. this finding could help couples and physicians evaluate better the outcome of surgery and then if required, plan on the use of other approaches, such as art to manage infertility without prolonged delay. 261archivio italiano di urologia e andrologia 2020; 92, 3 best waiting time for improving sperm parameter archivio italiano di urologia e andrologia 2020; 92, 3 m. ali ghaed, s. alireza makkian, a. moradi, r. maghsoudi, a. gandomi-mohammadabadi 262 acknowledgment we would like to show our gratitude to the rasoul akram hospital clinical research development center (rcrdc) for its technical and editorial assists. references 1. chen yw, niu yh, wang dq, et al. effect of adjuvant drug therapy after varicocelectomy on fertility outcome in males with varicocele-associated infertility: systematic review and meta-analysis. andrologia. 2018; 50:e13070. 2. vahidi s, moein m, nabi a, narimani n. effects of microsurgical varicocelectomy on semen analysis and sperm function tests in patients with different grades of varicocele: role of sperm functional tests in evaluation of treatments outcome. andrologia. 2018; 50:e13069. 3. agarwal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. urology. 2007; 70:532-8. 4. baigorri bf, dixon rg. varicocele: a review. semin intervent radiol. 2016; 33:170-6. 5. cayan s, shavakhabov s, kadioglu a. treatment of palpable varicocele in infertile men: a meta-analysis to define the best technique. j androl. 2009; 30:33-40. 6. williams dh, karpman e, lipshultz li. varicocele: surgical techniques in 2005. can j urol. 2006; 13 suppl 1:13-7. 7. al-kandari am, shabaan h, ibrahim hm, et al. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology. 2007; 69:417-20. 8. al-said s, al-naimi a, al-ansari a, et al. varicocelectomy for male infertility: a comparative study of open, laparoscopic and microsurgical approaches. j urol. 2008; 180:266-70. 9. abdel-meguid ta, al-sayyad a, tayib a, farsi hm. does varicocele repair improve male infertility? an evidence-based perspective from a randomized, controlled trial. eur urol. 2011; 59:455-61. 10. ghaed ma, mahmoodi f, alizadeh hr. prognostic factors associated with bilateral, microsurgical vasovasostomy success. middle east fertility society journal. 2018; 23:373-6. 11. goldstein m, gilbert br, dicker ap, et al. microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. j urol. 1992; 148:1808-11. 12. kibar y, seckin b, erduran d. the effects of subinguinal varicocelectomy on kruger morphology and semen parameters. j urol. 2002; 168:1071-4. 13. marmar jl, kim y. subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. j urol. 1994; 152:1127-32. 14. segenreich e, shmuely h, singer r, servadio c. andrological parameters in patients with varicocele and fertility disorders treated by high ligation of the left spermatic vein. int j fertil. 1986; 31:200-3. 15. breznik r, vlaisavljevic v, borko e. treatment of varicocele and male fertility. arch androl. 1993;30:157-60. 16. krause w, muller hh, schafer h, weidner w. does treatment of varicocele improve male fertility? results of the 'deutsche varikozelenstudie', a multicentre study of 14 collaborating centres. andrologia. 2002; 34:164-71. 17. rageth jc, unger c, darugna d, et al. long-term results of varicocelectomy. urol int. 1992; 48:327-31. 18. masterson ta, greer ab, ramasamy r. time to improvement in semen parameters after microsurgical varicocelectomy in men with severe oligospermia. can urol assoc j. 2019; 13:e66-e9. 19. practice committee of the american society for reproductive medicine; society for male reproduction and urology. report on varicocele and infertility: a committee opinion. fertil steril. 2014; 102:1556-60. 20. pilatz a, altinkilic b, kohler e, et al. color doppler ultrasound imaging in varicoceles: is the venous diameter sufficient for predicting clinical and subclinical varicocele? world j urol. 2011; 29:645-50. 21. tavalaee m, bahreinian m, barekat f,, et al. effect of varicocelectomy on sperm functional characteristics and dna methylation. andrologia. 2015; 47:904-9. 22. diegidio p, jhaveri jk, ghannam s, et al. review of current varicocelectomy techniques and their outcomes. bju international. 2011; 108:1157-72. 23. ughi g, dell'atti l, ricci c, daniele gp. (micro)surgical and percutaneous procedures in the management of varicocele: 25 years of experience. arch ital urol androl 2012; 84:79-83. 24. fukuda t, miyake h, enatsu n, et al. assessment of timedependent changes in semen parameters in infertile men after microsurgical varicocelectomy. urology. 2015; 86:48-51. 25. marmar jl, agarwal a, prabakaran s, et al. reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. fertil steril. 2007; 88:639-48. 26. ariagno ji, mendeluk gr, furlan mj, et al. computer-aided sperm analysis: a useful tool to evaluate patient's response to varicocelectomy. asian j androl. 2017; 19:449-52. 27. alargkof v, kersten l, stanislavov r, et al. relationships between sperm dna integrity and bulk semen parameters in bulgarian patients with varicocele. arch italurol androl. 2019; 91:125-129. 28. zini a, blumenfeld a, libman j, willis j. beneficial effect of microsurgical varicocelectomy on human sperm dna integrity. hum reprod. 2005; 20:1018-21. 29. smit m, romijn jc, wildhagen mf, et al. decreased sperm dna fragmentation after surgical varicocelectomy is associated with increased pregnancy rate. j urol. 2013; 189(1 suppl):s146-50. 30. inci k, hascicek m, kara o, et al. sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. j urol. 2009; 182:1500-5. 31. tournaye h. male factor infertility and art. asian j androl. 2012; 14:103-8. 32. al bakri a, lo k, grober e, et al. time for improvement in semen parameters after varicocelectomy. j urol. 2012; 187:227-31. 33. nieschlag e, hertle l, fischedick a, et al. update on treatment of varicocele: counselling as effective as occlusion of the vena spermatica. hum reprod. 1998; 13:2147-50. correspondence mohammad ali ghaed, md ghaed1982@gmail.com asaad moradi, md moradi.a@iums.ac.ir robab maghsoudi, md rmaghsudy@yahoo.com urology department, firoozgar hospital, iran university of medical sciences, tehran (iran) seyed alireza makkian, md alireza.makian@gmail.com iran university of medical sciences, tehran (iran) alireza gandomi-mohammadabadi, md (corresponding author) a.gandomi.researcher@gmail.com student research committee, school of medicine, iran university of medical sciences, tehran, iran stesura seveso 139archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. the evalution of mpmri combined with clinical parameters (i.e., psa density, digital rectal examination) instead scheduled prostate biopsies in the reevaluation of men enrolled in active surveillance protocols (4-7); therefore, mpmri quality and radiologist expertice represent a central topic in the decision making for prostate biopsy. the detection rate of cspca is directly related with the pi-rads score (8, 9) and the results depend on clinical parameters, the number of previous negative biopsies and the quality of targeted mpmri/trus fusion biopsy procedures; the gray zone of mpmri evaluation is still today represented by the diagnosis of a pi-rads 3 lesion that could harbour the presence of a clinically significant prostate cancer (cspca) in about 20-25% of the cases (1012). at the same time, the number of pi-rads score 3 diagnosed by radiologists should be limited to a low percentage among all the mpmri procedures similarly as reported by pathologists for the diagnosis of atypical small cell acinar proliferation. in this study, we report the detection rate for cspca in men with pirads score 3 diagnosed by reference vs affiliated radiological centers. patients and methods from january 2017 to december 2020, 950 men (median age 64 years; range: 47-75 years) with negative digital rectal examination underwent mpmri for abnormal psa values (median 6.3 ng/ml; range 2.9-102 ng/ml); 680 and 270 underwent initial and repeated prostate biopsy. in 500 men mpmri was performed at our hospistal imaging department considered aa a reference center; on the contrary, 450 patients were submitted to mpmri by outpatient radiological affiliated centers. all mpmri examinations were previously performed using a 1.5 tesla scanner equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo t2-weighted, and axial diffusion weighted imaging, and axial dynamic contrast (adc) enhanced mri were performed for each patient (4). all the mpmri index lesions characterized by a pi-rads (version 2) > 3 underwent targeted cores (tpbx: four cores) combined with extended systematic prostate introduction: the detection rate for clinically significant prostate cancer (cspca) in men with mpmri pi-rads score 3 diagnosed by affiliated radiology centers vs radiological reference center was evaluated. materials and methods: from january 2017 to december 2020, 950 men (median age 64 years) underwent mpmri for abnormal psa values (median 6.3 ng/ml). among the 950 patients who underwent mpmri 500 were evaluated by a reference center and 450 by outpatient radiological affiliated centers. all the mpmri index lesions characterized by a pi-rads 3 underwent targeted cores combined with extended prostate biopsy. two radiologists of the radiological reference center revised all the mpmri lesions 3. results: overall, 361/950 (38%) patients had a mpmri lesion pi-rads score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiological centers. the detection rate for ct1c cspca was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with pi-rads 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05). among the 241 pi-rads score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were downgraded (pi-rads scores < 3) and upgraded (pi-rads score 4) by the dedicated radiologists of the reference center. conclusions: in our series, about 35% and 15% of pi-rads score 3 lesions diagnosed by affiliated radiological centers were downgraded and upgraded when revised by experencied radiologists, therefore a second opinion is mandatory especially in men enrolled in active surveillance protocols in whom mpmri is recommended to reduce the number of scheduled repeated prostate biopsies. key words: prostate cancer; mri and prostate cancer; pi-rads score 3; transperineal targeted biopsy. submitted 21 february 2021; accepted 14 march 2021 introduction multiparametric magnetic resonance imaging (mpmri) is strongly recommended before biopsy for the diagnosis of clinically significant prostate cancer (cspca) (1) in order to reduce the risk of overdiagnosis and to improve the costeffectiveness of prostate biopsy (2). recently, the european association of urology guidelines (3) suggested mpmri pi-rads score 3 lesions diagnosed by reference vs affiliated radiological centers: our experience in 950 cases pietro pepe 1, giuseppe candiano 1, ludovica pepe 1, michele pennisi 1, filippo fraggetta 2 1 urology unit, cannizzaro hospital, catania, italy; 2 pathology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2021.2.139 summary archivio italiano di urologia e andrologia 2021; 93, 2 p. pepe, g. candiano, l. pepe, m. pennisi, f. fraggetta 140 biopsy (at least 12 cores); the procedure was performed transperineally using a tru-cut 18 gauge needle (bard; covington, ga, usa) under sedation and antibiotic prophylaxis (5). the tpbx was done using an hitachi 70 arietta ecograph, chiba, japan) supplied by a bi-planar trans-rectal probe (13). the data have been collected following the start criteria (14). two radiologists of the radiological reference center with 11 years of experience blinded to pre-imaging clinical parameters evaluated the mpmri data separately and independently. the detection rate for cspca in men with pirads score 3 diagnosed by affiliated vs radiological reference center was evaluated; in addition, all pi-rads 3 lesions diagnosed in the affiliated radiological centers were revised by the dedicated radiologists and compared with biopsy histology results. for statistical analysis a p value < 0.05 was considered statistically significant. results overall, 361/950 (38%) patients had a mpmri lesion pirads score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiology centers, respectively. the pi-rads 3 lesions were located in the peripheric and anterior zone of the gland in 190 and 171 cases; moreover, 151 (41.8%) vs 210 (58.2%) men underwent cognitive vs fusion targeted biopsy procedure, respectively. the detection rate for t1c cspca was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with pi-rads 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05) (table 1): in detail, 24 and 11 vs 25 and 15 of the cspca were located in the peripheric and anterior zone of the prostate, respectively. none had significant complications (clavien-dindo grade i) (15) from prostate biopsy that needed hospital admission. the clinical parameters (i.e., psa, weight, psa density) and the biopsy quantitative histology (i.e., number of positive cores, greatest percentage of cancer and grade group) is reported in table 1; a normal parenchyma was diagnosed in the remaining 286/361 (79.2%) men. the median diameter of pi-rads 3 index lesions was 10 mm. vs 9 mm. in men with cspca vs normal parenchyma, respectively. among the 241 pi-rads score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were respectively downgraded (pi-rads scores < 3) and upgraded (pi-rads score 4) by dedicated radiologist of the reference center. the presence of cspca was significantly correlated with the adc value (table 1). discussion the improvement of diagnostic imaging by mpmri has allowed targeted biopsies of the suspicious area, increasing the diagnosis of cspca and reducing the number of unnecessary systematic biopsy. although mpmri is strongly recommended in men candidate for prostate biopsy (3) or in men enrolled in active surveillance protocols (7), still today, systematic biopsy should be always combined with mpmri/trus fusion biopsy because the increased false negative rate (5, 14) of mpmri (about 20% of the cases) (6) and the variable diagnostic accuracy of the different mpmri/trus fusion biopsy platforms (17). while the risk of clinically significant in case of pirads 4-5 is well established, pirads 3 lesions are presented as equivocal and at low risk of aggressive disease with the identification of cspca is not neglegible (6, 8-11-12). the pi-rads 3 lesions identified on mpmri are considered to be “a gray area” in the diagnosis protocol of pca (18, 19). the main objectives regarding pirads 3 score are to accurately diagnose cspca and avoiding unnecessary biopsies that could have undesirable side effects on patients and thus, avoiding overdiagnosis and overtreatment. in a recent review, maggi et al. (20) demonstrated the superiority of combined target and systematic biopsy in detecting cspca in patients with pirads 3 lesions; moreover, they also found that combining pirads 3 score with a psad > 0.15 ng/ml/ml could improve the detection rate of cspca on prostate biopsy (21). in addition, to identify the pi-rads score at high risk for cspca irrespective of clinical findings many parameters have been reported: index lesion diameter, shape and location of the lesion and the adc values (6, 9, 11). wu et al. (22) showed that higher adc values (0.830×10-3 mm2/sec) were significantly associated with low-risk prostate cancer; on the contrary, kim et al. (23) reported a mean adc value for cspca equal to (0.741 ± 0.164) ×10-3 mm2/sec. in our series, the detection rate for t1c cspca was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with pi-rads 3 lesions diagnosed in the reference vs the affiliated radiological centers; in detail, among the 241 pi-rads score 3 lesions diagnosed by affiliated radiological centers 35.7% (86/241) and 15% (36/241) were downgraded (pi-rads scores < 3) and upgraded (pitable 1. quantitative biopsy histology, clinical parameters and adc values in men with pi-rads (prostate imaging-reporting and data system) score 3 lesions and clinically significant prostate cancer (cspca). radiological radiological p value reference center affiliated centers overall number of patients with cspca: 75/361 35/120 40/241 < 0.05 (26.7%) (16.6%) cspca cspca median psa values (ng/ml) 8.7 9.1 > 0.05 grade group (adc value) 35 pts 40 pts 1 (0.750 ± 0.162) 2 < 0.05 2 (0.635 ± 0.117) 28 19 < 0.05 3 (0.489 ± 0.093) 17 19 > 0.05 median number of positive tpbx cores 1.5 1.0 > 0.05 median number of systematic positive cores 4 (1-9) 5 (1-12) > 0.05 median gpc (range) 50% 50% > 0.05 median prostate weight (grams) 50 46 > 0.05 median mpmri lesion index diameter (mm) 10 9 > 0.05 psa: prostate specific antigen; tpbx: targeted transperineal fusion biopsy; gpc: greatest percentage of cancer for single core; adc: apparent diffusion coefficient; mpmri: multiparametric magnetic resonance imaging; pts: patients. rads score 4) by dedicated radiologist of the reference center. in addition, psa density and adc value of 0.747×10-3 mm2/sec, threshold obtained from roc curve analysis improved the diagnosis for cspca in the presence of pi-rads 3 lesions. regarding our results some considerations should be made. firstly, the results were evaluated on biopsy specimens and not on the entire prostate gland or by performing a template mapping biopsy; secondly, although our study represent the real life clinical practice a quality control of the affiliated radiological centers was unknown. finally, a greater number of patients and a centralized evaluation of mpmri results should be performed; moreover, among the 361 men with pi-rads score 3 only 210 (58.2%) underwent fusion targeted prostate biopsy. in conclusion, pi-rads 3 lesions exhibited aggressive features in a not negligible proportion of cases but a quality control of mpmri by experienced radiologists improve the accuracy of the procedure; a second opinion is mandatory especially in men enrolled in as protocols in whom clinical parameters (5, 24, 25) and mpmri (2628) are recommended to reduce the number of scheduled repeated prostate biopsies. references 1. kasivisvanathan v, rannikko as, borghi m, and precision study group collaborators. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med 2018; 378:1767-1777. 2. pepe p, pepe g, pepe l, et al. cost-effectiveness of multiparametric mri in 800 men submitted to repeat prostate biopsy: results of a public health model. anticancer res. 2018; 38:2395-2398. 3. mottet n, cornford p, van der bergh rcn, et al. eau oncology guideline: prostate cancer. 2020. 4. pepe p, garufi a, priolo gd, et al. accuracy of 3 tesla pelvic phased-array multiparametric mri in diagnosing prostate cancer at repeat biopsy. arch ital urol androl. 2014; 4:336-339 5. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores clin genitourin cancer 2021; s1558-7673(21)00027-6. 6. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol. 2018; 200:774-778, 2018. 7. pepe p, garufi a, priolo g, and pennisi m. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol 2016; 34:12491453. 8. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol. 2017; 51:260-263. 9. pepe p, cimino s, garufi a, et al. detection rate for significant cancer at confirmatory biopsy in men enrolled in active surveillance protocol: 20 cores vs 30 cores vs vs mri/trus fusion prostate biopsy. arch ital urol androl. 2016; 88:300-303. 10. steinkohl f, gruber l, bektic j, et al. retrospective analysis of the development of pirads 3 lesions over time: when is a follow-up mri reasonable? world j urol 2018; 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196:1613-1618. 17. westhoff n, siegel fp, hausmann d, et al. precision of mri/ultrasound-fusion biopsy in prostate cancer diagnosis: an ex vivo comparison of alternative biopsy techniques on prostate phantoms. world j urol. 2017; 35:1015-1022. 18. van der leest m, cornel e, israël b, et al. head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostatespecific antigen: a large prospective multicenter clinical study. eur urol. 2019; 75:570-578. 19. ahmed hu, el-shater bosaily a, brown lc, et al. diagnostic accuracy of multi-parametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. lancet. 2017; 389:815-822. 20. maggi m, panebianco v, mosca a, et al. prostate imaging reporting and data system 3 ccategory cases at multiparametric magnetic resonance for prostate cancer: a systematic review and meta-analysis. eur urol focus. 2020; 6:463-478. 21. roscigno m, stabile a, lughezzani g, et al. multiparametric magnetic resonance imaging and clinical variables: which is the best combination to predict reclassification in active surveillance patients? prostate int. 2020; 8:167-172. 22. wu x, reinikainen p, vanhanen a, et al. correlation between apparent diffusion coefficient value on diffusion-weighted mr imaging and gleason score in prostate cancer. diagn interv imaging. 2017; 98:63-71. 23. kim th, kim ck, park bk, et al. relationship between gleason score and apparent diffusion coefficients of diffusion-weighted magnetic resonance imaging in prostate cancer patients. can urol assoc j. 2016;e377-e382. 24. roscigno m, stabile a, lughezzani g, et al. the use of muktiparametric resonance imaging for follow-up patientes included in active suirvellance protocol, can psa density discriminate patients 141archivio italiano di urologia e andrologia 2021; 93, 2 mpmri pi-rads score 3 lesions diagnosed by reference vs affiliated radiological centers: archivio italiano di urologia e andrologia 2021; 93, 2 p. pepe, g. candiano, l. pepe, m. pennisi, f. fraggetta 142 at different risk of reclassification? clinical genitourinary cancer 2020; 18:e698-e704. 25. pepe p, dibenedetto g, pepe l, pennisi m. multiparametric mri vs select mdx accuracy in the diagnosis of clinically significant pca in men enrolled in active surveillance. in vivo 2020; 34: 393-396. 26. pepe p, davide d’urso, garufi a, et al. multiparametric mri apparaent diffusion coefficient (adc) accuracy in diagnosing clinically significant prostate cancer. in vivo 2017; 31:415-418. 27. lourenço m, pissarra p, vieira d, et al. lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece. arch ital urol androl. 2020; 91:218-223. 28. stanzione a, creta m, imbriaco m, et al. attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: a national survey among italian urologists. arch ital urol androl. 2020; 92:291-296. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital, via messina 829, catania (italy) giuseppe candiano, md urocandia@gmail.com ludovica pepe, md ludopepe97@gmail.com michele pennisi, md michepennisi2@virgilio.it filippo fraggetta, md filippofra@hotmail.com pathology unit, cannizzaro hospital, via messina 829, catania (italy) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3280 original paper no conflict of interest declared. 1863, several biological and epidemiological studies were conducted to demonstrate this. as a result of these studies, although contradictory opinions are present, it is stated that development of prostate cancer (pca) is associated with chronic prostatitis (1, 3). prostatitis, defined as inflammation of the prostate gland, is classified by the national institutes of health (nih) as acute bacterial prostatitis, chronic bacterial prostatitis, inflammatory prostatitis, noninflammatory prostatitis, and asymptomatic prostatitis (4). in a study of 68.675 male patients, the risk of developing pca was found to be increased in patients with a history of prostatitis and prolonged prostatitis symptoms (5). these findings show that chronic inflammation plays an important role in pca carcinogenesis (6). via altering tumor microenvironment, interleukins (il-8, il-6) released as a result of inflammation may lead to an increase in angiogenesis, broadening of tumor size, build-up of invasive characteristics, progression of pca, and cancer becoming more resistant to androgen blockade or chemotherapy (7, 8). there is no evidence that inflammation is related to tumor aggressive pca. because of the discrepancy between gleason score (gs) detected in prostate biopsy and gs of radical prostatectomy (rp) specimen, it is difficult to predict tumor aggressiveness, and this may change the appropriate treatment options for patients. in the literature, advanced age, serum prostate-specific antigen (psa) elevation, psa density (psad), and multi-parametric magnetic resonance imaging (mp-mri) have been reported to be predictors of gs upgrade (gsu) in various studies (9, 10). the increase in tumor aggressiveness resulting from chronic inflammation suggests that it may be a predictor for gsu. in the published literature, no study has examined the relationship between the presence of chronic inflammation associated with pca and gsu. the aims of this study was to determine the predictive effect of coexisting chronic prostatitis in pca diagnosed by prostate biopsy on gsu in rp specimen. materials and methods patient selection after obtaining institutional review board approval (2018/267) objective: this study aimed to determine the predictive effect of the presence of chronic prostatitis associated with prostate cancer (pca) in prostate biopsy on gleason score upgrade (gsu) in radical prostatectomy (rp) specimens. materials and methods: the data of 295 patients who underwent open or robotic rp with a diagnosis of localized pca following biopsy were retrospectively analyzed. patients were divided into two groups with and without gsu following rp. predictive factors affecting gsu on biopsy were determined. the impact of chronic prostatitis associated with prostate cancer on gsu was examined via logistic regression analysis. results: out of 224 patients with gleason 3+3 scores on biopsy, 145 (64.7%) had gleason upgrade, and 79 (35.2%) had no upgrade. whilst comparing the two groups with and without gleason upgrade in terms of patient age, prostate-specific antigen (psa) value, psa density (psad), prostate volume (pv), neutrophil/lymphocyte (n/l) ratio, number of positive cores, percentage of positive cores, and prostate imaging reporting and data system version 2 score, no statistically significant difference was detected. the presence of chronic prostatitis associated with pca was higher in the patient cohort with gsu in contrast to the other group (p < 0.001). according to the univariate logistic regression analysis, the presence of chronic prostatitis was identified to be an independent marker for gsu. conclusions: pathologists and urologists should be careful regarding the possibility of a more aggressive tumor in the presence of chronic inflammation associated with pca because inflammation within pca was revealed to be linked with gsu after rp. key words: prostate cancer; prostate biopsy; chronic prostatitis; prostate inflammation. submitted 16 march 2021; accepted 7 may 2021 introduction inflammation may play a role in the development and progression of many cancers (1). in various epidemiologic studies, it is noted that ulcerative colitis, esophagitis, and hepatitis cause an increased risk for the development of malignant neoplasm and that chronic inflammation accompanies 17% of all cancers (2). after rudolf virchow identified the relationship between inflammation and cancer in the presence of chronic inflammation in positive prostate biopsy is associated with upgrading in radical prostatectomy ekrem guner 1, yavuz onur danacioglu 1, yusuf arikan 1, kamil gokhan seker 1, salih polat 2, halil firat baytekin 3, abdulmuttalip simsek 1 1 university of health sciences, bakirkoy dr. sadi konuk training and research hospital, department of urology, istanbul, turkey; 2 amasya university medical faculty, department of urology, amasya, turkey; 3 university of health sciences, bakirkoy dr. sadi konuk training and research hospital, department of pathology, istanbul, turkey. doi: 10.4081/aiua.2021.3.280 summary 281archivio italiano di urologia e andrologia 2021; 93, 3 chronic inflammation and upgrading in radical prostatectomy for the study, the data of 295 patients who underwent prostate biopsy due to high psa levels after antibiotic therapy, psa elevation together with suspicious digital rectal examination (dre) or psa elevation together with mpmri findings and whose results showed prostate cancer and underwent radical prostatectomy from may 2012 to december 2018 were reviewed, retrospectively. patients receiving anti-androgen therapy, those with history of radiotherapy, patients with a previous biopsy history, those included in active surveillance (as), patients with primary metastatic pca, and subjects with incomplete data were excluded. transrectal ultrasound (trus)-guided (ge logic 9; general electric, milwaukee, wi, usa) prostate biopsy (trus-bx) was performed through an e8c 7.5-mhz transrectal linear array transducer placed in an automatic biopsy gun (acecut; taf, tochigi, japan) equipped with an 18-gauge biopsy needle (magnum; bard, covington, ga, usa). regions suspicious for malignancy on mpmri (targeted lesions) were sampled with two cores. this was followed by standard 10-core systemic biopsies that were taken from patients dependent on prostate volume. all mri target trus-bx and rp specimens were collected at our institution, and we obtained actual pathologic tissue slides for examination by two pathologists. the clinical and pathologic data included preoperative psa measured prior to dre and trus, psad, prostate volume (assessed by trus), gs of trus-bx and rp specimens, evidence of histologic chronic prostatitis on biopsy, number and percentages of positive cores in biopsy samples, the final (pathologic) gs of rp specimens, and prostate imaging reporting and data system version 2 (pirads) scores in mpmri. pathologic assessment all pathology specimens were evaluated by two experienced uropathologists. trus-bx specimens were analyzed in terms of the following: tumor type, gs, number of tumor localizations and positive core ratios, presence of perineural invasion, evidence of high-grade prostatic intraepithelial neoplasia (pin) in tumor-free areas, presence of atypical small acinar proliferation (asap), evidence of atrophy, and presence of chronic or active prostatitis along with its extent. rp specimens were assessed more thoroughly; the factors taken into consideration in addition to the parameters described above for trus-bx were as follows: intraductal component, predominant tumor localization and diameter, the status of surgical margins, seminal vesicle involvement, and bladder neck invasion. histopathologic diagnosis of chronic inflammation in the prostate was made by the presence of primarily lymphocytes (predominantly t lymphocytes) infiltrating the stromal and/or glandular component; neutrophils infiltrating the glands in some cases, even playing a role in development of luminal micro-abscesses or larger prostatic abscesses; macrophages to a lesser extent; plasma cells; and eosinophil leukocytes. the diagnosis of prostatitis was defined as chronic active prostatitis via the detection of neutrophils infiltrating the glandular epithelium within more than one gland and more than one core, or as chronic prostatitis in cases of uncertain neutrophilic infiltration by identification of increased number of lymphocytes (with or without histiocytes) forming aggregates in parenchyma, as well as infiltrating the glands. in our study, gs in acinar adenocarcinoma were compared between trus-bx and rp specimens for the same patient. in rp specimens, an increase in numerical value of gs or a change from a total score in trus-bx of 3+4 = 7 to a score of 4+3 = 7, was acknowledged as gsu (11). statistical analysis statistical analysis was performed using the statistical package of social sciences version 21 software package (ibm spss statistics; ibm corp., armonk, ny). the shapiro-wilk test was used to determine whether distributions of continuous variables were normal. the mean differences between two related groups of normally distributed data were compared by independent ttest, and the mann-whitney u test was used to compare non-normally distributed data. the effect of the presence of prostatitis on biopsy upon gleason score upgrade was examined using logistic regression analysis. the chisquare (χ2) test was used for comparison of qualitative independent variables within groups. a p value ≤ 0.05 was considered statistically significant. results a total of 295 patients with complete clinical and pathologic data who underwent open or robotic rp with the diagnosis of localized pca after biopsy were included in the study for analysis. overall, the mean age, psa, psad, and pv were respectively 61.4 ± 6 years, 9.5 ± 6 ng/ml, 23 ± 17.2 and 45.5 ± 17.3 cm3. histopathologic analysis following trus-bx revealed 224 (75.9%) patients with gs 3+3, 52 (17.6%) patients with gs 3+4, 15 (5%) patients table 1. patient characteristics. age (years, mean ± sd) 61.4 ± 6.0 psa value (ng/ml, mean ± sd) 9.5 (6.0) psa density (ng/ml2, mean ± sd) 23.0 (17.2) prostate volume, n (%) ≤ 35 83 35-65 173 ≥ 65 39 neutrophil/lymphocyte ratio (n/l) (mean ± sd) 5.2 (3.3) biopsy gleason score, n (%) 3+3 224 (75.9) 3+4 52 (17.6) 4+3 15 (5) 8 3 (1) 9-10 1 (0.3) no. of positive cores, n (%) 3.73 (2.1) percentages of positive cores, n (%) 35.9 (21.5) mr pi-rads category, n (%) ≤ 2 53 (17.9) 3 50 (16.9) 4 179 (60.6) 5 13 (4.4) prostatectomy gleason score, n (%) 3+3 79 (26.7) 3+4 131 (44.4) 4+3 47 (15.9) 8 21 (7.1) 9-10 17 (5.7) archivio italiano di urologia e andrologia 2021; 93, 3 e. guner, y. onur danacioglu, y. arikan, k. gokhan seker, s. polat, h. firat baytekin, a. simsek 282 with gs 4+3, 3 (1%) patients with a total gs of 8, and 1 (0.3%) patient with a total gs of 9-10. the median number of positive cores detected as cancer on biopsy was 3 (range, 1-12), and the mean percentage of positive cores was 30% (range, 6-100%). in mpmri performed prior to biopsy, the results indicated the following: 53 (17.9%) patients with a pirads 2, 50 (16.9%) patients with a pirads 3, 179 (60.6%) patients with a pirads 4, and 13 (4.4%) patients with a pirads 5 lesion. on histopathologic examination of rp specimens, 79 (26.7%) patients had gs of 3+3, 131 (44.4%) patients had gs of 3+4, 47 (15.9%) patients had gs of 4+3, 21 (7.1%) patients had gs of 8, and 17 (5.7%) patients had gs of 9-10 (table 1). based on these findings, 145 (64.7%) of the total 224 patients with a gs of 3+3 on trus-bx were identified as having gsu, and 79 (35.2%) had no upgrade (table 2). there was no statistically significant difference observed between the two groups with and without gsu in terms of patient age, psa value, psad, prostate volume, neutrophil/lymphocyte (n/l) ratio, number of positive cores, percentage of positive cores, and pirads score (table 3). the presence of chronic prostatitis associated with pca was higher in the gsu group in comparison with the other group (p < 0.001). according to the univariate logistic regression analysis, the presence of chronic prostatitis was found to be an independent predictor for gsu (or: 2.98, 95% ci, p < 0.001) (table 4). discussion ethnic origin, age, and family history are amongst the known risk factors of pca, yet there are many other probable risk factors currently being researched. epidemiologic, genetic, and experimental studies have suggested that chronic inflammation may be associated with pca, though this is unclear (12). although prostatitis is defined as inflammation of the prostate gland in terms of pathologic description, it has traditionally been used to express the clinical picture of urinary tract symptoms, inflammation, pain of prostate origin, and not fully understood etiopathogenesis. pathologically, evidence of neutrophils, eosinophils, lymphocytes, macrophages, and plasma cells in the parenchyma is presented as prostatitis (13). the incidence of prostatitis in the male population is 4.5-9%; it is as common as ischemic heart disease and diabetes in the population (14, 15). chronic asymptomatic inflammatory prostatitis is described as category iv according to the nih classification and as the presence of inflammatory cells in biopsy specimens of asymptomatic patients with high psa values (16). in patients with a psa value of > 4 ng/ml, the incidence of chronic prostatitis is reported as 42% (17). although no verifiable infectious agent has been identified, an increase in psa values may be present in cases where the rate of inflammation within the prostate is above 20% (18). inflammatory infiltrates include t lymphocytes, macrophages, plasma cells, and eosinophils. the presence of cd-204 macrophages and cd-3 t lymphocytes play a role in tumor development. the pro-carcinogenic inflammatory process leads to cell transformation by activation of transcription factor nf-kb and a consequent increase of tumor necrosis factor (tnf)-a and il-6 (19). in addition, il-30 has been shown to take part in pca stem-like cell regulation and is proven to be responsible for onset, vascularization, and increased tumor proliferation (20). in recent years, vav3 oncogene has been documented to cause both chronic prostatitis and pca (21). studies in the literature indicate that the presence of chronic prostatitis increases the risk of pca by table 2. radical prostatectomy grades stratified by biopsy gleason scores. biopsy gs 5-6 3+4 4+3 8 9-10 total radical prostatectomy gs 3+3 79 0 0 0 0 79 3+4 106 25 0 0 0 131 4+3 29 17 1 0 0 47 8 7 3 10 1 0 21 9-10 3 7 4 2 1 17 total 224 52 15 3 1 295 table 3. clinical and pathologic parameters with gleason score (gs) group: upgrading from biopsy gs 5-6 to gs > 6 at radical prostatectomy. variables upgrade (n = 145) no upgrade (n = 79) p value age 0.099 mean (sd) 61.5 (5.7) 60.3 (6.4) median (range) 61.0 (46-78) 60.0 (47-74) psa 0.902 mean 9.8 (6.3) 9.0 (4.5) median 8.0 (1.8-43.0) 7.5 (3.3-27.0) psa density 0.285 mean 22.3 (17.1) 22.2 (13.1) median 16.0 (4.8-122.8) 19.6 (5.3-67.5) prostate volume 0.282 ≤ 35 31 26 35-65 91 39 ≥ 65 23 14 nl ratio 0.148 mean 5.4 (3.4) 4.7 (2.7) median 4.9 (1.1-20.8) 4.3 (1.1-15.0) no. of positive cores 0.141 mean 3.75 (2.3) 3.1 (1.6) median 3.0 (1-12) 3.0 (1-8) percentages of positive cores 0.166 mean 36.1 (22.5) 30.4 (16.8) median 30.0 (6-100) 30.0 (8-83) mr pi-rads category 0.729 ≤ 2 34 15 3 21 16 ≥ 4 90 48 bx result < 0.001 pca with chronic prostatitis 82 24 pure pca 63 55 table 4. univariate logistic regression model to prediction of upgrading from biopsy gs 5-6 to gs > 6 at rp. variable or (95% ci) p value bx result pure pca ref pca with chronic prostatitis 2.983 (1.668-5.333) < 0.001 283archivio italiano di urologia e andrologia 2021; 93, 3 chronic inflammation and upgrading in radical prostatectomy 1.83-fold (22). some authors state that the use of aspirin or non-steroidal anti-inflammatory drugs (nsaids) decreases the risk of pca (23). apart from the chemokines and cytokines produced in chronic prostatitis, inflammatory cells provide a microenvironment favorable to tumor progression by increasing production of oxygen species, which induce oxidative dna damage, reducing dna repair, stimulating tumor growth and angiogenesis (12). in patients with pca not detected on the first biopsy, the incidence of pca was found to be higher in patients with histologically demonstrated chronic inflammation after the 5-year follow-up in comparison with patients without chronic inflammation (20% vs. 6%) (24). furthermore, evidence of chronic inflammation along with pca results in patients having a more aggressive and advanced disease. patients with high-grade inflammation surrounding malignant glands had significantly more advanced disease and higher postoperative biochemical recurrence (bcr) rates than patients with low-grade inflammation (25, 26). considering the current studies, it is thought that cooccurrence of pca and chronic inflammation might also be associated with the possibility of gsu, which is encountered in clinical practice with a 44% probability. in different studies, several markers such as higher psa, older age, higher percentage of positive cores, lower prostate volume, psad, and mp-mri findings have been identified as important indicators for upgrading and upstaging (9, 10). gsu may be associated with outcomes of rp including extra prostatic extension, positive surgical margin, and seminal vesicle invasion. this may lead us to be more selective in determining as patients and may result in bcr during follow-up of these patients (9). in our study, factors described in previous studies for gsu were also reviewed, yet the presence of chronic prostatitis on biopsy accompanying pca was the only significant marker for gsu according to logistic regression analysis. there are several studies in the literature in relation to the prediction of gsu using the n/l ratio prior to surgery. although caution is advised regarding gsu in patients with n/l ≥ 3, some studies reveal no relationship between this finding and gsu (27). the n/l ratio was not classified as a predictive factor for gsu in our study. the intraobserver match was 41-43% in the histopathologic assessment of trus-bx and rp specimens, but in our study, the possibility of misevaluation was eliminated via analysis of biopsy and rp specimens by two uropathologists. the point, as identified in our study, that the presence of chronic inflammation is a significant marker for gsu, is important for clinical practice and future studies. porcaro et al. (28) showed that patients diagnosed with low-risk pca in biopsy are a heterogeneous group, in fact, these patients may represent a higher disease than their psa and positive cores. on the other hand, gurel et al. (29) found that men with more intraprostatic inflammation in patients with prostate cancer had a higher risk of poor outcomes. as which is the first-line treatment plan for patients in the low risk group, is not a suitable treatment option in terms of gsu risk for patients with evidence of chronic inflammation. with the support of these studies in the future, we argue that one of the as exclusion criteria should be the presence of prostatitis in the biopsy. our study has some limitations that should be taken into consideration. first, this was designed as a retrospective study. we did not quantify the extent of inflammation within each prostate specimen. they could not determine the relationship between the degree of inflammation and tumor aggressiveness. we did not report the presence of other prostatic lesions such as high grade pin, postatrophic hyperplasia or proliferative inflammatory atrophy. due to the design of our study, it was not possible to assess the association of chronic inflammation presence with more aggressive outcomes. our findings should be confirmed using more distant end points such as metastasis and survival. conclusions the present study showed that inflammation within pca was associated with gsu after rp. hence, pathologists and urologists should be cautious about the possibility of a more aggressive tumor in the presence of chronic inflammation associated with pca. this may be due to inflammatory mediators promoting development of aggressive pca. our study is the only study to demonstrate the relationship between chronic inflammation and gsu. however, prospective studies are required in order to examine clinical reflection and the long-term outcomes of our study. references 1. cai t, santi r, tamanini i, et al. current knowledge of the potential links between inflammation and prostate cancer. int j mol sci. 2019; 20:3833. 2. jiang j, li j, yunxia z, et al. the role of prostatitis in prostate cancer: meta-analysis. plos one. 2013; 8:e85179. 3. sfanos ks, yegnasubramanian s, nelson wg, de marzo am. the inflammatory microenvironment and microbiome in prostate cancer development. nat rev urol. 2018; 15:11-24. 4. puhr m, de marzo a, isaacs w, et al. inflammation, microbiota, and prostate cancer. eur urol focus. 2016; 2:374-82. 5. cheng i, witte js, jacobsen sj, et al. prostatitis, sexually transmitted diseases, and prostate cancer: the california men's health study. plos one. 2010; 5:e8736. 6. neveu b, moreel x, deschênes-rompré m-p, et al. il-8 secretion in primary cultures of prostate cells is associated with prostate cancer aggressiveness. res rep urol. 2014; 6:27. 7. araki s, omori y, lyn d, et al. interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. cancer res. 2007; 67:6854-62. 8. nguyen dp, li j, tewari ak. inflammation and prostate cancer: the role of interleukin 6 (il-6). bju international. 2014; 113:986-92. 9. alchin dr, murphy d, lawrentschuk n. risk factors for gleason score upgrading following radical prostatectomy. minerva urol nefrol. 2017; 69:459-65. 10. dinh kt, mahal ba, ziehr dr, et al. incidence and predictors of upgrading and up staging among 10,000 contemporary patients with low risk prostate cancer. j urol. 2014; 194:343-9. 11. moussa as, li j, soriano m, et al. prostate biopsy clinical and pathological variables that predict significant grading changes in archivio italiano di urologia e andrologia 2021; 93, 3 e. guner, y. onur danacioglu, y. arikan, k. gokhan seker, s. polat, h. firat baytekin, a. simsek 284 patients with intermediate and high grade prostate cancer. bju international. 2009; 103:43-8. 12. doat s, cénée s, trétarre b, et al. nonsteroidal anti-inflammatory drugs (nsaid s) and prostate cancer risk: results from the epicap study. cancer med. 2017; 6:2461-70. 13. nickel jc, true ld, krieger jn, et al. consensus development of a histopathological classification system for chronic prostatic inflammation. bju international. 2001; 87:797-805. 14. clemens jq, meenan rt, rosetti mck, kimes t, calhoun ea. prevalence of and risk factors for prostatitis: population based assessment using physician assigned diagnoses. j urol. 2007; 178:1333-7. 15. teke k, danacıoglu yo, polat s. predictive parameters on the effect of ofloxacin treatment on the reduction of psa in patients with elevated psa level. yeni üroloji dergisi the new journal of urology. 2019; 14:166-75. 16. polackwich a, shoskes d. chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. prostate cancer prostatic dis. 2016; 19:132. 17. potts jm. prospective identification of national institutes of health category iv prostatitis in men with elevated prostate specific antigen. j urol. 2000; 164:1550-3. 18. carver bs, bozeman cb, williams b, venable dd. the prevalence of men with national institutes of health category iv prostatitis and association with serum prostate specific antigen. j urol. 2003; 169:589-91. 19. nguyen dp, li j, yadav ss, tewari ak. recent insights into nfκb signalling pathways and the link between inflammation and prostate cancer. bju international. 2014; 114:168-76. 20. sorrentino c, ciummo sl, cipollone g, et al. interleukin30/il27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization. cancer res. 2018; 78:2654-68. 21. liu y, mo jq, hu q, et al. targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. cancer res 2008; 68:6396-406. 22. perletti g, monti e, magri v, et al. the association between prostatitis and prostate cancer. systematic review and meta-analysis. arch ital urol androl. 2017; 89:259-65. 23. jafari s, etminan m, afshar k. nonsteroidal anti-inflammatory drugs and prostate cancer: a systematic review of the literature and meta-analysis. can urol ass j. 2009; 3:323. 24. delongchamps nb, de la roza g, chandan v, et al. evaluation of prostatitis in autopsied prostates—is chronic inflammation more associated with benign prostatic hyperplasia or cancer? j urol. 2008; 179:1736-40. 25. klink jc, bañez ll, gerber l, et al. intratumoral inflammation is associated with more aggressive prostate cancer. world j urol. 2013; 31:1497-503. 26. mcardle p, canna k, mcmillan d, et al. the relationship between t-lymphocyte subset infiltration and survival in patients with prostate cancer. br j cancer. 2004; 91:541. 27. özsoy m, moschini m, fajkovic h, et al. elevated preoperative neutrophil-lymphocyte ratio predicts upgrading at radical prostatectomy. prostate cancer prostatic dis. 2018; 21:100. 28. porcaro ab, siracusano s, de luyk n, et al. low-risk prostate cancer and tumor upgrading in the surgical specimen: analysis of clinical factors predicting tumor upgrading in a contemporary series of patients who were evaluated according to the modified gleason score grading system. curr urol. 2017; 10:118-125. 29. gurel b, lucia ms, thompson im jr, et al. chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. cancer epidemiol biomarkers prev. 2014; 23:847-56. correspondence ekrem guner, md (corresponding author) ekremguner@yahoo.com yavuz onur danacioglu, md dr_yonur@gmail.com yusuf arikan, md dryusufarikan@gmail.com kamil gokhan seker, md gkhnseker@hotmail.com abdulmuttalip simsek, md simsek76@yahoo.com university of health sciences, bakirkoy dr. sadi konuk training and research hospital, department of urology, istanbul (turkey) zuhuratbaba mh. tevfik saglam cd. no:11 bakirkoy, istanbul (turkey) salih polat, md salihpolat@gmail.com amasya university medical faculty, department of urology, amasya (turkey) akbilek mah. muhsin yazıcıoglu cad. no:7, amasya (turkey) orcid:0000-0002-7580-6872 halil firat baytekin, md baytekin2001@yahoo.com university of health sciences, bakirkoy dr. sadi konuk training and research hospital, department of pathology, istanbul (turkey) zuhuratbaba mh. tevfik saglam cd. no:11 bakirkoy, istanbul (turkey) 97archivio italiano di urologia e andrologia 2020; 92, 2 original paper pediatric-adolescent andrology: single centre experience nicola zampieri, francesco camoglio woman & child hospital, department of surgery, dentistry, paediatrics and gynecology; division of pediatric surgery, university of verona, italy. introduction: andrology is the medical specialty dealing with men’s health and reproductive system from birth to adulthood, including genital, hormonal, reproductive, sexual as well as psychological aspects; the aim of this study is to report our 10 year-experience material and methods: in september 2009, a pediatric andrology outpatient clinic was opened at the authors’ institution. the continuous request for access to the service, together with an increasingly helpful collaboration with local clinicians, has led to an increase in the number of treated patients. at the clinic, visits are performed for both surgical and medical consultations by the multidisciplinary medical group for the treatment of conditions in the adolescent patient. all patients are followed every 3, 6 and 12 months when indicated. patients with undescended testes were excluded because managed into a specific protocol. also patients with syndrome or metabolic diseases are excluded from the analysis. results: during the study period, september 2009-september 2019, the following conditions were managed: varicocele 1436 patients; gynecomastia 18 patients; penile curvature 89 patients; webbed penis 132 patients; hypospadias-related diseases 39 patients; erectile dysfunction 14 patients; obesity and abnormal semen analysis 47 patients. during the study period there was an increase for each category especially for medical reasons. conclusions: pediatric-adolescent andrology clinics should count on the expertise of different skilled professionals to cope with an ever-increasing number of requests and to offer the timely management of conditions that until very recently were considered social taboos or caused concern only in adulthood like the erectile dysfunction. the evolution of our society, which also means evolution of the mass media, should go hand in hand with the development of medicine, which needs to adjust to and prevent new healthcare issues. key words: pediatric andrology; varicocele; undescended testes; adolescent. submitted 7 january 2020; accepted 28 january 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.97 introduction andrology is the medical specialty dealing with men’s health and reproductive system from birth to adulthood, including genital, hormonal, reproductive, sexual as well as psychological aspects (1). regular andrological check-ups are essential to reveal possible problems and to receive thorough advice and information so that sexual and reproductive functions are well preserved. estimates report that about one in three males suffers from andrological diseases with rates varying according to the age: 27-30% of pediatric male subjects have reproductive and/or sexual conditions, especially cryptorchidism, varicocele, hypogonadism, congenital anomalies of the genitourinary tract and sexually transmitted diseases; in adulthood, 40% of men are affected by andrological diseases, in particular infertility and sexual problems. the main surgically correctable diseases to prevent hypofertility are varicocele (30%) and undescended testes (< 5%) (1-3). the origin of many of the andrological conditions appearing during adulthood is to be traced before the age of 18 years and sometimes even during gestation. the male gonad is extremely sensitive to external events even during gestation and soon after childbirth up until puberty (4-5). the andrological evaluation of pediatric patients is therefore extremely important for an early diagnosis of genital anomalies such as penile alterations or abnormal positions of the testis; early evaluation is helpful also to search for risk factors in terms of male general and sexual health. the aim of this study was to report the authors’ 10-year experience at the pediatric andrology outpatients clinic of their institution, focusing on the different aspects of surgically treated andrological diseases and on the type of andrological requests. materials and methods in september 2009, a pediatric andrology outpatients clinic was opened at the institution of authors. the continuous request for access to the service, together with an increasingly helpful collaboration with local clinicians, has led to an increase in the number of treated patients. at the clinic, visits are performed both for surgical conditions and for medical consultations when required by the multidisciplinary medical group for the treatment of conditions in the adolescent patient. through the review of the cases, the aim was to focus on the type of conditions and the ever-increasing requests for advice and treatment. the study excluded the patients with phimosis, undescended testes and hypospadias, although it included penile complications such as residual penile curvatures or requests for penile lengthening. upon specific request, some patients had hormonal tests and semen analysis performed. at the authors’ clinic, any patient who has accomplished his pubertal stage can perform semen analysis, even though he is a minor, provided that an informed consent has been signed by the patient together with his referring physician and his parzampieri_stesura seveso 17/06/20 10:13 pagina 97 archivio italiano di urologia e andrologia 2020; 92, 2 n. zampieri, f. camoglio 98 ents. for undescended testes the clinic adopts a specific follow-up procedure, which is not always performed by the same medical team (6). other diseases, such as klinefelter, metabolic diseases or oncologic conditions are managed with a multidisciplinary approach. depending on the different conditions, patients are followed every 3, 6 or 12 months. the clinic medical team includes 2 senior pediatric surgeons (1 with high specialty in andrology and urology), 2 registrars and 1 pediatric radiologist. results during the study period, september 2009-september 2019, the following conditions were managed: varicocele 1436 patients; gynecomastia 18 patients; penile curvature 89 patients; webbed penis 132 patients; hypospadias-related diseases 39 patients; erectile dysfunction 14 patients; obesity and abnormal semen analysis 47 patients. patients data and distribution are showed into table 1. varicocele: 548 patients during the study period received surgery with different techniques depending on the type of reflux (7-8). of these, 278 performed a spermiogram. once the pubertal development was accomplished, non-surgical patients were always offered to perform a follow-up spermiogram. gynecomastia: surgery was mainly requested for cosmetic reasons; only 18 cases out of the 69 managed at the clinic showed concomitant hyperplasia of the gland. in 1 case, carcinoma was diagnosed in situ. penile curvature: 89 patients; 27 had a lateral curvature between 60 and 90 degrees, 18 between 45 and 60 degrees and the remaining 44 had a curvature of less than 45 degrees. these included 15 ventral curvatures, 5 dorsal curvatures and 24 lateral curvatures. in 10 patients, exeresis of the traction plate with the addition of biological material resolved the penile curvature. webbed penis: all patients received surgery after one year from birth; in 24 patients the suprapubic fat was removed in addition to the reconstruction of the penoscrotal and penopubic junctions. hypospadias-related diseases: 39 patients; 15 had a residual ventral curvature between 15 and 30 degrees; the remaining patients required lengthening at puberty, with exeresis of the suspensory ligament. in two cases (pubertal patients) the diameter was increased with the addition of biological material. erectile dysfunction: none of these patients had a concomitant surgical condition. 12 patients reported the problem after the age of 15 years, after the first sexual intercourse was reported as being unsatisfactory. two patients over the age of 17 years made a continuous use of drugs. this group of patients included two male subjects over the age of 16 years who suffered from oncological conditions and had received a transplant. obesity and abnormal semen analysis: all the patients accessed the clinic mainly for the evaluation of the size of their external genitalia; all the patients were then offered to perform spermiogram. follow-up during the study period there was an increasing number of requests, with an increasing percentage of those patients requiring medical or aesthetic check. focusing on each specific field, there was a statistical significance increasing percentage between the year 2009-2014 and 2015-2019 (p < 0.05). excluding varicocele group where the percentage is stable during year (range between 475 and 576 visit per year with) the most significance differences were found into the penile curvature group (24 vs 65 cases), hypospadias related disease (12 vs 27 cases) and erectile dysfunction (1 vs 13 cases) (p < 0.05). about webbed penis there was an increasing demand but without statistical differences (59 vs 73 cases) probably because the main request was for phimosis and the final diagnosis for webbed penis. obesity group increased after our national register study about bariatric surgery in adolescent and for this reason it was not possible to add any data about the increasing requests respect to other subgroups (9). in all cases of varicocele, testicular hypotrophy remains the main indication for surgery. as reported in previous studies, all these patients had spontaneous continuous spermatic vein reflux (10-11). they were corrected according to their pubertal stage and a correlation was found between high fsh level and small ipsilateral testicular volume with the controls. for this group motility, morphology and sperm count were significantly reduced than for the patients with the same grade of varicocele and spermatic vein reflux who were treated conservatively (normal testicular size). in terms of hormone levels, only fsh varied significantly in patients with different grades of testicular hypotrophy; it was not possible to observe the same for lh, testosterone (tt), estradiol or prolactin levels, which were not different between operated and non-operated patients. the patients who received post-op semen analysis after 1 year showed a statistically significant improvement in motility and morphology. among non-operated patients, sperm morphology (head anomalies) was the main abnormal parameter, followed by motility and sperm count. these patients with abnormal semen analysis underwent surgery. none of the patients with gynecomastia had abnormal hormone parameters, but for all the operated patients the cumulatable 1. patient distribution. disease number of pts age range 2009-2014 2015-2019 varicocele 1436 13 ± 2.1 727 1436 184 underwent surgery 364 underwent surgery gynecomastia 18 14 ± 0.9 7 11 penile curvature 89 14 ± 3.7 24 65 webbed penis 132 5 ± 1.8 59 73 hypospadias related disease 39 13 ± 3.1 12 27 e.r. 14 16 ± 2.1 1 13 obesity 47 17 ± 1.2 2 45 zampieri_stesura seveso 17/06/20 10:13 pagina 98 tive testicular volume was smaller than for controls (p < 0.05); also, the adolescents with gynecomastia had a testicular volume smaller than those with other andrological disease such as varicocele. only 2 patients had semen analysis after surgery and the parameters were within the reference range. in the penile curvature group, 89 patients, 27 had a lateral curvature between 60 and 90 degrees, 18 between 45 and 60 degrees and the remaining 44 had a curvature of less than 45 degrees. these included 15 ventral curvatures, 5 dorsal curvatures and 24 lateral curvatures. in 10 patients, exeresis of the traction plate with the addition of biological material resolved the penile curvature. the increased request trough the period was probably related to a preventative campaign at school where our team each year performed 2-hour meetings with adolescents focusing about andrological disease. the same is done for female with the gynecologists. all the 132 patients with webbed penis had a surgical reconstruction of the penoscrotal junction and circumcision in case of tight phimosis; 24 patients had removal of suprapubic fat with a semi-circular incision in addition to the reconstruction of the penoscrotal and penopubic junctions. at the end of the follow-up period, 4 patients (aged between 12 and 15 years) underwent varicocelectomy. so far, no sexually active patient has reported any functional problems. even if the main indication for the first visit by the general pediatricians was phimosis, in the first 5 year period, during the years it is was possible to establish an increased request for this specific disease and not only was phimosis, due to the well-known disease by the general pediatricians. the group of patients with complications related to the correction of hypospadias within 18 months from birth was certainly the most difficult to manage. as it is known, the possible complications related to urethroplasty include fistulas and their strictures/stenoses as well as any possible complications or discomfort later during adolescence. 39 patients are currently followed at the clinic for residual ventral curvature between 15 and 30 degrees (15 patients) and for penile lengthening (5 patients aged between 15 and 18 years). 2 patients in this group also requested an increased penile diameter and were treated with a filler. the remaining 10 patients suffer from erection pain and 3 sexually active patients report pain during ejaculation. these last fields are treated and recognized especially in the second 5-year period, due to the multidisciplinary team approach. another group of patients, new in terms of type of condition, is represented by adolescents with erection problems. 14 patients from this group are currently followed at the clinic, all over 15 years of age and sexually active. none has been diagnosed with an organic disease, although most of the patients reported some discomfort during intercourse and a feeling of inadequacy with the partner. it is important to notice that no patient reported erectile dysfunction during masturbation. two patients reported the use and abuse of drugs and alcohol. in general, about 90% of the patients reported difficulties in maintaining the erection but not in its induction. two further patients accessed the clinic after receiving a transplant following a hematological disease. as reported in a previous study, after the clinical and radiological evaluation, they answered a questionnaire on the quality of their sexual life. both were without relapses and reported a reduced quality of erection, especially regarding maintenance (12). this group of patients is the example of the transitional age defect: the age group 13-18 years in the past was never considered, while female are constantly followed by gynecologists. the andrological evaluation and obesity in the pediatric-adolescent age is of recent interest; although this relation is well established for the adults, little has been done for the pediatric age group. the patients who are currently cared for at the authors’ clinic mainly requested first access for a genital evaluation, especially for concealed penis. the hormonal and semen analysis tests (performed on 14 patients out of 47) showed that the testicular volume of overweight/obese adolescents (bmi > 25) was smaller than in patients with a normal weight (p < 0.05). these patients also had a delay in pubertal development and a reduced quality of their semen (mainly indicated by morphologic abnormalities and reduced motility). the study patients did not show abnormal hormone levels (fsh, lh, tt, estradiol) even if the fsh level seems to be higher respect to normal weight patients. discussion andrology greatly trusts primary prevention to reduce the incidence of andrological diseases and conditions. clinical studies and primary prevention policies in andrology should be focused on the most vulnerable crucial phases of male gonad development that can be affected by a variety of external agents. the preservation of the genital and sexual health of young people also means protecting their fertility potential, a very important action within the broader scope of the interventions aimed at reducing the drop in the birth rate which is currently affecting modern society (13-15). it is therefore well established that most of the andrological problems have a prenatal origin and can be diagnosed, studied and treated before adulthood. as reported in a recent study, the prevalence of male adolescent that are followed by andrologists is very low, if compared to female; this could be a “gender” discrimination (16). although the development of the gonads is complex and not yet fully understood, there are some factors that could interfere with their correct anatomical development as well as with the successful pubertal development of the subject. a placental malfunction is associated with an abnormal andrological development: several studies described a relation between fetal growth restrictions and an increased risk of male reproductive problems, including hypospadias, cryptorchidism and testicular cancer (15-19). in addition, twin or triplet pregnancy and preterm birth were shown to be associated with non-gestational impaired reproductive development. again, an increased birth weight in males was also positively correlated with adult serum testosterone levels, while adult men born with lower birth weights were found to display features of hypogonadism, with reduced testicular size, lower 99archivio italiano di urologia e andrologia 2020; 92, 2 pediatric andrology follow-up zampieri_stesura seveso 17/06/20 10:13 pagina 99 archivio italiano di urologia e andrologia 2020; 92, 2 n. zampieri, f. camoglio 100 testosterone levels and higher lh values than controls born with weights within the reference range. other maternal factors can affect fertility: abnormal maternal glucose metabolism in pregnancy may be associated with an increased risk for genital malformation as well as maternal obesity, smoking, maternal serum estrogens, and estrogenic endocrine disruptor exposure (20-24). this point in mind, in order to safeguard the reproductive and sexual health of young men, a synergic approach involving pediatricians, general practitioners, doctors at family planning clinics and andrologists for the adults plays a key role together with the implementation of territorial networks that may enhance the integration of the know-how and expertise of all these health professionals. this is especially true in the extremely vulnerable period of life generally ranging from 11 to 18 years of age, when young male patients experience the transition to adult life and maturity from a reproductive and sexual point of view. if we exclude the cases treated for varicocele, which has a more consolidated follow-up, what emerged from the analysis of the cases treated at the authors’ clinic was a progressive increase in some conditions which were not reported by patients until recent years. the problems related to urethroplasty, obesity, gynecomastia, webbed penis, and erectile dysfunction seem to be common causes of concern related more to the adolescents’ increased awareness and sexual maturity than to real healthcare issues suggested by a territorial primary prevention system. two aspects deserve particular attention: the increase in obesity and in sexual dysfunctions in the adolescents can be considered important risk factors for the andrological health of adults. the merely functional aspect of the erectile dysfunction, if unrelated to conditions of surgical interest (outcome of penile surgery, bladder surgery, anorectal malformations, etc.), is complex to manage. many adolescents experience pubertal development, relationship with their body and with their partners in an increasingly confused context, deeply affected by complex social stereotypes. a recent study pointed out that the main problems reported in addition to pain during intercourse were erectile dysfunction and premature ejaculation (25-27). this latter aspect is difficult to be properly evaluated, since very often it is not clear what teenagers mean by “premature” ejaculation and if the real situation clashes with their expectations, or with what is considered as acceptable by their friends, by their readings on the internet or on the social media, as reported by many patients who accessed the authors’ clinic. a different approach should be used in case of patients with erectile dysfunction associated with a history of cancer. in fact, despite being disease-free, these patients feel discomfort since they consider themselves as cancer patients, as being “different”. in the authors’ experience, these patients are more easily treated because they have faster and more effective response mechanisms to the pathology and to their impaired physical condition than those young patients who have never experienced any pathological condition before (12). obesity in relation to male reproductive health is well recognized, especially in adulthood. obesity alters fertility and the fertility potential through various mechanisms, mainly the reduced quantity of testosterone used and converted into estrogen by the adipocytes and the reduced quality of the seminal fluid. although most of the obese adolescents are monitored for weight reduction primarily to reduce diabetes, hypertension, cardiac risk and orthopedic diseases, little action is taken in terms of fertility potential; in fact, for the obese patients the primary aim is weight loss to improve self-image, while their overall health status is kept in the background. the experience on adult patients treated both clinically and surgically for obesity showed a significant improvement in hormone levels and semen quality in those patients who obtained correct weight control, and this proved to be true for male and female patients alike (27-30). the above considerations should drive patients towards weight control not only for esthetic and certainly important functional reasons, such as reducing hypertension, arthropathies and diabetes, but also to safeguard their fertility potential. prevention policies should be gender specific, with the awareness that if many actions are currently implemented for the prevention of female conditions, little is done for male patients. for young male adults, an objective examination to the genitalia, comprehensive hormone panel tests and a spermiogram can help the diagnosis and early treatment of many conditions that may affect male fertility potential. pediatric-adolescent andrology clinics should count on the expertise of different skilled professionals to cope with an ever-increasing number of requests and to offer the timely management of conditions that until very recently were considered social taboos or caused concern only in adulthood like the erectile dysfunction. the evolution of our society, which also means evolution of the mass media, should go hand in hand with the development of medicine, which needs to adjust to and prevent new healthcare issues. references 1. zampieri n, bianchi f, patanè s, camoglio fs. infertility worldwide: the lack of global pediatric andrologists and prevention. in male reproductive health (eds. wei wu, francesco ziglioli and umberto maestroni) doi: 10.5772/intechopen.88459. 2. datta j, palmer mj, tanton c, et al. prevalence of infertility and help seeking among 15,000 women and men. hum reprod. 2016; 31: 2108-2118. 3. agarwal a, mulgund a, hamada a, chyatte mr. a unique view on male infertility around the globe. reprod biol endocrinol. 2015; 13:37-46. 4. juul a, almstrup k, andersson am, et al. possible fetal determinants of male infertility. nat rev endocrinol 2014; 10:553-562. 5. skakkebaek ne, rajpert-de meyts e, main km. testicular dysgenesis syndrome: an increasingly common development aspects.hum reprod. 2001; 16:972-978. 6. zampieri n, caridha d, patanè s, et al. elastonosographic evaluation of the post-operative morpho-volumetric recovery of the gonad in the cryptorchid patient. am j clin exp urol. 2019; 7:182-187. zampieri_stesura seveso 17/06/20 10:13 pagina 100 101archivio italiano di urologia e andrologia 2020; 92, 2 pediatric andrology follow-up 7. camoglio fs, zampieri n. varicocele treatment in paediatric age:relationship between type of vein reflux, surgical technique used and outcomes andrologia. 2016:; 48:389-392. 8. zampieri n, zuin v, corroppolo m, et al. relationship between varicocele grade, vein reflux and testicular growth arrest pediatr surg int. 2008; 24:727-30.. 9. castellani r, toppino m, favretti f, et al. national survery fro bariatric procedures in adolescents:long time follow-up. j pediatr surg. 2017; 52:1602-1605. 10. zampieri n, corroppolo m, zuin v, et al. longitudinal study of semen quality in adolescents with varicocele: to treat or not? urology. 2007; 70:989-993. 11. zampieri n, zuin v, corroppolo m, et al. varicocele and adolescents: semen quality after 2 different laparoscopic procedures. j androl. 2007; 28:727-33. 12. andreini a, zampieri n, costantini c, et al. chronic graft versus host disease is associated with erectile dysfunction in allogenic hematopoietic stem cell transplant patients: a single center experience. leuk lymphoma. 2018; 21:1-4. 13. brauner ev, hansen am, doherty da, et al. the association between in utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: the taine study. hum reprod. 2019; 34:1345-1355. 14. bouty a, ayers kl, pask a, et al. the genetic and environmental factors underlying hypospadias. sex dev. 2015; 9:239-259. 15. rae mt, kyle ce, miller dw, et al. the effects of undernutrition, in utero, on reproductive function in adult male and female sheep. anim reprod sci. 2002; 72:63-71. 16. olana s, mazzilli r, delfino m, et al. adolescence and andrologist: an imperfect couple. arch ital urol androl. 2018; 90:208211. 17. trabert b, chodick g, shalev v, et al. gestational diabetes and the risk of cryptorchidism and hypospadias. epidemiology. 2014; 25:152-153. 18. van der zanden lf, van rooij ia, feitz wf, fet al. aetiology of hypospadias: a systematic review of genes and environment. hum reprod update. 2012; 18:260-283. 19. nordenvall as, frisen l, nordenstrom a, et al. population based nationwide study of hypospadias in sweden, 1973 to 2009: incidence and risk factors. j urol. 2014; 191:783-789. 20. guerrero-bosagna cm, skinner mk. epigenetic transgenerational effects of endocrine disruptors on male reproduction. semin reprod med. 2009; 27:403-408. 21. hart rj, doherty da, mori ta, et al. features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age. hum reprod. 2019; 34:389-402. 22. bonde jp, flachs em, rimborg s, et al. the epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. hum reprod update. 2016; 23:104-125. 23. anway md, cupp as, uzumcu m, skinner mk. epigenetic transgenerational actions of ndocrine disruptors and male fertility. science. 2005; 308:1466-1469. 24. o'sullivan lf, byers es, brotto la, et al. a longitudinal study of problems in sexual functioning and related sexual distress among middle to late adolescents. j adolesc health. 2016; 59:318-324. 25. wiggins a, tsambarlis pn, abdelsayed g, levine la. a treatment algorithm for healthy young men with erectile dysfunction. bju int. 2019; 123:173-179. 26. o'sullivan lf, brotto la, byers es, et al. prevalence and characteristics of sexual functioning among sexually experienced middle to late adolescents. j sex med. 2014; 11:630-41. 27. wozniak se, gee ll,wachtel ms, frezza ee. adipose tissue: the new endocrine organ? a review article. dig dis sci. 2009; 54:1847-1856. 28. lima n, cavaliere h, knobel m, et al. decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat. int j obes relat metab disord. 2000; 24:14331437. 29. jensen tk, andersson a-m, jørgensen n, et al. body mass index in relation to semen quality and reproductive hormones among 1,558 danish men. fertil steril. 2004; 82:863-870. 30. hammoud ao, gibson m, peterson cm, et al. obesity and male reproductive potential. j androl. 2006; 27:619-626. correspondence nicola zampieri, md, phd (corresponding author) nicola.zampieri@aovr.veneto.it francesco saverio camoglio, md, prof francesco.camoglio@univr.it pediatric surgical unit, azienda ospedaliera universitaria integrata piazzale aristide stefani 1, 37100 verona (italy) zampieri_stesura seveso 17/06/20 10:13 pagina 101 stesura seveso 455archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. introduction the year 1962 recognized the first woman as a board-certified urologist in the united states (1). urology, like most other surgical disciplines of medicine, has traditionally been a male-dominated specialty. however, keeping pace with the quickly changing gender landscape, medical professions are also characterized by waves of feminization, with a steady and significant increase in the number of women working in urological practice and research over the recent years (2). although still a minority, female urologists tend to perform more gender-neutral index surgical procedures on female patients relative to their male counterparts (3). despite more women being attracted towards medicine, and qualifying as doctors, their career progression can be hindered by organizational barriers with rigid career structures that may favor their male counterparts (4). continued advancement of women in academic surgery is dependent on addressing these concerns including the lack of gender equality, effective mentorship, and work-life balance facilitating family responsibilities (5). the rising trends of invited female speakers at academic conferences present an opportunity for increased representation within urology leadership (6). we aimed to understand the perspectives of women urologists on the obstacles to their career development, and the impact of such hurdles on their professional roles in urological education, practice, and leadership, through a webinar-based survey. our objective was to understand the different barriers to career development experienced by female urologists, the gender disparity in urology, and the common factors affecting them. we also aimed to acknowledge the interest and involvement of female urologists in mentorship, leadership, and charity-based services. background: urology, traditionally a maledominated specialty, keeping pace with the quickly changing gender landscape, has been characterized by waves of feminization. this study aims to understand the perspectives of women urologists on the obstacles to their career development, and the impact of such hurdles on their professional roles in urological education, practice, and leadership. methods: 119 female urology residents/consultants were surveyed via a webinar-based platform, covering relevant questions on domains of academia, mentorship, leadership, parenting, and charity. statistical analysis was done using frequency distribution based on the responses. results: 46.8% of the respondents felt that there is an under-representation of women in academia. ‘having a good mentor’ was the most important factor for a novice to succeed in academia (68%). the most important trait in becoming a good leader was ‘good communication skills’ (35%), followed by ‘visionary’ (20%). the greatest challenge faced by leaders in the medical field was considered as ‘time management’ (31.9%). only 21.2% of the participants felt difficulty in having a work-personal life balance, whereas 63.8% of them found it difficult only ‘sometimes’. as a working parent, ‘the guilt that they are not available all the time’ was considered the most difficult aspect (59.5%), and ‘more flexible schedule’ was needed to make their lives as a working parent easier (46.8%). 34% of the respondents were affiliated with some charitable organizations. the biggest drive to do charity was their satisfaction with a noble cause (72.3%). conclusions: need for increased encouragement and recruitment of females into urology, and to support and nurture them in their career aspirations. key words: leadership; mentorship; academia; parenting; charity; women in urology; gender disparity. submitted 17 october 2021; accepted 26 october 2021 professional roles of female urologists: a webinar-based survey of perceptions and obstacles to career development sufyan ibrahim 1, 2, amelia pietropaolo 2, 3, nithesh naik 2, 4, anita patel 5, milap j. shah 2, 6, patricia zondervan 7, jean mcdonald 8, 9, bm zeeshan hameed 2, 6, bhavan prasad rai 2, 10, hadis karimi 11, bhaskar k. somani 2, 3, joanne cresswell 12 1 kasturba medical college manipal, manipal academy of higher education, manipal, india; 2 i-true (international training and research in uro-oncology and endourology) group; 3 department of urology, university hospital southampton nhs trust, southampton, uk; 4 faculty of engineering, manipal institute of technology, manipal academy of higher education, manipal, india; 5 global hospitals, maharashtra, india; 6 department of urology, kasturba medical college manipal, manipal academy of higher education, manipal, india; 7 academic medical center, university of amsterdam, netherlands; 8 north middlesex university hospital, sterling way, london, united kingdom; 9 weymouth street hospital, marylebone, london, united kingdom; 10 department of urology, freeman hospital, newcastle upon tyne ne7 7dn, united kingdom; 11 manipal college of pharmacy, manipal academy of higher education, manipal, india; 12 the james cook university hospital, south tees trust, middlesbrough, united kingdom. doi: 10.4081/aiua.2021.4.455 summary archivio italiano di urologia e andrologia 2021; 93, 4 s. ibrahim, a. pietropaolo, n. naik, et al. 456 methods a webinar titled “today’s women tomorrow’s leaders: urology leading the way” was conducted through an online platform with leading female urologists from india, united kingdom, and the netherlands as expert panelists. the target study population and potential respondents were female residents (urology trainees, registrars, and fellows) and urologists (consultants and practicing urologists). the webinar was attended by a total of 659 participants. a total of 43 different countries were represented by one or more participants in the webinar. out of the total number of participants attending the webinar, 65% (n = 428) identified themselves as female participants, of which 28% (n = 119) were female consultants or resident urologists, the responses of whom are included in this study. it is of interest that 35% of participants were male, and this may reflect increasing interest to make urology a more inclusive specialty. a structured poll-based survey to investigate the female-related obstacles was conducted simultaneously with the webinar in progress. the five cornerstone topics that were discussed by the eminent speakers in the webinar were under the aegis of (a) academia, (b) mentorship, (c) leadership, (d) parenting, and (e) charity in urology. the surveying content was initially drafted by the investigating team, which was then circulated and reviewed by the i-true working group. the study was approved by the survey and behavioural institutional ethics committee (iec) of kasturba medical college, manipal (reference no: 628-2020). this methodology is a relatively unique way of receiving responses and has not been widely used in previous surveys. the introduction specifying the objectives and target audience of the study were informed by the moderators of the session. implied consent was assumed when the respondent proceeded to the registration and completion of the webinar. the survey was anonymous. internet protocol (ip) restrictions were implemented, so one ip address could only complete the survey once. all the data were collected and were accessible only by the study investigators. statistical data analysis was done using spss (version-26) software. categorical data were presented with counts and percentages. graphs and charts were appropriately plotted. results a total of 11 different questions related to the five domains were asked during the webinar. a single best response was considered for every question by every pollrespondent. following are the results of responses from female urologists as mentioned in our inclusion criteria (n = 119) with their graphical representation in figure 1 and figure 2. the respondents felt that there is an under-representation of women in academia (46.8%), while 38.3% felt otherwise and 14.89% chose rather not to comment. according to the respondents, the most important factor for a novice to understand and succeed in academia was a good mentor’ (68%). the other traits that were considered important by others were ‘a natural flair for research’ (19.1%), ‘good project’ (8.5%) and ‘being good at statistics’ (4.2%); surprisingly ‘being a good writer’ (0%) was totally out of contention by respondents. a large fraction of our audience (44.6%) had a fixed or structured training module/program at their hospital/institute, but 27.6% did not have it and the other 27.6% had unstructured training modules. according to poll-respondents, the most important trait in becoming a good leader was ‘good communication skills’ (35%), followed by ‘visionary’ (20%). remarkably, an equal number of respondents (15%) considered the ‘ability to prioritize and focus’, ‘influencer/empowering’, and ‘patience or good listener’ as the most important qualities. the greatest challenge faced by leaders in the medical field was answered by a majority as ‘time management’ (31.9%), followed by ‘lack of resources’ and ‘coordination of work amongst members’ (25.5% each), ‘assigning a task as per the ability of the worker or resident’ (10.6%) and ‘patient mistrust’ (6.3%). an important and very pertinent issue highlighted during our webinar was that of a working parent. when polled if they have difficulty having a workpersonal life balance, 21.2% responded as ‘yes’ and 14.8% checked ‘no’. however, most of the respondents (63.8%) found it difficult to balance their work and family only ‘sometimes’. according to the respondents, the most difficult aspect that they consider as a working parent is that of ‘the guilt that they are not available all the time’ (59.5%), while others thought ‘lack of time with kids’ (19.1%), ‘lack of time with spouse’ (14.8%) and ‘unsupportive work colleagues’ (2.1%) as their important hurdles. positively, a small (4.2%) number of them believed that parenting and working are easy. ‘more flexible schedule’ was felt to be the most important factor that could make their lives as a working parent easier or better, by almost half of the respondents (46.8%). others considered ‘more supportive boss or co-worker’ (19.1%), ‘more meaningful work’ (14.8%), ‘telecommuting’ (12.7%), and ‘more help with chores or kids’ (6.3%) as the important factors for the same question. a total of 34% of the respondents were affiliated with some charitable organizations, a minor fraction (14.8%) were dubious with their response, and 51% were not associated with any. of all the promoting factors, the biggest drive and figure 1. the responses for trichotomous questions of the survey. 457archivio italiano di urologia e andrologia 2021; 93, 4 perceptions and obstacles to career development of female urologists important source of motivation for our respondents to do charity or be involved as a part of a charitable organization, was their satisfaction with a noble cause (72.3%). the people involved with the charity or cause in question was also a factor considered by many (10.6%). the desire to mix socially with other attendees (6.3%), no specified reason (6.3%), and for maintaining a social status (4.2%) were the lowly rated attributes for the given question. discussion while the discordant representation of women in urology is well-established, only a few studies have attempted to delineate the cause of this disparity and the confounding effects it has on their personal lives (7). to our knowledge, there are no studies available in the current literature which address the perception of women urologists spanning across a full circle of academia, mentorship, leadership, parenting, and charity simultaneously. although the majority of our poll-respondents agree to the existence of under-representation of females in urology, 38.3% however, felt that this was not so significant. this may be partly explained due to an increasing prevalence of female urologists in the recent past accounting for about 9.2% of the total workforce and about 21% of the under-45-year-olds in countries like the usa (6). such demographic trends have greatly improved the visibility of female urologists in developed countries, who are also at a greater likelihood of pursuing sub-specializations, and positively increasing their identification with leadership roles (8). however, a recent study has shown that despite specialization or seniority, female surgeons perform less complex cases than their male peers, hence more needs to be done to recruit and retain all under-represented minorities, as greater diversity helps improve the outcomes of the general population (9). there is no single ‘best approach’ involved in figure 2. representation of the responses by the participants (n = 119) to the questions on (a) leadership (b) parenting (c) academia, mentorship and charity. archivio italiano di urologia e andrologia 2021; 93, 4 s. ibrahim, a. pietropaolo, n. naik, et al. 458 training and navigating across academia, but the presence of mentors can foster a sense of professional identity and facilitate a novice experience through guidance, support, and encouragement (10). most of our participants (68%) felt that having a mentor, as a wise and trusted counselor, followed by a natural flair towards research are the keys to academic excellence. a healthy and strong mentormentee relationship stems based on consideration, great camaraderie, existing features of commonality, and virtues of confidentiality (11). leaders are people with the capability to explicitly articulate protocols, augment productivity, motivate team members to achieve the desired goal to create a sustainable change in any profession (12). the core traits of becoming a good leader-talent, drive, willpower, practical wisdom, loyalty, ethical behavior, emotional intelligence, integrity, self-awareness, and resilience are all very essential (13). our participants felt that exquisite communication skills are the most important attribute and a clear favorite prerequisite for charismatic leadership. this is in line with the expectations as interpersonal communication is the binding factor to show a leader’s assuredness, decision-making skills, and the ability to convey the strategies and outcomes of the vision and the mission to the team (14). the circumstances are no different for leaders in medicine who aim to improve the quality of healthcare (15). the main challenges, according to our poll-respondents, were the effective management of time, lack of resources, and coordination of work amongst members. this is indeed in conjunction with the other studies on leadership where proactive and focused personal time management was identified to be necessary for optimizing organizational productivity (16). this also highlights the persistent issue of imbalance in the allocation of resources for utilization despite being the central function of healthcare delivery systems (14). appropriate delegation of duties matching the amount of responsibility with capability and authority, with regular feedback, will help in empowering colleagues to reach their potential (17). work-personal life harmony is particular to every individual and thus attainment of a ‘balance’, if it exists, is a very subjective feeling, explaining the reluctance of poll-respondents in answering the question (18). it continues to be a very challenging issue, as according to the national physician burnout and suicide report 2020, urology topped the chart with 54% of practicing urologists reporting that they are victims of physician burnout (19). the prime reason for this was due to the administrative burden with too many bureaucratic tasks to fulfill, as driven by workplace and organizational culture. spending too many hours at work and lack of respect from colleagues were the other important reasons cited by many (19). this is in concordance with our results as participants felt that the guilt of not being available at all times was their biggest concern. parenting as female physicians may have additional challenges to address as they generally remain responsible for childcare and domestic activities compared to male counterparts, thus limiting their career advancement, while also feeling inadequate in performing the dual role (20). strategies need to be implemented while structuring the programs to help strike a synergy in their personal and professional lives (19). greater flexibility in the schedules, with allowance for dedicated maternity leaves for a longer duration, and support from employers and co-workers are the important contributors in this regard, as also evident from our survey (20). conclusions women play a vital role in all aspects of charity, leadership, academia, mentoring, and parenting. while urology is leading the way with more females taking up the specialty, gender disparity and traditional dogma is still a hindrance to it. although urological societies recognize this, more needs to be done to encourage female recruitment into urology and to support and nurture them in their career pathways. funding the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors’ contributions sufyan ibrahim and bm zeeshan hameed have given substantial contributions to the conception or the design of the manuscript. nithesh naik, amelia pietropaolo, milap shah, patricia zondervan and anita patel to acquisition, analysis and interpretation of the data. all authors have participated to drafting the manuscript, bhaskar k somani, bhavan prasad rai and joanne cresswell revised it 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of the surgical workforce. arch surg. 2012; 147:933-9. 19. medscape national physician burnout & suicide report 2020: the generational divide (internet). (cited 2020 sep 11). available from: https://www.medscape.com/slideshow/2020-lifestyle-burnout6012460#1 20. parsons wl, duke ps, snow p, edwards a. physicians as parents: parenting experiences of physicians in newfoundland and labrador. can fam physician. 2009; 55:808. correspondence sufyan ibrahim, md kasturba medical college manipal, manipal academy of higher education, manipal (india) amelia pietropaolo, md bhaskar k somani, md department of urology, university hospital southampton nhs trust, southampton (uk) nithesh naik, md faculty of engineering, manipal institute of technology, manipal academy of higher education, manipal (india) anita patel, md global hospitals, maharashtra (india) milap j shah, md bm zeeshan hameed, md zeeshanhameedbm@gmail.com department of urology, kasturba medical college manipal, manipal academy of higher education, manipal (india) patricia zondervan, md academic medical center, university of amsterdam, netherlands jean mcdonald, md north middlesex university hospital, sterling way, london (uk) bhavan prasad rai, md department of urology, freeman hospital, newcastle upon tyne ne7 7dn (uk) hadis karimi, md manipal college of pharmacy, manipal academy of higher education, manipal, india joanne cresswell, md the james cook university hospital, south tees trust, middlesbrough, united kingdom bm zeeshan hameed, professor (corresponding author) zeeshanhameedbm@gmail.com department of urology, kasturba medical college, manipal, manipal academy of higher education, manipal, india 576104 archivio italiano di urologia e andrologia 2021; 93, 126 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.26 countries and in north america (1). during the last years, we have seen a higher incidence of paediatric stones disease: 5-13% in western countries and 20% in saudi arabia, egypt, sudan, india and thailand (2). all ages of the childhood, and both genders can be affected equally. reasons are not clear and multiple factors have been suggested like obesity, changes in dietary habits with increased sodium intake, decreased calcium and water assumption and increasing use of fructose and antibiotics (1-3). the treatment is based on similar techniques as for adults, especially extracorporeal shock wave lithotripsy (swl) and endourological techniques (semirigid ureteroscopy urs, flexible retrograde intrarenal surgery rirs and percutaneous nehrolithotomy pnl). the aim of stone management in children should be complete stone clearance, prevention of new stone formation and re-growth, preservation of renal function, control of urinary tract infection, minimal invasiveness, less anesthesia, less radiation exposure, as few as possible surgical drainage procedures and correction of both the anatomic abnormalities and the underlying metabolic disorders (4). decision making for treatment strategies depends on the number, size, location, composition of stones and anatomy of the urinary system. in the last ten years due to miniaturization of endoscopic instruments and increased experience into retrograde and percutaneous treatment on adult patients, endourology has become the best approach to treat urinary stones in children. rirs is effective and has become a good option in the treatment of renal stones < 2 cm (4-6). the aim of this study is to report our single-centre experience in paediatric stone management with retrograde endoscopic procedures. results and complications of urs/rirs are discussed. materials and methods we retrospectively reviewed our experience in patients ≤ 16 years old affected by urinary stones who underwent urs/rirs procedures performed by two surgeons (af and sf) with expertise in endourology. twenty-eight patients were studied (19 male and 9 female), 2 of these suffering from bilateral renal stones and treated in separate surgical sessions. a total of 30 renal units (rus) underwent endoscopic procedures (urs, rirs or both). introduction: in the last years due to miniaturization of endoscopic instruments and percutaneous surgery, endourology has become very popular in paediatric urinary stone managment. we reported our single-centre experience in retrograde endoscopic procedures in children. results and complications of urs/rirs are discussed. materials and methods: we retrospectively reviewed our experience in patients ≤ 16 years old affected by urinary stones who underwent urs/rirs procedures performed by two surgeons with expertise in endourology. a total of 30 renal units (rus) underwent endoscopic procedures (urs, rirs or both). surgical complications according to the claviendindo’s classification and stone-free rate were evaluated at 3 months follow-up. success of urs was defined as stone-free status after single procedure while rirs success rate was considered as presence of residual stone fragments smaller than 4 mm at first procedure. results: the mean age of our patients was 8 years, range 216 years. a total of 30 renal units (rus) underwent 40 endourological procedures (23 urs and 17 rirs; 10 children underwent both procedures at the same time). 17/30 (56.6%) rus were pre-stented before surgery. the stone-free status was achieved in 23/30 renal units treated, with a 76.6% success rate. the remaining 7 patients had residual stones greater than 4 mm and underwent further treatments. after a second surgery the stone-free rate turned out to be 93.3% (28/30 renal units). conclusions: rigid and flexible ureteroscopy (urs/rirs) is a reliable technique for treatment of < 2 cm urinary stones in paediatric age group. it shows low rate of major complications and promising results in terms of stone-free rate. key words: flexible ureterescopy; paediatric stone disease; rirs; laser lithotripsy. submitted 8 september 2021; accepted 27 october 2021 introduction the management of paediatric urolithiasis is nowadays more common in the current urologic practice. it is well known as an endemic problem in developing countries, but the incidence of nephrolithiasis in the paediatric population has been steadily growing also in the european rigid and flexible ureteroscopy (urs/rirs) management of paediatric urolithiasis in a not endemic country summary stefania ferretti 1, monica cuschera 1, davide campobasso 2, claudia gatti 3, riccardo milandri 1, tommaso bocchialini 1, elisa simonetti 1, pietro granelli1, antonio frattini 2, umberto vittorio maestroni 1 1 urology unit, university-hospital of parma, italy; 2 urology unit, hospital of guastalla, azienda usl-irccs of reggio emilia, italy; 3 paediatric surgery unit, university-hospital of parma, italy. 27archivio italiano di urologia e andrologia 2021; 93, 1 urs-rirs in paediatric urolithiasis the data were collected in collaboration with the paediatric surgery unit at the university hospital of parma from january 2009 to may 2017. local ethical committee approval was obtained for data collection (protocol number: 490/2019/oss*/aoupr). all patients underwent preoperative blood tests, urine culture and in 78.5% of patients (22/28) a low dose “flash” ct-scan without contrast medium was performed before surgery; all patients underwent abdominal ultrasound. further evaluation (eg. mri-scan, voiding cistouretrography, renal scintigraphy) were performed only in selected cases. stone localization and size measurement were performed by non-contrast helical computed tomography (ct) scanning or kidneyureter-bladder (kub) radiographs/ultrasound exams. we considered 2 types of stone parameters: a. maximum length of the stones and b. surface area using tiselius’ formula (sa = length×width×π×0.25). procedures were performed with ultrathin 6.5/7fr or 8fr semirigid ureteroscope (storz, germany) or flexible ureteroscope x-flex2 7.5fr (storz, germany) in rirs. a 9.5fr ureteral access sheath (20 cm or 28 cm length – cook, usa) was inserted when possible. in no case active dilation of distal ureter was performed during surgery due the potential risk of secondary ureteral stricture or vesicoureteral reflux. stone fragmentation was achieved by 35 w holmium:yag laser lithotripsy device (quanta system, italy). a laser fiber of 200 or 273 micron was used. x-ray was administered by digital x-ray ev endurance philips with internal protocol reducing doses to ¼ of total adult’s dose. protective diaphragms were used for thyroid gland and genitalia because of the potential radiation risk. a routine preoperative antibiotic prophylaxis with a third generation cephalosporin or amoxicillin/clavulanic acid was administered to all patients and all procedures were performed under general anesthesia. after surgery, a ureteral catheter, mono-j or double-j was left in place based on the duration of the procedure, degree of ureteral edema and/or residual fragments. generally, the jjstent’s strings were left if we planned to leave the stent for up 10 days. a bladder catheter was left for 24-48 hours in all patients. the removed stones underwent spectrometric analysis. surgical complications according to the claviendindo’s classification and stone-free rate (assessed by abdominal ultrasound and “flash” helical ct-scan in doubtful cases) were evaluated at 3 months follow-up. all postoperative outcome data of patients referred from other centers (53%) were verified by telephone interview with the local physician and/or the parents. success of urs was defined as stone-free status after single procedure while rirs success rate was considered as presence of residual stone fragments smaller than 4 mm (clinical insignificant residual fragments) at first procedure. we reported the global success rate of both procedures at first step and second step (re-do surgery). results from january 2009 to may 2017, 28 children with urolithiasis were managed at our centre. ten preschoolage children (1-5 yrs) and 18 school-age children (6-16 yrs). the mean age of our patients was 8 years, range 216 years. urological comorbidities included: 7 recurrent urinary infections, 6 ureteropelvic junction dysplasias, 2 megaureters, 1 distal ureteral substenosis, 1 renal double district, 2 vesicoureteral refluxes, 5 observed metabolic disorders (3 idiopathic hypercalciurias, 1 cystinuria, 1 hyperoxaluria). relevant general comorbidities: 2 infant cerebral palsies, 1 thalassemia, 1 autism, 1 lowe syndrome, 1 amelogenesis imperfecta. previous urological surgery: 3 orchidopexies, 2 circumcisions, 2 pyeloplasties, 1 varicocele, 1 bulking agent injection for vesicoureteral reflux, 1 pyelolithotomy, 4 extracorporeal shock wave lithotripsies, 1 percutaneous nephrostomy; other procedures: 1 bowel resection for acute ischemic disease, 1 laparoscopic cholecystectomy, 1 removal of thoracic angiofibroma and 1 stabilization of the hips and femurs. a total of 30 renal units (rus) underwent 40 endourological procedures (23 urs and 17 rirs; 10 children underwent both procedures at the same time). in some cases a second look surgery was necessary. at the end of all surgical sessions 25 urs and 24 rirs were recorded. the average stone area was 1.15 cm2 and the range of maximum stone diameter was 5-24 mm. preoperative grade i and ii hydropnephrosis was present in 15 rus (11 grade i, 4 grade ii). no grade iii or iv was reported. 17/30 (56.6%) rus were pre-stented before surgery (16 double jj and 1 mono j); 15/17 in emergency for pain/fever (first access to paediatric surgery unit), 2/17 for ineffective previous ureteroscopy in other hospital; 13/30 rus were not pre-stented at first procedure with positive surgical results; the age ranged from 5 to 16 years and the procedures were 8 simple urs and 5 urs/rirs. in 12/24 rirs we inserted 9.5 fr ureteral access sheatuas (10/17 at first rirs and 2/7 at second rirs). none of the patients experienced access failure at surgery. demographic and preoperative data are shown in table 1. considering the total amount of procedures (surgery and redo surgery) 37 indwelling ureteral stents (29 double jj and 8 mono j) were placed. table 1. demographic and preoperative data. data patients age (years) 8 (2-16) sex (male/female) 19/9 lateralization (n) right 15 left 11 bilateral 2 stone location (%) ureter 35 pelvis 28 ci 16 cm 9 cs 7 upj 5 stone size: max lenght (mm) 5-24 stone surface area (cm2) 1,15 pre-operative hydronephrosis (rus), n (%) 15 (50) pre-operative stent insertion for rus, n (%) 17 mj 1 (5.8) dj 16 (94.2) archivio italiano di urologia e andrologia 2021; 93, 1 s. ferretti, m. cuschera, d. campobasso, c. gatti, r. milandri, t. bocchialini, e. simonetti, p. granelli, a. frattini, u.v. maestroni 28 the average time of indwelling stenting after first procedure was 14 days with a range of 2 to 57 days. during the procedure, the mean x-ray exposure time was 14 seconds, with a range of 2-72 seconds. the duration of operations was calculated from intubation to awakening from the anesthesia owing to different or logs in that period of time. average time recorded was 78 minutes with a range of 30 to 140 minutes. the mean hospital stay was 5 days with a range of 2-13 days. stones were composed of calcium oxalate (56.6%), calcium phosphate (10%), ammonium urate (10%), cystine (3.3%) and mixed (13.4%). the stone-free status was achieved in 23/30 renal units treated, with a 76.6% success rate. the remaining 7 patients had residual stones greater than 4 mm and underwent further treatments. after a second surgery the stone-free rate turned out to be 93.3% (28/30 renal units). in patients needing a surgical reoperation, the second procedure was performed after an average time of 74 days (14 days-330 days). the two failed children underwent renal swl after 5 months while the last one required a microperc® (polydiagnost) for a minor calyx’s residual stone one year later (table 2). according to the clavien-dindo’s classification, complications occurred in 10,8% of all 37 renal units treated. in particular, minor complications (grade i and ii) consisted of: fever during postoperative time (1 case), vomiting (1 patient with peg), hematuria (1 case) and urinary tract infection (1 case). no major complications (grade iii and iv) occurred. no patient needed blood transfusion. two patients died because of their concomitant medical conditions (cerebral palsy and lowe syndrome) 2 and 5 years after surgery, respectively. one patient affected by hypotrophic kidney before surgery one year later underwent nephrectomy. operative and post-operative outcomes are summarized in table 3. discussion nowadays minimally invasive endoscopic techniques – such as urs/rirs and mini-pnl – are considered the best approach for the treatment of paediatric urolithiasis in terms of efficacy and safety due to the miniaturization of the surgical instruments, the increasing incidence also in industrialized countries and the experience with adult patients (4-6). the patients we studied showed a high proportion of comorbidities: 42.8% urological malformations, 25% urinary tract infections, 25% non-urologic diseases and, finally, 17.8% metabolic disorders. these data demonstrate that paediatric nephrolithiasis is related to urologic malformations or infections and metabolic disorders (1-3). as many authors have pointed out, thanks to the introduction of flexible ureteroscopy it has become possible to treat both lower and upper urinary tract stones (7-9). this technique is suitable even when stones are located in tricky sites, such as lower calyces, or in case of renal and skeletal malformations where swl are not recommended. extracorporeal shock wave lithotripsy (swl) was introduced twenty years ago, the 2019 european guidelines on paediatric urolithiasis suggested for pelvic stones less than 2 cm this approach and rirs or micropnl as secondary treatment options. moreover, the stone-free rate is significantly affected by various factors. when the stone size increases (> 1.5/2 cm), the need for additional sessions increases in parallel. swl was found to be less effective for caliceal stones and particularly for lower caliceal stones. several studies reported stone-free rates varying between 50% and 62% (10). ather et al. also assessed that stone-free rate decreases with increasing stone size and in case of lower calyxes stones (11). although swl is a non-invasive technique, some stones would require multiple sessions with the need of general anaesthesia in younger children. for the treatment of our patients we used semi-rigid ureteroscopy in 34% of cases, flexible instruments in 32% of cases and both in 34% of cases (using semi-rigid to start the procedure and flexible to complete it). compared to adult urs, paediatric urs is still performed in a much smaller group of patients with an overtable 2. redo surgery data. data patients age (years) 7 (2-12) sex (male/female) 5/2 pre-operative stenting (n) 7/7 surgical procedures (n) rirs 5/7 urs&rirs 2/7 mean hospital-stay (days) 5.5 (3-14) post-operative stent insertion (n) mj 3/7 dj 4/7 mean stent-indewelling time (days) % 9 (2-35) stone-free status (n pts) % 5/7(71.4%) table 3. operative and postoperative outcomes. data patients type of procedures (total n) 25 urs 24 rirs uas insertion (n) 12/24 operative time (minutes) 77.7 (20-140) x-ray exposure (seconds) 14 (2-72) postoperative stent insertion for rus, n (%) 37 dj 29 (78.3) mj 8 (21.7) ureteral stent removal (days) 14 (2-57) hospital stay (days) 5 (2-13) stone composition (rus), n (%) 30 ca oxalate 17 (56.6) mixed 4 (13.4) ammonium urate 3 (10) calcium phosphate 3 (10) unknown 2 (6.7) cystine 1 (3.3) stone free rate after 1° procedure (rus), n (%) 23 (76.6) stone free rate after 2° procedure (rus), n (%) 28 (93.3) complications (rus), n (%) 4 (10.8) clavien i 2 clavien ii 2 clavien iii 0 clavien iv 0 clavien v 0 29archivio italiano di urologia e andrologia 2021; 93, 1 urs-rirs in paediatric urolithiasis all risk of complications or failure slightly higher than in adults (6, 12). the importance of expertise in endourological procedures (rigid/flexible) was essential to improve the success rate. for example, kucukdzman et al. reported an incidence of 3.7%-12% in paediatric ureteroscopy series for proximal ureteral stone migration (13). today, in many hospital realities, this aspect is not considered as a complication due to the possibility to manage the push-up of the stone in the renal cavities. to share knowledge between paediatric and adult surgeon (twin-surgeon model) as a tutor at the beginning of the learning curve could be the answer for higher and quickly levels of performances (14). the difficulty in performing ureteroscopy in children younger than 3 or 5 years (due to the smaller ureteral diameter) is well known (1516). our data show that 4 out 13 not pre-stented patients were up to five years old and no one experienced access failure to ureters. moreover, it is important to use ultrathin semirigid ureteroscopes for negotiation the access to the ureteral meatus with light hydro-dilation and, at the same time, permitting a passive ureteral dilation before retrograde procedures with or without ureteral access sheath (17, 2). the use of uas is under debate in the paediatric population for the potential risk of ureteral damage. in our experience, 12/24 rirs were performed with uas without complications; we believe that in renal stone smaller than 1 cm is not mandatory the use of ureteral access sheath like in adults. berettini et al. reported a good experience in 13 pts weighing < 20 kg who underwent to rirs with uas; all patients presented 2 weeks before surgery. in 93.8% of cases, the uas was inserted without complications and, at a mean follow up of 22 months, no long-term post-surgical complication was reported (15). erkurt et al. reported the positioning of uas in only 61.5% of cases and an incidence of 2 ureteral wall injuries due to sheath but without related complications at long-term follow up; in this population uas before rirs was inserted in 94.1% of pre-stented children and only 50% of non-stented patients (9). chu et al. found a decreased operative time, re-do surgery rates, improved sfr and reduced risk of ureteral injury with the use of uas in children pre-stented before rirs (16). at the end of the procedures, all patients had a stent with a general good tolerance except for 2 patients (7%) who complained severe dysuria. four children held the stent for more than one month while awaiting the second surgery; the prolonged time was due to complex clinical situations (cerebral palsy, two prolonged antibiotic therapies for other diseases). stent placement after endoscopic procedures is a controversial issue. the device allowed reduction of pain owing to local edema and also limited the risk of infection due ureteral obstruction for residual fragments. at the same time, however, it required a readmission to operating room for removal. in our experience, children older than 14 years were subjected to outpatient stent removal procedure with a mild premedication; in all the other cases a short deep sedation was required. we are convinced of the importance of leaving self-removal strings for less ten days of indwelling time. considering our patients, the stones showed an average surface area of 1.15 cm2 in accordance with the data from the literature (6-9). the stones that required a second procedure were located in the pelvis and lower renal calices; the initial stone burden and multiple locations played an important role in re-do surgery. lower pole stones seem to be more difficult to manage in particular when the stone is in an anterior calyx. several authors pointed out the necessity of multiple swl sessions for obtaining a stone-free status in kidney stones in more than 70% of children. we believe that ureteroscopy reduced the risk of additional general anesthesia sessions, allowed the possibility to treat different stone localizations and to reduce x-ray exposure respect to swl multiple procedures (18, 19). the data analyzed in our department show 76.6% stonefree rate after the first surgery and 93.3% stone-free rate after second look procedure in accordance with the literature which presents a variable stone-free rate between 77% and 100% (6-9, 17, 2). complications were evaluated according clavien-dindo’s classification with 10.8% of patients showing grade i and ii complications. no ureteral perforation was observed differently from a perforation rate of 2 to 7.3% reported in the literature in paediatric urs series (13). endoscopic management of urinary stones is increasingly used also in paediatric population. the limitations of our study include its retrospective nature and the small series of patients that is due to the location of our hospital (north italy) in a nonendemic geographic area for stones. on the other hand, our series is a homogeneous cohort of patients treated by only two surgeons with long experience in adult endourology (af and sf) rather than by surgeons with different levels of expertise influencing stone-free success and complication rate. a larger population-based trial would be essential for confirming these preliminary data. conclusions nephrolithiasis in paediatric patients is a relevant disease both in terms of incidence, which is sharply increasing; relapses are quite frequent and can reduce patient’s quality of life. evaluation of associated conditions such as urologic malformations, urinary tract infections, metabolic disorders, turns out to be fundamental in order to perform an early diagnosis and finally schedule a tailored treatment, with the least possible impact for the child. the choice of treatment has to be made considering patient's anatomical features and stone peculiarities (such as size and location). our study concludes that rigid and flexible ureteroscopy (urs/rirs) is a reliable technique for treatment of < 2 cm urinary stones in paediatric age group. it shows low rate of major complications and promising results in terms of stone-free rate. we hope that more and more integration will be possible between adult and paediatric urologists to make endourological procedures more familiar to the latter. references 1. bowen dk, tasian ge. pediatric stone disease. urol clin north am. 2018; 45:539-550. 2. eau guidelines. edn. presented at the eau annual congress amsterdam 2020. isbn 978-94-92671-07-3. archivio italiano di urologia e andrologia 2021; 93, 1 s. ferretti, m. cuschera, d. campobasso, c. gatti, r. milandri, t. bocchialini, e. simonetti, p. granelli, a. frattini, u.v. maestroni 30 3. atan a, balcı m. medical expulsive treatment in pediatric urolithiasis. turk j urol. 2015; 41:39-42. 4. samotyjek j, jurkiewicz b, krupa a. surgical treatment methods of urolithiasis in the pediatric population. dev period med. 2018; 22:88-93. 5. kılıç ö, akand m, van cleynenbreugel b. retrograde intrarenal surgery for renal stones part 2. turk j urol. 2017; 43:252-260. 6. whatley a, jones p, aboumarzouk o, somani bk. safety and efficacy of ureteroscopy and stone fragmentation for pediatric renal stones: a systematic review. transl androl urol. 2019; 8(suppl 4):s442-s447. 7. jaidane m, hidoussi a, slama a, et al. factors affecting the outcome of ureteroscopy in the management of ureteral stones in children. pediatr surg int. 2010; 26:501-4. 8. azili mn, ozcan f, tiryaki t. retrograde intrarenal surgery for the treatment of renal stones in children: factors influencing stone clearance and complications. j pediatr surg. 2014; 49:11615. 9 erkurt b, caskurlu t, atis g, et al. treatment of renal stones with flexible ureteroscopy in preschool age children. urolithiasis. 2014; 42:241-5. 10. ozgur tan m, et al. the impact of radiological anatomy in clearance of lower calyceal stones after shock wave lithotripsy in paediatric patients. eur urol. 2003; 43:188. 11. ather mh, noor ma. does size and site matter for renal stones up to 30-mm in size in children treated by extracorporeal lithotripsy? urology. 2003; 61:212-5. 12. somani bk, giusti g, sun y, et al. complications associated with ureterorenoscopy (urs) related to treatment of urolithiasis: the clinical research office of endourological society urs global study. world j urol. 2017; 35:675-681. 13. kucukdurmaz f, efe e, sahinkanat t, et al. ureteroscopy with holmium:yag laser lithotripsy for ureteral stones in preschool children: analysis of the factors affecting the complications and success. urology. 2018; 111:162-167. 14. somani bk, griffin s. ureteroscopy for paediatric calculi: the twin-surgeon model. j pediatr urol. 2018; 14:73-74. 15. berrettini a, boeri l, montanari e, et al. retrograde intrarenal surgery using ureteral access sheaths is a safe and effective treatment for renal stones in children weighing < 20 kg. j pediatr urol. 2018; 14:59.e159.e6. 16. chu l, sternberg km, averch td. preoperative stenting decreases operative time and reoperative rates of ureteroscopy. j endourol. 2011; 25:751-754. 17. azili mn, ozturk f, inozu m, et al. management of stone disease in infants. urolithiasis. 2015; 43:513-519. 18. aksoy y, yapanoglu t, özbey i. the efficacy and safety of extracorporeal shock wave lithotripsy in children. eurasian j med. 2009; 41:120-125. 19. muslumanoglu ay, tefekli ah, altunrende f, et al. efficacy of extracorporeal shock wave lithotripsy for ureteric stones in children. int urol nephrol. 2006; 38:225-9. correspondence stefania ferretti, md sferretti@ao.pr.it monica cuschera, md monica.cuschera@hotmail.it claudia gatti, md tintswal@libero.it riccardo milandri, md (corresponding author) riccardomilandri85@gmail.com tommaso bocchialini, md tommaso.bocchialini@libero.it elisa simonetti, md elisasimonetti88@gmail.com pietro granelli, md granellipietro@gmail.com umberto vittorio maestroni, md umaestroni@aopr.it via gramsci 14, 43126 parma (italy) davide campobasso, md d.campobasso@virgilio.it antonio frattini, md antonio.frattini@ausl.re.it via donatori di sangue, 42016 guastalla (italy) stesura seveso 369archivio italiano di urologia e andrologia 2022; 94, 3 letter to editor no conflict of interest declared. submitted 14 june 2022; accepted 17 june 2022 to the editor, the exact time to stop bladder cancer patient’s follow-up is not well known and there is not a clear recommendation on if and when stop to follow a patient managed for muscle invasive bladder cancer (mibc). major urological guidelines (1, 2) do not provide a precise indication on the timing of follow-up, and there is currently no real consensus on optimal time schedule. however, mibc is a disease with a high relapse rate of over 50% of patients at 5 years (considering local, distant and urothelial relapses), and very late recurrences have been detected in several patients after 5-years-tumor free periods (3, 4). furthermore, patients undergoing radical cystectomy require oncological but also functional follow-up, considering that complications related to urinary diversion are detected in 45% of patients during the first five years, reaching 54% after 15 years of follow-up (5). recently, we detected a very late urethral recurrence in a patient who underwent cystoprostatectomy and bricker’s ileal conduit urinary diversion in 2002 for mibc (pt2 g3 n0). the patient, a 73 y/o diabetic man, strong tobacco consumer, had abandoned the follow-up 10 years ago, after as many years of surveillance in which he was free from disease. in 2021 the patient had urethral bleeding and prepuce edema. the urethroscopy found a white, solid mass in the proximal urethra, that the biopsy confirmed to be a urothelial carcinoma. abdominal-penile mri found a neoplasia likely originated from the urethra and from the corpus spongiosum, invading both corpora cavernosa, and bilateral inguinal lymphadenomegaly. after six months of chemotherapy the patient underwent penectomy and lymphadenectomy. the definitive histological diagnosis was urothelial papillary carcinoma, with areas of squamous differentiation (pt3 g3 pn1). the aim of this letter is not to present in detail the case of this unlucky patient, and therefore many info are voluntarily omitted, but to put the light on the possible need of a life-long follow-up for patients with mibc who underwent radical cystectomy. as previously stated, there is currently no clear recommendation on the timing of follow-up required in mibc patients undergoing radical cystectomy. recently a risk-adapted schedule (6) has been proposed, based on the interaction between recurrence risk and competing health factors that could lead to individualized follow-up recommendations and may increase recurrence detection. however, this model has not yet been validated and has several limitations such as not considering histological variants (7), which are increasing and that might be responsible of greater rate of recurrences. to offer a patient-targeted follow-up, could become essential the use of biomarkers (8-10) currently available or in the experimental phase, capable of identifying the risk of recurrence and prognosis of different patients. this could lead to specific surveillance schedules, tailoring the patient's characteristics and recurrence risk (tnm, rare variants, urethral preservation, etc…). in this light, it is also essential to help the patient to stop smoking (11), in order to possibly reduce the risk of relapses, a factor that is often not investigated or stressed by the urologists. ultimately, in our opinion, the patient undergoing cystectomy is a patient who should be followed for life by the urologist, both from an oncological, functional and psychological point of view (12, 13). references 1. muscle-invasive and metastatic bladder cancer follow-up uroweb. accessed may 29, 2022. https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer/chapter/followup. 2. treatment of non-metastatic muscle-invasive bladder cancer: aua/asco/astro/suo guideline (amended 2020) american urological association. accessed may 29, 2022. https://www.auanet.org/guidelines/guidelines/bladder-cancer-non-metastatic-muscle-invasive-guideline. how long should we follow patients managed for muscle-invasive bladder cancer? lesson learned from a recent clinical practice aldo franco de rose 1, francesco vecco 1, 2, francesca ambrosini 1, 2, rafaela malinaric 1, 2, guglielmo mantica 1, carlo terrone 1, 2 1 irccs ospedale policlinico san martino, genova, italy; 2 università di genova, (disc), genova, italy. doi: 10.4081/aiua.2022.3.369 archivio italiano di urologia e andrologia 2022; 94, 3 a.f. de rose, f. vecco, f. ambrosini, r. malinaric, g. mantica, c. terrone 370 3. matsumoto k, kikuchi e, horiguchi y, et al. late recurrence and progression in non-muscle-invasive bladder cancers after 5-year tumor-free periods. urology. 2010; 75:1385-1390. 4. yoo sh, kim h, kwak c, kim hh, jung jh, ku jh. late recurrence of bladder cancer following radical cystectomy: characteristics and outcomes. urol int. 2019; 103:291-296. 5. hautmann re, volkmer b, egghart g, et al. functional outcome and complications following ileal neobladder reconstruction in male patients without tumor recurrence. more than 35 years of experience from a single center. j urol. 2021; 205:174-182. 6. stewart-merrill sb, boorjian sa, thompson rh, et al. evaluation of current surveillance guidelines following radical cystectomy and proposal of a novel risk-based approach. urol oncol semin orig investig. 2015; 33:339.e1-339.e8. 7. mantica g, simonato a, du plessis de, et al. the pathologist’s role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection. minerva urol e nefrol. 2018; 70:594-597. 8. sawazaki h, arai y, ito y, et al. expression of l-type amino acid transporter 1 is a predictive biomarker of intravesical recurrence in patients with non-muscle invasive bladder cancer. res reports urol. 2021; 13:603. 9. saoud r, sanford th, hewitt sm, apolo ab, agarwal pk. rapidly progressing urothelial carcinoma due to a rare tp53 (p.arg110pro) mutation: a case report and review of the literature. res reports urol. 2021; 13:181-184. 10. singh r, singh up, agrawal v, garg m. epithelial-to-mesenchymal transition based diagnostic and prognostic signature markers in non-muscle invasive and muscle invasive bladder cancer patients. mol biol rep. 2022; 49:7541-7556. 11. van osch fhm, jochems shj, reulen rc, et al. the association between smoking cessation before and after diagnosis and non-muscle-invasive bladder cancer recurrence: a prospective cohort study. cancer causes control. 2018; 29:675. 12. jensen bt, lauridsen sv, jensen jb. optimal delivery of follow-up care after radical cystectomy for bladder cancer. res reports urol. 2020; 12:471. 13. borghi c, manservigi m, milandri es, greco p, ippolito c, dell’atti. the impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions. arch ital di urol e androl. 2021; 93:255-261. correspondence aldo franco de rose, md aldofrancoderose@gmail.com francesco vecco, md (corresponding author) francesco.vecco@gmail.com irccs ospedale policlinico san martino, genova francesca ambrosini, md f.ambrosini1@gmail.com rafaela malinaric, md rafaela.malinaric@gmail.com guglielmo mantica, md guglielmo.mantica@gmail.com carlo terrone, md carlo.terrone@med.uniupo.it stesura seveso 305archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. introduction ureteral stents are commonly used implants in urology practice mainly to relieve the ureteral obstruction due to stones, fibrosis, malignancy, and extrinsic compression. it is also used in ureteral reconstructive surgery and iatrogenic ureteral injuries to promote ureteral healing (1). the ureteral stents are intended for temporary use and should be removed or replaced within a specific time frame; otherwise prolonged stent presence beyond the specific time known as forgotten stents can lead to complications like stent encrustation, fragmentation, obstruction, urosepsis, renal failure, and mortality (2). the incidence of forgotten ureteral stents is approximately 12% (2) and in the uk, a study reported that 13.6% of postoperative urology negligence claims are due to forgotten ureteral stents (3). divakaruni et al. (2) quote that men are 2.8 times more likely to have forgotten stents than females and patients without health insurance are 6 times more likely to have forgotten stents. alnadhari et al. (4) in their study of the management of 40 forgotten encrusted ureteral stents found that in 47.5% of forgotten eus were due to poor patient compliance and either patient ignored or forgot the physician’s advice about the timely removal of the ureteral stents; 30% of the cases failed to attend hospital for stent removal due to financial reasons, 12.5% of cases were due to delay in the endourological procedure following eswl, and 10% of cases were due to poor communication between the doctor and the patient. the cost of removal of forgotten encrusted stents is 6.9 times higher than the cost of timely stent removal because of additional costs involved in multiple interventions and it affects patient safety and quality of life (5). methods a retrospective analysis of 13 encrusted impacted ureteral stents in 12 patients treated in two hospitals between 2014 to 2021 was done. the inclusion criterion was failed ureteral stent removal by flexible cystoscopy under local anesthetic and clear evidence of stent encrustations on xray kub (kidney, ureter, and bladder) or computed tomogram kidney ureter and bladder (ct-kub). the primary outcome was successful removal of the encrusted impacted stent and the secondary outcome was the number and type of surgical procedures, operative time, hospiintroduction: we present our experience of the endourological management of encrusted ureteral stents (eus) and a literature review on forgotten encrusted ureteral stents. methods: a total of 13 encrusted ureteral stents from 12 patients were removed in two hospitals. the medical records were retrospectively analyzed for stent indication, indwelling time, clinical presentation, investigations, type and the number of surgical procedures, operative time, complications, duration of hospital stay, and the follow-up. results: five ureteral stents (us) inserted before eswl (extracorporeal shockwave lithotripsy) for renal stones, seven us for ureteric stones with ureteric colic, and one ureteral stent for post ureteroscopy procedure. the mean indwelling time was 15.07 ± 7.34 months with a range from 6 to 24 months. the mean kidney,ureter and bladder (kub) score of encrustation grading was 11.84 ± 2.07 with a range from 9 to 15. the encrusted stents were removed by a combination of cystolithotripsy, semi-rigid ureteroscopy (urs), retrograde intrarenal surgery (rirs), percutaneous nephrolithotomy (pcnl), and eswl. the average total number of procedures to remove one eus was 3 ± 1.08 with a range of 2 to 5 procedures. six encrusted stents were removed in one, five stents required two, one stent required three and one stent required four hospital admissions. the median operative time was 210 minutes with a range of 60 to 660 minutes per eus removal and the mean hospital stay was 2.69 ± 1.43 days with a range of 1 to 6 days. all patients had successful removal of encrusted stent and complete stone clearance with no major complications. in the follow-up, one patient had recurrent ureteric stone, one patient on regular stent exchange due to poor renal function and one patient developed significant ureteric stricture referred for reconstruction. conclusions: removal of forgotten encrusted impacted ureteral stents is challenging and requires a multimodal surgical approach. it adds significant costs to the health care system and in addition it affects patient safety and quality of life. patient education, avoiding unnecessary ureteral stent placement and a computerized stent monitoring system reduces the incidence of forgotten ureteral stents and their complications. key words: encrusted ureteral stent; bioflim; kub score; encrustation risk factor; computerized stent registry. submitted 9 june 2022; accepted 23 june 2022 management of encrusted ureteral stents: two center experience mohanarangam thangavelu 1, mohamed yehia abdallah 2, olubenga john isola 2, ahmed kotb 3 1 department of urology, ysbyty gwynedd, bangor, ll57 2pw, united kingdom; 2 department of urology, wrexham maelor hospital, wrexham ll13 7td, united kingdom; 3 northern ontario school of medicine, tbrhsc, 980 oliver road, thunder bay, ontario, canada. doi: 10.4081/aiua.2022.3.305 summary archivio italiano di urologia e andrologia 2022; 94, 3 m. thangavelu, m. yehia abdallah, o. john isola, a. kotb 306 tal stay, perioperative complications, and stone and stent free rates. all patients had preoperative renal function tests, urine cultures, x-ray kub, ct kub and in selective cases a dmsa (dimercaptosuccinic acid) renal radionuclide scan was done for patients with poor renal parenchyma. the degree of encrustation was graded by the kub score system based on imaging. treatment was planned based on the degree and location of stent encrustation (kub score), renal function, presence of urinary tract infection, and other comorbid conditions. appropriate antibiotics were administered prior to surgical intervention for positive urine cultures. initially, eswl was given a maximum of 3 sittings for proximal coil encrustations < 15 mm. all invasive endourological procedures started with clearing the bladder end encrustation by mechanical cysotolithopaxy by stone punch and some cases with laser energy through the cystoscope. for the ureteral body encrustation, a 7.5 fr semirigid ureteroscope was passed beside the encrusted stent from the ureteric orifice to work the way up towards the pelvicalyceal system using holmium laser energy for fragmentation. after clearing the ureteral body encrustation, a ureteral access sheath was placed and the proximal coil encrustation was cleared by a flexible ureteroscope (storz flex x2) and holmium laser. for denser and larger calcification of the proximal end, pcnl was done as a second sitting. stent fragmentation occurred during the retrograde ureteroscopy and the pieces were left in the pyelocaliceal system which were later retrieved during pcnl or rirs. for non-capacious ureter, additional (tandem) stents were inserted followed by ureteroscopy in 2 weeks. no undue force was used to pull the encrusted stent during any of the above procedures. all patients had postprocedural ureteral stent insertion which was removed in 2 weeks. in all our patients we dealt with the bladder and ureteral body encrustation first before dealing with proximal end encrustation with rirs or pcnl; only in a few patients eswl was given first for mild to moderate proximal end encrustation. the postoperative complications were graded according to the modified clavien dindo classification. all patients had postoperative x-ray kub before discharge and follow-up non-contrast ct kub and renal function in 4 months. results in our study 13, encrusted stents were removed from 12 patients with one patient with bilateral stents (table 1). the average encrustation grading score at the proximal end (k) was 3.15 ± 1.62, at the stent body (u) was 4.3 ± 0.85 and at the distal end (b) was 4.38 ± 0.76. the average overall arenas kub score was 11.84 ± 2.07 (table 2). in our study 3 patients with eus had eswl for the proximal end with poor results, and the majority of the stents were removed by cystolithoripsy, rigid urs, and rirs, and two stents had pcnl for the proximal end (figures 1-4). all the encrusted stents in our study were radio-opaque and 5 patients had a course of antibiotics for symptomatic utis with positive urine cultures prior to the procedure. the mean total number of procedures carried out was 3 ± 1.08 with a range of 2 to 5 per encrusted stent removal. all patients after the removal of the encrusted stent had post-operative ureteral stent which was removed with a flexible cystoscope within 14 days. the median operative time was 210 minutes with a range of 60 to 660 minutes and the mean hospital stay was 2.69 ± 1.43 days. no significant immediate postoperative complications were noted apart from mild haematuria in 6 and fever in 3 patients. three patients had insignificant residual stone fragments (< 3 mm) treated conservatively. at 12 months of review, 8 patients were stone-free, 2 patients lost follow-up, 1 patient required repeated stenting of a renal unit due to pre-existing poor renal function and 1 patient developed significant ureteric stricture referred for reconstruction surgery. discussion risk factors and mechanism of encrustation stent encrustation occurs when minerals from the urine table 1. demographic details. variables total no. mean range encrusted stents/patients 13/12 males/females 11/1 age-years 61.15 ± 13.22 29 to 84 side – right/left 7/6 stent indwelling time months 15.07 ± 7.34 6 to 24 stent indication pre eswl for renal stones 5 ureteric stones – colic 7 post ureteroscopy 1 reasons for delayed stent removal forgotten 9 delay in the secondary procedure 4 egfr (ml/min) 61.07 ± 23.28 28 to 90 urine culture (positive/no growth) patients 5/7 table 2. operative and postoperative details. variables no of pts. mean range encrustation grading kub score 11.84 ± 2.07 9 to 15 total number of procedures per encrusted stent removal 3 ± 1.08 2 to 5 total number of hospital admissions per encrusted stent removal 1.76 ± 0.92 1 to 4 total number of hospital stay per encrusted stent removal days 2.69 ± 1.43 1 to 6 total operative time per encrusted stent 249.61 ± 169.19 removal minutes median – 210 min 60 to 660 post operative complications clavien didno grade 1 6 clavien didno grade 2 3 12 months follow up patients stone/stent free 8 recurrent stone 1 ureteric stricture 1 lost follow up 2 combination of procedures per stent removal cystolithotripsy/urs/rirs/eswl 1 (7.6%) cystolithotripsy/urs/eswl 2 (15.3%) cystlithotripsy/urs/pcnl 2 (15.3%) cystolithotripsy/urs/rirs 8 (61.5%) 307archivio italiano di urologia e andrologia 2022; 94, 3 management of encrusted ureteral stents deposit on the outer and inner surface of the stent in both infected and non-infected urine environments. various factors like stent material, bacterial colonization, and patient-specific factors influence stent encrustation but the main risk factor is the duration of stent indwelling time. el-faquith et al. (6) in their study in 1991, reported stent encrustation rates of 9.2 % in 6 weeks, 47.5% between 6 to 12 weeks, and 76.3 % after 12 weeks of indwelling time. kawahara et al. (7) reported similar encrustation rates of 27%, 57%, and 76% at equivalent time intervals; 30% of the stents removed before 12 weeks showed luminal encrustation but only 4% of the patients had clinical symptoms of stent obstruction (6). bacterial colonization and bacterial biofilm play a critical role in stent encrustation but how it exactly triggers the encrustation process is poorly understood. tunney et al. reported (8) that 90% of the removed ureteral stents had bacterial colonization and 55% had adherent biofilm. shabeena et al. (9) reported 90% colonization rates in 120 days of ureteral stent insertion. escherichia coli, streptococcus spp, and pseudomonas spp are commonly isolated but no specific pathogens have been attributed to figure 1. xray kub right whole ureteral stent encrustation. figures 3, 4. endoscopic picture of lower end ureteral stent encrustation. 3. figure 2. x ray kub fine fragmentation and removal of the encrusted stent with ureteric catheter in place. 4. archivio italiano di urologia e andrologia 2022; 94, 3 m. thangavelu, m. yehia abdallah, o. john isola, a. kotb 308 triggering encrustation. newer studies on the urinary microbiome implicate that commensurate bacteria in urine rather than the pathogenic strains facilitate urolithiasis and stent encrustation (10). conditions like recurrent uti, chronic kidney disease, and diabetes mellitus increase the urinary bacterial load or the presence of urolithiasis risk factors like specific diets, history of stone disease, malabsorption disorders, and cancer chemotherapy facilitate stent encrustation (11). stent encrustation risk is high in pregnancy due to absorptive hypercalciuria and hyperuricosuria which require frequent stent changes in 4 to 6 weeks to avoid encrustation resulting in blocked stents. urinary infection with urease-producing bacteria like pseudomonas, proteus, and klebsiella spp hydrolyze urea into ammonia and carbon dioxide making urine alkaline and resulting in precipitation of ammonium, magnesium phosphate (struvite) on the stent surface. the encrustation rates correlated with stent diameter rather than stent length or patency and a study (7) reported 6 f stent developed more encrustation than the 7 f stent. the mechanism of stent encrustation is complex and all stents after insertion are immediately coated with a conditioning film made of patient-specific glycoproteins and materials from the urinary composition. further, the conditioning film may remain stable or could develop a bacterial biofilm that precipitates minerals on the stent surface causing stent encrustation; this provides a nidus for bacterial infection leading to urosepsis, obstruction, or renal failure (1, 12). presentation and complications the clinical presentation of the forgotten encrusted stent is variable. abdelaziz et al. (13) reported that predominant symptoms of forgotten stents were storage bladder symptoms, haematuria; other symptoms such as gross haematuria, flank, urethral and suprapubic pain were minimal as these patients tolerated the stent-related symptoms for more than 6 months. the asymptomatic patients are more prone to neglect or forget the stent and therefore develop serious complications that are time-related, such as encrustation, fragmentation, and obstruction. in our study 80% of patients with encrusted stents presented with intermittent haematuria, recurrent urinary tract infection (utis), storage urinary symptoms, flank pain, and no symptoms in 20%. challenges in the management of encrusted stents plain x-ray underestimates the stone burden and noncontrast computed tomography (ct) is essential for planning the treatment. the extent and location of encrustation, associated stone burden, renal function, and presence of urinary infection determine the treatment approach. active urinary infection should be treated appropriately and urosepsis due to obstructed infected kidney may require an initial percutaneous nephrostomy to stabilize the patient before any intervention. nephrectomy may be considered if there is poor renal parenchyma with a split function < 20%. arenas et al. (14) developed a kub grading system for encrusted ureteral stents. this system grades 1 to 5 according to the size of the calcification in or around the stent in the region of the kidney (k), ureter (u), bladder (b), and the total score represented as the kub score. they noted that the k score ≥ 3 was associated with multiple surgeries, multimodal surgery, operative time > 180 min, and lower stone-free rate, while the u score ≥ 3 was only associated with longer operative time and the b score ≥ 3 was associated with a lower stone-free rate. overall kub score ≥ 9 requires multiple surgeries, longer operative time and lower stone-free rates. our study results agree with the finding that multiple endourological procedures are required for total kub scores ≥ 9. the proximal stone burden is the main factor that determines the requirement of multiple surgeries and associated complications. in the presence of normal renal function, eswl is indicated for mild to moderate encrustation of renal end and proximal ureteral body encrustation. the lower encrusted segment in the bladder and in the ureteral part was always released first before dealing with surgical removal of the proximal end (15) apart from giving eswl for the proximal end of the encrusted stent. the bladder end and ureteral part of the encrusted stent were removed in pieces after releasing encrustation and cutting the stent with a holmium laser during urs, to create space for ureteral access sheath placement and rirs to deal with the proximal coil encrustation. pcnl is reserved for complex proximal end encrustation and for cases of rirs or eswl failures. open pyelolithotomy, cystolitotomy, or laparoscopic surgeries are sometimes required following the failure of endourological management. the treatment described is used as a guideline and should be tailored according to the individual patient, clinical assessment, surgeon's experience, and available resources. the approach should be in a stepwise multimodal fashion to remove the encrusted stent and achieve stone and stentfree status with the preservation of renal function (16). although majority of the encrusted ureteral stent need multimodal management, lio et al. (17) in their case series described a minimally invasive technique under fluoroscopy of removing and replacing obstructed encrusted ureteral stents in female patients under local anaesthetic, however the obstructed ureteral stents removed with this technique had obstruction mainly caused by intraluminal incrustation. monga et al. (18) reported a series of 22 forgotten ureteral stents left in situ for over 6 months and found that 68% were calcified, 18% fragmented, and 14% fragmented and calcified. in their series, which included 22 forgotten and 9 migrated stents, procedures to render stent free were ureteroscopy 52%, pcnl 26%, eswl 32%, cystolithotripsy 19%, open cystolithotomy 3%, simple nephrectomy 3% and multiple procedures were necessary in 19% of the patients. in our study of 13 encrusted ureteral stents, 50% had significant proximal encrustation, and all of them had bladder end and ureteral body encrustation; 61.5% of eus were removed by cystolithotripsy, urs and rirs, 15.3% by cystolithotripsy, urs and eswl, 15.3% by cystolithotripsy, urs and pcnl, 7.6% by cystolithotripsy, urs, rirs, and eswl. none of the encrusted stents were removed by open surgery in our study. from our results, the average total number of procedures carried out was 3 ± 1.08 with a range of 2 to 5 per eus removal and the average time of hospital stays was 2.69 ± 309archivio italiano di urologia e andrologia 2022; 94, 3 management of encrusted ureteral stents 1.43 days with a range of 1 to 6 days per eus removal. alnadhari et al. (4) in their study reported a mean of 2.25 urologic procedures needed per eus removal with a range of 1 to10 procedures performed in a single or multiple anesthetic sessions. encrustation prevention: stent materials and technology: stent biomaterials and coating substances could potentially alter bacterial adhesion thereby reducing bacterial colonization, bacterial biofilm formation, stent encrustation, and urosepsis. silicone is a highly biocompatible material that resists encrustation and biofilm formation but is not commonly used because of low tensile strength, higher friction co-efficiency, and its softness prone to kinking and compression (8, 19). the majority of currently used ureteral stents are made of polyurethane-based material with copolymers because of their favorable mechanical properties and low manufacturing cost (20). in vitro study by tunney et al. (8) compared encrustation rates of five different materials with an artificial solution similar to the urinary composition for 14 weeks. all developed some encrustation but silicone developed the least encrustation by 10 weeks followed by polyurethane, silitek, percuflex, and hydrogel coated polyurethane. stents coated with various materials could alter the stent surface to reduce bacterial adhesion and encrustation. hydrogel-coated polyurethane stent swells on contact with water and retains water to alter the stent surface to reduce bacterial adhesion and encrustation along with reduction of friction coefficiency for easier stent insertion (21). drug coated stents with silver nitrate, and ofloxacin have not proved to reduce biofilm or encrustation in clinical trials, moreover antibiotic-infused stents have the potential risk of developing antibiotic resistance (22). coating with heparin, a naturally occurring glycosaminoglycan anticoagulant exhibits antiadhesive properties which could reduce bacterial adhesion and prevent bacterial biofilm formation and encrustation (23) but results from clinical trials are contradictory and heparincoated stents are not regularly used in the clinical practice. silicone-coated polyurethane stents, newer stent coating materials like bacteriolytic enzymes, peptides, oxalate degrading enzymes, and essential oils have been explored (24), and all aimed to alter bacterial adhesion, biofilm formation, and reduce stent encrustation and urosepsis. metallic ureteral stents made of alloy are used in malignant ureteric obstruction has provided superior patency rates at 12 months compared with polyurethane stents requiring less frequent stent changes but still, stent encrustations occurred macroscopically in 22% and microscopically in all after an indwelling time between 8 to 14 months (25). biodegradable ureteral stents by constantly altering the stent surface could prevent bacterial adhesion and encrustation and it also eliminates the need for stent removal. currently available biodegradable materials made of natural or synthetic polymers have excellent biocompatibility with faster degradation which also reduces tissue inflammation useful in relieving the benign urinary obstruction. prospective multicenter human trials are required before routine use in clinical practice (26). similar to the prevention of urolithiasis, increased fluid intake and citrate supplements decreased the incidence of stent encrustation. computerized stent registry even in current times, ureteral stent logbooks and tracking cards are maintained for monitoring however, human error and negligence are fundamental causes for the failure of these manual systems. monga (27) reported that 10% of patients with forgotten stents fail to show up for scheduled stent retrieval despite being educated by physicians. similarly, 8.66% of patients were aware that they had ureteral stents but did not attend for stent removal (28). therefore patient education and awareness alone are not sufficient to prevent forgotten stents and related complications. the treating doctor and the hospital are responsible for both the monitoring and removal of ureteral stents and multiple level safety precautions should be implemented for the timely removal or replacement of the stent. computerized applications and electronic reminders appear to be reliable and efficient, and the utilization of automated algorithms has reduced the incidence of forgotten stents (28). lin et al. (28) retrospectively analyzed the monitoring of 12.440 ureteral stent placements in 10.105 patients registered on the auto registration monitoring system (arms) an automated program closely tied with the hospital billing system in taipei veterans general hospital over a period of 8 years. they reported 85.07% of patients who had their stents removed before the deadline were automatically detected. in the rest 14.93% of patients whose stents were not registered as removed it was found that 1.2% of patients had stents removed in other hospitals, 4.85% had died, 8.66% patients were aware of ureteral stents but did not come for stent removal and 0.21% of patients were not aware that they have ureteral stent which was placed in the operating room in non-urological patients. they reported that there were no new forgotten ureteral stents after the introduction of arms. development of a universally acceptable automated stent registry interface which could integrate with the existing hospital patient management system but also linked to the regional database would be ideal to monitor the ureteral stents after their insertion till their removal or replacement after the specific time interval. the healthcare safety investigation branch (hsib) from the uk published a report on the unplanned delayed removal of ureteric stents in october 2020 (29). the report showed the seriousness of the problem and made four safety recommendations including the development of a stone pathway, the use of a stent registry database, reviewing the british association of urology surgeons (baus) stent information leaflet, and clear communication with the general practitioner following patient discharge with stents. conclusions avoidance of unnecessary stent insertion is the key to the prevention of stent-related complications. patient education, judicious follow-up arrangements, computerized stent registry warning system could help in the timely removal of the stents, avoiding prolonged indwelling time which is the main risk factor for encrustation. removal of encrusted impacted stents requires a multiarchivio italiano di urologia e andrologia 2022; 94, 3 m. thangavelu, m. yehia abdallah, o. john isola, a. kotb 310 modal approach adding significant costs to the health care system and more importantly affecting patient safety and quality of life. ureteral stent technology is continuously evolving and current research should focus on developing biocompatible materials, newer coating substances, surface engineering, and stent design to reduce stent-related symptoms and complications. acknowledgement we thank dr arundoss gangadharan, consultant paediatrician, who helped in organizing the references in this article. references 1. lange d, bidnur s, hoag n, chew bh. ureteral stent-associated complications-where we are and where we are going. nat rev urol. 2015; 12:17-25. 2. divakaruni n, palmer cj, tek p, et al. forgotten ureteral stents: who's at risk? j endourol. 2013; 27:1051-4. 3. osman n, collins g. urological litigation in the uk national health service (nhs): an analysis of 14 years of successful claims. bju international 2011; 108:162-5. 4. alnadhari i, alwan m, salah m, ghilan a. treatment of retained encrusted ureteral double-j stent. arch ital urol androl 2019; 90:265-269. 5. sancaktutar a, h hs, bozkurt y, penbegül n, atar m. treatment of forgotten ureteral stents: how much does it really cost? a cost-effectiveness study in 27 patients. urol res. 2012; 40:317-25. 6. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol 1991; 146:1487-91. 7. kawahara t, ito h, terao h, et al. ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. j endourol. 2012; 26:178-82. 8. tunney mm, keane pf, jones ds, gorman sp. comparative assessment of ureteral stent biomaterial encrustation. biomaterials. 1996; 17:1541-6. 9. shabeena ks, bhargava r, manzoor map, mujeeburahiman m. characteristics of bacterial colonization after indwelling double-j ureteral stents for different time duration. urol ann. 2018; 10:71-75. 10. zampini a, nguyen a, rose e, et al. defining dysbiosis in patients with urolithiasis. sci rep. 2019; 9:5425. 11. beysens m, tailly to. ureteral stents in urolithiasis. asian j urol. 2018; 5:274-286. 12. tomer n, garden e, small a, palese m. ureteral stent encrustation: epidemiology, pathophysiology, management and current technology. j urol. 2021; 205:68-77. 13. abdelaziz ay wbf, mosharafa aa, abelrasoul ma, et al. forgotten ureteral stents: risk factors, complications and management. african journal of urology. 2018; 24:28-33. 14. arenas jl, shen jk, keheila m, et al. kidney, ureter, and bladder (kub): a novel grading system for encrusted ureteral stents. urology. 2016; 97:51-55. 15. lam j, gupta m. tips and tricks for the management of retained ureteral stents. j endourol. 2002; 16:733-41. 16. bultitude mf, tiptaft rc, glass jm, dasgupta p. management of encrusted ureteral stents impacted in upper tract. urology. 2003; 62:622-6. 17. de rose af, di grazia e, magnano san lio v, et al. complications of endourological procedures and their treatment. arch ital urol androl. 2020; 92:321-325. 18. monga m, klein e, castañeda-zúñiga w, thomas r. the forgotten indwelling ureteral stent: a urological dilemma. j urol. 1995; 153:1817-9. 19. barghouthy y, wiseman o, ventimiglia e, et al. silicone-hydrocoated ureteral stents encrustation and biofilm formation after 3week dwell time: results of a prospective randomized multicenter clinical study. world j urol. 2021; 39:3623-3629. 20. venkatesan n, shroff s, jayachandran k, doble m. polymers as ureteral stents. j endourol. 2010; 24:191-8. 21. ahmed e. hydrogel: preparation, characterization, and applications: a review.j adv res. 2015; 6:105-21. 22. singha p, locklin j, handa h. a review of the recent advances in antimicrobial coatings for urinary catheters. acta biomater. 2017; 50:20-40. 23. al-aown a, kyriazis i, kallidonis p, et al. ureteral stents: new ideas, new designs. ther adv urol. 2010; 2:85-92. 24. glinel k, thebault p, humblot v, pradier c, tjouenne. antibacterial surfaces developed from bio-inspired approaches. acta biomater. 2012; 8:1670-84. 25. kallidonis p, georgiopoulos i, kyriazis i, et al. the full metallic double-pigtail ureteral stent: review of the clinical outcome and current status. indian j urol. 2015; 31:8-14. 26. janssen p, tailly t. new stent technologies. urol clin north am. 2022; 49:185-196. 27. monga m. the dwell time of indwelling ureteral stents--the clock is ticking but when should we set the alarm? j urol. 2011; 185:387. 28. lin k, chen p, fan y, huang w. preventing forgotten double j ureteral stents in a high-volume service medical center: an autoregistration monitoring system. j chin med assoc. 2020; 83:382-385. 29. branch hsi. unplanned delayed removal of ureteric stent. healthcare safety investigation branch. https://www.hsib.org.uk/investigations-and-reports/unplanned-delayed-removal-of-ureteric-stents/ correspondence mohanarangam thangavelu, mbbs, febu, frcs (urology) (corresponding author) drtmohan@hotmail.com consultant urology, betsi cadwaladr university health board ysbyty gwynedd, bangor, ll57 2pw, united kingdom mohamed yehia abdallah, md, frcs (urology) mohamed.yehia@wales.nhs.uk olubenga john isola, md gbenga.isola@yahoo.co.uk department of urology, wrexham maelor hospital, wrexham, ll13 7td, united kingdom ahmed kotb, md drahmedfali@gmail.com northern ontario school of medicine, tbrhsc, 980 oliver road, thunder bay, ontario, canada. p7b 6v4 stesura seveso 323archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. when a patient is offered a urs for a ureteric stone, the possibility of spontaneous expulsion still exists before the procedure, eventually unnoticed by the patient. if no other measures are taken to detect persistence of stones before surgery, a “stoneless” or “negative” procedure (hence, unnecessary) would be performed (14). negative urs, with described rates up to 15%, represents a avoidable patient risk and use of medical resources (15-18). predicting negative urs preoperatively and cancelling the procedure would prevent this unnecessary burden (14). several factors predicting negative urs have been studied. smaller stone size is associated with increased probability of unnoticed expulsion and negative urs (15, 17); other reported factors include distal stone positioning (17) and female gender (15, 16). time since last imaging study does not appear to influence stoneless procedure rates (17). other potential influencing factors showed varying results (15-18). the objective of this paper is to describe rates and identify predictive factors of negative urs and to define strategies which would minimize patient and financial burden of these unnecessary procedures. materials and methods a retrospective cohort study analyzed all patients who underwent urs in our center over a period of 2 years. only procedures to treat ureteric stones were included; all were performed in the same center, with similar surgical equipment. several factors were reviewed, including patient age, gender and comorbidities, previous procedures, as well as clinical, laboratory and imaging findings. to comply with the purpose of the study, patients with negative urs were identified, and a potential correlation with the above-mentioned factors was investigated. patients who had negative urs were followed with ultrasound or computerised tomography (ct), and those with presence of stone suspected of retrograde migration were not included; patients in which complete urs was not feasible were also not included. statistical analysis was performed using spss 23®, including univariate mann-whitney and kruskalwallis tests, and a multivariate logistic regression model. results during the defined period, 262 patients underwent urs as planned treatment for ureteric stones while meeting the selection criteria. the population was 50.8% female, introduction: urolithiasis is common worldwide, with ureteric stones being a particular burden. ureteroscopy (urs) is one of the most useful procedures in treating ureteric stones not passed spontaneously; this procedure has a complication risk of 4%. negative urs, with described rates up to 15%, represents an avoidable patient risk and use of medical resources. objectives: to describe rates and identify predictive factors for negative urs and to define strategies which would minimize patient and financial burden from these unnecessary procedures. materials and methods: a retrospective cohort study analyzed patients who underwent urs in our center to treat ureteric stones over a period of 2 years. patient age, gender, and comorbidities, as well as laboratory and imaging findings, were analyzed. results: 262 patients underwent urs for ureteric stones. the female population was 50.8% with a mean age of 56.89 years. a total of 78 (29.8%) urs procedures were negative. univariate analysis showed a higher prevalence of negative urs in female patients, as well as in primary, smaller, and radiolucent stones. at multivariate analysis, a logistic regression model correctly classified 76% of patients, with smaller stone size and radiolucency being significant predictors of negative urs. discussion and conclusions: our center showed a high rate of negative urs, higher than commonly described in the literature. female patients tend to have an even higher rate, possibly due to unnoticed passage of stones. patients with small, radiolucent stones showed the highest rates of negative urs. key words: urolithiasis; ureteric; stone; ureteroscopy; negative. submitted 2 january 2021; accepted 2 july 2021 introduction urolithiasis is very common worldwide, with prevalence rates described in general population of 1-20% (1-4); countries with high standard of life show increasing rates over the past decades, with over 10% reported prevalence (5-7). ureteric stones pose a particular burden with frequent need of emergency visits and possible need for admittance and invasive procedures (7, 8). ureteroscopy (urs) is one of the most useful methods for treating ureteric stones not passed spontaneously (4, 10, 11). this procedure is generally considered safe, involving a complication risk of 4%, with many being performed in an outpatient basis (12-14). a mean overall cost of $2801 per procedure has been described in a systematic review (13). predicting negative ureteroscopy for stone disease – minimizing risk and cost miguel eliseu, roberto jarimba, pedro moreira, pedro simões, paulo temido, arnaldo figueiredo urology and renal transplantation department, coimbra hospital and university center, coimbra, portugal. doi: 10.4081/aiua.2021.3.323 summary archivio italiano di urologia e andrologia 2021; 93, 3 m. eliseu, r. jarimba, p. moreira, p. simões, p. temido, a. figueiredo 324 with a mean age of 56.89 years (sd +/15.705 years). patients had a mean stone size of 7.7 mm (sd +/mm); 47.8% of patients had stones between 5 and 9 mm. according to pre-procedure imaging, the lower ureter was the most common stone location (54.3%), followed by mid (23.7%) and upper ureter (22%). approximately 86.3% of stones studied were radiopaque on plain x ray of kidney-ureter-bladder (kub). regarding imaging techniques applied at initial diagnosis, renal ultrasound was most used (99.2% of patients); kub x-ray was performed in 90.2% of cases and ct in 78.6%. stenting in the acute setting was performed at physician discretion, with center policy including best practice guidelines; stenting was performed in cases with associated infection, compromised renal function or long-standing pain (over 14 days) irrespective of planned urs or not. a significant proportion of patients underwent ureteric stenting in the acute setting (57.5%; n = 146); of those proposed to urs after stenting, 67.8% (n = 99) underwent kub, 15.1% (n = 22) underwent ct, with 2.7% (n = 4) having both exams; 29 patients (19.9%) had no imaging between stenting and surgery. cases where no evidence of stones was found were not considered for urs. the mean time between the acute episode and subsequent urs was 61.8 days (+/27.076). in patients who underwent stenting prior to urs, mean time from stenting to surgery was 65.3 days (+/28.278). patient and stone characteristics are displayed in table 1. a total of 78 urs procedures were negative for stones, representing 29.8%. several factors were investigated in univariate analysis, which showed a higher prevalence of negative urs in female patients (p = 0.023), as well as in primary (p = 0.001), smaller (p = 0.010), and radiolucent stones (p = 0.035). these results are displayed in table 2. several other factors were analyzed, but not found to be predictors of negative urs (table 3). namely, anatomical stone position (p = 0.646), mean time between the acute episode and subsequent urs (p = 0.207) and mean time from stenting to surgery (p = 0.614) did not appear to influence the risk of negative ureteroscopy. there was also no significant difference between patients who did or did not undergo ct scan (negative urs rates of 28.6% vs 33.9%, p = 0.139). at multivariate analysis, a logistic regression model correctly classified 76% of patients, with smaller stone size (p = 0.026) and radiolucency (p = 0.011) being significant predictors of negative urs, and accounting for 47.7% of the variance. each mm increase in stone size, showed an impact on or for negative urs of 0.815 (expb=-0.204), while radiopaque stones showed an or table 1. patient/stone characteristics and acute episode clinical variables; frequencies represented in percentage of valid results and absolute number of cases excluding missing values in brackets. patient frequency in valid % (n) and stone characteristics excluding missing sex female 50.8% (133) male 49.2% (129) age in years 20-34 7.3% (19) 35-49 22.9% (60) 50-64 37% (97) 65-80 24.4% (64) 80 or more 8.4% (22) number of episodes *1 primary 81.5% (203) recurrent disease 18.5% (46) stone anatomical location upper ureter 22.0% (52) mid-ureter 23.7%(56) lower ureter 54.3% (128) radiopacity *2 radiopaque 86.3% (202) radiolucent 13.7% (32) medical expulsive therapy alfa-blockers 53.8% (141) corticosteroids 11.5% (30) perc. nephrostomy in acute episode (performed) 11.8% (30) jj stenting in acute episode (performed) 57.5% (146) *1 missing value in 12 cases with dubious history of stones (patient unsure and no previous imaging available); *2 based on kub; missing value in 26 cases that did not undergo kub and 2 cases for which kub was not available to the authors (from other institutions). table 2. significant variables in univariate analysis with respective rates of negative urs in each subgroup and corresponding p values. negative urs was more common in females, primary cases, small and radiolucent stones. clinical variables % negative urs p value primary 32.5% < 0.001 recurrence 8.7% female 36.1% 0.023 male 23.3% 0-4.9 mm 56.3% 0.010 5-9.9 mm 33.7% 10 mm or more 15.5 % radiopaque 19.8% 0.035 radiolucent 43.8% table 3. non-significant variables which did not show influence on the rate of negative urs. univariate non-significant patient frequency of negative p value and stone characteristics urb (%) age in years 20-34 47.4% 0.442 35-49 26.7% 50-64 30.9% 65-80 28.1% 80 or more 22.7% stone anatomical location upper ureter 25% 0.646 mid-ureter 28.6% lower ureter 27.3% diagnosis imaging including ct 28.6% 0.139 no ct 33.9% medical expulsive therapy alfa-blockers 33.1% 0.282 corticosteroids 40% none 27% time from acute episode to urs 0-29 days 28.6% 0.207 30-59 days 33.1% 60-89 days 27.9% ≥ 90 days 21.4% time from stenting to urs 0-29 days 35.7% 0.614 30-59 days 36.8% 60-89 days 37.9% ≥ 90 days 29.4% percutaneous nephrostomyin acute episode yes 30% 0.777 no 28.6% jj stenting in acute episode yes 36.3% 0.464 no 21.3% 325archivio italiano di urologia e andrologia 2021; 93, 3 predicting negative ureteroscopy for negative ureteroscopy of 0.240 (expb=-3.716). table 4 summarises these results. discussion and conclusions our center showed a high rate of negative urs, more than previously described in the literature. a recent systematic review suggests that a publication bias may exist, resulting in series with higher rates of urs not being submitted for peer review, leading to underestimation of its prevalence (19). stone position has been described in one previous study as an influencing factor, with distal stones resulting in higher negative urs rates (17); this did not seem to be the case with our population. in accordance with previously reported data (17) time to surgery from last imaging study or stenting also did not influence negative urs rates. of note, our series presents a significant number of pre-stented patients, more than in previously reported retrospective studies (15) and 19.9% of those did not undergo further imaging before urs. female patients tend to have a higher rate of negative urs, as described in two recent studies (15, 16). this is possibly explained by frequent unnoticed passage of stones (due to shorter urethral length and lower voiding pressure) or by a higher frequency of pelvic phleboliths mistaken as ureteric stones (19). patients with small, radiolucent stones showed the highest rates of negative urs; this is also in accordance with previously described series (15, 17). these patients would benefit the most from pre-operative repeat imaging studies, eventually with non-contrast ct, to identify and preclude unnecessary treatments and costs (14). prospective studies could help identify more precisely which imaging studies, in which patients and in what timeframe would impact the most in terms of change in planned treatment, to suggest clear guidelines regarding this matter. references 1. trinchieri a. epidemiology of urolithiasis.arch ital urol androl. 1996; 68:203-49. 2. trinchieri a. epidemiology of urolithiasis: an update. clin cases miner bone metab. 2008; 5:101-106. 3. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017; 35:1301-20. 4. turney bw, reynard jm, noble jg, keoghane sr. trends in urological stone disease. bju int. 2012; 109:1082-7. 5. rukin nj, siddiqui za, chedgy ecp, somani bk. trends in upper tract stone disease in england: evidence from the hospital episodes statistics (hes) database. urol int. 2017; 98:391-6. 6. hesse a, brändle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003; 44:709-13. 7. stamatelou kk, francis me, jones ca, et al. time trends in reported prevalence of kidney stones in the united states: 19761994. kidney int. 2003; 63:1817-23. 8. kim jw, kim jy, ahn st, et al. analysis of patients with urolithiasis visiting the emergency department between 2014 and 2016 in korea: data from the national emergency department information system. sci rep. 2019; 9:16630. 9. gomes j, vendeira p, ribau u, reis m. urolitíase e cólica renal. perspectiva terapêutica em urologia [urolithiasis and renal colic. therapeutic approach in urology]. acta med port. 2002; 15:369-80. 10. geraghty rm, jones p, somani bk.worldwide trends of urinary stone disease treatment over the last two decades: a systematic review. j endourol. 2017; 31:547-56. 11. pietropaolo a, proietti s, geraghty r, et al. trends of 'urolithiasis: interventions, simulation, and laser technology' over the last 16 years (2000-2015) as published in the literature (pubmed): a systematic review from european section of urotechnology (esut). world j urol. 2017; 35:1651-1658. 12. somani bk, giusti g, sun y, et al. complications associated with ureterorenoscopy (urs) related to treatment of urolithiasis: the clinical research office of endourological society urs global study. world j urol. 2017; 35:675-681. 13. geraghty rm, jones p, herrmann trw, et al. ureteroscopy is more cost effective than shock wave lithotripsy for stone treatment: systematic review and meta-analysis.world j urol. 2018; 36:1783-1793. 14. lloyd p, johnston t, coode-bate j, keoghane sr. a negative ureteroscopy for stone disease: is it acceptable and is it avoidable? urol new. 2018; 22(6). 15. katafigiotis i, sabler im, heifetz em, et al. “stoneless” or negative ureteroscopy: a reality in the endourologic routine or avoidable source of frustration? estimating the risk factors for a negative ureteroscopy. j endourol. 2018; 32:825-30. 16. lamberts rw, conti sl, leppert jt, elliott cs. defining the rate of negative ureteroscopy in the general population treated for upper tract urinary stone disease. j endourol. 2017; 31:266-71. 17. kreshover je, dickstein rj, rowe c, et al. predictors for negative ureteroscopy in the management of upper urinary tract stone disease. urology. 2011; 78:748-52. 18. prattley s, rice p, pietropaolo a, et al. predictors and results of negative ureteroscopy for treatment of consecutive ureteric stones done as a primary procedure: prospective outcomes from a university hospital. urol int. 2019; 103:143-148. 19. rice p, prattley s, somani bk.’negative ureteroscopy’ for stone disease: evidence from a systematic review. curr urol rep. 2019; 20:13. table 4. logistic regression model accounting for 47.7% of the variance in the dependent variable (probability of negative urs), correctly classifying 76% of patients; each mm increase in stone size with or of 0.815 and radiopaque stones with or of 0.240 for negative urs. applied variables significance (p) b exp (b) sex 0.234 stone size (absolute value in mm) 0.026 -0.204 0.815 primary vs recurrence 0.198 radiopacity 0.011 -3.716 0.240 correspondence miguel eliseu, md (corresponding author) mgl.nobre@gmail.com roberto jarimba rjarim-ba@gmail.com pedro moreira pedronetomoreira@gmail.com pedro simões pedrocorreiasimoes@gmail.com paulo temido ptemido@gmail.com arnaldo figueiredo ajcfigueiredo@gmail.com urology and renal transplantation department, coimbra hospital and university center praceta professor mota pinto, 3004-561 coimbra (portugal) stesura seveso 443archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. minimal despite moderate to severe hydronephrosis, or it may be severe without marked hydronephrosis. renal scans together with determination of the glomerular filtration rate constitute the standard method of evaluating the presence and severity of uuto (1). these investigations can be time-consuming and distressing for the patients, and are not sensitive or specific enough to identify all the cases requiring treatment. also, renal scans are expensive and not always available. therefore, there is a great need for the development of new methods to stratify and monitor patients, and the biomarker research field is a promising approach for this purpose. urinary as well as serum proteins provide information of the physiological condition in the kidney and have the potential to be used as prognostic tools for early disease detection and the choice of the optimal treatment and monitoring (1). the etiopathogenesis of renal damage and the progression of renal insufficiency in obstructive nephropathy consist of several processes at the cellular and molecular level. these include the hemodynamic response of the kidneys (i.e. decrease in blood flow mainly in the renal cortex, decrease in capillary wall permeability, infiltration of the interstitium by macrophages, reflux of filtrate through the damaged tubule wall into the interstitium, dilatation of renal tubules and apoptosis and accumulation of peeled tubular cells in the lumen of the renal tubules). this process proceeds under the influence of various enzymes, cytokines, chemokines, growth factors, signaling molecules, and genes. in recent years, several molecules have been identified that could potentially be used as biomarkers with promising results in both diagnosis and treatment, as well as a prognostic factors in children with uuto (2). a biomarker is defined as a parameter that can be measured objectively and is evaluated as an indicator of both normal physiological and pathogenic processes and/or pharmacological responses to a therapeutic intervention (3). epidermal growth factor (egf) is one of the well-known polypeptide growth factors which plays a fundamental role in the regulation of cell proliferation and differentiation (4). the kidney is one of the major sites of its production. thick ascending limb of henle’s loop and the disobjective: to evaluate the role of urinary monocyte chemotactic protein-1 (mcp1) and urinary epidermal growth factor (egf) in diagnosing of upper urinary tract obstruction (uuto). patient and methods: over a period of 6 months (january 2022 to june 2022) this prospective case control comparative study was conducted on 120 participants, 60 of them with uuto and 60 healthy controls. a morning urine sample of all participants was tested for egf and mcp-1. after taking a detailed history taking and laboratory and radiological evaluation. results: urinary mcp-1(umcp-1) was significantly (p-value = 0.000) increased in uuto group showing a mean ± sd of 518.10 ± 51.19 ng/l compared to a mean ± sd of 143.32 ± 58.03 ng/l in the controls, whereas a significantly (p-value = 0.000) decrease of urinary egf (uegf) was observed in patients with uuto compared to control group. a significant difference of uegf level and uegf/umcp1 ratio was observed between mild compared to moderate/severe uuto. conclusions: utilization of the urinary biomarker mcp1, egf and uegf/umcp1 ratio in patients with uuto can adequately be used as a simple, efficacious and noninvasive way in diagnosis of uuto. key words: upper urinary tract obstruction; urinary monocyte chemotactic protein-1 (umcp-1); urinary epidermal growth factor (uegf). submitted 27 october 2022; accepted 12 november 2022 introduction obstructed nephropathy is a frequent and demanding urological condition caused by a variety of diseases, such as pelviureteric junction obstruction (pujo), ureteric stone, ureteric stricture, and malignant ureteral obstruction either intra or extra luminal. the disease may occur in patients of any age. surgical intervention is necessary for moderate to severe cases, according to the degree and cause of the obstruction. hydronephrosis may be occur either unilateral or bilateral due to incomplete emptying. however, the extent of hydronephrosis does not prominently reflect the severity of uuto. obstruction may be urinary epidermal growth factor and monocyte chemotactic protein-1 as biomarkers of renal injury in patients with obstructed nephropathy eman m. el-dydamony 1, mohamed ahmad abdelaal 1, sammar ahmad kasim 2, doaa refaat ameen 3, doaa aly abd el-fattah 4 1 department of urology, faculty of medicine (for girls), al-azhar university, cairo, egypt; 2 department of internal medicine, faculty of medicine (for girls), al-azhar university, cairo, egypt; 3 department of biochemistry, faculty of medicine (for girls), al-azhar university, cairo,egypt; 4 department of clinical pathology, faculty of medicine (for girls), al-azhar university, cairo, egypt. doi: 10.4081/aiua.2022.4.443 summary archivio italiano di urologia e andrologia 2022; 94, 4 e. m. el-dydamony, m. ahmad abdelaal, s. ahmad kasim, d. refaat ameen, d. aly abd el-fattah 444 tal convoluted tubule being the main sites of egf production. it is considered as a mitogen for variant renal cells and has essential functional effects on intact glomeruli, proximal tubules and collecting ducts. also, it is a powerful trophic factor for tubular epithelial cells; so, its concentration in the urine may reflect the number of functional nephrons and it may be a good marker for assessment of renal function (5, 6). mcp-1is one of the most promising biomarkers of kidney injury, it is a chemokine protein that mediates monocyte chemotaxis (7). in the case of obstruction, its expression at the level of the renal tubules appears to be directly associated with the accumulation of these inflammatory cells within the interstitial space. thus, urinary excretion of mcp1 may be associated with the rate of monocyte infiltration and subsequent progression of interstitial renal fibrosis (8, 9). all studies have shown a high correlation between mcp1 levels in urine and the extent of tubular atrophy and interstitial fibrosis. mcp-1 mrna is undetectable in the normal kidney, but mcp-1 gene expression is markedly increased at the tubulointerstitial level in upjo biopsy samples and correlates with the extent of monocyte infiltration (10, 11). recently, urinary egf/mcp-1 ratio was suggested as an useful early biomarker of progressive renal damage for obstructive nephropathy. it can have a potential role in predicting the long term renal function outcome (12). patients and methods a prospective case control comparative study was conducted in the urology department on 120 participants, male and female , aged between 18-60 years who were selected from urology out-patient’s clinic of al-zahra'a hospital, al-azhar university from january 2022 to july 2022. the study was approved from the institutional ethics committee and all study participants provided written consent for inclusion in the study. participants were divided in to two groups as: group i: 60 patients with varying degrees of upper urinary tract obstruction (uuto) either unilateral or bilateral (obstruction was caused by ureteral stone, pujo or ureteral stricture). group ii: 60 healthy controls with no chronic illnesses including hypertension or kidney diseases. all participants were tested by urinary epidermal growth factor and urinary monocyte chemotactic protein. patients with end stage renal disease, malignant disease, aged below 18 or or more than 60 years, with thyroid disorders, acute or chronic inflammatory disease, autoimmune diseases as lupus nephritis, diabetic nephropathy, kidney transplants and pregnant female were excluded from the study. all subjects included in the study were subjected to history taking (onset and duration of the disease, medical and surgical history); full general and systemic examination; blood pressure measurement; complete blood count and serum urea, creatinine, and proteins measurement; liver function tests; glomerular filtration rate measurement (gfr); urine analysis. morning urine samples were collected in sterile containers from all subjects. samples were centrifuged at 2000-3000 rpm for 20 minutes then the supernatants were collected and were stored at -20°c until measurement. the concentration of urinary mcp1 and urinary egf were quantified using quantitative double-antibody sandwich elisa kits (bioassay technology laboratory, china, cat. no. e0124hu and e0144hu respectively). concentrations were expressed as ng/l. urine mcp-1 and egf were normalized to urine creatinine excretion (ng/mg urine creatinine). also participants underwent kidney/ureter/bladder (kub) x-ray, pelvic-abdominal ultrasound, and computed tomography (ct). the comparison between groups for qualitative data was done by using chi-square test. the comparison between groups for quantitative data and parametric distribution were done by using independent t-test. the comparison between more than two groups with quantitative data and parametric distribution were done by using one way anova test followed by post hoc analysis using lsd test when significant. spearman correlation coefficients were used to assess the correlation between two quantitative parameters in the same group. receiver operating characteristic curve (roc) was used in the quantitative form to determine sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), area under curve (auc) and best cut off point for the studied markers between groups. the confidence interval was set to 95% and the margin of error accepted was set to 5%. so, the pvalue was considered significant at the level of < 0.05. results the present study was conducted on 120 participants, including 60 patients with varying degrees of uuto (48 of them with ureteral stone, 4 with ureteral stricture and 8 with pujo). and 60 healthy controls. all of them were tested by urinary epidermal growth factor and urinary monocyte chemotactic protein to assess their role in diagnosis of uuto cases. in table 1 there is a statistically significant (p-value = 0.000) decrease of urinary egf (uegf) in patients with uuto with respect to control group. mean ± sd was (70.91 ± 17.90 ng/l) in control group, while it was 26.85 ± 10.82 ng/l) in the uuto group. urinary mcp-1 (umcp-1) values showed a statistically significant (pvalue = 0.000) increase in uuto group. uuto patients showed mean ± sd of 518.10 ± 51.19 ng/l compared to controls showing 143.32 ± 58.03ng/l. receiver operating characteristic (roc) curve analysis was used to determine the diagnostic profiles of uegf and umcp-1 in distinguishing patients with uuto from control healthy participants (table 2). using roc curve, it was shown that: • umcp1 can be used to discriminate between cases and control at a cutoff level of > 345.8, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). • umcp1/u creatinine can be used to discriminate between cases and control at a cutoff level of > 0.57, with 98.3% sensitivity, 96.7% specificity, 96.8% ppv and 98.3% npv (auc = 0.99 & p-value < 0.001). 445archivio italiano di urologia e andrologia 2022; 94, 4 urinary epidermal growth factor and monocyte chemotactic protein-1 as biomarkers of renal injury in patients with obstructed nephropathy • uegf can be used to discriminate between cases and control at a cutoff level of < 0.56.4, with 98.3% sensitivity, 96.7% specificity, 96.8% ppv and 98.3% npv (auc = 0.99 & p-value < 0.001). • uegf/u creatinine can be used to discriminate between cases and control at a cutoff level of < 0.075, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). • uegf/umcp1 can be used to discriminate between cases and control at a cutoff level of < 0.142, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). table 3 shows a significant difference between uegf level and uegf/u mcp1 ratio in mild vsmoderate/severe uuto. discussion currently, there is no gold standard for the assessment of renal obstruction in individual cases. the diagnosis in most cases is only possible by repeated investigations and comparisons of changes of the parameters during a longer follow up. frequently used investigations are grey-scale renal ultrasound, doppler ultrasound, radioisotope renography, excretory urography, contrast enhanced computed tomography and magnetic resonance urography. each of these modalities has its own merits and disadvantages, but none of them is ideal (13). a biochemical marker in the urine that could provide information to the obstructive nature of hydronephrosis would reduce the degree of invasiveness, subjectivity and operator dependent proficiency required of the currently available radiological modalities (14). consequently, the clinical usefulness of a bladder urine biomarker for aiding in the diagnosis of upper urinary tract obstruction is obviously appealing. the study done by madsen et al. demonstrated significantly increased uegf and umcp-1 levels in children with upjo, which normalized postoperatively. this indicates that egf and mcp-1 are regulated as a response to the obstruction, suggesting that they may be potential urinary biomarkers in hydronephrosis (15). in the present study there is a statistically significant (p-value = 0.000) decreased urinary egf (uegf) in patients with uuto with respect to control group. mean ± sd was 70.91 ± 17.90 ng/l in the control group, while it was 26.85 ± 10.82 ng/l in the uuto group, whereas urinary mcp-1 (umcp-1) values were significantly (p-value = 0.000) increased in uuto group. in uuto the mean ± sd was 518.10 ± 51.19 ng/l compared to 143.32 ± 58.03 ng/l in the controls. the maturation and proliferation of kidney cells occurs through the potential role of the egf receptor (egfr) and its ligand (egf) in cell division. lin et al. (16) stated that egfr and its ligand might function together as a trans activation complex that can bind to specific dna sequences to activate the gene expression required for highly proliferative activities. thus reductions in egf levels might reflect reduced egfr signalling. grandaliano et al. (11) reported significantly less urinary egf in a group with pujo than in controls in accordance with the finding of the present study. taranta-janusz et al. (17) showed increased levels of urinary mcp1 in patients developing kidney obstruction before undergoing surgical intervention. surgically table 1. comparison between control group and case group regarding the studied markers. control group cases group test value + p-value sig. no. = 60 no. = 60 umcp-1 (ng/l) mean ± sd 143.32 ± 58.03 518.10 ± 51.19 -37.516 0.000 hs range 58.2 268.5 423 598.8 umcp1/urinary creatinine (ng/mg creatinine) mean ± sd 42.41 ± 8.88 74.78 ± 7.89 -21.103 0.000 hs range 27.13 64.51 50.47 92.22 uegf (ng/l) mean ± sd 70.91 ± 17.90 26.85 ± 10.82 16.315 0.000 hs range 50.3 125.9 14 58.6 uegf/urinary creatinine(ng/mg creatinine) mean ± sd 10.22 ± 2.35 3.77 ± 1.27 18.700 0.000 hs range 7.85 16.76 1.94 7.19 uegf/umcp1 ratio (ng/ng) mean ± sd 0.25 ± 0.06 0.05 ± 0.02 25.358 0.000 hs range 0.162 0.385 0.022 0.122 p-value > 0.05: non significant; p-value < 0.05: significant; p-value < 0.01: highly significant; *: independent t-test. table 2. receiver operating characteristic curve (roc) for the studied markers to differentiate between cases group and control group. cut off auc sensitivity specificity ppv npv p-value umcp-1 (ng/l) > 345.8 1.0 100% 100% 100% 100% < 0.001 umcp1/urinary creatinine > 0.57 0.99 98.3% 96.7% 96.8 98.3 < 0.001 uegf (ng/l) < 56.4 0.99 98.3% 96.7% 96.8 98.3 < 0.001 uegf/urinary creatinine < 0.075 1.0 100% 100% 100% 100% < 0.001 uegf/umcp1 ratio (ng/ng) < 0.142 1.0 100% 100% 100% 100% < 0.001 auc: area under curve; ppv: positive predictive value; npv: negative predictive value. table 3. relation of grade of hydronephrosis with the studied markers. mild mod/severe test value + p-value sig. no. = 18 no. = 42 umcp-1 (ng/l) mean ± sd 531.9 ± 60.8 512.2 ± 45.9 287 0.1452 ns range 429.9 598.8 423 591 umcp1/urinary creatinine (ng/mg creatinine) mean ± sd 0.74 ± 0.08 0.74 ± 0.07 376 0.974 n range 0.58 0.86 0.5 0.92 uegf (ng/l) mean ± sd 32.2 ± 12.1 24.5 ± 9.4 212.5 0.008 s range 14 58.6 15.3 51.7 uegf/urinary creatinine (ng/mg creatinine) mean ± sd 0.04 ± 0.01 0.03 ± 0.01 221 0.001 s range 0.02 0.07 0.02 0.06 uegf/umcp1 ratio (ng/ng) mean ± sd 0.06 ± 0.02 0.04 ± 0.01 230 0.017 s range 0.03 0.1 0.02 0.12 p-value > 0.05: non significant; p-value < 0.05: significant; p-value < 0.01: highly significant; *: independent t-test. archivio italiano di urologia e andrologia 2022; 94, 4 e. m. el-dydamony, m. ahmad abdelaal, s. ahmad kasim, d. refaat ameen, d. aly abd el-fattah 446 managed cases revealed a significant difference in urinary mcp-1 levels in comparison with cases managed conservatively and control groups (p < 0.05). grandaliano and al. analyzed both mcp-1 expression on renal biopsies and urinary mcp-1 concentrations in severe pujo and found a four fold higher urinary mcp-1 concentration in studied children than in healthy controls (11). several studies have shown that children with upjo have a marked reduction of renal egf gene expression compared with controls but the role of urinary egf concentration in upjo is still not fully understood. grandaliano et al. demonstrated decreased mean egf urine excretion decreased egf mrna expression in the stenotic tissue after clinical ureteropelvic junction obstruction (18). at our study, roc curve analysis reveal that umcp1 can be used to discriminate between cases and control at a cutoff level of > 345.8, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). umcp1/u creatinine can be used to discriminate between cases and control at a cutoff level of > 0.57, with 98.3% sensitivity, 96.7% specificity, 96.8% ppv and 98.3% npv (auc = 0.99 & p-value < 0.001). uegf can be used to discriminate between cases and control at a cutoff level of < 0.56.4, with 98.3% sensitivity, 96.7% specificity, 96.8% ppv and 98.3% npv (auc = 0.99 & p-value < 0.001). uegf/u creatinine can be used to discriminate between cases and control at a cutoff level of < 0.075, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). finally, uegf/umcp1 can be used to discriminate between cases and control at a cutoff level of < 0.142, with 100% sensitivity, 100% specificity, 100% ppv and 100% npv (auc = 1.0 & p-value < 0.001). conclusions utilization of urinary biomarker mcp1, egf and uegf/ umcp1 ratio in patients with uuto can adequately be used as a simple, efficacious and noninvasive tool in diagnosis of uuto. also, there is a significant difference of uegf level and uegf/u mcp1 ratio between mild and moderate/severe uuto cases. references 1. mesrobian h-go, mitchell me, see wa, et al. candidate urinary biomarker discovery in ureteropelvic junction obstruction: a proteomic approach. j urol. 2010; 184:709-714. 2. seifriedova z, flogelova h, sarapatka j, et al. the use of biomarkers in the diagnosis and treatment of obstruction of the upper urinary tract in children. biomedical papers of the medical faculty of the university palacky, olomouc, czechoslovakia, 2022. 3. downing g. biomarkers definitions working group. biomarkers and surrogate endpoints. clin pharmacol ther. 2001; 69:89-95. 4. boonstra j. growth factor-induced signal transduction in adherent mammalian cells is sensitive to gravity. faseb j. 1999; 13:s35-42. 5. breyer ja, cohen s. the epidermal growth factor precursor isolated from murine kidney membranes (chemical characterization and biological properties). j biol chem. 1990; 265:16564-70. 6. harris rc. potential physiologic roles for epidermal growth factor in the kidney. am j kidney dis. 1991; 17:627-30. 7. moledina dg, isguven s, mcarthur e, et al. plasma monocyte chemotactic protein-1 is associated with acute kidney injury and death after cardiac operations. ann. thorac. surg. 2017; 104:613620. 8. yu l, zhou l, li q, et al. j elevated urinary lipocalin-2, interleukin-6 and monocyte chemoattractant protein-1 levels in children with congenital ureteropelvic junction obstruction pediatr urol. 2019; 15:44.e1-7. 9. karakus s, oktar t, kucukgergin c, et al. urinary ip10, mcp1, ngal, cystatin-c, and kim-1 levels in prenatally diagnosed unilateral hydronephrosis: the search for an ideal biomarker. urology. 2016; 87:185-92. 10. grandaliano g, gesualdo l, ranieri e, et al. monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitment. j am soc nephrol. 1996; 7:906-913. 11. grandaliano g, gesualdo l, bartoli f, et al. mcp-1 and egf renal expression and urine excretion in human congenital obstructive nephropathy. kidney int. 2000; 58: 182-192. 12. lucarelli g, mancini v, galleggiante v, et al. emerging urinary markers of renal injury in obstructive nephropathy. biomed res int. 2014; 2014:303298. 13. shokeir aa. the diagnosis of upper urinary tract obstruction. br j urol. 1999; 83:893-901. 14. palmer ls, maizels m, kaplan we, et al. urine levels of transforming growth factor-beta-l in children with ureteropelvic junction obstruction. urology. 1997; 50:769-73. 15. madsen mg, nørregaard r, palmfeldt j, et al. epidermal growth factor and monocyte chemotactic peptide-1: potential biomarkers of urinary tract obstruction in children with hydronephrosis. journal of pediatric urology. 2013; 9:838-45. 16. lin sy, makino k, xia w, et al. nuclear localization of egf receptor and its potential new role as a transcription factor. nat cell biol. 2001; 3:802-8. 17. taranta-janusz k, wasilewska a, debek w, waszkiewicz-stojda m. urinary cytokine profiles in unilateral congenital hydronephrosis. pediatr nephrol 2012; 27:2107-2113. 18. yi yang , xin zhou, hong gao, et al. the expression of epidermal growth factor and transforming growth factor-beta1 in the stenotic tissue of congenital pelvi-ureteric junction obstruction in children. j pediatr surg. 2003; 38:1656-60. correspondence eman m. el-dydamony, md (corresponding author) emanmohamed.8@azhar.edu.eg mohamed ahmad abdelaal, md maal_uro@yahoo.com department of urology, faculty of medicine (for girls), al-azhar university, cairo, egypt 377j+vhw, greek hospital st, as sarayat, el weili, cairo governorate 4391050 sammar ahmad kasim, md department of internal medicine, faculty of medicine (for girls), al-azhar university, cairo, egypt doaa refaat ameen, md department of biochemistry, faculty of medicine, (for girls), al-azhar university, cairo, egypt doaa aly abd el-fattah, md department of clinical pathology, faculty of medicine(for girls), al-azhar university, cairo, egypt stesura seveso 309archivio italiano di urologia e andrologia 2020; 92, 4 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.309 average of 3% to 4% every year (3, 4). kidney cancer represents today 3% of all tumors diagnosed in male and female over 70 years old (5). a growing body of evidence support the importance of treatments preserving kidney function (6, 7). additionally, since 25% of smrs are benign cortical tumors (eg. oncocytoma and angiomyolipoma) and another 25% are indolent with limited metastatic potential (eg. chromophobe, type 1 papillary renal cancer), several options for management of clinically localized renal masses have been reported, including active surveillance, thermal ablation and surgery that include radical and partial nephrectomy (8). active surveillance is an option for patients presenting small renal masses (< 4 m, clinical stage t1a) with a low likelihood of aggressive malignancy, procedure-limiting comorbidity, and/or limited life-expectancy (9). nephron-sparing surgery (nss) is considered the gold standard treatment for renal cell carcinoma (rcc) preferred for lesions less than 7 cm in diameter (clinical stage t1) (9). in order to of decrease pain, morbidity, kidney function damages, hospital stay, and operative time, various minimally invasive modalities for nss have been evaluated (6, 7, 10-12). thermal ablation, which may include cryoablation or radiofrequency ablation, may be used for small clinically localized masses (clinical stage t1a) and can be performed laparoscopically or percutaneously (9). eau guidelines suggest active surveillance, radiofrequency ablation and cryoablation for the treatment of elderly and/or comorbid patients with small renal masses, however the quality of the available data does not allow definitive conclusions regarding morbidity and oncological outcomes of cryoablation and radiofrequency ablation and the strength rating of this recommendation remain week (9). the aim of this study was to present our initial experience in terms of efficacy and safety of ct-guided percutaneous cryoablation for small renal masses. materials and methods study population after istitutional review board approval we retrospectively reviewed our prospectively kidney cancer database to evaluate outcomes of patients treated with ctbackground: today, the goal of surgery is to achieve oncological efficacy with the lowest complication rate. computed tomography (ct)-guided cryoablation is proposed as a safe and effective technique. we report, our series of small renal masses treated with cryoablation in elderly (> 70 years). methods: from may 2014 to april 2019, 32 patients with median (iqr) age of 75.5 years (range 71-80) with small renal masses (< t1a) diagnosis, clinical anesthesia contraindications to nephron-sparing surgery or patient’s will previous informed consent have been selected at our urology department. all patients underwent ct-guided cryoablation, preceded by needle biopsy. the cryoablation consisted in a procedure with an argon/helium gas-based system under local anesthesia. the follow-up included ct abdomen at 3, 6 and 12 months. the definition of incomplete treatment was the persistence of the lesion contrast enhancement (ce) at the end of the scan; the definition of relapse was the appearance of the ce to the 6-month control ct. results: the median follow-up was 30 months (iqr 1-59). the median size of the tumor was 3.85 cm (iqr 1.6-4.5). all patients underwent lesion biopsy resulting in diagnosis of renal cell carcinoma (rcc) in 29 patients (90.7%) and oncocytoma in 3 patients (9.3%). a median of 2 cryoprobes (iqr 13) was used and 2/3 cycles of freeze-thaw of the duration of 10 minutes or 5 minutes were performed. complications were: 3 asymptomatic transitional perirenal effusion, 2 lumbar pain well-controlled by analgesic drug. hospital stay was 2 days (range 1-3). no case showed incomplete treatment and local relapse or metastates at the ct abdomen-pelvis with contrast medium at 12 months. conclusions: this study shows the efficacy and safety of percutaneous cryoablation of small renal masses in elderly population. the procedure is easy to perform, with low complication rates and well tolerated by the elderly patients. key words: percutaneous renal cryoablation; kidney cancer; small renal masses; elderly; mini invasive. submitted 10 may 2020; accepted 10 june 2020 introduction extensive application of modern imaging techniques has led to more frequent incidental diagnosis of small renal masses (smrs) (1-3) with an increasing incidence by an mini invasive approaches in the treatment of small renal masses: tc-guided renal cryoablation in elderly summary oscar selvaggio 1, giovanni silecchia 1, matteo gravina 2, ugo giovanni falagario 1, giovanni stallone 3, luca macarini 2, giuseppe carrieri 1, luigi cormio 1, 4 1 university of foggia, department of urology and organ transplantation, foggia, italy; 2 university of foggia, department of radiology, foggia, italy; 3 university of foggia, department of nephrology, foggia, italy; 4 department of urology, bonomo teaching hospital, andria (bat), italy. selvaggio_stesura seveso 14/12/20 20:35 pagina 309 archivio italiano di urologia e andrologia 2020; 92, 4 o. selvaggio, g. silecchia, m. gravina, u.g. falagario, g. stallone, l. macarini, g. carrieri, l. cormio 310 guided percutaneous cryoablation. the following inclusion criteria were used: tumor diameter < 4 cm (t1a); comorbidity or clinical anesthesia contraindications to nephron-sparing surgery; residual renal masses in patients already undergoing surgery; kidney solitary condition; informed consent. exclusion criteria were lack of percutaneous access window, disease extending into renal vein or invading adjacent organs and tumor larger than 4 cm in a candidate for surgical treatment. all patients were seen in the clinic before ablation, history was recorded, physical examination was performed, relevant baseline laboratory values were measured, and dual-phase renal ct imaging was performed. all patients were counseled regarding all the treatment options available, after that a written informed consent was obtained. ct-guided percutaneous cryoablation all procedures were performed by the same team of urologists and interventional radiologists on a specific tc general electric medical system brightspeed. all patients were premedicated intravenously with 2 g cefazolin and ciprofloxacin 400 mg versus cotrimoxazole 2 fl in the case of allergy. patients were positioned prone or side, to facilitate probe insertion through a better percutaneous access window; for example, caused by descent of adjacent organs most often represented by bowel, on the ct bed and the ipsilateral flank was prepared and draped in a sterile fashion. a pre-procedural non-enhanced ct image was obtained to document tumor size and decide on access, number of probes and need for thermal protection for adjacent organs (hydrodissection). ct fluoroscopy was used to determine the optimum access site, with the help of a ct-mounted laser beam. the skin and underlying tissues were anesthetized with 10-15 ml of lidocaine 200 mg, then a tiny incision (2-3 mm) was made. before percutaneous cryoablation, all the patients underwent ct-guided needle biopsy of the lesion according to the current recommendation and at least 2 good quality biopsy cores using an 18g needle were taken (9). the cryoprobes were then inserted according to preoperative plans in order to create an “iceball” that would cover the lesion and provide at least 5 mm of ablation beyond the tumor margins. the cryoprobe advancement toward the mass and the extent of the iceball was monitorated intermittently with ct fluoroscopy. the tip of probe was positioned through the mass until to distal inner border of the lesion. the operations were performed using argon/helium gas-based system (endocare, healthtonics inc., austin tx, usa). such system uses a compressed argon for freezing and compressed helium for active thawing. with two exceptions, in which 1.7 mm diameter cryoprobes were used, all procedures were performed with 2.4 mm diameter cryoprobes. the number of cryoprobes used varied as a function of the lesion’s size: 8 patients treated with 1 probe, 18 pts with 2 probes, 6 pts with 3 probes. in seven cases, we have had a non-target organ (usually colon) that was closer than 1 cm to the tumor margin. in these cases, a chiba’s needle was inserted in the “fascia” of gerota and sterile water, mixed to 5-7 cc of contrast medium, was infused to keep the non-target organ away from the iceball. technical success was defined as completion of three ablation cycle: a 10-minutes freeze, 10-minutes active thaw and 10-minutes repeat freeze with the iceball covering the entire lesion and extending at least 5 mm beyond its border. at the end of the procedure, a ct image with contrast medium was performed to evaluate the complete cover of the lesion and possible local bleeding. the definition of incomplete treatment is the persistence of the ce at the end of the same. the patient was transferred to the recovery area and kept under observation. a blood count was performed 6 hour after the procedure and on postop day 1 before discharge. patients were discharged home unless overnight observation was deemed necessary as a result of complications or severity of symptoms. complications were recorded using the clavien-dindo classification and grade i and ii complications were follow-up visits follow-up visits were scheduled at 3-, 6-, 12-, 18-, 24and 36months after the procedure. a physical examination was performed along with measurement of relevant laboratory values. additionally, a dual-phase renal ct study was obtained at each follow-up visit. in order to minimize x-ray exposure follow-up images were acquired using a low dose protocol (low kilovolt, low milliampere). additionally, only sequences of the treatment region were taken during the procedure and at follow-up. all studies were read by the same interventional radiologist and compared to the baseline study. nonenhancement of the cryolesion was considered the primary radiographic hallmark of successful cryoablation. response to treatment was based on tumor enhancement and size on sequential images. complete lack of enhancement of a previously enhancing mass was considered complete response. response based on tumor size was less reliable initially, as many masses did not change in size on the first 3 months imaging study despite a gradual decrease thereafter. the existence of enhancement areas in the residual tumor mass after 6 months was considered an indication of local failure. statistical analysis outcomes of this study were cancer recurrence, metastasis and complications after percutaneous cryoablation. descriptive statistics was performed for the overall population. continuous variables were reported as median and interquartile whereas categorical variables were reported as rates. statistical analyses were performed using stata-se 14 (statacorp lp, college station, tx, usa). results preoperative characteristics of the study population are shown in table 1. final population included 20 men and 12 women with a median (iqr) age of 75.5 years (range 71-80 years) treated at our institution between may 2014 to april 2019. the median (iqr) size of the tumors was 3.85 cm (range 1.6-4.5). of the 32 treated patients, 30/32 (93.7%) had an incidentaloma and 2/32 (6.3%) were post-radiofreselvaggio_stesura seveso 14/12/20 20:35 pagina 310 quency ablation relapses. biopsy histological findings were the following: clear cell renal cell carcinoma (rcc) 20/32 (62.5%); chromophobe rcc 3/32 (9.3%); type 1 papillary 6/32 (18.7%); oncocytoma 3/32 (9.3%) (table 2). an average 2 cryoprobes (iqr: 1-3) have been used, depending on the size of the tumor, and were performed 2 cycles of freeze-thaw of the duration of 10 minutes each in 25 patients, and 3 cycles of 5 minutes each in 7 patients. 1.7 and 2.4 mm cryoprobes were used to minimize injury to the colon, we used thermal protective maneuvers in seven cases (21.8%). there were no cases of non-target organ damage. complications were: 3 effusion not clinically significant, transitional and perirenal which subsided spontaneously without intervention, 2 regressed back pain with analgesic therapy. no patient developed ablation related infection such as renal abscess, pyelonephritis or sepsis. percutaneous cryoablation of small renal cell carcinoma was accomplished safely in all 32 cases. no episodes of urinary extravasation, significant gross hematuria or urinary obstruction occurred. no other major operative complications were encountered. median hospital stay was 2 days (iqr: 13). median follow-up after the procedure was 30 months (iqr: 8-59); in none case, incomplete treatment and local relapse or metastases at ct abdomen-pelvis with contrast medium at 3, 6 and 12 months was detected. none of the 32 patients had clinical evidence of recurrent disease (confirmed with no enhancement within resolved tumor masses) at last follow-up. median tumor size before treatment was 3.16 cm (iqr: 1.6 to 5.5) (figure 1). after treatment, cryo-lesions size continued to decline over time. the relative reduction of the lesion size compared to preoperative values was 21.77% at 3-month follow-up (median size: 2.47 cm; iqr: 0.9 to 4.8), 31.93% at six-month follow-up (median size: 2.2 cm; iqr: 0.6 to 4.5 cm) and 45.91% at one-year follow-up (median size: 1.71 cm; iqr: 0.6 to 3.5 cm). figures 2 and 3 show the gradual decrease in the larger diameter of the lesions and the corresponding decrease in terms of percentage compared to the initial dimensions. the temporary increase in diameter of the cryolesions immediately following cryoablation is most likely due to edema in the tissue surrounding the tumor. the levels of postoperative creatinine were identical with preoperative levels. 311archivio italiano di urologia e andrologia 2020; 92, 4 tc-guided renal cryoablation in elderly table 1. patient demographics and tumor characteristics of 32 patients. table 2. perioperative and postoperativecharacteristics. figure 1. tumor in the middle right renal before cryoablation a); subsequent treatment b); lesion after 6 months c); lesion after 1-year d). variable cryoablation n = 32 age, years 75.5 (71-80) tumor diameter, cm 3.85 (1.6-4.5) gender, n (%) male 20 (62.5%) female 12 (37.5%) side right 14 (43.7%) left 18 (56.3%) asa score n (%) 1 6 (18.8%) 2 21 (65.6%) 3 5 (15.6%) tumor location, n (%) upper 8 (25.0%) middle 11 (34.4%) lower 13 (40.6%) diagnosis, n (%) incidentaloma 30 (93.7%) radiofrequency failure 2 (6.3%) variable cryoablation n = 32 hospital stay (d) 2 (1-3) hystological outcomes to biopsy, n (%) clear cells rcc 20 (62.5%) chromophobe rcc 3 (9.3%) type i papillary rcc 6 (18.7%) oncocytoma 3 (9.3%) follow-up, months 30 (8-59) complications, n (%) minor 5 (15.6%) major 0 (0.0%) recurrence of tumor 0 (0.0%) metastasis 0 (0.0%) selvaggio_stesura seveso 14/12/20 20:35 pagina 311 archivio italiano di urologia e andrologia 2020; 92, 4 o. selvaggio, g. silecchia, m. gravina, u.g. falagario, g. stallone, l. macarini, g. carrieri, l. cormio 312 discussion the choice between conservative or radical treatment for organ confined rcc in men over 70 years is a debated topic. in the last decades, the standard of care has slowly been expanding from radical nephrectomy to include robotic partial nephrectomy, laparoscopic nephrectomy, laparoscopic ablation and finally percutaneous ablation (14, 15). several questions such as efficacy and safety treatment, life expectancy, and cancer-specific survival advantage need to be taken into account. image guided percutaneous ablation is especially attractive for patients with small renal masses and a solitary kidney or multiple tumors, non-surgical candidates, pre dialysis patients and patients with diseases that may cause multiple rcc as von hippel-lindau disease or hereditary rcc. limited data are currently available in literature for assessing the role of percutaneous renal cryoablation. silverman et al. described a large number of percutaneous renal cryoablations under general anesthesia with mri guidance (16). image guidance for percutaneous renal cryoablation is alternated between mri, ct, and ultrasound (us). in the case of mri, the question is that system is expensive and limited in use but the ability of real time guidance and visualization of the iceball in multiple planes are the advantage, allowing the operator to achieve the safety margins of the cryolesion. bassignari et al. reported the practicability of us-guided percutaneous renal cryoablation to aim for future performance of this treatment by a urologist alone without the interventional radiologist because urologists have ultrasound experience (17). results of this study from our cohort of patients showed that ct-guided percutaneous cryoablation resulted in complete response for lesions as large as 4 cm. in all cases, it has a high efficacy rate, and its few complications are not only similar to those of other treatment modalities, but also appear to be reversible. percutaneous cryoablation with use of ct has the benefit of delaying/avoiding the end-stage renal disease by causing less renal injury. another advantage is to perform percutaneous cryoablation under spinal anesthesia avoiding the major complications or side effects that could derive from a general anesthesia considering that many patients have plurimorbidity as well as advanced age. other advantages of percutaneous cryoablation are faster recovery, repeatable, and lower cost. among all percutaneous ablative techniques, cryoablation has gained particular interest for small kidney cancer for painless during the treatment and it provides real-time image feedback of the ablation zone, especially when performed with ct guidance. furthermore, cryoablation is less likely to result in significant treatment-related injury because the extracellular matrix is less permanently destroyed by freezing, thereby allowing for epithelial regrowth and repair. the study pointed out that percutaneous cryotherapy provides, in elderly patients with small kidney cancer, an acceptable efficacy and safety in the absence of recurrence of disease and risk of metastasis in the short to medium follow-up (median follow-up: 30 months). this result is particularly encouraging considering that andrews et al. (18) highlights that there are no statistically significant differences in terms of local recurrence, metastases and risk of death from rcc among partial nephrectomy, radiofrequency ablation and cryoablation for ct1a patients. pierorazio et al. (8) shows similar cancer specific survival among partial nephrectomy and thermal ablations (radiofrequency and cryoablation), with some differences in renal functional and peri/postoperative outcomes that should be considered when choosing a management strategy, particularly in elderly patient. kitley et al. demonstrated in ct1a that cryotherapy had a lower overall survival than partial nephrectomy however at multivariable analisys adjusting for age and charlson comorbidity index, the rates of survival for the two treatments were similar (19). additionally, overall survival of patients based on tumor size prove similar rates of survival for tumors smaller than 2 cm. to our knowledge, these data suggest that elderly men with small renal cancer can take advantage from this local treatment. this is of clinical relevance in view of the figure 2. tumor size variation evaluated using ct scans at 3, 6, 12 months of follow-up. the figure represents tumor size of 24 patients with a follow-up of at least 12 months. each group of three columns represents a patients and age is specified below. figure 3. percentage variations in the major diameter of injuries. selvaggio_stesura seveso 14/12/20 20:35 pagina 312 313archivio italiano di urologia e andrologia 2020; 92, 4 tc-guided renal cryoablation in elderly fact that, as mentioned above, partial and ever more radical nephrectomy is usually not offered to elderly patients due to the risk of treatment-related complications, though their occurrence, like for most surgical procedures, is much linked to case volume (20). at the end, our data is similar to those published by atwell et al., who reported a technical success and efficacy rate of 95% with a median follow-up of 8 months (21). several guidelines and commentaries have highlighted the need for longer follow-up of ablation patients. our study has limitations: all patients were referred from a urology department so may have introduced a selection bias. additionally, even though the behavior of rcc is unpredictable, it is generally as low-growing cancer, and longer follow-up would be required to confirm the high degree of efficacy we documented in the present study. conclusions published preliminary results have shown that imageguided percutaneous cryoablation for small renal cancer is probably as safe and effective as laparoscopic cryoablation. results of this study confirm the very high efficacy rate and acceptable morbidity associated with this ct-guided percutaneous cryoablation. nonetheless, ct-guided percutaneous cryoablation offers compelling advantages compared with other treatment modalities, particularly in elderly patients, and has shown high efficacy rates and low risk for minor/major complications. references 1. jayson m, sanders h. increased incidence of serendipitously discovered renal cell carcinoma. urology. 1998; 51:203-5. 2. homma y, kawabe k, kitamura t, et al. increased incidental detection and reduced mortality in renal cancer--recent retrospective analysis at eight institutions. int j urol. 1995; 2:77-80. 3. decastro gj, mckiernan jm. epidemiology, clinical staging, and presentation of renal cell carcinoma. urol clin north am. 2008; 35:581-92. 4. saad am, gad mm, al-husseini mj, et al. trends in renal-cell carcinoma incidence and mortality in the united states in the last 2 decades: a seer-based study. clin genitourin cancer. 2019; 17:4657 e5. 5. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018; 68:394-424. 6. falagario ug, martini a, pfail j, et al. does race impact functional outcomes in patients undergoing robotic partial nephrectomy? transl androl urol. 2020; 9:863-869 7. martini a, falagario ug, cumarasamy s, et al. defining risk categories for a significant decline in estimated glomerular filtration rate after robotic partial nephrectomy: implications for patient follow-up. eur urol oncol. 2019:s2588-9311(19)30104-x. 8. pierorazio pm, johnson mh, patel hd, et al. management of renal masses and localized renal cancer: systematic review and meta-analysis. j urol. 2016; 196:989-99. 9. ljungberg b, albiges l, bensalah k, et al. eau guidelines on renal cell carcinoma 2018. european association of urology guidelines 2018 edition, vol. presented at the eau annual congress copenhagen 2018. arnhem, the netherlands european association of urology guidelines office, 2018. 10. gill is, novick ac, soble jj, et al. laparoscopic renal cryoablation: initial clinical series. urology. 1998; 52:543-51. 11. gill is, desai mm, kaouk jh, et al. laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. j urol. 2002; 167:469-7. 12. ukimura o, kawauchi a, fujito a, et al. radio-frequency ablation of renal cell carcinoma in patients who were at significant risk. int j urol. 2004; 11:1051-7. 13. de la rosette jj, opondo d, daels fp, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 14. corongiu e, grande p, di santo a, et al. safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. arch ital urol androl. 2019; 91:157-162. 15. tiscione d, cai t, luciani lg, et al. sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. arch ital urol androl. 2019; 91:30-34. 16. silverman sg, tuncali k, vansonnenberg e, et al. renal tumors: mr imaging-guided percutaneous cryotherapy--initial experience in 23 patients. radiology. 2005; 236:716-24. 17. bassignani m, moore y, watson l, theodorescu d. pilot experience with real-time ultrasound guided percutaneous renal mass cryoablation. j urol. 2004; 171:1620-3. 18. andrews jr, atwell t, schmit g, et al. oncologic outcomes following partial nephrectomy and percutaneous ablation for ct1 renal masses. eur urol. 2019; 76:244-51. 19. kitley w, sulek j, sundaram c, bahler cd. treatment trends and long-term survival associated with cryotherapy and partial nephrectomy for small renal masses in the national cancer database using propensity score matching. j endourol. 2019; 33:408-14. 20. kandasami sv, mamoulakis c, el-nahas ar, et al. impact of case volume on outcomes of ureteroscopy for ureteral stones: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014; 66:1046-51 21. atwell td, farrell ma, callstrom mr, et al. percutaneous cryoablation of 40 solid renal tumors with us guidance and ct monitoring: initial experience. radiology. 2007; 243:276-83. correspondence oscar selvaggio, md oscarsel@libero.it giovanni silecchia, md ugo giovanni falagario, md giuseppe carrieri, md luigi cormio, md university of foggia, department of urology and organ transplantation viale pinto 1, 71100 foggia (italy) matteo gravina, md luca macarini, md university of foggia, department of radiology, foggia, italy giovanni stallone, md university of foggia, department of nephrology, foggia, italy selvaggio_stesura seveso 14/12/20 20:35 pagina 313 227archivio italiano di urologia e andrologia 2018; 90, 4 original paper multidisciplinary approach to prostatitis vittorio magri 1, matteo boltri 2, tommaso cai 3, roberto colombo 4, salvatore cuzzocrea 5, pieter de visschere 6, rosanna giuberti 7, clara maria granatieri 1, maria agnese latino 9, gaetano larganà 9, christian leli 10, giorgio maierna 1, valentina marchese 11, elisabetta massa 1, alberto matteelli 11, emanuele montanari 12, giuseppe morgia 9, kurt g. naber 13, vaia papadouli 14, gianpaolo perletti 15, nektaria rekleiti 14, giorgio i. russo 9, alessandra sensini 8, konstantinos stamatiou 14, alberto trinchieri 16, florian me wagenlehner 17 1 asst nord milano, italy; 2 urology medical school, university of trieste, trieste, italy; 3 department of urology, santa chiara regional hospital, trento, italy; 4 synlab italia, castenedolo (bs), italy; 5 università degli studi di messina, messina, italy; 6 department of radiology and nuclear medicine, ghent university hospital, ghent, belgium; 7 sict società idrocolonterapia, milano, italy; 8 working group on sexually transmitted infections, italian association of clinical microbiologists, glist-amcli, italy; 9 department of urology, università degli studi di catania, catania, italy; 10 unit of microbiology, ss antonio, biagio and c. arrigo hospital, alessandria, italy; 11 department of infectious and tropical diseases, university of brescia, brescia, italy; 12 department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy; 13 technical university of munich, munich, germany; 14 tzaneio hospital; 15 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 16 urology unit, manzoni hospital, lecco, italy; 17 clinic for urology, pediatric urology and andrology, justus liebig university giessen, germany. report of the meeting prostatitis: a multidisciplinary approach (issues and controversies), milano, italy, 26-27 oct 2018 the modern clinical research on prostatitis started with the work of stamey and coworkers who developed the basic principles we are still using. they established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate and to differentiate the main categories of prostatitis. such categories with slight modifications are still used according to the nih classification: acute bacterial prostatitis, chronic bacterial prostatitis, chronic pelvic pain syndrome (cpps) and asymptomatic prostatitis. prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms of benign prostatic hyperplasia and prostatitis. chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system affecting surrounding neural tissue at molecular, structural and functional levels. clinical observations suggest that chronic inflammation correlates with chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) and benign prostatic hyperplasia (bph) and an history of clinical chronic prostatitis significantly increases the odds for prostate cancer. the nihniddk classification based on the use of the microbiological 4glasses localization test or simplified 2-glasses test, is currently accepted worldwide. the upoint system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments. the upoints algorithm implemented the original upoint adding to the urinary domains (u), psycho-social (p), organspecific (o), infection (i), neurological (n), muscle tension and tenderness (t) a further domain related to sexuality (s). in fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality summary no conflict of interest declared. doi: 10.4081/aiua.2018.4.227 of life of patients with cp/cpps. prostatic ultrasound represents the most popular imaging test in the work-up of either acute and chronic prostatitis although no specific hypo-hyperechoic pattern has been clearly associated with chronic bacterial prostatitis and cpps. use of a digital-processing software to calculate the extension of prostatic calcification area at ultrasound demonstrated a higher percentage of prostatic calcification in patients with chronic bacterial prostatitis. multiparametric magnetic resonance imaging (mpmri) is the current state-of-the art imaging modality in the assessment of patients with prostate cancer although a variety of benign conditions, including inflammation, may mimic prostate cancer and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions. bacteria can infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. enterobacteriaceae are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of enterococci has been reported. many strains of these uropathogens exhibit the ability to form biofilm and multidrug-resistance. sexually transmitted infections (sti) agents, in particular chlamydia trachomatis and mycoplasma genitalium, have been also considered as causative pathogens of chronic bacterial prostatitis. on the contrary the effective role in genital diseases of other "genital mycoplasmas" is still a much debated issue. sexually transmitted infections agents should be investigated by molecular methods in both patient and sexual partner. “next generation” investigations, such as cytokine analysis, cytological typing of immune cells could help stratifying the immune response. epigenetic dysregulamagri_stesura seveso 15/01/19 11:31 pagina 227 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 228 historical remarks (kurt g. naber) the modern clinical research on prostatitis started with the work by meares em jr. and stamey ta and coworkers, which stamey nicely summarized 27 years ago (1). now we have to see which of their achievements are still valid and which of them have to be reconsidered or even need to be replaced by new findings. in summary, stamey (1) stated that “prostatitis” is a common and frustrating problem for the urologist and the general practitioner. not only is there no generally accepted definition, but there are no clearly established criteria for making the diagnosis, and no definite pathophysiology. because very few authors have defined prostatitis and almost no two works use the same criteria for inclusion of patients within a study, few comparisons can be made from the findings of one author to those of another. except for true bacterial prostatitis, it is fair to comment that little more is known about prostatitis than was reported by hugh h young and his associates in 1906 (2). despite this rather pessimistic view, he and his coworkers developed the basic principles we are still using. together with meares they established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate. their four glass test results with first voided urine sample, midstram urine sample, expressed prostatic secretion and first voided urine sample after prostate massage were used together with the clinical symptoms to differentiate between the main categories of prostatitis: acute bacterial prostatitis (abp), chronic bacterial prostatitis (cbp), nonbacterial prostatitis, and prostatodynia. in principle, these categories with slight modifications were also used for the nih classifications: 1. acute bacterial prostatitis; 2. chronic bacterial prostatitis; 3. chronic pelvic pain syndrom (cpps); 3a. inflammatory; 3b. noninflammatory; and 4. asymptomatic prostatitis (3). in his review stamey also presented the principles concerning pharmacokinetics (pk) of antibiotics used for the treatment of acute and chronic bacterial prostatitis and the role of non-ionic diffusion of weak acids and bases across membranes with a ph gradient (1). he and his coworkers found out, that besides protein binding and lipid solubility the ph of the prostatic secretion on one side and the isoelectric point of the compound on the other side were playing a major role for drug penetration into the prostatic secretion which was considered crucial at least for the antibacterial therapy of cbp. at that time most studies were performed in a dog model (1). thereafter, many pk studies were also performed in humans, especially with fluotoquinolones considered the most appropriate antibiotics to treat cbp because of their broad spectrum, including most of the causative pathogens, and because most fluoroquinolones were neither pure acids nor bases, but amphoteric (zwitterionic) drugs with an isoelectric point between the two pka values (4). since cpps on the tion of inflammatory factors should be investigated according to systemic and compartment-specific signals. the search for biomarkers should also include evaluation of hormonal pathways, as measurement of estrogen levels in semen. antimicrobials are the first line agents for the treatment of bacterial prostatitis. the success of antimicrobial treatment depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations in prostate secretion and prostate tissue. acute bacterial prostatitis can be a serious infection with a potential risk for urosepsis for iinitial treatment of severely ill patients, intravenous administration of high doses of bactericidal antimicrobials, such as broad-spectrum penicillins, third-generation cephalosporins or fluoroquinolones, is recommended in combination with an aminoglycoside. use of piperacillin-tazobactam and meropenem is justified in presence of multiresistant gramnegative pathogens. the antibiotic treatment of chronic prostatitis is currently based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with chronic bacterial prostatitis. for the treatment of chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, whereas no differences were observed in microbiological and clinical efficacy between macrolides and tetracyclines for the treatment of infections caused by intracellular pathogens. aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant prostatitis. use of alpha-blockers in cp/cpps patients with urinary symptoms and analgesics +/non steroidal anti-inflammatory drugs (nsaid), in presence of pain demonstrated a reduction of symptoms reduction and an improvement of quality of life, although long term use of nsaid is limited by side effect profile. however, the multimodal therapeutic regimen by contemporary use of alphablockers, antibiotics and anti-inflammatory showed a better control of prostatitis symptoms than single drug treatment. novel therapeutic substances for the treatment of pain, such as the cannabinoid anandamide would be highly interesting to test. an alternative for the treatment of chronic prostatitis/chronic pelvic pain syndrome is phytotherapy, as primary therapy or in association with other drugs. quercetin, pollen extract, extract of serenoa repens and other mixtures of herbal extracts showed a positive effect on symptoms and quality of life without side effects. the association of cp/cpps with alterations of intestinal function has been described. diet has its effects on inflammation by regulation of the composition of intestinal flora and direct action on the intestinal cells (sterile inflammation). intestinal bacteria (microbiota) interacts with food influencing the metabolic, immune and inflammatory response of the organism. the intestinal microbiota has protective function against pathogenic bacteria, metabolic function by synthesis of vitamins, decomposition of bile acids and production of trophic factors (butyrate), and modulation of the intestinal immune system. the alteration of the microbiota is called “dysbiosis” causing invasive intestinal diseases pathologies (leaky gut syndrome and food intolerances, irritable bowel syndrome or chronic inflammatory bowel diseases) and correlating with numerous systemic diseases including acute and chronic prostatitis. administration of live probiotics bacteria can be used to regulate the balance if intestinal flora. sessions of hydrocolontherapy can represent an integration to this therapeutic approach. finally, microbiological examination of sexual partners can offer supplementary information for treatment. key words: chronic bacterial prostatitis; chronic pelvic pain syndrome; inflammation; antibiotic treatment; phytotherapy; dysbiosis. submitted 12 decembrer 2018; accepted 18 decembrer 2018 magri_stesura seveso 15/01/19 11:31 pagina 228 other side was considered a multifactorial disease with many pathophysiological causes a more symptom related approach was finally recommended. for this reason the nih-cpsi (5) and the upoint concept was developed (6). many other detailed investigations were performed thereafter, but not many had a great impact on the clinical practice so far. unfortunately the management of cpps remains still unsatisfactory for the patients as well as for the urologists. role of inflammation and infection in the determinism of benign prostatic hyperplasia and prostatitis. physiopathological aspects (salvatore cuzzocrea) in the spectrum of benign prostatic syndrome (pbs), chronic prostatitis (cp/cpps) and benign prostatic hyperplasia (bph) represent very important pathologies. prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms. the common inflammatory/neuroinfalmmatory aspects in cp/cpps and bph are represented by reactive astrocytes and activated microglia and involvement of the adaptive immune system, over expression of immune molecules such as chemokines and cytokines and increased oxygen and nitrogen reactive species concentration (ros/rns). chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system effecting surrounding neural tissue on a molecular, structural and functional levels. clinical observations suggest that chronic inflammation correlates with cp/cpps and bph, as prostate tissues often have infiltrating lymphocytes and macrophages around glandular elements. the principal therapeutics for treatment of an enlarged prostate are α-blockers and 5α-reductase inhibitors (5aris). alpha-blockers are often used as first-line therapy, as they relax muscles in the prostate and around the neck of the bladder and facilitate passage of urine but cannot reduce an enlarged prostate; in addition, these agents have side-effects such as first dose syncope, dizziness, tachycardia, hypotension, headache, asthenia, rhinitis and ejaculatory dysfunction. moreover, cannabinoids have been demonstrated to exert an important role in the resolution of inflammation via multiple mechanisms. in the light of the above, we designed a study to evaluate the anandamide congener npalmitoylethanolamide (pea) and the flavonoid polydatin (pld), as the formulation m(pea/pld), in terms of impact on the inflammatory process and oxidative stress in bph. recently, literature data reported that pea, an endogenous fatty acid amide of the nacylethanolamine family possess analgesic, antiinflammatory and neuroprotective actions, acting at different cellular targets such as immune cells; pea is classified as a “food for special medical purposes” by health authorities of the european union member states. pea treatment in animals has demonstrated the efficacy and great promise for its use in the treatment of a lot of different inflammatory disorders. nevertheless, pea lacks direct antioxidant action to counteract free radical development as well as dna, protein and lipid damage which are important events occurring in bph. polydatin (3,4,5trihydroxystilbene-3-β-single-d-glucoside), also known as polygonin, is a polyphenolic phytoalexin with potent anti-oxidative activity that can be isolated from numerous plant species and can be easily synthesized. our findings led us to assess the therapeutic effects of oral administration of a composite consisting of comicronized pea + polydatin m(pea/pol) in a model of testosterone-induced benign hyperplasia (bph) in terms of its therapeutic effects and efficacy as an anti-oxidant and antinflammatory drug (7). the results of our study show, for the first time, that m(pea/pol) has the ability to decrease prostate weight and dht production in bph-induced rats. these effects may be due to the antiinflammatory and apoptotic effects of m(pea/pol). preliminary results suggest that m(pea/pol) may exert therapeutic effect event in a model of cp/cpps. accordingly, these results support the hypothesis that m(pea/pol) should be further explored as a valid candidate for the treatment of bph. the i2 value. pooled analysis resulted in a crude odds ratio of 1.83, indicating a significant association between a history of prostatitis and prostate cancer (95% ci: 1.43 to 2.35; p < 0.00001) (5). the 1.83 odds ratio could be converted into a significant risk-ratio estimate of 1.63 (95% ci: 1.23 to 2.17). the set of pooled data showed considerable heterogeneity (i2 = 91%). sensitivity analysis performed by excluding an extreme outlier decreased heterogeneity (i2 = 81%) and resulted in an odds ratio equal to 1.55 (95% ci: 1.30-1.85, prostatitis and prostate cancer risk: meta-analysis (gianpaolo perletti) inflammation is a major risk factor for several types of cancer. conditions like ulcerative colitis, barrett’s esophagus, chronic urothelium inflammation and hepatitis can increase the likelihood of developing malignancies. in the last years, several studies investigated whether a history of clinical chronic prostatitis can be a risk factor for prostate cancer. a meta-analysis of such studies, performed on data published up to july 2012 indicates that clinical prostatitis may be moderately associated with prostate cancer, since the odds ratio between a history of prostatitis and prostate cancer was shown to be 1.64 (95% ci: 1.36 to 1.98) (8). after year 2012, new quality studies have been performed on over 7000 patients (911). thus, we deemed necessary to perform an updated meta-analysis to complement the data so far produced, and to further investigate the relationship between prostate cancer and previous exposure to chronic prostatitis. the main outcome of our systematic review was the association between a history of clinical chronic prostatitis (nih category ii or iii) and a histologically confirmed diagnosis of prostate cancer of any grade. out of 2794 de-duplicated records published between year 2000 and january 31st, 2017, we retrieved sixteen fulltext articles reporting the data of fifteen case-control studies including a total population of 422943 men. prostate cancer cases were 13942 (with previous history of prostatitis, n = 1806) and controls were 409001 (with 229archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 229 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 230 previous history of prostatitis, n = 57203). we analyzed binary data by calculating odds ratios and 95% confidence intervals (95% ci). we applied a random-effects model to the analysis of pooled data, and heterogeneity was assessed by calculating the i2 value. pooled analysis resulted in a crude odds ratio of 1.83, indicating a significant association between a history of prostatitis and prostate cancer (95% ci: 1.43 to 2.35; p < 0.00001) (12). the 1.83 odds ratio could be converted into a significant risk-ratio estimate of 1.63 (95% ci: 1.23 to 2.17). the set of pooled data showed considerable heterogeneity (i2 = 91%). sensitivity analysis performed by excluding an extreme outlier decreased heterogeneity (i2 = 81%) and resulted in an odds ratio equal to 1.55 (95% ci: 1.30-1.85, p < 0.00001). no significant publication bias was evidenced by the egger’s and begg's tests for funnel plot asymmetry. the ‘trim and fill’ method applied to the funnel plot imputed 3 missing studies and the resulting adjusted estimate of the odds ratio was 2.12 (95% ci: 1.38 to 3.22). detection bias was virtually present in all included studies, mainly due to the increased probability of prostate cancer detection in prostatitis patients repeatedly subjected to thorough clinical assessments. five among the included studies reported data assessed in 8015 african-american subjects. a subgroup meta-analysis was attempted, resulting in a non-significant crude odds ratio of 1.59 (95% ci: 0.71 to 3.57, p = 0.26). in conclusion, meta-analysis shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer. the odds ratio of 1.83, calculated on a larger patient population, is higher than the one reported by jiang (or = 1.6) (8), though association between exposure to prostatitis and cancer could not be demonstrated in african-american individuals. conversely, a recent meta-analysis showed a clear association in asian patients (or = 3.54, 95% ci: 2.60-4.82) (13) since – compared with caucasian men – in men of african descent the prostate cancer incidence is 60% higher and the mortality rate is up to 3 times greater, new quality studies performed on larger sample sizes are urgently needed to provide unequivocal evidence in this population. prostatitis: a condition still to be extensively investigated (vittorio magri, emanuele montanari) prostatitis is still an enigmatic disease due to the inconsistency of the epidemiological data, the uncertainty etiology, the inadequacy of the diagnosis and the absence of a standardized pharmacological treatment. the term prostatitis, which literally means "inflammation of the prostate", is currently used to describe a set of clinical conditions of uncertain etiology that are not always associated with a clear demonstration of the presence of an inflammatory process and that include painful pelvic symptoms, low urinary tract symptoms and sexual disorders that require differentiated treatment. the prevalence of these symptoms has been estimated at 8% of the adult male population (14). patients with prostatitis were initially classified into four groups of acute bacterial prostatitis, chronic bacterial prostatitis, chronic bacterial prostatitis and prostatodynia. from this classification derived the nih-niddk (national institute of health -national institutes of diabetes and digestive and kidney diseases) classification (15), which is currently accepted worldwide (table 1). these classifications are based on the use of the microbiological 4-glasses localization test of meares-stamey or of the simplified 2glases test (16, 17). the success of this examination requires an appropriate collection of the prostatic secretion after adequate prostatic massage. the upoint system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments (table 2) (18). to improve the clinical approach to prostatitis it is crucial to speak a shared language starting from what is already defined in the guidelines of the european association of urology (eau) (19) and other national guidelines like those of the prostate expert reference group (perg) of the national health service (nhs) (20). the answers of 266 out 1483 (17.9%) urologists associated to the società italiana di urologia (siu) who had been sent an e-mail questionnaire to describe the current methods of diagnosis and treatment of chronic prostatitis among italian urologists showed that a mean of 23 patients with symptoms of prostatitis presented to their clinics in a month. the majority of the respondents still prefers the collection of a narrative clinical history together with the clinical examination whereas the use of validated questionnaires is still not widespread. the nih-cpsi (national institute of health – chronic prostatitis symptom index) (5) was administered only by 17.29%. the most frequently used laboratory tests are the measurement of psa and the culture tests of semen and urine. the use of microbiological localization tests is still poorly widespread. the most common instrumental examinations were uroflowmetry and suprapubic ultrasound. transrectal ultrasound (trus) is used only by 10%. an extended protocol, such as that we adopted at our institution, should include: history and physical examination, administration of symptom questionnaires (nih-cpsi, ipss, iief-15 or -5, pedt, upoint or upoints), microbiological evaluation, prostatic ultrasound and uroflowmetry. in particular we suggest the use of the upoints algorithm that has implemented the original upoint proposed by skoskes (18). to the urinary domains (u), psycho-social (p), organ-specific (o), infection (i), neurological (n), muscle tension and tenderness (t) a further domain related to sexuality (s) was added (21). in fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality of life of patients with cp/cpps. in our experience we observed erectile dysfunction in 49.9% (although of mild severity in 75% of cases) and ejaculatory dysfunction in 59.9% (predominantly burning or ejaculatory pain and premature ejaculation) (22). according to perg (20) we also suggest to investigate the presence of irritable bowel syndrome. in fact, in a group of 232 patients we observed the concomitant presence of intestinal disorders (diarrhea or constipation, abdominal pain or bloating) in 69% and 60.5% of patients with chronic bacterial prostatitis or pelvic pain syndrome, respectively. furthermore, the possibility of a sexually transmitted infection starting from a urethral infection that spreads progressively to the prostate and to the accessory magri_stesura seveso 15/01/19 11:31 pagina 230 sexual glands has to be considered. gonococcal infection is infrequent today, but it is still frequent the finding of other sexually transmitted pathogens. in our experience we isolated with the 4-glasses test and/or seminal analysis chlamydia trachomatis in 26.8-33.6%, ureaplasma urealyticum in 56.3-59.7%, mycoplasma hominis in 7.3% and trichomonas vaginalis in 1.4-1.8%. finally it is recommended to correctly record the results of treatment on the basis of clinical criteria (nih-cpsi decrease of at least 4-6 points of the total score or at least 25% decrease of total score) or of microbiological criteria (eradication, persistence, relapse). sexual dysfunction and chronic prostatitis (giuseppe morgia) chronic prostatitis has an important role in men sexual function. sexual dysfunction is difficulty experienced by an individual or a couple during any stage of a normal sexual activity. it could be sexual desire disorders, sexual arousal disorder, orgasmic disorders, sexual pain disorders. the prevalence of sexual dysfunctions is: 2-40% for erectile dysfunction, 15-25% decreased interest or desire, 8-32% ejaculation dysfunction, 12-19% orgasm, 17% dyspareunia. prostatitis and sexual dysfunction are 2 common diseases, the prevalence of sexual dysfunction among men with cp/cpps was 62%. among chronic bacterial prostatitis symptoms one of the most important symptoms is pain with ejaculation, symptom also present among chronic pelvic pain syndrome symptoms, with erectile dysfunction and premature ejaculation. ejaculation pain is one of the most important and frequent chronic prostatitis symptoms, in fact in nih chronic prostatitis symptoms index there is a question on pain or burning during or after sexual climax. it could be the only manifestation of prostatitis. 24% of patients have regularly ejaculatory pain, 50% intermittently and only 26% of patients with cpps never experienced ejaculatory pain. there isn’t a single cause of post-ejaculatory pain. seminal infection, ejaculatory duct obstruction (with or without stones), neuromuscular spasm instigated by the muscular constriction of emission, interstitial cystitis could cause pain during ejaculation. premature ejaculation (pe) is male inability to inhibit ejaculation long enough for the partner to reach orgasm, time before 231archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis table 1. nih-niddk classification of prostatitis. category designation status of infection i acute bacterial prostatitis acute infection of prostate ii chronic bacterial prostatitis recurrent infection of prostate iii chronic non-bacterial prostatitis/chronic pelvic pain syndrome (cpps) no demonstrable infection iiia inflammatory wbc in semen/eps/post-prostatic massage urine iiib non-inflammatory no wbc in semen/eps/post-prostatic massage urine iv asymptomatic inflammatory prostatitis asymptomatic wbc: white blood cell, eps: expressed prostatic secretion. table 2. upoints classification for phenotypic domains (modified by shokes et al and magri et al.). domain diagnosis treatment urinary cpsi urinary score > 4 anticholinergic urgency, frequency or nocturia alpha-blockers post-void residual urine > 100 psychosocial clinical history of depression counseling ongoing antidepressant therapy antidepressant evidence of catastrophizing at interview and visits referral to psychologist organ specific specific prostate tenderness 5-ari leucocytosis in prostate fluid and/or vb3 phytotherapy (quercitin, pollen extracts, serenoa) hemospermia prostatic massage extensive prostate calcification alpha-blockers infection gram neg or enterococcus in prostate fluid or 4-glass test antibiotics neurological/systemic pain beyond abdomen or pelvis gabapentinoids irritable bowel syndrome history antidepressants fibromyalgia history specific treatments chronic fatigue syndrome history tenderness (skeletal muscles) palpable muscle spasm or trigger points in abdomen and pelvic floor skeletal muscle miorelaxants pelvic floor physiotherapy physical activity sexual dysfunction erectile dysfunction (iief questions 1-5 + 15 < 26 pde5-inhibitors orgasmic dysfunction evidence (iief 9+10 < 9) sexual desire impairment evidence (iief questions 11+12 < 9) magri_stesura seveso 15/01/19 11:31 pagina 231 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 232 ejaculation varied from 1 to 7 minutes after vaginal intromission. pe is an important sexual dysfunction strongly associated to cp/cpps, chronic bacterial prostatitis and prostatic inflammation. the prevalence of pe among men with cp/cpps is 40%. the rates of pe and possible pe assessed with the premature ejaculation diagnostic tool (pedt) significantly increased with an increase in pelvic pain severity, as assessed by the nih-cpsi. in the moderate to severe symptom group, 45.0% men demonstrated pe. in an italian study of 399 men with symptoms suggesting prostatitis (23), 220 patients (55%) had ejaculatory dysfunctions, more frequently in patients with bacterial chronic prostatitis with respect to patients with chronic pelvic pain syndrome. in particular chlamydia trachomatis infection is related to a major incidence of premature ejaculation in patients with cbp (37.2%), rather than common uropathogen bacteria (11.5%) (24). the incidence of erectile dysfunction is increasing with age, the prevalence of erectile dysfunction among men with cp/cpps was 29%. aetiology of ed in patients with cp/cpps could be vasculogenic arterial insufficiency and veno-occlusive disease, endocrine, neurogenic, psychogenic. in men with chronic prostatitis there is an arterial stiffness associated with nitric oxide-mediated vascular endothelial dysfunction and 50% patients have signs of pelvic floor spasm that decrease arterial penile inflow. hypogonadism is a common finding in men with ed. it has been postulated that sex hormones may also be an important factor in the development of prostatitis. differences have been reported in the frequency of 3 alleles near the phosphoglycerate kinase gene between patients with cpps and controls, a gene associated to familiar prostate cancer, hypospadias and specially androgen insensitivity (25). in patients with cp/cpps there is a higher serum level of androstenedione and testosterone, with a lower serum level of cortisol. in 10-19% of patients there are abnormalities in the afferent and efferent autonomic nervous systems associated to neuropathic pain, linked to erectile dysfunction. at least, cp/cpps is strongly linked with stress, anxiety and maladaptive responses to stressful situation, problems associated with erectile dysfunction. what kind of therapy we could use for sexual dysfunction? unfortunately, there are still few studies in sexual dysfunction treatment. alfuzosin 10 mg could be used for chronic prostatitis, improving ipps score and bother score (26), but this alpha-blocker improved sexual function with lower pain/discomfort and better rigidity and increased ejaculate. also use of doxazosin shows a reduction of nih-cpsi (27), but demonstrates a not yet clear role of alpha-blockers for sexual dysfunction in cp/cpps patients. trigger point release and paradoxical relaxation training of pelvic floor could also have considered in a multimodal therapy for chronic prostatitis. this training shows an improvement in pain, urinary and sexual scores after therapy, as assessed by pelvic pain symptom survey. phytotherapy represents an attracting option: treatment with curcumin and calendula extract improved significantly iief-5 and pedt in patients with cp/cpps type iii (28) and quercetin ameliorated erectile dysfunction in streptozotocin-induced diabetic rats (29). utility of ultrasound in patients with prostatitis: computerized analysis (matteo boltri) prostatic ultrasound represents the main imaging test in the work-up of either acute and chronic prostatitis. trus and transperineal (tpus) approaches are superior to transabdominal ultrasound with trus being more accurate (30). transrectal probes are divided into monoplanar, biplanar and end-fire according to transducer arrangement. the us anatomy of apex is well defined by linear probes, whereas end-fire probes better define the base. color-doppler mode, tissue harmonic imaging and contrast-enhanced techniques may provide additional information. utility of ultrasound in the evaluation of acute prostatitis might be of clinical interest in the differential diagnosis of parenchymal abscess (31) or in the detection of a significant post-voiding volume, which is an indication for temporary bladder catheterization. the role of ultrasound in the work-up of chronic bacterial prostatitis (cbp) and chronic pelvic pain syndrome (cp/cpps) is still debated. to date, no specific hypohyperechoic pattern has been clearly associated with cbp and cp/cpps. the detection of hypoechoic periurethral zone volume, posterior prostate lip thickness and bladder neck thickness might be a hallmark of cp/cpps (32). hyperechoic areas should be described in the ultrasound report because of their clinical significance. prostatic calcifications are common in the elderly, although younger people with cbp and cp/cpps also develop prostatic calcifications of varying size, that could be associated with: presence of a more intense chronic inflammation, positive cultures of the prostatic fluid, longer duration of symptomatology according to nih/cpsi score (33) and lower efficacy of antibiotic treatment in eradicating the infection of the prostate (34). for a long time the evaluation of the presence of prostate calcification has been based on subjective evaluations, ending in a qualitative dichotomy between patients “with” and “without” calcifications. the development of a standardized method for a quantitative assessment of such calcification has been advocated. transrectal images of the prostate acquired with a standard protocol can easily been analyzed using a digital-processing software, able to calculate the extension of calcification area. open-source software like imagej by nih are of great importance in making the access to this technology easier. the relation between the area of prostatic calcification and the prostate area can be expressed as a percentage. in a recent study it has been demonstrated that in a quantitative-based model, a higher percentage of prostatic calcification is more frequently observed in patients with chronic bacterial prostatitis and is related to worse urinary symptoms (35). the utility of an objective method could be of augmented interest either for researchers and clinician. 3d transrectal scanners integrated with a digital-processing software could lead to a better comprehension of the utility of this procedure. multiparametric magnetic resonance imaging of neoplastic and non-neoplastic lesions (pieter j.l. de visschere) multiparametric magnetic resonance imaging (mpmri) is the current state-of-the art imaging modality in the magri_stesura seveso 15/01/19 11:31 pagina 232 assessment of patients with suspected or confirmed prostate cancer (pc). it consists of morphological t2weighted images (t2-wi) supplemented with functional imaging techniques such as diffusion-weighted (dwi) imaging, dynamic contrast-enhanced imaging (dce) and/or mr spectroscopic imaging (mrsi). t2-wi exquisitely depicts the prostatic anatomy and pathology. dwi provides information about the amount of random movement of water molecules as determined by tissue density and cell organization. in dce, the prostate is repetitively scanned before and during intravenous bolus injection of contrast agent. mrsi demonstrates the relative concentrations of the cellular metabolites citrate and choline in the prostate. poorly differentiated pc can be detected on mpmri with high accuracy as it typically appears as a low signal intensity (dark) lesion on t2-wi, with restricted dwi, strong contrast enhancement on dce and high choline/citrate ratio on mrsi (36). currently, there is a trend to treat only patients with clinically significant pc. in patients with elevated psa, it is advantageous to perform mpmri of the prostate before a biopsy. when a suspicious lesion is detected on mpmri, a targeted biopsy can be performed. when a suspicious lesion is detected on mpmri, a targeted biopsy can be performed. when mpmri is normal, it has been shown that a biopsy postponed (provided that the patient is closely followed up), as alternative to systematic biopsies (37), but the debate is still ongoing about which strategy should be recommended (38). interpretation of mpmri may however be difficult, because every prostate exists of a mixture of histological conditions, which are highly variable in extent and distribution among patients and some of them may mimic pc. in our own study (36), we compared a series of whole-mount radical prostatectomy specimens with the corresponding mpmri images. pure normal prostate glands are iso-intense on t2-wi and the high signal intensity areas represent cystic atrophy (cya) or largegland variant of simple atrophy (sa). due to the high water content of cya it can easily be recognized on mpmri and pc can be excluded with high certainty. inflammation, adenosis, post-atrophic hyperplasia (pah) and high-grade prostatic intra-epithelial neoplasia (hgpin) may mimic well differentiated pc on mpmri because they all show indistinct low signal intensity on t2-wi, moderate contrast enhancement on dce and slightly decreased citrate concentrations on mrsi (39, 40). on dwi, there is a considerable overlap in imaging characteristics between inflammation and well-differentiated pc (41). the restricted diffusion in (peri)glandular inflammation may be explained by the high density of inflammatory cells. granulomatous prostatitis, a chronic inflammation that may develop after bacillus calmette-guerin therapy for bladder cancer, is a well-known mimicker of pc on mpmri. a variety of benign conditions may thus mimic pc and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions at mpmri. it is the challenging role of the radiologist to distinguish this multitude of benign or indolent conditions from aggressive forms of pc. causative pathogens of bacterial prostatitis (alessandra sensini, christian leli) any microorganism virtually can cause prostatitis. bacteria infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. enterobacteriaceae, especially escherichia coli, are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of enterococci has been reported (42, 43). many strains of these uropathogens exhibit the ability to form biofilm, which can be responsible of the treatment failure. moreover, the emergence of multidrug-resistant organisms, mostly by means of extended-spectrum beta-lactamases, ampc beta-lactamases and carbapenemases for enterobacteriaceae, vana gene for enterococci and meca/mecc genes for staphylococcus aureus, make antimicrobial therapy very challenging. fungal etiology is generally limited to patients with impaired immunity. sexually transmitted infections (sti) agents, in particular chlamydia trachomatis, have been also considered as causative pathogens of chronic bacterial prostatitis (44). due to the improvement of diagnostic technologies, recent studies supported the etiologic role of mycoplasma genitalium, a cell wall-deficient small bacterium belonging to the mycoplasmataceae family, as a true causative pathogen of sti and possibly of prostatitis. under the designation "genital mycoplasmas" are included other species, mycoplasma hominis, ureaplasma parvum and ureaplasma urealyticum. they are considered commensals of the lower female genital tract, indeed are frequently recovered from genital samples in asymtomatic subjects. their effective role in genital diseases of both women and men is still a much debated issue. likewise, if chronic prostatitis/chronic pelvic pain syndrome is really an infectious disease is still doubtful (45, 46). microbiological diagnosis and microbiological protocol proposals (maria agnese latino, alessandra sensini, christian leli) microbiological diagnosis is imperative to identify the etiologic agent of prostatitis (19, 20, 47-49). the midstream specimen of urine (msu) is the sample of choice to test in acute bacterial prostatitis. in presence of clinical signs suggestive of a blood-stream infection, a blood culture should be taken. the traditional meares-stamey 4glass test is recommended for the diagnosis of chronic bacterial prostatitis. the 2-glass test (also called nickel test) is an acceptable alternative. the analyses of data collected by a questionnaire sent to italian urologists showed that a higher number of seminal fluid cultures than meares-stamey test were performed for diagnosis of chronic bacterial prostatitis. semen culture is not recommended by the european guidelines because of low specificity due to possible contamination by urethral and skin bacteria. moreover, a diagnostic cut-off in colony count for symptomatic patients has not been determined. semen culture can be used for diagnosis in addition to meares-stamey test as 5th glass and results compared to the other samples. if used alone, it should be 233archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 233 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 234 preceded by a first 10-ml void as urethral specimen. all samples should undergo microscopic examination for the presence of leukocytes, culture for isolation of gramnegative or gram-positive bacteria and/or fungi and bacterial count, reporting also small numbers of colonies. in case of positive cultures, antimicrobial susceptibility testing should be performed, according to eucast rules. sexually transmitted infections agents should be investigated by molecular methods (test of choice) in both patient and sexual partner. analysis of total ejaculate in the diagnostic evaluation of bacterial prostatitis (vittorio magri) the possible diagnostic role of the microbiological examination of the seminal fluid is still controversial, due to the possible contamination of the fluid in the urethral passage and the presence of secretions from accessory glands (seminal vesicles, bulbo-urethral glands of cowper and urethral of litrrè). the eau guidelines (19) exclude the use of semen culture in the diagnosis of chronic prostatitis, although the recommendation strength is weak, and the perg (20) does not mention this test. on the other hand, in the nih/nidkk classification (16), microscopic examination of the seminal fluid in the definition of non-inflammatory cpps (iiib) and asymptomatic prostatitis (iv) is envisaged. furthermore, stamey himself (1) has argued that semen cultures may be likely reliable for the identification of gram negative infections and other authors have considered the use of this investigation if associated with a collection of urine vb1 (first voiding) and vb2 (midstream) or when it is not possible to obtain the expressed prostatic secretion (eps) sample with prostate massage (50, 51). in our experience in 81.7 and 99.9% of patients with chronic bacterial prostatitis and cp/cpps respectively it was not possible to obtain an eps sample and that the examination of the seminal fluid in patients with cbp allowed to demonstrate the presence of gram negative more frequently than in vb3 or eps (52). in a 565 series of samples with positive microbiological tests of seminal fluid and/or meares-stamey test samples 284 patients (52%) had a positive semen test in the presence of negative meares-stamey test, 153 (27.1%) negative seminal examination and meares-stamey positive test and 118 (20.9%) positive concordance of the two tests. these data agree with a previous study that showed that the semen examination is positive in 78.6% of samples of patients with chronic bacterial prostatitis and in no case of cp/cpps. this observation confirms what was said by nickel (53) that observed that the culture of the seminal fluid increased the number of patients classified as category ii, even in the absence of precise evidence of the literature and data that demonstrate a clinical improvement after antibiotic treatment of patients with positive culture of seminal fluid. subsequently, however, some numerically consistent studies (54, 55) have confirmed that the examination of the seminal fluid may be a good indicator of prostatic infection when the semen was analyzed together with the 4-glass test and a study showed a positive response after antibiotic treatment of infections diagnosed with semen examination. finally, the examination of the seminal fluid allows the identification of atypical sexually transmitted pathogens in high percentages (50% of cases with chlamydia infection and 73% of cases infected with ureaplama urealyticum and mycoplasma hominis. in conclusion, the microbiological examination of the seminal fluid may present a useful integration of the results of the meares-stamey test. role of biofilms: pathogenesis and therapeutic implications (tommaso cai) chronic bacterial prostatitis (cbp) is diagnosed by clinical symptoms and microbiological analysis by using biological samples from meares-stamey test; treatment with appropriate antibiotics is usually prescribed, in line with the european association of urology (eau) guidelines (42). several times, fluorquinolones are considered drugs of choice to treat patients with cbp, regardless of a bacterial isolation. antibiotic treatment usually improves the clinical symptoms, although short-term recurrences are reported frequently (56). it is probably due to the incomplete eradication of the causative pathogens, by phenotypical antibiotic resistance at the site of infection and/or lack of antibiotic penetration into prostate tissue. on the other hand, antimicrobial treatment is most effective in acute infection when bacteria are in the ‘planktonic’ state, before they form biofilms. the role of biofilm-producing bacteria in development of acute and chronic prostatitis have been recently discussed. bacteria living in a biofilm usually have significantly different properties compared with free-floating bacteria (planktonic) of the same species, as the dense and protected environment of the film allows them to interact in various ways (57). they benefit in this environment by an increased resistance to antibiotics, as the dense extracellular matrix and the outer layer of cells protect the interior of the community. moreover, it is well demonstrated that biofilm persisting bacteria, which are usually adherent to tissue surfaces through their own fimbriae and slime, represent the main limitation of antibiotic efficacy and the potential site of short-term infection recurrences. recently, bartoletti and cai demonstrated that biofilm-producing bacteria were commonly found in cbp patients and had a significant negative impact on the clinical response to antibiotic therapy (58). moreover, they demonstrated that the relief of symptoms seemed to be much more inversely related to the bacterial biofilm production than to apparent negative microbiological tests after treatment. on the other hand, cai et al. focused their attention on the role of bacterial biofilms in the genesis of prostate calcifications, suggesting a possible role of bacterial biofilm in the genesis of prostate calcifications and in the development of symptoms in chronic prostatitis (59). in this sense the role of prostate calcifications should be reconsidered. prostate calcifications are not only a sonographic sign of magri_stesura seveso 15/01/19 11:31 pagina 234 previous prostatitis but should be considered a locus for difficult-to-treat bacteria (organized in a biofilm and having the potential to persist after common antibiotic treatments) within the prostate tissue. the presence of a bacterial biofilm represents a chronic inflammatory stimulus that could lead to the development of symptoms related to the grade of inflammation and the immune response of the patients. in the case of high-grade inflammation, the patient could report urinary or pelvic pain. the fluctuating symptomatology reported by the majority of patients might be explained by variation in the inflammatory response to the development and maturation of the bacterial biofilm (59). the antibiotic treatment is probably effective in mitigating the grade of the infection but is not fully effective in eradicating the bacterial biofilm. future studies should be designed to explore whether effective eradication of the bacterial biofilm could be associated with a good mediumand long-term clinical outcome of treatment. resistance of germs to antibacterial drugs in patients with chronic bacterial prostatitis (cbp): the hellenic experience (konstantinos stamatiou, nektaria rekleiti, vaia papadouli) cbp is a very common and highly bothersome urologic condition. it remains poorly understood (14, 60, 61). despite progress in its management, many cases are undertreated and a significant number relapse . the reasons are practically unknown and include host, bacterial and treatment-related factors. inappropriate treatment, incomplete treatment and increased resistance of responsible bacteria to antibiotics have been proposed to contribute most (62-65). while the two first conditions can be easily rule out, the hypothesis of alteration of drug resistance patterns of responsible bacteria remains relatively unclarified. we planned a study to retrospectively investigate the resistance of microbes to antibacterials in patients with chronic bacterial prostatitis that had as secondary objective to determine whether the resistance of pathogens increases in patients with cbp recurrence. we studied bacterial isolates from urine and/or prostatic secretions or sperm cultures obtained from individuals with cbp visiting the prostatitis clinic of our department since its establishment (03/2009). patients underwent the meares-stamey test (a few cases underwent the 2-glass test). depending on medical history and specific symptoms, urethral smear and sperm cultures were additionally obtained from several patients. those presenting with febrile prostatitis were investigated by a midstream specimen of urine culture (muc) only. samples from patients diagnosed with chronic prostatitis for the first time were compared with those of patients with a history of chronic prostatitis and previous antibiotic treatment. the meares-stamey test was considered positive when: 1) bacteria grew in the culture of the eps and vb3/popm (post-prostate massage) urine sample but not in vb1 and vb2/prpm (pre-prostate massage) sample; 2) bacterial colonies in vb3 were higher than that of vb1 and vb2 samples. given that no standard cut-off level of the number of bacteria in both urine and prostate secretion samples exists for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. bacterial identification was performed using the vitek 2 compact system and susceptibility testing was performed by disc diffusion and/or the vitek 2 system. interpretation of susceptibility results was based on clinical and laboratory standards institute (clsi) guidelines. recorded demographical data and medical history of the patients were revised: patients suffering from conditions affecting either bacterial virulence or host response (eg. immunodeficiencies, abnormalities of the urogenital system) and individuals who received antibiotics or immunosuppressive treatment within 4 weeks from the visit were excluded from the study. the statistical analysis was performed using fisher’s exact test of significance. the accepted level of significance in this study was 0.05 (p value < 0.05 is significant). the locally appointed ethics committee approved the research protocol. a total of 548 bacterial isolates obtained from the eligible patients in 1324 visits owing to cbp recorded over a 6-year period (03/2009-05/2015) were analyzed. in 114 cases the number of colonies was quite similar in both vb2/pre-ppm and vb3/post-ppm cultures. these cases were excluded from the study. in addition 44 cases with negative cultures (despite presence of bacteria in eps/vb3/post-ppm) were also excluded from the study as possibly false negative since no previous antibiotic intake was reported. the remaining 390 out of 548 bacterial isolates diagnosed as cbp finally consisted the material of the study. of them, 253 (44 eps/sperm and 209 vb3/ppm) were from patients diagnosed with cbp for the first time (group a) and 137 (42 mid-stream urine, 51 eps/sperm and 44 vb3/ppm) were from patients with a history of cbp and previous antibiotic treatment (group b) (table 1 in supplementary materials). the most frequent pathogen -in both groups was e. coli. other frequent types were coagulase negative staphylococci (hominis & haemolyticus) and enterococcus spp. the overall frequency of gram (+) was greater than that of gram (-). of note, bacterial frequencies were similar in both groups (a and b) (table 2 in supplementary materials). most cases were found with one type of bacteria from each isolate (monomicrobial) however several cases in both groups (49 & 43) were identified with more than one type of bacteria from each isolate (polymicrobial) (table 3 in supplementary materials). regarding clinical relapses, pathogens most commonly associated were enterococcus faecalis, staphylococcus con and e coli. the mean time interval between chronic prostatitis relapses was 13.9 months (minimum 2 and maximum 56 months). in sperm cultures, in both groups, the most frequent isolate was enterococcus faecalis (13 and 8 respectively). a remarkably higher enterococcus faecalis isolate resistance was noticed in group b (69% vs 25%) (table 4 in supplementary materials). in urethral cell/discharge cultures staphylococcus con and clamydiae trachomatis were the most common pathogens in both groups (table 4). generally, a relatively increased resistance to quinolones was observed and a sufficient degree of susceptibility to the least used antibiotics (tmp-smx, tetracyclines, aminoglycosides, penicillins, and macrolides) (table 5 in supplementary 235archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 235 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 236 materials). in some cases cross resistance between ciprofloxacin and newest quinolones was not observed. the nature of this study explain the high rate (41.3%) of positive meares-stamey and/or 2-glass tests, however, combined with the fact that no cut-off level of the number of bacteria in both urine and prostate secretion samples was used for the diagnosis of cbp may indicate a relative high underdiagnoses rate. the low number of assessable epss in this study may indicate the need of better preparing (e.g. abstain from sexual intercourse for 3 to 5 days before s/m test). in confirmation to the above, the number of assessable epss in group b was greater probably because of the familiarization of patients of group b with the examination process. the proportion of gram-positive isolates in the current study is high. the reason explaining the above fact is unknown however it may be associated with the better understanding of the role of gram-positive bacteria in the development of the disease and the consequent awareness of clinicians and laboratory assistants. the rate of polymicrobial isolates was significantly higher in group b than in group a (31% vs 19%). the interpretation of this finding is twofold: on one hand it is possible that repeated antibiotic treatment reveals participating microbial members of prostate biofilm and in the other hand may suggest a chronic decline of the immune system function. our finding of increased resistance to quinolones has been previously described. combined with the finding of sufficient degree of susceptibility to the least used antibiotics this fact can be easily attributed explained by the over-prescription of quinolones in our country . high resistance rates of enterococci strains may reflect its intrinsic resistance to antibiotics. of note, differences in susceptibility between enterococci strains in monomicrobial isolates and polymicrobial isolates may be explained by genomic interactions. notably, the coexistent urethral infection found in patients of both groups indicates the continuity of the infection of the genitourinary tract system4. in addition, the fact that the findings from sperm cultures were comparable to those of eps and post pm cultures supports the supplementary role of sperm cultures to the mearesstamey test. finally, the wide variation in the number of colonies, the presence of different microorganisms in the same culture as well as the presence of con staphylococcus, strengthen the newer appreciation of chronic prostatitis as a biofilm disease. in conclusion, given the regional variation of the distribution of uropathogens and their susceptibility pattern to antibiotics, knowledge of the susceptibility of causative microorganisms to various antibiotics is necessary in order to select the optimal treatment thus providing better eradication rates and make the creation of drug-resistant strains less likely. medical treatment of chronic bacterial prostatitis (alberto trinchieri) chronic bacterial prostatitis (cbp) is a clinical entity defined by the isolation of bacteria in the prostatic secretion that according to national institutes of health national institute of diabetes and digestive and kidney diseases (nih niddkd) criteria is classified as category ii. the use of sequential bacteriologic localization cultures represents the most accurate method for diagnosing cbp. the most common organism associated with cbp is escherichia coli, although infections with klebsiella, enterobacter, proteus, pseudomonas, and enterococci have also been documented (66). in cbp patients biofilm-producing bacteria were frequently demonstrated as an explanation of the unsatisfactory response to antibiotic therapy (58). antimicrobials are the first line agents for the treatment of cbp (67). the success of antimicrobial treatment of chronic bacterial prostatitis depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations at the site of infection, that is prostate secretion and prostate tissue (68). diffusion of antibiotics in prostatic secretion/tissue to penetrate the prostatic epithelium, the drug must be lipid soluble, have minimal binding to serum protein and favorable size, shape and degree of ionization in order to diffuse across biological membranes in presence of a ph gradient (considering that ionized molecules do not cross epithelial membranes). the acid molecules reach greater concentrations in the plasma (ph 7.4) and the basic ones in the acidic prostatic fluid. beta-lactam drugs have a low pka and poor lipid solubility, and thus penetrate poorly into prostatic fluid; macrolides, tetracyclines and trimethoprim are bases showing excellent penetration into prostatic fluid and tissue. fluoroquinolones are amphoteric and have a more complex behavior acting either as zwitterions or neutral molecules depending on the medium. experimental results in the dog confirm this tendency (table 1 in supplementary materials). experimental animal studies are not easily transferred to the human clinic because the ph of the prostatic secretion in humans is less acidic and it is increased in chronic prostatitis. evaluation of tissue concentrations of antimicrobials measured on samples coming from endoscopic prostate resections after antibiotic administration confirms the good penetration of fluoroquinolones in prostatic tissues (table 2 in supplementary materials). clinical results of antibiotic treatment in cbp before 2000 there are only few randomized studies on the use of non-quinolone drugs in the treatment of cbp, the studies are underpowered so it is difficult to draw conclusions on the effectiveness of these treatments (table 3 in supplementary materials). in patients with cbp treated with trimethoprim/sulfamethoxazole (tmp/smx) cure rates of 0% to 71% were reported. when treatment was prolonged for over a 12week period the cure rate was about 40%. tetracyclines, especially doxycycline and minocycline, and macrolides have been extensively used to treat cbp. in a rct minocycline demonstrated better microbiological (45 vs 21%) and clinical (65 vs 46%) cure rates than cephalexin. in a small series, use of carbenicillin indanyl sodium has been associated with cure clinical and microbiological rates of 93 and 75% respectively and a rct of cbp treatment demonstrated similar cure rates of carbenimagri_stesura seveso 15/01/19 11:31 pagina 236 cillin and ofloxacin. amoxicillin-clavulanic acid or clindamycin were used to treat patients with prostatic infection resistant to empirical treatment with quinolones (50% anaerobic bacteria). in more recent years the antibiotic treatment of cbp was mainly based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with cbp due to their broad antibacterial spectrum and efficient distribution to the prostate tissue and glandular ducts (table 4 in supplementary materials). fluoroquinolones are generally well tolerated but in some patients prolonged use of quinolones may be contraindicated due to potential adverse effects in presence of various contraindications (history of tendonitis or long qt syndrome). randomized clinical trials the meta-analysis of perletti et al. took into consideration the rcts published between 1966 and 2012 (69). authors concluded that for the treatment of traditional pathogens the different fluoroquinolones used in the treatment of cbp have equal microbiological and clinical efficacy. the rate of adverse events of treatment also appeared to be equivalent. on the contrary, for the treatment of chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, both microbiologically and clinically. no differences were observed in microbiological and clinical efficacy and adverse effect between macrolides and tetracyclines for the treatment of patients with cbp caused by intracellular pathogens, both chlamidial and mycoplasma (table 5 in supplementary materials). alternative antibiotic regimens the increased emergence of bacterial resistance and the decline in newly developed antibiotics are limiting the armamentarium for the treatment of cbp. the possible options to counteract this problem are the increase in the dosage of the antibiotics already in use, the combination of antibiotics and the reintroduction of “old” antibiotics that were previously abandoned or not used for the treatment of cbp (table 6 in supplementary materials). aminoglycosides diffuse in the prostatic tissue and fluids although less than other antibiotics and in previous years, some aminoglycosides, such as kanamycin and streptomycin were successfully used in small series of patients with cbp. a recent larger study of the administration of aminoglycosides alone or in combination with a β-lactam antibiotic showed microbiological eradication and clinical remission in 79% of patients. genetic testing of patients for mutations predisposing to sensorineural deafness allowed safer administration of aminoglycosides. orally absorbed fosfomycin trometamol has also been proposed for the treatment of cbp because of its good penetration in prostatic tissue. a recent review found two small series and two case reports of patients with cbp treated with fosfomycin after treatment failure with fluorquinolones and tmp/smx (70). fosfomycin was administered orally (3 grams every 48 or 72 hours) for periods of 2 to 6 weeks, although in some critical cases it was administered for longer periods of up to 16 weeks. in the two series, microbiological cure rate > 50% and of clinical cure rate of 50-77% were reported. the results of these studies suggest that aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant cbp although their use should be still validated by randomized-controlled studies. an another option to improve the success rate of antibiotic treatment of cbp is the association of two antibiotics. in particular, macrolides can be associated with quinolones to exploit their ability to reduce biofilms growth. combination treatment of ciprofloxacin and azithromycin showed a 64.2% microbiological eradication rate after a 6-week cycle of therapy that reached 83.9% after a second 6-week cycle in patients showing persistence of infection or reinfection at the end of the first cycle of treatment. combination treatment showed high eradication rates of infection by both traditional uropathogens and unusual pathogens. an higher dose of ciprofloxacin (750 mg/daily) in combination with azithromycin (500 mg, thrice-weekly) for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to a 500 mg/daily dose for 6 weeks. locally injected antimicrobial drugs local injection of antibiotics into the prostate has been reported to be effective although no rct validated this modality of treatment the potential advantage of direct injection into the prostate should be to bypass the prostatic capsule to allows use of antimicrobials that are not easily concentrated in the prostatic tissue after oral administration. small case series showed encouraging results and a small rct (50 men with prostatic secretions sensitive to amikacin) demonstrated that anal submucosal injection of amikacin for 10 days significantly improved clinical and bacteriological cure rate at 3 months in comparison with intramuscular injection for the same period. adjuvant treatment with herbal products and probiotics a few rcts on adjuvant treatment with herbal products (mainly serenoa repens extract) and probiotics have been published (table 7 in supplementary materials) the combination treatment was able to improve the clinical (and in some studies the microbiological efficacy) of prulifloxacin in patients affected by cbp. in patients with cbp and irritable bowel syndrome a prolonged treatment with rifamixin and probiotics was effective in lowering the progression of prostatitis into more complicated forms of male accessory gland infections. length of treatment the optimal duration of antibiotic treatment for cbp has not been defined by controlled trials, although a study demonstrated the superiority of a 12 week tmp/smx treatment with respect to a 10 day course of the same antimicrobial agent. however a minimum duration of antibiotic treatment of 4 weeks should be considered. in a rct clinical success at the 6-month follow up of levofloxacin 750 mg/day for 2 or 3 weeks was inferior to the standard therapy with levofloxacin 500 mg/day for 4 weeks (71). chronic oral antibiotic suppression has been proposed to reduce or eliminate bacterial growth in the urine in order to limit the urinary symptoms of the disease. a chronic suppression approach only mandates adequate 237archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 237 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 238 drug levels in the urine and does not require penetrance of the prostate, thus many antibiotic choices with a safer side effect profile are available, such as nitrofurantoin and cephalosporins. low-dose trimethoprim (50 or 100 mg once daily), trimethoprim-sulfamethoxazole (40 and 200 mg once daily), and nitrofurantoin (50 or 100 mg once daily) are remarkably effective for this purpose. bacterial resistance: which antibiotics to use? (valentina marchese, alberto matteelli) enterobacteriaceae are the most common cause of either acute or chronic prostatitis. resistance to fluoroquinolones, considered the drug of choice for the management of prostatitis, has been increasing since 2000 (72). the progressive increase in fluoroquinolone resistance is also associated with the spread of extended spectrum β-lactamase (esbl), which are enzymes that confer resistance to most beta-lactam antibiotics with the exception of carbapenems and, in some selected cases, betalactam/beta-lactamase inhibitors (70). these enzymes are frequently associated with the expression of additional genes harboring resistance to other antimicrobial classes, such as fluoroquinolones and aminoglycosides (73). treatment of acute and chronic bacterial prostatitis represents always a challenge, as only few antimicrobials reach therapeutic concentrations in the prostate (72). high lipid solubility, a low degree of ionization, a high dissociation constant (pka, allowing diffusion of the unionized component into the prostate), low protein binding, and small molecular size enhance molecular penetration within prostate (72). only a limited number of agents adopted for infections due to multi-drug resistant (mdr) gram-negative bacteria (showing resistance to at least three different classes of antimicrobials) have these characteristics (72). in some cases, even if limited pharmacokinetic data available, they have been described to be effective in treating prostatitis (72). for severely ill patients, empirical coverage for mdr bacteria should be provided in presence of risk factors such as hospitalization, recent use of fluoroquinolones and/or beta-lactams, immunosuppression, recent invasive procedures (73). in all other cases, especially in chronic prostatitis, antimicrobial treatment should be guided by drug susceptibility test (dst). whenever possible outpatient treatment should be preferred, but the majority of antibiotics for mdr bacteria require parenteral administration. studies on site-specific pharmacokinetic and pharmacodynamic of piperacillin-tazobactam and meropenem justify their administration in susceptible gram-negative prostatitis (74, 75). prostate tissue penetration of colistin has not been studied and should possibly not be used. tigecycline undergoes minimal urinary excretion and is usually not considered the first choice for susceptible mdr gram-negative bacteria in urinary tract infections. nevertheless, few case reports describe the utilization of tigecycline in susceptible strains, with variable clinical and microbiological outcomes (76). so far, fosfomycin seems the most interesting drug for its susceptibility profile, prostate penetration and availability of oral administration. in patients with bacterial prostatitis caused by antimicrobial-resistant e. coli, oral fosfomycin has shown clinical cure rates of 50-77% and microbiological eradication rates above 50% (70). ceftolozane-tazobactam and ceftazidimeavibactam are two novel drugs which have been introduced for the management of mdr gram-negative infections. at the moment, there are no data on their utilization and penetration in prostate tissues. however, based on previously available data on cephalosporins prostate penetration, both are unlikely to be considered the primary choice in prostate infections, but further studies are needed to assess their possible role in this clinical setting. antibiotic-resistance, a public health problem (g. maierna) the problem of antibiotic resistance poses some questions. 1) when did it become a public health problem? 2) what is the answer of scientific societies to this problem? 3) how civil society deals with antibiotic resistance? in the 40s, shortly after the introduction of the antibiotic into the therapeutic armamentarium of the clinicians, there appeared the first bacterial resistance. from the 60s onwards it has been a progressive and constant increase of antibiotic resistances that has been overcome with the use of new molecules that were periodically synthesized and marketed. in the last decades it is no longer like that. the antibiotic resistance is still increased and many bacterial strains also became multi-resistant to various antibiotics (77-81). this modification of the bacterial ecosystem has been accompanied by progressive abandonment of the research for new anti-infective by most pharmaceutical companies. meanwhile the ecosystem has further changed and not only for the use and abuse of antibiotic therapy in the human field but also for the spread in the veterinary, zootechnical and aquaculture sectors. all this brought to recent finding of infections related to bacteria that are less sensitive to antibiotics available and always more often multi-resistant, if not even resistant to all the antibiotics tested and available. at this point the diffusion of bacterial resistance has so spread to make the phenomenon no longer a problem limited to some clinical cases to be treated in hospital but a global threat that we have to considered as a public health problem. in this last decade, in particular, it has started a run to find solutions (at least so hopefully). the alternative is a return to the pre-antibiotic era when there were no suitable drugs to treat most infections. of course, now there are the alarms of the scientific and health world to combat the phenomenon but the reaction of the political authorities and civil society is still ongoing. the g20 of health, held in argentina in 2018, like many other international meetings, confirmed the "one health" plan presented in may 2015 at the 68th world assembly who. everyone agrees for this global and synergistic action at world and national level promoting a collaborative and inter-sectorial commitment among the various operators of human and veterinary medicine, agriculture and food production and consumers. it is crucial to increase the level of awareness that a prudent and responsible use of antibiotics is necessary in order to counteract antimicrobial resistance that is a growing threat involving magri_stesura seveso 15/01/19 11:31 pagina 238 infections caused by bacteria, fungi, parasites, viruses to determine a progressive a reduction of efficacy of antibacterial, antifungal, antiparasitic and antiviral chemotherapeutic drugs. at this point the treatment of patients with infection becomes difficult, expensive and often impossible. for the most fragile, immunocompromised, and elderly this results in a prolongation of the disease, and in the hospitalization and always more often an increase in mortality. in the "one health" program of the who the objectives to be pursued are: improve awareness of antimicrobial resistance; reinforce knowledge with surveillance and research; reduce the incidence of infections; optimize the use of antimicrobial drugs; develop the necessary investments with adequate financial support. also in september 2015 the european parliament approved a resolution for the development of "one health" in human and animal health to limit multi-resistance to antimicrobials in these areas. at european level, the european center for disease prevention and control (ecdc), with its own specific prevalence studies conducted among 2011 and 2017 identified as a significant problem of public health related infections assistance and antimicrobial resistance. various microorganisms, taken into consideration for their characteristics of pathogenicity, resistance and epidemiology, are considered in these years a real emergency for their ability to resist the action of different antimicrobial agents with various resistance mechanisms. the american society of infectious diseases (idsa) in 2008 hasgrouped six pathogens in the acronym eskape from the initials of their names: enterococcus spp, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, enterobacter spp. the cdc quantified in 2008-2011 an annual number of infections supported by eskape equal to 130,000 cases with 15,000 related deaths. this evaluation proved to be just outdated for the period 2011-2017 when some microbial species, endowed with complex resistances, have shown an increase in their epidemic impact with resistance phenotypes more difficult to treat while other microbial species, not included in the eskape, have become clinically relevant as streptococcus pneumoniae, neisseriae gonorrhoeae, clostridium difficilis and candida spp. in hospitals, infections caused by antibiotic-resistant bacteria are now associated with greater morbidity and mortality as well as a longer hospitalization, compared to infections by susceptible bacteria. every year in the world, the antibiotic resistance determines 700,000 deaths of which 25,000 in europe with a cost of 1.5 billion euros. if the antibiotic resistance will remain at current levels of growth, the deaths could reach 10 million in 2050. for this, according to who, antimicrobial resistance is considered one of the biggest threats to public health due to its epidemiological impact. the who underlines how the inappropriate use of antibiotics has led to the phenomenon of antibiotic resistance. by using antibiotics in inappropriate doses and timing, treating non bacterial infections with antibiotics, using an intramuscular route when the oral route is appropriate, not following the guidelines of prescription or for inappropriate self-prescription or use of antibiotics beyond the necessary. some studies have shown that in hospital 30-50% use of antibiotics used is inappropriate and that improving prescription determines a reduction of antibiotic resistance and related hospital infections assistance. the final consequence of antibiotic resistance is the reduction of effectiveness of antimicrobial therapies puts at risk the anti-infective medical therapy that currently allows us to treat prosthetic infections, infections in severe oncological-haematological diseases and organ transplants and more. if the current prescribing behaviors and inappropriate use of antibiotics will not be changed, in 2050 the antibiotic resistance will cause more deaths from infection than cancer. hence the commitment to antibiotic government programs (antimicrobial stewardship) in order to improve: the prescription, with the use of optimal therapy regimens, diagnosis, surveillance and prevention of bacterial infections. all this with strategies of control of infections and their transmission in acute and long-term facilities; antimicrobial stewardship programs for antiinfective drugs; re-evaluation of the therapeutic potential of previous used anti-infective drugs; improvement of microbiological response times to reduce the duration of empirical therapy; development of new antimicrobial molecules. the american society of infectious diseases (idsa), in its guidelines, highlights how the antimicrobial stewardship (as) has a fundamental role in achieving prescriptive and responsible appropriateness, not only for the individual patient but for the whole general context of the ecosystem. moreover the activity of the infectious diseases department in the hospital and on the territory can help to sensitize the clinicians to follow the principles for the correct use of antibiotics with appropriate use that requires an adequate microbiological study before the prescription; prescription of the drug in the presence of infection and not colonization; correct administration by dose, time and duration in respect of pharmacokinetics and pharmacodynamics of the molecule (pk/pd); de-escalation of therapy based on microbiological tests and clinical parameters; optimal surgical prophylaxis by choice, time of administration and duration (82). management of chronic prostatitis/chronic pelvic pain syndrome (florian me wagenlehner) cp/cpps is a not well defined entity. in everyday clinical practice frequently the diagnosis is based upon pain symptoms in the abdomen or pelvis region radiating to adjacent areas and might be accompanied with lower urinary tract symptoms. painful prostate on palpation is also frequently described without any standardization of the investigation. usually rudimentary diagnosis is done, if at all including a urinalysis and possibly a urine culture. no further refined diagnosis is made and almost always prolonged and multiple antibiotics courses are prescribed, sometimes alpha blockers, or pain medication is added. the difficulties in the management of cp/cpps arise from the fact that it is a multifactorial condition, with diverse etiologies. so very different circumstances might lead to the same clinical picture, but possibly warrant different diagnosis and treatment. there is no objective diagnosis, such as a histology, that can proof the condition. there is no biomarker that can be used for diagnosis or follow up of patients, and there is lack of novel treatment strategies taking into account pathophysiological pathways. 239archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 239 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 240 in terms of diagnosis there is an agreement that infection should be ruled out by localization tests, as described early by stamey (1). to what extent ejaculate investigations could be beneficial is not entirely clear. ejaculate testing is frequently performed on routine examinations heading for mere culture, which frequently provides contamination samples, or in other words reflects the microbiome of the external genitalia. however “next generation” investigations, such as cytokine analysis, cytological typing of immune cells etc., that could help stratifying the immune response can nowadays be performed in clinical routine (83). epigenetic changes are frequently seen in chronic inflammatory diseases and should be investigated according to systemic and compartmentspecific signals for epigenetic dysregulation of inflammatory factors. by doing so a significant association with systemic and local epigenetic inactivation of a mast-cell recruiting molecule cxcr4, the receptor for cxcl12 was identified (83). the search for biomarkers should include various pathways, including hormonal pathways (84). in one study elevated local estrogen levels associated with an epigenetic down-regulation of the estrogen receptors was identified. investigating estrogen levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy (84). as pain is the main driver of reduced quality of life in patients suffering from cp/cpps (85), novel therapeutic substances for the treatment of pain would be therefore be highly interesting to test. anandamide is a cannabinoid (cb) produced on demand in response to elevated intracellular calcium levels in post-synapse. it is an endogenous agonist of the cb1 receptor which exerts potent inhibitory effects on pre-synaptic glutamate release. the fatty acid amide hydrolase (faah) is involved in the enzymatic regulation of anandamide and the inhibition of faah elevates levels of anandamide in hyperexcited synapse and potentially could reduce pain perception. in a phase 2 study a peripherally active faah inhibitor asp3652 was investigated in cp/cpps patients, as inhibition of faah is hypothesized to reduce the excitability of urinary tract afferents including nociceptors (86). the results of the study however did not show efficacy of asp 3652 on pain symptoms in patients with cp/cpps (86). most monotherapy studies in general have not been successful, since cp/cpps is a multifactorial disease with different pathophysiological causes. a phenotyping approach, the upoint concept, has therefore been recommended (6). this concept includes a multimodal therapy for cp/cpps in phenotyped patients, where each identified phenotype according to the enlarged upoints classification is treated separately (87). using such a treatment concept, a clinically appreciable reduction of ≥ 6 points of the total nih-cpsi score was achieved in 77.5% of patients subjected to combination therapy for a period of 6 months (87). role of multimodal therapy for treatment of chronic prostatitis (giorgio i. russo, gaetano larganà) prostatitis is considered the “black sheep” of the prostate family of disease, due to difficult to understand its causes and its definitive therapy. it can be considered one of the challenges that urologists have to face. in the last decade, in fact, google trend showed how the term “prostatitis” has been looking several times more compared to the past, like prostatitis and therapy, like prostatitis + phytotherapy and serenoa repens. what kind of therapy urologists could use against prostatitis? first of all, in case of diagnosis of prostatitis, antibiotics are the firstline agents for the treatment of cp, for 4-6 weeks. penicillin, fluoroquinolone, third-generation cephalo spo rin, macrolides could be used for cp/cpps. if patient has voiding low urinary tract symptoms (luts), alphablockers for 4-6 weeks are also used. the use of alphablockers demonstrates an average nih-cpsi total score reduction, an average pain e average voiding symptoms reduction with an increase of quality of life (88). if pain is present, simple analgesics +/non steroidal anti-inflammatory drugs (nsaids) can be used. different studies compare the use of rofecoxib and celecoxib against placebo. they demonstrate a pain reduction and a better quality of life (89). unfortunately, long-term use of antiinflammatory agents for cp/cpps is limited by complications due to side effect profile, moderate effect on symptoms (predominantly pain) and lack of data for their use. improvement of results has instead been reached by the contemporary use of alpha-blockers, antibiotics and anti-inflammatory (90), showing a better control of prostatitis symptoms than use of a single drug. in fact, unfortunately, no efficient monotherapeutic option is available. the best evidence-based management of cp/cpps is a multimodal therapeutic approach addressing the individual clinical phenotypic profile (91); antibiotics, alpha-blockers and anti-inflammatory, although they have an effect on the disease, cannot be recommended as first-line monotherapy but could be considered in a multimodal therapeutic regimen. a different and new point of view in the treatment of cp/cpps is to considered phytotherapy. it could be recommended as primary therapy or in association with other drugs to treat cp, because of their few side effects. the use of quercetin (500 mg twice a day), in man with chronic pelvic pain syndrome, show a better control urinary symptoms, a lower symptoms duration and a better quality of life against placebo (92). cernilton, a pollen extract, show a better control of pain and a 25% decrease in nih-cpsi score, with better quality of life against placebo, in cp/cpps patients (93). pollen extract was studied against placebo also in association with vitamins (deprox 500) for pain relief: after only 1 month from start of therapy it was observed a decrease of nih-cpsi score, although ipss remain constant. most important was the comparison between deprox 500 mg and ibuprofen 600 mg for early pain relief. pollen extract demonstrated a better quality of life and a major decrease in nih-cpsi score, avoiding all the side effect of the continuous use of nsaids like ibuprofen. eviprostat has an identical effect compared to pollen extract in patients with cp/cpps. ipss total score, ipss storage score, ipss voiding score after 4 and 8 week of treatment with cernilton or eviprostat showed no statically difference in results from baseline. another studied phytotherapy drug is serenoa repens. profluss, an associamagri_stesura seveso 15/01/19 11:31 pagina 240 tion of serenoa repens plus selenium and lycopene has better results in ipss score, qmax score than serenoa repens alone. in the last years other drug associations were studied for the treatment of patients with chronic prostatitis. an italian study reported about the association between curcumin and calendula (riflog) versus placebo. the results were encouraging, with a reduction of the nihcpsi score and changes of peak flow, iief-5, vas and pedt. moreover, as already mentioned before, multimodal therapy has greater effectiveness than a single therapy. riflog, in association with alpha-blocker and antibiotics, improves quality of life, qmax and reduced santorini ectasia and number of stamey positive patients. at last calendula officinalis could be another phytotherapy drug used in prostatitis, exploiting the numerous effect already studied and know, like antiflammatory, antioxidant, antiedematous or analgesic effects. prostatitis and intestinal diseases (clara maria granatieri) the association of cp/cpps syndrome with intestinal symptoms has been described in the literature. in our experience out of 232 patients suffering from prostatic inflammation, 146 (63.2%) frequently exhibited alterations of intestinal function (alternating constipation and diarrhea, abdominal pain and bloating) and previous urinary infections. the study of functional bowel pathologies (irritable bowel syndrome ibs, idp) has focused the attention on the intestinal microbiota. the interaction of bacterial intestinal flora interaction with food is the basis of many phenomena that influence the state of health or illness. in fact the microbiota, according to its composition and by means of the products of bacterial metabolism, influences the metabolic, immune and inflammatory response of the organism (94). an anti-inflammatory action occurs at the level of toll-like receptors (tlr); probiotics are able to regulate the balance if intestinal flora, so the tlr can correctly distinguish dangerous antigens from those that must be tolerated. reduced intake of fiber in the diet alters the intestinal microbiota, with reduced bacterial production of compounds modulating the immune response. to regulate the intestinal flora, proper nutrition is therefore crucial. numerous studies attest the important role of diet in proper formation and maintenance of the intestinal microbiome. epidemiological studies have correlated the increase of inflammatory pathologies with "modern" nutrition, the so called "western diet" that is the intake of large quantities of red meat, simple carbohydrates, fat, refined cereals and poor portions of vegetables, fruit and fish. the damages caused by this diet are due to the inability of the human genome to adapt to rapid changes in the environment, especially diet (95). the "mediterranean diet” is more similar to that of our ancestors and is considered the standard diet for human health (96). the complex cumulative nutritional effects of the foods rather than the intake of single macronutrients (proteins, carbohydrates, fats) and micronutrients (minerals and vitamins) play an important role in the protective effect of the mediterranean diet (96). the diet has its effects on inflammation both by direct action on the cells and regulation of the composition of intestinal flora. foods directly influence the immune response and therefore inflammation of intestinal and extra-intestinal tissue. intestinal cells, in particular enterocytes and immunocompetent cells, are equipped with complex systems for “sensing” foods and respond to them (97). in fact, intestinal cells express pattern recognition receptors, such as the tlr, the nod-like receptors (nlr) and the leucine rich alpha-2-glycoprotein1 (lrg1). they recognize both pathogen associated molecular patterns (pamps) and damage associated molecular patterns (damps). in fact an inflammation in the absence of pathogens can occur in all the tissues, in response to a wide range of stimuli, which cause stress and damage to cells (sterile inflammation) (98). in the sterile inflammation some nutrients are able to cause conditions of cellular stress. various damps are released from damaged cells and activate immune cell receptors (tlr, nlr, lrg1) which were originally identified as pamps sensors. in particular damps lead to the assembly of a cytosol protein complex, called inflammasome, which activates the caspase-1 protease with consequent activation and secretion of il-1beta. the nutrients can therefore interact with the intestinal epithelium and the cells of the system immune, as do viruses, bacteria and other environmental factors, activating the same pathways of cellular signals that activate or reduce inflammation. microbiota-eubiosis-dysbiosis (roberto colombo) the pool of bacteria and other microorganisms (viruses and prokaryotes) that lives in coexistence in the human intestine is called intestinal microbiota (99-107). the microbiota is made up of 100 trillion bacteria in a balanced composition of several divisions (phyla), genera and bacterial species, which can act as – "commensals" that do not provide any benefits or harm to the guest – "symbionts" mainly bifidobacteria and lattobacilli with probiotic activity – "pathobionts" resident bacteria with potential for pathological induction. the composition and concentration of bacterial genera and species differs in the various segments of the gastrointestinal tract from 102 in the stomach to 1012 in the colon. the intestinal microbiota implements 3 probiotic functions: – protective function against pathogenic bacteria from the outside and pathobiont bacteria: this action is carried out by anti-bacterial activity (bacteriocins) for space and nutrient competition and for slight acidification of the environment to inhibit the growth of pathogenic bacteria – metabolic function by synthesis of vitamins, decomposition of bile acids and above all production of short-chain, butyric, propionic and acetic fatty acids (butyrate is the trophic factor for intestinal mucosal cells) 241archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 241 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 242 – probiotic bacteria, especially bifidobacteria and lattobacilli, that also have the function of modulation of the intestinal immune system (galt: gut associated lymphoid tissue, 60% of the entire intestinal system); this occurs because the products of probiotic bacteria (lipopolysaccharides, peptidoglycans) stimulate specific receptors of the dendritic cells of the intestinal mucosa which, for this stimulation, produce interleukin 10 which stimulates the regulatory t lymphocytes that implement the modulation of the galt. in addition, the intestinal epithelial cells produce a mucous layer that covers the intestinal surface, consisting of mucin polymers that act as nutrients and sites of adhesion of probiotic bacteria. the balanced microbiota is in a state of “eubiosis” with welfare functions for the whole organism. the qualitative and quantitative alteration of the microbiota is called “dysbiosis” which, by altering the probiotic functions, causes invasive intestinal diseases and correlates with numerous systemic diseases. the causes of dysbiosis in adults are determined by drugs, stress, wrong diet, bad lifestyle, infections and food intolerances. dysbiosis can be "deficienct" when caused by drugs or stress or wrong fiber-free diet, or "stagnant" or "putrefactive" when foods such as fats and red meat that stimulate the flora to putrefactive activity prevail in the diet or, on the other side, when fermentable foods (legumes, citrus fruits, etc.) are excessive. a diagnostic innovation regards the evaluation of the dysbiotic action of colina (by excess of eggs) and carnitine (by excess of red meat). the dysbiotic flora induced by excess intake of these substances produces trimethylamine oxide (tmao). this product stimulates the formation of foam cells, inflammatory cells with oxidized ldl, which stimulate the formation of atheromatous plaque. tmao represents an important new cardiovascular risk marker. the presence of dysbiosis mainly determines low-grade inflammation with hyperstimulation of the immune system and endotoxaemia, because the dysbiotic bacteria produce substances that stimulate the receptors of dendritic cells inducing the production of inflammatory interleukins with increased reactivity of t17 and t1 lymphocytes to pro-inflammatory action. dysbiosis, as well as other stimuli, such as gluten, determine the secretion by intestinal cells of the zonulin protein, which acts on the "tight junctions" of the intestinal epithelial cells, causing increased intestinal permeability. dysbiosis, zonulin and consequent low-grade inflammation are the pathophysiological causes of the numerous diseases related to the alteration of the microbiota. the gastrointestinal pathologies are at first local (as leaky gut syndrome) developing food intolerances, subsequently they can worsen when there is a concomitant alteration of the balance of the brain intestinal axis (psychosocial hypersensitivity/excess of catecholamines) with ibs or vice versa when polymorphisms predisposing to inflammation cause the onset of a chronic inflammatory bowel diseases (ibd). dysbiosis can cause, for the pathophysiological factors mentioned above, systemic diseases such as diabetes mellitus (as the produced inflammatory factors as interleuchin-6, il6, and tumor necrosis factor, tnf) determine insulin resistance) or cardiopathies (due to production of trimethylamine oxidize, tmao) or allergies in atopic subjects or autoimmune diseases secondary to synovial migration of inflammatory cells or depression due to reduction of serotonin production by intestinal cells or cystitis and vulvovaginitis in the female caused by migration of pathobionts bacteria of the dysbiotic intestinal flora. the alteration of the microbiota is also related to obesity because of the alteration of the relationship between bacteroidetes and firmicutes that are the two main bacterial divisions that make up 90% of the intestinal microbiota whose relationship represents a main biodiversity index. this ratio is normally about 0.8, but in obesity it is changed with an increase of firmicutes that determines an increase in the ability to recover energy from the diet due to increased carbohydrate metabolism. low-grade inflammation, increased intestinal permeability, presence of pathobionts bacteria and trans-parietal migration may also be involved in the pathogenesis of acute and chronic prostatitis. repeated antibiotic therapies that often accompany the clinical process of urogenital and prostatic infections represent a factor that repeatedly feeds the dysbiosis related to these diseases highlighting the importance of the therapy with probiotic bacteria to restore the eubiosis and stop the vicious circle of dysbiosis-urogenital infections. bacterial therapy is based on the use of live probiotic bacteria, with correct taxonomic identity according to qualified presumption of safety (qps) and international depository authority (ida) status. the timing of administration of bacterial therapy should never be less than 21 days and the amount of live bacteria should never be less than one billion daily. hydrocolontherapy: therapeutic option in patients with chronic prostatitis and dysbiosis? (r. giuberti) the investigation on the intestinal microbiota in the cp/cpps has detected less alpha diversity of the microbiota respect to controls (lower presence of prevotella genus, to which an anti-inflammatory role is recognized) (108). the microbiota can generate, amplify and maintain a systemic or a local inflammatory condition, causing, as a consequence, a possible painful state, that could have a role in the etiology of the cp/cpps (109). dysbiosis with persistence of pathogenic noxae can activate mast cells causing chronic inflammation. bacteria belonging to the phylum proteobacteria have an outer membrane composed mainly of lipopolysaccharides (lps) that stimulate monocyte activity through various steps. lps are anchored to the external membrane of the bacteria and are released once bacteria die provoking a reaction from the organism with possible increase of the vascular permeability and consequent inflammatory state. they increase intestinal permeability through an intracellular mechanism that involves the up-regulation of tlr-4, which depends on the membrane expression of cd-14 (110). tlrs are receptors expressed on the membrane of sentinel cells such as macrophages, dendritic cells and antigen-presenting cells (apc). in particular, magri_stesura seveso 15/01/19 11:31 pagina 242 tlr-4 is crucial in the recognition of lps. the activation of tlrs in the intestinal microbiota by the presence of pathogenic microorganisms induces the triggering of the mechanisms of innate immunity and the onset of inflammatory phenomena. the condition of dysbiosis leads to an indirect dysfunction, therefore not primary but secondary, of the intestinal epithelia barrier which creates a way of entry into the organism, through the blood, of bacteria, giving rise to phenomena of bacterial translocation (bacteria in places other than those of origin). the alteration of intestinal permeability, due to lactobacilli and bifidobacteria deficiency, leads to loss of integrity of the mucosal barrier, passage of antigens in the submucosa and immune activation. the activation of the mast cells maintain an up-regulation with acute and chronic pro inflammatory consequences. recent studies have widely established that mast cells can also respond to non-ige dependent stimulation. in these cases, mast cells appear to undergo ultrastructural alterations of the granular nucleus, that appears dense with electrons, without the classic evidence of degranulation that is related to an increase of ige. a condition of chronic mild inflammation is developed that reverberates at the intestinal, prostatic and vaginal level. the best known triggers of this alternative activation path include bacterial toxins, neurotransmitters and stress that may be involved in the pathophysiology of ibs. patients with ibs have a 150% increase in mast cells compared to a control group. the involvement of mast cells in abdominal pain of patients with ibs has been widely demonstrated, in particular the presence of activated mast cells near the nerve endings, is related to the intensity and frequency of abdominal pain. mast cells represent the most active sentinels towards the external environment having a high quantity of receptors that can be activated by allergens such as food, drugs, cytokines. the mast cell can acts both by paracrine signaling, especially for the presence of pseudopods which can extend the inflammatory response to blood vessels and nerve endings, and autocrine signaling to itself because it has receptors to the substances that it releases. consequently, if the causes of its activation are not removed, the inflammatory process can become chronic. some studies have shown that dysbiosis can cause the release of zonulin which leads to the passage of endoluminal contents through the epithelial barrier with consequent release of pro-inflammatory cytokines. zonulin is a protein that regulates the junctions of the intestinal walls and ,if in excess, loosens them, favoring a state of intestinal permeability. it was first described in 2000 by fasano et al. at the celiac research center of the university of maryland school of medicine. who focused on the role of zonulin in intestinal tissues during the acute phase of coeliac disease (111). the values of zonulin may represent the reference parameter for the evaluation of the extent of the intestinal mucosa alteration and the consequent state of its permeability. the values found are significant of the progression of the inflammatory condition and correlated with clinical symptoms and can be a guide of the treatment. in 22-31% of patients with chronic bacterial prostatitis and chronic pelvic pain syndrome a condition of ibs can increase the severity of the pain symptom in the following regions: perineum, supra-pubic region, testes, penis, pelvis, inguinal region, rectum, pain in urination, pain during ejaculation and neuropathic pain (1). accordingly, the therapeutic approach could aim at restoring the intestinal microbiota through the examination of the stool, the rebalancement of the microbiota, an adequate diet and the application of hydrocolon therapy to eliminate bacterial over-growth and pro-inflammatory toxins generated by lipopolysaccharides (lps). the application of hydrocolon therapy in chronic prostatitis is based on the ability of a gentle and targeted flow of water entering the intestine during the treatment sessions to regenerate the intestinal environment, through the elimination of inflammatory components that reside in the microbiota. the regularity of the incoming flow through the targeted maneuvers of the operator, which operates on the water flow and pressure parameters in an appropriate manner, allows to create an environment favorable to the regrowth of a microbiota rich in lactobacilli and bifidobacteria that is essential to maintain the intestinal mucosal integrity and to guarantee an effective motor peristalsis. the application of hydrocolon therapy in vulvodinia has achieved a significant improvement of pain with concomitant decrease of inflammatory parameters. it is desirable that the application of the technique on subjects with cp/cpps can lead to an equally significant benefit, in association with therapies targeted to the restoration of a balanced intestinal microbiota and functional to the elimination of the noxae pathogenic of the inflammatory activation that can support the syndrome. the restoration of intestinal eubiosis, through the targeted integration of probiotics, guided by the examination of stools, a healthy and balanced dietary approach aimed at maintaining a balanced microbiota and hydrocolontherapy sessions can represent a new integrated therapeutic approach, centered on the multi-factorial biological etiology, that support a chronic inflammatory process as the cp/cpps could be defined. gynecological investigation of the partners of chronic bacterial prostatitis patients (elisabetta massa) the human vagina is the location of an ecosystem whom different participants (local microbial populations, local environment and host’s characteristics) always are in a dynamic equilibrium. this ecosystem is open to contaminations both from the external and from the intestinal environment, so it is susceptible to colonization from microorganism that can be symbiotic or pathogenic according to their bacterial counts and to their ability to modify the vaginal homeostatic mechanisms. all the participants to vaginal ecosystem (vaginal epithelium, ph, glycogen and lactobacillary flora) are modified along the different ages of a woman due to different hormonal production. a high oestrogen production, such as during puberty or pregnancy, stimulates the vaginal cells to proliferation and the glycogen storage. moreover, glycogen facilitates the lactic 243archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis magri_stesura seveso 15/01/19 11:31 pagina 243 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 244 acid production and the lowering of vaginal ph. moreover, the lactobacillary flora, divided in five groups following the predominant species (l. crispatus, l. gasseri, l. iners, mixed group e l. jensenii) (112), has a protective role because it stops the pathogens’ growth and their cohesion (113). all these mechanisms are the first line in vagina’s defences. furthermore, menstrual cycles , sexual activity, antibiotics or oral contraceptives assumption can modify the vaginal macrobiotic. the vaginal microbiota has an active role in the mechanisms of conception, pregnancy and delivery (time and modality) (114). in presence of disruption of vaginal homeostasis (due to alteration of control mechanisms or to different susceptibility of the host), there are vaginal infections (vaginitis) due to attack from external pathogens or dysbiosis (vaginosis) due to a quantitative redistribution of local flora. for a correct diagnosis, it is important to evaluate the patient’s clinical history, characteristic signs or symptoms, vaginal ph value, the fish’s odor test, the microscopic exam with or without staining and a cultural/molecular test. partners of 399 patients suffering from chronic prostatitis or chronic pelvis pain syndrome: who underwent to a vaginal, cervical or urethral swab showed the same pathogen isolated in male patients, namely enterobacteria, uraplasma uralyticum, gardnerella vaginalis and chlamydia. moreover, clinical characteristics of vaginal infections, their association with sexual transmitted diseases (std), the gynaecological and reproductive consequences and the obstetric complications have to be analysed (115-117). acknowledgement to konpharma srl for supporting the meeting prostatitis: a multidisciplinary approach (issues and controversies), milano, italy, 26-27 oct 2018. references 1. stamey ta. prostatitis. j royal soc med. 1981; 74:22-40. 2. young hh, geraghty jt, 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reproductive-age women. proc natl acad sci u s a. 2011; 108 suppl 1:4608-7. 113. lepargneur jp, rousseau v. protective role of the doderlein flora j.gynecol obstet biol reprod. 2002; 31:485-94. 114. the vaginal microenvironment: the physiologic role of lactobacilli. academic unit of reproductive and developmental medicine, university of sheffield, sheffield, united kingdom, 2018. 115. unemo m, bradshaw cs, hocking js, et al. sexually transmitted infection: challenges ahead. lancet infect dis. 2017; 17: e235-e279. 116. gruppo multidisciplinare “malattie infettive in ostetricia ginecologia e neonatologia” amcli-sigo-simast-simit-sin-sip – raccomandazioni, 2014. 117. vitali b, cruciani f, picone g, et al. vaginal microbiome and metabolome highlight signatures of bacterial vaginosis. eur j clin microbiol infect dis. 2015, 34:2367-76. 247archivio italiano di urologia e andrologia 2018; 90, 4 multidisciplinary approach to prostatitis correspondence vittorio magri, md vittorio.magri@virgilio.it urology – asst nord milano, milan, italy matteo boltri, md matteo.boltri@gmail.com urology medical school, university of trieste, trieste, italy tommaso cai, md ktommy@libero.it department of urology,santa chiara regional hospital, trento, italy roberto colombo, md roberto.colombo@synlab.it synlab italia srl via beato lodovico pavoni 18, 25014 castenedolo (bs) salvatore cuzzocrea, md salvatore.cuzzocrea@unime.it università degli studi di messina, messina, italy pieter de visschere, md, phd pieter.devisschere@ugent.be department of radiology and nuclear medicine, ghent university hospital, ghent, belgium gaetano larganà, md giuseppe morgia, md gmorgia@policlinico.unict.it departmento of urology, università degli studi di catania, catania, italy rosanna giuberti, md giuroti@gmail.com sict società idrocolonterapia, milan, italy clara maria granatieri, md clara.granatieri@gmail.com internal medicine, asst nord milano, milan, italy magri_stesura seveso 15/01/19 11:31 pagina 247 archivio italiano di urologia e andrologia 2018; 90, 4 v. magri, m. boltri, t. cai, et al. 248 maria agnese latino maglatino@gmail.com alessandra sensini, md alessandrasensini@yahoo.it working group on sexually transmitted infections italian association of clinical microbiologists, glist-amcli christian leli, md unit of microbiology, ss antonio, biagio and c. arrigo hospital, alessandria, italy. giorgio maierna, md giorgio.maierna@asst-nordmilano.it quality and risk management asst nord milano, milan, italy valentina marchese, md v.marchese@unibs.it alberto matteelli, md department of infectious and tropical diseases, university of brescia, piazzale spedali civili, 25123, brescia, italy elisabetta massa, md empmassa@gmail.com gynaecology asst nord milano, milan, italy emanuele montanari, md emanuele.montanari@unimi.it department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy kurt g, naber, md, phd kurt@nabers.de assoc. professor of urology technical university of munich, munich, germany -karl-bickleder-str. 44c, 94315 straubing, germany vaia papadouli, md nektaria rekleiti, md nekrek@gmail.com microbiology department, tzaneion hospital, piraeus, greece gianpaolo perletti, phd gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences,university of insubria, varese, italy giorgio i. russo, md giorgioivan1987@gmail.com department of urology, università degli studi di catania konstantinos stamatiou, md stamatiouk@gmail.com urology department, tzaneio hospital, piraeus, greece alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com urology unit, manzoni hospital, lecco, italy florian me wagenlehner, md florian.wagenlehner@chiru.med.uni-giessen.de clinic for urology, pediatric urology and andrology justus liebig university giessen, germany magri_stesura seveso 15/01/19 11:31 pagina 248 stesura seveso 221archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. dence worldwide, that affects the quality of life (qol) of patients and their partner’s. it is estimated that about 322 million men would suffer from ed global by the year 2025 (1). ed primarily affects men older than 40 years of age. ed prevalence ranges between 1-10% in men younger than 40 years (international consultation committee for sexual medicine). the prevalence increases with age in a range from 2% to 9% in men between the ages of 40 and 49 years, 20-40% in men aged 60-69 years and > 50% in men older than 70 years (2). to the ed onset contributes several environmental and lifestyle risk factors such as diabetes mellitus, hypertension, hyperlipidaemia, obesity, metabolic syndrome, depression, smoking and limited or absence of physical exercise (3-7). penile erection is a complex of events controlled by vascular, hormonal and neuronal systems (8). for what concerns the vascular component the endothelium plays a major role through the nitric oxide (no) pathway. indeed, the activation of the no pathway causes relaxation of smooth muscle in the penile corpus cavernous, leading to increased inflow of blood (9). no is synthesized within the endothelium starting by endothelial nitric oxide synthase (enos) and activates the soluble guanylyl cyclase (sgc) that leads to the formation of cyclic guanosine monophosphate (cgmp). the cgmp levels are tightly controlled by phosphodiesterases (pdes) (10). nowadays, medical interventions for ed management include oral drugs, intrapenile therapies (intra-urethral suppositories and intracavernous injections) and penile prosthesis implantation (11). the most widely used therapeutic approach relies on the use of phosphodiesterase type 5 (pde5) inhibitors (12-13). the pde5 response rate is about 70 %.and it is significantly lower in difficult-to-treat subpopulations (14). many studies have also shown that the dropout rate with pde5 inhibitors therapy is still more than 50% after one year (15). emerging shreds of evidence propose an increasing role of herbal-based dietary supplements and nutraceuticals in the management of ed, for their anti-oxidant, anti-inflammatory and anti-proliferative properties.(16). objective: to assess the efficacy of the combination of tadalafil 5 mg and nutritional supplements composed by panax ginseng, moringa oleifera and rutin on erectile function in men with mild and moderate vasculogenic ed. methods: we prospectively enrolled 86 patients divided into two groups a (45), b (33) in this multicenter randomized, doubleblind, placebo-controlled trial . drop out was 8 patients (3 patients in group a and 5 in group b). at screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the iief-5 questionnaire and the sep-2, sep-3. patients were randomized by a computergenerated list to receive either tadalafil 5 mg once daily plus nutritional supplement once daily (group a) or tadalafil 5 mg plus placebo with the same administration schedule (group b) for 3 months. blood samples, iief-5, sep-2 and sep-3 have been collected again after 3 months. cgmp was measured in platelets of 38 patients at baseline and after one months. results: mean age was 59.98 ± 6.90 (range 38-69), mean iief-5 score at baseline was 13.59 ± 3.90. after three months of treatment, iief-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group a and group b respectively). patients treated with tadalafil plus nutritional supplement showed a significantly higher increase in iief-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001;). no hormonal differences and metabolic effects were found. according cgmp result, nutritional supplements ameliorates and extends the activity of the chronic treatment. conclusions: iief-5 significant increase in group b, can be ascribed to the nutritional supplement properties and antioxidant effects of moringa oleifera, ginseng and rutin and this can enhance the endothelial no and cgmp production. key words: erectile dysfunction; pde5; dietary supplement; phosphodiesterase: natural health product. submitted 25 january 2021; accepted 5 march 2021 introduction erectile dysfunction (ed) has been identified as the most common sexual problem, with high prevalence and incia new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation vincenzo mirone 1, luigi napolitano 1, roberta d’emmanuele di villa bianca 2, emma mitidieri 2, raffaella sorrentino 2, arianna vanelli 3, domenico vanacore 2, carlotta turnaturi 2, roberto la rocca 1, giuseppe celentano 1, davide arcaniolo 4, giuseppe cirino 2 1 department of neurosciences, sciences of reproduction, and odontostomatology, university of naples federico ii, naples, italy; 2 department of pharmacy, school of medicine and surgery, university of naples, federico ii, naples, italy; 3 responsabile ricerca e sviluppo nutrilinea srl, varese, italy; 4 urology unit, department of woman child and of general and specialist surgery, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2021.2.221 summary archivio italiano di urologia e andrologia 2021; 93, 2 v. mirone, l. napolitano, r. d’emmanuele di villa bianca, et al. 222 the study aims to evaluate the efficacy of the combination of tadalafil 5 mg and nutritional supplements composed by panax ginseng, moringa oleifera and rutin on erectile function in men with mild and moderate vasculogenic ed. in order to address this issue, we applied two different approaches: i) the assessment of index of erectile function (iief) and sexual encounter profile (sep) that represent primary endpoints in clinical studies on ed (17); ii) the measurement of platelet cgmp content that represents biomarker of pde5 activity (18-19). methods the study consisted of two different phases: a clinical one and an experimental ex vivo one. in a multicenter randomized, double-blind, placebocontrolled trial we enrolled consecutive patients with vasculogenic ed attending urology clinic of university of naples “federico ii”, university of campania “luigi vanvitelli” and interdepartmental research center for sexual medicine (cirms), university of naples federico ii. inclusion criteria were: patient age between 18 and 69 years; mild to moderate ed for at least 6 months with a short form of international index of erectile function score (iief-5) > 7 and < 22; hypertension treated with ace inhibitors, beta-blockers or calcium antagonists and/or type 2 diabetes treated with oral hypoglycemic agents; the patient has been in a stable sexual relationship for > 3 months. patients have had to be naïve for pde5inhibitors treatment. exclusion criteria were: patients who had severe ed (iief-5 score < 8), ed due to endocrine disorders, premature ejaculation, previous pelvic surgery, peyronie’s disease, liver or renal failure, history of myocardial infarction, cardiovascular disease, stroke, unstable angina and heart failure within the previous 6 months, intake of nitrates, diabetes mellitus on insulin therapy, dyslipidemia under drug treatment, spinal cord injuries. at screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the iief-5 questionnaire and the sep (sep-2: «were you able to insert your penis into your partner's vagina?» and sep3 «did your erection last long enough for you to have sexual intercourse?»). patients who met inclusion criteria were randomized by a computer-generated list to receive either tadalafil 5 mg once daily plus nutritional supplement once daily (group a) or tadalafil 5 mg plus placebo with the same administration schedule (group b) for 3 months. blood samples, iief-5, sep-2 and sep-3 have been collected again after 3 months. all adverse events (aes) occurred during the study period were recorded. the study was carried out in accordance with the declaration of helsinki and gcp. all patients provided written informed consent. the protocol was approved by the ethical committee of federico ii university of napoli. nutritional supplement composition the nutritional supplement used for the study resulted from a combination of panax ginseng (500 mg), moringa oleifera (200 mg) and rutin (50 mg). the three components were assembled in a three-layer tablet that allows different timing for the release of active ingredients. human washed platelets blood samples were collected from additional patients who met inclusion and exclusion criteria described above. these subjects received tadalafil 5 mg/daily plus nutritional supplement 1 cpr/daily for one month. the blood samples were collected before (baseline) and after treatment. human washed platelets were obtained by blood (20 ml) samples collected by venipuncture. each sample was mixed with trisodium citrate (3.8% w/v 1:10 ratio) and then centrifuged at 150 x g for 10 min to obtain plateletrich plasma (prp) as a supernatant. washed platelets were prepared as previously described (18, 19). prp was centrifuged at 800 × g for 12 min after the addition of 1/10 volume acd solution (85 mm na3-citrate, 11 mm d-glucose, 71 mm citric acid, ph 4.4). the pellet was resuspended in ca+ 2/mg+ 2-free hepes-tyrode buffer (134 mm nacl, 12 mm nahco3, 2.9 mm kcl, 0.36 mm na2hpo4, 5 mm hepes, 5 mm glucose, 0.5% (w/v) bovine serum albumin, ph 7.4) and adjusted to 5 × 105 platelets/µl. the platelet number was determined by using a cell counter (act diff 2, instrument laboratory, milan, italy). cgmp measurement human washed platelets (5 × 105 platelets/µl) were incubated at 37 °c with vehicle or diethylamine nonoate (dea-nonoate, alexis; vinci biochem, vinci, italy), a stable donor of no at the concentration of 10 µm or 100 μm. the reaction was stopped after 30 minutes in liquid nitrogen. dea-nonoate spontaneously dissociates in a ph-dependent, first-order process with a half-life of 2 min at 37 °c, ph 7.4, to liberate 1.5 mol of no per mole of parent compound (20). platelet suspensions were hydrolyzed with hcl 3.3 m. the lysates were centrifuged (600 × g for 10 min) and cgmp measured in supernatants as described in the manufacture’s protocol of cgmp eia kit (cayman, vinci biochem, vinci, italy) (18). results a total of 86 patients were enrolled in the trial. 45 patients in group a and 33 patients in group b completed the study. mean age was 59.98 ± 6.90 (range 38-69), mean iief-5 score was 13.59 ± 3.90. table 1 showed the baseline characteristics of the two groups. no differences were noticed between groups in terms of age, baseline erectile function, comorbidities, blood tests except for total cholesterol, significantly lower in group a, and liver function tests, significantly higher in group a. after three months of treatment, iief-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0,0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group a and group b respectively, figure 1). patients treated with tadalafil plus nutritional supplement showed a significantly higher increase in iief-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001; figure 1). a total of 28 patients (36%) completely restored their erectile function (iief-5 ≥ 22) and no differences were noticed between the two groups (15/45 in group a vs 13/33 in group b, p = 0.58). regarding sep-2 and sep-3 questions, the proportion of "yes" responses to sep-2 and proportion of "yes" responses to sep-3 significantly increased in both groups (p < 0.0001, figure 2) with no differences between groups (p = 0.73 for sep-2; p = 0.83 for sep-3) (figure 2). treatment did not affect hormonal plasma levels (table 2). no differences were noticed in metabolic profile before and after treatment in both groups. table 3 shows adverse events related to treatment. the rate of aes is comparable between the two groups. ex vivo study the cgmp content was measured in platelets collected from 38 patients at baseline i.e. before treatment and after one month of treatment with tadalafil 5 mg once daily plus nutritional supplement once daily. the uneven number between before and after treatment is due to the patients that have not returned because of covid-19 pandemic. following one month treatment with tadalfil plus nutritional supplement significantly (panax ginseng, moringa 223archivio italiano di urologia e andrologia 2021; 93, 2 a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation table 1. baseline characteristics of patients. group a group b p value patients. n 45 33 mean age (range) 59.93 ± 6.75 (38-69) 60.06 ± 7.31 (43-69) 0.93 iief-5 mean (range) 13.18 ± 3.75 (8-20) 14.15 ± 4.09 (8-21) 0.28 sep2 % (n) %(n) 0.18 yes 80% (36) 66.7% (22) no 20% (9) 33.3% (11) sep3 0.60 yes 22.2% (10) 27.3% (9) no 77.8% (35) 72.7% (24) comorbidities % (n) % (n) hypertension 0.17 yes 97.8% (44) 90.9% (30) no 2.2% (1) 9.1% (3) diabetes yes 35.6% (16) 27.3% (24) no 64.4% (29) 72.7% (9) 0.44 lab values total testosterone 526.04 ± 128.49 481.97 ± 139.11 0.15 fsh 6.48 ± 1.96 6.16 ± 2.09 0.49 lh 6.13 ± 2.72 4.93 ± 2.72 0.06 prl 11.43 ± 8.32 12.11 ± 4.90 0.67 fasting blood glucose 106.80 ± 29.60 104.72 ± 27.00 0.75 total cholesterol 186.26 ± 28.61 201.60 ± 30.67 0.02 ldl 142.68 ± 29.69 140.51 ± 25.76 0.17 ast 33.35 ± 8.28 27.06 ± 8.78 0.002 alt 36.82 ± 9.17 30.81 ± 9.22 0.006 ggt 47.31 ± 7.55 38.03 ± 10.94 0.0001 figure 1. iief-5 score before and after three months of treatment with tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily), group a, or tadalafil (5 mg/daily) plus placebo, group b. both treatments significantly increased iief-5 score in each group compared to baseline (group a: 13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; group b: 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001). the treatment with tadalafil plus nutritional supplement (group a) significantly increased ieef-5 score compared to tadalafil plus placebo (group b) (p < 0.0001; +7.27 ± 2.2 and 4.9 ± 2.79, respectively). data expressed as mean ± s.d. were analyzed by one-way anova followed by bonferroni post-test. figure 2. sep-2 and sep-3 answers before and after three months of treatment with tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily), group a, or tadalafil (5 mg/daily) plus placebo, group b. both treatments significantly increased sep-2 and sep-3 in each group compared to baseline. data were analyzed by one-way anova followed by bonferroni post-test. there was no significant difference between group a and group b. table 2. hormonal levels before and after treatment. group a (before) group a (after) p value group b (before) group b (after) p value total testosterone 526.04 ± 128.49 532.34 ± 115.73 0.82 481.97 ± 139.11 485.57 ± 122.48 0.89 fsh 6.48 ± 1.96 6.50 ± 1.77 0.96 6.16 ± 2.09 6.19 ± 2.15 0.95 lh 6.13 ± 2.72 6.38 ± 2.62 0.68 4.93 ± 2.72 5.01 ± 2.62 0.89 prl 11.43 ± 8.32 12.61 ± 4.71 0.46 12.11 ± 4.90 12.39 ± 4.71 0.80 archivio italiano di urologia e andrologia 2021; 93, 2 v. mirone, l. napolitano, r. d’emmanuele di villa bianca, et al. 224 oleifera and rutin) (p < 0.05) increased the cgmp content in platelets stimulated with dea-nonoate 100 µm compared with the same concentration of deanonoate before the treatment i.e. at baseline (figure 3). discussion a variety of natural products, including isolated compounds from plants, have been tested for treatment of male sexual dysfunction (21). although guidelines do not give any specific recommendation for their use, natural extracts are potentially useful in the management and treatment of male sexual dysfunction (16). ginseng has been tested for its therapeutic properties, which include improving sexual function (22), physical performance (23), treating cancer (24), diabetes (25) and hypertension (26). data available suggest that ginseng has some testosterone-like effects and it could contribute to smooth muscle relaxation of the corpus cavernosum via no pathway (27). moringa oleifera has been long used in traditional medicine. many studies have reported its antioxidant, hypoglycaemic, anti-dyslipidaemia activities, tissue-protective (liver, kidneys, heart, testes, and lungs), analgesic, antihypertensive and immunomodulatory actions (28-30). rutin is a flavonoid glycoside characterized by antioxidant, antidiabetic, anti-lipid peroxidation actions. in particular, data suggest that rutin has antioxidant activity and increases testosterone levels in diabetic condition in preclinical studies. furthermore, it has been shown that in vitro rutin can inhibit pde5 and arginase increasing the availability of no and cgmp (31-33). this nutritional supplement formulation, containing a balanced content of moringa oleifera, rutin and ginseng, has designed to act as an endothelial protector to be used as an adjuvant in the treatment of ed. the efficacy of the nutritional supplement has been tested in a clinical study by performing a combination therapy with a low dose of chronic tadalafil regimen that has shown to improve the erectile function in vasculogenic patients. there were no significant differences between the groups in terms of baseline erectile function and presence of comorbidities. the addition of a daily capsule of the nutritional supplement to tadalafil 5 mg daily did not affect total testosterone, fsh, lh and prl values. although several animal and human studies suggested metabolic effects of moringa oleifera and rutin, in our study,we did not found anti-dyslipidemic and hypoglycemic activity, probably because this was a chronic effects and 3 months could be a limited time to observe the effect. in addition, human studies showed that moringa oleifera mainly determines a reduced post-prandial blood glucose levels and a long term reduction of hba1c, rather than fasting blood glucose and we did not assess these parameters as it was not the purpose of our study (34). the clinic al evaluation indicates a statistically significant effect on sexual function. the iief-5 score increased in group a of 7.27 points vs 4.90 in group b with a significant difference of 2.37 points that represents a 20% increase over the placebo treatment. there was no significant difference in sep2 and sep3 values between tadalafil plus nutritional supplement and tadalafil plus placebo. thus, the treatment with the formulation (panax ginseng, moringa oleifera and rutin) improves the ieef-5 score. the second part of the study was performed to validate the data obtained by using the questionnaires. indeed, as in this case, questionnaires are strongly biased by the placebo treatment. we have previously shown that platelet cgmp represents a suitable and objective biomarker of pde5-inhibitors efficacy in ed clinical studies. this evidence relies on the fact that i) pde5-inhibitors act by enhancing the no/cgmp signaling ii) pde5 is present in human platelets (35, 36) iii) treatment with pde5inhibitors increases platelet cgmp levels (18, 37). in particular, we have demonstrated that, following chronic treatment with vardenafil 5 mg/daily of ed patients, the platelet cgmp levels were significantly increased and well correlated (significantly) with the vss-rigiscan measuretable 3. adverse events. adverse event group a group b p value headache 6 4 nasal congestion 1 3 back pain 3 1 dyspepsia 0 1 myalgia 1 1 cough 0 1 insomnia 1 0 flushing 6 5 dizziness 2 2 total of adverse events reported 20 18 0.38 figure 3. effect of tadalafil (5 mg/daily) plus nutritional supplement (1 cpr/daily) on platelet cgmp of ed patients. the levels of cgmp, expressed as pmoles/ml, were measured in 5×105/μl platelet following stimulation with vehicle (v) or diethylamine (dea)-nonoate (10, and 100 μm). the cgmp content was evaluated before (•) or after one month of treatment (o). cgmp accumulation after treatment was significantly higher in platelets stimulated with deanonoate 100 µm compared to the same concentration of dea-nonoate before the treatment (*p < 0.05). data expressed as mean ± s.e.m. were analyzed by one-way anova followed by bonferroni post-test. 225archivio italiano di urologia e andrologia 2021; 93, 2 a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation ment (18). thus, the measurement of platelet cgmp from blood samples of patients represents an unbiased marker of activity. the analysis of platelets harvested from patients treated with the nutritional supplement plus tadalafil showed a significant increase in the cgmp levels when stimulated with dea-nonoate 100 µm. this result suggests that the treatment with the nutritional supplement ameliorates and extends the activity of the chronic treatment with tadalafil maintaining a significant more elevated levels of inhibition of pde5. in this context, it is important to stress that there are several clinical pieces of evidence that pde5-inhibitors effect can go beyond their half-life (18, 38). indeed, clinical data reported that men still have facilitated erections when the levels of pde5-inhibitors are below of the therapeutic plasmatic concentration (39-41). conclusions in conclusion, the significant increase of the iief-5 can be ascribed to the nutritional supplement properties. indeed, beyond the well-known antioxidant effects, moringa oleifera, ginseng and rutin, it has been reported that can enhance the endothelial no and cgmp production (41-43). references 1. shamloul r, ghanem h. erectile dysfunction. lancet. 2013; 381;153-165. 2. gareri p, castagna a, francomano d, et al. erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. int j endocrinol. 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abuohashish hm, ahmed mm, alkhamees oa. effect of rutin on diabetic-induced erectile dysfunction: possible involvement of testicular biomarkers in male rats. andrologia. 2017; 49. 32. oboh g, adebayo aa, ademosun ao, boligon aa. in vitro inhibition of phosphodiesterase-5 and arginase activities from rat penile tissue by two nigerian herbs (hunteria umbellata and anogeissus leiocarpus). j basic clin physiol pharmacol. 2017; 28:393-401. 33. zhang y, huang c, liu s, et al. effects of quercetin on intracavernous pressure and expression of nitrogen synthase isoforms in arterial erectile dysfunction rat model. int j clin exp med. 2015; 8:7599-605. 34. nova e, redondo-useros n, martínez-garcía rm, et al. potential of moringa oleifera to improve glucose control for the prevention of diabetes and related metabolic alterations: a systematic review of animal and human studies. nutrients. 2020; 12:2050. 35. beavo ja. cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. physiol rev. 1995; 75:725-48. 36. wallis rm, corbin jd, francis sh, ellis p. tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. am j cardiol. 1999; 83:3c-12c. 37. dunkern tr, hatzelmann a. the effect of sildenafil on human platelet secretory function is controlled by a complex interplay between phosphodiesterases 2, 3 and 5. cell signal. 2005; 17:331-9. 38. francis sh, morris gz, corbin jd. molecular mechanisms that could contribute to prolonged effectiveness of pde5 inhibitors to improve erectile function. int j impot res. 2008; 20:333-42. 39. moncada i, jara j, subirà d, et al. efficacy of sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic window. eur urol. 2004; 46:357-61. 40. young jm, feldman ra, auerbach sm, et al. tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: us trial. j androl. 2005; 26:310-8. 41. shabsigh r, seftel ad, rosen rc, et al. review of time of onset and duration of clinical efficacy of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction. urology. 2006; 68:689-96. 42. direk aekthammarat, panot tangsucharit, patchareewan pannangpetch, thanaporn sriwantana, nathawut sibmooh. moringa oleifera leaf extract enhances endothelial nitric oxide production leading to relaxation of resistance artery and lowering of arterial blood pressure. biomed pharmacother. 2020; 130:110605. 43. nandave m, ojha sk, joshi s, et al. moringa oleifera leaf extract prevents isoproterenol-induced myocardial damage in rats: evidence for an antioxidant, antiperoxidative, and cardioprotective intervention. journal of medicinal food. 2009; 12:47-55. correspondence vincenzo mirone, md luigi napolitano, md (corresponding author) nluigi89@libero.it roberto la rocca, md robertolarocca87@gmail.com giuseppe celentano, md department of neurosciences, sciences of reproduction, and odontostomatology, university of naples federico ii via sergio pansini 5, 80131 naples (italy) roberta d’emmanuele di villa bianca, md emma mitidieri, md raffaella sorrentino, md domenico vanacore, md carlotta turnaturi, md giuseppe cirino, md department of pharmacy, school of medicine and surgery, university of naples, federico ii, via d. montesano, 49, 80131 naples (italy) arianna vanelli, md responsabile ricerca e sviluppo nutrilinea srl, varese (italy) davide arcaniolo, md urology unit, department of woman child and of general and specialist surgery, university of campania "luigi vanvitelli", 80131 naples (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12427 1 original paper wide (2). it is estimated by the year 2025, 322 million men will suffer from ed (3). in a european study of men aged 30-80 years, the prevalence of ed was 19.2%, with a steep age-related increase from 2.3% to 53.4% (4). cardiovascular disease (cvd) is a leading cause of death and disability in men (5). in europe, deaths from cvd in those aged < 70 years old are a particular concern, with > 60 million potential years of life lost to cvd annually (6). the link between ed and cvd has been previously characterized primarily by shared risk factors (7-9). however, an emerging set of data indicates that ed is in fact an independent and strong marker of cvd risk (10-22). as we know, both diseases are consequences of systemic vascular disease and shared common risk factors. furthermore, they share the same pathological process: endothelial dysfunction (18). knowledge of this association justified the introduction in 2021 in the european society of cardiology (esc) guidelines on cardiovascular disease prevention in clinical practice of the recommendation to assess cardiovascular risk in men with evidence of erectile dysfunction, with recommendation level iia and evidence c (23). because of the quality of life (qol) burden it carries, ed may drive men to seek medical attention in the absence of other cardiovascular symptoms. thus, the presence of ed may provide the opportunity for cvd assessment and mitigation of its risks. the importance of evaluating cardiovascular risk in men with ed is now a critical factor for overall early stage management of cvd, especially in younger men (7, 9). in accordance with the european association of urology (eau) guidelines, sexual rehabilitation should only commence after a meticulous evaluation of the cardiovascular risk, alongside with an assessment of the individual's capabilities to engage in physical activity (7). despite these recommendations, recent research highlighted a deficiency in the evaluation of cvds in patients with ed by urologists: alarmingly, fewer than half of these clinicians undertook a combined assessment encompassing both cvd and ed (24). the princeton consensus (expert panel) conference, is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health (9). the iii princeton consensus (princeton 3) were published over a decade ago (9), and since then, several background and objectives: erectile dysfunction (ed) is an independent and strong marker of cardiovascular disease (cvd) risk. the princeton consensus aimed to evaluate and manage cardiovascular risk in men with ed and no known cardiovascular disease, focusing on identifying those requiring additional cardiologic work-up. it has recently been updated to the american population demographics, but european recommendations are needed. methods: it was developed a cross-sectional investigation including erectile dysfunction patients. data were collected from hospital registries. two risk stratification models were employed and compared: princeton consensus criteria (pc) and european society of cardiology (esc) cvd risk criteria. the objective was to stress the importance of the changes in iv princeton consensus recommendations in stratifying cvd risk in men with erectile dysfunction using a model validated in european men. results: a total of 137 patients with ed, with a mean age of 57.1 years old, were included. according to the pc criteria, 39.7% of the patients were “low risk”. when using esc criteria, the proportion of “low risk” patients were significantly lower (12%, p < 0.05). among “low risk” patients according to the pc, 52.5% and 20% were classified as high and very high risk according to esc criteria, respectively. one myocardial infarction was reported. the patient was classified as “low risk” according to the pc, but the esc criteria categorized him as “high risk”. conclusions: pc is less sensitive than esc recommendations detecting cvd. it raises concerns that urologists could be overlooking patients with undiagnosed cvd, consequently missing out on opportunities for prevention of major cardiovascular events (maces) and premature deaths. key words: erectile dysfunction; cardiovascular disease; iv princeton consensus. submitted 25 february 2024; accepted 1 june 2024 introduction erectile dysfunction (ed), defined as a man’s consistent or recurrent inability to attain and/or maintain penile erection enough for successful vaginal intercourse (1), is a common problem in men as they age. epidemiological data shows a high prevalence and incidence of ed worldreassessing cardiovascular risk stratification in men with erectile dysfunction joão lorigo 1, daniela m. gomes 2, 3, ana r. ramalho 1, 3, edgar t. silva 1, 3, patrícia a. mendes 1, 3, arnaldo figueiredo 1, 3 1 centro hospitalar e universitário de coimbra, coimbra, portugal; 2 unidade de saúde familiar serra da lousã, vilarinho, portugal; 3 faculdade de medicina da universidade de coimbra, coimbra, portugal. doi: 10.4081/aiua.2024.12427 summary archivio italiano di urologia e andrologia 2024; 96(4):12427 j. lorigo, d.m. gomes, a.r. ramalho, et al. 2 alternative risk models have been revised and validated for the prediction of cardiovascular risk in individual patients, according to their demographic background. the iv princeton consensus (princeton 4) were recently updated, addressing this disparity (25). the princeton 4 recommends the use of atherosclerotic cardiovascular disease (ascvd) model introduced by the american college of cardiology/american heart association (aha/acc) in 2013 (26) to estimate the cvd risk in all patients with organic vasculogenic ed. however, the ascvd score is not validated to the european population. of particular interest is the score2/score2-op developed by the esc, that was last updated in 2021 and is distinct for being the developed and validated for the european population (27). the present study aimed to stress the importance of the changes in princeton 4 recommendations in stratifying cvd risk in men with erectile dysfunction using a model validated in european men. methods this study was designed as a cross-sectional study to evaluate the adequacy of the princeton consensus (pc) for stratifying men with ed based on their cvd risk. the study drew upon a clinical series of patients with ed to conduct a comprehensive review. the study included all patients referred to the andrology department at a central hospital in portugal for the assessment and treatment of erectile dysfunction within the designated study timeframe (three-year period, from december 2019 to december 2022). all patients included in the analysis were diagnosed with organic ed according to the clinical data and all of them were interviewed by the same expert in andrological care to ensure consistency in data collection and evaluation. we collected demographic data, medical history, and cvd risk factors recorded in the hospital registries during a minimum follow-up period of 12 months. the proportion of positive stress test results and subsequent invasive cardiac procedures was documented. the occurrence of major adverse cardiovascular events (maces) was monitored during the study period. two risk stratification models were employed: classic princeton criteria (pc) and esc cvd risk criteria. to facilitate meaningful comparisons and clinical applicability, patients were subsequently categorized into "low risk" and "non-low risk" groups for all risk assessments. specifically, pc and esc lowest risk categories, pc low risk and esc low to moderate risk patients, respectively, were placed in the "low risk" category, whereas the leftovers were grouped under "non-low risk". for a visual representation of the risk groups recommended by the esc cvd risk stratification criteria, please refer to figure 1 (23). the esc guidelines (23) served as the basis for patient stratification in this study. following the esc panel's recommendations, individuals with a history of cvd were automatically categorized as not being at low risk for future maces, as depicted in figure 1. consequently, all patients with documented cvd were classified as "nonlow risk" for the analysis. those without previous cvd were stratified based on the score2/score2-op system. we utilized the heartscore calculator available on the esc online platform (https://www.heartscore.org/), which necessitates input regarding patients' age, sex, blood pressure, total hdl and ldl cholesterol levels, and smoking status. all relevant data were extracted from hospital registries. figure 1. patients’ categories and associated cvd risk according to esc guidelines. archivio italiano di urologia e andrologia 2024; 96(4):12427 3 reassessing cardiovascular risk stratification in men with erectile dysfunction the data were managed on and analysed using spss for windows. all values were expressed as mean (± standard deviation) or as percentages. standard descriptive analysis was performed to analyse the baseline characteristics of the study population. the categorized risk estimates derived from the different risk scores were compared using mcnemar test (as the risk scores were dichotomized as “low risk” or “high risk”). a p value < 0.05 was considered statistically significant. the study was conducted following the principles outlined in the declaration of helsinki. approval from the institutional review board were obtained. results our study included 137 patients with ed with a mean age of 57.1 ± 10.5 years old. the average body mass index (bmi) was 27.7 ± 4.1 kg/m2, and each patient had a median of 3 cvd risk factors. of the total population, 28.5% had diabetes mellitus (dm), 12.4% had chronic kidney disease (ckd), 6.6% had a previous stroke and 4.4% had a myocardial infarction (mi). baseline characteristic of the population are summarized in table 1. table 2 presents the categorization of patients based on various risk models, and table 3 provides a comparison between these models. figure 2 gives a visual representation of the distribution according to the model applied. according to the pc, approximately 39.7% of patients were classified as "low risk". however, when using alternative risk scores (esc criteria), the percentage of patients classified as being at the lowest risk group was significantly lower (12%, p < 0.05). within the "low risk" group according to the pc, 52.5% and 20% were classified as high and very high risk according to the esc criteria, respectively. patients without previously known cvd showed a mean 10-year risk of cvd events of 6.5% ± 3.5% according to the score2/score2-op. moreover, low, intermediate and high-risk patients according to pc showed a 10-year risk calculated with the score2/score2-op formula of 5.4% ± 3.2%, 7.6% ± 3.6% and 8.5% (n = 1), respectively. to address arbitrary cutoff values used for categorization in the score2/score2-op model, we utilized a roc curve (figure 3). our analysis pinpointed a 5% 10-year cvd risk threshold from the score2/score2-op model, offering table 1. patients’ characteristics. variables mean ± sd variables mean ± sd age (years) 57.1 ± 10.5 bmi (kg/m²) 27.7 ± 4.1 mean blood pressure (mmhg) 97.1 ± 13.3 total cholesterol (mg/dl) 175.8 ± 39.5 hdl cholesterol (mg/dl) 51.2 ± 18.5 ldl cholesterol (mg/dl) 103.7 ± 46.4 cardiovascular risk factors (%) ≤ 2 41.9% ≥ 3 58.1% figure 2. patient distribution according to the models applied. figure 3. roc curve. table 2. patients’ distribution according to the risk models applied. risk model n% iii princeton consensus low 39.7 intermediate 55.1 high 5.1 esc guidelines low to moderate 12 high 53.8 very high 34.2 score2/score2-op low to moderate 25.9 (patients apparently healthy) intermediate 57.4 high 16.7 table 3. patients’ distribution according to the risk models applied. risk models iii princeton consensus p (n%) low risk non-low risk esc model for patients with type 2 low risk 27.5% 3.9% < 0.05 diabetes mellitus, ckd, fh or non-low risk 72.5% 96.1% established ascvd (n%) esc model for apparently healthy patients low risk 40.7% 11.1% < 0.05 (score2/score2-op) (n%) non-low risk 59.3% 88.9% archivio italiano di urologia e andrologia 2024; 96(4):12427 j. lorigo, d.m. gomes, a.r. ramalho, et al. 4 the optimal balance of sensitivity and specificity when compared to the pc. of the men without cvd, 40.7% showed a 10-year risk below 5%, aligning with the proportion classified as “low risk” by the pc (39.7%). notably, within the pc "low risk" group, 40.7% still exhibited a 10year mace risk surpassing this threshold. among men who underwent stress testing, 10 patients (21.7%) tested positive for ischemia and were referred to the cardiology department. during follow-up, two maces were reported: 1 myocardial infarction (mi) and 1 ventricular tachycardia (vt). out of the 137 included patients, five underwent cardiac interventions (1 angioplasty, 1 bypass, 1 implantable cardioverter defibrillator (icd), 1 mitraclip and 1 valvuloplasty). the sole mi reported occurred in a patient classified as "low risk" according to the pc. however, the 47-year-old male with dm, according to the esc guidelines, was categorized as "high risk". nevertheless, there was no significant difference in the mi rate between the two models (p < 0.05). further information on these patients can be seen in table 4. discussion the association between ed and undiagnosed cvd has been extensively investigated since its initial recognition as an independent risk factor. a meta-analysis encompassing 12 prospective cohort studies identified ed as a predictive indicator for various cardiovascular outcomes: cardiovascular events (hr 1.44, 95% ci 1.27-1.63), cardiovascular mortality (hr 1.19, 95% ci 0.97-1.46), myocardial infarction (hr 1.62, 95% ci 1.34-1.96), cerebrovascular events (hr 1.39, 95% ci 1.23-1.57), and allcause mortality (hr 1.25, 95% ci 1.12-1.39) (28). another comprehensive literature review highlighted that ed precedes cardiac events by a period of 3 to 5 years, which responds to an important window of opportunity in the prevention of cardiovascular events (21). an umbrella review of systematic reviews and meta-analyses underscored the consistent finding that ed frequently precedes symptomatic cvd. this recognition equips healthcare practitioners with the opportunity to screen and identify high-risk patients at an early stage, ultimately contributing to prevent morbidity and mortality (27). similarly, gandaglia et al. found that ed patients with cardiovascular risk factors should be considered high risk, warranting comprehensive cardiovascular evaluations due to potential silent coronary artery disease (30). raheem et al. emphasized the responsibility of urologists, general practitioners, and primary care physicians to identify high-risk patients and refer them to cardiologists for assessment (31). due to the robust association between ed and cvd, major urological associations such as eau, aua and, more recently, esc advocate for systematic assessment of ed patients regarding their cvd risk (7, 23, 32). this approach recommends sexual rehabilitation exclusively for patients categorized as low risk, while those at higher risk require further cardiologic evaluation. this evaluation does not primarily focus on the patient's ability to tolerate pro-erectile medication, given the generally safe nature of these therapies (33). instead, it aims to determine the patient's physical capability to sustain the exercise intensity demanded by sexual activity. sexual activity between couples in a longstanding relationship equates to approximately 3 mets (metabolic equivalent of task), therefore completing 4 minutes of the standard bruce treadmill protocol (5-6 mets) without symptoms, arrhythmias, or a fall in systolic blood pressure (bp) confirms the safety of sexual activity (7, 9). the princeton 3 underscored that intermediate risk patients should undergo stress test to gauge exercise capacity prior to initiating proerectile therapy. high-risk patients are advised to undergo a thorough cardiologist assessment and optimization before embarking on rehabilitation (7, 32). a limitation of the princeton 3 was its insufficient consideration of varying degrees of severity associated with specific risk factors, such as age, dm, and lipid profile. while uncontrolled hypertension designates individuals as high risk, the consensus overlooked the progressive impact of aging, current lipid profile and glycaemic status, regarding them to mere contributors within the cumulative risk factor count. in contrast, the esc criteria (as shown in this study) and the ascvd score (as proposed in the princeton 4) demonstrates a more comprehensive, personalized and sensitive approach. as recently published (25), the princeton 4 suggests assessing all vasculogenic ed patients based on their 10year risk of cvd using the ascvd score. if the 10-year risk is 5-20%, coronary artery calcium (cac) testing is recommended before initiating pro-erectile treatment. patients with an abnormal cac test or an initial risk over 20% should be referred to preventive cardiology for rigorous risk factor control. our study supports and reinforces this new recommendation. the esc criteria encompass the exact age, blood pressure, lipid profile in risk evaluation, ckd stage and current glycaemic control. for instance, under the pc, a 40year-old smoker with hypertension and dyslipidaemia is classified as intermediate risk (owing to the presence of three risk factors, excluding sex). conversely, a 75-yearold smoker without comorbidities is labelled low risk. however, considering both individuals show normal lipid profile and blood pressure, the score2/score2-op model presents divergent outcomes. the first patient is designated low risk with a 2% 10-year cardiovascular event risk, while the second patient faces a substantially higher risk of 18% over the same period. however, the clinical significance of these disparities remains uncertain. while it is accepted that patients classified as intermediate risk by the pc should undergo a physical capacity assessment, there hasn't been a direct comparitable 4. characteristics of patients who underwent a cardiac procedure or a major adverse cardiovascular event (mace). patients mace cardiac iii princeton esc intervention consensus guidelines 1 not ocurred angioplasty non-low risk non-low risk 2 ocurred mi bypass low-risk non-low risk 3 ocurred vt icd non-low risk non-low risk 4 not ocurred mitraclip non-low risk non-low risk 5 not ocurred valvuloplasty non-low risk non-low risk archivio italiano di urologia e andrologia 2024; 96(4):12427 5 reassessing cardiovascular risk stratification in men with erectile dysfunction son with other risk models, nor has a definitive threshold for the 10-year cvd event risk, needing stress testing, been explored. yet, this approach appears the most patient-focused method for evaluating these patients. notably, there was only one reported case of myocardial infarction, and it occurred in a patient classified as "low risk" according to the pc criteria. in contrast, the esc criteria categorized that patient as "high risk". however, despite the different risk stratifications, the study did not find significant differences in the risk of maces between the "low risk" and "non-low risk" groups. this can be attributed to the infrequency of these events during the relatively brief study period, or, to a lesser extent, to a well-timed preventive intervention. using roc curves helped us pinpoint a 5% 10-year cvd risk threshold from the score2/score2-op model, which struck a balance between sensitivity and specificity when compared to the pc. however, we observed that for "low risk" patients defined by the pc, 40.7% of patients still exhibited a 10-year mace risk surpassing 5%. this finding underscore, again, the significant differences between these two models and the importance of selecting the appropriate model and cutoff values when assessing cardiovascular risk. this study possesses some limitations. firstly, its retrospective design renders it susceptible to potential biases in data collection. nonetheless, it's important to note that all patients underwent interviews conducted by the same urologist, and the quality of registries was classified as highly reliable. secondly, while the collected risk factors were considered dependable, the reference to the presence of family history of premature coronary artery disease were inconsistent and was consequently excluded from the analysis as a potential risk factor. finally, the limitations stemming from the sample size, potential data loss during follow-up, and its duration proved inadequate for comprehensively assessing the clinical implications regarding the incidence of maces between the models. ultimately, alternative risk models like the esc recommendations may enhance the assessment of patients with cvd. this stresses the pertinence of the updates in princeton 4, from the previous princeton 3. conclusions the study underscores that the pc exhibits lower sensitivity compared to the esc recommendations to stratify the cvd risk of european men. this disparity raises concern that urologists could be overlooking patients with undiagnosed cardiovascular disease, thereby missing critical opportunities for timely prevention of maces and premature deaths. this underscores the relevance of the updates in princeton 4 compared to the previous princeton 3. the eau guidelines should be revised accordingly, taking into account the optimal risk model for the european patient population. references 1. partin aw, peters ca, kavoussi lr, et al. campbell walsh wein urology: 3-volume set. elsevier; 2020. 2. selvin e, burnett al, platz ea. prevalence and risk factors for erectile dysfunction in the us. am j med. 2007; 120:151-157. 3. ayta ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-56. 4. braun m, wassmer g, klotz t, et al. epidemiology of erectile dysfunction: results of the “cologne male survey.” int j impot res. 2000; 12:305-311. 5. loscalzo j, fauci as, kasper dl, et al. harrison’s principles of internal medicine, twenty-first edition (vol.1 & vol.2). mcgraw hill professional; 2022. 6. townsend n, kazakiewicz d, lucy wright f. epidemiology of cardiovascular disease in europe. nat rev cardiol . published online 2022. doi:10.1038/s41569-021-00607-3 7. sexual and reproductive health. uroweb european association of urology. accessed august 23, 2023. https://uroweb.org/guidelines/sexual-and-reproductive-health 8. how to evaluate cardiovascular risk in a patient with erectile dysfunction. american college of cardiology. accessed august 23, 2023. https://www.acc.org/latest-in-cardiology/articles/2014/07/18/ 16/01/how-to-evaluate-cardiovascular-risk-in-a-patient-with-erectile-dysfunction 9. nehra a, jackson g, miner m, et al. the princeton iii consensus recommendations for the management of erectile dysfunction and cardiovascular disease. mayo clin proc. 2012; 87:766-778. 10. thompson im, tangen cm, goodman pj, et al. erectile dysfunction and subsequent cardiovascular disease. jama. 2005; 294:29963002. 11. schouten bw, bohnen am, bosch jl, et al. erectile dysfunction prospectively associated with cardiovascular disease in the dutch general population: results from the krimpen study. int j impot res. 2008; 20:92-9. 12. gazzaruso c, solerte sb, pujia a, et al. erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase inhibitors. j am coll cardiol. 2008; 51:2040-4. 13. araujo ab, hall sa, ganz p, et al. does erectile dysfunction contribute to cardiovascular disease risk prediction beyond the framingham risk score? j am coll cardiol. 2010; 55:350-6. 14. böhm m, baumhäkel m, teo k, et al. erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: the ongoing telmisartan alone and in combination with ramipril global endpoint trial/telmisartan randomized assessment study in ace intolerant subjects with cardiovascular disease (ontarget/transcend) trials. circulation 2010; 121:1439-46. 15. jackson g, boon n, eardley i, et al. erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus. int j clin pract. 2010; 64:848-57. 16. david batty g, li q, czernichow s, et al. erectile dysfunction and later cardiovascular disease in men with type 2 diabetes: prospective cohort study based on the advance trial. j am coll cardiol 2010; 56:1908-13. 17. dong jy, zhang yh, qin lq. erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. j am coll cardiol. 2011; 58:1378-85. 18. diaconu cc, manea m, marcu dr, et al. the erectile dysfunction as a marker of cardiovascular disease: a review. acta cardiol 2020; 75:286-292. archivio italiano di urologia e andrologia 2024; 96(4):12427 j. lorigo, d.m. gomes, a.r. ramalho, et al. 6 19. corona g, rastrelli g, isidori am, et al. erectile dysfunction and cardiovascular risk: a review of current findings. expert rev cardiovasc ther 2020; 18:155-164. 20. yannas d, frizza f, vignozzi l, et al. erectile dysfunction is a hallmark of cardiovascular disease: unavoidable matter of fact or opportunity to improve men’s health? j clin med res. 2021; 10:2221. 21. imprialos k, koutsampasopoulos k, manolis a, doumas m. erectile dysfunction as a cardiovascular risk factor: time to step up? curr vasc pharmacol 2021; 19:301-312. 22. seidu s, cebrián a, kunutsor sk, khunti k. erectile dysfunction, phosphodiesterase-5 inhibitor use and risk of cardiovascular disease and mortality in people with diabetes: a systematic review and metaanalysis. prim care diabetes 2022; 16:601-613. 23. visseren flj, mach f, smulders ym, et al. 2021 esc guidelines on cardiovascular disease prevention in clinical practice. eur heart j. 2021; 42:3227-3337. 24. kloner ra, burnett al, miner m, et al. princeton iv consensus guidelines: pde5 inhibitors and cardiac health. j sex med. 2024; 21:90-11. 25. goff dc jr, lloyd-jones dm, bennett g, et al. 2013 acc/aha guideline on the assessment of cardiovascular risk: a report of the american college of cardiology/american heart association task force on practice guidelines. circulation. 2014; 129(25 suppl 2):s49-s73. 26. li d, li x, peng e, et al. do urologists really recognize the association between erectile dysfunction and cardiovascular disease? sex med today 2020; 8:195-204. 27. score2 working group and esc cardiovascular risk collaboration. score2 risk prediction algorithms: new models to estimate 10year risk of cardiovascular disease in europe. eur heart j. 2021; 42:2439-2454. 28. vlachopoulos cv, terentes-printzios dg, ioakeimidis nk, et al. prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohort studies. circ cardiovasc qual outcomes. 2013; 6:99-109. 29. mostafaei h, mori k, hajebrahimi s, et al. association of erectile dysfunction and cardiovascular disease: an umbrella review of systematic reviews and meta-analyses. bju int. 2021; 128:3-11. 30. gandaglia g, briganti a, jackson g, et al. a systematic review of the association between erectile dysfunction and cardiovascular disease. eur urol. 2014; 65:968-978. 31. raheem oa, su jj, wilson jr, hsieh tc. the association of erectile dysfunction and cardiovascular disease: a systematic critical review. am j mens health. 2017; 11:552-563. 32. erectile dysfunction (ed) guideline american urological association. accessed august 28, 2023. https://www.auanet.org/ guidelines-and-quality/guidelines/erectile-dysfunction-(ed)-guideline 33. kostis jb, jackson g, rosen r, et al. sexual dysfunction and cardiac risk (the second princeton consensus conference). am j cardiol. 2005; 96:313-321. correspondence joão diogo abreu lorigo (corresponding author) joaolorigo@gmail.com centro hospitalar e universitário de coimbra rua vale rosal, lote 18, 1d, 3040-321, coimbra, portugal daniela gomes unidade de saúde familiar serra da lousã, vilarinho, portugal danielasmgomes20@gmail.com ana rita ramalho arita.gcr@gmail.com edgar silva edsilva.elv@gmail.com patrícia mendes patricia.a.mendes@chuc.min-saude.pt arnaldo figueiredo ajcfigueiredo@gmail.com centro hospitalar e universitário de coimbra, coimbra, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso 445archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. continence society (ics) as “passing large volume of urine during the main sleep period” (8, 9). among men complaining of nocturia, the prevalence rate of np is quite high, ranging from 76 to 88%, and up to 93% in those aged ≥ 65 years old (3). in a large community study, the prevalence of np was confirmed high, with a prevalence of 77.8% of the whole studied population (9); np has been demonstrated more prevalent in men with nocturia (91.9%) compared to those without this condition (70.1%) (10). thereby, a lot of males complaining of nocturia might be affected by an underlying condition of np, which might remain unidentified and consequently not adequately treated whether a bladder diary or a frequency volume chart (fvc) has not been used. males with luts including nocturia, usually perform uroflowmetry (uf) as a first step assessment, since these symptoms are commonly considered suggestive of bladder outlet obstruction (boo)/benign prostatic hyperplasia (bph). in these subjects, np is rarely investigated before the uf and, consequently, the prevalence of nocturia remains unknown. similarly, also most commonly luts associated with men with an underlying np condition who are candidates for uf is undetermined. np mainly influences the bladder storage phase, and therefore this disorder is not expected to play an essential role in the voiding phase. however, there is still no conclusive data showing, in real-life practice, the rate of men with an underlying np condition performing uf for luts and studies excluding with certainly an impact of np on uf results. this study aimed to assess the prevalence of np in males performing uf for luts and the influence of np on uf outcomes. we also evaluated whether np was significantly associated with nocturia, with other urinary symptoms investigated by ipss questionnaire, and with the bother due to luts in males scheduled for uf. finally, an analysis of the relationship between np and patient’s age was also performed. materials and methods between september 2017 and january 2019, all consecutive men with luts scheduled for uf execution were purpose: to assess the prevalence of nocturnal polyuria (np) in males performing uroflowmetry (uf) for lower urinary tract symptoms (luts), the impact of np on uf outcomes, and bladder emptying, the association between np and luts. materials and methods: men scheduled for uf were recruited in two centres. data collected were medical history, ipss, uf, post-void residual urine volume (pvr), 3-day frequency-volume charts (fvc). the np index was used to assess np with a threshold of ≥ 33%. the relationship between np and patient’s aging was assessed. results: 162 patients were included in the analysis. mean age was 70.95 ± 8.04 years. the prevalence of np was 54.9% (89/162). 110 (68%) patients reported nocturia, and among these, np was documented in 76 (69%). nocturia was found in 85% (76/89) of the population with np. total ipss score, ipss items #1, #2 and #7 showed a significant difference in men with np compared with those without. maximum flow rate and pvr did not significantly change comparing men with or without np. mean voiding volume (vv) of the night-time micturitions was significantly higher in men with np compared to those without np (532.1 ± 275.6 ml vs 175 ± 168.7 ml respectively, p < 0001), while mean vv day-time micturitions and mean vv at uf did not change between groups. conclusions: np had a high prevalence in men with luts performing uf. aged males were more commonly affected by np. data demonstrated a strong relationship between np and nocturia and increased urinary frequency while voiding symptoms were poorly related to np. key words: nocturnal polyuria; nocturia; uroflowmetry; lower urinary tract symptoms; male. submitted 12 january 2021; accepted 5 march 2021 introduction the complaining of lower urinary tract symptoms (luts) is one of the most common causes that lead men to seek urological attention. among luts, nocturia is one of the most bothersome (1) and it is frequently caused by nocturnal polyuria (np), even in neurological patients (2-6). np is a multifactorial disorder (7), defined by the international nocturnal polyuria in men performing uroflowmetry for lower urinary tract symptoms emanuele rubilotta 1, daniele castellani 2, marilena gubbiotti 3, matteo balzarro 1, giacomo maria pirola 3, rita righetti 4, pierpaolo curti 4, antonella giannantoni 5, maria angela cerruto 1, alessandro antonelli 1 1 urology clinic, a.o.u.i of verona, verona, italy; 2 department of urology, irccs inrca, ancona, italy; 3 department of urology, san donato hospital, usl toscana sud-est, arezzo, italy; 4 department of urology, aulss 9, ospedale mater salutis, legnago, italy; 5 functional and surgical urology unit, department of medical and surgical sciences and neurosciences, university of siena, siena, italy. doi: 10.4081/aiua.2021.4.445 summary archivio italiano di urologia e andrologia 2021; 93, 4 e. rubilotta, d. castellani, m. gubbiotti, et al. 446 screened in outpatient clinics of two tertiary hospitals for study inclusion. the experimental procedures were carried out in accordance with the declaration of helsinki. this research was registered in our department clinical audit. all patients signed written informed consent. data collected were a detailed medical history, selfadministered international prostate symptom score (ipss) questionnaire, uf, post-void residual urine volume (pvr) measured by ultrasound, and 3-day fvc, indicating “bedtime” and “waking time”. the 3-day fvc was delivered to patients at the time the uf was scheduled and was returned by patients on the day of uf execution. increased urinary frequency, urinary urgency, voided volume (vv), and nocturnal urine production were assessed by 3-day fvc. nocturia was defined as at least one episode of nocturnal voiding at 3-day fvc. the nocturnal polyuria index (npi) was used to assess np (8). npi is calculated by dividing the amount of nocturnal urine production by 24-hour production, and the threshold of 33% is the most accepted cut-off (8). therefore, we used a cut-off of npi ≥ 33% of the total 24-h urine production to diagnose np. thus, patients were divided into two groups: group a comprising males with npi < 33% (no np patients) and was the control group, and group b including men with npi ≥ 33% (np patients). inclusion criteria were age≥18 years, complete filling of both fvc and ipss, uf with a voided volume higher than 150ml as suggested by ics recommendation on good urodynamic practices (11). exclusion criteria were all conditions that could be confounding factors, as following: surgery of lower urinary tract (prostatectomy, radical prostatectomy, radical cystectomy, bladder, and urethral surgery), pelvic radiation, urolithiasis, double j stent, and urinary devices, and recurrent lower urinary tract infection. the relationship between np and maximum flow rate (qmax), vv at uf, and pvr after uf was evaluated. a comparison between the vv of the day-time and night-time micturitions was also assessed in each group. the vv of day-time and night-time micturitions and at uf were also compared between the two groups. the association between np and urinary symptoms was evaluated through the ipss questionnaire, analyzing the ipss total score and all ipss item scores. according to the last “ics report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction”, we divided the urinary symptoms reported by ipss questionnaire as following: ipss item #1 -feeling of incomplete bladder emptyingas a “postvoiding symptom”; ipss item #2 -increased urinary frequency, ipss item #4 urgency, ipss item #7 -nocturiaas “storage symptoms”; ipss item #3 -intermittency, ipss item #5 -slow urinary stream, ipss item #6 -straining to voidas “voiding symptoms” (9). the sub-analysis, according to patients’ age, was also performed, distributing the patients into three groups according to age: 1) < 65 years, 2) between 65 and 74 years, and 3) ≥ 75 years. statistical analysis statistical analysis was performed with ibm-spss v.17 for windows (ibm corp, armonk, ny, usa). student’s t-test and the mannwhitney u test were performed to compare continuous parametric and nonparametric variables, as appropriate. continuous variables were reported as mean ± sd. all values in the text and tables are expressed as mean ± sd. statistically significant results were p < or equal to 0.05. spearman correlations were used to test for the strength of linear association between variables along with the wilcoxon and mann-whitney. x2 test was also used. multiple linear regression analysis was performed evaluating np and the following variables: npi, total nocturnal diuresis, total daily (24 hours) diuresis, qmax, pvr, age, cardiologic disease and diuretic drugs. results during the study period, 254 men met inclusion criteria and were enrolled in the study. data on uf, pvr, and both ipss and 3-day fvc were completed in 162/254 (63.8%) patients, who were included in the analysis. table 1 shows the patients’ characteristics. mean age was 70.95 ± 8.04 years. among males aged lower than 65 years (group i), one patient was 47 years old, and the remaining were older than 52 years. eighty-eight (54.3%) patients were on urological therapy and 44 (27.1%) on cardiological treatment. only 15 (9.2%) patients were on diuretics, and 7 (4.3%) were diabetic. the prevalence of np was 54.9% (89/162 patients) with a mean npi of 34.4 ± 11.2. table 2 reports the rate of np according to age, and table 3 the comparison between the groups stratified by age. younger males were the smaller group (n = 34), but with the highest np rate (64.7%). 75% of the men affected by np were aged ≥ 65 years old. finally, we found a positive association between np and age only in the group of men 65-74 years-old (p < 0.05). one-hundred-ten (68%) patients reported nocturia, and among these, np was documented in 76 (69%). nocturia was found in 85% (76/89) of the population with np. total ipss score, ipss items #1, ipss items #2 and #7 showed a significant difference in men with np compared with those without this disorder (table 4). the maximum flow rate and pvr did not significantly change in the two groups of males (table 4). multiple regression analysis showed a significant correlation between np and npi, total nocturnal diuresis, total 24 h daily diuresis, age, cardiologic disease, and diuretic drugs (r = 0.96; p = 0.001), but not with qmax and pvr (r = 2; p = 0.8). table 1. patients’ characteristics. patients (n = 162) n (%) patients in cardiological therapy 44 (27.1) diuretic therapy 15 (9.2) non diuretic therapy for hypertension 24 (14.8) antiarrhythmics 9 (5.5) antiplatelets/anticoagulants 11 (6.7) diabetes therapy 7 (4.3) patients in urological therapies 88 (54.3) α1-blockers 62 (38.3) 5α-reductase inhibitors 25 (15.4) α1-blockers + 5α-reductase inhibitors 11 (6.8) phytotherapy 1 (0.6) 447archivio italiano di urologia e andrologia 2021; 93, 4 nocturnal polyuria in men performing uroflowmetry table 5 reports data on the comparison of the mean vv of the micturitions at night-time, day-time, and at uf between the two groups. mean vv of the night-time micturitions was significantly higher in men with the diagnosis of np compared to those without np recorded at fvc (p < 0001). mean vv of the micturitions during the daytime and measured at uf was not statistically different between the two groups. however, volumes were slightly higher in group a. in group a, the mean vv of micturitions at day-time was 222.1 ± 83.1 ml, while at nighttime was 175.2 ± 168.7 (p = 0.03). conversely, in group b mean vv of micturitions at day-time was significantly lower than at night-time, 213.7 ± 79.4 ml, and 532.1 ± 275.6 ml respectively (p = 0.0001). total daily (24-hours) diuresis was 757.8 ± 73.7 ml in group a, and 1095.6 ± 103.8 ml in group b (p < 0.0001). total nocturnal diuresis was 223.8 ± 64.1 ml in group a, and 587.1 ± 86.6 ml in group b (p < 0.0001). the mean nocturnal number of voids was 0.8 ± 0.7 in group a, and 1.9 ± 1 in group b (p < 0.0001). discussion to date, the prevalence of np in men candidates to uf for luts, and the impact of np on bladder emptying, have been poorly investigated (12). our study demonstrated a high np prevalence (54.9%) in men performing uf for luts. in this cohort, np was a common condition, identified by fvc in more than half of the cases. the rate of np was lower than the data reported in community studies (10, 13). nevertheless, it was comparable to the np prevalence reported in the caucasian population, and cohorts of men with luts (1416). the high rate of np in this selected population of men performing uf for luts may be explained by the age and comorbidities of the patients, and by the coexistence of np with other pathological conditions, such as boo/bph or overactive bladder (oab) syndrome, which may cause luts. another reason could be that np, due to the related luts, in some cases could be confused with other clinical conditions needing an investigation with uf. in our series, np had a relevant association with most of the storage symptoms, mainly nocturia, and with postvoiding symptoms, but not with voiding symptoms. at the same time, the parameters related to voiding and bladder emptying, such as qmax and pvr, did not change significantly between the two groups of patients. therefore, in our cohort, data on luts and uf demonstrated that np had a significant impact on the bladder filling phase, but only a limited effect on the voiding phase. men who referred mainly storage symptoms, complaining mostly of nocturia, and reported only a few voiding/postvoiding symptoms, were the most likely patients to be affected by np. these males should be investigated with fvc in addition to symptomatic questionnaires, and to uf with pvr, to avoid misleading diagnosis, useless examinations, and treatments. symptomatic questionnaires, as ipss, are useful to define the patient’s luts, but they are not able to identify np. these tools cannot assess whether nocturia was a symptom correlated to boo/bph or oab, or, conversely, to the large amount of nocturnal urine which, continuously filling the bladder, leads the patient to awake. this latter pathophysiological mechanism was demonstrated by our data, showing that the mean vv of night-time micturitions was significantly higher in men with nocturia and np. in males with unidentified np, when nocturia is mistakenly evaluated as a boo/bph or oab symptom, inappropriate therapies with alpha-blockers or anticholinergics agents may be offered to patients. the outcomes of these latter treatments have been reported as unsuccessful on np and poorly effective on nocturia, and thus should be avoided (3, 12, 16). in men with boo/bph, usually voiding symptoms are table 2. nocturnal polyuria prevalence according to patients’ age. age (years) npi < 33% npi ≥ 33% (n = 73) (n = 89) < 65 (n = 34) 12 (35.3) 22 (64.7%) 65-74 (n = 66) 34 (51.6%) 32 (48.4%) ≥ 75 (n = 62) 27 (43.6%) 35 (56,4%) tot n = 162 73 (45.0%) 89 (55%) npi: nocturnal polyuria index. table 3. comparison between patients with npi > 33% stratified by age. npi ≥ 33% < 65 (n = 34) 65-74 (n = 66) ≥ 75 (n = 62) p 22 (64.7%) 32 (48.4%) 0.4 32 (48.4%) 35 (56.4%) 0.05 22 (64.7%) 35 (56.4%) 0.5 npi: nocturnal polyuria index. table 5. comparison between voiding volume of day-time and nighttime micturition and voiding volume on uroflowmetry stratified according to nocturnal polyuria index. npi < 33% (n = 73) npi ≥ 33% (n = 89) p vv of night-time micturition, mean ± sd 175.2 ± 168.7 532.1 ± 275.6 0.0001 vv of day-time micturition, mean ± sd 222.1 ± 83.1 213.7 ± 79.4 0.5 vv at uf, mean ± sd 267.1 ± 136.3 246.7 ± 109.7 0.2 npi: nocturnal polyuria index; vv: voiding volume. table 4. correlations between np and ipss scores, maximum flow rate, and post-void residual urine volume. npi < 33% (n = 73) npi ≥ 33% (n = 89) p ipss score, mean ± sd item # 1 1.0 ± 1.5 1.2 ± 1.6 0.002 item # 2 1.0 ± 1.1 1.6 ± 0.9 0.00 item # 3 0.9 ± 1.4 1.4 ± 1.8 0.4 item # 4 0.7 ± 1.2 0.7 ± 1.4 1 item # 5 1.3 ± 1.5 1.6 ± 1.9 0.07 item # 6 0.4 ± 0.8 0.6 ± 1.3 0.2 item # 7 1.5 ± 0.4 2.5 ± 0.7 0.00 item # 8 1.9 ± 0.8 1.9 ± 1.1 0.06 total 6.5 ± 3.5 9.8 ± 6.7 0.00 qmax (mean ± sd) 13.4 ± 2.5 11.6 ± 2.6 0.08 pvr (mean ± sd) 40.05 ± 30.2 37.8 ± 20.9 0.2 npi: nocturnal polyuria index; ipss: international prostate symptom score; qmax: maximnum flow rate; pvr: post-void residual. archivio italiano di urologia e andrologia 2021; 93, 4 e. rubilotta, d. castellani, m. gubbiotti, et al. 448 prevalent, and abnormal uf parameters are often associated with this condition (17). conversely, our data showed that men with np had no voiding symptoms, and both qmax and pvr were not associated with np, because the uf outcomes did not significantly differ between men affected by np and males without np. these results support the finding that np is scarcely related to voiding dysfunctions, as was also supposed by a study on a small sample size of men with luts suggestive of bph performing uf (12). in this small population, the rate of np was 95%, and in 75% of these patients, np did not significantly vary after alpha-blockers therapy, although an increase in qmax was found in the treated men (12). hence, males with np may have concomitant boo/bph, but usually, the latter is not the leading cause of np. for this reason, conventional boo/bph treatments often poorly influence np conditions. the other pathological condition which should be distinguished from np is represented by oab syndrome, defined by “urinary urgency, usually accompanied by increased daytime frequency and nocturia, with or without urinary incontinence” (9). in our cohort, np was significantly associated with increased urinary frequency and nocturia, but not with urinary urgency, which is one of the most characterizing symptoms of oab (9). furthermore, oab syndrome is often accompanying by a reduced vv, which was not observed in np patients of our study. finally, the reporting of mainly storage symptoms, as frequency and nocturia, without urgency, and with no reduced vv at fvc, might be considered as a “red-flag” for differentiating between oab and np. an accurate assessment of luts and fvc, in addition to the other first-step office evaluations, may aid in the achievement of a correct differential diagnosis. our study confirmed previous data on the very close relationship between nocturia and np (2-4, 14, 15). the majority of the males with np reported concomitant nocturia (85%), due to the increased nocturnal urine production, which led them to awake. on the other hand, patients reporting nocturia also demonstrated a high rate of np (69%). therefore, in males affected by nocturia, a concomitant np should be supposed and should be investigated appropriately with fvc. furthermore, our study confirmed that, also in men performing uf for luts, severe nocturia associated with vv significantly lower at day-time than at night-time might warn on a condition of np (18). feeling of incomplete bladder emptying, a postvoiding symptom, was significantly associated with np. patients affected by np showed a higher severity of frequency and nocturia. therefore, men with np might be more concerned by the increased need to urinate, and consequently, they may have a greater sensation of not having completely emptied the bladder. furthermore, in men with np, the mean vv of the night-time micturitions was more than twice compared to the mean vv of the day-time, and significantly higher than the mean vv of micturitions at night of patients with no np. the excessive night-time urine production may cause recurrent nocturnal overstretching of detrusor fibers, as the high nocturnal vv documented, leading patients to a worse bladder emptying and, as a consequence, to a greater feeling of incomplete bladder emptying. moreover, the increased night-time bladder capacity may amplify the feeling of bladder filling even after micturition. these reasons may also explain the higher rate of increased urinary frequency in np males. the quality of life (ipss item #8) was not significantly associated with np in our study. patients enrolled during a uf, might have been more concerned by micturition and bladder emptying, which are poorly influenced by np. this could be a possible explanation of this finding and could be a limit of our study. np was more prevalent in younger males, but this result may be related to the low number of younger men included in our study. indeed, we found that np increased with age, showing that 75% of men with np were aged ≥ 65 years old. data also showed a significant association between np rate and age in the older males, although not in the oldest (> 75 years). the relationship between np and aging might be influenced by population selection, race, npi criteria, and sample size. most of the literature data on np have been reported considering the general population or in community cohorts. conversely, our cohort included only males with luts performing uf, with strict inclusion/exclusion criteria, and these parameters may have influenced our findings on aging. the strength of our study was the finding of the relevant prevalence of np on a large sample size of males performing uf for luts. our data also demonstrated that np has a limited impact on micturition and bladder emptying. these latter data could only have been hypothesized, but not documented, before our study. another strong point of our research was the identification, among the main storage symptoms, of those significantly associated with men with np who perform uf for luts, and the uncovering of the voiding/postvoiding symptoms most commonly reported by these patients. hence, the value of our study was to recognize the "warning symptoms" of men with np, among the males scheduled for the uf for luts. a limit of our study was the lack of repeated ufs, due to the real-practice design of the present research. another limit was the low sample size of the younger people, which was smaller than the other age groups. the choice of the npi threshold of 33% might be a further limitation of the study. however, we have used this cut-off because it is one of the most accepted. furthermore, there were only a few younger males in our study, and a lower threshold could have been useful in cohorts comprising younger patients than those enrolled in our study. a further limitation of the research is that np has been correlated only with the urinary symptoms reported by the ipss questionnaire, and not with all the luts. however, these symptoms are the most commonly complained by the males and assessed by clinicians. the strict inclusion/exclusion criteria led to reducing the number of males recruited in the study. the choice of these stringent parameters may have been a limit of this research, but allowed us to reduce potential biases and achieve more reliable data on the prevalence and impact of np in men with luts performing uf. conclusions in conclusion, our study highlighted that urologists should always look for np among men who report noc449archivio italiano di urologia e andrologia 2021; 93, 4 nocturnal polyuria in men performing uroflowmetry turia and mainly storage symptoms, and only mild emptying/postvoiding symptoms. both ipss and fvc are needed to diagnose np accurately, while uf with pvr assessment is useful for excluding potential associated pathological conditions. references 1. agarwal a, eryuzlu ln, cartwright r, et al. what is the most bothersome lower urinary tract symptom? individualand population-level perspectives for both men and women. eur urol 2014; 65:1211-17. 2. fujimura t, yamada y, sugihara t, et al. nocturia in men is a chaotic condition dominated by nocturnal polyuria. int j urol 2015; 22:496-501. 3. weiss jp, van kerrebroeck pev, klein bm, nørgaard jp. excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. j urol 2011; 186:1358-63. 4. chang sc, lin atl, chen kk, chang ls. multifactorial nature of male nocturia. urology 2006; 67:541-4. 5. haddad r, denys p, arlandis s, et al. nocturia and nocturnal polyuria in neurological patients: from epidemiology to treatment. a systematic review of the literature. eur urol focus 2020; 6:922-34. 6. birder la, van kerrebroeck pev. pathophysiological mechanisms of nocturia and nocturnal polyuria: the contribution of cellular function, the urinary bladder urothelium, and circadian rhythm. urology 2019; 133:14-23. 7. cornu jn, abrams p, chapple cr, et al. a contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management a systematic review and meta-analysis. eur urol. 2012; 62:877-90. 8. van kerrebroeck p, abrams p, chaikin d, et al. the standardisation of terminology in nocturia: report from the standardisation subcommittee of the international continence society. neurourol urodyn. 2002; 21:179-83. 9. d’ancona c, haylen b, oelke m, et al. the international continence society (ics) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. neurourol urodyn. 2019; 38:433-77. 10. van doorn b, blanker mh, kok et, et al. prevalence, incidence, and resolution of nocturnal polyuria in a longitudinal community-based study in older men: the krimpen study. eur urol. 2013; 63:542-7. 11. gammie a, drake mj. the fundamentals of uroflowmetry practice, based on international continence society good urodynamic practices recommendations. neurourol urodyn. 2018; 37: s44-s49. 12. koseoglu h, aslan g, ozdemir i, esen a. nocturnal polyuria in patients with lower urinary tract symptoms and response to alphablocker therapy. urology 2006; 67:1188-92. 13. swithinbank l v, vestey s, abrams p. nocturnal polyuria in community-dwelling women. bju int 2004; 93:523-7. 14. mariappan p, turner kj, sothilingam s, et al. nocturia, nocturia indices and variables from frequency-volume charts are significantly different in asian and caucasian men with lower urinary tract symptoms: a prospective comparison study. bju int. 2007; 100:332-6. 15. klingler hc, heidler h, madersbacher h, primus g. nocturia: an austrian study on the multifactorial etiology of this symptom. neurourol urodyn. 2009; 28:427-31. 16. yoong hf, sundaram mb, aida z. prevalence of nocturnal polyuria in patients with benign prostatic hyperplasia. med j malaysia. 2005; 60:294-6. 17. thorner da, weiss jp. benign prostatic hyperplasia: symptoms, symptom scores, and outcome measures. urol clin north am. 2009; 36:417-29. 18. presicce f, puccini f, de nunzio c, et al. variations of night-time and daytime bladder capacity in patients with nocturia: implication for diagnosis and treatment. j urol. 2019; 201:962-6. correspondence emanuele rubilotta, md emanuele.rubilotta@aovr.veneto.it matteo balzarro, md matteo.balzarro@aovr.veneto.it maria angela cerruto, md (corresponding author) mariaangela.cerruto@univr.it alessandro antonelli, md alessandro.antonelli@univr.it urology clinic, a.o.u.i of verona, verona (italy) daniele castellani, md d.castellani@inrca.it department of urology, irccs inrca, ancona (italy) marilena gubbiotti, md marilena.gubbiotti@gmail.com giacomo maria pirola, md giacomomaria.pirola@uslsudest.toscana.it department of urology, san donato hospital, usl toscana sud est, arezzo (italy) rita righetti, md rita.righetti@aulsslegnago.it pierpaolo curti, md pierpaolo.curti@aulss9.veneto.it department of urology, aulss 9, ospedale mater salutis, legnago (italy) antonella giannantoni, md antonella.giannantoni@unisi.it functional and surgical urology unit, department of medical and surgical sciences and neurosciences, university of siena, siena (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12404 1 letter to editor key words: bladder cancer; office fulguration; office laser; local bladder treatment; nmibc. submitted 20 february 2024; accepted 23 february 2024 to the editor, bladder cancer is one of the most common cancers in humans, representing the 7th and 17th type of neoplasm in both genders (1). its incidence and mortality are quite heterogeneous in different countries and are due to different risk factors, quality and prevalence of healthcare and the possibility of early diagnosis and treatment of the tumor and its potential recurrences (2-3). bladder cancer can be divided into muscle-invasive (mibc) and non-muscle invasive (nmibc). early detection of the primary tumors and the recurrences is of paramount importance to enable a better prognosis (3). while mibc is known to be treated very aggressively, i.e. with surgery, radiotherapy, and chemotherapy (4-8), nmibc has a better prognosis but still has a high recurrence rate despite measures such as the use of local drugs. although most of these recurrences in low-grade tumors guarantee a good prognosis if treated promptly with turb, they still pose a management problem for both the patient and the healthcare system. indeed, the patient is often forced to undergo multiple anesthesia, surgical and psychophysical stress related to hospitalization and the anxiety of the operation itself. furthermore, performing a transurethral resection of the bladder (turb) may lead to transport management issues and organization problems for the patient's family. from a healthcare perspective, hospitalization for turb requires an economic cost of several thousand euros, considering the cost of the surgical staff, the materials used during the operation and the hospital stay (9, 10). furthermore, this contributes to longer waiting lists, which also has a negative impact on other patients. this problem is highly relevant, given the organizational problems of healthcare systems and surgical waiting lists in the post-covid era (11). last but not least, there is the "green" problem considering that further hospitalization requires more surgical and hospital supplies, an increase in travel for patients and relatives, and thus an impact on the carbon footprint. the eau guidelines also include office-based fulguration and laser vaporization among the possible treatment options for nmibc (3). specifically, it states that that patients with a history of small ta lg/g1 lesions can undergo fulguration or laser vaporization on an outpatient basis for small papillary recurrences. outpatient treatment can be performed either by fulguration or using laser, generally under local anesthesia with instillation of intravesical lidocaine prior to the procedure and may warrant histologic examination by pre-fulguration biopsy. if hg is found, the patient can then be scheduled for turb in the following weeks. the literature now presents numerous reports on the efficacy and safety of performing office-based procedures for the treatment of nmibc (12-19). recently, vitug et al. evaluated the outcomes of fulguration in 270 patients with recurrent talg nmibc in an outpatient setting (20). the 10-year incidence of cancer-specific mortality (csm) and progression were office-based management of non-muscle invasive bladder cancer (nmibc): a position paper on current state of the art and future perspectives rosario leonardi 1, 2, francesca ambrosini 3, angelo cafarelli 4, 2, alessandro calarco 5, 2, renzo colombo 6, 2, domenico tuzzolo 2, ferdinando de marco 7, 2, giovanni ferrari 8, 2, giuseppe ludovico 9, 2, stefano pecoraro 10, 2, ottavio de cobelli 11, 2, carlo terrone 12, guglielmo mantica 12 1 casa di cura musumeci gecas, gravina di catania, italy; 2 urologi ospedalità gestione privata (urop), italy; 3 irccs policlinico san martino, genova, italy; 4 urology unit, villa igea, ancona, italy; 5 villa pia hospital, rome, italy; 6 department of urology, vita e salute san raffaele university, milan, italy; 7 i.n.i. grottaferrata, rome, italy; 8 hesperia hospital, modena, italy; 9 ospedale miulli, acquaviva delle fonti, bari, italy; 10 neuromed, avellino, italy; 11 department of urology, ieo european institute of oncology, irccs, milan, italy; 12 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy. doi: 10.4081/aiua.2024.12404 archivio italiano di urologia e andrologia 2024; 96(1):12404 r. leonardi, f. ambrosini, a. cafarelli, et al. 2 0% and 3.1%, respectively. they estimated a savings of nearly 7,000 canadian dollars per patient. the savings in economic terms have also been demonstrated by other authors in other contexts (15, 21-23). pedersen et al. in a prospective randomized controlled trial proved that laser photocoagulation in an outpatient setting is non-inferior to standard turb for the 4-month recurrence rate (24). halstuch et al. introduced an additional step, namely the use of a single dose of mitomycin (mmc), after performing office-based procedures such as fulguration (25). they found that a single dose of mmc instilled after fulguration was associated with longer recurrence free survival (rfs) compared to patients who did not receive mmc after the procedure, with no high-grade complications. one of the potential limitations of office-based procedures is the pain experienced by the patient. however, strock et al. evaluated the pain perceived by patients during the procedure and obtained satisfactory results in this respect. the vas scores after diagnostic cystoscopy report no or only mild pain in the totality of their case series. despite the current evidence, we are still far from knowing which patients are safe candidates for these procedures (number of lesions, size of lesions, number of previous turb with histologic pta lg/g1, age, etc.) and to consider these procedures the "standard of care" in selected patients. we believe that outpatient treatment of nmibc should be implemented for reasons of economic and environmental sustainability as well as for reasons of benefit to the patient, as illustrated previously. a stronger stance in national and international guidelines in favor of these procedures in selected patients could be of fundamental importance. however, for the committees to move further in this direction, the scientific community must bring results from further randomized trials, perhaps multicenter, which can make the scientific evidence stronger. furthermore, the definition of the ideal candidate for these procedures is un unmet need. since it is now clear that that the patients for whom the treatments are indicated are patients with relapses of a previous pta lg/g1 in the absence of rare variants of bladder cancer, some inclusion criteria need to be defined more precisely such as age, number of recurrences/papillary lesions, time since the last turb, etc. in this sense, the application of new biomarkers could become useful to define the patients with the highest risk and therefore not subject them to office-based treatment. furthermore, the definition of the patient eligible for these procedures is also fundamental. it has now been established that the patients for whom the treatments are indicated are patients with relapses of previous pta lg/g1 in the absence of rare variants of bladder cancer, some inclusion criteria must be defined in more detail such as age, the number of relapses/papillary lesions, time since last turb, etc. in this sense, the application of new biomarkers could become useful to define the patients most at risk and therefore not candidate to office-based treatment (26). in conclusion, we believe that the office-based management of nmibc should be much more under the spotlight of the scientific community. it is essential to properly define either the ideal candidates and the optimal settings. references 1. siregar gp, parwati i, noegroho bs, et al. the association between serum hypoxia inducible factor-1α level and urothelial bladder cancer: a preliminary study. arch ital urol androl. 2023; 95:11292. 2. macdonald a, mehrnoush v, ismail a, et al. history of infantile bcg immunization did not predict lamina propria invasion and/or high-grade in patients with non-muscle invasive bladder cancer. arch ital urol androl. 2023; 95:11380. 3. eau guidelines. edn. presented at the eau annual congress milan 2023. isbn 978-94-92671-19-6. 4. mantica g, smelzo s, ambrosini f, et al. port-site metastasis and atypical recurrences after robotic-assisted radical cystectomy (rarc): an updated comprehensive and systematic review of current evidences. j robot surg. 2020; 14:805-812. 5. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital urol androl. 2021; 93:15-20. 6. malinaric r, mantica g, balzarini f, et al. extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients should it be performed more often? arch ital urol androl. 2022; 94:144-149. 7. slovacek h, zhuo j, taylor jm. approaches to non-muscle-invasive bladder cancer. curr oncol rep. 2021; 23:105. 8. alvarez-maestro m, chierigo f, mantica g, et al. the effect of neoadjuvant chemotherapy among patients undergoing radical cystectomy for variant histology bladder cancer: a systematic review. arab j urol. 2021; 20:1-13. 9. joyce dd, sharma v, williams sb. cost-effectiveness and economic impact of bladder cancer management: an updated review of the literature. pharmacoeconomics. 2023; 41:751-769. 10. richters a, aben kkh, kiemeney lalm. the global burden of urinary bladder cancer: an update. world j urol. 2020; 38:1895-1904. 11. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67. 12. soloway ms. active surveillance or office fulguration for low grade ta bladder tumors: a win-win for patients and urologists. j urol. 2018; 199:1120-1122. 13. xu y, guan w, chen w, et al. comparing the treatment outcomes of potassium-titanyl-phosphate laser vaporization and transurethral electroresection for primary nonmuscle-invasive bladder cancer: a prospective, randomized study. lasers surg med. 2015; 47:306-11. 14. planelles gómez j, olmos sánchez l, cardosa benet jj, et al. holmium yag photocoagulation: safe and economical alternative to transurethral resection in small nonmuscle-invasive bladder tumors. j endourol. 2017; 31:674-678. 15. green da, rink m, cha ek, et al. cost-effective treatment of low-risk carcinoma not invading bladder muscle. bju int. 2013; 111:e78-84. 16. leonardi r, vecco f, iacona g, et al. tula dual: trans urethral laser ablation of recurrent bladder tumors in outpatient setting. arch ital urol androl. 2023; 95:11171. 17. ströck v, holmäng s. is bladder tumour fulguration under local anaesthesia more painful than cystoscopy only? scand j urol. 2020; 54:277280. 18. meeks jj, herr hw. office-based management of nonmuscle invasive bladder cancer. urol clin north am. 2013; 40:473-9. 19. o'neil bb, lowrance wt. office-based bladder tumor fulguration and surveillance: indications and techniques. urol clin north am. 2013; 40:175-82. 20. vitug c, lajkosz k, chavarriaga j, et al. long-term outcomes and cost savings of office fulguration of papillary ta low-grade bladder cancer. bju int. 2024; 133:289-296. 21. al hussein al awamlh b, lee r, chughtai b, donat sm, et al. a cost-effectiveness analysis of management of low-risk non-muscle-invasive bladder cancer using office-based fulguration. urology. 2015; 85:381-6. 22. wong ka, zisengwe g, athanasiou t, et al. outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and costeffective? bju int. 2013; 112:561-7. 23. svatek rs, hollenbeck bk, holmäng s, et al. the economics of bladder cancer: costs and considerations of caring for this disease. eur urol. 2014; 66:253-62. 24. pedersen gl, erikson ms, mogensen k, et al. outpatient photodynamic diagnosis-guided laser destruction of bladder tumors is as good as conventional inpatient photodynamic diagnosis-guided transurethral tumor resection in patients with recurrent intermediate-risk lowgrade ta bladder tumors. a prospective randomized noninferiority clinical trial. eur urol. 2023; 83:125-130. 25. halstuch d, lotan p, karchever i, et al. single-dose post-office fulguration mitomycin c instillation appears to improve recurrence-free survival in patients with low-grade noninvasive bladder cancer. clin genitourin cancer. 2023; 21:e320-e325. 26. malinaric r, mantica g, lo monaco l, et al. the role of novel bladder cancer diagnostic and surveillance biomarkers-what should a urologist really know? int j environ res public health. 2022; 19:9648. archivio italiano di urologia e andrologia 2024; 96(1):12404 3 office-based management of non-muscle invasive bladder cancer (nmibc) conflict of interest: the authors declare no potential conflict of interest. correspondence rosario leonardi, md leonardi.r@tiscali.it casa di cura musumeci gecas, gravina di catania (ct), italy francesca ambrosini, md f.ambrosini1@gmail.com guglielmo mantica, md guglielmo.mantica@gmail.com carlo terrone, md carlo.terrone@hsanmartino.it department of surgical and diagnostic integrated sciences (disc), university of genova, largo rosanna benzi 10, 16132, genova, italy angelo caffarell, md info@angelocafarelli.it urology unit, villa igea, ancona, italy alessandro calarco, md info@alessandrocalarco.com villa pia hospital, via folco portinari 5, rome, italy renzo colombo, md colombo.renzo@hsr.it department of urology, vita e salute san raffaele university, milan, italy domenico tuzzolo, md info@casadelsole.it urologi ospedalità gestione privata (urop), italy ferdinando de marco, md info@clinicavillamargherita.it i.n.i. grottaferrata, rome giovanni ferrari, md visite@giovanniferrariurologo.it hesperia hospital, modena giuseppe ludovico, md g.ludovico@miulli.it ospedale miulli, acquaviva delle fonti, bari, italy stefano pecoraro, md cup@diagnosticamedica.org neuromed, avellino, italy ottavio de cobelli, md ottavio.decobelli@unimi.it department of urology, ieo european institute of oncology, irccs, milan, italy cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 132 original paper no conflict of interest declared. (psa) and digital rectal examination (dre) are the common initial assessments for detection. a suspicious dre or a psa higher than 4 ng/ml are generally considered an indication for prostate biopsy (pb) (2). in fact, a suspicious dre is associated with a higher risk of pca independently of the psa levels (3). the gold standard for pca diagnosis is the transrectal ultrasound (trus)-guided pb. nonetheless this technique has some limitations. trus-guided pb may miss up to 20% of cancers (4). additionally, a large proportion of detected cancers are clinically insignificant (5), contributing to overdiagnosis and overtreatment of indolent tumors which may adversely impact quality of life without altering survival (6). multiparametric magnetic resonance imaging (mpmri) promises to overcome these problems, distinguishing significant from insignificant disease and avoiding unnecessary pb (7, 8). compared with radical prostatectomy specimens, mpmri detects 85-95% of clinically significant pca (cspca) (9) and has negative predictive values of 8394% (9, 10). additionally, mpmri preferentially detects cspca and thus may help to avoid unnecessary pb for benign or insignificant lesions, reducing overtreatment (8, 11). as a result, 64% of urologists consider mpmri useful to detect pca in biopsy-naïve men, while 97% consider it valuable in men with a prior negative biopsy (12). however, the systematic use of mpmri as a triage test in patients with suspicion of pca is still a matter of debate (13, 14). moreover, mpmri cost is not neglectable (8) and may delay pb. in order to avoid unnecessary costs and minimize time to diagnosis, it is necessary to establish which patients benefit the most from doing mpmri prior to trus-guided pb. we hypothesize that mpmri may not add value to the detection of pca in patients with a high clinical suspicion of cancer and mpmri could be dispensable in this group of patients, saving costs and time to diagnosis. the aim of this study is to determine if mpmri prior to pb is still useful in predicting pca and cspca in patients with high clinical suspicion of cancer, defined as psa > 10 ng/ml, psa-density (psad) > 0.15 ng/ml/cc or suspicious digital rectal examination (dre). objectives: multiparametric magnetic resonance imaging (mpmri) is a useful tool to diagnose prostate cancer (pca) but its cost is not negligible. in order to reduce costs and minimize time to diagnosis, it is necessary to establish which patients benefit the most from doing mpmri prior to prostate biopsy (pb). our aim was to test if mpmri still predicts pca and clinically significant pca (cspca) in patients with high clinical suspicion of cancer, defined as prostate specific antigen (psa) > 10 ng/ml, psa-density (psad) > 0.15 ng/ml/cc or suspicious digital rectal examination (dre). materials and methods: we retrospectively collected data on 206 patients who underwent mpmri before pb at our department from january 2017 to july 2018. mpmri results were classified using prostate imaging reporting and data system (pi-rads) version 2. in primary analysis, we evaluated the association of mpmri with pca and cspca and stratified this model for low and high clinical suspicion of cancer. in secondary analysis, we determined the rate of negative pb results in patients with high suspicion of cancer and compared theses rates with those obtained if only those with pi-rads 3-5 would be biopsied. results: in primary analysis and overall, mpmri was predictive of pca and cspca. in stratified analysis, mpmri was still significantly associated with cspca in patients with psa > 10 ng/ml and psad > 0.15 ng/ml/cc, but not in those with suspicious dre. in secondary analysis, negative result rates were lower if only patients with pi-rads 3-5 were biopsied, even in subgroups with high suspicion of cancer based on psa and psad. in patients with suspicious dre, however, the rate of negative results did not change significantly if only patients with pi-rads 3-5 were biopsied. conclusions: mpmri is still useful in predicting cspca in patients with psa > 10 ng/ml and psad > 0.15 ng/ml/cc. if dre is suspicious, though, mpmri might be no longer useful in the prediction of pca. key words: prostate cancer; psa; psa density; digital rectal examination; mpmri; pi-rads. submitted 17 february 2022; accepted 21 february 2022 introduction prostate cancer (pca) is the second most common cancer among men worldwide (1). serum prostate specific antigen do all patients with suspicious prostate cancer need multiparametric magnetic resonance imaging before prostate biopsy? sara teixeira anacleto 1, joana neves alberto 2, emanuel carvalho dias 1, 2, pedro sousa passos 3, mário cerqueira alves 2 1 department of urology hospital of braga, braga, portugal; 2 life and health sciences research institute (icvs), school of medicine, university of minho, 4710-057, braga, portugal; 3 department of urology hospital da senhora da oliveira, guimarães, portugal. doi: 10.4081/aiua.2022.1.32 summary 33archivio italiano di urologia e andrologia 2022; 94, 1 is magnetic resonance imaging always needed? materials and methods patients demographics and variables this study was performed in accordance with the declaration of helsinki and was approved by the ethics committee of hospital de braga. we retrospectively collected data on 594 patients who underwent trus-guided pb at the urology department of hospital de braga from january 2017 to july 2018. 206 patients who underwent mpmri before pb were included in our study. for patients who underwent repeated pb during this period, the last biopsy was taken as reference. data on age, previous biopsies, dre, psa, prostate volume (assessed by trus), psad, pi-rads and pb histological results were recorded. psad was determined only in patients who underwent trus before biopsy (psad = psa/prostate volume). dre was described as unequivocal (normal and abnormal) or doubtful (if no definitive conclusions could be made). mpmri mpmri was performed using a 1.5 tesla system. three sequences were used: t2-weighted, dynamic contrastenhanced and diffusion weighed images. for diffusion weighed images, b-values 0-1700 were used. apparent diffusion coefficient-maps were calculated using diffusion weighed images. suspicious lesions were scored according to the validated pi-rads version 2. in our study, the highest pi-rads score of each mpmri scan was used. taking into account the meaning of pi-rads categories (15) and similarly to other studies (16), pi-rads score was categorized in 1-2 (used as reference) and 3-5. trus-guided pb all men underwent randomized trus guided-pb. twelve randomized cores (6 from right lobe and 6 from left lobe) were taken with no additional cores to suspicious lesions. histopathological analysis was performed at our hospital. pca was classified according to the international society of urological pathology standards and cspca was defined as gleason score ≥ 7 (3+4). statistical analysis variables analyzed were age, previous biopsy (yes/no), dre, prostate volume, psad, pi-rads, pca and cspca. continuous variables were expressed as median and interquartile range (iqr). categorical variables were expressed as absolute and relative frequencies. for the primary analysis, the chi-squared test was performed to evaluate the association of mpmri with pca and cspca. thereafter, this model was stratified for different psa and psad cutoffs as well as dre. when n was low, fisher’s-exact test was used to evaluate this association. a p < 0.05 was considered to indicate statistical significance. for the secondary analysis, negative pb result rates and false negative rates of mpmri were also calculated. statistical analysis was performed using stata version 15. results patients’ demographics 206 patients underwent mpmri and were included in our study. patient’s characteristics, pi-rads scores and histological results are shown in table 1. median (iqr) age was 67 (61-72) years and median prostate volume was 45.9 (35-66) cc. median psa and psad were 8.55 (5.74-12.7) ng/ml and 0.17 (0.11-0.26) ng/ml/cc, respectively. dre was described as unequivocal for 130 patients, with 51 patients (24.76%) classified as suspicious. 79 patients (38.35%) patients had previously undergone pb for suspicious psa or dre. 34 patients (16.5%) had a normal mpmri pi-rads score (pi-rads 1-2) and 172 patients (83.5%) had a suspicious pi-rads (pi-rads 3-5). pb result was normal in 78 (37.86%) patients, while 128 (62.14%) had pca and 100 (48.54%) had cspca. prediction of prostate cancer and clinically significant prostate cancer as primary analysis, chi-squared test was used to test if pi-rads was a predictor of pca and cspca, with results shown in table 2. after, we stratified these results for low versus high clinical suspicion of pca, defined as psa ≤ 10 versus psa > 10 ng/ml, psad ≤ 0.15 versus psad > 0.15 ng/ml/cc and nortable 2. association of pi-rads with pca and cspca. prostate cancer significant prostate cancer n no cancer pca p no cancer cspca p 206 pi-rads 1-2 22 (64.71%) 12 (35.29%) < 0.001* 29 (85.29%) 5 (14.71%) < 0.001* pi-rads 3-5 56 (32.56%) 116 (67.44%) 76 (44.19%) 96 (55.81%) p: p-value; *chi-squared test. table 1. patients’ characteristics. variable n value age (years) median (iqr) 206 67 (61-72) previous biopsy 206 no n (%) 127 (61.65%) yes n (%) 79 (38.35%) dre 206 doubtful 76 (36.89%) unequivocal normal 79 (38.35%) suspicious 51 (24.76%) prostate volume (cc) median (iqr) 138 45.9 (35-66) psa (ng/ml) median (iqr) 206 8.55 (5.74-12.7) psa density (ng/ml/cc) median (iqr) 138 0.17 (0.11-0.26) pi-rads 206 1 18 (8.74%) 2 16 (7.77%) 3 38 (18.45%) 4 66 (32.04%) 5 68 (33.01%) prostate cancer 206 no % (n) 78 (37.86%) yes % (n) 128 (62.14%) clinically significant prostate cancer 206 no % (n) 106 (51.46%) yes % (n) 100 (48.54%) archivio italiano di urologia e andrologia 2022; 94, 1 s. teixeira anacleto, j. neves alberto, e. carvalho dias, p. sousa passos, m. cerqueira alves 34 mal dre versus suspicious dre, respectively (tables 3, 4). in our primary analysis, we found that pi-rads 3-5 was a significant predictor of both pca and cspca (p < 0.001). low vs. high risk based on psa after stratification in low vs. high risk based on psa, we found that in patients with low clinical suspicion of pca (psa ≤ 10 ng/ml), pi-rads 3-5 was a significant predictor of pca and cspca (p = 0.004 and p = 0.018, respectively) and that in patients with high psa levels (psa > 10 ng/ml), pi-rads 3-5 was also significantly associated with pca and cspca (p = 0.004 and p < 0.001, respectively). low vs. high risk based on psad in stratified analysis by clinical suspicion based on psad, we found that in patients with low clinical suspicion of cancer (psad ≤ 0.15 ng/ml/cc), pi-rads 3-5 was a predictor of cspca (p = 0.044). however, in this group, pirads 3-5 was not significantly associated with pca (p = 0.139). in patients with high clinical suspicion of pca (psad > 0.15 ng/ml/cc), pi-rads 3-5 was significantly associated with both pca and cspca (p < 0.001). low vs. high risk based on dre in stratified analysis by clinical suspicion based on dre, we found that in patients with low clinical suspicion of cancer (normal dre), pi-rads 3-5 was a predictor of both pca and cspca (p = 0.007 and p = 0.004, respectively). conversely, in patients with suspicious dre, pirads 3-5 was neither associated with pca nor with cspca (p = 0.168 and p = 0.571, respectively). noticeably, in this group of patients, only 4 patients (7.84%) with suspicious dre had normal mpmri findings (pi-rads 1-2) and out of them 2 (50%) had cspca. negative prostate biopsy (pb) result rates of prostate cancer and clinically significant prostate cancer as secondary analysis, we evaluated the rate of negative pb in the subgroup of patients with pi-rads 3-5. these results are shown in table 5. in total, 37.9% of patients biopsied had no pca and 51% no cspca. if only patients with pi-rads 3-5 were considered, negative pb rate dropped to 27.2% and 36.9% for pca and cspca respectively. the rate of patients with pca and cspca and pirads 1-2 who would not be biopsied or diagnosed with this approach (false negative rate) would be 5.8% and 2.4%, respectively. patients with high risk based on psa among patients with psa > 10 ng/ml, the rate of negative pb was 35.4% for pca and 43% for cspca. patients with psa > 10 ng/ml and pirads 3-5 did not have pca and cspca in 22.8% and 26.6% respectively. if among patients with psa > 10 ng/m, only those with pi-rads 3-5 were biopsied, the false negative rates would be 5.1% for pca and 1.3% for cspca. patients with high risk based on psad patients with psad > 0.15 ng/ml/cc had a negative pb result rate of 22.5% for pca and of 33.8% for cspca, respectively. patients with psad > 0.15 and pi-rads 3-5 had no pca in 12.5% and no cspca in 21.3%. if only patients with pirads 3-5 were biopsied, 5.0% of patients with pca and 2.5% of patients with cspca would be missed. patients with high risk based on dre patients with suspicious dre had no pca in 19.6% and no cspca in 29.4%. if only patients with suspicious dre and pi-rads 3-5 had undergone biopsy, 15.7% would have no pca and 25.5% would have no cspca. according to this approach, 3.9% of patients with suspicious dre and pi-rads 1-2 bearing pca or cspca would be missed. table 3. association of pi-rads with pca and cspca stratified for psa ≤ 10 ng/ml and > 10 ng/ml and psad ≤ 0.15 ng/ml/cc and > 0.15 ng/ml/cc. prostate cancer significant prostate cancer n no cancer pca p no cancer cspca p psa ≤ 10 ng/ml 127 pi-rads 1-2 12 (60.0%) 8 (40.0%) 0.004* 16 (80.0%) 4 (20.0%) 0.018* pi-rads 3-5 38 (35.51%) 69 (64.49%) 55 (51.40%) 52 (48.60%) psa > 10 ng/ml 79 pi-rads 1-2 10 (71.43%9 4 (28.57%) 0.004** 13 (92.86%) 1 (7.14%) < 0.001** pi-rads 3-5 18 (27.69%) 47 (72.31%) 21 (32.31%) 44 (67.69%) psad ≤ 0.15 ng/ml/cc 58 pi-rads 1-2 10 (71.43%) 4 (28.57%) 0.139** 13 (92.86%) 1 (7.14%) 0.044** pi-rads 3-5 21 (47.73%) 23 (52.27%) 27 (61.36%) 17 (38.64%) psad > 0.15 ng/ml/cc 80 pi-rads 1-2 8 (66.67%) 4 (33.33%) < 0.001** 10 (83.33%) 2 (16.67%) < 0.001** pi-rads 3-5 10 (14.71%) 58 (85.29%) 17 (25.0%) 51 (75.0%) p: p-value; *chi-squared test; **fisher’s exact test. table 4. association of pi-rads with pca and cspca stratified for normal and suspicious dre. prostate cancer significant prostate cancer n no cancer pca p no cancer cspca p normal dre 79 pi-rads 1-2 14 (70.0%) 6 (30.0%) 0.007* 18 (90.0%) 2 (10.0%) 0.004* pi-rads 3-5 21 (35.59%) 38 (64.41%) 32 (54.24%) 27 (45.76%) suspicious dre 51 pi-rads 1-2 2 (50.0%) 2 (50.0%) 0.168** 2 (50.0%) 2 (50.0%) 0.571** pi-rads 3-5 8 (17.02%) 39 (82.98%) 13 (27.66%) 34 (72.34%) p: p-value; *chi-squared test; **fisher’s exact test. table 5. negative pb result rates and false negative rates for pca and cspca globally and in patients with pi-rads 3-5 in different subgroups. pca cspca total pi-rads 3-5 total pi-rads 3-5 npbr npbr fnr npbr npbr fnr total 37.9% 27.2% 5.8% 51% 36.9% 2.4% psa > 10 ng/ml 35.4% 22.8% 5.1% 43% 26.6% 1.3% psad > 0.15 ng/ml/cc 22.5% 12.5% 5.0% 33.8% 21.3% 2.5% suspicious dre 19.6% 15.7% 3.9% 29.4% 25.5% 3.9% npbr: negative pb result rates; fnr: false negative rates. 35archivio italiano di urologia e andrologia 2022; 94, 1 is magnetic resonance imaging always needed? discussion to our knowledge, this is the first study to test mpmri accuracy in detection of pca stratified by clinical suspicion of cancer based on various clinical markers, including psa, psad, and dre. according to the european association of urology guidelines, mpmri before biopsy could improve the detection cspca in two different ways. first it allows to target specific lesions visible on mpmri. secondly, mpmri could be used as a triage test before biopsy, so that mpmri-pb would be performed only in case of a positive mpmri whereas patients with negative mpmri findings would not undergo prostate biopsy at all. based on this assumption most studies focused on using mpmri to avoid pb and diagnosis of clinical insignificant pca (17), rather than evaluating where mpmri can add value compared to standard clinical tools alone. the promis trial showed high sensitivity and high negative predictive value of mpmri for the detection of cspca, defined as gleason score ≥ 7 (4+3) or cancer core length ≥ 6 mm. however, the false-positive rate for mpmri was 49%, needing follow-up biopsy sampling to confirm suspicious findings. moreover, as negative and positive predictive values depend on prevalence, it becomes mandatory to pre-evaluate the risk of cspca in patients with a suspicion of pca (16). biomarkers and nomograms are very helpful in this setting, but standard clinical examination should remain of pivotal importance (18). our primary analysis among all included patients unsurprisingly demonstrated that mpmri pi-rads 3-5 was associated both with pca and cspca, as previously described (7-10). after stratification by clinical suspicion of pca, also as expected, in patients with low clinical suspicion of pca, defined as psa ≤ 10 ng/ml, psad ≤ 0.15 ng/ml/cc and normal dre, mpmri pi-rads 3-5 was significantly associated with pca in most evaluations (except for lowest psad values ≤ 0.15 ng/ml/cc) and with diagnosis of cspca in all evaluations. however, importantly we observed that among patients with high clinical suspicion of pca, defined as psa > 10 ng/ml and psad > 0.15 ng/ml/cc, mpmri pi-rads 3-5 remained significantly associated with cspca and pca. however, in patients with high clinical suspicion of pca based on dre, mpmri pi-rads 3-5 was not significantly associated with pca or cspca. the main explanation of this finding is that almost all patients with an unequivocal abnormal dre have a mpmri pi-rads of 3-5. altogether, these findings demonstrate an added value of mpmri even among patients with psa > 10 ng/ml and psad > 0.15 ng/ml/cc. patients with suspicious dre, however, might not benefit from mpmri for the pb diagnosis of cancer. our secondary analysis showed that the rate of negative pb results would drop significantly if pb was only performed in patients with pi-rads 3-5. the rate of negative pb results was 37.9% vs 27.2% for pca and 51% vs 36.9% for cspca when the total rate was compared with the rate in patients with pi-rads 3-5. even in subgroups with high clinical suspicion of cancer, defined as psa > 10ng/ml and psad > 0.15 ng/ml/cc, mpmri would be useful to avoid unnecessary pb. the rate of negative pb results was 35.4% vs 22.8% for pca and 43% vs 26.6% for cspca when total rate was compared with the rate in patients with pi-rads 3-5 and psa > 10 ng/ml and 22.5% vs 12.5% for pca and 33.8% vs 21.3% for cspca when total rate was compared with the rate in patients with pi-rads 3-5 and psad > 0.15 ng/ml/cc. mpmri was thus helpful in selecting patients with pca and cspca who needed to undergo pb even in the subgroup with high clinical suspicion of cancer, defined as psa > 10 ng/ml and psad > 0.15 ng/ml/cc. however, in patients with suspicious dre performing pb only in those with pi-rads 3-5 would not change significantly the rate of negative pb results. the negative pb result rate was 19.6% vs 15.7% for pca and 29.4% vs 25.5% for cspca when total rate was compared with the rate in patients with pi-rads 3-5. in addition, this 4% reduction was obtained at the cost of a false negative rate of 3.9%. therefore, in line with primary analysis’ findings, patients with suspicious dre do not benefit from mpmri before pb. for the first time, we specifically report the utility of mpmri in patients with high clinical suspicion of cancer. contrary to our hypothesis, when psa was > 10 ng/ml and psad > 0.15 ng/ml/cc, mpmri was still useful in discriminating pca and cspca. however, according to our hypothesis, if dre is suspicious, mpmri might no longer be necessary to aid in the pb diagnosis of cancer. it is true that omitting mpmri, many pcas of anterior gland could be undetected to the standard trus guidedpb (19), but several studies assessed the importance to detect anterior pca with discordant findings (20). the optimization of the trus guided-pb technique is, anyway, decisive. this study has some limitations. firstly, our gold standard was systematic pb and not targeted pb or final prostatectomy specimens and therefore some men with negative pb result may have had pca. secondly, mpmri images were reviewed by different radiologists, which may weaken internal validity, although this condition could represent better every day clinical practice. conclusions we think to report the first study to evaluate the accuracy of mpmri in patients with different clinical suspicion of pca. pi-rads 3-5 was predictive of cspca even when psa was > 10 ng/ml and psad > 0.15 ng/ml/cc. therefore, mpmri should be performed also in this set of patients with high clinical suspicion of cancer. in patients with suspicious dre, mpmri seems not to be significantly associated with cancer and it may be avoided to reduce costs and save time to diagnosis in this particular group of patients. references 1. center mm, jemal a, lortet-tieulent j, et al. international variation in prostate cancer incidence and mortality rates. eur urol. 2012; 61:1079-92. 2. aminsharifi a, howard l, wu y, et al. prostate specific antigen density as a predictor of clinically significant prostate cancer when the prostate specific antigen is in the diagnostic gray zone: defining the optimum cutoff point stratified by race and body mass index. j urol. 2018; 200:1-9. 3. galosi ab, palagonia e, scarcella s, et al. detection limits of sigarchivio italiano di urologia e andrologia 2022; 94, 1 s. teixeira anacleto, j. neves alberto, e. carvalho dias, p. sousa passos, m. cerqueira alves 36 nificant prostate cancer using multiparametric mr and digital rectal examination in men with low serum psa: up-date of the italian society of integrated diagnostic in urology. arch ital urol androl. 2021; 93:92-100. 4. rabbani f, stroumbakis n, kava br, et al. incidence and clinical significance of false-negative sextant prostate biopsies. j urol. 1998; 159:1247-50. 5. grenabo bergdahl a, wilderang u, aus g, et al. role of magnetic resonance imaging in prostate cancer screening: a pilot study within the goteborg randomised screening trial. eur urol. 2016; 70:566-73. 6. pokorny mr, de rooij m, duncan e, et al. prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (mr) imaging with subsequent mr-guided biopsy in men without previous prostate biopsies. eur urol. 2014; 66:22-9. 7. brizmohun appayya m, sidhu hs, dikaios n, et al. characterizing indeterminate (likert-score 3/5) peripheral zone prostate lesions with psa density, pi-rads scoring and qualitative descriptors on multiparametric mri. br j radiol. 2018; 91:20170645. 8. barnett cl, davenport ms, montgomery js, et al. cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. bju int. 2018; 122:50-8. 9. radtke jp, wiesenfarth m, kesch c, et al. combined clinical parameters and multiparametric magnetic resonance imaging for advanced risk modeling of prostate cancer-patient-tailored risk stratification can reduce unnecessary biopsies. eur urol. 2017; 72:888-96. 10. schroder fh, hugosson j, roobol mj, et al. screening and prostate cancer mortality: results of the european randomised study of screening for prostate cancer (erspc) at 13 years of follow-up. lancet (london, england). 2014; 384:2027-35. 11. meng x, rosenkrantz ab, mendhiratta n, et al. relationship between prebiopsy multiparametric magnetic resonance imaging (mri), biopsy indication, and mri-ultrasound fusion-targeted prostate biopsy outcomes. eur urol. 2016; 69:512-7. 12. stanzione a, creta m, imbriaco m, et al. attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: a national survey among italian urologists. arch ital urol androl. 2020; 92:291-296. 13. panebianco v, barchetti g, simone g,, et al. negative multiparametric magnetic resonance imaging for prostate cancer: what’s next? eur urol. 2018; 74:48-54. 14. mottet n, cornford p, van den bergh rcn, et al. eau-eanmestro-esur-isup-siog guidelines on prostate cancer. https:// uroweb.org/wp-content/uploads/eau-eanm-estro_esur_isup_ siog-guidelines-on-prostate-cancer-2021.pdf 15. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016; 69:16-40. 16. washino s, okochi t, saito k, et al. combination of prostate imaging reporting and data system (pi-rads) score and prostatespecific antigen (psa) density predicts biopsy outcome in prostate biopsy naive patients. bju int. 2017; 119:225-33. 17. ahmed hu, el-shater bosaily a, brown lc, et al. diagnostic accuracy of multi-parametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. lancet (london, england). 2017; 389:815-22. 18. cormio l, cindolo l, troiano f, et al. development and internal validation of novel nomograms based on benign prostatic obstructionrelated parameters to predict the risk of prostate cancer at first prostate biopsy. front oncol. 2018; 8:438. 19. komai y, numao n, yoshida s, et al. high diagnostic ability of multiparametric magnetic resonance imaging to detect anterior prostate cancer missed by transrectal 12-core biopsy. j urol. 2013; 190:867-73. 20. ekin rg, zorlu f, akarken i, et al. anterior apical cores in the initial prostate biopsy does not increase detection of significant prostate cancer. urol j. 2015; 12:2084-9. correspondence sara teixeira anacleto, md (corresponding author) sara.anacleto241@gmail.com emanuel carvalho dias, md emanueldias@med.uminho.pt department of urology, hospital of braga, braga (portugal) joana neves alberto, md joana.alberto26@gmail.com mário cerqueira alves, md mario.alves@hb.min-saude.pt life and health sciences research institute (icvs), school of medicine, university of minho, 4710-057, braga (portugal) pedro sousa passos, md pedrosousapassos@gmail.com department of urology, hospital da senhora da oliveira, guimarães (portugal) cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2020; 92, 3192 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.192 diagnosis and treatment of penile injury: ten years experience of an emergency department paolo panella, pietro pepe, michele pennisi urology unit, cannizzaro hospital, catania, italy. introduction: to evaluate the imaging accuracy in the diagnosis and clinical management of penile injury. materials and methods: from january 2010 to january 2020, 20 men (median age 40.2 years) were admitted to our emergency department with the diagnosis of penile injury; the penile trauma was related to sexual intercourse in 16 cases, masturbation in 3 cases and injury caused by the partner in 1 case. all the patients underwent accurate medical history, clinical examinations and diagnostic imaging. color doppler ultrasound (cdu) evaluation was performed by logiq e9 ecograph (general electric; milwaukee, wi) supplied with a linear probe small (7.5-10 mhz); magnetic resonance image (mri) examination was performed within 3-24 hours from the trauma using a 1.5 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) performing pre-contrast and post-contrast multi-planar turbo spin-echo t1 and t2-weighted sequences. results: 15/20 (75%) men with high suspicion of the tunica albuginea rupture underwent surgical exploration; conversely, 5/20 (25%) patients underwent conservative management. cdu detected 11/15 (73%) fractures of the penis and in 8 of them the length of the rupture was underestimated (more than 5 millimeters). on the contrary, mri diagnosed all the albuginea ruptures showed by surgical exploration, but underestimated the length of the lesions in 9/15 (60%) cases. the iief-5 score administered six months later penile trauma demonstrated a good performance in all the patients. conclusions: in our series, all the patients with a tunica albuginea rupture < 5 mm. diagnosed by mri were submitted to conservative management with a complete functional restitutio ad integrum. key words: penile injury; mri; cdu; imaging and penile trauma. submitted 17 may 2020; accepted 11 july 2020 tion. the pain and sound are made by a strain in the tunica albuginea that during erection become thin from 2 to 0.25-0.50 mm. reducing its elasticity and reaching, in case of rupture, an internal pressure of 1.500 mmhg (2). the lesions of tunica albuginea could be unilateral or bilateral involving the corpus spongiosum of the urethra (3, 4). the clinical presentation is characterized by the presence of gross hematoma of the penis that, in the majority of the cases, is deviated controlaterally to site of rupture. the presence of “butterfly hematoma” suggest the injury of the buck fascia (4, 5). the diagnosis is usually based on clinical history (the typical sound referred as “crack”) and clinical examination. in the presence of urethral injury the patient could refer urethral bleeding or hematuria combined with dysuria, urinary voiding symptoms and acute urinary retention. the diagnostic imaging is mandatory to evaluate the integrity of the tunica albuginea (site and length of the lesion) and the extension of the hematoma. color doppler ultrasound (cdu) and magnetic resonance imaging (mri) are highly recommended to evaluate the morphology of the penis to plan the best clinical management; cdu could underestimate the extension of corpora cavernosa lesion but it allow to easily evaluate the dorsal penis vascular complex. in this retrospective study, we report our experience regarding the role of imaging in the diagnosis and clinical management of patients with non-penetrating penile injury. materials and methods from january 2010 to january 2020, 20 men with median age of 40.2 years (range: 21-65) were admitted to our emergency hospital for non-penetrating penile injury. the penile trauma was related to sexual intercourse in 16 cases, masturbation in 3 cases and injury caused by the partner in 1 case; the clinical presentation of the patients at hospital admission are listed in table 1. all the patients underwent clinical examination, cdu and mri evaluation. ultrasound examination was performed by a logiq e9 ecograph (general electric; milwaukee, wi) supplied with a linear probe small (7.5-10 mhz) to evaluate the integrity of the tunica albuginea and dorsal vascular complex of the penis, the site and extension of the hematoma. all mri examinations were performed within 3-24 hours from the trauma using a 1.5 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) introduction the injury of corpora cavernosa is a very rare urological emergency with an estimated incidence of 1.02/100,000 male subjects per year in the united states (1, 2); the rupture of the penis is secondary to an abrupt deviation during erection to which follows sudden pain and a noise referred as “crack” with rapid loss of erection combined with subcutaneous hematoma. the fractures of the penis following non-penetrating trauma are most commonly sustained during sexual intercourse; rarely, the trauma could be induced by careless movement performed to stop the erection (manuever of taghaandan) or masturbasummary 07panella_stesura seveso 25/09/20 13:10 pagina 192 193archivio italiano di urologia e andrologia 2020; 92, 3 imaging and penile injury equipped with surface 32 channels phased-array coil placed around the pelvic area with the patient in the supine position. all patients were studied with pre-contrast and postcontrast multi-planar turbo spinecho t1weighted and t2-weighted (t2w) sequences (figure 1). the 15/20 (75%) men with high suspicion of penis rupture underwent surgical exploration; conversely, 5/20 (25%) patients underwent conservative management. in all cases the length of the penis lesion was measured with a centimeter during surgery. all the patients underwent follow up 1, 3 and 6 months from the trauma performing clinical evaluation, cdu and, in selected cases, mri of the penis; moreover, the international index erectile function-5 score (iief-5) was administered to evaluate the sexual performance. results overall, mri and cdu diagnosed 20/20 (100%) and 12/20 (60%) fractures of the tunica albuginea, respectively. in detail, cdu detected 11/15 (73%) fractures of the penis and in 8 of them the length of the rupture was underestimated (more than 5 millimeter “mm”) if compared with surgical exploration. mri diagnosed all the 15 (100%) ruptures of the tunica albuginea showed by surgical exploration (figure 2), but underestimated the length of the lesions in 9/15 (60%) cases; conversely, in 6/15 (40%) cases the extension of the lesion was superimposable or overestimated. in addition, mri detected 1/2 lesion (50%) of the corpus spongiosum (figure 3); 15/20 (75%) underwent surgery within 24 (12 cases) or 36 hours (3 cases) from the trauma; in all the cases, a table 1. clinical presentation of the 20 men with non-penetrating penile injury at hospital admission. clinical picture 20 cases (overall) hematoma 20 (100%) edema 14 (70%) sound of “crack” 12 (60%) pain 20 (100%) deviation of the penis 12 (60%) urethrorrhagia 1 (5%) table 2. location and side of the tunica albuginea rupture in the 15 patients submitted to surgical exploration. side of the trauma number of patients % latero-dorsal 2 13.3 latero-ventral 13 86.6 bilateral 2 13.3 distal 1 6.6 middle of the penis 9 60 proximal 5 33.3 urethral involvment 2 13.3 figure 2. ventral fracture of the tunica albuginea. t2 weighted sagittal image t1 weighted sagittal image pre-contrast post-contrast figure 3. fracture of the penis with corpus spongiosum involvement. t1 weighted sagittal image t1 weighted coronal image pre-contrast post-contrast figure 1. diagnostic flow-chart for selection of treatment of penile trauma. 07panella_stesura seveso 25/09/20 13:10 pagina 193 archivio italiano di urologia e andrologia 2020; 92, 3 p. panella, p. pepe, m. pennisi 194 large hematoma combined with edema of the penis was found. the site of the tunica albuginea injury is listed in table 2; median length of the lesion was 19 mm. (range: 5-30) with urethral involvement in 2 cases (13.3%). in 14/15 men (93.4%) the penis was deviated controlaterally to the site of rupture. all the patients submitted to surgical exploration underwent subcoronal approach, evacuation of hematoma and repair of the tunica albuginea using pds (polydioxanone) 2/0 in 5 cases e vicryl (polyglatin 910) 3/0 in 10 cases. at the end of surgery, an erection was induced to evaluate the presence of missed lesions and the absence of recurvatum. the urethral lesions were repaired using a slow absorption monofilament (monocryl 4/0 poliglecaprone 25) (table 3); moreover, all the patients underwent antibiotic prophylaxis (a third generation cephalosporin combined with teicoplanin) and 2.5 days (range: 2-5 days) from surgery were discharged; 3/15 (20%) men had minor complications following surgery: 1 case of hematoma treated conservatively, 1 case of pain during sexual activity and a case of penis recurvatum equal to 30°. five out of 20 patients (25%) were hospitalized 48/96 hours from the trauma (average hospital stay was 2.5 days, range 1-5 days), and underwent conservative management, because mri and cdu showed a lesion of the tunica albuginea < 5 mm. in 5 (100%) and 1 (20%) cases, respectively; moreover, a clinically significant hematoma was absent (table 4). mri vs cdu demonstrated a diagnostic accuracy in the diagnosis of tunica albuginea rupture equal to 100 vs 50%; at the same time, mri vs cdu underestimated the real lentht of the rupture in 9 (45%) and 12 (80%) cases, respectively. all the patients were encouraged to have sexual activity at least 6 weeks later the trauma; median follow up was 5.7 months (range: 3-9). the ieff-5 scores evaluated before and after the trauma of the penis are listed in table 5. discussion literature data recommend early surgical exploration of penis in the presence of tunica albuginea rupture to improve a rapid resolution of pain and to reduce the risk of ed, corpora cavernosa fibrosis, symptomatic scars of the penis or recurvatum (5-9). in the last years, the use of mri has improved the diagnosis of penile injury; saglam et al (10) reported in 122 patients a sensitivity and specificity of mri equal to 100 with a positive (ppv) and negative predictive value (npv) of 87.5 and 100%, respectively. at the same time, sokolakis et al. (11) on 43 patients showed a mri sensitivity, specificity, npv and ppv equal 100, 77.8, 100 and 90.5%, respectively. therefore, today, the use of mri combined with dedicated protocols is strongly recommended in the clinical evaluation of penile injury (6-8) to plan the best therapeutic treatment for each patient (12-18). despite the high accuracy, mri is not always used in the evaluation of penile trauma because expensive and little available in emergency. on the other hand, although cdu allows an easy and repeatable morfological and functional evaluation of the penis its accuracy results lower in comparison with mri (19). in our series, mri and cdu detected 100 (15/15 cases) vs 73% (9/15 cases) of the penile fractures submitted to surgical exploration; conversely, among the five (25%) patients who underwent conservative mri and cdu diagnosed a lesion of the tunica albuginea < 5 mm. in 100 (5/5 cases) vs 20% (1/5 cases) of the patients, respectively. during the follow up nobody referred functional clinical complications; moreover, the iief-5 score was predictive of a normal sexual activity in the 75% of the cases resulting superimposable with the results obtained in men who underwent surgery. regarding our results some considerations should be done. first, our study is retrospective and refer to a limited number of patients. secondly, we do not know the real extension of the tunica albuginea rupture in men submitted to conservative treatment. third, our considerations are based upon a very low number of cases but could be expression of a greater number of minor penile trauma with good prognosis that in the “real life” could be missed because don’t come to observation of the specialist. finally, multicentric and multidisciplinary studies should be encouraged to improve the use of mri in case of penile injury. in conclusion, in our series, all the patients with a tunica albuginea rupture < 5 mm. diagnosed by mri and submittable 5. initial and post trauma sexual performance evaluated by the international index erectile function-5 score (iief-5). iief-5 score before trauma (pts) after trauma (pts) normal (22-25) 15 (75%) 15 (75%) minimal de (17-21) 3 (15%) 3 (15%) minimal-moderate de (12-16) 2 (10%) 2 (10%) moderate de (8-11) 0 1 (5%) severe de (5-7) 0 0 de: erectile dysfunction; pts: patients. table 3. imaging, surgical data, complications and functional results in the 15 patients submitted to surgery. 15 patients cdu mri surgery complications iief-5 (overall) n (%) cm n (%) cm n (%) cm n (%) score right side 6 40 1-2 6 40 1.5-2 8 53.4 1-2.8 1 (6) 18 recurvatum 30° moderate ed left side 7 46.7 0.5-2 6 40 1-2 5 33.3 1-2.5 0 0 bilateral 2 13.3 2.5 2 13.3 2-2.5 2 13.3 2-3 1 (6) 22 coital pain urethra 0 1 6.6 2 2 13.3 2-3 1 (6) 22 coital pain cdu: colordoppler ultrasound; mri: magnetic imaging resonance; iief-5: international index of erectile function. table 4. imaging, complications and functional results in the 5 patients submitted to conservative management. 5 patients cdu mri complications iief-5 (overall) n (%) cm n (%) cm n (%) score right side 0 1 20 1 0 24 left side 1 20 0.5 4 80 0.5 0 22 cdu: colordoppler ultrasound; mri: magnetic imaging resonance; iief-5: international index of erectile function. 07panella_stesura seveso 25/09/20 13:10 pagina 194 195archivio italiano di urologia e andrologia 2020; 92, 3 imaging and penile injury ted to conservative management had a complete functional restitutio ad integrum. anyway, multicentric and multidisciplinary studies should be encouraged to improve the imaging accuracy in the evaluation of penile injury. references 1. rodriguez d, li k, apoj m, munarriz r. epidemiology of penile fractures in united states emergency departments: access to care disparities may lead to suboptimal outcomes. j sex med. 2019; 16:248-56. 2. de luca f, garaffa g, falcone m, et al. functional outcomes following immediate repair of penile fracture: a tertiary referral centre experience with 76 consecutive patients. scand j urol. 2017; 51:170-75. 3. anastasiou i, anastasiou a, katafigiotis i, et al. isolated corpus spongiosum injury after sexual intercourse. arch ital urol androl. 2019; 90:295-296. 4. kasaraneni p, mylarappa p, gowda rd, et al. penile fracture with urethral injury: our experience in a tertiary care hospital. arch ital urol androl. 2019; 90:283-287. 5. özorak a, hoşcan mb, oksay t, et al. management and outcomes of penile fracture: 10 years' experience from a tertiary care center. int urol nephrol. 2014; 46:519-22. 6. salonia a, bettocchi c, carvalho, et al. guidelines associates: eau sexual and reproductive health guidelines 2020. 7. yamaçake kg, tavares a, padovani gp, et al. long-term treatment outcomes between surgical correction and conservative management for penile fracture: retrospective analysis. korean j urol. 2013; 54:472-76. 8. gamal wm, osman mm, hammady a, et al. penile fracture: long-term results of surgical and conservative management. j trauma. 2011; 71:491-93. 9. al-shaiji tf, amann j, brock gb. fractured penis: diagnosis and management. j sex med. 2009; 6:3231-40. 10. saglam e, tarhan f, hamarat mb, et al. efficacy of magnetic resonance imaging for diagnosis of penile fracture: a controlled study. investig clin urol. 2017; 58:255-60. 11. sokolakis i, schubert t, oelschlaeger m, et al. the role of magnetic resonance imaging in the diagnosis of penile fracture in real-life emergency settings: comparative analysis with intraoperative findings. j urol. 2019; 202:552-57. 12. cozzi d, verrone gb, agostini s, et al. acute penile trauma: imaging features in the emergency setting. radiol med. 2019; 124:1270-80. 13. esposito aa, giannitto c, muzzupappa c, et al. mri of penile fracture: what should be a tailored protocol in emergency? radiol med. 2016; 121:711-18. 14. guler i, ödev k, kalkan h, et al. the value of magnetic resonance imaging in the diagnosis of penile fracture. int braz j urol. 2015; 41:325-28. 15. rosi g, fontanella p, venzi g, et al. 3t mr-guided minimallyinvasive penile fracture repair. arch ital urol androl. 2016; 88:68-69. 16. koifman l, barros r, júnior ra, et al. penile fracture: diagnosis, treatment and outcomes of 150 patients. urology. 2010; 76:1488-92. 17. pepe p, panella p, candiano g, et al. partial priapism secondary to idiophatic segmental thrombosis of corpora cavernosa. arch ital urol androl. 2012; 84:101-03. 18. pennisi m, grasso leanza f, panella p, pepe p. la rottura traumatica del pene. caso clinico e revisione della letteratura. contraccezione fertilità sessualità. 1992; 19:327-29. 19. dell'atti l, scarcella s, argalia g, et al. rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: presentation of a clinical case. arch ital urol androl. 2018; 90:143-144. correspondence paolo panella, md (corresponding author) ppanella5@gmail.com pietro pepe, md michele pennisi, md urology unit cannizzaro hospital via messina 829, catania (italy) 07panella_stesura seveso 25/09/20 13:10 pagina 195 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 78 original paper cure rate and lower incidence of complications, such as urinary tract infections, pelvic hematoma, and bladder/vaginal perforation (8, 9). the tot sling method is regarded as the gold standard in the treatment of female sui (10). retropubic polypropylene mesh supports the urethra without tension, which was originally used in the initial approach, has now been modified to provide the same therapeutic benefits with fewer complications (11, 12). by avoiding the retropubic area, the tot helps prevent hematoma and bladder perforation development in this area (13). these mid-urethral slings (mus) procedures, however, also have complications owing to the blind transit of the introducer needles via obturator foramen. although groin pain has been reported to occur at a rate of 2-7.5% in certain studies, more significant complications such as vascular injury may also occur (11). a novel minimally invasive technique for treating sui, known as single incision minislings (sims), was proposed as a way to reduce postoperative pain and eliminate blind passing trocars via the retzius space and obturator canal with less mesh (14, 15). in this study, we aimed to evaluate the safety and efficacy of surgeon-tailored polypropylene mesh (stm) through a needleless sims vs. standard tot in the treatment of female sui. methods the local ethics committee approved the protocol of the current trial of faculty of medicine for girls, al-azhar university (fmg-irb) met at faculty of medicine for girls, nasr city, cairo, egypt (registration number: 29042019). only women who were able to read and sign the informed consent were included. all procedures run in compliance with the standards of the declaration of helsinki (16). the reporting of the present manuscript followed the consort statement (17). study design and patients we conducted an open-label randomised controlled trial that included women with sui, who were scheduled to undergo surgical management at al zahraa university hospital in cairo, egypt, from february 2019 to june 2022. adult women with a confirmed diagnosis of sui through a positive stress test were included if they exhibited no response to pelvic floor exercise. there were no restrictions regarding the severity of sui or the presence of cystocele. we excluded women with tumours of the to evaluate the safety and efficacy of surgeon-tailored polypropylene mesh (stm) through a needle-less single incision mini-slings (sims) vs. standard trans-obturator tape (tot) in the treatment of female stress urinary incontinence (sui). methods: we conducted an open-label randomized controlled trial that included women with sui. eligible women were randomized in a 1:1 ratio to receive either standard tot or sims techniques. all procedures were performed using a surgeon-tailored polypropylene mesh and monofilament tape. results: a total of 60 women were included. the mean operative time was significantly longer in the standard tot group. the mean bleeding rate was significantly higher in the standard tot group (87.6 ± 10.6 cc) compared to the sims group (60.0 ± 8.1 cc). there was no urethral injury in both groups. transient thigh pain occurs in 12 cases (40 %) of the standard tot and no cases in the sims group (p < 0.001). after three months, there was no significant statistical difference between the result of the two groups as regard to cure or improvement rate. no failed cases were reported in both groups (p = 0.64). likewise, there was no significant difference between the two groups regarding patients' satisfaction rate. conclusions: sims was not inferior to standard tot. stm sims is a mini-invasive, relatively safe, reproducible, easy to perform in a short time, with excellent patient tolerability and minimal pain, allowing early return to work and economically effective surgical procedure for the treatment of female stress urinary incontinence. key words: contasure-needleless; single-incision needleless minisling; stress urinary incontinence; transobturator inside-out. submitted 28 march 2023; accepted 30 april 2023 introduction stress urinary incontinence (sui) is a complaint of involuntary urine leakage triggered by coughing, sneezing, exertion, or effort. according to age, geographic location, and race, sui prevalence varies from 5 to 61%, with yearly incidence rates of 4-11% and remission rates of only 4-5% (13). particularly in developing countries, sui continues to be a substantial health burden (3). there have been several surgical methods developed throughout time to treat female sui, including tension-free vaginal tape (tvt) and trans-obturator tape (tot) (4, 7). both of these surgical approaches are widely accepted for the treatment of sui. however, tot became more popular owing to its same single-incision needleless mini-sling technique for female stress urinary incontinence: a comparative study with standard transobturator inside-out technique eman ali, salah e. shebl, sayeda ibrahim urology department, faculty of medicine for girls, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11342 summary archivio italiano di urologia e andrologia 2023; 95, 2 eman ali, salah e. shebl, sayeda ibrahim 79 genitourinary organs, infection, neurogenic bladder, and pregnant women. eligible women were randomised in a 1:1 ratio to receive either standard tot or sims techniques. all procedures were performed using a surgeontailored polypropylene mesh and monofilament tape. preoperative assessment preoperatively, all women were assessed for the presentation, duration, and severity of sui through the questionnaire described by sand et al. (18). besides, patients were evaluated for associated genitourinary or neurological conditions and bowel habits. general medical, obstetric, and gynaecological histories were evaluated as well. all women underwent routine physical examination and preoperative laboratory assessment, including complete blood count (cbc), liver and renal functions, bleeding profile, and urine culture. abdominopelvic ultrasonography was performed for all women to assess post-void residual urine. all patients underwent cytometry preoperatively via andromeda urodynamic apparatus. surgical procedures in both groups: – patients received prophylactic antibiotics one hour before the procedure (1gm 3rd generation cephalosporin intravenously); figure 1 (a-h). standard transobturator tape (tot) procedure. a. paraurethral space was bluntly dissected (at 2 o’clock position) until the descending ischiopubic ramus was reached. b. tape applicator (needle) passing through tract created using out-in technique by supination movement. c. needle through tract with its tip out of vaginal incision. g. removal of excess tape outside the skin and closure of incision by vicryl 3/0. h. closure of vaginal incision by vicryl 3/0 in interrupted manner. d. mesh was fixed to the needle and drawn out through the thigh by pronation movement. e. receiving the needle on index finger through tract. f. suburethral straightening of the tape by using the back of a toothed forceps that was placed between the tape and the urethra. – procedures were performed under spinal anesthesia and in lithotomy position, with a 16 f bladder catheter insertion; – labia were retraced using a 3.0 silk stay suture; – a vaginal incision was done; – allis clamps were applied at each side of the midline to suspend the anterior vaginal wall; – hydrodissection of the vaginal mucosa was performed; – vaginal wall was incised 1 cm on the sagittal line starting 1 cm below the urethral meatus. in the standard tot group: – the mesh was prepared using a 30 x 30cm monofilament mesh; – periurethral fascia was dissected laterally using metzenbaum scissors toward the inferior pubic ramus at each side; – a skin incision was made at the adductor longus tendon base parallel to the clitoris; – a needle was passed from this incision to the vaginal incision; – surgeon-tailored mesh was fixed to the needle and guided throughout the thigh; – to obtain a tension-free procedure a non-toothed forceps was placed between the sling and the urethra to avoid twisting of the tape; archivio italiano di urologia e andrologia 2023; 95, 2 80 single-incision needleless mini-sling technique for female stress urinary incontinence – the patient was asked to cough to assess the correction of stress incontinence; – a 3-0 vicryl suture was used to close the skin and vaginal incisions in sub-cuticular and interrupted fashions, respectively; – the vagina was packed with a povidone-iodine-soaked pack, and the urethral catheter was connected to closed-bag drainage (figure 1). in the sims: – the mesh was prepared using 15 x 15 cm monofilament mesh (polypropylene mesh; prolene, ethicon ltd., uk) to prepare t-pocket shaped strips of a total length of 12.5 cm; figure 2 (a-l). needle-less single incision mini-sling (sims). c. suburethral longitudinal midline incision of anterior vaginal wall in presence of urethral catheter. e. paraurethral spaces blunt dissection (at 10 o’clock position) until the descending ischiopubic ramus was reached. f. hyperextention of the stm t pocket by the forceps. g. hyperextention of the t pocket of stm by the forceps at other end of the stm tape. j. the t-pocket was then extended inside the internal obturator muscles by opening the forceps. the forceps were then closed and pulled off the vagina. k. visualization of suburethral tape untwisted before closure of the wound. l. closure of vaginal incision by vicryl 3/0 interrupted suture. h. by hyperextension and closure of the forceps the stm was folded into surgical forceps by placing the forceps inside the tpocket followed by opening and closing the forceps. i. forceps with the folded mesh was introduced by a controlled push at 45° from the horizontal plane in the previous dissected paraurethral space until a “crack” was felt that signified the penetration of the internal obturator fascia. d. paraurethral space blunt dissection at 2 o’clock position until the descending ischiopubic ramus was reached. a. polypropylene mesh 30 x 30 cm that will be tailored as tapes. b. polypropylene strips or tapes (surgical tailored mesh) each one 1 cm x 30 cm prepared for package and sterilization by plasma machine. – dissection was made bilaterally to reach the ischiopubic ramus; – the t-pocket shaped mesh was then folded into surgical forceps, which were introduced at 45 degrees to the dissected paraurethral space until the internal obturator fascia was penetrated; – the surgeon opened the forceps to extend the t-pocket shaped mesh and removed the pulling sutures after full positioning; – a 3-0 vicryl suture was used to close the vaginal incisions in an interrupted fashion. the vagina was packed with a povidone-iodine-soaked pack, and the urethral catheter was connected to closed-bag drainage (figure 2). archivio italiano di urologia e andrologia 2023; 95, 2 eman ali, salah e. shebl, sayeda ibrahim 81 women in both groups received routine postoperative care, and the vaginal pack and catheter were removed 12 hours after the operation in uneventful cases. follow-up and study's outcomes all women were followed biweekly in the first postoperative month, then every month for three months. the follow-up visits consist of subjective assessment of sui symptoms through the sui questionnaire and urodynamic studies. the surgical outcome was categorized according to the questionnaire and abdominal leak point pressures (allp) into: success, in which there is no urinary leakage with stress and patient's satisfaction; improve; in which there was leakage with severe exertion only; and failed, in which there is a persistent leakage and patient's dissatisfaction. statistical analysis retrieved data were summarized and processed with ibm spss statistical software (version 25). descriptive statistics were used to describe continuous and categorical data, respectively. the hypothesis of significant difference between the techniques regarding postoperative outcomes and complications was tested using the chi-square test, with fisher exact whenever needed. the association between technique and continuous data was tested using the mann-whitney test. p-value < 0.05 was regarded as statistically significant. results a total of 60 women were included in the present study. the mean age of the standard and sims groups was 45.6 ± 7.9 and 42.3 ± 6.6 years old, respectively. none of the patients was nulliparous. the mean number of deliveries in the standard group was 3.6±1.7, compared to 3.9 ± 1.1 deliveries in the sims group. two patients had cesarean section (cs) in addition to their vaginal deliveries. seven cases had associated preoperative urinary tract infection. almost 90% of the patients had no previous surgery, three patients (5%) underwent an abdominal hysterectomy, and three patients (5%) underwent previous vaginal prolapse repair surgery. nine (30%) patients had grade i cystocele in the standard group, and six (20%) patients had grade ii cystocele. five (16.6%) patients had grade i cystocele on examination in the sims group. the mean duration of symptoms was 2.73 ± 1.36 years (range 1-5 years). four cases only (6.67%) in both groups had an alpp less than 50 ml, which indicate intrinsic sphincteric deficiency. the preoperative urodynamic studies showed a mean bladder capacity of 382.76 ± 34.26 ml. no patient had detrusor overactivity or significant residual urine preoperatively (table 1). the mean operative time was significantly longer in the standard tot group (17.0 ± 2.9 min) compared to the sims group (10.7 ± 1.8 min). the mean bleeding rate was significantly higher in the standard tot group (87.6 ± 10.6 cc) compared to the sims group (60.0 ± 8.1 cc). one case (3.33%) had bladder injury in the sims group, which needed cystoscopy revealing a small bladder injury that was repaired immediately by vicryl 4/0 in two layers. there was no urethral injury in both groups. none of the studied patients developed intraoperative vaginal wall laceration (table 2). concerning early complications, re-catheterisation was not needed in any patient as there was no retention of urine or significant residual urine postoperatively. the incidence of postoperative urinary tract infection (uti) was 10% and was treated medically according to culture and sensitivity. three patients (two in the standard tot and one in the sims group) developed a vaginal discharge. postoperative wound infection was not found in any cases. none of the studied patients developed urine retention. in terms of late complications, transient thigh pain occurs in 12 cases (40%) of the standard tot and no cases in the sims group (p < 0.001). after three months from operation, vaginal discharge was reported in two cases (6.7%) treated with the appropriate antibiotics, antifungals, and frequent vaginal douches. five cases (20%) had urinary tract infection which was treated medically according to culture and sensitivity. dyspareunia, vaginal erosions and de novo urgency were not reported during postoperative follow up (table 2). after three months, there was no significant statistical difference between the result of the two groups as regard to cure or improvement rate, wherein the standard tot group, 27 cases (90%) and three cases (10%) were succeeded and improved, respectively, compared to 28 cases (93.33%) and two cases (6.66%) in the sims group. no table 1. preoperative data of both groups. variables stm standard tot stm sims p-value n = 30 % n = 30 % age (years) mean ± sd 45.6 ± 7.9 42.3 ± 6.6 p = 0.086 delivery normal vaginal delivery 3.6 ± 1.7 3.9 ± 1.1 p = 0.561 cesarean section 0.07 ± 0.25 0.03 ± 0.18 menopausal status pre menopause 20 (66.7%) 24 (80%) p = 0.243 post menopause 10 (33.3%) 6 (20%) surgical history patients with no previous surgery 25 (83.3%) 29 (96.7%) p = 0.163 previous vaginal prolapse repair surgery 3 (10%) 0 (0%) previous abdominal hysterectomy 2 (6.7%) 1 (3.3%) per vaginal examination normal 15 (50%) 25 (83.3%) p = 0.008* mild cystocele 9 (30%) 5 (16.7%) moderate cystocele 6 (20%) 0 (0%) severity of preoperative incontinence rate mild (0-1 pad/day) 2 (6.7%) 3 (10%) p = 0.707 moderate (2-3 pad/day) 14 (46.7%) 16 (53.3%) severe (4-5 or more pad/day) 14 (46.7%) 11 (36.7%) allp < 50 ml 2 (6.66%) 2 (6.66%) 51-100 ml 12 (40%) 16 (53.33%) 101-150 ml 14 (46.66%) 12 (40%) 151-200 ml 2 (6.66%) 0 (0%) archivio italiano di urologia e andrologia 2023; 95, 2 82 single-incision needleless mini-sling technique for female stress urinary incontinence failed cases were reported in both groups (p = 0.64) (figure 3). likewise, there was no significant difference between the two groups regarding patients' satisfaction rate. in the standard tot group, 23 cases (76.7%) were very satisfied, compared to 22 cases (73.3%) in the sims group (p = 1.00). discussion in this study, we included two comparable groups of women with no significant differences in terms of age, bmi, parity, or menopausal status. in addition, there were no significant differences in results of pelvic examination or cough stress test between women of both groups before surgery. however, in terms of operative time, stm sims needed a mean operative time of 10.7 minutes, which was significantly less than the mean operative time (17 minutes) needed by the stm standard tot procedure. similarly, hasan et al., demonstrated that the mean operative time of the mini-sling procedure was 8.3 minutes compared to 16.5 minutes in the standard tot procedure (5). the mean operative time of the single incision tot procedure was nine minutes and seven minutes in the studies conducted by cabrera et al. (19) and navazo et al. (20), respectively. regarding intraoperative blood loss, our findings showed that the standard tot was associated with significantly higher procedure-related blood loss compared to stm sims. in the hasan et al. study, single incision tot patients had a lower average than regular tot patients (51.5 vs. 123.1 ml), respectively (5). according to a study done by magon and chopra on 51 individuals, the average volume of blood loss in the conventional tot was 78.76 ml (21). dobson et al. showed that the blood loss was more than 100 ml in 71% of cases (22). moore et al. reported an average intraoperative blood loss of 57 ± 22 ml in the standard tot and 36 ml in the single incision tot (23). in our study, the early postoperative complications were more common in the standard tot, including groin pain, uti, and vaginal infection. however, intraoperative complications and late postoperative complications were similar in both groups. likewise, in the hasan et al. trial, there was no significant difference in iatrogenic organ injury and postoperative complications between the two groups (5). when amati et al. completed their investigation, they found that just one patient in each group had a bladder injury that could be attributed to the simultaneous surgery. in the group of standard tot, there was one case (3.3%) catheterized for two weeks due to intraoperative bladder injury (24). navazo et al. reported a mean catheterization time of 2.02 days (20). cabrera et al. mentioned that after the standard tot, the mean catheterization time was 1.52 days in 5 patients with acute retention (19). retention that needed catheterization for more than 24 hours following routine tot resolved spontaneously in less than two days in one case described by magon and chopra (21). it has been found that the prevalence of dyspareunia after sims ranges from 3 to 8% (richter et al.) (25). in our study, it was observed that neither group suffered from urge incontinence, voiding difficulties, urine retention, urethral or bladder erosions, or dyspareunia. according to karakeçi et al., postoperative dyspareunia occurred in 21% of patients in the midurethral sling (mus) group and 20% of patients in the sims group (26). according to several clinical trials, the percentage of voiding problems after sims ranged from zero to eight percent (27, 29). the proportion of patients experiencing pain after the procedure was reported to reach up to 15.5% (25). although the groin and leg pain spontaneously resolved within a few weeks in many cases, it may be prolonged in some patients. during the short mid-term follow-up, karakeçi et al. preferred the sims technique since it caused less groin pain (26). also, sims was preferred and recommended by more incontinence-suffering women (30, 31). sims has reduced complication rates due to little retropubic dissection and the absence of blind needle and mesh path in the groin region (26). patients were released from the hospital within 24 hours following surgery in our study with no significant differences in postoperative hospital stays between the two techniques. in the study of magon and chopra, the average hospitalization time was 1.6 days; 45.8% of patients were released within 24 hours after surgery, 50.88% were discharged between 24 and 72 hours after surgery, and only 3.4% of patients had to remain in the hospital for more than three days because of intraoperative complications (21). postoperative hospital stay was not significantly different between the two procedure (standard tot: 2.95 days and single-incision tot: 2.65 days), with a mean of 1.04 days including both procedures when there were no concomitant operations and of 2.65 days when there were concomitant operations (24). stm standard tot patients had an objective cure rate of 90% after three months, with a 10% improvement and no failed cases reported, while stm sims patients had an objective cure rate of 93.33% after three months, with a 6.66% improvement and no failed cases reported. cabrera et al. studied 230 women who had undergone single incision tot and found that 86% of them were table 2. operative time and complication of both groups. variables stm standard tot stm sims p-value n = 30 % n = 30 % operative time (minutes) p = 0.000* • 8-11 0 0.0 20 66.7 • 12-18 22 73.3 10 33.3 • 19-25 8 26.7 0 0.0 operative time (minutes), mean ± sd 17.0 ± 2.9 10.7 ± 1.8 p = 0.000* intra-operative complications p = 0.313 bladder injury 1 (3.3%) 0 bleeding rate (cc), mean ± sd 87.6 ± 10.6 60.0 ± 8.1 p = 0.000* vaginal wall laceration 0 0 early postoperative complications p = 0.000* • groin pain 12 (40%) 0 (0%) • urinary tract infection 2 (6.7%) 1 (3.3%) • vaginal infection 2 (6.7%) 1 (3.3%) • urine retention 0 (0%) 0 (0%) late postoperative complications p = 0.554 • mesh erosions 0 0 • de novo urgency 0 0 • dyspareunia 0 0 • vaginal discharge 1 (3.34%) 1 (3.34%) • urinary tract infection 3 (10%) 2 (6.7%) archivio italiano di urologia e andrologia 2023; 95, 2 eman ali, salah e. shebl, sayeda ibrahim 83 objectively cured after a year, with 6% showing improvement and 8% being classified as failures (19), while navazo et al. studied 120 women who had undergone single incision tot and found that 84% were objectively cured after a year, with 8% showing improvement (20). there were no failed cases in the initial case series performed by delorme et al. on 32 women who had undergone the conventional tot and had a cure rate of 90.6% at one year (32). at one year following the standard tot operation, the objective cure rate was 88-92% and the subjective cure rate was 68-90%, according to published studies (33). in conclusion, our study showed that sims was not inferior to standard tot. stm sims is a mini-invasive, relatively safe, reproducible, and economically effective surgical procedure for the treatment of female stress urinary incontinence. the stm for sims was easy to insert in a short time operation. it demonstrated excellent patient tolerability with minimal pain, early return to work and normal activity, and low morbidity when compared to stm standard tot. stm sims should be considered as a low-cost alternative to the available commercial kits in the treatment of female sui, mainly for public health systems with few financial resources. randomized controlled studies with a longer duration of follow-up are needed to confirm our results. references 1. luber km. the definition, prevalence, and risk factors for stress urinary incontinence. rev urol. 2004; 6(suppl 3):s3-s9. 2. aoki y, brown hw, brubaker l, et al. urinary incontinence in women. nat rev dis prim. 2017; 3:17042. 3. reynolds w, dmochowski r, penson d. epidemiology of stress urinary incontinence in women. curr urol rep. 2011; 12:370-376. 4. shirvan mk, rahimi hr, darabi mahboub mr, sheikhi z. tension-free vaginal tape versus transobturator tape for treatment of stress urinary incontinence: a comparative randomized clinical trial study. urol sci. 2014; 25:54-57. 5. hasan mra, abdelmagid me, tagreda ia. sub-urethral mini sling versus transobturator vaginal tape for treatment of female stress urinary incontinence, one year follow-up. egypt j hosp med. 2019; 76:3176-3183. 6. nerli rb, kumar ag, koura a, et al. transobturator vaginal tape in comparison to tension-free vaginal tape: a prospective trial with a minimum 12 months follow-up. indian j urol. 2009; 25:321-325. 7. zyczkowski m, nowakowski k, kuczmik w, et al. tension-free vaginal tape, transobturator tape, and own modification of transobturator tape in the treatment of female stress urinary incontinence: comparative analysis. biomed res int. 2014; 347856. 8. rajamaheshwari n, varghese l. transobturator tapes are preferable over transvaginal tapes for the management of female stress urinary incontinence: for. indian j urol. 2009; 25:550-553. 9. gomes cm, carvalho fl, bellucci chs, et al. update on complications of synthetic suburethral slings. int braz j urol. 2017; 43:822-834. 10. khan fn, hamid a, wazir bs, et al. an evaluation of use of trans-obturator tape (tot) sling procedure in the current surgical management of female stress urinary incontinence. int j health sci (qassim). 2008; 2:118-125. 11. ford aa, rogerson l, cody jd, et al. mid-urethral sling operations for stress urinary incontinence in women. cochrane database syst rev. 2017; 7:cd006375-cd006375. 12. sergouniotis f, jarlshammar b, larsson p-g. urethral complications after tension-free vaginal tape procedures: a surgical management case series. world j nephrol. 2015; 4:396-405. 13. wu e, high r, lewis c, et al. retropubic mid-urethral slings and de novo urinary urgency and frequency: the role of retropubic hematomas. neurourol urodyn. 2021; 40:1686-1694. 14. leanza v, intagliata e, leanza a, et al. comparison between three mini-sling surgical procedures and the traditional transobturator vaginal tape technique for female stress urinary incontinence. g chir. 2014; 35:80-84. 15. abdel-fattah m, maclennan g, kilonzo m, et al. the sims trial: adjustable anchored single-incision mini-slings versus standard tension-free midurethral slings in the surgical management of female stress urinary incontinence. a study protocol for a pragmatic, multicentre, non-inferiority randomised con. bmj open. 2017; 7:e015111-e015111. 16. java. declaration of helsinki world medical association declaration of helsinki. bull world heal organ. 2013; 79:373-374. 17. schulz kf, altman dg, moher d, et al. consort 2010 statement: updated guidelines for reporting parallel group randomised trials (chinese version). j chinese integr med. 2010; 8:604-612. 18. sand pk, winkler h, blackhurst dw, culligan pj. a prospective randomized study comparing modified burch retropubic urethropexy and suburethral sling for treatment of genuine stress incontinence with low-pressure urethra. am j obstet gynecol. 2000; 182:30-34. 19. cabrera j, puyol m, sousa a, et al. minimal invasive surgical technique without needles. (contasure needleless) for the surgical treatment of stress urinary incontinence: a multicentric trial. eur urol suppl eur urol suppl. 2008; 7:147. 20. navazo r, sierra j, hidalgo c, et al. contasure needleless: a single incision tot for the surgical treatment of stress urinary incontinence. arch esp urol. 2009; 62:719-723. 21. magon n, chopra s. transobturator tape in treatment of stress urinary incontinence: it is time for a new gold standard. n am j med sci. 2012; 4:226-230. 22. dobson a, robert m, swaby c, et al. trans-obturator surgery for stress urinary incontinence: 1-year follow-up of a cohort of 52 women. int urogynecol j pelvic floor dysfunct. 2007; 18:27-32. 23. moore rd, jr m, m c. monarc transtobturator sling: combined analysis of one-year followup in nine countries with 266 patients. int urogynecol j pelvic floor dysfunct. 2006; 17:203-207. 24. amati lt me and lj contasure-needleless® compared with transobturator-tvt® for the treatment of stress urinary incontinence. int urogynecol j. 2001; 22:827-33. 25. richter he, albo me, zyczynski hm, et al. retropubic versus transobturator midurethral slings for stress incontinence. n engl j med 2010; 362:2066-2076. 26. karakeçi a, eftal tc, keleş a, et al. single-incision midurethral sling shows less pain and similar success rate in a short-term followup compared to the transobturator tape method in the treatment of stress urinary incontinence. turkish j urol. 2020; 46:63-68. archivio italiano di urologia e andrologia 2023; 95, 2 84 single-incision needleless mini-sling technique for female stress urinary incontinence 27. maturana ap, palos cc, ghersel fr, et al. randomized controlled trial comparing mini-sling with transobturator sling for the treatment of stress urinary incontinence. int urogynecol j. 2020; 31:1925-1931. 28. djehdian lm, araujo mp, takano cc, et al. transobturator sling compared with single-incision mini-sling for the treatment of stress urinary incontinence: a randomized controlled trial. obstet gynecol. 2014; 123:553-561. 29. pascom alg, djehdian lm, bortolini mat, et al. randomized controlled trial comparing single-incision mini-sling and transobturator midurethral sling for the treatment of stress urinary incontinence: 3-year follow-up results. neurourol urodyn. 2018; 37:2184-2190. 30. sangsawang b, sangsawang n. stress urinary incontinence in pregnant women: a review of prevalence, pathophysiology, and treatment. int urogynecol j. 2013; 24:901-912. 31. de vries am, heesakkers jpfa. contemporary diagnostics and treatment options for female stress urinary incontinence. asian j urol. 2018; 5:141-148. 32. delorme e, droupy s, de tayrac r, delmas v. transobturator tape (uratape). a new minimally invasive method in the treatment of urinary incontinence in women. progr urol. 2003; 13:656-659. 33. deval b, ferchaux j, berry r, et al. objective and subjective cure rates after trans-obturator tape (obtape) treatment of female urinary incontinence. eur urol. 2006 49:373-377. correspondence salah e. shebl, md (corresponding author) salahshebl@yahoo.com salahshebl@azhar.edu.eg urology department, faculty of medicine for girls al-azhar university, al zahraa university hospital, al-azhar university, abbasia, cairo, egypt sayeda ibrahim, md soso_uro@yahoo.com eman aly, md dr.emanaly200@gmil.com urology department, faculty of medicine for girls, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. 73archivio italiano di urologia e andrologia 2020; 92, 2 original paper summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.73 carlo maretti 1, salvatore privitera 2, davide arcaniolo 3, lorenzo cirigliano 4, adele fabrizi 5, michele rizzo 6, carlo ceruti 7, ilaria ortensi 8, stefano lauretti 9, tommaso cai 10, marco bitelli 11, fabrizio palumbo 12, alessandro palmieri 4 1 department of andrology , cirm medical center , piacenza, italy; 2 department of urology, university hospital “g. rodolico”, catania, italy; 3 unit of urology, university of campania “luigi vanvitelli” , naples, italy; 4 department of urology, university “federico ii”, naples, italy; 5 institute of clinical sexology, rome, italy; 6 department of urology, university of trieste, trieste, italy; 7 department of urology, university of turin, turin, italy; 8 altamedicaartemisia center, rome, italy; 9 department of urology, “s. caterina della rosa” clinic, rome, italy; 10 department of urology, “santa chiara hospital”, trento, italy; 11 department of urology, “san sebastiano martire” hospital, frascati, rome, italy; 12 department of urology, “san giacomo” hospital, monopoli, bari, italy. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology and on the basis of phylogeny, taxonomy and consolidated practice. the disease caused by the new coronavirus has been named ‘covid-19’ (where "co" stands for corona, "vi" for virus, "d" for disease and "19" indicates the year in which it occurred). the coronavirus study group formally associated this virus to the coronavirus that causes severe acute respiratory syndrome coronaviruses (sars-covs), classifying it as severe acute respiratory syndrome coronavirus 2 (sars-cov-2) (1-3). italy was the first european country, to state the outbreak of the infection. the italian council of ministers declared the state of health emergency on 31.01.2020. after the infection of 100.000 people in 100 countries the world health organization ruled a global pandemic on 11.03.2020 (4). on 13 march 2020 the italian government’s “i stay home” decree suspended all non-urgent and non-essential services, blocking people’s movements unless proven needs or emergencies. these same restrictive measures were then adopted by many other european countries with the aim of reducing the spread of the pandemic. moreover, according to the “i stay home” decree issued by the italian government people are forced stay home without outdoor activities or social contact with psychological implications and high impact on the quality of sexual life. based on available evidences, the italian society of andrology have tried to provide recommendations with the aim of helping people to face their sexual life in this peculiar period and healthcare professionals to establish an effective communication with their patients (5). evidence acquisition we performed a systematic literature search of pubmed, medline, web of science and google scholar using medical subject headings (mesh) indexes, keyword searches, and introduction coronavirus 2019 (covid-19) is an infectious disease caused by a virus first detected in patients with pneumonia in wuhan, the extensive capital of hubei province, china, at the end of december 2019. the coronavirus study group (csg) of the international committee on taxonomy of viruses (ictv), officially classified with the name of sars-cov-2 the virus provisionally called 2019-ncov by the world health organization, after having evaluated the novelties of the "new" human pathogen severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is the coronavirus that causes an infectious disease, called covid-19, first detected in patients with pneumonia in wuhan (people's republic of china) on december 2019. italy was the first european country to state the outbreak of the infection and its council of ministers declared the state of health emergency on 31.01.2020, then the world health organization ruled a global pandemic on 11.03.2020. the nasopharyngeal swab is based on the detection of virus rna and is the only reliable one for declaring covid-19 infection. the most common symptoms observed in covid-19 patients before hospitalization may be fever, chills, cough, dyspnea, asthenia, myalgia and/or arthralgia. this symptomatology can be often complicated in a dramatically increasing manner such as to require hospitalization starting from the third-fourth week. covid-19 outbreak has dramatically affected the quality of life by changing inter-personal relationships, community life and obviously sexual health. the purpose of this work, based on available evidence, is to provide recommendations to help the population to face their sexual life in this critical period. key words: covid-19, sexual-life; outbreak; recommendations; sia (italian society of andrology); sars-cov-2; reproductive health; sex; pandemic. submitted 14 may 2020; accepted 15 may 2020 maretti_stesura seveso 17/06/20 10:04 pagina 73 archivio italiano di urologia e andrologia 2020; 92, 2 c. maretti, s. privitera, d. arcaniolo, et al. 74 publication types until april 2020 for studies evaluating corona virus disease 2019 (covid-19) and its impact on population health and sexual and reproductive life. the search terms, limited to english language articles, included “covid-19”, “covid19”, “sars-cov-2”, “corona virus disease 2019”, “coronavirus”, “sexual-life”, “outbreak”, “reproductive health”, “pandemic”, “quarantine”. we also searched reference lists of relevant articles. we have finally evaluated the non-indexed literature and what was published on the web by the world health organization and the most important institutions with particular reference to the italian state. virus pathogenesis sars-cov-2 is mainly transmitted via respiratory droplets, even if other extra-pulmonary transmissions has been suggested. viral rna has also been found, with variable frequency, in the feces and blood of covid-19 patients. however, the possibility of infection from these materials is currently controversial (6). the pathogenesis of sars-cov-2 is complex and it is not fully defined because multiple factors can intervene and a wide range of clinical manifestations can be developed (7). the primary viral replication occurs in mucosal epithelium of upper respiratory tract. then the virus proceeds with further multiplication in lower respiratory tract and gastrointestinal mucosa (8). at this stage it is possible to observe an initial low-grade viremia. it is also possible to develop extra respiratory symptoms, implying multiple organ involvement, such as acute pain in the liver and in the heart, kidney failure, diarrhoea (9). ace2 receptors through which the virus enters the cells (10), is broadly expressed in nasal mucosa, bronchus, lungs, heart, oesophagus, kidneys, stomach, bladder, and ileum. these organs are vulnerable to sars-cov-2 (11, 12). ace2 receptors are also expressed in many other tissues, such as the testicle. clinicians are also studying the effects of sars-cov-2 on testicular tissues and potential consequences on fertility (13). a recent study suggests that the testis is a high-risk organ vulnerable to sars-cov-2 infection that may result in spermatogenic failure. these investigation states that the reproductive functions should be followed and evaluated in recovered covid-2019 male patients (14). another study, instead, does not reveal any influence of sars-cov-2 in the testis cells (e.g. germ cells, leydig cells, sertoli cells, etc). however, future studies are needed to evaluate the impact of covid-19 on male reproduction and pregnancy rate. furthermore, as more than 80% of those who are infected by the coronavirus are asymptomatic, the reproductive implications for these men would likely be favorable but they remain unknown right now (15). around 7 to 14 days after onset, the virus then begins a second attack which can determine a clinical worsening in patients. antibody production can be affected by a reduction in b lymphocyte that may occur early in the disease. pneumonia appears to be the most frequent serious manifestation of infection. pathological findings from severe covid-19 show pulmonary bilateral diffuse alveolar damage with signs of acute respiratory distress syndrome (ards) and in both lungs can be observed interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes. these pulmonary pathological findings extremely resemble those seen in sars and mers. ards is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the circulation and can have fatal consequences. covid-19 patients developing ards may require mechanical ventilation. ards development is due to an exuberant inflammatory response during sars-cov-2 infection. the pathological mechanism that causes pneumonia is still being studied but would seem to be linked to an excessive host immune reaction; the latter can be so massive that it is precisely labelled as a "cytokine storm". the cytokine storm determines the aggressive the protagonist of this “storm” is interleukin 6 (il-6) (16). the cause of this production of exuberant proinflammatory cytokines (ifn-α, ifn-γ, il-1β, il-6, il12, il-18, il-33, tnf-α, tgfγ, etc.) and chemokines (ccl2, ccl3, ccl5, cxcl8, cxcl9, cxcl10, etc.) is to be found in initial rapid viral replication, accompanied with massive epithelial cell death and an endothelial disfunction which generates an intravascular coagulation with generalized thrombotic phenomena. additionally, several studies have reported that lymphopenia is a common feature of covid-19, suggestive of a critical factor accounting for severity and mortality (9, 17, 18). molecular and serological analysis of covid-19 the nasopharyngeal swab is based on the detection of virus rna and is the only reliable one for declaring covid-19 infection. extraction and purification of rna is carried out by picking a little of biological material using a rapid molecular method named reverse realtime pcr (rrt-pcr), where the use of molecular probes makes this test extremely specific. the serological tests are still unreliable because they do not diagnose very recent infections and where the results must then be confirmed by the swabs. even if the serological tests could be the winning key for people monitoring, there is still no evidence on their reliability. serological tests are divided into two categories, quantitative and qualitative tests. qualitative tests include rapid tests that produce a high percentage of false negatives and false positives and therefore they are unreliable for now. in quantitative serological tests, the kinetics of the igm and igg antisars-cov-2 antibodies is different between patients under intensive or sub-intensive therapy and asymptomatic or pauci-symptomatic patients where the production of immunoglobulins (igm and igg) occurs with longer times. the quantitative tests are therefore unable to detect cov-2 infections early, due to poor sensitivity and the need to confirm, in case of positivity, with a further molecular test. to conclude, serological tests do not replace molecular tests but are complementary, especially in the case of asymptomatic subjects (19). moreover, serological tests seem interesting to collect epidemiological data and plan the future health-care strategies. covid-19 clinical presentation the most common symptoms observed in covid-19 patients before hospitalization may be fever, chills, cough, dyspnea, asthenia, myalgia and/or arthralgia. less common signs are nausea and vomit, nasal congestion, maretti_stesura seveso 17/06/20 10:04 pagina 74 hemoptysis, diarrhea, conjunctivitis (7). as recently reported by guan et al. fever was present in 43.8% out of 109 patients with covid-19, on admission, then it developed in 88.7% during hospitalization. the second most common symptom was dry cough (67.8%) while nausea or vomit (5.0%) and diarrhea (3.8%) were uncommon (20). this symptomatology can be often complicated in a dramatically increasing manner such as to require hospitalization starting from the third-fourth week. in severe cases, pneumonia, acute respiratory distress syndrome, sepsis, septic shock and endothelial dysfunction with diffuse thrombotic embolism can occur till to cause the patient's death especially for more fragile subjects or the presence of pre-existing comorbidities (21). it is important to remember that patients affected by covid-19 can be also asymptomatic or who report mild symptoms, thus contributing considerably to the spread of the virus in the community (21, 22). the purpose of our recommendations is to provide some guidelines based on the available evidences for a safe sexual life during covid-19 outbreak. virus trasmission to prescribe the correct behaviors to adopt for a safe sexual life it is essential to know, in details, the virus transmission modalities. regarding the human species, the transmission routes of the virus can be direct or indirect. the direct transmission of covid-19 occurs mainly through the inhalation of droplets that are generated when an infected person speaks, coughs or sneezes; the transmission mode is therefore linked to short-distance interhuman contact. for this reason, it is recommended a two-meter distance at least. in closed environments where droplets can remain as aerosol in the air, it is recommended to ventilate three times a day for at least 15 minutes each time. indirect infection can be transferred by animated vectors, such as animals (e.g. an infected person sneezing on the pet's fur) or inanimate (air, soil, food, personal effects, toys, paper sheets, money, plastic or metal surfaces, smart-phone, pc etc.) (23). sarscov-2 remains viable in aerosols for several hours and is more stable on plastic and stainless steel (72 h) than on copper and cardboard (3-4 h), and viable virus is detected after application to these surfaces (24). sars-cov-2 was found in the feces of infected people (8). in fact a transmission through anal intercourse cannot be excluded due to the possible presence of the virus on the penile glans mucosa. some authors found the virus in the urine in 6.9% of the recovered patients (25, 26). although there are not many available data, it would appear that the virus is not detectable in the vaginal fluid of women affected by covid-19 (27). there is no evidence to demonstrate the presence of the virus in the female and male reproductive system. infection implies the entry and possible multiplication in the organism of the virus that can lead to the latent (asymptomatic patients or who report mild symptoms) or full-blown state of the disease. during its course, infectious agents can infect other people. the infection index (r0) changes daily and in order to be safe r0 has to be below 1. in italy, depending on the various geographical area, it varies from 2.4 to 4.0 at the moment. although the main methods of infection occur by air, they can also occur through sexual contact (28, 29). psycho-sexuological implications of lockdown from a psychological point of view, the lockdown condition involves an increase in obsessive fear of contamination, feelings of uncertainty, dismay, worry, anxiety and depression. many people have feelings of anger, irritability, insomnia, fear, boredom, anxiety related to the economic situation and, in some cases, a real risk of post-traumatic stress disorder (30). people with previous emotional and psychological fragility are at risk, as well as couples with disabled children or other health problems, conflictual couples and especially those where domestic violence is present. social distancing slows down the spread of the virus, but it also forces us to repress or modify our need for closeness and relationship, leading us to reformulate our sexual life as well. according to the new york department of health guidelines (29), it is reasonably safe to have sexual intercourse between cohabiting partners, unless one or both partner have professional risk of infection or they do present one or mere covid-19 symptoms. condoms can reduce contact with saliva or feces, especially during oral or anal sex. in a study by hamermesh, it was found that the happiness of married individuals could have been slightly increased by isolation. this is not true for single people, where levels of happiness are diminished by losing their jobs and not being able to see other people (31). married people’s happiness rises with additional time spent with a spouse, while singles’ happiness falls as they spend more time alone. this pandemic allows us to think of a new sexual intimacy also mediated by sex toys and technology. in conclusion, people who are experiencing the current social distancing are more likely to report discomfort due to fear and risk perceptions that may have an impact on their sex and couple life, but safe sex between intimate couples can be an activity to support psychologically fragile people living in restricted areas for longer quarantine periods. however, proper considerations of the risk can increase resilience. during lockdown, sex between habitual partners without symptoms, and cohabiting since the beginning of the restrictions is to be considered a real tool to stay connected and relieve anxiety during forced cohabitation. finally, irritability, sadness, reduced or disturbed sleep, apathy, catastrophic thoughts that last a long time must warn us and eventually lead us to ask for help (32). recovered patients a patient, who previously manifested any symptoms associated to the infection by covid-19, is considered "clinically recovered" if clinical symptoms have been resolved. however, despite being clinically recovered, therefore asymptomatic, the patient can still present a positive oral swab at sars-cov-2. when a patient, in addition to symptoms of covid-19 disappearance, shows two negative results to oral swabs carried out consecutively, 24 hours apart from each other, is then considered a "healed patient" (33). patients that tested positive, if asymptomatic, have to repeat the test (two oral swabs 24 hours apart from each other) after 14 days from the first test. the same goes for the symptomatic 75archivio italiano di urologia e andrologia 2020; 92, 2 covid-19 and sex: recommendations from sia maretti_stesura seveso 17/06/20 10:04 pagina 75 archivio italiano di urologia e andrologia 2020; 92, 2 c. maretti, s. privitera, d. arcaniolo, et al. 76 patient after 14 days after the resolution of clinical symptoms, to verify that he/she has become negative(33, 34). in addition to the oral swab it could also be useful to perform an anal swab before discharging a patient, even if this is not routinely performed in clinical practice. recommendations for sexual life and reproductive health during covid-19 pandemic according to the previous discussed topics, these recommendations should be followed: • regular de-facto couple, if negative and if it had not been infected, would not have any problem in lockdown time. • there is evidence of oral-fecal transmission of the sars-cov-2, that’s to say analingus could represent a theoretical risk for virus spreading. • kissing can transmit the virus through saliva in case of an asymptomatic partner. • indirect infection through hands contamination. washing hands thoroughly is more important than ever. the necessary time for a good hand wash with soap have to be at least 40-60 seconds. you can also use an alcohol-based hand disinfectant (> 60% ethyl alcohol). • independently from a sexual intercourse in a familiar environment disinfect keyboards and touch screens that are shared with others. simple disinfectants containing 75% alcohol (ethanol) or 0.5% chlorine-based (bleach) can be used for the purpose. • sex toys can be used safely if washed with water and soap or disinfected as before suggested. • masturbation will not spread covid-19, if hands and any sex toys are carefully washed. • any close contact, including sex, with anyone outside family environment should be avoided. • try to have close contacts only with your partner, follow the recommendations previously given and remember that the virus can also spread with an asymptomatic partner. • avoid any other sex behaviors.. • it would be appropriate for the couple to discontinue temporarily any new medically assisted procreation (pma) treatments during outbreak as established by the ministerial decree and by the italian institute of health (35). • there is no strong evidence of a risk of vertical maternal-fetal transmission, although it is a well-recognized risk (36, 37). fetal distress and preterm delivery were reported in some other cases where infection occurred in the third trimester (38). pregnancy women have not a higher risk to contracting the virus compared to general population, but pregnancy itself is a risk factor for morbidity and death in previous flu epidemic (39). decision to become pregnant must be carefully considered in this period. conclusions covid-19 outbreak has dramatically affected the quality of life by changing inter-personal relationships, community life and obviously sexual health. the italian society of andrology, based on available evidence, provided recommendations to help people to face their sexual life in this critical period. author contributions cm conceived of the study and 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[epub ahead of print] 28. adhikari sp, meng s, wu yj, et al. epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid-19) during the early outbreak period: a scoping review. infect dis poverty. 2020; 9:29. 29. sex and covid the nyc health department may change recommendations as the situation evolves from 24.03.2020. https://www1.nyc.gov/assets/doh/downloads/pdf/imm/covid-sex-guidance.pdf 30. brooks sk, webster rk, smith le, et al. the psychological impact of quarantine and how to reduce it: rapid review of the evidence, lancet 2020; 395:912-20. 31. hamermesh ds. lockdowns, loneliness and life satisfaction. institute of labor economics, iza. 2020. 32. genadek kr, flood sm, moen p. for better or worse? couples' time together in encore adulthood. j gerontol b psychol sci soc sci. 2019; 74:329-338. 33. italian ministry of health c.s.s. march 2020. 34. zhang w, du rh, li b, et al. molecular and serological investigation of 2019-ncov infected patients: implication of multiple shedding routes. emerg microbes infect. 2020; 9:386-389. 35. position paper società italiana riproduzione umana (siru) covid-19. 10.03.2020. https://www.pmaumanizzata.com/ dasiruunataskforce.pdf 36. chen h, guo j, wang c, et al. clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records. lancet. 2020; 395:809-815. 37. dong l, tian j, he s, et al. possible vertical transmission of sars-cov-2 from an infected mother to her newborn. jama. 2020 mar 26. doi: 10.1001/jama.2020.4621. [epub ahead of print] 38. rasmussen sa, smulian jc, lednicky ja, et al. coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know. am j obstet gynecol. 2020; 222:415-426. 39. rasmussen sa, jamieson dj, bresee js. pandemic influenza and pregnant women. emerg infect dis. 2008; 14:95-100. 77archivio italiano di urologia e andrologia 2020; 92, 2 covid-19 and sex: recommendations from sia correspondence carlo maretti, md department of andrology, cirm medical center , piacenza 29121 (italy) salvatore privitera, md salvoprivi82@gmail.com department of urology, university hospital “g. rodolico”, via santa sofia 78, 95123 catania (italy) davide arcaniolo, md unit of urology, university of campania “luigi vanvitelli” , naples 80131 (italy) lorenzo cirigliano, md alessandro palmieri, md department of urology, university “federico ii” , naples 80138 (italy) adele fabrizi, md institute of clinical sexology, rome 00198 (italy) michele rizzo, md department of urology, university of trieste, trieste 34139 (italy) carlo ceruti, md department of urology, university of turin, turin 10126 (italy) ilaria ortensi, md altamedicaartemisia center, rome 00198 (italy) stefano lauretti, md department of urology, “s. caterina della rosa” clinic, rome 00176 (italy) tommaso cai, md department of urology, “santa chiara hospital”, trento 38122 (italy) marco bitelli, md department of urology, “san sebastiano martire” hospital, frascati, rome 00044 (italy) fabrizio palumbo, md department of urology, “san giacomo” hospital, monopoli, bari 70043 (italy) maretti_stesura seveso 17/06/20 10:04 pagina 77 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4464 original paper no conflict of interest declared. comorbidities such as chronic fatigue, loss of libido, erectile dysfunction, low haematocrit level, cardiovascular events, and decreased bone density (3). several studies consistently show significant relationships between serum testosterone and t2dm (4). many studies reported that 25% to 50% of type 2 diabetic males have lowered testosterone levels (5). hence, testosterone deficiency in t2dm has high clinical importance. although male hypogonadism (mhg) in t2dm has been investigated in many researches, the mechanism underlying the pathogenesis of testosterone deficiency in diabetes is still not fully understood yet (6). the majority of previous studies have assessed testosterone levels in elderly, obese males with t2dm (7). on other hand, it is well established that obesity is a major risk factor for type 2 diabetes and cardiovascular disease (8). several studies have linked male hypogonadism with being overweight or obese (9). large population-based studies have confirmed that obesity is the single most important factor associated with low testosterone, overriding the effects of age and comorbidities (10). therefore, it is unclear whether this is ascribable to the diabetic state per se, or because of other factors, such as obesity or age. hence, the role of the diabetic state in relation to the effects of obesity and comorbidities on testosterone levels in diabetic men is debatable (11). in this study, we tried to limit the confounding factor that affects the testosterone levels in diabetic males such as obesity. therefore, we aimed to investigate the prevalence and identify the predictors for testosterone deficiency among non-obese type 2 male diabetic patients. patients and methods study population this cross-sectional study was conducted at mansoura university's endocrinology, diabetes, and metabolism unit, specialized medical hospital, between march 2021 and august 2021. the mansoura faculty of medicine's institutional research board approved the study design. all study participants provided written informed consent. we enrolled 95 patients aged 25 to 65 who had been diagnosed with t2dm using the american diabetes association's diabetes diagnosis criteria. inclusion criteria were set as follows: males with type 2 background and aims: it is unclear whether male hypogonadism is ascribable to the diabetic state per se, or because of other factors, such as obesity or age. we aimed to investigate the prevalence and identify the predictors for testosterone deficiency among non-obese type 2 diabetic males. methods: this cross-sectional study was conducted on 95 nonobese type 2 diabetic males with bmi below 30. we evaluated the total testosterone (tt) levels to determine prevalence and risk factors of testosterone deficiency. serum tt ≤ 300 ng/dl defined testosterone deficiency. results: the prevalence of testosterone deficiency was 29.1%. testosterone deficient patients had statistically significantly higher visceral adiposity index (vai), waist, and triglyceride in comparison with normal testosterone patients. tt level correlated with vai, waist, bmi, lh, and age. vai was the only significant predictor of tt levels even after adjustment for age and bmi in regression analysis. furthermore, vai was a statistically significant risk factor for testosterone deficiency in binary logistic analysis. conclusions: testosterone deficient non-obese type 2 diabetic male patients had elevated vai, waist, and triglyceride. moreover, elevated vai was a risk factor for testosterone deficiency. vai could be an easily applicable and reliable index for the evaluation and prediction in type 2 non-obese diabetic males. key words: non-obese; t2dm; visceral obesity; testosterone; vai; males. submitted 5 march 2022; accepted 2 april 2022 introduction diabetes mellitus (dm) is a major cause of health concern due to its increasing prevalence rate worldwide. by the turn of the last decade, the international diabetes federation (idf) estimated that 404.7 million people worldwide had type 2 diabetes mellitus (t2dm), with the total number of diabetic patients expected to rise to 679.7 million by 2045 (1). one complication of type 2 diabetes (t2dm) is hypothalamic-pituitary-testicular axis (hpt axis) dysfunction. the hallmark of hpt axis dysfunction is characterized by subnormal testosterone levels in association with non-elevated luteinizing hormone concentrations. these abnormalities were not affected by the duration or severity of diabetes (2). testosterone deficiency is associated with many testosterone deficiency in non-obese type 2 diabetic male patients sherihan i. gouda 1, mohamed m. aboelnaga 1, ahmed m.g. elbeltagy 2, amro elbaz 1 1 endocrinology and diabetes unit, faculty of medicine, mansoura university, mansoura, egypt; 2 clinical pathology department, faculty of medicine, mansoura university, mansoura, egypt. doi: 10.4081/aiua.2022.4.464 summary 465archivio italiano di urologia e andrologia 2022; 94, 4 testosterone deficiency in non-obese type 2 diabetic male patients diabetes; body mass index below 30; history of normal pubertal development; a normal sense of smell for exclusion of kallman syndrome; age between 18 and 65. in contrast, patients were excluded from this study in case of: female sex; abnormal renal function; abnormal albumin levels; diabetes with macro albuminuria; liver disorders; heart failure; usea of drugs that may affect testosterone levels, such as replacement therapy and anabolic steroids; patients with known causes of hypogonadism; history of malignancy; autoimmune diseases; diseases of the endocrine system other than type 2 dm, including type 1 dm, pituitary disorders, and abnormal thyroid functions. all patients were divided into either a low testosterone group (tt ≤ 300 ng/dl) or a normal testosterone group (tt > 300 ng/dl). clinical assessment and anthropometric measurements all subjects underwent a comprehensive medical evaluation including medical history with special emphasis on diabetes duration, medication, smoking history, and diabetic complications history; physical examination and measurement of anthropometric parameters. the patient's height and weight were measured while they were dressed casually and were not wearing shoes. bmi was calculated by dividing weight (kg) by height square (m2). waist circumference (wc) was measured halfway between the inferior border of the last rib and the crest of the ilium at the end of expiration. following standard procedure, blood pressure was measured with a sphygmomanometer. vai was calculated for all participants using the following formula for males (12): vai: wc / [39:68 + (1.88 × bmi)] × tg/1:03 × 1:31/hdl. biochemical parameters after a 12-hour overnight fast, venous blood samples were collected from all patients between 8 a.m. and 10 a.m. including: complete blood count (cbc), fasting lipid profile that included triglycerides (tg), total cholesterol (tc), low-density lipoprotein (ldl), and high-density lipoprotein (hdl); serum creatinine; glycosylated haemoglobin (hba1c); fasting blood sugar; albumin; luteinizing hormone (lh); serum total testosterone. ldl-cholesterol was estimated according to the friedewald formula (tc minus hdl-cholesterol minus tgs/5 in mg/dl). visceral adiposity index (vai) was calculated for women and men according to the formulas. definition diabetes was defined as a fasting plasma glucose of 100 mg/dl or higher, hba1c of 6.5% or higher, or a previous diagnosis of type 2 diabetes. hypertension was defined as systolic blood pressure ≥ 140 mmhg, diastolic blood pressure ≥ 90 mmhg, current use of the antihypertensive drug. overweight was defined by a body mass index of at least 25 kg/m2. testosterone deficiency was defined as serum tt less than 300 ng/dl that is the lower limit of the normal range according to the american urological association guidelines (13). lh level above 9.4 iu/l was defined as hypergonadotropic hypogonadism, while lh levels below 9.4 iu/l were defined as hypogonadotropic hypogonadism (14). statistical analysis the statistical package for the social sciences (spss), version 23 was used to analyze the statistical data. continuous variables were presented as the mean ±standard deviation, and categorical variables were expressed as a proportion (%) whereas non-normally distributed data are expressed as the median (interquartile range). differences between groups of patients were compared by the mann-whitney u or student t-test for continuous variables and the chi-square test for categorical variables. the relationship between testosterone (the dependent variable) and other statistically significant correlated parameters in pearson correlation (the independent variables) was investigated using linear regression. the risk factors associated with testosterone deficiency were assessed using binary logistic regression, and the odds ratio (or) and 95 per cent confidence interval (ci) were calculated. p values less than 0.05 were considered statistically significant. results we enrolled ninety-six non-obese patients with type 2 dm in this cross-sectional study. among those diabetic patients, 27 (28.4%) were of normal weight, while 68 (71.6%) were overweight. their age ranged between 34 and 65 years. we observed that the prevalence of testosterone deficiency was 29.1% (28 patients). we observed high abnormal level of lh in 14 patients with low testosterone levels. the prevalence of hypergonadotropic hypogonadism was 50% of testosterone deficient patients. other clinical, anthropometric, and laboratory details of the patient were presented in table 1. table 1. general characteristics of the study population. n = 96 age (year) 51.41 ± 7.17 diabetic duration(year) 9.59 ± 4.18 smoker ratio 66 (47.1% ) insulin therapy 52 (37.1% ) body weight (kg) 86.69 ± 7.96 height (m) 1.78 ± .058 bmi (kg/m2) 28.245 (3.05) waist circumference(cm) 99.48 ± 9.68 systolic bp (mmhg) 135.00 (15) diastolic bp (mmhg) 85.00 (15) total cholesterol mg/dl 248.54 ± 43.29 ldl-c mg/dl 155.88 ± 47.98 hdl-c mg/dl 43.83 ± 6.85 triglycerides mg/dl 244.14±74.48 uacr mg/gm 28 (62) retinopathy 29 (30.2% ) hba1c % 8.5 ± 1.613 total testosterone ng/dl 405.71 ± 133.78 testosterone deficiency 28 (29.1%) lh miu/l 7.44 ± 2.67 vai 3.25 (1.58) data expressed as mean (interquartile range) according normality of distribution, data expressed as mean ± standard deviation or data expressed in parenthesis are percentage. bm: body mass index; wc: waist circumference; sbp: systolic blood pressure; dbp: diastolic blood pressure; ldl: low-density lipoprotein; hdl: high-density lipoprotein; uacr: urinary albumin creatinine ratio; hba1c: glycated hemoglobin; lh: luteinizing hormone; vai: visceral adiposity index. archivio italiano di urologia e andrologia 2022; 94, 4 s.i. gouda, m.m. aboelnaga, a.m.g. elbeltagy, a. elbaz 466 in the comparison between 28 patients in the low testosterone group (tt ≤ 300 ng/dl) and 68 patients in the normal testosterone group (tt > 300 ng/dl), we found that the low testosterone group had a statistically significant higher mean or median of vai, wc, and triglyceride in comparison with normal testosterone group. moreover, a higher percentage of patients complicated with retinopathy was observed in low testosterone groups. other differences between the two groups were shown in table 2. according to pearson correlations, tt was negatively correlated with vai (log), wc, bmi (log), and lh. on the other hand, tt was positively correlated to age. however, tt was not correlated with duration of diabetes, hba1c, or lipid parameters. we conducted a regression analysis to determine predictors of total testosterone levels as the dependent variable and age, bmi (log), lh, and vai (log) as the independent variables in our study patients. we observed that vai was the only significant predictor of tt levels (p-value = 0.41). furthermore, vai was a statistically significant predictor of tt levels even after adjustment for age and bmi as shown in tables 3, 4. the binary logistic regression was performed with hypogonadism as the dependent variable and age, overweight (defined by bmi more than 30), wc, lh, retinopathy, and vai (log) as the independent variables. we observed that the visceral adiposity index was a statistically significant risk factor for testosterone deficiency among nonobese type 2 diabetic males (p-value = 0.46). more data are available in table 5. discussion despite the high prevalence of male hypogonadism in type 2 diabetic, regardless of diabetic control status, the underlying mechanisms of hypogonadism pathogenesis in type 2 diabetes mellitus have not been fully clarified yet (15). in the same consent, the contribution of the diabetic status or hyperglycaemia on androgen levels in males is still debated. the strong association between type 2 diabetes with obesity, insulin resistance status, and aging may be the significant contributory factor in testosterone deficiency in type 2 dm patients rather than diabetes itself (16). the main result in this cross-sectional study is that visceral adiposity functional activity evaluated by vai is the main risk factor in type 2 diabetic males with bmi below 30. moreover, vai was the only predictor for testosterone levels in non-obese type 2 diabetic males even after adjustment for age and bmi, although testosterone levels table 2. comparison of clinical and laboratory characteristics of male type 2 dm patients with tt > 300 vs ng/dl those with tt ≤ 300 ng/dl. tt > 300 ng/dl (n = 68) tt ≤ 300 ng/dl (n = 28) p value age (year) 52.1 ± 7.29 49.71 ± 6.69 0.139 dm duration (year) 9.34 ± 4.27 10.21 ± 3.98 0.354 smoker ratio 30 (44.1%) 11 (39.2%) 0.821 height (m) 1.78 ± .06 1.7675 ± .05 0.290 body weight (kg) 86.54 ± 8.39 87.04 ± 6.96 0.785 bmi (kg/m2) 27.75 (3.44) 28.73 (2.13) 0.197 wc (cm) 98.24 ± 9.35 102.50 ± 9.95 0.049 systolic bp (mmhg) 135.00 (15) 137.50 (14) 0.218 diastolic bp (mmhg) 85 (15) 85 (13) 0.09 microalbumiric 24 (35.5%) 12 (42.8%) 0.497 retinopathy ratio 16 (23.5%) 13 (46.4%) 0.049 tv mg/dl 249.96 ± 41.94 245.11 ± 47.02 0.620 ldl-c mg/dl 158.51 ± 45.48 149.49 ± 53.93 0.405 hdl-c mg/dl 44.56 ± 7.53 42.07 ± 4.44 0106 tg mg/dl 234.43 ± 76 267.71 ± 66.14 0.046 hba1c % 8.36 ± 1.53 8.93 ± 1.7 0.111 lh miu/l 7.2 ± 1.85 8.02 ± 4.01 0.173 uacr mg/gm 28 (62.53) 28 (74) 0.812 vai 3.03 (1.54) 3.86 (1.77) 0.006 data are presented as the mean ± sd. median (iq range) or the number of patients in each group with percentages. bm: body mass index; wc: waist circumference; sbp: systolic blood pressure; dbp: diastolic blood pressure; ldl: low-density lipoprotein; hdl: high-density lipoprotein; tg: triglyceride;; hba1c: glycated hemoglobin; lh: luteinizing hormone; uacr: urinary albumin creatinine ratio; vai: visceral adiposity index. table 3. pearson correlation and stepwise multiple regression analysis between total testosterone levels with other statistically significant correlated independent factor. r p value b β p value age .218 .033 2.723 .146 .145 log bmi .213 .037 25.488 .040 .760 wc -.255 .012 -1.723 -.125 .352 lh -.222 .030 -8.630 -.172 .082 log vai -.278 .006 -164.284 -.208 .041 bm: body mass index; wc: waist circumference; lh: luteinizing hormone; vai: visceral adiposity index. table 4. association between total testosterone levels and other statistically significant correlated independent factors in regression analysis after adjustment for bmi and age. model 1 model 2 b β p value b β p value age 2.723 .146 .145 2.721 .146 .147 wc -1.723 -.125 .352 -1.638 .118 .397 bmi (log) 25.488 -.208 .760 4.984 .008 974 lh -8.630 -.172 .082 -8.654 -.173 .083 vai (log) -164.284 040 .041 -165.076 -.209 .041 model 1 adjusted for age and model 2 adjusted for bmi and age. bm: body mass index; wc: waist circumference; lh: luteinizing hormone; vai: visceral adiposity index. table 5. logistic regression analysis for risk factor of testosterone deficiency. b s.e wald p value or 95% c.i. for odds ratio lower upper age -.046 .037 1.563 .218 .956 .891 1.027 overweight -.802 .878 .834 .367 2.373 .363 15.536 waist .045 .033 1.891 .207 .344 .066 1.806 log vai 3.629 1.629 4.965 .046 1.436 1.007 2.048 retinopathy -1.138 .514 4.901 .060 .382 .140 1.043 lh .049 0.84 .308 .579 1.050 .883 1.249 b: estimated coefficient; s.e: standard error; ci: confidence interval; wc, waist circumference; vai: visceral adiposity index; lh: luteinizing hormone. 467archivio italiano di urologia e andrologia 2022; 94, 4 testosterone deficiency in non-obese type 2 diabetic male patients in our study correlated with anthropometric parameters such as bmi and waist circumference. vai as a index for visceral fat dysfunction is more reliable than other obesity parameters in predicting testosterone deficiency. low tt levels were strongly associated with increased vai in our cross-sectional study regardless of age, or diabetes status control. although many studies evaluated hypogonadism in diabetic patients, only a few studies evaluated obesity by vai. a recent population-based study among diabetic and nondiabetic observed that vai was the best predictor of male hypogonadism among different obesity indices (17, 18). likewise, vai is more reliable than other metabolic or anthropometric parameters in the evaluation of visceral adiposity effect on erectile dysfunction (19, 20). in this cross-sectional study, the prevalence of testosterone deficiency was 29.1 per cent. this prevalence of testosterone deficiency in type 2 diabetic males was lower than that reported in previous studies in egypt (21) and the middle east region (22). the difference is expected by the selection of our patients with bmi below 30. surprisingly, we have a high prevalence of hypergonadotropic hypogonadism. we observed high abnormal level of lh in 14 patients (50%) with low testosterone levels. in our study, we observed that other obesity parameters such as bmi or waist diameters correlated with testosterone levels in pearson correlation. however, bmi and wc were not a significant predictor for testosterone levels in regression analysis. several studies consistently reported a negative impact for obesity on testosterone levels (18, 19, 23). these results in non-obese type 2 diabetic male patients could point to the role of abdominal obesity in the pathogenesis of male hypogonadism in t2dm. the results in this study may indicate that adipose fat function may be important than fat mass. in this study, age correlated with testosterone levels. this result was in concordance with many previous studies that observed decreased levels of testosterone with aging in diabetic patients (11, 24, 25) and the general population (26). however few studies did not observe this link in type 2 diabetic patients (27, 28). in this study, we observed significantly higher triglyceride levels in testosterone deficient diabetics. however, hdlc levels were insignificantly different between the two groups. this may be attributed to the effect of patients’ selection and lifestyle such as exercise and diet that could affect hdl levels. many studies linked hypogonadism and dyslipidaemia (21, 22, 27). moreover, controlled trials on testosterone replacement observed favourable effects for testosterone on lipid profile in diabetics (29). however, the effect of dyslipidaemias on testosterone levels is still unexplored. vai includes anthropometric and metabolic parameters as tg or hdlc. hence, the correlation between testosterone and tg or hdl-c cannot be excluded. surprisingly, testosterone deficiency was not related to diabetic status. testosterone deficiency in this study did not correlate with glycated haemoglobin or the duration of diabetes. these results are in agreement with many studies in diabetics in general (28). however, our findings contradict another large study which correlated testosterone levels with diabetic status control (30). in this study, we found that non-obese diabetics with testosterone deficiency had higher significant retinopathy prevalence. however, we found non-significant different urinary albumin excretion between both groups. the effect of nephropathy was not assessed in this study as we excluded macro-albuminuria patients. micro-vascular complications were reported in many studies to correlate with low testosterone levels in males (21, 22, 31). although the pathophysiological mechanism of testosterone deficiency in type 2 dm is still not fully revealed, few mechanisms have been hypothesized. the role of inflammatory mediators such as tumour necrosis factoralpha and interleukin-1 beta was postulated. obesity is considered as a state of chronic inflammation (33). these mediators have been reported to suppress hypothalamic gonadotropin-releasing hormone (gnrh) at the hypothalamic level (34). insulin resistance is another mechanism that could be involved in hypogonadism pathogenesis. insulin resistance and brain insulin resistance, which was defined as impaired insulin action in the neuron (34). normal insulin response is required for the hpg axis's functional integrity to be maintained (35). according to one study, hyperinsulinemia caused by neuronal insulin receptor knockout can result in a 60-90% decrease in lh concentrations (33). another mechanism could be related to adipokines such as leptin and adiponectin which have been reported to have a permissive role in the regulation of the hypothalamic-pituitary-gonadal (hpg) axis. leptin resistance in the hypothalamus or other neurons may play a role in the pathogenesis of hypogonadism seen in obesity, insulin resistance, and t2dm (29). furthermore, leptin directly suppresses the stimulatory action of gonadotropins on the testicular leydig cells, reducing testosterone formation (28). furthermore, testosterone has a direct correlation with circulating adiponectin (36). finally, the aromatase enzyme converts testosterone to oestrogen in adipose tissue, resulting in hypothalamic-pituitary-gonadal axis inhibition and subsequent hypogonadism (37). in the light of those postulated mechanisms for male hypogonadism in diabetic patients, vai could be a valuable index for predicting male hypogonadism and is linked with these postulated mechanisms. vai by involving the metabolic parameters could reflect chronic inflammatory status. decreases in serum hdl and increases in triglycerides were reported to be linked with inflammatory status and mediators (38). likewise, vai was reported to be strongly correlated with insulin resistance estimated by homa-ir and metabolic syndrome (39, 40). furthermore, among the most commonly used adiposity assessment indices, vai has the strongest correlation with the most well-known adipocytokines in diabetic patients (41) and non-diabetic (42). finally, a population-based study observed that vai correlates with estradiol levels in males which reflect aromatase enzyme activity (43). hence, the vai value could better reveal the effects of wc, bmi, hdl, and tg on testosterone levels. this cross-sectional study cannot inform whether low testosterone is the cause or the result of visceral obesity. current evidence, however, suggests that this relationship is bidirectional (11). a two-way relationship between low testosterone levels and abdominal obesity archivio italiano di urologia e andrologia 2022; 94, 4 s.i. gouda, m.m. aboelnaga, a.m.g. elbeltagy, a. elbaz 468 was reported (44). weight loss could increase testosterone levels, indicating that testosterone deficiency is functional (45). weight loss bariatric surgery-induced resulted in a significant increase in testosterone levels (46). in contrast, lower testosterone level after androgen deprivation therapy is associated with weight gain (45). in our study, a higher prevalence of hypergonadtropic hypogonadism could point to an increased risk of t2dm with testosterone deficiency. this study is not devoid of some limitations, firstly the cross-sectional design. the second limitation was the relatively small case number that might limit the power to detect a difference. thirdly, because free testosterone levels can reflect the extent of testosterone's biological activities, free testosterone concentration should be used to assess hypogonadism. however, free testosterone determination is difficult, so free testosterone is frequently calculated with a formula in practical activity. finally, this study is a single-centre study in a tertiary hospital. therefore, patient selection bias might exist. this research highlights the value of an easily applicable tool such as the visceral adiposity index in predicting testosterone deficiency in non-obese diabetics. vai could be more reliable than other parameters in predicting testosterone deficiency in diabetics. in conclusion, the elevated vai index is associated with higher risks of testosterone deficiency in non-obese diabetic males. vai is an easily applicable reliable index for the prediction of male hypogonadism in non-obese type 2 diabetic male patients. references 1. hassan m, hatata ez, al-arman m, aboelnaga mm. urinary cystatin c as a biomarker of early renal dysfunction in type 2 diabetic patients. diabetes metab syndr. 2021; 15:102152. 2. gianatti ej, grossmann m. testosterone deficiency in men with type 2 diabetes: pathophysiology and treatment. diabet med. 2020; 37:174-186. 3. anupam b, shivaprasad c, vijaya s, et al. prevalence of hypogonadism in patients with type 2 diabetes mellitus among the indian population. diabetes metab syndr. 2020; 14:1299-1304. 4. gianatti ej, grossmann m. testosterone deficiency in men with type 2 diabetes: pathophysiology and treatment. diabet med. 2020; 37:174-186. 5. castellano-castillo d, royo jl, martínez-escribano a, et al. effects of shbg rs1799941 polymorphism on free testosterone levels and hypogonadism risk in young non-diabetic obese males. j clin med. 2019; 8:1136. 6. gianatti ej, grossmann m. testosterone deficiency in men with type 2 diabetes: pathophysiology and treatment. diabet med. 2020; 37:174-186. 7. grossmann m. low testosterone in men with type 2 diabetes: significance and treatment. j clin endocrinol metab. 2011; 96:23412353. 8. mozafar saadati h, sabour s, mansournia ma, et al. effect modification of general and central obesity by sex and age on cardiovascular outcomes: targeted maximum likelihood estimation in the atherosclerosis risk in communities study. diabetes metab syndr. 2021; 15:479-485. 9. fernandez cj, chacko ec, pappachan jm. male obesity-related secondary hypogonadism pathophysiology, clinical implications and management. eur endocrinol. 2019; 15:83-90. 10. lee dm, o'neill tw, pye sr, et al. the european male ageing study (emas): design, methods and recruitment. int j androl. 2009; 32:11-24. 11. ng tang fui m, hoermann r, et al. obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status. andrology. 2013; 1:906-912. 12. amato mc, giordano c, galia m, et al. visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. diabetes care. 2010; 33:920-922. 13. bhasin s, cunningham gr, hayes fj, et al. testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. j clin endocrinol metab. 2010; 95:25362559 (erratum in j clin endocrinol metab. 2021; 106:e2848) 14. tajar a, forti g, o'neill tw, et al. characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the european male ageing study. j clin endocrinol metab. 2010; 95:1810-8. 15. ganesh hk, vijaya sarathi ha, george j, et al. prevalence of hypogonadism in patients with type 2 diabetes mellitus in an asian indian study group. endocr pract. 2009; 15:513-520. 16. al-goblan as, al-alfi ma, khan mz. mechanism linking diabetes mellitus and obesity. diabetes metab syndr obes. 2014; 7:587-591. 17. turan e, öztekin ü. relationship between visceral adiposity index and male infertility. andrologia. 2020; 52:e13548. 18. haymana c, sonmez a, aydogdu a, et al. visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism. arch endocrinol metab. 2017; 61:282-287. 19. akdemir ao, karabakan m, aktas bk, et al. visceral adiposity index is useful for evaluating obesity effect on erectile dysfunction. andrologia. 2019; 51:e13282. 20. dursun m, besiroglu h, cakir ss, et al. increased visceral adiposity index associated with sexual dysfunction in men. aging male. 2018; 21:187-192. 21. ghazi s, zohdy w, elkhiat y, shamloul r. serum testosterone levels in diabetic men with and without erectile dysfunction. andrologia. 2012; 44:373-380. 22. al hayek aa, khader ys, jafal s, et al. prevalence of low testosterone levels in men with type 2 diabetes mellitus: a cross-sectional study. j family community med. 2013; 20:179-186. 23. fui mn, dupuis p, grossmann m. lowered testosterone in male obesity: mechanisms, morbidity and management. asian j androl. 2014; 16:223-231. 24. anupam b, shivaprasad c, vijaya s, et al. prevalence of hypogonadism in patients with type 2 diabetes mellitus among the indian population. diabetes metab syndr. 2020; 14:1299-1304. 25. tajar a, forti g, o'neill tw, et al. characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the european male ageing study. j clin endocrinol metab. 2010; 95:1810-1818. 26. zheng r, cao l, cao w, et al. risk factors for hypogonadism in male patients with type 2 diabetes. j diabetes res. 2016; 2016:5162167. 27. zheng r, cao l, cao w, et al. risk factors for hypogonadism in male patients with type 2 diabetes. j diabetes res. 2016; 2016:5162167. 469archivio italiano di urologia e andrologia 2022; 94, 4 testosterone deficiency in non-obese type 2 diabetic male patients 28. cai x, tian y, wu t, et al. metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. asian j androl. 2014; 16:146-152. 29. fukui m, tanaka m, hasegawa g, et al. association between serum bioavailable testosterone concentration and the ratio of glycated albumin to glycated hemoglobin in men with type 2 diabetes. diabetes care. 2008; 31:397-401. 30. šimoniene d, platukiene a, prakapiene e, et al. insulin resistance in type 1 diabetes mellitus and its association with patient's microand macrovascular complications, sex hormones, and other clinical data. diabetes ther. 2020; 11:161-174. 31. blaya r, blaya p, rhoden l, rhoden el. low testosterone levels and metabolic syndrome in aging male. curr pharm des. 2017; 23:4470-4474. 32. dandona p, dhindsa s. update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. j clin endocrinol metab. 2011; 96:2643-2651. 33. watanobe h, hayakawa y. hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. endocrinology. 2003; 144:4868-4875. 34. brüning jc, gautam d, burks dj, et al. role of brain insulin receptor in control of body weight and reproduction. science. 2000; 289:2122-2125. 35. elsaied ma, masallat d, abdel-hamid ia. correlation of adiponectin with testosterone in patients with and without type 2 diabetes and erectile dysfunction. am j mens health. 2019; 13:1557988318807049. 36. c. langer, b. gansz, c. goepfert et al. testosterone up-regulates scavenger receptor bi and stimulates cholesterol efflux from macrophages. biochemical and biophysical research communications 2002; 296:1051-1057 37. feingold kr, grunfeld c. the effect of inflammation and infection on lipids and lipoproteins. in: feingold kr, anawalt b, boyce a, et al., eds. endotext. south dartmouth (ma): mdtext.com, inc.; january 8, 2019. 38. ji b, qu h, wang h, et al. association between the visceral adiposity index and homeostatic model assessment of insulin resistance in participants with normal waist circumference. angiology. 2017; 68:716-721. 39. štepánek l, horáková d, cibicková l, et al. can visceral adiposity index serve as a simple tool for identifying individuals with insulin resistance in daily clinical practice?. medicina (kaunas). 2019; 55:545. 40. amato mc, pizzolanti g, torregrossa v, et al. visceral adiposity index (vai) is predictive of an altered adipokine profile in patients with type 2 diabetes. plos one. 2014; 9:e91969. 41. al-daghri nm, al-attas os, alokail ms, et al. visceral adiposity index is highly associated with adiponectin values and glycaemic disturbances. eur j clin invest. 2013; 43:183-189. 42. wang n, zhai h, han b, et al. visceral fat dysfunction is positively associated with hypogonadism in chinese men. sci rep. 2016; 6:19844. 43. blaya r, blaya p, rhoden l, rhoden el. low testosterone levels and metabolic syndrome in aging male. curr pharm des. 2017; 23:4470-4474. 44. grossmann m, hamilton ej, gilfillan c, et al. bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. med j aust. 2011; 194:301306. 45. pekgor s, duran c, berberoglu u, eryilmaz ma. the role of visceral adiposity index levels in predicting the presence of metabolic syndrome and insulin resistance in overweight and obese patients. metab syndr relat disord. 2019; 17:296-302. 46. aboelnaga em, aboelnaga mm, elkalla hm. metformin addition to androgen deprivation therapy effect on cancer prostate patients with type 2 diabetes diabetes metab syndr. 2021; 15:102251. correspondence sherihan i. gouda, md endocrinology and diabetes unit, faculty of medicine, mansoura university, mansoura (egypt) mohamed mosaad aboelnaga, md (corresponding author) dr.mhd.endocrine@gmail.com endocrinology and diabetes unit, faculty of medicine, mansoura university, 2 el gomhouria street, zip code: 35516, mansoura (egypt) ahmed mg elbeltagy, md clinical pathology department, faculty of medicine, mansoura university, mansoura (egypt) amro elbaz, md endocrinology and diabetes unit, faculty of medicine, mansoura university, mansoura (egypt) cop+ed+fisse 2006 203archivio italiano di urologia e andrologia 2020; 92, 3 case report a case is presented that demonstrates unusual long-term evolution of an infected calculi, culminating in the formation of a retroperitoneal abscess that fistulised to the pleural space, leading to a right pleural empyema. key words: infected kidney stone; perinephric abscess; empyema. submitted 26 january 2020; accepted 29 february 2020 no conflict of interest declared. doi: 10.4081/aiua.2020.3.203 infected kidney stone progressing to perinephric abscess and thoracic empyema antonio tufano 1, rocco minelli 2, giovanni di lascio 1, giampaolo delicato 3, giulio baffigo 3, stefano signore 3 1 department of maternal-child and urological sciences, sapienza rome university, policlinico umberto i hospital, rome, italy; 2 department life and health “v. tiberio”, university of molise, campobasso, italy; 3 department of urology, sant'eugenio hospital, rome, italy. introduction perinephric and renal abscesses are uncommon, but potentially lethal complications of urinary tract infection. a perinephric abscess is usually a complication of an urologic infection (1). a perinephric abscess affects the renal capsule and gerota’s fascia. these abscesses can extend from the gerota’s fascia into the psoas and transversalis muscles as well as the peritoneal cavity and the pelvis (2). renal calculi may harbour infection and cause localized obstruction. urinary tract obstruction is generally considered a predisposing factor to urinary tract infection (3). ascending urological infections towards the pleura are rare and only few cases are reported (4). here we describe a case of a 63 year-old woman with infected staghorn calculi of the right kidney who developed a perinephric abscess that extended across the diaphragm to cause an empyema as well. case report a 63 year-old women with a known history of recurrent urinary tract infections, including right-sided pyelonephritis presented because of fever (39°c). she was normotensive but tachycardic (130/min) and in respiratory distress. clinical examination showed signs of a large right pleural effusion but no abdominal tenderness. there was marked peripheral leucocytosis associated with a raised c-reactive protein (crp). imaging, including computed tomography (ct) of thorax and abdomen, showed extensive peri-bronchial thickening, right lower lobe consolidation and a complex right pleural effusion with thickened pleura (figires 1, 2). in the right subdiaphragmatic area, a small hypodense collection of about 3 centimeters in diameter was appreciated in contiguity with the diaphragmatic dome. the right kidney presents multiple hypodense areas of probable cystic nature and stones in thr middle and lower calyces and in the renal pelvis. the right kidney also demonstrated atrophic calcification, likely related to previous infections (figures 3, 4). a 24f intercostal catheter was urgently inserted with removal of 500 ml of turbid and exudative fluid which was cultured with growth of citrobacter koseri. subsequently a 8f nephrostomy catheter was placed in the right kidney with aspiration of purulent fluid positive for citrobacter. sensitivities to antibiotics were obtained and therapy with ceftazadime and meropenem was initiated obtaining a clinical improvement with reduction of fever and of the perirenal abscess size (2 cm). evaluation of renal function by dynamic scintigraphy with 99mtc-dtpa showed right kidney failure. an open right radical nephrectomy was then performed and subsequently cardiothoracic surgeons proceeded with video assisted thorascopic surgery (vats) to prevent the formation of a fibrothorax. conclusions perinephric abscesses can cause severe illness. the severity of the disease depends on the extent of the infection and the comorbidities of the patient. infection of the renal and perinephric space continues to be a serious urological problem with high mortality rate. a high index of suspicion, prompt diagnosis, appropriate antibiotics and surgical intervention may be effective in reducing mortality. references 1. thorley jd, jones sr, sanford jp. perinephric abscess. medicine. 1974; 53441-451. 2. sheinfeld j, erturk e, spataro rf, & cockett atk. perinephric abscess: current concepts. the journal of urology. 1987; 137:191194. 3. bichler kh, eipper e, naber k, et al. urinary infection stones. int j antimicrob agents. 2002;19:488-98. 4. stewart ze, shaker m, and david baxter j. urinary tract infection caused by citrobacter koseri in a patient with spina bifida, an ileal conduit and renal calculi progressing to peri-nephric abscess and empyema. urol. case rep. 2017; 11:22-24. summary 10tufano_stesura seveso 24/09/20 14:21 pagina 203 archivio italiano di urologia e andrologia 2020; 92, 3 a. tufano, r. minelli, g. di lascio, g. delicato, g. baffigo, s. signore 204 figure 1-2. computed tomography of thorax and abdomen, showing extensive peribronchial thickening, right lower lobe consolidation and right pleural effusion with thickened pleura. figure 3-4. tc showing right kidney atrophy with calcifications. correspondence antonio tufano, md antonio.tufano91@gmail.com giovanni di lascio, md department of maternal-child and urological sciences, sapienza rome university, policlinico umberto i hospital viale del policlinico 155, 00161 rome (italy) rocco minelli, md department life and health “v. tiberio”, university of molise, via francesco de sanctis 1, campobasso 86100 (italy) giampaolo delicato, md giulio baffigo, md stefano signore, md department of urology, sant'eugenio hospital, rome (italy) 10tufano_stesura seveso 24/09/20 14:21 pagina 204 stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11584 1 original paper intra and postoperative pain, they are associated with significant side effects (2). recently, a new regional analgesic technique, known as quadratus lumborum block (qlb), has been introduced for pain relief following abdominal surgery. this technique has been used successfully to provide postoperative analgesia for patients undergoing various types of abdominal surgeries, including renal surgeries (3-7). the qlb technique functions by blocking somatic nerve fibers that supply the abdominal wall, and it may potentially block the sympathetic nerve supply of the abdomen, inhibiting visceral pain (8). several modifications to the technique have been introduced, including injection into the posterior segment of the quadratus lumborum muscle (qlm) (qlb2), injection into qlm and the fascia of the psoas muscle using the trans-muscular approach (qlb3), and injection into the qlm itself (qlb4). it is apparent that this block is highly effective in providing analgesia from t7 to l1 dermatomes, and it affords analgesia to the anterior abdominal wall while reducing visceral pain (9). the current study presents a novel technique for providing anesthesia by fascial peripheral block with low-dose spinal anesthesia. the fascial block serves as the primary element of anesthesia for pcnl, and we are optimistic that it can be used as a standalone anesthesia. we utilized low-dose spinal anesthesia for cystoscopy, ureteric catheter insertion, and the long-term onset of qlb. this technique will serve as the foundation for further research aimed at reducing the requirement for general anesthesia, with its attendant complications, among high-risk patients. the present study aimed to evaluate the efficacy of combined low dose spinal anesthesia with quadratus lumborum block as an alternative to general anesthesia for patients undergoing pcnl. patients and methods a prospective study was conducted at the urology department of al-azhar university hospitals in cairo, egypt, from january 2021 to january 2022. the study included 60 patients who were deemed suitable background: general anesthesia in high-risk patients has many complications and needs long preoperative preparations and postoperative intensive care unit (icu). therefore the present study aimed to evaluate the efficacy of combined low-dose spinal anesthesia with quadratus lumborum block (qlb) as an alternative to general anesthesia for patients undergoing percutaneous nephrolithotomy. patients and methods: a prospective study was conducted at the urology department of al-azhar university hospitals in cairo, egypt, from january 2021 to january 2022. the study included 60 patients of asa ll-lll scheduled for percutaneous nephrolithotomy. all patients received low-dose spinal anesthesia (5 mg bupivacaine) and qlb (ql1-ql2-ql3) approaches. the primary observation parameter was the efficacy of this technique as an alternative to general anesthesia. the secondary parameters measured were evaluation of need for intraoperative narcotics, postoperative pain score (vas), and patients satisfaction as assessed using a 5-point likert scale. results: none of the patients was given general anesthesia, and intraoperative sedation was given to nineteen patients (32.2%). no hemodynamic changes were observed in all patients. there was a significant correlation between the use of intraoperative sedation and stone site, intraoperative blood loss, and hospital stay. pain intensity on vas at rest and movement was low until the 24th postoperative hour. patient satisfaction score was 3, 4, and 5 in 1 (1.7%), 4 (6.7%), and 55 (91.6%) patients, respectively. conclusions: combined low-dose spinal anesthesia with quadratus lumborum block is an effective alternative to general anesthesia in patients undergoing pcnl procedures with good postoperative analgesia. patients with lower calyceal punctures have a lower incidence of intraoperative sedation requirements. key words: quadratus lumborum block; low dose spinal anesthesia; percutaneous nephrolithotomy. submitted 12 july 2023; accepted 1 august 2023 introduction percutaneous nephrolithotomy (pcnl) is considered the standard method for managing large or complex renal calculi (1). although opioids are effective in controlling is quadratus lumborum block combined with low dose-spinal anesthesia an effective alternative to general anesthesia in patients undergoing percutaneous nephrolithotomy? tamer a. abouelgreed 1, ahmed m. elgarhy 2, adel elatreisy 1, tamer m. ewieda 2, wael m. ibrahim 2, othman saadeldien yahia 2, ahmed m. elnaggar 2, mohamed a. elbadawy 2, ali a. alkumity 2, yasser badran 1, mahmoud ali 1, aly gomaa 1, mohamed f. elebiary 1 & mahmoud aboelnasr 1 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 department anesthesia, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11584 summary archivio italiano di urologia e andrologia 2023; 95(3):11584 ta. abouelgreed, am. elgarhy, tm. ewieda, et al. 2 candidates for pcnl. the local ethics committee approved the research (registration number of: clinicaltrial.gov id nct04852874.), and all patients provided informed written consent to participate. the study adhered to ethical guidelines and regulations, ensuring the safety and confidentiality of all participants. we excluded patients with coagulopathy, mental retardation, airway problem, sleep apnea syndrome, pregnancy, and asa (iv). upon induction of anesthesia, an intravenous line was established for all patients and oxygen was administered at a rate of 3 liters per minute through a nasal cannula while vital signs were continuously monitored. spinal anesthesia was then administered using a 25-gauge (bd quincke spinal needle), which was inserted and directed towards the midline in order to access the intrathecal space between the l3 and l4 intervertebral space following successful dural puncture. a combination of 5 milligrams of bupivacaine (1 milliliter) and 25 micrograms of fentanyl (0.5 milliliters) were then administered via the intrathecal space. low-frequency ultrasound with a curved probe (6:15 mhs) (sonosite m turbo, fujifilm, bothel washington usa) was utilized in all patients, and a 22-gauge spinal needle (bd quink spinal needle) was used to administer the local anesthetic injection. the injection was performed with the patient in the lateral position. the needle tip was carefully positioned at the anterolateral border of the quadratus lumborum muscle (qlm) at its junction with the transversalis fascia (ql1). subsequently, the needle was placed between qlm and the erector spinae muscle (ql2) and between qlm and the psoas muscle (ql3). after ensuring the correct position of the needle, an injection of 0.25 ml/kg of 0.25% bupivacaine, along with 1.5 mg dexamethasone and 100 mg magnesium sulfate, was administered at each site of the quadratus lumborum muscle under ultrasound guidance. after performing the block, each patient was evaluated for effectiveness of the technique (accomplishing of the procedure with no need to general anesthesia with surgeon and patient satisfaction). intraoperative hemodynamics (bp, pulse, spo2) were measured at beginning then every 10 /min. intraoperative pain was assessed utilizing a 10 cm visual analog scale (vas), in case of vas > 4, narcotic was given in the form of 50 mcg fentanyl. the evaluation of postoperative analgesia was conducted at the conclusion of surgery, followed by assessments at 1, 2, 4, 8, 12, 16, 20, and 24 hours, utilizing the visual analogue scale (vas) both at rest and during movement. in cases where patients reported pain intensity exceeding a vas score of 4, intravenous infusion of paracetamol at a dose of 15 mg per kg was administered, limited to a maximum of 1000 mg per dose for analgesia purposes, with a maximum cumulative dose of 4000 mg over 24 hours. nonsteroidal medication was prescribed as a secondary option if the pain remained unresolved following the administration of paracetamol. adverse effects were monitored and documented, including but not limited to direct needle trauma to abdominal viscera, bleeding, prolonged muscle weakness, and hemodynamic instability. on the second postoperative day, perioperative patient satisfaction was assessed using a 5-point likert scale ranging from very dissatisfied (1) to completely satisfied (5). table 1. general descriptive data. min-max mean ± sd or f (%) age 34-65 50.5 ± 8.4 sex female 19 (31.7%) male 41 (68.3%) site of stones lower calyx 6 (10%) pelvis 11 (18.3%) pelvis, lower calix 28 (46.7%) pelvis, upper calyx 15 (25%) size of stones/cm 2-4 3.0 ± 0.5 hfu of stones 650-1500 1010.2 ± 162.0 urine analysis pus negative 53 (88.3%) pus positive 7 (11.7%) hb pre 12-16 13.4 ± 0.8 creatinine 0.7-1.5 1.1 ± 0.2 previous surgery no 44 (73.3%) yes 16 (26.7%) morbidity asa2 39 (65%) asa3 21 (35%) operative time/min 50-150 80.5 ± 16.7 blood loss/ml 80-700 248.0 ± 112.1 hospital stay/days 1-3 2.7 ± 0.5 ambulation after 2 hrs 40 (66.7%) after 3 hrs 20 (33.3%) map base 64-95 77.6 ± 6.4 map 10 m 62-91 76.8 ± 6.2 map 20 m 60-90 75.1 ± 6.9 map 30 m 66-95 79.6 ± 6.3 map 1 hour 68-95 80.9 ± 6.5 map 2 h 68-91 79.3 ± 5.4 map 4 h 68-91 81.4 ± 5.4 pulse base 66-785 92.4 ± 9.1 pulse 10 m 64-90 76.6 ± 6.0 pulse 20 m 75-99 84.2 ± 5.9 pulse 30 m 74-99 84.7 ± 5.9 pulse 1 h 75-96 84.2 ± 5.3 pulse 2 h 72-95 81.5 ± 4.7 pulse 4 h 73-93 83.2 ± 5.0 vas 10 2-4 2.9 ± 0.8 vas 30 2-5 3.0 ± 0.8 vas 1 h 2-5 3.2 ± 1.0 vas 2 h 2-5 2.9 ± 1.0 vas 2 h 2-5 3.2 ± 0.9 vas 4 h 2-5 3.2 ± 0.9 vas 8 h 2-5 2.8 ± 0.7 vas 16 h 2-5 3.1 ± 0.9 vas 24 h 2-5 3.2 ± 1.0 hb post 10.5-13 11.5 ± 0.6 blood transfusion no 60 (100%) yes 0 (0%) kub free 57 (95%) positive 3 (5%) us free 60 (100%) positive 0 (0%) success rate no 0 (0%) yes 60 (100%) intraoperative narcotics no 41 (67.8%) yes 19 (32.2%) age, size of stones, hfu of stones, hb pre and post, creatinine, operation time, blood loss, hosp. stay, pulse and vas parameters were represented as minmax and mean ± sd, while sex, site of stones, urine analysis, previous surgery, morbidity, blood transfusion, kub, us, success rate and intraoperative narcotics were represented as frequency and percent f (%). archivio italiano di urologia e andrologia 2023; 95(3):11584 3 combined low-dose spinal anesthesia with quadratus lumborum block for pcnl statistical analysis the statistical package for social science (spss) software, version 29 (spss inc., chicago, il, usa), was utilized for data analysis. categorical variables were presented as frequency and percentage, while numeric variables were presented as a mean and standard deviation. the paired-sample t-test was employed to determine the significance level between different data within the same group. a p value less than 0.05 was considered statistically significant. results sixty patients were included in the study. table 1 illustrates the patients' demographics, renal stone criteria, operative time, blood loss, and hospital stay. none of the patients was given general anesthesia, and intraoperative sedation was given to nineteen patients (32.2%). univariate analysis revealed a significant correlation between the use of intraoperative sedation and stone site, intraoperative blood loss, and hospital stay. specifically, patients with lower calyceal and combined pelvic and lower calyceal stones exhibited a statistically significant infrequent utilization of intraoperative sedation, 100% of patients with lower calyceal stones had no intraoperative sedation, while 71.4% of patients with combined pelvic and lower calyceal stones had no sedation (p = 0.02) (table 2). the mean intraoperative blood loss was significantly higher in patients requiring intraoperative sedation; it was 260.5 ml compared to 242.2 ml in patients who did not require intraoperative sedation (p = 0.03). similarly, the mean hospital stay was longer in patients receiveing intraoperative sedation (p = 0.05) (table 2). regarding patients who required narcotics, there were no significant differences in mean arterial pressure (map) or pulse rate at any point in time when compared to patients who did not require them (p-value > 0.05). similarly, there were no statistically significant differences in the stone-free rate between patients who required narcotics (94.7%) and those who did not (95.1%) (p-value > 0.05) (table 2). pain intensity on vas at rest and on the movement was low till the 24th postoperative hour (table 1). patient satisfaction score was 3, 4, and 5 in 1 (1.7%), 4 (6.7%), and 55 (91.6%) patients, respectively. discussion the qlb, originally described by blanco et al., is a variant of the transversus abdominis table 2. the associations of studied in relation of use of intraoperative narcotics. intraoperative narcotics risk assessment no n = 41 yes n = 19 p-value or (95% c.i) p-value age 50.6 ± 8.4 50.2 ± 8.5 0.9 1.0 (0.91.1) 0.8 sex female 13 (31.7%) 6 (31.6%) 0.9 1.0 (0.33.2) 0.9 male 28 (68.3%) 13 (68.4%) site of stones lower calyx 6 (14.6%) 0 (0.0%) 0.02 * pelvis 5 (12.2%) 6 (31.6%) 0.7 1.2 (0.43.9) 0.8 pelvis, lower calix 20 (48.8%) 8 (42.1%) 0.02 * 0.4 (0.20.9) 0.03 * pelvis, upper calyx 10 (24.4%) 5 (26.3%) 0.1 0.5 (0.21.5) 0.2 size of stones/cm 3.0 ± 0.5 3.0 ± 0.5 0.7 1.1 (0.33.5) 0.9 hfu of stones 1024.2 ± 157.9 0.9 1.0 (1.01.0) 0.6 urine analysis pus negative 38 (92.7%) 15 (78.9%) 0.1 3.4 (0.7-16.9) 0.2 pus positive 3 (7.3%) 4 (21.1%) hb pre 13.5 ± 0.8 13.0 ± 0.8 0.8 0.4 (0.21.0) 0.8 creatinine 1.1 ± 0.2 1.1 ± 0.2 0.7 1.0 (0.12.6) 0.9 previous surgery no 28 (68.3%) 16 (84.2%) 0.2 0.4 (0.11.6) 0.3 yes 13 (31.7%) 3 (15.8%) morbidity asa2 25 (61.0%) 14 (73.7%) 0.3 0.6 (0.21.9) 0.4 asa3 16 (39.0%) 5 (26.3%) op.time/min 80.6 ± 12.8 80.3 ± 23.4 0.08 1.0 (1.0 1.0) 0.9 blood loss/ml 242.2 ± 88.1 260. 5 ± 154.0 0.02 * 1.0 (1.01.0) 0.6 hosp. st./days 2.7 ± 0.5 2.8 ± 0.4 0.05 * 1.8 (0.56.1) 0.3 ambulation after 2 hrs 28 (68.3%) 12 (63.2%) 0.7 1.3 (0.43.9) 0.8 after 3 hrs 13 (31.7%) 7 (36.8%) map base 77.7 ± 6.8 77.3 ± 5.5 0.4 1.02 (0.41.34) 0.3 map 10 m 76.6 ± 6.1 77.3 ± 6.7 0.6 1.0 (0.91.2) 0.6 map 20 m 75.0 ± 6.9 75.2 ± 7.0 0.9 1.0 (0.91.1) 0.9 map 30 m 79.5 ± 6.4 79.8 ± 6.4 0.8 1.0 (0.91.2) 0.8 map 1 hour 80.8 ± 6.6 80.9 ± 6.7 0.7 1.0 (0.91.1) 0.8 map 2 h 78.9 ± 5.4 80.1 ± 5.4 0.8 1.1 (0.91.2) 0.4 map 4 h 81.1 ± 5.5 81.8 ± 5.2 0.96 1.0 (0.91.2) 0.5 pulse base 98.6 ± 110.1 79.1 ± 4.7 0.2 1.1 (0.71.21) 0.3 pulse 10 m 76.8 ± 6.1 76.3 ± 6.0 0.8 1.0 (0.91.1) 1.0 pulse 20 m 84.0 ± 6.1 84.6 ± 5.6 0.9 1.1 (1.01.3) 0.2 pulse 30 m 85.2 ± 6.2 83.5 ± 4.9 0.4 0.9 (0.81.1) 0.4 pulse 1 h 84.0 ± 5.4 84.5 ± 5.2 0.6 1.0 (0.81.2) 0.9 pulse 2 h 81.5 ± 4.8 81.5 ± 4.6 0.7 1.0 (0.91.1) 0.7 pulse 4 h 83.9 ± 4.8 81.9 ± 5.2 0.4 0.9 (0.81.0) 0.1 vas 10 3.0 ± 0.8 2.6 ± 0.7 0.7 1.15 (0.81.31) 0.3 vas 30 2.9 ± 0.9 3.1 ± 0.8 0.7 1.0 (0.41.1) 0.3 vas 1 h 3.2 ± 0.9 3.2 ± 1.1 0.1 1.3 (0.63.0) 0.5 vas 2 h 3.0 ± 1.0 2.6 ± 0.9 0.8 0.9 (0.51.8) 0.8 vas 2 h 3.3 ± 0.9 2.8 ± 0.8 0.3 0.7 (0.31.4) 0.3 vas4 h 3.2 ± 1.0 3.1 ± 0.8 0.09 0.5 (0.21.1) 0.07 vas 8 h 2.7 ± 0.7 2.8 ± 0.8 0.3 1.2 (0.52.5) 0.7 vas 16 h 3.1 ± 0.9 3.0 ± 0.9 0.4 1.1 (0.42.7) 0.9 vas 24 h 3.2 ± 0.9 3.2 ± 1.1 0.4 0.6 (0.31.5) 0.3 hb post 11.4 ± 0.6 11.6 ± 0.6 0.6 0.9 (0.51.7) 0.7 blood transfusion no 41 (100.0%) 19 (100.0%) n.a yes 0 (0.0%) 0 (0.0%) kub free 39 (95.1%) 18 (94.7%) 0.9 1.1 (0.112.7) 0.9 positive 2 (4.9%) 1 (5.3%) us free 41 (100.0%) 19 (100.0%) n.a positive 0 (0.0%) 0 (0.0%) success rate no 0 (0.0%) 0 (0.0%) n.a yes 41 (100.0%) 19 (100.0%) age, age, size of stones, hfu of stones, hb pre and post, creatinine, operation time, blood loss, hosp. stay, pulse and vas parameters were represented as minmax and mean ± sd, the data were analyzed by t test. while sex, site of stones, urine analysis, previous surgery, morbidity, blood transfusion, kub, us, success rate and intraoperative narcotics were represented as frequency and percent f(%); the data were analyzed by x2 test. or: odd ratio; c.i: confidence interval; p value calculated depend on log linear regression analysis. * p value < 0.05 is significant, ** p value < 0.01 is highly significant. archivio italiano di urologia e andrologia 2023; 95(3):11584 ta. abouelgreed, am. elgarhy, tm. ewieda, et al. 4 plane (tap) block that has four subtypes named on the location of the local anesthetic delivery in relation to the quadratus lumborum muscle. these subtypes include the lateral qlb, posterior qlb, anterior qlb, and intramuscular qlb. lateral qlb, also known as qlb type 1, was initially proposed. the posterior qlb is administered by depositing the local anesthetic between the posterior surface of the quadratus lumborum muscle and the medial lamina of the thoracolumbar fascia (tlf). like other interfascial blocks, the posterior qlb has a variable spread of the drug solution. however, it consistently spreads to the tap, around the quadratus lumborum muscle, and along the middle lamina of the tlf. the tlf contains a dense network of sympathetic nerve fibers of the abdomen. blocking these nerve fibers provides relief from sympathetic-mediated pain. furthermore, the injected drug may spread cranially to the lumbar paravertebral space along the tlf and endothoracic fascia, which may be responsible for the additional visceral and somatic block with wider width of analgesia (t7 to l4 dermatome) observed in posterior qlb compared to the more traditional tap block (1011). in this trial, we studied the efficacy of combined low dose spinal anesthesia with quadratus lumborum block as an alternative to general anesthesia for patients undergoing pcnl. we observed that this anesthesia technique is safe and feasible specifically in high-risk patient for general anesthesia. the results of previous studies are consistent with our own findings, which indicate that qlb provides effective postoperative analgesia with low vas scores and minimal need for additional analgesia. chen et al. observed that qlb reduced intraoperative sufentanil consumption and provided effective postoperative pain relief within 24 hours for patients undergoing pcnl procedures (12). kılıç and bulut reported that qlb effectively managed pain levels and reduced morphine consumption for up to 48 hours post-surgery in pcnl patients (13). in a randomized, double-blind, controlled, prospective study, raman and prabha found that qlb provided significantly longer analgesia duration compared to placebo in patients undergoing pcnl. they concluded that qlb is a viable option for prolonged postoperative pain control (11). similarly, peksoz et al. reported that qlb significantly reduced postoperative opioid consumption and vas scores compared to a control group for pcnl patients. opioid consumption was significantly lower in the qlb group compared to the control group at all times (14). in the current study, there was a significant correlation between the use of intraoperative sedation and stone site, intraoperative blood loss, and hospital stay. the mean intraoperative blood loss was significantly higher in patients requiring intraoperative sedation; similarly, the mean hospital stay was longer in patients receiving intraoperative sedation. interestingly, patients with lower calyceal stones, and patients with combined pelvic and lower calyceal stones had a statistically significant lower intraoperative sedation utilization; this can be explained with lower calyceal puncture in such patients accompanied with lower pain compared to middle and upper calyceal punctures. limitations of the study although our study was conducted prospectively focusing on a single anesthesia technique used to manage patients undergoing pcnl, it is not a comparative or randomized trial. additionally, we did not record the dermatomal distribution of analgesia in our patients. it is highly recommended that a prospective randomized study be conducted to evaluate the effectiveness of this technique. this approach will provide a more comprehensive understanding of the technique's potential benefits and limitations. conclusions combined low-dose spinal anesthesia with quadratus lumborum block is effective for patients undergoing pcnl procedures with good postoperative analgesia. patients with lower calyceal punctures have a lower incidence of intraoperative sedation requirements. references 1. ghani kr, andonian s, bultitude m, et al. percutaneous nephrolithotomy: update, trends, and future directions. eur urol. 2016; 70:382-396. 2. sauter ar, ullensvang k, niemi g, et al. the shamrock lumbar plexus block: a dose-finding study. eur j anaesthesiol. 2015; 32:764-70. 3. jin z, liu j, li r, et al. single injection quadratus lumborum block for postoperative analgesia in adult surgical population: a systematic review and meta-analysis. j clin anesth. 2020; 62:109715. 4. verma k, malawat a, jethava d, jethava dd. comparison of transversus abdominis plane block and quadratus lumborum block for post-caesarean section analgesia: a randomised clinical trial. indian j anaesth. 2019; 63:820-826. 5. baytar ç, yılmaz c, karasu d, topal s. comparison of ultrasound-guided subcostal transversus abdominis plane block and quadratus lumborum block in laparoscopic cholecystectomy: a prospective, randomized, controlled clinical study. pain res manag. 2019; 2019:2815301. 6. cardoso jm, sá m, reis h, et al. bloqueio do quadrado lombar tipo ii para uma gastrectomia subtotal em um paciente séptico [type ii quadratus lumborum block for a sub-total gastrectomy in a septic patient]. braz j anesthesiol. 2018; 68:186-189. 7. li x, xu zz, li yt, et al. analgesic efficacy of two approaches of ultrasound-guided quadratus lumborum block for laparoscopic renal surgery: a randomised controlled trial. eur j anaesthesiol. 2021; 38:265-274. 8. akerman m, pejcic n, velickovic i. a review of the quadratus lumborum block and eras. front med. 2018; 5:44-49. 9. blanco r. 271. tap block under ultrasound guidance: the description of a “no pops” technique. regional anesthesia and pain medicine 2007; 32:130-130 10. blanco r, ansari t, girgis e. quadratus lumborum block for postoperative pain after caesarean section: a randomised controlled trial. eur j anaesthesiol. 2015; 32:812-8. 11. raman r, prabha r. quadratus lumborum block for patients undergoing percutaneous nephrolithotomy: a randomized controlled study. anesth essays res. 2021; 15:174-178. archivio italiano di urologia e andrologia 2023; 95(3):11584 5 combined low-dose spinal anesthesia with quadratus lumborum block for pcnl 12. chen l, ji j, tian sun q, et al. retrospective study of quadratus lumborum block for postoperative analgesia in patients undergoing percutaneous nephrolithotomy. bmc anesthesiology. 2020; 20:1-9. 13. kılıç e, bulut e. quadratus lumborum block iii for postoperative pain after percutaneous nephrolithotomy. turk j anaesthesiol reanim. 2018; 46:272-275. 14. peksoz u, celik m, alici ha, et al. the effect of transmuscular quadratus lumborum block on postoperative opioid consumption in patients undergoing percutaneous nephrolithotomy: a randomized controlled study. cureus. 2021; 13:e18344. correspondence tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg adel elatreisy, md dr_adelelatreisy@yahoo.com yasser badran, md dryasserbadran@gmail.com mahmoud ali, md dr_mahmoud72@hotmail.com aly gomaa, md alygomaa68@yahoo.com mohamed f. elebiary, md dr_elebiary@yahoo.com mahmoud aboelnasr, md mdaboelnasr@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt ahmed m. elgarhy, md elgarhy_79@yahoo.com tamer m. ewieda, md tamerewieda@yahoo.com wael m. ibrahim, md waelelmahdy@gmail.com othman saadeldien yahia, md yahiadrothmansaadeldien@gmail.com ahmed m. elnaggar, md ahmed.elnaggar@azhar.edu.eg mohamed a. elbadawy, md dr.m.albadawy@gmail.com ali a. alkumity, md alkumityali74@gmail.com department anesthesia, al-azhar university, cairo, egypt . conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2018; 90, 140 original paper the impact of prostate artery embolization (pae) on the the physical history and pathophysiology of benign prostatic hyperplasia (bph) konstantinos stamatiou urology department, tzaneio hospital, piraeus, greece. aim: prostate artery embolization (pae) is a non invasive modality for the treatment of benign prostate hypertrophy (bph) related lower urinary tract symptoms (luts). as a relatively new procedure, data determining the clinical success is somehow scarce. in the present article we examine the current clinical outcome measures in order to identify the most accurate. results: current imaging outcome measures are consistent with clinical ones only in the group of patients with adenomatous-dominant bph while are inconsistent in patients with small sized adenomas. conclusions: additional studies and/or evaluation tools are needed in order to provide accurate evaluation of clinical success in the subgroup of patients with nonadenomatous-dominant bph while they may inspire new options and novel techniques for both bph treatment and treatment-follow up. key words: benign prostatic hyperplasia; lower urinary tract symptoms; prostate artery embolization. submitted 12 september; accepted 9 december 2018 summary no conflict of interest declared. a relatively new procedure, data determining the accurate evaluation of clinical success of pae is somehow scarce. in the present article we aim to investigate the potential role of elastography on the evaluation of clinical success of pae on the treatment of benign prostatic hyperplasia (bph). materials and methods a search was performed in medline, ncbi, pubmed, cochrane library and other electronic libraries using the terms: “prostate artery embolization and benign prostatic hyperplasia”. the articles selected were checked for the relevancy of their content to the discussed subject. the bibliographic information in the selected articles was checked for relevant publications that had not been included in the original search. results since 2008 when embolization of prostatic arteries for the treatment of luts associated with bph has been held for the first time, a total of 104 articles on pae were published. after being checked for the relevancy of their content to the discussed subject, 22 papers were discarded after lecture of summary and 61 after lecture of the full paper. finally, 21 peer-reviewed studies providing data on one or more clinical outcomes were retrieved. a recent meta-analysis of 6 large studies showed improvement in qmax, pvr, ipss, and qol endpoints at 12 months, with a low incidence of serious adverse effects (0.3%). another recent meta-analysis of three studies comparing pae with other treatments found greater maximum urine flow restoration and reduction in prostate volume in pae group in relation to controls (4). current experience shows also promising results in symptom remission and improvements in quality of life. however the overall number of pae patients and studies meeting reliability criteria is small. moreover, no generally accepted definition for clinical success exists (table 1). in fact, principal outcome assessment varies among studies and could be either objective or subjective, laboratory, clinical or both. for example, regaining the ability to urinate after pae is a measurable size whereas questionnaire-based self-reported improvement of both urination and qol are not. furthermore, as long as the exact mechanism by which doi: 10.4081/aiua.2018.1.40 introduction bph is a histologic diagnosis characterized by proliferation of the cellular elements of the prostate. this involves both stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the transition zone of the prostate (1). almost 50% of bph patients with enlarged prostate have luts (2). the last are the result of either mechanical obstruction due to glandular enlargement, or dynamic obstruction secondary to contraction of the smooth muscles of the prostate, urethra and bladder neck (3). mild symptoms usually do not require treatment however moderate and severe symptoms could be treated with either medical therapy or surgery. currently prostatic arterial embolization (pae) was emerged as a feasible procedure to treat lower urinary tract symptoms associated with bph. pae is the less invasive non pharmaceutical treatment. it is performed under local anaesthesia, usually by a right groin approach through the right femoral artery. it consists of selective embolization of prostatic arteries with small-diameter hydrophilic microcatheters and polyvinyl alcohol (pva) in order to cause interruption of arterial flow. initial studies showed that pae led to reduction of the prostatic volume, symptom remission and improvements in quality of life however, as stamatiou_stesura seveso 27/03/18 09:25 pagina 40 41archivio italiano di urologia e andrologia 2018; 90, 1 the impact of prostate artery embolization (pae) on the the physical history and pathophysiology of benign prostatic hyperplasia (bph) pae affects bph induced luts remains unclear, reduction in prostate volume and serum psa value may not be the most adequate outcome measures. in fact, clinical success – in terms of ipss and qmax – is not always analogous to prostate volume reduction. moreover, the reduction on prostate volume occurs progressively and stabilized within six months of the procedure. yet, up to 20% of patients undergoing pae show no prostate volume reduction 3 months after the procedure (5). a small mri study showed that reduction of the prostate volume after embolization was significant only in patients with infarcts (6). in this study infarcts were seen in only 70.6% of the subjects, exclusively in the central gland. however, a retrospective study showed that prostatic volume decrease occurs in both central and peripheral zones (7), a fact suggesting disproportion between infarcts and reduction of the prostate volume. although, a small mri study proposed infarcts to be a good predictor of clinical success after pae in patients with aur secondary to bph (8), it seems that it is not the case. a significantly high psa elevation occurs in the 24 hours after pae. during follow-up, mean psa decreases to a level significantly lower than at baseline. this is suspected to result from prostate inflammation and ischemia due to embolization and suggests prostate cellular apoptosis after pae (9). however, no statistically significant correlation was detected between psa level 24 hours after pae and prostate volume reduction at 3 months of follow-up (10). in contrast, a statistically significant negative correlation between psa level elevation 24 hours after pae and ipss decrease at 3 months of follow-up was reported (31). it should be mentioned that other conditions that can increase psa levels such as pre-existing inflammation, pre-treatment prostate manipulations (e.g. catheterization) and prostate size may bias this association. moreover ipss has inadequate sensitivity and specificity to be used as a stand-alone tool in the evaluation of clinical success of a new method such as pae. although, a study proposed psa elevation after pae to be a prognostic factor for predicting patient response to pae (31), more research is needed in order to confirm this suggestion. in fact, uncertainty regarding the role of pre-treatment prostatic volume in the successfulness of pae exists. bagla et al performed an analysis on 78 consecutive patients undergoing pae, comparing prostate volume groups (group 1 < 50 cm3; group 2, 50-80 cm3; group 3 > 80 cm3) at baseline and follow-up to assess for differences in outcomes of american urological association (aua) symptom index, quality of life (qol)-related symptoms, and international index of erectile function (iief). according to their result no statistically significant differences in the above parameters was found between groups (11). other authors suggest that patients with a smaller prostate (i.e., volume < 30 cm3) should excluded because pae is believed to work based on prostate volume reduction, which will be more limited in patients with almost normal sized prostates (12). in accordance to the above, little et al., found a statistically significant reduction in prostate volume following embolization with a median reduction of 34% (30-55) in the group of patients with adenomatous-dominant bph (adbph), compared to a mean volume reduction of 22% in the non-adbph group. ipss and qol score significantly improved in the adbph group while there was no deterioration in sexual function in either group post-pae (13). similarly, wang et al., found the clinical and imaging outcomes of pae to be better in patients with larger prostate glands than medium-sized ones (14). discussion the abovementioned findings may indicate a greater impact of pae induced ischaemia in the adenomatous than in the stromal element of the prostate gland. however, clinical effect occurs progressively and stabilized within six months, therefore it is possible that pae resolves dynamic obstruction also but at a slower rate. the exact mechanism by which pae resolves dynamic obstruction is the shrinkage of the enlarged prostate gland as a result of pae induced ischemic infarction. in contrast, the exact mechanism(s) by which pae resolves dynamic table 1. variability of main outcome criteria among studies. authors n. patients main outcome criteria li p et al, 2017 (18) 24 ipss, pvr, qmax, psa hwang jh et al, 2017 (19) 9 ipss, pv, qol, qmax little mw et al, 2017 (13) 12 mp-mri, ipss, eq-5d-5s rampoldi a et al, 2017 (20) 43 discontinuation of ibc, ipss, pv, qol, clavien ii bilhim t et al, 2016 (21) 183 24-hour post-pae psa, mri isaacson aj et al, 2016 (22) 12 ipss-qol pisco j et al, 2016 (23) 152 ipss, qol, need for additional treatment wang mq et al, 2016 (14) 157 ipss, qol, qmax, pv, pvr, and psa amouyal g et al, 2016 (24) 32 mean ipss, mean qol, mean qmax, mean pv de assis am et al, 2015 (10) 35 mri, uroflowmetry, ipss bagla s et al, 2015 (11) 78 aua symptom index, qol, or iief russo gi et al, 2015 (25) 287 ipss, iief-5, pf, pvr, ipss-qol ipss: international prostate symptom score, pvr: post void residual volume, psa: prostate-specific antigen, iief-5: international index of erectile function 5, qol: quality of life score, tpv transitional zone prostate volume, pv: prostatic volume (total volume and transition zone), eq-5d-5s: quality of life assessment 5d-5s, ibc indwelling bladder catheterization. table 2. histological and anatomical findings after pae and their clinical significance (15). histological and anatomical findings clinical significance fibroblast accumulation reparative process squamous metaplasia of the surrounding epithelium transitional process ribbons of neuthrophils, lymphocytes inflammatory process stamatiou_stesura seveso 27/03/18 09:25 pagina 41 archivio italiano di urologia e andrologia 2018; 90, 1 k. stamatiou 42 obstruction remains practically unknown (15). currently used imaging techniques are not providing relative information while knowledge on the histology of prostate tissue following pae is extremely limited. camara-lopes et al., described early prostate tissue histology changes after pae. along with embolic material (bright eosin-red spheroids filling the vessel lumens) they observed also areas of ischemic necrosis. the transition zone between necrotic and normal prostate tissue was characterized by inflammatory reactions containing ribbons of neuthrophils, lymphocytes and proliferated fibroblasts. nodular fibrosis with hyalinization as a consequence of the healing process was present in some areas associated with squamous metaplasia of the epithelium lining the surrounding glands (9). yet there are no studies examining long term prostate tissue histology changes after pae. however, given that psa values decreases to a level significantly lower than at baseline but no ejaculation disorders occur it could be assumed that prostate gland return in fully functional state after pae. as a matter of fact, metaplasia that occurs in response to necrosis and inflammation may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment and is reversible. on the other hand, the regained ability to urinate after pae may be associated with changes in stromal elements. because fibroblasts are typically activated following injury and are the main producers of extracellular matrix proteins, their role as reparative cells is widely recognized (16). fibroblasts may play a critical role in remodeling of the prostate following pae and thus, clinical success might be also related to the regained elasticity. the stiffness of a tissue, or its ability to resist deformation when subjected to an applied force, is indicative of the regenerative state in most organs in the body. tissue stiffness is largely defined by chemistry and associated micro-macro structure of the extracellular matrix (ecm). therefore, the ability to estimate ecm stiffness may assist in monitoring healing after pae and allow estimation of clinical success. currently, elastic properties, of biomaterials including stiffness or shear modulus, can be investigated by elastography. the last is the only specialized imaging-based method available to spatially map strain fields, it is costeffective and safe (17). studies comparing elastographic findings with the conventional outcome measures are needed in order to investigate the role for the elastography on the evaluation of the efficacy of pae on the treatment of bph. conclusion pae is a safe and efficient method for the treatment of both mechanical and dynamic component of bladder outlet obstruction in patients with bph. current imaging outcome measures are consistent with clinical ones in the group of patients with adenomatous-dominant bph while are inconsistent in patients with small sized adenomas. elastography may be useful for the evaluation of pae outcome in these patients while may shed light on the pathophysiology of bph and inspire new options and novel techniques for both treatment and follow up. references 1. auffenberg gb, helfand bt, mcvary kt. established medical therapy for benign prostatic hyperplasia. urol clin north am. 2009; 36:443-59. 2. roehrborn cg. pathology of benign prostatic hyperplasia. int j impot res. 2008; 20:s11-s18. 3. lawrentschuk n, perera m. benign prostate disorders. in: de groot lj, chrousos g, dungan k, et al., editors. endotext [internet]. south dartmouth (ma): mdtext.com, inc.; 2000. 4. shim sr, kanhai kj, koym, kim jh. efficacy and safety of prostatic arterial embolization: systematic review with meta-analysis and meta-regression. j urol. 2016: s0022-5347(16)31197-1. 5. yoshinaga em, galvao o, da motta-leal-filho jm, et al. magnetic resonance analysis of prostatic volume after prostatic artery embolization (pae) for treatment of benign prostatic hyperplasia (bph). j urol. 2013; 189(4s/supplement): e820 6. frenk ne, baroni rh, carnevale fc, et al. mri findings after prostatic artery embolization for treatment of benign hyperplasia. ajr am j roentgenol. 2014; 203(4):813-21. 7. lin yt, amouyal g, correas jm, et al.can prostatic arterial embolisation (pae) reduce the volume of the peripheral zone? mri evaluation of zonal anatomy and infarction after pae. eur radiol. 2016; 26:3466-73. 8. kisilevzky n, faintuch s. mri assessment of prostatic ischaemia: best predictor of clinical success after prostatic artery embolisation for benign prostatic hyperplasia. clin radiol. 2016; 71:876-82. 9. camara-lopes g, mattedi r, antunes aa, et al. the histology of prostate tissue following prostatic artery embolization for the treatment of benign prostatic hyperplasia. int braz j urol. 2013; 39:222-7. 10. assis am, rodrigues vcp, yoshinaga em, et al. prostatic artery embolization (pae) for treatment of benign prostatic hyperplasia in patients with prostates exceeding 90g: a prospective single center study. j vasc interv radiol. 2015; 26:87-93. 11. bagla s, smirniotopoulos jb, orlando jc, et al. comparative analysis of prostate volume as a predictor of outcome in prostate artery embolization. vasc interv radiol. 2015; 26:1832-8. 12. pereira k, halpern ja, mcclure td, et al. role of prostate artery embolization in the management of refractory haematuria of prostatic origin. bju int. 2016; 118:359-65. 13. little mw, boardman p, macdonald ac, et al. adenomatousdominant benign prostatic hyperplasia (adbph) as a predictor for clinical success following prostate artery embolization: an agematched case-control study. cardiovasc intervent radiol. 2017; 40:682-689. 14. wang mq, wang y, yan jy, yuan k, et al. prostatic artery embolization for the treatment of symptomatic benign prostatic hyperplasia in men ≥ 75 years: a prospective single-center study. world j urol. 2016; 34:1275-83. 15. sun f, crisóstomo v, báez-díaz c, sánchez fm. prostatic artery embolization (pae) for symptomatic benign prostatic hyperplasia (bph): part 2, insights into the technical rationale. cardiovasc intervent radiol. 2016; 39:161-9. 16. willems ie, havenith mg, de mey jg, daemen mj. the alphasmooth muscle actin-positive cells in healing human myocardial scars. am j pathol. 1994; 145:868-875. stamatiou_stesura seveso 27/03/18 09:25 pagina 42 43archivio italiano di urologia e andrologia 2018; 90, 1 the impact of prostate artery embolization (pae) on the the physical history and pathophysiology of benign prostatic hyperplasia (bph) 17. kim w, ferguson vl. application of elastography for the noninvasive assessment of biomechanics in engineered biomaterials and tissues. ann biomed eng. 2016; 44:705-724. 18. li p, wang c, cao q, zhang j, et al. prostatic arterial embolization followed by holmium laser enucleation of the prostate as a planned combined approach for extremely enlarged benign prostate hyperplasia. urol int. 2017 aug 3, [epub ahead of print]. 19. hwang jh, park sw, chang is, et al. comparison of nonspherical polyvinyl alcohol particles and microspheres for prostatic arterial embolization in patients with benign prostatic hyperplasia. biomed res int. 2017; 2017:8732351. (epub 2017 jun 22). 20. rampoldi a, barbosa f, secco s, migliorisi c, et al. prostatic artery embolization as an alternative to indwelling bladder catheterization to manage benign prostatic hyperplasia in poor surgical candidates. cardiovasc intervent radiol. 2017; 40:530-536. 21. bilhim t, pisco j, pereira ja, costa nv, et al. predictors of clinical outcome after prostate artery embolization with spherical and nonspherical polyvinyl alcohol particles in patients with benign prostatic hyperplasia. radiology. 2016; 281:289-300. 22. isaacson aj, raynor mc, yu h, et al. prostatic artery embolization using embosphere microspheres for prostates measuring 80-150 cm(3): early results from a us trial. j vasc interv radiol. 2016; 27:709-14. 23. pisco j, bilhim t, pinheiro lc, et al. prostate embolization as an alternative to open surgery in patients with large prostate and moderate to severe lower urinary tract symptoms. j vasc interv radiol. 2016; 27:700-8. 24. amouyal g, thiounn n, pellerin o, yen-ting l. clinical results after prostatic artery embolization using the perfected technique: a single-center study. cardiovasc intervent radiol. 2016; 39:367-75. 25. russo gi, kurbatov d, sansalone s, et al. prostatic arterial embolization vs open prostatectomy: a 1-year matched-pair analysis of functional outcomes and morbidities. urology. 2015; 86:343-8. correspondence stamatiou konstantinos, md (corresponding author) stamatiouk@gmail.com urology department, tzaneio hospital, 2 salepoula str. 18536 piraeus, greece stamatiou_stesura seveso 27/03/18 09:25 pagina 43 35archivio italiano di urologia e andrologia 2019; 91, 1 note of surgical technique the lest technique: treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia rosario leonardi department of urology and andrological surgery, musumeci gecas clinic gravina of catania, catania, italy. the objective of this study was to search for an alternative technique to relieve prostatic obstruction due to benign prostatic hyperplasia without affecting the ejaculatory function. the technical requirements are a laser with a wavelength well absorbed by water (good vaporizing effect) and at the same time by hemoglobin (good hemostatic effect) and laser fibers very resistant at high emission power allowing perfect vaporization in a contact mode. the aim of the technique is to avoid damage of the structures that allow the peripheral region of the prostate and the seminal vesicles to discharge their secretions into the posterior urethra. the orifices of the ejaculatory ducts must therefore be identified and preserved, damage of the ejaculatory ducts along their path inside the prostate must be avoided and the so called “genital sphincter” must be saved. the steps of the leonardi ejaculation sparing technique (lest) procedure are as follow: step 1 ejaculatory duct orifices must be identified and the limits of the vaporization section must be marked. step 2 bladder neck is cleaned of the prostate hypertrophic tissue saving, as much as possible, the smooth muscle fibers of the bladder neck. step 3 vapo-resection of the lateral lobe (or enucleation of the adenoma) is performed. step 4 cautious and meticulous preparation of the prostatic apexes is obtained with saving of the orifices of the ejaculatory ducts. an antegrade ejaculation is maintained in about 80% of cases in patients without a middle lobe, although in the presence of a middle lobe this rate drops to about 50%. key words: benign prostatic hyperplasia; prostatic obstruction; antegrade ejaculation; laser. submitted 25 january 2019; accepted 8 february 2019 summary no conflict of interest declared. in this paper we will describe the technique developed by our team, starting from the anatomical and functional premises that support it. furthermore, the process of the development of the technique over time will be reviewed and finally the surgical procedure aiming to achieve a complete removal of bladder neck obstruction with preservation of ejaculatory function will be described “step by step”. anatomy of the prostate the prostate is a glandular and stromal organ, single and median, located in the small pelvis between the base of the bladder and the urogenital diaphragm, behind the pubic symphysis and in front of the rectum. the first tract of the urethra, namely the prostate urethra, passes through the prostate from the base to its apex. the secretions of the prostate glands, seminal vesicles and testicles (corpuscular part of the seminal fluid) are voided into the lumen of the prostate urethra. the seminal fluid is made up for about 15-30% from prostate secretion, for about 50-70% from the fluids of the seminal vesicles and for less than 5% from the product of the testicles, deferential ampules, glands of cowper and urethral glands (2). the prostate is typically described as a chestnut shape with the base facing the bladder and the apex at the bottom, resting on the external urethral sphincter (3). histologically, it is composed of tubulo-alveolar glands whose ducts open into the prostate urethra. the gland can be clinically divided into the anterior lobe, the middle lobe, if present, and two lateral lobes. mcneal observed that the urethra separates the prostate into two regions, the ventral (fibromuscular) and the dorsal (glandular) one. approximately halfway between the apex and the base, the posterior wall of the urethra undergoes an acute angle (ventral angle of 35 degrees), which separates the urethra into a proximal segment and a distal segment. the orifices of the ejaculatory ducts and the verum montanum are located in the context of the distal segment. the glandular prostate can be divided into four distinct regions: peripheral zone, central zone, transition zone, and periurethral region (4) (figures 1, 2). in absence of prostatic hyperplasia (bph), the peripheral zone makes up about 70% of the gland. the transition doi: 10.4081/aiua.2019.1.35 introduction there is a growing interest to maintain a normal sexual function, after surgical management of bladder outflow obstruction due to benign prostatic hyperplasia (bpo). it is well known, that transurethral resection of the prostate (turp) strongly impacts on sexual function, not so much in terms of erection but, of course, in terms of antegrade emission of seminal fluid. this has led, in recent years, to the search for alternative techniques to relieve obstruction capable of preserving the ejaculatory function. unfortunately, most of these techniques had a limited diffusion due to both restricted indications (1) and reduced efficacy of obstruction removal. leonardi_stesura seveso 26/03/19 12:43 pagina 35 archivio italiano di urologia e andrologia 2019; 91, 1 r. leonardi 36 zone represents about 5-10% of the glandular tissue and is located at the angle that divides the tract of the urethra above and below the veru montanum. the central area surrounds and protects the ejaculatory ducts and constitutes about 25% of the glandular tissue. the fibromuscular zone that does not contain glandular tissue may, in some subjects, constitute about one third of the glandular volume (5). functional anatomy of the ejaculation ejaculation consists of three physiological phases. the first phase, also known as the preparation phase, is under the prevalent influence of the parasympathetic system with an increase in the secretory activity of the prostate glands and seminal vesicles. this is followed by a second phase, called emission phase, which culminates with a coordinated and peristaltic contraction of the smooth musculature of the vasa, ampoules, seminal vesicles and acinar prostatic glands. this results in the emission and accumulation of seminal fluid in the posterior urethra. this phenomenon creates the unstoppable sensation of ejaculation. the seminal fluid injected into the posterior urethra would drain into the bladder if an "anti-reflux" system was not activated by the alpha sympathetic system. initially, this anti-reflux system was exclusively identified with the bladder neck, but subsequently the histochemical studies of gosling et thompson identified this sphincter area in the pre-prostatic segment of the posterior urethra above the veru (6). bruschini et tanagho confirmed, by pharmacological and manometric studies, the presence of this area called "genital sphincter" (7) (figures 3, 4). this functional sphincter with mainly genital function begins in the bladder neck, continues with the smooth muscle fibers intrinsic to the urethra and is added to the urinary sphincter fibers incorporated in the prostate stroma and to the smooth muscle of prostate glandular elements (8). to summarize, it is a smooth muscle complex located in the area proximal to the opening of the ejaculatory ducts in the urethra. these muscles, in the phase in which the action of the sympathetic nervous system prevails, contracts preventing the reflux of the seminal fluid into the bladder (9). in case of bph, the transition zone is larger than in the normal prostate. the transitional zone compresses the peripheral zone moving it down its apical portion. in addition, in 36 to 70% of patients with bph there is a reduction or absence of ejaculate, which etiopathogenesis is still unclear. some authors argue that there may be a compression of the ejaculatory ducts, others that there may be an increase in the angle of the ducts in the terminal portion near their outlet into the urethra. the fact is that the glandular structure of the hypertrophic prostate (transition zone) loses its physiological structure, and the glands, overcrowded and newly formed, often do not produce an adequate volume of secretion compared to a normal gland (figure 5). histological studies with quantitative imaging analysis of prostate sections of symptomatic bph subjects stained with double enzyme immunoassay showed that, for each area examined, the percentage density of smooth muscle and connective tissue was significantly higher than those of glandular epithelium and glandular lumen area (medium sem) (10). from this finding it can be deducted that the prostate component of the seminal fluid, in the subject with bph, is significantly reduced. figure 1. the figure shows schematically a sagittal section of prostate . figure 2. 3d reconstruction of different zones of prostate. leonardi_stesura seveso 26/03/19 12:43 pagina 36 lest procedure (leonardi ejaculation sparing technique) as mentioned in the introduction, the development of the lest technique originates from the growing demand from the male population to be able to maintain an intact sexual function (erection and ejaculation) after an efficacious procedure of removal of bladder neck obstruction (11). although the gold standard of endoscopic surgical treatment for benign prostatic hyperplasia (bph) has been, until now, the transurethral resection of the prostate (turp), in recent years the supremacy of this procedure has been challenged by the introduction of new surgical devices and, above all, of endoscopic lasers capable of removing the prostate adenoma, that is the cause of cervical-urethral obstruction. these techniques have, in fact, reduced hospitalization times and the complications associated with turp (hemorrhage, incontinence) (12). until now, little attention was given to the maintenance of ejaculatory function, considering retrograde ejaculation as a minor side effect for the quality of life of the patient, if not as a tangible sign of a successful removal of obstruction. however, patients, if accurately interviewed, do not tolerate retrograde ejaculation, and, for many of them, this risk is the only reason that leads them to delay the procedure, even when mandatory, for fear of incurring this post-operative outcome (13, 14). we have therefore decided, on the basis of the anatomical-functional premises described above, to develop the lest technique, whose preliminary data have already been published in 2009 (15). we believed that a complete removal of obstruction, overlapping to that achievable by a successful turp, should not necessarily result in a retrograde ejaculation. this could be possible because the removal of hypertrophic tissue, as mentioned above, will reduce the volume of semen only by a small amount, since hypertrophic tissue produces a reduced amount of secretions. in fact the most volume of semen, especially in subjects with bph, comes from the glands of the peripheral zone and seminal vesicles. it was therefore necessary: 1. to conceive a technique that would not damage the structures that allow these anatomical regions to introduce their secretions into the posterior urethra. secretions of the peripheral region of the prostate and the seminal vesicles discharge their secretions at the base of the prostatic urethra above the veru (pre-montonal) through the orifices located in the region surrounding the veru montanum. the orifices of the ejaculatory ducts must therefore be identified and preserved. 2. to avoid damaging the ejaculatory ducts along their path inside the prostate, remembering that they are surrounded by the central part of the prostate and that they get closer and closer to the floor of the prostate urethra, as they approach their openings. 3. to save what tanagho, and after him other authors, called "genital sphincter", as previously described in the anatomical-functional premises. 4. to have the equipment adequate to develop an unobstructed prostatic lodge without damaging all the structures above described. lasers in relation to this latter point we had to exclude the devices used for traditional resection, aiming to find a laser with a suitable wavelength to be well absorbed by water (good vaporizing effect), and at the same time by hemoglobin (good hemostatic effect) (figure 6). it was also necessary to 37archivio italiano di urologia e andrologia 2019; 91, 1 the lest technique figure 3. glandular section along the urinary axis f anterior fibromuscular layer; bn bladder neck; pz peripheral zone; gs genital sphincter surrounding the premontanal urethra, ensuring with its contraction, during ejaculation, the orthodromic direction of the seminal flow. modified from f. basile et al. manual of semeiotics and surgical methodology. edra publisher 15 jan 2014. figure 4. intraoperative image depicting the genital sphincter (sg). figure 5. histological appearance of prostate glandular tissue in a normal subject and in a subject with benign prostatic hyperplasia. histology normal prostate benign prostatic hyperplasia leonardi_stesura seveso 26/03/19 12:43 pagina 37 archivio italiano di urologia e andrologia 2019; 91, 1 r. leonardi 38 choose a wavelength that did not have a significant effect of deep penetration into the tissues producing only a surface vaporization. this is to avoid the very annoying irritative symptoms due to the reabsorption of the coagulative necrosis produced in depth of the unremoved prostate tissue that was associated with the use of lasers already present on the market. the first laser we tried, able to have all the requirements above described, was a laser with 980 mm wavelength working at the power of 100 watts. since 2010 a significant improvement was achieved by the use of the new hpd 180 watts high power laser, and, by the production of fibers designed and built to work in contact and at high power. another improvement was done in 2016 with a new laser that is able to mix freely two wave lengths (980 nm and 1470 nm). this diode laser is capable of emitting two wavelengths of 980 nm and 1470 nm simultaneously along the same fiber. in practice it is possible to mix, according to the structure of the tissue to be vaporized, a prevalence of 980 nm with a stronger affinity for hemoglobin or 1470 nm with a higher absorption in water for less vascularized tissues. the low penetration of both wavelengths into the vaporized tissue (350 microns) (18) allows not only to reduce post-operative irritative symptoms but, at the same time, to safeguard the ejaculatory ducts. fibers from the very first attempts we realized the importance of using contact vaporization. the vaporization for irradiation, produced by the "side-firing fibers", is not able to sculpt the prostatic lodge with millimetric precision. the beam of light emitted by the fiber can create a more or less extended vaporization margin, depending on the distance of the emitting fiber from the prostate tissue. with the "side-firing fiber" a good vaporization is obtained keeping, theoretically, the fiber at a constant distance of 0.5 cm from the tissue to be vaporized. if this distance is not maintained, the radiation power on the tissue is reduced, creating coagulative necrosis instead of vaporization. in our previously published study we did not dispose of “contact” vaporizing fibers, so we had to use a trick that allowed us to use the side fibers in a contact mode. we set the laser to pulsed mode in order to reduce the stress on the fiber by allowing some cooling in the refractory phase of emission. the results obtained in the previous study were satisfactory in terms of removal of obstruction and maintaining the anterograde ejaculation (table 1). now we are using new fibers called twister of three sizes (normal, large and extra large) (16) (figure 7). the twister fiber is a special fiber with a quartz tip, with a 15° curvature at the tip, which allows perfect vaporizafigure 6. the figure shows at the left the absorption spectrum at wavelength 980 nm in water and hemoglobin, at the right the depth of penetration in the prostate tissue of 980 and other types of laser. figure 7. twister fiber xl. table 1. results of “side-firing” laser. modified by leonardi r.: preliminary results on selective light vaporization with the sidefiring 980 nm diode laser in benign prostatic hyperplasia: an ejaculation sparing technique. prostate cancer prostatic dis. 2009; 12:277-80. parameter baseline n = 52 3-month n = 52 12-month n = 22 ipss 18.4+/-5.8 7.5+/-5.9 6.0+/-0.6 ipss improvement % 59% 67% qmax ml/sec 7.5+/-4.1 20.9+/-8.4 19.7+/-1.4 qmax improvement % + 179% + 163% pvr ml 160+/-140 24+/-22 20.3+/-4.4 pvr improvement % 85% 87% ipss-qol 3.5+/-1.2 1.3+/-1.2 1.2+/-0.4 63% 66% ipss = international prostate symptom score pvr = postvoidal residual urine qmax = maximum flow rate qol = quality of life change from baseline for all parameters p < 0.0001 leonardi_stesura seveso 26/03/19 12:43 pagina 38 tion and/or engraving of the tissue, in a contact mode. the three measures are distinguished by the volume of the quartz tip and the measure has to be chosen according to the prostate volume that must be vaporized. the twister fiber is very resistant even when used at high emission powers, and allow, in almost all of cases, to conclude the procedure with a single fiber (17). these technological innovations have allowed us to be much faster in prostate vaporization, reaching a real speed of tissue removal of about 1.5 grams per minute. the indications have been extended to the treatment of increasingly voluminous prostates, but also allowed us to precisely sculpt the new prostate loggia with excellent control of the vaporization margins and, therefore, with a saving of the structures responsible for the anterograde ejaculation, that was crucial for developing the lest technique. the area to be preserved has been named by us as the “ejaculatory triangle” (figures 8, 9). surgical technique the patient who requires a lest procedure must be well informed about the technique that we are going to do, knowing well which are the success rates of the “ejaculation sparing” technique, in order not to feed false expectations. studies conducted by us have shown the possibility of maintaining an anterograde ejaculation in about 80% of cases in patients without a middle lobe. in the presence of a middle lobe, the rate drops to about 50%. the ideal feature of the patient for lest surgery is a bilobed prostate with a good percentage of peripheral prostate, well visible ejaculatory duct orifices (odes) and normal seminal vesicles. for this reason, we always practice a trans-rectal prostate ultrasound and flexible urethroscopy on our patients before surgery. the worst results are in prostate with voluminous medium lobe, non-visible odes and hypotrophic seminal vesicles. why most suitable prostates for lest should not have a middle lobe? we previously described which anatomical structures are responsible for the persistence of antegrade ejaculation, namely the smooth muscles that extends from the bladder neck along the first tract of the posterior urethra to the veru montanum. as we know, in the trilobal prostates, the middle lobe plays an important role in generating a severe obstruction and therefore, for a successful removal of obstruction, it is necessary to remove all the medium lobe from its origin, near to the veru montanum. this involves the removal of most of the ejaculatory triangle and a weakening of the bladder neck. this is the reason, in our opinion, why the presence of a voluminous middle lobe lowers the success rate of the intervention to about 50%. why is a good presence of peripheral prostate important? by removing most of the transition zone (reaching the surgical capsule), after the procedure prostate secretion is limited to the peripheral region, which pours its secretion on the floor of the prostate urethra (ejaculatory triangle). as far as seminal vesicles are concerned, we know that, under normal conditions, these structures contribute to producing about 65% of the volume of seminal fluid. having, therefore, two normotrophic seminal vesicles at ultrasound examination and two ode clearly visible at endoscopic examination, we can predict a good result in term of volume of liquid produced in the post-operative. procedure step by step step 1: identification of anatomical structures introduced the laser cystoscope with a 30° optic, the odes are identified and the limits of the vaporization section are marked (figure 10). 39archivio italiano di urologia e andrologia 2019; 91, 1 the lest technique figure 8. ejaculatory triangle. figure 9. ejaculatory triangle at the end of the procedure. figure 10. markers of the lower limit of the vaporesection. leonardi_stesura seveso 26/03/19 12:43 pagina 39 archivio italiano di urologia e andrologia 2019; 91, 1 r. leonardi 40 step 2: bladder neck preparation the vaporization starts with a power lower than the maximum usable for the type of fiber used, in order to avoid thermal shocks to the fiber itself. the bladder neck is cleaned of the prostate hypertrophic tissue that caused the obstruction, saving, as much as possible, the smooth muscle fibers of the neck and ensuring that the neck does not remain rigid after vaporization. we proceed with small incisions at 5 and 7 o'clock, taking care not to destroy the muscle fibers completely. it is always important to identify and preserve the bladder neck fibers . at the end of the vaporization, a clean cut is observed between the bladder mucosa and the prostate lodge (figures 11, 12). step 3: vapo-resection of the lateral lobes contact vaporization must always meet the criteria of symmetry. the prostatic lodge after removal of obstruction must be large and symmetrical. we start vapo-resection at the base of the lateral lobes so that the edges of the ejaculatory triangle are clearly defined. it should be noted that, in larger prostates, and if it is considered necessary to obtain abundant tissue to be subjected to histological examination, instead of carrying out a vapo-resection, a real enucleation of the adenoma (dilep) can be used. in these cases, enucleation is performed sparing the structures considered crucial to obtain an antegrade ejaculation (figure 13). this last step is perhaps the most delicate and important for the success of the procedure (figures 14, 15). the prostate apexes with the traditional turp are completely removed, believing that, in this way, the maximum removal of obstruction will be obtained. in fact, anatomical studies have shown that the prostate apex is only partly constituted by the transitional tissue causing the obstruction. part of the apexes are constituted by the peripheral area of the gland that has been moved down by the hypertrophy of transitional zone. a proof of this is that, at times, some prostate tumors, which are known to develop more frequently in the figure 11. start of vapo-resection from the bladder neck. figure 12. bladder neck after surgery. note the bloodless field, the well defined margin of vapo-resection with sparing of the neck and bladder mucosa that, when washing is stopped, prolapses inside the prostate neo lodge. figure 13. final result after dilep with lest technique. on the left trans-rectal ultrasound examination showing the large lodge with preservation of the neck. in the small box, endoscopic image of preservation of part of the apexes belonging to the peripheral zone of the gland. on the right endoscopic image showing preservation of the floor of the prostate urethra where the peripheral gland flow into. bladder urethra peripheral zone central zone seminal vesicles transitional zone anterior fiber-muscular area leonardi_stesura seveso 26/03/19 12:43 pagina 40 peripheral zone but not in the transition zone, are found in the biopsies of the apex. the peripheral part of the prostate tissue does not have a structure that could obstruct the urinary flow. its preservation guarantees the integrity of the genital sphincter and protects the outlets of the ejaculatory ducts during the vaporization phase of this area. another fundamental step for the success of the procedure is the preservation of the orifices of the ejaculatory ducts. in doing so, we ensure that the secretions from the seminal vesicles are introduced into the posterior urethra (figure 16). at this point the intervention can be considered completed. we administer an alpha-blocker in the first 20 days of the post-operative. the choice to administer the alphablocker is to avoid spasms of the smooth muscles of the bladder neck which, with the lest technique, is spared. we do not administer cortisone or painkillers because treatment with the above technique and with wavelengths 980/1470 does not produce significant irritative symptoms. the patient can resume normal sexual intercourse 20 days after surgery. references 1. hoepffner jl, fontaine e, benfadel s, et al. a modified cervicoprostatic incision technique in hypertrophic adenoma in young subjects desiring to preserve ejaculation. prog urol. 1994; 4:371-7. 2. segawa a. studies on secretory function of male sexual organs and their accessory glands. jap j urol. 1957; 48:869. 3. seisen t, rouprêt m, faix a, droupy s. the prostate gland: a crossroad between the urinary and the seminal tracts. prog urol. 2012; 22(suppl 1):s2-6. 4. selman sh. the mcneal prostate: a review. urology. 2011; 78:1224-8. 5. basile f, bellantone r, biondi a, et al. manuale di semeiotica e metodologia chirurgica, edra, 2014; isbn: 9788821434365. 6. gosling ja, thompson sa. a neurohistochemical and histological study of peripheral autonomic neurons of the human bladder neck and prostate. urol int. 1977; 32:269-76. 7. bruschini h, schmidt ra, tanagho ea. the male genitourinary sphincter mechanism in the dog. invest urol. 1978; 15:284-7. 8. belgrano e, et al. i disturbi dell’eiaculazione edizioni medico scientifiche, pavia 1995. 41archivio italiano di urologia e andrologia 2019; 91, 1 the lest technique figure 14. start of the vapo-resection of the apexes. figure 15. trans-rectal ultrasound image after dilep with lest technique. figure 16. preand post-surgery orifices of the learned ejaculators.ejaculatory ducts outlets bladder urethraperipheral zone seminal vesicles central zone transitional zone anterior fiber-muscular area bladder neck ejaculatory triangle apexes leonardi_stesura seveso 26/03/19 12:43 pagina 41 archivio italiano di urologia e andrologia 2019; 91, 1 r. leonardi 42 9. stockamp k, schreiter f. proceedings: function of the posterior urethra in ejaculation and its importance for urine control. urol int. 1974; 29:226-30. 10. shapiro e, hartano v, lepor v. anti-desmin vs. anti-actin for quantifying the area density of prostate smooth muscle. prostate. 1992; 20:259-67. 11. chung a, woo hh. preservation of sexual function when relieving benign prostatic obstruction surgically: can a trade-off be considered? curr opin urol. 2016; 26:42-8. 12. wang l, yu qy, liu y, et al. efficacy and safety of laser surgery and transurethral resection of the prostate for treating benign prostate hyperplasia: a network meta-analysis.asian pac j cancer prev. 2016; 17:4281-4288. 13. alwaal a, breyer bn, lue tf. normal male sexual function: emphasis on orgasm and ejaculation. fertil steril. 2015; 104:1051-60. 14. lue t, et al. sexual dysfunctions in men health clinical. manual of sexual medicine health publications ltd. 2004 isbn 09546956-1-5. 15. leonardi r. preliminary results on selective light vaporization with the sidefiring 980 nm diode laser in benign prostatic hyperplasia: an ejaculation sparing technique. prostate cancer prostatic dis. 2009; 12:277-80. 16. shaker hs, shoeb ms, yassin mm, shaker sh. quartz head contact laser fiber: a novel fiber for laser ablation of the prostate using the 980 nm high power diode laser. j urol. 2012; 187:575-9. 17. shaker h, alokda a, mahmoud h. the twister laser fiber degradation and tissue ablation capability during 980-nm highpower diode laser ablation of the prostate. a randomized study versus the standard side-firing fiber. lasers med sci. 2012; 27:959-63. 18. leonardi r, caltabiano r, lanzafame s. histological evaluation of prostatic tissue following transurethral laser resection (tular) using the 980 nm diode laser. arch ital urol androl. 2010; 82:1-4. correspondence rosario leonardi, md (corresponding author) leonardi.r@tiscali.it department of urology and andrological surgery, musumeci gecas clinic gravina of catania, catania (italy) leonardi_stesura seveso 26/03/19 12:43 pagina 42 stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11549 1 original paper penile trauma, diabetes mellitus, hypertension, congenital penile curvature, radical pelvic surgery, erectile dysfunction, obesity, smoking, hypertension, autoimmune diseases (rheumatoid arthritis, psoriatic arthritis, psoriasis), alcohol consumption, and dyslipidemia (1-11). the prevalence of pd ranges from 3.2 to 13.1% in western countries (12-17). however, pd prevalence is influenced by the geographic location of patients; prevalence in the asian region seems to be lower, with 5.0% in japan and 0.6% in china (18, 19). pd takes place in two phases, the first of which represents the active phase of the disease; the second phase represents the phase of stabilization. in the first phase, which has a duration of about 12-18 months, inflammation causes an overproduction of collagen with the relative formation of a fibrotic plaque which causes penile deformation (curvature, shortening, dip, indentation, hourglass, etc.) (20-22). the fibroblasts and myofibroblasts present in the disease area (plaque) can transform into osteoblasts with a relative production of calcified areas (22, 23). vernet et al. (2005) demonstrated that progenitor cells are present in the fibrotic plaque tissue of pd and in the normal tunica albuginea of the penis, which, in culture, can differentiate into other cell lines (23). during pd, the differentiation of these progenitor cells into osteoblasts and myofibroblasts is stimulated by the profibrotic cytokine transforming growth factor beta-1 (tgf-β1). this cell differentiation can also be activated during chronic inflammation, oxidative stress, and fibrosis, where tgf-β1 is upregulated (23). this cell differentiation into osteoblasts and the related plaque calcification in pd occurs in about 20-43% of cases (22-26). the stabilization phase represents the end of the progression of the disease; in this phase, there is no more penile pain and penile deformation has ceased to progress. the diagnosis of plaque calcification necessarily requires a penile ultrasound or other imaging methods (mri, ct) as the simple penile palpation is not able to recognize the calcification for sure (27-32). the aim of our study is to evaluate the impact of plaque calcification on the clinical symptoms of patients with pd. background: the aim of study was to evaluate the impact of plaque calcification on symptoms of patients with peyronie’s disease (pd) and to evaluate mental health in pd patients with or without calcification. methods: we performed a retrospective analysis of the clinical database of a single andrology clinic. we extracted 551 pd patients, and we sorted them into two groups: the first group included 201 pd patients with plaque calcification; the second group included 350 pd patients without plaque calcification. the inclusion criteria for both groups were as follows: aged between 21 and 81 years; thorough and available data on clinical history; baseline levels of blood glucose, glycosylated hemoglobin, cholesterol, and triglycerides; photographic documentation of the penile curvature; dynamic penile eco-color doppler ultrasound with plaque measurements and volume calculation; and completion of the generalized anxiety disorder—7 questionnaire, patient health questionnaire—9 (for depression), visual analog scale for penile pain measurements, and the international index of erectile function (iief) questionnaire. results: plaque calcification was present in 36.4% of cases. the presence of calcification affects the presence and severity of penile curvature. calcification is associated with the presence of hypertension. in pd patients, the prevalence of significant anxiety and significant depression was 89.1% and 57.3%, respectively. calcification is associated with the presence of anxiety and depression but does not lead to an increase in their prevalence. conclusions: in pd patients, the calcification was present in more than one third of cases. the size of the plaque calcification was < 15 mm in most cases. calcification influences the presence of the curve and influences its severity. there was a prominent prevalence of anxiety and depression in pd patients. key words: peyronie’s disease; plaque calcification; depression; anxiety. submitted 27 june 2023; accepted 14 july 2023 introduction peyronies’s disease (pd) is a chronic inflammatory disease that affects the tunica albuginea of the corpora cavernosa of the penis. pd has a genetic origin; however, it requires the concomitance of some risk factors. among these are calcification in peyronie's disease: its role and clinical influence on the various symptoms and signs of the disease, including psychological impact. our study of 551 patients gianni paulis 1, andrea paulis 2 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy. doi: 10.4081/aiua.2023.11549 summary archivio italiano di urologia e andrologia 2023; 95(3):11549 g. paulis, a. paulis 2 materials and methods study design we performed a retrospective analysis of the clinical database of a single andrology clinic. from the database, we extracted 551 pd patients who were examined in our urology/andrology clinic between january 2013 and april 2023. we divided all pd patients into two groups: the first group included 201 patients diagnosed with peyronie's disease (pd) and with plaque calcification; the second group included 350 pd patients without plaque calcification. all data were obtained from the available patient records. the diagnosis of penile calcification was made in all cases with a penile ultrasound examination performed by the same andrologist operator with a highresolution ultrasound device, philips hd 15 until the year of 2018, and thereafter with philips affinity 70 g (philips, washington, united states). the diagnosis of penile calcification was made when the hyperechoic area presented characteristic acoustic shadowing (33). this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki: all study subjects were contacted to provide their informed consent to participate in the study. sensitive data were anonymized to respect privacy according to legislative decree, 10 august 2018, n. 101, adapted to the gdpr (official gazette of the italian republic, general series n.205, dated 04-09-2018). inclusion criteria the inclusion criteria for both groups were as follows: aged between 21 and 81 years and available data of thorough clinical history examination (comprising all diseases) and the availability of the following blood tests: baseline blood glucose, glycosylated hemoglobin, cholesterol, and triglycerides. the diagnosis of peyronie's disease was made as follows: performing penile palpation for all pd patients and availability of a (i) photographic documentation of the penile deformation (according to kelâmi) with a goniometric measurement of the angulation and evaluation of the possible presence of the multiplanarity of the curvature (34) and a (ii) dynamic penile eco-color doppler ultrasound with plaque measurements and volume calculation (mm3, in three dimensions in mm) using an ellipsoid formula (volume = 0.524 x width x length x thickness) (35, 36). exclusion criteria the exclusion criteria were as follows: – for both groups, pd patients and non-pd patients aged under 21 years or over 81 years; – all patients who had not undergone the tests listed above. clinical data all clinical data (including the presence of concomitant diseases) were obtained from the clinical records of the 551 pd patients. in the clinical records of the 551 pd patients, the results of the following blood tests were searched: baseline blood glucose, glycosylated hemoglobin (hemoglobin a1c), cholesterolemia, and triglyceridemia. all pd patients were asked to complete the following questionnaires: visual analog scale (vas) questionnaire for pain measurement (37, 38); international index of erectile function (iief) for erectile function measurement (39); and two validated psychometric tests: the generalized anxiety disorder—7 questionnaire (gad-7, concerning anxiety) and the patient health questionnaire—9 (phq-9, concerning depression) (40, 41). the vas questionnaire consists of a 10 cm line drawn on paper, and each 1 cm point corresponds to a degree of pain intensity; the patient indicates their perceived pain point on this line. scores range from 0 (no pain) to 10 (most intolerable pain) (37). we considered the following interpretation vas: 1-5, mild/moderate pain; 67, severe pain; and 8-10, very severe pain (38). the iief erectile function questionnaire (for measuring possible erectile dysfunction) consists of 15 questions with 5 answers, and the final score varies from a minimum of 0 to 30. the interpretation of the score is: severe ed, from 0 to 10; moderate ed, 11 to 16; mild to moderate ed, 17 to 21; mild ed, 22 to 25; and no erectile dysfunction, 26 to 30 (39). we considered ed as present when the score was < 26. the gad-7 anxiety questionnaire consists of seven questions with four answers, and the final score ranges from 0 to 21. we interpreted this score as follows: least anxiety, 0-4; mild anxiety, 5-9; moderate anxiety, 10-14; and severe anxiety, 15-21 (40). in this study, we considered the presence of "significant" anxiety when the gad-7 score was > 9. the phq-9 questionnaire (patient health questionnaire— 9) includes 9 questions with 4 answers, and the final score ranges from 0 to 27. we interpreted this score as follows: minimal depression, 0-4; mild depression, 5-9; moderate depression, 10-14; moderately severe depression, 15-19; and severe depression, 20-27 (41). we considered the presence of "significant" depression when the phq-9 score was > 9 (moderate to severe depression). in accordance with the classification of levine et al. (24), the size of the calcification (measured in mm) was stratified into three groups according to the maximum size of the calcified zone: grade 1= punctiform or ≤ 3 mm; grade 2= > 3 mm and < 15 mm; and grade 3 = ≥ 15 mm or ≥ 2 plaques > 10 mm. study endpoints the primary endpoints of the study were the impact of calcification in pd patients on presence and severity of penile curvature, penile curve multiplanarity, presence and severity of ed, presence and severity of penile pain, presence and severity of anxiety, and presence and severity of depression. the secondary endpoints of the study were the impact on the presence of calcification of diabetes mellitus, hypertension (high blood pressure), dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia), cardiovascular diseases, and obesity and the prevalence of anxiety an depression in peyronie’s disease patients. statistical analysis we used medcalc statistical software (version 16.4.3, 2016) for the following statistical studies: chi-square two tailed test, relative risk (rr) test, odds ratio (or) test, and two-tailed t-test. for the statistical study of logistic regresarchivio italiano di urologia e andrologia 2023; 95(3):11549 3 calcification in peyronie's disease sion, we used agrimetsoft's software (2019). for the statistical study of the mann-whitney-wilcoxon test, we used statistics kingdom software (2017). for the statistical study of standard deviation, median, and interquartile range calculation (iqr), we used calculatorsoup® software (2006-2023). the impact of calcification on penile curvature severity in pd patients was investigated via a relative risk (rr) test after stratification of pd patients with calcification into two groups (group a, ≤ 45 degrees; group b, > 45 degrees). the impact of multiple calcifications on the multiplanarity of the penile curvature (when present) in pd patients was investigated using the odds ratio (or) test. the effect of calcification on the presence of ed in pd patients was investigated by comparing the median iief scores of patients with and without calcification. to calculate this comparison, we employed the two-tailed mannwhitney-wilcoxon test as well as the calculation of the median iief scores and the interquartile range (iqr). furthermore, to investigate the impact of calcification on ed presence in pd patients, we employed a logistic regression study. the impact of calcification on penile pain in pd patients, was investigated by comparing the median vas scores of patients with and without calcification. to calculate this comparison, we employed the two-tailed mann-whitneywilcoxon test as well as the calculation of the median vas scores and the iqr. furthermore, to investigate the impact of calcification on penile pain in pd patients, we employed a logistic regression study. the impact of calcification on the presence of anxiety in pd patients was investigated by comparing the mean and standard deviation (sd) of the gad-7 scores (of significantly anxious patients both with and without a calcification). to calculate this comparison using the gad-7 scores, we used the two-tailed mann-whitney-wilcoxon test as well as the calculation of the median scores and the iqr. furthermore, to investigate the impact of calcification on anxiety in pd patients, we employed a logistic regression study. the impact of calcification on the presence of depression in pd patients was investigated by comparing the mean and sd of the scores (phq-9) of significantly depressed patients with and without a calcification. to calculate this comparison using the phq-9 scores, we employed the two-tailed mann-whitney-wilcoxon test as well as the calculation of the median scores and iqr. furthermore, to investigate the impact of calcification on depression in pd patients, we employed a logistic regression study. the influence of diabetes mellitus, hypertension, hypercholesterolemia, cardiovascular diseases, and obesity on the presence of calcification in pd patients was investigated using the or test. in all statistical analyses, a 5% threshold for an alpha error was used to define statistical significance (significant p-value < 0.05). results in total, 551 patients with pd met the inclusion criteria for this study. the mean age was 49.55 years ± 12.17 years, range 21-81. we found that in the 551 patients affected by peyronie's disease, calcification was present in 36.4% of cases (201 cases). after dividing all pd patients into two groups according to the presence of plaque calcification, the first group included 201 pd patients with plaque calcification (mean age 49.57 years ± 12.19 years, range 21-81) and the second group included 350 patients diagnosed as pd patients without plaque calcification (mean age 49.54 years ± 12.18 years, range 21-73). in 107 cases, the penile calcifications were multiple (53.2% out of 201 cases, and 19.4% of all pd patients). having stratified the calcifications of 201 pd patients according to the classification proposed by levine et al. (23), we found the following results: grade 1 calcifications, 23 cases (11.4%); grade 2 calcifications, 130 cases (64.6%); and grade 3 calcifications, 48 cases (23.8%). the plaque calcification was < 15 mm (grade 1 and grade 2) in 76.1% of cases. out of a total of 551 pd patients, 499 had penile curvature (90.05% of cases), and the bend angle ranged from 5 to 100 degrees (mean 35.6 degrees ± 17.67). in the 201 pd patients with plaque calcification (group 1) the angle of curvature ranged from 5 to 100 degrees (mean 38.37 degrees ± 17.72); in the 350 patients with pd and without plaque calcification (group 2) the angle of curvature ranged from 5 to 100 degrees (mean 34.09 degrees ± 17.48). out of a total of 551 pd patients, 169 cases had a complex curve (multiplanarity) (30.67%), 217 erectile dysfunction (39.38% of cases), 296 penile pain (53.72% of cases), 491 significant anxiety (89.1% of cases), 317 significant depression (57.3% of cases), 32 diabetes mellitus (5.8% of cases), 103 hypertension (18.69% of cases), 56 dyslipidemia (10.16% of cases), 41 cardiovascular diseases (7.44%), and 31 were obese (5.6%). the clinical characteristics of the 551 pd patients, as a whole and divided by group 1 and group 2 are shown in table 1. the impact of plaque calcification on the presence and severity of penile curvature in pd patients the mean penile curvature degree of group 1 and group 2 were significantly dufferent (p = 0.009) (table 1). using the two-tailed mann-whitney-wilcoxon test, the medians of penile angulation degrees in patients with or without calcification were statistically different (with calcification = 39, iqr = 15; no calcification = 30, iqr = 25, p = 0.004) (p < 0.05). using the logistic regression test and considering the penile angulation degrees of all pd patients with or without calcification, the results we obtained are as follows: odds ratio = 1.013, (95% ci, 1.003 to 1.024), deviance 643.5, and p-value = 0.009 (p < 0.05). all statistical studies indicate that calcification has an influence on the presence and severity of penile curvature. the influence of calcification on penile curvature severity in pd pd patients with calcification were stratified into two groups (group a, ≤ 45 degrees; group b, > 45 degrees). there were 161 patients with calcification with a curve ≤ 45 degrees (80.09%), 40 with a curve > 45 degrees (19.90%); 309 patients without calcification had a curve ≤ 45 degrees (88.28%), and there were 41 patients with a curve > 45 degrees (11.71%). the resulting relative risk archivio italiano di urologia e andrologia 2023; 95(3):11549 g. paulis, a. paulis 4 of calcification on penile curvature severity was 0.22 (95% ci, 0.17 to 0.29, p < 0.0001). the z statistic was 10.4 (p < 0.0001). it was found that calcification has an influence on penile curvature severity. the impact of multiple calcifications on the multiplanarity of penile curvature in pd patients there were 35 patients with multiple calcifications and multiplanarity of the curve, and 72 without multiplanarity; there were 134 patients without multiple calcifications and with multiplanarity of the curve, and there were 310 without multiplanarity. the resulting odds ratio (or) was 1.12 (95% ci, 0.71 to 1.76, p = 0.610). the z-statistic was 0.509 (p > 0.05). these results indicate that calcification has no impact on the multiplanarity of curvature. the impact of calcification on the presence of erectile dysfunction (ed) in pd patients using the two-tailed mann-whitney-wilcoxon test the medians of the iief scores in patients with or without calcification were not statistically different (with calcification = 26, iqr = 2; no calcification = 26, iqr = 3, p = 0.1123) (p > 0.05). using the logistic regression test and considering the iief scores of all pd patients with or without calcification, odds ratio was 1.034, (95% ci, 0.971 to 1.102), deviance = 721.9, and p-value = 0.284 (p > 0.05). we found no correlation between the presence of calcification and iief score. the impact of calcification on the presence of penile pain in pd patients using the two-tailed mann-whitney-wilcoxon test the medians of the vas scores in patients with or without calcification were not statistically different (with calcification = 1, iqr = 4; no calcification = 1, iqr = 4, p = 0.536) (p > 0.05). using the logistic regression test and considering the vas scores of all pd patients with or without calcification, odds ratio was 1.019, (95% ci, 0.952 to 1.091), deviance = 722.7, and p-value = 0.572 (p > 0.05). we found no correlation between the presence of calcification and vas score. the impact of calcification on the presence of anxiety in pd patients using the two-tailed mann-whitney-wilcoxon test the medians of the gad-7 scores in patients with or without calcification were not statistically different (with calcification = 14, iqr = 7; no calcification = 14, iqr = 7, p = 0.764) (p > 0.05). using the logistic regression test and considering the gad-7 scores of all pd patients with or without calcification, odds ratio was 1.015 (95% ci, 0.976 to 1.056), deviance = 720.6, and p-value = 0.438 (p > 0.05). we found no correlation between the presence of calcification and gad-7 score. the impact of calcification on the presence of depression in pd patients using the two-tailed mann-whitney-wilcoxon test the table 1. clinical characteristics and results of the 551 pd patients, and the two subdivided groups (pd patients with and without calcifications). all n. 551 group 1 group 2 statistical analysis pd patients n. 201 pd patients n. 350 pd patients group-1 versus group-2 with calcified plaque without calcified plaque p-value (t-test) mean age (sd) 49.55 years 49.57 years 49.54 years 0.977 (± 12.17) (± 12.19) (± 12.18) means of the degrees of penile curvature (sd) 35.6 degrees 38.37 degrees 34.09 degrees 0.009 (± 17.67) (± 17.72) (± 17.48) variable all n. 551 group 1 group 2 p-value (𝝌2-test) pd patients n. 201 pd patients n. 350 pd patients with calcified plaque without calcified plaque n. cases (%) n. cases (%) plaque calcification 201 (36.4) 201 (100.0) 0 (0) / penile curvature 499 (90.05) 178 (88.5) 321 (91.7) 0.285 curvature multiplanarity 169 (30.67) 69 (34.3) 132 (37.7) 0.482 erectile dysfunction (ed) 217 (39.38) 77 (38.3) 140 (40.0) 0.763 penile pain 296 (53.7) 113 (56.2) 183 (52.2) 0.422 significant anxiety * 491 (89.1) 183 (91.04) 308 (88.0) 0.335 severe anxiety * 216 (39.2) 82 (40.79) 134 (38.28) 0.623 significant depression ** 317 (57.3) 125 (62.18) 192 (54.8) 0.112 severe depression ** 25 (4.5) 7 (3.48) 18 (5.1) 0.491 diabetes mellitus 32 (5.8) 11 (5.4) 21 (6.0) 0.947 hypertension 103 (18.69) 47 (23.38) 56 (16.0) 0.042 dyslipidemia 56 (10.16) 11 (5.4) 45 (12.8) 0.008 *** cardio-vascular diseases 41 (7.4) 13 (6.4) 28 (8.0) 0.623 obesity 31 (5.6) 14 (6.9) 17 (4.8) 0.400 sd = standard deviation. * significant anxiety is present when generalized anxiety disorder-7 (gad-7) questionnaire score > 9. severe anxiety is present when gad-7 score ≥ 15 (40). ** significant depression is present when patient health questionnaire-9 (phq-9) questionnaire score > 9. severe depression is present when phq-9 score ≥ 20 (41). *** although the p-value was found to be significant, this must be interpreted in favor of cases without calcification; in fact, in the 201 cases with calcification, dyslipidemia was present in 11 cases (5.47% of cases), while in the 350 cases without calcification, dyslipidemia was present in 45 cases (12.8% of cases). archivio italiano di urologia e andrologia 2023; 95(3):11549 5 calcification in peyronie's disease medians of the phq-9 scores in patients with or without calcification were not statistically different (with calcification = 12, iqr = 7; no calcification= 10, iqr = 8, p = 0.308) (p > 0.05). furthermore, using the logistic regression test and considering the phq-9 scores of all pd patients with or without calcification, odds ratio was 1.015, (95% ci, 0.979 to 1.052), deviance = 719.4, and pvalue = 0.404 (p > 0.05). we found no correlation between the presence of calcification and phq-9 score. diabetes, hypertension, dyslipidemia, cardiovascular disease, obesity in pd patients with plaque calcification in our study 32 pd patients had diabetes mellitus (5.8%); 26 were affected by type-2 diabetes; and 6 were affected by type-1 diabetes. the resulting or was 0.90 (95% ci, 0.428 to 1.922, p = 0.799) and z-statistic was 0.255 (p > 0.05). after separately studying the impact of type-1 and type-2 diabetes on the presence of calcification, the result of the pvalue was always > 0.05 (0.494 and 0.536, respectively). these results indicate that diabetes mellitus has no impact on calcification. among the 551 pd patients, 103 had hypertension (18.69%). in the 201 cases with calcification, hypertension was present in 47 cases (23.38% of cases), while in the 350 cases without calcification, hypertension was present in 56 cases (16.0% of cases). the resulting or was 1.6 (95% ci, 1.038 to 2.473, p = 0.03) and the z-statistic was 2.129 (p < 0.05). these results indicate that calcification is associated with the presence of hypertension. in our study 56 pd patients had dyslipidemia (high cholesterol and/or hypertriglyceridemia) (10.16%). the resulting or was 0.39 (95% ci, 0.191 to 0.777, p = 0.007) and z-statistic was 2.68 (p < 0.05). p-value was significant, but odds was lower in cases with calcification; in fact, in the 201 cases with calcification, dyslipidemia was present in 11 cases (5.47% of cases), while in the 350 cases without calcification, dyslipidemia was present in 45 cases (12.8% of cases). these results indicate that dyslipidemia has no positive impact on calcification. among the 551 pd patients, 41 had cardiovascular diseases (7.44%). the resulting or was 0.79 (95% ci, 0.402 to 1.572, p = 0.510) and z-statistic was 0.659 (p > 0.05). these results indicate that cardiovascular diseases have no impact on calcification. in our study 31 pd patients were obese (5.6%). the resulting or was 1.46 (95% ci, 0.706 to 3.042, p = 0.303) and z-statistic was 1.028 (p > 0.05). these results indicate that obesity has no impact on calcification. the impact of pd on anxiety and depression. anxiety • 4 out of 551 patients (0.7%) had minimal anxiety (gad-7 scores ranging from 0 to 4). • 54 out of 551 patients (9.8%) had mild anxiety (gad7 scores ranging from 5 to 9). • 275 out of 551 patients (49.9%) had moderate anxiety (gad-7 scores ranging from 10 to 14). • 216 out of 551 patients (39.2%) had severe anxiety (gad-7 scores ranging from 15 to 21). the prevalence of “significant anxiety” was 89.1% (491 out of 551 patients) (40). depression • 63 out of 551 patients (11.4%) had minimal depression (phq-9 scores ranging from 0 to 4). • 171 out of 551 patients (31.0%) had mild depression (phq-9 scores ranging from 5 to 9). • 201 out of 551 patients (36.4%) had moderate depression (phq-9 scores ranging from 10 to 14). • 91 out of 551 patients (16.5%) had moderately severe depression (phq-9 scores ranging from 15 to 19). • 25 out of 551 patients (4.5%) had severe depression (phq-9 scores ranging from 20 to 27). the prevalence of “significant depression” was 57.3% (317 out of 551 patients) (41). the prevalence of severe anxiety and severe depression in pd patients with or without plaque calcification are shown in table 1. results for the primary and secondary endpoints of the study are shown in table 2. table 2. results for primary and secondary endpoints of the study. primary endpoints impact statistical analysis yes or no p-value the impact of plaque calcification on the presence and severity of penile curvature yes < 0.05 presence and severity of erectile dysfunction no > 0.05 presence and severity of penile pain no > 0.05 presence and severity of anxiety no > 0.05 presence and severity of depression no > 0.05 the impact of multiple calcifications on penile curvature multiplanarity no > 0.05 secondary endpoints the impact of diabetes mellitus on the presence of calcification no > 0.05 the impact of hypertension on the presence of calcification yes < 0.05 the impact of dyslipidemia on the presence of calcification no < 0.05 * the impact of cardio-vascular diseases on the presence of calcification no > 0.05 the impact of obesity on the presence of calcification no > 0.05 the results regarding the prevalence of anxiety and depression in pd patients (secondary endpoints) are shown in table 1. * although the p-value was found to be significant, this must be interpreted in favor of cases without calcification; in fact, in the 201 cases with calcification, dyslipidemia was present in 11 cases (5.47% of cases), while in the 350 cases without calcification, dyslipidemia was present in 45 cases (12.8% of cases). archivio italiano di urologia e andrologia 2023; 95(3):11549 g. paulis, a. paulis 6 discussion in our study, in 551 patients affected by peyronie's disease, plaque calcification was present in 36.4% of cases. our results do not differ much from the percentage detected by levine et al. (34.1%) (24). unfortunately, the literature lacks studies focusing on the prevalence of calcification in peyronie's disease. two other classifications of penile calcifications in pd patients have been proposed. the classification proposed by bekos et al. categorizes patients according to the severity of calcification and echogenicity. this classification divides patients into three groups: a, b, and c. group a: a solitary hyperechoic zone without acoustic shadow; group b: multiple scattered moderately hyperechoic calcifications with acoustic shadow; and group c: densely calcified hyperechoic plaques with acoustic shadow (42). pawlowska and bianek-bodzak proposed the following classification of pd plaques: type 1 = thickening of the tunica albuginea without acoustic shadow; type 2 = moderately calcified plaque with a typical acoustic shadow; and type 3 = severely calcified plaques with complete shadowing (43). however, we believe that the classification proposed by levine et al. is more precise because it mainly considers the size of the calcifications. having stratified the calcifications of 201 pd patients according to the classification proposed by levine et al. (24), we found the following results: grade 1 calcifications, 23 cases (11.4%); grade 2 calcifications, 130 cases (64.6%); and grade 3 calcifications, 48 cases (23.8%). the calcification was < 15 mm (grade 1 and grade 2) in 76.1% of cases. our results differ markedly from those reported in levine's study that reported grade 1 calcifications in 40.8%, grade 2 calcifications in 27.6%, and grade 3 calcifications in 31.6%. we believe that the difference in the results of the two studies is due to the numerical difference in the two samples (201 versus 98 cases of levine’s study) (24). however, when examining the two studies, we noticed that grade 3 calcifications are less frequent (our study 23.8%; levine’s study 31.6%) than the total sum of grade 1 and grade 2 calcifications. in our study, it was found that calcification has an influence on the presence and severity of penile curvature (p < 0.05); this correlation is also present in the study conducted by levine et al. (24). our study found that the presence of calcifications in pd patients has no influence on the presence of erectile dysfunction and its severity, penile pain and its severity, and anxiety and depression and their severity. our study also found that the presence of multiple calcifications in pd patients has no influence on the presence of multiplanarity of penile curvature. in levine's study, the correlation between plaque calcification and multiplanar penile curvature or erectile dysfunction was not investigated. also in levine's study, no correlation was found between plaque calcification and penile pain (24), as well as no correlation was found between plaque calcification and emotional distress/anxiety (24). our study found that the presence of calcification in pd patients is not influenced by the presence of diabetes mellitus, dyslipidemia, cardiovascular diseases, and obesity. our results differ from those of the study by levine et al. where diabetes mellitus was found to influence the presence of plaque calcification (levine study, p = 0.012 versus our study, p = 0.799) (24). however, our study found that calcification in pd patients is associated with the presence of hypertension (p = 0.03); in contrast, in levine’s study, hypertension did not appear to influence the presence of plaque calcification (p = 0.865) (24). the prevalence of “significant anxiety” that we have found in pd patients (89.1% of cases) appears higher than the results of some studies which more generically refer to "distress" and "emotional" difficulties (80-81% of cases) (44, 45). in levine's study, the presence of "emotional distress" was found in 83% of cases of pd patients (24). in our study, we found the presence of "significant depression" in 57.3% of pd patients; this percentage is higher than that documented in nelson's studies (48%) (46, 47). it is most likely that the greater number of cases in our study (551 cases) compared to the 92 cases in nelson's study caused the disparity in the two results. conclusions our results indicate that in patients with peyronie's disease, plaque calcification is present in more than 1/3 of cases (36.4% of cases); this does not differ much from the data in the literature. we found that the size of the plaque calcification was < 15 mm in the majority of cases. in our study, it was found that plaque calcification has an influence on the presence and severity of penile curvature. we also found that calcification in pd patients is associated with the presence of hypertension. our results indicate that anxiety and depression have an important prevalence in pd patients; 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73:1199-1210. 24. levine l, rybak j, corder c, et al. peyronie's disease plaque calcification—prevalence, time to identification, and development of a new grading classification. j sex med. 2013; 10:3121-3128. 25. gelbard mk. dystrophic penile calcification in peyronie's disease. j urol. 1988; 139:738-740. 26. rainer qc, rodriguez aa, bajic p, et al. implications of calcification in peyronie's disease, a review of the literature. urology. 2021; 152:52-59. 27. andresen r, wegner heh, miller k, et al. imaging modalities in peyronie's disease an intrapersonal comparison of ultrasound sonography, xray in mammography technique, computerized tomography, and nuclear magnetic resonance in 20 patients. eur urol. 1998; 34:128-134. 28. hauck ew, hackstein n, vosshenrich r, et al. diagnostic value of magnetic resonance imaging in peyronie's disease−a comparison both with palpation and ultrasound in the evaluation of plaque formation. eur urol. 2003; 43:293-299. 29. pawlowska e, bianek-bodzak a. imaging modalities and clinical assesment in men affected with peyronie's disease. pol j radiol. 2011; 76:33-37. 30. mccauley jf, dean c. diagnostic utility of penile ultrasound in peyronie’s disease. world j urol. 2020; 38:263-268. 31. hatzimouratidis k, eardley i, giuliano f, et al. eau guidelines on penile curvature. eur urol. 2012; 62:543-552. 32. parmar m, masterson jm, masterson 3rd ta. the role of imaging in the diagnosis and management of peyronie's disease. curr opin urol. 2020; 30:283-289. 33. chou yh, tiu cm, pan hb, et al. high-resolution real-time ultrasound in peyronie's disease. j ultrasound med. 1987; 6:67-70. 34. kelâmi a. autophotography in evaluation of functional penile disorders. urology. 1983; 21:628-629. 35. eri lm, thomassen h, brennhovd b, håheim ll. accuracy and repeatability of prostate volume measurements by transrectal ultrasound. prostate cancer prostatic dis. 2002; 5:273-278. 36. lee js, chung bh. transrectal ultrasound versus magnetic resonance imaging in the estimation of prostate volume as compared with radical prostatectomy specimens. urol int. 2007; 78:323-327. 37. kahl c, cleland ja. visual analogue scale, numeric pain rating scale and the mcgill pain questionnaire: an overview of psychometric properties. phys ther rev. 2005; 10:123-128. 38. cepeda ms, africano jm, polo r, et al. what decline in pain intensity is meaningful to patients with acute pain? pain. 2003; 105:151-157. 39. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-830. 40. spitzer rl, kroenke k, williams jb, löwe b. a brief measure for assessing generalized anxiety disorder: the gad-7. arch intern med. 2006; 166:1092-1097. 41. kroenke k, spitzer rl, williams jb. the phq-9: validity of a brief depression severity measure. j gen intern med. 2001; 16:606613. 42. bekos a, arvaniti m, hatzimouratidis k, et al. the natural history of peyronie's disease: an ultrasonography-based study. eur urol. 2008; 53:644-650. 43. pawłowska e, bianek-bodzak a. imaging modalities and clinical assesment in men affected with peyronie's disease. pol j radiol. 2011; 76:33-37. archivio italiano di urologia e andrologia 2023; 95(3):11549 g. paulis, a. paulis 8 44. terrier je, nelson cj. psychological aspects of peyronie's disease. transl androl urol. 2016; 5:290-295. 45. smith jf, walsh tj, conti sl, et al. risk factors for emotional and relationship problems in peyronie’s disease. j sex med. 2008; 5:2179-2184. 46. nelson cj, diblasio c, kendirci m, et al. the chronology of depression and distress in men with peyronie's disease. j sex med. 2008; 5:1985-1990. 47. nelson cj, mulhall jp. psychological impact of peyronie's disease: a review. j sex med. 2013; 10:653-660. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2017; 89, 3186 original paper the impact of bladder neck sparing on urinary continence during laparoscopic radical prostatectomy; results from a high volume centre ali serdar gozen 1, yigit akin 2, mutlu ates 3, marcel fiedler 1, jens rassweiler 1 1 department of urology, slk-klinikum heilbronn, university of heidelberg, heilbronn, germany; 2 department of urology, izmir katip celebi university school of medicine, izmir, turkey; 3 department of urology, antalya teaching and research hospital, antalya, turkey. objective: to evaluate the effects of bladder neck reconstruction techniques on early continence after laparoscopic radical prostatectomy (lrp). materials and methods: this non-randomized retrospective study analyzed prospectively collected data concerning lrp. in total, 3107 patients underwent lrp between march 1999 and december 2016. exclusion criteria were preoperative urinary incontinence, previous history of external beam radiotherapy, co-morbities which may affect urinary continence such as diabetes mellitus and/or neurogenic disorders, irregular followup, and follow-up shorter than 24 months. all patients were divided into one of three groups, posterior reconstruction being performed in group 1 (n = 112), anterior reconstruction in group 2 (n = 762), and bladder neck sparing (bns) in group 3 (n = 987). demographic and pre-, peri-, and postoperative data were collected. multivariate analyses were performed to determine factors affecting early continence after lrp. results: 1861 patients were enrolled in the study. the mean follow-up period was 48.12 ± 29.8 months, and subjects’ mean age was 63.6 ± 6.2 years. there was no significant difference among the groups in terms of demographic or preoperative data. postoperative data, including oncological outcomes, were similar among the groups. the level of early continence was higher in group 3 than in the other groups (p < 0.001). multivariate analyses identified bns and age as parameters significantly affecting early continence levels after lrp (p < 0.001 and p < 0.001, respectively). bladder neck reconstruction provided less earlier continence than bns. key words: bladder neck; laparoscopy; surgery; prostate cancer; radical prostatectomy; urinary continence. submitted 10 may 2017; accepted 2 june 2017 summary no conflict of interest declared. successfully used as contemporary surgical options in organ-confined pca with similar oncological and fuctional results (4). however, the ralp procedure, including the robotic device,is still expensive. lrp thus still assumes a more important place among surgical treatment options for pca. although lrp can provide the well-known advantages of laparoscopy, urinary incontinence is one of the main functional problems that can concern patients after surgery. in addition, incontinence has an adverse impact on quality of life and causes indirect workforce losses (5). early continence is therefore important for rapid recovery after lrp. the level of continence ranges between 60% and 94% at short-term follow-ups (6, 7). this variation may be also due to different definitions of continence levels and different followup strategies. various surgical modifications, such as bladder neck sparing (bns), have been introduced for early continence (8, 9). however, in addition to surgical modifications for providing early continence, surgeons are also consistently developing new techniques for achieving continence in the light of improvements in endourological technology (10). nonetheless, the exact factors affecting urinary continence after lrp have not yet been clearly defined. additionally, to the best of our best knowledge, no comparison of techniques performed on the bladder neck, such as posterior reconstructions, anterior reconstructions and bns, in lrp have to date been reported in the literature. the purpose of thıs study was to investigate bns and bladder neck reconstruction techniques in term of providing early continence after lrp. materials and methods this study represents a non-randomized retrospective view of prospectively collected data. all patients fully understood the treatment and aim of the study and provided written informed consent. all data were recorded prospectively on a microsoft office excel spreadsheet. this series is part of an ongoing lrp project in our department. patient selection we identified 3107 patients undergoing lrp due to organconfined pca between march 1999 and december 2016. doi: 10.4081/aiua.2017.3.186 introduction prostate cancer (pca) is the most common solid organ cancer among men worldwide (1). although there are different ways to treat pca, radical prostatectomy (rp) is still the gold standard treatment modality for organ-confined pca (2, 3). nearly two-thirds of pca cases are confined to the prostate and can be treated by rp (3). recently, minimally invasive surgical techniques, such as laparoscopic radical prostatectomy (lrp) and robotic-assisted laparoscopic radical prostatectomy (ralp), have been gozen _stesura seveso 28/09/17 10:15 pagina 186 187archivio italiano di urologia e andrologia 2017; 89, 3 bns and early continence in lrp exclusion criteria were preoperative urinary incontinence, previous history of external beam radiotherapy, comorbidities which may affect urinary continence, such as diabetes mellitus and/or neurogenic disorders, irregular follow-up, and a follow-up duration of less than 24 months. finally, 1861 patients were enrolled into the study. all lrp patients were divided into three groups depending on bns or bladder neck reconstruction techniques in order to evaluating the impact of these on early continence after surgery. group 1 (n = 112) consisted of patients undergoing posterior reconstruction (dorsal reconstruction), group 2 (n = 762) of patients undergoing anterior reconstruction (ventral reconstruction), and group 3 (n = 987) of patients undergoing bns. subgroups based on early and late continence status were also established. factors affecting early continence were investigated. data collection patient data including age, body mass index (bmi), preoperative prostate specific antigen (psa), previous operations, co-morbidities, clinical stage, operation time, surgical methods used for bladder neck reconstruction, nerve sparing surgery, estimated blood loss (ebl), prostate volume, length of hospital stay, duration of urethral catheter, histopathological and oncological outcomes and urinary continence rates were recorded. potency was defined as erection sufficient for intercourse, with or without medication. patients were administered international index of erectile functions (iief) questionnaires, before and after surgery. patients with iief-5 scores ≤ 11 were regarded as having erectile dysfunction (ed). surgical techniques the heilbronn ascending lrp technique has been described previously in the literature (11, 12). pelvic lymph node dissections were performed in an extended fashion for patients with psa > 10 ng/ml and/or a gleason score > 6. urethro-vesical anastomoses were performed with continuous sutures as described by van velthoven, including reconstruction of the bladder neck (13). posterior reconstruction technique this technique was used in cases with a large prostate, with a large median lobe, with a possible bladder neck invasion and in case of a previous transurethral resection of prostate (group 1). the bladder neck should be reconstructed in these cases, after the necessary wide resection. posterior reconstruction began from the distal and close to the trigonal part of bladder neck to the superior part of the bladder neck using a running suture (3/0 vicryl-v-loc). the bladder neck should resemble a ‘reverse tennis racquet’ after the reconstruction (figure 1), as reported by sarle et al. (14) a dj stenting was necessary in 3 cases. anastomosis was performed after the bladder neck reconstruction using the van velthoven technique (10, 11). anterior reconstruction technique this procedure was performed in the case of bladder neck was larger than urethral lumen (group 2). our aim was to reconstruct the bladder neck based on its unique anatomical structures (15). we closed the bladder neck in the form of figure-of-eight stitches, on the ventral side (12 o clock) (figure 2.). the larger bladder neck has been adjusted in this way to the urethra. bladder neck sparing technique group 3 consisted of patients undergoing a full bladder neck preservation. briefly, the base of the prostate was hold to the ventral side by the application of traction to the urethral catheter balloon. the fatty space between the bladder and the anterior leaf of denonvilliers’ fascia was observed. blunt dissections were then performed using a right-angle dissector around the bladder neck. the anterior wall of the bladder neck was incised thereafter horizontally, and careful stepwise dissections were performed around the catheter, thus exposing the muscle fibers of bladder neck (figure 3.) follow-up and continence status cystography was performed in all cases, on the 7th day of surgery. if no leak was determined, the urethral catheter was removed. all complications were classified according to the modified clavien classification (16). indications for figure 1. posterior bladder neck reconstruction resembling a “reverse tennis racquet”. the arrow shows the tip of the racquet. figure 2. anterior bladder neck reconstruction with “figure-of-eight” stitches on the ventral side of the bladder neck. gozen _stesura seveso 28/09/17 10:15 pagina 187 archivio italiano di urologia e andrologia 2017; 89, 3 a. serdar gozen, y. akin, m. ates, m. fiedler, j. rassweiler 188 adjuvant hormone therapy and radiotherapy were determined using the walz score (17). self-administered modified international continence society questionnaires were used to evaluate early continence status. this was also evaluated by physical examination, including the valsalva or cough stress tests. all patients were advised to perform kegel's exercises after removal of the urinary catheter. no patients received any surgical treatment for stress urinary incontinence during 24-month follow-up after lrp. safety pads were applied before the tests. patients without urine leakage during coughing or sneezing, as well as those who stayed totally dry, were considered urinary continent. patients who were consistently dry but used a safety pad occasionally during normal daily activity (ie, work, exercise, and walking) were considered continent. patients who used more than one protective pad per day and/or who experienced urine leak during coughing, sneezing or nocturnally were considered incontinent. time to continence was classified into two time intervals; early (within 3 months after lrp), and late continence (4-24 months after lrp). continence status was evaluated at the 1st and 3rd month after lrp by physical examinations including the tests summarized above. continence status was then assessed at quarterly intervals within the first year and semi-annually thereafter. the bns and reconstruction techniques, nerve sparing surgical techniques, clinical stage, bmi, age, prostate volume, duration of urethral catheter use, and oncological results were evaluated using multivariate analyses in order to determine the factors affecting continence. all postoperative complications were evaluated based on modified clavien-dindo classifications (18). statistical analysis associations in the subgroups were examined using the chi square, one way anova and kruskal wallis tests. multivariate logistic regression analyses were performed to evaluate factors affecting early continence. all statistical tests were performed on statistical package for social sciences, version 16.0 (spss, chicago, il) software. statistical significance was set at p < 0.05. results the mean follow-up period was 48.12 ± 29.8 months, and mean age was 63.6 ± 6.2 years. mean values for demographic data are shown in table 1. no significant difference was determined among the groups in terms of demographic data. parameters including mean psa, clinical stage, and prostate volume were also comparable between the groups. these are summarized in table 2. operative and postoperative data are presented in table 3. no significant difference was determined between the groups in terms of operative time (p < 0.001). levels of nerve sparing surgical techniques, ebl, hospital stay, and duration of catheterization were similar among the groups (table 4). table 1. details of demographic and operative data. table 2. perioperative results of groups. parameter data mean age 63.9 ± 6.2 mean bmi 26.8 ± 1.2 mean psa 10 ± 3.7 mean prostate volume 36.2 ± 16.5 bmi: body mass index; psa: prostate specific antigen. figure 3. the bladder neck sparing surgical technique. anatomical dissections were able to be performed to separate the bladder neck and prostate. the yellow arrows shows the neurovascular bundle. parameter group 1 group 2 group 3 p (n = 112) (n = 762) (n = 987) value mean age (years) one way anova 64.5 ± 5.9 64 ± 5.9 63.7 ± 6.4 0.26 bmi (kg/m2) < 25 (n,%) 35 (30.7%) 242 (31.7%) 335 (33.6%) 0.76 chi square 25-30 (n,%) 43 (37.7%) 283 (37%) 377 (37.8%) > 30 (n,%) 36 (31.5%) 238 (31.1%) 284 (28.5%) mean psa (ng/ml) one way anova 10 ± 7 9.8 ± 6.4 10.1 ± 12.4 0.86 clinical stage (n, %) chi square t1 22 (19.2%) 150 (19.6%) 231 (23.1%) 0.42 t2 57 (50%) 367 (48%) 452 (45.3%) t3 35 (30.7%) 246 (24.6%) 313 (31.4%) prostate volume (cc) (n, %) chi square ≤ 50 93 (81.5%) 637 (83.4%) 844 (84.7%) 0.59 > 50 21 (18.4%) 126 (16.5%) 152 (15.2%) mean prostat volume one way anova) 38.6 ± 18.8 35.6 ± 18 36.4 ± 14.9 0.15 bmi: body mass index; psa: prostate specific antigen. gozen _stesura seveso 28/09/17 10:15 pagina 188 189archivio italiano di urologia e andrologia 2017; 89, 3 bns and early continence in lrp no significant difference were also determined in terms of pathological findings, including pathological stage, gleason score, positive surgical margins, and biochemical recurrence. complication rates were similar in the groups (table 5). forty-two (36.8%) patients in group 1.374 (49%) patients in group 2 and 601 (60.3%) patients in group 3 were continent 3 months after lrp. continence levels were similar between group 1 (posterior reconstruction) and group 2 (anterior reconstructions). the level of early continence was higher in group 3 than in the bladder reconstruction groups (p < 0.001). at multivariate analyses, bns and age were determined as parameters that significantly affected early continence levels after lrp (p < 0.001 and p < 0.001, respectively) (table 6). discussion urinary continence is an essential parameter for early recovery after lrp (19). surgical modifications have therefore been introduced in order to provide early continence after prostatectomy in patients with pca. bns and bladder neck reconstruction techniques can provide early continence after radical prostatectomy (20). all these surgical techniques can be performed during lrp, which includes the well-known benefits of laparoscopy (12). no published data, including comparisons of all surgical techniques with large numbers of patients, after lrp have to date been available. additionally, the exact factors involved in the provision of early continence had not been identified. to the best of our knowledge, this is the first series with large patient numbers to investigate early continence was investigated after lrp in terms of bns and bladder neck reconstruction techniques. on the basis of our results, bladder neck reconstruction techniques (group 1 and group 2) provided similar continence levels. high levels of early urinary continence were achieved with bns in younger patients after lrp. clinical stage, nerve sparing surgical technique, biochemical recurrence, and pathological stage did not significant affect early continence levels at multivariate analysis. stolzenburg et al. reported early continence using bns after lrp (21). chlosta et al. achieved similar results in their series of 194 lrp patients (22). our series involved 987 (53%) bns patients, 601 (60.3%) of whom were continent in the 3rd month of lrp. the bns technique contributes a sphincter mechanism which includes striated and smooth muscle fibres (23). additionally, the striated muscle fibers in the urethra are horseshoe-shaped and these also assist with continence. however, urological studtable 3. details of operative and postoperative data. parameter data mean operation time 212.3 ± 43.4 mean ebl 828.4 ± 440.6 mean hospital stay 10.2 ± 4.5 mean duration of catheter 9.4 ± 4.9 continence n = 1753, 94.1% biochemical recurrence n = 337, 18.1% ebl: estimated blood loss. table 6. factors effecting early continence status in multivariate logistic regression analyses. table 5. oncological and functional results of groups. table 4. peri and postoperative results of groups. parameter p value bns surgical technique < 0.001* anterior reconstruction 0.3 posterior reconstruction 0.4 clinical stage 0.47 age (year) < 0.001* bmi 0.15 prostate volume 0.28 preoperative psa 0.95 operation time 0.2 nerve sparing surgical technique 0.06 duration of urethral catheter 0.3 surgical margin 0.74 biochemical recurrence 0.55 bmi: body mass index; bns: bladder neck sparing; psa: prostate specific antigen *statistical significant p value parameter group 1 group 2 group 3 p (n = 112) (n = 763) (n = 996) value mean operation time (min.) 212 ± 45 217.3 ± 45.8 208.5 ± 41 < 0.001* nerve sparing surgery (n,%) 54 (47.3%) 375 (49.1%) 432 (43.3%) 0.052 mean ebl (ml) 775.4 ± 352.6 824.7 ± 468.4 837.2 ± 427.5 0.34 mean hospital stay (day) 9.7 ± 2.8 10.3 ± 3.3 10.3 ± 5.4 0.41 mean duration of catheter (day) 9.1 ± 4.1 9.4 ± 4.8 9.4 ± 5 0.86 abbreviations: ebl: estimated blood loss *statistical signifiant p value. parameter group 1 group 2 group 3 p (n = 114) (n = 763) (n = 996) value pt pt0-2 64 (56.1%) 474 (62.1%) 594 (59.6%) 0.35 pt3-4 50 (43.8%) 289 (37.8) 402 (40.3%) mean prostate volume (cc) 44.8 ± 20.4 44.4 ± 18.3 43.6 ± 17 0.59 mean pathological < 7 40 (35%) 340 (44.5%) 425 (42.6%) 0.23 gleason acore (n, %) 7 60 (52.6%) 348 (45.6%) 486 (48.7%) > 7 14 (12.2%) 75 (9.8%) 85 (8.5%) pozitive surgical margin 34 (29.8%) 178 (23.3%) 237 (23.7%) 0.31 early continence (n, %) 42 (36.8%) 374 (49%) 601 (60.3%) < 0.001* biochemical recurrence 21 (18.4%) 160 (20.9%) 196 (19.6%) 0.75 *statistical significant p value. gozen _stesura seveso 28/09/17 10:15 pagina 189 archivio italiano di urologia e andrologia 2017; 89, 3 a. serdar gozen, y. akin, m. ates, m. fiedler, j. rassweiler 190 ies have shown that these cannot sustain contraction over 60 sec. (24, 25) smooth muscle fibers of course assist continence. the bns technique permits the smooth muscle fibers to remain place. we tried to perform as many bns procedures in lrp cases as possible. during lrp, these fibers can be preserved more than with open surgical techniques through the well-known advantages of laparoscopy. rosenblatt et al. reported that bladder neck reconstruction surgical techniques may be required by 10-15% of lrp patients (26). rocco et al. described a surgical technique for bladder neck reconstruction and reported early continence as one advantage of this (27). in another study, they reported no significant complications associated with the posterior musculofascial plate reconstruction technique, and described reconstruction of the posterior musculofascial plate as encouraging in terms of earlier continence recovery (27). nevertheless, this subject is still controversial (28). posterior reconstruction was performed in 114 (4.4%) of our cases. the early continence level was 54% in lrp patients, lower than that achieved with bns (60.3%). we performed posterior bladder neck reconstruction in 71 (6.1%) cases. daouacher and walden recently described anterior and posterior reconstructions during lrp as safe and effective, without affecting voiding or surgical margins (29). in our recent series, anterior reconstruction was performed in 763 (40.9%) cases. both posterior and anterior reconstructions may provide early continence. however, the level of early continence was statistically significantly higher in group 3 (bns) than in the other groups. poon et al. compared the outcomes of bns with those of bladder neck repairing techniques as anterior and posterior reconstructions in a series of patients undergoing open radical prostatectomy (30). no significant difference was determined in early and late continence levels during follow-up. our series differs from that of poon et al. (30). the normal anatomy of the bladder neck was preserved by using laparoscopy in all patients in group 3. optic magnification of anatomical structures and the use of precision instruments may have contribute to the good results as well as the advanced laparoscopic techniques employed. katz et al. reported that a wide resection of the bladder neck can decrease positive margins on bladder neck (31). but, this may also have an adverse effect on continence after lrp. however, the positive surgical margin levels were similar among the groups in the present study. additionally, a positive surgical margin did not emerge as a significant factor in early continence at multivariate analyses. multivariate analysis identified mean age as a factor affecting early continence. kadono et al. reported age as a predictive factor for incontinence following minimally invasive surgical treatment of pca (32). kumar et al. investigated 3241 patients and concluded similar results (33). our data are comparable with those previous studies, and early continence was adversely affected by advanced age. this raises the question of early detection of pca. robot-assisted laparoscopic prostatectomy (ralp) can provide more anatomical details for surgeons during surgery (25). bns can thus be performed more accurately during ralp. tunc et al. reported their early continence results after ralp by presenting a novel technique for bns. our results are parallel to those of their study. we think that superior magnification can improve surgeons techniques and learning curves (25). early continence can thus be established after lrp/ralp, and this will in turn assist early recovery after surgery. the main limitation of this study is that numbers of patients in the groups were not similar, because our surgical technique did not usually require bladder neck reconstructions (34). the aim of the present series is to compare bns and bladder neck repairing techniques in lrp among large numbers of patients. to the best of our knowledge, this series is unique in the literature due to the features described.we recommend that surgeons make every effort to perform bns during lrp. conclusions bladder neck reconstruction surgical techniques and bns can provide good continence results after lrp. however, bns is significantly superior to bladder neck reconstruction techniques in terms of establishing early continence after lrp, notably in younger patients. additionally, bns involved more anatomical dissections without altering oncological outcomes.. more standardized and multi-centered studies are now needed to optimize current surgical techniques for providing early continence after lrp. references 1. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 2. jemal a, siegel r, ward e, et al. cancer statistics, ca cancer j clin. 2006; 56:106-30. 3. basillote jb, ahlering te, skarecky dw, et al. laparoscopic radical prostatectomy: review and assessment of an emerging technique. surg endosc. 2004; 18:1694-711. 4. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol. 2012; 62:405-17. 5. macdonald r, fink ha, huckabay c, et al. pelvic floor muscle training to improve urinary incontinence after radical prostatectomy: a systematic review of effectiveness. bju int. 2007; 100:76-81. 6. rassweiler j, schulze m, teber d, et al. laparoscopic radical prostatectomy: functional and oncological outcomes. curr opin urol. 2004; 14:75-82. 7. touijer k, eastham ja, secin fp, et al. comprehensive prospective analysis of outcomes between open and laparoscopic radical prostatectomy conducted in 2003 to 2005. j urol. 2008; 179: 1811-7. 8. klein ea. early continence after radical prostatectomy. j urol. 1992; 148:92-5. 9. lowe ba. comparison of bladder neck preservation to bladder neck resection in maintaining postrostatectomy urinary continence. urology. 1996; 48:889-93. 10. pastore al, palleschi g, messas a, et al. are early continence recovery and oncologic outcomes influenced by use of different devices in prostatic apex dissection during laparoscopic radical prostatectomy? j endourol. 2014; 28:1313-9. gozen _stesura seveso 28/09/17 10:15 pagina 190 191archivio italiano di urologia e andrologia 2017; 89, 3 bns and early continence in lrp 11.rassweiler j, marrero r, hammady a, et al. transperitoneal laparoscopic radical prostatectomy: ascending technique. j endourol. 2004; 18:593-9. 12. rassweiler j, hruza m, frede t, teber d. laparoscopic extraperitoneal ascending nerve-sparing radical prostatectomy: an effective and safe technique for apical tumors. j endourol. 2008; 22:2009-13. 13. van velthoven rf, ahlering te, peltier a, et al. technique for laparoscopic running urethrovesical anastomosis: the single knot method. urology. 2003; 61:699-702. 14. sarle r, tewari a, hemal ak, menon m. robotic-assisted anatomic radical prostatectomy: technical difficulties due to a large median lobe. urol int. 2005; 74:92-4. 15 kalisvaart jf, osann ke, finley ds, ornstein dk. posterior reconstruction and anterior suspension with single anastomotic suture in robot-assisted laparoscopic radical prostatectomy: a simple method to improve early return of continence. j robot surg. 2009; 3:149-53. 16. hruza m, weiss ho, pini g, et al. complications in 2200 consecutive laparoscopic radical prostatectomies: standardised evaluation and analysis of learning curves. eur urol. 2010; 58:733-41. 17. walz j, gallina a, saad f, et al.nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer. j clin oncol. 2007; 25:3576-81. 18. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 19. anceschi u, gaffi m, molinari c, anceschi c. posterior reconstruction and outcomes of laparoscopic radical prostatectomy in a high-risk setting. jsls. 2013; 17:535-42. 20. smolski m, esler rc, turo r, et al. bladder neck sparing in radical prostatectomy. indian j urol. 2013; 29:338-44. 21.stolzenburg ju, kallidonis p, hicks j, et al. effect of bladder neck preservation during endoscopic extraperitoneal radical prostatectomy on urinary continence. urol int. 2010; 85:135-8. 22. chłosta pl, drewa t, jaskulski j, et al. bladder neck preservation during classic laparoscopic radical prostatectomy point of technique and preliminary results. wideochirinne tech maloinwazyjne. 2012; 7:89-95. 23. koraitim mm. the male urethral sphincter complex revisited: an anatomical concept and its physiological correlate. j urol. 2008; 179:1683-9. 24. shafik a. a study of the continence mechanism of the external urethral sphincter with identification of the voluntary urinary inhibition reflex. j urol. 1999; 162:1967-71. 25. tunc l, gumustas h, akin y, et al. a novel surgical technique for preserving the bladder neck during robot-assisted laparoscopic radical prostatectomy: preliminary results. j endourol. 2015; 29:186-91. 26. rosenblatt a, bollens r, cohen eb. extraperitoneal laparoscopic radical prostatectomy, in: manual of laparoscopic urology, springer-verlag, isbn 978-3-540-74726-0, 2008, berlin heidelberg, pp. 63-89. 27. rocco f, gadda f, acquati p, et al. personal research: reconstruction of the urethral striated sphincter. arch ital urol androl. 2001; 73:127-37. 28. rocco b, cozzi g, spinelli mg, et al. posterior musculofascial reconstruction after radical prostatectomy: a systematic review of the literature. eur urol. 2012; 62:779-90. 29. daouacher g, waldén m. a simple reconstruction of the posterior aspect of rhabdosphincter and sparing of puboprostatic collar reduces the time to early continence after laparoscopic radical prostatectomy. j endourol. 2014; 28:481-6. 30. poon m, ruckle h, bamshad br, et al. radical retropubic prostatectomy: bladder neck preservation versus reconstruction. j urol. 2000; 163:194-8. 31. katz r, salomon l, hoznek a, et al. positive surgical margins in laparoscopic radical prostatectomy: the impact of apical dissection, bladder neck remodeling and nerve preservation. j urol. 2003; 169:2049-52. 32. kadono y, ueno s, kadomoto s, et al. use of preoperative factors including urodynamic evaluations and nerve-sparing status for predicting urinary continence recovery after robot-assisted radical prostatectomy: nerve-sparing technique contributes to the reduction of postprostatectomy incontinence. neurourol urodyn. neurourol urodyn. 2016; 35:1034-1039. 33. kumar a, samavedi s, bates as, et al. age stratified comparative analysis of perioperative, functional and oncologic outcomes in patients after robot assisted radical prostatectomy--a propensity score matched study. eur j surg oncol. 2015; 41:837-43. 34. rassweiler j, wagner aa, moazin m, et al. anatomic nervesparing laparoscopic radical prostatectomy: comparison of retrograde and antegrade techniques. urology. 2006; 68:587-91. correspondence ali serdar gozen, md, associate professor of urology ali.goezen@slk-kliniken.de marcel fiedler, md marcel.fiedler@slk-kliniken.de jens rassweiler, md, professor of urology jens.rassweiler@slk-kliniken.de department of urology, slk-klinikum heilbronn, university of heidelberg, am gesundbrunnen 20-26, d-74078 heilbronn, germany yigit akin, md, associate professor of urology yigitakin@yahoo.com department of urology, izmir katip celebi university school of medicine, 35060, izmir, turkey mutlu ates, md, associate professor of urology drmutluates@gmail.com department of urology, antalya teaching and research hospital, 07059, antalya, turkey gozen _stesura seveso 28/09/17 10:15 pagina 191 cop+ed+fisse 2006 165archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.165 my. gill et al. demonstrated that lpn was a viable alternative for treating selected renal tumour patients (3). moreover, in last decades, indications for lpn have progressively extended to tumors of greater diameter and stage (pt1b) (4). for these reasons, many preoperative score systems have been proposed in order to estimate the pre-operative risk, based on computed tomography (ct) scan and magnetic resonance imaging (mri). most commonly used are the padua (5) score and the renal system (6) score. both trans and retro peritoneal approach are commonly used by surgeons with the comparable surgical and functional outcomes (7), although the retro peritoneal access, on the one hand guarantees a more restricted working space and a worse exposure of the medial kidney facia, on the other, it allows an immediate access to the renal vessels and reduces the risk of injury to the intra peritoneal organs. the increasingly extreme use of partial nephrectomy is in terms of the size of the treated masses and of the comorbidity of the patients subjected to this procedure (solitary kidney, synchronous bilateral tumors, etc.) justifies the attention to the oncological and functional result, also in consideration of learning curves. surgical results were evaluated using mic-criteria (margin, ischaemia and complications) (8) that anticipated the trifecta-criteria (9). the only difference between the two score-systems is the length of ischaemia time (20 vs 25 minutes). herein, we report on postoperative outcomes of a single surgeon, single centre series of retroperitoneal lpn, in order to assess the correlation between preoperative parameters, including the individual nephrometric padua score, and post-operative outcomes, including mic score, in order to provide an evaluation for surgical risk evaluation also related to the surgeon experience. patients and methods we designed a monocentric, single surgeon retrospective nonrandomized study. a total of 147 patients, who underwent retroperitoneal lpn for malignancy from march 2014 to april 2018, were enrolled. all the anonymously collected data have been retrospectively evaluated. all procedures were performed by a single surgeon with a objectives: to evaluate surgical outcomes in a series of laparoscopic retroperitoneal partial nephrectomies. methods: a total of 147 patients who underwent laparoscopic retroperitoneal partial nephrectomy by a single surgeon were evaluated. pre-operative parameters (body mass index, asa score, tumour size, ctnm stage, padua score risk, surgeon experience) and intraoperative and postoperative outcomes (operative mean time, warm ischemia time, blood loss, transfusion rate, length of hospitalization, and margin-ischaemiacomplications [mic] success rate) were considered. results: for 134 patients (91.1%) the success of the treatment, defined by a mic = 3, was obtained. when the statistical significance of each of the independent variables was tested, surgeon’s experience added statistical significance to the prediction of operative time (p = 0.000), warm ischemia time (p = 0.000) and blood loss (p = 0.000); tumour size (p = 0.046) to the prediction mic (p = 0.010), operative time (p = 0.000), warm ischemia time (p = 0.003) and blood loss (p = 0.010); asa score to the length of hospitalization (p = 0.009). conclusions: laparoscopic retroperitoneal partial nephrectomy represents an adequate and safe technique for the treatment of t1 renal cancer. optimal mic success rate can be achieved, although intraoperative outcomes tend to be related to the learning curve even in a very experienced laparoscopic surgeon. length of hospitalization depends on general health condition of patients. key words: laparoscopy; partial nephrectomy; kidney neoplasms; retroperitoneal; padua score. submitted 10 may 2020; accepted 11 may 2020 introduction over the past few years, both robotic and laparoscopic partial nephrectomy (lpn) have emerged as a strong alternative to open partial nephrectomy due to several documented advantages including less blood loss, quicker recovery, less complications (1). in 2006, carini et al. presented their successful results of their long-term follow-up study of post-operative outcomes after open partial nephrectomy for pt1a tumours (2). the authors show favourable results as a cancer-specific survival (css) of 96.7% and 94.7% at, respectively, 5 and 10 years, with a progression-free survival (pfs) of 96% and 94% at 5 and 10 years, respectively. just 1.5% of patients developed a local recurrence, with no distant metastasis, far from the site of the previous tumorectopredictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy summary carmine sciorio 1, pier paolo prontera 2, salvatore scuzzarella 1, paolo verze 3, lorenzo spirito 3, lorenzo romano 3, alberto trinchieri 4 1 urology unit, manzoni hospital, asst lecco, lecco, italy; 2 urology unit, s.s. annunziata hospital, asl taranto, taranto, italy; 3 department of urology, university of naples federico ii, naples, italy; 4 urology department, irccs ca’ granda ospedale maggiore policlinico, milano, italy. 01sciorio_stesura seveso 24/09/20 14:10 pagina 165 archivio italiano di urologia e andrologia 2020; 92, 3 c. sciorio, p.p. prontera, s. scuzzarella, p. verze, l. spirito, l. romano, a. trinchieri 166 previous long-lasting experience in renal laparoscopy. exclusion criteria were as follows: a) distant metastases at the time of the diagnosis; b) previous retroperitoneal surgery. informed consent was administered and preoperative abdominal ct scan and/or mri were performed for all patients in order to assess maximum lesion diameter and clinical tnm staging (10). preoperative padua score (5) for each patient was calculated after the ct scan or mri evaluation performed by two different radiologists, considering the site of the lesion (polar or nonpolar), the extension (exophytic/endophytic), the location at the equator (lateral/medial), the involvement of the renal hilum and the excretory pathway. tumours were stratified in low (padua score: 6-7), medium (padua score: 1-2) and high risk (padua score: =/>10). age, gender, body mass index (bmi), american society of anesthesiologists (asa) score, comorbidities (such as diabetes and hypertension), blood loss, operative time (trocars-in to trocars-out), warm ischemia time, conversion rate to open surgery, pathological stage, tumour histotype according to the classification of the world health organization (who), nuclear grading according to fuhrman's classification (11) and surgical margins involvement have been evaluated. peri and post-operative complications (within the first 30 days) have also been recorded and classified in minor and major according to the clavien-dindo system (12) (grade 1-2 and 34 respectively). the surgeon's experience was assessed by dividing surgical procedures into 6 chronological groups according to his learning curve. finally, the successful rate for each procedure was estimated using validate m.i.c. system (8) (which considers ischemia time less than 20 minutes, absence of surgical margins involvement and no major post-operative complication). according to this trifecta system, each patient has received from 1 to 3 points. a descriptive statistical analysis of emerged data was performed. the continuous variables were reported as mean values and standard deviation while the categorical variables were reported as the number of cases (n°) and percentage (%) and their differences were correlated with the pearson x². multiple linear logistic regression was used to evaluate the predict effect of a set of pre-operative parameters (age, gender, bmi, asa, tumour size, tnm stage, padua score and surgeon’s experience) on different surgical outcomes as mic, blood loss, transfusion rate, operative time, warm ischemia time and length of hospitalization. all data were analysed using spss software and a p-value < 0.05 was defined as statistically significant. results a total of 147 patients (101 male and 46 female), who underwent retroperitoneal lpn from 2014 to 2018, were retrospectively enrolled mean age was 63 years (range 37-74). table 1 shows the baseline cohort characteristics and preoperative data.the assessed mean diameter of renal lesions at pre-operative ct scan was 3.55 cm +/-1.65. application of padua score system allow to stratify the surgical risk as follows: 79 (54% of the population) as low risk, 51 as intermediate risk (35%) and 17 as high risk (11%). intraoperative and postoperative results are shown in table 2. in 82 cases (56%) no ischemia was performed, whereas 64 patients received some warm ischemia time. in detail, 51 patients (35%) underwent less than 20 minutes warm ischemia, 10 (7%) from 20 to 29 minutes and 3 (2%) more than 30 minutes of warm ischemia. the global mean time of warm ischemia was 6.84 +/8.74 minutes. peri-operative complication rate was 1.4% and there was no case of conversion to open surgery. average hospitalization time was 6.01 +/5.43 days. pathological analysis of the lesions shows a prevalence of pt1a stage tumours (64%), followed by pt1b (19.7%). pathological stages pt2 and pt3 all together represent 2.7% of the cohort and 20 lesions (13.6%) appear to be no-clear cells tumours (cct). no positive surgical margin was observed. in our purpose, the success of the treatment was defined by mic = 3, and it was obtained in 134 patients (91.1%). at multiple linear logistic regression padua score, tnm stage (table 4), tumour size by pre-operative ct, bmi, asa and surgeon’s experience predicted the effect of mic success (p = 0.034), operative time (p = 0.000), warm ischemia time (p = 0.000), blood loss (p = 0.000) and length of hospitalization (p = 0.002). coefficient of determination r2 explain 10.7%, 34.7%, 26.7%, 23.4% and 16.2% of the variability of mic success, operative time, table 1. baseline cohort characteristics and preoperative evaluations (147 pts). median age, years 63 (37. 64) m/f ratio (pts) 101/46 bmi (kg/m2) 25.9 ± 3.2 right/left side (pts) 83 (57%)/64 (43%) average volume of lesions (radiological evaluation) 3.55 ± 1.65 cm padua score low 6-7: 79 pts (54%) intermediate 8-9: 51 pts (35%) high ≥ 10: 17 pts (11%) tumor site (polar/not polar) 99 pts. (67%)/48 pts. (33%) tumor site (exophytic/not exophytic/completely endophytic) 82 pts (56%)/56 pts (38%)/9 pts (6%) tumor site (lateral/medial) 90 pts (61%)/57 pts (39%) renal sinus involvement (yes/no) 8 pts (5%)/139 pts (95%) excretory system involvement (yes/no) 6 pts (4%)/141 pts (96%) table 2. intraoperative parameters of the cohort (147 pts). average operative time (min) 118 ± 35 warm ischemia (pts) no ischemia 82 (56%) < 20 minutes 51 (35%) 20–29 minutes 10 (7%) > 30 minutes 3 (2%) average time of warm ischemia (min) 6.84 ± 8.74 average blood loss (ml) 236 ± 186 average hospital stay (day) 6.01 ± 5.43 average n° of transfusions per patient 0.16 ± 0.65 percentage of transfused patients 7.5% (11/147) percentage of major complications 1.4% (2/147) 01sciorio_stesura seveso 24/09/20 14:10 pagina 166 warm ischemia time, blood loss and length of hospitalization. when the statistical significance of each of the independent variables was tested, surgeon’s experience added statistical significance to the prediction of operative time (p = 0.000), warm ischemia time (p = 0.000) and blood loss (p = 0.000); tumour size (p = 0.046) to the prediction mic (p = 0.010), operative time (p = 0.000), warm ischemia time (p = 0.003) and blood loss (p = 0.010); asa score to the length of hospitalization (p = 0.009). for 13 patients (8.9%) with mic < 3, failure was associated in a statistically significant way to lesion diameter (p = 0.000), tnm classification >/= pt1b (72.7% vs 95.7%) (p = 0.000), high risk calculated by padua score system (p = 0.006) (table 3). moreover, for all patients with mic < 3 we registered significantly longer times of warm ischemia (p = 0.000), longer operating times (p = 0.000) and greater blood loss (p = 0.002). for all no-cct mic was 3, with a successful rate of 100%. discussion the main goal of the present study was to evaluate the mic score rate in our series of patients treated by retroperitoneal lpn. secondary endpoints were the assessment of the correlation between pre-operative parameters, as padua score, and perioperative and postoperative outcomes. the successful rate obtained was elevate (mic = 3 was obtained in 91,1% of patients), comparable to that of gill's group (13) and to that of other robotic case studies (14). evaluation of some recent series excluded patients who had not undergone ischemia. by applying this criterion, our success rate would drop, although it should be underlined that in our series ischemia was not used even in many cases with high padua score and large diameter tumors. the exclusion of these patients from the study would be penalizing for the evaluation of our results. on the other hand, the mic evaluation resulted in a “flattening” of the results range upwards. for this reason, in our opinion, the indicators of surgical success should be more stratified, for example by rewarding the absence of ischemia or very low ischemia times (< 10 minutes). it is interesting to note that the learning curve for the examined procedure is long even for an experienced surgeon. in fact, the results obtained by a single surgeon, already an expert at the beginning of this experience, show a specific trend, with a significant improvement in perioperative and postoperative outcomes during the study period. however, the results in terms of mic are not significantly related to the experience of the surgeon, who, when he has sufficient initial experience in renal laparoscopy, is able to ensure the surgical success of the procedure even with longer operating times and a higher blood loss and transfusion rate. on the other hand, in the initial phase of the experience the surgeon tends to select cases with lower padua score (6-7), while in the continuation of the study were then considered more complex cases with higher padua score (> 10). more studies are needed to better investigate these relationships and provide the surgeon, both expert and on learning curve, with effective predictive tools to obtain the best results in terms of operative and oncological outcomes. the use of the traditional laparoscopic technique for partial retroperitoneal nephrectomy has disadvantages and advantages over the robot-assisted technique. numerous studies have compared the results of traditional laparoscopic partial nephrectomy (lpn) with those of roboticassisted partial nephrectomy (rapn). transperitoneal and retroperitoneal rapn are equally effective and safe in terms of warm ischemia time, estimated blood loss, rate of conversion and complications and positive surgical margins (15). in particular, retroperitoneal ralpn proved to be an excellent option for posterior and lateral tumors with reduced operational times and shortened lenghts of stay (16). some authors reported that rapn has short operating and ischemia times and less blood loss compared with lpn (17, 18), although other studies have shown no differences in terms of operative time, warm ischemia time, estimated blood loss and lenght of hospital stay (19, 20). a meta-analysis showed equivalent peri-operative outcomes of lpn and rapn, which added the advantage of a shorter warm ischaemia time (21). on the other hand, lpn implies lower healthcare costs and use of sutureless technique can reduce warm ischemia and operative time (22, 23). at the moment, the two techniques represent excellent 167archivio italiano di urologia e andrologia 2020; 92, 3 surgical outcomes of rpn table 4. correlation between surgical outcomes and pathological stage. pt1a pt1b pt2 pt3 others p-value mean padua score 7.41 ± 1.42 8.48 ± 1.7 9.50 ± 3.53 8 ± 0.0 7.35 ± 1.38 0.000 average time of ischemia 6.01 ± 7.71 11.62 ± 11.45 0 9.5 ± 13.43 4.25 ± 6.4 0.011 pathological tumor size (cm) 2.78 ± 1.07 4.71 ± 1.66 5.25 ± 5.3 5.75 ± 4.59 2.88 ± 1.24 0.000 mic=3 (pts) 90/94 20/29 2/2 2/2 20/20 0.000 table 3. patient characteristics with and without mic success (defined as mic = 3). patients characteristics mic success (134 pts) mic failure (13 pts) p-value average volume of lesions (radiological evaluation) 3.38 ± 1.58 5.30 ± 1.34 0.000 padua score pts: pts: 6-7 75 4 0.006 8-9 47 4 ≥ 10 12 5 tumor site pts: pts: exophytic 80 2 0.007 not exophytic 47 9 completely endophytic 7 2 ptnm pts: pts: pt1a 90 4 0.000 pt1b 20 9 pt2 2 0 pt3 2 0 others 20 0 tumor size (histopathological evaluation) 3.08 ± 1.5 cm 4.97 ± 1.47 cm 0.000 average time of warm ischemia (min) 5.16 ± 6.96 24.07 ± 6.14 0.000 average operative time (min) 115 ± 32 151 ± 51 0.000 blood loss (ml) 222 ± 155 385 ± 360 0.002 01sciorio_stesura seveso 24/09/20 14:10 pagina 167 archivio italiano di urologia e andrologia 2020; 92, 3 c. sciorio, p.p. prontera, s. scuzzarella, p. verze, l. spirito, l. romano, a. trinchieri 168 alternatives to the in the management of moderate to complex renal tumours with high padua scores. conclusions retroperitoneal lpn represents an adequate and safe technique for the treatment of t1 renal cancer. optimal mic success rate can be achieved, although intraoperative outcomes tend to progressively improve during the learning curve even in a very experienced surgeon. length of hospitalization depends on general health condition. references 1. de castro abreu al, cacciamani g, gill is. partial nephrectomy. in: sotelo r., arriaga j, aron m. 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"trifecta" in partial nephrectomy. j urol. 2013; 189:36-42. 14. bianchi l, schiavina r, borghesi m, et al. which patients with clinical localized renal mass would achieve the trifecta after partial nephrectomy? the impact of surgical technique. minerva urol nefrol. 2019 oct 10. doi: 10.23736/s0393-2249.19.03485-4. [epub ahead of print] 15. xia l, zhang x, wang x, et al. transperitoneal versus retroperitoneal robot-assisted partial nephrectomy: a systematic review and meta-analysis. int j surg. 2016; 30:109-15. 16. laviana aa, tan hj, hu jc, et al. retroperitoneal versus transperitoneal robotic-assisted laparoscopic partial nephrectomy: a matched-pair, bicenter analysis with cost comparison using timedriven activity-based costing. curr opin urol. 2018; 28:108-114. 17. pierorazio pm, patel hd, feng t, et al. robotic-assisted versus traditional laparoscopic partial nephrectomy: comparison of outcomes and evaluation of learning curve. urology. 2011; 78:813-9. 18. wang y, ma x, huang q, et al. comparison of robot-assisted and laparoscopic partial nephrectomy for complex renal tumours with a renal nephrometry score ≥7: peri-operative and oncological outcomes. bju int. 2016; 117:126-30. 19. masson-lecomte a, bensalah k, seringe e, et al. a prospective comparison of surgical and pathological outcomes obtained after robot-assisted or pure laparoscopic partial nephrectomy in moderate to complex renal tumours: results from a french multicentre collaborative study. bju int. 2013; 111:256-63. 20. simsek a, yavuzsan ah, colakoglu y, et al. comparison of robotic and laparoscopic partial nephrectomy for small renal tumours. arch ital urol androl. 2017; 89:93-96. 21. zhang x, shen z, zhong s, et al. comparison of peri-operative outcomes of robot-assisted vs laparoscopic partial nephrectomy: a meta-analysis. bju int. 2013; 112:1133-42. 22. corongiu e, grande p, di santo a, et al. safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. arch ital urol androl. 2019; 91:157-162. 23. tiscione d, cai t, luciani lg, et al. sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. arch ital urol androl. 2019; 91:30-34. correspondence carmine sciorio, md (corresponding author) carmine.sciorio@gmail.com salvatore scuzzarella, md s.scuzzarella@libero.it asst “a. manzoni” hospital lecco (italy pier paolo prontera, md pierpaolo.prontera@virgilio.it asl-ta “s:s. annunziata hospital taranto (italy) paolo verze, md pverze@gmail.com lorenzo spirito, md lorenzospirito@msn.com lorenzo romano, md loryromano@hotmail.it università federico ii napoli (italy) alberto trinchieri, md alberto.trinchieri@gmail.com urology department, irccs ca’ granda ospedale maggiore policlinico, milano (italy) 01sciorio_stesura seveso 24/09/20 14:10 pagina 168 stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11581 1 original paper introduction percutaneous nephrolithotomy (pcnl), which completely outperformed open surgical methods for kidney stone treatment, is now the standard therapy method for large stones (1). complete stone elimination with the fewest complications is the main objective of therapy. despite recent advancements, complications are still frequent (2). the clinical research office of the endourological society (croes) recorded complications in approximately onefifth of the subjects in the pcnl global study (3). in spite of the benefits of smaller incisions, less blood loss, and a quicker time to recover than with open surgery, complications after pcnl are still a serious problem. it has been reported that complications happen in 10.3% to more than 50% of pcnls (4). usually, patients with comorbidities and a lower functional level are at a higher risk for surgical complications (5). as per the modified clavien classification system, perioperative (intraoperative and early postoperative) complications have been divided into purpose: to report the result of percutaneous nephrolithotripsy (pcnl) via standard nephrostomy tract in a single training institution. the perioperative complications in relation to the comorbid state are particularly assessed. patients and methods: a prospective interventional study between january 2019 to november 2022, included 210 patients scheduled for pcnl. the average age was 40.3 ± 11.8 years (range 1867 years). patients were categorized into two groups. the first group comprised 146 cases (69 .5%) with no associated co-morbidities while the second group 64 (30.5%) had co-morbidities such as obesity in 4 cases (1.9%), hypertension (htn) in 24 cases (11.4%) cases, diabetes mellitus (dm) in 17 (8.1%) cases, history of recurrent stone surgery in 11 (5.2%) cases and more than one in 8 cases (3.8%). co-morbidities, stone burden, location of stone, time of surgery, stay in the hospital, further operations, and negative events were among the reported data. complications and the stone-free rate were the main outcome indicators. results: intraoperative complications were reported in 40 (18.8%) patients (18 group 1 and 22 group 2) during pcnl. bleeding occurred in 22 (10.5%) patients (9 group 1 and 13 group 2), blood transfusions were needed in 4 (1.9%) (2 group 1 and 2 group 2), extravasation was observed in 11 patients (5.2%) (6 group 1 and 5 group 2) and cardiac arrhythmia in 3 (1.4%) (1 group 1 and 2 group 2) patients. postoperative complications occurred in 61 patients (29%) (24 group 1 and 37 group 2) in the form of fever in 10 patients (4.8 %) (3 group 1 and 7 group 2) and prolonged leakage in 50 patients (23.8%) (21 group 1 and 29 group 2). one patient of group 2 died from postoperative sepsis. extravasation and postoperative leakage were higher in diabetic patients than in non-diabetics. stonefree rate was 60.5% (127 of 210). clinically significant residual fragments (csrfs) found in 70 cases (33.3%) (33 group 1 and 37 group 2). in 13 cases (6.2%) (5 group 1 and 8 group 2), clinically insignificant residual fragments (cirfs) were found. in 8 (3 group 1 and 5 group 2) of the 13 cases, spontaneous stone safety and efficacy of percutaneous nephrolithotripsy in comorbid patients: a 3 years prospective observational study tamer a. abouelgreed 1, hassan ismail 1, sameh s. ali 2, ayman k. koritenah 1, yasser badran 1, mahmoud ali 1, rasha ahmed 1, mohamed algammal 1, ahmed alrefaey 1, aly gomaa 1, mohamed f. elebiary 1, hany a. eldamanhory 1, abdelhamid a. khattab 3, nermeen m. abdelmonem 4, mohammad thabet alnajem 5, tamer g. abdlhamid 6, ahmed a. abdelwahed 7, salma f. abdelkader 7 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 department of radiology, sheikh khalifa general hospital, uaq, uae; 3 department of urology, damanhur teaching hospital, albuheira government, egypt; 4 department of radiology, thumbay university hospital, ajman, uae; 5 department of radiology, tawam hospital, alain, uae; 6 department of anesthesia, emirates specialty hospital, dubai, uae; 7 department of radiology, faculty of medicine, ain shams university, cairo, egypt. doi: 10.4081/aiua.2023.11581 summary passage was observed within 4-6 weeks of surgery. residual stones in three cases (1 group 1 and 2 group 2) were asymptomatic and 4 mm or less, whereas stones increased in two cases of group 2. among all factors studied, stone burden was significantly correlated to both intraoperative and postoperative complications. the occurrence of postoperative fever increased with large stone burden. conclusions: pcnl is a therapeutic modality that is effective, feasible, and safe for a wide range of patients with concurrent medical issues. a steep curve is required to reduce intraoperative and postoperative complications. key words: percutaneous nephrolithotripsy; nephrostomy; renal stones. submitted 10 july 2023; accepted 1 august 2023 archivio italiano di urologia e andrologia 2023; 95(3):11581 tamer a. abouelgreed, hassan ismail, sameh s. ali, et al. 2 five grades. grade 1 represents all occurrences that, if left untreated, might resolve spontaneously or require a simple bedside intervention, grade 2 is assigned when specific medications, such as antibiotics and blood transfusions, were necessary; grade 3 if endoscopic, surgical, or radiologic intervention was required; grade 4 in case of organ failures and damage to nearby organs; grade 5 in case of death (6). to lessen the complications related to pcnl, it’s crucial to carefully choose and prepare patients. renal bleeding is the most concerning pcnl complication, which may be so severe to require a blood transfusion. early complications of pcnl also include renal vein rupture, ureteral or renal pelvic perforations, duodenal or colonic perforations, injuries to the spleen and liver, sepsis, and retained stones (7). this study aimed to report the outcome of pcnl via standard nephrostomy tract in one training institution. the perioperative complications in relation to the comorbid state are particularly assessed. patients and methods between january 2019 to january 2022, 210 patients from inpatient department of the author’s institute who scheduled for pcnl, were enrolled into this prospective observational study. on average, they were 40.3 ± 11.8 years old (range 18-67 years). they were categorized into two groups. the first group included 146 (69.5%) cases with no associated co-morbidities while patients of the second group 64 cases (30.5%) had co-morbidities such as obesity in 4 cases (1.9%), hypertension (htn) in 24 cases (11.4%), diabetes mellitus (dm) in 17 cases (8.1%), history of recurrent stone surgery in 11 cases (5.2%). eight cases (3.8%) had more than one complication. all procedures performed in the study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of al-azhar university, faculty of medicine (urosurg 2023/0001). all the patients provided their informed consent that explained nature of procedure, its complications and possible clearance of his stones. preoperative workups included a full blood count, platelet count, serum creatinine, hemorrhage and coagulation profiles, and urine culture for all patients. intravenous urography (ivu), urinary tract ultrasonography, and non-contrast computed tomography (ncct) were all used in the radiologic assessment of patients. stone burden has been determined using radiographic examinations, and stones were classified as simple (isolated calyceal stones or isolated renal pelvis stonees) or complex (complete or partial staghorn stones, kidney pelvic stones accompanied by calyceal stones), irrespective of size. every subject underwent pcnl, which started with a cystoscopy and ureteral catheter insertion, all of the patients under study were placed in the prone position to acquire percutaneous access; then through a chiba needle, pelvicalyceal system was accessed under fluoroscopy. after a correct calyceal puncture, a 30f amplatz sheath has been inserted after the tract had been dilated with alken metal telescopic dilators. using a rigid 26-fr nephroscope, nephroscopy was carried out. when necessary, further tracts were made during the same session to gain access to all stones. a pneumatic swiss lithoclast was used to fragment the stone burden. by using antegrade nephrostography and fluoroscopy intraoperatively, the collecting system's integrity and stone removal were verified. at the conclusion of pcnl, a 22-fr nephrostomy tube has been inserted into the renal pelvis or the affected calyx. if the urine was clear or light pink on the first postsurgical day, the foley and ureteral catheters have been eliminated. the kidneys, ureters, and bladder were examined with a plain film. the nephrostomy tube was removed on the second postsurgical day after antegrade nephrostography showing that patients had clinically insignificant residual fragments (cirfs) < 4 mm or no residual stones and drainage of the ureter down to the bladder. if urinary leakage from the tract persisted for more than 24 to 48 hours after the nephrostomy tube was removed, a double-j catheter was deemed necessary. if a second pcnl session was planned due to remaining stones, the nephrostomy tube was left in place. the pcnl technique was deemed successful when the patient was either stone-free or had cirfs, which were defined as <4 mm, non-obstructive, non-infectious, and asymptomatic residual fragments. statistical analysis: spss was used to analyze the data, (version 13.0, spss inc., chicago, ill, usa). we compared the two groups using the student t test, mann-whitney u test, and chi-square test. the mean standard deviation was reported for quantitative variables. p values <.05 were deemed significant. results the study comprised 210 patients treated by pcnl. there were 132 men (group i 84 and group ii 48) and 78 women (group i 62 and group ii 16). the age was 40.3 mean ± sd ± 12.8 years; 40.2 ± 11.6 years in group i and 41.13 ± 13.2 years in group ii (p = 0.77). the average body weight index in groups i and ii was 29.5 ± 7.1 and 30.0 ± 8.2 kg/m2, respectively (p = 0.53) (table 1). mean stone burden was 7.5 ± 5.6 cm2 (range: 2.5-30 cm2); 7.3 ± 3.4 cm2 and 8.1 ± 4.8 cm2 in groups i and ii, respectively (p = 0.47). mean follow up was 41.2 ± 32.3 months in group i and 45.3 ± 24.3 months in groups ii (p = 0.79) (table 2). table 1. clinical c of treated patients. characteristics no. (210 cases) group i (n = 146) group ii (n = 64) age (mean ± sd) 40.3 ± 12.8 yrs 40.2 ± 11.6 41.13 ± 13.2 sex males 132/210 (62.9%) 84 48 females 78/210 (37.1%) 62 16 complaint pain 201/210 (95.7%) 141 60 hematuria 9/210 (4.3%) 5 4 mean body weight index (kg/m2) 29.5 ± 7.2 29.5 ± 7.1 30.0 ± 8.2 archivio italiano di urologia e andrologia 2023; 95(3):11581 3 pcnl in comorbid patients one-access subcostal pcnl was performed in 189 (90%) cases (group i 136 and group ii 53), while 21 (10%) cases underwent multi-tract pcnl (group i 10 and group ii 11). supracostal approach was indicated in four cases (1.9%) in group i. the average surgical time was 75.15 ± 32.75 mins (range 40 to 140). nephrostomy tube removal took an average of 2.86 ± 0.83 days (ranging from 3 to 8), and the mean hospital stay was 3.93 ± 3.17 days. no complications occurred intraoperatively in 82.9% (174/210) of the patients, while one or more complications have been noticed in 36 (17.1%) cases during pcnl. bleeding occurred in 22 (10.5%) patients; transfusions of blood were needed in 4 out of the 22 patients (table 3) whereas the remaining patients were successfully treated with conservative measures. postoperative complications occurred in 61 cases (29%). prolonged leakage following nephrostomy tube removal occurred in 50 (23.8%) patients. stenting was required in 8 patients (3.8%) because of persistent urine leakage. fifteen out of the 17 patients with diabetes mellitus developed prolonged leakage after pcnl. in 10 patients (4.8%), there was a transient fever that required antipyretics. nine out of the ten patients with fever had urosepsis, which was successfully managed with intravenous broad-spectrum antibiotics, but one patient who died from postoperative sepsis (table 3). no pleural injury neither hydrothorax nor hemothorax and no colonic injury developed in any of our cases. complications in relation to stone burden were observed in 49 (72%),77(60.6%) and 6 (40%) patients with stone size ≤ 3 cm2, 3.1-5 cm2 and > 5 cm2 respectively. conversely, no complications were reported in 19 (27.9%, 50 (39 %) and 9 (60%) patients with stone size ≤ 3 cm2, 3.1-5 cm2 and > 5 cm2 respectively (table 4). at three months after surgery, the total stone-free rate reached 60.5% (127 of 210). clinically significant residual fragments were found in 70 cases (33.3%) (33 group 1 and 37 group 2) whereas in 13 cases (6.2%) (5 group 1 and 8 group 2), clinically insignificant residual fragments were found. in 8 (3 group 1 and 5 group 2) of the 13 cases with clinically insignificant fragments, spontaneous stone passage was observed within 4-6 weeks of surgery. residual stones were asymptomatic and 4 mm or less in three cases (1 group 1 and 2 group 2), whereas stones increased in two cases of group 2. discussion despite the high rate of success of pcnl, major risks associated with percutaneous renal surgery involve blood loss requiring transfusion, fever, urinary tract infections, and injury to nearby organs (8, 9). according to olbert et al. (10), there are links between the result of pcnl and patientand stone-related parameters, including age of the patient, bmi, metabolic syndrome, and type and burden of stone. the pcnl morbidity is significantly influenced by the burden of stones (11). the most frequent complication in a study by lee et al. (12) on 500 patients who had undergone pcnl was hemorrhage, with a 12% rate of transfusion. the nephrostomy tract itself is a frequent source of hemorrhage during pcnl (8). the number of serious hemorrhages was recorded as < 8% (13). in the majority of such cases, conservative therapy is successful; in the study of tefekli et al. (6) no blood transfusion was required whereas mousavi-bahar et al. (14) reported a transfusion rate of 0.6%. in our study, the transfusion rate was 1.9% in agreement with vorrakitpokatorn et al. (9), who reported a 1.4%. transfusion rate. transfusions rates were reported to be 25% in early investigations, but they were significantly reduced due to advances in percutaneous stone removal techniques, and more recent studies have found that they are now between 1% and 2% (15). earlier investigations have proposed that diabetes, the table 2. stones characteristics and pcnl access in the two groups. stone and access criteria group i group ii mean stone burden: 7.5 ± 5.6 cm2 (range: 2.5–30 cm2) 7.3 ± 3.4 cm2 8.1 ± 4.8 cm2 classification of stones: simple: 49% (n = 103) 68 35 complex: 51% (n = 107) 78 29 mean operation time: 75 ± 32 minutes (range 40 to 140) 70 ± 20 72 ± 22 mean number of percutaneous access no.: 1.1 ± 0.5 (range: 1–5) single access: 90% (n = 189) 136 53 multi-tract accesses: 10% (n = 21) 10 11 percutaneous access location subcostal access: 98.1% (n = 206) 145 61 supracostal access: 1.9% (n = 4) 1 3 overall postsurgical result: mean duration of urethral catheterization: 1.08 ± 0.2 d (range: 2–4 d) 1.3 ± 0.1 d 1. 4 ± 0.8 d mean time with nephrostomy tube: 2.86 ± 0.83 d (range: 3–8 d) 2.53 ± 0.71 d 2.74 ± 0.22 d mean hospital stay was 3.93 ± 3.17 days (range: 3–15 d) ake 3.88 ± 2.07 d 4.03 ± 3.66 d table 3. intraoperative and postoperative complications. intraoperative complications no. of cases (%) group i (n = 146) group ii (n = 64) bleeding 22 (10.5%) 9 (6.2%) 13 (20.3%) transfusion 4 (1.9%) 2 (1.4%) 2 (3.1%) extravasation 11 (5.2%) 6 (4.1%) 5 (7.8%) cardiac arrhythmia 3 (1.4%) 1 (0.7%) 2 (3.1%) no complications 174 (82.9%) 130 (89%) 44 (68.7%) postoperative complications fever 10 (4.8%) 3 (2%) 7 (10.9%) leakage 50 (23.8%) 21 (14.4%) 29 (45.3%) death 1 (0.4%) (0.0%) 1 (1.6%) no complications 149 (71%) 122 (83.6%) 27 (42.2%) (either colonic or pleural) table 4. overall complications in relation to stone burden. stone burden complications occurred no complications ≤ 3 cm2 49 (72.1%) 19 (27.9%) 3.15 cm2 77 (60.6%) 50 (39.4%) > 5 cm2 6 (40%) 9 (60%) archivio italiano di urologia e andrologia 2023; 95(3):11581 tamer a. abouelgreed, hassan ismail, sameh s. ali, et al. 4 type of stone, and the size of the stone can all predict blood loss in pcnl (16). the incidence of bleeding complications was found to be 7.0% (109/1555) after telescopic dilatation of the track using large sheaths (27f, 28f, 30f) with 5.9% (208 /3533) requiring blood transfusion (17). obesity is thought to make pcnl more technically challenging, which could increase the chance of complications. however, impact of obesity on pcnl results and complications is not well defined. a negative effect of obesity on complication rate was found in bagrodia et al. (18). in a large recent series, 234 patients were divided into 4 groups based on their bmis as ideal body weight (< 25 kg/m2), overweight (25 to 29.9 kg/m2), obese (≥ 30 to 34.9 kg/m2), and severely obese (≥ 35 kg/m2). after stratification with regard to bmi, no statistically significant difference was observed in length of hospital stay, stone-free rate, rate of complications, or change in hematocrit. this was supported by a more recent study (19), which concluded that bmi was not related to a higher risk of hemorrhage and transfusions. in our study, the procedures were performed on obliquely prone that we found more suitable for proper puncture of the collecting system. pcnl is most effective when the patient is in the prone position although patient may be placed in any of the following positions: flat prone on a fluoroscopic table, deflected prone on a cushion, oblique prone on a fluoroscopic table, or oblique supine on a fluoroscopic table. the oblique supine position is favored by some urologists because they believe it makes it simpler to access the succeeding pcnl it must be highlighted that the kidney's axis differs when the patient is lying in an oblique supine position versus a flat prone position (7). the number and type of access is influenced by the treatment approach and by the stone size and location. some surgeons favor a standard access via the lower calyx with subsequent eswl therapy for stones not reachable through this access (20). others recommend using many tracts (such as the upper pole) in a single session to clear the collecting system (21). upper pole access offers the best manipulation in cases with stone burdens in the upper and lower calices but involves a slight increase in the rate of complications (i.e., pleural injury). a subcostal technique is usually used, though a supracostal technique is preferred in some cases, like those of proximal ureter stones, superior calyx stones, or staghorn stones. when selecting the supracostal technique, significant chest complication rates of roughly 5% must be taken into account (22). our policy was to use the subcostal approach. however, supracostal approach was needed in four patients (1.9%) due to stones extending into the upper calyx. we had no complications related to supracostal approach in the four cases. one-access subcostal pcnl was performed in 189 (90%) cases (group i had 136 and group ii had 53), while 21 (10%) underwent multi-tract pcnl (group i has 10 and group ii has 11). the average surgical time ranged from 55 to 90 minutes (10) although most studies overlook the variables that influence pcnl’s surgical time. in the current study, the average surgical time was 75.15 ± 32.75 minutes (range 40 to 140), which lies in the range described. takeuchi et al. (23) reviewed the clinical records of 1897 patients who underwent pcnl for renal calculi splitting them into 2 groups depending on their median surgical time (group 1: ≤ 60 min; group 2: > 60 min). the average operation time was 64.9 ± 27.6 minutes (with a range of 10-220 minutes). in the present study intraoperative extravasation occurred in 5.2% (11 cases) and was managed conservatively. the overall incidence of postoperative prolonged leakage was 23.8% although it was significantly higher in group ii compared to group i (45.3% versus 14.4%, p < 0.045). fifteen out of the 17 cases with diabetes mellitus developed prolonged leakage after pcnl. septicemia can occur as a result of an infection introduced through the renal access tract or because the stones are infected. individuals with infected urinary stones experience fever more frequently following pcnl than patients with sterile stones (24). prior to undergoing pcnl, a pyonephrotic kidney must be drained and prophylactic antibiotics must be taken. in the instance of sterile urine, antibiotics could be administered using single-dose or short-course prophylactic procedures without any significant differences between them. there are significant risk factors for postsurgical fever, including the length of the operation and the amount of irrigation fluid used. additionally, it is critical to avoid an increase in collecting system pressure, and operating times should be kept to a minimum (i.e., < 90 minutes). the literature reports sepsis rates up to 0.97% (25) although other series (26), reported lower incidence of such complication (0.3%). in our series, despite proper antibiotic therapy, a diabetic patient with staghorn stone died of urosepsis. he received prophylactic antibiotic, and his preoperative urine culture was negative. the surgical time was 120 minutes. the total stone-free rate in this study at three months was 60.5% (127 of 210), which was lower than previously reported. altunrende f et al. (27) reported total stone-free rate as 74.5%. the impact of case volumes on pcnl's efficacy and safety results was recently analyzed in a large database including data from 3933 patients (28). in high-volume centers, stone-free rates were higher (82.5% versus 75.1%; p < 0.001). high-volume centers had also a lower rate of complications (15.9% versus 21.7%; p = 0.002) and a shorter mean length of stay (3.4 versus 4.9 days). after controlling for stone burden, urine culture status, and the presence of staghorn stones, the stone free rate increased with case volume, while the complication rate and length of stay decreased. centers that undertook a large number of pcnls annually had better outcomes and the highest stone free rates have been found in centers with more than 120 cases annually (28). a study evaluated the natural history of cirfs (27) in 38 patients who had cirfs three months following pcnl (22% of the total) and were followed for a minimum of 24 months. during follow-up, 10 (26.3%) patients experienced a symptomatic episode that required medical treatment, whereas the other patients were asymptomatic. according to the radiologic evaluation, the size of the fragments increased in 8 (21.1%) cases while remaining stable or decreasing in 27 (71.1%) cases. a spontaneous stone passage occurred in three (7.9%) of the patients. in our study, cirfs were found in 13 cases (6.2%). eight archivio italiano di urologia e andrologia 2023; 95(3):11581 5 pcnl in comorbid patients of those 13 cases had spontaneous stone passage, whereas the size of the stones increased in two cases, and three had asymptomatic residual stones measuring 4 mm or less. clinical significant residual fragments (csrfs) were found in 70 cases (33.3%) and were managed by auxiliary swl treatment. according to margel et al. (29), pcnl is time-consuming and may necessitate auxiliary operations in patients who had previous open stone surgery due to scar tissue and anatomic changes in the operated kidney. in contrast, our research found no difference in the rate of complications between patients who had open stone surgery and those who did not, which is consistent with other studies (30). limitation of study we have relatively high complications rate because our institution is a training center for junior staff and young residents. conclusions pcnl represents an efficacious, feasible, and safe treatment modality that can be used in a wide range of patients with concomitant illnesses who need a steep curve for decreasing intraoperative and postoperative complications. references 1. karakoyunlu n, goktug g, sener nc, et al. a comparison of standard pcnl and staged retrograde furs in pelvis stones over 2 cm in diameter: a prospective randomized study. urolithiasis. 2015; 43:283e7. 2. jessen jp, honeck p, knoll 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25. aron m, yadav r, goel r. multi-tract percutaneous nephrolithotomy for large complete staghorn calculi. urol int. 2005; 75:327332. 26. osman m, wendt-nordahl g, heger k, et al. percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases. bju int. 2005; 96:875-878. 27. altunrende f, tefekli a, stein rj, et al. clinically insignificant residual fragments after percutaneous nephrolithotomy: mediumterm follow-up. j endourol. 2011; 25:941-945. 28. opondo d, tefekli a, esen t, et al.; croes pcnl study group. impact of case volumes on the outcomes of percutaneous nephrolithotomy. eur urol. 2012; 62:1181-7. archivio italiano di urologia e andrologia 2023; 95(3):11581 tamer a. abouelgreed, hassan ismail, sameh s. ali, et al. 6 29. margel d, lifshitz da, kugel v, et al. percutaneous nephrolithotomy in patients who previously underwent open nephrolithotomy. j endourol. 2005; 19:1161-1164. 30. sofikerim m, demirci d, gulmez i, karacagil m. does previous open nephrolithotomy affect the outcome of percutaneous nephrolithotomy? j endourol. 2007; 21:401-403. correspondence tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg hassan ismail, md drhassan_ismail@yahoo.com ayman k. koritenah, md dr_ayman.kotb@gmail.com yasser badran, md dryasserbadran@gmail.com mahmoud ali, md dr_mahmoud72@hotmail.com rasha ahmed, md rashaahmed1511@gmail.com mohamed algammal, md gemykarter2020@gmail.com ahmed alrefaey, md a7medrefa3y.ash@gmail.com aly gomaa, md alygomaa68@yahoo.com mohamed f. elebiary, md dr_elebiary@yahoo.com hany a. eldamanhory, md drhanyeldamanhory@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt sameh s. ali, md drsamehsaied@yahoo.com department of radiology, sheikh khalifa general hospital, uaq, uae abdelhamid a. khattab, md abdelhamed1123ufw@gmail.com department of urology, damanhur teaching hospital, albuheira government, egypt nermeen m. abdelmonem, md neermeeenmohamed@gmail.com department of radiology, thumbay university hospital, ajman, uae mohammad thabet alnajem, md mtnajem@gmail.com department of radiology, tawam hospital, alain, uae tamer g. abdlhamid, md dr_tamer_gamal@yahoo.com department of anesthesia, emirates specialty hospital, dubai, uae ahmed a. abdelwahed, md ahmed_abdelwahed@yahoo.com salma f. abdelkader, md cairo, egypt salmafathy4@gmail.com department of radiology, faculty of medicine, ain shams university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 481archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. introduction renal cancer represents 3% of all neoplasms in western countries. during the last few years, its incidence increased by 2% due to an increased amount of incidental radiological diagnosis, especially for small renal masses (< 4 cm of diameter) (1, 2), for which nephron sparing surgery is the treatment of choice (3). however, these small lesions can behave biologically different from other renal masses. it is estimated that 20-30% of small renal masses are benign and active surveillance is an acceptable tool that can be used to avoid the surgery and its related risks in this cohort of patients (2-4). the presence of ectopic adrenal tissue in the kidney, while benign, is a rare event that needs to be identified and distinguished from renal cancer. this condition can be divided into two entities based on the pathophysiological origin. first, “ectopic adrenal tissue” or “adrenal rest”, initially described by morgagni in 1740, is a congenital anomaly due to the migration, to other organs, of fragments of the primitive adrenal gland, and can be classified as “true” or “accessory” ectopy depending on the migration of the whole or part of the gland, respectively (5, 6). second, “adrenal-renal fusion”, first described by rokitansky in 1855 (7), could be divided into a “congenital” form when it is caused by failure of the retroperitoneal mesenchymal cells to stimulate adrenal capsule formation, or “acquired” form when it is a consequence of inflammation of the perirenal fat. consequently the adrenal gland becoming fused with the renal parenchyma, and become anatomically indivisible from the kidney (8). most ectopic adrenal tissue is located along the migration path of the urogenital system but it could be present also at the level of celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs (9). ectopic adrenal tissue can be present in 50% of newborns, usually regressing and persisting in only 1% of the adult population (10). it is not a rare condition and can manifest clinically as endocrine abnormalities due to secretory activity, mass effect or neoplastic transformations. additionally, due to the location where these lesions can arise, adrenal rest becomes part of the differential diagnointroduction: ectopic adrenal tissue in the kidney, including “ectopic adrenal tissue” and “adrenal-renal fusion”, is a rare event with a specific behavior which may be difficult to distinguish clinically from renal neoplasms. we performed a systematic review on ectopic adrenal tissue variants reported in the literature underlining its clinical aspects. methods: manuscripts which presented a case report or case series of ectopic adrenal tissue in the kidney were included even if published in original articles, reviews, or letters to the editor. a specific search on scopus®, pubmed®, and web of science® database was performed. only english language papers published in a period ranging between august 1991 and april 2020 were considered. additionally, a case we had at our institution is described, and its characteristics are included. data on clinical presentation, type of adrenal anomaly, location, anatomopathological and immune-histotype characteristics were collected. results: we identified 888 manuscripts. among these 29 were included in this systematic review. overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. in most cases, the diagnosis was made incidentally, or following investigation for flank pain, abdominal pain, or endocrinological disorders. ct scan frequently identified a solid vascularized lesion that was difficult to distinguish from renal neoplasm. adrenal fusion was mostly located at the level of the upper pole. adrenal rest was found in the renal parenchyma, renal hilum, or retroperitoneum in close proximity to the renal peduncle. often these ectopic adrenal tissue lesions follow a benign behavior and can be classified as functioning or non-functioning adenomas. rarely, they may experience neoplastic degeneration. the most frequently positive markers were inhibin, vimentin, melan-a, synaptophysin and anti-p450 scc. conclusions: ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics that need to be identified in order to arrive at a correct diagnosis and carry out appropriate treatment management. key words: intrarenal adrenal tissue; ectopic adrenal tissue; renal-adrenal fusion; adrenal rest; incidental renal masses; renal cancer; small renal mass. submitted 19 september 2021; accepted 23 september 2021 ectopic adrenal tissue in the kidney: a systematic review davide de marchi 1*, alessandro tafuri 2-4*, guglielmo mantica 5, aliasger shakir 6, federico scarfò 7, giovanni passaretti 1, salvatore smelzo 1, silvia proietti 1, lorenzo rigatti 1, roberta luciano 7, alessandro antonelli 3, vincenzo pagliarulo 2, rosario leonardi 1, guido giusti 1, franco gaboardi 1 1 department of urology, san raffaele hospital, milan, italy; 2 department of urology, “vito fazzi” hospital, lecce, italy; 3 department of urology, university of verona, azienda ospedaliera universitaria integrata verona, verona, italy; 4 department of neuroscience, imaging and clinical sciences, university "g. d'annunzio" of chieti-pescara, chieti, italy; 5 department of urology, university of genova, ospedale san martino, genova, italy; 6 usc institute of urology, catherine and joseph aresty department of urology, keck school of medicine, university of southern california (usc), los angeles, ca, usa; 7 department of pathology, san raffaele hospital, milan, italy. * equal contribution. doi: 10.4081/aiua.2021.4.481 summary archivio italiano di urologia e andrologia 2021; 93, 4 d. de marchi, a. tafuri, g. mantica, et al. 482 sis along with renal cell carcinoma and for this reason it must be correctly diagnosed (11). here, we report a systematic review of the literature on ectopic adrenal tissue while underlining its main clinical aspects. methods we performed a systematic review limited to case reports, case series and all formats reporting a case description on our specific topic. the purpose of this literature review is to describe the salient features of adrenal ectopia in order to assist the differential diagnosis process with renal neoplasms. for this reason, we considered only adrenal ectopias located at the renal level or in the retroperitoneum in close proximity to the renal pelvis in the study. a specific search on scopus®, pubmed®, and web of science® database was performed including “[(intrarenal adrenal tissue) or (ectopic adrenal tissue)] or [(renal box 1. case report. in november 2017, a 66 year-old man with a previous history of diabetes mellitus, hypertension, and benign prostatic hyperplasia came to our institution. due a single episode of hyperpyrexia associated with left flank pain, he performed an abdomen ultrasound with incidental finding of a left renal mass, and a following abdomen ct scan which confirmed the presence of an exophytic solid lesion of 10 x 14 mm, in the middle lateral margin of the left kidney (r.e.n.a.l. score 6a; p.a.d.u.a. 7 a), (figure 2 a-b-c-d). both adrenal glands had regular morphology, size and location. complete blood count, creatinine, urine analysis values were all within normal limits. given the small size of the neoformation, active surveillance of the neoformation was proposed to the patient but he preferred to remove the mass, and robot assisted left partial nephrectomy was performed in january 2018. a clampless enucleoresection was performed with a continuous suture on the resection bed by sliding suture technique with hem-o-lok. the post-operative period was regular and uncomplicated. the patient was discharged after three days. the definitive anatomopathological report reports “ectopic adrenal gland with renal tissue where occasional tubular thyroidization and minimal interstitial chromic nephritis” (figure 3 a-b). the follow up was negative. ultrasound of the abdomen and blood test with kidney function evaluation was negative. figure 1. prisma flowchart. 483archivio italiano di urologia e andrologia 2021; 93, 4 ectopic adrenal tissue in the kidney adrenal fusion) or (adrenal rest)] and [(kidney cancer) or (renal cancer) or (renal cell carcinoma)]” mesh terms. only manuscripts in english language published in a period ranging between august 1991 and april 2020 were considered (figure 1). all the manuscripts which presented a case report or case series were included even if published in original articles, reviews, or letters to the editor. two authors (d.d.m.) and (g.m.) independently reviewed the literature using inclusion and exclusion criteria. all disagreements about eligibility were resolved by discussion with a third reviewer (a.t.) until consensus was reached. this study was performed using guidelines set out by preferred reporting items for systematic reviews and metaanalysis (prisma) statement (12). additionally, a case at our institution is described, and its characteristics are included in the following evidence synthesis (box 1, tables 1-2). table 1. clinical and pathological characteristics of adrenal ectopias findings in the included studies. author type of article n° of case clinical presentations adrenal abnormalities ap report markers goren et al. 1991 (14) case report 1 case left lumbar pain adrenal rest ectopic adrenocortical adenoma ns chin et al. 1994 (6) case report 1 case incidental finding in patient with kidney neoplasia true heterotopia ectopic adrenocortical adenoma anti-p450 scc+ colberg et al. 1998 (15) case report 1 case abdominal pain and weight loss adrenal renal fusion adrenocortical adenoma pan cytokeratin cytokeratin 7ayala et al. 2000 (16) case report 1 case cushing’s syndrome adrenal rest ectopic adrenocortical adenoma ns souverijns et al. 2000 (17) case report 1 case hypertension adrenal rest ectopic adrenocortical adenoma vimentin + szumera et al. 2003 (11) case report 1 case ns adrenal rest ectopic adrenocortical adenoma vimentin + synaptophysin + cytokeratinema fan et al. 2004 (18) case report 1 case incidental findings in patients with metabolic syndrome adrenal renal fusion atrophic adrenal gland and renal cyst ns hsu et al. 2005 (19) case report 1 case incidental findings in patient with kidney neoplasia adrenal rest ectopic adrenocortical adenoma ns claahsen-van der grinten case report 1 case abdominal pain in patient with congenital adrenal rest adrenal rest tumour cytokeratins 8/18 + inhibin + et al. 2008 (20) adrenal hyperplasia ae1/ae3 epithelial membrane antigen cd68 cd10 placental-like alkaline phosphatase baydar et al. 2008 (32) case series 2 cases abdominal pain adrenal rest ectopic adrenocortical adenoma melan-a + inhibin + calretinin + emapancytokeratin eterotopic adrenal cortical tissue melan-a + synaptophysin + calretinin + ema cd68linder et al. 2009 (21) case report 1 case incidental finding renal adrenal fusion adrenocortical adenoma mart-1 + mak-6 + inhibin + cd10 hmb-45 – ae1/3 sma mahadevia et al. 2009 (22) case report 1 case abdominal pain adrenal renal fusion adrenocortical adenoma ns ye et al. 2009 (12) retrospective 9 cases 7 adrenal rest ectopic adrenocortical adenoma ns cases series 2 adrenal renal fusion louiset et al. 2010 (23) case report 1 case acth-independent cushing’s bilateral adrenocortical micronodular bilateral adrenocortical 17-α hydroxylase+ syndrome due to ppnad hyperplasia and adrenal rest micronodular hyperplasia and 21-α hydroxylase+ ectopic adrenocortical adenoma brč ić et al. 2011 (15) case report 1 case incidental finding adrenal rest ectopic adrenocortical adenoma hmb-45 + sma + melan-a + inhibin + calretinin+ ae1/3 cd10 ema cardinalli et al. 2012 (24) case report 1 case incidental finding in beckwith–wiedemann syndrome adrenal rest ectopic adrenocortical adenoma ns wang et al. 2012 (9) case report 1 case cushing’s syndrome adrenal rest ectopic adrenocortical adenoma ns yokoyama et al. 2013 (25) case report 1 case incidental finding adrenal rest adrenocortical carcinoma p450c17 + sf-1 + dhea-st + 3β-hsd + tong et al. 2014 (26) case report 1 case cushing’s syndrome adrenal rest ectopic adrenocortical adenoma melan-a+ hsd3b2+ cyp17a1+ godin et al. 2014 (27) case report 1 case incidental finding adrenal rest oncocytic adrenocortical adenoma ns griffin et al. 2015 (28) case report 1 case hypertension adrenal renal fusion multinodular adrenal cortical hyperplasia ns clair et al. 2015 (29) case report 1 case abdominal pain adrenal renal fusion adrenocortical adenoma ns liu et al. 2016 (33) case report and review 1 case endocrinological disorders: adrenal rest ectopic adrenocortical adenoma vimentin + inhibin α+ amenorrhea and virilization and melan-a + synaptophysin + obstruction urinary output nse + cd56 + ae1/ae3 +/pax 8 – s100 – chromogranin a zhang et al. 2016 (10) case report and review 1 case hypertension and bilateral limb weakness adrenal rest ectopic adrenocortical adenoma synaptophysin + cd56 + vimentin + ki-67 +(2%) inhibin α+ calretinin + chromogranin a cd117 cd10 ck7 ema ck-pan melan-a sappal et al. 2016 (34) case report and review 1 case incidental finding adrenal rest ectopic adrenocortical adenoma melan-a + pax 8 zhao et al. 2018 (30) case report 1 case cushing’s syndrome adrenal rest adrenocortical adenoma with ns myelolipoma metaplasia lee et al. 2018 (31) case report 1 case back pain adrenal rest adrenocortical carcinoma inhibin α+ vimentin + synaptophysin + melan a focal + bamford et al. 2018 (8) case report 1 case incidental finding in patient with bladder neoplasia adrenal renal fusion lu et al. 2018 (35) case report and review 1 case acth-independent cushing’s syndrome adrenal rest ectopic adrenocortical adenoma inhibition + melan-a + synaptophysin + vimentin + ae1/ae3 + hmb45 +/cd34 + current case case report and systematic review 1 case incidental finding adrenal rest heterotopic adrenocortical adenoma ns archivio italiano di urologia e andrologia 2021; 93, 4 d. de marchi, a. tafuri, g. mantica, et al. 484 results our online search identified 888 publications. sixty-five had all the inclusion criteria, and 29 were included in this systematic review. among these, 22 were single case reports (6, 8, 9, 13-31), 2 articles reported more than one case (11, 32), 4 were literature reviews with case report (10, 33-35), and 1 article was a letter to the publisher including a case reports (5). we therefore compared the cases present in the literature with one that happened in our center in january 2018 (box 1), evaluating the main characteristics. overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. the main aspects examined in this review of the literature were the clinical presentation, the type of adrenal anomaly found, the location of this anomaly, the definitive anatomopathological report and the presence of immunehistotypic markers (table 1). type of adrenal anomalies “adrenal rest” were present in 29 patients, “adrenal renal fusion” was present in 9 patients (table 1). all cases had adrenal cortex tissue, in the absence of heterotopia with regard to the medullary portion. we found 1 case of “true heterotopia” as published by chin table 2. ct characteristics characteristics of adrenal ectopias findings in the included studies. author location ct-presentation native adrenals hu mri differential diagnosis goren et al. 1991 (14) left renal hilum 8 cm solid mass with contrast enhancement ns ns ns oncocytoma, rcc chin et al. 1994 (6) right upper pole ns normal ns ns ns colberg et al. 1998 (15) right upper pole 2.9 cm solid mass ns ns ns ns ayala et al. 2000 (16) left renal hilum 3.5 cm mass normal ns ns ureteral tumor souverijns et al. 2000 (17) retroperitoneal mass close 5.5 cm mass with inhomogeneous to left renal vein peripheral contrast enhancement ns ns ns lymph node metastasis szumera et al. 2003 (11) left upper pole cystic lesion of 7 cm ns ns ns rcc fan et al. 2004 (18) right upper pole cystic renal mass (bosniak ii) wisp-like and thin 9-10 ns cystic rcc hsu et al. 2005 (19) retroperitoneal paracaval mass 5 cm contrast enhancing paracaval mass ns ns ns lymph node metastasis claahsen-van der grinten retroperitoneal mass beside 5 cm retroperitoneal mass et al. 2008 (20) rx left kidney with multinodular aspect ns ns ns ns baydar et al. 2008 (32) right upper pole 1.5 cm solid mass normal ns ns rcc left upper pole 2 mm mass at upper pole ns ns ns rcc linder et al. 2009 (21) right upper pole 4.5 cm solid mass with minimal amount of fat ns ns ns aml, rcc mahadevia et al. 2009 (22) left upper pole 2 cm mass with low attenuation normal basal: -19a. and heterogeneity phase: +58v. phase: +22 ns aml, rcc ye et al. 2009 (12) 1 mid pole left kidney, 6 superior pole ns ns ns ns rcc 2 superior pole ns ns ns ns rcc louiset et al. 2010 (23) right pararenal adrenal rest close 3.8 cm pararenal mass previous bilateral 28 ns ns to the renal hilum adrenalectomy brč ić et al. 2011 (15) right upper pole 2 cm cystic and solid mass with contrast enhancement ns ns ns aml, rcc cardinalli et al. 2012 (24) left renal hilum ns ns ns ns ns wang et al. 2012 (9) left upper pole ns bilateral adrenal ns 3 cm mass with fatty component ns atrophy and plentiful vascular supply yokoyama et al. 2013 (25) retroperitoneal mass between inferior 6,5 cm retroperitoneal mass normal ns ns ns vena cava and right kidney tong et al. 2014 (26) left renal hilum 2.7 mass in the left renal hilum atrophic ns ns ns godin et al. 2014 (27) left upper pole ns ns ns 4,8 cm heterogeneously rcc, enhancing mass pheocromocytoma griffin et al. 2015 (28) right superior pole ns ns ns ns cystic rcc clair et al. 2015 (29) left upper pole 2.5 cm heterogeneous mass ns ns hypointense on t2 papillary rcc, with contrast enhancing than renal cortex aml, rcc liu et al. 2016 (33) left renal hilum 2.7 cm well-circumscribed soft-tissue mass atrophic 35 to 161 ns aml, oncocytoma, with contrast enhancement with atrophic paraganglioma bilateral adrenals and rcc zhang et al. 2016 (10) right renal hilum 3*3 cm mass with contrast enhancement normal ns ns ns sappal et al. 2016 (34) right upper pole 2.7 cm mass with contrast enhancement lesions appeared inseparable ns ns rcc from the right adrenal gland zhao et al. 2018 (30) right renal hilum 3.6 cm solid mass with contrast enhancement. normal ns ns ns adrenal gland were normal lee et al. 2018 (31) mid pole right kidney 13 cm heterogeneous mass ns ns ns rcc bamford et al. 2018 (8) bilateral superior pole symmetrical well-defined low-attenuation no demonstrable fat plan between 55 ns ns subcapsular lesions each measuring 2.3 cm renal lesions and adrenals lu et al. 2018 (35) left renal hilum 3 cm well-circumscribed atrophic ns ns ns mass with athrophic bilateral adrenal glands current case mid pole of the left kidney 10 x 14 mm, in the middle lateral margin normal basal: 5a. ns rcc, aml of the left kidney phase: +90 v. phase: +60 485archivio italiano di urologia e andrologia 2021; 93, 4 ectopic adrenal tissue in the kidney et al. in 1994 (6). in this case, the absence of an adrenal gland on the right side and the presence of normal left gland on the preoperative ct scan suggests a true heterotopia. from our review, it emerged, that the most frequent form of adrenal heterotopia is the adrenal rest, and in alignment with these findings, our clinical case also had this form of adrenal abnormality. clinical presentation in 11 patients the diagnosis was incidental, in 8 patients the mass was found after clinical investigation was performed for flank or abdominal pain, in 7 patients presented with manifestations of endocrinological disorders, and in 3 patients, it was diagnosed during imaging evaluations which were performed for arterial hypertension refractory to therapy or metabolic syndrome. the onset of symptomatology was not reported in 9 patients derived from a retrospective case series (11). most of the clinical cases in the literature have been accidentally diagnosed during clinical investigations for abdominal or lower back pain, high blood pressure, or during diagnostic routines for concomitant neoplasms. seven cases showed endocrinological disorders such as cushing syndrome, primary hyperaldosteronism or were present in the context of congenital anomalies such as beckwithwiedemann syndrome (9, 16, 20, 23, 24, 26, 30, 33, 35). abdominal pain may be due to an ureteropelvic obstruction due to the mass effect of the neoplasm, as in the case presented by goren et al. (14) and lee et al. (31). in another five cases the abdominal pain was not motivated by the size or the location of the adrenal abnormalities (15, 20, 22, 29, 32). cushing syndrome was the most frequent clinical presentation when a secreting ectopic adrenal adenoma was reported (9, 16, 23, 26, 30, 35). the clinical presentation included moon facies, hirsutism, easy bruising and weakness, polydipsia and polyuria. elevated blood pressure refractory to anti-hypertensive drugs was also present. in these patients, surgical removal of the adrenal adenoma led to a regression of symptoms except for the case published by suverijns et al. in which the pressure remained high (10, 17, 28). in one case described by cardinalli et al. in 2012 the adrenal rest was diagnosed during complementary radiological studies in a patient with beckwith-wiedemann syndrome (bws) (24). bws is a growth disorder characterized by macrosomia, macroglossia, organomegaly, abnormalities of the ears, an increased risk for development of embryonal tumors and disorders of the adrenal gland. in this particular case the presence of ectopic adrenal tissue at the level of left renal hilum was associated with a myelolipoma but the authors concluded that a clear relationship between bws, adrenal adenoma and myelolipoma is unclear (24). in our case, the diagnosis was incidental during routine investigation. in fact, the patient did not report abdominal pain, and did not manifest any endocrinological abnormalities or elevated blood pressure. location and ct-presentation ct is considered the gold standard for the characterization of renal cancers. multiphase ct has a sensitivity of 90% to 99% and a specificity of 99% to 100%. in our review, mri was the method of choice for the study of renal mass only in two cases (9, 27). however, small kidney masses can exhibit similar behaviors making the differential diagnosis process difficult. renal adrenal fusion as described by rokitansky is due to the absence of adipose tissue that normally separates the adrenal gland and the upper pole of the kidney. in our review we identified 9 cases of renal adrenal fusion all located at the upper renal pole (table 2). among the 29 patients with adrenal rest, 17 had a localization at the kidney, 7 at the level of the renal hilum and 5 at the level of the retroperitoneum in close proximity to the renal peduncle (table 2). in patients with localization at the kidney, the lesion most commonly occurred in the upper pole, while only 3 patients, including our case, had a lesion located in the middle third of the kidney (11, 31). in this subgroup of patients, the differential diagnosis included clear cell renal cell carcinoma (ccrcc), angiomyolipoma (aml), oncocytoma, papillary renal cell carcinoma (prcc) and cystic rcc. in the remaining case reports with extra renal localization the differential diagnosis included lymph node metastases and ureteral tumors (table. 2). only 3 case reports present in our review reported the hounsfield units (hu) of the neoplasms. fan et al. found that the lesion had a hu of 9-10. in this case, given the radiographic characteristics of the lesion, the differential diagnosis included a cystic renal neoplasm (18). mahadevia et al. found a variation in hu depending on the phase of the study from -19 to +58 and +22. in this case the differential diagnosis was between aml and rcc (22). liu et al., reported a change in hu from 35 to 161. in this case the differential diagnosis included aml, oncocytoma, paraganglioma and rcc (33). in our case, the neoplasm showed a behavior similar to that described by mahadevia. in fact, the neoplasm had different hu -5, +90 and +60 according to the different phases of the ct study. also, in our case, the main differential diagnoses were aml and rcc. anatomopathological report more frequently these adrenal changes have a benign behavior and can be classified as functioning or nonfunctioning adenomas. however, in some cases, they may experience neoplastic degeneration as published by yokoyama et al. and lee et al. (25, 31). godin et al. in 2014 published the first case of adrenocortical heterotopic oncocytoma of the kidney. as reported, the additional cases present in the literature had extrarenal locations being localized at the spinal or retroperitoneum level (27). our case, according with the literature is one with a non-functioning adrenocortical adenoma (box 1 table 1). additionally, the absence or poor presence of fibrous tissue between the kidney and heterotopic tissue was commonly reported, and a contact between the adrenal tissue and the renal parenchyma is frequently described. this feature is also present in our case (figure 2). immune-histotypic markers the immunohistochemistry has a pivotal role in the final archivio italiano di urologia e andrologia 2021; 93, 4 d. de marchi, a. tafuri, g. mantica, et al. 486 diagnosis. in our review, 17 studies investigated the use of immunohistochemistry in the diagnostic phase. chin et al. in 1994, first used immunohistochemistry to establish the steroidogenic potential of the sample under examination (6). the kidney was incubated with adrenal ectopic tissue and specific antibodies for cytochrome p 450 scc (a mitochondrial enzyme implicated in the synthesis of steroid hormones), and a high response to the adrenal ectopic tissue was found. subsequently, further markers were used in the differential diagnosis. the most frequently positive markers were inhibin, vimentin, melan-a, synaptophysin and anti-p450 scc (table 1). our case report did not pose a diagnostic doubt and therefore, was not investigated with immunohistochemistry (figure 2). adrenal heterotopia is a rare condition, present in about 1% of the adult population. the main locations are celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs and this is due to the embryological development of the adrenal gland. adrenal heterotopia is a benign and asymptomatic condition; however, it can become evident clinically when endocrinological disorders manifest, neoplastic transformation occurs, or mass effect arises. in most cases it presents itself as an incidental finding during routine examinations performed for other causes and can mimic a solid lesion affecting parenchymatous organs, a retroperitoneal lesion compatible with a neoplasm or a metastasis if diagnosed during diagnostic investigations for other malignancies. having a heightened clinical suspicion for these neoplasms in the setting of small renal masses will improve detection and allow more appropriate therapeutic planning with important clinical implications. in this review, we considered the clinical characteristics of a subgroup of adrenal heterotopias such as those located at the renal, perirenal and retroperitoneal level in order to identify the main differences that can guide clinicians towards to a correct preoperative diagnosis. as we reported, clinical presentation can be very varied. in most cases, it is silent and diagnosed during routine exams. in other cases, if the adenoma is secreting hormones, it manifests itself with endocrinological disorders, hypertension refractory to medical therapy or abdominal pain. the most frequently occurring location of this lesion is at the level of the upper pole of the kidney with a typical morphology of solid lesion with fat content, and a hyper-vascularized pattern which includes differential diagnoses of aml or ccrcc (table 2). in these, an attenuation of -10 hu or less is similar to aml. a strong contrast during cmp with hu values greater than 100 with subsequent wash-out during the nephrogenic phase is similar to ccrcc. also, prcc has a more subtle enhancement pattern than ccrcc, further complicating the list of differentials (36). finally, it can also present itself as a complex cyst as published by fan et al. and, in this case the differential diagnosis is with cystic rcc (18). more frequently the anatomopathological report is a benign adenoma, however an adrenocortical neoplasm or other histological subtypes may be figure 2. “a-b”: renal neoformation localized to the middle third of the left kidney; “c-d”: adrenal glands with regular size, morphology and localization. figure 3. histopathological findings of an ectopic adrenal gland. normal kidney parenchyma with glomeruli and tubules can be seen (blue square). the right side is occupied by normal tissue of the adrenal gland, where cells belonging to the fasciculata and the reticularis can be spotted (yellow star). while the orthotopic adrenal gland is embedded and separated by the renal parenchyma by a fibrous capsule most of the time, in this case the glandular tissue appears to be embedded directly in the renal parenchyma, since it is directly adjacent to it without any visible capsule or connective tissue. 487archivio italiano di urologia e andrologia 2021; 93, 4 ectopic adrenal tissue in the kidney present sporadically as published by godin et al. in 2014 (27). in many of the cases present in this review, immunohistochemical markers were used, in fact the histological structure was not always correctly reported. this is especially true for cases of adrenocortical carcinoma and rarer histological subtypes. the characteristics that our clinical case carried, correspond to clinical characteristics presented in the literature. the diagnosis was incidental during routine investigation, no painful or endocrinological symptoms were present. when the definitive anatomopathological report showed a well differentiated adrenal adenoma, further immunohistochemical investigations could have been avoided. the main feature that distinguishes our clinical case is the localization at the level of the middle third of the kidney on the lateral margin which is present only in two other clinical cases (11, 31). in our case, we proposed active surveillance, given the size of the mass, however the patient chose surgery to relieve the anxiety of carrying a cancer diagnosis. we had not proposed a renal biopsy and the eau guidelines do not recommend a renal biopsy on a mass with contrast enhancement, given the high diagnostic accuracy of radiographic imaging. furthermore, biopsy is not currently a requirement for initiating active surveillance (3). in a recent systematic review, mir et al. found that less than 30% of patients included in retrospective active surveillance studies had a confirmatory biopsy (4). the diagnostic accuracy and safety of the method, previously controversial, are currently supported by a recent metaanalysis (37). in the absence of a definitive histology, active surveillance is based on initial dimensions and on its growth estimated as linear grow rate (cm/yr) but unfortunately growth is not an indicative parameter of the biology of a lesion, as even benign lesions can have a volumetric increase (4). on the contrary, a retrospective study done at columbia university showed that low growth rate lesions do not progress to metastatic disease (38). although it is a rare condition, adrenal heterotopia at the renal level presents itself as a contrast-enhancing neoplasm and therefore worthy of biopsy to avoid unnecessary surgery. certainly, in the presence of a lesion suspected of renal neoplasia, it is difficult to include within the differential diagnosis a condition with such a low incidence, but,the presence of endocrinological disorders, hypertension refractory to medical therapy can guide the differential diagnosis process. other symptoms such as abdominal pain, appear to be of lesser help in the diagnostic phase as it is linked to the localization of the neoplasm and to its size and not to a peculiar characteristic of the adrenal anomaly. the main location of the adrenal fusion is at the level of the superior pole, and adrenal rest can also be present in the retroperitoneum adjacenct to the renal pelvis. however, in some cases, such as ours, the adrenal ecotopia can also be localized at the level of the lateral margin of the kidney. this systematic review has intrinsic limitations such as the fact that it examines case series and case reports and the non-homogeneity of the cases taken into consideration. however, it underlines the main characteristics of the types of adrenal ectopic tissue in the kidney. the astute clinician should be cognizant of this condition in the evaluation of small renal masses due to its benign behavior, and its differentiation by renal cancer could require a renal biopsy because active surveillance is indicated in these patients. conclusions the increase in the incidence of small renal masses due to the diffusion of radiological imaging has led to a better understanding of the behavior of these neoformations. ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics which can clinically mimic a renal neoplasia and needs to be known in order to arrive at a correct diagnosis and carry out appropriate treatment management. references 1. ferlay j, colombet m, 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54:273-6. archivio italiano di urologia e andrologia 2021; 93, 4 d. de marchi, a. tafuri, g. mantica, et al. 488 14. goren e, engelberg is, eidelman a. adrenal rest carcinoma in hilum of kidney. urology. 1991; 38:187-90. 15. colberg jw, cai x, humphrey pa. unilateral adrenal heterotopia with renal-adrenal fusion. j urol. 1998; 160:116. 16. ayala ar, basaria s, udelsman r, et al. corticotropin-independent cushing's syndrome caused by an ectopic adrenal adenoma. j clin endocrinol metab. 2000; 85:2903-6. 17. souverijns g, peene p, keuleers h, vanbockrijck m. ectopic localisation of adrenal cortex. eur radiol. 2000; 10:1165-8. 18. fan f, pietrow p, wilson la, et al. adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. ann diagn pathol. 2004; 8:87-90 19. hsu th, kessler r. ectopic adrenal tissue as radiographic lymphadenopathy in renal cell carcinoma. int urol nephrol. 2005; 37:25-6. 20. claahsen-van der grinten hl, duthoi k, otten bj, et al. an adrenal rest tumour in the perirenal region in a patient with congenital adrenal hyperplasia due to congenital 3beta-hydroxysteroid dehydrogenase deficiency. eur j endocrinol. 2008; 159:489-91 21. linder b, hong y, jarrett t. intra-renal adrenal adenoma: a compelling addition to the differential diagnosis of renal mass. int j urol. 2009; 16:912-4. 22. mahadevia s, rozenblit a, milikow d, marinovich a. renaladrenal fusion: instance of an adrenal adenoma mimicking a solid renal mass at ct--case report. radiology. 2009; 251:808-12. 23. louiset e, gobet f, libé r, et al. acth-independent cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma. j clin endocrinol metab. 2010; 95:18-24. 24. cardinalli ia, de oliveira-filho ag, mastellaro mj, et al. a unique case of synchronous functional adrenocortical adenoma and myelolipoma within the ectopic adrenal cortex in a child with beckwithwiedemann syndrome. pathol res pract. 2012; 208:189-94 25. yokoyama h, adachi t, tsubouchi k, et al. non-functioning adrenocortical carcinoma arising in an adrenal rest: immunohistochemical study of an adult patient. tohoku j exp med. 2013; 229:267-70. 26. tong a, jia a, yan s, et al. ectopic cortisol-producing adrenocortical adenoma in the renal hilum: histopathological features and steroidogenic enzyme profile. int j clin exp pathol. 2014; 7:4415-21 27. godin k, bang n, tolkach y. case report: heterotopic intrarenally located adrenocortical oncocytoma. f1000res. 2014; 3:73. 28. boll g, rattan r, yilmaz o, tarnoff me. intraoperative identification of adrenal-renal fusion. j minim access surg. 2015; 11:205-6. 29. st clair s, machnicki s, yurovitsky a. adrenal renal fusion confusion: a case report of an adrenal cortical adenoma with adrenalrenal fusion. clin imaging. 2015; 39:695-8 30. zhao y, guo h, zhao y, shi b. secreting ectopic adrenal adenoma: a rare condition to be aware of. ann endocrinol (paris). 2018; 79:75-81. 31. lee jh, choi yd, cho nh. an intrarenal adrenocortical carcinoma arising in an adrenal rest. j pathol transl med. 2018; 52:416-419. 32. baydar d, aydin o. confusing cases: clear cell but not renal cell lesions in kidney. pathol int. 2008; 58:713-7. 33. liu y, jiang yf, wang yl, et al. ectopic adrenocortical adenoma in the renal hilum: a case report and literature review. diagn pathol. 2016; 11:40. 34. sappal s, sulek j, smith sc, hampton lj. intrarenal adrenocortical adenoma treated by robotic partial nephrectomy with adrenalectomy. j endourol case rep. 2016; 2:41-3. 35. lu d, yu n, ma x, et al. an ectopic adrenocortical adenoma in renal hilum presenting with cushing's syndrome: a case report and literature review. medicine (baltimore). 2018; 97:e13322. 36. van oostenbrugge tj, fütterer jj, mulders pfa. diagnostic imaging for solid renal tumors: a pictorial review. kidney cancer. 2018; 2:79-93. 37. marconi l, dabestani s, lam tb, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. eur urol. 2016; 69:660-673. 38. haramis g, mues ac, rosales jc, et al. natural history of renal cortical neoplasms during active surveillance with follow-up longer than 5 years. urology. 2011; 77:787-91. correspondence davide de marchi, md federico scarfò, md giovanni passaretti, md salvatore smelzo, md silvia proietti, md lorenzo rigatti, md leonardi rosario, md guido giusti, md franco gaboardi, md department of urology, san raffaele hospital, milan (italy) alessandro tafuri, md (corresponding author) tafuri.alessandro@gmail.com department of urology, university of verona, azienda ospedaliera universitaria integrata verona, piazzale stefani 1, 37126, verona (italy) guglielmo mantica, md department of urology, university of genova, ospedale san martino, genova (italy) aliasger shakir, md usc institute of urology, catherine and joseph aresty department of urology, keck school of medicine, university of southern california (usc), los angeles, ca (usa) roberta luciano, md department of pathology, san raffaele hospital, milan (italy) alessandro antonelli, md department of urology, university of verona, azienda ospedaliera universitaria integrata verona, verona (italy) vincenzo pagliarulo, md urology and andrology unit azienda ospedaliera 'vito fazzi', lecce, italy stesura seveso 319archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. remains unclear. the most recognized theory is abnormal wound healing and aberrant fibrosis following minor trauma to the erected penis (4). the association between pd and dupuytren contraction is a strong proponent of the fibrotic disease theory (5). although various types of drugs have been used to date in the acute phase of pd, there is currently no satisfactory and approved oral drug therapy. several experimental models in human cell cultures and rat models have provided new insights into the pathophysiology leading to the investigation of alternative approaches, including the phosphodiesterase type 5 inhibitors (pde5i) as an anti-fibrotic modality (6-7). pd is associated with erectile dysfunction (ed) in a percentage of patients ranging from 40 % up to 70% (3, 8). proven anti-fibrotic effect of pde5i in the experimental studies and high coexistence rate of ed with pd patients suggests that pde5i may contribute to the treatment of pd. however, very limited clinical studies were reported about this subject in the literature. we investigated whether the addition of pde-5i to combination therapy with colchicine and pentoxifylline (ptx) has any benefit on pd-related symptoms in patients with the acute phase of pd and ed. material and methods: this study was conducted according to the ethical standard laid down by the 1964 declaration of helsinki and its later amendments. medical and sexual history, physical examination, records of penile color doppler ultrasonography were retrospectively evaluated. patients with pd symptoms for no longer than 12 months and accompanied by ed were included into the study. as per our protocol, patients who were receiving any treatment for pd or ed, as well as those with psychosomatic ed, hypertension, coronary artery disease, diabetes mellitus, hormonal disorders, receiving longterm medication for any disease, alcoholism or smoke abuse were excluded. to rule out organic sexual dysfunctions and other underlying diseases, serum fasting blood glucose level, sex hormones and prolactin levels were also evaluated. in this retrospective and non-randomized clinical study, 6-year medical records of 636 patients who were treated for the acute phase of pd in our institute were revaluated. the review also elucidated that 186 of these patients were included into the study. patients were divided into two groups as group 1, who received ptx (400 mg, twice daily)-colchicine (0.5 mg, plus oral daily 50 mg sildenafil (n=107) and as group 2 received ptx objectives: the aim of this study was to investigate the impact of the addition of 50 mg daily sildenafil to pentoxifylline-colchicine combination therapy on the peyronie's plaque features in patients with the acute phase of peyronie's disease (pd). methods: in this retrospective and non-randomized clinical study, patients were divided into 2 groups as group 1; (n = 107) who received colchicine and pentoxyfillin plus 50 mg daily oral sildenafil, and as group 2; (n = 79) who received only colchicine and pentoxyfillin. patients were compared in terms of degree of curvature, pain in erection and erectile function at the baseline and at 6-month follow up. pain in erection and erectile function were evaluated by visual analogue scale (ef-vas), and the shortened version of the international index of erectile function (iief-5). improvement in the degree of curvature and change in ef-vas scores were primary endpoints of the study. change in iief-5 score was the secondary endpoint of the study. results: the two groups were statistically similar in terms of demographics and baseline features of pd. a statistically significant reduction in degree of curvature and ef-vas scores was shown in group 1 compared to group 2.there was also a significantly higher iief-5 score in group 1 compared to group 2. no significant side effects were detected in both groups during treatment period. conclusions: adding sildenafil to pentoxifylline-colchicine combination treatment seems to improve pd related symptoms in the acute phase pd. pde5i may contribute to relieve the peyronie's symptoms in ed patients through their antifibrotic effects. key words: peyronie; oral treatment; fibrosis; antifibrotic treatment. submitted 29 june 2022; accepted 2 july 2022 introduction peyronie’s disease (pd) is a fibrotic disorder of tunica albuginea with the formation of penile plaque. pd is a relatively common disorder, with an estimated prevalence of 1.5% in men between 30 and 40 years old and as high as 6.5% in older men (1). pd is characterized by progressive deformity and unstable plaque with painful erection in the acute phase;stabilization of the penile plaque and penile curvature are the major findings of the chronic phase which may require at least 6 months and up to 18 months (2-3). the exact etiology of plaque formation effects of long term sildenafil on the acute phase of peyronie’s disease in a combination treatment murat topcuoglu 1, murat çakan 2 1 department of urology, alaaddin keykubat university alanya training and research hospital, antalya, turkey; 2 department of urology, dışkapı yıldırım beyazıt training and research hospital, ankara, turkey. doi: 10.4081/aiua.2022.3.319 summary archivio italiano di urologia e andrologia 2022; 94, 3 m. topcuoglu, m. çakan 320 (400 mg, twice daily)-colchicine (0.5 mg, twice daily) (n=79) and who were reluctant to use of sildenafil or unable to purchase sildenafil due to financial reasons. patients with plaque calcification detected on penile ultrasonography were also excluded from the study. plaque calcification has been identified as a sign of chronic phase and potential poor predictor of response to treatment (9). disease duration, erectile pain, erectile function, and penile curvature were assessed at the baseline assessment. penile curvature was measured according to the kelami’s criteria with a goniometer by the same operator following artificial erection stimulated by intracavernosal vasoactive agent. the severity of erectile pain was assessed by erectile function visual analogue scale (efvas) score on a scale of 0-10, with 0 being no pain and 10 being severe pain. erectile function was evaluated through the shortened version of the international index of erectile function (iief-5) questionnaire. each question is scored on a scale of 1 to 5 and 5 is indicating best function. the collected database of baseline and outcomes at sixth month of treatment in both groups were compared in terms of penile curvature, ef-vas, and iief-5 scores. the primary endpoints of the study were the improvement in curvature and change in ef-vas scores. change in iief-5 score was the secondary endpoint of the study. statistical analysis mean, standard deviation, median lowest, median highest, frequency and ratio values were used in descriptive statistics of the data. the distribution of the variables was measured with the kolmogorov-smirnov test. the mannwhitney test was used to analyze quantitative independent data. chi-square test was used for the analysis of qualitative independent data and fisher test was used when the chi-square test conditions were not met. spss 22.0 program was used in the analysis. p value less than 0.05 was considered as statistically significant. results our retrospective review revealed that 636 patients with acute phase of pd were treated at our center during the study period. as per our protocol, 186 of 636 patients were enrolled in our study. the baseline characteristics of these patients are displayed in table 1. mean age was 56.1± 10.2 in group 1 and 53.54 ± 13.4 in group 2. there was no statistical difference between the groups in terms of demographics and pd characteristics at the baseline period. the mean duration of pd symptoms was 9.2 ± 2.1 months in group 1 and 8.9 ± 2.0 month in group 2 (no statistically significant difference between the groups). change in mean degree of curvature angle was 11.02 ± 2.3º and 6.6 ± 1.7º group 1 and group 2, respectively. although a significant difference in mean degree of curvature was shown in group 1 at the sixth month of the treatment compared to baseline, no significant change in mean degree of curvature was revealed in group 2 after the treatment period. ef-vas showed a significant reduction in both groups, with a statistically higher reduction in group 1 patients compared to group 2 patients (table 2). at sixth month treatment follow up, 68 of 107 patients (64%) in group 1 stated completely relief in pain during erection, while completely relief in pain was described by 37 of 79 patients (47%) in group 2. mean iief-5 scores increased from 12.78 ± 6.46 to 17.89 ± 82 in group 1 and from 11.86 ± 6.21 to 13.02 ± 6.78 in group 2 at the postoperative period. compared with the baseline values, the mean iief-5 scores in group 1 were significantly different at sixth month treatment follow up, while no significant changes were found in group 2 (table 2). no clinically significant side effects were observed in any patients in both groups. discussion our study investigated the addition of pde5i to conventional combined oral therapy in acute-phase pd and found that adding a pde5i to the conventional treatment of pd patients may be worthwhile, in the improvement of degree of curvature and erectile pain. the acute phase is characterized by painful erections, soft plaques, while the chronic phase is characterized by fibrotic/calcified plaque and stable disease. although spontaneous remission is reported in 3-13% of pd cases, the disease stabilizes or worsens in majority of the cases (10). to date, various oral medications have been used in the acute phase, including potassium aminobenzoate, colchicine, ptx, vitamin e, tamoxifen, orgotein, and carnitine acetyl ester table 1. mean baseline clinical characteristics of the patients. group 1 (n = 107) group 2 (n = 79) p age 56.1 ± 10.2 53.54 ± 13.4 0.456 duration of symptoms (months) 9.2 ± 2.1 8.9 ± 2.0 0.836 erectile function visual analog scale (ef-vas) score 6.89 ± 3.02 6.14 ± 2.78 0.642 degree of curvature (º) 35.1 ± 16.3 36.6 ± 17.8 0.696 iief-5 score 13.78 ± 6.46 14.10 ± 6.77 0.976 table 2. comparison of the groups at pre-treatment and post-treatment evaluation regarding peyronie plaque characteristics and iief-5 questionnaire. group 1 group 2 post-treatment comparison (n = 107) (n = 79) between the group 1 and group 2 pre-treatment post-treatment p pre-treatment post-treatment p p degree of curvature (º) 35.1 ± 16.3 24.08 ± 11.2 0.045 36.6 ± 17.8 30.0 ± 14.3 0.067 0.022 erectile function visual analog scale (ef-vas) score 6.89 ± 3.02 3.89 ± 1.06 0.024 6.14 ± 2.78 4.7 ± 1.78 0.039 0.038 iief-5 score 12.78 ± 6.46 17.89 ± 82 0.021 11.86 ± 6.34 13.02 ± 6.78 0.123 0.006 321archivio italiano di urologia e andrologia 2022; 94, 3 effects of sildenafil on peyronie’s disease (11). the clinical benefits of oral agents such as potassium aminobenzoate, ptx, colchicine, and coenzyme q10 have been reported in different studies and are considered as a part of single or multimodal therapy for clinical use, but no single oral pharmacotherapy has been approved for treatment by american urological association (aua) or european urological association (eau) (12, 13). ptx-colchicine combination is a preferred treatment alternative for pd patients in our clinic, which is associated with low side effect, low price, and proven success rates from previous studies. 10 ptx is an oral drug that works through mechanism that increase collagen metabolism, downregulate tgf-beta, and reduce fibrogenesis and has been used clinically in a variety of inflammatory and fibrotic conditions, such as radiation fibrosis, radiation proctitis, cystic fibrosis, radiation pneumonitis (14, 15). significant improvements in degree of curvature, plaque volume, pain intensity, and penile rigidity after ptx treatment support the effectiveness of the treatment in pd patients (16, 17). colchicine, a commonly used oral therapy, can significantly improve pain relief and penile curvature as monotherapy or in combination therapy (18). colchicine binds to tubulin, blocks mitosis, reduces inflammation and procollagen formation, and increases collagenase production. colchicine therapy appears to have conflicting results, and most studies show colchicine success in 30% to 50% of pd patients (18-19). although various oral treatments are effective in pd patients, the lack of consensus on oral treatment increases the trend towards alternative treatments. we assessed the effect of supplementation with 50 mg of sildenafil on the conventional therapy of pd. the use of pde5i in pd patients is supported by the fact that almost all pd patients suffer from ed and the proven effects of pde5i on both pathologies. several in vitro studies have shown that pde5i has a potential anti-fibrotic effect against peyronie's-like plaque (6-20). no and cyclic guanosine 3’,5’-monophosphate (cgmp) have anti-fibrotic actions with remarkable effects on collagen synthesis and myofibroblast differentiation. pde-5i shows anti-fibrotic effects by reducing collagen deposits and oxidative stress, inhibiting myofibroblast proliferation and profibrotic factor secretion (3). transforming growth factor b1 (tgfb1) is a key profibrotic factor, found in many tissues and demonstrated in human pd plaques, that was also shown at high levels in the serum of pd patients (21). following inhibition of pde-5, elevated levels of cgmp and camp activate protein kinase g, which play important role in the apoptosis and reduced collagen synthesis. the mentioned anti-fibrotic effects are also mediated by guanylate cyclase inducers by stimulating protein kinase g and inhibiting fibrotic mediators such as angiotensin 2 or activating tgf-b and rho activation (22, 23). an experimental study showed that sildenafil and oral ptx, a major pde4 inhibitor that increases camp synthesis, inhibited the development of pd-like plaques (24). previous studies have shown a strong relationship between ed and pd, ranging from 20% to 70% (3, 8, 25) çakan et al. indicated that one of the most common (68.5%) presenting symptom in pd is ed (26). ed may be the result of pd, or the two diseases may share common pathophysiological features. the possible mechanisms of development ed in pd include avoiding coitus due to performance anxiety, penile pain, difficulty in penetration and vascular insufficiency. although there are many well-designed experimental studies and animal models regarding the anti-fibrotic effects of pde5i, clinical trials investigating the effects pde5i as monotherapy or in a combination treatment are limited. in a retrospective study of patients with isolated septal scarring and no evidence of penile deformity, septal scarring was significantly regressed in the tadalafil group compared with control group (27). ozturk et al. investigated the effect of daily 50 mg of sildenafil on peyronie's plaque and observed a statistically significant reduction in pain, whereas there was no significant difference in penile curvature between the two groups (28). subjective and objective improvements in the characteristics of pd receiving daily doses of tadalafil were also reported by vernet et al. (20) it was shown that the addition of 25 mg sildenafil to collagenase histolyticum (cch) was superior to cch monotherapy in improving penile curvature (10). in contrast, palmieri et al. reported similar outcomes in tadafil-eswt group compared to eswt group (29). our study showed a significant improvement in degree of curvature and significant reduction in ef-vas score in the sildenafil received group, compared to the conventional treatment group. changes in degree of curvature and pain status were considered as the primary endpoints of the study. as expected, an improvement in the iief-5 score, a secondary endpoint of the study, was found to be more pronounced in the sildenafil-treated group. at this point, we did not evaluate the change in plaque size as a criterion for treatment success. some investigators have suggested that the evaluation of plaque size using any type of imaging is unnecessary, as these measurements are often inaccurate and changes in plaque size after treatment are not associated with changes in overall deformity and do not directly indicate treatment success (30). treatment of pd mainly depends on the severity of curvature and the degree of ed (12, 13). in addition peyronie’s plaque is not well formed in acute phase of the disease and possible spontaneous remission in plaque size can be expected in the acute phase. our study has some limitations which need to be considered while evaluating its findings. first, it is a retrospective, non-randomized study that can be affected by all potential weaknesses stemming from its retrospective design and six months of follow-up period of to evaluate the treatment outcomes is relatively short for this chronic disease. conclusions to our knowledge, this is the first clinical study in the relevant literature investigating the effect of pde5i in an oral combination therapy in pd patients. we showed that adding daily sildenafil 50 mg to colchicine and ptx combination treatment improves the pd’s related symptoms of patients in the acute phase of pd. considering the proven antifibrotic efficacy of pde5i, they may contribute to relieving peyronie's symptoms in patients with ed. further multicenter prospective studies with larger number of cases are needed to obtain more precise results. archivio italiano di urologia e andrologia 2022; 94, 3 m. topcuoglu, m. çakan 322 references 1. tunuguntla. hs. management of peyronie's disease a review. world j urol. 2001; 19:244-250. 2. kadioglu a, tefekli a, erol b, et al. retrospective review of 307 men with peyronie’s disease. j urol. 2002; 168:1075. 3. schwarzer u, sommer f, klotz t, et al. the prevalence of peyronie's disease: results of a large survey. bju int. 2001; 88:727-30. 4. bilgutay an, pastuszak aw. peyronıe's disease: a review of etiology, diagnosis, and management. curr sex health rep. 2015; 7:117131. 5. chung e, ralph d, kadioglu a, et al. evidence-based management guidelines on peyronie's disease. j sex med. 2016; 13:905-923. 6. 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surgical therapy. j androl 2000; 21:347-354. 12. hatzimouratidis k, eardley i, giuliano f, et al. eau guidelines on penile curvature. eur urol. 2012; 62:543-52. 13. nehra a, alterowitz r, culkin dj, et al. peyronie’s disease: aua guideline. j urol. 2015; 194:745-753. 14. chiao tb, lee aj. role of pentoxifylline and vitamin e in attenuation of radiation-induced fibrosis. ann pharmacother. 2005; 39:516-522. 15. safarinejad mr, asgari ma, hosseini sy, farid d. a double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic peyronie’s disease. bju int. 2009; 106:240-248. 16. alizadeh m, karimi f, fallah mr. evaluation of verapamil efficacy in peyronie's disease comparing with pentoxifylline. glob j health sci. 2014; 6(7 spec no):23-30. 17. brant wo, dean rc, lue tf. treatment of peyronie's disease with oral pentoxifylline. nat clin pract urol. 2006; 3:111-5. 18. prieto castro rm, leva vallejo me, regueiro lopez jc, et al. combined treatment with vitamin e and colchicine in the early stages of peyronie's disease. bju int. 2003; 91:522-4. 19. akkus e, breza j, carrier s, et al. is colchicine effective in peyronie’s disease? a pilot study. urology. 1994; 44:291-295. 20. vernet d, magee t, qian a, et al. phosphodiesterase type 5 is not upregulated by tadalafil in cultures of human penile cells. j sex med. 2006; 3:84-94. 21. el-sakka ai, hassoba hm, pillarisetty rj, et al. peyronie’s disease is associated with an increase in transforming growth factorbeta protein expression. j urol. 1997; 158:1391-1394. 22. dunkern tr, feurstein d, rossi ga, et al. inhibition of tgf-b induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. eur j pharmacol. 2007; 572:12-22. 23. wang-rosenke y, neumayer hh, peters h. no signaling through cgmp in renal tissue fibrosis and beyond: key pathway and novel therapeutic target. curr med chem. 2008; 15:1396-1406. 24. valente eg, vernet d, ferrini mg, et al. l-arginine and phosphodiesterase (pde) inhibitors counteract fibrosis in the peyronie's fibrotic plaque and related fibroblast cultures. nitric oxide. 2003; 9:229-44. 25. gholami ss, gonzalez-cadavid nf, lin cs, et al. peyronie’s disease: a review. j urol. 2003; 169:1234. 26. cakan m, akman t, oktar t, et al. the clinical characteristics of peyronie's patients with notching deformity. j sex med. 2007; 4:1174-1178. 27. chung e, deyoung l, brock gb. the role of pde5 inhibitors in penile septal scar modeling: assessment of clinical and radiological outcomes. j sex med. 2011; 8:1472-7. 28. ozturk u, yesil s, goktug hn, et al. effects of sildenafil treatment on patients with peyronie's disease and erectile dysfunction. ir j med sci. 2014; 183:449-53. 29. palmieri a, imbimbo c, creta m, et al. tadalafil once daily and extracorporeal shock wave therapy in the management of patients with peyronie’s disease and erectile dysfunction: results from a prospective randomized trial. int j androl. 2012; 35:190-195. 30. levine la, greenfield jm. establishing a standardized evaluation of the man with peyronie’s disease. int j impot res. 2003; 15:s103-s112. correspondence murat topcuoğlu, md muraturo@yahoo.com assistant professor, department of urology, alaaddin keykubat university, antalya (turkey) murat çakan, md muratcakandr@yahoo.com department of urology, dışkapı yıldırım beyazıt training and research hospital, ankara (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11533 1 original paper introduction although uncommon, primary sarcoma of the urinary bladder (sub) is an aggressive type of bladder cancer (bca), accounting for less than 1% of all bca. the most common risk factors for the development of this disease is smoking and previous exposure to radiotherapy (rt) and cyclophosphamide (1, 2). based on mesenchymal and epithelial components, sub can be classified as sarcomatoid carcinoma (sc) and carcinosarcoma (cs), both considered malignant biphasic tumors (mbt) by the world health organization having malignant epithelial and mesenchymal elements (3). more recently researchers have cast doubts on the significance of distinguishing between these two entities in both bladder and other solid malignancy as they consider these two histological subtypes as separate moments between epithelial (sarcomatoid carcinoma) and mesenchymal differentiation (carcinosarcoma) (4). usually, the epithelial element contains high-grade transitional-cell carcinoma with some epidermoid and/or glandular differentiation, while the heterologous element contains chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or rhabdomyosarcoma. both sc and cs cases are most common among older men, manifesting as fastgrowing, advanced-stage polypoid tumors (1-4). when the mesenchymal element lacks epithelial components, sub can be considered a true heterologous sarcoma (ts). usually, treatment of sub has been deduced from the management of urothelial carcinoma (uc) of the bladder. muscle-invasive uc of the bladder often results in distant metastasis after radical cystectomy, and therefore, neoadjuvant or adjuvant chemotherapy has been recommended as a part of a multimodal approach (5, 6). however, because of to the rarity of sub and the absence of randomized controlled trial in this setting, definitive conclusions about the optimal treatment option cannot be made. poor outcomes have been reported in patients with sub, whatever the treatment used. even after adjustpurpose or objective: primary sarcoma of the urinary bladder (sub) is a rare but aggressive form of bladder cancer (bca). available evidence on sub is limited to case reports and small series. the aim of the present multi-institutional study was to assess the clinical features, treatments, and outcomes of patients with sub. materials and methods: using a standardized database, 7 institutions retrospectively collected the demographics, risk factors, clinical presentation, treatment modalities and follow-up data on patients with sub between january 1994 and september 2021. the main inclusion criteria included bca with soft tissue tumor histology and sarcomatoid differentiation. results: fifty-three patients (38 men and 15 women) were identified. median follow-up was 18 months (range 1-263 months). median age at presentation was 69 years (range 16-89 years). twenty-six percent of patients had a prior history of pelvic radiotherapy (rt), and 37% were previous smokers. the main presenting symptoms at diagnosis were hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). american joint committee on cancer (ajcc) 8 th edition stage ii, iii and iv at diagnosis were 21%, 63% and 16%, respectively. treatment modalities included surgery alone (45%), surgery plus neoor adjuvant-chemotherapy (17%), surgery plus neoor adjuvant-rt (11%), rt with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant rt (2%) and palliative treatment (21%). rates of local and distant recurrences were 49% and 37%, respectively. five-year overall survival and progression-free survival (pfs) were 66.5% and 37.6%, respectively. no statistically significant differences in pfs between the treatment modalities were observed. conclusions: primary sub is a heterogeneous disease group, commonly presenting at advanced stages and exhibiting aggressive disease evolution. in contrast to urothelial carcinoma, the primary pattern of recurrence of sub is local, suggesting the need for multimodal approaches. continuous international collaborative efforts seem warranted to provide guidance on how to best tailor treatments based on sub-specific indices. key words: primary sarcoma of the urinary bladder (sub); bladder cancer. submitted 19 june 2023; accepted 1 july 2023 primary bladder sarcoma: a multi-institutional experience from the rare cancer network piero bettoli 1, 2, zhihuiamy liu 3, natalia jara 4, federico bakal 1, william wong 5, mario terlizzi 6, paul sargos 6, thomas zilli 7, juliette thariat 8, sebastian sole 4, 9, guillaume ploussard 10, sharad goyal 11, peter chung 3, alejandro berlin 3, claudio v. sole 4, 9 1 department of radiation oncology, fundación arturo lópez pérez, santiago, chile; 2 facultad de medicina, universidad de los andes, santiago, chile; 3 radiation medicine program, princess margaret cancer centre, university health network, university of toronto, toronto, on, canada; 4 department of radiation oncology, instituto de radiomedicina, santiago, chile; 5 department of radiation oncology, mayo clinic arizona, phoenix, usa; 6 department of radiation oncology, institute bergonie, bordeaux, france; 7 department of radiation oncology, geneva university hospital, geneva, switzerland; 8 department of radiation therapy, centre francoise baclese, caen, france; 9 facultad de medicina, universidad diego portales, santiago, chile; 10 department of urology, la croix du sud hospital, toulouse, france; 11 department of radiation oncology, george washington university hospital, washington dc, usa. doi: 10.4081/aiua.2023.11533 summary archivio italiano di urologia e andrologia 2023; 95(3):11533 p. bettoli, z. liu, n. jara, et al. 2 ing for tumor stage, overall survival (os) rates for sub vs high-grade, pure uc are 54% vs 77% at 1 year and 37% vs 47% at 5 years, respectively (4, 7). published data on sub only consist of case reports and limited case series. not much is understood of sub biology and behavior and its rarity does not permit to design specific treatment guidelines. thus, we intend to summarize the current multi-institutional knowledge of sub and present an overview of the epidemiology, clinical features, and management of this uncommon type of bca that can help clinicians to better tailor clinical decisions on this rare disease. methods data on sub from january 1994 to september 2021 from 7 institutions were retrospectively collected. international review board (irb) approval based on each country/institution was obtained for retrospective review of data. we only collected data from localized primary bladder tumors with soft tissue tumor histology, including sc, cs and ts. the data obtained included age, gender, country and institution, symptoms at the time of diagnosis, risk factors (smoking and rt exposure), tumor size, tumor location, margins and nodal status. sarcoma subtype, grade and specific immuno-histochemical markers of these tumors were noted. staging at the time of pathological diagnosis was based on the tnm (tumor, lymph node, metastasis) classification for genitourinary tumors. treatment modalities analyzed included cystectomy (radical, partial, other), rt (definitive, adjuvant, neo-adjuvant or palliative) and chemotherapy (neo-adjuvant, adjuvant, radio-sensitizer or palliative). overall survival (os), cancer-specific survival (css), disease-free survival (dfs), distant metastases (dm) and local control (lc) were calculated from diagnosis to the date of any specific event or the date of last follow-up in case an event did not occur. probabilities for os, css and dfs were determined by kaplan-meier estimates. local recurrence (lr) and dm were estimated using cumulative incidence function considering death as a competing risk. selective comparisons of survival curves were calculated by the log-rank test. multivariate models were not used because of the small number of patients and events. for statistical analyses the software program stata (version 13; college station, texas, usa) was used. results fifty-three patients were evaluated, 38 men (72%) and 15 women (28%), who had a median age at presentation of 69 years (range 16-89 years). twenty-six percent of patients had a prior history of pelvic rt; contrary to patients with transitional cell carcinoma, only 37% of patients had a history of tobacco use. symptoms at diagnosis were mainly hematuria (52%), pelvic pain (27%), and both hematuria and pelvic pain (10%). median tumor size was 4.5 cm (range 1.5-9.5 cm). extravesical spread (t3/t4) was the most common presentation of the primary tumor in 59% of cases. nodal metastases were identified in 35% of patients. ajcc 8th edition stage ii, iii and iv at diagnosis were 21%, 63% and 16%, respectively. the majority of tumors presented with high grade histology (88%). distribution of ts and mbt were 43% and 57%, respectively. leiomyosarcoma was the most common histology in the ts group (63%), followed by angiosarcoma (13%), pleomorphic undifferentiated sarcoma (10%), rhabdomyosarcoma (7%), chondrosarcoma of soft tissue (3%) and leiomyoma (3%). table 1 presents patient and tumor characteristics. seventy-three percent of patients underwent radical or partial cystectomy. specifically, treatment modalities included surgery alone (45%), surgery preceded or followed by either chemotherapy (17%) or radiotherapy (11%), definitive radiotherapy with concurrent chemotherapy (4%), neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy (2%) and palliative treatment (21%). treatment modalities are outlined in table 2. table 1. patient and tumor characteristics. patients characteristics n (%) age mean 69 gender male 38 (72) female 15 (28) prior history of rt 14 (26) tobacco exposure 20 (37) symptoms hematuria 28 (52) pelvic pain 14 (27) both 5 (10) other 6 (11) tumor size (median) 4.5 cm (1.5 -9.5) t stage t1/t2 22 (41) t3/t4 31 (59) nodal metastases 19 (35) ajcc ii 11 (21) iii 33 (63) iv 9 (16) malignant biphasic tumors (mbt) 23 (43) true sarcoma (ts) 31 (57) leiomyosarcoma 19 (61) angiosarcoma 7 (22) pleomorphic undifferentiated sarcoma 2 (7) rhabdomyosarcoma 2 (7) chondrosarcoma 1 (3) table 2. treatment modalities. treatment modalities n (%) surgery alone 24 (45) surgery plus neo-adjuvant or adjuvant chemotherapy 9 (17) surgery plus neo-adjuvant or adjuvant radiotherapy 6 (11) definitive radiotherapy with concurrent chemotherapy 2 (4) neo-adjuvant chemotherapy plus surgery plus adjuvant radiotherapy 1 (2) palliative 11 (21) archivio italiano di urologia e andrologia 2023; 95(3):11533 3 primary bladder sarcoma median follow-up was 18 months (range 1-263 months). local recurrence (lr) occurred in 49% of patients and distant metastases (dm) were present in 37%. five-year os and pfs were 66.5% and 37.6%, respectively. kaplanmeier curves for os and pfs and the cumulative incidence for lr and dm are shown in figures 1, 2, 3 and 4 respectively. when outcomes in subgroups were examined, a more advanced tumor stage (t2 vs t3/t4) correlated to shorter pfs (median pfs for t2-category was not reached and for t3/t4 was 8.4 months; p = 0.059). prior history of pelvic radiotherapy also related to lower pfs (7 vs 31 months, p = 0.0018) and os (9 vs 43 months, p = 0.0007). we found no statistically significant differences in pfs between treatment modalities or between the presence vs absence of epithelial components (ts and mbt). discussion although the occurrence of rare cancers in the general public is a serious health issue as a whole, acquiring statistically-reliable clinical trial data is difficult due to the low number of patients with an individual rare cancer type within specific areas (8). since most available literature on rare cancers is published as single-institution case reports, it is arduous to draw prognostic implications from these data; furthermore the impact of local practices on treatment outcomes is amplified when dealing with rare diseases. patients with rare neoplasm show significantly poorer results than patients with more common malignancies; mean 5-year survival for the former is up to 20% lower than for the latter (9). this is the case with primary sub, a disease comprising less than 1% of all bca, which poses a challenge in the treatment of this uncommon histological variant. poor outcomes have been reported in patients with sub, whatever the treatment used. the five-year overall survival (os) rate of the present cohort is 66.5%, which exceeds the findings of previous studies where survival rates at five years were consistently below 50% (4, 10, 11). this difference in outcomes can be attributed, at least partially, to two key factors within the study. firstly, this cohort predominantly consisted of a younger population, with a median age at presentation of 69 years, which is lower than other reports (4). younger patients have generally been associated with better treatment tolerance, higher overall fitness levels, and potentially more favorable disease characteristics, all of which could contribute to improved survival rates. secondly, the analysis encompassed both malignant biphasic tumors (cs and sc) and true heterologous sarcomas (ts). by including both types of tumors, we accounted for the inherent biological diverfigure 1. os 5-year rate 66.5% (53.3-83) figure 2. pfs 5-year rate: 37.6% (25.8-54.7). figure 3. lr 5-year rate: 49% (34-64). figure 4. dm 5-year rate: 36.9% (21.4-52.4). archivio italiano di urologia e andrologia 2023; 95(3):11533 p. bettoli, z. liu, n. jara, et al. 4 sity, variable clinical behavior of both entities and perhaps different outcomes. twenty-six percent of the patients of the cohort have a previous history of pelvic radiation therapy (rt), observing inferior outcomes in this subgroup compared to those without prior rt (median os of 9 vs. 43 months, p = 0.0007). is well known that radiation-induced sarcomas pose treatment challenges as they arise in areas with complications from previous treatments, making surgical removal difficult. retrospective analyses have shown poor prognosis in these patients compared to sporadic soft-tissue sarcomas, with 5-year os rates ranging between 32% and 45% (12) which are in line with the findings of this study. continuing with subgroup analyses, patients with extravesical spread (t3/t4) exhibit notable decreases in progression-free survival (pfs) compare to those with less advanced tumors (median pfs for t2-category was not reached and for t3/t4 was 8.4 months). the reduced pfs observed in this particular subgroup of patients (t3/t4) can be attributed to the higher likelihood of developing distant metastases, but also because of the complex relationship between advanced tumor stage and critical anatomical structures, resulting in a potentially decreased effectiveness of local treatment. data from pelvic sarcomas exemplify this last phenomenon, with successful attainment of a microscopically margin-negative resection (r0) surgery achieved only in 70% of cases (13). contrary to uc, where distant recurrence is the primary pattern, this study reveals that rates of local and distant recurrences observed were 49% and 37%, respectively. these findings hold significant implications, particularly considering that approximately 60% of patients in this cohort exhibit extra-vesical spread (t3/t4). the high rates of local failures observed emphasize the critical need for optimizing local therapies, particularly within the latter sub-group. typically, the treatment approach for sub has been extrapolated from the management of uc of the bladder, where cystectomy and chemotherapy are considered fundamental in a multimodality approach (5, 6). retroperitoneal sarcomas (rps) exhibit a behavioral pattern that aligns more closely with the presents findings, showing a higher incidence of local recurrence, which remains the primary cause of mortality (14). within this context, local recurrence and metastatic disease occur in approximately 50-60% and 20% of cases, respectively (15), mirroring the failure pattern observed in this study. the importance of local control drives management of rps, with surgery been the mainstay of curative intent therapy (16). complete gross resection (r0 or r1) has been associated with improved disease-free survival (17). however, even with a histologically negative margin (r0), local recurrence can still occur (18). considering the high incidence of local recurrences following surgery, neoadjuvant radiotherapy has emerged as an attractive yet controversial option for rps (19, 20). despite the retrospective nature of this study, and therefore hampered by its intrinsic biases, the high local failure rates seen in this cohort prompts the hypothesis that neoadjuvant radiotherapy as part of a multi-disciplinary approach for sub may play an important role in reducing loco-regional failure rate and improving, at least to some extent, the survival of this patients, especially in higher tumor stages (t3/t4) where r0 surgery with wide margins is more difficult to obtain and were poorer outcomes we have observed. although the existing evidence is limited, our retrospective data can provide valuable insights into this uncommon neoplasm, enabling clinicians to make more informed clinical decisions tailored to this rare disease. conclusions primary sub is a heterogeneous disease group, commonly presenting at advanced stages and exhibiting aggressive disease evolution. in contrast to uc, the primary pattern of recurrence of sub is local, suggesting the need for multimodal approaches. continuous international collaborative efforts seem warranted to provide guidance on how to best tailor treatments based on sub-specific indices. references 1. lopez-beltran a, pacelli a, rothenberg hj. carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. j urol. 1998; 159:1497-1503. 2. mukhopadhyay s, shrimpton ae, jones la. carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss. arch pathol lab med. 2004; 128:e8-e11. 3. wick mr, swanson pe. carcinosarcomas: current perspectives and an historical review of nosological concepts. semin diagn pathol. 1993; 10:118. 4. wright jl, black pc, brown ga, et al. differences in survival among patients with sarcomatoid carcinoma, carcinosarcoma, and urothelial carcinoma of the bladder. j urol. 2007; 178:2302-2307. 5. eau (european association of urology). guidelines on muscleinvasive and metastatic bladder cancer. 2021 edition. available at: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-andmetastatic/. 6. nccn (national comprehensive cancer network). bladder cancer. nccn clinical practice guidelines in oncology. available at: https://www.nccn.org/professionals/physician_gls/default.aspx#bladder. 7. lobo n, et al. what is the significance of variant histology in urothelial carcinoma? eur urol focus. 2020 jul 15; 6:653-663. 8. blay jy, coindre jm, ducimetière f, ray-coquard i. rare cancers: the value of research collaborations and consortia in rare cancers. lancet oncol. 2016; 17:e62. 9. desantis ce, kramer jl, jemal a. the burden of rare cancers in the united states. ca cancer j clin. 2017; 67:261-72. 10. zieschang h, koch r, wirth m, froehner m. leiomyosarcoma of the urinary bladder in adult patients: a systematic review of the literature and meta-analysis. urolint. 2019; 102:96-101. 11. li s. development and validation of a prognostic nomogram for predicting overall survival in patients with primary bladder sarcoma: a seer-based retrospective study. bmc urol. 2021; 21:162. 12. callesen lb, et al. radiation-induced sarcoma: a retrospective population-based study over 34 years in a single institution. clin oncol. 2021; 33:e232-e238. 13. lee js. management of pelvic sarcoma. eur j surg oncol. 2022; 48:2299-2307. archivio italiano di urologia e andrologia 2023; 95(3):11533 5 primary bladder sarcoma 14. brennan mf, antonescu cr, moraco n, singer s. lessons learned from the study of 10,000 patients with soft tissue sarcoma. ann surg. 2014; 260:416-21. 15. chouliaras k, senehi r, ethun cg, et al. recurrence patterns after resection of retroperitoneal sarcomas: an eight-institution study from the us sarcoma collaborative. j surg oncol. 2019; 120:340-7. 16. trans-atlantic rpswg. management of primary retroperitoneal sarcoma (rps) in the adult: a consensus approach from the transatlantic rps working group. ann surg oncol. 2015; 22:256-63. 17. singer s, antonescu cr, riedel e, brennan mf. histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. ann surg. 2003; 238:358-70, discussion 370-351. 18. stojadinovic a, leung dh, hoos a, jaques dp, lewis jj, brennan mf. analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas. ann surg. 2002; 235:424-34. 19. molina g, hull ma, chen yl, et al. preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma. j surg oncol. 2016; 114:814-20. 20. bonvalot s, gronchi a, le pechoux c, et al. preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (eortc-62092: strass): a multicentre, open-label, randomised, phase 3 trial. lancet oncol 2020; 21:1366-77. conference presentation bettoli p, liu za, jara n, et al. primary bladder sarcoma: a multi-institutional experience from the rare cancer network presentation number: po-1219: european society for radiotherapy and oncology (estro) congress; july 31 9facultad de medicina, universidad diego portales, santiago, chile. august 04, 2020; vienna, austria. correspondence piero bettoli, md (corresponding author) piero.bettoli@falp.org postal address 7591067 federico bakal, md federico.bakal@falp.org fundación arturo lópez pérez, santiago, chile zhihuiamy liu, md zhihuiamy.liu@uhn.ca peter chung, md peter.chung@rmp.uhn.ca alejandro berlin, md alejandro.berlin@rmp.uhn.ca princess margaret hospital, radiation oncology, toronto, canada natalia jara, md njarao@gmail.com sebastian sole, md sebasole@gmail.com claudio sole, md claudio.solep@iram.cl clinica instituto de radiomedicina (iram), santiago, chile facultad de medicina, universidad diego portales, santiago, chile william wong, md wong.william@mayo.edu mayo clinic arizona, radiation oncology, phoenix, usa mario terlizzi, md terlizzimario@yahoo.fr paul sargos, md p.sargos@bordeaux.unicancer.fr institute bergonie, radiation oncology, bordeaux, france thomas zilli, md thomas.zilli@hcuge.ch hospitaux universiaires de geneve, radiation oncology, geneve, switzerland juliette thariat, md jthariat@gmail.com centre francoise baclese, radiation oncology, caen, france guilaume ploussard, md g.ploussard@gmail.com la croix du sud hospital, urology department, quint fonsergrives, france sharad goyal, md shgoyal@mfa.gwu.edu george washington university hospital, radiation oncology, washington dc, usa conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 108 original paper muscle training is the most recommended treatment method, especially for stage 1 stress urinary incontinence (4). thus, pelvic floor muscle training (pfmt) has been recognized as the first-line therapy for urinary incontinence (5). women with the symptom of stress and mixed urinary incontinence who had the treatment of pfmt showed improvement in their symptoms of ui (4). the rationale for doing pfmt is to maximize the urethral pressure and improve the voluntary contraction of the muscle by improving pelvic floor muscle strength (6). in malaysia, the prevalence of ui among women was 17.3% while for antenatal cases it was 34.3% during their third trimester (3). however, compared with turkey, the prevalence of ui among pregnant women was high, with almost 80% with stress urinary incontinence (7). a study among antenatal women in kelantan showed women had a low level of knowledge regarding pfmt with only 5.8% doing pfmt (8). the result showed that the women knew the information regarding pfmt (9). whereas another finding in selangor stated that 46.6% of pregnant women had a good attitude towards pfmt (10). there is no standardized measurement tool that can be used to discern the type, severity, or bother attributed to ui at one time. in government hospitals and clinics throughout malaysia, a variety of forms of ui screening were identified. presently, to identify all the symptoms, women had to complete multiple questionnaires in one setting, and the healthcare professionals then had to determine how to interpret and assimilate the results of these different measures. one of the instruments with high accuracy levels to discern the types of urinary incontinence is michigan incontinence symptom index (m-isi) (11). unlike other ui questionnaires, the m-isi covers different aspects of ui that were essential for women's care and research. it also has been proved that the threshold scores for the m-isi could be used to screen for clinically relevant urinary incontinence (11). this study provided a simple and comprehensive instrument to measure types, severity, and bother related to ui among childbearing women. the aims were to identify the knowledge, attitude, and practice towards pelvic floor muscle training, to measure the ui using a validated misi questionnaire, and to identify the association between the ui and pfmt among childbearing women. objectives: this study aims to identify knowledge, attitude, and practice of pelvic floor muscle training (pfmt) and to identify the prevalence of urinary incontinence. materials and methods: the method used was a cross-sectional study. self-administered knowledge, attitude, and practice questionnaires were distributed among childbearing women attending maternal & child health clinics in the east coast region of malaysia. results: the findings revealed that most respondents (n = 896) had good or moderate knowledge (80.1%) and attitudes (77.3%) regarding pfmt but most of them (87.2%) still lacked practice. however, there was no association between urinary incontinence and pfmt practice. on the contrary, married women showed a higher risk of urinary incontinence. conclusions: the practice of pelvic floor muscle training should be recommended and emphasized to childbearing women by healthcare professionals. key words: attitude; knowledge; pelvic floor muscle training; practice; urinary incontinence; m-isi. submitted 10 march 2023; accepted 18 march 2023 introduction urinary incontinence (ui) is one of the worldwide health problems but is not considered life-threatening (1). most of the victims did not share their problems and kept silent until they were interviewed by healthcare professionals. a study identified factors that affect help-seeking behavior: not accepting incontinence as a disease, shame, non-optimal health care system, negative support of essential others and reduced quality of life (2). the risk factors for ui include menopause, increased body mass index, straining hard during defecation, coffee consumption and depression (3). the management of ui was divided into two, which are conservative and non-conservative treatment. the nonconservative treatment is the medical or surgical treatment, whereas the conservative treatment is non-costly. one of the conservative treatments is, pelvic floor muscle training, or known as kegel’s exercise. in 1948, dr. kegel, who invented the kegel exercise, stated that the cure rate after training pelvic floor muscles for women with different types of incontinence was 84%. besides, pelvic floor knowledge, attitude and practice towards pelvic floor muscle training among childbearing women nur fairuz mohd fauzey 1, siti mariam muda 2, haliza hasan 2, zalina nusee 3, muzaitul akma mustapa kamal basha 2 1 kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia; 2 department of special care nursing, kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia; 3 department of obstetrics & gynecology, kulliyah of medicine, international islamic university malaysia, kuantan, malaysia. presented as conference papers at the 8th v-binc at fon universitas indonesia. doi: 10.4081/aiua.2023.11298 summary archivio italiano di urologia e andrologia 2023; 95, 2 nur fairuz mohd fauzey, siti mariam muda, haliza hasan, zalina nusee, muzaitul akma mustapa kamal basha 109 materials and methods the study used a quantitative research method with crosssectional design. it was conducted at five government maternal & child health clinics in the east coast region in malaysia (kelantan, terengganu, pahang). the populations were childbearing women who attended the maternal and child health clinic. the inclusion criteria were malaysian women, aged 18 to 45 years old, and able to read in malay. the exclusion criteria included menopausal women, a history of mental health problems, and diagnosed chronic illness. the study included 2 parts: the first part was the recruitment process, and the second was the administration of two sets of questionnaires, m-isi screening test and a survey on knowledge, attitude, and practice of pelvic floor muscle training. figure 1 shows the process of recruitment of participants in this study. the sample size was calculated using the open-source calculation openepi version 3 using the odds ratio (or) from a previous study (10). using a 20% non-response factor, it was decided to have a total of 1219 childbearing women involved in the study. all the data obtained from the study were recorded and statistically analysed using statistical package for social science software, version 26.0. basic details of the participants and urinary incontinence were analysed using descriptive statistics, including mean and standard deviation or median with interquartile range for non-normally distributed data. a chi-square test was used to identify the association between urinary incontinence and pelvic floor muscle training and logistic regression was done to identify the predictors of urinary incontinence among childbearing women. this study obtained approval from the research committee at international islamic university malaysia (iium) (irec 2021-008) and national medical research register (nmrr) (nmrr-19-4172-51098). all participants consented and were involved in this study on a voluntary basis. results a total of 896 participants answered all questions yielding a 74% completion rate, with the power of the study being 100%. age distribution is shown in table 1. there were 506 participants (58.0%) who were multigravida (usually 3-5 pregnancies), while 30% were primigravida who had first-time experience in pregnancy. the majority of the participant were malay (99.5%), and the highest educational level was diploma/degree holder (48.8%). more than half of the participants (52.6%) were housewives, and in terms of monthly income, the majority of the participants (78.2%) were categorized in the lower household income group (b40), earning less than rm4,850 per month. the number of women with ui using the m-isi questionnaire was 173, with an estimated prevalence of 19.3% (table 2). as reported in table 3, 43.0% of the respondents had good knowledge of pfmt. most of the childbearing women had a moderate attitude toward pfmt (55.9%) and poor practice toward pfmt (87.2%). as reported in table 3, 43.0% of the respondents had good knowledge of pfmt. most of the childbearing women had table 1. socio-demographic characteristics. characteristics frequency percentage (%) age (years) (n = 887) < 20 28 3.2 21-30 432 48.7* 31-40 361 40.7 > 41 66 7.4 marital status (n=883) single 23 2.6 married 850 96.3* widow 10 1.1 gravida (n = 873) nulligravida 14 1.6 primigravida 262 30.0 multigravida 506 58.0* grand multigravida 91 10.4 ethnicity (n = 885) malay 881 99.5* chinese 2 0.2 india 2 0.2 educational level (n = 864) primary school 17 2.0 secondary school 401 46.4 diploma/degree 422 48.8* master/phd 24 2.8 occupation (n = 854) housewife 449 52.6* self-employed 92 10.8 government sector 175 20.5 private sector 135 15.8 student 3 0.4 monthly income** (n = 832) b40 (bottom 40%) 651 78.2* m40 (middle 40%) 168 20.2 t20 (top 20%) 13 1.6 *the highest score in each item; **malaysian household income classification. table 2. the prevalence of urinary incontinence. urinary incontinence frequency percentage (%) yes 173 19.3 no 723 80.7 figure 1. the process of recruitment of participants. archivio italiano di urologia e andrologia 2023; 95, 2 110 pelvic floor muscle training among childbearing women a moderate attitude toward pfmt (55.9%) and the majority reported a poor practice of pfmt (87.2%). table 4 depicted that there was a significant association between the level of knowledge of pfmt and ui (p = 0.001); it also showed a significant association between the level of attitude toward pfmt and ui (p = 0.009) but no significant association between level of practice of pfmt and ui (p > 0.05). good knowledge of pfmt (adjusted or = 0.69; 95% ci 0.41-1.19) and moderate knowledge of pfmt (adjusted or = 0.70, 95% ci 0.43-1.14) were negative predictors of ui, meaning that women with good/moderate knowledge are less likely prone to ui compared to those with poor knowledge. however, other socio-demographic factors, such as being married women, showed to be statistically significant towards the risk to be ui (p = 0.040). discussion the prevalence of ui among childbearing women in this study, which included the east coast region of malaysia, was lower than the one reported in a previous study, which evaluated the rate of ui among women aged > 18 years (12). however, the prevalence may vary with the place, population, and questionnaire that have been used. the various definitions of incontinence, the use of different questionnaires, settings, procedures, and the validity of self-report data all contributed to the variation in epidemiological data about the prevalence rate of ui (5). this study found that most of the childbearing women had a good knowledge of pfmt, similar to the previous study conducted at one of the teaching hospitals in malaysia (13). however, the respondents demonstrated a moderate attitude towards pfmt, contrary to the findings previously observed among antenatal women in kelantan (14). the pregnant women felt that pfmt had positive effects on their health, such as improved incontinence, pelvic organ prolapse, quality of life and increased sexual satisfaction (15). there was a positive change in attitude score after attending antenatal class (16), and as a result, education was a critical factor in improving women’s attitudes and motivation towards pfmt. the finding from this study showed that married women had a significant association with ui. married women were more likely to have ui than single women because they tend to have an older age, which becomes a risk factor for ui (17). being married women, earlier age at marriage, high parity, and old age were associated with the increase in ui among women in lahore (18). women do not practice pfmt, possibly due to a lack of information or awareness about doing this exercise during antenatal or postnatal periods. this can be seen in another study in which 44% of them reported lack of knowledge about the exercise and 96% stated that there was no guidance from healthcare professionals during the postpartum period in promoting pfmt (19). conclusions this study revealed that, although overall knowledge and attitude towards pfmt were good, women did not practice the exercise regularly. thus, it is recommended to healthcare professionals to play an essential role by providing more information as well as raising awareness about pfmt. the best method to give the information effectively is during consultation sessions and the antenatal class. acknowledgments: we would like to thank all participants involved in this study for their help and support. funding: this study was supported by the fundamental research grant scheme for research acculturation of early career researchers (racer) under ministry of higher education malaysia. acknowledgement of financial support: this work was supported by fundamental research grant scheme for research acculturation of early career researchers (racer) under ministry of higher education malaysia. references 1. mohd yusoff d, awang s, kueh yc. urinary incontinence among pregnant women attending an antenatal clinic at a tertiary teaching hospital in north-east malaysia. j taibah univ med sci. 2019; 14:39. table 3. the level of knowledge, attitude and practice towards pelvic floor muscle training. level frequency percentage (%) knowledge towards pelvic floor muscle training good 385 43.0 moderate 332 37.1 poor 179 20.0 attitude towards pelvic floor muscle training good 192 21.4 moderate 501 55.9 poor 203 22.7 practice towards pelvic floor muscle training good 32 3.6 moderate 81 9.2 poor 772 87.2 table 4. association between level of knowledge, attitude, and practice towards pelvic floor muscle training with urinary incontinence. variable urinary incontinence χ2 p-value yes (n = 173) n (%) no (n = 723) n (%) knowledge good 61 (35.3) 324 (44.8) 14.195 0.001 moderate 60 (34.7) 272 (37.6) poor 52 (30.1) 127 (17.6) attitude good 30 (17.3) 162 (22.4) 9.368 0.009 moderate 89 (51.4) 412 (57.0) poor 54 (31.2) 149 (20.6) yes (n = 169) n (%) no (n = 716) n (%) practice good 1 (0.6) 31 (4.3) 5.851 0.054 moderate 18 (10.7) 63 (8.8) poor 150 (88.8) 622 (86.9) significant value, p-value < 0.05. archivio italiano di urologia e andrologia 2023; 95, 2 nur fairuz mohd fauzey, siti mariam muda, haliza hasan, zalina nusee, muzaitul akma mustapa kamal basha 111 2. fakari fr, hajian s, darvish s, alavi majd h. explaining factors affecting help-seeking behaviors in women with urinary incontinence: a qualitative study. bmc health serv res. 2021; 21:1-10. 3. kaur dhillon h. urinary incontinence amongst malaysian women in selangor: prevalence, types and risk factors. world j public health. 2019; 4:10. 4. ptak m, ciećwiez s, brodowska a, et al. the effect of pelvic floor muscles exercise on quality of life in women with stress urinary incontinence and its relationship with vaginal deliveries: a randomized trial. biomed res int. 2019; 2019:5321864. 5. abrams p, smith ap, cotterill n. the impact of urinary incontinence on health-related quality of life (hrqol) in a real-world population of women aged 45-60 years: results from a survey in france, germany, the uk and the usa. bju int. 2015; 115:143. 6. malhotra n, chahal a. the effectiveness of pelvic floor exercises on symptoms in females with stress urinary incontinence. biosci biotechnol res commun. 2018; 11:681. 7. özdemir k, şahin s, özerdoğan n, ünsal a. evaluation of urinary incontinence and quality of life in married women aged between 20 and 49 years (sakarya, turkey). turk j med sci. 2018; 48:100-9. 8. ahmed ibrahim w. assess levels of knowledge, attitude and practice of the married women about pelvic floor muscles exercise. int j sci res. 2015; 6:2319. 9. rosediani m, nik rosmawati nh, juliawati m, norwati d. knowledge, attitude and parctice towards pelvic floor muscle exercise among pregnant women attending antenatal clinic in universiti sains malaysia hospital, malaysia. int med j. 2012; 19:37. 10. jaffar a, mohd-sidik s, nien fc, et al. urinary incontinence and its association with pelvic floor muscle exercise among pregnant women attending a primary care clinic in selangor, malaysia. plos one. 2020; 15:e0236140. 11. suskind am, dunn rl, morgan dm, et al. a screening tool for clinically relevant urinary incontinence. neurourol urodyn. 2015; 34:332-5. 12. baykuş n, yenal k. prevalence of urinary incontinence in women aged 18 and over and affecting factors. j women aging. 2020; 32:578-90. 13. jarni mf, mohamad my, kamarudzaman n. knowledge, attitude, and practice (kap) towards pelvic floor muscle exercise among the female population attending the obstetrics and gynaecology clinic at sultan ahmad shah medical centre (sasmec@iium). international journal of allied health sciences. 2021; 5:2521-2529. 14. muhammad j, muhamad r, husain nrn, daud n. pelvic floor muscle exercise education and factors associated with implementation among antenatal women in hospital universiti sains malaysia. korean j fam med. 2019; 40:45. 15. temtanakitpaisan t, bunyavejchevin s, buppasiri p, chongsomchai c. knowledge, attitude, and practices (kap) survey towards pelvic floor muscle training (pfmt) among pregnant women. int j womens health. 2020; 12:295-9. 16. habib m, sohail i, nasir m, nasir f. awareness, knowledge and practices of pakistani women towards pelvic floor muscle exercises (pfmes) during pregnancy. j soc obstet gynaecol pak. 2020; 10:121. 17. al kiyumi mh, al belushi zi, jaju s, al mahrezi am. urinary incontinence among omani women prevalence, risk factors and impact on quality of life. sultan qaboos univ med j. 2020; 20:45. 18. jawad z, malik a, khan s. prevalence of urinary incontinence in women in lahore: severity, associated factors and impact on daily life. age. 2021; 15:5. 19. alharqi hm, albattawi ja. assessment of knowledge and attitude of women towards postpartum exercise. j nurs health sci. 2018; 7:16. correspondence nur fairuz mohd fauzey kulliyyah of nursing, international islamic university malaysia, kuantan, malaysia siti mariam muda (corresponding author) sitimariam@iium.edu.my haliza hasan muzaitul akma mustapa kamal basha department of special care nursing, kulliyyah of nursing, international islamic university malaysia, kuantan, 25200, malaysia zalina nusee department of obstetrics & gynecology, kulliyah of medicine, international islamic university malaysia, kuantan, malaysia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper pathologies beyond its common use in the management of renal stones (1). furs can be used as a conservative treatment for urothelial tumors of the upper urinary tract (utuc) and can be used in the follow-up after radical treatment of utuc (2). however, the use of furs is not without drawbacks. significant complications, including urinary tract infection (uti) and ureteric trauma, are frequently reported (3). in one study, febrile uti was reported in 14.1% of patients submitted to flexible ureteroscopic lithotripsy (4). unfortunately, prevention of postoperative uti after furs remains a debatable issue. current practice lacks well-established clinical evidence based on randomized clinical studies and is mainly based on retrospective studies (5). to standardize the periprocedural systemic antimicrobial administration, the american urological association best practice policy statement was developed (6). however, real-world practice is widely variable, and observational studies show relatively low compliance with these recommendations (5-7). to guard against post procedural infection, the most common approach is single-dose antibiotic prophylaxis (8). on the other hand, some centers use more enhanced precautions, including centralized collection and examination of preoperative urine cultures, standardized antibiotic prophylaxis, and use of ureteral access sheath. even with these precautions, postoperative uti was encountered in 6.7% of patients (9). the present randomized study aimed to compare the rate of post-procedural uti in patients subjected to the standard antibiotic prophylaxis alone versus enhanced prophylactic measures. patients and methods a prospective randomized controlled study was conducted at the department of urology, armed forces hospital, alhada, ksa, from march 2018 to july 2022. the study protocol was approved by the local ethical committee of the institution, and informed written consent was obtained from all patients before enrollment. the study included all patients subjected to furs to manage ureterpurpose: to compare the rate of post-flexible ureteroscopy urinary tract infection (uti) in patients subjected to the standard antibiotic prophylaxis alone versus enhanced prophylactic measures. methods: a prospective randomized controlled study included 256 patients subjected to flexible ureteroscopy (furs) for ureteral or renal stones from march 2018 to july 2022. treatment groups included the standard antibiotic prophylaxis group (group 1, n=128) and the enhanced prophylaxis group (group 2, n=128). patients in group 1 were injected with intravenous fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 h postoperatively. patients in group 2 had urine culture ten days before the procedure; antibioticculture based was given for positive asymptomatic cases, while the procedure was deferred for active uti. results: the study groups were comparable regarding patient demographics, stone characteristics, operative time, and intraoperative complications. the overall hospitalization time was 1.68 ± 0.81 days. postoperative, and overall complications were significantly higher in group 1 (15.6% vs. 6.3%, p = 0.04 and 26.6% vs. 17.2%, p = 0.047), respectively. twenty patients (15.6 %) in the standard prophylaxis group were diagnosed with uti in comparison to 8 patients (6.3 %) in the enhanced prophylaxis group (p = 0.047). conclusions: urinary tract infection after furs could be reduced significantly by utilizing the suggested enhanced prophylactic approach. key words: antibiotic; prophylaxis; ureteroscopy; urinary tract infect. submitted 13 december 2022; accepted 22 january 2023 introduction flexible ureteroscopy (furs) has become one of the most reliable tools in upper urinary tract endourology. thanks to creative ancillary instruments such as graspers and baskets, effective energy sources, and digital and robotic enhancements, furs has expanded its diagnostic and therapeutic applications to many upper urinary tract randomized comparison of effect of standard antibiotic prophylaxis versus enhanced prophylactic measures on rate of urinary tract infection after flexible ureteroscopy el-sayed i. el-agamy 1, mohamed a. elhelaly 1, tamer a. abouelgreed 2, abdrabuh m. abdrabuh 3, mohamed f. elebiary 3, adel elatreisy 3, osama m. ghoneimy 3, basem a. fathi 3, mohamed zamra 4, khalid kutub 5 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt & department of urology, armed forced hospital, alhada, ksa; 2 department of urology, faculty of medicine, al-azhar university, cairo, egypt & gulf medical university, uae; 3 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 4 department of urology, alqasemi hospital, sharjah, uae; 5 department of urology, al aharq jospital, fujairah, uae. doi: 10.4081/aiua.2023.11084 summary archivio italiano di urologia e andrologia 2023; 95, 1 el-sayed i. el-agamy, mohamed a. elhelaly, tamer a. abouelgreed, et al. al or renal stones. exclusion criteria were symptomatic uti, use of rigid ureteroscope, and antegrade ureteroscopy. preoperatively, all patients were subjected to careful history taking, thorough clinical examination, and non-contrast computed tomography scan to evaluate the stone characteristics. patients were equally and randomly allocated into one of the two treatment groups, including the standard antibiotic prophylaxis group and the enhanced prophylaxis group. the sample size was calculated utilizing the g-power software program for statistical power 80% and type ii statistical error 20%. the total number of patients was 256, equally divided into the two groups (each group included 128 patients). patients in the standard antibiotic prophylaxis group were injected intravenously with fluoroquinolone one hour preoperatively, and oral antibiotics were used for 24 hours postoperatively. patients in the enhanced prophylaxis group had urine culture ten days before the procedure. patients with sterile cultures received standard antibiotic prophylaxis. in contrast, patients with polymicrobial preoperative urine culture (defined by a urine culture isolating at least three microorganisms, of which none is predominant) were treated with ceftriaxone from 48 hours before the procedure until one day after surgery. patients with positive urine culture were contacted to assess if they had symptoms of uti. in asymptomatic cases, according to the specific pathogens identified, a full course of antibiotics was started five days before surgery until 48 h after the intervention (figure 1). for those having a clinically significant infection, the intervention was deferred. in addition to the antibiotic prophylaxis, hydrophiliccoated ureteral access sheaths were systematically used in all cases. the primary outcome of the study was the occurrence of postoperative uti within 30 days from treatment. postoperative uti was defined as the occurrence of a temperature higher than 38 °c associated with pyuria figure 1. flow chart of the study population. archivio italiano di urologia e andrologia 2023; 95, 1 antibiotic prophylaxis for urinary tract infection after flexible ureteroscopy and/or bacteriuria without any other focal infectious sites. in a symptomatic patient, no routine urine culture was requested. statistical analysis data obtained from the present study were presented as number and percent or mean and standard deviation (sd). numerical data were compared using a t-test, while categorical data were compared using the chi-square test. logistic regression was used to identify predictors of outcome. all statistical operations were computed using spss 25 (ibm, usa), and a p-value less than 0.05 was considered statistically significant. results in total, 256 patients were included in the study; the mean age in years ± sd was 46.8 ± 12.9, the male to female ratio was 178/78, and all patients underwent furs for stone disease with laser lithotripsy. the mean stone number ± sd of the entire cohort was 2.5 ± 1, and the largest stone diameter was 2.1 ± 0.78. the stones were recurrent in 50% of patients and were associated with moderate hydronephrosis in 21.9% and mild hydronephrosis in 48.4%, whereas no hydronephrosis was associated in 29.7%. regarding the stone location, it was in the proximal ureter in 35.2%, in the kidney in 36.7%, and combined in 28.1%. pre-furs internal double j ureteric stents were placed in 26.5% of patients who presented with proximal ureteric obstructing stones and slight acute renal impairment, which was normalized after ureteric stenting. group 1 included patients subjected to the standard antibiotic prophylaxis protocol (n = 128). group 2 included patients subjected to the enhanced prophylaxis protocol (n = 128) who had sterile urine culture in 66 cases (51.6%), polymicrobial positive urine culture in 41 cases (32%), and isolated organism in 21 (16.4%). there were no significant differences between the study groups regarding patient demographics and stone characteristics, as illustrated in table 1. the overall hospitalization time was 1.68 ± 0.81 days, comparable between groups 1 and 2 with no significant difference (p = 0.35) (table 1). we reported an overall complication rate of 21.9% (56 cases). intraoperative complications were comparable between the study groups. conversely, postoperative, and overall total complications were significantly higher in group 1, as shown in table 2. all the reported complications were mccs grades i and ii that were managed conservatively. regarding post-furs urinary tract infection, 20 patients (15.6%) in the standard prophylaxis group were diagnosed with uti in comparison to 8 patients (6.3%) in the enhanced prophylaxis group with statistically significant difference (p = 0.047) (table 2). hospital readmission was mandatory in 10 cases (3.9%) for uti and urosepsis. in these cases we collected urine and blood samples for culture and started with empirical intravenous meropenem (1 gram every 8 hours). urine culture showed e. coli in 8 cases and klebsiella pneumonia in two, all sensitive to meropenem, and all patients were discharged after ten days of antibiotic course after confirmation of sterile urine. using binary logistic regression analysis, female gender [or (95% ci): 0.09 (0.018-0.46) and operative time [or (95%ci): 0.97 (0.94-0.99)] were significant predictors of postoperative uti at univariate analysis. however, only female sex remained significant at multivariate analysis [or (95% ci): 0.09 (0.017-0.49)] (table 3). table 1. comparison between the studied groups regarding the preoperative, operative, and postoperative data. parameters standard prophylaxis enhanced prophylaxis p value group 1 (n = 128) group 2 (n = 128 age (years) mean ± sd 47.4 ± 11.8 46.1 ± 14.3 0.67 male/female n 86/42 96/36 0.52 bmi (kg/m2) mean ± sd 30.4 ± 4.8 29.4 ± 4.2 0.42 associated morbidities n (%) hypertension 38 (29.9%) 34 (26.7%) 0.66 diabetes mellitus 62 (48.4%) 56 (43.8%) 0.45 previous stone operation n (%) 59 (45.3%) 70 (54.7%) 0.26 preoperative ureteral stent n (%) 36 (28.3%) 32 (25 %) 0.72 preoperative hydronephrosis n (%) none 36 (28.1%) 40 (31.3%) 0.52 mild 66 (51.6%) 58 (45.3%) moderate 22 (20.3%) 30 (23.4%) stone location n (%) kidney 44 (34.4%) 50 (39.1%) 0.7 ureter 50 (39.1%) 40 (31.2%) combined 34 (26.6%) 38 (29.7%) stones number mean ± sd 2.6 ± 1.1 2.4 ± 1 0.43 largest stone size (cm3) mean ± sd 2 ± 0.9 2.2 ± 0.7 0.31 operative time (min.) mean ± sd 117.4 ± 26.2 114.8 ± 22.7 0.63 hospitalization time, days 1.53 ± 0.7 1.63 ± 0.8 0.34 table 3. predictors of postoperative uti in the studied groups. univariate analysis multivariate analysis or 95% ci p value or 95% ci p value age 0.99 0.94-1.03 0.54 sex 0.09 0.018-0.46 0.004 0.09 0.017-0.49 0.005 diabetes 0.53 0.14-2.02 0.36 stone size 0.82 0.55-1.24 0.35 operative time 0.97 0.94-0.99 0.032 0.97 0.95-1.01 0.063 type of prophylaxis 0.22 0.044-1.09 0.063 0.19 0.033-1.14 0.069 table 2. complications rate among studied groups. parameters total group 1 group 2 p value (n = 256) (n = 128) (n = 128) overall complications 56 (21.9%) 34 (26.6%) 22 (17.2%) 0.04 intraoperative complications 28 (10.9%) 14 (10.9%) 14 (10.9%) 0.89 postoperative complications 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 mccs grading of complications grade 1 ureteric mucosal injury 12 (4.7%) 6 (4.7%) 6 (4.7%) 0.98 hematuria 16 (6.3%) 10 (3.9%) 6 (4.7%) 0.34 grade 2 uti 28 (10.9%) 20 (15.6%) 8 (6.3%) 0.047 readmission (within 8 weeks) 10 (3.9%) 8 (6.3%) 2 (1.7%) 0.038 archivio italiano di urologia e andrologia 2023; 95, 1 el-sayed i. el-agamy, mohamed a. elhelaly, tamer a. abouelgreed, et al. discussion urinary tract infections after furs are commonly seen in clinical practice. even in the absence of microbial invasion, the surgical procedure elicits a significant systemic inflammatory response related to the procedure's duration and can predispose to infectious complications (10). the present prospective study assessed the value of standard antibiotic prophylaxis versus enhanced prophylaxis in preventing utis after furs. postoperative uti was diagnosed in twenty patients (15.6%) in the standard prophylaxis group versus eight patients (6.3%) in the enhanced prophylaxis group (p = 0.047). the beneficial effects of enhanced prophylaxis are attributed to additional measures included in the protocol, namely the preoperative culture and treatment of identified infections and use of coated ureteral access sheaths. the relation between positive preoperative culture and postoperative uti in patients submitted to furs was discussed by the study by senocak et al. (11). in their paper, positive preoperative urine culture with multidrug resistance isolates was recognized as an independent risk factor of postoperative uti. of note, none of our patients had such isolates. also, in the study of alezra et al. (12), positive day-1 culture was a significant predictor of severe uti. in addition, the study of auge et al. (13) highlighted the value of ureteral access sheath (uas) in the reduction of postoperative uti after furs. similar conclusions were reported by the randomized study of özkaya et al. (14). they noted that using uas in impacted mid-upper ureteral stones was related to fewer infectious complications. the uas reduces the irrigation pressures transmitted to the renal pelvis and parenchyma (13). moreover, appropriate uas selection is essential to optimize the renal blood flow during furs. adequate renal blood flow is critical to maintain local immune defensive mechanisms (15). in our study, logistic regression analysis identified the female sex as an independent risk factor of postoperative uti. this finding conforms with the study of baboudjian et al. (9). their study showed preoperative polymicrobial urine culture and increased operative time as predictors of postoperative uti. our conclusions are also supported by the recent metaanalysis of ma et al. (16). in contrast, the study of baseskioglu et al. (17) recognized preoperative infection history, comorbidity score, and residual fragments as significant predictors of uti after furs, while the relevant risk factors in the study of ozgor et al. (18) were longer operation time, presence of renal abnormality and age ≤ 40 years. conclusions urinary tract infection after flexible ureteroscopy and laser lithotripsy could be reduced significantly by utilizing the suggested enhanced prophylactic approach. the female sex factor is the only independent predicting factor for the occurrence of post-furs urinary tract infections. references 1. alenezi h and denstedt jd. flexible ureteroscopy: technological advancements, current indications and outcomes in the treatment of urolithiasis. asian j urol. 2015; 2:133-141. 2. cho sy. current status of flexible ureteroscopy in urology. korean j urol. 2015; 56:680-688. 3. osther pjs. risks of flexible ureterorenoscopy: pathophysiology and prevention. urolithiasis. 2018; 46:59-67. 4. kim jw, lee yj, chung jw, et al. clinical characteristics of postoperative febrile urinary tract infections after ureteroscopic lithotripsy. investig clin urol. 2018; 59:335-341. 5. greene dj, gill bc, hinck b, et al. american urological association antibiotic best practice statement and ureteroscopy: does antibiotic stewardship help? j endourol. 2018; 32:283-288. 6. wolf js jr, bennett cj, dmochowski rr, et al. best practice policy statement on urologic surgery antimicrobial prophylaxis [published correction appears in j urol. 2008; 180:2262-3]. j urol. 2008; 179:1379-1390. 7. bapir r, bhatti kh, eliwa a, et al. infectious complications of endourological treatment of kidney stones: a meta-analysis of randomized clinical trials. arch ital urol androl. 2022; 94:97-106. 8. pietropaolo a, bres niewada e, skolarikos a, et al. worldwide survey of flexible ureteroscopy practice: a survey from european association of urology sections of young academic urologists and uro-technology groups. cent european j urol. 2019; 72:393-397. 9. baboudjian m, gondran tellier b, abdallah r, et al. predictive risk factors of urinary tract infection following flexible ureteroscopy despite preoperative precautions to avoid infectious complications. world j urol. 2020; 38:1253-1259. 10. zhong w, leto g, wang l, et al. systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy: a study of risk factors. j endourol. 2015; 29:25-28. 11. senocak c, ozcan c, sahin t, et al. risk factors of infectious complications after flexible uretero-renoscopy with laser lithotripsy. urol j. 2018; 15:158-163. 12. alezra e, lasselin j, forzini t, et al. prognostic factors for severe infection after flexible ureteroscopy: clinical interest of urine culture the day before surgery? prog urol. 2016; 26:65-71. 13. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004;18:3336. 14. özkaya f, sertkaya z, karabulut i, et al. the effect of using ureteral access sheath for treatment of impacted ureteral stones at mid-upper part with flexible ureterorenoscopy: a randomized prospective study. minerva urol nefrol. 2019;71:413-420. 15. sener te, tanidir y, bin hamri s, et al. effects of flexible ureteroscopy on renal blood flow: a prospective evaluation. scand j urol. 2018; 52:213-218. 16. ma yc, jian zy, yuan c, et al. risk factors of infectious complications after ureteroscopy: a systematic review and metaanalysis based on adjusted effect estimate. surg infect (larchmt). 2020; 21:811-822. archivio italiano di urologia e andrologia 2023; 95, 1 antibiotic prophylaxis for urinary tract infection after flexible ureteroscopy 17. baseskioglu b. the prevalence of urinary tract infection following flexible ureterenoscopy and the associated risk factors. urol j. 2019; 16:439-442. 18. ozgor f, sahan m, cubuk a, et al. factors affecting infectious complications following flexible ureterorenoscopy. urolithiasis. 2019; 47:481-486. correspondence el-sayed i. el-agamy, md abuamr1978@yahoo.com mohamed a. elhelaly, md elhelalymohammed@yahoo.com department of urology, faculty of medicine, al-azhar university, cairo, egypt & department of urology, armed forced hospital, alhada, ksa tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt. & gulf medical university, uae abdrabuh m. abdrabuh, md abdo197871@yahoo.com mohamed f. elebiary, md dr_elebiary@yahoo.com adel elatreisy, md dr_adelelatreisy@yahoo.com osama m. ghoneimy, md elgendyosama787@gmail.com basem a. fathi, md basemhara@gmail.com basemabdalla.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt mohamed zamra, md mohamedzomrah@gmail.com department of urology, alqasemi hospital, sharjah, uae khalid kutub, md abanis35@gmail.com department of urology, al sharq hospital, fujairah, uae conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 111archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.111 tures to other places, riots in prisons, etc.). at the declaration of a pandemic, the who added the risk of an “infodemia”, that is the dissemination of a considerable amount of information, coming from different and often unverifiable sources. providing the correct information would be an important issue to help and reduce contagiousness and so mortality. sars-cov-2 has widely spread in less than three months because of a globally interconnected world. sars-cov-2 appears to spare children while older population with concomitant morbidity are severely affected, in particular males (5, 6). the symptomatic picture includes various symptoms according to the evolution of the disease. the symptoms most commonly observed in patients before hospitalization may be fever, chills, dry cough, dyspnea, asthenia, myalgias and/or arthralgias, while nausea and vomit, nasal congestion, hemoptysis, diarrhea, conjunctival congestion are less common (7). this symptomatology can be complicated starting from the third/fourth week, often in a dramatically increasing manner such as to require hospitalization. in severe cases, pneumonia, acute respiratory distress syndrome, sepsis and septic shock, endothelial dysfunction with thromboembolism can occur till to the patient’s death (8). it is important to remember that the patient with sarscov-2 can also be asymptomatic or pauci-symptomatic, thus contributing to the spread of the virus in the community (9). in humans, the transmission pathways of the covid-19 virus are mainly direct, that is, through the respiratory tract with the inhalation of respiratory droplets that are generated when an infected person speaks, coughs or sneezes. viral transmission can also be indirect, i.e. mediated by inanimate vectors (soil, personal effects, paper sheets, money, plastic or metal surfaces, etc.) and in any case it will depend on the viral load present on that surface. relatively to the potential covid-19 sexual transmission, there are no definitive data. the impact on male fertility and the potential of the spermatozoa to serve as vectors for the sexual transmission of this disease are not clear yet, although some biological characteristics of spermatozoa must leave researchers open to these possithe sars-cov-2 (severe acute respiratory syndrome coronavirus 2) was first reported in december 2019, then its rapid spread around the world caused a global pandemic in march 2020 recording a high death rate. the epicenter of the victims moved from asia to europe and then to the united states. in this pandemic, the different governance mechanisms adopted by local health regional authorities made the difference in terms of contagiousness and mortality together with a community strong solidarity. this document analyzes the andrological urgencies management in public hospitals and in private practice observed in italy and in particular in two of the most affected italian regions: emilia-romagna and marche. key words: sars-cov-2; pandemic; andrology; public hospitals; private practice. submitted 9 january 2021; accepted 21 january 2021 introduction the international committee on taxonomy of viruses (ictv), responsible for defining the official classification of viruses and the taxonomy of the coronaviridae family, has officially classified under the name sars-cov-2 (severe acute respiratory syndrome coronavirus 2) the virus provisionally called by the world health organization (who) 2019-ncov and responsible for covid-19 cases ("co" stands for corona, "vi" for virus, "d" for disease and "19" indicates the year in which it occurred) (1-3). sars-cov-2 was identified for the first time in wuhan, in the province of hubei in china. italy was the first country outside of china involved by pandemic. the italian council of ministers declared the state of emergency from 31.01.2020. the italian prime minister extended some restrictive measures concerning gatherings and movements throughout the national territory with effect from 10th march. this logic of restrictions was above all to reduce the contagiousness (r0) of covid-19. the who declared the world pandemic on 11 march 2020 (4). who had warned each country of the risk of the "tsunami" of information, in particular fake news would have led to panic situations (supermarket raids, unnecessary visits to hospital emergency rooms, uncontrolled deparitalian experiences in the management of andrological patients at the time of coronavirus pandemic summary carlo maretti 1, andrea fabiani 2, fulvio colombo 3, alessandro franceschelli 3, giorgio gentile 3, franco palmisano 3, valerio vagnoni 3, luigi quaresima 4, massimo polito 5 1 department of andrology, cirm medical center, piacenza, italy; 2 unit of urology, surgical department, macerata hospital, area vasta 3, asur marche, macerata, italy; 3 andrology unit, university hospital s.orsola-malpighi, bologna, italy; 4 urology division at the civitanova marche hospital, civitanova marche, italy; 5 department of clinical and specialist sciences, division of urology, polytechnic university of the marche region medical school, ancona, italy. presented at the sieun congress ancona 30 november 1 december 2020 archivio italiano di urologia e andrologia 2021; 93, 1 c. maretti, a. fabiani, f. colombo, a. franceschelli, g. gentile, f. palmisano, v. vagnoni, l. quaresima, m. polito 112 bilities (10, 11). this document analyzes the various experiences of italian uro-andrologists in their hospital wards as well as in andrological private urgencies in emiliaromagna and marche, in this lockdown period. experiences in andrology management in italian centers during covid-19 pandemic department of andrology, cirm medical center, piacenza from 30.01.2020 when the italian council of ministers declared a state of health emergency, it was decided to study in details the dynamics transmission of covid-19 infection, trying to make a critical review of the scientific literature data in order to better manage a possible state of emergency. the perception of an individual threat, is the fear that triggers some physiological reaction of anxiety, which can also generate sexual troubles (erectile dysfunction, for example). working in the private sector of andrology, it was tried to protect patients and personnel adopting several precautions to limit the contagion (disposable surgical masks, shoe covers, gloves, aprons, headgears and visors). only urgent visits were scheduled and telematic advice was produced in required cases. on the first days of lockdown there was not any request for andrological visit and the ones previously booked were cancelled by the patients themselves. after about ten days, people with a probable erectile dysfunction of stressogenic nature, began to call for telematic suggestions. it was clear that confinement, the loss of the usual routine, and the reduction of social relationships had increased the sense of insecurity and anguish (12, 13). during the same period most of the urgent visits to males were related to infections (testicular, prostatic, urethral, glans or preputial), probably related to an increased frequency of sexual acts during the lockdown period. the patients were received individually, equipped with disposable ppe (personal protective equipment, the italian dpi ) waiting alone for their turn. no visits for couple infertility were performed, according to the indication claimed by national health authorities regarding the need to stop the search for children. uro-andrologic unit, policlinico di s.orsola, bologna from march 10, due to the measures introduced to limit the spread of the covid-19, our academic hospital established urgent measures to reduce outpatient procedures, use of operating theatres and non-urgent clinical activity. initially, the uro-andrologic department has been turned into medical department due to need for the management and treatment of patients with sars-cov2; then, urological procedures were referred to another centre with limited number of beds, reduction of operating theatres (from four to one per day) and priority for malignancy and obstructive uropathy conditions while andrological activities has been dramatically cancelled except for one case of three-components penile prosthesis reservoir removal for confirmed local infection. to date, no malignancies or other urgent andrological procedures were scheduled during the restriction. in this scenario, the staff of urology and andrology department has been used to enhance assistance in the medical departments in order to support the activity of internists. outpatient activities were limited to urgent consultations while patients with non-urgent (whenever possible consulted by telephone) have been postponed, pending provisions relating to the end of the lockdown. the psychological impact of the covid-19 outbreak among the whole and specifically andrological patients is still unknown. as expected, our web and facebook pages counted an increase in visualization as well as an increasing in requests regarding access to outpatient consultation. interestingly, most of the patients reported conditions related to psychological burden such as penile enlargement and erectile dysfunction surgery. department of surgery, section of urology, macerata hospital in this public community hospital in the marche region, the shift from patient centered medicine to a community centered approach was immediate. the cancellation of the scheduled operating sessions was the consequence of the need to make surgical decision no longer based on individual patients’ needs but on the availability of beds in intensive and sub-intensive care for the management of patients suffering from sars-cov-2, mainly from neighboring areas of the northern part of the region. the immediate cancellation meant the suspension of the surgical treatment of the non-oncological pathologies. in this situation, the andrological surgery, in its vast part, has suffered a drastic stop. circumcisions, peyronie’s disease or congenital recurvatum surgeries, varicocele and infertility surgeries, surgical treatment of erectile dysfunction have been cancelled. urology division in macerata hospital has a 10-bed ward and, normally, 6 full time urologists and 1 resident of the marche polytechnic university: before covid pandemic about 1000 surgical procedures and 4500 visits per year were performed. our attitude was prompted to define our surgical and outpatient activities by following the provisions elaborated by the reference scientific societies (13-16). however, the feeling was to be neglected by the medical direction regarding priorities in the planning of procedures. it was difficult to obtain anesthesiologist assistance in nononcological urological procedures (for example: ureteral stenting). the feeling was that it was forbidden to have pathology other than sars-cov-2. urology division was managed as a mixed ward hosting non-covid and covid patients who did not require intensive care support. one urologist per week was commanded to participate at medical activities, alone or alongside with internal medicine colleagues. consequently, from the beginning of the lockdown, the andrological activity was reduced to the management of several cases with complications such as phimosis whose surgery had been postponed, one spermatic cord torsion (figure 1), two testicular neoplasms, metastatic priapism (two cases), one penile cancer (figure 2) and three cases of mondor’s disease (figure 3). requests for advice in relation to non-acute testicular pain, even by telephone, were increased. there have been no cases of penile trauma which had been unusually more frequent in the 6 months preceding the pandemic. u.o.s. urologic surgery, azienda ospedali riuniti, ancona the marche region was the 5th italian region in terms of numbers of patients, hospitalized and deaths. the ospedali riuniti in ancona, which play the role of regional referral centre (hub), immediately gave its orders to convert surgical beds, thus limiting all the other surgical activity, in order to grant, for resuscitation purposes, and therefore to provide physician availability for emergency and non-intensive medical unit for covid. eight unit dedicated to covid were established in a few weeks. the elective andrological activity was interrupted. the urological ward was reduced to 15 of 22 beds and a waiting room (2 beds) was dedicated to patients admitted from emergency waiting the result of covid-test analysis. surgery was planned only for emergency/urgency, symptomatic tumors, kidney failure, infection, diseases with ongoing complications and traumatic events. urological and andrological outpatient activity, diagnostic ultrasound and cystoscopy, and endovesical chemo or bcg were temporary closed. to date, the lockdown throughout the country has greatly reduced the incidence of traumatic events related to road traffic and work activities. in the first 50 days we had to intervene on two traumas of the genital tract that happened due to working activities. we listed criteria to plan andrological surgery in agreement with our experience, the covid task force unit in our hospital and published guidelines on urological surgery (17-21). the andrological surgical activity included two orchiectomies for testicular cancer, one penile amputation with inguinal and ipsilateral pelvic lymph node dissection for penile cancer (figure 4) and one surgery for severe gangrenous necrotizing fasciitis of the genitals in a 58-year male with diabetes, hiv and drugs addiction. this case resolved after 75 days (figure 5). the overall surgical activity was reduced by 47% with 262 procedures from march 1st to may 30th 2020 compared to 492 during the same time period in 2019. however the urology resident training was guaranteed all the time also supported by web lessons (22). urology division at the civitanova marche hospital as soon as the pandemic from coronavirus emerged, the community hospital in civitanova marche was been converted into a covid-hospital, as well as most of the staff who were employed in it. all departments were progressively occupied by symptomatic covid-19 positive patients, diverting patients affected by other pathologies to other hospitals (macerata, ancona) and suspending the outpatient and surgical activity. from march 24, 2020, urologists started to work as an internist-type ward in shifts of medium-low care intensity, with a shift of 8 113archivio italiano di urologia e andrologia 2021; 93, 1 andrological patients at the time of covid-19 figure 1. spermatic cord torsion. pre(left) and post (right)-derotation testicle aspect. figure 3. mondor disease. clinical aspect (left) in a circumcised penis. ultrasound features (right) with thrombus (white star) occluding the dorsal superficial vein lumen. figure 4. simultaneous right inguinal and pelvic lymph node dissection through modified inguinal incision (surgical andrology unit, ospedali riuniti, ancona). figure 5. genitalia gangrene management (surgical andology unit, ospedali riuniti, ancona). figure 2. penile cancer localized in the inner part of the foreskin (a, b). in c and d were reported the dorsal (c) and ventral (d) post surgical aspects after sleeve circumcision (squamocellular carcinoma with sarcomatoid aspect, hpv induced, pt1nx). archivio italiano di urologia e andrologia 2021; 93, 1 c. maretti, a. fabiani, f. colombo, a. franceschelli, g. gentile, f. palmisano, v. vagnoni, l. quaresima, m. polito 114 hours a day. during their shifts, urologists were also called to perform urological consultations for positive covid-19 patients hospitalized in the various wards of the hospital; during this activity in the hospital, there was no request for some andrological advice. in addition to the hospital activity, private andrologist activity was continued by activating an online consultancy function with video consultations: this activity has proven to be safe, effective and pleasing to the patients who have used it. during this activity, five requests for advice for erectile deficit mainly of recent onset were received. the cause of these deficits is often psychogenic, probably linked to the state of prostration, inhibition related to social distancing and quarantine. therefore, it is important not to increase the patient's concern or treat him as an organic erectile deficit, but to deepen the diagnosis if it persists even after the lockdown phase. conclusions males and andrology community are still paying the price of a delay in the management of the pandemic, fueled by first conflicting messages and fake news. the key-role of andrologists in italy was to offer themselves to support covid patients and support andrological patients seeking help by web, phone and email. andrological surgery is still restricted in most hospitals and, especially in public setting, nevertheless how and when re-schedule suppressed operations is missing yet. the lack of epidemiological data on andrological pathologies in the lockdown period stimulated us to expose our experiences which, in addition to an interruption of the specialist activity in hospital structures, highlighted above all the andrological pathologies that had been managed in a private setting. references 1. lefkowitz ej, dempsey dm, hendrickson rc, et al. virus taxonomy: the database of the international committee on taxonomy of viruses (ictv). nucleic acids res. 2018; 46:d708-d717. 2. coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2. nat microbiol. 2020; 5:536-544. 3. song z, xu y, bao l, et al. from sars to mers, thrusting coronaviruses into the spotlight. viruses. 2019; 11:59. 4. decrete of the president of the council of ministers, italy, 8 march 2020. oj no. 59 of 8-3-2020 5. wölfel r, corman vm, guggemos w, et al. virological assessment of hospitalized patients with covid2019. nature. 2020; 581:465469. 6. hui dsc, zumla a. severe acute respiratory syndrome: historical, epidemiologic, and clinical features. infect dis clin north am. 2019; 33:869-889. 7. huang c, wang y, li x, et al. clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet. 2020; 395:497-506. 8. jin y, yang h, ji w, et al. virology, epidemiology, pathogenesis, and control of covid-19. viruses. 2020; 12:372. 9. borges do nascimento ij, cacic n, abdulazeem hm, et al. novel coronavirus infection (covid-19) in humans: a scoping review and meta-analysis. j clin med. 2020; 9:941. 10. aitken rj. covid-19 and human spermatozoa-potential risks for infertility and sexual transmission? andrology. 2020 jul 10:10.1111/andr.12859. 11. maretti c, privitera s, arcaniolo d, et al. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology. arch ital urol androl. 2020; 92:73-77. 12. brooks sk, webster rk, smith, le, et al. the psychological impact of quarantine and how to reduce it: rapid review of the evidence. lancet. 2020; 395:912. 13. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020 apr 24; 92:67-72. 14. simonato a, giannarini g, abrate a, et al. pathways for urology patients during the covid19 pandemic. minerva urol nefrol. 2020; 72:376-383. 15. ficarra v, novara g, abrate a, et al. urology practice during covid-19 pandemic. minerva urol nefrol. 2020; 72:369-375. 16. stensland kd, morgan tm, moinzadeh a, et al. considerations in the triage of urologic surgeries during the covid-19 pandemic. eur urol. 2020; 77:663-666. 17. martino p, galosi ab, bitelli m, et al. imaging working groupsocieta italiana urologia (siu); società italiana ecografia urologica andrologica nefrologica (sieun). practical recommendations for performing ultrasound scanning in the urological and andrological fields. arch ital urol androl. 2014; 86:56-78. 18. maselli g, cordari m, catanzariti f, et al. penile gangrene by calciphylaxis: an unusual clinical presentation in a patient with diabetic nephropathy on hemodialysis. j emerg med 2017; 52:e255e256. 19. galosi ab, capretti c, leone l, et al. pseudoaneurysm with arteriovenous fistula of the prostate after pelvic trauma: ultrasound imaging. arch ital urol androl. 2016; 88:317-319. 20. dell'atti l, cantoro d, maselli g, galosi ab. distant subcutaneous spreading of fournier's gangrene: an unusual clinical identification by preoperative ultrasound study. arch ital urol androl. 2017; 89:238-239. 21. dell'atti l, scarcella s, tallè m, et al. simultaneous curvature correction at the time of the penile fracture repair: surgical and functional outcomes. res rep urol. 2019; 11:105-110. 22. busetto gm, del giudice f, mari a, et al. how can the covid19 pandemic lead to positive changes in urology residency? front surg. 2020; 7:563006. correspondence carlo maretti, md carlomaretti@tin.it department of andrology, cirm medical center, piacenza, italy andrea fabiani, md andreadoc1@libero.it unit of urology, surgical department, macerata hospital, area vasta 3, asur marche, macerata, italy fulvio colombo, md fulvio.colombo@aosp.bo.it alessandro franceschelli, md alessandrofranceschelli@yahoo.it giorgio gentile, md dr.giorgio.gentile@gmail.com franco palmisano, md franco.palmisano@hotmail.it valerio vagnoni, md vagnoni.dr@gmail.com andrology unit, university hospital s.orsola-malpighi, bologna, italy luigi quaresima, md luigiquaresima@yahoo.it urology division at the civitanova marche hospital, civitanova marche, italy massimo polito, md max_polito@virgilio.it department of clinical and specialist sciences, division of urology, polytechnic university of the marche region medical school, ancona, italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12285 1 original paper the majority of occurrences of azoospermia are due to irreversible testicular illnesses that affect spermatogenesis. these conditions are frequently related to inflammatory, genetic, and endocrine issues. if no obvious causes are found, noa will be considered idiopathic. the affected testes are tiny and swollen (4, 5). male infertility can be brought on by a number of chromosomal or genetic disorders, including klinefelter syndrome, 47(xxy) syndrome, xx male syndrome, and ychromosome microdeletions (6). the foundation for spermatogenesis and male fertility in males is provided by spermatogonial stem cells (sscs). throughout the male reproductive life, sscs can maintain the self-renewal process, differentiate into spermatozoa, and pass on genetic material to the following generation (7). stem cell transplantation is one method of treatment for male infertility related to a problem with spermatogenesis. the reason for this is that stem cells are unspecialized cells being capable of self-renewal, regeneration, and cell differentiation. when existing spermatogonial cells are lost or injured, spermatogenesis can be restored by spermatogonial cells (sscs). therefore, stem cell transplantation represents an effective method for restoring spermatogenesis in individuals with cancer and other spermatogenic disorders (8). the mesenchymal stem cells (msc) multi-linear differentiation capacity, moderate immunogenicity, and active involvement in tissue repair and regeneration following migration to injured locations account for their widespread use. for clinical usage in cell-based therapeutics, mscs generally have an advantage over other types of stem cells (9). one of the primary sources of mscs is the bone marrow, and although aspirating the bone marrow is the most painful way to isolate mscs, it is also the most used method for cell therapy (10). the differentiation of mscs into the male or female germ cell epithelium can be induced using a specific combination of growth factors, chemicals and genetic modifications. distinct methods of differentiation induction have been devised to differentiate distinct types of mscs into male germ cells. retinoic acid, growth factors, minerals, background: non-obstructive azoospermia (noa) represents an infertility problem that is usually difficult to treat. such patients usually have testicular biopsy of germ cell aplasia or spermatogenic arrest. in recent decades, mesenchymal stem cells (mscs) had been studied thoroughly and proved safe and effective regarding their capability for trans-differentiation into different cell types. the aim of this study was to evaluate the effect of mscs local intratesticular injection in induction of spermatogenesis. patients and method: the current study included 87 infertile non-obstructive azoospermic patients. clinical assessment and repeated semen analysis with centrifugation were done to confirm azoospermia. karyotyping and azf study were done. some of the patients had previous testicular biopsy proving a lack of sperm in the testes. single intratesticular injection of purified mscs suspension was done. results: 20.7% of patients showed sperm in their semen after variable period of time. hormonal profile among treated patients showed significant improvement regardless success of treatment. also most of the treated patients appreciated the improvement of their sexual function and libido. conclusions: bone marrow derived mscs could be a new hope and therapeutic modality for treatment of refractory cases of noa. key words: stem cells; non-obstructive azoospermia (noa); spermatogenesis; semen analysis. submitted 14 january 2024; accepted 22 january 2024 introduction about 1% of males and up to 10-15% of infertile men have azoospermia, which is defined as the absence of sperm in the ejaculate upon evaluation of the centrifuged semen. in two thirds of instances, severe spermatogenic dysfunction, also known as non-obstructive azoospermia (noa), is the primary cause (1). azoospermia can be categorized as either obstructive (oa) or noa (2). many medications like antihypertensive medications and antidepressants might cause noa; all of them have the potential to disrupt spermatogenesis and even cause nonobstructive azoospermia (3). evaluation of human bone marrow mesenchymal stem cells in the treatment of non obstructive azoospermia mohamed a. alhefnawy 1, gamal elmorsy 2, sayed bakry 3, hesham el-amrosy 4, ibrahim mearaj 5, ebrahim a. sabra 6, osama m. badr 6, dalia ibraheem 7, taymour khalifa 5 1 urology, benha university, benha, egypt; 2 clinical pathology, faculty of medicine, al-azhar university, cairo, egypt; 3 genetic engineering, faculty of science for boys in cairo, al-azhar university, egypt; 4 clinical pathology, egypt ministry of health and population, cairo, egypt; 5 dermatology and andrology, faculty of medicine, al-azhar university, cairo, egypt; 6 animal cell and tissue culture, genetic engineering and biotechnology institute, sadat university, sadat city, egypt; 7 department of tissue engineering, faculty of science, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2024.12285 summary archivio italiano di urologia e andrologia 2024; 96(1):12285 m.a. alhefnawy, g. elmorsy, s. bakry, et al. 2 co-culture, conditioned medium, magnetic fields, and gene over-expression are a few examples of these (11). mild symptoms such as transitory fever, insomnia, nausea, vomiting, or mild changes at the administration site may occur as a side effect of mscs treatment, necessitating medical supervision and follow-up (12). as evidenced by improved expression of germ cell markers, a decrease in apoptosis-induced sterility, a reduction in oxidative stress, and an increase in testosterone production, mscs transplanted into the testes of noa demonstrated both activation of spermatogenesis and differentiation into germ cells. the inhibition of antisperm antibodies (asa) may also be a function of mscs (13). the implanted mscs produce a variety of growth factors, including the male germ cell potential factors transforming growth factor beta (tgf-) and bone morphogenetic proteins (bmps), which stimulate and restore the recipient's cellular function (14). the grey area about the effect of mscs local intratesticular injection to induce spermatogenesis has motivated the authors to conduct this study subjects and methods study design the current study was conducted following the ethical perspectives of helsinki declaration where ethical approval was obtained from the ethical and research committees of both benha and al azhar universities. the current study was conducted at the urology department, benha university and andrology outpatient clinic of international islamic institute for population studies and research, al-azhar university. the study was conducted throughout the period from january.2020 till january 2022. the study included 87 subjects with primary infertility, with non-obstructive azoospermia for at least 2 years durations. all cases were volunteers and informed by explaining complete details of the procedure (expected benefits and possible complications). a written consent was obtained from each patient. clinical trial registry at: clinicaltrials.gov/study/nct02025270 every patient underwent a thorough history-taking process, paying particular attention to the marital history (including age of the couple, length of marriage, and previous marriage clinical examination, paid particular attention to gigantism, dwarfism, myxedema, klinefelter syndrome, mongolism... etc. local examination was performed to check testicular volume, consistency, varicocele, cord anomalies, and vas alterations in order to rule out obstruction or scrotal enlargements, absence as well as congenital malformations of the testis. following a 2-7-day period of abstinence, the semen analysis was performed three times in a row in accordance with who guidelines to confirm azoospermia. follicle stimulating hormone (fsh), luteinizing hormone (lh), and testosterone measurements and testicular biopsy were used to estimate hormonal profiles and to discover histological patterns underlying azoospermia (such as scos and phases of spermatogenic arrest). karyotyping was done to display chromosomal abnormalities, such as the xx male syndrome and the klinefelter syndrome 47xxy. assessing y-chromosome microdeletions (azf) was done to identify the loci of spermatogenesis that were affected (a, b, or c). instrumentation • laminar air flow cabinet (biological safety cabinet) class 11 type a/b3. • octomax: for magnetic cell selection (miltenyi biotec, germany) macs multistand. • inverted phase – contrast microscope: for cell examination and counting. • light microscope: for cell counting (leitz). • water bath: for sampling preparations and manipulation. • humidified co2 incubator with air jacket: for cell stem cell cultivation, model mjpxc 50. • refrigerator to keep the media. • centrifuge (eppendorf): to centrifuge the sampling for separation, sedimentation. • sterile pasteur pipettes. • automatic pipettes (10-200 ul, scororex). • sterile tissue culture tubes & dishes. • hemocytometer: improved neuber. • vortex mixer: for sample mix & resuspending. media • macs buffer; auto macs rinsing solution (edta, phosphate buffered saline). • dulbecco’s phosphate buffers saline (phenol red, calcium and magnesium). • hisep lsm 1077: phicoll for cell separation (buffy coat layer). • alcohol 70% for sterilization. methods under complete aseptic condition, about 60 ml of bone marrow blood were aspirated from iliac bones. this volume is diluted with phosphate buffer saline (pbs). the diluted blood sample was gently layered to ficoll hypaque centrifugation was done to separate the buffy coat layer and aspirate this layer that present at the interphase between the plasma and ficoll carefully. this separated layer is also subjected to magnetic labeling and separation by cd105 microbeads and fcr blocking antibodies by octamacs apparatus to get finally pure mesenchaymal stem cells (msc). these cells are finally re-suspended in 1 ml of pbs. a 30 micr. of this volume are subjected to viability testing using trypan blue and counting by improved neuber hemocytometer. cell counting for cases ranged (3.7-5.2 mil/cm), viability around 98.4-99.2%. the extracted cells were injected into cortex of both testes of patients under local anesthesia. the patents were followed after 4 months from injection, by semen analysis, hormonal profile (fsh, lh and testosterone) and testicular volume. the follow up was every 2 months for at least one year. results this current study included 87 infertile male patients with a mean age of 35.87 ± 4.22 years in whom the archivio italiano di urologia e andrologia 2024; 96(1):12285 3 mesenchymal stem cells in the treatment of azoospermia repeated spermiogram revealed azoospermia. after mscs injection, 69 (79.3%) patients did not show sperm in their semen while the remaining 18 (20.7%) patients showed different numbers of sperm in their semen. the mean age of the non-responding group 36.9 ± 7.35 years. other clinical data and testicular biopsy results were illustrated in table 1. in the successful group, the surprising finding is the rate of responders with sertoli cell only syndrome (scos) (61.1%). the most prominent parameters among responding cases is normal karyotyping and absence of chromosome y azf micro deletion (table 1). table 1 demonstrated that there was a statistically significant decrease in the fsh and lh hormone levels as well as significant increase in the testosterone level after mscs therapy in the responding group more than the nonresponding group. karyotyping was the only variable showing statistically significant differences between successful and non-responding patients with scos (table 2). regarding patients with scos, fsh level after treatment showed significant differences between responding and non-responding. also fsh percentage of level changes after treatment showed statistically significant differences between both responding and non-responding patients. on the other hand, lh levels showed significant differences between scos responders and nonresponders either before or after treatment. also, the hormonal level change percentage was significantly different. moreover, testosterone showed significant differences between both groups regarding level before, after as well as change`s percentage. all successful cases of scos have normal karyotyping and absence of azf microdeletions (table 2). table 3 showed that fsh level and percentage of changes after treatment showed significant differences between successful vs. failed cases. there was no statistically significant differences among successful vs. failed cases with different levels of spermatogenic arrest as regards the testesterone and lh hormones although significant difference was noticed within each group before and after msc injection. table 1. comparison between successful vs. non responding cases (clinical, testicular biopsy before, genetic background and hormonal level before and after mscs therapy). failed success p value no of patients, n (%) 69 (79.3%) 1 (20.7%) age (mean ± sd) 36.9 ± 7.35 34.83 ± 5.85 0.269 testicular size before mscs therapy 0.227 normal, n (%) 35 12 small, n (%) 34 6 testicular examination before mscs therapy 0.231 normal, n (%) 61 17 varicocele, n (%) 7 0 cryptorchidism, n (%) 1 1 testicular biopsy before mscs therapy 0.084 primary spermatocyte, n (%) 9 2 secondary spermatocyte, n (%) 3 4 spermatid, n (%) 2 1 scos, n (%) 55 11 karyotyping before mscs therapy 0.070 normal 58 18 klinefelter 11 0 microdeletion before mscs therapy 0.779 normal 65 18 azf a 1 0 azf b 2 0 azf c 1 f s h (mean ± sd) before mscs therapy 24.70 ± 10.2 22.07 ± 5.5 0.301 after mscs therapy 19.68 ± 8.617 11.96 ± 2.97 < 0.001* p = 0.016 p < 0.001* % of changes 20.32 45.81 < 0.001* lh (mean ± sd) before mscs therapy 10.18 ± 4.75 7.03 ± 2.07 0.008* after mscs therapy 8.27 ± 3.679 5.143 ± 1.014 < 0.001* p = 0.023* p < 0.001* % of changes 18.76 26.84 0.01* testosterone (mean ± sd) before mscs therapy 2.367 ± 1.041 3.44 ± 0.66 < 0.001* after mscs therapy 3.52 ± 1.30 5.29 ± 0.77 < 0.001* p = 0.041 p < 0.001* % of changes 32.76 34.97 0.01* table 2. comparison between successful vs. non responding cases of scos (clinical & genetic background) and hormonal levels. failed success p value no of patients, n (%) 55 11 age (mean ± sd) 36.93 ± 7.45 35.09 ± 7.012 0.752 testicular size before mscs therapy 0.579 normal, n (%) 30 7 small, n (%) 25 4 testicular examination before mscs therapy 0.245 normal, n (%) 48 10 varicocele, n (%) 6 0 cryptorchidism, n (%) 1 1 karyotyping before mscs therapy < 0.001* normal 44 11 klinefelter 11 0 microdeletion before mscs therapy 0.214 normal 52 11 azf a 0 0 azf b 2 0 azf c 1 0 f s h (mean ± sd) before mscs therapy 19.67 ± 8.5 22.2 ± 5.87 0.093 after mscs therapy 15.2 ± 13.3 12.29 ± 2.25 < 0.007* p = 0.012* p < 0.001* % of changes 22.7 44.6 < 0.001* lh (mean ± sd) before mscs therapy 10.18 ± 4.7 6.7 ± 1.6 0.008* after mscs therapy 8.28 ± 3.65 4.96 ± 0.96 < 0.001* p = 0.003* p < 0.001* % of changes 18.6 26.11 < 0.001* testosterone (mean ± sd) before mscs therapy 2.35 ± 1.045 3.4 ± 0.818 < 0.003* after mscs therapy 3.5 ± 1.30 5.13 ± 0.8 < 0.001* p = 0.041 p = 0.04* 0.001* % of changes 32.9 33.7 < 0.004* archivio italiano di urologia e andrologia 2024; 96(1):12285 m.a. alhefnawy, g. elmorsy, s. bakry, et al. 4 discussion aside from the extremely rare occurrences of patients with hypogonadotropic hypogonadism, caroppo e. & colpi g. (15) came to the conclusion that azoospermia caused by spermatogenic malfunction is an incurable illness. mscs, also referred to as fibroblast precursor cells, are non-hematopoietic cells found in the bone marrow. according to standard criteria established by the international society for cellular therapy (isct), mscs must be plastic adhering and capable of differentiating into the osteoblast, adipocyte, and chondroblast lineages. frequently, they have low immunogenicity (16). mscs use paracrine and immunomodulatory pathways to provide their beneficial effects (17, 18). in their meta-analysis investigation, wang et al. (12) found no direct evidence that msc injection had the potential to cause tumours. additionally, no major safety incidents were noted. some research (19) have demonstrated that mscs can trans-differentiate into spermatogenetic cells in the right milieu. bm (bone marrow)-msctransplanted mice produced germ cells in vivo, according to several research (20, 21). bm-mscs have the ability to fuse with the local cells in the damaged area or to differentiate or trans-differentiate into multi-lineage cells, produce paracrine substances to entice the local stem cells to take part in tissue regeneration (22). pittenger et al. 2019 (23) concluded that msc infusion treatments had a very good safety profile during the previous 25 years, which was backed up by more than 950 registered msc clinical trials that were filed with the fda. in the present study, a single intratesticular injection of pure mscs was used to treat patients. out of 87 patients, 18 (or 20.7%) showed sperm in their semen at various times. in contrast to the successful case report of cassim & mohamed (24), using local injection with three sessions of intravenous msc infusion, our investigation used a single intratesticular injection. treatment with mscs had a favourable impact on hormone levels, decreasing fsh and lh levels and raising blood testosterone levels. improvements in sexual function and libido were reported alongside elevated testosterone levels in the treated subjects from the patient history. on the other hand, there were notable hormone level disparities between responding and non-responder patients, particularly following treatment. based on the observation of successful cases when the fsh level was double or more than the usual level, the baseline fsh level appeared to be of little use as a predictor of success. all the successful cases had normal karyotyping and no chromosomal abnormalities in the azf region. this might be seen as a reliable indicator of a successful outcome. all scos cases that are successful have normal karyotyping and no azf microdeletions, which was true for all cases that were successful despite having differing testicular biopsy results. the success rate for cases of scos was comparable to other non-obstructive azoospermic cases. this is also a strong indicator of mscs' capacity for homing and transdifferentiation. to summarize, the complete lack of spermatogonia is not a contraindication to msc therapy. although the hormonal profile significantly improved in the case of the classic klinefelter syndrome, no sperm were found in the seminal fluid despite decreased fsh, lh, and higher testosterone levels. this study's findings align with those of baghae et al. (25). no problems were noted during aspiration from the bm or during intra testicular injection in any of the instances that were monitored both during and after the mscs injection. based on neri's (26) findings, we avoided using in vitro numerous replications in this study because they could raise the danger of accumulating genetic and epigenetic modifications and having a negative impact on the cell biology and therapeutic characteristics, safety, and efficacy. according to an experimental investigation in the ram by fedder et al. (27), pathological testicular abnormalities such scar tissue and micro-calcifications were discovered regardless of the sperm retrieval method used. additionally, blood supply impairment was linked to it. furthermore, eliveld et al. (28) concluded that transient hypogonadism, which can persist up to 26 months, is demonstrated by testosterone levels that are below normal. he also noted that some patients' testicular volume had decreased, but only a small number of patients had erectile dysfunction (ed). because melancholy and anxiety may be the root of ed rather than hypogonadism, it was particularly prevalent in the group of men who had negative sperm retrieval results. conclusions regardless of baseline hormonal levels, local intratesticular injection therapy using human mscs may offer some hope for patients with refractory noa. acknowledgments thanks and gratitude must be extended to the late dr. bahgat abdelghafar elfiky, former head of animal biotechnology department, al-azhar university for his participation and great effort of this work. table 3. comparing hormonal levels among successful vs. failed cases with different levels of spermatogenic arrest. failed success p value no of patients, n (%) 14 7 age (mean ± sd) 36.9 ± 7.12 34.43 ± 3.2 0.3946 f s h (mean ± sd) before mscs therapy 19.45 ± 6.5 21.87 ± 4.94 0.403 after mscs therapy 16.1 ± 4.98 11.37 ± 2.06 0.30 p = 0.007* p < 0.001* % of changes 17.2 48 < 0.001* lh (mean ± sd) before mscs therapy 7.53 ± 2.86 7.57 ± 2.6 0.098 after mscs therapy 6.1 ± 1.96 5.5 ± 1.02 0.46 p = 0.082 p < 0.073 % of changes 19 31.3 0.0085* testosterone (mean ± sd) before mscs therapy 3.19 ± 1.13 3.51 ± 0.272 0.38 after mscs therapy 4.34 ± 1.18 5.26 ± 0.75 0.078 p = 0.041 p = 0.002* 0.001* % of changes 36.1 49.8 0.755 archivio italiano di urologia e andrologia 2024; 96(1):12285 5 mesenchymal stem cells in the treatment of azoospermia references 1. caroppo e and colpi gm. update on the management of nonobstructive azoospermia: current evidence and unmet needs. j clin med. 2021; 11:62. 2. wosnitzer m, goldstein m and hardy mp. review of azoospermia. spermatogenesis. 2014; 4:e28218. 3. boivin j, bunting l, collins ja, nygren kg. international estimates of 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therapies for male infertility: where are we now and where are we going? in dt carrell, pn schlegel, c racowsky, & l gianaroli (eds.), biennial review of infertility 2015 (vol. 4). switzerland: springer international publishing, pp. 17-39. 9. kim hj, park js. usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages. dev reprod. 2017; 21:1-10. 10. chikhovskaya jv, jonker mj, meissner a, et al. human testisderived embryonic stem cell-like cells are not pluripotent, but possess potential of mesenchymal progenitors. hum reprod. 2012; 27:210-21. 11. wei y, fang j, cai s, et al. primordial germ cell-like cells derived from canine adipose mesenchymal stem cells. cell prolif. 2016; 49:503-11. 12. wang y, yi h, song y. the safety of msc therapy over the past 15 years: a meta-analysis. stem cell res ther. 2021; 12:545. 13. ghasemzadeh-hasankolaei m, batavani r, eslaminejad mb, sayahpour f. transplantation of autologous bone marrow mesenchymal stem cells into the testes of infertile male rats and new germ cell formation. int j stem cells. 2016; 9:250-263. 14. wang f, liu c, zhang s, et al. transplantation of goat bone marrow mesenchymal stem cells (mscs) help restore spermatogenesis in endogenous germ cells-depleted mouse models. j integr agric 2013; 12:483-494. 15. caroppo e, colpi gm. hormonal treatment of men with nonobstructive azoospermia: what does the evidence suggest? j clin med 2021; 10:387. 16. chen c. from mesenchymal stem cell therapy to discovery of drug therapy for systemic sclerosis. university of southern california, proquest dissertations publishing, 2014; 3628-36. 17. liu f, qiu h, xue m, zhang s, zhang x, xu j, chen j, yang y, xie j. msc-secreted tgf-b regulates lipopolysaccharide-stimulated macrophage m2-like polarization via the akt/foxo1 pathway. stem cell res ther. 2019; 10:345. 18. zhang s, teo kyw, chuah sj, et al. msc exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. biomaterials. 2019; 200:35-47. 19. cakici c, buyrukcu b, duruksu g, et al. recovery of fertility in azoospermia rats after injection of adipose-tissue-derived mesenchymal stem cells: the sperm generation. biomed res int. 2013; 2013:529589. 20. lue y, erkkila k, liu py, et al. fate of bone marrow stem cells transplanted into the testis: potential implication for men with testicular failure. am j pathol. 2007; 170:899-908. 21. yang s, bo j, hu h, et al. derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules. cell prolif. 2012; 45:91-100. 22. zhang d, liu x, peng j, et al. potential spermatogenesis recovery with bone marrow mesenchymal stem cells in an azoospermic rat model. int j mol sci. 2014; 15:13151-65. 23. pittenger mf, discher de, péault bm, et al. mesenchymal stem cell perspective: cell biology to clinical progress. npj regen med. 2019; 4:22. 24. cassim mi, mohamed t. novel therapy for the treatment of male factor infertility due to non-obstructive azoospermia: a case report. crescent journal of medical and biological sciences. 2019; 6:129-131. 25. baghaei k, hashemi sm, tokhanbigli s, et al. isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow. gastroenterol hepatol bed bench. 2017; 10:208-213. 26. neri s. genetic stability of mesenchymal stromal cells for regenerative medicine applications: a fundamental biosafety aspect. int j mol sci. 2019; 20:2406. 27. fedder j, marcussen n, fedder mdk, engvad b. testicular damage following testicular sperm retrieval: a ram model study. biomed res int. 2017; 2017:2472805. 28. eliveld j, van wely m, meißner a, et al. the risk of teseinduced hypogonadism: a systematic review and meta-analysis. hum reprod update. 2018; 24:442-454. correspondence mohamed abdelrahman alhefnawy, md dr.mohamedalhefnawy@gmail.com assistant professor of urology, benha university fareed nada street 13518, banha, egypt gamal elmorsy, md gamalz7070@gmail.com assistant professor of clinical pathology, faculty of medicine, al-azhar university, cairo, egypt sayed bakry, md sbakry@azhar.edu.eg professor of genetic engineering, faculty of science for boys in cairo, al-azhar university, cairo, egypt hesham el-amrosy, md egypttala889@gmail.com consultant of clinical pathology, egypt ministry of health and population, cairo, egypt ibrahim mearaj, md mearaj@hotmail.com taymour khalifa, md taymour.khalifa@gmail.com professor of dermatology and andrology, al-azhar university faculty of medicine, cairo, egypt ebrahim sabra, md ebrahim.sabra@gebri.usc.edu.eg osama badr, md osama.badr@gebri.usc.edu.eg assistant professor of animal cell and tissue culture, genetic engineering and biotechnology institute, sadat university, sadat city, egypt dalia ibraheem, md daliaibraheem23@gmail.com department of tissue engineering, faculty of science, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 101archivio italiano di urologia e andrologia 2018; 90, 2 original paper recurrent bacterial symptomatic cystitis: a pilot study on a new natural option for treatment giulio del popolo, federico nelli department of neuro-urology, azienda ospedaliero-universitaria careggi, firenze, italy. objectives: the aim of our study was to explore the effectiveness of the combination of d-mannose, salicin, and lactobacillus acidophilus (la-14) in patients complaining recurrent symptomatic cystitis due to e. coli. materials and methods: from july 2013 to september 2014, 85 consecutive subjects (68 women and 17 men) affected by recurrent symptomatic cystitis were enrolled. of those, 46 (33 women and 13 men) suffered from neurogenic bladder. overall 78 patients received an initial 5-days regimen consisting on a tid oral combination of 1000 mg of d-mannose plus 200 mg of dry willow extract (salicin) (attack phase), followed by bid 7-days with 700 mg of d-mannose plus 50 mg (1x109 cfu) of lactobacillus acidophilus (la-14) (maintenance treatment). the maintenance treatment was repeated every 15 days for the next two months. patients’ symptoms were evaluated through a 3-days bladder diary and a visual analogic scale (vas). results: after treatment vas scores decreased from 8.07 ± 1.70 to 4.74 ± 2.07 (p = 0.001) in non-neurological patients (group a) and from 7.21 ± 1.90 to 3.74 ± 3.12 (p = 0.001) in the neurological patients (group b). a significant reduction of daily frequency was noted in both groups: from 14 ± 3 to 7 ± 3 (p = 0.001) in group a and from 15 ± 3 to 8 ± 3 (p = 0.001) in group b. a reduction of incontinence episodes in group a patients was observed, as well as in 12/39 group b. improvements were maintained during followup. conclusion: this therapeutic approach combining d-mannose with salicin (acute treatment) and lactobacillus acidophilus la-14 (maintaining treatment) seems to be effective in symptomatic bacterial utis. further larger and randomized control trials (rcts) are needed to confirm our results. key words: bacterial cystitis; uti; d-mannose; neurogenic bladder dysfunction, lactobacillus acidophilus la-14; salicin. submitted 19 march 2018; accepted 9 may 2018 summary no conflict of interest declared. other pathogens are proteus and klebsiella species, enterococci, group b streptococci and pseudomonas aeruginosa, but utis can be also due to the association of several pathogens with greater clinical impact and potential complications. women are more likely to be affected by uti than men, with an estimated incidence of 1 42 in 3 among females versus only 1 in 20 among males (14). the higher incidence of utis among women can be attributed to the shorter urethral length, which provides an effective barrier against bacterial contamination. utis can also be due to neurogenic bladder and it may result from decreased local immune defenses, impaired lower urinary tract function, bladder management (e.g. intermittent catheterism, indwelling catheter) and the coexisting condition of neurogenic bowel dysfunction. in any case an excessive use of antibiotics may also increase the uti risk by altering the normal microbiota and increasing bacterial resistance. treatment is generally multimodal and includes antibiotic and anti-inflammatory therapy together with dietary supplements and behavioral interventions. recommended preventive measures such as adequate water intake, rhythm in urinary voiding and non-antibiotic prophylaxis (e.g., cranberry, urine acidifiers, probiotics) are not yet supported by evidence (3, 4). d-mannose has long been studied and has been shown to be effective and safe in treating and preventing utis also in neurological populations such as multiple sclerosis (2). through its mechanism of action, it prevents bacterial colonization and invasion of the bladder by pathogens, and is effective in multiresistant upec (uropathogenic e. coli) infections (5). in vitro studies have shown that d-mannose binds and blocks fimh adhesins positioned on the tip of type 1 bacterial fimbriae. during bacterial colonization, fimh binds to the glycoprotein-containing carbohydrate receptors on the urinary epithelium. d-mannose acts as a competitive inhibitor of bacterial adhesion as it has a structure similar to the binding site of glycoproteic urothelial receptors; in sufficient concentrations in urine, d-mannose causes saturation of fimh adhesins and therefore prevents bacteria from binding to urothelial receptors. in vitro studies show that the local application of d-mannose decreased the adherence of e. coli, pseudomonas aeruginosa and streptococcus zooepidemicus to urothelial endometrial cells in horses. reduction of bacteriuria levdoi: 10.4081/aiua.2018.2.101 introduction urinary tract infections (utis) are among the most common infections in humans and affect both sexes and all age groups. among them, cystitis is a clinical syndrome characterized by dysuria, urinary frequency and urgency, with or without suprapubic pain. the most common cause of cystitis is bacterial from common pathogens of the lower urinary tract. bacterial cystitis is usually associated with bacteriuria and leukocyturia. in europe, escherichia coli (e. coli) is the most common uropathogen, accounting for up to 86% of all utis (1); archivio italiano di urologia e andrologia 2018; 90, 2 g. del popolo, f. nelli 102 els has also been confirmed by in vivo animal models of recurrent utis. a randomized, non-blind, placebo-controlled study to evaluate prophylaxis of recurrent urinary infections conducted on 308 women showed that dmannose used for 6 months at a dose of 2 g per day was significantly more effective than placebo and as effective as nitrofurantoin 50 mg in preventing recurrence (6, 7). salicin (an alcoholic b-glucoside between glucose and salicylic alcohol), has anti-inflammatory properties (8). lactobacilli possess antimicrobial properties that regulate the urogenital microbiota. lactobacillus acidophilus la-14 has shown excellent adherence to epithelial surfaces in vitro demonstrating inhibition of selected pathogens, including e. coli (9-12). the recurrence of urogenital infections leads to a change in local flora from a predominance of lactobacilli to coliform uropathogens. therefore, the use of systemic probiotics containing lactobacillus acidophilus that help to restore the microbiota has been proposed for the treatment and prophylaxis of bacterial urogenital infections (13). the aim of the present clinical study was to evaluate the feasibility and efficacy of a new combined 2-phase approach in order to treat neurological and non-neurological patients affected by recurrent symptomatic bacterial cystitis mainly due to e. coli. materials and methods between july 2013 and september 2014, consecutive subjects attending to our neuro-urology clinic with diagnosis of recurrent bacterial cystitis, were enrolled in our study. definition of symptomatic utis included the presence of at least 2 of the following symptoms: dysuria, new onset and/or worsening of urgency and/or urgency urinary incontinence, flank and/or suprapubic pain, worsening of muscle spasticity (in sci and ms patients) and/or autonomic dysreflexia (in sci patients) combined with a ≥ 105 cfu/ml at urine culture (in non-neurological) or ≥ 106 cfu/ml (in neurological population). only adults between 18 and 80 years-old were included. other inclusion criteria were: history of ≥ 3 acute episodes of recurrent symptomatic cystitis in the last year with at least two positive urine cultures for e. coli in the last 3 months before the screening, previous unsuccessful treatment with d-mannose and/or cranberry. exclusion criteria was the presence of positive urine culture not due to e. coli at the screening, pregnancy, breastfeeding, haematuria, fever, any uro-genital abnormalities at ultrasound, history of any allergies to salicylates and/or d-mannose, any use of antiobiotics for any reasons within the last two weeks before the enrollment and overall during the study. all patients received an initial 5-days regimen consisting on an oral combination of 1000 mg of d-mannose plus 200 mg of dry willow extract (salicin) three times daily (attack phase, morning-midday-evening always on a full stomach), followed by 7-days with 700 mg of d-mannose plus 50 mg (1x109 cfu) of lactobacillus acidophilus (la-14) twice daily (maintenance treatment, morning and evening on a full stomach). this latest combination (d-mannose plus la-14) was repeated at the same dosage for 15-days at each month for two months. changes in patients’ symptoms was monitored at baseline (t0), 2-weeks (t1), 12-weeks (end of treatment, t2) and at one month after the end of treatment (t3) by a 3-days bladder diary and the visual analogic scale (vas). the efficacy in preventing new recurrences was assessed by repeated urine cultures during follow-ups. results eighty-five patients were included in our study with a mean age of 45,2 years (range, 22-78). forty-six out of 85 were affected by neurogenic bladder (group b) due to spinal cord injury or multiple sclerosis (33 females and 13 males) with a mean age of 37,4 years (range, 25-54). thirty-seven out of 46 neurological patients were managed by intermittent catheterization regimen. seven patients in the group b missed the t2 follow up, then were considered as drop out. none of the 39 non-neurological patients (group a) dropped out during the study. patients with neurogenic bladder (group b) reported a decrease of mean vas scores from 7.21 ± 1.90 to 3.74 ± 3.12 starting from the first days of treatment until the end of the attack and maintenance phases (t1), and maintained the result at t2 and one month after the end of treatment (t3). symptoms at baseline were pain, urgency/frequency, urinary incontinence (table 1). again, a decrease of the mean vas scores during followup was also found in group a. this result was maintained at t2 and t3. the improvements in clinical symptoms in both groups (e.g. dysuria, frequency, urgency) were already significant 2 weeks after (t1) the beginning of treatment and these results were confirmed after the maintenance therapy (t2) and 1 month after the end of treatment (t3) (table 2). in particular, group a showed a significant decrease from 14.0 ± 2.6 to 6.9 ± 1.3 (p = 0.001) in daily urinary frequency at t1, a reduction that was maintained both at t2 (6.5 ± 1.2) and one month after the end of treatment (t3) 6.2 ± 0.9. in group b, a significant reduction in daily urinary frequency from 15 ± 3 to 8 ± 3 (p = 0.001) was observed at t1, a reduction that was maintained both at t2 and one month after the end of treatment (t3). table 1. symptoms at baseline. group a group b pts n° pts n° pain > 3 on vas scale 33/39 15/39 urgency/frequency ≥ 8 times/day 39/39 26/39 incontinence episodes 12/39 table 2. mean vas score pre and during treatment in both population. group a group b vas score t0 8.07 (± 1.70) 7.21 (± 1.9) vas score t1 4.74 (± 2.07) 3.74 (± 3.12) vas score t2 4.45 (± 2.19) 3.51 (± 2.32) vas score t3 4.24 (± 2.23) 3.40 (± 2.20) in this group b we observed also a reduction of the incontinence episodes at the 3-days bladder diary in 11 patients managed by intermittent catheterization ranging from 4.2+/0.60 (t0) to 2.8 +/1,33 (t2) (p > 0.001). no significant side effect was reported during the treatment. discussion urinary tract infections are still a major problem in clinical practice. advances in antibiotic therapy have allowed clinicians to decrease the duration of treatment and drastically reduce the complications associated with utis but they have not reduced uti frequency. on the other hand, an indefinite antibiotic prophylaxis would lead to selection of multiresistant microbial strains and exposure of the patients to serious infectious complications. various publications emphasize the importance of a moderate use of antibiotics. for this reason, research has focused on enhancing exogenous antibacterial defenses in the bladder. an attack treatment with d-mannose and salicin, followed by maintenance and/or prophylaxis therapy with d-mannose and probiotics was found to be effective in the treatment of urological infections, including recurrent bacterial cystitis (predominantly due to e. coli) also in different populations (neurological vs non-neurological) d-mannose acts to promote the elimination of bacteria from the bladder and lactobacillus acidophilus helps to rebalance the intestinal flora, thus reducing the presence of e. coli, which could reach the bladder via the urethra. the administration of d-mannose in combination with salicin results in an additive antiinflammatory activity of the two components in the treatment of inflammation and pain in addition, d-mannose and probiotics, administered in combination rather than separately, have demonstrated a surprising complementary activity resulting in a bacteria-repelling effect, which, unlike bactericidal or bacteriostatic effects, allows removal of the pathogenic bacteria/bacilli. although statistics was limited due to the small number and heterogeneity of patients, the study shows that this combination may be effective in resolving sympoms of uti. in addition, with the use of this proposed treatment we avoided to repeat antibiotics even in case of e. coli positivity during follow-up because of early solved acute symptoms at the first evaluation which was maintained also one month after the end of treatment. we are conscious that the main limit of this single-arm study was the lack of placebo-control. again no comparisons with other possible treatment combinations or single use of any of these solutions was done, although we intentionally included patients who were already unsuccessfully treated with d-mannose and/or cranberry before study. conclusions in our experience we found that the administration of an initial combination of d-mannose and salicin and a maintenance and/or prophylactic combination of dmannose and probiotics, in particular lactobacillus acidophilus, could be effective in the treatment and prophylaxis of recurrent cystitis with e. coli infection both in non-neurological and neurological patients. the treatment effectiveness can be measured with the resolution of cystitis-related symptoms. this combination treatment could be also promising as adjuvant therapy due to its bacteria-repelling, antiinflammatory and analgesic properties and rebalancing effects on the intestinal flora, leading to reduced antibiotic use and resistance. these positive results, obtained with these treatment and schedule, should be validated by further larger and randomized studies. references 1. flores-mireles al, walker jn, caparon m, hultgren sj. urinary tract infections: epidemiology, mechanisms of infection and treatment options. nat rev microbiol 2015; 13:269-284. 2. phé v, pakzad m, haslam c, et al. open label feasibility study evaluating d-mannose combined with homebased monitoring of suspected urinary tract infections in patients with multiple sclerosis. neurourol urodyn. 2017; 36:1770-1775. 3. jepson rg, williams g, craig jc. cranberries for preventing urinary tract infections. cochrane database syst rev. 2012; 10:cd001321 4. juthani-mehta m, van ness ph, bianco l, et al. effect of cranberry capsules on bacteriuria plus pyuria among older women in nursing homes. jama. 2016; 316:1879-1887. 5. hickling dr, nitti vw. management of recurrent urinary tract infections in healthy adult women. rev urol. 2013; 15:41-48. 6. kranjc̆ec b, papeš d, altarac s. d-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. world j urol. 2014; 32:79-84. 7. altarac s, papes d. use of d-mannose in prophylaxis of recurrent urinary tract infections (utis) in women. bjui. 2014; 9-10. 8. khayyal mt, el-ghazaly ma, abdallah dm, et al. mechanisms involved in the anti-inflammatory effect of a standardized willow bark extract. arzneimittelforschung. 2005; 55:677-87. 9. shim yh, lee sj, lee jw. antimicrobial activity of lactobacillus strains against uropathogens. pediatr int. 2016; 58:1009-1013. 10. ibrahem kh, hasan s. studying the ability of lactobacillus bacteria inhibit the growth of uropathogens and their adhesion to uroepithelial cells. j college of basic education. 2009; 60:73-84. 11. todorov sd, furtado dn, saad sm, et al. bacteriocin production and resistance to drugs are advantageous features for lactobacillus acidophilus la-14, a potential probiotic strain. new microbiol. 2011; 34:357-70. 12. lactobacillus acidophilus la-14. technical memorandum. danisco. 13. barrons r, tassone d. use of lactobacillus probiotics for bacterial genitourinary infections in women: a review. clin ther. 2008; 30:453-6. 14. foxman b, barlow r, d'arcy h, et al. urinary tract infection: self-reported incidence and associated costs. ann epidemiol. 2000; 10:509-515. 103archivio italiano di urologia e andrologia 2018; 90, 2 symptomatic cystitis a new natural treatment correspondence giulio del popolo, md dpgiulio@gmail.com federico nelli, md department of neuro-urology, azienda ospedaliero-universitaria careggi l.go g. alessandro brambilla, 3 firenze, italy stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4460 original paper no conflict of interest declared. pelvic ganglia to smooth muscles and the endothelial cells of the corpora cavernosa (4). low testosterone levels are associated with decreased libido, ed, decreased energy, depressive symptoms, and fatigue (5). changes in testosterone levels after covid-19 may not only increase the severity of ed but also cause ed alone (6). the relationship between covid-19 and testosterone is based on contracting the disease, the severity of the disease and progression of the disease. covid-19 makes use of transmembrane protease serine 2 (tmprss2) to penetrate into the host cell and androgen receptors are transcription supportive for tmprss2. the higher the testosterone level, the easier it is for covid-19 to penetrate into the host via this mechanism (7). besides, tmprss2 is up-regulated in prostate cancer where it supports tumor progression, thus these patients may have a higher risk of sars-cov-2 infection. tmprss2 inhibitors may be useful for the treatment or prevention of covid-19 (8). on the contrary, some other studies have reported that low testosterone levels are associated with acute respiratory distress syndrome (ards) by increasing proinflammatory cytokines and they intensify covid-19 infection in elderly men (9). ed which is caused by covid-19 appears to be associated with both vascular endothelial damage and reduction in testosterone level. even though the studies in the last year mostly focused on primary disease due to the pandemic, in some studies, covid-19 and its effects on sexual life have begun to be revealed and suggestions are made in terms of sexual health, especially through andrology associations (10), but the results on effects of covid-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory (11). our study aimed to figure out the factors which may play a role in the development of ed in our patients with covid-19 and the effect of testosterone level on the prognosis of covid-19. materials and methods study design and patients our study has been designed after being approved by the republic of turkey ministry of health and the local ethics committee (ethical committe approval number: 1303/27.01.2021) and 210 patients who were admitted objective: we aimed to investigate the relationship between covid-19 and erectile dysfunction (ed) and the effect of serum testosterone level on the disease prognosis. methods: between april-december 2020, 70 patients who were admitted with a complaint of ed after having covid-19 and whose serum testosterone level was checked for varicocele, premature ejaculation, and infertility reasons before covid-19. the patients filled the international index of erectile function (iief-5) and their testosterone level was checked. the questionnaire was arranged to assess the first month before covid-19 and after covid-19. testosterone levels of the patients before and after covid-19 were compared. the relationship between testosterone levels and hospitalization in the intensive care was evaluated. results: it was revealed that testosterone levels and iief-5 scores after covid-19 in all patients were statisticaly and significantly different compared to the period before covid-19 (p < 0.05). testosterone levels of patients in need of intensive care were significantly higher than those without any need of intensive care (p < 0.05). conclusions: our study has presented that covid-19 may cause ed and high testosterone levels increase the rate of hospitalization in the intensive care by intensifying the disease. key words: covid-19; erectile dysfunction; testosterone. submitted 18 september 2021; accepted 9 october 2021 introduction the global coronavirus disease (covid-19) results in a cytokine storm that leads to the development of microthrombosis and diffuse intravascular coagulation (dic) (1). despite the fact that lungs are the organs which are primarily targeted in cytokine storm, the cardiovascular system is also affected. the autopsies which were performed showed that there were signs of endothelial damage, pulmonary embolism, bleeding at multiple levels including alveolar, microangiopathy, and vascular dysfunctions in the form of vasculitis (2). the relationship between erectile dysfunction (ed) and covid-19 develops due to vasculogenic and hormonal causes which were caused by the primary disease. the vasculogenic damage and ed are also seen as predictors of a cardiovascular pathology which may be observed in patients in the future (3). testosterone, which is the most important hormone in male erection, modulates almost every component involved in erectile function, from the erectile dysfunction and testosterone levels prior to covid-19 disease: what is the relationship? kadir karkin, ergün alma department of urology, health sciences university, adana city training and research hospital, adana, turkey. doi: 10.4081/aiua.2021.4.460 summary 461archivio italiano di urologia e andrologia 2021; 93, 4 erectile dysfunction and testosterone in covid-19 to our clinic with a complaint of ed between aprildecember 2020 were evaluated prospectively. written consent forms were obtained from all patients who participated in the study. in order to figure out the erectile conditions of the patients, the iief-5 questionnaire, fiveitem short version of the international index of erectile function (iief-ef), was used. this questionnaire was designed in a form assessing the first month before covid-19 infection and the period after covid-19. according to this form, scores between 5-7 were considered as severe, 8-17 as moderate, 17-21 as mild and 22-25 as no ed. male patients with an elapsed time at least six months after covid-19 and who did not have ed according to the iief-5 score before covid-19 infection, and whose testosterone level was measured for varicocele, premature ejaculation, infertility reasons in the last year were included in our study. furthermore, beck depression scale was used to determine the current depressive states of the patients. patients with minimal depression (0-9) according to this scale were included in the study. the patients who had comorbidities before covid-19 such as obesity, hypertension, diabetes or heart disease, the patients who have used drugs (such as beta blocker) that can cause ed during and after covid-19, the patients with who had an increase in smoking and alcohol use after covid-19, the patients with an elapsed time of less than 6 months after covid-19, the patients whose testosterone levels were not known before covid-19, the patients who did not have a minimal depression level according to the beck depression scale, the patients with an iief-5 score of 21 and below, the patients who had treatment for ed before covid-19, whose detailed medical history could not be taken and who did not have education level enough to fill in iief-5 form were not included in the study. after being evaluated according to the exclusion criteria, our study was carried on with 70 patients. the ages of the patients, their results of covid-19 polymerase chain reaction (pcr) test, testosterone level, reports consistent with covid-19 observed in thoracic computed tomography (ct) and the presence of hospitalization in intensive care unit were recorded. the patients were evaluated after being classified under three different groups according to their ages. the patients aged between 20-40 were recorded in group 1, the ones aged between 40-60 were recorded in group 2 and the ones aged 60 or over were recorded in group 3. the levels of serum testosterone before and after covid-19 were compared among the groups. the relationship between the levels of testosterone and the hospitalization in the intensive care unit and ed states of the patients hospitalized in the intensive care unit were evaluated. data collection the electronic hospital information system was used to get epidemiological data, including demographic, clinical and laboratory findings. considering the circadian rhythm of testosterone release, the total testosterone which were measured in the venous blood sample between 7 and 11 in the morning were recorded. peripheral venous blood samples were evaluated in the central laboratory of adana city training and research hospital by using the standard procedures. biochemical hormonal parameters were measured by siemens advia 1800 automatic biochemistry analyser (siemens healthcare diagnostics inc, laboratory diagnostics, advia centaur xpt, erlangen, germany, manufactured in ireland). statistical analysis spss 23.0 package program (ibm, armonk, ny) was used in the statistical analysis of data. categorical measurements were summarized as numbers and percentages, continuous measurements were summarized as mean, standard deviation and minimum-maximum. the appropriateness of the variables to normal distribution was investigated by using kolmogorov-smirnov/shapiro-wilk tests. mann-whitney u test and wilcoxon test were used in the groups which do not agree with normal distribution. spearman correlation analysis was benefited from in the comparison of the relationship between the numerical variables. statistical significance level was taken as 0.05 in all tests. results the mean age in our study was 52.3 ± 13.5 years. when the groups were considered, it was seen that 22.9% (n = 16) of the patients were in group 1, 47.1% (n = 33) were in group 2 and 30% (n = 21) were in group 3. the mean iief score of the patients was 23 before covid-19 and 11.03 after covid-19 (table 1). no statistical difference was observed between the patient’s age and the rate of hospitalization in the intensive care unit (p > 0.05). a statistically significant difference was observed between the iief scores of the patients with and without intensive care need in the period after covid-19 (p < 0.05). testosterone levels of patients with intensive care need were significantly higher than those of the patients without intensive care need (p < 0.05) (table 2). testosterone levels after covid-19 were found significantly lower than the testosterone levels before covid19 (p < 0.001). in all three groups, it was seen that testosterone levels and iief scores after covid-19 were statistically and significantly different compared to the ones before covid-19 (p < 0.05). as the age of the patients increased, iief scores after covid-19 and testosterone levels before and after covid-19 were found to be significantly lower (p < 0.05). also, there was a statistically significant relationship between iief scores and testosterone levels (p < 0.05). while there was a positive corretable 1. demographic data and mean iief according to the patient groups. age frequency (n) percentage (%) 20-40 16 22.9 40-60 33 47.1 60 and over 21 30 mean ± sd mediann (min-max) age 52.33 ± 13.51 56 (22-74) iief score before covid 23.5 ± 1.57 23 (22-25) iief score after covid 11.03 ± 3.76 11 (5-18) archivio italiano di urologia e andrologia 2021; 93, 4 k. karkin, e. alma 462 lation between the testosterone level findings, the iief scores before covid-19 (r = 0.383) and the iief scores after covid-19 (r = 0.423) of the patients who participated in the study, there was a negative correlation between the ages of the patients and the iief scores before covid-19 (r = -0.675) and the iief scores after covid-19 (r = -0.557) (p < 0.05) (table 3). discussion we showed with this study that covid-19 causes ed in all age groups, reducing testosterone levels seriously. moreover, we also oberved that the higher the testosterone levels during covid-19, the more severe the disease progresses. to the best of our knowledge, a similar study suggesting that covid-19 causes ed has not been published before in the related literature. ed is multidimensional and commonly male sexual dysfunction involves a change in any component of the erectile response, including organic, relational, and psychological. non-endocrine (neurogenic, vasculogenic, and iatrogenic) and endocrine pathways may cause ed (12, 13). endothelial dysfunction equals erectile dysfunction or vice versa (ed-ed). it is presented in the literature that the prevalence of ed can be up to 30% in young men and that the rare of ed is further increased in elderly due to diseases of coronary and penile arteries (14-16). in covid-19 infection, the ace enzyme, which provides access to host cells, is expressed by endothelial cells and the fragile vascular bed is affected preparing the ground for the development of ed (17-22). testosterone deficiency is one of the most important hormonal causes of ed development. testosterone modulates almost all components of the erectile mechanism, down to the endothelial cells in the corpus cavernosum. current eau guidelines recommend to measure baseline testosterone levels in all men who admit with a complaint of ed (7). araujo et al. showed in their studies that the testosterone levels of 24% of men aged between 30-79 were below 300 and 5.6% of them had symptomatic androgen deficiency (23). yassin et al. reported that testosterone replacement therapy (trt) improved erectile function in hypogonadal men who previously received phosphodisterase-5 inhibitor (pde5i) before (24). rizk et al. suggested that the use of trt as monotherapy in patients with mild ed was effective (25). our present study shows that patients of all age groups are affected, although ed which develops after covid-19 seems to affect more elderly patients. it was also revealed that testosterone levels of the patients were significantly lower in all age groups, especially in elderly patients. in covid-19 infection, leydig cells in the testicles are damaged and this testicular damage causes a decrease in serum testosterone levels (26). ling ma et al. reported that testosterone/luteinizing hormone (lh) ratios were significantly lower in patients with covid-19 infection (27). vanhorebeek et al. observed that there was a decrease in testosterone level in the acute phase of covid-19 (28). also okçelik reported that testosterone levels decreased during acute covid-19 infection and especially in patients with pulmonary involvement (29). it was also concluded in our study that the significant decrease in the testosterone levels of patients after covid-19 is an indicator of a possible testicular damage and this finding supports the studies in the literature. testosterone is a hormone which has an effect not only on the erection mechanism but also on many functions in the body. inflammation is known to be suppressed as a result of the decrease in pro-inflammatory cytokines and the increase of anti-inflammatory cytokines while responding to infections. it was shown in the study of mohamad et al. that testosterone suppresses inflammation by increasing anti-inflammatory cytokines and decreasing pro-inflammatory cytokines (30). malkin et al. conducted a crossover study with 27 men with symptomatic androgen deficiency. they concluded that testosterone treatment decreased pro-inflammatory cytokine levels and increased the concentration of interleukins, which are some of the anti-inflammatory cytokines (31). although table 2. rates of hospitalization in the intensive care according to groups, evaluation of hospitalization in the intensive care and iief score before and after covid-19 and correlation between the hospitalization in the intensive care and testosterone level. 20-40 40-60 60 and over p (n = 16) (n = 33) (n = 21) n (%) n (%) n (%) hospitalization in the intensive care yes 5 (31.2) 11 (33.3) 6 (28.6) .93 no 11 (68.8) 22 (66.7) 15 (71.4) iief score before covid iief score after covid p median (min-max) median (min-max) hospitalization in the intensive care no 24 (22-25) 13 (5-18) < .001 yes 23 (22-24) 8 (5-13) < .001 p .95 < .001 testosterone level p median (min-max) hospitalization in the intensive care no 291 (112-531) < .001 yes 390 (180-680) table 3. comparison of the iief scores and testosterone levels before and after covid-19, evaluation of the iief scores and testosterone levels before and after covid-19 according to groups and correlation between testosterone level, age and iief score. mean ± sd p iief score before covid 23.5 ± 1.57 < .001 iief score after covid 11.03 ± 3.76 testosterone level before covid 345.67 ± 109.48 < .001 testosterone level after covid 297.31 ± 96.04 according to groups 20-40 40-60 60 and over p (n = 16) (n = 33) (n = 21) median (min-max) median (min-max) median (min-max) iief score before covid 24(23-25) 23 ( 22-25) 22 (22-23) .9 iief score after covid 14(6-18) 11 (5-18) 8 (5-17) < .001 testosterone before covid 400 (213-531) 390 (122-680) 225 (112-423) < .001 testosterone after covid 300 (230-449) 300 (100-600) 200 (100-400) < .001 testosterone level age r p r p iief score before covid 0.383 .001 -0.675 < .001 iief score after covid 0.423 < .001 -0.557 < .001 463archivio italiano di urologia e andrologia 2021; 93, 4 erectile dysfunction and testosterone in covid-19 our study did not focus on any evaluation in this direction, we assume that the low testosterone level in patients after covid-19 may have contributed to inflammation. we also believe that the investigation of the effect of trt on the clinical findings of the patients should be supported by prospective studies. during the cytokine storm caused by covid-19, low testosterone can also affect the prognosis of the disease. jiawei et al. have suggested in their study that testosterone may play a role in the chain of events leading to the progression of covid-19 infection due to the cytokine storm. it was concluded with this study that there may be a negative correlation between ace2 expression and covid-19 mortality as a result of suppression of ace2 expression by inflammatory cytokines accompanying the decrease in androgens and oestrogens in the elderly (32). giagulli et al. has shown that testosterone can make men susceptible to a common covid-19 infection compared to oestrogen, and low serum testosterone levels in severe patients make men, especially older, susceptible to poor prognosis or death (33). papadopoulos et al. reported that low testosterone levels are associated with ards increasing the severity of covid-19 infection in elderly men and they added that normal testosterone levels may also provide some slight protection against covid-19 (13). similar studies in the literature support a relationship between the need for intensive care and low testosterone levels in covid-19 infection (34, 35). studies have also been reported that testosterone affects by using a different mechanism apart from the cytokine mechanism during covid-19 infection. it has been reported in the study of lii et al. that the first biological step which is necessary for the potential infectivity of covid-19 is to activate ace2 as the entry receptor and to use cellular transmembrane protease serine 2 (tmprss2) to prepare spike protein (36). hoffmann et al. showed in their study that viral spread and pathogenesis are provided in infected hosts by spike proteins becoming ready by tmprss2 (37). heurich et al. presented in their study that tmprss2 can also break down ace2 for viral entry and that androgen receptor activity is a requirement for the transcription of the tmprss2 gene (38). there are studies reporting that high testosterone levels are associated with poor prognosis in covid-19 through this mechanism. wambier et al. reported that the hyperandrogenic phenotype may be associated with increased viral load, increased viral spread, and severity of lung involvement for covid-19 (39). it was reported by rozhivanov et al. that both tmprss2 expression and a more severe course of coronavirus infection were observed in men with hyperandrogenism. in this context, some researchers suggested the creation of androgen deprivation with drug treatments for men at high risk of developing covid-19 (40). there are some contrasting views in the literature on the effect of testosterone level on covid-19 prognosis and further studies are required to support them. the results of our study showed that patients with high testosterone levels need intensive care more and this supports the studies in the literature claiming that high testosterone level is a poor prognostic factor for covid-19. there are some limitations of our study. our study reflects the results of one centre and includes a limited number of patients. besides, although we have excluded many factors that cause ed (such as obesity, hypertension, diabetes or heart disease), the ed mechanism is dependent on a lot of factors that our study may not have been able to evaluate adequately since a non-ed vital disease is discussed. other limitations are that the psychological state of the patients may have affected the iief-5 score, and conditions such as varicocele and infertility may cause low testosterone levels, which may affect our results. however, to the best of our knowledge, our study is one of the first studies showing that covid-19 causes erectile dysfunction and there are only a limited number of studies in the literature on this subject. we hope that our study will make a considerable contribution to the literature with this aspect. conclusions covid-19 can cause erectile dysfunction in men of all age groups, and high testosterone increases the rate of hospitalization in the intensive care unit by intensifying the disease. acknowledgment we would like to thank the adana city hospital urology clinic for their contribution. 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181:271-280.e8. 38. heurich a, hofmann-winkler h, gierer s, et al. tmprss2 and adam17 cleave ace2 differentially and only proteolysis by tmprss2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. j virol. 2014; 88:1293-1307. 39. wambier cg, goren a. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection is likely to be androgen mediated. j am acad dermatol. 2020; 83:308-309. 40. rozhivanov rv, andreeva en, melnichenko ga, mokrysheva ng. androgens and antiandrogens influence on covid-19 disease in men. probl endokrinol (mosk). 2020; 66:77-81. correspondence kadir karkin, md (corresponding author) kadir_karkin@msn.com ergün alma, md health sciences university, adana city training and research hospital, department of urology, 01330, adana (turkey) 11archivio italiano di urologia e andrologia 2020; 92, 1 original paper prognostic value of p16ink4a overexpression in penile cancer mário pereira-lourenço 1, duarte vieira e brito 1, miguel eliseu 2, noémia castelo-branco 3, joão pedro peralta 1, ricardo godinho 1, paulo conceição 1, mário reis 1, carlos rabaça 1, amílcar sismeiro 1 1 urology department portuguese institute of oncology coimbra, coimbra, portugal; 2 urology and kidney transplant department coimbra hospital university centre, coimbra, portugal; 3 pathology department portuguese institute of oncology coimbra, coimbra, portugal. introduction: penile cancer is rare, accounting for less than 1% of all male cancers in industrialized countries. it is most common in areas of high prevalence of hpv, being a third of cases attributed to the carcinogenic effect of hpv. tumour cells infected with hpv overexpress p16ink4a, as such p16ink4a has been used as a surrogate of hpv infections. objective: to evaluate the prognostic factor of p16ink4a overexpression in penile cancer. methods: retrospective analysis of patients diagnosed with penile cancer, submitted to surgery in a portuguese oncological institution in the last 20 years (n = 35). histological review of surgical pieces and immunohistochemical identification of p16ink4a. relation between p16ink4a and the following factors were studied: age, histological subtype, tumour dimensions, grade, tnm stage, perineural invasion, perivascular invasion, disease free survival (dfs) and cancer specific survival (css). results: p16ink4a was positive in 8 patients (22.9%). identification of p16ink4a did not correlate with none of the histopathological factors. in this work we identified a better dfs and css in patients positive for p16ink4a (dfs at 36 months was 100.0% vs. 66.7%; css at 36 months was 100.0% vs. 70.4%), although without statistical significance (p > 0.05). in multivariate analysis of histopathological factors studied, only n staging correlated with dfs and css (p = 0.017 and p = 0.014, respectively). discussion: the percentage of cases positive for p16ink4a is smaller than the one found in literature, which can suggest a less relevant part of hpv infection in the oncogenesis of penile cancer in the studied population. identification of p16ink4a did not relate with other clinicopathological factors. tendency for a more favourable prognosis in patients with p16ink4a agrees with results found in literature. the most relevant factor for prognosis is nodal staging. conclusions: penile cancer positive for p16ink4a shows a trend for better survival, although the most relevant factor is nodal staging. key words: penile cancer; hpv; p16; prognosis. submitted 29 august 2019; accepted 1 september 2019 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.11 introduction in industrialized countries, penile cancer is rare, having an incidence of approximately 1/100000 in europe and the united states of america, accounting for less than 1% of all male cancers (1-3). however, in other regions of the world, particularly south america, southeast asia and parts of africa, the incidence of penile cancer is much greater, accounting for about 2% of all male cancers, although in some countries it can reach 10% (4, 5). the incidence of penile cancer increases with age, reaching a peak in the six decade, although it can occur in much younger patients (1, 6). penile cancer is most common in areas with high prevalence of hpv, with a third of cases attributed to the carcinogenic effects of hpv (1, 7). other risk factors identified where: phimosis (8, 9), chronic penile inflammation/ lichen sclerosus (10), psoralene and phototherapy with ultraviolet radiation a (11), smoking (8), residing in rural areas/low socioeconomical level (12, 13) and multiple sexual partners (8). in relation to penile cancer, hpv dna was identified in 30-40% of cases, varying in accordance to histological subtype. the histological subtypes most associated with hpv are basaloid penile squamous cells carcinoma (pscc) (76%), mixed warty-basaloid pscc (82%) and warty pscc (39%). the usual pscc and papillary pscc are not associated with hpv (14, 15). although the classic pscc is normally characterized as non-related to hpv, a recent metanalysis identified an association in over 30% of cases (16). the subtypes of hpv most commonly associated with penile cancer are 16 and 18 (17). the world health organization (who), utilizing the hypothesis of independent pathways of carcinogenesis, categorizes pscc regarding hpv (18, 19). the prognostic value of the association with hpv is still controversial, with recent studies showing a better outcome in hpv associated penile cancer (20-22), while others do not show significant differences (18, 23). various methods can be used to detect hpv in tumour cells, such as pcr amplification to detect hpv dna. due to the overexpression of p16ink4a in hpv infected cells, p16ink4a expression can be used as a surrogate of active hpv infections (16). in cervical cancer and in other squamous cell carcinomas, expression of p16ink4a is used as a marker for the presence of high-risk hpv (17-19). progression and regression of low grade intraepithelial cervical cancer can be estimated utilizing p16ink4a and mark a better cancer specific survival (css). however, the lourenco_stesura seveso 01/04/20 18:52 pagina 11 archivio italiano di urologia e andrologia 2020; 92, 1 m. pereira-lourenço, d. vieira e brito, m, eliseu, n. castelo-branco, j.p. peralta, r. godinho, p. conceição, m. reis, c. rabaça, a. sismeiro 12 correlation between expression of p16ink4a and hpv infection in penile cancer is still controversial (24). the main aim of this paper is to evaluate the prognostic value of p16ink4 expression in penile cancer. other goals are to evaluate the epidemiologic association between hpv and penile cancer in portugal (indirect assessment by assessing expression of p16ink4a) and to evaluate the association between hpv and histological subtypes of pscc and the initial staging of the disease. methods patient selection and data collection retrospective analysis of all patients with the primary diagnosis of penile cancer treated in a portuguese oncological institution, in the last 20 years. retrospective evaluation of patient data. pathological and immunohistochemistry evaluation all surgical specimens of the identified patients were revaluated for this study. the material was fixed in 10% formol, embedded in paraffin and stained with haematoxilin-eosine, and was reviewed by a genitourinary pathologist that determined the histologic subtyping and the pathological grade using the morphologic criteria presented in the who classification of tumours of the penis of 2016 and tumour staging was made according the ajcc cancer staging manual of 2017 (19, 25). immunohistochemical analysis was performed on the benchmark-ultra platform (ventana r). antigenic retrieval was performed using the ultraview universe dab detection kit (ventana r). slides were then incubated with monoclonal antibody to p16ink4a (mouse clone e6h4, cintec r p16 histology, ventana r). the bond polymer refine detection system (ventana) was used for secondary antibody and visualization. cervical squamous cell carcinoma was used as positive control, and benign skin as negative control. cases were scored by a genitourinary pathologist. to define the expression patterns of p16ink4a, the classification of cubila et al. (26) was adapted, and overexpression of p16ink4a was defined as diffuse, continuous, and strong nuclear and cytoplasmic staining of the neoplastic cells. discontinuous, focal and weak staining as well the absence of staining was interpreted as negative for p16ink4a overexpression. statistical analysis the program spss 21 was used for statistical analysis. we used the mann-whitney test to assess the relation between clinical and pathological characteristics and p16ink4a. survival related to each individual factor were calculated by the kaplen-meyer curves. multivariate analysis utilizing cox regression was utilized for the impact of clinical and pathological factors on survival. results clinicopathological data the total number of patients was 35, the median age was 69 (range 33-90 years) and the median tumour size was of 2.5 cm (range, 0.4-12.0). eight patients (22.9%) presented with positive p16ink4a test. relating to t staging, 1 (2.9%) presented with tis, 13 (37.1%) t1, 11 (31.4%) t2 and 10 (28.6%) t3. the clinicopathological results are summarized in table 1. p16ink4a immunoexpression the relation between p16ink4a expression and the remaining clinicopathological results are summarized in table 2. p16ink4a immunoexpression did not correlate in a significant way (p > 0.05) with none of studied factors. p16ink4a immunoexpression and prognosis the median follow-up was 63 months (range 6-204). the kaplan-meyer curves of disease-free survival (dfs) and cancer specific survival (css) in relation to p16ink4a immunoexpression are presented in figures 1, 2, respectively. although a tendency to a longer survival with positive p16ink4a immunoexpression, this was not statically significant (dfs: p = 0.219; css: p = 0.067). the dfs and css at 3 years for patients with positive p16ink4a immunoexpression were 100.0% and 100.0%, respectively. the dfs and css at 3 years for patients with negative p16ink4a immunoexpression were 66.7% and 70.4%, respectively. other clinicopathological factors and prognosis the disease-free survival and cancer specific survival in relation to t stage, n stage, tumour grade, perineural invasion and perivascular invasion were evaluated. in relation to dfs, the following factors were associated with higher survival: t stage t ≤ 1 (p = 0.002) and n = 0 (p < 0.001). table 1. clinicopathological results. n (%) age (years) • < 65 13 (37.1%) • ≥ 65 22 (62.9%) pscc histologic subtype • usual 28 (80%) • warty 3 (8.6%) • verrucous 2 (5.7%) • mixed warty-basaloid 2 (5.7%) dimension (cm) • < 4 26 (74.8%) • ≥ 4 9 (25.7%) p16ink4a • positive 8 (22.9%) • negative 25 (78.1%) differentiation grade • g1 14 (40%) • g2 15 (42.9%) • g3 6 (17.1%) t stage • ≤ 1 14 (40.0%) • > 1 21 (60.0%) lymph node metastasis • no 26 (74.3%) • yes 9 (25.7%) died of the disease • no 26 (74.3%) • yes 9 (25.7%) lourenco_stesura seveso 01/04/20 18:52 pagina 12 analysing css the following factors presented statistically significant improved survival: age < 65 years (p = 0.042), stage t ≤ 1 (p = 0.005), stage n = 0 (p < 0.001). in a multivariate cox regression analysis with the previously described factors and hpv, the model was statistically significant in relation with dfs and css, although only n stage presented with statically relevance (p = 0.017 and p = 0.014, respectively). discussion in this study, we identified 22.9% of p16ink4a positive pscc, a value smaller than the one calculated by a recent metanalysis, which identified p16ink4a in 42.6% (95% ci; 36.2-47.0) worldwide (2995 cases) and 44.9% (95% ci; 38.4-51.1) in europe (16). a spanish study (bar celona), interesting to compare due to the geographic proximity with portugal, identified a p16ink4a positivity in 34.0% of 72 cases (22). in order to understand this result, it is essential to comprehend the meaning of positive p16ink4a and its correlation with the physio-pathological role of hpv infection in penile cancer. the most sensitive method for the detection of hpv in tumoral tissue is pcr amplification (27). due to the strong correlation between active hpv and p16ink4a overexpression in neoplastic cells, it has been used as a surrogate marker for hpv (28). the incorporation of high-risk hpv (hrhpv) in the host genome, leads to the overexpression of oncoproteins (e7 and e6). the protein e7 binds to retinoblastoma protein, leading to the increased expression of p16 (tumour suppressing protein). this overexpression can be used as a reliable marker for high-risk hpv infection (26). sensitivity and specificity of p16ink4a expression in hr-hpv was 100% and 57%, respectively (29). this lack of specificity leads some authors to defend that identification of hpv dna is fundamental (30). according to cubilla et al., positivity for p16ink4a in penile cancer has a strong correlation with the presence of hr-hpv (26). in the presence of a negative p16ink4a, infection with a low risk hpv genotype or absence of hpv infection can be suspected (24). in the previously addressed metanalysis by olesen et al. (16), 79.6% of hpv positive cases presented with a positive p16ink4a, while 18.5% of hpv negative cases also presented with positive p16ink4a. one of the explana13archivio italiano di urologia e andrologia 2020; 92, 1 p16ink4a overexpression in penile cancer figure 1. disease free survival for p16ink4a positive and negative patients. figure 2. cancer specific survival for p16ink4a positive and negative patients. table 2. relation between p16ink4a expression and the remaining clinicopathological results. n (%) age (years) • < 65 2 (25.0%) 11 (40.7%) 0.425 • ≥ 65 6 (75.0%) 16 (59.3%) pscc histologic subtype • usual 6 (75%) 22 (81.5%) 0.800 • warty 1 (12.5%) 2 (7.4%) • verrucous 0 (0.0%) 2 (7.4%) • mixed warty-basaloid 1 (12.5%) 1 (3.7%) dimension (cm) • < 4 6 (75.0%) 20 (74.1%) 0.318 • ≥ 4 2 (25.0%) 6 (22.2%) differentiation grade • g1 4 (50.0%) 10 (37.0%) 0.510 • g2 3 (37.5%) 12 (44.4%) • g3 1 (12.5%) 5 (18.5%) perineural invasion • no 7 (87.5%) 4 (14.8%) 0.871 • yes 1 (12.5%) 23 (85.2%) lymphovascular invasion • no 7 (87.5%) 24 (88.9%) 0.915 • yes 1 (12.5%) 3 (11.1%) t stage • ≤ 1 3 (37.5%) 11 (40.7%) 0.871 • > 1 5 (62.5%) 16 (59.3%) lymph node metastasis • no 8 (100.0%) 18 (66.7%) 0.062 • yes 0 (0.0%) 9 (33.3%) died of the disease • no 8 (100.0%) 18 (66.7%) 0.062 • yes 0 (0.0%) 9 (33.3%) lourenco_stesura seveso 01/04/20 18:52 pagina 13 archivio italiano di urologia e andrologia 2020; 92, 1 m. pereira-lourenço, d. vieira e brito, m, eliseu, n. castelo-branco, j.p. peralta, r. godinho, p. conceição, m. reis, c. rabaça, a. sismeiro 14 tions for this variation and apparent incoherence may be the cut-off value used to consider a positive p16ink4a, although olesen et al. did not find a significant difference between different cut-offs (16). two recent reviews identified a prevalence of hpv positive pscc (identified by pcr amplification) of 33.1% (31) and 39.4% (32). nevertheless, various authors consider that a tumour can only be considered hpv positive if it presents with double positivity for hpv and p16ink4a (16, 18, 33). in an interesting way, positivity for p16ink4a correlates with the presence of high-risk hpv subtypes (hpv 16, hpv18 e hpv59) (18). in this work there was no correlation between p16ink4a and histologic subtype. in the case of usual pscc, 6 (21.4%) were p16ink4a positive. concerning warty pscc, mixed pscc (basaloid + warty) and verrucous pscc, the number of p16ink4a positive patients was 1 (33.3%), 1 (50%) and 0 (0%) respectively. the last world health organization (who), divides pscc in tumours related to hpv and non-related to hpv, as there may be prognostic importance in this division (19). curiously, usual pscc is identified as non-related with hpv (as are papillary, verrucous, sarcomatous and others), although data collected from literature indicates a prevalence of hpv dna in usual pscc of 32.2% and positive p16ink4a of 36.9% (16). our results and data from analysed literature, indicates that the classification usual pscc as independent of hpv is limited. in relation to warty pscc and mixed basaloid-warty pscc (both classified as tumours related to hpv), literature indicates positivity for p16ink4a in > 90% of cases (16). the low number of warty and mixed basaloid-warty pscc in our series does not allow for sustained comparations, although they corroborate the limitations present on the suggest classification presented by the who. in our work we did not directly study the presence of hpv, as such we cannot logically study the different hpv subtypes associated with pscc. in developed and undeveloped countries, the predominant hrhpv associated with pscc is hpv-16 as shown by several studies. although uncommon in european countries, hpv-18 is the second most prevalent in pscc in the world (22, 34). in the metanalysis conducted by olesen et al., hpv16 (68.3%), followed by hpv6 (8.1%%) and hpv18 (6.9%). were the predominant oncogenic subtypes (16). in our study, we did not find any relation between p16ink4a and other histologic characteristics. pone et al. did not find a relation between p16ink4a and other histologic characteristics (size, clinical stage, histological grade, or lymphatic or perineural invasion), although identified a relation with histologic subtype (24). our series did not present with any basaloid tumour, although literature indicates a relation between positive p16ink4a and this histological subtype (26). ferrándiz-pulido et al. identified a connection between positive p16ink4a and histological differentiation (p16ink4a was associated with g3/4) and histological subtype (22). some works distinguish between penile epithelial neoplasia (pen) and pscc in evaluating the importance of hpv and p16ink4a, as most of pen (> 70%) are hpv+. we decided not to exclude the single patient with pen from our work, as positivity for p16ink4a between pen and pscc are very similar (49.5% vs. 41.6%, respectively) (16). analysing prognosis, we did not find, in this work, a significant statistical relation between p16ink4, dsf and css. nevertheless, there is a clear trend for a better outcome in patients positive for p16ink4a with only one patient presenting with recurrence and no case of disease related mortality. the absence of statistical significance is probably related with the low number of p16ink4a positive tumours in our sample. various works have studied the effect of hpv and p16ink4a in the prognosis of pscc. regarding the effect hpv in dfs, afonso et al. (112 patients, median follow-up of 20 months) and lorenzo et al. (30 patients, median follow-up of 24 months) did not detect significant differences (35, 36). scheiner et al. (72 patients) reported a better dfs at 5 years, although without statistical significance (37). concerning the effects of hpv in css, in the review by sand et al. (649 patients, 174 hpv+) a better css for patients hpv positive was noted (hr 0.61; 95% ci: 0.38-0.98) (32). analysing the effects of hpv in overall survival (os), studies did not show a significant relation (32, 38). tang et al. described a better dfs in patients positive for p16ink4a (119 patients, 59 p16ink4a positive, median follow-up of 30 months) (44). however, other works did not show a relation between p16ink4a and dfs. the effect of p16ink4a in css was studied by sand et al. (review of 414 patients, 191 positive for p16ink4a) with a hr of 0.45 (95% ci: 0.300.69) for patients positive for p16ink4a (32). the percentage of patients alive 4 or 5 years after diagnosis range from 69% to 100% for p16ink4a positive and from 51% to 77% if p16ink4a negative (22, 23, 29, 39-43). all the study-specific hrs are below 1 and ranging from 0.21 to 0.81, however only one (40) was statistically significant. regarding os, pone et al. reported a better os in patients positive for p16ink4a, with a hr of 0.88 (95%ci: 0.49-1.59) (24). zargar-shoshtari et al. found that men with penile cancer positive for p16ink4a had a significant better os compared with negative p16ink4a (hr = 0.33; 95% ci: 0.130.85) in a multivariable model adjusting for pathological nodal status, adjuvant chemotherapy and age (42). tang et al. did not find a connection between p16ink4a and os (44). in this work, due to the discharge from follow-up of some patients and limitation in the quality of data collection outside our institution, we did not calculate os. in general, bibliography demonstrates a better survival for patients positive for hpv, as reported in other tumours related with hpv (vulvar, oropharyngeal) (32). sand et al., in the previously referred metanalysis, that analysed the hr of css of p16ink4a and css of hpv positive patients, discovered that the hr of css p16ink4a positive patients was lower than that of hpv positive patients. this could suggest that p16ink4a expression may be a stronger predictor of css than hpv, similar to studies of neck and head cancer (32). the prognostic value of hpv is still uncertain. some have suggested that the presence of a viral infection (hpv), might increase immune surveillance, making hpv positive cancer less aggressive than non-viral cancers (21). in univariate analysis with other clinicopathological factors, a significant relation was found between t staging and n staging with dfs and css, while age > 65 years lourenco_stesura seveso 01/04/20 18:52 pagina 14 presented with lower css. in multivariate analysis, only n staging correlated with survival. a work by wen et al. (135 patients), reported a relation between n staging (clinical and pathologic) and css. in multivariate analysis, only pathologic n staging related with css (absence of relation between css and age, presence of phimoses, smoking, type of surgery, t stage or grade) (46). our study presented with some limitations. our series presents a limited number of patients, with only eight p16ink4a positive patients, which limits statistical results. in our work we did not evaluate the presence of hpv dna, which can be relevant to corroborate the know connection between p16ink4a status. lastly, due to the number present in our series, we did evaluate the influence of other factors that might influence prognosis, particularly the use of adjuvant or neoadjuvant therapies. conclusions penile cancer positive for p16ink4a present with a trend for better outcome, although the most relevant factor is node stage. the probable prognosis importance of p16ink4a corroborates the indication for its 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with special emphasis on hpv status in penile carcinoma. virchows arch. 2019; 475:211-21. 19. moch h, cubilla al, humphrey pa, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. eur urol. 2016; 70:93-105. 20. djajadiningrat rs, jordanova es, kroon bk, et al. human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. j urol. 2015; 193:526-31. 21. lont ap, kroon bk, horenblas s, et al. presence of high-risk human papillomavirus dna in penile carcinoma predicts favorable outcome in survival. int j cancer. 2006; 119:1078-81. 22. ferrándiz-pulido c, masferrer e, de torres i, et al. identification and genotyping of human papillomavirus in a spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(ink4a) expression, and prognosis. j am acad dermatol. 2013; 68:73-82. 23. bezerra al, lopes a, santiago gh, et al. human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. cancer. 2001; 91:2315-21. 24. martins va, pinho jd, teixeira júnior aal, et al. p16ink4a expression in patients with penile cancer. plos one. 2018; 13:e0205350. 25. amin mb, greene fl, edge sb, et al. the eighth edition ajcc cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. ca cancer j clin. 2017; 67:93-9. 26. cubilla al, lloveras b, alejo m, et al. value of p16(ink)4(a) in the pathology of invasive penile squamous cell carcinomas: a report of 202 cases. am j surg pathol. 2011; 35:253-61. 27. halec g, alemany l, lloveras b, et al. pathogenic role of the eight probably/possibly carcinogenic hpv types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer. j pathol. 2014; 234:441-51. 28. rietbergen mm, snijders pj, beekzada d, et al. molecular characterization of p16-immunopositive but hpv dna-negative oropharyngeal carcinomas. int j cancer. 2014; 134:2366-72. 15archivio italiano di urologia e andrologia 2020; 92, 1 p16ink4a overexpression in penile cancer lourenco_stesura seveso 01/04/20 18:52 pagina 15 archivio italiano di urologia e andrologia 2020; 92, 1 m. pereira-lourenço, d. vieira e brito, m, eliseu, n. castelo-branco, j.p. peralta, r. godinho, p. conceição, m. reis, c. rabaça, a. sismeiro 16 29. steinestel j, al ghazal a, arndt a, et al. the role of histologic subtype, p16(ink4a) expression, and presence of human papillomavirus dna in penile squamous cell carcinoma. bmc cancer. 2015; 15:220. 30. sakamoto j, shigehara k, nakashima k, et al. etiological role of human papillomavirus infection in the development of penile cancer. int j infect dis. 2019; 78:148-54. 31. alemany l, cubilla a, halec g, et al. role of human papillomavirus in penile carcinomas worldwide. eur urol. 2016; 69:953-61. 32. sand fl, rasmussen cl, frederiksen mh, et al. prognostic significance of hpv and p16 status in men diagnosed with penile cancer: a systematic review and meta-analysis. cancer epidemiol biomarkers prev. 2018; 27:1123-32. 33. braakhuis bj, snijders pj, keune wj, et al. genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. j natl cancer inst. 2004; 96:998-1006. 34. rubin ma, kleter b, zhou m, et al. detection and typing of human papillomavirus dna in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. am j pathol. 2001; 159:1211-8. 35. afonso la, carestiato fn, ornellas aa, et al. human papillomavirus, epstein-barr virus, and methylation status of p16. j med virol. 2017; 89:1837-43. 36. di lorenzo g, perdonà s, buonerba c, et al. cytosolic phosphorylated egfr is predictive of recurrence in early stage penile cancer patients: a retropective study. j transl med. 2013;11:161. 37. scheiner ma, campos mm, ornellas aa, chin ew, ornellas mh, andrada-serpa mj. human papillomavirus and penile cancers in rio de janeiro, brazil: hpv typing and clinical features. int braz j urol. 2008; 34:467-74; discussion 75-6. 38. mannweiler s, sygulla s, tsybrovskyy o, et al. clear-cell differentiation and lymphatic invasion, but not the revised tnm classification, predict lymph node metastases in pt1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area. urol oncol. 2013; 31:1378-85. 39. mcdaniel as, hovelson dh, cani ak, et al. genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. cancer res. 2015; 75:5219-27. 40. gunia s, erbersdobler a, hakenberg ow, et al. p16(ink4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study. j urol. 2012; 187:899-907. 41. bezerra sm, chaux a, ball mw, et al. human papillomavirus infection and immunohistochemical p16(ink4a) expression as predictors of outcome in penile squamous cell carcinomas. hum pathol. 2015; 46:532-40. 42. zargar-shoshtari k, spiess pe, berglund ae, et al. clinical significance of p53 and p16(ink4a) status in a contemporary north american penile carcinoma cohort. clin genitourin cancer. 2016; 14:346-51. 43. bethune g, campbell j, rocker a, et al. clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a north american population. urology. 2012; 79:1092-7. 44. tang dh, clark pe, giannico g, et al. lack of p16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection. j urol. 2015; 193:519-25. 45. guerrero d, guarch r, ojer a, et al. hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma. bju int. 2008; 102:747-55. 46. wen s, ren w, xue b, et al. prognostic factors in patients with penile cancer after surgical management. world j urol. 2018; 36:435-40. correspondence mário pereira-lourenço, md (corresponding author) mariolourenco88@gmail.com duarte vieira e brito, md joão pedro peralta, md ricardo godinho, md paulo conceição, md mário reis, md carlos rabaça, md amílcar sismeiro, md urology department portuguese institute of oncology coimbra, coimbra (portugal) rua maria bourbon bobone, n57, re/esq, coimbra, 3030-481, portugal miguel eliseu, md urology and kidney transplant department coimbra hospital university centre, coimbra (portugal) noémia castelo-branco, md department portuguese institute of oncology coimbra, coimbra (portugal) lourenco_stesura seveso 01/04/20 18:52 pagina 16 stesura seveso archivio italiano di urologia e andrologia 2020; 92, 4386 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.4.386 comparison of penile prosthesis types' complications: a retrospective analysis of single center erdem kisa, mehmet zeynel keskin, cem yucel, murat ucar, okan yalbuzdag, yusuf ozlem ilbey tepecik training and research hospital, urology department, izmir (turkey). leable)”. inflatable prostheses are further classified into two groups as two-piece and three-piece prostheses. although semirigid (malleable) pps are more durable and less expensive, they can experience more erosion as they are constantly rigid. on the other hand, inflatable pps allow use in flaccid and erect states and offer cosmetic advantage, however, possessing a more complex structure may result in mechanical failure over time (2-6). currently, two-piece and three-piece pps constitute 75% of ppi surgeries worldwide, while in our country, semirigid (malleable) pps are used at higher rates due to the reimbursement conditions of the social security institution and the higher cost of inflatable pps (7-11). although ppi surgery is associated with patient and partner satisfaction, certain complications may arise during and after this operation (12-14). these include; intraoperative complications such as urethra perforation, cavernosal crossover, and crural perforation, as well as complications encountered in the postoperative period such as wound site infection, hematoma, lower urinary tract symptoms, bending during intercourse, breakage of the prosthesis, concorde deformity, and mechanical failure, particularly in multi-piece types. among factors that influence these complications, the role of diabetes type 2 (dm) and history of radical pelvic surgery (rps) has been contended in the literature (10, 15-17). the aim of this study was to evaluate the clinical outcomes and surgical complications after ppi performed at our institution on patients with various causes of ed, compare complication rates associated with semirigid (malleable) and inflatable pps, and investigate the factors that influence these complications. materials and methods approval of the institutional ethics committee was obtained. we retrospectively reviewed the records of 116 men with ed who had 131 penile prostheses implanted in our clinic due to end-stage ed between january 2010 and march 2019. the initial surgery included 115 primary implants and one revision case, who had undergone the initial operation at another institution. a further 15 men had two revision operations. three patients with insufficient data and two cases, who had pps implanted at another centre and demanded removal without replacement, were excluded from the study. for all the patients, demographic characteristics, duration of ed time, size of implanted pp, complications data, and patient satisfaction objectives: the aim of this study was to compare clinical outcomes and complication rates associated with semirigid (malleable) and inflatable penile prostheses (pps) and investigate the factors that influence these complications. material and methods: the records of 131 patients who had undergone penile prosthesis implantation (ppi) in our clinic due to erectile dysfunction (ed) between january 2010 and march 2019 were retrospectively reviewed. the initial surgery included 116 primary implants and 15 men had two revision operations. patients were assigned to two groups as semirigid (malleable) ppi (group 1) and inflatable ppi (group 2) patients, and obtained data were compared across these two groups. results: group 1 included 93 patients, while group 2 included 38 patients. postoperative complication rates of group 1 were 8.6% (n = 8), and group 2 were 21% (n = 8), and the comparison of postoperative complication rates revealed a statistically significant difference between the two groups (p = 0.025). the majority of these complications (50%) was constituted by mechanical failure associated with inflatable pps. when patients were further segregated as those with and without diabetes type 2 (dm) and those who had and had not undergone radical pelvic surgery (rps), the comparison of complication rates across these subgroups did not yield any significant difference. conclusions: we determined in this study that semirigid (malleable) pps were associated with lower complication rates compared to the inflatable group, particularly with regard to mechanic failure, and that dm and history of rps did not make a difference in complication rates in patients planned to undergo ppi. key words: penile prosthesis; penile prosthesis implant; erectile dysfunction; impotence; radical surgery; satisfaction. submitted 1 june 2019; accepted 1 september 2019 introduction penile prosthesis implantation (ppi) treatment has been offered for over 40 years with high surgical success in patients with erectile dysfunction (ed) who either do not respond to pharmacological treatments such as oral phosphodiesterase type 5 (pde5) inhibitors and less invasive intracavernosal vasocactive agents or reject these treatments (1). penile prostheses (pps) are categorized into two groups as non-inflatable and inflatable prostheses. non-inflatable pps are also referred to as “semirigid (malsummary 387archivio italiano di urologia e andrologia 2020; 92, 4 comparison of penile prosthesis types' complications were evaluated. patients were assigned to two groups as semirigid (malleable) ppi (group 1) and inflatable ppi (group 2) patients, and obtained data were compared across these two groups. indications for ppi were failure or intolerance of medical treatment, confirmation of ed by doppler ultrasound, and severe ed. all men routinely underwent medical and psychiatric consultation before the surgery. the operative field was disinfected with povidone-iodine 10 min before the surgical intervention. preoperative antibiotic prophylaxis, such as vancomycin, was given the night before the surgery and for 3 days postoperatively. oral antibiotic prophylaxis with ciprofloxacin was continued through the 7th postoperative day. all the pps were implanted through penoscrotal incisions. the implant and surgical sites were irrigated with gentamicin in saline prior to implantation. the corpus cavernosum usually was dilated with hegar dilators, though an otis urethrotome was deemed necessary in two cases. a foley catheter was inserted at the end of the procedure and removed 1 day later. the patients were discharged 1-2 days postoperatively. surgical complications were recorded in detail. peroperative and postoperative complications were evaluated separately and compared between the groups. postoperative complications were divided into two groups as ‘early’ (complications occurring within 30 days of surgery) and late (complications occurring after 30 days of surgery). prosthesis function was evaluated 1 month after surgery and then annually until lost to follow-up. our patients were asked during control visits if they were satisfied, or unsatisfied with the prosthesis in general. they were evaluated at or within 12 months of the postoperative period, in most cases through face-to-face interviews. however, in some patients who failed to visit the clinics, follow-up was assessed through telephone interviews. statistical analyses the groups were assessed for normal distribution using the shapiro wilk test. statistical difference between the groups were analyzed with independent sample t test mann whitney u test. chi-square test was used for cross comparison. a p-value < 0.05 was considered statistically significant. all analyses were made by ibm spss v22. results data obtained from all patients were reviewed to determine duration of ed time, causes of ed, pre-prosthetic treatment of primary patients, type of implanted pp, size of implanted pp, perioperative and postoperative complications (table 1). the most common factor implicated in the ed etiology of patients was dm with a rate of 41.2% (n = 54), followed by rps with a rate of 20.6% (n = 27). of 54 dm patients, 26 (48.1%) were on oral antidiabetics and 28 (51.8%) on insulin therapy. overall perioperative complication (urethra perforation and cavernosal crossover) rate was 1.5% (n = 2). in one of these, where urethra perforation had been encountered during the cavernousal dilation stage of ppi and the procedure had been postponed, only one side of the semirigid (malleable) pp could be implanted in the second surgical session due to difficulty in dissection. all perioperative complications were resolved during surgery, and the operations were completed successfully. the overall postoperative complication rate was 12.2 % (n = 16). table 1. demographics; duration, etiology and treatment of erectile disfunction (ed); characteristics, complications and satisfaction of penile prostheses (pps). number of patients 131 median age, year (min-max.) 59 (28-74) mean ± sd 58.4 ± 8.3 median duration of ed time, year (min-max.) 3 (1-21) mean ± sd 4 ± 3.6 causes of ed of primary patients, n, (%) • idiopathic 22 • comorbidity dm (diabetes type 2) 54 (41.2%) hypertension 26 myocardial infarction 11 by-pass surgery 5 chronic obstructive pulmonary disease 2 cerebrovascular occlusion 1 • rps (radical pelvic surgery) radical prostatectomy 24 (18.3%) radical cystectomy 3 (2.2%) • pelvic radiotherapy 7 • priapism 1 • peyronie’s disease 9 penis fracture 1 pre-prosthetic treatment of primary patients • phosphodiesterase 5 (pde5) inhibitors 114 on-demand 101 daily 13 • cavernosal injection 1 • vascular surgery 1 ppi • primary implants 116 (88.5%) • revision implants 15 (11.4%) type of implanted pp, n, (%) • semi-rigid (malleable) prostheses 93 (70.9%) • inflatable prostheses 38 (29%) two-piece 36 (94.7%) three-piece 2 (5.2%) size of implanted pp, n, (%) • median size, diameter, cm (min-max.) 10 (9-13) • median size, length, cm (min-max.) 18.5 (12-25) perioperative complications, n (%), note 2 (1.5%) • urethra perforation 1, during dilatation, postpone • cavernosal crossover 1, during dilatation • crural perforation 0 postoperative complications 14 (10.6%) • early superficial wound infection 4, resolved with antibiotherapy hematoma located on scrotum 1, resolved at follow-up • late bending during intercourse 1, revision lower urinary tract symptoms 1, history of turp penile prosthesis breakage 2, revision concord deformity 1, revision mechanical failure 4, revision overall complications 16 (12.2%) patient satisfication, n (%) satisfied 105/131 (80.1%) not satisfied 16/131 (19.8%) archivio italiano di urologia e andrologia 2020; 92, 4 e. kisa, m. zeynel keskin, c. yucel, m. ucar, o. yalbuzdag, y. ozlem ilbey 388 revision surgery was needed for 11.4% (15/131) of the pps inserted. of these 15 patients who underwent revision ppi, 12 had undergone the primary surgery at our clinic and three at external centers. the median time until ppi revision was determined as 36 months (1-192 months). overall, 80.1% (105/131) of the men were satisfied with the results. group 1 included 93 patients, while group 2 included 38 patients. the comparison of data from group 1 and group 2 patients have been summarised in table 2. in group 1, one patient had to be implanted with differentsized pps on the right and left sides, whereas in group 2, six patients were implanted with pps of discrepant sizes. postoperative complication rates of group 1 were 8.6% (n = 8), and group 2 were 21% (n = 8), and the comparison of postoperative complication rates revealed a statistically significant difference between the two groups (p = 0.025). among postoperative complications, mechanical failure was detected in four patients, all of whom were group 2 patients who had inflatable (two-piece) ppis. when patients were further segregated as those with and without dm and those who had and had not undergone rps, the comparison of complication rates across these subgroups did not yield any significant difference (tables 3, 4). discussion ppi has been used effectively in patients who do not respond to oral therapies such as pde5 inhibitors and to intracavernosal injection therapy (1). although this treatment method offers high patient and partner satisfaction, it may be associated with certain perioperative and postoperative complications (2-13). among these complications, most notable are the pp infections and mechanical failure that arise in the postoperative period. in the recent years, technological advancements in pps and advances in the surgical procedure technique have resulted in a partial decrease in these rates (18). although inflatable pps are utilized more commonly across the world, semirigid (malleable) pps have been utilized at greater rates in our country due to low economic status of the patients, high cost of inflatable pps, and reimbursement conditions of the social security institution (7-11). in this study, we aimed to compare the complication rates associated with semirigid (malleable) and inflatable pps that we implant at our clinic as well as to compare these rates between patients with and without dm and patients with and without history of rps. the two groups demonstrated no statistical differences with regard to perioperative complications. comparison of postoperative complication rates across groups revealed a statistically higher rate for the inflatable group. the majority of these complications was constituted by mechanical failure associated with inflatable pps. also, the comparison of complication rates in patients with or without dm or history of rps showed no difference of overall complication rates. although semirigid (malleable) pps are less expensive and more durable, they are disadvantaged in terms of cosmetic appearance due to a constant state of erection. on the other hand, inflatable pps offer more physiological erections but may lead to mechanical failure in the postoperative period. in the literature, mechanical failure rates vary from 0-5% for semirigid (malleable) pps to 23% for inflatable pps (2, 3, 10, 13). a study conducted by lotan et al. reported that the complication-free rate was 87% for semirigid (malleable) pps, whereas it was 50% for inflatable pps (19). in our study, while no difference was detected between the groups with regard to perioperative complications, a statistically higher postoperative complication rate was determined in the inflatable group (21%) compared to the semirigid (malleable) group (6.4%). half of the postoperative complications in the inflatable group were accounted by mechanical failure. in the literature, whether post-ppi infective complications are more prevalent among patients with dm has been controversial. although there are publications that corroborate the role of dm as a risk factor for postopertable 2. study outcomes by type of prosthesis. semirigid ppi inflatable ppi p (n = 93) (n = 38) median age, year (min-max.) 59 (38-74) 61 (28-69) 0.667 mean ± sd 58.6 ± 7.5 58.1 ± 9.8 median duration of ed time, year (min-max.) 3 (1-20) 2 (1-21) 0.229 mean ± sd 4.2 ± 3.5 3.7 ± 4 size of implanted pp, n, (%) • median size, diameter, cm (min-max.) 10 (9-13) 18.5 (12-25) 0.256 • median size, length, cm (min-max.) 12.5 (12-12.5) 19 (14.5-22) 0.349 perioperative complications, n (%) 2 (2.1%) 0 0.502 • urethra perforation 1 (1%) 0 • cavernosal crossover 1 (1%) 0 • crural perforation 0 0 postoperative complications 6 (6.4%) 8 (21%) 0.025 early superficial wound infection 2 2 hematoma located on scrotum 0 1 late bending during intercourse 1 0 lower urinary tract symptoms 1 0 penile prosthesis breakage 2 0 concord deformty 0 1 0.074 mechanical failure 0 4 overall complications 8 (8.6) 8 (21%) table 3. comparison of overall complication rates of patients with and without diabetes type 2 (dm). dm dm p (n = 73) (n = 58) no complication 66 (90.4%) 49 (84.4%) 0.421 overall complications 7 (9.5%) 9 (5.5%) table 4. comparison of overall complication rates of patients with and without radical pelvic surgery (rps). dm dm p (n = 73) (n = 58) no complication 86 (86%) 29 (93.5%) 0,356 overall complications 14 (14%) 2 (6.4%) 389archivio italiano di urologia e andrologia 2020; 92, 4 comparison of penile prosthesis types' complications ative infections, there are also contradictory studies. penidri et al. stated in their metanalysis that dm could be a risk factor for pp infection, although this could not be completely clarified (15). the relation of rps history with perioperative and postoperative complication rates has also been contended in the literature. in a study by cuneyd et al., erosion rates in semirigid (malleable) pps were higher in the rps group, compared to patients with other comorbidities, however, postoperative complication rates were reported to be similar across groups. they connected these high erosion rates to fibrosis that develops in the cavernosal tissue after rps (10). on the other hand, in a study by lane et al., it was stressed that three-piece pp surgery had comparable postoperative complication rates in patients with and without rps history, and therefore, could be utilized safely in these patients (17). in our study, there were no differences between patients with and without dm and between patients with and without history of rps with regard to perioperative and postoperative complication rates. the limitations of our study include its dependence on retrospective data, lack of partner satisfaction data as it could not be evaluated for all patients, and absence of long-term follow up data of patients. conclusions ppi surgery has been performed worldwide in the treatment of ed, on patients who do not respond to oral and intracavernosal therapies. although inflatable pps possess a more cosmetic and physiological structure, they cannot be used in all patients in our country due to their higher cost and the reimbursement conditions of our social security system. semirigid (malleable) pps constitute the most commonly utilized pps at our clinic despite certain disadvantages. in conclusion, we determined in this study that semirigid (malleable) pps were associated with lower complication rates compared to the inflatable group, particularly with regard to mechanic failure, and that dm and history of rps did not make a difference in complication rates in patients planned to 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implant: scientific advances and technological innovations over the last four decades. transl androl urol. 2017; 6:37-45. 19. lotan y, roehrborn cg, mcconnell jd, et al. factors influencing the outcomes of penile prosthesis surgery at a teaching institution. urology. 2003; 62:918-21. correspondence erdem kisa, md, febu (corresponding author) drerdemkisa@hotmail.com mehmet zeynel keskin, md zeynel_akd@hotmail.com cem yucel, md meclecuy@hotmail.com murat ucar, md drmuratucar@hotmail.com okan yalbuzdag, md drozgurcakmak577@yahoo.com yusuf ozlem ilbey, md ozlemyusufilbey@hotmail.com tepecik training and research hospital, urology department, yenişehir mah, gaziler cad. no:468, konak/izmir (turkey) cop+ed+fisse 2006 115archivio italiano di urologia e andrologia 2021; 93, 1 review no conflict of interest declared. doi: 10.4081/aiua.2021.1.115 ent species are responsible for zoonoses, infecting mammals such as bats, cats, dogs, various rodents (1), and eventually passing to humans. seven types of coronaviruses have been identified that have caused infections in humans so far; humanity has already challenged epidemics caused by these viruses, last of which were severe acute respiratory syndrome (sars) in 2003 and middle east respiratory syndrome (mers) in 2012 (2). in december 2019 in the chinese town of wuhan several cases of acute respiratory syndrome were reported; etiological agent was found to be severe acute respiratory syndrome coronavirus 2 (sars-cov2); infectious cases spread rapidly through continents. transmission occurs most frequently through droplets and contact but the virus has also been identified in saliva, faeces and urine (3, 4). lu et al. (5) first described the mechanism of infection: the virus binds to the angiotensin 2 converting enzyme (ace2) through glycoproteins membrane s; the s1 domain deals with the binding with the host cell while the s2 domain is responsible for the fusion of the membranes undergoing a proteolytic priming by the transmembrane serine protease tmprss2(6) (figure 1). the ace2 enzyme is strongly expressed in lung, kidney, cardiac, gastrointestinal, bladder and testicular cells (7). in the testis it is found in both in the cells of the seminiferous ducts, in particular spermatogonia, and in the cells of leydig and sertoli (8). hence the hypothesis that the testicle may be a reservoir of the disease. the aim of this study focuses on the search for results regarding the parameters of male fertility, the pathological aspects of the testicle and the presence of the virus in the seminal fluid. materials and methods a systematic search of the peer reviewed literature was conducted on pubmed, google scholar and medline databases until 30 december 2020. a combination of medical subject headings (mesh) terms was used. the keywords were: “covid” ,“male fertility”, “infertility” “sperm”, “testosterone” and “quality”. all titles and abstracts published in english were evaluated. all studies were considered, with the exception of those performed on animals, comments, letters, editorials and case reports. the initial search yielded a total of 47 articles. the articles deemed objectives: the aim of this review is to summarize, following a timeline, the current knowledge regarding the effects of the sars-cov2 virus on male fertility, researching the pathological and clinical results of the studies published in the last year. methods: a systematic research was performed on the major international online databases; thirty-five articles were selected. results: a statistically significant reduction in testosterone levels and sperm quality in subjects with covid-19 has been highlighted in several papers; however, in many cases the tests have been conducted in patients with active disease and long-term consequences are still not known. some studies have confirmed the presence of the virus in the testis in a low percentage of patients; viral presence in sperm has only been found in one study. testicular discomfort, which could indicate viral orchitis, was highlighted in several works, with an incidence of up to 19% percent of patients. the presence of inflammatory lymphocytic infiltrates, igg and inflammatory cytokines have been documented in several works; pathological signs of inflammation were found in 60.9% of testicular biopsies performed in one study. the entry of the virus into the testis cells, both stromal and seminal cells appeared to be angiotensin converting enzyme-2 (ace2) mediated, as it also occurs in other tissues. dna fragmentation, reactive oxygen species (ros) formation, autoantibody production and ace2 mediated effect have all been hypothesized as cause of cellular damage. conclusions: the results on effects of covid-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory.certain mechanisms of testicular damage are still to be assessed, as any risk categories like age, ethnicity, or others. as for the transmission of the virus through sperm, there is insufficient evidence to ensure that this cannot happen. key words: covid-19; sars-cov-2; male fertility; infertility; sperm. submitted 11 january 2021; accepted 21 january 2021 introduction coronaviridae are single-chain rna viruses, with an envelope covered with spikes that give the viruses the typical "crown" appearance. there are four subtypes (alpha, beta, gamma and delta) and among these differcovid-19 and male fertility: taking stock of one year after the outbreak began summary rocco francesco delle fave, giordano polisini, gianluca giglioni, arnaldo parlavecchio, lucio dell’atti, andrea benedetto galosi division of urology, university hospital “ospedali riuniti”, school of medicine, department of clinical, special and dental sciences, marche polytechnic university, ancona, italy. presented at the sieun congress ancona 30 november 1 december 2020 archivio italiano di urologia e andrologia 2021; 93, 1 r.f. delle fave, g. polisini, g. giglioni, a. parlavecchio, l. dell’atti, a.b. galosi 116 valid were selected discarding the duplicates and then the off topic articles; a total of 35 articles strictly related to our issue were finally evaluated and reviewed by the authors. results covid-19 and fertility parameters a study published in march 2020 (9) performed on 81 patients with active disease hospitalized for moderate and severe symptoms showed that serum luteinizing hormone (lh) was significantly increased compared to a control group of 100 patients without symptoms and negative nasopharyngeal swab; furthermore, testosterone (t) to lh ratio and follicle stimulating hormone (fsh) to lh ratio were significantly decreased. there also was a strong association in multivariate regression analysis between high levels of c reactive protein (rcp) and low t/lh ratio; although there may be other factors involved, such as stress and the use of corticosteroids that may have altered the hypothalamus-pituitary-gonadal axis, the risk of hypogonadism in covid patients was highlighted for the first time. this was followed by other works that demonstrated the condition of hypotestosteronemia in sick and recently recovered patients (10, 11). in august, a cohort study by holtmann et al. (12) was published. sperm samples were analyzed from 18 patients one month after recovery from covid and 14 control cases. in patients who had covid with mild symptoms that did not require hospitalization, there was no impact on sperm quality in the short one-month follow-up; patients who had moderate symptoms had worse sperm quality (sperm concentration, total number of sperm per ejaculate, total number of progressive motility, total number of complete motility). one among these patients also had testicular symptoms (discomfort). xu h et al. (13) published in andrology a study on 39 patients with covid-19. the authors studied after recovery and compared to 22 controls subject. they found neither significant changes in blood testosterone, fsh and lh levels, nor associations between disease duration or severity and testosterone levels. there was a statistically significant negative association (p < 0.001) between blood estradiol levels and disease duration, as it was lower in patients who had had long illness, i.e. greater than 50 days, compared to the subgroup with normal-term disease. three possible explanations for table 1. findings about fertility parameters authors n° of testosterone lh fsh semen other findings patients levels quality ma et al. (9) 81 =/↓ ↑ ↓t/lh, ↓t/fsh, associazione fra alti livelli di pcr e basso t/lh rastrelli et al. (10) 31 ↓ lower baseline levels of t nd cft (free-testosterone) levels predict poor prognosis and mortality schroeder et al. (11) 88 ↓ high estradiol level in both male e female sars-cov2 patients holtmann et al. (12) 18 ↓ ↓ sperm concentration, n° of sperm per ejaculate, motility xu et al. (13) 39 = = = negative correlation between high estradiol levels and disease duration table 2. findings about pathologic aspects of the testis in covid-19 patients. authors n° of covid in testis lynphocytic cytokines other findings patients biopsy infiltration song et al. (14) 13 no shen et al. (15) 3 ace2 levels are greather at 30 y yang et al. (16) 12 1 cd3+, cd8+ variable tubular damage (> 50%) li et al. (17) 29 no cd3+, cd8+ il-6, tnf (60.9%) achua et al. (18) 7 3 + (in 14.2%) spikes at electronic microscope in 1 case; high ace2 levels in patients with impaired spermatogenesis figure 1. covid-19 virus replication cycle. this difference have been hypothesized, identifying the possible cause in the variation in estradiol levels in the direct cellular damage from the virus, in the massive inflammatory response of the organism or in the use of some drugs, such as corticosteroids (table 1). covid-19 and testis pathological aspects in april 2020 a study by the nanjing medical university showed that testicular biopsy was performed on a patient who died of covid-19, looking for viral rna; also, sperm samples of 13 patients were analyzed. viral rna was not found in any of the samples (14). in august 2020 shen q et al. (15) observed that the expression of ace2 in the testis is related to age, has a peak around 30 years and very low from 60 years onwards. young men might therefore be more at risk for reproductive disorders than older men and very young children. in european urology focus, yang et al. (16) analyzed the testicles of 12 patients who died from covid with an average age of 65 and found tissue damage in more than half of them (cellular damage and necrosis in both germinal and sertoli cells, tubules, edema and mild inflammation of the interstitium with t lymphocytes). damage to the seminal tubules was classified into three groups: absent, mild (< 10%. 2 cases), moderate (10-50%. 5 cases) and severe (> 50%. 4 cases). these findings were compared with 5 control subjects who died for causes other than covid. in 2 cases no tubular damage and in 3 cases mild tubular damage was found. the virus was found in the lungs of 10 out of 12 patients, but only in 1 patient was it found in the testis. li h et al. (17) performed histopathological examinations on testicular and epididymal specimens, and also performed tunel assay and immunohistochemistry on 6 patients who died of covid and 23 who recovered from covid, identifying the presence of interstitial edema, congestion, red blood cells exudate in the testis and epididymis, thinned seminiferous tubules with high apoptosis rate, interstitial t lymphocytes infiltrate interstitial, igg in the seminiferous ducts and increase of il-6 and tnf; finally they showed oligozoospermia in 39.1% of the subjects and in 60.9% of cases a leukocyte infiltrate. subsequently, other authors analyzed the results of 6 autopsies of casualties from covid-19 infection and 3 control cases with negative swab who had died from other causes; results were published in the world journal of man's health. also, a testicular biopsy from living with active disease was analyzed. the samples were studied by histo-morphological examination and electron microscope. three of the six positives had abnormal spermatogenesis. one of the six patients had a testicular lymphocyte and macrophage infiltrate as from inflammation. the testicular cells of four covid patients were examined with electron microscopy and of these 1 had visible spike particles, the same in which inflammatory infiltrate was present; spikes were also found in the testicular biopsy sample from the living patient. using immune-fluorescence they quantitatively assessed the presence of the ace2 receptor and showed a correlation between low expression of the ace2 receptor in patients with normal spermatogenesis and high expression in patients with impaired spermatogenesis, i.e. pathological sertoli cells, hypospermia, early maturation arrest, sclerosis of the seminiferous ducts (18) (table 2). covid-19 findings in semen as already mentioned, in the study by song et al. (14) the virus was not found in the semen of 13 infected patients; twelve patients were recovering, one of them was in the acute phase of the disease. also, an italian group in rome searched for the viral rna in the sperm and urine of a volunteer patient eight days after the virus diagnosis using pcr without findings (19); the same result has been obtained by ning et al. (20) who searched for the nucleocapsid (n) and orf1 genes with the pcr method in 17 sperm samples, 9 of which from patients with active disease and 8 from cured patients. a cohort study from beijing detected the virus in the seminal fluid of 6 out of 38 patients analyzed; two thirds of these six patients were in the acute phase of the disease while one third of them were recovering (21). in june 2020 pan et al. (22) searched with the pcr technique the viral genome of the virus in 34 patients, most of them about one month after diagnosis (range from 8 to 75 days). also in this case, the n genes of the nucleocapsid and the orf1ab gene were searched in particular. the virus was not detected in any of them. six patients (19%) complained of testicular discomfort suggesting viral orchitis. in the aforementioned holtmann study (12) the viral rna presence was investigated in sperm with the pcr technique, dividing patients into three groups: patients with moderate symptoms (only 4 patients), convalescents (14 patients) and control group (other 14 subjects). in none of these specimens the virus was found (table 3). discussion viruses so far known to cause orchitis include hepatitis b and c viruses, human papilloma virus, flu virus, herpes simplex virus, epstein-barr virus, coxsackie virus, hiv, zika virus, ebola virus, arbovirus, marburgvirus and the sars-cov virus (23). there are various hypotheses on the mechanism of testicular inflammation. sars-cov2 could, through various pathogenic pathways, increase oxidative stress, increase dna methylation and fragmentation and decrease male fertility. also direct cellular damage is possible through the ace enzyme on leidig cells and spermatocytes (24, 25). the blood-testis barrier (btb) is responsible for protecting 117archivio italiano di urologia e andrologia 2021; 93, 1 covid-19 and male fertility table 3. findings about sperm presence of the virus. authors n° of patients presence of the virus and details song et al. (14) 13 no paoli et al. (19) 1 no ning et al. (20) 17 no li et al. (17) 38 yes, 6 patients, four with active disease pan et al. (22) 34 no holtman et al. (12) 18 no archivio italiano di urologia e andrologia 2021; 93, 1 r.f. delle fave, g. polisini, g. giglioni, a. parlavecchio, l. dell’atti, a.b. galosi 118 seminal cells from the immunity system, especially t lymphocytes. during active viraemia, persistent high temperature from fever can tamper with the blood-testis barrier and cause the passage of viruses. this is demonstrated by the fact that normally only a few cd3 and cd8 lymphocytes are found in the interstitium in the testes. in patients with sars, there is an increase in t lymphocytes and macrophages of 4.5% and 11.7% respectively (26) and in igg immunoreaction. this indicates that the barrier is compromised in these patients. dna damage is the result of apoptosis and excessive production of ros and inflammation and can lead to an increase in the dna fragmentation index (dfi) with consequent infertility. since dfi is useful for assessing changes in fertility, it could be introduced as an additional method of diagnosing infertility in covid patients (27-28). very interesting data comes from genetic studies; wang et al. (29) showed that spermatogonia with an ace2 + expression similar to lung at2 cells are only 1.28% of all spermatogonia, while in the study by pan et al. (22) only 4 on 6490 testicular cells studied contained both the ace2 gene and tmprr2; these data could indicate that in most cases the virus does not directly affect the testicle. inflammatory cytokines, such as il-6, may also play a role in the inflammatory response; it has been shown that its concentration is high in patients with covid (30). even the hypothesis of production of anti-sperm antibodies (asa) following damage to the blood-testicular barrier may be valid (31, 32). in patients with sars-cov2, the use of inhibitors of the renin angiotensin system unfortunately does not confer protective effects on the testis in terms of cell mortality, probably not even with regard to spermatozoa (33). the studies analyzed, although of high quality, have some limitations. first of all, the number of patients studied is limited; furthermore, the follow-up is so short that the possible future implications and the impact that sars-cov-2 infection can have on long-term male fertility are not known. however, it may be important to perform a covid screening during fertility treatment, for which there are already guidelines for conduct for fertility care, identified and summarized in the study of papathanasiou (34) from 4 publications by the european society of human reproduction and embryology (eshre), american society for reproductive medicine (asrm), british fertility society/association of reproductive and clinical scientists (bfs/arcs) and canadian fertility and andrology society (cfas). for patients who are interested in sperm cryopreservation, some rules should be followed. adiga sk (35) illustrated that the measures aimed at minimizing the risk of viral contamination in sperm cryopreservation are: blood tests before starting treatment, fully follow the correct protocols of cryopreservation and proper washing of gametes and embryos during preservation with sterile ln2. although in some studies the virus has been identified in the testes and there is significant evidence of hypogonadism and hypotestosteronemia, further data is needed to better understand the effects of this virus on reproductive organs, to identify how the virus eventually affects fertility parameters and to ensure that the testis is not a virus reservoir (36). to date, no cases of virus transmission from sperm have been recorded. however active patients and patients recovered from covid-19 are advised against donating sperm and performing assisted fertilization (37). references 1. su s, wong g, shi w, et al. epidemiology, genetic recombination, and pathogenesis of coronaviruses. trends in microbiology 2016; 24:490-502 2. ferran garcìa j, alvarez gonzales jg, corral molina jm. infección por sars-cov-2: implicaciones para la salud sexual y reproductiva. una declaraciòn de la posición de la asociación espanola de andrología, medicina sexual y reproductora (asesa). rev int androl. 2020; 18:117-123. 3. john hopkins university of medicine, coronavirus resource center, 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f, et al. potential risks of sars-cov-2 infection on reproductive health. reprod biomed online. 2020; 41:89-95. 33. yokoyama y, aikawa t, takagi h, et al. association of reninangiotensin-aldosterone system inhibitors with mortality and testing positive of covid-19: meta-analysis. j med virol 2020 oct 10; 10.1002/jmv.26588. 34. papathanasiou a. covid-19 screening during fertility treatment: how do guidelines compare against each other? j assist reprod genet 2020; 37:1831-1835. 35. adiga sk, tholeti p, uppangala s, et al. fertility preservation during the covid-19 pandemic: mitigating the viral contamination risk to reproductive cells in cryostorage, reprod biomed online 2020; 41:991-997. 36. dell’atti l, galosi ab. the role of the serum testosterone levels as a predictor of prostate cancer in patients with atypical small acinar proliferation at the first prostate biopsy. asian j androl. 2018; 20:15-18. 37. maretti c, privitera s, arcaniolo d, et al. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology. arch ital urol androl. 2020 jun 23; 92:73-77. correspondence rocco francesco delle fave, md dellefavefrancesco@alice.it giordano polisini, md gio.pol.93@gmail.com gianluca giglioni, md piallu88@gmail.com arnaldo parlavecchio, md aldoparl90@gmail.com lucio dell’atti, md, phd (corresponding author) dellatti@hotmail.com andrea benedetto galosi, md a.b.galosi@univpm.it division of urology, university hospital “ospedali riuniti”, marche polytechnic university via conca 71, 60126 ancona (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11588 1 original paper introduction two-thirds of end-stage renal disease (esrd) patients undergo hemodialysis (hd), one-quarter have kidney transplants, and one-tenth require peritoneal dialysis (1). for hd, three access procedures are commonly used: an autogenous arteriovenous fistula (avf), a prosthetic bridging graft (bg), and an indwelling central venous catheter. the ideal access should be durable, easily punctured, provide a sufficient flow rate for efficient dialysis, and have a low complication rate (2). the autogenous avf was approved by the kidney disease outcome quality initiative (kdoqi) recommendations as to the first-line technique for vascular access since it tends to get closer and closer to meeting these standards (3). although avf is the first option for permanent vascular access, it is required at least 6-8 weeks pass after its construction before using it (4, 5). furthermore, persistent respiratory failure, ischemia steal syndrome, and patients with severe cardiac failure may not be suitable for avf (6, 7). the bgs should not be punctured before 14 days and are not recommended as primary vascular access. as a result, both permanent and temporary cuffed tunneled catheters are used in these cases and in those with acute hd (8, 9). if the patient needs access for longer than a month, tunneled catheters should be used (10). according to a recent report, approximately 80% of those with esrd will require a hemodialysis catheter during their long-term treatment (11). anatomical landmarks are used in traditional hemodialysis catheter insertion methods. the absence of a pulsatile flow pattern and the dark color of venous blood indicate successful cannulation. based on landmarks, success rates range from 60% to more than 90%, with the reported risk of complications ranging from 5% to 20% (12). anatomical landmark methods have a higher failure rate, require more attempts, and have a higher complication rate (13). long-term problems such as thrombosis, infections, and central venous stricture, as well as early complications like pneumothorax, arterial puncture, and puncture site hematoma, have been attributed to hd catheters (14). in 1973, the first description of catheter objective: to point out our experience and assess the efficacy and safety of real-time ultrasound-guided central internal jugular vein (ijv) catheterization in the treatment of hemodialysis patients. methods: this retrospective study comprised 150 patients with end-stage renal disease (esrd) who had real-time ultrasonography (us)-guided ijv hd catheters placed in our hospital between march 2019 and march 2021. patients were examined for their demographic data, etiology, site of catheter insertion, type (acute or chronic) of renal failure, technical success, operative time, number of needle punctures, and procedure-related complications. patients who have had multiple catheter insertions, prior catheterization challenges, poor compliance, obesity, bony deformity, and coagulation disorders were considered at high-operative risk. results: all patients experienced technical success. in terms of patient clinical features, an insignificant difference was observed between the normal and high-risk groups (p-value > 0.05). of the 150 catheters, 62 (41.3%) were placed in high-risk patients. the first-attempt success rate was 89.8% for the normal group and 72.5% for the high-risk group (p = 0.006). ijv cannulation took less time in the normal-risk group compared to the highrisk group (21.2 ± 0.09) minutes vs (35.4 ± 0.11) minutes, (p < 0.001). there were no serious complications. during the placing of the catheter in the internal jugular vein, four patients (6.4%) experienced arterial puncture in the high-risk group. two participants in each group got a small neck hematoma. one patient developed a pneumothorax in the high-risk group, which was managed with an intercostal chest tube insertion. conclusions: even in the high-risk group, the real-time us-guided placement of a central catheter into the ijv is associated with a low complication rate and a high success rate. even under us guidance, experience lowers complication rates. real-time usguided is recommended to be used routinely during central venous catheter insertion. key words: central hd catheters; hemodialysis; central hd catheters; real-time ultrasound. submitted 17 july 2023; accepted 30 july 2023 the outcome of ultrasound-guided insertion of central hemodialysis catheter ehab m. abdo 1, tamer a. abouelgreed 2, waleed e. elshinawy 1, nehal farouk 1, hassan ismail 2, amal h. ibrahim 3, samar a. kasem 3, lobna kh. sakr 4, naglaa m. aboelsoud 4, nermeen m. abdelmonem 5, salma f. abdelkader 6, ahmed a. abdelwahed 6, anas a. qasem 7, mosab f. alassal 8, ahmed a. aboomar 9 1 department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt; 2 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 3 department of internal medicine, nephrology unit, faculty medicine, al-azhar university, cairo, egypt; 4 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 5 department of radiology, thumbay university hospital, ajman, uae; 6 department of radiology, faculty of medicine ain shams university, cairo, egypt; 7 department of internal medicine, faculty medicine, zagazig university, zagazig, egypt; 8 department of vascular surgery, saudi german hospital, ajman, uae; 9 department of internal medicine, nephrology unit, faculty of medicine, tanta university, tanta, egypt. doi: 10.4081/aiua.2023.11588 summary archivio italiano di urologia e andrologia 2023; 95(3):11588 e.m. abdo, t.a. abouelgreed, w.e. elshinawy, et al. 2 implantation into the ijvs using us guidance was published (15). to lower the arterial puncture risk, us guidance has been followed (16). as a result, the national kidney foundation suggested using real-time ultrasound to guide the central venous catheters’ insertion, to improve insertion success and reduce placement-related complications as well as fluoroscopic screening for proper catheter tip localization after tunneled catheter insertion (5). in the real-time us, the us probe can be positioned longitudinally, leading to a long-axis view on the screen, or transversely relative to the vessel, resulting in a cross-sectional image of the vessel on the screen. the cross-sectional image offers the advantage of enhanced vein imaging in association with the artery and other anatomic structures, which may help prevent accidental arterial puncture (17). the needle, on the other hand, is only visible as a hyperechoic point in the cross-sectional picture, which may or may not be the needle's tip. the entire needle, as well as the needle tip depth, are visible on the us image when utilizing the long-axis view, decreasing posterior venous wall puncture (18). the current research aimed to assess the complication rate and technical success and provide our center's experience with real-time us-guided ijv central cannulation for hd patients. materials and methods this retrospective study included all patients who had usguided internal jugular vein (ijv) central hd catheters placed at our facility between march 2019 and march 2021. all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of the faculty of medicine, al-azhar university (fmg-irb). the medical records of 150 participants with esrd were examined. demographic data like age and gender were collected and analyzed. other information like the etiology and type (acute or chronic) of renal failure, operative time, number of needle punctures, technical success, site of catheter insertion, and procedure-related complications were also collected and analyzed. patients were considered high risk if they had multiple catheter insertions, had prior catheter difficulties, had poor compliance, were obese, had disturbed conscious levels, had a bony deformity, or had a blood coagulation disorder. prior and post-insertion chest x-ray findings were reviewed. prior to catheter implantation, all participants underwent full blood count, and coagulation profiles were examined. fresh frozen plasma was used when necessary. for the procedure, all patients signed a written informed consent form. permanent tunneled catheters were silicon-based and featured two lumens with a diameter of 14-15 f. depending on the body size of the participant, the length was optimized (19, 23, or 28 cm). the catheters' dacron cuffs were around 5 cm away from the exit point, providing a barrier to infections and stability by forming fibrous tissue around them. all procedures were carried out in the main operating room, which has a portable us machine (esaote mylab one, mecan medical, china) and a portable c-arm machine available all the time. vascular surgery consultants or senior specialists carried out all procedures. the skin overlying the intended insertion location was prepared, cleaned, and draped while the patient was supine. ijvs were used for permanent catheters first on the right and then on the left (in case of thrombosis or stenosis of the right one). if both veins are obstructed, the subclavian vein was utilized. using a 7 mhz linear probe, the internal jugular vein was visualized horizontally. after monitoring the carotid artery on the medial side and the internal jugular vein on the lateral side, the vein's compressibility and the artery's pulsatility were investigated (figure 1). cannulation of the ijv was attempted. the operator noticed the needle's pathway while centering a large-bore needle (16 g, 10 cm) under the middle of the probe at a 45° slope to the skin (figure 2). figure 1. visualizing the carotid artery and the ijv using real-time us. figure 2. a needle is directed towards the middle of the probe at a 45° slope to the skin to cannulate the ijv. figure 3. detection of a flush of blood coming out of the ijv. archivio italiano di urologia e andrologia 2023; 95(3):11588 3 the outcome of ultrasound-guided insertion of central hemodialysis catheter the needle path shows up as a spot in the horizontal view and a hyperechoic line in the longitudinal view, with ringdown artifacts. when a flush of blood was detected, the us probe was taken down and the conventional seldinger method was performed under fluoroscopic guidance (figure 3) and (figure 4). statistical analysis was carried out by spss for windows version 13.0. the mean ± and standard deviation of numerical variables were calculated. the paired student, t-test, or mann-whitney u test was utilized for intergroup comparisons. p values less than 0.05 was significant statistically. results 150 hd patients were categorized into two groups: normal (88) and high-risk (62). female patients represent (64.7%, and 35.4%) respectively, while male patients represent (65.3% and 64.5%) respectively. the patients' mean ages were 55 (37 to 74) for the normal group and 54 (37 to 75) for the high-risk group. table 1 presents the clinical characteristics of the study patients. the nephrology clinics referred 126 patients (84%), while other clinics referred the remaining (16%). diabetes mellitus was esrd’s most common etiology, accounting for 54 individuals (36%), and hypertension in 22 (14.6%). other causes like chronic glomerulonephritis, polycystic kidney disease, obstructive uropathy, and unknown accounted for 49.4% of patients. in the normal group, 79 (89.7%) catheters were inserted through the right ijv, while 9 (10.2%) catheters were inserted through the left ijv. thirty-two catheters (51.6 percent) were inserted through the right ijv in the high-risk group, while 30 (48.3 percent) were inserted through the left ijv.70 (79.5%) participants within the normal group and 23 (37.1%) participants within the high-risk group had their first dialysis session after catheterization; the remaining patients were already on regular hd therapy and required new vascular access because of the failed previous one. 21 (33.8%) of the high-risk group referred to us due to catheter malfunction. for the high-risk group, fresh frozen plasma was given to 5 patients prior to the procedures due to abnormalities in the coagulation profile. ijv cannulation was performed on all patients. the normal group's first-attempt success rate was 89.8%, while the high-risk group was 72.5% (p = 0.006). the high-risk group took longer to cannulate ijv than the normal-risk group (35.4 ± 0.11) minutes versus (21.2 ± 0.09) minutes (p < 0.001) table 2. during the study, no serious complications took place. arterial puncture did not occur in either of the patients in the normal group, but it did occur in four patients (6.4%) within the high-risk group during catheter insertion in the ijv (p = 0.017). two patients in each group got a small neck hematoma. after placing a left ijv tunneled table 1. patient’s clinical characteristics. patient’s normal group high-risk group p-value characteristics (n = 88) (n = 62) age (years) # mean ± sd 55.15 ± 10.96 54.19 ± 10.98 0.598 range 37-74 37-75 gender ▲ 0.888 female 31 (64.7%) 22 (35.4%) male 57 (65.3%) 40 (64.5%) comorbidities ▲ ihd 23 (26.1%) 15 (24.1%) 0.782 dm 48 (54.5%) 38 (61.2%) 0.416 htn 51 (57.9%) 39 (62.9%) 0.540 # independent sample t-test; ▲: chi-square test; p-value > 0.05 ns. table 2. the number of venous cannulation attempts and average procedure time. normal group high-risk group p-value (n = 88) (n = 62) number of attempts ▲ 1 79 (89.8%) 45 (72.5%) 0.006* 2 9 (10.2%) 14 (22.6%) 0.039* > 2 non 3 (4.9%) 0.037* average procedure time (35.4 ± 0.11) minutes (21.2 ± 0.09) minutes < 0.001** # independent sample t-test; ▲ chi-square test; p-value > 0.05 ns; * p-value < 0.05 s; ** p-value < 0.001. figure 4a. progression of the catheter inside a subcutaneous tunnel. figure 4b. peeling the peel-away sheath. figure 4c. testing the catheter for smooth blood flow (right). archivio italiano di urologia e andrologia 2023; 95(3):11588 e.m. abdo, t.a. abouelgreed, w.e. elshinawy, et al. 4 permanent catheter, one patient in the high-risk group developed a pneumothorax, which was managed by inserting an intercostal chest tube. discussion traditionally, anatomical feature sites have been used for central venous access placement. despite this, the landmark procedure was associated with a statistically significant risk of complications and failure rate due to the patients' abnormal anatomy and probable vascular pathology, as well as depending on the individual operators' proficiency (19). prior studies conducted reported a 35% failure rate for central vein catheterization using anatomic landmarks alone, with published complication rates ranging from 5% to 40% (20). the us access guidance has lately become commonly utilized as a quality indicator to prevent procedure-related sequelae. realtime ultrasonography has been utilized for directing interventional procedures in a variety of situations for many years and has become a clinical practice standard. because of technological advancements and enhanced image quality, real-time ultrasound allowed for the location of the appropriate target vessel and optimized puncture site. anatomical variation is easily identified, and venous thrombosis is excluded (21). there is strong evidence that using real-time ultrasound guidance for vascular access increases the procedure's safety and efficacy when compared to anatomical landmarks. numerous studies have found that using ultrasonography during central venous catheterization improves clinical and technical success and reduces technical difficulties (22). in a study comparing the us guided central venous catheterization to the anatomical landmark technique, the total rate of success was estimated to be higher in the us-guided technique (98% vs. 90%), and the first attempt success rate was higher in the us-guided technique (80 vs. 60 %). with us-guided catheterization, the complication rate was also significantly smaller (arterial puncture, 1% vs 8% pneumothorax, 0 vs 4% and neck hematoma, 4% vs 10%) (23). us guidance was found to significantly minimize the probability of arterial puncture (p = 0.002) in a randomized study (9). the blind technique was not preferred in our study, even in emergencies, because the portable us machine was available in the operating room around the clock. furthermore, only the real-time method was used, rather than the static technique, as european best practice guidelines strongly suggested that real-time ultrasound guidance, rather than ultrasound assistance, be used routinely for both longand short-term central venous access (strong consensus) (100%) (19). in our research, we found an insignificant difference between the normal and highrisk groups regarding the patient’s clinical characteristics (p-value > 0.05). the most common cause of esrd was diabetic nephropathy. in this current study, the total success rate was (100%) and the first attempt's success rate was 82.6% (89.8 % for the normal group and 72.5 % for the high-risk group). nine cases (10.2%) in the normal group required more than one attempt, while 17 cases (27.5%) in the high-risk group needed further attempts. in the high-risk group, three cases needed 3 attempts (one case was due to obesity, another patient had previous catheter difficulties, and the third was due to poor compliance). during this research, there were no recorded major complications. the overall rate of arterial puncture was (2.6%). during catheter insertion in the ijv, only individuals in the high-risk group had an inadvertent arterial puncture. two patients in each group got a minor neck hematoma. in the high-risk group, one patient developed pneumothorax after placing a left ijv tunneled permanent catheter which was managed with an intercostal chest tube insertion. our results regarding higher success rate and low complication rate were comparable to the results of the above-mentioned studies (9, 22). the current study's high success rate and low complication rate could be attributed to the use of us guidance, the procedures being performed by competent physicians, and the preferential use of ijvs as access sites. even under us guidance, the physician's experience, according to tordoir et al., is an important determinant of the complication rate (4). no difference was found by geddes et al. between experienced and inexperienced physicians when us advice was utilized (24). in our report, we exclusively utilized subclavian veins in patients with ijv occlusions because they are no longer used routinely due to the risk of central venous stenosis. conclusions real-time ultrasound has been indicated as a means to improve success rates, shorten operation time, and lower the number of complications associated with hd catheter implantation in ijvs. even when using us guidance, prior catheter placement experience reduces complication rates. ultrasound guidance is becoming a standard technique that should be recommend in all cases. references 1. maaz abbasi, glenn m chertow, and yoshio n hall. end-stage renal disease. bmj. 2010; 7:1-16. 2. michael b. silva, jr and brajesh k.lal. decision making in vascular surgery by jack l. cronenwett, and robert b. rutherford. copyright 2001. chapter 72:354-359. 3. vascular access 2006 work group. clinical practice guidelines for vascular access. am j kidney dis. 2006; 48 (suppl 1):s176-247. 4. tordoir j, canaud b, haage p, et al., european best practice guidelines on hemodialysis (ebpg) on vascular access, nephrology dialysis transplantation. 2007; 22(suppl 2): 88-117. 5. national kidney foundation. k/doqi clinical practice guidelines for vascular access. am j kidney dise. 2000; 37(suppl 1): s137-s180. 6. ori y, korzets s, katz m, et al. the contribution of an arteriovenous access for hemodialysis to left ventricular hypertrophy, am j kidney dis. 2002; 40:745-752. 7. bay wh, van cleef s, owens m. the hemodialysis access: preferences and concerns of patients, dialysis nurses and technicians, and physicians. am j nephrol. 1998; 18:379-383. 8. rayner hc, pisoni rl, gillespie bw, et al. creation, cannulation, and survival of arteriovenous fistulae: data from the dialysis outcomes and practice patterns study. kidney int. 2003; 63:323-330. 9. rayner hc, besarab a, brown ww, et al. vascular access results archivio italiano di urologia e andrologia 2023; 95(3):11588 5 the outcome of ultrasound-guided insertion of central hemodialysis catheter from the dialysis outcomes and practice patterns study (dopps): performance against kidney disease outcomes quality initiative (k/doqi) clinical practice guidelines. am j kidney dis. 2004; 44:s22-s26. 10. weijmer mc, vervloet mg, ter wee pm. compared to tunnelled cuffed haemodialysis catheters, temporary untunnelled catheters are associated with more complications already within 2 weeks of use. nephrol dial transplant. 2004; 19:670-7. 11. saran r, li y, robinson b, et al. us renal data system 2015 annual data report: epidemiology of kidney disease in the united states. am j kidney dis. 2016; 67:a7-a8. 12. gupta pc, burli p. ultrasound-guided vascular access. j indian coll cardiol. 2016; 6s:92-94. 13. tammam tf, el-shafey em, tammam hf. ultrasound-guided internal jugular vein access: comparison between short axis and long axis techniques. saudi j kidney dis transplant. 2013; 24:707-713. 14. zeki a, meltem g, sami u, et al. placement of hemodialysis catheters with a technical, functional, and anatomical viewpoint. int j nephrol. 2012; 302826:5. 15. ozersky dj, olson rm, coons hg, et al. doppler controlled needle director: a useful adjunct to angiography. radiology. 1973; 109:221-2. 16. oguzkurt l, tercan f, kara g, et al. us-guided placement of temporary internal jugular vein catheters: immediate technical success and complications in normal and high-risk patients. eur j radiol. 2005; 55:125-9. 17. troianos ca, hartman gs, glas ke, et al. special articles: guidelines for performing ultrasound-guided vascular cannulation: recommendations of the american society of echocardiography and the society of cardiovascular anesthesiologists. anesth analg 2012; 114:46-72. 18. stone mb, moon c, sutijono d, blaivas m. needle tip visualization during ultrasound-guided vascular access: short-axis vs longaxis approach. am j emerg med. 2010; 28:343-347. 19. jenssen c, brkljacic b, hocke m, et al. efsumb guidelines on interventional ultrasound (invus). part vi − ultrasound-guided vascular interventions. ultraschall med. 2016; 37:473-476. 20. denys bg, uretsky bf, reddy ps. ultrasound-assisted cannulation of the internal jugular vein.a prospective comparison to the external landmark guided technique. circulation. 1993; 87:1557-1562. 21. lorentzen t, nolsoe cp, ewertsen c, et al., efsumb guidelines on interventional ultrasound (invus), part i. general aspects (long version). ultraschall med. 2015; 36:e1-14. 22. christoph f. dietrich, et al., ultrasound-guided central vascular interventions, comments on the european federation of societies for ultrasound in medicine and biology guidelines on interventional ultrasound. j thorac dis. 2016; 8:e851-e868. 23. srceva mj, sazdov d, todorova zn. comparative analysis of ultrasound-guided central venous catheterization compared to blind catheterization. pril (makedon akad nauk umet odd med nauki). 2017; 38:107-114. 24. geddes cc, walbaum d, fox jg, mactier ra. insertion of internal jugular temporary hemodialysis cannulae by direct ultrasound guidance--a prospective comparison of experienced and inexperienced operators. clin nephrol. 1998; 50:320-5. correspondence ehab m. abdo, md ehababdo48@yahoo.com waleed e. elshinawy, md waleed.elshinay82@gmail.com nehal farouk, md dr.nehalfarouk@yahoo.com department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt tamer a. abouelgreed, md (corresèonding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg hassan ismail, md drhassan_ismail@yahoo.com department of urology, faculty of medicine, al-azhar university, cairo, egypt amal h. ibrahim, md mkellany@yahoo.com samar a. kasem, md summerahmed1983@yahoo department of internal medicine, nephrology unit, faculty medicine, al-azhar university, cairo, egypt lobna kh. sakr, md lobnakhaled910@hotmail.com naglaa m. aboelsoud, md nglaa.mahmoud@gmail.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. nermeen m. abdelmonem, md neeermeeenmohamed@gmail.com department of radiology, thumbay university hospital, ajman, uae salma f. abdelkader, md salmafathy4@gmail.com ahmed a. abdelwahed, md department of radiology, faculty of medicine ain shams university, cairo, egypt anas a. qasem, md department of internal medicine, faculty medicine, zagazig university, zagazig, egypt mosab f. alassal, md department of vascular surgery, saudi german hospital, ajman, uae ahmed a. aboomar, md ahmed_abo_omar12@yahoo.com department of internal medicine, nephrology unit, faculty medicine, tanta university, tanta, egypt archivio italiano di urologia e andrologia 2020; 92, 2102 original paper summary no conflict of interest declared. doi: 10.4081/aiua.2020.2.102 the pathological and clinical features of anterior lesions of prostate cancer: evaluation in a single cohort of patients daniele d’agostino 1, paolo corsi 1, michele colicchia 1, daniele romagnoli 1, gian maria busetto 2, matteo ferro 3, alessandro tafuri 4, matteo cevenini 5, federico mineo bianchi 5, marco giampaoli 5, angelo porreca 1 1 department of urology, abano terme hospital, abano terme (pd), italy; 2 department of urology, università “la sapienza”, roma, italy; 3 european institute of oncology, milan, italy; 4 department of urology, university of verona, italy; 5 department of urology, university of bologna, italy. introduction prostate cancer (pca) is the second most frequently diagnosed tumor in males globally (1). many national and international efforts are ongoing to improve pca diagnosis, treatment, and, ultimately, the quality of life of patients (2). the majority of tumors have an indolent clinical course, although some cancers have an aggressive and potentially lethal evolution, if they are not promptly treated. pca is often found in the peripheral area of the prostate gland, although histopathological studies from radical prostatectomy (rp) samples have shown that up to 30% of clinically significant neoplasms (cspca) can be located in the anterior portion of the gland (apca), and these are increasing in prevalence (3, 4). cancers that arise in the anterior zone may be difficult to palpate by digital rectal examination (dre), and are often missed (5). moreover, transrectal ultrasound (trus)-guided prostate biopsy fails to accurately assess the anterior zone of the prostate, where cancers may not be sampled. various studies have shown that targeted mri/ultrasound fusion biopsy (tb), compared with standard biopsy (sb), is associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer (6-8). many authors (4, 5) report that there is no difference in terms of gleason grade (gg) iv or v rate between patients with apca or posterior (p)pca, although apca has smaller tumor volume and shows a higher rate of positive surgical margins after rp when compared with ppca (5, 9). additionally, anterior cancers tend to be more aggressive than posterior ones, so early detection of anterior prostate cancer is clinically important (9-11). the aim of the present study is to compare the detection of anterior and posterior pca in a contemporary cohort of caucasian patients, admitted to the hospital for suspected pca diagnosis and to evaluate clinical and pathological features between apca and ppca. the investigation was prompted by the finding that, in our practice of rp specimens, tumor volume is lower and gg is higher in a majority of cases, when the index tumor is predominantly located in the anterior region of the gland, compared to the posterior zone. introduction. the aim of our work is to evaluate the principal differences of the pathological features in prostate cancer (pca) lesions comparing those in the anterior region of the gland (apca) to those in the posterior zone (ppca) among patients who underwent to robotic-assisted radical prostatectomy (rp). material and methods. a total of 85 consecutive patients (mean age 66; iqr 62-71) with clinically suspected pca were studied with multiparametric magnetic resonance of prostate before prostate biopsies. the prostate biopsies were rm-guided (60 inbore biopsy (mr-gb) and 25 fusion-biopsy (fb). a total of 72 cases were eligible for robotic rp. an experienced genitourinary pathologist reviewed the histopathology of the tissue specimens of the patients after rp. the exclusion criteria were as follows: previous hormonotherapy, radiotherapy and chemotherapy for others cancers. results. based on the histological diagnosis, after rp, 68 anterior prostate cancer, and 107 posterior lesions were found. we further subcategorized lesions into peripheral and central zones for each the anterior and posterior lesions. the specific distribution of lesions by pathologic stage was: t2 = 74 (42.3%), t3a = 87 (49.7%), t3b = 12 (6.9%), t4 = 2 (1.1%) cases. tumor volume of posterior neoplasms ranged from 0.04 to 20.35 cm3, with a median of 3.39 cm3. anterior tumor volume ranged from 0.17 to 15 cm3, with a median volume of 2.54 cm3: ppca were larger than apca but the difference in size was not significant. the prostate cancer grade group (gg) i was distributed as 16.6% and 36% in anterior and posterior lesions cases. gg ii and iii was 43.8% and 31.5% in anterior and posterior cases, respectively. comparatively, gg iv-v showed 39.6% and 32.5% for anterior and posterior lesions respectively (p < 0.001). extraprostatic extention of neoplasm (epe) was found more frequently in anterior cases (31.4%) than in in posterior cases (25.1%), but without significant difference. lymphovascular invasion was similar in both the groups: 24% and 28.6% in anterior and posterior group, respectively. anterior lesions showed a significantly higher rate of lymph node metastasis (9.3%) than posterior lesions (3.4%) (p < 0.005). conclusion. in our study, we have found epe, often associated with worse prognosis, more frequently (but not significantly) present in anterior lesions among pca patients. although posterior lesions are often related to pt3b stage, in our findings, anterior lesions were more often associated with a more aggressive neoplasm with more frequent nodal involvements. key words: prostate cancer; anterior lesion; multiparametric magnetic resonance. submitted 7 may 2020; accepted 13 may 2020 porreca_stesura seveso 17/06/20 10:13 pagina 102 103archivio italiano di urologia e andrologia 2020; 92, 2 anterior lesions of prostate cancer materials and methods a total of 85 consecutive patients (mean age 66; iqr 6271) with clinically suspected pca were enrolled at our institution between january 2016 and january 2019. all enrolled patients had been studied with multiparametric magnetic resonance (mpmri) of prostate before prostate biopsies. we identified 386 suspected lesions at mpmri (excluding the lesion of transitional zone we included in the evaluation 229 lesions of posterior region and 157 in anterior region of prostate). the demografics and radiological details of cohort are summarized in table 1. the prostate biopsies were all rm-guided, inbore biopsy (mr-gb) and fusion-biopsy (fb). according to the risk category, patients were offered active surveillance (as), robot assisted radical prostatectomy (rarp), or radiation therapy (rt). all details are clarified in table 2 a total of 72 cases were eligible for robotic rp. the study was a retrospective analysis with the approval by the ethics committee institutional review board of abano policlinic and signed informed consent was provided by all patients. an experienced genitourinary pathologist reviewed the histopathology of the tissue specimens of the patients after rp. the pathologist, reviewing all prostatectomy tissue sections, identified pca foci larger than 5 mm in diameter. the exclusion criteria were as follows: previous hormonotherapy and radiotherapy, chemotherapy for others cancers. based on the histological diagnosis, 68 anterior and 107 posterior lesions were found. we also subcategorized the lesions into peripheral and central zones for each anterior and posterior group. the specific distribution of lesions by pathologic stage was: t2 = 74 (42.3%), t3a = 87 (49.7%), t3b = 12 (6.9%), t4 = 2 (1.1%) cases (ref table 3). pathology protocol the radical prostatectomy specimens were fixed in 10% formalin and cut into approximately 5 mm sections by hand as follows: apex and base in coronal plane, seminal vesicles in sagittal plane, and mid-gland in transverse plane, perpendicular to the long axis of the urethra. the 5-mm paraffin-embedded slices blocks were sectioned into 5μm-thick sections and stained with hematoxylin and eosin (h&e). dedicated pathologists examined surgical specimens, which were processed according to the stanford protocol (30). isup grade group system was applied to classify tumors (31). surgical margins were reported positive when cancer invaded the inked surface of the specimen. lymph nodes were assessed for histopathology after hematoxylin and eosin staining. immuno-histochemical staining was performed when appropriate. in each case, the number of removed lymph nodes and lni was reported. prostate and nodal specimens were then staged according to the 2010 ajcc staging system for pca (18). perioperative-features in each case, clinical pelvic lymph node staging (cn) was table 1. overall and stratified according to bioptic status clinical and radiologic features of patients undergoing target biopsy of prostatic anterior lesion identified at mpmri. overall posterior anterior p-value (n = 386) lesions lesions (n = 229) (n = 157) age median 66 67 66 0.7 iqr 62-71 61-72 63-71 psa (ng/ml) median 7 6.7 7.7 0.02 iqr 5-9.2 4.8-9.1 5.2-10.1 prostate volume (ml) median 53.7 55 51.2 0.5 iqr 42-69.1 43-69.7 38.1-67.8 psa density median 0.12 0.12 0.15 < 0.001 iqr 0.09-0.18 0.09-0.16 0.09-0.23 dre (%) negative 260 (67.4) 161 (70.3) 106 (67.5) 0.5 positive 126 (32.6) 77 (33.6) 47 (29.9) previous trus-gb (%) 141 (36.6) 69 (30.1) 72 (45.9) 0.002 pirads score (%) 3 145 (37.6) 105 (45.9) 40 (25.5) < 0.001 4 136 (35.2) 83 (36.2) 53 (33.8) 5 105 (27.2) 41 (17.9) 64 (40.8) index kesion diameter (mm) median 14 13 16 < 0.001 iqr 11-19 9-17 12-23 index kesion site (%) peripheral 277 (71.8) 183 (79.9) 94 (59.9) < 0.001 central 109 (28.2) 46 (20.1) 63 (40.1) iqr: interquartile range; trus-gb: transrectal ultrasound-guided biopsy; psa: prostatic specific antigen; dre: digito-rectal examination. table 2. overall and stratified according to fusion and in-bore biopsy bioptic outcomes of patients undergoing target biopsy of prostatic anterior lesion identified at mpmri. overall posterior anterior p-value (n = 386) lesions lesions (n = 229) (n = 157) targeted biopsy technique (%) mr-gb 217 (56.2) 118 (51.5) 99 (63.1) 0.3 fusion 169 (43.8) 111 (49.5) 58 (36.9) number of cores taken median 12 12 12 0.09 iqr 2-14 2-14 2-14 positive cores * median 1 1 2 < 0.001 iqr 0-3 0-2 1-3 gleason grade (%) negative 138 (35.8) 102 (44.5) 36 (22.9) 1 64 (16.6) 38 (16.6) 26 (16.6) 2 90 (23.3) 37 (16.2) 53 (33.8) < 0.001 3 65 (16.8) 35 (15.3) 30 (19.1) 4 26 (6.7) 15 (6.6) 11 (7) 5 3 (0.8) 2 (0.9) 1 (0.6) indication (%) no treatment 138 (35.8) 102 (44.5) 36 (22.9) active surveillance 43 (11.1) 32 (14) 11 (7) < 0.001 rp 175 (45.3) 72 (31.4) 103 (65.6) rt 23 (6) 18 (7.9) 5 (3.2) adt 7 (1.8) 5 (2.2) 2 (1.3) mr-gb: magnetic resonance-guided biopsy; adt: androgen deprivation therapy; rt: radiotherapy; rp: radical prostatectomy. porreca_stesura seveso 17/06/20 10:13 pagina 103 archivio italiano di urologia e andrologia 2020; 92, 2 d. d’agostino, p. corsi, m. colicchia, et al. 104 performed by axial imaging modalities (computed tomography ct or mri). enlarged pelvic nodes larger than one centimeter in diameter were staged as cn1 disease. the metastatic status was investigated by both axial imaging and total bone scan modalities. patients were staged according to 2010 american joint committee on cancer (ajcc) staging system for pca (7th edition) (18). pca patients were divided into low, intermediate and high risk, according to the d’amico risk classification (19). in high risk patients in the rarp group, extend pelvic lymph node dissection (eplnd) was performed (20, 21). in intermediate risk patients, the decision to perform an extended lymph node dissection was mainly based on pre-operative nomograms showing a risk of lymph node invasion greater than 5% (22). in low risk patients, the decision to perform an eplnd was based on clinical factors indicating increased risk of tumor upgrading and lymph node invasion in the surgical specimen (23). skilled and experienced surgeons performed rarp with eplnd using the da vinci robot surgical system (intuitive surgical, inc, sunnyvale, ca, usa). all procedures were performed through a trans-peritoneal approach with anterograde prostatic dissection (24). urethro-vesical anastomosis was performed using barbed sutures as previously described (25-26). the lymph node dissection template included bilateral external iliac lymph nodes until the crossing of the ureter and the external iliac artery. statistical analysis continuous variables were expressed as median and interquartile range (iqr) whereas categorical variables were expressed as frequencies with percentages. the independent-samples t-test and chi-square test were used to compare means and frequencies between the two groups, respectively. all data were statistically analyzed using spss v 21 for macintosh. results median age was 66 (iqr 63-71) and 67 (range 61-72) years among anterior and posterior lesions cases, respectively. mean serum psa level was 7.7 ng/ml (iqr 5.210.1) in anterior cases and 6.7 ng/ml (iqr 4.8-9.1) in posterior cases. tumor volume of posterior neoplasms ranged from 0.04 to 20.35 cm3, with a median of 3.39 cm3.tumor volume of anterior cases ranged from 0.17 to 15 cm3, with a median volume of 2.54 cm3. this difference in size was not statistically significant (p > 0.05). the gg i was distributed as 16.6% and 36% in anterior and posterior lesions cases, respectively. ggii and iii was 43.8% and 31.5% in anterior and posterior cases, respectively. gg iv-v was 39.6% and 32.5% for anterior and posterior lesions, respectively (p < 0.001). extraprostatic extension of neoplasm (epe) was found more frequently in anterior cases (31.4%) than in in posterior cases (25.1%), but without significant difference (p > 0.05). pathologic stages among patients with primary posterior lesions were as follows: 42.3% in pt2, 49.7% in pt3a, 6.9% in pt3b, and 1.1% in t4. among patients with anterior primary lesions, in 38.0% were in pt2 stage, 5.3% were in pt3a, 5.6% were in pt3b, and 11.1% in t4. lymphovascular invasion was similar in both the groups: 24% and 28.6% in anterior and posterior group respectively. anterior lesions showed a significantly higher rate of lymph node metastasis (9.3%) than in posterior lesions (3.4%) (p < 0.005). discussion in the literature, the imaging techniques for prostate cancer are in constantly evolving, and several different examination techniques play a fundamental role in the diagnosis, staging (27), and choice of therapeutic approach (28). in particular, the localization of prostate cancer foci with table 3. overall pathologic outcomes of patients who underwent radical prostatectomy (n = 72). overall pathologic stage (%) t2 74 (42.3) t3a 87 (49.7) t3b 12 (6.9) t4 2 (1.1) pathologic isup grade (%) 1 10 (5.7) 2 70 (40) 3 56 (32) 4 34 (19.4) 5 5 (2.9) pathologic nodal status (%) n0 113 (64.6) n1 10 (5.7) nx 52 (29.7) positive surgical margins (%) 11 (6.3) pathologic index lesion (%) anterior 68 (39.9) posterior 107 (61.1) mpmri: multiparametric magnetic resonance imaging; adt: androgen deprivation therapy; rt: radiotherapy; rp: radical prostatectomy; * among those with positive biopsies. table 4. uniand multivariate analysis model predicting features of patients who underwent. univariate analysis multi-variate analysis or (95% ci) p-value or (95% ci) p-value age (yrs) 1.09 (1.05-1.12) < 0.001 1.07 (1.03-1.12) 0.002 psa (ng/ml) 1.12 (1.06-1.17) < 0.001 1.15 (1.06-1.24) 0.001 prostate volume (ml) 0.98 (0.97-0.99) < 0.001 0.97 (0.95-0.98) < 0.001 digito-rectal examination 5.99 (3.69-9.71) < 0.001 7.03 (3.76-13.16) < 0.001 previous trus-gb 1.55 (1.02-2.35) 0.04 1.03 (0.59-1-8) 0.9 n of bioptic cores 1.02 (0.99-1.06) 0.3 pirads score 3 ref. ref. 4 5.63 (3.27-9.68) < 0.001 4.08 (2.17-7.67) < 0.001 5 17.27 (9.17-32.53) < 0.001 9.6 (3.77-24.45) < 0.001 index lesion diameter (mm) 1.08 (1.05-1.12) < 0.001 0.98 (0.92-1.03) 0.7 mpmri index lesion location posterior ref. < 0.001 ref. 0.01 anterior 2.41 (1.59-3.65) 2.09 (1.19-3.68) targeted biopsy with clinical cspca (gs ≥ 7) cspca: clinically significant prostate cancer; psa: prostate specific antigen; trus-gb: transrectal ultrasound-guided biopsy; mpmri: multi-parametric magnetic resonance imaging. porreca_stesura seveso 17/06/20 10:13 pagina 104 105archivio italiano di urologia e andrologia 2020; 92, 2 anterior lesions of prostate cancer mpmri is crucial in the planning the best diagnostic plane and surgical approach, for example, in robotic surgery (29-31). the pathological and biological features of prostate cancer lesion have been analyzed by numerous studies. the anatomical and biological behavior of apca are unique, and the definition varies. in the study by villers and colleagues, they defined the anterior borders of the prostate as the region of parenchyma at least 2.1 cm anterior to the posterior capsule which is an area that the transrectal biopsy needle characteristically fails to reach (32). anatomically, this is a portion of the prostate anterior to the urethra which includes areas of mcneal’s transition zone, the anterior fibromuscular stroma and the anterior horns of the peripheral zone. these features make the use of mri-guided prostate biopsy techniques indispensable to obtain a correct therapeutic approach; late identification of anterior lesions significantly affects disease prognosis and surgical outcomes (extra-prostatic extension and positive surgical margins). here, we have studied the differences between neoplasms arising from anterior and posterior gland. in retrospective studies of rp, it is reported that over 50% of tumors are located in anterior prostate (33-34). in agreement with the literature, we found 40% of lesions were located in anterior gland. at the time of diagnosis, anterior lesions were bigger than posterior ones, because apca are commonly more advanced and have positive surgical margins (psm) on rp specimens so therefore they can carry more risk for the patient (35). however, the findings from the present investigation do not support the observed trend from the literature, that anterior lesions have a lover gg than posterior (36-37). we found that anterior lesions have a higher gg than posterior lesions (p < 0.005) and a more advanced local stage at the time of detection, even in presence of a smaller volume of neoplasm. anatomy of the anterior extraprostatic space which spans across the apex through the base, is unique in that the capsule is vaguely defined and is covered with fibromuscular shielding (anterior fibromuscular stroma) afms (8). not only does the lack of capsular structure makes it difficult to define epe and psm in these regions, but the particular histological structure may provide an alternative route through which malignant cells can spread and gain access to the lymphatic drainage system. in most studies in literature, apca are reported to be associated with lower rate of epe while psm rate was higher compared to posterior cancers. differences in epe between anterior and posterior lesions result from mechanical/anatomical distinctions, rather than biological differences (38), thought we have found that epe was slightly more common in anterior lesions, but not statistical so. to better clarify this discrepancy, further anatomopathological studies must be carried out. in accordance with the literature, the present study has found higher rates of seminal vesicles invasion (pt3b) in the posterior lesions than in the anterior lesions, probably correlated to the anatomical location of the seminal vesicle (39). certainly, an interesting aspect is represented by lymph node diffusion. in our cohort, more lymph nodal involvement has been found in anterior lesions than in posterior ones. this study has some limitations predominantly related to the retrospective design and the small size of the cohort. additionally, selection bias may be due to patients who underwent mri and fusion prostate biopsy were not all patients with a clinical suspect of pca. clinicians were used to suggest mri (+/biopsy) in more challenging clinical scenario. moreover, the patients who underwent rp could be a selected subgroup of patients with a longer life expectancy and/or with a more aggressive pca since lowrisk pca might have been managed expectantly with active surveillance. certainly, a prospective evaluation of pathological and clinical features and long term follow-up of apca with a major number of cases will be useful to better investigate the real impact of pca location within the gland. conclusions our anatomo-topographic study shows that the anterior prostatic lesions, although smaller than posterior tends to have a higher pathological grade. in contrast with others, we have found epe, often associated at a worse prognosis, more likely present in anterior lesions. although, posterior 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2020; 92, 2 d. d’agostino, p. corsi, m. colicchia, et al. 106 12. cerantola y, haberer e, torres j, et al. accuracy of cognitive mri-targeted biopsy in hitting prostate cancer-positive regions of interest. world j urol. 2016; 34:75-82. 13. gayet m, van der aa a, beerlage hp, et al. the value of magnetic resonance imaging and ultrasonography (mri/us)-fusion biopsy platforms in prostate cancer detection: a systematic review. bju int. 2016; 117:392-400. 14. tan n, lin w-c, khoshnoodi p, et al. in-bore 3-t mr-guided transrectal targeted prostate biopsy: prostate imaging reporting and data system version 2-based diagnostic performance for detection of prostate cancer. radiology. 2016; 283:130-9. 15. schiavina r, vagnoni v, d'agostino d, et al. 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"in-bore" mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation arch ital urol androl. 2020; 91:224-229. 32. villers a, puech p, flamand v, et al. partial prostatectomy for anterior cancer: short-term oncologic and functional outcomes. eur urol. 2017; 72:333-342. 33. koppie tm, bianco fj jr, kuroiwa k, et al. the clinical features of anterior prostate cancers. bju int. 2006; 98:1167-1171. 34. takahashi h, epstein ji, wakui s, et al. difference in prostate cancer grade, stage, and ocation in radical prostatectomy specimens from united states and japan. prostate 2014; 74:321-5. 35. volkin d, turkbey b, hoang an, et al. multiparametric magnetic resonance imaging (mri) and subsequent mri/ultrasonographyfusion-guided biopsy increase the detection of anteriorly located prostate cancers. bju int. 2014; 114:e43-e49. 36. hossac t, patel mi, huo a, et al. location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. j urol. 2012; 188:781-5. 37. mygatt j, sesterhenn i, ronser i, et al. anterior tumors of the prostate: clinicopathological features and outcomes. prostate cancer prostatic dis. 2014; 17:75-80. 38. al-ahmadie ha, tickoo sk, olgac s, et al. anterior-predominant prostatic tumors: zone of origin and pathologic outcomes at radical prostatectomy. am j surg pathol. 2008; 32:229-35. 39. hossac t, patel mi, huo a, et al. location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. j urol. 2012; 188:781-5. correspondence daniele d’agostino, md (corresponding author) dott.dagostino@gmail.com paolo corsi, md pcorsi@casacura.it michele colicchia, md mcolicchia@casacura.it daniele romagnoli, md dromagnoli@casacura.it angelo porreca, md department of urology, abano terme hospital piazza cristoforo colombo 1, 35031, abano terme (pd) (italy) gian maria busetto, md gianmaria.busetto@uniroma1.it department of urology, università “la sapienza”, roma matteo ferro, md matteo.ferro@ieo.it european institute of oncology, milan alessandro tafuri, md aletaf@hotmail.it matteo cevenini, md matteoceve@gmail.com federico mineo bianchi, md federico.mineobianchi@gmail.com department of urology, university of verona marco giampaoli, md mgiampaoli@casacura.it department of urology, university of bologna porreca_stesura seveso 17/06/20 10:13 pagina 106 cop+ed+fisse 2006 77archivio italiano di urologia e andrologia 2021; 93, 1 case collection no conflict of interest declared. doi: 10.4081/aiua.2021.1.77 gram. invasive lobular carcinoma (ilc) accounts for 14% of all breast cancers; however due to the large incidence ilc affects a large number of women. metastatic spread is the single most significant predictor of poor survival. patients with distant metastases have a five-year survival rate of 27% (2008-2014). typical breast cancer metastatization sites are bones, liver, lungs and brain, but many other localizations have been described in literature, including gynecological organs and peritoneum. fallopian tube metastasis from non-gynecological malignancies are rarely described in literature especially from breast cancer (1). the aim of this report is to describe our experience regarding an unusual case of breast cancer metastasis in a middle age woman focusing on the diagnosis process and clinical management. case report a 61-year-old woman with a history of lobular breast cancer presented incidental finding of left hydronephrosis at a ct scan of the chest during oncological follow-up. this patient was treated 4 years before with right radical mastectomy and subsequent adjuvant ormonotherapy and radiotherapy. in her history there was a subtotal hysterectomy with finding of uterine carcinoma in situ. the subsequent ct scan of the abdomen showed a bilateral hydroureteronephrosis with an unclear thickening of the distal ureteral wall. a thin circumferential thickening of the rectum was also described. due to these findings a diagnostic ureteroscopy and a colonscopy were perfomed; a biopsy of the suspicious tissue was performed and in both cases the pathology results were negative. a repeat ct scan of the abdomen after 2 months revealed circumferential thickening of the rectum and the last ileal loop, bilateral hydronephrosis, thickening of wide ligaments with inhomogeneity of the annexial region bilaterally. a large peritoneal “sausage”shaped mass was described. the patient underwent a pet-ct showing a increased uptake of the intestine areas but turned out to be negative in the pelvis. on physical examination the patient was found to have a palpable mass in the right upper quadrant this collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. case 1: a case of left hydronephrosis referred four years after a right radical mastectomy for lobular breast carcinoma was described. computed tomography scan revealed a left hydronephrosis with dilated ureter up to the proximal third. an exploratory laparoscopy was performed and the definitive histopathology examination showed a recurrence of the carcinoma with a right tubal metastasis and peritoneal carcinosis. case 2: a rare case of an extensive penile squamous cell carcinoma in a young man. the patient was treated with radical surgery and modified inguinal lymphadenectomy. no recurrence was noticed so far. case 3: a rare case of left sided inferior vena cava (ivc) in a patient diagnosed with renal cell cancer who underwent open left partial nephrectomy. case 4: a case of urethrorrhagia, caused by a recent trauma from an urinary catheter placed in a patient submitted to gastric resection due to a neoplastic pathology. urethrorrhagia only temporarily responded to conservative treatment and ultimately resolved by coagulation with an endoscopic approach. key words: penile cancer; hpv; rare tumors; urethrorrhagia; endoscopy; coagulation. submitted 26 july 2020; accepted 28 september 2020 case 1 hydronephrosis as unusual presentation of metastatic lobular breast cancer (di domenico antonia, benelli andrea, beverini martina, rutigliani mariangela, introini carlo) introduction breast cancer is currently the most common malignancy in women, with an observed incidence rate of 127.5 cases per 100.000 women per year according to the surveillance, epidemiology and end results (seer) prooncological cases and complications in urology summary massimiliano bernabei 1, antonia di domenico 2, gil falcao 3, charalampos fragkoulis 4, andrea benelli 2, martina beverini 2, luís campos pinheiro 3, cabrita carneiro 3, nicolò fabbri 5, ioannis glykas 4, salvatore greco 6, carlo introini 2, konstantinos ntoumas 4, georgios papadopoulos 4, mariangela rutigliani 7, panagiotis stamatakos 4, joão vasco barreira 8 1 department of urology, azienda usl di ferrara, lagosanto, italy; 2 urology department, e.o. galliera, genoa, italy; 3 urologist, lisbon, portugal; 4 urology department, general hospital of athens “g. gennimatas”, athens, greece; 5 unit of general surgery, azienda unità sanitaria locale di ferrara, lagosanto, italy; 6 department of morphology, surgery and experimental medicine, university of ferrara, ferrara, italy; 7 pathology unit, e.o. galliera, genoa, italy; 8 medical oncologist, lisbon, portugal. archivio italiano di urologia e andrologia 2021; 93, 1 m, bernabei, a, di domenico, g. falcao, et al. 78 of the abdomen. an exploratory laparoscopy was than performed with evidence of intense pelvic tissue thickening, in particular a mass was evidenced in right pelvis that as first hypothesis was compatible with hydrosalpinx. peritoneal and cecal nodules were biopsied. macroscopic examination of the resected specimen showed fallopian tube congestion with lumen in part ectasic in part reduced and thickened and edematous wall. microscopic section showed small and relatively uniform tumor cells growing in single line and solid. the mitotic index was 3 mitoses/10 high power fields (hpf). by immunohistochemistry, the tumor cells were positive for cytokeratin 7 (clone sp52, prediluited, ventana), gata 3 (clone l50-823, prediluited, cell marque), estrogen (clone sp1, prediluited, ventana), progesterone (clone 1e2, prediluited, ventana). they were negative for her 2 (clone 4b5, 1/100, ventana), e-cadherin (ep700y, prediluited, cell marque) cytokeratin 20 (clone sp33 prediluited, ventana). ki-67 (clone 30-9, prediluited, ventana) immunostaining showed nuclear labeling in 20% of the cells. we diagnosed metastases of invasive lobular breast cancer to the fallopian tube (figure 1). actually the patient is alive and undergoing chemotherapy with partial radiologic regression of the peritoneal mass. she still needs bilateral double j ureteral stents in order to protect the renal function during chemotherapy. conclusions breast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for patients aged 20-59 years. the interval between diagnosis of primary and metastatic disease is described in literature between 5 and 20 years; in our case the presentation was after 4 years from the primary treatment (2). metastatic patterns of breast carcinoma have been studied, suggesting two important factors impacting the site of tumor spread: the estrogen receptor (er) status and the pathology of cancer (ductal versus lobular). lobular carcinoma is not the most common histological subtype of breast carcinoma, but it is the most frequent related to gastrointestinal, gynecological and peritoneal metastases. in a series of 100 cases, rabban et al. found that the two main primary tumors metastasizing to the fallopian tube were colon (35%) and the breast (15%) (3). carcinomatosis can occur in 2.6% of cases. the literature rarely mention peritoneal metastasis from breast cancer, and peritoneal recurrences are described after a variable time interval between 5 and 10 years from the diagnosis of primary breast cancer. this late onset might not always be related to a late metastasis development rather than to a late metastasis detection, which results very difficult in the absence of any specific symptom. moreover, modern imaging techniques resulted scarcely accurate in peritoneal carcinomatosis diagnosis (2). to our knowledge, this is the first reported case of tubal metastasis and peritoneal carcinomatosis from a lobular breast cancer diagnosed by an incidental finding of hydronephrosis. this case emphasizes the role of the fallopian tubes as a potential conduit between the gynecological tract and the peritoneal cavity. references 1. bigorie v, morice p, duvillard p, et al. ovarian metastases from breast cancer: report of 29 cases. cancer. 2010; 116:799-804. 2. winston cb, hadar o, teitcher jb, et al. metastatic lobular carcinoma of the breast: patterns of spread in the chest, abdomen, and pelvis on ct. ajr am j roentgenol. 2000; 175:795-800. 3. rabban jt, vohra p, zaloudek cj. nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. am j surg pathol. 2015; 39:35-51. case 2 squamous cell carcinoma of the penis (gil falcão, cabrita carneiro, luís campos pinheiro, joão vasco barreira) introduction penile cancer is uncommon. the incidence of penile cancer increases with age with a peak in the sixth decade, but it does occur in younger men. about one third of cases are attributed to hpv-related carcinogenesis. squamous cell carcinoma accounts for over 95% of penile malignancies. early inguinal lymphadenectomy in clinically node-negative patients is superior for longterm patient survival compared to later lymphadenectomy with regional nodal recurrence. patient education is an essential part of follow-up. in patients with long-term survival after penile cancer treatment, sexual dysfunction, voiding problems and cosmetic penile appearance may adversely affect the patient’s quality of life (qol). since penile cancer is rare, patients should be referred to a center with experience and expertise in local treatment, pathological diagnosis, chemotherapy and psychological support for penile cancer patients. case report the authors present a clinical case of a man in the fifth decade of life with no comorbidities. the presenting feacase 1 figure 1. a) metastatic lobular carcinoma of breast growing beneath tubal epithelium. (hematoxylin-eosin staining magnification 20x). b) immunohistochemical estrogen slide showing diffuse and intense positive of the majority of tumor cells (estrogen, magnification 20x). c) metastatic lobular carcinoma: immunostaining with gata 3 shows a characteristic canalicular pattern (gata3, magnification 20x). d) the ki-67 proliferation index is 20% (ki-67 mib1, magnification 20x). ture was a 4-years onset history of a penile lesion. at the clinical examination we highlight complete dissociation of foreskin with exposure of corpora cavernosa, lesion of bulky dimension about 5-10 cm, no palpable inguinal lymph nodes, purulent exudate (figure 1). the histopathological findings of a biopsy of the lesion were compatible with a squamous cell carcinoma (scc) with overexpression of p16. staging was performed with thoraco-abdominal-pelvic computed tomography (ct) which revealed a voluminous penile mass, centered on the dorsum of the penis, involving cavernous bodies, spongy body and urethra; the mass contacted the scrotum, with no evident cleavage plan and with no distant sign of disease. at the multidisciplinary evaluation, the patient was proposed for surgical approach. the histopathological report of the radical penectomy with modified radical lymphadenectomy revealed a squamous cell carcinoma pt3g2n0, r0. discussion in industrialized countries, penile cancer is uncommon. the incidence of penile cancer increases with age with a peak in the sixth decade, but it does occur in younger men. about one third of cases are attributed to hpvrelated carcinogenesis. a significantly better five-year disease-specific survival has been reported for hpv-related compared with hpv-negative cases. squamous cell carcinoma accounts for over 95% of penile malignancies. it is not known how often scc is preceded by premalignant lesions. early inguinal lymphadenectomy in clinically node-negative patients is superior for long-term patient survival compared to late lymphadenectomy for regional nodal recurrence. local recurrence is easily detected by physical examination, by the patient himself or his physician. patient education is an essential part of follow-up. in patients with long-term survival after penile cancer treatment, sexual dysfunction, voiding problems and cosmetic penile appearance may adversely affect the patient’s quality of life (qol). however, there is very few data on sexual function and qol after treatment for penile cancer. since penile cancer is rare, patients should be referred to a center with experience and expertise in local treatment, pathological diagnosis, chemotherapy and psychological support for penile cancer patients. this case is a reminder of how the perception of individual skin findings can lead to the diagnosis of malignant tumors. it also embodies a rare clinical observation, which justifies reporting this case with the purpose to highlight the importance of a multidisciplinary team in the management of cancer patients (1). references 1. joura e, jenkins d, guimera n. vulvar, penile, and scrotal human papillomavirus and non–human papillomavirus cancer pathways, in d. jenkins, f. xavier bosch (eds) human papillomavirus providing and using a viral cause for cancer, academic press 2020, pages 219-230. case 3 left sided inferior vena cava in a patient diagnosed with renal cell carcinoma (charalampos fragkoulis, ioannis glykas, panagiotis stamatakos, georgios papadopoulos, konstantinos ntoumas) introduction inferior vena cava (ivc) is a large retroperitoneal vein responsible for the deoxygenated blood transportation from the lower extremities and the abdomen through diaphragm to the right atrium. anatomically is formed by the confluence of the right and left iliac veins at the level of l5 vertebrae. after its formation it lies along the right anterolateral aspect of the vertebral column and passes through the central tendon of the diaphragm around the t8 vertebral level (1). many anatomic anomalies of the ivc are described. most clinically significant are left sided ivc, double ivc, intrahepatic ivc agenesis and total absence of infrarenal ivc (2). left sided ivc has a suspected prevalence up to 0.5% and it is caused by the regression of the right supracardinal vein and the persistence of the left supracardinal vein (3). injuries of the ivc may occur during operations of the right kidney. although major vascular injuries involving ivc during laparoscopic or open partial nephrectomy are rare, it is of outmost importance to recognize major anatomic landmarks and to identify anatomic anomalies prior to surgery in order to be able to face any intraoperative complication (4). therefore, recognizing left sided inferior vena cava variation before surgery through the imaging techniques is very important for the surgeon’s preparation of possible vascular damage. case report we present a case of a 75-year-old male who was referred to our department due to a 5 cm left renal tumor located in the lower pole. in the ct performed we recognized ivc located in the left of the midline as well as total aplasia of superior vena cava (figure 1). vein drainage above the diaphragm was performed through the vein system of azygos and hemiazygos veins. left renal vein was drained straight to the ivc but as ivc was located to the left side, it did not pass in front of the aorta as usual (figure 2). a successful open partial nephrectomy was performed by a retroperitoneal approach. the patient was informed in detail by the treating physician for inclusion in the case presentation and signed an informed consent prior to participation. in the form the 79archivio italiano di urologia e andrologia 2021; 93, 1 oncology and complications case 2 figure 1. a-b: at clinical examination complete dissociation of foreskin with exposure of corpora cavernosa, lesion of bulky dimension about 5-10 cm, no palpable inguinal lymph nodes, purulent exudate. a. b. archivio italiano di urologia e andrologia 2021; 93, 1 m, bernabei, a, di domenico, g. falcao, et al. 80 patient has given his consent for his images and other clinical information to be reported in the journal. the patient understands that his name and initials will not be published. conclusions left sided inferior vena cava is an exceedingly rare entity. recognizing this rare anatomic variation before surgery through the imaging techniques is very important for the surgeon’s preparation of possible intraoperative complications. references 1. petik b. inferior vena cava anomalies and variations: imaging and rare clinical findings. insights imaging. 2015; 6:631-9. 2. kaufman ja, waltman ac, rivitz sm, geller sc. anatomical observations on the renal veins and inferior vena cava at magnetic resonance angiography. cardiovasc intervent radiol. 1995; 18:153-157. 3. giordano jm, trout hh. anomalies of the inferior vena cava. j vasc surg. 1986; 3:924-8. 4. mcallister m, bhayani sb, ong a, et al. vena caval transection during retroperitoneoscopic nephrectomy: report of the complication and review of the literature. j urol. 2004; 172:183-185. case 4 endoscopic treatment of recurrent urethrorrhagia (massimiliano bernabei, nicolò fabbri, salvatore greco) lesions of the urethra due to urethral catheterization or dislocation of the catheter itself are well known and may sometimes occur with urethrorrhagia and subsequent anemia. the causes may be found in "false paths", stenosis, urethro-penile fistulas, or more rarely, pseudoaneurysms of the bulbar arteries of the penis. the goldstandard treatment consists of percutaneous angioembolization (1, 2). we introduce a case of urethrorrhagia, caused by a recent trauma from the urinary catheter, only temporarily responding to conservative treatment and ultimately resolved by the endoscopic approach. case report a 72-year-old man was admitted to the general surgery unit of our hospital in lagosanto (ferrara) for gastric resection due to a neoplastic pathology. before undergoing surgery, he first underwent a cycle of neoadjuvant chemotherapy. in his clinical history, he reported colic diverticulosis, hemorrhoidal syndrome, bilateral inguinal hernioplasty, and mild thrombocytopenia of unknown origin. in the pre-operative period, the patient had reported pollakiuria and dysuria, without requiring urological or medical examinations. the postoperative observation period was complicated with an accidental self-removal of the urinary catheter, accurately positioned before surgery, with a consequent nocturnal episode of urethrorrhagia. the patient did not need the repositioning of the catheter because of spontaneous urination and was discharged after ten days since the operation, with a regular postoperative course and with the urological indication to take tamsulosin 0.4 mg/day combined with dutasteride 0.5 mg/day at home. two days after being discharged, the patient underwent another episode of urethrorrhagia at home, which resolved spontaneously. after three more days (on the 15th postoperative day), the patient presented again to emergency ward for recurrent urethrorrhagia, but this third episode was more persistent and severe. blood exams documented anemization (hemoglobin levels ranging from 9.4 to 8 g/dl in the few hours of stay at the emergency room). it was positioned "per uretram" a latex catheter (20 ch diameter) and tranexamic acid was administered both locally and orally. due to only partial resolution of the bleeding, it was admitted to our urology department. during the hospital stay, the treatment consisted of compression of both penile shaft and perineum with local application of ice; he also needed to be transfused with two units of concentrated red blood cells. after rapid resolution of the urethrorrhagia, a modest urethral bleeding persisted and, in the hypothesis of a lesion of the distal urethra, peri-catheter endo-urethral injection of etilefrine was administered, resulting in an apparent and rapid regression of bleeding. however, urethrorrhagia presented again two days later, contextually with the evacuation of some clots from the bladder catheter and suprapubic pain symptoms. we, therefore, decided to consider the patient eligible for urgent operative urethro-cystoscopy, to carry out a bladder washing, waiting for angiography and, if necessary, percutaneous angioembolization. because of the unavailability of these procedures in our hospital, it was planned to refer the patient to our reference hub hospital in cona (ferrara). the introduction of the cystoscope (olympus) allowed us to highlight a hyperemic urethral area of about 1 cm, located immediately before the membranous tract of urethra at 7 o’clock position, without evidence of active bleeding. retrograde endoscopy ruled out further lesions, allowing, once in the bladder, to find and contextually evacuate several intraluminal clots. during the case 3 figure 1. ct showing ivc located in the left of the midline as well as total aplasia of superior vena cava. case 3 figure 2. left renal vein draining straight to the ivc but as ivc was located to the left side not passing in front of the aorta as usual. 81archivio italiano di urologia e andrologia 2021; 93, 1 oncology and complications execution of the final antegrade urethroscopy, monopolar diathermocoagulation (dtc) was performed on part of the margin of the a forementioned urethral lesion (figure 1). after removing the instrument, a two-way “tiemann” catheter (20 ch) was then placed. the latter was removed on the third postoperative day, with discharge at home the next day after satisfactory spontaneous normochromic urination. after a further three months of observation, the patient resulted to have no more episodes of urethrorrhagia or abdominal pain symptoms, and the urinary dynamics always remained regular. conclusions urethral lesions are well known and frequent in urology, although they result in urethrorrhagia only on rare occasions (3). in cases where this event occurs, conservative treatment (i.e. transurethral catheterization associated with perineal compression) allows resolution in most cases. if this approach is not effective, the more usual alternative is radio-guided angioembolization. unfortunately, this procedure may not be readily available in all hospital centers, as it happened for our hospital. to date, only a few reports of endoscopic treatment, as alternative to angioembolization, have been reported in the literature.what we suggest, in the case that radiologicalinterventional treatment (angiography and percutaneous embolization) is not immediately available, is the endoscopic approach. this procedure should aim to endoluminal compression (4), but also to coagulation of any possible active bleeding. furthermore, in case of significant bleeding, as happened in our case, simple bladder washing may be not effective due to the formation of blood clots that need to be removed with an endoscopic procedure. the "gold standard" treatment should be cystoscopy followed by angiography with embolization; unfortunately, the lack of interventional radiology in our hospital led us to choose an endoscopic attempt to stop bleeding as the first option. in the postoperative period, careful monitoring of the urine color, as well as of the patient’s hemodynamic and hematochemical parameters, to exclude any occult bleeding, could be sufficient to avoid further radiological-guided procedures that are not free from possible complications, even functional, as impotence. references 1. radhakrishnan s, marsh r, sheikh n, et al. urethral catheter induced pseudoaneurysm of the bulbar artery. int j urol. 2005; 12:922-4. 2. bettez m, aubé m, sherbiny me, et al. a bulbar artery pseudoaneurysm following traumatic urethral catheterization. can urol assoc j. 2017; 11:e47-e49. 3. campos sj, besser pn, aguirre ap, et al. urethrorrhagia secondary to traumatic penile pseudoaneurysm. urol case rep. 2016; 7:10-13. 4. schober jp, iqbal s, marcantonio a, maclachlan l. endoscopic management of a trauma-induced urethral pseudoaneurysm. j endourol case rep. 2019; 5:96. correspondence antonia di domenico, md antonia.didomenico@galliera.it andrea benelli, md (corresponding author) andrebenne@gmail.com andrebene85@hotmail.com martina beverini, md martina.beverini@live.it mariangela rutigliani, md mariangela.rutigliani@galliera.it carlo introini, md carlo.introini@galliera.it e.o galliera, genoa (italy) gil falcão, md (corresponding author) gilfalcao145@gmail.com cabrita carneiro, md jpcabritacarneiro@gmail.com luís campos pinheiro, md luiscampospinheiro@gmail.com joão vasco barreira, md joaovascobarreira@gmail.com lisbon, portugal charalampos fragkoulis, md harisfrag@yahoo.gr ioannis glykas, md (corresponding author) giannis.glykas@gmail.com panagiotis stamatakos, md pvstamatakos@gmail.com georgios papadopoulos, md gipapadopoulos@yahoo.gr konstantinos ntoumas, md ntoumask@yahoo.com urology department, general hospital of athens “g. gennimatas”, athens (greece) massimiliano bernabei, md m.bernabei@ausl.fe.it nicolò fabbri, md (corresponding author) n.fabbri@ausl.fe.it salvatore greco, md salvatore.greco@unife.it azienda usl di ferrara, via valle oppio, 2, lagosanto, italy university of ferrara, ferrara, italy case 4 figure 1. a) urethroscopy with visualization of the right ventral bulbar urethral lesion, just before the membranous tract. b) monopolar coagulation of the margins of the urethral lesion c) completion of coagulation d) final result. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper death, contributing to their excess mortality in comparison to the general population (2). therefore, until recently, any form of active neoplasia was regarded as a contraindication to renal transplantation, and a waiting period between cancer treatment and transplantation was mandatory. the decision on the waiting period for transplantation in patients with a history of treated cancer is mainly based on the cincinnati transplant tumor registry (3), with times varying from two to at least five years, depending on the type of tumor. however, this study published more than twenty years ago has several drawbacks that may not reflect the actual epidemiology of current diagnosed cancers: treatment and staging were not defined, and many diagnostic, therapeutic and prognostic tools have improved over these last years. therefore, nowadays, there is not enough evidence to support a fixed waiting period before transplantation. besides, there is growing recent evidence suggesting that the increased risk of cancer by immunosuppression is restricted to particular subtypes, while others may not be affected. cancers at highest risk are viral-induced cancers such as lymphomas and kaposi sarcoma, and those caused by impaired immune surveillance or via direct dna damage by anti-rejection drugs such as skin and lip cancers (4). although renal cell carcinoma (rcc) of native kidneys is one of the most common tumors in renal transplant recipients, accounting for 8% of malignancies in this population (5), it has been shown that its incidence is lower during transplantation than during graft nonfunctioning periods without immunosuppression (6). a typical feature of esrd is a higher incidence of rcc, where it can be up to ten times higher than the general population, being found in 4% of dialyzed or renal transplant patients (7). the main risk factor for rcc is acquired cystic kidney disease (ackd), which increases with duration of dialysis (8), and seems to regress after successful transplantation. thus, a longer waiting period for transplantation may paradoxically increase the risk of this kidney dysfunction-related cancer. since the outcomes of rcc after kidney transplantation and its prognosis under immunosuppressive regimens remain poorly understood with conflicting evidence, we aimed to evaluate clinical and pathological characteristics of rcc of native kidneys in esrd patients, and to compare the risk of recurrence and survival according to their dialysis or transplantation status at the time of diagnosis. introduction: kidney transplantation requires immunosuppression, traditionally regarded as a risk factor for progression in all malignancies. based on the cincinnati registry, a waiting period before transplantation is therefore mandatory. however, recent evidence suggests this increased risk is restricted to particular tumors, whereas others like renal cell carcinoma (rcc) are not negatively affected. we aimed to compare oncological outcomes of rcc in native kidneys of end-stage renal disease (esrd) patients, according to their transplantation or dialysis status. material and methods: retrospective analysis of all esrd patients diagnosed with rcc between 2010 and 2020 in our center. recurrence-free survival (rfs) and overall survival (os) were estimated with kaplan-meier curves. multivariable cox regression model was used to evaluate their association with kidney transplantation. results: clinical and pathological characteristics were similar between groups. kidney transplant recipients had similar risk of recurrence (hazard ratio [hr] 0.40, 95% confidence interval [ci) 0.04-4.46, p = 0.458) and overall survival (hr 0.34, 95%ci 0.07-1.77, p = 0.202) as dialyzed patients. on multivariable cox regression model, presence or absence of transplantation was not significantly associated with rfs (p = 0.479) or os (p = 0.236). time on dialysis was the only independent predictor of worse survival (hr 1.86, 95%ci 1.18-2.93, p = 0.008). conclusions: most rcc in native kidneys of esrd patients are low-grade, low-stage and exhibit favourable pathological and outcome features. immunosuppression does not seem to have an impact on oncological outcomes, but an increased time on dialysis seems to be associated with worse overall survival. therefore, waiting time for transplantation for these tumors could be reduced. key words: kidney transplantation; immunosuppression; dialysis; renal cell carcinoma; recurrence; overall survival; waiting period. submitted 6 february 2023; accepted 17 february 2023 introduction renal transplantation is the most successful treatment for end-stage renal disease (esrd) owing to its superior survival and quality of life compared to other replacement therapies (1). however, it requires immunosuppression, traditionally being regarded as a risk factor for increased tumor incidence and progression. the increased incidence of cancer in this population is a significant cause of renal cell carcinoma in native kidneys before transplantation when will we stop waiting? jorge correia, bernardo teixeira, gonçalo mendes, avelino fraga, miguel silva-ramos department of urology, centro hospitalar universitário do porto, portugal. doi: 10.4081/aiua.2023.11240 summary archivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos materials and methods study design and patient selection in this observational retrospective, single-center, cohort study, we evaluated data on all consecutive patients with esrd diagnosed with rcc of native kidneys and submitted to radical nephrectomy between 2010 and 2020. overall, 40 rcc cases were identified in this population based on post-operative histopathological staging. they were subsequently stratified according to their kidney transplantation or dialysis status at the time of diagnosis, and clinical, pathological and oncological outcomes were compared between groups. we excluded from analysis patients diagnosed with rcc while on dialysis who later received a renal transplant, and patients with regional or distant metastatic disease. renal transplant patients diagnosed with rcc, with later graft failure leading to resuming of dialysis were included in the kidney transplant cohort. perioperative and socio-demographic data, clinical and histopathological characteristics and survival outcomes were extracted from medical records. pre-operative staging and surgical technique all patents were evaluated preoperatively with computed tomography (ct) of the abdomen, pelvis and chest to confirm localized disease, and with biochemical blood work with creatinine. all patients were treated with radical nephrectomy, performed by either an open approach through flank incision or laparoscopic approach by standard transperitoneal four-trocar technique, based on patient and surgeon preference. lymph node dissection was not performed in any patient, since there was no nodal involvement suspected based on preoperative imaging or intraoperatively enlarged nodes. all kidney transplant patients were on standard immunosuppressive regimen, and no modification to this scheme due to oncological concerns was made at the time of rcc diagnosis or during follow-up. pathological evaluation all surgical specimens were processed according to standard pathological procedures. all lesions were confirmed to be malignant renal cell carcinomas. tumors were staged according to the 7th edition of the american joint committee on cancer tnm classification (9) and the histological subtype was assigned according to the 2016 world health organization (who) classification of kidney tumors (10). tumors were graded according to the international society of urological pathology grading classification (11). tumor multifocality was defined as the presence of two or more synchronous lesions in the same kidney, pathologically confirmed to be rcc. tumor bilaterality was defined as the presence of synchronous lesions in both kidneys at the time of diagnosis. follow-up patients were followed every 6 months during the first year after surgery, yearly until 3 years, and once every 2 years thereafter. follow-up consisted of medical history and appropriate physical examination, routine blood work and imaging re-evaluation. oncological outcomes comprised recurrence-free survival (rfs) and overall survival (os). both survival outcomes were evaluated from the date of surgery to time of event or, when lost to follow-up, the last documented outpatient visit with his physician. recurrences were treated with surgical excision, and patients continued on regular follow-up. statistical analysis categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations, or medians and interquartile ranges (iqr) for variables with skewed distributions. normal distribution was checked using shapiro-wilk test or skewness and kurtosis. univariate logistic regression was used to investigate the association between baseline patient and pathological characteristics and the transplantation or dialysis status. continuous variables were compared with the use of paired student’s t-test or mann-whitney test for variables with normal and skewed distribution, respectively. categorical variables were compared with the use of table 1. ppla score system for renal papillae (16). kidney transplant dialysis p value (n = 22) (n = 18) demographic characteristics age (years) 57.7 ± 11.0 57.7 ± 11.0 0.999 sex, n (%) male 19 (86%) 18 (100%) 0.238 female 3 (14%) 0 (0%) asa score, n (%) ≤ 3 21 (95%) 8 (44%) < 0.001 > 3 1 (5%) 10 (56%) bmi (kg/m2) 25.0 ± 3.38 25.9 ± 3.04 0.387 time on dialysis before diagnosis (months) (iqr) 38.5 (13-60) 28.0 (11-42) 0.430 time on immunosuppression (months) (iqr) 136.5 (66-182) gfr (ml/min/1.73 m2), n (%) < 15 1 (5%) 18 (100%) < 0.001 15-30 4 (18%) > 30 17 (77%) clinical and pathological characteristics size (mm) 29.27 ± 16.78 38.11 ± 21.14 0.148 t stage, n (%) pt1a 18 (82%) 11 (61%) 0.184 pt1b 3 (14%) 5 (28%) pt2a 1 (4%) 0 (0%) pt2b 0 (0%) 0 (0%) pt3a 0 (0%) 2 (11%) histological subtype, n (%) clear cell 12 (55%) 8 (44%) 0.714 papillary (type 1 and 2) 6 (27%) 8 (44%) clear cell papillary 2 (9%) 1 (6%) other 2 (9%) 1 (6%) isup grade, n (%) grade 1-2 21 (95%) 11 (61%) 0.014 grade 3-4 1 (5%) 7 (39%) tumor multifocality, n (%) 3 (14%) 4 (22%) 0.680 tumor bilaterality, n (%) 1 (5%) 1 (6%) 0.884 asa = american society of anesthesiologists; bmi = body mass index; gfr = glomerular filtration rate; iqr = interquartile range; isup = international society of urological pathology. archivio italiano di urologia e andrologia 2023; 95, 1 renal cell carcinoma and transplantation teristics were homogeneous between populations. most of the patients had pt1a disease (82% transplant vs 61% dialysis, p = 0.184), with median tumor size 3-4 cm. the most frequent histological subtype was clear cell (cc) rcc, closely followed by papillary (prcc) which was slightly more frequent in the dialysis group, albeit without statistically significant difference (p = 0.714). 3 (7.5%) patients presented with clear cell papillary rcc (ccprcc). dialyzed patients were more likely to have higher grade disease (5% kidney transplant vs 39% dialysis, p = 0.014). overall, 7 (18%) and 2 (5%) patients presented with tumor multifocality and bilaterality respectively, similarly distributed between groups. over a median follow-up of 41 months (iqr 22-71), 3 recurrences occurred: 1 in kidney transplants (from ccrcc) and 2 in dialyzed patients (1 ccrcc, 1 prcc). all the 3 recurrences occurred in the contralateral kidney with the same histological subtype, and neither any of these recurrent patients nor from the remaining overall cohort later progressed to regional node or distant metastatic disease. figure 1 shows the probability of freedom from recurrence following nephrectomy according to kidney transplant or dialysis status. median time to recurrence was not reached in any group (nr, 95% confidence interval (ci) not evaluable (ne) ne), with 5-year rfs of 96% (95%ci 91-99) and 89% (95%ci 79-98) for kidney transplant and dialyzed patients, respectively (log-rank p = 0.443). kidney transplant patients did not show an increased risk of recurrence [hazard ratio (hr) 0.40, 95%ci 0.04-4.46, p = 0.458]. on multivariable cox figure 1. kaplan-meier estimates of recurrence-free survival (a) and overall survival (b) following radical nephrectomy, comparing kidney transplant (kidney tx) and dialysis patients. fisher’s exact test or the chi-square test, as appropriate. kaplan-meier survival curves were calculated for each group of esrd patients and log-rank (mantel-cox) test calculated for difference or equivalence between treatment groups, censoring patients without the event at their date of last follow-up. a multivariate cox proportional hazards regression model was fit with time to recurrence and time to death of any cause as the dependent variables, and clinical and pathological characteristics as the independent variables, to identify independent prognostic factors of rfs and os. all reported p values are two-sided, with a p value less than 0.05 indicating statistical significance. statistical analyses were performed using the statistical package for the social sciences (spss®), version 24.0 (ibm corp., armonk, ny, usa). results demographic and pathological characteristics of the cohort stratified by kidney transplant or dialysis status at the time of diagnosis are shown in table 1. kidney transplant recipients and dialysis accounted for 22 (55%) and 18 (45%) patients, respectively. mean age at the time of diagnosis was 58 years old, and the majority of patients in both groups were male (93% overall). demographic characteristics were similar between groups, except for a lower asa score being more common in the kidney transplant cohort (asa score ≤ 3, 95% kidney transplant vs 44% dialysis, p < 0.001). median time on dialysis until diagnosis was similar (p = 0.430). pathological characarchivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos regression analysis (table 2), adjusting for clinical and pathological confounders, presence or absence of kidney transplant (and consequently immunosuppression) was not significantly associated with rfs (hr 0.42, 95%ci 0.04-4.65, p = 0.479). likewise, the time on immunosuppression was not an independent predictor of rfs (hr 0.98, 95%ci 0.95-1.02, p = 0.322). there were 7 deaths during follow-up, 2 in kidney transplant and 5 in dialysis patients. no cancer-related deaths were seen. most deaths were related to cardiovascular disease (71% overall; 100% kidney transplant and 60% dialysis). median time to death was not reached in any group (hr 0.34, 95%ci 0.07-1.77, p = 0.202). 5-year os was 91% (95%ci 78-99) for kidney transplant recipients and 72% (95%ci 59-85%) for dialyzed patients (log-rank p = 0.181). on multivariable analysis, neither the presence or absence of transplantation (hr 0.04, 95%ci 0.01-7.78, p = 0.236) nor the time on immunosuppression (hr 1.00, 95%ci 0.98-1.02, p = 0.862) were significantly associated with os. the only independent predictor of worse survival was time on dialysis (hr 1.86, 95%ci 1.18-2.93, p = 0.008). discussion considering that malignancy is a major cause of death after transplantation, a systematic screening for the presence of any active/latent cancer or a past history of cancer is mandatory when evaluating candidates for renal transplantation (12). however, previous history of malignancy and the role of immunosuppression as a causative risk factor for recurrence is still controversial, particular in certain subtypes of malignancy such as rcc, making it difficult to decide if the patient is suitable for transplantation and, if so, how long should the waiting period be. few studies have focused on the oncological outcomes of native kidneys rcc in esrd patients, all retrospective and most of them noncomparative, providing conflicting results. farrugia et al. (2) have shown that previous history of neoplasia was an independent risk factor for post-transplant death from malignancy. in a large swedish cohort of more than 10000 solid organ transplant recipients, brattström et al. (13) have found a 30% increased mortality risk for patients with a previous history of neoplasia. nevertheless, this risk was mainly driven by recipients of nonkidney transplants: mortality was increased by 20% in kidney recipients and by 80% among other organs recipients. besides, after stratification by waiting time between cancer treatment and transplantation, there was no association of increased mortality in kidney recipients, irrespective of waiting period. a two-fold increased risk of cancer-specific death was seen in transplant patients with a history of previous cancer other than kidney compared to rcc, regardless of waiting time. on the contrary, viecelli et al. (14), using data from the australian and new zealand dialysis and transplant registry, reported no significant association of previous cancer history with cancer-specific survival (css) or os in kidney transplant recipients. similarly, a recent nationwide norwegian study found that kidney recipients with a history of neoplasia had a similar os and graft survival as recipients without such cancer, and although cancer mortality was increased, particularly during the first 5 years, a short waiting period was not associated with all-cause or recurrent cancer mortality (15). in line with the most recent evidence, in our cohort, kidney transplant patients did not have an inferior rfs or os compared to dialyzed patients. moreover, on multivariable cox regression model, the presence or absence of transplant (and consequently immunosuppression) was not significantly associated with the risk of recurrence or increased mortality. in fact, the only independent predictor of an inferior survival was time on dialysis (hr 1.86, p = 0.008), which means that the common policy of a 2year waiting period before transplantation would translate into a 3-4-fold increased risk of death. cardiovascular disease remains a major cause of death in dialyzed patients (16) and since most esrd patients are elderly, it is possible that a longer waiting period will eventually lead to death, not due to cancer recurrence, but due to the burden of dialysis (17). reducing unnecessary lengthy waiting times could improve the care of these patients, optimizing timely transplantation. in accordance with our results, several studies have shown the safety of transplantation and immunosuppression in patients with a history of native kidney rcc. in a multicentric study from 24 centres conducted by the french urological association, gigante et al. (18) compared oncological outcomes of rcc in 213 transplanted and 90 dialyzed patients and reported higher 5-year rfs and css in the transplanted population. on multivariable analysis, presence of kidney transplant was not associated with css, with only t stage remaining an independent predictor of inferior survival. similarly, in a single-centre study comparing outcomes of native kidneys rcc in renal transplant recipients with a population with rcc without transplant, klatte et al. (19) showed that the presence of transplant did not affect css and os, and that most rcc were low-stage, low-grade with a favourable table 2. multivariable cox regression model predicting rfs and os after radical nephrectomy. rfs os hazard ratio 95% ci p value hazard ratio 95% ci p value kidney transplant, yes vs no 0.42 0.04-4.65 0.479 0.04 0.01-7.78 0.236 age, years 0.92 0.82-1.02 0.098 1.04 0.94-1.15 0.464 asa score, > 3 vs ≤ 3 5.39 0.49-59.87 0.170 0.31 0.01-8.18 0.487 time on dialysis, years 1.05 0.61-1.82 0.855 1.86 1.18-2.93 0.008 time on immunosuppression, months 0.98 0.95-1.02 0.322 1.00 0.98-1.02 0.862 histological subtype, non-clear cell vs clear cell 0.605 0.06-6.70 0.682 0.62 0.08-5.06 0.658 t stage, ≥ t1b vs t1a 5.78 0.52-63.78 0.152 0.50 0.01-44.35 0.762 isup grade, g3-4 vs g1-2 2.03 0.18-22.58 0.564 0.55 0.02-14.55 0.718 size, mm 1.03 0.98-1.08 0.276 1.00 0.92-1.08 0.945 asa = american society of anesthesiologists; ci = confidence interval; isup = international society of urological pathology; os = overall survival; rfs = recurrence-free survival. p values < 0.05 are shown in bold type. archivio italiano di urologia e andrologia 2023; 95, 1 renal cell carcinoma and transplantation outcome. tnm stage and grade were the only predictors of worse survival. a recent systematic review aimed to compare oncological outcomes of urological cancer in patients who subsequently received a kidney transplant or remained on dialysis (20). for rcc of native kidneys, rfs, css and os were similar between groups, with most of recurrences occurring in the contralateral kidney without impact on survival. the main prognostic factors for recurrence were stage, grade and histological subtype, with the authors concluding that immunosuppression didn’t modify the natural history of rcc. in our cohort, no metastasis (apart from recurrences in the contralateral kidney) or cancer-related deaths occurred, precluding any conclusion about these oncological outcomes. this contrasts with most of previous studies and could be related to the fact that only patients with localized disease with more favourable prognosis were included. however, in our opinion, a reduction or even elimination of waiting period would only be feasible in these lowstage cancers, making assumptions more reliable. for high-risk rcc, we believe that a waiting period according to the cincinnati registry is still adequate due to the considerable risks of recurrence and progression. several studies have highlighted the distinctive clinical and pathological features of rcc in esrd comparing to sporadic rcc (19, 21, 22). in line with these reports, we have also found that rcc occurred mainly in young male patients, were generally small and had low stage and grade, with a high incidence of multifocality and bilaterality. we found a higher incidence of papillary subtype compared to the general population and a substantial prevalence of ccprcc. ccprcc is a new but rare entity, first listed in the who 2016 renal tumor classification, that has an indolent course with no cases of metastasis reported to date (23). although also occurring in nonesrd patients, it is speculated that its prevalence is increased in dialyzed patients. although rcc of native kidneys of esrd patients seem to exhibit more favourable pathological and outcome features, the exact reason for its less aggressive behaviour still has to be determined. possible reasons for this better prognosis include a specific molecular pathway related to ackd not yet identified, or an earlier diagnosis due to more frequent imaging than the general population. there are no high-level evidence-based recommendations regarding screening for rcc in esrd patients, and no prospective studies on the cost-effectiveness of this approach. due to the higher incidence of rcc in this population and the fact that this risk increases with duration of dialysis, several authors have advocated regular screening in pretransplant and post-renal transplant recipients (19, 20, 24). in line with these studies, we also believe that regular screening of native kidneys should be part of pretransplant evaluation in order to diagnose rcc at lower stage and grade, allowing the feasibility of a shorter waiting period for renal transplantation. we acknowledge several limitations in our study. first, in line with previous reports, we recognize that our study is limited by its observational design and that the results should be interpreted within the limits of retrospective data. although it is unlikely that randomised controlled trials will be conducted in this setting due to ethical and logistical difficulties, well-designed prospective cohort studies are needed to confirm the safety of a reduced waiting period. second, this was a single-center study with a small sample size, which only included patients with localized disease. however, in order to evaluate the safety of reducing the waiting period for transplantation, we felt that it would be more appropriate to exclude patients with regional nodal or distant metastasis, as these are high-risk patients for recurrence or progressive disease even in the absence of immunosuppression, making comparisons more homogeneous and reliable. nevertheless, it precluded any conclusion on the effect of immunosuppression in pn+ and/or m+ patients. third, the low number of events in our cohort may have hampered our survival estimates and precluded further analysis on css. on the other hand, this low number reflects the favourable prognosis that most of these indolent tumors have. conclusions our study shows that most rccs in native kidneys of renal transplant and dialyzed patients are incidental lowgrade and low-stage cancers. these tumors exhibit many favourable clinical, pathological and outcomes features. kidney transplant recipients with rcc do not have increased risk of recurrence or death compared to dialyzed patients. immunosuppression doesn’t seem to have an impact on oncological outcomes, but an increased time on dialysis seems to be associated with worse overall survival. therefore, waiting time for transplantation for these tumors could be reduced. well-designed prospective studies are needed to confirm our findings. references 1. wolfe ra, ashby vb, milford el, et al. comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. n engl j med. 1999; 341:1725-1730. 2. farrugia d, mahboob s, cheshire j, et al. malignancy-related mortality following kidney transplantation is common. kidney int. 2014; 85:1395-1403. 3. penn i. evaluation of transplant candidates with pre-existing malignancies. ann transplant. 1997; 2:14-17. 4. piselli p, serraino d, segoloni gp, et al. risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, italy 1997-2009. eur j cancer. 2013; 49:336-344. 5. kliem v, kolditz m, behrend m, et al. risk of renal cell carcinoma after kidney transplantation. clin transplant. 1997; 11:255258. 6. yanik el, clarke ca, snyder jj, pfeiffer rm, engels ea. variation in cancer incidence among patients with esrd during kidney function and nonfunction intervals. j am soc nephrol. 2016; 27:1495-1504. 7. moudouni sm, lakmichi a, tligui m, et al. renal cell carcinoma of native kidney in renal transplant recipients. bju int. 2006; 98:298-302. 8. choyke pl. acquired cystic kidney disease. eur radiol. 2000; 10:1716-1721. archivio italiano di urologia e andrologia 2023; 95, 1 j. correia, b. teixeira, g. mendes, a. fraga, m. silva-ramos 9. edge sb, compton cc. the american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. ann surg oncol. 2010; 17:1471-1474. 10. moch h, cubilla al, humphrey pa, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. eur urol. 2016; 70:93-105. 11. delahunt b, cheville jc, martignoni g, et al. the international society of urological pathology (isup) grading system for renal cell carcinoma and other prognostic parameters. am j surg pathol. 2013; 37:1490-1504. 12. kälble t, lucan m, nicita g, sells r, burgos revilla fj, wiesel m. eau guidelines on renal transplantation. eur urol. 2005; 47:156-166. 13. brattström c, granath f, edgren g, et al. overall and causespecific mortality in transplant recipients with a pretransplantation cancer history. transplantation. 2013; 96:297-305. 14. viecelli ak, lim wh, macaskill p, et al. cancer-specific and allcause mortality in kidney transplant recipients with and without previous cancer. transplantation. 2015; 99:2586-2592. 15. dahle do, grotmol t, leivestad t, et al. association between pretransplant cancer and survival in kidney transplant recipients. transplantation. 2017; 101:2599-2605. 16. johansen kl, chertow gm, foley rn, et al. us renal data system 2020 annual data report: epidemiology of kidney disease in the united states. am j kidney dis. 2021; 77(4 suppl 1):a7-a8. 17. au eh, chapman jr, craig jc, et al. overall and site-specific cancer mortality in patients on dialysis and after kidney transplant. j am soc nephrol. 2019; 30:471-480. 18. gigante m, neuzillet y, patard jj, et al. renal cell carcinoma (rcc) arising in native kidneys of dialyzed and transplant patients: are they different entities? bju int. 2012; 110:e570-573. 19. klatte t, seitz c, waldert m, et al. features and outcomes of renal cell carcinoma of native kidneys in renal transplant recipients. bju int. 2010; 105:1260-1265. 20. boissier r, hevia v, bruins hm, et al. the risk of tumour recurrence in patients undergoing renal transplantation for endstage renal disease after previous treatment for a urological cancer: a systematic review. eur urol. 2018; 73:94-108. 21. breda a, lucarelli g, rodriguez-faba o, et al. clinical and pathological outcomes of renal cell carcinoma (rcc) in native kidneys of patients with end-stage renal disease: a long-term comparative retrospective study with rcc diagnosed in the general population. world j urol. 2015; 33:1-7. 22. tsuzuki t, iwata h, murase y, et al. renal tumors in end-stage renal disease: a comprehensive review. int j urol. 2018; 25:780786. 23. chen wj, pan cc, shen sh, et al. clear cell papillary renal cell carcinoma an indolent subtype of renal tumor. j chin med assoc. 2018; 81:878-883. 24. denton md, magee cc, ovuworie c, et al. prevalence of renal cell carcinoma in patients with esrd pre-transplantation: a pathologic analysis. kidney int. 2002; 61:2201-2209. correspondence jorge correia md (corresponding author) jorgericardocorreia@gmail.com bernardo teixeira, md bernardolat@gmail.com gonçalo mendes, md goncalo.grilomendes@gmail.com avelino fraga, md avfraga@gmail.com miguel silva-ramos, md miguelsilvaramos@gmail.com department of urology, centro hospitalar universitário do porto largo do prof. abel salazar, 4099-001 porto, portugal conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 1118 letter to editor no conflict of interest declared. introduction in recent years, the surgical techniques for sex reassignment surgery in male-to-female (mtof) transsexualism have been standardized and improved with better functional and aesthetic results, therefore increasing patients’ satisfaction. feminizing genital reconstruction is a complex surgical procedure that can be performed by using several skills such as penile skin inversion, penoscrotal flap, enterovaginoplasty. this challenging surgery is done by specific steps that could be related to other procedures in uro-andrological field, especially for benign conditions. in this context, mtof reassignment surgery could represent a complete training model for future urologists. here, we aim to describe all surgical steps of feminizing genital reconstruction as a core urological surgical training for young urologists. mtof reassignment surgery from november 2016 to december 2019, all resident doctors in urology training were involved in mtof reassignment surgery. the basic steps of the feminizing genital reconstruction for gender dysphoria were described as follow: 1. orchiectomy after anesthesia is induced, the patient is placed in the lithotomic position. an inverted u-shaped incision on the posterior surface of the scrotum is performed, the incision is extended through subcutaneous tissue so that the urethral corpus spongiosum and corpora cavernosa are bilaterally exposed (figure 1). subsequently, bilateral orchiectomy is performed by dissecting and suturing both spermatic cords at the level of external inguinal rings (figure 2). once this is done, the proximal end of these structures will retract into the inguinal canal, in order to close bilaterally external inguinal ring to avoid future weakness that can lead to inguinal hernia (1). 2. penile degloving a circumferential subcoronal incision is made, allowing outwards folding of the penile skin downward to the base in order to expose the corpora. the penile skin is transected from the corpus spongiosum and the corpora cavernosa. a cylindrical penile skin flap is created and dissected from the albuginea, being careful to preserve the vitality of the skin, this flap will provide the anterior wall of the neovagina (figure 3). 3. penectomy the corpus spongiosum is isolated starting from the crura up to the penile glans. through a bilateral incision of the buck’s fascia, a plane is created between the tunica albuginea and the dorsal neurovascular bundle, whose connection to the glans is meticulously preserved. the glans is detached from the corpora cavernosa without danger and neurovascular bundle isolation is held in a retrograde fashion (figure 4). the corpora are then excised as proximally as possible (1). 4. creation of a prostatorectal space fibers of bulbocavernosus muscles are divaricated on the midline and the bulbar urethra is completely freed. the central tendon of the perineum is incised, and an accurate, blunt dissection is performed in order to create a wide space between core urological surgical training: the pivotal role of feminizing genital reconstruction for gender dysphoria gianmartin cito 1*, elena rovero 1*, francesco sessa 1, simone sforza 1, girolamo morelli 2, arturo lo giudice 3, lorenzo masieri 1, andrea minervini 1, riccardo bartoletti 2, giorgio ivan russo 3, andrea cocci 1 1 department of urology, careggi hospital, university of florence, florence, italy; 2 department of urology, cisanello hospital, university of pisa, pisa, italy; 3 department of urology, university of catania, catania, italy. * these authors contributed equally to the work. key words: sex reassignment; male to female; surgery; urology; gender. submitted 25 november 2021; accepted 3 december 2021 doi: 10.4081/aiua.2022.1.118 119archivio italiano di urologia e andrologia 2022; 94, 1 sex reassignment training surgical model the rectum and the prostate, where the neovagina will be placed. the denonvillier’s fascia is identified, and the blunt dissection continues through this avascular plane, transecting the medial fibers of the elevator ani muscles (figure 5). the penile-scrotal cylinder of skin is placed into the neo-cavity, forming the neovagina and sutured to the denonvillier’s fascia (1). 5. creation of the neourethra after the bulb of penis is completely excised, the distal urethra is reduced at the pubic symphysis and passed through a second incision, more ventrally, so as to obtain a y-shaped. the distal part of the urethral stump is spatulated and the urethro-cutaneous anastomosis is performed, with the apex fixed to the anterior portion of pubis. this becomes the reference point for positioning the neoclitoris, which will be framed by urethral mucosa. the urethral bulb is carefully removed in order to avoid its bulging during sexual arousal and dyspareunia (figure 6). the creation of the urethra-clitoris complex gives to the neoclitoris a mucosal environment providing adequate lubrication; furthermore, the two layers suture permits a reciprocal vascular support, useful in case of urethral or clitoral ischemia (2). main findings we analyzed how the learning curve of mtof reassignment surgery could influence the skills of the same resident in practicing simpler andrological procedures as lead surgeon, assisted by his tutor. after performing 10 feminizing genital reconstructions as assistant surgeon, the resident performed 64 andrological procedures as lead surgeon, at the end of his training period with the tutor in the operating room (table 1). no postoperative complications occurred. operating times, as well as hospitalization times were comparable to those performed by the tutor. after the first 10 procedures, the mean operating time decreased of 20 minutes (sd ± 5; p < 0.05) and the mean blood loss decreased of 80 ml (sd ± 15; p < 0.05). the perineal approach using the inverted u-shaped incision on the posterior surface of the scrotum, the dissection and suture of spermatic cords at the external inguinal rings and the bilateral orchiectomy helped the learning curve of the resident for the radical orchiectomy to treat testicular torsion (n = 5). likewise, it helped to practice bilateral orchiopexy for testicular retraction (n = 10), that is generally performed with vertical perineal incision or homolateral transversal incision; by the way it was possible to facilitate to learn the inguinal approach, the exteriorization and asportation of the spermatic cord and testicle, that must be preferred in case of testicular cancer. the acquired expertise in gonadic surgery helped also to learn the procedure of hydrocelectomy in case of tense and large hydrocele (n = 5). once a scrotal median incision is performed, the fluid is aspirated, the testicle exposed, and the sac everted to avoid a recurrence. the process of penile degloving in mtof reassignment surgery facilitated the performance for the treatment of congenital or acquired penile curvature (nesbit’s corporoplasty, n = 2). in this table 1. andrological procedures performed by resident, as lead surgeon, at the end of his training period with the tutor in the operating room. figure 1. inverted u-shape incision on the posterior aspect of the scrotum, centrally prolonged on the penis. figure 2. isolation of the testis and spermatic cord, before the ligature at the external inguinal ring. figure 3. penile degloving. figure 4. asportation of corpora cavernosa after isolation of neurovascular bundle. figure 5. creation of a prostatorectal space or neovaginal cavity, we can appreciate the prostate with denonvillier’s fascia. figure 6. conservation of bulbar urethra and reduction urethral bulb. procedure total circumcision 25 orchiopexy 10 varicocelectomy 10 radical orchifunicolectomy 5 hydrocelectomy 5 corporoplasty 2 penile prosthesis implantation 3 meatoplasty 2 radical or partial penectomy 2 archivio italiano di urologia e andrologia 2022; 94, 1 g. cito, e. rovero, f. sessa, s. sforza, g. morelli, a. lo giudice, l. masieri, a. minervini, r. bartoletti, g.i. russo, a. cocci 120 case, the best approach for penile skin degloving is a circumcisional incision 0,5-1 cm below the coronal sulcus deepened until the whitish buck’s fascia, continued by blunt and sharp dissection (3). circumcision and dissection with dartos fascia preservation, to obtain a complete penile degloving, is normally performed during feminizing genital reconstruction for gender dysphoria. this training simplifies the learning ability of other surgical steps such as circumcision (n = 25), in case of severe phimosis or the preservation of the dorsal neurovascular bundle, required during corporoplasty. moreover, the penoscrotal approach is widely used to implant penile prosthesis for the treatment of erectile dysfunction (n = 3) (4). the feminizing genital reconstruction helped also to get skills concerning functional anatomy of the penis, that allowed the resident to practice in radical penectomy for penile cancer (n = 2) (5). the preparation of the urethral stump before the urethrocutaneous anastomosis for the creation of the neourethra in feminizing genital reconstruction was useful to learn procedures of meatoplasty, performed in case of urethral strictures (n = 2) (6). lastly, sex reassignment surgery requires expertise of the inguinal canal anatomy, that is conductive in varicocele treatment (n = 10). the inguinal approach involves a 3-5 cm incision over the inguinal canal, the opening of the external oblique aponeurosis and the delivery of the spermatic cord. all internal spermatic veins are identified and dissected under microscopy and then ligated with sutures or surgical clips. the vas deferens, vasal vessels, testicular artery and as many lymphatic channels as possible are preserved. in conclusion, assisting to complex andrological procedures, as mtof reassignment surgery, seems to have a positive influence in facilitating the learning curve of other simpler procedures in young urologists. thus, the challenging steps of feminizing genital reconstruction could be a core urological training in performing surgery for andrology conditions. references 1. mirone v, imbimbo c, verze p, arcaniolo d. transgender rencostructive surgery. in: austoni e (ed). atlas of reconstructive penile surgery. 1st edn. (pacini editore medicina, 2010) pp.419-432. 2. trombetta c, liguori g, bertolotto m (eds). management of gender dysphoria: a multidisciplinary approach. (springer, milan, heidelberg, new york, dordrecht london, 2015). 3. fabiani a, fioretti f, pavia mp, et al. buccal mucosa graft in surgical management of peyronie's disease: ultrasound features and clinical outcomes. arch ital urol androl. 2021;93:107-110. 4. bayrak o, erturhan s, seckiner i, et al. comparison of the patient's satisfaction underwent penile prosthesis; malleable versus ambicor: single center experience. arch ital urol androl. 2020; 92:25-29. 5. moulavasilis n, yiannopoulou k, frangoulis m, et al. a surgical approach to squamous cell carcinoma of penis that also resolved the psychological dysfunction of the patient. arch ital urol androl. 2020; 92:58-60. 6. gentile g, martino a, nadalin d, et al. penile-scrotal flap vaginoplasty versus inverted penile skin flap expanded with spatulated urethra: a multidisciplinary single-centre analysis. arch ital urol androl. 2020; 92:186-191. correspondence gianmartin cito, md gianmartin.cito@gmail.com elena rovero, md elena.rovero@stud.unifi.it francesco sessa, md francesco_sessa@hotmail.it simone sforza, md simone.sforza1988@gmail.com lorenzo masieri, md lorenzo.masieri@meyer.it andrea minervini, md andreamine@libero.it andrea cocci, md, phd (corresponding author) cocci.andrea@gmail.com department of urology, careggi hospital, university of florence, largo brambilla 3, 50134, florence (italy) girolamo morelli, md girolamomorelli@gmail.com riccardo bartoletti, md riccardo.bartoletti@hotmail.com department of urology, cisanello hospital, university of pisa, via piero trivella, 56124, pisa (italy) arturo lo giudice, md arturologiudice@gmail.com giorgio ivan russo, md giorgioivan1987@gmail.com department of urology, university of catania, via plebiscito, 628, 95124, catania (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12483 1 case report urgency department she underwent an abdominal ultrasound which showed a markedly thickened urinary bladder (max 10.4 mm), with finely corpuscular contents as of blood nature and bilateral hydronephrosis (figure 1). blood tests demonstrated a slight increase in serum creatinine (1.42 mg/dl) and mild anemia (hbg 11.3 g/dl). contrastenhanced ct scan showed diffuse and marked thickening of the entire urinary bladder (10.4 mm max) with contextual inhomogeneity of the perivesical fat, particularly affecting the retzius space, bilateral hydronephrosis and numerous osteolytic skeletal lesions affecting the vertebral metameres from d10 to l2, proximal diaphysis of the left femur and left iliac wing (figure 2). we decided to proceed with a transurethral resection of the bladder. cystoscopy showed a bladder with little distensibility and erythematous mucosa, in the absence of clear vegetating neoplasms. the ureteral meatuses could not be recognized. we then proceeded to perform a turb for hemostatic and biopsy purposes. turb specimen showed proliferation of cells ck19+, ck34be12+, pgr+, er(figure 3) compatible with poorly differentiated epithelial neoplasia and suspected of breast cancer primitiveness. the poor performance status made the patient ineligible for any oncological therapy. discussion brc is the most frequent cancer in women worldwide. the most common sites of metastasis are bone, lung, liver and brain. the urinary bladder is rarely involved, being only about 4.5% of all bladder metastases derived from solid tumors (2) and typically the majority of cases are secondary to direct invasion by pelvic neoplasms (3). bladder metastases deriving from brc accounts for about 2.4% of all bladder metastases (2), they usually are expression of systemic disease (9) and rarely occur as solitary metastases (4). a review of the literature showed about 65 cases of brc bladder cancer metastases published (5). the majority of brc bladder metastases derives from an invasive lobular carcinoma (ilc) rather than an invasive ductal carcinoma (idc): ilc has in fact a particular tropism for serosal surfaces such as gastrointestinal and gynecological tracts, and from these two last sites metastases can then spread to the bladder (6). they can present as exophytic mass, thickening of the bladder wall or nonspecific mucosal phlogistic areas. breast cancer (brc) is the most frequently diagnosed malignancy in woman and most brc related deaths are due to metastasis. brc frequently metastasizes to the lymph nodes, liver, lung, bone and brain while the urinary bladder is considered as an unusual site for breast metastasis. we report a case of bladder metastasis identified in a patient with past brc history, presenting with hematuria, low urinary tract symptoms, and hydronephrosis. key words: bladder metastasis; breast cancer; breast cancer metastasis. submitted 16 march 2024; accepted 28 march 2024 introduction brc is the most frequently diagnosed malignancy in women with an estimated 1.6 million new cancer cases diagnosed worldwide (1). incidence of brc show variability across different countries. it is highest in australia, europe and north america, reflecting discrepancies in early diagnosis and in the entity of risk factors. although we actually have effective screening programs and therapies, it remains the leading cause of death because of metastatic disease. brc in fact usually metastasizes to lymph nodes, bone, lung and liver, while bladder metastasis is very uncommon, accounting for about 2.4% of all bladder metastasis (2). we present the case of 75-year-old woman with severe hematuria and a history of breast cancer. case report in january 2023 we hospitalized a 75-year-old woman suffering from dementia from the emergency department due to the appearance of severe hematuria and dysuria. her past medical history showed hypothyroidism, hypercholesterolemia, bilateral hearing loss. in 2018 she underwent a left nipple sparing mastectomy and contextual axillary lymphadenectomy. histopathological examination showed an infiltrating lobular carcinoma pt2g2n2 (6/15 positive lymph nodes, re=90% rpg=34% ki67=18% her2: +--). the patient at the time was not eligible for adjuvant chemotherapy due to the time since diagnosis, so she received letrozole and locoregional radiotherapy from 03/27/2019 to 05/03/2019. the patient then adequately adhered to the follow-up protocol. at the emergencyan unusual “linitis plastica” like breast cancer bladder metastasis riccardo farci 1, simona tolu 1, matilde trombetta 2, alessandro murgia 1, andrea solinas 1 1 department of surgery, unit of urology, ares sardegna, asl sulcis, sirai hospital, carbonia, italy; 2 pathology department, ares sardegna asl cagliari, ss. trinità hospital, cagliari, italy. doi: 10.4081/aiua.2024.12483 summary archivio italiano di urologia e andrologia 2024; 96(2):12483 r. farci, s. tolu, m. trombetta, et al. 2 the most common clinical presentation is characterized by asymptomatic gross hematuria, lower urinary tract symptoms in case of detrusor involvement, flank pain because of hydronephrosis with renal failure and sepsis, but early stages can be asymptomatic (7). the diagnostic workshop of the patient must include ultrasounds, ct scans and cystoscopy. endoscopy can be used to stop hematuria by transurethral resection of bladder (turb) (7), possibly to visualize ureteral meatus in case of need for ureteral stent placement, but most of all to obtain biopsy samples. despite of all, the past clinical history of the patient remains fundamental in formulating the suspicion of bladder metastases. prognosis is similar to that of any metastatic brc, with an average survival of 18-30 months (8), while the gold standard treatment is a combination of endocrine therapy and chemotherapy. radiotherapy also can have a role in controlling hematuria. figure 1. ultrasound of the bladder showing diffuse bladder wall thickening. figure 2. ct scan demonstrating thickening of urinary wall. figure 3. histopathology image of specimen: demonstration of pr positive brc cells. archivio italiano di urologia e andrologia 2024; 96(2):12483 3 breast cancer bladder metastasis conclusions brc urinary bladder metastases are a rare disease and the differential diagnosis compared to other pathologies with similar symptoms can be complex, and the physician need to take into consideration this possibility in all women with past history of brc presenting with urinary symptoms (9). references 1. torre la, bray f, siegel rl, et al. global cancer statistics, 2012. cca cancer j clin 2015; 65:87-108. 2. bates aw, baithun sl. the significance of secondary neoplasms of the urinary and male genital tract. virchows arch. 2002; 440:640-647. 3. cormio l, sanguedolce f, di fino g, et al. asymptomatic bladder metastasis from breast cancer. case rep urol. 2014; 2014:672591. 4. zagha rm, hamawy kj. solitary breast cancer metastasis to the bladder: an unusual occurrence. urol oncol. 2007; 25:236-239. 5. karjol u, jonnada p, cherukuru s, et al. bladder metastasis from breast cancer: a systematic review. cureus 2020; 12:e7408. 6. ferlicot s, vincent-salomon a, médioni j, et al. wide metastatic spreading in infiltrating lobular carcinoma of the breast. eur j cancer. 2004; 40:336-341. 7. ramsey j, beckman en, winters jc. breast cancer metastatic to the urinary bladder. ochsner journal information. 2008; 8:208-212. 8. gennari a, conte p, rosso r, et al. survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies.. cancer. 2005; 104:1742-1750. 9. de rose af, balzarini f, mantica g, et al. late urinary bladder metastasis from breast cancer. arch ital urol androl. 2019; 91:60-62. correspondence riccardo farci, md (corresponding author) riccardo.farci@aslsulcis.it urology department andrea solinas, md urology department andreasolinas@aslsulcis.it simona tolu, md simona.tolu@aslsulcis.it oncology department alessandro murgia, md alessandro.murgia@aslsulcis.it radiology department ares sardegna asl sulcis, sirai hospital via ospedale, 09013 carbonia, italy matilde trombetta, md matilde.trombetta@aslcagliari.it pathology department, ares sardegna asl cagliari, ss. trinità hospital via is mirrionis 92, 09121 cagliari, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso 475archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. grows in the southern united states, particularly in florida and south carolina (2). sr is commonly used throughout the world to treat benign prostatic hyperplasia (bph) and prostatitis. although its mechanism of action has not fully been demonstrated yet, it is mainly used on the assumption that sr is a 5a-reductase inhibitor, consequently blocking the conversion of testosterone to dihydrotestosterone (dht) a biologically more active hormone (2, 3). in the literature, however, several studies have proved that sr, besides being very selective for the prostate gland, has, above all, pro-apoptotic, anti-inflammatory, and antioxidant properties (4-21). normally used sr doses vary between 320 and 450 mg/day. the aim of this study is to clarify whether sr is able to cause negative effects on male sexual function. such belief is circulating in non-medical social networks and is maintained by patients as a result of web surfing. not infrequently, even in our clinics, we encounter patients suffering from bph or prostatitis who underwent treatment of varying length with sr, who claim to have noticed a significant reduction in their erectile potency, and in some cases even in their libido. many web forums in the world discuss the alleged negative effects of sr, equating them directly to the post-finasteride syndrome; unfortunately, once pseudo-confirmation is found by surfing the net, a belief quickly and easily goes viral. is it possible that sr may have a nocebo effect and therefore negatively impact the health of patients, regardless of any real pharmacological adverse effect (22)? the aim of this work was to assess whether sr can cause negative effects on male sexual function. we therefore carried out an in-depth systematic review and metaanalysis in accordance with the prisma guidelines (23). materials and methods this review was conducted in accordance with the preferred reporting items for systematic reviews and metaanalyses (prisma) guidelines (23). the review protocol was submitted for registration on the prospero platform (id 287140). two electronic databases (pubmed and embase) were searched for articles published up to 30 september 2021. the search was performed using the following terms: (serenoa repens or saw palmetto or sabal background: serenoa repens (sr) is a plant used to treat benign prostatic hyperplasia and prostatitis. we know that sr act as a 5α-reductase inhibitor, moreover, several studies have proved that sr has anti-inflammatory and antioxidant properties. there is some belief among patients that sr may negatively impact male sexual function. such belief is circulating in non-medical social networks and is perhaps maintained by patients as a result of incorrect web surfing. however, it is also possible that sr may exert a “nocebo” effect thus negatively impacting on the general well-being of patients. objective: the aim of this study is to investigate whether sr is causing negative effects on male sexual function. methods: to ascertain the effect of sr on male sexual function, we conducted a systematic review and meta-analysis, by performing an electronic database search in accordance with the prisma guidelines. results: out of 20 included papers, 8 papers reported comparisons of sr with placebo, and 7 studies reported comparisons of sr with tamsulosin. the standardized mean difference of changes from baseline scores of sexual function was not significantly different between sr and placebo (smd: 0.43, 95% ci: 0.18 to 1.05; i^2 = 95%). similarly, no significant mean differences in the male sexual function-4 (msf-4) test scores were found between sr and tamsulosin (smd: -0.31, 95% ci: -0.82 to 0.19; i^2 = 90%). conclusions: we found no statistically significant differences between negative effects on sexual function in patients treated with sr compared to patients who received placebo. the results of our meta-analysis are similar to those of other systematic reviews. studies are warranted to ascertain whether any such effects might occur as a result of a nocebo effect. key words: serenoa repens; adverse effects; nocebo effect; male sexual health. submitted 30 november 2021; accepted 3 december 2021 introduction serenoa repens (sr), also known as saw palmetto, sabal serrulata, and american dwarf palm tree, is a plant originally used by native americans (seminole and miccosukee tribes) both as food and to cure urogenital ailments (1). the plant belongs to the arecaceae family and mainly serenoa repens and its effects on male sexual function. a systematic review and meta-analysis of clinical trials gianni paulis 1, andrea paulis 2, gianpaolo perletti 3, 4 1 department of uro-andrology, castelfidardo medical team, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy; 3 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 4 faculty of medicine and medical sciences, ghent university, belgium. doi: 10.4081/aiua.2021.4.475 summary archivio italiano di urologia e andrologia 2021; 93, 4 g. paulis, a. paulis, g. perletti 476 serrulata) and (orgasm or ejaculation or erectile dysfunction or sexual dysfunction, physiological). relevant data were also hand-searched through other sources. we considered randomized controlled trials (rcts) with an open-label or single/double blinded design published in english without time constraints. we included studies involving male subjects taking serenoa repens extracts to treat a prostatic condition, compared with placebo, or with various drugs prescribed for benign prostatic hyperplasia (bph) (e.g., alpha adrenoceptor blockers, alpha-reductase inhibitors). the following outcomes were considered: (i) the rate of sexual dysfunction (erectile dysfunction, ejaculatory dysfunction, dysorgasmia, loss of libido), and/or the changes of scores of questionnaires measuring sexual function. the brief male sexual function inventory (bmsfi) is a questionnaire to measure male sexual function covering sexual drive (two items), erection (three items), ejaculation (two items), perceptions of problems in each area (three items), and overall satisfaction (one item) (24). the international index of erectile function (iief) is a 15item questionnaire addressing five relevant domains of male sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) (25). an abridged, five-item version of the iief-5 can also be administered for the evaluation of erectile dysfunction (26). increasing severity of sexual function is associated with lower scores of bmsfi and iief. the male sexual function4 item (msf-4) questionnaire is a concise survey evaluating four items (interest in sex, quality of erection, achievement of ejaculation, and achievement of orgasm). lower scores of this instrument are associated with better preserved sexual function (27). two independent authors performed title and abstract screening of all retrieved records to delete duplicates and to exclude reports that did not meet the inclusion criteria. a second round of full-text screening to confirm/exclude the inclusion of retrieved studies and to extract relevant information was performed by 2 authors using a standardized form. the publication bias was assessed in the presence of at least 5 trials. it was analyzed by visually inspecting funnel plots and by performing the egger’s and begg’s tests using the metaessentials 1 software (rotterdam school of management, erasmus university, the netherlands). statistical analysis was performed using the revman5 software. meta-analysis was performed using a random effects model. dichotomous data (presence/absence of sexual dysfunction) or continuous data reporting changes of mean values of sexual function scores and number of per-protocol or intent-to-treat patients were extracted. for dichotomous data we calculated odds ratios (or), for continuous data presented as pre-vs. post-therapy mean differences, we calculated inverse variance weighted standardized mean differences. for all analyses we calculated 95% confidence intervals (ci). heterogeneity was assessed by calculating the i^2 value with 95% cis, and interpreted as follows: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. a summary of findings table was generated, and the quality of the evidence emerging from meta-analyses including at least 3 studies was rated according to grade criteria. results a prisma flow diagram illustrates the results of the study selection process (see figure 1). we retrieved 29 papers: 7 papers from pubmed, 17 papers from embase and 5 from other sources (handsearching). four duplicate papers were removed, and 5 papers were excluded as they were found to be not related to this review. figure 1. a prisma flow diagram. 477archivio italiano di urologia e andrologia 2021; 93, 4 serenoa repens and sexual function out of the 20 remaining papers, we selected 8 papers reporting comparisons of sr with placebo. three records were discarded after full-text reading (two were lacking information on sexual outcomes and one reported only information on sexual hormones). other 7 studies reported comparisons of sr with tamsulosin. two studies were excluded because serenoa repens was administered in association with other herbal products and one because sr was administered in combination with tamsulosin versus tamsulosin alone. two studies compared sr with finasteride; one was excluded because sr was administered in combination with other herbal products. three studies compared a sr extract with other herbal products. two were discarded because of lack of information on sexual function and one because sr was administered in a formulation containing other herbal products. the characteristics of the 10 studies finally included in this systematic review, and the evaluation of risk of bias are presented in the “supplementary materials”. quantitative analysis was limited to five studies comparing therapy with a sr extract with placebo, and to four studies comparing a sr extract with tamsulosin (28-36). a study comparing a sr extract with finasteride was only qualitatively evaluated (37). to evaluate differences in sexual dysfunction between treatment arms we calculated standardized mean differences, as included trials used different sexual function scales. the standardized mean difference of changes from baseline scores was not significantly different between sr and placebo (smd: 0.43, 95% ci: -0.18 to 1.05; 5 trials, 922 patients; z = 1.37, p = 0.17; egger’s p = 0.16; begg’s p = 0.32). this analysis was characterized by considerable heterogeneity (i^2 = 95%) (figure 2). no significant mean differences in the msf-4 test scores were found between sr and tamsulosin (smd: -0.31, 95% ci: -0.82 to 0.19; 3 trials, 826 patients; z = 1.21, p = 0.22; i^2 = 90%) (figure 3). however, random-effects meta-analysis revealed that treatment with sr is associated with significantly lower odds of ejaculatory disorders compared to tamsulosin (odds ratio = 0.10, 95% ci: 0.01 to 0.92; 2 trials, 164 participants, z = 2.03, p = 0.04, i^2 = 0%), compared to placebo (see figure 4) (34,35). final results are reported in table 1. discussion although the quality of evidence grade of our meta-analysis is low (see table 1), we found no statistically significant differences between negative effects on sexual function in patients treated with sr compared to patients who received placebo or tamsulosin. this suggests that sr does not appear produce negative figure 2. statistical analysis: differences in sexual dysfunction between treatment with serenoa repens and placebo. figure 3. statistical analysis: differences in the msf-4 test scores between treatment with serenoa repens and tamsulosin. figure 4. statistical analysis: ejaculatory disorders after treatment with serenoa repens and tamsulosin. archivio italiano di urologia e andrologia 2021; 93, 4 g. paulis, a. paulis, g. perletti 478 effects on male sexual function. such view is supported by two studies (marks et al., 2000; pytel et al., 2002) which did not detect a reduction in the serum levels of male sex hormones (testosterone, dihydrotestosterone) after treatment with sr (38, 39). the results of our meta-analysis are similar to those of other authoritative systematic reviews, where sr was proved to have no negative impact on male sexual function (40-42). it should furthermore be evaluated whether the negative effect of sr on male sexuality reported by a number of patients both in our clinics and on internet forums may be generated by neuropsychological mechanisms. this is where the concept of nocebo comes in. a nocebo effect is generated when a patient’s beliefs and negative expectations cause a worsening of the individual’s health status (22). the psychological mechanisms underlying this pesky effect seem to include negative expectations concerning treatment, high levels of anxiety, and classic conditioning (43). a study by mondaini et al. (2007) provides a very interesting analysis of the causal role of “negative expectations” on the nocebo effect, after patient have been informed of the possible side effects of a therapeutic substance (44). in this study, which included 107 patients suffering from bph, two treatment groups were created, with finasteride 5 mg/day and a treatment length of 12 months. patients of group 1 (52 patients) were also not informed of the risk of side effects on their sexuality; patients of group 2, instead, were told of the possible – albeit rare – onset of sexual problems such as erectile dysfunction (ed), decreased libido, and ejaculation disorders. the results, after treatment with finasteride 5 mg/day for 12 months, were the following: group 1, adverse sexual side effects 15.3 % (ed 9.6%, decreased libido 7.7%, ejaculation disorders 5.7%); group 2, adverse sexual side effects 43.6% (ed 30.9%, decreased libido 23.6%, ejaculation disorders 16.3%). the significantly higher rate of sexual dysfunctions in group 2 compared to group 1 clearly proves that the nocebo effect had a significant impact on the greater number of occurrences of sexual problems in the patients of group 2 (44). it is possible that sr may also have a "nocebo" effect and therefore negatively impact the health of patients. conclusions based on the results of our review, sr does not appear to cause negative effects on male sexuality; should any such effects occur, they may be ascribed to a nocebo effect. adequately powered studies are needed to confirm this hypothesis. in such a case to reduce the likelihood of a nocebo effect, when mentioning possible side effects during the informed consent process prior to treatment, it may be necessary to structure the information to patients by avoiding the classic “negative” narrative frame (percentage of possibility of having a specific side effect), employing instead a “positive” approach, providing information about the percentage of patients who are likely not to experience any side effects. a more in-depth knowledge of the mechanisms that cause the nocebo effect, will help to minimize its impact in the clinical activity of general practitioners and specialists alike. acknowledgments we thank dr. pasquale del vecchio for bibliometric and data management analysis. references 1. bennet bc, hicklin jr. uses of saw palmetto (serenoa repens, arecaceae) in florida. economic botany. 1998; 52:381-393. 2. duborija-kovacevic n, jakovljevic v, sabo a, et al. tolerability table 1. summary of findings. serenoa repens compared with placebo or active drug (tamsulosin) patient or population: patients with benign prostatic hyperplasia settings: outpatient intervention: serenoa repens extract comparators: placebo or active comparator (alpha adrenoceptor blocker) outcomes intervention vs. number of participants quality of the evidence comparator results (studies) (grade) sexual (dys)function, sd units the sexual function score in the serenoa repens 922 ⊕⊕⊝⊝ [assessed using different sexual function scales] groups was on average 0.43 sds (95% ci: -0.18 to 1.05) (5) low higher than in the placebo groups. reasons for downgrading: – inconsistency (considerable heterogeneity) – indirectness (subjectiveness) of evidences sexual (dys)function, sd units the score of the msf-4 test in the 826 ⊕⊕⊝⊝ [assessed using the male sexual function 4-items test] tamsulosin groups was on average (3) low 0.31 sds (95% ci: -0.82 to 0.19) reasons for downgrading: lower than in the serenoa repens groups. – inconsistency (considerable heterogeneity) – indirectness (subjectiveness) of evidence sd: standard deviation; ci: confidence interval; msf-4: male sexual function 4-items test. grade working group grades of evidence. high quality: further research is very unlikely to change our confidence in the estimate of effect. moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. 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prospective study of the efficacy of serenoa repens, tamsulosin, and serenoa repens plus tamsulosin treatment for patients with benign prostate hyperplasia. int urol nephrol. 2007; 39:879-886. archivio italiano di urologia e andrologia 2021; 93, 4 g. paulis, a. paulis, g. perletti 480 36. latil a, pétrissans mt, rouquet j, et al. effects of hexanic extract of serenoa repens (permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. prostate. 2015; 75:1857-1867. 37. carraro jc, raynaud jp, koch g, et al. comparison of phytotherapy (permixon®) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. prostate. 1996; 29:231-240. 38. marks ls, partin aw, epstein ji, et al. effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. j urol. 2000; 163:1451-1456. 39. pytel ya, vinarov a, lopatkin n. et al. long-term clinical and biologic effects of the lipidosterolic extract of serenoa repens in patients with symptomatic benign prostatic hyperplasia. adv ther. 2002; 19:297-306. 40. vela-navarrete r, alcaraz a, rodríguez-antolín a, et al. efficacy and safety of a hexanic extract of serenoa repens (permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (luts/bph): systematic review and meta-analysis of randomised controlled trials and observational studies. bju int. 2018; 122:1049-1065. 41. novara g, giannarini g, alcaraz a, et al. efficacy and safety of hexanic lipidosterolic extract of serenoa repens (permixon) in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. euro urol focus. 2016; 2:553-561. 42. cai t, cui y, yu s, et al. comparison of serenoa repens with tamsulosin in the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis. am j mens health. 2020; 14: 1557988320905407. 43. colloca l, barsky aj. placebo and nocebo effects. n engl j med. 2020; 382:554-561. 44. mondaini n, gontero p, giubilei g, et al. finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon?. j sex med, 2007; 4:1708-1712. correspondence gianni paulis, md (corresponding author) paulisg@libero.it department of uro-andrology, castelfidardo medical team, rome (italy) andrea paulis, clinical psychologist andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome (italy) gianpaolo perletti, phd gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 28 original paper factor for ubc. exposure to chemical compounds, particularly aromatic amines and polycyclic aromatic hydrocarbons, parasitic infection, along with genetic predisposition are also considerable risk factors (1, 4). approximately 25% of newly diagnosed ubc are invasive, requiring radical surgery or radiotherapy (1, 2, 5). unfortunately, the disease outcome is still poor despite systemic therapy (1). five-year overall survival (os) and disease-specific survival (dss) rates for ubc are 57.2% and 77.3%, respectively (2). early detection of ubc is important to improve patient’s outcome, since the treatment can be delivered aggresively. hypoxia inducible factor (hif)-1α is a regulatory protein produced in hypoxic microenvironment that consists of two subunits. its expression is found in several solid tumors including ubc, lung, breast, ovary, prostate, and kidney cancers. the binding of hif-1α with its receptor initiates cell proliferation, migration, and invasion in ubc (3, 6, 7). additionally, hif-1α is also closely related to angiogenesis (3, 7-9). in this study, we aimed to evaluate the association between hif-1α and stage and grade of ubc. our findings may provide insight regarding earlier diagnosis, prompt management, improved outcome, and possible therapeutic method for ubc. methods this was a case-control study conducted in januarydecember 2022 at haji adam malik hospital medan, indonesia. the inclusion criteria for case group was subject aged 18 years or older and diagnosed with ubc based on histopathological examination. beside diagnosing ubc, biopsy specimen from case group underwent hematoxylin and eosin staining to determine stage and grade of disease. all histopathological examinations were conducted at department of pathology of universitas sumatera utara. control group included healthy subjects who came to the hospital for general check-up or healthy hospital employers. exclusion criteria was previous history of introduction: we aim to evaluate the association between serum hypoxia inducible factor (hif)-1α level and stage and grade of urothelial bladder cancer (ubc). methods: a case-control study was conducted at haji adam malik hospital medan, indonesia. inclusion criteria for case group was subject aged 18 years or older and diagnosed with ubc based on histopathological examination. control group consisted of gender and age matched healthy subjects. serum hif-1α level was determined using elisa method. data was analyzed with chi square, mann whitney, and independent t tests. results: a total of 80 subjects were enrolled and divided into case and control groups equally. most subjects were males with mean age of 69.65 years for case group and 68.25 years for control group. most subjects had advanced primary tumor and lymph node stages. only 30% subjects had metastasized ubc. higher serum hif-1α level was observed in case group (p < 0.001). serum hif-1α level was strongly associated with metastasis stage (p < 0.001), followed by lymph node (p = 0.005) and primary tumor (p = 0. 013) stages. serum hif-1α level was not associated with grading (p = 0.134). conclusions: serum hif-1α level is associated with staging but not grading of ubc. key words: hif-1α; grade; stage; urothelial bladder cancer. submitted 5 march 2023; accepted 2 april 2023 introduction urothelial bladder cancer (ubc) is the 7th and the 17th most common cancer globally in men and women, respectively (1). this subtype is responsible for more than 90% bladder cancer cases (2, 3). annually, there are 110.500 men and 70.000 women diagnosed with new ubc cases worldwide. the disease is more frequent in developed countries (1). every year, 38.200 cases were diagnosed in european union and 17.000 subjects died due to ubc (1, 2). smoking is the most important risk the association between serum hypoxia inducible factor-1α level and urothelial bladder cancer: a preliminary study ginanda putra siregar 1, 2 *, ida parwati 3 *, bambang sasongko noegroho 4 *, ferry safridai 4 *, gerhard reinaldi situmorang 5, raden yohana 6, astrid feinisa khairani 7 1 doctoral study program, faculty of medicine, universitas padjadjaran, bandung, indonesia; 2 division of urology, department of surgery, faculty of medicine, universitas sumatera utara, medan, indonesia; 3 department of clinical pathology, faculty of medicine, universitas padjadjaran, bandung, indonesia; 4 department of urology, faculty of medicine, universitas padjadjaran, bandung, indonesia; 5 department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia; 6 division of oncology, department of surgery, faculty of medicine, padjadjaran university, bandung, indonesia; 7 department of biomedical sciences, faculty of medicine, universitas padjadjaran, bandung, indonesia. * these authors contributed equally to this paper. doi: 10.4081/aiua.2023.11292 summary archivio italiano di urologia e andrologia 2023; 95, 2 g. putra siregar, ida parwati, b. sasongko noegroho, et al. 29 malignancy, bladder lesion due to methastasis from distant primary cancers, patients receiving systemic therapy for badder cancer, patients with diabetes mellitus, chronic kidney disease, and cerebrovascular disease. we did gender and age mathcing between the two groups. all subjects received explanation regarding this study and were asked to sign informed consent. subjects unwilling to participate in this study were excluded. serum sample was obtained from each subject in case group. evaluation of serum hif-1α level was conducted at research and esoteric laboratory jakarta, indonesia. we used hif-1α human elisa kit (thermo fisher scientific inc., waltham, usa) to determine serum hif-1α level in this study. data was analyzed using statistical package for social science (spss) software. categorical data was presented in frequency and percentage while numerical data was presented in median and range if it was not normally distributed. otherwise, it was presented in mean and standard deviation. chi square test was utilized to determine relationship between categorical variables while mann whitney and independent t tests were used to determine the relationship between categorical and numerical data. all statistical analyses were conducted at confidence interval of 95%. a p value of < 0.05 was considered significant. results a total of 80 subjects were enrolled in this study. all subjects were divided into the two groups equally. in case group mean age of subjects was 69.65 years and males subjects were prevalent. most subjects had advanced primary tumor and lymph node involvement. only 30% subjects in the case group had metastasized ubc. significantly higher serum hif-1α level was observed in case group compared to control group (table 1). from statistical analysis, we found that serum hif-1α level was strongly associated with metastatic ubc (p < 0.001), followed by ubc with lymph node involvement (p = 0.005) and primary tumor (p = 0. 013) stage. overall, serum hif-1α level was associated with ubc staging (p = 0.008) but not grading (p = 0.134) (table 2). discussion as most solid tumors grow, the need of oxygen for their metabolism is increased. this situation creates hypoxic condition (6, 10). hypoxic condition upregulates several proteins including hif-1α that it is important for adaptation of tumor, including ubc, in hypoxic condition. angiogenesis or neovascularization is the end point of this adaptation (3, 4, 6), hypoxia is also the culprit of treatment resistance in many cancers (8, 10) and hif-1α is one of the underlying etiologies (11-13). binding of hif-1α with its receptor in the nucleus promotes cell proliferation, migration, and invasion. overexpression of hif-1α is associated with progression and recurrence of ubc (4, 6). the expression of hif-1α in bladder cancer cells is also influenced by several other factors, such as elevated serum copper level and decreased serum zinc level (4). in ubc, hif-1α expression was higher compared to normal tissue (4, 8). the expression of hif-1α in patients with bladder cancer was in line with the expression of vascular endothelial growth factor (vegf) (r = 0.606). we know that vegf is important in neovascularization and growth of malignant tissue (4). this finding was confirmed by theodoropoulos et al. who found in their study that hif-1α was positively associated with histological grade of ubc. this association was mediated by vegf expression and microvessel density (mvd). patients with high hif-1α expression tended to have advanced disease and unfavorable outcome (8). badr et al. also reported similar findings showing that hif-1α expression is significantly higher in patients with bladder cancer despite its etiology. the level of urinary hif-1α was also able to discriminate between malignant and non-malignant tumor with sensitivity and specificity of 82.1% and 63.3%, respectively. in contrast with our results, this study failed to demonstrate significant relationship between hif-1α and ubc stage and grade (9). table 1. baseline characteristics of subjects. characteristics case control p (n = 40) (n = 40) mean age, years ± sd 69.65 ± 7.01 68.25 ± 7.74 0.400 a gender, n (%) male 30 (75%) 32 (80) 0.592 a female 10 (25%) 8 (20%) primary tumor stage (t), n (%) na na t1+t2 10 (25%) t3+t4 30 (75%) lymph node stage (n), n (%) na na n0 18 (45%) n1 22 (55%) metastasis stage (m), n (%) na na m0 28 (70%) m1 12 (30%) median hif-1α level, pg/ml (range) 345 (142-587) 123 (94-234) < 0.001 * b sd: standard deviation; a chi square test; b mann whitney test; * p < 0.05. table 2. association between serum hif-1α level and staging and grading of ubc. variables mean hif-1α levels, pg/ml ± sd p primary tumor stage (t) t3+t4 389 ± 126.66 0.013 * t1+t2 273.4 ± 103.89 lymph node stage (n) n1 410.45 ± 115.4 0.005 * n0 298.56 ± 123.42 metastasis stage (m) m1 477 ± 95.16 < 0.001 * m0 310 ± 110.34 staging 3+4 395.67 ± 124.11 0.008 * 1+2 273.4 ± 103.89 grading high grade 378 ± 131.42 0.134 low grade 306.4 ± 117.04 sd: standard deviation; * p < 0.05. archivio italiano di urologia e andrologia 2023; 95, 2 30 serum hypoxia inducible factor-1α level and urothelial bladder most patients with ubc expressed high hif-1α. tumor size, histological grade, tumor invasion, and recurrence of ubc were also associated with high hif-1α expression. in line with previous study, this effect was linked to vegf and mvd. disease free survival (dfs) of ubc was independently influenced by hif-1α (p = 0.011) (7). deniz, et al. supported these findings with their study. immunoreactivity of hif-1αwas in concordance with stage and histologic grade of ubc. immunoreactivity of hif-1α was also related to vegf (p < 0.001) and mvd (p = 0.002) (14). another study by theodoropoulos, et al. in 2005 reported that hif1α expression is more common in high grade ubc. it was also positively correlated with increased proliferative activity, apoptotic rate, and mvd. however, they found no association between hif-1α alone and prognosis of ubc. the prognosis of ubc was associated with both hif-1α and mutation in p53 nuclear protein (5). a study conducted by fus, et al. reported a contradictive result. they found that the expression of hif-1α is significantly lower in high grade ubc. negative correlation was also reported between the expression of hif-1α and mvd (3). we found that serum level of hif-1α in case group is significantly higher compared to control group (p < 0.001). serum hif-1α was also higher in advanced ubc stage, including primary tumor, lymph node, and metastasis stage. higher serum hif-1αwas also observed in advanced ubc grade but the difference was not statistically significant. there were several limitations in our study. we did not analyze risk factors for ubc other than gender and age. we also did not analyze variables that influence the level of serum hif-1α. the kit we used to determine serum hif1α level was also different which may have given different result. additional study, preferably a meta-analysis, is requested to determine the association between serum hif-1α level and progression of ubc. conclusions there was a significant association between serum hif1α level and staging of ubc. serum hif-1α level may aid in early diagnosis, prompt management, and improved outcome of patients with ubc. references 1. burger m, catto jwf, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013; 63:234-41. 2. martin jw, jefferson fa, huang m, et al. a california cancer registry analysis of urothelial and non-urothelial bladder cancer subtypes: epidemiology, treatment, and survival. clin genitourin cancer. 2020; 18:e330-6. 3. fus lp, pihowicz p, koperski l, et al. hif-1α expression is inversely associated with tumor stage, grade and microvessel density in urothelial bladder carcinoma. pol j pathol. 2018; 69:395-404. 4. mortada wi, awadalla a, khater s, et al. copper and zinc levels in plasma and cancerous tissues and their relation with expression of vegf and hif-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study. environ sci pollut res int. 2020; 27:15835-41. 5. theodoropoulos ve, lazaris ac, kastriotis i, et al. evaluation of hypoxia-inducible factor 1 alpha overexpression as a predictor of tumour recurrence and progression in superficial urothelial bladder carcinoma. bju int. 2005; 95:425-31. 6. xue m, li x, li z, chen w. urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding rna that enhances hypoxic bladder cancer cell proliferation, migration, and invasion. tumour biol. 2014; 35:6901-12. 7. chai c, chen w, hung w, et al. hypoxia-inducible factor-1alpha expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma. j clin pathol. 2008; 61:658-64. 8. theodoropoulos ve, lazaris ac, sofras f, et al. hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. eur urol. 2004; 46:200-8. 9. badr s, salem a, yuosif ah, et al. hypoxia inducible factor-1alpha and microvessel density as angiogenic factors in bilharzial and nonbirharzial bladder cancer. clin lab. 2013; 59:805-12. 10. darmadi d, ruslie rh. association between prothrombin induced by vitamin k absence-ii (pivka-ii) and barcelona clinic liver cancer (bclc) stage, tumor size, portal venous thrombosis in hepatocellular carcinoma patients. sains malays. 2021; 50:475-80. 11. shigeta k, hasegawa m, hishiki t, et al. idh2 stabilizes hif1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. embo j. 2023; 42:e110620. 12. darmadi d, ruslie rh, pakpahan c. vascular endothelial growth factor levels difference among hepatocellular cancer patients based on barcelona clinic liver cancer staging. open access maced j med sci. 2021; 9:797-800. 13. ruslie rh, darmadi d, siregar ga. vascular endothelial growth factor (vegf) and neopterin levels in children with steroid sensitive and steroid-resistant nephrotic syndrome. med arch. 2021; 75:133-7. 14. deniz h, karakok m, yagci f, guldur me. evaluation of relationship between hif-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas. int urol nephrol. 2010; 42:103-7. correspondence ginanda putra siregar, md (corresponding author) ginandasir@gmail.com doctoral study program, faculty of medicine, universitas padjadjaran, bandung, indonesia and division of urology, department of surgery, faculty of medicine, universitas sumatera utara, medan, indonesia ida parwati, md department of clinical pathology, faculty of medicine, universitas padjadjaran, bandung, indonesia bambang sasongko noegroho, md ferry safridai, md department of urology, faculty of medicine, universitas padjadjaran, bandung, indonesia gerhard reinaldi situmorang, md department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia raden yohana, md division of oncology, department of surgery, faculty of medicine, padjadjaran university, bandung, indonesia astrid feinisa khairani, md department of biomedical sciences, faculty of medicine, universitas padjadjaran, bandung, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 112 review although sglt2 inhibitors have been initially employed in the treatment of type 2 diabetes, their clinical use was later extended to the treatment of other conditions such as heart failure, chronic kidney disease and obesity. in patients with type 2 diabetes, the administration of sglt2 inhibitors has been associated with an increased incidence of urogenital infections, which may be linked to high glucose levels in the urine. the rate of urogenital side effects may be different in non-diabetic patients. the aim of this study was to review the risk of urogenital infections in non-diabetic patients taking sglt2 inhibitors. materials and methods: we conducted a systematic review and meta-analysis by searching pubmed and embase for randomized controlled trials (rcts) reporting urogenital adverse effects in non-diabetic patients treated with sglt2 inhibitors. odds ratios for urogenital infections were calculated using random effect mantel-haenszel statistics. results: out of 387 citations retrieved, 12 eligible rcts were assessed for risk of bias and included in the meta-analysis. compared to placebo, sglt2 inhibitors were associated with increased odds of genital infections (or 3.01, 95% ci: 1.934.68, 9 series, 7326 participants, z = 5.74, p < 0.0001, i2 = 0%) as well as urinary tract infections (or 1.33, 95% ci: 1.13-1.57, risk of urogenital infections in non-diabetic patients treated with sodium glucose transporter 2 (sglt2) inhibitors. systematic review and meta-analysis rawa bapir 1, 16, kamran hassan bhatti 2, 16, ahmed eliwa 3, 16, herney andrés garcía-perdomo 4, 16, nazim gherabi 5, 16, derek hennessey 6, 16, vittorio magri 7, 16, panagiotis mourmouris 8, 16, adama ouattara 9, 16, gianpaolo perletti 10, 16, joseph philipraj 11, 16, konstantinos stamatiou 12, 16, musliu adetola tolani 13, 16, lazaros tzelves 8, 16, stefan d. anker 14, alberto trinchieri 15, 16, noor buchholz 16 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 urology unit, asst fatebenefratelli sacco, milan, italy; 8 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 9 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 10 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 department of urology, tzaneio general hospital, 18536 piraeus, greece; 13 division of urology, department of surgery, ahmadu bello university/ahmadu bello university teaching hospital, zaria, kaduna state, nigeria; 14 department of cardiology and bcrt (campus cvk), charité universitätsmedizin berlin, germany; 15 urology school, university of milan, milan, italy; 16 u-merge ltd. (urology for emerging countries), london-athens-dubai *. authors 1-16 have equally contributed to the paper and share first authorship. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2023.11509 summary 9 series, 7326 participants, z = 4.05, p < 0.0001, i2 = 0%). when four trials investigating the effects of sglt2 inhibitors in populations including both diabetic and non-diabetic patients were considered, administration of sglt2 inhibitors in diabetic patients was associated with significantly higher odds of genital infections but not urinary tract infections compared to patients without type 2 diabetes. in patients taking placebo, the odds for urinary tract infections were significantly increased in diabetic patients compared to non-diabetic patients. conclusions: the risk of genital infections is increased also in non-diabetic patients taking sglt2 inhibitors although at a lesser extent that in diabetics. a careful assessment of the local anatomical conditions and of the history of previous urogenital infections is desirable to select those patients who need more intense follow-up, possibly combined with prophylactic measures of infections during treatment with sglt2 inhibitors. key words: sodium glucose transporter 2 (sglt2) inhibitors; urinary tract infections; genital infections; candidiasis; heart failure; chronic kidney disease; obesity. submitted 4 june 2023; accepted 5 june 2023 archivio italiano di urologia e andrologia 2023; 95, 2 r. bapir, k. hassan bhatti, a. eliwa, et al. 113 introduction sodium glucose transporter 2 (sglt2) inhibitors have been recently introduced in the treatment of type 2 diabetes (t2dm). the most frequently administered sglt2 inhibitors are canagliflozin, dapagliflozin, and empagliflozin. the sglt2 transporter is responsible for reabsorption of more than 90% of renal glucose from the urine filtered by renal glomeruli. in diabetic patients, administration of a sglt2 inhibitor reduces the renal glucose threshold, resulting in glycosuria and in the lowering of plasma glucose levels. in patients with t2dm, administration of sglt2 inhibitors as monotherapy or in combination with other antidiabetic agents was shown to lower hba1c, to induce weight loss and to decrease blood pressure (1). somehow unexpectedly, sglt2 inhibitors were found to be potentially useful in the management of heart failure (2). in addition, studies in patients with chronic kidney disease, showed that sglt2 inhibitors reduced the risk of a decline of renal function or end-stage kidney disease regardless of the presence or diabetes (3, 4). due to these favorable characteristics, sglt 2 inhibitors are increasingly prescribed not only in patients with type 2 diabetes mellitus, but also in patients with cardiovascular and renal diseases. interestingly, sglt2 inhibitors have also proven to be effective in lowering body weight in obese patients without type 2 diabetes (5). although sglt2 inhibitors are generally well tolerated, increased rates of genital and urinary tract infections have been reported (6, 7). the increased frequency of genital infections in diabetic patients treated with sglt-2 inhibitors may be explained by high urinary glucose concentrations that can promote the growth of fungi on the surface of the genital mucous membranes. however, the concentration of glucose in the urine of diabetic patients taking sglt-2 inhibitors may be lower compared to the one measured in non-diabetic patients who are receiving sglt-2 inhibitors for other conditions. for this reason, the risk of genital infections in patients taking sglt-2 inhibitors for conditions other than type 2 diabetes may be different compared to patients with type 2 diabetes. the aim of this systematic review and metanalysis was to evaluate the evidence describing the prevalence of genitourinary infections in non-diabetic patients receiving sglt2 inhibitors for different conditions. materials and methods protocol and registration the review was conducted in accordance with the preferred reporting items for systematic reviews and metaanalyses (prisma) guidelines (8). the protocol for this review was registered on the prospero platform (registration number: crd42022375951). types of studies we considered articles written in english, reporting randomized controlled trials (rcts) evaluating the side effects of sglt2 inhibitors, administered to diabetic or non-diabetic patients (i) for prevention of heart failure, (ii) for preserving renal function in end-stage kidney disease or (iii) for weight loss. types of patients participants of both sexes were involved irrespective of their age or ethnicity. types of interventions administered to patients patients on treatment with sglt2 inhibitors or placebo were included in the present review. outcomes the outcome considered for this review was the assessment of the prevalence of genital or urinary infections in subjects taking sglt2 inhibitors compared to those not taking this treatment. search strategy two electronic databases (pubmed and embase) were searched for records published up to january 31st, 2023. broad search strings, based on mesh terms, were used (e.g., [sodium glucose co-transporter-2 or canagliflozin or dapagliflozin or empagliflozin) and (urinary tract infections or genital infections or balanitis or vulvovaginitis or candidiasis or fournier gangrene]). relevant data were also hand-searched by browsing reference lists of reviews and trial reports, or other sources. duplicate references were excluded. data collection and analysis selection of studies and data extraction title and abstract screening to exclude documents that did not meet the inclusion criteria was performed independently by four authors (two for each database). selected titles were downloaded for full-text reading, for final inclusion and for extraction of relevant information. controversies were resolved by one independent researcher. a prisma flow diagram was drawn to summarize the process of study selection. data extraction was performed by four authors using a standardized form. the following data were extracted from each study report: author(s), publication year, study design, population, intervention, prevalence of genital and urinary infections. in case of missing or insufficient information, we considered the impact of missing data on the meta-analysis results. quality evaluation on methodology three authors independently performed the quality assessment by identifying potential biases using the cochrane risk of bias tool (9). the following potential sources of bias were considered: randomization process (d1), deviations from the intended interventions (d2), missing outcome data (d3), measurement of the outcome (d4) and selection of the reported result (d5). disagreements were resolved by discussion. risk of bias was not used to exclude studies. statistical analysis statistical analysis was performed using the metaessentials-1 software (rotterdam school of management, erasmus university, the netherlands). dichotomous data (presence/absence of urinary or genital stone disease) and number of subjects archivio italiano di urologia e andrologia 2023; 95, 2 114 urogenital infection and sglt2 inhibitors were extracted to calculate odds ratios (or), confidence intervals (ci) to odds-ratios, and z statistics (random-effects model, mantel-haenszel method). assessment of heterogeneity study heterogeneity was assessed by the i2 statistic, reported with 95% cis, and interpreted as of lesser importance (i2 ≤ 40%), moderate (i2 = 30%-60%), substantial (i2 = 50%-90%) or considerable (i2 ≥ 75%), according to cochrane criteria. sensitivity analysis was planned if considerable heterogeneity of pooled analyses including at least 4 studies was detected. assessment of reporting bias publication bias was assessed by funnel plot in the presence of at least 4 trials in each meta-analysis. if a potential bias was suspected by visual inspection of the plots, the begg’s and egger’s tests were used to test funnel plots symmetry and to confirm or exclude the presence of publication bias. the ‘trim and fill’ missing study imputation approach was applied to funnel plots; if missing studies were imputed by this procedure, adjusted overall effect sizes (odds ratios) were calculated and presented in the plots. publication bias analysis was performed using the metaessentials-1 software (rotterdam school of management, erasmus university, the netherlands). results database search resulted in 387 retrieved records (medline = 104, embase = 283). subsequent screening of title and abstract restricted the number of records to 42. four additional studies were retrieved by handsearching the references of selected studies. after removal of 5 duplicates, we considered 41 articles for full-text evaluation. full-text evaluation resulted in the exclusion of 29 articles for the following reasons: one review article, 15 reports dealing only with type-2 diabetes patients, 2 articles reporting a comparison of sglt2 inhibitors with other drugs, one letter to the editor, 5 papers reporting the results presented in other included studies, 2 studies reporting short-term administration of sglt2 inhibitors, one article dealing with cost-benefit of sglt2 inhibitors treatment, 3 reports non presenting safety data. the remaining 12 articles were included in the qualitative systematic review. out of them, nine were included in the meta-analysis. included studies three studies included overweight or obese patients without dm type 2 receiving (i) canagliflozin or (ii) canagliflozin plus phentermine or (iii) dapagliflozin plus exenatide (10-12). in the diamond trial, dapagliflozin was administered to non-diabetic patients with chronic kidney disease and proteinuria (13). in another study, the effect of dapagliflozin was evaluated in nondiabetic patients with heart failure and reduced ejection fraction (14). in the remaining 7 studies, sglt2 inhibitors were administered in populations that included both patients with type 2 diabetes and non-diabetic patients with heart failure (emperorpreserved, emperor-reduced, emperial, dapa-hf, deliver) or chronic kidney disease (dapa-ckd, empa-kidney) (15-21). data divided by diabetic status were available in two studies in the primary publication (16, 21). in two other studies we obtained from the authors data presented according to diabetes status (22, 23). data extracted by the studies are presented in supplementary table 1. quality assessment and risk of bias analysis of the 12 included studies, only one was classified as high risk (14), two studies were classified as having some figure 1. prisma flow diagram of the record retrieval and selection process. archivio italiano di urologia e andrologia 2023; 95, 2 r. bapir, k. hassan bhatti, a. eliwa, et al. 115 concerns (11, 16), and nine studies (10, 12, 13, 15, 17-21) were assessed as low risk of bias (supplementary figure 1). the study classified as high risk was assessed as having high risk of bias for the randomization process and presented some concerns with regard to deviations from intended intervention. the other two studies presented some concerns about randomization. meta-analysis meta-analysis was performed on 9 trials in which data were presented separately according to diabetes status. non-diabetic patients urinary tract infections sglt2 inhibitors vs placebo (9 studies) there was a statistically significant difference in the odds of urinary tract infections in patients treated with sglt2 inhibitors compared to placebo (or 1.33, 95% ci: 1.131.57, 9 series,7326 participants, z = 4.05, p < 0.0001, i2 = 0%) (figure 2). although publication bias analysis did not detect a significant asymmetry of the funnel plot (p = 0.31, egger’s test; p = 0.14, begg’s test ), the “trim and fill” strategy imputed three missing studies on the left side of the funnel plot (shown in the supplementary figure 2); the resulting adjusted odds ratio was 1.30 (95%ci, 1.1-1.55). genital infections sglt2 inhibitors vs placebo similarly, a statistically significant difference in the odds of genital infections was observed when sglt2 inhibitors were compared to placebo (or 3.01, 95% ci: 1.93-4.68, 9 series, 7326 participants, z = 5.74, p < 0.0001, i2 = 0%) (figure 3). publication bias analysis did not detect a significant asymmetry of the funnel plot (p = 0.95, egger’s test; p = 0.29, begg’s test ). non-diabetic vs diabetic patients urinary tract and genital infections treatment with sglt2 inhibitors (4 studies) in four studies comparing diabetic vs. non-diabetic patients taking sglt2 inhibitors for heart failure or chronic kidney disease, we did not find a statistically significant difference of the odds for urinary tract infection (or 1.34, 95% ci: 0.83-1.59, 4 series, 7317 participants, z = 1.34, figure 2. odds for urinary tract infections in non-diabetic patients taking sglt2 inhibitors. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in patients treated with sglt2 inhibitors. figure 3. odds for genital infections in non-diabetic patients taking sglt2 inhibitors. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in patients treated with sglt2 inhibitors. figure 4. odds for urinary tract infection in diabetics vs non-diabetics taking sglt2 inhibitors. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in diabetic patients. archivio italiano di urologia e andrologia 2023; 95, 2 116 urogenital infection and sglt2 inhibitors p = 0.091, i2 = 0%) (figure 4). however, significantly higher odds were found in diabetic patients for genital infections (or 1.36, 95% ci: 1.07-1.72, 4 series, 7317 participants, z = 4.08, p < 0.0001, i2 = 0% (figure 5). although publication bias analysis of the odds for urinary tract infections did not detect a significant asymmetry of the funnel plot (p = 0.09, egger’s test; p = 0.49, begg’s test), the “trim and fill” strategy imputed two missing studies on the left side of the funnel plot (shown supplementary figure 2); the resulting adjusted odds ratio was 1.11 (95%ci, 0.861.43). funnel plots of the odds for genital infections showed asymmetry (p = 0.13, egger’s test; p = 0.042, begg’s test); two missing studies on the left side of the funnel plot were imputed by “trim and fill” (shown in the supplementary material); the resulting adjusted odds ratio is significant (1.33; 95%ci, 1.08-1.63). urinary tract and genital infections placebo (4 studies) in the same four studies including diabetic vs. non-diabetic patients with heart failure or chronic kidney disease taking placebo, we found a statistically significant odds ratio for urinary tract infections (or 1.30, 95% ci: 1.071.58, 4 series,7312 participants, z = 4.29, p < 0.0001, i2 = 0%) (figure 6). publication bias analysis did not detect a significant asymmetry of the funnel plot (p = 0.75, egger’s test; p = 0.99, begg’s test ). the odds for genital infection were not significantly higher in diabetic versus non-diabetic patients taking placebo (or 1.14, 95% ci: 0.36-3.66, 4 series,7312 participants, z = 0.37, p = 0.35, i2 = 7.15%) (figure 7). discussion the effect of high urinary levels of glucose on the risk of urinary tract and genital infections is not fully investigated. although it is well known that diabetes is an important risk factor for urinary tract infections (24), the possible role of high urine glucose concentrations in the pathogenesis of urinary tract infections has not been confirmed. the causes of the increased risk of urinary tract infections in diabetic patients has been attributed to multiple factors including alterations in the immune response, metabolic abnormalities and neurological and nephrological complications (25). in an in-vitro study, addition of glucose (up to a concentration of 1000 mg/dl) to urine enhanced the growth rate of pathogenic urinary isolates (26). in a clinical study higher levels of glucosuria were associated with higher rate of asymptomatic bacteriuria (27), although this finding was not confirmed by other authors (28) and in a large series of women with either type 1 or type 2 diabetes, glucosuria was not associated with the development of symptomatic urinary tract infections (29). treatment with sglt2 inhibitors of patients with type 2 diabetes was associated with a small increase in incidence of urinary tract infections, with no increase in serious or upper urinary tract infections (30). figure 5. odds for genital infection in non-diabetics vs diabetics taking sglt2 inhibitors. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in diabetic patients. figure 6. odds for urinary tract infection in non-diabetics vs diabetics on placebo. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in diabetic patients. figure 7. odds for genital infection in non-diabetics vs diabetics on placebo. odds ratios of single studies and of the pooled analysis are presented. the values at the right of the no-effect bar show higher odds of infection in diabetic patients. archivio italiano di urologia e andrologia 2023; 95, 2 r. bapir, k. hassan bhatti, a. eliwa, et al. 117 the role of high urine glucose levels in the pathogenesis of genital mycotic infections in men and women is based on more robust considerations. candida species are polymorphic fungi that may colonize skin and mucosal surfaces acting as opportunistic pathogens (31, 32). the first phase of infection is adhesion of yeast forms to receptors on epithelial cells, which is mediated by adhesins and invasins (33) subsequently, the filamentous hyphae are responsible for the formation of a biofilm on the superficial mucosa of the host (34). colonization is favored by a carbohydrate-rich environment, which is a source of energy for producing biofilms that protect fungal cells from external agents (35-37). the high incidence of genital infections in patients with uncontrolled glycemia can be attributed to different pathophysiological mechanisms (38). infection can be favored by glucose, a viable nutrient for the growth of the fungi in the urine and in the secretions. furthermore, in vitro studies have shown that high glucose levels facilitate the adhesion of candida to cells through intercellular adhesion molecule 1 expression (39). in addition, infections are more frequent in diabetic patients also due to compromised cellular immunity and to functional changes in polymorphonuclear cells, monocytes, and lymphocytes (40). meta-analyses including large populations of patients with type 2 diabetes treated with sglt2 inhibitors demonstrated an up-to-four times increased risk of genital yeast infections for both genders in comparisons with placebo or other anti-hyperglycemic medications (41). according to some authors, the risk of candida colonization and infection after sglt2 inhibitors is even higher in real world practice (42). yokoyama et al. (42) found that among the patients who were initially negative for candida, 37% converted to a positive culture after treatment with sglt2 inhibitors and 16% developed symptomatic vulvovaginitis. this finding can be explained by urinary glucose excretion and the subsequent deposition of urine with high glucose content on the genital mucosa. on the other hand, the magnitude of the glucosuric effect of sglt2 inhibitors in non-diabetic patients may be less pronounced than the one observed in diabetic patients. in a phase 1 study in healthy men, canagliflozin (i) decreased in a dosedependent fashion the renal threshold for glucose, with maximal reduction to approximately 60 mg/dl, (ii) increased mean 24-h urinary glucose excretion and (iii) reduced postprandial plasma glucose (43). in another phase 1 study, canagliflozin significantly increased 24-h urinary glucose excretion in obese patients, but there were no significant changes in fasting plasma glucose and mean 24-h plasma glucose (44). in a phase 2b study in overweight and obese subjects without type 2 diabetes, mean 24-h urinary glucose excretion of 45-60 g was observed after canagliflozin administration (10). the effect of sglt2 inhibitors on glucose excretion may be different in euglycemic subjects compared to diabetic patients because of sglt1 activity. sglt1 is a low-capacity, high-affinity transporter that mediates approximately 5% of glucose reabsorption in the s3 (distal) segment of the proximal tubule whereas sglt2 is a high-capacity, low-affinity glucose transporter which is responsible for the reabsorption of approximately 90-95% of glucose in the s1 and s2 segments of the proximal tubule (45). conversely, when sglt2 is inhibited, a larger rate of glucose is reabsorbed by sglt1, resulting in excretion of only 50-60% of filtered glucose (46). in fact, animal studies confirmed that the contribution of sglt1 to renal glucose reabsorption is greater under lower glycemic conditions than under hyperglycemic conditions (47). in our meta-analysis, the risk of genital infections and, to a lesser extent, of urinary tract infections was increased also in non-diabetic patients taking sglt2 inhibitors. similarly, a previous meta-analysis showed no statistically significant different rates of genital and urinary tract infections in large series of patients taking sglt2 inhibitors for treating type 2 diabetes or heart failure or chronic renal disease (48). our meta-analysis also demonstrated that odds of genital infection after taking sglt2 inhibitors are higher in diabetic patients than in non-diabetics. diabetic status is therefore a risk factor for genital infections in patients taking sglt2 inhibitors, although a primary care database study did not find an increased risk of infection in patients with higher hba1c levels (49). however, even non-diabetic patients treated with sglt2 inhibitors must be carefully monitored for the onset of genital infections, especially in the presence of risk factors such as female gender, higher bmi and history of previous genital infection that are independently associated with risk for genital infection in patients treated with sglt2 inhibitors (49). similarly, male patients with foreskin phimosis may be at increased risk of developing a fungal infection because the moist, warm space underneath the foreskin promotes yeast growth, especially when hygiene is poor. conclusions genital infections in patients taking sglt2 inhibitors are usually easily treated with appropriate antimycotic treatment. however, sglt2 inhibitors may significantly increase the risk of serious infections. for this reason, it is advisable to adequately inform patients, who must be aware of the possible risks of genital infection. increased hygiene measures should be recommended (e.g., frequent washing of the genital area, if possible after each urination). subgroups of patients showing a markedly increased risk of genital infections when treated with sglt2 inhibitors should be identified for closer follow up; 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304:e414-23. 48. staplin n, roddick aj, emberson j, et al. net effects of sodiumglucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials. eclinicalmedicine. 2021; 41:101163. 49. mcgovern ap, hogg m, shields bm, et al. mastermind consortium. risk factors for genital infections in people initiating sglt2 inhibitors and their impact on discontinuation. bmj open diabetes res care. 2020; 8:e001238. 50. cooke g, watson c, deckx l, et al. treatment for recurrent vulvovaginal candidiasis (thrush) cochrane database syst rev. 2022; 1:cd009151. correspondence rawa bapir, md dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti, md kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar ahmed eliwa, md ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt herney andrés garcía-perdomo, md herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi, md ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey, md derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland vittorio magri, md vittorio.magri@asst-fbf-sacco.it urology unit, asst fatebenefratelli sacco, milan, italy panagiotis mourmouris, md thodoros13@yahoo.com lazaros tzelves, md lazarostzelves@gmail.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece adama ouattara, md adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio general hospital, 18536 piraeus, greece musliu adetola tolani, md adetolatolani@yahoo.com division of urology, department of surgery, ahmadu bello university/ ahmadu bello university teaching hospital, zaria, kaduna state, nigeria stefan d. anker, md s.anker@cachexia.de department of cardiology and bcrt (campus cvk), charité universitätsmedizin berlin, 13353 berlin, germany alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com urology school, university of milan, milan (italy) orcid 0000-0002-9394-8292 noor buchholz, md noor.buchholz@gmail.com sobeh's vascular and medical center, dubai health care city, dubai, united arab emirates conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 51archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. observed during long-term conservative follow-up of these patients (2). ub is generally seen in patients over age 80 in both genders, although identified more precisely in men, in terms of standardization. a korean study reported higher frequencies for ub in men (40.2%) than in women (12%) over age 80 (3). there are studies reporting symptom recovery after prostate surgery in these patients (4), although other studies claimed only slight clinical recovery (5). low urine flow rate is a common feature among the patients with ub and bo. voiding pressure-flow study can be used for differentiation in indeterminate cases. (2). because of the invasive nature of the pressure-flow study, a non-invasive method is welcomed. there may be a correlation between detrusor contraction index and the ratio of micturition volume and average physiological bladder capacity. this ratio, also known as voiding efficiency (ve), was addressed in the articles on pressure-flow studies and ub in the literature, although the topic is insufficiently studied. materials and methods clinical data of the patients and the algorithm in the study, data of 4454 patients who underwent pfs in the period between january 2007-january 2015 was examined. male patients having a minimum of 2 uroflowmetry and postvoid residual urine measurements were enrolled. patients of female gender (n = 1208), patients with urological malignancies that may affect lut symptoms (bladder cancer, prostate cancer, etc.) (n = 386), calculi in the bladder and lower end of the ureter (n = 102), active infection and asymptomatic bacteriuria (n = 406), transurethral intervention history (n = 908), previous lut symptoms due to neurogenic causes (n = 1005), catheter before and after urodynamics or performing clean intermittent catheterization (cic) (n = 155), decayed patients, bedridden patients suffering mobilization problems (n = 102), and patients with missing data (n = 89) were excluded from the study. a total of 93 patients with complete data and without exclusion criteria were included in the study. detailed urological history and physical examination data were evaluated in all the included patients. uroflowmetric measurements (aymed urodynamic sysobjective: we assessed the efficacy of voiding efficiency (ve) to distinguish between underactive bladder (ub) and bladder outlet obstruction (bo) without using pressure flow studies (pfs). materials and methods: in male patients, uroflowmetry and post-void residual (pvr) urine data and subsequent pressure flow studies (pfs) data were examined retrospectively. bladder outlet obstruction index (boi) and bladder contractility index (bci) were calculated from patients' pfs values. patients with bci < 100 and boi < 40 were grouped as ub group and patients with bci > 100 and boi > 40 were grouped as boo group. ve was computed as a percentage of volume voided compared to the pre-void bladder volume. results: in total we examined 93 patients, 44 in ub and 49 in bo group. there was no statistically significant difference between the two groups in relation to qmax value (p = 0.38). however, total voiding time, time to reach the maximum urinary flow rate and voided volume showed statistically significant difference between the two groups (p < 0.001). average ve was 63.6 + 2.43% and 46.2 + 2.63%) for ub and bo groups respectively and the difference was statistically significant (p < 0.001). ub can be diagnosed with at least 95% sensitivity and 88% specificity in men over age 80. conclusions: non-invasive uroflowmetry and ve measurements were able to differentiate between ub and boo patients, presenting with identical clinic features, but different findings of pfs. key words: underactive bladder; bladder outlet obstruction; voiding efficiency; urodynamics. submitted 20 january 2022; accepted 2 february 2002 introduction reduced detrusor contraction, also named detrusor underactivity or underactive bladder (ub), means prolonged voiding at low pressure, without any obstruction from urodynamic and clinical point of view. this definition has been frequently included in the terminology. in his study published in 2015, chapple defined ub as a symptom complex including prolonged voiding time with or without a feeling of complete bladder emptying, difficulty in initiating voiding, diminished sense of bladder filling and a slow voiding flux (1). ub may interfere with bo, which also leads to lower urinery tract (lut) symptoms. this interference leads to failure of the planned surgery in these patients. conversely, chronic retention or progression to surgery were not frequently non-invasive diagnosis of under active bladder: a pilot study mehmet yoldas tepecik training and research hospital urology clinic, izmir, turkey. doi: 10.4081/aiua.2022.1.51 summary archivio italiano di urologia e andrologia 2022; 94, 1 mehmet yoldas 52 tems, istanbul, turkey) were performed at least two times before urodynamic testing and residual urine volume after uroflowmetry was assessed by suprapubic ultrasound measurement (logiq c2, ge medicalsystems, jiangsu p. r. china). those with uroflowmetry measurement ≥ 150 ml were included in the evaluation. algorithm the algorithm of the study is shown in figure 1. figure 1. algorithm of the study. 53archivio italiano di urologia e andrologia 2022; 94, 1 non-invasive diagnosis of underactive bladder uroflowmetry and measurement of postvoid residual urine all patients performed at least 2 uroflowmetric measurements prior to urodynamic evaluation and the average was calculated. they were asked to come to test with a full bladder. uroflowmetry was performed while the patient was standing comfortably and alone. uroflowmetry data including maximum urinary flow rate (qmax) and voided volume were noted. for each patient, postvoid residual urine volume was determined by ultrasonography (us) by multiplying distances at sagittal, transverse and vertical axis of the bladder by 3.14/6 and noted for all patients (6). voiding efficacy was calculated as voided volume on uroflow/pre-void bladder capacity measured on ultrasound. urodynamic evaluation before urodynamics, patients interrupted 3 days in advance drugs that can affect lut symptoms, in accordance with the international continence society guidelines (7). urine culture and antibiogram were done in all cases to exclude any possible risk of infection. patients with a negative culture were eligible for pressure flow studies with prior quinolone prophylaxis. for pressure flow studies, a two-way 6 f urodynamic catheter (mediana, ads, ankara, turkey) and a 12 f rectal balloon catheter (ud-cath, aymed, istanbul, turkey) were used. pressure flow studies started with an empty bladder while the patient was alone in a quiet room in sitting position. bladder contractility index (bci) was determined during pressure-flow studies, by adding 5 times the maximum urinary flow (qmax) value following the voiding command, to the detrusor pressure at the moment of maximum flow volume following the voiding command, (5 qmax + pdetqmax). the values ≤ 100 were defined as underactive bladder (ub) (8). bladder outlet obstruction index (boi), also known as the abrams-griffiths (ag) number, was also determined during pressure-flow studies, by substracting twice the maximum flow value following the voiding command, from the value of detrusor pressure during the moment of maximum flow (pdetqmax) 2qmax). boi was considered positive for the values ≥ 40 (9). boi < 40 and bci > 100 (healthy normal population), boi > 40 and bci < 100 (patıents wıth both bladder outlet obstructıon and hypoactıve bladder) were excluded. statistical methods spss 15.0 (statistical package for the social sciences) (spss inc, chicago, il, usa) statistical package was used in the statistical analysis of the data. kolmogorov-smirnov goodness-of-fit test was used to assess compliance with the normal distribution of data. descriptive statistics of the data were calculated. significance of differences between the groups was determined by mann-whitney u-test. statistically significance was accepted as p < 0.05. cut-off values of the statistically significant parameters were evaluated by the roc curve. results a total of 93 patients with eligible and complete data were assigned to group ub (boi < 40 and bci < 100; n = 44) and group bo (boi > 40 and bci > 100; n = 49). mean age was 64.18 ± 1.66 years for group bo and 78.54 ± 1.68 years for the group ub. mean age was higher in the ub group, with a statistically significant difference between two groups (p < 0.001) (table 1). a korean study evaluated relationship between clinical pictures of ub and bo with age and gender, and reported higher prevalance of ub with aging when compared to bo in the male group, whereas an inverse relationship was observed for the female group that showed higher increase of bo prevalence with age compared to ub (3). in our study which included only male patients age was higher in the ub group compared to the bo group. according to the korean study, ub group displayed an accelerated increase with age compared to bo group. patients over 85 years of age constituted 40% of the ub group and 26% of the bo group. interestingly, bo showed a decrease after the age of 75 (figure 2). we explain this finding as some kind of compensation caused by bo as the result of an increased effort against table 1. demographic, uroflowmetric and postvoid residual urine data of the patients. parameters ub group bo group p value number of patients 44 49 mean age (year) 78.54 ± 11.6 64.18 ± 11.1 < 0.001 uroflowmetric parameters time to start voiding after the command (sec) 11.95 ± 1.82 10.89 ± 1.06 0.731 maximum urinary flow (ml/sec) 11.36 ± 0.70 10.46 ± 0.59 0.387 mean urinary flow (ml/sec) 7.59 ± 0.43 6.53 ± 0.40 0.061 postvoid residual urine volume (ml) 381.4 ± 45.53 296.93 ± 25.57 0.208 figure 2. patient groups by age. archivio italiano di urologia e andrologia 2022; 94, 1 mehmet yoldas 54 increased resistance preventing ub development at advanced ages. in accordance with this explanation, a decreased ub incidence and an increased bo incidence was shown among female aged over 75 years in the korean study (3). additionally, we think ub has a closer correlation with aging but bo pathogenesis is multifactorial. in the analysis of the two groups with regard to uroflow parameters; mean time to start voiding after the command was 11.95 ± 1.82 seconds in the ub group and 10.89 ± 1.06 seconds in the bo group and there was no statisticaly significant difference between the groups (p = 0.731). mean value for maximum urinary flow was 10.46 ± 0.59 ml/sec in the ub group and 11.36 ± 0.70 ml/sec in the bo group, with a not significant difference between the groups (p = 0.387). mean flow rate was 7.59 ± 0.43 and 6.53 ± 0.40 ml/sec, respectively for ub and bo, again with an insignificant difference (p = 0.061). measurement of postvoid residual urine volume showed that, mean residual volume was 381.47 ± 45.53 ml in the ub group and 296.93 ± 45.0 ml in the bo group, with an insignificant difference between the groups (p = 0.208). mean voided volume was 666.90 ± 38.84 ml in the ub group and 213.46 ± 13.67 in the bo group, with a statistically significant difference between the groups (p < 0.001). with regard to bladder voiding efficiency, ub group performed at 66.02 ± 2.43% and bo group at 45.53 ± 2.63% efficiency (p < 0.001). a statistically significant difference was detected between the two groups for ve. in the analysis for determining the cut-off by the roc curve, the area under the curve of maximum diagnostic value for ve was 0.771(±0.052) (figure 3). from this study, we can deduce that patients in the bo group were able to empty their bladders more effectively than ub group. as the best cut-off points, separate roc curve analysis for ve showed 93% sensitivity and 60% specificity. in short, ub group performed voiding at high efficiency while bo at lower efficiency levels (table 1). in the pressure-flow study; first sensation of bladder filling (early desire to void) was detected at mean volumes of 150.8 ± 64.77 ml in ub group, although not detected in 6 patients, and 117.7 ± 64.52 ml in bo group. first desire to void occurred at average bladder filling of 243.5 ± 100.62 ml in ub group and 177.1 ± 83.86 ml in bo group. strong desire to void (urgency) occurred at average bladder filling of 355.6 ± 130.66 ml in ub group and 294.4 ± 145.78 ml in bo group. mean maximum bladder capacity was 544.7 ± 167.45 ml in ub group and 355.1 ± 133.48 ml in bo group. all parameters were determined to be higher, in the patients of ub group. mean qmax valus measured during pressure-flow studies was 4.2 ± 3.96 in ub group and 6.5 ± 3.98 ml/sn in bo group. mean vesical pressure value recorded at maximum measured flow was 34.1 ± 21.31 cm h2o in ub group and 101.1 ± 40.02 cm h2o in bo group. vesical pressure values were higher in bo group, as expected. average bladder contractility index was 48.8 ± 27.21 in ub group and 132.5 ± 37.83 in bo group. average a-g number was 20.0 ± 8.82 in ub group and 88.0 ± 40.69 in bo group (table 2). discussion bladder's ability to contract is well known to decrease with increasing age in both genders, causing pathologies resulting in ub and bo as well as causing lut symptoms. age-dependant impairment in ub is closely related with structural impairment of detrusor muscle. structural changes are related with intense band decreases, decreased density of axonal connections, decreased collatable 2. urodynamic data of the patients. figure 3. roc curves voiding efficiency. bladder sensation during filling ub group bo group first sensation of bladder filling (early desire to void) 150.8 ± 64.77 ml 117.7 ± 64.52 ml absent in 6 patients absent in 1 patient first desire to void 243.5 ± 100.62 ml 177.1 ± 83.86 ml strong desire to void (urgency) 355.6 ± 130.66 ml 294.4 ± 145.78 ml maximum bladder capacity 544.7 ± 167.45 ml 355.1 ± 133.48 ml pressure-volume studies qmax (ml/sec.) 4.2 ± 3.96 ml/sec 6.5 ± 3.98 ml/sec pdetqmax (cmh2o) 34.1 ± 21.31 cmh2o 101.1 ± 40.02 cmh2o bladder contractility index (pdetqmax + 5qmax) 48.8 ± 27.21 132.5 ± 37.83 a-g number (pdetqmax –2qmax) 20.0 ± 8.82 88.0 ± 40.69 55archivio italiano di urologia e andrologia 2022; 94, 1 non-invasive diagnosis of underactive bladder gen/muscle ratio, changes in muscarinic receptors, as determined by ultrastructural studies by electron microscopy (10). bo secondary to benign prostatic hyperplasia is well known to increase with age. clinical features and prognosis of ub are not clearly defined and any diagnostic method has not been developed but the gold standard of urodynamics. its prevalence in the elderly population is unclear (11). diagnosis of bo with urodynamic testing has been shown to increase success rate of transurethral resection of the prostate. up to date, many studies emphasized the need for urodynamic diagnosis of bo to define three different conditions as obstructive, intermediate and non-obstructive (12). these studies are mostly based on post-operative observations of the patients who underwent an operation for bo having previously had a tur-p. pdet/qmax values decreased postopeartively in the obstructive group, decreased insignificantly in the equivocal group and remained unchanged in the non-obstructive group (13, 14, 15). ub and bo present with the same clinical symptoms and uroflowmetric findings although they are totally opposite clinical entities requiring completely different treatment. surgery is usually the treatment of choice for bo, while it is rather unusual for ub, where medical treatment (cholinergic agonists, cholinesterase inhibitors, etc.), clean intermittent catheterization and conservative approach are more prominent. urodynamic testing, which is the gold standard method, is an invasive diagnostic method used for differential diagnosis in these two clinical entities. in this context, in order to differentiate between these two types of clinical conditions, we attempted to use the non-invasive ve parameter for differential diagnosis. to the best of our knowledge, such a study has not been performed so far. ve was defined for the first time by abrams in 1979 as a measure of bladder contractility against urethral resistance and presented as a percentage figure representing the degree of bladder emptying (13). subsequent studies of abrams developed a combination nomogram of 6 groups according to the bci and the boi. they noted that including ve to this nomogram would be more appropriate to decide both surgical and medical treatment modalities and to interpret the progression of the disease. in 1995, bosch has evaluated the correlation and variation of this percentage value with aging, bladder contractility and urethral resistance (16), but voiding efficiency was calculated after urodynamic testing and was not utilized as a differential diagnostic tool. a korean study evaluated relationship between clinical pictures of ub and bo with age and gender, and reported higher prevalance of ub with aging when compared to bo in the male group, whereas an inverse relationship was observed for the female group that showed higher increase of bo prevalence with age compared to ub (3). in our study, which included only male patients, age was higher in the ub group compared to the bo group. according to the korean study, ub group displayed an accelerated increase with age compared to bo group. patients over 85 years of age constituted 40% of the ub group and 26% of the bo group. interestingly, bo showed a decrease after the age of 75 (figure 1). we explain this finding as some kind of compensation caused by bo as the result of an increased effort against increased resistance preventing ub development at advanced ages. in accordance with this explanation, a decreased ub incidence and an increased bo incidence was shown among female aged over 75 years in the korean study (3). additionally, we think ub has a closer correlation with aging bevause bo pathogenesis is multifactorial. our patients in the ub group displayed higher values for voided volume, total voiding time and ve percentage than those in the bo group. average values for ve were 66.02 ± 2.43% and 45.53 ± 2.63% (p < 0.001) for the patients of ub and bo group, respectively. to conclude, patients in the ub group voided larger volumes in longer time periods and more efficiently. even if not exactly the same as in our study, in the study by bosch et al., the relationship of ve with age, urethral resistance and bladder contractility were evaluated and a closer and directly proportional relationship was determined between urethral resistance and ve (16). a nomogram with the ve values was developed in the study by bosch et al. suggesting its use for analysing potential future retention risks of these patients in the future, although longterm results were not obtained in this study. unlike our study, bosch et al. measured post-voidal residual urine volume by catheterization. they checked if the bladder was completely emptied or not by instilling an opaque material obtaining much more realistic values, although the measurements were performed just after the pressureflow studies. in our study ve was used for differential diagnosis between ub and bo achieving statistically significant difference. abrams et al. developed a nomogram divided into 9 separate columns according to qmax and pdet/qmax values obtained by flowmetric measurements to estimate whether medical, surgical or conservative approach is needed. it was also mentioned that addition of ve to this nomogram would provide a stronger estimation of correlations (13). it is apparent that voiding time increases with increased voided volume for ub and bo groups, having equal average flow rates in the uroflowmetric measurements. voided volume was found considerably higher in the ub group. we realized that our patients in the ub group had larger bladder capacity, which is the main factor affecting voided volume and voiding time. in a different way, it can be stated that patients with bo have smaller bladder capacity and thus void in lesser volumes and for shorter time. a limitation of our study may be not having examined boi between 20 to 40 and using a cut-off of 40 (ag-number) as in the korean study. conclusions in this retrospective study on 93 male patients, we intended to develop an alternative non-invasive diagnostic tool instead of invasive pressure-flow testing, which is recognized as the gold standard for differential diagnosis between ub and bo patients presenting with identical clinical pictures. in conclusion, ub can be diagnosed with at least 93% sensitivity and 60% specificity in men over the age of 80, with uroflowmetry measurment showing a archivio italiano di urologia e andrologia 2022; 94, 1 mehmet yoldas 56 46% voiding efficiency. however, long-term prospective studies with larger populations are obviously needed in the follow-up of these patients to evaluate retention and upper urinary tract involvement rates. references 1. chapple cr, osman ni, birder l, et al. the underactive bladder: a new clinical concept? eur urol. 2015; 68:351-3. 2. thomas aw, cannon a, bartlett e, et al.the natural history of lower urinary tract dysfunction in men: minimum 10-year urodynamic follow-up of untreated detrusor underactivity. bju int. 2005; 96:1295. 3. jeong sj, kim hj, lee yj, et al. prevalence and clinical features of detrusor underactivity among elderly with lower urinary tract symptoms: a comparison between men and women. korean j urol. 2012; 53:342. 4. han dh, jeong ys, choo ms, et al. the efficacy of trans urethral resection of the prostate in the patients with weak bladder contractility index. urology. 2008; 71:657. 5. thomas aw, cannon a, bartlett e, et al. the natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on 23 the outcom eafter trans urethral resection of the prostate with a minimum 10-year urodynamic follow-up. bju int. 2004; 93:745. 6. hakenberg ow, ryall rl, langlois sl, marshall vr. the estimation of bladder volume by sonocystography. j urol. 1983; 130:249-51. 7. schafer w, abrams p, liao l, et al. good urodynamic practices: uroflowmetry, filling cystometry,and pressure-flow studies. neurourol urodyn. 2002; 21:261. 8. abrams p. bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. bju int. 1999; 84:14. 9tubaro a, la vecchia c. uroscreening study group. the relation of lower urinary tract symptoms with life style factors and objective measures of benign prostatic enlargementand obstruction:an italian survey. eur urol. 2004; 45:767. 10. hotta h, morrison jf, sato a, et al. the effects of aging on the rat bladder and its innervation. jpn j physiol. 1995; 45:823. 11. taylor ja 3rd, kuchel ga. detrusor underactivity: clinical features and pathogenesis of an underdiagnosed geriatric condition. j am geriatr soc. 2006; 54:1920-32. 12. abrams p, buzelin jm, griffiths d, et al. the urodynamic assessment of lower urinary tract symptoms. proceedings of the 4th international consultation of benign prostatic hyperplasia (bph) 1997. edited by denis l, griffiths k, khoury s, et al. plymouth: plymbridge distributors. 1998; 323-77. 13. abrams p, griffiths d. the assessment of prostatic obstruction from urodynamic measurements and from residual urine. br j urol. 1979; 51:129. 14. schafer w. basic principles and clinical application of advanced analysis of bladder voiding function. urol clin n am. 1990; 17:553. 15. griffiths dj, vanmastrigt r, bosch r. quantification of urethral resistance and bladder function during voiding, to the with special reference to the effects of prostate size reduction on urethral obstruction due to benign prostatic hyperplasia. neurourol urodyn. 1989; 8:29. 16. bosch jlhr, kranse r, vanmastrigt r, et al dependence of male voiding efficiency on age, bladder contractility and urethral resistance: development of a voiding efficiency nomogram. j urol. 1995; 154:190. correspondence mehmet yoldas, md (corresponding author) yoldas_2297@hotmail.com tepecik training and research hospital urology clinic, izmir, turkey stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12228 1 original paper prostate volume and the post-voiding residual urine (1). transurethral resection of the prostate (turp) has been the milestone surgical option for bph for many years despite the relatively high complication rates observed in patients with enormous prostatic volume (2). in the last decades, however, endoscopic enucleation of the prostate (eep) techniques have been rapidly developed and implemented into the urological armamentarium. the main idea was to adjust the open procedure to the endoscopic approach. in addition, eep techniques have been associated with improved outcomes in terms of the removed percentage of prostatic volume as well as minimized surgical intervention (3). although eep techniques evolved as a promising alternative to conventional turp, they seem to show a steeper learning curve. according to current literature, the completion of the learning curve needs the performance of 40 to 60 cases (4). apart from the development of endoscopic surgical techniques, the simultaneous evolution of laser technology and laser devices has also played an important role in the expansion of eep (5). the rapid development of the established holmium: yttrium-aluminum-garnet (ho: yag) laser was followed by the integration of the thulium fiber laser (tfl). tfl produces a wavelength of 1940 nm, while the penetration depth is 0.077 mm. the pulse energy ranges from 0.025 to 6 j, and the frequency may reach up to 2400 hz (6). these technical aspects show a laser with a precise cutting function, which is convenient for the handling of soft tissues. this fact is also confirmed by experimental studies showing that tfl is associated with higher efficiency and safer profile in tissue application compared to ho: yag (7). consequently, tfl has recently been widely integrated into eep techniques (thuflep). the aim of the current study is to present our initial experience and early outcomes of thuflep with the use of thefiberdust™ (quanta system, samarate, italy) in patients with bph. materials and methods the current study is a retrospective single-center study conducted at the urology department of the university purpose: the aim of the present, retrospective study was to describe our initial experience and early outcomes of thulium fiber laser enucleation of the prostate (thuflep) with the use of the fiberdust™ (quanta system, samarate, italy) in patients with benign prostate hyperplasia. methods: from june 2022 to april 2023, all patients who underwent endoscopic enucleation of the prostate at urology department of the university hospital of patras were included. a single surgeon utilizing the same standardized operative technique performed all the surgeries. the primary endpoints included the uneventful completion of the operation, the surgical time and any minor or major complication observed intraor post-operatively. results: twenty patients with benign prostate hyperplasia were treated with thuflep. all the surgeries were completed successfully and uneventfully. the enucleation phase of the operation was completed in a mean time of 45 ± 9.1 min, while the average time needed for the morcellation was 17.65 ± 3.42 min. no significant complications were observed intraor post-operatively. the average hemoglobin drop was calculated to be 0.94 ± 0.71 g/dl. conclusions: all the operations were successfully and efficiently completed with the use of the fiberdust™ (quanta system, samarate, italy) in thuflep. significant blood loss or major complications were not observed. key words: benign prostatic hyperplasia; enucleation; prostate; thuflep; thulium. submitted 23 december 2023; accepted 27 december 2023 introduction lower urinary tract symptoms (luts) constitute a major concern for many men over 50 years old. the symptoms may usually be caused by the presence of enlarged prostatic adenomas, a condition known as benign prostatic hyperplasia (bph). bph constitutes a major healthcare burden, affecting almost one out of four men in their lifetime (1). the treatment options include both conservative and surgical approaches. treatment decision-making process is based on the grade of the symptoms, the renal function, the endoscopic enucleation of the prostate with thulium fiber laser (thuflep). a retrospective single-center study angelis peteinaris 1*, vasileios tatanis 1*, paraskevi katsakiori 1, theodoros spinos 1, solon faitatziadis 1, kristiana gkeka 1, anastasios natsos 1, theofanis vrettos 2, evangelos liatsikos 1, 3, panagiotis kallidonis 1 1 department of urology, university of patras, patras, greece; 2 department of anesthesiology and icu, university of patras, patras, greece; 3 department of urology, medical university of vienna, vienna, austria. * the authors contributed equally to the study. doi: 10.4081/aiua.2024.12228 summary archivio italiano di urologia e andrologia 2024; 96(1):12228 a. peteinaris, v. tatanis, p. katsakiori, et al. 2 hospital of patras. the study was approved by the institutional ethics committee. informed consent was obtained from all the participants. study design from june 2022 to april 2023, all patients with bph treated at our department with thuflep using the fiberdust™ (quanta system, samarate, italy) were included in the study. a single expert surgeon with experience in eep techniques conducted all the surgeries and the follow-up management of the participants. patients with prostatic volume under 80 cm3, serious coagulation disorders, neurogenic bladder, concomitant bladder stones, or a history of urethral strictures were excluded from the study. data collection the preoperative patients’ data included age, height, weight, and body mass index (bmi). the preoperative use of alpha-1 adrenoreceptor antagonists (a-blocker) and 5-alpha reductase inhibitors (5-ari) was recorded as well as the history of acute urinary retention (aur) or permanent catheterization. all patients underwent abdominal ultrasound for the estimation of the prostate volume, uroflowmetry for the evaluation of the maximum flowrate (qmax) and blood exams for the investigation of hemoglobin (hgb) level. the international prostate symptom score (ipss) was used for the evaluation of symptoms’ severity. the perioperative data included the record of enucleation and morcellation time as well as the presence of intraand postoperative complications. the volume of enucleated prostatic adenoma was estimated based on the histopathological report. postoperatively, all patients underwent blood exams on the first post-operative day and afterwards in case any complication occurred. the catheter removal was scheduled on the first postoperative day if no hematuria was present and a trial without catheter (twoc) was performed. surgical technique the surgical approach used was based on the description of the en bloc enucleation of the prostate by saitta et al. (8). the patient was placed in lithotomy position under general or epidural anesthesia. the irrigation bags were placed 1 m above the surgical table. cefuroxime was administered intravenously 1-hour preoperatively and afterward, twice a day during hospitalization. urethrocystoscopy with the use of a resectoscope (karl storz se & co. kg, tuttlingen, germany) was conducted for the observation of the anatomical landmarks, the sphincter limits, the ureteral orifices and their distance from the adenoma and the possibility of any pathological finding in the urethral lumen and the bladder. the power settings used were 60 w (2jx30hz). minor differentiations were used in a few cases with harder tissue and/or persistent hemorrhage. the diameter of the laser fiber used was 550 μm. the initial incision was a marking of the external sphincter connecting 11 and 1 o’clock. a second incision between the fifth and seventh hour was conducted alongside the verumontanum. the next step was the connection of these initial incisions, aiming at the demarcation of the sphincter from the prostate apex. the importance of minimization of mechanical stress and the activation of the laser for the gentle tissue dissection after the early apical release of the prostate should be underlined as it is believed to contribute to the postoperative continence maintenance. the gradual deepening of the incisions until the prostate capsule was crucial. after the capsule was observed, the dissection became circumferential respecting the plane of enucleation starting from 6 o’clock with direction to 12 o'clock (figure 1). the resectoscope was rotated for better placement of the laser fiber and avoidance of mechanical pressure for dissection. the same movements were followed for the gradual detachment of the adenoma. the proximal detachment of the prostate for the bladder entry was conducted through the anterior enucleation plane, followed by careful circumferential release of the adenoma. the ureteral orifices were reobserved before the final dissection of the prostate from the capsule near the bladder neck. the detached adenoma was then freely pushed into the bladder. meticulous hemostasis was conducted exclusively with the use of the laser with no need for additional electrocautery use. the importance of this step should be underlined as clear view is crucial for the uneventful morcellation process. the final step of the procedure was the replacement of the resectoscope with a 26 fr nephroscope (karl storz se & co. kg, tuttlingen, germany). for maximal irrigation conditions and prevention of bladder collapse during morcellation, the inflow of irrigation fluid was facilitated simultaneously through the inflow and outflow lumens of the nephroscope. the morcellator (quanta blade, quanta system, samarate, italy) was placed into the bladder through the working channel of the nephroscope. a 22 fr 3-way urethral catheter was placed into the bladder, and bladder irrigation was used at least until the patient returned to the department. figure 1. start of the prostate enucleation from 6 o’clock and circumferential development towards 12 o’clock. archivio italiano di urologia e andrologia 2024; 96(1):12228 3 endoscopic enucleation of the prostate with thulium fiber laser (thuflep) follow-up post-operative evaluation was performed 1, 3, 6 and 12 months after the surgery. the follow-up examination included the record of incontinence or additional symptoms, ultrasonography of the urinary tract as well as qmax and ipss measurement. the presence of incontinence was defined as the use of at least one pad per day. endpoints the successful completion of the surgeries, the duration of the procedures (divided into enucleation and morcellation time), the volume of enucleated prostate and the documentation of complications based on the claviendindo classification were the primary endpoints of the study (9). enucleation and morcellation time were defined as the time between the first and the last activation of the laser and the time between the first and the last activation of the morcellator, respectively. the secondary endpoints of the study were the hemoglobin decrease (the difference between the pre-operative and the last postoperative sample) and the differentiation of the qmax and ipss preand post-operatively (as postoperative qmax and ipss defined the values of the last follow-up). additionally, the catheterization and hospitalization duration as well as the presence of postoperative incontinence were also evaluated. statistical analysis all the quantitative data are presented as mean values and standard deviations, while the qualitative variables are presented as numbers and rates. results in total, 20 patients were included in the study. the mean follow-up was 10.2 ± 2.04 months. the participants had a mean age of 72.5 ± 6.4 years. the mean bmi was calculated to be 27.59 ± 3.53 kgr/m2. more specifically, the average height was 1.72 ± 0.08 m, while the mean weight was 81.1 ± 10.05 kg. in addition, the mean preoperative prostate volume as measured in the abdominal ultrasound was 112.75 ± 28.9 ml. preoperatively, nine (45%) and eleven (55%) patients used 5-ari and a-blocker, respectively. additionally, six (30%) patients had a prior history of aur, while seven (35%) patients were catheterized (table 1). the completion of all the procedures was successful without any intraoperative event. the mean time of enucleation was 45 ± 9.1 min. the average morcellation duration was calculated to be 17.65 ± 3.42 min. the mean hemoglobin decrease was 0.94 ± 0.71 g/dl (table 2). the average catheterization and hospitalization duration were 1.15 ± 0.37 and 1.7 ± 1.38 days, respectively. two patients presented persistent hematuria after the discontinuance of irrigation; thus, the catheterization was prolonged until the second postoperative day (claviendindo i). one patient presented postoperative aur without hematuria. the catheter was placed again, and twoc was successful during the second postoperative day (clavien-dindo i). finally, two patients presented with fever 12 hours postoperatively. the antibiotic regimen was not modified, and the twoc was not postponed and was performed successfully in both of them. nevertheless, the hospitalization was prolonged until they were fit for discharge (clavien-dindo i) (table 2). the mean volume of enucleated prostate was 76.85 ± 20.87 ml, while an average rate of 68.34 ± 11.43% of the prostate was enucleated. the mean preand post-operative qmax were 7.6 ± 3.35 ml/s and 21.75 ± 3.30 ml/s, respectively. the average increase of qmax was estimated to be 14.15 ± 4.43 ml/s. concerning ipss, the preand post-operative mean values were calculated to be 22.75 ± 2.22 and 9.2 ± 3.04, respectively. the average ipss decrease was 13.55 ± 3.9. one (5%) patient presented with incontinence (use of one pad daily) (table 3). table 1. demographic and preoperative data. variable outcomes age (mean ± sd) 72.5 ± 6.4 years height (mean ± sd) 1.72 ± 0.08 m weight (mean ± sd) 81.1 ± 10.05 kg bmi (mean ± sd) 27.59 ± 3.53 kg/m2 prostate volume (mean ± sd) 112.75 ± 28.9 ml 5-ari (n, %) 9 (45%) a-blocker (n, %) 11 (55%) aur (n, %) 6 (30%) permanent catheterization (n, %) 7 (35%) qmax (mean ± sd) 7.6 ± 3.35 ml/s ipss (mean ± sd) 22.75 ± 2.22 sd: standard deviation; bmi: body mass index; 5-ari: 5-alpha reductase inhibitor; a-blocker: alpha-1 adrenoreceptor antagonist; aur: acute urinary retention; qmax: maximum flow rate; ipss: international prostate symptom score. table 3. postoperative and functional outcomes. variable outcomes enucleated prostatic volume (mean ± sd) 76.85 ± 20.87 ml mean enucleation rate (mean ± sd) 68.34 ± 11.43% qmax increase (mean ± sd) 14.15 ± 4.43 ml/s ipss decrease (mean ± sd) 13.55 ± 3.9 incontinence (n, %) 1 (5%) sd: standard deviation; qmax: maximum flow rate; ipss: international prostate symptom score. table 2. intraand perioperative outcomes. variable outcomes enucleation time (mean ± sd) 45 ± 9.1 min morcellation time (mean ± sd) 17.65 ± 3.42 min hemoglobin drop (mean ± sd) 0.94 ± 0.71 g/dl catheterization duration (mean ± sd) 1.15 ± 0.37 days hospitalization duration (mean ± sd) 1.7 ± 1.38 days complications (n, %) 5 (25%) clavien-dindo i 5 (25%) clavien-dindo ii 0 (0%) clavien-dindo > ii 0 (0%) sd: standard deviation. archivio italiano di urologia e andrologia 2024; 96(1):12228 a. peteinaris, v. tatanis, p. katsakiori, et al. 4 discussion the wide adoption of lasers in the urological field is partially due to their great hemostatic properties (10). various laser devices and a plethora of surgical techniques’ modifications have gradually been developed and enriched the enucleation process, making it an appealing and efficient treatment option for bph. in this clinical retrospective study, we aimed to present our operative and functional outcomes. twenty thuflep procedures in patients with enlarged prostate glands (> 80 cm3) were performed. a sphincter preservation technique with a high-power laser device was adopted and modified. the surgeries were completed successfully. the enucleation and morcellation times were 45 ± 9.1 min and 17.65 ± 3.42 min, respectively. postoperatively no significant hemoglobin drop was detected. despite the reported complication rate of 25%, all of them were clavien-dindo i and consequently, the mean catheterization and hospitalization durations were not influenced. additionally, on average 68.34 ± 11.43% of the total prostatic volumes were enucleated while the postoperative functional outcomes were encouraging. fraundonfer and gilling described the first eep using laser, followed by morcellation in 1998, developing the enucleation technique described by hiraoka et al. (11, 12). the initial description of laser enucleation of the prostate was the 3-lobe detachment including 14 patients. lasers’ adaptation and rapid evolution played a major role in the implementation of multiple techniques and the gradual evolution of the original one (13). the early recognition and preservation of the sphincter and the easier development and safe dissection of the surgical plane have led to increased popularity of the en bloc technique. the enrichment of the technique with several modifications has also minimized the residual prostatic volume (8, 14). the latest addition and adjustment of tfl devices have significantly contributed to the wider eep implementation. one of the main advantages of tfl is the greater efficiency regarding the management of hemorrhage. this is partially because of the shallow tissue penetration and the pulsed wavelength delivery (15). nevertheless, holmium lasers have been widely used and investigated in terms of safety and efficiency for eep. the comparison between the two lasers has been the ground for many studies and discussions between surgeons and researchers. according to hartung et al., recent bibliography on eep suggests that both laser types are associated with great and comparable outcomes in terms of the luts improvement and the pattern of voiding characteristics after the surgery (16). in compliance with the structural function of tfl, hartung et al. noticed that holmium laser enucleation of the prostate (holep) was found to be partially inferior to thuflep regarding the postoperative incontinence rates and hemostasis. in their randomized controlled trial, enikeev et al. compared tfl and turp in terms of efficiency (17). the superiority of thuflep in terms of resection percentage, grade and frequency of complications and duration of hospital stay was demonstrated. the experience and convenience of the urologist as well as the availability of surgical means in each setting are the factors that determine the surgical treatment of bph. in the present clinical study, we presented our retrospectively collected data of 20 patients regarding the outcomes of thuflep using fiberdust™. a comparative study including 234 participants was published by pirola et al. (18). the researchers conducted a retrospective match-pair analysis, dividing the 234 patients’ sample into 117 participants who underwent holep and 117 who were treated with thulep for bph. the authors reported that the median enucleation time was 70 min (58.0-87.3 iqr) and 70.5 min (58-104 iqr) for the thulep and the holep group, respectively. in addition, they observed that the median morcellation time was 12.12 min (9.5-14.5 iqr) and 11.5 min (8-16 iqr) in the same groups. the current study revealed that the mean enucleation time was 45 ± 9.1 min, and the average morcellation duration was 17.65 ± 3.42 min. in addition, the holep group demonstrated an intraoperative complication rate of 5.7% and the thulep group 7%. the hemoglobin decrease was 0.9 g/dl (range: 0.3-1.67) and 0.5 g/dl (range: 0.3-1.1) for the holmium and the thulium groups, respectively. in the current study, no intraoperative complication was observed and the average hemoglobin decrease was 0.94 ± 0.71 g/dl. the followup evaluation (ipss, qmax and incontinence rates) presented similar results in the two studies. in addition, in the current one, it was calculated that 68.34 ± 11.43% of the adenoma was removed. a retrospective clinical study including 125 patients with prostate volume larger than 80 ml was conducted by chang et al. (19). the patients were treated with thulep by a single experienced surgeon. the authors reported that the mean prostate volume before surgery was 106.80 ± 45.77ml and it was reduced by about 74.17 ± 11.27% after the treatment. additionally, the authors demonstrated that ipss postoperatively was 7.35 ± 5.89 and qmax at the three-month follow-up was 23.20 ± 6.87ml/s. in the current study, the mean postoperative ipss and qmax were 9.2 ± 3.04 and 21.75 ± 3.30 ml/s, respectively. enikeef et al. demonstrated the efficiency of thuflep by conducting a retrospective study including 130 patients with prostate volume over 80 ml and comparing eep to open prostatectomy (20). similar operation duration but significantly less hospitalization in favor of eep were described. in addition, the incontinence rate was 1.1% for the thuflep group which is in agreement with our results. besides, a mean hemoglobin drop of 1 g/dl was demonstrated, while the catheter was successfully removed during the first 24 hours after the operation in 79% of the patients. the present study included 20 cases with bph treated with thuflep. nevertheless, the current study is not without limitations. firstly, the urologist who conducted all the procedures was an experienced surgeon, who specializes in eep and has conducted more than 100 cases before the initiation of the study. therefore, the learning curve could not be evaluated. additionally, the sample size was relatively small and further prospective studies with larger cohorts and longer follow-up are deemed necessary to confirm our findings. however, the objective of the study was to present our initial experience and patients’ outcomes with the thuflep in bph. the advantages of the enucleation technique have been thoroughly analyzed and a promising trend in outcomes has been revealed. archivio italiano di urologia e andrologia 2024; 96(1):12228 5 endoscopic enucleation of the prostate with thulium fiber laser (thuflep) conclusions we presented the surgical and early functional outcomes of thuflep with the use of fiberdust™ (quanta system, samarate, italy) in patients with bph. all the cases were successfully completed without intraoperative complications, major postoperative complications, or significant blood loss. the functional outcomes reported are in agreement with the current literature. references 1. lee swh, chan emc, lai yk. the global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. sci rep 2017; 7:7984. 2. cornu jn, ahyai s, bachmann a, et al. a systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. eur urol 2015; 67:1066-96. 3. elzayat ea, elhilali mm. holmium laser enucleation of the prostate (holep): long-term results, reoperation rate, and possible impact of the learning curve. eur urol 2007; 52:1465-71. 4. brunckhorst o, ahmed k, nehikhare o, et al. evaluation of the learning curve for holmium laser enucleation of the prostate using multiple outcome measures. urology 2015; 86:824-9. 5. nair sm, pimentel ma, gilling pj. a review of laser treatment for symptomatic bph (benign prostatic hyperplasia). curr urol rep 2016; 17:45. 6. denstedt j, gabrigna berto fc. thulium fiber laser lithotripsy: is it living up to the hype? asian j urol 2023; 10:289-97. 7. doizi s, germain t, panthier f, et al. comparison of holmium:yag and thulium fiber lasers on soft tissue: an ex vivo study. j endourol 2022; 36:251-8. 8. saitta g, becerra jea, del álamo jf, et al. 'en bloc' holep with early apical release in men with benign prostatic hyperplasia. world j urol 2019; 37:2451-8. 9. pan tt, li sq, dai y, qi jx. observation of complications assessed by clavien-dindo classification in different endoscopic procedures of benign prostatic hyperplasia: an observational study. medicine 2023; 102:e32691. 10. katta n, santos d, mcelroy ab, et al. laser coagulation and hemostasis of large diameter blood vessels: effect of shear stress and flow velocity. sci rep 2022; 12:8375. 11. fraundorfer mr, gilling pj. holmium:yag laser enucleation of the prostate combined with mechanical morcellation: preliminary results. eur urol 1998; 33:69-72. 12. hiraoka y. a new method of prostatectomy, transurethral detachment and resection of benign prostatic hyperplasia. nihon ika daigaku zasshi. 1983; 50:896-8. 13. oh sj. current surgical techniques of enucleation in holmium laser enucleation of the prostate. invest clinl urol 2019; 60:333-42. 14. scoffone cm, cracco cm. the en-bloc no-touch holmium laser enucleation of the prostate (holep) technique. world j urol 2016; 34:1175-81. 15. schembri m, sahu j, aboumarzouk o, et al. thulium fiber laser: the new kid on the block. turk j urol 2020; 46:s1-s10. 16. hartung fo, kowalewski kf, von hardenberg j, et al. holmium versus thulium laser enucleation of the prostate: a systematic review and meta-analysis of randomized controlled trials. eur urol focus 2022; 8:545-54. 17. enikeev d, netsch c, rapoport l, et al. novel thulium fiber laser for endoscopic enucleation of the prostate: a prospective comparison with conventional transurethral resection of the prostate. iju 2019; 26:1138-43. 18. pirola gm, saredi g, codas duarte r, et al. holmium laser versus thulium laser enucleation of the prostate: a matched-pair analysis from two centers. ther adv urol 2018; 10:223-33. 19. chang c-h, lin t-p, huang j-y. safety and effectiveness of highpower thulium laser enucleation of the prostate in patients with glands larger than 80 ml. bmc urol 2019; 19:8. 20. enikeev d, okhunov z, rapoport l, et al. novel thulium fiber laser for enucleation of prostate: a retrospective comparison with open simple prostatectomy. j endourol 2019; 33:16-21. correspondence angelis peteinaris, md peteinarisaggelis@gmail.com vasileios tatanis, md (corresponding author) tatanisbas@gmail.com department of urology, university of patras medical school, rio, patras, 26500, greece paraskevi katsakiori, md vkatsak@upatras.gr theodoros spinos, md thspinos@otenet.gr solon faitatziadis, md solonasfait@gmail.com kristiana gkeka, md kristianagkeka@gmail.com anastasios natsos, md a.natsos@gmail.com panagiotis kallidonis, md pkallidonis@yahoo.com theofanis vrettos, md teovret@gmail.com department of anesthesiology and icu, university of patras, patras, greece evangelos liatsikos, md liatsikos@yahoo.com department of urology, medical university of vienna, vienna, austria conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4390 original paper no conflict of interest declared. introduction prostate cancer (pca) represents a major health problem as it is the second most commonly diagnosed malignancy among males leading to severe morbidity and mortality (1). pca presents a wide variety of clinical behavior ranging from tumors of low metastatic potential to highly aggressive tumors characterized by a high risk of biochemical failure and metastasis development after initial treatment (2). as several molecular pathways and oncogenes are involved in pca progression to lethal disease, understanding the genetic and molecular differences separating indolent from highly aggressive tumors is the cornerstone of risk stratification and selection of best treatment available. the pi3-k-akt molecular pathway, found to be upregulated in 30-50% of pca patients, regulates a variety of cellular function including cell survival and proliferation, cell growth and differentiation and cell cycle progression and metabolism (3). the phosphate and tensin homolog gene (pten), a tumor suppressor gene located on chromosome 10q23.3, is quite frequently mutated in pca patients and acts as a regulator of pi3-k-akt molecular pathway (4). erg oncogene (ets related gene) is a member of the ets gene family located in chromosome 21q22.2 (5). in 50% of pca patients erg is involved as a fusion protein with transmembrane protease, serine 2 (tmprss2), a protein encoded by tmprss2 gene located in 21q22.3 (6). although ets fusion is encountered early in the carcinogenesis process, the presence of the fusion protein is also associated with poorly differentiated tumors, higher stage disease as well as lymph node involvement (7). as far as it concerns the clinical impact of pten loss combined with the presence of ets fusion protein, both preclinical and clinical studies suggest that the co-existence of these aberrations may be indicative of poor prognosis (8). the aim of this study is to evaluate the clinical impact of pten loss and erg rearrangement in terms of oncologic results in patients diagnosed with localized pca who underwent radical prostatectomy. materials and methods data were collected in a prospective way from a total of 74 patients who underwent open radical retropubic objectives: phosphate and tensin homolog gene (pten) acts as a regulator of pi3-kakt molecular pathway. ets related gene (erg), an oncogene located in chromosome 21q22.2, is involved in prostate cancer (pca) by serine 2 (tmprss2), a protein encoded by tmprss2 gene. the aim of this study is to evaluate the clinical impact of pten loss and erg rearrangement in terms of oncologic results in patients diagnosed with localized pca who underwent radical prostatectomy. materials and methods: prospective data were collected from a total of 74 patients who underwent open radical retropubic prostatectomy for localized pca and immunohistochemical study was performed in tissue samples. the primary antibodies for anti-erg antibody as well as anti-pten antibody were obtained from dako. erg was considered positive if at least 20% of the evaluated cells were stained at least with medium intensity. pten protein loss was considered when the intensity of cytoplasmic and nuclear staining was mild or entirely negative across > 10% of tumor cells. results: homogenous loss of pten was associated with higher clinical international society of urological pathology (isup) grade (p = 0.018) while no statistical significant association was present regarding the presence of erg rearrangement with either isupc or isupp. after a median follow up of 34 months, 24 patients developed biochemical recurrence. no statistical significant correlation of erg status with biochemical recurrence was noted while pten was associated with biochemical recurrence development in a statistical significant way. lastly the combination of pten loss with erg rearrangement presence was detected more often in higher isupc and isupp as well as biochemical recurrence development, although in a non statistical significant way. conclusions: homogenous and heterogenous pten loss was associated with biochemical recurrence. no association of erg and biochemical recurrence was noted. the combination of pten loss and erg rearrangement presented a trend for higher isupc and isupp as well as biochemical recurrence but not in a statistical significant way. key words: erg; pten; prostate cancer; radical prostatectomy. submitted 18 july 2022; accepted 24 july 2022 clinical impact of erg and pten status in prostate cancer patients underwent radical prostatectomy charalampos fragkoulis 1, ioannis glykas 1, lazaros tzelves 2, panagiotis velissarios stamatakos 1, georgios papadopoulos 1, georgios stathouros 1, athanasios dellis 3, konstantinos ntoumas 1, akrivi kostopoulou 4, charalampos deliveliotis 2, athanasios papatsoris 2 1 department of urology, general hospital of athens “g. gennimatas”, athens, greece; 2 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece; 3 1st department of urology, school of medicine, laiko hospital, national and kapodistrian university of athens, athens, greece; 4 department of pathology, general hospital of athens “g. gennimatas”, athens, greece. doi: 10.4081/aiua.2022.4.390 summary 391archivio italiano di urologia e andrologia 2022; 94, 4 erg and pten status in prostate cancer prostatectomy for localized pca during the years 2017 and 2018. demographic information, psa levels at diagnosis and clinical tnm stage were recorded. all patients underwent bone scan and ct scan prior to surgery for staging purpose. patients with psa levels above 20 ng/dl were excluded from the study. histopathological examination of radical prostatectomy specimens defined the pathological stage, histopathological type as well as the gleason score. patients were followed up by psa testing every three months until biochemical recurrence defined as psa levels above 0.2 ng/dl. immunohistochemical study was performed in paraffinembedded formalin-fixed tissue samples. sections of 4mm were mounted on tomo slides and fixated in oven at 70-80°c, de-waxed in xylene and then underwent through decreasing concentrations of alcohol. for antierg antibody, the primary antibody was obtained from dako (flex monoclonal rabbit rabbit anti-human erg, clone ep111, ready-to-use). after heat-induced epitope retrieval and a ph9 buffer, the sections were incubated for 1h with the antibody and counterstained in hematoxylin. for anti-pten antibody, the primary antibody was obtained from dako [monoclonal mouse anti-human pten (concenctrate) clone 6h2.1]. after heat-induced epitope retrieval and ph9 buffer, the sections were incubated for 1h in 1:100 of the primary antibody, followed by 15min in linker. counterstain was performed with hematoxylin. erg was considered positive if at least 20% of the evaluated cells (neoplastic or with hgpin) were stained at least with medium intensity (figure 1). endothelial cells were used as positive control. a tissue sample was considered to have pten protein loss if the intensity of cytoplasmic and nuclear staining was mild or entirely negative across > 10% of tumor cells, compared with surrounding benign glands and/or stroma, used as positive controls for pten protein expression. if the neoplastic cells showed pten loss in 10-90% of neoplastic cells, it was considered heterogeneous pten protein loss. if neoplastic cells showed pten protein loss in > 90%, it was considered homogeneous pten loss. regarding statistical methodology, continuous variables were expressed using medians, minimum-maximum values and interquartile range, while categorical variables using numbers and proportions. fisher’s exact test or chi square test and kruskal-wallis test were used to analyze data, since after testing for distributions non-normality was detected. when a statistical significance was noted, pairwise comparisons were used to detect which exact groups differ. pairwise comparisons were performed whenever a statistical significance was detected, using the dunn’s procedure. statistical significance was set at p = 0.05. all analyses were done with ibm spss statistics 25.0 software (spss inc., chicago, il.). results median age was 70 years and median psa was 7.3 ng/dl. demographics as well as clinical and pathological isup grade and tnm stage are presented in table 1. pten status was defined as homologous loss in 15 patients, heterologous loss in 43 patients and as intact in 16 patients. erg rearrangement was present in 29 patients and absent in 45. in terms of correlation of pten status with isup grade, homogenous loss was associated with higher clinical isup grade (p = 0.018) while the medians of intact-homogeneous groups differed significantly for median isup pathology grade (p = 0.022) (table 2). on the other hand, no statistical significant association table 1. patients’ demographics. number of patients 74 age (median) 70 psa 7.3 ng/dl clinical isup (number of patients) 1 23 2 17 3 20 4 7 5 7 pathology isup (number of patients) 1 10 2 25 3 24 4 7 5 8 pathology tnm pt2 50 pt3a 14 pt3b 10 table 2. pten status correlation with isupc and isupp. median isupc median isupp homogeneous loss 3 3 heterogeneous loss 2 3 intact 1 2 p-value 0.018 * 0.022 ** * using kruskall-wallis h test, the medians of intact-homogeneous groups differed significantly for median isupc grade. ** using kruskall-wallis h test, the medians of intact-homogeneous groups differed significantly for median isupp grade. figure 1. positive erg staining using anti-human erg antibody. archivio italiano di urologia e andrologia 2022; 94, 4 c. fragkoulis, i. glykas, l. tzelves, et al. 392 was present regarding the presence of erg rearrangement with either isupc or isupp (table3). after a median follow up of 34 months, 24 patients developed biochemical recurrence defined as psa levels above 0.2 ng/dl. no statistical significant correlation of erg status with biochemical recurrence was noted (table 4). on the other hand, both homogenous and heterogenous loss was associated with biochemical recurrence development in a statistically significant way (table 5). as far as it concerns the combination of pten loss with erg rearrangement presence, a trend in higher isupc and isupp as well as biochemical recurrence development was detected, although in a non-statistical significant way. among patients who presented with combined pten homogenous loss and erg rearrangement, 56% presented with biochemical recurrence during follow up. the combination of pten homogenous loss combined with no erg rearrangement also presented high rates of biochemical failure (66%). nevertheless, this group consisted only of 6 patients, thus no strong evidence could be extracted regarding this combination. discussion it is nowadays well established that pca is a disease presented with a wide clinical heterogeneity. spectrum includes from indolent tumors of low clinical significance to highly aggressive tumors of high probability of biochemical recurrence after local treatment as well as severe metastatic potential. currently, risk stratification for biochemical recurrence development after radical prostatectomy for patients with localized disease stratifies patients into three groups based on psa, gleason score and tnm status (9). to further stratify patients according to molecular and genetic profile, it is of great interest to develop novel markers based in the genomic instability characterized by activation of oncogenes or deactivation of tumor suppressor genes. pten is a tumor suppressor gene located in chromosome 12q23.3 acting as a regulator of the pi3-k-akt molecular pathway (4). the pi3-k-akt pathway, frequently upregulated in pca patients, is an important intracellular molecular pathway regulating crucial cellular functions including cell proliferation, growth, differentiation, cell cycle progression, metabolism and survival (3). several growth factors including epidermal growth factor (egf), platelet derived growth factor (pdgf) and insulin like growth factor (igf) initiate the activation of the pi3-k-akt pathway by activating tyrosine kinase receptors promoting the phosphorylation of pi3k at the cell membrane level. phosphorylated pi3k becomes active and promotes the conversion of pip2 to pip3. this event leads to the phosphorylation of akt mediated by pdk1 (10). akt plays an important role in carcinogenesis and tumor progression mainly by interfering with antiapoptotic pathways (11). moreover, it may influence the activity of tumor suppressor gene p53 (12). akt also interacts with the androgen receptor promoting nuclear translocation in an androgen independent manner (13). activated akt has also a profound role in carcinogenesis by promoting cell growth and protein synthesis through the regulation of the mammalian target of rapamycin (mtor) pathway (14). pten suppressor gene protein product is a dual lipid phosphatase which acts as a negative regulator of the pi3-kakt pathway. pten protein removes the 3-phosphatase from pip3 converting it back to pip2 thus inhibiting the phosphorylation of akt (4, 10). in addition, genomic stability is also influenced by pten protein through involvement with the mapk signaling network which affects both directly and indirectly the androgen receptor activity (14). since pten is the most commonly tumor suppressor gene mutated in pca, pten loss may act as a prognostic marker associated with poor oncological outcomes and may facilitate the selection of patients who are more likely to benefit from intensive definite treatment modalities (15). pten mutations are more frequently encountered in metastasis providing further evidence that pten loss is associated with the disease progression (16). more specifically, pten deletion is associated with higher disease stage among patients with gleason score 7 (17). a metaanalysis involving 26 published studies with a total of 8097 patients presented that intact pten status results in less aggressive disease and lower gleason score (18). results from a multicenter analysis support that pten deletion is strongly associated with seminal vesicle involvement as well as extracapsular extension (19). furthermore, homologous, and heterologous pten loss is associated with greater risk of biochemical recurrence compared with no pten loss (20, 21). in a meta-analysis including 2,154 cases with positive expression of pten and 1.006 pten deletion cases, pten positive expression was associated with prolonged biochemical free survival (22). nevertheless, patients with homologous pten loss present worst prognosis in terms of biochemical free survival (23). lotan et al., presented data supporting that only homologous pten loss is associated with worst biotable 3. erg status and correlation with isupc and isupp. median isupc median isupp erg (+) 2 3 erg (-) 2 3 p-value 0.836 0.993 table 4. biochemical recurrence and erg status (chi-square test). no biochemical recurrence biochemical recurrence p-value (%) (%) negative erg 29 (64.4) 16 (35.6) 0.475 positive erg 21 (72.4) 8 (27.6) table 5. biochemical recurrence and pten status (chi-square test). no biochemical recurrence biochemical recurrence p-value (%) (%) heterogeneous loss 31 (72.1) 12(27.9) 0.031 homogeneous loss 6 (40) 9 (60) intact 13 (81.3) 3 (18.7) 393archivio italiano di urologia e andrologia 2022; 94, 4 erg and pten status in prostate cancer chemical free survival, while heterogenous loss has the same impact as pten intact status (24). as far as it concerns lymph node involvement, it is more frequently encountered in patients with pten deletion (25). ets related gene (erg) is an oncogene member of the ets gene family located in chromosome 21q22.5. it encodes erg protein which is involved in pca carcinogenesis and progression as a fusion protein with transmembrane protease, serine 2 (tmprss2), a protein encoded by tmprss2 gene located in 21q22.3 (5, 6). tmprss2:erg fusion is the most common ets family rearrangement and is detected in 50% of pca patients (26). such rearrangement leads to neoplastic phenotype by overexpressing transcription factors which are important from the first step of carcinogenesis (27). erg rearrangement is encountered rarely in indolent pca tumors and it is usually associated with more advanced stage with either extracapsular extension or seminal vesicles involvement (28, 29). furthermore, it presents an independent prognostic value regarding both biochemical and clinical recurrence, especially among grade group 4 or 5 patients (30). among patients with localized pca treated with radical prostatectomy, tmprss2-erg fusion was associated with higher tumor stage but not with other oncological parameters (31). on the other hand, lee et al. demonstrated that positive erg status is frequently present among patients with perineural invasion or positive apical margins (32). quite interesting is the fact that erg status among pca patients is characterized by racial disparities. highest frequencies of erg rearrangements are encountered among caucasian descents, lower frequencies among african americans and even lower prevalence among asian men. in asian cohorts, erg positive status was more frequent in low gleason score and low stage patients in contrast with western cohorts (33). as tmprss2-erg fusion is not a frequent genomic alteration among asian pca patients it has limited significance in clinical practices in asian populations (34). in a metaanalysis including 6744 patients, liu et al. conclude that erg status is not correlated with biochemical free survival or recurrence free survival (35). in non-surgical cohorts, erg expression is associated with advanced stage, higher probability of metastasis as well as increased mortality (36). as far as it concerns immunohistochemistry as a method of pten and erg status evaluation, the technique presents 100% sensitivity and 97.8% specificity for detecting pten genomic alterations (37). although most studies use fish in order to detect pten alterations, immunohistochemistry using commercially available antibodies is a validated method with similar results as high concordance is present between the two methods (38, 39). characterization of erg status by immunohistochemistry in prostate tissue has also an excellent correlation with fish and is validated method to be used in clinical practice (40). erg fusion protein is often accompanied by pten loss, a condition which further up regulates the akt pathway leading to more aggressive cancer progression (41). early in the carcinogenesis process, pten loss and subsequent low pten protein results in genomic instability. such instability may provoke erg fusion and thus a synergistic action in akt pathway leading to poor prognosis (10, 41). regarding the relationship between pten and erg status in terms of oncological results, brady et al. presented that combined loss of pten with negative erg expression leads to a trend over immediate recurrence after surgery but not in a statistically significant way (42). on the other hand, mehra et al. concluded that patients who exhibited erg rearrangement and loss of pten had no significant difference in time to recurrence compared to patients with wild-type erg and loss of pten (21). a proposed method for risk stratification in a non-surgical cohort including patients treated with androgen deprivation therapy suggests that worst clinical outcome is among patients with decreased pten intensity without erg positivity. patients with positive erg expression presented intermediate risk for lethal disease regardless pten status (43). in an analysis of 80 pca patients no patient with low grade disease bared concurrent tmprss2-erg fusion and pten loss (44). in a large radical prostatectomy cohort including 815 patients, loss of pten in erg negative patients was predictive of secondary therapies as well as shorter disease specific survival (45). it is quite clear that although great interest exists in determining the role of combined pten status with erg fusion no solid conclusions can be made as data remain conflicting (46, 47). to our knowledge this is the first study evaluating the role of individual pten and erg status and their possible combination regarding oncological results in men who underwent radical prostatectomy. disadvantages of the present study include the relatively low sample which underpowered statistical analysis and the fact that pten and erg status was examined only by immunohistochemistry and not by fish. conclusions homogenous and heterogenous pten loss was associated with biochemical recurrence in pca patients treated with radical prostatectomy. no association of erg status and biochemical recurrence was noted. the combination of pten loss and erg 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gao t, mei y, sun h, et al. the association of phosphatase and tensin homolog (pten) deletion and prostate cancer risk: a metaanalysis. biomed pharmacother. 2016; 83:114-121. 19. troyer da, jamaspishvili t, wei w, et al. a multicenter study shows pten deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer. prostate. 2015; 75:1206-15. 20. jamaspishvili t, patel pg, niu y, et al. risk stratification of prostate cancer through quantitative assessment of pten loss (qpten). j natl cancer inst. 2020; 112:1098-1104. 21. mehra r, salami ss, lonigro r, et al. association of erg/pten status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. med oncol. 2018; 35:152. 22. xie h, xie b, liu c, wang j, xu y. association of pten expression with biochemical recurrence in prostate cancer: results based on previous reports. onco targets ther. 2017; 10:5089-5097. 23. geybels ms, fang m, wright jl, et al. pten loss is associated with prostate cancer recurrence and alterations in tumor dna methylation profiles. oncotarget. 2017; 8:84338-84348. 24. lotan tl, wei w, morais cl, et al. pten loss as determined by clinical-grade immunohistochemistry assay is associated with worse recurrence-free survival in prostate cancer. eur urol focus. 2016; 2:180-188. 25. switlyk md, salberg ub, geier om, et al. pten expression in prostate cancer: relationship with clinicopathologic features and multiparametric mri findings. ajr am j roentgenol. 2019; 19:1-9. 26. pettersson a, graff re, bauer sr, et al. the tmprss2:erg rearrangement, erg expression, and prostate cancer outcomes: a cohort study and meta-analysis. cancer epidemiol biomarkers prev. 2012; 21:1497-509. 27. park k, tomlins sa, mudaliar km, et al. antibody-based detection of erg rearrangement-positive prostate cancer. neoplasia. 2010; 12:590-8. 28. krstanoski z, vokac nk, zagorac a, et al. tmprss2:erg gene aberrations may provide insight into pt stage in prostate cancer. bmc urol. 2016; 16:35. 29. fisher kw, zhang s, wang m, et al. tmprss2-erg gene fusion is rare compared to pten deletions in stage t1a prostate cancer. mol carcinog. 2017; 56:814-820. 30. kidd sg, bogaard m, carm kt, et al. in situ expression of erg protein in the context of tumor heterogeneity identifies prostate cancer patients with inferior prognosis. mol oncol. 2022; 16:2810-2822. 31. yılmaz ö, berber u, okçelik s, et al. tmprss2-erg gene fusion in turkish patients with localized prostate cancer: results of radical prostatectomy specimens. turk j urol. 2016; 42:60-3. 32. lee sr, choi yd, cho nh. association between pathologic factors and erg expression in prostate cancer: finding pivotal networking. j cancer res clin oncol. 2018; 144:1665-1683. 33. baohong j, sedarsky j, srivastava s, et al. erg tumor type is less frequent in high grade and high stage prostate cancers of chinese men. j cancer. 2019; 10:1991-1996. 34. kong dp, chen r, zhang cl, et al. prevalence and clinical application of tmprss2-erg fusion in asian prostate cancer patients: a large-sample study in chinese people and a systematic review. asian j androl. 2020; 22:200-207. 35. liu r, zhou j, xia s, li t. the impact of pten deletion and erg rearrangement on recurrence after treatment for prostate cancer: a systematic review and meta-analysis. clin transl oncol. 2020; 22:694702. 36. khosh kish e, choudhry m, gamallat y, et al. the expression of proto-oncogene ets-related gene (erg) plays a central role in the oncogenic mechanism involved in the development and progression of prostate cancer. int j mol sci. 2022; 23:4772. 37. lotan tl, gurel b, sutcliffe s, et al. pten protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. clin cancer res. 2011; 17:6563-73. 38. lotan tl, heumann a, rico sd, et al. pten loss detection in prostate cancer: comparison of pten immunohistochemistry and pten fish in a large retrospective prostatectomy cohort. oncotarget. 2017; 8:65566-65576. 39. lotan tl, wei w, ludkovski o, et al. analytic validation of a clinical-grade pten immunohistochemistry assay in prostate cancer by comparison with pten fish. mod pathol. 2016; 29:904-14. 40. navaei ah, walter ba, moreno v, et al. correlation between erg fusion protein and androgen receptor expression by immunohistochemistry in prostate, possible role in diagnosis and therapy. j cancer. 2017; 8:2604-2613. 41. squire ja. tmprss2-erg and pten loss in prostate cancer. nat genet. 2009; 41:509-10. 395archivio italiano di urologia e andrologia 2022; 94, 4 erg and pten status in prostate cancer 42. brady l, carlsson j, baird am, et al. correlation of integrated erg/pten assessment with biochemical recurrence in prostate cancer. cancer treat res commun. 2021; 29:100451. 43. bismar ta, hegazy s, feng z, et al. clinical utility of assessing pten and erg protein expression in prostate cancer patients: a proposed method for risk stratification. j cancer res clin oncol. 2018; 144:2117-2125. 44. hernández s, font-tello a, juanpere n, et al. concurrent tmprss2-erg and slc45a3-erg rearrangements plus pten loss are not found in low grade prostate cancer and define an aggressive tumor subset. prostate. 2016; 76:854-65. 45. lahdensuo k, erickson a, saarinen i, et al. loss of pten expression in erg-negative prostate cancer predicts secondary therapies and leads to shorter disease-specific survival time after radical prostatectomy. mod pathol. 2016; 29:1565-1574. 46. ullman d, dorn d, rais-bahrami s, gordetsky j. clinical utility and biologic implications of phosphatase and tensin homolog (pten) and ets-related gene (erg) in prostate cancer. urology. 2018; 113:59-70. 47. fragkoulis c, glykas i, dellis a, et al. clinical impact of combined pten and erg rearrangements in localized prostate cancer. arch ital urol androl. 2021; 93:84-85. correspondence charalampos fragkoulis, md harisfrag@yahoo.gr ioannis glykas, md giannis.glykas@gmail.com panagiotis velissarios stamatakos, md (corresponding author) pvstamatakos@gmail.com georgios papadopoulos, md gipapadopoulos@yahoo.gr georgios stathouros, md gstathouros@yahoo.gr konstantinos ntoumas, md ntoumask@yahoo.com department of urology, general hospital of athens “g. gennimatas”, athens (greece) lazaros tzelves, md lazarostzelves@gmail.com charalampos deliveliotis, md chdeliveli@gmail.com athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens (greece) athanasios dellis, md aedellis@gmail.com 1st department of urology, school of medicine, laiko hospital, national and kapodistrian university of athens, athens (greece) akrivi kostopoulou, md akrivikostopoulou@hotmail.com department of pathology, general hospital of athens “g. gennimatas”, athens (greece) cop+ed+fisse 2006 37archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. introduction benign prostatic hyperplasia (bph) represents one of the most common diseases in ageing men, affecting over 210 million men worldwide. up to 50% of men over 50 years experience lower urinary tract symptoms (luts) from bph, requiring medical or surgical therapy (1). although medical therapy could provide, in selected patients, satisfying results, the superior efficacy and cost-effectiveness of surgery have led more patients and physicians to prefer the surgical approach (2, 3). in addition, urinary retention, impaired renal function and dilatation of the upper urinary tract secondary to obstruction represents a strong indication toward a surgical approach (4). the european association of urology (eau) guidelines currently recommends, for prostate larger than 80 ml, simple prostatectomy, bipolar or monopolar enucleation or laser enucleation/vaporization of the prostate (5). before the introduction of minimally invasive techniques, as well as novel endoscopic laser approach, open simple prostatectomy (osp) was considered the gold standard treatment. despite favorable functional outcomes, which comprehend decreased symptoms score, increased flow and decreased post-void residual, osp is usually associated with substantial peri and postoperative complications (including prolonged catheterization time, increased estimated blood loss and length of hospital stay), reaching a morbidity rate of 42% and a transfusion rate of 24% (6). in order to overcome those limitations, a variety of minimally invasive surgical techniques have been explored to treat large obstructing prostate adenomas. since the first laparoscopic simple prostatectomy (lsp) described by mariano et al., the minimally invasive approach for bph has widely and quickly extended, up to include the robotic approach, the robot-assisted simple prostatectomy (rasp) (7, 8). minimal invasive simple prostatectomy, including laparoscopic or robot-assisted approach, presents similar efficacy and safety compared to osp, although data are still lacking and both procedures should be considered as under investigation (9, 10). the aim of our study was to compare peri and postoperative outcomes of rasp and lsp in two experienced centers. purpose: robotic-assisted simple prostatectomy (rasp) is a novel surgical procedure for the management of obstructive symptoms caused by enlarged prostate glands. before the introduction of minimally invasive techniques, the standard approach was the open simple prostatectomy (osp). the aim of our study was to compare intraoperative and perioperative outcomes of robotic (rasp) and laparoscopic (lsp) simple prostatectomy. methods: we retrospectively analyzed data from patients who underwent minimally invasive simple prostatectomy at the urological department of portogruaro hospital, portogruaro, and at the urological department of “san bassiano” hospital, in bassano del grappa, from march 2015 to december 2020. data collected from medical records included age, body mass index, prostate volume, operative time, preoperative international prostatic symptoms score (ipss), postoperative ipss, time with drainage, blood transfusion, intraoperative complications, perioperative complications and length of hospital stay. results: robotic-assisted (n = 25) and laparoscopic simple prostatectomy (n = 25) were performed with a transvesical approach. no significant differences were observed regarding baseline characteristics, body mass index, prostate volume and ipss. operative time was lower in the laparoscopic group (122 min vs 139 min) (p = 0.024), while hospital stay was lower in the robotic group (4 days vs 6 days) (p = 0.047). conclusions: robotic-assisted simple prostatectomy is a safe technique with results comparable to laparoscopic simple prostatectomy, encompassing the advantage of a shorter hospitalization. considering the costs and the limited availability of robotic-assisted simple prostatectomy, laparoscopic simple prostatectomy is a valid and safe alternative for experienced surgeons. key words: minimally invasive simple prostatectomy; benign prostatic hyperplasia; laparoscopy; robotic-assisted surgery. submitted 3 february 2022; accepted 9 february 2022 minimally invasive simple prostatectomy: robotic-assisted versus laparoscopy. a comparative study michele amenta 1, francesco oliva 1, biagio barone 2, alfio corsaro 1, davide arcaniolo 3, antonio scarpato 2, gennaro mattiello 2, lorenzo romano 2, carmine sciorio 4, tommaso silvestri 5, giovanni costa 5, felice crocetto 2, antonio celia 5 1 urology unit, azienda ulss n.4 veneto orientale, portogruaro, italy; 2 department of neuroscience, reproductive sciences and dentistry, university of naples federico ii, naples, italy; 3 department of woman, child and general and specialized surgery, urology unit, university of campania luigi vanvitelli, naples, italy; 4 unit of urology, asst manzoni, lecco, italy; 5 department of urology, san bassiano hospital, bassano del grappa, italy. doi: 10.4081/aiua.2022.1.37 summary archivio italiano di urologia e andrologia 2022; 94, 1 m. amenta, f. oliva, b. barone, et al. 38 methods consecutive patients who underwent minimally invasive prostatectomy from march 2015 to december 2020 at the urological department of portogruaro hospital, portogruaro, and urological department of “san bassiano” hospital, bassano del grappa, were retrospectively analyzed. no specific criteria were used to assign patients to either laparoscopic or robotic procedures. prostate volume was assessed by transrectal ultrasound (trus). all procedures, in both hospitals, were performed by an experienced surgeon as first operator. data collected from medical records were age, body mass index, prostate volume, surgical approach, operative time, blood loss, time with drainage, blood transfusions, intraoperative complications, pre and postoperative international prostate symptom score (ipss) (collected at least 6 months after surgery), perioperative complications and length of hospital stay. no patients underwent prior abdominal/pelvic surgery. laparoscopic simple prostatectomy after the induction of general anesthesia, the patient was positioned supine and in slight trendelenburg on the surgical table. the procedure was performed via transperitoneal approach. a skin incision was made at the umbilical level, entering the abdominal cavity using the hasson technique and inducing the pneumoperitoneum at 20 mmhg. five trocars were successively positioned, after the insertion of a 18 f urinary catheter. a 12-mm hasson trocar for the insertion of 0° optic was placed at the umbilical incision while another 12 mm trocar was positioned along the right margin of lateral rectus, a finger lower on umbilical line, for the insertion of the harmonic, monopolar scissors, or needle driver. a 5 mm trocar was positioned on the contralateral side (left margin of lateral rectus) for the insertion of a bipolar grasper or needle driver while a 12 mm trocar was placed laterally (8-10 cm from the umbilical trocar) on the right side. finally, a 5 mm trocar for the suction device was similarly positioned, contralaterally (figure 1). the fat covering the prostatic capsule was dissected, while bladder and prostate were identified by moving the urinary catheter. a longitudinal incision was performed approximately 1cm below the bladder neck. stay sutures were placed between the edges of the open bladder to skin on each side. ureteral ostia were consequently identified while harmonic was used for the exposure and development of the plane between the surgical prostate capsule and the adenomatous tissue, proceeding, bluntly, towards the prostatic apex. using the urinary catheter to facilitate the identification of nearby structures, the dissection proceeded until the whole adenomatous tissue has been freed, separating, carefully, the urethra. after the excision of the adenoma, the specimen was temporarily placed in the lateral prostatic fossa, waiting for further removal. trigonization was accomplished by two or four sutures of 2-0 vycril placed posteriorly to the bladder neck and to the internal posterior prostatic fossa. the urinary bladder catheter was then replaced with a 22f irrigation catheter. robotic-assisted simple prostatectomy camera port (12 mm) was placed in a midline supraumbilical position. a 12-mm assistant port was placed about 3 cm medially to the right iliac crest. on the lefthand side, an 8-mm robotic port, for the fourth arm, was inserted exactly in the corresponding position of the 12mm assistant port on the right side. two robotic 8-mm trocars were placed para-rectally on the leftand righthand sides in a more caudal position, at a distance of about 10 cm from the camera port. lastly, a 5-mm assistant port was placed midway between the camera port and the right robotic port. the procedure was then identical to the laparoscopic one (figure 2). statistical analysis descriptive statistics were reported as median and interquartile range (iqr) for continuous variables, while frequencies and percentages were obtained for categorical figure 1. trocar configuration for laparoscopic simple prostatectomy. figure 2. trocar configuration for robotic-assisted simple prostatectomy. 39archivio italiano di urologia e andrologia 2022; 94, 1 minimally invasive simple prostatectomy variables. according to the non-normality of data, assessed via the kolmogorov-smirnov test, mood’s median test was utilized, considering, as statistically significant, p < 0.05. statistical analysis was performed using ibm spss statistics® software (ibm corp. released 2017; ibm spss statistics for windows, version 25.0. armonk, ny). results 50 simple prostatectomies were performed with a minimally invasive approach. 25 were performed as lsp and 25 as rasp. all cases were successfully performed without proceeding to open surgery conversion and no patient repositioning or change in port assignment/redocking was needed. median age of patients involved was 71.5 (58-81) while median bmi was 25 (20-38) kg/m2. both groups were comparable in terms of age, bmi, prostate volume and preoperative ipss (table 1). regarding operative findings, both groups were comparable in terms of blood loss, transfusion rate and complications, albeit patients who underwent rasp reported a longer operative time (139 min; iqr 108225) compared to patients who underwent lsp (122 min; iqr 110-150) (p = 0.024). overall, median length of hospitalization was 5 days, with a slightly shorter hospitalization in rasp patients (4 days; iqr 3-6) compared to lsp patients (6 days; iqr 4-10) (p = 0.047). median drainage time was 4 days. all patients had urinary catheter until hospital discharge. five patients needed a transfusion, and four intraoperative complications were recorded. postoperative ipss score was comparable in both groups. discussion our results suggest that both laparoscopic and robotic prostatectomy can be associated with limited blood loss, short postoperative recovery, and low postoperative complications. compared to osp, those characteristics represent a clear advantage. osp is indeed a demanding procedure, associated with significant perioperative morbidity, that correlates with prostate volume, and blood loss (6). minimally invasive approaches as lsp and rasp allow minimizing blood losses due to different factors: the use of cauterizing instruments during the enucleation of the adenoma from the surgical capsule; the compressive effect of insufflation gas on vessels; the better visualization of bleeding points provided by a better view. the increased field of view associated with both techniques permit, indeed, to manage perioperative bleeding and avoid potentially serious complications as urethral injury, ostia injury or improper dissection plane. as result, the utilization of osp is steadily decreasing, in favor of minimally and endoscopic approaches, considering, in particular, comparative results in terms of functional outcomes (11-13). in addition, the use of a minimally invasive approach reduces operative time and length of hospital stay, although its cost-effectiveness is still controversial (14, 15). in our study, we sought to compare operative and functional outcomes of both minimally invasive approaches, lsp and rasp. despite both techniques could be performed via transperitoneal or extraperitoneal approach, in order to minimize potential biases and further considering our higher experience with the laparoscopic transperitoneal approach, both procedures were performed as transperitoneal (16). in addition, we performed in both techniques (lsp and rasp) a transvesical approach. the reason is related, partly to the higher experience with this technique, partly to the possibility of directly visualizing the prostatic adenoma, exploring the bladder and, more importantly, the bladder neck. a possible limitation of this approach, however, is related to the limited visualization of the apex and the potential difficulty in controlling bleeding compared to the retropubic (or millin) technique. the latter permit, indeed, to properly visualize the remnant adenoma and properly expose the prostate, allowing better control of bleeding (17). despite those differences, however, clinical outcomes are similar (18). although data are quite explicative, a few comments are interesting. as reported by our findings, lsp reported a shorter operative time compared to rasp. this could be related, however, to the time needed to dock and prepare the robot, consistently with data reported in the literature (19). similarly, blood loss and transfusion rates among both approaches were comparable, as well as complications rates (20). finally, the length of hospital stay was slightly favoring rasp and this could be explained by an improved field of view which permit to avoid unnecessary maneuvers on the gastrointestinal tract and, consequently, a faster recovery. anyway, this difference was quite clinically insignificant and could be also related to differences related to nonmedical factors. lastly, although we did not mainly consider the transurethral approach, it has to be acknowledged that the use of novel and powerful lasers which permit, safely and effectively, the enucleation of large prostatic adenomas, represents an important and feasible alternative to osp in minor centers which do not have the robotic-assisted surgery or enough experience with the laparoscopic approach. in particular, as reported by schiavina et al., with the same effectiveness in clinical outcomes, holmium laser enucleation of the prostate (holep) yielded significantly lower costs compared to osp (2174.15€ versus 4064.97€) (21). however, a relative limitation of holep is related to the necessity of performing at least 25-50 cases to achieve a significant efficacy in this approach (22). we are conscious of several limitations afflicting our study. firstly, the retrospective nature of our work. secondly, the table 1. baseline and perioperative outcomes. lsp n = 25 rasp n = 25 p age, years 72 (65–79) 71 (58–81) 0.572 bmi 25,5 (21–30) 25 (20–38) 0.776 prostate volume, ml 141 (100–210) 135 (94–245) 0.777 operative time, min 122 (110–150) 139 (108–225) 0.024 blood loss, ml 150 (100-500) 150 (50-250) 0.753 preop ipss 29.5 (23–35) 29 (22–32) 0.777 postop ipss 7 (3–9) 3 (2–7.25) 0.396 drainage time, days 5 (3–7) 5 (2–12) 0.396 blood transfusion 4 (16%) 1 (4%) 0.346 intraop complication 2 (8%) 2 (8%) 0.602 periop complication 2 (8%) 4 (16%) 0,663 lenght of hospital stay, days 6 (4–10) 4 (3–6) 0.047 archivio italiano di urologia e andrologia 2022; 94, 1 m. amenta, f. oliva, b. barone, et al. 40 limited sample size, partly explained by the limited use of robotic-assisted surgery for non-oncologic diseases. thirdly, the lack of a standardized follow-up and the potential differences 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front surg. 2021; 8:695318. 10. lucca i, shariat sf, hofbauer sl, klatte t. outcomes of minimally invasive simple prostatectomy for benign prostatic hyperplasia: a systematic review and meta-analysis. world j urol. 2015; 33:563-70. 11. pariser jj, pearce sm, patel sg, bales gt. national trends of simple prostatectomy for benign prostatic hyperplasia with an analysis of risk factors for adverse perioperative outcomes. urology. 2015; 86:721-6. 12. li j, cao d, peng l, et al. comparison between minimally invasive simple prostatectomy and open simple prostatectomy for large prostates: a systematic review and meta-analysis of comparative trials. j endourol 2019; 33:767-76. 13. esposito c, masieri l, castagnetti m, et al. letter to the editor: robot-assisted and minimally invasive pediatric surgery and urology during the covid-19 pandemic: a short literature review. j laparoendosc adv surg tech a. 2020; 30:915-8. 14. ahmed k, ibrahim a, wang tt, et al. assessing the cost effectiveness of robotics in urological surgery a systematic review. bju international. 2012; 110:1544-56. 15. demir a, günseren k, kordan y, et al. open vs laparoscopic simple prostatectomy: a comparison of initial outcomes and cost. j endourol. 2016; 30:884-9. 16. stolzenburg ju, kallidonis p, kyriazis i, et al. robot-assisted simple prostatectomy by an extraperitoneal approach. j endourol. 2018; 32:s39-s43. 17. noguera rs, rodríguez rc. open adenomectomy: past, present and future. curr opin urol. 2008; 18:34-40. 18. carneiro a, sakuramoto p, wroclawski ml, et al. open suprapubic versus retropubic prostatectomy in the treatment of benign prostatic hyperplasia during resident's learning curve: a randomized controlled trial. int braz j urol. 2016; 42:284-92. 19. pavan n, zargar h, sanchez-salas r, et al. robot-assisted versus standard laparoscopy for simple prostatectomy: multicenter comparative outcomes. urology. 2016; 91:104-10. 20. autorino r, zargar h, mariano mb, et al. perioperative outcomes of robotic and laparoscopic simple prostatectomy: a european-american multi-institutional analysis. eur urol. 2015; 68:86-94. 21. schiavina r, bianchi l, giampaoli m, et al. holmium laser prostatectomy in a tertiary italian center: a prospective cost analysis in comparison with bipolar turp and open prostatectomy. arch ital urol androl. 2020; 92:82-88. 22. gürlen g, karkin k. does holmium laser enucleation of the prostate (holep) still have a steep learning curve? our experience of 100 consecutive cases from turkey. arch ital urol androl. 2021; 93:412-7. correspondence michele amenta, md michele.amenta@aulss4.veneto.it francesco oliva, md francesco.oliva88@gmail.com alfio corsaro, md alfio.corsaro@aulss4.veneto.it urology unit, azienda ulss n.4 veneto orientale, portogruaro (italy) biagio barone, md (corresponding author) biagio.barone@unina.it antonio scarpato, md antonioscarpato1992@gmail.com gennaro mattiello, md drmattiellogennaro@gmail.com lorenzo romano, md loryromano@hotmail.it felice crocetto, md felice.crocetto@unina.it department of neuroscience, reproductive sciences and dentistry, university of naples federico ii, naples (italy) davide arcaniolo, md davide.arcaniolo@unicampania.it department of woman, child and general and specialized surgery, urology unit, university of campania luigi vanvitelli, naples (italy) carmine sciorio, md unit of urology, asst manzoni, lecco (italy) carmine.sciorio@gmail.com tommaso silvestri, md tommaso.silve@gmail.com giovanni costa, md gioc30@hotmail.it antonio celia, md antoniocelia@virgilio.it department of urology, san bassiano hospital, bassano del grappa (italy) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3356 original paper no conflict of interest declared. cells necrosis. emergency medical intervention is required, treated on a flaccid, non-painful state, to minimize potential irreversible consequences, such as corporal fibrosis and permanent erectile dysfunction (ed) (2-3). episodes lasting < 36 hrs may still respond to corporal blood aspiration and a-adrenergic agents, e.g. phenylephrine, unlike in delayed cases (> 72 h) that then often require surgical intervention, creating a permanent shunt between the cavernous bodies and the glans or the spongious urethra (4-5). it is intuitable that all patients affected by ischemic priapism lasting over 36 hours, have no chance to regain any erectile function (not even supported by drugs) (6). in the light of this, early penile prosthesis (pp) implantation in refractory ip has been proposed by some authors (1-7). actually, with the immediate pp insertion of either malleable and inflatable, can offer many advantages for these patients: resolving painful erection, providing sufficient rigidity for satisfactory intercourses, and counteracting inevitable penile shortening, which are cavernous fibrosis consequences (8, 9). moreover, the immediate implant of pp is easier to perform while, rather than if delayed which may be technically challenging, with higher complication rates and the need to implant downsized cylinders (9). in case of the acute pp insertion, the technical complexity of surgery, the cost-related issue and the possible unavailability of the devices in many centers or in emergency settings must be considered as critical points. in this study, we report our experience with the use of particular non-inflatable prosthesis, made of soft silicon (spp), in the surgical management of a refractory ip. patients and methods in this retrospective study, we identified men affected by ip attending our emergency department in a tertiary referral center from may 2017 to october 2019 who underwent early spp placement. the patient’s work-up consisted of: a) detailed medical history review for sickle cells disease, malignancy, hematological conditions such as thrombophilia or other hemoglobinopathies, assumption of pharmaceutical compounds or illicit drugs; b) general physical and andrologobjective: the aim of this study is to assess the management of refractory ischemic priapism (ip) by the immediate insertion of a soft penile prosthesis (spp). patients and methods: we identified men affected by ip who underwent early spp placement from may 2017 to october 2019. all patients underwent a detailed medical history review; intraoperative, postoperative features and adverse events were recorded. we evaluated the penile lengthening and bending, presence of complementary erection, ability to have sexual intercourse, postoperative sexual life satisfaction (international index of erectile function [iief] questionnaire question number 5). a cost-analysis was included. results: a total of six patients were identified. median time (range) since onset was 78 (48-108) hours with a mean age (sd) of 33 (6.9) years. median operative time (range) was 82 minutes (62-180). no complications were recorded. median follow-up was 9 months (range 3-17). no significant loss of penile length, neither penile angulation was recorded. despite a transient reduction of penile sensitivity, all patients reported satisfactory sexual intercourse (mean score question number 5 from iief-5 of 4). the cost of spp was € 1769,00 with a surgeryrelated reimbursement fee from the national health system of € 3856,75. conclusions: the insertion of a spp for patients with refractory ip results in immediate pain relief, preservation of sexual function and penile size, with a higher surgery reproducibility in an emergency. in addition to this, financial and resource burdens of ip on the health-care system can be potentially reduced. key words: priapism; soft tutors; penile prosthesis; virilis; ischemic priapism; early implantation. submitted 2 march 2021; accepted 20 april 2021 introduction ischemic priapism (ip) is a pathological condition presenting itself as a persistent erection marked by the rigidity of the corpora cavernosa with little or no cavernous arterial inflow accounting for more than 95% of all priapism episodes (1). beyond 4 hours, ip is considered a compartment syndrome which severely compromises cavernous circulation, leading to progressive destruction of cavernous sinusoids and consequently smooth muscle immediate insertion of a soft penile prosthesis as a new option for a safe and cost-effective treatment of refractory ischemic priapism franco palmisano 1, valerio vagnoni 2, alessandro franceschelli 2, giorgio gentile 2, fulvio colombo 2 1 asst fatebenefretalli-sacco, luigi sacco university hospital, department of urology, milan, italy; 2 andrology unit, department of urology and gynecology, sant’orsola university hospital, bologna, italy. doi: 10.4081/aiua.2021.3.356 summary 357archivio italiano di urologia e andrologia 2021; 93, 3 soft penile prosthesis treating ischemic priapism ical examination; c) comprehensive laboratory tests, including a complete blood count, white blood count with blood cell differential, platelet count, coagulation profile and fetal hemoglobin assessment; d) cavernosal blood sample for gas analysis. intraoperative, postoperative features and adverse events were recorded. follow-up was based on a standard internal protocol that consisted of scheduled re-evaluations, considering the following items: postoperative question number 5 from iief-5, the onset of penile bending (if any), presence of complementary erection, ability to have sexual intercourse, possible penile shortening and any troubles in genital sensitiveness. the healthcare-related costs of treatment were included in this analysis. this study was conducted according to the guidelines and principles of the declaration of helsinki and the standard ethical conduct of research involving humans; after the approval from the ethical committee for this clinical research, all patients signed an informed consent agreeing to supply their anonymous data for this and for future studies. surgical technique and technical considerations the spp insertion was performed by the same experienced surgical team. a longitudinal incision, along the scrotal raphe, is made 1 cm below the penoscrotal junction. a scott or lone-star retractor is helpful in maintaining the exposure. a traction stitch through the glans penis is mandatory to obtain adequate stretching of the cavernous bodies. after dissection of the dartos layer, the urethra is identified and laterally mobilized; a bilateral longitudinal corporotomy (at least 3 cm) is then performed on the ventral aspect of two corpora cavernosa. the use of blunt scissors within the corpora, under direct vision, helps to minimise the risk of urethral injury or crossover, not infrequent in the case of extensive fibrosis of the apex. bleeding is generally minimal and any coarse clots are evacuated. after an extensive corporal irrigation with antibiotic solution, the insertion of the soft medicalgrade silicone virilis i™ (giant medical, cremona, italy) axial implant (ø 10 mm) is performed, shaping and adapting its length to that of the corpora cavernosa, in the maximal stretch condition. the limited diameter of the prosthetic cylinders allows the peripheral displacement of the residual erectile tissue, making it possible for the subsequent realization of a complementary erection. bilateral corporotomy are closed with running sutures. in our practice, a closed suction drain is always inserted. results a total of six patients underwent the spp insertion for refractory ip treatment. median time (range) since onset was 78 (48-108) hours with a mean age (sd) of 33 (6.9) years. three cases were referred from other centers after having had unsuccessful conservative management with aspiration and intracorporal injection of alpha-adrenergic agonists. two of the patients reported a medical history of sickle cells disease; all of them denied the assumption of either any pharmaceutical compound or illicit drugs. in one case, a new diagnosis of sickle cell disease was made. low-flow priapism was confirmed with the gas evaluation of cavernosal blood, revealing blood hypoxia and acidosis in all cases. median operative time (range) was 82 minutes (62-180). no intraoperative complications and no subsequent infection were recorded. median follow-up was 9 months (range 3-17). no significant loss of penile length, neither penile angulation or apical extrusion was recorded. despite a transient reduction of penile sensitivity, all patients have been satisfied with the results of the surgery (mean score question number 5 from international index of erectile function of 4), and all were successfully engaging in satisfactory sexual intercourse. the cost of spp was € 1769,00 with a surgery-related reimbursement fee from the national health system of € 3856.75. cost analysis comparing different types of pp are reported in table 1. discussion the aim of the present study was to evaluate the outcomes of spp placement surgery for men with refractory or delayed ip in an emergency situation, as a possible alternative to the traditional inflatable or malleable implants. albeit the number of treated patients is limited, the spp implantation seem to be an effective option for the surgical treatment of ip, with a low risk of complications and high patient satisfaction. of clinical importance, our results revealed no significant loss of penile length or de-novo angulation at the follow-up. to the best of our knowledge, this is the first report on the use of this device in a priapism setting, with a reduction of surgery-related technical expertise required and national public health-care costs.this strategy could be an attractive chance for patients to maintain, at least in part, their natural erectile response. if case of unsatisfactory rigidity for penetration at follow-up, the spp can be replaced by an upsized hydraulic pp with no risk of penile retraction. as this is an emergency condition requiring immediate intervention, the treatment for recent onset ip episode is sequential, going from conservative measures such as aspiration of cavernous blood and irrigation with saline solution to surgical shunts, while in cases with > 36 hours onset, even if surgical interventions can obtain detumescence, the benefits of preserving erectile function are scarce (10). to date, relative indications for immediately implanting a pp in acute ip include (1): table 1. cost-analysis comparing different types of penile prosthesis (please note that the reported costs may vary in different centers and between different countries). surgery-related penile potential national health prosthesis economic service reimbursement cost benefit soft penile prosthesis € 3856,75 € 1768,00 + € 2088,75 (4% vat included) malleable penile prosthesis € 3856,75 € 2600,00 + € 1256,75 (4% vat included) 3-piece inflatable penile prosthesis € 3856,75 € 7964,51 € 4107,76 (4% vat included) archivio italiano di urologia e andrologia 2021; 93, 3 f. palmisano, v. vagnoni, a. franceschelli, g. gentile, f. colombo 358 • ischaemia that has been presented for more than 36 hours; • failure of aspiration and sympathomimetic intracavernous injections; • failure of distal and proximal shunting (although in delayed cases, implantation might be considered ahead of shunt surgery) • mri or corporal biopsy evidence of corporal smooth muscle necrosis. the early versus delayed placement of a pp has been a topic of debate. the immediate insertion of a penile prosthesis has been recommended to avoid the difficulties and complications presented with delayed surgery in the presence of corporal fibrosis. early surgery also offers the opportunity to maintain penile size, which is inevitably compromised by delayed surgery (7). during early pp implantation, the corporal dilatation is generally easy; however, distal perforation can occur in 6% of patients who have previously undergone previous needles and shunt procedures, especially when a malleable device is placed (11, 12). moreover, a six-fold infection rate higher than virgin implant has been reported, with a 12% of revision rate at 16 months (913). on the other hand, delayed insertion of pp must face inevitable penile fibrosis which is particularly challenging even for experienced surgeons. this often results in penile shortening, in a down-sized pp, in complication rates as high as 65%, a 30% of infection rate, and a pp survival – for inflatable devices – of 50% at 1 year (13, 14). no clear indication on the ideal type of implant to be used in priapism setting has been given. in the largest series reported by ralph in 2009, 86% underwent the immediate insertion of a malleable device (7). in addition to this, zacharakis et al. noted, in patients that previously underwent malleable pp placement for ip, a median upsize of 1 cm at the time of implant exchange and a patient satisfaction rate of 90% after 3 months (15). on the other hand, sedigh et al. table 2. soft penile prosthesis in a refractory ischemic priapism setting: key points. figure 1. proposed algorithm for the management of ischemic priapism (adapted from zacharakis et al. (9). mri: magnetic resonance imaging. • cheaper devices • costs fully covered by the surgery-related national health service reimbursement • higher availability of the device in an emergency setting • simpler and faster surgery • prompt pain resolution • maintain penile size • good coital function (association of residual erection) • in case of later inflatable penile prosthesis exchange, later upsizing of the cylinders is allowed 359archivio italiano di urologia e andrologia 2021; 93, 3 soft penile prosthesis treating ischemic priapism remarked the cosmetic and functional superiority of inflatable pp, leading to a higher satisfaction rate (11). in the light of this, placing a malleable device followed by an inflatable prosthesis exchange means to subject the patient to 2 separate operations (11). the authors also proposed a copious antibiotic use and a conscious and aggressive sizing of the prosthesis placement against the risk of prosthetical infection and loss of length (11). the advantages of using spps in a prolonged ip are shown in table 2. these flexible devices were first proposed by louis subrini in 1982 and then successively popularized by austoni et al. in 2005 for the treatment of peyronie's disease, with the goal of avoiding penile retraction typically caused by traditional surgery for this condition (16, 17). the idea of spp as ideal prosthetic model for treating ip comes from our thirty-year experience with the use of these prostheses in the treatment of peyronie’s disease where they represent a good option, incorporating technical simplicity and surgical time-sparing, offering good aesthetic and functional results. a pre-operative mri, when available, can provide useful features regarding the state of the residual erectile tissue. in this context, these findings must be integrated with the macroscopic aspect of the tissue observed intraoperatively: in young patients, with apparent partial sparing of the cavernous tissue, a spp could represent a less invasive solution than a malleable or inflatable prosthesis allowing greater acceptance by the patient who, thanks to the complementary erection, could benefit from a lower psychological impact deriving from this condition (figure 1). as also recently underlined by zaazaa et al., cavernous tissue preservation and subsequent tumescence would transform the implant’s artificial erection to a more normal physiological and satisfactory one, with higher satisfaction rate (18). potential economic benefits in positioning a malleable penile prosthesis in an ip context have been suggested by tausch et al. (19). although they ruled that prosthesis itself represents only 5% of the total cost treating these patients, specifically $3.850, the surgery results in a durable cure that provides relief in all cases without need for prolonged treatment of subsequent erectile dysfunction. in addition to this, a considerable consumption of health-care resources was stressed with an average us $ 83.818, whereas in 4 emergency room visits, 2 hospital admissions, 1.5 shunt procedure, 5 irrigation and drainage have been included in the analysis (19). the present case series has shown how convenient the use of spps is and can potentially reduce the financial and resource burdens of ip on the health-care system. the potential economic benefits must be interpreted considering different limitations: shunt procedure is not included in this analysis. moreover, the costs of pp can vary between different hospitals and different countries. in addition to this, the reimbursement fee from the national health system may also vary in different regions of our country, sometimes falling to € 1800.00. despite this, spp placement is completely covered by the surgery-related reimbursement of the national health-care system and for this reason the devices can always be available in the operating rooms even in an emergency situation. conclusions the insertion of a spp for patients with refractory (delayed) ip results in immediate pain relief, preservation of sexual function and penile size, with a higher surgery reproducibility in an emergency situation. the case series reported shows a low risk of complications and high patient satisfaction. in addition to this, financial and resource burdens of ip on the health-care system can be potentially reduced. references 1. salonia a, eardley i, giuliano f, et al. eau guidelines on priapism. edn. presented at the eau annual congress madrid 2015. 978-94-92671-07-3. publisher: eau guidelines office. place published: arnhem, the netherlands. http://www.uroweb.org/guidelines/online-guidelines/. 2. el-bahnasawy ms, dawood a, farouk a. low-flow priapism: risk factors for erectile dysfunction. bju int. 2002; 89:285-90. 3. spycher ma, hauri d. the ultrastructure of the erectile tissue in priapism. j urol. 1986; 135:142-7. 4. lue tf, broderick g. evaluation and nonsurgical management of erectile dysfunction and priapism. in campbell mf, retik ab eds, campbell’s urology, 7th edn. philadelphia, pa: wb saunders co., 2002, pp. 1619-71. 5. burnett al, sharlip id. standard operating procedures for priapism. j sex med. 2013; 10:180-94. 6. reddy ag, alzweri lm, gabrielson at, et al. role of penile prosthesis in priapism: a review. world j mens health. 2018; 36:4-14. 7. ralph dj, garaffa g, muneer a, et al. the immediate insertion of a penile prosthesis for acute ischaemic priapism. eur urol. 2009; 56:1033-8. 8. zacharakis e, raheem aa, freeman a, et al. the efficacy of the t-shunt procedure and intracavernous tunneling (snake maneuver) for refractory ischemic priapism. j urol. 2014; 191:164-8. 9. zacharakis e, garaffa g, raheem aa, et al. penile prosthesis insertion in patients with refractory ischaemic priapism: early vs delayed implantation. bju int. 2014; 114:576-81. 10. broderick ga, gordon d, hypolite j, levin rm. anoxia and corporal smooth muscle dysfunction: a model for ischemic priapism. j urol. 1994;151:259-62. 11. sedigh o, rolle l, negro cl, et al. early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. int j impot res. 2011; 23:158-64. 12. salem ea, el aasser o. management of ischemic priapism by penile prosthesis insertion: prevention of distal erosion. j urol. 2010; 183:2300-3. 13. martínez-salamanca ji, mueller a, moncada i, et al. penile prosthesis surgery in patients with corporal fibrosis: a state of the art review. j sex med. 2011; 8:1880-9. 14. mishra k, loeb a, bukavina l, et al. management of priapism: a contemporary review. sex med rev. 2020; 8:131-139. 15. zacharakis e, de luca f, raheem aa, et al. early insertion of a malleable penile prosthesis in ischaemic priapism allows later upsizing of the cylinders. scand j urol. 2015; 49:468-471. 16. subrini l. flexible penile implants in the restoration of erectile function. ann urol. 1993; 27:183-91. archivio italiano di urologia e andrologia 2021; 93, 3 f. palmisano, v. vagnoni, a. franceschelli, g. gentile, f. colombo 360 17. austoni e, colombo f, romanò al, et al. soft prosthesis implant and relaxing albugineal incision with saphenous grafting for surgical therapy of peyronie's disease: a 5-year experience and long-term follow-up on 145 operated patients. eur urol. 2005; 47:223-9. 18. zaazaa a, mostafa t. spontaneous penile tumescence by sparing cavernous tissue in the course of malleable penile prosthesis implantation. j sex med. 2019; 16:474-478. 19. tausch tj, zhao lc, morey af, et al. malleable penile prosthesis is a cost-effective treatment for refractory ischemic priapism. j sex med. 2015; 12:824-6. correspondence franco palmisano, md (corresponding author) franco.palmisano@hotmail.it asst fatebenefretalli-sacco, luigi sacco university hospital, department of urology via giovanni battista grassi 74, 20157, milan (italy) valerio vagnoni, md alessandro franceschelli, md giorgio gentile, md fulvio colombo. md andrology unit, department of urology and gynecology, sant’orsola university hospital, bologna (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12496 1 original paper as a result of the extensive utilization of the more available and higher precision imaging techniques, the prevalence of renal cell carcinoma is on the rise, particularly notable in tumors ranging between 2 to 4 cm (2, 3). the rcc’s biology is intricate, and although nearly 33% of all kidney masses first present signs of systemic disease, yet a significant number of localized renal masses show a tendency to progress slowly (4). surgical management is still the primary treatment option. due to the ongoing evolution of imaging technologies, particularly the enhancements seen in ultrasonography, there has been a discernible augmentation in the identification of rccs at an early stage (5). there are numerous therapeutic options for kidney tumors, including excision via partial nephrectomy (pn) or radical nephrectomy (rn), ablative procedures, or active observation (6). the determination of surgical approaches is substantially impacted by factors such as the volume and precise anatomical location of the neoplasm. further considerations shaping the chosen surgical approach and intervention include the skillset and experience of the surgeon, the capabilities of the operating facility, and established procedural norms within the medical practice (7). increasing evidence implies a link connecting the pathological and anatomical characteristics of the renal tumors (8-10), however objective measurements of renal mass anatomy have only recently been described (7, 11-13). in recent times, there has been a discernible demand for precise anatomical characterization of renal masses, prompting the emergence of new scoring systems tailored to offer objective guidance in surgical decision-making processes. two predominant systems have garnered widespread attention: the renal nephrometry score (rns) which was established by kutikov and uzzo (2009) and objectively quantifies relevant kidney tumor anatomy characteristics using a scoring system; the preoperative aspects and dimensions used for anatomical classification (p.a.d.u.a.) approach which was proposed by ficarra et al. (2009) and closely resembles the renal score, offering an alternative anatomical assessment (7, 14, 15). scoring algorithms have been created and verified to appropriately evaluate the likelihood of postsurgical adverse events and to reflect the introduction: the third most prevalent malignant neoplasm involving the urinary tract is renal cell carcinoma (rcc), encompassing nearly 3.5% of the entire cancers afflicting the body. the aim of this research was to explore how the r.e.n.a.l. nephrometry score relates to the decisions made regarding surgery in individuals with localized rcc. methods: this prospective study, assessed patients with localized parenchymal renal masses (stages i and ii) tentatively diagnosed as rcc. utilizing preoperative multiphasic renal ct scans and mri, the r.e.n.a.l. score categorized masses for nephrometry values. inclusion criteria involved collecting patient data, and data collection utilizing a structured format focusing on the nephrometry grading system. results: the study included 64 patients aged (mean ± sd) 49.78 ± 12.35 yrs. undergoing renal mass surgery, there were 17 (26.5%) low, 28 (43.8%) moderate and 19 (29.7%) high-complexity lesions. all patients with a low nephrometry score (n = 17) underwent partial nephrectomy, and all cases with a high score (n = 19) underwent radical nephrectomy. for those with a moderate nephrometry score (n = 28), 13 (46.4%) underwent partial nephrectomy, while the remaining 15 (53.6%) cases underwent radical nephrectomy. morbidity was low, and no mortality occurred at 180 days. patients who had lesions fully above or below polar lines were less likely to need blood transfusions. a trend towards higher fuhrman grades in patients receiving transfusions suggests a potential link between tumor aggressiveness and bleeding risk conclusions: our findings provide insight on the utilization of the r.e.n.a.l. nephrometry score in forecasting perioperative, post-surgical, and oncological results. such data might help optimize surgical methods and pre-operative patient counseling. key words: r.e.n.a.l. nephrometry score; renal mass complexity; surgical approach; hemoglobin drop; blood transfusion prediction. submitted 24 march 2024; accepted 6 april 2024 introduction the third most prevalent malignant neoplasm involving the urinary tract is renal cell carcinoma (rcc), encompassing nearly 3.5% of the entire cancers afflicting the body (1). the association of anatomical renal mass complexity with surgical approach, hb drop, and the rate of blood transfusion shakhawan hama amin said 1, lusan abdulhameed arkawazi saiwan 1, mzhda sahib jaafar 1, nadhm kanabi majeed 1, rawa bapir 2, 3, 4, ismaeel aghaways 1, abdullah a. qadir 1, 2, berun a. abdalla 2, 4, ayoob asaad mohammed abid 1, fahmi h. kakamad 1, 2, 4 1 college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq; 2 smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq; 3 department of urology, sulaymaniyah teaching hospital, sulaymaniyah, kurdistan, iraq; 4 kscien organization, hamdi street, azadi mall, sulaymaniyah, kurdistan, iraq. doi: 10.4081/aiua.2024.12496 summary archivio italiano di urologia e andrologia 2024; 96(3):12496 s. hama amin said, l. abdulhameed arkawazi saiwan, m. sahib jaafar 2 complexity of renal tumors (16). the aim of this research was to explore how the r.e.n.a.l. nephrometry score relates to the decisions made regarding surgery in individuals with localized rcc. methods study design this prospective study design was approved by the institutional research ethics committee, and all patients were granted informed consent. preoperative multiphasic renal ct scans with intravenous contrast injection were performed on all patients, with magnetic resonance imaging (mri) serving as additional imaging. r.e.n.a.l. score was used to assess the kidney tumor. masses with nephrometry values of 4 to 6 were categorized as to be mildly complicated for resection, those with scores ranging from 7 to 9 were classed as moderate complexity, and those with scores between 10 to 12 were labeled high complexity. the nephrometry score of a kidney tumor might vary from 4a (1+1+1+a+1) to 12ph (3+3+3+ph+3) [1]. in this investigation, the r.e.n.a.l. score was utilized to evaluate patients with renal tumors managed at our hospital with radical nephrectomy or partial nephrectomy, conducted through both open and laparoscopic approaches. inclusion and exclusion criteria data for inclusion criteria regarding clinical features, histopathological specimens, and cross-sectional images, as well as surgical and postsurgical outcomes, were gathered from the medical database. sample size & sampling procedures this study was done prospectively on 64 patients who had localized parenchymal renal mass (stages i and ii) that was tentatively diagnosed as rcc and were planned for surgery. data collection procedures a structured data abstraction format with items targeting the nephrometry grading system was applied. the r.e.n.a.l. score was established in 2009 (7) and is based on the five most repeatable aspects of a solid renal mass's anatomy: (r)adius (the largest diameter of the tumor in centimeters) to which points were assigned as 1 (≤ 4 cm), 2 (> 4 but < 7 cm), and 3 (≥ 7 cm); (e)xophytic/endophytic properties (points were designated as 1 in cases where 50% or more of the tumor exhibited exophytic growth, 2 when less than 50% of the tumor demonstrated exophytic characteristics, and 3 in instances where the tumor displayed entirely endophytic characteristics); (n) component (nearness) of the tumor to the collecting system or sinus and for which points were assigned as 1 (≥ 7 mm), 2 (> 4 but < 7 mm), and 3 (invading, touching, or within 4 mm); (a) indicates the anterior or posterior location of the tumor which was designated as a non-numerical suffix that describes the location of the tumor with respect to the kidney midline plane as assessed on axial images (the tumor is designated with the suffix “x” when it cannot be specified as either anterior or posterior; (l) designates the location of tumor in relation to polar lines. standardized points (1-3 points per descriptor) were given to each parameter, excluding the anterior or posterior component. an additional suffix “h” is used to highlight a hilar tumor. the literature review was done by carefully selecting papers from reputable journals and omitting those from predatory sources based on predetermined criteria of kscien’s list (17). results in this study, a total of 64 patients were included, encompassing 28 males and 36 females. the patients had the surgery through an open approach except for five (7.8%) table 1. presents clinical characteristics of the 64 patients enrolled in this study. variables n. patients (%) demographics age (mean ± sd) 49.78 ± 12.35 yrs. sex male 28 (43.8%) female 36 (56.2%) tumors side right 28 (43.8%) left 36 (56.2%) past medical history no 38 (59.4%) htn 16 (25%) dm 4 (6.3%) htn+dm 6 (9.4%) bmi < 18.5 0 (0%) 18.5-24.9 20 (31.3%) 25-29.9 30 (46.9%) > 30 14 (21.9%) blood transfusion yes 16 (25%) no 48 (75%) type of management radical 34 (53.1%) partial 30 (46.9%) presentation on symptomatic incidental 41 (64.1%) symptomatic 23 (35.9%) symptom of presentation asymptomatic 39 (60.9%) right loin pain 8 (12.5%) left loin pain 10 (15.6%) anemia 2 (3.1%) hematuria 5 (7.8%) asa 1 29 (45.3%) 2 25 (39.1%) 3 9 (14.1%) 4 1 (1.6%) stage 1 50 (78.1%) 2 14 (21.9%) nephrometry score low 17 (26.5%) middle 28 (43.8%) high 19 (29.7%) archivio italiano di urologia e andrologia 2024; 96(3):12496 3 anatomical renal mass complexity and surgery patients who had laparoscopic surgery. among them 30 (46.9%) patients underwent partial nephrectomy, while 34 patients (53.1%) underwent radical nephrectomy. among these patients, 41 (64.1%) had an incidental finding of a renal tumor, while 23 (35.9%) presented with symptoms. of these, 28 (43.8%) had a right-sided renal tumor, while 36 (56.2%) had a left-sided renal tumor. most of our patients were diagnosed with clear-cell rcc on final histopathology (n = 60). the remaining cases consisted of multilocular cystic rcc (n = 1), renal oncocytoma (n = 2), and renal angiomyolipoma (n = 1). sixteen patients (25%) received perioperative blood transfusions, while 48 (75%) did not (table 1). the general 180-day morbidity in the current investigation was low, including pleural injury (n = 3), urinary leakage (n = 1), and patients requiring postoperative blood transfusion (n = 6). the mortality rate was zero after 180 days of follow-up. there were 17 (26.5%) low, 28 (43.8%) moderate and 19 (29.7%) high-complexity lesions (table 1). all patients with a low nephrometry score (n = 17) underwent partial nephrectomy, and all cases with a high score (n = 19) underwent radical nephrectomy. for those with a moderate nephrometry score (n = 28), 13 (46.4%) underwent partial nephrectomy, while the remaining 15 (53.6%) cases underwent radical nephrectomy (table 2). additionally, table 2 provides post-operative follow-up data, examining the connections between hbdrop and postoperative creatinine change with different nephrometry scores. the nephrometry scores were categorized as low, moderate, and high, and the data are reported as mean ± sd. for the variable "hb drop", the following values were observed: for low nephrometry score: 1.02 ± 0.65, for moderate nephrometry score 1.50 ± 0.83; for high nephrometry score 1.53 ± 0.78 (with a p-value of 0.093). for the variable “postoperative creatinine change", the data aer as follows: for low nephrometry score 0.14 ± 0.19; for moderate nephrometry score 0.12 ± 0.20; for high nephrometry score 0.08 ± 0.21 (with a p-value of 0.705 ) (table 2). the anatomical location data based on the nephrometry score reveals important details about the renal masses under study. the mean maximum dimension and standard deviation (sd) was measured at 1.96 ± 0.73. the nature of the masses is described in terms of endophytic and exophytic characteristics, with 37.5% of the masses being predominantly exophytic, 48.5% showing a 50% exophytic nature, and 14.1% being primarily endophytic (table 3). regarding their location, 31.3% of the masses are prioritized anteriorly [designated as 'priority (a)'], while the same percentage is located posteriorly ['priority (p)']. an additional 37.4% of the masses are categorized as 'uncertain (x).' the proximity of the masses to the renal hilum is also noted, with 12.5% located at or above 7 units away, 15.6% situated between 4 and 7 units, and the majority, 71.9%, being located within 4 units of the hilum (table 3). polar relationships further characterized the masses, with 53.1% positioned exclusively under or upwards of the polar lines. another 20.3% of the masses crossed the polar line, while the remaining 26.6% were distributed such that 50% of the mass either crosses the polar line, extends across the axial renal midline, or is fully situated amidst the polar lines. these factors collectively provide insights into the lesion's size, endophytic or exophytic nature, its specific location, proximity to the hilum, and its relationship to the polar lines. this data distribution is detailed in table 3. a comparative analysis was conducted between patients who received blood transfusions and those who did not. the mean maximum diameter for patients receiving blood transfusions was 2.25 ± 0.77, while those who did not receive transfusions had a mean diameter of 1.87 ± 0.70 (p = 0.077). patients with tumors ≥ 50% exophytic nature received transfusion in 4/24, those with < 50% exophytic nature tumors received in 7/32, and patients with endophytic tumors on 5/9 (p = 0.065). patients with tumors in anterior location had transfusion in 5/20, patients with tumors in posterior location in 5/20 and patients with tumors in unknown location in 6/24 (p =1.00). in regards to the nearness with hilum, patients with a distance ≥ 7 units received blood in 1/8, and those with distances > 4 but < 7 units in 1/10, and for distances ≤ 4 units, 14/46 received blood (p = 0.274). in regard to polar relation, the table 3. anatomical characteristics of dimension nephrometry scores. variables n (%) maximum diameter (mean ± sd) 1.96 ± 0.73 endophytic/exophytic >= 50% exophytic 24 (37.5%) < 50% exophytic 31 (48.5%) endophytic 9 (14.1%) location anterior (a) 20 (31.3%) posterior (p) 20 (31.3%) unknown (x) 24 (37.4%) nearness to hilum >= 7 8 (12.5%) >4 but < 7 10 (15.6%) <= 4 46 (71.9%) polar relation entirely above the upper or below the lower polar 34 (53.1%) lesion crosses polar line 13 (20.3%) > 50% of mass is across polar line, or mass crosses 17 (26.6%) the axial renal midline, or mass is entirely between the polar lines table 2. surgical approach stratified by nephromtery score and relationships between hb-drop and postoperative creatinine change with nephrometery score. variables nephromtery score n (%), sd, mean p-value types of management low moderate high partial 17 (56.6%) 13 (43.3%) 0 (0%) < 0.001 radical 0 (0%) 15 (44.1%) 19 (55.8%) post-operative value hb drop 1.02 ± 0.65 1.5 ± 0.83 1.53 ± 0.78 0.093 postoperative creatinine change 0.14 ± 0.19 0.12 ± 0.20 0.08 ± 0.21 0.705 archivio italiano di urologia e andrologia 2024; 96(3):12496 s. hama amin said, l. abdulhameed arkawazi saiwan, m. sahib jaafar 4 analysis showed that 5/34 of the cases with mass entirely above or below the polar lines received a blood transfusion, whereas transfusion were received in 3/13 of those with lesions that crossed polar lines (p = 0.042). the results from this comparative evaluation are summarized (table 4). the number of patients by type of management, radical or partial, revealed that the type of surgery was based on the anatomical scores (table 5). an investigation was conducted to explore the association between nephrometry scores and hemoglobin decline in the context of blood transfusion. the transfusion rate was correlated with nephrometry score (table 6). patients with low, moderate, and high nephrometry scores had transfusions in 2/15, 6/28, and 8/19, respectively (p = 0.093. additionally, mean ± sd values for hb drop for those who received a blood transfusion or not are presented in (table 6). furthermore, table 6 delved into the investigation of the relationship between blood transfusion and fuhrman grade, with information presented as counts and percentages (n%). for patients who did not receive blood, fuhrman grade 1 accounted for 60.9% (28 cases), fuhrman grade 2 for 37% (17 cases), and fuhrman grade 3 for 2.1% (1 case). patients who received blood were 5/33 in fuhrman grade 1 group, 11/28 in fuhrman grade 2 group and 0/1 in fuhrman grade 3 group (p = 0.094). these findings are comprehensively presented in (table 6), contributing to the insight into the interplay between nephrometry scores, hemoglobin decline, and fuhrman grade in the studied cohort. discussion the third most prevalent malignant neoplasm involving the urinary tract is rcc, encompassing nearly 3.5% of the entire cancers afflicting the body (1). an approximate 54.390 new diagnoses and 13.010 mortalities in 2008 were attributed to rcc (18). most diagnoses nowadays are unintentional. in the past, symptoms such as weight loss, hematuria, or a palpable flank bulge would indicate the condition. the reason for this change is because more cross-sectional diagnostic imaging is being used. as a result, at least 48-66% of rcc diagnoses have been established based on asymptomatic, incidental renal masses table 4. comparison of clinical features in blood transfusion groups. blood transfusion yes no p-value maximum diameter (mean ± sd) 2.25 ± 0.77 1.87 ± 0.70 0.077 endophytic/exophytic 0.065 >= 50% exophytic 4 (16.6) 20 (83.4) < 50% exophytic 7 (21.9) 25 (78.1) endophytic 5 (55.5) 4 (44.5) location 1.000 anterior (a) 5 (25) 15 (75) posterior (p) 5 (25) 15 (75) unknown (x) 6 (25) 18 (75) nearness to hilum 0.274 >= 7 1 (6.3) 7 (14.6) > 4 but < 7 1 (6.3) 9 (18.8) <= 4 14 (87.4) 32 (66.7) polar relation 0.042 entirely above the upper or below the lower polar 5 (14.7) 29 (85.3) lesion crosses polar line 3 (23) 10 (77) > 50% of mass is across polar line, or mass crosses the axial renal midline, 8 (47.1) 9 (52.9) or mass is entirely between the polar lines table 5. surgical approach of renal cell carcinoma. blood transfusion yes no p-value maximum diameter (mean ± sd) 1.53 ± 0.57 2.35 ± 0.64 < 0.001 endophytic/exophytic < 0.001 >= 50% exophytic 19 (63.3%) 5 (14.7%) < 50% exophytic 11 (36.7%) 20 (58.8%) endophytic 0 (0%) 9 (26.5%) location 0.199 anterior (a) 10 (33.3%) 10 (29.4%) posterior (p) 12 (40%) 8 (23.5%) unknown (x) 8 (26.7%) 16 (47.1%) nearness to hilum < 0.001 >= 7 8 (26.7%) 0 (0%) > 4 but < 7 10 (33.3%) 0 (0%) <= 4 12 (40%) 34 (100%) polar relation < 0.001 entirely above the upper or below the lower polar 25 (83.3%) 9 (26.5%) lesion crosses polar line 3 (10%) 10 (29.4%) > 50% of mass is across polar line, or mass crosses the axial renal midline, 2 (6.7%) 15 (44.1%) or mass is entirely between the polar lines table 6. relationship between nephrometry score and hb drop with blood transfusion and relationship of blood transfusion with fuhrman grade. p-value blood transfusion n (%) variables no yes 0.093 nephrometry score 15 (31.3%) 2 (12.5%) low 22 (45.8%) 6 (37.5%) moderate 11 (22.9%) 8 (50%) high 0.479 1.34 ± 0.79 ± 0.80 1.50 hb drop (mean ± sd) 0.094 furhman grade 28 (60.9%) 5 (31.2%) 1 17 (37%) 11 (68.8%) 2 1 (2.1%) 0 (0%) 3 archivio italiano di urologia e andrologia 2024; 96(3):12496 5 anatomical renal mass complexity and surgery (19). both the incidence of rcc and the rate of rcc therapies have risen consistently over the last three decades with lower-stage migration (20). the treatment of localized rcc is a therapeutic challenge due to the diversity of tumor appearances and unique patient circumstances. surgical management, such as pn and rn, is the main treatment option for localized rcc. a number of factors, including the size, location, and intricacy of the tumor, influence the decision to perform a particular surgery (21). the r.e.n.a.l. nephrometry score employs imaging-derived characteristics of kidney tumors to measure tumor complexity objectively, facilitating decisions regarding the selected technique and strategy. postoperative results in individuals receiving open or minimally invasive pn have been correlated with the r.e.n.a.l score. the current study underscores the effectiveness of the r.e.n.a.l nephrometry score in forecasting surgical complexity and postsurgical morbidity. the results of this investigation correspond with past studies that have highlighted the connection between surgical technique selection and tumor architecture. one standardized and objective tool for preoperative decisionmaking is the r.e.n.a.l-ns. it gives urologists a useful tool for determining the optimal surgical approach and evaluating the complexity of renal masses. these findings provide credence to the hypothesis that anatomicallybased tailored renal mass surgery might lead to improved clinical outcomes (22). according to this study, anatomic tumor features like size and location have a profound effect on preoperative outcomes and the prognosis that follows surgery. according to our findings, renal masses' preoperative radiographic and anatomic characteristics can predict the mass's pathologic characteristics. the r.e.n.a.l. nephrometry score, as the primary rating algorithm established to gauge renal tumor architecture concerning surgical resectability, was utilized in this study. excision is the usual course of treatment for individuals with a solid renal tumor. active observation, operative excision, and thermal ablative procedures are all effective therapeutic options for suitably chosen individuals with a clinical stage t1 kidney tumor, as new american urological association guidelines have shown (23). r.e.n.a.l nephrometry scores range through 4 to 12 points. lesions that have a collective score of 4, 5, or 6 on nephrometry are classified as low complexity. meanwhile tumors with cumulative points of 7 to 9 points are considered intermediate complexity, and masses scored between 10 to 12 are classified as high complexity lesions. a suffix of a or p, and x adds a descriptive component to the system, signifying the anterior or posterior location of the mass, whereas a h is used for hilar tumors (7). of the 68 patients in the current study, 34 (53.1%) underwent rn and 30 (46.9%) underwent pn based on their nephrometry scores: 17 (26.5%) were low complexity, followed by 28 (43.8%) intermediate complexity and 19 (29.7%) high complexity. haidar et al. found a relationship connecting r.e.n.a.l score and surgical technique choice. pn was done in 75.6% of cases with low score, 54.6% of instances with moderate level (p = 0.004), and only 11.7% of those with high score (p < 0.001) (24). in our study, 46.9% of 68 patients underwent partial nephrectomy, with 56.6% having a low score and 43.3% having a moderate score. the remaining patients underwent radical nephrectomy, with 44.1% and 55.8% having intermediate and high scores, respectively. to define the anatomical aspects of a kidney mass, another approach called preoperative aspects and dimensions used for an anatomical (padua) was established. with the exception of defining the sinus lines and assessing the physical connection between the tumor and the renal sinus, or urine collecting system, this system is comparable to the nephrometry score. the c-index method was finally presented to ascertain the centrality of a tumor. the distance separating the mass and the kidney centers must be calculated using a sophisticated geometric approach utilizing cross-sectional imaging (25, 26). whenever medically feasible, most globally recognized standards recommend doing a partial nephrectomy for t1a tumors. approaches to solid renal tumor care include deciding whether to remove the entire kidney or only the tumor with a clean surgical margin, as well as whether to use an open or laparoscopic surgical technique. it was demonstrated that tumor volume increases the likelihood of malignant vs benign pathology, high-grade versus lowgrade illness, and clear cell versus papillary histology (27). in our study, all patients with a low nephrometry score got partial nephrectomy, while all patients with a high score had radical nephrectomy. those with a moderate score (46.4%) got partial nephrectomy, while the rest (53.6%) had radical nephrectomy. one of the most difficult components of rcc therapy is preventing perioperative problems while maintaining patient safety (28). the study identified just a few cases of pleural injury, urinary incontinence, and the need for postoperative blood transfusions. the lack of mortality throughout the 180-day follow-up period is reassuring, showing that anatomically complex surgical decisions do not threaten patient safety. in terms of perioperative blood transfusions, the study revealed that a quarter of the patients needed them, although the rest did not. this study stresses the need of accurately calculating perioperative blood loss, which can affect surgical technique and postoperative therapy. in challenging cases, efforts to decrease blood loss and the need for transfusions, such as precision surgical techniques and advanced hemostatic therapies, should be considered. haider et al. revealed that individuals with an elevated r.e.n.a.l. score experienced more adverse perioperative results in comparison to those with a lower score. subjects with a high r.e.n.a.l score (19.4% vs 6.3%, p = 0.018) were three folds more likely to get blood transfusions than those with a low score (24). out of the 68 patients in the current study, 16 had blood transfusions, the majority, 8 (50%) had high scores, followed by 6 (37.5%) with moderate scores and 2 (12.5%) with low scores. there is ongoing debate regarding the ability of the r.e.n.a.l. nephrometry scoring technique to reliably forecast malignancy and high histopathological grades in small kidney tumors. osawa et al. found that despite the fact that r.e.n.a.l. nephrometry scores were effective in distinguishing the benign and malignant kidney masses, as well as lowand high-grade kidney tumors, histopathoarchivio italiano di urologia e andrologia 2024; 96(3):12496 s. hama amin said, l. abdulhameed arkawazi saiwan, m. sahib jaafar 6 logical examination yielded superior performance in this regard (29). further investigations have demonstrated a profound relationship between the r.e.n.a.l. score and both tumor grade (p < 0.0001) and histology (p < 0.0001). this suggests that as tumor volume rises, there is a higher probability of malignancy, particularly highgrade and clear-cell tumors, upon histological examination (30). the consequence of rcc tumor complexity on oncologic results remains to be definitively made. this current research revealed that the r.e.n.a.l. score played a predictive role in key oncologic outcomes. for instance, individuals exhibiting lower r.e.n.a.l. scores demonstrated markedly higher survival rates in contrast to those presenting higher nephrometry scores. similarly, tumors with elevated r.e.n.a.l. scores showed more likelihood of experiencing recurrence and progression. conclusions the r.e.n.a.l. nephrometry scoring system offers a versatile, advantageous, and replicable tool for quantifying the key aspects of renal anatomy. the cumulative nephrometry score was shown to be linked with operative decision-making. specifically, the anatomical characteristics of a kidney tumor foretell the utilization of different surgical approaches. references 1. shaaban ms, abou youssif tm, mostafa a, et al. role of renal nephrometry scoring system in planning surgical intervention in patients with localized renal masses. egy j radiol nucl med. 2015; 46:1175-81. 2. 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pathology: a preoperative nomogram using the renal nephrometry score. eur urol. 2011; 60:241-8. correspondence shakhawan hama amin said lusan abdulhameed arkawazi saiwan mzhda sahib jaafar nadhm kanabi majeed ismaeel aghaways abdullah a. qadir ayoob asaad mohammed abid college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq rawa bapir berun a. abdalla berun.anwer95@gmail.com smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq fahmi h. kakamad (corresponding author) fahmi.hussein@univsul.edu.iq doctors city, building 11, apartment 50, sulaimani, iraq conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 41archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. sought to provide an overview of de novo t2 muscle invasive bladder cancer of patients who underwent a radical cystectomy in thunder bay in order to identify the characteristics of patients with clinically localized muscle invasive bladder carcinoma and to determine their clinical and pathological outcomes. methods this is a cross-sectional study that retrospectively examined the medical records of 59 patients with documented organ confined de novo t2 muscle invasive bladder cancer confirmed on a diagnostic turbt who underwent radical cystectomy over a 2 year-period. clinical and pathological characteristics of turbt and cystectomy were retrieved. the analysis was conducted using ibm spss software (version 19.0, spss inc., illinois, usa). the continuous data was presented as mean or median with standard deviation and compared using independent t-test while the categorical data was in percentages and compared using the chisquare test. statistical significance was defined as p < 0.05. a multivariate regression analysis was performed to identify the significant risk factors for upstaging. results the mean age of the patients was 67 ± 8.8 years. those aged under 60 years old accounted for 27.1% of the sample. eighty percent of patients were male. based on final pathological results, upstaging was noted in 59.3% (t3 in 27.1% and t4 in 32.2%). thirty-six percent had node-positive disease. prostate adenocarcinoma was incidentally discovered in 20 (34%) of patients. significant high-grade prostate cancer was found in 50% of patients. twenty patients (34%) had their surgery delayed for more than 12 weeks. overall, 14 patients received neoadjuvant chemotherapy (nac) (table 1). younger patients (aged ≤ 60 years) had a higher prevalence of pathological upstaging (68.7% vs. 45.8%), as well as a higher chance of positive lymph nodes (37.5% vs. 34.9%), whereas older patients (age > 60) had a higher rate of incidental prostate cancer (34.9% vs. 31.3%). however, these findings were not statistically significant (table 2). upstaging was observed in 30% of patients who had surobjective: this study aimed to investigate the clinical and pathological characteristics of patients with de novo muscle-invasive bladder cancer (mibc) who underwent radical cystectomy in northern ontario. methods: this is a retrospective cross-sectional study of patients with de novo t2 mibc who underwent radical cystectomy over a 2-year-period in thunder bay regional health sciences centre. clinical and pathological characteristics of trans urethral resection of bladder tumors and cystectomy specimens were analyzed. results: of the 59 patients aged 67 ± 8.8 years, predominated by males (80%), 27.1% were younger than age 60. after surgery, upstaging was noted in 59.3% (t3 in 27.1% and t4 in 32.2%) while node positive was noted in 36% of patients. prostate adenocarcinoma was incidentally discovered in 20 (34%) of patients with 50% considered significant (gleason score ≥ 7). downstaging was found in those who had neoadjuvant chemotherapy (p = 0.001). conclusions: the high prevalence of younger ages (less than 60), a high rate of upstaging, the presence of high-grade incidental prostate cancer, and lymph node positives in t2 de novo mibc in northern ontario, warrants further investigation of potential causes and risk factors at individual, public, and population health levels in the region. key words: bladder cancer; cystectomy; northern ontario. submitted 10 november 2021; accepted 8 december 2021 introduction according to global cancer statistics, 3% of all new diagnosed cancer and 2.1% of all cancer mortality are due to bladder cancer (1). bladder cancer is linked to a number of important risk factors, the most prominent of which are smoking, occupational and environmental exposure to carcinogens, and conditions that cause chronic bladder irritation (2). toxins found in the environment, such as aromatic amines like benzidine and 2-naphthylamine, have been linked to up to 27% of bladder cancers (3). a recent study could identify that patients older than 70year-old with significant comorbidities have less favourable outcomes (4). the projected average annual new cases of bladder cancer in 2018-2022 in ontario has been estimated at 1950 for males and 660 for females (5). with this knowledge, we adverse pathological outcomes of patients with de novo muscle invasive bladder cancer in northern ontario vahid mehrnoush, shahrzad keramati, asmaa ismail, waleed shabana, ahmed zakaria, hazem elmansy, walid shahrour, owen prowse, ahmed kotb urology department, northern ontario school of medicine, thunder bay regional health centre, ontario, canada. doi: 10.4081/aiua.2022.1.41 summary archivio italiano di urologia e andrologia 2022; 94, 1 v. mehrnoush, s.keramati, a. ismail, w. shabana, a. zakaria, h. elmansy, w. shahrour, o. prowse, a. kotb 42 gery delayed for more than 12 weeks, whereas upstaging was found in 74.3% of those who had surgery within 12 weeks, which is statistically different (p = 0.001). not surprisingly, nac was performed more in the delayed group (92.8%) (table 3). a significant difference in upstaging was found between those who had nac, 3 (21.4%), and those who did not, 11 (78.6 %) (p = 0.001). however, the invasion to the lymph nodes was not lower in those who received nac compared to those who did not (table 4). multivariate regression analysis revealed that nac was the only factor associated with upstaging, while there was no significant association with other risk factor including age, gender, and waiting time to surgery (table 5). the pathology in those who received nac are approximately 60% less likely to show upstaging (or = -0.38, ci 95% = -0.74-0.02) (table 5). discussion the current case series in northern ontario draws attention to the high prevalence of mibt in patients younger table 1. characteristics of patients with preoperative t2 transitional cell carcinoma. variable value mean age (years) 67 ± 8.8 (51-88) age groups ≤ 60 16 (27.1%) > 61 43 (72.9%) sex males 47 (80.0%) females 12 (20.0%) stage t0 9 (15.3%) ta/t1 6 (10.1%) t2 9 (15.3%) t3 16 (27.1%) t4 19 (32.2%) positive lymph nods no 38 (64.0%) yes 21 (36.0%) incidental prostate cancer no 39 (66.0%) yes 20 (34.0%) grade of prostate cancer 3 + 3 10 (50.0%) 3 + 4 8 (40.0%) 4 + 3 2 (10.0%) waiting time to surgery (weeks) mean ± sd 13 ± 8 wait time (weeks) < 6 21 (36.0%) 612 18 (30.0%) > 12 20 (34.0%) neoadjuvant chemotherapy (nac) no 45 (76.0%) yes 14 (24.0%) table 2. comparison of the findings based on age. age < 60 > 60 p value n = 16 n = 43 sex males 13 (81.2%) 34 (79.1%) 1.0 females 3 (18.8%) 9 (20.9%) waiting time to surgery < 12 9 (56.2%) 30 (69.8%) 0.3 > 12 7 (43.8%) 13 (30.2%) neoadjuvant chemotherapy (nac) no 11 (68.7%) 34 (79.1%) 0.5 yes 5 (31.3%) 9 (20.9%) stage < t3 5 (31.3%) 19 (44.2%) 0.5 t3/ t4 11 (68.7%) 24 (45.8%) lymph nodes invasion negative 10 (62.5%) 28 (65.1%) 1.0 positive 6 (37.5%) 15 (34.9%) prostate cancer no 11 (68.7%) 28 (65.1%) 1.0 yes 5 (31.3%) 15 (34.9%) table 3. comparison of operation waiting time categories against clinical and pathological staging. waiting time to surgery < 12 weeks < 12 weeks p value n = 39 n = 20 mean age 68 ± 8 65 ± 9 0.2 stage < t3 10 (25.7%) 14 (70%) 0.001 t3/t4 29 (74.3%) 6 (30%) lymph nodes negative 23 (59%) 15 (75%) 0.2 positive 16 (41%) 5 (25%) neoadjuvant chemotherapy (nac) yes 1 (2.6%) 13 (65%) 0.001 no 38 (97.4%) 7 (35%) table 4. comparison of patients with or without neoadjuvant chemotherapy (nac) against clinical and pathological staging. neoadjuvant chemotherapy no yes p value (nac) n = 45 n = 14 mean age (years) 68 ± 9 64 ± 7 0.1 stage < t3 13 (28.9%) 11 (78.6%) 0.001 t3/t4 32 (71.1%) 3 (21.4%) lymph nodes negative 28 (62.2%) 10 (71.4%) 0.7 positive 17 (37.8%) 4 (28.6%) table 5. multivariate regression analysis for factors associated with upstaging. odds ratio 95% confident interval p value lower limit upper limit age -0.23 -0.51 0.04 0.097 gender 0.04 -0.28 0.36 0.809 neoadjuvant chemotherapy -0.38 -0.74 -0.02 0.041 * waiting time to surgery -0.08 -0.44 0.28 0.659 * p-value < 0.05 is significant. 43archivio italiano di urologia e andrologia 2022; 94, 1 muscle invasive bladder cancer in northern ontario than 60 years (27.1%), with a high rate of upstaging (68.7%) in this young group of patients. the findings indicate that approximately 60% of clinically t2 mibc were t3/t4 at final pathology. another highlight is the high rate of clinically significant prostate cancer (50%) in patients with incidental prostate cancer. in terms of treatment, the findings showed that nac was underutilized in northern ontario (76% did not receive nac) and that no significant association was found between receiving nac or delaying surgery and upstaging. the majority of our patients were male, which was consistent with the literature (80% male vs. 20% female). our findings suggest that bladder cancer should not be emphasized in a purely geriatric population in northern ontario. the causes of bladder cancer in the younger age group, however, have not been well documented in the literature. according to the findings of a study conducted in montreal (canada), natural gas combustion products, aromatic amines, cadmium compounds, photographic products, acrylic fibers, polyethylene, titanium dioxide, and chlorine were found to have weak evidence of being risk factors for bladder cancer. occupational exposures such as motor vehicle drivers, particularly among drivers in the motor transport industry, who were more likely to drive full time than drivers in other industries, textile dyers, construction painters, metal machinists and sheet metal workers, and aromatic amines were responsible for 6.5 percent of bladder cancer incidence (6). another canadian case control study discovered that miners, metal workers, mechanics, and male hairdressers were more likely to develop bladder cancer. they assumed that exposure to various combustion products and/or oils was a common theme in these occupations (7). epidemiological studies in canada and other countries, including the united states, italy, and france discovered that carcinogenic chemicals in tap water, such as chloroform and other trihalomethanes, are linked to an increased risk of bladder cancer (8, 9). peculiar environmental conditions can also expose this population to risk factors. northern ontario is one of the leading mining regions for nickel, copper, uranium, zinc, gold, platinum, and silver. northern ontario's economy is built on forestry, transshipment, and manufacturing industries such as textile, steel, pulp, and paper. moreover, northern ontario is the transshipment point of agriculture products across canada (10). from the standpoint of public health, the high prevalence of younger age (60 years old) with mibc in northern ontario appears to necessitate a transdisciplinary approach that includes medical, logistical, and municipal sectors to identify the risk factors and implement a multilevel strategy to address this issue. the findings of our study revealed that a high percentage of patients with clinically t2 mibc turned into t3/t4 with positive lymph nodes after cystectomy, and that the majority of these patients undergo surgery in less than 12 weeks. according to the pathological results of radical cystectomy, 59.3% of patients were diagnosed at the most advanced stages (t3/t4), and 36% developed node-positive disease. it is concerning to diagnose patients at such advanced stages. these findings also emphasize early investigation which leads to earlier diagnosis and intervention with the expectation of a better outcome. in our study; the use of nac was associated with 60% less likely finding of upstaging on final pathology and so a part of adverse pathological outcomes may be explained by the underutilization of nac. in general, delay in cancer diagnosis and treatment is classified into patient delay, health care provider delay, delay in service provider, and finally, treatment delay (11). it has been proposed that differences in socioeconomic status, rural or urban residency, and immigration status can all contribute to disparities in screening, diagnosis staging on presentation, and treatment services (12). despite enormous efforts to provide equity in health care, the distribution of the population due to the geographic characteristics of northern ontario impede some regions from timely access and health monitoring. moreover, there is only one hospital in all of northern ontario that provide urological cancer care. this results in a long waiting list, making timely access to equitable care more difficult for the population. further research is also needed to investigate and identify the factors associated with bladder cancer patients' delayed diagnosis and late-stage presentation in northern ontario. according to our findings, prostate cancer, which is the third leading cause of cancer death in canadian males (5), was discovered incidentally (34%) during a cystectomy, which is consistent with literature reported 23-54% (13, 14). however, 50% of our patients had significant prostate cancer (gleason score ≥ 7 out of 10), which is notably higher than literature. djaladat et al. studied 1964 patients with primary transitional cell carcinoma of the bladder who underwent radical cystectomy. thirty six percent of the patients (n = 559) had incidental prostate cancer with the gleason scores ≤ 6 for 458 (82%) patients (14). another study by mazzucchelli et al. found that the majority (81.3%) of incidentally detected prostate cancers by radical cystoprostoctomy had a gleason score of 4 or less (15). hiros et al. reported 68% of incidental prostate cancer were low grade (gleason scores less than 6) and 32% were high grade (16). one study found that overall survival for patients with incidental prostate cancer was lower than for patients without (28.1 ± 27.5 month vs 45.5 ± 35 month). given the significant impact on overall survival, they highlighted the importance of paying closer attention to this concurrent pathology (13). therefore, given the high prevalence of high grade prostate cancer in our population, it may be practical to assign a greater importance to performing prostate cancer screening during bladder cancer work-up, regardless of the patients’ age. furthermore, additional workup such as mri to rule out prostate cancer is required if a patient chooses trimodal therapy. radical cystectomy is the standard treatment for patients with mibc (17). however, the time of performing cystectomy is controversial. some literature has shown that cysarchivio italiano di urologia e andrologia 2022; 94, 1 v. mehrnoush, s.keramati, a. ismail, w. shabana, a. zakaria, h. elmansy, w. shahrour, o. prowse, a. kotb 44 tectomy after 12 weeks is not associated with an unfavorable outcome (18, 19) while a population-based study and the european association of urology have recommended to not delay cystectomy for more than 3 months due to the increasing risk of progression and mortality (20). based on canadian urological association guideline, the optimal timing of radical cystectomy where nac has not been administered is within six weeks of turbt (21). according to our findings, upstaging was observed in 29 (74.3%) and 6 (30%) of patients who had surgery < 12 weeks and > 12 weeks, respectively. the lower likelihood of upstaging in > 12 week surgery waiting time can be interpreted that the delay in surgery for the sake of receiving nac does not negatively affect the staging and progression. in our study, a lower upstaging rate was found in those who had nac compared to those who did not (21.4% vs 71.1%). however, nac did not significantly decrease the invasion to lymph nodes. the advantages of nac in patients with mibc have been reported in literature. nac is recommended to improve the outcome of radical cystectomy which is the gold standard of treatment in mibc with a 5-year survival of about 50% (22). accordingly, it seems that the rate of perioperative nac in ontario, canada follows an increasing trend from 19% in 2009 to 27% in 2013 (23). however, the rate of perioperative nac in our study was only 23.7%. despite the survival benefit, practicing nac has been underutilized in northern ontario. the finding of this study may prompt urologists and medical oncologists to incorporate nac more frequently in their practice. due to the lack of clinical outcomes, our findings cannot be interpreted as supporting or opposing the controversial opinions on surgery before or after 12 weeks. however, the findings suggest that the surgical delay of more than 12 weeks due to the nac may not negatively impact the pathological outcomes. the interpretation of the current study's results may be limited by the small sample size. furthermore, including only one center negatively affects the external validity of the results while having a positive impact on improving the internal validity of the study. we can conclude that the high rate of pathological upstaging detected in more than half of the patients undergoing radical cystectomy in this study warrants performing multidisciplinary quality improvements including pathology, medical and radiation oncology, and urology. moreover, the high prevalence of younger ages (aged less than 60), upstaging, lymph positive in t2 de novo mibc, call for further investigation of possible causes of delay and potential risk factors for bladder tumors at individual, public, and population health levels in northern ontario. references 1. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2018; 68:394424. 2. bachir bg, kassouf w. cause-effect? understanding the risk factors associated with bladder cancer. expert rev anticancer ther. 2012; 12:1499-1502. 3. delclos gl, lerner sp. occupational risk factors. scand j urol nephrol. suppl 2008; 218:58-63. 4. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital di urol e androl. 2021; 93:15-20. 5. pless b. health promotion and chronic disease prevention in canada: research, policy and practice. [updated 2021 february 4 , cited 2016 april 21. https://www.canada.ca/en/public-health/services/reports-publications/health-promotion-chronic-disease-prevention-canada-research-policy-practice/vol-41-no-2-2021.html. accessed june 28,2021. 6. siemiatycki j, dewar r, nadon l, et al. occupational risk factors for bladder cancer: results from a case-control study in montreal, quebec, canada. am j epidemiol. 1994; 140:1061-80. 7. gaertner rrw, trpeski l, johnson kc. a case-control study of occupational risk factors for bladder cancer in canada. cancer causes control. 2004; 15:1007-19. 8. villanueva cm, fernández f, malats n, et al. meta-analysis of studies on individual consumption of chlorinated drinking water and bladder cancer. j epidemiol community health. 2003; 57:166-73. 9. villanueva cm, cantor kp, king wd, et al. total and specific fluid consumption as determinants of bladder cancer risk. int j cancer. 2006; 118:2040-47. 10. wise s, horn m, geoffrey e. “ontario.” encyclopedia britannica, october 29 2020. https://www.britannica.com/place/ontarioprovince. accessed may 19, 2021. 11. ukwenya ay, yusufu lmd, nmadu pt, et al. delayed treatment of symptomatic breast cancer: the experience from kaduna, nigeria. s afr j surg. 2008; 46:106-10. 12. singh gk, williams sd, siahpush m, et al. socioeconomic, ruralurban, and racial inequalities in us cancer mortality: part i-all cancers and lung cancer and part ii-colorectal, prostate, breast, and cervical cancers. j cancer epidemiol. 2011; 2011:107497. 13. sruogis a, ulys a, smailyte g, et al. incidentally found prostate cancer and influence on overall survival after radical cystoprostatectomy. prostate cancer 2012; 2012:1-5. 14. djaladat h, bruins mh, skinner ec, et al. incidental prostate cancer in patients with radical cystectomy for bladder cancer. j clin oncol. 2013; 31:s225. 15. mazzucchelli r, barbisan f, scarpelli m, et al. is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant? am j clin pathol. 2009; 131:279-83. 16. hiros m, selimovic m, spahovic h, et al. transrectal ultrasoundguided prostate biopsy, periprostatic local anesthesia and pain tolerance. bosn j basic med sci. 2010 feb; 10:68-72. 17. degeorge kc, holt hr, hodges sc. bladder cancer: diagnosis and treatment. am fam physician. 2017; 96:507-14. 18. nielsen me, palapattu gs, karakiewicz pi, et al. a delay in radical cystectomy of >3 months is not associated with a worse clinical outcome. bju int. 2007; 100:1015-20. 19. ayres be, gillatt d, mcphail s, et al. a delay in radical cystectomy of >3 months is not associated with a worse clinical outcome. bju int. 2008; 102:10-45. 20. milowsky mi, rumble rb, booth cm, et al. guideline on muscle45archivio italiano di urologia e andrologia 2022; 94, 1 muscle invasive bladder cancer in northern ontario invasive and metastatic bladder cancer (european association of urology guideline): american society of clinical oncology clinical practice guideline endorsement. j clin oncol. 2016; 34:1945-52. 21. kulkarni gs, black pc, sridhar ss, et al. canadian urological association guideline: muscle-invasive bladder cancer. can urol assoc j. 2019; 13:230-38. 22. porter mp, kerrigan mc, donato bmk, et al. patterns of use of systemic chemotherapy for medicare beneficiaries with urothelial bladder cancer. urol oncol. 2011; 29:252-58. 23. booth cm, karim s, brennan k, et al. perioperative chemotherapy for bladder cancer in the general population: are practice patterns finally changing? urol oncol. 2018; 36:89.e13-89.e20. correspondence vahid mehrnoush, md vahidmehrnoush7@gmail.com shahrzad keramati, md shz.keramati@gmail.com asmaa ismail, md asmaaismail0782@gmail.com waleed shabana, md waleed.shabana@gmail.com ahmed zakaria, md aszakaria81@yahoo.com hazem elmansy, md hazemuro100@yahoo.com walid shahrour, md walid.shahrour@gmail.com owen prowse, md owenprowse@rogers.ca ahmed kotb, md, phd, frcs urol, febu (corresponding author) drahmedfali@gmail.com assistant professor northern ontario school of medicine tbrhsc 980 oliver road, thunder bay, on, canada. p7b 6v4 305archivio italiano di urologia e andrologia 2017; 89, 4 original paper longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients treated with conventional medical and dietetic therapy simone brardi 1, gabriele cevenini 2, vanni giovannelli 3, giuseppe romano 4 1 hemodialysis unit, s. donato hospital, arezzo, italy; 2 department of medical biotechnologies, university of siena, italy; 3 urology unit, s. donato hospital, arezzo, italy; 4 urology unit, s. maria della gruccia hospital, montevarchi, italy. objective: this longitudinal prospective observational type study was conceived with the aim to examine the impact on renal resistive index (rri) of the variables that we can manipulate with therapeutic and or dietetic interventions in a chronic kidney disease population in order to known which of these variables was statistically related to changes in rri and therefore could become the object of the greatest therapeutic effort. material and methods: this study was undertaken between may 2016 to may 2017 in the outpatient nephrology and urology clinic of san donato hospital in arezzo. the study population (84 patients: 47 males and 37 females) was randomly selected among the chronic kidney patients (with various degrees of renal impairment) affected by hypertension and or diabetes mellitus. after a comprehensive medical examination these patients were submitted to determination of serum creatinine, glycated hemoglobin, 24-hour urinary albumin excretion and finally renal doppler ultrasonography. then the patients were submitted to a full therapeutic and dietetic intervention to ameliorate the renal impairment by a wide range of actions and after on average a one-year interval were submitted again to a new medical examination and a second determination of serum creatinine, glycated hemoglobin, 24-hour urinary albumin excretion and a new renal doppler ultrasonography too. results: the comparison between basal and final data revealed a slight reduction in the mean of bilateral renal resistance indices (delta rri: -0.0182 ± 0.08), associated to a slight increase in the mean glomerular filtration rate (delta gfr: 0.8738 ± 10.95 ml/min/1.73 m2), a reduction in mean body weight (delta weight: -1.9548 ± 5.26 kg) and mean bmi (delta bmi: -0.7643 ± 2.10 kg/m2) as well as a reduction in the mean systolic blood pressure (delta systolic blood pressure: -8.8333 ± 25.19 mmhg). statistical analysis showed statistically significant correlations (p < 0.05) between delta rri and delta weight (p < 0.03), delta bmi (p < 0.02) and delta systolic blood pressure (p < 0.05). conclusion: despite the many limitations the our study clearly identifies the targets (yet widely known) to act on to prevent kidney alterations related to rri and provides further evidence, if any, of the utility of rri as a key parameter in monitoring patients with chronic renal failure and as a valuable tool to drive the clinical efforts to contrast the kidney disease. key words: longitudinal prospective observational type study; renal ultrasonography; renal resistive index; chronic kidney patients; conventional medical and dietetic therapy. submitted 15 september 2017; accepted 26 september 2017 summary no conflict of interest declared. introduction the renal resistive index (rri) in segmental and interlobar arteries of the kidney is calculated on the basis of pourcelot’s equation as the ratio of the difference between the maximum systolic velocity (vs) and the enddiastolic velocity (vd) to the maximum systolic velocity: ri = (vs-vd)/vs (1). normal rri values in adults are in the range of 0.47-0.70 with a difference between two kidneys of < 5-8% (2). rri has shown to be related with glomerulosclerosis, arteriolosclerosis and tubulointerstitial lesions more than others morphologic parameters like renal length and cortex area (3). although rri examinations do not recognize among different renal medical pathologies, patients with higher rri (< 0.7) generally show more severe arteriolosclerosis than others with normal (< 0.65) or high normal rri (0.65 ≤ ri < 0.7) so that in mild to moderate renal dysfunction rri predicts ckd progression and poor outcome especially when rri ≥ 0.7 (3-6). also in the patients affected by diabetic nephropathy (where rri is higher in comparison with those affected by others kidney diseases with an equivalent gfr) in both < 60 and > 60 years old subjects and even in subjects on ras inhibitors therapy or not, sugiura et al. (7) proved that a rri > 0.7 is an independent predictor of the risk of worsening renal function. renal resistive index is therefore tightly related to renal arteriolosclerosis (4) and represents an integrated index of arterial compliance, pulsatility and downstream microvascular impedance. moreover since rri is markedly affected by renal (renal interstitial and venous pressure) and systemic (aortic stiffness, pulse pressure) determinants (8) rri not only predicts renal prognosis (9), as already mentioned, but also gives information regarding general atherosclerotic damage. thus currently, rri is accepted as a well-known marker of renal vascular and interstitial damage, corresponding to an increased total cardiovascular risk (10). to this regard we can cite a study where rri, measured at interlobar arteries, shown to be associated with the doi: 10.4081/aiua.2017.4.305 brardi1_stesura seveso 03/01/18 09:46 pagina 305 archivio italiano di urologia e andrologia 2017; 89, 4 s. brardi, g. cevenini, v. giovannelli, g. romano 306 severity and duration of essential hypertension (11) while in 426 patients with essential hypertension was also demonstrated that impairment of renal hemodynamics, as assessed by an increased rri, was associated with an increased risk of cardiovascular and renal outcomes (12). moreover it is also known that rri decreases with use of renin angiotensin system (ras) inhibitors, due to the hemodynamic changes induced by these antihypertensive agents. (13) anyway there are some points that still need to be clarified and among these it is not known whether and how much dietetic and therapeutic interventions may affect rri (10) except for the fact that rri, as already mentioned, is known to decrease with use of ras inhibitors (13) and that it is also known that intensive blood pressure lowering to the recommended values is associated with a significant improvement of intrarenal arterial functional properties and renal function (14). moreover longitudinal population studies are still needed to clarify whether doppler changes in intrarenal arteries may be associated to an improvement in the cardiovascular and renal outcome in the hypertensive patients (15). so with the aim to examine the impact on rri of the variables that we can manipulate with therapeutic and or dietetic interventions in a chronic kidney disease population we concept this pivotal longitudinal prospective study in order to known which of these variables was statistically related to changes in rri and therefore it could become the subject of the greatest therapeutic effort. materials and methods this study was undertaken between may 2016 to may 2017 in the outpatient nephrology and urology clinic of san donato hospital in arezzo. the study population was randomly selected among the chronic kidney patients (with various degrees of renal impairment) and affected by hypertension and or diabetes mellitus with exclusion of those with obstructive uropathy, acute or chronic glomerulonephritis, tubulointerstitial renal diseases, renal artery stenosis and malignant disease. the same population was already treated by a variety of drugs including ras inhibitors too. so we enrolled 84 patients (47 males and 37 females, with an average age of 74.5 ± 11 years) almost all with hypertension (except only four) and affected by diabetes mellitus with a rate of 54%. the average glomerular filtration rate (gfr) (calculated by the ckd epi equation) (16), was 43 ± 18 ml/min/1.73 m2 (table 1). after the evaluation of medical history and physical examination, comprehensive of the recording of weight and height, a measure of blood pressure was taken with a mercury sphygmomanometer applied around each patient’s non-dominant arm after the patient had rested for 15 minutes in a sitting position and with his/her arm placed at the level of the heart. two consecutives blood pressure recordings, taken at 5 minute interval, were averaged to provide clinic sistolic and diastolic blood pressure values. then these patients were submitted to determination of serum creatinine, glycated hemoglobin, 24-hour urinary albumin excretion and finally renal doppler ultrasonography. all examinations were carried out by the same nephrologist experienced in ultrasound examination using the same ultrasound device that was a logiq s7 (ge medical systems italy s.p.a. milan, italy) sonographic system equipped with 3 to 5 mhz transducers. doppler signals were obtained from the interlobar arteries from the upper, middle and lower third of both kidneys and resistive index was calculated as the average of 6 measurements (3 from each of the 2 kidneys) taken for each patient. the doppler angle was chosen as close to 0° as possible and special care was taken not to compress the kidney and not to have the patient performing valsalva maneuver because both of them can increase the renal resistive index value. we recorded also the diameters in the longitudinal axis of each kidney and finally the cortical thickness of each kidney, measured in the portion closer to the upper pole and the lower pole of the same kidney. then the patients were submitted to a full therapeutic and dietetic intervention to ameliorate the renal impairment by a wide range of actions such as removal of nephrotoxic drugs (eg. metformine, hydroclorothiazide diuretics, etc.), improvement of blood pressure and proteinuria by a strengthened therapy and/or by introducing, in relation to blood pressure control and the entity of proteinuria, new antihypertensive medications among which ras inhibitors and/or non-dihydropyridine calcium channel blockers (17) (considering not all the population or even most of it was treated by ras inhibitors). furthermore it was ameliorated the control of the diabetes by new drugs or higher doses of pre-existing drugs. eventually, when it was indicated, it was introduced an hypoproteic, hyposodic and hypoglicemic as well as hypocaloric diet (18, 19). after on average a one-year interval the same patients were submitted again to physical examination comprehensive of the recording of weight and clinic blood pressure measurement performed with the same modalities above mentioned. then these patients were also submitted to a second detertable 1. baseline characteristics of the population enrolled. parameter average standard deviation age (years) 74.5 11 weight (kg) 77.0 13.1 body mass index (kg/m2) 29.0 4.1 glomerular filtration rate (ml/min/1.73 m2) 43 18 24-hour urinary albumin excretion (gr/24) 0.4 0.9 glycated haemoglobin (%) 6.3 0.9 renal resistive index (as bilateral mean of renal resistive index) 0.7 0.0 systolic blood pressure (mmhg) 128.7 18.3 diastolic blood pressure (mmhg) 78.7 11.5 mean arterial pressure (mmhg) 95.4 11.1 brardi1_stesura seveso 03/01/18 09:46 pagina 306 mination of serum creatinine, glycated hemoglobin, 24hour urinary albumin excretion and eventually to a new renal doppler ultrasonography carried out by the above mentioned nephrologist experienced in ultrasound investigation and by using the same ultrasound device. statistics the bivariate linear pearson correlation analysis was applied to variable changes, by evaluating the coefficients r and r-squared. a statistical significance of 95% was considered to assess the association between variables. results the comparison between basal and final control (that we named delta as the variation of a variable between basal and final control) revealed a slight reduction in the mean value of bilateral renal resistive index (delta rri: -0.0182 ± 0.08), associated with a slight increase in the mean glomerular filtration (delta gfr: 0.8738 ± 10.95 ml/min/1.73 m2), a reduction in mean body weight (delta weight: -1.9548 ± 5.26 kg) and in mean bmi (delta bmi: -0.7643 ± 2.10 kg/m2) as well as a reduction in the mean systolic blood pressure (delta systolic blood pressure: -8.8333 ± 25.19 mmhg), mean diastolic blood pressure (delta diastolic blood pressure: -5.0000 ± 15.76 mmhg) and mean arterial pressure (delta mean arterial pressure: -6.2778 ± 17.83 mmhg). on the contrary there was a substantial invariance in average proteinuria (delta proteinuria: 0.0477 ± 0.69 mg/24h) and a slight increase in average glycated haemoglobin (delta glycated haemoglobin: 1.3667 ± 2.61%) (table 2). hence these data were analyzed in order to know what were the parameters whose variation could be significantly associated with the abovementioned change in resistance indices. statistical analysis showed statistically significant correlations (p < 0.05) between delta rri and delta weight (p < 0.03), delta bmi (p < 0.02) and delta systolic blood pressure (p < 0.05). discussion it has to first point out that the population enrolled for our study was composed by chronic kidney failure patients with an average glomerular filtration rate of 43 ± 18 ml/min/1.73 m2 that should be considered as a moderate stage of ckd and not as an advanced stage of ckd, since it is known that patients with advanced stages of ckd (gfr < 30 ml/min/1.73 m2) do not show differences in rri values, because advanced local alterations (vascular and interstitial) on rri exceed systemic factors like pulse pressure (20, 21). furthermore, in order to explain the correlation of the rri with systolic blood pressure, we underline that it is widely known that systemic hemodynamics and peripheral arterial resistance and compliance have been demonstrated to affect the doppler arterial waveform signal obtained in the intrarenal arteries. more in detail a number of studies explored the association of the rri with aortic (central) pulse pressure or peripheral (brachial) pulse pressure. all these studies consistently demonstrated a significant and direct association between the rri and central or peripheral pulse pressure independent of other covariates (15, 22-26). more in detail when renal resistance is increased, renal blood flow declines for a given perfusion pressure and because the decline is more prominent in diastole than in systole it leads to an increase in rri (27). it was also known that stiffening of the aorta and large conduit arteries wall, that is characteristic of the chronic renal failure patients (28) as well as of aging (29), increases systolic blood pressure and decreases diastolic blood pressure, thereby increasing pulse pressure (that is the difference between systolic and diastolic blood pressure) and is a strong predictor of cardiovascular and cerebrovascular mortality (29). more in detail verhave et al. (29), in a cohort of 212 patients with never treated isolated systolic hypertension, found an inverse relationship between pulse pressure and glomerular filtration rate that was only present in patients of 60 years of age or older as the population of our study that was with an average age of 74.5 ± 11 years. in effect the calcium can be deposited into either the intimal (as a rule for older patients with a clinical history of atherosclerosis and conventional risk factors for atherosclerotic disease) or medial layers of the vasculature and calcium deposition in the medial layer, a common finding in end-stage renal disease, is associated with stiffening of the vasculature, resulting in adverse cardiovascular outcomes (28). it is also known that insulin resistance, which is highly prevalent in diabetes mellitus type 2 and hypertension, is associated with several metabolic abnormalities, namely, obesity, essential hypertension, dyslipidemia, inflammation and impaired glucose metabolism (30). more in detail, since 1996 steinberg et al. (31) first demonstrated that obesity is associated with peripheral endothelial dysfunction, which may be related to insulin resistance. as then insulin resistance is closely related with systemic atherosclerosis (32) and increased rri is related with atherosclerotic renal artery damage too (33) so that rri it is considered a sensitive marker of atherosclerosis and it is believed that an increased insulin resistance may be independently related with increased rri (30). in this way since a relevant component of the insulin resistance is the overweight (34) and in fact our population showed bmi values close to the obesity with an aver307archivio italiano di urologia e andrologia 2017; 89, 4 longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients... table 2. variation (delta) of the variables between basic and final evaluation. parameter average standard deviation n. delta rri -0.0182 0.08 84 delta weight -1.9548 5.26 84 delta bmi -0.7643 2.10 84 delta gfr 0.8738 10.95 84 delta proteinuria 0.0477 0.69 84 delta hba1c 1.3667 2.61 84 delta systolic blood pressure -8.8333 25.19 84 delta diastolic blood pressure -5.0000 15.76 84 delta mean arterial pressure -6.2778 17.83 84 brardi1_stesura seveso 03/01/18 09:46 pagina 307 archivio italiano di urologia e andrologia 2017; 89, 4 s. brardi, g. cevenini, v. giovannelli, g. romano 308 age basal bmi of 29 ± 4.1 kg/m2, we suppose that the reduction of weight and bmi obtained during the study by the dietetic therapy, which led a final average bmi of 28.3 ± 4.1 kg/m2, may have reduced the entity of the insulin resistance so obtaining a reduction of the rri. about the lack of correlation between rri and proteinuria it is possible that rri could be correlated with albumin excretion only in later stages when albumin excretion reaches a certain limit. these observations may also account for the common finding of an increase in rri values in patients with diabetes even if with normal urinary albumin (10, 35). therefore since rri significantly correlates with the degree of proteinuria by resulting higher in patients with macroalbuminuria (> 300 μg/mg creatinine) than in patients with normal urinary albumin or with microalbuminuria (35) and being in our study proteinuria of a modest entity (average basal proteinuria: 0.49 ± 0.97 gr/24h) with a substantial invariance over the course of the study, this could explain why we did not find a statistically correlation between rri and proteinuria. finally about the lacking relationship between rri and glycated haemoglobin we note that poor control of blood glucose, as represented by increased hba1c, affected the magnitude of decrease in rri in patients with type 2 diabetes (36). in fact rri is mainly influenced by renal microcirculation and systemic factors such as atherosclerosis of big vessel and pulse pressure and in our population we recorded a slightly increase of delta hba1c too (10). conclusions about the relationship between delta rri and delta blood systolic pressure our data are in line with the already known concept that a strict blood pressure control is necessary for renoprotection and clearly suggest a beneficial effect of a similar intensive blood pressure reduction. in effect it was already demonstrated that a significant blood pressure lowering to recommended values is associated with a significant improvement of intrarenal arterial functional properties and renal function (14). similarly obesity is a major risk factor for essential hypertension, diabetes, and other comorbid conditions that contribute to the development of chronic kidney disease (37). in fact obesity among the his many adverse effects raises blood pressure by increasing renal tubular sodium reabsorption, impairing pressure natriuresis, and causing volume expansion via activation of the sympathetic nervous system and renin-angiotensin-aldosterone system ultimately leading to glomerular injury that exacerbates hypertension and worsens renal injury (37). in accordance with hall et al. (37) we suppose therefore that a body weight reduction, via caloric restriction and increased physical activity, is an important first step for the management of obesity, hypertension, and chronic kidney disease. despite its many limitations our study clearly identifies the targets (yet widely known) to act on in order to prevent glomerulosclerosis, arteriosclerosis and tubule interstitial lesions that have shown to be related to rri more than to others morphologic parameters like renal length and cortex area (3, 38). furthermore it provides further evidence, if any, of the utility of rri as a key parameter in monitoring patients with chronic renal failure (38) and as a valuable tool to drive the clinical efforts to contrast the kidney disease. references 1. pourcelot l. applications cliniques de l’examen doppler transcutanè. in peronneau p (ed). velocimetrie ultrasonore doppler. paris. seminare institut national de la santè et de la recherche medicale. 1975; pp 213-40. 2. lubas a, kade g, niemczyk s. renal resistive index as a marker of vascular damage in cardiovascular diseases. int urol nephrol. 2014; 46:395-402. 3. hanamura k, tojo a, knugasa s, et al. the resistive index is a marker of renal function, pathology, prognosis, and responsiveness to steroid therapy in chronic kidney disease patients. int j nephrol. 2012; 139565. 4. ikee r, kobayashi s, hemmi n, et al. correlation between the resistive index by doppler ultrasound and kidney function and histology. am j kidney dis. 2005; 46:603-9. 5. parolini c, noce a, staffolani e, et al. renal resistive index and long-term out come in chronic nephropathies. radiology. 2009; 25283:888-896. 6. quaia e, bertolotto m. renal parenchymal diseases: is characterization feasible with ultrasound? eur radiol. 2002; 12:2006-2020. 7. sugiura t, wada a. a resistive index predicts renal prognosis in chronic kidney disease. nephrol dial transplant. 2009; 24:27802785. 8. tublin me, bude ro, platt jf. the resistive index in renal doppler sonography: where do we stand? ajr am j roentgenol. 2003; 180:885-892. 9. radermacher j, ellis s, haller h. renal resistance index and progression of renal disease. hypertension. 2002; 29:699-703. 10. afsar b, elsurer r. increased renal resistive index in type 2 diabetes: clinical relevance, mechanisms and future directions. diabetes metab syndr. 2016; pii: s1871-4021(16)30172-2. 11. veglio f, provera e, pinna g, et al. renal resistive index after captopril test by echo-doppler in essential hypertension. am j hypertens. 1992; 5:431-6. 12. doi y, iwashima y, yoshihara f, et al. renal resistive index and cardiovascular and renal outcomes in essential hypertension. hypertension. 2012; 60:770-777. 13. leoncini g, martinoli c, viazzi f. change in renal resistive index and urinary albumin excretion in hypertensive patients under long-term treatment with lisinopril and nifepidine gits. nephron. 2002; 90:169-173. 14. lubas a, zelichowski g, prochnicka a, et al. renal vascular response to angiotensin ii inhibition in intensive antihypertensive treatment of essential hypertension. arch med sci. 2010; 4:533-538. 15. cauwenberghs n, kuznetsova t. determinants and prognostic significance of the renal resistive index. pulse. 2015; 3:172-178. 16. levey as, stevens la, et al. a new equation to estimate glomerular filtration rate. ann intern med. 2009; 150:604-612. 17. the gisen group (gruppo italiano di studi epidemiologici in nefrologia). randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal brardi1_stesura seveso 03/01/18 09:46 pagina 308 renal failure in proteinuric, non-diabetic nephropathy. lancet 1997; 349:1857-63. 18. shah bv. patel zm. role of low protein diet in management of different stages of chronic kidney disease practical aspects. bmc nephrology. 2016; 17:156. 19. di iorio b, de santo ng, anastasio p, et al. the giordanogiovannetti diet. j nephrol. 2013; 26 (suppl 22):s143-52. 20. kawai t, kamide k, onishi m, et al. usefulness of the resistive index in renal doppler ultrasonography as an indicator of vascular damage in patients with risk of atherosclerosis. nephrol dial transplant. 2011; 26:3256-3262. 21. heine gh, reichart b, ulrich c, et al. do ultrasound renal resistance index reflect systemic rather than renal vascular damage in chronic kidney disease? nephrol dial transplant. 2007; 22:163-170. 22. ponte b, pruijm m, ackermann d, et al. reference values and factors associated with renal resistive index in a family-based population study. hypertension. 2014; 63:136-142. 23. kuznetsova t, cauwenberghs n, knez j, et al. doppler indexes of left ventricular systolic and diastolic flow and central pulse pressure in relation to renal resistive index. am j hypertens. 2015; 28:535-545. 24. hashimoto j, ito s. central pulse pressure and aortic stiffness determine renal hemodynamics: pathophysiological implication for microalbuminuria in hypertension. hypertension. 2011; 58:839-846. 25. stea f, sgrò m, faita f, et al. relationship between wave reflection and renal damage in hypertensive patients: a retrospective analysis. j hypertens. 2013; 31:2418-2424. 26. tedesco ma, natale f, mocerino r, et al. renal resistive index and cardiovascular organ damage in a large population of hypertensive patients. j hum hypertens. 2007; 21:291-296. 27. shimizu y, itoh t, hougaku h, et al. clinical usefulness of duplex ultrasonography for the assessment of renal arteriosclerosis in essential hypertensive patients. hypertens res. 2001; 24:13-7. 28. london gm, guérin ap, marchais sj, et al. arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. nephrol dial transplant. 2003; 18:1731. 29. verhave jc, fesler p, du cailar g, et al. elevated pulse pressure is associated with low renal function in elderly patients with isolated systolic hypertension. hypertnesion. 2005; 45:586-91. 30. afsar b, elsurer r, sezer s, et al. insulin resistance is associated with increased renal resistive index independent of other factors in newly diagnosed type 2 diabetes mellitus and hypertensive patients. metabolism clinical and experimental. 2010; 59:279-284. 31. steinberg ho, chaker h, leaming r, et al. obesity/insulin resistance is associated with endothelial dysfunction. implications for the syndrome of insulin resistance. j clin invest. 1996; 97:2601-10. 32. hills sa, balkau b, coppack sw, et al. the egir-risc study (the european group for the study of insuline resistance: relationship between insulin sensitivity and cardiovascular disease risk). i. methodology and objectives. diabetologia. 2004; 47:566-70. 33. pontremoli r, viazzi f, martinoli c, et al. increased renal resistive index in patients with essential hypertension: a marker of target organ damage. nephrol dial transplant. 1999; 14:360-5. 34. schindler th, cardenas j, prior jo, et al. relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function. j am coll cardiol. 2006; 47:1188-95. 35. hamano k, nitta a, ohtake t, et al. association of renal vascular resistance with albuminuria and other macroangiopathy in type 2 diabetic patients. diabetes care. 2008; 31:1853-1857. 36. tawaniki h, nishizawa y, kawagishi t, et al. decrease in glomerular filtration rate in japanese patients with type 2 diabetes is linked to atherosclerosis. diabetes care. 1998; 21:1848-55. 37. hall me, do carmo jm, da silva aa, et al. obesity, hypertension and chronic kidney disease. international journal of nephrology and renovascular disease. 2014; 7:75-88. 38. spatola l, andrulli s. doppler ultrasound in kidney disease: a key parameter in clinical long-term follow-up. j ultrasound. 2016; 19:243-250. 309archivio italiano di urologia e andrologia 2017; 89, 4 longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients... correspondence simone brardi, md hemodialysis unit, s. donato hospital, arezzo, italy gabriele cevenini, md department of medical biotechnologies, university of siena, italy vanni giovannelli, md urology unit, s. donato hospital, arezzo, italy giuseppe romano, md urology unit, s. maria della gruccia hospital, montevarchi, italy brardi1_stesura seveso 03/01/18 09:46 pagina 309 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2144 original paper no conflict of interest declared. non-muscle invasive disease, bladder cancer can often recur or even progress (2). currently, radical cystectomy (rc) is considered as the gold standard for treating muscle-invasive bladder cancer (1). unfortunately, it continues to be one of the surgical procedures with the highest rates of morbidity and mortality to date (3). although chronological age is an important risk factor for development of intraand peri-operative complications, several concurrent losses in resources, should be considered in the estimation of surgical risk (4). actually, frailty has been recognized as the most important predictor of poor postoperative outcomes. although there is still no consensus on clinical definition of frailty (6), some authors refer to it as “a state of reduced physiologic reserve beyond that would be expected with normal aging”. it is thought to be the final product from the cumulative effect of multiple physiologic changes over time (5). fried et al. designed a list that could help clinicians in assessing general physical state of patients and listed these components as a part of frail phenotype: a) self-reported weight loss; b) self-reported exhaustion; c) low energy expenditure; d) slow gait speed; e) weak grip strength (6). frail patients have a compromised pulmonary function, decreased time to desaturation, higher hypoxia and hypercarbia. altered renal and hepatic functions are also frequent, with consequent decreased drug metabolism, dehydration, electrolyte disbalance and increased haemorrhagic and drug toxicity risk. lastly, because of the sarcopenia and generally reduced serum albumin, they are more prone to hypothermia and are more sensitive to effect of the anaesthetics (7). consequently, a frail patient is more vulnerable to a stressor event and has a lower capacity of recovery after the stressor stimulation ceases. furthermore, the prevalence of frailty increases with age. considering that the life expectancy has increased by more than two years per decade since the 1960s (8), the proportion of elderly population diagnosed with bladder cancer undergoing cystectomy has been rising as well. although not conducted on a frail population, berger et al. published a retrospective, multicenter study comparing the rates of complications in ureterocutaneostomy (ucs) and urinary diversion using bowel. they observed reduced operative time, shorter stay in intensive care unit introduction and objectives: radical cystectomy (rc) continues to be standard of care for muscle-invasive bladder cancer and recurrent or refractory nonmuscle invasive bladder cancer. unfortunately, it has high rates of perioperative morbidity and mortality. one of the most important predictors of postoperative outcomes is frailty, while the majority of complications are diversion related. the aim of our study was to evaluate safety of extraperitoneal cystectomy with ureterocutaneostomy in patients considered as frail. materials and methods: we retrospectively collected data of frail patients who underwent extraperitoneal cystectomy with ureterocutaneostomy from october 2018 to august 2020 in a single center. we evaluated frailty by assessing patients' age, body mass index (bmi), nutritional status by malnutrition universal screening tool, overall health by rai (risk analysis index) and asa (american society of anaesthesiologists) score, and laboratory analyses. we observed intraoperative outcomes and rates of perioperative (within 30 days) and early postoperative (within 90 days) complications (clavien-dindo classification). we defined extraperitoneal cystectomy with ureterocutaneostomy as safe if patients did not develop clavien dindo iiib, or worse, complication. results: a total of 34 patients, 3 female and 31 male, were analyzed. the median age was 77, bmi 26, rai 28, asa 3 and the majority had preexisting renal insufficiency. blood analyses revealed presence of severe preoperative hypoalbuminemia and anemia in half of our cohort. intraoperative median blood loss was 250 cc, whilst operative time 245 min. during perioperative period 60% of our cohort developed clavien dindo ii complication and during early postoperative period 32% of patients required readmission. one death occurred during early postoperative period (2.9%). after 12 months of follow-up, we observed stability of the renal function for most patients. conclusions: we believe that extraperitoneal cystectomy with ureterocutaneostomy could be considered as a treatment option for elderly and/or frail patients. key words: bladder cancer; extraperitoneal cystectomy; ureterocutaneostomy; frailty; feasibility. submitted 14 january 2022; accepted 16 april 2022 introduction when both sexes are considered, bladder cancer is one of the most common cancers worldwide, sitting at the 7th place (1). although the majority of patients present with extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients should it be performed more often? rafaela malinaric 1, guglielmo mantica 1, federica balzarini 1, carlo terrone 1, massimo maffezzini 2 1 department of urology, san martino hospital, university of genoa, genoa, italy; 2 department of urology, hospitals of legnano and magenta, milan, italy. doi: 10.4081/aiua.2022.2.144 summary 145archivio italiano di urologia e andrologia 2022; 94, 2 extraperitoneal cystectomy in fragile patients and significantly lower complication rates (graded as clavien iii-v) in ucs group (9). moreover, a great part of data present in the literature reports that most perioperative and postoperative complications are diversion realted (10). when treating frail patients, the main goal is, when possible, to achieve radicality, or, when this is not achievable, to provide a patient a decent quality of life. in fact, by performing cystectomy, patients will not experience anymore recurrent hematuria, suprapubic pain, lumbar discomfort, dysuria or urinary retention. a lot of studies demonstrated successful outcomes after surgery performed on frail patients, but there is little evidence on patients undergoing radical cystectomy (11-13). therefore, the aim of our study was to evaluate the safety of extraperitoneal cystectomy with ucs performed on frail and/or elderly patients. materials and methods study design we retrospectively collected clinical and pathological data of frail patients who underwent extraperitoneal cystectomy with ucs from october 2018 to august 2020 in a single center. patients were considered frail if they met 3 or more of the following criteria: advanced age (> 70), low or high body mass index (bmi) (< 18 and > 25), altered nutritional status [malnutrition universal screening tool (must) > 1] (14) and altered general physical health [risk analysis index (rai) > 25] (15), american society of anesthesiology (asa) score > 3 (16), preoperative anemia (< 12 g/dl), renal insufficiency [serum creatinine (crs) > 1.3 g/dl, egfr < 60] and hypoalbuminemia (< 3 mg/dl). the must questionnaire considers three factors: bmi, unintentional weight loss and inability of the oral nutritional intake due to acute illness (> 5 days). after appropriate evaluation, risk of malnutrition can be appropriately designated as low risk (score 0), medium risk (score 1), high risk (score 2 or more) (14). risk analysis index is a simplified porock's 6-months mortality index developed in 2015. it assesses age, sex, presence of malignancy, medical comorbidities, residence, cognition and daily activities. once the questionnaire is filled, the score matches the risk of perioperative and postoperative complications development (15). lastly, patients were assigned their asa score (16). evaluating patients in this, more holistic manner, we were able to identify the most fragile, sarcopenic, malnourished patients with highly catabolic disease that could benefit from extraperitoneal cystectomy with ucs. preoperatively all patients underwent ct or mri imaging in order to complete clinical staging. consent form was obtained from all the patients prior to surgery. all patients were operated by one, same surgeon (m.m.) with more than 200 extraperitoneal cystectomies performed and 2 decades of experience in the field of open, uro-oncologic surgery. female patients who were considered frail and with advanced disease underwent genital sparing extraperitoneal cystectomy, whilst frail male patients underwent standard extraperitoneal cystectomy. lymph node dissection was performed only in significant, clinically evident lymphadenopathy (gross and palpable lymph nodes). frail patients with non-metastatic disease underwent radical extraperitoneal cystectomy with standard lymph node dissection (up to the common iliac arteries). all patients received ucs as urinary diversion, and all the procedures were performed using the open approach. intraoperatively 4.8 ch "bracci pattern" ureteral catheters were positioned. two weeks postoperatively "bracci" catheters were substituted with ureteral catheters in polyurethane (wiruthan). eras protocol was implemented, when possible, with epidural catheter positioning, antithrombotic prophylaxis with heparin 100 units/kg/24h (fractioned in two doses) for 3-4 weeks, antibiotic prophylaxis with clindamycin 1200 mg/24h and metronidazole 1000 mg/24h (both fractioned in two doses) for 48 hours postoperatively. in case of allergies, they were substituted by piperacillin/ tazobactam 13.5 g/24h (fractioned in three doses). all drugs were adjusted based on cardiac, renal and hepatic function. postoperatively patients entered our standard follow-up protocol, with ct scans repeated quarterly or biannually, complete blood panel, urinalysis and urine cytology, depending on the intent of cystectomy (curative or not) and their final pathology findings. ureteral catheters were substituted in ambulatory setting every 3-4 weeks in absence of infections, calcifications and obstruction. data collection and classification of complications patients’ information was collected from hospital database. we assessed duration of the surgery, anaesthesia protocol and blood loss, whilst data regarding histopathological reports were recorded according the tnm classification approved by the union international contre le cancer (uicc) (8th edn.) (17). subsequently, we observed duration of the hospital stay, hematologic and biochemical alterations, perioperative (within 30 days) and early postoperative (within 90 day) complications (clavien dindo classification) (18) and readmission rates. outcomes we hypothesized that this surgical technique would be a safer approach when treating frail and elderly patients, decreasing the risk of perioperative morbidity and mortality. we considered extraperitoneal cystectomy with ucs a safe procedure if patients did not develop any clavien dindo > iiib complication. statistical analysis descriptive statistics included frequencies and proportions for categorical variables. means, medians, and interquartile ranges (iqr) were reported for continuously coded variables. we considered age, bmi, must score, asa score, rai score, preoperative and postoperative laboratory results, tumor pathological stage and postoperative outcomes. the mann-whitney and fisher’s exact test examined the archivio italiano di urologia e andrologia 2022; 94, 2 r. malinaric, g. mantica, f. balzarini, c. terrone, m. maffezzini 146 statistical significance of mean and distribution differences among patients with or without complications. the characteristics of patients with and without complications were compared with the mann-whitney and fisher’s exact tests, accordingly. all tests were two sided with a level of significance set at p < 0.05. r software environment for statistical computing and graphics (version 4.1.3) was used for all analyses (r core team 2021). r: a language and environment for statistical computing. r foundation for statistical computing, vienna, austria. available at: url https://www.r-project.org/.) results patient population and perioperative characteristics we collected data of 34 patients, 3 (8.8%) females and 31 (91.2%) males, that met the frailty criteria. the median follow-up was 12 (5.75-15.25) months. the majority of the patients (86%) were 70 years old or older, with median age of 77.5 (iqr 71.1-80.2), and were smokers (58.8%). median bmi was 26 and most of them already had preexisting renal insufficiency (median crs 1.33 mg/dl (iqr 1.17-1.62), with an egfr 35.5). seventeen (50%) patients reported unvoluntary weight loss three months prior to surgery, 12 (35%) were medium risk for malnutrition, while 5 (15%) were high risk. all the high-risk patients were referred to the specialized dietitian (table 1). median rai score was 28 (iqr 25.0-31.0), in fact 30 (88%) patients scored over 25. furthermore, most patients (23, 68%) were classified as asa 3 (tables 1-2). thirty-three (97%) patients had a preoperative hypoalbuminemia (serum albumin ≤ 3 g/dl) and 22 (64.7%) anemia (hemoglobin ≤ 12.5 g/dl) (table 2). overall, 27 (79.4 %) patients presented with symptomatic disease including suprapubic pain, recurrent macrohematuria and urinary retention (table 2). seven patients (20.5%) presented with bcg refractory disease. none of the patients underwent neoadjuvant chemotherapy because of late stage of the disease, or because of the general health status and advanced age. one patient did, however, undergo pelvic radiotherapy that caused actinic hematuria and severe anemization (table 2). cystectomy was radical in 23 patients (68%) and palliative in 11 (34%) with no lymphadenectomy (table 1). median duration of surgery (skin-to-skin) was 245 (124420) minutes and registered blood loss was 250 (100800) ml. eras protocol was applied in all eligible patients (20 patients, 59%). on the contrary, 14 patients underwent general anesthesia with use of opioids for analgesia. on the final histopathological examination 4 (12%) patients had a pta urothelial tumor, 5 (14%) pt1, 9 (27%) pt2, 7 (20%) pt3 and 9 (27%) pt4, respectively. a mean of 8 lymph nodes per patients was removed and 4 patients (12%) had lymph node metastases. the same number of patients (4, 12%) had a distant organ metastasis ab initio. furthermore, in our cohort for 11 (32%) patients the surgery was not radical, and they did not undergo pelvic lymph node dissection. finally, 5 (15%) patients had a positive surgical margin, all with pt4 tumor. clinical outcome median hospital stay was 13 (range 7-87) days. postoperatively, renal function remained stable (median creatinine increase was 0.09 mg/dl) for the majority of patients. two patients had a major drop [from 6.2 mg/dl to 5.0 mg/dl on 3rd postoperative day (pod) and from 6.0 mg/dl to 4.4 mg/dl on 3rd pod], one had a major increase (from 3.8 mg/dl to 7.2 mg/dl 3rd pod). noticeably, the same patient who had an increase in crs,table 1. descriptive characteristics of 34 patients treated with extraperitoneal cystectomy and ureterocutaneostomy from october 2018 to august 2020 characteristics n = 34 * age, (years) 77.5 (71.1, 80.2) female 3 (8.8%) male 31 (91.2%) bmi, (kg/m2) 26.0 (24.0, 30.0) preoperative creatinine, (mg/dl) 1.33 (1.17, 1.60) preoperative albumin, (g/dl) 3.20 (2.62, 3.77) preoperative hemoglobin (g/dl) 12.15 (10.7, 13.28) must score 0 17 (50%) 1 12 (35%) 2 5 (15%) asa score 1 1 (2.9%) 2 9 (26%) 3 23 (68%) 4 1 (2.9%) rai 28.0 (25.0, 31.0) * median (iqr); n (%). table 2. general patients' characteristics and number/percentage of patients divided by various subgroups. characteristics n = 34 * age ≥ 75 years 33 (97%) history of smoking 20 (58.8%) bmi ≤ 21 or ≥ 25 (kg/m2) 24 (70.6) preoperative albumin < 3 g/dl 33 (97%) preoperative hemoglobin < 12.5 g/dl) 22 (64.7%) asa score ≥ 3 25 (73.5%) rai score ≥ 25 30 (88.2%) bcg refractory disease 7 (20.5%) pathological stage > ct3 16 (47%) cn+ 8 (23.5%) cm+ 4 (11.7%) clinical symptoms 27 (79.4%) more than one variable combined 34 (100%) * n (%). 147archivio italiano di urologia e andrologia 2022; 94, 2 extraperitoneal cystectomy in fragile patients had a pt4 bladder cancer at the final pathology and a severe preoperative and postoperative hypoalbuminemia. subsequently, he developed surgical site infection (ssi) during hospital stay and later required readmission. most patients passed gas in the 2nd pod (21 pts, 62%, range 1-3 pod) and one third of patients passed feces in 5th pod (10, 30%, range 3-15 pod). perioperative complications during hospital stay 20 (58.8%) patients developed clavien dindo >/= ii grade complication [12 ssi, 2 paralytic ileus, 1 acute kidney injury, 15 blood transfusions, 4 urinary tract infections (utis), 2 atrial fibrillations and 1 lymphocele]. eight (24%) patients developed more than one complication requiring simultaneous administration of antibiotics and blood components. only 2 (5.9%) patients developed clavien dindo iii complication (two deep subfascial infections, of which one with simultaneous evisceration). both patients were treated with vacuum assisted closure therapy (vac) (19), and the patient with evisceration underwent surgical correction using linberg flap technique. a strong association between perioperative hypoalbuminemia and ssi was noted. all the patients with ssi (12, 35.29%) had a marked hypoalbuminemia (≤ 3 g/dl) on the 3rd pod and the majority of them (10 patients) had it also preoperatively, being at medium/high risk of malnutrition. an association between bmi (> 25) and septicemia was observed in 6 patients of 8 (75%) who developed fever. higher rates of complications and readmission rates were noted in patients that had asa score > 3 and presented medium/high risk of malnutrition. during perioperative period there were no deaths observed due to the surgical complications. postoperative complications during early postoperative period (within 90 days) 11 (32%) patients required a readmission. most of complications were infectious, refractory to the antibiotic therapy administered by general medicine physician: 2 ssis (5.9%) and 5 utis (14.7%). less frequent complications were: 2 lymphoceles (5.9%), 1 pulmonary thromboembolism (2.9%) and 1 intestinal subocclusion (2.9%). all were classified as clavien dindo grade ii (table 3). rates of readmission showed a similar trend. patients with complications had a significantly higher rai score if compared with patients without complications (p = 0.027) (table 4). lastly, one death occurred during early postoperative period (2.9%) due to recurrent utis and sepsis (table 3). at median postoperative follow-up of 12 (5.75-15.25) months, 7 (20%) patients were dead, 4 due to the disease progression and 3 due to non-cancer specific causes. sixteen (47%) patients were alive without evidence of the disease recurrence. discussion and conclusion remarks approximately 25% of newly diagnosed patients with bladder cancer presented as muscle invasive disease (1), and 2% as locally advanced (pt4) (20), with high probability of manifesting irritative lower urinary tract symptoms (luts), suprapubic pain and gross hematuria. therefore, advanced bladder cancer can be significantly disabling and can worsen patients' quality of life. eau guidelines recommend radical cystectomy as the first treatment option1, mainly because of its' superiority regarding overall survival (os) and cancer specific survival (css) when compared to bladder sparing treatments such as radiotherapy, turbt-t or chemotherapy alone (21). moreover, these treatments could actually make patients' quality of life deteriorate by exacerbating the local symptoms or causing treatment-related symptoms (e.g. actinic colitis) (22). on the contrary, if left untreated, 38% of the patients will present metastasis within 6 months of initial diagnosis (21). radical cystectomy was first described in 1940s and was associated with extremely elevated perioperative mortality, up to 33% (23), but few decades later mortality rates stabilized at 2-5% (3). some authors described up to 13.7% mortality rates during early postoperative period for frail patients (24), whilst some tertiary centers report extremely low rates, as low as 0.5%, that could be explained by patient selection table 4. descriptive characteristics of 34 patients treated with extraperitoneal cystectomy and ureterocutaneostomy from october 2018 to august 2020, stratified by complications. characteristics complication no, n = 14 * yes, n = 19 * p-value ** age, (years) 76.7 (72.3, 80.0) 77.8 (71.8, 80.5) > 0.9 bmi, (kg/m2) 25.0 (23.1, 26.8) 27.0 (25.0, 30.5) 0.082 preoperative creatinine, (mg/dl) 1.27 (1.13, 1.48) 1.40 (1.19, 1.76) 0.3 preoperative albumin, (g/dl) 3.11 (2.62, 3.79) 3.30 (2.80, 3.71) 0.7 must score 0.6 0 7 (50%) 9 (47%) 1 6 (43%) 6 (32%) 2 1 (7.1%) 4 (21%) asa score 0.11 1 1 (7.1%) 0 (0%) 2 5 (36%) 3 (16%) 3 7 (50%) 16 (84%) 4 1 (7.1%) 0 (0%) rai 26.5 (25.0, 28.8) 30.0 (27.5, 33.0) 0.027 * median (iqr); n (%). ** wilcoxon rank sum exact test; wilcoxon rank sum test; fisher's exact test. table 3. clavien-dindo grading in relation to perioperative and early postoperative period. n = 34 * n = 34 * complication perioperative early postoperative (clavien-dindo) (within 30 days) (within 90 days) i 0 (0%) 0 (0%) ii 20 (58.8%) 11 (32.4%) iiia 1 (2.9%) 0 (0%) iiib 1 (2.9%) 0 (0%) iv 0 (0%) 0 (0%) v 0 (0%) 1 (2.9%) * n (%). archivio italiano di urologia e andrologia 2022; 94, 2 r. malinaric, g. mantica, f. balzarini, c. terrone, m. maffezzini 148 bias, although it is a well-known fact that high-volume centers tend to have less periand postoperative complications (25). furthermore, one study revealed that the probability of undergoing radical cystectomy for elderly patients is five-fold lower than for younger ones (26). consequently we asked ourselves the following questions. should we deny a surgical option to patients in our cohort who were considered frail? could we instead treat those frail patients with extraperitoneal cystectomy followed by ureteral diversion to the abdomen wall that is reputed as the simplest form of urinary diversion with lower complication rates, morbidity and mortality (27)? furthermore, when longo et al. assessed the quality of life in patients treated with ileal conduit and ucs using the bladder cancer index, patients reported the same level of discomfort equally in both groups (28). in our study we confirmed findings previously reported in the literature. in fact, in our cohort median blood loss and operative time were reduced, when compared to reports of intraperitoneal radical cystectomy with bowel diversion. de nunzio et al. described even more reduction in operative time, but that could be due to different surgical technique or more experienced second surgeon (29). the association between some preoperative characteristics of the patients and rates of complications were previously reported in the literature (30, 31). the association between perioperative hypoalbuminemia and risk of wound infection was also reported by other authors (32). similar observations were made for bmi and septicemia and for anemia, asa > 3 and rai score > 25 and development of deep subfascial wound infection with evisceration or needing readmission. moreover, in our cohort, there were no complications such as anastomotic leakage, hematomas or mechanical bowel obstructions, and at the end of perioperative period we did not observe any death although we had one death in the early postoperative period. due to this experience, we believe that performing an extraperitoneal cystectomy with ucs and implementation of the eras protocol, the risk of intestinal complications such as paralytic ileus, gastroparesis and electrolytic imbalance are significantly lowered, as well as likelihood of urinary fistulas. where the surgery was only palliative, we avoided lymphadenectomy and, thus, lymphocele and all the related consequences. these are the main reasons why we consider extraperitoneal cystectomy with ucs a safer surgical technique when treating frail patients. however, our study is not without limits. firstly, it is a retrospective study on a small cohort of patients. secondly, some patients may have not undergone correct staging of disease as they did not undergo the lymphadenectomy. furthermore, patients, although all considered frail, were not homogeneous. they, in fact, differed in age, clinical manifestation of disease, bmi, stage, laboratory findings, malnourishment risk and not all patients underwent eras protocol. furthermore, there is no control group due to the fact that this surgery is reserved only for the patients that would otherwise be considered unfit for surgery. however, the aim of this study was to evaluate the safety of extraperitoneal cystectomy with ucs in frail patients, and it is also the main reason why having a more homogeneous cohort is difficult, if not impossible. nevertheless, this technique should be evaluated on larger cohorts. we do believe it is our duty to evaluate patients in more holistic manner in order to choose the right surgical approach. we should inform patients about the risks we are taking and use all preoperative tools at our disposal in order to prepare patients for this battle (e.g. could we administer intravenous albumin?). and while for the 'fit-for-surgery' patients there is continuously more evidence for robotic-assisted radical cystectomy (33), we do believe that the 'frail patients' category is somehow forgotten. open extraperitoneal cystectomy with ucs could be considered as a surgical option for those who are categorized as 'unfit', especially if it could be radical and ensure patients a disease-free residual life. we do, however, have to perform an accurate preoperative evaluation and the surgery should be performed by an experienced surgeon who is comfortable with extraperitoneal approach to the bladder. references 1. eau non-muscle-invasive bladder cancer 2021 guidelines, https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/. 2. cambier s, sylvester rj, collette l, et al. eortc nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage ta-t1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus calmette-guerin. eur urol. 2016; 69:60-9. 3. fedeli u, de paoli a, corti mc, et al. perioperative mortality and long-term survival after radical cystectomy: a population-based study in a southern european country on 4,389 patient. urol int. 2020; 104:559-566. 4. schuurmans h, steverink n, lindberg s, et al. old or frail: what tells us more? j gerontol a biol sci med sci 2004; 59:m962-5. 5. morley je, vellas b, van kan ga, et al. frailty consensus: a call to action j am med dir assoc 2013; 14:392-7 6. fried lp, tangen cm, walson j, et al. frailty in older adults: evidence for a phenotype j gerontol a biol sci med sci. 2001; 56:m146156. 7. khan kt, hemati k, donovan al. geriatric physiology and the frailty syndrome anesthesiol clin. 2019; 37:453-474. 8. https://ec.europa.eu/eurostat/statistics-explained/index.php?title= mortality_and_life_expectancy_statistics. 9. berger i, wehrberger c, ponholzer a, et al. impact of the use of bowel for urinary diversion on perioperative complications and 90-day mortality in patients aged 75 years or older urol int 2015; 94:394. 10. hautmann re, de petriconi rc, volkmer bg. lessons learned from 1,000 neobladders: the 90-day complication rate j urol 2010; 184: 990. 11. drudi ml, ades m, landry t, et al. scoping review of frailty in vascular surgery j vasc surg. 2019; 69:1989-1998.e2. 12. sioutas g, tsoulfas g. frailty assessment and postoperative outcomes among patients undergoing general surgery surgeon. 2020; 18:e55-e66. 149archivio italiano di urologia e andrologia 2022; 94, 2 extraperitoneal cystectomy in fragile patients 13. hirpara hd, kidane b, rogalla p, et al. frailty assessment prior to thoracic surgery for lung or esophageal cancer: a feasibility study. support care cancer. 2019; 27:1535-1540. 14. cawood al, walters er, sharp ske, et al. self-screening' for malnutrition with an electronic version of the malnutrition universal screening tool ('must') in hospital outpatients: concurrent validity, preference and ease of use. br j nutr. 2018; 120:528-536. 15. melin aa, schmid kk, lynch tg, et al. preoperative frailty risk analysis index to stratify patients undergoing carotid endarterectomy. j vasc surg. 2015; 61:683-9. 16. https://www.asahq.org/standards-and-guidelines/asa-physicalstatus-classification-system. 17. tnm classification of malignant tumors. uicc international union against cancer. 8th edn., g.m. brierley jd, wittekind c., editor. 2017, wiley-blackwell and uicc: new york, usa. 18. clavien pa, barkun j, de oliveira ml, et al. 'the clavien-dindo classification of surgical complications: five year experience' ann surg. 2009; 250:187-96. 19. yadav s, rawal g, baxi m. vacuum assisted closure technique: a short review. pan afr med. 2017; 28:246. 20. maisch p, lunger l, duwel c, et al. outcomes of palliative cystectomy in patients with locally advanced pt4 bladder cancer. urol oncol. 2021; 39:368.e11-368.e17. 21. gild p, nguyen dd, fletcher sa, et al. contemporary survival rates for muscle-invasive bladder cancer treated with definitive or nondefinitive therapy. clin genitourin cancer. 2019; 17:e488-e493. 22. ploussard g, daneshmand s, efstathiou ja, et al. critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review.eur urol 2014; 66:120-137. 23. jewett hj, lewis el. infiltrating carcinoma of the bladder; curability by total cystectomy. j urol. 1948; 60:107-118. 24. llorente c, guijarro a, hernandez v, et al. effect of hospital volume on 90-day mortality after radical cystectomy for bladder cancer in spain. world j urol. 2020; 38:1221-1228. 25. afshar m, goodfellow h, jackson-spence f, et al. centralisation of radical cystectomies for bladder cancer in england, a decade on from the ‘improving outcomes guidance’: the case for super centralisation. bju int. 2018; 121:217-224. 26. williams sb, huo j, kosarek cd, et al. 'population-based assessment of racial/ ethnic differences in utilization of radical cystectomy for patients diagnosed with bladder cancer' cancer causes control. 2017; 28:755-66. 27. nieuwenhuijzen ja, de vries rr, bex a, et al. urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. eur urol. 2008; 53:834-44. 28. longo n, imbimbo c, fusco f, et al. complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. bju int. 2016; 118:521-6. 29. de nunzio c, cicione a, leonardo f, et al. extraperitoneal radical cystectomy and ureterocutaneostomy in octogenarians. int urol nephrol 2011; 43:663-667. 30. kavukoglu ö, coskun a, sabuncu k, et al. is it possible to reduce the complications and mortality of patients undergoing radical cystectomy? effectiveness of pre-operative parameters. a prospective study. arch ital urol androl. 2021; 93:379-384. 31. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital urol androl. 2021; 93:15-20. 32. mayr r, gierth m, zeman f, et al. sarcopenia as a comorbidityindependent predictor of survival following radical cystectomy for bladder cancer. j cachexia sarcopenia muscle 2018; 9:505-13. 33. mantica g, smelzo s, ambrosini f, et al. port-site metastasis and atypical recurrences after robotic-assisted radical cystectomy (rarc): an updated comprehensive and systematic review of current evidences. j robot surg. 2020; 14:805-812. correspondence rafaela malinaric, md (corresponding author) rafaela.malinaric@gmail.com guglielmo mantica, md gugliemo.mantica@gmail.com federica balzarini, md balzarini.federica90@gmail.com carlo terrone, md carlo.terrone@med.unipo.it san martino hospital, university of genoa, genoa (italy) massimo maffezzini, md massimo.maffezzini@gmail.com department of urology, hospitals of legnano and magenta, milan (italy) stesura seveso 373archivio italiano di urologia e andrologia 2022; 94, 3 letter to editor no conflict of interest declared. submitted 3 july 2022; accepted 9 july 2022 to the editor, erectile dysfunction (ed) is defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance (1). ed represents one of the most important male sexual dysfunctions with a prevalence of 52% and affecting more than 150 million men worldwide (estimated to be 322 million worldwide for 2025) (2-4). in the last years, several dietary supplements and herbal remedies have been introduced alone or in combinations with other treatments. these products have been used in traditional medicine for their aphrodisiac proprieties or as compounds that increase sexual arousal, libido, potency (erection) and/or sexual pleasure. panax ginseng (korean ginseng), tribulus terrestris (tribulus), epimedium gradiflorum (horny goat weed), lepidium meyenii (maca), ginkgo biloba (ginkgo), eurycoma longifolia jack (tongkat ali), and pausinystalia johimbe (yohimbine), b complex vitamins, zinc, trace minerals, l-arginine, aspartate and dehydroepiandrosterone (dhea) have been reported as the most used products on the market (5-6). despite the increasing use, very low scientific evidence has been described, particularly regarding efficacy, safety, extractions, and dosage. mobile phone applications (mhas) are mobile software programs, providing information and support to patients in many fields including health. nowadays, more than 325,000 mhas are available and widely used in the healthcare setting, to provide information about several medical conditions including sexual dysfunction, but the scientific evidence is very poor (7). in our previous study we analyzed mhas for ed using the mobile application rating scale (mars scale) and reported their adherence to european urology guidelines. mars is a multidimensional instrument evaluating engagement (items assessing the extent to which the app engages target users), functionality (items assessing how easy the app is to navigate and the overall app performance), esthetics (items assessing visual appearance and style), information (items assessing accuracy, quality, and quantity of the app), app subjective quality, and app-specific, showing a very acceptable reliability and validity) (8). we found an overall low quality of mhas and poor adherence to eau guidelines. among treatments they suggested there were both herbal interventions and non-herbal nutraceuticals, alone or in combinations. over the time several studies suggested herbal interventions in ed management with a high scientific support. balasubramanian et al. in a recent meta-analysis reported the most popular erectile dysfunction supplements available on online marketplaces: ginseng is the most popular followed by l-arginine, and tongkat ali (9). interestingly, none of the analyzed apps reported any of the supplements in this list or the most popular used ones. furthermore, ginseng and larginine as shown by borrelli et al. are the only two supplements that showed an effective efficacy in ed treatment (10). mhas suggested using (table 1): garlic, bryonia laciniosa, butea superba, ginger, ginkgo biloba, carrots, pomegranate juice, onion, almonds and clove. garlic (allium sativum) represents one of the oldest plants, recognized for its health benefits in cardiovascular diseases (11). the most important bioactive component is s-allyl cysteine (sac) which possesses antioxidant property (12). bryonia laciniosa is characterized by antimicrobial, larvicidal, anti-inflammatory, cytotoxic, analgesic, and antipyretic activities and it is very used in india as a tonic and enhancer of sexual behaviors. butea superba increased intracavernous pressure and cavernous smooth muscle relaxation (13). one mha suggested using ginger, the only nutraceutical that showed to enhance inos activity in vitro. other mha suggested products were carrots that improve sexual function and desire through testosterone enhancing; pomegranate juice which is characterized by antioxidant activity (anthocyanins) and involved in endothelial nitric oxide (no) levels regulation; in the end, onion which is a source of hydrogen sulfide and quercetin, involved in erection and antioxidant pathway respectively (14, 15). almond is characterized by antistress, antidiabetic, antihypertensive and antioxidant proprieties (16, 17). many of these home remedies have not reported a great scientific support and few studies have been conducted on human, with several drawbacks: regarding garlic, nishimatsu et al. reported his experience in 24 men using a preparation containing garlic extract, ginseng, oriental bezoar, velvet antler, cuscuta seed and epimedium herb, with improvement of ed (18). despite all this, the negative role of oxidative stress and of endothelial dysfunction in ed pathophysiology is well established, and all dietary supplements suggested reported antioxidant effects. according to the current data no strong scientific evidence supports nutraceutical products suggested by mhas. therefore, further work, and more involvement of healthcare are necessary to improve the quality of scientific evidences reported by mhas. natural treatments for erectile dysfunction: a focus on mobile health applications luigi napolitano, luigi cirillo, giovanni maria fusco, marco abate, vincenzo morgera, gianluigi cacace, giuseppe celentano, biagio barone, lorenzo spirito, vincenzo mirone, roberto la rocca department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples, italy. doi: 10.4081/aiua.2022.3.373 archivio italiano di urologia e andrologia 2022; 94, 3 l. napolitano, l. cirillo, g.m. fusco, m. abate, et al. 374 references 1. pastuszak aw. current diagnosis and management of erectile dysfunction. curr sex health rep. 2014; 6:164-76. 2. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 3. romano l, granata l, fusco f,, et al. sexual dysfunction in patients with chronic gastrointestinal and liver diseases: a neglected issue. sex med rev. 2021; s2050-0521(21)00039-1. 4. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl. 2021; 93:221-6. 5. kuchakulla m, narasimman m, soni y, et al. a systematic review and evidence-based analysis of ingredients in popular male testosterone and erectile dysfunction supplements. int j impot res. 2021; 33:311-7. 6. corazza o, martinotti g, santacroce r, et al. sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and ginkgo biloba. biomed res int. 2014; 2014:841798. 7. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-6. 8. stoyanov sr, hides l, kavanagh dj, et al. mobile app rating scale: a new tool for assessing the quality of health mobile apps. jmir mhealth uhealth. 2015; 3:e27. 9. balasubramanian a, thirumavalavan n, srivatsav a, et al. an analysis of popular online erectile dysfunction supplements. j sex med. 2019; 16:843-52. 10. borrelli f, colalto c, delfino dv, et al. herbal dietary supplements for erectile dysfunction: a systematic review and meta-analysis. drugs. 2018; 78:643-73. 11. brace ld. cardiovascular benefits of garlic (allium sativum l). j cardiovasc nurs. 2002; 16:33-49. 12. colín-gonzález al, santana ra, silva-islas ca, et al. the antioxidant mechanisms underlying the aged garlic extractand s-allylcysteineinduced protection. oxid med cell longev. 2012; 2012:907162. 13. tocharus c, smitasiri y, jeenapongsa r. butea superba roxb. enhances penile erection in rats. phytother res. 2006; 20:484-9. 14. gur s, kadowitz pj, sikka sc, et al. overview of potential molecular targets for hydrogen sulfide: a new strategy for treating erectile dysfunction. nitric oxide biol chem. 2015; 50:65-78. 15. zhang w, wang y, yang z, et al. antioxidant treatment with quercetin ameliorates erectile dysfunction in streptozotocin-induced diabetic rats. j biosci bioeng. 2011; 112:215-8. 16. siriwardhana sskw, shahidi f. antiradical activity of extracts of almond and its by-products. j am oil chem soc. 2002; 79:903-8. 17. adefegha sa, oboh g, oyeleye si, ejakpovi i. erectogenic, antihypertensive, antidiabetic, anti-oxidative properties and phenolic compositions of almond fruit (terminalia catappa l.) parts (hull and drupe) in vitro. j food biochem. 2017; 41:e12309. 18. nishimatsu h, kitamura t, yamada d, et al. improvement of symptoms of aging in males by a preparation leopin royal containing aged garlic extract and other five of natural medicines comparison with traditional herbal medicines (kampo). aging male off j int soc study aging male. 2014; 17:112-6. table 1. app characteristics. name of application android/apple/both producer category nutraceutical product erectile dysfunction treatment android revolxa inc. medicine asian ginger, ginkgo biloba erectile dysfunction remedy 2021 android maftal almafary education asian ginger, ginkgo biloba erectile dysfunction remedies android statesapps health and fitness garlic, cloves, fruit nut mix, onion, drumstick, butea superba home remedies android cutepad studio medicine ginger, onion, pomegranate juice, almonds, garlic, carrots herbal cure android novaradix medicine bryonia 101 natural home android xl tech apps garlic correspondence luigi napolitano, md luiginap89@gmail.com luigi cirillo, md (corresponding author) cirilloluigi22@gmail.com giovanni maria fusco, md giom.fusco@gmail.com marco abate, md marcoabate5@gmail.com biagio barone,md biagio.barone@unina.it vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com lorenzo spirito, md lorenzospirito@msn.com vincenzo mirone, md mirone@unina.it roberto la rocca, md robertolarocca87@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, (italy) via sergio pansini n 5, naples (na) (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11605 1 original paper introduction the guidelines of the american and european urological associations advise to treat stones larger than 2 cm the percutaneous nephrolithotomy (pcnl) including the patients with horseshoe kidneys (hsk) (1). this in hsk is usually performed in the prone position, allowing entry through the upper pole and providing good access to the collecting system. several case series have investigated prone pcnl in patients with hsk. however, in patients with normal kidney anatomy, the supine position is reliable and safe in most cases, but it is unknown whether the supine position is adequate in patients with hsk (2). the purpose of this study was to describe the results of pcnl in hsk in three different surgical institutions and to evaluate the impact of supine position during surgery, comparing pre-operative and post-operative data, complications, and stone status after surgery. setting, patients and outcomes we conducted a retrospective analysis of procedures performed between 2017 and 2022 that studied supine minipcnl in patients with horseshoe kidney. all patients were evaluated with non-contrast ct as the preferred preand post-operative imaging method. we evaluated 10 minipcnls performed in three medical centres including s. croce and carle cuneo hospital (4 cases), cannizzaro hospital (3 cases) and mater dei clinic of catania (3 cases). the following pre-operative data were collected in all patients: gender, age, side, mean stone size and density (using hounsfield classification derived from ct scan), number of stones for single patient, stone position frequencies, mean pre-intervention values of creatinine and egfr. the change in haemoglobin, hematocrit, creatinine and egfr were assessed between the most recent preopobjective: the percutaneous nephrolithotomy (pcnl) in horseshoe kidneys (hsk) is usually performed in the prone position, allowing entry through the upper pole and providing good access to the collecting system. however, in patients with normal kidney anatomy, the supine position is reliable and safe in most cases, but it is unknown whether the supine position is adequate in patients with hsk. the purpose of this study was to describe the results of pcnl in hsk in three different surgical institutions and to evaluate the impact of supine position during surgery, comparing pre-operative and post-operative data, complications, and stone status after surgery. material and methods: between 2017 and 2022, a total of 10 patients underwent percutaneous renal surgery for stone disease in hsk. all patients were evaluated preand postoperatively with non-contrast ct. we evaluated patients (age and gender), stones characteristics (size, number, side, site and density ), and outcomes. the change in haemoglobin, hematocrit, creatinine and egfr were assessed between the most recent preoperative period and the first postoperative day. procedure success was defined as stone-free or presence of ≤4 mm fragments (clinically insignificant residual fragments – cirf). complications were registered and classified according to clavien-dindo grading system, during the 30 day postoperative period and clavien scores ≥ 3 were considered as major complications. statistical analysis was performed using “r 4.2.1” software, with a 5% significance level. we also compared pre-operative and post-operative data using “wilcoxon signedrank test”. results: no statistical difference was observed between preoperative and post-operative renal function data. at one post operative day ct scan, an overall success rate of 100% was registered. 9/10 patients were completely free from urolithiasis (stone-free rate: 90%), while 1/10 patients had ≤4 mm residual stone fragments (cirf rate: 10%). no cases of intraoperative complications were registered. post-operative complications were reported in 1/10 patients. a patient developed urosepsis (defined as sirs with clinical signs of bacterial infections involving urogenital organs clavien-dindo grade ii) after procedure, and was treated with intravenous antibiotic therapy successfully. conclusions: this study shows that in patients with hsk minipcnl in supine position allows to achieve good stone free rate with a very low morbidity. according to our series, the supine mini percutaneous nephrolithotomy in horseshoe kidney orazio maugeri 1, eugenio di grazia 2, 3, letterio d’arrigo 4, roberta agliozzo 1, gianluca calvano 1, federica trovato 1, christian di gaetano 1, giuseppe trefiletti 1, salvatore privitera 1, giorgio ivan russo¹, sebastiano cimino 1 1 urology section, department of surgery, university of catania,catania, italy; 2 endourology unit, casa di cura villa azzurra, siracusa, italy; 3 endourology unit, casa di cura mater dei, catania, italy; 4 urology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2023.11605 summary described technique for pcnl in hsk should be an option. nevertheless these results must be confirmed by further studies. key words: galdakao modified supine valdivia; horseshoe kidney; percutaneous nephrolithotomy. submitted 23 july 2023; accepted 31 august 2023 archivio italiano di urologia e andrologia 2023; 95(3):11605 o. maugeri, e. di grazia, l. d’arrigo, et al. 2 erative period and the first postoperative day. procedure success was defined as stone-free or presence of ≤ 4 mm fragments clinically insignificant residual fragments (cirf) (3). complications were registered and classified according to clavien-dindo grading system, during the 30 day postoperative period and clavien scores ≥ 3 were considered as major complications (4). preparation and operative technique all procedures were performed by three experienced endourologists. placement was chosen based on surgeon preference. all surgeons are trained and experienced with pcnl in supine position. the positions used for pcnl were the complete supine or supine modified galdakaovaldivia (gmsv). after positioning the patient, it is important to mark the inferior edge of the 12th rib, the iliac crest and the posterior axillary line on the patients ‘skin in order for the surgeon to maintain his or her orientation after the patients are draped. for the valdivia modified by galdakao the patient’s legs are placed in a modified lithotomy position with both legs in stirrups in order to facilitate simultaneous percutaneous antegrade access and ureteroscopic retrograde to the urinary system. all procedures started with retrograde pyelography. after these propaedeutic steps, a ureteral access sheath (uas) was positioned (9.5, 10/12 or 12/14 ch) in 6/10 cases depending on the ureteral diameter and compliance and position used. in some patients, and precisely in 6/10, it was decided to place an ureteral sheath with the aim to perform a flexible ureteroscopy to obtain stone clearance. nevertheless, horseshoe kidney unfavourable anatomy made retrograde approach unfeasible, then switching to real-time pcnl was carried out. in all patients the puncture was performed with ultrasound/radiological guidance followed by a “single-step dilation”. a 12 fr mini nephroscope mip m (karl storz, berlin gmbh, germany) was used for stone fragmentation and removal. lithotripsy was performed in 9 cases with holmium yag laser (550 µ fiber laser) and lithoclast ems in 1 case. an intraoperative stone-free status was verified with fluoroscopy and flexible nephroscope. a 8 fr nephrostomy tube and 6 fr x 26 cm ureteral stent was placed in all cases at the end of surgery. statistical analysis statistical analysis was performed using “r 4.2.1” software, with a 5% significance level. qualitative variables were reported as numbers and percentages. quantitative discrete variables were described as median interquartile range (iqr) values, while quantitative continuous variables were reported as mean standard deviation (ds) values. we also compared pre-operative and post-operative data using “wilcoxon signed-rank test”. results patient characteristics demographics and stones characteristics are reported in table 1. mean age was 54.7 (sd: 10,18). male sex percentage was 90% (9 patients) and female sex percentage was 10%, (1 patient). 2 (20%) vs 8 (80%) stones were located in the right and left kidney; in detail, 3 (30%) stones were located in the lower pole and 7 stones (70%) in the renal pelvis, respectively. the median stone size was 23.3 mm (sd: 6), in 1/10 (10%) case the stones were multiple; ct stone density was 1233 (hu) (sd: 54). peri-operative data and outcomes mean operative time was 110 (sd: 11.17) minutes (table 2). mean post-operative serum creatinine and egfr at day 1 after surgery were 0.86 (sd: 0.2) mg/dl and 93.10 (sd: 12.55) ml/min/1.73m2, while preoperative values were 0.8 (sd: 0.22) mg/dl and 95.50 (sd: 15.48) ml/min/1.73m2. nevertheless, any statistical difference was observed between pre-operative and post-operative renal function data (p = 1 and p = 0.294 respectively), as listed in table 3. table 3. pre-operative and post-operative data. pre-operative mean post-operative mean p-value creatinine (mg/dl) 0.85 (sd: 0.22) 0.86 (sd: 0.20) 1 egfr (ml/min/1.73 m2) 95.50 (sd: 15.48) 93.10 (sd: 12.55) 0.294 hemoglobin (g/dl) 14.62 (sd: 2.05) 13.61 (sd: 1.89) 0.012 hematocrit (%) 43.73 (sd: 6.63) 40.23 (sd: 6.40) 0.009 table 1. patient’s demographic data and baseline characteristics. age, years mean (sd) 54.7 (sd: 10.18) gender, n (%) male: 9 (90%) female: 1 (10%) side, n (%) left: 8 (80%) right: 2 (20%) past kidney stone interventions, n (%) yes: 0 no: 10 (100%) number of stones/single patient 1 (iqr: 1-1.25) stone size (mm) 23.3 (sd: 6) stone density hu 1233 (sd: 54) stone site n° of patients (%) upper calyx: 0 middle calyx: 0 inferior calyx: 3 (30%) renal pelvis: 7 (70%) mean pre-intervention creatinine (mg/dl) 0.85 (sd: 0.22) mean pre-intervention egfr (ml/min/1.73 m2) 95.50 (sd: 15.48) table 2. surgical outcomes and features. diameter access, mean (sd) 16,16 (sd: 6.69) calyx of puncture upper: 5 (50%) middle: 5 (50%) lower: 0 dilation technique balloon: 3 (30%) serial: 7 (70%) energy, n (%) laser: 9 (90%) ultrasonic: 1 (10%) pneumatic: 0 combined: 0 surgical time (minutes) 110 (sd: 11, 17) amplatz-sheath yes: 10 (100%) no: 0 post-operative stent yes: 10 (100%) no: 0 archivio italiano di urologia e andrologia 2023; 95(3):11605 3 supine pcnl in hsk at one day ct scan, an overall success rate of 100% (10/10) was registered. 9/10 patients were completely free from urolithiasis (stone-free rate: 90%), while 1/10 patients had ≤ 4 mm stone fragments in the same renal localization of previously treated lithiasis (cirf rate: 10%). at stone analyses, 5 (50%) patients were found to have calcium oxalate monohydrate stones (com), 1 (10%) patient had calcium oxalate dihydrate stones (cod), and 4 (40%) patients had mixed calcium-uric acid stones (mixed ca-ua) table 4. complications no cases of intraoperative complications were registered. post-operative complications were reported in 1/10 patients (10%). the patient developed urosepsis (defined as sirs with clinical signs of bacterial infections involving urogenital organs clavien-dindo grade ii) after procedure. septic complication was treated with intravenous antibiotic therapy successfully, without necessity of transfer to intensive care unit. none “late” post-operative complication emerged during the follow-up until the visit at third month after surgery. all complications are reported in table 5. there were no hollow visceral injuries, which indicates that supine operations have a lower risk of any abdominal or thoracic injuries. there were no ira complication and renal function was normal in all the patients. a non-contrast ct scan was performed in all cases during the first post-operative day and for the first follow up after 30 days. discussion horseshoe kidney (hsk) is the most common fusion defect of the kidneys, although it amounts to only about 0.25% of the population (5). there is no clear genetic cause for, but the incidence is higher in those with chromosomal disorders such as edward syndrome (67%), turner syndrome (from 14% to 20%) and down syndrome (1%) (68). in 1522, carpi described hsk during autopsies for the first time (9). he identified functioning renal masses present on both sides of the vertebral column fused together with ureters that remain uncrossed from the renal hilum to the urinary bladder (10). in most cases the fusion occurs at the lower pole, but it may occur at the upper pole (11). due to fusion, malrotation and anatomical defects, hsk shows high insertion and lateralization of the ureter which causes urine stasis with a consequent greater risk of hydronephrosis, infection and stone formation (9). although ureteropelvic junction obstruction is the most common complication associated with hsk, pawar et al. estimated that that 36% of patients with a horseshoe kidney will develop nephrolithiasis throughout their life (12). about treatment of renal stones, all surgical techniques can be used in patients with hsk, but success rates are usually lower than in kidneys with regular anatomy, especially with external shockwave lithotripsy (eswl) (13, 14). the guidelines of the american and european urological associations recommend the use of pcnl to treat renal stones larger than 2 cm 1. in patients with normal kidney anatomy, this procedure is performed in the supine position, but in patients with hsk many surgeons prefer to use the prone position because it allows access through the upper pole and provides good access to the collecting system 2. however, it is unknown whether the prone position is more adequate than supine approach to treat renal stones in patients with hsk. most urologists believe that pcnl should be performed in the prone position in patients with hsk and that access should be obtained through the upper pole, which is usually subcostal and offers a straight way to most calyces. the results are good, and the technique is well-established. however, the supine position for pcnl is gaining popularity worldwide, even in the us, where it was less used (15). using this position, it is not necessary to turn the patient prone and therefore, the total operative time can be reduced 2. this position has also been used for complex cases, showing similar effectiveness (16). a group used to perform pcnl in the supine position, facing hsk, would probably tend to use that position. however, until now, little information was available to support this choice. therefore, this study shows that supine mini-pcnl in the horseshoe kidney, as performed in several centres, can achieve optimal results. vicentini et al. in a multicentric comparison study retrospectively analyzed 106 pcnls performed for complex stones in hsk in the prone and supine positions (17). the analysis of their large cohort of patients confirmed that supine pcnl is also suitable in hsk because it is characterized by a lower complication rate and shorter operating time. in our study, we aimed to answer the question of whether supine pcnl is an option as good as prone pcnl for complex kidney stones in case of hsk. our date show that the supine pcnl seems to be suitable for complex stones in the horseshoe kidney, as the immediate success, complications, transfusion rates and operative times were like those found in the literature in the prone position. furthermore, sepsis and visceral injury rates were significantly low or absent, showing a possible safer profile for the supine position. our hypothesis is that during the supine position there is less chance of pyelovenous urinary reflux due to the lower intrarenal pressure compared to prone cases, as the better irrigation flow through the amplatz sheath is intuitive. this could explain the lower table 4. stone composition to spectrophotometric analysis. stone composition. no. (%) value calcium oxalate monohydrate 5/10 (50%) calcium oxalate dihydrate 1/10 (10%) mixed 4/10 (40%) table 5. clinical complications following mini-pcnl classified according to clavien-dindo grading system. clavien-dindo number description treatment grade system of patients grade i 1/10 1: nausea and vomiting anti-emetics and supportive care grade ii 1/10 1: urosepsis antibiotic therapy grade iii a grade iii b grade iv a archivio italiano di urologia e andrologia 2023; 95(3):11605 o. maugeri, e. di grazia, l. d’arrigo, et al. 4 sepsis rate observed in our cases. our study included patients from three different centres, the demographics were similar in all groups, and we used a comprehensive prospective database which reduced the possibility of bias in the similarity of results regarding position. the surgeries were performed by different expert endourologists, not just one surgeon. another positive point of our study was that all patients underwent a preand postoperative non-contrast ct scan, making outcome evaluations more accurate. conclusions this study shows that mini-pcnl in supine position allows to achieve good stone free rate with a very low morbidity in patients with hsk. according to our series, the described technique for supine pcnl in hsk should be an option. nevertheless, these results must be confirmed by further studies. references 1. c. türk, a. neisius, a. petrík, et al. european association of urology 2021, eau guidelines on urolithiasi, 2021. 2. li j, gao l, li q, et al. supine versus prone position for percutaneous nephrolithotripsy: a meta-analysis of randomized controlled trials. int j surg. 2019; 66:62-71. 3. osman y, harraz am, el-nahas ar, et al. clinically insignificant residual fragments: an acceptable term in the computed tomography era? urology. 2013; 81:723-726. 4. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008; 53:184-190. 5. schiappacasse g, aguirre j, soffia p, et al. ct findings of the main pathological conditions associated with horseshoe kidneys. brit j radiol. 2015; 88:20140456. 6. cereda a and carey jc. the trisomy 18 syndrome. orphanet journal of rare diseases. 2012; 7:81. 7. ranke, michael b, saenger p. turner's syndrome. lancet. 2001; 358:309-314. 8. bhattarai b, kulkarni ah, rao st, mairpadi a. anesthetic consideration in downs syndrome--a review. nepal med coll j. 2008; 10:199-203. 9. natsis k, piagkou m, skotsimara a, et al. horseshoe kidney: a review of anatomy and pathology. surg radiol anat. 2014; 36:517-26. 10. cook wa, stephens fd. fused kidneys: morphologic study and theory of embryogenesis. birth defects orig artic ser. 1977; 13:327-40. 11. glodny b, petersen j, hofmann kj, et al. kidney fusion anomalies revisited: clinical and radiological analysis of 209 cases of crossed fused ectopia and horseshoe kidney. bju int. 2009; 103:224-35. 12. pawar as, thongprayoon c, cheungpasitporn w, et al. incidence and characteristics of kidney stones in patients with horseshoe kidney: a systematic review and meta-analysis. urol ann. 2018; 10:87-93. 13. kartal i, çakıcı mç, selmi v, et al. retrograde intrarenal surgery and percutaneous nephrolithotomy for the treatment of stones in horseshoe kidney; what are the advantages and disadvantages compared to each other? cent european j urol. 2019; 72:156-162. 14. gokce mi, tokatli z, suer e, et al. comparison of shock wave lithotripsy (swl) and retrograde intrarenal surgery (rirs) for treatment of stone disease in horseshoe kidney patients. int braz j urol. 2016; 42:96-100. 15. tzou dt, metzler is, usawachintachit m, et al. ultrasound-guided access and dilation for percutaneous nephrolithotomy in the supine position: a stepby-step approach. urology. 2019; 133:245-246. 16. vicentini fc, perrella r, souza vmg, et al. impact of patient position on the outcomes of percutaneous neprolithotomy for complex kidney stones. int braz j urol. 2018; 44: 965-971. 17. vicentini fc, mazzucchi e gökçe, et al. percutaneous nephrolithotomy in horseshoe kidneys: results of a multicentric study. j endourol. 2021; 35:979-984. correspondence orazio maugeri, md (corresponding author) omaugeri@gmail.com urology section, department of surgery, university of catania via s.sofia, 78 95123 catania eugenio di grazia, md eugeniodigrazia@hotmail.com endourology unit, casa di cura villa azzurra, siracusa, italy endourology unit, casa di cura mater dei, catania, italy letterio d'arrigo, md eliodarrigo@gmail.com urology unit, cannizzaro hospital, catania, italy roberta agliozzo, md roberta.agliozzo@outlook.it gianluca calvano, md gianluca.calvano10@gmail.com federica trovato, md fede-tr@hotmail.it christian di gaetano, md christian.digaetano@gmail.com giuseppe trefiletti, md peppetrefiletti@gmail.com salvatore privitera, md salvoprivi82@gmail.com giorgio ivan russo, md giorgioivan1987@gmail.com sebastiano cimino, md ciminonello@hotmail.com urology section, department of surgery, university of catania, catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12263 1 letter to editor key words: pyeloplasty; robotic surgery; urology; minimally invasive. submitted 7 january 2024; accepted 22 january 2024 to the editor pelvi-ureteric junction obstruction (pujo) is a well-recognised clinical entity characterised by functionally significant impairment of drainage of urine at the level of the pelvi-ureteric junction due to extrinsic or intrinsic obstruction and is encountered both by adult and paediatric urologists alike. management of pujo has been surgical historically, and the gold standard has been an open anderson-hynes dismembered pyeloplasty (1). this remains the gold standard with a success rate greater than 90% (2). minimally invasive surgery to correct pujo was introduced in 1984 by arthur smith using an endopyelotomy technique. since its introduction the technique has evolved and performed in multiple ways using electricity, laser and cold knife to cut the puj. the routine use of endopyelotomy became questionable however due to lower success rates than open pyeloplasty (3). in the united kingdom and many other affluent nations there has been a paradigm shift in the last 20 years towards minimally invasive techniques and the standard of care now is a robotassisted laparoscopic pyeloplasty (ralp), due to shorter hospital stay, quicker recovery and improved cosmetic results (2). however, robotic surgery is associated with increased costs, often beyond what is affordable for many countries. this poses a challenging question – do the benefits of robotic pyeloplasty outweigh the increased cost? and if so, is it justifiable to deny patients this benefit, purely based on their geographical location? moretto et al., recently sought to address this challenge by correlating perioperative and functional outcomes of open and robotic pyeloplasty with their cost effectiveness (2). in their trial 91 patients were included, 48 underwent an open pyeloplasty and 43 a ralp and the authors found similar success rates and operating times but statistically significant lower intraoperative blood loss and early postoperative complication rate and better cosmetic results with ralp. predictably, the authors found a budget gap between surgical methods related to the cost of the robotic equipment. they found that the total cost of a ralp was € 8.700.90 ± € 1.274.70 and the open pyeloplasty group had a total cost of € 6.327.10 ± € 2.404.40. in parallel, similar trends and outcomes have been demonstrated in the treatment of the paediatric population with pelvi-ureteric junction obstruction. table 1 summarises different trials and the costs associated with ralp, laparoscopic and open pyeloplasties (2-5). others have taken this exploration further. mjaess et al. ran a cost analysis of robot assisted radical cystectomy in europe (6). they have found that costs varied significantly across european countries and were mainly attributed to the length of stay and operating time, rather than robotic instrumentation. robotic pyeloplasty: technological global panacea or geo-surgical nightmare? panagiotis nikolinakos 1, 5, nikolaos chatzikrachtis 1, ivo donkov 1, elisavet kotsi 2, georgios antonoglou 3, ioannis alexandrou 4, nikolaos zavras 5, joseph m. norris 6 1 department of urology, west middlesex university hospital, chelsea & westminster hospital nhs foundation trust, london, uk; 2 department of pediatrics, penteli children’s hospital, 8 ippokratous str, 15236 athens, greece; 3 department of urology, royal surrey county hospital, royal surrey nhs foundation trust, guildford, surrey, uk; 4 department of pediatric surgery, pendeli children’s hospital, 8 ippokratous str, 15236 athens, greece; 5 department of pediatric surgery, school of medicine, attikon university hospital, national and kapodistrian university of athens, 12462 athens, greece; 6 ucl division of surgery & interventional science, university college london, london, uk. doi: 10.4081/aiua.2024.12263 table 1. literature summary of cost of ralp, laparoscopic and open pyeloplasty. authors country source currency cost of ralp cost of lp cost of op sun (4) china asian j surg (2022) € (cn¥) 7985 ± 364 2880 ± 447 (61464.75 ± 2800.53) (22169.52 ± 3442.15) moretto (2) italy j clin med (2023) € 8700.9 ± 1274.7 6327.1 ± 2404.4 casella (5) usa j urol (2013) € 14192 14867 ($) (15337) (16067) archivio italiano di urologia e andrologia 2024; 96(1):12263 panagiotis nikolinakos, nikolaos chatzikrachtis, ivo donkov, elisavet kotsi, et al. 2 they concluded that reducing these might decrease the cost of robot-assisted radical cystectomy and make it more widely accessible. it is plausible that these conclusions can also be translatable to ralp. lam et al. have analyzed the uptake and accessibility of surgical robots in england and revealed their cost to be exceeding £1 million per unit (7). this financial burden poses challenges for many hospitals, in particular those in less economically affluent countries. consequently, these hospitals, may be unable to provide robotic procedures to patients, limiting access to the improved outcomes associated with them. perhaps one solution to aid in solving this discrepancy could be to increase the competition in the market and to centralise further the robotic centres, aiming for economies of scale to make the robot more cost-effective. it appears that the majority of extant evidence suggests that ralp for pujo would be mostly advantageous compared to an open pyeloplasty (2). however, given the increased associated costs, it appears likely that the advantages of robotic surgery are not available to all patients, with big discrepancies even inside europe. key changes are now needed to reduce the healthcare disparities highlighted here, including, increasing uptake with increasing market competition (such as with the versius robot, and others) with the hope that it would drive down costs. the royal college of surgeons of england has a yearly global appeal, and in 2023 this aimed to support global access to paediatric surgery, and perhaps as an extension from this, an appeal for access to robotic surgery could follow. accessible surgical robots will help usher in a new era for patients and surgeons alike in both adult and paediatric urology, and would help us to meet the common goal of delivering the highest quality of surgical care, regardless of global location. funding j.m. norris has received funding from the mrc (uk) and rcseng. references 1. gonzález st, rosito te, bujons a, et al. multicenter comparative study of open, laparoscopic, and robotic pyeloplasty in the pediatric population for the treatment of ureteropelvic junction obstruction (upjo). international braz j urol (internet). 2022; 48:961-8. 2. moretto s, gandi c, bientinesi r, et al. robotic versus open pyeloplasty: perioperative and functional outcomes. journal of clinical medicine (internet). 2023; 12:2538. 3. nadu a, mottrie a, geavlete p. ureteropelvic junction obstruction: which surgical approach? european urology open science 2009; 8:778-81. 4. sun l, zhao d, shen y, et al. laparoscopic versus robot-assisted pyeloplasty in infants and young children. asian j surg. 2022; 46:868-73. 5. casella dp, fox j, schneck fx, et al. cost analysis of pediatric robot-assisted and laparoscopic pyeloplasty. j urol 2013; 189:1083-6. 6. mjaess g, diamand r, aoun f, et al. cost-analysis of robot-assisted radical cystectomy in europe: a cross-country comparison. eur j surg oncol 2023; 49:1511-8. 7. lam k, clarke j, purkayastha s, kinross j. uptake and accessibility of surgical robotics in england. int j med robot. 2021; 17:1-7. correspondence panagiotis nikolinakos, md, msc (corresponding author) pnikolinakos@yahoo.gr nikolaos chatzikrachtis, md nikolaos.chatzikrachtis@nhs.net ivo donkov, md i.donkov@nhs.net department of urology, west middlesex university hospital, chelsea & westminster hospital nhs foundation trust, twickenham road, isleworth, london, tw7 6af, uk elisavet kotsi, md elisabethkotsi@gmail.com department of pediatrics, penteli children’s hospital, 8 ippokratous str, 15236 athens, greece georgios antonoglou, md georgios.antonoglou@nhs.net department of urology, royal surrey county hospital, royal surrey nhs foundation trust, guildford, surrey, uk ioannis alexandrou, md inalexandrou@hotmail.com department of pediatric surgery, pendeli children’s hospital, 8 ippokratous str, 15236 athens, greece nikolaos zavras, md nzavras@med.uoa.gr department of pediatric surgery, school of medicine, attikon university hospital, national and kapodistrian university of athens, 12462 athens, greece. joseph norris, md josephnorris@nhs.net ucl division of surgery & interventional science, university college london, london, uk conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper treatment especially in case of uric acid stones (4). however, men and women with ksd often resort to using self-medication. adherence to lifestyle and change behavior represent one of the important issues to prevent a recurrence. in this contest mobile health applications (mha) offers a great opportunity to support lifestyle changes (5). recently several apps have been developed worldwide and their use has increased in the last few years, particularly for medical and surgical conditions (6). despite their number and widespread use, quality assessments are still a problem. to avoid this, in the last few years, several instruments have been developed. among these, the most used tool is mobile application rating scale (mars) (7, 8). many mhas have been developed for assessing and managing ksd, representing an important tool for patients. however, despite their potential utility, much effort must be made regarding the quality, the validation, and the adherence to guidelines. to the best of our knowledge, there are no studies reporting the quality of apps for ksd and their adherence to guidelines. the aim of this study is to give an overview of apps for ksd, currently freely available on the market to evaluate the quality and the adherence to guidelines. material and methods search strategy we performed an observational cross-sectional descriptive study of all smartphone apps for patients about ksd available on the ios and android platforms and evaluated their adherence to eau guidelines. on 2 november 2022, three authors (m.a., l.c. and g.m.f.) separately conducted a search in google play store for android phones and apple app store for iphones with the keywords ‘kidney stone’, “kidney stone disease”, ‘‘kidney stone treatment” and ‘‘kidney stone diagnosis” using the search tab. authors used a wide array of keywords due to the search strategy of google play store and apple app store which is based on finding keywords in titles, app descriptions and tags. other searches of information provided in books or other formats were excluded. authors screened separately in apple app store and google play store apps during the search by reading the title and description in the app store. a fourth author introduction: mobile health applications (mhas) represent an interesting issue to assist and improve the quality of life of patients affected by kidney stone disease (ksd). despite this, their scientific quality and adherence to guidelines are not yet addressed. material and methods: on 2 november 2022, we conducted an observational cross-sectional descriptive study of all mhas on ksd. a search in the apple app store and google play store was performed. we reviewed all mobile apps from apple app store and google play store for ksd and evaluated their usage in screening, prevention, management, and adherence to eau guidelines. results: in total 13 mha were included in the final analysis. all mhas, 4 (30.8%) from the apple app store and 9 (69.2%) from the google play store are geared towards the patient. engagement ranged from 1.73 to 4.06; functionality ranged from 3.17 to 4.75; aesthetics ranged from 1.9 to 4.12; information ranged from 2.25 to 4.27, and subjective quality ranged from 1.58 to 3.23. mhas reported low and medium adherence to eau guidelines. conclusions: mhas provide a very useful assistance in several medical fields, including ksd. despite mhas development is constantly increasing, the scientific validation, content, and quality are not yet solved. future research is necessary to improve the quality of the apps and promote new user designed, and high-quality apps. key words: app; e-health; mobile phone; kidney stone; mars. submitted 11 december 2022; accepted 28 december 2022 introduction kidney stones disease (ksd) is one of the most common urinary tract diseases, with a prevalence of 15-25% (1), and it seems to have increased in the last quarter of the 20th (2). approximately 80% of kidney stones are composed of calcium oxalate (caox) mixed with calcium phosphate (cap), followed by uric acid, struvite and cystine which account for 9%, 10% and 1% of stones, respectively (3). several risk factors have been identified as well as geographical, ethnic, dietary, and genetic factors. nowadays, many treatments are available: shockwave lithotripsy, ureteroscopic fragmentation, percutaneous nephrolithotomy etc. or medical mobile health applications in kidney stone disease management: a reliable support for patients? luigi cirillo 1, celeste manfredi 2, biagio barone 1, vincenzo morgera 1, gianluigi cacace 1, francesco mastrangelo 1, francesco di bello 1, marco abate 1, davide arcaniolo 2, lorenzo spirito 2, felice crocetto 1, roberto la rocca 1, massimiliano creta 1, francesco paolo calace 1, giovanni maria fusco 1, luigi napolitano 1 1 unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii”, naples, italy; 2 unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2023.11076 summary archivio italiano di urologia e andrologia 2023; 95, 1 l. cirillo, c. manfredi, b. barone, v. morgera, et al. (l.n.) resolved any discrepancies. at the beginning all apps were reported in excel form and, according to the exclusion criteria, were screened. all mhas regarding ksd, providing a service to patients, in english, and free to download were included in this analysis. apps not specifically focused on ksd, apps not allowing access to all users and those not available in english were excluded. successively, all reviewers downloaded and installed the apps on their personal mobile device. they interacted for twenty minutes with each app to explore its features before completing the mars and evaluated their adherence to eau guidelines. to assess apps, they were downloaded to either an android or an ios device. if apps were available in both app stores, the ios version was assessed. a total of 41 apps were found by our search, 29 of them were from the google play store (android) and 12 of them were from the apple app store (ios). of the total, 27 apps were screened after removing apps not in english and not regarding ksd. of the total screened apps, 14 apps met excluding criteria and were removed. in particular, one app resulted in both stores. two apps reported the same name and had similar features in both apple app store and google play store but had different producers: both apps were analyzed. finally, 13 apps were eligible for the final evaluation. the search strategy was conducted according to the prisma statement (figure 1). table 1 shows the analyzed apps characteristics. the 13 suitable ksd apps were evaluated by three authors on a 5-point likert scale based on mars characteristics. data extraction on 31 october 2022 reviewers discussed methods of recording data to ensure standardized modality and a predefined excel form was created to collect data. the followfigure 1. prisma. table 1. general characteristics. name of application android/apple/both download producer category focus stone md kidney stones both n.a. nariman gadzhiev medicine diet, prevention, surgical management, eau tutorial videos oxipur-gout & kidney stones apple n/a baliza gmbh food & drink diet, prevention stone pass: kidney stones apple n/a know stone llc health & fitness calculator of stone pass vs surgery kidney stone scoring apple n/a putu angga risky raharja health & fitness calculator for stone free status after pcnl kidney stone symptoms & treatment android 50000 fall in love studio medicine epidemiology, definition, causes, prevention, symptoms, diagnosis, treatment kidney stone scoring android 1000 imedical apps health & fitness calculator for stone free status after pcnl stone diet renal gall bladder kidney gallbladder android 5000 sendgroupsms.com health & fitness definition, diagnosis, risk factors, prevention, home remedies kidney stones removal remedies android 10000 statesapps health & fitness home remedies, treatment kidney stone treatment faq android 1000 things to do health & fitness definition, symptoms, risk factors, causes, prevention, diagnosis, treatment home remedies for kidney stones android 100 karanbir singh health & fitness definition, risk factors, causes, diagnosis, prevention, home remedies oxalate counts (kidney stones) android 5000 denise anderson health & fitness diet/, prevention calculator of oxalate in food home remedies for kidney stones android 100 salim garba usman health & fitness definition, home remedies reduce stones android 1000 shakeel health & fitness epidemiology, causes, definition, risk factors, diet archivio italiano di urologia e andrologia 2023; 95, 1 kidney stone and mobile health application ing data were extracted from mha: title, language, customers, costs, source (google play store or apple app store), field/disease, rating/feedback from the users and service provided. assessment of app quality mobile application rating scale (mars) was used to assess apps’ quality as performed in our previous work (8). assessment of app adherence to eau guidelines an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) based on section 5 of the eau guidelines of ksd has been created (10). three independent reviewers (urologists with high experience in kidney stones disease) analyzed separate apps for their adherence to eau guidelines. according to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. a score of ‘‘0’’ indicated no adherence to guidelines. a score of ‘‘1’’ indicated a weak adherence. a score of ‘‘2’’ indicated a partial or moderate adherence. a score of ‘‘3’’ indicated strong adherence. a mean score for each category was calculated from the scores given by each reviewer. the possible score on the checklist ranged from 0 to 15 for each app. to facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (11-15). statistical analysis adherence checklist was assessed via continuous variables with total mean value reported. concordance among examiners was assessed utilizing the independent samples kruskal-wallis test, considering a p value > 0.05 as an indicator of concordance among examiners as the null hypothesis was “same distribution of variables across the examiners”. results in total 13 apps were included in the final analysis: 9 (69.2%) from the apple app store and 4 (30.8%) from the google play store. six (46.2%) provided information about treatment and five (38.5%) provided information about diagnosis and overall information. ksd risk factors were mentioned in some mha. data about downloads were available for 9 apps out of the 13 reviewed. downloads were not available for mhas presented in the apple app store. the most downloaded app was “kidney stone symptoms & treatment” in which more than 50000 downloads were reported. all the apps were planned to be used by patients. rating was available only for the app “oxipurgout & kidney stones” for which a five star review was reported. cumulative mars scale scores are represented in table 2. graphical depictions of variables assessed by the three independent examiners are reported in figure 2, while mean total mars score and mean subjective quality are reported in figure 3. figure 4 reports the mean total score for eau adherence checklist according to different examiners. both mars score assessment, as single domains as well as total mean score, and eau adherence checklist score were concordant among different examiners (p = 0.368). engagement the score in this section was based on a 5-point likert scale in 5 subscales (entertainment, interest, customization, interactivity and target-group). the mean score was 2.35. scores ranged from 1.73 to 4.06 out of 5. the “stone md: kidney stones” app (apple ios) produced by nariman gadzhiev received the highest score for the engagement. this app contains interactive features for dietary management, water intake, urine ph, prevention of kidney stones. it also contains information about surgical management, with eau tutorial videos explaining several surgical techniques. functionality the score of the functionality section was based on a 5point likert scale in 4 subscales (performance, ease of use, navigation and gestural design) and the mean score was 3.68. scores ranged from 3.17 to 4.75. “stone md: kidney stones” app (apple ios) achieved the maximum score. aesthetics the aesthetics section was formed by a 5-point likert table 2. mars cumulative scores. name of application engagement functionality aesthetics information mean app subjective quality (section a) (section b) (section c) (section d) (a+b+c+d) (section e) stone md: kidney stones 4.06 4.75 4.12 4.27 4.4 3.23 oxipur-gout & kidney stones 3 3.58 3.17 2.77 3.13 2.18 stone pass: kidney stones 2.4 4.08 3.28 2.78 3.14 2.02 kidney stone scoring(apple) 2.27 3.67 2.64 2.87 2.86 2.08 kidney stone symptoms & treatment 2.47 3.58 2.44 3.19 2.92 2.18 kidney stone scoring(android) 2.27 3.67 2.64 2.87 2.86 2.08 stone diet renal gall bladder 2.13 3.17 2.53 2.25 2.52 1.93 kidney stones removal remedies 1.86 3.48 1.9 2.27 2.38 1.58 kidney stone treatment faq 2.13 3.33 2.65 3 2.78 2.25 home remedies for kidney stones(karanbir singh) 1.87 3.5 2.12 2.72 2.55 1.67 oxalate counts (kidney stones) 1.93 3.5 2.63 2.5 2.64 1.93 home remedies for kidney stones(salim garba usman) 1.73 3.65 2.34 2.52 2.56 1.75 reduce stones 2.47 3.91 2.64 2.53 2.89 1.92 archivio italiano di urologia e andrologia 2023; 95, 1 l. cirillo, c. manfredi, b. barone, v. morgera, et al. figure 2. mars scale score according to examiners. (a) mean engagement (b) mean functionality (c) mean aestethic (d) mean information. figure 3. (e) mean mars score (f) mean app subjective quality according to examiners. archivio italiano di urologia e andrologia 2023; 95, 1 kidney stone and mobile health application scale in 3 subscales (layout, graphics, visual appeal) and the average score was 2.7. scores ranged from 1.9 to 4.12 out of 5 and “stone md: kidney stones” app (apple ios) produced by nariman gadzhiev reached the maximum aesthetic score. information the information section was formed by a 5-point likert scale in 7 subscales and the mean score was 2.81. score ranged from 2.25 to 4.27. the “stone md: kidney stones” app (ios apple) produced by nariman gadzhiev achieved the highest score in information. subjective quality the subjective quality section consisted of 4 items. the mean score was 2.06, with scores ranging from 1.58 to 3.23. “stone md: kidney stones” app reached the maximum score. eau adherence checklist we evaluated the eau guidelines adherence in 13 apps. eau adherence scores are represented in table 3. the ks definition was reported in 9 (69.2%) apps; physiopathology was reported in 6 (46.2%) apps; risk factors were reported in 9 (69.2%) apps; diagnosis was reported in 9 (69.2%) apps; treatment was reported in 13 (100%) apps. the highest score was reported by kidney stone symptoms and treatment (android) produced by fall in love studio with an overall eau adherence score of 10.67. this app contains information about definition, epidemiology, causes and prevention, symptoms, diagnosis and treatment of ksd. only one of the 13 evaluated apps reached the maximum score of 3 in treatment, while none of the apps reached 3 in the other domanis. discussion mobile application represented a valid instrument both for patients and for physicians to manage chronic diseases, as previously assessed (9, 11-13). furthermore, the clinical utility of mhas is required to be assessed as the adherence to eau guidelines for the condition considered. thus, the aim of the study was to give an overview of currently available mhas for ksd, to assess their quality and the adherence to eau guidelines. indeed, to the best of our knowledge, although several studies have been published, none figure 4. mean total score for eau adherence checklist according to examiners. table 3. eau adherence checklist cumulative scores. name of application definition physiopathology risk factors diagnosis treatment (0-3) (0-3) (0-3) (0-3) (0-3) stone md: kidney stones 0.33 0.67 1 0.67 3 oxipur-gout & kidney stones 0 0 0.67 0 0.67 stone pass: kidney stones 0.33 0 0 0.33 1 kidney stone scoring (apple) 0 0 0 1 1 kidney stone symptoms & treatment 2.33 1.67 2 2.67 2 kidney stone scoring (android) 0 0 0 1 1 stone diet renal gall bladder 1 2 1.33 0.67 0.67 kidney stones removal remedies 0.33 0 0.33 0 1 kidney stone treatment faq 1.67 0.67 1.33 1.33 1.67 home remedies for kidney stones (karanbir singh) 0.67 0.33 1.33 1 1 oxalate counts (kidney stones) 0 0 1 0 0.33 home remedies for kidney stones (salim garba usman) 0.33 0 0 0 0.67 reduce stones 1.67 0.67 1 0.67 0.33 archivio italiano di urologia e andrologia 2023; 95, 1 l. cirillo, c. manfredi, b. barone, v. morgera, et al. analyzed the adherence to eau guidelines. we addressed this void and identified several noteworthy observations. first of all, mhas for ksd represent a very interesting topic and several papers have been published in the last few years. from our analysis, the quality of apps considered was between “2” defined as “poor” and 3, defined as “acceptable”, according to mars cumulative results. particularly, the “functionality” section ranked the highest point (3.68). as previously shown in our study on mhas for erectile dysfunction, apps were developed without healthcare support and the most important tool was their usability (9). indeed, jupp et al. showed that “functionality” had the highest score in mhas for oncology patients. these findings are in agreement with jupp et al. and o’connor et al. works. they previously observed that the apps were generally better designed in terms of their usability but may have several lacks in behavioral methodology related to long-term usage (14, 15). this suggests that mhas are easy to navigate and efficient and, specifically, could represent a crucial tool for mhas geared for kds patients. according to eau adherence, the “treatment” was reported in 100% of mhas while only 46.2% of apps treated the physiopathology of ksd. consequently, this observation could affect the ksd prevention strategy. indeed, ksd patients could not be aware of dietary regimens that cause their condition, continuing an unsafe lifestyle. recently lòperz et al. evaluated, in a prospective multicenter study on 37 ksd patients, the usefulness and acceptability of the smart lit-control® ph meter connected with a mha (mylit-control(r) app) used by ksd patients for home monitoring of urine ph (16). the study showed that the app was useful and acceptable, with a high compliance rate (87.6%) and good satisfaction (mean score of 6.0). according to eau guidelines, the circadian fluctuation of ph could suggest a predisposing condition to urolithiasis such as the presence of an "acidic arrest” (when the value is constantly < 5.8) or a renal tubular acidosis (rta) (when the value is constantly > 5.8). both conditions could negatively affect the quality of life (qol) and the prognosis of the patients (17). ksd patients could benefit from mobile applications to screen rapidly their condition, such as the urinary ph, and to prevent subsequent pathological diseases. although, a larger prospective study with a longer follow-up period may be required to ensure the applicability and the usefulness of the mhas in the prevention of the urolithiasisrelated disease. moreover mckenzie et al. reported that mhas were a well-established tool for measuring fluid intake, without providing crucial information regarding the importance of hydration. actually, the fluid intake (2.5-3.0l/day) combined to the diet represented the most important general preventive measure with a very beneficial cost-effectiveness (18). recently, khambati et al. reported only 50% adherence to fluid intake (19), while streeper et al. showed an increasing interest of patients in making lifestyle changes and increasing fluid consumption. these shifts are promising, and mhas must promote them. the lifestyle changes must be spread through the mhas, highlighting the importance of hydration in the prevention of ksd and urolithiasis-related diseases. the apps should be more comprehensive and informative to support patients’ adherence to prevention guidelines. additionally, the major concern of the urolithiasis was the recurrence rate. thus, mhas should inform ksd patients also of a metaphylaxis protocol (20). as previously assessed, the implementation of metaphylaxis reduced the rate and risk of recurrent urolithiasis (21). indeed, becker et al. developed a mobile app (stonemd: kidney stones) to increase compliance in stone metaphylaxis (22). the app calculated the individual risk of a new stone episode, and improved patient compliance and reduced the risk of stone formation. our results corroborated previous data. indeed “stone md: kidney stones” reached the highest score in different mars domains. this suggests that healthcare support is necessary in mhas development. despite this another mha, kidney stone symptoms and treatment, reached the highest score of adherence to eau guidelines. these data suggest that healthcare involvement in mhas development is not related to better guidelines adherence. finally, shahmoradi et al. aimed to develop and evaluate a self-care mha for patients with urinary tract stones. this is a challenging issue that could transform the management of ksd where the patient became the main character. mhas should consider patient needs assessment and participation of clinical and health information specialists to define the better management protocol of prophylaxis, metaphylaxis and treatment of ksd patients. according to shamoradi, this addressed issue should be considered a model for designing and creating better mhas (23). our study has several strengths: first of all, we examined for the first time the content, the quality, and the adherence to eau guidelines about ksd; we performed a rigorous search, screening, and analysis on apple and google stores; reviewers had experience in mars scale using. to avoid the inter-variability analysis among the three investigators, each app was independently evaluated, and a cumulative final point was measured and discussed by a fourth impartial author. the main limitation of our study is the number of apps subjected to the qualitative assessment. furthermore, the reproducibility of the research turns out to be complex due to the working method of the app store and google play store (the visibility of apps depends on the device and on the country where the search is performed); the exclusion criteria, which led to the exclusion of paid apps; the guidelines developed for healthcare and not for patients and the constant production of new mha. taken together, our analysis definitely assessed the low quality of apps available on ksd. however, it could represent a starting point to produce high-quality and informative apps, easy to use. indeed, mhas represent a key instrument to spread eau guidelines adherence among ksd patients, nowadays. currently, the information provided by mobile apps is not satisfactory but improvable. indeed, mhas should elucidate exhaustively the prophylaxis and metaphylaxis protocols to reduce the risk and the recurrence of kidney stones, enlightening the role of lifestyle (fluid intake, diet and physical activities) as the most useful preventive measure. conclusions nowadays, mhas represent a key instrument to spread eau guidelines adherence among ksd patients. archivio italiano di urologia e andrologia 2023; 95, 1 kidney stone and mobile health application currently, the information provided by mobile apps must be improved. indeed, mhas should join exhaustively the prophylaxis and metaphylaxis protocols to reduce the risk and the recurrence of kidney stones, enlightening the role of lifestyle (fluid intake, diet and physical activities) as the most useful preventive measure. thus, patients should use the mhas without avoiding physician consultations. references 1. sohgaura a, bigoniya p. a review on epidemiology and etiology of renal stone. am. j. drug discov. dev. 2017; 7: 54-62 2. curhan gc. epidemiology of stone disease. urol clin north am. 2007; 34:287-93. 3. khan sr, pearle ms, robertson wg, et al. kidney stones. nat rev dis primers. 2016; 2:16008. 4. frassetto l, kohlstadt i. treatment and prevention of kidney stones: an update. am fam physician. 2011; 84:1234-42. 5. spring b, gotsis m, paiva a, spruijt-metz d. healthy apps: mobile devices for continuous monitoring and intervention. ieee pulse. 2013; 4:34-40. 6. mirone v, creta m, capece m, et al. telementoring for communication between residents and faculty physicians: results from a survey on attitudes and perceptions in an academic tertiary urology referral department in italy. arch ital urol androl. 2021; 93:450-454. 7. stoyanov sr, hides l, kavanagh dj, et al. mobile app rating scale: a new tool for assessing the quality of health mobile apps. jmir mhealth uhealth. 2015; 3:e27. 8. stec ma, arbour mw, hines hf. client-centered mobile health care applications: using the mobile application rating scale instrument for evidence-based evaluation. j midwifery womens health. 2019; 64:324-329. 9. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 10. davalbhakta s, advani s, kumar s, et al. a systematic review of the smartphone applications available for coronavirus disease 2019 (covid19) and their assessment using the mobile app rating scale (mars). medrxiv [preprint]. 2020 jul 4:2020.07.02.20144964. update in: j med syst. 2020; 44:164. 11. napolitano l, cirillo l, fusco gm, et al. premature ejaculation in the era of mobile health application: a current analysis and evaluation of adherence to eau guidelines. arch ital urol androl. 2022; 94:328-333. 12. napolitano l, cirillo l, fusco gm, et al. natural treatments for erectile dysfunction: a focus on mobile health applications. arch ital urol androl. 2022; 94:373-374. 13. fusco gm, cirillo l, abate m, et al. male infertility, what mobile health applications “know”: quality analysis and adherence to european association of urology guidelines. arch ital urol androl. 2022; 94:470-475. 14. o'connor sr, kee f, thompson dr, et al. a review of the quality and content of mobile apps to support lifestyle modifications following a transient ischaemic attack or 'minor' stroke. digit health. 2021; 7:20552076211065271. 15. jupp jcy, sultani h, cooper ca, et al. evaluation of mobile phone applications to support medication adherence and symptom management in oncology patients. pediatr blood cancer. 2018; 65:e27278. 16. lópez jm, mainez ja, mora christian j, et al. usefulness and acceptability of a smart ph meter and mobile medical app as a monitoring tool in patients with urolithiasis: short-term prospective study. arch esp urol. 2022; 75:60-68. 17. geraghty rm, davis nf, tzelves l, et al. best practice in interventional management of urolithiasis: an update from the european association of urology guidelines panel for urolithiasis 2022. eur urol focus. 2022:s2405-4569(22)00144-4. 18. philip-mckenzie y, jamnadass e, hameed bz, et al. a content analysis of 'water apps' and prevention of urological diseases: do apps really help? cent european j urol. 2020; 73:187-192. 19. khambati a, matulewicz rs, perry kt, nadler rb. factors associated with compliance to increased fluid intake and urine volume following dietary counseling in first-time kidney stone patients. j endourol. 2017; 31:605-610. 20. streeper nm, lehman k, conroy de. acceptability of mobile health technology for promoting fluid consumption in patients with nephrolithiasis. urology. 2018; 122:64-69. 21. banov p, ceban e. the efficacy of metaphylaxis in treatment of recurrent urolithiasis. j med life. 2017; 10:188-193. 22. becker b, gadzhiev n, popiolek m, et al. smartphone-app für patienten mit nierensteinen [a mobile app for patients suffering from kidney stones]. urologe a. 2018; 57:577-582. 23. shahmoradi l, azizpour a, bejani m, et al. prevention and control of urinary tract stones using a smartphone-based self-care application: design and evaluation. bmc med inform decis mak. 2021; 21:299. correspondence luigi cirillo, md cirilloluigi22@gmail.com biagio barone, md biagio193@gmail.com vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com francesco mastrangelo, md f.mastrangelo91@gmail.com francesco di bello, md fran.dibello12@gmail.com marco abate, md marcoabate5@gmail.com davide arcaniolo, md davide.arcaniolo@gmail.com felice crocetto, md felice.crocetto@gmail.com roberto la rocca, md robertolarocca87@gmail.com massimiliano creta, md max.creta@gmail.com francesco paolo calace, md fra.calaca@gmail.com luigi napolitano, md dr.luiginapolitano@gmail.com giovanni maria fusco, md (corresponding author) giom.fusco@gmail.com unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii” via sergio pansini 5, 80131 naples, italy celeste manfredi, md manfredi.celeste@gmail.com lorenzo spirito, md lorenzospirito@msn.com unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples (italy) conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2021; 93, 188 original paper presented at the sieun congress ancona 30 november 1 december 2020 no conflict of interest declared. doi: 10.4081/aiua.2021.1.88 cancer (pca). aim of as is to defer or avoid treatments preventing the side effects after active treatments (urinary incontinence and erectile dysfunction) (1). biopsy criteria for as vary from one protocol to another: in the original as was offered only for men with small gleason score (gs) 3+3 = 6 pca according to epstein criteria of indolent pca (2-3), but now in few programs the criteria include men with more extensive gs 3+3 = 6 lesions and even some with gs 3+4 (5). upgrading beyond the low-risk cancer found initially has been reported in 35-45% during the first year of follow-up using systematic biopsies (sb) (6, 7). early disease upgrading likely indicates that the initial biopsy findings were inaccurate therefore a more accurate characterization of prostate pathologic findings from the beginning of as (and during follow-up) would be desirable. magnetic resonance imaging and mri-us fusion biopsy (fb) has been shown to help characterizing pathologic findings more accurately than sb, leading to improved detection of significant pca. use of this new biopsy method has not yet fully evaluated among men undergoing active surveillance (7-9). we present our experience using mri-us fb in men undergoing as of pca. materials and methods this retrospective single center study included 620 consecutive patients who underwent fb between may 2016 and january 2019. we selected from our database only patients on as. all patients had at least one suspicious lesion at mpmri, that were performed in different centers as it often happens in community setting without a central review. the suspicious lesions were scored according to the pi-rads classification v.2. fb were performed with koelis™ system (koelis, meylan, france), using koelis trinity™ platform.koelis™ system creates a precise and highly detailed 3d map of the prostate integrating 3d ultrasound, elastic fusion and organ-based tracking®. all the biopsies considered in the study were performed with a transrectal approach, as reported in our initial experienceby 3 experienced urologists dedicated to fb (10). biopsy were performed and specimens collected according to italian guidelines (11). pca was considered clinically significant in case of findings of aim: the upgrading or staging in men with prostate cancer (pca) undergoing active surveillance (as), defined as gleason score (gs) ≥ 3+4 or more than 2 area with cancer, was investigated in our experience using the software-based fusion biopsy (fb) methods: we selected from our database, composed of 620 biopsies, only men on as according to criteria of john hopkins protocol (t1c, < 3 positive cores, gs = 3+3 = 6). monitoring consisted of psa measurement every 3 months, a clinical examination every 6 months, confirmatory fb within 6 months and then annual fb in all men. the suspicious mri lesions were scored according to the prostate imaging reporting and data system (pi-rads) classification version 2. fb were performed with a transrectal elastic free-hand fusion platform. the overall and clinically significant cancer detection rate was reported. secondary, the diagnostic role of systematic biopsies was evaluated. results: we selected 56 patients on as with mean age 67.4 years, mean psa 6.7 ng/ml and at least one follow-up mri-us fusion biopsy (10 had 2 or 3 follow-up biopsies). lesions detected by mri were: pirads-2 in 5, pirads-3 in 28, pirads-4 in 18 pts and pirads-5 in 5 patients. in each mri lesion, fb with 2.1 ± 1.1 cores were taken with a mean total cores of 13 ± 2.4 including the systematic cores. the overall cancer detection rate was 71% (40/56): 62% (25/40) in target core and 28% (15/40) in systematic core. the overall significant cancer detection rate was 46% (26/56): 69% (18/26) in target vs 31% (8/26) in random cores. conclusions: the incidence of clinical significant cancer was 46% in men starting active surveillance, but it was more than doubled using mri/us target biopsy 69% (18/26) rather than random cores (31%, 8/26). however, 1/3 of disease upgrades would have been missed if only the targeted biopsies were performed. based on our experience, mri/us fusion target biopsy must be associated to systematic biopsies to improve detection of significant cancer, reducing the risks of misclassification. key words: fusion biopsy; mri-us guided fusion biopsy; prostate cancer; active surveillance. submitted 14 january 2021; accepted 27 january 2021 introduction active surveillance (as) is currently the most rapidly growing management strategy for men with low risk prostate mri/us fusion prostate biopsy in men on active surveillance: our experience summary vito lacetera 1, angelo antezza 2, alessio papaveri 2, emanuele cappa 1, bernardino cervelli 1, giuliana gabrielloni 1, michele montesi 1, roberto morcellini 1, gianni parri 1, emilio recanatini 1, valerio beatrici 1 1 azienda ospedaliera ospedali riuniti marche nord, division of urology, pesaro, italy; 2 università politecnica delle marche-azienda ospedaliera ospedali riuniti torrette di ancona, italy; 89archivio italiano di urologia e andrologia 2021; 93, 1 mri/us fusion prostate biopsy gleason score > 6, or more than 2 cores of gleason score 6 (or more than 1 core outside the target) as suggested by criteria of many as protocols. the overall and clinically significantcancer detection rate (ocdr, cs cdr) of koelis™ system was obtained. secondary the diagnostic role of additional sb was evaluated (figures 1-3). results we selected from our database 56/620 patients on as with at least 1 follow-up fb. the characteristics of the 56 patients (summarized in table 1) were: mean age 67.4 years (ci ± 8.8); mean psa 6.7 ng/ml ± 3.1; mean prostate volume 49.2 ± 21 ml. lesions detected by mri: pirads 2 = 5 pts; pirads 3 = 28 pts; pirads 4 = 18 pts; pirads 5 = 5 pts. 46 pts had only 1 confirmatory fb, 7 pts had 2 follow-up fb, 3 pts had 3 follow-up fb. mean cores from each mri target lesion were 2.1 ± 1.1; mean total cores were 13 ± 2.4. overall pca detection rate was 71% (40/56); overall significant pca (gleason score > = 3+4) detection rate was = 46% (26/56); pca in target core = 62% (25/40); pca in random core = 28% (15/40); significant pca in target cores = 69% (18/26); significant pca in systematic core = 31% (8/26) (as summarized in table 2). table 1. characteristics of the patients. number of patients 56 age (years), mean (ci) 67.4 ± 8.8 psa (ng/ml), mean (ci) 6.7 ± 3.1 prostate volume (ml), mean (ci) 49.2 ± 21 pirads of targets (maximum score in case of multiple targets) pirads 2 5 pirads 3 28 pirads 4 18 pirads 5 5 mean target cores 2.1 ± 1.1 mean total cores 13 ± 2.4 figure 1. fusion + systematic biopsy in a patient on active surveillance: 3 targets on a pirads 3 lesion in tza right middle gland and 13 random cores avoiding the previous tracks (blue cores). results: 2 positive cores gs 3+3 = 6 on target lesion, as was continued. figure 2. anterior-posterior view shows the target core inside the anterior tz pirads 3 lesion at mri. figure 3. confirmatory biopsy in a 54 yo patient on as: fusion biopsy (6 target and 6 sistematyc cores) was pca positive in 3/6 cores (gs 4+3 = 7). patient undergone to rarp (final pathology confirmed a gs = 4+3 = 7 pt2r0n0). table 2. results. characteristic number overall pca detection rate 71% (40/56) significant pca detection rate 46% (26/56) pca detected in target cores 62% (25/40) pca in detected in systematic cores 28% (15/40) significant pca detected in target cores 69% (18/26) significant pca detected in systematic cores 31% (8/26) archivio italiano di urologia e andrologia 2021; 93, 1 v. lacetera, a. antezza, a. papaveri, et al. 90 discussion among the devices used for fb, koelis™ is supported by severalrobust evidences (12-14), showing a cdr ranging from 48% to 80%. we compared our results with nassiri et al. (15), who analyzed 259 men (196 with gs 3+3 and 63 with gs 3+4) who were diagnosed by mri/us fb (period 20092015) and who underwent subsequent fb for as long as 4 years of as: 63% of men with gs 3+4 were upgraded by the third surveillance year, compared with 18.0% of men with initial gs 3+3 (p < 0.01). moreover, 97% of all upgrades (32/33) occurred within an mri-visible or a tracked site of tumor, rather than a previously-negative systematic site. jayadevan et al. (17) analyzed men with a new diagnosis of gleason grade group (gg) 1 pca (period 2009-2017). the initial diagnostic biopsy was performed by various methods in community settings and within one year from diagnosis, all the men underwent confirmatory fb. confirmatory biopsy and all follow-up biopsies were performed using a mri-guided biopsy system. the end point was a finding of at least gg3 disease during follow-up, which then excluded those patients from active surveillance. of 332 patients in the total cohort of as, 114 had normal findings on confirmatory biopsy, 175 had gg1 disease, and 43 had gg2 disease. there were 39 patients (11.7%) with upgrading to at least gg3 during the study period with 43% of upgraded cases detected only by target biopsies (tb) and 46% d only by sb. thus, if only one biopsy method was implemented, at least 43% of disease upgrades would have been missed. similar findings were seen in improvement in the detection of aggressive prostate cancer by targeted biopsies using multiparametric mri findings (mri-first) and the prospective assessment of image registration in the diagnosis of prostate cancer (pairedcap) trials (17, 18). an analysis of patients undergoing as by frye et al. (19) at the national cancer institute also found that the combination of sb and tb should be used during as followup, given that only 30% of pathologic disease upgrades were identified by sb alone. the efficacy of the combination of both biopsy techniques has been recently confirmed a by klots et al. (20) and ma et al. (21). in order to reduce side effects of systematic biopsy, several non-invasive strategies has been proposed (22). the psa-density, as supported by roscigno et al. (23), was used with a cut-off ≥ 0.20 ng/ml to improve the predictive accuracy of mpmri results for reclassification of patients in as, whereas a psad value < 0.10 ng/ml identifies a lower risk of harboring clinically significant cancer. nowadays, the combination of target and sb represents the standard for patients on as; our study strengthens this recommendation, showing that additional random cores improved the overall cdr of 28% and clinically significant cdr of 31%. conclusions fb represents a useful tool to address many of the limitations of contemporary systematic biopsy. according to most recent evidences and our experience, we believe that mri/us fusion biopsy improve overall cancer detection rate, clinical significant cancer detection rate and risk stratification among men on active surveillance. our data suggest that confirmatory and follow-up fusion biopsies with mri guidance when associated to sb provide a more accurate risk assessmentin order to reduce the oncological risks of as. references 1. cooperberg mr. active surveillance for low-risk prostate cancer an evolving international standard of care. jama oncol. 2017; 3:1398-1399. 2. gasparrini s, cimadamore a, mazzucchelli r, et al. pathology and molecular updates in tumors of the prostate: towards a personalized approach. expert rev mol diagn. 2017; 17:781-789. 3. montironi r, santoni m, mazzucchelli r, et al. prostate cancer: from gleason scoring to prognostic grade grouping. expert rev anticancer ther. 2016; 16:433-40. 4. mazzucchelli r, galosi ab, lopez-beltran a, et al. pathological issues in biopsy specimens of men with prostate cancer eligible for active surveillance. arch ital urol androl. 2014; 30;86:314-8. 5. klotz l. active surveillance for prostate cancer: overview and update. curr treat options oncol. 2013; 14:97-108. 6. dinh kt, mahal ba, ziehr dr et al. incidence and predictors of upgrading and upstaging among 10,000 contemporary patients with low risk prostate cancer. j urol. 2015; 194:343-349. 7. barrett t, haider ma. the. emerging role of mri in prostate cancer active surveillance and ongoing challenges. ajr am j roentgenol. 2017; 208:131-139. 8. elkhoury ff, simopoulos dn, marks ls. targeted prostate biopsy in the era of active surveillance. urology. 2018; 112:12-19. 9. kasivisvanathan v, rannikko as, borghi m, et al. precision study group collaborators. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med. 2018; 378:1767-1777. 10. lacetera v, cervelli b, cicetti a, et al. mri/us fusion prostate biopsy: our initial experience. arch ital urol androl. 2016; 88:296-299. 11. fandella a, scattoni v, galosi a, et al. italian prostate biopsies group: 2016 updated guidelines insights. anticancer res. 2017; 37:413-424. 12. baco e, rud e, eri lm, et al. a randomized controlled trial to assess and compare the outcomes of two-core prostate biopsy guided by fused magnetic resonance and transrectal ultrasound images and traditional 12-core systematic biopsy. eur urol. 2016; 69:149-156. 13. ukimura o, gross me, de castro abreu al, et al. a novel technique using three-dimensionally documented biopsy mapping allows precise re-visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel. prostate. 2015; 75:863-71. 14. mozer p, rouprêt m, le cossec c, et al. first round of targeted biopsies using magnetic resonance imaging/ultrasonography fusion compared with conventional transrectal ultrasonography-guided biopsies for the diagnosis of localised prostate cancer. bju int. 2015; 115:50-7. 15. nassiri n, margolis dj, natarajan s, et al. targeted biopsy to detect gleason score upgrading during active surveillance for men with low versus intermediate risk prostate cancer. j urol. 2017; 197:632-639. 16. jayadevan, et al. magnetic resonance imaging–guided confirma91archivio italiano di urologia e andrologia 2021; 93, 1 mri/us fusion prostate biopsy tory biopsy for initiating active surveillance of prostate cancer jama netw open. 2019; 2:e1911019. 17. rouvière o, puech p, renard-penna r, et al. mrifirst investigators. use of prostate systematic and targeted biopsy on the basis of multiparametric mri in biopsy-naive patients (mrifirst): a prospective, multicentre, paired diagnostic study. lancet oncol. 2019; 20:100-109. 18. elkhoury ff, felker er, kwan l, et al. comparison of targeted vs systematic prostate biopsy in men who are biopsy naive: the prospective assessment of image registration in the diagnosis of prostate cancer (pairedcap) study jama surg. 2019; 154:811-818. 19. frye tp, et al. magnetic resonance imaging-transrectal ultrasound guided fusion biopsy to detect progression in patients with existing lesions on active surveillance for low and intermediate risk prostate cancer. j urol. 2017; 197:640-646. 20. klotz l, loblaw a, sugar l, et al. active surveillance magnetic resonance imaging study (asist): results of a randomized multicenter prospective trial. eur urol. 2019; 75:300-309. 21. ma tm, tosoian jj, et al. the role of multiparametric magnetic resonance imaging/ultrasound fusion biopsy in active surveillance. eur urol. 2017; 71:174-180. 22. cimadore a, scarpelli m, raspolini mr, et al. prostate cancer pathology: what has changed in the last 5 years. urologia 2020; 87:3-10. 23. roscigno m, stabile a, lughezzani g, et al the use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. correspondence vito lacetera, md (corresponding author) vlacetera@gmail.com emanuele cappa, md cappa.emanuele@gmail.com bernardino cervelli, md bernardo.cervelli@ospedalimarchenord.it giuliana gabrielloni, md giuliana.gabrielloni@ospedalimarchenord.it michele montesi, md michele.montesi@ospedalimarchenord.it roberto morcellini, md roberto.morcellini@ospedalimarchenord.it gianni parri, md gianni.parri@ospedalimarchenord.it emilio recanatini, md emilio.recanatini@ospedalimarchenord.it valerio beatrici, md valerio.beatrici@ospedalimarchenord.it urologist, azienda ospedaliera ospedali riuniti marche nord, pesaro, division of urology a.o. ospedali riuniti marche nord, piazzale cinelli 4, 61121 pesaro (italy) angelo antezza, md angelo.antezza@yahoo.it alessio papaveri, md alessio.papaveri1@gmail.com resident in urology, università politecnica delle marche-azienda ospedaliera ospedali riuniti torrette di ancona (italy) stesura seveso 53archivio italiano di urologia e andrologia 2020; 92, 1 case report surgical treatment of large hemangioma of the scrotum in a young adult male massimo iafrate 1, nicolò leone 1, cesare tiengo 2, filiberto zattoni 1 1 università degli studi di padova, dipartimento di scienze oncologiche chirurgiche e gastroenterologiche, clinica urologica, padova, italy; 2 università degli studi di padova, dipartimento di neuroscienze, chirurgia plastica ricostruttiva ed estetica, padova, italy. a 24-year-old male came to our clinic for a volumetric increase of a suspected scrotal hemangioma with thrombosis episodes. the ultrasound rose the suspicion of hemangioma and the magnetic resonance (mr) of the scrotum confirmed the suspicion. the mass was surgically removed and histopathology described a hemangioma cavernous. the postoperative course was regular and no subsequent relapse was shown in 5 months follow-up. key words: andrology; hemangioma; scrotum; scrotal surgery; scrotal mass. submitted 3 february 2020; accepted 29 february 2020 summary no conflict of interest declared. doi: 10.4081/aiua.2020.1.53 introduction hemangiomas are the most common vascular neoplasms in children with an incidence in the first year of age ranging from 3 to 10%. the most frequent localizations are head, neck, trunk, and extremities. hemangiomas of the scrotum are rare conditions in adult. many researchers consider them benign neoplasms originating from a congenital vascular anomaly (1). case report after a written informed consent was obtained from the participant for the publication of this case report, we present a 24-year-old student male with a history of suspected scrotal hemangioma known from the age of 14 progressively growing over the past 12 months. in the previous 36 months, he went to the emergency room three times for hemangioma thrombosis which was conservatively treated. in medical history, he reported the removal of a lipoma in the sacral region and no previous traumas of genitalia. no significant family history was present. the physical examination showed a soft vascular mass of about 3 x 7 cm positioned in the middle part of the scrotum (figure 1). the testicles with their funiculum were completely independent from the vascular mass. the remaining physical examination did not show any other significant finding. hematology, biochemistry, renal, liver function and hormonal panel were in range. mri of the scrotum documented the presence of a lesion of 6 x 7 x 7 cm made of venous structures dilated developing in the context of the inferior-internal wall of the right scrotum containing some phlebolites, compatible with hemangioma. the lesion was in close contact with the right cavernous body but did not infiltrate buck's fascia. surgical excision was therefore planned. in general anesthesia, a diamond-shaped incision was made in the scrotal skin. with the dissection of the subcutaneous tissue, we identified the hemangioma inside the scrotum. after careful isolation of the neoplasm from the funicular structures and the testicles, we identified the site of origin at the perineal level on the buck’s fascia. the vessels were then tied to the site of origin with sutures, followed by complete removal of the hemangioma and sent to histological examination (figure 2). a scrotal drainage in extraction and a bladder catheter were placed. subcutaneous and skin have been sutured with detached points and a compressive dressing has been applied. the drainage and the catheter were removed the next day. the postoperative course was uneventful. histopathological examination showed the presence of skin and subcutaneous tissue with vascular proliferation consisting of ectasic vessels with thin walls compatible with scrotal hemangioma. after 5 month, at the follow-up visit, the scar was nearly unrecognizable and there were no signs of recurrence (figure 3). discussion cavernous hemangiomas of the scrotum are usually present since birth but come to the attention of the physician only during adolescence due to their unaesthetic aspect. generally, they are painless masses but sometimes they can be associated with symptoms (pain and bleeding). the imaging helps to characterize the lesion, to assess the extent of the hemangioma, and to detect associated anomalies. scrotal ultrasonography, however, is frequently not diriment for the diagnostic characterization. a hemangioma may be hypo or hyperechoic. the most typical finding is a mass of soft tissue containing phlebolites (small calcifications). the presence of phlebolites is characteristic of cavernous hemangioma. ct and mri provide a simple and non-invasive method for the diagnosis and the determination of the extent of these lesions as well as their relationship with adjacent structures. for such reasons, these imaging techniques are considered mandatory before a surgical program (2). the therapeutic choice must take into account different aspects, from the size and the location of the neoplasm to the esthetic outcome. in the literaiafrate_stesura seveso 03/04/20 12:10 pagina 53 archivio italiano di urologia e andrologia 2020; 92, 1 m. iafrate, n. leone, c. tiengo, f. zattoni 54 ture, good results are reported for small lesions both with nd: yag laser or carbon dioxide and with intralesional sclerotherapy. the surgical excision of these tumors of the genital area is burdened with the risk of bleeding due to the high vascularization and the possibility to develop unsightly scars (3). in this case, the surgical option was preferred since there were close relationships with the corpora cavernosa and we needed to avoid treatment options with high odd of necrosis of the erectile tissues. conclusions the cavernous hemangioma of the scrotum is a rare entity and a diagnostic evaluation with mri is mandatory in order to have a complete evaluation of the anatomic extension of the lesion. surgical excision is a therapeutic choice with safe and satisfactory results, especially for large lesions in adulthood. references 1. lin cy, sun gh, yu ds, et al. intrascrotal hemangioma. arch androl. 2002; 48:259-65. 2. djouhri h, arrivé l, bouras t, et al. diffuse cavernous hemangioma of the rectosigmoid colon: imaging findings. j comput assist tomogr. 1998; 22:851-5. 3. lee jm, wang jh, kim hs. multiple cavernous hemangiomas of the glans penis, penis, and scrotum. korean j urol. 2008; 49:92-94. figure 1. physical examination showed a soft vascular mass positioned in the middle part of the scrotum. figure 2. complete removal of the hemangioma for histological examination. figure 3. 5-month follow-up with no signs of recurrence. correspondence massimo iafrate, md (corresponding author) massimo.iafrate@unipd.it nicolò leone, md nicolo.leone@gmail.com filiberto zattoni, md filiberto.zattoni@unipd.it clinica urologica di padova via giustiniani 2 35100 padova (italy) cesare tiengo, md cesare.tiengo@unipd.it dipartimento di neuroscienze, chirurgia plastica ricostruttiva ed estestetica, padova (italy) iafrate_stesura seveso 03/04/20 12:10 pagina 54 stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper patients and methods this is a retrospective study including patients with pathologically proven stage i seminoma, who presented to the national cancer institute, cairo university, during the period from 2005 to 2019. data was retrieved from the patients' medical records. the collected data included age, pathological subtype, post-operative stage, date and type of surgery, pre & post-operative tumor markers, details of adjuvant treatment, patterns of failure and patients' status at last follow up. all patients had inguinal orchiectomy followed by staging computed tomography (ct) of abdomen & pelvis to exclude nodal or distant disease and serum tumor marker assessments (alpha-fetoprotein and beta-hcg). patients who were kept under active surveillance, were followed every 3 months in the first 2 years. in each visit history and physical examination was performed, serum tumor markers levels (ldh, beta-hcg, alpha-fetoprotein) were obtained, and imaging was done every 6 months. in the third year of follow up, the interval of the visits was every 6 months and imaging and markers were ordered annually. in the following years of follow up, the interval was annually with no imaging unless clinically indicated. all patient were adherent to the follow up schedule. in patients who received adjuvant chemotherapy, one cycle of carboplatin (auc 7, based on the formula 7x [glomerular filtration rate (gfr, ml/min) +25 mg] was given to all patients except one patient who was given two cycles. patients were kept under follow up every 6 months in the first and second year then follow up was annually, with serum tumor markers (ldh, beta-hcg, alpha-fetoprotein) obtained at each visit and imaging if clinically indicated. in patients who received adjuvant radiation radiotherapy; the field of radiation was para-aortic lymph nodes field (paln). the field extended from t11/t12 superiorly till l5/s1 inferiorly using anterior-posterior-posterio-anterior (ap/pa) field arrangement or multiple (4) fields. clinical target volume (ctv) comprised the para-caval, pre-caval and inter aorto-caval nodes. the prescribed dose was (25.5gy/1.5gy/17 fraction) or (19.8gy/1.8gy/11 fraction). following the end of the course, follow up was every 6 months in the first and second year then kept annually. background: the mainstay for management of stage i seminoma is high inguinal orchiectomy with post-orchiectomy therapeutic options including active surveillance, chemotherapy or radiation therapy. objectives: to analyze different post-orchiectomy treatment modalities outcomes of stage i seminoma patients presented to nci, cairo university in the period from 2005-2019. patients and methods: a retrospective review of all patients' records with clinical stage i seminoma who presented to our institute in the period from 2005-2019 was done. adjuvant treatment details were extracted, and we compared overall survival (os) and disease free survival (dfs) for different modalities and changes in patterns of care over this period. results: thirty-five patients were identified with thirty three patients eligible for analysis. median age was 35 years (range, 19-52). fourteen patients were kept under active surveillance, eleven patients received adjuvant carboplatin and eight patients received adjuvant radiation to para-aortic chain. five-year os was 100% for all patients regardless post-operative approach. five-year dfs was 100% for patients who received adjuvant chemotherapy or radiotherapy versus 93% for patients who were kept under active surveillance (p = 0.03). conclusions: clinical stage i seminoma is a favorable disease entity with favorable disease related outcomes regardless postoperative approach. active surveillance is reasonable and safe given equal survival to active treatment. key words: seminoma; stage i; surveillance; radiotherapy; chemotherapy. submitted 18 december 2022; accepted 31 december 2022 introduction testicular cancers are rare tumors with an incidence of less than 1% of all male tumors (1). the standard management of testicular tumors starts with high inguinal orchiectomy followed by a stage and pathology dictated management (2). clinical stage i seminoma has a very favorable outcome after surgery (3). management options for stage i disease have evolved over the past decades from adjuvant radiation to para-aortic chain to chemotherapy with single agent carboplatin and finally moving to active surveillance with equal survival among all strategies (4). herein, we review our experience and changes in patterns of care over time. stage i seminoma: outcome of different treatment modalities and changes in patterns of care. a single institution experience manar mahmoud sayed 1, azza mohamad nasr 1, ibtesam mohamad saad eldin 2, yasser anwar abdelazim 1 1 department of radiation oncology, national cancer institute, cairo university, egypt; 2 department of clinical oncology, faculty of medicine, cairo university, egypt. doi: 10.4081/aiua.2023.11057 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. mahmoud sayed, a. mohamad nasr, i. mohamad saad eldin, y. anwar abdelazim statistical methodology data management and analysis was performed using statistical package for social sciences (spss) vs. 25. numerical data were checked for normality and were statistically described as means (standard deviations) or medians (ranges) as appropriate. categorical data were described as numbers and percentages. survival analysis was done using kaplan-meier method with comparison between two or more survival curves using log rank test with bonferroni adjustment when necessary. all statistically significant factors on kaplan-meier analysis entered the multivariate cox regression analysis using forward likelihood-ratio (lr) method for variable selection. hazard ratios were computed for significant factors in the last step of cox-regression with 95% confidence interval estimates. all tests were 2 tailed and p-value < 0.05 was considered statistically significant. all the patients treated with different modalities were compared in terms of overall survival (os), disease-free survival (dfs), loco-regional control (lrc) and metastaticfree survival (mfs). os was calculated from the date of diagnosis to the date of death or last follow-up, disease free survival (dfs) was calculated from the date of surgery to the date of locoregional recurrence or metastasis whichever comes first. metastasis free survival (mfs) was calculated from the date of surgery to the date of metastasis. para-aortic nodal relapse was not considered as metastatic event but a loco-regional failure. time to loco-regional control (lrc) was calculated from the date of surgery to the date of loco-regional recurrence. results in the period from 2005 to 2019, thirty five patients with clinical stage i seminoma presented to national cancer institute, cairo university. thirty three patients were included in our analysis and two patients were excluded from survival analysis due to lost follow up. median age in our cohort was 35 years (range, 19-52). thirty two patients (91%) had classic subtype and three patients (9%) had spermatocytic subtype. patients' clinical and demographic characteristics are summarized in table 1. fourteen patients (42%) were kept under active surveillance, eight patients (24%) received adjuvant radiation therapy to para-aortic nodal chain and eleven patients (34%) received adjuvant carboplatin, with 10 patients receiving only 1 cycle and one patients receiving 2 cycles. patients' clinical and demographic data in each arm are summarized in table 2. five-year overall survival rate was 100% in the whole cohort and median overall survival was not reached. no overall survival difference was seen between patients who were subjected to active treatment and patients who were kept under active surveillance. in terms of disease-free survival, five year dfs rate was 100% for patients who received active treatment (whether chemotherapy or radiotherapy) versus 93% for patients who were kept under active surveillance (p = 0.03). among those who were kept under active surveillance, one patient developed para-aortic nodal recurrence after 4 years. he was managed by salvage chemotherapy (3 cycles bep) and he achieved complete response and was disease free till data cutoff. in terms of loco-regional control (lrc), five-year lrc was 100% for patients who received active treatment (chemotherapy or radiotherapy) versus 93% in patients who were kept under active surveillance (p = 0.03). we tested proposed factors that would affect disease local control (namely, rete testis invasion and tumor size), however, none of them had a significant difference in relation to lrc in univariate analysis. fifteen patients had rete-testis invasion versus 18 patients without invasion, with 5 year lrc of 80 versus 100 percent, respectively (p = 0.439). sixteen patients had tumor size > 4 cm versus seventeen patients with tumor size < 4 cm, with five year lrc 100 percent and 75 percent, respectively (p=0.317). in terms of metastasis-free survival (mfs), five-year mfs rate was 100% in all patients, regardless the modality used. there has been a change in the pattern of care in our study population over the studied years. in the period from 2005 till 2009 the majority of the patients were treated with adjuvant radiation therapy. in the period from 2010 till 2014 chemotherapy was the modality of choice, while in the recent years from 2015 till 2019 active surveillance was the treatment of choice (figure 1). table 1. demographic, clinical data and pathological subtypes in patients of stage i seminoma. n = 35 n (%) age (median 35, range 19-52) < 35 20 (57) > 35 15 (43) history of undescended testis yes 6 (17) no 29 (83) history of contralateral seminoma yes 1 (3) no 34 (97) pathological subtypes classic 32 (91) spermatocytic 3 (9) anaplastic 0 (0) table 2. characteristics of the patients in each modality. active surveillance chemotherapy radiotherapy (14) (11) (8) age < 35 11 4 5 > 35 3 7 3 history of undescended testis 2 3 1 history of contralateral seminoma 1 0 0 pathological subtype classic 14 9 7 spermatocytic 0 2 1 archivio italiano di urologia e andrologia 2023; 95, 1 management of clinical stage i seminoma discussion this retrospective study included 33 patients with stage i seminoma who presented to nci cairo university in the period from 2005 to 2019. several epidemiological and clinical factors were studied as well as treatment strategies potentially influencing disease-free survival (dfs) in addition to overall survival (os) and loco regional recurrence (lrr). in our study the median os was not reached, with 5 year overall survival 100% in stage i seminoma. this is consistent with many other data. for example, a five-year survival of 99.0% was reported in seer statistics published in the year 20165. in another large cohort study of ncdb involving 33,094 patients, a ten year survival rate of 95% was reported for patients who received active treatment and 93.4% for patients who were kept under active surveillance (4). in another series coming from a tertiary portuguese center addressing testicular cancer, the five year survival rate for seminoma patients' was 100 percent (6). the 5 year disease-free survival in patients received adjuvant radiotherapy to para-aortic chain or single agent carboplatin was 100 percent, which is consistent with the study conducted by oliver et al. comparing adjuvant 1 cycle carboplatin versus radiotherapy showing relapsefree survival rates at 5 years of 94.7 and 96 percent, respectively (7). the 5 year dfs and the 5-year loco-regional control in our study was 93% in arm of surveillance with complete cure of the relapse and 100% in both radiation and chemotherapy groups. in a study conducted by dieckmann et al., the use of one course of adjuvant carboplatin, surveillance and radiotherapy were compared to each other. the results showed a disease-specific survival of 100% irrespective of the post-operative approach. crude relapse rates were 8.2, 2.4, 5.0, and 1.5% for surveillance, radiotherapy, 1 cycle carboplatin, and 2 cycles carboplatin, respectively, after a median follow up of 30 months. in this study, all recurrences were salvageable leading to a disease-specific survival rate of 100 percent, with no statistical difference in the incidences of relapses among the four treatment arms (log-rank, p = 0.0573) (8). in this study, the proposed risk factors of local recurrence in stage i seminoma (namely, rete-testis invasion and tumor size > 4 cm) didn’t show any adverse impact on local control for patients. in comparison to literature, this might be a little bit different. a risk-adapted adjuvant management was adopted by the swedish and norwegian testicular cancer group based on their prospective trial involving almost 900 patients. the study population developed 69 relapses; with 29 relapses among patients who were managed by surveillance and 40 relapses in patients managed with adjuvant 1 cycle carboplatin. the invasion of the rete testis [hazard ratio (hr) 1.9, p = 0.011] and tumor diameter > 4 cm (hr 2.7, p < 0.001) were identified as risk factors for disease relapse. in patients without any of these factors, the relapse rate was 4.0% for patients in surveillance arm versus 2.2% in patients receiving adjuvant carboplatin. in patients with one or two risk factors, the relapse rate was 15.5% in patients managed by surveillance versus 9.3% in patients receiving adjuvant carboplatin (9). in another systematic review including nineteen studies addressing prognostic factors for disease relapse in clinical stage i seminoma patients' managed by surveillance (10), rete testis invasion was identified as a significant factor for relapse in only 4 out of 13 studies, while tumor size was a significant factor for relapse in 10 out of 14 studies. the authors' conclusion was that size of tumor is the most important prognostic factor for disease relapse, but the authors failed to define a clear cutoff value for tumor size and that rete-testis invasion was a minor risk factor for disease recurrence. however, the most recent version of nccn guidelines still recommends for active surveillance as the preferred option of management for patients with clinical stage i seminoma, regardless tumor size or rete-testis invasion, given the equal survival of surveillance versus active treatment, potential long term treatment toxicities especially with the expected long term survival of the patients and high salvage rates of any recurrences, provided that patients will commit to the surveillance protocol (11). this study also shows a change in our pattern of care with time from adjuvant radiation to para-aortic chain towards single agent carboplatin and active surveillance, given the change in the international guidelines. study limitations include the retrospective nature of the study with the inherent selection bias in this type of studies (reserving active treatment for fit and younger patients or those who cannot adhere to the follow up schedule), the heterogeneous groups of patients with imbalance between treatment arms and lack of qol assessment with each treatment modality. in summary, our study highlights and confirms the data stating that stage i seminoma can be treated by different adjuvant modalities (radiotherapy, carboplatin or active surveillance) with similar outcomes in terms of dfs, lrc and os. active surveillance remains an appealing treatment option given similar survival compared to active treatment and complete cure after salvage with chemotherapy in relapsing patients. figure 1. change in the patterns of care along time from 2005 till 2019. archivio italiano di urologia e andrologia 2023; 95, 1 m. mahmoud sayed, a. mohamad nasr, i. mohamad saad eldin, y. anwar abdelazim references 1. seer cancer statistics factsheets: testicular cancer. national cancer institute. bethesda, md. 2020. 2. jones rh, vasey pa. part i: testicular cancer--management of early disease. lancet oncol. 2003; 4:730-7. 3. mead gm, fossa sd, oliver rt, et al. randomized trials in 2466 patients with stage i seminoma: patterns of relapse and follow-up. j natl cancer inst. 2011; 103:241-9. 4. glaser sm, vargo ja, balasubramani gk, beriwal s. surveillance and radiation therapy for stage i seminoma-have we learned from the evidence? int j radiat oncol biol phys. 2016; 94:75-84. 5. seer cancer statistics factsheets: testicular cancer. national cancer institute. bethesda, md. 2016. 6. andré marques-pinto, ana inês gomes, joana febra, et al. specialist management of testicular cancer: report of the last 10 years at a portuguese tertiary referral academic centre. arch ital urol androl. 2021; 93:153-157. 7. oliver rt, mead gm, rustin gj, et al. randomized trial of carboplatin versus radiotherapy for stage i seminoma: mature results on relapse and contralateral testis cancer rates in mrc te19/eortc 30982 study (isrctn27163214). j clin oncol. 2011; 29:957-62. 8. dieckmann kp, dralle-filiz i, matthies c, et al. testicular seminoma clinical stage 1: treatment outcome on a routine care level. j cancer res clin oncol. 2016; 142:1599-607. 9. tandstad t, ståhl o, dahl o, et al. treatment of stage i seminoma, with one course of adjuvant carboplatin or surveillance, riskadapted recommendations implementing patient autonomy: a report from the swedish and norwegian testicular cancer group (swenoteca). ann oncol. 2016; 27:1299-304. 10. zengerling f, kunath f, jensen k, et al. prognostic factors for tumor recurrence in patients with clinical stage i seminoma undergoing surveillance-a systematic review. urol oncol. 2018; 36:448-458. 11. nccn clinical practice guidelines in oncology (nccn guidelines®) for testicular cancer v.2.2022. ©national comprehensive cancer network, inc. 2022. correspondence manar mahmoud sayed, md manar.mahmoud54@yahoo.com azza mohamad nasr, md nasrazza2@hotmail.com yasser anwar abdelazim, md (corresponding author) yasser.anwar@nci.cu.edu.eg department of radiation oncology, national cancer institute, cairo university, egypt kasr el ainy street, cairo, egypt, 11796 ibtesam mohamad saad eldin, md ibtessamsaad@yahoo.com department of clinical oncology, faculty of medicine, cairo university, egypt al kasr el ainy, old cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11906 1 original paper semen analysis (2). defective sperm motility in the form of decreased progressive motility or absence of motility is defined as asthenozoospermia which is usually accompanied by oligozoospermia or teratozoospermia (3). harbouring above 85% morphologically abnormal sperms in semen is considered teratozoospermia (ts). ts is classified into monomorphic and polymorphic. in monomorphic ts, all sperms have the same morphological abnormality while in polymorphic type, there are different varieties of abnormal sperm morphologies (4). calbindin 2 (calb 2; calretinin; 29 kda calbindin) is a calcium binding protein that is mostly secreted in the nervous system as well as the ovary, the adrenal glands, and the testis. the main function of calb 2 is to buffer intracellular calcium ion to stop ca2+ overload as well as a ca2+ receptor (5). ca2+, which is also a second messenger in the cytoplasm, plays an essential role in different physiological functions such as cell proliferation and apoptosis (6). additionally, it regulates the synthesis of reproductive hormones (7). the primary studies revealed that the highest calb 2 was secreted in the cytoplasm of leydig cells of adult rats in synchrony with androgen level so postulating that calb 2 might prompt steroidogenesis (8). increment in viability and proliferation of leydig cells by calb 2 was attributed to inhibition of mitochondrial related apoptotic pathway through inducing erk1/2 and akt pathways as well as supressing cell apoptosis (9). interestingly, calb 2 can be deployed as a marker of normal and neoplastic leydig cells of the testis as well as diagnosing atypical leydig cell tumor (10). non obstructive azoospermia (noa) and oat of unknown causes are common and are noticed in a high sector of infertile men. however, the underlying molecular mechanisms of these conditions remain unknown (11). we aimed to assess seminal calb 2 expression in men with different semen parameters as well as to investigate potential correlations between seminal calb 2 and different semen parameters in oat patients. furthermore, we aimed to find any correlation between seminal calb 2 and reproductive hormones in noa patients. objectives: we aimed to assess seminal calbindin 2 (calb 2) expression in men with different semen parameters as well as its correlation with reproductive hormones in azoospermic patients and different semen parameters in oligoasthenoteratozoospermic patients. calb 2 is also known as calretinin and 29 kda calbindin. materials and methods: this prospective study was performed on 96 cases from the andrology outpatient clinic divided into 3 groups as follows: group 1 including 32 non obstructive azoospermic (noa) patients, group 2 including 32 patients with oligoasthenoteratozoospermia (oat), and group 3 including normozoospermic individuals as controls. semen analysis and estimation of seminal calb 2 concentrations by enzyme linked immunosorbent assay (elisa) technique were performed for all participants. reproductive hormones were measured in nonobstructive noa patients. results: the mean seminal calb 2 level was higher in oat patients compared to noa patients and controls (7.8 ± 1.30 ng/ml, 7.3 ± 0.80 and 7.4 ± 1.0, respectively). furthermore, the study had shown strong positive correlations between calb 2 and sperm normal forms in controls and oat patients. in contrast, there was no significant correlation between seminal calb 2 and any of the reproductive hormones measured in noa patients. conclusions: seminal calb 2 may play a role in increasing the abnormal forms in oat patients. key words: non obstructive azoospermia; oligoasthenoteratozoospermia; normozoospermia; seminal calb 2 (calretinin & 29 kda calbindin); reproductive hormones. submitted 2 october 2023; accepted 9 october 2023 introduction abnormalities in the form of oligozoospermia, asthenozoospermia, teratozoospermia and high percentage of sperm dna fragmentation are associated with decreased probability to conceive (1). oligozoospermia is classically defined when sperm count is below 10m/ml. 15 m is the 5% percentile of the new 2021 who manual for seminal calbindin 2 level in azoospermia and oligoasthenoteratozoospermia and its correlation with seminal and hormonal parameters sameh fayek gamalel din 1, noha abdelhafeez abdelkader 2, mohamed yousry el-amir 1, asmaa anter sayed ahmed 3, hesham fouad abdel-latif 1, mohamed farag azmy 4 1 department of andrology, sexology and stds, kasr al-ainy faculty of medicine, cairo university, cairo, egypt; 2 department of clinical and chemical pathology, faculty of medicine, beni-suef university, beni-suef, egypt; 3 egypt ministry of health & population, cairo, egypt; 4 department of andrology, sexology and stds, faculty of medicine, beni-suef university, beni-suef, egypt. doi: 10.4081/aiua.2023.11906 summary archivio italiano di urologia e andrologia 2023; 95(4):11906 s. fayek gamalel din, n. abdelhafeez abdelkader, m. yousry el-amir, et al. 2 patients and methods the current prospective study was conducted in the andrology outpatient clinic during the period from april (2021) till january (2022). approval by the local research and ethical committee was obtained that conforms to helsiniki declaration (2013) (fmburec/09052021) (12). written informed consents were obtained from the patients who were involved in the study. the study was performed on 96 randomized patients using simple numbering method. they were divided into 3 groups as follows: group (1) comprised of 32 noa patients. group (2) comprised of 32 patients with oat. group (3) comprised of 32 patients with normal semen parameters as controls. inclusion criteria of the patients any infertile patient with normal testicular volume was included. exclusion criteria of the patients any patient with varicocele, smoker, leukocytospermia, abnormal karyotyping and finally evidence of severe uncontrolled medical diseases was excluded from the study. inclusion criteria of the controls any healthy age matched individual was recruited in group 3. sample size was calculated using g power. at least 89 participants should be included in the three groups using f tests ancova: fixed effects, main effects and interactions as well as a priori analysis (13). the participants were asked about any relevant medical history and were subjected to clinical examination. also, 5 cc blood was withdrawn from each participant for hormones investigation [fsh, lh, total testosterone, estradiol, prolactin (prl)] and semen analysis. furthermore, all participants were asked about a history of hernia repair, scrotal surgery, pelvic surgery, endoscopic urethral instrumentation, or genitourinary infection. testicular volume of all participants was routinely determined by prader’s orchidometer. furthermore, scrotal duplex was done for all participants to exclude varicocele. semen analysis semen samples were collected by masturbation following abstinence for 3-4 days. a special wide-mouth container was used to collect semen and incubated at 37°c until semen was liquefied. semen analysis was then performed within 1 hour following the who manual criteria (5th edition, 2010) (14). duplicate semen analyses were performed twice at the beginning and 3 months after initiating the study and the average of the two values was used for analysis. the same investigator performed all semen analyses to optimize repeatability (15). seminal analysis was carried out within 30 minutes after liquefaction. the volume, viscosity, ph and appearance of semen were evaluated together with sperm concentration, progressive and total motility and morphology. sperm concentration was evaluated using a makler counting chamber (irvine scientific, santa ana, ca, usa) under an optical microscope (nikon, nikon europe b.v., amsterdam, the netherlands) at 200x magnification. sperm morphology was evaluated by using pre-coloured glasses (testsimplets) and the eosin y test was applied to evaluate sperm vitality. determination of calb 2 human calb 2 was determined using calretinin elisa kits supplied by sinogeneclon biotech co., ltd. cat. no.: sg00383. this kit uses the sandwich-elisa principle with sensitivity 0.01 ng/ml and detection range 0.06-4 ng/ml. the microtiter plate of the calretinin elisa is coated with a capture antibody. the diluted sample was added and any antigen present bound to capture antibody. after a washing step, the detecting antibody (biotinylated anti-calretinin antibody) was added and bound to antigen. after another washing step the enzyme conjugate streptavidinperoxidase was added and bound to detect the antibody. the following substrate tmb/peroxidase reaction was monitored at 450 nm (reference wavelength at 620 nm). determination of reproductive hormones in noa patients blood samples were obtained from azoospermic patients, and then samples were left to clot for 1 hour at room temperature or overnight at 2-8°c before centrifugation for 20 min at 1000×g at 2-8°c. the supernatant was collected to carry out the assay. follicle stimulating hormone (fsh) was determined using elisa kits supplied by elabscience biotechnology, inc, united states. cat. no.: e-elh1143. this kit used the sandwich-elisa principle with sensitivity 0.94 miu/ml and detection range 1.56-100 miu/ml. luteinizing hormone (lh) was determined using elisa kits supplied by elabscience biotechnology, inc, united states. cat. no.: e-el-h6019. this kit used the sandwich-elisa principle with sensitivity: 0.1miu/ml and detection range 0.16-10miu/ml. serum prolactin was measured according to human prolactin (prl) onestep elisa kit (boster biological technology, pleasanton ca, usa, catalog # ek7006) with analytical sensitivity 11.7 pg/ml and assay range 15.6-1000 pg/ml. testosterone was determined using elisa kits supplied by mybiosource, inc., san diego, usa. cat. no.: mbs580035. estradiol was determined using elisa kits supplied by thermo fisher scientific, inc. third avenue waltham, ma usa. cat. no.: kaq0621. this kit used the sandwich-elisa principle with sensitivity: 5 pg/ml and detection range 13-935 pg/ml. statistical analysis analysis of data was performed using spss v. 23 (statistical package for social science) for windows. mean, standard deviation (sd), minimum and maximum were used to describe quantitative variables whereas number (no.) and percentages (%) were used to describe qualitative variables. shapiro/kolomogrov tests of normality were utilized to test for normality. the chi square test was used to determine the statistical difference of the categorical data between the two groups. pearson correlation was used to test the correlation between different quantitative variables. results there was no significant difference between the studied participants regarding their baseline characteristics (table 1). archivio italiano di urologia e andrologia 2023; 95(4):11906 3 seminal calb 2 and azoospermia and oat furthermore, one case had atrophic right testis and 3 cases presented with small testis in noa patients. there were three cases with absent right epididymis and 4 cases with absent vas deferens in the same group. additionally, the medians of fsh, lh, testosterone, e2, and prolactin in noa patients were 5.40, 6.35, 4.50, 42.00 and 7.50, respectively. furthermore, there was no significant difference between noa, oat and normozoospermic participants regarding seminal calb 2 level (7.3 ± 0.80 ng/ml; 7.8 ± 1.40 ng/ml; 7.4 ± 1.0 ng/ml, p = 0.15, respectively). although seminal calb 2 levels in noa and oat groups were not significantly different to levels of normozoospermic participants (p > 0.05), yet, there was a higher predictive role of seminal calb 2 levels in predicting oat cases compared to azoospermic cases (table 2, figures 1-2). moreover, there were significant linear strong positive correlations between sperm normal forms and seminal calb 2 levels in normozoospermic and oat cases (tables 3-4). table 2. cutoff values, area under the curve (auc), sensitivity, specificity, positive predictive values and negative predictive values of seminal calb 2 in azoospermic and oligoasthenoteratozoospermic (oat) cases. azoospermic cases oat cases p-value 0.92 0.15 cut off 7.2500 7.7500 auc 0.493 0.609 sensitivity 60 % 50% specificity 46% 66% positive predictive value 60% 50% negative predictive value 45% 65% table 3. correlation between seminal calbindin 2 (calb 2) and age and semen parameters in normozoospermic participants. normozoospermic cases seminal calb 2 (ng/ml) age pearson correlation (r) 0.055 p-value 0.77 sperm concentration (106/ml) pearson correlation (r) -0.072 p-value 0.71 sperm total motility (%) pearson correlation (r) 0.285 p-value 0.13 sperm normal forms (%) pearson correlation (r) 0.709 p-value 0.00 p value was calculated using pearson correlation. table 4. correlation between seminal calbindin 2 (calb 2) and age and semen parameters in oligoasthenoteratozoospermic (oat) cases. oat cases seminal calb 2 (ng/ml) age pearson correlation (r) -0.596 p-value 0.00 sperm concentration (106/ml) pearson correlation (r) -0.088 p-value 0.64 sperm total motility (%) pearson correlation (r) 0.347 p-value 0.06 sperm normal forms (%) pearson correlation (r) 0.763 p-value 0.00 p value was calculated using pearson correlation. figure 1. receiver operating characteristic curve for prediction of non obstructive azoospermia (compared with normozoospermia) using seminal calretinin level. figure 2. receiver operating characteristic curve for prediction of oligoathenoteratospermia (compared with normozoospermia) using seminal calretinin level. table 1. sociodemographic characteristics of the participants. group (1) group (2) group (3) p value azoospermic patients oligoasthenoteratozoospermic normozoospermia (n = 30) (oat) (n = 30) (n = 30) mean sd mean sd mean sd age (years) 33.3 ± 10.4 30.4 ± 8.1 29 ± 6.7 0.15 marital status n % n % n % single 5 16.7 married without offspring 16 53.3 30 100 married with offspring 9 30.0 30 100 p value was calculated using chi-square test. archivio italiano di urologia e andrologia 2023; 95(4):11906 s. fayek gamalel din, n. abdelhafeez abdelkader, m. yousry el-amir, et al. 4 however, there was a significant linear strong negative correlation between age and seminal calb 2 levels in oat cases (table 4). finally, there was no significant linear correlation between seminal calb 2 levels and any of the reproductive hormones measured in noa cases (table 5). discussion the present study is a case-control study conducted comparing seminal calb 2 expression in men with normal semen parameters, oat and noa. the mean seminal calb 2 level was higher in oat cases compared to azoospermic cases and controls. although, the values of seminal calb 2 levels in oat and azoospermic cases were not significantly different compared to normozoospermic participants, there was a higher predictive role of seminal calb 2 levels in predicting oat cases compared to noa cases. moreover, there was no significant linear correlation between seminal calb 2 level and any of the reproductive hormones measured in noa cases. on the other hand, there were significant linear strong positive correlations between sperm normal forms and seminal calb 2 levels in normozoospermic and oat cases. there was a high significant linear negative correlation between age and seminal calb 2 level in oat cases. bar-shira maymon et al. (16) demonstrated that the expression of calb 2 in abnormal sertoli cells in non-obstructive azoospermia contributes to the multifactorial etiology of spermatogenic failure. in the same context, gamalel din et al. (17) demonstrated a negative impact of seminal calb 2 on sperm normal forms in patients with varicocele (17). furthermore, oat patients showed the highest median seminal calb 2 compared to the patients of other 2 groups in the current study. this can be explained by the fact that oat patients would have more immature sertoli cells compared to azoospermic patients and controls. thus, they have increased levels of calb 2 expression by the seminiferous epithelium and consequently have increased levels of seminal calb 2. this agrees with gamalel din et al. (2023) who demonstrated that patients with bilateral varicocele had higher seminal calb 2 compared to unilateral varicocele (17). interestingly, the current study did not show any correlation between calb 2 and any of the reproductive hormones measured in noa cases. on the contrary, several studies have demonstrated a potential link between calb 2 and steroidogenesis and reproductive hormones. firstly, steroidogenesis in leydig cells can be enhanced by increased free ca2+ (18). in the same context, altobelli et al. (2017) had detected calb 2 immunoreactivity in human fetal testis, testis leydig cells, seminiferous epithelium and epididymal epithelial cells (13). they assumed that calb 2 is involved in the processes of production and/or secretion of hormones as well as in all calcium dependent differentiation processes that occur during gonadal development suggesting its involvement in steroidogenesis and spermatogenesis (13). however, the role played by calb 2 cannot be precisely determined similarly to other calciumbinding proteins that behave differently in the presence of this ion to the extent that they are classified as “ca-buffer” or “ca sensor” proteins (19). this uncertainty of their exact role is due to the possible exposure of their hydrophobic residues after binding with calcium (19). admittedly, our study is no free from limitations. firstly, the small sample size can be considered as a major limitation. moreover, the inability to use immunohistochemistry in the azoospermic cases to properly localize the site of production of calb 2 can be regarded as another limitation. also, not including cases of obstructive azoospermia could be seen as an additional limitation. besides, another limitation was including one case with atrophic right testis and 3 cases with small testis in noa patients. finally, we were unable to evaluate reproductive hormones in all participants. conclusions in brief, seminal calb 2 may play a role in increasing the abnormal forms in oat cases. references 1. milachich t, dyulgerova-nikolova d. the sperm: parameters and evaluation. in innovations in assisted reproduction technology. intechopen; 2020. 2. boitrelle f, shah r, saleh r, et al. the sixth edition of the who manual for human semen analysis: a critical review and swot analysis. life. 2021; 11:1368. 3. asero p, calogero ae, condorelli ra, et al. relevance of genetic investigation in male infertility. j endocrinol invest. 2014; 37:415-427. 4. perrin a, morel f, moy l, et al. study of aneuploidy in largeheaded, multiple-tailed spermatozoa: case report and review of the literature. fertil steril. 2008; 90:1201-e13. 5. schwaller b. calretinin: from a “simple” ca2+ bufer to a multifunctional protein implicated in many biological processes. front neuroanat. 2014; 8:3. 6. stevenson l, allen wl, proutski i, et al. calbindin 2 (calb2) regulates 5-fuorouracil sensitivity in colorectal cancer by modulating the intrinsic apoptotic pathway. plos one. 2011; 6:e20276. 7. xu w, zhu q, liu s, et al. calretinin participates in regulating steroidogenesis by plc-ca2+-pkc pathway in leydig cells. sci rep. 2018; 8:1-10. table 5. correlations between seminal calbindin 2 (calb 2) and age and reproductive hormones in azoospermic patients. azoospermic cases seminal calb 2 (ng/ml) age pearson correlation (r) 0.032 p-value 0.87 fsh pearson correlation (r) -0.329 p-value 0.17 lh pearson correlation (r) -0.307 p-value 0.22 total testosterone pearson correlation (r) -0.282 p-value 0.29 estradiol pearson correlation (r) -0.173 p-value 0.46 prolactin pearson correlation (r) -0.167 p-value 0.59 p value was calculated using pearson correlation. archivio italiano di urologia e andrologia 2023; 95(4):11906 5 seminal calb 2 and azoospermia and oat 8. liu s. expression of calretinin in the testes of rats at diferent development stages. j reprod med. 2014; 21:70-76. 9. xu w, zhu q, zhang b, et al. protective effect of calretinin on testicular leydig cells via the inhibition of apoptosis. aging. 2017; 9:1269. 10. augusto d, leteurtre e, de la taille a, et al. calretinin: a valuable marker of normal and neoplastic leydig cells of the testis. appl immunohistochem mol morphol. 2002; 10:159-162. 11. nasirpour h, key ya, kazemipur n, et al. association of rubella, cytomegalovirus, and toxoplasma infections with recurrent miscarriages in bonab-iran: a case-control study. gene cell tissue. 2017; 4:e60891. 12. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-4. 13. altobelli gg, pentimalli f, d'armiento m, et al. calretinin immunoreactivity in the human testis throughout fetal life. j cell physiol. 2017; 232:1872-1878. 14. world health organization (who). who laboratory manual for the examination and processing of human semen. 5th ed. geneva: who: 2010; p.271. 15. alahmar at, sengupta p, dutta s, calogero ae. coenzyme q10, oxidative stress markers, and sperm dna damage in men with idiopathic oligoasthenoteratospermia. clin exp reprod med. 2021; 48:150. 16. bar-shira maymon b, yavetz h, yogev l, et al. detection of calretinin expression in abnormal immature sertoli cells in non-obstructive azoospermia. acta histochem. 2005; 107:105-12. 17. gamalel din sf, zeidan a, salam maa, et al. seminal calbindin 2 in infertile men with varicocele: a prospective comparative study. reprod sci. 2023; 30:3077-3083. 18. ascoli m. immortalized leydig cell lines as models for studying leydig cell physiology. in a. h. payne & m. p. hardy (eds) contemporary endocrinology: the leydig cell in health and disease. humana press (usa). 2007; pp. 373-381. 19. baimbridge kg, celio mr, rogers jh. calcium-binding proteins in the nervous system. trends in neurosciences. 1992; 15:303-308. correspondence sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg mohamed el-amir, md yousr82@kasralainy.edu.eg hisham foaad, md hisham.foaad@kasralainy.edu.eg department of andrology and stds kasr al-ainy, faculty of medicine cairo university, al-saray street, el manial, cairo, 11956, egypt noha abdel kader, md noha.abdelkader@med.bsu.edu.eg department of clinical and chemical pathology, faculty of medicine, beni-suef university, beni-suef, egypt asmaa anter, md allahtaim2@gmail.com egypt ministry of health & population, cairo, egypt mohamed azmy, md mohamed.azmy@med.bsu.edu.eg department of andrology, sexology and stds, faculty of medicine beni-suef university, beni-suef, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 129archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. these better outcomes in survival rate have been achieved because of the widespread use of cross-sectional imaging in recent years, leading to an increase in incidental detection (6, 7), that contribute to better prognostic factors and tnm staging, therefore leading to the best treatment approach (8). the gold standard treatment is surgical management: radical nephrectomy (rn) and partial nephrectomy (pn). rn can be performed open or laparoscopically (robotassisted or not). pn has been widely used in the last few years because of improvements in surgical techniques, surgical apparatus and increased diagnosis of small rcc, and should be prioritized in the setting of solitary kidneys, bilateral renal tumors and advanced chronic kidney disease (ckd) (9, 10). due to the preservation of renal function with pn, some studies suggest better overall survival in comparison with rn (11, 12). although a randomized controlled trial (eortc 30904) (13) did not confirm this finding for tumors < 5 cm. each of these procedures has specific complications which should be considered before the surgery is indicated. in terms of hemorrhage, urine leak/fistula and reoperation for complications, rn versus pn were 1.2% vs. 3.1%, 0% vs. 4.4%, and 2.4% vs. 4.4%, respectively (13). rn increases the risk for ckd (11, 14, 15) and has an increased cardiovascular-specific mortality in comparison with pn (12, 16). from the 210 million brazilian inhabitants, about 80% of patients rely on public health services, also known as sistema único de saude (sus) for medical treatment. são paulo city has one of the largest populations worldwide, and in 2018, it had about 34 million medical appointments relying on sus (17, 18). hospitals of the public health system charge the procedures according to the codes and receive a predetermined fixed amount of reimbursement for each code. we hypothesize that high volume centers with experienced staff and standardized protocols may provide lower morbidity and costs related to rcc treatment, hence providing a higher standard of care for such patients. the outcomes of such investigation may lead to referral recommendations to concentrate procedures in such institutions. the aim of this study was to describe and compare the outcomes and costs of oncological radical and partial nephrectomies in the sao paulo public health system, brazil, from 2008 to 2019, and to compare data objective: the aim of this study was to describe and compare the outcomes and indirect costs of oncological radical (rn) and partial nephrectomies (pn) in hospitals from the são paulo public health system, brazil. materials and methods: an ecologic retrospective study was performed from 2008 to 2019, using the tabnet platform of the brazilian unified health system department of informatics. hospitals were classified according to volume of surgeries (low and high-volume, and also into four quartiles according to volume of surgeries), and with or without medical residency program in urology. the results were compared between groups. results: in the period analyzed were performed 2.606 rn in 16 hospitals. data available for pn ranged only from 2013-2019 and included 1.223 surgeries comprising 15 hospitals. overall mortality rates were 0.41% for pn and 2.87% for rn. the length of hospital stay was significantly higher in low-volume hospitals for both rn and pn (8.97 vs. 5.62 days, p = 0.001, and 7.75 vs. 4.37 days, p = 0.001, respectively), and also for the rn in hospitals without residency program in urology (9.37 vs. 6.54 days, p = 0.03). when the volume of surgeries was divided into four quartiles, the length of hospital stay and icu hospitalization days were significantly higher in the first quartile hospitals for rn (p = 0.016) and pn (p = 0.009), respectively. the mortality rates and indirect costs were not different considering pn and rn in the different types of hospitals. conclusions: the length of hospital stay was significantly lower for both pn and rn in high-volume hospitals, and also for rn in hospitals with residency program in urology. key words: nephrectomy; renal cell carcinoma; mortality rates; teaching hospital. submitted 25 march 2022; accepted 31 may 2022 introduction renal cell carcinoma (rcc) derives from the renal cortex, comprising approximately 85% of all primary renal neoplasms. it mostly affects older adults, presenting between 50 years and 70 years along with known risk factors, such as smoking, obesity and hypertension. it represents 2-3% of all cancers, its incidence has been increasing worldwide, being 5.8 per 100.000, and it is the most lethal of common urological cancers, although the five-year survival rate has doubled over the last 60 years from 34% in 1954 to 75% between 2009 and 2015 (1-5). outcomes of nephrectomy for renal cell carcinoma: an ecologic retrospective study in a middle-income country alexandre dib partezani, hugo octaviano duarte-santos, breno santos amaral, alan roger gomes barbosa, marcelo apezzato, joão brunhara, bianca bianco, gustavo caserta lemos, arie carneiro department of urology, hospital israelita albert einstein, são paulo, sp, brazil. doi: 10.4081/aiua.2022.2.129 summary archivio italiano di urologia e andrologia 2022; 94, 2 a. dib partezani, h. octaviano duarte-santos, b. santos amaral 130 among hospitals volume, and with or without medical residency program in urology. methods an ecologic retrospective study was performed from 2008 to 2019 using the tabnet platform of the department of information technology of the brazilian public health system (datasus). this database consists of an open data source, containing information about procedures performed in the brazilian public health system (sistema único de saúde sus), available at https://datasus.saude.gov.br/. procedure codes used for this study were total nephrectomy in oncology (code 0416010075) and partial nephrectomy in oncology (code 0416010210). the study was approved by the research ethics committee of the “hospital israelita albert einstein” (approve code caae: 17208019.0.0000.0071 and date of approval 07/10/2019) and was performed in accordance with relevant guidelines and regulations. participants' informed consent is not applicable. outcomes analyzed included number of surgeries, mortality rate during hospital stay, length of hospital stay, length of intensive care unit (icu) stay, and indirect costs. since data related to cost for each hospitalization were not available, indirect cost was calculated as the total amount paid per year for each institution according to each procedure divided by the total number of hospitalizations related to the same procedure. hospitals were classified as lowand high-volume surgery centers, and were divided into two groups using a cut-off of 10 surgeries per year for pn (19) from 2013 to 2019, and 20 surgeries per year for rn (20) from 2008 to 2019, to consider it as a high-volume center. we also divided the hospital volume of surgeries in four quartiles according to the caseload per year. besides, we classified the centers with and without a medical residency program in urology. comparisons were then made among groups. statistical analysis statistical analysis was performed using spss 13.0 (spss for mac os x, spss, inc., chicago, il, usa). data normality was verified using the shapiro-wilk test. the mannwhitney and kruskal-wallis tests were used to compare non-normal variables and t-test or anova for variables with normal distribution. proportions were analyzed using the chi-square test (mortality rate). statistical significance was considered when p < 0.05. results table 1 summarizes data for overall rn and pn. a total of 2.606 rn were performed from 2008 to 2019. the procedures were performed in 16 institutions, of which seven (43.7%) presented medical residency program in urology. regarding the volume of surgeries, the low volume group consisted of 12 hospitals and the high volume group consisted of four hospitals. overall mortality rate was 2.87%. data available for pn ranged only from 2013 to 2019 and included 1.223 surgeries. the procedures were performed in 15 institutions, of which seven (46.7%) presented medical residency program in urology. considering the volume of surgeries, the low volume group consisted of 11 hospitals and the high volume group consisted of four hospitals. overall mortality rate was 0.41%. table 2 summarizes the length of hospital stay, icu hospitalization days, intrahospital mortality and indirect costs for rn and pn according to the volume of surgeries. the length of hospital stay was significantly higher in low-volume than in high-volume hospitals in both types of surgeries, pn and rn (7.75 days vs. 4.37 days, p = 0.001; and 8.97 days vs. 5.62 days, p = 0.001, respectively). the average icu hospitalization days was also higher in low-volume hospitals; however, there was no statistical significance difference for both pn and rn (1.22 days vs. 0.77 days, p = 0.142; and 2.09 days vs. table 1. overall mean length of hospital stay, icu hospitalization, intrahospital mortality and indirect costs of partial nephrectomy and radical nephrectomy between 2008 and 2019 in são paulo. variables radical nephrectomies partial nephrectomies hospitals (n) 16 15 total of surgeries (n) 2606 1223 hospitals with residency in urology a 7 (43.7%) 7 (46.7%) hospitals volume (n) low-volume 12 11 high-volume 4 4 length of hospital stay b (days) 8.13 (2.78) 6.85 (5.93) icu hospitalization b (days) 1.87 (2.48) 1.09 (0.50) intrahospital mortality b 75 (2.87%) 5 (0.41%) indirect costs b (r$) 2614.17 (358.89) 28782.16 (52632.61) a these variables are presented as total number and percentage (%). b these variables are presented as mean and standard deviation (sd). icu: intensive care unit. r$: brazilian real. table 2. length of hospital stay, intensive care unit hospitalization days, intrahospital mortality and indirect costs of partial nephrectomy and radical nephrectomy analyzed according to lowand high-volume hospitals from 2008 to 2019 in são paulo. variables radical nephrectomy partial nephrectomy low-volume high-volume p-value low-volume high-volume p-value length of hospital staya (days) 8.97 5.62 0.001 c 7.75 4.37 0.001 d (2.73) (0.41) (6.76) (0.63) icu hospitalizationa (days) 2.09 1.22 0.808 d 1.22 0.77 0.142 c (2.87) (0.08) (0.52) (0.30) intrahopitalar mortalityb 27/931 48/1675 0.959 e 1/323 4/900 0.741 e (2.90%) (2.86%) (0.3%) (0.44%) indirect costsa (r$) 2612.08 2620.43 37970.19 3515.08 (405.18) (204.89) 0.969 c (59357.94) (4715.69) 0.151 d a these variables are presented as mean and standard deviation (sd). b this variable is presented as number/total of surgeries and percentage (%). c t-test. d mann-whitney test. e chi-square test. icu: intensive care unit, r$: brazilian real. 131archivio italiano di urologia e andrologia 2022; 94, 2 outcomes of nephrectomy in brazilian public health 1.22 days, p = 0.808, respectively). mortality rates were similar for both lowand high-volume hospitals. when considering pn, there was one death out of 323 surgeries performed in low-volume hospitals and four deaths out of 900 surgeries performed in high-volume hospitals (0.3% mortality rate vs. 0.44% mortality rate, p = 0.741). this can also be observed in rn, with 27 deaths out of 931 surgeries performed in low-volume hospitals and 48 deaths out of 1675 surgeries performed in high-volume hospitals (2.9% mortality rate vs. 2.86% mortality rate, p = 0.959). indirect costs were higher in low-volume hospitals when considering pn, with an average of r$ 37970.19 per patient when compared to high-volume hospitals, which had an average of r$ 3,515.08 per patient. however, this difference was not statistically significant (p = 0.151). in the rn group, average indirect costs were very similar between lowand high-volume hospitals (r$ 2,612.08 vs. r$ 2,620.43; p = 0.969). table 3 summarizes the length of hospital stay, icu hospitalization days, intrahospital mortality and indirect costs for rn and pn according to the volume of surgeries divided into four quartiles. the length of hospital stay was also significantly different considering rn: in the first quartile hospitals was observed a higher length of hospital stay compared to fourth quartile hospitals (p = 0.015). no difference was observed regarding pn. the icu hospitalization days were higher in the first quartile hospitals; however, there was no statistical difference considering rn. regarding pn, hospitals in the first quartile presented statistically higher icu hospitalization days when compared to hospitals in the third (p = 0.032) and fourth (p = 0.039) quartiles. mortality rates were not different among quartiles for both pn and rn. indirect costs were higher in first quartile hospitals for both pn and rn, however, no statistical difference was observed among the quartiles. table 4 summarizes the length of hospital stay, icu hospitalization days, intrahospital mortality and indirect costs for rn and pn according to the hospitals with and without medical residency program in urology. a total of 2.232 rn were performed in hospitals with medical residency program in urology (85.6%) and 374 (14.4%) in hospitals without medical residency program in urology. regarding rn, the length of hospital stay was significantly shorter in hospitals with medical residency in urology (6.54 days vs. 9.37 days; p = 0.03). considering pn, none of the outcomes were statistically difference between hospitals with and without medical residency program in urology, although indirect costs were 4.5 times higher in hospital without medical residency program in urology (r$ 45298.93 vs. r$ 9905.85; p = 0.205). discussion in this study, we described and compared the outcomes and indirect costs of rn and pn in the sao paulo public health system, brazil, from 2008 to 2019, and compared data considering the hospitals volume of surgeries, and with or without medical residency program in urology. from the perspective of the brazilian public healthcare system, our findings showed that, both for rn and pn, length of hospital stay was significantly lower in high-volume hospitals, while indirect costs and icu stay also trended favorably for high-volume hospitals, although no statistical difference was found between lowand highvolume hospitals. the volume of surgeries divided into four quartiles disclosed that for rn, in the first quartile hospitable 4. length of hospital stay, intensive care unit hospitalization days, intrahospital mortality and indirect costs of partial and radical nephrectomies performed in hospital with and without medical residency program in urology from 2008 to 2019 in são paulo. variables radical nephrectomy partial nephrectomy with residency without residence p-value with residency without residence p-value in urology in urology in urology in urology length of hospital stay a (days) 6.54 9.37 0.03 c 5.26 8.24 0.350 d (1.56) (2.95) (1.08) (8.03) icu hospitalization a (days) 1.24 2.36 0.390 d 0.87 1.31 0.099 c (0.34) (3.30) (0.30) (0.58) intrahopitalar mortality b 67/2232 8/374 0.357 e 4/979 1/244 1 e (3.00%) (2.13%) (0.40%) (0.40%) indirect costs a (r$) 2536.48 2674.59 0.464 d 9905.85 45298.93 0.205 d (287.62) (412.39) (11713.02) (68954.31) a these variables are presented as mean and standard deviation (sd). b this variable is presented as number/total of surgeries and percentage (%). c t-test. d mann-whitney test. e chi-square test. icu: intensive care unit. r$: brazilian real. table 3. length of hospital stay, intensive care unit hospitalization days, intrahospital mortality and indirect costs of partial nephrectomy and radical nephrectomy according to hospitals volume (quartiles) from 2008 to 2019 in são paulo. variables radical nephrectomy partial nephrectomy quartile p-value quartile p-value 1 2 3 4 1 2 3 4 number of hospitals 4 4 4 4 --4 3 4 4 --range of cases 1-16 17-107 136-218 248-788 --1-7 8-42 50-59 79-506 --length of hospital stay a (days) 11.16 8.50 7.26 5.62 0.016 c* 7.55 10.49 5.15 4.37 0.570 d (2.11) (3.02) (1.76) (0.41) (3.35) (11.16) (1.19) (0.63) icu hospitalization a (days) 3.58 1.49 1.20 1.22 0.945 d 1.75 1.43 0.74 0.77 0.009 c ** (4.98) (0.80) (0.49) (0.08) (0.35) (0.34) (0.32) (0.30) intrahopitalar mortality b 1/31 4/191 22/709 48/1675 0.900 e 0/13 0/85 1/225 4/900 0.930 e (0.032%) (0.020%) (0.031%) (0.028%) (0%) (0%) (0.004%) (0.004%) costs a (r$) 2843.95 2501.48 2490.81 2620.43 0.803 c 86293.02 25543.88 14154.38 4715.69 0.147 d (580.88) (194.45) (345.12) (204.89) (99667.48) (40322.65) (14106.48) (2357.84) a these variables are presented as mean and standard deviation (sd). b this variable is presented as number/total of surgeries and percentage (%). c anova test. d kruskal wallis test. e chi-square test. icu: intensive care unit. r$: brazilian real. * post hoc analysis showed difference between hospitals in the first quartile and fourth quartile (p = 0.015). ** post hoc analysis showed difference among hospital in the first quartile and third (p = 0.032) and fourth (p = 0.039) quartile. archivio italiano di urologia e andrologia 2022; 94, 2 a. dib partezani, h. octaviano duarte-santos, b. santos amaral 132 tals was observed a higher length of hospital stay compared to fourth quartile hospitals, whereas the mean icu hospitalization days were higher in the first quartile hospitals when compared to hospitals in the third and fourth quartiles for pn. mortality rates and indirect costs were not different among quartiles for both pn and rn. regarding the hospitals with and without medical residency program in urology, the length of hospital stay was significantly lower in hospitals with residency program in urology for rn. these data underscore the importance of concentrating complex procedures in specialized centers, so as to pursue optimized results. rn and, especially pn, are procedures that have a significant learning curve. the competence acquisition results in a composite outcome including a combination of operative time, complications, and surgical success. in 2004, gaston et al. (21) demonstrated the learning curve of residents for hand-assisted laparoscopic nephrectomy, according to difficulty scores and procedure duration, stabilized after the 6th nephrectomy. on the other hand, rouach et al. (22) demonstrated that at least 10 partial nephrectomies are necessary to gain domain regarding the steps of the surgery. when performed by more experienced doctors, the length of surgery and outcomes may be optimized. baezsuarez et al. (23) demonstrated that a cutoff of 50 nephrectomies performed by the same surgeon decreased perioperative outcomes, including hospital stay length. this might explain why our analysis demonstrated no statistical difference in the length of stay when comparing pn in hospitals with and without medical residency program in urology, but there was a significantly lower length of stay when comparing rn in these groups of hospitals. following rn and pn, specific care needs to be taken in the postoperative setting. therefore, it is expected that hospitals with a greater volume of procedures already have postoperative protocols established with icus and wards, favoring a rapid discharge from hospitals. this may also explain why the length of stay was significantly lower for both rn and pn in high-volume than in low-volume hospitals. gozen et al. (24) observed that the learning curve for retroperitoneal laparoscopic radical nephrectomy was shorter for the surgeons who had no or limited experience in open surgery, and that were trained by surgeons who had previous experience in open surgery but no laparoscopic training, although these surgeons operated on a significantly higher number of patients with more advanced diseases. recently, spampinato et al. (25) concluded that assuming an adequate case volume and a proper exposure to surgical techniques, junior surgeons can readily achieve comparable levels of expertise compared with senior practitioners, and urological surgical outcomes is not only directly influenced by the individual surgical experience but also by the experience of the surgical team. a possible explanation for the longer hospital stay in patients undergoing rn (8.13 days) when compared to those for pn (6.85 days), found in our analysis may be that patients submitted for rn hypothetically had larger tumor volumes, were more fragile and required longer/larger surgeries, leading to an important metabolic and inflammatory response. these patients also had a longer icu length of stay (1.87 days vs. 1.09 days for rn and pn, respectively) and higher intrahospital mortality rates (2.87% vs. 0.41% for rn and pn, respectively), probably for the same reasons as hypothesized above. pn is known to be a more complex surgery, in most cases, when compared to rn. to perform pn, there is a need for a wide range of materials available in the operating room, especially if performed laparoscopically. this includes, among others, disposable polymer clips, laparoscopic bulldogs, absorbable sutures and eventually hemostatic agents. for this reason, an increase in costs is expected for the health system when pns are performed. this was visible in our analysis, where the average cost of hospitalization for pn was r$ 28,782.16 compared to r$ 2,614.17 for rn hospitalization. there was no statistical difference in costs when comparing hospital volume and with or without medical residency in urology, but this may be explained by the fact that brazilian health system (sus) reimburse the same value to every hospital for each procedure, and the individual cost for each patient is not accounted for. values of total hospitalization may vary if the patient has been submitted for different procedures during the same hospitalization, and this is one of the limitations of the analysis of costs presented here. considering the available details, a discussion can be commenced regarding the possibility of referring patients for the treatment of rcc to high-volume centers with the objective of shortening the length of hospital stay by focusing on a higher bed turnover; a scenario in which elective surgeries are sometimes cancelled due to the lack of hospital beds. the centralization of the treatment of rcc could be made the part of a public health policy to establish rcc-treatment reference hospitals and improve rcc surgical outcomes. per the data, it is noted that one single institution inflated the values paid (reimbursements) for partial nephrectomies in hospital without medical residency in urology and in low-volume hospital groups. this institution is a hospital specializing in the treatment of pediatric urological pathologies and received r$ 401,162.11 for performing two pn in the period analyzed. there is no plausible explanation for this amount due to limitations of publicly available data. this study also has other limitations. the data available in the online health system database considers only the details of one single hospitalization per patient, so mortality data and costs involving following hospitalizations after discharges are not considered in this study. the costs are indirect costs represented by modality of reimbursement of brazilian health system. for an appropriate comparison of costs, it should be necessary to estimate direct costs in each hospital considering cost for personnel, disposables, time of use of operatory theatre and hospitalization. what can be stated is that national health service does not reimburse higher fares to high-volume hospitals. moreover, the data were restricted to inform only the major types of surgery performed, and details such as time of procedure, patient age, specific complications and technique (open or laparoscopic) were not available. also, the data were collected from a secondary source that is fueled by health professionals, who often do not fill out the forms correctly, therefore interfering in statistical analysis and results. in addition, our findings may not be representative of the entire 133archivio italiano di urologia e andrologia 2022; 94, 2 outcomes of nephrectomy in brazilian public health brazilian population, since we analyzed data only from the são paulo city, although this is the most populous city in the country. a final limitation is that hospitals with residency are the hospitals with the higher number of beds, so it is difficult to establish if better outcome is related to residency program or to high-volume. conclusions in summary, the length of hospital stay was significantly lower for patients who underwent pn and rn in highvolume hospitals, and also in hospitals with medical residency in urology for rn. references 1. atkins, mb; choueiri, tk. epidemiology, pathology, and pathogenesis of renal cell carcinoma. waltaham, ma: wolters kluwer, 2020. 2. campbell sl. malignant renal tumors. in: wein a, kavoussi l, partin a, peters c. ed. campbell-walsh urology. 11th. philadelphia, pa: elselvier, 2016, chapter 57, p.1314-1364. 3. siegel r, naishadham d, jemal a. cancer statistics, 2013. ca cancer j clin. 2013; 63:11-30. 4. ferlay j, colombet m, soerjomataram i, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries and 25 major cancers in 2018. eur j cancer. 2018; 103:356-387. 5. jemal a, bray f, center mm, et al. global cancer statistics. ca cancer j clin. 2011; 61:69-90. 6. parsons jk, schoenberg ms, carter hb. incidental renal tumors: casting doubt on the efficacy of early intervention. urol. 2001; 57:1013-5. 7. decastro gj, mckiernan jm. epidemiology, clinical staging, and presentation of renal cell carcinoma. urol clin north am. 2008; 35:581-92. 8. brierley jd. tnm classification of malignant tumors. uicc international union against cancer. in: sobin lh, gospodarowicz mk, wittekind c. tnm classification of malignant tumors. 7th. chichester, west sussex: wiley-blackwell, 2009. 9. huang wc, levey as, serio am, et al. chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. lancet oncol. 2006; 7:735-40. 10. sciorio c, prontera pp, scuzzarella s, et al. predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy. arch ital urol androl. 2020; 92:165-168. 11. kim sp, murad mh, thompson rh, et al. comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. j urol. 2012; s0022-5347(12)05254-8. 12. huang wc, elkin eb, levey as, et al. partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes? j urol. 2009; 181:55-61. 13. van poppel h, da pozzo l, albrecht w, et al. a prospective, randomised eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol. 2011; 59:543-52. 14. adams kf, leitzmann mf, albanes d, et al. body size and renal cell cancer incidence in a large us cohort study. am j epidemiol. 2008; 168:268-77. 15. scosyrev e, messing em, sylvester r, et al. renal function after nephron-sparing surgery versus radical nephrectomy: results from eortc randomized trial 30904. eur urol. 2014; 65:372-7. 16. kates m, badalato gm, pitman m, mckiernan jm. increased risk of overall and cardiovascular mortality after radical nephrectomy for renal cell carcinoma 2 cm or less. j urol. 2011; 186:1247-53. 17. ibge. estimativas da população residente para os municípios e para as unidades da federação brasileiros com data de referência de 1o de julho de 2019. saúde, m. d. rio de janeiro, rj, brasil: ibge 2019. available at https://www.ibge.gov.br/estatisticas/sociais/populacao/9103-estimativas-de-populacao.html?=&t=o-que-e. 18. boletim ceinfo saúde em dados. ano xviii. são paulo, sp, brasil: secretaria municipal de saúde 2019. available at https://www.prefeitura.sp.gov.br/cidade/secretarias/saude/epidemiologia_e_informacao/index.php?p=258529. 19. couapel jp, bensalah k, bernhard jc, et al. is there a volumeoutcome relationship for partial nephrectomy? world j urol. 2014; 32:1323-9. 20. birkmeyer jd, siewers ae, finlayson ev, et al. hospital volume and surgical mortality in the united states. n engl j med. 2002; 346:1128-37. 21. gaston ke, moore dt, pruthi rs. hand-assisted laparoscopic nephrectomy: prospective evaluation of the learning curve. j urol. 2004; 171:63-7. 22. rouach y, timsit mo, delongchamps nb, et al. néphrectomie partielle laparoscopique: courbe d'apprentissage d'un interne en urologie sur un modèle porcin [laparoscopic partial nephrectomy: urology resident learning curve on a porcine model]. prog urol. 2008; 18:344-50. 23. baez-suarez y, amaya-nieto j, garcia-lopez a, giron-luque f. hand-assisted laparoscopic nephrectomy:evaluation of the learning curve. transplant proc. 2020; 52:67-72. 24. gozen as, gherman v, akin y, et al. evaluation of the complications in laparoscopic retroperitoneal radical nephrectomy; an experience of high volume centre. arch ital urol androl. 20171; 89:266-271. 25. spampinato g, binet a, fourcade l, et al. comparison of the learning curve for robot-assisted laparoscopic pyeloplasty between senior and junior surgeons. j laparoendosc adv surg tech a. 2021; 31:478-483. correspondence alexandre partezani ale.partezani@gmail.com hugo octaviano duarte-santos, md hugosantos90@gmail.com breno amaral, md drbrenoamaral@gmail.com alan roger gomes barbosa, md alan_roger@hotmail.com marcelo apezzato, md mapezzato@uol.com.br joão brunhara, md jbrunhara@gmail.com bianca bianco, md (corresponding author) bianca.bianco@einstein.br gustavo lemos, md gustavo.lemos@einstein.br arie carneiro, md arie.carneiro@einstein.br department of urology, hospital israelita albert einstein av albert einstein 627, são paulo, sp, cep 05652-900 (brazil) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2158 original paper no conflict of interest declared. vation can have serious consequences on the surgeon, affecting his ability to maintain his mental and motor abilities. studies show that sleep deprivation can have the same effect as alcohol intoxication on the surgeon’s abilities (3-6). it has been reported that there is an increase in the number of surgical complications and mortality when surgeries are performed after the professionals normal working hours (4-6). kidney transplant (kt), although not being an urgent procedure, is most of the times executed at late hours, even ate dawn. the reasons for such are several and include: the complex organization needed to distribute renal grafts, elective surgery that occupies surgical theatre and the need to prepare the receptor for surgery (7). the main reason for such high number of late procedures is the need to reduce cold ischemia time (cit) as much as possible in kt, as larger cit relates to worst graft function, smaller survival time of graft and higher patient mortality (8). although, studies show that with an 18 hours window of cit there isn´t a significant difference in outcomes (9, 10). on the other hand, it has been described that surgical factors and the existence of complications influence the outcome of kt (11, 12). as such, it is pertinent to address what can be more favourable, having the lowest cit possible or having a “fresh” surgical team with hypothetically smaller number of complications. for reason external to the surgical team, cit was longer in specific cases up to the point where it was relevant to decide between performing surgery at night or in the morning. if waiting until morning could cause cit to be considered unsafe, procedures were conducted at later hours, being the group with the largest cit the one that could not wait any more time. to our knowledge, there are only five large scale studies that studied this problem concerning kidney transplantation, with conflicting results and comparing different hours from the ones in this work (7, 13-16). materials and methods study design retrospective analyses of all kt occurring in the urology and kidney transplant service of the “centro hospitalar e universitário de coimbra”, portugal, between june 1980 introduction: to reduce cold ischemia time (cit), many kidney transplants are performed in the early morning. conducting complex surgeries in the early morning may influence the surgeon's technical capacity and rate of surgical complications (sc). aim: evaluate the influence of surgery start hour (ssh) regarding duration of surgery (ds), immediate diuresis (id), sc and acute rejection (ar); evaluate the influence of cit regarding sc, id, and ar. methods: 2855 cadaveric transplants performed between june 1980 and march 2018 were retrospectively evaluated. regarding ssh, two groups were created: group m (00: 00h-05.59h, n = 253) and group d (06: 00h 23: 59h, n = 2602). analyzing the impact of ssh on ds, id, sc and ar. evaluate the relationship between cit (< 18h, 18-30h and > 30h) on id, sc and ar utilizing univariate and multivariate statistical analysis with spss. results and conclusion: groups m and d were comparable in all evaluated demographic variables (p > 0.05), except cold ischemia time (group m with higher cit, p < 0.001). regarding univariate analysis, surgery start hour did not influence ds (p = 0.344), and sc (p = 0.264), but related with higher id (p = 0.028) and ar (p = 0.018). cit related with immediate diuresis (p = 0.020) and acute rejection (p < 0.001) but did not relate with complications (p = 0.734). regarding multivariate analysis, ssh only influenced immediate diuresis (p = 0.026) and did not influenced acute rejection (p = 0.055). cit influenced immediate diuresis (p = 0.019) and acute rejection (p < 0.001). surgery start hour influences immediate diuresis. with this study, we conclude that the priority must be a short cold ischemia time. key words: early morning transplantation; kidney transplantation; kidney transplant complications; immediate diuresis; surgery starting hour. submitted 9 january 2021; accepted 23 february 2021 introduction medical error and its influence on the health of patients is an important and current subject in modern medicine. in 1999, the institute of medicine of the united states of america reported that medical errors where responsible for one hundred thousand annual deaths and had a global cost of 29 billion dollars (1). sleep deprivation increases the risk of medical error, so far as being called the achilles heel of the medical profession (2). sleep depriearly morning kidney transplantation: perioperative complications mário pereira lourenço, miguel eliseu, duarte vieira brito, joão carvalho, edgar tavares-silva, lorenzo marconi, pedro moreira, pedro nunes, belmiro parada, carlos bastos, arnaldo figueiredo urology and renal transplantation department, coimbra university hospital centre, coimbra, portugal. doi: 10.4081/aiua.2021.2.158 summary 159archivio italiano di urologia e andrologia 2021; 93, 2 early morning kidney transplantation and july 2018. patients with combined transplant (pancreas, lung, heart and liver) and from living donor where excluded, being selected 2855 consecutive transplants. the resulting population was divided into two groups based on the surgery start hour (ssh): group m (00:00h05:59h) and group d (06:00h-23:59h). four outcomes where defined and measured based of ssh: duration of surgery (ds), the number of surgical complication (sc), immediate diuresis (id) measured on the operating table and acute rejection (ar) of the graft. the population was equally studied on the cit and its influence in the id, ar and ds. surgical team composition was not gathered in this study, but in the institution where the analysis was performed the presence of residents is not dependant of the hour of transplant. being most teams composed of a senior surgeon and a resident. data collected was inserted in multiple labour laws, surgeons on the transplantation department are exclusively allocated to the task after normal working hours, having the right to rest after night procedures. definitions marginal donor was defined as having at least one of the following characteristics: over 60 years old, over 50 years and arterial hypertension, death by cerebral vascular accident or serum creatine level of over 1.5 mg/dl (17, 18). acute rejection was defined as worsening of graft function on the first year, having been admitted a clinical diagnosis (increase in creatine blood level, imagological alteration, need for corticoid treatment) or histologic (kidney biopsy). immediate diuresis was defined by the observation of urinary output in patients with no need for dialysis on the first week after kidney transplant. surgical complications were divided in: urologic (urinary fistula, ureteric stenosis, ureteric necrosis), vascular (arterial or venous thrombosis, arterial stenosis, vascular anastomosis dehiscence), lymphocele, haemorrhage (need of surgical revision or transfusion), wound dehiscence, incisional hernia and others. statistical analysis baseline and demographic characteristics of group m and d were compared using the chi-squared test for categorical variables and the student’s t test for continuous variables. univariate analysis of the effects of ssh and cit in outcomes were described using the chi-squared test. multivariate analysis was conducted by applying the logistic regression method. results demographic characteristics between 00:00 hours and 05:59 hours there were 253 cadaveric transplants in contrast to 2602 in the other time period. demographic characteristic of group m and group d are summarized in table 1. in comparison, more patients from the group m presented cit superior to 30 hours (p < 0.001). all other characteristics were similar. mean surgical time for group (group d is further divided) is summarized in table 2. univariate analysis the effects of surgical star hour in the outcomes defined (ds > 3 hours, id, sc e ar) are summarized in table 3. the effects of cit on the same outcomes (except duration of surgery) are summarized in table 4. multivariate analysis the effects of ssh and cit when analysed together (multivariate analysis) are summarized in table 5. table 1. demographic characteristic of the population. populational demographic characteristic group m group d p value number of patients 253 2602 marginal donor (%/n) 50.6% (128) 50.2% (1307) 0.932 age of receptor (y) 46.6 ± 13.9 45.6 ± 13.7 0.291 sex of receptor 0.458 male 69.2% (175) 66.9% (1740) right side implant 79.8% (202) 2131 (81.9%) 0.828 number of transplants (%/n) 0.608 1 94.5% (239) 5.5% (14) > 1 94.4% (2457) 14.6% (155) number of arteries of the graft 0.953 1 78.3% (198) 22.7% (55) > 1 78.7% (2047) 21.3% (553) cold ischemia time (%/n) < 0.001 < 18h 38.3% (97) 38.7% (1004) 10-30h 53.9% (134) 58.6% (1521) > 30h 8.7% (22) 2.8% (72) table 3. effect of surgery starting hour in outcomes of renal transplant. group m group d p value surgery duration > 3 hours 20.6% (52) 18.1% (472) 0.344 immediate diuresis 71.1% (180) 79.0% (2055) 0.028 surgery complications 20.9% (53) 18.1% (471) 0.264 vascular 5.9% (15) 4.1% (107) urologic 5.5% (14) 6.5% (168) lymphocele 2.0% (5) 1.4% (37) bleeding 6.3% (16) 3.3% (85) wound dehiscence 1.2% (3) 1.6% (42) abscess 0.4% (11) hernia 0.4% (11) other 0.4% (10) acute rejection 25.3% 18.9% 0.018 table 2. mean surgery duration time in relation to surgical starting time. surgery start hour % (n) mean duration of surgery (min) grupo m 00:00-05:59 8.8% (253) 157.2(45-330) grupo d 06:00-11:59 12.9% (366) 165.9 (55-555) 12:00-17:59 40.3% (1151) 149.1 (45-615) 18.00-23:59 38.0% (1085) 152.1 (45-390) total 2855 153.5 (45-615) archivio italiano di urologia e andrologia 2021; 93, 2 m. pereira lourenço, m. eliseu, d. vieira brito, j. carvalho, e.tavares-silva, l. marconi, p. moreira, p. nunes, b. parada, c. bastos, a. figueiredo 160 discussion this work presents the highest number of patients analysed in relation to surgery start hour and its possible effects in kidney transplantation. defined ssh was different when compared with other articles. in two different studies kienz-wagner et al. and fechner et al. divided patients in groups of 08:00h-19:59h and 20:00h-07:59h (7,14). seow et al. divided ssh in 07:30h-17:59h; 18:00h-23:59h; 00:00h-07:29h (13), while shaw et al. and emmanouilidis divided the groups into periods of 3h (15, 16). we chose to divide ssh in two blocks of 00:00h-05:59h and 06:00-23:59h such as to reinforce the effects of physical tiredness and sleep deprivation at dawn. although, group m clearly presented a smaller number of patients, the high number of patients allows for reliable comparisons. other distinct aspects are the outcomes studied, as most studies analyse the perioperative complications and renal graft survival. in this article we found favourable to try and relate fatigue of the surgeon and short-term outcomes, such as surgery duration, immediate diuresis and surgical complications. as short to median term outcome we evaluated the rate of ar. the m and d groups are comparable in relation to all variables studied, except in cit of the graft (table 1), it being superior in group m. these results are logical, as they represent grafts that where implanted “at any hour” as a way to prevent achieving critical cit time that could possibly stop the realization of the transplant. utilizing univariate analysis, ssh influenced significantly the id and ar, not having influenced the ds or the number of sc (table 3). in a similar significant analysis, cit influenced the same outcomes (table 4). as group m and d where distinct in relation to cit, multivariate analysis was conducted (table 5) showing that ssh influenced the id but did not alter the rate of ar. kienzl-wagner and seow also did not find a relationship between ssh and the number of surgical complications while fechner et al. demonstrated a larger number of vascular complications in kt conducted during the night period (7, 13, 14). shaw et al. in their analysis evidenced a larger number of urologic complications during 03:0005:59h and a higher number of any complications between 00:00-02:59h (15). emmanouilidis et al. also demonstrated higher likelihood for the need of reoperation during the 03:00-05:59h interval (16). duration of surgery was not influenced by the ssh, although there isn´t sufficient data from literature regarding this specific outcome. one danish study, analysing the effects of sleep deprivation on the cognitive and technical abilities of surgeons, evidenced that surgeons can compensate for changes to their circadian rhythm, what may explain the results obtained in our study (19). on this study, ssh significantly influenced id. in the work by kenzl-wagner there was also a lower rate of id in the nocturnal group (63.4% vs. 69.9%), although, without statistical significance. in that review, the author justified that tendency by the existence of a larger number of surgeries with marginal donor in the nocturnal group, what was not observed with our study. one simple justification could be that group m has a higher cit, but changes to this outcome, id, are maintain even after multivariate analysis. notwithstanding the absence of a clear answer for this relation, it is known that a delay of graft function is associated with poorer outcomes and higher risk of graft loss, as show in a previous study done by our transplant centre (20). the rate of ar in the m and d groups where 25.9% and 18.9%, respectively. on multivariate analysis a distinct association between ssh and ar was not found, consistent with the results from kienzl-meyer et al. (14). the key factor that influenced graft function was cit. as it is showed by our work, cit has a significant influence in id and ar (8, 10, 21, 22). although, studies suggest similar outcomes in the cit time frame of less than 18h, one study conducted by debout et al. demonstrated that with every hour of cit the probability of graft failure increases (hazard ratio: 1.013) and that the time frame of 18 hours can be suboptimal (9, 10). the same work stated the existence of a relation between cit and graft failure (8). nevertheless, the recent study by emmanouilidis et al., demonstrated that in the time frame of less than 23.5 hours of cti, it is unfavourable to perform kt with the ssh in the 03:00-05:59h period (16). the effects of sleep deprivation and of ssh has been studied in other specialities and surgeries. regarding hepatic transplantation, lonze et al. stated that surgery conducted in the nocturnal period was not associated with a higher number of complications but related with longer sd and risk of short term mortality (23). analysing thoracic organ transplant, george et al. did not identify differences between outcomes in patients whose surgery was conducted at night (24). other works in pancreatic surgery, heart, trauma surgery did not find worst outcome with late ssh (25-28). there were some limitations to this study, starting with the retrospective analysis of collected data, the definition of early morning surgery (00:00-05:59) is arbitrary and may not relate precisely with the fatigue state of the surgical team. regarding ar its characterization was expanded to include clinic and histologic diagnoses. it was decided not to assess the relation between ssh and graft survival table 4. effects of cold ischemia time in the outcomes of kidney transplant. cold ischemia time < 18h 18-30h > 30h p immediate diuresis 81.4% (900) 77.2% (1277) 66.0% (62) 0.020 surgery complications 18.4% (203) 18.1% (299) 21.3% (20) 0.734 acute rejection 14.4% (159) 22.0% (364) 41.5% (39) < 0.001 table 5. multivariate analysis of the effect of surgery starting hour and cold ischemia time in the outcomes of kidney transplant. outcome variable p immediate diuresis ssh 0.026 cit 0.019 surgery complications ssh 0.282 cit 0.796 acute rejection ssh 0.055 cit < 0.001 161archivio italiano di urologia e andrologia 2021; 93, 2 early morning kidney transplantation as we considered there were no negative outcomes in the short term, and any data extrapolation would be too complex to explain. conclusions conducting kt at dawn showed no association with sd, sc or ar. however, it is connected with lower id. the cit strongly influences id and ar. in summary, data collected in this study support that ssh should prioritize cit, making sure cit is the lowest possible. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. acknowledgment the authors of this article would like to give special reference to doctors antónio roseiro, vítor dias and francisco rolo whom without their continuous and valuable work in the area of kidney transplant this work would not be possible. references 1. kohn l. to err is human: an interview with the institute of medicine's linda kohn. jt comm j qual improv. 2000; 26:227-34. 2. gaba dm, howard sk. patient safety: fatigue among clinicians and the safety of patients. n engl j med. 2002; 347:1249-55. 3. borman kr, fuhrman gm; association program directors in surgery. "resident duty hours: enhancing sleep, supervision, and safety": response of the association of program directors in surgery to the december 2008 report of the institute of medicine. surgery 2009; 146:420-7. 4. chen cl, chen y sen, liu pp, et al. living related donor liver transplantation. j gastroenterol hepatol. 1997; 12: s342-345. 5. rothschild jm, keohane ca, rogers s, et al. risks of complications by attending physicians after performing nighttime procedures. jama. 2009; 302:1565-72. 6. gray a. united kingdom national confidential enquiry into perioperative deaths. minerva anestesiol. 2000; 66:288-92. 7. fechner g, pezold c, hauser s, et al. kidney's nightshift, kidney's nightmare? comparison of daylight and nighttime kidney transplantation: impact on complications and graft survival. transplant proc. 2008; 40:1341-4. 8. debout a, foucher y, trébern-launay k, et al. each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation. kidney int. 2015; 87:343-9. 9. van roijen jh, kirkels wj, zietse r, et al. long-term graft survival after urological complications of 695 kidney transplantations. j urol. 2001; 165:1884-7. 10. opelz g, döhler b. multicenter analysis of kidney preservation. transplantation. 2007; 83:247-53. 11. król r, ziaja j, chudek j, heitzman m, et al. surgical treatment of urological complications after kidney transplantation. transplant proc. 2006;38:127-30. 12. agüera fernandez lg, robles je, rosell d, et al. análisis multivariado del impacto de las complicaciones quirúrgicas en el trasplante renal (multivariate analysis of the impact of surgical complications in renal transplant). arch esp urol. 1994; 47:999-1006. 13. seow yy, alkari b, dyer p, riad h. cold ischemia time, surgeon, time of day, and surgical complications. transplantation. 2004; 77:1386-9. 14. kienzl-wagner k, schneiderbauer s, bösmüller c, et al. nighttime procedures are not associated with adverse outcomes in kidney transplantation. transpl int. 2013; 26:879-85. 15. shaw tm, lonze be, feyssa el, et al. operative start times and complications after kidney transplantation. clin transplant. 2012; 26:e177-83. 16. emmanouilidis n, boeckler j, ringe bp, et al. risk balancing of cold ischemic time against night shift surgery possibly reduces rates of reoperation and perioperative graft loss. j transplant. 2017; 2017:5362704. 17. gopalakrishnan g, gourabathini sp. marginal kidney donor. indian j urol. 2007; 23:286-93. 18. chapman jr. marginal kidneys for transplantation. bmj 2015; 351:h3856. 19. amirian i. the impact of sleep deprivation on surgeons' performance during night shifts. dan med j. 2014; 61:b4912. 20. moreira p, sá h, figueiredo a, mota a. delayed renal graft function: risk factors and impact on the outcome of transplantation. transplant proc. 2011; 43:100-5. 21. salahudeen ak, haider n, may w. cold ischemia and the reduced long-term survival of cadaveric renal allografts. kidney int. 2004; 65:713-8. 22. hernández d, estupiñán s, pérez g, et al. impact of cold ischemia time on renal allograft outcome using kidneys from young donors. transpl int. 2008; 21:955-62 23. lonze be, parsikia a, feyssa el, et al. operative start times and complications after liver transplantation. am j transplant. 2010; 10:1842-9. 24. george tj, arnaoutakis gj, merlo ca, et al. association of operative time of day with outcomes after thoracic organ transplant. jama. 2011; 305:2193-9. 25. araujo rl, karkar am, allen pj, et al. timing of elective surgery as a perioperative outcome variable: analysis of pancreaticoduodenectomy. hpb (oxford). 2014; 16:250-62. 26. heller ja, kothari r, lin hm, et al. surgery start time does not impact outcome in elective cardiac surgery. j cardiothorac vasc anesth. 2017; 31:32-36. 27. zafar sn, libuit l, hashmi zg, et al. the sleepy surgeon: does night-time surgery for trauma affect mortality outcomes? am j surg. 2015; 209:633-9. 28. dalton mk, mcdonald e, bhatia p, et al. outcomes of acute care surgical cases performed at night. am j surg. 2016; 212:831-836. correspondence mário pereira lourenço, md (corresponding author) mariolourenco88@gmail.com miguel eliseu mgl.nobre@gmail.com duarte vieira brito duartevbrito@hotmail.com joão carvalho joao.andre.mendes.carvalho@gmail.com edgar tavares-silva edsilva.elv@gmail.com lorenzo marconi lorenzooliveiramarconi@gmail.com pedro moreira pedronetomoreira@gmail.com pedro nunes ptnunes@gmail.com belmiro parada parada.belmiro@gmail.com carlos bastos cabastos@netcabo.pt arnaldo figueiredo ajcfigueiredo@gmail.com urology and renal transplantation department. coimbra university hospital centre rua maria bourbon bobone, nº57, re/esq, 3030-481, coimbra (portugal) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2244 original paper no conflict of interest declared. tus to an irritating environment of the diaper (diaper dermatitis) is the common pathologic cause of this condition (3). post circumcision meatal stenosis may also result from ischemia of the meatal mucosa secondary to damage to the frenular artery (2). patients with ms can present with symptoms of voiding difficulties, such as pinpoint meatus, difficulty to aim or an upward and forceful urinary stream, dysuria, urgency, frequent and prolonged urination. therefore, untreated ms can lead to urinary tract infections and kidney problems (1). to confirm the diagnosis, detailed history and physical exam including observation of urination and examining the urethral opening are evaluated carefully (1). regarding the methods of circumcision, it was hypothesized by graves that ms is more common after a plastibell circumcision (2). meatotomy is a simple common procedure for the treatment of ms that can be performed with minimal instrumentation and in this procedure, the ventrum of the meatus is crushed with a straight clamp and then the crushed ventral tissue is incised sharply with fine-tipped scissors (1). side effects of meatotomy are bleeding during or after meatotomy, mild discomfort for the first day following the operation, recurrence, pain, dysuria, and dysuria induced urinary retention, infection, edema, and spraying of the urine stream as a consequence of edema for a while (2-4). among all the complications mentioned above, bleeding could be a matter of utmost importance in which clamping time might have played a key role. the clamping times recommended in previous literature were between 60 seconds to 3 minutes (1, 4-7). in these circumstances, we could not find any study that shows us if there is any correlation between clamping time and bleeding during and after meatotomy procedure. therefore, we conducted a study to find out the optimal clamping time in meatotomy. materials and methods study design the ethics committee of shiraz university of medical sciences approved the protocol of the study (ir.sums.med.rec. objective: during meatotomy procedure for children with meatal stenosis (ms), a straight clamp used as a hemostat on the ventrum of the meatus before incised with scissors for clamping and holding bleeding from the site of operation. the aim of this study was to evaluate the optimum clamping time for meatotomy in children with ms. materials and methods: all the patients with ms between 2014 to 2019 were enrolled in this retrospective study. patients with uncircumcised penis, traumatic catheterization, any kind of penile abnormality such as hypospadias or penile curvature, and active urinary tract infection (uti) were excluded. the indication of meatotomy was a pinpoint meatus that develops with dorsal or lateral deflection of the urinary stream and high-velocity urine flow. during meatotomy procedure, clamping time was examined in different groups such as 2, 3, and 4 minutes. the main symptoms of presentation and ultrasonography (us) findings were recorded and compared between groups. to assess the optimum time clamping, postoperative bleeding was noted carefully in all groups. the success rate was recorded at onemonth postoperative follow-up in the clinic. results: of the 120 patients with ms who underwent a meatotomy procedure, there were 40 (33.3%) participants in each group. the main symptoms were painful urination and urine stream deviation that represented in 54 (46%) patients. bladder wall thickness was the main pre-operation finding in the us which was observed in 67 (55.8%) patients. in comparison between the groups related to clamping time, bleeding was observed and required suturing when clamping was applied for 2 minutes in 4 (3.3%) patients (p = 0.016). with a minimum follow-up of 12 months, no recurrent meatal stenosis was reported. conclusions: clamping time for more than 2 minutes may prevent bleeding during and after meatotomy. key words: bleeding; clamping time; meatal stenosis; meatotomy. submitted 10 march 2021; accepted 2 may 2021 introduction one of the most common complications after circumcision is meatal stenosis (ms) which occurs in approximately 9%-10% of patients (1). ms is defined as narrowing of the opening of the external urethral meatus less than 2 mm (2). prolonged exposure of the delicate meaoptimal clamping time in meatotomy procedure for children with meatal stenosis: experience with 120 cases mehdi shirazi 1, 2, umayir chowdhury 3, faisal ahmed 4*, mohammad-bagher rajabalian 1, hossein-ali nikbakht 5, khalil al-naggar 4, ebrahim al-shami 4 1 department of urology, shiraz university of medical sciences, shiraz, iran; 2 histomorphomettery and stereology research center, shiraz university of medical sciences, shiraz, iran; 3 school of medicine, shiraz university of medical sciences, shiraz, iran; 4 urology research center, al-thora general hospital, department of urology, ibb university of medical since, ibb, yemen; 5 social determinates of health research center, department of biostatics and epidemiology, faculty of medicine, babol university of medical sciences, babol, iran. doi: 10.4081/aiua.2021.2.244 summary 245archivio italiano di urologia e andrologia 2021; 93, 2 clamping time in meatotomy 1397.507). this is a retrospective study, which included all the patients with ms during five years from july 2014 to september 2019, which evaluated by one single pediatric urologist were enrolled in this study. patients with uncircumcised penis, traumatic catheterization, prior penile surgery, any penile abnormality such as hypospadias or penile curvature, and active urinary tract infection (uti) were excluded. written informed consent was taken from the patient’s parents before the operation and the benefit and risk of this procedure were explained. the indication of meatotomy was a pinpoint meatus that develops with dorsal or lateral deflection of the urinary stream and highvelocity urine flow (8). during meatotomy procedure, clamping time was checked in different groups such as 2, 3, and 4 minutes. the demographic characteristics such as skin eruption around meatus, age, history of allergy, age of circumcision, us finding, main symptoms, and quality of voiding after operation were recorded and compared between groups. to assess the optimum time clamping, postoperative bleeding was noted carefully in all groups. the success rate was recorded at one-month postoperative follow-up in the clinic. surgical procedure all procedures were done under general anesthesia in the supine position. minimal skin prep and drape of the genitalia were done with iodopovidone. then one jaw of a well-lubricated mosquito hemostat was introduced into the ventral aspect of the urethral meatus to a depth of approximately 2-3 mm, depending on the severity of stenosis and patient age. then, by closing the hemostat, the ventral tissue was crushed. clamping time was checked in different groups such as 2, 3, and 4 minutes. then crushed tissue was divided gently with a fine-tipped scissor. a small amount of antibiotic was placed over the raw edges (8). the meatotomy site was shown to the parents and the surgeon demonstrated how to open the meatus two times daily to apply dexpanthenol-chlorhexidine cream for 2 weeks (9). surgical outcome during the procedure bleeding of the surgical site was recorded by a pediatric urologist and if occurred, firstly pressure on the edges performed and if not stopped then it would be sutured with 6/0 polyglactin suture material. quality of voiding and symptoms were asked from the patient’s family and meatal opening using visual inspection was recorded in the outpatient clinic one month after the operation. statistical analysis the mean ± sd and median, inter-quartile range (iqr), described the quantitative variables, and frequency (percent) was used for qualitative variables. we assessed the normality as the assumption of the variables in the study by the kolmogorov-smirnov test. when data were non-normally distributed, the non-parametric test was used. the chi-square test was used to assess a probable statistically significant difference between qualitative variables for limitations on the observed frequency of fisher's exact test. anova was applied to compare the difference of means between more than two different levels or the non-parametric krusal wallis test was applied. the collected data were analyzed by spss version 20. a p-value less than 0.05 was considered statistically significant. result the patient's characteristics were summarized in table 1. of the 120 patients diagnosed with ms were enrolled in this study. the mean patient age was 50.88 ± 29.73 months. the time between circumcisions to meatotomy procedure was 49.5 ± 30.84 months. skin eruption around meatus was found in 6 (5.0%) patients. all coagulation tests (pt, ptt, inr, and platelet) were normal in all patients. related to symptoms of ms, the main symptoms were painful urination and urine stream deviation which represented in 54 (46%) patients. other symptoms were summarized in table 2. bladder wall thickness was the main pre-operation finding in us which represented in 67 (55.8%) patients. us finding were summarized in table 2. voiding quality at one month after operation excellent in 79 (65.8%) patients, improved in 38 (31.7%) patients, and partially improved in 3 (2.5%) of patients and at long term (12 months) follow-up remained without symptoms. in comparison between the groups related to clamping table 1. main characteristics of patients. p value 4 min clamping 3 min clamping 2 min clamping total number variables time (40) time (40) time (40) 120 0.031 60.07 ± 33.74 49.85 ± 30.76 42.73 ± 21.39 50.88 ± 29.73 age (months) a 1.000 2 (33.3) 2 (33.3) 2 (33.3) 6 (5.0) skin eruption around meatus b 0.265 2 (14.2) 6 (42.9) 6 (42.9) 14 (11.7) history of allergy b 0.19 2.47 ± 2.35 3.51 ± 5.87 3.39 ± 3.78 3.12 ± 4.24 age at circumcision (months) c 0.016 0 (0) 0 (0) 4 (100) 4 (3.3) bleeding b p-values of < 0.05 were considered significant. a: data was presented as mean ± sd; b: data was presented as n (%); c: median (iqr). table 2. us finding and symptoms of patients. p value 4 min clamping 3 min clamping 2 min clamping total 120 variables main symptoms b 0.010 18 (33.3) 18 (33.3) 18 (33.3) 54 (46) painful urination and urine stream deviation 9 (37.5) 4 (16.7) 11 (45.8) 24 (20) stream narrowing and infrequent voiding 10 (62.5) 5 (31.3) 1 (6.3) 16 (13.3) urge incontinence and retention 2 (16.7) 5 (41.7) 5 (41.7) 12 (10) no symptoms 0 (0.0) 8 (61.5) 5 (38.5) 13 (10.7) prolonged time of micturition us finding before operation b 0.877 23 (34.3) 21 (31.3) 23 (34.3) 67 (55.8) bladder wall thickness 5 (31.3) 6 (37.5) 5 (31.3) 16 (13.4) unilateral mild hydronephrosis 2 (50) 2 (50) 0 (0) 4 (3.3) bilateral mild hydronephrosis 10 (30.3) 11 (33.3) 12 (36.4) 33 (27.5) normal us finding us, ultrasonography. p-values of < 0.05 were considered significant. b data was presented as n (%). archivio italiano di urologia e andrologia 2021; 93, 2 m. shirazi, u. chowdhury, f. ahmed, m.-bagher rajabalian, h.-ali nikbakht, k. al-naggar, e. al-shami 246 time, there was no statistically significant difference among the groups in terms of skin eruption around meatus, history of allergy, circumcision method, us finding, voiding quality after one month of operation, and meatal width. however, the mean age in 2 minutes group was younger than another group (p = 0.031). significant bleeding was observed and required suturing when clamping time was for 2 minutes in 4 (3.3%) patients (p = 0.016). painful urination and urine stream deviation was the main symptoms in all groups (p = 0.010). besides, with a minimum follow-up of 12 months, no recurrent ms was reported. discussion the main cause of ms is circumcision. it is usually common in jews and muslims and this problem is highly detected in israel, where most boys are ritually circumcised in early infancy (3). different methods are approved to perform neonatal circumcision but three techniques are used regularly: the mogen clamp, the gomco clamp, and the plastibell device. previously published articles revealed that neonatal circumcision using plastibell device with intact frenulum technique decreases the rate of delayed ms (10), whatever in our study frequency of ms between the sleeve and the plastibell methods was not statically significant between groups. sever ms is a late complication that is mainly noticed 12 years after circumcision which is simply treated by meatotomy. meatotomy is a simple common procedure for the treatment of ms that can be performed with minimal instrumentation and in this procedure, the ventrum of the meatus is crushed with a straight clamp and then the crushed ventral tissue is incised sharply with fine-tipped scissors (1). side effects of meatotomy are bleeding during or after the procedure, mild discomfort for the first day following the operation, recurrence, pain, dysuria, dysuria induced urinary retention, infection, edema, and spraying of the urine stream as a consequence of edema for a while (2-4). among all the complications mentioned above, bleeding could be a matter of utmost importance in which clamping time might have played a key role. the clamping times recommended in previous literature were between 60 seconds to 3 minutes table 3 shows the earlier published study with clamping time and complications (1, 3-9, 11-13). david ben-meir et al. noted that bleeding occurred in two patients who received sedation and general anesthesia and one patient who received penile block and general anesthesia. clamping time in all patients was one minute. however, children who had bleeding had various degrees of skin reaction (edema and blanching) and they concluded that blanching may have increased the risk of bleeding due to fragility of tissue or the difficulty in cutting precisely through the crush line made by the hemostat (3). james et al. recommended that clamping for three minutes reduces bleeding and facilitates placement of sutures (5). our result was similar to the previous studies and showed significant bleeding was observed and required suturing when the clamping time was for 2 minutes. parisa and associates evaluated 87 children with ms and they concluded that decreased urine stream is a common symptom which was seen among 54% of patients with ms. besides, increased bladder wall thickness was the most common finding in ultrasonography (us) which was revealed in 82% of the patients (14). our result was similar to the previous study. david et al. assessed the quality of void at 24 hours and 1 month after meatotomy (3). in agreement with this study, we also evaluated the quality of voiding one month after surgery, and in our opinion; this time was enough for the meatus to heal. local anesthesia was highly recommended in recent studies. however, it is important to mention that restlessness and anxiety, especially in the patient less than 4 years, is the main limitation for local anesthesia in meatotomy procedure. besides, meatoplasty under general anesthesia had a lower recurrence rate compared to meatotomy under local anesthesia (0.2% vs 3.5%) (3, 6, 8). although in some parts of the world like our country (iran) the cost of a meatotomy under ga and meatotomy under local anesthesia might be roughly the same (8). mahmoudi et al. mentioned that us might not be necessary for every patient with ms after meatotomy. however, it is recommended to perform the radiologic study in cases of specific symptom continuation. we agree with him and we also did not perform any us after meatotomy procedure unless specific symptom was found in post-surgical follow-up (15). the current study had some limitations. firstly, the small size number of patients. secondly, the lack of longterm follow-up. thirdly, the surgeon's propensity to operate could be biased by their propensity to diagnosis ms and this could affect the rates cited. fourthly, it is hard to assess the quantity of bleeding by laboratory investigation and the amount of bleeding and the need for suturing was assessed by pediatric urologist. finally, it was a retrospective analysis. table 3. summary of published studies with clamping time, type of anesthesia and complications. study patients type of clamping time complication number anesthesia (minutes) neheman (9) 25 general 2 mild meatal stenosis in 3 patients fronczak (8) 55 topical repeated meatotomy in 3 patients wang (1) general 1 no complication priyadarshi (12) 48 local 2-3 penile numbness in 2 patients for 1 day ben-meir (3) 76 general/local 1 bleeding in 3 patients, laryngospasm in 2 patients lane (5) 3 no complication cubillos (11) 85 general 1 no complication roth (7) 100 local 5 no complication elkhafifi (13) 86 general 1–2 no complication 247archivio italiano di urologia e andrologia 2021; 93, 2 clamping time in meatotomy conclusions the main symptoms of ms are painful urination and urine stream deviation. additionally, clamping time for more than 2 minutes may prevent bleeding during and after meatotomy. however, this observation needs to be validated in a large number cohort study with long-term post-procedural follow-up. acknowledgments the authors would like to thank shiraz university of medical sciences, shiraz, iran and, also the center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. references 1. wang m-h. surgical management of meatal stenosis with meatoplasty. j vis exp. 2010. 2. van howe rs. incidence of meatal stenosis following neonatal circumcision in a primary care setting.clin pediatr. 2006; 45:49-54. 3. ben-meir d, livne pm, feigin e, et al. meatotomy using local anesthesia and sedation or general anesthesia with or without penile block in children: a prospective randomized study. j urol. 2011; 185:654-7. 4. ajemian ep, lichtwardt jr, gonzalez j, et al. technique for avoiding stricture following urethral meatotomy. j urol. 1961; 86:340-2. 5. lane jw. modified technique of urethral meatotomy in males. urology. 1986; 27:170. 6. cartwright pc, snow bw, mcnees dc. urethral meatotomy in the office using topical emla cream for anesthesia. j urol. 1996; 156:857-9. 7. roth rb. office urology. j postgrad med. 1971; 49:109-13. 8. fronczak c, villanueva c. clinic meatotomy under topical anesthesia.j pediatr urol. 2017; 13:499. e1-. e3. 9. neheman a, rappaport yh, darawsha ae, et al. uroflowmetry before and after meatotomy in boys with symptomatic meatal stenosis following neonatal circumcision-a long-term prospective study. urology. 2019; 125:191-5. 10. karami h, abedinzadeh m, moslemi mk. assessment of meatal stenosis in neonates undergoing circumcision using plastibell device with two different techniques. res rep urol. 2018; 10:113. 11. cubillos j, george a, gitlin j, et al. tailored sutureless meatoplasty: a new technique for correcting meatal stenosis. j pediatr urol. 2012; 8:92-6. 12. priyadarshi v, puri a, singh jp, et al. meatotomy using topical anesthesia: a painless option. urol ann. 2015; 7:67. 13. elkhafifi mh. presentation and management of postcircumcision meatal stenosis at hawari center, benghazi, libya: a clinical review of 86 cases. libyan int med univ j. 2019; 4:69. 14. saeedi p, ahmadnia h, akhavan rezayat a. evaluation of the effect of meatal stenosis on the urinary tract by using ultrasonography. urol j. 2017; 14:3071-4. 15. mahmoudi h. evaluation of meatal stenosis following neonatal circumcision. urol j. 2005; 2:86-8. correspondence mehdi shirazi, md shirazim@sums.ac.ir umayir chowdhury, md umayir09@gmail.com mohammad-bagher rajabalian, md mj.rajabalian@yahoo.com urology office, faghihi hospital, zand blvd., shiraz (iran) faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com urology office, al-thora general hospital, alodine street, ibb (yemen) hossein-ali nikbakht, md ep.nikbakht@gmail.com social determinates of health research center, babol university of medical sciences, babol (iran) khalil al-naggar, md alnajjarkh1234@gmail.com ebrahim al-shami, md alshami_ebrahim@yahoo.com urology office, althora general hospital, alodine street, ibb (yemen) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):1294 1 original paper transabdominal ultrasound (us) as a preferred non-invasive radiological imaging method for evaluating the urinary system. transabdominal ultrasound (us) as a preferred non-invasive radiological imaging method for evaluating the urinary system. limitations of transabdominal us in providing detailed information about bladder dynamics are acknowledged, especially concerning the morphology of bladder neck, which can vary based on factors such as body position and urine volume. recent studies on ultrasonographic examination of bladder neck dynamics in women highlight the importance of understanding these dynamics (3, 4). the specific aspects evaluated in these studies, such as mucosal thickness, morphology of trigonum and bladder floor, and anteroposterior angle of the bladder wall, demonstrate the complexity of assessing bladder function (3-6). this suggests a focus on understanding how the bladder neck behaves in patients with oab compared to those without this condition methods before study initiation, approval was obtained from the ethics committee of tepecik education and research hospital (approval number: 2023/08-31), and consent forms from the patients who agreed to participate in the study were obtained. the study was conducted in accordance with the principles of the declaration of helsinki. patients with kidney disease, stone disease, a history of urinary system interventions, active urinary tract infections, a history of multiple drug use, and anomalies detected in urinary system by ultrasound were excluded from the study. this prospective study was conducted between october 2023 and december 2023. among the patients who visited our clinic due to urinary symptoms between the mentioned dates, 29 female patients diagnosed with overactive bladder (oab) were planned to be included in the study group (group i). additionally, 30 female patients who did not exhibit urinary symptoms were planned to be included in the control group (group ii). ultrasonographic examination the patients were assessed in the supine position, as it provides the most stable bladder conditions during the examination. following a period for allowing patients to aim: the aim of this study was to compare the differences between angles of bladder neck in girls with overactive bladder and those in healthy ones using transabdominal ultrasonography. materials and methods: this study consists of 28 girls complicated with overactive bladder (group i) and 40 healthy girls (group ii). the anteroposterior vesical wall angle (apva), urethroposterior vesical wall angle (upva), urethroanterior vesical wall angle (uava), thickness of bladder mucosa, distance of urethral orifices, and distance between ureter and urethra orifice were measured in supine position using transabdominal ultrasonography. the results were compared between the two groups. results: uava in group i was higher than group ii (135.2 ± 12.2 mm vs. 117.4 ± 14.0 mm; p = 0.009). upva was smaller in group i than group ii (114.6 ± 19.5 mm vs. 135.3 ± 16.5 mm; p = 0.014). the distance between the ureteral orifices was 31.8 ± 8.5 mm in group i and 17.0 ± 4.1 mm in group ii (p < 0.001). there was no statistically significant difference between groups in terms of apva, bladder mucosa thickness, and distance between ureter and urethra orifice (p > 0.05). conclusion: bladder neck dynamics may play an important role in overactive bladder pathophysiology due to differences in upva, uav, and location of ureteral orifices in this patient population. key words: overactive bladder; ultrasonography; bladder. submitted 18 january 2024; accepted 15 february 2024 introduction overactive bladder (oab) is a dysmotility disorder characterized by various symptoms, including a sudden urge to urinate, urinary incontinence, and frequent urinary tract infections. it is associated with the overstimulation of the detrusor muscle during the bladder's filling phase. in some cases, individuals, especially women, may contract pelvic floor muscles voluntarily by squatting and applying pressure to the urethra with their heels to prevent urinary incontinence (1). while factors such as age, chronic neurological diseases, diabetes, and spinal injuries can contribute to oab in adults, the etiology of this disorder in women is not fully understood. diagnosing oab in women involves a comprehensive approach, including lower urinary tract ultrasonography (us), urodynamic examination, and a detailed patient history (2). differences in bladder neck angles between female patients with overactive bladders and healthy peers mehmet yoldas, mehmet zeynel keskin 1 tepecik training and research hospital urology clinic, izmir, turkey. doi: 10.4081/aiua.2024.12294 summary archivio italiano di urologia e andrologia 2024; 96(2):1294 m. yoldas, m. zeynel keskin 2 achieve bladder fullness, the examination was conducted by scanning the suprapubic abdominal wall in both sagittal and transverse planes. initially, the three-dimensional measurement of urine in the bladder was performed, followed by the calculation of bladder volume firstly, we assessed bladder volume, bladder wall thickness, the presence of trabeculation, and any additional pathology. subsequently, we examined the localization of both kidneys, their contours, and the structure of the pelvicalyceal system. following that, we measured kidney sizes and parenchymal thicknesses. the mucosal thickness of the bladder wall was measured within a distance of up to 2 cm from the bladder neck, while the distance between the bladder smooth muscle layer and the mucosal surface was measured to include the mucosal-submucosal low-echo area. the diameters of both ureteral orifices were then measured at the axial plane. additionally, we determined whether the ureteral orifices opened to the bladder in the normal position. the bladder neck was easily visualized as a 'v' depression in the sagittal plane, and the urethrovesical junction was identified. a line parallel to the urethra was drawn throughout the urethra from the level of the urethrovesical junction. the anteroposterior vesical wall angle (apva), urethroposterior vesical wall angle (upva), and urethroanterior vesical wall angle (uava) were measured. the apva of the bladder neck was calculated by measuring the angle between the anterior wall (anterior base plate) and the posterior wall in the sagittal plane. the upva between the urethra and the posterior vesical wall and the uava between the urethra and anterior wall were then measured. subsequently, the distance between the ureteral orifices and between the ureteral and urethral orifices was measured on the axial plane. measurement is shown in figure 1. statistical analysis all data were analyzed using pasw version 18.0 (spss inc., chicago, il, usa). descriptive data were expressed as mean ± sd. differences between the two groups were assessed using the mann-whitney u test for categorized variables and student’s t-test for continuous variables. a p-value of < 0.05 was considered statistically significant. results the age range of the patients was 25 to 49 years, with no difference in age and weight observed between the two groups (table 1). uava was higher in group i than in group ii (138.4° ± 11.2° vs. 115.2° ± 13.4°, respectively; p = 0.008), whereas upva was lower in group i than in group ii (118.1° ± 18.5° vs. 138.2° ± 17.7°, respectively; p = 0.012). the mean distance between the ureteral orifices was 41.7 ± 7.5 mm in group i and 25.0 ± 3.2 mm in group ii (p = 0.000). no significant difference in the results of other measurements for the lower urinary system was observed between the two groups (p > 0.05; table 1). figure 1. measurement of anteroposterior vesical wall angle (apva), urethroposterior vesical wall angle (upva), and urethroanterior vesical wall angle (uava). archivio italiano di urologia e andrologia 2024; 96(2):1294 3 differences in bladder neck angles discussion the current study revealed that patients with overactive bladder (oab) exhibited decreased upva values, increased uava values, and an increased distance between orifices. a prior study, albeit with a limited number of adult patients, identified bladder neck changes associated with post-hormonal alterations in bladder neck fibroblast activity (5). considering that our participants were female patients in the hormonally active period, we support the validity of this hypothesis for the oab patient group in our study. we propose that the variances in upva and uava of the bladder neck among oab patients may be linked to changes in the bladder wall attributed to excessive detrusor activity. sugaya et al., who determined anteroposterior vesical wall angle (apva) values in healthy individuals aged 0-29 years (6), found that children under 10 years old had lower apva values. those over 10 years old, however, exhibited values similar to adults that were associated with hormonal changes. however, at present, no study has comprehensively investigated bladder neck angles during adulthood. lower urinary tract disorders are prevalent in childhood, with anatomical issues, neurological impairments, and behavioral disorders in toilet training identified as etiological factors (7). additionally, goessaert et al. demonstrated that children experiencing daytime urinary incontinence had a twofold increased risk of sudden feelings of urination and urinary incontinence in adulthood. furthermore, song et al. (8) found that individuals with complaints of constipation and urinary incontinence in adulthood had similar issues during childhood. these studies suggest a potential pathological link between childhood and adult disorders. if symptoms persist from childhood to adulthood, as suggested by the aforementioned studies, it becomes crucial to understand the pathophysiology of the disease during childhood and implement appropriate treatment, prioritizing the lifelong well-being of the patient the strength of our study lies in being the first to explore bladder neck angles in women, confirming that women diagnosed with oab exhibit alterations in bladder neck angles. however, a notable limitation of the current study is the relatively small number of cases and our exclusive focus on women. conclusions despite the link between oab in childhood and similar urinary symptoms in adulthood, the pathophysiology of this relationship has not been fully elucidated. we posit that a more detailed investigation of the bladder neck and its dynamics could yield significant insights not only for the diagnosis and treatment of the disorder during childhood but also for addressing similar symptoms in adulthood. our findings, indicating changes in bladder neck angles among women diagnosed with oab, suggest a potential role of these changes in the pathophysiology of oab in girls. additionally, the measurement of bladder neck angles could serve as a diagnostic tool for oab. therefore, further large-scale studies are needed to uncover different approaches for the treatment of this disease. references 1. drake mj. fundamentals of terminology in lower urinary tract function. neurourol urodyn 2018; 37:13-19. 2. chen lc, kuo hc. pathophysiology of refractory overactive bladder. lower urinary tract symptoms 2019; 11:177-181. 3. sugaya k, nishijima s, oda m, et al. transabdominal vesical sonography of urethral syndrome and stress incontinence. int j urol; 2003: 10:36-42. 4. tafuro l, montaldo p, iervolino lr, et al. ultrasonographic bladder measurements can replace urodynamic study for the diagnosis of nonmonosymptomatic nocturnal enuresis. bju int. 2010; 105:108-111. 5. lo ts, ng kl, hsieh wc, et al. ultrasonography and clinical outcomes following anti-incontinence procedures (solyx™ tape): a 3year post-operative review. int urogynecol j. 2022; 33:2749-2759. 6. sugaya k, nishijima s, oda m, et al. ultrasonographic changes of the female bladder neck during development. int j urol. 2002; 9:668671. 7. fotter r, riccabona m. functional disorders of the lower urinary tract in children. radiologe. 2005; 45:1085-1091. 8. goessaert as, schoenaers b, opdenakker o, et al. long-term followup of children with nocturnal enuresis: increased frequency of nocturia in adulthood. j urol. 2014; 191:1866-1870. 9. song qx, wang l, cheng x, et al. the clinical features and predictive factors of nocturnal enuresis in adult men. bju int. 2020; 126:472-480. table 1. comparison of demographic and study results between both groups. parameter study group 1 control group 2 p (n = 29) (n = 30) age (year) 37.4 ± 2.5 38.1 ± 1.9 0.401 weight (kg) 66.0 ± 9.2 68.2 ± 10.1 0.509 anterior-posterior vesical angle 126.5 ± 15.7 113.4 ± 15.4 0.079 urethro-anterior vesical angle 138.4 ± 11.2 115.2 ± 13.4 0.008 urethro-posterior vesical angle 118.1 ± 18.5 138.2 ± 17.7 0.012 bladder volume (mm3) 59.2 ± 24.1 61.5 ± 41.3 0.845 mucosa thickness in bladder neck (mm) 1.9 ± 0.7 1.6 ± 0.6 0.327 length of urethra (mm) 43.9 ± 8.7 39.1 ± 8.7 0.656 ureteral–urethral orifice distance (mm) 29.2 ± 8.7 28.9 ± 7.9 0.994 distance between the ureteral orifices (mm) 41.7 ± 7.5 25.0 ± 3.2 0.000 data were expressed in mean ± sd (standard deviation). correspondence mehmet yoldas, md (corresponding author) yoldas_2297@hotmail.com mehmet zeynel keskin, md zeynel_akd@hotmail.com republic of turkey ministry of health izmir provincial health directorate izmir university of health sciences tepecik training and research hospital urology clinic, izmir, turkey; yenişehir, gaziler cd no:468, 35020 konak/izmir conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 146 original paper no conflict of interest declared. introduction coronavirus disease 2019 (covid-19) is caused by a novel beta-coronavirus known as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), firstly isolated in wuhan, hubei province of china (1-3). since the first cases of sars-cov-2 reported in december 2019 in china, other asian countries, such as thailand, japan and the republic of korea, reported increasing cases of covid-19 in january 2020, leading the world health organization (who) to declare international public health emergency in the same month and, with the diffusion of contagion in europe and north america, world pandemic in march 2020 (4). in order to limit the contagion, many countries instituted strict lockdown to flatten the epidemic curve and relieve the pressure on hospitals, permitting the activity only for essentials supply chains businesses and emergency/oncological healthcare services. the consequences related to social isolation, fear of infection and, particularly, the disruption of routine life, provoked severe detrimental and long-lasting psychosocial effects as anxiety and depression, increasing the prevalence of stress and trauma-related disorders in the population (5). due to these premises and to the evidence that several urological conditions (as benign prostatic hyperplasia, overactive bladder, urge urinary incontinence, interstitial cystitis and bladder pain syndrome) were triggered or worsened after or during stressful events, the aim of our study was to explore how psychosocial consequences of covid-19 affected lower urinary tract symptoms, considering in addition economic consequences and quarantine measures (6, 7). materials and methods study design an anonymous cross-sectional, web-based closed survey between healthy subject was conducted, timed from march to may 2020, during lockdown period. the participants were recruited by an invitation distributed through direct e-mail and facebook. since its introduction in 2004, facebook is the third most popular website in the world, with 1.65 billion monthly active users. facebook is widely used among midlife and older adults, objective: coronaviruses (covs) are a group of rna viruses involved in several human diseases affecting respiratory, enteric, hepatic, and neurological systems. covid-19 was identified in 2020 and was named sars-cov-2. to limit worldwide contagion, many countries instituted a lockdown, which conducted to disruption of routine life. in fact, pandemic was associated with several stresses among population, such as loss of employment, deaths of family members, friends, or colleagues, financial insecurity, and isolation. this led to long-lasting psychosocial effects as anxiety and depression, increasing the prevalence of stress and traumarelated disorders in the population. the aim of this study was to investigate the correlation between lower urinary tracts symptoms (luts) and stress/depressive symptoms during covid-19 pandemic. materials and methods: an anonymous cross-sectional webbased survey (comprehending anthropometric data, education level, occupation status, smoking and alcohol habits, current therapies, quarantine and covid-19 infection status) was conducted from march to may 2020 in italy. luts were examined through national institute of health-chronic prostatitis symptom index (nih-cpsi) and genitourinary pain index (gupi). hamilton depression rating scale (hdrs) was utilized to evaluate depressive and anxiety symptoms. non-parametric kruskal-wallis h test was used for statistical analysis. results: a total of 356 out of 461 subjects fully completed the survey, with a response rate of 77.2%. data showed that subjects involved in economic difficulties, quarantine measures or with increased hdrs reported a significative statistic worsened urinary symptoms (h(3) = 11.731, p = 0.008), quality of life, (h(3) = 10.301, p = 0.016), total nih-cpsi/gupi score (h(3) = 42.150, p = 0.000), and quality of life (h(3) = 48.638, p = 0.000). conclusions: covid-19 pandemic provoked several alterations in everyday life. although general lockdown, quarantine and social distancing have been necessary to prevent virus spreading, this had long term effects on all population in terms of mental and physical health. nih-cpsi and gupi scores increased linearly with stress and anxiety levels measured at hdrs, confirming worse luts in subjects who suffered anxiety and stress from covid-19 pandemic. key words: covid-19; luts; nih-cpsi; anxiety; stress; hdrs. submitted 3 february 2022; accepted 9 february 2022 lower urinary tract symptoms and mental health during covid-19 pandemic biagio barone *, luigi de luca *, luigi napolitano, pasquale reccia, felice crocetto, massimiliano creta, raffaele vitale, vincenzo francesco caputo, raffaele martino, luigi cirillo, giovanni maria fusco, massimiliano trivellato, giuseppe celentano, roberto la rocca, domenico prezioso, nicola longo department of neurosciences, reproductive and odontostomatological sciences of university of naples "federico ii", naples, italy. * equally contributing authors. doi: 10.4081/aiua.2022.1.46 summary 47archivio italiano di urologia e andrologia 2022; 94, 1 luts and mental health during covid-19 pandemic as well as reported by published studies with 63% of adults aged 50-64 and 56% of people 65 and older that use this platform. several published studies reported this platform as a validated method of recruiting study participants for survey research (8, 9). the questionnaire was designed using the google form application included in the google drive office suite (google llc) and formulated in italian, with the aim of increasing the response rate. the study was conducted according to the guidelines of the world medical association declaration of helsinki and to the current european gdpr privacy policy. webbased survey was conducted according to the checklist for reporting results of internet e-surveys (10). subjects were informed at the beginning of the survey about purpose of the study, data storing and principal investigators (l.d and b.b). data obtained were collected and stored on personal cloud of principal investigators, utilizing a two-step verification. survey comprehended a first section with inclusion criteria, anthropometric data, education level, occupation status, smoking and alcohol habits, current therapies, quarantine and covid-19 infection status. we defined as positive infection status, subjects with a diagnosis through nasopharyngeal swab at the time of the survey; suspicion infection status, subjects with clinical diagnosis (imaging or symptoms) in absence of nasopharyngeal swab at the time of the survey. regarding quarantine status, we considered, in addition to the patients with diagnosed covid-19 infection, subjects without covid-19 infection but who had a close contact with a positive patient, according to the definition of center for disease control and prevention (cdc) (individual who has had closer than < 6 feet for ≥ 15 min with people with a positive diagnosis for covid-19, whether symptomatic or asymptomatic). inclusion criteria were: subjects over 18 years-old, without explainable urinary symptoms (urolithiasis, urinary infection, stress incontinence). surveys not completely filled out were excluded by further analysis. second section of the survey comprehended national institute of health-chronic prostatitis symptom index (nih-cpsi) for males and genitourinary pain index (gupi) for females (11, 12). third section of the survey comprehended, finally, hamilton depression rating scale (hdrs) (13). survey was tested by all investigators in order to verify usability and technical functionality. successively, survey was submitted, through google forms, to the most used social networks. statistical analysis descriptive statistics included means and standard deviations for continuous variables while frequencies and percentages were obtained for categorical variables. nonparametric kruskal-wallis h test was used to determine differences between groups, according to normality assumptions examined with kolmogorov-smirnov test, and was performed on nih-cpsi/gupi subscales (pain, urinary symptoms, quality of life) and total results, stratifying the analysis for: covid-19 infection status, economic consequences, quarantine measures, and hdrs total score. finally, kruskal-wallis h test was performed to compare hdrs score grading (0-7: no depression; 817: mild depression; 18-24: moderate depression; > 24: severe depression) to nih-cpsi/gupi parameters. all statistical analyses were performed using international business machines corporation statistical product and service solutions (ibm spss) software for windows (version 25.0., ibm corp, armonk, ny, usa). statistical significance was defined as p < 0.05. results a total of 356 out of 461 subjects fully completed the survey, for a completion rate of 77.2%. descriptive statistics obtained are reported in table 1. covid-19 infection status we compared the results of nih-cpsi/gupi and hdrs in subjects with diagnosed (n = 4), negative (n = 329) and suspected (n = 23) covid-19 infection. covid-19 infection status reported statistically significant differences for pain (h(2) = 6.825, p = 0.033) and quality of life (h(2) = 6.187, p = 0.045) subscales, while no statistically significant differences were reported for urinary symptoms subscale (h(2) = 0.716, p = 0.699), total score (h(2) = 5.667, p = 0.059) and hdrs score (h(2) = 3.491, p = 0.175). in particular, negative infection status subjects reported in pain subscale a mean rank of 178.64 table 1. descriptive statistics of subjects involved. mean standard deviation age 36.49 12.236 height (in m) 1.70 0.08 weight 72.28 17.11 bmi 24.77 4.65 frequency percentage sex male 182 51.1 female 174 48.9 marital status single 201 56.5 married/in a couple 135 37.9 divorced 16 4.5 widow/widower 4 1.1 education level low 10 2.8 medium 110 30.9 high 236 66.3 working status employed 237 66.6 unemployed 119 33.4 covid-19 infection status negative 329 92.4 suspicion 23 6.5 positive 4 1.1 economic consequences financial hardship 113 31.3 job loss 13 3.6 quarantined 68 19.1 diabetes 10 2.8 hypertension 30 8.4 obese 20 5.6 depression 7 2 asthma 34 9.6 copd 3 0.8 cardiovascular disease 10 2.8 alcohol 76 21.3 smoking 103 28.9 archivio italiano di urologia e andrologia 2022; 94, 1 b. barone, l. de luca, l. napolitano, et al. 48 while suspicious infection status subjects reported a mean rank of 158.65 and, finally, positive infection status subjects reported a mean rank of 281.13. analogously, negative infection status subjects reported in quality-of-life subscale a mean rank of 179.97 compared to suspicious infection status subjects (mean rank of 143) and positive infection status subjects (mean rank of 261.88). economic consequences we compared the results of nih-cpsi/gupi and hdrs in subjects who suffered financial hardship (n = 113) or job loss (n = 13) compared to no economic consequences (n = 230). economic consequences were classified as none, financial hardship, or job loss. statistically significant differences were reported for urinary symptoms (h(3) = 11.731, p = 0.008), quality of life (h(3) = 10.301, p = 0.016), total score (h(3) = 14.537, p = 0.002) and hdrs score (h(3) = 20.706, p = 0.000), while no statistically significant difference was reported for pain subscale (h(3) = 6.242, p = 0.100). mean ranks for urinary symptoms were 165.27 for no economic consequences, 204.9 for financial hardship and 175.46 for job loss. mean ranks for quality of life were, similarly: 167.68 (no consequences), 193.12 (financial hardship) and 237.85 (job loss). mean ranks for total score were 163.01 (no consequences), 205.54 (financial hardship), and 212.69 (job loss). finally, mean rank for hdrs score were 158.88 (no consequences), 209.19 (financial hardship), and 226.35 (job loss). quarantine measures we compared the results of nih-cpsi/gupi and hdrs in subjects who underwent to quarantine measures (n = 68) compared to who had no restrictions (n = 288). hdrs score was statistically significant different between subjects who underwent to quarantine measures (e.g: direct contact with infected patients) and not (h(1) = 7.179, p = 0.007), reporting a mean rank of 208.53 for subjects in quarantine versus 171.41 for those who underwent no measures. no statistically significant differences were instead reported for pain (h(1) = 3.130, p = 0.077), urinary symptoms (h(1) = 0.596, p = 0.440) and quality of life subscales (h(1) = 2.616, p = 0.106). similarly, no statistically significant difference was reported for nihcpsi/gupi total score (h(1) = 2.088, p = 0.148) hdrs score grading according to hdrs score grading, we divided subjects in four groups: no depression (n = 187), mild depression (n = 133), moderate depression (n= 26) and severe depression (n = 10). we further correlated hdrs score grading with nih-cpsi/gupi results, reporting statistically significant differences for pain (h(3) = 40.093, p = 0.000), urinary symptoms (h(3) = 42.150, p = 0.000), quality of life (h(3) = 48.638, p = 0.000) and total score (h(3) = 66.480, p = 0.000). in particular, mean ranks for pain were 155.02 for no depression, 195.76 for mild depression, 217.10 for moderate depression and 287.70 for severe depression. similarly, mean ranks for urinary symptoms were 147.97 (no depression), 203.04 (mild depression), 245.33 (moderate depression) and 249.40 (severe depression). mean ranks for quality of life were similarly: 148.84 (no depression), 198.70 (mild depression), 249.77 (moderate depression) and 279.10 (severe depression). finally, mean ranks for total score were 140.25 (no depression), 208.18 (mild depression), 254.56 (moderate depression) and 301.35 (severe depression). discussion the covid-19 pandemic has embodied several stresses such as loss of employment, deaths of family members, friends, or colleagues, financial insecurity, and isolation from others (14). the social isolation, the fear of contagion and the imposed limitations, have created a fertile substrate for anxiety and post-traumatic stress disorders development (15). in addition, the impossibilities to work, socialize with others and to engage in physical activities produced increased distress levels and contributed to overall decline in health, further aggravating the psychobiological impact of the outbreak (16). stressful events could alter body homeostasis, triggering and/or aggravating several pathologies and diseases (17). however, if this relation is well-known and demonstrated for gastrointestinal, dermatologic and cardiovascular diseases, interactions between elevated stress levels and urological conditions remain controversial (18). in the urological field, covid-19 pandemic has increased sexual disturbances, as reported by the decreased erectile function and increased premature ejaculation incidence in men, together with a decreased pde5i interest (as reported on google trend analysis) (19, 20). regarding urinary disturbances, animal models have indeed shown how social stress could impair bladder function, up to developing a proper generalised bladder mucosal inflammation (21). a study by ullrich et al. showed on men with bph a worsening of symptoms when subjects were exposed to standardized laboratory stress tasks (22). similarly in women, the prevalence of overactive bladder and other luts were increased among subjects with increased occupational stress (23). lower urinary tract symptoms (luts) conversely, have been associated with acute and chronic stress, and with other stress-related pathologies, such as gastroenterological complaints, irritable bowel syndrome, vulvodynia, dyspareunia and even odontostomatological conditions (24, 25). due to these premises, we evaluated the relationship between stressful events, as covid-19 worldwide pandemic, and urological manifestations, excluding subjects with explainable causes for luts. furthermore, we analysed how mental health correlated with luts. in addition, although we reported in our cohort of subjects different comorbidities which could have impacted the results of our survey, none of them reached the statistical significance at the statistical analysis. regarding covid-19 infection status, we reported increased nih-cpsi/gupi score for pain and quality of life subscales in subjects with active or suspicion infection. although we suggest that these results were associated more with the stressful event itself rather than a direct interaction of coronavirus, our data is consistent with recent hypotheses reported in literature. dhar et al. indeed, reported 39 covid-19 patients who developed 49archivio italiano di urologia e andrologia 2022; 94, 1 luts and mental health during covid-19 pandemic de novo urinary symptoms while kaya et al. similarly, reported 46 covid-19 patients with increased storage symptoms during hospitalization (26, 27). however, due to the limited number of subjects diagnosed with covid-19 infection in our study, the results obtained are obviously weakened and limited. when economic consequences of lockdown and worldwide pandemic were analysed, we reported increased score in urinary symptoms and quality of life subscales together with an increased overall nih-cpsi/gupi score. hdrs score was increased as well. although the definition of financial hardship is quite subjective, job and financial insecurity have serious consequences on physical and mental health of individuals (28). among several adverse health outcomes, increased psychosomatic symptoms as anxiety and depression are reported(29). the presence of increased hdrs score for subjects with financial hardship or job loss was indeed perfectly consistent with data reported in literature. similarly, subjects which suffered financial hardship or job loss during lockdown reported increased urinary symptoms and a worsened quality of life. also in this case, we suggest that the increased psychological burden linked to the difficult socioeconomical situation influenced symptoms manifestations (30). similarly, when quarantine measures were considered, hdrs score increased in subjects quarantined. as reported by giallonardo et al., social distancing and quarantine have detrimental effects on mental health, both in general population and in psychiatric patients, thus confirming the consistence of our data (31). no significant differences in nih-cpsi/gupi score however were reported. finally, we correlated hdrs score with nih-cpsi/gupi score. we reported significant differences for every subscale and total score. as far as we know, there is only a study correlating hdrs score and luts: skalski et al. used hdrs and ipss score on 102 patients treated for depression, reporting a significant correlation between severity of depressive symptoms and severity of luts (32). our study confirms this correlation, showing increasing nih-cpsi/gupi score with increasing results of hdrs score. we are conscious of several limitation of our study: firstly, the retrospective and self-reported nature or our study; secondly, a relatively low sample size for exploring interactions between covid-19 infection or quarantine measures and luts; thirdly, the geographical limitation of our results; fourthly, an overall low mean age which could represent the decreased and heterogeneous use of internet-based instruments of older subjects, potentially excluding them from our study (33). finally, the restricted number of properly diagnosed covid-19 patients limits the reliability of our results regarding covid-19 and urinary symptoms. conclusions covid-19 pandemic has provoked notable alterations in everyday life. although general lockdown, quarantine and social distancing have been necessary in order to prevent virus spreading, detrimental effects of strict lockdown could have long term effects on population in terms of mental and physical health. the association between stressful events and increased luts has been explored during lockdown in southern italy, confirming a preponderant role of stress and anxiety in luts development and suggesting a bidirectional relationship between mental health and urological symptoms. further studies are required to fully evaluate this relationship and explore the direct effect of sars-cov-2 on luts. references 1. guan wj, ni zy, hu y, et al. clinical characteristics of coronavirus disease 2019 in china. n engl j med. 2020; 382:1708-20. 2. creta m, sagnelli c, celentano g, et al. sars-cov-2 infection affects the lower urinary tract and male genital system: a systematic review. j med virol. 2021; 93:3133-3142. 3. napolitano l, barone b, crocetto f, et al. the covid-19 pandemic: is it a wolf consuming fertility? int j fertil steril. 2020; 14:159-160. 4. world health o. novel coronavirus (2019-ncov): situation report, 19. geneva: world health organization, 2020 2020-02-08. report no. 5. rossi r, socci v, talevi d, et al. covid-19 pandemic and lockdown measures impact on mental health among the general population in italy. front psychiatry. 2020; 11:790. 6. breyer bn, cohen be, bertenthal d, et al. lower urinary tract dysfunction in male iraq and afghanistan war veterans: association with mental health disorders: a population-based cohort study. urology. 2014; 83:312-9. 7. martin s, vincent a, taylor aw, et al. lower urinary tract symptoms, depression, anxiety and systemic inflammatory factors in men: a population-based cohort study. plos one. 2015; 10:e0137903. 8. bosak k, park sh. characteristics of adults' use of facebook and the potential impact on health 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for adults with major depressive disorder using equipercentile linking to clinical global impression scale ratings: analysis of pharmacogenomic research network antidepressant medication pharmacogenomic study (pgrn-amps) data. hum psychopharmacol. 2016; 31:185-92. 14. sani g, janiri d, di nicola m, et al. mental health during and after the covid-19 emergency in italy. psychiatry and clinical neurosciences. 2020; 74:372. 15. castelli l, di tella m, benfante a, romeo a. the spread of covid-19 in the italian population: anxiety, depression, and posttraumatic stress symptoms. can j psychiatry. 2020; 65:731-732. 16. stanton r, to qg, khalesi s, et al. depression, anxiety and stress archivio italiano di urologia e andrologia 2022; 94, 1 b. barone, l. de luca, l. napolitano, et al. 50 during covid-19: associations with changes in physical activity, sleep, tobacco and alcohol use in australian adults int j environ res public health 2020; 17:4065. 17. yaribeygi h, panahi y, sahraei h, et al. the impact of stress on body function: a review. excli j. 2017; 16:1057-72. 18. dimsdale je. psychological stress and cardiovascular disease. j am coll cardiol. 2008; 51:1237-46. 19. deger md, madendere s. erectile dysfunction treatment with phosphodiesterase-5 inhibitors: google trends analysis of last 10 years and covid-19 pandemic. arch ital urol androl. 2021; 93:361-5. 20. ates e, kazici hg, yildiz ae, et al. male sexual functions and behaviors in the age of covid-19: evaluation of mid-term effects with online cross-sectional survey study. arch ital urol androl. 2021; 93:341-7. 21. mingin gc, peterson a, erickson cs, et al. social stress induces changes in urinary bladder function, bladder ngf content, and generalized bladder inflammation in mice. am j physiol regul integr comp physiol. 2014; 307:r893-r900. 22. ullrich pm, lutgendorf sk, kreder kj. physiologic reactivity to a laboratory stress task among men with benign prostatic hyperplasia. urology. 2007; 70:487-92. 23. zhang c, hai t, yu l, et al. association between occupational stress and risk of overactive bladder and other lower urinary tract symptoms: a cross-sectional study of female nurses in china. neurourol urodyn 2013; 32:254-60. 24. li z, huang w, wang x, zhang y. the relationship between lower urinary tract symptoms and irritable bowel syndrome: a metaanalysis of cross-sectional studies. minerva urol nefrol. 2018; 70:386-92. 25. crocetto f, coppola n, barone b, et al. the association between burning mouth syndrome and urologic chronic pelvic pain syndrome: a case-control study. j oral pathol med 2020; 49:829-34. 26. dhar n, dhar s, timar r, et al. de novo urinary symptoms associated with covid-19: covid-19-associated cystitis. j clin med res. 2020; 12:681-2. 27. kaya y, kaya c, kartal t, et al. could luts be early symptoms of covid-19. int j clin pract. 2020:e13850. 28. nella d, panagopoulou e, galanis n, et al. consequences of job insecurity on the psychological and physical health of greek civil servants. biomed res int 2015; 2015:673623. 29. mucci n, giorgi g, roncaioli m, et al. the correlation between stress and economic crisis: a systematic review. neuropsychiatr dis treat. 2016; 12:983-93. 30. alradhawi m, shubber n, sheppard j, ali y. effects of the covid-19 pandemic on mental well-being amongst individuals in societya letter to the editor on "the socio-economic implications of the coronavirus and covid-19 pandemic: a review". int j surg 2020; 78:147-8. 31. giallonardo v, sampogna g, del vecchio v, et al. the impact of quarantine and physical distancing following covid-19 on mental health: study protocol of a multicentric italian population trial. front psychiatry. 2020; 11:533 32. skalski m, przydacz m, sobanski ja, et al. coexistence of lower urinary tract symptoms (luts) with depressive symptoms in patients suffering from depressive disorders. psychiatria polska. 2019; 53:939-53. 33. van boekel lc, peek st, luijkx kg. diversity in older adults' use of the internet: identifying subgroups through latent class analysis. j med internet res. 2017; 19:e180. correspondence biagio barone, md biagio.barone@unina.it luigi de luca, md luigideluca86@gmail.com luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com pasquale reccia, md reccia.pasquale1@gmail.com felice crocetto, md felice.crocetto@unina.it massimiliano creta, md max.creta@gmail.com raffaele vitale, md r.vitale0210@gmail.com vincenzo francesco caputo, md vincitor@me.com raffaele martino, md raffaele.martino88@yahoo.it luigi cirillo, md cirilloluigi22@gmail.com giovanni maria fusco, md giomfusco@gmail.com massimiliano trivellato, md massimiliano.trivellato@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com roberto la rocca, md robertolarocca87@gmail.com domenico prezioso, md domenico.prezioso2@unina.it nicola longo, md nicolalongo.20@yahoo.it department of neurosciences, reproductive and odontostomatological sciences of university of naples "federico ii", naples, italy stesura seveso 345archivio italiano di urologia e andrologia 2022; 94, 3 review no conflict of interest declared. antagonists (a-blockers) plus 5-alpha reductase inhibitors is the standard medical therapy for bph, since the trial medical therapy for prostatic symptoms (mtops) exhibited lower rates of bph clinical progression in individuals who received this pharmacotherapy versus those who received placebo (1, 6). pharmacotherapy can be associated with adverse drug events, which can be harmful especially in frail individuals, such as orthostatic hypotension, falls, depression and suicidal ideation (1, 7-11). alpha-blockers act by decreasing smooth muscle tone in the prostate gland and bladder neck, while 5-alpha reductase inhibitors act by decreasing the volume of the prostate (1, 12). thus, the use of 5-a reductase inhibitors is not indicated in patients with low-volume prostate glands, as they will not have any particular benefit (1). frailty, is a clinical syndrome that can lead to increased side effects of pharmacotherapy and more rapid symptom progression, thus altering the balance of the potential harms and benefits of each intervention undertaken (1, 2, 13, 14). luts, affecting more than 50% of the male geriatric population, lead to a reduced quality of life and increased risk of falls, thus contributing to overall mortality (15-18). luts in the elderly population can be multifactorial, having as causality non urologic causes including psychosomatic manifestations (16, 19). the difficulty of diagnosing and treating this urologic syndrome has been the hallmark of the effort to associate this complex entity with a novel age related risk factor, namely frailty (16). methods in this non-systematic review, pubmed and medline databases were thoroughly searched from 1990 to march of 2022, using the terms: “benign prostatic hyperplasia” and “frailty” or “decreased muscle mass”. databases were screened independently by one author and rechecked by other two authors. any disputes were solved by a fourth author (figure 1). from the studies screened, the original studies, as shown in table 1, were used in order to conduct the investigation of the potential interplay between the two entities under evaluation. studies concerning animal models were excluded. background: world population is aging. the number of individuals aged over 65 are expected to be 71 million only in the us. 43% of this population will be men. benign prostatic hyperplasia (bph), defined as the benign neoplasm of the prostate gland affects 8% of men by their forties, but 90% of men over 90 years old. lower urinary tract symptoms (luts) can be caused by an enlarged prostate, and it seems to be associated more with older and frailer individuals. methods: the purpose of this study is to review the potential interplay between frailty syndrome and benign prostatic hyperplasia. a thorough medline/pubmed non-systematic literature review was conducted from 1990 to march of 2022. the terms used for the search were “frailty and benign prostatic hyperplasia” and “low muscle mass and benign prostatic hyperplasia”. results: it seems that, frailty poses a negative impact on the prognosis of patients with bph, as it is associated with increased incidence of luts. in addition, frailty seems to be a strong predictor concerning surgical procedure failure and mortality following invasive procedures for bph. prostatic stent placement on the other hand appears to be the ideal solution for frail patients. conclusions: bph has a strong association with frailty and increasing age. key words: frailty; benign prostatic hyperplasia; transurethral resection of the prostate; transurethral laser induced prostatectomy; prostatic stent. submitted 26 june 2022; accepted 22 july 2022 introduction benign prostatic hyperplasia (bph) is the normal histological process of prostate gland enlargement due to aging and can lead, in many cases, to bladder outlet obstruction (13). in that case, bph in older men can cause lower urinary tract symptoms (luts) which can be treated, in the early stages, by medications (1, 2). one third of men older than 75 years old with newly diagnosed luts will begin pharmacotherapy for bph (1, 3). bph is common in older men, as 21% of men aged over 70 years old can experience nocturia, 22% can experience the feeling of incomplete bladder emptying and 57% a decrease in urinary stream pressure (4, 5). combination therapy with alpha-adrenergic receptor frailty and benign prostatic hyperplasia: the thrilling underlying impact themistoklis ch. bellos 1, lazaros i. tzelves 1, ioannis s. manolitsis 1, stamatios n. katsimperis 1, marinos v. berdempes 1, andreas skolarikos 1, nikolaos d. karakousis 2 1 2nd department of urology, sismanoglio general hospital of athens, athens, greece; 2 primary healthcare, internal medicine department, amarousion, attica, greece. doi: 10.4081/aiua.2022.3.345 summary archivio italiano di urologia e andrologia 2022; 94, 3 t. ch. bellos, l.i. tzelves, i.s. manolitsis, s.n. katsimperis, m.v. berdempes, a. skolarikos, n.d. karakousis 346 results according to bauer et al. frail patients were more likely to have higher american urological association symptom index (auasi) scores (p < 0.001) (both in voiding and storage sub-scores), higher maximum flow rate (p = 0.02) and decreased post-void residuals (p < 0.01) compared with robust individuals (1). serum psa (p = 0.61) and prostate volume (p = 0.15) were comparable between the groups (1). frail individuals experienced more pronounced adverse events (aes) from medications, which can stem from their overall worse status (higher body mass indexbmi), worse systolic blood pressure, worse physical and mental health, polypharmacy) (p < 0.01) in comparison with robust men of the same chronological age (1). frailty was not associated with risk for bph progression randomized in placebo or finasteride monotherapy (1). however, in the group receiving doxazosin monotherapy, frailty and pre-frailty seems to be more associated with clinical bph progression, as proven by the increased rates of indwelling catheters or acute urinary retention episodes (ahr: 2.64; 95%; ci: 0.86-7.1) (1). in another study of bauer et al., an association between phenotypic frailty and luts severity was demonstrated (3). in this study, the authors exhibited that the prevalence of moderate and severe luts was 46% and 13% respectively in frail men compared to 37% and 5% in robust men (moderate luts: hr: 1.4; 95%; ci: 1.1-1.7) (severe luts: hr: 2.5; 95%; ci: 1.8-3.6) (3). those data were independent concerning the age, comorbidities or luts treatment and persisted among men who did not experience urinary incontinence (3). compared to mild luts, the risk for mobility limitation was increased in people with moderate (hr: 1.35; 95% ci: 1.12-1.63) and severe luts (hr: 1.98; 95%; ci: 1.48-2.64) (20). patients with severe (hr: 1.62; 95%; ci: 1.07-2.43) and moderate luts (hr: 1.32; 95%; ci: 1.05-1.67) experienced more restrictions in daily activities (20). luts were not associated with limitation of cognitive tasks (20). in addition, another study by the same author demonstrated that the prevalence of frailty was higher in severe and moderate luts (7%, 11% and 18% for mild, moderate and severe luts respectively) (21). similarly, in a korean population study by jang et al., phenotypic frailty was prevalent in 43% of men with severe luts and in 16% and 7% of men with moderate and mild luts respectively (22). according to bauer et al., frail patients could be diagnosed more frequently with bph (22% vs 14% in non-frail individuals), overactive bladder (oab) (25% vs 11% in non-frail individuals) and mixed bph/oab (16% vs 12% in non-frail individuals) (16). moreover, people with bph were 1.7 times more likely to be assessed as frail (or: 1.70; 95%; ci: 1.14-2.55) with the tugt (timed up to go test) test (16). according to soma et al. frailty was positively associated with luts (hr: 2.13; 95%; ci: 2.48-3.06), oab (hr: 2.07; 95%; ci: 1.31-3.29) and higher prevalence of nocturia (23). according to eredics et al., intraoperative complications, duration of postoperative catheterization and length of hospitalization was identical in frail and non-frail patients undergoing transurethral resection of the prostate (turp) (24). however, success rate of surgery was 80.6% in fit and 75% in frail patients, while 3-month success rates were 95.2% and 83.3% for non-rail and frail respectively (24). post-void residual (pvr) was less than 50 ml in both cohorts (24). pichon et al., showed that frail patients had lower success rate at 3 months (55%) compared to non-frail patients (95%) (p < 0.05) following turp (25). the immediate postoperative success rate was 85% vs 41% in non-frail and frail cohorts respectively (25). higher morbidity was also noted in the frail groups compared to the control group (44% vs 15%) (p < 0.05) (25). suskind et al., demonstrated that 95% of nursing home patients who underwent de-obstructive surgery (turp or transurethral laser induced prostatectomy-tulip) were recatheterized at 12 months, whilst 30% of them have passed away (26). figure 1. flow chart. 347archivio italiano di urologia e andrologia 2022; 94, 3 frailty and benign prostatic hyperplasia: the thrilling underlying impact according to sethi et al., prostatic stent placement is more advantageous in frail patients with bladder outlet obstruction (boo); 62.5% of the patients had a significant pvr difference with 550 ml before the procedure and 80 ml postoperatively respectively (p < 0.0001) (27). two thirds of those patients continued to void without assistance (27); 37.5% experienced procedure failure with stent migration, occlusion, urinary retention refractory to the procedure and irritative voiding symptoms (27). discussion according to this non-systematic narrative review we concluded that it seems to be an increased incidence of frailty in the elderly patients experiencing severe and moderate luts, as measured by the auasi and international prostate symptom score (ipss) scales. frail catheterized patients, undergoing turp or tulip, have higher incidence of re-catheterization or even death. prostatic stents seem to have higher success rates in the frail and elderly. most of the studies included in this systematic review have large sample number. however, there are certain limitations. these studies may include heterogeneous population and use different tools of frailty quantification. most of the studies were observational, retrospective, and non-randomized, except one. even this study did not randomize patients based on frailty. all the aforementioned factors, necessitate the implementation of a larger multicenter randomized survey that uses a common tool for frailty assessment. increased age is one of the most common risk factors for luts (16, 28). although luts coexist with frailty, it is unknown which condition preexists, although many theories have been suggested for each temporal direction (16). with increasing age, several genitourinary and neural changes coexist, that can lead to decreased bladder capacity and increased bladder sensation (16, 29). luts can interfere with daily routine table 1. studies concerning the potential interplay between bph and frailty. authors (ref) year, study study population findings exclusion criteria frailty assessed by: bph/luts progression assessed by: bauer (1) bauer (16) bauer (20) eredics (24) sethi (27) bauer (21) jang (22) soma (23) pichon (25) suskind (26) 2021, rct 2021, prospective 2021, retrospective 2020, retrospective 2017, retrospective 2020, retrospective 2018, cross-sectional 2019, retrospective 2017, prospective 2016, retrospective 3047 men, who were treated with doxazosin monotherapy, finasteride monotherapy, placebo or combination 2026 men over 65 years with bph, oab, mixed bph/oab 2716 men ≥ 71 years 54 patients ≥ 75 years who underwent turp 144 patients with obstructive urinary symptoms or indwelling catheter who had a memokath stent inserted 5,979 men ≥ 65 years 492 men ≥ 65 years and were ambulatory 710 people ≥ 60 years 60 patients ≥ 60 years who underwent turp 2869 nursing home residents aged ≥ 65 years who underwent turp or tulip frailty independently associated with bph clinical progression and aes higher incidence of those diagnosis in frail patients vluts severity is associated with mobility and adl limitations among older men fit patients benefit from turp while frail do not prostatic stent is superior to turp for frail patients higher incidence of phenotypic frailty among elderly with moderate and severe luts the prevalence of frailty and other geriatric conditions higher in those with severe urologic symptoms people with luts more frail patients without urinary catheter, patients with prostate cancer, psa > 15 ng/ml ,patients unfit for anesthesia, patients with prior prostatic surgery poor baseline functional status and having foley catheter preoperative is associated with higher risk of turp or tulip failure anticholinergic except glaucoma cancer, neurologic disease, indwelling catheter, continuous incontinence baseline self-reported functional limitations not mentioned not mentioned not mentioned patients living in a nursing home, hospitalized or bed riden not mentioned geriatric assessment can predict the outcome of turp in the elderly not mentioned fi containing 68 potential deficits tugt 1. mobility (2-3 blocks or 10 steps) 2. adl (any difficulty bathing, showering or transferring) 3. cognition 7 item chsa frailty scale not mentionedphysician or anesthesiologist assessment/ not suitable for turp cardiovascular health study index (low mean mass, weakness, exhaustion, slowness and low physical activity) frailty phenotype (exhaustion, inactivity, slowness, weakness and weight loss) fp, fds, mfi bga, cga adl, survival after surgery, foley catheter status auasi scale (luts progression, acute urinary retention, urinary incontinence, uti or sepsis, increase of serum creatinine at least 1.5 mg/dl attributable to bph) based on database diagnosis divided into bph, oab, mixed bph/oab auasi already diagnosed already diagnosed auasi score ipss questionnaire ipss questionnaire already diagnosed already diagnosed rct: randomized control trial; bph: benign prostatic hyperplasia; aes: adverse events; fi: fried index; auasi: american urological association symptom index; uti: urinary tract infection; oab: overactive bladder; tugt: timed up to go test; adl: activities of daily living; turp: transurethral resection of the prostate; chsa: canadian study of health and aging; ipss: internation prostate symptom score; fp: frailty phenotype; fds: frailty discriminant score; mfi: modified frailty index; bga: brief geriatric assessment; cga: comprehensive geriatric assessment; tulip: transurethral laser induced prostatectomy. archivio italiano di urologia e andrologia 2022; 94, 3 t. ch. bellos, l.i. tzelves, i.s. manolitsis, s.n. katsimperis, m.v. berdempes, a. skolarikos, n.d. karakousis 348 and daily exercise thus increasing the risk of frailty (16, 30, 31). luts and frailty can be caused by a common mechanism, which includes insulin resistance and increased inflammatory markers, which are probably associated with luts progression (16, 32, 33). aging is associated with an increase in fat mass and decline of muscle mass and strength (34, 35). muscle mass decreases 35% between the age of 20 and 80 years old (34). loss of strength can subsequently lead to physical function impairment and increased vulnerability (34, 36). multimorbidity is a common trait among the geriatric population (37). frailty can be defined as the accumulation of health deficits and functional problems which are thought to lead to greater susceptibility to physical stressors (1). this is caused by the depletion of body physical reserves (1). frailty can encompass also cognitive and psychosocial changes associated with many conditions (1). according to a recent medical consensus, frailty is defined as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death” (1). although frailty encompasses chronological age in its definition, it is a more accurate marker of biological age (1). associations between chronological age and bph are well established. however, associations between bph and frailty or even biological age have been scarce till now (1). the most common clinical characteristics of frailty include weakness and slowness, which are usually associated with storage luts in older women (16). frailty preponderance is 36-88% depending of the measurement used (4). there are many tools and indexes used to assess frailty. one of the most common tools was developed by fried et al. (4). this assessment concerns the frailty phenotype and is based on the cardiovascular health study. this model assesses muscle mass decline, strength, endurance, balance, walking performance and low physical activity (4). other indexes and scores of frailty used are the frailty index of accumulative deficits (ficd), the geriatric 8 score (g8 score), the simplified fiveitem index (sfi), the american society of anesthesiologists (asa) physical status classification, the mini-cognitive test (mini-cog), the clinical frailty scale (cfs), the eastern cooperative oncology group (ecog) performance status, the cumulative illness score rating-geriatrics (cisr-g), the charlson comorbidity index (cci), the study of osteoporotic fractures (sof) index, the “fatigue, resistance, ambulation, illness, loss of weight” (frail) index, the comprehensive geriatric assessment (cga) and the multidimensional prognostic index (mpi) (38-41). there has been a novel effort in hypogonadal frail patients to reduce the frailty symptoms with the use of testosterone replacement therapy (34, 42, 43). however, testosterone use is not devoid of complications with more striking negative effects on cardiovascular system quite possibly due to polycythemia (34, 42, 43). the hypothesis for increased probability for prostate cancer on testosterone replacement therapy has not yet been proven (34, 42, 43). novel compounds termed selective androgen receptor modulators (sarms) that act selectively on androgen receptor could revolutionize testosterone replacement therapy (2). it seems they could provide the anabolic effects without the possible complications (2). however, more studies are needed to validate this. conclusions older men presenting with non-neurogenic luts to a urology clinic are more likely to be frail. frailty is a systemic marker of biological age that can possibly mediate a good association between chronological age and symptoms of bph. currently, frailty and other markers of increased biological age are not targeted by any intervention meant for bph, as most of them take into account only the mechanism of prostatic obstruction. the only intervention with clinical benefit could be prostatic stent placement. therefore, screening older men with luts using simple tests and indexes, would be appropriate when the presence of frailty could change the diagnosis or even the treatment. this approach could lead to the development of new therapeutic strategies incorporating specific measures targeting frailty per se such as physical activity, nutritional intervention or even individually tailored geriatric models. references 1. bauer sr, walter lc, ensrud ke, et al. assessment of frailty and association with progression of benign prostatic hyperplasia symptoms and serious adverse events among men using drug therapy. jama netw open. 2021; 4:e2134427. 2. omwancha j, brown tr. selective androgen receptor modulators: in pursuit of tissue-selective androgens. current opinion in investigational drugs. 2006; 7:873-81. 3. welliver c, feinstein l, ward jb, et al. trends in lower urinary tract symptoms associated with benign prostatic hyperplasia, 2004 to 2013: the urologic diseases in america project. j urol. 2020; 203:171-8. 4. suskind am. frailty and lower urinary tract symptoms. curr urol rep 2017; 18:67. 5. platz ea, smit e, curhan gc, nyberg lm, giovannucci e. prevalence of and racial/ethnic variation in lower urinary tract symptoms and noncancer prostate surgery in u.s. men. urology. 2002; 59:877-83. 6. mcconnell jd, roehrborn cg, bautista om,, et al. the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. new engl j med. 2003; 349:2387-98. 7. oelke m, becher k, castro-diaz d, et al. appropriateness of oral drugs for long-term treatment of lower urinary tract symptoms in older persons: results of a systematic literature review and international consensus validation process (luts-forta 2014). age ageing. 2015; 44:745-55. 8. welk b, mcarthur e, fraser la, et al. the risk of fall and fracture with the initiation of a prostate-selective alpha antagonist: a population based cohort study. bmj 2015; 351:h5398. 9. coupland cac, hill t, dening t, et al. anticholinergic drug exposure and the risk of dementia: a nested case-control study. jama intern med. 2019; 179:1084-93. 10. sarkar rr, parsons jk, bryant ak, et al. association of treatment with 5alpha-reductase inhibitors with time to diagnosis and mortality in prostate cancer. jama intern med. 2019; 179:812-9. 11. duan y, grady jj, albertsen pc, helen wu z. tamsulosin and 349archivio italiano di urologia e andrologia 2022; 94, 3 frailty and benign prostatic hyperplasia: the thrilling underlying impact the risk of dementia in older men with benign prostatic hyperplasia. pharmacoepidemiol drug saf. 2018; 27:340-8. 12. abrams p, chapple c, khoury s,, et al. evaluation and treatment of lower urinary tract symptoms in older men. j urol. 2013; 189(1 suppl):s93-s101. 13. walston j, bandeen-roche k, buta b, et al. moving frailty toward clinical practice: nia intramural frailty science symposium summary. j am geriatr soc. 2019; 67:1559-64. 14. platz ea, joshu ce, mondul am, et al. incidence and progression of lower urinary tract symptoms in a large prospective cohort of united states men. j urol. 2012; 188:496-501. 15. wei jt, calhoun e, jacobsen sj. urologic diseases in america project: benign prostatic hyperplasia. j urol. 2008; 179(5 suppl):s75-80. 16. bauer sr, jin c, kamal p, suskind am. association between lower urinary tract symptoms and frailty in older men presenting for urologic care. urology. 2021; 148:230-4. 17. noguchi n, chan l, cumming rg, et al. a systematic review of the association between lower urinary tract symptoms and falls, injuries, and fractures in community-dwelling older men. aging male. 2016; 19:168-74. 18. akerla j, pesonen js, poyhonen a, et al. impact of lower urinary tract symptoms on mortality: a 21-year follow-up among middleaged and elderly finnish men. prostate cancer prostatic dis. 2019; 22:317-23. 19. lepor h. pathophysiology of lower urinary tract symptoms in the aging male population. rev urol. 2005; 7 suppl 7:s3-s11. 20. bauer sr, cawthon pm, ensrud ke, et al. lower urinary tract symptoms and incident functional limitations among older community-dwelling men. j am geriatr soc. 2022; 70:1082-1094 21. bauer sr, scherzer r, suskind am, et al. co-occurrence of lower urinary tract symptoms and frailty among communitydwelling older men. journal of the american geriatrics society. 2020; 68:2805-13. 22. jang iy, lee ck, jung hw, et al. urologic symptoms and burden of frailty and geriatric conditions in older men: the aging study of pyeong chang rural area. clin interv aging. 2018; 13:297-304. 23. soma o, hatakeyama s, imai a, et al. relationship between frailty and lower urinary tract symptoms among communitydwelling adults. low urin tract symptoms 2020; 12:128-36. 24. eredics k, meyer c, gschliesser t, et al. can a simple geriatric assessment predict the outcome of turp? urol. int. 2020; 104:367-72. 25. pichon t, lebdai s, launay cp,, et al. geriatric assessment can predict outcomes of endoscopic surgery for benign prostatic hyperplasia in elderly patients. j endourol. 2017; 31:1195-202. 26. suskind am, walter lc, zhao s, finlayson e. functional outcomes after transurethral resection of the prostate in nursing home residents. j am geriatr soc. 2017; 65:699-703. 27. sethi k, bozin m, jabane t, et al. thermo-expandable prostatic stents for bladder outlet obstruction in the frail and elderly population: an underutilized procedure? investig clin urol. 2017; 58:447-52. 28. coyne ks, wein aj, tubaro a, et al. the burden of lower urinary tract symptoms: evaluating the effect of luts on health-related quality of life, anxiety and depression: epiluts. bju international. 2009; 103 suppl 3:4-11. 29. suskind am. the aging overactive bladder: a review of agingrelated changes from the brain to the bladder. curr bladder dysfunct rep. 2017; 12:42-7. 30. silva v, grande aj, peccin ms. physical activity for lower urinary tract symptoms secondary to benign prostatic obstruction. cochrane database syst rev. 2019; 4:cd012044. 31. coyne ks, sexton cc, kopp z, et al. assessing patients' descriptions of lower urinary tract symptoms (luts) and perspectives on treatment outcomes: results of qualitative research. international journal of clinical practice. 2010; 64:1260-78. 32. russo gi, castelli t, urzi d, et al. emerging links between nonneurogenic lower urinary tract symptoms secondary to benign prostatic obstruction, metabolic syndrome and its components: a systematic review. int j urol. 2015; 22:982-90. 33. siddiqui ny, helfand bt, andreev vp, et al. biomarkers implicated in lower urinary tract symptoms: systematic review and pathway analyses. j urol. 2019; 202:880-9. 34. hijazi ra, cunningham gr. andropause: is androgen replacement therapy indicated for the aging male? annu rev med. 2005; 56:117-37. 35. bhasin s, buckwalter jg. testosterone supplementation in older men: a rational idea whose time has not yet come. j androl. 2001; 22:718-31. 36. roubenoff r, hughes va. sarcopenia: current concepts. the journals of gerontology series a, biological sciences and medical sciences. 2000; 55:m716-24. 37. dartigues jf, le bourdonnec k, tabue-teguo m, et al. co-occurrence of geriatric syndromes and diseases in the general population: assessment of the dimensions of aging. j nutr health aging. 2022; 26:37-45. 38. pyrgioti ee, karakousis nd. b12 levels and frailty syndrome. j frailty sarcopenia falls. 2022; 7:32-7. 39. kostakopoulos na, karakousis nd. frailty assessment and postoperative complications in urologic oncology operations. j frailty sarcopenia falls. 2020; 5:57-61. 40. pilotto a, custodero c, maggi s, et al. a multidimensional approach to frailty in older people. ageing res rev. 2020; 60:101047. 41. dent e, kowal p, hoogendijk eo. frailty measurement in research and clinical practice: a review. european journal of internal medicine. 2016; 31:3-10. 42. hackett gi. testosterone replacement therapy and mortality in older men. drug saf. 2016; 39:117-30. 43. tan rs, salazar ja. risks of testosterone replacement therapy in ageing men. expert opin drug saf. 2004; 3:599-606. correspondence themistoklis bellos md (corresponding author) bellos.themistoklis@gmail.com lazaros tzelves, md lazarostzelves@gmail.com ioannis manolitsis, md giannismanolit@gmail.com marinos berdempes, md marinosberdebes@hotmail.com andreas skolarikos, md andskol@yahoo.com nikolaos d. karakousis, md karak2727@gmail.com sismanogliou 1, 2nd department of urology, sismanoglio general hospital of athens, 15126 athens, greece stamatios katsimperis, md stamk1992@gmail.com primary healthcare, internal medicine department, amarousion, attica, greece stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4380 original paper no conflict of interest declared. sels can be disastrous, resulting in massive bleeding that requires blood transfusions and opening the abdomen in the most hustle way to save lives. so hilar dissection and control of renal vessels are the most critical steps in laparoscopic nephrectomy. multiple techniques have been utilized for these steps and several studies have reported their experience with renal pedicle control (2-9). rapp et al. used the technique of en bloc hilar ligation. they deployed a stapler across the renal hilum without individual dissection of the renal artery and vein (9). resorlu et al. found that en bloc ligation of both the renal artery and vein using a stapler is an easy and reliable technique that allows safe and fast control of the renal pedicle during laparoscopic nephrectomy (2). this technique is successful also in laparoscopic nephroureterectomy, without the need for separation between the renal vessels (8). the hilar dissection is even more difficult in laparoscopic nephrectomy after past surgeries (10-11), or in cases with an inflammatory process such as xanthogranulomatous pyelonephritis (xgp) (12). to the best of our knowledge, gd had not been used for this purpose (we explored research published in pubmed and medline). articles were published using the gd in laparoscopic sacrocolpopexy (13) and during liver surgery (14-15). since there have been previous reports of gia malfunction, there has been an attempt to safely and inexpensively use both wires and hem-o-loc clips simultaneously for renal vein control (6). patients and methods from july 2002 to october 2020, all patients that underwent laparoscopic nephrectomy by the same surgeon were examined. out of 525 cases undergoing laparoscopic nephrectomy, there were 288 consecutive cases, which had a transperitoneal approach and had all the necessary information according to the working protocol. the cases were divided into two groups. in the first group (i), a flexible goldfinger dissector (goldfinger dissectorethicon endo surgery, johnson and johnson, new brunswick, nj, usa) was used for the dissection of the renal hilum and a vascular stapler (endo gia universal vascular stapler, objective: to test the employment of the goldfinger dissector (gd) to bypass and en bloc stapling of renal hilus without vascular dissection. thus far no study has experimented the use of this integrated technique. patients and methods: from july 2002 to october 2020, clinical data were collected from 288 patients who underwent transperitoneal laparoscopic nephrectomies. they were divided into two groups: using gd with en bloc stapling (n = 174, group i) or the separation and ligation method (n = 114, group ii) using the same endo gia universal (vascular) stapler. comparative analysis was carried out between the two groups, examining blood loss, operative time, intra and postoperative complications and hospital stay. results: the mean age was 58.3 and 55.1 years in group i and ii, respectively. ratio of 90/84 and 55/59 males/females was found in group i and ii, respectively.blood loss was 65.5 ml and 188.9 ml, operative time was 156.5 and 189.2 minutes, wound infection occurred in three patients in each group (1.7% and 2.6%), ileus in 4 (2.3%) and 1 (0.87%), atrial fibrillation in 1 (0.57%) and 0%, incisional hernia in 0 (0%) and 2 (1.75%), deep vein thrombosis (dvt) in 0 (0%) and 1 (0.87%), conversion to open surgery in 2 (1.15%) and 5 (4.39%), mean hospital stay 3.5 days and 4 days in group i and ii, respectively. conclusions: routine use of the gd and en bloc stapling of the renal pedicle in laparoscopic nephrectomy is safe and useful. this technique can decrease blood loss, operative time, and have some benefit in conversion to open surgery. key words: goldfinger dissector; laparoscopic nephrectomy; en bloc; gia vascular stapler; hilum dissection. submitted 25 november 2022; accepted 2 december 2022 introduction since the original report of a successful laparoscopic nephrectomy by clayman et al. in 1991, laparoscopic nephrectomy has become an alternative to traditional open surgery (1). this procedure is considered technically difficult because of the vessel injury risk, leading to massive hemorrhage during renal pedicle management (2). there is no doubt that the main and dangerous part of laparoscopic nephrectomy is the dissection of the kidney blood vessels, as minimal trauma of the large blood vesgoldfinger bypassing and en bloc stapling without dissection of renal vessels during laparoscopic nephrectomy murad asali 1, 2, muhammad asali 3, 4, 5 1 urology department, barzilai medical center, ben gurion university of the negev, beer sheva, israel; 2 assuta medical center, beer sheva, ramat hyal, ben gurion university of the negev, beer sheva, israel; 3 international school of economics, tbilisi, georgia; 4 iza, bonn, germany; 5 school of international and public affairs, columbia university, new york. doi: 10.4081/aiua.2022.4.380 summary 381archivio italiano di urologia e andrologia 2022; 94, 4 stapling of renal vessel during laparascopic nephrectomy medtronic parkway minneapolis, mn, usa) was used to close and cut the kidney hilus without separating the renal vessels. in the second group (ii) a dissection of the blood vessels was carried out, and the closure of the renal artery and renal vein separately was done with the same previously cited stapler. there were various causes for nephrectomy including cancers, benign tumours or dysfunctional kidneys. all cases were operated by one surgeon (ma), and in all cases there was a transperitoneal surgical approach. the surgical technique is the same in both groups up until access to the kidney hilum. five trocars were used on the right side (two 5 mm, two 12 mm and one 11 mm) and four were used on the left (5 mm, 11 mm, and two of 12 mm). the patient was laying on the flank, with the operated side upwards, in the position of lateral decubitus. the abdominal cavity was entered with medialization of the colon and dissection of duodenum when operating the right side. the ureter was identified and cut between clips and dissected towards the kidney hilum. the kidney was dissected outside the boundaries of gerota's fascia. from this step the surgical approach was different between the two groups. in the first group, the gd device was inserted caudal and posterior to the renal hilus tissue creating a small window above the hilum of the kidney and under the adrenal to have the feeling of controlling the whole hilum (figure 1). at this moment, the gd is removed, and with all devices kept in place without movement, a 60 mm vascular gia stapler is inserted for ligation and dividing (figure 2). in contrast, in the second group the dissection was continued between the renal artery and renal vein in the renal hilum until they were completely separated, and then the stapler was used on the renal artery and later on the renal vein individually. the tip of the stapler was visualized beyond the hilum and free from any adjacent tissue before engaging the stapler mechanism. the first group (i) consisted of 174 cases in which the entire hilum was closed together (en bloc stapling) by using gd. the second group (ii) consisted of 114 cases in which a dissection was performed between the artery and renal vein and the closure of each blood vessel was done separately with gia from the same company. we evaluated the following clinical and perioperative data: age at surgery; sex; laterality; history of ureteroscopy, percutaneous nephrolithotomy (pcnl), peritoneal or retroperitoneal operations, pyonephrosis, nephrostomy insertion; complications, estimated blood loss (ebl), operation time, and length of stay (los). operation time was defined as the time from the beginning (incision) to the end of procedure (closure of the skin). results the mean age was 58.3 and 55.1 years in group i and ii respectively. ratio of 90/84 and 55/59 males/ females were observed in group i and ii respectively (table 1). blood loss was 65.5 ml and 188.9 ml, operative time was 156.5 and 189.2 minutes, wound infection occurred in three patients in each group (1.7% and 2.6%), ileus in 4 (2.3%) and 1 (0.87%), atrial fibrillation in 1 (0.57%) and 0%, incisional hernia in 0 (0%) and 2 (1.75%), deep vein thrombosis (dvt) in 0 (0%) and 1 (0.87%), in group i and ii respectively (table 2). conversion to open surgery occurred in 2 (1.15%) and 5 (4.39%), mean hospital stay was 3.45 days and 3.9 days in group i and ii, respectively. table 1. patient demographics. gd and en bloc-i hilum dissection-ii difference (std. dev.) (std. dev.) [p-value] age mean (years) 58.3 55.1 3.2 (16.77) (20.41) [0.155] male 90 (51.7%) 55 (48.2%) 3.5% (0.50) (0.50) [0.565] stricture side right 80 (46%) 54 (47%) -1% (0.50) (0.50) [0.818] left 94 (54%) 60 (53%) 1% (0.50) (0.50) [0.818] observations (n) 174 114 standard deviations in parentheses. p-values in square brackets. figure 1. goldfinger bypassing the renal hilus. figure 2. gia vascular stapleren bloc stapling of renal hilus. table 2. post-operative complications. gd and en bloc-i hilum dissection-ii (%) (% wound infection ileus 3 (1.7%) 3 (2.6%) 4 (2.3%) 1 (0.87%) atrial fibrillation 1 (0.57%) 0 (0%) incisional hernia 0 (0%) 2 (1.75%) dvt 0 (0%) 1 (0.87%) observations (n) 8 7 total (%) 4.6% 6.1% dvt: deep vein thrombosis. archivio italiano di urologia e andrologia 2022; 94, 4 m. asali, m. asali 382 discussion laparoscopic nephrectomy has become a standard surgery since the description of the surgery by clayman et al. in 1991 (1). the difficulty arises when dissecting the kidney hilum, separating the renal blood vessels, as an injury and bleeding from the blood vessels vastly increases the chances of a conversion to open surgery, rendering the patients losing all the advantages of the laparoscopic surgery over the open one. early on, chan et al. described the technique of rapid ligation of the renal hilum, and in their technique, they proposed a dissection of the renal vein, which is anterior, and tying all the posterior tissue (posterior packet) containing the renal artery, and subsequently closing the renal vein separately, thus providing a safe and quick approach to closing the hilum (17). in several studies there was a discussion regarding dissection of blood vessels, and cases where blood vessel were ligated en bloc due to the fear to separate blood vessels when there was no progress with the surgery or for other reasons in the attempt to control the blood vessels (2, 4, 67, 9, 16). the efficacy of en bloc method has also been observed during laparoscopic nephroureterectomy in the first part of the surgery, before the completion of the ureteral dissection from the bladder (7-9). table 3 shows the list of peritoneal and retroperitoneal surgeries that were done before laparoscopic nephrectomy in the same kidney unit. a difference was shown only in the number of ureteroscopies between the two groups (p < 0.05). this difference in ureteroscopies should not be relevant because these procedures have not much effect on the tissues around the kidney hilus and should not affect the results. history of pcnl, peritoneal and retroperitoneal operations, pyonephrosis and percutaneous nephrostomy, were not different when comparing the two groups (table 3). in the current study we compared group i and ii, and we found a significant difference in the average surgery time and in bleeding in favor of the group that used gd with closing and cutting the kidney hilum en bloc at the same time. the values of our study were not higher when compared to other series where even longer times and higher volumes were observed (table 4). one of the reasons for this difference is that some cases were at the beginning of the learning curve, whereas years later duration of surgeries became shorter, yet the significant advantage of group i over group ii is apparent. the differences in conversion rate from laparoscopic surgery to open surgery and complications also were in favor of the first group (table 4), but the difference is not statistically significant. the average bleeding is much lower in the first group compared to the second, and relatively lower than other world series (table 4). we observed a statistically difference in hospital stay, although most patients were discharged three days post-surgery. we have no information about the use of the gd device in laparoscopic nephrectomy in other world series, although whoever is trying this device can feel full confidence when bypassing the entire renal hilum from all directions. the use of the device allows to evaluate the entire thickness of the tissue before employment the giastapler. if tissue appears to be too bulky, it can be divided by the same gd to identify another surgical plane in order to safely employ the giastapler twice without seeing the blood vessels. in both groups, the nephrectomy was performed for various reasons as detailed in table 5 including cancerous renal table 3. prior peritoneal or retroperitoneal operations and invasive procedures. gd and en bloc-i hilum dissection-ii difference (std. dev.) (std. dev.) [p-value] urs 0.376 0.254 0.121*** (0.49) (0.44) [0.029] pcnl 0.046 0.079 -0.033 (0.21) (0.27) [0.277] rp. operation 0.238 0.227 0.011 (0.43) (0.42) [0.830] pyonephrosis 0.231 0.234 -0.003 (0.42) (0.43) [0.963] pcn 0.150 0.216 -0.066 (0.36) (0.41) [0.169] peritoneal 0.438 0.456 -0.018 operation (0.50) (0.50) [0.763] observations (n) 174 114 urs: ureteroscopy, pcnl: percutaneous nephrolithotomy, rp: retroperitoneal, pcn: percutaneous nephrostomy. *** p-value < 0.05. table 4. transperitoneal laparoscopic nephrectomy series dealing with renal vessels. reference d/e n bl ot conversion complications hs ml min. % % days resorlu et al. (2) e 27 225 98 0 3.7 5.1 conradie et al. (7) e 93 32 56 2.1 2.2 2.9 ma et al. (4) e 33 75.2 99.6 3 12.1 4.8 zhang et al. (5) d 191 94.8 171.5 0.52 4.2 5.6 sherer et al. (16) e 433 155 169 1.4 1.4 this study: asali et al. e 174 65.5 156.5 1.15 4.6 3.45 (68.81) (45.21) (0.11) (0.21) (0.87) d 114 188.9 189.2 4.39 6.1 3.90 (306.44) (53.64) (0.21) (0.24) (1.98) difference e-d -123.50 -32.75 -3.2 -1.5 -0.45 [p-value] [0.000] [0.000] [0.124] [0.577] [0.023] p-value < 0.05 *** *** *** adj. difference -128.64 -31.79 -3.49 -2.07 -0.49 [p-value] [0.000] [0.000] [0.115] [0.468] [0.019] p-value < 0.05 *** *** *** d: vascular dissection; e: en bloc stapling; hs: hospital stay; gia: endo vascular gia: medtronic, h: hem-o-lock; ot: operating time; bl: blood loss; min.: minute. device used in all studies is gia, except for d. zhang et al. which is h/gia. adj. difference refers to the statistical difference in the respective variable between the two groups when controlling for the demographic variables of age, gender, and right or left kidney. *** p-value < 0.05. table 5. kidney pathology. group no rcc ucc pyelo./hydro./nf. aml onco. xgp as. en bloci 174 74 26 74 4 2 0 1 dissectionii 114 30 20 65 0 2 4 1 rcc: renal cell carcinoma; ucc: urothelial cell carcinoma; pyelo: pyelonephritis; hydro: hydronephrosis; nf: nonfunctioning kidney; aml: angiomyolipoma; onco: oncocytoma; xgp: xanthogranulomatous pyelonephritis; as: angiosarcoma. 383archivio italiano di urologia e andrologia 2022; 94, 4 stapling of renal vessel during laparascopic nephrectomy tumors (renal cell carcinoma, urothelial cell carcinoma, angiosarcoma), some benign tumors (oncocytoma, angiomyolipoma), and chronic renal inflammatory processes related to history of recurrent urinary tract infections or stone disease. although the causes of nephrectomy are different, the surgery performed in all the cases was the same, and the kidney was always dissected on a plane outside the gerota's fascia even when it was affected by an inflammatory non-tumor process, because this surgical plane is less involved in the inflammatory process as shown by ma et al. (4). laparoscopic nephrectomy outside gerota's fascia of the kidney could reduce the difficulty of procedure (4). the strength of this article is related to several factors. first, it was introduced the use of an endoscopic device for the purpose of bypassing the renal blood vessels, that was never used elsewhere in the world for this purpose. secondly, the larger number of cases in which ligation of renal blood vessels was carried out simultaneously (en bloc) in relation to other most known series in the world. thirdly, all cases were operated by a single surgeon. finally, in all cases gd and vascular gia-stapler from the same companies were used. the major limitation of our study is that data were acquired in a retrospective manner. conclusions routine use of the gd and en bloc stapling of the renal pedicle in laparoscopic nephrectomy is safe and useful. this technique can decrease blood loss, operative time and have some benefit in conversion to open surgery. references 1. clayman rv, kavoussi lr, soper nj, et al. laparoscopic nephrectomy: initial case report. j urol. 1991; 146:278-82. 2. resorlu b, oguz u, polat f, et al. comparative analysis of pedicular vascular control techniques during laparoscopic nephrectomy: en bloc stapling or separate ligation? urol int. 2015; 94:79-82. 3. yang f, zhou q, li x, xing n. the methods and techniques of identifying renal pedicle vessels during retroperitoneal laparoscopic radical and partial nephrectomy. world j surg oncol. 2019;17:38. 4. ma l, yu y, ge g, li g. laparoscopic nephrectomy outside gerota fascia and en bloc ligation of the renal hilum for management of inflammatory renal diseases. int braz j urol. 2018; 44:280-287. 5. zhang l, yao l, li xs, et al. technique of renal pedicle control in transperitoneal laparoscopic nephrectomy: experience of 191 cases by a single surgeon. beijing da xue xue bao yi xue ban. 2014; 18;46:537-40. 6. janetschek g, bagheri f, abdelmaksoud a, et al. ligation of the renal vein during laparoscopic nephrectomy: an effective and reliable method to replace vascular staplers. j urol. 2003; 170:1295-7. 7. conradie mc, urry rj, naidoo d, et al. advantages of en bloc hilar ligation during laparoscopic extirpative renal surgery. j endourol. 2009; 23:1503-7. 8. ou ch, yang wh, tzai ts. en bloc stapling of renal hilum during hand-assisted retroperitoneoscopic nephroureterectomy in dialysis patients. urology. 2008; 72:589-92. 9. rapp de, orvieto ma, gerber gs, et al. en bloc stapling of renal hilum during laparoscopic nephrectomy and nephroureterectomy. urology. 2004; 64:655-9. 10. aminsharifi a, goshtasbi b. laparoscopic simple nephrectomy after previous ipsilateral open versus percutaneous renal surgery. jsls. 2012; 16:592-6. 11. aminsharifi a, taddayun a, niroomand r, et al. laparoscopic nephrectomy for nonfunctioning kidneys is feasible after previous ipsilateral renal surgery: a prospective cohort trial. j urol. 2011; 185:930-4. 12. asali m, tsivian a. laparoscopic nephrectomy in xanthogranulomatous pyelonephritis. cent european j urol. 2019; 72:319-323. 13. talla p, ekotomati m, o'leary t, ben ali n. the use of the goldfinger dissector (gd) in laparoscopic sacrocolpopexy. front med (lausanne). 2018; 31;5:155. 14. cai lx, wei fq, yu yc, cai xj. can retrohepatic tunnel be quickly and easily established for laparoscopic liver hanging maneuver by goldfinger dissector in laparoscopic right hepatectomy? j zhejiang univ sci b. 2016; 17:712-21. 15. troisi ri, montalti r. modified hanging maneuver using the goldfinger dissector in laparoscopic right and left hepatectomy. dig surg. 2012; 29:463-7. 16. sherer ba, chow ak, newsome mj, et al. en bloc stapling of the renal hilum during laparoscopic nephrectomy: a double-institutional analysis of safety and efficacy. urology. 2017; 105:69-75. 17. chan dy, su lm, kavoussi lr. rapid ligation of renal hilum during transperitoneal laparoscopic nephrectomy. urology. 2001; 57:360-2. correspondence muhammad asali, md, professor ma90002611@gmail.com school of international and public affairs, columbia university, new york murad asali, md (corresponding author) dr.muradasali@gmail.com department of urology, barzilai medical center ben gurion university, beer sheva, sokolov 26/99, 8430905 cop+ed+fisse 2006 101archivio italiano di urologia e andrologia 2021; 93, 1 original paper no conflict of interest declared. doi: 10.4081/aiua.2021.1.101 ureterectomy (su) with ureteral reimplantation could be an option in selected cases with low grade distal ureteral tumour or impaired renal function and high grade distal utuc (2-4). in these cases, the ureteral reimplantation became challenging due to the reduction of length of the ureter necessary for oncological radicality. the advent of robotic surgery with its 3-d magnified view, 7 degree of freedom and steadiness of instruments and camera, allowed to overcome the limitations of the conventional laparoscopic and open approaches for the reconstruction. thank to this more complex robotic tension-free ureteral reimplantation procedures have been described, such as psoas hitch (ph) techniques (5). the feasibility and safety surgical profile of the robotassisted su with ureteral reimplantation was reported by several authors (6-12). however, some of these studies focused on surgical technique and functional outcomes concentrating patients with heterogeneous aetiology and short follow up. while other studies focused on oncologic outcomes with no consistent on surgical technique considered. under this light, we aim to assess intra-, peri-, postoperative and oncological outcomes of a single centre series of patients with distal utuc, exclusively treated with raphur tension-free reimplantation, with a minimum follow-up of one year. the safety of the procedure was evaluated in agreement with the standardized methodology to report complications proposed by european association of urology (eau) guidelines (13). materials and methods study population we retrospectively analyzed 11 patients with distal utuc treated with raphur between october 2013 and 2017. all patients presented non-metastatic disease. all surgeries were performed by two surgeons with extensive experience in robotic surgery. the study protocol was approved by the institutions’ medical ethics committees and all patients provided informed consent. surgical techniques of robot-assisted segmental ureterectomy with psoas hitch ureteral reimplantation the ureter is identified at the bifurcation of the common introduction: according to the urology guidelines, in selected cases of distal upper tract urothelial carcinoma (utuc) segmental ureterectomy (su) can be offered. there is no consensus in the surgical technique of preference. robot-assisted su could be an option to overcome all the limitations of open and laparoscopic techniques. we describe our first experience of robot assisted su with psoas hitch ureteral reimplantation (raphur). materials and methods: 11 patients underwent raphur for distal utuc between 2013 and 2017 in a single centre. pre-, intra-, and postoperative outcomes were assessed. conventional imaging was performed after 1, 3, 6 months and 1 year from surgery as follow up protocol. we retrospectively evaluated the technical feasibility, oncological and functional outcomes. results: median age was 71 years (57-91). the median length of the ureteral defect was 23 mm (10-40). median preoperative creatinine level was 1.22 mg/dl (0.7-1.85) and median egfr was 57.5 ml/min/1.73m2 (31-80). five (45.5%) patients were symptomatic and 7 (63.6%) had hydronephrosis. median operative time was 185 min (120-240), with a median blood loss of 100 ml (50-300). no case required conversion to open surgery. overall, only 1 (9%) patient developed clavien dindo ≥ 3 postoperative complications. average hospital stay was 7 (2-9) days. mean postoperative creatinine was 1.05 mg/dl (0.8-1.85) and mean postoperative egfr was 72 (36-83). during a median follow up time of 25.5 months (12-53), 4 (36.4%) patients experienced recurrence of urothelial cancer at conventional imaging follow up and 2 (18.2%) died due to its progression. conclusions: in our initial experience raphur can be proposed to selected cases of distal ureteral carcinoma with optimal perioperative and functional outcomes. however, cancer control may be undermined compared to nephroureterectomy. thus, further prospective studies are needed to confirm our findings. key words: robotics; segmental ureterectomy; ureter; urothelial carcinoma; psoas hitch reimplantation. submitted 9 january 2021; accepted 21 january 2021 introduction open radical nephroureterectomy represents the treatment option for the management of distal upper tract urothelial carcinoma (utuc) (1, 2). however, segmental robot-assisted segmental ureterectomy with psoas hitch ureteral reimplantation: oncological, functional and perioperative outcomes of case series of a single centre summary erika palagonia 1, 2, 3, simone scarcella 1, lucio dell’atti 1, giulio milanese 1, peter schatteman 2, 3, frederiek d’hondt 2, 3, geert de naeyer 2, 3, andrea galosi 1, alexandre mottrie 2, 3 1 division of urology, united hospital of ancona, school of medicine marche polytechnic university, ancona, marche, italy; 2 orsi academy, melle, belgium; 3 department of urology, onze lieve vrouw hospital, moorselbaan 164, 9300, aalst, belgium. presented at the sieun congress ancona 30 november 1 december 2020 archivio italiano di urologia e andrologia 2021; 93, 1 e. palagonia, s. scarcella, l. dell’atti, g. milanese, p. schatteman, f. d’hondt, g. de naeyer, a. galosi, a. mottrie 102 iliac artery and cautiously mobilized caudally until the identification of the disease segment. after mobilization of the bladder, the segment of the ureter involved by cancer is clipped before its dissection in order to avoid tumor seeding, then the disease segment is dissected and sent for frozen section. a formal bladder cuff is excised for oncological radicality and a regional lymph nodes dissection is also performed. the ureter is spatulated anteriorly for 2 cm. to perform a ph, a 2-0 non-absorbable suture is used to fix the external part of the ipsilateral dome of the bladder to the psoas muscle and its tendon. this allows to perform a tension-free reimplantation and to provide a strong and durable fixation with a low risk of genito-femoral nerve and iliac vessel injury (14). a longitudinal incision of 3-4 cm is made at the level of the bladder dome along the anterolateral surface. the ureter is spatulated and inserted inside a sub-mucosal tunnel developed at the cranial part of the bladder. then a mucosa to mucosa anastomosis is performed using 4-0 monocryl suture in a running way. a double j stent is placed in a retrograde fashion using a guide wire. thereafter, the bladder is closed with 30 cm 2-0 v-lock suture in double layer. variable definition and follow-up preoperative variables consisted of age at surgery, gender, comorbid conditions (charlson comorbidity index) (15), previous abdominal surgery, preoperative haematuria, preoperative hydronephrosis at computer tomography (ct) scan, side of the disease, length of the ureteral disease at preoperative ct scan, preoperative symptoms, preoperative serum creatinine and estimated glomerular filtration rate (egfr). follow-up consisted of control visit at 1, 6 months and then annually with consecutive serum creatinine, egfr analysis and clinical evaluation of symptoms. conventional imaging such as abdominal ct scan, abdominal ultrasound and cystoscopy were performed to exclude cancer recurrence after 1 month, 3, 6 months and yearly or in case of lower urinary tract symptoms and haematuria after surgery. study outcomes and statistical analysis intraoperative outcomes (operative time, blood loss, intraoperative complications) were assessed and reported according to satava classification, perioperative outcomes (length of stay, urinary catheter and stent removal) were also assessed (16). intermediate-term postoperative functional outcomes (postoperative serum creatinine and egfr), hydronephrosis at conventional imaging and presence of symptoms were also evaluated. postoperative complications were collected according to clavien-dindo (cd) classification system, moreover the quality criteria of accuracy recommended by the eau guidelines on reporting and grading of complications were fulfilled (supplementary table 1) (13). 90-day readmission rate was also evaluated. pathological reports were assessed. cancer recurrence and mortality was assessed. medians and ranges, as well as frequencies and proportions were reported for continuous or categorical variables, respectively. for all statistical analyses, sps software environment for statistical computing was used. results all the descriptive characteristics of the study population are recorded in table 1. median follow-up was 25.5 months (12-53). nine (81.8%) patients were male and 2 table 1. baseline characteristics. variables overall (n = 11) age (yr), median (range) 71 (57-91) gender, n (%) • male 9 (81.8) • female 2 (18.2) charlson comorbidity index, n (%) 0 2 (18.2) 1 3 (27.3) ≥ 2 6 (54.5) abdomen previous surgery, n (%) 9 (81.8) aetiology, n (%) • low-stage urothelial tumour 6 (54.5) • high-stage urothelial tumour 5 (45.5) side, n (%) • left 8 (72.7) • right 3 (27.3) length disease (mm), median (range) 23 (10-40) preoperative hydronephrosis at ct scan, n (%) 7 (63.6) preoperative haematuria, n (%) 4 (36.4) pre-operative symptoms, n (%) • yes 5 (45.5) • no 6 (54.5) table 2. intraoperative and perioperative outcomes. post-operative outcomes. intra and perioperative outcomes variables overall (n = 11) operating time (min), median (range) 185 (120-240) blood loss (ml), median (range) 100 (50-300) intraoperative complications, n (%) 0 length of stay (days), median (range) 7 (2-9) catheter removal (days), median (range) 10 (2-20) stent removal (days), median (range) 21 (15-44) post-operative outcomes variables overall (n = 11) 90-day postoperative complications clavien ≥ ii, n (%) 2 (18.2) post-operative creatinine (mg/dl), median (range) 1.05 (0.8-1.85) post-operative egfr (ml/min/1.73 m2), median (range) 72 (36-83) post-operative hydronephrosis, n (%) 1 (9) readmission, n (%) 1 (9) table 3. summary of 90 day postoperative complications. overall complications (n = 4) 36.4% category type of complication n clavien dindo i prolonged catheterization due to leakage at cystography 1 (n = 3, 27.3%) transitory sensory loss of the leg (femoral or saphenous nerve damage) 2 clavien dindo iii iiia: lymphocele* treated with percutaneous drainage 1** (n = 1, 9%) *lymphocele was defined as any clearly definable fluid collection and was considered clinically significant when requiring treatment. ultrasound examination was used to detect lymphoceles. ** patient readmitted. (18.2%) female. disease side was right in 3 (27.3%) patients and left in 8 (72.2%). median age was 71 years (57-91). the median length of the ureteral defect was 22.6 mm (10-40 mm). median pre-operative creatinine level was 1.2 mg/dl (0.72-1.50) and median estimated glomerular filtration rate (egfr) was 58,00 ml/min/1.73m2 (3180). 5 (45.5%) patients were symptomatic, 4 (36.4%) presented macrohematuria and 3 (27.3%) had ipsilateral flank pain. 7 (63.3%) had preoperative hydronephrosis at abdomen ct scan. median operative time was 185 min (120-240), with a median blood loss of 100 ml (50-300) (table 2). all surgeries were completed without conversion to open technique. no intraoperative complications were recorded. overall, 1 (9%) of the patients developed a postoperative complication classified with clavien dindo ≥ 3, the patient developed a lymphocele after few weeks from surgery and he was readmitted to the hospital to insert a percutaneous drainage through radiological intervention (table 3). median hospital stay was 7 (2-9) days. the vas score was optimal (0) at discharge moment. bladder catheter was removed after cystogram and with a median of 10 (2-20) days while the double j ureteral stent was removed after a median of 21 (15-44) days. median postoperative creatinine was 1.05 mg/dl (0.8-1.85) and median postoperative egfr was 72 ml/min/1.73m2 (36-83). pathological stage was pta in 4 (36,4%) cases, pt1 in 4 (36.4%) cases, pt2 in 1 (9%) case and pt3 in 2 (18.2%) cases (table 4). only 1 (9%) patient had positive lymph nodes after surgery (pt2 n2). no positive surgical margins were found. during a median follow up time of 25.5 (12-53) months, 4 (36.4%) patients experienced recurrence of urothelial cancer at conventional imaging or cystoscopy. three (27.3%) of these cases experienced intravesical cancer recurrence, and the patients underwent trans-urethral resection. adjuvant chemotherapy was performed on 3 (27.3%) patients. two (18.2%) patients died due to its progression; 1 (9%) patient died due to cardiological problems after 1 year from surgery. discussion the international associations of urology identified open radical nephroureterectomy as the gold standard treatment for utuc (1). however, evidences showed how the management of utuc should be individualized to tumor’s risk and patient’s characteristics. in this scenario the kidney sparing surgery could be an option in selected cases with low grade distal ureteral tumor or impaired renal function and high grade distal utuc, thus su gives the similar oncological outcomes with the advantage of renal function preservation (2-4). in these cases, the ureteral reimplantation became challenging due to the reduction of length of the ureter necessary for oncological radicality. with the advent of robotic surgery, and the advantages it brings, its use for utuc management is increasingly widespread worldwide. our first experience of distal utuc treated with robot assisted su and subsequent psoas hitch ureteral reimplantation provides new data confirming the feasibility and safety profile of this procedure in selected cases. furthermore we fulfilled the 14-item standardized reporting tool for postoperative complications as supported by eau guidelines (13). unlike the study of campi et al. on robotic su and robotic nephroureterectomy our study standardized the surgical 103archivio italiano di urologia e andrologia 2021; 93, 1 robot-assisted ureterectomy with ureteral reimplantation supplementary table 1. postoperative complications: quality criteria for accurate and comprehensive reporting of surgical outcome. criteria 1. define the method of accruing data* retrospective data collection based on chart review and patient interview 2. define who collected the data data were collected by dedicated data manager 3. indicate the duration of follow-up* 90 d 4. include outpatient information* outpatient information were collected 5. include mortality data and causes of death* mortality and cause of death were collected 6. include definitions of complications* complications were defined as any deviation from the ideal postoperative course 7. define procedure-specific complications* procedure-specific complications were defined and collected 8. report intraoperative and postoperative complications separately intraoperative and postoperative complications were reported separately 9. use a severity grading system for postoperative complications* the clavien-dindo system was used 10. postoperative complications should be presented in a table either by grade or by complication type postoperative complications were presented in a table by complication type 11. include risk factors* the charlson comorbidity-index was prospectively collected for all patients. 12. include readmissions and causes data on readmissions were collected 13. include reoperations, types and causes data on reoperation, types and causes were collected 14. include the percentage of patients lost to follow-up 0 patients were lost to 90d follow up *outcomes in common with the martin criteria. table 4. pathological report and oncologic outcomes. pathological report pta n (%) g1 3 (27.3) g2 1 (9) pt1 n (%) g2 2 (18.2) g3 2 (18.2) pt2 n (%) g3 1 (9) pt3 n (%) g3 2 (18.2) n0 n (%) 10 (89) n1 n (%) 0 n2 n (%) 1 (9) positive surgical margins 0 oncologic outcomes cancer recurrence n (%) 4 (36.4) adjuvant chemotherapy n (%) 3 (27.3) trans-urethral resection n (%) 3 (27.3) mortality n (%) 2 (18.2) archivio italiano di urologia e andrologia 2021; 93, 1 e. palagonia, s. scarcella, l. dell’atti, g. milanese, p. schatteman, f. d’hondt, g. de naeyer, a. galosi, a. mottrie 104 table 5. series on distal ureteral robotic reimplantation for utuc. ca mp i rn u, ra ph ur , mu ltic en tre (3 ), 81 (ro bo tic ): 10 : 17 (1 0– 46 ) 46 ,7% of 15 me dia n: 14 0 me dia n: 18 0 me dia n: 4 ( 3– 7) me dia n: 21 no t re po rte d no t 60 , o ver all no t re po rte d δeg fr : -1 no t re po rte d et al. 20 19 ure ter on eo cys tos tom y 8 s urg eo ns 15 (u ret ere cto my ) 4 ( ra ph ur ) pts 26 ,7% (11 0– 22 0) (10 0– 21 0) (14 –3 8) rep ort ed 66 int rav esc ica l (ne ph rou ret ere cto my ) 20 % ips ilat era l ure ter mc cla in ure ter on eo cys tos tom y, sin gle 6 ( rob oti c) 4: 3b no t 16 .7 me an : 2 68 .5 me an : 7 2.5 me an : 1 .8 me an : 3 3 28 -56 7 t o 1 0 16 .6 no t re po rte d no t re po rte d no t re po rte d et al. 20 12 ra ph ur , cen tre (ra ph ur ) rep ort ed (18 8– 40 0) (< 30 –1 50 ) (12) (28 –3 9) ure ter ou ret ero sto my fife r ra ur , r ap hu r, sin gle 55 (ro bo tic ): 10 no t 40 % of me dia n: 22 4 me dia n: me an 1. 6 me dia n: 6 no t re po rte d no t 3.6 ov era ll no t re po rte d no t re po rte d 3 p ts et al. 20 14 ra bf ur , e nd -to en d cen tre 35 ra ph ur rep ort ed 10 pt s (18 4– 25 4) 50 (2 5-1 00 ) ove ral l ove ral l rep ort ed (hy dro ne ph ros is) an ast om osi s, of 10 pt s ove ral l ure ter oly sis , ure ter oli tho tom y els am ra ure ter on eo cys tos tom y, sin gle 20 (ro bo tic ): 6 ( rob oti c) no t no t me dia n: 23 6 me dia n: 10 0 me dia n: 2 me dia n: 4 me dia n: 38 me dia n: 8 no t re po rte d no t re po rte d δc rea tin ine no t re po rte d et al. 20 14 ra ph ur , r ab fu r cen tre 6 ( ra ph ur ) rep ort ed rep ort ed (21 9-3 05 ) (63 -20 0) (24) of of 20 ro bo tic (29 -45 ) o f 2 0 (810 ) o f (9, 5% of m ajo r me dia n: 0 5 s urg eo ns 85 (la pa ros co pic ) of 20 ro bo tic of 20 ro bo tic 20 ro bo tic rob oti c 20 ro bo tic co mp lica tio ns) 25 (o pe n) mu sch ra ph ur , r ab fu r, sin gle 16 4: no t 25 % of 4 p ts me dia n: 25 0 no t me dia n: 7.5 me dia n: 11 no t re po rte d no t 75 ov era ll, no t re po rte d no t re po rte d no t re po rte d et al 20 13 ure ter al en d-t o-e nd cen tre 2 ( ra ph ur ) rep ort ed (15 3-3 20 ) rep ort ed (535 ) o ver all ove ral l rep ort ed 10 0 o f 4 pt s an ast om osi s, 3 s urg eo ns me dia n: 32 0 lic h g reg oir , (21 8-3 20 ) ure ter on eo cys tos tom y lym ph ad en ect om y) he ma l ra ur , r ap hu r, mu ltic en tre (2 ) 44 : 5 no t no t me an : 1 90 me an : 1 00 me an 3, 5 me an : 1 0 no t re po rte d no t 4.5 ov era ll no t re po rte d no t re po rte d 0 ( rad ion uc lid e et al. 20 10 en do -to en d 18 (d ist al) rep ort ed rep ort ed (16 0-2 40 ) of 5 p ts of 5 p ts of 5 p ts rep ort ed sci nti gra ph y) an ast om osi s, 12 (p rox im al) of 5 p ts (ne ph rou ret ere cto mi es 10 (a bla tive ) an d 4 ( mi sce lla ne ou s) ne ph rou ret ere cto mi es) sc him pf ra ur , r ap hu r, sin gle 11 6: no t no t me an an d me an : 8 1 me an : 2 .4 me dia n: 12 42 da ys ra ng e 27 ov era ll no t re po rte d no t re po rte d no t re po rte d et al. 20 09 ra bf ur cen tre 1 ( ra ph ur ) rep ort ed rep ort ed me dia n: 18 9 (25 -30 0) me dia n 2 (153 ra ng e) (710 ) (14 5-2 40 ) ove ral l (15) ove ral l ove ral l ove ral l hydronephrosis and/or ureteral stenosis at postoperative imaging postoperative functional outcomes (mean serum creatinine and egfr) post-operative symptoms evaluated with vas score post-operative complications rate (%) catheter removal (days) stent time (days) follow up (months) los (days) blood loss (ml) operative time (min) tcc recurrence rate (%) length of the stricture mm (median or mean) number of patients treated for distal utuc overall number of patients (n) centre (n) procedure study 105archivio italiano di urologia e andrologia 2021; 93, 1 robot-assisted ureterectomy with ureteral reimplantation procedure of ureteral reimplantation after su (9). indeed, they presented 15 patients who underwent robot-assisted su, out of them 5 patients were treated with primary ureteroureterostomy, 4 with ureteroneocystostomy, 4 with psoas hitch ureteroneocystostomy and 2 were tumor of the pelvis treated with robotic pyeloplasty (9). this factor generalizes the feasibility and safety results of the surgical technique but confirms that su can be a valid option in terms of oncological outcomes. previously mcclain collected a series of robotic su with long follow up, demonstrating the efficacious and durable management of robotic surgery on distal utuc, but they reported only 6 patients treated with different procedures (10). a direct comparison with other available robotic series on distal ureteral reimplantation is difficult because these studies are clustering outcomes for different ureteral reimplantation techniques and patients with different etiological disease, considering also other pathologies besides urothelial carcinoma (table 5) (6-8). furthermore, there is a lack of data in terms of postoperative evaluation (i.e.: symptoms evaluation, functional outcomes, radiologic imaging follow-up, oncological outcomes) which does not allow an adequate analysis of use of robotic platform in case of ureteral cancer. our study, with a minimum of one year follow-up and complete postoperative data, aims to validate the use of su exclusively with raphur techniques for distal utuc, supporting its feasibility, safety and reproducibility. our results were reported below. first of all, we reported good operative and perioperative outcomes: the median ot, blood loss and los were 185 min (range: 120-240 min), 100 ml (range: 50-300 ml) and 7 days (range: 2-9) respectively; median catheter and dj stent removal were respectively 10 (range: 2-20 days) and 21 days (range: 15-44 days). these findings cannot fairly be compared with other available robotic series given the heterogeneity of the ureteral reimplantation techniques included and the clustering of the outcomes reported (table 5). second, we fulfilled the standardized methodology recommended by eau guidelines on grading and reporting postoperative complications (13) (supplementary table 1). this confirms high reliability of data report on postoperative complications. the overall rate of complications was 36.4%. of these, only one complication requiring additional percutaneous intervention (cd iiia) for lymphocele drainage. the safety profile of raphur techniques is also supported by the absence of intraoperative complication. all postoperative outcomes (i.e. symptoms, functional outcomes and oncological outcomes) were assessed. renal function improved with a d = 0.2 in median serum creatinine and with median egfr becoming 72 ml/min/1.73 m2 (range: 36-83) from 58. the vas score at discharge and last follow-up were acceptable. all these findings strongly confirm that the robotic approach for distal utuc is feasible and offers an excellent alternative to open surgery in terms of functional and oncologic outcomes with the benefits of minimally invasive surgery. to the best of our knowledge, our study represents the largest series available so far (considering the rarity of the condition) from a single robotic high-volume centre of robot-assisted ureteral reimplantation for distal utuc exclusively treated with raphur (table 5). despite these results, our study has several limitations. the retrospective nature of the current analysis and the small sample size, considering the rarity of the condition and the exclusivity of the treatment, are the main limitations. furthermore, there is a lack of a control group treated with open or laparoscopic approach for direct comparison on surgical terms, or a control group of nephroureterectomy for comparison on oncological outcomes. however, it must be considered that the main goal of the current study was to report these refined robotic surgical techniques for distal utuc with psoas hitch ureteral reimplantation. conclusions in our experience raphur can be proposed to selected cases of distal ureteral carcinoma of low-grade disease or in patients with impaired renal function and high-grade disease with optimal perioperative, functional and oncologic outcomes. however, cancer control may be undermined compared to nephroureterectomy. thus, further prospective studies are needed to confirm our findings. acknowledgements thank to professor alexandre mottrie, the erus educational working group and the yau working group on robot-assisted surgery. references 1. margulis v, shariat sf, matin sf, et al. outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. cancer. 2009; 115:1224-33. 2. mazzucchelli r, scarpelli m, galosi ab, et al. pathology of upper tract urothelial carcinoma with emphasis on staging. vol. 27, international journal of immunopathology and pharmacology. england. 2014; p. 509-16. 3. colin p, ouzzane a, pignot g, et al. comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large french multicentre study. bju int. 2012; 110:1134-41. 4. jeldres c, lughezzani g, sun m, et al. segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. j urol. 2010 apr; 183:1324-9. 5. uberoi j, harnisch b, sethi as, et al. robot-assisted laparoscopic distal ureterectomy and ureteral reimplantation with psoas hitch. j endourol. 2007; 21:368-72. 6. hemal ak, nayyar r, gupta np, dorairajan ln. experience with robot assisted laparoscopic surgery for upper and lower benign and malignant ureteral pathologies. urology. 2010; 76:1387-93. 7. fifer gl, raynor mc, selph p, et al. robotic ureteral reconstruction distal to the ureteropelvic junction: a large single institution clinical series with short-term follow up. j endourol. 2014; 28:1424-8. 8. elsamra se, theckumparampil n, garden b, et al. for benign and malignant ureteral lesions: a comparison of over 100 minimally invasive cases. 2014; 28:1455-9. 9. campi r, cotte j, sessa f, et al. robotic radical nephroureterectomy and segmental ureterectomy for upper tract urothelial carcinoma: a multi-institutional experience. world j urol. 2019; 37:2303-11. archivio italiano di urologia e andrologia 2021; 93, 1 e. palagonia, s. scarcella, l. dell’atti, g. milanese, p. schatteman, f. d’hondt, g. de naeyer, a. galosi, a. mottrie 106 10. mcclain pd, mufarrij pw, hemal ak. robot-assisted reconstructive surgery for ureteral malignancy: analysis of efficacy and oncologic outcomes. j endourol. 2012; 26:1614-7. 11. schimpf mo, wagner jr. robot-assisted laparoscopic distal ureteral surgery. jsls j soc laparoendosc surg. 2009; 13:44-9. 12. musch m, hohenhorst l, pailliart a, et al. robot-assisted reconstructive surgery of the distal ureter: single institution experience in 16 patients. 2013; 773-83. 13. mitropoulos d, artibani w, graefen m, remzi m. eau guidelines on reporting and grading of complications after urologic surgical procedures. 2016. 14. maldonado pa, slocum pd, chin k, corton mm. anatomic relationships of psoas muscle: clinical applications to psoas hitch ureteral reimplantation. am j obstet gynecol. 2014; 211:563.e1-6. 15. charlson m, szatrowski tp, peterson j, gold j. validation of a combined comorbidity index. j clin epidemiol. 1994; 47:1245-51. 16. satava rm. identification and reduction of surgical error using simulation. minim invasive ther allied technol. 2005; 14:257-61. correspondence erika palagonia, md erika.palagonia@gmail.com simone scarcella, md simoscarc@gmail.com lucio dell’atti, md dellatti@hotmail.com giulio milanese, md g.milano972@gmail.com andrea galosi, md galosiab@yahoo.it division of urology, united hospital of ancona, school of medicine marche polytechnic university via conca 71, 60126 ancona (italy) peter schatteman, md peter.schatteman@olvz-aalst.be frederiek d’hondt, md frederiek.dhondt@olvz-aalst.be geert de naeyer, md geert.de.naeyer@olvz-aalst.be alexandre mottrie, md alexandre.mottrie@olvz-aalst.be department of urology, onze lieve vrouw hospital moorselbaan 164, 9300 aalst (belgium) stesura seveso 389archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. other assisting specialists like medical oncologists, radiologists, and pathologists (3). analysis of many mdcs versus standard community care consistently showed that mdcs were associated with “changes in staging/diagnosis, initial management plans, higher rates of treatment, shorter time to treatment after diagnosis, better survival, and adherence to clinical guidelines” (4). patient satisfaction and feeling of well-being was also increased due to the patient feeling well informed in treatment decisions (5). the mdc approach allows multiple specialists contribute to the treatment decisions, which has been shown to remove physician bias toward the modality of treatment provided (4). the enthusiasm for unifying the referral process of prostate cancer was developed due to tendency of urologist and radiation oncologist who received the primary referral to suggest therapy that they offer (6). in 2007, a diagnostic assessment program (dap) for prostate cancer was developed in north york general hospital and further was mandated by cancer care ontario for lung, colorectal and prostate cancers. the goal act of dap is to improve timely access to care for prostate cancer patients. early evidence showed that the dap reduced wait times from cancer suspicion to radiotherapy by on average 2 months compared to standard community practice (7). in the efforts to reduce waiting time, multiparametric magnetic resonant imaging (mpmri) is strongly recommended in men candidate for prostate biopsy or in men enrolled in active surveillance protocols (8). in a recent report, the surveyed physician reported less than 4 weeks waiting time to get mpmri with further acceleration of diagnostic process (9). a dap has been established in thunder bay, ontario since 2018. it is not clear if data collected from the dap in southern ontario can be extrapolated to a more rural and remote location with a different population, less healthcare resources, and vast geographical coverage. in a recent report on the influence of socioeconomic and geographical factors on prostate cancer diagnosis, only 17% of patients presented with localised prostate cancer live in rural area less than 4000 inhabitants (10). we herein report the results of a retrospective analysis of the referral process before and after the implementation of the dap, as well as the adherence to the guidelines. background: in 2018, our institute launched the diagnostic assessment program (dap) for prostate cancer. it enabled quick access to a urologist for patients presented to family physician with elevated psa and allowed fast multidisciplinary patient care. we aim to document our data over 2 years in comparison to data before implementation of dap and its impact on the degree of adherence to canadian guidelines. methods: from april 2016 to april 2020, 880 patients who were evaluated for prostate cancer at thunder bay regional health sciences centre (tbrhsc) were included in this study. patients’ characteristics, clinical data, waiting times and line of treatment before and after implementation of dap were calculated and statistically analysed. results: the median waiting time to urology consultation was significantly reduced from 68 (iqr 27-168) days to 34 (23-44) days (p < 0.001). the time from patient’s referral to prostate biopsy decreased substantially from 34 (20-66) days to 18(1125) days after dap (p < 0.001). after dap, the percentage of gleason 6 detected prostate cancers were significantly increased (19.7% to 30%) (p = 0.02). after dap, rate for intermediate-risk patients elected for external beam radiotherapy (from 53.5% to 57.9%, p = 0.53) and radical prostatectomy (from 34.5% to 39.4%, p = 0.47) increased. more compliance to canadian guidelines was observed in intermediate risk patients (88% vs 97.3%, p =.008). conclusions: implementation of dap has led to a notable reduction of waiting time to urology consult and prostate biopsy. there is significant increase in gleason 6 detected prostate cancer. increased compliance to canadian guidelines was detected in intermediate risk patients. key words: prostate cancer; diagnostic assessment program; prostate biopsy. submitted 21 september 2021; accepted 17 october 2021 introduction prostate cancer (pca) is the second commonly diagnosed malignancy in men worldwide (1). the diversity in treatment options among different risk groups of prostate cancer necessitate cooperation amongst different specialities and substantial patients’ involvement (2). it is important that patients diagnosed with prostate cancer get assessed promptly, preferably in multidisciplinary clinics (mdc) that are composed of radiation oncologists, urologist and diagnostic assessment program for prostate cancer: lessons learned after 2 years and degree of compliance to canadian guidelines waleed shabana, ahmed kotb, daniel tesolin, mohammed f.k. ibrahim, kristi dolcetti, amy boucher, mohammed bassuony, kevin ramchandar, ahmed s. zakaria, hazem elmansy, walid shahrour northern ontario school of medicine, thunder bay, ontario, canada. doi: 10.4081/aiua.2021.4.389 summary archivio italiano di urologia e andrologia 2021; 93, 4 w. shabana, a. kotb, d. tesolin, et al. 390 patient and methods electronic medical records for patients referred with suspected diagnosis of prostate cancer to our institute between 2016 and 2020 were reviewed and enrolled in this retrospective study after obtaining ethical board committee approval. in 2018, diagnostic assessment program (dap) for prostate cancer was implemented in our institute where any patient referred with elevated psa and/or suspicious digital rectal exam was briefly evaluated by the dap coordinator. a structured referral form for each patient was created includin patient demographics, psa, digital rectal exam, family history of prostate cancer, and other available clinical data. expediated approach was used for the evaluation of the patients in specialized dap clinic. all patients were evaluated by a urologist who discussed the management plan. for patients diagnosed with prostate cancer, all clinical data were discussed in our multidisciplinary genitourinary oncology weekly meeting. finally, these patients get two separate meetings with both the urologist and the radiation oncologist before making a treatment decision (figure 1). patient cohort the initial registry included all patients referred with suspected diagnosis of prostate cancer. patients with prior diagnosis of prostate cancer were excluded from the study. patients were stratified into 2 groups according to the date of referral. group i included patient referred to our institute before may 2018 while group ii included patient referred after that. data obtained included patient’s age, referral date, referral reason, psa level, date of biopsy, tumor stage, gleason score (gs), percent core involvement, and treatment decision. patients were classified into three risk groups according to the d’amico criteria (11). for elaborating the effect of dap implementation, patients’ variables and designated treatment options were compared before and after dap configuration in the two study groups. moreover, within each risk group, the chosen treatment was compared with the bench-mark recommendation of the canadian guidelines. statistical analysis categorical variables were presented through numbers and percentages, and compared between groups using fisher’s exact test. the median and interquartile range (iqr) were calculated and compared using the mannwhitney test. patients’ data was analysed using spss version 26 (ibm corp., armonk, ny). statistical significance was defined as a two-tailed p-value less than 0.05. results over the four years of the study, a total of 570 patients were included in the study. one hundred sixty-eight patients were investigated for suspicion of prostate cancer before dap implementation and 402 of them were referred after dap initiation and allocated to the post dap group. thirty-one patients had negative biopsy in the pre-dap group while 107 patients were negative in the post-dap group. the median age of patients in the pre-dap and post-dap groups was 67 and 71 years, respectively (p = 0.14). the distribution of clinicopathological data per group were presented in table 1. by comparing the two study groups it was shown that, median waiting time for receiving urology consultation and prostate biopsy were substantially reduced (68 to 34 days and 34 to 18 days respectively, p < 0.001). additionally, the proportion of patients who had a negative prostatic biopsy increased significantly (p = 0.03). the percentage of gleason 6 detected prostate adenocarcinoma was increased (19.7% vs 30.5%, p = 0.02) while gleason 7 detected one were significantly decreased (50% vs 29.6%, p = 0.002). after dap, rate of intermediaterisk patients elected for external beam radiotherapy (from 53.5% to 57.9%, p = 0.53) and radical prostatectomy (from 34.5% to 39.4%, p = 0.47) increased. figure 1. patient flow through the multidisciplinary genitourinary cancer clinic after dap. 391archivio italiano di urologia e andrologia 2021; 93, 4 diagnostic assessment program for prostate cancer following dap, 97.3% of intermediate-risk patients received a treatment according to canadian guidelines 1st line recommendation which was significantly higher than the rate prior to dap (88% vs 97.3%, p = 0.008) (figure 2, table 2). discussion a centralised, organised system with a multidisciplinary approach is critical for expediting the delivery of diagnostic cancer assessment services (12). the diagnostic assessment program is an evidence-based approach that originates from published literature, environmental scan and the opinion of related expertise who reach to a consensus on the standard organized diagnostic assessment services in ontario (13). one of the critical issues in approaching the prostate cancer cases is the time gap between diagnosis and the provided treatment. according to a prospective canadian study, the median of waiting time for prostate cancer diagnosis was about 81 days (14). in an irish prospective study evaluating rapid access diagnostic clinic, the median waiting time from referral date to urology consultation was 13 days (range, 1-37) (15). the calgary prostate institute's rapid access clinic (rac) reported a median wait time of 21 days from referral by primary care provider to prostate biopsyv (16). in our series, we reported 34 days median waiting time from referral to urology consultation. the differences in the median waiting time in the irish (15), calgary institute (16) and our study may be attributed to the differences in catchment areas and the unique geographical characteristic of northern ontario. the area of coverage of northwestern ontario goes up to 526.000 km2, with numerous remote reserves and smaller towns. the changes of gleason grade detection in relation to changes in referral pathway have been previously studies. gilliland et al. described gleason grade migration in response to change in detection method from incidental finding to screening (17). in a comparative study evaluating prostate cancer rapid access diagnostic clinic, o’kelly et al. reported a downward migration in gleason grades with significant increase in gleason 6 detected prostate cancer (51% vs 18%) (18). guy et al., on the other hand, reported decrease in diagnosing low risk disease and increase in intermediate risk disease after initiation of multidisciplinary diagnostic assessment programme (5). we also identified increase in low-risk prostate cancer. these differences in results may be due to variability in studies design and discrepancies between multidisciplinary approach or diagnostic assessment program. additionally, we think that the facilitation of the referral process has led to an increase in the number of referrals which might have caused the increase in the number of cases with low-risk prostate cancer. the higher grade prior to dap can also be attributed to the effect of the us task force recommendation (19, 20). there is a growing interest in literature to link the multidisciplinary approach for prostate cancer management and the degree of care patients received and guidelines adherence. in a study of 630 patients from 3 tertiary care centers, aizer et. al. reported that patients managed through multidisciplinary approach were opted to active surveillance more than patients managed by a single speciality (64% vs 30%; p < 0.001) (21). the investigators concluded that multidisciplinary approach would lead to more adherence to national comprehensive cancer network (nccn) guidelines for very low risk prostate cancer and avoidance of unnecessary treatments. in our study, we aimed to look at the intermediate risk group as the options are clearer with fewer variabilities compared to the guideline’s recommendation for the lower or higher risk groups. another group of investigators noted significant adherence to nccn guidelines compared to the period before initiation of multidisciplinary clinic in intermediate risk group (89.8% vs. 76%, p = 0.01), while it was not statistically significant in table 1. comparison of frequency of demographic variables and potential risk factors in each study group. demographic pre-dap group post-dap group p-value n = 168 n = 402 age years median (iqr3-iqr1) 67 (69-63) 71 (72-69) 0.14 serum psa level (mg/dl) median (iqr3-iqr1) 7.3 (7.6-6.5) 6.9 (7.1-6.4) 0.08 waiting time for urology consultation (days) median (iqr3-iqr1) 68 (168-27) 34 (44-23) < 0.001 waiting time for prostate biopsy (days) median (iqr3-iqr1) 34 (66-20) 18 (25-11) < 0.001 number of positive prostate biopsy core median (iqr3-iqr1) 4 (6-4) 4 (7-4) 0.23 percentage of cancer involvement median (iqr3-iqr1) 30 (50-25) 35 (45-30) 0.27 negative biopsy 31 (18.4%) 107 (26.6%) 0.03 gleason 6 33 (19.7%) 123 (30.5%) 0.02 gleason 7 84 (50%) 119 (29.6%) 0.001 gleason > 8 20 (11.7%) 53 (13.2%) 0.1 table 2. primary treatment for intermediate risk category. figure 2. distribution of treatment choice for intermediate risk group. treatment options pre-dap post-dap p-value n = 84 n = 119 active surveillance (n) 6 (7.1%) 0 radical prostatectomy (n) 29 (34.5%) 47 (39.5%) 0.47 radiation therapy (n) 45 (53.5%) 69 (57.9%) 0.53 hormonal therapy (n) 4 (4.7%) 3 (2.5%) 0.7 archivio italiano di urologia e andrologia 2021; 93, 4 w. shabana, a. kotb, d. tesolin, et al. 392 low-risk (100% vs. 99%, p = 0.43) and high-risk patients (100% vs. 95%, p = 0.26) (22). similarly, our results showed significant adherence to canadian guidelines in the intermediate risk group (p = 0.008). our study is not void of limitations. firstly, the retrospective nature of our study is considered a design limitation. secondly, all participants in this research were seen in our tertiary care facility, a context that facilitates the implementation of multidisciplinary clinics more easily than community hospitals with geographical restrictions. lastly, our data analysis is limited to 4 years period and a longer time would warrant more accurate results. conclusions implementation of dap has led to a notable reduction of waiting time to urology consult and prostate biopsy. there is significant increase in gleason 6 detected prostate cancer. increased compliance to canadian guidelines was detected in intermediate risk patients. references 1. d’agostino d, corsi p, colicchia m, et al. the pathological and clinical features of anterior lesions of prostate cancer: evaluation in a single cohort of patients. arch ital urol androl. 2020; 92:102. 2. horwich a, hugosson j, de reijke t, et al. prostate cancer: esmo consensus conference guidelines 2012. ann oncol. 2013; 24:1141-62. 3. valicenti rk, gomella l, el-gabry e, et al. the multidisciplinary clinic approach to prostate cancer counseling and treatment. semin. urol. oncol. 2000; 18:188-191. 4. pillay b, wootten ac, crowe h, et al. the impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: a systematic review of the literature. cancer treat rev. 2016; 42:56-72. 5. guy d, ghanem g, loblaw a, et al. diagnosis, referral, and primary treatment decisions in newly diagnosed prostate cancer patients in a multidisciplinary diagnostic assessment program. can urol assoc j. 2016; 10:120. 6. keyes m, crook j, morris wj, et al. canadian prostate brachytherapy in 2012. can urol assoc j. 2013; 7:51-8. 7. sethukavalan p, zhang l, jethava v, et al. improved wait time intervals for prostate cancer patients in a multi-disciplinary rapid diagnostic unit compared to a community-based referral pattern. can urol assoc j. 2013; 7:244. 8. pepe p, candiano g, pepe l, et al. mpmri pi-rads score 3 lesions diagnosed by reference vs affiliated radiological centers: our experience in 950 cases. arch ital urol androl. 2021; 93:139-142. 9. stanzione a, creta m, imbriaco m, et al. attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: a national survey among italian urologists. arch ital urol androl. 2020; 9:291. 10. pereira-lourenço m, vieira e brito d, peralta jp, et al. influence of sociodemographic factors on treatment's choice for localized prostate cancer in portugal. arch ital urol androl. 2020; 92:45-49. 11. d'amico av, whittington r, schultz d, et al. outcome based staging for clinically localized adenocarcinoma of the prostate. j urol. 1997; 158:1422-1426. 12. brouwers m, crawford j, elison p, et al. organizational standards for diagnostic assessment programs. toronto (on): cancer care ontario; 2007 jun 15 (in review 2011 sep). program in evidence-based care evidence-based series organizational standards for dap in review 13. brouwers m, oliver tk, crawford j, et al. cancer diagnostic assessment programs: standards for the organization of care in ontario. curr oncol. 2009; 16:29-41. 14. grunfeld e, watters jm, urquhart r, et al. a prospective study of peri-diagnostic and surgical wait times for patients with presumptive colorectal, lung, or prostate cancer. br j cancer. 2009; 100:56-62. 15. forde jc, o'connor km, casey l, et al. a rapid access diagnostic clinic for prostate cancer: the experience after one year. ir j med sci. 2011; 180:505-8. 16. kavanagh ag, lee jc, donnelly b. time to treatment of prostate cancer through the calgary prostate institute rapid access clinic. can j urol. 2008; 15:3975-3979. 17. gilliland fd, gleason df, hunt wc, et al. trends in gleason score for prostate cancer diagnosed between 1983 and 1993. j urol. 2001; 165:846-850. 18. o'kelly f, thomas az, murray d, et al. emerging evidence for gleason grade migration and distance impact in prostate cancer? an analysis of the rapid access prostate clinic in a tertiary referral center: st. vincent's university hospital, dublin (2009-2011). ir j med sci. 2013; 182:487-91. 19. moyer va,us preventive services task force. screening for prostate cancer: u.s. preventive services task force recommendation statement. ann int med. 2012; 157:120-134. 20. butler ss, muralidhar v, zhao sg, et al. prostate cancer incidence across stage, nccn risk groups, and age before and after uspstf grade d recommendations against prostate-specific antigen screening in 2012. cancer. 2020; 126:717-724. 21. aizer aa, paly jj, zietman al, et al. models of care and nccn guideline adherence in very-low-risk prostate cancer. j natl compr canc netw 2013; 11:1364-72. 22. korman h, lanni tjr, shah c, et al. impact of a prostate multidisciplinary clinic program on patient treatment decisions and on adherence to nccn guidelines: the william beaumont hospital experience. am j clin oncol. 2013; 36:121-125. correspondence walid shabana, md (corresponding author) waleed.shabana@gmail.com ahmed kotb, md kotba@tbh.net daniel tesolin, md dtesoln@nosm.ca mohammed ibrahim, md ibrahimm@tbh.net kristi dolcetti, md dolcetk@tbh.net amy boucher, md bouchra@tbh.net mohammed bassuony, md bassunm@tbh.net kevin ramchandar, md ramchnk@tbh.net ahmed zakaria, md aszakari81@yahoo.com hazem elmansy, md elmancyh@tbh.net walid shahrour, md walid.shahrou@gmail.com urology department, northern ontario school of medicine, 146 court street south, thunder bay, on p7b 2x6, canada stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12525 1 original paper introduction azoospermia, defined as lack of spermatozoa in ejaculate samples, affects 1% of all men and 10-15% of individuals with infertility (1, 2). moreover, about 60% of men with azoospermia have non-obstructive azoospermia (noa) that occurs by severe defects during spermatogenesis procedure (3). cryopreservation of spermatozoa after biopsy of testicular tissue prevent from repetitions of biopsy in azoospermic cases (4). conventional cryopreservation methods are not appropriate in these cases owing to limited numbers of spermatozoa which are lost during freezing and thawing techniques (5). therefore, the concept of single spermatozoa cryopreservation (ssc) was proposed in 1997 by cohen et al. (6) who used empty zona pellucida for freezing. after that, various cryo-devices and methods were designed to increase fertilization chance in cases with limited number of sperm (7). in this regard, some details of this technique, such as selecting proper spermatozoa before freezing, requir much more attention. in these cases, sperm specimen obtained from testicular tissue usually poses little or no motility. using spermatozoa with no motility in icsi procedure negatively affects clinical outcomes (8). therefore, it is noteworthy to find a method for selecting viable spermatozoa before freezing in order to optimize thawing outcomes (especially sperm motility) with less possible adverse effects on sperm biological characteristics. in case of absent or poor movement of testicular sperm specimen, different methods including hypoosmotic swelling test (hos), sperm tail flexibility test and in-vitro culturing are available to enhance motility of testicular sperm (9, 10). the mentioned methods might adversely affect sperm functions and biological characteristics. for instance, hos test causes water entrance to spermatozoa resulting in membrane expansion which finally leads to cell membrane lysis and death (11). pentoxifylline (ptx), sperm activation chemical agent, is a phosphodiesterase (pde) inhibitor that is able to improve sperm motility by increasing cyclic adenosine monophosphate (c-amp) levels and protein kinase a (pka) activity. ptx is a user-friendly and easy method to identify viable spermatozoa from immotile spermatozoa (12). background: single sperm cryopreservation (ssc) is a specific technique especially used in individuals with small numbers of sperm who suffered from non-obstructive azoospermia (noa). testicular specimens possess poor motility and low population of viable spermatozoa. therefore, sperm selection methods such as applying pentoxifylline (ptx) may improve motility in these cases. the main aim of this study was to evaluate the protective effects of ptx on testicular spermatozoa before and after performing ssc. methods: thirty testicular samples were obtained from men with azoospermia. this study was conducted in two phases. phase 1 evaluated the effect of ptx for sperm selection before ssc. twenty testicular samples were divided to two experimental groups: ssc without (i) and with ptx treatment (ii). for ptx treatment spermatozoa were incubated with ptx at 37°c for 30 min and only motile spermatozoa were selected for ssc. in phase 2, ten testicular samples were cryopreserved with ssc and warming procedure was carried out in droplet with and without ptx. motility and viability rates, morphology by motile sperm organelle morphology examination (msome), dna fragmentation by sperm chromatin dispersion test (scd) and mitochondrial membrane potential (mmp) were evaluated. results: in phase 1, post warm motility rate was higher in ptx exposed group compared to the unexposed group (25.6 ± 8.13 vs. 0.85 ± 2.1) (p > 0.00). recovery rate, viability and morphology were not significantly different between groups. dna integrity and mmp were also similar between both groups. in phase 2 although motility increased in ptx group compared to without ptx group (29.30 ± 12.73 vs. 1.90 ± 2.64) (p > 0.00), the viability rate was not different (70.40 ± 12.12 vs. 65.30 ± 11.87). all above mentioned parameters were similar between the two ssc groups. conclusions: supplementation of testicular spermatozoa with ptx before cryopreservation increases motility and did not have adverse effects on viability, morphology, dna integrity and mmp. ptx could be used as sperm selection method before single sperm cryopreservation, but ptx could not maintain motile the most of viable testicular sperms. key words: non-obstructive azoospermia; pentoxifylline; testicular sperm; single sperm cryopreservation. submitted 29 march 2024; accepted 6 april 2024 pentoxifylline treatment as a safe method for selecting viable testicular spermatozoa before cryopreservation of a small numbers of spermatozoa in azoospermia individuals keivan lorian 1, 2, serajoddin vahidi 3, fatemeh dehghanpour 2, fatemeh anbari 2, azam agha-rahimi 2 1 international campus, shahid sadoughi university of medical science, yazd, iran; 2 research and clinical center for infertility, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran; 3 andrology research center, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran. doi: 10.4081/aiua.2024.12525 summary archivio italiano di urologia e andrologia 2024; 96(2):12525 k. lorian, s. vahidi, f. dehghanpour, f. anbari, a. agha-rahimi 2 to our knowledge, ptx as sperm selection method has not been used in ssc technique. the main aim of this study is to investigate the effect of ptx on sperm motility, morphology, viability, dna fragmentation and mitochondrial membrane potential by incubation of noa testicular samples in ptx (as sperm selection method) before and after applying ssc technique using cryo-vial device. methods and materials study design this study was performed from 22 june 2023 to 28 september 2023 at yazd reproductive sciences institute. it was was approved by ethics committee of shahid sadoughi university of medical sciences (ir.ssu.medicine.rec.1401.016). written informed consents were obtained from the men who referred to yazd infertility center for treatment before collection of samples. the study was conducted in two phases. phase 1: 1. testicular sperm specimens were collected surgically by tese and micro-tese from 20 azoospermic men. 2. selected spermatozoa were randomly divided into two experimental groups: (i): ssc without ptx treatment (control) and (ii): ssc with ptx treatment. 3. testicular spermatozoa were prepared, and the suspension was divided and poured in two culture dishes (one for control group and the other one for ptx group. 4. in both groups the spermatozoa were selected first based on tail movement and then by tail flexibility gently by a icsi injection micropipette (nikon, japan) equipped with a micromanipulator. 5. in control group, twenty spermatozoa were randomly selected and placed in hos medium and the percentage of viable spermatozoa was determined. 6. the viability and motility of fresh testicular samples were also reported. 7. the remaining spermatozoa were cryopreserved. 8. in ptx group, the selected spermatozoa transferred to the ptx droplets and after that, only motile spermatozoa were selected for ssc. phase 2: 1. in this phase, spermatozoa were selected from tese and micro-tese samples from 10 azoospermic men. 2. about one-hundred testicular spermatozoa or more were selected as previous described and cryopreserved by ssc technique on several cryotops. 3. for warming, cryotops were randomly divided to be warmed in (i): sperm washing medium without ptx (control) or (ii) in sperm washing medium with ptx in the same concentration as phase 1 (figure 1). testicular sperm preparation and processing seminiferous tubules fragments were poured in large culture dishes consisting of sperm washing medium (bio chrome, berlin, germany) supplemented with 5 mg/ml human serum albumin (hsa, vitrolife, englewood, co). seminiferous tubules were recognized by applying a stereomicroscope and the stainless blades were used to remove blood clots. after that, extruded testicular tissue was washed in sperm washing medium supplemented with 5 mg/ml hsa to remove the blood and then placed to the central-well dish (falcon, usa) consisting of fresh sperm medium. tubules mechanical dispersion was performed by mincing repeatedly using stainless blades. the media containing spermatozoa was centrifuged at 300g for 10 min. after removing the supernatant, the collected pellet was resuspended in 1 ml of sperm washing medium supplemented with 5 mg/ml hsa and used for single sperm cryopreservation (13). single sperm cryopreservation and warming procedure testicular samples (1-3 μl droplet) were added to 5 μl droplet of sperm washing medium supplemented with 5 mg/ ml hsa on icsi dish (falcon, 1006 dish) (figure 1b). sperm cells were collected using icsi injection micropipette (nikon, japan) equipped with a micromanipulator (figure 1c). for single sperm cryopreservation cryotop vial device (cvd) was used. in previous study, we designed a new carrier which contains cryotop (kitazato, japan) and cryovial (nest, china) (14) (figure 1a). selected spermatozoa were placed on 0.5 m sucrose (sigma-aldrich) diluted 1:1 with sperm washing medium (final concentration 0.25 m sucrose) droplet on the cryotop strip by using the icsi pipette (figure 1d, e). then, the polypropylene strip was placed into the cryovial and closed carefully (figure 1f). cryovial directly plunged into liquid nitrogen (figure 1g). the samples were maintained in liquid nitrogen at least 72 h pre warming (15). for warming procedure, cryotops were removed from cryovials and cryotop strip was placed directly in a pre-warmed 5 μl droplet of sperm washing medium supplemented with 5 mg/ ml hsa on icsi dish at 37°c. cryotop was washed with 10 μl droplets to remove all spermatozoa remain on cryotop strip (figure 1i). pre-warmed oil (ovoil; vitrolife, sweden) was poured on droplet with spermatozoa. after 30 min incubation at 37°c, to aspirate sperm cells a micropipette equipped with micromanipulator on an inverted microscope was used. finally, retrieved spermatozoa were transferred to a new droplet of sperm washing medium supplemented with 5 mg/ml hsa (15). in phase 2, in addition to warming in sperm washing medium, warming was also performed in ptx droplet (figure 1j). treatment of testicular spermatozoa with ptx for ptx preparation, 3.6 mm stock solution of ptx (sigma, st. louis, mo, usa) was provided by adding 1 mg ptx powder to 1 ml sperm washing medium supplemented with 5 mg/ml has. this solution can be stored at 4°c for up to 7 days. to prepare working solution, the stock solution was diluted 1:1 with sperm washing medium. the final concentration of ptx in the specimen was 1.76 mm. selected spermatozoa by icsi injection micropipette (nikon, japan) equipped with a micromanipulator were added to the ptx droplet, which was overlaid with pre-warmed oil (ovoil; vitrolife, sweden). testicular sperm samples were incubated in ptx droplets at 37°c for 30 min. the droplet was investigated for viable and motile spermatozoa and then, selected by icsi injection micropipette and transferred to the new droplet for freezing (16). in phase 2, if spermatozoa were not motile, the viability was checked with hos test. archivio italiano di urologia e andrologia 2024; 96(2):12525 3 pentoxifylline and spermatozoa cryopreservation figure 1. steps of study design. cvd: cryotop vial device, pvp: polyvinylpyrrolidone, icsi: intracytoplasmic sperm injection, ln: liquid nitrogen, hsa: human serum albumin (figure is original and never used before). a. cryotop vial device (cvd) was used for single sperm cryopreservation. this device consists of vial, a screw cap, cryotop, soft foam and a fine polypropylene strip. b. droplets of testicular spermatozoa and pvp droplet for needle stabilization. c. sperm cells were collected using a icsi injection micropipette equipped with a micromanipulator. d. sperm cells were placed into the ptx droplet and in the droplets without ptx. e. both culture dishes were transferred to the incubator. f. spermatozoa incubated with and without ptx were placed into the sucrose droplet on the tip of the cryotop and then, the cryotops were inserted into cryovial and closed with screw cap tightly. g. cryovials were transferred to the ln tank. h. for warming cryovials were removed from ln tank and placed into the ln foam box. i. cryotops were removed from cryovials and cryotop strip was placed directly in a pre-warmed 5 μl droplet of sperm washing medium supplemented with 5 mg/ml hsa on icsi dish at 37◦c. archivio italiano di urologia e andrologia 2024; 96(2):12525 k. lorian, s. vahidi, f. dehghanpour, f. anbari, a. agha-rahimi 4 sperm parameters evaluation to assess sperm recovery, motility and viability an inverted microscope system was used. sperm recovery rate was recorded by below formula: number of post-warm sperm /number of cryopreserved sperm × 100. sperm motility and viability were determined by post-thaw motility and viability, respectively (15). for viability assessment after thawing, motile spermatozoa were considered viable, while for immotile spermatozoa hypo-osmotic swelling test (hos) was performed. the sum of motile and nonmotile sperms in the medium was calculated. hypo-osmotic swelling test (hos) the spermatozoa were selected by using a icsi injection micropipette (nikon, japan) equipped with a micromanipulator and then the tail of spermatozoa was placed in 5µl of hypo-osmotic droplet. coiled tail patterns viable spermatozoa indicated. for preparing hos medium, the sperm washing medium was diluted 1:1 with distilled water (17). fine sperm morphology evaluation the morphology of spermatozoa was evaluated applying an inverted microscope at high magnification using motile sperm organelle morphology examination (msome) technique (nikon eclipse te300). medium droplets were placed into the glass-bottom dish (gwst 1000; will co.) and sperm cells were transferred to it by using a icsi pipette equipped with a micromanipulator. sperm cells were then assessed under high magnification (6600 ×) using an inverted microscope with high-power differential interference contrast optics. morphological assessment was carried out on monitor and spermatozoa were categorized in to three groups (high, medium and lowquality) according to the shape of the spermatozoa (sperm head, vacuoles, and base) (18). dna fragmentation evaluation the sdfa kit (tehran, iran) was used to assess sperm dna fragmentation by sperm chromatin dispersion (scd) test. briefly, low-melting-point agarose gel droplet (5 μl) was placed onto the pre-coated slide. selected spermatozoa by icsi injection micropipette (nikon, japan) equipped with a micromanipulator were gently added to the agarose gel droplet and small coverslips were placed on the slide. after that, the staining procedure was done according to the kit instructions. then, slides were assessed by a bright field microscope according to the halo size. spermatozoa with no or small halos showed dna fragmentation while, spermatozoa with medium or large halos considered as intact dna. percentage of spermatozoa with dna fragmentation was recorded (16). sperm mitochondrial membrane potential (mmp) evaluation sperm mitochondrial membrane potential (mmp) was assessed by tetraethylbenzimidazolylcarbocyanine iodide (jc-1) mitochondrial membrane potential assay kit (cayman chemical co, ann arbor, mi, usa; cat #10009172). the sperm cells were placed in jc-1 working solution droplets by the icsi pipette equipped with micromanipulator. after that, samples were incubated at 37°c for 30 min in dark environment. then, the cells were examined by fluorescence microscope (olympus bx51, japan) according to manufacturer’s instructions. spermatozoa with an orange fluorescence dye were considered as having high mitochondrial membrane potential (active mitochondria, jc1+). the percentage of cells with a high mitochondrial membrane potential were recorded (15). statistical analysis data were analyzed by the statistical package for the social sciences (spss) version 20 (ibm, california, united states). data were expressed as mean ± sd. kolmogorov-smirnov test was used to test the normality of data. independent sample t test and mann-whitney test were used for comparing the data with normal and abnormal distribution, respectively between two cryo-groups groups. paired sample t test was used for comparing the fresh group with cryo-groups. plotted graphs were carried out with graphpad prism 8.4.2 (graphpad software, inc., san diego, ca, usa). p < 0.05 was considered significant. figure 2. sperm parameters. recovery (a), viability (b) and motility (c) of testicular spermatozoa incubated with ptx before single sperm cryopreservation (phase 1). data are presented as mean ± sd. ***p<0.001 (analysis by mann-whitney test). a and b analysis by independent samples t test. archivio italiano di urologia e andrologia 2024; 96(2):12525 5 pentoxifylline and spermatozoa cryopreservation results phase 1 (ptx treatment before cryopreservation) post-warmed spermatozoa parameters in phase 1 results of sperm parameters showed that recovery rate after scc was similar between ptx and control groups (87.00 ± 7.07 vs. 87.70 ± 6.74) (figure 2a). the viability of fresh testicular samples, which was at first selected by tail flexibility and twitching movement and then confirmed by hos test, was about 98%. the percentage of viable spermatozoa decreased in ptx and control groups compared to the fresh group (71.55 ± 11.36 vs. 66.80 ± 11.09 and vs. 98.8 ± 3.15, p > 0.001). no remarkable changes were observed in viability rates between the two ssc groups (figure 2b). the percentage of fresh motile testicular spermatozoa was about 11.75%. after incubation with ptx, only the motile spermatozoa (approximately, 100% motile spermatozoa) were selected for ssc in the ptx group. exposure of testicular samples with ptx before freezing significantly increased the motility rate of post-thawed spermatozoa compared to the unexposed group (25.65 ± 8.13 vs. 0.85 ± 2.10) (figure 2c p > 0.001). post-warmed sperm dna fragmentation and mitochondrial membrane potential in phase 1, comparison of dna fragmentation results between cryopreservation groups showed that ptx did not significantly alter dna fragmentation percentage (32.6 ± 4.18 vs. 31.10 ± 4.15) (figure 3a). the percentage of spermatozoa with active mitochondrial membrane potential in phase 1 was not different between two cryopreservation groups (50.20 ± 9.15 vs. 49.25 ± 9.12) (figure 3b). post-warmed fine sperm morphology the percentages of high (10.40 ± 6.85 vs. 9.30 ± 6.30), medium (53.30 ± 15.71 vs. 51.30 ± 15.52) and low (33.90 ± 14.48 vs. 38.00 ± 13.91) quality spermatozoa in phase 1 were not different between ptx and control groups (figure 4a-c). figure 4. fine sperm morphology. morphology of sperm classified in three groups high (a), medium (b) and low (c) quality after incubation in ptx before single sperm cryopreservation (phase 1). data are presented as mean ± sd and analysis by independent samples t test. figure 3. dna fragmentation index (dfi) (a) and mitochondrial membrane potential (mmp) (b) after incubation with ptx before single sperm cryopreservation (phase 1). data are presented as mean ± sd and analysis by independent samples t test. archivio italiano di urologia e andrologia 2024; 96(2):12525 k. lorian, s. vahidi, f. dehghanpour, f. anbari, a. agha-rahimi 6 phase 2 (ptx treatment after cryopreservation) post-warmed spermatozoa parameters in phase 2, recovery rate was similar between ptx and control groups (84.70 ± 11.26 vs. 85.80 ± 9.15) (figure 5a). the percentage of fresh viable testicular spermatozoa, which were selected as in phase 1, was about 98.5% and decreased in both ssc groups compared to the fresh group (70.40 ± 12.12 vs. 65.30 ± 11.87 and vs. 98.5 ± 2.10, p > 0. 001). moreover, there were no significant changes between the two ssc groups in viability rate (figure 5b). the percentage of fresh motile testicular spermatozoa was about 10%. after warming, the percentage of motile spermatozoa which were incubated with ptx was significantly increased compared to the spermatozoa without ptx incubation (29.30 ± 12.73 vs. 1.90 ± 2.64) (figure 5c p > 0. 001).comparison of motility (29.30 ± 12.73) and viability (70.40 ± 12.12) in ptx group in phase 2 were significantly different (p > 0. 001). this result showed that after ptx not all viable spermatozoa could be motile. post-warmed sperm dna fragmentation and mitochondrial membrane potential in phase 2, dna fragmentation was similar between the two ssc groups (28.70 ± 4.64 vs. 29.50 ± 3.97) (figure 6a). in phase 2, spermatozoa with active mitochondrial membrane potential were similar in the two cryopreservation groups (55.30 ± 6.73 vs. 55.40 ± 5.81) (figure 6b). post-warmed fine sperm morphology in phase 2, high (17.50 ± 11.50 vs.16.10 ± 11.68), medium (51.60 ± 12.86 vs. 52.70 ± 15.16) and low (30.90 ± 11.51 vs.31.20 ± 17.47) quality testicular spermatozoa rates were similar between ptx and control groups (figure 7a-c). figure 5. sperm parameters. recovery (a), viability (b) and motility (c) of testicular spermatozoa incubated with ptx after single sperm cryopreservation (phase 2). data are presented as mean ± sd and analysis by independent samples t test. ***p < 0.001 versus control and ptx groups. figure 6. dna fragmentation index (dfi) (a) and mitochondrial membrane potential (mmp) (b) after incubation with ptx before single sperm cryopreservation (phase 1). data are presented as mean ± sd and analysis by independent samples t test. archivio italiano di urologia e andrologia 2024; 96(2):12525 7 pentoxifylline and spermatozoa cryopreservation discussion the cryopreservation of sperm with ssc technique is beneficial to reduce the times of sperm retrieval techniques by freezing spermatozoa (without testicular tissues, debris and round cells) on a significant number of cryotop. therefore, using this method increased the oocyte retrieval times in these groups of patients. we previously reported that ssc using cvd (14) and sucrose medium (15) was a suitable strategy for cryopreservation of testicular sperm. tese or micro-tese samples may have 10 or more than 100 spermatozoa, which it is not practical to place all together on a cryotop. in this regard, viable spermatozoa with good morphology should be selected. selecting viable spermatozoa based on sperm tail flexibility depends on skill and experience of the embryologist. using safe chemical substance like ptx could resolve the weakness of sperm tail flexibility method (19). although some studies evaluated the safety of ptx on cryopreserved testicular sperms after thawing in conventional freezing method, it is not clear whether testicular sperm exposure to ptx before cryopreservation make it more vulnerable to cryo-damage. mahaldashtian et al. concluded that ptx exerts beneficial effects on post-thawed sperm motility and increased 2pn and embryo formation without detrimental impacts on sperm dna integrity (16). xian et al. supplemented the sperm freezing media with ptx for assessing testicular sperm motility during cryopreservation and warming procedures and reported that ptx enhances testicular sperm motility (20). the recovery rate, number of spermatozoa that were retrieved after freezing, is an essential factor that can show the efficacy of cryo-devices. our recovery rate was about 87% which is in accordance with other researches that applied similar cryo-devices (21, 22). also, the viability rate after ssc in both phases was about 60% in agreement with our previous report (15). in both phases of this study, at first, tail movement and flexibility method was applied to select viable spermatozoa. the hos test showed that about 98% of these spermatozoa were viable. this indicated that, if these methods are used properly, a significant number of viable spermatozoa could be selected. moreover, we showed that the incubation of testicular sperm, before and after ssc, with ptx enhances sperm motility, although no significant difference was observed between groups in sperm viability. the similarity of post-warming viability between groups showed that ptx does not exert detrimental effects on sperm in cryo-warmed process. in phase two, 26% of spermatozoa were motile after warming in ptx, while the viability rate was more than 60%. probably the cryo-damage to spermatozoa caused that most of viable sperm cannot be motile after ptx exposure. therefore, using ptx after ssc when the numbers of spermatozoa are limited is not practical for selecting viable spermatozoa. exposure of testicular spermatozoa to ptx before and after ssc did not show adverse effect on fine morphology. nabi et al. incubated ejaculated spermatozoa samples with 3.6 mmol/l ptx for 30 min at 37ºc after vitrification warming and showed that ptx did not alter ultrastructural aspects of spermatozoa (23). in another study, mahaldashtian et al. reported that treatment of oligoasthenoteratozoospermic samples with ptx did not change the vacuole status of sperm head (24). sperm chromatin integrity and structure are a determining factor in fertility potential. it is vital to inseminate the oocytes with spermatozoa that have intact dna. our results showed that ptx did not alter dna integrity of testicular samples when applied before and after freezing between groups. this finding is in agreement with other studies that showed ptx does not have harmful impacts on dna/chromatin status in tese (16) and asthenozoospermic cases (25, 26). mmp is related to normal sperm parameters including motility and viability. mitochondria are the main source of adenosine triphosphate generation that is vital for sperm motility and cellular phenomena including capacitation, hyper activation and acrosome reaction (27). according to our results, mmp was similar between ptx exposed and non-exposed group before and after ssc. previously it was figure 7. fine sperm morphology. morphology of sperm classified in three groups high (a), medium (b) and low (c) quality incubated in ptx after single sperm cryopreservation (phase 2). data are presented as mean ± sd and analysis by independent samples t test. archivio italiano di urologia e andrologia 2024; 96(2):12525 k. lorian, s. vahidi, f. dehghanpour, f. anbari, a. agha-rahimi 8 reported that ptx did not exert any detrimental effect on sperm mmp (24). conclusions adding ptx at safe concentration as sperm selection method before ssc of testicular samples, could select the viable sperm without intensifying the adverse effects of cryo-damage. however, it seems that using ptx after warming, when numbers of spermatozoa are limited, is not practical for selecting viable spermatozoa, because the most of viable sperm cannot be motile after ptx exposure during warming procedure. references 1. cetinkaya m, onem k, zorba ou, et al. evaluation of microdissection testicular sperm extraction results in patients with nonobstructive azoospermia: independent predictive factors and best cutoff values for sperm retrieval. urology journal. 2015; 12:2436-43. 2. cocuzza m, alvarenga c, pagani r. the epidemiology and etiology of azoospermia. clinics. 2013; 68:15-26. 3. modarresi t, hosseinifar h, hampa ad, et al. predictive factors of successful microdissection testicular sperm extraction in patients with presumed sertoli cell-only syndrome. int j fertil steril. 2015; 9:107-12. 4. abdelhafez f, bedaiwy m, el-nashar sa, et al. techniques 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intracytoplasmic sperm injection? an embryologist's view. andrology. 2015; 3:156-62. 20. xian y, jiang m, liu b, et al. a cryoprotectant supplemented with pentoxifylline can improve the effect of freezing on the motility of human testicular sperm. zygote. 2022; 30:92-7. 21. endo y, fujii y, shintani k, et al. single spermatozoon freezing using cryotop. journal of mammalian ova research. 2011; 28:47-52. 22. sun j, chen w, zhou l, et al. successful delivery derived from cryopreserved rare human spermatozoa with novel cryopiece. andrology. 2017; 5:832-7. 23. nabi a, khalili ma, talebi ar, et al. in-vitro application of pentoxifylline preserved ultrastructure of spermatozoa after vitrification in asthenozoospermic patients. urology journal. 2017; 14:4038-43. 24. mahaldashtian m, khalili ma, vatanparast m, et al. the effect of pentoxifylline and calcium ionophore treatment on sperm cell biology in oligoasthenoteratozoospermia samples. zygote. 2023; 31:85-90. 25. asokan y, honguntikar sd, uppangala s, et al. in situ viability detection assays induce heat-shock protein 70 expression in spermatozoa without affecting the chromatin integrity. andrologia. 2015; 47:958-65. 26. nabi a, khalili ma, fesahat f, et al. pentoxifylline increase sperm motility in devitrified spermatozoa from asthenozoospermic patient without damage chromatin and dna integrity. cryobiology. 2017; 76:59-64. 27. boguenet m, bouet p-e, spiers a, et al. mitochondria: their role in spermatozoa and in male infertility. hum reprod update. 2021; 27:697-719. correspondence keivan lorian, phd international campus, shahid sadoughi university of medical science, yazd, iran serajoddin vahidi, md andrology research center, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, yazd, iran fatemeh dehghanpour, phd fatemeh anbari, phd azam agha-rahimi, phd (corresponding author) 63rahimi@gmail.com research and clinical center for infertility, yazd reproductive sciences institute, shahid sadoughi university of medical sciences, bouali avenue, safayieh, yazd, iran conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12358 1 original paper materials and methods from january 2011 to january 2023, 2,405 men (median age: 64 years; range: 41-86 years) underwent extended (median 20 cores; range: 16-22) or saturation (spbx: median 26 cores; range: 22-30) transperineal prostate biopsy for the suspicion of cancer (9-11). informed consents were obtained from all participants included in the study following institutional ethical committee approval. before biopsy the patients underwent pelvic mpmri using a 1.5 and 3.0 tesla scanner (achieva 3t; philips healthcare best, the netherlands) equipped with surface 16-channel phased-array coil; multi-planar turbo spinecho t2-weighted, axial diffusion weighted imaging (high b-value 2000 s/mm2), and axial dynamic contrast enhanced mri were performed for each patient (12). the systematic biopsy was performed transperineally and mpmri lesions with pi-rads score > 3 (1.380/2.405 equal to 57.4% of the cases) were submitted to targeted biopsy (tpbx: four cores performing a transperineal cognitive approach, anterior zone of the gland) or a fusion guided-biopsy (hitachi 70 arietta ecograph, chiba, japan) (13-15). all the patients were sedated and received a single intraoperative dose of antibiotic prophylaxis. the detection rate for cspca has been evaluated (16); moreover, the clavien-dindo grading system for the classification of biopsy complications was used (17). all the 180 men with pi-rads score 5 had not dysuria, irritative urinary symptoms or stranguria. in 155/180 (86.1%) patients a stage t1c pca was diagnosed, and 145/155 (93.5%) of them (table 1) were classified as cspca (international society of urologic pathology “isup grade group “gg” > 2); in detail, 85/145 (58.6%), 30/145 (20.7%) and 30/145 (20.7%) cspca were diagnosed in the peripheric, anterior or both zones of the prostate, respectively. the median total psa was 8.9 ng/ml (range: 2.7-95 ng/ml); moreover, quantitative biopsy histology, psa density (psad), psa free/total are listed in table 1. spbx diagnosed 5/155 (3.2%) cspca and 8/155 (5.2%) indolent pca located outside the pi-rads 5 lesions. in the remaining 25/180 (13.9%) patients with absence of cancer: 1/25 (4%) had a specific granulomatous prostatitis (mycobacterium tubercolosis), 8/25 (32%) an aspecific granulomatous prostatitis, and 16/25 (64%) a normal parenchyma. none of the patients had significant complications (only clavien-dindo grade i) following prostate introduction: to evaluate the accuracy of psma pet/ct in men with mpmri pi-rads score 5 negative biopsy histology. materials and methods: from january 2011 to january 2023, 180 men with pi-rads score 5 underwent systematic plus mpmri/trus biopsy; 25/180 (13.9%) patients had absence of cancer and six months from biopsy were submitted to: digital rectal examination, psa and psa density exams, mpmri and 68gapsma pet/ct evaluation (standardized uptake value “suvmax” was reported). results: in 24/25 (96%) patients psa and psa density significantly decreased, moreover, the pi-rads score was downgraded resulting < 3; in addition, median suvmax was 7.5. only 1/25 (4%) man had an increased psa value (from 10.5 to 31 ng/ml) with a confirmed pi-rads score 5, suvmax of 32 and repeated prostate biopsy demonstrating a gleason score 9/isup grade group 5 pca. conclusions: the strict follow up of men with pi-rads score 5 and negative histology reduce the risk of missing cspca especially if psma pet/ct evaluation is in agreement with downgrading of mpmri (pi-rads score < 3). key words: prostate cancer; psma pet/ct; mpmri; pi-rads score 5. submitted 5 february 2024; accepted 18 february 2024 introduction multiparametric magnetic image resonance (mpmri) is recommended in men with suspicion prostate cancer (pca) (1), but, still today, systematic prostate biopsies should be always combined with mpmri/trus fusion biopsy due to the false negative rate (2-4) of mpmri (15-20% of the cases) (5). the aggressiveness of clinically significant (cspca) is correlated with the mpmri prostate imaging reporting and data system (pi-rads) scores; the detection rate for cspca of suspicious mpmri lesions performing targeted biopsy ranges from 65.3 to 83.8% (6) and in the presence of a suspicious area with pi-rads score 5 ranges from 59.2 to 86% of the cases (7, 8). therefore, a negative biopsy in men with pi-rads score 5 need a thorough clinical follow up to avoid missing cspca diagnosis. in our study, the follow up of men with negative biopsy histology of pi-rads score 5 lesions has been reported including prostate-specific membrane antigen (psma) positron-emission tomography (pet/ct) evaluation. negative biopsy histology in men with pi-rads score 5: is it useful psma pet/ct evaluation? pietro pepe 1, ludovica pepe 2, michele pennisi 1 1 urology unit, cannizzaro hospital, catania, italy; 2 department of human pathology in adult and developmental age "gaetano barresi", university of messina, italy. doi: 10.4081/aiua.2024.12358 summary archivio italiano di urologia e andrologia 2024; 96(2):12358 p. pepe, l. pepe, m. pennisi 2 biopsy, requiring hospital admission. the men with granulomatous prostatitis underwent specific antibiotic therapy followed by laboratory showing negative culture of urine and semen; moreover, the urine and sperm search for mycobacterium tuberculosis test including the semen polymerase chain reaction (pcr) (tb-pcr) were negative. the clinical follow up of patients without proven diagnosis of pca including psma pet/ct evaluation has been reported. results all the 25 men with pi-rads score 5 and negative histology six months from biopsy underwent: digital rectal examination (dre), psa, psad, mpmri and psma pet/ct evaluation (table 2). pet/ct imaging was performed using a ct-integrated pet scanner (biograph 6; siemens, knoxville, tn, usa); 68ga-psma-11 was given to patients via an intravenous bolus; images were processed to obtain pet, ct, and pet-ct fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm. the location of focal uptake on 68ga-psma pet/tc, three-dimensional size, and standardised uptake value (suvmax) values were reported on a per-lesion basis with a sextant scheme (18, 19). twenty-four (96%) patients did not underwent repeated prostate biopsy because psa significantly decreased, moreover, the initial pi-rads score 5 was significantly downgraded by a repeated mpmri to pi-rads score < 3 (table 2); in addition, median suvmax was 7.5 (range: 432). only 1/25 (4%) man, who was submitted 3 years before to transurethral prostate resection for benign prostate enlargement, had an increased psa value (from 10.5 to 31 ng/ml) with a confirmed pi-rads score 5 and intraprostatic suvmax of 32 and suspicious bone metastases; tpbx and systematic biopsy demonstrated the presence of a gleason score 9/isup gg5 pca (6/24 positive cores) located in the anterior zone of the prostate that extended outside the gland. discussion multiparametric mri has improved the cost-effectiveness of prostate biopsy by reducing the risk of overdiagnosis and number of unnecessary procedures (20, 21). although mpmri is strongly recommended in men candidate to prostate biopsy or enrolled in active surveillance protocols (2, 22, 23), extended or spbx should be always combined with mpmri/trus fusion biopsy because the false negative rate of mpmri (24) and the variable accuracy of mpmri/trus fusion biopsy platforms (25). the correlation of the pi-rads score to the diagnosis of aggressiveness cancer has been well established; westphalen et al. (7) and otti et al. (8) showed in men with pi-rads score 5 a detection rate for cspca equal to 59.2 and 86%, respectively; we previously reported a detection rate of cspca in the 86.7% of 105 men with pi-rads score 5 who underwent repeated prostate biopsy (26). the systematic prostate biopsy detects only 3.4% of cspca in case of negative mri/trus targeted biopsy of pi-ras score 5 lesions (27). therefore, the presence of a negative histology of a pi-rads score 5 lesion needs an accurate follow up to avoid the risk of missing a high grade cspca; the use of psa, psad, risk calculator, urinary genetic tests, and the repetition of mpmri allow to reduce the risk of harboring a cspca. in this respect, a second opinion regarding initial mpmri (28) and histology evaluation (29) should be performed to decrease the risk of false negative results. recently, psma-pet/ct has been proposed for the diagnosis of primary intraprostatic cancer (18, 19, 30, 31); the table 1. clinical parameters in 155 men with prostate cancer and pi-rads score 5 submitted to systematic plus fusion targeted biopsy (tpbx). quantitative biopsy histology pi-rads score 5 number of patients (pts) 155 pts initial biopsy 70/155 (45%) repeat biopsy 85/155 (55%) cspca 145/180 (86.1%) median mpmri index lesion diameter 23 millimeter (range) (16-31) detection of cspca (isup gg > 2) 145 pts systematic prostate biopsy 137 (94.5%) tpbx 138 (95.2%) median number of positive cores 13 tpbx (range) 3 (2-4) systematic biopsy (range) 10 (7-20) median gpc 75% tpbx (range) 80% (60-100%) systematic biopsy (range) 75% (50-100%) psa density (range) 0.21 (0.16-0.26) psa free/total (range) 12% (7-32%) median prostate weight (grams) 50 (20-130 grams) isup: international society of urologic pathology grade groups; mpmri: multiparametric magnetic resonance image; gpc: greatest percentage of cancer; pi-rads: prostate imaging reporting and data system. table 2. clinical follow up (six months from prostate biopsy) in 25 men with initial pi-rads score 5 and negative histology for prostate cancer. biopsy aspecific *specific normal cspca histology granulomatous granulomatous parenchyma isupgg5 prostatitis prostatitis number of patients 8 cases 1 case 15 cases 1 case initial biopsy 6 (75%) 1 (100%) 7 (46.6%) 1 (100%) repeat biopsy 2 (25%) 8 (63.4%) median psa (range) 6.2 ng/ml 3.2 ng/ml 4.7 ng/ml 31 ng/ml (1.5-10.8) (3.1-12.7) psa density (range) 0.12 0.13 0.15 0.25 (0.10-0.18) (0.12-0.16) dre negative negative negative negative pi-rads score < 2 4 (50%) 7 (46.5%) pi-rads score 3 4 (50%) 1 8 (63.4%) pi-rads score 4 pi-rads score 5 1 (100%) 68gapsma pet/ct 7 8 7 32 median suvmax (range: 4-10) (range 5-11) (4-11) dre: digital rectal examination; pi-rads: prostate imaging reporting and data system; dre: digital rectal evaluation; *mycobacterium tubercolosis; gapsma pet/ct: gallium prostate-specific membrane antigen positron-emission tomography; suvmax: standardized uptake value; isup gg: international society of urologic pathology grade groups. archivio italiano di urologia e andrologia 2024; 96(2):12358 3 psma pet/ct and negative pi-rads 5 biopsy presence of focal uptake on psma-pet/ct (suvmax) and the maximal dimensions of pet-avid lesions have been correlated with the presence of cspca (32). although there is a range of proposed cut-offs to detect cspca from suvmax (33-35), the concordance between preoperative psma pet/tc evaluation and definitive prostate specimen ranges from 81.2 (36) to 96% (37). many anatomic feature, benign conditions and technical pitfalls could mimic prostate cancer on mpmri (38,39); the analysis of mpmri parameters (dwi signal intensity and adc values) combined with noninvasive test could help to separate benign lesions from cspca (40-42). gottlieb et al. (43) reported that men with previous specific granulomatous prostatitits the presence of a pi-rads score ≤ 3 may not required prostate biopsy; in our experience, 16 men with initial pi-rads score 5 and negative histology demonstrated six months later a pi-rads score < 3 with normal clinical parameters (psa, dre, psad) (26). recently, wong et al. (44) in 29 men with pirads score 4-5 and negative biopsy histology reported that a suvmax > 20 was correlated with the presence of cspca in our series, 25/180 (13.9%) patients with pi-rads score 5 had negative biopsy histology; six months from prostate biopsy the reduction of psa and psad in 24/25 (96%) patients combined with the downgrading of pirads score from 5 to < 3 allowed to avoid a repeated prostate biopsy; at the same time, psma pet/ct evaluation showed suvmax (median 7.5) values not suspicious for cspca resulting in agreement with the mpmri results. only one man (4%) had an increased psa value (31 ng/ml) with pi-rads score 5, suvmax of 32 and tpbx combined with systematic biopsy demonstrated the presence of a gleason score 9/isup gg5 pca. in definitive, the strict clinical follow up of men with negative histology of pi-rads score 5 lesions reduce the risk of missing cspca especially if psma pet/ct evaluation is in agreement with downgrading of mpmri (pi-rads score < 3). regarding our results some considerations should be done. firstly, the results were not evaluated on the entire prostate gland. secondly, we do not know if the presence of a mpmri pirads score 3 (13 cases) was predictive of cspca because a new biopsy was not performed. third, a greater number of patients should be evaluated. finally, a longer follow up is needed. conclusions a significant reduction of psa and psad values combined with the downgrading of pi-rads score to < 3 allow to avoid a repeated prostate biopsy in men with initial pirads 5 and negative biopsy; 68gapsma pet/ct evaluation, in our series, was in agreement with mpmri results. references 1. lin y, yilmaz ec, belue mj, turkbey b. prostate mri and image quality: it is time to take stock. eur j radiol 2023; 161:110757. 2. pepe p, garufi a, priolo g, pennisi m. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol 2016; 34: 1249-1253. 3. 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68ga-psma pet/ct targeted biopsy for the diagnosis of clinically significant prostate cancer compared with transrectal ultrasound guided biopsy: a prospective randomized single-centre study. eur j nucl med mol imaging 2021; 48:483-492. 37. liu y, yu h, liu j, et al. a pilot study of 18f-dcfpyl pet/ct or pet/mri and ultrasound fusion targeted prostate biopsy for intra-prostatic pet-positive lesions. front oncol 2021; 11:612157. 38. rais-bahrami s, nix jw, turkbey b, et al. clinical and multiparametric mri signatures of granulomatous prostatitis. abdom radiol (ny) 2017; 42:1956-1962. 39. chatterjee a, thomas s, oto a prostate mr: pitfalls and benign lesions abdom radiol (ny) 2020; 45:2154-2164. 40. gordetsky jb, ullman d, schultz l, et al. histologic findings associated with false-positive multiparametric magnetic resonance imaging performed for prostate cancer detection. hum pathol 2019; 83:159-165. 41. kawada h, kanematsu m, goshima s, et al. multiphase contrast-enhanced magnetic resonance imaging features of bacillus calmette-guérin-induced granulomatous prostatitis in five patients. korean j radiol 2015; 16:342-348. 42. pepe p, pepe l, curduman m, et al. ductal prostate cancer staging: role of psma pet/ct. arch ital urol androl. 2024; 96:12132. 43. gottlieb j, princenthal r, cohen mi. multi-parametric mri findings of granulomatous prostatitis developing after intravesical bacillus calmette-guérin therapy. abdom radiol (ny) 2017; 42:1963-1967. 44. wong lm, koschel s, whish-wilson t, et al. investigating psmapet/ct to resolve prostate mri pirads4-5 and negative biopsy discordance. world j urol 2023; 463-469. correspondence pietro pepe, md piepepe@hotmail.com ludovica pepe, md ludopepe97@gmail.com michele pennisi, md michepennisi2@virgilio.it urology unit, cannizzaro hospital, via messina 829, catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 47 original paper urologist armamentarium is the ureteral access sheath (uas), to access the proximal collecting system. the use of uas has the proposed advantages of lowering the intrarenal pressure that probably decreases the complications related to infection, increasing irrigation flow and facilitating multiple reinsertions and withdrawals of the ureteroscope during surgery (4, 5). however, these benefits are associated with the cost of increased insertion forces and greater risk for ureteral wall injury, and possible failed insertion. proposed higher stone free rates with uas use and cost-effectiveness are too much debated (6-8). uas has multiple designs across multiple brands. although safety has been demonstrated, there have been few studies comparing designs of different companies in the hands of practicing urologists in vivo. we aimed to compare two commonly used uass regarding functional characteristics, safety profile and effectiveness of each. this information will help guide urologists in product selection when performing ureteroscopy. methods after institutional review board (irb) and ethical committee approval, patients with proximal ureteral or kidney stones requiring flexible ureterorenoscopy and uas placement in our tertiary center were enrolled in the prospective clinical trial after signing the informed consent. patients less than 18 years old or patients with ureteric stricture were excluded. patients were randomized to the use of boston scientific navigator hdtm (nhd) (group i) or of cook flexortm (cf) (group ii) uas. randomization was performed by investigator using closed envelope technique. the data of both cohorts were prospectively obtained and analyzed. traxer grading system for uas-related injuries was used for classification and comparison of intraoperative ureteric injuries (8). primary outcome was incidence of sheath related intraoperative complications while the difficulty of uas placement, length of procedure (lop), post-operative complications, patient-reported complaints/phone calls/emergency department (ed) visits, postoperative hydronephrosis were secondary outcomes. the two uas brands have a design of outer hydrophilic sheath and smooth-tapered inner coaxial dilator. the cf outer sheath is specialized with coil construction core. the inner dilator of nhd has a stiff body and a more flexobjective: we aimed to evaluate and compare the functional characteristics, safety profile and effectiveness of two commonly used ureteral access sheaths (uas) during flexible ureteroscopy. methods: after institutional review board approval, patients with proximal ureteral or kidney stones requiring flexible ureteroscopy and uas were prospectively randomized to group i or group ii according to the type of access sheath used. primary outcome was incidence of intraoperative complications. results: eighty-eight patients were enrolled in the study, 44 patients in each group. sheath size 12/14 fr was used in both cohorts. median (iqr) stone size was 10 mm (7-13.5) and 10.5 mm (7.37-14) in group i and ii respectively (p = 0.915). nineteen and twenty patients, in group i and ii respectively, were pre-stented. subjective resistance with insertion of the uas was observed in 9 and 11 patients in group i and ii respectively (p = 0.61) while failed insertion was encountered in one patient in group i. traxer grade 1 ureteral injury was noted in 5 and 6 patients in group i and ii respectively while grade 3 injury was seen in 1 patient for both cohorts (p = 0.338). there was less resistance for uas placement in pre-stented patients (p = 0.0202) but without significant difference in ureteric injury incidence (p = 0.175). emergency department visits were encountered in 7 (group i) and 5 patients (group ii) (p = 0.534). conclusions: the studied uass were comparable regarding safety and efficacy in the current study. pre-stented and dilated ureters had less resistance to insertion although this was not reflected on incidence of ureteric injury. key words: ureteroscopy; urolithiasis; ureteral access sheath; ureteral trauma. submitted 11 january 2023; accepted 22 january 2023 background ureterorenoscopy continues to be one of the most common procedures performed in urology practice, being a minimally invasive option for treatment of nephrolithiasis and ureterolithiasis. technological advances in both the size and flexibility of ureteroscopes have been integral to removing larger stones with a higher stone free rate. the continued advancement of the technology surrounding holmium: yag lasers, graspers, and baskets have continued to widen the application of ureteroscopy (1, 2). there are multiple instruments available on the market to aid in the performance of ureteroscopy (3). one tool in the comparison of commonly utilized ureteral access sheaths: a prospective randomized trial mohamed elsaqa 1,2, zain hyder 1, kim thai 1, katherine dowd 1, amr el mekresh 1, kristofer wagner 1, belur patel 1, patrick lowry 1, marawan m. el tayeb 1 1 baylor scott & white medical center, temple, tx usa; 2 alexandria university faculty of medicine, alexandria, egypt. doi: 10.4081/aiua.2023.11149 summary archivio italiano di urologia e andrologia 2023; 95, 2 mohamed elsaqa, zain hyder, kim thai, et al. 48 ible tip while cf inner dilator has a stiff tip tapered to 6 fr diameter. the nhd is available in 3 sizes of 11/13 fr, 12/14 fr, and 13/15 fr whereas cf is available in 12/14 and 14/16 in addition to smaller diameters of 9.5/11.5 and 10.7/12.5 fr. statistical analysis all statistical analysis was performed using the commercially available sas version 9.4 (statistical analysis software) (sas institute inc., cary, nc, usa). frequencies and percentages were used to describe categorical variables while medians and interquartile ranges (or means and standard deviations where appropriate) were used to describe continuous variables. a chi-square test or fisher’s exact test were used to test for comparison of categorical variables according to the expected cell counts while two-sample t-test (or wilcoxon rank-sum test when appropriate) was used for comparison of quantitative variables. the significance level was set at a p-value < 0.05. results between february 2017 and february 2020, 88 patients were prospectively enrolled in the study. forty-four patients were included in each group. sheath of 12/14 french was used in both cohorts. patients' demographics were comparable with no statistical significance between both cohorts except for higher rate of preoperative alpha blocker use in group ii. median (iqr) stone size was 10 (7-13.5) mm and 10.5 (7.37-14) in group i and ii respectively (p = 0.915). thirty-nine patients had ureteric stents previously inserted (pre-stented) at the time of flexible ureteroscopy, nineteen and twenty patients, in group i and ii respectively (table 1). median (iqr) operative time was 54 (41-78) and 51 (3672) minutes in group i and ii respectively (p = 0.302). subjective resistance with insertion of the uas was observed in 9 patients in group i vs. 11 patients in group ii (p = 0.61). there was one failure of insertion of the uas in group i. there was a statistically less resistance for placement of the uas noted in pre-stented patients’ cohort (p = 0.0202). it was also noted that patients with preoperative hydronephrosis had significantly less resistance to uas placement (p = 0.0493). there was no significant difference in resistance to insertion between patients who had preoperative alpha blocker use or not (p = 0.34). regarding sheath-related ureteric trauma, a total of 13 (16%) injuries were observed; 7 and 6 injuries in group i and ii respectively. out of 13 patients with ureteric injury, 8 patients were not previously stented (p = 0.175). taxer grade 1 ureteral injury was noted in 6 patients in the group i vs 5 patients in group ii. taxer grade 3 injury was seen in 1 patient for both cohorts (p = 0.338) (table 2). need for opioid analgesia and patients’ phone calls were comparable between both groups (p = 0.247, 0.669 respectively) return to the ed was encountered in 7 and 5 patients from group i and ii respectively (p = 0.534). the complains were mainly related to pain and hematuria. there was no association with sheath complication and return to ed. within follow up of 3 months, one patient in group 2 had persistent hydronephrosis although imaging has excluded occurrence of ureteric stricture. discussion the benefits of the uas in ureteroscopy and retrograde intrarenal surgery (rirs) are still controversial. de coninck et al., in their systemic review, showed that uas helps increasing flow of irrigation and decreasing intrarenal pressure but the impact of uass on stone-free rates, ureteroscope protection or damage, postoperative pain, risk of ureteral strictures, and cost-effectiveness are still controversial (4). in another recent review article, wong et al have concluded that no evidence exists for higher stone free rate with the use of uas but facilitates multiple and rapid passages of the ureteroscope during the procedure. according to wong et al, larger uas diameters > 12/14 fr were associated with lower intrarenal pressure and greater efficacy at the cost of increased forces during insertion, greater risk for ureteral wall injury, and lower insertion success rates (6). regarding the uas size choice, yoshida et al. have evaluattable 1. preoperative patient criteria in both groups. group i (n = 44) group ii (n = 44) p value age, years, mean (sd) 59.1 (2.3) 53.9 (2.5) 0.13 sex, n (%) male 21 (48%) 25 (57%) 0.393 female 23(52%) 19(43%) stone size, mm, median (iqr) 10 (7-13.5) 10.5 (7.37-14) 0.915 stone side, n (%) right 18 (40%) 14 (32%) 0.414 left 24 (54.5%) 27 (61.3%) bilateral 2 (4.5%) 3 (6.8%) alpha blocker use, n (%) 15 (34%) 28 (63%) 0.005 stone location, n (%) renal 41 45 0.305 upper ureter 7 13 mid ureter 0 1 lower ureter 2 3 hydronephrosis, n (%) 23 (52%) 30 (68%) 0.127 preop uti, n (%) 6 (13.6%) 12 (27.2%) 0.112 pre-stenting, n (%) 19 (43.1%) 20 (45.4%) 0.83 table 2. perioperative outcome data. group i (n = 44) group ii (n = 44) p value operative time, min, median (iqr) 54 (41-78) 51 (36.5-72.25) 0.302 anesthesia time, min, median (iqr) 100 (74.5-121.5) 104 (76.5-118.5) 0.779 resistance to introduction, n (%) 9 (20.4%) 11 (25%) 0.61 failed insertion, n (%) 1 (2.27%) 0 0.314 string on stent 23 (52%) 25 (56.8%) 0.66 op. sheath complication, n (%) 7 (15.9%) 6 (13.6%) 0.763 ureteral injury grade, n (%) garde 1 6 (13.6%) 5 (11.3%) 0.338 grade 2 0 0 grade 3 1 (2.27%) 1 (2.27%) need for opioid analgesia, n (%) 16 (36.3%) 11 (25%) 0.247 phone calls, n (%) 22 (50%) 20 (45.4%) 0.669 ed-return, n (%) 7 (15.9%) 5 (11.36%) 0.5344 po hydronephrosis, n (%) 0 1 (2.27%) 0.314 archivio italiano di urologia e andrologia 2023; 95, 2 49 ureteral access sheaths ed different uas ≤ 10/12 f regarding the intrapelvic pressure in an ex-vivo porcine kidneys. they showed that 9.5/11.5 f uas were associated with excessive intrapelvic pressure (10). sener et al have recommended sheath size 10/12 f as the first choice during flexible ureterorenoscopy for good irrigation and lower rate of ureter injury than 12/14 f uas (11). de et al. compared the physical characteristics of nhd, cf and other two new single-wire system uass in ex-vivo study. they reported that nhd is more slippery and more rigid with larger outer diameter while cf had shorter and stiffer tip and appeared less traumatic (more force was required for tip perforation) (12). in a similar ex-vivo study, patel et al also compared the physical and mechanical characteristics of nhd uas versus glidewaytm and pathwaytm uass supplied by terumo. they reported superiority for nhd regarding safety and ease of use (13). loftus et al have compared the same two investigated uas brands in a randomized clinical trial. in contrary of our study, all the patients included in their study were not pre-stented. loftus et al used different uas sizes and they crossed over patients who fail insertion of one uas type to the other. they reported overall sheath placement success rate of 87.8% with no difference between both types although nhd was subjectively easier to insert and was successful in 3 out of 7 (43%) patients who failed insertion of cf. they have reported some factors associated with high-grade (grade 2 or 3) ureteral injury as male gender, difficult subjective insertion, longer time of sheath insertion and high stone burden (14). in the current study, the insertion success rate was 98.8% with no significant difference between both groups. the two uass appeared comparable on many fronts, including ease of placement, ureteral injury rates, operative times, and return to ed rates. of note, our results showed less resistance to insertion was seen with preoperative hydronephrosis and ureteric stenting although no difference regarding ureteric injury. similarly, yuk et al. have reported that pre-stenting was associated with higher uas placement success although had no effect on overall operative outcomes (15). other studies have investigated the use of alpha blockers on uas force of placement. koo et al have reported that preoperative use of alpha blockers was associated with lower uas insertion force (16). however, contradictory results were reported by erturhan et al in another study (17). in our cohort, the preoperative usage of alpha blockers prior to uas placement was not associated with an easier subjective uas clinical placement. study by stern et al. demonstrated that high-grade injury due to uas placement has around a 1.8% stricture rate and this rate was similar to that reported without use of uas (8). aykant et al., in a prospective randomized study, have recently reported the rates of low-grade ureteral injury rate of 23.1% while high-grade injury rate was 8.9%. after 1-year, the ureteral stricture was 1.6%. they reported that use of 12/14 f uas was associated with higher risk of high-grade injuries although there was no difference in ureteral stricture formation compared to use of 9.5f/11.5 f sheath (18). there were only two high grade ureteral injuries noted in the current study. all ureteral injuries were treated with stent placement for 2-4 weeks. on follow up, only 1 patient had persistent hydronephrosis and no patients were noted to have ureteral stricture at follow up of 3 months. our study adds to growing literature that the nhd and cf have similar safety profiles and have a broad range of clinical application. limitations of the study include small study group and lack of stone-free rate assessment. further studies could be used to target stone size and determine the effect of sheath usage on stone clearance rates. conclusions the two commonly utilized ureteral access sheath brands are equally safe and effective for utilization during flexible ureteroscopy and retrograde intrarenal surgery. prestented and dilated ureters show less resistance to insertion although this was not associated with lower incidence of associated ureteric injury. informed consent: the study and informed consent were approved by baylor scott & white institutional review board (irb no: 18-4720). all patients have signed an informed consent prior to participation to the study. references 1. doizi s, traxer o. flexible ureteroscopy: technique, tips and tricks. urolithiasis. 2018; 46:47-58. 2. rodríguez-monsalve herrero m, doizi s, keller ex, et al. retrograde intrarenal surgery: an expanding role in treatment of urolithiasis. asian j urol. 2018; 5:264-273. 3. inoue t, okada s, hamamoto s, fujisawa m. retrograde intrarenal surgery: past, present, and future. investig clin urol. 2021; 62:121-135. 4. de coninck v, keller ex, rodríguez-monsalve m, et al. systematic review of ureteral access sheaths: facts and myths. bju int. 2018; 122:959-969. 5. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33-6. 6. wong vk, aminoltejari k, almutairi k, et al. controversies associated with ureteral access sheath placement during ureteroscopy. investig clin urol. 2020; 61:455-463. 7. meier k, hiller s, dauw c, et al. understanding ureteral access sheath use within a statewide collaborative and its effect on surgical and clinical outcomes. j endourol. 2021; 35:1340-1347. 8. stern jm, yiee j, park s. safety and efficacy of ureteral access sheaths. j endourol. 2007; 21:119-23. 9. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-4. 10. yoshida t, inoue t, abe t, matsuda t. evaluation of intrapelvic pressure when using small-sized ureteral access sheaths of ≤ 10/12f in an ex vivo porcine kidney model. j endourol. 2018; 32:1142-1147. 11. sener te, cloutier j, villa l, et al. can we provide low intrarenal pressures with good irrigation flow by decreasing the size of ureteral access sheaths? j endourol. 2016; 30:49-55. archivio italiano di urologia e andrologia 2023; 95, 2 mohamed elsaqa, zain hyder, kim thai, et al. 50 12. de s, sarkissian c, torricelli fc, et al. new ureteral access sheaths: a double standard. urology. 2015; 85:757-63. 13. patel n, monga m. ureteral access sheaths: a comprehensive comparison of physical and mechanical properties. int braz j urol. 2018; 44:524-535. 14. loftus cj, ganesan v, traxer o, et al. ureteral wall injury with ureteral access sheaths: a randomized prospective trial. j endourol. 2020; 34:932-936. 15. yuk hd, park j, cho sy, et al. the effect of preoperative ureteral stenting in retrograde intrarenal surgery: a multicenter, propensity score-matched study. bmc urol. 2020; 20:147. 16. koo kc, yoon jh, park nc, et al. the impact of preoperative αadrenergic antagonists on ureteral access sheath insertion force and the upper limit of force required to avoid ureteral mucosal injury: a randomized controlled study. j urol. 2018; 199:1622-30. 17. erturhan s, bayrak ö, şen h, et al. can alpha blockers facilitate the placement of ureteral access sheaths in retrograde intrarenal surgery? turk j urol. 2019; 45:108-112. 18. aykanat c, balci m, senel c, et al. the impact of ureteral access sheath size on perioperative parameters and postoperative ureteral stricture in retrograde intrarenal surgery. j endourol. 2022; 36:1013-1017. correspondence mohamed elsaqa, md (corresponding author) mohamed.elsaqa@alexmed.edu.eg division of urology, department of surgery, baylor scott & white health, 2401 s. 31st street, temple, tx 76508 zain hyder, md zain.hyder@bswhealth.org kim thai, md kthai88@gmail.com katherine dowd, md katiedowd12@gmail.com amr el mekresh, md elsaqa2020@yahoo.com kristofer wagner, md kristofer.wagner@bswhealth.org belur patel, md belur.patel@bswhealth.org patrick lowry, md patrick.lowry@bswhealth.org marawan m. el tayeb, md marawan.eltayeb@bswhealth.org baylor scott & white medical center, temple, tx, usa conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2160 original paper no conflict of interest declared. according to recent studies, dynamic contrast enhancement (dce) use has been resized in pi-rads version 2.1, restricted to the interpretation of ambiguous findings in the peripheral zone (2, 4-6). particularly, its role is limited to upgrading category pi-rads score 3 to pi-rads score 4 (2, 5). however, this upgrading could be unnecessary in decision-making (performing biopsy or not) (7). in addition, mp-mri protocol has some disadvantages, including longer time and higher cost, and the use of gadolinium-based contrast agents that may be problematic for patients with a glomerular filtration rate < 30 ml/min; moreover, the risk of potential brain accumulation is well described (8). for these reasons some authors have proposed a short protocol, using the biparametric mri (bp-mri) (9-11). the diagnostic value of bp-mri in detecting suspected lesions in the peripheral zone (pz) and the transitional zone (tz) has been validated (10-11) and is justified because: a) ensures lesion identification and localization in any prostatic area; b) avoids the use of gadolinium-dtpa; c) examination lasts about 15 minutes; d) allows money saving. with this paper, we tried to put together our experience with prostate mri and that regarding the cost-analysis of imaging studies. this study investigates cost-effectiveness of patients with suspect pca, tailoring an approach based on risk stratifications for a both safe and cost-effective management. the objective of this simulated cost-effectiveness study is therefore to determine the potential cost-effectiveness of bp-mri protocol compared to mp-mri for pca diagnosis. materials and methods target population target population includes a hypothetical cohort of 10,000 men aged between 50-79 years of age, with psa level > 3 ng/ml and no previous prostate biopsy. the base case was a 65-year-old man, performing prostatic mri because of elevated psa levels and/or clinically significant dre. these demographic features are based on the median age of the pca onset (1, 12). the model was tested by age groups in order to examine the cost-effectiveness, given varying levels of cancer prevalence and life expectancy. objectives: to compare the cost-effectiveness of a short biparametric mri (bp-mri) with that of contrast-enhanced multiparametric mri (mp-mri) for the detection of prostate cancer in men with elevated prostatespecific antigen (psa) levels. materials and methods: we compared two diagnostic procedures for detection of prostate cancer (pca), bp-mri and mp-mri, in terms of quality-adjusted life years (qaly), incremental costeffectiveness ratio (icer) and net monetary benefit (nmb) for a hypothetical cohort of 10,000 patients. we compared two scenarios in which different protocols would be used for the early diagnosis of prostate cancer in relation to psa values. scenario 1. bp-mri/mp-mri yearly if > 3.0 ng/ml, every 2 years otherwise; scenario 2. bp-mri/mp-mri yearly with age-dependent threshold 3.5 ng/ml (50-59 years), 4.5 ng/ml (60-69 years), 6.5 ng/ml (70-79 years). results: bp-mri was more effective than the comparator in terms of cost (160.10 € vs 249.99€) qalys (a mean of 9.12 vs 8.46), icer (a mean of 232.45) and nmb (a mean of 273.439 vs 251.863). bp-mri was dominant, being more effective and less expensive, with a lower social cost. scenario 2 was more cost-effective compared to scenario 1. conclusions: our results confirmed the hypothesis that a short bi-parametric mri protocol represents a cost-efficient procedure, optimizing resources in a policy perspective. key words: cost-effectiveness analysis; magnetic resonance imaging; multiparametric mri; bi-parametric mri; prostatic cancer. submitted 14 march 2022; accepted 25 april 2022 introduction prostate cancer (pca) is very common in men and is frequently associated with long-term survival in affected subjects (1). in most cases, it remains asymptomatic for a long time; about 29% of localized pca is classified as very low or low risk with slow growth (1-2). conventionally, suspicion of pca is based on digital rectal examination (dre) and/or elevated prostate specific antigen (psa), and is then typically confirmed by prostate biopsy (1, 3). according to pi-rads v2.1 guideline, multiparametric mri (mp-mri) proved to be valuable in the pca diagnostic process in men with high levels of psa (2, 3). cost-effectiveness analysis of short biparametric magnetic resonance imaging protocol in men at risk of prostate cancer niccolò faccioli 1, elena santi 2, giovanni foti 3, pierpaolo curti 2, mirko d’onofrio 1 1 department of radiology, g.b. rossi hospital, università di verona, verona, italy; 2 department of radiology, mater salutis hospital, legnago, verona, italy; 3 department of radiology, irccs sacro cuore don calabria hospital, negrar, verona, italy. doi: 10.4081/aiua.2022.2.160 summary 161archivio italiano di urologia e andrologia 2022; 94, 2 biparametric mri cost-effectiveness in prostate cancer detection since it was a simulated study, no patients or animals were involved, and ethical approval or informed consent were not necessary. procedures compared the procedures assessed in the model are: strategy 1. detecting prostate cancer with non-contrast bp-mri; strategy 2. detecting prostate cancer with mp-mri. using our base case, we first observed the optimal strategy. then, we compared costs and qalys among the two strategies. we evaluated the cost-effectiveness of each strategy for three age groups with a different pca prevalence. several economic-based models assessed some hypothetical screening strategies based on psa thresholds, in relation to age categories (11-16). our analysis, based on age and psa stratification, try to better understand the potential impact of bp-mri on qaly and costs. we weighted pros and cons of two hypothetical different scenarios, joining psa values and bp-mri/mp-mri: scenario 1. bp-mri/mp-mri yearly if > 3 ng/ml, every 2 years otherwise; scenario 2. bp-mri/mp-mri yearly with age dependent threshold 3 ng/ml (50-59), 4.5 ng/ml (60-69), 6.5 ng/ml (70-79). study design and decision analysis model we conducted a simulation study based on a model of decision analysis, according to the guidelines established by the panel on cost-effectiveness in health and medicine (17). in this case study, two variables are considered: cost and clinical effectiveness. this study is performed from a health care perspective, and we consider only direct costs of diagnostic tests, assessing whether bp-mri adds enough value to justify costs. in the first case, the tree will produce the expected survival rate, in the second the life expectancy in years, and finally, in the third case, the life expectancy in qalys. other variables are incremental cost-effectiveness ratio (icer) and net monetary benefit (nmb) (table 1). using an analysis software (openmarkov; cisiad, uned, madrid, spain), we tried to assess prospectively whether bp-mri is convenient compared to the current strategy (mp-mri). in a cost-effectiveness analysis, we refer to an incremental cost threshold considered economically sustainable and therefore acceptable. we identify the optimal strategy with a wtp of € 30.000 per qaly earned, threshold calculated on average daily earnings based on eurostat statistics for 2017 (18). we set the time horizon to 10 years. the entire cohort is distributed in final health states, each associated with a volume of costs. quality of life our model (state-transition model) demands to define the "health states" and therefore to specify the "transition rules" linked to the corresponding health status. like quality of life indicators, health utilities specify the patient’s experience of disease and are included in the model. to calculate the total qalys for each diagnostic strategy, we based on previously published data (19-20) and quality of life scores obtained from health-related quality of life questionnaires. we used the short form health survey (sf-12) memorial anxiety scale for prostate cancer (max-pc), the decisional conflict scale (dcs), the centre of epidemiologic studies depression scale (ces-d) and the eysenck personality questionnaire (epq) 11-16 as tools to measure general health-related quality of life and anxiety. details of these questionnaires have been described in literature (20-22). qalys are calculated by multiplying the duration of time spent in a health state by this utility score associated with that health state. sources of probabilities and cost estimates table 2 lists all parameters of the model. at our institution, prostate mri is performed on a 1.5t scanner (philips medical systems, healthcare, eindhoven, the netherlands). we suggest a bp-mri protocol with axial t1w gradientecho sequence with fat-suppression technique (thrive) imaging, multiplanar t2w fse imaging, axial dwi sequence and apparent diffusion coefficient (adc) map calculation. direct medical costs, analyzed from a health care perspective, included costs of diagnostic procedures, calculated considering the initial investment of equipment, additional costs during use, maintenance costs, years of use, personnel costs, materials used (provided by the hospital technical department). direct cost of mp-mri was 249.44 €, direct cost of bp-mri was 160.10 €. performance characteristics and utility values of crosssectional imaging were derived from published information: prevalence of prostate cancer, probability of detecting clinically significant cancer (table 2) (23). sensitivity rates of bp-mri and mp-mri in the detection of pca are 86.7% (80.8, 91.3%) and 93.9% (87.9-99.9%) respectively (4, 6, 11, 23-25). specificity values of bp-mri and mp-mri in the detection of pca are 90.9% (87.4-93.6) and 88.1% (84.3-91.3), respectively (table 3) (4, 6.24-26). bp-mri had a high accuracy (89.1%) and negative predictive value (92.7%) for clinically significant prostate cancer (gleason score ≥ 3+4, and/or volume > 0.5cc, and/or table 1. description of terms “qaly”, “icer”, “nmb” and “wtp”, and how they are calculated. qaly quality-adjusted life years are a measure of longevity, in units of years of life, adjusted for the ‘quality’ of life during those years. it is the arithmetic product of life expectancy and a measure of the quality of the remaining life years (quality of life coefficient). a way of determining the quality of a particular health state is to use a standard descriptive systems questionnaire. icer the incremental cost-effectiveness ratio is a statistic used in cost-effectiveness analysis to summarize the cost-effectiveness of a health care intervention. it is defined by the difference between two possible interventions: icer = (c1 c0) ÷ (e1 e0), where c1 and e1 are the cost and effect in the intervention group and where c0 and e0 are the cost and effect in the control care group. nmb net monetary benefit represents the value of an intervention in monetary terms when a willingness to pay threshold is known. nmb is calculated as: (incremental benefit x threshold) – incremental cost. wtp a willingness-to-pay threshold, according to the world health organization (who), represents “an estimate of what a consumer of health care might be prepared to pay for the health benefit”. archivio italiano di urologia e andrologia 2022; 94, 2 n. faccioli, e. santi, g. foti, p. curti, m. d’onofrio 162 extraprostatic extension) (10-11). life expectancy was estimated from eurostat statistics life tables (18). sensitivity analysis we performed univariate sensitivity analysis to calculate any variations of each single parameter. its execution involves recalculating each value of the parameter of interest. it allows us to identify the threshold beyond which, for the variation of that parameter, the diagnostic strategy is no longer optimal. then, we performed a probability sensitivity analysis by recompiling 10.000 times at random for each parameter. this approach simultaneously considers the uncertainty of each parameter using the monte carlo simulation. we assigned a beta distribution to utilities and a range distribution to costs. table 1 shows the results of the univariate sensitivity analysis and the costs of our model. nmb is defined as the difference between the value of the benefits obtained and the cost of obtaining them and may be calculated as follows: nmb = δqaly • wtp δcost, where wtp (willingness to pay) is the cost-effectiveness acceptability threshold considered in the analysis. results baseline analysis using bp-mri for diagnosis costed 160.10 €, yielded an average qaly of 9.12 and an average nmb of 273,439. diagnosis of a pca performed with mp-mri costed 249.99€ per patient, yielded an average of 8.46 qaly and an average nmb of 251,863. icer was 496.33 for 50-59 years’ group, 111.68 for 60-69 years’ group, and 89.34 for 70-79 years’ group (table 4). for the base case, bp-mri is identified as an optimal procedure at a willingness to pay 30.000 € per qaly gained. for scenario 1 (table 5), mean costs per patient were respectively 3602.25€ for bp-mri and 5612.4€ for mp-mri. for bpmri, corresponding mean qaly was 9, mean icer was 395.79 and mean nmb 266.397. for mp-mri mean qaly was 8.9, mean icer was 630.16 and mean nmb was 261.387. in case of scenario 2 (table 4), mean costs per patient were respectively 3191.32 € for bp-mri and 4972.17€ for mp-mri. for bp-mri, corresponding mean table 2. model inputs. parameter value sensitivity source values prevalence of cancer in men aged 51–60 years 0.44 0.00–0.90 1, 31 prevalence of cancer in men aged 61–70 years 0.65 0.00–0.90 1, 31 prevalence of cancer in men aged 71–80 years 0.71 0.00–0.90 1, 31 probability cancer is clinically significant 0.50 0.00–0.90 1, 31 prevalence of pca in men with abnormal psa 61% 53%, 69% 1, 31 incidence of significant pca in psa ranges, mg/l, 1 to < 3.0 9% 1, 31 incidence of significant pca in psa ranges, mg/l, 3.0–10.0 12% 1, 31 incidence of significant pca in psa ranges, mg/l, > 10.0 40% 1, 31 dre findings, normal 6% 1, 31 dre findings, abnormal 57% 1, 31 prostate volume, ml, 25-40 cm3 8% 1, 31 prostate volume, ml, 40 60 cm3 19% 1, 31 prostate volume, ml, > 60 cm3 27% 1, 31 model duration 10 years 5, 10 years long-term and short-term assessed starting age 50 55, 70 23 cost of mpmri scan 249.44 € hospital technical department cost of bpmri scan 160.10 € hospital technical department psa threshold 3.0 ng/ml 14, 15 pca = prostate cancer; psa = prostate specific antigen; dre = digital rectal examination; mp-mri = multi-parametric magnetic resonance imaging; bp-mri = bi-parametric magnetic resonance imaging. table 3. comparison of diagnostic accuracy of the abbreviated biparametric versus the full multiparametric protocol. parameter abbreviated biparametric full multiparametric source protocol protocol sensitivity (%) * 86.7 (80.8, 91.3) 93.9 (87.9, 99.9) 24-28 specificity (%) * 90.9 (87.4, 93.6) 88.1 (84.3, 91.3) 24-28 positive predictive value * 82.4 (76.1, 87.5) 78.4 (72.0, 83.90 24-28 negative predictive value * 92.7 (89.5, 95.2) 92.6 (89.8, 95.5) 24-28 overall diagnostic accuracy * 89.1 (86.2, 91.6) 87.6 (84.6, 90.3) 24-28 * data in parentheses are 95% cis. table 4. qaly, icer and nmb among the 2 strategies (bp-mri, mp-mri). 50-59 y 60-69 y 70-79 y qaly bp-mri 9.08 9.09 9.19 qaly mp-mri 8.9 8.29 8.19 icer 496.33 111.68 89.34 nmb bp-mri 272.239 272.539 275.539 nmb mp-mri 266.750 245.839 243.000 (dominated) (dominated) (dominated) qaly = quality adjusted life years; icer = incremental cost effectiveness ratio; nmb = net monetary benefit; mp-mri = multi-parametric magnetic resonance imaging; bp-mri = bi-parametric magnetic resonance imaging. table 5. costs, qaly, icer and nmb among 2 scenarios. scenario cost bp-mri qaly, icer, nmb cost mp-mri qaly, icer, nmb bp-mri mp-mri scenario 1 3602.25 € mean qaly 9 5612.4€ mean qaly 8.9 screen yearly if psa > 3.0 ng/ml, every 2 years mean icer 395.79 mean icer 630.16 otherwise mean nmb 266,397 mean nmb 261,387 dominated scenario 2 3191.32 € mean qaly 9.09 4972.17€ mean qaly 9 screen yearly with age dependent threshold (mean) mean icer 342.58 (mean) mean icer 554.65 3.5 (50–59), 4.5 (60–69), 6.5 (70–79) mean nmb 269,508 mean nmb 265,027 dominated 163archivio italiano di urologia e andrologia 2022; 94, 2 biparametric mri cost-effectiveness in prostate cancer detection qaly was 9.09, mean icer was 342.58 and mean nmb 269.508. for mp-mri mean qaly was 9, mean icer was 554.65, mean nmb 265,027. mp-mri procedure was dominated. using the icer decision rule, we can see that the most cost-effective option is bp-mri, and all other options are dominated. probabilistic cost-effectiveness sensitivity analysis we built a cost-effectiveness acceptability curve representing the probability of a scenario to be cost-effective related to one or more comparators, related to threshold values of wtp. in case of scenario 1, for a willingness to pay of € 30.000/qaly, there is 96% probability of bp-mri being the optimal procedure; the probability of mp-mri being optimal is 4%. the probabilistic sensitivity analysis indicates that bp-mri is dominant and cost-effective in 96% when wtp is 30.000 €/qaly earned. in case of scenario 2, for example in the 50-59 years group, when willingness to pay is above € 10.000/qaly, performing bp-mri is always the most beneficial decision. tornado analysis (figure 1) identified only two parameters that significantly affected the nmb: cost of mp-mri and cost of bp-mri. discussion we performed a cost-effective evaluation of a short protocol bp-mri for pca detection. then, we correlated its use in two hypothetical scenarios with introduction of psa threshold and age stratification. bp-mri was dominant (more effective and less expensive) over mp-mri with an icer that was below the acceptability threshold values considered (30.000 €/qaly earned). overall, both bp-mri and mp-mri proved to be highly effective diagnosing clinically significant cancer across age groups. bp-mri has a slightly higher qaly value, probably due to the lack of contrast media and a shorter examination, which provide better patient comfort. we also considered two possible scenarios with psa value introduction, the first with a psa threshold > 3 ng/ml for all ages, the second based on the increasing value of psa according to age (27). the best scenario in terms of costeffectiveness is the second, with an average cost of €3191.32 for bp-mri and €4972.17 for mp-mri. our analysis also revealed that even a minimal improvement in bp-mri sensitivity leads to a high cost-effectiveness ratio thanks to savings due to avoiding contrast media. consequently, bp-mri has a better icer and nmb than mp-mri. sensitivity analyses indicated a cost-saving of €89.34 for each bp-mri performed instead of mp-mri, representing significant earnings for national health system (nhs). differences in qaly are small and fluctuate steadily from 0.1 to 1. although mri is an expensive procedure, this approach has brought the best nmb, with spending values within the wtp threshold, with appropriate use of public money. our analysis, based on age and psa stratification, suggests that it can be cost-effective in all age and psa categories we studied (11-14, 2728). use of contrast enhanced transrectal ultrasound (cetrus) was also proposed but, unlike liver or pancreatic lesions, contrast enhanced ultrasound is less suitable in figure 1. a tornado diagram for 50-59 years’ group. the horizontal axis represents the variation in the expected utility for each parameter. archivio italiano di urologia e andrologia 2022; 94, 2 n. faccioli, e. santi, g. foti, p. curti, m. d’onofrio 164 pca detection (29-31). the most common comparative diagnostic methods respect to mri are trus, ce-trus and, more recently, micro-ultrasound; these methods can be better evaluated by a dedicated future study (32). our study shows that bp-mri effectively has a significant role detecting pca; also, it could reasonably reduce the number of biopsies, thanks to its high sensitivity in identification and in localization of index lesions < 5 mm and < 7 mm (33). this approach leads to a reduction in biopsies amount, which represents a considerable spending, as well as a significant impact on the patient’s life. psa screening may be useful to reduce mortality related to pca (14, 16, 33). with a psa cut off value of 3 ng/ml, the positive predictive value is 24%, compared to 10% in case of a threshold of 1.0 ng/ml (24, 27, 29, 33). a higher threshold leads to greater specificity and reduced sensitivity, minimizing the number of unnecessary negative biopsies. diagnosis and management of pca can be implemented by multivariate stratification based on patient risk (psa, dre, age), associated with bp-mri (scenario 2). some trials show that stratifying patients can be a winning strategy to maximize benefits and reduce costs for both diagnosis and therapy (14, 29-37). an important implication of bp-mri, however, regards the pirads assessment categories, as already well explained in pirads guidelines v2.1 (2). the pirads 3 category for a finding in pz will be not upgraded, as the dce sequence is not performed; thus, the proportion of pirads 3 will increase, with a decrease in the amount of pirads 4 (611, 37, 38). this reallocation could lead to further investigations for the patient, with subsequently diagnostic pathway modifications and additional costs. nevertheless, our hypothesis is validated by the recent changes of pi-rads system, where dce’s role is to distinguish pi-rads 3 versus pi-rads 4 lesions, in case of t2 dwi/adc mismatch (25-31, 34-37). it is important to note that our study is retrospective and based on hypothetical constructs with inherent limitations, as many economic models, and the results are based on findings of excellence centers. real-life could be different. some clinical hypotheses have been formulated about age ranges and age limits. in addition, patients were assumed not to have contraindications to the contrast agent. psa presents some risks inherent in its low specificity: high rate of false-positives, biopsy complications, risk of overdiagnosis and overtreatment, with consequent sexual and urinary problems (17, 30). a short protocol may not be suitable for all patients and specific individual needs: for example, imaging of tumor extension and local recurrence may require additional sequences or the use of dce. we agree with pirads v2.1 guideline, which recommends dce use in following cases: previous negative biopsies and increase of psa; suspicion of disease and no findings on prior bp-mri; previous prostate surgery; hip orthopedic implants that could degrade dwi weighted imaging. our results confirmed the hypothesis that a short mri protocol represents a possible cost-effective strategy, optimizing resources in a policy perspective. this study investigates cost-effectiveness of patients with suspect pca, tailoring an approach based on risk stratifications for a both safe and cost-effective management, keeping in mind medicolegal implications, as for other pathologies. furthermore, we suggest the inclusion of bp-mri as surveillance diagnostic test in patients with suspect pca, putting this improvement into a prospective long-term evolution in health economics and without any presumption to replace the existing protocols. we believe that this paper could represent a starting point to rediscuss the importance of the mri protocol according to the risk stratification of patients. conclusions in an efficient multidisciplinary model that takes care of the patient with suspect pca, from the beginning to the diagnosis, bp-mri is valuable for its high sensitivity in lesions identification, with similar results with respect to mp-mri. bp-mri is cost-effective and economically sustainable in the perspective of nhs and therefore can represent a valid diagnostic option, being a potential viable alternative to mp-mri. references 1. associazione italiana dei registri tumori (airtum) working group 2014 www.registri-tumori.it/cms/it/airtumwg2014. 2. turkbey b, rosenkrantz ab, haider ma, et al. prostate imaging reporting and data system version 2.1: 2019 update of prostate imaging reporting and data system version 2. eur urol. 2019; 76:340-351. 3. dickinson l, ahmed hu, allen c, et al. magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a european consensus meeting. eur urol. 2011; 59:477-494. 4. van der leest m, israël b, cornel eb, et al. high diagnostic performance of short magnetic 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review. plos one. 2017; 12:e0171704. 9. lee ss, lee dh, song wh, et al. usefulness of bi-parametric magnetic resonance imaging with b=1,800 s/mm² diffusion-weighted imaging for diagnosing clinically significant prostate cancer. world j mens health. 2020; 38:370-376. 10. girometti r, cereser l, bonato f, zuiani c. evolution of prostate mri: from multiparametric standard to less-is-better and different-is better strategies. eur radiol exp. 2019; 3:5. 165archivio italiano di urologia e andrologia 2022; 94, 2 biparametric mri cost-effectiveness in prostate cancer detection 11. kuhl ck, bruhn r, krämer n, et al. abbreviated biparametric prostate mr imaging in men with elevated prostate-specific antigen. radiology. 2017; 285:493-505. 12. teixeira anacleto s, neves alberto j, carvalho dias e, et al. do all patients with suspicious prostate cancer need multiparametric magnetic resonance imaging before prostate biopsy? arch ital urol androl 2022; 4:32-36. 13. hao s, karlsson a, heintz e, et al. cost-effectiveness of magnetic resonance imaging in prostate cancer screening: a microsimulation study. value health. 2021; 24:1763-1772. 14. roth ja, gulati r, gore jl, et al. economic analysis of prostatespecific antigen screening and selective treatment strategies. jama oncol. 2016; 2:890-898. 15. booth n, rissanen p, tammela tlj, et al. cost-effectiveness analysis of psa-based mass screening: evidence from a randomised controlled trial combined with register data. plos one. 2019; 14:e0224479. 16. fenton jj, weyrich ms, durbin s, et al. prostate-specific antigenbased screening for prostate cancer: a systematic evidence review for the u.s. preventive services task force. rockville (md): agency for healthcare research and quality (us); 2018. 17. sanders gd, neumann pj, basu a, et al. recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine. jama. 2016; 316:1093-1103. 18. eurostat, statistical office of the european communities, labour market statistics. luxembourg, 2011. issue number 48/2012. 19. sanghera s, mohiuddin s, coast j, et al. modelling the lifetime cost-effectiveness of radical prostatectomy, radiotherapy and active monitoring for men with clinically localised prostate cancer from median 10-year outcomes in the protect randomised trial. bmc cancer. 2020; 20:971. 20. harat a, harat m, martinson m. a cost-effectiveness and quality of life analysis of different approaches to the management and treatment of localized prostate cancer. front oncol. 2020; 10:103. 21. roth a, nelson cj, rosenfeld b, et al. assessing anxiety in men with prostate cancer: further data on the reliability and validity of the memorial anxiety scale for prostate cancer (max-pc). psychosomatics. 2006; 47:340-347. 22. garvelink mm, boland l, klein k, et al. decisional conflict scale use over 20 years: the anniversary review. med decis making. 2019; 39:301-314. 23. smith dp, king mt, egger s, et al. quality of life three years after diagnosis of localised prostate cancer: population based cohort study. bmj. 2009; 339:b4817. 24. scialpi m, prosperi e, d'andrea a, et al. biparametric versus multiparametric mri with non-endorectal coil at 3t in the detection and localization of prostate cancer. anticancer res. 2017; 37:1263-1271. 25. sherrer rl, glaser za, gordetsky jb, et al. comparison of biparametric mri to full multiparametric mri for detection of clinically significant prostate cancer. prostate cancer prostatic dis. 2019; 22:331-336. 26. boesen l, nørgaard n, løgager v, et al. assessment of the diagnostic accuracy of biparametric magnetic resonance imaging for prostate cancer in biopsy-naive men: the biparametric mri for detection of prostate cancer (bidoc) study. jama netw open. 2018; 1:e180219. 27. faria r, soares mo, spackman e, et al. optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate mr imaging study (promis). eur urol. 2018; 73:23-30. 28. weiss j, martirosian p, notohamiprodjo m, et al. implementation of a 5-minute magnetic resonance imaging screening protocol for prostate cancer in men with elevated prostate-specific antigen before biopsy. invest radiol. 2018; 53:186-190. 29 hugosson j, roobol mj, månsson m, et al. a 16-yr follow-up of the european randomized study of screening for prostate cancer. eur urol. 2019; 76:43-51. 30. faccioli n, dietrich cf, foti g, et al. activity-based cost analysis of including contrast-enhanced ultrasound (ceus) in the diagnostic pathway of focal pancreatic lesions detected by abdominal ultrasound. ultraschall med. 2019; 40:618-624. 31. faccioli n, santi e, foti g, d'onofrio m. cost-effectiveness analysis of including contrast-enhanced ultrasound in management of pancreatic cystic neoplasms. radiol med. 2022; 127:349-359. 32. chessa f, schiavina r, ercolino a, et al. diagnostic accuracy of the novel 29 mhz micro-ultrasound "exactvutm" for the detection of clinically significant prostate cancer: a prospective single institutional study. a step forward in the diagnosis of prostate cancer. arch ital urol androl. 2021; 93:132-138. 33. schröder fh, hugosson j, roobol mj, et al. screening and prostate cancer mortality: results of the european randomised study of screening for prostate cancer (erspc) at 13 years of follow-up. lancet. 2014; 384:2027-2035. 34. mezrich jl, weinreb jc. financial and medicolegal implications of focused/fast abdominopelvic mri exams. abdom radiol 2022; 47:471-474. 35. johansson k, mustonen h, nieminen h, et al. mri follow-up for pancreatic intraductal papillary mucinous neoplasm: an ultrashort versus long protocol. abdom radiol 2022; 47:727-737. 36. russo f, mazzetti s, regge d, et al. diagnostic accuracy of single-plane biparametric and multiparametric magnetic resonance imaging in prostate cancer: a randomized noninferiority trial in biopsy-naive men. eur urol oncol. 2021; 4:855-862. 37. galosi ab, palagonia e, scarcella s, et al. detection limits of significant prostate cancer using multiparametric mr and digital rectal examination in men with low serum psa: up-date of the italian society of integrated diagnostic in urology. arch ital urol androl. 2021; 93:92-100. 38. pepe p, candiano g, pepe l, et al. mpmri pi-rads score 3 lesions diagnosed by reference vs affiliated radiological centers: our experience in 950 cases. arch ital urol androl. 2021; 93:139-142. correspondence niccolò faccioli, md (corresponding author) niccolo.faccioli@aovr.veneto.it mirko d’onofrio, md mirko.donofrio@univr.it department of radiology, g.b. rossi hospital, università di verona, piazzale l.a. scuro, 10 37134, verona, italy elena santi, md elesanti87@gmail.com pierpaolo curti, md pierpaolo.curti@aulss9.veneto.it department of urology, mater salutis hospital, via carlo gianella, 1 37045 legnago, verona, italy giovanni foti, md gfoti81@gmail.com department of radiology, irccs sacro cuore don calabria hospital, negrar, verona, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11897 1 original paper this reason, treatments that prevent or delay adt may be beneficial. salvage radical prostatectomy for recurrence after radiotherapy is an accepted alternative although it is a demanding surgical procedure involving serious morbidity and risk of surgical complications (14) . optimal local treatment of recurrence is controversial, with alternative treatments depending on availability of instrumentation and risk, age and comorbidities of the patient (2, 15). new treatment modalities with minimally invasive techniques such as percutaneous cryotherapy and thermal ablation, have gained popularity for treatment of men with prostate cancer (2). use of cryotherapy for treatment of prostate cancer (pca) dates back to 1960, although at the time it was associated with multiple and drastic complications (16). with technical advances, cryotherapy has resurfaced as a safe and interesting technique in treating prostate cancer in the recurrence and primary setting, with little toxicity (16, 17). cryoablation implies the freezing of tissue to promote tissue destruction with direct and indirect mechanisms of action, with a fast freeze phase, followed by slow heating and a repeat cycle (18-20). optimal duration of freezing and temperature are debatable with various protocols existing, but most studies report critical cellular damage at temperatures below -20ºc (20). prostate cryosurgery has been increasingly used for focal treatment of primary and recurrent for prostate cancer, utilizing the same thermal and biological principles for different settings (6, 21, 22). in our centre cryosurgery has been utilized mostly in the context of recurrence, therefore our study aims to evaluate recurrence free survival and time to further treatments associated with cryotherapy. material and methods patient selection and variables all male patients submitted to cryotherapy as salvage treatment during follow-up for prostate cancer in our institution between january 2014 and december 2022 were evaluated. patients with localized recurrence submitted to hormone treatment were excluded. all patients were submitted to conventional staging with ct to the chest, abdomen and pelvis and a bone scintigraphy previously to treatment background: most men diagnosed with prostate cancer will be candidates for active treatment and 20 to 50% of patients treated with organ preserving strategies recur within the prostate. optimal treatment of recurrence is controversial. prostate cryosurgery has been increasingly used as primary, recurrence and focal treatment for prostate cancer. methods: we analysed 55 patients submitted to cryotherapy as salvage treatment after recurrence. results: study population presented with a mean age of 70.9 ± 6.2 years, mean initial psa of 7.6 ng/ml and average prostate volume by ultrasound of 43.2 ± 14.7 grams. mean follow-up was of 18.0 months. biochemical free survival at one year of follow-up was of 85%. conclusions: cryotherapy can be an effective and safe treatment for recurrence after primary curative treatment failure. key words: prostate cancer; recurrence; cryotherapy. submitted 1 october 2023; accepted 23 october 2023 introduction most men diagnosed with prostate cancer will be candidates for active treatment, being, in most cases, treated with radiotherapy with external beams or brachytherapy or radical surgery (1, 2). depending on risk factors, about 20 to 50% of patients treated with organ preserving strategies recur within the prostate with some of them benefiting from additional treatments(2-4). most patients receive androgen deprivation treatment (adt) for recurrence although they still are candidates for curative treatment with local salvage treatment (3, 5, 6). recurrence after radical surgery (two psa values superior to 0.2 ng/ml after previous undetectable psa) involves different treatment options when compared to recurrence after radiotherapy (psa values higher than 2 ng/ml plus nadir) (7). treatment options for recurrence after surgery include observation, salvage radiotherapy (ideally when the psa is lower than 2 ng/ml) and adt while most patients treated with previous radiotherapy cannot be irradiated again (7). progression of prostate cancer is highly dependent on testosterone and this represents the rationale for treatment with adt (8, 9). hormonal therapies are associated with side effects derived from hypogonadism, such as increased cardiovascular risk, cognitive deterioration, sarcopenia among other important effects (8, 10-13). for salvage cryotherapy for prostate cancer duarte vieira e brito, jose alberto pereira, ana maria ferreira, mario lourenço, ricardo godinho, bruno pereira, pedro peralta, paulo conceiçao, mario reis, carlos rabaça urology department portuguese institute of oncology coimbra, portugal. doi: 10.4081/aiua.2023.11897 summary archivio italiano di urologia e andrologia 2023; 95(4):11897 d. vieira e brito, j.a. pereira, a.m. ferreira, et al. 2 in order to exclude extra prostatic disease and in case of doubt with pet-psma. biopsy to the prostate was not performed in most patients. patients were evaluated at baseline and at 3,6,12,18,24 and after every 6 months until change of treatment due to biochemical failure under phoenix criteria. continence was evaluated at every evaluation and a basal reference was obtained. surgical technique patients were submitted to whole gland prostate cryotherapy utilizing cryocare cs™ (third generation cryoablation system). cryoprobes were introduced transperineally, using a hands-free, under real-time bi-plane transrectal ultrasonography guidance. the procedure was conducted utilizing argon gas. a rectal thermal sensor was introduced as well as a sensor placed at the external sphincter and a urethral warmer was introduced. two freeze cycles are performed (10-min freezing per cycle), with active warming in the first cycle and passive after the second cycle; the formed ice-ball and the temperatures are monitored up to 5 min after the second freezing cycle is completed; the cryoprobe, sensors and warming catheter device are removed after the second cycle, and a foley catheter is placed to be removed after one week. patients are discharged on the same day. statistical analysis pearson chi-square, mann-whitney and kolmogorov smirnov tests were used to compare quantitative and categorical variables. unconditional binary logistic regression was used to evaluate the independent association between possible predictors of recurrence. statistical significance in this study was set as p < 0.05. statistical analysis was performed using ibm spss®, version 27.0 for windows. results of a total of 70 patients submitted to cryotherapy were considered; 55 were evaluated after exclusion of 15 to current usage of androgen deprivation treatment. patients were then divided in two groups for comparison: patients with biochemical failure (group 1) and patients with no failure of treatment (group 2). as a whole, study population presented with a mean age of 70.9 ± 6.2 years, a mean initial psa of 7.6 ng/ml and average prostate volume by ultrasound of 43.2 ± 14.7 grams. mean follow-up was of 18.0 (± 13.4) months. regarding previous treatments, 36 (65,4%) patients were submitted to radiotherapy, 16 (29.1%) to brachytherapy and 3 (5.5%) to previous cryotherapy. a total of 19 (34.5%) patients presented with recurrence at a mean of 23.2 ± 16.7 months. biochemical free survival at one year of follow-up was of 85%, with 43 patients achieving this length of follow up and 2 patients with recurrence at six months. minimum follow-up was of 6 months, achieved by all 55 patients (date of first patients treatment failure), and maximum of 60 months. in regards of immediate post-operative complications (first week) the most frequent was perineal hematoma in 6 (10.9%) patients, followed by urinary retention in 2 (3.6%) patients. long term complications are described in table 1. mean psa values in group 1 and group 2 are described in table 2. when comparing between isup table 2. average psa values between groups. group 1 group 2 p psa 8.6 7.8 0.4 psa at 3 months 3.2 1.6 0.03 psa at 6months 3.9 1.4 0.001 psa at 12 months 4.3 1.5 0.000 prostate volume 44 cc 43cc 0.27 mean follow-up 29.5 months 23.8 months 0.20 age 69.5 71.0 0.53 table 1. long term side effects of treatment. complication number percentage none reported 34 61.8 light urinary incontinence 7 12.7 severe urinary incontinence 3 5.5 haematuria 1 1.8 fistula 1 1.8 urge incontinence 7 12.7 ureteral stenosis 2 3.6 figure 1. patients survival. archivio italiano di urologia e andrologia 2023; 95(4):11897 3 salvage cryotherapy for prostate cancer grades, volume and age between groups a non-significant p value were obtained. other population characteristics are summarized in table 3. over half of patients were submitted to an mri and 23.6% to pet psma previous to treatment allowing for the exclusion of extra prostatic disease and better treatment planning, that can explain our low rates of incontinence, due to better patient selection. discussion patients with localized recurrence present with an opportunity for salvage therapies with a curative intent, although with the current widespread usage of adt, most patients receive hormonal therapies for biochemical failure after curative treatment (23). androgen deprivation treatment can be responsible for considerable side effects and worse quality of life (24). in our cohort of patients treatment failure, defined by the phoenix criteria (as currently no validated definition exists for cryotherapy) occurred in 19 (34.5%), with an average time to recurrence of 23.2 months, signifying that patients were spared the side effects of testosterone deprivation therapy for almost two years, with little morbidity associated. a recent study analysing biochemical failure after treatment found rates of recurrence at 12 months of 15% and 19% at two years. our data in terms of recurrence are similar to these studies although longer follow-up is needed (25). most surgical options are associated with considerable morbidity for the patient, with great impact on quality of life and very high degrees of incontinence and fistula (7, 26). salvage radical surgery presents with a biochemical recurrence free rate of 34-83% at five years, depending on the study considered, that is similar to the rates for minimal invasive procedures (14, 27). functional outcomes differ significantly between treatment options although most patients present already with a low erection capacity after previous treatment with radiotherapy. after surgery (salvage radical prostatectomy), almost no patient retains erectile function and 25% of patients presents with severe incontinence and significantly lower rates of continence compared to other salvage treatments or surgery as primary treatment (28, 29). high intensity focused ultrasound (hifu) is also available for treatment for localized prostate cancer with continence rates superior to 50% but inferior to what has been reported for cryotherapy (26). in our study, 34 patients 61.8% did not report any significant side effects, a rate higher than average. the most common side effects were both urge incontinence and mild urinary incontinence reported in 7 patients, less severe when compared to side effects reported after salvage prostatectomy where severe continence is present in 25% of patients (7, 26, 29). only one patient presented with a fistula; he was a 72-year-old patient submitted to prior brachytherapy with combined radiotherapy for isup 5 disease. on the contrary, many patients submitted to radical surgery suffer from bladder neck contracture, anastomotic leakage with one third of patients presenting with clavien 3 or higher complications (26). our study shows that, with the currently improved equipment and technique, cryosurgery should be considered as a valid and important option for patients after failure of primary treatment with little toxicity. although patients were not biopsied previously to treatment previous histology reported 5 patients with isup 4 and 3 with isup 5: only 2 patients of the isup 4 group presented with failure and none in the other group at an average follow-up of 21.6 and 18.6 months respectively, indicating a possibly important role in high grade disease. when psa values between the two groups were considered, initial psa was non-significantly different, as all other variables considered for direct comparison. differences of values at 3,6 and 12 months were statistically significant with p values of 0.03,0.001 and 0.000 respectively. accordingly, lower psa values at these intervals predicts treatment success and longer recurrence free survival, similarly to what was reported (25). limitations of our study include utilization of the phoenix criteria to determine biochemical failure, designed initially for radiotherapy, as no current guidelines exist to define failure after cryotherapy, the retrospective nature of our study, relative short average follow-up time and lack of confirmatory biopsy of assumed failure. conclusions cryotherapy can be an effective and safe treatment for recurrence after primary curative treatment failure, allowing for delay or even eliminate the need for adt, sparing patients the unnecessary toxicity and complications from salvage radical prostatectomy with little and in most cases manageable side effects. references 1. finley ds and belldegrun as. salvage cryotherapy for radiationrecurrent prostate cancer: outcomes and complications. curr urol rep. 2011; 12:209-15. 2. autran-gomez am, scarpa rm, chin j. high-intensity focused ultrasound and cryotherapy as salvage treatment in local radiorecurrent prostate cancer. urol int. 2012; 89:373-9. 3. duijzentkunst da, et al. focal salvage therapy for local prostate cancer recurrences after primary radiotherapy: a comprehensive review. world j urol. 2016; 34:1521-1531. 4. golbari nm and katz ae. salvage therapy options for local prostate cancer recurrence after primary radiotherapy: a literature review. curr urol rep. 2017; 18:63. table 3. population characteristics. number percentage isup 1 11 20.0 isup 2 23 41.8 isup 3 13 23.6 isup 4 5 9.1 isup 5 3 5.5 no prostate mri 25 45.5 prostate mri 30 54.5 no pet-psma 42 76.4 pet psma 13 23.6 archivio italiano di urologia e andrologia 2023; 95(4):11897 d. vieira e brito, j.a. pereira, a.m. ferreira, et al. 4 5. lomas dj, woodrum da, mynderse la. salvage ablation for locally recurrent prostate cancer. curr opin urol. 2021; 31:188-193. 6. bauman g, et al. cryosurgery versus primary androgen deprivation therapy for locally recurrent prostate cancer after primary radiotherapy: a propensity-matched survival analysis. cureus. 2020; 12:e7983. 7. artibani w, et 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cryomedicine: new mechanisms of biological tissue injury following low temperature exposure. experimental study. klin khir. 2009; (78):80-5. 20. gage aa and baust j. mechanisms of tissue injury in cryosurgery. cryobiology. 1998; 37:171-86. 21. becher e, lepor h. oncological control following partial gland ablation for intermediate-risk prostate cancer. urol oncol. 2020; 38:671-677. 22. shah tt, et al. early-medium-term outcomes of primary focal cryotherapy to treat nonmetastatic clinically significant prostate cancer from a prospective multicentre registry. eur urol. 2019; 76:98-105. 23. bruce jy, et al. current controversies in the management of biochemical failure in prostate cancer. clin adv hematol oncol. 2012; 10:716-22. 24. kongnyuy m, et al. salvage focal cryosurgery may delay use of androgen deprivation therapy in cryotherapy and radiation recurrent prostate cancer patients. int j hyperthermia. 2017; 33:810-813. 25. tan wp, et al., oncological and functional outcomes for men undergoing salvage whole-gland cryoablation for radiation-resistant prostate cancer. eur urol oncol. 2023; 6:289-294. 26. abufaraj m, siyam a, ali mr, et al. functional outcomes after local salvage therapies for radiation-recurrent prostate cancer patients: a systematic review. cancers (basel). 2021; 13:244. 27. gontero p, et al. salvage radical prostatectomy for recurrent prostate cancer: morbidity and functional outcomes from a large multicenter series of open versus robotic approaches. j urol. 2019; 202:725-731. 28. marquis a, et al. nightmares in salvage robot-assisted radical prostatectomy after primary radiation therapy for prostate cancer: a step by step tutorial. eur urol open sci. 2022; 43:62-67. 29. pfister d, et al. salvage radical prostatectomy after local radiotherapy in prostate cancer. curr opin urol. 2021; 31: 194-198. correspondence duarte vieira e brito, md (corresponding author) duartevbrito@hotmail.com casa da aveleira, pencelo, guimaraes 4800-110 jose alberto pereira, md joseaclpereira@gmail.com ana maria ferreira, md anaferreira6842@gmail.com mario lourenço, md mariolourenco88@gmail.com ricardo godinho, md ricardogodinhoandrade@gmail.com bruno pereira, md brunoalexpereira@gmail.com pedro peralta, md joaopedroperalta@gmail.com paulo conceiçao, md 3605@ipocoimbra.min-saude.pt mario reis, md reismario58@gmail.com carlos rabaça, md carlosrabaca@gmail.com urology department portuguese institute of oncology coimbra, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12026 1 original paper introduction benign prostatic hyperplasia (bph) is a disease of high prevalence and its natural history shows that 25% of men are affected by bothersome lower urinary tract symptoms (luts) caused by bladder outflow obstruction during their lifetime (1, 2). there are many devised treatment options to treat bph. initial medical therapy may be effective for mild to moderate symptoms. patients with moderate or severe symptoms may still require surgical intervention in presence of objective measurements that indicate greater obstruction. in the past, transurethral resection of the prostate (turp) was considered the gold standard procedure for bph treatment. turp was associated with high rates of morbidity, including bleeding, sexual dysfunction, stress incontinence, urethral strictures, and longer length of stay (3, 4). recently, many innovative surgical procedures using thermal energy steam, or prostate artery embolization or mechanical dilation with urolift have been introduced (5, 6). the aim of all of them is to maintain a strategic distance from the complications associated with turp whereas keeping comparable results. rezum is recommended for men ≥ 50 year of age with bph and prostate volumes extending from 30 cm3 to 80 cm3. its use is suggested for the treatment of enlargement of the central zone and/or a middle lobe. in general, the prostate is ablated through convective warm water vapor, produced through radiofrequency (7, 8). this procedure has been detailed within the literature to result in a significant reduction in luts in patients with bph, with high safety profile (9). rezum has too illustrated advancement in symptoms scores compared to medical therapy (10, 11). another recognized key advantage of rezum treatment is the low rate of sexual affection post-operatively, which may be a watched key complication of other treatments for bph, such as turp (10). the aim of this study is to evaluate safety and efficacy of rezum therapy as a minimally invasive modality for management of benign prostatic hyperplasia in patients with prostate volume < 80cc and those with prostate volume > 80cc. objective: to evaluate safety and efficacy of rezum therapy as a minimally invasive modality for management of benign prostatic hyperplasia in patients with prostate volume < 80cc and those with prostate volume > 80cc. methods: between june 2020 and february 2023, a total of 98 patients diagnosed with bph and managed by rezum were included in this study. patients were divided based on their prostate volume of either less than 80 cc or greater than 80 cc. we evaluated several parameters related to their condition, including prostate volume, post-voiding residual (pvr) before and after surgery, number of treatments received, maximum urine flow rate (qmax) before and after surgery and mean follow-up periods. results: the mean age was 68 years (sd 11.2). the median prostatic volume was 62 cc (iqr 41, 17). a maximum of 9 treatments were administered. six months was determined to be the average post-operative follow-up period (iqr: 3.5-7.2). the mean preoperative total psa was 2.7 (iqr 1, 2), preoperative mean pvr was 79.8 cm3, preoperative mean qmax was 8.2 ml/s (iqr 4.7-10.5), and median post-operative days until catheter removal was four days (iqr 3,1). post-operative pvr was 24.7 cm3 (iqr 18.2, 29.4) and the mean post-operative qmax was 18.3 ml/s (sd 6.3). qmax levels significantly increased, by an average of 8.2 ml/s (sd 7.13) (p < 0.001). similarly, a decrease of average pvr of 97.28 cm3 (sd 95.85) (p < 0.001) was detected, which is a substantial reduction. between prostates less 80cc and those over 80cc, there were no appreciable differences in qmax or pvr (p-values: 0.435 and 0.431, respectively). conclusions: from our study, we conclude that rezum water vapor thermal therapy, as a minimally invasive modality, is an effective and safe surgical option for management of benign prostatic hyperplasia of men with moderate to severe lower urinary tract symptoms (luts). this procedure has been shown to be effective in patients with varying larger prostate volumes. key words: hyperplasia; prostate; rezum. submitted 24 october 2023; accepted 11 november 2023 evaluation of rezum therapy as a minimally invasive modality for management of benign prostatic hyperplasia: a prospective observational study tamer a. abouelgreed 1, 2, ayman k. koritenah 1, yasser badran 1, ibrahim tagreda 1, mohamed algammal 1, hesham abozied 1, hany a. eldamanhory 1, hossam a. shouman 1, abdelhamid a. khattab 3, munira ali 4, mohammad thabet alnajem 5, ahmed a. abdelwahed 6 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 gulf medical university, ajman, uae; 3 department of urology, damanhur teaching hospital, albuheira government, egypt; 4 department of radiology, thumbay university hospital, ajman, uae; 5 department of radiology, tawam hospital, alain, uae; 6 department of radiology, ain shams university, cairo, egypt. doi: 10.4081/aiua.2023.12026 summary archivio italiano di urologia e andrologia 2023; 95(4):12026 t.a. abouelgreed, a.k. koritenah, y. badran, et al. 2 materials and methods between june 2020 and february 2023, a total of 98 patients diagnosed with bph and managed by rezum on the urology department of the institution of the authors were included in this prospective observational study. all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of thumbay university hospital (affiliated with gulf medical university, rec #: 432/2020). written informed consent was obtained from the patients for their anonymized information to be published in this article. the rezum procedure utilizes the flow of water vapor to deliver heat to the prostate tissue in short bursts of 9 seconds. at our hospital, patients underwent rezum therapy in the operating room under general anesthesia. following the procedure, all patients had catheters of varying sizes inserted. the data collected included basic demographic information such as age and ethnicity, as well as preoperative and postoperative values. additionally, we recorded the number of treatments administered, the time taken for catheter removal (twoc), the average follow-up time, and any complications that arose. due to non-compliance from some patients, it was not feasible to utilize standardized symptom questionnaires for assessment purposes. furthermore, we categorized patients into two groups based on their prostate volume of either less than 80 cc or greater than 80 cc. statistical methods the ibm statistical package for the social sciences (spss) software, version 25.0 (ibm corp., armonk, ny), was used to enter and analyze the data. preand postoperative values of parameters as psa, qmax, and pvr were compared. the wilcoxon signed-rank test was applied since the change was negatively skewed and the data were paired. statistics were judged significant at a 0.05 p-value. additionally, we used a nonparametric mann-whitney u test to examine if the preoperative prostatic volume was connected to the change in qmax and pvr. results this prospective observational study comprised 98 patients with benign prostatic hyperplasia who underwent rezum surgery at thumbay university hospital (affiliated to gulf medical university) between june 2020 and february 2023. the mean age was 68 years (sd 11.2) (table 1). overall, 54.2% (51/96) of the patients had prostate gland volumes that were less than 80 cc and 45.8% (45/96) of the patients had prostate gland volumes that were more than 80 cc. the mean prostatic volume was 69 cc (sd 34.19), while the median prostatic volume was 62 cc (iqr 41,17). a maximum of 9 treatments were administered, with a mean of 4.2 treatments into the median lobe. six months was determined to be the average post-operative follow-up period (iqr: 3.5-7.2). the mean preoperative total psa in our sample was 2.7 (iqr 1,2), mean preoperative pvr was 79.8 cm3, mean preoperative qmax was 8.2 ml/s (iqr 4.7-10.5), and the median post-operative days until catheter removal was four days (iqr 3.1). mean postoperative pvr was 24.7 cm3 (iqr 18.2, 29.4) and mean post-operative qmax was 18.3 ml/s (sd 6.3) (table 1). qmax levels significantly increased, by an average of 8.2 ml/s (sd 7.13) (p < 0.001). similarly a decrease of average pvr by 97.28 cm3 (sd 95.85) (p < 0.001) was detected, which is a substantial reduction (table 2). between prostates less 80cc and those over 80cc, there were no appreciable differences in qmax or pvr (p-values: 0.435 and 0.431, respectively) (table 3). our study's complications included two occurrences of urinary tract infections (uti), which were treated with oral antibiotics, and five instances of hematuria, which resolved on its own. due to the catheter's temporary post-operative presence, several patients experienced slight discomfort. none of the patients who underwent this treatment reported any sexual difficulties. regarding the use of post-operative medtable 1. general demographical data. mean/median sd/iqr age 68 11.2 prostate volume 62 41, 17 preoperative psa total 2.7 1,2 preoperative qmax 8.2 4.7, 10.5 preoperative pvr 79.8 42.4, 115.0 twoc 4 3,1 post-op qmax 18.3 6.3 post-op pvr 24.7 18.2, 29.4 qmax: peak urinary flow; psa: prostate-specific antigen; pvr: post-void residual; twoc: time to removal of catheter. table 2. mean changes in qmax and pvr. mean sd median percentile 25 percentile 75 p-value change in qmax 8.2 7.13 5.60 3.42 11.90 < 0.001 change in pvr -97.28 95.58 -71.50 -142.00 -31.10 < 0.001 qmax: peak urinary flow; pvr: post-void residual. table 3. mean changes in measures of qmax and pvr in relation to prostate volume between the studied groups. mean sd median percentile 25 percentile 75 p-value change in qmax prostate volume <=80 7.65 5.66 6.62 2.80 12.30 0.435 >80 12.88 13.10 6.10 3.20 28.10 change in pvr prostate volume <=80 29.3 25.8 22.2 15.8 28.4 0.431 >80 31.2 21.7 27.6 17.8 46.7 qmax: peak urinary flow; pvr: post-void residual. archivio italiano di urologia e andrologia 2023; 95(4):12026 3 therapy for management of benign prostatic hyperplasia ications, patients stopped using their medications within three months of the procedure. discussion benign prostatic obstruction (bpo) is one of the most frequently diagnosed conditions of the male genitourinary tract. globally, bpo results in 1,2 million surgical procedures annually. the range of interventions available to treat bph has broadened in recent years. quality of life (qol) and healthcare spending may be impacted in ageing men because of luts due to enlargement of the prostate (luts) (12). rezum presented itself as a new surgical innovation, providing satisfactory clinical results while offering a safe and low-risk side effect profile (3). its recommended by the the american urological association (aua) and the european urological association (eua). in addition to the existing interventions of prudent waiting and lifestyle modifications, pharmacotherapy, and surgical management for luts, it has historically been difficult for patients with bph to remain compliant with the medical treatments offered (e.g. 5-alpha reductase, phosphodiesterase, etc.). these treatments provide symptomatic relief but at the expense of side-effects that threaten compliance (3). in this study, we have highlighted the effectiveness of rezum therapy through comparing the preoperative and post-operative outcomes in our institution among different patients with enlarged prostate including volumes greater than 80cc. our study showed no significant difference in qmax or pvr among prostate volumes of less than 80cc versus greater than 80cc. historically, turp has been the gold standard of bph treatment. turp provided patients with clinically meaningful improvements in luts. however, turp’s major disadvantage is its complications, particularly bleeding and sexual dysfunctions (12). rezum has several advantages over turp. first, it improves clinical outcomes while maintaining sexual function. second, it has minimal bleeding. third, it can be performed without general anesthesia. this may be beneficial for some elderly patients. fourth, it has been studied for cost-effectiveness in the usa compared to turp long term follow-up, demonstrating that rezum is comparable in health and cost-effectiveness (13, 14). while clinical improvement with turp was increased, the literature has shown an overall cost reduction with rezum due to the lower adverse effects (14, 15). randomized control trials have also shown a reduction in symptomatic luts at four years with an average ipss improvement with rezum therapy of 47% (10). lastly, due to covid-19 and the benefit of reducing operative time, rezum has proven to be a good choice with each procedure being reported to take about 17.5 minutes compared with 60-90 minutes for turp (16). the efficacy of rezum in the arab population has not been extensively studied since the introduction of this novel therapy. however, in the uk it has been reported on the preoperative experience of rezum, as described in the study of maximilian et al. (17). our study has demonstrated the benefit of rezum therapy amongst the arab population, based on improvements in qmax, pvr, and patient symptom reporting. our population did not have any patient with catheter dependency, 29 of whom were on medical treatment (30.2%). within 90 days’ post-operatively, our patients had discontinued their previous medications, this results going in line with the single office experience of mollengarden et al. (18). our study focused on postoperative changes in pvr and qmax as objective measures of improvement in postoperative outcomes. at three months follow up, we observed a significant average increase in qmax and a significant decrease in pvr, in line with other internationally published papers (17, 19). we also looked at the relationship between preoperative prostatic volume and changes in qmax and pvr. in our sample, there was no statistically significant relationship. this was in contrast to garden et al., who found that men with larger (> 80cc) prostates showed more profound qmax and pvr changes than men with smaller prostates (< 80cc) (19). medication sideeffects can lead to patients not adhering to treatment for bph; for example, cindolo et al. (20), showed that adherence was 29% after one year of treatment with at least 6 months of therapy in a population based cohort study of 1,5 million men. in our experience, patients have only needed medical treatment temporarily after surgery, while no medications were needed for symptom control after 90 days from the procedure. this alone may increase the acceptance of the procedure and increase the adoption rate. in addition to reducing the need for medication and improving quality of life, rezum is also a well-tolerated procedure (21). one of the main drawbacks of temporary catheterization after surgery is that it can take an average of 4 days to heal, and our patients have reported discomfort during this time. in our study, complications have included uti that was managed with antibiotics only, as well as four cases of spontaneous resolving hematuria. no patients needed to be readmitted for any reason, and no patients reported sexual dysfunction up to the most recent follow-up. this is consistent with published data, as dixon et al. found no clinically relevant changes in sex function over 2 years. mcvary et al. reported a single treatment of water vapor therapy with no adverse effects on sex function over a 3-year period, which is in contrast to medical treatment that results in worsening erectile dysfunction and libido (9, 10). lastly, the population that requires surgery for bph includes an older group of men, many of whom may be on anti-coagulants and have multiple underlying conditions. rezum is an excellent choice as it does not require the interruption of anticoagulants and does not require general anesthesia. limitations. in our study median lobe size was not sufficiently measured to adequately evaluate the effect of this measurement on outcome and response to rezum. our small sample size of patients with prostate size > 80cc emphasizes the need for larger, more robust prospective studies to elucidate rezum outcomes in patients with larger prostates. conclusions from our study, we conclude that rezum water vapor thermal therapy as a minimally invasive modality is effective and safe surgical option for management of benign prostatic hyperplasia of men with moderate to severe archivio italiano di urologia e andrologia 2023; 95(4):12026 t.a. abouelgreed, a.k. koritenah, y. badran, et al. 4 luts. this procedure has been shown to be effective in patients with varying larger prostate volumes. acknowledgments thanks to prof. dr. hossam hamdy, president of gulf medical university for his suggestion. references 1. speakman m, kirby r, doyle s, ioannou c. burden of male lower urinary tract symptoms (luts) suggestive of benign prostatic hyperplasia (bph) focus on the uk. bju int. 2015; 115:508-519. 2. lee swh, chan emc, lai yk. the global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. sci rep. 2017; 7:7984. 3. foster he, dahm p, kohler ts, et al. surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: aua guideline amendment 2019. j urol. 2019; 202:592-8. 4. guo rq, yu w, meng ys, et al. correlation of benign prostatic obstruction-related complications with clinical outcomes in patients after transurethral resection of the prostate. kaohsiung j med sci. 2017; 33:144-51. 5. jones p, rai bp, nair r, somani bk. current status of prostate artery embolization for lower urinary tract symptoms: review of world literature. urology. 2015; 86:676-81. 6. jones p, rajkumar gn, rai bp, et al. medium-term outcomes of urolift (minimum 12 months follow-up): evidence from a systematic review. urology. 2016; 97:20-4. 7. green z, westwood j, somani bk. what's new in rezum: a transurethral water vapour therapy for bph. curr urol rep. 2019; 20:39. 8. mynderse la, hanson d, robb ra, et al. rezum system water vapor treatment for lower urinary tract symptoms/benign prostatic hyperplasia: validation of convective thermal energy transfer and characterization with magnetic resonance imaging and 3-dimensional renderings. urology. 2015; 86:122-7. 9. dixon cm, cedano er, pacik d, et al. two-year results after convective radiofrequency water vapor thermal therapy of symptomatic benign prostatic hyperplasia. res rep urol. 2016; 8:207-16. 10. mcvary kt, rogers t, roehrborn cg: rezum water vapor thermal therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia: 4-year results from randomized controlled study. urology. 2019; 126:171-9. 11. gupta n, rogers t, holland b, et al. three-year treatment outcomes of water vapor thermal therapy compared to doxazosin, finasteride and combination drug therapy in men with benign prostatic hyperplasia: cohort data from the mtops trial. j urol. 2018; 200:405-13. 12. aboutaleb h, ali ta, zaghloul a, amin mm. efficacy of bipolar ‘button’ plasma vaporisation of the prostate compared to green laser vaporisation for benign prostatic obstruction. journal of clinical urology. 2018; 11: 350-356. 13. arezki a, sadri i, couture f, et al.: reasons to go for rezum steam therapy: an effective and durable outpatient minimally invasive procedure. world j urol. 2021; 39:2307-13. 14. ulchaker jc, martinson ms. cost-effectiveness analysis of six therapies for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. clinicoecon outcomes res. 2018; 10:29-43. 15. darson mf, alexander ee, schiffman zj, et al. procedural techniques and multicenter postmarket experience using minimally invasive convective radiofrequency thermal therapy with rezum system for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. res rep urol. 2017; 9:159-68. 16. johnston m, shah t, emara a, et al. rezum water vapour ablation therapy for benign prostatic hyperplasia: preoperative results from the united kingdom. j urol. 2019; 201: e1-e2. 17. johnston mj, noureldin m, abdelmotagly y, et al. rezum water vapour therapy: promising early outcomes from the first uk series. bju int. 2020; 126:557-8. 10.1111/bju.15203. 18. mollengarden d, goldberg k, wong d, roehrborn c. convective radiofrequency water vapor thermal therapy for benign prostatic hyperplasia: a single office experience. prostate cancer prostatic dis. 2018; 21:379-85. 19. garden eb, shukla d, ravivarapu kt, et al. rezum therapy for patients with large prostates (≥ 80 g): preoperative clinical experience and postoperative outcomes. world j urol. 2021; 39:3041-8. 20. cindolo l, pirozzi l, fanizza c, et al. drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. eur urol. 2015; 68:418-25. 21. mcvary kt, holland b, beahrs jr. water vapor thermal therapy to alleviate catheter-dependent urinary retention secondary to benign prostatic hyperplasia. prostate cancer prostatic dis. 2020; 23:303-308. correspondence tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt & gulf medical university, ajman, uae ayman k. koritenah, md dr_ayman.kotb@gmail.com yasser badran, md dryasserbadran@gmail.com ibrahim tagreda, md itagreda@yahoo.com mohamed algammal, md gemykarter2020@gmail.com hesham abozied, md aboziedhesham@gmail.com hany a. eldamanhory, md drhanyeldamanhory@gmail.com hossam a. shouman, md drhossamshouman@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt abdelhamid a. khattab, md abdelhamed1123ufw@gmail.com department of urology, damanhur teaching hospital, albuheira government, egypt munira ali, md muniraali1@gmail.com department of radiology, thumbay university hospital, ajman, uae mohammad thabet alnajem, md mtnajem@gmail.com department of radiology, tawam hospital, alain, uae ahmed a. abdelwahed, md ahmed_abdelwahed@yahoo.com department of radiology, ain shams university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 413archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. shown that active monitoring of pca would achieve a similar overall survival as radical treatment, while enduring less treatment related side-effects (2). however, in this same cohort, active surveillance (as) had a higher risk of disease progression and of metastatic disease (3). if for low-risk pca, as is looked at as the mostly consensual choice, for intermediate-risk pca, focal therapies (fts) are being studied in an attempt to allow a treatment that assures less morbidity while allowing acceptable oncological outcomes. the improvement in imaging modalities, mainly the mri, has allowed to improve diagnostic accuracy and localization of regions of interest for directed treatment, which allows ft to be considered in selected patients (4). despite being considered experimental treatments, fts are viewed by some as a potential treatment choice for intermediate-risk pca with a favorable safety profile (5). our goal was to describe medium-term oncological outcomes for patients with intermediate-risk localized pca treated primarily with high-intensity focused ultrasound (hifu) or cryotherapy. methods we conducted an observational, single-center, cohort study, evaluating data on all consecutive patients undergoing ft (hifu or cryotherapy) for intermediate-risk localized pca. patients were included if they fulfilled the following criteria: > 18 years, treatment naïve for pca at the moment of ft, multi-parametric magnetic resonance (mpmri) and subsequent biopsy, diagnosis of intermediate-risk localized pca having primary ft (either hifu or cryotherapy) between the years 2009 and 2018. patients were excluded if: no mpmri was performed by any reason or if they had hormonal therapy as a bridge for ft. using these criteria, we identified 150 patients after querying our continuously maintained institutional database. definitions we defined intermediate-risk pca as per the current nccn prostate cancer guidelines (6): at least one of the intermediate-risk factors – ct2b-ct2c, gleason grade objectives: focal therapies (fts) are promising techniques for the treatment of localized prostate cancer. we assessed the medium-term oncological outcomes of intermediate-risk prostate cancer (pca) treated with hifu or cryotherapy. materials and methods: one-hundred and fifty consecutive patients with intermediate-risk pca, treated between 2009 and 2018 at a single center were included. primary study outcome was failure-free survival (ffs), defined as absence of additional treatment, systemic progression or prostate cancer related death. results: thirty-seven (25%) patients underwent cryotherapy and 113 (75%) hifu. median age was 69 (iqr 62-72) years, with 36 (24%) presenting palpable disease on rectal examination, and median total psa of 7.85 (iqr 5.75-10.62) ng/ml. patients were followed for a median of 61 (iqr 48-82) months. ffs at 2 and 4 years was of 75.6% and 53.6%, respectively. survival from whole gland or systematic treatment at 2 and 4 years was of 78.9% and 53.9%, respectively. patients with ffs presented lower total psa nadir (1.89 vs 3.25 ng/ml, p < 0.001), higher % psa reduction at 3 months (66.1% vs 49.3%, p < 0.001), and at nadir (75.5% vs 55.8%, p < 0.001). other characteristics such has the treatment modality, age, prostate size, initial total psa, ct stage, international society of urological pathology (isup), tumor location and biopsy results by region did not differ between patients failing and not failing ft. complications were uncommon (13%), with only onr (1%) patient having clavien-dindo grade > ii. no deaths due to treatment were registered. conclusions: at medium-term, fts for intermediate-risk pca presented good oncological results, with an excellent safety profile. key words: prostatic neoplasms; cryotherapy; focal therapy; ablation. submitted 21 october 2022; accepted 30 october 2022 introduction current standard treatment options for localized prostate cancer (pca) include active surveillance and radical treatment (surgery or radiotherapy) (1), which has been known to have negative impacts on quality of life (2). protect trial results (3), first published in 2014, have medium-term oncological outcomes of intermediate-risk prostate cancer treated with hifu or cryotherapy. a single center 10-year experience nuno dias 1, 2, lara rodriguez-sanchez 1, gianmarco colandrea 1, 3, petr macek 1, xavier cathelineau 1 1 urology department, institut mutualiste montsouris, paris, france; 2 urology department, são joão hospitalar and university center, porto, portugal; 3 unit of urology, division of experimental oncology, uri urological research institute, irccs san raffaele scientific institute, vita-salute san raffaele university, milan, italy. doi: 10.4081/aiua.2022.4.413 summary archivio italiano di urologia e andrologia 2022; 94, 4 n. dias, l. rodriguez-sanchez, g. colandrea, p. macek, x. cathelineau 414 group 2-3, total psa 10-20 ng/ml; without having high or very high-risk factors – any of ct3+, gleason grade group 4-5, psa ≥ 20 ng/ml or >4 cores with gleason grade group 4 or 5. we further stratified patients between the categories of favorable intermediate (all of the following: having 1 intermediate-risk factor, gleason grade group 1 or 2, and < 50% of biopsy cores positive) and unfavorable intermediate-risk (at least one of the following criteria: having 2 or 3 intermediate-risk factors, gleason grade group 3, and ≥ 50% of biopsy cores positive) prostate cancer. clinically significant prostate cancer (cspca) was defined as gleason grade group [or international society of urological pathology (isup) grade] ≥ 2. data collection data was collected from our continuously updated database and patient records. we recorded age at time of treament, pre-operative total psa, clinical t staging, prostate volume, initial mpmri results, initial biopsy results, date of ft and type of ft performed. we obtained follow-up data including total psa values, mri and biopsies results. we registered if patients developed disease biochemical, imagiological and histological recurrences; if there was a need for subsequent treatment and its indication, overall survival, prostate cancer specific survival and last followup date. procedures multi-parametric mri was performed at community centers. if there was a disagreement between radiologist and urologist interpretation, it was reviewed with an in-house urologist specialized in uro-oncological imaging, and repeated if advised. prostate biopsies were performed in our center, transrectally, with a 12-core systematic biopsy and 2-4 targeted samples being obtained from suspicious lesions, defined as score prostate imaging reporting & data system (pirads) ≥ 3. among patients with suspicious lesions on imaging, 3 regions of interest were considered. target zone cancer was considered when pca was identified on the targeted samples obtained from suspicious mri lesions. near target zone cancer was considered when pca was identified on randomized samples obtained from a region adjacent to the suspicious lesion location. away from target zone cancer was considered when pca was identified on randomized samples obtained from a region not adjacent to the suspicious lesion location. cryotherapy (n = 37) was performed using the various devices, using a previously described standard technique (7), for all cases. hifu was performed using ablatherm® fusion (edap) (n = 29) and focal one® (edap) (n = 84), through an evolving technique (8), until arriving at what we use today. after an initial learning period, the energy to use was typically chosen based on lesion location, with cryotherapy being preferred for anterior tumors and hifu for peripheral tumors. in patients with well delimited lesions on mri and no extra-lesion cspca disease we performed uniquely a targeted ft. patients with mri lesions and ipsilateral perilesion cspca disease on systematic biopsy, we performed targeted ft with a widened field. patients with mri lesions and ipsilateral cspca disease on systematic biopsy cores non-adjacent to the lesion site, we performed hemiablation. patients with bothering emptying symptoms underwent tur-p in the 2 weeks prior to the ft procedure. study outcomes primary study outcome was failure free survival (ffs), defined as absence of additional gland-directed (being focal or radical) or systemic treatment, metastatic disease or pca related death. other study outcomes included biochemical recurrence free survival, metastasis free survival, overall survival, adverse events and complications classified by the clavien-dindo system. follow-up the recommended follow-up strategy consisted in performing psa measurements every 3 months during the 1st year after treatment and every 6 months thereafter, performing mpmri 1 month and 1, 2 and 3 years after treatment and performing control biopsies 1, 2 and 3 years after ft. additional repeat mri and biopsies were performed if clinically judged indicated, based on various criteria. if patients declined to perform imaging and/or biopsies, they would remain in surveillance based on total psa measurement alone, on a 3-6 months basis. treatment failure was considered when a patient was submitted to any additional pca directed treatment, apart from complementary ft during the first 3 months after initial treatment. patients were classified as having biochemical recurrence using the phoenix criteria (4) measurement of total psa higher than nadir total psa + 2 ng/ml. in patients with recurrent or persistent disease, treatment was decided on a case-by-case basis. statistics statistical analysis was performed with ibm® spss® v27 software. categorical variables are presented as frequencies and percentages, and were compared using chisquared analysis or fisher’s exact test, as appropriate. continuous variables are presented as means and interquartile ranges (iqr), and were compared using nonparametric mann-whitney u tests. statistically significance was set as p < 0.05. all reported p values are twosided. kaplan-meier survival curves were calculated for failure-free survival according to described variables. logrank test was used to calculate for difference between groups. patients with peri-treatment transurethral prostate resection (tur-p) were excluded from total psa reduction analysis. the study has received approval from the local ethics committee, and all research was conducted respecting the latest version of helsinki’s declaration. patients were provided information on their pca disease and available standard treatment modalities (active surveillance, radical prostatectomy, radiotherapy), that fts were not standard of care and have chosen ft as their desired treatment choice. they provided consent agreeing to participate in this research on ft oncological results. 415archivio italiano di urologia e andrologia 2022; 94, 4 intermediate-risk prostate cancer treated with hifu or cryotherapy results pre-treatment patient characteristics among 150 patients with intermediate-risk pca, 37 (25%) underwent cryotherapy and 113 (75%) hifu (table 1). the median age was 69 (iqr 62-72) years, with 114 (76%) patients having no palpable disease on digital rectal examination. median total psa was of 7.85 (iqr 5.75-10.62) ng/ml, with 46 (31%) of patients having an initial total psa between 10-20 ng/ml and none higher than 20 ng/ml. the mean prostate volume was 40 (iqr 35-48) ml. regarding nccn risk groups, 117 (78%) patients had intermediate favorable pca and 33 (22%) intermediate unfavorable pca; 37 (25%) presented with isup 1, 109 (73%) with isup 2 and 4 (3%) with isup 3 pca. a total of 115 (77%) patients had suspicious lesions present on mpmri. when analyzing biopsy results by region among the 126 (84%) patients with suspicious lesions on mri: 93 (74%) had cspca 46 (37%) had cspca only on suspicious lesions; 31 (25%) had cspca on suspicious lesions and lesion-adjacent systematic biopsy cores; 8 (6%) had cspca only on lesion-adjacent systematic biopsy cores; 4 (3%) had cspca only on non-lesion-adjacent systematic biopsy cores; 3 (2%) had cspca on suspicious lesions, lesion-adjacent and non-lesion-adjacent systematic biopsy cores; 1 (1%) had cspca on lesion-adjacent and nonlesion-adjacent systematic biopsy cores but not on suspicious lesions; 0 (0%) had cspca on suspicious lesions and non-lesion-adjacent systematic biopsy cores. primary outcome failure free survival patients were followed for a median time of 61 (iqr 48-82) months. over all treated patients, the ffs at 2, 4, 5 and 7 years was of 75.6%, 53.6%, 42.1% and 27.3%, respectively. survival from whole gland or systematic treatment at 2 and 4 years was of 78.9% and 53.9%, respectively. table 2 lists studied factors and their association with the need of additional treatment. table 1. patient clinical characteristics. characteristics value (n = 150) treatment, n (%) cryotherapy 37 (25) hifu 113 (75) treatment year, n (%) 2009-2012 22 (15) 2013-2015 65 (43) 2016-2018 63 (42) age, median (iqr) 69 (62-72) prostate volume (ml), median (iqr) 40 (35-48) total psa (ng/ml), median (iqr) 7.85 (5.75-10.62) initial total psa < 10 ng/ml, n (%) 104 (69) initial total psa 10-20 ng/ml, n (%) 46 (31) ct stage, n (%) ct1c 114 (76) ct2a 18 (12) ct2b 13 (9) ct2c 5 (3) biopsy overall isup grade, n (%) 1 37 (25) 2 109 (73) 3 4 (3) nccn risk group, n (%) intermediate favorable 117 (78) intermediate unfavorable 33 (22) pi-rads score 1-2 24 (16) suspicious mri, with no pi-rads score * 11 (7) 3 27 (18) 4 65 (43) 5 23 (15) biopsy results by region, n (%) ** cspca @ suspicious lesion(s) 80 (63) cspca @ lesion-adjacent systematic biopsy cores 43 (34) cspca @ non-lesion-adjacent systematic biopsy cores 8 (6) tumor per specific locations, n (%) anterior zone 16 (11) apex 23 (15) base 51 (34) bilateral 11 (7) if peri-treatment tur-p, n (%) 21 (14) total psa nadir (ng/ml), median (iqr) 2.52 (1.59-4.51) time to psa nadir (months), median (iqr) 3.0 (3.0-9.8) psa % reduction, median (iqr) @ 3 months 55 (39-72) @ nadir 62 (45-78) * exams performed before pi-rads classification v1 was published. ** results taking into consideration 126 patients with mri suspicious for prostate cancer. table 2. patients’ characteristics according to necessity of salvage treatment and univariate analysis. characteristics failure free non-failure free univariate (n = 53) (n = 97) p-value treatment, n (%) 0.553 cryotherapy 15 (28) 22 (23) hifu 38 (72) 75 (77) age, median (iqr) 66 (61-2) 69 (63-74) 0.245 prostate volume (ml), median (iqr) 41.0 (35.0-47.0) 40.0 (34.0-50.0) 0.835 total psa (ng/ml) 0.580 initial tpsa < 10 ng/ml, n (%) 35 (66) 69 (71) initial tpsa 10-20 ng/ml, n (%) 18 (34) 28 (29) ct stage, n (%) 1.000 ct1c 40 (75) 74 (76) ct2a-c 13 (25) 23 (24) biopsy overall isup grade, n (%) 0.436 1 16 (30) 21 (22) 2 35 (66) 74 (76) 3 2 (4) 2 (2) nccn risk group, n (%) 0.542 intermediate favorable 43 (81) 74 (76) intermediate unfavorable 10 (19) 23 (24) tumor per specific locations, n (%) anterior zone 8 (15) 8 (8) 0.268 apex 11 (21) 12 (12) 0.235 base 15 (28) 36 (37) 0.287 bilateral 5 (9) 6 (6) 0.520 total psa nadir (ng/ml), median (iqr) 1.89 (0.96-2.81) 3.25 (1.93-5.68) < 0.001 time to psa nadir (months), median (iqr) 6 (3-12) 3 (3-6) < 0.001 psa % reduction, median (iqr) @ 3 months 66.1 (53.1-78.3) 49.3 (26.9-63.4) < 0.001 @ nadir 75.5 (61.6-84.7) 55.8 (36.6-68.0) < 0.001 if psa % reduction @ 3 months, n (%) > 30% 38 (97) 55 (72) 0.002 > 50% 31 (79) 36 (47) < 0.001 > 70% 18 (34) 13 (17) < 0.00 archivio italiano di urologia e andrologia 2022; 94, 4 n. dias, l. rodriguez-sanchez, g. colandrea, p. macek, x. cathelineau 416 patients who needed additional treatment were more likely to have higher total psa nadir (3.25 vs 1.89 ng/ml, p < 0.001), lower time to psa nadir (3 vs 6 months, p < 0.001), lower total psa reduction at 3 months (49.3% vs 66.1%, p < 0.001), lower total psa reduction at nadir (55.8% vs 75.5%, p < 0.001). other characteristics such has the treatment modality, age, prostate size, initial total psa, ct stage, isup, nccn risk group, tumor location and biopsy results by region did not differ between patients failing and not failing ft. kaplan meier-analysis showed a significant difference for psa reduction > 70% (log-rank test p = 0.002) (figure 1a), but not for initial total psa (log-rank test = 0.915) (figure 1b), isup grade (log-rank test = 0.560) (figure 1c) or nccn sub-risk group (log-rank test = 0.676) (figure 1d). other variables not presented also haven’t shown differences on the kaplan-meier analysis (treatment energy, age, prostate volume, clinical stage, cspca locations and tumor location). the additional selected treatment for the 97 (65%) patients who failed ft was radiotherapy + hormonal therapy in 37 (25%), radiotherapy in 6 (4%), radical prostatectomy in 16 (11%), hormonal therapy in 12 (8%), hifu in 12 (8%), brachytherapy in 10 (7%) and cryotherapy in 4 (3%). median time to additional treatment was of 45.5 (iqr 21.8-61.0) months. reasons for further treatment are presented on table 3. treatment complications nineteen (13%) patients presented treatment related complications. one (1%) patient had a clavien-dindo table 3. reasons for first additional treatment being performed. reason for treatment value (n = 150) isup 1 infield persistence + psa and/or image progression 6 (4.0%) isup 2 infield persistence 3 (2.0%) new isup 1 outfield 5 (3.3%) new isup ≥ 2 outfield 20 (13.3%) infield progression to isup 2 1 (0.7%) infield progression to isup ≥ 3 13 (8.7%) isup 2 infield recurrence 14 (9.3%) in & outfield isup ≥ 2 27 (18.0%) biochemical recurrence +/image progression 6 (4.0%) figure 1. kaplan-meier analysis showing failure free survival according to (a) psa reduction > 70% at 3 months (log-rank test p = 0.002), (b) initial total psa categories (log-rank test = 0.915), (c) isup grade (log-rank test = 0.560), and (d) nccn sub-risk group (log-rank test = 0.676). a. b. c. d. 417archivio italiano di urologia e andrologia 2022; 94, 4 intermediate-risk prostate cancer treated with hifu or cryotherapy grade i complication: hematuria needing hospitalization for continuous bladder irrigation. twelve (8%) patients had clavien-dindo grade ii complications: 11 (7%) urinary retentions, 6 (4%) acute bacterial prostatitis, 3 (2%) acute orchitis, 1 (1%) intense perineal pain. one (1%) patient had a clavien-dindo grade iiib complication, a recto-cutaneous fistula needing colostomy. no deaths due to treatment were registered. biochemical recurrence after treatment a total of 88 (59%) patients presented biochemical recurrence according to the phoenix criteria, with median time to psa failure of 24.0 months. patients with biochemical recurrence were younger than patients without biochemical recurrence (66 vs 70 years, p = 0.035). other studied factors were not statistically different between patients with and without biochemical recurrence (table 4). other follow-up data nadir total psa was reached at a median time of 3.0 (iqr 3.0-9.8) months. mri was performed at least once for 125 (83%) patients during the first 3 years; in 68 patients at 1 month and 79 at 1 year, being positive in 10 (15%) and 44 (56%) patients, respectively. control biopsies were performed at least once for 122 (81%) patients during the first 3 years; in 96 cases during the first year. presence of cspca on biopsy after treatment was detected in 79 (53%) patients; in 31 (21%) cases with cspca only on previous treated area and/or its borders, 20 (13%) with only outfield cspca and 28 (19%) in both infield and outfield areas. systemic progression was found in 10 (7%) patients, with 4 (3%) presenting with pelvic lymph node disease and 6 (4%) with other metastatic progression. patients who developed metastatic disease were in 1 case a patient with initial total psa of 12.1 ng/ml and highvolume isup 1 pca, with total psa of 16.4 ng/ml 3 months after hifu, who had retroperitoneal metastasis on re-staging; and 5 cases of patients with initial total psa > 10 ng/ml and cspca, who had biochemical recurrence, underwent additional treatment, but had disease progression with metastasis detected 30-72 months after. three (2%) patients died during follow-up, both due to reasons unrelated to pca. discussion this study represents our experience as one of the first centers treating patients with intermediate-risk pca with fts, and shows our experience since the beginning of this practice. as such, during this time period treatment instruments have evolved, patient selection criteria have been refined, and knowledge has improved. we report the oncological outcomes of 150 consecutive patients with intermediate-risk localized pca treated with either cryotherapy (25%) or hifu (75%). 144 patients were followed longer than 24 months, with a median follow-up time of 61 (iqr 48-82) months. although a big proportion of patients (65%) were submitted to additional treatments (with 71 in 97 of those cases being treated with whole-gland or systemic treatment), the median time of ffs was of 45.5 (iqr 21.8-61.0) months, which means that ft resulted in a substantial delay to radical treatment for a big proportion of patients. the safety profile of the treatment was good, with only 1 patient having a complication clavien-dindo ≥ 3. only 10 (7%) of patients presented disease progression, with 6 (4%) as metastatic disease, and there were no deaths related to pca. it has the limitations of being a single center retrospective study, capturing patients during a long timeframe, in which treatment instruments, diagnostic methods, and disease comprehension has evolved. we also note that the first cases included account to 2009 when ft treatments were undergoing their first discovery period. in addition, since some patients referred to us for treatments come from other big distances their follow-up is sometimes changed to a local physician after an initial time of stable disease, leading to some early censoring of patients who have good outcomes. these 2 factors may tilt our results to seem worse than current practice. with the debate on ft for intermediate-risk disease still ongoing (9, 10), we believe gathering to be important in counseling patients who search for non~radical treatment options; or wish to change from active surveillance to active treatment due to desire to act and fear of progression, which are reasons as common as common as disease progression (11, 12). regarding oncological safety, groups as the imperial college london have reported on their experience. on a propensitable 4. patients’ characteristics according to biochemical recurrence free survival and univariate analysis. characteristics biochemical biochemical univariate recurrence free recurrence p-value (n = 62) (n = 88) treatment, n (%) 0.702 cryotherapy 14 (23) 23 (26) hifu 48 (77) 65 (74) age, median (iqr) 70 (64-73) 66 (61-71) 0.035 prostate volume (ml), median (iqr) 40.5 (32.75-48.25) 40 (35-49.25) 0.782 total psa (ng/ml) 1.000 initial tpsa < 10 ng/ml, n (%) 43 (69) 61 (69) initial tpsa 10-20 ng/ml, n (%) 19 (31) 27 (31) ct stage, n (%) 0.442 ct1c 45 (73) 69 (78) ct2a-c 17 (27) 19 (22) biopsy overall isup grade, n (%) 0.699 1 17 (27) 20 (23) 2 44 (71) 65 (74) 3 1 (2) 3 (3) nccn risk group, n (%) 0.165 intermediate favorable 52 (84) 65 (74) intermediate unfavorable 10 (16) 23 (26) tumor per specific locations, n (%) anterior zone 8 (13) 8 (9) 0.592 apex 9 (15) 14 (16) 0.824 base 16 (26) 35 (40) 0.083 bilateral 3 (5) 8 (9) 0.365 total psa nadir (ng/ml), median (iqr) 2.28 (1.02-4.19) 2.73 (1.80-4.65) 0.085 time to psa nadir (months), median (iqr) 5 (3-11) 3 (3-8) 0.580 psa % reduction, median (iqr) @ 3 months 57.14 (43.24-76.28) 55.43 (37.56-68.70) 0.517 @ nadir 64.16 (46.97-79.06) 62.16 (42.58-77.13) 0.522 archivio italiano di urologia e andrologia 2022; 94, 4 n. dias, l. rodriguez-sanchez, g. colandrea, p. macek, x. cathelineau 418 ty-score matched study (13) comparing oncological outcomes between patients who underwent ft or radical prostatectomy at their center, they report a ffs (95% ci) at 3, 5 and 8 years of 86% (81-91%), 82% (77-88%) and 79% (73-86%) for radical prostatectomy and of 91% (8795%), 86% (81-92%) and 83% (76-90%) after ft (p = 0.12). their report shows similar oncological outcomes between both modalities. however, this was a retrospective study and the groups compared after matching included 38.2% and 37.0% patients with isup 1 pca. recently, reddy et al. (14) published the largest reported cohort on ft: a multi-center study including 1379 men undergoing hifu for localized pca treatment, with 66% in the intermediate-risk group. they reported an overall ffs rate of 69% at 7 years. of note is that in their protocol, a second hifu treatment regardless of timing is allowed and was performed in 252 patients, placing the re-treatment free survival at 7 years at 43%. for intermediate-risk patients, they report a ffs of 83% at 5 years, and 68% at 7 years. in this study, no patients developed metastasis or died due to pca, and 7 (0.5%) patients had complications with clavien-dindo score > 2 (14). their nominal ffs was higher than in our current report since the 2 year time-frame. however, we note that the authors allowed for a second ft without considering a treatment failure, and their retreatment-free survival at 7 years was of 49% and the whole-gland or systemic treatment survival at 7 years was of 78%, which is also above our reported values. complications were in line with our current study, with serious events being rare. in a multi-center study including 703 men with low or intermediate-risk pca receiving ft, % psa reduction was found to be an independent predictor of any additional treatment, with ffs at 5 years of approximately 70%, 50% and 20%, for % psa reductions of 0%, 50%, and close to 100%, respectively (15). the same association was found in our study, with this factor seeming a possible measure that can help setting up an adequate follow-up strategy and counseling patients on risk of disease recurrence. although here we do not report on functional outcomes, many groups have reported good results with ft, with 94-100% pad-free rate regarding urinary incontinence and 47-86% erectile function (16). with ft on the rise in both recognition and availability (17, 18), our current and other’s reports (19) show that clinicians have been treating patients with higher risks both on and off trial, as some patients express a desire to undergo ft outside of those criteria, searching for a chance of benefit (avoiding or delaying complications) when treatment is advised but there is no immediate threat to life, as is the case of localized intermediate-risk pca. while urological guidelines (1, 6) still consider ft as experimental treatments, the german society of urology (20) has published in 2022 a list of recommendations considering ft an option for patients with unilateral low-risk pca who decline “standard therapies” and active surveillance, but reminding of the available data being insufficient to access ft oncological effectiveness. other publication has reported on a delphi-method consensus meetings of 47 ft experts recommending allowing treatment of low and intermediate-risk pca with volume up to 3 ml in 1 hemi-gland, if total psa lower than 10 ng/ml (21). the oncological and functional reported outcomes for ft in pca have also been reported in at least 72 studies, with 8 different energy modalities and including 5827 patients (19). however, those are mostly from single-arm stage 2 studies. to add to the current data, we would like next years to bring us results on randomized controlled trials for ft versus radical treatment and active surveillance, with populations of mainly intermediate-risk pca patients. those trials will need to prove both efficacy and safety of ft. conclusions this series adds information on the outcomes of ft in the treatment of localized intermediate-risk pca. the oncological control and survival without whole-gland or systemic treatment were satisfactory. in those who needed additional treatment, ft delayed its need in a reasonable amount of time, with a very good side-effect profile. with a low percentage of metastatic disease and no pca related deaths, this study advocates for allowing ft as a treatment option in selected cases of intermediate-risk disease. randomized controlled trials comparing ft with active surveillance and radical treatments are needed to further establish the role of those treatments. references 1. mottet n cp, vand den bergh rcn, briers e, et al. eau eanm estro esur isup siog guidelines on prostate cancer. european association of urology 2022. 2. lane ja, donovan jl, young gj, et al. functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [protect] study). bju int. 2022; 130:370-380. 3. lane ja, donovan jl, davis m, et al. active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the protect randomised phase 3 trial. lancet oncol. 2014; 15:1109-18. 4. lomas dj, ahmed hu. all change in the prostate cancer diagnostic pathway. nat rev clin oncol. 2020; 17:372-81. 5. kasivisvanathan v, emberton m, ahmed hu. focal therapy for prostate cancer: rationale and treatment opportunities. clin oncol (r coll radiol). 2013; 25:461-73. 6. network ncc. nccn clinical practice guidelines in oncology prostate cancer. version 1.2023. 7. redondo c, srougi v, da costa jb, et al. focal cryotherapy: step by step technique description. int braz j urol. 2017; 43:995-6. 8. claros or, tourinho-barbosa rr, carneiro a, et al. hifu focal therapy for prostate cancer using intraoperatory contrast enhanced ultrasound. arch esp urol. 2019; 72:825-30. 9. gontero p, marra g, teber d, et al. making a case "against" focal therapy for intermediate-risk prostate cancer. world j urol. 2021; 39:719-28. 10. wang az, lebastchi ah, o'connor lp, et al. making a case "for" focal therapy of the prostate in intermediate risk prostate cancer: current perspective and ongoing trials. world j urol. 2021; 39:729-39. 419archivio italiano di urologia e andrologia 2022; 94, 4 intermediate-risk prostate cancer treated with hifu or cryotherapy 11. mcintosh m, opozda mj, o'callaghan m, et al. why do men with prostate cancer discontinue active surveillance for definitive treatment? a mixed methods investigation. psychooncology. 2022; 31:1420-30. 12. bokhorst lp, valdagni r, rannikko a, et al. a decade of active surveillance in the prias study: an update and evaluation of the criteria used to recommend a switch to active treatment. eur urol. 2016; 70:954-60. 13. shah tt, reddy d, peters m, et al. focal therapy compared to radical prostatectomy for non-metastatic prostate cancer: a propensity score-matched study. prostate cancer prostatic dis. 2021; 24:567-74. 14. reddy d, peters m, shah tt, et al. cancer control outcomes following focal therapy using high-intensity focused ultrasound in 1379 men with nonmetastatic prostate cancer: a multi-institute 15-year experience. eur urol. 2022; 81:407-13. 15. stabile a, orczyk c, giganti f, et al. the role of percentage of prostate-specific antigen reduction after focal therapy using highintensity focused ultrasound for primary localised prostate cancer. results from a large multi-institutional series. eur urol. 2020; 78:155-60. 16. fujihara a, ukimura o. focal therapy of localized prostate cancer. int j urol. 2022; 29:1254-1263. 17. jain al, sidana a, maruf m, et al. analyzing the current practice patterns and views among urologists regarding focal therapy for prostate cancer. urol oncol. 2019; 37:182 e1-e8. 18. marra g, ploussard g, ost p, et al. focal therapy in localised prostate cancer: real-world urological perspective explored in a cross-sectional european survey. urol oncol. 2018; 36:529 e11-e22. 19. hopstaken js, bomers jgr, sedelaar mjp, et al. an updated systematic review on focal therapy in localized prostate cancer: what has changed over the past 5 years? eur urol. 2022; 81:5-33. 20. borkowetz a, blana a, bohmer d, et al. german s3 evidencebased guidelines on focal therapy in localized prostate cancer: the first evidence-based guidelines on focal therapy. urol int. 2022; 106:431-9. 21. tay kj, scheltema mj, ahmed hu, et al. patient selection for prostate focal therapy in the era of active surveillance: an international delphi consensus project. prostate cancer prostatic dis. 2017; 20:294-9. correspondence nuno dias, md (corresponding author) nunodiasds@gmail.com gianmarco colandrea, md colandrea.gianmarco@hsr.it lara rodriguez-sanchez, md rodriguezsanchezlara@gmail.com petr macek, md petr.macek@imm.fr xavier cathelineau, md xavier.cathelineau@imm.fr urology department, institut mutualiste montsouris; 42 bd jourdan; 75014 paris (france) stesura seveso 235archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.235 prostate cancer with cribriform pattern: exclusion criterion for active surveillance? rui miguel bernardino 1, rita carvalho 2, luis severo 1, marta alves 3, ana luisa papoila 3, luis campos pinheiro 1 1 urology department, central lisbon hospital center, lisbon, portugal; 2 pathology department, central lisbon hospital center, lisbon, portugal; 3 epidemiology and statistics unit, research center, central lisbon hospital center, lisbon, portugal. introduction: following the 2014 international society of urological pathology meeting, a rapidly growing body of evidence by several researchers has been demonstrating a poor prognosis in association with cribriform morphology. the aim of our study was to describe the presence of cribriform foci in specimens of radical prostatectomies and to evaluate whether demographic and clinical characteristics are associated with the presence of cribriform pattern. materials and methods: this cohort study was based on 70 radical retropubic prostatectomies specimens collected between 2012 and 2016 and evaluated for the association of the cribriform pattern with age, prostate-specific antigen at surgery day, gleason on biopsy, gleason after radical prostatectomy, extracapsular extension, vesicles invasion, margins, multiparametric magnetic resonance imaging, and post-operative radiotherapy. results; from the univariable analysis, biochemical prostatespecific antigen recurrence (p = 0.001), extracapsular extension (p = 0.003), pre-operative prostate-specific antigen (p = 0.017), vesicles invasion, (p = 0.038) and post-operative radiotherapy (p < 0.001) showed an association with the presence of cribriform pattern. there was also a significant difference of cribriform pattern and gleason 7 in needle biopsy (p = 0.020) and cribriform pattern and gleason 8 or 9 in radical prostatectomy specimen (p = 0.036). conclusions: in our study, the increase in preoperative prostate-specific antigen had a high association with cribriform pattern. further evidence is needed to discriminate preoperative prostate specific antigen values that might potentially be associated with the presence of cribriform pattern. raising our knowledge about the cribriform pattern can be an excellent opportunity to correctly identify and treat patients who will eventually die from prostate cancer, sparing treatment in those who will not. key words: cribriform pattern; prostate cancer; radical prostatectomy. submitted 2 march 2020; accepted 15 march 2020 summary introduction the gleason pattern (gp) 4 has been assigned to most cribriform patterns, because of the understanding that invasive cribriform carcinoma is relatively aggressive (1). cribriform is characterized by a "solid proliferation with multiple, punched out lumina without intervening stroma" (2). following the 2014 international society of urological pathology (isup) meeting, a rapidly growing body of evidence by several researchers has been demonstrating a poor prognosis in association with cribriform morphology (3). dong et al. (4) showed that, after 10 years of follow-up, 13% of patients with cribriform architecture morphology at radical prostatectomy (rp) developed metastasis compared to 2.6% with gp 4 without cribriform morphology. other studies supported the information that the presence of any cribriform was associated with higher biochemical recurrence (5-6). cribriform lesions in their pure form on rp specimens were found to be poorly visible on multi-parametric magnetic resonance imaging (mpmri), namely only 17% of foci were visible (7). sarbay et al. (8) demonstrate that diagnosing all cribriform patterns, at least gp 4, would significantly affect further therapeutic options and prognosis. the aim of our study is to access the cribriform foci on the rp specimens, and to evaluate whether demographic and clinical characteristics are associated with the presence of cribriform pattern (cp). materials and methods this cohort study was based in 70 radical retropubic prostatectomies specimens collected between 2012 and 2016 in our department. all the patients had a mpmri pre-operatively. the study was approved by institutional ethics committee, and informed consent was obtained from all patients. patients treated with cryotherapy, radiotherapy, or androgen deprivation pre-operatively were excluded. the prostate-specific antigen (psa) was measured at the day of the surgery and in the last consultation before the beginning of the study. a postoperative serum psa above 0.2 ng/ml was considered as a biochemical prostate-specific antigen recurrence (bpr) (9). each prostate was sampled according to the standardized laboratory's protocol by the original reporting pathologist: specimens fixed in 10% neutral buffered formalin for at least 24h, serial sectioning into 0.3 mm thick sections of the whole prostate, paraffin embedding and 4 μm thick sections stained with h&e. all the specimens were evaluated by the same pathologist with the aim of identifying the presence of a cribriform pattern. this pattern was considered to be present archivio italiano di urologia e andrologia 2020; 92, 3 r.miguel bernardino, r. carvalho, l. severo, m. alves, a.luisa papoila, l. campos pinheiro 236 when confluent epithelial proliferations with multiple lumina and no intervening stroma were observed (figure 1), and also when the cribriform formation was attached to only one edge of the gland, resulting in the less common glomeruloid pattern (figure 2). cases with comedonecrosis were not observed. for some cases with cribriform areas with smooth contours, immunohistochemistry (p63 and ck34be12) was applied to distinguish from high-grade prostate intraepithelial neoplasia (pin) and intraductal carcinoma. statistical analysis characteristics of study patients were described using the median and interquartile range (iqr: 25th percentile75th percentile) for continuous variables and frequencies (percentages) for categorical variables. to study the association between cribriform foci and clinical and demographic variables, logistic regression models were used. odd ratios were estimated with corresponding 95% confidence intervals (ci). the following variables were considered in the univariable analysis: age, psa at surgery day, gleason on biopsy, gleason after radical prostatectomy, extracapsular extension, vesicles invasion, margins, mpmri, and postoperative radiotherapy. those variables attaining a p-value < 25 in the univariable analysis were selected as candidates for the multivariable model. discriminative ability and calibration of the model were assessed by the area under the receiver-operating characteristic curve (auc) and the hosmer-lemeshow test (figure 3), respectively. the level of significance a = 0.05 was considered. all data were analyzed using the statistical package for the social sciences for windows 22.0 (ibm corp. released 2013. ibm spss statistics for windows. armonk, ny: ibm corp.). results out of 70 specimens of patients with radical retropubic prostatectomy included in the study, 23 (32.9%) had a cribriform pattern. the median age at diagnosis was 66 years (range 60-70) for patients with cribriform pattern and 65 years (range 60-68) for patients who do not have cribriform pattern at radical prostatectomy specimen. the pathologic characteristics of the study sample are presented in table 1. the grade group distribution of the 70 specimens was as follow: 14 (20%), 27 (38.6%), 14 (20%), 5 (7.1%), 6 (8.6%), 3 (4.3%) and 1 (1.4%) were gleason 3+3, 3+4, 4+3, 4+4, 4+5, 5+4 and 3+5, respectively. furthermore, for cases with cp, 14 (60.9%), 12 (52.2%) and 5 (21.7%) had extraprostatic extension (epe), surgical margin (sm) and vesicles invasion, respectively. on the other hand, for cases without cp, 11 (23.4%), 15 (31.9%) and 2 (4.3%) had epe, sm and vesicles invasion, respectively. by previous definition of psa failure, 7 (30.4%) of the patients with cp and only 1 (2.2%) without cp showed bpr. of those who had bpr, 7 (87.5%) had cribriform pattern, while from those who did not had bpr, only 16 (26.2%) had cribriform pattern. concerning radiotherapy, 16 (69.6%) of the patients with cp have done adjuvant radiotherapy, while only 7 (30.4%) with cp have not been submitted to rt. from the univariable analysis, bpr (p = 0.001), epe (p = 0.003), pre-operative psa (p = 0.017), vesicles invasion (p = 0.038) and rt (p < 0.001) showed an association with the presence of cribriform pattern (table 2). there was no statistically significant difference between the presence of cp and positive margins (p = 0.105), mpmri pirads 4 (p = 0.609) and 5 (p = 0.254), gleason score 7 in rp specimen (p = 0.131) or gleason score 8 or 9 in needle biopsy (p = 0.429). on the other hand, there was a significant difference with cp pattern and gleason 7 in needle biopsy (p = 0.020) and with cp and gleason 8 or 9 in rp specimen (p = 0.036) (table 2). figure 1. confluent epithelial proliferations with multiple lumina and no intervening stroma. figure 2. cribriform formation attached to only one edge of the gland, resulting in the less common glomeruloid pattern. figure 3. good discriminative ability to distinguish between patients with and without cribriform pattern with an auc = 0.79 (95% ci: 0.67-0.91). results of multivariable model showed that for each unit increase in pre-operative psa, there was a 14.2% increase (or-estimate = 1.14; 95% ci: 1.01-1.29; p = 0.033) in the odds of cribriform pattern. it was also observed that patients with extracapsular extension have a 5-fold increase in the odds of having cribriform pattern (or-estimate = 5.35; 95% ci: 1.68-17.02; p = 0.005). the multivariable model showed a good discriminative ability to distinguish between patients with and without cribriform pattern with an auc = 0.79 (95% ci: 0.670.91) (figure 3). the hosmer-lemeshow goodness-of-fit test showed a good calibration (p = 0.377). discussion cribriform tumours are now recognized as highly aggressive and with worse prognosis compared to other morphologies. this means that enhancing the understanding of cribriform cancer biology is of the utmost importance to precisely identify and treat men that will eventually die of prostate cancer, while sparing treatment in those who will not (10). what could be the implication of a cribriform pattern in clinical practice? in a study by kenneth et al. (11) that involved 153 men who underwent rp, 76 with psa failure (> 0.2 ng/ml) were matched to 77 men without failure. in high-grade pattern frequencies, 54.9% showed a cp. this pattern was also present in 61% of psa failure cases. according to the multivariable analysis, the cp had the highest odds ratio for psa failure. in another study, 241 consecutive rp specimens were reviewed. the presence of poorly formed glands, fused glands, and cp was recorded for each case. the types of architectural patterns presented were associated with patient outcome. twenty-two of 165 patients (13.3%) with cp adenocarcinoma develop metastasis, whereas 2 of 76 (2.6%) without a cp developed metastasis at a median postoperative follow-up of 10.0 years. they concluded that the presence of a cp was an independent predictor for bpr as well as metastasis after rp (12). in the present study, we investigated the association of age, preoperative psa, gleason on biopsy, gleason after rp, epe, vesicles invasion, positive margins, bpr, mpmri and post-operative radiotherapy with the presence of cp. in the univariable analysis, epe, vesicles invasion, preoperative psa and adjuvant rt showed significant association in the presence of cp. there was also a statistical significance between cp and bpr. of those who had bpr, 87.5% had cp, while those who did not had bpr, only 26.2% had cp. in the multivariable analysis, only epe and pre-operative psa revealed a statistically significant association with cp. use of active surveillance in select favorable intermediate-risk patients (gleason 3+4) has been proposed (13). some groups have argued that cribriform morphology itself outperforms the percentage of gleason pattern 4 involvement for prognostication and should be used to determined candidates for active surveillance. in this context, cp might be a valuable additional parameter in selecting patients for active surveillance. in this study, we found that rp specimens with cp had a significantly higher likelihood of seminal vesicle invasion and extraprostatic extension compared to specimens without cp. the presence of cp was also associated with an advanced pathological stage (gleason 8 or 9) compared to those without cp. presently, the only way accepted to identify the presence of the cribriform morphology is through tissue analysis. holemans et al., identified psa as independent predictor (odds ratio 3.5; 95% confidence interval 1.2-9.4, p = 0.02) for cribriform architecture on radical prostatectomy (14). in our study, the increase in preoperative psa had a high association with cp. further evidence is needed to discriminate preoperative psa values that might potentially be associated with the presence of cp. we believe it is also worth to explore the value of prostate-specific membrane antigen ligands, to accurately detect the presence of the cribriform morphology and possibly treat it. since tumors 237archivio italiano di urologia e andrologia 2020; 92, 3 prostate cancer with cribriform pattern table 1. clinical characteristics of the patients by group. with cribriform pattern without cribriform n = 23 pattern preop psa (per ng/dl)* 9.10 (6.04-15.44) 6.04 (4.86-8.45) epe, n (%) positive 14 (60.9) 11 (23.4) negative 9 (39.1) 36 (76.6) bpr, n (%) yes 7 (30.4) 1 (2.2) no 16 (69.6) 45 (97.8) rt, n (%) yes 16 (69.6) 11 (23.9) no 7 (30.4) 35 (76.1) sm, n (%) positive 12 (52.2) 15 (31.9) negative 11 (47.8) 32 (68.1) vesicles invasion, n (%) positive 5 (21.7) 2 (4.3) negative 18 (78.3) 45 (95.7) * values are expressed as median (interquartile range); bpr, biochemical prostate-specific antigen recurrence; epe, extraprostatic extension; sm, surgical margin; psa, prostate specific antigen. table 2. univariable regression analysis, dependent variable: cribriform pattern. variables odds ratio estimates 95% ci p-value age (years)* 1.01 0.93 1.10 0.811 preop psa 1.14 1.02 1.27 0.017 gleason in needle biopsy** 7 3.82 1.24 11.80 0.020 8 or 9 2.17 0.32 14.71 0.429 gleason in rp specimen** 7 3.50 0.69 17.76 0.131 8 or 9 7.00 1.14 42.97 0.036 epe 5.09 1.74 14.93 0.003 vesicle invasion 6.25 1.11 35.20 0.038 margins 2.33 0.84 6.47 0.105 mpmri*** 4 1.40 0.39 5.08 0.609 5 2.80 2.59 0.254 adjuvant rt 7.27 2.38 22.23 < 0.001 * for each one-year increase of age; ** reference category: 6; *** reference category: 2 or 3; ci, confidence interval; epe, extracapsular extension; psa, prostate specific antigen; rt, radiotherapy; p-values obtained by logistic regression models. archivio italiano di urologia e andrologia 2020; 92, 3 r.miguel bernardino, r. carvalho, l. severo, m. alves, a.luisa papoila, l. campos pinheiro 238 with cp are characterized by specific genetic and molecular alterations, it would be possible to define the molecular profile of the neoplasm either in the tissue or in liquid biopsies (urine or blood) (9). it is important to differentiate these patients that would otherwise be selected for active surveillance and abstained of immediate treatment. conclusions according our study, we found that patients with cp had higher preoperative psa levels, higher rate of epe, seminal vesicles invasion, positive sm in final pathology, higher rate of adjuvant radiation therapy and bcr in postoperative course. the evidence for the distinct adverse prognostic impact of invasive cribriform cancer has increased rapidly in recent years, so it is really important to ask our pathologists to specifically report the presence of cp in the pathology report. excessive treatment of non-lethal prostate cancer has been a critical area in the approach to prostate cancer treatment, so raising our knowledge about the cribriform pattern can be an excellent opportunity to correctly identify and treat patients who will eventually die from prostate cancer, sparing treatment in those who will not. it might be important to consider cribriform growth as an exclusion criterion for active surveillance in gleason score 3+4 = 7 patients. references 1. quian j, jenkins rb, bostwick db, detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization, mod. pathol. 1997; 10:1113-1119. 2. kweldam cf, wildhagen mf, steyerberg ew, et al. cribriform growth is highly predictive pospostoperative metastasis and disease specific death in gleason score 7 prostate cancer. mod pathol. 2015; 28:457-464. 3. epstein ji, egevad l, amin mb, et al. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016; 40:244-252. 4. dong f, yang, wang c, et al. architectural heteroneneity and cribriform pattern predict adverse clinical outcome for gleason grade 4 prostatic adenocarcinoma. amj surg pathol. 2013; 37:1855-1861. 5. trudel d, downes mr, sykes j, et al. prognostic impact of intraduztal carcinoma and large cribriform carcinoma architecture after prostatectomy in a contemporary cohort. eur j cancer. 2014; 50:1610-1616. 6. kir g, sarbay bc, gumus e, topal cs, the association of the cribriform pattern with outcome for prostatic adenocarcinomas. pathol res pract. 2014; 210:640-644. 7. truong m, feng c, hollenberg g, et al. a comprehensive analysis of cribriform morphology on mr/us fusion biopsy correlated with radical prostatectomy specimens. j urol. 2018; 199:106-113. 8. sarbay bc, kir g, topal cs, et al. significance of the cribriform pattern in prostatic adenocarcinomas. pathol res pract. 2014; 210:554.557. 9. moul jw: prostate specific antigen only progression of prostate cancer. j urol. 2000; 163:1632-1642 10. montironi r, cimadamore a, gasparrini s, et al. prostate cancer with cribriform morphology:diagnosis, aggressiveness, molecular pathology and possible relationships with intraductal carcinoma. expert rev anticancer ther. 2018; 18:685-693. 11. iczkowski ka, torkko kc, kotnis gr, et al., digital quantification of five high-grade prostate cancer patterns, including the cribriform pattern, and their association with adverse outcome. am j clin pathol. 2011; 136:98-107. 12. dong f, wang c, farris b, et al., impact on the clinical outcome of prostate cancer by the 2005 international society of urological pathology modified gleason grading system. am j surg pathol. 2012; 36:838-843. 13. morlacco a, cheville jc, rangel lj. adverse disease features in gleason score 3+4 "favourable intermediate-risk" prostate cancer: implications for active surveillance. eur urol. 2016; 72:442-447. 14. hollemans e, verhoef ei, chris h, et al. large cribriform growth pattern identifies isup grade 2 prostate cancer at high risk for recurrence and metastasis. mod path. 2019; 32:139-146. correspondence rui miguel bernardino, md (corresponding author) ruimmbernardino@gmail.com luis severo, md luis campos pinheiro, md urology department, central lisbon hospital center, lisbon (portugal) rita carvalho, md pathology department, central lisbon hospital center, lisbon (portugal) marta alves, md ana luisa papoila, md epidemiology and statistics unit, research center, central lisbon hospital center, lisbon (portugal) stesura seveso 355archivio italiano di urologia e andrologia 2022; 94, 3 review no conflict of interest declared. voiding after stress incontinence procedures are amongst possible causes” (2). although the prevalence of female boo has not yet been thoroughly studied, it is estimated to be between 2.7 and 23% (3). ics defines dysfunctional voiding as “an intermittent and/or fluctuating flow rate due to involuntary intermittent contractions of the peri-urethral striated or levator muscles during voiding in neurologically normal women. this type of voiding may also be the result of an acontractile detrusor (abdominal voiding) with electromyography (emg) or video-urodynamics required to distinguish between the two entities” (2). benign prostatic hyperplasia (bph) represents the most common cause of boo in males, being supported by several nomograms that aid in the diagnosis. in contrast, the etiology of boo in women is diverse, being subdivided into anatomical and functional. whereas anatomic causes consist mainly of anatomical conditions leading to obstruction of the bladder outlet [pelvic organ prolapse (pop), post-anti-incontinence procedures, strictures, fibrosis or urethral diverticula], functional boo results from the inability to achieve a proper relaxation of the urethral sphincter during bladder emptying [primary bladder neck obstruction, neurogenic detrusor external sphincter, dyssynergia, non-neurogenic dysfunctional voiding (abnormal contraction of periurethral muscle), and fowler’s syndrome (failure of urethral relaxation)] (4). most boo validated questionnaires were developed for prostate pathology and mention prostate specific wording in them. therefore, in addition to a lack of standardized, widely accepted and accurate nomograms, urodynamic criteria and validated questionnaires and quality of life surveys to evaluate female boo, there is an unmet need of biologic markers to this aim. having an easy to obtain, accurate urine biomarker will be valuable when evaluating and counselling patients with lower urinary tract symptoms (5). accordingly, we conducted a systematic review of studies assessing the role of urinary biomarkers in female boo. materials and methods systematic literature review we performed a systematic review of studies utilizing urinary biomarkers of female bladder outlet obstruction folobjective: diagnosis of bladder outlet obstruction (boo) in females is often challenging, not only because of the overlap in storage and voiding symptoms in women with various etiologies of lower urinary tract (lut) dysfunction but also due to the lack of standardized urodynamic criteria to define the condition. there is an unmet need of biologic markers to evaluate boo in females as an adjunct to other clinical criteria. we sought to elucidate the role of urinary biomarkers in female boo. material and methods: we performed a systematic review of studies involving urinary biomarkers in female boo. the search was performed in pubmed. a total of 58 papers were retrieved and 2 were included for final analysis. results: currently, there are no validated biologic markers for female boo available. having a biomarker that can be obtained through a urine sample will be an invaluable tool to evaluate and counsel patients with lut symptoms and possible boo. the use of ngf as an indicator of boo in female patients seems to be promising: ngf levels are elevated in women with boo when compared with normal controls. conclusions: we found that ngf levels may be applied as a useful biomarker in the diagnosis and evaluation of female patients with boo symptoms. it will not completely replace other clinical diagnostic tools such as formal urodynamic testing but play a role as a supplement to it. nevertheless, further studies should be conducted to establish ngf levels as a female boo biomarker and a routine testing modality. key words: urinary biomarkers; bladder outlet obstruction; female; female bladder outlet obstruction. submitted 12 may 2022; accepted 6 june 2022 introduction diagnosis of bladder outlet obstruction (boo) in females is often challenging, not only because of the overlap in storage and voiding symptoms in women with various etiologies of lower urinary tract dysfunction but also due to the lack of standardized urodynamic criteria to define the condition (1). the international continence society (ics) defines boo as “generic term for obstruction during voiding. it is a reduced urine flow rate and/or presence of a raised pvr and an increased detrusor pressure. it is usually diagnosed by studying the synchronous values of urine flow rate and detrusor pressure and any pvr measurements. a urethral stricture or obstruction due to higher degrees of uterovaginal prolapse or obstructed systematic review of urinary biomarkers of female bladder outlet obstruction (fboo) andreia bilé silva 1, paulo jorge dinis 2, luís abranches monteiro 1 1 hospital de egas moniz, lisboa, portugal; 2 hospital cuf, lisboa, portugal. doi: 10.4081/aiua.2022.3.355 summary archivio italiano di urologia e andrologia 2022; 94, 3 a. bilé silva, p.j. dinis, l. abranches monteiro 356 lowing the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines. comprehensive search strategies were used to identify all relevant studies investigating the use of urinary biomarkers in female bladder outlet obstruction. the search was performed in medline using search medical subject headings (mesh) terms “bladder outlet obstruction”, “female”, “women”, “urine marker”, “urine biomarker”, “biomarker”, “marker”, “urine”, until the end of 2021 using the string [(bladder outlet obstruction) and (women) and (urine marker)] or [(bladder outlet obstruction) and (female) and (urine biomarker)] or [(bladder outlet obstruction) and (female) and (urinary marker)] or [(bladder outlet obstruction) and (biomarker) and (female)] or [(bladder outlet obstruction) and (marker) and (female)]. only english-language publications were considered. studies including boo in males only were excluded. commentaries were excluded. basic research studies were excluded and only studies in humans were included. we did not find multiple reports on the same patient cohort. study review methodology two authors (a.b.s. and l.a.m.) reviewed and selected studies independently; ; disagreements were resolved by discussion and consensus. titles and abstracts were used to screen for initial study inclusion. full texts of studies thought to meet or possibly meet the study inclusion were then reviewed. the same reviewers extracted relevant data independently using standardized data collection forms. data retrieved from the reports include publication details (year of publication and authors), methodological components, and trial characteristics (sample size and outcomes measures). the association between urinary biomarkers and boo in females was recorded. risk of bias assessment a formal exclusion of studies due to risk of bias (rob) assessment was not carried out as none of the existing rob scales were felt to be appropriate for this systematic review. data synthesis data synthesis was made after a thorough search through current literature on the diagnosis and management of female boo, with a specific focus on translational research in the field of urinary biomarker. several potential urine biomarkers of female boo have been studied in a basic research setting, nerve growth factor (ngf) currently representing the most widely accepted one as it represents the only investigated in humans and, specifically, in females. data was stratified by the physiology of voiding and boo, the basic knowledge on urinary ngf production and role and the relationship between ngf and boo in female patients. results literature search results in total, 58 citations were retrieved from the medline database. after removing duplicates and screening of titles and abstracts, 56 citations were excluded from further analysis. figure 1 shows the prisma flow diagram of the study. a total of 2 studies were included in the systematic review, one consisting of a nonrandomized comparative study of urinary ngf levels between female patients deemed to have boo and their asymptomatic counterparts (5) and the other being a narrative review of the literature on evaluation and diagnosis of boo in women (1). figure 1. prisma flow diagram of the study. 357archivio italiano di urologia e andrologia 2022; 94, 3 urinary biomarkers of fboo physiology of voiding and boo in the setting of boo, a pathologic increase in outlet resistance is recorded, conducting to a more forceful contraction of the detrusor muscle to generate urine flow across the outlet. this dysfunction results in functional and anatomical changes in the detrusor as well as in the neural networks involved in the process (1). whereas boo in males is mainly due to benign prostatic hyperplasia (bph), the causes are more varied in females, being subdivided into anatomic and functional. among anatomic causes, urethral distortion secondary to pelvic organ prolapse (pop), iatrogenic boo caused by antiincontinence procedures, intrinsic etiologies (strictures, fibrosis, urethral diverticula), should be considered. functional boo results from primary bladder neck obstruction (failure of bladder neck relaxation), neurogenic detrusor external sphincter dyssynergia, non-neurogenic dysfunctional voiding (abnormal contraction of periurethral muscle) and fowler’s syndrome (1, 5). basic knowledge on ngf production and role multiple biomarkers have been studied as potential indicators of boo in females. ngf is produced by bladder smooth muscle cells, urothelial cells, and sensory afferent neurons. the role of ngf in the neurotrophic effects associated with obstruction was first described in 1991 by steers et al. (6). under normal conditions, ngf levels in the urine are low. increased urinary ngf levels are associated with bladder inflammation secondary to chemical irritation, detrusor overactivity, and boo. it has been hypothesized that, through mechanical stretching, ngf expression in the bladder wall may increase leading to a reduced sensory threshold resulting in urgency or a reduced threshold for mediating detrusor hyperactivity. liu and kuo demonstrated that urinary ngf is elevated in male patients with boo plus overactive bladder (oab) symptoms compared with normal controls. studies support the role of ngf in bladder overactivity, irritative voiding symptoms and afferent pathways plasticity. the increased concentration of ngf can reduce the threshold or increase excitability in the afferent fibers leading to increased bladder sensation or overactivity. expression of ngf is modulated by intervention, being reduced after medical or surgical treatment of the obstruction (1, 5). relationship between ngf and boo in female patients a prospective study conducted in 2015 assessed the urinary ngf levels in 10 women with anatomic boo and compared those to 10 asymptomatic female controls. all females referred for evaluation and management of boo from pop or previous incontinence surgery were screened for enrollment. boo was caused by pop in 6 patients, post-incontinence procedure in 5 patients and both etiologies in 1 patient. the urinary ratio between ngf and creatinine (cr) levels in the patients with boo (mean 20.8 pg/mg) were significantly higher (p = 0.0001) than the levels in the control group (5.6 pg/mg). a weak positive correlation between urinary ngf level and the symptoms severity (evaluated by the urinary distress inventory-6 symptom score) was reported. a significant decrease in mean urinary ngf/cr to 6.50pg/mg (p = 0.01) was recorded after treatment of the conditions responsible for the anatomic boo (prolapse repair, sling excision). furthermore, the decreases in ngf/cr levels after treatment correlated with subjective improvement in the symptoms of patients as demonstrated by decreased udi-6 survey scores and objective improvement as demonstrated by increased flow rates. therefore, urinary ngf looks like a promising tool for women with suspected anatomic boo as a diagnostic and an objective assessment of the therapeutic effects of surgical and medical interventions in women with boo (1, 5). discussion boo in women is less understood than in men, as symptoms are scarce and misleading. due to anatomical and physiological differences, the boundaries of normality are less well defined, and urodynamic diagnosis is often unsatisfactory and not universally accepted. voiding dysfunction consists of a combination of boo and detrusor underactivity (du) in both sexes. boo, as an increased outlet resistance to flow, cannot be separated from detrusor function: the balance between these two parameters will define a broader concept of voiding dysfunction. increased urethral resistance in women is not as common as in men, but far from rare. in a retrospective study that included 1142 women, 192 (19%) were diagnosed with boo. functional sphincteric obstruction was diagnosed in 70 women (36%). the most common anatomical cause of boo was previous anti-incontinence surgery, followed by urethral stricture, diagnosed in 21% and 20% of patients, respectively. the most common presenting symptoms were storage phase symptoms of daytime and night-time urinary frequency. hence, boo should be suspected in women with refractory luts, especially those presenting with urinary frequency (7). female voiding dysfunction has often a presentation similar to other conditions, lacking specific symptoms or signs. it was found in 23% of patients with oab. boo is more frequent than du and should be suspected in patients with higher night-time frequency, presence of detrusor overactivity and a high post-void residual. instead, du should be suspected in patients with a smaller voided volume (8). several combinations of nomograms were tested to increase the accuracy of diagnosing boo and detrusor underactivity (du) among women with luts (9). evidence on tests used to diagnose female bladder outlet obstruction was recently reviewed. the available evidence on diagnostic tests for female bladder outlet obstruction is limited and heterogeneous. the most common test used was found to be pressure-flow studies with or without fluoroscopy, which remains the current standard for diagnosing bladder outlet obstruction in women (10). yet, as these methodologies frequently find blurred boundaries, are expensive, not widely available, and invasive, alternative or clarifying tests are needed. currently, no biologic markers for boo to use as an adjunct to the evaluation and monitoring of lower urinary tract symptoms in women in parallel with nomograms, urodynamics, validated questionnaires, or quality-of-life surveys are available. having a biomarker that can be easarchivio italiano di urologia e andrologia 2022; 94, 3 a. bilé silva, p.j. dinis, l. abranches monteiro 358 ily obtained through a urine sample will be an invaluable tool to evaluate and counsel patients with lower urinary tract symptoms and possible boo (5). the prospective study included in the review demonstrates that the use of ngf as an indicator of boo in female patients is adequate. women with boo presented elevated urinary ngf/cr levels when compared with normal controls and these levels significantly decreased with appropriate surgical treatment. nevertheless, the low number of patients included in this study represents its main limitation. the results are consistent and significant but further information regarding the diagnostic and appraisal potential of the urine biomarker are still missing (5). even though clinical studies in males and basic research studies were not included in the systematic review, several other parameters have been the object of investigation in these settings, namely urinary molecules. prior to being studied in females, urinary ngf has been proved to be elevated in men with boo and to decrease in association with reduction of the prostate volume and relief of boo making it a potential tool not only to diagnose but also to monitor the improvement of boo in patients with bph (5, 11). prostaglandin e2 the micturition reflex is stimulated by prostaglandins, which decrease the necessary threshold to trigger detrusor contraction through capsaicin-sensitive afferent nerves (12). prostaglandins, such as prostaglandin e2 (pge2), show increased levels in conditions such as oab, detrusor overactivity (do) and boo (13, 14). atp urothelial cells release atp into the urine in response to bladder stretch. it may play a major sensory role on pelvic afferent nerve fibers (15). a rat model demonstrated an increase in urothelial atp release due to partial boo induction (16). in males with boo due to bph, there seems to be a higher release of atp into the urine. the results suggest that urinary atp may be a high-sensitive non-invasive biomarker of boo with additional potential discriminative value of detrusor function when comparing bph patients with low urinary flow rates. furthermore, atp levels may represent a surrogate marker for the degree of obstruction (17, 18). mrna and mirna boo is responsible for significant organ remodeling which conducts to lower urinary tract symptoms and accompanying urodynamic changes in bladder function. boo patients have mrna and mirna expression profiles correlated with urodynamic findings. the molecular changes in boo might indicate an increasing involvement of mirnas in the control of bladder function from the overactive to underactive/acontractile states. thus, mrna and mirna might represent markers of detrusor competence (19, 20). oxidative stress markers partial boo leads to an increase in tissue and systemic oxidative stress markers and cytokines in basic research models. a rise in 8-hydroxydeoxyguanosine (8-ohdg) in urine and malondialdehyde (mda) in plasma of rabbits was documented along with a limited total oxidant capacity in plasma (21); a rise in the number of plasma-myeloidderived suppressor cells (mdscs), interferon-gamma, interleukin-10 and aldosterone was observed in a rat model (22); elevated levels of f2-isoprostane were noted in a chronic injury mouse model of partial boo (23). detrusor muscle biopsy although the focus of this review is on urinary biomarkers of female boo, there is emerging evidence on muscular hypertrophy as an indicator of this condition, as revealed by pathological analysis of detrusor specimens. firstly, myohypertrophy was shown to be present in men with boo (24). afterwards, wang et al., proved this phenomenon to be present in female boo and to be related to the degree and duration of obstruction with the female controls not displaying this sort of ultrastructural changes (25, 26). novel biomarkers future developments may involve further studies on nod-, lrrand pyrin domain-containing protein 3 (nlrp3) inflammasome, a sensor of cellular damage in the urothelium (27), piezo1, a mechanically activated ion channel present in the detrusor muscle and suburothelial layer implicated in sensation of bladder stretch (28), nicotinic acetylcholine receptors in parasympathetic bladder pelvic ganglion neurons, which expression has been shown to be increased due to its upregulation in boo (29). the study is not without limitations. it reflects the lack of information on the topic and the unmet need of translational studies in the field of urinary biomarkers of boo in female patients. while the evidence on the use of ngf as a biomarker of female boo grows, many questions on its validity remain including its specificity, sensitivity, costand time-effectiveness. conclusions even though these results indicate that ngf levels may be applied as a useful biomarker in female patients with boo symptoms, research on biomarkers of boo is lacking and further investigation is needed. the use of ngf as a biomarker will not completely replace other clinical diagnostic tools such as formal urodynamic testing although it will probably be considered as a supplement to it. nevertheless, further studies should be conducted in order to establish ngf levels as a female boo biomarker and a routine testing modality. furthermore, this systematic review underlines the unmet need of urinary biomarkers of female boo. references 1. martinez l, khavari r. new frontiers in molecular and imaging research on evaluation and diagnosis of bladder outlet obstruction in women. curr bladder dysfunct rep 2017; 12:291-297. 2. haylen bt, de ridder d, freeman rm, et al. an international urogynecological association (iuga)/international continence 359archivio italiano di urologia e andrologia 2022; 94, 3 urinary biomarkers of fboo society (ics) joint report on the terminology for female pelvic floor dysfunction. neurourol urodyn. 2010; 29:4-20. 3. blaivas jg, groutz a. bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. neurourol urodyn. 2000; 19:553-64. 4. meier k, padmanabhan p. female bladder outlet obstruction: an update on diagnosis and management. curr opin urol. 2016; 26:334-41. 5. chan r, munoz a, wenker ep, et al. the association of urinary nerve growth factor levels with bladder outlet obstruction in women. female pelvic med reconstr surg. 2015; 21:111-5. 6. steers wd, kolbeck s, creedon d, tuttle jb. nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. j clin invest. 1991; 88:1709-15. 7. malde s, solomon e, spilotros m, et al. female bladder outlet obstruction: common symptoms masking an uncommon cause. low urin tract symptoms. 2019; 11:72-77. 8. santis-moya f, calvo ci, rojas t, et al. urodynamic and clinical features in women with overactive bladder: when to suspect concomitant voiding dysfunction? neurourol urodyn. 2021; 40:15091514. 9. mytilekas kv, oeconomou a, sokolakis i, et al. defining voiding dysfunction in women: bladder outflow obstruction versus detrusor underactivity. int neurourol j. 2021; 25:244-251. 10. pang kh, campi r, arlandis s, et al. diagnostic tests for female bladder outlet obstruction: a systematic review from the european association of urology non-neurogenic female luts guidelines panel. eur urol focus. 2021; s2405-4569(21)00231-5. 11. wada n, matsumoto s, kita m, et al. decreased urinary nerve growth factor reflects prostatic volume reduction and relief of outlet obstruction in patients with benign prostatic enlargement treated with dutasteride. int j urol. 2014; 21:1258-62. 12. kim jc, park ey, seo si, et al. nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. j urol. 2006; 175:1773-6. 13. kuo hc. potential biomarkers utilized to define and manage overactive bladder syndrome. low urin tract symptoms. 2012; 4 suppl 1:32-41. 14. mikhailidis dp, jeremy jy, dandona p. urinary bladder prostanoids--their synthesis, function and possible role in the pathogenesis and treatment of disease. j urol. 1987; 137:577-82. 15. vlaskovska m, kasakov l, rong w, et al. p2x3 knock-out mice reveal a major sensory role for urothelially released atp. j neurosci. 2001; 211:5670-7. 16. shiina k, hayashida ki, ishikawa k, kawatani m. atp release from bladder urothelium and serosa in a rat model of partial bladder outlet obstruction. biomed res. 2016; 37:299-304. 17. chen z, liu y, zhao m, et al. urinary atp may be a biomarker for bladder outlet obstruction and its severity in patients with benign prostatic hyperplasia. transl androl urol. 2020; 9:284-294. 18. silva-ramos m, silva i, oliveira jc, correia-de-sá p. increased urinary adenosine triphosphate in patients with bladder outlet obstruction due to benign prostate hyperplasia. prostate. 2016; 76:1353-63. 19. gheinani ah, kiss b, moltzahn f, et al. characterization of mirna-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction. jci insight. 2017; 2:e89560. 20. von siebenthal m, besic m, gheinani ah, et al. urinary mirna profiles discriminate between obstruction-induced bladder dysfunction and healthy controls. sci rep. 2021; 11:10204. 21. lin wy, chen cs, wu sb, et al. oxidative stress biomarkers in urine and plasma of rabbits with partial bladder outlet obstruction. bju int. 2011; 107:1839-43. 22. lin wy, hsieh cc, yang ty, et al. transient increase in circulating myeloid-derived suppressor cells after partial bladder outlet obstruction. j urol. 2014; 192:1569-73. 23. clayton db, stephany ha, ching cb, et al. f2-isoprostanes as a biomarker of oxidative stress in the mouse bladder. j urol. 2014; 191(5 suppl):1597-601. 24. brierly rd, hindley rg, mclarty e, et al. a prospective evaluation of detrusor ultrastructural changes in bladder outlet obstruction. bju int. 2003; 91:360-4. 25. wang a, brammah s, tse v, chan l. comparison of ultrastructural features in female and male bladder outlet obstruction: a potential role for diagnostic detrusor muscle biopsy. j urol. 2015; 193 (suppl 4): e1105. 26. fusco f, creta m, de nunzio c, et al. progressive bladder remodeling due to bladder outlet obstruction: a systematic review of morphological and molecular evidences in humans. bmc urol. 2018; 18:15. 27. hughes fm jr, hill hm, wood cm, et al. the nlrp3 inflammasome mediates inflammation produced by bladder outlet obstruction. j urol. 2016; 195:1598-1605. 28. michishita m, yano k, tomita ki,, et al. piezo1 expression increases in rat bladder after partial bladder outlet obstruction. life sci. 2016; 166:1-7. 29. chung hc, lee ck, park kh, jeong sw. bladder outlet obstruction causes up-regulation of nicotinic acetylcholine receptors in bladder-projecting pelvic ganglion neurons. brain res. 2015; 1602:111-8. correspondence andreia bilé silva, md (corresponding author) andreiabile@campus.ul.pt luís abranches monteiro, md abranchesmonteiro@gmail.com hospital de egas moniz paulo jorge dinis, md pj.s.dinis@gmail.com hospital cuf cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 118 original paper no conflict of interest declared. prevalence in the region (4). prostate cancer is expected to become the most common cancer in males in 2020 (4). a general goal of this study was to estimate the level at which psa value and prostate volume value are indicative for a biopsy procedure in the lebanese population. the primary objective was to evaluate the diagnostic strength of prostate specific antigen density (psad) versus psa level in the lebanese men in correlation with biopsy outcomes to avoid unnecessary prostate biopsy. the secondary objectives of the study were: 1) to identify age-related cutoffs which may be used in the clinical practice for the diagnosis of prostate cancer, 2) to identify a cutoff for the psa level which may be used in the clinical practice for the diagnosis of the prostate cancer, 3) to identify a cutoff for the psad level which may be used in the clinical practice for the diagnosis of the prostate cancer. methods study design and patient population this study was a retrospective chart review, conducted in bahman hospital, including patients who were screened for prostate cancer and underwent prostate biopsy. all patients were admitted to bahman hospital during the last 15 years, between january 2006 and december 2019. patients were selected according to predefined inclusion and exclusion criteria (table 1) and psa testing was primarily used to screen for prostate cancer. accordingly, patients were chosen, and data was collected and submitted for statistical calculation and further analysis. the protocol was reviewed and granted written study approval from the research committee in the lebanese university, and approval from the ethical committee of the hospital. the study was conducted in accordance with the us code of federal regulation 45-cfr-46.107, 21-cfr56.107, good clinical practice ich section 3 and the principles laid down by the 18th world medical assembly (helsinki, 1964) and all applicable amendments. all participants had a designated code. records will be stored, and none can access the sheets except the researchers. the sample size was estimated on the assumption of an incidence of prostate cancer in the lebanese males of objective: being the second most common cancer in men, prostate cancer detection relies on laboratory tests, imaging, and surgical procedures, although biopsy remains the mainstay in diagnosis of prostate cancer. no clear cut-off of prostate specific antigen density (psad) for suspecting prostate cancer has been established in the lebanese population. our primary objective was to evaluate the diagnostic strength of the psad value versus total prostate specific antigen (tpsa) level in the lebanese men in correlation with biopsy outcome to avoid unnecessary prostate biopsy. methods: a retrospective study of 347 patients with history of prostate biopsy done for cancer suspicion included tpsa, prostate volume, and prostate density values and results of prostate biopsy. data was collected from bahman hospital and statistical analysis of the mean values of tpsa, prostate volume and psad in different age groups was done. significance of the results was tested using. results: on average, patients with negative biopsies were younger and they had lower tpsa levels, lower psad values and larger prostate volume compared to patients with positive biopsies. a psad cutoff of 0.185 ng/ml2 revealed the highest predictive strength for prostate cancer (6 times risk) compared with other parameters. these findings were mainly referred to patients with psa > 10 ng/ml. conclusions: a multifactorial approach must be conducted including all parameters in order to decide upon the need for prostate biopsy. psad proved to be a good marker in favor or against a prostate biopsy with a cut-off of 0.185 ng/ml2, especially in patients with tpsa level higher to 10 ng/ml. a multicenter study was recommended for better and more reliable results and more precise cut-offs. key words: psad; prostate biopsy; psa; age; prostate volume. submitted 22 september 2021; accepted 15 october 2021 introduction normal ranges of prostate specific antigen (psa) and prostate volume vary among ethnicities and communities at different geographic locations and of different socioeconomic statuses (3). therefore, pathological psa and prostate volume values might as well vary between ethnicities (3). in the lebanese men, prostate cancer incidence is expected to reach 69 cases per 100000 by 2020, the highest predictive value of psa density in the diagnosis of prostate cancer in lebanese men ali msheik 1, mohamed mohanna 2, ali mhanna 3, ali kanj 4, mohamad moussa 5, assaad mohanna 4 1 pgy-1 neurosurgery, faculty of medical sciences, lebanese university, beirut, lebanon; 2 pgy-1 internal medicine, faculty of medical sciences, lebanese university, beirut, lebanon; 3 pgy-1 general surgery, faculty of medical sciences, lebanese university, beirut, lebanon; 4 radiology department, bahman hospital, beirut, lebanon; 5 chairman of general surgery and urology department, faculty of medical sciences, lebanese university, beirut, lebanon. doi: 10.4081/aiua.2022.1.18 summary 19archivio italiano di urologia e andrologia 2022; 94, 1 psa density in the diagnosis of prostate cancer 1503 new cases in 2018 and a 5-year prevalence of 3405 according to globocan (5). hence, we estimated a minimum sample size of 10% of the estimated prevalence that is 300 patients who must fulfill the inclusion and exclusion criteria as shown in table 1. data collection the researchers contacted the “archive department” manager at bahman and set a schedule to reach the medical records and collect the data. an electronic validated database was used in the data collection process. the data includes the following: demographic characteristics (age), laboratory results (psa ng/ml), transabdominal prostate ultrasound results (prostate volume ml) and histology results (gleason score). prostate specific antigen density was calculated by dividing the psa value by the prostate volume. a gleason score ≥ 7 was used to define a clinically significant prostate cancer (cspca). statistical analysis data was analyzed using the spss version 22. a descriptive analysis was done, and variables were presented as per their type. the categorical variables were presented as frequency and proportions. the continuous variables were presented as frequency, mean, median and standard deviation. a binary logistic analysis was done to test the factors predicting the biopsy outcome. the dependent variable was “biopsy outcome”. the correlation was tested between the dependent variable and the secondary variables using the chi-square and fisher exact test. in addition, non-parametric tests were used as kruskas wallis test and mann-whitney test. a statistically significant correlation was set at 5% (p-value less than 0.05). results demographic results the mean age of the patients was 66.2 (± 8.8) with a minimum of 43 years and a maximum of 90 years. the median age was 66 years. prostate cancer and laboratory values the mean prostate volume was 59.2 (± 30.8) ml with a minimum of 12 ml and a maximum of 214 ml. the median prostate volume was 53 ml. the mean psad was 0.56 (± 1.15) ng/ml2 with a minimum of 0.04 ng/ml2 and a maximum of 9.75 ng/ml2. the median prostate density was 0.18 ng/ml2 (table 2). the mean psa level was 24.56 (± 42.57) ng/ml with a minimum of 2 ng/ml and a maximum of 394 ng/ml. the median psa level was 10 ng/ml (figure 1). histology results histology demonstrated that 49.6% of patients had benign prostatic tissue (bph, prostatitis), 5.2% had low-grade prostate cancer (gleason score = 6), and 45.2% had clinically significant prostate cancer cspca (gleason score ≥ 7) (figure 2). table 1. inclusion and exclusion criteria utilized in the study. inclusion criteria exclusion criteria psa level ≥ 3 ng/ml past diagnosis of prostate cancer transabdominal prostate us result available incomplete patient record histologically confirmed diagnosis of cspca table 3. correlation between variables and biopsy outcome. biopsy outcome n mean std. deviation 95% confidence interval for mean min-max p value lower bound upper bound age benign 172 63.38 8.30 62.13 64.63 44-87 0.000 prostate cancer 175 69.03 8.42 67.77 70.28 43-90 psa ng/ml benign 172 11.47 11.89 9.68 13.26 2-100 0.000 prostate cancer 175 37.42 55.93 29.07 45.76 3.5-394 prostate volume (ml) benign 172 64.66 34.40 59.48 69.84 13-214 0.003 prostate cancer 175 53.92 25.92 50.06 57.79 12-175 density (ng/ml2) benign 172 0.23 0.30 0.18 0.27 0.04-1.98 0.000 prostate cancer 175 0.89 1.52 0.66 1.11 0.05-9.75 figure 1. distribution of psa levels. table 2. prostate volume and density. prostate volume (ml) density (ng/ml2) mean 59.25 0.56 median 53.00 0.18 std. deviation 30.84 1.15 minimum 12.00 0.04 maximum 214.00 9.75 percentiles 25 39.00 0.12 50 53.00 0.18 75 72.00 0.44 archivio italiano di urologia e andrologia 2022; 94, 1 a. msheik, m. mohanna, a. mhanna, a. kanj, m. moussa, a. mohanna 20 factors affecting the biopsy outcome a statistically significant correlation existed between age, psa, prostate volume, and psad and the biopsy outcome (mann-whitney test; p < 0.05) (table 3). the results showed that age was higher in prostate cancer patients (mean = 69.03 years) in comparison to patients with benign prostatic tissue (mean = 63.4 years) (p < 0.0001); psa was significantly higher in prostate cancer patients (mean = 37.4 ng/ml) in comparison to patients with benign prostatic tissue (mean = 11.5 ng/ml) (p < 0.0001); prostate volume was significantly higher in patients with benign prostatic tissue (mean = 66.7 ml) in comparison to prostate cancer patients (mean = 53.9 ml) (p = 0.003) and psad was significantly higher in prostate cancer patients (mean = 0.89 ng/ml2) in comparison to patients with benign prostatic tissue (mean = 0.23 ng/ml2) (p < 0.0001). a binary logistic analysis was done to identify the factors predicting the biopsy outcome. the results showed that the biopsy outcome is affected by three variables: patients’ age (p = 0.000), psa (p = 0.000), and prostate volume (p = 0.000). the logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “cspca” when patient’s age is high, psa level is high and prostate volume is low. cutoff by age: factors affecting the biopsy outcome patients were distributed into two groups according to median of age (65). the first group was aged less than 65 (148 patients) and the second group was aged 65 years and more (199 patients). a statistically significant correlation existed between the age groups and the biopsy outcome (chi-square; p < 0.0001) (table 4). the results showed that 70.9% of the patients aged 65 years and more, had prostate cancer and 56.4% of the patients aged less than 65 years had no prostate cancer. in the group of patients aged less than 65 years, a statistically significant correlation existed between psa, and psad and biopsy outcome (mann-whitney test; p < 0.05) (table 5). the results showed that psa was higher in prostate cancer patients (mean = 33.1 ng/ml), and psad was significantly higher in prostate cancer patients (mean = 0.81 ng/ml2) comparing to patients with benign prostatic tissue. in the group of patients aged more than 65 years, a statistically significant correlation existed between psa, prostate volume, and psad and the biopsy outcome (mannwhitney test; p < 0.05) (table 5). the results showed that psa was higher in prostate cancer patients (mean = 39.2 ng/ml), prostate volume was lower in prostate cancer patients (mean = 56.5 ng/ml), and psad was significantly higher in prostate cancer patients (mean = 0.92 ng/ml2) comparing to patients with benign prostatic tissue. a binary logistic analysis was done to identify the factors affecting the biopsy outcome in the patients aged less than 65 years. table 4. correlation between age and biopsy outcome. age total p value 40-64 years 65-90 years biopsy outcome benign 97 75 172 < 0.0001 56.4% 43.6% 100.0% prostate cancer 51 124 175 29.1% 70.9% 100.0% total 148 199 347 42.7% 57.3% 100.0% figure 2. distribution of the patients according to biopsy outcome. table 5. correlation between the variables and biopsy outcome. age variables biopsy outcome n mean std. deviation 95% confidence interval for mean min-max p value lower bound upper bound 40-64 years psa ng/ml benign 97 10.35 11.32 8.07 12.63 2-85 0.010 prostate cancer 51 33.15 67.00 14.30 51.99 4-394 prostate volume (ml) benign 97 57.10 29.98 51.05 63.14 13-200 0.038 prostate cancer 51 47.73 14.82 43.56 51.89 22-78 density (ng/ml2) benign 97 0.23 0.30 0.17 0.29 0.04-1.98 0.002 prostate cancer 51 0.81 1.67 0.34 1.28 0.05-7.30 65-90 years psa ng/ml benign 75 12.91 12.52 10.03 15.79 3.7-100 0.000 prostate cancer 124 39.17 50.89 30.13 48.22 3.5-300 prostate volume (ml) benign 75 74.45 37.36 65.85 83.04 21-214 0.000 prostate cancer 124 56.47 28.95 51.33 61.62 12-175 density (ng/ml2) benign 75 0.23 0.30 0.16 0.30 0.04-1.89 0.000 prostate cancer 124 0.92 1.46 0.66 1.18 0.06-9.75 21archivio italiano di urologia e andrologia 2022; 94, 1 psa density in the diagnosis of prostate cancer the results showed that the gleason score was affected by psa (p = 0.012), and prostate volume (p = 0.048). the logistic analysis showed that the biopsy outcome was at risk times “1” to deviate to be “cspca” when psa level was high and prostate volume was low. a binary logistic analysis was done to identify the factors affecting the biopsy outcome in the patients aged more than 65 years. the results showed that the biopsy outcome was affected by two variables: psa (p = 0.000), and prostate volume (p = 0.003). the logistic analysis showed that the biopsy outcome was at risk times “1” to deviate to be “cspca” when: psa level was high and prostate volume was low. cutoff by psa: factors affecting the biopsy outcome patients were distributed into two groups according to median of psa (10). the first group had a psa level less than 10 ng/ml (168 patients) and the second group had a psa level 10 ng/ml and more (179 patients). a statistically significant correlation existed between the psa groups and the biopsy outcome (chisquare; p < 0.0001) (table 6). the results showed that 63.1% of the patients, who had a psa equal to 10 ng/ml and more, were diagnosed with prostate cancer and 63.1% of the patients who had a psa less 10 ng/ml were not diagnosed with prostate cancer. a patient with a psa equal to 10 ng/ml and more had a risk of 2.9 to have a prostate cancer. a binary logistic analysis was performed to predict the factors affecting the biopsy outcome in patients having a psa level less than 10 ng/ml. the results showed that the biopsy outcome is affected by two variables: the age (p = 0.000), and the prostate volume (p = 0.049). the logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “cspca” when: the age is high and prostate volume is low. a binary logistic analysis was performed to predict the factors affecting the biopsy outcome in the patients having a psa level equal to 10 ng/ml and more. the results showed that the biopsy outcome was affected by two variables: age (p = 0.004), and psad (p = 0.000). the logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “cspca” when the age is high and at risk of “6” times” when psad is high. cutoff by psa density: factors affecting the biopsy outcome a statistically significant correlation existed between psad groups and the biopsy outcome (chi-square; p < 0.0001) (table 7). the results show that 66.5% of the patients, who had a psad more than 0.185, were diagnosed with prostate cancer and 65.9% of the patients who had a psad less than 0.185 were not diagnosed with prostate cancer. a patient with a high psad had a risk of 3.8 to have a prostate cancer. a statistically significant correlation existed between the psa density groups and the biopsy outcome in each of the two age groups (chi-square; p < 0.05) (table 8). the results showed that 46.7% of the patients aged less than 65 years, who had a psa equal to 10 ng/ml and more, were diagnosed with prostate cancer with an odds ratio equal to 2.5. in addition, 77% of the patients aged 65 years and more, who had a psa equal to 10 ng/ml and more, were diagnosed with prostate cancer with an odds ratio equal to 4.5. a statistically significant correlation existed between the median psad and the biopsy outcome when the psa level was ≥ 10 ng/ml. the risk of being diagnosed with prostate cancer was 4.2% higher (95% ci 0.263-0.691) when the psa was more than 10 ng/ml (p < 0.0001) (table 9). discussion in this study, the profiles of patients submitted to prostate biopsy were outlined. the variables considered were tpsa (total psa), prostate volume, psad, age and prostate bioptable 6. correlation between the psa and the biopsy outcome. biopsy outcome p value or ci (95%) benign prostate cancer psa psa 3–9.9 ng/ml 106 62 < 0.0001 2.927 1.89-4.53 63.1% 36.9% psa 10–19.9 ng/ml 66 113 36.9% 63.1% table 7. correlation between the psa density and the biopsy outcome. biopsy outcome p value or ci (95%) benign prostate cancer psa psad < 0.184 114 59 < 0.0001 3.831 2.45-5.98 65.9% 34.1% psad > 0.185 58 115 33.5% 66.5% table 8. correlation between the psa density and the biopsy outcome in terms of the age groups. age psad gleason score p value risk ci (95%) benign prostate cancer 40-64 years psad < 0.184 65 23 0.010 2.473 1.234-4.956 73.9% 26.1% psad > 0.185 32 28 53.3% 46.7% 65-90 years psad < 0.184 49 36 < 0.0001 4.554 2.465-8.416 57.6% 42.4% psad > 0.185 26 87 23.0% 77.0% * chi-square test. table 9. individual risk of benign and prostate cancer with psa level ≥ 3 ng/ml by psa density. psa psad biopsy outcome p value risk ci (95%) benign prostate cancer lower upper psa 3–9.9 ng/ml < 0.184 ng/ml2 87 82.1% 47 77.0% 0.432* 0.827 0.522 1.309 > 0.185 ng/ml2 19 17.9% 14 23.0% psa > 10 ng/ml < 0.184 ng/ml2 27 40.9% 12 10.6% 0.000* 0.427 0.263 0.691 > 0.185 ng/ml2 39 59.1% 101 89.4% * chi-square test. archivio italiano di urologia e andrologia 2022; 94, 1 a. msheik, m. mohanna, a. mhanna, a. kanj, m. moussa, a. mohanna 22 sy findings. the results showed that age, tpsa level, prostate volume, and psad were important factors to consider in the decision of whether to do a biopsy of prostate or not. this study showed that each of these factors has a certain median relative to which the positive predictive value (ppv) of prostate cancer at prostate biopsy differs. age first, about age, the results showed that above two thirds of the biopsies proved evidence of high grade cancer (gleason > 7) in patients older than 65 years, while less than half biopsies done in patients younger than 65 years diagnosed cspca. accordingly, advanced age added one times risk to the detection of cspca. hence, patients older than 65 years who had urinary symptoms that advocated prostate pathology proved to be candidates for a prostate biopsy with a high ppv for prostate cancer. these findings were anticipated in the literature. more than 65% of prostate cancer patients are expected to be above 65 years of age (6). volume we reported a one-time risk of prostate cancer detection in association with a low prostate volume in both age groups. of note, the mean of prostate volume was higher in bph patients compared to prostate cancer patients in either age groups. however, we observed an increase of mean volume with age in both bph and prostate cancer patients. this sheds light of the possibility of concomitant occurrence of bph and of its evolution before or along with prostate cancer. many studies in the literature confirmed that in patients with small volume prostates, psa levels superior to 4 ng/ml and suspicious on digital rectal examination (dre) were more likely to show pathological evidence of prostate cancer at biopsy (7, 8). a retrospective study by camur et al. noted that prostate volume has no significant effect on upgrading in active surveillance of appropriate patients9. this result addressed the prostate volume as a single factor, conversely correlation of volume with psa level proved that volume has a role in the of prostate cancer in the indication to prostate biopsy. psa evaluation of psa levels showed that a value of 10 ng/ml (0.38 nmol/l) represented a median that departed values similarly to what was observed for age with a median value of 65 years. in fact, 52% of the patients in this study had a psa superior to 10 ng/ml. the prevalence of prostate cancer in this psa group was remarkably differentiable with the psa value. nearly, two-thirds of patients whose psa level was below 10 ng/ml have benign biopsy outcome compared to two-thirds of patients who have proved cspca on their prostate biopsy with a psa level above 10 ng/ml. these values were concordant with the findings reported by schmid et al. (10), whereas according to park et al. (11) and kobayashi et al. (12), there is no significant different detection rate of cancer and pathological findings between the group with tpsa 2-4 ng/ml and 4-10 ng/ml. in the present study patients were divided in only two groups according to psa (4-9.9 ng/ml and > 10 ng/ml). nevertheless, a tpsa level higher to the 10 ng/ml median added a risk of 1 times to the detection of cspca, similarly to the age factor. of note, the mean psa level increased in either bph or prostate cancer patients as they grow old similarly to the increase of prostate volume observed between the two age groups (19-28% relative increase in mean prostate volume versus 18-29% increase in mean psa levels). the joint increase of both age and psa in relation to the outcome of prostate biopsy demonstrated that none of the two factors could be a major predictive value by itself. a psa value higher to the cutoff (10 ng/ml) was predictive of a high risk of prostate cancer if the patient’s age was higher of the age cutoff (65 years old). in fact, for a psa value above 10 ng/ml, no more than 50% of prostate biopsies demonstrated a prostate cancer unless the age was superior to 65 years. dre, trus and tpsa level are commonly used methods of screening for prostate cancer. the detection of any abnormality in the prostate volume through dre or trus, and the detection of a higher than age-related tpsa level are usually followed by an ultrasound or mri-guided biopsy of the prostate to rule out prostate cancer. on note, tpsa was initially utilized as a post-operative laboratory test for recurrence detection. its implementation as a screening method has lowered morbidity associated with prostate biopsies and the number of unnecessary biopsies, and allowed earlier detection of cspca up to 81% as compared to dre alone (13). psad benson et al. in 1992, introduced the concept of psad, to correct psa value by prostate volume to differentiate patient with high volume benign disease from those with prostate cancer (14). however, many authors questioned this concept, because the utilization of psad with a cutoff of 0.15 ng/ml2 showed a sensitivity of only 60% (14). the diagnostic efficacy of psa density has been thoroughly discussed in relation to its stratification for each psa level interval showing that for tpsa levels higher than 10ng/ml, a high prostate density indicated a 6 times risk of cspca detection on a prostate biopsy. this finding defined prostate density as an extremely important tool for the indication of a biopsy for this tpsa level interval. when the tpsa level is higher to 10 ng/ml, the risk of diagnosing a prostate cancer for a prostate density higher than 0.185 ng/ml2 was 4.2% (95% ci 0.2630.691) higher. on the contrary, when psa level is below 10 ng/ml, a high prostate density value proved to be unreliable using the 0.185 ng/m2 cut-off. conversely, in the psa interval with higher incidence of prostate cancer, the risk of prostate cancer at biopsy dropped when psad is below the 0.184 ng/ml2 cut-off. in addition, the joint evaluation of age and prostate density showed that higher values of both was predictive of a higher risk of prostate cancer detection on a prostate biopsy (77% of the patients whose psad and age were superior to the considered cutoffs had prostate cancer compared to only 26% when both parameters were inferior to the considered cutoffs). the results from this study confirmed previous reports on the value of psad in the biopsy indication. jue et al. demonstrated that psad is better in predicting prostate 23archivio italiano di urologia e andrologia 2022; 94, 1 psa density in the diagnosis of prostate cancer cancer versus the use of psa level or prostate volume alone (15). similarly, stephan et al. showed the psa density to perform better than the tpsa level for patients whose psa level ranged between 2 and 20 ng/ml (16). van iersel et al., similarly to many other authors, concluded that the psad cutoff to distinguish between prostate cancer and bph could be 0.15 ng/ml2 where a higher value is significant of a higher malignancy probability (17). although similar results were obtained in this retrospective study with a psad cut-off of 0.185 ng/ml2 and 0.13 ng/ml2, these values are population specific and their variance relied on a multitude of factors (18). the reliability of the prostate volume measurement dramatically affects the significance of cut-offs used for biopsy decisions. two methods were implemented in the calculation of the prostate volume: the ellipsoid method or planimetric method. stone et al. found that the three plane method (ellipsoid method) had a variability of 30% compared to the 3d-planimetric method which showed only 5% variation. furthermore, holmang et al. stated that the 3-plane method underestimated the volume by 20% compared to the 3d-planimetric method (19). hence, the higher is the accuracy of the method of volume assessment, the better psad would assess the need for a prostate biopsy and the less unnecessary biopsies would be made. in a multi-centric study of 773 patients, catalona et al. (20) considered lowering the psad cut-off to 0.078 ng/ml2, because at that cut-off, 95% of tumors would be detected. in the present study, for a tpsa level between 3 and 9.9 ng/ml, when the psad cut-off value of 0.184 ng/ml2 was utilized, only 42.4% of cspca patients would have been diagnosed with prostate biopsy with a 57% specificity. a p-value of 0.432 for this tpsa level rendered the results less reliable. for a tpsa > 10 ng/ml, using a psad cut-off of 0.184 ng/ml2, the utilization of prostate biopsy was 89.4% sensitive and 40.9% specific, with a p-value of < 0.0001. lowering the cut-off to 0.09 ng/ml2, sensitivity increased to 96% while specificity decreased to 35%. this result could be justified by the fact that 89.4% of cspca patients have a psad superior to 0.185 ng/ml2 compared to only 59.1% of benign patients being superior to the aforementioned value. lowering the psad cut-off led to a new distribution of patients as shown in table 10 and consequently to a change of sensitivity. it can be intuitive of the fact that most prostate cancer patients have relatively high psad and that lowering the psad cut-off recruited more patients into this category and favored an increase of the sensitivity and decrease in the specificity. therefore, this study proved psad was a good predictor of the biopsy outcome for tpsa ranging between 4 to 20 ng/ml. psad cut-off of 0.18 ng/ml/cc could minimize the number of unnecessary biopsies. consideration of a lower cutoff may promote better sensitivity with a slight decrease in the false negative results, which remains acceptable for a screening test. however, the acknowledgment of a psad cut-off mandates further studies for an optimal value that balances the sensitivity and false negative results of the prostate biopsy. study limitations every study has limitations and this study is no exception. the limitations can be sorted under two titles. population the number of the patients and the fact that they were from the same hospital limited the credibility of our results. a multicenter study with a larger population size will impart to those results more credibility, render them more reliable, help achieve more precise cut-offs, averages of minimal standard deviation, and allow generalization of the findings as representative of the whole population. retrieval of data the missing data prevented the estimation of the positive predictive value (ppv), negative predictive value (npv), sensitivity and specificity of the prostate biopsy procedure. this limited the comparison of the results versus other studies. references 1. rogers oc, anthony l, rosen dm, et al. psa-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer. oncotarget. 2018; 9:22436-22450. 2. prcic a, begic e, hiros m. usefulness of total psa value in prostate diseases diagnosis. acta inform med. 2016; 24:156-61. 3. mittal rd. reference range of serum prostate-specific antigen levels in indian men. indian j med res. 2014; 140:480-1. pmid: 25488440; pmcid: pmc4277132. 4. shamseddine a, et al. cancer trends in lebanon: a review of incidence rates for the period of 2003-2008 and projections until 2018. popul health metr. 2014; 12:4. 5. https://gco.iarc.fr/today/data/factsheets/populations/422-lebanonfact-sheets.pdf 6. instituto brasileiro de geografia e estatística; ministério do planejamento, orçamento e gestão. estimativas populacionais 1980-2010: brasil, regiões geográficas e unidades da federação. rio de janeiro (brasil): ibge; 2010. [citado em 15 de junho de 2010]. disponível em: http://www.ibge.gov.br 7. nickel jc. inflammation and benign prostatic hyperplasia. urol clin north am. 2008; 35:109-15 8. çamur e, coskun a, kavukoglu o, et al. prostate volume effect on gleason score upgrading in active surveillance appropriate patients. arch ital urol androl. 2019; 91:93. 9. babaian rj, fritsche ha, evans rb. prostate-specific antigen and prostate gland volume: correlation and clinical application. j clin lab anal. 1990; 4:135-7. 10. bell n, et al. canadian task force on preventive health care. table 10. redistribution of patients with psa > 10 ng/ml after lowering psad cut-off to 0.09 ng/ml2. biopsy outcome psad prostate cancer benign > 0.09 ng/ml2 109 43 < 0.09 ng/ml2 4 23 archivio italiano di urologia e andrologia 2022; 94, 1 a. msheik, m. mohanna, a. mhanna, a. kanj, m. moussa, a. mohanna 24 recommendations on screening for prostate cancer with the prostatespecific antigen test. cmaj. 2014; 186:1225-34. 11. park hk, hong sk, byun ss, lee se. comparison of the rate of detecting prostate cancer and the pathologic characteristics of the patients with a serum psa level in the range of 3.0 to 4.0 ng/ml and the patients with a serum psa level in the range 4.1 to 10.0 ng/ml. korean j urol. 2006; 47:358-61. 12. kobayashi t, nishizawa k, ogura k, et al. detection of prostate cancer in men with prostate-specific antigen levels of 2.0 to 4.0 ng/ml equivalent to that in men with 4.1 to 10.0 ng/ml in a japanese population. urology. 2004; 63:727-31. 13. gomes r, rebello lefs, araújo fc, et al. a prevenção do câncer de próstata: uma revisão da literatura. ciencia & saude coletiva. 2008; 13:235-46. 14. benson mc, et al. prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. j urol. 1992; 147:815-6. 15. jue js, et al. re-examining prostate-specific antigen (psa) density: defining the optimal psa range and patients for using psa density to predict prostate cancer using extended template biopsy. urology. 2017; 105:123-128. 16. stephan c, et al. the ratio of prostate-specific antigen (psa) to prostate volume (psa density) as a parameter to improve the detection of prostate carcinoma in psa values in the range of < 4 ng/ml. cancer. 2005; 104:993-1003. 17. van iersel mp, witjes wp, de la rosette jj, oosterhof go. prostate-specific antigen density: correlation with histological diagnosis of prostate cancer, benign prostatic hyperplasia and prostatitis. br j urol. 1995; 76:47-53. 18. ediz c, akan s, temel mc, yilmaz o. the importance of psadensity in active surveillance for prostate cancer. arch ital urol androl. 2020; 92:136. 19. holmäng s, lindstedt g, mårin p, hedelin h. serum concentration of prostate-specific antigen in relation to prostate volume in 50 healthy middle-aged men. scand j urol nephrol. 1993; 27:15-20. 20. catalona wj, et al. comparison of percent free psa, psa density, and age-specific psa cutoffs for prostate cancer detection and staging. urology. 2000; 56:255-60. correspondence ali msheik, (corresponding author) newpie@mail.com pgy-1 neurosurgery, faculty of medical sciences, lebanese university, beirut (lebanon) mohamed mohanna pgy-1 internal medicine, faculty of medical sciences, lebanese university, beirut (lebanon) ali mhanna pgy-1 general surgery, faculty of medical sciences, lebanese university, beirut (lebanon) ali kanj, md radiologist, bahman hospital, beirut (lebanon) mohamad moussa, md urologist, chairman of general surgery and urology department, faculty of medical sciences, lebanese university, beirut (lebanon) assaad mohanna. md radiologist, head of radiology department, bahman hospital, beirut (lebanon) cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2021; 93, 192 review no conflict of interest declared. doi: 10.4081/aiua.2021.1.92 dence of those significant pca undetected in screening trials that are even now responsible of specific mortality and are called “escapes cancers”. the occurrence of one of the above scenarios is overwhelming for the patients and unpredicted for the physician. then we addressed limitations and reasons to understand why early significant cancer may be still missed nowadays. these issues of multidisciplinary interest had been subdivided and deepened under four main arguments: the radiological point of view, biochemical and clinical point of view, pathological point of view and focus on pi-rads 3 lesions: transition zone (tz) vs peripheral zone (pz). biochemical and clinical point of view evaluate the presence of pca in case of men with low psa level is a new challenge to reduce the mortality due to pca and increase the detection in case of disease risk. the national comprehensive cancer network (nccn) (version 2020.1) described the low level of psa as the presence of a serum psa < 3 ng/ml according to beckman standard, which cut-off is 4.0 ng/ml. this value translated to who is 3.0 ng/ml. over time the international guidelines changed dramatically based on results of milestone studies by thompson et al. (4). they presented a clinical trial in which 9459 men were analysed for a pca prevention trial (pcpt): 2950 men presented a psa level < 4.0 ng/ml and negative dre. all the population received biopsy at the end study per protocol. the prevalence of pca was 15.2% in the group with low psa level and the incidence of cspca is summarized in table 1. that means that there is a cspca also in patients with low psa level. to limit the number of patients to undergo prostate biopsy other clinical evaluations need to be considered: dre, imaging, prostate volume, age and genetic risk. advantage must be balanced to probability of prostate biopsy complications (5). digital rectal examination and psa the decision to do a prostate biopsy can change after the dre. based on this fact, halpern et al. analysed the dre of 35,350 men and stratified the results by psa level and reasons why significant prostate cancer is still missed in early stage were investigated at the 22nd national sieun (italian society of integrated diagnostic in urology, andrology, nephrology) congress took place from 30th november to 1st december 2020, in virtual modality. even if multiparametric magnetic resonance (mr) has been introduced in the clinical practice several, limitations are emerging in patient with regular digital rectal examination (dre) and serum prostate specific antigen (psa) levels approaching the normal limits. the present paper summarizes highlights observed in those cases where significant prostate cancer may be missed by psa or imaging and dre. the issue of multidisciplinary interest had been subdivided and deepened under four main topics: biochemical, clinical, pathological and radiological point of view with a focus on pi-rads 3 lesions. key words: prostate cancer; prostate needle biopsy; radical prostatectomy; diagnosis; magnetic resonance imaging. submitted 9 january 2021; accepted 21 january 2021 introduction the present paper summarizes highlights in the field of prostate cancer (pca) focusing on significant types that do not rise serum psa, those that are undetected by imaging or those that are unpalpable. this issue rises several implications such as development of early pca and limitations in cancer detection using updated technologies (1, 2). the knowledge is useful for patient and physician information before any further invasive diagnostic procedure such as biopsy or before any therapy of concurrent benign prostatic hyperplasie (bph) (3). the believes of most men is that every cancer is detected if we use magnetic resonance given that prostatic specific antigen (psa) and digital rectal examination (dre) may miss sometimes early cancer, therefore prostate mpmr (magnetic resonance) imaging is extremely required even if is not clinically indicated. as examples of this we refer to two clinical scenarios commonly observed in clinical practice: the first, is t1b pca detected after bph surgery in patients with in-range psa and normal dre, the second, the incidetection limits of significant prostate cancer using multiparametric mr and digital rectal examination in men with low serum psa: up-date of the italian society of integrated diagnostic in urology summary andrea b. galosi 1, erika palagonia 1, simone scarcella 1, alessia cimadamore 2, vito lacetera 3, rocco f. delle fave 1, angelo antezza 1, lucio dell’atti 1 1 division of urology, school of medicine, università politecnica delle marche, ancona, italy; 2 division of pathology, school of medicine, università politecnica delle marche, ancona, italy; 3 division of urology, azienda ospedaliera marche nord, pesaro, italy. presented at the sieun congress ancona 30 november 1 december 2020 93archivio italiano di urologia e andrologia 2021; 93, 1 significant prostate cancer with low psa dre positivity (6). overall, the incidence of clinically significant pca was higher in men with suspicious dre independently of the psa level. furthermore, the results highlight that in patients with psa level between 3-4.9 ng/ml the positivity of dre increased the risk of clinically significant pca from 9.2% to 15.7%; in patients with a level between 2-2.9 from 3.5% to 6.5%; between 1-1.9 ng/ml from 1.2% to 2.3% and in patients with a psa < 1 ng/ml from 0.2% to 0.7%. positive dre is correlated with cancer even at low level of psa. age and psa another important aspect is the age of this men and how the time could influence the probability of develop pca. in particular, a study analysed the probability of men to develop a pca after 25 years from the first assessment (7). in the range from 37 to 42 years of age with a low psa level the risk to have a pca metastasis after 25 years increased with concentrations in the highest 10th of psa (≥ 1.3 ng/ml) and the highest quarter of psa (≥ 0.9 ng/ml). in the range of 45 to 49 years of age the risk to develop cancer metastasis or to die for pca increased in patients with a psa level in the highest decile (≥ 1.6 ng/ml) and the highest quarter of psa ≥ 1.1 ng/ml. psa velocity lifelong psa trend can help for rigorous follow-up of young men. this evaluation is called psa velocity (psav) and calculates how quickly psa rises over time. the increase in psa is greater in patients who have a higher risk of developing a lethal pca (8). there is a cut-off level of 0.35 ng/ml per year of psav which could individualize patients with the risk of death from pca. men having a psav above 0.35 5 to10 years before the diagnosis of the tumor, had a relative risk of pca death of 10.7 compared to men with a lower psav. these results were confirmed extending the retrospective analysis to 15 years, with a relative risk of 4.7. moreover, vickers et al. assessed that only 8% of men with a psa < 2.5 ng/ml and negative dre had a psav over 0.35 ng/ml/year and that in this population the risk to develop a pca was 18% while in a population with a lower psav the risk was 14% (9). however, the risk of cspca is not high in both the two groups. these considerations can help us to better evaluate and follow certain young patients with normal psa and negative dre. psa density and mpmr psa densisty (psad) is obtained dividing serum total psa value by prostate volume calculated by imaging (transrectal ultrasound or mpmr) (10). since 1990, the psad enhanced the specificity of cancer detection in men with a normal dre and an intermediate psa level (11). recently, several studies demonstrated that the combination of psad and mpmri findings allows the better risk stratification in a cohort of biopsy-naive and previously negative biopsy patients. pagniez et al. increased the negative predictive value of mpmri from 84.4% to 90.4% by using the psad with a cut off of 0.15 ng/ml/cc (12). even in cancer active surveillance an emerging body of evidence is growing. roscigno et al. evaluated the role of psad in identifying patients presenting a different risk of reclassification at confirmatory or follow-up biopsy: higher psad was associated with higher risk of reclassification for all pi-rads lesions (13). psad was an independent predictor of reclassification using 0.20 as cut-off. furthermore, bhat et al. showed that none of the patients in active surveillance presented a risk of disease reclassification in case of pi-rads scores of 1 to 3 and psad 0.15 ng/ml/cc as upper limit (14). psad might spare some men from the morbidity associated with a prostate biopsy and diagnosis of low-grade prostate cancer, therefore should be included in the flow-chart of prostate cancer diagnosis. low or normal psa and mpmr the negative predictive value (npv) of mpmr is variable: in literature there are many studies that report a npv more than 80% and others that set this value around 60% (15). the main variable to set npv is the type of population taken into account for the analysis. if we considered a population with a low risk of pca the nvp is 50%, this means that a negative mpmri in a patient halves the risk of pca, but a very high residual risk remains. on the other hand, in a population with a high risk of pca, the mpmri can even reach a npv of 88%. the patient's baseline risk must be valuated and there are calculators used to determine the patient's risk (by example, prostate cancer risk calculators) (16). long-term npv has been addressed in a recent study: 84% of patients with negative mpmr were free of cancer even after 4 years of follow-up, whereas 16% developed pca although only 4% developed a cspca (17). characterization of the familiar history and genetic there are men with low psa level, negative mpmri and unpalpable disease with pca (18). these men have usually familiar history of pca and undergo premature serial psa exams, clinic visits, and rectal examination. the genetic tests are suggested in men with one brother or father or two or more male relatives with one of the following: diagnosed with pca at age less than 60 years (recommended), any of whom died of pca (recommended), any of whom had metastatic pca (recommend) (19). genetic testing should be considered in men with family history of 2 or more cancers in hereditary breast and ovarian cancer, or lynch syndrome in any relatives on the same of the family (especially if diagnosed at age < 50 years) (20). the brca2 mutation leads to a three times greater risk of death (21). there are many other important aspects of genetics that have been identified over the years by numerous studies. first, carriers of brca1 and mostly brca2 mutations are at high risk of developing pca. germline mutations in the brca genes, mainly in brca2, also have implications in the prognosis and management of the disease, with meditable 1. correlation of psa level, prostate cancer (pca) and high grade pca (gleason score ≥ 7) (from thompson et al. 2004). psa level ng/ml 3.1-4 2.1-3.0 1.1-2.0 0.6-1.0 < 0.5 men with pca (n = 449) 26.9% 23.9% 17.0% 10.1% 6.6% men with high grade pca (gleason score ≥ 7) (n = 67) 25% 19.1% 11.8% 10% 12.5% archivio italiano di urologia e andrologia 2021; 93, 1 a.b. galosi, e. palagonia, s. scarcella, a. cimadamore, v. lacetera, r.f. delle fave, a. antezza, l. dell’atti 94 an cause-specific survival (css) for carriers of 2.1 years compared with 12.4 years for non-carriers (22). secondly, lynch syndrome is a type of inherited cancer syndrome associated with germline mutations mainly in the msh2 and msh6 genes; affected individuals are at an increased risk for colorectal cancer but also for other associated tumors including utero and ovary, stomach and small bowel, pancreas, ureter or renal pelvis, biliary tract, brain and prostate. the risk of developing pca in this patients is twofold higher than general population (23). criteria of hereditary pca from john hopkins university (jhu) included at least 3 first-line relatives with pca or cases of pca in three generations, as well as 2 relatives with pca < 56 years of age (24). approximately 8% of young pca patients have hereditary pca. the recommendation of the national comprehensive cancer network (nccn) is to use next generation sequencing to sequence the multigene panel, which includes at least brca1, brca2, atm, brip1, chek2, nbn, hoxb13, mlh1, msh2, msh6 and pms2 (25). men with age between 45-75 years with psa < 1 ng/ml, dre normal or psa 1-3 ng/ml and dre normal are often underestimated, this led to correctly frame the patient who needs annual checks for pca early detection. however, a personalised risk-adapter strategy for early detection pca could be associated with an important risk reduction of over-diagnosis and over-biopsy (26, 27). pathological point of view: definition of cspca although epstein criteria have a suboptimal accuracy for predicting significant pca, the pathological concept of significant prostate cancer is a lesion with volume of > 0.2 ml, a gleason grade ≥ 7 or extraprostatic extension (28), the index lesion is defined as the larger and/or containing high grade tumor (pattern 4 or 5) (29). these values were defined assessing 185 patients who underwent radical prostatectomy with a median of five years follow-up in which epstein et al. demonstrated that none of the patients with palpable tumors clinical t2 with a volume < 0.2 cc had extra-prostatic extension (epe) or biochemical recurrence (bcr) (30). however, there was a high incidence of multifocal pca and consequently summing the volumes of many small prostate tumors would result in a total volume higher than 0.2 ml, although actually there is no evidence that these smaller multifocal tumors impact on the prognosis of the index tumor (31). in the era of cognitive guided fusion biopsies, in the last years several studies showed that imaging driven biopsy help to target the cancer properly increasing the grading assessment through biopsy (32, 33). pca is considered a paradigm of morphologic heterogeneity and the role of the pathologist and of biopsy technique assumes great importance for the choice of treatment and appropriate follow-up (26). grade group 1 (gleason score 3+3 = 6), pathologically composed of individual discrete wellformed separated glands, is very homogeneous with an excellent prognosis (34, 35). in a population of 20845 men with clinically localized pca treated by radical prostatectomy in four different american hospitals, epstein et al. did not observe distant metastasis or cancer-specific mortality in a subgroup of more than 6000 men with organ-confined and negative margins with pure gleason score 6 disease; the risk of progression in this group is approaching 0% (36). despite these results, we must consider that not all tumors that “look good” from a clinical point of view (psa < 3 ng/ml, negative dre, negative transrectal ultrasound, pi-rads 3 at mpmr) are also good from the histological and molecular point of view. kamoun et al. subdivided prostate tumors in three different genetical signatures profiled on dna methylation, snp arrays and mrna arrays. molecular subtype “s2” tumors, which mainly included isup group 1 and 2, present with tmprss2-erg fusions with constancy in other molecular subgroups and were also characterized by an almost total absence of mutations in pten, in the phosphoinositol kinase pathway and in p53. however a little percentage of isup 3 and 4 tumors was represented also in this class (37). cribriform histology and intraductal carcinoma while pure gleason score 6 prostate cancers have an excellent outcome in terms of progression, absence of distant metastasis and disease-free survival, areas of cribriform pattern 4 histology, intraductal carcinoma and pca with reactive stroma are characterized by aggressive genetic alterations and worse oncological outcomes. presence of pattern 4 with cribriform histology must be reported because its presence and its quantitative representation (in terms of percentage) aggravate prognosis (38). cribriform can be confused by an inexperienced pathologist with other histotypes like glomeruloid glands, fused glands and poorly formed glands. hollemans et al. distinguished cribriform type into two groups: small cribriform (< 12 lumina) and large cribriform (> 12 lumina): patients with large invasive cribriform growth belong to a more aggressive subgroup with an increased risk for biochemical recurrence and metastasis (39). intraductal carcinoma (idc-p) is pathologically recognized by its cribriform or solid growth pattern distending preexistent acini and prostatic ducts with preservation of basal cells; in most cases idc-p is closed associated to presence of high grade pca and high volume cancers (40). percentage of grade 4, grade 4 cribriform pattern and the presence of intraductal carcinoma at biopsy have an important impact on the prognosis. the presence of intraductal growth or invasive cribriform cancer at biopsy outperforms percentage grade 4 in predicting outcome of gleason score 3+4 = 7 pca: in 370 men with gs 3+4 = 7 prostatic cancer was demonstrated that invasive cribriform and/or intraductal carcinoma are independent parameters for bcr after radical prostatectomy, while percentage of gleason group 4 is not. the majority of idc-p derived from adjacent highgrade invasive carcinoma via retrograde spreading of cancer cells along benign ducts and acini; a small group of idc-p may represent the transformation of precancerous intraductal proliferation induced by various oncogenic alterations (41). the prevalence of idc-p increased significantly from 2.1% in low-risk patient up to 56.0% in metastatic or recurrent pca patients (42). interestingly, in patients treated with androgen deprivation therapy (adt) or chemotherapy, idc-p was reported in 60% of pca indicating that idc-p may correlate with the development of castration-resistant prostate cancer. 95archivio italiano di urologia e andrologia 2021; 93, 1 significant prostate cancer with low psa pca with reactive stroma another important overview is focused on pca with reactive stroma (also called stromogenic pca), that is, by definition, composed by at least 50% reactive stroma (stroma/epithelium ratio ≥ 1). the prototypic “stromogenic” carcinoma is of the classic acinar subtype, with well-formed glands surrounded by an evident amount of stroma. this pathological feature is correlated with a worse prognosis; in samples with high reactive stroma, metabolites and genes linked to immune functions and extracellular matrix remodeling are significantly upregulated (43). psa negative prostatic tumors psa has been used as serum marker for pca screening in the male population, but its specificity is low due to its production by normal epithelial tissue. psa antibody is currently used in immunohistochemistry to determine whether tumor masses of unknown origin can be assigned to a prostate cancer. however, some prostatic tumors do not express psa in immunohistochemistry and do not determine increases in psa levels in the blood (34). in poorly differentiated tumors or metastatic foci, psa expression might be decreased or even lost. pca with neuroendocrine differentiation often lost psa expression (44). more specific markers such as psma and nkx3.1 are now available to overcome the limited sensitivity of psa (figure 1) (45). moreover, other tumor types, although rare, such as prostatic stromal and smooth muscle tumors, both benign and malignant, solitary fibrous, neural, germ cell, hematopoietic and melanocytic tumors, can form a palpable mass in the prostate, without giving an increase of the serum psa (46). psa screening alone is not sufficient to exclude a prostatic tumor; a physical inspection with digital rectal examination is highly recommended and should not be replaced by a psa screening alone. the role of mpmr according to the most recent update of the european urology association guidelines, the introduction of mpmr in the diagnostic pathway in all patients with psa elevation leads to significant improvement of clinically significant pca detection (2). the lesion detected by imaging is then targeted by biopsies under the guide of mri/ultrasound fusion technology. this increases the detection of cspca, lowering the detection of insignificant disease. also “biopsy naïve” patients have a benefit with a mr evaluation. however, it is of outmost importance that a negative mr does not exclude the possibility of significant pca. moreover, deciding whether or not is safe to avoid a biopsy in a naïve patient with negative imaging should also rely on psad, digital rectal evaluations, nomograms, new biomarkers and family history (10). the promis study showed that the use of mpmri reduces of a 5% the detection rate of indolent cancers lowering the need of biopsy in 27% of patients (47). moreover, the application of mpmr/trus fusion biopsy technology increased of a 18% the rate of diagnosis of cspca compared to the traditional systematic biopsy. the need of systematic biopsy is underlined by several studies that reported a significant percentage (5% up to 16%) of cspca missed by mr-guided biopsy. results found by rouvière et al. highlighted the role of systematic biopsy to detect cspca in men with abnormal psa and negative imaging/dre (48). they stated that the mpmr in biopsy naïve patients can improve cspca detection rate using target biopsy plus concurrent systematic biopsy. any differences in detection rate of high grade cancers (isup grade ≥ 2) was observed between targeted and systematic biopsies, but they found a significant improvement (plus 5% up to 7%) using the combination of both techniques (48). are we ready to avoid biopsy in negative mpmr? yes, since the benefit is reduced in both detection of indolent disease and number of men undergoing biopsy. however, from 5% to 20% of cspca have negative mpmr imaging (49). this rate of undetected cspca should guide the clinician to the best tailored strategy for the single patient balancing monitoring versus early biopsy approach in terms of morbidity of biopsy and delayed cancer diagnosis. in patients with psa below the limit and normal dre, the mpmr is not indicated and not supported by guidelines (2). therefore, based on available knowledge, the use of mpmr as a screening tool in patients with normal psa and negative dre must be discouraged. the negative predictive value (npv) of mpmr changes significatively in relation to the risk of pca in a population, where the incidence of cancer is low (normal psa) the diagnostic performance dropped significatively to 50%, while in high risk is up 88%. to improve the npv of mpmr in men with normal psa, other factors such as genetic, psad or psav should be evaluated to select those men with higher risk to have cancer (50). a recent and very interesting study estimated the risk to detect cancer over the time after a negative mpmr at baseline (17). after 4 years of follow-up, they found 84% of patients remained free of cancer and overall 16% figure 1. hematoxylin & eosin-stained section of a prostate cancer bone metastasis (a) with a focal expression of psa (b) and a diffuse and strong expression of psma (c) and nkx 3.1 (d). archivio italiano di urologia e andrologia 2021; 93, 1 a.b. galosi, e. palagonia, s. scarcella, a. cimadamore, v. lacetera, r.f. delle fave, a. antezza, l. dell’atti 96 developed pca but only 4% cspca. although of its several limitations (e.g. control group, highly selected cases in referral centre), this study shows that a negative mpmr predict a lower risk over the time to develop cspca: 4% (1 man every 20) compared to 8% of calculated risk for a man to be diagnosed with clinically significant pca throughout his lifetime. limits of mpmr despite the wide acknowledged improvements cited in the previous paragraph and being advocate as the reference standard for prostate radiological imaging, mpmr is not exempt from drawbacks. according to quon et al., mpmr missed up to 20% of cspca lesions or underestimated its size (51). after a second-look of mr imaging, 58% of the missed lesions were not confirmed as benign findings. in fact, this technique needs further implementations to reduce inter-observer variability and to reduce false negative rates. the radiologist's experience is shown to be a key factor in imaging interpreting and pca recognition. a recent study analysed the different reports of 9 radiologists on the same mpmri by comparing their experience (52). among pi-rads 2 results, the possibility of finding clinically significant pca in the biopsy ranged from 15 to 35%. the detection of any type of pca in pi-rads 2 ranged from 15 to 75%. in 2018 johnson et al. analysed the mpmri performed on 588 patients before radical prostatectomy, using a 3 tesla mri in a single institution with expert radiologists (48). overall, the mpmri detected 541 out of 1213 pathologic lesions, which represent a sensitivity of 45%, a positive predictive value of 81% and a false positive rate of 19%. therefore larger (> 0.5 ml), high grade and solitary tumors were more likely to be detected. comparing mpmr and surgical specimens, 90% of the non-cspca were missed, but also the 40% of gleason score 3+4, the 26% of gleason score 4+3 and the 22% of gleason score ≥ 8. in a recently published review, chatterjee et al. found that the inter-observer variability and lack of standardisation in reporting radiological findings are the most important interpretative drawbacks (53). they described a variety of interpretative and technical pitfalls that influenced negatively mpmr performances: 1) different anatomic features can simulate pca such as the anterior fibromuscular stroma, the periprostatic venous plexus and the pseudocapsule of the transitional zone (tz); 2) others histologic benign conditions such as inflammation and prostatitis, could mimic pca; 3) postbiopsy haemorrhage, prostatic calcifications associated with benign prostatic hyperplasia nodules in the transitional zone; 4) technical artifacts or image distortion due to endorectal coil placements and motion artefacts. the low-intensity t2 signal and the heterogeneity of enhancement patterns in the peripheral zone are reported to reduce the diagnostic yield of mpmr (53). improvements of mr imaging: pi-rads 2.1 the first version of the prostate imaging reporting and data system (pi-rads v1) released in 2012 by the european society of urogenital radiology and then updated to version 2.0 in 2015 has been considered and adopted as the reference standard tool to report and early detect pca. the most reported limit of this scoring system is the inter-reader concordance ratio (moderate), which limits the diagnostic performance of this system. moreover, despite technological improvements, the study of the transition zone remains challenging if compared to the peripheral zone due to the presence of benign hyperplasia as a mimic of pca (2). in 2019 the pi-rad system was updated to version 2.1 with leading changes regarding the transition zone mpmri conundrum (54). the most important ones are: 1) the definition of atypical nodules in the tz and the downgrading to category score 1 of the completely encapsulated nodules (encapsulated or homogeneous circumscribed defined as pi-rads 2 in the previous category system); 2) the characterisation of these nodules trough diffusion weighted imaging (dwi) features to improve detection and localization of pi-rads 3 areas. focus on pi-rads 3 lesions in the tz vs pz mri lesions pi-rads 3 are termed as “equivocal” for the presence of clinically cspca. pi-rads 3 represents a “grey zone” that needs to be further investigated to solve the issue of biopsy or not biopsy. they could be malignant lesions but mostly they are benign lesions or nonsignificative cancer (55). the pi-rads version 2 uses a 5-point scale based on the likelihood (probability) that a combination of mpmr findings on t2-weighted imaging (t2w), diffusion-weighted imaging (dwi), and dynamic contrast enhancement (dce) correlates with the presence of a clinically significant cancer depending on cancer volume (> 0.5 ml), location and background tissue within the prostate gland. the peripheral zone (pz) of the prostate has a high risk of develop prostate cancer compared to the transizion zone (tz). therefore, doubtful mr imaging (defined as pirads 3) has different diagnostic value taken into account prostatic anatomical zones. this is supported by yang et al. who analyzed cancer detection rate in 683 patients with pi-rads 3 lesions of the pz and tz (56). they reported 37% cancer detection and 18.7% of cspca in the pz, while in the tz the overall cancer detection was 16.4% and the rate of cspca was 6.0%. furthermore, using a psad greater than 0.15 and age greater than 68 years, they calculated that 24% of biopsy could be omitted by losing only one cspca, with a sensitivity of 80% and a negative predictive value of 92.3%. they conclude that significant cancer is uncommon in tz and the active surveillance is the optimal choice, especially among patients without risk factors such as those with low psad. many studies report that mpmr is very reliable as a negative predictive value, but it depends on prevalence of disease in the population studied and the a priori risk of developing disease. since, pi-rads 3 does not identify the same risk of cancer in different prostate zones, the predictive value of pi-rads 3 should be considered as low in the tz respect to pz. however, the estimating of the predictive value of pirads 3 lesions has methodological bias because it do not represent the primary endpoint of published studies, 97archivio italiano di urologia e andrologia 2021; 93, 1 significant prostate cancer with low psa as maggi et al. very recently underlined after an extensive review (57). in 28 studies with 10.176 patients (56.5% with pca and 40.0% with cspca), 1,759 men with targeted biopsies on pi-rads 3 lesions were retrieved: the overall rate of cspca detection was 36% and 18.5%. the combination technique (targeted and systematic biopsy) has the better detection rate of 37% versus the 24% of exclusive targeted biopsy. there is no significantly relevant difference between version 1 and version 2 of pi-rads in the detection of prostate cancer (57). however, they did not differentiate the cancer detection comparing prostatic zones. byun et al. evaluated the pi-rads v2.1 diagnostic performances and inter-reader agreement on the pca detection in the tz comparing results with the previous version (58). their results demonstrated that the last version has both higher sensitivity and specificity for the overall detection of pca for category higher than 3 lesions, independently of the prostatic zone. furthermore, they reported a reduction of proportion of category 3 lesions, while the detection rates of cspca at this cut-off value significantly increased accordingly with the inter-reader agreement. same findings were confirmed by wang et al. that also suggested that pi-rads version 2.1 improves the overall detection rates of pca, specifically in the tz zone, compared to v2.0 (54). recently, several studies evaluated the role of psad as predictive variable to predict cspca in pi-rads 3 lesions: a cut-off 0.15 ng/ml/cc was the most significant positive predictive value for detect cspca. hansen and ullrich et al. confirm that the choice to execute biopsies in the group of pi-rads 3 with psad > 0.15 ng/ml/cc permit to avoid 53.4% of biopsies in this population of patients (59, 60). also venderink et al. calculated that 42% patients with pi-rads 3 lesions and psad less than 0.15 could avoid biopsy with the loss of only 6% of cs pca (95% c.i. 2-15) (61). lowering the cut-off to 0.12 they spared 26% of avoidable biopsies without losing any cspca (61). schoots et al. reviewed the probability of cspca in pi-rads 3 lesions observed in biopsy naïve, previous negative biopsy, and active surveillance patients: they retrieved 21%, 16% and 17% of cspca, respectively (62). they focused on size of the lesion: pi-rads 3 lesions in both peripheral zone (pz) and transition zone (tz) greater than 10 mm should be re-classified as pi-rads 4 according to their results. other than diameter, the decision to proceed with the biopsy must include clinical elements such as psad, psav and previous biopsies. the risk of missing cspca must be discussed with the patients and balanced against saving biopsies (side effects) and overdiagnosing of insignificant pca on an individual basis. van der sar et al. investigated retrospectively outcomes such as window of curability and complication and costs of clinical surveillance compared to immediate biopsy (63). all outcomes were not influenced by both strategies as well as the risk profile of the cancers appeared similar. the large part of patients preferred clinical surveillance (57%) compared to immediate biopsy (43%). frye et al. monitoring pi-rads 3 lesions in active surveillance reported a rate of progression of 20% precisely on the area of the target lesion pi-rads 3 compared to 29% of overall progression (64). therefore, we can assume that defer the biopsy in pirads 3 lesion in the tz can be a safe strategy, as we suggested in a flow-chart summarized in the figures 2, 3. figure 2. clinical pathway in biopsy naïve patient with pi-rads 3 lesions. figure 3. clinical pathway in biopsy negative patient with pi-rads. archivio italiano di urologia e andrologia 2021; 93, 1 a.b. galosi, e. palagonia, s. scarcella, a. cimadamore, v. lacetera, r.f. delle fave, a. antezza, l. dell’atti 98 in conclusion the management pi-rads 3 lesion should be based on shared decision to immediate biopsy or follow-up considering the following points: 1) estimation of prostate cancer risk based on nomograms and risk calculators, 2) use carefully mpmr in patients with low risk of cspca and normal psa, 3) mr should be done in quality checked centers (controlled incidence of pi-rads 3 lesions and correlation between radiological and pathological finding), 3) lower urinary tract symptoms 4) use 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197:640-6. correspondence andrea b. galosi, md (corresponding author) a.b.galosi@univpm.it department of clinical sciences, politecnica delle marche university via conca 71, 60126 ancona, italy erika palagonia, md erika.palagonia@gmail.com simone scarcella, md simoscarc@gmail.com rocco f. delle fave, md checcoboss90@gmail.com angelo antezza, md angelo.antezza@yahoo.it lucio dell’atti, md dellatti@hotmail.com division of urology, school of medicine, università politecnica delle marche, ancona (italy) alessia cimadamore, md a.cimadamore@staff.univpm.it division of pathology, school of medicine, università politecnica delle marche, ancona (italy) vito lacetera, md vito.lacetera@gmail.com division of urology, azienda ospedaliera marche nord, pesaro (italy) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3348 original paper no conflict of interest declared. introduction peyronie’s disease (pd) is a chronic inflammatory disease of the tunica albuginea of the corpora cavernosa, involving the formation of a fibrous or even calcified plaque which almost always causes penile curvature and/or deformity (divot, hourglass deformity, shortening). it is often associated with penile pain, especially in younger patients, but it is not rare for pain to be absent; the disease is also associated with erectile dysfunction (ed) (in over 30% of cases) and a depressive state in a large percentage of cases (48%) (1-3). although the exact etiology of the disease is unknown, according to the most credited theory, injury, or micro-traumas to the tunica albuginea of the corpora cavernosa of the penis play a decisive role in its pathogenesis (4-7). penile trauma, by causing delamination of the layers of the tunica albuginea with consequent rupture of the small perforating blood vessels, is thought to result in the formation of a small hematoma which triggers the inflammatory process (5, 6). supposedly, fibrin accumulation then causes recruitment of inflammatory cells (neutrophils and macrophages), with consequent overproduction of pro-inflammatory fibrogenic cytokines and reactive oxygen species (ros) (7-12). once the inflammatory process has been triggered, the subsequent chain of biochemical events is then thought to result in hyperproliferation of fibroblasts and myofibroblasts, leading to excessive production and deposition of collagen at the site (8). genetic predisposition is certain to play a fundamental role in the possibility of developing the disease, with an autosomal dominant inheritance pattern (13-16). several epidemiological studies have found that disease prevalence in adult males varies between 3.2% and 13%; a study by la pera et al. (2001) detected a 7.1% prevalence of pd in italian males (17-19). the disease generally affects adult males of 50-60 years of age, but in the past few years a considerable increase in pd incidence has been reported in patients under 40 years of age (10.8%-16.9% of cases) (20, 21). in its first stages, pd is characterized by the presence of an inflammatory area (corresponding to the plaque) in which fibroblasts and myofibroblasts produce excess collagen (8, 22, 23). several studies have shown that local hyperproduction of collagen peyronie’s disease is a chronic inflammatory disease involving the formation of plaque in the tunica albuginea of the corpora cavernosa, resulting in penis deformity. it is often associated with penile pain, especially in younger patients, but it is not rare for pain to be absent; the disease is also associated with erectile dysfunction and a depressive state in a large percentage of cases. objective: aim of our study was to explore the basic knowledge base and diagnostic and therapeutic practice patterns in peyronie's disease (pd) of a large number of physicians belonging to the italian andrology society (sia). methods: our survey is based on two questionnaires which were e-mailed to the members of the sia. the first questionnaire explored diagnostic and therapeutic practice patterns of sia physicians, while the second questionnaire focused on their knowledge of the disease, as well as their training and level of experience in the specific field. we then planned to compare our outcomes with similar pd surveys from other countries. results: the first questionnaire was answered by 142 sia physicians. the second questionnaire was answered by 83 sia physicians. most respondents (74.6%) chose penile ultrasonography as first-line diagnostic approach and 47.1% prefer to perform a color doppler ultrasound after pharmaco-induced erection. concerning the therapeutic practice patterns in active stage of the disease, most respondents (99.29%) prefer conservative medical therapy. additionally, most respondents (64.78%), when failure of conservative treatment had been established, considered surgical treatment necessary, specifically corporoplasty, which may be associated with other techniques. conclusions: the results of our survey show that, in comparison to their foreign counterparts, italian sia uro-andrologists have a more proactive diagnostic approach right from when patients first present. when pd is still in its active stage, sia uro-andrologists mostly opt for medical therapy. in advanced disease or if conservative treatment fails, our survey indicates a greater preference for surgical treatment. answers to the theoretical knowledge questions showed that sia physicians have a good understanding of the disease’s etiology, epidemiology, and clinical picture, and of the appropriate indications for treatment. key words: peyronie’s disease; penile curvature; erectile dysfunction; peyronie’s disease treatment; practice patterns; survey. submitted 28 june 2021; accepted 9 august 2021 urologists’ knowledge base and practice patterns in peyronie’s disease. a national survey of members of the italian andrology society gianni paulis 1, francesca pisano 2, alessandro palmieri 3, tommaso cai 4, fabrizio palumbo 5, bruno giammusso 6 1 peyronie’s care center, department of uro-andrology, castelfidardo medical team, rome, italy; 2 department of urology, fundacio puigvert, autonomous university of barcelona, spain; 3 department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii, naples, italy; 4 department of urology, santa chiara regional hospital, trento, italy; 5 department of urology, di venere hospital, bari, italy; 6 urology clinic, policlinic “morgagni”, catania, italy. doi: 10.4081/aiua.2021.3.348 summary 349archivio italiano di urologia e andrologia 2021; 93, 3 peyronie’s disease sia survey in pd is directly connected with elevated production of pro-inflammatory fibrogenic cytokines, among which the most important are transforming growth factor beta-1 (tgfß1) and platelet-derived growth factor (pdgf) (6, 24-26). the natural history of the disease has two stages: an initial remodeling phase, which is the inflammatory stage and lasts about 12-18 months; the second phase consists in stabilization of the disease: in this phase, pain is typically absent, while the penile deformity stops progressing (27-29). conservative medical treatment is indicated in the first (active) stage and includes oral therapy, local intralesional therapy, and physical treatment: vitamin e, colchicine, tamoxifen, potaba, antioxidants, etc.; injections with verapamil, pentoxifylline, hyaluronic acid, corticosteroids, collagenase clostridium histolyticum (cch/xiaflex-xiapex), interferon-α2b (ifna2b); extracorporeal shock wave therapy (eswt), iontophoresis, penile extender devices, vacuum devices, etc. (30-37). in particular, use of cch was approved in the usa in 2013 by the us food and drug administration (fda) only in patients with stable pd; the same guidelines were issued by the american urological association, which recommends its use in stable disease (38). however, use of cch has recently been proposed even in the acute (initial) phase of the disease (32, 39). surgical therapy is indicated when the disease has been stable for at least 6 months and sexual intercourse has become impossible due to the presence of severe penile deformity or treatment-resistant ed; surgical treatment is also indicated when there is extensive calcification of the plaque, or when patients want a rapid, assured result (40-44). despite the ample range of treatments proposed in the literature, there is no complete consensus among urologists about modality of therapeutic approach; this is partly due to an incomplete knowledge of the pathophysiological mechanisms of the disease. it is a fact that none of the therapeutic options mentioned in international guidelines on pd has a grade a recommendation (45-48). over the past few years, several articles have been published that focused on pd surveys and questionnaires (49-54). the surveys described in the articles explored and assessed the basic knowledge and different diagnostic and therapeutic approaches of urologists, and these articles also found that practice patterns vary, especially with regards to treatment. aim of our study was to explore the basic knowledge and diagnostic and therapeutic practice patterns in pd in a large number of physicians belonging to the italian andrology society (sia). materials and methods the survey was carried out last year (2020). two questionnaires were e-mailed by the sia office to all its uroandrologist members. a reminder e-mail was then sent to non-responders about one month after the initial mailing. no compensation was offered for completion of the questionnaires. the questionnaires used templates from the google doc web platform (docs.google.com). they were shared with and approved by the sia board and scientific committee. the first questionnaire comprised 5 multiple-choice questions and explored the diagnostic and therapeutic approach of sia physicians (see table 1) (some questions required more than one answer as first question). the second questionnaire (see table 2) contained 15 multiple-choice questions. the first 11 questions explored the uro-andrologists' basic knowledge on pd. the remaining 4 questions focused on the physicians' specialty, as well as their level of experience and clinical practice in the specific field. the analysis of the results did not require any particular statistical software, since we merely collected the percentages of answers to each question. finally, adequacy of answers to the treatment-specific questions of the second questionnaire was assessed based on current approaches in the scientific literature on pd. results the first questionnaire was answered by 142 specialists (urologists and andrologists). the second questionnaire was answered by 83 specialists (urologists and andrologists). results are reported in table 1 and 2. discussion most sia respondents chose penile ultrasonography as first-line diagnostic approach (74.6%); most respondents prefer to perform a color doppler ultrasound after pharmaco-induced erection (47.1%), while the remaining 27.4% opt for a flaccid penile ultrasound, using color doppler ultrasound with pharmaco-induced erection only in cases where ed is also present. however, it must be pointed out that 9.1% of sia respondents believes simple palpation of the penile nodule to be a sufficient diagnostic method. in most other similar surveys on pd in the literature (4954), diagnosis is not discussed; when it was included as an item, penile ultrasonography was deemed to be necessary in 22% to 28.2% of cases (52, 54). although international guidelines do not consider penile ultrasound mandatory, our survey shows instead that most italian uro-andrologists who responded to the sia questionnaire (75.3%) believes a diagnostic imaging test should be performed (40, 45-48). with regards to therapeutic practice patterns in active stage pd, we found that in almost all cases sia respondents (99.29%/141 out of 142) favor conservative medical therapy. in our survey, the conservative approach almost always (85.9%/122 out of 142) consisted in oral therapy associated most of the time with a physical treatment (vacuum device, eswt, ultrasound therapy, iontophoresis, laser therapy) or penile injections (collagenase, verapamil, and/or corticosteroid, etc.). the oral therapy varies: besides several antioxidants (see results), it includes colchicine, potaba, pentoxifylline, and pde-5 inhibitors. comparing our survey with other existing surveys in the literature, we found the closest approach to ours to be that of the us survey in which larochelle & levine (2007) found that 72% of urologists preferred medical treatment for pd, while 29% did not believe any treatment was necessary, and 28% preferred surgery only in case of associated severe curvature (50). in our survey, however, the "non-therapeutic" approach was only supported by one respondent out of archivio italiano di urologia e andrologia 2021; 93, 3 g. paulis, f. pisano, a. palmieri, t. cai, f. palumbo, b. giammusso 350 table 1. replies to first questionnaire. questions answers % (number) 1) after first seeing patients presenting with peyronie's disease, i simply perform palpation and locate the penile plaque 17.6% (25 out of 142) before proceeding to treatment… i refer the patient for a flaccid penile ultrasound 27.4% (39 out of 142) i refer the patient for a penile dynamic doppler ultrasound 47.1% (67 out of 142) (*) i refer the patient for a penile dynamic doppler ultrasound only with concomitant ed 26.05% (37 out of 142 i refer the patient for an mri of the corpora cavernosa 0.7% (1 out of 142) (*) i refer the patient for the above-mentioned exam even though i did not find any palpable nodule 9.1% (13 out of 142) other palpation and photograph of erect penis 0.7% (1 out of 142) unspecified penile ultrasonography 0.7% (1 out of 142) photograph of erect penis 4.2% (6 out of 142) stretched penile length measurement 0.7% (1 out of 142) invalid answers 0.7% (1 out of 142) 2) your first therapeutic approach in patients with peyronie's conservative medical therapy 99.2% (141 out of 142) disease (in its active stage, when it has not stabilized) surgical therapy 0% (0) is the following no therapy 0.7% (1 out of 142) 3) if you opt for a conservative medical approach, oral therapy + physical treatment (generic oral antioxidants, vitamin e, colchicine, avocado + soybean, potaba, what treatment do you prescribe? pentoxifylline, pde-5 inhibitors), various types of physical treatment (vacuum device, eswt, ultrasound, laser therapy, iontophoresis with verapamil and/or cortisone, iontophoresis with pentoxifylline and/or verapamil) 35.9% (51 out of 142) oral therapy only 17.6% (25 out of 142) oral antioxidants (single or in combination: vitamin e, propolis, blueberry, astaxanthin, paba, arginine, centella asiatica) 76.0% (19 out of 25) vitamin e + tamoxifen 4.16% (1 out of 25) antioxidants + colchicine 4.0% (1 out of 25) potaba 4.0% (1 out of 25) oral cortisone 4.0% (1 out of 25) antioxidants + oral cortisone 4.0% (1 out of 25) unspecified 4.0% (1 out of 25) penile injections only 7.7% (11 out of 142 ) collagenase (cch) with modeling 63.6% (7 out of 11) verapamil 9.09% (1 out of 11) verapamil + corticosteroid -9.09% (1 out of 11) prp (platelet rich plasma) 9.09% (1 out of 11) unspecified agent 9.09% (1 out of 11) physical treatment only 3.5% (5 out of 142) vacuum device 20.0% (1 out of 5) eswt 20.0% (1 out of 5) iontophoresis 20.0% (1 out of 5) iontophoresis + eswt 20.0% (1 out of 5) iontophoresis + eswt + ultrasound therapy 20.0% (1 out of 5) oral therapy + penile injections 32.3% (46 out of 142) oral therapy + physical treatment + penile injections 0.7% (1 out of 142) oral therapy + vacuum device 0.7% (1 out of 142) conservative medical therapy on a case-by-case basis 0.7% (1 out of 142) no therapy 0.7% (1 out of 142) 4) how long after the start of conservative medical treatment after 3 months 21.1% (30 out of 142) do you consider it to have failed? after 6 months 44.3% (63 out of 142 after 9 months 9.8% (14 out of 142) after 12 months 19.01% (27 out of 142) after no exact time limit 0.7% (1 out of 142) inadequate answers 4.9% (7 out of 142) 5) if conservative medical treatment fails, what do you do? i refer the patient for surgery 64.7% (92 out of 142) corporoplasty 21.8% (31 out of 142) corporoplasty + grafting 4.9% (7 out of 142) corporoplasty + implant 5.6% (8 out of 142) corporoplasty + implant only if ed is present 2.8% (4 out of 142) plaque excision + grafting 7.7% (11 out of 142) plaque excision + grafting + implant 2.1% (3 out of 142) it depends on the specific case 14.7% (21 out of 142) unspecified surgical treatment 4.9% (7 out of 142) i try out another medical treatment 31.6% (45 out of 142) intraplaque collagenase (cch) injection with modeling 4.9% (7 out of 142) intraplaque corticosteroid injection 0.7% (1 out of 142) intraplaque corticosteroid injection + antioxidants 0.7% (1 out of 142) generic intraplaque injection 2.1% (3 out of 142) injections with verapamil or orgotein + antioxidants 0.7% (1 out of 142) oral antioxidants 1.4% (2 out of 142) generic iontophoresis (no drug specified) 0.7% (1 out of 142) eswt 4.2% (6 out of 142) eswt + iontophoresis 0.7% (1 out of 142) vacuum device 0.7% (1 out of 142) unspecified physical treatment 0.7% (1 out of 142) oral antioxidants + unspecified physical treatment 0.7 % (1 out of 142) oral antioxidants + iontophoresis with pentoxifylline 0.7% (1 out of 142) new therapy attempt with a different unspecified drug 0.7% (1 out of 142) it depends on the case 11.9% (17 out of 142) no answer 3.5% (5 out of 142) (*) = possible further answer ed = erectile dysfunction; mri = magnetic resonance imaging; eswt = extracorporeal shock wave therapy: pde-5 = phosphodiesterase-5 inhibitors; cch = collagenase clostridium histolyticum; prp = platelet rich plasma. 351archivio italiano di urologia e andrologia 2021; 93, 3 peyronie’s disease sia survey 142 (0.7%). with respect to the practice of "not treating" pd patients, in their 2015 survey of urologists belonging to the american urology association (aua), sullivan et al. found that 26% of specialists believed pd to be a condition that does not warrant any treatment, while 59% of urologists decided to initiate medical treatment, and 38% of urologists thought an initial period of observation was necessary before deciding on any treatment (52). a pd survey by hauck et al. (2005) found that 62% of german urologists preferred medical treatment, while 26.9% preferred surgical treatment, and only 6.8% did not consider any treatment warranted (49). when comparing the treatment approaches found by our survey with the treatment practice patterns of foreign colleagues, we obtained the following results. a recent us pd survey (oberlin et al., 2016) found that 82% of urologists opted for intralesional injections, while in 18% of cases a surgical approach was preferred (53). a korean pd survey published in 2014 found that in the initial phase of the disease most urologists preferred oral therapy with the following agents: vitamin e (80.2%), phosphodiesterase-5 (pde-5) inhibitors (27.4%), potaba (20.1%), carnitine (16.7%), colchicine (11.7%), tamoxifen (10.4%), pentoxifylline (7.0%). however, 71.9% of korean urologists also used intralesional injections, while 41.8% preferred to start intralesional therapy only when oral therapy had failed (54). in their illinoisand wisconsin-based pd survey, larochelle & levine (2007) found that 81% of urologists recommended vitamin e for pd patients, the next most frequent therapeutic choice (35%) was treatment with potaba, and only 15%-20% of urologists preferred instead medical treatment with non-steroidal anti-inflammatory drugs (nsaids), colchicine, penile injections with steroids, interferon, verapamil, and topical verapamil (50). in their german survey, hauck et al. (2005) analyzed the practice patterns of urologists who preferred a conservative medical treatment and found that 57.8% of them used the table 2. replies to second questionnaire. questions answers % (number) 1) the prevalence of peyronie's disease: is < 1% 4.8% (4 out of 83) varies in the literature between 3.2% and 13% 67.4% (56 out of 83) varies in the literature between 1% and 3% 27.7% (23 out of 83) 2) peyronie's disease is very rare in patients under 40 years of age the statement is correct 57.8% (48 out of 83) the statement is wrong 42.1% (35 out of 83) 3) erectile dysfunction is associated with peyronie's disease… in about 30% of cases 50.6% (42 out of 83) in about 10%-20% of cases 26.5% (22 out of 83) in over 50% of cases 22.8% (19 out of 83) 4) pain is always present in peyronie's disease the statement is wrong 89.1% (74 out of 83) the statement is correct 10.8% (9 out of 83) 5) symptoms of depression are present in over 40% of patients with peyronie's disease the statement is correct 68.6% (57 out of 83) the statement is wrong 31.3% (26 out of 83) 6) in peyronie's disease, partial calcification of the plaque indicates with certainty the statement is wrong 81.9% (68 out of 83) that the disease has stabilized the statement is correct 18.07% (15 out of 83) 7) can peyronie's disease be treated? yes, but treatment must be adapted to disease stage 87.9% (73 out of 83) there is no treatment 8.4% (7 out of 83) the disease resolves spontaneously in most cases 3.6% (3 out of 83) 8) when is surgical treatment preferable? after at least 6-12 months since the plaque has stopped growing and/or when curvature is so severe as to prevent intercourse 98.7% (82 out of 83) never 1.2% (1 out of 83) in all cases 0% (0 out of 83) 9) when is corporoplasty indicated? when curvature is so severe as to prevent intercourse and penile pain is absent 87.9% (73 out of 83) when curvature is severe 9.6% (8 out of 83) when the patient desires it 2.4% (2 out of 83) 10) what surgical option is the most indicated in stable peyronie's disease associated corporoplasty with or without grafting 50.6% (42 out of 83) with severe curvature without erectile dysfunction? plaque excision + corporoplasty with grafting 44.5% (37 out of 83) penile implant 4.8% (4 out of 83) 11) in your opinion, which of the following is the most valid etiology hypothesis the disease arises in genetically predisposed individuals after penile injury (low-grade or major trauma) 80.7% (67 out of 83) idiopathic 13.2% (11 out of 83) autoimmune hypothesis 6.02% (5 out of 83) 12) your medical training: urology specialty 72.2% (60 out of 83) andrology specialty 13.2% (11 out of 83) urology specialty + andrology specialty 8.4% (7 out of 83) endocrinology specialty + andrology specialty 2.4% (2 out of 83) urology resident 3.6% (3 out of 83) 13) main field of clinical practice urology and andrology in equal measure 38.5% (32 out of 83) prevalent andrology practice 27.7% (23 out of 83) prevalent urology practice 25.3% (21 out of 83) general urology 8.4% (7 out of 83) 14) number of patients with peyronie's disease seen each month < 5 39.7% (33 out of 83) between 5 and 10 44.5% (37 out of 83) 10 or more 15.6% (13 out of 83) 15) level of experience and years in practice < 5 years 18.3% (15 out of 83) between 5 and 10 years 18.3% (15 out of 83) between 10 and 20 years 16.9% (14 out of 83) > 20 years 46.9% (39 out of 83) archivio italiano di urologia e andrologia 2021; 93, 3 g. paulis, f. pisano, a. palmieri, t. cai, f. palumbo, b. giammusso 352 following oral agents (in decreasing order of preference): potaba, vitamin e, tamoxifen, colchicine. among urologists who opted for medical treatment, 13.83% used injection therapy with the following agents (in decreasing order of preference): corticosteroids, verapamil, superoxide-dismutase (sod). among urologists opting for conservative medical treatment, 28.37% preferred physical treatment with the following methods (in decreasing order of preference): eswt, radiation therapy, iontophoresis (49). sullivan et al. (2015), in their pd survey of members of the american urology association, found that physicians who had decided to treat their patients conservatively favored the following therapies (in decreasing order of preference): oral therapy (81%) with vitamin e, colchicine, potaba; intralesional injection therapy (9%) with verapamil, corticosteroids, interferon (52). in our survey of sia members, a broad majority of physicians judged therapeutic failure to occur when the initial conservative therapy gave no results after 6-12 months (73.23/104 out of 142); additionally, most uro-andrologists (64.78%/92 out of 142), when failure of conservative treatment had been established, considered surgical treatment necessary, specifically corporoplasty, which may be associated with other techniques (grafting, plaque excision/incision, penile implant). comparing our survey to other surveys in the literature, we found no comparable questions on the time after which medical therapy is seen as having failed. whereas with respect to the therapeutic approach taken when conservative treatment has failed, in other surveys we found that 67.6% of korean urologists decided surgical treatment was indicated, specifically corporoplasty (84.1%/190 out of 226), plaque excision/incision + grafting (42.9%/97 out of 226), or prosthesis implant (14.2%/32 out of 226) (54). in our second questionnaire, in response to the question about the prevalence of pd, most sia respondents (67.4%) answered that prevalence of the disease varies between 3.2% and 13%, and this matches the data in the literature (12, 55, 56). we found the same question regarding disease prevalence in the us survey by larochelle & levine (2007) which established that 41% of interviewed urologists believed pd occurs in less than 1% of men (50). the pd survey by sullivan et al. (2015) found that 21% of urologists believed the prevalence of pd to be less than 1%, while 5% believe the prevalence to be over 10% (52). our second questionnaire also asked whether pd is very rare in patients under 40 years of age; 57.8% of sia respondents believes pd is very rare in this age group, while the remaining respondents believe this is false. we only found a similar question in the u.s. survey by larochelle & levine (2007) which reported that only 9% of responding urologists believe pd cannot present in men under 40 years of age (50). the literature on this topic informs us that pd is all but rare in patients under 40; as a matter of fact, a number of articles report a 10.8%-16.9% incidence in this age group (20, 21). a more recent article by stuntz et al. (2016) should be mentioned, in which a study of a large sample of us population found that the mean age of pd patients has decreased and is now 48.9 years, and prevalence of the disease in the 18-to-34-year age range is as high as 29.76% (57). the answers to our survey in response to the question about whether ed is present in pd showed that most sia members (50.6%) believe ed is associated with pd in about 30% of cases, and this matches the data in the literature (58-60). a similar question in the larochelle & levine pd survey revealed that 37% of responding urologists did not believe there is a close association between pd and ed (50). in answer to the same question, in the pd survey by sullivan et al. (2015), 40% of urologists stated that ed is present in pd in less than 30% of cases (52). in the korean pd survey, on the other hand, only 2.1% of korean urologists found ed in patients with pd (54). the international literature on ed in patients with pd reports that ed is present in a proportion that varies between 31.5% and 60.1% (3, 17, 29, 40, 58, 59). analyzing the question in our survey on the presence of pain in pd, 89.15% of sia members believes pain is not always present in pd. in the korean survey, 13.5% of korean urologists found erection to be painful in patients with pd (54). in the international literature, incidence of pain in pd varies between 20% and 70% (1, 17, 60). in response to our survey question on the presence of symptoms of depression in pd, most sia members (68.6%) answered that symptoms of depression are present in pd patients in over 40% of cases. in response to a similar question in the pd survey by sullivan et al. (2015) most respondents (75%) stated that a diagnosis of depression can be made in less than 25% of pd patients (52). in the literature, the prevalence of psychological problems in pd patients is very high, ranging from 62.4% to 81% of cases (30, 59, 61, 62). an interesting study published by nelson (2008) on the same topic detected a 48% prevalence of clinically significant depression in patients suffering from pd (63). with respect to our survey question on partial calcification of plaque and its clinical significance in terms of disease state, most sia uro-andrologists (81.96%) believes this situation does not necessarily correspond to disease stabilization. the above-mentioned pd surveys had no similar questions. however, an interesting article by levine et al. (2013) dealt with this topic in depth, postulating that plaque calcification does not appear to be an indicator of mature, stabilized disease, as in their study the authors detected that in 54.2% of patients with plaque calcification, symptoms had arisen less than 6-12 months earlier (64). when asked whether it is possible to treat pd, 87.9% of sia uro-andrologists answered affirmatively, specifying that treatment must be adapted to disease stage. a more detailed account of the type of practice patterns has already been given with regard to treatment-specific questions. when asked in what cases surgical therapy is preferable, 98.7% of sia members answered that a surgical approach is indicated in the stable stage of the disease, when the plaque has stopped growing at least 6-12 months before and/or penile deformity already makes sexual intercourse impossible. this choice of surgery in case of stable disease or severe curvature is widely supported in the literature and by international urology guidelines (28, 30, 38, 40, 41, 47, 48, 65-69). with respect to the question on the correct indication for the performance of corporoplasty, 87.9% of sia uroandrologists answered they believed this type of surgery to 353archivio italiano di urologia e andrologia 2021; 93, 3 peyronie’s disease sia survey be indicated in patients with severe penile curvature and in the absence of penile pain, a sign of disease stabilization. there is broad consensus in the field of urology on this approach, as well (28, 30, 38, 40, 41, 47, 48, 65-69). with respect to the correct surgical indication in stable pd associated with severe curvature and in the absence of ed, 50.6% of sia members answered that they opt for corporoplasty, reflecting – even in this case – the most frequent approach in the international literature. in answer to the question on their opinion on which of the most frequent etiology hypotheses for pd is more likely valid, 80.7% of sia uro-andrologists believes pd onset occurs in genetically predisposed subjects and following penile injury (low-grade or major trauma). the remaining specialists believe the more likely etiology is autoimmune (6%) or idiopathic (13.2%). even in this case, the majority opinion (80.7%) in our survey is supported by several studies (4-7, 13-16, 70-73). our questionnaire also included a question on the specialist training of the physicians who participated in the survey. the answers yielded the following data: urology specialty in 72.2% of cases; andrology specialty in 13.2% of cases; urology specialty + andrology specialty in 8.4% of cases; endocrinology specialty + andrology specialty in 2.4% of cases; urology residents were 3.6%. it must be borne in mind, however, that this result reflects the training of sia members who participated in the survey and is very likely not identical with the training of all sia practitioners. the specific question on what clinical field respondent mainly practiced was answered as follows: urology and andrology in equal measure in 38.5% of cases; prevalent andrology practice in 27.7% of cases; prevalent urology practice in 25.3% of cases: general urology practice in 8.4% of cases. with respect to the number of patients suffering from pd who are seen each month by sia physicians, the result was the following: between 5 and 10 patients per month in 44.5% of cases; fewer than 5 patients per month in 39.7% of cases; 10 or more patients per month in 15.6% of cases. with respect to their experience and years in practice, sia members answered as follows: over 20 years in 46.9% of cases; between 5 and 10 years in 18.3% of cases; between 10 and 20 years in 16.9% of cases; less than 5 years in 18.3% of cases. we were able to find a few data to compare the training, prevalent clinical practice, and level of experience of the physicians who participated in our survey with those of respondents of other pd surveys. in the pd survey carried out by sullivan et al. (2015) among members of the american urology association, 75% of respondents described their practice as general urology; over half of respondents reported an interest in sexual medicine, 40% of respondents considered themselves as specialists in sexual medicine (52). in the pdsurvey by oberlin et al. (2016), only 5.3% of responding urologists also had a subspecialty in andrology (53). in the pd survey by shindel et al. (2008), out of the total number of urology specialists, 8.8% had received specific training in andrology (51). in the korean survey, the median duration of practice since completing specialty training was 12 years (range, 0-41 years); 59% of urologists had a clinical experience of over 10 years; 66% of respondents had seen fewer than five pd patients per year, while 16.6% of urologists managed more than 10 pd patients per year (54). conclusions the results of our survey indicate that italian sia uroandrologists, compared to their foreign counterparts, have a more proactive diagnostic approach right from when pd patients first present. furthermore, a preference for conservative medical treatment appears evident in our survey when pd is still in its active stage, at initial presentation, and in most cases; conservative treatment consists in oral therapy, which may be associated with physical treatment and injections. in advanced disease or in case of failure of the initial conservative treatment, our survey instead shows a greater preference for a surgical approach (corporoplasty with or without grafting, associated with prosthesis implant in case of associated ed). with regards to theoretical knowledge, the answers to our survey showed that italian sia physicians have in-depth knowledge of the etiology of the disease, its epidemiology, as well as its clinical presentation and correct therapeutic indications. from the point of view of medical training, our survey found that 96.3% of sia respondents is a specialist in urology or a specialist in andrology, while 10.8% specialized in two fields (urology, andrology, or endocrinology). furthermore, 63.8% of italian sia physicians who participated in our survey reported having between 10 and over 20 years of experience in clinical practice. collaborators (uro-andrologists who participated in the survey): andriani egidio, angelozzi giovanni, artegiani antonio, azzarito giuseppina, barletta davide, barrese francesco, belgrano emanuele, benvenuto sara, bianchi bruno, bierti sergio, bitelli marco, bizzotto leonardo, boeri luca, bottone francesco, branchina antonino, buono girolamo, caraceni enrico, casarico antonio, cassutti valter, castiglioni mirco, certo marco, chiancone francesco, cocci andrea, colombo fulvio, cornacchia michele, corretti giorgio, corvasce antonio, d'elia carolina, de grande gaetano, de luca francesco, de pasquale filippo, de santis claudio, de stefano lorenzo, dehó federico, della camera pier andrea, delle rose augusto, di domenico dante, di filippo aldo, di franco carmelo agostino, di gregorio leonardo, di palma paolo, di trapani danilo, fabiani andrea, fiordelise stefano, fiorillo alessandro, forte saverio, giammusso bruno, giovannone riccardo, godano adriana, granata antonio maria, guerani attilio, guttilla andrea, iannotta luca, irianni gabriele, izzo alessandro, la pera giuseppe, lacava gregorio, larocca lorenzo, laruccia nicola, lauretti stefano, letizia piero, liguori giovanni, littara alessandro, mahlknecht alois, malvestiti gianmario, manica michele, manno giuseppe, maruccia serena, mastrocinque giuseppe, mavilla luca, mazziotti raffaele, mercenaro maurizio, michetti paolo maria, milioto vincenzo, militello andrea, mondaini nicola, montalcini gino, morrone giancarlo, motta maurizio, natali alessandro, negro carlo, olivieri valerio, palumbo fabrizio, archivio italiano di urologia e andrologia 2021; 93, 3 g. paulis, f. pisano, a. palmieri, t. cai, f. palumbo, b. giammusso 354 paolini riccardo, papini alessandro, passavanti giandomenico, paulis gianni, pavan nicola, pavone carlo, pescatori edoardo, pezzoni fabio, piubello giorgio, polito chiara, polito massimo, principi emanuele, ragni francesca, raimoldi annibale, ressa gaetano, risi oreste, rizzo giorgio, rolle luigi, ruoppolo michele, russino giovanni, russo giorgio, saccomanni mauro, salacone pietro, salhi jamal, salvia giuseppe, sarto giuseppe, savino antonio, scalvini tiziano, scroppo fabrizio, soli marcello, sorrentino michelangelo, speroni alberto, tiscione daniele, titta matteo, tripodi vincenzo, turchi paolo, ughi gianni, vagnoni valerio, vecchio daniele, vedovo francesca, vella riccardo. references 1. pryor jp, ralph dj. clinical presentations of peyronie’s disease. int j impot res. 2002; 14:414-417. 2. nelson cj, diblasio c, kendirci m, et al. the chronology of depression and distress in men with peyronie’s disease. j sex med. 2008; 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93:107-110. 43. asali, m. intralesional injection of the calcium channel blocker verapamil in peyronie's disease: a critical review. arch ital urol androl. 2020; 92:253. 44. de rose af, ambrosini f, mantica g, et al. prepuce-sparing corporoplasty as a safe alternative for patients with acquired penile curvature. arch ital urol androl. 2020; 92:182. 45. hatzimouratidis k, eardley i, giuliano f, et al. eau guidelines on penile curvature. eur urol 2012; 62:543-552. 46. nehra a, alterowitz r, culkin dj, et al. peyronie’s disease: aua guideline. j urol. 2015; 194:745-753. 47. chung e, ralph d, kagioglu a, et al. evidence-based management guidelines on peyronie's disease. j sex med. 2016; 13:905-923. 48. bella aj, lee jc, grober ed, et al. canadian urological association guideline for peyronie's disease and congenital penile curvature. can urol assoc j. 2018; 12:e197-e209. 49. hauck ew, bschleipfer t, haag sm, et al. assessment among german urologists of various conservative treatment modalities for peyronie's disease. results of a survey. urologe a. 2005; 44:11891196. 50. larochelle jc, levine la. a survey of primary-care physicians and urologists regarding peyronie's disease. j sex med. 2007; 4:1167-1173. 51. shindel aw, bullock tl, brandes s. urologist practice patterns in the management of peyronie's disease: a nationwide survey. j sex med. 2008; 5:954-964. 52. sullivan j, moskovic d, nelson c, et al. peyronie's disease: urologist's knowledge base and practice patterns. andrology 2015; 3:260264. 53. oberlin dt, liu js, hofer md, et al. an analysis of case logs from american urologists in the treatment of peyronie's disease. urology. 2016; 87:205-209. 54. ko yh, moon kh, lee sw, et al. urologists' perceptions and practice patterns in peyronie's disease: a korean nationwide survey including patient satisfaction. korean j urol. 2014; 55:57-63. 55. dibenedetti db, nguyen d, zografos l, et al. a population-based study of peyronie's disease: prevalence and treatment patterns in the united states. adv urol. 2011; 2011:9. 56. stuntz m, perlaky a, des vignes f, et al. the prevalence of peyronie's disease in the united states: a population-based study. plos one. 2016; 11:e0150157. 57. weidner w, schroeder-printzen i, weiske wh, sexual dysfunction in peyronie's disease: an analysis of 222 patients without previous local plaque therapy. j urol. 1997: 157:325-328. 58. kadioglu a, sanli o, akman t, et al. factors affecting the degree of penile deformity in peyronie disease: an analysis of 1001 patients. j androl. 2011; 32:502-508. 59. paulis g, romano g, paulis, a. prevalence, psychological impact, and risk factors of erectile dysfunction in patients with peyronie’s disease: a retrospective analysis of 309 cases. res rep urol. 2016; 8:95103. 60. paulis g, cavallini g. clinical evaluation of natural history of peyronie’s disease: our experience, old myths and new certainties. inflamm allergy drug targets. 2013; 12:341-348. 61. smith jf, walsh tj, conti sl, et al. risk factors for emotional and relationship problems in peyronie’s disease. j sex med. 2008; 5:21792184. 62. gelbard mk, dorey f, james k. the natural history of peyronie’s disease. j urol. 1990;144:1376-1379. 63. nelson cj, diblasio c, kendirci m, et al. the chronology of depression and distress in men with peyronie’s disease. j sex med. 2008; 5:1985-1990. 64. levine l, rybak j, corder c, et al. peyronie's disease plaque calcification-prevalence, time to identification, and development of a new grading classification. j sex med. 2013; 10:3121-3128. 65. kadioglu a, akman t, sanli o, et al. surgical treatment of peyronie’s disease: a critical analysis. eur urol. 2006; 50:235-248. 66. kendirci m, hellstrom wj. critical analysis of surgery for peyronie's disease. curr opin urol. 2004; 14:381-388. 67. jalkut m, gonzalez-cadavid n, rajfer j. peyronie’s disease: a review. rev. urol. 2003; 5:142-148. 68. hellstrom wj, bivalacqua tj. peyronie’s disease: etiology, medical, and surgical therapy. j androl. 2000; 21:347-354. 69. levine la, burnett al. standard operating procedures for peyronie's disease. j sex med. 2013; 10:230-244. 70. dolmans gh, werker pm, de jong ij, et al. wnt2 locus is involved in genetic susceptibility of peyronie's disease. j sex med. 2012; 9:1430-1434. 71. sharma kl, alom m, trost l. the etiology of peyronie’s disease: pathogenesis and genetic contributions. sex med rev. 2020; 8:314323. 72. gonzalez-cadavid nf. mechanisms of penile fibrosis. j sex med. 2009; 6(suppl. 3):353-362. 73. chung e, de young l, brock gb. rat as an animal model for peyronie’s disease research: a review of current methods and the peerreviewed literature. int j impot res. 2011; 23:235-241. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo medical team, rome (italy) francesca pisano, md francescapisano85@gmail.com department of urology, fundacio puigvert, autonomous university of barcelona (spain) alessandro palmieri, md info@alessandropalmieri.it department of neurosciences, reproductive sciences and odontostomatology, university of naples federico ii, naples (italy) tommaso cai, md ktommy@libero.it department of urology, santa chiara regional hospital, trento (italy) fabrizio palumbo, md palumbo.fab@gmail.com department of urology, di venere hospital, bari (italy) bruno giammusso, md bgiammusso@hotmail.it urology clinic, policlinic “morgagni”, catania (italy) stesura seveso 253archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.253 intralesional injection of the calcium channel blocker verapamil in peyronie's disease: a critical review murad asali 1, muhammad asali 2 1 assuta medical center, ben gurion university of the negev, beer sheva, israel; 2 international school of economics, tbilisi, georgia; iza, bonn, germany; and school of international and public affairs, columbia university, new york. objective: to assess the effectiveness of an intralesional injection of verapamil in men with peyronie’s disease (pd). materials and methods: the data provided in the current review are based on a thorough review of the available original articles on pd retrieved with a systematic literature search using pubmedmedline, and the cochrane central register of controlled trials, up to december 2019, to identify studies dealing with peyronie’s disease and its treatment. included were only original articles, that we thoroughly evaluated. we searched for the primary and secondary terms of: “peyronie’s disease,” “penile curvature,” “erectile dysfunction,” “verapamil and peyronie’s disease,” “calcium channel blocker,” and “intralesional injection.” results: the initial search of the databases yielded a total of 1240 studies (pubmed: 1058; cochrane: 182), as of december 2019. seventy studies were removed due to duplication. further 986 studies were removed due to not being in english (except for one study by arena f. for which we got a translation form italian), being about animal experimentations, not being full-text, and not being clinical trials. likewise, studies not referring at all to verapamil were excluded (148). from the remaining 36 full-text articles we focused on 13 studies which met the inclusion criteria, mainly being deemed relevant to the context of this study. conclusions: calcium channel blockers have been shown in both in vitro and in vivo studies to inhibit the synthesis and secretion of extracellular matrix molecules, as well as to increase collagenase activity. patients with localised plaque are the best candidates for intralesional injections of verapamil. the beneficial effects of intralesional verapamil are apparent within the first three months. for patients who respond to treatment, the injections should be continued for six months. patients who fail to respond to intralesional verapamil or whose angulation is greater than 30° at presentation should be considered candidates for surgery. injection of verapamil is clinically safe for patients with peyronie’s disease, and it appears to induce a rapid, beneficial effect in patients for the reduction of plaque size. intralesional verapamil injection for peyronie’s disease could reduce pain, decrease penile curvature, and improve sexual function. key words: peyronie’s disease, verapamil, calcium channel blocker, penile curvature, erectile dysfunction. submitted 2 march 2020; accepted 15 march 2020 summary introduction peyronie’s disease (pd) was described in the eighteenth century by de la peyronie as an induration of the male sexual organ’s tunica layers (1). the estimated rate of the disease is 3.2% to 8.9% (2, 3). although more than 260 years have elapsed since de la peyronie's description, the disease is not yet well understood. no perfect treatment is available, and many surgical and non-surgical approaches have been suggested and used in practice. illiams and thomas were the first to describe the natural course of the disease, and they claimed that all of the patients they followed maintained the same plaques, unchanged over time; therefore, they suggested that these patients should be followed and that there was no need for any treatment. when their data were examined later, however, it was found that there were not sufficient follow-up studies conducted and that the followup varied from patient to patient (4). gelbard et al. and, later, kadioglu et al. claimed that pd is a progressive disease in most cases and that only in a few cases is the disease ameliorated without treatment (5, 6). in a retrospective review of men with pd, at least one risk factor for systemic vascular disease was identified in 67.5% of patients, and hypercholesterolemia and diabetes were the most common. patients with at least one risk factor were at a significantly higher risk for severe penile deformity. their data showed that penile deformities were disabling (greater than 30°) in 62.5% of cases. risk factors, such as serum lipid abnormalities, diabetes, and hypertension, seemed to have a significant impact on the severity of symptoms and on outcomes (6). despite the lack of understanding of the aetiology and pathophysiology of the disease, there has been some success with non-surgical approaches, including with vitamin e (tocopherol) (7), colchicines (8), tamoxifen (9), and potaba (potassium paraaminobinzoate) (10); similarly, different intracavernosal injections have been suggested, including collagenase (11), steroids (12), orgotein (13), interferon alpha 2b (14), and verapamil (a calcium channel blocker) (15-18), and other nonsurgical treatments have been attempted, including radiation (19) and extra-corporeal shockwave therapy (20). it should be noted that vitamin e, colchicine, and tamoxifen can provide some benefit, but there have been no large placebo-controlled trials of these agents (7-9). materials and methods literature search we carried out a systematic search in pubmed and medline and the cochrane central register of controlled trials, up to december 2019, to identify studies dealing archivio italiano di urologia e andrologia 2020; 92, 3 m. asali, m. asali 254 with peyronie’s disease and its treatment. included were only original articles, that we thoroughly evaluated. we searched for the primary and secondary terms of: “peyronie’s disease”, “penile curvature”, “erectile dysfunction”, “verapamil and peyronie’s disease”, “calcium channel blocker” and “intralesional injection”. studies selection and evaluation only results from original studies were included. the search further imposed the restrictions that: the articles being in english; the studies being performed on humans; that they exist as full-text studies; including clinical trials; referring to verapamil and focused on the figure 1. prisma flow diagram. figure 2. risk of bias analysis treatment of this condition. further, studies which were deemed irrelevant or repetitive were excluded. we used the revised quality assessment of diagnostic accuracy studies (quadas-2) tool to assess the risk of bias (rob) of the reviewed studies. results the initial search of the databases yielded a total of 1240 studies (pubmed: 1058; cochrane: 182), as of december 2019. seventy studies were removed due to duplication. further 986 studies were removed due to not being in english (except for one study by arena f. for which we got a translation form italian), being about animal experimentations, not being full-text, and not being clinical trials. likewise, studies not referring at all to verapamil were excluded (148). from the remaining 36 full-text articles we focused on 13 studies which met the inclusion criteria, mainly being deemed relevant to the context of this study. figure 1 presents a prisma flow diagram of the studies’ search and selection. figure 2 reports the rob assessment for each of the individual studies, according to the quadas-2 tool. the distribution of rob (low risk, unclear risk, high risk) is also outlined in figure 2 across the four different domains of risk (patient selection, index test, reference standard, and flow and timing). discussion technique the physician should perform local anaesthesia using a penile block technique with 10 ml bupivacaine 0.5%, should feel and locate the patient’s penis plaque and should hold it between two fingers. at one entrance of the skin, the needle should then be passed into and out of the plaque. to prevent haematoma, the patient is asked to compress the penis over the puncture site. the standard dosage is 10 mg of verapamil diluted in 10 ml of 0.9% saline, while the solution is distributed into the plaque using a 25-gauge needle. it should be noted that levine et al. were the first authors to report that 10 mg verapamil resulted in the best overall response with no toxicity (16). the patient is asked to avoid sex for the 24 hours following each treatment (15, 16). blood pressure and heart rate should be monitored throughout the procedure for the first 3 months and may be discontinued later. to prevent incidental injury to the dorsal nerve fibres or dorsal arteries, the needle should be inserted into the dorsolateral or lateral side, depending on the location of the plaque. precaution should be taken not to inject the drug into the corpus cavernosum. slight, gentle pressure on the syringe is required for injection into the tunica albuginea, whereas injection into the corpus cavernosum does not require pressure (17). treatment is recommended once every two weeks; once-a-week treatment can lead to inflammatory reactions (16). the recommended duration of treatment is six months, but if no response is achieved in three months, additional verapamil injections are not recommended (15). background, analysis, and findings the use of the calcium channel blocker verapamil began in the 1980s and has continued into the twentieth century because of its influence on the production of fibroblasts in the extracellular matrix. kelly showed that exocytosis in the extracellular matrix, including of collagen, fibronectin, and glycosaminoglycan, is calcium iondependent (21). askey et al. showed that verapamil inhibits fibroblast secretion (22). experiments on animals have shown that verapamil decreases peritoneal adhesions (23). other work has shown that verapamil has an effect on the expression of collagen by its excessive activity and that it actually changes the collagenase activity and extracellular matrix structure changes caused by burns (24). anderson et al. investigated the influence of verapamil on fibroblasts derived from excised peyronie’s plaques in a laboratory model, and they found that verapamil had the greatest effect on cell proliferation, compared to other agents, including colchicine, interferon alpha -2b, and prostaglandin e-1 (25). an intracellular balance of ingredients is important so that the production and destruction of fibroblasts play an important role in healing and creating a scar, and the importance of calcium blockers lies in their effect on different levels on fibroblast activity, including production, excretion, and destruction. therefore, calcium blocker therapy could slow, stop, or even reverse the progression of pd. in 1994, levine et al. published a series of the first cases with injections of verapamil into plaques in cases of pd. of the cases reported in this series, there was a decrease in pain in 91%, an improvement in the curvature of the penis in 42%, and an improvement in erectile dysfunction in 58%. the injections were given every other week for six months at a dose of 10 mg per treatment (16). a year later, another series showed once again 255archivio italiano di urologia e andrologia 2020; 92, 3 verapamil in peyronie’s disease table 1. modality and results of treatment of peyronie's disease with verapamil. reference no` dose (mg) treatments per week/ i/t/e % pain % curvature sexual function length of treatment (weeks) resolved improvement improvement % di stasi sm, et al. (12) 47 5 + 8 mg dex. 4/6 t+e yes 57 51% regained erectile activity levine la 1997 (15) 38 10 2/24 i 97 76 72% improvement in sexual function levine la 1994 (16) 14 10 2/24 i n/a 42 83% plaquerelated changes in erectile function rehman j (17) 7 10-27 1/24 i 100 29 43% quality of erection arena f (26) 39 10 2/24 i 90.9 50 23.1% rigidity improvement greenfield jm, et al. (29) 23 10 2/12 e n/a 65 66% erectile function satisfaction “no`” is the number of patients treated with verapamil and completed the study; “i” stands for injection; “t” for transdermal; “e” for electromotive drug administration; and “dex.” for dexamethasone. archivio italiano di urologia e andrologia 2020; 92, 3 m. asali, m. asali 256 an improvement in penile curvature as a result of a verapamil injection once every other week for six months, but the improvement was not obvious in cases in which the duration of illness was more than one year (26). teloken, however, showed that there was no difference between steroids and verapamil injections but emphasised that the injections were near, and not into, the plaques (27). in 1998, rehman et al. published their study, which was the first prospective, randomised study of pd. in that study, verapamil injections were administered into the plaques weekly for six months. according to their results, there was improvement in penile curvature but without statistical significance. erectile dysfunction improved, penile girth increased, and there was a decrease in plaque volume. the authors concluded that the best results were observed in cases with penile curvature of less than 30 degrees (17). levine (1997), studying 46 cases that had been treated with injections of verapamil into the plaques, given every two weeks for six months, found that pain lessened in 97% of the cases, curvature improved in 54% of the cases, and erectile dysfunction improved in 72% of the cases (15). a study of a series of 156 cases with pd showed an improvement in penile curvature in 60% of the cases, an increase in penile girth in 83% of the cases, an improvement in rigidity distal to the plaque in 80% of the cases, and improvement in erectile dysfunction in 71% of the cases (18). other researchers, due to pain at the injection sites and the fears of the patients, have used local verapamil as a gel (28); because of problems with absorption, however, they applied verapamil gel to the penile skin and simultaneously used a local electric current. in a double-blind, prospective study with a control group (table 1), comparing verapamil to saline in two groups receiving electrical stimulation to improve the results, there was an improvement in penile curvature but no significant difference between the groups. the authors concluded that verapamil gel treatment with electric stimulation is a therapeutic option for patients with mild penile curvature who do not want to receive injections (29). in another prospective study (table 1) assessing verapamil and steroid injections, using electrical stimulation at the same time, to improve penetration of the drug into the tunica, compared with lidocaine and electrical stimulation as a control, there was improvement in penile curvature and a decrease in plaque volumes (12). as mentioned before, the studies that examined potaba, vitamin e, colchicine, tamoxifen, and acetyl-l carnitine failed to show consistent beneficial effects on pd, with the exception of potaba, which may obtain a decrease of plaque size and curvature. it may be better to use intralesional injection therapy for pd as a first-line therapy, along with oral medication (30). abern et al. used a combination of penile traction, intralesional verapamil, and oral therapies for pd, showed that there was a trend toward measured curvature improvement and a significant gain in stretched penile length. this combination could be an acceptable nonsurgical treatment for pd (31). a recent study using penile traction therapy with the new device penimaster pro in a group of patients with stable pd, achieved good results including reduction in curvature, increased stretched penile length, and improvement in international index of erectile function (iief-ef) score with minimal side effects (32). penile stretching as a treatment for pd was reviewed by cowper et al. who concluded that penile stretching is an effective therapy for pd (33). rice et al. reviewed twelve studies with 1025 patients using plaque incision and grafting (pig). they concluded that pig is indicated for men with complex or severe penile curvature and, despite a multitude of incision types and grafting materials having been used, no individual technique has proven superiority (34). barbosa et al. concluded that there is no consensus on which surgical technique achieves better results or fewer complications; therefore, the decision on which technique to use is a matter of surgeon preference. studies comparing distinctive techniques and either opening or not opening the tunica albuginea should be performed to support surgical decision making (35). in a survey, which represents one of the largest studies on the management of pd, members of the european society of sexual medicine and of various andrology and urology societies across europe, with the majority (78%) being urologists, were contacted via email and newsletters and asked to fill in an online questionnaire. the survey comprised 56 items developed by an expert consensus of the educational committee of the european society of sexual medicine. in the end, 401 participants responded to the entire survey. primary treatment options were oral (65%), counseling (57%), and topical/local therapy (30%). among oral drug users, tadalafil 5 mg was the most commonly used (57%), followed by vitamin e (40%). regarding intralesional therapy, collagenase clostridium histolyticum was the leading drug (34%), followed by calcium channel blockers (17%). considering surgical procedures, the original nesbit technique was the preferred procedure (33%). the conclusion in the study was that one third of experts and two thirds of patients were dissatisfied with the currently available pd treatment options (36). vactosertib, a novel, orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaques in a rat model of pd. vactosertib induced significant regression of fibrotic plaques in pd rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-smad2, which recovered erectile function. vactosertib also abrogated tgf-b1-induced enhancement of extracellular matrix protein production and hydroxyproline content in pd fibroblasts in vitro by hindering the tgf-b1-induced smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast trans-differentiation. in view of the critical role of tgf-b and the smad pathway in the pathogenesis of pd, inhibition of this pathway with an alk5 inhibitor may represent a novel, targeted therapy for pd (37). dosage and complications the therapeutic level for cardiac arrhythmia or hypertension using a calcium channel blocker is between 0.01 and 0.2 micromoles; in contrast, the therapeutic level needed to affect collagen synthesis is 100 micromoles, so to affect collagen synthesis and avoid toxic levels in serum, there is a need in pd to inject the material into 257archivio italiano di urologia e andrologia 2020; 92, 3 verapamil in peyronie’s disease the plaques (38). levine and goldman, in their 156-case series, reported overall complications in six cases (4%), nausea in three cases, and transient headaches, without any changes in blood pressure and without any cases of cardiac arrhythmia. three cases noted pain for less than a week. in most cases, there was local ecchymosis with no clinical significance, and no treatment was needed. there were no cardiovascular events (18). additionally, in rehman et al.’s series, in which the patients received a weekly intralesional injection, there were no long-term complications, neither local nor systemic, although there was some ecchymosis that disappeared a short time later (17). conclusions peyronie’s disease can occur with different combinations of pain and curvature, depending on the levels of plaque in the tunica albuginea or in the dorsal side of the penis, and with erectile dysfunction. the treatment approach is still non-surgical during the first year of the disease. treatments include common agents, including vitamin e and potaba, or drug injections into the tunica layers. treatments with steroids or orgotein are not recommended because there are no prospective studies with control groups. verapamil treatment has been presented in prospective randomised study with a control group. verapamil injection into plaques in pd can affect the activity of fibroblasts on several levels, including the proliferation, synthesis, and secretion of proteins in the extracellular space. it also affects collagen breakdown. these changes can slow, stop, or even reverse the progression of the disease. many studies investigating pd and the use of intralesional verapamil injections have shown decreased pain, improvement in penile curvature, improvement in erectile dysfunction, increased penile girth, and postponement of surgery. in cases that were treated with verapamil injections and that were submitted to surgery later, the use of verapamil injections did not compromise the surgical results. treatment with oral medications has shown negligible improvement of the disease. treatment with injections into the plaques with verapamil, collagenase or interferon have shown good results, and these injections are considered first-line treatments. for a better understanding of the pathophysiology of the disease, there is a need for more extensive studies on the subject. it may be that the preferred future treatment lies in a combination of drugs. patients with localised plaque are the best candidates for intralesional injections of verapamil. the beneficial effects of intralesional verapamil are apparent within the first three months. for patients who respond to treatment, the injections should be continued for six months. patients who fail to respond to intralesional verapamil or whose angulation is greater than 30° at presentation should be considered candidates for surgery. injection of verapamil is clinically safe for patients with peyronie’s disease, and it appears to induce a rapid, beneficial effect in patients for the reduction of plaque size. intralesional verapamil injection for peyronie’s disease could reduce pain, decrease penile curvature, and improve sexual function. references 1. de la peyronie f. sur quelques obstacles qui s’opposent al’ejaculation naturelle de la semence. mem de l’acad roy de chir. 1743; 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[epub ahead of print] 38. lee rc, ping ja. calcium antagonists retard extracellular matrix production in connective tissue equivalent. j surg res. 1990; 49:463-466. correspondence murad asali, md (corresponding author) muradasali@hotmail.com assuta medical center, ben gurion university of the negev sokolov 26/99, beer sheva 8430905 (israel) muhammad asali international school of economics, tbilisi (georgia; iza, bonn (germany); and school of international and public affairs, columbia university, new york (united states) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper established, yet the majority will not be diagnosed with urological cancer and the cause will be attributed to transient benign physiological conditions, including uti, ul or bpe. the extent of investigation and timing of this investigation in not well defined. taking in consideration the finitude of available resources, it would be important to prioritize the patients with more risk of suffering from urological cancer, to quickly diagnose, evaluate and treat. there are known risks factors to urological cancer, such as smoking history, exposure to occupational chemical and dyes or pelvic radiation, but there is no algorithm available that allow the physicians to estimate an approximate risk of bladder malignancy. with our study we intend to help physicians assessing the likelihood of urologic malignancy based in general clinic, laboratory, and image data. the aim of the study was to identify predictive factors of bladder cancer among patients presenting with hematuria. patients and methods patients eligible for this study were referred to urology appointment by the general practitioner (gp) or from de emergency department because of hematuria, between january 1, 2017 and december 31, 2019. patients otherwise asymptomatic who were referred due to incidental imaging findings suspicious of bladder cancer or upper tract urothelial carcinoma were excluded. all patients had cystoscopy and upper tract imaging. main outcome of interest was bladder cancer diagnosis, defined as presence of urothelial carcinoma in pathological study after transurethral bladder resection (turb) according to tnm whow tumor classification and european association of urology risk classification. variables such as demographics, imaging and clinical factors were evaluated (including age, gender, smoker status, anticoagulation or antiaggregating drug use, previous pelvic irradiation, number of hematuria episodes, presence of lower urinary tract symptoms (luts), urine culture positivity, back pain, history of urolithiasis, fever, ultrasound and cystoscopy results). the demographic and clinical features are shown in table 1. statistical analysis descriptive statistics were calculated for all patients introduction: the presence of blood in the urine should be promptly investigated to rule out urological malignancies, bladder cancer being the most frequent. given its frequency among general population and the lack of unlimited health resources in an era of cost-effectiveness, it is important to prioritize patients with higher risk of malignancy. objectives: to identify predictive factors of bladder cancer among patients presenting with hematuria. patients and methods: we retrospectively reviewed 296 cases referred to our department for hematuria. we evaluated different demographic, clinical and ultrasound features to uncover possible associations with diagnosis of bladder cancer in those patients, to estimate the individual risk of being diagnosed with bladder cancer during the investigation of hematuria. results: a total of 296 patients were studied for hematuria between january 1, 2017 and december 31, 2019, 23.6% of those having ultimately bladder cancer confirmed after transurethral resection. older age, male gender (or 2.727, p = 0.069), a history of smoking (or 3.84, p < 0.05), recurrent hematuria (or 3.396, p < 0.05) and positive ultrasound exam for bladder cancer (or 30.423, p < 0.05) were identified as predictors of bladder cancer in patients with hematuria. conclusions: this study suggests that it is possible to reliably estimate the risk of bladder cancer in patients with hematuria, using clinical and imaging data to help defining who should be investigated first and in whom the investigation could be postponed. key words: bladder cancer; hematuria; smoking; ultrasound; male gender. submitted 20 november 2022; accepted 22 november 2022 introduction hematuria is defined as presence of blood in urine. it can either be microscopic (only detected in urinalysis and with variable definition among regions) or macroscopic. hematuria is one of the most frequent causes of referral to emergency department or urology appointment. there are many etiologies, most being benign, like urinary tract infection (uti), benign prostatic enlargement (bpe) or urolithiasis (ul) but the existence of a subjacent urological cancer, most often bladder cancer, must be dismissed. the need to investigate almost all patients who present with macroscopic and microscopic hematuria is well predicting bladder cancer risk in patients with hematuria. a single-centre retrospective study roberto jarimba 1, 2, vasco quaresma 1, joão pedroso lima 1, 2, miguel eliseu 1, 2, edgar tavares da silva 1, 2, pedro moreira 1, arnaldo figueiredo 1, 2 1 urology and renal transplantation department, centro hospitalar e universitário de coimbra, coimbra, portugal; 2 faculty of medicine, university of coimbra, portugal. doi: 10.4081/aiua.2023.11026 summary archivio italiano di urologia e andrologia 2023; 95, 1 r. jarimba, v. quaresma, j. pedroso lima, m. eliseu, e. tavares da silva, p. moreira, a. figueiredo included in the present study. the crude association between each individual categorical covariate and bladder cancer diagnosis was accessed by chi-square and binary logistic regression. all analysis were conducted using ibm spss statistics version 26. all comparisons were made using 2-sided tests, with p < 0.05 considered statistically significant. results a total of 296 patients were studied for hematuria between january 1, 2017 and december 31, 2019. overall, 23.6% of those patients were diagnosed with bladder cancer after turb results. clinical and imaging predictors were found to be statistically significative. some are well known risk factors for bladder cancer: patients diagnosed with bladder cancer were older (73.74 vs 66.8 years, p < 0.05); men had roughly 2.5 times (or: 2.519, p < 0.05) more risk of being diagnosed with bladder cancer; patients ever exposed to tobacco had 3.8 times (or 3.852, p < 0.05) more risk of bladder cancer. the number of hematuria episodes and urine microbiology seem to have a predictive value for the diagnosis of bladder cancer, in univariate analysis. patients with multiple episodes of hematuria have a higher risk of being diagnosed with bladder cancer (or: 2.093, p < 0.05) vs patients with a single episode. an identification of bacteria in the urine microbiology was inversely correlated with bladder cancer diagnosis (or: 0.737, p < 0.05); a total of 29 patients had a positive urine culture, none of those were found to have bladder cancer. ultrasound evaluation had a sensitivity and specificity for bladder cancer of 71% and 87%, respectively. while there was a bladder cancer suspicion at ultrasound examination in 70% of the patients with subsequent diagnosis of bladder cancer, only 16% of patients diagnosed with bladder cancer had a normal ultrasound evaluation. those patients were older (or: 1.084, p = 0.011) and had more frequently a smoking history (or: 4.503, p = 0.048). the second most common finding in the ultrasound exam among patients diagnosed with bladder cancer was unilateral hydronephrosis, found in 6.6% of those patients. in the multivariate analysis, using a binary logistic regression, age, tobacco exposure, multiple episodes of hematuria and a positive ultrasound were found to be correlated with risk of bladder cancer. the calculated model showed an accuracy of 86.5%, with a sensitivity of 64.9% and a specificity of 93.1%. twelve (15.4%) out of 78 patients with suspected bladder cancer at cystoscopy had negative histology for bladder cancer after turb. among patients studied for microscopic hematuria (10.6% of the total), only 6% were diagnosed with bladder cancer. all patients with microscopic hematuria diagnosed with bladder cancer were male older than 40 years of age and had ultrasound positive for bladder. only 1.4% and 0.3% of the patients were diagnosed with upper tract urothelial carcinoma and renal cell carcinoma, respectively. among patients with a diagnosis other than bladder cancer, 25% had prostatic bleeding, 15.9% uti-related hematuria and 8.1% were diagnosed with urolithiasis. results are shown in table 2. table 1. demographic and clinical features of patients referred because of hematuria. total (n = 296) non-bc (n = 226) bc (n = 70) age (years) 68.45 ± 15.94 66.81 ± 15.92 73.74 ± 14.92 gender female 95 (32.1%) 84 (37.2%) 11 (15.7%) male 201 (67.9%) 142 (62.8%) 59 (84.3%) tobacco never user 225 (76%) 184 (81.8%) 41 (58.6%) ever user 48 (16.2%) 28 (12.4%) 20 (28.6%) not known 23 (7.8%) 14 (6.2%) 9 (12.9%) hematuria episodes > 1x 147 (49.7%) 103 (45.6%) 44 (62.9%) 1x 118 (39.9%) 98 (43.4%) 20 (28.6%) microscopic hematuria 31 (10.5%) 25 (11.1%) 6 (8.6%) urine culture negative 216 (73.2%) 161 (71.6%) 55 (78.6%) positive 29 (9.8%) 29 (12.9%) 0 (0%) not known 50 (16.9%) 35 (15.6%) 15 (21.4%) ultrasound normal 126 (42.9%) 115 (42.9%) 11 (15.9%) suspicious 76 (25.9%) 27 (12%) 49 (71%) urolithiasis 31 (10.5%) 28 (12.4%) 2 (4.3%) renal mass 12 (4.1%) 12 (5.3%) 0 bladder wall thickness 8 (2.7%) 8 (3.6%) 0 hydronephrosis 13 (4.4%) 9 (4%) 4 (5.8%) prostate enlargement 18 (61%) 18 (8%) 0 vesical blood clot 1 (1.7%) 1 (0.4%) 0 bladder stone 3 (1%) 3 (1.3%) 0 suspicion of utuc 1 (0.3%) 1 (0.4%) 0 anticoagulation/anti aggregation no 180 (60.8%) 135 (59.7%) 45 (64.3%) yes 116 (39.2%) 91 (40.3%) 25 (35.7%) pelvic radiation no 281 (95.3%) 215 (95.6%) 66 (94.3%) yes 14 (4.7%) 10 (4.4%) 4 (5.7%) uti suspicion no 224 (75.7%) 167 (73.9%) 57 (81.4%) yes 72 (24.3%) 59 (26.1%) 13 (18.6%) back pain no 249 (84.7%) 187 (83.1%) 62 (89.9%) yes 45 (15.3%) 38 (16.9%) 7 (10.1%) fever no 286 (96.6%) 216 (95.6%) 70 (100%) yes 10 (3.4%) 10 (4.4%) 0 previous luts no 183 (61.8%) 139 (61.5%) 44 (62.9%) yes 104 (35.1%) 79 (35%) 25 (35.7%) not known 9 (3%) 8 (3.5%) 1 (1.4%) urolithiasis history no 268 (90.5%) 201 (88.9%) 67 (95.7%) yes 28 (9.5%) 25 (11.1%) 3 (4.3%) cystoscopy normal 130 (43.9%) 130 (57.5%) 0 dubious 25 (8.4%) 21 (9.3%) 4 (5.7%) suspicious 78 (26.4%) 12 (5.3%) 78 (94.3%) prostate enlargement 50 (16.9%) 50 (22.1%) 0 bladder trabeculation 6 (2%) 6 (2.7%) 0 urethral stenosis 3 (1%) 3 (1.3%) 0 bladder stone 3 (1%) 3 (1.3%) 0 uti: urinary tract infection; luts: lower urinary tract symptoms. archivio italiano di urologia e andrologia 2023; 95, 1 bladder cancer and hematuria discussion our study, as others (1), highlights the need for investigating almost every patient presenting with hematuria. in our cohort, the overall probability of being diagnosed with bladder cancer throughout the investigation of hematuria was 23.6%. nice states that a signal or a symptom associated with ≥ 3% risk of cancer should prompt referral for diagnostic test (2) and many patients want that investigation be made for a symptom associated ≥ 1% risk of cancer (3). american urology association (aua) recommends that all patients with visible hematuria and patients with microscopic hematuria (≥ 3 red blood cells/high-power field), aged ≥ 35 years, should be investigated (4). in an era of relative lack of health resources when compared with demands, it is of the most importance to prioritize patients regarding diagnostic procedures (i.e. cystoscopy, ct scan). this way, patients with higher probability of bladder cancer can be prioritized to receive said tests, and patients with lower probability being safely postponed (but studied nonetheless). we were not able to define thresholds for strictly riskbased categories, but the data allow us to roughly estimate the risk of bladder cancer in a single patient. some predictors for bladder cancer were uncovered, as age, gender, tobacco exposure history, number of episodes of visible hematuria and ultrasound evaluation. older patients, male (or 2.843, p = 0.061), a history of smoking (or 3.852, p < 0.05), with recurrent hematuria (or 3.471, p < 0.05) and positive ultrasound exam for bladder cancer (or 31.663, p < 0.05) are at highest risk and should be investigated promptly. univariate analysis showed that negative urine culture was a risk factor for bladder cancer, but not in multivariate analysis. none of patients with a positive urine culture at the moment of hematuria had a subsequent diagnosis of bladder cancer. in our study, ultrasound had sensibility of 71% and specificity of 87% for bladder cancer. it can be a good screening test but cannot be an alternative to cystoscopy, because 16% of patients diagnosed with bladder cancer had a normal ultrasound evaluation. in patients investigated for non-visible hematuria the diagnostic rate of bladder cancer was 8.6% and all of them had a positive ultrasound. according to our results and in agreement with national board of health and welfare of sweden (5), it seems plausible that patients with nonvisible hematuria with a negative ultrasound evaluation are at low risk of bladder cancer and the investigation can be postponed. we uncovered some new clinical predictors for bladder cancer in patients with hematuria, like recurrent hematuria and a negative urine culture. our study has some limitations. it is a retrospective study with a relatively small number of patients that limits the statistically power of the analysis. urinary cytology was not included in co-variates, because, in our department most patients collect a bladder washing during cystoscopy procedure. the incidence of bladder cancer in our cohort is probably higher than its real incidence in overall patients with hematuria because it represents the detection rate in a secondary care setting. this study suggests that it is possible to reliably estimate the risk of bladder cancer in patients with hematuria, using clinical and imaging data to manage available healthcare resources without compromising the standard of care. references 1. tan ws, feber a, sarpong r, et al. who should be investigated for haematuria? results of a contemporary prospective observational study of 3556 patients. eur urol. 2018; 74:10-4. 2. national collaborating centre for cancer (uk). suspected cancer: recognition and referral. london: national institute for health and care excellence (nice); 2015 jun. 3. banks j, hollinghurst s, bigwood l, et al. preferences for cancer investigation: a vignette-based study of primary-care attendees. lancet oncol. 2014; 15:232-40. 4. davis r, jones js, barocas da, et al. american urological association. diagnosis, evaluation and follow-up of asymptomatic microhematuria (amh) in adults: aua guideline. j urol. 2012; 188 (6 suppl):2473-81. 5. malmström p-u. time to abandon testing for microscopic haematuria in adults? bmj. 2003; 326:813-5. table 2. univariate and multivariate analysis for predictors of bladder cancer in patients with hematuria. predictors of bladder cancer for 265 visible hematuria referrals univariate multivariate or ci or ci age (years) 1.047 * 1.012-1.080 gender (0 = f, 1 = m) 2.519 * 1.236-5.131 2.843 0.952-8.489 ever smoker 2.876 * 1.435-5.764 3.852 * 1.301-11.405 hematuria episodes (0 = 1, 1 = > 1x) 2.093 * 1.153-3.801 3.471 * 1.435-8.395 urine culture (0 = neg, 1 = pos) 0.737 * 0.677-0.802 0.496 0.698-2.100 ultrasound suspicion 24.425 * 11.483-51.955 31.633 * 12.867-77.772 test �2 d� p overall model evaluation r square nagelkerke 0.545 goodness-of-fit test hosmer & lemeshow 8.531 8 0.383 uf: female; m: male; neg: negative; pos: positive. * p < 0.05. correspondence roberto jarimba, md (corresponding author) robertojarimba@chuc.min-saude.pt vasco quaresma, md vpdquaresma@gmail.com miguel eliseu, md mgl.nobre@gmail.com joão pedroso lima, md joaopedrosolima@gmail.com edgar tavares da silva, md edsilva.elv@gmail.com pedro moreira, md pedronetomoreira@gmail.com arnaldo figueiredo, md, phd ajcfigueiredo@gmail.com serviço de urologia, centro hospitalar e universitário de coimbra rua professor mota pinto 3004-561, coimbra (portugal) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 129 letter to editor key words: erectile dysfunction; pde5i; recreational drug. submitted 2 april 2023; accepted 6 april 2023 to the editor, in 1998 sildenafil was approved by the food and drug administration as first line therapy for erectile dysfunction. since then, phosphodiesterase type 5 inhibitors (pde5i) represent the first-line treatment of erectile dysfunction (ed), improving physiological erectile function, sexual orgasmic function, psychological self-esteem, couples’ relationship, and quality of life (1). sildenafil represents the most used recreational drugs (2, 3). this could be due to its popularity/familiarity, the presence of more than 30 generic sildenafil and to the significantly lower costs compared to other pde5i as well as tadalafil (2). the population of pde5i users is different in terms of demographics, sexual behaviors, attitudes in general/sexual health, and demands for ed treatments (4). nowadays pde5i are very popular drugs and one of the most important problems is their recreational use (5). mostly young men bypassed health care prescriptions (hcp) and obtained these drugs through uncontrolled sources, on the internet market (6, 7). there are several risks related to recreational use of pde5i: a certain portion of drugs available on the internet are contaminated by counterfeits and unapproved generics (1, 8). alshahrani et al. reported that in saudi arabia population, the most important reason in using pde5i for recreational use is curiosity (38.5%) followed by enhancing self-confidence (25.6%), increasing erection duration (10.3%) and improving ejaculation problems (5.1%). all these people bought the pde5i from drug stores (73.9%), without a medical prescription (9). similar data were reported by attia et al. in egyptian males: in 58.35% of cases pde5i were used for pleasure, followed by increasing intercourse duration/frequency (15.6%). in 62% of cases egyptian males obtained them from friends, relatives, and colleagues (62%) or by themselves (25%) or from pharmacists (6.7%), and only 5.4% after medical consultation (1, 10). bechara et al. reported that 21.5% of healthy men between 18 and 30 years old used pde5i as a recreational drug, mostly associated with alcohol or other drugs as well as illicit drugs, and psychotropic medications. this could explain the high incidence of adverse events, mainly related to vasodilator effects (6, 11) with the use of the cannabis, an inhibitor of the cytochrome p450 3a4 hepatic microsomal isoenzyme that is involved into pde5i metabolism (12, 13). kimura et al. reported that 45.4% of japanese men bypassed hcp interaction to obtain pde5i, 23.4% of men obtained it from friends and 22.0% obtained it via the internet (8). korkes et al. reported a recreational use in 9% of young men, although they considered themselves with perfect erectile function. of these, 46.7% had used pde5i more than three times, and 71.4% had mixed them with alcohol (7). harte et al. reported the same effect in users and nonusers, with a lower erectile confidence and overall satisfaction in the first group (14). in this scenario it should be necessary to provide more education with the aim to decrease the number of pde5i users without prior hcp consultation (7, 15). further work on the risk or potential health problems in such conditions is encouraged to improving the information in the general population, creating a collaborative effort between pharmacists, health professionals, and policy makers is necessary to avoid selling medication without a medical prescription and to give adequate and scientific information regarding pde5i use and misuse. references 1. attia aa, abdel-hameed aks, amer maem, et al. study of the prevalence and patterns of phosphodiesterase type 5 inhibitor use among sexually active egyptian males: a national cross-sectional survey. andrologia. 2019; 51:e13364. 2. huang sa, lie jd. phosphodiesterase-5 (pde5) inhibitors in the management of erectile dysfunction. p t. 2013; 38:407-19. recreation use of phosphodiesterase type 5 inhibitors, the other side of erectile dysfunction giovanni maria fusco 1, luigi cirillo 1, francesco mastrangelo 1, francesco romano 1, ernesto di mauro 1, gianluigi cacace 1, gianluca spena 1, annamaria iannicelli 2, corrado aniello franzese 3, vincenzo mirone 1, roberto la rocca 1, luigi napolitano 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy; 2 department of translational medical sciences, university of naples "federico ii", naples, italy; 3 asl napoli 3 sud, naples, italy. doi: 10.4081/aiua.2023.11350 archivio italiano di urologia e andrologia 2023; 95, 2 g.m. fusco, l. cirillo, f. mastrangelo, f. romano, et al. 130 3. atsbeha bw, kebede bt, birhanu bs, et al. the weekend drug; recreational use of sildenafil citrate and concomitant factors: a crosssectional study. front med (lausanne). 2021; 8:665247. 4. mulhall jp, hassan ta, rienow j. sexual habits of men with ed who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries. int j clin pract. 2018; 72:e13074. 5. cirillo l, fusco gm, di bello f, et al. sexual dysfunction: time for a multidisciplinary approach? arch ital urol androl. 2023; 95:11236. 6. bechara a, casabé a, de bonis w, et al. recreational use of phosphodiesterase type 5 inhibitors by healthy young men. j sex med. 2010; 7:3736-42. 7. korkes f, costa-matos a, gasperini r, et al. recreational use of pde5 inhibitors by young healthy men: recognizing this issue among medical students. j sex med. 2008; 5:2414-2418. 8. kimura m, shimura s, kobayashi h, et al. profiling characteristics of men who use phosphodiesterase type 5 inhibitors based on obtaining patterns: data from the nationwide japanese population. j sex med 2012; 9:1649-1658. 9. alshahrani s, ahmed af, gabr ah, al ansari a, el-feky m, elbadry ms. phosphodiesterase type 5 inhibitors: irrational use in saudi arabia. arab journal of urology. 2016; 14:94-100. 10. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl. 2021; 93:221-226. 11. ahmed af, alshahrani s, morgan a, et al. demographics and sexual characteristics of sex-enhancing medication users: study of a web-based cross-sectional sample of sexually active men. arab journal of urology. 2017; 15:366-371. 12. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 13. schnetzler g, banks i, kirby m, et al. original research—ed pharmacotherapy: characteristics, behaviors, and attitudes of men bypassing the healthcare system when obtaining phosphodiesterase type 5 inhibitors. j sex med 2010; 7:1237-1246. 14. harte cb, meston cm. recreational use of erectile dysfunction medications and its adverse effects on erectile function in young healthy men: the mediating role of confidence in erectile ability. j sex med 2012; 9:1852-1859. 15. napolitano l, cirillo l, fusco gm, et al. natural treatments for erectile dysfunction: a focus on mobile health applications. arch ital urol androl. 2022; 94:373-374. correspondence giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md cirilloluigi22@gmail.com francesco mastrangelo, md f.mastrangelo91@gmail.com francesco romano, md romanofrancesco92@libero.it gianluca spena, md spena.dr@gmail.com ernesto di mauro, md ernesto.dimauro@unina.it gianluigi cacace, md naples cacace.gianlu@gmail.com vincenzo mirone, md mirone@unina.it roberto la rocca, md robertolarocca87@gmail.com luigi napolitano, md dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy annamaria iannicelli, md annamaria.iannicelli@unina.it department of translational medical sciences, university of naples "federico ii", via pansini 5, 80131, naples, italy corrado aniello franzese, md corradofranzese@libero.it asl napoli 3 sud, naples, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso 341archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. the world health organization (who) declared it a pandemic on march 11, 2020 (2). the who generated a global epidemiological situation report based on the national data received from each country and turkey was reported as having the highest number of cases in the european region (33% of all cases in europe, 194.476 new cases total, and 2.306 new cases per 1 million population) (3). the first covid-19 case in turkey was identified on the same day the who declared the global pandemic. several measures limiting individual and social life were quickly implemented by the turkish government. people have been living with these limitations, and the accompanying physical, psychological, economic, and social effects, for a long time. it was inevitable that sexual health, defined by the who as the physical, emotional, mental, and social well-being of an individual, would also be affected during this period (4). quarantine measures and some of the limitations in daily life imposed during the recent severe acute respiratory syndrome (sars), h1n1 influenza, middle east respiratory syndrome (mers), and ebola epidemics have been reported to negatively affect sexual life (5). the covid-19 pandemic has significantly affected the quality of life, with negative effects on interpersonal relationships, community life, and sexual health (6). a few studies have evaluated the effects of the covid-19 pandemic on sexual life during the first months of the pandemic; however they mostly focused on investigating sexual behaviors rather than sexual function, and presented various opinions (7, 8). the effects of this prolonged pandemic, which has reshaped all our lives, on sexual behavior patterns and sexual function are not yet known. in this study, we evaluated the medium-term effects of the covid-19 pandemic on sexual function and behaviors in men with heterosexual partners. materials and methods study design in this cross-sectional study, men were asked to complete a 34-item online questionnaire, which took approximately 20 minutes, consisting of multiple-choice and open-ended questions evaluating their sexual function and behaviors between november 06 and december 06, 2020. the questionnaire, which was created using a turkish online survey objective: to evaluate the long-term effects of the coronavirus disease 2019 (covid-19) pandemic on sexual functions and behavior in men with heterosexual partners. materials and methods: a total of 602 participants completed an online questionnaire, shared via social networks, between november 20 and december 20, 2020. pre-pandemic sexual intercourse frequency, international erectile dysfunction index (iief-15) score, intravaginal ejaculatory latency time (ielt), premature ejaculation diagnostic tool (pedt) score, and activities during sexual intercourse were compared to the ones during the pandemic. in addition, the effects of various variables on participants’ sexual functions were evaluated and analyzed according to age groups. results: the mean number of weekly sexual intercourse during the pandemic was 1.7+1.7, which was significantly lower than in the pre-pandemic period (p < 0.001). the ed score was significantly lower during the pandemic (p < 0.001) compared to the pre-pandemic period, however orgasmic function (p = 0.016), sexual intercourse satisfaction (p < 0.001), general satisfaction (p < 0.001), and pedt scores (p = 0.004) were significantly higher. there was no significant difference in ielt before and during the pandemic (p = 0.391). full-time employment and low education level were risk factors for developing ed and pe. the negative affect of the pandemic on sexual life was most prominent in the > 65 age group. although kissing, oral and anal sex, and face-to-face sex positions decreased during the pandemic in all age groups, kissing and face-to-face sex positions remained the most preferred sexual behavior pattern (p = 0.002). there was no reduction in risky sexual behavior in the majority of the participants. conclusions: at the end of one year with covid-19, a decrease in erectile function and an increase in pe incidence were observed in men. despite this, there was an increase in sexual desire and satisfaction. although there were some changes in sexual behavior, the majority of pre-pandemic habits continued. key words: coronavirus disease 2019 (covid-19); erectile dysfunction; premature ejaculation; sexual behavior; mid-term effect. submitted 1 march 2021; accepted 21 april 2021 introduction coronavirus disease 2019 (covid-19) caused by the sars cov-2 virus first appeared in wuhan, china, in december 2019 (1). it quickly spread across the globe, and finally male sexual functions and behaviors in the age of covid-19: evaluation of mid-term effects with online cross-sectional survey study erhan ates, hakan gorkem kazici, ahmet emre yildiz, saparali sulaimanov, arif kol, haluk erol aydin adnan menderes university school of medicine, department of urology, aydin, turkey. doi: 10.4081/aiua.2021.3.341 summary archivio italiano di urologia e andrologia 2021; 93, 3 e. ates, h. gorkem kazici, a. emre yildiz, s. sulaimanov, a. kol, h. erol 342 platform (http://www.surveey.com), was delivered to the participants online via social networks. the inclusion criteria of the study were being a heterosexual male older than 18 years, having an active sexual life that had continued for at least 6 months in the pre-pandemic period, no history of radical pelvic surgery, sexual dysfunction, or psychiatric disorder, and not having covid-19. we evaluated men with heterosexual partners, because it has been reported that performing sexual activity with a partner provides higher sexual satisfaction than activity alone (9), and since the intravaginal ejaculation latency time (ielt) was used for evaluation of ejaculation function. inclusion criteria were presented on the survey entry page on the website, and those who met these conditions and agreed to participate were asked to fill out the survey. sociodemographic data, medical history, and personal habits were investigated in the first part of the study. age, education, marital status, work situation, income level during the pandemic, the number of individuals living at home during the pandemic, comorbidities, smoking, and alcohol use were evaluated. the second part of the study focused on evaluating changes in sexual behaviors such as the number of episodes of intercourse per week, ielt, sexual activities during intercourse, risky sexual activities, and changes in sexual attitudes such as the timing of intercourse during the day, during the pandemic, compared to the pre-pandemic period. in addition, the psychological effects of information about the pandemic obtained from news sources (television, radio, newspapers, magazines, and social media applications such as table 1. comparison of demographic data between group 1 and group 2. characteristic total (n = 602) n (%) group 1 (n = 211) n (%) group 2 (n = 391) n (%) p value marital status 0.001 single 240 (39.9) 104 (49.3) 136 (34.8) married 362 (60.1) 107 (50.7) 255 (65.2) education level 0.002 high school and below 165 (27.4) 65 (30.8) 100 (25.5) university 291 (48.3) 111 (52.6) 180 (46.0) master or above 146 (24.3) 35 (16.6) 111 (28.4) working frequency (during pandemic) 0.437 not working 122 (20.3) 38 (18.0) 84 (21.5) part time 131 (21.8) 48 (22.7) 83 (21.2) full time 171 (28.4) 67 (31.8) 104 (26.6) home office 178 (29.6) 58 (27.5) 120 (30.7) change in incomelevel (during pandemic) < 0.001 decreased 235 (39.0) 106 (50.2) 129 (33.0) increased or not changed 367 (61.0) 105 (49.8) 262 (67.0) change in the number of sexual partners(during pandemic) < 0.001 decreased 133 (22.1) 85 (40.3) 48 (12.3) increased or not changed 469 (77.9) 126 (59.7) 343 (87.7) change in the number of people lived together 0.043 decreased 45 (7.5) 22 (10.4) 23 (5.9) increased or not changed 557 (92.5) 189 (89.6) 368 (94.1) alcohol and smoking use 0.122 smoking 106 (17.6) 42 (19.9) 64 (16.4) alcohol 119 (19.8) 31 (14.7) 88 (22.5) both of them 172 (28.6) 65 (30.8) 107 (27.4) none of them 205 (34.1) 73 (34.6) 132 (33.8) comorbidities 0.018 no 482 (80.1) 180 (85.3) yes 120 (19.9) 31 (14.7) 0.021 diabetes mellitus 32 (5.1) 12 (5.6) hypertension 33 (5.2) 6 (2.8) coronary artery disease 18 (2.9) 3 (1.4) congestive heart failure 2 (0.3) 0 (0) others 62 (9.9) 14 (6.5) communication tools (during pandemic) 0.319 television 448 (41.2) 147 (43.2) 301 (40.2) radio 55 (5.1) 14 (4.1) 41 (5.5) social media (facebook, twitter, instagrametc.) 480 (44.1) 153 (45.0) 327 (43.7) newspaper, magazine 105 (9.7) 26 (7.6) 79 (10.6) the effect of pandemic news on psychological status 0.064 good 218 (36.2) 66 (31.3) 152 (38.9) bad 384 (63.8) 145 (68.7) 239 (61.1) have you had sexual intercourse at different times of the day during the pandemic compared to before the pandemic? 0.086 yes 271 (45.0) 85 (40.3) 186 (47.6) no 331 (55.0) 126 (59.7) 205 (52.4) risky sexual behavior during the pandemic < 0.001 decreased 98 (16.3) 66 (31.3) 32 (8.1) increased or not changed 186 (30.4) 58 (27.5) 128 (32.8) i never engage in risky sexual behavior 318 (52.8) 87 (41.2) 231 (59.1) 343archivio italiano di urologia e andrologia 2021; 93, 3 male sexual function in covid-19 pandemic facebook, twitter, instagram, and whatsapp), and whether such news had a negative effect on their sexual activity during the pandemic were investigated. in the third part of the study, sexual functioning including erection and ejaculation were evaluated using internationally validated questionnaires. this study complied with the relevant ethical regulations (institutional ethics committee protocol number: 2020/117). all participants reviewed and signed the informed consent page prior to filling out the online survey on the website. evaluation of sexual function the international index of erectile function (iief-15), which was translated and validated by the turkish andrology association in 2002, was used to investigate five areas of male sexual function, including erectile function, orgasmic function, sexual desire, sexual satisfaction, and general satisfaction before and during the pandemic (10). in our study, participants with an iief score < 26 were considered to have erectile dysfunction (ed), and those ≥ 26 were considered to have normal erectile function. participants were asked to choose their ielt from one of the following options: < 1 min, 1-3 min, 3-25 min, and ≥ 25 min. the premature ejaculation diagnostic tool (pedt), a 5-item questionnaire that evaluates the control, frequency, minimum stimulation, distress, and interpersonal difficulties of ejaculation, the turkish version of which has been validated, was used in the evaluation of premature ejaculation (pe) before and during the pandemic (11). in our study, participants with a pedt score of ≥ 9 were considered to have pe. participants who reported a decrease in the number of episodes of sexual intercourse per week during the pandemic were classified as group 1, and those who reported an increase or no change as group 2. in addition, participants were divided into three groups according to their ages: < 40 years, 40-65 years, and ≥ 65 years. the changes in these groups from before and during the pandemic were compared. also, the characteristics of men who had normal erectile function before the pandemic, but had newly developed ed and pe during the pandemic, were evaluated by logistic regression analysis. statistical analyses the survey data were evaluated using spss software (ver.21.0 for windows; spss inc, chicago, il, usa). the compliance of continuous variables with normal distribution was investigated using visual (histogram and probability graphs) and analytical (kolmogorov-smirnov/ shapiro-wilk tests) methods. for the descriptive statistics, mean and standard deviation were used for data that fitted the normal distribution, and the median and minimummaximum for data that did not fit the normal distribution. chi-square test was used to determine whether there was a difference between categorical variables. student’s t-test or one-way anova were used to compare continuous variables with parametric properties in independent groups, and mann-whitney u test or kruskal-wallis analysis of variance were used to compare continuous variables without parametric properties in independent groups. the t-test was used to compare continuous variables with parametric properties in dependent groups, the wilcoxon test was used to compare continuous variables with non-parametric properties in dependent groups, and mcnemar’s chi-square test was used to compare categorical variables in dependent groups. p value of < 0.05 was considered statistically significant. results a total of 1.309 men participated in the study. the data of 602 participants who completed the questionnaire and met the inclusion criteria were evaluated. the response rate was 45.9%. the mean age of all participants was 36.1 ± 11.6 years. while the mean weekly frequency of sexual intercourse was 2.1 ± 1.5 in the pre-pandemic period, it was 1.7 ± 1.7 during the pandemic (p < 0.001). of the participants, 35% (n = 211) were in group 1 and 65% (n = 391) in group 2. the demographic characteristics of all participants and the distribution of these characteristics according to both groups are summarized in table 1. erectile function score during the pandemic was significantly lower (p < 0.001) than before the pandemic, while orgasmic function (p = 0.016), sexual intercourse satisfaction (p < 0.001), general satisfaction (p < 0.001), and pedt (p = 0.004) scores were significantly higher (table 2). all subdomains of iief-15 were significantly lower in group 1 than in group 2. however, the pedt score was higher in group 1, but not statistically significant (p = 0.055). no significant difference was found in self-reported ielt scores before and during the pandemic (p = 0.391) (figure 1). while a significant decrease was observed in sexual behaviors such as kissing, oral sex and face-to-face sex positions during the pandemic, a significant increase was observed in non-face-to-face positions (table 3). during the pandemic, 45% (n = 271) of participants had intercourse at times of the day that differed from their pre-pandemic routine habits. among 284 who reported risky sexual behaviors such as sexual intercourse without condoms, multiple partners, intercourse with new acquaintances and/or sex workers in the pre-pandemic period, only 98 (34.5%) reported a decrease in these behaviors during the pandemic. evaluation according to age groups indicated that all iief15 subdomains were significantly lower in the ≥ 65 years age group compared to other groups during the pandemic. in addition, their pedt scores were significantly higher than other age groups. in terms of sexual behaviors, kissing, and face-to-face sex positions decreased during the pandemic in all age groups but remained the most common sexual behavior pattern (p = 0.002). the data of 39 participants (8.8%) who had normal erectile function (iief score ≥ 26) before the pandemic, but developed ed of varying degrees (iief < 26) during the pandemic, and 25 (5.3%) participants who did not have pe complaints (pedt score < 9) before the pandemic, but were assessed as having pe during the pandemic (pedt score ≥ 9), were evaluated separately. when the factors affecting the development of ed and pe during the pandemic were examined with univariate analysis, ed was significantly more common in full-time workers (odds ratio: 5.011, 95% confidence interval: 1.191-21.090, p = 0.028), while pe was significantly more common in archivio italiano di urologia e andrologia 2021; 93, 3 e. ates, h. gorkem kazici, a. emre yildiz, s. sulaimanov, a. kol, h. erol 344 men with a lower education level (odds ratio: 1.892, 95% confidence interval: 0.708-5.056, p = 0.040) (table 4). most of respondents obtained information about the covid-19 pandemic through social media applications (facebook, twitter, instagram, whatsapp) (44.1%) and television (41.2%). among the participants, 63.8% stated table 2. comparison of male sexual functions according to pre-pandemic, post-pandemic, group 1 and group 2, and age groups. international index of erectile function-15 (iief-15) premature ejaculation diagnostic tool (pedt) erectile function orgasmic function sexual desire intercourse satisfaction overall satisfaction (max. score 30) (max. score 10) (max. score 10) (max. score 15) (max. score 10) before pandemic (n = 602) mean (sd) 26.9 (5.2) 3.9 (1.7) 3.7 (1.7) 5.3 (2.1) 4.0 (2.0) 4.1 (6.5) median (min-max) * 30 (6-30) 4 (2-10) 4 (2-10) 5 (0-12) 4 (0-10) 0 (0-20) during pandemic (n = 602) mean (sd) 26.5 (6.0) 4.1 (2.2) 3.9 (2.0) 6.0 (2.0) 4.9 (2.2) 4.3 (6.3) median (min-max) * 30 (6-30) 4 (2-10) 4 (2-10) 6 (0-11) 4 (0-10) 0 (0-20) p value < 0.001 0.016 0.082 < 0.001 < 0.001 0.004 group 1 (n = 211) mean+sd 25.6 (6.6) 4.0 (2.2) 3.7 (2.0) 5.9 (1.7) 4.6 (1.9) 4.9 (6.5) median (min-max) * 30 (6-30) 4 (2-10) 3 (2-10) 6 (0-11) 4 (0-10) 0 (0-20) group 2 (n = 391) mean+sd 26.9 (5.6) 4.4 (2.1) 4.3 (2.1) 6.2 (2.4) 5.5 82.5) 4.0 (6.2) median (min-max) * 30 (6-30) 4 82-10) 4 (2-10) 6 (0-11) 6 (0-10) 0 (0-20) p value 0.008 0.005 < 0.001 0.043 < 0.001 0.055* before pandemic < 40 years (n = 436) mean+sd 28.3 (3.6) 3.9 (1.7) 5.0 (2.9) 7.2 (1.8) 6.3 (1.7) 3.5 (6.3) median (min-max) * 30 (8-30) 4 (2-8) 5 (2-10) 7 (0-9) 6 (0-9) 0 (0-20) 40-65 years (n = 145) mean+sd 24.7 (5.7) 4.0 (1.8) 4.0 (1.7) 5.6 (1.9) 4.3 (1.8) 5.0 (6.5) median (min-max) * 26 (8-30) 4 (2-8) 4 (2-8) 5 (0-11) 4 (0-10) 2 (0-20) > 65 years (n = 21) mean+sd 13.9 (6.6) 3.9 (1.7) 3.6 (1.6) 5.2 (2.2) 3.8 (1.9) 8.3 (7.6) median (min-max) * 15 (6-30) 4 (2-10) 4 (2-8) 5 (0-12) 4 (0-10) 12 (0-19) p value < 0.001 0.993 0.006 < 0.001 < 0.001 < 0.001 during pandemic < 40 years (n = 436) mean+sd 28.0 (4.4) 4.9 (2.2) 6.0 (2.5) 7.4 (1.2) 6.7 (1.2) 3.7 (6.1) median (min-max) * 30 (6-30) 4 (2-8) 7 (2-10) 7 (4-10) 6 (4-10) 0 (0-20) 40-65 years (n = 145) mean+sd 23.7 (6.9) 4.5 (2.2) 4.7 (2.1) 6.1 (2.1) 5.0 (2.3) 5.6 (6.2) median (min-max) * 25 (6-30) 4 (2-10) 4 (2-10) 6 (0-11) 4 (0-10) 4 (0-20) > 65 years (n = 21) mean+sd 14.4 (6.5) 4.0 (2.1) 3.5 (1.8) 5.9 (1.9) 4.8 (2.1) 9.6 (6.8) median (min-max) * 15 (6-30) 4 (2-10) 3 (2-10) 6 (0-11) 4 (0-11) 12 (0-19) p value < 0.001 0.007 < 0.001 < 0.001 < 0.001 < 0.001 sd: standard deviation. * statistical significance was evaluated in the data expressed as median (min-max). figure 1. self-reported ielt scores before and during the pandemic. 345archivio italiano di urologia e andrologia 2021; 93, 3 male sexual function in covid-19 pandemic that they were psychologically negatively affected by this information, and 30.9% attributed their decrease in frequency of sexual intercourse during the pandemic to the news obtained from the press and social media (figure 2). discussion this is the first study to evaluate medium-term effects of the covid-19 pandemic on sexual function and behavior in men. in this study, as in many reports in the literature, the number of episodes of sexual intercourse was taken as the basis for sexual health evaluation. although there are studies defending the contrary (12), one of the main factors determining sexual satisfaction remains the frequency of sexual intercourse (13). sexual satisfaction is both the result and indicator of a healthy sex life (14). an online survey study conducted in some southeast asian countries involving participants with a high level of education, reported that there was no significant difference in the frequency of sexual intercourse during the table 4. univariate analysis of erectile dysfunction and premature ejaculation. figure 2. the reasons reported by the participants for the decrease in sexual activities during the pandemic. univariate analysis erectile dysfunction premature ejaculation or p %95 ci or p %95 ci age 1.002 0.903 0.974-1.030 0.995 0.833 0.953-1.039 education level 1.191 0.627 0.589-2.410 1.892 0.040 0.708-5.056 working frequency (during pandemic) 5.011 0.028 1.191-21.090 1.192 0.786 0.337-4.214 change in income level (during pandemic) 0.732 0.348 0.381-1.404 0.438 0.098 0.164-1.166 marital status 0.835 0.601 0.425-1.641 1.352 0.540 0.514-3.556 change in the number of sexual partners (during pandemic) 0.542 0.084 0.270-1.086 2.164 0.309 0.489-9.585 change in the number of people lived together 0.967 0.957 0.286-3.273 1.301 0.801 0.169-10.043 comorbidities 3.148 0.060 0.953-10.402 0.587 0.326 0.203-1.700 the effect of pandemic news on psychological status 0.589 0.160 0.281-1.232 1.241 0.666 0.465-3.308 table 3. comparison of sexual intercourse and sexual activities by pre-pandemic and post-pandemic, group 1 and group 2, and age groups. number of sexual intercoursein a week, sexual activities, n (%) mean (sd) kissing oral sex anal sex face-to-face nonface-to-face sex positions (e.g. missionary) sex positions (e.g. doggystyle) before pandemic (n = 602) 2.1 (1.5) 488 (29.9) 246 (15.1) 42 (2.6) 522 (32.0) 332 (20.4) during pandemic (n = 602) 1.7 (1.7) 402 (28.3) 200 (14.1) 33 (2.3) 429 (30.2) 357 (25.1) p value < 0.001 < 0.001 < 0.001 0.064 < 0.001 0.023 group 1 (n = 211) 1.0 (1.0) 130 (28.0) 73 (15.7) 12 (2.6) 129 (27.8) 120 (25.9) group 2 (n = 391) 2.1 (1.9) 272 (28.4) 127 (13.3) 21 (2.2) 300 (31.3) 237 (24.8) p value < 0.001 0.554 age (before pandemic), year < 40 years (n = 436) 1.8 (1.9) 279 (27.5) 168 (16.6) 23 (2.3) 289 (28.5) 255 (25.1) 40-65 years (n = 145) 1.6 (1.1) 104 (29.1) 31.0 (8.7) 10 (2.8) 121 (33.8) 92 (25.7) > 65 years (n = 21) 0.8 (0.5) 19 (38.8) 1 (2.0) 0 (0.0) 19 (38.8) 10 (20.4) p value 0.017 0.002 archivio italiano di urologia e andrologia 2021; 93, 3 e. ates, h. gorkem kazici, a. emre yildiz, s. sulaimanov, a. kol, h. erol 346 covid-19 pandemic compared to the pre-pandemic time (15). li et al. (8) found that during the pandemic, 37% of respondents experienced a decrease in the frequency of sexual intercourse and 25% in sexual desire. these reductions were greater in men than in women, and a decrease in sexual satisfaction was found in 32% of the men. jacob et al. (7) found that young age, male gender, being married, and consuming alcohol were associated with increased sexual activity. an increased number of days spent in self-isolation also positively affected the frequency of sexual intercourse. studies reporting a decrease in the frequency of sexual desire and intercourse concluded that limited living space, prolonged decrease in domestic privacy, increase in differences of opinion between the spouses, and exacerbation of previous conflicts were reasons for the changes in sexual behavior. in addition, the effects of various pandemic-related stress factors, together with anxiety and depression caused by economic deterioration have also been reported (16). although there are conflicting reports, most studies reported that the severity of anxiety and depression was correlated with the loss of sexual desire (17). in our study, although there was a decrease in the frequency of sexual intercourse, there was an increase in sexual desire and satisfaction. various physical factors such as the requirement to live apart from their partner, and staying away from their partner due to fear of getting sick may have affected the frequency of sexual intercourse during this period (18). however, the increase in sexual desire may be a result of the individual’s internal struggle in dealing with the long-term negative psychological factors. mollaioli et al. (19) reported that all types of sexual activity have protective effects against anxiety and mood disorders related to quarantine in both sexes. however, it is not necessary to have a lot of sexual intercourse for sexual health and satisfaction (12). although there is no evidence that covid-19 is transmitted through sexual intercourse, the close contact of partners due to the nature of sex creates a potential risk for sars-cov-2 transmission through respiration and saliva. this, in addition to other factors, can lead to avoidance of sexual activity during the pandemic despite a healthy partner (20). even if intercourse is not avoided, activity preferences during intercourse may be affected. culha et al. (21) reported that foreplay, kissing, oral, and anal sex were less common and that couples preferred non-face-to-face sexual positions during the covid-19 pandemic. however, baran and aykac (22) reported that the vast majority of couples did not fear covid-19 transmission during sex, and married couples had the least amount of fear. in our study, only 14.6% of men stated that their sex life was negatively affected due to the fear of infecting themselves or their partner. face-to-face positions such as the missionary position in vaginal intercourse as well as kissing, oral, and anal sex decreased compared to the pre-pandemic period, but face-to-face positions remained the preferred type of sexual behavior during the pandemic. in addition, we found that only 34.5% of men who reported risky sexual activities in terms of transmission such as sexual activity without a condom, multiple partners, and intercourse with new acquaintances or sex workers during the pre-pandemic period reduced such activities during the pandemic. however, a decrease in risky sexual behaviors has been reported in the early stages of the pandemic (8). erectile function was evaluated with international erectile function indices (iief-5, iief-15), and a decrease was found in the early stages of covid-19 compared to the pre-pandemic period (22). fang et al. (23) stated that men reported worsening of erectile function and ejaculation control ability during the pandemic. in that study, it was observed that 31.9% of participants had a decrease in their iief-5 scores, and 17.9% had an increase in their pedt scores. in our study, the erection score was significantly lower but all other subdomains of iief-15 were significantly higher during the pandemic. the number of men who reported their ielt as < 1 minute during the pandemic was higher than before the pandemic. in addition, there was a significant increase in the pedt score compared to the pre-pandemic period. in the european urology guideline, it has been reported that pe is affected by low education level, absence of physical activity, and religious beliefs (a majority of muslim countries have higher levels of pe) (24). stress and limitation of movement in a country with a majority muslim population such as turkey might therefore be expected to cause an increase in pe. however, we did not find any risk factor other than a low education level in the univariate analysis of respondents with newly developed pe during the pandemic. with advanced age, low testosterone levels in men increase the loss of libido and negatively affect sexual behavior, thus reducing the quality of sexual life (25). it is not surprising that erectile function also decreases due to androgen deficiency and increased stress factors. we found that erectile function and sexual desire were lower in the older age group. when we evaluated pe according to age groups, we found that during the pandemic pedt scores were higher in men ≥ 65 years of age. our study had some limitations. the data were selfreported. requesting information from the pre-pandemic period may have created memory difficulties for participants and introduced bias. other than those of the international questionnaires, our questions were non-validated. in addition, because we wanted to keep the number of questions low to make participation easier, we did not evaluate their current anxiety and/or depression status with approved questionnaires. we only included participants who did not have a known psychiatric problem. however, participants reported that they were psychologically negatively affected by news about covid-19 and that this affected their sexual life the most. this can be considered a separate limitation. society's perception of sexuality is effective in shaping individual sexual behavior. this may limit generalization of our results. we believe that the results of our study, conducted in turkey, where the culture is a blend of the values of both western and eastern civilizations, can contribute to knowledge about changes in sexual function and behavior during the covid-19 pandemic. conclusions it has been one year since the start of the covid-19 pandemic. in our study of men in turkey, frequency of sex347archivio italiano di urologia e andrologia 2021; 93, 3 male sexual function in covid-19 pandemic ual intercourse and erectile function have decreased, although sexual desire and sexual satisfaction have both increased. in addition, complaints of pe have increased. in terms of sexual behavior, pre-pandemic habits have continued, including engaging in risky sexual behavior. references 1. zhu n, zhang d, wang w, et al. a novel coronavirus from patients with pneumonia in china. n engl j med. 2019; 382:727-33. 2. world health organization, (2020). 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(december 22, 2020). coronavirus disease (covid-19) weekly epidemiological update and weekly operational update-22 december 2020. retrieved from https://www.who.int/publications/m/item/weekly-epidemiologicalupdate---22-december-2020. 4. glasier a, gülmezoglu am, schmid gp, et al. sexual and reproductive health: a matter of life and death. lancet. 2006; 368:1595-607. 5. brook sk, webster rk, smith le, et al. the psychological impact of quarantine and how to reduce it: rapid review of the evidence. lancet 2020; 395:912-20. 6. maretti c, privitera s, arcaniolo d, et al. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology. arch ital urol androl. 2020; 92:73-7. 7. jacob l, smith l, butler l, et al. challenges in the practice of sexual medicine in the time of covid-19 in the united kingdom. j sex med. 2020; 17:1229-36. 8. li w, li g, xin c, et al. challenges in the practice of sexual medicine in the time of covid-19 in china. j sex med. 2020; 17:1225-8. 9. brod s, costa rm. satisfaction (sexual, life, relationship, and mental health) is associated directly with penile-vaginal intercourse, but inversely with other sexual behavior frequencies. j sex med. 2009; 6:1947-1954. 10. akkus e, kadioglu a, esen a, et al. prevalence and correlates of erectile dysfunction in turkey: a population-based study. eur urol. 2002; 41:298-304. 11. serefoglu ec, cimen hi, ozdemir at, et al. turkish validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. int j impot res. 2009; 21:13944. 12. muise a, schimmack u, impett ea. sexual frequency predicts greater well-being, but more is not always better. soc psychol personal sci. 2015; 7:295-302. 13. gillespie bj. correlates of sex frequency and sexual satisfaction among partnered older adults. j sex marital ther. 2017; 43:403-23. 14. palha-fernandes e, alves p, lourenço m. sexual satisfaction determinants and its relation with perfectionism: a cross-sectional study in an academic community. sexual and relationship therapy, doi: 10.1080/14681994.2019.1677884. 15. arafat smy, alradie-mohamed a, kar sk, et al. does covid19 pandemic affect sexual behaviour? a cross-sectional, crossnational online survey. psychiatry res. 2020; 289:113050. 16. ko ny, lu wh, chen yl, et al. changes in sex life among people in taiwan during the covid-19 pandemic: the roles of risk perception, general anxiety, and demographic characteristics. int j environ res public health. 2020; 17:5822. 17. beutel me, burghardt j, tibubos an, et al. declining sexual activity and desire in men-findings from representative german surveys, 2005 and 2016. j sex med. 2018; 15:750-6. 18. döring n. how is the covid-19 pandemic affecting our sexualities? an overview of the current media narratives and research hypotheses. arch sex behav. 2020; 49:2765-78. 19. mollaioli d, sansone a, ciocca g, et al. benefits of sexual activity on psychological, relational, and sexual health during the covid-19 breakout. j sex med. 2021; 18:35-49. 20. scorzolini l, corpolongo a, castilletti c, et al. comment on the potential risks of sexual and vertical transmission of covid-19. clin infect dis. 2020; 71:2298. 21. culha mg, demir o, sahin o, altunrende f. sexual attitudes of healthcare professionals during the covid-19 outbreak. int j impot res. 2021; 33:102-9. 22. baran o, aykac a. the effect of fear of covid-19 transmission on male sexual behaviour: a cross-sectional survey study. int j clin pract. 2021; 75:e13889. 23. fang d, peng j, liao s, et al. an online questionnaire survey on the sexual life and sexual function of chinese adult men during the coronavirus disease 2019 epidemic. sex med. 2021; 9:100293. 24. salonia a, bettocchi c, carvalho j, et al. sexual and reproductive health. eau guidelines 2020. edn. presented at the eau annual congress amsterdam 2020. isbn 978-94-92671-07-3. 25. forbes mk, eaton nr, krueger rf. sexual quality of life and aging: a prospective study of a nationally representative sample. j sex res. 2017; 54:137-48. correspondence erhan ates, associate professor of urology (corresponding author) drerhanates@yahoo.com hakan gorkem kazici, md hgkazici@yahoo.com ahmet emre yildiz, md aemreyildiz@gmail.com saparali sulaimanov, md sulaimanovsaparali@gmail.com arif kol, assistant professor of urology drarifkol@hotmail.com haluk erol, professor of urology halukerol@yahoo.com department of urology, aydin adnan menderes university school of medicine, 09010, aydin (turkey) cop+ed+fisse 2006 57archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. urologic trauma (1-9). the internet is an important and easily accessible source of information. more than 80% of patients look for medical advice or informative contents about their conditions on the web (10). among all social media, youtube is a video-sharing platform which allows people to upload or watch videos. it is the second most visited website, with more than 500 hours of content uploaded every minute, from 80 different countries and five billion videos watched every day (11). in current literature, several previous studies have already examined youtube video on medical topic (11-14). internet users may look for information on cystoscopy on youtube to be aware of what to expect from the procedure to reduce possible distress, pain or anxiety (15). to the best of our knowledge, we are the first to analyze the quality of youtube information on cystoscopy. the aim of the current study was to investigate the quality of youtube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users. materials and methods search strategy and video selection criteria on the 26th of february 2021, a systematic search on youtube was conducted. the key word used was “cystoscopy”. before selecting the videos, to avoid suggestions based on previous research, any personal accounts were logged out and a virtual private network (vpn) software was set in the united states. no research filter was applied. the first 120 videos (6 pages) were examined (16). as a youtube default setting, the videos were sorted by relevance. the exclusion criteria applied were (figure 1): videos showing different procedures (n = 14), videos without audio (n = 13), videos about topic of other disciplines (n = 7), webinars (n = 7), and videos not in english language (n = 4). for duplicates (n =3), only one was considered. finally, videos part of a compilation were considered as single. for each suitable video, the variables collected were length (in seconds), number of thumbs up and thumbs down, number of channel subscribers, number of views, number of comments, number of videos with disabled comments, objective: the internet is an important and easily accessible source of information. the aim of the current study was to investigate the quality of youtube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users. materials and methods: the search term “cystoscopy” was used on youtube platform and the first 120 youtube videos were analyzed. to assess the video quality patient education materials assessment tool (pemat) for audiovisual (a/v) materials (understandability and actionability sections), misinformation score and global quality score (gqs) were used. results: of all 120 videos, 72 were included in the analyses. of all videos, 59.7% (n = 43), and 40.3% (n = 29) were targeted to general public and healthcare workers. moreover, “technical aspects” was the main topic addressed (n = 29, 40.3%). the median pemat a/v understandability and actionability scores were 50.0% (iqr: 39.1-70.0) and 66.7% (iqr: 33.3100.0), respectively. the median misinformation score ranged from 1.0 to 3.0. according to gqs, 22 (30.6%), 26 (36.1%), 16 (22.2%), 8 (11.1%) videos were poor, generally poor, moderate, and good, respectively. no video was evaluated as excellent. conclusions: today, youtube videos on cystoscopy are more frequently uploaded by healthcare workers, who share information about specific aspects of this procedure. however, the quality of youtube contents on cystoscopy is still poor. therefore, currently users interested in cystoscopy cannot rely on youtube to get good informative material on this topic. in consequence, future authors should focus on improving the quality of video contents on cystoscopy. key words: urethrocystoscopy; social media; urology; internet; pemat. submitted 5 november 2021; accepted 20 december 2021 introduction cystoscopy is an endoscopic procedure used to explore the bladder and the urethra in their entirety. it is used with diagnostic, therapeutic and follow-up purposes in oncological, such as bladder cancer or upper tract urothelial carcinoma, and non-oncological conditions, such as lower tract urinary symptoms, urinary incontinence, chronic pelvic pain, recurrent urinary tract infections or looking for cystoscopy on youtube: are videos a reliable information tool for internet users? carmine turco 1, claudia collà ruvolo 1, simone cilio 1, giuseppe celentano 1, gianluigi califano 1, massimiliano creta 1, marco capece 1, roberto la rocca 1, luigi napolitano 1, francesco mangiapia 1, lorenzo spirito 1, simone morra 1, alberto melchionna 1, ferdinando fusco 2, vincenzo mirone 1, nicola longo 1 1 department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples “federico ii”, italy; 2 department of woman, child and general and specialized surgery, university of campania “luigi vanvitelli”, naples, italy. doi: 10.4081/aiua.2022.1.57 summary archivio italiano di urologia e andrologia 2022; 94, 1 c. turco, c. collà ruvolo, s. cilio 58 persistence on youtube (defined as days between the date of upload and the date of analysis), video author (defined as associations, academic hospitals/university, no academic hospitals, healthcare worker, patients, others), video target (general public or healthcare workers) and video topic (explanation to patient, personal experience, and technical aspects). finally, video power index (vpi), calculated as like ratio (thumbs up x 100/thumbs up + thumbs down) multiplied by view ratio (views/persistence time) divided by 100, was used as an indicator of popularity, as previously done (11). quality and misinformation assessment tools the videos quality was independently assessed by two urology residents [a junior (third year) and a senior (fifth year)]. a third investigator (an associate professor) sorted any differences, and consensus was achieved among reviewers. the following video quality assessment tools were used: the patient education materials assessment tool for audio-visual content (pemat a/v), the misinformation score and the global quality score (gqs). first, the pemat a/v is an instrument to establish the understandability and the actionability of informative audiovisual contents for patients on different topics. understandability and actionability are respectively evaluated by 13 plus 4 questions. each question can be answered with three options: “agree”, “not agree” and “not applicable”. the final score is a percentage: the higher is the percentage, the more understandable and/or actionable is the material (11). second, a misinformation score was appositely created for the study. it consisted of five items: 1) good explanation of the topic, 2) indications are clear, 3) good execution of the procedure, 4) european association of urology (eau) guidelines concordance and 5) pathological cases are showed. each item was evaluated by five possible different levels of agreement/disagreement (1 = strongly disagree, 2 = disagree, 3 = not agree or disagree, 4 = agree, 5 = strongly agree) (11). the lower was the result, the higher was the misinformation level. finally, gqs is a scale evaluating the overall quality and the clinical utility of each video (11). the five permitted options ranged from 1 (poor quality, poor flow of the site, most information missing, not at all useful for patients) to 5 (excellent quality and excellent flow, very useful for patients). the higher was the score, the better was the quality of the video. statistical analyses descriptive statistics were presented as medians and interquartile ranges (iqr) for continuously coded variables or counts and percentages for categorically coded variables. chi-square test and kruskal-wallis test examined the statistical significance in proportions and medians differences. cohen kappa statistics was used to measure the reliability of the investigator's evaluations of the videos. pearson’s test was used to assess potential correlations between the variables. in all statistical analyses, r software (www.rproject.org) environment for statistical computing and graphics (r version 4.0.0) and microsoft excel 2019 were used. all tests were two-sided with a level of significance set at p < 0.05. results videographic characteristics of all 120 videos examined, 72 were eligible (table 1). the median length was 160.5 seconds (iqr: 109.8-403.5, range: 39-1092), the median number of views was 13787.5 (iqr: 2306.2-52604, range: 94-910019) and the median persistence time on youtube was 1437.5 days (iqr: 835.8-2029.8, range: 75-4105). moreover, across the sample, the median number of thumbs up, thumbs down, comments and subscribers were 40.0 (iqr: 7.0147.0, range: 0-2151), 5.0 (iqr: 1.0-18.5, range: 0-278), 2.0 (iqr: 0-16.8, range: 0-475) and 5930.0 (iqr: 653.822025, range: 5-3160000), respectively. furthermore, 15 videos (20.8%) had disabled comments. of all videos, 43.1% (n = 31), 1.4% (n = 1), 8.4% (n = 6), 18.0% (n = 13), 19.4% (n = 14) and 9.7% (n = 7) were produced by associations, academic hospitals or universities, no academic hospitals, healthcare worker, patients, others, respectively. additionally, 59.7% (n = 43), and 40.3% figure 1. prisma diagram depicting inclusion and exclusion criteria of youtube video search. 59archivio italiano di urologia e andrologia 2022; 94, 1 quality of videos about cystoscopies on youtube (n = 29), were targeted to general public and healthcare workers, respectively. finally, technical aspects was the main topic addressed (n = 29, 40.3%), followed by explanation to patient (n = 27, 37.5%) and personal experience (n = 16, 22.2%). video quality assessment the median pemat a/v understandability score was 50.0% (iqr: 39.1-70.0), and the median pemat a/v actionability score was 66.7% (iqr: 33.3-100.0). according to video target (general public vs healthcare workers) a statistically significant difference was recorded for understandability (55.6 vs 40.0%, p = 0.01), but not for actionability (66.7 vs 66.7%, p = 0.7) (table 2a). the cohen kappa statistic was used to measure the reliability of the investigator’s assessments between the two evaluation times. the cohen kappa recorded was 0.46 for the actionability score and 0.17 for the understandability score. the median misinformation score ranged from 1.0 (item 3: good execution of the procedure; item 5: pathological cases are showed) to 3.0 (item 1: good explanation of the topic; item 4: eau guidelines concordance). according to video target (general public vs healthcare workers), no statistically significant difference was recorded. moreover, a median overall misinformation score ≤ 2.5 was recorded in 68.1% (n = 49) videos vs 31.9% (n = 23) videos with a median overall misinformation score > 2.5 (table 2b). according to gqs, 22 (30.6%), 26 (36.1%), 16 (22.2%), 8 (11.1%) videos were poor, generally poor, moderate, and good, respectively. no video was evaluated as excellent. according to video target (general public vs healthcare workers), no statistically significant differences were recorded (table 2c). variable correlations we tested for possible correlations. first, we examined possible correlations between videographic characteristics (length in seconds, thumbs up, thumbs down, number of views, persistence on youtube, channel subscribers and vpi) and quality assessment tools (pemat understandability and actionability scores, misinformation score and gqs). second, possible correlations within quality assessment tools were performed. we recorded a statistically significant positive correlation between pemat a/v understandability and misinformation score (r = 0.50, p ≤ 0.001) and between pemat a/v actionability scores and misinformation score (r = 0.42 p ≤ 0.001). conversely, no statistically significant result was recorded between the other correlations (r coefficients ranged from -0.14 to 0.21, all p ≥ 0.1). discussion youtube is the second most visited platform and allows people to upload video table 1. videographic characteristics of 72 youtube videos on “cystoscopy” recorded on the 26th of february 2021. videographic characteristics overall value length, sec median (iqr) 160.5 (109.8-403.5) range 39-1092 thumbs up, n median (iqr) 40.0 (7.0-147.0) range 0-2151 thumbs down, n median (iqr) 5.0 (1.0-18.5) range 0-278 subscribers, n median (iqr) 5930.0 (653.8-22025) range 5-3160000 views, n median (iqr) 13787.5 (2306.2-52604) range 94-910019 comments, n median (iqr) 2.0 (0-16.8) range 0-475 disabled comments, n (%) no 57 (79.2) yes 15 (20.8) persistence on youtubetm (days) median (iqr) 1437.5 (835.8-2029.8) range 75-4105 author, n (%) associations 31 (43.1) academic hospitals universities 1 (1.4) no academic hospitals 6 (8.4) healthcare worker 13 (18.0) patients 14 (19.4) others 7 (9.7) target, n (%) general public 43 (59.7) healthcare workers 29 (40.3) video topic, n (%) technical aspects 29 (40.3) explaination to patient 27 (37.5) personal experience 16 (22.2) vpi, n median (iqr) 8.8 (2.2-31.1) range 0-4609.88853 iqr: interquartile range; vpi: video power index. table 2. a) patient education materials assessment tool for audio-visual content (pemat a/v) score, b) misinformation score and c) global quality score (gqs) of 72 youtube videos on “cystoscopy” recorded on the 26th of february 2021. variable overall value general public healthcare workers p-value n = 72 n = 43 (59.7%) n = 29 (40.3%) a) pemat a/v, (%) understandability median (iqr) 50.0 (39.1-70.0) 55.6 (40.8-72.7) 40.0 (30.0-58.3) 0.01 actionability median (iqr) 66.7 (33.3-100.0) 66.7 (33.3-100.0) 66.7 (33.3-100.0) 0.7 b) misinformation 1) good explanation of the topic median (iqr) 3.0 (2.0-4.0) 3.0 (2.0-4.0) 3.0 (2.0-4.0) 0.3 2) indications are clear median (iqr) 2.0 (1.0-3.0) 3.0 (1.5-3.0) 2.0 (1.0-3.0) 0.2 3) good execution of the procedures median (iqr) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-2.0) 0.4 4) eau guidelines concordance median (iqr) 3.0 (2.0-3.0) 3.0 (2.0-3.0) 3.0 (2.0-3.0) 0.2 5) pathological cases are showed median (iqr) 1.0 (1.0-2.0) 1.0 (1.0-1.5) 1.0 (1.0-4.0) 0.7 overall misinformation score ≤ 2.5 49 (68.1) 30 (69.8) 19 (65.5) 0.9> 2.5 23 (31.9) 13 (30.2) 10 (34.5) c) gqs poor 22 (30.6) 13 (30.2) 9 (31.0) generally poor 26 (36.1) 15 (34.9) 11 (37.9) moderate 16 (22.2) 10 (23.3) 6 (20.7) 0.9 good 8 (11.1) 5 (11.6) 3 (10.3) excellent 0 (0) 0 (0) 0 (0) iqr: interquartile range; eau: european association of urology. archivio italiano di urologia e andrologia 2022; 94, 1 c. turco, c. collà ruvolo, s. cilio 60 regarding health topics. however, currently, no filter or revision progress of video contents exists. in consequence, youtube can represent a risk for misinformation. since cystoscopy is recommended both for diagnosis and follow up of oncological and non-oncological conditions, we took into consideration the importance of this procedure and the impact of a correct information on youtube. therefore, the aim of the current study was to evaluate the quality of youtube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users. to the best of our knowledge, no previous investigators examined the quality of youtube contents on cystoscopy procedure. we addressed this void and identified several noteworthy observations. first, we recorded that approximately 80% of videos were uploaded by hospitals and/or healthcare workers and approximately 60% of videos were targeted to general public. moreover, the main topic addressed concerned technical aspects (40%), such as the assembly of a cystoscope or the preparation of a sterile draping. in consequence, according to our results, today youtube is more frequently managed by people with a medical background, rather than no-medical educated individuals, in terms of uploading contents regarding cystoscopy. therefore, it would be expected that videos uploaded by healthcare workers should be characterized by good quality contents. thus, it is important to evaluate video contents to confirm or not this expectation. second, considering the pemat a/v tool, we recorded an overall understandability score of 50.0% and, specifically, a higher understandability score was recorded in video targeted to general public (55.6%), relative to healthcare workers (40.0%). conversely, we recorded a higher overall actionability score (66.7%), relative to understandability, and no differences were recorded between video targets. according to shoemaker at al., a pemat a/v score < 70% is considered poorly understandable and poorly actionable (17). in consequence, nowadays youtube videos regarding cystoscopy are more actionable than understandable but are still considered as not sufficient quality videos. similarly, to our results, previous studies regarding other medical topics recorded low understandability and actionability scores. for example, salama et al. (18) evaluated 53 videos on hypospadias recording an understandability and an actionability score of 54.5 and 21.8%, respectively. moreover, rubel et al. (19) analyzed the quality of 40 youtube videos on sinusitis and obtained an understandability and an actionability score of 46.3 and 57.7%, respectively. in conclusion, future authors should focus on uploading better quality videos to achieve higher pemat a/v scores, regardless of the topic. third, considering the misinformation score, the lowest median score was recorded for item 3 (“good execution of the procedure”) and item 5 (“pathological cases are showed)”. consequently, viewers interested in cystoscopy may not be sufficiently informed on how the procedure is executed or how their conditions appear. moreover, none of the questions proposed reached the maximum score. consequently, according to the misinformation score appositely created for this study, none of the video analyzed could grant a complete information to viewers. fourth, similarly to the results recorded from the other quality assessment tools applied, gqs also indicated a low video quality. indeed, almost 70% of videos were considered as poor or generally poor and none was evaluated as excellent. these observations were confirmed even when the videos were analyzed according to video target: both general public and healthcare workers targeted videos were mostly evaluated as low quality. fifth, we recorded a positive correlation between pemat a/v understandability score and misinformation score (r = 0.50) and between pemat a/v actionability score and the misinformation score (r = 0.42). in consequence, the more the video was understandable and/or actionable, the higher was the quality of information. these results corroborated our findings, implying that all the tools used demonstrated concordantly a low youtube video quality on cystoscopy. conversely, no statistically significant correlations were found between quality assessment tools and videographic characteristics. the lack of correlations may be interpreted as an independent relationship between the quality content and the users’ interaction with the youtube videos. in consequence, today videos aspects such as views, thumbs up, thumbs down or number of subscribers cannot be used as a quality indicator, in a positive or negative interpretation. for example, loeb et al. recorded a negative correlation between scientific quality and viewer engagement, measured as views/mo (-0.24; p = 0.004) or thumbs up/views (-0.20; p = 0.015), indicating that even videos highly watched were characterized by poor quality information (20). taken together, although mostly of youtube videos on cystoscopy are uploaded by hospitals and/or healthcare workers, the quality is still low according to pemat a/v score, misinformation score and gqs. youtube users, that may be even represented by patients undergoing a cystoscopy, could not get access to sufficiently good quality contents. in consequence, youtube today cannot be recommended as a reliable source of medical information about this procedure. therefore, since the internet searching is becoming an everyday habitude, future video authors need to focus on uploading higher quality videos to provide better contents to avoid misinformation. as a practical implication, it could be useful to create a proper guideline on cystoscopy approved by urological associations with the intent to guide authors in the video making process. on the other hand, new quality assessment tools might be developed to verify medical contents which are continuously uploaded on youtube. our work is not devoid of limitations. first, search results could change in every moment based on the interactions video-users, so our study represented only a frame of the current situation. second, due to the methodology used, which allowed us to include 72 videos, contents providing different information could have been excluded. third, some videos might not be included in our analysis due to search terms. nonetheless, we assumed that video authors meant to use “cystoscopy” in the title or as keyword. finally, the video quality assessment was a subjective evaluation. to reduce this problem, three different investigators independently analyzed the videos. although these limitations, the present study may be considered as a snapshot of the current information on youtube videos regarding cystoscopy. 61archivio italiano di urologia e andrologia 2022; 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93:366-9. 14. capece m, di giovanni a, cirigliano l, et al. youtube as a source of information on penile prosthesis. andrologia. 2021; e14246. 15. kim hj, kim jw, park hs, et al. the use of a heating pad to reduce anxiety, pain, and distress during cystoscopy in female patients. int urogynecology j. 2019; 30:1705-10. 16. megaly m, khalil c, tadros b, tawadros m. evaluation of educational value of youtube videos for patients with coeliac disease. int j celiac dis. 2016; 4:102-4. 17. shoemaker sj, wolf ms, brach c. development of the patient education materials assessment tool (pemat): a new measure of understandability and actionability for print and audiovisual patient information. patient educ couns. 2014; 96:395-403. 18. salama a, panoch j, bandali e, et al. consulting «dr. youtube»: an objective evaluation of hypospadias videos on a popular videosharing website. j pediatr urol. 2020; 16:70.e1-70.e9. 19. rubel ke, alwani mm, nwosu oi, et al. understandability and actionability of audiovisual patient education materials on sinusitis. int forum allergy rhinol. 2020; 10:564-71. 20. loeb s, sengupta s, butaney m, et al. dissemination of misinformative and biased information about prostate cancer on youtube. eur urol 2019; 75:564-7. correspondence carmine turco, md car.turco87@gmail.com claudia collà ruvolo, md (corresponding author) c.collaruvolo@gmail.com simone cilio, md simocilio.av@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com gianluigi califano, md gianl.califano2@gmail.com massimiliano creta, md max.creta@gmail.com marco capece, md drmarcocapece@gmail.com roberto la rocca, md robertolarocca87@gmail.com luigi napolitano, md luiginap89@gmail.com francesco mangiapia, md mangiapiaf@gmail.com lorenzo spirito, md lorenzospirito@msn.com simone morra, md simonemorra@outlook.com alberto melchionna, md alb.melchionna@gmail.com vincenzo mirone, md mirone@unina.it nicola longo, md nicola.longo@unina.it department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples “federico ii”, italy ferdinando fusco, md ferdinando-fusco@libero.it department of woman, child and general and specialized surgery, university of campania “luigi vanvitelli”, naples, italy cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2020; 92, 3196 case report no conflict of interest declared. doi: 10.4081/aiua.2020.3.196 bone pain palliation outcomes and possibility of radium-223 re-treatment in mcrpc viviana frantellizzi 1, julia lazri 2, mariano pontico 3, arianna pani 4, giuseppe de vincentis 2 1 department of molecular medicine, sapienza university of rome, rome, italy; 2 department of radiological sciences, oncology and anatomical pathology, sapienza university of rome, rome, italy; 3 ph.d., program in morphogenesis & tissue engineering, “sapienza” university of rome, rome, italy; 4 clinical pharmacology and toxicology, university of milan, milan, italy. objective. bone secondary localizations from metastatic castration-resistant prostate cancer are associated with an increase in mortality and a reduction in the patient’s quality of life. radium-223 is a targeted alpha-therapy approved for the treatment of mcrpc (metastatic castration resistant prostate cancer) patients with symptomatic bone metastases. to our knowledge, no previous study has been performed assessing the bone pain palliation outcomes following radium-223 therapy. materials and methods. a mcrpc patient with symptomatic bone localizations and relevant bone pain symptoms has been subjected to radium-223 treatment. pain was assessed over time from the first administration of radium-223 to follow-up. results. after radium-223 treatment, patient showed a significant bpi (brief pain inventory) decline from 7 to 4 and a concomitant partial regression of multiple bone hot spots in the bone scan exam. three months after the last infusion of radium-223, further bpi decline (from 4 to 2) with bone scan depicting stable disease was observed. however, after 6 months from radium-223 treatment end, bpi increased from 2 to 10. conclusions. taking into account the effectiveness on bone pain relief and the low toxicity profile showed by radium-223 treatment, we encourage further analysis on large cohort to investigate the clinical outcome after radium-223 treatment, in terms of bone pain palliation, together with the possibility of radium-223 re-treatment in selected patients.. key words: radium-223 dichloride; bone pain; palliative treatment; mcrpc. submitted 28 january 2020; accepted 18 february 2020 summary introduction prostate cancer (pca) in men worldwide is the second most common cancer (1, 2). most subjects with metastatic pca, following a median of 18-24 months of endocrine therapy, no longer respond to traditional androgen deprivation therapy (adt) (3, 4) and are categorized as castration-resistant prostate cancer (crpc), leading to disease progression (5, 6). crpc disease progression is characterized by the presence of pain-inducing bone metastases (90% of patients), with the increase in total alkaline phosphatase (talp) and prostate-specific antigen (psa) levels (7, 8). the development of bone metastases is associated with an increase in mortality and a reduction in the patient’s health-related quality of life (qol) (9-11). treatment options for metastatic crpc (mcrpc) have recently and include cytotoxic therapy (e.g., docetaxel, cabazitaxel), immunotherapy, oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), bone health agents (e.g., denosumab and zoledronic acid) and targeted alpha-therapy (radium-223 dichloride) (12-14). radium223 has been approved for the treatment of patients with mcrpc with symptomatic bone metastases and no known visceral metastatic disease (15). this radiopharmaceutical have a dual mechanism of action, destroying bone-metastatic cancer cells and affecting tumor-induced pathological bone activity (16). currently, radium-223 is approved as monotherapy or in combination with a luteinizing hormone-releasing hormone (lhrh) analogue for the treatment of adult patients with mcrpc who are in progression after at least two prior lines of systemic therapy (other than lhrh analogues), or ineligible for any available systemic mcrpc treatment (17). pharmacovigilance risk assessment committee (prac) of european medicines agency (ema) carried out a review on radium-223 after data from a clinical study suggested that patients treated with radium-223 in combination with abiraterone and prednisone/prednisolone could be at risk of dying earlier and had more fractures than patients given placebo with abiraterone and prednisone/prednisolone (18). the above recommendations are based on the assessment of data resulting from a randomized, double-blind, placebo-controlled phase iii trial (era-223), which showed an increased incidence of skeletal-related events (sre) (28.6% vs 11.4%), a possible reduction in median overall survival (os) (30.7 months vs 33.3 months, hr 1.195, p = 0.13) and an increased risk of radiological non-bone progression (hr 1.376, p = 0.07) among patients receiving radium-223 in combination with abiraterone acetate plus prednisone/prednisolone (n = 401) compared to patients receiving placebo in combination with abiraterone acetate plus prednisone/prednisolone (n = 405) (19). despite several clinical trials and prospective studies have been carried out aiming to investigate the outcomes of radium-223 therapy in terms of os, progression-free survival (pfs), sre and multiple qol parameters (20), to our knowledge, in the literature there are no studies assessing specifically the bone pain palliation outcomes, as an independent factor, following the end of radium-223 treatment. the following study 08fantellizzi_stesura seveso 24/09/20 14:19 pagina 196 197archivio italiano di urologia e andrologia 2020; 92, 3 bone pain palliation and radium-223 re-treatment describes a mcrpc patient, presenting a significant reduction of bone pain during the therapy, followed by further bone pain palliation after the first 3 months following the end of radium-223 therapy without modification of pain-relieving medications. materials and methods a 77 years-old man was diagnosed with pca (gleason score 9, 4+5) in february 2014. he began adt with triptorelin and bicalutamide for 19 months. furthermore, after 2 years from the diagnosis, he has been treated with external beam radiation therapy (ebrt) to secondary bone lesions on the right pelvis. he came to our attention in november 2016 with a psa recurrence (psa 168 ng/ml) despite adt, his testosterone level was 0.34 ng/dl), therefore he was diagnosed with mcrpc. the patient presented positive 99mtc-hdp bone scan imaging with increased uptake in the cranium, in both scapulae, in the left humerus and radius, in multiple ribs and vertebrae, in the pelvis and in the left femur (figure 1a). the ct scan was negative for visceral metastasis. he was defined as a poly-metastatic patient (6-20 metastatic foci). therefore, we started radium-223 treatment. the brief pain inventory by numeric rating scale (bpi) value was 7 in spite of nonsteroidal antiinflammatory drug (nsaid) (ketorolac) and acetaminophen treatment. results after 6 cycles of radium-223 treatment, bpi declined from 7 to 4 without modification of pain-relieving medications. the bone scan performed in april 2017 showed a partial regression of multiple bone hot spots (figure 1b). the patient reported further improvement with bpi that declined from 4 to 2 after 3 months from the last administration of radium-223 treatment with stable disease resulting in the bone scan. nevertheless, at 6 months follow-up bpi increased from 2 to 10 without modification of pain-relieving medications. pain score measurements during and after the radium-223 treatment are shown in figure 2. the patient showed progression in the 99mtc-hdp bone scan performed in october 2017, after 6 months from the end of the radium-223 therapy (figure 1c), with extension of the areas of pathological uptake previously reported. unfortunately, after 13 months of follow-up, the patient died for multi-organ failure. figure 1a. baseline 99mtc-hdp bone scan imaging. figure 1b. end-of treatment 99mtc-hdp bone scan imaging. figure 1c. 99mtc-hdp bone scan imaging at 6 months follow-up. figure 2. bpi trend over time. 08fantellizzi_stesura seveso 24/09/20 14:19 pagina 197 archivio italiano di urologia e andrologia 2020; 92, 3 v. frantellizzi, j. lazri, m. pontico, a. pani, g. de vincentis 198 discussion in this study, we presented the case of an mcrpc patient treated with radium-223, showing bone pain reduction during the therapy which continued with a further decline for the next 3 months after the end treatment. nevertheless, after 6 months from radium-223 treatment, bpi suddenly increased from 2 to 10 with the radiological progression of disease described in several bone districts, revealed with bone scan. the phase 3 trial alsympca showed a significant effect of radium-223 on os and a delay in median time to the first sre (21). in the meantime, several retrospective studies reported a difference in median os between patients who received 1 to 4 versus 5 to 6 injections, demonstrating that a higher number of radium-223 injections was associated with prolonged os (median os of 6.2 months, versus 17.9 months) (22). alsympca show furthermore that radium-223 patients reduced the risk of need for ebrt for bone pain and notably delayed the time to first use of opioids (23). this is associated with significant palliation of bone pain by the radiopharmaceutical. however, alsympca was not planned to evaluate the effect of radium-223 on pain; any response to pain observed or lack of it was not considered a reason to stop treatment with radium-223. the effect of treatment on pain was not systematically documented as it was not one of the objectives of the study. currently, patients receive up to six intravenous injections of radium-223, 55 kbq/kg in 4-week intervals. there have been recent studies of retreatment with radium-223 (24). one of these is the open-label, phase 1/2 study (nct01934790) (25). this study, including 44 patients with no disease progression in bone during the first treatment and presence of later progression, that received radium-223 re-treatment, up to 6 additional radium-223 injections, showed that retreatment with radium-223 was well tolerated with favorable effects on disease progression. another ongoing phase ii study (nct02023697) evaluated standard dose (55 kbq/kg every 4 weeks up to 6 injections) versus high dose (88 kbq/kg every 4 weeks up to 6 injections) and versus extended standard dose (55 kbq/kg every 4 weeks up to 12 injections) (26, 27). in literature has been already showed how radium-223 could significantly extend os, associated with a delay in median time to the first symptomatic sre, meaningful improvement in qol and bone pain palliation (23, 28). several trials showed that radium-223 is well tolerated and has a favorable hematologic safety profile (29), with a low incidence of myelosuppression (30). such safety is confirmed from long-term safety alsympca analysis up to 3 years from first injection, which indicated that radium-223 remained still well tolerated, with low myelosuppression incidence and no new safety concerns (31). it is possible to postulate that some patients after initial treatment may derive benefit from extended treatment with radium-223. the open-label, phase 1/2 nct01934790 trial (25) showed that re-treatment with radium-223 sustained benefit on disease and progression was well tolerated. in particular, it showed a low incidence of clinical events such as symptomatic sre or radiographic bone progression. furthermore, in this study talp declined from baseline values after re-treatment, suggesting a continuation of the biologic effects of radium-223; moreover, the median os increased to 24.4 months at the end of the 2-year active follow-up period. a further study focused on these patients confirms its safety in a 2-year active follow-up analysis, especially with regards to the minimal hematologic toxicity and efficacy outcome from 2-year follow-up of the retreatment with radium-223. in view of these remarkable results and based on our wide experience, we could reasonably assume that this patient would have provided clinical benefits if he continued the radium-223 therapy. conclusions further analysis should be conducted on a large cohort to evaluate the clinical outcome in terms of bone pain palliation after radium-223 treatment and the possibility, considering the low toxicity profile, of re-treatment in selected patients. ethical approval this study has been approved by the local ethical committee. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent informed consent was obtained from all individual participants included in the study. research involving human participants and/or animals this article does not contain any studies with animals performed by any of the authors. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2016. ca cancer j clin. 2016; 66:7-30. 2. santer fr, erb hh, mcneill rv. therapy escape mechanisms in the malignant prostate. semin cancer biol. 2015; 35:133-44. 3. sciarra a, gentilucci a, silvestri i, et al. androgen receptor variant 7 (ar-v7) in sequencing therapeutic agents for castratrion resistant prostate cancer: a critical review. medicine (baltimore) 2019; 98:e15608. 4. ricci m, frantellizzi v, bulzonetti n, de vincentis g. reversibility of castration resistance status after radium-223 dichloride treatment: clinical evidence and review of the literature. int j radiat biol. 2019; 95:554-561. 5. cornford p, bellmunt j, bolla m, et al. eau-estro-siog guidelines on prostate cancer. part ii: treatment of relapsing, metastatic, and castration-resistant prostate cancer. eur urol. 2017; 71:630-42. 6. lowrance wt, roth bj, kirkby e, et al. castration-resistant prostate cancer: aua guideline amendment 2015. j urol. 2016; 195:1444-52. 08fantellizzi_stesura seveso 24/09/20 14:19 pagina 198 199archivio italiano di urologia e andrologia 2020; 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44:1671-8. 18. o'sullivan jm, heinrich d, james nd, et al. the case against the european medicines agency's change to the label for radium223 for the treatment of metastatic castration-resistant prostate cancer. eur urol. 2019; 75:e51-e2. 19. smith m, parker c, saad f, et al. addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (era 223): a randomised, double-blind, placebo-controlled, phase 3 trial. the lancet. oncology. 2019; 20:408-19. 20. saad f, gillessen s, heinrich d, et al. disease characteristics and completion of treatment in patients with metastatic castrationresistant prostate cancer treated with radium-223 in an international early access program. clin genitourin cancer. 2019; 17:348355.e5 21. parker c, nilsson s, heinrich d, et al. alpha emitter radium223 and survival in metastatic prostate cancer. n engl j med. 2013; 369:213-23. 22. sartor o, coleman r, nilsson s, et al. effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. the lancet. oncology. 2014; 15:738-46. 23. nilsson s, cislo p, sartor o, et al. patient-reported quality-oflife analysis of radium-223 dichloride from the phase iii alsympca study. ann oncol. 2016; 27:868-74. 24. sartor ao, heinrich d, mariados n, et al. radium-223 (ra223) re-treatment (re-tx): first experience from an international, multicenter, prospective study in patients (pts) with castration-resistant prostate cancer and bone metastases (mcrpc). journal of clinical oncology. 2016; 34(suppl 2):197. 25. sartor o, heinrich d, mariados n, et al. re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases. prostate. 2019; 79:1683-91. 26. parker cc, pascoe s, chodacki a, et al. a randomized, doubleblind, dose-finding, multicenter, phase 2 study of radium chloride (ra 223) in patients with bone metastases and castration-resistant prostate cancer. eur urol. 2013; 63:189-97. 27. nct02023697. radium-223 dichloride 50 kbq/kg (55 kbq/kg after implementation of nist update) versus 80 kbq/kg (88 kbq/kg after implementation of nist update), and versus 50 kbq/kg (55 kbq/kg after implementation of nist update) in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to the bone. https://clinicaltrials.gov/ct2/show/ results/nct0202369. 28. nilsson s, larsen rh, fossa sd, et al. first clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. clin cancer res. 2005; 11:4451-9. 29. prelaj a, rebuzzi se, buzzacchino f, et al. radium-223 in patients with metastatic castration-resistant prostate cancer: efficacy and safety in clinical practice. oncol lett. 2019; 17:1467-76. 30. de vincentis g, follacchio ga, frantellizzi v, et al. 223radichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature. aging clin exp res. 2018; 30:677-680. 31. vogelzang nj, coleman re, michalski jm, et al. hematologic safety of radium-223 dichloride: baseline prognostic factors associated with myelosuppression in the alsympca trial. clin genitourin cancer. 2017; 15:42-52.e8. correspondence viviana frantellizzi, md, phd viviana.frantellizzi@uniroma1.it department of molecular medicine, sapienza university of rome viale regina elena 324, 00161 rome (italy) julia lazri, md julia.lazri@uniroma1.it giuseppe de vincentis, md, phd giuseppe.devincentis@uniroma1.it department of radiological sciences, oncology and anatomical pathology, sapienza university of rome, viale regina elena 324, rome (italy) mariano pontico, md mariano.pontico@uniroma1.it ph.d program in morphogenesis & tissue engineering, “sapienza” university of rome, viale regina elena 324, rome (italy) arianna pani, md arianna.pani@gmail.com clinical pharmacology and toxicology, university of milan, l.go de benedetti 1, milan (italy) 08fantellizzi_stesura seveso 24/09/20 14:20 pagina 199 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4396 original paper no conflict of interest declared. introduction prostate cancer (pca) is the most common neoplasm in men and accounts for 27% of all cancers diagnosed (1). in developed countries, population awareness and wide prostatic specific antigen (psa) screening has resulted in an early on-set detection, with most cases being discovered as localized disease and therefore being eligible for definitive therapy, including radical prostatectomy or radiotherapy (2). surgical excision of the prostate may be carried out either with a retropubic open approach or with the laparoscopic or robot-assisted technique (2). the goal of radical prostatectomy, is eradication of the disease with preservation of continence and erectile functions (3). due to high-costs of acquiring and maintaining robotic equipment, the retropubic open approach is still being practiced alongside newer methods worldwide, providing excellent results in patient survival rates and quality of life (4). in this study we aimed to evaluate two methods of anaesthesia (general and combined epidural-spinal) in patients undergoing open retropubic radical prostatectomy and define whether these may have an impact on the oncological outcome and safety of the procedure. materials and methods the study was conducted at the 2nd urology university department of sismanoglio hospital in athens greece, from august 2020 to july 2022, after being approved by the institutional review board of the hospital. patients with clinically localized pca and eligible for radical retropubic prostatectomy (rrp), were preoperatively allocated to receive either combined epidural and spinal anaesthesia (cesa) or general anaesthesia (ga). all patients were preoperatively informed about both methods of anaesthesia and signed a consent form. patients with a medical history of severe heart disease, haemostasis disorders, previous pelvic surgery and lung disease were excluded from the study. a body mass index (bmi) value was calculated for all patients, preoperatively, as weight in kg divided by squared height in meters (kg/m2). there are 4 bmi categories underweight (< 18.5), normal weight (18.5-24.9), overweight (25-29.9) and obesity (> 30). objective: the aim of this study is to determine if patients undergoing radical retropubic prostatectomy with localized prostate cancer under combined (epidural-spinal) anaesthesia have any benefit over patients undergoing the procedure under general anaesthesia. material and methods: patients with clinically localised prostate cancer, scheduled for radical retropubic prostatectomy, were allocated to undergo the operation under either general anaesthesia (ga) or under combined (epidural-spinal) (cesa) anaesthesia. several parameters were recorded both preoperatively (medical history, biometric data, psa, biopsy gleason score) and postoperatively (blood pressure, heart rate, haemoglobin levels, operation time and total hospital stay). in addition, mean arterial pressure, change in heart rate, total blood loss, blood transfusions, sas score, intravenous fluid administration and operation time were also noted down intraoperatively. patient pain levels and total satisfaction were evaluated using appropriate questionnaires. at the 12-month follow-up, biochemical recurrence using psa levels and urinary continence status were evaluated. results: a total of 60 patients were included (30 in each group). intraoperatively, mean map and heart rate change was higher in the ga group (map+7,46, hr+27) and mean sas was higher in the cesa group (+0.93). the time needed for patients’ recovery was faster (-3.5 min) and hospitalization was shorter for patients in the cesa group (-0.6 days). intraoperative blood loss, time for induction and duration of operation were not significantly different. mean postoperative drop of haemoglobin was greater in the ga group (+0.56) while blood transfusions, vas pain scores and amount of intravenous fluids did not differ significantly between the two groups. no complications were reported. patient satisfaction and urinary continence were comparable between the groups and there were no cases of biochemical recurrence. conclusions: radical retropubic prostatectomy can safely be performed under combined (spinal epidural anaesthesia, with possible benefits of lower blood loss, less post-operative complications and earlier discharge. both procedures have equal oncological and functional outcomes at the 12-month follow-up. key words: prostatic neoplasm; radical prostatectomy; complications; combined anaesthesia. submitted 12 october 2022; accepted 31 october 2022 the effects of method of anaesthesia on the safety and effectiveness of radical retropubic prostatectomy konstantinos pikramenos 1, maria zachou 2, eleftheria apostolatou 1, dimitrios papadopoulos 3, maria mitsogianni 4, athanasios papatsoris 1, ioannis varkarakis 1, iraklis mitsogiannis 1 1 2nd urology department, sismanoglio hospital, national and kapodistrian university of athens, greece; 2 gastroenterology department, sismanoglio hospital, athens greece; 3 anaesthesiology department, evgenidio hospital, national and kapodistrian university of athens, greece; 4 4th department of medical oncology, hygeia hospital, athens, greece. doi: 10.4081/aiua.2022.4.396 summary 397archivio italiano di urologia e andrologia 2022; 94, 4 anesthesia effects on radical prostatectomy patients in the ga group were premedicated with intravenously administered (iv) midazolam (2 mg) and fentanyl (100 mcg). a simple oxygen mask was applied. induction was performed using iv propofol (2.5-3 mg/kg) and lidocaine (40 mg); at that time dexamethasone 8 mg, metoclopramide 10 mg and omeprazole 40 mg were also administered. after successful tracheal intubation, total intravenous anaesthesia (tiva) was maintained by administering propofol (0.05 mg/kg/sec iv) and remifentanil (0.2 mcg/kg/sec iv). pain management was achieved by administering paracetamol (1g iv) and ramadol (100 mg iv) whereas muscle relaxation was obtained by vecuronium (0.6 mg/kg iv). cesa group was performed using an epidural 18g needle and a spinal 27g needle, which were inserted in the l2-l3 or l3-l4 interspace. induction was carried out by spinal intrathecal administration of levobupivacaine (2.63ml of 0.5%) whereas mild sedation was achieved by midazolam (5 mg iv in bolus). all patients were administered dexamethasone 8 mg, metoclopramide 10 mg and omeprazole 40 mg iv, at that time. maintenance was performed 75 minutes after induction and obtained using an epidural administration of levobupivacaine (4-5 ml of 0.5%). an epidural catheter was maintained until successful completion of the procedure and removed in the recovery room. the medications used for both types of anaesthesia are presented in table 1. all patients in both groups received a standard postoperative regimen of intravenous paracetamol (1 g x 4 for the first 2 days) and cefoxitin (1 g x 3 until discharge); a prophylactic dose of enoxaparin was also given subcutaneously for 2 weeks, starting from postoperative day 2. if a patient was experiencing pain that could not be alleviated using the standard analgesic regimen, extra tramadol was administered on demand and recorded by the reviewer. several parameters were recorded intraand postoperatively. the time (minutes) required for induction of anaesthesia, the operation time and the total postoperative time (defined as that required for patients’ recovery, i.e., from completion of the operation to patient transfer to the recovery room) were noted down. intraoperative haemodynamic status was constantly being monitored by measuring systolic pressure (sp) and diastolic arterial pressure (dp) and heart rate every 15 minutes; the mean arterial pressure (map) was also being calculated using the formula map=dp+1/3(sp-dp). haemoglobin levels, both preoperative and at specific times postoperatively (at the 12th, 24th and 48th postoperative hours) were also measured. in addition, total blood loss (litres of fluid collected by suction during surgery which were categorised in < 100 ml, 100-600 ml and > 1000 ml), fluids administered intravenously during surgery (in litres) and the surgical apgar score (sas) (5) were calculated. postoperatively, total hospitalization days, patient pain intensity using the visual analogue scale (vas) and any need for extra analgesics were recorded. vas is based on a linear “zero” (no pain) to “ten” (worst pain possible) scale. patients were asked to quantify their pain on that scale, at three different postoperative time points (after 6, 24, and 48 hours). complications from the cardiovascular and respiratory systems as well as those related to the anaesthetic techniques were recorded; in addition, postoperative headache, nausea and vomiting and any signs of potential nerve damage (manifested as inability to gain leg motility) were also assessed and recorded before hospital discharge (6, 7). all patients upon discharge filled in a short assessment of patient satisfaction (saps) questionnaire (8) measuring their overall satisfaction for the care they received. in saps, satisfaction is measured in a scale of 0 to 28, with 0 to 10 equals to “very dissatisfied”, 11-18 equals to “dissatisfied”, 19-26 equals to “satisfied” and 27-28 equals to “very satisfied”. patients were followed for up to 12 months postoperatively. psa levels were measured at the 6th and 12th month to record a potential biochemical recurrence. at the same time, patients were asked to assess their urinary continence by completing the international consultation on incontinence questionnaire (9) urinary incontinence short form. statistical analysis was carried out using spss 24.0. mean values, standard deviations, median values, interquartile range (iqr) and histograms were used to describe quantitative variables whether the data followed the normal distribution. collected data for systolic blood pressure, diastolic blood pressure, heart rate and haemoglobin were used with new quantitative variables being created by calculating the differences between the aforementioned timepoints for each one of these variables. the kolmogorovsmirnov test was run to check the normality of the distributions. the student's t-test or the non-parametric mannwhitney u test were used to compare quantitative variables between the two groups, depending on whether the data followed the normal distribution. a kruskal-wallis test (nonparametric equivalent of the one-way anova) was used to make comparisons among the bmi-categories in cesa and ga group. moreover, linear or logarithmic models were used to check for differences between the studied groups, taking into account other factors (e.g., demographic and clinical characteristics). in case of asymmetrical distribution, logarithmic transformations of the variables were used. significance levels were bilateral and the statistical significance were set at p < 0.05. results overall, 60 patients were included in the study (30 in each group). both groups were demographically compatable 1. anaesthetic techniques in the study groups. anaesthesia stage combined epidural spinal anaesthesia general anaesthesia premedication none midazolam 2 mg bolus iv fentanyl 100 mcg bolus iv induction levobupivacaine 0.5% 2.6-3cc spinal intrathecal lidocaine 40 mg bolus iv midazolam 5 mg iv propofol 2,5-3 mg/kg bolus iv dexamethasone 8 mg iv dexamethasone 8 mg iv metoclopramide 10 mg iv metoclopramide 10 mg iv omeprazole 40 mg iv omeprazole 40 mg iv maintenance levobupivacaine 0.5% 4-5cc epidural propofol 0.05 mg/kg/sec iv remifentanil 0.2 mcg/kg/sec iv paracetamol 1 g iv tramadol 100 mg iv vecuronium 0.6 mg/kg iv recovery room paracetamol 1g iv paracetamol 1g iv iv = intravenous; mg = milligram; g = grams; kg = kilograms; mcg = microgram. archivio italiano di urologia e andrologia 2022; 94, 4 k. pikramenos, m. zachou, e. apostolatou, et al. 398 rable and homogeneous with regard to age, height, weight, smoking habit, alcohol use, history of diabetes mellitus, biopsy gleason score and preoperative psa. preoperative characteristics are presented in table 2. intraoperative map was found to be significantly higher in the ga group [85.13 ± 11.84] vs. cesa group [77.67 ± 5.66] (p = 0.036) (figure 1). furthermore, patients in the ga group exhibited higher heart rate intraoperatively when compared to the preoperative measurement, as opposed to those in the cesa group who exhibited lower heart rate than the preoperative measurement (ga: +25 (17), cesa: -2 (7), (p < 0.01). intraoperative blood loss, as collected by the suction, did not differ significantly between the two groups. time for anaesthesia induction was identical in both groups (13.6 ± 3.5 min in the cesa group vs. 13.6 ± 2.9 min in the ga group, p > 0.05). duration of the operation in the cesa and ga groups was 127 ± 17.29 min and 126.33 ± 10.93 min, respectively (p > 0.05). however, the time needed for patients’ recovery and transfer to the recovery room was significantly shorter in the cesa group (16.13 ± 4.9 min) as compared to that in the ga group (19.6 ± 3.5) (p = 0.03). statistically significant difference was also noticed in the mean intraoperative sas (8.13 ± 0.63 in the cesa group vs. 7.2 ± 1.37 in the ga group, p < 0.03). a sas score ≤ 6 was recorded in 6 patients (20%) in the ga group in comparison to none in the cesa group (figure 2). hospitalisation was significantly shorter for patients in the cesa group compared to those of the ga group (2.6 ± 0.5 vs. 3.2 ± 0.41, respectively, p = 0.003). postoperative mean drop of haemoglobin was 1.5 ± 0.81 in the cesa group vs. 2.06 ± 1.1 in the ga group (p = 0.029), indicating a statistically significant difference in blood loss in favour of the combined anaesthesia. blood transfusion was required in 1 patient in the cesa group and 2 patients in the ga group (p = 0.54). vas score was found to be equal between the two groups and all patients reported only mild pain 48 hours after the surgery, contrary to moderate and severe pain reported on the day of surgery and 24 hours after. data regarding haemoglobin changes and vas score are listed in tables 3, 4. figure 1. map values in the cesa and ga groups. table 2. demographic and oncological characteristics of patients. demographics cesa (n = 30) ga (n = 30) 95% ci, p-value mean ± sd mean ± sd age (years) 66.93 ± 5.66 66.40 ± 4.89 (-3.42, 4.49), 0.78 * height (m) 1.72 ± 0.078 1.75 ± 0.044 (-0.08, 0.01), 0.140 * weight (kg) 78.8 ± 10.57 81.87 ± 14.96 (-12.75, 6.62), 0.52 * asa physical status (ii/iii) 23/7 20/10 ns ** preoperative psa (ng/ml) 6.81 ± 3.06 8.01 ± 2.78 (-3.38, 0.99), 0.27 * gleason score ns ** 6 6/30 4/30 3+4 10/30 8/30 4+3 8/30 10/30 8 6/30 7/30 9 0/30 1/30 cesa = combined epidural and spinal anaesthesia; ga = general anaesthesia; asa = american society of anaesthesiologists; psa = prostate-specific antigen; ns = non-significant. * independent samples t-test. ** pearson chi-square test. table 3. haemoglobin change within the first 48 hours. hb change cesa group ga group p-value * mean ± sd mean ± sd pre-op/post-op -2.06 ± 1.1 -1.5 ± 0.81 0.029 24h – after surgery -0.9 ± 0.59 -1.18 ± 0.84 0.305 48h – 24h -0.28 ± 0.73 -0.48 ± 0.71 0.439 48h – after surgery -1.18 ± 0.66 -1.67 ± 0.93 0.113 48h – before surgery -3.24 ± 1.19 -3.18 ± 1.19 0.771 pre-op: pre operatively; post-op: post operatively. * independent samples t-test. table 4. vas score within the first 48 hours. vas cesa group ga group p-value * day of surgery 6.47 ± 0.51 6.53 ± 0.51 0.720 24h after surgery 5.13 ± 0.51 5 ± 0.53 0.487 48h after surgery 3.2 ± 0.41 3.33 ± 0.48 0.417 sd: standard deviation; cesa: combined epidural spinal anaesthesia; ga: general anaesthesia; vas: visual analog scale. * independent samples t-test. cesa = combined epidural and spinal anaesthesia; ga = general anaesthesia; sas = surgical apgar score; map = mean arterial pressure. figure 2. sas scores in the cesa and ga groups. cesa = combined epidural and spinal anaesthesia; ga = general anaesthesia; sas = surgical apgar score; map = mean arterial pressure. 399archivio italiano di urologia e andrologia 2022; 94, 4 anesthesia effects on radical prostatectomy no complications were reported across any group and none of the patients in the cesa group reported either post-subarachnoid puncture headache or any nerve damage or difficulty in regaining leg motility. in the cesa group, there was no case with a need for the anaesthesia to be dynamically converted to ga during surgery. additional postoperative analgesic requirements as well as the daily amount of intravenous fluids did not differ significantly between the two groups, (cesa: 2933 ± 703.7 ml daily vs. ga: 3000 ± 845.15 ml, p = 0.945). all patients in both groups reported to be satisfied with the care they received (p > 0.05); also regain of urinary continence was comparable between the two groups after 12 months. lastly, there were no cases of biochemical recurrence in either group at the 6th and 12th postoperative months. when participants were sub-analysed according to bmi categories, there were no underweight patients, 24 of normal weight (cesa: 10, ga: 14), 26 overweight (cesa: 16, ga: 10) and 10 obese patients (cesa: 4, ga: 6). a higher heart range change was observed in obese patients in the ga group when compared to overweight and normal patients (32 vs 25 and 23, respectively; p = 0.002). there was no difference of statistical importance between any other factors, when comparing each bmi group of ga. in the cesa bmi groups, there were no statistical differences for any of the factors. discussion in this comparative study, all patients undergoing rrp for organ-confined pca under either general or combined (epidural and spinal) anaesthesia were safely treated and discharged without any major complications. time for induction of anaesthesia and surgical time were the same in both groups. in addition, no post-subarachnoid puncture headaches, nerve damages or difficulty in regaining leg motility were recorded in the cesa group whereas no cases of vomiting and/or postoperative delirium were found in the ga group. in the ga group, intraoperative heart rate was recorded higher and there was a greater drop in the post-operative mean haemoglobin value, when compared to the cesa group, potentially indicating a greater blood loss in patients under ga. nonetheless the amount of fluids retrieved by the suction was similar in both groups, hence one has to assume that a greater amount of blood was held within the gauzes during surgery. this parameter however was not measured in our study. shir y et al. (10) also demonstrated mean intraoperative blood loss to be significantly higher in patients undergoing surgery under ga compared to those receiving epidural anaesthesia (respective mean values 1940 and 1490 litres) and similar in those receiving combined general/epidural anaesthesia (mean 1810 litres); they concluded that epidural anaesthesia did not reduce bleeding, it was rather the administration of ga that increased intraoperative haemorrhage (10). the authors recognised positive pressure ventilation to be a potential contributing factor, due to the increase in intrathoracic pressure and decrease in venous return to the heart that causes (11), which in turn results in increased peripheral venous pressure (12) and consequent increased bleeding during surgery (13). however, contrary to the results of shir y et al., we found no difference in blood transfusions between the 2 groups. significantly lower blood loss with combined epidural/ga, compared to general alone, was also reported by others (14, 15). sas was statistically different between the groups, with patients in the cesa group having an overall higher mean score, indicating a potentially reduced risk for postoperative complications. it is noteworthy that a sas score < 6, which is deemed a threshold for increased risk for major complications, was reported in 20% of patients in the ga group, compared to none in the cesa group. this potentially implies a greater risk for postoperative complications in those receiving ga. postoperative complications may delay not only patients’ recovery and discharge from hospital but also return to their normal activities with an overall reduction in their quality of life (16). nevertheless, the potential safety benefits of cesa over ga, need to be further investigated in larger-scale studies. both groups reported equal vas scores, with higher pain levels reported immediately after surgery and a constant reduction thereafter. in the literature, there have been reports indicating lower pain levels in patients receiving cesa. dunet f et al. (15) demonstrated an improvement in required postoperative analgesics, within the first 48 hours, in patients undergoing rrp under combined general/epidural anaesthesia over patients receiving ga alone. this observation however, was not confirmed in the present study. patients receiving cesa remained in the operating theatre for a shorter period of time (average -3.5 minutes), compared to those receiving ga, and furthermore their hospitalisation was significantly shorter (-0.6 days). a shorter operating theatre and hospital stay is beneficial for both patients and health services alike, because it reduces patients’ exposure to specific pathogens, reduces anxiety and, at the same time, reduces costs (15, 17). by streamlining the cesa technique for rrp, the duration of surgery will further decrease, leaving time for more operations, thereby increasing hospital incomes (18). medical economics are equally important to other aspects of medicine and treatment options, apart from being personalized, should be cost-effective (19). in general, application of techniques which enable provision of the best health care possible, while reducing risks of hospitalacquired infections and at the same time, requiring less funds, is of great importance. overall satisfaction at the time of discharge was similar in both groups and after a one-year of follow-up, no biochemical recurrences and no difference in the incidence of urinary incontinence, were reported. these results, which are in line with other reports (20), indicating that both methods of anaesthesia are safe to perform with equal oncological and functional results. bmi is another important factor that may potentially influence various parameters during the operation. we have noticed a higher intraoperative hr change in obese patients receiving ga, compared to those in the cesa group. this finding, combined with the higher drop in the mean postoperative haemoglobin level, may indicate a greater blood loss in obese patients. however, due to the archivio italiano di urologia e andrologia 2022; 94, 4 k. pikramenos, m. zachou, e. apostolatou, et al. 400 small number of obese patients (10) included in the study, no clear inference can be drawn on this issue. cai t et al. (21), in their study of 78 patients undergoing radical prostatectomy, reported an increased blood loss in obese patients compared to patients with normal weight; nonetheless the differences were not statistically significant. in contrast to our results, cai et al. also found that obese patients were significantly more likely to have urinary incontinence postoperatively compared to nonobese patients, a finding not observed in our study. lastly, it should be noted that the data presented in this study apply only to patients undergoing open radical prostatectomy and not to those undergoing laparoscopic or robotic procedures. a potential advantage of either form of anaesthesia in these procedures should be investigated in separate studies. conclusions open rrp carried out under combined spinal/epidural anaesthesia is a safe procedure to perform and is associated with less intraoperative blood loss and potentially reduced risks of postoperative complications. it may lead to a shorter total operation time and reduced hospitalization, while providing similar oncological and functional outcomes. further studies are needed to reliably confirm the substantial role of combined anaesthesia in this major oncological operation. references 1. siegel rl, miller kd, fuchs he, jemal a. cancer statistics, 2022. ca cancer j clin 2022; 72:7-33. 2. sebesta em, anderson cb. the surgical management of prostate cancer. semin oncol. 2017; 44:347-357. 3. lepor h. a review of surgical techniques for radical prostatectomy. rev urol 2005; 7(suppl 2):s11-7. 4. kim sp, shah nd, karnes rj, et al. hospitalization costs for radical prostatectomy attributable to robotic surgery. eur urol. 2013; 64:11-6. 5. gawande aa, kwaan mr, regenbogen se, et al. an apgar score for surgery. j am coll surg. 2007; 204:201-8. 6. hinkelbein j, lamperti m, akeson j, et al. european society of anaesthesiology and european board of anaesthesiology guidelines for procedural sedation and analgesia in adults. eur j anaesthesiol. 2018; 35:6-24. 7. horlocker tt. complications of spinal and epidural anesthesia. anesthesiol clin north am. 2000; 18:461-85. 8. hawthorne g, sansoni j, hayes l, et al. measuring patient satisfaction with health care treatment using the short assessment of patient satisfaction measure delivered superior and robust satisfaction estimates. j clin epidemiol. 2014; 67:527-37. 9. avery k, donovan j, peters tj, et al. iciq: a brief and robust measure for evaluating the symptoms and impact of urinary incontinence. neurourol urodyn. 2004; 23:322-30. 10. shir y, raja sn, frank sm, brendler cb. intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia. urology. 1995; 45:993-9. 11. nanas s, magder s. adaptations of the peripheral circulation to peep. am rev respir dis. 1992; 146:688-93. 12. morgan bc, martin we, hornbein tf, et al. hemodynamic effects of intermittent positive pressure respiration. anesthesiology. 1966; 27:584-90. 13. distefano vj, klein ks, nixon je, andrews et. intra-operative analysis of the effects of position and body habitus on surgery of the low back. a preliminary report. clin orthop relat res. 1974(99):51-6. 14. tikuisis r, miliauskas p, samalavicius ne, et al. epidural and general anesthesia versus general anesthesia in radical prostatectomy. medicina (kaunas). 2009; 45:772-7. 15. dunet f, pfister c, deghmani m, et al. clinical results of combined epidural and general anesthesia procedure in radical prostatectomy management. can j urol. 2004; 11:2200-4. 16. archer s, pinto a, vuik s, et al. surgery, complications, and quality of life: a longitudinal cohort study exploring the role of psychosocial factors. ann surg. 2019; 270:95-101. 17. kofler o, prueckner s, weninger e, et al. anesthesia for open radical retropubic prostatectomy: a comparison between combined spinal epidural anesthesia and combined general epidural anesthesia. prostate cancer. 2019; 2019:4921620. 18. gardner ta, bissonette ea, petroni gr, et al. surgical and postoperative factors affecting length of hospital stay after radical prostatectomy. cancer. 2000; 89:424-30. 19. salonia a, crescenti a, suardi n, et al. general versus spinal anesthesia in patients undergoing radical retropubic prostatectomy: results of a prospective, randomized study. urology. 2004; 64:95-100. 20. tsui bc, rashiq s, schopflocher d, et al. epidural anesthesia and cancer recurrence rates after radical prostatectomy. can j anaesth. 2010; 57:107-12. 21. cai t, cocci a, di maida f, et al. visceral adiposity is associated with worse urinary and sexual function recovery after radical prostatectomy: results from a longitudinal cohort study. arch ital urol androl. 2021; 93:285-290. correspondence konstantinos pikramenos, md (corresponding author) kpikramenos@gmail.com eleftheria apostolatou, md apostolatoy1989@gmail.com athanasios papatsoris, md agpapatsoris@yahoo.gr ioannis varkarakis, md medvark3@yahoo.com iraklis mitsogiannis, md imitsog@med.uoa.gr 2nd urology department, sismanoglio hospital, national and kapodistrian university of athens, greece maria zachou, md zachou.maria@yahoo.com gastroenterology department, sismanoglio hospital, athens greece dimitrios papadopoulos, md dimitris76papadopoulos@yahoo.gr anaesthesiology department, evgenidio hospital, national and kapodistrian university of athens, greece maria mitsogianni, md mitsogiannimaria@gmail.com 4th department of medical oncology, hygeia hospital, athens, greece stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12214 1 original paper physiological mechanisms: urethral hypermobility and intrinsic sphincter deficiency (isd) (2). while in the former case there is a more consensual treatment strategy, the latter has a less unanimous management approach. artificial urinary sphincter (aus) is a treatment option for women with severe sui after failure of previous urinary incontinence surgeries and/or as a primary procedure in severe isd (3, 4). however, since it is a challenging technique with high risk morbidity and due to the paucity of longterm follow-up, its current role in the surgical treatment of sui is still lacking evidence. according to the european association of urology guidelines, aus should be implanted only as a last resort procedure and only in expert centers. the panel recommends synthetic sling, colposuspension and autologous sling as first options in these patients. when proposing aus, it is important to inform the patients of the high risk of complications, mechanical failure, or need for explantation (level of evidence 3, grade of recommendations: weak) (3). we report 18-year experience of aus laparoscopic implantation in clinique du pré, assessing the long-term efficacy and risk factors for surgical revision and definitive explantation of aus laparoscopic implantation in female patients. materials and methods a retrospective and descriptive review of all female patients submitted to aus implantation between april 2005 and march 2023 was conducted. eighty-one females with sui as a result of isd were treated with laparoscopic implantation of the ams 800 urinary control system (boston scientific, marborough, ma, usa). all patients were diagnosed with isd based on clinical history, physical examination and urodynamics, namely maximum urethral closure pressures (mucp) and valsalva leak point (vlpp). manual dexterity was determined as no evidence of cognitive impairment, extremity weakening or tremor. inclusion criteria included: motived women with type iii incontinence, with proper dexterity and with no cervical urethral hypermobility; negative marshall/bonney or ulmsten test (urine leakage on straining or coughing not corrected by urethral support); mucp under 20 cmh2o and a vlpp under 60 cmh2o; and normal detrusor funcintroduction and objectives: artificial urinary sphincter (aus) is a treatment option for women with stress urinary incontinence (sui) after failure of previous surgery or as a primary procedure in severe intrinsic sphincter deficiency (isd). the aim of the study was to assess the long-term efficacy and risk factors for surgical revision and definitive explantation of aus laparoscopic implantation in female patients. methods: a retrospective review of all women submitted to aus implantation between april 2005 and march 2023 was conducted. the aus was implanted via transperitoneal laparoscopic approach, by two experienced surgeons. the primary endpoint was postoperative continence. continence was defined as no leakage and no pad usage or leakage and/or pad usage with no impact on social life and failure as leakage and/or pad usage impacting social life. as secondary outcomes, clinical predictive factors for aus revision and definitive explantation were evaluated. results: in the last 18 years, females with a mean age of 68 ± 12 years-old were submitted to laparoscopic implantation of aus. early overall complication rate was 16%, but only one case was clavien-dindo ≥ 3. after a median follow-up of 67 months, 22.2% of the patients needed a device revision, the majority due to mechanical device dysfunction. aus definitive explantation was performed in 16%, mainly due to urethral/vaginal erosion (9.9%) and infection (6.2%). patients with age ≥ 70 years and follow-up ≥ 10 years significantly predisposed for device revision. at the time of the last follow-up, 72% of the patients were keeping the urinary continency. conclusions: laparoscopic aus implantation in females is an effective treatment for sui due to isd. meanwhile, adequate patient selection, multidisciplinary evaluation and careful expectation management are essential to achieving good results, concerning their significant complication rate. key words: artificial urinary sphincter; female urinary incontinence; intrinsic sphincter deficiency; laparoscopy. submitted 20 december 2023; accepted 23 december 2023 introduction stress urinary incontinence (sui) in women is a prevalent and bothersome condition with significant impact on quality of life (1). it is mainly attributed to two pathoeighteen years of experience in laparoscopic implantation of artificial urinary sphincter in women with intrinsic sphincter deficiency débora araújo 1, pierre-emmanuel bryckaert 2, miguel miranda 3, vasco rodrigues 4, nicolas de saint aubert 2, johann menard 2, eric mandron 2 1 urology department, centro hospitalar vila nova de gaia/espinho epe, vila nova de gaia, portugal; 2 urology department, clinique du pré, technopôle université, le mans, france; 3 urology department, centro hospitalar universitário lisboa norte epe, lisboa, portugal; 4 urology department, centro hospitalar universitário de são joão epe, porto, portugal. doi: 10.4081/aiua.2024.12214 summary archivio italiano di urologia e andrologia 2024; 96(1):12214 d. araújo, p.-e. bryckaert, m. miranda, et al. 2 tion and bladder compliance. previous anti-incontinence procedures or the presence of genital prolapse were not a contraindication for aus implantation. patients with urge incontinence alone or previously submitted to pelvic radiotherapy were excluded. the aus was implanted via transperitoneal laparoscopic approach, by two experienced surgeons, according to a previous described technique (5, 6). in cases of 132 concomitant genitourinary prolapse, laparoscopic anterior and posterior mesh sacrocolpopexy was carried out before inserting the aus components, according to a previous described technique (7, 8). informed consent was obtained from all patients. patients were assessed at 6 weeks (sphincter activation), on periodical follow-up visits at 3-, 6and 12-months post-operative and yearly subsequently. data collected included demographic and baseline characteristics; surgical procedure details; post operative results and complications; revision for partial or total component replacement, deactivation and definitive explantation rates, as well as their causes; and current continence. the primary endpoint was postoperative continence. continence was defined as no leakage and no pad usage or leakage and/or pad usage with no impact on social life and failure as leakage and/or pad usage impacting social life. the results were evaluated short term (1 year after implantation) and long term (at last follow-up), based on clinical interviews. as secondary outcomes, clinical predictive factors of aus revision and definitive explantation were assessed. statistical analyses were performed using ibm spss statistics software version 25. categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations, or medians and interquartile ranges for variables with skewed distributions. pearson's chi-squared or fisher's exact test were used to test for associations in categorical variables. simple and multiple logistic regression were performed to determine clinical predictive factors of need of revision and definitive explantation aus surgery. a p-value ≤ 0.05 was considered statistically significant. results in the last 18 years, 81 females with a mean age of 68 ± 12 years-old were submitted to laparoscopic implantation of aus. all patients reported continual use of pads (> 3 pads/day). the median body index mass (bmi) was 29 kg/m2 (iqr 25-35). the patients' medical history included hypertension (49.4%), anxiety/depression (17.3%), diabetes (17.3%), smoking (14.8%) and asthma or others pulmonary diseases (16.0%). in 4 patients (5.1%), isd resulted from an underlying neurological condition (three myelomeningocele and one spinal cord injury). most of the patients had previous pregnancies (64.5%) and the mean number of deliveries per patient was 2 ± 1. a total of 12 patients underwent to a primary aus implantation without previous urogynecological surgeries as a result of severe isd. regarding previous surgeries, 38.3% underwent a hysterectomy, 84% incontinence surgery (mainly midurethral slings) and 27.1% prolapse surgery (mainly laparoscopic sacropromontofixation). a history of other abdominal or pelvic surgeries was present in 49.4% of patients, for example appendicectomy or cholecystectomy. on urodynamics, median mucp was 16 cmh2o (iqr 12-20). patients’ characteristics are summarized in table 1. mean operative time was 115 ± 40 minutes (range to 50-190 min). no case of laparotomy conversion was reported. in 6 cases, simultaneous laparoscopic anterior and posterior sacrocolpopexy was carried out. intraoperative blood loss was negligible with no need of blood transfusion. the most frequently chosen cuff length was 7 cm (48.6%) and all patients had balloon pressure of 61-70 cmh2o in the reservoir. the average length of hospital stay was 2 days (with a range of 1 to 8 days). there were no intraoperative complications, except for one small vaginal perforation (less than 1 cm). it was immediately repaired in two layers with resorbable sutures and without any comorbidity involved. early overall complication rate was 16% (n = 13). most were clavien-dindo as acute pelvic pain, urinary tract infections and acute urinary retention. just one case of clavien-dindo ≥ 3 was observed: a sepsis due to sphincter infection with necessity of aus removal; the follow-up of this patient was lost. considering the functional outcomes in the first 12 months, 77 patients were continent (96.3%) and 3 (3.8%) had unchanged incontinence. after a median follow-up of 67 months (iqr 14-110), 48 of the patients were continent (72%). the follow-up was lost in 14 cases. eighteen patients needed a device revision (22.2%). all revision surgeries were performed laparotable 1. patient characteristics. variables value no, patients included (n) 81 age (years) [mean ± sd] 68 ± 12 body mass index (kg/m2 ) [median (iqr)] 29 (25-35) diabetes, n (%) 14 (17.3) hypertension, n (%) 40 (49.4) smoking, n (%) 12 (14.8) anxiety or depression, n (%) 14 (17.3) asthma or others pulmonary diseases, n (%) 13 (16.0) previous birth number, [mean ± sd] 2 ± 1 history of pelvic urogynecological surgery, n (%) hysterectomy 31 (38.3) vaginal 7 (9.3) suprapubic 19 (25.3) laparoscopy 1 (1.3) missing data 4 (4.9) anti-incontinence surgery 69 (85.2) tot procedure 48 (59.3) tvt procedure 7 (8.6) burch procedure 9 (11.1) marshall-marchetti procedure 3 (3.7) artificial urinary sphincter (vaginal approach) 2 (2.5) surgical prolapse repair 14 (17.3) laparoscopic sacrocolpopexy 8 (9.9) abdominal sacrocolpopexy 2 (2.5) vaginal prolapse repair 3 (3.7) missing data 1 (1.2) others previous laparoscopic surgeries, n (%) 40 (49.4) maximum urethral closure pressure (cmh2o) [median (iqr)] 16 (12-20) tot: transobturador tape; tvt: transvaginal tape. archivio italiano di urologia e andrologia 2024; 96(1):12214 3 laparoscopic implantation of artificial urinary sphincter scopically. most of them were needed to mechanical device dysfunction (n = 12, 14.8%) such as perforation of the cuff/balloon/tubing or depressurization of the system. failure in achieving continence, need for pump reposition and periurethral atrophy with cuff dislodgement (loss of weight in obese patients) were additional reasons for device revisions (n = 6, 7.4%). the mean time between implantation and device 197 exchange due to mechanical problems was 76 ± 49 months. patients with age ≥ 70 years and follow-up ≥ 10 years significantly predisposed for device revision (or = 0.27, 95% ci [0.08, 0.93], p = 0.04 and or = 5.5, 95% ci [1.67, 18.1], p = 0.01, respectively). nine patients (11.1%) required aus deactivation. the main reasons were decreased manual dexterity or cognitive ability due to diseases such as rheumatism, dementia and bedridden patients. these pathologies resulting in poor bladder emptying with high postvoiding residues, frequent urinary tract infections and incontinence were the main reasons to aus deactivation. two of these patients had permanent catheterization and the others used adsorbent pads. aus definitive explantation was performed in thirteen patients (16%), mainly due to urethral/vaginal erosion (n = 8, 9.9%) and infection (n = 5, 6.2%). the median time between implantation and definite explantation was 38 months (iqr 2-75). diabetes, history of previous prolapse surgery or history of other previous abdominal or pelvic surgeries are significantly associated with definitive explantation rate on univariate analyses but not in multivariate analyses. discussion aus implantation in females is an effective long-term treatment for sui due to isd with a good postoperative success rate. with a median follow-up of 6-years, 72% of the patients were continent. the excellent functional outcomes of aus in female patients with siu due to isd have been reported for decades (9). the definition of isd is controversial, however, most authors advocate the use of a combination of clinical and urodynamic criteria. the combined presence of a negative urodynamic evaluation and negative marshall-bonney and ulmsten tests is the most favoured scenario to aus implantation in women with non-neurogenic sui (10). peyronnet et al performed a systematic review and showed the complete continence rates and improved incontinence ranged from 61.1% to 100% and 81% to 100%, respectively, regardless of the surgical approach (11). reus et al demonstrated that the outcome “zero to one pad” varied between 58% and 100% in the female aus implantation (12). comparing to other siu surgeries, as transobturador tape outcomes, the cure rate was lower in females with isd combined with fixed urethra (67%) (13). women with low urethral closure pressure, isolated or combined with a lack of urethral mobility, have an increased risk of refractory sui after midurethral slings, as high as 75% (14). the main theorical advantage of aus over other surgical options for female sui due to isd is that it is the only anti-incontinence procedure that can mimic the physiological function of the sphincter with the ability to restore both normal storage and voiding function by increasing the outlet resistance at rest when the cuff is closed but maintaining low resistance during the voiding phase with the cuff being opened (11) despite its efficacy there is a non-negligible associated morbidity. the revision rate (22.2%), including mechanical failure (14.8%) and explantation rate (16%), is comparable to those in the current literature. a recent systematic review reported revision rates ranging between 6 to 45%, with mechanical failure between 2% to 41%. the explantation rate due to infection and/or erosion varied between 2% to 31% (12). peyronnet et al also reported explantation rates up to 45% (11). during the last decades, the retropubic open approach was the most popular, but the rise of minimally invasive surgical approaches reduced the inherent morbidity (9). the main advantage of laparoscopic and robotic-assisted approach is the easier access to the pelvis and better dissection of the bladder neck with better visualization, especially in obese patients (15). mandron and coltable 2. simple and multiple logistic regression analyses of clinical parameters in predicting device revision (n = 18) and aus definitive explantation (n = 13). device revision aus definitive explantation variables simple logistic multiple logistic simple logistic multiple logistic regression regression regression regression p value 95% ci or p value p value 95% ci or p value age ≥ 70 years 0.03 0.080.93 0.27 0.04 0.46 obesity 0.23 0.08 diabetes 0.50 0.04 0.36 hypertension 0.31 0.73 smoking 0.06 0.40 asthma or others pulmonary diseases 0.72 1.00 obstetric history 0.98 0.76 history of previous hysterectomy 0.95 0.55 history of previous anti-incontinence surgeries 1.00 1.00 history of previous prolapse surgeries 0.37 0.04 0.13 history of other abdominal or pelvic surgeries 0.06 0.08 0.03 0.06 mucp ≤ 16 0.71 1.00 aus surgery time > 10 years 0.01 1.6718.1 5.5 0.01 0.28 surgery time ≥ 120 minutes 0.81 0.13 0.337 aus: artificial urinary sphincter; mucp: maximum urethral closure pressure. archivio italiano di urologia e andrologia 2024; 96(1):12214 d. araújo, p.-e. bryckaert, m. miranda, et al. 4 leagues were the first teams to publish their preliminary experience in laparoscopic aus implantation in the late 2000s. some of these patients were included in this cohort. they reported good results, as 82.6% of the patients were continent at a mean follow-up of 26.1 months (6). in the last years, several series with a roboticassisted approach were published, including “anterior” robotic technique and more recently a “posterior” technique (16-18). considering the laparoscopic or robotic approaches, the continence rate reported as zero pads ranged from 63% to 83% in female patients, similar to what demonstrated in open technique (42 to 86%) (12). to our knowledge, there was only one study comparing robotic to open approach and reported a significantly decrease in intraand postoperative complications rate with similar continence results (17). robotic approach allows lower technical complexity, enhanced dexterity, better mobility of the instruments and physiological tremor filtering relatively to the laparoscopic route (9, 19). given the limited information available in literature, it is still early to compare the performance and safety of the different surgical techniques and further prospective studies are required. we believe that the differences in complication and explantation rates between centers can be explained by distinct levels of experience. there was low level of evidence-based data, with significant clinical and methodological heterogeneity across studies. most of the studies had a limited number of patients, had mainly short-term follow-up and were single-center retrospective in nature. the venus study is a prospective cohort study in recruitment with the purpose to evaluate the outcomes of female aus surgery involving 25 european centers, including robotic assisted, laparoscopic and open patients. when compared to other works, our results are similar with the ones from larger series which may reflect that surgical experience and high volume could favour successful outcomes. as the aus implantation is more demanding than sling procedures, specialized centers with a proper training are required to perform this surgery (10). therefore, we believe that aus implantation must be restrict to a limited number of hospitals/centers worldwide. it was advocated that the specialized centers are trained in making the correct diagnosis, had experience to perform other surgical interventions for sui (not limiting the patients’ choice) and, more importantly, had experience in managing the complications of aus implantation (10). the optimal time to aus implantation was unknown and aus was rarely used as a first surgical intervention. some authors support performing the procedure after failure of at least one and a maximum of two previous interventions. the number of previous anti-incontinence procedures decreases the success rate of aus and increases the risk of erosion (10, 12, 16). in our study the number of previous surgeries did not correlate with the success rate. however, we demonstrate that advanced age and long-term aus (more than 10 years) significantly predisposed for device change. the median time until mechanical failure was 76 months, which corresponds to approximately 6 years of device survival. device failure was managed by either exchange of the damaged component or by total replacement, without the need of definitive explantation. chung et al advised that all patients need to be informed that the risk for potential revision surgery increases with time; in his cohort the median time of aus revision surgery was 88 months and he demonstrated that women with more than 35 years had more revision or removal surgery for cuff erosion and infection (20). other study reported that a presence of higher bmi (more than 30 kg/m2) and multiple surgeries were associated with higher revision rates (21). in the literature, the major risk factors for explantation are pelvic irradiation, age > 70 years, neurological pathology and history of pelvic surgery, including the burch procedure and sacral colpopexy (16, 22, 23). in our cohort, history of diabetes, previous prolapse surgery or other previous abdomino-pelvic surgeries may predispose for definitive explantation, although these association were not statistically significant. our study had several limitations. first, the single-center, retrospective design of the study and the fact that the procedures were performed by two surgeons with extensive experience in the implantation of aus, limit the generalization of the results to centers with a low volume of procedures. second, the absence of a validated incontinence questionnaire, since our surgeries started 18 years ago, to evaluate patient satisfaction. thirdly, larger studies, prospective and randomized, are required to properly evaluate the value of laparoscopic female aus implantation compared with the open or robotic approaches and other therapeutic options (eg, pubovaginal sling). regarding the risk factors of surgical revision and definitive aus explantation, more studies are needed. conclusions laparoscopic aus implantation in females is an effective treatment for sui due to isd. meanwhile, adequate patient selection, multidisciplinary evaluation and careful expectation management are essential to achieving good results, concerning their significant complication rate. the patients should be informed about the high risk of complications, need to surgical revision, mechanical failure or need for explantation. more studies are needed to identify the best approach and best candidates for the surgical intervention. references 1. hampel c, artibani w, espuña pons m, et al. understanding the burden of stress urinary incontinence in europe: a qualitative review of the literature. eur urol. 2004; 46:15-27. 2. osman ni, li marzi v, cornu jn, drake mj. evaluation and classification of stress urinary incontinence: current concepts and future directions. eur urol focus. 2016; 2:238-44. 3. eau guidelines. edn. presented at the eau annual congress milan 2023. isbn 978-94-92671-19-6. 4. abrams p, andersson ke, apostolidis a, et al. 6th international consultation on incontinence. recommendations of the international scientific committee: evaluation and treatment of urinary incontinence, pelvic organ prolapse and faecal incontinence. neurourol urodyn. 2018; 37:2271-2. 5. ferreira c, brychaert pe, menard j, mandron e. laparoscopic implantation of artificial urinary sphincter in women with intrinsic sphincter deficiency: mid-term outcomes. int j urol. 2017; 24:308-13. archivio italiano di urologia e andrologia 2024; 96(1):12214 5 laparoscopic implantation of artificial urinary sphincter 6. mandron e, bryckaert pe, papatsoris ag. laparoscopic artificial urinary sphincter implantation for female genuine stress urinary incontinence: technique and 4-year experience in 25 patients. bju int. 2010; 106:1194-8. 350 7. rozet f, mandron e, arroyo c, et al. laparoscopic sacral colpopexy approach for genito-urinary prolapse: experience with cases. eur urol. 2005; 47:230-6. 8. mandron e, bryckaert pe. prolapsus et colpocèle antérieure. double promontofixation cœlioscopique. technique. ann urol (paris). 2005; 39:247-56. 9. peyronnet b, greenwell t, gray g, et al. current use of the artificial urinary sphincter in adult females. curr urol rep. 2020; 21:53. 10. chartier-kastler e, van kerrebroeck p, olianas r, et al. artificial urinary sphincter (ams 800) implantation for women with intrinsic sphincter deficiency: a technique for insiders? bju int. 2011; 107:1618-26. 11. peyronnet b, o’connor e, khavari r, et al. ams‐ 364 800 artificial urinary sphincter in female patients with stress urinary incontinence: a systematic review. neurourol urodyn. 2019; 38(s4). 12. reus cr, phé v, dechartres a, grilo nr, et al. performance and safety of the artificial urinary sphincter (ams 800) for non neurogenic women with urinary incontinence secondary to intrinsic sphincter deficiency: a systematic review. eur urol focus. 2020; 6:327-38. 13. haliloglu b, karateke a, coksuer h, et al. the role of urethral hypermobility and intrinsic sphincteric deficiency on the outcome of transobturator tape procedure: a prospective study with 2-year follow-up. int urogynecol j. 2010; 21:173-8. 14. lo ts, pue lb, tan yl, wu py. risk factors for failure of repeat midurethral sling surgery for recurrent or persistent stress urinary incontinence. int urogynecol j. 2016; 27:923-31. 15. leal ghezzi t, campos corleta o. 30 years of robotic surgery. world j surg. 2016; 40:2550-7. 16. costa p, poinas g, ben naoum k, et al. long-term results of artificial urinary sphincter for women with type iii stress urinary incontinence. eur urol. 2013; 63:753-8. 17. peyronnet b, vincendeau s, tondut l, et al. artificial urinary sphincter implantation in women with stress urinary incontinence: preliminary comparison of robot-assisted and open approaches. int urogynecol j. 2016; 27:475-81. 18. gondran-tellier b, boissier r, baboudjian m, et al. robot-assisted implantation of an artificial urinary sphincter, the ams-800, via a posterior approach to the bladder neck in women with intrinsic sphincter deficiency. bju int. 2019; 124:1077-80. 19. peyronnet b, capon g, belas o, et al. robot assisted ams-800 artificial urinary sphincter bladder neck implantation in female patients with stress urinary incontinence. eur urol. 2019; 75:169-75. 20. chung e, cartmill ra. 25-year experience in the outcome of artificial urinary sphincter in the treatment of female urinary incontinence. bju int. 2010; 106:1664-7. 21. chung e, navaratnam a, cartmill ra. can artificial urinary sphincter be an effective salvage option in women following failed anti-incontinence surgery? int urogynecol j. 2011; 22:363-6. 22. thomas k, venn sn, mundy ar. outcome of the artificial urinary sphincter in female patients. j urol. 2002; 167:1720-2. 23. vayleux b, rigaud j, luyckx f, et al. female urinary incontinence and artificial urinary sphincter: study of efficacy and risk factors for failure and complications. eur urol. 2011; 59:1048-53. correspondence débora araújo, md deboracerqueiraaraujo@gmail.com urology department, centro hospitalar vila nova de gaia/espinho epe conceição fernandes st., 4434-502, vila nova de gaia, portugal pierre-emmanuel bryckaert, md bryckaert@wanadoo.fr nicolas de saint aubert, md nicolas.desaintaubert@gmail.com johann menard, md johann.menard@orange.fr eric mandron, md dr.mandron@wanadoo.fr urology department, clinique du pré, technopôle université rené laennec 13 avenue, 72000 le mans, france miguel miranda, md msmmmiranda@gmail.com urology department, centro hospitalar universitário lisboa norte epe professor egas moniz avenue, 1649-028 lisbon, portugal vasco rodrigues, md ocsav.1992@gmail.com urology department, centro hospitalar universitário de são joão epe professor hernâni monteiro avenue, 4200-319 porto, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2248 case report no conflict of interest declared. case report we present the case of a female patient aged 72-year-old who previously underwent sacral-colpopexy because of anterior vaginal compartment prolapse. the patient underwent surgery to remove the mesh, due to the pain she had had since it was placed. a mid-line laparotomy was performed removing completely the mesh. at 48 hours after intervention, the patient started feeling an intense pain in the left renal fossa that was not relieved with anti-inflammatories and morphic drugs, as well as nausea and vomiting. ct scan showed left uretero-hydronephrosis with complete ureteral dilation from a few centimetres above the bladder. moreover, it was observed free perirenal fluid. based on these findings, it was decided emergency surgery performing retrograde pyelography. during pyelography (figure 1), it was checked stop in retrograde pass contrast about 4 cm from the bladder. with the increase of the instillation pressure of contrast in the ureter, a filiform passage of contrast was observed through the stop area. at that time, a ureteroscopy was decided, introducing a 9.5 f semi-rigid instrument to the problem area (figure 2). under direct vision, concentric closure of the ureter lumen could be observed, suspecting iatrogenic suture of the ureter. a guide pass was achieved through the central area of the stenotic area, verifying its correct location with intraoperative fluoroscopy. due to the availability of holmium laser, an endoureterotomy was performed in the 12h central position on the tip, with laser parameters of 1j-10hz. almost instantaneously, the stenotic area was opened, showing the polyglactin suture that entered from the outside of the ureter to the inside and leaving the ureter tract with a good caliber without resistance to the passage of the ureteroscope. in the rest of the ureter no injuries were evidenced. a 6 f ureteral stent was maintained for one month. during follow-up, the patient remained asymptomatic and without dilation of the left system on imaging tests. discussion the use of holmium laser for the endoscopic treatment of intraluminal ureteral sutures has been previously described, with correct resolution in all cases. the summary of the published literature is summarized in table 1 (2-5). although reconstructive surgery is the most accepted treatment for ureteral injury, there are reports of cases where endourologic treatment led to correct resolution of the problem. we present the case of a female patient aged 72-year-old who was previously underwent sacralcolpopexy because of anterior vaginal compartment prolapse. the patient underwent surgery to remove the mesh, due to the pain she had had since it was placed. a mid-line laparotomy was performed removing completely the mesh. at 48 hours after intervention, the patient started feeling an intense pain in the left renal fossa that was not relieved with anti-inflammatories and morphic drugs. in the diagnostic ureteroscopy, it was found iatrogenic suture of the ureter. due to the availability of holmium laser, an endoureterotomy was performed in the 12h central position on the tip, with laser parameters of 1j-10hz. a 6f ureteral stent was maintained for one month. during follow-up, the patient remained asymptomatic and without dilation of the left system on imaging tests. although we accept that open reconstruction is the gold standard treatment for ureteral trauma, we describe holmium laser endoureterotomy as a promising technique to consider in the event of ureteral intraluminal ligation. key words: ureteral trauma; endourology; holmium laser. submitted 2 february 2021; accepted 5 february 2021 introduction ureteral injury represents only 1-2,5% of urologic trauma. the main cause of ureteral injury is in 75% of the cases iatrogenic by urologic, gynaecologic, or colorectal surgery. ureteral injury diagnosis must be suspected since there are no specific signs to identify it. patient symptoms will depend on the degree of the wound, location, or the type of damage (perforation, ligation, transection). computed tomography urography (ctu) and anterograde or retrograde pyelography presents high sensibility for ureteral trauma diagnosis (1). although reconstructive surgery is the most accepted treatment for ureteral injury, there are reports of cases where endourologic treatment led to correct resolution of the problem. various procedures have been described from resolution of urinary leak by means of ureteral stent to ureteral realignment in case of complete transection (1). in this study, we present a case of an iatrogenic ureteral ligation with an intraluminal suture resolved by laser endoureterotomy. here we describe the key points of the surgery as well as review similar cases reported in literature. endoscopic treatment of intraluminal ureteral suture with holmium laser jorge panach-navarrete, maría negueroles-garcía, josé maría martínez-jabaloyas department of urology, university clinic hospital of valencia, facultat de medicina i odontologia, universitat de valència, valencia, spain. doi: 10.4081/aiua.2021.2.248 summary 249archivio italiano di urologia e andrologia 2021; 93, 2 treatment of intraluminal ureteral suture as can be seen in the review, endoscopic ureterotomy is a successful surgery which can prevent the patient from a more aggressive surgery. as shown in table 1, the use of the balloon dilatation catheter or the weeks of permanence of the stent are not clearly defined. in our experience, the clinical course of the patient was optimal without the use of a balloon and with maintenance of the stent for 4 weeks. from our point of view, it is a simple endourological procedure if you are used to ureteroscopy. the main limiting factor could be the availability of laser in case of emergency surgery, so the possibility of its use must be foreseen. although we accept that open reconstruction is the gold standard treatment for ureteral trauma, we describe a promising technique to consider in the context of ureteral intraluminal ligation. references 1. bryk dj, zhao lc. guideline of guidelines: a review of urological trauma guidelines. bju int. 2016; 117:226-34. 2. hao z, zhang l, zhou j, et al. minimally invasive management of iatrogenic ureteral injuries with ureteroscope facilitated by holmium yttriumaluminum-garnet laser. int sch res notices. 2014; 2014:307963. 3. bagley dh, schultz e, conlin mj. laser division of intraluminal sutures. j endourol. 1998; 12:355-7. 4. lawrentschuk n, rogerson j, bolton dm. use of holmium laser for removal of an intraluminal ureteric suture. int j urol. 2004; 11:916-8. 5. klett de, mazzone a, summers sj. endoscopic management of iatrogenic ureteral injury: a case report and review of the literature. j endourol case reports. 2019; 142-144. table 1. endoscopic treatment of intraluminal sutures, summary of published cases. figure 1. retrograde pyelography where a retrograde stop in the contrast passage was found about 4 cm from the bladder. by increasing the instillation pressure of contrast in the ureter, a filiform passage (white arrow) of contrast was observed through the stop area. figure 2. image of ureteroscopy. (a) guide passage through the stenotic area. (b) endoureterotomy with holmium laser in position 12h on the guide. (c) image of the injured area once the stenosis has been incised. the white arrow indicates the polyglactin suture, with the gray arrow the area of the ureter wall incised with laser. author number balloon weeks success postoperative of cases dilatation catheter of stent complication hao, z. (2) 12 yes 12 weeks 100% no bagley, d.h. (3) 1 no 6 weeks 100% no lawrentschuk (4) 1 no 2 weeks 100% no klett, d.e. (5) 1 no 8 weeks 100% no correspondence jorge panach-navarrete, md (corresponding author) jorge.panach@uv.es maría negueroles-garcía, md maria.negueroles@gmail.com josé maría martínez-jabaloyas, md, phd marjabaloyas@gmail.com department of urology, university clinic hospital of valencia, facultat de medicina i odontologia, universitat de valència, valencia, spain av blasco ibáñez, 17, cp 46010 valencia, spain cop+ed+fisse 2006 archivio italiano di urologia e andrologia 2022; 94, 180 original paper no conflict of interest declared. in at least half of sexual intercourses” (2). most recently, international society for sexual medicine (issm) has defined pe as a male sexual dysfunction condition that has significant negative consequences for the man, his partner, and the couple as a whole, creates difficulties in interpersonal relationships, and is associated with a decrease in quality of life (3, 4). despite this, most men do not seek help for pe, and most doctors do not sufficiently question this issue (5, 6). there are few studies and limited information on men's attitudes towards sexual problems and their seeking help for this. the global study of sexual attitudes and behaviors (gssab), which surveyed 13625 men, reported that a large proportion of men (77.8%) did not consult a doctor or other healthcare professional about their sexual problems, and only 18.0% of the participants sought medical help (7). in the same study, 23.7% of men have reported pe and some of the reasons why men with a sexual dysfunction, including pe, did not consult a doctor were not taking it seriously and thinking that sexual dysfunction is an age-appropriate and acceptable condition. patients may be reluctant to discuss their pe complaint with a doctor due to the feeling of embarrassment and stigma associated with sexual dysfunction and disabilities (8). the premature ejaculation prevalence and attitudes (pepa) survey study reported that despite awareness of prescription treatments for pe, only 9.0% of men consulted a doctor regarding their pe complaints (9). moreover, some studies have revealed that 45% of men expect their doctors to initiate the discussion about sexual problems (10) and 60% believe that doctors should routinely ask about patients’ sexual health (11). in this study, we evaluated men whose ejaculatory function inquiry indicated presence of pe. we aimed to evaluate their clinical characteristics, factors affecting their attitude towards the recommended treatment, and the effect of presence of comorbidity on treatment seeking behavior and treatment acceptance in these patients. we also compared these characteristics with those of men presenting with spontaneous complaint of pe. materials and methods after the approval of the local ethics committee (protocol no: 2020/138), the data of male patients aged 18-75 purpose: to evaluate the clinical characteristics of men presenting for other complaints whose ejaculatory function inquiry indicated premature ejaculation (pe). methods: the data of 536 pe patients, including those who presented with the complaint of pe (group 1) and those presenting with other complaints who were diagnosed with pe (group 2) as a result of ejaculatory function inquiry using estimated intravaginal ejaculation latency time (ielt) and premature ejaculation diagnostic tool (pedt), were retrospectively evaluated. age, pe type, comorbidities, recommended treatments, and treatment acceptance status of all patients were recorded. these characteristics were compared for each group. results: among all the patients, those who presented with pe complaints constituted 22.4%. among the patients with both pe and ed, 98.1% applied with ed complaint and only 1.9% with pe complaint. the percentage of patients with one comorbidity was significantly higher in group 2 (p = 0.032). 90.1% of all patients and 88.5% of patients in group 2 accepted the recommended treatment for pe. the mean age and comorbidities were significantly higher in patients that refused the treatment. the most common reason for treatment refusal was the patients' lack of expectation for treatment. conclusions: this study shows that men more frequently tend to seek treatment for ed than pe, and treatment acceptance rate may be higher when the patients with pe complaints who don’t seek treatment are reached through ejaculatory function inquiry. the presence of comorbidities negatively affects the treatment expectation and acceptance as well as treatment seeking behavior of men with pe. key words: sexual attitude; ejaculatory function inquiry; premature ejaculation; treatment seeking; comorbidity. submitted 6 september 2021; accepted 14 october 2021 introduction one of the main purposes of human sexuality is pleasure and this has led men to learn to control ejaculation in order to increase both their partner’s and their own pleasure. over time, the ability to control ejaculation has become one of the most important indicators of a couple's sexual health (1). in 1970, masters and johnson defined premature ejaculation (pe) as “the inability to achieve the ejaculation period that will enable the partner to reach orgasm the importance of inquiring the ejaculation function in men with premature ejaculation who do not actively seek treatment erhan ates, ahmet emre yildiz, hakan gorkem kazici, saparali sulaimanov, arif kol, haluk erol aydin adnan menderes university school of medicine, department of urology, aydin, turkey. doi: 10.4081/aiua.2022.1.80 summary 81archivio italiano di urologia e andrologia 2022; 94, 1 treatment seeking in premature ejaculation years who presented to the urology outpatient clinic between january 2015 and march 2020 were retrospectively reviewed. a total of 536 patients diagnosed with pe for the first time were included in the study. to avoid that our treatment proposal could be affected by the patient's previous treatment experiences we excluded from the study patients who had previously applied to any health institution due to pe or received previous treatment for pe. we also excluded patients who had delayed ejaculation or anejaculation, who were not sexually active or had multiple partners, and whose full data could not be accessed in the records. the patients were divided into two groups. group 1 consisted of patients that applied to the urology outpatient clinic with complaints of pe. group 2 included patients that presented with another urological complaint and were found to have pe when ejaculatory function was actively questioned. the ejaculatory functions of patients who reported having problems were evaluated using international questionnaires. the study was based on the estimated intravaginal ejaculation latency time (ielt) reported by the patients. patients were classified as lifelong pe and acquired pe based on the definition of pe made by issm in 2014 (3, 12), where lifelong pe is defined as ejaculation within approximately 1 minute before or after vaginal penetration all the time or almost all the time since the first sexual experience, while acquired pe was defined as a clinically significant and disturbing reduction in ielt and ejaculation of about 3 minutes or less. in addition, men with incidental and situational experiences of decreased ability to delay ejaculation, and men with normal and even long ejaculation time were considered as subtypes of natural variable pe and premature-like ejaculatory dysfunction (pled), respectively (13). validated turkish version of premature ejaculation diagnostic tool (pedt) was used in the evaluation of pe (14). pedt score was calculated according to the answers of the patients. those with a total score > 9 were considered to have pe. the erectile status of those who reported erectile dysfunction (ed) was evaluated with the international index of erectile function (iief-5) questionnaire which was translated and validated by the turkish andrology association in 2002 (15). total score < 22 was considered as ed. patients’ age, pe type, smoking status, comorbidities, the recommended treatment for pe (medical or psychotherapy), the names of the medical agents, their acceptance of the treatment, and if not, the reasons for refusal were recorded. the relationship between the characteristics of pe and the factors affecting treatment acceptance according to the reasons for presentation was evaluated using appropriate statistical methods. statistical methods research data were evaluated using spss software (ver.21.0 for windows; spss inc, chicago, il, usa). the compliance of continuous variables to normal distribution was investigated using visual (histogram and probability graphs) and analytical methods (kolmogorovsmirnov/shapiro-wilk tests). the descriptive statistics of the study were shown as mean and standard deviation for data conforming to the normal distribution and as median, minimum and maximum for data that did not conform to the normal distribution. the chi-square test was used to show whether there was a difference between categorical variables. when comparing independent groups, student-t test was used to compare continuous variables with parametric properties, while mann whitney u test was used to compare continuous variables with nonparametric properties. p value of < 0.05 was considered statistically significant. results of the 536 pe patients evaluated in the study, 22.4% (n: 120/536) were in group 1 and 77.6% (n: 416/536) were in group 2. the mean age of all patients was 43.06 ± 12.3 years and the mean age of group 1 (39.49 ± 11.29 years) was significantly lower than that of group 2 (44.09 ± 12.49 years) (p < 0.001) (table 1). the pe type analysis showed that 41.8% of the patients (n: 224/536) had lifelong pe, 54.1% (n: 290/536) had acquired pe, and 4.1% had pe subtypes of natural variable pe (n: 14/536) and pled (n: 8/536). the mean age of patients with lifelong pe was significantly lower than that of the acquired group (p < 0.001) and pe subtypes (p = 0.006) (figure 1). the most common pe type in both groups 1 and 2 was acquired pe. ielt was < 1 min in 82.1% of patients with lifelong pe (n: 184/224) and between 1-2 min in 17.9% (n: 40/224). in total, 39.9% of the patients (n:214/536) had both ed and pe: 3.3% in group 1 (n: 4/120) and 50.5% in group 2 (n: 210/416). ed was the most common reason for application to the urology outpatient clinic, followed by infertility and lower urinary tract symptoms (luts) (figure 2). as a result, while 98.1% (n: 210/214) of the patients with both ed and pe presented with ed complaints, only 1.9% (n: 4/214) gave priority to pe. table 1. comparison of groups according to application complaint. total group 1 group 2 p value (n = 536) (n = 120) (n = 416) age (year) (mean ± sd) 43.06 ± 12.3 39.49 ± 11.29 44.09 ± 12.49 < 0.001 pe type (n, %) 0.982 lifelong 224 (41.8) 51 (42.5) 173 (41.6) acquired 290 (54.1) 64 (53.3) 226 (54.3) natural variant 14 (2.6) 5 (4.2) 9 (2.2) pled 8 (1.5) 8 (1.9) treatment status (n, %) 0.017 accept 483 (90.1) 115 (95.8) 368 (88.5) reject 53 (9.9) 5 (4.2) 48 (12.5) smoking (n, %) 101 (18.8) 18 (15) 83 (20) 0.222 comorbidities (n, %) single comorbidity 226 (42.1) 32 (26.7) 194 (46.6) 0.032 cardiovasculary diseases 85 (37.6) 12 (37.5) 73 (37.6) 0.046 oncological diseases 12 (5.3) 2 (6.2) 10 (5.2) 1.000 neurological diseases 15 (6.6) 5 (15.6) 10 (5.2) 0.344 endocrinological diseases 7 (3.1) 7 (3.6) 1.000 chronic systemic diseases 30 (13.3) 6 (18.8) 24 (12.4) 0.747 psychiatric disorder 5 (2.2) 5 (2.6) 0.592 dm 72 (31.9) 7 (21.9) 65 (33.4) 0.006 multiple comorbidities 56 (10.4) 9 (7.5) 47 (11.3) 0.028 sd: standard deviation; pe: prematüre ejaculation; pled: prematüre like ejaculatory dysfunction; dm: diabetes mellitus. archivio italiano di urologia e andrologia 2022; 94, 1 e. ates, a. emre yildiz, h. gorkem kazici, s. sulaimanov, a. kol, h. erol 82 among all patients, 18.8% (n: 101/536) were smokers and 14.1% (n: 76/536) had a concomitant disease such as diabetes mellitus (dm) and hyperthyroidism, which are risk factors for pe. at least one comorbidity was present in 42.1% (n: 226/536) of all patients, while 10.4% (n: 56/536) had multiple comorbidities. among all comorbidities, the most common were cardiovascular system (cvs) diseases (37.6%) such as coronary artery disease, hypertension, hyperlipidemia and heart failure. the percentage of patients with a comorbidity was significantly higher in group 2 (46.6%) than in group 1 (26.7%) (p = 0.032). the increase in cvs disease (p = 0.046) and dm (p = 0.006) was statistically significant. in addition, the incidence of cvs diseases (p < 0.001) and dm (p < 0.001) was significantly higher in patients with acquired pe compared to the other groups. the percentage of patients that complied with the recommended treatment for pe was 90.1% (n: 483/536). while at least one medical agent was given as pe treatment to 86% of these patients, psychotherapy was recommended to 4.1% of them. the most common medical agent recommended to the patients was dapoxetine (figure 3). fifty-three patients (9.9%) refused the recommended treatment. in group 1, 95.8% of the patients (n: 115/120) accepted the recommended treatment, while in group 2 this number was 88.5% (n: 368/416). the number of patients that accepted the treatment in both groups was significantly higher than those who did not accept it (p = 0.017). the mean age of the patients that accepted the treatment (42.5 + 12 years) was significantly lower than the mean age of those who did not accept the treatment (47.3 + 14 years) (p = 0.017) (table 2). as the age got older, the rate of accepting the treatment decreased. the age range with the lowest treatment acceptance rate was 60 years and over (p = 0.019). the percentage of figure 1. comparison of mean ages of premature ejaculation types. figure 2. the most common non-pe reasons for application to the urology outpatient clinic. 83archivio italiano di urologia e andrologia 2022; 94, 1 treatment seeking in premature ejaculation presence of cvs (p < 0.001), oncological (p < 0.001), neurological disease (p = 0.011) and endocrine disorders (p = 0.027) except hyperthyroidism in patients who refused treatment was significantly higher than the group that accepted the treatment. when asked about the reasons for not accepting the treatment, 66% of the patients (n: 35/53) stated that they did not care to prolong their ejaculation time with treatment, so there was no treatment expectation for pe and 13.2% (n: 7/53) did not want a new medical treatment due to the use of multiple drugs for their comorbidities (figure 4). in group 1, 4.2% of the patients (n: 5/120) that thought that the treatment might be effective and sought treatment for pe, did not accept the treatment due to high drug cost and concerns about drug side effects. discussion premature ejaculation is considered the most common male sexual dysfunction with a prevalence rate of 20-30% (9, 16, 17). despite this, patients suffering from pe do not easily seek medical treatment. they are mostly detected in epidemiological studies because of the use of the broad definition of sexual dysfunction. the very low help-seeking behavior of men who reported pe in previous prevalence studies indicates that referral to physician is much lower than reported (9). as a matter of fact, only 22.4% of our pe cases applied with the complaint of pe. it has been reported that cultural factors and health-related beliefs rather than socioeconomic factors such as education levels and income levels may play a more determining role in the frequency of seeking medical help for sexual problems (7). the belief that sexual problems are not medical problems, the thought that ejaculatory problems are temporary or caused by the daily stress of life, lack of information about current treatment strategies or confusion about which medical specialist to consult are listed as factors that may reduce the patient's desire to seek treatment (8). embarrassment about discussing the situation with anyone, doubting that any medication could help them control their ejaculation, and worrying about being addicted to a drug have also been shown as reasons for not seeking treatment. in addition, nowadays there is a scientific understanding that assumes that ejaculation control is not a natural but a cultural phenomenon. puppo v and puppo g (18) reported that pe, in which ejaculation and orgasmic physiology is not impaired, is table 2. comparison of groups according to treatment acceptance. total group 1 group 2 p value (n = 536) (n = 483) (n = 53) age (year) (mean ± sd) 43.06 ± 12.3 42.5 + 12 47.3 + 14 0.017 age groups (year) (n, %) 0.019 < 30 100 (18.6) 93 (19.3) 7 (13.2) 30-60 389 (72.6) 353 (73.1) 36 (67.9) > 60 47 (8.8) 37(7.7) 10 (18.9) pe type (n, %) 0.833 lifelong 224 (41.8) 202 (41.8) 22 (41.5) acquired 290 (54.1) 262 (54.2) 28 (52.8) natural variant 14 (2.6) 14 (2.9) pled 8 (1.5) 5 (1.1) 3 (5.7) smoking (n, %) 101 (18.8) 88 (18.2) 13 (24.5) 0.265 comorbidities (n, %) 226 (42,1) 177 (36.6) 49 (92.4) cardiovasculary diseases 85 (15.8) 66 (13.7) 19 (35.8) < 0.001 oncological diseases 12 (2.3) 6 (1.2) 6 (11.3) < 0.001 neurological diseases 15 (2.8) 10 (2.1) 5 (9.4) 0.011 endocrinological diseases hyperthyroidism 4 (0.7) 3 (1.9) 1 (0.6) 0.341 others 3 (0.6) 1 (0.2) 2 (3.8) 0.027 chronic systemic diseases 30 (5.6) 25 (5.2) 5 (9.4) 0.204 psychiatric disorder 5 (0.9) 4 (0.8) 1 (1.9) 0.407 dm 72 (13.4) 62 (12.8) 10 (18.9) 0.222 sd: standard deviation; pe: prematüre ejaculation; pled: prematüre like ejaculatory dysfunction; dm: diabetes mellitus. figure 3. recommended medical agents for treatment. archivio italiano di urologia e andrologia 2022; 94, 1 e. ates, a. emre yildiz, h. gorkem kazici, s. sulaimanov, a. kol, h. erol 84 not a disease, and female orgasm can be achieved by continuing non-coital sexual acts after male ejaculation. jannini et al. (1) stated that pe should be considered as a symptom rather than a disease. consequently, 37% of men with pe reported that they have learned to live with this condition (9). serefoglu et al. (19) evaluated 512 men with pe complaints and reported that 10.0% of them sought treatment for pe, 27.9% of them planned to receive treatment, and 66% did not think to consult a doctor. in the same study, the proportion of patients seeking treatment was higher in men with acquired pe (26.53%) and lifelong pe (12.77%), while it was lower in males with natural variable pe (6.47%) and pled (1.75%). gao et al. (20) showed that men with acquired pe seek more treatment (17.12% vs 14.58%) and plan to seek treatment (36.30% versus 27.08%) compared to men with lifelong pe. on the other hand, in another study serefoglu et al. (21) reported that patients with lifelong pe (62.5%) seek more pe treatment than those with acquired pe (16.1%). zhang et al. (22) supported this finding by reporting that the majority of 1,988 patients who applied to the outpatient clinic had lifelong pe (35.6%). these data reveal important evidence that the majority of patients seeking treatment for pe complaints are lifelong and acquired pe patients and that there is a difference in the prevalence of pe subtypes. in our study, the majority of patients seeking treatment had acquired (53.3%) and lifelong (42.5%) pe, followed by natural variable pe (4.2%) group. none of the patients presenting with pled sought the treatment. in the gssab study, 23.7% of men reported pe and 17.0% reported ed (7). although self-reported pe is more common than self-reported ed in the literature (23) and pe is considered to be the most common self-reported male sexual dysfunction, men seek far more medical help for ed than pe (7, 24). in our study, we found that 98.1% of the patients with both pe and ed applied to the clinic due to ed and only 1.9% due to pe. therefore, ed appeared as a sexual problem requiring more medical help. various studies have shown that the presence of a comorbidity such as hypertension, obesity, dm, coronary artery disease, and stroke is associated with sexual dysfunction such as decreased libido, ed and ejaculatory dysfunction in men (25, 26). serefoglu et al. (19) reported that men with pe complaints had more comorbidities compared to those without, and the incidence of all comorbidities except for neurological disorders is significantly higher in patients with acquired pe. other studies have also revealed that men with acquired pe have a high incidence of comorbid diseases such as high mean body mass index (bmi), dm, hypertension, chronic prostatitis, sexual desire disorder, and ed (20, 21, 27, 28). similarly, mean age is higher in patients with acquired pe compared to other pe subtypes (21, 22, 27). in our study, age, presence of cvs diseases and dm were significantly higher in patients with acquired pe. the pepa study reported that although men with pe see pe as a problem for themselves or their partners, a significant portion of them think that pe is a normal part of aging or that the problem will be solved with increasing sex frequency, therefore these patients do not seek treatment (9). in our study, the mean age of patients that applied with the complaint of pe was lower, and as the patients got older, the treatment seeking behavior and treatment acceptance rate for pe decreased significantly. in this study, we evaluated the effects of comorbidities on seeking treatment and accepting the recommended treatment for pe and observed that people seeking treatment for pe had less comorbidities. in addition, we found that the rate of acceptance of treatment decreased significantly in the presence of cvs, neurological, oncological, and endocrine diseases. we think that decrease in treatment expectation and treatment seeking behavior for pe in presence of comorbidities is associated with unwillingfigure 4. reasons for patients to refuse treatment. 85archivio italiano di urologia e andrologia 2022; 94, 1 treatment seeking in premature ejaculation ness to use multiple medications and possible side effects. although majority of men do not seek help for pe, one study reported that 45% of men expected their doctors to initiate the discussion about sexual problems (10), and 60% believed that physicians should routinely question the sexual health of patients (11). while this is the case, in order to increase their general well-being, sexual health, and quality of life, it is apparent that men should be more active participants of the conversation with their physicians. as a matter of fact, we questioned the ejaculatory function of patients who applied for reasons other than pe, identified pe in 416 patients and treated pe in 88.5% of them. the majority of those who did not want treatment for pe were people who did not expect treatment to be beneficial. although 4.2% of the patients applied to the clinic with complaints of pe, they did not accept the recommended medical treatment due to high drug cost and concern for drug side effects. to the best of our knowledge, this study is the first study in the literature that investigated the importance of ejaculation function inquiry in the detection of patients not seeking help for pe, and the effect of comorbidity on treatment seeking behavior as well as acceptance of treatment for pe. however, our study had some limitations. it is not a routine procedure of our clinic to question the sexual function of every male patient who applies to the outpatient clinic for reasons other than sexual function complaints. physicians who do not deal with andrology do not tend to question sexual health. this situation prevented us from detecting more pe patients. there are studies suggesting that the partner should also be evaluated so that pe treatment can be optimized and results can be measured accurately (29). the absence of an evaluation about the partner can be considered as a limitation. in addition, retrospective design of the study, the fact that some of the patients who were given treatment were not followed up regularly, and the inability to evaluate the treatment compliance and treatment results can be considered as the limitations of the study. conclusions the results of this study show that men tend to seek more treatment for ed compared to pe. the treatment acceptance rate may be higher if patients that did not seek treatment for their pe complaints are reached through sexual health inquiry that include pe. this reveals the importance of such inquiry. in addition, the presence of comorbidity emerges as a factor that negatively affects the treatment-seeking behavior of men with pe, as well as treatment expectation and acceptance. therefore, we find it useful and recommend that every patient who applies to the andrology or even urology outpatient clinic is questioned about their ejaculatory function. references 1. jannini ea, ciocca g, limoncin e, et al. premature ejaculation: old story, new insights. fertil steril. 2015; 104:1061-73. 2. masters w, johnson v. human sexual inadequacy. teratology. 1970:465-70. 3. althof se, mcmahon cg, waldinger md, et al. an update of the international society of sexual medicine’s guidelines for the diagnosis and treatment of premature ejaculation (pe). j sex med. 2014; 11:1392-422. 4. rowland dl, patrick dl, rothman m, gagnon dd. the psychological burden of premature ejaculation. j urol. 2007; 177:1065-70. 5. read s, king m, watson j. sexual dysfunction in primary medical care: prevalence, characteristics and detection by the general practitioner. j public health med. 1997; 19:387-91. 6. shabsigh r, rowland d. the diagnostic and statistical manual of mental disorders, fourth edition, text revision as an appropriate diagnostic for premature ejaculation. j sex med. 2007; 4:1468-78. 7. moreira edj, brock g, glasser db, et al. help-seeking behaviour for sexual problems: the global study of sexual attitudes and behaviors. int j clin pract. 2005; 59:6-16. 8. rowland dl. psychological impact of premature ejaculation and barriers to its recognition and treatment. curr med res opin. 2011; 27:1509-18. 9. porst h, montorsi f, rosen rc, et al. the premature ejaculation 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validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. int j impot res. 2009; 21:139-44. 15. akkus e, kadioglu a, esen a, et al. prevalence and correlates of erectile dysfunction in turkey: a population-based study. eur urol. 2002; 41:298-304. 16. nicolosi a, laumann eo, glasser db, et al. sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. urology. 2004; 64:991-7. 17. laumann eo, paik a, rosen rc. sexual dysfunction in the united states: prevalence and predictors. jama. 1999; 281:537-44. 18. puppo v, puppo g. comprehensive review of the anatomy and physiology of male ejaculation: premature ejaculation is not a disease. clin anat. 2016; 29:111-9. 19. serefoglu ec, yaman o, cayan s, et al. prevalence of the complaint of ejaculating prematurely and the four premature ejaculation syndromes: results from the turkish society of andrology sexual health survey. j sex med. 2011; 8:540-8. 20. gao j, zhang x, su p, et al. prevalence and factors associated with the complaint of premature ejaculation and the four premature ejaculation syndromes: a large observational study in china. j sex med. 2013; 10:1874-81. archivio italiano di urologia e andrologia 2022; 94, 1 e. ates, a. emre yildiz, h. gorkem kazici, s. sulaimanov, a. kol, h. erol 86 21. serefoglu ec, cimen hi, atmaca af, balbay md. the distribution of patients who seek treatment for the complaint of ejaculating prematurely according to the four premature ejaculation syndromes. j sex med. 2010; 7:810-5. 22. zhang x, gao j, liu j, et al. distribution and factors associated with four premature ejaculation syndromes in outpatients complaining of ejaculating prematurely. j sex med. 2013; 10:1603-11. 23. mcmahon cg, lee g, park jk, adaikan pg. premature ejaculation and erectile dysfunction prevalence and attitudes in the asiapacific region. j sex med. 2012; 9:454-65. 24. moreira ed, glasser db, nicolosi a, et al. sexual problems and help-seeking behaviour in adults in the united kingdom and continental europe. bju int. 2008; 101:1005-11. 25. mccabe mp, sharlip id, lewis r, et al. risk factors for sexual dysfunction among women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. j sex med. 2016; 13:153-67. 26. monga tn, lawson js, inglis j. sexual dysfunction in stroke patients. arch phys med rehabil. 1986; 67:19-22. 27. basile fasolo c, mirone v, gentile v, et al. premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001--a study of the italian society of andrology (sia). j sex med. 2005; 2:376-82. 28. porst h, mcmahon cg, althof se, et al. baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials. j sex med. 2010; 7:2231-42. 29. verze p, la rocca r, spirito l, et al. premature ejaculation patients and their partners: arriving at a clinical profile for a real optimization of the treatment. arch ital urol androl. 2021; 93:42-7. correspondence erhan ates, md, associate professor of urology (corresponding author) drerhanates@yahoo.com ahmet emre yildiz, md aemreyildiz@gmail.com hakan gorkem kazici, md hgkazici@yahoo.com saparali sulaimanov, md sulaimanovsaparali@gmail.com arif kol, md, assistant professor of urology drarifkol@hotmail.com haluk erol, md, professor of urology halukerol@yahoo.com aydin adnan menderes university school of medicine, department of urology, aydin, (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11524 1 original paper routine practice of the endourologists, especially after the introduction of the hydrophilic coated uass with the hub-locking mechanisms and in a study that compared the commonly used uass they concluded that there were no differences between them as regard safety and efficacy. also, less resistance during the insertion of uas was noted in the pre-stented and dilated ureters (5, 6). uas can allow repeated access to the renal pelvis without trauma to the ureter, improve visibility, protect the ureteroscope, improve drainage and allow rapid extraction of stone fragments (7, 8). also, uas will lower intra-renal pressures, which may reduce pyelovenous backflow, leading to a decrease in the risk of infectious complications (9). the routine use of uas for standard urs remains somewhat controversial (10). uass can directly damage the ureteral wall and compromise ureteral blood flow transiently (11, 12). the major aim of this study was to assess the efficacy, safety, and feasibility of employing uas during flexible ureteroscopy for the removal of renal stones 2 cm in size or larger. material and methods this retrospective study compared the effectiveness of flexible ureteroscopy with and without uas in the treatment of renal stones 2 cm or larger at “al-azhar” and “benha university hospitals”. 495 consecutives flexible ureteroscopies were accomplished from january 2021 to february 2023 for kidney and ureter calculi. from them, 112 patients had renal stones 2 cm or more (60 patients with the use of uas and 52 patients without). inclusion criteria included patients with renal stones ≥ 2 cm, while exclusion criteria were patients with ureteric stones or combined renal and ureteric stones, patients with kidney calculi < 2 cm, patients with related congenital renal abnormalities and cases with incomplete records of postoperative data (figure 1). the “faculty of medicine for girls at al-azhar university in cairo (fmg-irb)” in nasr city, cairo, egypt, had accepted the study's protocol with “approval number: 1657”. all procedures were performed under the helsinki declaration. as this was a retrospective study, the necessity for obtaining informed permission was waived. we retrieved the following data for all patients of the study: introduction: the rate of success of retrograde intrarenal surgery (rirs) for treating urinary tract stones is high, and the procedure is growing in popularity. the routine use of ureteral access sheath (uas) remains somewhat controversial. the aim of this study was to assess the efficacy and safety of employing uas during flexible ureteroscopy for treating renal stones ≥ 2 cm. methods: this retrospective study was accomplished from january 2021 to february 2023. from 495 consecutives flexible ureteroscopies, 112 patients had renal stones ≥ 2 cm (60 patients with the use of uas and 52 patients without). the stone-free status was verified after 8 weeks of operation. results: the average diameter of the renal stones in non-uas or uas treated groups was 22.5 mm and 22.6, respectively. none of the groups differed significantly in terms of stone side, stone size, stone position, or hounsfield unite but there was significant difference (p < 0.001) among two groups as regard pre-operative stenting (cases with uas had 23.3% pre-operative stenting). conclusions: it is not always necessary to use uas in conjunction with flexible ureteroscopy and laser lithotripsy to treat renal calculi bigger than or equal two cm. without the assistance of uas, the surgery may be carried out successfully and safely. key words: retrograde intrarenal surgery; laser lithotripsy; ureteral access sheath; kidney calculi. submitted 15 june 2023; accepted 14 july 2023 introduction the rate of success of retrograde intrarenal surgery (rirs) for treating urinary tract calculi is high, and the procedure is growing in popularity (1, 2). the first reported introduction of a guide tube (with a polytetrafluoroethylene coating, a length of 38 cm and a diameter of 3 mm) through the ureteral orifice to pass a completely passive flexible ureteroscope was by takayasu and aso in 1974 (3). its initial use was accompanied by a high rate of complications; 12 of 43 cases had ureter perforation (eight of them due to ureteral sheath and four cases to other causes) (4). in spite of those bad results, the use of ureteral access sheath (uas) did not stop, and technological development made it more easy and safe to use uas during the the outcomes of flexible ureteroscopy for renal calculi of 2 cm or more with and without the use of ureteral access sheath: a retrospective study basem a. fathi 1, ahmed a. elgammal 1, tamer a. abouelgreed 1, osama m. ghoneimy 1, ahmed y. aboelsaad 2, mohamed a. alhefnawy 3 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 department of urology, faculty of medicine, al-azhar university, damietta, egypt; 3 department of urology, faculty of medicine, benha university, egypt. doi: 10.4081/aiua.2023.11524 summary archivio italiano di urologia e andrologia 2023; 95(3):11524 b.a. fathi, a.a. elgammal, t.a. abouelgreed, o.m. ghoneimy, a.y. aboelsaad, m.a. alhefnawy 2 age, sex, main presentation, previous surgeries, associated comorbidities, renal function, location and density of the stones, intra and after surgery details, surgery duration, stenting duration, stone-free rates (sfr) and any auxiliary procedures. a semi-rigid ureteroscope was used to check the ureter up to the level of the pelvis for any abnormalities and to widen the ureter while the patient was under general anaesthesia and in the lithotomy position. another safety guide wire was utilized throughout. the decision for using uas or not was strictly based on surgeon's preference and not on patient and stone characteristics. the uas is inserted into the patient at the beginning of the surgery under fluoroscopic guidance, with the sheath's tip resting at the ureteropelvic junction. the flexor® uas (cook medical) was used; it is a hydrophilic, soft, twopiece device consisting of an inner tapered obturator that is detachable and an outside functioning sheath that may be any of three lengths (20, 28, or 35). it is offered in a choice of two sizes “10/12f and 12/14f”. the dimension of the sheath is determined by the anatomy of the case and the endoscope being utilized. the flexible ureteroscope was positioned over a wire under fluoroscopic guidance on direct vision in circumstances where the uas was not employed. all stones were fragmented to a very small sizes by means of holmium laser (30 w litho quantasystem, lumenis pulse™ 120h boston scientific) using a 365 -µm holmium laser fiber with power settings of 0.8-1.5 j at 10-15 hz, except in lower calyceal stones where a 200-µm fiber was used. two kinds of flexible ureteroscopes were used for all surgeries: “otu-100sr wiscope® single-use digital flexible ureteroscope and lithovue™ single-use digital flexible ureteroscope boston scientific”. after laser lithotripsy, stones were repositioned in the collecting system, and pieces were removed using a nitinol basket if needed. patients underwent either plain abdominal x-rays with ultrasonography or a non-contrast-enhanced spiral computed tomography (ct) scan for radiolucent stones to verify stone-free status after 8 weeks from operation. success was considered when there was no residual stone or if the residual stone was less than 5 mm. table 1. comparison of baseline parameters between studied groups. without uas with uas p n = 52 n = 60 demographics age (years) mean ± sd 42.1 11.6 40.7 10.5 0.505 range 23 73 20 67 sex males n, % 30 57.7% 38 63.3% 0.542 females n, % 22 42.3% 22 36.7% history medical absent n, % 46 88.5% 52 86.7% 0.987 htn n, % 3 5.8% 4 6.7% niddm n, % 2 3.8% 3 5.0% htn&dm n, % 1 1.9% 1 1.7% surgical absent n, % 32 61.5% 37 61.7% 1 pnl n, % 2 3.8% 2 3.3% swl n, % 9 17.3% 11 18.3% urs n, % 6 11.5% 7 11.7% pyelolithotomy n, % 2 3.8% 2 3.3% urs and swl n, % 1 1.9% 1 1.7% main presentation loin pain present n, % 52 100.0% 60 100.0% hematuria absent n, % 42 80.8% 48 80.0% 0.919 present n, % 10 19.2% 12 20.0% laboratory data pus cell mean ± sd 9.3 17.9 10.3 17.6 0.755 range 0 100 0 100 urine culture absent n, % 40 76.9% 48 80.0% 0.285 e-coli n, % 9 17.3% 8 13.3% klebsiella n, % 3 5.8% 1 1.7% staphyloccocus areus n, % 0 0.0% 3 5.0% blood urea (mg/dl) mean ± sd 32.0 7.6 32.1 7.4 0.964 range 18 46 18 46 serum creatinine (mg/dl) mean ± sd 1.0 0.2 1.0 0.3 0.324 range 0.10 1.50 0.50 1.90 figure 1. a schematic representation of the study. archivio italiano di urologia e andrologia 2023; 95(3):11524 3 the outcomes of flexible ureteroscopy for renal calculi of 2 cm or more with and without the use of ureteral access sheath statistical analyses revisions, coding, tabulation, and introduction of the acquired data to a computer were made utilizing statistical package for social science (ibm corp. released 2017. ibm spss statistics for windows, version 25.0. armonk, ny: ibm corp). in order to assess the statistical significance difference between two study groups means, student t test was used. when comparing two non-parametric groups, the mann-whitney test was utilized for analysis. 𝝌2 test was utilized to analyse the correlation among two categorial quantities. a probability (p) is regarded as statistically significant if less than 0.05 at ci (confidence interval) 95%. results the existing research was performed on 52 patients without uas (first group) and 60 cases with uas (second group). the indications of ureteroscopy were the failure of other therapies, comorbidities, skeleto-muscular deformity, body habitus and patient preference. no significant differences were found among both groups concerning demographic data, history (medical and surgical), presentation and laboratory data (table 1). additionally, there were no notable variations among the groups concerning the calculi side, dimension, position and hounsfield unit, as shown in table 2. the average dimension of the renal calculi in non-uas or uas treated groups was 22.5 mm and 22.6, respectively. the mean hardness was 953.6 hu in the first group and 953.1 hu in the second group. another finding is that there was significant difference (p < 0.001) among both groups as regard preoperative stenting (cases with uas had 23.3% pre-operative stenting) (figure 2). additionally, as demonstrated in table 3 and figure 3, there were no discernible differences among the study groups in terms of intraor post-intervention complications. two cases were intra-operatively converted to standard percutaneous nephrolithotomy (pcnl) in each group based on the surgeon's decision. we also found that cases without uas required another intervention in 17.3% (5 cases required a 2nd session of urs, and 4 cases required a session of swl), while those with uas required another intervention in 10% (4 cases required 2nd session of urs and 2 cases required a session of swl), with no observable variations among the two groups. in addition, no obvious alterations were found between groups configure 2. pre and postoperative stenting among studied groups. table 2. comparison of stone characteristics between studied groups. stone characteristics without uas with uas p n = 52 n = 60 side left n, % 25 48.1% 29 48.3% 0.978 right n, % 27 51.9% 31 51.7% stone size (mm) mean ± sd 22.5 2.0 22.6 2.5 0.839 range 15 26 14 27 stone location pelvis n, % 29 55.8% 34 56.7% 0.987 upper calyx n, % 7 13.5% 9 15.0% middle calyx and pelvis n, % 8 15.4% 9 15.0% pelvis &lower calyx n, % 8 15.4% 8 13.3% hounsfield units mean ± sd 953.6 341.8 953.1 337.2 0.994 range 250 1700 250 1700 table 3. comparison of complications between studied groups. without uas with uas p n = 52 n = 60 intraoperative complication mucosal injury absent n, % 45 86.5% 52 86.7% 0.984 present n, % 7 13.5% 8 13.3% bleeding absent n, % 43 82.7% 47 78.3% 0.563 present n, % 9 17.3% 13 21.7% failed absent n, % 50 96.2% 56 93.3% 0.684 present n, % 2 3.8% 4 6.7% perforation absent n, % 52 100% 59 98.3% 0.350 present n, % 0 0.0% 1 1.7% false passage absent n, % 50 96.2% 57 95.0% 0.768 present n, % 2 3.8% 3 5.0% converted to other procedure absent n, % 50 96.2% 58 96.7% 0.884 present n, % 2 3.8% 2 3.3% post-operative complication infection absent n, % 47 90.4% 53 88.3% 0.726 present n, % 5 9.6% 7 11.7% fever absent n, % 49 94.2% 56 93.3% 0.845 present n, % 3 5.8% 4 6.7% pain (loin or suprapubic) absent n, % 32 61.5% 34 56.7% 0.601 present n, % 20 38.5% 26 43.3% hematuria absent n, % 42 80.8% 45 75.0% 0.465 present n, % 10 19.2% 15 25.0% other complications absent n, % 51 98.1% 58 96.7% 0.645 present n, % 1 1.9% 2 3.3% archivio italiano di urologia e andrologia 2023; 95(3):11524 b.a. fathi, a.a. elgammal, t.a. abouelgreed, o.m. ghoneimy, a.y. aboelsaad, m.a. alhefnawy 4 cerning operative time, stent duration and readmission (table 4 and figure 4). hospital readmissions were due to fever and persistent pain. discussion though pcnl was the first-line treatment of renal calculi greater than 2 cm, many studies demonstrated that rirs can be a safer and effective alternative in managing renal stones 2 cm or more (13-15). according to a recent comprehensive study by de coninck et al., uas installation is not something that should be done routinely during rirs. it may be used only in cases when gaining access to the ureter is challenging, when treating patients with stones who have an elevated risk of infection complications, or in cases where visibility is poor owing to insufficient irrigation fluid outflow. the authors also draw the conclusion that, in the near future, the reasons for using a uas might become less due to the advancement of smaller size single-use flexible digital ureteroscope (improved outflow by allowing more space between the ureteral wall and flexible ureteroscope), thulium fiber laser, and pressuremeasuring instruments and integrated aspiration technology (16). in our study, we compared the utilization or not of uas in treating renal stones 2 cm. except for the fact that pre-stenting the ureter was much more common in the group that employed uas, we found no statistically differences in the examined parameters between the two groups. aboumarzouk et al. performed a meta-analysis and a comprehensive review of studies using flexible ureteroscopy and laser lithotripsy to treat renal calculi more than 2 cm. nine studies involving 445 patients reported an average sfr of around 93.7 percent. the mean number of operations per patient was 1.6. the average time of operations was 82.5 minutes. sfr for stones between 2 and 3 cm was considerably higher than those for stones > 3 cm (95.7 % vs 84.6 %; p = 0.01). the researchers concluded that laser lithotripsy performed using a flexible ureteroscope could be an alternative to pcnl for individuals with calculi ≥ 2 cm table 4. comparison of operative time and outcome between studied groups. without uas with uas p n = 52 n = 60 operative time (min) operative time (min) mean ± sd 81.4 4.5 82.8 13.6 0.469 range 75 90 43 100 outcome stone free rate after the first procedure n, % 43 82.7% 54 90.0% 0.257 another intervention 9 17.3% 6 10.0% free after 2 sessions of urs n, % 5 55.6% 4 66.7% 0.667 free after one swl session post-urs n, % 4 44.4% 2 33.3% 0.667 stent duration (days) mean ± sd 24.6 7.1 24.0 6.0 0.650 range 15 45 15 45 readmission absent n, % 47 90.4% 56 93.3% 0.731 present n, % 5 9.6% 4 6.7% figure 3. complications among studied groups. figure 4. the stone-free rate among (a) with uas and (b) without uas. archivio italiano di urologia e andrologia 2023; 95(3):11524 5 the outcomes of flexible ureteroscopy for renal calculi of 2 cm or more with and without the use of ureteral access sheath (15). scotland et al., in their study for treating large renal calculi (average dimension 2.75 cm) in 167 patients achieved a sfr in the first session of 57.1%, 90.2% in the second session and 94.0% in the third session. in their study, significant complications occurred in patients who had received uass, which were utilized in 47% of cases. it was determined that either one or many sessions of retrograde ureteroscopic lithotripsy could be used to successfully treat large kidney calculi (17). in the present study, we found that intra and post-operative complications were less in the group treated without uas, although there was no significant difference. also, the sfr after the first procedure was 82.7% in the group treated without uas and 90.0% in the other group, although again the difference was not significant. nine cases in the group treated without uas (17.3%) and six cases in the other group (10.0%) required a second intervention. meier et al., in their study on 5316 patients who underwent primary flexible ureteroscopy used the uas in 1969 patients (37.7%) and found that those in whom a uas was used had increased visits to the emergency department and hospitalization (p < 0.05) compared to those without uas use. they concluded that using uas is not without risk and uas should be judiciously employed (18). grasso et al. did not use a uas in their study on managing 2 cm or more stones in the upper urinary tract. the study included 51 patients with 66 large upper urinary tract stones. the rate of success was 76% next to the initial procedure, 91% after a second session of flexible ureteroscopy and laser lithotripsy, and 93% after a third endoscopic session. in conclusion, they found that large upper urinary tract stones could be treated appropriately and efficiently with flexible ureteroscopy and laser lithotripsy (19). el-anany et al. performed a study that included thirty patients with a renal stone of more than 2 cm managed with either a semi-rigid ureteroscope or flexible ureteroscopy and laser lithotripsy without using the uas. the success rate was 77% (23 of the 30 patients), with a negligible incidence of complications. of the other seven patients, three of them converted to pcnl and four to extracorporeal shock wave lithotripsy (eswl). if there was a lot of debris remaining after fragmentation, they employed two ureteric catheters with “a 5 f catheter in the most dependent calyx and a 6 f catheter in the upper calyx” for constant irrigation (100 ml/h of saline with 80 mg/l of gentamicin). they determined that a retrograde endoscopic approach employing laser lithotripsy was a secure and successful means of treating big renal calculi (20). palmero et al. performed a retrospective review of 106 patients with renal calculi 2 cm or more who underwent rirs with uas in all cases. the average calculi size was 2.46 cm. the success rates was 73.6% (for a single procedure) and 93.4% for retreatment with a 6.7% postoperative minor complication rate. they concluded that for renal stones 2 cm or more, rirs is a valid alternative to pcnl with few complications and a high success rate (21). similarly, in a separate study by al-qahtani et al., on 120 patients with renal stones more than 2 cm, they achieved stone-free status in 58.5% after the first session, 87% after the second session, and 96.7% after the third session. they concluded that flexible ureteroscopy using a holmium laser is a successful and safe treatment with little morbidity. it could be an alternative to pcnl, especially for stone burdens from 2 to 3 cm (22). another recent study was performed by huang et al. to treat renal stones 2 cm or greater. in 279 patients with a mean stone diameter of 26.5 mm sfr was 61.9% at the first, 82.9% at the second, and 89.5% at the third procedure. fever was the most common complication, with a 15.1% overall complication rate. the conclusion was that rirs could be utilized to treat large kidney stones (2 to 4 cm) with an acceptable complication rate and efficacy (23). this study has some limitations; the first is being retrospective in nature with selection bias. second, the follow-up time is short, so long-term complications couldn’t be assessed. the third, there were three surgeons and not only one who performed the operations in both groups. last, stone-free rate was not assessed by the same modality in all cases, with plain abdominal radiography with ultrasonography being done in most of the cases. ct scan was only done in patients with radiolucent stones. conclusions it is not always necessary to use uas in conjunction with flexible ureteroscopy and laser lithotripsy to treat renal stones of 2 cm or more in diameter. without the assistance of uas, the surgery may be carried out successfully and safely. more studies are needed to corroborate this finding; ideally, they would be prospective and randomized and include long-term follow-up. references 1. kılıç ö, akand m, van cleynenbreugel b. retrograde intrarenal surgery for renal stones part 2. turk j urol. 2017; 43:252-260. 2. heers h, turney bw. trends in urological stone disease: a 5-year update of hospital episode statistics. bju international. 2016; 118:785789. 3. takayasu h, aso y. recent development for pyeloureteroscopy: guide tube method for its introduction into the ureter. j urol. 1974; 112:176-178. 4. newman rc, hunter pt, hawkins if, finlayson b. the ureteral access system: a review of the immediate results in 43 cases. j urol. 1987; 137:380-383. 5. monga m, bhayani s, landman j, et al. ureteral access for upper urinary tract disease: the access sheath. j endourol. 2001; 15:831-834. 6. elsaqa m, hyder z, thai k, et al. comparison of commonly utilized ureteral access sheaths: a prospective randomized trial. arch ital urol androl. 2023; 95:11149. 7. vanlangendonck r, landman j. ureteral access strategies: proaccess sheath. urol clin north am. 2004; 31:71-81. 8. abrahams hm, stoller ml. the argument against the routine use of ureteral access sheaths. urol clin north am. 2004; 31:83-87. 9. auge bk, pietrow pk, lallas cd, et al. ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation. j endourol. 2004; 18:33-36. 10. loftus cj, ganesan v, traxer o, et al. ureteral wall injury with ureteral access sheaths: a randomized prospective trial. j endourol. 2020; 34:932-936. archivio italiano di urologia e andrologia 2023; 95(3):11524 b.a. fathi, a.a. elgammal, t.a. abouelgreed, o.m. ghoneimy, a.y. aboelsaad, m.a. alhefnawy 6 11. lallas cd, auge bk, raj gv, et al. laser doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement. j endourol. 2002; 16:583-590. 12. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-584. 13. tiselius hg, ackermann d, alken p, et al. guidelines on urolithiasis. eur urol. 2001; 40:362-371. 14. ben saddik ma, al-qahtani sejiny s, ndoye m, et al. flexible ureteroscopy in the treatment of kidney stone between 2 and 3 cm. progr urol. 2011; 21:327-332. 15. aboumarzouk om, monga m, kata sg, et al. flexible ureteroscopy and laser lithotripsy for stones >2 cm: a systematic review and meta-analysis. j endourol. 2012; 26:1257-1263. 16. de coninck v, somani b, sener et, et al. ureteral access sheaths and its use in the future: a comprehensive update based on a literature review. j clin med. 2022; 11:5128. 17. scotland kb, rudnick b, healy ka, et al. retrograde ureteroscopic management of large renal calculi: a single institutional experience and concise literature review. j endourol. 2018; 32:603-607. 18. meier k, hiller s, dauw c, et al. understanding ureteral access sheath use within a statewide collaborative and its effect on surgical and clinical outcomes. j endourol. 2021; 35:1340-1347. 19. grasso m, conlin m, bagley d. retrograde ureteropyeloscopic treatment of 2 cm. or greater upper urinary tract and minor staghorn calculi. j urol. 1998; 160:346-351. 20. el-anany fg, hammouda hm, maghraby ha, elakkad ma. retrograde ureteropyeloscopic holmium laser lithotripsy for large renal calculi. bju international. 2001; 88:850-853. 21. palmero jl, castelló a, miralles j, et al. results of retrograde intrarenal surgery in the treatment of renal stones greater than 2 cm. actas urol esp. 2014; 38:257-262. 22. al-qahtani sm, gil-deiz-de-medina s, traxer o. predictors of clinical outcomes of flexible ureterorenoscopy with holmium laser for renal stone greater than 2 cm. adv urol. 2012; 2012:543537. 23. huang js, xie j, huang xj, yuan q, et al. flexible ureteroscopy and laser lithotripsy for renal stones 2 cm or greater: a single institutional experience. medicine. 2020; 99:e22704. correspondence basem a. fathi, md (corresponding author) basemhara@gmail.com; basemabdalla.8@azhar.edu.eg ahmed a. elgammal, md aelgammal36@gmail.com tamer a. abouelgreed, md dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg osama m. ghoneimy, md elgendyosama787@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt ahmed y. aboelsaad, md aboelsaadurology@hotmail.com department of urology, faculty of medicine, al-azhar university, damietta, egypt mohamed a. alhefnawy, md dr.mohamedalhefnawy@gmail.com department of urology, faculty of medicine, benha university, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper tion to castration resistance, during which progression occurs despite continued suppression of testosterone. this is referred to as metastatic castration-resistant prostate cancer (mcrpc) (2). treatment of mcrpc has evolved over the last decade, with results from large randomized clinical trials leading to the approval of several new agents showing an overall survival (os) benefit in patients with mcrpc, both preand post-chemotherapy-based regimens (3, 4). abiraterone acetate (aa) is an important agent in the treatment of advanced prostate cancer. it is a selective inhibitor of androgen biosynthesis which potentially and irreversibly blocks cyp17, a crucial enzyme in estrogen and testosterone synthesis. it was primarily approved for the treatment of metastatic castrate-resistant prostate cancer after failure of androgen deprivation therapy (5). however, it is important to acknowledge that, although aa is effective in both preand post-chemotherapy setting, discrepancies exist regarding its effectiveness, with only a fraction of patients actually benefiting in the long term. prostate-specific antigen (psa) is widely used to monitor prostate cancer and its decline after chemotherapy has been acknowledged as a valid surrogate for os at 3 months (6). although, the role of psa response after new hormonal generation agents remains uncertain (7, 8). the aim of this study is to evaluate the efficacy and safety of aa in mcrpc patients, regarding early psa response as a prognostic marker of os. materials and methods patients with confirmed mcrpc treated with first line abiraterone between 2013 and 2020 at hospital garcia de orta and centro hospitalar barreiro montijo were considered for analysis. psa value at baseline, at four, eight, and twelve weeks were required for study inclusion. exclusion criteria included absence of baseline values. demographics and baseline characteristics such as prior docetaxel exposure were recorded, as well as routine lab studies including psa, neutrophil to lymphocyte ratio (nl ratio), and hemoglobin (hgb) at start of treatment, when available (table 1). the primary investigation of interest was psa decline as a objectives: abiraterone acetate (aa) is an important agent in the treatment of advanced prostate cancer. it was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mcrpc) after failure of androgen deprivation therapy. there is still no available strong data regarding the impact of early decline of prostate-specific antigen (psa) in the overall survival. the aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (os) in metastatic castration-resistant prostate cancer when treated with abiraterone acetate. materials and methods: a dual center, retrospective, cohort study on patients diagnosed with mcrpc treated with abiraterone between 2013 and 2020 was performed. primary endpoint was to demonstrate the efficacy of aa, with the analysis of psa decline, and the correlation with overall survival. results: the cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. a psa response of > 30% and > 50% at 60 and 90 days was associated with improved os. multivariate analysis revealed that a 60 day psa decline of > 30% was predictive of overall survival. median os of diagnosed mcrpc patients was 28 months. docetaxel pre-treatment was not associated with longer os. the median duration of drug exposure for patients submitted to aa was found to be 14 months. conclusions: early psa response rate can offer clinically meaningful information and can be considered a surrogate of longer os. a > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mcrpc patients treated with abiraterone. key words: abiraterone; mcrpc; psa; overall survival; progression free survival. submitted 2 december 2022; accepted 31 december 2022 introduction prostate cancer is the second most commonly diagnosed malignancy in men around the world with an estimated 1.111.700 new cases and 307.500 deaths per year (1). metastatic prostate cancer is characterized by a period during which suppression of serum testosterone with androgen deprivation therapy (adt) is sufficient to control disease. unfortunately, this period is followed by transiprostate-specific antigen response after abiraterone treatment in mcrpc: psa as a predictor of overall survival alexandre mendonça macedo 1, rita gameiro marques 2, margarida cunha andré 1, nuno silva figueira 1, miguel leal carvalho 1 1 urology department, hospital garcia de orta epe, almada, portugal; 2 oncology department, centro hospitalar barreiro montijo, barreiro, portugal. doi: 10.4081/aiua.2023.11052 summary archivio italiano di urologia e andrologia 2023; 95, 1 a. mendonça macedo, r. gameiro marques, m. cunha andré, n. silva figueira, m. leal carvalho predictor of overall psa response and survival. psa was procured at four, eight, and twelve weeks. psa response was defined as > 30% decrease from the psa at the start of treatment. psa responses > 50% decrease from the psa at the start of treatment were also analyzed. kaplan-meier analyses were used to estimate overall survival differences between groups at each time point. associations between psa response and survival were evaluated via univariate cox regression analysis for ≥ 30% and ≥ 50% response at four, eight, and twelve weeks and with multivariate cox regression models regarding these parameters. data analysis was completed via ibm spss software. 84 male patients diagnosed with mcrpc that experienced treatment failure with one or more lines of treatment (hormonal manipulation or chemotherapy) were selected and abiraterone acetate (1.000 mg daily) along with prednisone (5 mg twice daily) was administered. results in this dual institution retrospective study, a total of 112 mcrpc patients were considered. after strict analysis, only 84 patients with a median age of 71 ± 9 years were included for statistical review. 67,9% showed a good response in psa reduction. a psa response of > 30% and > 50% at 60 days was associated with improved os (log rank 13.7, p < 0.001, log rank 5,6, p = 0.018) as compared to subjects without such a decline (figure 1 and figure 2). there was also a strong correlation of psa response of > 30% and > 50% at 90 days (log rank 6.7, p = 0.009 and log rank 3.7, p = 0.043) which was associated with improved os (figure 3 and figure 4). multivariate analysis revealed that 60-day psa decline of > 30% was predictive of overall survival (hr 0.995, 95% ci 0.13-0.57, p = 0.001). roc curve showed that psa value at 60 days is a highly specific tool to determine overall survival with a cut-off value of > 30% (auc 0.754, p = 0.001) and it could be used as a clinical tool to determine patients that most benefit from treatment with abiraterone (figure 5). median os of diagnosed mcrpc patients was 28 months. docetaxel pre-treatment in this study was not associated with longer os (log rank: 0.024, p = 0.878) (figure 6). table 1. psa decline > 50% at 60 days; log rank 5.6, p = 0.018. baseline characteristics n median total patients 84 age (years) 84 71 +/9 years psa at diagnosis 84 57.73 ng/dl [ir 136] gleason score (median) 84 7 [ir 2] neutrophil/lymphocytes ratio 84 2.3 [ir 1.28] patients without prior docetaxel 64 patients with prior docetaxel 20 abiraterone duration (months) 84 14 time until progression of disease with abiraterone (months) 84 12 psa response (%) 84 67.9% hematologic toxicity with abiraterone 2 figure 1. psa decline > 30% at 60 days log rank 13.7, p < 0.001. figure 2. psa decline > 50% at 60 days. figure 3. psa decline > 30% at 90 days. log rank 6.7 p = 0.009. figure 4. psa decline > 50% at 90 days. log rank 63.7 p = 0.043. archivio italiano di urologia e andrologia 2023; 95, 1 psa after abiraterone the median duration of drug exposure for crpc who received aa was found to be 14 [ir 16] months. regarding adverse events, two patients revealed hematologic toxicity, which didn’t lead to treatment discontinuation. discussion there is a growing number of therapeutic options capable of extending survival in mcrpc patients. despite that, there is a lack for biomarkers that can simultaneously guide treatment decisions and predict which patients will benefit the most from these treatments. aa and enzalutamide have shown clinical efficacy in multicenter phase iii rct’s (9), although evidence is not clear regarding which drug results in a better clinical and biochemical response. some evidence suggests there is a better biochemical response in favor of enzalutamide versus abiraterone, particularly in those patients submitted to previous taxane therapy (10). however, in patients achieving biochemical response, this advantage is not consistent what suggests that there is a need for prognostic biochemical markers to predict which patients will benefit the most from each novel hormonal agent. thus, the development of new surrogate markers for clinical outcomes is becoming increasingly important with the emergence of multiple lines of treatment with better survival benefit for mcrpc patients. psa remains a questionable surrogate for survival in latestage prostate cancer. prostate cancer clinical trials working group (pcwg) 2 states that the clinical significance of a post-therapy psa decline remains controversial and advises against its early use. in fact, an increase in serum psa, or ‘flare’, may occur in some patients before they experience a subsequent and sometimes significant psa decline. this is why pcwg2 recommends securing a sufficiently large drug exposure window and avoid relying on serum psa decline as a surrogate for clinical benefit. perhaps even more importantly, the group advises not to interpret a rise in serum psa as progression and early withdrawing a therapy from which the patient may benefit (11). nonetheless, drugs targeting androgen receptor (ar) signaling, such as aa, may have a different association to an early psa decrease, since psa is a pharmacodynamic biomarker of androgen receptor signaling in absence of aberrations on the psa promoter or key regulators of psa production and secretion. the results of this study are consistent with rescigno et al. study (12) in which a psa response > 30% was a predictor of os at four weeks. additionally, these results reported a psa response > 30% and > 50% as statistically significant for os at 60 and 90 days which suggests that early decline of this biomarker could be used as a clinical tool to monitor treatment response and as a prognostic marker for these patients. furthermore, it demonstrates the potential role of early psa decline as a cost-effective tool to monitor mcrpc patients and identify which patients will benefit the most from this therapy. some limitations of this study should be noted regarding it’s retrospective nature and a relatively small sample size. conclusions abiraterone acetate is a drug of choice for crpc and also for those who had previously received one or two chemotherapy regimens. this data suggests that clinicians could utilize early psa response as a predictor of subsequent events after aa therapy. it supports a meaningful and stronger clinical benefit of early psa response as a prognostic factor. the results of this study showed that aa significantly lowered the psa values and prolonged overall survival in metastatic castration resistant prostate cancer patients who had progressed after first-line or second-line treatment. early psa response rate can provide clinically meaningful information and can be considered a surrogate of longer os. a > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provide an important clinical tool to predict subsequent events in mcrpc patients treated with abiraterone and, according to our study, they should be used in clinical practice to determine which patients will have a better clinical response and as a prognostic marker. references 1. torre la, et al. global cancer statistics, 2012. ca cancer j clin. 2015; 65:87-108. figure 6. docetaxel pre-treatment. log rank 0.024, p = 0.878. figure 5. roc curve. archivio italiano di urologia e andrologia 2023; 95, 1 a. mendonça macedo, r. gameiro marques, m. cunha andré, n. silva figueira, m. leal carvalho 2. sartor o, de bono js. metastatic prostate cancer. n engl j med. 2018; 378:645-657. 3. ryan cj, smith mr, de bono js, et al. abiraterone in metastatic prostate cancer without previous chemotherapy. n engl j med. 2013; 368:138-148. 4. beer tm, armstrong aj, rathkopf de, et al. enzalutamide in metastatic prostate cancer before chemotherapy. n engl j med. 2014; 371:424-33. 5. fizazi k, scher hl, molina a et al. abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the cou-aa 301 randomised, double-blind, placebo-controlled phase iii study. lancet oncol. 2012; 13:983-925. 6. schlack k, krabbe lm, fobker m, et al. early prediction of therapy response to abiraterone acetate using psa subforms in patients with castration resistant prostate cancer. int j mol sci. 2016; 17:1520. 7. facchini halabi a, armstrong aj, sartor o, et al. prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with secondline chemotherapy. j clin oncol. 2013; 31:3944-3950. 8. verzoni e, de giorgi u, derosa l, et al. predictors of long-term response to abiraterone in patients with metastatic castration-resistant prostate cancer: a retrospective cohort study. oncotarget. 2016; 7:40085-40094. 9. izumi k, mizokami a, namiki m, et al. enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (enable study for pca): a study protocol for a multicenter randomized phase iii trial. bmc cancer. 2017; 17:677. 10. jarimba rs, eliseu mn, pedroso lima j, et al. novel hormonal agents for metastatic castration-resistant prostate cancer: comparing outcomes. a single-center retrospective study. arch ital urol androl. 2021; 93:393-8. 11. gomella lg, oliver sartor a. the current role and limitations of surrogate endpoints in advanced prostate cancer. urol oncol. 2014; 32:28.e1-9. 12. rescigno p, lorente d, bianchini d, et al. prostate-specific antigen decline after 4 weeks of treatment with abiraterone acetate and overall survival in patients with metastatic castration-resistant prostate cancer. eur urol. 2016; 70:724-731. correspondence alexandre mendonça macedo, md (corresponding author) alex.m.macedo89@gmail.com hospital garcia de orta, epe av. prof. torrado da silva, 2801-951 almada, portugal margarida cunha andré, md margaridamcandre@gmail.com nuno silva figueira, md nunofigueira456@gmail.com miguel leal carvalho, md uro.miguelcarvalho@gmail.com urology department, hospital garcia de orta epe, almada (portugal) rita gameiro marques, md ritagameiros@gmail.com oncology department, centro hospitalar barreiro montijo, barreiro (portugal) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 499archivio italiano di urologia e andrologia 2021; 93, 4 letter to editor no conflict of interest declared. to the editor, in 1952, after many centuries, the varicocele was treated to resolve infertility. from celsus to modern surgical techniques, over the centuries, many surgeons have proposed numerous treatment options, some very traumatic others more "physiological" (1-14). cases of varicocele have been treated because they were associated with "melancholic blood" or were associated with pain or were associated with infertility. however, since the latest clinical research, varicoceles have been treated mainly because they are associated with infertility, although recently the treatment of varicoceles, in the era of medical assisted procreation, has been questioned (15-17). therefore, there are some fundamental points to clarify. why do patients with varicoceles become infertile? patients with subclinical varicoceles are now surgically treated if there is alteration of the semen, why do we have to operate a patient with varicocele if we can use assisted reproduction? a fundamental point is to clarify the role of varicocelectomy on the pregnancy rate; does it make sense to perform expensive (robotic varicocelectomy), or potentially harmful (x-ray embolization) surgical treatments if we then have to resort to assisted reproduction? what treatment can we offer to adolescents or what therapeutic procedure should we do for adolescents? finally, are we therefore returning to treat varicocele only if associated with pain, because for infertility we will have assisted reproduction? with respect to the history of surgical procedures proposed to treat varicocele, “innovative” were osborn and ogston who, between 1880 and 1886, proposed a trans-scrotal treatment using a hairpin (without closing the artery) and a glowing needle. was this perhaps the first "bipolar cautery" varicocelectomy? (9, 13) however, it is interesting to note that from the earliest treatment in history, corner, skillen, o'conor, and robson reported numerous complications and raised doubts on the real benefit of the procedure (4-6, 11). tait in 1904 was the first to introduce clear guidelines about clinical indications for varicocelectomy: one should operate large varicocele (or painful varicocele) including cases with testicular atrophy or marked endo-phlebitis and varicocele causing the rejection of candidates for certain positions (army and navy). in his "guidelines" he also added more information about who should be treated: voluminous and painful varicocele equivalent to an appreciable deformity and smaller varicocele at the patient's repeated request to be rid on an infirmity. finally, he added a last important chapter: one should never operate varicocele in genitourinary hypochondriacs or in neurasthenics and in case of simple dilatation of the veins inducing no symptoms (the most common form of varicocele) (7). in comparison to the, more or less invasive, treatments proposed from celsus onwards, to the surgical indications proposed in the past, to the results of the first cases treated in history and to the related post-operative complications, what have we learned or modified with respect to the past? perhaps the only answer we can give is that we still know very little about varicocele and its treatment. references 1. marmar jl. the evolution and refinements of varicocele surgery. asian j androl 2016; 18:171-8. 2. coutts we. orchidopexy for varicocele. a method for treating varicocele by means of living tissue. ann surg. 1928; 88:1093-5. 3. porrit ae. the injection treatment of hydrocele, varicocele, burse and nevy. proc r soc med 1931; 24: 971-975. varicocele and varicocelectomy: which news from the past? nicola zampieri woman & child hospital, department of surgery, dentistry, paediatrics and gynecology; division of pediatric surgery, university of verona, italy. key words: varicocele; treatment; option; fertility. submitted 12 october 2021; accepted 12 october 2021 doi: 10.4081/aiua.2021.4.499 archivio italiano di urologia e andrologia 2021; 93, 4 n. zampieri 500 4. o’connor j. the radical cure of varicocele. br med j. 1921; 1:783-789. 5. skillen pg. a consideration of the varicocele operation and avoidance of post-operative induration. ann surg. 1920; 72:508-510. 6. corner em, nitch car. the immediate and remote results of the high operation for varicocele. br med j 1906; 27:191-193. 7. tait d. contribution to the study of varicocele. cal state j med. 1904; 2:363-367. 8. curling tb. varicocele treated by pressure. med chir trans. 1846; 29:259-268. 9. osborn s. the treatment of varicocele by acu-pressure of spermatic vein. br med j. 1880; 1:52. 10. duncan j. clinical observations of the subcutaneous ligature of varix and varicocele. br med j. 1881; 2:37-38. 11. robson awm. treatment of varicocele by excision. br med j. 1886; 27:389-390. 12. ogston a. the operation for varicocele. ann surg. 1886; 4:120-123. 13. noske hd, weidmer w. varicocele a historical perspective. world j urol. 1999; 17: 151-157. 14. keetly cb. the cure of varicocele. ann surg. 1888; 8: 205-207. 15. turgut h. the effect of varicocelectomy on the pregnancy rate in patients with severe oligospermia. niger j clin pract. 2020; 23:1744-1747. 16. schlegel pn, sigman m, collura b, et al. diagnosis and treatment of infertility in men: aua/asrm guideline part ii. j urol. 2021; 20:44-45. 17. kimura m, nagao k. role of varicocele repair for male infertility in the era of assisted reproductive technologies. reprod med biol. 2014; 13:185-192. correspondence nicola zampieri, prof., md, phd nicola.zampieri@aovr.veneto.it pediatric fertility lab woman & child hospital, department of surgery, dentistry, paediatrics and gynecology; division of pediatric surgery, university of verona, italy piazzale aristide stefani 1, 37100 verona (italy) stesura seveso 219archivio italiano di urologia e andrologia 2020; 92, 3 original paper no conflict of interest declared. doi: 10.4081/aiua.2020.3.219 a global snapshot of endourology residency training asad ullah aslam 1, 2, joseph philipraj 1,3, sayed jaffrey 1,4, noor buchholz 1 1 u-merge ltd. (urology for emerging countries), london, uk*; 2 dept. of urology, letterkenny university hospital, saolta healthcare group, ireland; 3 department of urology, mahatma ghandi medical college & research institute, sri balaji vidyapeeth, pondicherry, india; 4 dept. of urology, university college hospital, galway clinic and bons secours hospital, galway, ireland. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com background: urology has become more complex over the last decades with surgical sophisticated technologies such as endoscopy, laparoscopy and robotic surgery. as these minimally invasive methods gain popularity throughout the world, this has led in some countries to a serious training gap as compared to other countries, and between generations of surgeons within national training systems. there is a huge heterogeneity in urological training between countries, whether developed or developing. this paper attempts to shed some light onto global urological training, comparing a significant number of various national systems, and to outline global tendencies in urological training. it will enable interested readers to see where their own system stands in international comparison, and hopefully enable them to identify training needs to achieve global quality standards. materials & methods: this is a questionnaire-based assessment which was sent to 240 members of u-merge from 62 countries. in addition, there is ample literature on the requirements of structured training programs and assessments, and we have tried to briefly outline the key points in this paper. results: we received responses from 32 countries urology residency training is hugely heterogenous between countries. only 44% of nations use a structured training program with assessments. others use the halstedian apprenticeship approach. notably, some developing countries do use modern teaching and assessment methods, whereas some developed countries still use the outmoded apprenticeship model. for the interested reader, results have been tabled in detail, and training systems described country by country. conclusions: our results have shown a huge heterogeneity in quality urology training between countries and within continents. in systems without national structure of training, it can be assumed that such differences exist even between hospitals/ training institutions. there is no doubt in times of globalization with resident and doctor migration and exchanges that training needs structure and standardization. the still huge gap in developing countries to catch up and be able to afford latest surgical and learning technologies need to be addressed with the help of responsible outreach programs. key words: surgical training; urology; endourology; performance assessment; dops; dry lab; wet lab; simulator training; global education. submitted 2 march 2020; accepted 15 march 2020 summary introduction an estimated 5 billion people lack access to any surgical care. this despite surgical diseases accounting for 1130% of the global health care burden (1). this implies an urgent need to quality-train more surgeons in all specialties globally. historically, surgical training, and urological training as a surgical sub-specialty as well, followed the halstedian tradition of defined apprenticeship. this includes basically observation, modelling and graded participation in surgical activities. this model of training is characterized through long working hours, poorly defined training goals, and a lack of focus on research and evidence-based best practice. in this traditional system, assessment and evaluation of the trainees’ performance is outmoded, significantly subjective, with standards ill-defined and not uniformly applied (2). the optimal method to monitor and assess trainees, for example in endoscopy, has not been formally determined (3). urology has become more complex over the last decades with increasing medical and surgical sophisticated technologies such as endoscopy, laparoscopy and robotic surgery. as these minimally invasive methods gain popularity throughout the world, this has led in some countries to a serious training gap as compared to other countries (4), and between generations of surgeons within national training systems. there is a huge heterogeneity in urological training between countries, whether developed or developing (5, 6). most countries have a urological training duration of around 5 years, but this may include rotations in nephrology, pediatric surgery, gynecology, general surgery, anesthesia, pathology and others (4). numerous recent studies have shown that trainees remain dissatisfied with their training in urology in many countries (7-12). the educational landscape in urology training is changing and adapting to modern learning methods. globalization of demands and services also means there clearly is a need for a standardized and structured urological training for global use. this must also include competency-based assessment, certification and re-certification (3). naturally, these changes are adopted by various countries in various ways and speeds. this has led at the current time to a wide variation of training quality between countries and training systems. u-merge is a urological educational platform. its members are active in international teaching & training in many countries globally. therefore, the authors have seen firsthand huge differences in structures and quality of urological training programs. programs may vary from the oldarchivio italiano di urologia e andrologia 2020; 92, 3 a. ullah aslam, j. philipraj, s. jaffrey, n. buchholz 220 fashioned apprenticeship model with a see one, do one, teach one approach, to highly structured, sometimes nationalized training programs using modern technologies such as virtual, simulated and telemedical training. this paper attempts to shed some light onto global urological training, comparing a significant number of various national systems, and to outline global tendencies in urological training. we focus on endourology and pediatric endourology training as representative for recent technological changes in urology. this paper will enable interested readers to see where their own system stands in international comparison, and hopefully enable them to identify training needs to achieve global quality standards. materials and methods this paper is based on a questionnaire which was sent in 2015 to 240 members of u-merge from 62 countries (appendix 1). u-merge members are consultant level academic urologists in their respective countries. the questionnaire addressed • structure and duration of the urology training program • training in basic urology and endourology (if any) • sub-specialty training in pediatric urology • assessment structure • availability of simulated training options. no funding has been obtained to conduct this study. results cumulative results of 240 questionnaires emailed to u-merge members in 60 countries, we received 37 (15.4%) responses from 32 countries. twenty-one (56%) of these have no structured training program. urology training follows an apprenticeship model. the other 16 have a structured training program. endourology training can be integrated into the mainstream residency training or have its own defined training period. duration of training within structured programs varies from 0.5 to 6 years. in 7 (18%) countries, urology residency training can be completed without gaining competency in endourology. 8 (21%) do not require urs, 17 (46%) do not require furs/rirs, and 18 (48%) do not require pcnl competency. 3 (8%) countries require endourology training in children (table 1). as per specific endourological procedures, 22 (59%) of countries require their trainees to be independently competent in urs, 5 (13%) to be competent with assistance, and 2 (5%) require mere exposure during training. in 10 (27%) urs training has not been specified. for furs/rirs, the numbers are 9 (24%), 10 (27%), 6 (16%), and 13 (35%), respectively. for pcnl the numbers are 6 (16%), 13 (35%), 9 (24%), and 12 (32%), respectively. for endourological procedures in children, independent competency is usually not required to complete urology residency. 4 (11%) of countries require table 1. structured urology training programs and endourology components by country. country structured duration endourology completion of training completion of training completion of training completion of training completion of training endourology training program without competence without competence without competence without competence without competence training (years) in endouro procedures in urs in furs/rirs in pcnl in endouro in children algeria no not applicable yes no no no yes austria no not applicable yes no no no yes australia yes 6 yes no no no yes bangladesh no not applicable yes yes yes yes yes brazil yes 0,5 yes no yes no yes bulgaria yes 1 yes no no no yes canada no not applicable yes no no yes yes china no not applicable yes no no yes yes colombia no not applicable yes no yes yes yes egypt no not applicable yes no yes no yes el salvador no not applicable yes yes yes yes yes france no not applicable no no no no yes germany yes 5 yes no yes yes yes greece no not applicable yes no yes yes yes india yes 5 yes no yes yes yes iran yes 2 yes no yes yes yes iraq yes 3 yes yes yes yes yes ireland yes 6 no no no no yes 1italy no not applicable yes yes yes yes yes kenya yes 4 yes no no no yes kurdistan yes 1 no no no no yes moldova no not applicable yes no yes yes yes morocco yes 5 yes yes yes yes yes nepal yes 3 no no no no no oman no not applicable yes yes yes yes yes pakistan yes 6 yes no no no yes panama no not applicable yes no no no yes romania no not applicable yes no no no yes serbia no not applicable yes no no yes yes south africa no not applicable no no no no no spain no not applicable yes yes yes yes yes sweden yes 5 yes no no no yes syria no not applicable yes no yes yes yes tunisia yes 2 no no no no no uae no not applicable yes yes yes yes yes uk yes 5 no no no no yes ukraine no not applicable yes no no no yes competency with assistance by trainers, and 3 (8%) require some exposure during training. some countries offer post-residency training on a fellowship level: 3 (8%) for furs/rirs, 6 (16%) for pcnl, and 6 (16%) for pediatric procedures, respectively (table 2). twenty-one (56%) countries have defined a minimum procedure number for endourology training: 20 (54%) for urs, 13 (35%) for furs/rirs, 18 (48%) for pcnl, and 7 (19%) for pediatric endourological procedures. indicative numbers vary widely: 10-450 for urs, 10-100 for furs/rirs, 6-250 for pcnl, and 2-300 for pediatric procedures, respectively (table 3). twenty-six (70%) countries have no structured performance assessment during training in place. 19 (51%) rely on a general assessment, 12 (32%) perform regular audit, 9 (24%) use examinations as a tool of assessment, and 14 (38%) apply formal direct observation of procedural skills (dops) (table 4). regarding simulated surgical skills training, 7 (19%) have a “dry lab” facility for urs at their disposal, another 7 (19%) have a “wet lab” training option for urs. 6 (16%) have these as a compulsory training part in their programs. each 6 (16%) countries offer either for furs/ rirs training, and 6 (16%) offer “dry lab” and 5 (13%) “wet lab” training for pcnl. each 3 (8%) use these as compulsory part of training (table 5). results by country as mentioned before, twenty-one (56%) countries have no structured training program (figure 1). urology training follows an apprenticeship model. another 16 have a structured training program of varying duration and performance assessments (figure 2). in the following we present a short summary for the urological training in all responder countries in alphabetical order. the following 21 countries have no structured training program: 1. algeria the completion of urological training includes competence in urs (semi-rigid ureteroscopy), furs/rirs (flexible ureteroscopy/retrograde intrarenal surgery) and pcnl (percutaneous nephrolithotomy), with exception of endourological procedures in children. trainees are expected to perform a minimum of 10 cases each of urs and furs/rirs. in addition, fifteen pcnl with trainer assistance is a requirement. there is compulsory wet lab training on animal models for urs, furs/rirs and pcnl. no structured method of performance assessment has been specified. 2. austria for endourological procedures (urs, furs/rirs, pcnl) a combined minimum case load of 150 procedures is required. there is no specified level of competence for these endourologal procedures in children. there is no 221archivio italiano di urologia e andrologia 2020; 92, 3 global urology training table 2. core competencies required in endourology by country. country urs perform urs perform urs urs lwarn urs not furs/rirs furs/rirs furs/rirs furs/rirs furs/rirs pcnl pcnl perform pcnl pcnl learn pcnl not endourol in endourol in endourol in endourol in endourol in independently with exposure at specialist specified perform perform with exposure learn at not specified perform with exposure at specialist specified children children children children learn children assistance fellowship level independently assistance specialist independently assistance fellowship level perform perform with exposure at specialist not specified fellowship level independently assistance fellowship level algeria yes yes yes yes yes austria yes yes yes yes australia yes yes yes yes bangladesh yes yes yes yes brazil yes yes yes yes bulgaria yes yes yes yes canada yes yes yes yes yes yes yes china yes yes yes yes colombia yes yes yes yes egypt yes yes yes yes el salvador yes yes yes yes france yes yes yes yes germany yes yes yes yes greece yes yes yes yes india yes yes yes yes iran yes yes yes yes iraq yes yes yes yes yes yes yes yes yes ireland yes yes yes yes italy yes yes yes yes kenya yes yes yes yes yes yes kurdistan yes yes yes yes moldova yes yes yes yes morocco yes yes yes yes nepal yes yes yes yes yes yes yes oman pakistan yes yes yes yes panama yes yes yes yes romania yes yes yes yes serbia yes yes south africa yes yes yes yes spain yes yes yes yes sweden yes yes yes yes yes yes yes yes yes yes yes yes syria yes yes yes yes tunisia yes yes yes yes uae yes yes yes yes uk yes yes yes yes ukraine yes yes yes yes archivio italiano di urologia e andrologia 2020; 92, 3 a. ullah aslam, j. philipraj, s. jaffrey, n. buchholz 222 table 3. minimum endourology procedure numbers required by country. country min no. urs min urs indicative furs/rirs min no. furs/rirs pcnl min no. pcnl indicative endourology in chilidren endourology in children all 4 procedures not of case load no. of case load number of caseload indicative numbers of caseload numbers min no. of caseload indicative numbers combined case numbers specified algeria yes yes 10 yes 10 yes 15 no 0 not mentioned austria yes yes not mentioned yes not mentioned yes not mentioned yes not mentioned 150 australia yes yes 100 yes 75 yes 15 no 0 not mentioned bangladesh no no 0 no 0 no 0 no 0 no brazil yes yes 12 no no yes 6 no no bulgaria yes yes 50 yes 10 yes 10 no no not mentioned canada no no not mentioned no not mentioned no not mentioned no not mentioned not mentioned china no no not mentioned no not mentioned no not mentioned no not mentioned not mentioned colombia no no no no no not mentioned egypt yes yes 60 yes 20 yes 30 yes 10 not mentioned el salvador no no no no no no no no no not mentioned france no yes 50 yes 50 yes 20 no no not mentioned germany no yes 50 no no no no no no not mentioned greece no no no no no no no no no not mentioned india yes yes 20 yes 20 yes 5 yes 2 not mentioned iran yes yes 70 no no yes 50 yes 10 not mentioned iraq yes yes 450 yes 30 yes 60 yes 300 not mentioned ireland yes yes 50 yes 50 yes 10 no no not mentioned italy no no yes kenya yes yes 50 yes 50 yes 30 no no not mentioned kurdistan yes yes 200 yes 100 yes 250 yes 20 not mentioned moldova no no yes morocco no no no no no no no no no not mentioned nepal yes yes 200 yes 25 yes 100 no not mentioned not mentioned oman yes pakistan yes yes 400 no no yes 250 no no not mentioned panama no yes romania yes yes 20 no no yes 20 no no not mentioned serbia yes yes 50 no no no no no no not mentioned south africa no no no no no no no no no not mentioned spain no no no no no no no no no not mentioned sweden no no no no no no no no no not mentioned syria no no no no no no no no no not mentioned tunisia yes yes not mentioned no no yes 20 no no not mentioned uae no no yes uk yes yes 50 yes 50 yes 10 yes 10 not mentioned ukraine no no no no no no no no no not mentioned country general assessment of performance audit formal examination/viva direct obs of procedure skills (dops) several of above assessments no specific assessment algeria no no no no no yes austria yes yes yes no yes no australia yes yes yes yes yes no bangladesh no no no no no yes brazil no no no no no yes bulgaria not mentioned not mentioned not mentioned not mentioned yes no canada not mentioned not mentioned not mentioned not mentioned yes no china no yes no yes yes yes colombia not mentioned not mentioned not mentioned not mentioned yes yes egypt yes no yes yes yes yes el salvador no no no no no no france yes yes yes yes yes yes germany no no no no no no greece yes no no yes yes yes india yes no no no no yes iran yes yes no yes yes yes iraq yes yes yes yes yes yes ireland yes yes no yes yes yes italy kenya yes yes yes yes yes yes kurdistan yes yes no yes yes yes moldova no no no no no no morocco yes no no no no yes nepal yes yes yes no yes yes oman no pakistan yes yes yes no yes yes panama no no no no no no romania no no no no no no serbia yes no no no no yes south africa yes no no yes yes yes spain no no no no no no sweden no no no yes no yes syria not mentioned not mentioned not mentioned not mentioned yes yes tunisia yes yes no yes yes yes uae uk yes no yes yes yes yes ukraine yes no no no no yes table 4. performance assessments by country. 223archivio italiano di urologia e andrologia 2020; 92, 3 global urology training compulsory dry or wet lab training. the assessment is via general assessment of performance, audit and formal examination with viva by the trainers. 3. bangladesh trainees can achieve completion of training without proven competence in furs/rirs, pcnl and endourological surgery in children. they are required to perform some urs and pcnl with trainer assistance. endourology in children is later taught at fellowship level. indicative numbers of procedure and performance assessment methods are not specified. 4. canada urs and furs/rirs are a requirement for completion of training with candidates expected to perform these procedures independently. endourology in children and pcnl is taught at fellowship level post-residency. model training is not compulsory. various method of assessment of performance are in place. 5. china for completion of training, urs with trainer assistance is required. however, trainees are expected to have had exposure to furs and pcnl. there is no specified endourology training in children. there is dry lab training for urs and wet lab training for furs and pcnl, albeit not compulsory. audit and dops are used for assessment. 6. colombia urs is mandatory and trainees are expected to perform it independently. furs and pcnl with trainer assistance are required. endourology in children is not regulated. there is no model training and no specific assessment structure in place. 7. egypt trainees can complete their training without gaining independent level competence in furs/rirs and endourological procedures in children. twenty and 10 assisted or observed cases in furs and paediatric endourology, respectively, are indicative, albeit not mandatory. urs and pcnl procedures are compulsory for the trainee to perform independently, with indicative numbers of 60 and 30, respectively. there is no compulsory model training. assessment of performance is via formal examination with viva and dops. 8. el salvador there is no specified mandatory requirement for any endourological procedures. indicative numbers, provision of model training, or assessment methods are not specified. 9. france there is no structured endourology training program. however, it is mandatory to achieve competence in urs, furs/rirs and pcnl. endourological procedures in children is not a mandatory requirement. fifty cases each for urs and furs/rirs, and 20 cases of pcnl are indicative, with numbers unspecified for paediatric endourology. there are dry and wet labs for each of these procedures. however, model training is not compulsory. country urs drylab urs wetlab urs compulsory furs drylab furs wetlab furs compulsory pcnl drylab furs wetlab furs compulsory algeria no yes yes no yes yes no yes yes austria no no no no no no no no no australia no no no no no no no no no bangladesh no no no no no no no no no brazil ns ns no ns ns no ns ns no bulgaria yes no yes yes no yes yes no no canada no no no no no no no no no china yes no no yes yes no yes yes no colombia no no no no no no no no no egypt no no no no no no no no no el salvador no no no no no no no no no france yes yes no yes yes no yes yes no germany no yes yes no no no no no no greece no no no no no no no no no india yes no no yes no no yes no no iran no no no no no no no no no iraq no yes yes no yes yes no yes yes ireland no no no no no no no no no italy no no no no no no no no no kenya no no no kurdistan no no no moldova no yes yes no no no no no no morocco no no no nepal no no no no no no no no no oman no info pakistan no no no panama no no no romania no no no serbia yes yes no yes yes no yes yes no south africa no no no no no no no no no spain no no no no no no no no no sweden yes yes no yes yes no no no no syria no no no no no no no no no tunisia yes no yes no yes no yes no yes uae no info uk no no no no no no no no no ukraine no no no no no no no no no table 5. availability and integration of dry & wet lab model training into the training program by country. archivio italiano di urologia e andrologia 2020; 92, 3 a. ullah aslam, j. philipraj, s. jaffrey, n. buchholz 224 figure 1. countries with no structured (endourology) training and indicative numbers of procedures (empty bars indicate no minimum number specified). figure 2. ountries with structured (endourology) training programs: duration of training. 225archivio italiano di urologia e andrologia 2020; 92, 3 global urology training assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 10. greece urs is a mandatory requirement with no specified indicative numbers. completion of training is possible without further competence in endourology. there is no provision of model training. assessment of performance is via general assessment and dops. 11. italy there are no competence requirements for endourology. indicative numbers are unspecified. there is no provision of model training. assessment methods are not specified. 12. moldova trainees are expected to gain independent level competence in urs for completion of training with unspecified indicative numbers. there is compulsory urs wet lab on animal models. the performance assessment method is unspecified. 13. oman endourology is not a mandatory requirement for completion of training. there are no specified indicative numbers, model training or assessment methods. 14. panama urs, furs/rirs and pcnl are mandatory requirements for completion of training, however indicative numbers are not specified. dry and wet labs are not available, and there is no specified method of assessment. 15. romania although there is lack of structured endourology training, for completion of training it is mandatory to achieve competence in urs, furs/rirs and pcnl. urs and pcnl are expected to be performed independently, furs with trainer assistance. twenty cases for urs are indicative. dry and wet labs are not compulsory, and assessment of competency is not specified. 16. serbia urs and furs/rirs are mandatory requirements to complete training with 50 cases for urs as indicative number. dry and wet labs for each of these procedures are accessible by trainees, but not compulsory. competency is assessed by general assessment. 17. south africa it is mandatory to achieve competence in endourology for completion of training. trainees are required to gain competence in all procedures (urs, furs/rirs, pcnl and paediatric endourology). level of competence is not specified with no indicative numbers. there are no dry or wet labs. assessment of performance is via general assessment and dops. 18. spain trainees are not required to gain competence in endourology to complete training. there are no specified indicative numbers, lab provisions or assessment methods. 19. syria trainees are required to gain independent level competence in urs with exposure to pcnl and assistance in paediatric endourology. furs training is not specified. there are no minimum case numbers and model training. assessment of performance is not specified. 20. united arab emirates there is no specific training program. 21. ukraine urs, furs/rirs and pcnl are mandatory for completion of training, however core competency, indicative numbers and lab provision are not specified. there is a general assessment of competency. the following 16 countries do have a structured training program (figure 3): 1. australia the training program runs for 6 years. it is mandatory to achieve competence in endourology for completion of training such as independent level competence in urs and furs/rirs. performance of pcnl with assistance is a requirement. paediatric endourology is learned at fellowship level. indicative numbers include 100 urs, 75 furs/rirs, and 15 pcnl with no specified numbers for paediatric endourology. dry and wet labs are not provisioned. assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 2. brazil a 6 month endourology program is in existence with mandatory expertise in urs. pcnl with assistance and exposure to furs/rirs is deemed satisfactory. twelve urs and 6 pcnl are indicative for completion of training. there are no specified numbers for paediatric endourology. lab training is not provisioned and there is no specified method of assessment of competence. 3. bulgaria an endourology program of 1-year duration exists with trainees expected to perform urs independently and pcnl with assistance. exposure to furs/rirs is mandatory. paediatric endourology is learned at fellowship level. indicative numbers for each of these procedures are 50 urs, 10 each furs/rirs and pcnl. a dry lab is compulsory for each category, with the exception of endourology in children. assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 4. germany a 5-year urology training program is in place. endourology training comprises of mandatory urs. furs/rirs, pcnl and endourology in children is not specified. fifty urs procedures are indicative. wet lab for urs is compulsory. assessment of performance is via several methods. 5. india expertise in urs is mandatory as part of a 5-year uroarchivio italiano di urologia e andrologia 2020; 92, 3 a. ullah aslam, j. philipraj, s. jaffrey, n. buchholz 226 logical training program. furs/rirs and pcnl are accepted to be performed with assistance. paediatric endourology is not specified. indicative numbers include 20 for urs, 20 for furs/rirs, 5 for pcnl and 2 in paediatric endourology. there is a provision of dry lab for each of these procedures, albeit not compulsory. assessment of performance is via general assessment. 6. iran an endourology program runs for 2 years with independent expertise in urs being mandatory. pcnl and paediatric endourology exposure is necessary, whereas furs/rirs is not specified. seventy urs, 50 pcnl and 10 paediatric endourology cases are indicative. there is no provision of dry and wet labs. assessment of performance is via several methods including audit, general assessment and dops. 7. iraq endourology training for 3 years is mandatory, however trainees can finish training without gaining independent level competence in either of the endourology procedures with exception being urs. a minimum of 450 cases of urs, 30 of furs/rirs, 60 of pcnl and 300 of paediatric endourology are indicative. there is provision of dry and wet labs for each of these procedures which are compulsory. assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 8. ireland a 6-year training program exists, with a structured endourology training. urs, furs/rirs and pcnl are mandatory, with paediatric endourology learned at fellowship level. trainees are required to gain independent level competence in urs and furs/rirs, with pcnl figure 3. countries with structured endourology training and indicative numbers of procedures required (empty bars indicate no number specified). 227archivio italiano di urologia e andrologia 2020; 92, 3 global urology training performed with trainer assistance. indicative numbers 50 urs, 50 furs, and 10 pcnl. there is no provision of lab training. assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 9. kenya urs, furs/rirs and pcnl are mandatory to achieve competence in endourology for completion of a 4-year training program. paediatric endourology is performed at fellowship level hence not a requirement for completion of training. trainees are expected to perform urs and furs/rirs independently, and pcnl with assistance. fifty cases each for urs and furs/rirs, and 30 cases of pcnl are indicative. lab is not provisioned. assessment of performance is via several methods including audit, general assessment, formal examination and viva with dops. 10. kurdistan a one-year structured endourology training program makes it mandatory for trainees to be independently proficient to perform urs and furs/rirs, and pcnl to be performed with assistance. there is no specified paediatric endourology training. two hundred cases for urs, 100 for furs/rirs, 250 cases of pcnl, and 20 paediatric endourology cases are indicative. there is no provision of lab training. several methods such as general assessment, audit and dops are used for assessment. 11. morocco the training program comprises endourology training and runs for 5 years. trainees are required to gain exposure to urs, furs/rirs and pcnl in order to complete their training. endourological procedures in children are not a mandatory requirement. there are no specified indicative numbers, and no lab training. general assessment of performance exists to assess competency. 12. nepal it is mandatory to achieve competence in endourology for completion of training of a 3-year training. trainees are required to gain independent level competence in urs, with furs/rirs and pcnl to be performed with trainer assistance. endourological procedures in children are not a mandatory requirement. two hundred cases for urs, 25 for furs/rirs, and 100 cases of pcnl are indicative, with no particularly specified numbers for paediatric endourology. there is no provision of lab training. audit, general assessment, formal examination and viva are in place to assess competency of training. 13. pakistan a 5-year program exists with mandatory endourology training. trainees are required to gain independent level competence in urs, with furs/rirs and pcnl performed with trainer assistance. endourological procedures in children are not a mandatory requirement. four hundred cases for urs and 250 cases of pcnl are indicative, with no particularly specified numbers for furs/rirs and paediatric endourology. there is no provision of dry and wet labs for each of these procedures. several methods exist including audit, general assessment, formal examination and viva to assess competency. 14. sweden it is a mandatory requirement to achieve competence in endourology for completion of a 5-year training program. trainees are required to gain independent level competence in urs, furs/rirs and pcnl in order to complete their training. endourological procedures in children and indicative numbers are not specified. there are dry and wet labs for urs and furs/rirs, which are however not compulsory. assessment is via dops. 15. tunisia a 2-year training program exists comprising of endourology training in urs and furs/rirs. pcnl is learned at fellowship level. paediatric endourology is not specified. trainees are required to gain independent level competence in urs. twenty pcnl performed with assistance are indicative. a compulsory dry lab for urs and pcnl exists with optional furs wet lab. assessment is via audit, general assessment, formal examination and dops. 16. united kingdom the uk training program runs for 5 years with mandatory competence in urs, furs/rirs and pcnl. endourological procedures in children are not a mandatory requirement. trainees are required to perform urs and furs/rirs independently, with pcnl exposure, and no specified paediatric endourology. fifty cases each for urs and furs/rirs, and 10 cases of pcnl, as well as 10 cases of paediatric endourology as indicative. there is no compulsory lab training. competency assessment is via several methods including audit, general assessment, formal examination, viva and dops. discussion our results have shown that there is a huge heterogeneity between training systems in various countries. this has previously been confirmed by others (5,6). urological training, although embracing modern learning technologies in many countries, is far from ideal in most places. inevitably, that will lead to huge differences in the training quality as well. in europe, there is a general lack of standardized training curricula. great differences exist between training requirements in different countries. trainees complain about a lack of confidence when performing major surgical procedures, non-compliance with european working hour regulations, a worrisome risk of burn-out and a negative impact on their work-life balance (6). irish residents complain mainly about a lack of operative experience (7). in spain, trainees find their training inadequate because of a lack of supervision, trainers completing their own training needs first, and a lack of operative experience (10). in germany, 45% of trainees feel unprepared for their future roles. 85% complain about a lack in structured training, evaluations, and transparency. another complaint is economic constraints during training (8). throughout south america, training, accreditation and re-certification are highly heterogenous and far archivio italiano di urologia e andrologia 2020; 92, 3 a. ullah aslam, j. philipraj, s. jaffrey, n. buchholz 228 from being standardized. in addition, academic activities are not properly valued (5). turkish residents report a lack of surgical exposure, and of encouragement for any academic activities (11). in tunisia, most trainees in urology were dissatisfied with their training (9). training is further compromised by reduced working hours for training as well as an increasing threat of litigation (12). all these studies confirm that there is a dire need to improve training quality in urology internationally. not only may patient safety be compromised, but even the trainees themselves will face a future that they do not feel ready for, and that they are not adequately trained for. so how could one achieve a meaningful improvement? it appears that a well-structured training approach is key to ensure a surgeon’s professional growth in the safest way for the patients (4). structured training is in place in some countries who may serve as a model for others. structuring the training may start with the right candidate selection. a surgeon needs compassion, communication skills, and should be perceptive and dedicated, besides manually skilled (2). structuring this crucial initial step of training, recruitment should be at least regional, if not national. candidates must undergo a validated assessment by objective, well-trained and experienced assessors. the process should be overseen by national authorities such as colleges or deaneries. this way each candidate will have the same chances and will undergo the same assessment, decreasing the chance of subjective bias. the uk system may serve here as an example (13). the next step to structure would be the training program itself. most modern training programs have already moved from a “see one, do one, teach one” approach to a structured learning – at least in minimally invasive treatment options –, and from e-learning to skills labs and modulated training settings (14). a structured training program will encompass a better definition of training goals and skills, specialization, structured evaluation, standardization of exams and include research (8). simulation-based training can indeed address many concerns of the old apprenticeship model, such as patient safety, efficient acquisition of complex surgical skills, overcoming the learning curve, and cost-effectiveness (4, 15). improved structured training should include structured scheduling of activities, use of peer training, elearning, access to simulation training on high fidelity models and/ or animals, trainee information on all available resources, effective tutoring, research, and evidence based practice learning (2, 9, 16,17). a consensus has been reached on markers defining the quality of a surgical training program (18): trainer – trainee relationship operative exposure supervision feed back structures and organization of training structured teaching programs no training is effective without assessment of the competency and proficiency achieved by the trainee. however, assessments are often perceived as haphazard, subjective and non-transparent (5, 8). in structured simulation training programs, the most commonly used tools for objective assessment are (15): technical skills assessment global rating scale of performance rating scores questionnaires and post-training surveys structured assessment by use of video recording motion tracking software. another established, effective and valuable tool in surgical training assessment is the direct observation of procedural skills (dops) (19, 20). in any case, trainee assessment has to move away from the mere measure of the number of surgical procedures to mediation of competencies and skills as markers of competency (21, 22). a consensus statement has been reached on the quality markers of training assessment (18): trainee feedback trainer feedback timetable structure trainee improvement. however, there are also barriers to effective training assessment which we must bear in mind. these are uncertainty on what to document, concern of a negative impact on faculty popularity amongst trainees, lack of clear standards, and lack of effective remediation options (23) according with the mission of urology for emerging countries (u-merge), the authors looked at a wide array of urological training in various countries. it is notable that structured training programs do not only exist in developed countries, and old-fashioned apprenticeship models do still prevail in some developed countries although modern learning options are readily available there, albeit not implemented. especially but not only in the developing world, urological training is marred by inconsistency, lack of structure, and lack of focus on research and evidence-based practice (2). this is where an international and/or global training approach comes into play. more affluent countries could afford to help less fortunate countries to establish sustainable, capacity-building educational collaborations that are essential to address the global burden of global disease. international collaboration can lead the way towards competency-based training, assessment of technical skills by international standards, longterm trainer proficiency, and community-specific quality initiatives (24). established tools for this purpose are an online curriculum, visiting educator trips, expert surgeon involvement, trainee competency tracking and identification of local outreach partners (25). however, any collaboration towards standardized and structured training needs to be responsible, meaning responding to locally identified needs, training projects according to local contexts, and a general working towards self-sufficiency of the trainees (26). our results have shown a huge heterogeneity in quality urology training between countries and within continents. in systems without national structure of training it 229archivio italiano di urologia e andrologia 2020; 92, 3 global urology training can be assumed that such differences exist even between hospitals/training institutions. there is no doubt in times of globalization with resident and doctor migration and exchanges that training needs structure and standardization. the still huge gap in developing countries to catch up and be able to afford latest surgical and learning technologies need to be addressed with the help of responsible outreach programs. there is ample literature on the requirements of structured training programs and assessments, and we have tried to briefly outline the key points in this paper. references 1. campain nj, kailavasan m, chlawe m, et al. an evaluation of the role of simulation training for teaching surgical skills in subsaharan africa. world j surg. 2018, 42:923-929. 2. ather mh, siddiqui t. urology training in the developing world: the trainer’s perspective. arab j urol. 2013. http://dx.doi.org/ 10.1016/j.aju.2013.07.001 3. anderson jt. assessments and skills improvement for endoscopists. best pract res clin gastroenterol. 2016, 30:453-471. 4. sarikaya s, meneses ad, cacciamani ge, rivas jg. future of urology training. arch esp urol. 2018; 71:158-163. 5. angulo jc, figueroa c, gomez r, et al. current status of urological training in south america. arch esp urol. 2018; 71:23-33. 6. carrion dm, gomez rivas j, esperto f, et al. current status of urological training in europe. arch esp urol. 2018; 71:11-17. 7. o’sullivan ke, byrne ks, walsh tn. basic surgical training in ireland: the impact of operative experience, training, program allocation and mentorship on trainee satisfaction. ir j med sci. 2013; 182:687-692. 8. struck jp, cebulla a, ralla b, koenig j. structured training curriculum for urological residents: chances and limits. urologe a. 2019; 58:109-113. 9. naouar s, binous my, braiek s, el kamel r. training of tunisian future urologists: how to improve it. tunis med. 2018; 96:401-404. 10. soria f, villacampa f, serrano a, et al. training program in endourological surgery. future perspectives. arch esp urol. 71:89-96. 11. sarikaya s. needs, realities and expectations for urology training: questionnaire-based study. arch esp urol. 2018; 71:18-22. 12. lovegrove ce, abe t, aydin a, et al. simulation training in upper tract endourology: myth or reality? minerva urol nefrol. 2017; 69:579-588. 13. nhs health education england: training and development (urology) https://www.healthcareers.nhs.uk/explore-roles/doctors/ roles-doctors/surgery/urology/training-and-development. accessed 29.11.2019. 14. van der poel h, brinkman w, van cleynenbreugel b, et al. training in minimally invasive surgery in urology: european association of urology/ international consultation of urological diseases consultation. bju int. 2016; 117:515-530. 15. atesok k, satava rm, marsh jl, hurwitz sr. measuring surgical skills in simulation-based training. j am acad orthp surg. 2017; 25:665-672. 16. de vries ah, van luijk sj, scherpbier aj, et al. high acceptability of a newly developed urological practical skills training program. bmc urol. 2015; 15:93. 17. schiavina r, borghesi m, dababneh h, et al. the impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy. arch ital urol androl. 2018; 90:1-7. 18. siau k, dunckley p, valori r,, et al. joint advisory group on gastrointestinal endoscopy. changes in scoring of direct observation of procedural skills (dops) forms and the impact on competence assessment. endoscopy. 2018; 50:770-778. 19. khanghahi m, azar ef. direct observation of procedural skills (dops) evaluation method: systematic review of evidence. med j islam repub iran. 2018; 32:45. 20. heidenreich a, salem j, paffenholz p, pfister d. interdisciplinary education in urology: innovations for better training. urologe a. 2019; 58:870-876. 21. forbes n, mohamed r, raman m. learning curve for endoscopy training: is it all about numbers? best pract res clin gastroenterol. 2016; 30:349-356. 22. singh p, aggarwal r, zevin b, et al. a global delphi consensus study on defining and measuring quality in surgical training. j am coll surg. 2014; 219:346-353. 23. sanfey h. assessment of surgical training. surgeon. 2014; 12:350-356. 24.wagner jp, schroeder ad, espinoza jc, et al. global outreach using a systematic, competency-based training paradigm for inguinal hernioplasty. jama surg. 2017; 152:66-73. 25. sue gr, covingtonwc, chang j. the resurg global training program: a model for surgical training and capacity building in global reconstructive surgery. ann plast surg. 2018; 81:250-256. 26. macpherson l, collins m. training responsibly to improve global surgical and anaesthesia capacity through institutional health partnerships: a case study. trop doct. 2017; 47:73-77. correspondence asad ullah aslam, md asadullahaslam@gmail.com dept. of urology, letterkenny university hospital, saolta healthcare group (ireland) joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma ghandi medical college & research institute sri balaji vidyapeeth, pondicherry (india) sayed jaffrey, md jaffry@urology.ie dept. of urology, university college hospital, galway clinic and bons secours hospital, galway (ireland) noor buchholz, md (corresponding author) scientific-office@u-merge.com u-merge scientific office athens/greece stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11513 1 original paper (cs i) have very good prognosis with an overall survival rate of 98% (3). even metastatic patients have a good prognosis with a 5-year survival rate of 72-86% (3). despite modern staging procedures, approximately 15% of clinical stage i seminoma patients have subclinical metastatic disease (in the retroperitoneum) and will relapse after orchidectomy alone (4). unselected cs i patients managed by active surveillance (as) have shown an overall risk of relapse of 12-20% at five years (5). identification of cs i seminoma patients who are at a high risk of recurrence has largely been based on two prognostic factors: primary testicular tumour size, and the presence or absence of rete testis invasion (3, 6). patients with and without both risk factors have a 32% and 6% risk of relapse, respectively (7). patients with one risk factors had 12% risk of relapse (8). three management approaches have been investigated: surveillance, adjuvant radiotherapy and carboplatin (6, 914). the adjuvant treatment results were compared in large clinical trials and showed that a single injection of carboplatin at seven times the area under the curve dose (auc) was noninferior to rt in preventing metastatic relapse and, in addition, may reduce the risk of subsequent contralateral testicular cancer (10). furthermore, radiotherapy is associated with increased morbidity and late effects, in particular the risk of secondary cancers (15). the priority for those patients with low stage disease is limiting the burden of therapy and treatment-related toxicity without compromising cancer control. the optimal management strategy for stage i seminoma seems to be a matter of debate and controversy. the aim of this study was to evaluate the clinical outcomes of real-world patients with csi seminoma treated in a national referral centre. furthermore, we aimed to analyse prognostic factor influencing treatment choice and oncological outcomes. patients and methods the present study was approved by coimbra’s university hospital (chuc) and faculty of medicine (fmuc) ethical boards ce-026/2022. using the institutional prospective tgct database, we selected patients with histologically proven pure seminoma after inguinal orchiectomy. routine staging at diagnosis consisted in computed tomography (ct) introduction: stage i seminoma has a very good prognosis, yet approximately 15% have subclinical metastatic disease and will relapse after orchidectomy alone. several management approaches have been investigated. we aimed to evaluate the clinical outcomes of real-world patients with stage i seminoma, analysing prognostic factors influencing treatment choice and oncological outcomes. methods: retrospective, single institution study, with 55 patients diagnosed with clinical stage i seminoma between 2007 and 2020. selected patients were analysed regarding three management approaches surveillance, adjuvant radiotherapy and adjuvant carboplatin auc7. overall survival and progressionfree survival outcomes were analysed. predictors of treatment choice were determined, and predictors of recurrence were analysed in patients on active surveillance. results: the median follow-up time was 91 months (13-165). overall survival at 10 years was 98.2%. stage i seminoma patients had a 1-, 3and 10-year progression free survival of 98%, 94% and 89%, respectively. three-year progression free survival was 92.0% for those on active surveillance (ic95%, 91.5-92.5%), 95.2% for carboplatin (ic95%, 94.8-95.6%) and 100% for those on adjuvant radiotherapy (p > 0.05). all relapses on active surveillance protocols occurred during the first 24 months. overall, 43% of patients who underwent adjuvant treatment reported adverse effects of therapy, with higher incidence on radiotherapy group (63%). conclusions: stage i seminoma have excellent prognosis, high cure rates, and low treatment-associated morbidity. active surveillance is a safe modality when applied to selected patients. adjuvant radiotherapy and adjuvant chemotherapy with carboplatin show similar results, with fewer adverse effects on chemotherapy arm. key words: seminoma; surveillance; radiotherapy; adjuvant chemotherapy; recurrence. submitted 8 june 2023; accepted 14 july 2023 introduction the incidence of testicular germ cell tumours (tgct) has increased during recent decades and continues to rise (1). stage i seminoma is the most common presentation of tgct and accounts for approximately 40% of all occurrences (2). patients presenting with clinical stage i surveillance as a safe and effective option for treatment of stage i seminoma vasco quaresma 1, 2, *, diogo henriques 2, *, lorenzo marconi 1, 2, joão lorigo 1, ana-marta ferreira 1, roberto jarimba 1, 2, pedro nunes 1, 2, arnaldo figueiredo 1, 2, belmiro parada 1, 2 1 urology department, centro hospitalar e universitário de coimbra, portugal; 2 faculty of medicine of the university of coimbra, portugal. * both authors equally contributed as first co-authors. doi: 10.4081/aiua.2023.11513 summary archivio italiano di urologia e andrologia 2023; 95(3):11513 v. quaresma, d. henriques, l. marconi, et al. 2 of thorax, abdomen, and pelvis, with additional clinical history and physical examination. all included patients had serum tumour markers before and after orchiectomy α-fetoprotein (afp) and β-human chorionic gonadotropin (bhcg). the selected patients were retrospectively analysed and assigned to three management approaches surveillance, adjuvant radiotherapy and carboplatin. therapeutic modality was assigned after multidisciplinary uro-oncology discussion and informed discussion with patients. treatment decision was influenced by pathological characteristics and risk factors, serum tumour markers and patient option. patients undergoing adjuvant carboplatin had a single dose of intravenous carboplatin on an outpatient basis, calculated according to calvert equation dose of carboplatin (mg) = area below curve 7 mg/ml/min x (gfr + 25). 16 patients treated with radiotherapy had a total of 20-24 gray (gy) directed to the para-aortic and ipsilateral iliac fields. most of included patients were followed with clinical assessment and serum tumour markers every 3 months in the first year, every 6 months until third year, and then yearly. ct of thorax, abdomen and pelvis was performed biannually in the first two year and then yearly. co-primary endpoints were the overall survival (os) and disease-free survival (dfs). overall survival was defined as the time from orchiectomy to death from any cause. progression-free survival was defined as the time from orchiectomy to imagological disease progression. increased serum tumour markers were not considered as recurrence. secondary endpoints were the evaluation of risk factor at the time of diagnosis and safety assessment according to national cancer institute common terminology criteria for adverse events version 4.0. statistical analysis descriptive analyses were performed using standard summary statistics. overall survival, progression-free survival, and duration of response were estimated with the use of the kaplan-meier method. predictors of adjuvant treatment decision were determined by qui-square test of independency (with yates correction). in the analysis of overall survival, patients who were alive had their data censored at the time of last contact. in the analysis of progression-free survival, patients who were alive and without disease progression had their data censored at the time of last tumour assessment. cox multivariate analysis were performed to adjust survival for risk factors (rete testis invasion and dimensions) and adjuvant treatment. medians are reported with corresponding 95% confidence intervals (cis). results from 157 patients with tcgt followed between 2007 and 2020, 55 patients had clinical stage i seminoma at diagnosis. the selected patients were retrospectively analysed and assigned to three management approaches surveillance, adjuvant radiotherapy and carboplatin. diagram is show in figure 1. we included a total of 55 patients of testicular seminoma with no evidence of metastatic disease at the time of diagnosis (cs i seminoma). median patient age was 35 years (range: 24 to 66). pre-operatively, 7 patients (13%) showed elevated serum bhcg (> 5 mu/ml), and an additional 19 patients (35%) had high serum ldh levels (> 248 u/l). all patients were preand postorchiectomy afp negative, and bhcg levels normalized after orchiectomy. median tumour dimension was 40 mm (range: 7 to 120 mm). most specimens (57%) showed tumour confined to testis, with no lymphovascular invasion (pt1). demographic characteristics of patients and disease at the diagnosis according to treatment modality are summarized on table 1. of the included patients, 25 underwent an active surveillance protocol and 30 were submitted to adjuvant therapy 8 radiotherapy and 22 carboplatin auc 7. most patients on active surveillance (60%) had no risk factors of recurrence on initial management (rete testis invasion or size > 4 cm). only 16% had lymphovascular invasion and 4% showed positive pre-operative tumour markers. conversely, risk factors (rete testis invasion or size > 4 cm) were present on 83% of the patients in adjutable 1. demographic and disease characteristics. characteristic surveillance carboplatin radiotherapy p value (n = 25) (n = 22) (n = 8) age yrs. median 33 35 36 t-test range 26-66 24-54 25-41 p > 0.05 pre-operative serum tumor markers positive 7 (28%) 11 (50%) 3 (37%) x2 negative 18 (72%) 11 (50%) 5 (63%) p > 0.05 stage ia 3 (12%) 14 (64%) 3 (37%) x2 ib 22 (88%) 8 (36%) 5 (63%) p < 0.05 rete testis invasion yes 5 (20%) 12 (55%) 5 (37%) x2 no 20 (80%) 10 (45%) 3 (63%) p > 0.05 tumour dimension (cm) median 3 5 4 t-test range 1.2-12 1-12 2.2-8 p > 0.05 bhcg: β-human chorionic gonadotropin; ldh: lactate dehydrogenase. figure 1. assignment of selected patients to three management approaches surveillance, adjuvant radiotherapy and carboplatin. archivio italiano di urologia e andrologia 2023; 95(3):11513 3 surveillance for stage i seminoma vant treatment groups. therefore, we conducted a comparative analysis on baseline characteristics, which verified that only pt stage was statistically different between treatment groups. considering subgroups of adjuvant treatment, 86% patients on carboplatin group and 75% on radiotherapy had one or two risk factors. comparative analysis is summarized on table 2. tumour maximal dimensions (p < 0.05) and limphovascular invasion (p < 0.05) were predictors of adjuvant treatment decision in this setting. median time from orchiectomy to adjuvant treatment was 37 days (range 24-92). survival analysis median follow-up time was 91 months (range 13 165 months), with 98% of patients being followed for more than 2 years. no patient was lost to follow-up. ten-year overall survival (os) was 98.2%, with an average overall survival of 162 months (95% ci, 157 to 167 months) median not reached (figure 2). one patient died due to febrile neutropenia following second line chemotherapy. at the time of present analysis, relapses were observed in 5 patients. stage i seminoma patients had a 1-, 3and 10year pfs of 98%, 94% and 89%, respectively. three-year pfs was 92.0% for those on active surveillance (95% ci, 91.5 to 92.5%), 95.2% for carboplatin (95% ci, 94.8 to 95.6%) and 100% for those on adjuvant radiotherapy, with no statistically difference between groups of treatment (p > 0.05). pfs analysis is illustrated on figure 3. median time to relapse for patients with tumour recurrence was 21 months (range: 9-64). all relapses on active surveillance protocols occurred during the first 24 months (9 and 21 months). adjuvant treatment groups showed later relapses carboplatin at 13 and 57 months and radiotherapy at 64 months. all relapses were retroperitoneal and detected on follow up ct scan. no patient had symptoms on relapse. these patients were treated with second line therapy with 4 cycles of bep (bleomycin, etoposide, and cisplatin). of those, 4 patients were free of disease at last follow up. one patient on surveillance group died of the disease, as mentioned before, after relapse and second line treatment. one patient on radiotherapy group showed seminoma on contralateral testis and was submitted to orchiectomy. safety safety analysis was performed with retrospective analysis of clinical records in the adjuvant treatment groups. treatment-related adverse events of any grade were reported in 43% of the patients. patients on carboplatin group reported 27% grade 1-2 events, with no grade 3-5 events. most common adverse effect of chemotherapy was nausea and vomitus. radiotherapy group had 63% reported adverse events, with 13% grade ≥ 3. one patient had secondary neoplasia after radiation treatment. predictors of recurrence we analysed the potential predictors of recurrence in patients with no adjuvant treatment. elevated preoperative β-hcg (> 5 mu/ml), pt > 1, rete testis invasion, and tumour size > 4 cm were not predictors of recurrence in patients on active surveillance (pearson x2; p > 0.05). two patients with no risk factors for relapse (rete testis figure 2. overall survival. ten-year overall survival (os) was 98.2%, with an average overall survival of 162 months (95% ci, 157 to 167 months) median not reached. figure 3. pfs analysis. three-year pfs was 92.0% for those on active surveillance (95% ci, 91.5 to 92.5%), 95.2% for carboplatin (95% ci, 94.8 to 95.6%) and 100% for those on adjuvant radiotherapy, with no statistically difference between groups of treatment (p > 0.05). table 2. risk factor and treatment groups. active surveillance adjuvant therapy (n = 25) (n = 30) rete testis invasion and/or size > 4 cm 15 (40%) 25 (83%) > pt1 4 (16%) 20 (66%) serum tumor markers 1 (4%) 6 (20%) archivio italiano di urologia e andrologia 2023; 95(3):11513 v. quaresma, d. henriques, l. marconi, et al. 4 invasion or > 4 cm) recurred on follow up, both in as group. three patients who recurred after adjuvant treatment, had both risk factors. table 3 shows the recurrence rates despite treatment modality. to eliminate the effect of adjuvant treatment, we conducted a cox regression with the following predictors: adjuvant treatment, rete testis invasion and dichotomous dimensions. there were no differences in pfs in the model (x2 = 0.95; p > 0.05). adjusted hazard ratio (hr) for adjuvant treatment was 0.6 (95% ci, 0.1 to 4.0, p = 0.5). adjusted hr of 1.3 for rete testis invasion (95% ci, 0.1 to 15.2, p = 0.8) and hr of 2.2 for dimensions (95% ci, 0.2 to 17.3, p = 0.4). discussion approximately 76% of patients with testicular seminoma in a portuguese referral centre present with stage i disease at diagnosis, results that are comparable to recent epidemiologic studies and a previous portuguese referral centre study (1, 17). these patients have excellent prognosis, with high cure rates (3). therefore, the treatment of stage i seminoma mostly addresses the principles of fast diagnosis and staging, short time between diagnosis and orchiectomy, and precise and fast decision of adjuvant treatment, aiming to avoid deaths without increasing the morbidity of treatment. adjuvant treatment recommendation mostly relies on a risk adapted strategy and last decision must be made by the individual patient. in stage i seminoma, primary testicular tumour size and invasion of the rete testis have been identified as predictors for relapse (7, 9). although, two recent systematic reviews have questioned the prognostic value of these risk factors, and so far, there is no ideal prognostic factor for relapse in patients with stage i seminoma (3, 18). both systematic reviews highlighted the low quality of the studies included and that the level of evidence is too low to recommend the use of these pathological risk factors to drive adjuvant treatment decisions (3, 18). nevertheless, absence of rete testis invasion together with a tumour diameter < 4 cm is associated with a very low risk of recurrence (6%) (19). therefore, these are the most suitable patients for as. in our centre experience, both tumour maximal dimensions (continuous) and lymphovascular invasion influenced the choice of adjuvant treatment. using dimensions as a continuous variable may help counseling patients about their expected tumor recurrence risk (12). risk factors of relapse were analysed on as patients to eliminate the bias of adjuvant treatment. pre-operative β-hcg; rete testis invasion; dimensions; > pt1 were not significant predictors of relapse. in the evaluation of recurrence without considering treatment modality, only 4% patients relapsed with no risk factors. patients with risk factors recurred in 6%. although the global model was not significant, patients with rete testis invasion (hr of 1.3) and higher dimensions (hr of 2.2) were associated with worse pfs. overall survival in the csi seminoma in our centre was 98.2%. os was comparable to most studies, and confirms excellent prognosis and high cure rates, even in the longer follow up of our design. nine percent of patients had recurrence of disease. at 3-year pfs no treatment modality showed to be superior, although more patients were free of disease in adjuvant treatment group at this time cut-off. patients on as showed earlier relapses (first 24 months) which justifies an intense follow up with ct scan in the first two years. growing experience with active surveillance has demonstrated that nearly 80% of csi seminoma can expect to be cured without adjuvant treatment, and almost all recurrences can be successfully rescued (14). possible disadvantages of clinical surveillance are incremental costs, need of patient compliance to the follow-up protocol, psychological distress, and the chance of early relapses (20). low number of relapses in our study support active surveillance as a safe option with comparable results to adjuvant treatment. both patients who relapse in as are alive and free of disease. as allows to mitigate the morbidity of adjuvant therapies, complying with the principles of treatment of testicular neoplasms when good selection criteria are applied. patients on adjuvant treatment groups presented more aggressive characteristics at orchidectomy (size, vascular invasion and pt), as well as a higher percentage of positive markers preoperatively. as discussed earlier, pfs was similar, even with more aggressive disease at diagnosis. radiotherapy, once the treatment of choice, is being abandoned as adjuvant treatment. despite long term pfs of 96% and os of 98%, significantly morbidity is associated with this modality, especially a two to three-fold increased risk of second malignancies (21). our experience also shows a low number of patients who underwent radiotherapy, confirming the tendency to abandon this modality in stage i seminoma, which confirms the change in pattern of care indicated by previous studies (22). carboplatin generally has excellent tolerability and is not associated with grade 3 or 4 adverse effects. on the other hand, rt presented more frequent adverse effects and the risk of secondary neoplasia. given the low age at diagnosis of patients with testicular neoplasia, one of the main objectives in treatment must be decreased morbidity. study limitations where its low number of participants, retrospective design, and the lack of inclusion criteria in the different modalities. conclusions patients with stage i seminoma have excellent prognosis, high cure rates, and low treatment-associated morbidity. active surveillance is a safe modality, with results comparable to other modalities, when applied to selected patients. intense follow up on the first 2 years after orchiectomy is mandatory. adjuvant radiotherapy and adjuvant chemotherapy with carboplatin show similar results, with fewer adverse effects in patients who underwent chemotherapy. table 3. predictors of recurrence. cs i (n = 55) rete testis invasion and/or size > 4 cm (n = 34) no risk factors (n = 21) recurrence disease free recurrence disease free 3 (5.5%) 32 (58.2%) 2 (3.6%) 18 (32.7%) archivio italiano di urologia e andrologia 2023; 95(3):11513 5 surveillance for stage i seminoma references 1. park js, kim j, elghiaty a, ham ws. recent global trends in testicular cancer incidence and mortality. medicine. 2018; 97:e12390 2. powles tb, bhardwa j, shamash j, et al. the changing presentation of germ cell tumours of the testis between 1983 and 2002. bju int 2005; 95:1197-1200. 3. boormans jl, mayor de castro j, marconi l, et al. testicular tumour size and rete testis invasion as prognostic factors for the risk of relapse of clinical stage i seminoma testis patients under surveillance: a systematic review by the testicular cancer guidelines panel. eur urol. 2018; 73:394-405. 4. kollmannsberger c, tandstad t, bedard pl, et al. patterns of relapse in patients with clinical stage i testicular cancer managed with active surveillance. j clin oncol. 2015; 33:51-57. 5. groll rj, warde p, jewett mas. a comprehensive systematic review of testicular germ cell tumor surveillance. crit rev oncol hematol. 2007; 64:182-197. 6. warde pr, gospodarowicz mk, goodman pj, et al. results of a policy of surveillance in stage i testicular seminoma. int j radiat oncol biol phys. 1993; 27:11-15. 7. aparicio j, maroto p, garcía del muro x, et al. prognostic factors for relapse in stage i seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the spanish germ cell cancer group (sgccg). ann oncol. 2014; 25:2173-2178. 8. aparicio j, maroto p, garcía del muro x, et al. prognostic factors for relapse in stage i seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the spanish germ cell cancer group (sgccg). annals of oncology. 2014; 25:2173-2178. 9. tandstad t, ståhl o, dahl o, et al. treatment of stage i seminoma, with one course of adjuvant carboplatin or surveillance, riskadapted recommendations implementing patient autonomy: a report from the swedish and norwegian testicular cancer group (swenoteca). ann oncol. 2016; 27:1299-1304. 10. oliver rtd, mason md, mead gm, et al. radiotherapy versus single-dose carboplatin in adjuvant treatment of stage i seminoma: a randomised trial. lancet. 2005; 366:293-300. 11. oliver rtd, mead gm, rustin gjs, et al. randomized trial of carboplatin versus radiotherapy for stage i seminoma: mature results on relapse and contralateral testis cancer rates in mrc te19/eortc 30982 study (isrctn27163214). j clin oncol 2011; 29:957-962. 12. chung p, mayhew la, warde p, et al. management of stage i seminomatous testicular cancer: a systematic review. clin oncol. 2010; 22:6-16. 13. fischer s, tandstad t, wheater m, et al. outcome of men with relapse after adjuvant carboplatin for clinical stage i seminoma. j clin oncol. 2017; 35:194-200. 14. aparicio j, garcía del muro x, maroto p, et al. multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage i seminoma. ann oncol. 2003; 14:867-872. 15. fosså sd, horwich a, russell jm, et al. optimal planning target volume for stage i testicular seminoma: a medical research council randomized trial. medical research council testicular tumor working group. j clin oncol. 1999; 17:1146-1154. 16. calvert ah, newell dr, gumbrell la, et al. carboplatin dosage: prospective evaluation of a simple formula based on renal function. j clin oncol. 1989; 7:1748-1756. 17. marques-pinto a, gomes ai, febra j, et al. specialist management of testicular cancer: report of the last 10 years at a portuguese tertiary referral academic centre. arch ital urol androl. 2021; 93:153-157. 18. zengerling f, kunath f, jensen k, et al. prognostic factors for tumor recurrence in patients with clinical stage i seminoma undergoing surveillance—a systematic review. urologic oncology: seminars and original investigations. 2018; 36:448-458. 19. aparicio j, maroto p, muro xg del, et al. risk-adapted treatment in clinical stage i testicular seminoma: the third spanish germ cell cancer group study. j clin oncol. 2011; 29:4677-4681. 20. sharda nn, kinsella tj, ritter ma. adjuvant radiation versus observation: a cost analysis of alternate management schemes in early-stage testicular seminoma. j clin oncol. 1996; 14:2933-2939. 21. zagars gk, babaian rj. stage i testicular seminoma: rationale for postorchiectomy radiation therapy. int j radiat oncol biol phys. 1987; 13:155-162. 22. mahmoud sayed m, nasr am, saad eldin im, abdelazim ya. stage i seminoma: outcome of different treatment modalities and changes in patterns of care: a single institution experience. arch ital urol androl. 2023; 95:11057. correspondence vasco pedro duarte quaresma, md (corresponding author) vpdquaresma@gmail.com rua antónio manso cunhavaz, lote 2, 5ºb, 3030-779, coimbra, portugal lorenzo marconi, md joão lorigo, md ana-marta ferreira, md roberto jarimba, md pedro nunes, md arnaldo figueiredo, md belmiro parada, md urology department, centro hospitalar e universitário de coimbra, portugal diogo henriques, md faculty of medicine of the university of coimbra, portugal conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 75archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. fibrous and inelastic; it often leads to penile deformation (the so-called 'recurvatum penis') (1). la peyronie's disease tends to be underdiagnosed and undertreated, and in italy it affects about 7% of the male population aged between 50 and 70. several studies indicate a prevalence in adult men between 3.2 and 13.1% and an incidence of 15.9% after radical prostatectomy (2). two stages of the disease are recognized: the first, the so-called inflammatory stage, characterized by painful erections and the development of fibrous nodules, and the second, the so-called stabilized fibrotic stage, in which the plaques are consistent, hard, fibrotic-calcific and cause deformities (recurvatum) of the penis, sometimes to the extent that coitus becomes difficult if not impossible. the disease is often unruly (3). spontaneous resolution is rare (3-13%), with most patients either progressing with the disease (30-50%) or stabilizing (45-65%). general factors such as autoimmune diseases, vitamin deficiencies, enzymatic alterations, neurohormonal imbalance, local factors like microtrauma, local vasculitis and predisposing factors including age, family history and collagenopathies have been suggested as causes. the most common risk factors are diabetes, hypertension, smoking, alterations in lipid metabolism and the association with dupuytren's disease (retraction of the palmar aponeurosis) (4-6). the treatment can be medical or surgical, thus medical treatment is mainly intended for patients in the early stages of the disease, i.e. when pain is present and the plaques are not yet intensely fibrotic or calcified (1). there are many therapeutic options, ranging from the use of oral treatments with drugs belonging to different pharmacological categories (anti-inflammatory drugs, vitamins, potassium paraminobenzoate, tamoxifen, etc.); shock waves; intraplate injections with steroid drugs, collagen, vasodilators, interferons; and iontophoresis (transdermal delivery of polarized drugs by means of a bipolar electric current) (1-3). medical therapy with iontophoresis is a non-invasive therapy that enables the drug applied to penetrate inside the corpora cavernosa without using needles or other invasive procedures (7). levine and estrada in 2003 conclusively demonstrated the efficacy of iontophoresis after measuring verapamil concentrations (very elevated) in the albuginea of patients operated for ppi and treated precociously with objectives: la peyronie's disease tends to be underdiagnosed and undertreated. in italy it affects about 7% of the population aged between 50 and 70 years old. the aim of this study is to evaluate the quality of life of patients undergoing iontophoretic therapy with verapamil and treatment outcomes at a two-year interval. materials and methods: this study evaluated 128 patients subjected to treatment cycles over a period of two years. questionnaires were administered to the patients at the beginning and end of each cycle of iontophoretic therapy in order to monitor the degree of presumed anxiety, depression, pain and the associated quality of life. result: this prospective descriptive observational study included 128 patients aged between 42 and 74 years presenting pain during erection and/or coital intercourse, which ceased in 108 cases, diminished in 12 and remained present in 4. concerning the penile deviation, which was present in all patients (128 cases), it disappeared in 6 cases, regressed in 90 cases, while it remained unchanged in 32 cases. as for the plaque consistency on palpation, in 42 patients the plaque was no longer present, in 50 cases the consistency diminished, while in 36 patients it remained unchanged. none of the cases evidenced an aggravation of the clinical condition. 57% of the evaluated patients had high levels of anxiety in the first cycle of iontophoretic sessions and low levels of depression. anxiety decreased in 32% of cases. depression was not related to pain but to sexual dysfunction. about 80 % of the patients assessed had an increase in quality of life at the end of the two-year follow-up. conclusions: in conclusion, it can be claimed that iontophoresis combined with verapamil therapy can improve patients' quality of life and offer them psychophysical well-being and an acceptable sexual relationship, thus decreasing anxiety and depression levels. key words: la peyronie's disease; penis induration; iontophoresis; local therapy; qol. submitted 12 november 2021; accepted 21 december 2021 introduction induratio penis plastica, or "la peyronie’s disease", is a connective tissue disease involving the tunica albuginea of the corpora cavernosa of the penis and characterized by an inflammatory plaque that becomes progressively more quality of life of patients with la peyronie's disease undergoing local iontophoresis therapy: a longitudinal observational study tatiana bolgeo 1, roberta di matteo 1, menada gardalini 1, denise gatti 1, antonio maconi 1, carmelo boccafoschi 2 1 sc infrastructure research training innovation, department of integrated activities research innovation, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy; 2 city of alessandria clinic monza polyclinic, alessandria, italy. doi: 10.4081/aiua.2022.1.75 summary archivio italiano di urologia e andrologia 2022; 94, 1 t. bolgeo, r. di matteo, m. gardalini, d. gatti, a. maconi, c. boccafoschi 76 iontophoresis (verapamil) (8). the aim of the present study was to assess the quality of life of patients undergoing treatment with iontophoresis and treatment outcomes at a twoyear interval. pain, quality of sexual life, stress and depression disorders were monitored (9, 10). the following questionnaires and scales were used: numerical rating scale (nrs) (for pain assessment); gad -7, general anxiety disorder-7 scale (for the assessment of anxiety); beck depression inventory (bdi) (for the assessment of depression) and qol quality of life index questionnaire (for assessment of quality of life). all instruments are described in the following (materials and methods) paragraph. materials and methods the study evaluated 128 patients treated as outpatients at the città di alessandria clinic and at an outpatient private clinic. the patients underwent cycles of treatment over a two-year period according to the scheme illustrated below. each cycle included 12 sessions (two sessions per week for about three months). at the end of each cycle the patient suspended treatment for a period of one month. assessment scales and a questionnaire were administered before and at the end of each therapy cycle. iontophoresis is a medical treatment, whereby a drug is released into the body through intact skin (transcutaneous administration) using a low-intensity electric current produced by a special generator. essentially, it could be considered a 'needle-free' injection. the advantages of administering drugs in this way are mainly that: – without systemic administration (oral, intramuscular, intravenous) possible side effects of the drug can be minimized – applying the drug directly to the disease affected body site, treatment and symptom regression time can be reduced – enabling the introduction of the active ingredient alone, without the presence of conveyors (excipients), can protect against adverse reactions – allowing the ions to bind to certain protoplasmic proteins, increasing residence time (half-life) in the anatomical sites concerned, can reduce the quantity of drug implemented for the same disease compared to other administration approaches. – permitting to hyperpolarize nerve endings. having overcome all the drawbacks of taking a drug orally or by infiltration, it is now an advantage to apply the substance directly to the area to be treated, thus reducing the treatment time, with consequent faster symptom regression. the second advantage is the possibility of introducing only the active ingredient of the drug, in an ionic form, without the excipients, which are often the source of variable adverse reactions. the third advantage is that the drug, in an ionic form, binds to specific protoplasmic proteins, increasing the time it spends in the anatomical sites concerned (half-life), which leads to a reduction in the quantities of drug needed for the same condition compared to other administration approaches. the drug used may have either a positive or negative polarity, and in accordance with this, it is placed respectively on the cathode or anode, i.e., on the electrode of the same polarity, while the other electrode will be soaked in water. by applying the electric field, the electricity will carry the drug across the epidermal barrier. verapamil is one of the most commonly used drugs. injected into the plaque, it acts on fibroblasts by inhibiting the formation of extracellular collagen and free radicals. levine administered to 38 men 4 mg of verapamil every 2 weeks for 24 weeks. all patients were assessed before and after treatment with an echography, rating scales and questionnaires. the results evidenced a remission of pain in 97%, an improvement in sexual function in 72% and a reduction in the curvature in 54% of patients (1, 4, 5). local assessment the parameters used to assess the effectiveness of the treatment were: plaque consistency, penile deviation, and pain during erection and/or coitus. the development of the condition, both in a regressive as in a progressive sense, was evaluated both clinically and by echography and in some cases also by self-photography. in terms of the results, an overall assessment was given, distinguishing between: • unchanged or worsened; if the parameters described above had not undergone any change or had worsened. • improved; when there had been a resolution of the pain or an improvement in one of the previously described parameters; • cured; when, in addition to the absence of pain and plaques, there was also complete resolution of the penile deviation. instruments used for evaluation at the beginning and at the end of each cycle of iontophoretic therapy, the scales and questionnaires listed below were submitted to the patients with the aim of monitoring the level of presumed anxiety, depression and pain and the consequent quality of life. numerical rating scale nrs (downie, 1978; grossi, 1983) this is a one-dimensional quantitative 11-point numerical pain rating scale; the scale requires the practitioner to ask the patient to select the number that best describes the intensity of his or her pain, from 0 to 10, at that precise moment. the quality of life index ql-index (spitzer et al., 1981) the euroqol is a generic health questionnaire that includes 5 dimensions: mobility, self-care, usual activities, pain, anxiety/depression. for each dimension the questionnaire investigates whether the subject has severe problems, moderate problems, or no problems at all. the questionnaire also includes a visual analogical scale from 0 to 100 to indicate the perceived level of health status of the respondent. the eq-5d is a widely used instrument in many countries. it is also recommended for use in studies evaluating the cost-effectiveness of interventions. generalized anxiety disorder scale (gad-7) the gad-7 (spitzer et al., 2006) is a self-completed 7-question questionnaire (likert scale 0 to 3) for the assessment of the anxiety condition (cut-off ≥ 8). the beck depression 77archivio italiano di urologia e andrologia 2022; 94, 1 la peyronie's disease inventory (bdi) is a self-assessment tool consisting of 21 multiple-choice items. according to beck, depressed patients are characterized by a negative triad, i.e. negative representations of themselves, the present and the future. statistical analysis since this is an exploratory observational study, the scales used to measure the quality of life of patients have been analyzed with descriptive methods. as a bivariate correlation coefficient the pearson correlation coefficient r was calculated. descriptive statistics were used for all variables using spss version 25. results this is a prospective observational study. a total of 128 patients aged between 42 and 74 years were assessed. twenty-four of these patients had never undergone any treatment before, while the remaining (104) had undergone one or more treatments both systemically and locally. the total dosage in milligrams of the drug used is 4 mg per session. in no case was it necessary to suspend the treatment due to complications. considering the various parameters, pain in erection and/or coitus disappeared in 108 (87.1%) cases while it regressed in 12 and remained present in 4 patients. there were no cases of worsening (table 1). pain variations along the two years of treatment are presented in figure 1. regarding penile deviation, which was present in 128 cases, it disappeared in 6 cases, regressed in 90 cases, while it remained unchanged in 32 cases and worsened in 0 cases. finally, as far as the consistency of the plaque is concerned, in 42 patients the plaque disappeared, in 50 cases the consistency of the plaque regressed, while in 36 patients it remained unchanged. there were no cases of worsening (figure 2). regarding the levels of anxiety and depression we can state that about 57% of patients evaluated had high levels of anxiety (average 2 on the individual items of the scale) in the first cycle of iontophoretic sessions and low levels of depression (average 15). anxiety decreased in 32% of cases even though the treatment did not bring immediate benefits (table 2). in the following months depression scores averaged 18 by the end of the first year and averaged 14 (no depression) in the second year of treatment. depression was not related to pain but to sexual dysfunction (table 3). the eq-5 questionnaire in the examined population (128 patients) did not reveal any problems in the areas of: ability to move, personal care, habitual activities. table 1. clinical results. clinical parameters patients disappeared regressed unchanged worsened n f % f % f % f % pain during erection and/or coitus 124 108 87.1 12 9.7 4 3.2 0 0.0 penile deviation 128 6 4.7 90 70.3 32 25.0 0 0.0 plaque consistency 128 42 32.8 50 39.1 36 28.1 0 0.0 table 2. results of the scale gad 7 (anxiety). gad 7 0/3 i cycle ii cycle iii cycle iv cycle anxiety 3 months 3 months 3 months 3 months total score mean value std dev mean value std dev mean value std dev mean value std dev first year 10.53 4.17 8.21 3.11 8.42 3.04 8.55 3.07 second year 8.38 3.11 8.52 3.18 8.37 3.25 8.11 3.02 table 3. results bdi (depression). bdi: 0/3 i cycle ii cycle iii cycle iv cycle depression 3 months 3 months 3 months 3 months total score mean value std dev mean value std dev mean value std dev mean value std dev first year 15.34 5.42 15.47 4.92 17.63 5.71 18.44 6.17 second year 14.92 6.55 14.47 5.40 14.23 5.30 13.98 5.15 figure 1. graphical representation of pain variation along the two years of treatment. archivio italiano di urologia e andrologia 2022; 94, 1 t. bolgeo, r. di matteo, m. gardalini, d. gatti, a. maconi, c. boccafoschi 78 critical issues emerged in the areas of pain and discomfort, anxiety, or depression. in these domains the levels were almost always at a maximum for the first year of assessment and this resulted in low levels of quality of life. the most frequently reported value (according to a score between 0 and 100) was between 30 and 50 in the first year of treatment and between 60 and 80 in the second year of treatment. at the end of the two years of treatment, quality of life improved and levels of anxiety and depression decreased in 68% of cases (table 4). discussion based on the above results, it can be observed that the most relevant data is that on the symptom of erection and/or coital pain. in fact, this pain disappeared or regressed in a high percentage of cases (120 patients, i.e., 97%). as far as penile deviation is concerned, the results were extremely encouraging, since in 90 cases (94%) there was regression and in 42 patients (70%) this also led to the disappearance of the plaque (p < 0.001). regarding the plaque, the results seem positive, particularly in cases where therapy was started at an early stage, where the plaque was single with a fibrous consistency and its diameter was less than 2 cm. however, the reported results are difficult to compare with the case histories and experience of others because they are not perfectly homogeneous, and under certain aspects, due to difficulty in objectively quantifying the plaques. in our opinion, in fact, the diagnostic tool, rather than being useful for the morphological evaluation and/or for the extension of the plaque, it may help to monitor over time disease progression or to evaluate the therapeutic efficacy. as to the questionnaire and scales submission, from the analysis of the relative data it is evident that pain diminished from the third session of the first iontophoresis cycle. mean values are reported in the table 5. table 5. mean values of numerical rate scale (pain) along the follow up of patients. nrs i cycle ii cycle iii cycle iv cycle (0/10) pain 3 months 3 months 3 months 3 months mean value std dev mean value std dev mean value std dev mean value std dev first year 7.73 2.08 6.38 2.42 4.27 1.95 3.43 2.03 second year 3.28 1.94 3.04 1.85 2.40 1.68 1.13 1.07 table 4. results of the scale eq (quality of life). patients n = 128 eq 1/3 i cycle ii cycle iii cycle iv cycle generic health 3 months 3 months 3 months 3 months first year mean value std dev mean value std dev mean value std dev mean value std dev mobility 1.43 0.61 1.31 0.59 1.27 0.52 1.31 0.59 salf-care 1.22 0.42 1.18 0.39 1.14 0.35 1.18 0.39 usual activities 1.25 0.45 1.23 0.44 1.20 0.42 1.23 0.44 pain 2.75 0.43 2.72 0.53 2.70 0.55 2.71 0.53 anxiety/depression 2.88 0.32 2.90 0.30 2.87 0.36 2.88 0.32 eq: vas scale 0/100 perceived level of health status 36.41 16.11 38.24 15.39 40.91 16.92 41 18.32 second year mobility 1.22 0.50 1.20 0.47 1.16 0.39 1.05 0.21 salf-care 1.13 0.34 1.07 0.26 1.06 0.24 1.02 0.12 usual activities 1.16 0.36 1.13 0.33 1.12 0.32 1.06 0.24 pain 2.53 0.59 2.41 0.69 2.41 0.69 2.23 0.81 anxiety/depression 2.52 0.57 2.49 0.58 2.42 0.60 2.20 0.60 eq: vas scale 0/100 perceived level of health status 60.86 18.37 65.47 20.49 66.25 21.05 71.27 19.43 figure 2. clinical results (graphics). 79archivio italiano di urologia e andrologia 2022; 94, 1 la peyronie's disease as illustrated in the table and in the graph, pain had a linear regression trend throughout the two-year period in patients who underwent regular cycles. the levels of anxiety and depression were variable, since patients associated many times the result of the therapy with the effectiveness of sexual performance, which unfortunately did not always improve with the disappearance of the plaques and there is a lack of patient awareness of other factors, which might influence their quality of life. there are no recent studies, that have examined the levels of anxiety and depression in patients suffering from this condition, so a monitoring over time and the involvement of other centres at a national level would be worthwhile. another value of considerable importance emerged from the submission of the qol 5. the data showed that about 80 % of the patients assessed had an increase in quality of life at the end of the two-year follow-up. the importance of including qol among the parameters for assessing the quality of care is effectively underlined by the american college of physicians, which states: "assessment of the patient's physical, psychological, and social functioning is an essential part of clinical diagnosis, a crucial determinant of treatment choices, a measure of their effectiveness, and a guide for long-term care planning". in measuring health-related quality of life, there is broad consensus regarding its subjective, multidimensional nature and the aspects that are most likely to be affected by disease and should therefore always be considered. these aspects can be summarized in three main dimensions: physical, psychological, and social. the data analysis revealed that as pain decreased, the value of quality of life increased: cycle 1/year 1 r = -0.3 (p < 0.001 ic = 95%), cycle 1/year 2 r = -0.7 (p < 0.001 ic = 95%), cycle 4/year 2 r = -0.8 (p < 0.001 ic = 95%). in summary, we can affirm that therapy with iontophoresis gives good results from the first applications, i.e. in the inflammatory phase. it is therefore important to act in the phase preceding the formation of sclerotic plaques that is prior to the so-called degenerative phase. conclusions depression and anxiety disorders occur in up to 25% of patients with medical conditions. about 85% of patients with depression have significant anxiety, and 90% of patients with an anxiety disorder have depression. the symptoms may initially seem vague and non-specific. a careful anamnesis and screening with appropriate tests should be used to make the diagnosis. once the diagnosis has been made, rating scales can identify the severity of the condition and help monitor the progress of treatment. both a depressive disorder and a specific anxiety disorder require appropriate treatment. for these reasons, in the case of a patient with peyronie's disease, it is essential to monitor the progress of treatment from the very beginning of patient care. in conclusion, it can be asserted that iontophoresis combined with verapamil therapy can improve the patients’ quality of life and offer them psychophysical well-being with an acceptable sexual relationship, thus decreasing the levels of anxiety and depression. the improvement in the patients' quality of life induces them to continue therapy cycles with regularity and determination. further national and international studies are required to strengthen the results obtained. references 1. mulhall jp, alex b, choi jm. predicting delay in presentation in men with peyronie’s disease. j sex med. 2010; 7:2226-30. 2. paulis g, romano g, paulis l, barletta d. recent pathophysiological aspects of peyronie’s disease: role of free radicals, rationale, and therapeutic implications for antioxidant treatment-literature review. adv urol. 2017; 2017:4653512. 3. di maida f, cito g, lambertini l, et al. the natural history of peyronie’s disease. world j mens health. 2021; 39:399-405. 4. la pera g, pescatori es, calabrese m, et al. peyronie’s disease: prevalence and association with cigarette smoking. a multicenter population-based study in men aged 50-69 years. eur urol. 2001; 40:525-30. 5. bivalacqua tj, purohit sk, hellstrom wj. peyronie’s disease: advances in basic science and pathophysiology. curr urol rep. 2000; 1:297-301. 6. dibenedetti db, nguyen d, zografos l, et al. a population-based study of peyronie’s disease: prevalence and treatment patterns in the united states. adv urol. 2011; 2011:282503. 7. montorsi f, salonia a, guazzoni g, et al. transdermal electromotive multi-drug administration for peyronie’s disease: preliminary results. j androl. 2000; 21:85-90. 8. trost lw, gur s, hellstrom wjg. pharmacological management of peyronie’s disease. drugs. 2007; 67:527-45. 9. coyne ks, currie bm, thompson cl, smith tm. the test-retest reliability of the peyronie’s disease questionnaire. j sex med. 2015; 12:543-8. 10. coyne ks, currie bm, thompson cl, smith tm. responsiveness of the peyronie’s disease questionnaire (pdq). j sex med. 2015; 12:1072-9. correspondence tatiana bolgeo tbolgeo@ospedale.al.it roberta di matteo (corresponding author) rdimatteo@ospedale.al.it menada gardalini mgardalini@ospedale.al.it denise gatti dgatti@ospedale.al.it antonio maconi amaconi@ospedale.al.it sc infrastructure research training innovation, department of integrated activities research innovation, azienda ospedaliera ss antonio e biagio e cesare arrigo, alessandria, italy carmelo boccafoschi cboccafoschi@virgilio.it city of alessandria clinic monza polyclinic, alessandria, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 120 review midshaft penis are the most commonly affected sites by pf (1, 4). clinically, the onset of pf is usually accompanied by a loud cracking sound, followed by penile localized swelling, bruises, pain, and immediate detumescence. many reviews report that the diagnosis of penis fractures can depend exclusively on clinical findings, based on patient history and physical examination (2, 5). multiple studies have reported that a wide diversity of investigations are useful in the diagnosis of pf as x-ray imaging, doppler ultrasound, retrograde urethrocystography (rgu), flexible cystoscopy, and magnetic resonance imaging (mri) (6-8). however, it is unnecessary to use radiological investigations in most cases where the history and the clinical examination are sufficient to confirm the diagnosis. the x-ray imaging may still be required in some cases, especially in patients with atypical clinical presentation (9). some authors consider the doppler ultrasound as the preferred radiological tool for investigating penile trauma cases given that it is a non-invasive and inexpensive procedure. on the other hand, mri is the most accurate test in diagnosing the pf as it shows high contrast resolution between tissues and identifies the pathological processes of soft tissues. studies also reported that it can be used in the evaluation of the urethral injury, although it is not commonly used because of its low cost-effectiveness and long execution time (10, 11). rug is the gold standard for urethra evaluation. the rug is easy to perform on trauma patients at the bedside: 20 to 30 ml of diluted watersoluble contrast is injected into the urethral meatus, before x-raying. a positive rug will show contrast outside the urethral serpentine cylinder. retrograde urethrograms are sensitive in detecting urethral injuries but can't pinpoint their location and are operator-dependent (12). previous reports demonstrated that urethral injuries are present in 1-38% of the pf cases. patients with an associated urethral injury can present with blood at the meatus, leading to hematuria and urinary retention (5, 13, 14). however, these findings are not specific as previous case reports indicated that some pf cases with associated urethral injuries had no suspected symptoms. thus, investigations, particularly urine analysis and retrograde urethrogram (rgu), are of paramount importance for identifications of associated urethral injuries (15). accurate identification of urethral injuries is critical before pf repair to avoid the risk of postoperative complications, including urethral stricture and urethrocutaneous fistula (16). however, due to the rarity of the disease, little literature has been published so purposes: penile fracture (pf) with associated urethral injury has been described as a rare condition yet a serious urological emergency. we conducted this systematic review to address the current literature concerning the etiology, presentations, intra-operative findings, site of injury, and complications of pf with associated urethral injury, materials and methods: the present systematic review was limited to human-based studies published in english language, and reporting clinical data on pf cases with associated urethral injuries. a comprehensive search of the literature was conducted on five electronic databases from their inception to may 2022: medline via pubmed, web of science, google scholar, scopus, and ebsco host. results: a total of 15 studies were included encompassing 1671 patients with pf. out of 1665 patients with pf retrieved from the case series studies, 65 patients had associated urethral injuries giving a point prevalence of 3.9%. the vast majority of the patients had blood on the meatus and hematuria suggestive of urethral injury (57/59; 96.6%). forty patients had partial urethral disruption and the rest of the patients had a complete rupture. all patients received primary urethroplasty as the main modality of treatment. the median hospital stay was two days and the median duration of transurethral catheterization was 21 days. five patients (8.5%) developed urethral stricture; other complications included penile curvature (6.7%), palpable fibrosis (6.7%), and erectile dysfunction (3.4%). conclusions: urethral injuries are uncommon, but serious findings, in patients with pf. primary urethroplasty appears to achieve satisfactory outcomes with a low incidence of short and long-term complications. key words: penile fracture; urethra; urethral injury; systematic review. submitted 12 december 2022; accepted 7 april 2023 introduction penile fracture (pf) with associated urethral injury has been described as a rare condition yet a serious urological emergency (1). pf is characterized by signification injury of corpus cavernosum anatomy due to profound trauma or manipulation of an erect penis; while traumas to the flaccid penis or the suspensor ligament are not usually considered as pf (2, 3). commonly, pf is caused by severe bending of the erect penis during sexual intercourse, masturbation, rolling over during sleep, and powerful methods of sexual arousal. to a lesser extent, pf can result from direct trauma or fall onto the erect penis. the basal and the presentation and outcomes of penile fracture with associated urethral injury: a systematic literature review salah e. shebl urology department, faculty of medicine for girls, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11082 summary archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 121 far concerning the presentation and outcomes of pf with associated pf. therefore, we conducted this systematic review to address the current literature concerning the etiology, presentations, intra-operative findings, site of injury, and complications of pf with associated urethral injury. materials and methods the present systematic review receives prospero id 342298 and adhered to the recommendations of the recent version of the cochrane collaboration handbook and the moose statement (17, 18). eligibility criteria and literature search the present systematic review was limited to human-based studies, published in the english language, and reporting clinical data on pf cases with associated urethral injuries. there were no limitations regarding the date of publication or study design. studies were excluded if they were review articles, duplicate datasets, or they had no separate data on patients with associated urethral injuries. besides, we excluded conference abstracts with no available full texts. a comprehensive literature search was conducted on five electronic databases from their inception to may 2022. these bibliographic databases were: medline via pubmed, web of science, google scholar, scopus, and ebsco host. various combinations of the following queries were utilized: penile, penis, fracture, injury, urethra. following the literature search, retrieved citations were imported to endnote x7 for duplicates removal. unique records were then screened through two stages: the first stage was a screening by titles and abstracts, while the second stage was an full-text evaluation of potentially eligible abstracts for final inclusion in the present systematic review. quality assessment the quality assessment of the included case reports and case series was conducted using murad's tool (19), which is specifically designed to evaluate the methodological quality of case reports and case series. this tool consists of eight criteria that cover four primary domains: selection, ascertainment, causality, and reporting. two independent reviewers conducted the quality assessment of the included studies, in case of any discrepancies figure 1. prisma flow diagram. archivio italiano di urologia e andrologia 2023; 95, 2 122 the presentation and outcomes of penile fracture with associated urethral injury between the reviewers, a consensus was reached through discussion or, if necessary, by involving a third reviewer. data extraction standardized data extraction was done using excel software for data retrieval and processing. the following data were extracted from each eligible study: year of publication, country, study design, number of patients with pf, number of cases with confirmed urethral injuries, cause of pf, presentation of urethral injury, location of the injury, intraoperative findings, need for supra-pubic cystostomy tube, treatment, complications, hospital stay, and duration of follow-up. results a total of 7242 records were retrieved from online search and 12 records were identified by manual searching. of them, 4201 records were screened after duplicates removal. after the initial screening, 55 full texts were retained for a full evaluation. out of them, 40 studies were excluded as they were narrative or systematic review (n = 8), animal models (n = 3), irrelevant (n = 16), simulation-based studies (n = 6), or they had no data on urethral injuries (n = 7). finally, 15 studies were included in the present systematic review (see prisma flow diagram; figure 1). general characteristics of the included studies and prevalence of urethral injuries six retrospective studies (20-25), two prospective study (26, 27), and seven case reports were included in the present systematic review (21, 28-34). two from india, two from egypt, two from the united states, and one from serbia, italy, slovenia, canada, china, peru, tunisia, brazil and uk each. the median time from injury to presentation was six hours (range 1-48.5 hours) and the median time of follow-up was 21 months (1-107 months). a total of 1671 patients with pf were retrieved from the included studies. out of them, 65 patients had associated urethral injuries giving a point prevalence of 3.9% (table 1). quality assessment of included studies the quality assessment of the included studies was conducted using murad's tool. in terms of selection, eight studies did not report that this was their whole experience on penile fracture or provide a clear selection process. regarding ascertainment, the majority of the studies (14 out of 15) adequately ascertained exposure and outcomes, while one study failed to do so. alternative causes that could explain the observation were clearly ruled out in 12 of the included studies. most studies (10 out of 15) adequately followed their patients, while five studies lacked sufficient follow-up period. reporting: the majority of the studies (11 out of 15) provided sufficient details to allow other investigators to replicate the research or practitioners to make inferences related to their own practice. however, four studies did not provide enough details in their reports. overall, the quality assessment revealed that most studies had adequately ascertained exposure and outcome, and provided sufficient reporting details. however, some studies did not meet all the causality criteria (supplementary table 1). presentation of the included cases among the 65 patients with associated urethral injuries, the most common cause of fracture was sexual intercourse (41/65; 69%), followed by masturbation (8/65; 13.5%) and rolling over (6/65; 10.1%). with regard to the classic presentation of pf, the most common presentations were hematoma (34/65; 57%) and penile swelling (33/65; 55.9%), followed by aubergine sign/egg-plant deformity (30/65; 50.8%) and crackling sound (29/65; 49.1%). the vast majority of the patients had blood on the meatus and hematuria suggestive of urethral injury (57/65; 87.6%). the most commonly affected location of the included patients was proximal shaft (21/65; 35.5%) followed by midshaft (19/65; 32.2%). the vast majority of the patients had unilateral corporal involvement (54.2%), mainly on the right side (30.5%). forty patients had partial urethral disruption and the rest of the patients table 1. general characteristics of the included studies. authors, year country study design median time from the time mean hospital total cases confirmed of injury to the time of follow-up stay of penile urethral presentation to the hospital (months) (days) fracture injury amit et al, 2013 (20) india retrospective case series na 34.3 2 34 8 kasaraneni et al, 2019 (27) india prospective observational 6 24 2 75 12 derouiche et al, 2007 (22) tunisia retrospective case series 10 18 14 312 10 raheem et al, 2014 (6) egypt retrospective case series 5.5 72.6 2.1 246 12 ibrahiem et al, 2010 (23) egypt retrospective case series 48.5 107 2.3 155 14 barros et al, 2018 (26) brazil prospective observational na na na 175 27 mercado-olivares et al, 2018 (34) peru case report 19 na na 281 1 ouanes et al, 2021 (24) tunisia retrospective case series 1 to 5 12 na 138 15 hughes et al, 2021 (33) uk case report na na na 1 1 boncher et al, 2010 (39) usa case report 8 48 na 1 1 tang et al, 2018 (25) usa retrospective case series 1.2 ± 1.03 21 (1-73) na 62 13 ge et al, 2021 (31) china case report na 12 na 1 1 garofalo et al, 2015 (30) italy case report 1 12 2 1 1 jagodic̆ et al, 2007 (29) slovenia case report 6 12 13 1 1 hoag et al, 2011 (28) canada case report 1 1 2 1 1 archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 123 had a complete rupture. two studies reported the utilization of rgu for the evaluation of pf and associated urethral injuries (tables 2 and 3). treatment and outcomes of the included cases all patients received primary urethroplasty as the main modality of treatment. besides, 15 patients needed a supra-pubic cystostomy tube. fifty-one patients received medications to prevent erection in the form of estradiol, diazepam, sildenafil, and amyl nitrite. the median hospital stay was two days and the median duration of transurethral catheterization was 21 days. five patients (8.5%) developed urethral stricture; other complications included penile curvature (6.7%), palpable fibrosis (6.7%), and erectile dysfunction (3.4%) (table 4). discussion urethral injuries can concurrently occur in patients with pf and a considerable proportion of these injuries are missed at initial diagnosis, despite being widely considered as a serious complication. if not discovered and managed early, associated urethral injuries can dramatically lead to short and long-term complications in patients with pf (2). however, due to the rarity of the disease, little literature has been published so far concerning the presentation and outcomes of pf with associated urethral injury. table 3. the distribution of intraoperative findings and location of injury among the included patients. authors, year intra operative findings location of injury partial complete proximal midshaft distal bilateral unilateral right left urethral urethral shaft shaft corporal corporal corporal corporal disruption disruption of penis of penis involvement involvement involvement involvement amit et al, 2013 (20) 7 1 6 na na 1 7 5 2 kasaraneni et al, 2019 (27) 11 1 6 2 4 1 11 4 6 derouiche et al, 2007 (22) 10 0 5 4 1 0 10 6 4 raheem et al, 2014 (6) 1 11 0 12 0 12 0 0 0 ibrahiem et al, 2010 (23) 11 3 na na na na na na na barros et al, 2018 (26) na na na na na na na na na mercado-olivares et al, 2018 (34) na na 0 0 1 0 1 1 0 ouanes et al, 2021 (24) na na 118 0 20 0 138 na na hughes et al, 2021 (33) na na 0 0 1 0 1 0 1 boncher et al, 2010 (39) na na 0 0 1 0 1 1 0 tang et al, 2018 (25) na na 23 18 21 na na na na ge et al, 2021 (31) 0 1 1 0 0 na na na na garofalo et al, 2015 (30) 0 1 1 0 0 0 1 1 0 jagodic̆ et al, 2007 (29) 0 1 1 0 0 na na na na hoag et al, 2011 (28) 0 1 1 0 0 1 0 0 0 table 2. the distribution of causes and presentations among the included patients. authors, year causes of penile fractures presentation of penile fracture sexual rolling blunt forced masturbation urethral hematoma crackling penile bladder aubergine retention intercourse over injury penile bleed or sound swelling palpable sign/egg-plant of urine pending eccymosis deformity amit et al, 2013 (20) 6 0 0 0 2 6 0 6 0 na 6 na kasaraneni et al, 2019 (27) 9 2 1 0 0 11 0 7 0 3 12 3 derouiche et al, 2007 (22) 0 4 0 0 6 10 0 10 0 2 10 2 raheem et al, 2014 (6) 11 0 0 1 0 12 12 0 12 0 0 3 ibrahiem et al, 2010 (23) 7 na na 0 na 13 14 na 14 0 0 na barros et al, 2018 (26) 69 0 0 5 16 na na na na na na na mercado-olivares et al, 2018 (34) 1 0 0 0 0 0 1 0 0 0 0 0 ouanes et al, 2021 (24) 47 na na 62 na na na na na na na na hughes et al, 2021 (33) 1 0 0 0 0 1 1 1 0 0 0 0 boncher et al, 2010 (39) 1 0 0 0 0 0 1 1 1 0 1 0 tang et al, 2018 (25) 41 0 0 19 2 12 44 34 62 0 0 0 ge et al, 2021 (31) 1 0 0 0 0 1 1 1 1 0 0 0 garofalo et al, 2015 (30) 1 0 1 0 0 1 1 1 1 0 0 0 jagodic̆ et al, 2007 (29) 1 0 0 0 0 1 1 1 1 1 0 1 hoag et al, 2011 (28) 1 0 1 0 0 1 1 0 1 0 0 0 archivio italiano di urologia e andrologia 2023; 95, 2 124 the presentation and outcomes of penile fracture with associated urethral injury therefore, we conducted this systematic review to address the current literature concerning the pf with associated urethral injury. our results highlighted that there are currently 65 published cases of pf with associated urethral injuries giving a point prevalence of 3.9%. such findings are in line with a large case-series of 312 pf cases from the middle east, in which ten cases had associated urethral injuries (22). other reports from the middle east reported similar findings (35). on the contrary, reports from europe and the united states demonstrated a much higher prevalence of associated urethral injuries, affecting up to onethird of pf cases (36-38). it is not clear why patients from the middle east had a lower prevalence of associated urethral injuries; however, it was reported that a large number of pf in the middle east is attributed to the widespread practice of “taghaandan”, which is a low-energy trauma with a low possibility of urethral injuries (35, 32). we also postulated that the low prevalence of associated urethral injuries can be attributed to a large number of pooled cases with pf from the middle east and the dependence on clinical examination, without further investigations, which might have led to under-detection of associated urethral injuries. as previously mentioned, the proximal and midshaft penis are the most commonly affected sites by pf; while sexual intercourse and masturbation account for the vast majority of pf (1, 4). these findings appear to apply also to patients with associated urethral injuries; in this review, we found that the most common cause of fracture was sexual intercourse, followed by masturbation and rolling over; while the majority of the cases had proximal and midshaft fractures. clinically, the presence of urethral injuries is suspected when there is blood at the meatus, with or without hematuria, on examination; besides, urine analysis and rgu can be useful for identifications of associated urethral injuries (15). however, as demonstrated by this systematic review, some pf cases may not exhibit specific symptoms for urethral injuries (see table 3). besides, urine analysis and rgu exhibited false-negative results in some case-series (15, 39). thus, a careful intraoperative inspection of the urethra is recommended in all cases with pf to avoid missed injuries. to our knowledge, there is no published systematic review that has attempted to explore the presentation and outcomes of pf cases with associated urethral injuries; nonetheless, we acknowledge the existence of several limitations in our review. all included studies suffered from substantial methodological flaws that can affect the quality and generalizability of our findings. the outcome measurements are subjective and postoperative erectile and voiding functions have not been assessed using validated tools. in conclusion, urethral injuries are uncommon, but serious findings, in patients with pf. the clinical presentation of patients with urethral injuries usually involves urethral bleeding and hematuria. the diagnosis of associated urethral injuries can be established by clinical examination with the limited role of imaging studies. thus, a careful intraoperative inspection of the urethra is recommended in all cases with pf in order to avoid missed injuries. primary urethroplasty appears to achieve satisfactory outcomes with a low incidence of short and longterm complications. nonetheless, the current published literature is still limited by the low number of published cases and low quality of published reports; thus, further studies are needed to characterize the presentation and outcomes of pf with association urethral injuries. acknowledgment the authors thank the study participants, trial staff, and investigators for their participation. references 1. mahapatra rs, kundu ak, pal dk. penile fracture: our experience in a tertiary care hospital. world j mens health. 2015; 33:95. table 4. the treatment and outcomes of injury among the included patients. authors, year treatment supra-pubic medication median duration hospital complications cystostomy to prevent of transurethral stay penile palpable erectile stricture uti tube erection catheterization (days) (days) curvature fibrosis dysfunction urethra amit et al, 2013 (20) primary urethroplasty not used estradiol 21 2 0 0 1 0 0 kasaraneni et al, 2019 (27) primary urethroplasty not used estradiol 21 2 1 0 0 1 2 derouiche et al, 2007 (22) primary urethroplasty used diazepam 13 14 0 0 0 0 0 raheem et al, 2014 (6) primary urethroplasty used in 5 patients sildenafil® 22.5 2.1 2 3 1 1 0 ibrahiem et al, 2010 (23) primary urethroplasty not used pge1 na 2.3 na 1 na 1 0 barros et al, 2018 (26) na na na na na na na na na na mercado-olivares et al, 2018 (34) primary urethroplasty na na na na 0 0 0 0 0 ouanes et al, 2021 (24) primary urethroplasty na na na na na na na na na hughes et al, 2021 (33) primary urethroplasty na na na na na na na na na boncher et al, 2010 (39) primary urethroplasty na diazepam 28 na 0 0 0 0 0 tang et al, 2018 (25) primary urethroplasty used amyl nitate na na 0 0 0 0 0 ge et al, 2021 (31) primary urethroplasty na na 12 na na na na na na garofalo et al, 2015 (30) primary urethroplasty used na na 2 1 0 0 1 0 jagodic̆ et al, 2007 (29) primary urethroplasty used diazepam 12 13 0 0 0 1 0 hoag et al, 2011 (28) primary urethroplasty used na 28 2 na na na na na archivio italiano di urologia e andrologia 2023; 95, 2 s.e. shebl 125 2. eke n. fracture of the penis. br j surg. 2002; 89:555-65. 3. el-sherif ae, dauleh m, allowneh n, vijayan p. management of fracture of the penis in qatar. br j urol. 1991; 68:622-5. 4. ateyah a, mostafa t, nasser ta, et al. penile fracture: surgical repair and late effects on erectile function. j sex med. 2008; 5:1496502. 5. zargooshi j. sexual function and tunica albuginea wound healing following penile fracture: an 18-year follow-up study of 352 patients from kermanshah, iran. j sex med. 2009; 6:1141-50. 6. raheem aa, el-tatawy h, eissa a, et al. urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption. arch ital urol androl. 2014; 86:15-9. 7. kamdar c, mooppan umm, kim h, gulmi fa. penile fracture: preoperative evaluation and surgical technique for optimal patient outcome. bju int. 2008; 102:1640-4. 8. saglam e, tarhan f, hamarat mb, et al. efficacy of magnetic resonance imaging for diagnosis of penile fracture: a controlled study. investig clin urol. 2017; 58:255-60. 9. pavan n, tezzot g, liguori g, et al. penile fracture: retrospective analysis of our case history with long-term assessment of the erectile and sexological outcome. arch ital urol androl. 2014; 86:359-70. 10. choi mh, kim b, ryu ja, et al. mr imaging of acute penile fracture. radiographics. 2000; 20:1397-405. 11. murray ks, gilbert m, ricci lr, et al. penile fracture and magnetic resonance imaging. int braz j urol. 2012; 38:287-8. 12. rosenstein di, alsikafi nf. diagnosis and classification of urethral injuries. urol clin north am. 2006; 33:73-85. 13. koifman l, cavalcanti ag, manes ch, et al. penile fracture experience in 56 cases. int braz j urol. 2003; 29:35-9. 14. mydlo jh. surgeon experience with penile fracture. j urol. 2001; 166:526-9. 15. gedik a, kayan d, yamis s, et al. the diagnosis and treatment of penile fracture: our 19-year experience. ulus travma acil cerrahi derg. 2011; 17:57-60. 16. shaeer o. methylene blue-guided repair of fractured penis. j sex med. 2006; 3:349-54. 17. higgins jpt, thomas j, chandler j, et al. cochrane handbook for systematic reviews of interventions. cochrane handbook for systematic reviews of interventions. 2019, pp 1-694. 18. stroup df, berlin ja, morton sc, et al. meta-analysis of observational studies in epidemiologya proposal for reporting. jama. 2000; 283:2008-12. 19. murad mh, sultan s, haffar s, bazerbachi f. methodological quality and synthesis of case series and case reports. bmj evid bas med. 2018; 23:60-3. 20. amit a, arun k, bharat b, et al. penile fracture and associated urethral injury: experience at a tertiary care hospital. j can urol assoc. 2013; 7:e168-70. 21. raheem aa, el-tatawy h, eissa a, et al. urinary and sexual functions after surgical treatment of penile fracture concomitant with complete urethral disruption. arch ital urol androl 2014; 86:15-9. 22. derouiche a, belhaj k, hentati h, et al. management of penile fractures complicated by urethral rupture. int j impot res. 2008; 20:111-4. 23. ibrahiem ehi, el-tholoth hs, mohsen t, et al. penile fracture: long-term outcome of immediate surgical intervention. urology. 2010; 75:108-11. 24. ouanes y, saadi mh, haj alouene h, et al. sexual function outcomes after surgical treatment of penile fracture. sex med. 2021; 9:100353. 25. tang z, yang l, wei q, et al. management and outcomes of penile fracture: a retrospective analysis of 62 cases with long-term assessment. asian j androl. 2018; 20:412. 26. barros r, silva mis, antonucci v, et al. primary urethral reconstruction results in penile fracture. ann r coll surg engl. 2018; 100:21-5. 27. kasaraneni p, mylarappa p, gowda rd, et al. penile fracture with urethral injury: our experience in a tertiary care hospital. arch ital urol androl 2019; 90:283-7. 28. hoag na, hennesse k, so a. penile fracture with bilateral corporeal rupture and complete urethral disruption: case report and literature review. can urol assoc j. 2011; 5:e23. 29. jagodic k, erklavec m, bizjak i, et al. a case of penile fracture with complete urethral disruption during sexual intercourse: a case report. j med case rep. 2007; 1:14. 30. garofalo m, bianchi l, gentile g, et al. sex-related penile fracture with complete urethral rupture: a case report and review of the literature. arch ital urol androl 2015; 87:260-1. 31. ge g, wang h, chen y, et al. complete urethral injury in the penile fracture: a case report and literature review. transl androl urol. 2021; 10:969. 32. boncher na, vricella gj, jankowski jt, et al. penile fracture with associated urethral rupture. case rep med. 2010; 2010:791948. 33. hughes s, elbaroni w, o’donoghue j, williams m. atypical presentation of a vertical penile fracture. bmj case reports cp. 2021; 14:e243353. 34. mercado-olivares f, antonio grandez-urbina j, farfan-daza g, et al. case report: double penile fracture. f1000research. 2018; 7. f1000res. 2018; 7:1828. 35. zargooshi j. penile fracture in kermanshah, iran: report of 172 cases. j urol. 2000; 164:364-6. 36. fergany af, angermeier kw, montague dk. review of cleveland clinic experience with penile fracture. urology. 1999; 54:352-5. 37. bitker mo, belin j, jardin a, chatelain c. “faux pas du coit” with associated rupture of corpora cavernosa and urethra. urology. 1988; 32:447-8. 38. agarwal mm, singh sk, sharma dk, et al. fracture of the penis: a radiological or clinical diagnosis? a case series and literature review. can j urol. 2009; 16:4568-75. 39. mydlo jh, hayyeri m, macchia rj. urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical findings. urology. 1998; 51:616-9. correspondence salah e. shebl, md (corresponding author) salahshebl@yahoo.com salahshebl@azhar.edu.eg urology department, faculty of medicine for girls al-azhar university urology department, alzahraa university hospital, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11593 1 original paper numerous animal studies including models of castrated rodents were useful to mimic the hypogonadism medical condition and evaluate the effects of androgen depletion on the cognitive functions (6). multiple tasks were used to assess the spatial learning and working memory abilities of castrated rodents varying from navigating toward hidden platform in a pool of water in the morris water maze test (7), to look for displaced objects in the novel object recognition and location tests (8). although, the mechanism by which testosterone influences the working of spatial memory is poorly understood, many of the animal studies showed a positive correlation between high/optimum testosterone level and better cognitive abilities in males including improved spatial memory (9, 10). moreover, on a physiological level it has been reported that testosterone deficiency caused metabolic disorders including changes in body composition, fat distribution (11) and promoted oxidative stress and inflammation (12). the main treatment for hypogonadism in men is testosterone replacement therapy (trt). therapeutic options for trt varied from oral and injectable testosterone administration to patches and testosterone gels. innovations and advances in trt during the years have enhanced the role and safety of the use of testosterone as a metabolic hormone and had beneficial effects on obesity, cardiovascular and hepatic diseases (13). many research data nonetheless consolidated the long-term side effects of the trt. in fact, long-term use of trt has been associated with elevated oncologic risks mainly in the prostate (14) as well as the likelihood of developing obstructive sleep apnea and erythrocytosis (15). therefore, potential alternatives, mainly plants and their derived natural substances, are being studied to replace and/or minimize the trt side effects. for instance, onion supplementation was positively correlated to an increase in luteinizing hormone (lh) production and has been proven to reduce testis oxidative stress (16). ginger supplementation effect on intoxicated rats was also hypothesized to reduce oxygen species production and lipid peroxidation in the gonads thus improving testosterone level (17). arthrospira platensis also commercialized under the name of spirulina is a cyanobacterium which captured the scientists and food industry’s attention during the last few decades for its high nutritional as well as potential theraobjective: androgen deficiency is associated with multiple biochemical and behavioral disorders. this study investigated the effects of testosterone replacement and spirulina platensis association on testosterone deficiency-induced metabolic disorders and memory impairment. methods: adult male rats were randomly and equally divided into four groups and received the following treatments for 20 consecutive days. control group: non-castrated rats received distilled water. castrated group received distilled water. testosterone treated group: castrated rats received 0.20 mg of testosterone dissolved in corn oil by subcutaneous injection (i.p.). spirulina co-treated group: castrated rats received 0.20 mg of testosterone (i.p.) dissolved in corn oil followed by 1000 mg/kg of spirulina per os. results: data showed that castration induced an increase in plasma alt, ast, alkaline phosphatase (pal), cholesterol, and triglycerides level. castrated rats showed a great elevation in sod and cat activities and mda and h2o2 levels in the prostate, seminal vesicles, and brain. testosterone deficiency was also associated with alteration of the spatial memory and exploratory behaviour. testosterone replacement either alone or with spirulina combination efficiently improved most of these biochemical parameters and ameliorated cognitive abilities in castrated rats. conclusions: testosterone replacement either alone or in combination with spirulina improved castration-induced metabolic, oxidative, and cognitive alterations. key words: castration; testosterone; spirulina platensis; cognition; oxidative stress. submitted 18 july 2023; accepted 30 july 2023 introduction with aging men can develop several cognitive and metabolic impairments due to the reduction in endogenous testosterone production (1). androgen deficiency is referred to as hypogonadism, it is a health issue that can occur within men aged from 40 to 80 years old and includes fatigue, cognitive and mood disorders as clinical symptoms (2). it is also associated with common medical conditions such as hypertension, diabetes, and obesity (3). in fact, a very common consequence of testosterone deficiency in men is a decline in some forms of memory such as episodic and working memory (4, 5). effects of testosterone replacement on lipid profile, hepatotoxicity, oxidative stress, and cognitive performance in castrated wistar rats oumayma boukari, wahid khemissi, soumaya ghodhbane, aida lahbib, olfa tebourbi, khemais ben rhouma, mohsen sakly, dorsaf hallegue laboratory of integrated physiology, department life sciences, faculty of sciences of bizerte, university of carthage, jarzouna 7021, bizerte, tunisia. doi: 10.4081/aiua.2023.11593 summary archivio italiano di urologia e andrologia 2023; 95(4):11593 o. boukari, w. khemissi, s. ghodhbane, a. lahbib, o. tebourbi, k. ben rhouma, m. sakly, d. hallegue 2 peutic values (18-20). the huge interest in spirulina is essentially due to its high protein level and the protein quality as it contains essential amino acids as well as the availability of vitamins and minerals notably vitamin b12, iron and calcium (21). many human and animal studies on the effects of spirulina intakes have been reported, yet their results varied regarding the duration of administration, the doses and target groups. in fact, evidence from animal studies were in favour of a potential reproprotective effect of spirulina particularly by enhancing antioxidant enzymes activities, hence restoring the production of testosterone in bifenthrin-intoxicated mice (22),and mitigating pro-inflammatory cytokines in furan exposed rats (23). additionally, a previous study showed that spirulina supplementation could prevent the memory impairment in senescence-accelerated mice through counteracting oxidative stress damages (24) which calls attention to the possible beneficial effect of spirulina in mitigating memory and metabolic impairment induced by testosterone deficiency in castrated group. the present study was assigned to analyse the effects of testosterone replacement with or without spirulina combination on castration-induced metabolic, oxidative stress and cognitive alterations in adult male wistar rats. materials and methods animals male wistar rats weighing 155-250 gr at the beginning of the experiment, purchased from pasteur institute, tunisia, were housed in separate cages under controlled conditions of temperature (25°c) and a 12:12 light/dark cycle. all animals were provided with water and food ad libitum. all rats were acclimatized 10 days prior to the beginning of the experiment. animals were cared for in compliance with the institutional ethics committee code of practice for the care and use of animals for scientific purposes. the experimental protocols were approved by the ethics committee of faculty of sciences, bizerta, tunisia. castration surgery the castration surgery was performed under ether anaesthesia. all rats were bilaterally castrated, each testis was excised through a small incision at the posterior end of the scrotum and then ligated. the testis was exposed by performing a transverse resection on both scrota in the supine position, and the spermatic cord and blood vessels were ligated and resected (25). experimental design ten days after surgery, rats were randomly assigned in 4 groups, five animals per group, and treated for 20 consecutive days as follows: group 1 (control group): non-castrated rats received distilled water orally (10 ml/kg). group 2: castrated group (ct) was given distilled water orally after castration (10 ml/kg). group 3: testosterone treated group (tt) castrated rats received 5 mg/kg of testosterone (sigmaaldrich,co, st louis, mo, usa) dissolved in corn oil by subcutaneous injection (26). group 4: spirulina co-treated group (sp) castrated rats received 5 mg/kg of testosterone dissolved in oil by subcutaneous injection followed by 10 ml/kg orally of spirulina (1000 mg/kg) (bioalgues tunisia). during the experiment period, all rats were monitored daily for body weight. behavior tests were performed at the end of the treatments. biochemical analyses rats were sacrificed by decapitation under slight ether anesthesia. blood was collected in edta tubes and centrifuged at 4°c at 4000 rpm for 15 minutes. plasma was recuperated and stored at -25°c for further biochemical determinations. organs, brain, prostate, and seminal vesicles were immediately dissected out, washed in saline solution, weighed, and stored for further oxidative stress measurement. cholesterol, triglycerides, alkaline phosphatase (pal), aspartate aminotransferase (ast) and alanine aminotransferase (alt) were determined using commercial analysis kits (biomaghreb, tunisia) according to the manufacturer’s instructions. oxidative stress measurement tissue was homogenized in tris-buffered saline (tbs). the homogenate was centrifuged at 4°c at 9000 rpm for 10 minutes and supernatants were collected. protein level was estimated by bradford method (27). superoxide dismutase (sod) and catalase (cat) activities were measured in tissue homogenates according to misra and fridovich (28) and aebi methods (29) respectively. lipid peroxidation was assessed by measuring the malondialdehyde (mda) level according to the draper and hadley method (30). hydrogen peroxide (h2o2) level was measured according to jabri et al. (31). behavioural testing animals were habituated to the arena the day following the 20 days of treatment and then submitted to the object location test (olm) (32) and the novel object recognition test (nor) 24 hours later (33). both behavioural tests were performed between 08:00 am and 03:00 pm (figure 1). figure 1. object location (olm) and novel object recognition (nor) tests. archivio italiano di urologia e andrologia 2023; 95(4):11593 3 metabolic and cognitive effects of testosterone replacement assessment of spatial memory using object location memory test (olm) the arena was a metal circular area with a 50 cm wall and divided into 1 central and 6 peripheral parts of equal surface. testing consisted of one habituation day and one olm testing day. on both days, testing was performed between 8:00 am and 04:00 pm and rats were brought to the testing room 15 minutes prior to the start of the testing. during the habituation day, rats were free to explore the vacant arena for 15 minutes. on the olm testing day, two trials were performed, training and testing trials. during the training trial, two identical objects were placed 5 cm away from the wall such that they are counterbalanced in the arena, each rat was placed then in the centre of the arena and allowed to explore it for 5 minutes. rats were placed back into their cages following the training trial for a 1h interval between trials. during the testing trial, one of the objects was moved to a quadrant diagonal from the other object, each rat was then replaced in the arena and allowed to explore for 5 minutes. the apparatus was cleaned with 30% alcohol and dried prior to the start of each trial for every rat. rat movements were tracked and recorded using the debut video recorder program. a rat is considered exploring an object when its nose was within 2 cm from the object. touching and sniffing activities were counted as exploration, while sitting on the object was not. rats who don't meet these criteria were excluded from all analyses. to analyse cognitive performance, the following data were measured: the time spent exploring the object moved to a novel place (t1), the object remaining in the familiar place (t2), and the investigation time (%) i.e., which represents the percentage of the time spent in exploring the objects relative to the total time of the trial. indexes measurements were also considered (34). discrimination index (d1) represented the ability of the rat to distinguish the new object location from the familiar one; this index varies between -1 and +1 with a positive value indicating more preference for the displaced object. d1 is calculated as follows d1 = (t1-t2)/(t1+t2). recognition index (r1) represented the percentage of time spent exploring the displaced object relative to the total exploration time and was calculated as follows: r1=t1/(t1+t2) ×100. assessment of spatial memory using novel object recognition memory test (nor) an hour after the olm last testing trial, the familiar object was replaced with a novel object. rats were placed in the centre of the arena and allowed to explore it for 5 minutes comprising one old object that was used in the last trial of the olm test and one novel object. the arena was cleaned with 30% alcohol and air-dried prior to the commencement of each trial for every rat. rat movements were tracked and recorded using the debut video recorder program. to analyse cognitive performance, the following data were collected: time spent in exploring the novel object(t1), the familiar object(t2), and the investigation time (%), which represents the percentage of the time spent in exploring the objects relative to the total time of the trial. the indexes that were considered were: the discrimination index (d1) representing the ability of the rat to distinguish the novel object from the familiar one (this index varies between -1 and +1 with a positive value indicating more preference for the novel object); the recognition index (r1) representing the percentage of time spent with the novel object relative to the total exploration time. the indexes were calculated respectively as follows d1 = (t1-t2) /(t1+t2); r1=t1/(t1+t2) ×100 (34). statistical analyses statistical analysis of data was performed using a one-way analysis of variance (anova) followed by tukey's post hoc test for multiple comparison. data were expressed as mean ± standard error of the mean. a value of p < 0.05 was considered statistically significant. data were analysed using graphpad prism 5 software. results serum biochemical analyses as shown in table 1, castrated rats expressed statistically increased plasma levels of alt, ast, pal, cholesterol, and triglycerides compared to control group. in contrast, testosterone replacement (tt) alone or in combination with and spirulina (sp) restored these parameters to normal levels. evaluation of antioxidant enzyme activities data showed that castration increased significantly sod and cat activities in the prostate, seminal vesicles, and the brain in comparison with the control group (table 2). importantly, testosterone replacement significantly ameliorated the abnormal levels of the antioxidant enzymes in the three tissues compared to control levels. however, cotreatment with spirulina did not significantly improve these effects in sp group. evaluation of hydrogen peroxide (h2o2) and lipid peroxidation levels figures 2,3 and 4 showed that mda levels respectively in prostate, seminal vesicles, and brain, were significantly higher in castrated group in comparison with control group. these increases were associated with a significant increase in h2o2 levels as compared with control group. a significant and identical decrease in mda and h2o2 tissue contents was noticed in tt and sp groups as compared to castrated rats. indeed, there were no remarkable changes in these oxidative stress parameters between control, tt and sp groups. table 1. biochemical parameters in control, castrated, testosterone and spirulina treated rats. parameters control ct tt sp alt (u/l) 35.35 ± 3.39 88.90 ± 7.5 * 46.81 ± 6.62 # 41.85 ± 5.28 # ast (u/l) 17.50 ± 0.95 32.38 ± 3.88 * 23;98 ± 2.66 24.33 ± 3.11 pal (u/l) 18.70 ± 1.92 56.93 ± 7.39 * 30.02 ± 3.45 # 20.43 ± 1.17 # cholesterol (g/l) 1.09 ± 0.12 1.97 ± 0.13 * 1.29 ± 0.07 # 1.06 ± 0.11 # triglycerides (g/l) 1.25 ± 0.14 3.10 ± 0.14 * 1.78 ± 0.09 # 1.75 ± 0.15 # values are expressed as mean ± sem. ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. alt: alanine aminotransferase; ast: aspartate aminotransferase; pal: alkalin phosphatase. * p < 0.05 as compared to control group. # p < 0.05 as compared to ct group. archivio italiano di urologia e andrologia 2023; 95(4):11593 o. boukari, w. khemissi, s. ghodhbane, a. lahbib, o. tebourbi, k. ben rhouma, m. sakly, d. hallegue 4 table 2. effect of testosterone replacement in combination or not with spirulina on antioxidant enzymes activities in prostate, seminal vesicles, and brain tissues in castrated rats. prostate seminal vesicles brain sod cat sod cat sod cat (u/mg proteins) (umol/min/mg protein) (u/mg proteins) (umol/min/mg proteins) (u/mg proteins) (umol/min/mg proteins) c 6.73 ± 1.32 74.02 ± 8.65 13.28 ± 1.59 93.65 ± 10.56 12.67 ± 1.82 73.90 ± 4.1 ct 13.4 ± 1.45 * 165 ± 15.13 * 40.72 ± 4.26 * 199.4 ± 23.83 * 54.57 ± 5.67 * 140.8 ± 10.89 * tt 7.45 ± 1.58 130.8 ± 3.35 * 30.49 ± 1.65 * 137.7 ± 18.88 22.28 ± 0.99 # 97.63 ± 3.23 # sp 11.68 ± 1.83 109.2 ± 6.18 # 23.92 ± 1.83 # 124 ± 19.05 # 22.48 ± 1.41 # 96.82 ± 4.31 # values are expressed as mean ± sem. c: control; ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. sod: superoxide dismutase; cat: catalase. * p < 0.05 as compared to control group. # p < 0.05 as compared to ct group. figure 2. effect of testosterone replacement in combination or not with spirulina on prostate mda and h2o2 levels of castrated rats. values are expressed as mean ± sem. ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. mda: malondialdehyde; h2o2: hydrogen peroxide; * p < 0.05 compared to control group. # p < 0.05 as compared to ct group. figure 3. effect of testosterone replacement in combination or not with spirulina on seminal vesicles mda and h2o2 levels in castrated rats. values are expressed as mean ± sem. ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. mda: malondialdehyde; h2o2: hydrogen peroxide; * p < 0.05 compared to control group. # p < 0.05 as compared to ct group. figure 4. effect of testosterone replacement in combination or not with spirulina on brain mda and h2o2 levels in castrated rats values are expressed as mean ± sem. ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. mda: malondialdehyde; h2o2: hydrogen peroxide; * p < 0.05 compared to control group. # p < 0.05 as compared to ct group. archivio italiano di urologia e andrologia 2023; 95(4):11593 5 metabolic and cognitive effects of testosterone replacement assessment of memory performances in the olm trial, castrated rats exhibited statistically decreased investigation time as compared to control group, while no significant difference in the investigation time was noticed between the control, tt and sp groups (table 3). compared with the other groups, castrated rats displayed less preference for the displaced object in the novel place since they spent equal time exploring the object remained in the familiar location and the displaced one. moreover, the comparison of the discrimination index between control and castrated group revealed a significant lower index in ct group as compared to control, tt and sp treated groups. in nor tests, the investigation time was also significantly decreased in castrated group as compared to control group. this effect was totally reversed in testosterone and testosterone plus spirulina treated groups. furthermore, control, tt, and sp treated groups showed a clear tendency to explore the novel object rather than the familiar object. in fact, these rats showed a significantly higher recognition index in comparison to castrated group and spent more than 75% of their investigation time with the novel object. castrated rats showed no preference for the novel object as they displayed a decreased recognition index as compared to control group. the comparison of the discrimination index between castrated and control group showed that castrated rats had a significantly decreased index as compared to control group which showed a non-distinguish of the novel object. however, treated rats with testosterone alone or in combination with spirulina displayed a comparable discrimination index to the control group and a significant increase in the discrimination index value as compared to the castrated group. discussion testosterone is a key hormone that has been known for its major role in carbohydrates, lipids, and proteins metabolism (35, 36). testosterone deficiency has been linked to an increase in body fat mass, impairment in glucose and lipid tolerance, as well as oxidative stress imbalance; all these factors can contribute to metabolic disorders (37). in this regard, we assessed castration effect on adult male rats and evaluated whether testosterone could mitigate physiological perturbations induced by testosterone deficiency. in addition, we investigated the possible potential of the filamentous cyanobacterium, spirulina platensis, to enhance the androgen effect in castrated rats. our results revealed that plasma levels of cholesterol and triglycerides were remarkably increased after castration in ct rat group in comparison with the control group. our findings are in harmony with previous studies of testosterone deficiency effect on lipid profiles in aging male rats (38) and orchiectomized rats (39). testosterone level appears to have complicated relationship with cholesterol metabolism regulation and its associated anomalies, in a matter of facts low testosterone levels is associated with pro atherogenic lipid profiles in men (2), particularly lower levels of the high-density lipoprotein cholesterol (hdl-c). as steroid hormones can bind and interact with specific dna domains it has been suggested that testosterone is involved in the molecular metabolism of cholesterol within the liver through the upregulation of several genes namely the hepatic lipase (hl), the scavenger b1 receptor (sr-b1) (40), and the nuclear liver x receptor (lxr) (41). both hl and sr-b1 mediate and facilitate the uptake of hdl into hepatocytes, thereby stimulate the cholesterol uptake and efflux. studies demonstrated that increased activity of sr-b1 and hl were linked to cholesterol level lowering effect of testosterone administration (40). it was also suggested that testosterone is involved in the liver uptake of low-density lipoprotein cholesterol (ldlc) through the modulation of the pcsk9-ldlr pathway, thus the clearance of ldl-c from circulation (42). importantly, our study showed that plasma lipid profile perturbations were reversed by testosterone replacement either alone or in association with spirulina in castrated rats. our results are in line with previous studies which have demonstrated that testosterone replacement therapy (43) and spirulina platensis supplementation (44) ameliorated serum cholesterol and triglycerides levels respectively in castrated or high fat diet-fed rats. liver enzymes such as transaminases (alt, ast) and alp are sensitive biomarkers widely used to assess liver injury (45). thus, these intracellular proteins are released into the blood upon hepatocyte damage. our results showed that in castrated rats, these enzymes greatly increased in plasma above normal value. however, supplementation with testosterone or testosterone plus spirulina were effective in improving these liver damage biomarkers. oxidative stress is a major mechanism of tissue injury, it is induced by the imbalance between the production of the oxygen reactive species (ros) and the antioxidant system (46). it is generally caused by lipid accumulation, and dna damages and leads to the loss of organ functions. the occurrence of oxidative stress is linked to aging, aging-related diseases and diverse clinical conditions including diabetes and heart diseases (47, 48). previously, it has been shown that low testosterone level table 3. effect of testosterone replacement in combination or not with spirulina on castrated rats’ behaviour during olm and nor tests. object location memory test novel object recognition test control ct tt sp control ct tt sp investigation time (%) 11 ± 0.83 5.61 ± 0.37 * 8.22 ± 0.97 8.67 ± 0.83 14.47 ± 1.19 3.94 ± 0.57 * 11.80 ± 0.44 # 11.94 ± 0.43 # recognition index 78.31 ± 0.43 38.50 ± 3.15 * 77.51 ± 0.46 # 77.85 ± 0.97 # 81.27 ± 1.65 34.35 ± 2.43 * 75.66 ± 1.37 # 77.85 ± 1.95 # discrimination index 0.56 ± 0.008 -0.23 ± 0.07 * 0.55 ± 0.009 # 0.56 ± 0.01 # 0.63 ± 0.03 -0.31 ± 0.04 * 0.51 ± 0.02 # 0.55 ± 0.03 # values are expressed as mean ± sem. ct: castrated group; tt: testosterone treated group; sp: testosterone and spirulina co-treated group. * p < 0.05 as compared to control group. # p < 0.05 as compared to ct group. archivio italiano di urologia e andrologia 2023; 95(4):11593 o. boukari, w. khemissi, s. ghodhbane, a. lahbib, o. tebourbi, k. ben rhouma, m. sakly, d. hallegue 6 is correlated to an imbalance of the oxidative stress status. in the study of mancini et al. (49), sixteen patients with hypogonadism were compared to ten healthy patients to investigate the role of testosterone in the oxidative stress mechanism showing that a lipid antioxidant enzyme coenzyme q10 (coq10) was reduced in the hypogonadism condition and that the testosterone replacement therapy resulted in an increase in coq10 serum level (49). furthermore, in vitro assays showed that low testosterone treatment could decrease lipid peroxidation and the ros production in tm3 leydig cells (50). in the present study we revealed that castrated rats showed a remarkable increase in sod and cat activities in the prostate, seminal vesicles, and the brain in comparison with the control group. whereas testosterone replacement result in a significant increase in the level of these antioxidant enzymes. however, cotreatment with spirulina did not significantly improve these effects towards tt group. testosterone deficiency also significantly increased both mda and h2o2 levels in prostate, seminal vesicles, and brain, in comparison with control group. interestingly, administration of testosterone either alone or in combination with spirulina restored these changes induced by castration. our results are consistent with previous studies that have showed that oral administration of spirulina prevented repro-toxicity by mitigating lipid peroxidation in testis of furan-intoxicated rats (23) and counterbalancing the perturbation of antioxidant enzymes in cadmium-intoxicated mice (51). however, the fact that spirulina cotreatment did not enhanced the positive effects of testosterone in castrated rats suggested that androgen actions might involve other mechanisms unrelated to oxidative stress. the loss of bioavailable testosterone in male is associated with a dysfunction in androgen responsive tissues including the brain. a vast majority of human and animal studies demonstrated that testosterone deficiency causes a decline in cognitive performance (52) and affective behaviour in males (53). some data reported conflicting results and supported a non-consistent effect of androgens (54). studies on molecular mechanism of androgen action on the brain indicated that testosterone have a direct impact on glial cells thereby can modulate the myelinisation mechanism, synapse, and dendritic branching number as well as neuron growth (55). it has also been shown that even though gonadotropic neurons do not express androgen receptors, testosterone can modulate these neurons through a neuropeptide called kisspeptin which is not only expressed in the hypothalamic-pituitary-gonadal axis (hpg) but also in the limbic regions of the brain implicated in the emotional and cognitive behaviour (mills et al., 2018. however, the exact causality of the relationship between testosterone levels and brain functions is still not firmly established. in our study we performed olm and nor cognitive tests to assess the spatial memory performance in rats. our data demonstrated that castration caused less interest in exploring objects in both the olm and nor trials. likewise, the discrimination index of ct group displayed a negative value which indicate the incapacity of castrated rats to distinguish the novel object and the novel location of the object. these findings are along with previous results of pintana et al. (56), that showed a cognitive decline in rats with testosterone deprivation. whereas rats who received testosterone replacement of 0.20 mg/kg spent significantly more time exploring objects than castrated group and showed a significantly greater preference for the displaced and the novel object in comparison to castrated rats. coherently, testosterone replacement displayed a positive discrimination index and a higher recognition index in comparison to ct group. our findings contradicted the results of borbélyovà et al. (57) who reported no effect of low testosterone concentration neither acute testosterone treatment on the exploratory behaviour and memory performance assessed by the open field test in aged and castrated male rats. this difference in results can be explained by several limitations namely the difference in the treatment period and the behavioural tests used. castrated rats who received spirulina co-treatment also exhibited significantly more time exploring the objects in the arena, they displayed a higher discrimination and recognition index as compared to castrated group. in agreement with our results, previous data showed that spirulina could improve memory deficit induced by scopolamine in rats through modulation of oxidative stress imbalance (58). further, wang et al. (59), reported that spirulina could impart appreciable relief in l-methionine induced cognitive deficit in rats by counterbalancing the acetylcholinesterase activity and brain oxidative enzymes activity. conclusions this study demonstrated that testosterone deficiency led to an increase in plasma cholesterol and triglycerides as well as ast, alt, and pal levels associated with unbalanced oxidative status and cognitive impairment. testosterone replacement could counteract these castration-induced changes. however, there were no notable effects when testosterone was combined with spirulina in castrated rats. further investigations are needed to understand the underlying mechanisms of testosterone deficiency-induced alterations. acknowledgements authors express their sincere thanks to professor youssef krichen, ceo of bio algae tunisia company for the free supply of phycocyanin and dr sihem ben hassine for her technical assistance. references 1. swerdloff rs, wang c, hines m, gorski m. effect of androgens on brain and other organs during development and aging, psychoneuroendocrinology. 1992; 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127:220. 59. wang p, wang y, zhang q, et al. amelioration of cognitive deficits by spirulina platensis in l-methionine-induced rat model of vascular dementia. pharmacogn mag. 2020; 16:133. correspondence oumayma boukari oumayma.boukari@gmail.com wahid khemissi w.khemissi2007@gmail.com soumaya ghodhbane ghodhbanes@yahoo.fr aida lahbib lahbib.aida@gmail.com olfa tebourbi tebourbi.olfa@gmail.com khémaïs ben rhouma k.benrhouma2015@gmail.com mohsen sakly (corresponding author) mohsensakly@gmail.com dorsaf hallegue dorsafhallegue@yahoo.fr laboratory of integrated physiology, department life sciences, faculty of sciences of bizerte, university of carthage, jarzouna 7021, bizerte, tunisia conflict of interest: the authors declare no potential conflict of interest. stesura seveso 189archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. introduction obesity is considered a risk factor for urinary stone formation. a recent meta-analysis based on 7 large cohorts in the united states, china and japan computed a relative risk for kidney stone formation of 1.21 per 5 units of increment in body mass index (bmi) (1). this scientific evidence is robust although it is mainly dependent on observations collected from cohorts in the united states. for this reason, one might question the extension of these findings to other countries. in fact, the population of the united states is characterized by a dietary pattern that contains important risk factors for stone formation (a high animal protein load, a significant acid load due to lack of fruit and vegetable consumption). furthermore, morbid obesity (bmi ≥ 40) is much more prevalent in the population of the united states than in any other country excluding pacific islands (2). in fact, the prevalence of morbid obesity in the united states is high and is constantly increasing. from 2000 to 2010 the prevalence rate of a bmi > 40 increased by 70% (from 3.9% to 6.6%) and the prevalence of bmi > 50 has increased even more (from 0.27 to 0.55%) (3). morbid obesity levels are also increasing in other countries but with much lower rates (< 2%) (4-6). morbid obesity or type iii obesity has a different impact on health than moderate obesity by increasing the risk and severity of many cardiovascular and non-cardiovascular comorbidities. particularly, it was observed that 98% of subjects with morbid obesity have at least one lithogenic risk factor identified on 24-hour urine collection (7). the obese population of the united states is therefore a different populaobjective: to collect evidence on the rate of obesity in renal stone formers (rsfs) living in different climatic areas and consuming different diets. materials and methods: data of adult renal stone formers were retrospectively collected by members of u-merge from 13 participant centers in argentina, brazil, bulgaria (2), china, india, iraq (2), italy (2), nigeria, pakistan and poland. the following data were collected: age, gender, weight, height, stone analysis and procedure of stone removal. results: in total, 1689 renal stone formers (1032 males, 657 females) from 10 countries were considered. average age was 48 (±14) years, male to female ratio was 1.57 (m/f 1032/657), the average body mass index (bmi) was 26.5 (±4.8) kg/m2. the obesity rates of rsfs in different countries were significantly different from each other. the highest rates were observed in pakistan (50%), iraq (32%), and brazil (32%), while the lowest rates were observed in china (2%), nigeria (3%) and italy (10%). intermediate rates were observed in argentina (17%), bulgaria (17%), india (15%) and poland (22%). the age-adjusted obesity rate of rsfs was higher than the age-adjusted obesity rate in the general population in brazil, india, and pakistan, whereas it was lower in argentina, bulgaria, china, italy, and nigeria, and similar in iraq and poland. conclusions: the age-adjusted obesity rate of rsfs was not higher than the age-adjusted obesity rate of the general population in most countries. the relationship between obesity and the risk of kidney stone formation should be reconsidered by further studies carried out in different populations. key words: urinary calculi; obesity; diet, body mass index. submitted 1 april 2021; accepted 25 may 2021 obesity rates in renal stone formers from various countries elenko popov 1, 2, murtadha almusafer 1, 3, arben belba 1, 4, jibril o. bello 1, 5, kamran hassan bhatti 1, 6, luca boeri 1, 7, kaloyan davidoff 1, 2, bm zeeshan hameed 1, 8, adam haliński 1, 9, ita pfeferman heilberg 1, 10, hongyi hui 1, 11, kremena petkova 1, 12, bapir rawa 1, 13, fernanda guedes rodrigues 10, iliya saltirov 1, 12, francisco r. spivacow 1, 14, alberto trinchieri 1, noor buchholz 1 1 u-merge ltd.* (urology for emerging countries), london, uk; 2 acibadem city clinic tokuda hospital, sofia, bulgaria; 3 college of medicine, university of basrah, basrah, iraq; 4 ospedale santo stefano, prato & casa di cura villa donatello, sesto fiorentino, italy; 5 department of surgery, urology unit, university of ilorin teaching hospital, nigeria; 6 urology department, hamad medical corporation, doha, qatar; 7 department of urology, irccs ca’ granda ospedale maggiore policlinico, university of milan, milan, italy; 8 department of urology, kasturba medical college, manipal, karnataka, india; 9 private medical center "klinika wisniowa" zielona gora, poland; 10 nephrology division, universidade federal de são paulo (unifesp), são paulo, brazil; 11 department of urology, renji hospital, shanghai jiaotong university school of medicine, shanghai, china; 12 department of urology and nephrology, military medical academy, sofia, bulgaria; 13 smart health tower, sulaymaniyah, kurdistan region, iraq; 14 instituto de investigaciones metabólicas (idim), buenos aires, argentina. * u-merge ltd. (urology in emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2021.2.189 summary archivio italiano di urologia e andrologia 2021; 93, 2 e. popov, m. almusafer, a. belba, et al. 190 tion from obese populations observed in other countries in that it includes a higher percentage of morbid obese subjects. on the other hand, rates of overweight and obesity in a population consuming a mediterranean diet were not different in renal stone formers with respect to a control population matched by age and gender (8) suggesting a prevalent role of the dietary pattern for the risk of stone formation (9). the aim of the present study was to collect more evidence on the rate of obesity in renal stone formers living in different climatic areas and consuming different diets. age and sex adjusted rates of obesity in stone formers from different countries were compared with already known obesity rates for each corresponding country. materials and methods data were collected by 13 participating centers in argentina, brazil, bulgaria (n = 2), china, india, iraq (n = 2), italy (n = 2), nigeria, pakistan and poland under the umbrella of u-merge. each participating center collected retrospectively data of consecutively observed adult (> 18 years) renal stone former patients (rsfs) by reviewing charts of patients who passed spontaneously a stone or had extracorporeal or endourological treatment for stone removal. for each patient, the following information was collected: age, gender, weight, height, stone analysis (optional), procedure of removal (spontaneous passage, swl, pnl, urs, open surgery). any method of stone analysis was accepted, but the methodology had to be known and registered. excel files containing anonymised data from each patient and numbered consecutively were mailed to the coordinating center (umerge scientific office). each center retained the list of the corresponding names of the participants in their own original files at their institution. bmi was computed from weight and height of each subject. obesity was defined as a body mass index (bmi) ≥ 30 kg/m2. tables reporting the number of subjects with obesity for each age and sex group were built. the obesity rates of rsfs in different countries were adjusted by the age distribution in the general population of each country, in order to compare them with age adjusted obesity rates in the general population of the corresponding country obtained from estimated worldwide trends in obesity by ncd risk factor collaboration (ncd-risc) (2). briefly, rsfs of each country were grouped by sex and class age. age and sex specific rate of obesity of rsfs of each subgroup was multiplied by the corresponding age and sex specific weight of that country. the weights used in the age-adjustment of obesity data are the proportion of the population of each country within each age and sex group according to the estimates prepared by the population division of the department of economic and social affairs (desa) of the united nations secretariat (10). the weighted rates are then summed across the age and sex groups to give the age and sex adjusted rate of obesity for rsfs of each country (table 1). age adjusted obesity rates of male and female rsfs from each country were compared with age adjusted obesity rate of male and female general population obtained from estimated worldwide trends in obesity by ncd-risc (2). finally, obesity rates in rsfs with stones of different chemical composition were calculated. statistical analysis was carried out using the statistical package for the social sciences (spss). chi square analysis was used to compare rates of obesity in different groups. mean values of age and bmi were compared by one-way anova, and differences between groups were evaluated by post hoc bonferroni analysis. a p-value < 0.05 was considered statistically significant. results in total, 1689 renal stone formers (1032 males, 657 females) from 10 countries (argentina, brazil, bulgaria, china, india, iraq, italy, nigeria, pakistan, poland) were considered. most of the cases were observed in the period 2016-2019. only the series from argentina included patients observed over a longer period from 2005 to 2017. average age was 48 (±14) years, male to female ratio was 1.57 (m/f 1032/657), average bmi was 26.5 (±) 4.8 kg/m2). average age, m/f ratio and average bmi in series from different countries are shown in table 2. the average age values in the different series were significantly different (p = 0.000). the highest average age was observed in patients from table 2. mean age, m/f ratio and mean bmi of rsfs from different countries. argentina brazil bulgaria china india iraq italy nigeria pakistan poland n° 300 216 183 90 33 246 428 31 50 112 m 179 (60%) 114 (53%) 112 (61%) 59 (66%) 26 (79%) 154 (63%) 267 (62%) 17 (55%) 41 (82%) 63 (56%) f 121 (40%) 102 (47%) 71 (39%) 31 (34%) 7 (21%) 92 (37%) 161 (38%) 14 (45%) 9 (18%) 49 (44%) age 45 +/-11 42 +/-12 50 +/-13 51 +/-13 48 +/-11 46 +/-14 56 +/-14 44 +/-14 38 +/-8 48 +/-14 bmi 25.8 +/-4.4 28.3 +/-5.8 26.2 +/-3.8 24.2 +/-2.9 26.0 +/-4.2 28.3 +/-4.7 25.1 +/-4.3 26.2 +/-2.4 30.4 +/-6.7 26.7 +/4.6 ua % 11% § 29% * 6% * 34% * 16% § 25% * 33% * bmi = body mass index; ua% = rate of uric acid containing stones; § present series; * other series from the same institution. table 1. an example of computation of age-adjusted obesity rate (italy-males). class age obesity rate in rsf weight of class ages in italy (5) age adjusted 18-39 1/29 = 0.034 0.30 0.010 40-59 17/130 = 0.130 0.38 0.049 > 60 9/108 = 0.083 0.32 0.026 total 27/267 = 0.101 1.00 0.085 10.1% 8.5% italy, while the lowest average age was observed in patients from pakistan. the average age of patients from italy was significantly higher than that of patients from bulgaria (p = 0.000), iraq (p = 0.000), pakistan (p = 0.000), nigeria (p = 0.000), poland (p = 0.000), argentina (p = 0.000) and brazil (p = 0.000). the average age of patients from pakistan was significantly lower than that of patients from bulgaria (p = 0.000), iraq (p = 0.003), china (p = 0.000), india (p = 0.039), italy (p = 0.000), poland (p = 0.000) and argentina (p = 0.046). the average age of patients from bulgaria and china was significantly higher than that of patients from pakistan (p = 0.000 and p = 0.000), argentina (p = 0.007 and p = 0.007) and brazil (p = 0.000 and p = 0.000) and the average age of patients from brazil was higher than that of patients from poland (p = 0.002) and iraq (p = 0.005). male to female ratio was in favor of men in all countries, with the percentage of men ranging from 53 to 63% in most countries except pakistan and india where males accounted for 82 and 79%, respectively. the average bmi values of patients in different countries were significantly different (p = 0.000). in particular, the average bmi was highest in patients from pakistan, iraq and brazil. the average bmi of patients in pakistan was significantly higher than that of patients in bulgaria (p = 0.000), china (p = 0.000), india (p = 0.001), italy (p = 0.000), nigeria (p = 0.004), poland (p = 0.000), argentina (p = 0.000) and brazil (p = 0.000). the average bmi of patients in iraq was significantly higher than the average bmi of patients in bulgaria (p = 0.000), china (p = 0.000), italy (p = 0.000) and argentina (p = 0.000). the average bmi of brazilian patients was intermediate, being higher than that of patients in bulgaria (p = 0.001), china (p = 0.000), italy (p = 0.000) and argentina (p = 0.000). the lowest average bmi value was observed in patients from china being lower than that of bulgaria (0.0024) and poland (p = 0.007). crude and age-adjusted obesity rates in male and female rsfs from different countries in comparison of ageadjusted obesity rates in the male and female general population are shown in table 3. in both, males and females, the age-adjusted rate of obesity in rsfs was higher than the age-adjusted rate of obesity in the general population in brazil, india, and pakistan, whereas it was lower in argentina, bulgaria, china, italy, and nigeria, and similar in iraq and poland. the obesity rates of rsfs were significantly different from country to country. the highest rates were observed in pakistan (50%), iraq (32%), and brazil (32%), while the lowest rates were observed in china (2%), italy (10%), and nigeria (3%). intermediate rates were observed in argentina (17%), bulgaria (17%), india (15%), and poland (22%). these differences were maintained when obesity rates were adjusted by age in reference to a pool of all series. in a sample of 666 patients (409 males and 257 females) with stone analysis, obesity rate was 13.3% (61/456) for calcium oxalate stones, 4.7% (1/21) for calcium phosphate, 8.5% (6/70) for mixed calcium phosphate/calcium oxalate, 18.8% (13/69) for uric acid, 20.8% (5/24) for mixed calcium oxalate/uric acid. no obese patients were observed for infection (struvite) (0/21) and cystine stones (0/5). mean age (56±14 vs 50±14 years, p = 0.000), mean bmi (27.2±4.6 vs 25.0±4.2, p = 0.000) and obesity rates 18/86 (21%) vs 75/580 (13%) were higher in patients who formed uric acid-containing stones than in those of patients forming other type of stones. in the present series, rate of uric acid containing stones was 16% in italy and 11% in argentina and, from data of other series collected in the same centers participating to the present study, 29% in bulgaria, 6% in china, 34% in india, 25% in iraq, 25% in pakistan and 33%in poland discussion in 2006, a prospective study of 3 large cohorts demonstrated that a bmi > 30 is associated with an increased risk of kidney stone formation for both, men and women (11). some authors emphasized the presence of high rates of obesity in rsfs in some countries, whilst other authors did not confirm this finding in other countries (table 4) (8, 12-20). 191archivio italiano di urologia e andrologia 2021; 93, 2 obesity rates in renal stone formers table 3. crude and age-adjusted obesity rates in male and female rsfs from different countries in comparison of age-adjusted obesity rates in male and female general population. country gender rsfs rsfs obesity rsfs obesity general population obese/total rate (crude) rate (adjusted) obesity rate 2016 argentina t 51/300 (17%) 17% m 32/179 (18%) 17.8% 15.9% 28.2% f 19/121 (16%) 15.7% 15% 30.1% brazil t 70/216 (32%) m 36/114 (31%) 31.5% 32.5% 19.2% f 34/102 (33%) 33.3% 31.9% 26.4% bulgaria t 32/183 (17%) m 18/112 (16%) 16.0% 15.3% 26.3% f 14/71 (19%) 19.7% 17.7% 25.2% china t 2/90 (2%) m 1/59 (2%) 1.6% 1.5% 6.1% f 1/31 (3%) 3.2% 3.3% 6.8% india t 5/33 (15%) m 3/26 (11%) 11.5% 11.0% 2.8% f 2/7 (28%) 28.5% 59.5% 5.3% iraq t 78/246 (32%) m 45/154 (29%) 29.2% 22.5% 24.3% f 33/92 (36%) 35.8% 32.3% 38.3% italy t 43/428 (10%) m 27/267 (10%) 10.1% 8.5% 20.9% f 16/161 (10%) 9.9% 9.5% 20.4% nigeria t 1/31 (3%) m 17 0 0 4.8% f 1/14 (7%) 7.1% 4.5% 13.6% pakistan t 25/50 (50%) m 20/41 (49%) 48.7% 20.7% 6.2% f 5/9 (55%) 55.5% 24.1% 11.7% poland t 25/112 (22%) m 18/63 (28%) 28.5% 27.9% 24.6% f 7/49 (14%) 14.2% 14.6% 23.2% total t 332/1689 (20%) m 200/1032 (19%) f 132/657 (20%) archivio italiano di urologia e andrologia 2021; 93, 2 e. popov, m. almusafer, a. belba, et al. 192 the assessment of the significance of the obesity rate in a given population on one hand, and the comparison of obesity rates in different populations on the other hand are complex because one must take into account the age and gender distribution of the population as well as the chemical composition of the stones. our study shows that obesity rates among rsfs in different countries range between 0 and 48.7% in men, and 7.1% and 55.5% in women. these differences are maintained after age adjustment according to the general population’s age distribution, with rates ranging between 0 and 32.5% in men, and 3.3% and 59.5% in women, respectively. these wide oscillations can be explained by the different age distributions in different countries, but also by different spectra of stone composition, dietary patterns and different climatic conditions. in general, the rate of obesity tends to increase with increasing age, so it is possible that in populations with an older age distribution there may be a higher prevalence of obesity. to the contrary, in this study, series with higher average ages, such as those observed in italy, bulgaria and china, had the lowest obesity rates among both, men (1.6-16%) and women (3.2-15.7%), respectively. on the other hand, the ranking of obesity rates in different countries does not vary after the rates have been adjusted by age taking as a reference the pooled population of all the series. another potential determinant of obesity rate among rsfs is the type of stone. obesity tends to be more frequent in uric acid stone formers (21). uric acid stones have a different prevalence in different countries. in our series obesity rates were higher in pakistan, iraq and brazil. the former two have reported a higher frequency of uric acid stones (22, 23), which was also observed in some parts of brazil (24). in contrast, the lowest obesity rates were observed in countries where the frequency of uric acid stones is low, such as china, nigeria and, to a lesser extent, italy (25-27). one of the major determinants of the epidemiology of uric acid stones is climate, as higher environmental temperatures and humidity increase skin loss of fluids resulting in a reduction in urinary volumes, a decrease of ph values and, consequently, an increased urinary saturation for uric acid (28, 29). in fact, in our study, the countries with the highest rates of uric acid stones are characterized by higher environmental temperatures (30). the finding of obesity rates in rsfs equal to or even lower than those observed in the general population of most countries can be explained by the interaction of several factors specific to each population. obesity is the result of the imbalance between dietary energy intake and energy expenditure that is modulated by the individual genetic characteristics that affect the absorption and metabolism of nutrients. in table 5 the different patterns of dietary energy intake, levels of physical activity and consumption of healthy and unhealthy foods in the general population of countries involved in the present study are summarized (31-33). in countries with the lowest dietary energy intake, such as india, pakistan and nigeria, the lowest obesity rates were observed, but also in china, where dietary energy intake has an intermediate value, the obesity rate is low in view of the high levels of physical activity. in other countries with intermediate energy intake values table 4. obesity rates of rsfs of different countries (from the highest to the lowest). author, year country n° obesity rate overweight semins, 2010 united states 1935 m+1322 f 49.9%-49.0% 34.1%-20% abu ghazaleh and budair, 2013 jordan 8346 42.3 % 25.8% chou, 2011 taiwan 907 38.8% 33.5% saenz, 2012 spain 346 28.6% 43.6% funes, 2016 paraguay 73 23.3 39.7% negri, 2008 argentina 799 20.3% 40.6% siener, 2004 germany 527 9.9% 44.6% daudon, 2006 france 1931 m+f 8.4%-13.5% 27.1%-19.6% trinchieri, 2016 italy 1698 8.3% 31.9% oda, 2014 japan 238 m+82 f 2.1%-0% 24.4%-12.2% table 5. rates of obesity, estimated energy intake, levels of physical inactivity and quality of dietary pattern of the general population in countries involved in this surveycomparison of age-adjusted obesity rates in male and female general population. country obesity energy physical quality of dietary pattern (ncd-riskco) intake inactivity (nutricode) m-f kcal/day (fao) * (who) argentina 28.2-30.1 3030 41.6% (t) healthy foods very low 37.6% (m) unhealthy foods low/mod 45.3% (f) brazil 19.2-26.4 3120 47.9% (t) healthy foods moderate 40.4% (m) unhealthy foods high 53.3% (f) bulgaria 26.3-25.2 2760 38.6% (t) healthy foods moderate 35.6% (m) unhealthy foods low/moderate 41.4% (f) china 6.1-6.8 2990 14.1% (t) healthy foods low 16.0% (m) unhealthy foods low 12.2% (f) india 2.8-5.3 2360 34.0% (t) healthy foods low 24.7% (m) unhealthy foods very low 43.9% (f) iraq 24.3-38.3 52.0%(t) healthy foods moderate 39.5% (m) unhealthy foods low/moderate 64.6% (f) italy 20.9-20.4 3650 41.4% (t) healthy foods low/mododrate 36.2% (m) unhealthy foods moderate 46.2% (f) nigeria 4.8-13.6 2710 27.1% (t) healthy foods moderate 24.7% (m) unhealthy foods low 29.6% (f) pakistan 6.2-11.7 2280 33.7% (t) healthy foods very low 24.4% (m) unhealthy foods low 43.3% (f) poland 24.6-23.3 3410 32.5% (t) healthy foods low/moderate 31.5% (m) unhealthy foods high/moderate 33.4% (f) 193archivio italiano di urologia e andrologia 2021; 93, 2 obesity rates in renal stone formers but reduced levels of physical activity, such as brazil and argentina, high obesity rates are observed similarly to those of countries with higher energy intakes, such as italy and poland. finally, the highest levels of obesity were observed in iraq where lowest levels of physical activity were reported. obesity rate in rsfs was higher than in the general population in brazil, which is, a country with a high consumption of unhealthy foods (34, 35). the other two countries where obesity rates were increased in rsfs, namely pakistan and india, are not characterized by a high consumption of unhealthy foods, but have a low consumption of healthy foods such as fruits, vegetables, beans and legumes, nuts and seeds, whole grains, milk, total polyunsaturated fatty acids, fish, plant omega-3s, and dietary fibers (33). admittedly, our study has some limitations such as the retrospective study format, the small number of subjects observed in some countries, the heterogeneous nature of data, the variability in the population pattern and nature of cohorts and the availability of the chemical examination of the stones only in some series particularly, series observed in some areas of large countries are representative only for those specific areas, notably shanghai (china), lagos (nigeria), pakpattan (pakistan) and manipal (karnataka-india) and obesity rates cannot be translated to populations of countries with several million inhabitants. in fact, the populations of these countries are made up of different ethnicities with different genetic characteristics and different culture and religion influencing eating habits and lifestyle. in conclusion, obesity rates among patients with urinary stones are variable in different countries. higher obesity rates were observed in countries with a high prevalence of uric acid stones. on the other hand, obesity rates observed in rsfs tend to overlap with the rates observed in the general population, with equal or lower values even after adjustment by age. accordingly, the role of obesity on the risk of kidney stones formation should be confirmed by further studies carried out in different populations. references 1. aune d, mahamat-saleh y, norat t, riboli e. body fatness, diabetes, physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies. eur j epidemiol. 2018; 33:1033-1047. 2. ncd risk factor collaboration (ncd-risc). worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. lancet. 2017; 390:2627-2642. http://www.ncdrisc.org/data-downloads-adiposity.html 3. sturm r, hattori a. morbid obesity rates continue to rise rapidly in the united states. int j obes (lond). 2013; 37:889-891. 4. malta dc, silva agd, tonaco lab, et al. time trends in morbid obesity prevalence in the brazilian adult population from 2006 to 2017. cad saude publica 2019; 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phenotypes in brazilian adults: a population-based cross-sectional study. public health nutr. 2019; 22:3377-3383. correspondence elenko popov, md shennyp@yahoo.com kaloyan davidoff, md shennyp@yahoo.com acibadem city clinic tokuda hospital sofia, bulgaria murtadha almusafer, md dralmusafer@yahoo.com college of medicine, university of basrah basrah, iraq kamran hassan bhatti, ms urology kamibhatti92@gmail.com urology department, hamad medical corporation doha, qatar arben belba, md arbenbelba@gmail.com ospedale santo stefano, prato and casa di cura villa donatello, sesto fiorentino, florence, italy jibril o. bello, md jabarng@yahoo.com department of surgery, urology unit, university of ilorin teaching hospital ilorin, nigeria luca boeri, md dr.lucaboeri@gmail.com department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy adam haliński, md adamhalinski@gmail.com private medical center "klinika wisniowa" zielona gora, poland bm zeeshan hameed, md zeeshanhameedbm@gmail.com department of urology, kasturba medical college manipal, karnataka, india ita pfeferman heilberg, md ita.heilberg@gmail.com fernanda guedes rodrigues, msci rd fernanda.gr91@gmail.com nephrology division, universidade federal de são paulo (unifesp) são paulo, brazil hongyi hui, md 1095340463@qq.com department of urology, renji hospital, shanghai jiaotong university school of medicine, shanghai, china kremena petkova, md dr_petkova@yahoo.com iliya saltirov, md saltirov@vma.bg department of urology and nephrology, military medical academy sofia, bulgaria bapir rawa, md dr.rawa@yahoo.com smart health tower sulaymaniyah , kurdistan region, iraq francisco r. spivacow, md frspivacow@gmail.com instituto de investigaciones metabólicas (idim) buenos aires, argentina alberto trinchieri, md alberto.trinchieri@gmail.com u-merge ltd. (urology for emerging countries), scientific office athens, greece & school of urology, university of milan milan, italy noor buchholz, md (corresponding author) noor.buchholz@gmail.com u-merge ltd. (urology for emerging countries), scientific office athens, greece archivio italiano di urologia e andrologia 2017; 89, 3182 original paper day case laparoscopic radical prostatectomy hamid abboudi 1, patrick doyle 2, mathias winkler 1 1 departments of urology and 2 anaesthesia, charing cross hospital, imperial college healthcare nhs trust, london, uk. background: to evaluate the feasibility of performing laparoscopic radical prostatectomy (lrp) as a day case procedure while maintaining patient satisfaction and safety. herein we report our experience, selection criteria, and discharge criteria for day case lrp.  methods: we performed a prospective study with 32 patients undergoing extraperitoneal lrp. these patients were counselled before the procedure that they would go home the same evening of the procedure.  pain scores and quality of life data were recorded day 1 postoperatively via a telephone consultation. the patients underwent routine blood tests on day 2 and an outpatient review on day 7 and regularly thereafter via an assigned key worker. socio-demographic data, comorbidities, and outcomes were collected for analysis. results: all patients were successfully discharged the same day of surgery. mean patient age was 62 years with a mean body mass index of 25. mean operative time was 147 minutes, and estimated blood loss was 101 ml. three patients were treated for post operative urinary tract infections; two patients developed infected lymphoceles which required percutaneous drainage and one patient required re-catheterisation due to a burst catheter balloon. of these six complications four patients required re-admission. post-operative pain, nausea and vomiting were low whilst patient satisfaction scores were unanimously high in all patients surveyed. conclusions: the early experience with extraperitoneal lrp as a same day surgery is promising although patients who are at high risk of lymphocele should be excluded. preoperative patient counselling and selection is paramount. patient satisfaction is not adversely affected by the shortened stay. surgeon experience, a well-motivated patient, meticulous attention to detail through an integrated pathway, a multidisciplinary team and adequate postoperative assessment are essential. key words: day surgery; laparoscopy; laparoscopy malignant disease; prostate cancer. submitted 16 may 2017; accepted 2 july 2017 summary no conflict of interest declared. over the years such that it has become standard practice for patients to spend 1-2 nights in hospital after minimally invasive radical prostatectomy with benefits to both patients and healthcare providers. these incentives for early discharge, however, must always be trumped by the patient’s best interest i.e. safety and in particular readmission rates. in 2012 we reported the evolution of a care pathway for lrp that set out to systematically reduce the impact of surgery to the patient through thorough patient preparation and complete minimization of perioperative symptoms (7). our aim was to evaluate the feasibility of performing lrp as a day case procedure while maintaining patient satisfaction and safety. herein we report our experience and to our knowledge the first in the published literature the selection and discharge criteria and outcomes for day case lrp.  patients and methods patients were considered for same day discharge if they met the following conditions: asa 1 or 2, bmi < 30, short procedure with minimal blood loss, minimal perioperative opioids, watertight anastomosis, minimal discomfort or malaise, drain not required and responsible adult at home. demographics, perioperative and follow up data were prospectively collected and recorded on a database. patients received a standardized general anaesthetic with fentanyl as the opioid of choice intra-operatively and transversus abdominis plane (tap) blocks with bupivacaine 0.5% were routinely performed for all patients (figure 1). towards the end of surgery they received paracetamol and a non-steroidal anti-inflammatory drug. invasive monitoring was not utilized. post-operative pain in the initial recovery period was managed with morphine sulfate as required. once on the ward, patients received regular paracetamol, diclofenac and oxynorm as required. all of the patients were scheduled as the first case of the day to allow for clinical assessment by the consultant urologist before discharge in the evening of surgery. all cases were performed by an experienced surgeon who had performed > 100 lrps using the technique described by stolzenburg which utilizes extraperitoneal balloon dissection (8). extra attention was given to careful haemostasis which included the use of intracorporeal haemostatic adjuncts such as surgiflotm and surgiceltm. doi: 10.4081/aiua.2017.3.182 introduction since schuessler first described the technique over 20 years ago (1), laparoscopic radical prostatectomy (lrp) has been established as an effective minimally invasive surgical treatment option for localised prostate cancer with the advantages of decreased blood loss, decreased analgesic requirements and earlier hospital discharge and convalescence compared with open radical prostatectomy (2-6). hospital stays have shortened dramatically abboudi_stesura seveso 28/09/17 10:12 pagina 182 183archivio italiano di urologia e andrologia 2017; 89, 3 day case laparoscopic radical prostatectomy generally the use of drains was avoided. a leak test with 250cc of normal saline was always performed to guarantee a strong and watertight anastomosis and avoid anastomotic leak. no special restrictions were placed on resident or fellow participation, which received modular training as customary in teaching hospitals. post operatively patients were allowed to eat and drink as soon as they wished and early mobilization was encouraged. patients were provided with direct telephone contact details of the surgeon and specialist nurse in case of any early complications not recognized prior to discharge (appendix a). patients were followed up with a telephone consultation and questionnaire on the first day post-operatively to address safety concerns and accurate prospective capturing of complications. patients were specifically asked to score their level of post-operative pain and nausea and vomiting and satisfaction on a linear scale from 1-5 with 1 being no pain/very satisfied and 5 representing dissatisfaction and worst pain imaginable (appendix a). nurse led trial without catheter took place seven days post operatively where the catheter was removed without prior cystogram. routine catheter urine and midstream urine cultures were obtained to seek out proactively and treat infections at the time of catheter removal and again at first outpatient review. outpatient review was arranged early at 30 days for the same reason. all complications were classified according to the modified clavien-dindo system. results patient demographics, relevant pre-operative clinical and pathological data are illustrated (table 1). between june 2009 and december 2014, 353 laparoscopic radical prostatectomies were performed. of these 32 were deemed suitable for same day discharge. in total all 32 patients were discharged on the same day. the median time spent in hospital was 12 hours (7am to 7pm) and the latest discharge time was 8pm. mean total operative time (i.e. from skin to skin) was 147 minutes. the mean estimated blood loss was 101 ml. seven patients had bilateral pelvic lymph node dissection. there were no significant perioperative complications in this series of patients. in total six patients developed postoperative complications of which 4 required re-admission (table 2). three patients were treated for post-operative urinary tract infections; two patients developed infected lymphoceles which required percutaneous drainage and one patient required re-catheterization due to a burst catheter balloon (equipment failure). no events requiring general anaesthetic were observed (clavien 3b). sixteen of the 32 patients agreed to participate in the survey portion of the study. the other sixteen patients were not surveyed on day 1 postoperatively, but did not have any immediate issues on review of their medical records. all patients were discharged from hospital in the evening of their surgery without complication. table 1. demographic data and salient descriptive statistics of day case prostatectomy patients. day case patients (n = 32) age (years) 62 pre-op psa (ng/ml) 8.58 clinical stage (%) t1c 56 t2 a/b 31 t2c 13 pre op gleason sum (%) 3+3 = 6 41 3+4 = 7 50 4+3 = 7 3 4+5 = 9 6 operating time (min) 147 blood loss (ml) 101 transfusion rate 0 conversion 0 los (days) 0 table 2. clavien-dindo classification of complications for cohort. day case patients (n = 32) asa class 1 12 class 2 20 clavien none 0 1 0 2 3 3a 3 3b 0 4a 0 4b 0 5 0 figure 1. transverse ultrasound view of classic ‘crescent shape’ of the fascial layers splitting between ioam and tam on injection of local anaesthetic. abboudi_stesura seveso 28/09/17 10:12 pagina 183 archivio italiano di urologia e andrologia 2017; 89, 3 h. abboudi, p. doyle, m. winkler 184 all patients reported post-operative satisfaction scores of 1 (n-14) or 2 (n-2) out of 5. post-operative pain was deemed minimal in 14 out of 16, with one patient scoring their pain 3 out of 5 and one patient scoring their pain 4 out of 5. similarly day 1 nausea and vomiting was absent in all patients. functional outcomes were assessed at 3 months post lrp (table 3). twenty-seven patients were dry, whilst four patients were using 1-2 pads per day, and one patient required 3 or more pads per day. in terms of erectile dysfunction (ed) 14 patients were completely potent, nine patients had partial ed, four patients could not achieve erections and five patients were not interested in sexual activity. at 46 months median follow up 11 of the 32 patients showed evidence of biochemical recurrence, with no prostate cancer related deaths in the series. all eleven patients went on to have salvage radiotherapy. discussion there continues to be growing concern over the cost of national health services in the united kingdom. resources are limited and our aging population continues to expand. several studies have looked at the potential economic effect of laparoscopic versus open versus robotic surgery prostate cancer. robotic surgery adds significant additional costs to the hospital, with several studies showing cost advantages with laparoscopic over robotic prostate surgery when excluding case volume. our aim was to investigate whether the procedure could be performed as a same day surgical procedure, which to our knowledge has not been reported with respect to lrp. one night in hospital amounts to approximately £700 a night thus such a pathway amounts to a substantial saving if implemented safely. further theoretical cost advantages to the hospital include a greater reimbursement tariff for day case procedures over in-patient stay as well as the cost savings with regards to a hospital bed saving. with regards to the united kingdoms national health service, the aim should be to perform more day case prostatectomies in order to negotiate higher tariffs with the clinical commissioning groups so that hospitals could be reimbursed for an ‘outpatient prostatectomy’ and ultimately decrease overall costs. the authors recognize that this may not be applicable to other healthcare systems, however the benefits of reduced time in hospital such as early mobility, reduced infection risk and psychological benefits of being at home are transferrable to the wider healthcare community. the incentives for early discharge, however, must always be trumped by the patient’s best interest and thus there is a need to maintain a low threshold for admitting a patient following lrp. consequently careful case selection and a review by the senior operating surgeon prior to discharge should be mandatory. utilizing the extra-peritoneal approach minimizes the chances of post-operative ileus and other bowel complications and has the potential to reduce time in hospital. this was also shown with the robotically assisted approach in a small patient cohort (9). patients with a bmi > 30 are more likely to have surgical complications and pose challenges to the anaesthetist and surgeon alike. such patients lead to a more technically challenging dissection with narrowing of the operative field within the extraperitoneal space. we therefore opted to admit such patients for observation. we found that patients could be discharged home the same day of the surgical procedure if they met strict criteria that we set without increased perioperative complications. we also performed follow up satisfaction surveys and found that all patients who completed the survey were satisfied with their experience and that they stayed for the appropriate amount of time. the observed complications are in line with contemporary series except a high rate of infected lymphoceles in 2 of 7 patients with pelvic lymphadenectomy. this is reflected in a high readmission rate of 12%. we conclude that it is best to insert a post-operative drain for a minimum of 24 hours after extended lymphadenectomy and patients be given the choice of being discharged with the drain in situ or being admitted overnight for observation. we also acknowledge that in order to increase the yield of day case surgery candidates, including selected patients who have a drain left in situ as potential day case candidates would be safe. discharging patients with drains postoperatively is routine practice in some surgical disciplines and therefore should not preclude lrp patients from similar benefits. the success of this technique is in the standardized, team approach in the context of a well-motivated medically fit patient. it was realized early that the majority of pain arises from the anterior abdominal wall after extraperitoneal lrp. as such, minimizing post-operative pain through a transabdominal plane (tap) block within the pathway and sparing use of opioids to overcome postoperative nausea and vomiting have proved effective (7). the majority of patients only needed a combination of paracetamol and nsiads for post-operative pain. the probability of side effects from opioids for break-through pain was minimized by switching from tramadol (partial agonist and antagonist) to oxynorm, which has an improved side effect profile. we report the outcomes of a pilot cohort of patients, without a control group to compare to. we aim to conduct studies of suitable patients to further validate the findings reported. the percentage of patients surveyed was also low and thus any further studies should aim to have a higher participation from included patients. furthermore we utilized an unvalidated questionnaire tool that was constructed in house by the research team. in future validated surveys such as the patient judgment table 3. functional and oncological outcomes. continence number erectile number of patients dysfunction of patients dry 27 potent 14 1-2 pads/day 4 mild ed 9 3 or more pads/day 1 no erections 4 not interested in erections 5 total 32 32 abboudi_stesura seveso 28/09/17 10:12 pagina 184 185archivio italiano di urologia e andrologia 2017; 89, 3 day case laparoscopic radical prostatectomy system-24 (pjs-24) questionnaire should be utilized. the pjs-24 gives a global overall satisfaction with care rating and 9 multi-item satisfaction components. the pjs-24 has been validated for hospital quality assurance and shown to accurately reflect and capture issues of patients undergoing prostatectomy (10, 11). a cost analysis compared to the standard patient pathway would be a welcome addition to the literature and would provide further evidence for the feasibility of such a pathway. conclusion the early experience with extraperitoneal lrp with same day discharge home is promising. preoperative  patient  counselling and selection is paramount.  patient  satisfaction is not adversely affected by the shortened stay. surgeon experience, a well-motivated patient, meticulous attention to detail through an integrated pathway, a multidisciplinary team and adequate postoperative assessment are essential. references 1. schuessler w, schulam p, clayman r, kavoussi l. laparoscopic radical prostatectomy: initial short-term experience. urology. 1997; 50:854-7. 2. eden cg, neill mg, louie-johnsun mw. the first 1000 cases of laparoscopic radical prostatectomy in the uk: evidence of multiple “learning curves”. bju int. 2009; 103:1224-30. 3. rassweiler j, stolzenburg j, sulser t, et al. laparoscopic radical prostatectomy–the experience of the german laparoscopic working group. eur urol. 2006; 49: 113-19. 4. stolzenburg j, kallidonis p, minh d, et al. endoscopic extraperitoneal radical prostatectomy: evolution of the technique and experience with 2400 cases. j endourol. 2009; 23:1467-72 5. touijer k, eastham j, secin fp, romero otero j, et al. comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conducted in 2003 to 2005. j urol. 2008; 179:1811-17. 6. bhayani sb, pavlovich cp, hsu ts, et al. prospective comparison of short-term convalescence: laparoscopic radical prostatectomy versus open radical retropubic prostatectomy. urology. 2003; 61:612-16. 7. dudderidge t, doyle p, mayer e, et al. evolution of care pathway for laparoscopic radical prostatectomy. j endourol. 2012; 26:660-665. 8. stolzenburg j, kallidonis p, minh d, et al. endoscopic extraperitoneal radical prostatectomy: evolution of the technique and experience with 2400 cases. j endourol. 2009; 23:1467-1472. 9. martin a, nunez r, andrews j, et al. outpatient prostatectomy: too much too soon or just what the patient ordered. urology. 2010; 75:421-424. 10. litwin ms, shpall ai, dorey f. patient satisfaction with short stays for radical prostatectomy. urology. 1997; 49:898-906. 11. hays rd, larson c, nelson e, batalden p. hospital quality trends: a short-form patient-based measure. med care. 1991; 29:661-668. correspondence hamid abboudi, md mathias winkler, md mathias.winkler@imperial.nhs.uk department of urology, charing cross hospital, imperial college healthcare nhs trust london (uk) patrick doyle, md department of anaesthesia, charing cross hospital, imperial college healthcare nhs trust london (uk) abboudi_stesura seveso 28/09/17 10:12 pagina 185 stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12104 1 original paper 80% of cap cases are localized, and the survival rate for localized cases is over 99% (2). the treatment of localized cap involves a combination of modalities, and radiation therapy is a standard treatment option recognized as an alternative to radical prostatectomy. conventional normo-fractionated radiation therapy is the most commonly used treatment option for localized cap, but it has a major drawback: it requires a long treatment duration and repetitive patient’s displacement, which can cause fatigue and adding financial burden. short-term therapies with similar efficacy and toxicity to other radiation therapy techniques are needed. hypofractionated radiation therapy (2.4 to 3 gy) in cap is recommended by several scientific studies (3). advances in imaging and radiation therapy have led to the development of ultra-fractionated radiation therapy techniques, such as stereotactic body radiation therapy (sbrt). however, there is a lack of scientific evidence for sbrt in the treatment of localized cap. this study aims to present the clinical and biological results in terms of efficacy and tolerance of sbrt in localized cap, according to the experience of radiotherapy department of the casablanca cancer center (ccc) of the international university hospital cheikh khalifa. materials and methods study and patient characteristics this is a retrospective, descriptive, observational study conducted at a single center, which included 27 patients with localized prostate adenocarcinoma treated with curative intent using sbrt at the ccc radiotherapy department between 2017 and 2021. the median age of patients was 66 years, and the three quarters of the patients had a psa level less than 10 ng/ml. the gleason score was 6 in 59.3% of patients, 7 in 40.7%. regarding the tumor stage 14.8% were classified as t1 and 85,2% as t2. according to the d’amico classification, 33.3% of patients were low-risk, 51.9% were intermediate-risk, and 14.8% were high-risk (table 1). protocols and techniques the decision to treat with sbrt was made during multiintroduction: prostate cancer is the most common urological cancer, and its incidence is increasing. radical prostatectomy and radiotherapy are the primary treatments for localized forms. stereotactic body radiotherapy (sbrt), a new and innovative therapy, has been validated for some cancer localizations but not yet for localized prostate cancer. our study aims to report the efficacy and tolerance results of sbrt for localized prostate cancer. materials and methods: this is a retrospective study of 27 patients with localized prostate cancer (cap) who were treated with sbrt in our department from 2017 to 2021 using transponders for tumor tracking. the dose was 36.25 gy delivered in five fractions of 7.25 gy. the delineation and doses of organs at risk were determined based on the recommendations of the sfro and the tg101 report of medical physics. all patients were treated using a latest-generation linear accelerator (true beam stxò). results: acute toxicities were observed in 33.3% of cases, with 22.2% grade 1 or 2 genitourinary (gu) and no grade 3 while 11.1% gastrointestinal (gi) toxicities were reported as grade 1-2 (7.4%) and one case grade 3 (3.7%). late grade 1 or 2 gu toxicity was observed in 14.84% of cases, with no reports of late gi toxicity. after a 26-month follow-up period, the biochemical failure-free survival rate was 92.6%. conclusions: the results of our study are consistent with the existing literature and support the safety and effectiveness of sbrt as a treatment option for localized prostate cancer (cap). in the united states, both astro and the nccn recognize sbrt as a valid treatment option for localized cap. ongoing phase iii trials are being conducted to further substantiate these long-term results and to establish sbrt as the future standard of care for localized cap. key words: localized prostate cancer; stereotactic radiotherapy; toxicity; efficacy. submitted 17 november 2023; accepted 23 december 2023 introduction prostate cancer (cap) is a common cancer, with approximately 1.4 million new cases reported globally in 2020 (1). it accounts for 14.1% of all human cancers and is the fifth leading cause of cancer-related deaths, responsible for 375.000 deaths each year. in the united states, about revolutionizing localized prostate cancer treatment: stereotactic radiotherapy “moroccan experience” asmâa naim 1, 2, 3, zineb lahlou 1, 2, othmane kaanouch 3, 4, abdelajalil heddat 1, 2, 5, safae mansouri 6 1 faculty of medicine, mohammed vi university of sciences and health, casablanca, morocco; 2 research unit, mohammed vi center for research and innovation, rabat, morocco; 3 radiotherapy department of casablanca cancer center, university international hospital cheikh khalifa, casablanca, morocco; 4 hassan first university of settat, high institute of health sciences, laboratory of sciences and health technologies, bp 555, 26000, settat, morocco; 5 urology department, university international hospital cheikh khalifa, casablanca, morocco; 6 faculty of medicine, university hassan ii, casablanca, morocco. doi: 10.4081/aiua.2024.12104 summary archivio italiano di urologia e andrologia 2024; 96(1):12104 a. naim, z. lahlou, o. kaanouch, a. heddat, s. mansouri 2 disciplinary consultation meetings (rcps) for all patients. the first step in the sbrt treatment process involved the placement of three electromagnetic transponders, by an urologist under general anesthesia, by ultrasound guidance. in fact the urologist sets up two transponders at the base and one at the apex. these transponders were used to track the tumor during prostate irradiation with the calypso® repositioning system. patients were positioned in a supine position with their hands crossed on their chest and immobilized using restraints such as footrests, headrests, and logs under their knees. a simulation scan was then performed 6 to 15 days after transponder placement with average of 11 days, with sub-millimeter sections. the target volumes for treatment were determined based on the icru 91 report, which involved a systematic fusion of dosimetric scanner images and previously obtained prostate mri images. the gross tumor volume (gtv) corresponded to the clinical target volume (ctv) gtv=ctv (4), whereas the planning target volume (ptv) was defined by adding a 3 mm posterior safety margin and a 5 mm margin in other directions to the gtv/ctv. organs at risk (oars), including the bladder, rectum, urethra, penile bulb, anal canal, and right and left femoral heads, were delineated following the recommendations of the french society of oncological radiotherapy (sfro) (5). all patients received the dose of 36.25 gy in five fractions and were treated using a true beam stx linear accelerator with real-time automatic correction for target translational and rotational motion thanks to calypso® system. outcomes patients were monitored for treatment tolerance and effectiveness following each irradiation session. evaluations were done 1 month after treatment, every three months for the first year, every 6 months for the next 3 years, and annually thereafter. physicians reported any toxicities, which were classified as acute if they occurred within 90 days of treatment and late if they developed after 90 days, using ctcae v5 (6). the study's primary endpoint was the incidence of biochemical or clinical failure. biochemical recurrence was defined according to the phoenix criteria (7). overall survival was defined as death from any cause. results the entire tumor volume (ctv) received 100% of the prescribed dose, while the planning target volume (ptv) received 95% coverage. the dose constraints for the organs at risk (oars) were met for all patients (table 2) and the principals parameters of irradiation are summarized in table 3. table 3. irradiation parameters of our patients. mean maximum minimum prostate dose (gy) 36.25 36.25 36.25 fractionation (gy) 7.25 7.25 7.25 number of fractions 5 5 5 total duration of radiotherapy (days) 10 14 9 maximum dose (gy) 43.41 45.3 38.94 maximum dose (%) 119.9 125 111.3 minimum dose (gy) 34.47 37.3 30.39 minimum dose (%) 95.1% 102% 84% table 2. dose constraints for the organs at risk (oar) in our series. reference patients oar contraints constraints mean min max bladder v 18.3 gy < 15 cc 13.54 2.14 34 v 37 gy < 10 cc 0,7 0 2.16 v 35.5 gy < 5 cc 1 0 3.45 rectum v 25 gy < 20 cc 4.7 0.31 14 v 36.25 gy < 1 cc 0.43 0 1.77 v 36.25 gy < 5% 1 0 10 v 33.625 gy < 10% 3 0 11.74 v 29 gy < 20% 5 0.061 17 v 18.125 gy < 50% 17.69 3.48 44 d max = 38 gy 38 32 39.66 femoral heads v 30 gy < 10 cc 0 0 2 urethra v 47 gy < 20% 0 0 0 penile bulb v 30 gy < 3 cc 0 0 0.77 v 50 gy < 0.5 cc 0 0 0 v 29.5 gy < 50% < 0% 0 56 table 1. ppla score system for renal papillae (16). median age 66 years (53-76) initial psa data medium 8.9 ng (5-17) = 5 ng/ml 2 (7.4%) 5-10 ng/ml 18 (66.7%) 10.115 ng/ml 5 (18.5%) > 15 ng/ml 2 (7.4%) isup classification group 1 (3+3) 16 (59.3%) group 2 (3+4) 6 (22.2%) group 3 (4+3) 5 (18.5%) group 4 (4+4) 0 group 5 (4+5 ou 5+4) 0 tnm classification t1cn0m0 4 (14.8%) t2an0m0 11(40.8%) t2bn0m0 8 (29.6%) t2cn0m0 4 (14.8%) d’amico classification low risk 9 (33.3%) intermediate risk 14 (51.9%) high risk 4 (14.8%) androgen deprivation therapy (adt) yes 12 (44.5%) non 15 (55.5%) archivio italiano di urologia e andrologia 2024; 96(1):12104 3 stereotactic radiotherapy for prostate cancer acute toxicity during and after the 90 days of radiotherapy, we observed 29.6% grade 1-2 genitourinary (gu) and gastrointestinal (gi) toxicity, and one patient (3.7%) presented grade 3 acute gi toxicity exacerbated by an abscess treated surgically (table 4). late toxicity we observed 14.8% (n = 4) grade 2 late urinary toxicity, including urethral stricture resolved by drilling in 11.1% of patients and haematuria related to bladder cancer in one patient. no late gi toxicity was detected (table 4). biological control at 26 months, the biochemical relapse-free survival rate was 92.5% (n = 25), and two patients had a biological recurrence. all patients were alive when we performed our analysis except one who died by pulmonary embolism caused by associated lung cancer. discussion biological rationale the biologically equivalent dose (bed) formula is used to explain cell sensitivity to larger fraction sizes. the formula is bed = nd [1 + d/(α/β)], where n is the number of radiation fractions, and d is the dose size per fraction. the bed formula shows that increasing the dose per fraction, or hypofractionation, has a greater impact on tissues with a low α/β ratio compared to those with a high ratio. if the tumor's α/β ratio is lower than the surrounding tissues' α/β ratio (assumed to be between 3 and 5 for bladder and rectum), then increasing the dose per fraction will increase the bed for the tumor more than for the normal tissues, improving the therapeutic ratio. many publications suggest that the α/β ratio for cap is around 1.5 gy (8-11), indicating that hypofractionated radiotherapy may improve the efficacy of treatment. this differential sensitivity to fractionation between the tumor and normal tissue favors the use of hypofractionated radiotherapy for cap (12-13). furthermore, higher bed is associated with improved local control (14). benefits of sbrt in cap the radiobiological data indicate that sbrt is a more effective treatment for localized cap than conventional radiotherapy. moreover, sbrt provides several other benefits, including a reduction in treatment duration and better quality of life for patients due to fewer treatment sessions (15). sbrt is also more logistically cost-effective for radiation therapy departments and may have financial benefits in systems with fractional reimbursement. studies have shown that 5-fraction prostate sbrt is a cost-effective and non-invasive treatment with equivalent results to conventional radiotherapy or surgery without compromising patient safety (16). acute toxicity several trials have studied the acute toxicity of sbrt in patients with localized cap. our study found that nearly a quarter of patients had grade 1-2 gu acute toxicity and none had grade 3 or higher toxicity. two patients had grade 1-2 gi toxicity (bleeding, discomfort, or mucosal discharge), and one patient developed grade 3 acute gi toxicity (abscess) probably due to receiving a d100 on 10% of the rectal volume, which was higher than the group average. our results found the same conclusions reported in the literature (table 5). late toxicity several studies have examined the toxicity profiles of different radiotherapy treatments for cap, with a focus on sbrt. one study found that while sbrt and intensity-modulated radiation therapy (imrt) had similar rates of genitable 4. results of acute and late toxicities. acute toxicity acute toxicity late toxicity late toxicity grade 1-2 grade ≥ 3 grade 1-2 grade ≥ 3 gu cystitis 22.2% (6) 0% (0) 0% (0) 0% (0) hemorrhage 0% (0) 0% (0) 3.7% (1) 0% (0) urethral stricture 0% (0) 0% (0) 11.1% (3) 0% (0) gi proctitis 7.4% (2) 3,7 (1) 0% (0) 0% (0) table 5. results of trials on the efficacy of sbrt in localized prostate cancer. studies number endpoints dose ptv number α/β ratio allocated median brfs (%) of patients (gy) (gy) of fractions (gy) time (days) follow-up (month) sbrt conv. pace b (2012-2018) 874 toxicity 36.25 40 5 *7.25 7 à 14 60 on going ssrb hypo-rt-pt (2005-2015) 1200 toxicity ssrb 47.7 7 * 6.8 3 16 (15-17) 60 84% 84% qol sharp 2017 40 toxicity ssrb 33.5 5 *6.7 1.5 41 90% nc r.m. meier 309 toxicity ssrb 40 36,25 5 * 8 5 à 11 61 97.1% nc king and al. 2013 67 toxicity ssrb 32 94% nc katz and al. 2006-2009 67 toxicity ssrb qol 35 5*7.25 5 96 94.4% nc 36.25 93.4% jackson and al. 2013-2018 6000 toxicity ssrb 36.25 5*7.25 2.5 30 95.3% nc our study 27 toxicity ssrb 36.25 40 5*7.25 1.5 9 26 92.6% nc conv.: conventional; nc: not comparative; brfs: biological relapse-free survival; qol: quality of life. archivio italiano di urologia e andrologia 2024; 96(1):12104 a. naim, z. lahlou, o. kaanouch, a. heddat, s. mansouri 4 tourinary (gu) and gastrointestinal (gi) toxicities, sbrt patients had a higher risk of urinary fistula (17). another meta-analysis estimated rates of late grade 3 gu and gi toxicities over 5 years of follow-up (18). the hypo-rt-pc and pace b trials found no significant differences in late gu and gi toxicities between treatment groups, although the ultra-hypofractionation group in the former had an increase in gu toxicity at 1-year follow-up (19, 20). another study found that sbrt was associated with a higher rate of gu toxicity, potentially due to the lower α/β ratio in urinary tract tissue compared to gi tissue. ongoing trials are investigating the long-term toxicity and efficacy of sbrt in low and intermediate-risk cap patients (23). effectiveness of sbrt studies have indicated that ultra-hypofractionated radiotherapy, also known as sbrt, is a secure and efficient treatment option for patients with intermediate and highrisk localized cap (21-22).the randomized phase iii hypo-rt-pc trial and pace b trial have reported comparable recurrence-free survival rates with sbrt and conventional radiotherapy, indicating that sbrt may be a viable alternative for these patients (19-20). katz et al.'s research has also revealed outstanding long-term control with low toxicity, demonstrating sbrt's potential as a promising treatment option for localized cap (23). additionally, the multicenter study by meier et al. has shown higher rates of overall survival and biological control with sbrt when compared to imrt, reinforcing the demonstration of the efficacy of sbrt for cap treatment (17). although the addition of androgen deprivation therapy (adt) is recommended for unfavorable intermediaterisk patients, further research is needed to determine if sbrt alone can suffice (24). our findings exhibit a high degree of similarity to the results of the main trials, specifically in terms of biological relapse-free survival (brfs), as indicated in table 6. conclusions stereotactic radiotherapy (sbrt) has emerged as a recent treatment option for managing localized cap and offers a multitude of benefits, including radiobiological, logistical, and financial advantages. numerous studies have demonstrated that sbrt is comparable to conventionally fractionated radiotherapy for intermediate to high-risk cap patients. this treatment has the potential to achieve satisfactory levels of acute and late genitourinary and gastrointestinal toxicity, consistent with radiobiological principles. our findings indicate that ultra-hypofractionation should be regarded as a safe and effective treatment for localized cap. at present, several phase iii trials are ongoing to validate sbrt as the best standard treatment for all localized cap, such as the sparc trial and pace c. however, the potential advantages of combining androgen deprivation therapy with sbrt remain unclear. acknowledgments we thank all the staff of department of radiotherapy and urology hospital international cheikh khalifa, casablanca, morocco. we thank all the staff of medical physics of cheikh khalifa international hospital, casablanca, morocco: kamal saidi, hanae elgouach. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021; 71:209-49. 2. siegel rl, miller kd, jemal a. cancer statistics, 2017. ca cancer j clin. 2017; 67:7-30. 3. langrand-escure j, de crevoisier r, llagostera c, et al. dose constraints for moderate hypofractionated radiotherapy for prostate cancer: the french genito-urinary group (getug) recommendations. cancer/radiothérapie. 2018; 22:193 8. 4. wilke l, andratschke n, blanck o, et al. icru report 91 on prescribing, recording, and reporting of stereotactic treatments with small photon beams. strahlenther onkol. 2019; 195:193-8. 5. noël g, antoni d, barillot i, chauvet b. délinéation des organes à risque et contraintes dosimétriques. cancer/radiothérapie. 2016; 20:s36-60. 6. freites-martinez a, santana n, arias-santiago s, viera a. using the common terminology criteria for adverse events (ctcae table 6. study results of acute sbrt toxicity in localized cap. studies number endpoints dose ptv number α/β ratio allocated acute gu toxicity acute gi toxicity of patients (gy) (gy) of fractions (gy) time (days) sbrt conv. sbrt conv. pace b (2012-2018) 874 toxicity 36.25 40 5 * 7.25 7 à 14 g2: 23.2% g2: 27.2% g2: 10.1% g2: 12.1% ssrb hypo-rt-pt (2005-2015) 1200 toxicity 47.7 7 * 6.8 3 16 (15-17) g2: 28% g2: 23% g2: 10% g2: 7% ssrb qol sharp 2017 40 toxicity 33.5 5 * 6.7 1.5 g2: 20.5% nc g2: 13% nc ssrb r.m. meier (20) 309 toxicity 40 36.25 5 * 8 5 à 11 g2: 26% nc g2: 8% nc ssrb our study 27 toxicity 36.25 40 5 * 7.25 1.5 9 g1-2: 22.2 nc g1-2: 7.4% nc ssrb g3: 3.7% conv.: conventional; nc: not comparative; ssrb: biological relapse-free survival; qol: quality of life. archivio italiano di urologia e andrologia 2024; 96(1):12104 5 stereotactic radiotherapy for prostate cancer version 5.0) to evaluate the severity of adverse events of anticancer therapies. actas dermosifiliogr (engl ed) 2021; 112:90-2. 7. roach m, hanks g, thames h, et al. defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the rtog-astro phoenix consensus conference. int j radiat oncol biol phys. 2006; 65:965-74. 8. fowler j, chappell r, ritter m. is alpha/beta for prostate tumors really low? int j radiat oncol biol phys. 2001; 50:1021-31. 9. leborgne f, fowler j, leborgne jh, mezzera j. later outcomes and alpha/beta estimate from hypofractionated conformal three-dimensional radiotherapy versus standard fractionation for localized prostate cancer. int j radiat oncol biol phys. 2012; 82:1200-7. 10. brenner dj, martinez aa, edmundson gk, et al. direct evidence that prostate tumors show high sensitivity to fractionation (low α/βratio), similar to late-responding normal tissue. int j radiat oncol biol phys. 2002; 52:6-13. 11. miralbell r, roberts sa, zubizarreta e, hendry jh. dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β = 1.4 (0.9-2.2) gy. int j radiat oncol biol phys. 2012; 82:e17-24. 12. avkshtol v, dong y, hayes sb, et al. a comparison of robotic arm versus gantry linear accelerator stereotactic body radiation therapy for prostate cancer. res rep urol. 2016; 8:145-58. 13. zaorsky ng, palmer jd, hurwitz md, et al. what is the ideal radiotherapy dose to treat prostate cancer? a meta-analysis of biologically equivalent dose escalation. radiother oncol. 2015; 115:295-300. 14. boustani j, grapin m, laurent pa, et al. the 6th r of radiobiology: reactivation of anti-tumor immune response. cancers. 2019; 11:860. 15. dee ec, muralidhar v, arega ma, et al. factors influencing noncompletion of radiation therapy among men with localized prostate cancer. int j radiat oncol biol phys. 2021; 109:1279-85. 16. lischalk jw, kaplan id, collins sp. stereotactic body radiation therapy for localized prostate cancer. cancer j. 2016; 22:307-13. 17. meier rm, bloch da, cotrutz c, et al. multicenter trial of stereotactic body radiation therapy for lowand intermediate-risk prostate cancer: survival and toxicity endpoints. int j radiat oncol biol phys. 2018; 102:296-303. 18. pan hy, jiang j, hoffman ke, et al. comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. j clin oncol. 2018; 36:1823-1830. 19. brand dh, tree ac, ostler p, et al. pace trial investigators. intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (pace-b): acute toxicity findings from an international, randomised, open-label, phase 3, noninferiority trial. lancet oncol. 2019; 20:1531-1543. 20. widmark a, gunnlaugsson a, beckman l, et al. ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the hypo-rt-pc randomised, non-inferiority, phase 3 trial. lancet. 2019; 394:385 95. 21. madsen bl, hsi ra, pham ht, et al. stereotactic hypofractionated accurate radiotherapy of the prostate (sharp), 33.5 gy in five fractions for localized disease: first clinical trial results. int j radiat oncol biol phys. 2007; 67:1099-105. 22. jackson wc, silva j, hartman he, et al. stereotactic body radiation therapy for localized prostate cancer: a systematic review and meta-analysis of over 6,000 patients treated on prospective studies. int j radiat oncol biol phys. 2019; 104:778-789. 23. katz a. stereotactic body radiotherapy for low-risk prostate cancer: a ten-year analysis. cureus. 2017; 9:e1668. 24. bian sx, kuban da, levy lb, et al. addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer. ann oncol. 2012; 23:2346 52. correspondence asmaa naim, md doc.a.naim@gmail.com zineb lahlou, md lahlouzineb@outlook.fr faculty of medicine, mohammed vi university of sciences and health, casablanca, morocco othmane kaanouch, md othmane.kaanouch@gmail.com radiotherapy department of casablanca cancer center, university international hospital cheikh khalifa, casablanca, morocco hassan first university of settat, high institute of health sciences, laboratory of sciences and health technologies, bp 555, 26000, settat, morocco abdeljalil heddat, md abdeljalilheddat@yahoo.fr faculty of medicine, mohammed vi university of sciences and health, casablanca, morocco safae mansouri, md m-safae@hotmail.fr faculty of medicine, university hassan ii, casablanca, morocco conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11528 1 original paper introduction one of the most common birth anomalies in children is undescended testis (udt), with estimates ranging from 1 to 4.6% of full-term newborn males affected by one or both testes failing to descend (1). congenital udt is caused by the failure of the first or second stage of testicular descent. some theories about the causes of udt include primary testicular hormonal dysfunction, secondary hormonal dysfunction (hypothalamic-pituitary axis deficiency or placental failure to produce chorionic gonadotropin), and anatomical defects in the mechanism of descent (2). testicular maldevelopment in children with udt is characterized by disturbed tubular structure, mainly by decreased germ cells and quantitative and qualitative changes in the leydig cells. these tubular alterations are detectable from the udt's first or second year of life (3). the histologic disturbances in the udt might be related to the increased testicular exposure to elevated extra scrotal temperature (4). intra-abdominal testis with a short spermatic cord that does not allow the surgeons to place it in the scrotum represents approximately 30% of all udt cases (5). there is no consensus regarding the best operation because of the testicular artery and vein length, which limits the distal placement of the testis into the scrotum. for these particular cases, the surgical solution proposed is first-stage superficial inguinal orchiopexy, then scrotal orchiopexy, tow-stage laparoscopic fowler-stephens orchiopexy, and/or autotransplantation (6). the testis's temperature is 2 to 4°c below the core body (6). scrotal thermoregulation serves to liberate the large amount of heat produced during spermatogenesis. several supporting mechanisms like thin skin with abundant vascularization, numerous sweat glands, and the absence of subcutaneous fat facilitate heat exchange and maintain the testicular temperature below body temperature (7). purpose: in this study, we aimed to build a 3d reconstruction computed simulation model and to establish a regression equation for detecting the testis's temperature by its location after first staged open orchidopexy in children with abdominal undescended testis (udt) and short spermatic cords. methods: in this cross-sectional study, we enrolled 31 children with abdominal udt and short spermatic cords who underwent first staged orchiopexy between 2017 and 2020. using ultrasonography to obtain the testis's location distance from the skin surface (x1), external iliac vessel (x2), and internal inguinal ring (x3), we input the data into a 3d reconstruction computed simulation along with comsol to calculate the testicular temperature. we also used multivariate regression to establish the testicular temperature regression equation from the gathered data. result: the mean age of the participants was 4.47 ± 1.21 years. the mean size of the operated testis was 0.39 ± 0.13 cc. the mean distance of the testis from x1, x2, and x3 was 3.27 ± 1.25 mm, 21.06 ± 6.42 mm, and 27.19 ± 10.09 mm, respectively. the testicular temperature regression equation derived from testis location was calculated by the formula: 34.57 + 0.0236 x1 2 0.0105 x2 0.0018 x3. the concordance for testis temperature calculated via the computational method and regression equation was 83%. conclusions: the current study provided a reference value for the testicular temperature of children with abdominal udt and short spermatic cords after the first stage of orchiopexy. a testicular temperature regression equation can be established based on the testis location, which will provide relevant information for the testicular development assessment, disease diagnosis, and follow-up, and possibly determination of the time of the second stage of orchiopexy. key words: abdominal testis; temperature; short spermatic cord; finite element; referential values; simulation method. submitted 1 july 2023; accepted 27 july 2023 reference value of testicular temperature measured by finite element analysis after first staged inguinal orchidopexy in children with abdominal testis and short spermatic cord mehdi shirazi 1, 2, ali eslahi 1, 3, mohsen ostovari 4, faisal ahmed 5, ahmed zaid 1, mohammad reza askarpour 1, hossein-ali nikbakht 6, zeinab gholami 7, sania shirazi 8 1 department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 2 histomorphomettery and stereology research center, shiraz university of medical sciences, shiraz, iran; 3 shiraz geriatric research center, shiraz university of medical sciences, shiraz, iran; 4 department of medical physics and biomedical engineering, school of medicine, shiraz university of medical sciences, shiraz, iran; 5 department of urology, school of medicine, ibb university, ibb, yemen; 6 social determinants of health research center, department of biostatics and epidemiology, faculty of medicine, babol university of medical sciences, babol, iran; 7 department of radiology, school of medicine, shiraz university of medical sciences, shiraz, iran; 8 student research committee, shiraz university of medical sciences, shiraz, iran. doi: 10.4081/aiua.2023.11528 summary archivio italiano di urologia e andrologia 2023; 95(3):11528 m. shirazi, a. eslahi, m. ostovari, et al. 2 in udt patients, monitoring the testis's temperature can provide valuable information for assessing disease progression and therapeutic efficacy and might help choose optimal surgery timing. however, it is impossible to measure temperature distribution directly inside the human body to validate simulation because of ethical considerations. alternative approaches have been proposed to model scrotal cutaneous thermoregulation based on the automatic control theory, such as the computed tomographybased finite element model (ct-fem) (8, 9). pham et al. used comsol fem for the thermal simulation of testis to understand the dynamics of temperature change with time and location throughout the testicle after heat was applied to the surface of the testicle (10). few detailed studies on the testis's temperature have been performed in the superficial inguinal region after the first stage of open orchiopexy. the anatomical heterogeneity and the diverse geometry of the testis in the superficial inguinal area make it impossible to accurately predict the testis's temperature in this location with the usual methods (11). the present study aimed to build a 3d reconstruction computed simulation model and to establish a regression equation for detecting the testis's temperature by its location after first staged open orchidopexy in children with abdominal (udt) and short spermatic cords. materials and methods the ethics committee of shiraz university of medical sciences approved the study protocol (ir.sums.med.rec.1397. 598) which was in accordance with the declaration of helsinki. additionally, each participant’s family provides written informed consent. study design in this retrospective cross-sectional study, from june 2017 to june 2020, we enrolled 31 patients with previous abdominal udt and short spermatic cord that underwent the first stage of superficial inguinal orchiopexy at least six months prior to selection in shiraz university hospital (shaheed faghihi hospital, ali asghar hospital, and namazi hospital). exclusion criteria patients with congenital anomalies, scrotal orchidopexy, previous orchiectomy, prior hernia surgery, or other pathological conditions affecting the development of the external genitalia were excluded. a computational model for calculating the testis temperature it is impossible to directly measure temperature distribution inside the human body to validate simulation due to ethical considerations. in this study, we used a computed tomography-based finite element model to estimate the temperature inside the body. this method consisted of several steps, which can be described as follows: 1. measuring essential and influential parameters of the testis using ultrasonography (us) imaging: before performing an inguinal testis ultrasound examination, adequate reassurance was given. the patients were placed in a supine position and covered with a towel. palpation was performed to assess the testis in the superficial inguinal area. a us system with high-frequency broadband linear transducer (10 mhz) and high resolution (ws850; samsung, seoul, south korea) was used to determine the structure and volume of the testis. testis's volume was calculated using the ellipsoid formula: (volume = 0.523 × length × thickness × width). the testis's structure was assessed in grayscale with the same gain, focus, and depth settings. measurements of the distance were taken by the testis's distance from the skin surface (x1), external iliac vessel (x2), and internal inguinal ring (x3) to the testis. table 1 shows these measurement results. 2. building a computational phantom: to build the model, we used a computed tomography (ct) scan of a patient, and using image segmentation and image processing methods, different organs in the abdominal and inguinal areas were segmented from ct images. the entire image set consisted of 250 ct image slices, each 3 mm in slice thickness and of a matrix size of 512 × 512 pixels (12, 13). then, the segmented anatomical regions were used to create a 3d model (able software, lexington, ma) using mimics innovation suite software toolbox. after that, the 3d model was transformed into 3-matics software to generate a computational volumetric model. 3. examining the equations and heat transfer in the computer model using comsol software: to solve the heat transfer equations and calculate the temperature of different parts, we converted the computational model created by 3-matics software into executable formats in the comsol software (12, 14). then, the initial processing of these models was performed to solve the heat transfer equations (15). the final model consisted of the skin surface (x1), external iliac vessel (x2), internal inguinal ring (x3), and testis, and the area between them was filled with soft tissue with specific thermodynamic properties to better represent the testis environment in the patient’s body (16). also, the outside ambient temperature, abdominal cavity temperature, iliac artery temperature, and skin surface temperature in the upper scrotal region were considered based on previous studies to be 27°c, 37°c, 36.5°c, and 32°c, respectively (17). using these constant temperature regions and solving the bio-heat equation with the finite element method in comsol software, the temperature of other parts inside the abdomen, testis, and soft tissue around it were calculated. for each patient, the parameters of the testis distance from the skin surface (x1), external iliac vessel (x2), internal inguinal ring (x3), and testis volume were applied in a computational model. (figure 1). 4. establish a regression equation: in order to establish an equation between the parameters measured in the us imaging and the temperature calculated for the testis in a computer simulation, we sought consultation with a statistician. we were advised to use a multivariate regression statistical model (table 1). 5. statistical analysis: statistical analysis was performed archivio italiano di urologia e andrologia 2023; 95(3):11528 3 finite element analysis for testicular temperature using spss (ibm spss, version 22, armonk, new york: ibm corp). descriptive statistics for variables were calculated as mean and standard deviation. multivariate linear regression was used to estimate the relationship between the measured variables with us (distance from skin surface, iliac vessels, and internal inguinal ring) and testis temperature calculated with computer simulation. then, mathematical formula was represented by an equation. this analysis presented standard and non-standard regression coefficients and their 95% confidence interval. finally, bland-altman plots and pitman’s tests were applied to compare and agree for two temperatures checked by simulation and mathematical formula assessment methods. p-values less than 0.05 were considered significant. results the mean age of the participants was 4.47 ± 1.21 years (range 2.5-7 years). 11 (35.5%) children had left udt, while 20 (64.5%) children had right udt. the mean size table 1. data of the testis volumes, temperatures, and the distance from variable locations in all the patients. figure 1. (a and b): a computer model created in comsol software. no distance from external iliac distance from internal inguinal distance from the skin testis temperature by computer testisvolume testis temperature by fitting vessels (mm) ring (mm) surface (mm) simulation (°c) (ml) formula* (°c) 1 22 11 7 35.44 0.24 35.48185411 2 9 8 3 34.73 0.23 34.67952861 3 24 35 2 34.51 0.56 34.35409452 4 16 29 5 35.02 0.34 34.94528678 5 13 17 2 34.5 0.29 34.50285529 6 32 21 2.3 34.32 0.64 34.32592489 7 21 30 4.5 34.82 0.28 34.77862047 8 5 8 2.2 34.65 0.55 34.62340101 9 12 17 4 34.85 0.37 34.79679894 10 19 18 5 35.04 0.62 34.93381565 11 23 18 2.3 34.43 0.49 34.4261874 12 25 39 5.6 35.06 0.67 34.98242921 13 19 41 1.8 34.29 0.42 34.377823 14 24 19 3 34.52 0.45 34.50144957 15 17 28 3.5 34.64 0.37 34.63545896 16 22 31 2.5 34.4 0.36 34.43561217 17 25 30 2.3 34.35 0.22 34.38317657 18 18 12 4.5 34.88 0.37 34.84313672 19 16 23 3.5 34.81 0.27 34.65513524 20 30 37 2 34.33 0.42 34.28725284 21 18 28 3 34.54 0.29 34.54817069 22 25 39 1.9 34.25 0.38 34.32703646 23 19 23 4 34.35 0.34 34.71211013 24 27 35 2.3 34.3 0.73 34.35296973 25 24 28 3.8 34.43 0.39 34.61346789 26 34 39 2 34.25 0.25 34.2414723 27 18 30 3 34.53 0.31 34.5445124 28 25 34 2.9 34.42 0.35 34.4495474 29 22 39 3 34.68 0.45 34.48592786 30 30 41 3.5 34.64 0.24 34.47478277 31 19 35 4 34.41 0.25 34.69016043 * the formula is: t(°c) = 34.57 + 0.0236 x1 2 0.0105 x2 0.0018 x3. archivio italiano di urologia e andrologia 2023; 95(3):11528 m. shirazi, a. eslahi, m. ostovari, et al. 4 of the operated testis was 0.39 ± 0.13 ml (ranging from 0.22-0.73 ml). the mean distances of the testis from the skin surface, external iliac vessel, and internal inguinal ring were 3.27 ± 1.25 mm, 21.06 ± 6.42 mm, and 27.19 ± 10.09 mm, respectively. the mean testis temperature was 34.59 ± 0.28°c (ranged 34.25-35.44°c). table 2 demonstrates the patient and testis characteristics (table 2). establish a regression equation using multivariate regression, the testicular temperature regression equation derived from its location was calculated by the formula: t = 34.57 + 0.0236 x1 2 0.0105 x2 0.0018 x3 (equation. 1) while x1 = distance from skin (mm), x2 = distance from iliac vessels (mm), x3 = distance from the internal inguinal ring (mm), t = temperature of testes center (°c). prediction of the simulation method using linear regression the results showed that the three measured variables (distance from skin, iliac vessels, and internal inguinal ring) together predicted 83% of the testis's temperature changes, which was statistically significant (table 3). also, the results showed that the distance from the skin surface variable had a robust and positive correlation with the simulated temperature of the testes. also, the iliac vessels had a low inverse correlation with the simulated temperature, which was statistically significant. however, the internal inguinal ring had a weak inverse correlation, which was insignificant and had a minor role in prediction. the bland-altman plot from standard and formula limits of agreement for temperatures were between -0.229 to 0.240, with a mean difference of 95% ci: 0.005 (-0.038 to 0.048) and a range of 34.24 to 35.45. the spread around the mean for temperatures shows consistent variations across all levels, and only a few participants fell outside the limit of the agreement. the mean difference was not associated with the means of the two methods, confirming an acceptable level of agreement (pitman's test of difference invariance: r = 0.223, n = 31, p = 0.229) (figure 2). discussion to our knowledge, this is the first series of pediatric orchiopexies reported from a single institution, and the table 2. characteristics of the patients and testis (n = 31). variables mean ± sd (range) mean age (years) 4.47 ± 1.21 (2.5-7) mean testis size (ml) 0.39 ± 0.13 (0.22-0.73) mean testis temperature (°c) * 34.59 ± 0.28 (34.25-35.44) mean distance from the skin surface (mm) 3.27 ± 1.25 (1.8-7) mean distance from iliac vessels (mm) 21.06 ± 6.42 (5-34) mean distance from internal inguinal ring (mm) 27.19 ± 10.09 (8-41) table 3. the relationship between simulated testis temperature and three measurement indicators. variable coefficients (b) standard error beta 95% confidence interval p-value lower upper distance from the skin (mm) 2 0.024 0.002 0.823 0.019 0.028 0.000 distance from iliac vessels (mm) -0.011 0.004 -0.237 -0.020 -0.001 0.026 distance from the internal inguinal ring (mm) -0.002 0.003 -0.065 -0.008 0.004 0.538 multiple r = 0. 912; r square = 0.832; adjusted r square = 0.813. figure 2. a: scatter plots for temperatures between the simulation method and mathematical fitting formula; pearson's correlation (r = 0.912, p = < 0.001), b: bland-altman plot for agreement of temperatures checked by the simulation method and mathematical fitting formula. archivio italiano di urologia e andrologia 2023; 95(3):11528 5 finite element analysis for testicular temperature first to be accompanied by a finite element model for assessing the testicular temperature and establishing a regression equation by its location after open first staged superficial inguinal orchiopexy in children with abdominal udt and short spermatic cords. our model provides great value for the testicular development assessment, and it may be possible to decide on the time of the second stage of orchiopexy. the thermal modeling of human tissue is important as a tool to investigate the effect of external heat sources and to predict abnormalities in the tissue. the modeling of heat transport in human tissue was first introduced by pennes based on the heat diffusion equation (18). the equation is normally called pennes’ bioheat equation and is frequently used for the analysis of heat transfer in human tissues. the topic of temperature increase in human tissue after exposure to electromagnetic waves has been of interest for several years. there are some experimental studies in animals such as rats, cows, and pigs (9). however, the results may not represent the practical behavior of human tissues. finite element image evaluation of the scrotal surfaces is an easy and quick solution, shown to be a practical, noninvasive, and risk-free technique, as was previously shown for other species (9, 19). wessapan et al. developed a 3d model of the human head to investigate the specific absorption rate and temperature distributions in the human head and testis during exposure to mobile phone radiation (9, 19). keangin et al. carried out a numerical simulation of liver cancer treated using a complete mathematical model that considered the coupled model of electromagnetic wave propagation and heat transfer (20). although many advanced transport models of biological tissue have been proposed, the minimum data requirement and easy implantation of pennes’ bioheat model, still make it a good approximation and a widely used model of heat transfer in biological tissues. in this study, a case of simulated results was validated against the results with the model studied by kang et al. (11). we used the computer simulation method to evaluate the testis parameters of udt patients and the relationships of these variables with testis temperatures. according to this method, it has been reported that the counter-current heat-exchange mechanism involving the spermatic artery and the pampiniform plexus represents the primary system that controls the testis' temperature to preserve normal spermatogenesis (21). a computerassisted model of the counter-current heat-exchange mechanism at the testicular vascular pedicle simulates the normalization of the upset heat-exchange gradient mechanism through the correction of the physical parameters and, consequently, the rheology of the blood flow in the pampiniform plexus, considering the testis as a reservoir for space-variable, time-constant heat dissipation (22). in our study, the testis temperature was not correlated with age and testis volume. in the same manner, mieusset et al. reported that the testis temperature was not associated with age, empty intra-scrotal cavity, and the simultaneous rectal temperature (3). kenneth et al. measured the intratesticular and scrotal skin temperatures in 34 men who had undergone scrotal or inguinal surgical procedures. scrotal temperatures were measured before and after a dry scrotal shave. the intratesticular temperature was measured under direct vision with a needle thermistor, revealing a strong correlation between the intratesticular and scrotal skin temperatures. these observations suggest that scrotal skin temperature measurements might help detect elevations of intratesticular temperature (23). similarly, our result showed that the distance from the external iliac vessel and skin surface had a more significant effect on the testis temperature (p = 0.0012, 0.0037), respectively. the positive correlation between the testis temperature and distance from the skin surface and the external iliac vessel reveals the interdependence between the scrotum areas in the testis thermoregulation, which was in line with the result of ruediger et al. study (24). in our study, the correlation between the temperatures of the testis and the distance from the internal inguinal ring was less significant in comparison to other parameters that affect the testis temperature (p = 0.1943). this poor correlation can be explained by a lesser heat exchange area. according to kastelic et al., the ambient temperature had a significant effect on the temperature of the lower region of the scrotum, a negligible impact on the temperature of the upper region, and an intermediate effect on the temperature of the middle region of the scrotum (25). the dominant process in the heat energy transfer between the testis and their surroundings is the heat conduction process. the following equation expresses the rate of heat transfer: ∆𝑄 = -𝑘𝐴𝛻𝑻 (equation. 2) ∆𝑡 k is the conductivity coefficient, a is the contact crosssection, and is the temperature gradient. the negative sign in this formula indicates that heat transfers from the higher temperature region to the lower temperature region. the temperature gradient (𝛻t) is defined as the temperature ratio of two environmental points to their spatial distance (26, 27). since, in udt patients, heat transfer through the testis and temperature reduction is disrupted, we aim to find the location that provides better heat emission to cool down the testis. in the abdomen, heat sources are the main arteries and the body's core region in the thermoregulation system that have a temperature higher than that of the testicles, and the heat sink area is the skin surface through which heat energy is transferred out of the body. during udt surgery, it is impossible to change such parameters as thermal conductivity (k) and the cross-sectional area of the testis and the surrounding tissues (a), whereas the location of the testis is the only parameter that the surgeon can adjust. the surgeon can control the temperature gradient by changing the distance between the testicles and the heat sources or the heat sinks. there is a temperature gradient between the testis and the three areas of the internal inguinal ring, external iliac vessel, and skin surface. the temperature of the external iliac vessel and the internal inguinal ring are equal to the core body temperature and higher than the temperature of the testis, but the temperature of the skin surface is close to the ambient temperature and is lower than that of the testis (6). the results of this study show that among the three archivio italiano di urologia e andrologia 2023; 95(3):11528 m. shirazi, a. eslahi, m. ostovari, et al. 6 parameters of distance from the skin surface (x1), distance from the iliac vessel (x2), and distance from the internal inguinal ring (x3), the x1 parameter has more influence on the testicular temperature than others. in equation 1, the coefficient of x1 is positive, so when the distance from the skin decreases, the central temperature of the testis decreases. therefore, the most suitable position to place the testicles is the closest distance from the skin. equation 1 also shows that between x2 and x3, the influence of the x2 on the testis temperature is more dominant than x3. the coefficients of x2 and x3 are negative. therefore, the proper position is the one that is farthest from the iliac arteries and internal inguinal ring. this study had several limitations, such as its retrospective nature, the lack of a control group, and the small sample size. also, the testis size before surgery and contralateral intra-scrotal testis temperatures in children were not checked. we detected the heterogenicity of the testis size and age among the patients. the period between surgery and temperature checking was six months at least. therefore, this is just an observational report requiring validation with a large sample size and randomized criteria. because the thermal factors involved in the heat exchange of children’s environment are not all determinable, these models are valuable only when the children's thermal conditions and environment are both known or may be controlled. conclusions the current study provided a reference value for the testicular temperature of boys with abdominal udt and short spermatic cords after the first stage of orchiopexy. a testicular temperature regression equation derived from its location can be established, which will provide relevant information for the testicular development assessment, disease diagnosis, and follow-up, and possibly for deciding on the time of the second stage of orchiopexy. acknowledgments the authors would like to thank shiraz university of medical sciences, shiraz, iran, the center for development of clinical research of nemazee hospital, and dr. nasrin shokrpour for editorial assistance. references 1. kurz d. current management of undescended testes. curr treat options pediatr. 2016; 2:43-51. 2. hutson jm, li r, southwell br, et al. germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism? front endocrinol (lausanne). 2012; 3:176. 3. mieusset r, fouda pj, vaysse p, et al. increase in testicular temperature in case of cryptorchidism in boys. fertil steril. 1993; 59:1319-21. 4. humphrey g, najmaldin a, thomas d. laparoscopy in the management of the impalpable undescended testis. br j surg. 1998; 85:983-5. 5. wang cy, wang y, chen xh, et al. efficacy of single-stage and two-stage fowler-stephens laparoscopic orchidopexy in the treatment of intraabdominal high testis. asian j surg. 2017; 40:490-4. 6. shiraishi k, takihara h, matsuyama h. testicular temperature and the effects of orchiopexy in infants with cryptorchidism. j urol. 2021; 206:1031-7. 7. ismail e, orlando g, pompa p, et al. time-domain analysis of scrotal thermoregulatory impairment in varicocele. front physiol. 2014; 5:342. 8. imai k. computed tomography-based finite element analysis to assess fracture risk and osteoporosis treatment. world j exp med. 2015; 5:182-7. 9. wessapan t, rattanadecho p. temperature induced in the testicular and related tissues due to electromagnetic fields exposure at 900 mhz and 1800 mhz. int j heat mass transf. 2016; 102:1130-40. 10. pham s, schultz js. testicular thermoregulation with respect to spermatogenesis and contraception. j therm biol. 2021; 99:102954. 11. kang z, wang f, udayraj. an advanced three-dimensional thermoregulation model of the human body: development and validation. int commun heat mass transf. 2019; 107:34-43. 12. gür y. additive manufacturing of anatomical models from computed tomography scan data. mol cell biomech. 2014; 11:249-58. 13. zukowska m, rad ma, górski f. additive manufacturing of 3d anatomical models-review of processes, materials and applications. materials (basel). 2023; 16:880. 14. sander im, mcgoldrick mt, helms mn, et al. three-dimensional printing of x-ray computed tomography datasets with multiple materials using open-source data processing. anat sci educ. 2017; 10:383-91. 15. steinberger a. effects of temperature on the biochemistry of the testis. in: zorgniotti aw, editor. temperature and environmental effects on the testis. boston, ma: springer us; 1991. p. 33-47. 16. popovic m, pantovic pavlovic m, pavlovic m. ghosts of the past: elemental composition, biosynthesis reactions and thermodynamic properties of zeta p.2, eta b.1.525, theta p.3, kappa b.1.617.1, iota b.1.526, lambda c.37 and mu b.1.621 variants of sars-cov2. microb risk anal. 2023; 24:100263. 17. taylor na, tipton mj, kenny gp. considerations for the measurement of core, skin and mean body temperatures. j therm biol. 2014; 46:72-101. 18. pennes hh. analysis of tissue and arterial blood temperatures in the resting human forearm. 1948. j appl physiol (1985). 1998; 85:5-34. 19. siriwitpreecha a, rattanadecho p, wessapan t. the influence of wave propagation mode on specific absorption rate and heat transfer in human body exposed to electromagnetic wave. int j heat mass transf. 2013; 65:423-34. 20. keangin p, rattanadecho p, wessapan t. an analysis of heat transfer in liver tissue during microwave ablation using single and double slot antenna. int j heat mass transf. 2011; 38:757-66. 21. sheehan mm, ramasamy r, lamb dj. molecular mechanisms involved in varicocele-associated infertility. j assist reprod genet. 2014; 31:521-6. 22. tritto g. computer-assisted simulation model of the counter-current heat-exchange mechanism at the testicular vascular pedicle. proceedings of the annual international conference of the ieee engineering in medicine and biology society; 1988 4-7 nov. 1988. archivio italiano di urologia e andrologia 2023; 95(3):11528 7 finite element analysis for testicular temperature 23. kurz kr, goldstein m. scrotal temperature reflects intratesticular temperature and is lowered by shaving. j urol. 1986; 135:290-2. 24. de ruediger fr, chacur mgm, alves fcpe, et al. digital infrared thermography of the scrotum, semen quality, serum testosterone levels in nellore bulls (bos taurus indicus) and their correlation with climatic factors. j semina: ciências agrárias. 2016; 37:221-32. 25. kastelic j, cook r, coulter g, et al. environmental factors affecting measurement of bovine scrotal surface temperature with infrared thermography. anim reprod sci 1996; 41:153-9. 26. kaviany m. heat transfer physics. 2 ed. cambridge: cambridge university press; 2014. 27. lienhard jh, lienhard jh. a heat transfer textbook. 4th edition. ed. newburyport: dover publications; 2013. correspondence mehdi shirazi shirazim@sums.ac.ir ali eslahi alieslahi@yahoo.com dpt of urology, school of medicine, shiraz university of medical sciences, shiraz, iran faisal ahmed fmaaa2006@yahoo.com mohsen ostovari mohsen.ostovari@gmail.com ahmed zaid ahmadzaid333@gmail.com mohammad reza askarpour askarvip2@gmail.com hossein-ali nikbakht ep.nikbakht@gmail.com zeinab gholami gholamii.zb@gmail.com sania shirazi saniashirazi046@gmail.com conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11514 1 original paper ovary. ar gene in humans is present on the x chromosome (2). there is a significant role of androgens and their receptors in male bladder development and functioning. ar has also been shown in urothelium and bladder submucosa. it also regulates the storage of urine and other functions of the urinary tract. activation of ar correlates with progression of growth of urothelial cancer (uc) (2). hence we aimed to study ar expression in bladder urothelial carcinomas and assess its association with stage and grade of the disease. methods the institutional ethics committee approved the study. this retrospective study included ucs from the urinary bladder received in the pathology department of a tertiary care center of coastal south india between january 2013 and december 2018. uc were classified as per the world health organization classification 2016 (9). the urothelium in bladder biopsies of non-neoplastic conditions served as controls. cases in which paraffin blocks were not available or had inadequate tissue for immunohistochemistry (ihc) were excluded. the samples underwent routine processing with formalin fixation and were embedded in paraffin. three microns thickness sections were used for ihc. ihc was performed using anti-ar [ready-to-use mouse monoclonal primary antibody kit (biogenex)] on the appropriate tumor blocks following the manufacturer’s instructions. the secondary antibody used was dako real envision/hrp (labeled polymer, code k5007) against rabbit and mouse primary antibodies. the ar expression was considered positive based on the german immunoreactive score as shown in table 1 (11). a descriptive analysis of data was done using the software package spss version 21.0. cross tables were generated to compare the neoplastic and non-neoplastic groups and associations between the groups were analyzed using the chi-square test and student t-test. odds ratio (or) was calculated to establish the association between ar and urothelial carcinomas. a p-value < 0.05 was considered statistically significant. background: bladder carcinoma (bc) ranks second among the genitourinary cancers worldwide. influence of androgens and expression of androgen receptors in neoplasms are recent findings which were implicated in the development of bc. we aimed to study androgen receptor (ar) expression in bladder urothelial neoplasms and correlate its expression with grade and stage of the tumor. methods: immunohistochemistry (ihc) was done on samples collected in a tertiary care hospital over one year consisting of 71 urothelial bc and 20 non-neoplastic urothelial conditions. two pathologists graded the ihc and nuclear staining was considered as positive expression. results: ar was expressed in 23.9% (17/71) of bladder urothelial neoplasms. ar was expressed in 25.7% and 22.3% of high and low-grade tumors and 25% and 22.3% of non-muscle-invasive and muscle-invasive bc. ar expression had no significant correlation with gender, age (> 50 years), muscle invasion or grade. ar expression was significantly absent in non-neoplastic conditions (p = 0.018). conclusions: ar has varied expression in bc and it is relatively lower in this study population. key words: bladder cancer; urothelial neoplasms; androgen receptor expression. submitted 9 june 2023; accepted 14 july 2023 introduction bladder cancer (bc) ranks second among the genitourinary cancers worldwide with over 12 million cases annually (1, 2). about 95% of bladder tumors are of epithelial type and the diagnosis is mainly dependent on cellular dysplasia and muscle invasion. metastasis is a late phenomenon in bc (3). the occurrence of bc is higher in men than in women because men are more exposed to industrial chemicals and cigarette smoke, which contain amines. however, even in the absence of these carcinogens, men are more prone to bc. in this context, androgen receptor (ar) could be proposed as another potential reason for the difference (4). androgens were discovered in 1936 and are steroidal hormones that are secreted by adrenal cortex, testes, and immunohistochemical expression of androgen receptors in urothelial carcinoma of urinary bladder. is it significant? experience from coastal india disha jindal 1, pooja k suresh 2, saraswathy sreeram 2, ramesh holla 3, hema kini 2, sridevi hb 2, amanda christina pinto 2 1 kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india; 2 department of pathology, kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india; 3 department of community medicine, kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india. doi: 10.4081/aiua.2023.11514 summary archivio italiano di urologia e andrologia 2023; 95(4):11514 d. jindal, p.k. suresh, s. sreeram, r. holla, h. kini, h.b. sridevi, a.c. pinto 2 immunohistochemical ar nuclear expression was seen in 23.9% of the cases (n = 17) figure 2. ar expression was not associated with age of the patients, gender, grade and stage of the tumor (table 3). positive ar expression was seen in 23.9% of neoplastic samples (figure 1d-e) while ar expression was completely absent in non-neoplastic lesions. this was statistically significant (p = 0.018) (table 4). table 2. clinical-pathological features of uc cases (n = 71). variables cases (n) percentage (%) gender male 63 88.7% female 8 11.2% age in years < 50 7 90.1% > 50 64 9.9% muscle invasiveness absent 44 62% present 19 38% histologic grade high 35 50.7% low 36 49.3% figure 1. ar expression in urothelial carcinoma. a. urothelial carcinoma showing papillary pattern (he stain, 10x); b. urothelial carcinoma – low grade (he stain, 40x); c. urothelial carcinoma – high grade (he stain, 40x); d-e. immunohistochmical expression of ar receptors in urothelial carcinomas (ar ihc stain, 10x). figure 2. distribution of androgen receptor expression in uc. table 4. ar in neoplastic and non-neoplastic urothelial lesions. ar expression negative positive total neoplastic 54 17 71 (78%) non-neoplastic 19 0 19 (22.0%) total 73 (100%) 17(100%) 90 (100%) table 1. ar expression calculated by german immunoreactive score. percentage proportion intensity intensity final score = proportion score final of immunoreactive cells score of staining score x intensity score interpretation 0% 0 negative 0 0-1 negative (0) 1-10% 1 weak 1 2-4 weakly positive (1+) 11-50% 2 moderate 2 6-8 moderately positive (2+) 51-80% 3 strong 3 9-12 strongly positive (3+) 81-100% 4 table 3. association of ar expression with age, gender, grade and stage. ar expression p-value negative positive positive positive 0 1+ 2+ 3+ age (years) < 50 5 (71.4%) 2 (28.6%) 0 (0%) 0 (0%) 0.09 > 50 49 (66.2%) 3 (4.1%) 9 (12.2%) 13 (17.5%) gender men 48 (76.2%) 4 (6.3%) 8 ( 12.6%) 3 (4.7%) 0.85 women 6 (75%) 1 (12.5%) 1 ( 12.5%) 0 (0%) grade low 28 (77.8%) 2 (5.5%) 6 ( 16.7%) 0 (0%) 0.2 high 26 (74.2%) 3 (8.5%) 3 (8.5%) 3 (8.5%) muscle invasion non invasive 33 (75%) 3 (6.8%) 7 ( 15.9%) 1 (2.3%) 0.5 invasive 21 (77.8%) 2 (7.4%) 2 (7.4%) 2 (7.4%) results during the study period, we received 220 bladder biopsies or specimens from transurethral bladder resections. out of them 71 specimens of ucs were included in the study based on the inclusion and exclusion criteria. the mean age at presentation of uc cases was 62 years (age range: 36-91 years) with a male predominance (63 men and 8 women). high grade tumor was seen in 50.7% (35/71) of cases and muscle invasive uc in 38% (19/71) of tumors (table 2, figure 1a-c). archivio italiano di urologia e andrologia 2023; 95(4):11514 3 ar expression in bladder urothelial neoplasms discussion androgens are considered to have a pivotal role in urothelial carcinogenesis. ar expression had a significant impact on modern oncological breast cancer treatment. in this study, immunohistochemical expression of ar was analyzed in the urothelial neoplasms. expression of ar was seen in 23.9% of the cases of urothelial neoplasms. a study conducted by mir et al. (13) showed ar expression in 12.9% of bladder tumors, miyamoto et al. (11) in 42% of tumors and boorjiana et al. (14) in 53.1%. the rate observed in this study is within a similar range with differences in the expression in urothelial neoplasm that could be attributed to ethnicity, sample sizes, antibody clones, ihc techniques and scoring methodologies. an interesting, subtle yet significant observation in this study was the variation in ar expression between nonneoplastic and neoplastic urothelial lesions. ar expression was completely absent in non-neoplastic lesions whereas it was positive in 23.9% of neoplastic lesions. mashhadi et al. had previously reported 22% of ar-positivity in cases with no expression in the controls (10). a meta-analysis with five studies conducted by chen et al. (15) showed negative correlation between expression of ar and bc predisposition. data from studies by izumi et al. suggested a low expression of ar (p = 0.02) in bc as compared to non-neoplastic urothelial tissues (16). ar expression was noted in 25.7% of high grade bc and 22.3% of low-grade bc. tumor grade was not associated statistically with ar expression. ide et al. showed significant androgen loss in bc with higher grade compared with lower grades (p < 0.001) (17). data from a study conducted by miyamoto et al. showed lower expression of ar in high-grade bc (36%) compared to the low grade tumours (55%; p = 0.0232) (11). this brings forward a potential utility of ar ihc of bladder lesions as a marker to exclude benign nature if expressed. ar ihc could be helpful in the differential diagnoses between basal cell hyperplasia or transitional metaplasia versus a low-grade urothelial carcinoma. the validation of these results is an area for further research. furthermore, ar expression in other malignancies like lymphoma or other varieties of carcinoma versus urothelial carcinoma could be evaluated. in the present study there was a downregulation of ar expression with muscle invasion. ar expression was seen in 22.3% of mibc and 38.9% of nmibc. mir et al. showed expression of ar in 9% of nmibc as compared with 15.1% of mibc (p = 0.059) (13). miyamoto et al. also reported lower expression of ar in mibc (33%) compared to nmibc (51%; p = 0.018) (11). wagih et al. and szabados et al. also showed similar results (18, 19). a therapeutic implication of ar expression in urothelial carcinomas could be the use of ar inhibitors to prevent uc growth in presence of androgens and to prevent chemotherapy resistance (20). limitations of our study are absence of data on treatment and follow-up and incomplete data on progression and recurrence. few of our cases were excluded due to nonavailability of the tissue in the block for ihc. this also reduced the sample size of our study. conclusions ar has varied expression in bc and it is relatively lower in this study population. the expression of ar in bladder cancer had no significant correlation with gender, age (50 years), muscle invasion or grade of the tumor. ar expression was downregulated in mibc albeit without any statistical significance, thereby precluding its role in targeted therapy. references 1. ploeg m, aben kk, kiemeney la. the present and future burden of urinary bladder cancer in the world. world j urol. 2009; 27:289-93. 2. li p, chen j, miyamoto h. androgen receptor signaling in bladder cancer. cancers. 2017; 9:20. 3. humphrey pa, moch h, cubilla al, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part b: prostate and bladder tumours. eur urol. 2016; 1-14. 4. miyamoto h, yang z, chen yt, et al. promotion of bladder cancer development and progression by androgen receptor signals. j national cancer institute. 2007; 99:558-68. 5. izumi k, ito y, miyamoto h, et al. expression of androgen receptor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence. oncotarget. 2016; 7:14153. 6. kawahara t, inoue s, kashiwagi e, et al. enzalutamide as an androgen receptor inhibitor prevents urothelial tumorigenesis. am j cancer res. 2017; 7:2041. 7. zhuang yh, bläuer m, tammela t, tuohimaa p. immunodetection of androgen receptor in human urinary bladder cancer. histopathology. 1997; 30:556-62. 8. necchi a, vullo sl, giannatempo p, et al. association of androgen receptor expression on tumor cells and pd-l1 expression in muscle-invasive and metastatic urothelial carcinoma: insights for clinical research. clinical genitourinary cancer. 2018; 16:e403-10. 9. hata s, ise k, azmahani a,et al. expression of ar, 5αr1 and 5αr2 in bladder urothelial carcinoma and relationship to clinicopathological factors. life sciences. 2017; 190:15-20. 10. mashhadi r, pourmand g, kosari f, et al. role of steroid hormone receptors in formation and progression of bladder carcinoma: a case-control study. urology journal. 2014; 11:1968-73. 11. miyamoto h, yao jl, chaux a, et al. expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. bju international. 2012; 109:1716-26. 12. nam jk, park sw, lee sd, chung mk. prognostic value of sexhormone receptor expression in non-muscle-invasive bladder cancer. yonsei med j. 2014; 55:1214-21. 13. mir c, shariat sf, van der kwast th, et al. loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study. bju international. 2011; 108:24-30. 14. boorjian s, ugras s, mongan np, et al. androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. urology. 2004; 64:383-8. 15. chen j, cui y, li p, et al. expression and clinical significance of androgen receptor in bladder cancer: a meta-analysis. molecular and clinical oncology. 2017; 7:919-27. 16. izumi k, ito y, miyamoto h, et al. expression of androgen receparchivio italiano di urologia e andrologia 2023; 95(4):11514 d. jindal, p.k. suresh, s. sreeram, r. holla, h. kini, h.b. sridevi, a.c. pinto 4 tor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence. oncotarget. 2016; 7:14153. 17. ide h, inoue s, miyamoto h. histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: a meta-analysis of immunohistochemical studies. plos one. 2017; 12:e0174746. 18. wagih m, kamel m. evaluation of androgen receptor status in urothelial carcinoma of the urinary bladder in egyptian patients: an immunohistochemical study. afr j urol. 2020; 26:1. 19. szabados b, duncan s, choy j, et al. androgen receptor expression is a predictor of poor outcome in urothelial carcinoma. front. urol. 2022; 2:863784. 20. tripathi a, gupta s. androgen receptor in bladder cancer: a promising therapeutic target. asian j urol. 2020; 7:284-90. correspondence disha jindal, mbbs student kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india pooja k suresh, additional professor (corresponding author) puja4444@gmail.com saraswathy sreeram, associate professor hema kini, professor sridevi hb, additional professor amanda christina pinto, assistant professor department of pathology, kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india ramesh holla, associate professor department of community medicine, kasturba medical college, mangalore, manipal academy of higher education, manipal, karnataka, india conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 31 original paper ber of systematic needle cores and the best imaging procedure to use for omitting or postponing scheduled repeated biopsies; in this respect, multiparametric magnetic resonance imaging (mpmri) is strongly recommended in as follow up (4, 5). recently, prostate-specific membrane antigen (psma) inhibitors conjugated with the radionuclides 68gallium (68ga) and 18fluoride (18f) have been well-explored and successfully translated for the clinical diagnosis of pca (6, 7). moreover, tumour uptake, which represents psma expression (standardised uptake value “suvmax), resulted highly correlated with the gleason score of the primary prostatic tumour (9). however, a limited number of studies have focused on the primary prostatic lesion (8, 9). 68ga-psma positron emission tomography/computed tomography (pet/ct) has shown to be sensitive for the detection of primary prostatic lesions and regional lymphadenopathy (10, 11). recently, the use of 68ga-psma pet/ct combined with mpmri has been suggested to improve the accuracy to identify men suitable for active surveillance (12). the aim of this study is to prospectively evaluate the diagnostic accuracy of 68ga-psma pet/ct in the diagnosis of cspca (grade group ≥ 2) (13) in men enrolled in as protocol. materials and methods from may 2013 to december 2021 200 men aged between 52 and 74 (median age 63) with very low risk pca were enrolled in an as protocol study. after institutional review board and ethical committee approval were granted, informed consents were obtained from all participants included in the study. presence of the following criteria defined eligibility: life expectancy greater than 10 years, clinical stage t1c, psa below 10 ng/ml, psa density (psa-d) < 0.20, ≤ 2 unilateral positive biopsy cores, gleason score 6/international society of urologic pathology (isup) grade groups (gg) 1, maximum core percentage of cancer (gpc) ≤ 50% (3). all the patients underwent confirmatory biopsy 6-12 months later the pca diagnosis previous mpmri evaluation. during the follow up 48/200 (24%) men were upgraded and 10/200 (5%) men autonomously decided to leave the as protocol. after five introduction: to evaluate the accuracy of 68ga-prostate specific membrane antigen (psma) positron emission tomography/computed tomography (pet/ct) in the diagnosis of clinically significant prostate cancer (cspca: grade group ≥ 2) in men enrolled in active surveillance (as) protocol. materials and methods: from may 2013 to december 2021 200 men aged between 52 and 74 years (median age 63) with very low risk pca were enrolled in an as protocol study. during the follow up 48/200 (24%) men were upgraded and 10/200 (5%) decided to leave the as protocol. after five years from confirmatory biopsy (range: 48-60 months) 40/142 (28.2%) consecutive patients were submitted to mpmri and 68ga-psma pet/ct imaging examinations before scheduled repeated biopsy. all the mpmri (pi-rads ≥ 3) and 68ga-pet/tc standardized uptake value (suvmax) ≥ 5 index lesions underwent targeted cores (mpmri-tpbx and psma-tpbx) combined with transperineal saturation prostate biopsy (spbx: median 20 cores). results: multiparametric mri and 68ga-psma pet/ct showed 18/40 (45%) and 9/40 (22.5%) lesions suspicious for pca. in 3/40 (7.5%) men a cspca (gg2) was found; 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results. conclusion: although 68psma pet/ct did not improve the detection for cspca of spbx (1 false negative result equal to 33.3% of the cases), at the same time, would have spared 31/40 (77.5%) scheduled biopsies showing a better diagnostic accuracy in comparison with mpmri (83.3% vs. 70.2%). key words: prostate cancer; 68ga-psma pet/ct; active surveillance; pca. submitted 18 march 2023; accepted 28 march 2023 introduction active surveillance (as) has become an alternative to radical treatment of low/very low risk prostate cancer (pca), reducing the risk of overtreatment and improving quality of life of the patients (1-3). however, the time of confirmatory biopsy has been established within one year from initial diagnosis (4) there are no data regarding the num68ga-psma pet/ct evaluation in men enrolled in prostate cancer active surveillance pietro pepe 1, ludovica pepe 1, marinella tamburo 2, giulia marletta 2, francesco savoca 1, michele pennisi 1, filippo fraggetta 3 1 urology unit, cannizzaro hospital, catania, italy; 2 radiotherapy unit, cannizzaro hospital, catania, italy; 3 pathology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2023.11322 summary archivio italiano di urologia e andrologia 2023; 95, 2 p. pepe, l. pepe, m. tamburo, g. marletta, f. savoca, m. pennisi, f. fraggetta 32 years from confirmatory biopsy (range: 48-60 months), also in the presence of stable clinical parameters, the last 40/142 (28.2%) consecutive patients were submitted to mpmri and 68ga-pet/ct imaging examinations before scheduled repeated biopsy. all mpmri examinations were performed using a 1.5 or 3.0 tesla scanner, equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spinecho t2-weighted (t2w), axial diffusion weighted imaging (dwi) and axial dynamic contrast enhanced (dce) were performed for each patient. the mpmri lesions characterized by prostate imaging reporting and data system (pirads) version 2 (4) scores ≥ 3 were considered suspicious for cancer; two radiologists blinded to pre-imaging clinical parameters evaluated the mpmri data separately and independently; moreover, one urologist with more than 25 years of experience performed the biopsy procedure (4). pet/ct imaging was performed using a ct-integrated pet scanner (biograph 6; siemens, knoxville, tn, usa). 68gapsma was prepared with a fully automated radiopharmaceutical synthesis device based on a modular concept (eckert & ziegler eurotope, berlin, germany). 68ga-psma-11 was given to patients via an intravenous bolus (mean, 144 ± 12 mbq; range, 122-188 mbq), and the pet acquisition was started at a mean of 58 ± 12 min (range, 50-81 min) afterward. scans were acquired in 3-dimensional mode with an acquisition time of 3 min per bed position. emission data were corrected for randoms, dead time, scatter, and attenuation and were reconstructed iteratively using ordered-subsets expectation maximization (4 iterations, 8 subsets) followed by a postreconstruction smoothing gaussian filter (5 mm in full width at half maximum). for attenuation correction, a low dose unenhanced ct scan was performed from the skull base to the middle of the thigh. images were processed to obtain pet, ct, and pet-ct fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm by two experienced nuclear medicine specialists, who were blinded to the clinical data. the location of focal uptake on 68ga-psma pet/tc (figure 1), three-dimensional size, and suvmax values were reported on a per-lesion basis with a sextant scheme (apex, midgland, and base, each split into left and right) (4). all the mpmri (pi-rads score ≥ 3) and 68gapet/tc index lesions (suvmax ≥ 5) (14) underwent cognitive targeted cores (mpmritpbx and psma-tpbx: four cores) combined with saturation prostate biopsy (spbx: median 20 cores; range 18-22). the procedure was performed transperineally using a tru-cut 18 gauge needle (bard; covington, ga, usa) under sedation and antibiotic prophylaxis (15). the prostate targeted cores were done using an hitachi 70 arietta ecograph, chiba, japan) supplied by a bi-planar trans-rectal probe (16) performing a free-hand cognitive approach. results the clinical parameters of the 40 men enrolled in active surveillance protocol are listed in table 1. multiparametric mri and 68ga-psma showed 18/40 (45%) and 9/40 (22.5%) lesions suspicious for pca those were submitted to targeted cores combined with spbx. in detail, mpmri pi-rads score resulted ≤ 2 vs. 3 vs. 4 in 22 (55%) vs. 15 (37.5%) vs. 3 (7.5%) men. the average intraprostatic suvmax and tumor dimension was 4.6 g/ml (range: 3.2-19.8) and 7.0 mm (range 4-12 mm), respectively; only 9/40 (22.5%) men had a suvmax ≥ 5 (range: 5.1-19.8), moreover, 68ga-psma pet/tc showed two suspicious areas in correspondence of iliac ala and spinal cord those resulted negative for metastases at targeted mri for bone evaluation. in 3/40 (7.5%) men a cspca (gg2) was found: both patients had a gpc equal to 20% with a number of positive cores equal to 3 and 4, respectively, moreover psa density was 0.15, 0.16 and 0.18, respectively. 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc table 1. clinical parameters of 40 men enrolled in active surveillance protocol submitted to scheduled biopsy. figure 1. 68ga-prostate-specific membrane antigen (psma) pet/ct: presence of high vs. low suspicious area of clinically significant prostate cancer in the right (a) vs. left lobe (b) of prostate gland (axial valuation) with a standardized uptake value (suvmax) equal to 88.8 vs. 6.5, respectively. a. b. clinical and biopsy findings gg1 40 patients median psa (range: 4.5-12.5 ng/ml) 4.8 median psa density (range: 0.10-0.20) 0.15 median gpc (range: 10-50%) 40% median number of positive cores 2 percentage of positive cores 98% mpmri 18 pi-rads score ≥ 3 (45%) 68ga-psma pet/ct 9 suspicious for pca (22.5%) gg: international society of urological pathology grade group; mpmri: multiparametric magnetic resonance imaging; psa: prostate specific antigen; gpc: greatest percentage of cancer; psma: prostate specific membrane antigen; pi-rads: prostate imaging reporting and data system; pet/tc: positron emission tomography/computed tomography. archivio italiano di urologia e andrologia 2023; 95, 2 33 68ga-psma pet/ct and active surveillance demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results; in detail, one patient had pi-rads score 2 and suvmax of 6.8 and the second patient had pi-rads score 3 and suvmax equal to 4.5 g/ml. in addition, mpmri and 68ga-psma pet/tc showed a diagnostic accuracy in the diagnosis of cspca equal to 70.2 and 83.3%, respectively. discussion the estimated risk-free treatment at 15 years in men enrolled in as with gg1 pca is equal to 58% (1). although mpmri is strongly recommended in the revaluation of men in as (2, 5, 6), still today, scheduled systematic repeated prostate biopsies are recommended to reduce the false negative rate for cspca of mpmri equal to 15-20% of the cases (16); at the same time, the number of cores performed at initial and repeat evaluation is directly correlated with a lower risk of reclassification (6) during the follow up allowing to postpone scheduled repeated prostate biopsy in favour of clinical findings (i.e., psa density, risk calculator) (17-19) and imaging revaluation (mpmri) (5, 6). in the last years, 68ga-psma-pet/ct has been suggested to improve the clinical staging of high-risk pca and disease recurrence (20, 21); at the same psma pet/ct has been proposed for the diagnosis of primary intraprostatic cancer (22, 23). the presence of focal uptake on psmapet/ct (suvmax) and the maximal dimensions of petavid lesions have been correlated with the presence of cspca (24, 25). there is a range of proposed cut-offs to detect cspca from suvmax 3.15 to up suvmax 9.1 (26, 27); the concordance between preoperative psma pet/tc evaluation (suvmax, dimension of the lesion) and definitive prostate specimen ranges from 81.2% (28) to 96% (29); moreover, psma pet/mri seems reduce false positive rate of pet/ct (about 8% of cases) (30). in our series, 68ga-psma-tpbx vs. mpmri-tpbx vs. spbx diagnosed 2/3 (66.6%) vs. 2/3 (66.6%) vs. 3/3 (100%) cspca, respectively. in detail, mpmri and 68ga-psma pet/tc demonstrated 16/40 (40%) vs. 7/40 (17.5%) false positive and 1 (33.3%) vs. 1 (33.3%) false negative results. in addition, mpmri and 68ga-psma pet/tc showed a diagnostic accuracy in in the diagnosis of cspca equal to 70.2 and 83.3%, respectively. in definitive, still today, diagnostic imaging should not replace scheduled prostate biopsy but is mandatory to detect targeted lesions suspicious for cspca; in addion, several biochemical parameters, such as germline evaluation or phi (prostate health index), could be helpful in decrease the ratio of scheduled biopsy. among our results some considerations should be made. first, the number of patients evaluated was low. secondly, the results should be evaluated in the entire prostate specimen and not in biopsy histology; a more detailed histological evaluation of patients who underwent biopsy upstaging would be of interest, for example by adding supplementary staining for psma on the biopsy samples. third, the low rate of reclassification (7.5% of the cases) could be explained because the patients previously underwent spbx plus mpmri evaluation before confirmatory biopsy. four, 68ga-psma pet/tc evaluation could be proposed in men with negative mpmri or in the presence of claustrophobia, severe obesity or cardiac pacemaker (13); moreover, a 68ga-psma pet/tc fusion platform would have increased the accuracy of targeted prostate biopsy. in conclusion, although 68psma pet/ct did not improve the detection for cspca of spbx (1 false negative result equal to 33.3% of the cases), at the same time, would have spared 31/40 (77.5%) scheduled biopsies showing a better diagnostic accuracy in comparison with mpmri (70.2% vs. 83.3%). references 1. carlsson s, benfante n, alvim r, et al. long-term outcomes of active surveillance for prostate cancer: the memorial sloan kettering cancer center experience. j urol 2020; 203:1122-1127. 2. briganti a, fossati n, catto jwf, et al. active surveillance for low-risk prostate cancer: the european association of urology position in 2018. eur urol 2018; 74:357-368. 3. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol 2017; 51:260-263. 4. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. clin genitourin cancer 2021; 19:305-308. 5. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol 2018; 200:774-778. 6. caglic i, sushentsev n, gnanapragasam vj, et al. mri-derived precise scores for predicting pathologically-confirmed radiological progression in prostate cancer patients on active surveillance. eur radiol 2021; 31:2696-2705. 7. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. eur urol 2020; 77:403-417. 8. privé bm, israël b, schilham mgm, et al. evaluating f-18psma-1007-pet in primary prostate cancer and comparing it to multi-parametric mri and histopathology. prostate cancer prostatic dis. 2021; 24:423-430. 9. uprimny c, kroiss as, decristoforo c, et al. 68ga-psma-11 pet/ ct in primary staging of prostate cancer: psa and gleason score predict the intensity of tracer accumulation in the primary tumour. eur j nucl mol imaging 2017; 44:941-949. 10. zhang q, zang sm, zhang ce, et al. comparison of 68gapsma11 pet-ct with mpmri for preoperative lymph node staging in patients with intermediate to high-risk prostate cancer. j transl med 2017; 15:230-38. 11. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer research 2022; 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42:1495-1498. 21. kwan tn, spremo s, teh aym, et al. performance of ga-68 psma pet/ct for diagnosis and grading of local prostate cancer. prostate international 2021; 9:107-112. 22. ma l, zhang wc, ya-xin hao yx, hao yx. current state of prostate-specific membrane antigen pet/ct imaging-targeted biopsy techniques for detection of clinically significant prostate cancer j med imaging radiat oncol 2022; 66:776-780. 23. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. eur urol 2020; 77:403-417. 24. demirci e, kabasakal l, sahin oe, et al. can suvmax values of ga-68-psma pet/ct scan predict the clinically significant prostate cancer? nucl med commun 2019; 40:86-91. 25. rüschoff jh, ferraro da, muehlematter uj, et al. what's behind 68ga-psma-11 uptake in primary prostate cancer pet? investigation of histopathological parameters and immunohistochemical psma expression patterns. eur j nucl med mol imaging 2021; 48:4042-4053. 26. franklin a, yaxley wj, raveenthiran s, et al. histological comparison between predictive value of preoperative 3-t multiparametric mri and 68ga-psma pet/ct scan for pathological outcomes at radical prostatectomy and pelvic lymph node dissection for prostate cancer. bju int 2021; 127:71-79. 27. liu y, yu h, liu j, et al. a pilot study of 18 f-dcfpyl pet/ct or pet/mri and ultrasound fusion targeted prostate biopsy for intra-prostatic pet-positive lesions. front oncol 2021; 11:612157. 28. kalapara aa, nzenza t, pan hyc, et al. detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology. bju int 2020; 126:83-90. 29. xue al, kalapara aa, ballok ze, et al. 68ga-prostate-specific membrane antigen positron emission tomography maximum standardized uptake value as a predictor of gleason pattern 4 and pathological upgrading in intermediate-risk prostate cancer. j urol 2022: 207:341-349. 30. bhanji y, rowe sp, pavlovich cp. new imaging modalities to consider for men with prostate cancer on active surveillance. world j urol world j urol 2022; 40:51-59. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md ludopepe97@gmail.com francesco savoca, md michele pennisi, md michepennisi2@virgilio.it urology unit, cannizzaro hospital via messina 829, catania, italy marinella tamburo, md marinellatamburo@virgilio.it giulia marletta, md marlettagiulia1@gmail.com radiotherapy unit, cannizzaro hospital, catania, italy filippo fraggetta, md filippofra@hotmail.com pathology unit, cannizzaro hospital, catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12452 1 original paper symptoms, sexual and psychosocial disturbances (1). the importance of recognizing the psychological impact of cp/cpps has been taken into primary consideration by the upoint phenotyping and therapeutic algorithm (2), which rates a specific “psychosocial” domain in the frame of the work-up of chronic prostatitis (cp) patients. it is suggested to use self-administered questionnaires to assess depression and anxiety and to measure negative thoughts associated with pain. the implementation of the upoint system with the evaluation of a sexual domain (“s”) has further extended the evaluation of patients with cp/cpps who frequently present with significant rates of erectile and orgasmic dysfunction (3). the aim of this study was an in-depth assessment of the complex correlations between somatic, psychological, and sexual disorders in cp/cpps patients. methods study design and endpoints we performed a cross-sectional study on a cohort of patients with cp-cp/cpps, consecutively enrolled among patients attending two outpatient clinics. the study was ethically approved by the local ethics committee of tzaneio hospital (protocol 8295/05-05-2022) and complied with the requirements of the helsinki declaration. the primary endpoint of the study was the association between the total and subdomain scores (pain, voiding symptoms, quality of life) of the national institute of health-chronic prostatitis symptom index (nih-cpsi) (4), and the total score of the patient health questionnaire-9 (phq-9), a self-administered tool focusing on the presence and severity of depression (5). secondary endpoints of the study included the assessment of an association between the scores (i) of the nih-cpsi questionnaire, (ii) of the international prostate symptom score (ipss) (6), (iii) of the erectile function domain of the international index of erectile function (iief) (7), and (iv) of the premature ejaculation diagnostic tool (pedt) (8) (independent variables), and the scores of the following psychosocial tests: (i) the phq-9 questionnaire (5), (ii) the purpose: chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is characterized by a multiform clinical presentation requiring a differentiated treatment based on different phenotypes including the psychosocial and sexual domains. the aim of this study was assessing the complex correlations between somatic, psychological, and sexual symptoms of cp/cpps patients. materials and methods: we performed a cross-sectional study on patients attending a prostatitis clinic. patients were administered the following questionnaires: national institutes of healthchronic prostatitis symptom index (nih-cpsi), international prostate symptom score (ipss), international index of erectile function (iief), premature ejaculation diagnostic tool (pedt), patient health questionnaire-9 (phq-9), generalized anxiety disorder 7-item (gad-7), oxford happiness questionnaire (ohq), and temperament evaluation of memphis, pisa, paris and san diego autoquestionnaire (temps-a). results: linear regression analyses show highly significant correlations between scores of the nih-cpsi and the scores of the gad-7, phq-9 and ohq psychometric questionnaires. ipss scores correlate significantly with the psychometric scores only when a non-parametric analysis is performed. iief and pedt sexual function scores did not correlate with any of the psychometric tests. nih-cpsi scores correlate positively with most of the temps-a profiles but the hyperthymic profile correlated negatively with the total and qol nih-cpsi and with pedt scores. conclusions: scores measuring anxiety, depression, and psychological well-being in patients with cp/cpps are strictly correlated with prostatitis-like symptoms although they are poorly correlated with symptoms of prostatism, as measured by ipss, and not correlated with scores of sexual dysfunctions, as measured by iief and pedt. a hyperthymic temperament may temperament may increase resilience against the disease. key words: chronic prostatitis; chronic pelvic pain syndrome; depression; anxiety; affective temperaments. submitted 3 march 2024; accepted 7 march 2024 introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) is a common clinical condition presenting with a variety of signs and symptoms including chronic pain, voiding psychological and sexological assessment of patients with chronic prostatitis konstantinos stamatiou 1, vittorio magri 2, margherita trinchieri 3, alberto trinchieri 4, gianpaolo perletti 5 on behalf of mediterranean study group for prostatitis and prostatic diseases 1 department of urology, tzaneio hospital, pireus, greece; 2 urology unit, asst fatebenefratelli sacco, milan, italy; 3 psichiatry unit, asst rhodense, g. salvini hospital, garbagnate (milan), italy; 4 school of urology, university of milan, milan, italy; 5 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy. doi: 10.4081/aiua.2024.12452 summary archivio italiano di urologia e andrologia 2024; 96(1):12452 k. stamatiou, v. magri , m. trinchieri, et al. 2 generalized anxiety disorder 7-item questionnaire (gad-7) (9), (iii) the oxford happiness questionnaire (ohq) (10), and (iv) the temperament evaluation of memphis, pisa, paris and san diego autoquestionnaire (temps-a, 39-item short version), which includes 5 domains, focusing on the presence of cyclotimic, depressive, irritable, hyperactive and anxious personalities (11). patient selection criteria we included adult patients (>/= 18 years) who agreed to participate in the study, referring for long-standing (at least 18 months) documented signs and symptoms of category ii cp or category iii cp/cpps assessed according to nih criteria (12) after a thorough work up including clinical and laboratory assessments. exclusion criteria were: signs and symptoms present for a period shorter than 6 months; recent (< 8 weeks) category i acute bacterial prostatitis; neoplasia, indwelling catheters; nephrostomy; any chronic and/or painful and/or disabling illness significantly affecting the quality of life, potentially generating anxiety or depression; recent events (< 3 months) that may have had a considerable impact on the psychological profile of patients, possibly acting as confounders in this study (e.g., the loss of a child or spouse, divorce, loss of a job, other traumatic events). data collection at referral, patients were informed about the aim of the study and reassured about the anonymous handling of their data. after signing an informed consent, patients underwent a thorough urological examination after being interviewed about their clinical history. patients were also asked to fill the questionnaires listed above. questionnaires were collected by the consulting urologist and uploaded in a study database. personal data were rendered anonymous in such a manner that patients were no longer identifiable in the database. data were analyzed by a member of the research group (gp) in a blinded fashion. statistical analysis median and interquartile range (iqr) or mean and standard deviation were used as measures of the central tendency and data dispersion of non-continuous and continuous variables, respectively. simple linear regression simple linear regression was performed to analyze the significance of associations between baseline scores of the nih-cpsi, ipss, iief (short version) and pedt questionnaires (independent variables), and the scores of the phq9, gad-7, ohq and temps-a (39-item short version) questionnaires (dependent variables in the present prediction model). both nonparametric (kendall’s rank coefficient ‘tau’) and parametric (pearson’s product-moment ‘rho’) correlation coefficients were calculated, to take into account the existence of non-linear relationships between the bivariates. sample size calculation to estimate the effect size for sample size calculation, we referred to the koh et al. (13) trial, reporting a significant correlation between the nih-cpsi and phq-9 scores (p = 0.009), resulting in a spearman’s coefficient (r) equal to 0.307. sample size calculations was performed using the g*power 3.1.3 software (14). we computed that a sample of 127 patients was required to analyze by simple linear regression (one predictor) the primary endpoint of the study, namely, the correlation between the nih-cpsi total score and the phq-9 depression score, with 95% power, a 5% alpha error probability, a f^2 effect size of 0.104 and a f^2 coefficient equal to 0.0942. logistic regression analysis simple binary logistic regression analysis was performed to ascertain the goodness of fit of models whereby the increasing symptom scores of tests (e.g., the nih-cpsi) showing significant linear correlation with psychometric scores, would be significant predictor of dichotomized psychometric outcomes (e.g., no depression vs. moderate-to-severe depression). the null hypothesis for the logistic regression was the absence of an association between the symptom score predictor and the psychologic condition dichotomic outcome. the coefficients of the logistic functions, the intercepts, the odds ratios, and the confidence intervals related to the odds ratios (95%ci) were calculated. the statistical significance of the model was evaluated by means of the wald test and the likelihood ratio test. the hosmer/lemeshow test was performed to evaluate the goodness-of-fit of the models, and the nagelkerker^2 value was be calculated. for the hosmer and lemeshow test, the null hypothesis was that the number of expected dichotomic psychological disturbances – when the entire patient cohort is divided into 10 groups of approximately similar size – is not significantly different from the same outcomes observed in the overall logistic model. values > 0.05 of the probability associated with the zero hypothesis indicated an acceptable goodness-of-fit. for statistical analysis only two-tailed tests were performed, 95% confidence intervals were calculated, and the conditional probability of a type i error, in the presence of a true null hypothesis, was set at < 0.05. statistical softwares statistical analysis of linear and logistic regressions was carried out in the “r” software environment for statistical computing and graphics (https://www.r-project.org/). logistic regression analysis was performed using the car and lmtest packages. the hosmer and lemeshow goodness-of-fit test was performed with the resource selection package, whereas the nagelkerke pseudo (y)-r2 was calculated using the rcompanion package. odds ratios and 95% cis for the model were calculated using the epidisplay package. intergroup differences between questionnaire scores were analyzed with the two-tailed mann-whitney-wilcoxon test, using the r platform. results one hundred and forty-one consecutive patients were prospectively enrolled for the study between january 1st and november 30th, 2022. the median age of patients archivio italiano di urologia e andrologia 2024; 96(1):12452 3 psychosexologic assessment in prostatitis was 48 (iqr, 18). the median year of first diagnosis of cp was 2018. baseline clinical and psychological symptoms are shown in table 1. linear regression table 2 shows the results of linear regression analyses comparing the scores of the nih-cpsi, ipss, iief and pedt questionnaires with the gad-7, phq-9 and oxford questionnaires. the results show highly significant correlations between all domains (pain, voiding, quality of life impact and total scores) of the nih-cpsi test and the scores of the gad7, phq-9 and oxford psychometric questionnaires. conversely, the ipss, iief and pedt tests correlate poorly and, in most cases, not significantly with any of the psychometric tests, except for ipss, whose scores correlate significantly with the scores of the gad-7, phq-9 and oxford tests only when a non-parametric analysis is performed (the kendall’s tau). temperament profiling table 3 shows the results of linear regression analyses comparing the scores of the nih-cpsi, ipss, iief and pedt questionnaires with the scores of basic patient temperament profile, measured with the temps-a test. highly significant correlations were found between nihcpsi scores (total score and pain, voiding and qol subscores) with most of the temps-a profiles. an exception was the hyperthymic profile, which correlated significantly and negatively with the total and qol nih-cpsi scores. in other words, a less severe impact of prostatitis on total and qol nih-cpsi correlated with higher hyperthymic scores. conversely, the ipss, iief and pedt tests correlate poorly and in almost all cases not significantly with any of the temps-a profile scores. exceptions were the significant correlation of the ipss scores with the temps-a depressive profile and the significant negative correlation of pedt scores with the hyperthymic temps-a profile. logistic regression models we tested the nih-cpsi and the ipss interval scores as predictors versus dichotomized outcomes of the gad-7, phq-9 and oxford happiness scores. dichotomization was as follows: for the gad-7 test, a score equal or higher than 5 predicted mild to severe anxiety according to spitzer et al. (2006) (9); for the phq-9 test a score equal or higher than 10 predicted moderate to severe depression according to kroenke et al. (2001) (5), and for the oxford happiness test a score equal to 3.5 was the cutoff to discriminate between happy or unhappy responses (hills & argyle, 2002)(15). table 1. baseline scores of clinical symptom tests and psychological questionnaires. test median score interquartile range nih-cpsi (total) 18 16 nih-cpsi (pain domain) 9 9 nih-cpsi (voiding domain) 3 4 nih-cpsi (qol impact domain) 6 5 ipss 7 9 iief 26 8.5 pedt 4 5.5 gad-7 7 7.25 phq-9 6 5 mean score standard deviation temps-a cyclothymic 0.38 0.29 temps-a depressive 0.32 0.30 temps-a irritable 0.21 0.24 temps-a hyperthymi 0.53 0.28 temps-a anxious 0.33 0.38 oxford happiness 3.68 0.54 nih-cpsi: national institutes of health chronic prostatitis symptom score (qol, impact of the disease on the quality of life). ipss: international prostate symptom score. iief (1-5,15), short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). pedt: premature ejaculation diagnostic tool. gad-7: general anxiety disorder-7. phq-9, patient health questionnaire-9. temps-a: temperament evaluation of memphis, pisa, paris and san diego auto-questionnaire version. table 2. psychological profiling of chronic prostatitis patients included in our study according to the gad-7, phq-9 and oxford happiness questionnaires. scores are analyzed by linear regression against the total or subdomain scores of the nih_cpsi, ipss, iief and pedt tests. correlation coefficients are shown. statistically significant differences are shown in bold. nih-cpsi, total score nih-cpsi, pain domain nih-cpsi, voiding domain nih-cpsi, qol domain kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) gad-7 0.285 (< 0.0001) 0.413 (< 0.0001) 0.316 (< 0.0001) 0.439 (< 0.0001) 0.188 (0.0023) 0.271 (0.0011) 0.283 (< 0.0001) 0.407 (< 0.0001) phq-9 0.365 (< 0.0001) 0.464 (< 0.0001) 0.392 (< 0.0001) 0.475 (< 0.0001) 0.218 (0.0004) 0.290 (0.0004) 0.375 (< 0.0001) 0.469 (< 0.0001) oxford happiness score -0.230 (0.002) -0.335 (0.001) -0.229 (0.002) -0.335 (0.001) -0.1 (0.20) -0.21 (0.043) -0.21 (0.005) -0.288 (0.006) ipss iief (1-5,15) pedt gad-7 0.170 (0.026) 0.191 (0.075) -0.129 (0.094) -0.119 (0.27) 0.09 (0.25) 0.179 (0.096) phq-9 0.198 (0.009) 0.267 (0.012) -0.077 (0.32) -0.052 (0.63) 0.085 (0.27) 0.114 (0.29) oxford happiness score -0.168 (0.024) -0.17 (0.102) 0.138 (0.067) 0.189 (0.078) -0.097 (0.20) -0.131 (0.22) nih-cpsi: national institutes of health chronic prostatitis symptom score. ipss: international prostate symptom score. iief (1-5,15): short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). pedt: premature ejaculation diagnostic tool. gad-7: general anxiety disorder-7. phq-9, patient health questionnaire-9. archivio italiano di urologia e andrologia 2024; 96(1):12452 k. stamatiou, v. magri , m. trinchieri, et al. 4 bivariate analysis comparing all nih-cpsi scores (pain, micturition, impact on qol and total scores) with gad-7. phq-9 and oxford happiness resulted in significant prediction models (table 4). the only exception was the model comparing the voiding nih-cpsi domain with the oxford test of happiness. analysis of the predictor significance and goodness-of-fit of all models showed statistical significance in all cases, apart from the comparison of the voiding nih-cpsi domain with the oxford test of happiness (table 5). conversely, logistic regression models comparing ipss predictor scores against dichotomized anxiety (gad-7), depression (phq-9) or happiness (oxford) outcomes were found to be not statistically significant (table 4). this was confirmed by the predictor significance and goodness-of-fit parameters shown in table 5. severity of cp symptoms in patients showing various degrees of happiness, depression and anxiety we investigated whether any significant difference could be observed by dichotomizing our population into two cohorts. cohorts included patients with moderate/severe table 3. temperament profiling of chronic prostatitis patients included in our study according to the temperament evaluation of memphis, pisa, paris and san diego auto-questionnaire (temps-a). temps-a scores are analyzed by linear regression against the total or subdomain scores of the nih_cpsi, ipss, iief and pedt tests. statistically significant differences are shown in bold. nih-cpsi, total nih-cpsi, pain domain nih-cpsi, voiding domain nih-cpsi, qol domain kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) kendall’s tau (p) pearson's r (p) temps-a cyclothymic 0.411 (< 0.0001) 0.590 (< 0.0001) 0.433 (< 0.0001) 0.612 (< 0.0001) 0.206 (0.0009) 0.344 (< 0.0001) 0.369 (< 0.0001) 0.512 (< 0.0001) depressive 0.367 (< 0.0001) 0.503 (< 0.0001) 0.362 (< 0.0001) 0.479 (< 0.0001) 0.257 (< 0.0001) 0.361 (< 0.0001) 0.355 (< 0.0001) 0.468 (< 0.0001) irritable 0.366 (< 0.0001) 0.485 (< 0.0001) 0.402 (< 0.0001) 0.512 (< 0.0001) 0.216 (0.001) 0.296 (0.0003) 0.310 (< 0.0001) 0.390 (< 0.0001) hyperthymic -0.115 (0.058) -0.172 (0.042) -0.944 (0.127) -0.132 (0.12) -0.051 (0.42) -0.075 (0.37) -0.132 (0.03) -0.186 (0.02) anxious 0.288 (< 0.0001) 0.393 (< 0.0001) 0.326 (< 0.0001) 0.421 (< 0.0001) 0.184 (0.006) 0.237 (0.004) 0.222 (0.0008) 0.302 (0.0002) ipss iief (1-5,15) pedt cyclothymic 0.126 (0.11) 0.147 (0.17) -0.10 (0.20) -0.166 (0.12) -0.026 (0.74) 0.044 (0.68) depressive 0.233 (0.004) 0.294 (0.005) -0.06 (0.45) -0.006 (0.94) 0.076 (0.36) 0.126 (0.24) irritable 0.11 (0.24) 0.049 (0.65) 0.116 (0.18) 0.123 (0.25) -0.032 (0.71) -0.06 (0.55) hyperthymic -0.051 (0.51) -0.84 (0.44) 0.143 (0.071) 0.20 (0.059) -0.199 (0.012) -0.263 (0.013) anxious 0.067 (0.43) 0.11 (0.31) -0.15 (0.078) -0,138 (0.19) -0.0042 (0.96) -0.0065 (0.95) nih-cpsi: national institutes of health chronic prostatitis symptom score. ipss: international prostate symptom score. iief (1-5,15): short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). pedt: premature ejaculation diagnostic tool. temps-a: temperament evaluation of memphis, pisa, paris and san diego auto-questionnaire version. table 4. logistic regression models for generalized anxiety disorder (gad-7 test), depression (phq-9 test), or degree of happiness (oxford test) as function of the score of the nih-cpsi test (total score and pain, voiding symptoms and impact on the quality of life subdomains) and of the ipss test. significant results are shown in bold. psychometric test logistic model prostatitis/prostate symptom scores (predictor) (outcome) parameters nih-cpsi, total score nih-cpsi, pain domain nih-cpsi, voiding domain nih-cpsi, qol domain ipss gad-7 intercept ± se -0.356 ± 0.37 -0.435 ± 0.31 0.285 ± 0.29 -0.56 ± 0.39 0.101 ± 0.37 corfficient ± se (p) 0.073 ± 0.020 (0.0003) 0.142 ± 0.034 (< 0.0001) 0.141 ± 0.07 (0.05) 0.220 ± 0.059 (0.0002) 0.045 ± 0.033 (0.183) odds ratio (96% ci) 1.08 (1.03-1.12) 1.15 (1.08-1.23) 1.15 (1-1.33) 1.25 (1.11-1.4) 1.05 (0.98-1.12) el50 4.88 3.07 2.03 2.58 2.23 phq-9 intercept ± se -2.93 ± 0.54 -2.717 ± 0.49 -1.96 ± 0.36 -2.79 ± 0.57 -1.131 ± 0.39 corfficient ± se (p) 0.093 ± 0.021 (< 0.0001) 0.159 ± 0.030 (< 0.0001) 0.218 ± 0.072 (0.002) 0.227 ± 0.067 (0.0007) 0.014 ± 0.033 (0.668) odds ratio (96% ci) 1.1 (1.05-1.15) 1.17 (1.09-1.27) 1.24 (1.08-1.43) 1.26 (1.1-1.43) 1.01 (0.95 to 1.08) el50 31.65 17.06 8.99 12.31 78.21 oxford happiness score intercept ± se 2.09 ± 0.52 2.29 ± 0.51 1.51 ± 0.42 1.92 ± 0.52 1.741 ± 0.51 corfficient ± se (p) -0.075 ± 0.026 (0.0038) -0.155 ± 0.05 (0.0023) -0.201 ± 0.11 (0.072) -0.177 ± 0.074 (0.014) -0.999 ± 0.051 (0.051) odds ratio (96% ci) 0.93 (0.88-0.98) 0.86 (0.77-0.95) 0.82 (0.66-1.02) 0.84 (0.73-0.97) 0.9 (0.82-1) el50 27.76 14.74 7.51 10.85 17.42 nih-cpsi: national institutes of health chronic prostatitis symptom score (qol, impact of the disease on the quality of life of patients). ipss: international prostate symptom score. iief (1-5,15): short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). gad-7: general anxiety disorder-7. phq-9: patient health questionnaire-9. se: standard error. 96% ci: 95% confidence interval. el50: median effective level, i.e., symptom score associated with 50% probability of the psychometric test outcome. archivio italiano di urologia e andrologia 2024; 96(1):12452 5 psychosexologic assessment in prostatitis versus absent or very mild anxiety or depression. the oxford score was also used to distinguish patients showing a happiness versus little or no happiness. dichotomization thresholds are indicated in the previous paragraph. table 6 shows that the pain, quality of life impact, and total scores of the nih-cpsi test are significantly higher in patients with moderate to severe depression or anxiety and in patients with a poor oxford happiness score. a significantly higher nih-cpsi voiding score was related to moderate to severe depression, but no difference was observed between patients with or without symptoms of anxiety and between patients reporting or not psychological well-being. the ipss score was significantly higher in patients showing a poor oxford happiness score. discussion the bidirectional relationship between psychological disturbances and prostatitis is complex, with several factors interacting or interfering with each other (16). our findings can be divided into two sections, the first evaluating correlations between measures of anxiety, depression, and psychological well-being and the scores of symptoms associated with cp/cpps as measured with nih-cpsi and questionnaires evaluating sexual function (iief or table 5. predictor significance and goodness-of-fit parameters of the logistic regression models shown in table 3. psychometric test test prostatitis/prostate symptom scores (predictor) (outcome) nih-cpsi, total score nih-cpsi, pain domain nih-cpsi, voiding domain nih-cpsi, qol domain ipss gad-7 wald c2 = 12.86, p = 0.00035 c2 = 17.11, p < 0.0001 c2 = 3.75, p = 0.05 c2 = 13.63, p = 0.00022 𝜒2 = 1.77, p = 0.18 likelihood ratio c2 = 14.91, p = 0.0001 c2 = 20.16, p < 0.0001 c2 = 4.06, p = 0.043 c2 = 15.50, p < 0.0001 𝜒2 = 1.87, p = 0.17 hosmer & lemeshow 𝜒2 = 19.24, p = 0.013 𝜒2 = 4.22, p = 0.83 𝜒2 = n.a. 𝜒2 = 1.62, p = 0.99 𝜒2 = 35.93, p < 0.0001 nagelkerke 𝜓r2 = 0.364 𝜓r2 = 0.652 𝜓r2 = 0.318 𝜓r2 = 0.701 𝜓r2 = 0.078 phq-9 wald c2 = 17.76, p < 0.0001 c2 = 16,49, p < 0.0001 c2 = 9.20, p = 0.0024 c2 = 11.38, p = 0.00074 𝜒2 = 0.18, p = 0.67 likelihood ratio c2 = 21.93, p < 0.0001 c2 = 20.02, p < 0.0001 c2 = 9.54, p = 0.002 c2 = 13.20, p = 0.00027 𝜒2 = 0.18, p = 0.67 hosmer & lemeshow 𝜒2 = 5.87, p = 0.661 𝜒2 = 1.66, p = 0.98 𝜒2 = 0.85, p = 0.99 𝜒2 = 1.87, p = 0.98 𝜒2 = 5.01, p = 0.75 nagelkerke 𝜓r2 = 0.469 𝜓r2 = 0.648 𝜓r2 = 0.591 𝜓r2 = 0.645 𝜓r2 = 0.0081 oxford happiness score wald c2 = 8.36, p = 0.038 c2 = 9.27, p = 0.023 𝜒2 = 3.21, p = 0.072 c2 = 5.99, p = 0.014 𝜒2 = 3.80, p = 0.051 likelihood ratio c2 = 9.34, p = 0.022 c2 = 10.73, p = 0.0011 𝜒2 = 3.28, p = 0.069 c2 = 6.50, p = 0.011 c2 = 3.91, p = 0.047 hosmer & lemeshow 𝜒2 = 6.83, p = 0.55 𝜒2 = 6.94, p = 0.54 𝜒2 = 3.22, p = 0.919 𝜒2 = 0.83, p = 0.999 𝜒2 = 7.77, p = 0.45 nagelkerke 𝜓r2 = 0.293 𝜓r2 = 0.485 𝜓r2 = 0.315 𝜓r2 = 0.412 𝜓r2 = 0.201 nih-cpsi: national institutes of health chronic prostatitis symptom score (qol, impact of the disease on the quality of life of patients). ipss: international prostate symptom score. iief (1-5,15): short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). gad-7: general anxiety disorder-7. phq-9: patient health questionnaire-9. se: standard error. 96% ci: 95% confidence interval. p: statistical probability of an alpha error. el50: median effective level, i.e., symptom score associated with 50% probability of the psychometric test outcome. n.a.: not available. table 6. severity of cp symptoms in patients showing various degrees of happiness, depression and anxiety. statistically significant differences are shown in bold. gad-7 0-4 gad-7 5-21 p phq-9 1-9 phq-9 10-27 p oxford oxford p median (iqr) median (iqr) (mann-whitney) median (iqr) median (iqr) (mann-whitney) happiness >3.5 happiness </=3.5 (mann-whitney) median (iqr) median (iqr) nih-cpsi total score 15 (14) 21 (19) 0.0003 18 (14) 28 (15) 0.0002 12 (15) 19 (9) 0.0074 nih-cpsi pain score 7 (9) 11(9) 0.0002 8 (8) 13 (9.5) < 0.0001 4.5 (10) 10 (5) 0.0083 nih-cpsi voiding score 2 (3) 3 (3.5) 0.073 2 (4) 4 (5) 0.0024 2 (3) 3 (3) 0.21 nih-cpsi quality of life impact score 5 (5) 7 (6) 0.0003 6 (4) 10 (5) 0.0005 5 (6) 7 (3) 0.025 ipss score 6 (10) 8 (8) 0.27 7 (8.75) 8 (10) 0.15 6 (9) 8 (10) 0.048 iief score 27 (4.5) 25 (10) 0.123 25.5 (9) 26 (8) 0.88 26 (6.75 27 (14) 0.41 pedt score 4 (4.75) 5 (6) 0.37 4 (5.5) 2.5 (6.25) 0.34 4 (5) 4 (5) 0.63 nih-cpsi: national institutes of health chronic prostatitis symptom score. ipss: international prostate symptom score. iief (1-5,15): short international index of erectile function (sum of questions 1, 2, 3, 4, 5, 15). pedt: premature ejaculation diagnostic tool. gad-7: general anxiety disorder-7. phq-9, patient health questionnaire-9. archivio italiano di urologia e andrologia 2024; 96(1):12452 k. stamatiou, v. magri , m. trinchieri, et al. 6 the lack of a relationship between psychological dysfunctions and sexual functioning in a cp/cpps population could be explained by a prevalent impact of other factors in the pathogenesis of sexual dysfunction in cp/cpps subjects (inflammatory cytokines, vascular dysfunction) (24). information on the impact of personality traits in cp/cpps patients is scarce. in the present study, we administered temps-a, which is an instrument suitable for measuring traits which could make subjects vulnerable to affective episodes. affective temperaments (depressive, anxious, irritable, hyperthymic, and cyclothymic) are regarded as subclinical manifestations and high-risk states for various affective disorders and some somatic diseases (25). in our series, scores for depressive, anxious, irritable, and cyclothymic characters were significantly and positively correlated with nih-cpsi scores, showing that all these tracts may increase the clinical expression of the disease. on the contrary, a hyperthymic character was negatively correlated with the severity of total nih-cpsi scores and nih-cpsi qol sub score. temperaments affected the international prostate symptom score (ipss) with a similar trend, although correlation was statistically significant only for depressive temperament. in fact, as above discussed, both ipss and nihcpsi (voiding domain) score voiding dysfunctions, but ipss focuses more on voiding symptoms related to bladder neck obstruction (incomplete emptying, intermittency, weak stream and straining) rather than to storage symptoms, that are mainly related to prostatitis. affective temperaments showed a limited influence on scores of sexual functions in our series, although pedt scores were negatively correlated with hyperthymic scores. the negative correlation of pedt scores with hyperthymic temperament scores confirms that this personality trait could be present in subjects who are able to better manage symptoms associated with prostatitis. a limitation of this study was the lack of a cohort of healthy controls, that would have been useful to better define the clinical relevance of the levels of psychological dysfunction observed in our patients with cp/cpps. in addition, the study design did not include measures of catastrophism and perceived stress for a more complete assessment of the psychological profile of patients. previous studies confirmed an association between catastrophizing and pain intensity and quality of life whereas data on the influence of stress are less consistent (16). another aspect that would have deserved more attention is the interrelationship between patients and their spouses, that could have an impact on painful symptoms (26). all these aspects will be the goal of future studies. conclusions our results confirm the strict correlation between scores measuring anxiety, depression and well-being and scores of prostatitis-like symptoms. in particular, the presence on anxiety disorders is predicted at very low nih-cpsi values. ipss, an assessment tool for measuring symptoms of patients with prostatism is more focused on bladder neck obstruction symptoms and correlated poorly with measures of anxiety, depression and well-being. no correlations were observed between scores measuring pdt), the second studying the correlation of cp/cpps symptom intensity and different personality traits. among patients with cp/cpps, a higher rate of psychiatric disorders as diagnosed by a psychiatrist using a semi-structured interview was previously observed (17). the higher rate of patients with cp/cpps on psychiatric drugs can also be considered a reliable measure of the association between an existing substrate of psychiatric conditions and the subsequent onset of chronic prostatitis (18, 19). a recent metanalysis (20) found several case-control studies showing higher scores of psychological disturbances in cp/cpps using a variety of diagnostic tools. some of those series showed a correlation of symptoms measured with nih-cpsi and the severity of psychological dysfunctions. the results of our study confirm a good correlation between nih-cpsi scores (total, pain, voiding symptoms and, qol) and measures of depression, anxiety, and psychological well-being although median values of these measures are indicative of mild disturbances. however, the question whether chronic prostate inflammation is the cause of anxiety or depression, or, on the contrary, a chronic depressive or anxious condition can generate or enhance the symptoms of chronic prostatitis remains still unsolved. in our series, logistic regression analysis of increasing nih-cpsi score as predictor of the dichotomized gad-7 test outcome (absent versus mild-to-severe anxiety) showed that anxiety in at least 50% of cases (el50) is predicted by very low levels of the nih-cpsi total score (4.88), pain score (3.07), voiding score (2.03) and qol score (2.58). this finding could suggest that an anxious profile may be a “background” feature independent from the prostatitis syndrome. in other words, it may be hypothesized that traits of preexisting anxiety may be part of the general psychological profile of an individual, and that this may precede the manifestation of chronic prostatitis and, when the syndrome presents, lead to an exaggerated perception of its symptoms. on the contrary, poor correlation of ipss scores with gad-7, phq-9 and oxford scores may be explained by the structure of the ipss questionnaire that is designed to assess symptoms of prostatism including voiding symptoms related to bladder neck obstruction rather than filling or irritative symptoms that are typical of prostatitis. when our cp/cpps patients with and without psychological disorders were separately assessed, the total nihcpsi scores and the sub scores for pain and qol were higher in patients with psychological dysfunction compared to those without. conversely, voiding sub scores were different in patients with depression but not in those with anxiety or psychological distress. this finding suggests that pain symptoms are crucial in the comorbidity of cp/cpps and depression or anxiety. although the prevalence of erectile dysfunction was high in our series (52% of patients showed an iief score ≤ 26), we did not find significant correlations between anxiety, depression and psychological well-being scores and the iief-5 and pedt scores. this observation contrasts with the common knowledge that psychological disorders negatively impact sexual function (21-23). on the contrary, archivio italiano di urologia e andrologia 2024; 96(1):12452 7 psychosexologic assessment in prostatitis psychological conditions and those measuring erectile and ejaculatory dysfunction. information on temperamental profiling of patients with prostatitis-like symptoms is limited, although depressive, anxious, irritable, and cyclothymic temperaments are associated to more severe prostatitis symptoms whereas hyperthymic temperament seems to be protective against symptoms of prostatitis and ejaculatory dysfunction. references 1. propert kj, mcnaughton-collins m, leiby be, et al. chronic prostatitis collaborative research network. a prospective study of symptoms and quality of life in men with chronic prostatitis/chronic pelvic pain syndrome: the national institutes of health chronic prostatitis cohort study. j urol. 2006; 175:619-23. 2. shoskes da, nickel jc, dolinga r, prots d. clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity. urology. 2009; 73:538-42. 3. magri v, wagenlehner f, perletti g, et al. use of the upoint chronic prostatitis/chronic pelvic pain syndrome 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hypertension and affective temperaments-a cross-sectional observational study in primary care settings. eur j gen pract. 2014; 20:247-52. 26. tripp da, nickel jc, shoskes d, koljuskov a. a 2-year followup of quality of life, pain, and psychosocial factors in patients with chronic prostatitis/chronic pelvic pain syndrome and their spouses. world j urol. 2013; 31:733-9. correspondence konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio hospital, pireus, greece vittorio magri, md vittorio.magri@asst-fbf-sacco.it urology unit, asst fatebenefratelli sacco, milan, italy margherita trinchieri, md margherita.trinchieri@gmail.com psichiatry unit, asst rhodense, g. salvini hospital, garbagnate (milan), italy. alberto trinchieri, md alberto.trinchieri@gmail.com school of urology, university of milan, milan, italy gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. (corresponding author) gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11361 1 original paper introduction worldwide, nephrolithiasis is one of the commonest urologic diseases. in the last decades, the prevalence of nephrolithiasis has changed, with prevalence ranges from 7% to 13%, 5% to 9%, and 1% to 5% in north america, europe, and asia, respectively (1). the wide prevalence ranges among countries reflect several multifactorial conditions including age, sex, race, climate, occupation, dietary habits, fluid intake, genetic and metabolic diseases (2). in asia, the prevalence and incidence of urolithiasis have increased in most of the countries specifically more in the south asian countries than in the north asian countries (5.5% to 11.6% compared to 2.6% to 7.2%, respectively) (3). this is because of the higher temperature and excessive sunshine exposure in the south countries than that in the north countries. saudi arabia is located in the west asian region and due to its high temperature and semiarid climate the prevalence of urinary tract stones was documented to be rising. during the period from 1989 through 2008, the prevalence rate of urolithiasis has been increased from 6.8% (4) to 19.1% (5). renal stone recurrence is a devastating health problem, which affects the patients’ health-related quality of life (6), as well as represents an extra economic burden for its management (7). in a prospective study, trinchieri et al. studied the stone recurrence rate and risk after a first stone episode and found that 27% of patients developed symptomatic stone recurrence at mean follow-up of 7.5 years. in addition, age at onset of the disease was significantly lower for patients with ≥ 2 recurrence than those who had only 1 or no recurrence (8). among asian countries, the reported recurrence rate of urolithiasis in the first year was about 6% to 17%, and at 5 years reaching up to 53%, while the lifetime risk of urinary stones recurrence is estimated to be 60% to 80% (9). in saudi arabia, abdel-halim et al. reported a recurrence rate of renal stone ranging from 38.6% to 53.2% (4). studies evaluating the risk factors of renal stone recurrence are not common. our study aimed to explore the demographic characteristics of primary renal stones forobjectives: we evaluated the baseline characteristics, and risk factors of renal stone recurrence among saudi arabian patients after successful primary stone treatment. materials and methods: in this cross-sectional comparative study, we reviewed the medical records of patients who presented consecutively with a first renal stone episode from 2015 to 2021 and were followed-up by mail questionnaire, telephone interviews, and/or outpatient clinic visit. we included patients who achieved stone-free status after primary treatment. patients were divided into two groups: group i (patients with first episode renal stone) and group ⅱ (patients who developed renal stone recurrence). the study outcomes were to compare the demographics of both groups and to evaluate the risk factors of renal stone recurrence after successful primary treatment. we used student’s t-test, mann whitney test or chi-square (𝝌2) to compare variables between groups. cox regression analyses were used to examine the predictors. results: we investigated 1260 participants (820 males and 440 females). of this number, 877 (69.6%) didn’t develop renal stone recurrence and 383 (30.4%) had recurrence. primary treatments were percutaneous nephrolithotomy (pcnl), retrograde intrarenal surgery (rirs), extracorporeal shock wave lithotripsy (eswl), surgery and medical treatment in 22.5%, 34.7%, 26.5%, 10.3%, and 6%, respectively. after primary treatment, 970 (77%) and 1011 (80.2%) of patients didn’t have either stone chemical analysis or metabolic work-up, respectively. multivariate logistic regression analysis revealed that male gender (or: 1.686; 95% ci, 1.216-2.337), hypertension (or: 2.342; 95% ci, 1.439-3.812), primary hyperparathyroidism (or: 2.806; 95% ci, 1.510-5.215), low fluid intake (or: 28.398; 95% ci, 18.158-44.403) and high daily protein intake (or: 10.058; 95% ci, 6.400-15.807) were predictors of renal stone recurrence. conclusions: male gender, hypertension, primary hyperparathyroidism, low fluid intake and high daily protein intake increase the risk of renal stone recurrence among saudi arabian patients. key words: renal stone; risk factors; recurrence; saudi arabia. submitted 5 april 2023; accepted 28 may 2023 evaluation of risk factors for recurrent renal stone formation among saudi arabian patients: comparison with first renal stone episode mohammed alshehri 1, hind alsaeed 2, malath alrowili 2, faisal alhoshan 3, ali abdel raheem 4, 5, ayman hagras 5, 6 1 department of urology, king abdullah bin abdulaziz university hospital, princess nourah bint abdulrahman university, riyadh, saudi arabia; 2 princess nourah bint abdulrahman university, riyadh, saudi arabia; 3 prince sultan military hospital, taif, saudi arabia; 4 department of urology, king saud medical city, riyadh, saudi arabia; 5 department of urology, tanta university hospital, tanta, egypt; 6 division of urology, surgery department, sharurah armed forces hospital, sharurah, saudi arabia. doi: 10.4081/aiua.2023.11361 summary archivio italiano di urologia e andrologia 2023; 95(3):11361 m. alshehri, h. alsaeed, m. alrowili, f. alhoshan, a. abdel raheem, a. hagras 2 mer, as well as the risk factors of renal stone recurrence after successful primary treatment in saudi arabia. we believe that the results of this study may provide an insight into ways that can help us to prevent the recurrence of renal stones. materials and methods study design and ethical statement a prospective cross-sectional comparative study was carried out at four saudi arabia's tertiary centers in riyadh, taif and sharurah cities. the study was approved by the institutional review boards and ethical committee of princess nourah bint abdulrahman university and was performed in accordance with the ethical standards and the helsinki declaration (institutional review board “irb” registration number: h-01-r-059). all patients included in our study signed a written informed consent. we reviewed the medical records of patients who presented consecutively with a first renal stone episode from 2015 to 2021 at urology departments of the participating centers. from march 2020 through march 2021, patients were interviewed either during their follow-up visits in the clinic or by telephone interviews to fill out a questionnaire. a total of 1260 patients completed the questionnaires successfully. patients were divided into two groups: group i (patients with first episode renal stone) and group ii (patients who developed renal stone recurrence). inclusion and exclusion criteria patients aged ≥ 18 years old with history of successful primary renal stone treatments (i.e., medical or surgical) were included in the current study. we excluded patients with remaining stones after the initial stone episode, patient who had urinary tract malformation, urinary tract obstructive disease, history of pyeloplasty or ureteric reimplantation surgery, renal failure, chronic gastric diseases, and incomplete questionnaire data. patients' characteristics demographic and baseline patients' characteristics were retrieved from our database including age, gender, body mass index (bmi), medical comorbidities such as diabetes mellitus (dm), hypertension (htn), cardiac diseases…etc, city of residency, nationality, family history of urolithiasis, and history of recurrent urinary tract infection (uti). moreover, data regarding renal stone were gathered such as primary or recurrent renal stone, time to first recurrence, frequency of recurrence, previous treatment methods (either surgical or medical), chemical analysis of the stone, and routine metabolic work-up after successful primary treatment. follow-up all patients were followed-up after treatment at 6 weeks, 3 months then yearly until the last visit. routine postoperative imaging study included kidney-ureter-bladder (kub) x-ray, urinary ultrasound (uus), or computed tomography (ct) scan that were performed according to the surgeon preference and/or stone radiopacity. stonefree status was defined as non-obstructing residual stone fragments of ≤ 2 mm in size detected at 3 months postoperatively on postoperative imaging studies (10). recurrent renal stone was defined as new stone formation and/or stone growth during routine follow-up that was diagnosed radiologically (11). patients' lifestyle information regarding the level of physical activity per week and dietary habits were obtained through asking the patients to complete a previously published (12, 13) non-validated self-administered questionnaire including selected items (1 question for physical activity and 5 questions for dietary habit). questionnaires were disseminated among patients either in the clinic during follow up visits and/or through telephone calls. the commonest dietary habits that are associated with increased risk of stone formation and recurrence include; low fluid intake (< 1 liter/day), high salt diet (> 10 g/day), high protein intake (> 100 g/day), lowcalcium diet (≤ 400 mg/day), and high intake of oxalate containing foods (14). outcome measurement the primary outcome was to compare groups in order to evaluate the predictors of renal stone recurrence after successful primary treatment. the secondary outcome was to assess demographic characteristics of stone formers in saudi arabia. statistical analysis continuous variables were illustrated as mean ± standard deviation (sd) or median and interquartile range (iqr), whereas categorical variables were illustrated as frequency and percentages (%). to compare variables of group i and group ii, we used the student’s t-test, mann whitney test or chi-square (𝝌2) test to examine the statistical significance of normally distributed data, nonparametric data, or categorical data, respectively. a univariable and multivariable cox regression analyses were used to examine the predictors of renal stone recurrence. all tests were twosided and p value of less than 0.05 was considered statistically significant. all tests used the spss version 23 software (ibm spss statistics, ibm corp., armonk, ny, usa). results a total of 1260 participants (820 males and 440 females) with history of successful renal stone primary treatment completed the questionnaire and were included in our study. baseline patients’ clinical and demographic data are summarized in (table i). median patients’ age was 29 years (iqr: 23-41), and median bmi was 25.3 kg/m2 (iqr: 21.8-29). the incidence of htn was 10.2% and phpt was 5.8%. most of patients 811 (64.4%) are living in the central region of the country. previous primary treatments were pcnl, rirs, eswl, surgery and medical treatment in 283 patients (22.5%), 437 patients (34.7%), 334 patients (26.5%), 130 patients (10.3%), and 76 patients (6%), respectively. among the participants, 383 patients (30.4%) had recurrent renal stone and 877 patients (69.6%) didn’t develop recurrence after primary stone treatment. the median follow-up period from the onset of primary stone treatment was 32 archivio italiano di urologia e andrologia 2023; 95(3):11361 3 predictors of renal stone recurrence months (iqr: 24-41). the median time to first recurrence of renal stone was 29 months (iqr: 14-35). after successful primary treatment, 970 (77%) and 1011 (80.2%) of patients didn’t have either stone chemical analysis or metabolic work-up, respectively. the comparison of patients with primary and recurrent renal stones is showed in (table 2). no significant differtable 1. baseline characteristic of patients with renal stone in saudi arabia (n = 1260). age (yr): mean ± sd 32.5 ± 12.4 median (iqr) 29 (23-41) bmi (kg/m2): mean ± sd 25.9 ± 6.1 median (iqr) 25.3 (21.8-29) bmi classification, n (%) underweight (< 18.5) 82 (6.5%) normal (18.5-24.9) 525 (41.7%) overweight and obese (> 25) 653 (51.8%) gender, n (%) female 440 (34.9%) male 820 (65.1%) chronic diseases, n (%) htn 129 (10.2%) dm 98 (7.8%) asthma 106 (8.1%) hypercholesterolemia 101 (8%) phpt 73 (5.8%) gout 27 (2.1%) residency, n (%) central region 811 (64.4%) eastern region 225 (17.9%) western region 125 (9.9%) southern region 55 (4.4%) northern region 44 (3.5%) nationality, n (%) saudi 1191 (94.5%) other 69 (5.5%) physical activity, n (%) low (≤ 1 day/week) 504 (40%) moderate (2-4 days/week) 548 (43.5%) high (≥ 5 days/week) 208 (16.5%) recurrence of kidney stones, n (%) first time 877 (69.6%) recurrent ≥ 2 times 383 (30.4%) family history of renal stone, n (%) no 854 (67.8%) yes 406 (32.2%) history of uti, n (%) no 721 (57.2%) yes 539 (42.8%) dietary habits, n (%) high salt diet (> 2 gm/day) 256 (20.3%) low fluid intake (< 1 l/day) 459 (36.4%) high protein intake (≥ 3 times/week) 763 (60.6%) low calcium intake (≤ 400 mg/day) 205 (16.3%) high oxalate containing foods 158 (12.5%) stone chemical analysis, n (%) yes 290 (23%) no 251 (19.9%) nobody asked 719 (57.1%) stone type, n (%) calcium oxalate 120 (9.5%) calcium phosphate 44 (3.5%) cystine 54 (4.3%) struvite 72 (5.7%) unknown 970 (77%) metabolic workup, n (%) yes 249 (19.8%) no 294 (23.3%) nobody asked 717 (56.9%) previous treatment, n (%) pcnl 283 (22.5%) rirs 437 (34.7%) eswl 334 (26.5%) surgery 130 (10.3%) controlled diet + medical ttt 76 (6%) uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. table 2. comparing characteristic of patients with first time and recurrent renal stones. primary stone recurrent stone p-value variables (group i, n = 877) (group ii, n = 383) age (yr), mean ± sd 31.3 ± 12.1 35.1 ± 12.6 0.000 bmi (kg/m2), mean ± sd 25.9 ± 6.1 26.2 ± 6.3 0.421 bmi classification, n (%) underweight 56 (6.4%) 26 (6.8%) 0.492 normal 375 (42.8%) 150 (39.2%) overweight and obese 446 (50.9%) 207 (54%) gender, n (%) female 340 (38.8%) 100 (26.1%) 0.000 male 607 (61.2%) 283 (73.9%) hypertension (htn), n (%) 73 (8.3%) 56 (14.6%) 0.001 diabetes (dm), n (%) 63 (7.2%) 35 (9.1%) 0.253 asthma, n (%) 71 (8.1%) 35 (9.1%) 0.581 hypercholesterolemia, n (%) 62 (7.1%) 39 (10.2%) 0.071 hyperparathyroidism, n (%) 41 (4.7%) 32 (8.4%) 0.013 gout, n (%) 15 (1.7%) 12 (3.1%) 0.137 residency, n (%) central region 580 (66.1%) 231 (60.3%) 0.133 eastern region 156 (17.8%) 69 (18%) western region 82 (9.4%) 43 (11.2%) southern region 33 (3.8%) 22 (5.7%) northern region 26 (3%) 18 (4.7%) nationality, n (%) saudi 835 (95.2%) 356 (93%) 0.105 other 42 (4.8%) 27 (7%) physical activity, n (%) low 363 (41.4%) 141 (36.8%) 0.300 moderate 371 (42.3%) 177 (46.2%) high 143 (16.3%) 65 (17%) history of uti, n (%) no 479 (54.6%) 242 (63.2%) 0.005 yes 398 (45.4%) 141 (36.8%) family history, n (%) no 607 (69.2%) 247 (64.5%) 0.101 yes 270 (30.8%) 136 (35.5%) dietary habits, n (%) high salt diet (yes) 180 (20.5%) 76 (19.8%) 0.782 low fluid intake (yes) 191 (21.8%) 268 (70%) 0.000 high protein intake (yes) 507 (57.8%) 256 (66.8%) 003 low calcium intake (yes) 151 (17.2%) 54 (14.1%) 0.168 high oxalate intake (yes) 105 (12%) 53 (13.8%) 0.358 stone type, n (%) calcium oxalate 49 (5.6%) 71 (18.5%) 0.000 calcium phosphate 20 (2.3%) 24 (6.3%) cystine 24 (2.7%) 30 (7.8%) struvite 36 (4.1%) 36 (9.4%) unknown 748 (85.3%) 222 (58%) previous treatment, n (%) pcnl 203 (23.1%) 80 (20.9%) 0.654 rirs 307 (35%) 130 (33.9%) eswl 232 (26.5%) 102 (26.6%) surgery 84 (9.6%) 46 (12%) controlled diet + medical ttt 51 (5.8%) 25 (6.5%) uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. archivio italiano di urologia e andrologia 2023; 95(3):11361 m. alshehri, h. alsaeed, m. alrowili, f. alhoshan, a. abdel raheem, a. hagras 4 ence was found in most variables (p > 0.05). mean patients’ age was 35.1 ± 12.6 yr. in group i compared to 31.3 ± 12.1 yr. in group ii (p = 0.000). more male patients were present in group ii compared to group i (73.9% vs. 61.2%, p = 0.000, respectively). the rates of htn, phpt, low fluid intake, and high daily protein diet were significantly higher in group ii (14.6% vs. 8.3% in group i, p = 0.001), (8.4% vs. 4.7% in group i, p = 0.013), (70% vs. 21.8 % in group i, p = 0.000) and (66.8% vs. 57.8% in group i, p = 0.003), respectively. univariate logistic regression analysis showed that age, male patients, htn, phpt, history of uti, low fluid intake, and high daily protein intake were associated with increased risk of renal stones recurrence (p < 0.05). multivariate logistic regression analysis revealed that male patients (or: 1.686; 95% ci, 1.216-2.337), htn (or: 2.342; 95% ci, 1.439-3.812), phpt (or: 2.806; 95% ci, 1.510-5.215), low fluid intake (or: 28.398; 95% ci, 18.158-44.403) and high daily protein intake (or: 10.058; 95% ci, 6.400-15.807) were predictors of renal stone recurrence. discussion in this prospective study, the risk factors and baseline characteristics of renal stone formers, as well as the predictors of recurrent renal stone formations were investigated in saudi arabian. a total of 1260 patients (820 males and 440 females) were included in the analysis. the rate of kidney stone recurrence after successful primary stone treatment was 30.4% among the participants. the results demonstrated that male gender, htn, phpt, low oral fluid intake and high daily protein intake were potential risk factors for recurrent kidney stone formation. we believe that the result of our study may provide better insight into the prevention of kidney stones recurrence through proper control and management of its risk factors. renal stone recurrence is a common disease. patients with renal stones have an increase chance of forming another stone in the future. stones can recur as long as 10 years after the first episode (8). in our cohort, the overall renal stone recurrence rate was 30.4%. among them, 11.3% of patients had two-time recurrences, 9.8% had three-time recurrences, and 9.4% had four-time recurrences. our results are in accordance with previous study reporting the recurrence rate of nephrolithiasis recurrence of 38.6% to 53.2% in saudi arabia (4). in the present study, the median time of renal stone recurrence was 29 months (iqr: 14-35). generally, following the initial episode, nephrolithiasis carries a high recurrence rate of 3.4 per 100 person-years, 7.1 after the second episode, 12.1 after the third episode, and 17.6 after the fourth episode or higher (15). moreover, the natural cumulative recurrence stone rate was estimated to be 6 to 17%, 35%, and 52% at one year, five years, and ten years, respectively (15). our study showed that the recurrent kidney stone rate was found to be significantly higher in men (56.6%) than in women (44.4%). in addition, male gender was identified as a predictor for nephrolithiasis recurrence. this may be attributed to the hormonal differences between men and women. in women, estrogen stimulates the secretion of citric acid in urine and regulates the synthesis of 1,25-dihydroxy-vitamin d which are considered protective factors against nephrolithiasis. on the other hand, men’s androgen induces the urinary accumulation of uric acid, calcium, and oxalate which increase the risk of kidney stone formation (16, 17). of note, 10.2% of the cases in our study had htn and the odds of recurrent renal stone in htn cases was 2.34 compared with non-htn cases. sahng et al. found that the risk of renal stone formation was directly associated with the incidence of htn (18). interestingly, in a recent study 29.7% of patients with nephrolithiasis had htn (19). in a recent systematic review and meta-analysis, htn was found to be one of the risk factors for renal stone recurrence (20). it worth note that, the exact mechanism of renal stone formation in patients with htn remains unclear, and only few studies have examined it. table 3. univariate and multivariate analysis of predictors of recurrent renal stone ≥ 2 times in saudi patients. univariable analysis multivariable analysis variable or (95% ci) p-value or (95% ci) p-value age 1.025 (1.015-1.035) 0.000 bmi 1.008 (0.989-1.028) 0.421 bmi classification: underweight ref normal 0.862 (0.521-1.424) 0.561 overweight and obese 1.000 (0.610-1.637) 0.999 male patient 1.794 (1.401-2.298) 0.000 1.686 (1.216-2.337) 0.002 htn 1.886 (1.301-2.734) 0.001 2.342 (1.439-3.812) 0.001 dm 1.299 (0.844-2.001) 0.234 asthma 0.142 (0.747-1744) 0.540 hypercholesterolemia 1.490 (0.979-2.268) 0.063 phpt 1.859 (1.152-3.001) 0.011 2.806 (1.510-5.215) 0.001 gout 1.859 (0.862-4.010) 0.114 residency: central region ref eastern region 1.111 (0.805-1.532) 0.523 western region 1.738 (0.935-3.231) 0.081 southern region 1.647 (0.956-2.932) 0.072 northern region 1.317 (0.883-1.963) 0.177 saudi patient 0.663 (0.403-1.092) 0.107 physical activity: low ref moderate 1.228 (0.943-1.600) 0.127 high 1.170 (0.823-1.664) 0.381 history of uti 1.426 (1.114-1.825) 0.005 renal stone family history 1.238 (0.960-1.595) 0.099 dietary habits: high salt diet 0.959 (0.710-1.294) 0.782 low fluid intake 8.370 (6.383-10.976) 0.000 28.398 (18.158-44.403) 0.000 high protein intake 1.471 (1.144-1.892) 0.003 10.058 (6.400-15.807) 0.000 low calcium intake 0.789 (0.563-1.105) 0.168 high oxalate intake 1.181 (0.828-1.683) 0.358 previous treatment: pcnl ref rirs 1.075 (0.772-1.495) 0.670 eswl 1.116 (0.788-1.580) 0.538 surgery 1.390 (0.892-2.164) 0.145 diet + medical ttt 1.244 (0.722-2.143) 0.432 uus: ultrasound scan, ctu; computed tompgraphy; htn: hypertension; dm: diabetes mellitus; bmi: body mass index; phpt: primary hyperparathyroidism; uti: urinary tract infection; pcnl: percutaneous nephrostomy; rirs: retrograde intrarenal surgery; eswl: extracorporeal shockwave lithotripsy. archivio italiano di urologia e andrologia 2023; 95(3):11361 5 predictors of renal stone recurrence frequent changes in the levels of blood pressure have a direct effect on the urinary microbiomes, which may stimulate nephrolithiasis (21). dietary habits play an important role in the renal stone formation. excessive meat consumption and low fluid intake were considered as main risk factors for nephrolithiasis. our study showed that in patients with recurrent kidney stones high protein intake rate was significantly higher (66.8%) than in primary stone formers (57.8%), similarly low fluid intake was significantly higher (70% vs. 21.8%). high protein intake leads to acidification of urine, which stimulate the formation of calcium oxalate stone (22). xu et al. found that each 500 ml increase in water intake was significantly associated with a reduced risk of kidney stone formation (rr = 0.93; 95% ci: 0.87, 0.98; p < 0.01). additionally, daily water intake > 2000 ml decreases the risk of first kidney stone formation by at least 8% compared to 1500 ml (23). phpt is one of the listed risk factors for renal stone formation. it has been estimated that 20% of patients with phpt have nephrolithiasis, and approximately 5% of patients who presented with renal stones have phpt (24). our results are in agreement with the aforementioned results. notably, 73 patients (5.8%) have phpt in our cohort analysis. moreover, the rate of patients with recurrent renal stone and phpt was significantly higher (8.4%) than those without phpt (4.7%), in addition, the odds of recurrent renal stone in phpt patients was 2.8 compared with non-phtp patients. the current study has limitations and strengths. the strength points of our study are the following: a prospective study, large sample size (n = 1260), and extensive data gathering for the factors of interest related to stone formation and recurrence (e.g., age, sex, bmi, medical comorbidities, dietary habits, area of residency etc.). however, our study does not devoid of limitations, and the results have to be interpreted with caution. for instance, the short median follow-up period (32 months) may be not enough to estimate the actual rate of renal stone recurrence. non-recurrent stone formers in this study are “patients who formed a first stone” although they may develop stone recurrence after longer follow-up period. also, stone composition and metabolic work-up results are unknown in 77% and 80.2% of patients, respectively. excluding those 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2020; 10:79-85. 20. wang k, ge1 j, han w, et al. risk factors for kidney stone disease recurrence: a comprehensive meta-analysis. bmc urology. 2022; 22:62. 21. liu f, zhang n, jiang p, et al. characteristics of the urinary microbiome in kidney stone patients with hypertension. j transl med. 2020; 18:130. 22. nasir sj. the mineralogy and chemistry of urinary stones from the united arab emirates. qatar univ sci j. 1999; 18:189-202. 23. xu c, zhang c, wang xl, et al. self-fluid management in prevention of kidney stones: a prisma-compliant systematic review and dose-response meta-analysis of observational studies. medicine (baltimore). 2015; 94:1042. 24. parks j, coe f, favus m. hyperparathyroidism in nephrolithiasis. arch intern med. 1980; 140:1479-81. correspondence mohammed alshehri, md mohammedalshehri95@yahoo.com department of urology, king abdullah bin abdulaziz university hospital, princess nourah bint abdulrahman university, riyadh, saudi arabia hind alsaeed, md alsaeedhindx@gmail.com princess nourah bint abdulrahman university, riyadh, saudi arabia malath alrowili, md pc435000386@gmail.com princess nourah bint abdulrahman university, riyadh, saudi arabia faisal alhoshan, md fmialhoshan@gmail.com prince sultan military hospital, taif, saudi arabia ali abdel raheem, md, phd (corresponding author) aliraheem82@yahoo.com a-hassan@ksmc.med.sa urology consultant, urology department, king saud medical city, riyadh, saudi arabia lecturer of urology, urology department, tanta university hospital, tanta, egypt ayman hagras, md ahagras80@yahoo.com department of urology, faculty of medicine, tanta university, tanta, egypt division of urology, surgery department, sharurah armed forces hospital, sharurah, saudi arabia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2132 original paper no conflict of interest declared. introduction prostate cancer (pca) is the second most common cancer among men and represents the fifth cause of cancer death worldwide (1). the diagnosis of pca represents a challenge for urologist as too many indolent tumors are still diagnosed after random or systematic prostate biopsy (2, 3). thus, in the era of active survelliance, it is crucial to identify patients with clinically significant pca (cspca) (4). historically, standard ultrasound (us) has been utilized for the diagnosis of pca with very low accuracy (5, 6). advances in multiparametric magnetic resonance imaging (mpmri) techniques have improved the diagnostic accuracy of pca and nowadays mpmri represents the mainstay of pca diagnosis (7). recently, precision study demonstrated that mpmri-targeted biopsies increased diagnostic yield compared with systematic biopsies, particularly for cspca, and reduces overdetection of clinically insignificant pca (8). however, to date, high quality prostate mri is not always available in all the centers and mpmri still remain an expensive and time-consuming test: therefore, we are far to consider it as a triage test in the detection of cspca (9). over time, several enhanced ultrasound techniques such as the colour/power doppler, and contrast-enhanced transrectal ultrasound (trus) have been used in an attempt to improve the accuracy of ultrasonography. however, these techniques have showed modest improvements over conventional trus, and their clinical use is limited (10, 11). recently, a novel us technology based on 29 mhz, exactvutm micro-ultrasound devices, has been proposed for the evaluation of prostatic gland for the diagnosis and staging of pca and for the execution of fusion biopsy (12). exactvutm is a new imaging modality that operates at high frequency (29 mhz). throughout the prostate risk introduction and objective: exactvutm is a real-time micro-ultrasound system which provides, according to the prostate risk identification using microultrasound protocol (pri-mus), a 300% higher resolution compared to conventional transrectal ultrasound. to evaluate the performance of exactvutm in the detection of clinically significant prostate cancer (cspca). materials and methods: patients with prostate cancer diagnosed at fusion biopsy were imaged with exactvutm. cspca was defined as any gleason score ≥ 3+4. exactvutm examination was considered as positive when pri-mus score was ≥ 3. pri-mus scoring system was considered as correct when the fusion biopsy was positive for cspca. a transrectal fusion biopsy-proven cspca was considered as a gold standard. sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) and area under the receiver operator characteristic (roc) curve (auc) were calculated. results: 57 patients out of 68 (84%) had a cspca. pri-mus score was correctly assessed in 68% of cases. regarding the detection of cspca, exactvutm ’s sensitivity, specificity, ppv, and npv was 68%, 73%, 93%, and 31%, respectively and the auc was 0.7 (95% ci 0.5-0-8). for detecting cspca in the transition/anterior zone the sensitivity, specificity, ppv, and npv was 45%, 66%, 83% and 25% respectively ant the auc was 0.5 (95% ci 0.2-0.9). accounting only the cspca located in the peripheral zone, sensitivity, specificity, ppv, and npv raised up to 74%, 75%, 94%, 33%, respectively with auc 0.75 (95% ci 0.5-0-9). conclusions: exactvutm provides high resolution of the prostatic peripheral zone and could represent a step forward in the detection of cspca as a triage tool. further studies are needed to confirm these promising results. key words: prostate cancer; imaging; detection rate; microultrasound; pri-mus score. submitted 7 february 2020; accepted 8 february 2021 diagnostic accuracy of the novel 29 mhz micro-ultrasound “exactvutm” for the detection of clinically significant prostate cancer: a prospective single institutional study. a step forward in the diagnosis of prostate cancer francesco chessa 1, 2, riccardo schiavina 1, 2, ercolino amelio 1, caterina gaudiano 3, davide giusti 3, lorenzo bianchi 1, 2, cristian pultrone 1, 2, emanuela marcelli 4, concetta distefano 1, luca lodigiani 5, eugenio brunocilla 1, 2 1 division of urology, irccs azienda ospedaliero universitaria di bologna; 2 department of urology, university of bologna, s. orsola-malpighi university hospital, bologna, italy; department of experimental, diagnostic and specialty medicine (dimes), cardio-nephro-thoracic sciences doctorate, university of bologna, bologna, italy; 3 division of radiology, irccs azienda ospedaliero universitaria di bologna; 4 laboratory of bioengineering, department of experimental diagnostic and specialty medicine (dimes), university of bologna, bologna, italy; 5 product manager ab medica, italy. doi: 10.4081/aiua.2021.2.132 summary 133archivio italiano di urologia e andrologia 2021; 93, 2 diagnostic accuracy of the novel 29 mhz micro-ultrasound “exactvutm” for the detection of clinically significant prostate cancer identification using micro-ultrasound (pri-mus) protocol, suspicious regions can be characterized, stratified, and targeted, similar to the prostate imaging-reporting and data system (pi-rads) protocol for mpmri (12, 13). the aim of our study was to evaluate the diagnostic accuracy of exactvutm ultrasound in the detection of cspca in a cohort of patients with pca previously diagnosed with targeted mpmri/toshiba aplio 500tm fusion biopsy. materials and methods study population after internal review board approval, between june 2018 and september 2018, 83 consecutive patients with biopsy proven pca made by targeted mpmri/trus fusion biopsy were registered into a prospective database and evaluated with exactvutm ultrasound. in the absence of a validated learning curve, the first fifteen patients were excluded in order to reduce operator bias. fusion biopsy was performed by one experienced urologist using the toshiba aplio 500tm system. inclusion criteria were: 1) presence of one single index lesion on mpmri according to the prostate imaging reporting and data system version 2 (pirads-v2) (14), 2) mpmri/ultrasound fusion biopsy performed at our department 3) diagnosis of pca. each patient included had complete demographic, clinical and pathologic parameters. study design this prospectively recorded study included male patients referred to our tertiary center with diagnosis of pca. first, patients underwent mpmri which led to the identification of an index lesion defined as pirads-v2 score ≥ 3. thereafter a fusion biopsy was carried out. all patients with biopsy proven pca at the level of the index lesion were imaged with 29mhz exactvutm transrectal micro-ultrasound. imaging all the mpmri examinations were performed before the biopsy, with a 1.5-t whole body scanner (signa hdxt; ge healthcare, milwaukee, wi, usa) and a standard 8channel pelvic phased-array surface coil combined with a disposable endorectal coil (medrad, indianola, pa). parameters of mpmri sequences and study acquisition were performed as previously reported in detail (15). all mri images were analysed by one expert uroradiologist, according to the 2012 european society of urogenital radiology guidelines (16). the presence of pca on mpmri was defined as equivocal, likely or highly likely according to the pirads-v2 score. biopsy protocol all men underwent transrectal fusion biopsy with the toshiba apliotm 500 scanner (canon medical systems corporation) equipped with an end-fire 8-5.5 mhz transducer. after uploading the mri images into the archive of the ultrasound machine (us), the registration between mri and us images was done in the axial plane. the fusion technique used an electromagnetic field tracking system, composed of an electromagnetic transmitter adjacent to the patient, as well as an electromagnetic sensors attached to the us transducer. after local anaesthesia with 10 ml of lidocaine, a side by side images of us and mri was obtained. once that the index lesion was identified and marked, 3-5 cores were taken according to the size of the index lesion. further random biopsy was taken in biopsy-naïve patients. histopathologic analysis histopathologic biopsy analysis was performed by a single experienced uro-pathologist according to international society of urological pathology standards (17, 18). clinically significant prostate cancer was defined as any gleason score ≥ 7. exactvutm micro-ultrasound imaging all patients underwent 29mhz exactvutm transrectal micro-ultrasound at least 3 weeks after the fusion biopsy. one uro-radiologist and one urologist with extensive expertise in prostate imaging but naïve to micro-ultrasound, were trained by an experienced mentor to use the exactvutm probes. investigators and mentor were blinded to the mpmri and to the pathologic report. prostate risk identification using micro-ultrasound (primus) is an evidence-based scale for exactvutm, developed to characterize tissue and stratify suspicious regions, as with pi-rads for mpmri (12). as previously described by ghai, the echoic characteristics of the prostate gland were analysed and dichotomized in a 5 point-risk scale (table 1) (12). table 1. echoic findings and corresponding primus risk assessment. primus risk score exactvu microultrasound findings primus 1 small regular ducts, “swiss cheese” with nother heterogeneity or bright echoes primus 2 some hyperechoic with or without ductal patches (possible ectatic glands or cysts) primus 3 mild heterogeneity or bright echoes in hyperechoic tissue primus 4 hetereogeneous cauliflower/smudgy/mottled appearance or bright echoes (possible comedonecrosis) primus 5 irregular shadowing (originating in prostate, not prostate border) or mixed echo lesions, or irregular prostate and/or peripheral zone border figure 1. parasagittal micro-ultrasound of the right lateral edge of the prostate. the exactvutm shows mottled tissue consistent with pri-mus grade 4 on the base of the prostate (red line underlines the lesion). archivio italiano di urologia e andrologia 2021; 93, 2 f. chessa, r. schiavina, e. amelio, c. gaudiano, d. giusti, l. bianchi, c. pultrone, e. marcelli, c. distefano, l. lodigiani, e. brunocilla 134 according to pri-mus protocol, exactvutm imaging consisted of a five steps procedure: 1) identifying the prostate border; 2) identifying the peripheral zone; 3) identifying the transition/anterior zone; 4) identifying any suspicious features in the peripheral (figure 1), transition (figure 2) and anterior zone (figure 3) and their nearness to the prostatic capsule (figure 4); 5) assign a pri-mus risk score based on previously reported features 12. exactvutm imaging was considered positive when the pri-mus score was ≥ 3. statistical analysis patient’s demographic and detection performance of exactvutm were analysed descriptively. for generating metrics of accuracy, the risk strata from the biopsy report was dichotomized to a non-clinically significant pca and a clinically significant pca. the presence of a “fusion biopsy proven cspca” was set as the gold standard and then the exactvutm detection rate was evaluated. primus scoring system was considered as correct when the exacvu findings matched with the location of the cspca at fusion biopsy. sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) and area under the receiver operator characteristic curve (auc) were calculated. chi square test was used to evaluate the correlation between pri-mus score and cspca. statistical analysis were performed using spss statistics 20 (ibm corp, armonk, ny, usa). results the demographic and clinical characteristics of the 68 patients available for the final analysis are shown in table 2. mean age at diagnosis was 63 years (± 8.6) and mean psa value was 9.6 ng/ml (± 2.8). digital-rectal examination was suspicious for pca in 17 men (25%). table 2. clinical characteristics of 68 patients in the study group. parameters value age mean ± sd 63.4 ± 8.6 median (iqr) 67.5 (56-71) psa ng/ml mean ± sd 9.6 ± 2.8 median (iqr) 9.0 (7-12) dre, n (%) positive 17 (25) prostate volume, ml mean ± sd 42 ± 16.4 median (iqr) 37 (31-52) prior negative biopsy, n (%) 23 (34) mpmri score, n (%) pi-rads 3 28 (41.2) pi-rads 4 36 (52.9) pi-rads 5 4 (5.9) transition/anterior lesions, n (%) 14 (20.6) targeted mpmri/ultrasound fusion biopsy cores per patient mean ± sd 4 ± 0.6 median (iqr) 4 (4-4) total positive cores mean ± sd 3 ± 1.1 median (iqr) 3 (2-4) pri-mus score, n (%) pri-mus 1 10 (14.7) pri-mus 2 16 (23.5) pri-mus 3 18 (26.5) pri-mus 4 17 (25.0) pri-mus 5 7 (10.3) figure 2. the exactvutm shows bright echoes and “cauliflower” area (arrow) consistent with pri-mus grade 4 on the transition zone of the prostate. figure 3. “smudgy/mottled” tissue consistent with pri-mus 4 in the anterior part of the prostate (red line underlines the lesion). figure 4. lateral micro-ultrasound of the left lobe of the prostate. the exactvutm shows mottled tissue consistent with pri-mus grade 4 causing irregular prostate border (arrow). 135archivio italiano di urologia e andrologia 2021; 93, 2 diagnostic accuracy of the novel 29 mhz micro-ultrasound “exactvutm” for the detection of clinically significant prostate cancer twenty-three patients (34%) had a previous negative random biopsy. mean prostate volume was 42 ml (± 16.4). mean number of cores taken in the index lesion were 4 (± 0.6), mean number of positive cores was 3 (± 1.1), 20% of the index lesions were in the transition/anterior zone and pri-mus score ≥ 3 was found in 42 (62%) patients. table 3 depicts in detail the pathological features of the targeted mpmri/ultrasound fusion biopsy: 57 patients out of 68 (84%) had a cspca. gleason score 3+3 was found in 11 patients (16.2%), gleason score 3+4 was found in 44 patients (64.7%), gleason score 4+3 was found in 6 patients (8.8%) and gleason score ≥ 8 was found in 7 patients (10.3%). table 3. pathological characteristics of 68 patients in the study group. parameters value biopsy gleason score, n (%) 6 11 (16.2) 7 (3+4) 44 (64.7) 7 (4+3) 6 (8.8) 8 or greater 7 (10.3) table 4. performance characteristic of exactvutm ultrasound in the detection of prostate cancer in the overall population. detection rate 72% positive predictive value 94% figure 5. receiver operating characteristic curve of exactvutm in the detection of clinically significant prostate cancer. figure 6. receiver operating characteristic curve of exactvutm in the detection of clinically significant prostate cancer located in the peripheral zone. figure 7. receiver operating characteristic curve of exactvutm in the detection of clinically significant prostate cancer located in the anterior/transition zone. archivio italiano di urologia e andrologia 2021; 93, 2 f. chessa, r. schiavina, e. amelio, c. gaudiano, d. giusti, l. bianchi, c. pultrone, e. marcelli, c. distefano, l. lodigiani, e. brunocilla 136 diagnostic accuracy of the exactvutm e micro-ultrasound table 4 shows the pooled detection rate (dr) and ppv of exactvutm e imaging for the diagnosis of pca. overall, exactvutm micro ultrasound had dr and ppv of 72% and 94%, respectively. considering exclusively the cspca (figure 5), sensitivity, specificity, ppv, and npv in the detection of cspca was 68%, 73%, 93%, and 31%, respectively and the auc was 0.706 (95% ci 0.5-0-8). accounting the anatomic distribution of the index lesions using the pirads-v2 scheme, the sensitivity, specificity, ppv, and npv were 45%, 66%, 83%, 25% with auc 0.540 (95% ci 0.2-09) for the detection of cspca in the transition/anterior zone, while for the cspca located in the peripheral zone the sensitivity, specificity, ppv, and npv raised up to 74%, 75%, 94%, 33%, with auc 0.754 (95% ci 0.5-0-9) (figures 6, 7). figure 8 shows the correlation between pri-mus score and presence of pca: there were no cases of pri-mus 1-2 in gs 3+3 pca. in gleason score 3+4 pca patients, primus was false negative in 18 (40%; p = 0.05) cases (pri-mus grade 1-2). however, for gleason score 4+3 or higher, exactvutm was always (100%; p = 0.05) reported as positive (primus ≥ 3). figure 9 depicts graphically the correlations between pri-mus score and presence of cspca: among the 57 cspca, in 39 (68%) cases exactvutm was considered as positive (primus ≥ 3; p = 0.01). discussion the biggest issue linked to pca workup is represented by the need to avoid overdiagnosis of low-grade tumours and the prominence of cspca detection. trans-rectal ultrasound (trus) has been widely used for the diagnosis and staging of pca, showing poor sensitivity in identifying neoplastic lesion, often indistinguishable from normal tissue. traditionally, men with a clinical suspicion of pca underwent a random transrectal ultrasonography-guided biopsy, which has a rough overall detecfigure 8. detailed report of the pri-mus score assignment in a cohort of 68 patients. figure 9. correlation between pri-mus score and clinically significant prostate cancer in 68 patients. table shows the chi square analysis. 137archivio italiano di urologia e andrologia 2021; 93, 2 diagnostic accuracy of the novel 29 mhz micro-ultrasound “exactvutm” for the detection of clinically significant prostate cancer tion rate of 30-50% (19-21). nowadays, mpmri seems to be the best imaging technique for the prostate, with a negative predictive value of 90% and an accuracy of 98% in diagnosing significant cancers (22, 23). indeed mpmri is increasingly performed before prostate biopsy, leading to fewer men who underwent biopsy, higher detection rate of cspca and reducing the overdetection of clinically insignificant cancer (8). however, to date, mpmri is burdened by some contraindications such as claustrophobia and pacemakers ant its widespread diffusion is limited by high costs, steep learning curve reporting the mri findings and it is also a time consuming test. since conventional trus have shown an overall detection rate of 30-50%, in the last two decades, a multitude of enhanced ultrasound devices have been proposed with the aim to improve the accuracy of ultrasonography (19-21). contrast-enhanced trus (ce-trus) was first described in 1968, it’s based on air bubbles that remains inside the blood vessels showing the increased tumour vascularity (23). ce-trus have shown a detection rate of 30-60% and nowadays is mainly used in other medical specialities such as detection of liver malignancies (24). colour doppler is another tool that have been proposed to improve the ultrasound performance, showing an overall detection rate of 20% (25). recently, the exactvutm system has been introduced in the market as a real-time micro-ultrasound system capable of providing 300% higher resolution (down to 70 μm) compared to conventional trus (26). ghai et al., in a recent publication, developed the pri-mus protocol, based on the exactvutm findings, demonstrating promising levels of accuracy for the detection of cspca (12). some results of our study are noteworthy: first, to our knowledge this represents one of the few prospective series of patients investigating the accuracy of exactvutm imaging in the detection of cspca. second, our study demonstrated that the improved visualization of prostatic parenchyma lead to an improved detection of cspca. exactvutm ultrasound shows an overall sensitivity and specificity of 68% and 73%, respectively with an auc of 0.7. these results are consistent with those previously described by ghai et al. who have showed an auc of 74% for cspca. similarly, pavolvich et al. using a different high frequency probe (21mhz) found improved accuracy in the detection of high grade pca compared to conventional trus (84% vs 60%) (10). third, since primus protocol was developed for peripheral zone lesions, we found differences in the exactvutm ’s accuracy basing on their location. indeed, as expected, we found some false-negative and false-positive results, particularly when the index lesions were in the transition/anterior zone. it is well known that trus has lower detection rate for the anterior zone, and trusguided biopsy miss the 80% of anterior pca (27). in our series, the sensitivity for transition/anterior lesions was 45%, but it raises up to 74% for the peripheral lesions. similarly, to pirads score, pri-mus score has been developed to ease the characterization of prostatic lesions, to standardize the imaging methodology and to provide a scoring system to differentiate the risk of carcinoma in each zone of the prostate. as pirads, primus score evaluation requires experience and can be burdened by interobserver discrepancy. in our series, pri-mus was correctly assessed in 68% of cases. as expected, the widest rates of misinterpretations were for low-intermediate (pca gleason score ≤ 3+4), in higher gleason score no misinterpretations were observed. despite our limited experience, we gained surprisingly high sensitivity and specificity. these promising results, suggests a potential use of exactvutm both as a triage tool, discerning the best patients candidates to underwent mpmri and as well as an alternative to mpmri in centers where this technology is not yet available. the low value of npv can be explained by our limited practice with this new technology and by the small sample size. further studies with larger cohorts are needed to clarify the true potential of micro-ultrasound devices. unfortunately, the lack of similar studies using exactvutm probe, made comparison more challenging. our study has some limitations: first all the investigators were naïve to micro-ultrasound devices and to pri-mus protocol. second, even though investigators were blinded to the previous clinicopathological findings, all patients underwent a previous fusion biopsy, which scars can be detected by exactvutm ultrasound, affecting the index lesion detection rate. third, the number of the patient’s cohort is quite limited, but it inevitably depends on the novelty of this diagnostic tool and the prospective design of the study. fourth, we used the mpmri-targeted fusion biopsy as a reference standard, even if the ideal gold standard for assessing the true diagnostic performance of an imaging tool actually remains the final pathology in radical prostatectomy specimens. moreover, our study shows the accuracy of exactvu in the detection of cspca, since all patients included in analysis already had a previous diagnosis of pca. in conclusion, exactvutm showed a promising and quite high accuracy in the detection of cspca as assessed by targeted mpmri/fusion biopsy. exactvutm provides high resolution of the prostatic peripheral zone and represents a step forward in the detection of cspca. these results encourage the use of exactvutm as a triage test and can help clinicians in the selection of borderline patients candidate to mpmri. further studies with larger cohort taking in account as reference the pathologic specimen of radical prostatectomy 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"in-bore" mri-guided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. clin genitourin cancer. 2017; 15:417-427. 7. hamoen ehj, de rooij m, witjes ja, et al. use of the prostate imaging reporting and data system (pi-rads) for prostate cancer detection with multiparametric magnetic resonance imaging: a diagnostic meta-analysis. eur urol. 2015; 67:1112-1121. 8. kasivisvanathan v, rannikko as, borghi m, et al. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med. 2018; 378:1767-77. 9. schiavina r, chessa f, borghesi m, et al. state-of-the-art imaging techniques in the management of preoperative staging and restaging of prostate cancer. int j urol. 2019; 26:18-30. 10. pavlovich cp, cornish tc; mullins jk, et al. high-resolution transrectal ultrasound: pilot study of a novel technique for imaging clinically localized prostate cancer urol oncol. 2014; 32:34.e27-32. 11. halpern ej, frauscher f, strup se, et al. prostate: high-frequency doppler us imaging for cancer detection radiology. 2002; 225:71-77. 12. ghai s, eure g, fradet v. assessing cancer risk on novel 29 mhz micro-ultrasound images of the prostate: creation of the micro-ultrasound protocol for prostate risk identification. j urol. 2016; 196:562-9. 13. lughezzani g, saita a, lazzeri m, et al. comparison of the diagnostic accuracy of micro-ultrasound and magnetic resonance imaging/ultrasound fusion targeted biopsies for the diagnosis of clinically significant prostate cancer. eur urol oncol. 2019; 2:329-332. 14. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging—reporting and data system: 2015, version 2. eur urol. 2016; 69:16-40. 15. schiavina r, bianchi l, borghesi m, et al. mri displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. j endourol. 2018; 32:315-321. 16. antunes hp, parada b, carvalho j, et al. prognostic value of subclassification (pt2 stage) of pathologically organ-confined prostate cancer: confirmation of the changes introduced in the 8th edition of the american joint committee on cancer (ajcc) staging system. arch ital urol androl. 2018; 90:191-194. 17. barentsz jc, richenberg j, clements r, et al. esur prostate mr guidelines 2012 eur radiol. 2012; 22:746-757. 18. epstein ji, egevad l, amin mb, et al. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016; 40:244-52. 19. durkan gc, sheikh n, johnson p, et al. improving prostate cancer detection with an extended-core transrectal ultrasonographyguided prostate biopsy protocol. bju international. 2002; 89:33-39. 20. porreca a, d'agostino d, vigo m, et al. "in-bore" mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation. arch ital urol androl. 2020; 91:224-229. 21. bertaccini a, consonni p, schiavina r, et al. prostate biopsy: approaches arch ital urol androl. 2005; 77(3 suppl 1):24-7. 22. prayer-galetti t, ficarra v, franceschini r. et al. when to carry out prostate biopsy arch ital urol androl. 2005; 77(3 suppl 1):3-16. 23. haffner j, lemaitre l, puech p, et al. role of magnetic resonance imaging before initial biopsy: comparison of magnetic resonance imaging-targeted and systematic biopsy for significant prostate cancer detection. bju int. 2011; 108:e171-8. 24. kuru th, fütterer jj, schiffmann j, et al. transrectal ultrasound (us), contrast-enhanced us, real-time elastography, histoscanning, magnetic resonance imaging (mri), and mri-us fusion biopsy in the diagnosis of prostate cancer. eur urol focus. 2015; 1:117-126. 25. taverna g, morandi g, seveso m, et al. colour doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling. bju int. 2011; 108:1723-7 26. ghai s, van der kwast t. suspicious findings on micro-ultrasound imaging and early detection of prostate cancer. urol case rep. 2017; 16:98-100. 27. schouten mg, van der leest m, pokorny m. why and where do we miss significant prostate cancer with multi-parametric magnetic resonance imaging followed by magnetic resonance-guided and transrectal ultrasound-guided biopsy in biopsy-naïve men? eur urol. 2017; 71:896-903. correspondence francesco chessa, md (corresponding author) francesco.chessa@live.it francesco.chessa3@unibo.it riccardo schiavina, md rschiavina@yahoo.it ercolino amelio, md amelio.ercolino@studio.unibo.it lorenzo bianchi, md lorenzo.bianchi13@unibo.it cristian vincenzo pultrone, md cristian.pultrone@gmail.com concetta distefano, md concetta.distefano@aosp.bo.it eugenio brunocilla, md eugenio.brunocilla@unibo.it department of urology, university of bologna, s. orsola-malpighi university hospital, via pelagio palagi 9 40130, bologna (italy) caterina gaudiano, md caterina.gaudiano@aosp.bo.it davide giusti, md davide.giusti@studio.unibo.it division of radiology, irccs azienda ospedaliero universitaria di bologna, bologna (italy) emanuela marcelli, md emanuela.marcelli@unibo.it laboratory of bioengineering, department of experimental diagnostic and specialty medicine (dimes), university of bologna, bologna (italy) luca lodigiani, md lodigiani.luca@abmedica.it product manager ab medica (italy) cop+ed+fisse 2006 121archivio italiano di urologia e andrologia 2022; 94, 1 letter to editor no conflict of interest declared. key words: covid-19; vaccination; penile mondor; phlebitis. submitted 9 january 2022; accepted 16 january 2022 dear editor, the pandemic spread of coronavirus 2 infection (sars-cov-2), determining the coronavirus disease 2019 (covid-19), had devastating consequences globally with several waves affecting social and economic life. the use of masks, physical distancing, testing of exposed or symptomatic persons, contact tracing and isolation have helped limit the transmission where they have been rigorously applied; however, these actions have proved not sufficient to limit the virus spread. the vaccinations are needed to reduce the morbidity and mortality of covid-19 (1). two vaccine types have been developed using two different technologies: viral vectors (vaxzevria; astrazeneca) and mrna (comirnaty-pfizer and mrna-1273moderna). aside from transient local and systemic reactions, no safety concerns were identified from vaccination. nevertheless, there are several concern in the public opinion about the possible consequences on uro-genital system, both in men and women. we know that exist evidence suggesting no embryo and gametes infections by sars-cov-2 and no consequences on fertility potential after vaccination (2). thrombosis is the most severe and nontypical adverse effects of vaccine. similarly to covid-19 infection, in which we recognized a predisposition to both venous and arterial thromboembolism due to excessive vascular and systemic inflammation, endothelial dysfunction, cytokine storm, hypoxia and immobilization, after vaccination there is a growing evidence of thrombotic vaccine-related events (2). during the first wave in 2020, we had already reported an increase in outpatient evaluations of patients complaining of a vascular andrological disease, known as penile mondor disease (pmd) (1). the pmd occurs with palpable subcutaneous cord-like indurations beneath the penile skin (figure 1). usually, pmd is an under-reported benign, self-limited disease that resolves spontaneously in four to eight weeks. the pmd under reporting may be because the lesion is often non painful and self-resolving. most patients refrain from seeking medical attention, and when they do, sometimes even physicians pay little attention to the lesion. the pmd pathogenesis can be demonstrated by virchow’s triad. triggering factors for endothelial damage intersect with underlying risk of blood stasis and hypercoagulability. for example, pmd may occur after frequent, vigorous, prolonged sexual activity, prolonged erection, urogenital infection and sexually transmitted diseases, pelvic surgery, penile trauma, prolonged sitting position, hematologic disease or thrombophilia. the intersection between the three virchow’s factors allows for blood clot formation in pmd typically isolated to the superficial dorsal vein with associated phlebitis (3, 4). covid-19 infection is also related to pmd, based on several cases report published in the last years (5). nothing is reported in the literature regarding the possible relationship between vaccination against covid-19 and pmd. however, in our daily clinical practice, in the last three months, we have recorded an increase in outpatient assessments of pmd. we refer to 5 cases whose clinical data are reported in table 1. covid-19 vaccination and penile mondor disease. there is any relationship? andrea fabiani 1, alessandra filosa 2, daniele maglia 1, emanuele principi 1, silvia stramucci 3 1 urology unit, surgery department, macerata civic hospital, area vasta 3 asur marche, italy; 2 pathology unit, asur marche area vasta 5, ascoli piceno, italy; 3 urologic clinic, marche polytechnic university, ancona, italy. doi: 10.4081/aiua.2022.1.121 table 1. clinical data of 5 cases. patient age vaccine type vaccination month outpatient evaluation month coagulation abnormal sex activity hystory clinic 1 25 pfizer july october normal no silent 2 37 moderna september december normal no silent 3 21 moderna august november normal no silent 4 24 pfizer august december normal no silent 5 28 pfizer july october normal no silent archivio italiano di urologia e andrologia 2022; 94, 1 a. fabiani, a. filosa, d. maglia, e. principi, s. stramucci 122 anamnesis and physical examinations were conducted to evaluate any possible cause of pmd. all patients underwent fast abdominal ultrasound and penile ecocolordoppler in flaccidity. laboratory tests with particular interest on coagulation state were performed. only the symptomatic patients (2/5) were treated with analgesic. only one case (1/5) received low molecular weight heparin for 15 days. all patient reported complete recovery from symptoms and subcutaneous cord-like indurations complained at the presentation. pmd usually affect men at 20 to 40 years of age and in our little case series age ranged between 24 and 37 years. all performed vaccination 4 or 5 months before with mrna-comirnatypfizer (3 cases) and mrna-1273-moderna (2 cases). no patients declared prolonged or unusual sexual activity. the clinical histories were silent for any possible hypercoagulability status. vaccinations were the only possible pathogenetic factors linking the 5 young patients. the questions arising from this real-life experience are basically two. is it therefore possible that there is a pathogenetic link between pmd and vaccination anti covid-19? is there any possibility of identifying subjects predisposed to the onset of this vascular disease after vaccination? although the pmd clinical course is very often self-limiting, in a scenario characterized by an annual anti-covid vaccination, may be important to always inform young male about the eventuality of developing pmd and alert general practitioners and referral specialists about the possible increase in the pmd response. from a diagnostic or therapeutic point of view, we don’t identify the need to change the usual attitude. we must continue to reassure the patient and to treat symptomatic cases since pmd can cause significant patient anxiety and embarrassment and may be easily confused with more concerning conditions. our aim is to urge the andrological scientific community to perform a large-scale data collection that allows us to define a correct answer to our questions. references 1. maretti c, fabiani a, colombo f, et al. italian experiences in the management of andrological patients at the time of coronavirus pandemic. arch ital urol androl. 2021; 93:111-114. 2. ruan y, hu b, liu z, et al. no detection of sars-cov-2 from urine, expressed prostatic secretions, and semen in 74 recovered covid-19 male patients: a perspective and urogenital evaluation. andrology. 2021; 9:99-106. 3. manimala nj, parker j. evaluation and treatment of penile thrombophlebitis (mondor's disease). curr urol rep. 2015; 16:39. 4. solinas a. thrombosis of the posterior scrotal vein associated with essential thrombocytemia: report of a case. arch ital urol androl. 2020; 92:112-113 5. lessiani g, boccatonda a, d'ardes d, et al. mondor's disease in sars-cov-2 infection: a case of superficial vein thrombosis in the era of covid-19. eur j case rep intern med. 2020; 7:001803. figure 1. clinical appearance (left, thin arrow) and ultrasound feature (right, arrow) of penile mondor disease. correspondence andrea fabiani, md (corresponding author) andreadoc1@libero.it surgery dpt, section of urology, asur marche area vasta 3 macerata hospital, via santa lucia, 60100, macerata (italy) alessandra filosa, md phd alessandra.filosa@sanita.marche.it pathology unit, asur marche area vasta 5, ascoli piceno (italy) daniele maglia, md emanuele.principi@sanita.marche.it emanuele principi, md emanuele.principi@sanita.marche.it surgery dpt, section of urology asur marche area vasta 3, macerata hospital, macerata (italy) stramucci silvia, md silvia.stramucci@gmail.com urologic clinic, marche polytechnic university, ancona (italy) stesura seveso 291archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. introduction metabolic syndrome (mets) is a clinical entity consisting of a cluster of hyperglycemia/insulin resistance, obesity, dyslipidemia and hypertension (1). mets is documented as a traditional risk factor for atherosclerotic cardiovascular disease (1, 2) and has become a global health problem with increasing prevalence, paralleling the increasing incidence of obesity and poor eating habits (3). it is well known that overweight and obese men are at increased risk of prostate enlargement and erectile dysfunction (4). furthermore, there is accumulating evidence that metabolic syndrome is associated with some common forms of cancer, as well as it poses a negative impact on cancer morbidity and mortality (5). this association sounds reasonable, since obesity, diabetes, and dyslipidemia have already been shown to be interrelated with some forms of cancer (6-8). nowadays, prostate cancer (pca) is the second most common male malignancy worldwide with established risk factors being increasing age, ethnic origin, and heredity (9). association between pca and mets comprise a matter of debate among published literature. data suggest that single components of mets, such as hypertension and central obesity, are related with a significantly greater risk of pca (10). in contrast, patients suffering from > 3 components of mets are found to have a reduced risk for pca (11). the purpose of this study is to evaluate whether mets correlates with pca diagnosis and gleason score (gs), in a sample of greek patients who underwent prostate biopsy in a tertiary, high volume, pca center. materials and methods study design clinical data were collected from a prospective database in a tertiary pca center, from consecutive patients who underwent transrectal, ultrasound-guided prostate biopsy between 2018-2019. patients were eligible for inclusion introduction and objective: even though the only established risk factors for prostate cancer (pca) are age, ethnic origin and family history, there are data suggesting that environmental factors, such as the presence of metabolic syndrome (mets), may also play a role in the etiology of the disease. the aim of this study is to correlate mets with pca diagnosis and gleason score (gs) in patients undergoing transrectal ultrasound guided prostate biopsy. materials and methods: this is a prospective, single-center study including 378 patients who underwent transrectal ultrasound guided prostate biopsy in our department during the years from 2018 to 2019. patients were divided into two groups according to the presence of pca. group a included 197 patients diagnosed with pca while group b consisted of 181 patients without pca in their biopsy result. multiple variables such as the presence of mets and its components were evaluated in correlation to the presence of pca and pca characteristics. statistical analysis was performed using the ibm spss statistics v.23 program. results: mean psa value was 8.7 ng/dl in the pca group and 7.1 ng/dl in the non pca group, respectively. mets was diagnosed in 108 patients (54.8%) with pca and 80 patients (44.2%) without pca and the difference was statistically significant. hypertriglyceridemia was the mets component with statistically higher frequency in pca patients. furthermore, the prevalence of mets was higher in higher gleason score pca (gs ≥ 4+3) patients vs lower gleason score pca (gs ≤ 3+4) patients. more specifically, mets, hypertriglyceridemia, and low hdl levels were independent factors associated with higher gleason score pca (gs ≥ 4+3). conclusions: patients suffering from mets who undergo prostate biopsy present with higher rates of pca diagnosis and higher gs in comparison with patients with a normal metabolic profile. key words: metabolic syndrome; prostate cancer; association of metabolic syndrome with prostate cancer; metabolic syndrome and prostate cancer characteristics; metabolic syndrome and high gleason score prostate cancer. submitted 17 june 2021; accepted 10 july 2021 association of metabolic syndrome with prostate cancer diagnosis and aggressiveness in patients undergoing transrectal prostate biopsy charalampos fragkoulis 1, ioannis glykas 1, lazaros tzelves 2, konstantinos stasinopoulos 3, lazaros lazarou 2, andreas kaoukis 4, athanasios dellis 5, georgios stathouros 1, georgios papadopoulos 1, konstantinos ntoumas 1 1 department of urology, general hospital of athens ‘’g. gennimatas’’, athens, greece; 2 2nd department of urology, national and kapodistrian university of athens, school of medicine, sismanoglio hospital, athens, greece; 3 department of urology, general hospital of lakonia, sparta, greece; 4 department of cardiology, general hospital of athens ‘’g. gennimatas’’, athens, greece; 5 2nd department of surgery, aretaieion hospital, school of medicine, national and kapodistrian university of athens, athens, greece. doi: 10.4081/aiua.2021.3.291 summary archivio italiano di urologia e andrologia 2021; 93, 3 c. fragkoulis, i. glykas, l. tzelves, k. stasinopoulos, l. lazarou, a. kaoukis, a. dellis, g. stathouros, g. papadopoulos, k. ntoumas 292 when there was a clinical suspicion for pca, based on elevated total psa values (> 4 ng/ml) or increasing trends of psa values compared to previous results. a multiparametric magnetic resonance imaging (mpmri) was not an essential component of our diagnostic algorithm, but when performed, reports indicating pirads 4 or 5 lesions, were an absolute indication to perform a biopsy. patients presenting with psa values > 20 ng/ml or signs suggestive of metastatic disease, were excluded. biopsy technique the protocol for transrectal biopsy in our center uses the systematic approach, with 6 cores from each prostatic lobe in biopsy-naïve patients. in case images from a mpmri were available, we also targeted suspicious lesions (cognitive biopsy), but no fusion protocol was followed. patients received orally antibiotic prophylaxis two days before and two days after biopsy. assessment of metabolic syndrome parameters diagnosis of metabolic syndrome was based on the american heart association criteria (1). a patient suffering from metabolic syndrome should present with three or more of the following five criteria: a) fasting glucose level ≥ 100 mg/dl (or prescription for treatment of diabetes mellitus), b) blood pressure ≥ 130/85 mmhg (or prescription for treatment of hypertension), c) triglycerides levels ≥ 150 mg/dl (or prescription for treatment of hypertriglyceridemia), d) hdl cholesterol level < 40 mg/dl and e) central obesity, defined as a waist circumference ≥ 102 cm (table 1). patients were asked regarding the use of drug regimen for management of diabetes, hypertension, and hypertriglyceridemia and in those patients, who did not follow any prescription, we measured fasting blood glucose levels and triglyceride levels. to assess hypertension, we performed blood pressure measurements at least on three occasions and also asked patients to present with a diary of measurements (three times daily for a week). in case abnormal blood pressure measurements were noted, a cardiology referral was made, and patient was considered to suffer from hypertension. we measured the waist circumference at our center using a scaled tape at the level above umbilicus, taking care to avoid skin compression and after patients exhaled. all patients underwent a measurement of hdl levels. other variables collected were age, psa value, bmi, and gleason score according to biopsy results. patients were divided in two groups according to pca diagnosis: group a included patients with a positive biopsy and group b those without malignant disease. all patients were informed regarding the aims and design of the study and were included after signing an informed consent. the institutional review board of the hospital approved study protocol before initiation and all patients were managed according to the principles of helsinki declaration. statistical analysis continuous variables are described as means ± sds or medians depending on whether there was normal distribution or not, while categorical variables are described with proportions. we performed independent sample ttest for comparing continuous variables when assumption for normality was met, as indicated by shapirowilk test. if normality assumption was not met, comparison of continuous variables was performed using mannwhitney u test. comparison of categorical variables was performed either with chi-square or fisher’s exact test, depending on the number of observations in each cell of the variable. binary logistic regression was performed to detect the effect of age, mets and each one of the five components (central obesity, triglycerides > 150 mg/dl, hdl < 40 mg/dl, diabetes mellitus, and hypertension) on occurrence of prostate cancer. linearity of the continuous variables used in the regression model regarding the logit of dependent variable was assessed with the boxtidwell procedure. a bonferroni correction was applied using all terms in the model created. based on this test, all continuous independent variables were linearly associated to the logit of the dependent variable. no significant outliers were detected during performance of the binomial regression model. all analyses were performed using ibm spss statistics v. 23 (ibm spss statistics for windows, version 23.0. armonk, ny: ibm corp.). results prospective data collection was performed for 378 patients within the two-year period of the study (20182019). mean patient age, body mass index and waist circumference did not differ significantly between the two groups (table 2). mean psa value was 8.7 ng/dl in the pca group and 7.1 ng/dl in the non pca group, respectively (p < 0.001). besides psa value, both triglycerides (166 vs 146 mg/dl, p < 0.001) and hdl cholesterol (46 vs 44.4 mg/dl, p < 0.001) were higher in patients diagnosed with prostate cancer (table 2). table 2. baseline patient characteristics. patients with pca patients without pca p-value no patients, n (%) 197 (52.1) 181 (47.9) age (years) 64.6 (8) 65 (7.2) 0.620 psa (ng/ml) 8.7 (3.2) 7.1 (2.4) < 0.001 bmi (kg/m2) 28.6 (3) 27.9 (2.7) 0.178 waist circumference (cm) 108 (8.6) 104.3 (7.7) 0.233 triglycerides (mg/dl) 166 (50) 146 (39) < 0.001 hdl (mg/dl) 46 (8.3) 44.4 (6.7) < 0.001 pca = prostate cancer. * numbers are presented as means (± sd). table 1. american heart association criteria for diagnosis of metabolic syndrome. 1. fasting glucose ≥ 100 mg/dl (or drug therapy for hyperglycemia) 2. blood pressure ≥ 130/85 mmhg (or drug therapy for hypertension) 3. triglycerides ≥ 150 mg/dl (or drug therapy for hypertriglyceridemia) 4. hdl cholesterol < 40 mg/dl (or drug therapy for reduced hdl) 5. waist circumference ≥ 102 cm 293archivio italiano di urologia e andrologia 2021; 93, 3 association between metabolic syndrome and prostate cancer diagnosis mets was diagnosed in 108 patients (54.8%) with and 80 patients (44.2%) without pca (p = 0.039). patients with pca more frequently suffered from abnormal levels of triglycerides, compared to healthy patients (59.9% vs 42.5% respectively, p = 0.001), as shown in table 3. mets was diagnosed in 42 patients (65.6%) with higher gleason score pca (gs ≥ 4+3) and in 66 patients (49.6%) with lower gleason score pca (≤ 3+4), p = 0.035. (table 4). individual components of metabolic syndrome did not differ significantly in patients with higher gleason score pca, compared to those with lower gleason score pca disease (table 4). age (or 1.061, 95% c.i.: 1.0161.107, p = 0.007) and presence of metabolic syndrome (or 5.949, 95% c.i.: 1.503-23.543, p = 0.011) seem to increase the risk for higher gleason score pca occurrence, while hypertriglyceridemia (or 0.309, 95% c.i.:0.104-0.916, p = 0.034) and low hdl (or 0.260, 95% c.i.: 0.102-0.659, p = 0.005) seem to be protective factors according to logistic regression analysis (table 5). further analysis was implemented regarding the associations between age and mets and its components with pca (supplementary table 1). triglycerides > 150 mg/dl were associated with pca (p = 0.012). additional analysis was conducted regarding the associations between age and mets and its components and highest gleason score pca (gs ≥ 4+4) (supplementary table 2). age was significantly associated with high gleason score pca in the study population (p = 0.007). discussion mets is described as a multi-level risk factor combining insulin resistance, abnormal adipose fat deposition, hypertension, increased levels of triglycerides and low levels of hdl cholesterol. as a risk factor, it is associated with a high risk of atherosclerotic cardiovascular disease and type 2 diabetes (1, 2). additionally, mets is associated with some common forms of cancer, with existing data suggesting that it can negatively affect cancer mortality (5). although the only established risk factors for pca development include age, ethnic origin, and family history there are data suggesting that environmental factors, such as eating habits or physical activity, may also play a role in the etiology of the disease. the adoption of poor eating habits combined with reduced physical activity may be an explanation for the rising rates of pca in asian populations living in the united states, compared to lower incidence of pca in asia (12). nevertheless, there is no curtable 3. comparison of metabolic syndrome components between patients with and without prostate cancer (pca). patients with pca patients without pca p-value * n (%) n (%) mets 108 (54.8) 80 (44.2) 0.039 central obesity 139 (70.6) 110 (60.8) 0.061 high triglycerides 118 (59.9) 77 (42.5) 0.001 low hdl 45 (22.8) 45 (24.9) 0.645 diabetes mellitus 81 (41.1) 75 (41.4) 0.950 hypertension 125 (63.5) 111 (61.3) 0.670 mets = metabolic syndrome. * comparisons between groups were performed using chi-square test. table 4. chi-square for metabolic syndrome components on higher gleason score pca vs lower gleason score prostate cancer (pca). patients with higher patients with lower p-value gleason score pca gleason score pca (gs ≥ 4+3) n (%) (gs ≤ 3+4) n (%) mets 42 (65.6) 66 (49.6) 0.035 central obesity 50 (78.1) 88 (66.2) 0.086 high triglycerides 40 (62.5) 78 (58.6) 0.605 low hdl 10 (15.6) 35 (26.3) 0.096 diabetes mellitus 23 (35.9) 58 (43.6) 0.305 hypertension 43 (67.2) 82 (61.7) 0.450 mets = metabolic syndrome; pca = prostate cancer; gs = gleason score. * comparisons between groups were performed using chi-square test. table 5. variables associated with higher gleason score prostate cancer (pca) (gs ≥ 4+3). p value odds ratio (or) 95% c.i. lower higher age 0.007 1.061 1.016 1.107 metabolic syndrome 0.011 5.949 1.503 23.543 central obesity 0.912 1.059 0.381 2.943 triglycerides > 150 mg/dl 0.034 0.309 0.104 0.916 hdl < 40 mg/dl 0.005 0.260 0.102 0.659 diabetes mellitus 0.102 0.531 0.249 1.134 hypertension 0.685 0.844 0.373 1.913 supplementary table 1. variables associated with pca. p value odds ratio (or) 95% c.i. lower higher age 0.579 0.992 0.965 1.020 metabolic syndrome 0.552 0.780 0.343 1.772 central obesity 0.551 1.195 0.666 2.144 triglycerides > 150 mg/dl 0.012 2.310 1.201 4.446 hdl < 40 mg/dl 0.935 1.022 0.611 1.708 diabetes mellitus 0.570 0.870 0.539 1.405 htn 0.957 1.013 0.631 1.627 supplementary table 2. variables associated with high grade pca (gs ≥ 4+4). p value odds ratio (or) 95% c.i. lower higher age 0.007 1.090 1.024 1.161 metabolic syndrome 0.348 2.464 0.375 16.179 central obesity 0.459 1.738 0.402 7.512 triglycerides > 150 mg/dl 0.294 0.450 0.102 1.997 hdl < 40 mg/dl 0.147 0.371 0.097 1.416 diabetes mellitus 0.663 0.789 0.271 2.295 hypertension 0.841 0.887 0.275 2.863 archivio italiano di urologia e andrologia 2021; 93, 3 c. fragkoulis, i. glykas, l. tzelves, k. stasinopoulos, l. lazarou, a. kaoukis, a. dellis, g. stathouros, g. papadopoulos, k. ntoumas 294 rent evidence suggesting that dietary preventing measures may reduce the risk of pca development, since the outcomes of the selenium and vitamin e cancer prevention trial (select) failed to show significant results (13). existing evidence about the association of pca with mets is conflicting (14). a series of meta-analyses have demonstrated contradictory results regarding the presence of a significant association between mets and pca incidence. esposito et al. in their meta-analysis, reported that metabolic syndrome was associated with a 12% increase in prostate cancer risk (10). in this metanalysis the association between mets and pca was significant in the european studies, but not in the u.s. and asian studies included. risk estimations of pca for higher values of body mass index, dysglycemia or dyslipidemia were not significant, while on the contrary the remaining two components of mets, namely hypertension and waist circumference > 102 cm, were associated with a significantly greater risk of prostate cancer. therefore, mets is weakly associated with the risk of pca with different results reported from several geographical locations (10). furthermore, in a canadian population-based, case-control study by blanc-lapierre et al., the association between mets and pca was also investigated (11). nearly 2000 men (1937) with incidental prostate cancer, aged ≤ 75 years and diagnosed between 2005 and 2009 were evaluated and their detailed lifestyle, medical history, and anthropometric measures, were collected. a history of mets (≥ 3 components) was associated with a reduced risk of prostate cancer, suggesting a synergistic interaction of the components. findings from this study were consistent with a reverse association between mets and prostate cancer risk (11). moreover, the meta-analysis performed by xiang et al. failed to detect any association between the two entities, a result probably originating both from the heterogeneity of included studies and the fact that the individual components of the metabolic syndrome might exert antagonistic actions between them. however, it was demonstrated that the metabolic syndrome is related to prostate cancer of higher gleason score or advanced clinical stage or even increased prostate cancer-specific mortality (15). on the other hand, a non-systematic review by de nunzio et al., suggests an association between mets and its mediators which affect the prostate microenvironment with the initiation and clinical progression of benign prostate hyperplasia and pca, although these molecular pathways remain incompletely described (16). more recently, in a study by bhindi et al, including 2.235 patients with prostate cancer, of whom 22.1% had metabolic syndrome, it was demonstrated that although no individual component of metabolic syndrome was independently associated with cancer, there was an increasing association between the number of metabolic abnormalities and both the diagnosis and grade of cancer (17). as far as it concerns the pathophysiology of mets, central obesity is considered to be the initial step for the development and the progression of the disease. as a result of dysfunctional adipose fat deposition, proinflammatory cytokines and other molecules are released leading to insulin resistance (18). these proinflammatory substances, triggered by central obesity and resulting into insulin resistance, include resistin, leptin, interleukin 6 (il-6), tumor necrosis factor alpha (tnf-a), fibrinogen, plasminogen, and c-reactive protein (crp) (2). a potential molecular mechanism explaining the correlation of mets and pca is based on insulin resistance. insulin-growth-factor 1 (igf-1) levels are increased in patients presenting with insulin resistance. igf-1 may stimulate growth of both androgen sensitive and androgen independent human pca cell lines in vitro (19). moreover, a polymorphism within the leptin genetic sequence leading to increased leptin production, was associated with higher risk of advanced pca disease (19). on a population level, metformin users were found to be at a decreased risk of pca diagnosis compared to nonusers (20). on the other hand, in 540 diabetic participants of the reduction by dutasteride of prostate cancer events (reduce) study, metformin use was not significantly associated with pca and therefore not advised as a preventive measure (21). a meta-analysis of 14 large prospective studies did not show any association between blood total cholesterol, high-density lipoprotein (hdl) cholesterol, low-density lipoprotein (ldl) cholesterol levels and the risk of either overall pca or high-grade pca (22). results from the reduce study also did not show a preventive effect of statins on pca risk (21). within the reduce study, obesity was associated with lower risk of low-grade pca in multivariable analyses, but increased risk of high-grade pca (23). in addition, obesity is characterized by low serum levels of adiponectin, which is believed to have anti-angiogenetic and possible antitumor properties, but its role has not been fully understood yet (24). the findings of our study agree with those of similar studies, as that of de nunzio, which also implies an association between metabolic syndrome and high-grade prostate cancer (25). more specifically, among italian men with elevated psa level or abnormal digital rectal examination, mets was present in 44% of all patients. although mets was not associated with more frequent diagnosis of pca overall, it was associated with an increased risk of gleason score 7 or higher disease (25). although the exact molecular pathways remain incompletely described, a possible association with pca may be present, triggered by proinflammatory cytokines, chronic prostate inflammation, and hormones such as leptin and adiponectin. western culture and way of life is often characterized by poor dietary habits and less physical exercise and is commonly adopted in greece. the present study presents data suggesting that greek patients presenting with elevated levels of psa or abnormal digital rectal examination have an increased risk of pca detection after a prostate biopsy when they fulfill the criteria for mets diagnosis. moreover, these patients have a trend to present with a worse gleason score when compared to patients not suffering from mets. a potential limitation is that patients were recruited only at one large, metropolitan center with no patients from remote areas included. another possible limitation is the relatively small sample size of 378 patients. to our knowledge this is the first greek study correlating mets with pca cancer diagnosis and gs in patients undergoing transrectal ultrasound guided prostate biopsy. 295archivio italiano di urologia e andrologia 2021; 93, 3 association between metabolic syndrome and prostate cancer diagnosis conclusions mets is a complex disorder with multiple organ targets and severe effects on public health. thus, it is quite important for urologists to be familiar with mets, to recognize it and consult their patients accordingly as simple alterations in lifestyle habits may prevent or delay the occurrence high gleason score pca development. it is mandatory to further investigate the correlation of mets with pca with studies involving higher numbers of patients. references 1. huang pl. a comprehensive definition for metabolic syndrome. dis model nech. 2009; 2:231-237. 2. grundy sm. metabolic syndrome: a multiplex cardiovascular risk factor. j clin endocrinol metab. 2007; 92:399-404. 3. ford es, giles wh, mokdad ah. increasing prevalence of the metabolic syndrome among u.s. adults. diabetes care. 2004; 27:2444-2449. 4. parazzini f, artibani w, carrieri g, et al. effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: results from the 2018 #controllati survey. arch ital urol androl. 2020; 91:245-250. 5. zhou jr, blackburn gl, walker wa. symposium introduction: metabolic syndrome and the onset of cancer. am j clin nutr. 2007; 86:s817-s819. 6. renehan ag, tyson m, egger m, et al. body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. lancet. 2008; 371:569-578. 7. nicolucci a. epidemiological aspects of neoplasms in diabetes. acta diabetol. 2010; 47:87-95. 8. jafri h, alsheikh-ali aa, karas rh. baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid altering therapy. j am coll cardiol. 2010; 55:2846-2854. 9. ferlay j, soerjomataram i, dikshit r, et al. cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. int j cancer. 2015; 1; 136:e359-86. 10. esposito k, chiodini p, capuano a, et al. effect of metabolic syndrome and its components on prostate cancer risk: meta-analysis. j endocrinol invest. 2013; 36:132-139. 11. blanc-lapierre a, spence a, karakiewicz pi, et al. metabolic syndrome and prostate cancer risk in a population-based case-control study in montreal, canada. bmc public health. 2015; 18; 15:913. 12. hsing aw, sakoda lc, chua jr s. obesity, metabolic syndrome and prostate cancer. am j clin nutr. 2007; 86:843-857. 13. lippman sm, klein ea, goodman pj, et al. effect of selenium and vitamin e on risk of prostate cancer and other cancers: the selenium and vitamin e cancer prevention trial (select). jama. 2009; 301:39-51. 14. fragkoulis c, glykas i, gkialas i, et al. the role of nutrition in the prevention of prostatic adenocarcinoma. j buon. 2017; 22:1085-1086. 15. xiang yz, xiong h, cui zl, et al. the association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence. j exp clin cancer res. 2013; 13; 32:9. 16. de nunzio c, aronson w, freedland sj, et al. the correlation between metabolic syndrome and prostatic diseases. eur urol 2012; 61:560-570. 17. bhindi b, locke j, alibhai sm, et al. dissecting the association between metabolic syndrome and prostate cancer risk: analysis of a large clinical cohort. eur urol. 2015; 67:64-70. 18. gustafson b, hammarstedt a, andersson cx, et al. inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. arterioscler thromb vasc biol. 2007; 27:2276-2283. 19. buschemeyer iii wc, freedland sj. obesity and prostate cancer: epidemiology and clinical implications. eur urol. 2007; 52:331-343. 20. preston ma, riis ah, ehrenstein v, et al. metformin use and prostate cancer risk. eur urol. 2014; 66:1012-20. 21. freedland sj, hamilton rj, gerber l, et al. statin use and risk of prostate cancer and high-grade prostate cancer: results from the reduce study. prostate cancer prostatic dis. 2013; 16:254-9. 22. yupeng l, yuxue z, pengfei l, et al. cholesterol levels in blood and the risk of prostate cancer: a meta-analysis of 14 prospective studies. cancer epidemiol biomarkers prev. 2015; 24:1086-93. 23. vidal ac, howard le, moreira dm, et al. obesity increases the risk for high-grade prostate cancer: results from the reduce study. cancer epidemiol biomarkers prev. 2014; 23:2936-42. 24. brakenhielm e, veitonmaki n, cao r, et al. adiponectin induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. proc natl acad sci usa 2004; 101:24762481. 25. de nunzio c, freedland sj, miano r, et al. metabolic syndrome is associated with high grade gleason score when prostate cancer is diagnosed on biopsy. prostate 2011; 71:1492-1498. correspondence charalampos fragkoulis, md harisfrag@yahoo.gr georgios stathouros, md gstathouros@yahoo.gr georgios papadopoulos, md gipapadopoulos@yahoo.gr konstantinos ntoumas, md ntoumask@yahoo.com ioannis glykas, md (corresponding author) giannis.glykas@gmail.com department of urology, general hospital of athens g. gennimatas leof. mesogeion 154 athens (greece) lazaros tzelves, md lazarostzelves@gmail.com lazaros lazarou, md lazarou_laz@hotmail.com 2nd department of urology, national and kapodistrian university of athens, school of medicine, sismanoglio hospital, athens (greece) konstantinos stasinopoulos, md konstasinopoulos@gmail.com department of urology, general hospital of lakonia, sparta (greece) andreas kaoukis, md andreaskaoukis@yahoo.gr department of cardiology, general hospital of athens ‘’g. gennimatas’’, athens (greece) athanasios dellis, md aedellis@gmail.com 2nd department of surgery, aretaieion hospital, school of medicine, national and kapodistrian university of athens, athens (greece) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3278 original paper no conflict of interest declared. cer (pca) were diagnosed in portugal in 2020, equivalent to 20% of all malignancy in men (1). in terms of incidence, pca ranks first followed by colorectal cancer (19%) and lung cancer (11.6%) (1). pca is a highly heterogeneous disease and therefore, the european association of urology (eau) has established a risk group classification based on initial serum prostate-specific antigen (psa), biopsy gleason score (gs), and clinical stage. there are several therapeutic strategies available according to the risk group (2). as a diagnostic assay, psa clinical utility is ambiguous due to the lack of specificity and sensitivity for pca, leading to many pointless biopsies with possibility of complications for the patient and potential overdiagnoses of lowrisk tumors and its overtreatment (3). in terms of prognosis, gs has a key role as a predictor of pca clinical outcome (4). donald gleason developed this grading scoring system in 1966 (5). during the evolution and establishment of the gs grading system, multiple refinements were introduced to improve its performance. in 2014, the international society of urological pathology (isup) proposed a modified grading system classification (isup grading system) based on gs, after reviewing in detail the main limitations of the previous 2005 version. this reviewed version of isup grading system was further adopted and disseminated worldwide by world health organization in 2016 (6, 7). in recent years, there has also been a great development in the imaging field. the availability of multiparametric magnetic resonance imaging (mpmri) in current clinical practice has revolutionized pca diagnosis and staging. magnetic resonance targeted fusion biopsy (mri-tb) tends to be a valuable diagnostic method and more accurate for detecting clinically significant pca (isup > 2 or gs > 7) than conventional strategies (psa, digital rectal examination (dre), and systematic biopsy) (8-10). despite scientific debate, several studies have shown that isup score of prostate biopsies is not always in concordance with the pathological report of rp specimens even when mri-tb is performed (11, 12). the transrectal ultrasound-guided biopsy (trus-b) of the prostate may omit high-grade tumors areas because it is not targeted to a specific suspicious lesion but a random biopsy. on the objectives: the aim of this study was to compare the risk of international society of urological pathology (isup) score upgrading between magnetic resonance imaging targeted fusion biopsy (mri-tb) and transrectal ultrasound-guided biopsy (trus-b) in the final radical prostatectomy (rp) specimen pathological report. materials and methods: this retrospective single center study included 51 patients with prostate cancer (pca) diagnosed with mri-tb and 83 patients diagnosed with trus-b between october/2019 and july/2021. we compared the rates of isup score upgrading between both groups after robotic-assisted radical prostatectomy (rarp) and the specific transition of each isup score based on biopsy modality. the rate of isup score concordance and downgrading were also assessed. to define the intra and interobserver concordance for each isup score in biopsy and rp specimen for each biopsy modality, the cohen’s kappa coefficient was calculated. isup scores and biopsy modality were selected for multivariate analysis and a logistic regression model was built to provide independent risk factors of isup score upgrading. results: the difference of the rate of upgrading between mri-tb group and trus-b group was statistically significant (p = 0.007) with 42.2% of patients of trus-b group experiencing an upgrade in their isup score while only 19.6% in mri-tb group. concordance and downgrading rates did not statistically differ between the two groups. strength of concordance using cohen’s kappa coefficient was fair in both groups but higher in mri-tb group (trus-b group k = 0.230; p < 0.001; concordance: 47% vs. mri/tb group k = 0.438; p < 0.001; concordance: 62.7%). biopsy modality and isup 1 on biopsy were independent predictors of isup upgrading after rp. conclusions: mri-tb is highly accurate with lower risk of pca upgrading after rp than trus-b. patients with isup 1 on biopsy have greater susceptibility to upgrading their isup score. key words: gleason score; isup score; mri-tb; prostate cancer; trus-b; upgrading. submitted 30 july 2022; accepted 20 august 2022 introduction according to data from the global cancer observatory, published in march 2021, 6750 new cases of prostate canmagnetic resonance imaging target fusion biopsy vs. transrectal ultrasound-guided biopsy a comparative study of isup score upgrading risk in the final radical prostatectomy specimen thiago guimarães 1, miguel gil 1, mariana medeiros 1, vanessa andrade 1, joão guerra 1, hugo pinheiro 1, francisco fernandes 1, joão pina 1, joão lopes dias 2, luís campos pinheiro 1 1 department of urology, centro hospitalar universitário de lisboa central, lisbon, portugal; 2 department of radiology, centro hospitalar universitário de lisboa central, lisbon, portugal. doi: 10.4081/aiua.2022.3.278 summary 279archivio italiano di urologia e andrologia 2022; 94, 3 risk of isup score upgrading other hand, targeted biopsy may overestimate the presence of a high-grade tumor (13). the potential for undertreatment or overtreatment resulting from the lack of correlation between the isup score of the prostate biopsy and rp specimen may seriously impair the patient’s quality of life and prognosis. here we aim to compare isup score of prostate biopsy and rp specimen when mri-tb or trus-b is performed and identify potential predictive factors associated with isup score upgrading. materials and methods study design and case selection we retrospectively analyzed a database of prospectively collected demographics and clinicopathological data from our institution. all consecutive patients subjected to robotic-assisted radical prostatectomy (rarp) by four different surgeons, between 10/2019 and 07/2021 were included in the study cohort. those patients were divided into 2 groups according to the biopsy modality used for pca diagnosis: mri-tb group or trus-b group. patients underwent prostate biopsy due to psa elevation (> 4 ng/ml), abnormal dre, or/and at least suspicious abnormalities in ultrasound or mpmri findings. we decided that patients who were submitted to neoadjuvant hormones or chemotherapy and/or radiotherapy before surgery should be excluded because these treatments may influence the histopathology of the rp specimen. patients with pca diagnosed by transurethral resection of the prostate (turp) were also discharged. patient’s age at diagnosis, preoperative serum psa, the time interval between biopsy and surgery, prostate specimen volume, isup score of the biopsy and rp specimen, and also other features of the pathological rp specimen including pathological stage, surgical margins, and presence of cribriform pattern were also examined. imaging acquisition and mri-tb protocol mri-tb was performed in all patients with mpmri-detected abnormalities (pirads > 3-5). the imaging acquisition protocol followed the pi-rads v. 2.1 criteria according to the european society of urogenital radiology, based on the dwi and t2wl sequences (14). in our institution, all mpmri examinations were performed with a 3t mri scanner (magnetom skyra, siemens, erlangen, germany). all suspected lesions were evaluated by a genitourinary radiologist with expertise in mpmri, unblinded to clinical information, and further discussed with the urologist for the identification and demarcation of suspicious lesions as well as possible landmarks. all outside patients sent to our hospital with previous mpmri abnormalities findings were also reviewed by a genitourinary radiologist and urologist. all mri-tb were performed using a mpmri and transrectal ultrasound fusion software mim symphony bxtm (mim software inc, ohio, usa) and a cart-based ultrasound system (bk pro focus ultrasound system, bk medical, massachusetts, usa). at our institution, this mri-tb has been used since 2017 by two experienced urologists. the patients were placed in lithotomy position, and subjected to general or spinal anesthesia after antibiotic prophylaxis and rectal and perineal disinfection. we obtained at least 4 cores of each selected target of the prostate and systematic biopsies using a transperineal ultrasound-guided prostate biopsy approach with the ultrasound probe in the rectum. trus-b protocol all trus-b were performed using a cart-based ultrasound system hitachi eub-7500a (2013, hitachi, ltd, tokyo, japan). trus-b were performed by 6 urologists of our department. the patients were placed in the left lateral decubitus position and subjected to a periprostatic nerve block (10 ml of 1% lidocaine) after rectal povidone-iodine disinfection by enema in addition to antimicrobial prophylaxis. a double-sextant protocol was used with a collection of 2 fragments in the apex, middle and base regions, bilaterally, resulting in a total of 6 regions covered and 12 fragments. pathological assessment of biopsy and rp specimen all biopsies and rp specimens were examined and reported by a selected team of genitourinary pathologists. the processing and histopathological reports by the pathologists of biopsies and rp specimens followed the eau guidelines recommendations (2). the pca was classified using the modified isup grading system (6, 7): isup 1 = table 1. characteristics of study population. mri-tb trus-b total p value group group total (n) 51 83 134 age (years; median [iqr]) 69 (7) 64 (11) 67 (9) 0.001* preoperative serum psa (ng/ml; median [iqr]) 6.95 (5.03) 7.81 (5.57) 7.4 (5.60) 0.126 prostate specimen volume (g; median [iqr]) 48 (22) 41 (13) 42 (16) 0.109 the time interval between biopsy and surgery (days; median [iqr]) 117(125) 126(143) 120 (129) 0.521 biopsy isup score 0.098 isup 1 (n %) 7 (13.7%) 8 (9.6%) 15 (11.2%) isup 2 (n %) 17 (33.3%) 49 (59.0%) 66 (49.3%) isup 3 (n %) 20 (39.2%) 18 (21.7%) 38 (28.4%) isup 4 (n %) 5 (9.8%) 5 (6.0%) 10 (7.5%) isup 5 (n %) 2 (3.9%) 3 (3.6%) 5 (3.7%) pathology specimen isup score 0.352 isup 1 (n %) 4 (7.8%) 5 (6.0%) 9 (6.7%) isup 2 (n %) 18 (35.3%) 27 (32.5%) 45 (33.4%) isup 3 (n %) 27 (52.9%) 42 (50.6%) 69 (51.5%) isup 4 (n %) 0 (0.0%) 1 (1.2%) 1 (0.8%) isup 5 (n %) 2 (4.0%) 8 (9.6%) 10 (7.5%) pathology specimen cribform pattern 0.031* yes (n %) 3 (5.9%) 16 (19.3%) 19 (14.2%) no (n %) 48 (94.1%) 67 (80.7%) 115 (85.8%) pathological stage 0.482 pt2 (n %) 25 (49.0%) 40 (48.2%) 65 (48.5%) pt3a (n %) 23 (45.1%) 33 (39.8%) 56 (41.8%) pt3b (n %) 3 (5.9%) 10 (12.0%) 13 (9.7%) positive surgical margins 0,035* yes (n %) 21 (41.2%) 50 (60.2%) 71 (53%) no (n %) 30 58.8%) 33 (39.8%) 63 (47%) surgeon 0.082 a (n %) 10 (19.6%) 33(39.8%) 43 (32.1%) b (n %) 12 (23.5%) 19(22.9%) 31 (23.1%) c (n %) 19 (37.3%) 20(24.1%) 39 (29.1%) d (n %) 10 (19.6%) 11(13.3%) 21 (15.7%) iqr: interquartile range; mri-tb: magnetic resonance imaging targeted fusion biopsy; psa: prostate-specific antigen; trus-b: transrectal ultrasound-guided biopsy. archivio italiano di urologia e andrologia 2022; 94, 3 t. guimarães, m. gil, m. medeiros, et al. 280 gs ≤ 6; isup 2 = gs 7 (3+4); isup 3 = gs 7 (4+3); isup 4 = gs 8 (4+4); isup 5 = gs 9 or gs10. statistical analysis our primary endpoint in this study was the risk of isup score upgrading for each modality of biopsy. the rate of concordance and downgrading were also assessed. descriptive statistics were used for patients’ demographic. approximation to gaussian distribution for continuous variables was not met on the shapiro-wilk test. accordingly, a non-parametric statistic was used. continuous variables were compared using mann-whitney test. to define the intra and interobserver concordance for each isup score in biopsy and rp specimen evaluation for each biopsy modality, the cohen’s kappa coefficient was calculated. categorical variables were analyzed by chi-square test. isup scores and biopsy modality were selected for multivariate analysis and a logistic regression model was built. the models’ goodness of fit was assessed by the hosmer-lemeshow test (hl) test. statistical significance was considered for p < 0.05. all statistical analysis was performed using spss v.25 (ibm spss statistics for macos, version 25.0. armonk, ny: ibm corp.). results groups characteristics group’s baseline characteristics of patients subjected to prostate biopsy between october/2019 and july/2021 are detailed in table 1. overall, there were 51 patients in the mri-tb group and 83 patients in trus-b group. there were no statistically significant differences in preoperative serum psa, prostate specimen volume, the time interval between biopsy and surgery, isup score of biopsy and rp specimen, pathological t stage, and surgeons between both groups. patients were statistically different in age (p < 0.001), presence of cribriform pattern (p = 0.031) and positive margins (p = 0.035). figure 1 and 2 show the different distribution of isup scores between each biopsy group and the rp specimen pathology. the total proportions of isup score in mri-tb were: isup 1 13.7%, isup 2 33.3%, isup 3 39.2%, isup 4 9.8% and isup 5 3.9%. in trus-b group, the proportions were: isup 1 9.6%, isup 2 59%, isup 3 21.7%, isup 4 6% and isup 5 3.6% (in each group, most pca in biopsy were isup 2 or isup 3). at final rp specimen pathology report, the total proportions of isup scores in mri-tb group were: isup 1 7.8%, isup 2 35.3%, isup 3 52.9%, isup 4 0% and isup 5 4%. in trus-b group the proportion were: isup 1 6%, isup 2 32.5%, isup 3 50.6%, isup 4 1.2% and isup 5 9.6% (in each group, most pca in rp specimen were isup 2 or isup3). isup score concordance rates from biopsy and rp specimen in study cohort and in each group the table 2 shows the rate of concordance or not (downgrading or upgrading) between biopsy and pathological isup scores in all study cohort and the two groups. the rate of upgrading between mri-tb group and trus-b group was statistically significant (p = 0.007) with 42.2% of patients of trus-b group experiencing an upgrade in their isup score while only 19.6% in mri-tb group. concordance and downgrading rates did not statistically differ between the two groups. specific isup scores transition between biopsy and rp specimen specific isup scores transition between biopsy and rp specimen when considering all study cohort is depicted in table 3. the major rates of upgrading were seen in table 2. isup score downgrading, concordance and upgrading per groups. isup score study group downgrading concordance upgrading mri-tb group (n %) 9 (17.7%)* 32 (62,7%)** 10 (19.6%)*** trus-b group (n %) 9 (10.8%)* 39 (47%)** 35 (42.2%)*** total (n %) 18 (13.4%)* 71 (53%)** 45 (33.6%)*** imri-tb: magnetic resonance imaging targeted fusion biopsy; trus-b: transrectal ultrasound-guided biopsy; *: downgrading rates; **: concordance rates; ***: upgrading rates. figure 1. distribution of isup score after mri-tb and rp specimen pathological examination. mri-tb: magnetic resonance imaging targeted fusion biopsy; rp: radical prostatectomy. figure 2. distribution of isup score after trus-b and rp specimen pathological examination. trus-b: transrectal ultrasound-guided biopsy; rp: radical prostatectomy. table 3. isup score downgrading, concordance and upgrading rates in both groups (mri-tb group plus trus-b group). isup score – rp specimen total isup score-biopsy isup 1 isup 2 isup 3 isup 4 isup 5 (n%) isup 1 (n %) 6 (40%)** 6 (40%)*** 3 (20%)*** 0 (0%)*** 0 (0%)*** 15 (100%) isup 2 (n %) 3 (4.5%)* 33 (50%)** 27 (41%) 0 (0%)*** 3 (4.5%)*** 66 (100%) isup 3 (n %) 0 (0%)* 5 (13.2%)* 30 (78.9%)** 0 (0%)*** 3 (7.9%)*** 38 (100%) isup 4 (n %) 0 (0%)* 1 (10%)* 5 (50%)* 1 (10%)** 3 (30%)*** 10 (100%) isup 5 (n %) 0 (0%)* 0 (0%)* 4 (80%)* 0 (0%)* 1 (20%)** 5 (100%) total (n) 9 45 69 1 10 134 rp: radical prostatectomy; *: downgrading rates; **: concordance rates; ***: upgrading rates. 281archivio italiano di urologia e andrologia 2022; 94, 3 risk of isup score upgrading patients with isup 1 and 2 in biopsy (60% and 50% of those patients upgraded their initial isup score respectively). in trus-b group there were a higher upgrading rates in isup 1 and 2 (62.5% and 53%) while in mri-tb group, the rates of upgrading were notable higher in isup 1 (57.2%) (table 4 and table 5, respectively). strength of concordance using cohen’s kappa coefficient was fair in both groups but higher in mri-tb group (trus-b group k = 0.230; p < 0.001; concordance: 47%/mri/tb group k = 0.438; p < 0.001; concordance: 62.7%). demographics, clinical and pathological features according to upgrade status overall, isup of 89 patients was upgraded in the final pathological report against 45 whose isup was not upgraded. on univariate analysis, as displayed in table 6, there were no statistically significant differences in patients who were upgraded or not in psa, prostate specimen volume, time interval between biopsy, presence of surgical positive margins or cribform patterns in pr specimen. upgrading of biopsy isup score were associated with the biopsy modality (higher in trus-b biopsy figure 3) and isup score in biopsy (p = 0.07 and p = 0.001, respectively). in our regression logistic model, biopsy modality and isup 1 on biopsy were independent predictors of isup upgrading after rp (table 7). discussion the current way to further evaluate the prostate when there is a doubt of a tumor is with a prostate biopsy. however, with only a small sample of prostate tissue collected by a needle, physicians may not have a representative knowledge of the main structural features of cancer to predict its aggressiveness. gs and consequently isup score grading system are an essential prognostic tool in pca and are included in many risk predictor normograms (4, 15, 16). the concordance between the isup score of biopsies and the rp specimens is essential to confirm the physicians and patients’ expectations regarding the risk group in which the cancer is assigned, the most appropriate treatment strategy, and the patient’s prognosis. unfortunately, the expected concordance does not always meet expectations and pca aggressiveness might be underestimated or overestimated resulting in a delay of treatment in patients initially qualified for active surveillance (as); table 6. isup upgrading status univariate analysis. upgrading non-upgrading upgrading p-value status group group total (n) 89 45 age standard (ng/ml; median [iqr]) 68 (9) 66 (24) 0.245 preoperative serum psa (ng/ml; median [iqr]) 7.25 (5.14) 7.7 (6.25) 0.481 prostate specimen volume (ng/ml; median [iqr]) 44 (19.75) 41 (12) 0.061 the time interval between biopsy and surgery (standard) (days; median [iqr]) 122 (129) 112 (125) 0.984 biopsy isup score 0.001* isup 1 (n %) 6 (40%) 9 (60%) 0.022* isup 2 (n %) 36 (54.5$) 30 (45.5%) 0.004* isup 3 (n %) 35 (92.1%) 3 (7.9%) < 0.001* isup 4 (n %) 7 (70%) 3 (30%) 1.000 isup 5 (n %) 5 (100%) 0 (0%) biopsy modality 0.07* mri-tb (n %) 41 (80.4%) 10 (19.6%) trus-b (n %) 48 (57.8%) 35 (42.2%) surgical margins (n (%)) 0.247 negative (n %) 45 (50.6%) 44 (49.4%) positive (n %) 18 (40%) 27 (60%) cribform pattern 0.170 negative (n %) 79(88.8%) 36 (80%) iqr: interquartile range; mri-tb: magnetic resonance imaging targeted fusion biopsy; psa: prostate-specific antigen; trus-b: transrectal ultrasound-guided biopsy. table 7. isup upgrading status multivariate analysis. isup score biopsy variable p value odds ratio ci 95% isup 1 0.028* 6.579 1.230-35.204 isup 2 0.134 2.877 0.723-11.451 isup 3 0.244 0.353 0.061-2.036 ci: confidence interval. table 4. isup score downgrading, concordance and upgrading rates (mri/tpb group). isup score – rp specimen total isup score-biopsy isup 1 isup 2 isup 3 isup 4 isup 5 (n%) isup 1 (n %) 3 (42.9%)** 3 (42.9%)*** 1 (14.3%)*** 0 (0%)*** 0 (0%)*** 7 (100%) isup 2 (n %) 1 (5.9%)* 12 (70.6%)** 4 (23.5%)*** 0 (0%)*** 0 (0%)*** 17 (100%) isup 3 (n %) 0 (0%)* 3 (15%)* 17 (85%)** 0 (0%)*** 0 (0%)*** 20 (100%) isup 4 (n %) 0 (0%)* 0 (0%)* 3 (60%)* 0 (0%)** 2 (40%)*** 5 (100%) isup 5 (n %) 0 (0%)* 0 (0%)* 2 (100%)* 0 (0%)* 0 (0%)** 2 (100%) total (n) 4 18 27 0 2 51 rp: radical prostatectomy; *: downgrading rates; **: concordance rates; ***: upgrading rates. table 5. isup score downgrading, concordance and upgrading (trus-b group). isup score – rp specimen total isup score-biopsy isup 1 isup 2 isup 3 isup 4 isup 5 (n%) isup 1 (n %) 3 (37.5%)** 3 (37.5%)*** 2 (25%)*** 0 (0%)*** 0 (0%)*** 8 (100%) isup 2 (n %) 2 (4.1%)* 21 (42.9%)**23 (46.9%)*** 0 (0%)*** 3 (6.1%)*** 49 (100%) isup 3 (n %) 0 (0%)* 2 (11.1%)* 13 (72.2%)** 0 (0%)*** 3 (16.7%)*** 18 (100%) isup 4 (n %) 0 (0%)* 1 (20%)* 2 (40%)* 1 (20%)** 1 (20%)*** 5 (100%) isup 5 (n %) 0 (0%)* 0 (0%)* 2 (66.7%)* 0 (0%)* 1 (33.3%)** 3 (100%) total (n) 5 27 42 1 8 83 rp: radical prostatectomy; *: downgrading rates; **: concordance rates; ***: upgrading rates. figure 3. upgrading status comparison between mri-tb group and trus-b group. mri-tb: magnetic resonance imaging targeted fusion biopsy; trus-b: transrectal ultrasound-guided biopsy. archivio italiano di urologia e andrologia 2022; 94, 3 t. guimarães, m. gil, m. medeiros, et al. 282 undertreatment in case of high-risk pca that could benefit not from monotherapy (surgery or radiation) but multimodal therapy or clinical trial; or overtreatment in patients disqualified to a low-risk disease after surgery who would be better candidates for as (2). risk normograms may also be imprecise in terms of whether or not pelvic lymphadenectomy is required. therefore, it’s not surprising that previous studies have reported an increased risk of biochemical recurrence, distant metastasis, and death when isup score is underestimated (17-20). the vast majority of those studies only assessed the upgrading risk regarding trus-b, the most widely accepted method for pca diagnosing. therefore, this study provides further evidence of the clinical utility of mri-tb in daily clinical practice. the lower reliability of trus-b in our study is aligned with the results obtained by kvale et al. and other historical studies that have determined the upgrading risk when a systematic biopsy is performed (21). we demonstrated that 42.2% of patients in the trus-b group were upgraded. in fact, our results are similar to king et al. study’ which reported a gs upgrading rate after trus-b of 35-43% (22). however, it should be noted that those studies used the gs system to classify pca, rather than isup score which ranges from 1 to 5 with gleason score 9 and 10 assigned to isup 5. therefore, our study does not assess the risk of upgrading from gleason score 9 to 10. nevertheless, it should be recognized that we use isup grading system, a more recent and updated grading system which is based on gs. there are a few studies in the literature that specifically assessed the transition of isup scores between prostate biopsy and rp. when both modalities of biopsy are compared, as shown in table 8, previous studies reported different upgrading rates but lower when magnetic resonance imaging ultrasound guided biopsy is performed (23-25). mri-tb provides a lower incidence of isup score upgrading, although there is still a non-negligible risk of upgrading of 19.6%. the major rates of upgrading were detected in patients with isup 1 in both groups. this has implications mainly for those patients who have postponed rp due to active surveillance. on the other hand, 53% (vs. 23.5% in mritb group) of patients classified as isup 2 after trus-b were upgraded. these data are consistent with data from the study by de lucca et al. who demonstrated a lower risk of isup 2 upgrading after mri-tb vs. systematic biopsy (26). in our study, 6.8% (n = 3) of those patients with isup 2 in the trus-b group upgraded to isup 5 (vs. 0% in the mri-tb group) as demonstrated in table 5. despite a small number of patients, this is particularly relevant when patients with isup 2 in the biopsy are subjected to radiotherapy. due to the lack of confirmatory isup score of rp specimen, those patients are at risk of undertreatment. in addition to the biopsy modality, to be classified as isup 1 in biopsy was identified as a predictive risk for upgrading in multivariate analysis. as suggested by altok et al., when the rp specimen is analyzed, a “regression to the mean gs7” (isup 2-3) appears also to occur with our data even with patients who graduated as isup 1 in the biopsy, with 100% of patients transiting to isup 2-3 (27). in fact, one of the challenges of the pathologist is to differentiate gleason patterns 3 and 4 due to several reasons based on inherent subjectivity of reporting borderlinecases (28). therefore, it is essential to have a dedicated and experienced team of pathologists to minimize variations in interpretations of isup score and discrepancy between biopsy and rp specimens. although our study did not find a relation between prostate specimen volume and upgrading risk, many studies report a higher risk of upgrading in prostate of smaller size (25). we expected that the longer the time interval between biopsy and surgery, the greater the risk of upgrading but we did not find this relation in our study (21). our study has several limitations concerning its retrospective and non-randomized design. it was also a single-institution study that targeted portuguese population. other limitations are the small number of patients in each group and heterogeneity between the two groups; the non-inclusion of other variables likely to be related to upgrading risk according to previous studies such as the number of cores collected, biopsy core lengths and psa density (23, 29). other variables, such as the specific number, extent, location and pirads classification of suspicious lesions on mpmri, and their respective association with the pca diagnosis in both biopsy cores and surgical specimens were not assessed in our study. however, lourenço et al. suggest that pca multifocality can be an indicator of isup upgrading risk in patients who were discordant in mpmri location of the suspicious lesions either in the cognitive fusion biopsy cores or pr specimens (30). nevertheless, we believe that this study reinforces the key role of mri as a diagnostic and staging tool in pca. physicians should be aware of potential upgrading risk factors during the decision-making process. the development of normograms and biomarkers that can predict the risk of upgrading may be essential to improve the assertiveness of the clinical decision (31-33). according to lacetera et al., the incidence of clinically significant pca in patients under as protocol is higher in the subgroup of patients who underwent confirmatory and follow-up mri-tb vs. random biopsy (69% vs. 31%) (34). we strongly recommend that patients on as protocol should be counseled about the risk of isup upgrading and informed about the advantage of mri-tb to detect clinically significant pca. conclusions mri-tb is highly accurate with lower risk of pca upgrading after rp than trus-b. patients with isup 1 on biopsy table 8. our study and selected previous series that evaluated the risk of upgrading. series citation groups patients (n) upgrading (%) p value guimarães et al. mri-us 51 19.6% trus-b 83 42.2% 0.07* (25) mri-us 73 16.4% trus-b 89 31.5% 0.027* (24) mri-us 145 33.5% trus-b 221 31.7% 0.8 (23) mri-us 92 26.9% trus-b 137 73.1% 0.027* mri-tb: magnetic resonance imaging targeted fusion biopsy; trus-b: ttansrectal ultrasound-guided biopsy. 283archivio italiano di urologia e andrologia 2022; 94, 3 risk of isup score upgrading have greater susceptibility to upgrading and we strongly recommend mpmri on patients in as protocol. additional studies are necessary to identify predictive risk factors for isup score upgrading to better categorize patients into risk groups and select the best treatment option according to the biological behavior of pca and prognosis. references 1. world health organization international agency for research on cancer (iarc). globocan 2020: estimated cancer incidence, mortality and prevalence in portugal in 2020 [internet]. 2021 [cited 2022 jul 20]. available from: https://gco.iarc.fr/today/data/factsheets/populations/620-portugal-fact-sheets.pdf 2. mottet n, van den bergh rcn, briers e, et al. eau-eanmestro-esur-siog guidelines on prostate cancer-2020 update. part 1: screening, diagnosis, and local treatment with curative intent. eur urol. 2021; 79:243-262. 3. adhyam m, gupta ak. a review on the clinical utility of psa in cancer prostate. indian j surg oncol. 2012; 3:120-129. 4. sauter g, steurer s, clauditz ts, et al. clinical utility of quantitative gleason grading in prostate biopsies and prostatectomy specimens. eur urol. 2016; 69:592-598. 5. gleason df. classification of prostatic carcinomas. cancer chemother rep. 1966; 50:125-128. 6. epstein ji, egevad l, amin mb, et al. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016; 40:244-252. 7. moch h. who-isup-graduierungssystem für nierenkarzinome [the who/isup grading system for renal carcinoma]. pathologe. 2016; 37:355-360. 8. wallis cjd, haider ma, nam rk. role of mpmri of the prostate in screening for prostate cancer. transl androl urol. 2017; 6:464-471. 9. abd-alazeez m, kirkham a, ahmed hu, et al. performance of multiparametric mri in men at risk of prostate cancer before the first biopsy: a paired validating cohort study using template prostate mapping biopsies as the reference standard. prostate cancer prostatic dis. 2014; 17:40-46. 10. vourganti s, rastinehad a, yerram n, et al. multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. j urol. 2012; 188:2152-2157 11. luzzago s, petralia g, maresca d, et al. pathological findings at radical prostatectomy of biopsy naïve men diagnosed with mri targeted biopsy alone without concomitant standard systematic sampling. urol oncol. 2020; 38:929.e11-929.e19. 12. calio bp, sidana a, sugano d, et al. risk of upgrading from prostate biopsy to radical prostatectomy pathology does saturation biopsy of index lesion during multiparametric magnetic resonance imaging-transrectal ultrasound fusion biopsy help? j urol. 2018; 199:976-982. 13. bullock n, simpkin a, fowler s, varma m, kynaston h, narahari k. pathological upgrading in prostate cancer treated with surgery in the united kingdom: trends and risk factors from the british association of urological surgeons radical prostatectomy registry. bmc urol. 2019; 19:94. 14. weinreb jc, barentz jo, choyke pl, et al. pi-rads prostate imaging-reporting and data system, v2.1 [internet]. 2019 [cited 2022 jul 18]. available from: https://www.acr.org/-/media/acr/ files/rads/pi-rads/pirads-v2-1.pdf 15. briganti a, larcher a, abdollah f, et al. updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. eur urol. 2012; 61:480-487. 16. memorial sloan kettering cancer center. prostate cancer nomograms [internet]. [cited 2022 jul 19]. available from: https://www.mskcc.org/nomograms/prostate 17. corcoran nm, hong mk, casey rg, et al. upgrade in gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence. bju int. 2011; 108:e202-e210. 18. dogan s, yıldız ky, sakaogulları zs. the value of gleason score upgrade in predicting biochemical recurrence after radical prostatectomy. bosphorus med j 2021; 8:88-92. 19. bakavicius a, drevinskaitc m, daniunaite k, et al. the impact of prostate cancer upgrading and upstaging on biochemical recurrence and cancer-specific survival. medicina (kaunas) 2020; 56:61. 20. kovac e, vertosick ea, sjoberg dd, et al. effects of pathological upstaging or upgrading on metastasis and cancer-specific mortality in men with clinical low-risk prostate cancer. bju int. 2018; 122:1003-1009. 21. kvåle r, møller b, wahlqvist r, et al. concordance between gleason scores of needle biopsies and radical prostatectomy specimens: a population-based study. bju int. 2009; 103:1647-1654. 22. king cr, long jp. prostate biopsy grading errors: a sampling problem?. int j cancer. 2000; 90:326-330. 23. xu n, wu yp, li xd, et al. risk of upgrading from prostate biopsy to radical prostatectomy pathology: is magnetic resonance imaging-guided biopsy more accurate?. j cancer. 2018; 9:3634-3639. 24. rührup j., preisser f., theißen l, et al. mri-fusion targeted vs. systematic prostate biopsy-how does the biopsy technique affect gleason grade concordance and upgrading after radical prostatectomy? front surg. 2019; 6:55. 25. kayano p.p., carneiro a., castilho t.m.l., et al. comparison of gleason upgrading rates in transrectal ultrasound systematic random biopsies versus us-mri fusion biopsies for prostate cancer. int. braz j. urol. 2018; 44:1106-1113. 26. de luca s, fiori c, bollito e, et al. risk of gleason score 3+4=7 prostate cancer upgrading at radical prostatectomy is significantly reduced by targeted versus standard biopsy. minerva urol nefrol. 2020; 72:360-368. 27. altok m, troncoso p, achim mf, matin sf, et al. prostate cancer upgrading or downgrading of biopsy gleason scores at radical prostatectomy: prediction of "regression to the mean" using routine clinical features with correlating biochemical relapse rates. asian j androl. 2019; 21:598-604. 28. epstein ji. prostate cancer grading: a decade after the 2005 modified system. mod pathol. 2018; 31(s1):s47-s63. 29. corcoran nm, casey rg, hong mk, et al. the ability of prostate-specific antigen (psa) density to predict an upgrade in gleason score between initial prostate biopsy and prostatectomy diminishes with increasing tumour grade due to reduced psa secretion per unit tumour volume. bju int. 2012; 110:36-42. 30. lourenço m, pissarra p, brito dv et al. lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece. arch ital urol androl. 2020; 91:218-223. archivio italiano di urologia e andrologia 2022; 94, 3 t. guimarães, m. gil, m. medeiros, et al. 284 31. wang x, zhang y, zhang f, et al. predicting gleason sum upgrading from biopsy to radical prostatectomy pathology: a new nomogram and its internal validation. bmc urol. 2021; 21:3. 32. qin xp, lu qj, yang ch, et al. crmp4 cpg hypermethylation predicts upgrading to gleason score ≥ 8 in prostate cancer. front oncol. 2022; 12:840950. 33. wang t, dong l, sun j, et al. mir-145-5p: a potential biomarker in predicting gleason upgrading of prostate biopsy samples scored 3+3=6. cancer manag res. 2021; 13:9095-9106. 34. lacetera v, antezza a, papaveri a, et al. mri/us fusion prostate biopsy in men on active surveillance: our experience. arch ital urol androl. 2021; 93:88-91 correspondence thiago guimarães, md (corresponding author) tguimaraesandrade@gmail.com miguel gil, md miguel_gil@live.com.pt mariana medeiros, md mmariana.medeiros92@gmail.com vanessa andrade, md andrade.vanessa2@gmail.com joão guerra, md joaoguerra93@gmail.com hugo pinheiro, md hugopinheiro1985@hotmail.com francisco fernandes, md e-mail: franciscof14@hotmail.com joão pina, md joaompina@gmail.com joão lopes dias, md joaolopesdias85@gmail.com luís campos pinheiro, md luiscampospinheiro@gmail.com rua josé antónio serrano, 1150-199 lisbon (portugal) stesura seveso 431archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. to pay for this reduction in diameter is one common channel for both irrigation and accessories, resulting in decreased irrigation flow. good irrigation means good vision (1), poor irrigation means poor vision. it is clear that the key factor determining the best outcome of the intervention is based on the quality of the vision with containment of complications in association with reasonable operating times. in our belief, the most important safety maneuvers are the positioning of a safety guidewire, the use of low pressures and avoiding to force the advancement of the instrument. during semirigid ureteroscopy, whether it is for stones or for cancer, one of the essential conditions is certainly the quality of vision that can be implemented by better tools like digital cameras but remains very conditioned by the quality of the medium in which the camera is immersed. moreover, there are concerns about the changes in the intra-pelvic pressure (ipp) that might reach critical levels, resulting in pyelovenous, pyelolymphatic, and pyelointerstitial backflow with subsequent systemic inflammatory response syndrome and sepsis. the association between surgery time and post-operative infectious complications was discussed in several studies in literature involving > 7.000 patients. according to the primary overall meta-analysis result, patients with longer operation time (min) are more vulnerable for infectious complication (or = 1.03, 95% ci:1.01-1.04, i2 = 70.6%, p = 0.001). according to the subgroup analysis, patients with longer operation time (min) are vulnerable or postoperative fever/urinary tract infections (or = 1.02, 95% ci:1.01-1.03, p < 0.001, i2 = 15.2%, p = 0.308) and also vulnerable for post-operative systemic inflammatory response syndrome/urosepsis (or:1.08, 95% ci 1.021.14, p = 0.009, i2 = 69.4%, p = 0.0017) (2, 3). the rationale of our study is to make a comparison between endoscopic procedures performed with the use of a standard guidewire and a ureteral catheter, which allow to create a continuous flow, so that the intake liquid is given by the instrument and the outflow by the ureteral catheter. that variation generates a potentially nonstop laser procedure with reduced operating-time, better vision, and a decreased risk of high intra pelvic pressure. this procedure can be called “active guidewire” technique, because of the active role of the ureteral catheter. background: one of the greatest challenges in semi-rigid ureteroscopies, for both stones and tumors, is the control of endoscopic vision and the maintenance of low intracavitary liquid pressure. we present a comparison between two operative techniques: in the first method an ordinary guide wire (diameter 0.032'') is used for the procedure; in the second one a 5 fr ureteral catheter replaces the guidewire (we called it “active guidewire”) methods we compared 50 semirigid ureteroscopies (surs) performed using the active guidewire with another 50 procedures conducted with a classic guidewire. we evaluated the difference in operating times, quality of endoscopic vision, periprocedural infections rate and stone-free rate. results: the use of active guidewire has considerably reduced the standardized operating times per unit stone-volume by about 39%. vision quality has improved considerably thanks to the continuous flow in-and-out. consequently, periprocedural infections decreased (3% vs 30%) and the stone-free rate rose from 86% to 92%. discussion and conclusions: employing an “active guidewire” instead of the standard guidewire, the risk of complications related to high pressures and operating time is considerably lower, as well as better treatment quality thanks to the cleaner vision. this technique has proven to be safe as well as easy to apply, and in our belief is to be preferred whenever the ureter accepts without forcing, both the presence of the catheter and the semi-rigid 7 f ureteroscope. key words: ureteroscopy; ureter; guidewire; ureteral stones; retrograde intrarenal surgery; lithotripsy. submitted 12 july 2021; accepted 25 august 2021 introduction and background in ureteral pathologies where indication is endoscopic treatment such as stones or urothelial tumors, the growing technological progress has led to a more frequent use of minimally invasive operative techniques including semi-rigid ureteroscopy and rirs (retrograde intrarenal surgery). all of these operating techniques use irrigation to permit the best possible endoscopic vision and simple safety maneuvers to minimize the risk of complications. advances in technology have also generated ureterorenoscopes with increasingly smaller diameters, but the price the active guidewire technique versus standard technique as different way to approach ureteral endoscopic stone treatment alessandro calarco 1, marco frisenda 1, 3, emilio molinaro 1, 3, niccolò lenci 2 1 department of urology, “cristo re” hospital fondation, rome, italy; 2 department of urology, “a. gemelli” academic hospital, catholic university of sacred heart, rome, italy; 3 department of urology, policlinico umberto i, “la sapienza” university, rome, italy. doi: 10.4081/aiua.2021.4.431 summary archivio italiano di urologia e andrologia 2021; 93, 4 a. calarco, m. frisenda, e. molinaro, n. lenci 432 methods to overcome the problems of the current technique, such as poor vision and interruption of the flow at high intrarenal pressures, we describe the differences between the two techniques and in particular the advantages seen in the population treated with the active guidewire. in this technique the safety guidewire is replaced by a pollack ureteral catheter (cook medical®) thus becoming an active, and no longer passive, element during the procedure. the “active guidewire” has a diameter of 5 f, with a soft tip at its head, and it is positioned in place of the safety guidewire, thus connecting the renal pelvis with the outside. the pollack catheter has an internal size of 4 fr. a 6,5/7 f storz® semirigid ureteroscope is used and it has a 4 f irrigation channel. the two 4 f channels give us a perfect balance with in and out irrigation flow. a polytetrafluoroethylene (ptfe)-coated guidewire was used as standard guidewire. a ptfe-nitinol guidewire with hydrophilic tip was used when the stone was impacted. for statistical evaluation ibm© spss statistics program (illinois, chicago, v. 24) was used. pearson's chi-square, pearson correlation analysis and student's test were used. statistical significance was evaluated at p < 0.05. we took in consideration 100 patients undergoing semirigid ureterorenoscopy (surs) for ureteral stones. hydronephrosis was present in 60% of the patients. no double j (jj) stent was inserted before the surgery, in any case (table 1). all patients had a clinical evaluation, urine dipstick analysis with additional culture and sensitivity testing if a urinary tract infection (uti) was suspected, a measurement of serum creatinine level, abdominal ultrasonography (us) and a plain abdominal x-ray. patients with positive pre-operative urine culture (n. 4) were treated with specific antibiotics until complete remission (verified performing new urine culture and blood test). preoperative additional computed tomography (ct) was used, according to the level of serum creatinine and stone radiolucency, in that patients in which us and x-ray were not adequate for the diagnosis. patients were placed in the lithotomy position and received prophylactic parenteral antibiotics before the procedure, which was performed under spinal or general anesthesia. a retrograde pyelogram was performed to define the anatomy and visualize any filling defect. we created two groups. group a: 50 patients underwent “active guidewire” technique and 50 underwent standard technique. the ureteral catheter was used until the end of the procedure in all patients of group a instead of the standard guidewire. group b: 50 patients underwent standard procedure with the aid of traditional guidewire. the initial phases of both the surgical procedures were similar, up to the step of replacing the standard guidewire with the active one. firstly, using a cystoscope, a urethrocystoscopy was performed to exclude any other urethral or bladder pathologies. then a ptfe standard guidewire was placed in the ureter and the cystoscope removed. a second guidewire through the operative channel of 7 f ureteroscope was used to reach the stone, passing the instrument between the two guidewire. if the ureter appeared compliant and the stone was not completely obstructing the lumen, we removed the ureteroscope and we replaced the standard guidewire with a 5 f pollack catheter, left aside the stone until the end of the procedure. this step was performed with the help of the fluoroscopy and contrast enhancement. finally, the ureteroscope was reintroduced to begin the lithotripsy. holmium-yag laser was used for stone dusting or fragmentation. operating time was considered from the beginning of the procedure (operator introduced the guidewire in the ureteral meatus) to the end (operator placed the ureteral stent). we evaluated as endpoints: – reduction of operating times related to the volume of the stone. – quality of endoscopic view (expert operator opinion ac). – reduction of the number of procedure-related urinary tract infections (utis) by monitoring the leukocytes blood values before and after surgery. – stone free rate (sfr) valuated by 30 days no-ce ct scan. all procedures were performed by the same operator in high volume center with the same type of semi-rigid ureteroscope. patient’s data collected, including age, gender, side, stone location (proximal, intermediate or distal ureteral). results we observed a statistically significant reduction (p = 0.01) in operating times of the procedure performed with the “active guidewire” compared to the control group, standardizing the operating times and relating them to the volume of the stone. we calculated a coefficient given by the ratio between the operating time (min) and the volume of the stone (mm3). this coefficient was 39% lower in the procedures conducted with active guidewire (5.72 vs 9.40) (table 2). pearson correlation analisys was conducted, that demostrates a direct correlation in favour of the active guidewire technique (r = 0.208, p = 0.035) (table 3). in 10 patients of group a we found a reduction in posttable 1. patient demographics. patient, n 100 mean age years (range, median) 54 (28-86, 56) men, n (%) 63 (63) women, n (%) 37 (37) proximal ureteral stone, n (%) 32 (32) intermediate ureteral stone, n (%) 26 (26) distal ureteral stone, n (%) 42 (42) hydronephrosis, n (%) 78 (78) side right/left (%) 49/51 (49/51) previous rirs (%) 0 (0) indwelling double-j stent, (%) 0 (0) 433archivio italiano di urologia e andrologia 2021; 93, 4 ureteral stone treatment: 2 techniques comparison operative leukocytosis, thanks to the resolution of hydronephrosis. in the remaining 40 patients of group a we witnessed a postprocedural increase of the white blood cell count (< 20%). the mean increase of white blood cell count across all procedures performed with active guidewire was 3% compared to pre-operative blood cell count. two of these patients had postoperative fever and leukocytosis > 20.000 wbc/mm3, treated with antibiotic therapy. all patients in group b showed rising white blood cell count, with an average white blood cell growth of 30%. statistical analysis demonstrates a significative difference in reduction of leukocytosis, number of mucosal slippage and post-operative fever (table 2). in group b, 5 episodes of ureteral mucosal injury occurred, which led to an early conclusion of the procedure and the placing of a ureteral stent. stone free rate (sfr) was 92% and 86% respectively in “active guidewire” and standard guidewire group. no significant differences occurred on this field (table 2). pearson correlation analysis demonstrated an indirect correlation between the endoscopic technique and operating time (r = -0.532, p < 0.001), mucosal slippages (r = -0.246, p = 0.012) and postoperative leukocytosis (r = -0.654, p < 0.001) (table 3). discussion a compliant ureter is defined as a ureter ≥ 12 f and so it should allow the easy passage of a semirigid 7 f ureteroscope with a safety guidewire (3 f) aside or “active guidewire” (5 f) (4). the usage of a ureteral catheter instead of the standard guidewire has some remarkable advantages. first of all, the quality of vision, in particular during laser lithotripsy, is absolutely better than the standard technique because the generated powder is immediately expelled through the catheter, thanks to the constant antegrade flow. stone powder is not in suspension in our working area. the second advantage, directly connected to the first, is represented by a lower risk of ureteral mucosal injury due to a better vision (figure 1). in group b, we observed 5 episodes of ureteral mucosal injury, occurred during laser lithotripsy. the cause of these injuries was the imperfect vision of the operating field, due to the stone powder and the necessity of a reduced or discontinuous inflow, in order to not push-up the stone. in fact, no ureteral tears or damage occurred in group a, because of a perfect vision of the ureteral field. finally, it allows to reduce intrarenal pressure peaks. during the semi-rigid ureteroscope progression in ureter, the ippmax (intrapelvic pressure max) reaches high levels in renal pelvis; the use of pumpes also induces critical levels of ippmax. excessive irrigation pressures can be detrimental, leading to pyelolymphatic and pyelovenous backflow and consequent development of sepsis (1, 5). the use of a pollack ureteral catheter during ureteroscopy, allow an excape way for saline irrigation preventing high pressure peaks. we were not able to evaluate the real renal pelvis ippmax in the two groups, but we suppose that the presence of the 5 f ureteral catheter in pelvis can create a useful way of outflow. we think that the lower number of post-operative leukocytosis and fevers in group a could be due to this expedient. in summary, a better vision of the operative area, the reduction of operating time and the low rate of leukocytosis can traslate in better results for this kind of surgery. in addition, during semi-rigid ureteroscopy it is mandatory to interrupt the treatment every time the antegrade flow ceases, due to the filling of the excretory route, because of the absence of a continuous flow of the instrument. so the usage of the ureteral catheter reduces the ippmax, post-operative utis and allows a faster hospital table 2. data analysis. “active guidewire” standard guidewire p-value completed procedures surs (%) 50 (50) 50 (50) average age 55 53 average ratio operating time\stone volume (min\mm3) 5.72 9.4 0.01 mean increased postoperative leukocytosis in percentage 3 30 < 0.01 mucosal injury (%) 0 (0) 5 (10) < 0.01 postoperative fever (%) 1 (2) 8 (16) < 0.01 stone-free rate (%) 46 (92) 43 (86) 0.914 table 3. pearson correlation analysis. variable person coefficent p-value endoscopic technique – operating time -0.532 < 0.001 endoscopic technique – postoperative leukocytosis -0.654 < 0.001 endoscopic technique – mucosal slippage -0.246 0.012 endoscopic technique – operating time\stone volume (min\mm3) 0.208 0.035 figure 1. clear vision of operative area with the use of an active guidewire. archivio italiano di urologia e andrologia 2021; 93, 4 a. calarco, m. frisenda, e. molinaro, n. lenci 434 discharge of the patient (6-8). it results in a decrease of hospitalization costs. conclusions if we consider the kidney as a closed system, without a discharge for saline irrigation during semi-rigid ureteroscopy, we have to consider that the most part of time is actively used (antegrade flow, good vision and lithotripsy) but a really long period of time is spent passively (discharge of the kidney), so it leads to a temporary interruption of the procedure. in our experience the “active guidewire technique” has proven to be safe as well as easy to apply in selected cases. the use of a small semi-rigid ureteroscope (7 f) is mandatory, because of the 5 f diameter of the ureteral catheter. we believe that this technique, compared to the use of the traditional guide wire, is to be preferred whenever the ureter allows the presence of the catheter and the semirigid 7 f ureteroscope (for a total of 12 f) in its lumen, avoiding forcing the passage of the instrument. the size of the catheter is acceptable, in consideration of the frequent use of ureteral sheaths with even larger diameters (from 12 to 14 fr) in endoscopic urological surgery (9). the decompression of the pelvic-caliceal system leads to avoid pressure spikes, which might decrease infectious complications. furthermore, the risk of complications related to high pressures and operating time is lower, as well as better treatment quality thanks to cleaner vision (10-12). many authors suggested that high intrarenal pressure during ureteroscopy and iatrogenic trauma of the pelvicalyceal system during instrumental manipulations are the most probable mechanisms that lead to other life-threatening complications such as urinomas, perirenal abscesses and subcapsular, perirenal and retroperitoneal hematoma, reported with an incidence up to 2,2% (13, 14, 16, 17). nevertheless, the use of “active guidewire” can decrease the ippmax and let urs safer by acting as a safeguard against the consequences of increased ipp, even under manual pumping and forced irrigation (15). it needs a laboratory study to assess the real value of the ipp and the differences in the two surgical approaches. the comparison also needs a larger cohort of study to be better statistically evaluated in order to standardize a different and often safer approach to ureteral and renal stone. ethics approval and consent to participate all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. each patient agreed to allow the use of their clinical data for the study and signed an informed consent. this study doesn’t require the approval by the ethics committee for its conception. availability of data and materials the data that support the findings of this study are available on request from the corresponding author ac. the data are not publicly available for containing personal information that could compromise research participant privacy. funding this study was not funded by any institution. author contributions (initials name and surname): (i) conception and design: ac, nl (ii) administrative support: mf, em (iii) provision of study materials or patients: ac (iv) collection and assembly of data: ac. nl (v) data analysis and interpretation: nl, mf, em (vi) manuscript writing: all authors (vii) final approval of manuscript: all authors. references 1. michel ms, honeck p, alken p. conventional high pressure versus newly developed continuous-flow ureterorenoscope: urodynamic pressure evaluation of the renal pelvis and flow capacity. j endourol. 2008; 22:1083-1085. 2. ma yc, jian zy, yuan c, et al. risk factors of infectious complications after ureteroscopy: a systematic review and meta-analysis based on adjusted effect estimate, surg infect. 2020; 21:811-822. 3. southern jb, higgins am, young aj, et al. risk factors for postoperative fever and systemic inflammatory response syndrome after ureteroscopy for stone disease. j endourol. 2019; 33:516-522. 4. fulla j, prasanchaimontri p, rizk a, loftus c, et al. ureteral diameter as predictor of ureteral injury during ureteral access sheath placement. j urol. 2021; 205:159-164. 5. li t, sun xz, lai dh, et al. fever and systemic inflammatory response syndrome after retrograde intrarenal surgery: risk factors and predictive model. kaohsiung. j med sci. 2018; 34:400-408. 6. moses ra, ghali fm, pais vm, jr, hyams e. unplanned hospital return for infection following ureteroscopy can we identify modifiable risk factors? j urol. 2016; 195:931-936. 7. mitsuzuka k, nakano o, takahashi n, satoh m. identification of factors associted with postoperative febrile urinary tract infection after ureteroscopy for urinary stones. urolithiasis. 2016; 44:257262. 8. blackmur jp, maitra nu, marri rr, et al. analysis of factors association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. j endourol. 2016; 30:963-969. 9. boulalas i, de dominicis m, defidio l. semirigid ureteroscopy prior retrograde intrarenal surgery (rirs) helps to select the right ureteral access sheath. arch ital urol androl. 2018; 90:20-24. 10. ogreden e, oguz u, demirelli e, et al. categorization of ureterooscopy complications and investigation of associated factors by using the modified clavine classification system. turk j med sci. 2016; 46:686-694. 11. somani bk, giusti g, sun y, et al. complications associated with ureterorenoscopy (urs) related to treatment of urolithiasis: the clinical research office of endourological society urs global study. world j urol. 2017; 166:538-540. 12. proietti s, dragos l, somani bk, buttice s, talso m, emliani e, et al. in vitro comparision of maximum pressure developed by irrigation systems in a kidney model. j endourol. 2017;31:522-527. 435archivio italiano di urologia e andrologia 2021; 93, 4 ureteral stone treatment: 2 techniques comparison 13. de coninck v, keller ex, somani b, et al. complications of ureteroscopy: a complete overview. world j urol. 2020; 38:21472166. 14. bai j, li c, wang s, et al. subcapsular renal haematoma after holmium: yttrium-aluminium-garnet laser ureterolithotripsy. bju int. 2012; 109:1230-1234. 15. hyams es, munver r, bird vg, et al. flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience j endourol. 2010; 24:1583-1588. 16. xu l, lig life-threatening subcapsular renal hematoma after flexible ureteroscopic laser lithotripsy: treatment with superselective renal arterial embolization. urolithiasis. 2013; 41:449-451. 17. meng hz, chen sw, chen gm, et al. renal subcapsular hemorrhage complicating ureterolithotripsy: an unknown complication of a know day-to-day procedure. urol int. 2013; 91:335-339. correspondence alessandro calarco, md alecalarco@gmail.com marco frisenda, md (corresponding author) marco.frisenda57hu@gmail.com emilio molinaro, md emilio.molinaro89@gmail.com department of urology, “cristo re” hospital fondation, rome (italy) niccolò lenci, md lenci.niccolo@live.com department of urology, “a. gemelli” academic hospital, catholic university of sacred hearth, rome, italy stesura seveso 379archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. owing to provides the best cancer-specific survival in muscle-invasive patients (3, 4). rc provides excellent local control with a local recurrence rate of 4% in patients with lymph node-negative (5). rc is associated with significant complications, including death, with wide variability in reported postoperative morbidity and mortality rates. in a study of 1142 patients managed by shabsigh et al., the serious complication rate was 13% and the mortality rate within 30 days was 1.5% (6). although the mortality rate has decreased over the past decade, early morbidity rates have remained at ranging from 11 to 68% (3, 7, 8). whether the disease is organ-confined to the or not and the patient's comorbidity status (age-adjusted charlson comorbidity index acci) are defined indicators of mortality and complications after radical cystectomy (9). putting forth a marker that can predict complications can be a prominent attempt to reduce mortality and morbidity. in line with this goal, and hence that there is no prospective study on this subject in the literature, we aimed to examine the usability of serum albümin. simultaneously, we also examined hematocrit values, agedependent charlson comorbidity index (acci), bmi, and operation time. materials and methods all patients scheduled to view radical cystectomy for bc between 2015 and 2016 in the urology clinic of kartal lütfi kırdar city hospital were examined prospectively. a total of 60 patients underwent radical cystectomy operation, and since five patients were out of follow-up, 55 cases, six females and 49 males were included in the study. ethics committee approval was obtained from our hospital's ethics committee for our study, and all subjects signed an informed consent form (irb number 514/65/4). patient's age, bmi, acci score, preoperative serum albumin, hematocrit (hct), urea-creatinine values, operation time, pre-and post-cystectomy pathological stages, diversion type, amount of blood transfusion, type of complications, intestinal functions (gas-stool output time), the transition time to oral nutrition, total parenteral nutrition (tpn) time, the length of hospital stay, the duration of drainage catheter and reoperations, patients' mortality objective: to evaluate the relationship between serum albumin, hematocrit (htc), age-dependent charlson comorbidity index, body mass index (bmi), and deleted operation time in predicting mortality and complications associated with radical cystectomy. materials and methods: all patients planned for radical cystectomy owing to bladder cancer were investigated prospectively between 2015 and 2016 in our clinic. a total of 55 cases were included in the study. patients' characteristics, preoperative serum albumin values, hematocrit level, age-dependent charlson comorbidity index (cci), body mass index and deleted operation time, drainage catheter time, gas-stool expulsion time were recorded. the patients were followed up for 90 days. results: age of cases, charlson comorbidity index scores, and hct were not different in patients with or without complications (overall) or severe complications nor in patients who died or survived after the procedure. the albumin value of the cases with observed mortality and complications was significantly lower than that of the cases with no mortality and complications. in multivariate and univariate analysis, low albumin level was established to be meaningful in predicting mortality and serious complications. the cut-off point for albumin, according to mortality, was found to be 4.1. mortality within 90 days was 16.3% (n = 9). conclusions: we have evaluated albumin as a marker that could indicate both mortality and the presence of severe complications after radical cystectomy and urinary diversion. key words: albumin; bladder cancer; complications; cystectomy; mortality. submitted submitted 28 july 2021; accepted 9 september 2021 introduction bladder cancer (bc) is the 7th most commonly diagnosed cancer in males, while it degrades to 11th when both genders are taken into account (1); 75% of patients with bc present with disease non-muscle invasive bladder cancer at the first consult. patients with muscle-invasive bladder tumors often present with progressed disease and approximately 20% of them are patients who progress from lower stages (2). the cancer-specific mortality rate of muscle-invasive bladder cancer (mibc) can be predicted to increase up to 85% if left untreated (2). radical cystectomy (rc) and pelvic lymph node dissection (plnd) is the standard treatment for localized mibc is it possible to reduce the complications and mortality of patients undergoing radical cystectomy? effectiveness of pre-operative parameters. a prospective study övünç kavukoglu, alper coskun, kubilay sabuncu, emre çamur, gökhan faydaci department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. doi: 10.4081/aiua.2021.4.379 summary gastrointestinal system (gis) with a 47.3% rate (n = 26). second most frequent complications with a 36.4% rate (n = 20) were infectiouscomplications; wound/skin-related complications followed with 14.5% rate (n = 8). in the relationship between the variety of complications and albumin value, the rate of wound/skin and neurological complications in patients with albumin below 3.5 was significantly higher than in those with a value over 3.5 (p = 0.019, p = 0.002) (table 2). according to clavien complication status and severity, age, charlson comorbidity index, operation times, hct values, gas-stool output times did not show a statistically significant difference (p > 0.05). likewise, when the albumin values were examined according to the complication status and severity, no albumin value of 3.5 or less was observed in any of the cases without complications and with mild complication severity. besides, the albumin value of the patients with complications was found to be significantly lower than the cases without complications (p = 0.013; p < 0.05) (table 3). while there is no statistically significant difference between age, charlson comorbidity index, bmi, operation time, hct value, gas-stool output time and mortality, the same is not current for albumin. in fact, 55.6% of the cases with mortality had an albumin value of 3.5 and below, and 8.7% of the cases with no mortality had an albumin value below 3.5 (table 4). the cut-off point for albumin considering mortality was found to be 4. accordingly, it is significant that the albumin value of the cases with mortality is 4.1 and below. this cut-off value's sensitivity is 100%, the specificity is 52.17%, the positive predictive value is 29 and the negative predictive value is 100. the area under the roc curve was 82% for the standard error of the area 6.7% (figure 1). archivio italiano di urologia e andrologia 2021; 93, 4 ö. kavukoglu, a. coskun, k. sabuncu, e. çamur, g. faydaci 380 and morbidity until the postoperative 90th day and their application for any reason to the hospital, were recorded for each patient. also, they routinely were called for follow-up visits in the postoperative first and third months. we preferred a well-described method, as clavien dindo classification system (ccs), for evaluation of postoperative complications (10, 11). statistical analysis was conducted using ncss (number cruncher statistical system) 2007 (kaysville, utah, usa). the quantitative and qualitative variables were analyzed with student's t-test, mann whitney u test, pearson chi-square test, fisher's exact test, and fisher freeman halton test. a p value < 0.05 was considered to indicate statistical significance. results the mean age of the patients was 65.27 ± 9.38, bmi 26.21 ± 4.17 kg/m2, hct 37.90 ± 5.37, albumin values ranged from 2.2 to 4.9, with an average of 4.03 ± 0.55. operation times averaged 273.15 ± 74.30 minutes and gas-stool output time 3.92 ± 1.60 days. the patients' demographic characteristics, preoperative laboratory values, postoperative results, charlson scores, clavien complication scores were outlined in table 1. the majority of postoperative complications are related to table 1. patients characteristics findings. pre-operative parameters min-max (median) mean ± ss age (years) 38-85 (65) 65.27 ± 9.38 n % bmi (kg /m2) normal 45.50 overweight 34.50 obese 20.00 gender female 6 10.9 male 49 89.1 hemoglobin 9.2-16 (12.1) 12.45 ± 1.80 hematocrit 27.7-48.8 (37.6) 37.90 ± 5.37 albumin 2.2-4.9 (4.1) 4.03 ± 0.55 urea 12-135 (39) 44.65 ± 20.77 creatinine 0.6-4.7 (1.1) 1.33 ± 0.87 neoadjuvant chemotherapy radiotherapy/ 0-4 (0) abdominal surgery no 40 72.7 yes 15 27.3 charlson score ≤ 2 9 16.4 3-4 28 50.9 ≥ 5 18 32.7 clavien dindo (n=39) 2 15 38.5 3 11 28.2 4 4 10.3 5 9 23.1 peri-operative parameters positive no 41 75.9 surgical margin yes 14 24.1 operation time (min) 160-540 (257.5) 273.15 ± 74.30 postoperative parameters re-operation no 44 80.0 yes 11 20.0 intensive care unit time (day) 0-31 (1) 2.42 ± 5.43 gas output time (day) 1-8 (3) 2.88 ± 1.45 stool output time (day) 1-9 (4) 3.92 ± 1.60 transition time to oral nutrition (day) 1-11 (4) 4.00 ± 1.79 tpn time (day) 0-10 (4) 4.10 ± 2.35 drainage catheter staying time (day) 4-19 (8.5) 9.74 ± 3.53 length of hospital stay (day) 2-46 (10) 12.78 ± 9.65 table 2. the type of complications and comparing with albumin. pre-operative parameters albumin test value > 3.5 ≤ 3.5 p n (%) n (%) gastrointestinal system no 26 (56.5) 3 (33.3) χ2 = 1.624 yes 20 (43.5) 6 (66.7) 0.281b infection no 32 (69.6) 3 (33.3) χ2 = 4.270 yes 14 (30.4) 6 (66.7) 0.059 b genitourinary system no 43 (93.5) 8 (88.9) χ2 = 0.235 yes 3 (6.5) 1 (11.1) b0.522 b hematological/vascular no 42 (91.3) 8 (88.9) χ2 = 0.053 yes 4 (8.7) 1 (11.1) 1.000 b cardiac no 44 (95.7) 8 (88.9) χ2 = 0.668 yes 2 (4.3) 1 (11.1) b0.421 b wound/skin no 42 (91.3) 5 (55.6) χ2 = 7.739 yes 4 (8.7) 4 (44.4) 0.019 b * pulmonary no 41 (89.1) 7 (77.8) χ2 = 0.873 yes 5 (10.9) 2 (22.2) 0.321 b neurological no 43 (93.5) 5 (55.6) χ2 = 9.746 yes 3 (6.5) 4 (44.4) 0.002 b ** metabolic no 41 (89.1) 8 (88.9) χ2 = 0.000 yes 5 (10.9) 1 (11.1) 1.000 b musculoskeletal system no 45 (97.8) 9 (100.0) χ2 = 0.199 yes 1 (2.2) 0 (0.0) 1.000 b b fisher’s exact test; *p < 0.05; **p < 0.01. 381archivio italiano di urologia e andrologia 2021; 93, 4 complications of radical cystectomy lished. the sensitivity of these models (model 1, 2) for the cases with mortality was 44.4% and 79.2% and the specificity rate was 66.7% and 93.5%, overall accuracy was 85% and 74.4%, respectively. additionally, albumin's onetable 3. comparison of operation time, bmi and albumin values according to the presence of complications and their severity. figure 1. diagnostic screening tests and roc curve outcomes of albumin by mortality. overall complications test value complication severity test value no (n = 16) yes (n = 39) p mild (n = 15) severe (n = 24) p age (years) min-max (median) 51-77 (63) 38-85 (67) t = 0.864 38-81 (75) 53-85 (66) t = 0.053 mean ± ss 63.56 ± 7.76 65.97 ± 9.98 0.392 d 65.87 ± 11.78 66.04 ± 8.94 0.958 d bmi (kg/m2) min-max (median) 22-34.1 (25.5) 17.6-36.3 (25.4) t = -0.288 17.6-34.0 (23) 22.1-36.3 (25.8) t = 2.215 mean ± ss 26.46 ± 3.92 26.10 ± 4.31 0.774 d 24.26 ± 4.21 27.25 ± 4.04 0.033 d * charlson score min-max (median) 2-6 (3.5) 0-8 (4) z = -1.641 0-5 (4) 2-8 (4) z = -0.944 mean ± ss 3.62 ± 1.20 4.10 ± 1.70 0.101 a 3.60 ± 1.40 4.42 ± 1.81 0.345 a operasyon time min-max (median) 180-450 (255) 160-540 (257.5) t = -0.539 180-540 (250) 160-390 (270) t = -0.468 mean ± ss 264.69 ± 69.84 276.71 ± 76.72 0.592 d 284.00 ± 97.43 271.96 ± 61.62 0.643 d hematocrit min-max (median) 33.4-46.5 (40) 27.7-48.8 (37.5) t = 1.548 31.6-47.0 (37.6) 27.7-48.8 (36.45) t = -0.930 mean ± ss 39.63 ± 4.32 37.19 ± 5.64 0.128 d 38.25 ± 4.99 36.53 ± 6.01 0.359 d bmi (n%) normal 7 (43.8) 18 (46.2) χ2 = 0.367 9 (60.0) 9 (37.5) χ2 = 2.611 overweight 5 (31.3) 14 (35.9) 0.832 e 5 (33.3) 9 (37.5) 0.283 c obese 4 (25.0) 7 (17.9) 1 (6.7) 6 (25.0) charlson score ≤ 2 3 (18.8) 6 (15.4) χ2 = 0.706 3 (20.0) 3 (12.5) χ2 = 1.115 3-4 9 (56.3) 19 (48.7) 0.716 c 8 (53.3) 11 (45.8) 0.675 c ≥ 5 4 (25.0) 14 (35.9) 4 (26.7) 10 (41.7) albumin min-max (median) 3.7-4.8 (4.25) 2.2-4.9 (4) t = 2.563 3.-4.9 (4.2) 2.2-4.8 (4) t = -2.499 mean ± ss 4.26 ± 0.31 3.94 ± 0.60 0.013 d* 4.23 ± 0.35 3.76 ± 0.66 0.007 d ** albumin > 3.5 16 (100.0) 30 (76.9) χ2 = 4.415 15 (100.0) 15 (62.5) χ2 = 7.313 ≤ 3.5 0 (0.0) 9 (23.1) 0.046 b * 0 (0.0) 9 (37.5) 0.007 b ** a mann whitneyutest; b fisher’sexact test; c fisher freeman halton test; d student-ttest; e pearson chi-squaretest; *p < 0.05; **p < 0.01. to examine factors that affect the severity of complications and mortality, two separate logistic regression models derived from age, bmi, albumin value, preoperative hct value and charlson index variables were estabarchivio italiano di urologia e andrologia 2021; 93, 4 ö. kavukoglu, a. coskun, k. sabuncu, e. çamur, g. faydaci 382 point rising could decrease the prospect of mortality by 0.014 (1/71) times and of serious complications by 0.057 (1/17) times. similarly, it was found that a one-unit decrease in hct value would increase the likelihood of mortality by 1.273 times, while a one-unit increase in bmi value would increase the likelihood of severe complications by 1.4 times. b coefficients obtained in the logistic regression models (model 1, 2) are shown in table 5. discussion radical cystectomy (rc) is the primary treatment modality for patients with muscle-invasive urothelial cancer of the bladder (1). increasing patient age, female gender, more than two comorbidities, having undergone previous pelvic surgery, stage of the disease (extravesical disease) and obesity are factors that will increase complications and mortality (6, 7, 12-14). also, the experience of the surgeon, perioperative blood loss and operation time are important items. assessment of comorbidities of patients is of great significance in predicting mortality and morbidity. the american society of anesthesiologists (asa) score is frequently used for this goal. however, we used the charlson comorbidity index (cci) in our study (15). considering their comorbidity index, we divided the patients into three groups: 2 mild, 3-4 moderate, and ≥ 5 severe. we observed that patients with 5 and above have serious complications. in the study by koppie et al., overall survival was demonstrated decreasing in patients with high comorbidity considering the comorbidity index, but recurrence-free survival was not affected. again maffezini et al. in his study, a cci of more than 3 was found to be associated with survival (16). it is also noteworthy that patients with high comorbidities had been performed less lymph node dissection and less postoperative chemotherapy (9). the complication percentage of our study is 70.9%. this value is higher than the literature obviously. (6, 15, 1820). whereas these literature values included 30-day morbidity and mortality, we analyzed 90-day. although most of the complications come into being were complaints that would not be classified as serious complications, we found the serious complication rate (claviendindo: 3-5) 43.6% (n: 24), severe complication clavien dindo 4-5 23.6%. the mortality rate within 90 days postoperatively is 16.3% (n = 9). we did not find a significant relationship between mortality and complication rates with bmi, charlson comorbidity index, preoperative hematocrit values and operation time in univariate analysis. as for the multivariate analysis, we observed that the hematocrit value is strongly related to predicting mortality and bmi is also significant in the presence of severe complications. however, it would not be wrong to say that we found the most significant results in our study when we analyzed the albumin values. albumin is an important marker to predict mortality and severe complication in both univariate and multivariate analyses. in addition, our results showed us that wound/skin and neurological complications were significantly higher if albumin values are low. undernourishment is a well-known risk factor for complications (21-23). serum albumin has been shown that is a determinant of nutritional status and is a prominent marker of prognosis and progression in many types of cancer in previous studies (24, 25). in the study by gregg at al., they have categorized patients with preoperative albumin value of 3.5 and below, those with bmi < 18.5 and patients with pre-operative weight loss of more than 5% were as patients with malnutrition (23). in another study that had been done with similar logic, the preoperative albumin value was found to be significant in predicting complicatable 4. charlson comorbidity index, bmi, hct, and albumin values by mortality. mortality test value yes (n = 46) no (n = 9) p age (years) min-max (median) 38-84 (65) 57-85 (70) z = -1.162 mean ± ss 64.63 ± 9.45 68.56 ± 8.80 0.245 a bmi (kg/m2) min-max (median) 17.6-36.3 (25.4) 22.1-32 (24.8) z = -0.228 mean ± ss 26.28 ± 4.30 25.83 ± 3.64 0.820 a charlson score min-max (median) 0-8 (4) 2-7 (5) z = -0.995 mean ± ss 3.80 ± 1.51 4.78 ± 1.71 0.320 a hematocrit min-max (median) 27.7-48.0 (37.7) 30.0-48.8 (37.5) z = -0.262 mean ± ss 37.94 ± 5.27 37.71 ± 6.20 0.794 a bmi (n %) normal 20 (43.5) 5 (55.6) χ2 = 0.835 overweight 17 (37.0) 2 (22.2) 0.725 c obese 9 (19.6) 2 (22.2) charlson score ≤ 2 8 (17.4) 1 (11.1) χ2 = 2.341 3-4 25 (54.3) 3 (33.3) 0.343 c ≥ 5 13 (28.3) 5 (55.6) albumin (n %) > 3.5 42 (91.3) 4 (44.4) χ2 = 12.077 ≤ 3.5 4 (8.7) 5 (55.6) 0.003 b ** albumin g/dl min-max (median) 2.7-4.9 (4.2) 2.2-4.1 (3.3) z = -3.028 ort ± ss 4.15 ± 0.45 3.44 ± 0.66 0.002 a ** albumin cut-off > 4.1 24 (52.2) 0 (0.0) χ2 = 8.331 ≤ 4.1 22 (47.8) 9 (100.0) 0.003 b ** a mann whitneyutest; b fisher’sexact test; c fisher freeman halton test; *p < 0.05; **p < 0.01. operation time was excluded. table 5. logistic regression models for factors affecting mortality and complication severity. β p odds ratio confidence interval (or) for or low high model 1. mortality age -0.079 0.412 0.924 0.766 1.116 bmi -0.039 0.792 0.961 0.717 1.289 albumin -4.294 0.005 0.014 0.001 0.272 hematocrit 0.242 0.036 1.273 1.016 1.595 charlson score 0.457 charlson (2-5) -0.192 0.919 0.825 0.020 34.123 charlson (> 5) 1.140 0.569 3.128 0.062 158.545 constant 11.709 0.230 121625.915 model 2. complication severity age 0.021 0.736 1.022 0.902 1.158 bmi 0.337 0.027 * 1.400 1.039 1.887 albumin -2.857 0.025 * 0.057 0.005 0.704 hematocrit -0.010 0.917 0.991 0.828 1.184 charlson score 0.822 charlson (2-5) -0.978 0.531 0.376 0.018 8.040 charlson (> 5) -0.956 0.603 0.384 0.011 14.063 constant 3.135 0.661 22.993 *p < 0.05. 383archivio italiano di urologia e andrologia 2021; 93, 4 complications of radical cystectomy tions and mortality after radical cystectomy. it was predicted that better postoperative outcomes could be achieved with preoperative nutritional support (26). the study by djaladat et al. investigated the relationship between asa score and albumin with survival; they established that a high asa score was associated with increased complication rates and low serum albumin with recurrence-free overall survival. as a result of albumin being so vital, the idea of albumin supplementation to patients had come into question, but studies have shown that it does not cause better results and may cause undesirable effects (26, 27). similarly, when the patients who were given tpn (total parenteral nutrition) and not given were investigated, no difference was obtained in the complication rates and infectious complications (such as intraabdominal abscess and peritonitis) increased in patients who received tpn (28). we can indicate the study's limitations as follows; it is a single-center study, the number of patients is insufficient, a single surgeon did not perform operations, complications, mortality and was not calculated according to the pathological stages of the patients, our follow-up period is short. we thought that it would cause us to have difficulty in distinguishing cancer-specific survival from postoperative mortality in a more extended follow-up period. therefore, we considered that the 3-month period is optimal duration. the fact that our results are similar to the literature may bring a criticism that the study does not contribute to literature at first. although accepting this as a self-criticism, our research was designed prospectively, point that it is different from existing studies. another subject of criticism is that the patients' postoperative albumin values were not compared with the preoperative values. frankly, we believe that this may be the subject of a different study. it is valuable that albumin gives such significant statistical results with a small patient population. however, it would not explain the high mortality and complications with only preoperative data-besides, the lack of patient outcomes who underwent laparoscopic and robotic surgery acceptable an issue of criticism. our results are generally concordant with the literature. we believe that the fact that these supportive data were obtained prospectively will make our study privileged. conclusions finding a marker that predict the mortality and complications that may occur after radical cystectomy may be help to prepare the patient before surgery and manage the patient after surgery. as a result, albumin was found to be meaningful in predicting both mortality and the presence of serious complications. we believe that our results will give an opinion for future randomized controlled multicenter studies. thus, it may be possible to minimize complications and mortality. references 1. babjuk m, böhle a, burger m, et al. eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. eur urol. 2017; 71:447-461. 2. prout gr, marshall vf. the prognosis with untreated bladder tumors. cancer. 1956; 9:551-558. 3. lawrentschuk n, colombo r, hakenberg ow, et al. prevention and management of complications following radical cystectomy for bladder cancer. eur urol. 2010; 57:983-1001. 4. meyer jp, blick c, arumainayagam n, et al. a three-centre experience of orthotopic neobladder reconstruction after radical cystectomy: revisiting the initial experience, and results in 104 patients. bju int. 2009; 103:680-683. 5. morris ds, weizer az, ye z, et al. understanding bladder cancer death: tumor biology versus physician practice. cancer. 2009; 115:1011-1020. 6. shabsigh a, korets r, vora kc, et al. defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. eur urol. 2009; 55:164-74. 7. novara g, marco vd, aragona m, et al. complications and mortality after radical cystectomy for bladder transitional cell cancer. j urol. 2009; 182:914-921. 8. bostrom pj, mirtti t, kössi j, et al. twenty-year experience of radical cystectomy for bladder cancer in a medium-volume centre. scand j urol nephrol suppl. 2009; 43:357-364. 9. koppie tm, serio am, vickers aj, et al. age-adjusted charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. cancer. 2008; 112:2384-2392. 10. clavien pa, sanabria jr, strasberg sm. proposed classification of complications of surgery with examples of utility in cholecystectomy. surgery. 1992; 111:518-526. 11. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 12. kim hl, steinberg gd. complications of cystectomy in patients with a history of pelvic radiation. urology. 2001; 58:557-560. 13. mastroeni f, aragona m, caldarera e, et al. deep venous thrombosis in patients undergoing salvage radical cystectomy. arch esp urol. 2001; 54:839-841. 14. arumainayagam n, mcgrath j, jefferson kp, gillat da. introduction of an enhanced recovery protocol for radical cystectomy. bju int. 2008; 101:698-701. 15. charlson me, pompei p, ales kl, mackenzie cr. j chronic dis. 1987; 40:373-383. 16. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital urol androl. 2021; 93:15-20. 17. frazier ha, robertson je, paulson df. complications of radical cystectomy and urinary diversion: a retrospective review of 675 cases in 2 decades. j urol. 1992; 148:1401-1405. 18. konety br, allareddy v, herr h. complications after radical cystectomy: analysis of population-based data. urology. 2006; 68:5864. 19. brannan w, fuselier ha, ochsner m, randrup er. critical evaluation of 1-stage cystectomy--reducing morbidity and mortality. j urol. 1981; 125:640-642. 20. skinner dg, crawford ed, kaufman jj. complications of radical cystectomy for carcinoma of the bladder. j urol. 1980; 123:640-643. archivio italiano di urologia e andrologia 2021; 93, 4 ö. kavukoglu, a. coskun, k. sabuncu, e. çamur, g. faydaci 384 21. gibbs j, cull w, henderson w, et al. preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the national va surgical risk study. arch surg. 1999;134:36-42. 22. djaladat h, bruins hm, miranda g, et al. the association of preoperative serum albumin level and american society of anesthesiologists (asa) score on early complications and survival of patients undergoing radical cystectomy for urothelial bladder cancer. bju int. 2014; 113:887-893. 23. gregg jr, cookson ms, phillips s, et al. effect of preoperative nutritional deficiency on mortality after radical cystectomy for bladder cancer. j urol. 2011; 185:90-96. 24. liu j, dai y, zhou f, et al. the prognostic role of preoperative serum albumin/globulin ratio in patients with bladder urothelial carcinoma undergoing radical cystectomy. urol oncol. 2016; 34:484 e1-484e8. 25. gupta d, lis cg. pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. nutr j. 2010; 9:69. 26. garg t, chen ly, donat m. preoperative serum albumin is associated with mortality and complications after radical cystectomy. bju int. 2014; 113:918-923. 27. gore jl, lai j, setodji cm, et al. mortality increases when radical cystectomy is delayed more than 12 weeks: results from a surveillance, epidemiology, and end results-medicare analysis. cancer. 2009; 115:988-996. 28. brennan mf, pisters pw, posner m, et al. a prospective randomized trial of total parenteral nutrition after major pancreatic resection for malignancy. ann surg. 1994; 220:436-444. correspondence övünç kavukoglu, md ovunckavukoglu@hotmail.com alper coskun, md (corresponding author) alpercoskun62@yahoo.com kubilay sabuncu, md kubilaysabuncu@yahoo.com emre çamur, md emre.camur@outlook.com gökhan faydaci, md faydacig@yahoo.com department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11662 1 original paper introduction the presence of lower urinary tract (lut) symptoms in children without congenital anatomical or neurological abnormalities indicates functional bladder disorders, and the international children's continence society (iccs) recommends using the term "daytime lut conditions" for these cases (1). initial evaluation of children presenting with lut symptoms includes physical examination, urinalysis, symptom scores, voiding diary (vd), uroflowmetry, and residual urine measurement. vd is a highly useful tool that allows to show voiding habits, features of bladder function and is characterized by being an easy, non-invasive, no cost method. a properly completed vd provides information about maximum voiding volumes (mvv), mean voiding volumes (mvv), nocturnal urine volumes, voiding frequency (vf), presence and type of incontinence, enuresis, and fluid intake habits (2). it is recommended to be applied for at least 2 days in iccs and european urology association (eau) guidelines (1-3). however, some studies have reported similarities in vv between days at three-day vd (4, 5). franck et al. reported that one-day vd was correlated with three-day vd and emphasized that one-day vd could be sufficient to evaluate lut functions in children (5). however, a symptom score that gives information about the severity of symptoms was not evaluated together with vd parameters in these studies. we hypothesized that the vv and vf between days may vary depending on the severity of the symptoms. therefore, in this study, it was aimed to compare vv and vf values between days according to bladder capacity and symptom score. materials and methods children who applied to the pediatric urology clinic due to lut symptoms between 2022 and 2023 were includaim: the voiding diary (vd) yields crucial insights into voiding volumes (vv), voiding frequency (vf), and management habits in children with lower urinary tract (lut) dysfunction. it is recommended to be conducted for a minimum of 2 days. nevertheless, certain studies have indicated similarities in voided volumes between days in a three-day vd. this study aims to compare vv and vf values across days based on bladder capacity and symptom scores. materials and methods: children who applied to the pediatric urology clinic due to lut symptoms between 2022 and 2023 were included in the study. retrospective evaluation was conducted on the records. children with neurological deficits and incomplete data were excluded from the study. all children were assessed following the guidelines of iccs and eua and underwent a 3-day voiding diary. mean vv and vf values of the whole group for each day were compared and subgroup analyzes were performed in terms of gender, voiding dysfunction symptom score (vdss), bladder capacity (bc), and diagnoses. results: a total of 109 (53 girls (48.6%), 56 boys (51.4%)) children with a median age of 8 (3-17) were included in the study. 77 (70.6%) children were diagnosed with overactive bladder, 8 (7.4%) with dysfunctional voiding, and 24 (22%) with monosymptomatic enuresis nocturne. the mean vvs between days were similar in the whole group (p = 0.759). moreover, the mean vv of the first day was similar to the average of both the first two days and the three days (p = 0.021, p = 0.490). also, the maximum and minimum vvs were similar between days (p = 0.942, p = 0.160, respectively). in subgroup analyses based on gender, bladder capacity, and symptom score, mean vv was also found to be similar. vf values were found to be significantly different between days. there was also a difference between vf values in children with vdss > 8.5 (p = 0.012) and bc/ebc (%) > 65 (p = 0.030). in subgroup analysis for diagnoses, mean and maximum vv and vf were similar between the groups, except for vf (p = 0.026) in oab. conclusion: while the voided volumes of children with non-neurogenic lut dysfunctions appear to be consistent across the days of the vd, variations in vf might arise, especially among children with a vdss of > 8.5 and normal bladder capacity. as a result, we believe that using a vd spanning at least two days could enhance diagnostic accuracy and help prevent unnecessary treatment. are voiding volumes and frequencies different in the three-day voiding diary in children with lower urinary tract dysfunction? raziye ergun 1, cagri akin sekerci 2, mehmet cetin 3, mohammad yasir sahak 3, selcuk yucel 2, tufan tarcan 3, 4 1 pediatric urology, kocaeli derince training and research hospital, kocaeli, turkey; 2 department of urology, division of pediatric urology, school of medicine, marmara university, istanbul, turkey; 3 department of urology, school of medicine, marmara university, istanbul, turkey; 4 department of urology, school of medicine, koç university, istanbul, turkey. doi: 10.4081/aiua.2023.11662 summary key words: voiding diary; lower urinary tract dysfunction; bladder; incontinence; children. submitted 15 august 2023; accepted 2 september 2023 archivio italiano di urologia e andrologia 2023; 95(3):11662 r. ergun, c. akin sekerci, m. cetin, m. yasir sahak, s. yucel, t. tarcan 2 ed in the study. the records were evaluated retrospectively. ethical approval was obtained from the local ethics committee before the study (09.2023.674). children with congenital genitourinary system anomalies such as ectopic ureter, duplicated collecting system, posterior urethral valve, bladder diverticula, epispadias, exstrophy vesica, etc., and congenital or acquired neurological deficits such as myelodysplasia, cerebral palsy, sacral agenesis, spinal cord injury, central and peripheral neural system malignancy, and children with missing data were excluded from the study. all children were evaluated in accordance with iccs and eua recommendations and underwent vd for 3 days (2). mean vv and vf values of the whole group for each day were compared and subgroup analyzes were performed. the first subgroup analysis was made by gender. the second subgroup was created according to voiding dysfunction symptom score (vdss) (6). vdss by akbal et al. was filled in by all parents. children were divided into two groups as below and above the cut-off value of 8.5 showing lut dysfunctions. the third subgroup was formed according to bladder capacity (bc). bladder capacity is calculated as: uroflowmetry voided volume + residual urine volume. the koff formula was used to calculate the expected bladder capacity (ebc) by age (7). bc/ebc of less than 65% was considered a low-capacity bladder (8). the last subgroup was formed according to diagnoses overactive bladder (oab), dysfunctional voiding, monosymptomatic nocturnal enuresis (mne). decreased vf was accepted as < 4 per day, normal vf 4-7 per day, and increased vf > 7 per day. statistical analysis data were analyzed using the ibm statistical package for the social sciences version 22 (ibm spss statistics for windows, chicago, il, usa). the normality of the distribution of the variables was evaluated using the shapirowilk test. as the distribution of continuous variables did not show a normal distribution, comparison of independent and dependent groups were done with mannwhitney u test and wilcoxon signed ranks test, respectively. mc-nemar test was used for binary categorical dependent data and fisher's exact test was used for independent data. the p value < 0.05 was accepted as statistically significant. results a total of 109 (53 girls (48.6%), 56 boys (51.4%)) children with a median age of 8 (3-17) were included in the study. 77 (70.6%) children were diagnosed with oab, 8 (7.4%) with dysfunctional voiding, and 24 (22%) with mne. the mean vvs between days were similar in the whole group (p = 0.759) (table 1). moreover, the mean vv of the first day was similar to the average of both the first two days and the three days (p = 0.021, p = 0.490). also, the maximum and minimum vvs were similar between days (1st day = 215.29+/-116.10 and 70.51+/54.56 ml, 2nd day = 222.09+/-249.86 and 71.75+/-56.82 ml, 3rd day = 205.99+/-110.98 and 69.15+/-44.83 ml, p = 0.942, p = 0.160). in subgroup analyses based on gender, bladder capacity, and symptom score, mean vv was also found to be similar (table 1). vf values were found to be significantly different between days. there was also a difference between vf values in children with vdss > 8.5 (p = 0.012) and bc/ebc (%) > 65 (p = 0.030) (table 2). in addition, 72 (66.1%) normal vf, 5 (4.6%) decreased vf, 32 (29.4%) increased vf were detected in first day; 75 (68.8%) normal vf, 10 (9.2%) decreased, 24 (22%) increased vf in second day; 77 (70.6%) normal vf, 6 (5.5%) decreased vf, 26 (23.9%) increased vf in third day (table 3). when subgroup analysis was performed table 3. comparison of number of decreased, normal and increased vf between days. 1st day 2nd day 3rd day decreased vf 5 (4.6%) 10 (9.2%) 6 (5.5%) normal vf 72 (66.1%) 75 (68.8%) 77 (70.6%) increased vf 32 (29.4%) 24 (22%) 26 (23.9%) total 109 109 109 p 1st & 2nd = 0.016, p 1st & 3rd = 0.237, p 2nd & 3rd = 0.289. decreased vf < 4x per day, normal vf = 4-7x per day, increased vf > 7x per day. table 2. comparison of voiding frequencies in voiding diary. 1st day vf 2nd day vf 3rd day vf p value (mean+/-sd) (mean+/-sd) (mean+/-sd) all patients (n = 109) 6.67+/-2.53 6.15+/-2.59 6.23+/-2.74 0.011 boys (n = 56) 7.03+/-2.78 6.35+/-2.66 6.38+/-2.51 0.054 girls (n = 53) 6.25+/-2.24 5.88+/-2.47 5.54+/-2.99 0.138 vdss < 8.5 (n = 33) 6.06+/-2.13 5.37+/-1.84 5.75+/-1.90 0.663 vdss > 8.5 (n = 76) 6.93+/-2.66 6.43+/-2.79 6.43+/-3.02 0.012 bc/ebc (%) < 65 (n = 51) 6.74+/-2.67 6.39+/-2.64 6.21+/-2.41 0.162 bc/ebc (%) > 65 (n = 58) 6.61+/-2.43 5.94+/-2.55 6.24+/-3.03 0.030 vf: voiding frequency, vdss: voiding dysfunction symptom score, bc: bladder capacity, ebc: expected bladder capacity. table 1. comparison of voiding volume in voiding diary. 1st day mean vv (ml) 2nd day mean vv (ml) 3rd day mean vv (ml) p value (mean+/-sd) (mean+/-sd) (mean+/-sd) all patients (n = 109) 134.11+/-69.83 127.30+/-69.43 131.10+/-64.69 0.759 boys (n = 56) 125.51+/-60.47 121.37+/-69.47 127.22+/-61.21 0.099 girls (n = 53) 144.62+/-78.03 134.28+/-70.30 136.62+/-68.74 0.488 vdss < 8.5 (n = 33) 172.54+/-84.19 166.15+/-89.36 165.33+/-73.02 0.636 vdss > 8.5 (n = 76) 117.42+/-55.36 110.43+/-50.82 116.23+/-54.87 0.334 bc/ebc (%) < 65 (n = 51) 122.72+/-70.52 108.66+/-57.64 115.11+/-58.53 0.345 bc/ebc (%) > 65 (n = 58) 144.12+/-68.25 143.68+/-75.07 145.15+/-67.03 vv: voiding volume, vdss: voiding dysfunction symptom score, bc: bladder capacity, ebc: expected bladder capacity. archivio italiano di urologia e andrologia 2023; 95(3):11662 3 are voiding volumes and frequencies similar in the voiding diary? according to diagnoses, mean and maximum vv and vf were similar between the groups, except for vf (p = 0.026) in oab (table 4). discussion vd is a highly useful tool that allows to show voiding habits, features of bladder function and is characterized by being an easy, non-invasive, no cost method. a properly completed vd provides information about vv, vf, presence and type of incontinence, enuresis, and fluid intake habits. although at least two or three days of vd is recommended, it is known that this form is difficult for parents to fill out, especially during school days. therefore, in the present study, we compared the parameters of one-, two-, and three-day vds and evaluated the consistency of the one-day vd. although we found similar mean vv between days in subgroup analysis according to gender, ibss and ratio to ebc, we observed statistically differences in vf. interestingly, even if there was a change in mean vfs between days, they were found to be remained within the normal daily voiding frequency. hence, we believe that the clinical significance of this statistical difference between vfs should be considered with suspicion. however, since there can be a transition between normal and pathological voiding frequencies, as shown in table 3, we think that children with ibss > 8.5 or with bladder capacity below 65% according to ebc should be evaluated more carefully in terms of vf. there are a limited number of studies in the literature comparing vd between days in children. in the study of franck et al., in which they evaluated the voiding diaries of 89 children (59 mne, 30 oab), it was reported that the vf, mean vv, and nocturnal volume were similar between the three days, but the maximum voiding volumes gradually decreased (5). they found that first day had 96% sensitivity, 71% specificity, and 75% overall accuracy in estimating bladder capacity. one of the interesting findings of the study is that the maximum vvs were lower than ebc in both the oab (1st day: 69%, 2nd day: 67%, 3rd day: 53%) and mne (1st day: 67%, 2nd day: 61%, 3rd day: 58%) groups. the authors stated that one day's vd may be sufficient to evaluate lut dysfunctions and shows good correlation with the three-day chart. unlike these results, present study showed that vvs are similar in all group and sub-group analyses but there are differences between vfs. although the ages were similar between the two studies (8 years), only 45.7% of patients in this study had mean vv below 65% of ebc. also, franck et al. study, unlike ours (oab %70.6), had an mne (66.2%) dominant study group. despite these differences, mean vvs were consistent between days in both studies. in another study evaluating 92 children with lut symptoms, mean vv, maximum vv, and fluid intake were shown to be similar between 2and 3-day vd (4). in addition, high number of voids numbers and low bladder capacities were found to be close to each other. moreover, 2and 3day vfs (7.05+/-3.83 & 6.87+/-3.85, p = 0.007) were reported to be different, similar to present study. it has been emphasized once again that a two-day vd may be sufficient for the evaluation of children with lut dysfunctions. the prominent feature of the current study is the evaluation of vv and vf by creating subgroups according to symptom score and bladder volumes. on the other hand, while vvs are similar between vd days, there are studies recommending longer vds before moving on to invasive testing and other treatment modalities. elmer et al. examined the impact of 1-day and 3-day voiding diaries on the test and treatment preferences of urogynecologists (9). in this study involving 186 women with urinary incontinence and other lower urinary tract symptoms, they found that a 1-day voiding diary led to a higher utilization of urine culture, urodynamics, cystoscopy, and other imaging techniques compared to a 3day voiding diary. likewise, they mentioned that shorter voiding diaries increased the probability of suggesting treatment methods like clean intermittent catheterization, pelvic floor rehabilitation, and surgical interventions. nevertheless, they found a best agreement between the two voiding diaries for conservative approaches such as fluid restriction and scheduled voiding and medical treatments (kappa: 0.64, 0.61, 0.51, respectively). thus, the authors recommend a three-day vd prior to invasive tests and treatments. however, to the best of our knowledge, we did not find any studies that investigated the impact of voiding diary duration on invasive tests and treatment preferences in children. completely and accurately filling out the three-day vd seems to be another challenge for patients. in a study conducted by the symptoms of lower urinary tract dysfunction research network (lurn), a three-day vd was requested from 1064 (510 men, 545 women) volunteer participants with a mean age of 58.8 years (10). however, 84.8% (n = 902) of the participants returned a baseline voiding diary, and only 49.7% (n = 448) of them were completely filled out in terms of fluid intake and voiding records. while 57 patients filled less than three days, 306 patients were missing vvs, and 62 patients were lacking in fluid intake. younger age and lower education levels were found to be associated with a higher probability of not submitting a diary or submitting an table 4. comparison of mean and maximum voiding volumes and voiding frequencies according to diagnoses. diagnosis 1st day 2nd day 3rd day p value (mean+/-sd) (mean+/-sd) (mean+/-sd) oab (n = 77) mean vv (ml) 130.11+/-73.25 126.81+/-74.18 127.71+/-67.75 0.798 maximum vv (ml) 209.63+/-121.05 228.48+/-292.29 199.77+/-112.28 0.743 vf 6.93+/-2.62 6.30+/-2.80 6.46+/-2.96 0.026 dv (n = 8) mean vv (ml) 164.87+/-71.14 152.12+/-45.67 171.87+/-63.33 0.792 maximum vv (ml) 293.75+/-129.27 255.00+/-85.52 303.75+/-149.87 0.565 vf 5.87+/-1.55 5.75+/-1.16 5.62+/-2.13 0.183 mne (n = 24) mean vv (ml) 136.66+/-56.87 120.58+/-59.61 128.37+/-51.34 0.376 maximum vv (ml) 207.29+/-86.48 190.62+/-84.18 193.33+/-75.66 0.831 vf 6.12+/-2.45 5.83+/-2.25 5.70+/-2.11 0.602 oab: overactive bladder, dv: dysfunctional voiding, mne: monosymptomatic enuresis nocturne, vv: voiding volume, vf: voiding frequency. archivio italiano di urologia e andrologia 2023; 95(3):11662 r. ergun, c. akin sekerci, m. cetin, m. yasir sahak, s. yucel, t. tarcan 4 unusable diary. additionally, female gender was linked to a higher likelihood of submitting an unusable diary or a usable but incomplete diary. to the best of our knowledge, we believe that this process is more challenging for parents, even though there is no available data regarding appropriately filled voiding diary returns in children. we are aware that parents often express difficulties in completing voiding diaries, particularly when children are at school and engaged in play, or when the parents themselves are at work. in our own practice, we suggest completing the voiding diaries during weekends and holidays to facilitate this process. the present has some limitations. we did not include fluid intakes of vds in this study. we did not compare patients' control vds after appropriate treatment. we did not perform subgroup analysis according to age groups, but we tried to compensate for this deficiency by proportioning the expected bladder capacity. we didn't investigate whether one-day and three-day vds go on preference of treatment modalities. conclusions although the voiding volumes of children with non-neurogenic lut dysfunctions are similar between the days of the vd, there may be differences in the voiding frequencies particularly in children with ibss > 8.5 and normal bladder capacity. therefore, we think that at least two daily voiding diary will contribute to strengthen the diagnosis and avoid overtreatment. references 1. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn. 2016; 35:471-81. 2. bauer sb, nijman rj, drzewiecki ba, et al. international children's continence society standardization report on urodynamic studies of the lower urinary tract in children. neurourol urodyn. 2015; 34:640-7. 3. radmayr c, bogaert g, burgu b, et al. day-time lower urinary tract conditions. eau guidelines on paediatric urology. 2023:44-8. 4. lopes i, veiga ml, braga aa, et al. a two-day bladder diary for children: is it enough? j pediatr urol. 2015; 11:348.e1-4. 5. franck hhm, guedes acs, alvim yfs, et al. one-day voiding diary in the evaluation of lower urinary tract symptoms in children. int braz j urol. 2023; 49:89-96. 6. akbal c, genc y, burgu b, et al. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. j urol. 2005; 173:969-73. 7. koff sa. estimating bladder capacity in children. urology. 1983; 21:248. 8. nevéus t, von gontard a, hoebeke p, et al. the standardization of terminology of lower urinary tract function in children and adolescents: report from the standardisation committee of the international children's continence society. j urol. 2006; 176:314-24. 9. elmer c, murphy a, elliott jo, book nm. twenty-four-hour voiding diaries versus 3-day voiding diaries: a clinical comparison. female pelvic med reconstr surg. 2017; 23:429-32. 10. cameron ap, wiseman jb, smith ar, et al. are three-day voiding diaries feasible and reliable? results from the symptoms of lower urinary tract dysfunction research network (lurn) cohort. neurourol urodyn. 2019; 38:2185-93. correspondence raziye ergun, md raziye_ergun@hotmail.com pediatric urology, kocaeli derince training and research hospital, kocaeli, turkey mehmet cetin, md m.cetin_47@hotmail.com mohammad yasir sahak, md m.yasirsahak@gmail.com department of urology, school of medicine, marmara university, istanbul, turkey selcuk yucel, md drsyucel@yahoo.com department of urology, division of pediatric urology, school of medicine, marmara university, istanbul, turkey tufan tarcan, md tufan@marmara.edu.tr department of urology, school of medicine, marmara university, istanbul, turkey department of urology, school of medicine, koç university, istanbul, turkey cagri akin sekerci, md (corresponding author) cagri_sekerci@hotmail.com assoc. professor of urology department of urology, division of pediatric urology, school of medicine, marmara university, istanbul, turkey fevzi çakmak mah., muhsin yazicioglu cad. no:10 ust kaynarca/ pendik/ istanbul, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4408 original paper no conflict of interest declared. location (3). trying to improve safety and effectiveness of treatment, new techniques such as laparoscopy have become an effective alternative (4-6). the results have shown that both laparoscopic nephroureterectomy and hand-assisted laparoscopic nephroureterectomy had comparable, if not superior, perioperative and postoperative and similar oncological outcomes (6). technological advances made to achieve shorter and less morbid operations, have led to the next step of utuc treatment, which is the use of the robotic platform. results from multiple studies and the experience of various surgeons worldwide has shown that rrnu share equivalent oncologic outcomes at short-term follow up, while also displaying very low peri-operative morbidity and complications (7, 8). although robotic radical nephroureterectomy (rrnu) represents a promising alternative to currently existing methods of treatment, there is a surprising paucity of studies comparing rrnu and ornu. all available data originate from retrospective studies limited by important selection biases. our study represents the first prospective comparison of these two techniques regarding their efficacy and safety in the treatment of utuc. materials and methods we enrolled 45 consecutive patients who suffered from non-metastatic, upper urinary tract urothelial carcinoma from september 2019 to march 2021 and underwent radical nephroureterectomy. the surgeries took place in two different academic centres by experienced surgeons. in the former, the operations were performed by three different surgeons, each of whom had performed more than 50 open nephroureterectomies. in the latter, all the operations were carried out by the same surgeon with a vast experience in robotic upper tract surgeries (more than 300). patients were divided in two groups: group a consisted of 29 patients (open approach) and group b consisted of 16 patients (robotic approach). the exclusion criteria of the patients for the study were the following: patients with history of other urological managements and patients with contraindications for laparoscopic surgery. the institutional review board has approved the study protocol and all patients have signed an informed consent. purpose: to test the efficacy and safety profile of robotic radical nephroureterectomy compared to the open approach. methods: we enrolled 45 consecutive patients who suffered from non-metastatic, upper urinary tract urothelial carcinoma from september 2019 to march 2021 and underwent radical nephroureterectomy. patients were divided in two groups: group a consisted of 29 patients (open approach) and group b consisted of 16 patients (robotic approach). the factors which were taken into consideration were age, sex, body mass index, tumour size, side and grade, cancer stage, asa score, operation time, drain removal time, foley time, hospitalization time, estimated blood loss, surgical margins, preoperative and postoperative creatinine, hct and bladder recurrences. statistical analysis was performed with the use of spss version 26 and p < 0.05 was the cut-off for reaching statistical significance. results: the mean age in group 1 was 67.12 years and in group 2 68.12 years, whereas the mean body mass index (bmi) in group 1 was 26.54 kg/m2 and in group 2 25.20 kg/m2. operative time was better in group a (124 vs 186 mins p < 0.001) and estimated blood loss were better in group b compared to group a (137 vs 316 ml p < 0.001). length of stay (los) was significantly less in the robotic group (5.75 vs 4.3 days p = 0.003) and the same applied for time required for drain removal (4.5 vs 3.3 days p = 0.006). conclusions: robotic radical nephroureterectomy is a safe and efficient alternative to open approach. it provides a favorable perioperative profile in patients suffering from upper urinary tract carcinoma without metastasis. key words: robotic radical nephroureterectomy; open radical nephroureterectomy; prospective analysis; complications. submitted 31 august 2021; accepted 13 october 2021 introduction upper urinary tract urothelial carcinoma (uutc) represents a relatively rare entity, as it accounts for 5% of these neoplasms with an estimated annual incidence of 2 cases per 100.000 inhabitants (1), but because 60% of these malignancies are invasive at the time of diagnosis their management is of crucial importance (2). according to european association of urology, open radical nephroureterectomy (ornu) with bladder cuff excision remains the gold standard treatment of high-risk utuc, regardless of tumour is robotic radical nephroureterectomy a safe alternative to open approach: the first prospective analysis panagiotis mourmouris 1, omer burak argun 2, lazaros tzelves 1, mustafa bilal tuna 2, maria gourtzelidou 1, andreas tziotis 1, ali riza kural 1, andreas skolarikos 2 1 2nd department of urology, athens medical school, national and kapodistrian university of athens, sismanogleio general hospital, athens, greece; 2 department of urology, acıbadem mehmet ali aydınlar university, acibadem maslak hospital, istanbul, turkey. doi: 10.4081/aiua.2021.4.408 summary 409archivio italiano di urologia e andrologia 2021; 93, 4 robotic radical nephroureterectomy the da vinci xi system was used for the robotic procedures. we followed the same technique for performing rrnu as already published (9). open nu procedures were based on the standard approach 2 with bladder cuff excision (10). the factors which were taken into consideration were age, sex, body mass index, tumour size, side and grade, cancer stage, asa score, operation time, drain removal time, foley time, hospitalization time, estimated blood loss, surgical margins, preoperative and postoperative creatinine, hct and bladder recurrences. complications were categorized according to clavien dindo system (11). continuous variables are described as mean ± standard deviation (sd) and categorical variables as proportions. comparison of continuous outcomes was performed using student’s t-test for normally distributed data and mann-whitney test for non-normally distributed data. distribution of data was checked using the shapiro-wilk test. categorical variables were compared between the two groups, using chi-square and fisher’s exact test, as dictated by the frequency of observations. statistical analysis was performed with the use of spss version 26 and p ≤ 0.05 was the cut-off for reaching statistical significance. results the study included 45 patients from which 7 were female (5 in group a and 2 in group 2) and 38 males. the basic characteristics of the patients are shown in table 1. the mean age in group 1 was 67.12 years and in group 2 68.12 years, whereas the mean body mass index (bmi) in group 1 was 26.54 kg/m2 and in group 2 25.20 kg/m2, without any statistically significant difference between them. a right sided tumor was found in 13 patients in group a and 4 patients in group b, whereas 14 patients in group a and 10 in group b had tumors in the renal calyces or pelvis. the two groups were matched in terms of asa score (p = 0.07) and tumor size (p = 0.5). operative time was better in group a (124 vs 186 mins p < 0.001) and estimated blood loss were better in group b compared to group a (137 vs 316 ml p < 0.001). two patients in group a and no patient in group b required transfusion. length of stay (los) was significantly less in the robotic group (5.75 vs 4.3 days p = 0.003) and the same applied for time required for drain removal (4.5 vs 3.3 days p = 0.006). the periand postoperative results are shown in table 2. in group a, 16 patients suffered postoperative complications: 7 patients suffered from fever, 2 from hematoma, 3 from wound infection, 2 required transfusion, 1 from paralytic ileus and 1 suffered a myocardial infarction whereas from group b 3 patients suffered postoperative complications, 2 patients with fever and 1 with hematoma. the complications’ classification according to clavien-dindo score is shown in table 3. discussion the use of the robotic platform for the management of uutc has evolved since the first reports of retroperitoneal (12) and intraabdominal operations (13, 14) that may have also utilized other approaches (open or laparoscopic) for the nephrectomy or the ureterectomy. the surgeon’s experience has increased and new “hybrid” techniques have emerged, eliminating the basic disadvantage of the robotic platform, namely the need for redocking to perform ureteral excision (15, 16). robotic approach yielded satisfactory oncological outcomes, even for table 1. basic patients characteristics. group a (n = 29) group b (n = 16) p value age (years) 67.12 (12.19) 68.12 (9.0) 0.8 sex (male/female) 24/5 14/2 1.0 bmi (kg/m2) 26.54 (1.95) 25.20 (1.85) 0.12 tumor size (mm) 36.2 (20.09) 33.0 (10.73) 0.59 laterality (right) 13 4 0.71 tumor location intra renal 14 10 0.06 ureter 15 6 asa score 2.56 (0.89) 2.06 (0.25) 0.07 preoperative creatinine (mg/dl) 1.16 (0.43) 1.23 (0.30) 0.09 preoperative hct 38.85 (4.91) 41.71 (3.52) 0.06 asa score (american society of anesthesiologists score); bmi (body mass index). continuous outcomes are presented as mean values (± standard deviation). table 3. post-operative complications. clavien dindo classification group a group b p value no complications 13 13 0.28 grade i 12 1 grade ii 3 2 grade iii 0 0 grade iv 1 0 grade v 0 0 table 2. peri and postoperative outcomes. group a group b p value operative time (min) 124,37 (25.74) 186.25 (34.03) < 0.001 drain removal time (days) 4.5 (1.21) 3.3 (0,94) 0.006 foley removal time (days) 11.43 (5.29) 3,37 (0.80) < 0.001 length of stay (days) 5.75 (1.43) 4.3 (1.08) 0.003 estimate blood loss (ml) 316.87 (93.87) 137.5 (78.52) < 0.001 positive surgical margins 8/29 0/16 0.004 postoperative creatinine (mg/dl) 1.4 (0.47) 1.43 (0.39) 0.8 postoperative hct 31.90 (4.37) 37.71 (4.05) 0.003 pathological t stage 0.01 ta 5 6 t1 9 2 t2 1 3 t3 13 5 t4 1 0 tumour grade 0.06 low grade 8 9 high grade 21 7 bladder recurrence 3 1 0.33 archivio italiano di urologia e andrologia 2021; 93, 4 p. mourmouris, o.burak argun, l. tzelves, et al. 410 advanced disease, with studies reporting a 5-year recurrence free survival of 57.1% in a series including 28.3% patients with pt3 and 6.7% pt4 disease (17). in the same pace, one of the biggest studies so far enrolling patients from three high volume robotic surgery centers, reported a low high grade complication rate (2.6%) with excellent intraand post-operative results, suggesting this approach as a viable alternative to the gold standard open approach (18). the technology advancements of the robotic platform with the development of the davinci xi system provided the surgeon’s more tools towards increasing experience in this approach, while decreasing operation room time (19). recently published data in the literature, emphasize the auxiliary role of robotic radical nephroureterectomy in the management of uutc. the next step was comparing this approach to the open technique, which remains the gold standard therapy according to global guidelines. available data in existing literature, consist of studies that enrolled patients mainly from open and pure laparoscopic approaches, while robotic approach cases in these series represented a minority. even though some of these studies have large sample sizes, all of them are retrospective and their level of evidence is relatively low, due to the inherited bias of the retrospective nature (20, 21). in another study, multivariate logistic regression revealed a significant favorable impact of robotic approach in postoperative complications but not for intraoperative ones (22). as for the functional outcomes of the procedure, it is documented in the literature that rnu may be a risk factor for acute kidney injury resulting in renal function decline after this procedure (23). in our cohort, in both groups, patients suffered from postoperative creatinine decline, nevertheless when the two groups were compared no statistically significant difference was found relative to this factor. a relatively recent study provided data for the oncological superiority of the robotic approach, since this approach showed significantly longer progression free, cancer specific and overall survival (p < 0.05) (6). nevertheless, in this study the open surgeries were performed in patients of most advanced stage and with negative prognostic factors (like lymph node metastasis). a recent systematic review and meta-analysis of a vast number of patients provided useful insights on the comparison of the open, laparoscopic, and robotic approach: the rrnu showed the lowest estimated blood loss (ebl) and the onu the highest (163 ml vs 419.99 ml) with onu showing higher odds of transfusion. operative time was shorter for onu whereas rrnu showed both lower length of stay (los) and intraoperative complications. nevertheless, the meta-analysis is significantly limited from the retrospective studies which were analyzed (only 1 rct and 2 prospective studies none of which included robotic cases) and most patients included were derived from non-comparative studies. consequently, in this meta-analysis the distribution is in favor of onu and lrnu so the data on robotic technique might be weak (24). our study represents the first prospective comparison between open and robotic approach. the two groups were matched for most significant factors that could affect final outcomes, except from t stage, which it is not likely to have an impact to most of perioperative outcomes. we found a favorable profile of the robotic approach when compared to its open counterpart: better los, ebl, hct decrease, need for transfusions and removal of drains and catheters. we also found significant difference in positive surgical margins, but this is possible due to the most advanced stage of tumors that were operated with the open approach. the basic difference from the literature is operation time which was lesser in the open approach but again this can be justified because the robotic approach requests docking of the robot and changing of the instruments position for the ureterectomy. the small sample size comprises a limitation of this study, necessitating the conduct of larger prospective cohorts, ideally after patient randomization. nevertheless, this limitation is partly equilibrated by the prospective nature of our study and the limitation of potential biases that it provides. another potential limitation is the relatively short follow-up (1-5 months), but the study was designed to address the efficacy and safety of these procedures by comparing their perioperative outcomes. conclusions robotic radical nephroureterectomy is a safe and efficient alternative to open approach. it provides a favorable perioperative profile in patients suffering from upper urinary tract carcinoma without metastasis. future prospective or randomized trials can assess its efficiency versus open approach in terms of oncological outcomes. references 1. siegel rl, miller kd, jemal a. cancer statistics, 2019. ca cancer j clin. 2019; 69:7-34. 2. margulis v, shariat sf, matin sf, et al. outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. cancer. 2009; 115:1224-33. 3. rouprêt m, babjuk m, compérat e, et al. european association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update. eur urol. 2018; 73:111-22. 4. nouralizadeh a, tabatabaei s, basiri a, et al. comparison of open versus laparoscopic versus hand-assisted laparoscopic nephroureterectomy: a systematic review and meta-analysis. j laparoendosc adv surg tech a. 2018; 28:656-81. 5. mullen e, ahmed k, challacombe b. systematic review of open versus laparoscopic versus robot-assisted nephroureterectomy. rev urol. 2017; 19:32-43. 6. lee h, kim hj, lee se, et al. comparison of oncological and perioperative outcomes of open, laparoscopic, and robotic nephroureterectomy approaches in patients with non-metastatic upper-tract urothelial carcinoma. plos one. 2019; 14:e0210401. 7. hu cy, yang ck, huang cy, et al. robot-assisted laparoscopic nephroureterectomy versus hand-assisted laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma: a matched comparison study. biomed res int. 2015; 2015:918486. 8. campi r, cotte j, sessa f, et al. robotic radical nephroureterectomy and segmental ureterectomy for upper tract urothelial carcinoma: a multi-institutional experience. world j urol. 2019; 37:2303-11. 411archivio italiano di urologia e andrologia 2021; 93, 4 robotic radical nephroureterectomy 9. argun ob, mourmouris p, tufek i, et al. radical nephroureterectomy without patient or port repositioning using the da vinci xi robotic system: initial experience. urology. 2016; 92:136-9. 10. li wm, shen jt, li cc, et al. oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. eur urol. 2010; 57:963-9. 11. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 12. rose k, khan s, godbole h, et al. robotic assisted retroperitoneoscopic nephroureterectomy -first experience and the hybrid port technique. int j clin pract. 2006; 60:12-4. 13. nanigian dk, smith w, ellison lm. robot-assisted laparoscopic nephroureterectomy. j endourol. 2006; 20:463-5. 14. park sy, jeong w, ham ws, et al. initial experience of robotic nephroureterectomy: a hybrid-port technique. bju int. 2009; 104:1718-21. 15. pugh j, parekattil s, willis d, et al. perioperative outcomes of robot-assisted nephroureterectomy for upper urinary tract urothelial carcinoma: a multi-institutional series. bju int. 2013; 112:e295300. 16. zargar h, krishnan j, autorino r, et al. robotic nephroureterectomy: a simplified approach requiring no patient repositioning or robot redocking. eur urol. 2014; 66:769-77. 17. aboumohamed aa, krane ls, hemal ak. oncologic outcomes following robot-assisted laparoscopic nephroureterectomy with bladder cuff excision for upper tract urothelial carcinoma. j urol. 2015; 194:1561-6. 18. de groote r, decaestecker k, larcher a, et al. robot-assisted nephroureterectomy for upper tract urothelial carcinoma: results from three high-volume robotic surgery institutions. j robot surg. 2020; 14:211-9. 19. patel mn, aboumohamed a, hemal a. does transition from the da vinci si to xi robotic platform impact single-docking technique for robot-assisted laparoscopic nephroureterectomy? bju int. 2015; 116:990-4. 20. rodriguez jf, packiam vt, boysen wr, et al. utilization and outcomes of nephroureterectomy for upper tract urothelial carcinoma by surgical approach. j endourol. 2017; 31:661-5. 21. tinay i, gelpi-hammerschmidt f, leow jj. trends in utilisation, perioperative outcomes, and costs of nephroureterectomies in the management of upper tract urothelial carcinoma: a 10-year population-based analysis. bju int. 2016; 117:954-60. 22. pearce sm, pariser jj, patel sg, et al. the effect of surgical approach on performance of lymphadenectomy and perioperative morbidity for radical nephroureterectomy. urol oncol. 2016; 34:121.e15-21. 23. tafuri a, odorizzi k, di filippo g, et al. acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: a single-centre experience. arch ital urol androl. 2021; 93:9-14. 24. veccia a, antonelli a, francavilla s, et al. robotic versus other nephroureterectomy techniques: a systematic review and meta-analysis of over 87.000 cases. world j urol. 2020; 38:845-52. correspondence panagiotis mourmouris, md, phd (corresponding author) thodoros13@yahoo.com lazaros tzelves, md lazarostzelves@gmail.com maria gourtzelidou, md mariaeirinigr@gmail.com andreas tziotis, md tziotis.and@gmail.com andreas skolarikos, phd andskol@yahoo.com 2nd department of urology, athens medical school, national and kapodistrian university of athens, sismanogleio general hospital, athens (greece) omer burak argun, md drburakargun@gmail.com mustafa bilal tuna, md mustafabilaltuna@gmail.com ali riza kural, phd arkural@gmail.com department of urology, acıbadem mehmet ali aydınlar university, acibadem maslak hospital, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3328 original paper no conflict of interest declared. medications (selective serotonin reuptake inhibitors [ssri], tricyclic antidepressants, phosphodiesterase type 5 inhibitors and analgesics), local anesthetics or sprays, and behavioral therapies (sexual therapy). however, men with pe often resort to using self-medication for shame reasons (9). therefore, mobile applications (apps) could represent a valid tool to support health behavior and medical information about pe (10, 11). in the last years, more than 300.000 apps have been developed (12) and their use has increased during sars-cov-2 pandemic (13-16). apps can be downloaded from “play store” for android and “app store” for ios (17). several mhas have been produced in different medical and surgical fields including the urological and andrological fields (18-20). mhas have been developed to assist patients in several conditions (21, 22). optale et al. reported their experience in a pilot study on 35 patients with pe using a mobile coaching app for therapeutic exercises (23). data reported improvement of the 5-question premature ejaculation diagnostic tool (pedt) and the 4-question premature ejaculation profile (pep) in people who used the app compared the non-users (23). despite their number and widely use, quality assessments are still a problem. to avoid this, in the last years, several instruments have been developed. among these, the most used tool is mobile application rating scale (mars) (2426). several mhas have been developed for assessing and management of pe, representing an important tool for patients. however, despite their potential utility, much effort must be made regarding the quality, the validation, and the adherence to guidelines. to the best of our knowledge, there are no studies reporting the quality of apps for pe and their adherence to guidelines. the aim of this study is to give an overview of apps for pe, currently free available on the market to evaluate the quality and the adherence to guidelines. materials and methods search strategy we performed an observational cross-sectional descripintroduction: several mobile health applications (mhas) have been developed to assist and improve the quality of life of patients affected by premature ejaculation, but the scientific quality and adherence to guidelines are not yet addressed. materials and methods: on 25 may 2022, we conducted a search in the apple app store and google play store. we reviewed all mobile apps from apple app store and google play store for premature ejaculation and evaluated their usage in screening, prevention, management, and adherence to eau guidelines. results: in total 9 mha were reviewed. all mhas are geared towards the patient and provide information about diagnoses and treatment of pe. the mean score were 2.87, 3.69, 2.77, 2.55, 2.86 for engagement, functionality, aesthetics, information, and subjective quality respectively. mhas reported low and medium adherence to eau guidelines. conclusions: mhas provide different services in many medical fields, including male sexual dysfunction. their development is constantly increasing, but the problems of scientific validation, content, and quality are not yet solved. much future research is necessary to improve the quality of the apps and promote new user designed, and high-quality apps. key words: app; e-health; mobile phone; premature ejaculation; mobile application rating scale (mars). submitted 23 june 2022; accepted 1 july 2022 introduction premature ejaculation (pe) is among the most prevalent male sexual dysfunction worldwide affecting 30-50% of men with a high impact on the quality of life (qol) of patients and partners (1-6). according to eau guidelines, pe is defined as ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, inability to delay ejaculation on all or nearly all vaginal penetrations (7). several causes of pe like psychological issues (depression, stress, anxiety), traumatic sexual experience, diabetes, hypertension, hyperthyroidism, alcoholism and recreational drugs have been described (8). nowadays, many treatments are available: systemic premature ejaculation in the era of mobile health application: a current analysis and evaluation of adherence to eau guidelines luigi napolitano 1, luigi cirillo 1, giovanni maria fusco 1, marco abate 1, alfonso falcone 1, vincenzo morgera 1, gianluigi cacace 1, luigi de luca 1, pasquale reccia 1, claudia mirone 2, felice crocetto 1, giuseppe celentano 1, simone morra 1, biagio barone 1, ciro imbimbo 1, nicola longo 1, vincenzo mirone 1, roberto la rocca 1 1 department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples, italy; 2 multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2022.3.328 summary 329archivio italiano di urologia e andrologia 2022; 94, 3 premature ejaculation in the era of mobile health application tive study of all smartphone apps for patients about pe available on the ios and android platforms and evaluated their adherence to eau guidelines. on 25 may 2022, we conducted a search in google play store for android phones and apple app store for iphones with the keywords ‘premature ejaculation’, ‘premature ejaculation treatment’ and ‘premature ejaculation diagnosis’ using the search tab. we used a wide array of keywords due to the search strategy of google play store and apple app store which is based on finding keywords in titles, app descriptions and tags. other searches of information provided in books or other formats were excluded. two authors (gmf, ma) screened separately in app store and google play store apps during the search by reading the title and description in the app store. a third author (lc) resolved any discrepancies. at the beginning all apps were reported in excel form and, according to the exclusion criteria, were screened. all mhas regarding pe, providing a service to patients, in english, and free to download were included in this analysis. apps not specifically focused on pe, apps not allowing access to all users and those not available in english were excluded. successively, all reviewers downloaded and installed the apps on their personal mobile device. they interacted for twenty minutes with each app to explore its features before completing the mars and evaluated their adherence to eau guidelines. to assess apps, they were downloaded to either an android and an ios device. if apps were available in both app stores, the ios version was assessed. a total of 840 apps were found by our search, 816 of them were from the google play store (android) and 24 of them were from the apple app store (ios). of the total, 249 apps were screened after removing duplicates and paid apps. of the total screened apps, 196 apps met excluding criteria and were removed. in particular 1 app resulted in both stores. the app from the apple app store was analyzed. in total, 53 apps were eligible for the final evaluation and were downloaded. finally, 9 apps were included in the final review after removing 44 apps that met exclusion criteria after download. a flow diagram based on the prisma statement (figure 1) was included for the selected apps (27). table 1 shows the analyzed apps characteristics. the 9 premature ejaculation apps were evaluated by four members of the research team on a 5-point likert scale based on mars characteristics. data extraction on 27 may 2022 reviewers discussed methods of recording data to ensure standardized modality and a predefined excel form was created to collect data. the following data were extracted from mha: title, language, customers, costs, source (google play store or apple app store), field/disease, rating/feedback from the users and service provided. assessment of app quality to assess apps’ quality, mobile application rating scale (mars) was used. mars is a multidimensional instrument of 23 structured questions evaluating engagement, functionality, esthetics, information, app subjective quality, and app-specific, showing a very acceptable reliability and validity. mars is composed of 19 items grouped in four categories of perceived app quality: engagement (five items assessing the extent to which the app engages target users); functionality (four items assessing how easy the app is to navigate and the overall app performance); aesthetics (three items assessing visual appearance and style); information (seven items assessing accuracy, quality, and quantity of the app), and 1 category of subjective quality. each category score is the mean of the different items, rated on a 5-point likert-type scale (from 1 = inadequate to 5 = excellent) within its category. the mean of the 4 app quality category scores is used to calculate overall quality score and the final score range from 0 to 5. a score of between 1 and 2/5 is considered as ‘poor’ quality, while 3/5 is ‘acceptable’ and at least 4/5 is ‘good’ quality. if scores differed by a single point, reviewers use the mean of the two ratings, while if scores differing by more than a single point, reviewers solve the discrepancy through discussion and consensus agreement. mean scores were calculated for each domain and an overall quality score was calculated based on the aggregated mean values for each of the four domains. the mean score for subjective quality is calculated. figure 1. prisma. archivio italiano di urologia e andrologia 2022; 94, 3 l. napolitano, l. cirillo, g.m. fusco, et al. 330 assessment of app adherence to eau guidelines an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) based on section 5 of the eau guidelines of pe has been created. two independent reviewers (urologist with high experience in male sexual dysfunction) analyzed separately apps for their adherence to eau guidelines. according to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. a score of ‘‘0’’ indicated no adherence to guidelines. a score of ‘‘1’’ indicated a weak adherence. a score of ‘‘2’’ indicated a partial or moderate adherence. a score of ‘‘3’’ indicated strong adherence. where coding scores differed by 1 point, the average of the two ratings was taken. if there was a greater than 1-point discrepancy, a third author reviewed apps and resolved the discrepancy. the possible score on the checklist ranged from 0 to 15 for each app. to facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (11-15). results in total 9 apps were included in the final analysis: 4 from the apple app store and 5 from the google play store. four apps (44%) provided information about treatment; 2 (22%), 3 (33%) provide information about diagnosis and overall information respectively. pe risks factors were mentioned in some mha. data about downloads were available for 5 apps out of the 9 reviewed. downloads were not available for mhas presented in the apple app store. the most downloaded app was last longer in bed & control premature stamina of which more than 100.000 downloads were reported. all the apps were planned to be used by patients. no information about mha rating was available. mars scale scores are represented in table 2. engagement the score in this section was based on a 5-point likert scale in 5 subscales (entertainment, interest, customization, interactivity and target-group). the mean score was 2.87. scores ranged from 2 to 4 out of 5. the “premature ejaculation” app (android) produced by nature healthy care received the highest score for the engagement. this app contains pe definitions, as well as information about diagnosis and treatment. functionality the score of the functionality section was based on a 5-point likert scale in 4 subscales (performance, ease of use, navigation and gestural design) and the mean score was 3.69. scores ranged from 2.75 to 4.5. “last longer in bed & control premature stamina” app (android) produced by masterpiece achieved the maximum score. aesthetics the aesthetics section was formed by a 5-point likert scale in 3 subscales (layout, graphics, visual appeal) and the average score was 2.77. scores ranged from 1.33 to 3.3 out of 5, and “premature ejaculation” produced by nature healthy care reached the maximum aesthetics score. information the information section was formed by a 5-point likert scale in 7 subscales and the mean score was 2.55. score ranged from 1 to 3.6. the “smart saa” (apple) produced by table 1. app characteristics. name of application android/ download producer category focus apple/both premature ejaculation tools apple n.a. putu angga risky raharja medicine informative, definition test pedt pea-last longer in bed apple n.a. smarter health solution llc health and wellness informative, definition treatment exercises slow down last longer apple n.a. slow down health inc medicine exercises smart saa apple n.a pergali ltd health and wellness informative, definition test last longer in bed & control premature stamina android 100.000 + masterpieceapps lifestyle treatment my sex doctor android 10.000+ mysd ltd lifestyle definition my sex doctor lite android 10.000+ mysd ltd lifestyle definition premature ejaculation android 5000 + nature healthy care entertrainment definition diagnosis treatment premature ejaculation: information and treatment android 1000+ hemisphere studio health and fitness definition diagnosis treatment table 2. mars scale scores. name of application engagement functionality aesthetics information mean app subjective (section a) (section b) (section c) (section d) (a+b+c+d) quality (section e) premature ejaculation tools 2 4 1.33 2 2.33 2 pea-last longer in bed 3.8 3.25 3 3.33 3.34 3.25 slow down last longer 3.4 2.75 3 2.66 2.95 3 smart saa 3.6 3.75 3 3.6 3.49 2.75 last longer in bed & control premature stamina 3 4.5 3 1 2.88 1.75 my sex doctor 2 4 3 2 2.75 3 my sex doctor lite 2 4 3 2 2.75 3 premature ejaculation 4 4 3.3 3.6 3.72 4 premature ejaculation: information and treatment 2 3 2.3 2.8 2.52 3 331archivio italiano di urologia e andrologia 2022; 94, 3 premature ejaculation in the era of mobile health application pergali ltd and “premature ejaculation” produced by nature healthy care achieved the highest score of 3.6. these two apps respectively offer information and test for pe, and definition, diagnosis, and treatment options for pe. subjective quality the subjective quality section consisted of 4 items. the mean score was 2.86, with scores ranging from 1.75 to 4. “premature ejaculation” app reached the maximum score. eau adherence checklist we evaluated the eau guidelines adherence in 9 apps. eau adherence scores are represented in table 3. the pe definition was reported in 8 (88.9%) apps, the score ranged from 2 to 3 (mean 2.25); physiopathology was reported in 7 (77.8%) apps, the score ranged from 1 to 2 (mean 1.57); risk factors were reported in 4 (44.4%) apps, the score ranged from 1 to 2 (mean 1.5); diagnosis was reported in 9 (100%), the score range from 1 to 3 (mean 1.67); treatment was reported in 5 (55.6%), the score ranged from 1 to 3 (mean 2.6). the overall score ranged from 2 to 13 (mean 7). the highest score was reported by “premature ejaculation” (android) produced by nature healthy care. only two of the nine evaluated apps reached the maximum definition score of 3 in definition, while none of the apps reached 3 in physiopathology and risk factors. finally, only one app and four apps reached the maximum respectively in diagnosis and treatment. discussion the current study aimed to evaluate the overall quality mhas for pe and their adherence to eau guidelines. to the best of our knowledge, no previous studies examined this topic. we addressed this void and identified several noteworthy observations. first, despite the high number of mhas no standardized evaluation method has been assessed, but many studies suggest combining the use of different scores. in the present study we used mars to evaluate the apps’ quality. mars was a tool widely used in several previous published studies. in this study, the mean scores of the mars categories are dramatically low and mhas are inadequate to assist patients. “information” and “esthetics” show the lowest score, 2.55 and 2.77 respectively. “functionality” reported the highest score (3.69). as previously showed in our study on mhas for erectile dysfunction, apps were developed without healthcare support and the most important tool is their usability (28). jupp et al. showed that “functionality” is the highest score in mhas for oncology patients (29). this suggests that mhas are easy to navigate and efficient and represent an important skill for mhas geared for the patients. the overall low quality of mhas seems to be related to their commercial tone. furthermore, our results indicate that healthcare and medical institutions are still missing the potential of reaching patients through this technology, and therefore the mha were a field of only commercial initiatives. in fact, only three (33%) of mha were considered acceptable. the same results were reported in other studies using mars to evaluate different medical conditions (30). amor-garcía et al. report a score of 2.98 analyzing genitourinary cancer (17); kwan et al. and knitza et al. report scores of 3.48 and 3.85 in apps for rheumatology conditions (31, 32). this suggests that overall mhas regardless of diseases and fields require general improvements, in particular, healthcare involvement in mha development is mandatory. second, most mhas had low or medium adherence to eau guidelines. the highest adherence is reported in pe definition and treatment. “premature ejaculation” (android) produced by nature healthy care shows the highest score (13) and the high adherence to eau guidelines. this is not surprising, because nature healthy care produce several apps in different medical fields. mhas report a wide options of treatment for pe including behavioural and medical options. according to the literature, treatment of pe includes pharmacological and non-pharmacological treatment as well as psychotherapy and behavioral therapies (masturbation before coitus (precoital masturbation) “stop-start” and “squeeze” techniques, use of multiple condoms, and pelvic floor exercise). pelvic floor exercise/kegel exercises help strengthen pelvic floor muscles to provide better ejaculation control. ischiocavernous, bulbocavernosus muscles, and sphincters, play an important role in sexual function, with high electromyographic activity and rhythmic contractions during the ejaculatory period (8, 33-35).in a prospective quasi-randomized controlled trial, jiang et al. reported that penis-root masturbation (prm) and kegel exercise (ke) have effects on ppe and ke was less effective than prm. eau guidelines report weak evidence about behavioural and psychotherapy treatments for pe (7). despite these, our search show 27 mhas for ke as pe treatment. our study has several strengths: first of all, we examined for the first time the content, the quality, and the adherence to eau guidelines about pe; we performed a rigorous search, screening, and analysis on apple and google stores; reviewer had experience in mars scale using. the main limitation of our study is the number of apps subtable 3. eau adherence checklist scores. name of application definition physiopathology risk factors diagnosis treatment total (0-3) (0-3) (0-3) (0-3) (0-3) premature ejaculation tools n.a n.a n.a 2 n.a. 2 pea-last longer in bed 3 1 n.a 1 3 8 slow down last longer 2 1 2 2 3 10 smart saa 2 n.a n.a 2 n.a. 4 last longer in bed & control premature stamina 2 1 1 1 3 8 my sex doctor 2 2 n.a. 1 n.a. 5 my sex doctor lite 2 2 n.a. 1 n.a. 5 premature ejaculation 3 2 2 3 3 13 premature ejaculation: information and treatment 2 2 1 2 1 8 archivio italiano di urologia e andrologia 2022; 94, 3 l. napolitano, l. cirillo, g.m. fusco, et al. 332 jected to the qualitative assessment. furthermore, the reproducibility of the research turns out to be complex due to the working method of the app store and google play store (the visibility of apps depends on the device and on the country where the search is performed); the exclusion criteria, which led to the exclusion of paid apps; the guidelines developed for healthcare and not for patients and the constant production of new mha. conclusions the use of mhas for pe represents an unexplored topic, with much future perspective. mhas have been reported as an integral part of patients’ lives, and although from year to year, their numbers are constantly increasing, the overall quality is still low. the problems of scientific validation content and quality in mha for pe are not yet solved. further several studies are needed to improve the quality, accessibility, user-designed, and high-quality of apps. references 1. gao j, zhang x, su p,, et al. prevalence and impact of premature ejaculation in outpatients complaining of ejaculating prematurely: using the instruments of intravaginal ejaculatory latency time and patient-reported outcome measures. int j impot res. 2014; 26:94-9. 2. sjögren fugl-meyer k, fugl-meyer ar. sexual disabilities are not singularities. int j impot res. 2002; 14:487-93. 3. 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smartphone-based therapeutic exercises for men affected by premature ejaculation: a pilot study. sex med. 2020; 8:461-71. 24. terhorst y, philippi p, sander lb, et al. validation of the mobile application rating scale (mars). moitra e, curatore. plos one. 2020; 15:e0241480. 25. dantas lo, carvalho c, prando bc, et al. mobile health technologies for the management of rheumatic diseases: a systematic review of online stores in brazil. clin rheumatol. 2021; 40:2601-9. 26. moglia ml, nguyen hv, chyjek k, et al. evaluation of smartphone menstrual cycle tracking applications using an adapted applications scoring system. obstet gynecol. 2016; 127:1153-60. 27. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021; 372:n71. 28. luigi napolitano, giovanni maria fusco, luigi cirillo, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 29. jupp jcy, sultani h, cooper ca, et al. evaluation of mobile phone 333archivio italiano di urologia e andrologia 2022; 94, 3 premature ejaculation in the era of mobile health application applications to support medication adherence and symptom management in oncology patients. pediatr blood cancer. 2018; 65:e27278. 30. narrillos-moraza á, gómez-martínez-sagrera p, amor-garcía má, et al. mobile apps for hematological conditions: review and content analysis using the mobile app rating scale. jmir mhealth uhealth. 2022; 10:e32826. 31. kwan yh, ong wj, xiong m, et al. evaluation of mobile apps targeted at patients with spondyloarthritis for disease monitoring: systematic app search. jmir mhealth uhealth. 2019; 7:e14753. 32. knitza j, tascilar k, messner em, et al. german mobile apps in rheumatology: review and analysis using the mobile application rating scale (mars). jmir mhealth uhealth. 2019; 7:e14991. 33. jiang m, yan g, deng h, et al. the efficacy of regular penis-root masturbation, versus kegel exercise in the treatment of primary premature ejaculation: a quasi-randomised controlled trial. andrologia. 2020; 52:e13473 34. pastore al, palleschi g, fuschi a, et al. pelvic floor muscle rehabilitation for patients with lifelong premature ejaculation: a novel therapeutic approach. ther adv urol. 2014; 6:83-8. 35. pischedda a, fusco f, curreli a, et al. pelvic floor and sexual male dysfunction. arch ital urol androl. 2013; 85:1-7. correspondence luigi napolitano luiginap89@gmail.com luigi cirillo, md (corresponding author) cirilloluigi22@gmail.com giovanni maria fusco, md giom.fusco@gmail.com marco abate, md marcoabate5@gmail.com biagio barone,md biagio.barone@unina.it alfonso falcone, md alfonso.falcone01@gmail.com vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com felice crocetto, md felice.crocetto@gmail.com simone morra, md simonemorra@outlook.com luigi de luca, md luigideluca86@gmail.com pasquale reccia, md reccia.pasquale1@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com nicola longo, md nicolalongo20@yahoo.it ciro imbimbo,md ciro.imbimbo@unina.it vincenzo mirone, md mirone@unina.it roberto la rocca, md robertolarocca87@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii", naples, italy via sergio pansini n 5, naples (italy) claudia mirone, md claudiamirone@outlook.it multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples (italy) stesura seveso 375archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. specifically to remote clinical services and was first adopted in the 1950’s when an american psychiatrist connected to a prison through a closed-circuit television to provide mental health services (3). in recent years, with the advancement of mobile technologies, the adoption and accessibility of telemedicine has significantly increased, after covid-19 pandemic declaration in several clinical and surgical fields including urology (410). advantages of remote care include reduction of the use of resources in health centers, improving access to care (3). moreover, telemedicine has the potential to reduce the risk of direct transmission of infectious agents (11). approximately 15 million americans receive remote medical assistance yearly (2). the urological literature on telehealth is sparse. the telemedicine experience in urology spans from new patient consultations to telesurgery to post-operative rounds and even virtual house calls (12). in details, telemedicine has been described in patients with hematuria, prostate cancer, urinary stones, pelvic organ prolapse, urinary infections, and urinary incontinence (2). the aim of the present study was to explore attitudes and perceptions by urologic patients toward the use of telemedicine in the context of patient-physicians communication during the post-operative follow-up in a large academic tertiary urology referral department in italy. materials and methods questionnaire an anonymous 15 multiple choice questions (formulated in italian with the aim of increasing the response rate) questionnaire was administered to a total of 955 patients who had visited the outpatient department of urology at university federico ii, naples, from september 2020 to april 2021 the questionnaire was composed of three sections: a first one to assess respondents’ demographics (age, sex, urologic disease) a second one to evaluate their attitudes using telemedicine, and a third to evaluate perintroduction: telemedicine is a most used tools in various medical and surgical scenarios. the aim of the present study was to explore attitudes and perceptions by urologic patients toward the use of telemedicine in the context of patient-physicians communication during the post-operative follow-up in a large academic tertiary urology referral department in italy. materials and methods: an anonymous questionnaire consisting of 15 multiple choice questions was designed including three sections: respondents’ demographics, attitudes, and perceptions towards the use of telemedicine. invitations to participate to this anonymous questionnaire was given to outpatients attended at urology department, university of naples federico ii. results: in total 697 responses were received (participation rate 73%). the frequency of telemedicine use was described as frequently, occasional, rarely, and never by 41.6%, 30.4%, 15.1%, and 12.6% of respondents, respectively. whatsapp messenger used by 59.5% of respondents and telephone call (34.3%) were the most common type of tools. satisfaction in using telemedicine was reported as very satisfied, satisfied, neutral, dissatisfied, and very dissatisfied by 39.6%,41.4%,10%,7% and 2% of respondents respectively. overall, 43.7%% of participants individuated limited interaction and risk of misdiagnosis as the major limit of telemedicine. conclusions: telemedicine represents the future of medical practice due to several benefits as well as convenience, increased access to care and decreased healthcare costs. key words: telemedicine; telehealth; healthcare; virtual healthcare; urology. submitted 28 july 2022; accepted 2 august 2022 introduction telehealth represents a rapidly evolving field of medicine. it is defined as the use of information technology and telecommunications to provide access to health assessment, consultation, diagnosis, intervention, super-vision, and information across distance (1, 2). telemedicine refers perceptions and attitudes toward the use of telemedicine for the postoperative outpatient urological care during the covid-19 pandemic in an academic hospital in southern italy vincenzo mirone 1, giuseppe celentano 1, claudia collà ruvolo 1, luigi cirillo 1, giovanni maria fusco 1, marco abate 1, simone morra 1, francesco di bello 1, gianluigi califano 1, claudia mirone 2, gianluigi cacace 1, vincenzo morgera 1, roberto la rocca 1, marco capece 1, nicola longo 1, luigi napolitano 1, massimiliano creta 1 1 department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples, italy; 2 multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2022.4.375 summary archivio italiano di urologia e andrologia 2022; 94, 4 v. mirone, g. celentano, c. collà ruvolo, et al. 376 ceptions towards telemedicine. questions about attitudes toward use of telemedicine included: tools adopted (telephone call, e-mails, whatsapp, others), context in which telemedicine was used, content of multimedia data shared. questions about perceptions investigated the perceived usefulness of telemedicine and the potential developments. respondents were invited to "strongly agree", "moderately agree", "slightly agree", "strongly disagree", "moderately disagree", "slightly disagree" with a series of statements about perceptions. some questions required a single answer while others gave the respondents the choice to select as many answers as they felt appropriate. data analysis data were expressed as mean (standard deviation) and raw numbers and percentages of survey answers. statistical analyses were two-sided using a significance level of 0.05. all statistical analyses were performed with spss version 17.0 (spss, inc., chicago, il) software. results in total 697 responses were received (participation rate 73 %). all patients were caucasian. of them, 572 patients (82%) were male and 125 (18%) were female. mean (sd) patients’ age was 67.5 (5.3) years. in details the number of patients aged between 18-34, 35-54, 55-74, and those aged > 75 were 12 (1.7%), 16 (2.3%), 466 (66.8%), and 203 (29.1%), respectively. concerning educational level, the number of patients with elementary school or no title, middle school diploma, high school diploma, and university degree were 104 (15%), 139 (20%), 175 (25%), and 279 (40%), respectively. as regards the occupational status of respondents, the number of them working, retired and unemployed were 367 (52.6%), 265 (38.1%), and 65 (9.3%), respectively. the disease for which patients received outpatient post-operative care were bladder cancer (n = 209, 30%), prostate cancer (n = 160, 23%), kidney cancer (n = 69, 10%), testis cancer (n = 4, 0.5%), penis cancer (n = 2, 0.3%), obstructive uropathy (n = 105, 15%), urolithiasis (n = 69, 10%), urinary tract infections (n = 4, 0.5%) and others (n = 75, 10.7%). overall, 267 patients (38.3%) were in the early post-operative follow-up (within 30 days from surgery) and 430 (61.7%) in the late post-operative follow-up (> 30 days from surgery). table 1 describes attitudes toward the use of telemedicine. figure 1 describes the frequency of telemedicine use according to patients’ age. perceptions about the usefulness and limits of telemedicine in the context of outpatient posttable 1. attitudes of patients toward telemedicine. n (%) frequency of telemedicine use frequently 290 (41.6) occasionally 212 (30.4) rarely 109 (15.7) never 86 (12.3) use of telemedicine during the covid-19 pandemic compared to the pre-pandemic period increased 387 (63.4) remained stable 159 (25.9) decreased 65 (10.7) purpose of availing telemedicine facility booking and appointment 246 (40.2) consultation 322 (52.7) treatment 43 (7.1) tools adopted telephone call 209 (34.3) whatsapp messages 364 (59.5) video-call 24 (3.9) e-mail 2 (0.3) other 12 (1) media-contents shared video 3 (0.8) audio 129 (32.1) text 220 (54.7) photo 50 (12.4) reason for not using telemedicine i don’t know the existence of this type of medical service 42 (48.9) i don’t know how to use this type of medical service 19 (22.5) i don’t trust telemedicine 13 (14.7) my technical conditions do not allow me to use telemedicine 8 (9.3) other reasons 4 (4.6) willingness to continue using telemedicine after covid-19 pandemic yes 416 (68.1) not 195 (31.9) satisfaction with telemedicine use very satisfied 242 (39.6) satisfied 253 (41.4) neutral 61 (10) dissatisfied 43 (7) very dissatisfied 12 (2) figure 1. percentage of telemedicine use according to patients’ age. 377archivio italiano di urologia e andrologia 2022; 94, 4 perceptions and attitudes toward the use of telemedicine for the postoperative outpatient urological care during the covid-19 pandemic... operative follow-up are reported in table 2. figure 2 describes the percentage of patients reporting specific challenges in availing telemedicine. discussion in the last years, several surgeons have incorporated telemedicine into preand post-operative visits and specialty consultations (13). the use of telemedicine modalities for perioperative care has been reported to represent a cost-effective strategy and has been associated with a relatively high rate of patient satisfaction (13). urologists described the successful use of telemedicine in several settings: shared decision-making counseling for prostate cancer treatment, administration of behavioral therapies for urinary incontinence, and post-operative follow-up care (13). more recently, the covid-19 pandemic has radically changed the landscape of health care and has further stimulated the use of telemedicine (13-14). attitudes and perceptions toward the use of telemedicine by patients varies significantly across the word and according to the setting of adoption. to our knowledge this represents the first time a survey investigating the attitudes and perceptions about telemedicine by urology patients referring to an outpatient department in southern italy. interestingly, 72% of respondents declared to having frequently or occasionally used telemedicine during the covid19 pandemic. not surprisingly, the percentage of patients declaring to use telemedicine rarely or never increased with increasing age with most patients never using medicine being aged > 75 years. of note, about half of patients declaring to have never used telemedicine did not know the existence of this type of medical service. these findings point out the current limits of telemedicine, mainly il old people, for which lack of knowledge and confidence with telemedicine may represent a significant barrier. whatsapp messenger was the most frequently adopted tool by respondents during remote communication. accordingly, a comprehensive systematic review presented compelling evidence that whatsapp messenger is a promising system when used as a communication tool between health care professionals and the general public (15). limited patient-physician interaction and risk of misdiagnosis were perceived as limitations of telemedicine by most respondents. accordingly, many criticize that telehealth may adversely affect continuity of care. online interactions are perceived as impersonal and dangerous because the virtual provider does not offer the benefit of a complete medical history and physical examination (15-18). therefore, telehealth should be considered as table 2. perceptions about the usefulness and limits of telemedicine in the context of outpatient post-operative follow-up of urological patients (n = 697). agree strongly agree moderately agree slightly disagree slightly disagree moderately disagree strongly n (%) n (%) n (%) n (%) n (%) n (%) telemedicine, in combination with in-person appointments, is useful in improving patientphysician communication in the post-operative period 229 (32.9) 264 (38) 75 (10.8) 87 (12.5) 26 (3.7) 16 (2.1) telemedicine, in combination with in-person appointments, is useful in improving the quality of assistance in the post-operative period 248 (35.6) 196 (28,1) 111 (15,9) 86 (12.3) 35 (5.1) 21(3) telemedicine, in combination with in-person appointments, is useful in improving the interpretation of findings from laboratory and radiological investigations 222 (31.7) 175 (25.1) 139 (20) 139 (20) 15 (2.2) 7 (1) telemedicine, in combination with in-person appointments, is useful in improving the interpretation of clinical findings 211 (30.3) 158 (22.6) 189 (27.1) 114 (16.4) 18 (2.6) 7 (1) telemedicine, in combination with in-person appointments, is helpful in reducing unnecessary visits to hospitals 306 (43.9) 175 (25.1) 111 (16) 70 (10) 35 (5) 0 (0) telemedicine, in combination with in-person appointments, is helpful in reducing costs of post-operative follow-up 258 (37) 141 (20.2) 203 (29.1) 63 (9) 32 (4.7) 0 (0) telemedicine, in combination with in-person appointments, is helpful in improving patients’ adherence to prescriptions 315 (45.3) 227 (32.6) 72 (10.3) 57 (8.2) 26 (3.6) 0 (0) telemedicine, in combination with in-person appointments, is helpful in helps in the prompt recognition of complications and side effects 256 (36.8) 154 (22.1) 104 (14.9) 111 (15.9) 72 (10.3) 0 (0) figure 2. percentage of patients reporting specific limitations in availing telemedicine (n = 611). archivio italiano di urologia e andrologia 2022; 94, 4 v. mirone, g. celentano, c. collà ruvolo, et al. 378 an adjunct and best used to supplement in-person visits (15). although vulnerable security and privacy was perceived as a limit of telemedicine by only 8.3% of patients, this issue deserve careful attention. according to morris et al., despite the widespread use of whatsapp, clinicians are either failing in their ethical, legal, regulatory, and clinical responsibility to keep records of whatsapp consults, or are not reporting how they do so or that they do so (19). unfortunately, the literature does not report any clear “best practices” for recordkeeping, or the secure storage of patient information obtained and there is a need to raise awareness on this issue and to urgently provide viable guidance (19). interesting is patient satisfaction with use of telemedicine. we reported an overall good satisfaction using this technology: 39.6% and 41.4% of respondents reported satisfaction and very satisfaction respectively. our data corroborated results of previous published studies. holzman et al. reported high grade of satisfaction with telemedicine compared to in person visits in pediatric urology outpatient patients (20). a high satisfaction of patients in telehealth experience compared to in person visit were also reported by polinski et al. and by ambrosini et al. (21-22). despite advantages using telemedicine, some disadvantages and barriers as well as performing physical examinations, possibilities for technical difficulties, security breaches, and regulatory barriers have been reported (23). limited interaction and misdiagnosis were the most reported barriers in our survey, 43.7% and 25.2% respectively. the topic is very important with several legal and economic aspects. our data corroborated findings reported in previous studies: chandhanayingyong reported an overall misdiagnosis rate of 40%, with over-diagnosis of 12% and under-diagnosis of 27% using teleconsultation using the mobile phone multimedia messaging service (mms) in emergency orthopedic patients (24). spear at al. in a survey on 781 patients that experienced telemedicine, reported as main disadvantages the lack of hands-on care, the lack of intimacy, and technical difficulties (25). our study has some limitations: first of all, the simple size represents a small group of the providers in the academic setting, and it is limited to academic urology experience. telemedicine represents the future of medical practice including several benefits as well as convenience, increased access to care and decreased healthcare costs. further studies are necessary to improve clinical, administrative, and research aspects to expand the use of telemedicine among patients. references 1. ayoub ch, el-asmar jm, abdulfattah s, el-hajj a. telemedicine and telementoring in urology: a glimpse of the past and a leap into the future. front surg. 2022; 9:811749. 2. novara g, checcucci e, crestani a, et al. telehealth in urology: a systematic review of the literature. how much can telemedicine be useful during and after the covid-19 pandemic? eur urol. 2020; 78:786-811. 3. mirone v, creta m, capece m, et al. telementoring for communication between residents and faculty physicians: results from a survey on attitudes and perceptions in an academic tertiary urology referral department in italy. arch ital urol androl. 2021; 93:450454. 4. melchionna a, collà ruvolo c, capece m, et al. testicular pain and youtube™: are uploaded videos a reliable source to get information? int j impot res. 2022 feb 8. doi: 10.1038/s41443-022-00536w. epub ahead of print. 5. capece m, di giovanni a, cirigliano l, et al. youtube as a source of information on penile prosthesis. andrologia. 2022; 54:e14246. 6. morra s, collà ruvolo c, napolitano l, et al. youtubetm as a source of information on bladder pain syndrome: a contemporary analysis. neurourol urodyn. 2022; 41:237-245. 7. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-216. 8. creta m, sagnelli c, celentano g, et al. sars-cov-2 infection affects the lower urinary tract and male genital system: a systematic review. j med virol. 2021; 93:3133-3142. 9. barone b, de luca l, napolitano l, et al. lower urinary tract symptoms and mental health during covid-19 pandemic. arch ital urol androl. 2022; 94:46-50. 10. sen v, aydogdu o, yonguc t, et al. telerounding & telementoring for urological procedures. arch ital urol androl. 2016; 88:206207. 11. gerundo g, collà ruvolo c, puzone b, et al. personal protective equipment in covid-19: evidence-based quality and analysis of youtube videos after one year of pandemic. am j infect control. 2022; 50:300-305. 12. castaneda p, ellimoottil c. current use of telehealth in urology: a review. world j urol. 2020; 38:2377-2384. 13. connor j, zheng y, houle k, cox l. adopting telehealth during the covid-19 era: the urologist's perspective. urology. 2021; 156:289-295. 14. di bello f, collà ruvolo c, cilio s, et al. testicular cancer and youtube: what do you expect from a social media platform? int j urol. 2022; 29:685-691. 15. giordano v, koch h, godoy-santos a, et al. whatsapp messenger as an adjunctive tool for telemedicine: an overview. interact j med res. 2017; 6:e11. 16. boehm k, ziewers s, brandt mp, et al. telemedicine online visits in urology during the covid-19 pandemic-potential, risk factors, and patients' perspective. eur urol. 2020; 78:16-20. 17. ellison lm, nguyen m, fabrizio md, et al. postoperative robotic telerounding: a multicenter randomized assessment of patient outcomes and satisfaction. arch surg. 2007; 142:1177-81. 18. pinar u, anract j, perrot o, et al. preliminary assessment of patient and physician satisfaction with the use of teleconsultation in urology during the covid-19 pandemic. world j urol. 2021; 39:1991-1996. 19. morris c, scott re, mars m. whatsapp in clinical practice-the challenges of record keeping and storage. a scoping review. int j environ res public health. 2021; 18:13426. 20. holzman sa, davis-dao ca, khoury ae, et al. telemedicine and patient satisfaction during the covid-19 pandemic: a case-con379archivio italiano di urologia e andrologia 2022; 94, 4 perceptions and attitudes toward the use of telemedicine for the postoperative outpatient urological care during the covid-19 pandemic... trol study of outpatient pediatric urology patients. j child health care. 2021:13674935211058272. 21. polinski jm, barker t, gagliano n, et al. patients' satisfaction with and preference for telehealth visits. j gen intern med. 2016; 31:269-75. 22. ambrosini f, di stasio a, mantica g, et al. covid-19 pandemic and uro-oncology follow-up: a "virtual" multidisciplinary team strategy and patients' satisfaction assessment. arch ital urol androl. 2020; 92:78-79. 23. gajarawala sn, pelkowski jn. telehealth benefits and barriers. j nurse pract. 2021; 17:218-221. 24. chandhanayingyong c, tangtrakulwanich b, kiriratnikom t. teleconsultation for emergency orthopaedic patients using the multimedia messaging service via mobile phones. j telemed telecare. 2007; 13:193-6. 25. spear kl, auinger p, simone r, et al. patient views on telemedicine for parkinson disease. j parkinsons dis. 2019; 9:401-404. correspondence vincenzo mirone, md mirone@unina.it department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples (italy) giuseppe celentano, md dr.giuseppecelentano@gmail.com claudia collà ruvolo, md c.collaruvolo@gmail.com luigi cirillo, md cirilloluigi22@gmail.com giovanni maria fusco, md giom.fusco@gmail.com marco abate, md marcoabate5@gmail.com simone morra, md simonemorra@outlook.com francesco di bello, md fran.dibello12@gmail.com gianluigi califano, md gianl.califano2@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com vincenzo morgera, md vincemorgera87@gmail.com roberto la rocca, md robertolarocca87@gmail.com marco capece, md drmarcocapece@gmail.com nicola longo, md nicola.longo@unina.it massimiliano creta, md max.creta@gmail.com luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology, urology unit, university of naples "federico ii" via sergio pansini n 5, naples (na), campania (italy) claudia mirone, md claudiamirone@outlook.it multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples (italy) 171archivio italiano di urologia e andrologia 2019; 91, 3 original paper the comparative analysis of the three dilatation techniques in percutaneous nephrolithotomy: which one is safer? aytac sahin, fatih uruc department of urology, fatih sultan mehmet research and training hospital, istanbul, turkey. objectives: introduction of the “access sheath” is one of the most important steps of the percutaneous nephrolithotomy (pnl) intervention. in creating the access tract, various dilatators (balloon, metal) are used and different need-based dilatation tools were developed. in this study, we aimed to compare the mechanical amplatz dilatation (ad), balloon dilatation (bd) and one-shot dilatation (osd) methods in a retrospective manner. methods: a total of 182 patients (127 males and 55 females), who underwent pnl surgery in urology department of fatih sultan mehmet research and training hospital between january 2016 and september 2018, were included in this study. results: the average age was 47.34 ± 12.68 years (age range 15-80) and average bmi was 27.15 ± 5.01 kg/m2 (range between 17.12 and 40.75 kg/m2). there was a prominent difference in terms of operation duration (p = 0.032). meaningful difference was found among the groups in terms of dilation fluoroscopy time (p = 0.001), with a notable shorter time in osd group than the others (p < 0.05). beside this, there was no difference between the ad and bd groups in terms of fluoroscopy times (p > 0.05). also, there was no difference among the groups by clavien complication rate (p > 0.05). there was a prominent difference among the groups in terms of hemoglobin decrement (p = 0.012; p < 0.05). the hemoglobin decrease in osd group was significantly lower than in ad and bd groups (p < 0.05; p < 0.01). on the contrary, there was no meaningful difference between ad and bd groups with this regard (p > 0.05). conclusions: as a result, we have concluded that the use of osd modality in pnl interventions could be superior to other methods with respect to its feasibility, cost-effectiveness, shorter radiation exposure / fluoroscopy time and it could be a preferable way of treatment especially in developing countries. key words: percutaneous nephrolithotomy; dilatation techniques; one shot dilatation. submitted 30 may 2019; accepted 26 july 2019 summary no conflict of interest declared. kidney excision and removal of the kidney stones by inserting an access sheath between the kidney and subcutaneous region. pnl has become an important alternative to open surgery approach in urolithiasis treatment, with respect to its minimal invasive feature (3). in current clinical practice, extracorporeal shock wave lithotripsy (eswl), pnl, retrograde intrarenal surgery (rirs), combined approach of these methods and other laparoscopic methods are used. due to minimal complication rates, fast elimination of big stones, quicker recovery, short hospitalization periods, increased quality of life and minimal loss of working capacity, the european association of urology (eau) has recommended the pnl method as primary option for treatment of kidney stones larger than two cm in diameter (2). introduction of the “access sheath” is one of the most important steps of the pnl intervention. in creating the access tract, various dilatators (balloon, metal) are used and different need-based dilatation tools were developed. in this study, we aimed to compare the mechanical amplatz dilatation (ad), balloon dilatation (bd) and one-shot dilatation (osd) methods in retrospective manner. materials and nethods a total of 182 patients (127 males and 55 females), who underwent pnl surgery at urology department of fatih sultan mehmet research and training hospital between january 2016 and september 2018, were included in this study. all participants were thoroughly examined and evaluated prior to surgical intervention. patients who have positive bacterial contamination in urinary culture, hemorrhagic diathesis condition or any systemic comorbidity were previously treated according to the diagnosed disorder and subsequently included to the study. only individuals with serious coagulopathy were excluded. retrograde pyelography imaging was taken from all the patients. pnl surgery was applied to all patients in prone position with assisted retrograde pyelography imaging. after calyceal access to kidney, ad method was applied to 66 patients, bd method in 55 patients and osd in 61 patients. average age, calculi diameter, body mass index, operation duration, radiation doi: 10.4081/aiua.2019.3.171 introduction urolithiasis is a frequently encountered illness with prevalence rates highly variable according to region and population worldwide (1). urolithiasis treatment can be applied by using conservative, medical or surgical methods according to the patient’s status and characteristics of the stone (2). percutaneous nephrolithotomy (pnl) can be defined as sahin2_stesura seveso 30/09/19 18:21 pagina 171 archivio italiano di urologia e andrologia 2019; 91, 3 a. sahin, f. uruc 172 exposure during the surgical intervention, hemoglobin decrement rate, clavien complication score and treatment costs were compared in the three groups, radiation exposure time elapsed during dilatation was defined as the time period between the insertion of the 18 gauge needle and the placement of ampltaz sheath. surgical operation was carried out by two urology specialists. in osd method, renal cavities were punctured by using 18 gauge needle and guide-wire was inserted into collecting system after urinary flow was observed. following this initial step, co-axial dilator of 10 f of diameter was pushed forward through the guide-wire. amplatz dilators up to 30 f were further pushed into the kidney with rotation movement and access sheath was placed over amplatz dilator, which enables a wide entry tract for nephroscopic examination. statistical analysis spss statistics 22 (ibm spss, turkey) program was used for statistical analysis of the data obtained. descriptive statistical data were obtained (average, standard deviation, frequency), kruskall wallis test was used to compare non-normal parameters for more than 2 groups and mann whitney u testwas used to compare differences between two independent groups. results the mean age was 47.34 ± 12.68 years (range 15-80) and average bmi was 27.15 ± 5.01 kg/m2 (range between 17.12 and 40.75 kg/m2) (table 1). there was a prominent difference in terms of operation time (p = 0.032). significant difference was found among the groups in terms of dilation fluoroscopy time (p = 0.001), with a notable shortening in osd group than the others (p < 0.05). beside this, there was no difference between the ad and bd groups in terms of fluoroscopy times (p > 0.05). also, there was no difference among the groups for clavien complication rates (p > 0.05). there was a prominent difference among the groups in terms of hemoglobin decrement (p = 0.012; p < 0.05). the hemoglobin decrease in osd group was significantly lower than in ad and bd groups (p < 0.05; p < 0.01). on the contrary, there was no statistically significant difference between the ad and bd groups with this regard (p > 0.05) (table 2). discussion with the development of minimally invasive treatment of urinary calculi, pnl has become one of the main treatments for large kidney and upper ureteral stones (4). one of the most fundamental steps of pnl surgery is to establish safe and effective access. however, complications in this process such as tract dilation failure, hemorrhage and perforation of the renal parenchyma or collecting system are not uncommon (5). the dilation of the nephrostomy tract is a central step of pnl intervention, and is usually performed by three dilation methods: ssemi rigid fascial dilators (amplatz) over an 8f guide catheter, metal telescopic dilatators (mtd) and nephrostomy balloon dilatators (bd). each dilation method has advantages and disadvantages. in the past, there have been many attempts and modifications to obtain the best results with minimal kidney damage (68). when it comes to the radiation exposure issue, bd and osd methods have an obvious superiority to md and ad methods, attributed to their easy-to-use aspect with one-pass dilation technique and shorter intervention time. in addition to this, there are also some cons of the latter mechanical methods including the displacement of guide-wire and access sheath during the multipass dilation entries, perforation in collecting tubule system and hemorrhage (9). although there is a general consensus that bd is a more reliable and efficient method than the metallic and plastic dilator use in the literature, it has been reported in a multi-centric study that there was longer mean operation time, more bleeding amount and higher transfusion rates with bd (10). in a meta-analysis study in which four different dilation methods have been evaluated in 6820 patients submitted to pnl, it has been reported that osd method requested shorter fluoroscopy time and less hemoglobin loss, when compared with the mtd method. in the same study, a statistically remarkable difference has been reported between bd and mtd in terms of blood transfusion rates and it has also been mentioned that bd had an advantage over mtd approach in terms of shorter intervention times and lower transfusion rate in patients who have not undergone open kidney surgery operation before. this meta-analysis research has also pointed out that osd could be preferred in most patients that have to be operated by pnl (11). likewise, we have observed less fluotable 1. demographic data. mechanical balloon one-shot dilatation dilatation dilatation average age (years) 48.86 45.94 46.5 male/female (n) 48/18 39/16 40/21 body mass index (kg/m2) 27.06 27.28 27.13 stone surface area (cm2) 5.4 4.8 4.28 table 2. evaluation of the parameters according to the operations carried out. mechanical balloon one-shot p dilatation dilatation dilatation mean ± sd (median) mean ± sd (median) mean ± sd (median) surgery time (mins) 117.73 ± 49.53 (120) 104.92 ± 35.86 (120) 99.1 ± 39.34 (90) 0.032* scopy time in dilatation (sec) 30.05 ± 6.87 (28) 27.02 ± 4.06 (27) 25.39 ± 3.23 (25) 0.001** clavien score 1.35 ± 0.62 (1) 1.29 ± 0.58 (1) 1.15 ± 0.36 (1) 0.197 hemoglobin level (mg/dl) 1.44 ± 1.3 (1) 1.39 ± 1.24 (1) 0.92 ± 0.44 (0,8) 0.012* kruskallwallis test *p < 0.05 **p < 0.01 sahin2_stesura seveso 30/09/19 18:21 pagina 172 roscopy use and hemoglobin decrement in osd method in the current study. in a meta-analysis study including large series of participants, it has been reported that bleeding was significantly higher with balloon dilation method (9.4%), when compared with telescopic/serial dilation (6.7%). it has also been mentioned in the same study that there was a need for more transfusions for balloon dilation interventions (7.0%) than telescopic/serial dilations (4.9%) (12). moreover, hemorrhage risk gets higher when a consecutive dilator is displaced to insert a larger one, because of the space remained after the removal. in some papers, single-increment dilation has been suggested as an easyto-apply and safe method to achieve better outcomes (13). in a study by frattini et al., it has been reported that there was a significant decrement in fluoroscopy time in comparison of the mtd, bd and osd groups (14). li et al. found that osd was a more reliable method, because of shorter insertion and fluoroscopy times (15). in another prospective series with 320 participants, harrech et al. reported that osd was also a reliable and feasible method, which could also be used in pnl procedures performed in supine position (16). it has been emphasized in the literature that tract dilation failure was a crucial issue, which could be encountered especially in cases with renal hypermobility condition. harrech et al. reported the dilation tract failure rate as three percent (16). in our study, we did not had failures of access tract dilation with osd orocedure. consequently, in our retrospective study, average fluoroscopy time and decrease in hemoglobin were found better by using osd technique than ad and bd. consequently our opinion is that osd method is the safer and simpler technique. conclusions as a result, we conclude that the use of osd modality in pnl interventions could be superior to other methods with respect to its feasibility, cost-effectiveness, shorter radiation exposure/fluoroscopy times and it could be a preferable way of treatment especially in developing countries. references 1. stoller ml. urinary stone disease; in tanagho ea mc aninch jw 17th edition smith’s general urology, mcgraw hill medical 2008. 2. türk c, skolarikos a, neisius a, et al. guidelines on urolithiasis: european association of urology, 2019. 3. peng px, lai sc, ding zs, et al. one-shot dilation versus serial dilation technique for access in percutaneous nephrolithotomy: a systematic review and meta-analysis. bmj open. 2019; 9:e025871. 4. tomaszewski jj, smaldone mc, schuster t, et al. factors affecting blood loss during percutaneous nephrolithotomy using balloon dilation in a large contemporary series. j endourol. 2010; 24:20711. 5. ozok hu, sagnak l, senturk ab, et al. a comparison of metal telescopic dilators and amplatz dilators for nephrostomy tract dilation in percutaneous nephrolithotomy. j endourol. 2012; 26:630-4. 6. patil av. a novel 5-part percutaneous access needle with guidewire technique (5-pang) for percutaneous nephrolithotomy: our initial experience. urology. 2010; 75:1206-8. 7. baldwin dd, maynes lj, desai pj, et al. a novel single step percutaneous access sheath: the initial human experience. j urol. 2006; 175:156-61. 8. maynes lj, desai pj, zuppan cw, et al. comparison of a novel one-step percutaneous nephrolithotomy sheath with a standard twostep device. urology. 2008; 71:2237. 9. hajiha m, baldwin dd. new technologies to aid in percutaneous access. urol clin north am. 2019; 46:225-243. 10. yamaguchi a, skolarikos a, buchholz np, et al. operating times and bleeding complications in percutaneous nephrolithotomy: a comparison of tract dilation methods in 5,537 patients in the clinical research office of the endourological society percutaneous nephrolithotomy global study. j endourol. 2011; 25:933-9. 11. dehong c, liangren l, huawei l, qiang w. a comparison among four tract dilation methods of percutaneous nephrolithotomy: a systematic review and meta-analysis. urolithiasis. 2013; 41:523-30. 12. lopes t, sangam k, alken p, et al. clinical research office of the endourological society percutaneous nephrolithotomy study group. the clinical research office of the endourological society percutaneous nephrolithotomy global study: tract dilation comparisons in 5537 patients. j endourol. 2011; 25:755-62. 13. xiong j, shi y, zhang x, et al. chinese one shot dilation versus sequential fascial dilation for percutaneous nephrolithotomy: a feasibility study and comparison.urol j. 2019; 16:21-26. 14. frattini a, barbieri a, salsi p, et al. one shot: a novel method to dilate the nephrostomy access for percutaneous lithotripsy. j endourol. 2001; 15:919-23. 15. li y, yang l, xu p, et al. one-shot versus gradual dilation technique for tract creation in percutaneous nephrolithotomy: a systematic review and meta-analysis. urolithiasis 2013; 41:443-8. 16. el harrech y, abakka n, el anzaoui j, et al. one-shot dilation in modified supine position for percutaneous nephrolithotomy: experience from over 300 cases. urol j. 2014; 11:1575-82. 173archivio italiano di urologia e andrologia 2019; 91, 3 dilation in percutaneous nephrolithotomy correspondence aytac sahin, md (corresponding author) draytacsahin@gmail.com fatih uruc, md drfatihguruc@gmail.com department of urology, fatih sultan mehmet research and training hospital, istanbul, turkey sahin2_stesura seveso 30/09/19 18:21 pagina 173 stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4492 review no conflict of interest declared. background: overactive bladder (oab) symptoms of frequency, urgency and urge incontinence are frequently associated with known neurological diseases like multiple sclerosis (ms), spinal cord injury (sci), parkinson’s disease (pd), stroke. objective: the aim of our study was to review the efficacy of pharmacological and non-pharmacological treatments for neurogenic overactive bladder. materials and methods: we searched two electronic databases (pubmed and embase) for randomized controlled trials focusing on pharmacological and non-pharmacological medical treatments for overactive bladder symptoms associated with neurological diseases published up to 30 april 2022. results: a total of 157 articles were retrieved; 94 were selected by title and abstract screening; after removal of 17 duplicates, 77 records were evaluated by full-text examination. sixty-two studies were finally selected. the articles selected for review focused on the following interventions: anticholinergics (n = 9), mirabegron (n = 5), comparison of different drugs (n = 3), cannabinoids (n = 2), intravesical instillations (n = 3), botulinum toxin (n = 16), transcutaneous tibial nerve stimulation (ttns) (n = 6), acupuncture (n = 2), transcutaneous electrical nerve stimulation tens (n = 4), pelvic floor muscle training (pfmt) (n = 10), others (n = 2). anticholinergics were more effective than placebo in decreasing the number of daily voids in patients with pd (mean difference [md]1.16, 95 % ci 1.80 to 0.52, 2 trials, 86 patients, p < 0.004), but no significant difference from baseline was found for incontinence episodes and nocturia. mirabegron was more efficacy of overactive neurogenic bladder treatment: a systematic review of randomized controlled trials rawa bapir 1, 14, kamran hassan bhatti 2, 14, ahmed eliwa 3, 14, herney andrés garcía-perdomo 4, 14, nazim gherabi 5, 14, derek hennessey 6, 14, vittorio magri 7, 14, panagiotis mourmouris 8, 14, adama ouattara 9, 14, gianpaolo perletti 10, 14, joseph philipraj 11, 14, konstantinos stamatiou 12, 14, alberto trinchieri 13, 14, noor buchholz 14 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 asst nord milano, milan, italy; 8 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 9 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 10 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 department of urology, tzaneio general hospital, 18536 piraeus, greece; 13 urology school, university of milan, milan, italy; 14 u-merge ltd. (urology for emerging countries), london-athens-dubai * authors 1-14 have equally contributed to the paper and share first authorship. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2022.4.492 summary effective than placebo in increasing the cystometric capacity in patients with ms (mean difference [md] 89.89 ml, 95 % ci 29.76 to 150.01, 2 trials, 98 patients, p < 0.003) but no significant difference was observed for symptom scores and bladder diary parameters. ttns was more effective than its sham-control in decreasing the number of nocturia episodes (md -1.40, 95 % ci -2.39 to -0.42, 2 trials, 53 patients, p < 0.005) but no significant changes of oab symptom scores were reported. pfmt was more effective than conservative advice in decreasing the iciq symptom score (md, -1.12, 95 % ci -2.13 to -0.11, 2 trials, 91 patients, p = 0.03), although the number of incontinence episodes was not significantly different between groups. conclusions: the results of the meta-analysis demonstrate a moderate efficacy of all considered treatments without proving the superiority of one therapy over the others. combination treatment using different pharmacological and non-pharmacological therapies could achieve the best clinical efficacy due to the favorable combination of the different mechanisms of action. this could be associated with fewer side effects due to drug dosage reduction. these data are only provisional and should be considered with caution, due to the few studies included in metaanalysis and to the small number of patients. key words: overactive bladder; urinary incontinence, urge; multiple sclerosis; ischemic stroke; parkinson disease; anticholinergics; mirabegron; cannabinoids; transcutaneous tibial nerve stimulation (ttns); pelvic floor muscle training (pfmt). submitted 5 november 2022; accepted 15 november 2022 493archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder introduction voiding dysfunction often develops in patients with underlying neurological diseases. patients may present with overactive bladder (oab) symptoms of frequency, urgency and urge incontinence. oab in patients with known neurological diseases (neurogenic overactive bladder) is related to disturbances of the neurological control of micturition. oab symptoms are highly prevalent among patients with multiple sclerosis (ms), spinal cord injury (sci), parkinson’s disease (pd), various neurological diseases, and stroke. this was shown by a recent study demonstrating oab symptoms in over 50% of these patients (1). symptoms vary from mild lower urinary tract symptoms (luts), that are often poorly recognized or misdiagnosed in men as prostatic disease, to severe clinical conditions like those observed after spinal cord injury (sci). the severity of symptoms depends on the type and degree of damage to the nervous system. as the neurological condition progresses, the bladder function progressively deteriorates, and becomes more difficult to treat. incontinence frequently develops as a consequence of disease progression. conservative management includes pharmacological treatment to reduce the contractility of the detrusor muscle, behavioral therapy and biofeedback, electrical stimulation, or chemical denervation procedures (instillation of capsaicin and resiniferatoxin or intradetrusorial injection of botulinum toxin). no single treatment exists for neurogenic oab due to the complexity and individual variability of the underlying neurological diseases. treatment should be tailored to the individual patient, also considering that conventional treatment programs for non-neurogenic oab could lack clinical efficacy in neurogenic patients. several systematic reviews have been published in the last 15 years to evaluate the evidence concerning the different treatments for neurogenic oab (2-13). in 2012, madhuvrata and coworkers (2) published a systematic review and meta-analysis on anticholinergic treatment of adult neurogenic oab, which updated and completed a previous systematic review assessing the efficacy and tolerability of anticholinergic agents in patients with oab associated to multiple sclerosis (3). a more recent systematic review evaluated the effectiveness and safety of intravesical oxybutynin therapy for patients with neurogenic oab (4). two recent systematic reviews addressed the results of pelvic floor muscle training (pfmt) for bladder dysfunction in patients with multiple sclerosis (5, 6). one of these systematic reviews extended its analysis to the results of peripheral tibial nerve stimulation (ptns) (6). a systematic review addressed the outcomes of ptns in the treatment of lower urinary tract dysfunction including neurogenic bladder. ptns was found to be effective in up to 100% of patients with neurological pathologies, although this review was based on non-randomized studies (7). a meta-analysis evaluated the results of studies focusing on sacral neuromodulation (snm) in patients with neurogenic lower urinary tract dysfunction (8). finally, several systematic reviews with metanalysis evaluated the treatment of overactive bladder syndrome with botulinum toxin injection (9-15). although a relevant bulk of information from previous systematic reviews is available, certain specific aspects, such as efficacy mirabegron and new anticholinergic agents in neurogenic bladder have not yet been addressed. other issues, such as efficacy of ptns in neurogenic bladder, need to be corroborated by randomizes studies. the aim of our study was to review the efficacy of treatments for neurogenic oab focusing on recent clinical evidence, including studies focusing on mirabegron and on new anticholinergic agents. materials and methods the review was conducted in accordance with the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines (16). it has been registered on the prospero platform (registration number: crd42022347165). types of studies, inclusion criteria we considered randomized controlled trials (rcts), with single/double blinded design without time constraints. we included studies involving adult patients of both sexes subjected to pharmacological and non-pharmacological medical treatment for overactive bladder symptoms associated with neurological diseases including post-ischemic stroke, parkinson’s disease and multiple sclerosis. outcomes the following outcomes were considered: number of daytime voids and night-time voids (nocturia); number of incontinence and urgency episodes; modification of scores measuring urinary symptoms and quality of life; change of urodynamic measurements (cystometric capacity, peak pressure, volume at 1st contraction). the overactive bladder symptom score (oab-ss) is a diagnostic tool divided in four domains, administered to patients for self-evaluation of voiding symptoms. the score ranges between 0 and 15 (15 = most severe symptoms). the international consultation on incontinence questionnaire overactive bladder (iciq) is a questionnaire for evaluating overactive bladder and related impact on quality of life (qol) and outcome of treatment in men and women in research and clinical practice across the world. it is based on a 0-16 overall score with greater values indicating increased symptom severity. search strategy two electronic databases (pubmed and embase) were searched for articles in english, published up to 30 april 2022. record search and retrieval was performed using strings based on the combination of various mesh terms: (urinary bladder, overactive; urinary incontinence, urge; multiple sclerosis; ischemic stroke; parkinson disease): (treatment) and (urge urinary incontinence or overactive urinary bladder or detrusor overactivity) and (multiple sclerosis or parkinson disease or ischemic stroke). relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, clinical trial registers such as www.clinicaltrials.gov, www.clinicaltrialsregister.eu, etc.). selection of studies retrieved papers were independently screened by two archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 494 authors by title and abstract to exclude documents that did not meet the inclusion criteria. duplicate references were deleted. full texts of selected papers were downloaded to confirm/reject inclusion and to extract relevant information. controversies were resolved by a third researcher. a prisma flow diagram summarizes the study selection process (figure 1). data extraction (supplementary materials pico tables) data extraction was performed by four authors using a standardized form. the following information was obtained from each study: author(s), publication year, study design, population, interventions, comparisons, outcomes/endpoints. in case of missing or insufficient information, we analyzed the reason for incompleteness and considered the impact of missing data on the meta-analysis results. quality evaluation (supplementary materials rob evaluation) two authors independently performed the quality assessment by identifying potential biases using the 2019 cochrane risk of bias tool (rob) 2 (17). study quality was assessed against pre-defined criteria in relation to randomization process (d1), deviations from the intended interventions (d2), missing outcome data (d3), measurement of the outcome (d4) and selection of the reported result (d5). disagreements were resolved by discussion. the presence of high risk of bias was not used as a criterion to exclude studies from analysis. publication bias was planned to be assessed by funnel plot in the presence of at least 5 trials in each metaanalysis. if a potential reporting bias was found by visual inspection of the plots, the berg and egger tests were used to test funnel plots symmetry and to confirm the presence/absence publication bias. a summary of findings table was generated, and the quality of the evidence emerging from meta-analyses including at least 3 studies was rated according to grade criteria. statistical analysis statistical analysis was performed using the revman5 software. mean differences, 95% confidence intervals (ci) and z statistics were calculated (random-effects model, inverse variance method). study heterogeneity was assessed by calculating the i^2 (and 95% ci), which was interpreted as of lesser importance (i^2 ≤ 40%), moderate (i^2 = 30%-60%), substantial (i^2 = 50%-90%) or considerable (i^2 ≥ 75%), according to cochrane criteria. sensitivity analysis was planned in case substantial or considerable heterogeneity of pooled analyses including at least 5 studies. results in total, 157 records (97 from medline, 60 from embase) were retrieved by database searching; 94 papers were included after title and abstract screening (62 from medline, 32 from embase). after removal of 17 duplicates, we evaluated 77 papers by full-text reading. twelve studies were excluded: five studies reported data contained in other included studies, a study evaluated the expression of cb1 and cb2 receptors after sublingual administration of spray cannabidiol, an article contained a review of the literature, two studies focused on non-neurogenic oab, one study addressed a pediatric population, two studies were open-label. sixty-two studies were finally selected (figure 1) table 1 lists the 62 studies included in this review, according to underlying disease and type of treatment. quantitative analysis was limited to the comparisons of mirabegron vs. placebo, anticholinergics vs. placebo, ttns figure 1. flow diagram. 495archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder vs. sham intervention, and pfmt vs. controls. other outcomes were not analyzed quantitatively because several extensive meta-analyses were previously published. anticholinergics we found 9 papers evaluating the effects of anticholinergics (18-26). three papers compared anticholinergic agents with placebo for treatment of overactive bladder in patients with parkinson disease (n = 2), multiple sclerosis or spinal cord injury (n = 1) (18-20). quantitative analysis of two studies (18, 19) in patients with parkinson disease demonstrated that anticholinergics were more effective than placebo in decreasing the number of day voids (mean difference [md], -1.16, 95% ci 1.80 to 0.52, 2 trials, 86 patients, z = 3.56, p < 0.004). changes from baseline number of incontinence and nocturia episodes were not significantly different between anticholinergics and placebo (md, -0.44, 95% ci -1.23 to 0.35, 2 trials, 86 patients, z = 1.08, p = 0.28, and md, -0.36, 95% ci -1.17 to 0.45, 2 trials, 86 patients, z = 0.87, p = 0.39, respectively) (figure 2). adverse events associated with anticholinergics as dry mouth, constipation, and blurred vision are well known and may lead to therapy discontinuation. in a study comparing solifenacin or oxybutynin with placebo the most common treatment emergent side effects were dry mouth and urinary tract infections although most events were considered mild in severity (20). dry mouth was observed more frequently in patients taking oxybutyinin (17%) then in those receiving solifenacin (4.2-7.8%) or placebo (2.3%). changes from baseline in vas dry mouth score were significantly higher in the oxybutynin group than in placebo whereas there was no difference of vas dry mouth score between solifenacin group and placebo. in another study, solifenacin was well tolerated but a case of urinary retention was observed in the treatment group (11%). xerostomia and constipation were also observed (18). during the treatment with fesoterodine 4 mg there was no serious adverse event and no urinary retention episode in both fesoterodine and placebo groups. xerostomia (3%) and constipation (3%) were observed in the treatment group (19). one study demonstrated that short-term treatment using oral extended-release oxybutynin 5 mg once daily was safe and well tolerated compared to placebo (with no onset of delirium) in older female nursing home participants with mild to severe dementia (21). four studies compared the outcome of the treatment with anticholinergic agents administered at different dose, or as different formulations, or via different routes (22-25). oral trospium chloride at standard dosage was compared with oral trospium chloride administered at adjustable doses. a therapeutic response was achieved in 58% of patients in the adjustable dose group and in 72% of those in the standard dose group (p = 0.23). rates of side effects were similar between groups (35% vs 37%) (22). oral treatment with oxybutynin immediate release was compared to intravesical oxybutynin or atropine. the increase in maximum bladder capacity was higher with intravesical application, also causing less frequent and less severe side effects (23, 24). propiverine extended-release (er) was compared with table 1. studies retrieved divided by treatment. treatment design n° of studies disease mirabegron compared to placebo 5 pd (3), ms or sci (2) anticholinergics compared to placebo 3 pd (2), ms or sci (1) compared to placebo to evaluate the cognitive effects of oxybutynin 1 old people with cognitive impairment oral trospium, standard vs. adjustable dose 1 neurogenic detrusor overactivity oral oxybutynin ir vs. intravesical oxybutynin or atropin 2 neurogenic detrusor overactivity propiverine ir vs. er 1 neurogenic detrusor overactivity propiverine vs. oxybutynin 1 neurogenic detrusor overactivity comparison of drugs mirabegron vs. darifenacin 1 poststroke oxybutyinin+trospium vs. oxybutynin+solifenacin 1 neurogenic detrusor overactivity milnacipran vs. paroxetine 1 neurogenic detrusor overactivity cannabinoids compared to placebo 2 ms intravesical instillations capsaicin compared to saline 2 spinal cord lesions neurogenic detrusor overactivity nociceptin/orphanin fq 1 neurogenic detrusor overactivity botulinum toxin compared to placebo 13 neurogenic detrusor overactivity trigone excluding vs. trigone including 2 comparison of different doses 1 transcutaneous tibial nerve stimulation (ttns) compared to sham 3 compared to pelvic floor muscle training 1 compared to oxybutynin 2 acupuncture 2 pd, poststroke transcutaneous electrical nerve stimulation (tens) compared to sham 3 poststroke (3) compared to oxybutynin 1 pelvic floor muscle training (pfmt) compared to controls 6 pd (2), ms (2), poststroke (2) pfmt+electrostimulation vs. pfmt 3 ms (3) compared to intravaginal neuromuscular electrical stimulation or to ttns 1 others deep brain stimulation/ intradetrusor adipose stem cells (adsc) injections 2 pd archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 496 propiverine immediate-release (ir). the latter showed slightly better tolerability compared to propiverine er (25). the effects of propiverine and oxybutynin were compared in a study by stöhrer et al. both treatments increased maximum cystometric capacity and lowered maximum detrusor pressure during the filling phase with no significant differences between treatment groups. adverse events were reported less frequently in the propiverine arm compared to the oxybutynin group (63.0% versus 77.8%) (26). mirabegron we retrieved five rcts comparing mirabegron vs. placebo in patients with oab and parkinson disease (n = 3) (27-29) or spinal cord injury/multiple sclerosis (n = 2) (30, 31). three studies evaluated the clinical results of mirabegron treatment in patients with parkinson disease. changes from baseline values of the oab-ss score, day void rates or of incontinence and urgency episodes were not significantly different between mirabegron and placebo (md, -2.01, 95% ci -4.24 to 0.21, 2 trials, 212 patients, z = 1.78, p = 0.08; md, -0.80, 95% ci, -3.04 to 1.43,2 trials, 227 patients, z = 0.71, p = 0.48; md, -0.11, 95% ci -3.12 to 2.91, 2 trials,195 patients, z = 0.07, p = 0.94; md, -0.56, 95 % ci -1.88 to 0.75, 3 trials, 227 patients, z = 0.84, p = 0.40; respectively) (figure 3, panels a, b, c and d). two studies evaluated changes of urodynamic values in patients with spinal cord injury/multiple sclerosis treated with mirabegron. mirabegron was more effective than placebo in increasing cystometric capacity (md, 89.89 ml, 95% ci 29.76 to 150.01, 2 trials, 98 patients, z = 2.93, p < 0.003). changes from baseline values of peak pressure and volume at first contraction were not significantly different between mirabegron and placebo (md, 13.34 cm2, 95% ci -55.70 to 29.01, 2 trials, 97 patients, z = 0.62, p = 0.54 and md, 22.92 ml, 95 % ci 20.78 to 66.63,2 trials, 98 patients, z = 1.03, p = 0.30, respectively) (figure 4 a, b and c). in general, the rate of treatment emergent adverse events was similar in the mirabegron and placebo groups and the degree of adverse events was mild or moderate in most cases. a major safety concern with mirabegron is cardiovascular safety because of beta-adrenergic stimulation. in three studies changes in cardiovascular parameters were actively assessed demonstrating no significant changes of mean systolic and diastolic blood pressure, pulse rate, and qtc interval during mirabegron treatment (28, 30, 31). the risk of urinary retention is another concern associated to mirabegron treatment. data from two studies (27, 31) showed no significant change of mean post-voiding residual volume or proportion with pvr > 100 ml, figure 2. a, changes from baseline number of incontinence in patients with parkinson disease treated with anticholinergics vs. placebo; b, changes from baseline number of night voids in patients with parkinson disease treated with anticholinergics vs. placebo; c, changes from baseline number of day voids in patients with parkinson disease treated with anticholinergics vs. placebo. diamonds on the left side of the no-effect line indicate decreased numbers of episodes in patients treated with active drugs (anticholinergics) compared to placebo. mean differences with 95% confidence intervals and heterogeneity statistics (i^2) are shown. a. day voids b. incontinence c. nocturia 497archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder whereas in a study a case with pvr > 100 was described in mirabegron group but not in placebo (28). comparison between various drugs three studies compared the efficacy and safety of different drugs used for treatment of neurogenic oab. in patients who had ischemic stroke, mirabegron and darifenacin showed similar improvement of bladder diary parameter without deterioration of cognitive function (32). both combination of trospium chloride with oxybutynin, and solifenacin with oxybutynin improved subjective and urodynamic urinary parameters, though side effects were higher in patients taking oxybutyinin plus solifenacin (33). a study proposed the use of serotonin and noradrenaline reuptake inhibitors (snris) as an alternative to anticholinergic treatment in order to minimize antimuscarinic or cardio-suppressive effects. snris are currently used for treatment of depression, though the snri duloxetine has been used to treat stress urinary incontinence thanks to its activity on the urinary sphincter, presumably via serotoninergic and adrenergic receptors of the sacral onuf’s nucleus. snris lack anticholinergic properties, unlike conventional figure 3. a, changes from baseline values of oab-ss scores after mirabegron vs. placebo in patients with parkinson disease; b, changes from baseline number of day voids after mirabegron vs. placebo in patients with parkinson disease; c, changes from baseline number of urgency episodes after mirabegron vs. placebo in patients with parkinson disease; d, changes from baseline number of incontinence episodes after mirabegron vs. placebo in patients with parkinson disease. diamonds on the left side of the no-effect line indicate decreased numbers of episodes or symptom scores in patients treated with mirabegron compared to placebo. mean differences with 95% confidence intervals and heterogeneity statistics (i^2) are shown. c. urgency b. day voids a. oab-ss d. incontinence archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 498 antidepressants, and stimulation of serotoninergic receptors seems to suppress bladder contractility. for this reason, snris could have a role in the treatment of neurogenic oab. a study compared the effect of the snri milnacipran on oab symptoms compared to paroxetine, a selective serotonin reuptake inhibitor (ssri) lacking adrenergic effect. milnacipran, but not paroxetine, improved the quality of life of patients by reducing daytime urinary frequency and by increasing the bladder capacity (34). cannabinoids two studies reported the effect of cannabis-containing medicines in patients with overactive bladder and multiple sclerosis (35, 36). cannabinoids (cannabis extract, δ9-tetrahydrocannabinol or thc, nabiximols or sativex) were used to treat oab in patients with ms. cannabis extract and thc reduced incontinence episode rates by 38% and 33%, respectively. sativex, an endocannabinoid system modulator, significantly reduced nocturia episodes and daytime voids. dizziness (16%), disorientation (6%) and dissociation (6%) were observed during treatment. intravesical instillations in two studies, a single intravesical instillation of capsaicin significantly decreased voiding frequency and incontinence episodes, increased the maximum cystometric capacity and decreased the maximum detrusor pressure (37, 38). capsaicin diluted in ethanol solvent caused significant side effects in 70% of cases, whereas side effects were limited using a glucidic solvent. the therapeutic effect of capsaicin is time-limited with no significant efficacy observed after three months. intravesical instillations of nociceptin/orphanin fq also decreased urine leakages and increased the voiding bladder capacity without significant side effects (39). botulinum toxin thirteen studies evaluated the effect of botulinum toxin intra-detrusor injection compared to saline injection in patients with neurogenic detrusor overactivity associated with spinal injury or multiple sclerosis (40-52). intravesical botulinum toxin treatment proved to be effective and safe for the treatment of neurogenic detrusor overactivity. transient adverse events were urinary retention, figure 4. a, changes of cystometric capacity values in patients with spinal cord injury/multiple sclerosis treated with mirabegron vs. placebo; b, changes of peak pressure values in patients with spinal cord injury/multiple sclerosis treated with mirabegron vs. placebo; c, changes of volume at 1st contraction values in patients with spinal cord injury/multiple sclerosis treated with mirabegron vs. placebo. diamonds on the right side of the no-effect line indicate increased cystometric capacity (a) and volume at first contraction (c) in patients treated with mirabegron compared to placebo. diamonds on the right side of the no-effect line indicate decreased peak pressure in patients treated with mirabegron compared with placebo. mean differences with 95% confidence intervals and heterogeneity statistics (i^2) are shown. cystometric capacity peak pressure volume at first contraction 499archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder hematuria, muscle weakness, and urinary tract infection. two studies compared the effect of injections in the detrusor excluding the trigone with injections including the trigone (53, 54). a study compared the effect of the administration of two different doses of botulinum toxin type a (55). most of these studies were included in recently published meta-analyses. our search added to published systematic reviews three studies which were published after 2017. kennelly et al. reported pooled data from two phase 3 studies assessing the safety and efficacy of abobotulinumtoxina (abobonta) in patients with neurogenic detrusor overactivity who were routinely performing clean intermittent catheterization. treatment with abobont-a significantly reduced incontinence episodes per week in comparison to placebo (p < 0.001) and significantly increased the volume per void denys et al. compared the administration of abobotulinumtoxina by 15 intra-detrusor injections in comparison to 30 injections (43). both 15 and 30 injections administration modes decreased the daily number of incontinence episodes and improved urodynamic parameters in patients with ndo. honda et al. described the results of the administration of onabotulinumtoxina in japanese patients with neurogenic detrusor overactivity, demonstrating reduction of urinary incontinence episodes and improvement of urodynamic parameters (47). transcutaneous tibial nerve stimulation (ttns) six studies reported the results of ttns in neurogenic oab. three studies compared active treatment with sham treatment (56-58) and 3 compared ttns with other treatments such as pelvic floor muscle training (59) or oral anticholinergics (n = 2) (60, 61). ttns reduced urinary frequency, urgency, and incontinence episodes in comparison to placebo. quantitative analysis of two studies comparing ttns with sham treatment in patients with parkinson disease shows that ttns was more effective than sham in decreasing the number of nocturia episodes (md, -1.40, 95% ci -2.39 to -0.42, 2 trials, 53 patients, z = 2.79, p < 0.005). changes from baseline of oab scores were not significantly different between ttns and sham (md 2.87, 95% ci -17.25 to 11.51, 2 trials, 53 patients, z = 0.39, p = 0.70) (figure 5a, b). in a study including patients with multiple sclerosis, quality of life scores (sf-qualiveen), overactive bladder symptom scores (usp) and rates of urgency episodes were improved after both pfmt and ttns but no differences between the two groups were observed (59). ttns was compared to oxybutynin (5 mg bid) in patients with oab and multiple sclerosis. ttns showed a less significant reduction of oab-s (overactive bladder symptoms) and oab-q (overactive bladder quality of life) scores in comparison to oxybutynin, though the latter was associated with a higher rate of side effects (35%) (60). in another study including women with neurogenic bladder, the association of ttns with tolterodine 4 mg improved urgency symptoms (61). acupuncture the effect of acupuncture and electroacupuncture was reported in 2 studies in patients with parkinson’s disease and post-stroke oab. in pd patients, acupuncture associated with a low dose of tolterodine (1 mg bid) improved daily rates of frequency and incontinence as well as mean urine volumes more than full-dose tolterodine (2 mg bid) (62). in post-stroke patients, electroacupuncture treatment improved the perceived severity of oab symptoms in comfigure 5. a, changes from baseline of oab scores in patients with parkinson disease treated with ttns vs sham treatment; b, changes from baseline of the number of night voids in patients with parkinson disease treated with ttns vs sham treatment. diamonds on the left side of the no-effect line indicate decreased numbers of episodes or symptom scores in patients treated with ttns compared to sham treatment. mean differences with 95% confidence intervals and heterogeneity statistics (i^2) are shown. a. oab-ss b. nocturia archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 500 parison with standard care, though no significant differences were observed in bladder diary parameters and quality of life scores (ssqol). both acupuncture and electroacupuncture were well tolerated (63). transcutaneous electrical nerve stimulation (tens) transcutaneous electrical nerve stimulation has been used to treat post-stroke neurogenic overactive bladder. positive pads were usually placed in the region of the second sacral level of the vertebral column and negative pads were placed at the level of the middle and lower third of the junction between the posterior superior iliac spine and the ischial node. treatments were administered 30 minutes once a day for 60-90 days, in the form of unidirectional square waves with different combinations of pulse duration and frequency. in three studies, tens was compared to sham treatment for treatment of post-ischemic stroke urinary incontinence, whereas one study compared tens to anticholinergic drugs (64-67). tens improved symptom scores, voiding diary parameters (daily micturition, nocturia, urgent urination, and urge ui), and urodynamic findings (maximum cystometry volume, flow rate, pressure of detrusor in the end of the filling phase). in the study comparing tens with anticholinergics, the former was superior than the latter. pelvic floor muscle training six studies evaluated the outcome of behavioral therapy, including pelvic floor muscle training (pfmt) in comparison with controls (2 in parkinson disease, 2 in incontinence post-stroke, 2 in multiple sclerosis) (68-73). the quantitative analysis of the results of two studies in patients with parkinson disease comparing pelvic floor muscle training with conservative advice, demonstrated that pfmt was more effective than the latter in decreasing the values of the iciq score (md -1.12, 95% ci -2.13 to -0.11, 2 trials, 91 patients, z = 2.17, p = 0.03). the number of incontinence episodes from baseline was not significantly different between pfmt and controls (md, 0.41, 95% ci -2.84 to 2.03, 2 trials, 91 patients, z = 0.33, p = 0.74) (figure 6). other studies compared pfmt plus vaginal electrostimulation to home pfmt in patients with multiple sclerosis (74-77). in patients with multiple sclerosis and luts, the association of pfmt (with emg feedback) and intravaginal nmes significantly improved pelvic floor muscle assessment findings and oab-v8 scores more than pfmt alone and the association of pfmt with ttns. three studies from the same group compared outcomes of pfmt alone with pfmt with vaginal electrostimulation in women with luts in multiple sclerosis. oab-v8 scores, quality of life and perineal musculature contraction were improved after both treatments, although a greater increase was obtained with the addition of electrostimulation. other studies deep brain stimulation (dbs), a surgical treatment for motor symptoms in advanced pd, showed improvement of luts in pd patients (78). intra-detrusor injections of adipose stem cells (adsc) were also used to treat pd-related oab symptoms. a single adsc injection significantly improved symptom scores and voiding diary parameters (79). figure 6. a, changes from baseline of iciq-oab scores in patients with parkinson disease treated with pelvic floor muscle training vs. conservative advice; b, changes from baseline of the incontinence episodes in patients with parkinson disease subjected to the same treatments. diamonds on the left side of the no-effect line indicate decreased numbers of episodes or symptom scores in patients treated with pfmt compared to advice. mean differences with 95% confidence intervals and heterogeneity statistics (i^2) are shown. b. incontinence a. iciq score 501archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder discussion anticholinergics anticholinergics are the first-line choice for the pharmacologic treatment of oab. they are used to stabilize the detrusor muscle and improve bladder compliance because detrusor smooth contraction is initiated via release of acetylcholine. the major disadvantage of oral anticholinergics are the side effects that result in treatment discontinuation in up to 70% of patients, depending on the duration of treatment. furthermore, a potential risk of cognitive decline and worsening of gait in patients with pd has been recently suggested. in 2009, a cochrane systematic review assessed the efficacy and tolerability of anticholinergic agents in patients with overactive bladder associated to multiple sclerosis (ms) (3). only three rcts were considered suitable for analysis. an older randomized cross-over study compared methantheline bromide, flavoxate chloride and meladrazine tartrate (hebjorn 1977) (81). a more recent study found reduced symptoms after oxybutynin compared to propantheline (gajewski 1986) (82). finally, a study found no significant difference in term of efficacy between oral oxybutynin and intravesical atropine, although side effects and quality of life were in favor of the latter (fader 2007) (83). the authors concluded that evidence was insufficient to demonstrate any benefit from the administration of anticholinergics for urinary symptoms in multiple sclerosis. in addition, high rates of adverse effects were reported, with 20% of patients who had to withdraw from oral treatment. in a systematic review by madhuvrata et al. (2), eight rcts comparing anticholinergic drugs with placebo in adult neurogenic oab were included. the metanalysis of three studies showed higher maximum cystometric capacity, higher volume at first contraction, and lower maximum detrusor pressure after anticholinergics compared to placebo. on the contrary, no significant changes in frequency of micturition or incontinence episodes per 24 hours were observed. the present review included three rcts (18-20) comparing anticholinergics with placebo, which were published after the review of madhuvrata et al. in patients with parkinson disease, anticholinergics were more effective than placebo in decreasing the number of day voids, though the number of incontinence episodes and nocturia were not significantly decreased. the most frequent side effect was dry mouth which was observed in 17% of the patients taking oxybutynin. similarly, the meta-analysis of madhuvrata et al. (2) showed statistically significantly higher dry mouth with anticholinergic drugs compared with placebo (32 vs 7%), but did not report any statistically significant difference in any other adverse event, nor in withdrawal rates due to adverse events (8 vs 2%). there were no statistically significant differences in any of the outcomes between oxybutynin and other anticholinergics nor among different doses and preparations of anticholinergic drugs. a meta-analysis of rcts on the efficacy and safety of anticholinergic drugs for non-neurogenic overactive bladder (83) concluded that extended-release formulations showed some advantages when compared to immediate release ones, both in terms of efficacy and safety. no significant advantage was observed after transdermal delivery compared to oral intake. in general, dose escalation obtained some improvements in term of efficacy, although it was associated with a significant increase in the rate of adverse events. tolterodine ir was associated with less adverse events than oxybutynin ir. in our review, we included three studies comparing the effect of the treatment with anticholinergic agents administered at different doses or with different formulation. oral trospium chloride at standard doses and at adjustable doses showed similar therapeutic responses and similar rates of side effects (22). similarly, when compared to propiverine ir, propiverine er showed a slightly better tolerability (25). a comparison of propiverine vs. oxybutynin showed no significant differences in the increase of maximum cystometric capacity and decrease of maximum detrusor pressure during the filling phase. adverse events were reported less frequently in the propiverine arm compared to the oxybutynin group (63.0% versus 77.8%) (26). shen et al. (4) recently reviewed randomized and non-randomized studies evaluating effectiveness and safety of intravesical oxybutynin therapy for patients with neurogenic detrusor overactivity compared to oral oxybutynin. in studies in adults, maximum bladder capacity increased and detrusor pressure at maximum bladder decreased more after intravesical oxybutynin than after oral treatment. after treatment, 76.9% of adult patients were considered “dry or improved”. side effects were reported in 13.5% of cases and 6.6% of patients withdraw for side effects. our review did not add any new study on intravesical anticholinergic administration to shen’s meta-analysis. combined administration of two different anticholinergic drugs instead of standard of care (a single antimuscarinic drug administered at maximum of recommended dosage) was proposed to improve efficacy without affecting tolerability. combined administration of trospium chloride with oxybutynin and solifenacin with oxybutynin (33) improved subjective and urodynamic urinary parameters, although side effects were higher in patients taking oxybutyinin plus solifenacin. mirabegron mirabegron is a beta-3 adrenoceptor agonist that mediates bladder relaxation and facilitates the filling phase by stimulating beta-3 adrenoceptors. mirabegron is commonly used for idiopathic oab treatment because of its efficacy, comparable to that of anticholinergic drugs, but with a better tolerability profile (84, 85). however, mirabegron may affect the cardiovascular system causing hypertension, increased heart rate, arrhythmias, and headache (86). patients with neurogenic oab could be more exposed to such side effects because of potential disturbances of the vegetative nervous system. in particular, this could be the case in patients with sci above the t6 level that is above the outflow of splanchnic sympathetic fibres. our meta-analysis partially supported the efficacy of mirabegron in patients with neurogenic overactive bladder. the cystometric capacity was increased after archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 502 mirabegron in patients with ms, although peak pressures and volume at 1st contraction were not significantly increased. symptom scores and bladder diary parameters were not significantly changed in patients with pd. cardiovascular parameters were not significantly affected by mirabegron treatment although patients at risk for cardiovascular disease were excluded from most trials. mirabegron was compared to darifenacin in the treatment of oab in patients with a history of cerebrovascular accident (32). no differences in bladder diary parameters were observed between groups. no patients developed intolerable severe adverse effects and no deterioration in the cognitive function assessed using moca-b scores was observed in either arm. cannabis-containing medicines cannabis-containing medicines were used in the treatment of oab in patients with multiple sclerosis. the potential mechanism of action of those medicines is not fully elucidated, although it could be mediated by cb1 receptors or by transient receptor potential vanilloid 1 (trpv1) receptor in the bladder. in our review, two rcts were included, showing that treatment with thc or cannabidiol (cbd) reduced episodes of incontinence, daytime voids and nocturia. other oral treatments a possible alternative to anticholinergics is milnacipran, a serotonin and noradrenaline reuptake inhibitor (snri) which can suppress bladder contractility by stimulating serotoninergic receptors. in a single study, this drug was able to reduce daytime urinary frequency and to increase bladder capacity (34). intravesical instillations prevention of micturition reflex to trigger bladder overactivity represents a possible alternative to drugs blocking smooth muscle contraction like anticholinergics. drugs like capsaicin, rtx, and nociception/orphanin fq have an effect on the unmyelinated c-fiber afferent limb of the micturition reflex. instillations of both capsaicin and nociceptin/orphanin fq were able to decrease incontinence rates and to improve urodynamic parameters in patients with neurogenic oba (37-39). botolinum toxin injections botulinum toxin has been used for many years in the treatment of severe neurogenic overactive bladder refractory to standard treatment. in 2007, duthie et al. published a systematic review on the treatment of overactive bladder syndrome with botulinum toxin injections. the review, which was updated in 2011 (9), included patients affected by either neurogenic oab or idiopathic oab. botulinum toxin injection was superior to placebo in all studies included in the analysis, with an effect lasting for several months depending on the dose and the type of toxin used. other systematic reviews with meta-analysis were subsequently published to confirm the efficacy and safety of this treatment. zhang et al. (10) retrieved eight rcts focusing on efficacy and safety of onabotulinumtoxina in patients with neurogenic detrusor overactivity (ndo), published up to september 2012. infiltrations with onabotulinumtoxina improved maximum cystometric capacity and decreased maximum detrusor pressure compared to placebo. the treatment was more frequently associated with utis than placebo. no dose-related differences of efficacy and side effects were observed when regimens based on 300 u or 200 u doses were compared. similarly, zhou et al. (11) searched databases (up to november 2013) to identify rcts focusing on the effect of onabotulinumtoxina for treatment of ndo. the authors included four studies in their analysis, which confirmed a dose-independent reduction of the number of urinary incontinence episodes per week, the increase of maximum cystometric capacity, and the reduction of maximum detrusor pressure compared to placebo. onabotulinumtoxina was more often associated with the onset of utis, hematuria and urinary retention. mehta et al. (12) retrieved 14 studies from 1980 to june 2012, demonstrating improvements of postvoid residual urine volume, reflex detrusor volume, bladder capacity, bladder compliance, and catheterization frequency (p < 0.01) after administration of botulinum toxin type a (btx-a). wu et al. (13) searched the literature up to may 2017 and included five rcts in their analysis. btx-a intra-detrusorial infiltrations reduced the number of urinary incontinence episodes per day and per week compared to placebo and increased maximum cystometric capacity and decreased maximum detrusor pressure at week 6. btx-a administration was more frequently associated with urinary tract infections. ni et al. (14) searched the literature up to june 2016 for papers reporting the outcomes of studies focusing on repeated btx-a injections in adult patients with ndo. they included 18 retrospective or prospective cohort studies, but no rct. the meta-analysis demonstrated that repeated btx-a injections allowed sustained improvements in patients with ndo, with a stable and low rate of adverse events. jo et al. (15) searched for rcts assessing the efficacy and safety of onabotulinumtoxina, administered in different injection sites, for treatment of oab. the authors included studies performed in adults treated for both neurogenic detrusor overactive bladder and idiopathic oab. trigone-including injections demonstrated more significant improvement in symptom score, higher complete dryness rates, and lower rates of incontinence episodes compared to trigone-sparing injections. moreover, lower detrusor pressure and higher volume at first desire to void were observed with trigoneincluding injection. we added three recently published studies assessing the effect of abobotulinumtoxina in patients with ndo on clean intermittent catheterization (49), comparing the performance of abobotulinumtoxina by 15 intra-detrusor injections with a 30-injection regimen (43), and describing the results of the administration of onabotulinumtoxina in japanese patients (47). abobotulinumtoxina showed its efficacy in treating patients with ndo compared to placebo even when the number of injections was reduced and the efficacy of onabotulinumtoxina was confirmed in an asian population. 503archivio italiano di urologia e andrologia 2022; 94, 4 treatment of overactive neurogenic bladder pelvic floor muscle training (pfmt) and non-invasive electrical stimulation a recent metanalysis addressed studies that evaluated pfmt in multiple sclerosis patients with luts in the period between 1990 and 2019. kajbafvala et al. (5) found that pfmt significantly reduced urinary incontinence episodes and neurogenic bladder symptoms measured according to oab-vs scores. according to the perfect scheme for assessment of pelvic floor muscle function, pfmt increased the overall endurance and power of the pelvic floor musculature. one metanalysis by vecchio and coworkers evaluated the effectiveness of peripheral tibial nerve stimulation (ptns) and pelvic floor muscle training (pfmt) for bladder dysfunction in ms, on the basis of data retrieved up to october 2021 (6). the authors found no significant differences in voided volume after pfmt. however, according to the perfect scheme assessed at 3 months, endurance and fast contraction of pelvic floor muscles were significantly improved (p = 0.002). papers on pfmt (without or with electrostimulation) in patients with ms which were retrieved in our review were also previously included in these reviews. we retrieved four additional studies reporting about pfmt in patients with pd (n = 2) or with post-stroke oab (n = 2). meta-analysis of two studies in patients with pd, showed that pfmt could improve oab symptoms in pd, though the number of episodes of incontinence was not significantly decreased. in men and women with post-stroke oab symptom scores, bladder diary parameters and pelvic floor function and strength were improved. gaziev et al. (7) reviewed the efficacy of ttns in the treatment of lower urinary tract dysfunction, including overactive bladder. the authors found that ttns was effective in 37-100% of patients with oab. four rcts were retrieved; importantly, these studies did not distinguish between neurogenic and idiopathic oab. the above cited metanalysis by vecchio et al. (6) showed significant improvements of daytime frequency, nocturia, urgency incontinence and voided volume after three months of ptns (p < 0.001) in patients with ms. a significant improvement in maximum cystometric capacity was also observed. our review added three studies evaluating the effect of ptns in patients with pd or post-stroke oab. quantitative analysis of two studies comparing ttns with sham treatment in patients with pd tentatively indicates that ttns is more effective than sham in decreasing the number of nocturia episodes. tens improved urinary symptoms also in patients with post-ischemic stroke by reducing urinary urgency and frequency. acupuncture and electroacupuncture also proved to be effective in patients with pd and in post-stroke patients. finally, transcutaneous electrical nerve stimulation (tens) was successfully used to treat post-stroke neurogenic oab. treatment improved voiding diary parameters and urodynamic findings and showed to be superior to anticholinergics. sacral neuromodulation a systematic review evaluated the results of studies on sacral neuromodulation (snm) in patients with neurogenic lower urinary tract dysfunction. data published between 1998 to march 2020 were retrieved. the review included retrospective or prospective clinical studies, cohort studies, and case reports. a meta-analysis of 21 studies demonstrated a 66.2% success rate of snm test stimulation; another meta-analysis of 24 studies reported a 84.2% success rate of permanent smn. loss of effectiveness, infection, pain at implant site, and lead migration were observed in 4.7%, 3.6%, 3.2%, and 3.2% of cases, respectively. the clinical effect of smn for neurogenic lower urinary tract dysfunction was comparable to the outcomes obtained in idiopathic populations. conclusions although all treatments have proven efficacy, there is no therapy that can be considered clearly superior to the others. in fact, the treatment of neurological bladder must be tailored to the individual patient, and often requires the combination of different forms of complementary treatment. combination of different pharmacological treatments, or associating pharmacological treatments and non-pharmacological treatments, can allow reduction of the dosage of drugs, thus minimizing the side effects which represent a limitation of their usage in therapy. a caveat: evidence from our quantitative analysis is fragmentary and does not allow to draw robust conclusions. our data are only provisional and should be considered with caution, due to the few studies included in metaanalysis and to the small number of patients included in each study. references 1. przydacz m, chlosta m, golabek t, chlosta p. population-based study of prevalence, bother and behavior related to treatment for lower urinary tract symptoms and overactive bladder among polish neurogenic patients. brain sci 2021; 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21:960-967. 86. rosa gm, ferrero s, nitti vw, et al. cardiovascular safety of β3adrenoceptor agonists for the treatment of patients with overactive bladder syndrome. eur urol. 2016; 69:311-323. correspondence rawa bapir dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar ahmed eliwa ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt herney andrés garcía-perdomo herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi, md ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey, md derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland vittorio magri, md vittorio.magri@virgilio.it asst nord milano, milan, italy panagiotis mourmouris, md thodoros13@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece adama ouattara, md adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobodioulasso, burkina faso gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio general hospital, 18536 piraeus, greece alberto trinchieri, md alberto.trinchieri@gmail.com urology school, university of milan, milan (italy) noor buchholz, md noor.buchholz@gmail.com sobeh's vascular and medical center, dubai health care city, dubai, united arab emirates stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 74 original paper introduction sexual dysfunctions (sd) are a broad spectrum of conditions such as decreased sexual desire, ejaculatory disorders, erectile dysfunction, orgasmic changes, painful intercourse, and insufficient vaginal lubrication (1-3). they are very common worldwide and have a negative impact on male and female quality of life (qol) (4). the etiopathogenesis of sd is multifactorial and it can be related to age, comorbidities, psychological or emotional state, hormonal imbalance, couple difficulties, and medical therapies (5). several studies reported the frequent association between sd and rheumatic diseases (rd) (6, 7). although many hypotheses have been proposed to explain this association, the exact mechanism is not identified yet. in patients with rheumatoid arthritis (ra), sd ranged from 31% to 76% of all cases (8). pain and depression seem to be the principal factors involved in sd in rheumatoid arthritis (9). vaginal discomfort or pain during intercourse occur in women affected by sjogren syndrome, systemic lupus erythematosus, and systemic sclerosis (10, 11). depression, pain, and fatigue can affect the sexual function of patients with fibromyalgia (12), premature ejaculation, erectile dysfunction and global sexual dysfunction in patients with ra (13, 14). a multidisciplinary approach to rheumatic diseases is therefore often mandatory. consequently, rheumatologists should know and introduction: sexual dysfunctions (sd) are frequently encountered in patients with rheumatologic diseases. in this scenario, a multidisciplinary approach to rheumatologic diseases is often mandatory. the aim of this survey was to assess whether italian rheumatologists routinely explore sexual health of their patients, their knowledge on the topic, and the barriers to discussing sd in clinical practice. methods: a 32-items anonymous questionnaire was mailed to members of the italian society of rheumatology (rheumatologists and residents in rheumatology training) in february 2023. the questionnaire aimed to determine attitudes, knowledge, and practice patterns regarding the discussion of sd with rheumatologic patients. a descriptive analysis of responses was performed. results: a total of 162 responses were received. overall, 50.0% of respondents occasionally asked patients about sd related to their rheumatologic pathologies, while 37.1% never did so. respondents declared that patients occasionally (82.3%) or never (16.1%) reported sd related to rheumatologic diseases. the main barriers to discussing sexual health were lack of time during medical examination (46.6%), patients’ discomfort (44.8%), and lack of knowledge/experience (39.7%). overall, 41.9% and 33.9% of respondents respectively totally and partially agreed that rheumatologists should routinely investigate patients' sexual health. most of the respondents (79.0%) thought that discussing sexual health problems could help patients cope with their rheumatologic diseases. of all respondents, 74.2% felt the need to broaden their personal knowledge about sd. finally, 45.9% and 34.4% of respondents respectively partially and totally agreed that training courses for rheumatologists could be helpful in the management of sexual health in rheumatological patients. conclusions: sd was not routinely discussed in rheumatology practice, still remaining a neglected issue. the most frequent explanations for the lack of attention toward sd were lack of time, patients’ discomfort, and lack of knowledge/experience. sexual dysfunctions of rheumatological patients are a neglected issue: results from a national survey of italian society of rheumatology luigi napolitano 1, ilenia pantano 2, lorenzo romano 1, luigi cirillo 1, celeste manfredi 3, francesco mastrangelo 1, giovanni maria fusco 1, daniele mauro 2, lorenzo spirito 3, roberto la rocca 1, davide arcaniolo 3, corrado aniello franzese 4, carmine sciorio 5, marco romano 6, marco de sio 3, vincenzo mirone 1, francesco ciccia 2 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 2 department of precision medicine, university of campania "luigi vanvitelli", naples, italy; 3 unit of urology, department of woman, child and general and specialized surgery, university of campania "luigi vanvitelli", naples, italy; 4 asl napoli 3 sud, naples, italy; 5 urology unit, ospedale alessandro manzoni, lecco, italy; 6 department of precision medicine and hepatogastroenterology unit, aou university luigi vanvitelli, naples, italy. doi: 10.4081/aiua.2023.11337 summary most of the respondents expressed the possible usefulness of attending sd courses to improve knowledge about these conditions. key words: sexual dysfunction; rheumatology; barrier; rheumatological disorders. submitted 26 march 2023; accepted 30 march 2023 archivio italiano di urologia e andrologia 2023; 95, 2 l. napolitano, i. pantano, l. romano, et al. 75 explore the sexuality of their patients for proper management, including referral to the appropriate health professionals (15). despite this, sexual counseling in patients with rd is a neglected issue nowadays. most of the evidence shows that it is also a neglected problem in other specialist fields such as cardiology, neurology and gastroenterology. several reasons such as lack of knowledge/training, lack of time during visits, and embarrassment have been reported (16-20). to the best of our knowledge, there are no study evaluating how the rheumatologists discuss and manage their patients' sexual problems. the aim of this survey was to assess whether italian rheumatologists routinely explore sexual health of their patients, their knowledge on the topic, and the barriers to discussing sd in clinical practice. materials and methods the questionnaire a national cross-sectional anonymous online questionnaire was sent to all members (specialists and residents) of italian society of rheumatology (sir) in february 2023. the questionnaire was designed by two authors (i.p. and l.r.) and structured according with questionnaires used in other studies after a literature review (11,15). a full professor of rheumatology (f.c.) was interviewed to analyze the survey, which was adjusted according to his feedback and comments. the questionnaire was designed using google forms (google llc, mountain view, ca, usa). a brief letter explaining the objectives of the study was sent with the questionnaire. all respondents had to fully complete the questionnaire before submission, since all questions were flagged as mandatory. after submission, users could not review neither amend their answers. reminder e-mails were sent to non-responders 1 and 2 months after the initial mailing. no incentives were offered for participation in the survey. the questionnaire comprised 30 questions focusing on: demographic data of respondents; frequency of discussing sexual health with patients during visit; rheumatologist’s level of knowledge on sexual dysfunction; rheumatologist’s level of knowledge on phosphodiesterase type 5 inhibitors (pde5is); perceived barriers to address sexual issues; knowledge about referring patients with sd. some questions had only one possible answer, others gave the possibility of multiple answers. a part of questions had multiple selectable options, others had an open answer. the questionnaire was detailed in supplementary table 1. given the nature of the study, it was not necessary to obtain ethics committee approval. all respondents consented to the publication of the collected data. a descriptive analysis of the results of survey was performed. categorical variables were presented as frequencies and percentages, continuous variables were reported as means and ranges. no normality test or power analysis was performed. results demographic data of respondents a total of 162 responses were received. overall, 50.0% of respondents were female, 48.4% male, and 1 subject did not declare gender (1.6%). age was mainly between 30 and 40 years old (56.4%). most of the respondents were rheumatologists (77.4%), while a minority consisted of rheumatology residents (22.6%). regarding the workplace, 62.9% of respondents worked in university hospitals, 17.2% in non-university hospitals, and 12.9% were self-employed. work experience was reported > 10 years by 51.6% of respondents. frequency of discussing sexual health with patients during visit overall, 50.0% of respondents occasionally asked patients about sd related to their rheumatologic pathologies, while 37.1% never did so. on the other hand, respondents declared that patients occasionally (82.3%) or never (16.1%) reported sd related to rheumatologic diseases. subjects reporting sd were mainly men < 50 years old (40.3%), men < 40 years old (35.5%), men whose age was between 40-50 years old (30.6%), and women < 40 years old (30.6%). men mainly complained about erectile dysfunction (57.4%) and loss of libido (27.9%). women mainly complained about sexual pain (including dyspareunia, vaginismus, and noncoital pain disorder). fibromyalgia was the rheumatologic disease most associated with sd (58.3%), followed by systemic sclerosis and dermatomyositis (21.7%) and sjogren syndrome (11.7%). management of sd and perceived barriers to discussing sexual health overall, 41.9% and 33.9% of respondents respectively totally and partially agreed that rheumatologists should routinely investigate patients' sexual health. most of the respondents (79.0%) thought that discussing sexual health problems could help patients cope with their rheumatologic diseases. related to this, 37.1% and 22.6% of respondents respectively totally and partially disagreed that discussing sexual health was only the responsibility of andrologists and gynecologists. besides, 37.7% and 29.9% of respondents respectively occasionally and often suggested patients to undergo an andrological/gynecological evaluation for sexual health problems. the main barriers to discussing sexual health were lack of time during medical examination (46.6%), patients’ discomfort (44.8%), and lack of knowledge/experience (39.7%) (figure 1). rheumatologist knowledge about sd and sexually impacting drugs of all respondents, 74.2% felt the need to broaden their personal knowledge about sd. besides, 43.5% believed that medicine courses lack sufficient knowledge about sexual health. finally, 45.9% and 34.4% of respondents respectively partially and totally agreed that training courses for rheumatologists could be helpful in the management of sexual health in rheumatological patients. overall, 71.0% of respondents said they were aware that some rheumatologic drugs have the potential to cause sd. the drugs most associated with sd were antidepressants (82.8%) and immunosuppressors (24.1%). moreover, 61.3% of respondents reported that patients occasionally relate sd to rheumatologic therapy, but 71.0% of physicians did not change therapy when sd were reported. of all respondents, 78.7% always referred to specialists in archivio italiano di urologia e andrologia 2023; 95, 2 76 rheumatologists and sexual dysfunction case of patients who need pharmacological treatment for sd. besides, 41.9% and 33.9% respectively reported that patients never or rarely used pde5is autonomously. finally, 88.5% of respondents were aware of pde5is inhibitors side effects that most of them (75.4%) identified only with flushing and headache. discussion sd have been reported to be common in rheumatologic patients and several risk factors as well as pain, fatigue, stiffness, disability, psychological state, hormonal imbalance, or side effects of medications can contribute to these conditions. there is no doubt that sexuality impacts on the qol, and represents a fundamental part of medical history, with a great significance in the lives of patients with rd. the reasons for sd are multifactorial and comprise diseaserelated factors, physiological factors, and therapy. despite this, sd in rheumatologic settings remains a neglected issue. this study represents the first italian nationwide survey to investigate the attitude, knowledge, practice, and barriers among rheumatologists in discussing sd in patients with rheumatologic disorders. we reported a gap between rheumatologists' attitudes and their daily practices regarding sd. indeed, although rheumatologists agreed with the importance of discussing sexual issues with their patients, they did not address it in their clinical practice. these data corroborated findings of previous published studies: 87.1% of rheumatologists addressed sd in their patients and 16.1% of patients did not refer to sd. in our recent publication about sd and gastroenterological disease, we reported that 71% of gastroenterologists never or infrequently addressed sd in patients with gastrointestinal disorders, and only 4% of patients refer their sd to their own gastroenterologist (20). similar results were reported by nicolai et al. and van ek et al. in cardiology and nephrology practice respectively (16, 21), while sobecki et al., reported that 63% of obstetrician and gynecologists routinely assess patients’ sexual activities but only 40% investigate their sd (22). insufficient time during visits (46.6%), followed by patients’ embarrassment (44.8%), and lack of training, are the most important reasons that contributed to not assess sd in the daily practice. on the contrary other healthcare professionals as well as gastroenterologists, cardiologists, nephrologists, neurologists, and neurosurgeons reported that the most important reasons are lack of knowledge and training, insufficient time during the visits and embarrassment (19). despite these, 34.4% of rheumatologists are conscious that a specific training in sexual medicine could be useful in sd treatments. these findings confirmed the data reported by romano et al. among gastroenterologists. adequate and standardized training should be mandatory to help healthcare in management of sd, in fact nowadays the lack of education represents a widespread problem for several healthcare. fibromyalgia represents the most frequent rheumatologic disorder (58.3%) related to sd (20). collado-mateo at al. reported a prevalence of 76% of sexual problems among women with fibromyalgia compared to 15% in healthy controls, in particular among those aged 50 or over (23). it is associated with menopause, psychiatric comorbidities, and high degree of musculoskeletal pain (24). one of the most important therapies in rd consist of antidepressants, that are notoriously related to sd (2526). our responders reported that antidepressants represent the most common drugs related to sd (82.8%), followed by immunosuppressive medication (24.1%). due to this, sometimes a multidisciplinary approach in sd is necessary (26-29). to the best of our knowledge, this is the first study focused on the behavior and knowledge of rheumatologists regarding the sd of their patients. however, our results should be read and interpretated according to several limitations, mainly including the small sample size, the use of a non-validated questionnaire, and the inclusion of a limited sample of respondents by country and age. future research is therefore needed to confirm and further our findings on the topic. in conclusion, sd is not routinely discussed in rheumatology practice, still remaining a neglected issue. the most frequent explanations are lack of time, patients’ discomfort, and lack of knowledge/experience. however, sexual health remains an essential issue in the lives of patients with rd, which should always be addressed by rheumatologists in order to start a correct counseling and an adequate multidisciplinary management. specific training on sd could be one of the most important steps to improve the practice of rheumatologists in this regard. figure 1. perceived barriers to discussing sexual health by rheumatologists. archivio italiano di urologia e andrologia 2023; 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95, 2 23 original paper accounts for approximately 75% of all bc lesions at initial presentation; this percentage is even greater in younger patients (< 40). the high prevalence of nmibuc can be attributed to its long-term survival and reduced risk of cancer-specific mortality compared to muscle-invasive (t2-4 stages) tumors (1). these tumors are restricted to the mucosa (ta, cis) or submucosa (t1), and are treated by trans-urethral resection. although trans-urethral resection of bladder tumors (turbt) by itself can totally remove ta/t1 lesions, they frequently recur and can progress to mibc. the recurrence rate of such tumors is 50 to 70%. as a result, all patients should be considered for adjuvant intravesical instillation (ivi) therapy and surveillance, based on their risk stratification (2). the most important step in the management of nmibuc is the transurethral resection procedure. this procedure is crucial for the complete removal of all visible/suspicious lesions and for proper grading and staging by sampling of detrusor muscle; thus, determining the next appropriate treatment (2). because of the high risk of recurrence and progression following primary resection, adjuvant therapy and long-term surveillance should be considered in all patients (3). there is evidence that treatment with bacillus calmette-guérin immunotherapy following primary resection can lower cancer recurrence rates and progression to more advanced stages (4). c-erbb-2 is a tyrosine kinase transmembrane protein that is related to epidermal growth factor receptor (egfr) family and it is known as her2/neu (human epidermal growth factor receptor-2). its expression in urinary bladder transitional cell carcinoma has been described, and it has been proposed that its expression increases with tumor grade and recurrence of urothelial cancer. bladder urothelial carcinomas with c-erbb-2 expression have poor prognosis, hence background: transurethral resection (tur) followed by adjuvant therapy is still the treatment of choice of non-muscle-invasive bladder urothelial carcinoma (nmibuc). however, recurrence is one of the most troublesome features of these lesions. early second resection and adjuvant bcg therapy has been shown to improve the outcome. objective: to evaluate the prognostic value of c-erbb-2 (her2/neu) expression status in non-muscle-invasive bladder urothelial carcinoma cases, before and after intravesical bacillus calmette guerin (bcg immunotherapy). materials and methods: her2/neu expression was studied in 120 (ta-t1) non-muscle-invasive urothelial carcinoma cases. the expression was evaluated and compared to the expression after bacillus calmette guerin (bcg) immunotherapy. results: her2/neu expression in low and high grade of the nonmuscle-invasive urothelial carcinoma was (38%) and (83%) respectively. the difference of the expression rates by tumor grade was statistically significant. in recurring lesions post bcg therapy, c-erbb-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). conclusions: the her2/neu expression increased as the tumor grade rose. the reduction in expression following bcg treatment in non-invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor. key words: transurethral resection; non-muscle-invasive urothelial carcinoma; c-erbb-2; bacillus calmette guerin; immunohistochemistry. submitted 14 march 2023; accepted 1 april 2023 introduction non-muscle-invasive bladder urothelial carcinoma (nmibuc) is the most common type of urinary bladder carcinoma. it her2/neu expression status of post bcg recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones mohamed yousef ali 1, ahmed yousef aboelsaad 2, ahmed m. abdel gawad 2, tamer a. abouelgreed 3, ahmed a. el gammal 3, osama m. ghoneimy 3, eman m. el-dydamony 3, ahmed a. alrefaey 4, eslam mohamed 5, sherif azzam 5, ayman abdelmohaymen 6, yasien mohammed 1, mohammed s. abdelwahed 1, 7, ahmed fawzi a. elsayed 2, basem a. fathi 3, nosaiba m. abd alrahim 8, abeer s. farag 9, alaa r. mahmoud 10, hasan ismail mohamed 4, seth horsu 11, abdulkarim hasan 1 1 pathology department, faculty of medicine, al-azhar university, cairo, egypt; 2 urology department, damietta faculty of medicine, al-azhar university, damietta, egypt; 3 urology department, faculty of medicine for girls, al-azhar university, cairo, egypt; 4 urology department, faculty of medicine, al-azhar university, cairo, egypt; 5 clinical oncology department, faculty of medicine, al-azhar university, cairo, egypt; 6 surgical oncology department, faculty of medicine, al-azhar university, cairo, egypt; 7 pathology department, faculty of medicine, university of jeddah, jeddah, saudi arabia; 8 clinical pathology department, faculty of medicine for girls, al-azhar university, cairo, egypt; 9 pathology department, faculty of medicine for girls, al-azhar university, cairo, egypt; 10 urology department, faculty of medicine, al-azhar university, assiut, egypt; 11 histopathology department, st. vincent’s university hospital, dublin, ireland. doi: 10.4081/aiua.2023.11313 summary archivio italiano di urologia e andrologia 2023; 95, 2 m. yousef ali, a. yousef aboelsaad, a.m. abdel gawad, et al. 24 it can be used as a prognostic clinical biomarker (5). the goal of this study is to evaluate the c-erbb-2 (her2/neu) immunostaining status in non-muscle-invasive bladder urothelial carcinoma cases, before and after intravesical bacillus calmette guerin (bcg) immunotherapy. patients and methods this work was conducted at our institution over the period between march 2016 to february 2020. it included 120 cases (86 men and 34 women; mean age 52.3 ± 11.4, range 41-70 years) with recurrent urothelial tumors confined to the bladder. all patients had a history of transurethral resection of bladder tumor (turbt) and full dose bcg therapy for primary nmibuc lesions. before removal of the tumor, each patient had a history taken, physical examination, urinalysis, an ultrasound scan (uss), and ct scan. turbt was performed under classical white light using the 26-fr. continuous-flow karl storz resectoscope with distilled water for irrigation. the aim of resection was complete removal of all visible/suspicious lesions and their underlying muscularis propria. the tumor and its related underlying muscle were sent separately labelled for histopathologic assessment. tumors were staged and graded according to the who/isup classification 2016 with external consultation when indicated. we selected patients who had nmibuc (ta-t1) without carcinoma in situ (cis) after pathological examination. a second look cystoscopy was then performed after 2 weeks of the initial resection to ensure no residual lesion. patients were then followed up for intravesical instillation (ivi) of bcg. bcg was instilled for six consecutive weeks, as an induction dose, starting 15-21 days after turbt to enable surface urothelium to recover (6). two weeks after the last instillation, surveillance cystoscopy was carried out, with random cold-cup biopsies taken from the ex-tumor site and its vicinity, as well as from other regions of the bladder, to detect recurrence. the emergence of histopathologically confirmed urothelial tumor in the bladder, regardless of stage, was characterized as recurrence. since the biopsies were negative, our patients received a maintenance dose of bcg (3-weekly instillations, given at 3, 6, 12, 18, 24, 30 and 36 months). histopathology prepared h&e slides were analyzed and examined microscopically by the histopathologists to confirm the diagnosis according to the diagnostic criteria defined by the latest who/isup classification 2016. immunohistochemistry her2/neu immunostaining an automatic immunohistochemical staining device (benchmark xt; ventana medical system, tucson, arizona, usa) was used to stain formalinfixed paraffin-embedded tissue sections, according to the manufacturer's instructions. briefly, 5-mm-thick sections were cut on poly-llysine-coated adhesive slides and dried for 30 minutes at 62°c. after epitope retrieval by standard heat treatment for 30 minutes in ethylene diamine tetra acetic acid (ph 8.0) in an autostainer, the samples were incubated with mouse polyclonal antibodies to c-erbb-2 (dilution1: 500, clonea0485; labvision/neomarker, fremont, california, usa). the slices were then counterstained with harris hematoxylin after being treated with biotinylated anti mouse immunoglobulins, peroxidase-labeled streptavidin (lsab kit; labvision), and 3.30-diaminobenzidine. breast cancer slices fixed in paraffin were used as positive controls. membrane staining was assessed. this step was evaluated independently and jointly by the histopathologists. her2/neu expression the percentage of stained cells and intensity of staining were ranged from 0 to 3+, as follows: no staining (0), low intensity and incomplete membrane staining in less than 10% of cells (1+), low intensity and full membrane staining in more than 10% of cells (2+), and high intensity and total membrane staining in more than 10% of cells (3+). tumors with scores 0 and 1+ were considered to be negative, while those with scores 2+ and 3+ were considered positive (7). statistical analysis the collected data were arranged, tabulated, and statistically analyzed using spss software statistical computer package version 16 (spss inc., chicago, illinois, usa). student's t-test was used to evaluate the difference between two means. the mann-whiney test was used to compare two different groups, while the wilcoxon signed rank test was used to compare two related groups. the threshold for significance was set at less than 0.05. results the 120 included patients had nmibuc lesions, with a tumor size of 8-20 mm. the lesions were detected by uss in 58 patients and by ct in the remaining 62 patients. immunohistochemical findings c-erbb-2 expression was found in 77 of 120 primary nmibuc cases (64.16%) (table 1) with expression ranging from weak (score 2 +) in 29 cases to strong (score 3 +) in 48 cases (figures 1 and 2). when the score and tumor grade were compared, it was observed that c-erbb-2 was expressed in 19 out of 50 in low-grade cases (38%). in high grade cases, c-erbb-2 was expressed in 58 out of 70 instances (83%), with expression ranging from weak (score 2 +) in 19 cases to strong expression (score 3 +) in 39 cases. c-erbb-2 expression in high grade urothelial table 1. c-erbb-2 expression in of the primary nmibc lesions. groups no c-erbb-2 expression -ve +ve no (%) total/no (%) 0 +1 +2 +3 non-invasive urothelial carcinoma low grade 50 21 10 10 9 19/50 (38%) 77/120 (64.2%) high grade 70 12 0 19 39 58/70 (83%) p value < 0.05 mann-whitney test used. bcg, bacillus calmette guerin. archivio italiano di urologia e andrologia 2023; 95, 2 25 her2/neu expression after bcg for bladder carcinomas carcinoma was significantly higher when compared to low grade one (p < 0.05). hence, with increasing tumor grade, there was a statistically significant rise in c-erbb-2 expression. c-erbb-2 was found in 38 out of 120 cases (31.6%) of recurring lesions post bcg therapy with expression ranging from weak (score 2 +) in 28 cases to strong (score 3 +) in 10 cases. interestingly, its expression was found only in 8 only out of 50 low grade (16%), and in 30 out of 70 high grade (42.9%) recurring lesions. this drop in c-erbb-2 expression in recurring cases after bcg therapy was statistically significant (p < 0.005) when compared to its expression in the same group before therapy. discussion histologically, 90% of bladder cancer lesions are of urothelial origin. at the time of diagnosis, 20-25% of these lesions are muscle-invasive (staget2 or higher); the rest are nonmuscle-invasive, previously called superficial bladder cancer. only (8-12%) of all nmibc tumors may progress to muscle-invasive bladder urothelial carcinoma (mibuc) (8). the commonly employed scoring systems for initial risk stratification of nmibuc lesions and for prediction of their risk of recurrence and progression after ivi of bcg, are based on clinicopathologic factors: age, gender, tumor (number, diameter, grade, and staging), prior recurrence status, and concurrent cis (9). aside from these clinicpathologic criteria, it would be advantageous if biological markers could contribute in the risk categorization of nmibuc lesions and in predicting their risk of recurrence and progression after ivi therapy. molecular biomarkers such as fgfr3, p53, p63 and epidermal growth factors, and their prognostic role have been investigated in many studies (10, 11, 12). according to the latest eau guidelines, the role of these biomarkers in the current era of personalized cancer management is promising, especially in the patients' categorization based on molecular classification (2). regrettably, existing evidence is still inconclusive, and these biomarkers are not yet ready for routine use in clinical practice (13). c-erbb-2 is a tyrosine kinase receptor that belongs to the epidermal growth factor receptor family. it regulates the cell cycle and promotes cell growth. c-erbb-2-positivity rates have been found to vary between populations in studies. the majority of c-erbb-2 expression investigations in bladder cancer have been conducted on mibc, with expression ranging from 9% to 81% (14). another tyrosine kinase dysregulation of axl receptor and its ligand growth arrest specific gene was also studied in urinary bladder carcinoma and showed a close relation to tumor stage and tumor grade, but still further figure 1. non-muscle-invasive bladder urothelial carcinoma (nmibuc) limited to lamina propria (low grade t1) (a) h&e x200, (b) positive (score +2) for c-erbb-2 (membranous) 200, (c) the same cases after b.c.g therapy negative for c-erbb-2 (score zero) x 200. figure 2. non-muscle-invasive bladder urothelial carcinoma (nmibuc) limited to lamina propria (high grade t1) (a) h&e x200, (b) strong positive (score + 3) for c-erbb-2 (membranous) x 100, (c) the same cases after b.c.g therapy negative for c-erbb-2 (score 1) x 100. a b c a b c archivio italiano di urologia e andrologia 2023; 95, 2 m. yousef ali, a. yousef aboelsaad, a.m. abdel gawad, et al. 26 studies are recommended to assess its role in tumor prognosis (15, 16). however, there are few reports of c-erbb-2 status in nmibuc. c-erbb-2 protein overexpression has been found in 4-13% of nmibucs in a few studies (12, 17). in the current study, we investigated the immunohistochemistry expression of c-erbb-2 in 120 patients with recurrent nmibuc, comparing it with the expression of their primary lesions. we found that c-erbb-2 expression was seen in 64.16% (77 cases) of the primary tumors and there was a significant relationship between c-erbb-2 expression, in both recurrent and initial lesions, with tumor grade. there is a statistically significant increase in c-erbb-2 expression as tumor grade rises. these results were in line with those of hegazy et al. in 2015 and agrawal et al. in 2020 (10, 12), who found a relation between greater tumor grade and increased c-erbb-2 expression. bcg immunotherapy post turbt remains the most effective treatment for reducing the risk of nmibuc recurrence and progression. patients with recurrent nmibuc (with or without cis) are frequently administered adjuvant intravesical bcg (18). according to hegazya et al. and morgan et al. (10, 19), bcg adjuvant therapy for nmibuc lowered the incidence of c-erbb-2 expression with favorable outcomes. in our research, we observed a significant drop in c-erbb-2 expression in recurrent lesions (38/120) when compared to their primary ones (77/120) (p < 0.05). overall, an accurate assessment of c-erbb-2 status is recommended in nmibuc lesions for proper patient selection to bcg therapy. in primary lesions, the c-erbb-2 immunoreactivity should be assessed before initiation of bcg immunotherapy. if there is recurrence, the c-erbb-2 expression of the recurring lesion should be performed and compared with the primary one. in case of down expression, one can consider adjuvant bcg therapy. future studies, particularly ongoing c-erbb-2 targeted therapy trials, will undoubtedly shed further light on the significance of c-erbb-2 in bladder cancer management and treatment. however, bcg production has shown its limits, with recent worldwide bcg shortage (20). conclusions this study contributes to our understanding of c-erbb-2 expression in urothelial carcinoma. it supports the role of c-erbb-2 immunostaining in nmibuc lesions since the expression increased with increase tumor grade. our findings also suggest the importance of bcg therapy in the treatment of these cases although further studies on the role of this marker in recurrent lesions are highly recommended. ethical approval: provided from damietta faculty of medicine under id number: dfm-irb-00012367 23-03003. references 1. compérat e, larré s, roupret m, et al. clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. virchows arch. 2015; 466:589. 2. babjuk m, burger m, compérat em, et al. european association of urology guidelines on non-muscle-invasive urothelial carcinoma of the bladder (tat1 and carcinoma in situ) 2019 update. eur urol. 2019; 76:639-657. 3. de goeij l, westhoff e, witjes ja, et al. the urolife study: protocol for a dutch prospective cohort on lifestyle habits in relation to non-muscle-invasive bladder cancer prognosis and health-related quality of life. bmj open. 2019; 9:e030396. 4. malmström pu, sylvester rj, crawford de, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non-muscle-invasive bladder cancer. eur urol. 2009; 56:247-256. 5. zhao j, xu w, zhang z, et al. prognostic role of her2 expression in bladder cancer: a systematic review and meta-analysis. int urol nephrol. 2015; 47:87-94. 6. babjuk m, burger m, compérat e. eau guidelines on non-muscle-invasive bladder cancer. arnhem, the netherlands: european association of urology; 2022. https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/ 7. ramezani m, siami, s, rezaei m, et al. immunohistochemical study of c-erbb2/her2 tumor marker in primary malignant brain tumors. preprints.org 2018, 2018120017. https://doi.org/10.20944/ preprints 201812.0017.v1. 8. ali my, el-esawy bh. her2/neu expression in urothelial dysplasia, carcinoma in situ, and superficial urothelial carcinoma and its value in assessing the response to bcg therapy. egyptian journal of pathology. 2014; 34:25-31. 9. remy e, rebouissou s, chaouiya c, et al. a modeling approach to explain mutually exclusive and co-occurring genetic alterations in bladder tumorigenesis mathematical model of bladder tumorigenesis. cancer res. 2015; 75:4042-4052. 10. hegazy r, kamel m, salem ea, et al. the prognostic significance of p53, p63 and her2 expression in nonmuscleinvasive bladder cancer in relation to treatment with bacille calmette-guerin. arab j urol. 2015; 13:225-230. 11. kumar s, prajapati o, vaiphei k, et al. human epidermal growth factor receptor 2/neu overexpression in urothelial carcinoma of the bladder and its prognostic significance: is it worth hype? south asian j cancer. 2015; 4:115-117. 12. agrawal v, bharti n, pandey r. human epidermal growth factor receptor 2 (her2) gene amplification in non-muscle invasive urothelial bladder cancers: identification of patients for targeted therapy. arab journal of urology. 2020; 18:267-72. 13. eriksson p, rovira c, liedberg f, et al. a validation and extended description of the lund taxonomy for urothelial carcinoma using the tcga cohort. sci rep. 2018; 8:1-2. 14. bellmunt j, werner l, bamias a, et al. her2 as a target in invasive urothelial carcinoma. cancer med. 2015; 4:844-852. 15. akgül m, baykan ö, çağman z, et al. gas6 expression and tyrosine kinase axl sky receptors: their relation with tumor stage and grade in patients with bladder cancer. arch ital urol androl. 2021; 93:148-152. 16. mitrakas l, gravas s, karasavvidou f, et al. endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer. arch ital urol androl. 2021; 93:143-147. 17. lim sd, cho ym, choi gs, et al. clinical significance of substaging and her2 expression in papillary non-muscle invasive urothelial cancers of the urinary bladder. j korean med sci. 2015; 30:1068-1077. archivio italiano di urologia e andrologia 2023; 95, 2 27 her2/neu expression after bcg for bladder carcinomas 19. morgan be, salup r, morgan mb. differential c-erbb-2 and vegf expression following bcg immunotherapy in superficial papillary transitional cell carcinoma of the bladder. urol oncol. 2002; 7:67-72. 20. trigo s, gonzalez k, di matteo l, et al. bacillus calmette-guerin vaccine and bladder cancer incidence: scoping literature review and preliminary analysis. arch ital urol androl. 2021; 93:1-8. correspondence mohamed yousef ali, md mohamedyousef79@gmail.com abdulkarim hasan, md (corresponding author) abdulkarim.hasan@azhar.edu.eg pathology department, faculty of medicine, al-azhar university, 11884 cairo, egypt telephone &amp; fax: 0020224012932 conflict of interest: the authors declare no potential conflict of interest. 18. sylvester rj, brausi ma, kirkels wj, et al. long-term efficacy results of eortc genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus calmette-guerin, and bacillus calmette-guerin plus isoniazid in patients with intermediate-and high-risk stage ta t1 urothelial carcinoma of the bladder. eur urol. 2010; 57:766-773. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3262 original paper no conflict of interest declared. the bricker ureteral implantation in an end-to-side fashion using running sutures (7). according to the literature, the ureteroileal stricture (uis) rate using this technique ranges between 3%-20% (7-10). a frequently used anastomotic technique in urinary diversions is that described by wallace, in which the end of the intestine is sutured to the end of the ureter (11). it is already known that this technique has the lowest complication rate comparing to other ureterointestinal anastomosis (12), including its usage in orthotopic bladder reservoirs (13, 14). nevertheless, only a few studies favour this technique in orthotopic neobladder (5, 6, 15). the objective of this study was to establish the reliability of technique selection strategy for ureteroileal anastomosis, based upon patients characteristics; additionally, we aimed to compare perioperative outcomes and ureteroileal anastomotic stricture rate in a contemporary series of patients who underwent open rc followed by reconstruction of modified hautmann neobladder. materials and methods study design and patients we compared 30 matched paired patients who underwent hautmann neobladder with single chimney and bricker anastomotic technique (2, 3) with 30 matched paired patients who underwent hautmann neobladder with chimney modification consisting of a longer ureteral spatulation (3-4 cm) combined with end-to-end ureteroileal anastomosis (wallace type i) and 6-8 cm long isoperistaltic tubularised chimney (16). long-term results, including uretero-ileal stenosis (uis) and postoperative complications rate (graded according to clavien-dindo system) at 2-year follow-up, were available for analysis. the main differences between techniques were the length of the ureteral spatulation, the chimney size and the endto-end running suture ureteroileal anastomosis (figure 1). patient characteristics included three aspects: ureteral length after retro-sigmoidal tunneling, chimney size and diameter of distal ureter after dissection and preparation for anastomosis. when the ureteral length was similar on objective: we aimed to establish the reliability of technique selection strategy for ureteroileal anastomosis (bricker vs. wallace) by comparing perioperative outcomes, complications, and anastomotic stricture rate in a contemporary series of patients who underwent open radical cystectomy followed by reconstruction of modified hautmann neobladder. materials and methods: a total of 60 patients underwent radical cystectomy and modified hautmann neobladder, of whom 30 patients (group i) with bricker anastomotic technique were compared to 30 matched paired patients with end-to-end ureteroileal anastomosis (group ii). long-term results, including ureteroileal stricture (uis) and postoperative complication rate at two year follow up were available. the choice of anastomosis type was successively based on chimney size, ureteral length after retro-sigmoidal tunneling and diameter of distal ureter. postoperative complications were graded according to the clavien-dindo system. results: ureteroileal stricture rate was 6.6% in group i vs. 0% in group ii, after three months (p < 0.05), while anastomotic leakage rate was 6.6% vs. 3.3% (group i vs group ii) between the two groups for the same follow up period (p > 0.05). high-grade complications (clavien iii-v) were more in bricker group as compared to wallace group and the difference was significant (20% vs 10.3%, p = 0.03). conclusion: our preliminary outcomes demonstrate that this selection strategy seems to be clinically reliable, with lower incidence of postoperative complications in wallace group. key words: orthotopic bladder substitution; urinary diversion; reconstructive urology; selection strategy; surgical technique. submitted 25 may 2021; accepted 25 june 2021 introduction in both male and female patients, orthotopic bladder substitution has become the preferred method of urinary diversion post radical cystectomy (rc) for malignant disease (1). among different reconstructive modalities, ileal neobladder with hautmann or studer reservoir is a frequent orthotopic diversion and several modified techniques have been described (2-6). the standard technique for uretero-enteric anastomosis is technique selection of ureteroileal anastomosis in hautmann ileal neobladder with chimney modification: reliability of patient-based selection strategy and its impact on ureteroentric stricture rate dejan djordjevic 1, svetomir dragicevic 1, marko vukovic 2 1 urology clinic, euromedik general hospital, belgrade, serbia; ² urology clinic, clinical centre of montenegro, podgorica, montenegro. doi: 10.4081/aiua.2021.3.262 summary 263archivio italiano di urologia e andrologia 2021; 93, 3 technique selection for ureteroileal anastomosis in orthotopic diversion both sides, wallace was preferred; when disparate, bricker was performed (12, 17). moreover, if the ureters were transected at the level of common iliac vessels [diffuse carcinoma in situ (cis)], chimney length was 10-12 cm and bricker anastomosis was performed (2, 3); if ureters were divided more distally, as close to the bladder as possible, wallace anastomosis on 6-8 cm long chimney was preferred (16). the third decision was based on the diameter of distal ureteral end, after the ureter has been divided and prepared for anastomosis. when distal ureteral end was more than double size of normal diameter (long-standing hydronephrosis), wallace was preferred. if distal end was of a normal caliber, the choice of anastomotic technique was based upon other two variables. the inclusion and exclusion criteria are presented in the patient flowchart (figure 2). bladder cancer (bca) patients scheduled for definitive treatment were recruited from the urology clinic at the clinical centre of serbia. the surgical protocol had been approved by the university of belgrade institutional review board and registered with the ethical committee of clinical centre of serbia and conducted in accordance with the principles of the declaration of helsinki from the world medical association. the surgery comprised rc with standard pelvic lymph node dissection (plnd), which was followed by reconstruction of hautmann neobladder with chimney modification. eligible patients were aged ≥ 30 yr and had bca clinical stage t2-t3/n0/m0. patients were excluded if they had previous pelvic radiation, clinical stage t4 or n1-n3/m1, positive frozen-section urethral biopsy, extensive prior abdominal surgery, serum creatinine level of > 2.0 ng/ml and any history of upper urinary tract malignancy (4). complications were reported according to the modified clavien-dindo classification system (18). reservoir-related complications included obstructive or non-obstructive hydronephrosis, uis, pyelonephritis, anastomotic leakage, metabolic acidosis and vesicoureteral reflux (vur). uis was diagnosed when there was evidence of obstruction on imaging (symptomatic hydronephrosis), worsening renal function or infection (18). non-obstructive hydronephrosis was defined as a distended intrarenal collecting system on imaging without evidence of uis or other mechanical obstruction and was confirmed by intravenous urography (ivu) or computed tomography (ct). of note, pyelonephritis was designated as a positive urine culture in association with foul smelling urine and fever (19). perioperative outcomes were systematically and prospectively collected at surgery and during hospitalization and each complication classified as early (< 3 months) or late (> 3 months after surgery). patient interviews were conducted by medical doctors and according to european association of urology (eau) guidelines on reporting and grading of complications (20). in this study we aimed to establish an optimal technique selection strategy for ureteroenteric anastomosis (bricker vs. wallace) based on patient characteristics and evaluated according to difference in early and late perioperative complications and postoperative healthrelated quality of life (hrqol). outcomes measures and follow up postoperatively, all patients were placed on the identical treatment pathway and follow-ups were scheduled every 3-4 months during the first year and semi-annually in the second (19). renal function was measured by serum creatinine, hydronephrosis was examined by abdominal ultrasound or computed tomography, and vur was assessed by voiding cystography (6). diagnostic imaging (kidney ultrasound, ct abdomen/pelvis and chest radiography) was performed annually or when clinically indicated. abdominal ultrasound (us) was performed immediately before discharge of patients to deterfigure 1. differences between two techniques: a) modified hautmann neobladder with long chimney and bricker ureteroileal anastomosis (group i); b) our modified technique with short afferent limb, similar ureteral length on both sides and wallace anastomotic type (group ii). figure 2. patient flowchart describes selection criteria for surgical approach. a. b. archivio italiano di urologia e andrologia 2021; 93, 3 d. djordjevic, s. dragicevic, m. vukovic 264 mine the pouch capacity and post voiding residue (pvr). the acidosis was monitored using the base excess by venous blood gas analysis, initially every three days followed by weekly, depending on the blood gas values. the european organization for the research and treatment of cancer (eortc) quality-of-life core questionnaire (qlq-c30) version 3 was used to measure hrqol (21, 22). continence rates and time intervals between clear intermittent catheterizations (cics) obtained at the end of 2-year follow up were recorded. cic was recommended for patients with a postvoid residual volume (pvr) of >150 ml. statistical analysis statistical analysis was performed with spps v16.0 (spps, chicago, il, usa). blood loss, operative time, and time to discharge (hospital stay) were assessed as continuous variables and tested for normality using the kolmogorov test. the student t test and mann whitney u test were used to determine statistical significance. the difference between obtained values was considered significant when p < 0.05. descriptive statistics such as mean (sd) values and percentages, generated with spss, were also included. results clinicopathological features and perioperative outcomes are summarized in table 1. the two groups were similar for gender, age, asa class and bmi. all patients had transitional cell carcinoma and the tumor stage ranged from t2 to t3 n0-3/m0. the followup time for the entire cohort was 2 years. the mean operative time was 270 ± 42.3 min and 240 ± 33.6 min in the first and second group respectively (p = 0.3). the distribution of postoperative complications is shown in table 2. a total of 135 complications were recorded in 40/60 (66.6%) patients. 105 complications (77.7%) occurred in the first 90 days, with the remaining 30 complications (22.2%) occurring between 90 days and one year postoperatively. the majority of complications (44/60, 73.3%) were classified as low-grade with 41.6% in grade i and 31.6% in grade ii. high-grade (claviendindo grade iii-v) complications were seen in 10/60 (16.6%) patients. grade iii, iv and v complications were observed in 11.6%, 1.6% and 3.3% of the patients, respectively (table 3). the overall mortality rate was 3.3% (2/60). high-grade complications were less in wallace group as compared to bricker group, and the difference was significant (3/30, 10% vs. 6/30, 20%, p = 0.03). following 3 months, hydronephrosis was observed in eight patients (26.6%) in group i and six (20%) in group ii, (p = 0.2) (grade i-iii clavien). consequent to hydronephrosis, uis was seen in two ureters (6.6%) in group i but none in group ii (grade iii clavien). moreover, one out of two patients with uis required surgical treatment (grade iiib clavien). these differences were statistically significant (p = 0.0063). additionally, the anastomotic leakage rate was higher in the first group, although not significantly (6.6% vs. 3.3%, p = 0.06) (grade i/iiia clavien). table 1. clinicopathological features and perioperative outcomes between group i and ii. mean (sd)/percentage (%) clinicopathological characteristics group i (n = 30) group ii (n = 30) p value age (years) 63 (7.2) 68 (6.6) 0.6 bmi, kg/m², mean (sd) 27.2 (2.6) 26.1 (3.2) 0.8 male, n (%) 22 (73.3) 24 (80.0) 0.2 female, n (%) 8 (26.6) 6 (20) 0.1 asa score, n (%) 2 17 (56.6) 18 (62) 0.3 ≥ 3 13 (43.3) 11 (38) 0.09 pathologic stage, n (%) t2 23 (76.6) 25 (83.3) 0.1 t3 7 (23.4) * 4 (13.3) 0.03 lnp patients, n (%) 4 (13.3) 5 (16.6) 0.7 operative time (min), sd 270 (42.3) 240 (33.6) 0.3 estimated blood loss (ml), sd 340 (150) 400 (210) 0.06 hospital stay (days), sd 18 (4.6) 19 (3.4) 0.6 transfusion rate, n (%) 7 (23.3) 5 (16.6) 0.08 * statistically significant difference between two groups (p < 0.05). bmi: body mass index; asa: american society of anaesthesiologists; lpn: lymph node positive. table 2. postoperative complications of 60 patients with muscle invasive bladder cancer who underwent radical cystectomy and modified hautmann neobladder with bricker (group i) or wallace (group ii) ureteroileal anastomosis. mean (sd)/percentage (%) clinicopathological characteristics group i (n = 30) group ii (n = 30) p value early late early late paralitic ileus, n (%) 8 (26.6) 0 9 (30) 0 0.7 wound infections, n (%) 2 (6.6) 1 (3.3) 1 (3.3) 3 (10) 0.4 blood transfusions for anemia, n (%) 9 (30) 0 10 (33.3) 0 0.5 pelvic hematoma, n (%) 2 (6.6) 0 1 (3.3) 0 0.1 lymphorrhea, n (%) 6 (20) 1 (3.3) 4 (13.3) 2 (6.6) 0.08 pneumonia, n (%) 0 4 (13.3) 1 (3.3) 3 (10) 0.1 reservoir related complications early late early late renal insufficiency, n (%) 0 1 (3.3) 0 0 0.07 vesicoureteral reflux (vur), n (%) 4 (13.3) 3 (10) * 3 (10) 1 (3.3) 0.03 grade i 2 2 2 1 grade ii 1 1 1 0 grade iii 1 0 0 0 grade iv 0 0 0 0 hydronephrosis, n (%) 8 (26.6) 1 (3.3) 6 (20) 3 (10) * 0.02 unilateral 8 1 0 2 bilateral 0 0 6 2 pyelonephritis, n (%) 4 (13.3) 0 5 (16.6) 0 0.4 i.v antibiotics only 1 0 2 0 oral antibiotics only 3 0 3 0 anastomotic leakage rate, n (%) 2 (6.6) 0 1 (3.3) 0 0.09 anastomotic stricture rate (uis), n (%) 2 (6.6) * 1 (3.3) 0 0 0.04 metabolic acidosis, n (%) 6 (20) 1 (3.3) 5 (16.6) 2 (6.6) * 0.04 * statistically significant difference between two groups (p < 0.05). 265archivio italiano di urologia e andrologia 2021; 93, 3 technique selection for ureteroileal anastomosis in orthotopic diversion nine patients (15%) required interventions under general or local anesthesia for the management of high-grade (≥ iii) complications. four patients from the first group required invasive treatment of early reservoir-related complications (13.3%), which was significantly higher compared to the wallace group (3.3%; p = 0.01). three patients underwent percutaneous nephrostomy for ureteroileal anastomotic stricture or anastomotic leak in both groups, whereas two patients from the first group had percutaneous drainage for lymphocele or pelvic collection. only one patient from the bricker group developed local tumor recurrence (3.3%) (grade iiia), which was treated endoscopically (table 3). neoadjuvant chemotherapy was performed in 16 patients (27.1%), while adjuvant treatment received only one examinee (1.7%). at the end of the 2-year follow-up, two patients with vur in group i had improved after cics (grade i clavien). in addition, five out of six patients with hydronephrosis had improved with or without treatment. however, one case with uis related unilateral hydronephrosis resulted in a non-functional kidney despite the treatment for the stricture (grade iv clavien). serum creatinine was less than 1.4 mg/dl preoperatively in all patients and it remained within the normal ranges, during the follow-up in both groups, except in the patient with kidney failure. complete daytime continence at one year was achieved in 28 patients (93.3%) in the first group and 26 patients (89.6%) in the second group, with no statistical differences however (p > 0.05). complete night time continence was achieved in 24 (80%) and 25 patients (86.2%), respectively (p > 0.05). patient self-rated emotional and social functional scales were similar between groups. discussion the first description of hautmann neobladder with chimney modification was published by lipper and theodorescu (2) consisting of a 5-10 cm isoperistaltic chimney with an end-to-side ureteroileal anastomosis. the study included three patients with short follow-up; no postoperative complications were reported, demonstrating that the technique employed was a promising modification to the original hautmann neobladder. in 2000, a more comprehensive study was performed on 50 patients with invasive bca (3), using 8-12 cm tubularised isoperistaltic ileal chimney. this technique proved to be safe and feasible, easy to perform and created a reliable ureterointestinal anastomosis (bricker) without tension, which resulted in a relatively low uis rate (6%). on the other hand, hautmann et al. (23) reported that freely refluxing wallace anastomosis to the afferent limb of the orthotopic reservoir has the lowest non-tumor related anastomotic stricture rate (5.4% compared to 16.3% using bricker technique). furthermore, kouba et al. (12) revealed a statistically significant difference in uis rate between bricker and wallace anastomotic techniques (3.7% vs. 0), in favour with the latter. despite these results, the success and complications of two techniques are still debatable and no definite conclusion regarding the optimal anastomotic technique for orthotopic diversion has been made. the reason for this may be the lack of clear selection criteria for each anastomotic technique, instead of simple surgeon preference (12, 24). a recent study (17), suggesting an individualized selection strategy for deciding upon the type of uretero-ileal anastomosis (bricker vs. wallace), showed acceptable low rate of ureteral strictures (3.1%) and confirmed clinical reliability of research. the technique selection was based on several individual patient factors, including tumor characteristics, ureteral anomalies and ureteral length. in our study, however, chimney size and diameter of distal ureter, together with ureteral length after retro-sigmoidal tunneling were considered as selection criteria to decide upon the type of ureteroileal anastomosis. the results we reported here revealed higher incidence of uis using bricker technique (6.6%), after three months follow-up; on the other hand, this complication was not detected using wallace anastomosis on shortened tubularised isoperistaltic chimney. since this type of stricture remains the most challenging and difficult of all ureteral strictures to treat (25, 26), any technical modification that aims to decrease or prevent uis is recommended (17). our modified wallace technique consisted of longer ureteral spatulation and short chimney, seemed to be effective in reducing the occurrence of both uis and anastomotic leakage during followup period. moreover, a shorter chimney may also play a role in reflux prevention, due to the fact that a shorter limb allows the use of longer segments of the lower ureters that participate in reflux prevention (27). all these findings together bolster the assertion that proper patient selection and meticulous ureteral handling of distal ureter, as well as a shorter intestinal chimney with end-to-end running suture ureteroileal anastomosis, may be essential to minimize the risk of postoperative reservoir-related complications. table 3. classification of postoperative complications and treatment options for reservoir-related complications after radical cystectomy and construction of modified hautmann reservoir with bricker (group i) or wallace (group ii) ureteroileal anastomosis. postoperative complications group i (n = 30) group ii (n = 30) p value & treatment early late early late clavien-dindo classification 19 (63.3) * 9 (30) 16 (53.3) 10 (33.3) 0.03 grade i 8 (26.6) 4 (13.3) 9 (30) 4 (13.3) grade ii 7 (23.3) 2 (6.6) 5 (16.6) 5 (16.6) * grade iii (iiia/iiib) 4 (13.3) * 1 (3.3) 2 (6.6) 0 grade iv (iva/ivb) 0 1 (3.3) 0 0 grade v (death) 0 1 (3.3) 0 1 (3.3) treatment, n (%) 15 (50) * 7 (23.3) * 6 (20) 4 (13.3) 0.01 antegrade stent placement 1 0 0 0 percutaneus nephrostomy (pcn) 1 1 1 0 balloon dilatation of strictures 2 0 0 0 surgical repair of strictures 1 0 0 0 intraabdominal drainage 2 0 0 0 intermitent catheterization (cics) 8 6 5 4 * statistically significant difference between two groups (p < 0.05). archivio italiano di urologia e andrologia 2021; 93, 3 d. djordjevic, s. dragicevic, m. vukovic 266 oncologic factors were an important consideration in our series. although the wallace technique has the lowest rate of uis, it not recommended for patients with increased risk of recurrent tumors (bladder cis) (4,11). in our study, however, patients with multifocal bladder cis were selected exclusively for bricker anastomotic technique, after obtaining negative frozen-section urethral biopsy. therefore, oncologic limitations of direct end-to-end ureteroileal anastomosis were clinically insignificant in our cohort with conclusion that wallace technique may become the preferred anastomotic approach, in properly selected patients. it is questionable, however, why the bricker group was associated with high postoperative complications rate (clavien-dindo grade iii-13.3%), where incidence of uis was higher than expected (1, 3, 23). since the obesity may impair the outcome of ureteroileal anastomosis after rc (17), we assumed that higher bmi of patients within bricker group, associated with short mesentery and extensive dissection of the distal left ureter, led to significantly higher rate of uis, comparing to wallace group. incidence of cics after neobladder construction is generally 4-25% in males and up to 53% in females (28, 29). in our study, however, 16.9% of patients still required cics at the end of first year. nevertheless, during the initial three months post-surgery, hydronephrosis had improved after cics in 50% of patients within the second group, whereas only one patient required an invasive procedure for the treatment of hydronephrosis (pcn). the limitations of this study are the small size of groups of patients and the short follow-up periods. despite that, we found an acceptable rate of ureteroenteric strictures, vur and anastomotic leakage, lower than that found in the conventional technique. furthermore, our research was conducted with no clear protocol for administration of neoadjuvant or adjuvant chemotherapy, as this was left to the discretion of the uro-oncologist board. in addition, the unusually high rate of anastomotic leakage in patients within the first group could lead to research bias regarding effectiveness of our modified hautmann neobladder with wallace anastomotic technique. single surgeon experience could be the major reason for this bias, which should be addressed by involving other highly trained surgeons. conclusions our preliminary outcomes demonstrated that this patient-based selection strategy for ureteroileal anastomosis in orthotopic urinary diversion after rc seems to be clinically reliable and favors wallace anastomotic technique over the bricker approach. references 1. hautmann re, abol-enein h, davidsson t, et al. icud-eau international consultation on bladder cancer 2012: urinary diversion. eur urol. 2013; 63:67-80. 2. lippert mc, theodorescu d. the hautmann neobladder with a chimney: a versatile modification. j urol. 1997; 158:1510-2. 3. hollowell cm, christiano ap, steinberg gd. technique of hautmann ileal neobladder with chimney modification: interim results in 50 patients. j urol. 2000; 163:47-50. 4. sevin g, soyupek s, armagan a, et al. ileal orthotopic neobladder (modified hautmann) via a shorter detubularised ileal segment: experience and results. bju int. 2004; 94:355-59. 5. bianchi g, sighinolfi mc, pirola gm, micali s. studer orthotopic neobladder: a modified surgical technique. urology. 2016; 88:22225. 6. shigemura k, yamanaka n, imanishi o, yamashita m. wallace direct versus anti-reflux le duc ureteroileal anastomosis: comparative analysis in modified studer orthotopic neobladder reconstructions. int j urol. 2012; 19:49-53. 7. studer ue, burkhard fc, schumacher m, et al. twenty years experience with an ileal orthotopic low-pressure bladder substitute: lessons to be learned. j urol. 2006; 176:161-66. 8. lypczinski w, glazar b, bak m, et al. strategy in preventing of uretero-intestinal anastomosis strictures in patients with low-pressure intestinal neobladder. przegl lek. 2012; 69:181-83. 9. helmy aly a, ezzat a, hamed a. orthotopic neobladder reconstruction after radical cystectomy in patients with a solitary functioning kidney: clinical outcome and evaluation. j egypt natl canc inst. 2011; 23:133-40. 10. micali s, de carli p, milano r, et al. double-j ureteral stents: an alternative to external urinary stents in orthotopic bladder substitution. eur urol. 2001; 39:575-79. 11. mcdouglas ws. use of intestinal segments and urinary diversion. in: walsh pc, retik ab, vaughan ed jr, wein aj (eds). campbell’s urology. saunders, philadelphia, pa, 2002; pp. 3745-88. 12. kouba e, sands m, lentz a, et al. a comparison of the bricker versus wallace ureteroileal anastomosis in patients undergoing urinary diversion for bladder cancer. j urol. 2007; 178:945-48. 13. pantuck aj, han kr, perrotti m, et al. uretroenteric anastomosis in continent urinary diversion: long-term results and complications of direct versus nonrefluxing techniques. j urol. 2000; 163:450-55. 14. hautmann re, de petriconi rc, volkmer bg. 25 years of experience with 1000 neobladders: long-term complications. j urol. 2011; 185:2207-12. 15. hautmann re. surgery illustrated surgical atlas ileal neobladder. bju int. 2010; 105:1024-35. 16. djordjevic d, vukovic m. functional results of hautmann neobladder with chimney modification and wallace ureteroileal anastomosis: initial experience with 22 patients. int braz j urol. 2021; 47:426-435. 17. liu l, chen m, li y, et al. technique selection of bricker or wallace ureteroileal anastomosis in ileal conduit urinary diversion: a strategy based on patients characteristics. ann surg oncol. 2014; 21:2808-12. 18. kanno t, inoue t, kawakita m, et al. perioperative and oncological outcomes of laparoscopic radical cystectomy with intracorporeal versus extracorporeal ileal conduit: a matched-pair comparison in a multicenter cohort in japan. int j urol 2020; 27:559-565. 19. al hussein al awamlh b, wang lc, et al. is continent cutaneous urinary diversion a suitable alternative to orthotopic bladder substitute and ileal conduit after cystectomy. bju int. 2015; 116:805-14. 20. mitropoulos d, artibani w, graefen m, et al. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. eur urol. 2012; 61:341-9. 267archivio italiano di urologia e andrologia 2021; 93, 3 technique selection for ureteroileal anastomosis in orthotopic diversion 21. aaronson nk, ahmedzai s, bergman b, et al. the european organization for research and treatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. j natl cancer inst. 1993; 85:365-376. 22. singh v, yadav r, sinha rj, gupta dk. prospective comparison of quality of life outcomes between ileal conduit urinary diversion and orthotopic neobladder reconstruction after radical cystectomy: a statistical model. bju int. 2014; 113:726-732. 23. hautmann re, volkmer bg, schumacher mc, et al. long-term results of standard procedures in urology: the ileal neobladder. world j urol. 2006; 24:305-314. 24. evangelidis a, lee ek, karellas me, et al. evaluation of ureterointestinal anastomosis: wallace vs. bricker. j urol. 2006; 175:1755-8. 25. kurzer e, leveillee rj. endoscopic management of ureterointestinal strictures after radical cystectomy. j endourol. 2005; 19:677-82. 26. farnham sb, cookson ms. surgical complications of urinary diversion. world j urol. 2004; 22:157-67. 27. hassan abol-enein, nuzhat faruqui, nashwa barakat, shokeir aa. does the afferent tubular segment in an orthotopic bladder substitution compromise ureteric antireflux properties? an experimental study in dogs. arab j urol. 2012; 10:125-30. 28. hautmann re, paiss t, de petriconi r. the ileal neobladder in women: 9 years of experience with 18 patients. j urol. 1996;155:76-81. 29. ali-el-dein b, el-sobky e, hohenfellner m, ghoneim ma. orthotopic bladder substitution in women: functional evaluation. j urol. 1999; 161:1875-80. correspondence dejan djordjevic, md, phd, urologist dejanurl@gmail.com svetomir dragicevic, md, urologist dejanurl@gmail.com urology clinic, euromedic general hospital bulevar umetnosti 29, 11000 belgrade (serbia) marko vukovic, md (corresponding author) marko.vukovic09@gmail.com department of urology, clinical centre of montenegro ljubljanska bb, 81000 podgorica (montenegro) cop+ed+fisse 2006 123archivio italiano di urologia e andrologia 2022; 94, 1 letter to editor no conflict of interest declared. key words: aristolochic; tcc; herbal; balkan nephropathy. submitted 3 january 2022; accepted 19 january 2022 to the editor, aristolochic acid is one of major causes for upper tract urothelial carcinoma, especially in younger population. while it is mentioned as a cause in guidelines, little is actually known about the toxin by urologists. we are aiming in our letter to provide some direct and clear information to ourselves that would help us to know more about that toxin and how it can adversely affect our patients. what is aristolochic acid? aristolochic acid is an acid obtained from a plant that grows in several areas of the world. its use was started in china as an herbal medicine that was used to treat many diseases, then was advanced to be used in many herbal medications sold over the shelf worldwide (1). why people use that herbal drug? this herbal supplement was long used as a miracle supplement for weight loss. other less common uses were arthritis and menstrual problems (1). in balkan areas; that herb was mixed with wheat used for home baked bread. importance to urologists aristolochic acid were found to be significantly associated with interstitial nephritis, end stage renal disease. this is currently known as a major cause of balkan nephropathy (2). this was also proved to be a carcinogenic causing upper urinary tract urothelial carcinoma (3). a recent study (2017) looked for the oncological outcomes of patients with upper tract urothelial carcinoma exposed to aristolochic acid. this was found to be significantly associated with higher rate of local and contralateral upper tract recurrence, as well as higher rate for intravesical recurrence (4). a recent meta-analysis and systematic review (2021) confirmed the same findings of higher rate of intravesical and contralateral recurrence for patients exposed to aristolochic acid, as well as worse overall and disease specific survival (5). authorities’ action and obstacles the toxic and carcinogenic effect of aristolochic acid was raising concerns since 1999. food and drug administration (fda) released warning in 2001 about the use of that herbal supplement and started to recall products from the market containing the acid. this was followed in 2004 by a warning from health canada regarding the use of the supplement with an alert to the canadian border to prevent importing the drug in any form (6, 7). why aristolochic acid is a concern 20 years following authorities’ action? the concerns for aristolochic acid are still existent for three important reasons. first; unlike other known factors as smoking, studies did show that patients that stopped the use of aristolochic acid for more than 5 years were still at the same risk and worse oncological outcomes for upper tract urothelial carcinoma, similar to patients with recent exposure. it seems that exposure produces a permanent genetic alteration that keeps risking the patients’ cancer development despite of cessation of exposure (4). the second problem is the natural growth of the plant in many areas of the world. while the plant may be avoided because of the known risks, studies have confirmed that the toxins of the plant can spread through the soil and affect other vegetables and fruits that can become contaminated by the toxins. that soil contamination leaching into rivers raised some concerns about water contamination in endemic areas where just drinking water may be imposing a risk for aristolochic acid exposure. another natural risk is through butterflies that can act as an intermediate host for the herbal contamination (8, 9). chan et al. could recently (2016) identify aristolochic acid in corn, wheat grains and soil samples taken from balkan areas (10). more recent studies confirmed the same findings as the root vegetables in balkan areas were found to be extensively contaminated with aristolochic acid (11, 12). the last risk is through aristolochic acid: what urologists should know mohanarangam thangavelu, asmaa ismail, ahmed zakaria, hazem elmansy, walid shahrour, owen prowse, ahmed kotb northern ontario school of medicine, thunder bay, ontario, canada. doi: 10.4081/aiua.2022.1.123 archivio italiano di urologia e andrologia 2022; 94, 1 mohanarangam thangavelu, asmaa ismail, ahmed zakaria, et al. 124 table 1. plants containing aristolochic acid (from fda 2020). plant name aristolochia spp. aristolochia acuminata lam. syn. aristolochia tagalachamp. aristolochia argentina griseb. aristolochia baetica linn. syn. aristolochia bracteolatalam. aristolochia bracteata retz. aristolochia chilensis bridges in lindl. aristolochia cinnabarina c.y. cheng & j.l. wu aristolochia clematitis l. aristolochia contorta bunge aristolochia cymbifera mart. & zucc. aristolochia debilis siebold & zucc. syn. aristolochia longa thunb. syn. aristolochia recurvilabrahance syn. aristolochia sinarumlindl. aristolochia elegans mast. syn. aristolochia hasslerianachodat aristolochia esperanzaekuntze aristolochia fangchi y.c. wu ex l.d. chow & s.m. hwang aristolochia fimbriata cham. aristolochia indica l. aristolochia kaempferi willd. syn. aristolochia chrysops(stapf) e.h. wilson ex rehder syn. aristolochia feddei h. lév. syn. aristolochia heterophyllahemsl. syn. aristolochia mollis dunn syn. aristolochia setchuenensisfranch. syn. aristolochia shimadaihayata syn. aristolochia thibeticafranch. syn. isotrema chrysops stapf syn. isotrema heterophylla(hemsl.) stapf syn. isotrema lasiops stapf aristolochia kwangsiensischun & f.c. how syn. aristolochia austroszechuanica c. b. chien & c. y. cheng aristolochia macrophylla lam. syn. aristolochia sipho l'hér. aristolochia manshuriensiskom. syn. hocquartia manshuriensis(kom.) nakai syn. isotrema manshuriensis(kom.) h. huber common/alternative name aristolochia guan mu tong guang mu tong oval leaf dutchman's pipe ukulwe birthwort ma dou ling tian xian teng mil homens ma dou ling tian xian teng qing mu xiang sei-mokkou (japanese) birthwort long birthwort guang fang ji fang ji mokuboi (japanese) kwangbanggi (korean) fang chi kou-boui (japanese) indian birthwort yellowmouth dutchman's pipe dutchman's pipe manchurian birthwort manchurian dutchman's pipe guang mu tong kan-mokutsu (japanese) mokuboi (japanese) kwangbanggi (korean) plant name aristolochia maurorum l. ristolochia mollissima hance aristolochia pistolochia l. aristolochia rigida duch. aristolochia rotunda linn. aristolochia serpentaria l. syn. aristolochia serpentariavar. hastata (nutt.) duch. aristolochia serpentaria l. syn. aristolochia serpentariavar. hastata (nutt.) duch. aristolochia watsoni wooton & standley or aristolochia watsonii wooton & standley syn. aristolochia porphyrophylla pfeifer aristolochia westlandii hemsl. or aristolochia westlandi hemsl. aristolochia zollingerianamiq. syn. aristolochia kankauensissasaki syn. aristolochia roxburghianasubsp. kankauensis (sasaki) kitam. syn. hocquartia kankauensis(sasaki) nakai ex masam. syn. aristolochia tagala var. kankauensis (sasaki) t. yamaz. asarum canadense linn. syn. asarum acuminatum(ashe) e.p. bicknell syn. asarum ambiguum (e.p. bicknell) daniels syn. asarum canadense var. ambiguum (e.p. bicknell) farw. syn. asarum canadense var.reflexum (e.p. bicknell) b.l. rob. syn. asarum furcatum raf. syn. asarum medium raf. syn. asarum parvifolium raf. syn. asarum reflexum e.p. bicknell syn. asarum rubrocinctumpeattie asarum canadense linn. syn. asarum acuminatum(ashe) e.p. bicknell syn. asarum ambiguum (e.p. bicknell) daniels syn. asarum canadense var. ambiguum (e.p. bicknell) farw. syn. asarum canadense var.reflexum (e.p. bicknell) b.l. rob. syn. asarum furcatum raf. syn. asarum medium raf. syn. asarum parvifolium raf. syn. asarum reflexum e.p. bicknell syn. asarum rubrocinctumpeattie asarum himalaicum hook. f. & thomson ex klotzsch or asarum himalaycum hook. f. & thomson ex klotzsch asarum splendens (f. maek.) c.y. cheng & c.s. yang bragantia wallichii r.br. specimen exists at new york botanical gardens. tropicos does not list this species as a synonym for any thotteaspecies. kew gardens herbarium does not recognize the genera bragantia. until additional information is obtained the name used is as cited in j. nat. products 45:657–666 (1982) common/alternative name virginia snakeroot serpentaria virginia serpentary virginia snakeroot serpentaria virginia serpentary wild ginger indian ginger canada snakeroot false coltsfoot colic root heart snakeroot vermont snakeroot southern snakeroot wild ginger indian ginger canada snakeroot false coltsfoot colic root heart snakeroot vermont snakeroot southern snakeroot tanyou-saishin (japanese) do-saishin (japanese) currently existing other herbal supplements widely used worldwide. while the intentional inclusion of aristolochic acid is currently not allowed, contamination of the available herbal supplement with aristolochic acid is a continuous risk. abdullah et al. (2017) examined 573 different samples lacking aristolochic acid as one of the ingredients. they could identify the substance in 206 samples (36%). this was a surprising fact that 1/3 of herbal supplements in market could be contaminated with aristolochic acid (13). what are the herbs that can possibly contain aristolochic acid? there were many plants reported in a monograph published in 2018 that can possibly contain aristolochic acid. most of these herbs have common names that are far away from the original toxin name including dutchman’s pipe, virginia snakeroot, canada snakeroot, wild ginger and indian ginger (14). more recently, fda updated its plant lists providing warning to the manufacturers and the public against the use of large numbers of herbs that can potentially harbour the toxin (15). table 1 illustrate the plants having the toxin. 125archivio italiano di urologia e andrologia 2022; 94, 1 aristolochic acid are there ongoing ways for population protection against the toxin exposure? herbal medicine is being used worldwide as an alternative medicine that can augment the traditional medicine. the main issues are the large number of plants that can be harbouring the toxin together with possible language barriers and the use of english names to some herbs that can be completely different and not presenting the herb containing the toxin. there is no guaranteed current way to confirm the absence of toxin from available herbal medicine. in 2018; four dna sequences were identified in a large study as possible target areas to detect the toxin out of eleven different plants. these dna sequences were bcl, matk, its2 and trnh-psba (16). dna barcoding is promising and ongoing way to detect most of the herbs that can be having the toxin, although it may still miss some uncommon herbs. conclusions aristolochic acid is a currently existing possible risk factor for the development of nephropathy and upper tract urothelial carcinoma. its actual contribution to new cases diagnosed with upper tract urothelial carcinoma may be underestimated. awareness programs to the public for possible herbal supplements contamination with aristolochic acid as well as testing all herbal supplements for possible contamination should be implemented. dna barcoding is able to identify most common herbs containing aristolochic acid but may be still missing uncommon herbs. references 1. luciano rl, perazella ma. aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. drug saf. 2015; 38:55-64. 2. jelakovic b, dika ž, arlt vm, et al. balkan endemic nephropathy and the causative role of aristolochic acid. semin nephrol. 2019; 39:284-296. 3. rouprêt m, babjuk m, burger m, et al. european association of urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. eur urol. 2021; 79:62-79. 4. zhong w, zhang l, ma j, et al. impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. onco targets ther. 2017; 10:5775-5782. 5. kang yc, chen mh, lin cy, et al. aristolochic acid-associated urinary tract cancers: an updated meta-analysis of risk and oncologic outcomes after surgery and systematic review of molecular alterations observed in human studies. ther adv drug saf. 2021; 12:2042098621997727 6. http://wayback.archive-it.org/7993/20171114232638/https://www.fda.gov/food/recallsoutbreaksemergencies/safetyalertsadvisories/ ucm095272.htm. accessed online on december 29, 2021. 7. https://www.canada.ca/en/news/archive/2004/07/health-canada-advises-consumers-not-use-products-containing-aristolochic-acid.html. accessed online on december 29, 2021. 8. chan ck, liu y, pavlovic nm, chan w. aristolochic acids: newly identified exposure pathways of this class of environmental and food-borne contaminants and its potential link to chronic kidney diseases. toxics. 2019; 7:14. 9. li w, chan ck, liu y, et al. aristolochic acids as persistent soil pollutants: determination of risk for human exposure and nephropathy from plant uptake. j agric food chem. 2018; 66:11468-11476. 10. chan w, pavlovic nm, li w, et al. quantitation of aristolochic acids in corn, wheat grain, and soil samples collected in serbia: identifying a novel exposure pathway in the etiology of balkan endemic nephropathy. j agric food chem. 2016; 64:5928-34. 11. au ck, zhang j, chan ck, et al. determination of aristolochic acids in vegetables: nephrotoxic and carcinogenic environmental pollutants contaminating a broad swath of the food supply and driving incidence of balkan endemic nephropathy. chem res toxicol. 2020; 33:2446-2454. 12. draghia lp, lukinich-gruia at, oprean c, et al. aristolochic acid i: an investigation into the role of food crops contamination, as a potential natural exposure pathway. environ geochem health. 2021; 43:4163-4178. 13. abdullah r, diaz ln, wesseling s, rietjens im. risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (moe) approach. food addit contam part a chem anal control expo risk assess. 2017; 34:135-144. 14. https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono100a-23.pdf. accessed online on january 17, 2022. 15. https://www.accessdata.fda.gov/cms_ia/importalert_141.html. accessed online on january 18, 2022. 16. dechbumroong p, aumnouypol s, denduangboripant j, sukrong s. dna barcoding of aristolochia plants and development of species-specific multiplex pcr to aid hptlc in ascertainment of aristolochia herbal materials. plos one. 2018; 13:e0202625. correspondence mohanarangam thangavelu, md drtmohan@googlemail.com asmaa ismail, md asmaaismail0782@gmail.com ahmed zakaria, md aszakaria81@yahoo.com hazem elmansy, md hazemuro100@yahoo.com walid shahrour, md walid.shahrour@gmail.com owen prowse, md owenprowse@rogers.ca ahmed kotb, md (corresponding author) drahmedfali@gmail.com urology department, northern ontario school of medicine, 146 court street south, thunder bay, on p7b 2x6, canada. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4436 original paper no conflict of interest declared. ation of renal fibrosis (4). the infiltrating lymphocytes, monocytes/macrophages and mast cells activate and produce reactive oxygen species (ros) after infection and release fibrogenic cytokines and growth factors (5, 6). the resulting damage causes interstitial inflammation, collagen deposition and disruption of the normal tubular arrangement. as a result, permanent parenchymal damage and scar formation occur, which are accompanied by tubular atrophy and interstitial fibrosis (7). even if the infection is treated and vur is corrected, the inflammatory process continues and scars may, therefore, develop (1). it is known that the complete blood count parameters vary qualitatively and quantitatively in inflammatory processes (8) and that the neutrophil-to-lymphocyte ratio (nlr) is effective in predicting inflammation (9). platelets also contribute to increased inflammation by enhancing the secretion of cytokines at the beginning of inflammation (10). mean thrombocyte volume (mpv) level can be used as an indicator of platelet functions (11). tc-99m dimercaptosuccinic acid (dmsa) scintigraphy is the gold standard in detecting the development of renal scars after pyelonephritis (12). pyelonephritic inflammatory changes in the kidney occur immediately and can be detected with dmsa. while some of these acute changes resolve within 6 months, some lead to renal scarring (13). currently, the development of scars in patients cannot be predicted as there is no easily accessible predictive marker for renal scar development. if such a marker is identified, improvements can be made in the follow-up and treatment algorithm of patients with vur. the present study aims to compare the nlr and mpv values in patients having vur with and without renal scarring. to the best of our knowledge, this is the first study on the topic. materials and methods the hospital records of patients diagnosed with vur using voiding cystourethrography (vcug) between january 2008 and august 2020 were retrospectively reviewed. ethics committee approval was granted by our faculty ethics committee (hru/16.06.27). patients' age, frequency of past uti episodes, use of prophylactic antibiotics, physical examination findings, blood urea nitrogen and creatinine, complete blood count, complete urinalysis, objectives: vesicoureteral reflux (vur) exacerbates the risk of renal scarring by establishing a ground for pyelonephritis. it is known that the inflammatory process is more influential than the direct damage caused by bacterial infection in the development of renal scars after pyelonephritis. therefore, the present study aims to investigate the relationship between renal scarring and systemic inflammatory markers in patients with vur. material and methods: hundred and ninety-two patients (116 females, 76 males) diagnosed with vur were divided into two groups based on the presence or absence of renal scarring and into three groups according to the grade of vur (low, moderate and high). neutrophil count, lymphocyte count, mean platelet volume (mpv) and neutrophil-to-lymphocyte ratio (nlr) were compared among the groups. results: of the 192 patients, 102 had renal scarring. the age and gender distribution did not differ significantly between the groups with and without renal scarring (p > 0.05). however, the grade of reflux and lymphocyte count were significantly higher in the group with renal scarring (p < 0.05), and the nlr was significantly lower in the group with renal scarring (p < 0.05). the lymphocyte count was significantly higher (p < 0.05) and nlr was significantly lower in the high-grade vur group (p < 0.05). however, mpv values did not differ significantly (p > 0.05) between the groups. conclusions: nlr can be used to predict renal scarring in patients with vur, especially in the period of 3-6 months after the first attack of infection, and may even serve as a candidate marker for treatment selection. however, larger series and prospective studies are needed. key words: vesicoureteral reflux; neutrophil-to-lymphocyte ratio; pyelonephritis; renal scarring. submitted 15 october 2021; accepted 28 october 2021 introduction vesicoureteral reflux (vur) is a functional and anatomical disorder that can result in renal scarring, hypertension and end-stage renal failure (1). vur predisposes the patients to urinary tract infection (uti) and pyelonephritis and increases the risk of scarring in the kidney (2). renal scarring is an important cause of hypertension and chronic renal failure (crf) in children and young adults (3). the etiopathogenesis of renal scarring has not been clearly understood. however, lymphocytes play an important role in the initiis there a relationship between renal scarring and neutrophil-to-lymphocyte ratio in patients with vesicoureteral reflux? mehmet demir, i̇smail yağmur, eyyup sabri pelit, bülent katı, eser ördek, halil çiftçi department of urology, harran university, sanliurfa, turkey. doi: 10.4081/aiua.2021.4.436 summary 437archivio italiano di urologia e andrologia 2021; 93, 4 renal scarring and neutrophil-to-lymphocyte ratio urine culture, ultrasound (usg), vcug and dmsa findings were examined. the vcug findings of the patients were evaluated according to the standards of the international reflux study in children (14). most of the patients were admitted to our clinic with the pre-diagnosis of vur after acute infection, for further investigation, some of them were diagnosed with vur after acute infection and for follow-up and treatment, and some of them were directly admitted to our clinic because of recurrent uti. no new vcug was performed in patients diagnosed with vur and referred to our clinic. imaging was performed in our hospital for patients who were referred with a pre-diagnosis of vur and did not have vcug. dmsa scintigraphs, provided that they were performed 3-6 months after the occurrence of uti, were examined. dmsa scintigraphies taken during the acute infection period were not included in the study. the renal parenchymal scar was defined as cortical thinning, volume loss, decreased dmsa uptake and renal contour irregularities. neutrophil count, lymphocyte count and mpv values were recorded by examining the results of complete blood count at the time of dmsa acquisition, and it was established that the patients had no active infection by demonstrating a sterile urine culture. patients with malignant diseases and those on chronic anti-inflammatory drug therapy were excluded from the study. patients with secondary vur caused by other factors, such as neurogenic bladder and posterior urethral valve, and those with voiding dysfunction were excluded from the study. hundred and ninety-two patients with accessible data were included in the study. the patients were divided into two groups based on the presence or absence of renal scarring and into three groups according to the grade of vur (mild: grades i-ii, moderate: grade iii; high: grades iv-v). neutrophil count, lymphocyte count, mpv values and nlr were compared among the groups. statistical methods mean, standard deviation, median, minimum, maximum value frequency and percentage were used for descriptive statistics. kolmogorov-smirnov test was employed to check the distribution of the variables. mann-whitney u test was used for the comparison of the quantitative data. chi-square test was used for the comparison of the qualitative data. spss 26.0 was used for the statistical analysis. results of the 192 patients with vur, 116 were females, and 76 were males. the mean age of the patients was 5.4 ± 5 years. of the patients, 124 had unilateral and 68 had bilateral vur (table 1). the age and gender distribution did not differ significantly between patients with and without renal scarring (p > 0.05). the rates of renal scarring were 9%, 32.5%, 57.1%, 67.3% and 65.6% in patients with grade i, ii, iii, iv and v vur, respectively. the vur grade and lymphocyte counts were significantly higher (p < 0.05) and the neutrophil count and nlr were significantly lower (p < 0.05) in the group with renal scarring than in the group without renal scarring. the mpv values did not differ significantly (p > 0.05) between the groups with and without renal scarring (table 2). according to the grade of reflux, the patients were divided into three groups, that is, low (grades i-ii), intermediate (grade iii) and high (grades iv-v) vur groups. lymphocyte count was significantly higher in the highgrade vur group than in the lowand moderate-vur groups (p < 0.05). nlr was significantly lower in the high-grade vur group than in the lowand moderatevur groups (p < 0.05). however, neutrophil count and mpv values did not differ significantly according to the grade of vur (p > 0.05) (table 3). in the sub-data analysis, the patients who were divided into three groups (low, moderate and high) according to the degree of reflux were further divided into two groups based on the presence or absence of renal scarring. the neutrophil count was significantly lower in scar-positive patients with low-grade (grades i-ii) vur (p < 0.05) than in scar-negative patients. however, lymphocyte count and nlr did not differ significantly (p > 0.05) (table 4). table 1. demographic data of the patients. min-max median mean ± sd/n-% age 0.10 36.00 4.00 5.40 ± 5.00 gender girl 116 60.4% boy 76 39.6% side right 43 22.4% left 81 42.2% bilateral 68 35.4% grade i 11 5.7% ii 40 20.8% iii 63 32.8% iv 46 24.0% v 32 16.7% neutrophil 1.10 10.80 4.70 4.78 ± 1.89 lymphocyte 1.30 9.90 3.70 4.07 ± 1.55 nlr 0.20 4.06 1.22 1.37 ± 0.79 mpv 4.20 10.70 6.20 6.36 ± 0.99 nlr: neutrophil lymphocyte ratio; mpv: mean platelet volume. table 2. comparison of patients with and without renal scarring. scar (-) scar (+) p mean ± sd/n-% median mean ± sd/n-% median age 5.80 ± 6.36 4.00 5.04 ± 3.37 4.00 0.620 m gender girl 54 60.0% 62 60.8% 0.912 x2 boy 36 40.0% 40 39.2% side right 19 21.1% 24 23.5% 0.492 x2 left 42 46.7% 39 38.2% bilateral 29 32.2% 39 38.2% grade i 10 11.1% 1 1.0% 0.000 x2 ii 27 30.0% 13 12.7% iii 27 30.0% 36 35.3% iv 15 16.7% 31 30.4% v 11 12.2% 21 20.6% neutrophil 5.19 ± 1.70 4.90 4.42 ± 1.98 4.40 0.002 m lymphocyte 3.71 ± 1.25 3.60 4.39 ± 1.71 3.80 0.020 m nlr 1.59 ± 0.83 1.38 1.16 ± 0.70 0.99 0.000 m mpv 6.28 ± 0.92 6.10 6.43 ± 1.04 6.30 0.395 m m: mann-whitney u test; x2: chi-square test; statistically significant results are in bold italics (p < 0.05). nlr: neutrophil lymphocyte ratio; mpv: mean platelet volume. archivio italiano di urologia e andrologia 2021; 93, 4 m. demir, i̇. yağmur, e. sabri pelit, b. katı, e. ördek, h. çiftçi 438 neutrophil count, lymphocyte count and nlr did not differ significantly (p > 0.05) between scar-positive and scarnegative patients with moderate (grade iii) vur (table 4). the lymphocyte count was significantly higher (p < 0.05) and the neutrophil count and nlr were significantly lower (p < 0.05) in scar-positive patients with high-grade (grades iv-v) vur than in scar-negative patients (table 4). discussion vur increases the risk of renal scarring by establishing a ground for uti and pyelonephritis. if the necessary precautions are not taken and the condition is not treated in a timely manner, vur causes reflux nephropathy and crf develops in 25%-60% of these patients (15). the reflux of the infected urine back to the kidney does not always cause parenchymal damage and renal scar in vur (16). it has been shown that the inflammatory process is more influential than the direct damage caused by bacterial infection in renal scar development after pyelonephritis (17, 18). it has been suggested that even if the infection is treated and vur is corrected, the inflammatory process that has already started continues and therefore scar may develop (1, 15). partial benefits of the use of corticosteroids combined with antibiotic therapy have been observed in animal studies based on the hypothesis that the development of renal scarring can be reduced by preventing the inflammatory process (19). in a recent double-blind, placebo-controlled study conducted by shaikh et al., patients who were treated for uti were divided into two groups. one group received antibiotics and placebo, while the other group received antibiotics and corticosteroids. the development of the renal scar was found to be lower in the group in which corticosteroids were added to the treatment although the difference was not statistically significant (20). based on the results of the study, it was argued that better results could be achieved by adding corticosteroids to the treatment of patients predicted to develop pyelonephritis and renal scarring. urinary inflammatory biomarkers such as tgf-b1, vegf, and mcp-1 (15), interleukin-18 (il-18) are known to play a role in renal ischemia-reperfusion and acute kidney injury, and procalcitonin (pct) and crp serum inflammation markers have proven to be reliable in vur patients (21). however, an easy-to-reach biomarker predicting renal scar is still not available. the nlr is a simple, useful parameter that is used as a systemic inflammation marker. it has been widely employed to predict the outcomes of oncological, cardiovascular, gastrointestinal and hematogenous infections (22). it has been proposed as a marker of infection in patients with sepsis and has been reported to be associated with the severity of the disease (23). in the study performed by terradas et al., increased mortality was demonstrated in patients with bacteraemia who had an nlr of > 7 (24). in another study, it has been reported that the risk of sepsis increased after percutaneous nephrolithotomy in patients with an nlr of ≥ 2.5 (25). based on the data from literature, we hypothesised that there might be a relationship between renal scarring and complete blood count parameters. hence, we analysed the complete blood count parameters of patients diagnosed with vur. the nlr was 0.99 (1.16 ± 0.7) in the group with renal scarring and 1.38 (1.59 ± 0.83) in the figure 1. the relationship between nlr and renal scarring. table 4. comparison of patients with and without renal scarring according to the grade of reflux. scar (-) scar (+) p mean ± sd/n-% median mean ± sd/n-% median grade i-ii neutrophil 4.95 ± 1.55 4.80 4.38 ± 2.73 3.30 0.038 m lymphocyte 3.59 ± 1.25 3.30 3.28 ± 0.71 3.10 0.619 m nlr 1.53 ± 0.66 1.41 1.45 ± 1.05 0.97 0.202 m mpv 6.19 ± 0.89 6.10 6.36 ± 0.94 6.40 0.398 m grade iii neutrophil 5.39 ± 1.49 5.20 4.79 ± 1.91 4.75 0.173 m lymphocyte 3.78 ± 1.35 3.90 4.08 ± 1.61 3.50 0.835 m nlr 1.71 ± 0.98 1.45 1.36 ± 0.71 1.45 0.285 m mpv 6.42 ± 1.04 6.40 6.40 ± 0.96 6.30 0.867 m grade iv-v neutrophil 5.32 ± 2.08 4.90 4.18 ± 1.79 3.95 0.020 m lymphocyte 3.82 ± 1.18 3.60 4.91 ± 1.79 4.50 0.016 m nlr 1.57 ± 0.89 1.31 0.96 ± 0.52 0.83 0.001 m mpv 6.26 ± 0.84 6.10 6.48 ± 1.13 6.25 0.652 m m: mann-whitney u test; statistically significant results are in bold italics (p < 0.05). nlr: neutrophil lymphocyte ratio; mpv: mean platelet volume. table 3. comparison of patients according to the grade of reflux. grade i-ii grade iii grade iv-v p mean ± sd/n-% median mean ± sd/n-% median mean ± sd/n-% median age 7.50 ± 7.14 7.00 5.14 ± 3.71 5.00 4.23 ± 3.67 4.00 0.005 k gender girl 40 78.4% 39 61.9% 37 47.4% 0.002 x2 boy 11 21.6% 24 38.1% 41 52.6% side right 12 23.5% 15 23.8% 16 20.5% 0.124 x2 left 28 54.9% 25 39.7% 28 35.9% bilateral 11 21.6% 23 36.5% 34 43.6% neutrophil 4.79 ± 1.93 4.50 5.05 ± 1.75 5.10 4.56 ± 1.95 4.45 0.146 k lymphocyte 3.51 ± 1.13 3.10 3.95 ± 1.50 3.60 4.55 ± 1.69 4.20 0.001 k nlr 1.51 ± 0.78 1.28 1.51 ± 0.84 1.45 1.16 ± 0.72 1.01 0.004 k mpv 6.23 ± 0.90 6.10 6.41 ± 0.99 6.30 6.40 ± 1.04 6.15 0.540 k k: kruskal-wallis (mann-whitney u test); x2: chi-square test; statistically significant results are in bold italics (p < 0.05). nlr: neutrophil lymphocyte ratio; mpv: mean platelet volume. 439archivio italiano di urologia e andrologia 2021; 93, 4 renal scarring and neutrophil-to-lymphocyte ratio group without renal scarring. we found that nlr was low in patients with renal scars (figure 1), and a relationship was discerned between the grade of reflux and nlr (figure 2). therefore, we considered that nlr can be used to predict renal scarring. risk factors precipitating the development of renal scarring have been identified in patients with vur (26). one of these factors is the severity of the reflux. the risk of renal scar developing after pyelonephritis increases with the severity of vur (27, 28). in a study involving 303 children with uti who were under 2 years of age, stokland et al. showed that the risk of renal scarring was elevated in tc-99m dmsa scintigraphy in cases with high-grade vur (29). in the carried out by bandari et al., the rates of renal scarring were 33%, 33%, 40%, 50% and 80% in patients with grade i, ii, iii, iv and v vur, respectively (30). similarly, jaukovic et al. found renal scars in 26% of the children with low-grade vur and in 56% of the children with high-grade vur (31). in our study, the renal scar rates were 9%, 32.5%, 57.1%, 67.3% and 65.6% in patients with grade i, ii, iii, iv and v vur, respectively. as seen in vur studies in the literature and in the present study, the rate of scarring increased as the grade of reflux increased (figure 3). however, not all patients with high-grade reflux develop renal scarring and those with low-grade reflux can also develop renal scars since the inflammatory process and immune response progress differently in each patient (17, 32). in the subdata analysis of our study, the lymphocyte count was significantly higher (p < 0.05) and the neutrophil count and nlr were significantly lower (p < 0.05) in patients with renal scarring who had high-grade (grades iv-v) reflux than in those without renal scarring. we identified a relationship between renal scarring and nlr in patients with high-grade (grades iv-v) vur. although our study did not establish this relationship in the low and moderate (grades i, ii and iii) reflux groups, we think that nlr could be the reason why some patients develop renal scarring while others with a similar grade of vur do not. currently, requesting dmsa scintigraphy and performing vcug for those with dmsa uptake are recommended as a top-down approach in the first-line workup after febrile uti (13). vur occurs in 24%-39% of patients with acute pyelonephritis detected by dmsa scintigraphy (33). in a systematic review by shaikh et al., dmsa changes were found in the acute phase in 57% of the patients after the first uti episode and these changes were observed in 15% of the patients during follow-up (32). therefore, repeat dmsa imaging 6-12 months later is recommended to determine the long-term outcomes in patients with signs of acute pyelonephritis (34). however, dmsa screening in children is impractical and expensive (20). in addition, dmsa between the ages of 1-3 has disadvantages such as the need for sedation during scintigraphy (35) and irradiation (36). therefore, we think that nlr can be used as a parameter in predicting renal scarring and that dmsa scintigraphy can reduce the number of shots. limitations our study has some limitations. the first limitation is the retrospective study design. since the number of febrile uti episodes in the study patients and whether they received an effective therapy are unknown, these data were not included in the study. similarly, because we are a tertiary health centre, patients are referred from external centres. therefore, most of the patients do not have complete blood count data for the acute period. therefore, infection parameters pertaining to the acute infection period were not included in the study. we think that the relationship between the complete blood parameters at the time of acute infection and renal scar formation should be examined with prospective studies. conclusions we opine that nlr can be used as a parameter to predict renal scarring in patients with vur and may even be a guiding marker candidate for treatment selection. in addition, we anticipate that the number of dmsa scans, which are costly and relatively difficult to implement, can be reduced in this manner. however, these findings need to be confirmed by well-designed prospective studies. references 1. tekgül s, riedmiller h, hoebeke p, et al. european association of urology. eau guidelines on vesicoureteral reflux in children. eur urol. 2012; 62:534-42. figure 3. the relationship between the grade of reflux and renal scarring. figure 2. relationship between the grade of vur and nlr. archivio italiano di urologia e andrologia 2021; 93, 4 m. demir, i̇. yağmur, e. sabri pelit, b. katı, e. ördek, h. çiftçi 440 2. sirin a, emre s, alpay h, et al. etiology of chronic renal failure in turkish children. pediatr nephrol. 1995; 9:549-52. 3. chertin b, abu arafeh w, kocherov s. endoscopic correction of complex cases of vesicoureteral reflux utilizing vantris as a new nonbiodegradable tissue-augmenting substance. pediatr surg int. 2014; 30:445-8. 4. anders hj, ryu m. renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. kidney int. 2011; 80:915-925. 5. nikolic-paterson dj. cd4+ t cells: a potential player in renal fibrosis. kidney int. 2010; 78:333-5. 6. cendron m. reflux nephropathy. j pediatr urol. 2008; 4:414-21. 7. jahnukainen t, chen m, celsi g. mechanisms of renal damage owing to infection. pediatr nephrol. 2005; 20:1043-53. 8. kapci m, turkdogan ka, duman a, et al. biomarkers in the diagnosis of acute appendicitis. j clin exp invest. 2014; 5:250-255 9. turkmen k, erdur fm, ozcicek f, et al. platelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patients. hemodial int. 2013; 17:391-6. 10. mantovani a, cassatella ma, costantini c, jaillon s. neutrophils in the activation and regulation of innate and adaptive immunity. nat rev immunol. 2011; 11:519-31. 11. bath p, algert c, chapman n, neal b. progress collaborative group. association of mean platelet volume with risk of stroke among 3134 individuals with history of cerebrovascular disease. stroke. 2004; 35:622-6. 12. hains ds, cohen hl, mccarville mb, et al. elucidation of renal scars in children with vesicoureteral reflux using contrast-enhanced ultrasound: a pilot study. kidney int rep. 2017; 2:420-4. 13. blumenthal i. vesicoureteric reflux and urinary tract infection in children. postgrad med j. 2006; 82:31-5. 14. duckett jw, bellinger mf. a plea for standardized grading of vesicoureteral reflux. eur urol. 1982; 8:74-7. 15. morozova o, morozov d, pervouchine d, et al. urinary biomarkers of latent inflammation and fibrosis in children with vesicoureteral reflux. int urol nephrol. 2020; 52:603-610. 16. gordon i, barkovics m, pindoria s, et al. primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. j am soc nephrol. 2003; 14:739-44. 17. bille j, glauser mp. protection against chronic pyelonephritis in rats by suppression of acute suppuration: effect of colchicine and neutropenia. j infect dis. 1982; 146:220-6. 18. roberts ja, roth jk jr, domingue g, et al. immunology of pyelonephritis in the primate model. v. effect of superoxide dismutase. j urol. 1982; 128:1394-400. 19. haraoka m, matsumoto t, takahashi k, et al. suppression of renal scarring by prednisolone combined with ciprofloxacin in ascending pyelonephritis in rats. j urol. 1994; 151:1078-80. 20. shaikh n, shope tr, hoberman a, et al. corticosteroids to prevent kidney scarring in children with a febrile urinary tract infection: a randomized trial. pediatr nephrol. 2020; 35:2113-2120. 21. yavuz s, anarat a, bayazıt ak. interleukin-18, crp and procalcitonin levels in vesicoureteral reflux and reflux nephropathy. ren fail. 2013; 35:1319-22. 22. bolat d, topcu yk, aydogdu o, et al. neutrophil to lymphocyte ratio as a predictor of early penile prosthesis implant infection. int urol nephrol. 2017; 49:947-953. 23. zahorec r. ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. bratisl lek listy. 2001; 102:5-14. 24. terradas r, grau s, blanch j, et al. eosinophil count and neutrophil-lymphocyte count ratio as prognostic markers in patients with bacteremia: a retrospective cohort study. plos one. 2012; 7:e42860. 25. sen v, bozkurt ih, aydogdu o, et al. significance of preoperative neutrophil-lymphocyte count ratio on predicting postoperative sepsis after percutaneous nephrolithotomy. kaohsiung j med sci. 2016; 32:507-513. 26. lee yj, lee jh, park ys. risk factors for renal scar formation in infants with first episode of acute pyelonephritis: a prospective clinical study. j urol. 2012; 187:1032-6. 27. goldman m, bistritzer t, horne t, et al. the etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux. pediatr nephrol. 2000; 14:385-8. 28. zaffanello m, cataldi l, brugnara m, et al. hidden high-grade vesicoureteral reflux is the main risk factor for chronic renal damage in children under the age of two years with first urinary tract infection. scand j urol nephrol. 2009; 43:494-500. 29. stokland e, hellström m, jacobsson b, et al. renal damage one year after first urinary tract infection: role of dimercaptosuccinic acid scintigraphy. j pediatr. 1996; 129:815-20. 30. bandari b, sindgikar sp, kumar ss, et al. renal scarring following urinary tract infections in children. sudan j paediatr. 2019; 19:25-30. 31. jaukovic l, ajdinovic b, dopudja m, krstic z. renal scintigraphy in children with vesicoureteral reflux. indian j pediatr. 2009; 76:1023-6. 32. shaikh n, ewing al, bhatnagar s, hoberman a. risk of renal scarring in children with a first urinary tract infection: a systematic review. pediatrics. 2010; 126:1084-91. 33. levtchenko e, lahy c, levy j, et al. treatment of children with acute pyelonephritis: a prospective randomized study. pediatr nephrol. 2001; 16:878-84. 34. biassoni l, chippington s. imaging in urinary tract infections: current strategies and new trends. semin nucl med. 2008; 38:56-66. 35. gordon i. issues surrounding preparation, information and handling the child and parent in nuclear medicine. j nucl med. 1998; 39:490-4. 36. smith t, gordon i, kelly jp. comparison of radiation dose from intravenous urography and 99tcm dmsa scintigraphy in children. br j radiol. 1998; 71:314-9. correspondence mehmet demir, md (corresponding author) drdemir02@gmail.com ismail yagmur, md dr_iyagmur@hotmail.com eyyup sabri pelit, md dreyyupsabri@hotmail.com bülent katı, md bulentkati@yahoo.com eser ördek, md dr_eseser@hotmail.com halil çiftçi, md halilciftci63@hotmail.com harran university. faculty of medicine urology department sanliurfa (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 note on surgical technique without any short-term complications (mean follow-up 20 months), the sexual medicine society of north america (smsna) recommends that silicone injections and any penile augmentation procedure should be considered experimental surgery (3, 6). this is due to the lack of sufficient data to support the safety and efficacy of these procedures and the fact that several complications requiring surgical correction have been published in multiple case series and reports (3, 7). the severity and complexity of complications may range from silicone migration to the development of erectile dysfunction, penile deformity, infection, and late granulomatous reactions requiring surgical silicone excision (3, 8). partial excision without skin grafting has been described in the past with suboptimal esthetic results (9). since 1993, penile degloving, foreign body removal, circumferential excision of penile skin and resurfacing with a split-thickness skin graft (stsg) has been the most reproduced and successful option due to its technical ease and superiority compared to flaps (10). in this paper, we describe a yet unpublished surgical approach of partial skin excision and resurfacing with a stsg with good functional and cosmetic outcomes for treatment of post-silicone penile injection late complication for girth augmentation (figures 1, 2). methods surgical technique: partial degloving and resurfacing with stsg the patient is placed under general anesthesia in supine position. wide spectrum antibiotic prophylaxis is given (piperacillin-tazobactam). the patient needs to be prepped and draped in a sterile manner, including the antero-lateral (left or right) thigh for stsg harvest. a silk traction suture is placed at the penis glans (this traction will be kept after the procedure). penile physical examination is performed under general anesthesia to delineate the affected area that will have to be resected (figure 3). a partial circumcising incision at the base of the corona is performed from 3 to 9 o’clock, or more if the foreign material extends forward, and the incision is extended down the dorsal aspect of the penile shaft, surrounding all the affected area where foreign material can be palpated (figure 4). then, the siliconoma is carefully dissected off the buck’s fascia introduction: siliconoma represents an inflammatory tissue response to extravasated silicone. penile enhancing silicone injections have been described for over 50 years. most of the publications report complications including negative effects on penile appearance and function which require corrective procedures. penile circumferential skin and siliconoma excision with skin grafting has been described in multiple case reports and series as an effective and feasible option to remove the silicone and achieve good esthetic results. methods: we describe a simple and feasible single stage procedure removing the siliconoma with adjacent non-viable skin while preserving 50% of healthy penile skin and resurfacing the defect with a split-thickness skin graft to treat a long-term complication of penile silicone injection associated with recurrent infections and a chronic skin ulceration. conclusion: partial excision of the affected penile skin and siliconoma with defect resurfacing with a split-thickness skin graft is a feasible with good functional and cosmetic outcomes. key words: penis; siliconoma; penile silicone injection; penile reconstruction; penile enlargement. submitted 12 january 2023; accepted 30 january 2023 introduction the penis has long been considered an essential part of masculinity, and its size and girth have been related to virility, sexual performance and even power. various cultures around the world have historically described rituals and processes involving penile manipulations to increase size and girth (1). exposure to pornographic content may lead men to have distorted perceptions of the normal size and appearance of genitalia and consequently seek out esthetic procedures (2, 3). the average penile length and girth are 9 cm and 9-10 cm respectively in a flaccid state, and 14-16 cm and 12-13 cm respectively in an erect state (3). most men seeking out length and/or girth augmentation have normal penile parameters and may suffer from penile dysmorphophobia (3, 4). filler injections to increase penile girth date back to the early 1900s, when liquid paraffin and other mineral oils were used. these substances frequently caused severe adverse effects, including infection and risk of penile loss. eventually, liquid injectable silicone began to be used (3, 5). although there have been reports of satisfactory results alternative surgical management of penile siliconoma using partial degloving and resurfacing manuel belmonte chico goerne 1, abdulghani khogeer 1, 2, peter davison 3, serge carrier 1, melanie aubé-peterkin 1 1 department of urology, mcgill university health center, montreal, canada; 2 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 3 department of plastic surgery, mcgill university health center, montreal, canada. doi: 10.4081/aiua.2023.11150 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. belmonte chico goerne, a. khogeer, p. davison, s. carrier, m. aubé-peterkin dorsal nerves that could be coursed through the siliconoma and hard to be spared. the siliconoma and overlying abnormal skin must be completely excised up to the suprapubic area, or wherever its limit is located, and the affected segment must be removed (figure 7). the ventral penile skin is preserved as our technique is for cases where the dorsal aspect of the penis is affected while the ventral is intact, healthy, and vascularized. if dissection extents proximally to the proximal corporal bodies, it’s better to fix them to the suprapubic tissue with 3-0 pds or similar, to exteriorize the penile shaft and avoid loss of length, also, doing this fixation prevents a potential dead space, and subsequent seroma formation. after the removal of the foreign material and the corporal bodies fixation, the removed skin is templated and measured for skin graft. a distal 0.014 inch stsg is harvested from the previously prepped donor area (we suggest the thigh) using a dermatome, then, the graft is slightly fenestrated to prevent hematoma formation. the stsg is inset with plain gut sutures (preferably 4-0 chromic), and then adjusted accordingly to the penile defect, so the excess graft is tailored to fit the defect (figure 8). once the graft is fixed, a 16-fr urinary catheter is installed. there are plenty dressing options that can be used for these kinds of procedures; a good option is an adaptic™ dressing. a single layer of adaptic™ dressing can be applied, and then, a tailored black vacuum assisted closure (vac) sponge is placed over the stsg; the remainder of the vac dressing is applied in the usual fashion (figure 9). then, the penile traction has to be kept to prevent disadherence of the vac dressing. to do so, we sugfigure 1. ulceration extending through all layers of the skin and subcutaneous tissue, exposing buck’s fascia. figure 2. complete ulcer healing after two months of dressing. figure 3. palpable silicone on the dorsal aspect of the penile shaft extending to the suprapubic area. figure 7. complete excision of the siliconoma and overlying abnormal skin up to the suprapubic area. figure 8. split-thickness skin graft application on the dorsal penile defect and sutured by 4-0 chromic. figure 4. partial circumcising incision at the base of the corona from 3 to 9 o’clock extended down the dorsal aspect of the penile shaft. figures 5, 6. siliconoma dissection off the buck’s fascia and the dorsal neurovascular bundle. figure 9. single layer adaptic™ dressing and vacuum assisted closure sponge were placed over the graft. and the dorsal neurovascular bundle (figures 5, 6). at this point, we must be careful of damaging the branches of the archivio italiano di urologia e andrologia 2023; 95, 1 surgical management of penile siliconoma gest a protective outer sheath, which can be tailored with an empty 1000 cc saline plastic bottle or similar, and then create a small opening where the suture can be fixed in a manner the penis is kept straight (important to avoid excessive traction). finally, the graft harvest site is draped with xeroform™ and a dry dressing. after the surgery, the vac and urinary catheter were removed on post-operative day five, when usually the graft has taken; if necessary, they can be kept longer. once the patient is discharged, daily dressing changes and a silver nitrate dressing on the donor site are mandatory to secure an optimal healing (figure 10). subsequently, on post-operative day 12, the stsg has an excellent take (figure 11), and the donor site shows signs of a good healing. the postoperative pain is mild and usually triggered by erections. glans numbness might be reported in cases of aggressive neurovascular bundle dissection or when the foreign material was markedly adherent. after one month, the penis usually shows an excellent healing with an excellent esthetic outcomes, achieving patient’s satisfaction (figures 12, 13). after two months, the improving continues; typically, the painful erections and glans numbness subside (figure 14). discussion penile enhancement procedures continue to be offered despite multiple case reports and series published in current medical literature depicting potentially devastating complications ranging for erectile dysfunction to penile deformity and even penile loss (3, 7, 8). despite small case series describing «successful» short-term follow-up with penile fillers (3), there are no current formal society guidelines supporting the use of these procedures. furthermore, these experimental procedures lack standardization, and no prospective trials or studies on large cohorts currently demonstrate their safety and feasibility. the defects and complications resulting from enhancement procedures can be difficult to manage, and to do so, reconstructive penile surgery is needed, which of the existing techniques will be used vary depending on the extent of the imperfection, and the involvement of different structures. currently, two of the most used are the scrotal flap (dartos fascio-myo-cutaneous flap) and the circumferential penile skin excision with stsg resurfacing. the goal of any of these reconstructive surgery techniques is to retrieve penis functionality and aspect. the scrotal flaps provide high aesthetic results and postoperative satisfaction with high flap viability, and they can be used for the treatment of various urogenital defects, regardless of its severity (11). surgical methods of this technique range from single-sided scrotal axial flap for defect closure to a combination of multistage stacked flap methods; scrotal axial flaps always requires an intact donor site and they are often used for patients with defects due to penile enhancement injections (11). stsg is an easy and effective technique capable of covering large surfaces of skin loss, and at the same time provide excellent functional and aesthetic outcomes (12). to perform this technique, usually the penile skin is excised, extending to the scrotum if necessary, preserving dartos as much as possible, since it facilitates the graft mobility. after dissection is done, and the graft harvested, it is placed over the defect and tacked in with sutures (usually chromic), securing it at the base and the neo-ventral raphe that is created (for this a total penile degloving is needed) (12). in this paper, we describe a partial penile skin degloving and stsg resurfacing, which to our knowledge is the first manuscript in current medical english literature to do so, as circumferential penile skin excision with stsg resurfacing has only been described to date. despite good esthetic and erectile function results obtained with circumferential penile skin excision, it was hypothesized by the authors that a partial penile degloving limited to the affected area would decrease the morbidity of the procedure, the risk of figure 10. home discharge on day five with daily dressing changes and a silver nitrate dressing on the donor site. figure 11. postoperative day 12, excellent take of the graft. figure 12. excellent esthetic outcomes and healing at one month. figure 13. excellent esthetic outcomes and healing at one month.. figure 14. two months after the procedure. archivio italiano di urologia e andrologia 2023; 95, 1 m. belmonte chico goerne, a. khogeer, p. davison, s. carrier, m. aubé-peterkin vascular or nerve damage while preserving normal and well vascularized native penile tissue. a smaller defect also decreases the morbidity of the stsg harvest site. currently, one of the most described alternative options for penile and scrotal reconstruction either post silicone excision or trauma (iatrogenic, burns, animal bites, gunshots, self-mutilation, circumcision, etc.) is the scrotal flap technique (13, 14). this technique is mostly used in cases with extensive penile scarring, concurrent scrotal migration and when the use of stsg is not possible (13). finally, proper patient counseling prior to silicone excision and penile reconstruction is primordial to address all possible future functional or esthetic outcomes. patient should be informed about the risk of penile skin and glans hypoesthesia, erectile dysfunction, penile curvature, residual silicone materials and any graft related complications. conclusions injection of foreign materials such as silicone for penile enhancement may lead to devastating complications and this practice is not currently supported by formal society guidelines. partial excision of the affected penile skin and siliconoma with resurfacing of the defect with a stsg is a feasible reconstructive technique in select cases with areas of intact penile anatomy while limiting the potential morbidity of circumferential penile degloving and a large stsg donor site defect. references 1. francoeur r, perper t, scherzeer na. descriptive dictionary, and atlas of sexology. greenwood press, new york; 1991. 2. alter gj, salgado cj, chim h. aesthetic surgery of the male genitalia. semin plast surg. 2011; 25:189-195. 3. bizic mr, djordjevic ml. penile enhancement surgery: an overview. emj urology. 2016; 4:94-100. 4. vardi y, har-shai y, gil t, gruenwald i. a critical analysis of penile enhancement procedures for patients with normal penile size: surgical techniques, success, and complications [published correction appears in eur urol. 2009; 55:1002. harshai, yaron [corrected to har-shai, yaron]]. eur urol. 2008; 54:1042-1050. 5. oates j, sharp g. nonsurgical medical penile girth augmentation: experience-based recommendations. aesthet surg j. 2017; 37:10321038. 6. yacobi y, tsivian a, grinberg r, kessler o. short-term results of incremental penile girth enhancement using liquid injectable silicone: words of praise for a change. asian j androl. 2007; 9:408-413. 7. silberstein j, downs t, goldstein i. penile injection with silicone: case report and review of the literature. j sex med. 2008; 5:2231-2237. 8. lee t, choi hr, lee yt, lee yh. paraffinoma of the penis. yonsei med j. 1994; 35:344-348. 9. lighterman i. silicone granuloma of the penis. case reports. plast reconstr surg. 1976; 57:517-519. 10. cavalcanti ag, hazan a, favorito la. surgical reconstruction after liquid silicone injection for penile augmentation. plast reconstr surg. 2006; 117:1660-1661. 11. adamyan rt, kamalov aa, ehoyan mm, et al. scrotal tissues: the perfect material for urogenital reconstruction. plast reconstr surg glob open. 2020; 8:e2948. 12. alwaal a, mcaninch jw, harris cr, breyer bn. utilities of split-thickness skin grafting for male genital reconstruction. urology. 2015; 86:835-839. 13. asanad k, banapour p, asanad s, et al. scrotal flap reconstruction for treatment of erectile dysfunction following penile enhancement with liquid silicone. urol case rep. 2018;20:75-77. 14. moussa m, abou chakra m. scrotal dartos-fascio-myocutaneous flaps for penis reconstruction after iatrogenic skin shaft sub-amputation. j surg case rep. 2019; 2019:rjz206. correspondence manuel belmonte chico goerne, md manuel.belmontecg@gmail.com abdulghani khogeer, md dr-abdulghani@hotmail.com serge carrier, md serge.carrier@mcgill.ca melanie aube-peterkin, md (corresponding author) melanie.aube-peterkin@mcgill.ca department of urology, mcgill university health center 1001 boulevard decarie, suite d05.5331, montreal, quebec h4a 3j1 (canada) peter davison, md peter.davison@mcgill.ca department of plastic surgery, mcgill university health center, montreal (canada) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 459archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. ter techniques and thinner suture materials reduce the rate of complications (1). better wound dress materials and surgery with or without stent were also discussed to improve the results. seniors had experienced that patients with same characteristics, operated with the same technique and material by the same surgeon had different results. the difference may be depending on subclinical inflammation that may be a predictor about these unexpected complications. the neutrophils and the lymphocytes are the main cellular components of the immune system of human being. during an infection the level of white blood cells may vary depending on the stage of the disease, the patient’s immunologic features and the etiology of the infection. increment in the level of neutrophils and reduction in the level of lymphocytes shows a possible infection (2). all these parameters can be measured in complete blood count (cbc). physiological immune response of circulating white blood to various stressful events such as tissue injury, severe trauma characterized by major surgery, burns, sepsis syndrome consists in elevation of neutrophils and decrease of lymphocyte counts. this inflammatory response sometimes causes fibrosis and poor neovascularization which are the main factors for poor wound healing (3). it is shown that spongiofibrosis with urethral stricture was related with inflammation (4, 5). several medications with anti-inflammatory effect have been used to treat urethral strictures either systematically or locally (6-10). in adult’s series, it was reported that neutrophillymphocyte ratio (nlr) revealed the inflammatory status of the urethral tissue predicting urethral stricture after non-hypospadias surgery (11). also, nlr was shown as a marker to predict for systemic inflammatory response syndrome after flexible ureteroscopic lithotripsy (12). subclinical systemic inflammation may have impact on the outcomes of hypospadias repair in children. preoperatively the number of white blood cell (wbc) and neutrophils, nlr, platelet-lymphocyte ratio (plr) or mean platelet volume (mpv) may predict complications after hypospadias surgery, but this was not studied yet. the objective: surgeons observed that the outcomes after the same repair technique in the same type of hypospadias performed by the same surgeon may be different. there may be some indeterminate factors that influence the results such as subclinical inflammation. our study evaluated the predictor values of inflammatory hematologic parameters on the complications after hypospadias repair. materials and methods: we retrospectively reviewed the data of patients who underwent hypospadias repair between january 2016 and january 2019 in our clinic. age at surgery, hypospadias type, repair technique, complications were recorded. patients who underwent snodgrass repair by a single surgeon were included in the study while patients who underwent different techniques or procedures that were performed by other surgeons were excluded. the levels of white blood cell, neutrophil, lymphocyte, platelet and monocyte, the mean platelet volumes were recorded from blood test that were performed one day before surgery. neutrophil-lymphocyte ratio (nlr), plateletlymphocyte ratio (plr), and other parameters were analyzed to determine their relationship with complications after hypospadias surgery. results: wbc and neutrophil levels were statistically higher in patients with complications (p = 0.006 and 0.017 respectively). other hematological parameters were not different between patients with or without complications. to predict the complications, the wbc cutoff was 9500/mm3, the neutrophil cutoff was 3000/mm3. conclusions: wbc and neutrophil values were statistically significant in predicting the complications after snodgrass repair in patients with hypospadias. our result determined no relation between complications and nlr, plr. key words: hypospadias; leukocyte; neutrophil; nlr; complication. submitted 11 september 2022; accepted 24 september 2022 introduction hypospadias repair is one of the most common surgery in pediatric urology. more than 100 different procedures were described to obtain better results, but complication rates are still a challenge for the surgeons. however betdo preoperative leukocyte and neutrophil levels have a predictive value on the complications of hypospadias repair in children? ahsen karagözlü akgül 1, sadık abidoğlu 1, ayten ceren bakır 2, embiye adalı 3, gürsu kıyan 4, halil tuğtupe 5 1 marmara university faculty of medicine, department of pediatric surgery, division of pediatric urology, istanbul, turkey; 2 ministry of health, marmara university pendik education and research hospital, department of pediatric surgery, istanbul, turkey; 3 st. helens and knowsley teaching hospitals, department of pediatric accident and emergency medicine; 4 marmara university faculty of medicine, department of pediatric surgery, istanbul, turkey; 5 tuğtepe center of pediatric urology and pediatric surgery, istanbul, turkey. doi: 10.4081/aiua.2022.4.459 summary archivio italiano di urologia e andrologia 2022; 94, 4 a. karagözlü akgül, s. abidoğlu, a. ceren bakır, e. adalı, g. kıyan, h. tuğtupe 460 aim of the present study is to investigate the relationship between the hematologic parameters and the complications after hypospadias repair in children. materials and methods institutional review board approval was obtained before chart review and data analysis with the reference number of 09.2020.1155. informed consent was approved by the parents of all patients. records of the children who underwent hypospadias repair between january 2015 and january 2019 in our clinic were reviewed. data collected included age of the patients, types of hypospadias, repair techniques, suture materials, surgeons who performed the hypospadias repair, follow-up time, complications, and hematological parameters. hematological parameters including white blood count (wbc), neutrophil, lymphocyte, monocytes, platelet counts, and mean platelet volume were recorded from the complete blood count (cbc) which was performed the day before surgery. patients with hypospadias who underwent tubularized incised plate urethroplasty (tipu) repair by a single surgeon (ht) were included. patients with abnormal wbc values for their age in the complete blood count the day before the operation were excluded. patients with follow up time shorter than 12 months and incomplete data were not recorded. in the study period 522 patients who underwent hypospadias repair were recorded. 59 patients whose complete blood count was not performed the day before the surgery, 6 patients whose wbc values were not within the normal range for their age, 163 patients who underwent two-session hypospadias repair or who underwent hypospadias repair with another technique, 99 patients who were operated by other surgeons, and 32 patients who underwent caudal anesthesia, whose effect on the outcomes after hypospadias repair is controversial, were excluded from the study (figure 1). patients were divided into two groups depending on the presence of complication. hematological parameters detected from cbc were statistically analyzed whether if they are related with complications or not. operative technique all procedures were performed under general anesthesia and penile block was performed at the beginning of the procedure. sterile urine was controlled with urine culture 3-7 days before the surgery. antibiotic prophylaxis was applied one-hour prior the surgery. all patients underwent tipu technique by the same surgeon (ht). the urethral plate was tabularized over a 6 fr urethral catheter in two layers, the first layer with continuous subcuticular 7/0 coated polyglactin sutures and the second layer with interrupted 7/0 coated polyglactin sutures. tourniquet for less than 15 minutes was used while the dissection of glandular wings. a pedicle flap from dartos fascia was prepared and placed on the neourethra. glanduloplasty was done with 6/0 polydioxanone sutures. subcutaneous epinephrine was not used during surgery. the 6 fr urethral catheter was left in place for seven days postoperatively. the patients were followed up in the second week, first month and third month postoperatively. follow-up continues with outpatient visits every 3 months in the first year and once a year thereafter. patients were evaluated for penile cosmetics, meatal and urethral stenotable 1. demographic features and hematological parameters of patients in the groups. complication (-) complications (+) mean ± sd/n-% median mean ± sd/n-% median p age at surgery (months) 43.5 ± 32.9 33.5 45.5 ± 38.4 29.0 0.874 m type of the hypospadias distal 101 80.2% 21 56.8% 0.008 x2 midpenile 22 17.5% 12 32.4% 0.082 x2 proximal 3 2.4% 4 10.8% 0.078 x2 wbc (x103) 8.8 ± 2.5 8.5 10.2 ± 3.0 9.7 0.006 m neutrophil 3356 ± 1563 3000 4176 ± 2054 3700 0.017 m lymphocyte 4302 ± 1726 4100 4630 ± 2372 4300 0.529 m monocyte 808 ± 462 700 803 ± 246 700 0.303 m hb 12.0 ± 1.1 11.9 12.0 ± 1.1 11.9 0.810 m plt (x103) 316.0 ± 83.4 313.5 325.5 ± 86.1 313.0 0.563 m nlr 0.9 ± 0.5 0.8 1.4 ± 1.6 0.9 0.240 m plr 83.6 ± 34.7 80.2 102.7 ± 116.9 85.9 0.876 m mlr 0.2 ± 0.2 0.2 0.2 ± 0.2 0.2 0.768 m mpv 7.7 ± 0.8 7.6 7.8 ± 0.8 7.7 0.504 m mmann-whitney u test. x2 chi-square test. wbc: white blood cell; hb: hemoglobin; plt: platelet; nlr: neutrophil-lymphocyte ratio; plr: platelet-lymphocyte ratio; mlr: monocyte-lymphocyte ratio; mpv: mean platelet volume. figure 1. flowchart. 461archivio italiano di urologia e andrologia 2022; 94, 4 wbc/nlr predicting outcome of hypospadias sis, urethrocutaneous fistula and for other complications with physical examination, calibration of the neourethra with 6-8 fr catheter and voiding video. statistical analysis in the descriptive statistics of the data, mean, standard deviation, median, minimum, maximum, frequency and ratio values were used. the distribution of variables was measured with the kolmogorov-smirnov test. the mann-whitney u test was used in the analysis of quantitative independent data. chi-square test was used in the analysis of qualitative independent data, and fisher-exact test was used when the chi-square test conditions were not met. roc curve was performed to analyze the capacity of hematological parameters in predicting the complication of hypospadias repair. probability chart was performed to determine the possibility of complications after surgery. cut off values were determined according to youden index. spss 27.0 program was used in the analysis. all p-values less than 0.05 were considered statistically significant. results one hundred sixty-three patients were analyzed retrospectively. the median age of the patients was 32 months (table 1). of the patients, 122 had distal hypospadias, 34 had midpenile hypospadias, and 7 had proximal hypospadias. there were 126 patients without complication and 37 with complications. the complications were urethral fistula in 19 patients, urethral stricture requiring reoperation in 3 patients, urethral diverticula in 3 patients, dehiscence (partial or complete) in 4 patients and mild meatal stenosis that solved with dilatation in 8 patients. patients were divided into two groups according to the presence of complications and there was no difference between groups in case of age at operation (p > 0.05) (table 1). the ratio of complications in patients with distal hypospadias was lower than the ratio of complications in patients with mid-penile and proximal hypospadias (p = 0.008). wbc and neutrophil levels were statistically higher in patients with complications (p < 0.05) (table 1, figure 2). nlr, plr and other hematological parameters were not different between patients with or without complications (table 1). although area under curve (auc) was not so high, significant effectiveness of wbc value was observed in predicting patients with and without complications (table 2). wbc value was found to be a significant variable in the occurrence of complications. the cut off value of wbc to predict the complications was 9500 m/mm3, the sensitivity was 56.8%, specificity was 70.6%, (figure 3), positive prediction was 36.2%, and negative prediction was 84.8%. in predicting the patients with and without complications, the neutrophil count was also statistically significant (table 2). the neutrophils cut off value to predict the complications was 3000 m/mm3, the sensitivity was 70.3%, specificity was 51.6% (figure 3), positive prediction was 29.9%, and negative prediction was 85.5%. there was no statistically significant difference in nlr, plr, mpv and also wbc and neutrophils between patients with or without urethral fistula (p > 0.05). table 2. area under curve for wbc and neutrophil values. auc 95% cl p wbc 0.647 0.544 0.751 0.006 neutrophil 0.629 0.527 0.731 0.017 wbc: white blood cell; auc: area under curve. figure 2. wbc: white blood cell. figure 3. graphics of sensitivity and specificity of wbc and neutrophil values. archivio italiano di urologia e andrologia 2022; 94, 4 a. karagözlü akgül, s. abidoğlu, a. ceren bakır, e. adalı, g. kıyan, h. tuğtupe 462 discussion complications of hypospadias repair are reported frequently in the previous literature (1, 13). especially the complications of the tipu which is a commonly used technique are well known by pediatric urologists. the main complications of this technique are urethral stricture, meatal stricture, urethral fistula, and dehiscence (14). to reduce the complication rate, surgeons used better suture materials, preferred waterproof and tension free suture lines, using dartos flap on the neourethra, etc. (15). but it is observed that results were different in patients with the same hypospadias type who underwent exactly same repair technique with using high-quality suture materials by same experienced surgeon. the reasons of this difference are not clear yet. subclinical inflammation may be a factor for complications of hypospadias surgery and our study revealed that wbc or neutrophil value could be predictors for these complications. wbc differs in the systemic inflammation. this inflammatory response sometimes causes fibrosis and poor neovascularization which are the main factors for poor wound healing (3). hampson et al. reported subepithelial inflammation results with spongiofibrosis (5). mundy reported a review article in 2011 and determined that 40% of urethral strictures were related with inflammation (4). sciarra et al. (6) used anti-inflammatory drugs to reduce urethral complications after turp. based on the same mechanism, several medications including colchicine (16), mitomycin-c (7), triamcinolone (8), and corticosteroids (9), which all have anti-inflammatory effects, have been used to treat urethral strictures either systematically or locally. therefore, subclinical systemic inflammation may have impact on the outcomes of hypospadias repair. level of leukocyte and neutrophils, neutrophil-to-lymphocyte ratio (nlr), plateletto-lymphocyte ratio (plr) and mean platelet volume (mpv) are simple markers that can reflect the inflammation which can easily be obtained from cbc (18-21). this study evaluated the predictive values of the wbc, neutrophils, nlr, plr and mpv on the results of hypospadias repair. the best of our knowledge, this study is the first study that evaluate the value or capacity of hematological parameters in predicting the complications of hypospadias repair in children. there are three studies that evaluated the impact of these parameters in recurrence of urethral stricture after surgical treatment in adults (10, 11, 22). topaktas et al. (22) had reported 117 adult cases with urethral stricture who underwent urethroplasty and assessed the correlation between the systemic inflammation markers and recurrence rate of urethral stricture after surgery. they determined that neutrophil, lymphocyte counts, or their ratio are not the predictors for recurrence urethral stricture after urethroplasty. urkmez et al. (11) reported a study to determine the impact of these parameters in predicting the course of the urethral stricture and its recurrence in adults and they emphasized that by using nlr, inflammatory status of the urethral tissue can be revealed, and possible urethral stricture recurrence can be predicted. gül et al. (10) reported the value of hematologic parameters in predicting urethral stricture after transurethral resection of prostate and determined that plr can be used to predict the urethral stricture. our results revealed that wbc value and neutrophil counts are related with complications after hypospadias repair (figure 4). however, other parameters such as nlr, plr, mlr, and mpv were not indicative of postoperative complications. urkmez et al. (11) reported that the cut-off value of nlr in detecting the recurrence after internal urethrotomy was 2.25 with a sensitivity of 70% and specificity of 67.7%. our study revealed that the cut off value of wbc to predict the complications was 9500 m/mm3 (auc: 0.647, p = 0.006), the sensitivity was 56.8%, positive prediction was 36.2%, specificity was 70.6%, and negative prediction was 84.8%. the neutrophil’s cut off value to predict the complications was 3000 m/mm3 (auc: 0.629, p = 0.017), the sensitivity was 70.3%, positive prediction was 29.9%, specificity was 51.6%, and negative prediction was 85.5%. the major limitation of our study is its retrospective design. we did not analyze the penile lengths of the patients such as glans diameter, width of the plate and depth of the groove. although some studies suggested that these measurements have impact on the outcomes of the hypospadias repair (23-25), bush and snodgrass argue that there is no effect of these factors on postoperative complications (26). single surgeon and single operative technique with exactly the same details such as penile block and tourniquet use, also not using caudal block and local epinephrine are the superiority of our study. the considerable number of patients of this study is another superiority. conclusions wbc and neutrophil values were higher in pediatric patients with complications who underwent tipu repair by single surgeon. other hematological parameters such figure 4. possibility graphics for wbc and neutrophil values. 463archivio italiano di urologia e andrologia 2022; 94, 4 wbc/nlr predicting outcome of hypospadias as nlr, plr, mlr were not related with complications after hypospadias repair. our results revealed that postponing the hypospadias surgery may be more appropriate in patients with high blood wbc and neutrophil values. references 1. retik ab, atala a. complications of hypospadias repair. urol clin north am. 2002; 29:329-339. 2. dursun a, ozsoylu s, akyildiz bn. neutrophil-to-lymphocyte ratio and mean platelet volume can be useful markers to predict sepsis in children. pak j med sci 2018; 34:918-922. 3. chapman d, kinnaird a, rourke k. independent predictors of stricture recurrence following urethroplasty for isolated bulbar urethral strictures. j urol. 2017; 198:1107-1112. 4. mundy ar, andrich de. urethral strictures. bju international. 2011; 107:6-26. 5. hampson la, mcaninch jw, breyer bn. male urethral strictures and their management. nat rev urol. 2014; 11:43-50. 6. sciarra a, salciccia s, albanesi l, et al. use of cyclooxygenase-2 inhibitor for prevention of urethral strictures secondary to transurethral resection of the prostate. urology. 2005; 66:1218-1222. 7. mazdak h, meshki i, ghassami f. effect of mitomycin c on anterior urethral stricture recurrence after internal urethrotomy. eur urol. 2007; 51:1089-1092. 8. tabassi kt, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j. 2011; 8:132-136. 9. zhang k, qi e, zhang y, et al. efficacy and safety of local steroids for urethra strictures: a systematic review and meta-analysis. j endourol. 2014; 28:962-968. 10. gül m, altıntas e, kaynar m, et al. the predictive value of platelet to lymphocyte and neutrophil to lymphocyte ratio in determining urethral stricture after transurethral resection of prostate. turk j urol. 2017; 43:325-329. 11. urkmez a, topaktas r, ozsoy e, et al. is neutrophil to lymphocyte ratio a predictive factor for recurrence of urethral stricture? rev assoc med bras. 2019; 65:1448-1453. 12. bai r, gao l, jiang l, et al. the validity of neutrophil/lymphocyte ratio as a predictive factor for systemic inflammatory response syndrome after flexible ureteroscopy lithotripsy. urol j. 2022; 19:17-21. 13. faasse ma, liu db. early vs. late-presenting urethroplasty complications after hypospadias repair: a retrospective analysis of patient follow-up. j pediatr urol. 2017; 13:354.e1-354.e5. 14. snodgrass w, villanueva c, bush nc. duration of follow-up to diagnose hypospadias urethroplasty complications. j pediatr urol. 2014; 10:208-211. 15. hadidi at. history of hypospadias: lost in translation. j pediatr surg. 2017; 52:211-217. 16. urkmez a, topaktas r, ozsoy e, et al. is neutrophil to lymphocyte ratio a predictive factor for recurrence of urethral stricture? rev assoc med bras. 2019; 65:1448-1453. 17. carney kj, house j, tillett j. 38: effects of dviu and colchicine combination therapy on recurrent anterior urethral strictures. j urol. 2007; 177:14-14. 18. polat n, yildiz a, yuksel m, et al. association of neutrophil-lymphocyte ratio with the presence and severity of rheumatic mitral valve stenosis. clin appl thromb hemost. 2014; 20:793-8. 19. alkhouri n, morris-stiff g, campbell c, et al. neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease. liver int. 2012; 32:297-302. 20. raungkaewmanee s, tangjitgamol s, manusirivithaya s, et al. platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. j gynecol oncol. 2012; 23:265-273. 21. kim ey, lee jw, yoo hm, et al. the platelet-to-lymphocyte ratio versus neutrophil-to-lymphocyte ratio: which is better as a prognostic factor in gastric cancer? ann surg oncol. 2015; 22:4363-4370. 22. topaktas r. hematologic parameters and neutrophil/lymphocyte ratio in the prediction of urethroplasty success. int braz j urol. 2019; 45:369-375. 23. holland aja, smith ghh. effect of the depth and width of the urethral plate on tubularized incised plate urethroplasty. j urol. 2000; 164:489-491. 24. tugtepe h, thomas dt, calikli z, et al. a new objective scoring system for the prediction of complications after hypospadias surgery. in: 29th congress of espu abstract book; 2018:96. 25. sarhan o, saad m, helmy t, et al. effect of suturing technique and urethral plate characteristics on complication rate following hypospadias repair: a prospective randomized study. j urol. 2009; 182:682-686. 26. bush nc, snodgrass w. pre-incision urethral plate width does not impact short-term tubularized incised plate urethroplasty outcomes. j pediatr urol. 2017; 13:625.e1-625.e6. correspondence ahsen karagözlü akgül, md (corresponding author) ahsenkaragozlu@yahoo.com sadık abidoğlu, md s_abidoglu@yahoo.com marmara university, pendik education and research hospital, department of pediatric surgery, division of pediatric urology fevzi çakmak, muhsin yazıcıoğlu cd. no:10, 34899 pendik, istanbul (turkey) ayten ceren bakır, md aytenceren@gmail.com fevzi çakmak, muhsin yazıcıoğlu cd. no:10, 34899 pendik, istanbul (turkey) embiye adalı, md embiye.mba@gmail.com apartment 503, west africa house, 25 water street, liverpool, l2 0rg (united kingdom) gürsu kıyan, md gursukiyan@gmail.com fevzi çakmak, muhsin yazıcıoğlu cd. no:10, 34899 pendik, istanbul (turkey) halil tuğtupe, md htugtepe@yahoo.com küçükbakkalköy mah. işıklar cad, şenlik sokağı no:14/a, 34750 ataşehir/istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12363 1 case report case report a 76-year-old man presented as an outpatient at apuane hospital (massa, italy) in january 2022, having noticed a volumetric increase in the scrotum for some years (figure 1). his past medical history was significant only for a remote history of childhood exanthematous diseases and a picture of initial decline in cognitive function. the patient did not report recent trauma or episodes of scrotum-perineal pain. on physical examination, an enlarged scrotum with a firm mass that was not tender to palpation was noted. an in-office ultrasound identified uneven tissue and the presence of a reflective foreign body. an abdominal-pelvic ct scan confirmed the presence of a radio-opaque, ‘beaded’ foreign body in the scrotum (figure 2) with testicles in place and uninjured. one week later, he was admitted to the hospital. under assisted spinal anesthesia in the lithotomy position, a scrotoperineal access was performed using a cruciate ‘mercedes-like’ incision. the median incision of the cross allowed the opening of the scrotal bags and the vaginal tunics, with isolation of the right and left spermatic cords, and of the testicles, bilaterally. the spermatic cords were isolated and the testicles secured and lateralized with a wider exposure of the operative field. surgical exploration revealed the presence of an abscess with a capsule adherent to the surrounding tissues that was clearly identifiable. the capsule was gently detached from the surrounding planes where it had created strong adhesions. the detachment was guided by the finger with tactile perception of the foreign body retained inside the abscess. during the procedure, the abscess capsule burst open, causing brown pus to ooze out; liquid cultures were sent. the foreign body was kept in place until complete excision of the sheath to create a guide for the direction of the abscess capsule in order to completely excise it. the foreign body was found to be a 10-cm stainless steel nail (figure 3). once the abscess and the foreign body were removed, a surgical toilet was performed, including multiple washings of the field with povidone iodine and hydrogen peroxide. the final washing was carried out with abundant saline solution. a povidone iodine gauze and two suction background: the retention of foreign bodies inside the body during ludic/sexual procedures or for traumatism represents one of the causes of visits to accident and emergency departments that often requires surgical removal of the foreign body. however, there are cases where the discovery of such foreign bodies takes place after many years, as in patients that are slightly compromised from a neuro-sociological point of view. case presentation: a 76-year-old male presented to an outpatient urological examination due to an increase in scrotal volume. at the ultrasound check, an acoustic interference from a solid object was detected, for which computed tomography was requested. the computed tomography scan revealed the presence of an elongated metal body in the perineum. the removal of the foreign body in the operating theatre was then scheduled. a 10 cm long stainless-steel nail located within an abscessed foreign body granuloma was identified and removed via a scrotal access. four days later, a new surgical toilet was performed due to minimal necrosis of the skin flaps. the patient then performed three more dressings in the operating theatre during the following week. healing took place by secondary intention until a perfect healing of the surgical wound was obtained. conclusions: removal of foreign bodies from the perineum in case of infection can be challenging. careful attention and postoperative dressings are crucial for the success of the case. key words: abscess; foreign body; infection; perineal wound. submitted 6 february 2024; accepted 10 february 2024 introduction the choice of access, strategy, and timing for the removal of foreign bodies is determined by their shape, size, location, and potential mobility. they often require careful and sometimes multidisciplinary planning for strategy optimization. although it remains uncommon in everyday practice, a rapid surgical exploration of penetrating scrotal injury is nevertheless required to accurately evaluate the involvement of genitourinary and reproductive organs (1). in this paper, we describe the sensitive management of a patient with a rare finding of a nail of about 12 cm lodged in the scrotum and enclosed within an abscess. management of an elderly patient with retention of a steel nail in the scrotum: a case report iacopo meneghetti 1, novella cesta 2, luca mosillo 1, simone belli 1, daniele bianchi 1, maurizio de maria 1 1 urology department, hospital apuane, massa, italy; 2 infectious diseases department, hospital apuane, massa, italy. doi: 10.4081/aiua.2024.12363 summary archivio italiano di urologia e andrologia 2024; 96(2):12363 i. meneghetti, n. cesta, l. mosillo, et al. 2 drains (airtight) were left in place with partial closure of the superficial planes. a second look was scheduled on the fourth postoperative day. during the second look, the tips of the skin flaps appeared blackish as a sign of ischemic suffering for a few millimeters from the free edge, so they were trimmed with a cold knife until bleeding vital tissue was reached. the wound was again cleaned with povidone iodine, and one suction drain was again applied. two days later, a third look found vital tissues, so deep-tissue debridement of the wound was performed. at fourth and fifth look in the operating theatre on the eighth and tenth days, respectively, a deep disinfection of the field was performed and the skin flaps were brought together so that there was no tension, leaving a very small space in the center of the star with the aim of healing by secondary intention. during the remaining hospitalization, the patient was treated daily with povidone iodine disinfection. he was discharged on the 16th postoperative day with a bladder catheter. antibiotic therapy with intravenous ceftriaxone 2gr q24h was empirically started. a blood culture was negative for bacteria, and no microbiological growth was detected in the samples collected during surgery. because of the persistence of elevated serum c-reactive protein (17 ng/ml), on the third postoperative day, the therapy was modified in piperacillin/tazobactam 4.5 gr q8h by the infectious diseases consultant and continued for three weeks. the patient removed the bladder catheter on the 30th day as an outpatient, with clear urine output and no postvoiding residue. dressings were applied at home by the patient daily and every week in the clinic for six weeks. at the final check-up at two months, the wound was completely healed and the patient was fine. discussion an operation to remove a foreign body must always be planned in detail. a ct is essential to evaluate the location of the foreign body and associated abscess structures and the organs involved. the surgeon also needs a ct to be able to choose the best access to ensure adequate exposure of the fields, as not completely cleaning of an infected area is the first step for the therapeutic failure. figure 1. aspect of the preoperative clinical picture of the case. note the increase in scrotal volume due to the retention of the foreign body. figure 2. ct scan evidenced the presence of an abundant, apparently biloculated effusion in the scrotal area which cranially reached the left gluteal region. in the scrotal area, the presence of a linear metallic image was also noted. figure 3. extracted stainless steel nail and capsules of the abscess surrounding the foreign body. archivio italiano di urologia e andrologia 2024; 96(2):12363 3 steel nail in the scrotum the ‘mercedes-like’ scrotal incision was a winning choice, as it allowed a wide exposure of the field on the perineal plane with the incision on the scrotal raphe, along with bilateral exposure of the testicles with a single median cut. each arm of the cross measured approximately 5 cm, with vertical midline incision on the scrotal raphe to the base of the scrotum, the point at which the center of the cross was therefore located. the other two arms were directed laterally, thus distancing themselves from the anus. in our opinion, a strong point of the procedure was the complete removal of the surrounding abscess capsule, thanks to the use of the tactile sensation, which, in following the nail, allowed a delicate and relatively safe excision. unfortunately, with the opening of the abscess cavity, the surrounding tissues became contaminated. these were promptly washed thoroughly in order to reduce the risk of spreading the infection to the surrounding field. a key concept for the healing all wounds, with particular attention to dirty areas such as the perineal region, is keeping them clean and uncontaminated (2). also, hartz et al. reported that in their experience of 100 patients with perineal wounds, those who received primary closure with immediate suction drainage had the best outcomes compared to those left open with simple packing and those who had non-suction perineal drainage (3). we used hydrogen peroxide in the first procedure and the two following daily dressings in the ward due to its action on anaerobic bacteria. however, its aggressive action on the tissues prompted us to limit its use in subsequent dressings for fear of injuring the tissues and delaying their healing. in fact, uncontrolled hydrogen peroxide generation in tissues can result in chronic inflammation, which could contribute to delayed healing of the wound (4). in our centre, we tend to use and prefer the use of povidone iodine both for the dressing of infected wounds and for the dressing of ordinary surgical wounds, due to its broad antimicrobial spectrum, lack of resistance, efficacy against biofilms, good tolerability, and effect on excessive inflammation (5). the prompt identification and cleaning of the ischemic flaps were crucial for a speedy recovery and improved survival. during the first three postoperative days, there were no signs of local or systemic worsening of the picture, and for this reason, we waited until the fourth postoperative day when the ischemic flaps were promptly identified. an earlier debridement, in our opinion, would not have allowed us to identify the affected areas where curettage should be carried out. kline et al. suggested a low threshold for returning to the operating room for examination under anesthesia and additional surgical debridement within 24 to 48 hours, especially in patients with extensive initial debridement (6). we extended the antibiotic therapy from the time of the procedure until discharge on day 21. in principle, it is recommended that antibiotic therapy be interrupted when operative procedures other than a dressing are no longer indicated and control of the infectious source has been achieved. lauerman et al., evaluating antibiotic duration and outcomes in fournier’s gangrene, showed no difference in outcomes in patients receiving fewer than seven days of therapy compared with longer durations (7). conclusions the management of patients with foreign bodies inserted into the perineum must be guided by common sense and cardinal principles, as each case is a story unto itself. when the case is complicated by an infection, great attention and care must be taken to prevent it from evolving into a situation of extensive or systemic infection that is much more complex to manage. references 1. morey af, metro mj, carney kj, et al. consensus on genitourinary trauma: external genitalia. bju int. 2004; 94:507-15. 2. del pino a, abcarian h. the difficult perineal wound. surg clin north am. 1997; 77:155-74. 3. hartz rs, poticha sm, shields tw. healing of the perineal wound. arch surg. 1980; 115:471-4. 4. zhu g, wang q, lu s, et al. hydrogen peroxide: a potential wound therapeutic target? med princ pract. 2017; 26:301-308. 5. bigliardi pl, alsagoff sal, el-kafrawi hy, et al. povidone iodine in wound healing: a review of current concepts and practices. int j surg. 2017; 44:260-268. 6. kline bp, jeganathan na. necrotizing soft tissue infections of the perineum. clin colon rectal surg. 2022; 35:237-243. 7. lauerman mh, kolesnik o, sethuraman k, et al. less is more? antibiotic duration and outcomes in fournier’s gangrene. j trauma acute care surg. 2017; 83:443-448. correspondence iacopo meneghetti, md, febu (corresponding author) iacopo.meneghetti@tiscali.it luca mosillo, md luca.mosillo@uslnordovest.toscana.it simone belli, md daniele bianchi, md maurizio de maria, md urology department, hospital apuane, massa, italy novella cesta, md infectious diseases department, hospital apuane, massa, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3330 original paper no conflict of interest declared. (eswl), which is really the first option, percutaneous nephrolithotomy (pcnl), flexible ureteroscopy, laparoscopic ureterolithotomy, and open ureterolithotomy (1). on the other hand, novel equipment for endoscopic stone fragmentation and improved expertise of many urology surgeons in laparoscopic surgeries have limited the indications for open surgery (2). where the endoscopic access is impossible or inefficient due to the anatomy of the ureter or size of the stone, the ureterolithotomy laparoscopic technique can be another viable option to open surgery, which may be performed via retroperitoneal laparoscopic ureterolithotomy (rlp) or transperitoneal laparoscopic ureterolithotomy (tplu) (3). skolarikos et al. attempted to determine the evidence level and recommendation score for the laparoscopic technique for removal of the stone. laparoscopic ureteral surgery has the greatest degree of evidence. when compared to open ureterolithotomy, it is entirely feasible and has a reduced post-surgical morbidity. it is often used to treat large impacted calculi or when endoscopic ureteral surgery and eswl have failed (1). tplu is recommended for the less experienced surgeons; moreover, it provides more workspaces and allows for more accurate recognition of anatomical structures. on the other hand, prior surgery of the abdomen with the high risk of adhesions may be a restrictive factor (4). in this study, we represent our experience of tplu for proximal ureteric stone in 60 cases. materials and methods study design the ethics committees of shiraz university of medical sciences approved this project (approval code# ir.sums.med.rec.1399.585), and it was carried out in compliance with the helsinki declaration. in a cross-sectional study, which was also conducted retrospectively, the patients who had undergone tplu for proximal ureteral stone more than 15 mm between june 2017 and purpose: we aim to review our experience of transperitoneal laparoscopic ureterolithotomy (tplu) for proximal ureteric stone more than 15 mm. patients and methods: between june 2017 to december 2020, sixty patients with a history of unsuccessful extracorporeal shock wave lithotripsy (eswl) and/or failed ureteroscopy for impacted ureteral calculi more than 15 mm who accepted tplu were enrolled in our study. the patients' demographic information and post-treatment results were gathered and analyzed, retrospectively. results: the patients' mean age was 46.25 ± 12.56 years. the mean size of the stone was 20.11 ± 4.76 mm. 37 (61.7%) patients had severe hydronephrosis (hdn) and 46 (76.7%) stones were radio-opaque. almost all of the patients underwent tplu by a single urologist. the mean operation time was 72.86 ± 6.07 minutes without intraoperative complication (only 3 stones had upward migration to the pyelocaliceal system). the main operative blood loss was 88.86 ml. the average length of stay in the hospital was 45.8 ± 8.11 hours. the stone free rate (sfr) at discharge was 57 (95%). the overall complication rate was 27 (45%). regarding early complications, fever was found in 8 (13.3%) patients, and 3 patients (5%) had paralytic ileus. the rate of urine leak was 8.3%, and 8 (13.3%) patients required blood transfusions. in multivariate analysis, the multiple stones, bigger stone in size, incomplete sfr, longer duration of hospital admission, and severe hdn were associated with a high early complication rate (p = 0.05, 0.04, < 001, 0.03, and 0.01, respectively). conclusions: tplu is a harmless option for managing proximal ureteric stone as a primary procedure or salvage procedure with good outcomes and acceptable complication rates. key words: proximal ureteral stones; laparoscopy; ureterolithotomy; transperitoneal approach; complication. submitted 16 june 2021; accepted 9 july 2021 introduction proximal ureteric calculi could be handled in a variety of different ways such as extracorporeal shock wave lithotripsy outcome of transperitoneal laparoscopic ureterolithotomy (tplu) for proximal ureteral stone > 15 mm: our experience with 60 cases ali eslahi 1, 2, faisal ahmed 3, mohammad rahimi 1, seyed hamed jafari 4, seyyed hossein hosseini 1, saleh al-wageeh 5, pegah mohammad zadeh shirazi 1, khalil al-naggar 3, ebrahim al-shami 3, mohammad hossein taghrir 6 1 department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 2 shiraz geriatric research center, shiraz university of medical sciences, shiraz, iran; 3 urology research center, al-thora hospital, department of urology, ibb university of medical since, ibb, yemen; 4 medical imagining research center, shiraz university of medical sciences, shiraz, iran; 5 department of general surgery, ibb university of medical science, ibb, yemen; 6 trauma research center, shahid rajaee (emtiaz) trauma hospital, shiraz university of medical sciences, shiraz, iran. doi: 10.4081/aiua.2021.3.330 summary 331archivio italiano di urologia e andrologia 2021; 93, 3 transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone december 2020 in our referral centers (nemazi teaching hospital and ali-asghar teaching hospital, shiraz, southern iran) were considered for this study. during this period, 60 patients were enrolled in our study. inclusion criteria patients who accepted tplu in our center, including those with failed and/or refused eswl or ureteroscopy, impacted stones, stones larger than 15 mm, and stones located in the proximal ureter (between the ureteropelvic junction and the upper edge of the pelvis). exclusion criteria patients with stone less than 15 mm, uncorrected coagulopathy, active urinary tract infection (uti), contraindication to general anesthesia, previous surgery in the ureter or abdomen, and urinary tract abnormality. data collection the information about gender, age, size of ureteral stones, laterality, stone opacity, main symptoms, amount of hydronephrosis (hdn), operating time, blood loss, stonefree rate (sfr), postoperative hospital stay, complications, stone analysis, and data on follow-up, time of follow-up, stone recurrence, and other complications were collected retrospectively. also, a full blood count (cbc) and a renal function test (bun and creatinine), urine analysis and urine culture were done. those with positive cultures were treated with proper antibiotic and admitted with sterile urine for operation. all patients were admitted 12 hours before the operation and received parenteral hydration and a single dose of prophylactic antibiotic. they were definitely diagnosed before operation, using the results of plain abdominal x-ray, ultrasonography (us), intravenous urography (ivu), and abdominal pelvic computed tomography (ct) scan (5). all of them were informed that they would be monitored for three months after the surgery. in a ct scan, the stone-free rate (sfr) was identified as the absence of any residual stone. prolonged drainage was defined as urine leakage requiring drainage for more than 3 days. also, paralytic ileus was defined as absence of bowel sound lasting for over 36 hours. in order to figure out what factors could influence the rate of early complications, we evaluated the preoperative factors such as age, gender, body mass index (bmi), laterality, stone size, main symptoms, previous surgery (eswl, urs), serum creatinine, amount of hdn and stone opacity, and operation factors such as the mean operative time, bleeding, sfr and hospital stay; then, we compared them with early complications such as need to a second procedure, blood transfusion, fever, ileus, urinary leakage, and stent migration. operative technique all the procedures were carried out by one skilled urologist (a.e.), who specialized in urologic laparoscopic surgery. after anesthesia induction, the patients were put in flank position while the table of operation was flexed. a pneumoperitoneum of 12-15 mm hg was obtained by a veress needle placed into the abdominal cavity through the umbilicus. the operation was carried out through three ports; the first was a 10 mm camera trocar implanted two finger breadths lateral and upper to the umbilicus or lateral umbilical depending on the patient's stature and the other 2 ports were developed at the iliac fossa (10 mm) and subcostal (5 mm) in the mid-clavicular line in cases of the left side, while in the case of the right side, a 5 mm port was placed in the right iliac fossa, and a 10 mm port in the subcostal area in the mid-clavicular line. in certain circumstances, an extra port at the flank was placed for the assistant. in right-side cases, a fourth 5 mm trocar is sometimes implanted for retraction of the liver. the ureter was detected after reflection of the colon, and the stone was found and removed via electrocautery vertical ureterotomy. after that, a 6 f ureteral feeding catheter was implanted as a double j stent, and the ureteral incision was sutured with 5/0 vicryl sutures. the calculi were removed in a sac via the 10 mm port using a 5 mm scope. a small drain was implanted and removed until the fluid level dropped below 20 ml, and the ureteral catheter was removed 7-10 days later via cystoscopy. statistical analysis the mean ± sd, median, and inter-quartile range (iqr) described the quantitative variables, and for qualitative variables, frequency (percent) was used. non-parametric test was used if data distribution was not standard. chisquare test was used to assess the potential statistically significant difference. anova was applied to compare the difference of the means between more than two different levels. a p value of 0. 05 or less was considered statistically significant. spss version 20 was used to analyze the data. results table 1 shows the patients’ characteristics and perioperative details. the mean age of the patients was 46.25 ± 12.56 years. the mean size of the stone was 20.11 ± 4.76 mm. there were 40 (66.6%) males and 20 (33.4%) females; 36 (60%) ureteral calculi were on the left side and 24 (40%) on the right side. the mean bmi of the patients was 23.66 ± 35.1 kg/m2 (range 18-35); 31 (51.7%) patients were selected for tplu as the primary procedure, 21 (35%) patients had failed eswl, and 8 (13.3%) had failed ureteroscopy (urs). about 37 (61.7%) patients had severe hdn and 46 (76.7%) stones were radiopaque. the main symptoms at presentation were flank pain which was present in 24 (40%) patients. all procedures were carried out via laparoscopy, with no switch to open ureterotomy. mean operation time was 72.86 ± 6.07 min (range 60-85 minutes). the overall operative blood loss was 88.86 ml (range 21-200 ml). the hospital stay was 45.8 ± 8.11 hours (range 36-72 hours). the sfr at discharge was 95%. during the surgery, 3 (5%) patients were reported to have ureteral calculus that had moved to the pyelocaliceal system. stones were captured in the pyelocaliceal system by passing a semirigid ureteroscope via one of the ports and then via ureteral incision. then, the stones were removed using non-crushing grasping forceps. the mean time resuming the oral intake was 24.2 ± 2.8 hours. the mean drain removal time in our study was 3.3 days (range 2-7). archivio italiano di urologia e andrologia 2021; 93, 3 a. eslahi, f. ahmed, m. rahimi, et al. 332 regarding early complication, fever was found in 8 (13.3%) patients who were treated with antipyretic therapy. three patients (5%) had paralytic ileus which resolved with observational management, and 2 (3.3%) of those patients had uti which was treated with antibiotic therapy. stent migration was seen in 6 (10%) patients. additionally, the rate of urine leak was 8.3%. eight (13.3%) patients required blood transfusions to restore the hemodynamic state. regarding late complications, over a mean follow-up period of 10.8 ± 6.6 (range 3-24) months, 2 patients (3.3%) experienced stone recurrence (table 2). regarding stone analysis, calcium oxalate stone was seen in 28 (46.7%) patients, uric acid in 11 (18.3%), struvite in 9 (15%), mixed stone in 8 (13.3%), and cystine in 4 (6.7%). we additionally compared preoperative, operative factors and sfr with early complications and found that multiple stone, large stone, incomplete sfr, longer duration of hospital stay, and severe hdn were associated with a higher early complication rate with a p value of 0.05, 0.04, < 001, 0.03, and 0.01, respectively (table 3). discussion eswl, pcnl, rlu and urs are standard treatment options for proximal ureteral calculi (6). however, the eswl lower stone-free rate, possibility of increasing the risk of hypertension and diabetes mellitus in the long-term, and possible need for multiple treatment sessions are the main limitations of this procedure since complete stone removal is the target (7, 8). after eswl, re-treatment is needed in up to 36% of cases. approximately 7% of ureteral stones treated with ureteroscopic therapy required additional operations, and approximately 1-10% required open surgical approach. many of these additional interventions increased the patient's morbidity. as a result, tplu is a table 1. characteristics of the patients. table 2. intraoperative and postoperative data. variables gender (male/female) 40/20 age (year) a 46.25 ± 12.56, (22-77) bmi (kg/m2) a 23.66 ± 35.1, (18-35) stone size (mm) a 20.11 ± 4.76 history of failed (eswl/ urs) b 21 (35%)/8 (13.3%) pre-op hemoglobin (mg/dl) a 13.85 ± 0.91, (12-16) main symptoms of presentation b flank pain 24 (40%) vomiting 9 (15%) hematuria 8 (13.3%) fever 8 (13.3%) creatinine rise 7 (11.7%) abdominal pain 4 (6.7%) indication for laparoscopy b primary procedure 31 (51.7%) history of failed eswl 21 (35%) history of failed urs 8 (13.3%) laterality (left/right) 36/24 degree of hdn b no 2 (3.3%) mild 5 (8.3%) moderate 16 (26.7%) severe 37 (61.7%) stone opacity b radiopaque 46 (76.7%) radiolucent 14 (23.3%) a data was presented as mean ± sd, range, and b data was presented as n (%). bmi; body mass index, eswl; extracorporeal shock wave lithotripsy, hdn; hydronephrosis, urs; ureteroscopy. variables operation time (minutes) a 72.86 ± 6.07, (60-85) stone free rate b 57 (95%) hospital admission (hours) a 45.8 ± 8.11, (36-72) post-op hemoglobin (mg/dl) a 13.10 ± 1.04, (10.5-15) drain removal (days) 3 (2-7) blood loss (mm) a 88.86 ± 45.23, (21-200) early complications b 27 (45%) stone migration 3 (5%) blood transfusion 8 (13.3%) fever/uti confirmed 8 (13.3%), 2 (3.3%) ileus 3 (5%) urinary leakage 5 (8.3%) late complications b recurrence of stone 2 (3.3%) a data was presented as mean ± sd, range, and b data was presented as n (%). uti; urinary tract infection. table 3. preoperative and intraoperative data in patients without/with early complications. variable no (n = 33) yes (n = 27) p value age (years) a 45.97 ± 12.87 (22-70) 46.84 ± 12.18 (32-77) 0.80 sex b male 29 11 0.32 female 12 8 bmi (kg/m2) a 23.53 ± 3.69 (19-35) 23.94 ± 3.17 (18-30) 0.36 laterality b left 25 11 0.82 right 16 8 stone opacity b radiolucent 12 2 0.11 radiopaque 29 17 amount of hdn b no 2 0 0.01* mild 1 4 moderate 12 4 severe 28 9 history of failed urs b no 36 16 0.70 yes 5 3 history of eswl b no 25 14 0.33 yes 16 5 stone size (mm) a 18.85 ± 3.38 (14-30) 22.31 ± 6.23 (15-35) 0.04* number of stones b single 37 16 0.05* multiple 1 6 pre-op hemoglobin (mg/dl) a 13.87 ± 0.92 (12-16) 13.81 ± 0.90 (12-15) 0.94 operation time (minutes) a 72.04 ± 5.69 (60-85) 74.63 ± 6.65 (65-85) 0.20 blood loss (ml) a 90 ± 43 (23-200) 86 ± 51 (21-200) 0.57 hospital admission (hours) b 36 13 4 0.03* 48 28 12 72 0 13 stone free rate b complete 41 16 0.00* non complete 0 3 p-values < 0.05 were considered significant. a mean ± sd (range), b number. bmi; body mass index, eswl; extracorporeal shock wave lithotripsy, hdn; hydronephrosis, urs; ureteroscopy. 333archivio italiano di urologia e andrologia 2021; 93, 3 transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone viable option for handling these difficult stones (9). laparoscopic ureteral surgery is progressively replacing the open surgery as the surgeon’s experience improves. it is accompanied with reduction in the overall morbidity as well as decrease in hospital stay, and improved cosmetic outcomes with comparable functional outcomes (10). it is a valuable alternative to open ureterolitholithotomy as the first option for proximal ureteric calculi greater than 15 mm in today’s world of minimally invasive surgery (3). furthermore, proximal location of ureteral stone and stone impaction are the primary predictors of unfavorable urs effects (11). laparoscopy can be performed with two methods, tplu or rlu, with the primary determinant of the choice being the surgeon's preference and experience. the disadvantages of the rlu include a small working space, which might cause difficulties with orientation, visualization, organ trapping, trocar spacing, and freeing periureteral inflammatory adhesions due to long impaction time of the stone (12). furthermore, damage to intraperitoneal organs and hernia can arise following balloon inflation of the extraperitoneal cavity. complication rate, number of medications for pain relief required, duration of the hospital stay, and time required to resume daily activities after the procedure were similar in transperitoneal and retroperitoneal approaches (9, 10). the mean age of the patients in our study was 46.25 years with a range of 22 to77 years and male to female ratio of 2:1. the mean age of the patients in the study of el-feel et al. was 39.8 years with a range of 13 to 60 years (13). the most common indication of tplu in our study was primary procedure for impacted upper stones in 51.7% of patients, followed by failed eswl in 35%, and failed urs in 13.3% of cases. our results are similar to previous papers such as those of huan et al. (14), el-moula et al. (2), and nasseh et al. (15). in our report, 61.7% of patients had severe hdn. hsiao et al. investigated the effect of hdn on the outcome of eswl of a single upper ureteral calculus and found that in patients with stone more than 10 mm, the outcome of eswl was poor if the hdn was moderate or severe. other procedures like ureteroscopic therapy and laparoscopic surgery can be used as the primary therapy or when a first session of eswl fails (16). therefore, there are not major differences of our study compared with other studies. in the study by wani et al., the main symptom was flank pain which presented in 80% of patients and it was followed by burning micturition in 36.6% of patients (17). similarly, in our study, 40% of patients had flank pain, 15% vomiting, and 13.3% fever. the mean bmi in our study was 23.66 ± 35.1 kg/m2 (range 18-35 kg/m2). similarly, the mean bmi reported in a previous study was 22.5 ± 2.20 kg/m2 (range 19.3-27.9 kg/m2) (14). mean size of the stone in our study was 20.11 ± 4.76 mm and, similarly, el-feel et al. reported a mean stone size of 1.9 ± 0.7 mm (13). the operation time of our study was shorter than those of al-sayyad who reported a mean time of 107 ± 49.5 minutes (4) and of el-feel et al. who reported a mean operation time of 145 ± 42 minutes (13). the shorter operative time may be due to the high number of cases who undergo laparoscopy via tpul method in our center. furthermore, the operation was accompanied with reduced operative blood loss, with a mean of 88 ml in our study, which was consistent with previous studies such as that by el-feel et al. (13). the time of operation gradually reduces with developing of skills and experience. the global issues that affect the time of operation are the time to identify the ureter, identification of the stone location, skillful passage of the catheter stent with antegrade approach, and quick intracorporeal suturing of the ureter. identification of the ureter might be difficult and frustrating (18, 19). in our study, we had problematic ureteric identification in some patients. we think that identification of the ureter and stone is not easy in the patients with previous double j stent placement because the amount of hdn is insignificant and the total course of the ureter is dilated. sweeping in distal to proximal direction should be avoided during dissection since the stone could migrate to the pyelocaliceal system. the easiest method to find the ureter is to identify the psoas muscle and look anteriorly for the ureter. if that's not sufficient, it can be identified in front of the iliac vessels (18). in our report, 3 (5%) patients had ureteral stones that moved to the pyelocaliceal system during the procedure. the stone was chased in the pyelocaliceal system using a semi-rigid ureteroscope which entered via one of the ports and then via the site of ureterotomy. the stones were then extracted using non-crushing grasping forceps (18, 20). there was no intra-operative complication in this study and all the laparoscopic procedures were completed successfully; none of them had to be converted to open surgery. this can be attributed to careful patient selection and the operative surgeon's expertise. the sfr of 83100% and a low conversion rate confirmed the safety and efficiency of tplu performed by experienced surgeons (1). simforoosh et al published a large-scale study of ureteral laparoscopic surgery on 123 participants; the rlu vs. tplu approach was compared for proximal ureteral stone. the total sfr was 96.7% and the operative time of the tplu was shorter (137 vs. 171 min; p = 0. 02). minor complications were observed in 11.4% of patients. the migration of the stone necessitated switching to open surgery in one patient (21). compared with previous series, we had an acceptable sfr of 95%. in our study the mean removal time of drain was 3.3 days (range 2-7), which was like reported by other articles such as that of you et al. which removed the drain after 3.1 ± 1.3 days in the laparoscopy stented group (22). mean hospital stay in this study was 45.8 ± 8.11 (36-72) hours, which was consistent with matias et al., who reported a 3.3 days of hospital stay after operation (23). the overall number of post-op complications in this study was 25 (41%). however, most of our complications were minor and easily managed. the most common complication of tplu is prolonged urinary leakage which is observed when the site of ureterotomy is not sutured or when stenting of the ureter is not used (1). we did laparoscopic suturing and inserted a ureteral catheter as a stent in all the cases of tplu. urine leakage in the present study was seen in 5 (8.3%) patients; in persistent leakage, the position of feeding tube catheter was evaluarchivio italiano di urologia e andrologia 2021; 93, 3 a. eslahi, f. ahmed, m. rahimi, et al. 334 ated, and if it was migrated, it was taken out and the leak was prevented by the insertion of double j stent. in another study of rlu approach on 50 patients with large ureteric stone (1.5 cm), 20% of the patients experienced urinary leakage, necessitating secondary drainage with a double j stent (24). in the study carried out by gaur et al., the prolonged leakage of urine (more than 7 days) was seen in 20 out of 101 patients although in 14 of these patients the site of ureterotomy was not sutured and the stenting of the ureter was not used (25). el-feel et al. reported about tpul in 27 patients. they experienced postoperative paralytic ileus in one patient (13). in our study, paralytic ileus was observed in 3 (5%) patients and resolved with observational management in 2-5 days. colon mobilization, blood and urine spill in the peritoneal cavity, as well as visceral dissection and retraction during the procedure might be the main factors for paralytic ileus. keeley et al. reviewed their experience with tplu in 14 patients; in their study, low grade fever was detected in one patient (26). in the study by khalil and coworkers, postoperative fever was observed in 15.4% of the tplu group (27). in our study, low grade fever was present in 8 (13.3%) patients which relieved by administration of a suitable antipyretic drug. more non-opaque stones and ileus could explain this higher rate of fever (28). furthermore, uti was documented in 2 (3.3%) of those patients, which was treated with suitable antibiotic therapy. blood transfusion was needed to restore the hemodynamic state in 8 (13.3%) patients. in the study by khalil and coworkers, the need for blood transfusion in the tplu group was 15.4% (27). chen et al., comparing safety and efficacy between tplu and rlu for proximal ureteral stones > 10 mm, mentioned that the overall rate of blood transfusion was 2.8% (12). our explanation for the high rate of blood transfusion might be due to mild anemia in our patients and previous eswl, which caused extensive adhesions making difficult dissection and obscured anatomy leading to excessive bleeding. in adjunct to preoperative factors, operative factors and sfr may be associated with early complication rate in our study. we found that multiple stones, larger stone size, non-sfr status, longer duration of hospital stay, and severe hdn were associated with high early complication rate. it is important to mention that the significance of the stone size was due to the total stone size calculated by non-contrast ct scan, and the single large stone did not significantly have an effect on the complication rate. sing et al. compared the tplu and rlu in a prospective randomized study and stated that treating proximal and mid-ureteral stone, larger stone, and impacted stones with tplu were correlated with additional pain, more tramadol necessity, ileus, and prolonged hospital stays than rlu (29). el-feel et al. reported tpul in 27 patients and analyzed the factors that may affect the operation time concluding that bmi, laterality, and stone level had no statistically significant effect on the mean operative time (13). according to huri et al., prolonged hospital stay and operative time can be attributed to larger stones and excessive urinary leakage. however, in their view, the general achievement is that ureteral laparoscopic surgery is a viable and appropriate method, particularly for calculi that cannot be effortlessly treated with endoscopic surgery (30). the small sample size and retrospective nature of this study were our major limitations together with lack of comparison with other procedures. in fact, swl and urs are more likely considered for primary treatment of proximal ureteral stone. while tplu could also produce an acceptable result, its use would be limited due to greater difficulty and trauma. indeed, given the procedures and practice, as well as the patients' circumstances, the best approach is the safest for patients. furthermore, we have limited our study to the short-term assessment of tplu. after all, tplu damages the natural structure of the ureter. the long-term effects of tplu are still unknown, and further research is needed to draw definitive conclusions. conclusions our study supports the results of previous studies, suggesting tplu as a harmless choice for treating proximal ureteral calculi as a primary procedure or salvage procedure with excellent outcomes and acceptable complications. additionally, larger stone size, multiple stones, incomplete stone-free rate, longer duration of hospital stay, and severe hydronephrosis were associated with a high rate of early complication. acknowledgements the authors would like to thank shiraz university of medical sciences, shiraz, iran and also center for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. references 1. skolarikos a, papatsoris ag, albanis s, assimos d. laparoscopic urinary stone surgery: an updated evidence-based review. urol res. 2010; 38:337-44. 2. el-moula mg, abdallah a, el-anany f, et al. laparoscopic ureterolithotomy: our experience with 74 cases. int j urol. 2008; 15:593-7. 3. leonardo c, simone g, rocco p,, et al. laparoscopic ureterolithotomy: minimally invasive second line treatment. int urol nephrol. 2011; 43:651-4. 4. al-sayyad a. laparoscopic transperitoneal ureterolithotomy for large ureteric stones. urol ann. 2012; 4:34-7. 5. ahmed f, askarpour mr, eslahi a, et al. the role of ultrasonography in detecting urinary tract calculi compared to ct scan. res rep urol. 2018; 10:199-203. 6. kartal i, baylan b, çakıcı m, et al. comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones. arch ital urol androl. 2020; 92:39-44. 7. hong y, ye h, yang b, et al. ultrasound-guided minimally invasive percutaneous nephrolithotomy is effective in the management of pediatric upper ureteral and renal stones. j invest surg. 2020:1-5. 8. ahmed f, askarpour m-r, eslahi a, et al. the role of ultrasonog335archivio italiano di urologia e andrologia 2021; 93, 3 transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone raphy in detecting urinary tract calculi compared to ct scan. res rep urol. 2018; 10:199. 9. wani mm, durrani am. laparoscopic ureterolithotomy: experience of 60 cases from a developing world hospital. j minim access surg. 2018; 15:103-8. 10. yasui t, okada a, hamamoto s, et al. efficacy of retroperitoneal laparoscopic ureterolithotomy for the treatment of large proximal ureteric stones and its impact on renal function. springerplus 2013; 2:600. 11. el-nahas ar, el-tabey na, eraky i, et al. semirigid ureteroscopy for ureteral stones: a multivariate analysis of unfavorable results. j urol. 2009; 181:1158-62. 12. chen h, chen g, chen h, et al. comparison of the safety and efficacy between transperitoneal and retroperitoneal approach of laparoscopic ureterolithotomy for the treatment of large (>10mm) and proximal ureteral stones: a systematic review and meta-analysis. urol j. 2020; 18:11-18. 13. el-feel a, abouel-fettouh h, abdel-hakim am. laparoscopic transperitoneal ureterolithotomy. j endourol. 2007; 21:50-4. 14. yang h, yu x, peng e, et al. urgent laparoscopic ureterolithotomy for proximal ureter stones accompanied with obstructive pyelonephritis: is it safe and effective without preoperative drainage? medicine (baltimore). 2017; 96:e8657. 15. nasseh h, pourreza f, kazemnejad leyli e, et al. laparoscopic transperitoneal ureterolithotomy: a single-center experience. j laparoendosc adv surg tech a. 2013; 23:495-9. 16. hsiao hl, huang sp, wu wj, et al. impact of hydronephrosis on treatment outcome of solitary proximal ureteral stone after extracorporeal shock wave lithotripsy. kaohsiung j med sci. 2008; 24:507-13. 17. wani r, para m. transperitoneal laparoscopic management of ureteric stones: a prospective study. world journal of minimal access surgery 2020, 8:1 (monday, november 16, 2020). 18. farooq qadri sj, khan n, khan m. retroperitoneal laparoscopic ureterolithotomy--a single centre 10 year experience. int j surg. 2011; 9:160-4. 19. radfar mh, valipour r, narouie b, et al. role of the gonadal vessels on the stone lodgment in the proximal ureter: direct observation during laparoscopic ureterolithotomy. arch ital urol androl. 2018; 90:163-5. 20. kadyan b, sabale v, mane d, et al. large proximal ureteral stones: ideal treatment modality? urol ann. 2016; 8:189-92. 21. simforoosh n, basiri a, danesh ak, et al. laparoscopic management of ureteral calculi: a report of 123 cases. urol j. 2007; 4:138-41. 22. you jh, kim yg, kim mk. should we place ureteral stents in retroperitoneal laparoscopic ureterolithotomy?: consideration of surgical techniques and complications. korean j urol. 2014; 55:511-4. 23. matias db, alvim rg, ribas m, et al. laparoscopic treatment of ureterolithiasis: our experience. actas urol esp. 2009; 33:667-9. 24. derouiche a, belhaj k, garbouj n, et al. retroperitoneal laparoscopy for the management of lumbar ureter stones. prog urol. 2008; 18:281-7. 25. gaur dd, trivedi s, prabhudesai mr, madhusudhana hr, gopichand m. aa. bju int. 2002; 89:339-43. 26. keeley fx, gialas i, pillai m, et al. laparoscopic ureterolithotomy: the edinburgh experience. bju int. 1999; 84:765-9. 27. khalil m, omar r, abdel-baky s, et al. laparoscopic ureterolithotomy; which is better: transperitoneal or retroperitoneal approach?turk j urol. 2015; 41:185-90. 28. zhu w, li j, yuan j, liu y, et al. a prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. bju int. 2017; 119:612-8. 29. singh v, sinha rj, gupta dk, et al. transperitoneal versus retroperitoneal laparoscopic ureterolithotomy: a prospective randomized comparison study. j urol. 2013; 189:940-5. 30. huri e, basok ek, ugurlu o, et al. experiences in laparoscopic removal of upper ureteral stones: multicenter analysis of cases, based on the turkurolap group. j endourol. 2010; 24:1279-82. correspondence ali eslahi, md alieslahi@yahoo.com mohammad rahimi, md mohammadrahimi888@gmail.com seyyed hossein hosseini, md shhosseini_6687@yahoo.com pegah mohammad zadeh shirazi, md mohammadzadeh.sh6@gmail.com department of urology, school of medicine, shiraz university of medical sciences, shiraz (iran) faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com urology office, al-thora hospital, alodine street, ibb (yemen) seyed hamed jafari, md hamed338@yahoo.com medical imagining research center, shiraz university of medical sciences, shiraz, (iran) saleh al-wageeh, md alwajihsa78@gmail.com department of general surgery, ibb university of medical science, ibb (yemen) khalil al-naggar, md ebrahim al-shami, md urology office, al-thora general hospital, alodine street, ibb (yemen) alshami_ebrahim@yahoo.com mohammad hossein taghrir, phd mhtaghrir@gmail.com urology office, faghihi hospital, zand blvd., shiraz (iran) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 letter to editor sexual health impairment is one of the most important issues worldwide, with an increasing number of men and women affected. specifically in male sexual dysfunction (sd), several risk factors were established such as atherosclerosis, hypertension, diabetes mellitus, smoking or obesity. the co-presence of more than one of risk factors identifies a condition, defined as the metabolic syndrome (mets), related directly to the sd. however, not all the physicians involved in the mets management routinely discussed the sexual impairment, increasing the bothering feelings of patients. furthermore, the lack of knowledge, insufficient time, lack of attention, ambiguities about responsibility, insufficient training and experience, shared among physicians, regarding the communication and treatment of sexual dysfunction, are all reported factors involved in undervaluation of sd. the current paper represents a warning to the experts, with the aim of increasing the awareness of sd among clinicians and to promote the education, training and collaboration with sex therapists, through a multidisciplinary team, that can lead to a holistic approach in sd assessment and treatment. key words: erectile dysfunction; mets; libido; sexual health. submitted 3 february 2023; accepted 17 february 2023 to the editor, sexual dysfunction (sd) includes erectile dysfunction (ed) defined as the persistent inability to attain and/or maintain penile erection sufficient to permit satisfactory sexual performance, ejaculation disorders, orgasmic dysfunctions, and disorders of sexual interest/desire (1). sexual health is an important aspect of our patients' lives, with a high impact on patients and partners quality of life and sd represents one of the most important problems worldwide, affecting a growing number of men and women (2-8). several risk factors have been identified in male sexual dysfunction (msd) such as atherosclerosis, hypertension, hyperlipidemia, diabetes mellitus, smoking, obesity, sedentary lifestyle, chronic alcohol use, benign prostate hyperplasia (9). in most of patients diagnosed with sd there is a concomitant presence of more than one risk factor. the metabolic syndrome (mets) also known as syndrome x and insulin resistance syndrome, is the term that consists of a cluster of disease states abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, proinflammatory state, and prothrombotic state (10). mets may cause ed through multiple mechanisms. all components of mets are frequently found in the obese population. abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia. furthermore, several diseases and medical or surgical treatments such as radical pelvic surgery can significantly affect sexual health (11). collaboration between different specialists can be useful in some patients with many risk factors as well as chronic disease and multiple drugs treatments when the conventional treatments are not effective alone. despite this, previous published studies reported that most specialists do not address sexual problems during routine visits. nicolai et al. reported that in a setting of patients with cardiovascular disease sexual dysfunction is not routinely discussed in the cardiology practice (12). msd in particular ed shares the same risk factors of coronary artery disease. in fact, several studies have suggested that chronic inflammation and circulating inflammatory markers affect systemic endothelial function. chronic inflammation may, therefore, represent a link between ed and cardiovascular diseases (cvd) (13). according to montorsi et al. in patients with coronary artery disease (cad), ed comes before cad in the majority by an average of 2 up to 3 years (14). ed onset and severity are associated with increased expression of markers of inflammation. markers and mediators such as c-reactive protein (crp), intercellular adhesion molecule 1, interleukin (il)-6, il-10, il-1b, and tumor necrosis factor alpha (tnf-a) were found to be expressed at higher levels in patients with ed (15). furthermore, several cardiovascular drugs as well as diuretics, and b-blockers may negatively affect sexual function (16). this lack of information is against several cardiological consensus which recommended to assess sd in patients with cardiovascular risk factors and disease. perez-garcia lf et al. in a systematic review of the literature reported that male patients with rheumatic diseases have higher rates of sd, which also sexual dysfunction: time for a multidisciplinary approach? luigi cirillo, giovanni maria fusco, francesco di bello, vincenzo morgera, gianluigi cacace, ernesto di mauro, francesco mastrangelo, lorenzo romano, francesco paolo calace, roberto la rocca, luigi napolitano department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii", naples, italy. doi: 10.4081/aiua.2023.11236 summary archivio italiano di urologia e andrologia 2023; 95, 1 l. cirillo, g.m. fusco, f. di bello, et al. seems to occur at a younger age compared to healthy controls. most of these patients remain undiagnosed and uninformed about sd due to lack of specialists investigation (17). van ek et al. reported some findings in patients suffering from chronic kidney disease (ckd). in fact, dutch nephrologists do not discuss sexual function routinely with their patients, despite a high incidence of sd both in men and women (18). in fact, men suffering from ckd reported ed, reduced libido and difficulty in reaching an orgasm, while female patients reported impaired vaginal lubrication, loss of arousal and desire, dysmenorrhea, and difficulty in reaching an orgasm. in patients undergoing renal dialysis there is a higher rate of sd, around 65% for men and 70% for women respectively. in neurosurgical and gastroenterological setting there are similar results: korse et al. reported that 72% of dutch neurosurgery do not counsel patients about sexual dysfunction (19); romano et al. reported that italian gastroenterologist never/infrequently investigated sd with their patients and, similarly, most patients never discussed sd during the visit (20-22). our findings show that despite sexuality is an important aspect of holistic care, it is not addressed in the healthcare system. physician should therefore investigate medical and sexual history. given the personal and social implications of sexual dysfunction it is not an easy task. hence, expert-guided, validated and standardized sexual inventories, structured interviews and self-reported questionnaires (for example iief-5 for ed) can help both inexperienced and seasoned clinicians to address sexual health and related conditions. the lack of knowledge, insufficient time, lack of attention, ambiguities about responsibility, insufficient training and experience regarding the communication and treatment of sexual dysfunction, are the most reported factors involved in undervaluation of sd. to avoid this, first it is necessary: an appropriate knowledge of sd, education, training and collaboration with sex therapists. it could be useful to create appropriate courses, and partnership through a multidisciplinary team of healthcare, that can lead to a holistic approach in assessment and treatment. references 1. rew kt, heidelbaugh jj. erectile dysfunction. am fam physician 2016; 94:820-7. 2. flynn ke, lin l, bruner dw, et al. sexual satisfaction and the importance of sexual health to quality of life throughout the life course of u.s. adults. j sex med.2016; 13:1642-50. 3. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl 2022; 94:211-6. 4. napolitano l, cirillo l, fusco gm, et al. natural treatments for erectile dysfunction: a focus on mobile health applications. arch ital urol androl 2022; 94:373-4. 5. mirone v, napolitano l, d’emmanuele di villa bianca r, et al. a new original nutraceutical formulation ameliorates the effect of tadalafil on clinical score and cgmp accumulation. arch ital urol androl 2021; 93:221-6. 6. napolitano l, cirillo l, fusco gm, et al. premature ejaculation in the era of mobile health application: a current analysis and evaluation of adherence to eau guidelines. arch ital urol androl 2022; 94:328-33. 7. fusco gm, cirillo l, abate m, et al. male infertility, what mobile health applications «know»: quality analysis and adherence to european association of urology guidelines. arch ital urol androl 2022; 94:470-5. 8. di bello f, creta m, napolitano l, et al. male sexual dysfunction and infertility in spinal cord injury patients: state-of-the-art and future perspectives. j pers med. 2022; 12:873. 9. napolitano l, barone b, crocetto f, et al. the covid-19 pandemic: is it a wolf consuming fertility? int j fertil steril. 2020; 14:159-60. 10. dong jy, zhang yh, qin lq. erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. j am coll cardiol. 2011; 58:1378-85. 11. zippe c, nandipati k, agarwal a, raina r. sexual dysfunction after pelvic surgery. int j impot res. 2006; 18:1-18. 12. nicolai mpj, both s, liem ss, pelger rcm, et al. discussing sexual function in the cardiology practice. clin res cardiol 2013; 102:329-36. 13. vlachopoulos c, rokkas k, ioakeimidis n, stefanadis c. inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. eur urol. 2007; 52:1590-600. 14. montorsi p, ravagnani pm, galli s, et al. association between erectile dysfunction and coronary artery disease. role of coronary clinical presentation and extent of coronary vessels involvement: the cobra trial. eur heart j. 2006; 27:2632-9. 15. carneiro fs, webb rc, tostes rc. emerging role for tnf-a in erectile dysfunction. j sex med. 2010; 7:3823-34. 16. nicolai mpj, liem ss, both s, et al. a review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice. neth heart j 2014; 22:11-9. 17. perez-garcia lf, te winkel b, carrizales jp, et al. sexual function and reproduction can be impaired in men with rheumatic diseases: a systematic review. semin arthritis rheum. 2020; 50:557-73. 18. van ek gf, krouwel em, nicolai mp, et al. discussing sexual dysfunction with chronic kidney disease patients: practice patterns in the office of the nephrologist. j sex med. 2015; 12:2350-63. 19. korse ns, nicolai mpj, both s, et al. discussing sexual health in spinal care. eur spine j 2016; 25:766-73. archivio italiano di urologia e andrologia 2023; 95, 1 title sexual dysfunction 20. romano l, zagari rm, arcaniolo d, et al. sexual dysfunction in gastroenterological patients: do gastroenterologists care enough? a nationwide survey from the italian society of gastroenterology (sige). dig liver dis 2022; 54:1494-501. 21. romano l, granata l, fusco f, et al. sexual dysfunction in patients with chronic gastrointestinal and liver diseases: a neglected issue. sex med rev. 2022; 10:620-31. 22. romano l, pellegrino r, sciorio c, et al. erectile and sexual dysfunction in male and female patients with celiac disease: a cross-sectional observational study. andrology. 2022; 10:910-8. correspondence luigi cirillo, md cirilloluigi22@gmail.com giovanni maria fusco, md giom.fusco@gmail.com francesco di bello, md (corresponding author) fran.dibello12@gmail.com vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com ernesto di mauro, md ernesto.dimauro@unina.it francesco mastrangelo, md fmastrangelo91@gmail.com lorenzo romano, md lorenzo.romano@unina.it francesco paolo calace, md fra.calace@gmail.com roberto la rocca, md roberto.larocca@unina.it luigi napolitano, md luiginap89@gmail.com department of neurosciences, reproductive sciences and odontostomatology, school of medicine, university of naples "federico ii" via sergio pansini n°5, 80138 naples (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso 217archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. among the pathophysiologic mechanisms proposed for priapism development in the sca population, the acute ischemic priapism (ip) (veno-occlusive, low flow) type is represented by painful and rigid penile erection (1, 4). acute ip is a medical emergency that should be prevented and managed immediately to preserve the function of erectile tissue (5). in this ip population, aspirated blood gas analysis of the corpus cavernosum usually reveals hypoxia, hypercapnia, and acidosis (4). in addition, penile doppler ultrasound (pdus) has improved the diagnosis of ip by demonstrating very low or absent arterial blood flow in the corpus cavernosum (6). nevertheless, the risk of corpora cavernosal fibrosis and partial or complete impotence in sca patients with ip suggests the need for careful evaluation and new diagnostic techniques (4). because of the vasculopathy, chronic hemolysis, and veno-occlusive pathogenesis of sca, multiple hematologic markers are needed to predict the outcome of ip in sca patients. the role of platelet count (plt) and mean platelet volume (mpv) in these veno-occlusive mechanisms is well documented (7-11). previous studies confirmed the association between ip, defined as a vasculogenic disease, and platelet activation leading to higher mpv (9, 10). therefore, platelet volume indices (pvis) can be measured as potential laboratory parameters for diagnosis and treatment of ip. to our knowledge, the role of laboratory pvis, such as mpv, platelet distribution width (pdw), and plateletcrit (pct), as prognostic markers for ip in sca patients at steady-state has not yet been analyzed. the aim of this paper was to determine the diagnostic and cutoff values of pvis such as mpv, pdw, and pct for the detumescence outcomes of acute ip in sca patients. patients and methods study population one hundred thirteen (113) sca patients with steadystate were admitted to the emergency room with priapism. of those case series, only 56 cases presenting acutely with ip were included in this research and required immediate intervention to avoid fibrosis of cavernosal tissues and subsequent erectile dysfunction. fiftyobjective: this study aimed to evaluate the predictive value of platelet volume indices (pvis), such as mean platelet volume (mpv), platelet distribution width (pdw), and plateletcrit (pct), as prognostic parameters of detumescence in acute ischemic priapism (ip) patients with sickle cell anemia (sca) in steady-state who received intracavernosal injections of phenylephrine with aspiration and saline irrigation. methods: fifty-six sca patients with acute ip and 54 healthy male control subjects were included in the research. priapism was diagnosed by penile doppler ultrasound and corporal blood gas tests before intervention. measurements of pvis (mpv, pdw, and pct) and tlc were ordered for all participants. additionally, the duration of priapism was recorded. the area under the curves was calculated by receiver operating characteristic (roc) regression analysis. results: the detumescence rate was 71.4% after the intervention. compared to the control group, priapic sca patients showed significantly higher plt (p = 0.011), mpv (p = 0.002), pdw (p = 0.032), pct values (p = 0.022), and tlc (p = 0.027). higher mpv, pdw, and pct values were observed in unsuccessful detumescence patients compared to the resolution group (p < 0.05). statistically significant cutoff values for persistent priapism were measured by roc as plt: ⩾ 254x103/µl; mpv: ⩾ 13.2 fl; pdw: ⩾ 15.6 fl; pct: ⩾ 24%; and tlc ≥ 8.5x103/l. priapism duration of ≤ 17.9 hours was significantly related to detumescence rate (p = 0.000). multivariable logistic regression analysis showed that priapism duration and higher mpv are prognostic parameters for detumescence in sca. conclusions: the higher mpv and duration of priapism can be used as parameters for evaluating detumescence outcomes in steady-state sca with acute ip. key words: sickle cell anemia; acute ischemic priapism; platelet volume indices. submitted 31 may 2022; accepted 4 june 2022 introduction sickle cell anemia (sca) is a polymorphic genetic disorder characterized by recurrent inflammatory damage and episodic vaso-occlusive complications such as acute chest syndrome, acute scrotal pain, and priapism (1, 2). priapism is a persistent and prolonged penile erection lasting > 4 hours that occurs in 35% of sca patients (3, 4). platelet volume parameters as a tool in the evaluation of acute ischemic priapism in patients with sickle cell anemia essa a. adawi, mazen a. ghanem department of urology, jazan university, ksa, jazan, saudi arabia. doi: 10.4081/aiua.2022.2.217 summary archivio italiano di urologia e andrologia 2022; 94, 2 essa a. adawi, mazen a. ghanem 218 four (54) healthy control males from the subjects undergoing medical examination in our hospital were included in our study for comparison. ages of the patients and controls were similar. the control participants had no history of priapism, malignancy, pelvic trauma, surgery, or hematologic disease. the research protocol for the study was approved by the institutional reviewer board of the faculty of medicine at jazan university, saudi arabia and was conducted in accordance with the principles of the helsinki declaration. selection criteria inclusion criteria: patients (aged 19-54 years) with sca who complained of an acute episode of priapism for the first time and were aware of having scd were included. suspected ip was diagnosed by pdus by demonstration of absent or low cavernous blood flow (6). ip was confirmed by aspiration of hypoxic and dark blood from the corpora cavernosa and typical blood gas analysis values (po2 < 30 mmhg, pco2 > 60 mmhg, ph < 7.25) before any intervention (4). included sca participants were identified by qualitative and/or quantitative hemoglobin electrophoresis at ph 8.6 on cellulose acetate paper. steady-state sca was diagnosed according to criteria defined by ballas sk et al. (12). exclusion criteria: sca patients were included after excluding non-ip by blood gas analysis in the corporeal aspiration and normal blood flow levels in the cavernosal arteries in pdus. excluded patients were also those with myeloproliferative disorders and leukemic diseases. patients with a history of strokes, recurring or previous priapism attacks, or hospitalization for an acute painful crisis within the previous year were excluded. patients with a history of pelvic surgery and trauma, newly diagnosed coronary artery disease, active infectious disease, malignancy, immunological disease, or those taking antiplatelet or anticoagulant medication were all excluded. clinical examination all sca patients underwent a complete physical examination with a detailed history as soon as possible after initial presentation of priapism. abdominal, perineal, and digital rectal examinations were also performed to exclude any evidence of trauma, pelvic infection or malignancy or the presence of any other systemic symptomatology associated with scd, such as a sickle crisis. a comprehensive history included information on the duration of priapism, any medication used, the presence of pain, and any previous history of priapism. physical examination of the penis was essential to determine the extent and degree of rigidity, the involvement of the corpora cavernous bodies, and the presence of penile tenderness. in this study, priapism was defined as a persistent painful erection lasting more than 1 hour without orgasm and ejaculation and requiring medical therapy (13). during intervention, decisions regarding continuing the combination of aspiration, irrigation, and intracavernous injection (ici) or proceeding with immediate surgical interventions were guided by the clinicians. all acute ip cases were treated by ici therapy with phenylephrine in combination with aspiration and irrigation with 0.9% saline. ici can be repeated every 3-5 minutes until detumescence occurs, with a maximum of 1 mg administered within one hour. a physician should monitor the heart rate and blood pressure (14). after repeated intervention, patients were evaluated for the resolution of priapism, which was indicated by the disappearance of corporal rigidity by exam, the absence of acidosis by cavernous blood gas testing, and the return of cavernosal artery flow by pdus (14, 15). laboratory evaluation peripheral blood samples were collected in tubes containing edta-k2 (potassium ethylenediaminetetraacetic acid) anticoagulant before any form of priapism intervention from patients and control subjects. samples were analyzed within one hour of the patient’s referral (16-18). an automated blood cell counter (sysmex corp., japan) was used to measure plt, pvis (mpv, pdw, and pct), and total leukocyte count (tlc). statistical analysis analyses were conducted using ibm spss version 24.0 (armonk, ny). continuous variables were tested for normality of distribution with the kolmogorov-smirnov test. depending on the distribution, data was presented as means, standard deviation (sd), or medians with the interquartile range (iqr). differences in the means were compared using the unpaired student’s t-test for normally distributed data, whereas the non-parametric mannwhitney u test was carried out for comparing medians of non-normally distributed data. chi-squared tests were carried out to analyze categorical variables. receiver operating characteristic (roc) curve analysis was performed to find out cut-off values and areas under the curve (auc) for potential predictive values. multivariable logistic regression analysis was conducted to identify the potential risk factors. a p-value of 0.05 was used as a threshold of significance. results the demographic and clinical characteristics of the studied patients are summarized in table 1. in the ip and the control group, the median ages were 41.2 (iqr: 33.245.2) and 42.7 (iqr: 34.2-46.2) years, respectively. the median time of duration of priapism was 17.9 (iqr: 8.526.4) hours. forty (71.4%) sca patients were found to have detumescence during intracavernosal intervention. the remaining 16 (28.6%) patients received immediate spongiocavernosal surgical shunting with tunneling for persistent priapism. in terms of duration of priapism, a priapism event ≤ 17.9 hours in duration (n = 25, 44.6%) was statistically significantly correlated to the detumescence rate in sca patients (p = 0.000).on the contrary, plt and pvis (mpv, pdw, and pct) had no significant relationship with the duration of priapism (p = 0.130, p = 0.087, p = 0.145, and p = 0.245, respectively). in the acute ip group, the medians of plt, mpv, pdw, and pct were 254 x103/µl (iqr: 227-296), 13.2 fl (iqr: 10.5-14.1), 16.9 fl (iqr: 15.8-19.2), and 0.35% (iqr: 0.23-0.38), respectively. the medians of plt, mpv, pdw, and pct of the ip cases were detected to be significantly higher than those in the control group (p = 219archivio italiano di urologia e andrologia 2022; 94, 2 acute ischemic priapism and platelets indices 0.011, p = 0.002, p = 0.032, and p = 0.022, respectively) (table 2). ppersistent priapism in sca cases had higher mpv, pct, and pdw than those in the detumescence group, which was statistically significant (p = 0.001, p = 0.042, and p = 0.035, respectively). regarding the median tlc, there was a statistically significant difference among groups (p = 0.027) (table 2). additionally, sca cases with priapism resolution had a significantly lower tlc than those in the persistent group (p = 0.046). the evaluation made with roc curve analysis detected that cut-off levels for plt, mpv, pdw, pct, tlc, and duration of priapism for the prediction of priapism resolution were 254x103/µl, 13.2 fl, 15.6 fl, 24%, 8.5x103/l and 17.9 hours, respectively. the corresponding sensitivities were 62.5%, 81.3%, 75%, 69.8%, 68.8%, and 87.5%, and the corresponding specificities were 55.0%, 67.5%, 12.5%, 37.5%, 42.5%, and 62.5%. the area under the curves (auc) for plt, mpv, pdw, pct, tlc, and duration of priapism were 0.652 (p = 0.079), 0.811 (p = 0.000), 0.630 (p = 0.130), 0.548 (p = 0.574), 0.521 (p = 0.807), and 0.842 (p = 0.000), respectively (table 3). based on a multivariable logistic regression model after grouping predictor factors, both duration of priapism and mpv showed their independent prognostic impact on the outcome of priapism in steady-state sca patients (table 4). discussion the potential pathogenic and diagnostic roles of platelets in vascular pathologies have been described in many papers. the plt and related platelet volume indices (pvis) have been identified as markers of thrombocyte reactivity in various vascular and urological diseases (17-20). priapism is a vascular disease with a veno-occlusive mechanism and endothelial damage as its main pathophysiological basis (20). platelet hematological parameters play a significant role in ip pathophysiology. however, there is relatively little data on pvis (mpv, pdw, and pct) in priapic patients, as well as, their relationship with the outcome of primary emergency ici of phenylephrine and the combination of aspiration and irrigation in sca patients with acute ip (9, 10). in the study by sönmez et al. (9), the relationship between ip and high plt and mpv was confirmed to be significant, similarly to the study by ufuk et al. (10). however, pct was not included in the platelet parameters analyzed in this series, and statistical studies were performed with predictive and cutoff values in ip patients without sca. the significance of our study was the addition of pct, besides plt, mpv, and pdw, and the statistical calculation of their cutoff values as suspected predictive factors in acute ip with sca. in this study, ip men with sca had higher pvis (mpv, pdw, and pct) when compared to men who had never experienced priapism. even so, mpv had a strong sensitivity (81.3%) effect on ip pathogenesis. plt, mpv, pdw, and pct levels of the detumescence cases also revealed a statistically significant cut-off of 254x103/µl, table 1. demographic and clinical data amongst steady-state sca patients with acute ischemic priapism (ip). numbers of patients 56 age at presentation, yrs * 41.2 (33.2-45.2) follow-up, yrs * 3.4 (2.6-4.2) priapism duration, hrs * 17.9 (8.5-26.4) penile doppler us (blood flow) n (%) absent 53 (94.6) low 3 (5.4) penile aspiration outcome †, n (%) non-resolution with full rigidity 16 (28.6) detumescence 40 (71.4) values are presented as median (interquartile range, iqr). † intracavernosal injections (ici) of phenylephrine with aspiration and 0.9% saline irrigation. table 2. hematologic parameters amongst steady-state sca men with acute ischemic priapism and controls in men without sca. parameter ischemic priapism group control group p-value * platelet count (plt) (x 103/µl) 254 (227-296) 249 (238-253) 0.011 mean platelet volume (mpv) (fl) 13.2 (10.5-14.1) 7.6 (7.3-13.4) 0.002 platelet distribution width (pdw) (fl) 16.9 (15.8-19.2) 14.3 (5.7-15.7) 0.032 plateletcrit (pct) (%) 0.35 (0.23-0.38) 0.32 (0.27-0.38) 0.022 total leucocyte count (tlc) (x103 l) 14.3 (7.4-21.1) 11.2 (8.4-13.2) 0.027 values are presented as median (interquartile range, iqr). * mann-whitney u test. table 4. multivariate analysis of the risk factors for the corporal detumescence outcomes. or 95% ci p-value platelet count (plt) (x103/µl) 0.623 0.177-2.195 0.462 mean platelet volume (mpv) (fl) 8.895 1.000-79.089 0.050 platelet distribution width (pdw) (fl) 2.005 0.219-18.362 0.538 plateletcrit (pct) (%) 0.602 0.129-2.800 0.517 total leucocyte count (tlc) (x103 l) 0.267 0.051-1.389 0.117 priapism duration (hrs) 26.079 2.401-283.259 0.007 or: odds ratio; ci: confidence interval. table 3. prediction of the corporal detumescence outcomes according to the cut-off values of plt, mpv, pdw, pct, tlc, and duration of priapism. cut-off value auc p-value 95% ci sensitivity (%) specificity (%) platelet count (plt) 254x103/µl 0.652 0.079 0.499-0.804 62.5% 55% mean platelet volume (mpv) 13.2 fl 0.811 0.000 0.676-0.946 81.3% 67.5% platelet distribution width (pdw) 15.6 fl 0.630 0.130 0.442-0.819 75% 12.5% plateletcrit (pct) 24% 0.548 0.574 0.370-0.727 69.8% 37.5% total leucocyte count (tlc) 8.5x103 µl 0.521 0.807 0.360-0.682 68.8% 42.5% priapism duration 17.9 hrs 0.842 0.000 0.709-0.977 87.5% 62.5% auc, area under curve; ci, confidence interval. archivio italiano di urologia e andrologia 2022; 94, 2 essa a. adawi, mazen a. ghanem 220 13.2 fl, 15.6 fl, and 24% in priapic sca patients as an indicator for cavernosal function. moreover, the mpv value of unsuccessful detumescence patients revealed a higher significant cut-off of 13.2 fl than that of 9.11 fl for priapic cases without sca as a parameter for erectile tissue function (10). according to this study, the mpv has been suggested to have a role in the detumescence response in sca patients who received ici phenylephrine with aspiration and saline irrigation. despite the encouraging resolution of corporal rigidity in this study, 28.6% of patients are still experiencing persistent priapic attacks. those patients have a negatively significant correlation with higher mpv. those patients with a higher mpv had a very low chance of improvement in their corporal rigidity in terms of the absence of cavernosal artery inflow and persistent acidosis. this finding was supported by increased thrombocyte activity, which is associated with increased thromboxane a2 synthesis, soluble p-selectin, and intravascular thrombosis in sca (21). in our report, the high incidence of hemolysis in sca results in a lowering of no bioavailability and down regulation of phosphodiesterase type 5 protein expression, which impairs penile vascular reactivity (22). also, the increased mpv triggers and increases corporal veno-occlusive dysfunction, leading to hypoxia and microvascular thrombosis of the corpora cavernosa (1, 7, 23). consequently, high mpv can be used as a biomarker for the recovery of erectile tissue function in sca patients with acute ip. interestingly, we found a significantly increased pdw in acute ip patients with sca compared to healthy controls, with a positive relationship with detumescence. even so, pdw levels of unresolved priapism showed a higher significant cut-off of 15.6 fl for cavernosal damage. however, ufuk et al. found that the pdw levels were similar between ip patients without sca and control healthy subjects, even though the platelet count was significantly lower in ip patients than in controls (10). nonetheless, other investigators have observed that pdw is a specific sign of active platelet release for developing thromboembolic disorders (7, 24). the increased pdw in sca with priapism is mainly related to the up-regulated production and average volume of megakaryocytes. additionally, we detected a higher pct with its effect on priapism resolution among those patients. this is in accordance with the adawi et al. study that demonstrated higher pct levels with significant implications on testicular torsion outcome among patients with steady-state sca (18). mutlu et al. found that values of pct are low with little effect on thrombosis processes (19). these findings demonstrated the significant role of priapism in the regulation of platelet count, and pvis values in steady-state sca patients. in our study, tlc was significantly increased in acute ip with a predictive outcome on detumescence found in sca as a result of acute inflammation and excessive hemolysis, which is associated with active hematopoiesis (10). this inflammation promotes vascular endothelial adherence to sickle erythrocytes, which is associated with the release of cytokines, causing veno-occlusion dysfunction (25). moreover, the high tlc in sca patients with and without priapism was demonstrated by ahmed et al. (26). interestingly, madu et al. found a positive relationship between low levels of tlc and the development of priapism, which is contrary to our observation (8). these conflicting studies could be related to differences in various factors such as study design, sickle cell genotype, precipitating factors, genetic factors, effects of intervention, and laboratory methods, all of which can change the hematological values of priapic patients with sca (8, 16, 27). in general, the prognostic value of a complete blood count includes other biomarkers (eosinophil, and reticulocyte count), has been associated with the development of acute ip in men with sca (8, 11, 13). furthermore, in this report, patients with priapism > 17.9 hours had a positive correlation for predicting erectile tissue recovery. similar results were found in other retrospective studies that observed cavernosal necrosis was more common with prolonged durations of > 12 hours. in ip, the histological damage in the erectile tissue appears to be time dependent. in patients with priapism < 12 hours, interstitial edema and minor endothelial defects predominate in the smooth muscle. on the contrary, extensive necrosis of the smooth muscle cells was detected after priapism lasting > 48 hours (28, 29). moreover, the presence of intravascular clots inside the cavernous sinuses causes venous obstruction and recurrent priapism (30). nonetheless, the duration of priapism had no significant effects on the pvis in this retrospective case series. this may be due to the fact that not all cases who presented with a prolonged duration had a complete venous outflow occlusion, which may be related to stuttering priapism, which is associated with intermittent periods of detumescence, or because of focal necrosis/ fibrosis in the infracted corpora secondary to ischemic compartment syndrome in acute ip (4, 6, 14). our results confirmed an independent poor outcome of ip management for sca patients with both increased mpv and longer priapism duration. their measured cutoff levels were detected to have a significant relationship with the priapism outcome. however, such retrospective analysis has many limitations. the number of ip cases included in the analysis was relatively small. we did not evaluate other etiologies of acute priapic attacks, such as leukemia or thalassemia. in addition, the normal ranges of platelet indicators need adjustment. also, the lack of association between priapism and genetic factors associated with sca may indeed limit the statistical power of our study. moreover, the diagnosis of ip was established mainly after clinical parameters and cavernosal aspiration, both of which are prone to error (6). also, these populations should be investigated for asymptomatic erectile dysfunction because of the high risk of vascular dysfunction associated with sca. conclusions in summary, this study shows that increased pvis in sca may have a beneficial role in the veno-occlusive pathogenesis of ip, which was associated with cavernosal damage. furthermore, prolonged duration of priapism with a high mpv may be a predictive parameter for the development of corpora fibrosis in men with acute priapic attacks. additionally, the use of laboratory mpv factor 221archivio italiano di urologia e andrologia 2022; 94, 2 acute ischemic priapism and platelets indices may guide the physician to identify high-risk sickle cell men presenting with acute ip, which is considered for primary nonsurgical resolution of the priapic event. prospective clinical protocols involving large populations and different priapism types are also warranted to improve this issue. acknowledgments the authors would like to thank manaji m. ba-baeer for his editorial and valuable assistance. references 1. bivalacqua tj, musicki b, kutlu o, burnett al. new insights into the pathophysiology of sickle cell disease-associated priapism. j sex med. 2012; 9:79. 2. claudino ma, fertrin ky. sickling cells, cyclic nucleotides, and protein kinases: the pathophysiology of urogenital disorders in sickle cell anemia. anemia. 2012; 2012:1-13. 3. adeyoju ab, olujohungbe ab, morris j, et al. priapism in sickle cell disease; incidence, risk factors and complications-an international multicenter study. bju int. 2002; 90:898. 4. broderick ga, kadioglu a, bivalacqua tj, et al. priapism: pathogenesis, epidemiology, and management. j sex med. 2010; 7:476. 5. berger r, billups k, brock g, et al. report of the american foundation for urologic disease (afud) thought leader panel for evaluation and treatment of priapism. int j impotence res. 2001; 13(suppl 5):s39. 6. von stempel c, zacharakis e, allen c, et al. mean velocity and peak systolic velocity can help determine ischaemic and nonischaemic priapism. clin radiol. 2017; 72:611. 7. ciftci h, yeni e, demir m, et al. the mean platelet volume be a risk factor for vasculogenic erectile dysfunction? world j mens health. 2013; 31:215. 8. madu aj, ubesie a, ocheni s, et al. priapism in homozygous sickle cell patients: important clinical and laboratory associations. med princ pract. 2014; 23:259. 9. sönmez mg, kara c, karaibrahimoglu a, et al. ischemic priapism: can eosinophil count and platelet functions be positive predictive factors in etiopathogenesis. can urol assoc j. 2017; 11:e297. 10. ufuk y, hasan y, murat u, et al. does platelet activity play a role in the pathogenesis of idiopathic ischemic priapism? int braz j urol. 2016; 42:118. 11. alkindi s, almufargi ss, pathare a. clinical and laboratory parameters, risk factors predisposing to the development of priapism in sickle cell patients. exp biol med. 2020; 245:79. 12. ballas sk, lieff s, benjamin lj, et al. definitions of the phenotypic manifestations of sickle cell disease. am j hematol. 2010; 85:6. 13. cita kc, brureau l, lemonne n, et al. men with sickle cell anemia and priapism exhibit increased hemolytic rate, decreased red blood cell deformability and increased red blood cell aggregate strength. plos one. 2016; 11:e0154866. 14. salonia a, eardley i, giıliano f, et al. european association of urology guidelines on priapism. eur urol. 2014; 65:480. 15. burnett al, sharlip id. standard operating procedures for priapism. j sex med. 2013; 10:180. 16. lancé md, van oerle r, henskens ymc, marcus ma. do we need time adjusted mean platelet volume measurements? lab. hematol. 2010; 16:28. 17. ghanem ma, adawi ea, hakami na, et al. the predictive value of the platelet volume parameters in evaluation of varicocelectomy outcome in infertile patients. andrologia 2020; 52:e13574. 18. adawi ea, ghanem ma, ghanem am, et al. high platelet distribution width can independently predict testicular survival in testicular torsion among steady state sickle cell anemia patients. world jnl ped surgery. 2022; 5:e000358. 19. mutlu h, artis t, erden a, akca z. alteration in mean platelet volume and platelet crit values in patients with cancer that developed thrombosis. clin appl thromb hemost. 2013; 19:331. 20. chu sg, becker rc, berger pb, et al. mean platelet volume as a predictor of cardiovascular risk: a systematic review and metaanalysis. j thromb haemost. 2010; 8:148. 21. ridgley j, raison n, sheikh mi, et al. ischaemic priapism: a clinical review. j urol. 2017; 43:1. 22. champion hc, bivalacqua t, takimoto e, et al. phosphodiesterase-5a dysregulation in penile erectile tissue is a mechanism of priapism. proc natl acad sci usa. 2005; 102:1661. 23. braekkan sk, mathiesen eb, njølstad i, et al. mean platelet volume is a risk factor for venous thromboembolism: the tromsø study, tromsø, norway. j thromb haemost. 2010; 8:157. 24. wang jj, wang yl, ge xx, et al. prognostic values of plateletassociated indicators in resectable lung cancers. technol cancer res treat. 2019; 18:1533033819837261. 25. makis ac, hatzimichael ec, bourantas kl. the role of cytokines in sickle cell disease. ann hematol. 2000; 79:407. 26. ahmed sg, ibrahim ua, hassan aw. hematological parameters in sick cell anemia patients with and without priapism. ann. saudi med. 2006; 26:439. 27. conran n, fattori a, saad sto, costa ff. increased levels of soluble icam-1 in the plasma of sickle cell patients are reversed by hydroxyurea. am j hematol. 2004; 76:343. 28. zacharakis e, raheem aa, freeman a, et al. the efficacy of the t-shunt procedure and intracavernous tunneling (snake maneuver) for refractory ischemic priapism. j urol. 2014; 191:164. 29. ortac m, cevik g, akdere h, et al. anatomic and functional outcome following distal shunt and tunneling for treatment ischemic priapism: a single-center experience. j sex med. 2019; 16:1290. 30. upadhyay j, shekarriz b, dhabuwala cb. penile implant for intractable priapism associated with sickle cell disease. urology. 1998; 5:638. correspondence essa a. adawi, md dr.adawi@gmail.com mazen a. ghanem, md (corresponding author) mazenghanem99@yahoo.co.uk department of urology, jazan university, ksa, jazan, saudi arabia stesura seveso 361archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. dicted that 322 million men around the world will have ed by 2025 (2). the increasing prevalence of ed leads to a more significant economic burden. at this point, oral phosphodiesterase-5 inhibitors (pde5i) are the first choice of treatment for ed because they are safe, efficient, costeffective and non-invasive (3). pde5i which were approved by the food and drug administration (fda) for ed and other diseases are shown on the timeline (4, 5) (figure 1). considering sexual disorders, patients may not feel comfortable to share their problems with the doctors. then they can try to find out how to treat their sexual problems by themselves on the web (6). a survey from the national men’s health week showed that 44% of men who developed symptoms of ed, would hesitate to look for a treatment, and 11% of them would not visit a doctor if they decide they might need a medical treatment like pde5i (7). google trends (gt) is one of these search tools which provides worldwide data about the popularity of searched items during a period. thus, gt has been continuously used more by marketing specialists for gathering information about potential client interest, as well as differences in that interest by geographic location and time. in the medical area, gt has been used to specify patient interest in surgical procedures and medical treatments (8). therefore, we aimed to analyze the trend change of the most popular pde5i over time including covid-19 pandemic and geography by using gt data. we also aimed to reveal the possible reasons for the trend changes of pde5i in terms of time and geography. materials and methods gt produces worldwide search volume info since 2004, offering time-period and category patterns according to a specific term. gt is able to generate a “line-graph”, showing how interest has increased or decreased over a period within specific territories. the search values for specific terms are indexed as relative search volume (rsv), which is presented on a scale from 0-100. a value of rsv 100 indicates the highest search trends, while 50 represents half of the searches. however, 0 demonstrates that no sufficient data were found for the term. by using the estimated annual rsv (arsv) annual percentage objectives: we aimed to analyze the trend change of the most popular phosphodiesterase-5 inhibitors (pde5i) over time and geography by using google trends (gt) data in 10 years period and covid-19 pandemic. materials and methods: gt is able to generate a “line-graph”, showing how interest has increased or decreased over a period within specific territories. the search values for specific terms are indexed as relative search volume (rsv), which is presented on a scale from 0-100. avarage annual percentage change (aapc) and rsv were analyzed to evaluate gain or loss of interest in trends. search terms were generated for food and drug administration (fda)-approved pde5i; tadalafil, sildenafil, vardenafil, avanafil, and their most-used brand names. the data was within “worldwide” from 1 january 2010, to 31 december 2020, using the ‘‘global’’ query category. results: the overall interest in pde5i has doubled. sildenafil has become the most trend pde5i of today with a regular increase (aapc: 0.016, p < 0.01). although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised and tadalafil has become the 2nd most popular pde5i recently (aapc: 0.007, p < 0.01). for vardenafil there has been a decreased interest (aapc: -0.009, p < 0.01). there is no significant change in avanafil trend (aapc: 0.000, p: 0.5). all pde5i interest on gt decreased notably from february to june 2020. but after june, search trends reached the level before the covid-19 period in a month. conclusions: these findings show us, with its increasing prevalence, erectile dysfunction (ed) has become a major public health problem. people from different geographies search the internet for ed treatment options. patients should be informed that ed may be the first sign of many comorbid diseases, and patients with ed should be referred to a health institution for diagnosis and treatment. key words: google trends; erectile dysfunction; phosphodiesterase type-5 inhibitors; health behaviors; real-world evidence. submitted 28 april 2021; accepted 14 june 2021 introduction erectile dysfunction (ed) is the recurrent or persistent inability of men to achieve and/or maintain adequate penile erections for satisfactory sexual performance (1). it is preerectile dysfunction treatment with phosphodiesterase-5 inhibitors: google trends analysis of last 10 years and covid-19 pandemic müslim doğan değer 1, serdar madendere 2 1 department of urology, edirne sultan 1st murat state hospital, edirne, turkey; 2 department of urology, gümüşhane state hospital, gümüşhane, turkey. doi: 10.4081/aiua.2021.3.361 summary archivio italiano di urologia e andrologia 2021; 93, 3 m. doğan değer, s. madendere 362 change (apc), linear trends in rsv were shown. to measure variations in arsv between 2 join points, apc was evaluated. estimated average apc (aapc) and respective confidence of intervals (cis) were used to determine linear trends of arsv during the whole period. aapc analysis in rate during a period is provided by a natural log-linear model ([ln(y)=xb]). a negative value of aapc shows a decreasing rsv and a positive rate refers to increased interest. a log (x+1) transformation was used to the whole dataset if a dependent variable was zero. to assess any inflection points with a significant difference in the trend’s slope, a permutation test was used. when slopes were identified or not the trends were called non-constant or constant, respectively. the kendall trend tau test was applied to compare data which is collected over time for trends decreasing or increasing consistently. search terms were generated for fdaapproved pde5i; tadalafil, sildenafil, vardenafil, avanafil, and their most-used brand names. the data was within “worldwide” from 1 january 2010, to 31 december 2020, using the ‘‘global’’ query category. data obtained from search terms were plotted in polynomial trend lines. moreover, international trends for each pde5i individually were searched and shown in a separate figure. all trend and statistical analyses were performed using microsoft excel v.16.0 (redmond, wash) and spss v.24.0 (spss inc., chicago, il, usa). results trends in geographic locations interest in sildenafil was mostly high in south america and europe, interest in vardenafil was highest in the eastern european and asian countries. interest in tadalafil was not superior especially in a specific region. the highest interest in avanafil was in mediterranean countries (figure 2) (table 1). trends in interest over time the overall interest in pde5i has doubled in the last 10 years. the leading trend was vardenafil from 2010 to figure 1. milestones in the development of phosphodiesterase type 5 inhibitors. figure 2. international trends in phosphodiesterase5 inhibitors.the world map shows the countries with the highest google trends search volumes for each search term. the darker regions indicate the places where the search terms are more likely to be searched. if a region on the map isn't highlighted, it doesn't mean the term is not used in that region, however, it is less popular than other regions. 363archivio italiano di urologia e andrologia 2021; 93, 3 web searches for erectile dysfunction treatments 2013, but it has been decreasing over time (aapc: -0.009, p < 0.01). sildenafil has become the most trend pde5i of today with a regular increase (aapc:0.016, p < 0.01). although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised geometrically like sildenafil, and tadalafil has become the 2nd most popular pde5i recently (aapc: 0.007, p < 0.01). avanafil has not become widespread and its trend has shown slight movement in the last 1 year, but it has not been a competitor in general (aapc: 0.000, p: 0.5) (figure 3) (table 2). the global interest in the term "erectile dysfunction" on gt has been substantially lower than the interest in all pde5i. there was no relationship between the pde5i interest and the interest in global erectile dysfunction issue. trends in interest in covid-19 period all pde5i interest on google trend decreased notably from february to june 2020. but after june, search trends reached the level before the covid-19 period in a month. then the increase-decrease routine continued as before (figure 3). discussion with the aging population and the increase of comorbid diseases, ed has become more prevalent. accordingly, the demand for ed treatments is increasing (9, 10). because pde5i are both non-invasive and more costeffective treatments of ed compared to other methods (3, 11), we can see a rising interest in them over the world in the last 10 years in our results. jena et al. found a strong correlation between web searches for human immunodeficiency virus (hiv) terms and hiv regional incidence rates in the united states (us) (12). tijerina et al. found also a correlation between breast surgery procedures search terms and annual case volumes of breast procedures performed in the us (13). similarly, in our study, there was a correlation between the trend rate and the amount of pde5i sales in europe (14). we demonstrated that people initially search for treatment options for ed on the web, then they buy the most suitable one for themselves. on this point, there is a risk that can endanger patients’ health. countrefeit pde5i have been an important problem in both well-developed and developing countries. they are cheaper and easy to obtain table 2. aapc results of pde5i queries from 2010 until 2020. pde5i lower upper aapc lower upper test *p-value endpoint endpoint ci ci statistic sildenafil 2010 2020 0.016 0.015 0.017 0.874 < 0.01 vardenafil 2010 2020 -0.009 -0.0010 -0.0010 -0.806 < 0.01 tadalafil 2010 2020 0.007 0.006 0.008 0.791 < 0.01 avanafil 2010 2020 0.000 0.000 0.000 0.192 0.5 ci: confidence interval; aapc: avarage annual percentage change; pde5i: phosphodiestarese-5 inhibitors. * the kendall trend tau test was applied to define p value. table 1. most trend five countries for each pde5i. figure 3. google trends relative search volume for phosphodiesterase-5 inhibitors by month, january 2010 to december 2020. sildenafil vardenafil tadalafil avanafil finland japan brazil italy chile russia vietnam portugal colombia ukraine france egypt argentina bulgaria india france peru israel united arab emirates china archivio italiano di urologia e andrologia 2021; 93, 3 m. doğan değer, s. madendere 364 through the web (15). considering the side effects of the drugs and their interactions with other drugs, the patient may be harmed. moreover, clinical examination is necessary because ed can be the first symptom of cardiovascular diseases, also multiple risk factors and comorbidities are generally associated with ed (16). both to prevent the use of counterfeit medicines and ensure the correct use of fda-approved pde5i, patients’ awareness should be raised to see a doctor when they have ed. when the trends of pde5i are interpreted separately, it is seen that sildenafil has a clear superiority in recent years. according to the “conser” survey conducted by the italian society of andrology, the speed of action is the most important factor for both physicians and patients when choosing a pde5i. on this point, a new oro-soluble form of sildenafil offers advantages (17). comparing the total numbers of pde5i prescriptions in europe, sildenafil is superior to tadalafil and vardenafil in the literature similar to our results of search trends (14). being the first product in the market, brand name recognition, high efficacy and patient satisfaction are the main factors that maintain the popularity of sildenafil. another important point is the lower cost of sildenafil compared to other pde5i. hansen et al. showed that ed treatment with sildenafil was a costeffective alternative compared to vardenafil and tadalafil (18). moreover, sildenafil searches seem to be prominent, especially in latin american countries. successful results in ed treatment with sildenafil in latin america may have made sildenafil popular in this region (19). on the other hand, higher prescription rates of tadalafil in a prospective study in latin america show that trends in the region may change in times advancing (20). our study shows that the trend of tadalafil has increased significantly and tadalafil has become popular in many countries from different continents recently. this popularity in different geographies can be interpreted with the high satisfaction of patients. the long duration of action of tadalafil gives the freedom to have unplanned sexual intercourse. this takes away timing concerns and provides sexual self-confidence, especially for the young men with mild sexual dysfunction (21). no interaction with fatty food is another advantage of tadalafil (22). other important developments that increased the use of tadalafil were the approval for bph and suggestions for the early use after radical prostatectomy (23, 24). additionally, the increase in vardenafil trend in 2011 can be explained with the international study conducted with a large patient group in this period (25). this study may have increased the interest in vardenafil on web searches. however, the interest in vardenafil in the later period appears to be less than sildenafil and tadalafil. in addition to this, there is no significant peak of avanafil trend in the last 10 years. less generic drugs of avanafil and vardenafil compared to sildenafil and tadalafil may also have made this difference in trends (15). on the other hand, high trends of avanafil in mediterranean countries and vardenafil in the eastern european and asian countries can be investigated with further studies in these regions. mulhall et al. indicated that patients who were previously prescribed sildenafil were more likely tended to continue with the same medication compared with patients who have previously prescribed tadalafil or vardenafil (26). on the other hand, there are contradictory results that show that patients are more likely to prefer tadalafil after experiencing sildenafil (27). a study from canada showed that most patients and physicians preferred tadalafil instead of sildenafil (28). thus, additional prospective studies are necessary to provide advanced insights into this issue. in february 2020, when the covid-19 pandemic started, a trend decreases up to 20% was observed in all pde5i. higher interest in covid-19 related searches can be a reason of this decrease. moreover, sexual behaviors seem to be negatively affected by the pandemic because of quarantine rules, multiple contact restrictions and fear of contamination (29). karagöz et al. found that the frequency of sexual intercourse decreased in both sexes during the pandemic period compared to the pre-pandemic period (30). however interestingly 3 months later the trend of pde5i came back to old levels and then started to rise again. considering that stress and anxiety increase the frequency of ed, as well as the need of pde5i. so, the pandemic affected the pde5i trend both badly and well. to the best of our knowledge, this is the first study that focuses on the differences of pde5i on google searches from the aspect of time and geography. our study has some limitations. firstly, gt data are anonymous and do not give the possibility for analyzing sub-population groups. besides, we only had access to rsv and access to raw data was not possible. furthermore, because the internet is more popular among the young population there may be inadequate data for older men. lastly, search terms except english languages are not considered. however, we believe that our results reveal the current pde5i search trends on the web. conclusions in conclusion, people from different geographies search the internet for ed treatment options. patients should be informed that ed may be the first sign of many comorbid diseases, and patients with ed should be referred to a health institution for diagnosis and treatment. in recent years apart from the first months of the covid-19 pandemic, interest and search volume for pde5i has increased continuously. these findings show us that ed has become a major public health problem with its increasing prevalence. studies with broad participation are needed to examine different geographical trends in detail. references 1. hatzimouratidis k, amar e, eardley i, et al. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol. 2010; 57:804-814. 2. aytaç ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-56. 3. rezaee me, ward ce, brandes er, et al. a review of economic evaluations of erectile dysfunction therapies. sex med rev. 2020; 8:497-503. 4. chen l, staubli sel, schneider mp, et al. phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. eur urol. 2015; 68:674-80. 365archivio italiano di urologia e andrologia 2021; 93, 3 web searches for erectile dysfunction treatments 5. tzoumas n, farrah te, dhaun n, et al. established and emerging therapeutic uses of phosphodiesterase type 5 inhibitors in cardiovascular disease . br j pharmacol. 2020; 177:5467-5488 6. cacciamani ge, bassi s, sebben m, et al. consulting “dr. google” for prostate cancer treatment options: a contemporary worldwide trend analysis. eur urol oncol. 2019; 1:1-8. 7. national study shows u.s. men avoid the doctor. available at: 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(viagratm). j drug eval. 2003; 1:225-246. 20. rubio-aurioles e, reyes la, borregales l, et al. a 6 month, prospective, observational study of pde5 inhibitor treatment persistence and adherence in latin american men with erectile dysfunction. curr med res opin. 2013; 29:695-706. 21. raheem aa, kell p. patient preference and satisfaction in erectile dysfunction therapy: a comparison of the three phosphodiesterase-5 inhibitors sildenafil, vardenafil and tadalafil. patient prefer adherence. 2009; 3:99-104. 22. wright pj. comparison of phosphodiesterase type 5 (pde5) inhibitors. int j clin pract. 2006; 60:967-975. 23. cantrell ma, baye j, vouri sm. tadalafil: a phosphodiesterase5 inhibitor for benign prostatic hyperplasia. pharmacotherapy. 2013; 33:639-649. 24. montorsi f, brock g, stolzenburg ju, et al. effects of tadalafil treatment on erectile function recovery following bilateral nervesparing radical prostatectomy: a randomised placebo-controlled study (reactt). eur urol. 2014; 65:587-596. 25. van ahlen h, zumbé j, stauch k, hanisch ju. the real-life safety and efficacy of vardenafil (realise) study: results in men from europe and overseas with erectile dysfunction and cardiovascular or metabolic conditions. j sex med. 2010; 7:3161-3169. 26. mulhall jp, mclaughlin tp, harnett jp, et al. medication utilization behavior in patients receiving phosphodiesterase type 5 inhibitors for erectile dysfunction. j sex med. 2005; 2:848-855. 27. eardley i, mirone v, montorsi f, et al. an open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. bju int. 2005; 96:1323-1332. 28. lee j, pommerville p, brock g, et al. physician-rated patient preference and patientand partner-rated preference for tadalafil or sildenafil citrate: results from the canadian “treatment of erectile dysfunction” observational study. bju int. 2006; 98:623-629. 29. maretti c, privitera s, arcaniolo d, et al. covid-19 pandemic and its implications on sexual life: recommendations from the italian society of andrology. arch ital urol androl. 2020; 92:73-77. 30. karagöz ma, gül a, borg c, et al. influence of covid-19 pandemic on sexuality: a cross-sectional study among couples in turkey. int j impot res. 2020 dec 16:1-9. doi: 10.1038/s41443-020-003784. epub ahead of print. correspondence müslim doğan değer, md department of urology, edirne sultan 1st murat state hospital, edirne (turkey) serdar madendere, md (corresponding author) serdarmadendere@gmail.com department of urology, gümüşhane state hospital hasanbey mahallesi, 29000, gümüşhane (turkey) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4434 original paper no conflict of interest declared. and the usa (2). in 2020, 36 068 new cases were diagnosed, and 13 211 men died due to pec (1). the incidence increases with age with a peak in the sixth decade (3). in portugal, pec represents the 30th most common cancer with 119 new cases diagnosed in 2020 (4). pec metastatic spread complies with the route of anatomical drainage, beginning with the inguinal lymph nodes (superior medial zone of the inguinal region and, afterwards, central inguinal nodes) followed by the pelvic lymph nodes. whenever inguinal lymph nodes are palpably enlarged, radical inguinal lymph node dissection (rilnd) should be the diagnostic and therapeutic approach (2). other diagnostic tools have already been evaluated. positron-emission tomography (pet) computed tomography (ct) using 18-f-fluorodeoxyglucose (18ffdg-pet-ct) has shown good accuracy confirming inguinal metastasis and detecting systemic disease (8299% sensitivity for iln metastasis in patients with clinically evident disease) whereas magnetic resonance imaging (mri) with lymphotrophic nanoparticles (ferumoxtran10, ferucarbotran, ultrasmall superparamagnetic iron oxides) might be an adequate choice for the evaluation patients with a limited physical and/or clinical exam (100% sensitivity and 97% specificity). even though ultrasound-guided biopsy may allow for the pathological diagnosis of disease in clinically positive patients, they will ultimately require radical inguinal lymph node dissection as for local staging. the risk of distant metastasis whenever inguinal lymph nodes are palpable is high deeming radiographical evaluation with ct or mri necessary (5). the involvement of locoregional lymph nodes represents the most clinically significant prognostic factor for patients with pec (6). the recurrence free and overall survival are largely dependent on iln disease burden with a significant decrease in the 5-year survival in patients with positive deep pelvic lymph nodes (0-12%) versus patients with a single involved inguinal node (80%) (7). the surgical excision of clinically positive lymph nodes is decisive for patient survival as it may result in cure. nevertheless, rilnd might be delayed by physicians and patients due to its anticipated postoperative morbidity leading to worsened overall survival (8). the complicaobjective: management of patients with penile cancer (pec) with palpable inguinal lymph nodes (ilns) relies on radical iln dissection (rilnd). low burden of nodal metastatic disease may lead to long-lasting survival with surgical management. nevertheless, rilnd involves significant postoperative morbidity. we compared the complications of patients undergoing rilnd with (rilnd-t) and without (rilnd-0t) placement of a collagen-fibrin sealant patch on the resection bed. materials and methods: we conducted an observational retrospective study. data from men submitted to rilnd-t and rilnd-0t from jan/2001 to feb/2022, in a tertiary care centre were compared. the primary endpoint was the overall incidence of complications until 1 month after the procedure and their respective severity in both cohorts (clavien-dindo classification system). secondarily, length of hospital stay (lohs) was analysed. the placement of a collagen-fibrin sealant patch was left at the surgeon’s discretion. results: seven patients underwent rilnd-t and 20 underwent rilnd-0t, respectively. there were no differences in pathologic tnm stage nor in the total number of ilns removed (17 ± 4 vs. 20 ± 8, p = 0.37). overall, 23 (85.2%) patients had complications. the complication rate was similar in both cohorts (85.7% vs 85%, p = 0.73). surgical wound infection (3/7 vs. 11/20) and lymphocele (4/7 vs. 11/20) were the most reported complications. patients undergoing rilnd-t were discharged faster (mean length of hospital stay 9 ± 3 vs 19 ± 20 days, p = 0.22). conclusions: the application of a collagen-fibrin sealant patch on the resection bed does not seem to reduce the postoperative complication rate in patients undergoing rilnd. nevertheless, a trend towards a shorter lohs in patients with rilnd-t cannot be excluded and should be validated by further studies with a higher number of patients. key words: penile cancer; radical inguinal lymph node disssection; radical inguinal lymphadenectomy; complications of radical inguinal lymph node dissection. submitted 3 august 2022; accepted 21 august 2022 introduction penile cancer (pec) is a rare neoplasm representing the 32nd most common cancer worldwide (1). it displays an overall incidence of around 1/100.000 males in europe does the placement of a collagen-fibrin sealant reduce complications of radical inguinal lymph node dissection – comparative study in patients with penile cancer andreia bilé silva 1*, joão nuno pereira 2*, rui freitas 2, isaac braga 2, joão carvalho 2, josé sanches magalhães 2, vítor silva 2, francisco lobo 2, antónio morais 2 1 hospital de egas moniz centro hospitalar de lisboa ocidental, lisboa, portugal; 2 instituto português de oncologia francisco gentil do porto, porto, portugal. * andreia bilé silva and joão nuno pereira contributed equally. doi: 10.4081/aiua.2022.4.434 summary 435archivio italiano di urologia e andrologia 2022; 94, 4 does the placement of a collagen-fibrin sealant reduce complications of radical inguinal lymph node dissection... tions of rilnd can be as high as 50% (9), ranging from seroma and hematoma formation to wound infection and even more severe complications such as difficulty in ambulating, deep venous thrombosis (dvt) and chronic lymphoedema. more recent studies have reported a lower morbidity in about 25% of cases (10). meticulous surgical technique with careful tissue handling along with avoidance of electrocauterization, modified incision lines, suction drainage devices, videoendoscopic surgery, omentoplasty and placement of a collagen-fibrin sealant patch have already demonstrated efficacy in achieving hemostasis after liver and kidney surgery (11), in preventing leakage after lung surgery (12), and in reducing lymphatic fluid production after mediastinal (13) and axillary (14) lymph-node dissection and, therefore, minimise postoperative morbidity (15). additionally, there is evidence that the placement of a fibrin glue sealant is beneficial towards reducing the complication rates in rilnd, namely seroma (16). on the other hand, evidence of benefit due to vacuum suction in rilnd for pec (17), sealants in rilnd for melanoma (18), or collagen-fibrin sealant patch in ilnd in vulvar cancer (19) is still lacking. to our knowledge, this is the first observational study reporting the efficacy of placing a collagen-fibrin sealant patch (tachosil®) in the resection bed of patients with pec submitted to rilnd. materials and methods our study complies with the strobe (strengthening the reporting of observational studies in epidemiology) guidelines for observational original research studies. a retrospective observational study was conducted at a tertiary oncological care centre. consecutive patients with pec who underwent any kind of inguinal lymph node dissection (ilnd) between january of 2000 and february of 2022 were identified. from the 214 patients with pec initially retrieved, 110 did not undergo ilnd and were excluded from the study. patients who underwent ilnd other than rilnd, namely modified ilnd (n = 54) or dynamic sentinel ilnd (n = 23) were excluded. rilnd technique was the same in all patients included. it involved an incision parallel and 1-2 cm inferior to the inguinal ligament. skin flaps were created preserving the scarpa’s fascia to avoid necrosis. rilnd comprised the traditional boundaries margin of the external inguinal ring until the anterior superior iliac spine (asis), superiorly, the asis and a line drawn 20cm inferiorly, laterally, the pubic tubercle and a line drawn 15 cm inferiorly from it, medially, and a line connecting both lateral and medial limits. a long saphenous vein ligation was usually performed at the apex of the femoral triangle. sartorius muscle transposition might be done to cover the femoral vessels. placement of tachosil® on the resection bed was left at the surgeon’s discretion. cohorts were compared based on the placement of tachosil® during the rilnd. a single patch of tachosil® was applied, with the yellow active side onto the resection bed, after blood and other fluids were cleaned. the patch had to extend around the inguinal lymphadenectomy area and maintained in place for at least 3 min. data was obtained through the available consultation records. data concerning clinical history (including risk factors for pec), physical examination and pathological results were collected. patients’ comorbidities were documented and assessed with charlson comorbidity score (cci). pertaining to the surgical procedure, surgical reports were examined and data on the surgical technique and amount of blood loss were gathered. postoperative complications after rilnd were defined as those that occurred immediately after surgery, whether during the initial hospital stay or within 30 days of rilnd. rilnd postoperative complications were quantified using the clavien-dindo classification system for surgical complications (20). hospitalization records were available. amount of drainage volume, duration of drain placement and deambulation start were assessed. all complications were followed until resolution and hospital discharge and, when applicable, surgical interventions of major complications were recorded by their specific date and type of procedure required. readmissions during the first 30 postoperative days were determined as well as the hospitalization reason and duration. statistical analysis the primary outcome was the overall complication rate in both cohorts. secondary endpoint measures were the incidence of each complication in rilnd-t and rilnd0t groups. to determine whether the data had a gaussian distribution, gaussian curve and kolmogorov-smirnov test were used. comparisons of the continuous variables between groups were made using the student’s t-test for normally distributed and mann-whitney u for not normally distributed variables. the chi-squared and fisher’s exact tests were used to compare categorical variables. statistical analyses were performed using spss 25.0 (ibm software division, somers, ny, usa). all reported p values are two-sided, and p values < 0.05 were considered to indicate statistical significance. results a total of 27 patients with pec submitted to rilnd were collected for the present study. while 7 patients underwent rilnd-t, 20 patients underwent rilnd-0t. table 1 displays patient demographics, surgical outcomes and lymph node counts. the mean age (70 ± 7 vs 64 ± 14 years, p = 0.32), cci (6 ± 2 vs 5 ± 2, p = 0.35) and body mass index (bmi 25 ± 4 vs 27 ± 4 kg/m2, p = 0.27) were comparable in both cohorts. the majority of patients (n = 26) had confirmed conventional squamous cell carcinoma of the penis (sccp), with only one patient having a mixed warty-basaloid subtype. the primary penile tumour grade (table 2) was similar in both cohorts (p = 0.42) as well as lymphovascular invasion (14.8% vs 29.6%, p = 0.85). patients had a mean 17 ± 4 and 20 ± 8 lymph nodes harvested in the rilnd-t and in the rilnd-0t group (p = 0.37), respectively. the median largest diameter lymph node with tumour present was 2.7 (range 0.5-5-3) and 3.7 (range 0.4-6.5) cm (p = 0.65). archivio italiano di urologia e andrologia 2022; 94, 4 a. bilé silva, j. nuno pereira, r. freitas, i. braga, j. carvalho, j. sanches magalhães, v. silva, f. lobo, a. morais 436 the mean length of hospital stay after rilnd was longer in the cohort without placement of collagen-fibrin sealant patch (9 ± 3 vs 19 ± 20 days, p = 0.22). the mean time to ambulation was 2 ± 1 in both cohorts (p = 0.16). inguinal suction drains were kept in place for a mean of 5 ± 3 and 5 ± 1 days (p = 0.55). a detailed summary of clinical nodal staging and pathological staging can be found in tables 3 and 4, respectively. overall, of the 27 patients with pec included in the present study, 23 (85.2%) had at least one postoperative complication and 20 patients having more than a single complication (88 instances of complications overall). the complication rate was similar in both cohorts (85.7% vs 85%, p = 0.73) and when analysing the complications on a per patient basis, there was a comparable mean number of 3 complications per patient in both groups (p = 0.88). the most commonly encountered complications were lymphocele (57.1% vs 55%, p = 0.4) and wound infection (42.9% vs 55%, p = 1). vascular and neural injuries were not noted. all of the complications recorded were clavien-dindo ii grade or less. a total of 3 patients were readmitted due to complications, 1 from the rilnd-t (1/7) and 2 (2/20) from the rilnd-0t cohort. the hospital readmission time was similar in both groups (11 and 10 days, respectively). none of the patients were submitted to surgical exploration nor surgical management of major complications. table 5 shows complication rates and type as categorised by the clavien-dindo classification. discussion the present study reports the experience from a portuguese high-volume oncological care centre. it details the postoperative complication rates from rilnd, as categorised by the clavien-dindo classification system, from january of 2001 until february of 2022 with and without placement of collagen-fibrin sealant patch on the resectable 1. patient demographic characteristics, surgical outcomes and lymph node counts. characteristics rilnd-t rilnd-0t p age, in years (mean ± standard deviation) 70 ± 7 64 ± 14 0.32 bmi, in kg/m2 (mean ± standard deviation) 25 ± 4 27 ± 4 0.27 length of hospital stay, in days (median, range) 9 ± 3 19 ± 20 0.20 post-surgical walk day (mean ± standard deviation) 2 ± 1 2 ± 1 0.16 post-surgical drain removal (mean ± standard deviation) 5 ± 3 5 ± 1 0.55 total number of lymph nodes taken (mean ± standard deviation) 17 ± 4 20 ± 8 0.37 total number of positive lymph nodes (mean ± standard deviation) 1 ± 1 4 ± 4 0.13 largest lymph node size, in cm (median, range) 2.7, 0.5-5.3 3.7, 0.4-6.5 0.65 rilnd-t: radical inguinal lymph node dissection with tachosil® placement; rilnd-0t: radical inguinal lymph node dissection without tachosil® placement; bmi: body mass index. table 2. penile tumour grade. characteristics rilnd-t rilnd-0t p tumour grade, in percentage 0.42 – well-differentiated (g1) 26.7 0 – moderately differentiated (g2) 40 80 – poorly differentiated (g3) 33.3 20 – undifferentiated (g4) 0 0 rilnd-t: radical inguinal lymph node dissection with tachosil® placement; rilnd-0t: radical inguinal lymph node dissection without tachosil® placement. table 4. pathological staging, pec and nodes. characteristics rilnd-t rilnd-0t p tumour stage, in percentage 0.81 – cis 0 0 – pt1 21.1 14.3 – pt2 42.1 42.9 – pt3 36.8 42.9 – pt4 0 0 nodal stage, in percentage 0.35 – pn0 20 42.9 – pn1 5 14.3 – pn2 20 0 – pn3 55 42.9 rilnd-t: radical inguinal lymph node dissection with tachosil® placement; rilnd-0t: radical inguinal lymph node dissection without tachosil® placement; cis: carcinoma in situ. table 5. complication incidence rates according to clavien-dindo classification. characteristics rilnd-t rilnd-0t p chronic lymphoedema, n (percentage) 1 (14.3) 1 (5) 0.46 – clavien-dindo grade i, in percentage 14.3 5 deep venous thrombosis, n (percentage) 1 (5) 0 (0) – clavien-dindo grade ii, in percentage 5 0 lymphocele, n (percentage) 4 (57.1) 11 (55) 0.4 – clavien-dindo grade i, in percentage 42.9 55 – clavien-dindo grade ii, in percentage 14.3 0 lymphorrhea, n (percentage) 3 (42.9) 9 (45) – clavien-dindo grade i, in percentage 42.9 45 neural injury, n (percentage) 0 (0) 0 (0) skin necrosis, n (percentage) 2 (28.6) 6 (30) 0.75 – clavien-dindo grade i, in percentage 2 20 – clavien-dindo grade ii, in percentage 0 10 vascular injury, n (percentage) 0 (0) 0 (0) wound dehiscence, n (percentage) 3 (42.9) 4 (20) 0.48 – clavien-dindo grade i, in percentage 15 42.9 – clavien-dindo grade ii, in percentage 5 0 wound infection, n (percentage) 3 (42.9) 11 (55) – clavien-dindo grade ii, in percentage 42.9 55 table 3. clinical node staging. characteristics rilnd-t rilnd-0t p nodal stage, in percentage 0.21 – cn0 57.1 15 – cn1 0 15 – cn2 28.6 35 – cn3 14.3 35 rilnd-t: radical inguinal lymph node dissection with tachosil® placement; rilnd-0t: radical inguinal lymph node dissection without tachosil® placement. 437archivio italiano di urologia e andrologia 2022; 94, 4 does the placement of a collagen-fibrin sealant reduce complications of radical inguinal lymph node dissection... tion bed. to our knowledge, this is the first observational study reporting the efficacy of placing a collagen-fibrin sealant patch in the resection bed of patients with pec submitted to rilnd. previous series on complication rates state results averaging 40-70% (21). although we report a higher overall complication rate, all of the patients had minor complications (clavien-dindo i and ii) which translated into a regular postoperative management in most cases. lymphocele and wound infection were the most common complications (57.1% vs 55% and 42.9% vs 55%, respectively). a high rate of complications was seen in both groups (more than 85% of the patients had some sort of complication). nevertheless, none of the complications were graded higher than ii, as assessed by the clavien-dindo classification. measures to avoid complications during rilnd several studies have been conducted in order to find validated measures to reduce morbidity. careful tissue handling and avoiding electrocautery as well as preserving the saphenous vein and postoperative measures to improve drainage (stocking, bandaging, inguinal pressure dressings or vacuum suction) minimise postoperative morbidity (10, 22, 23). a systematic review and meta-analysis (24) on surgical techniques to reduce postoperative lymphoedema reported that sparing the long saphenous vein, fascia preserving dissection, pedicled omental flap and microsurgery are efficient. when available, minimallyinvasive surgical approaches (laparoscopic, robot-assisted) for inguinal lymphadenectomy, in small series, have been reported to significantly reduce post-operative morbidity except for the rate of lymphoceles (10, 17, 25-27). collagen-fibrin sealant patch as an adjuvant to reduce rilnd complications as previously stated, collagen-fibrin sealant patch and other similar fibrin-based sealants have already been studied in different fields as surgical adjuvants to reduce lymphadenectomy-related morbidity, namely, lymphorrhea, lymphoceles, and lymphoedema. the reported results are conflicting. in breast cancer patients undergoing axillary lymph node dissection, the fibrin-based sealant reduced the overall lymphatic drainage amount, which allowed an earlier removal of closed suction drains; on the other hand, other studies noted no significant differences regarding the incidence and severity of the above-mentioned complications (28, 29). it was also investigated in patients with endometrial cancer: even though the placement of tachosil® in laparoscopic pelvic lymphadenectomy translated into a significantly lower prevalence of lymphocele, there was no significant difference regarding the symptomatic forms of lymphocele (30). the outcomes after collagen-fibrin sealant patch placement on the resection bed are inconsistent. accordingly, a meta-analysis from 2014 (25) concluded that the available evidence is not robust enough to recommend the use of fibrin-based sealants in inguinofemoral lymphadenectomy for malignant conditions, especially considering the additional cost for these products. overall, our results suggest that collagen-fibrin sealant patch did not seem to be effective in improving postoperative complications both in quantity and in severity as assessed by the clavien-dindo classification. additionally, in our study, the inguinal drains were not removed earlier in the cohort submitted to rilnd-t (on average, on the fifth postoperative day in both groups). nevertheless, there is a trend towards a shorter length of hospital stay in patients who underwent placement of the collagen-fibrin sealant agent. pitfalls because of the relative rarity of penile cancer, there was a paucity of patients undergoing rilnd with and without placement of collagen-fibrin sealant patch on the resection bed. future studies, grouping together multiple patient series from different centres, might help overcome this by providing a greater database of patients, which is required to achieve statistical significance. furthermore, by combining patient data from multiple centres, variability of patient demographics and surgical technique could be unbiased and therefore externally validated for the general patient experience. furthermore, because of the retrospective nature of the present study, data collection was limited to what was reported initially at the time of patient care and during the follow-up. this is largely the reason why complication reporting was limited to 30 days postoperatively; there were difficulties in collecting long-term follow-up data. accordingly, the small dimension of the study does not allow to exclude completely a potential effect of collagenfibrin sealant patch for all complications, although results of our study refute its utility and data previously gathered in other studies suggest that it is improbable. conclusions the significant morbidity associated with rilnd for penile cancer treatment highlights the relevance of adopting techniques that minimise and avoid complications. with better understanding of the possible complications after rilnd and its rate, attitudes towards diminishing their incidence may be implemented. by tailoring periand postoperative care accordingly, outcomes may be improved. there seems to exist a clear trend towards a lower length of hospital stay in patients in whom the collagen-fibrin sealant patch was placed surgically on the resection bed. even though we did not prove collagen-fibrin sealant patch placement on the resection bed of patients undergoing rilnd to improve the outcomes, we cannot completely exclude a potential beneficial effect of this approach without having conducted a prospective randomised trial. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021; 71:209-249. 2. hakenberg ow, minhas es, necchi a, et al. eau guidelines on penile cancer 2020. eur assoc urol guidel 2020 ed [internet]. 2020; 1-38. available from: http://uroweb.org/guideline/penile-canarchivio italiano di urologia e andrologia 2022; 94, 4 a. bilé silva, j. nuno pereira, r. freitas, i. braga, j. carvalho, j. sanches magalhães, v. silva, f. lobo, a. morais 438 cer/ lk penile cancer uroweb%7chttp://uroweb.org/guideline/ penile-cancer/%7c fg 0. 3. barnholtz-sloan js, maldonado jl, pow-sang j, guiliano ar. incidence trends in primary malignant penile cancer. urol oncol 2007; 25:361-7. 4. world health organization. portugal global cancer observatory. globocan 2020 [internet]. 2020; 501:1-2. available from: https://gco.iarc.fr/today/data/factsheets/populations/620-portugal-fact-sheets.pdf 5. leone a, diorio gj, pettaway c, et al. contemporary management of patients with penile cancer and lymph node metastasis. nat rev urol 2017; 14:335-47. 6. pow-sang mr, ferreira u, pow-sang jm, et al. epidemiology and natural history of penile cancer. urology 2010; 76(2 suppl 1):s2. 7. leijte jap, kerst jm, bais e, et al. neoadjuvant chemotherapy in advanced penile carcinoma. eur urol 2007; 52:488-94. 8. gopman jm, djajadiningrat rs, baumgarten as, et al. predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort. bju int. 2015; 116:196-201. 9. stuiver mm, djajadiningrat rs, graafland nm, et al. early wound complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. eur urol 2013; 64:486-92. 10. koifman l, hampl d, koifman n, et al. radical open inguinal lymphadenectomy for penile carcinoma: surgical technique, early complications and late outcomes. j urol. 2013; 190:2086-92. 11. siemer s, lahme s, altziebler s, et al. efficacy and safety of tachosil® as haemostatic treatment versus standard suturing in kidney tumour resection: a randomised prospective study. eur urol. 2007; 52:1156-63. 12. anegg u, lindenmann j, matzi v, et al. efficiency of fleece-bound sealing (tachosil®) of air leaks in lung surgery: a prospective randomised trial. eur j cardio-thoracic surg. 2007; 31:198-202. 13. czerny m, fleck t, salat a, et al. sealing of the mediastinum with a local hemostyptic agent reduces chest tube duration after complete mediastinal lymph node dissection for stage i and ii non-small cell lung carcinoma. ann thorac surg. 2004; 77:1028-32. 14. moore m, burak we, nelson e, et al. fibrin sealant reduces the duration and amount of fluid drainage after axillary dissection: a randomized prospective clinical trial. j am coll surg 2001; 192:591-9. 15. baggio s, laganà as, garzon s, et al. efficacy of a collagen-fibrin sealant patch (tachosil®) as adjuvant treatment in the inguinofemoral lymphadenectomy for vulvar cancer: a double-blind randomized-controlled trial. arch gynecol obstet 2019; 299:1467-74. 16. fawzy a, balbaa ma, gaber a. role for fibrin glue (sealant) in seroma reduction after inguinal lymphadenectomy; a randomized controlled trial. int j surg. 2021; 89:105950. 17. tauber r, schmid s, horn t, et al. inguinal lymph node dissection: epidermal vacuum therapy for prevention of wound complications. j plast reconstr aesthet surg 2013; 66(3):390-6. 18. gerken alh, dobroschke j, reißfelder c, et al. tissue sealants for the prevention of lymphoceles after radical inguinal lymph node dissection in patients with melanoma: a systematic review and individual patient data meta-analysis. j surg oncol 2019; 119:728-36. 19. saner fa, schötzau a, mackay g, et al. fibrin-thrombin sealant does not reduce lymphocele formation in patients with inguinofemoral lymphadenectomy for vulvar cancer. cancer manag res. 2019; 11:3575-3582. 20. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240:205-13. 21. spiess pe, hernandez ms, pettaway ca. contemporary inguinal lymph node dissection: minimizing complications. world j urol 2009; 27:205-12. 22. thuret r, sun m, lughezzani g, et al. a contemporary population-based assessment of the rate of lymph node dissection for penile carcinoma. ann surg oncol 2011; 18:439-46. 23. protzel c, alcaraz a, horenblas s, et al. lymphadenectomy in the surgical management of penile cancer. eur urol 2009; 55:107588. 24. abbas s, seitz m. systematic review and meta-analysis of the used surgical techniques to reduce leg lymphedema following radical inguinal nodes dissection. surg oncol 2011; 20:88-96. 25. weldrick c, bashar k, o’sullivan ta, et al. a comparison of fibrin sealant versus standard closure in the reduction of postoperative morbidity after groin dissection: a systematic review and metaanalysis. eur j surg oncol 2014 2022; 40:1391-8. 26. cui y, chen h, liu l, et al. saphenous vein sparing during laparoscopic bilateral inguinal lymphadenectomy for penile carcinoma patients. int urol nephrol 2016; 48(3):363-6. 27. kumar v, sethia kk. prospective study comparing video-endoscopic radical inguinal lymph node dissection (veilnd) with open radical ilnd (oilnd) for penile cancer over an 8-year period. bju int 2017; 119:530-4. 28. vinchant m, bonneau c, lesavre m, et al. interest of a thrombin and fibrinogen combipatch in preventing breast cancer seroma after lymph node dissection. gynecol obstet fertil 2013; 41:583-7. 29. lacoste c, ouldamer l, body g, marret h. does the use of tachosil allow to reduce the morbidity of axillary dissection? gynecol obstet fertil 2013; 41:141-3. 30. grimm c, polterauer s, helmy s, et al. a collagen-fibrin patch (tachosil®) for the prevention of symptomatic lymphoceles after pelvic lymphadenectomy in women with gynecologic malignancies: a randomized clinical trial. bmc cancer 2014; 14:365 correspondence andreia bilé silva, md andreiabile@campus.ul.pt hospital de egas moniz centro hospitalar de lisboa ocidental, lisboa, portugal joão pereira, md jnp.urologia@gmail.com rui freitas, md rui.azevedo.freitas@gmail.com isaac braga, md isaac.braga@gmail.com joão carvalho, md joao.andre.mendes.carvalho@gmail.com josé sanches magalhães, md sanmagalh@gmail.com vítor silva, md vitormoreira.silva@gmail.com francisco lobo, md lobfrancisco@gmail.com antónio morais, md morais.aj@gmail.com instituto português de oncologia francisco gentil do porto, porto, portugal stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3366 letter to editor no conflict of interest declared. to the editor, radical prostatectomy (rp) is one of the preferred treatments for localized prostatic cancer and although surgical complications have been reduced over the years, urinary incontinence and erectile dysfunction are still common and significantly impact the patient’s life (1). therefore, adequate patient education and counselling before rp is essential. informed consent (ic) is a crucial element of doctor-patient interaction, and it must ensure that patients receive and understand all the information regarding their diseases and treatments. implicit in providing ic is assessing the patient’s understanding, since accessible communication enables them to make informed decisions consciously and autonomously about their health status (2, 3). ic assumes higher relevance in surgery since it comprises invasive procedures, related consequences, and greater anxiety levels from patients (4). several studies demonstrate that patients’ education about their clinical process leads to lower anxiety levels and low existing postoperative complications (4, 5). recent studies showed that animated illustrations, with audio explanations, led to better learning and processing of information, reducing the gap between patients with lower and higher health literacy levels (6). with this preliminary study, we aimed to determine the benefit of a video-based educational tool on the patient’s health information compared to a healthcare provider’s verbal explanation. we also intend to evaluate the impact of the patient’s educational level in this process. materials and methods patient population men over 18 years old, with different educational levels and followed at the urology department of hospital de braga, submitted to a rp, open or laparoscopic, between november and december 2020. there were no exclusion criteria. study design presentation of an educational animated video by the health care provider to the study group on the preoperative consultation before getting the ic for the rp. this video contained general information about the procedure: postoperative period, potential complications, and reasons to seek medical help. representative frames of the video are shown in figure 1. for this preliminary study, the sample population was randomly divided into two groups: control group (verbal explanation before providing the ic) and study group (educational animated video before the ic). after the preoperative consultation, each group would answer two questionnaires. questionnaires we created both questionnaires having as an example, a previous and similar study of the european association of urology (cronbach’s alpha coefficient of 0.861) (7). each questionnaire included: nine patient satisfaction questions, regarding the contentment about the information they received during the preoperative consultation, and before signing the ic; two multiple-choice knowledge questions, regarding patient-s knowledge about rp. statistical analysis for analytical purposes, the patient satisfaction answers (qscore) involved five options: strongly agree (5 points), agree (4 points), i do not know (3 points), disagree (2 points) and strongly disagree (1 point). the maximum score was 45 points. in the two knowledge questions (pscore), each patient received one point per corrected item. the variable pscore was dichotomised, so those who answered none or one correct answer were coded 0, and those who responded correctly to both questions were coded 1. a similar process was conducted for the variable educational level, as patients who studied until the primary educational level were coded 0 and those who studied secondary educational level, or more were coded 1. a p-value < 0.05 was considered as statistically significant, and the confidence interval (ci) used was 95%. digital informed consent on radical prostatectomy surgery a turning point on patient communication means pedro sousa passos 1, 2, nuno carvalho 1, sara teixeira anacleto 1, mário cerqueira alves 1, paulo oliveira mota 1, 3 1 department of urology, hospital de braga, portugal; 2 department of urology, hospital de guimarães, portugal; 3 institute of life and health sciences, university of minho, portugal. submitted 8 june 2021; accepted 9 july 2021 doi: 10.4081/aiua.2021.3.366 367archivio italiano di urologia e andrologia 2021; 93, 3 digital informed consent for radical prostatectomy results sample description 32 patients were included in this preliminary study, and all subjects completed and returned the questionnaires. the groups were divided in: control group: 21 patients, that did not visualise the educational animated video and only received verbal information from their healthcare giver before signing ic; study group: 11 patients that visualized the educational animated video before signing ic. as shown in table 1, most of the participants in both groups had studied until primary education level (81.0% vs 63.6%). video’s impact on patient satisfaction questions in this section of the questionnaire and, by comparing the medians of satisfaction scores, we found that patients from the study group presented statistically significantly higher satisfaction levels qscore = 44.0 (2.00), than those from the control group qscore = 32.0 (6.00); p < 0.001. video’s impact on patient knowledge questions in this section of the questionnaire and according to the results, we concluded that the study group subjects gave more correct answers than those from the control group. educational level’s impact on patient satisfaction questions we did not find any significant differences on patients’ satisfaction questions between patients with “until primary level of education” variable qscore = 36.0 (11.5) and those with “secondary level of education” qscore = 42.0 (15.5); p = 0.326. educational level’s impact on patient knowledge questions patients with lower educational level failed more questions than those with higher educational level. we performed fisher’s exact test, and results showed that pscore is dependent on educational level (p = 0.038; phi = .404). figure 1. representative frames of the video presented to the study group before ic. archivio italiano di urologia e andrologia 2021; 93, 3 p. sousa passos, n. carvalho, s. teixeira anacleto, m. cerqueira alves, p. oliveira mota 368 patient satisfaction questions predictors we performed a multiple linear regression to predict patients’ satisfaction using “video visualization” and “educational level” as variables. these were coded as no video visualization = 0 and video visualization = 1; primary educational level = 0 and secondary level of education or more = 1. video visualization was the only statistically significant predictor. patients who watched the video, from the study group, had 10.8 (95% ci 6.59 to 15.0) more points than those from the control group, as shown in table 2. patient knowledge questions predictors for patients’ knowledge predictors, we performed a binary logistic regression and, as presented in table 3, video visualization was statistically significantly (p = 0.004). pscore was coded as one correct answer = 0 and two correct answers = 1. patients who visualized the video were 3.12 (95% ci 2.78 to 186) times more likely to correctly answer both questions. discussion using an educational animated video to communicate health information to patients is associated with higher levels of patients’ satisfaction and knowledge about the surgical procedure. this study also suggests that educational level can influence the patient’s understanding of health information. video-based education has shown promising early results. in 2002, mayer showed that illustrations help create a mental image; therefore, facilitate learning and overlapping text-based learning (8). on their study, abed et al., using image illustration and due to the video’s portability and repeatability, showed that an educational animation can increase patients’ understanding and information acquisition and their satisfaction with the health care provided (9, 10). in this study, we confirmed that subjects who only received verbal information had wrong ideas about the procedure they were undertaking, reinforcing the need for new alternatives to explain and better inform patients. we verified that we could increase patients’ knowledge by showing the educational video since the study group had statistically significantly higher p scores. although patient´s satisfaction scores did not statistically differ amid different education levels, those with higher education levels performed better on knowledge questions. these results meet what the literature suggests. we found that patients who visualized the video scored higher on patient satisfaction and knowledge questions, concluding that accessible information can influence the way patients understand clinical information and eventually, positively impact clinical outcomes (4, 11, 12). conclusions empowering patients with knowledge improves clinical outcomes, patient’s compliance and it should be a fundamental philosophy of clinical excellence. addressing to current times, the covid-19 pandemic has proven the importance of accurate information and showed the significance of providing people with accessible and correct health information. it is important to enable everyone to make informed decisions and ensure that they can act as a public health agent, which will undeniably positively affect the worldwide population. references 1. daniyal m, siddiqui za, akram m, et al. epidemiology, etiology, diagnosis and treatment of prostate cancer. asian pac j cancer prev. 2014; 15:9575-8. 2. sousa j, araújo m, matos j. consentimento informado:panorama atual em portugal. revista portuguesa de ortopedia e traumatologia. 2015; 23:6-17. 3. osime oc, okojie o, osadolor f, mohammed s. current practices and medico-legal aspects of preoperative consent. east afr med j. 2004; 81:331-335. 4. winter m, kam j, nalavenkata s, et al. the use of portable video media vs standard verbal communication in the urological consent process:a multicentre, randomised controlled, crossover trial. bju international. 2016; 118:823-828. 5. armstrong aw, alikhan a, cheng ls, et al. portable video media for presenting informed consent and wound care instructions for skin biopsies: a randomised controlled trial. br j dermatol. 2010; 163:1014-1019. table 2. results of the multiple linear regression for qscore, to predict patients’ satisfaction. unstandardised standardised 95% confidence coefficients coefficients interval for b b std. error β t p-value lower upper bound bound constant 32.9 1.26 26.0 < 0.001 30.3 35.5 video 10.8 2.06 0.708 5.24 < 0.001 6.59 15 educational level -0.918 2.26 -0.055 -0.406 0.688 -5.55 3.71 table 1. descriptive statistics of the education level variable in each group. until primary educational level secondary education or more total frequency (n) control group 17 (81.0%) 4 (19%) 21 study group 7 (63.6%) 4 (36.4%) 11 table 3. results of the logistic regression for pscore. b std. wald df p-value exp 95% confidence error (b) interval for b lower bound upper bound educational level 2.25 1.16 3.78 1 0.052 9.47 0.98 91.2 video 3.12 1.07 8.48 1 0.004 22.7 2.78 186 (constant) -2.10 0.75 7.79 1 0.005 0.12 369archivio italiano di urologia e andrologia 2021; 93, 3 digital informed consent for radical prostatectomy 6. meppelink cs, van weert jc, haven cj, smit eg. the effectiveness of health animations in audiences with different health literacy levels: an experimental study. j med internet res. 2015; 17:e11. 7. bach t, behrendt m, tanidir y, et al. harnessing new media tools in patient information. eur urol. 2018; 74:685-687. 8. mayer re. multimedia learning. psychology of learning and motivation. academic press. 2002; 41:85-139. 9. wilson ea, park dc, curtis lm, et al. media and memory: the efficacy of video and print materials for promoting patient education about asthma. patient educ counsel. 2010; 80:393-398. 10. green mj, peterson sk, baker mw, et al. effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomised controlled trial. jama. 2004; 292:442-452. 11. idriss nz, alikhan a, baba k, armstrong aw. online, video-based patient education improves melanoma awareness: a randomised controlled trial. telemed j e health. 2009; 15:992-997. 12. luck a, pearson s, maddem g, hewett p. effects of video information on pre colonoscopy anxiety and knowledge: a randomised trial. lancet. 1999; 354:2032-2035. correspondence pedro de sousa passos, md pedrosousapassos@gmail.com nuno carvalho, md nunofsc9@gmail.com sara teixeira anacleto, md sara.anacleto241@gmail.com mário cerqueira alves, md mcerqueiraalves@gmail.com paulo oliveira mota, md damota.paulo@gmail.com largo bairro do jardim 3, 4900-467 viana do castelo (portugal) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2134 original paper no conflict of interest declared. nostic and therapeutic method even if, this technique, has been associated with significant complications (bleeding, bladder perforation, obturator nerve reflex, and even bladder explosion) (3). another problem is incomplete primary endoscopic resection with absence of muscle tissue in the samples and uncertainty of the margins, which often leads to reprogramming, especially in t1, a second look tur after forty days from the first intervention, with an increase in costs for public health and discomfort for patients, especially in this period of pandemic not yet fully resolved (4). we know that turbt “incising and scattering” procedure contradicts the basic surgical oncologic principles of take out the tumor “en bloc” with sure margins of resection and histopathology evaluation of wall invasion. another problem is the possible seeding of exfoliated cancer cells (5). each urologist has his/her own experience in endoscopic treatment of bladder tumors, which refers, in particular, to the type of energy used during the surgical procedure. monopolar energy in cutting loop is the most used current for the treatment of nmibc although it is correlated with some adverse events including blood loss or disorder of electrolyte balance for mannitol absorption. recently, use of bipolar energy has spread due to reduced risk of metabolic alterations and improved precision of resections (6-8). in 1984, food and drug administration (fda) approved the use of laser in bladder resection. in the last 10 years, various types of laser energy have been used for the endoscopic treatment of bladder cancer, due to their efficient tissue vaporization and hemostatic effect as well as high safety (holmium and thullium, in particular). the use of laser surgery helps in “en bloc” resection and can provide an intact tissue specimen for a more accurate pathological evaluation; it also reduce the risk of dissemination of malignant cells (9-11). our study, therefore, aims to verify if diode laser “en-bloc” surgery of bladder tumors could be able to improve the diagnostic rate and to reduce the risk of positive margins and incomplete resection of the bladder base implant of the neoplasm. we want also to evaluate safety and reduction of catheterization and hospitalization time. introduction: bladder cancer is one of the most common tumors among the general population. the first surgical approach to the tumor is often the transurethral resection with monopolar or bipolar loop. recently, laser energy has become an alternative for resection of small bladder tumor, because it allows to obtain high quality samples with the “en bloc” technique. our study aims to show the results of endoscopic diode laser treatment of bladder tumor up to three centimeters in maximum diameter. materials and methods: 189 patients underwent “en bloc” resection with diode dual length laser (980 nm-1470 nm). follow up was over 12 months. patients age range was from 45 to 75 years. maximum diameter of the lesions was 3.0 cm. for each patient, a cold forceps biopsy sample was performed. results: all samples collected presented detrusorial layer. pathological exam showed: 28 (14.8%) ta, g1-g2; 7 (3.7%) t3, g2-g3; 14 (7.4%) t1, g2-g3 and 140 ( 74.1%) ta, g2-g3. no complications occurred during or after surgery. at a median follow-up period of 6 months, we had no recurrence in the previous site of tumor. in the follow up at 3/6/12 months in 4 cases we had recurrence in different sites of bladder wall. conclusions: laser “en bloc” resection is an effective, feasible, and safe treatment for bladder tumor. it could be a valid alternative to monopolar and bipolar resection in small bladder cancer treatment. key words: laser; bladder tumor; endoscopic resection; en-bloc; diode. submitted 8 june 2022; accepted 15 june 2022 introduction bladder cancer is one of the most common tumors of the genitourinary system. more than 81.000 new cases resulting in 17.100 deaths have been estimated in 2022 in the united states (1). moreover, bladder cancer confers the largest financial burden per patient of all types of malignant tumors. this is because of its high recurrence and progression rate, which requires lifelong monitoring and repeated treatment (2). most cases (75%) are non muscleinvasive bladder cancer (nmibc), and transurethral resection of bladder tumor (turbt) is regarded as the standard diagendoscopic laser en bloc removal of bladder tumor. surgical radicality and improvement of the pathological diagnostic accuracy rosario leonardi 1, alessandro calarco 2, lorenzo falcone 1, vincenzo grasso 1, marco frisenda 3, antonio tufano 3, pietro viscuso 3, antonio rossi 2, lorenzo memeo 4 1 casa di cura musumeci gecas, gravina di catania (ct), italy; 2 “cristo re” hospital, rome, italy; 3 department of maternal-infant and urological sciences, "sapienza" rome university, policlinico umberto i hospital, rome, italy; 4 iom (istituto oncologico del mediterraneo), viagrande (ct), italy. doi: 10.4081/aiua.2022.2.134 summary 135archivio italiano di urologia e andrologia 2022; 94, 2 diode laser en bloc removal of bladder tumor materials and methods from january 2015 to february 2022, 189 patients underwent “en bloc” resection with the laser. random cold forceps biopsy samples were also taken. the total operation time, pathologic result, and intraoperative and postoperative complications were recorded. each patient was followed up for ≥ 12 month. patients age range was from 45 to 75 years, and 20% of patients were females. we used a diode dual length laser (980 nm-1470 nm). the two waves length can be freely mixed. a power of 15/20 watts with a mix of 85% of 980 and 15% of 1470 was used. the conical front emitting laser fiber of 1000 micron was used. we treated bladder tumor of a diameter up to 3.0 cm of maximum diameter. maximum number of lesions was 2. the time of the operation depended on the size of the neoplasm, from a minimum of 20 min, for neoplasms smaller than one centimeter up, to 45 min for neoplasms with a maximum diameter of 3.0 cm results the “en bloc” resection of tumors was successful in all cases. the resected tumors were intact with detectable margins and the detrusor muscle architecture was always available for pathologic evaluation. definitive pathological analysis resulted in: 28 (14.8%) cases of ta,g1-g2; 7 (3.7%) t2,g2-g3, 14 (7.4%) t1,g2-g3 and 140 (74.1%) ta,g2-g3 (figure 1). no complications occurred during or after surgery. no bladder wall perforation was observed. the specimens were extracted from the bladder cavity from the outer channel of the resectoscope that was used like e trocar. morcellator was not used. all patients were able to return home the day after operation without catheter. after patients dismission, we observed 2 events of late hematuria, resolved with the recommendation of high hydration. at a median follow-up period of 6 months, we had no recurrence in the previous site of tumor. in the follow up at 3/6/12 months the recurrence in other sites of bladder was of 28 cases without any case of progression. discussion the evolution of technology, over the last few years, has made possible to significantly improve the endoscopic treatment of bladder tumors, especially for nmibcs. nowadays, in particular, great attention is given to the use of lasers for the “en-bloc” treatment of small bladder tumors. the holmium and thulium lasers are of certain efficacy and safety, despite the limited differences in terms of operating time compared to monopolar and bipolar energy (12). on the other hand, improvements have been made in term of obturator nerve reflex, transient hematuria, postoperative bladder irritation and catheterization and hospitalization time (13). further advantages of “en bloc” resection are samples of better quality and less residual tumor (14). the diode laser has recently been widely used in the treatment of benign prostatic hyperplasia and showing high efficacy and tolerability (15, 16). the main advantage of the diode laser is its high hemostatic capacity, which makes it more effective especially in patients on antiplatelet and anticoagulant therapy (17). there are currently not many studies regarding the use of diode lasers in the treatment of bladder tumors. our preliminary data, therefore, appear to be of particular interest as they allow us to observe how this type of laser can also be safely used on bladder wall. the absence of complications and the precision of the treatment made it possible to obtain samples of excellent quality. in all cases the detrusor layer was included in the sample (figure 2), avoiding the patient to perform second look tur. the “en bloc” resection, if compared with traditional turb, allows the histological evaluation of a larger and anatomically oriented portion of the bladder wall. this could increase the detection of small foci of neoplastic cells in the sub-urothelial tissue or in the tonaca muscolaris and have an impact in the correct staging of the tumor. figure 1. a. low power image of the “en bloc” resection of a pta urothelial papillary carcinoma low grade with intense lymphocytic infiltrate of the suburothelial connective tissue. the tumor is totally resected and the deep resection margin is on normal tissue. b. a case of mibc diagnosed by “en bloc” surgery. it was possible to highlight, in a precise way, the depth of invasion of the tumor in the muscular strates of the detrusor (pt2 urothelial carcinoma). figure 2. a. anatomic operative specimen obtained by “en bloc” removed bladder neoplasia. b. a detail of the “en bloc” sample showing the deep resection margin on normal tissue (4x). a. b. a. b. archivio italiano di urologia e andrologia 2022; 94, 2 r. leonardi, a. calarco, l. falcone, et al. 136 the limit of “en-bloc” method are obviously large tumors, as they cannot be extracted from the resectoscope without causing injury to the sample or having to use a morcellator, which would make the sample not evaluable by the pathologist. according to our experience, the most common sites in which the “en bloc” laser surgery of invasive non-muscle bladder neoplasms becomes unsurpassable is when they are located close to the ureteral meatus (figure 3). we usually use the narrow band imaging (nbi) system to better define the margins of the neoplasm that are marked before starting the “en bloc” removal procedure (figure 4). in doing so, we have never had positive margins. in these cases, it is possible to remove the neoplasm without having to resect the meatus as often happens with traditional surgery (figure 5). the most difficult site for tumor removal is the posterior wall. in these cases, an accurate section plane must be achieved by proceeding lateromedially from both sides and subsequently, from bottom to top, to completely eradicate the neoplasm with its implant base. the upper locations, often difficult for traditional surgery, does not present any problem for “en bloc” laser surgery. in these cases, we proceed in a proximal distal direction after having identified the right section plane. the neoplasm is gradually pulled from the wall with its implant base until it is completely removed by cutting the flap of mucosa that holds it adhering to the wall. the use of 1000 micron fiber to move or lift the neoplastic tissue adhering to the muscular wall is of great help. the muscle fibers are put in tension and in doing so it becomes easy to proceed quickly in dissecting the muscular plane (figure 6). an important trick to have a bloodless field is to gradually photo-coagulate the small vessels that are encountered in the dissection, and which often are identified by transparency, before engraving the tissue. it should be noted that, based on the reduced thickness of the bladder wall of the woman, when we implement an “en bloc” in a female subject, we always operate with a medium-low bladder filling in order not to thin the bladder wall. conclusions the results of our study have shown that laser “en-bloc” resection is an effective, feasible, and safe alternative to monopolar and bipolar loop energy for bladder tumor resection. it is able to reduce the second-look turb in figure 3. bladder tumor that laps the upper border of the left ureteral orifice. figure 6. the tumor with the muscle tissue of the implant base is above the right section of the picture. the laser fiber is used to tension the muscle fibers and better define the incision line. figure 4. the use of nbi allows us to better identify the limits of the tumor. figure 5. a. perfectly spared ureteral orifice with millimeter incision of the neoplasm. b. ureteral orifice preserved during urination. c the tumor resected by en bloc technique floating inside the bladder cavity. d. tumor extracted ready to be sent for histopathological examination. a. b. c. d. 137archivio italiano di urologia e andrologia 2022; 94, 2 diode laser en bloc removal of bladder tumor case of t1 or for absence of the muscular tissue in the sample of first resection. it was associated with no complications and allows accurate oncological pathologic evaluation. it is associated to a reduced hospitalization and catheterization time. the laser “en bloc” surgery of nmibc can be considered, in our preliminary experience, an evolution of endoscopic surgery of bladder cancer. references 1. american cancer society. cancer facts & figures 2022. atlanta, ga: american cancer society; 2022. 2. richters a, aben kkh, kiemeney lalm. the global burden of urinary bladder cancer: an update. world j urol. 2020; 38:1895-1904. 3. rozanec jj, secin fp. epidemiología, etiología, prevención del cáncer vesical (epidemiology, etiology and prevention of bladder cancer.). arch esp urol. 2020; 73:872-878. 4. cumberbatch mgk, foerster b, catto jwf, et al. repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review. eur urol. 2018; 73:925-933. 5. territo a, bevilacqua g, meneghetti i, et al. en bloc resection of bladder tumors: indications, techniques, and future directions. curr opin urol. 2020; 30:421-427. 6. mao x, zhou z, cui y, et al. outcomes and complications of bipolar vs. monopolar energy for transurethral resection of bladder tumors: a systematic review and meta-analysis of randomized controlled trials. front surg. 2021; 8:583806. 7. burke n, whelan jp, goeree l, et al.. systematic review and metaanalysis of transurethral resection of the prostate versus minimally invasive procedures for the treatment of benign prostatic obstruction. urology. 2010; 75:1015-22. 8. puppo p, bertolotto f, introini c, et al. bipolar transurethral resection in saline (turis): outcome and complication rates after the first 1000 cases. j endourol. 2009; 23:1145-9. 9. xu j, wang c, ouyang j, et al. efficacy and safety of transurethral laser surgery versus transurethral resection for non-muscle-invasive bladder cancer: a meta-analysis and systematic review. urol int. 2020; 104:810-823. 10. korn sm, hübner na, seitz c, et al. role of lasers in urology. photochem photobiol sci. 2019; 18:295-303. 11. enikeev d, shariat sf, taratkin m, et al. the changing role of lasers in urologic surgery. curr opin urol. 2020; 30:24-9. 12. long g, zhang y, sun g, et al. safety and efficacy of thulium laser resection of bladder tumors versus transurethral resection of bladder tumors: a systematic review and meta-analysis. lasers med sci. 2021; 36:1807-1816. 13. razzaghi mr, mazloomfard mm, yavar m, et al. holmium laser in comparison with transurethral resection of the bladder tumor for non-muscle invasive bladder cancer: randomized clinical trial with 18-month follow-up. urol j. 2021; 18:460-465. 14. hashem a, mosbah a, el-tabey na, et al. holmium laser enbloc resection versus conventional transurethral resection of bladder tumors for treatment of non-muscle-invasive bladder cancer: a randomized clinical trial. eur urol focus. 2021; 7:1035-1043. 15. mithani mh, khalid se, khan sa, et al. outcome of 980 nm diode laser vaporization for benign prostatic hyperplasia: a prospective study. investig clin urol. 2018; 59:392-398. 16. leonardi r. the lest technique: treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. arch ital urol androl. 2019; 91:35-42. 17. zhang j, li j, wang x, et al. efficacy and safety of 1470-nm diode laser enucleation of the prostate in individuals with benign prostatic hyperplasia continuously administered oral anticoagulants or antiplatelet drugs. urology. 2020; 138:129-133. correspondence rosario leonardi, md (corresponding author) urologialeonardi@gmail.com lorenzo falcone, md lorenzo.falcone@gmail.com vincenzo grasso, md vincenzo.grasso@gmail.com casa di cura musumeci gecas, gravina di catania (ct) (italy) alessandro calarco, md alecalarco@gmail.com antonio rossi, md antonio.rossi@uniroma1.it “cristo re” hospital, rome (italy) marco frisenda, md marco.frisenda57hu@gmail.com pietro viscuso, md pietro.viscuso@uniroma1.it antonio tufano, md antonio.tufano@uniroma1.it department of maternal-infant and urological sciences, "sapienza" rome university, policlinico umberto i hospital, rome (italy) lorenzo memeo, md lorenzo.memeo@gmail.com iom (istituto oncologico del mediterraneo), viagrande (ct) (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13156 1 original paper complex multiple renal stones face various problems during pcnl, including a higher occurrence of residual calculus and the need for multiple tracts. compared to procedures using single tracts, multiple percutaneous tracts have a higher risk of bleeding and complication rates (2, 3). over time, the pcnl technique changed, moving from multisite multi puncture, single-site single puncture to single-site multi puncture. in 2011, m. lezrek reported renal displacement procedure to make superior calyx easily reached (4). as the years go, in 2018, single site multi puncture supine (sms) pcnl modified the renal displacement technique by lezrek using a 18g needle to reach superior calyx easily to performed access the lower, middle, and upper renal pole to treat staghorn and multiple renal stones through a single skin incision giving cosmetic advantage due to less tissue injury (figure 1). this study aimed to determine the outcomes sms procedure in patients with complex renal stones. methods study population the design of this study is a cohort retrospective study. data on patient demography, surgical technique, and outcome of operation was acquired through medical records. all cases were sampled to acquire the number of patients required. the inclusion criteria for this study was being a patient who underwent sms pcnl from march 2019 to december 2022. patients with anatomical abnormalities were excluded from the study. the patients were divided into 3 groups: 2 punctures, 3 punctures, and 4 punctures. data on gender, age, body mass index (bmi), comorbidity, and stone size were collected preoperatively. evaluation of outcome after procedure was done two weeks after the procedure with kidney-ureter-bladder (kub) x-ray. guy’s stone system (gss) score was obtained on the base of ncct images. gss used was as follows (5): grade i: a solitary stone in the mid/lower pole with simple anatomy or a solitary stone in the pelvis with simple anatomy; grade ii: a solitary stone in the upper pole with simple anatomy or multiple stones in a patient with simple anatomy or any solitary stone in a patient with abnormal anatomy; grade iii: multiple stones in a patient with introduction: since percutaneous nephrolithotomy (pcnl) was introduced in 1976, it has been the standard procedure for large renal stones. over time, the pcnl technique changed and developed into various techniques. we introduce single site multipuncture supine (sms) pcnl to give cosmetic advantage due to less tissue injury in complex renal stone. this study aimed to determine the outcome sms pcnl procedure in patients with complex renal stones diseases. materials and methods: this study was a retrospective study including all patients with kidney stones who had undergone sms pcnl at the urology department of saiful anwar general hospital from march 2019 until december 2022. all sms pcnl procedures were performed by a single operator. the patients were divided into three groups that included that were treated with 2, 3, and 4 punctures. the data were collected using spss ver. 25. result: ninety-three patients were included in this study. the characteristics of the patient such as gender, age, bmi were not significantly different among the groups. the outcome of sms pcnl procedure showed low complication rate during operation in 2-,3-,and 4-puncture groups (3.2%, 7.4%, 0%, respectively). the stone free rate (sfr) showed no significant difference between the 3 groups (p = 0.496). the sfr was 85.7% in 2-puncture, 77.8% in 3-puncture, 66.7% in 4-puncture group. the auc of guy’s stone score with cut off value was 3.5 (auc = 0.549, p-value = 0.541, ci 95%). conclusions: single site multi puncture pcnl is safe and efficient approach to complex renal stones. single site multipunctures supine pcnl is comparable with other techniques of pcnl and gives minimal tissue injury that would benefit for cosmetic. key words: multipunctures; outcome; pcnl; renal stone. submitted 26 september 2024; accepted 28 september 2024 introduction in urologic practice, renal stone disease is challenging because of its enormous stone burden and recurrence. the goal of renal stone management is a minimally invasive, effective, and with minor complication surgery (1). since fernstrom described percutaneous nephrolithotomy (pcnl) in 1976, it has been the standard procedure for large renal stones, usually more than 2 cm. patients with single site multi puncture supine (sms) pcnl procedure in patient with complex renal stone: one incision, why should more? paksi satyagraha, reza amorga, taufiq nur budaya urology department, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2024.13156 summary archivio italiano di urologia e andrologia 2024; 96(4):13156 p. satyagraha, r. amorga, t. nur budaya 2 abnormal anatomy or stones in a calyceal diverticulum or partial staghorn calculus; grade iv: staghorn calculus or any stone in patient with spina bifida or spinal injury. any complication during the operation or untoward event was noted using the clavien-dindo classification (6). the outcome of sms pcnl was determined by the stone free rate, operative time, delta hemoglobin, delta creatinine, and hospital stay. data were collected and analyzed statistically using the spss software ver 25. quantitative data were expressed as mean ± standard deviation (sd) and median. qualitative data were expressed as frequency and percentage. gender, comorbidity and guy’s stone system were analyzed with chi square. bmi, stone size, delta hemoglobin, delta creatinine, operative time and hospital stay were analyzed with kruskall wallis and dunn. this study was approved by the health research ethics commission of saiful anwar general hospital. surgical technique the pcnl procedures were performed under general or epidural anesthesia. we used the barts' flank-free' modified supine position. a relatively horizontal tract allows low intrarenal pressures and easy washout of fragments. an 18-gauge needle was used to perform the percutaneous puncture under c-arm-guidance and fluoroscopy after retrograde pyelography (rpg) from ureteral catheter; then a guidewire with a j-tip super stiff rigid shaft was inserted. under continuous fluoroscopic observation, the needle's proximal end was steadily moved in the cephalic direction (figure 2). as a result of the lezrek maneuver, the kidney was moved caudally. at the same time, a forceps twists the needle's body and secures it to the drape (figure 3). the calyx of the upper pole is punctured, and a tract was made (figure 4). furthermore, the natural axis of the kidney was slightly inverted, with the lower pole tilted medially and the upper pole oriented laterally. the upper calyxes were redirected downward and closer to the cutaneous entry as a result. therefore, the targeted calyx was shown more clearly. the next punctures that needed to reach the stone are entered through the same incision as the first puncture and dilation is conducted using alken dilator until 30 fr and amplatz 30 fr was inserted, followed by the insertion of standard size 26 fr nephroscope or even 12 fr nephroscope (mini pcnl). lithotripsy with following fragments’ evacuation was done. the operations were completed with the insertion of a 20-fr nephrostomy tube or 12 fr naso-gastric tube into the tract. this technique which describes multipunctures pcnl was done through a single skin incision (7). kub was performed to evaluate the residual stone. stone more than 5 mm were defined as residual stone (8). results of 98 patients with renal stones who had undergone sms pcnl, 93 patients were included in this study. five figure 1. a. post operative scar with one incision. b. post operative scar with two incision. figure 2. a guidewire was inserted through a middle calyx puncture to protect the urothelium from the needle distal end during needle bending. figure 4. the kidney is several millimeters lower after caudal renal displacement, and the upper pole calyx is available. figure 3. the first needle's body is progressively bent and secured to the drape. the superior calyx is punctured at the point where the first needle enters. archivio italiano di urologia e andrologia 2024; 96(4):13156 3 single site multi puncture supine (sms) pcnl procedure in patient with complex renal stone... patients were excluded because they have kidney anatomical abnormality (n = 5). the patients were divided into three groups based on the number of punctures done during pcnl operation: 63 patients with 2 punctures, 27 patients with 3 punctures, 3 patients with 4 punctures. comparison of the patient’s age at the time of surgery between the groups showed a value of 0.491 (p > 0.05), which mean no significant difference. in this study, the number of male patients (55.6%, 70.4%, 66.7% respectively) was more than females in all the 3 groups (44.4%, 29.6%, 33.3% respectively). both body mass index (bmi) and gender showed no significant difference between 2-, 3-, and 4puncture groups (p 0.410, p 0.800, respectively). in our study, the comparison of the presence of comorbidities showed 0.874 (p < 0.05), indicating that there was no significant difference. mean stone size was larger in 4 puncture group (5.16 cm) than 2 and 3 puncture group (3.09 cm, 4.05 cm, respectively). the comparison of stone complexity (guy’s scoring system) showed that there was a not significant difference between the 3 groups (p = 0.893) (table 1). we analyze the outcome between 2-puncture, 3-puncture, and 4-puncture groups. there was no significant difference in the complications between the three groups (p = 0.618). in the 2and 3-puncture groups there were 2 patient in each group (3.2%, 7.4%, respectively) who had complications; differently from the 4-puncture group where there was no complication. three patients (one patient who underwent 2-puncture procedure and 2 patients who underwent 3-puncture procedure) needed blood transfusion (clavien grade ii) because hemoglobin dropped more than 2 mg/dl in the first 24 h post-operatively. one patient in the 2-puncture group developed septic condition (clavien grade ivb). stone-free status was achieved in 85.7%, 77.8%, 66.7% of patients in 2-, 3-, and 4-puncture group, respectively (table 2). there was a significant difference (p = 0.000) in operation time between 3 groups. two-puncture group has less operative time (55 min) than the 3and 4-puncture groups (76 and 86, respectively). hospital stay of patients has a significant difference (p = 0.000), whereas fourpuncture group had a longer median hospital stay (4 days) than 2-puncture and 3-puncture groups (2 and 3 days, respectively). there was no significant difference table 1. patient characteristic. single site multi puncture (sms) single site multi puncture (sms) single site multi puncture (sms) p 2 puncture 3 puncture 4 puncture n = 63 n = 27 n = 3 freq % freq % freq % age, years, mean ± sd 50.74 ± 10.1 53.48 ± 9.69 52.67 ± 10.01 0.491 gender 0.410 male 35 55.6 % 19 70.4 % 2 66.67% female 28 44.4 % 8 29.6 % 1 33.33% bmi, kg/m2, mean ± sd 25.16 ± 4.46 25.22 ± 3.60 25.68 ± 3.99 0.800 comorbidity 0.874 no 43 68.3% 20 74.1% 2 66.67% yes 20 31.7% 7 25.9% 1 33.33% heart disease 2 3.2% 1 33.33% chronic kidney disease (ckd) 4 6.3% 5 18.5% asthma 1 1.6% diabetes mellitus 9 14.3% 2 7.4% 1 33.33% hypertension 4 6.3% obesity 4 6.3% 1 3.7% stone size, cm, mean ± sd 3.09 ± 1.36 4.05 ± 1.33 5.16 ± 1.25 0.001 guy’s scoring system (gss) 0.893 grade i 0 0 0 0 0 0 grade ii 22 34.9% 10 37% 1 33.3% grade iii 32 50.8% 12 44.5% 1 33.3% grade iv 9 14.3% 5 18.5% 1 33.3% table 2. the outcome between 2 punctures, 3 punctures, and 4 punctures of the sms procedure. the number of puncture of sms 2 3 4 p freq % freq % freq % complication: 0.618 no 61 96.8% 25 92.6% 3 100% yes, based on clavien dindo classification, grade i 0 0% 0 0% 0 0% ii (bloodtransfusion) 1 1.6% 2 7.4% 0 0% iii 0 0% 0 0% 0 0% ivb (sepsis) 1 1.6% 0 0% 0 0% stone free 0.496 no 9 14.3% 6 22.2% 1 33.3% yes 54 85.7% 21 77.8% 2 66.6% archivio italiano di urologia e andrologia 2024; 96(4):13156 p. satyagraha, r. amorga, t. nur budaya 4 in ∆hb (p = 0.165), ∆creatinine (p = 0.418) between 2-, 3-, and 4puncture groups (table 3). comparison of stone free and complication rates based on stone complexity grade (guy’s stone scoring system) are shown in table 4. guy’s scoring system (gss) was a valuable tool to predict the stone free rate and complication associated with sms pcnl. in this study, area under curve (auc) of gss with a cut off value of 3.5 was 0.549 (p-value = 0.541, ci 95%). the roc analysis revealed that gss predicted complication with a level of prediction accuracy of 79.57% and predicted the stone free with a prediction accuracy of 68.82% (figure 5). discussion pcnl is considered the first-line management for renal stones larger than 2 cm and also for complex renal stone. percutaneous renal surgery has seen a rise in success rates and a decrease in complications because to advancements in endourologic equipment and lithotripsy devices. patients with complex multiple renal calculi are a special challenge for pcnl because they more likely have residual stone. multiple access approach (puncture or tracts) is still controversial. multiple punctures are necessary to prevent second-look procedure (rirs or eswl) although they are frequently linked to an increased risk of bleeding (3). successful puncture is always the first step in a safe and efficient pcnl, especially for complex renal stones. in our study, there was no sigtable 4. the outcome between 2 punctures, 3 punctures, and 4 punctures of the sms procedure. stone complexity grade (guy's stone score) p-value gss ii (n = 33) gss iii (n = 45) gss iv (n = 15) n % n % n % stone free 0.487 yes 27 81.8% 36 80.0% 14 93.3% no 6 18.2% 9 20.0% 1 6.7% complication 0.630 no 31 93.9% 43 95.6% 15 100.0% yes 2 6.1% 2 4.4% 0 0.0% complication/clavien dindo score 0.635 no 31 93.9% 43 95.6% 15 100.0% ii (bleeding) 2 6.1% 1 2.2% 0 0.0% iv (sepsis) 0 0.0% 1 2.2% 0 0.0% gss: guy’s stone score. table 3. the comparison of operative time, hospital stay, delta hemoglobin, and creatinine between 2, 3, and 4 punctures of the sms procedure. number of puncture p 2 (n = 63) 3 (n = 27) 4 (n = 3) mean ± sd median (min-max) mean ± sd median (min-max) mean ± sd median (min-max) operative time (minute) 55.97 ± 19.26 55.0 (20.0-120.0) 76.11 ± 23.93 70.0 (36.0-120.0) 86.67 ± 15.28 90.0 (70.0-100.0) 0.000 hospital stay (day) 2.25 ± 0.54 2.0 (1.0-3.0) 2.96 ± 0.59 3.0 (2.0-4.0) 3.67 ± 0.58 4.0 (3.0-4.0) 0.000 delta hb 0.94 ± 0.62 0.9 [(-0.1)-2.5] 1.17 ± 0.87 1.2 [(-1.6)-3.3] 1.07 ± 0.38 0.9 (0.8-1.5) 0.165 delta creatinine 0.11 ± 0.41 0.1 [(-1.5)-1.8] 0.21 ± 0.57 0.1 [(-0.9)-1.9] 0.22 ± 0.17 0.2 (0.1-0.4) 0.418 figure 5. analysis receiver operating characteristic curve for guy’s stone score for prediction of stone free and complications of percutaneous nephrolithotomy. archivio italiano di urologia e andrologia 2024; 96(4):13156 5 single site multi puncture supine (sms) pcnl procedure in patient with complex renal stone... nificant difference of complication rate among the 3 groups (p = 0.618). similarly to previous studies, multi-tract when compared with single tract pcnl, showed no significant difference in term of complication (2). in this study 1 patient in the 2-puncture group (1.6%) and 2 patients (7.4%) in the 3-puncture group required blood transfusion showing a low rate in comparison with the rate reported by hegarty and desai, who observed a transfusion rate of 12.4% (9). bleeding is the most reported major complication of pcnl. in present study, we compared the ∆hemoglobin between the 3 groups. there was no significant difference between the 3 groups. akman et al. reported that the number of accesses is one of the two predictive indicators for total blood loss and request of transfusion. furthermore, multiple accesses increased transfusion requirements 4.46 times compared with single tract approaches. the mean decrease of hb was 1.67 g/dl in the single tract group and 2.25 g/dl in the multiple tract group (10). in the present study, mean ∆hb in 3-puncture group (1.17 g/dl) was slightly higher than the mean ∆hb in 2and 4-puncture group (0.94 g/dl, 1.07 g/dl, respectively) and showed to be not different with differences of hemoglobin reported in other studies. there was an improvement in serum creatinine levels in the 3 groups. this result is similar to a previous study, which showed a significant improvement 2 weeks after the procedure of serum creatinine level with respect to preoperative values (11). this could be explained by the obstructive nature of stones in our study, despite prior reports showing there was a significant rise in serum creatinine in cases of multiple puncture pcnl for patients who are known cases of renal insufficiency. various factors including larger stones, complex stones, and multiple accesses require longer operative times, which usually result in enhanced complication rates, such as bleeding. in present study, there was a significant difference of the operative time between the 3 groups (p = 0.000). four-puncture group had longer operative time (86 min) than 2-puncture group (55 min) and 3-puncture group (76 min). the operative times in 4-puncture was longer because the stones are more complex and larger. previous studies established a cut off point of operative time of 58 minutes for necessitating blood transfusion. for operative time more than 58 minutes, blood transfusion requirement increased 2.81 times (10). differently by the present study, jiao et al reported no significant different operative time between single access and multi access pcnl (md = -42.78 min, 95% ci (0-85.49 to -0.07), p = 0.05) (12). multiple punctures may be associated with an increased risk of bleeding. this can also affect the length of inpatient stay. in the present study, there was a significant difference (p = 0.000) of hospital stay between the 3 groups (2.2 days, 2.96 days, 3.67 days, respectively). differently from the present study, jiao et al. showed that single access and multi access group were similar (md = -0.59, 95% ci (-3.59 to 2.41), p = 0.70) (12). labadie et al. in their retrospective study showed the low gss score to be significantly associated with stone free rate (p = 0.002) and the auc was 0.634 (95% ci 0.5660.702) (13). in another retrospective study it was found that the auc of gss was 0.739 (95%ci, 0.665-0.813) and it was demonstrated that gss has a good predictive rate for stone free rate (14). differently, in our study, gss showed a cut off value of 3.5 with auc of 0.549 (p-value = 0.541, 95%ci) that was not enough strong to predict stone free status and complications, because there were some confounding factor such as presence of comorbidity that can affect outcome of multiple punctures. we encountered several limitations in our study, including lack of stone composition, short follow-up, and small population samples especially in 4-puncture group. further, large scale multicenter prospective studies and reduction of confounding factors can help in predicting stone free and complication rates. conclusions single site multi puncture pcnl is an approach to larger and complex renal stone. this method is safe and efficient. this technique is comparable with others technique of pcnl and creates less tissue injury that would benefit cosmetic result. references 1. shalaby mm, abdala ma, aboul-ella ha, et al. single puncture percutaneus nephrolithomy for management of complex renal stones. bmc res notes. 2009; 2:62. 2. liang t, zhao c, wu g, et al. multi tract percutaneus nephrolithotomy combined with ems lithotripsy for bilateral complex renal stones: our experience. bmc urology. 2017; 17:1-5. 3. verma a, tomar v, yadav s. complex multiple renal calculi: stone distribution, pelvicalyceal anatomy and site of puncture as predictor of pcnl outcome. springerplus 2016; 5:1356. 4. lezrek m, bazine k, ammani a, et al. needle renal displacement techinque for the percutaneus approach to the superior calix. j endourol. 2011; 25:1723-1726. 5. thomas k, smith nc, hegarty n, glass jm. the guy’s stone scoregrading the complexity of percutaneous nephrolithotomy procedures. urology 2011; 78:277-81. 6. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann. surg. 2009; 250:187-196. 7. ilham m. paksi s, andri k. a novel technique single site multipunctures supine pcnl: case series report. jurnal urologi indonesia 2024; 31:55-60. 8. ermis o, bhaskar s, thomas r, et al. definition, treatment and outcome of residual fragments in staghorn stones. asian j urol. 2020; 7:116-21. 9. hegarty nj, desai mm. percutaneus nephrolithotomy requiring multiple tracts: comparison of morbiditiy with single tract procedures. j endourol. 2006; 20:753-60. 10. akman t, binbay m, sari e, et al. factor affecting bleeding during percutaneus nephrolithotomy: single surgeon experience. j endourol. 2011; 25:327-333. 11. elawady h, mostafa de, mahmoud ma, et al. is multiple tracts percutaneous nephrolithotomy (pcnl) safe modality in management archivio italiano di urologia e andrologia 2024; 96(4):13156 p. satyagraha, r. amorga, t. nur budaya 6 of complex renal stones? a prospective study: single center experience. african j urol. 2018; 24:308-314. 12. jiao b, ding z, luo z, et al. singleversus multiple-tract percutaneous nephrolithotomy in the surgical management of staghorn stones or complex caliceal calculi: a systematic review and metaanalysis. biomed res int. 2020; 2020:8817070. 13. labadie k, okhunov z, akhavein a, et al. evaluation and comparison of urolithiasis scoring systems used in percutaneous kidney stone surgery. j urol. 2015; 193:154-159. 14. kumar u, tomar v, yadav ss, et al. stone score versus guy's stone score prospective comparative evaluation for success rate and complications in percutaneous nephrolithotomy. urol ann. 2018; 10:76-81. correspondence paksi satyagraha (corresponding author) uropas.fk@ub.ac.id taufiq nur budaya taufiq_uro.fk@ub.ac.id reza amorga amorga.reza@gmail.com urology department, saiful anwar general hospital malang, jalan jaksa agung suprapto 2, klojen, malang, east java 65112, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper mediated acute respiratory distress syndrome (2), but therapeutic options to improve semen parameters remain very limited (3, 4). multiple studies demonstrated impaired semen quality parameters in men after clinically present coronavirus disease 2019 (covid-19) covid-19 disease, strongly indicating potential effects of this novel rna-virus on male fertility (5-7). less is known about the recovery time of sperm quality deterioration after patients’ convalescence. considering current evidence it seems likely that multiple mechanisms are involved in the pathogenesis of male fertility disruptions after covid-19 disease, including oxidative stress triggered by sars-cov-2 induced inflammation, testicular immune response and direct viral replication in male reproductive tissues (8-10). as underlying cellular processes remain an under-researched issue, targeted interventions to counteract semen parameter decline in male covid-19 patients or support sperm quality recovery are lacking. however, excess oxidative stress in the testicular environment has been shown to drastically impair spermatogenesis (11, 12). although the ability of certain micronutrient supplements to improve semen parameters is well documented (13, 14), no previous study has investigated the effects of dietary supplements on sperm quality following viral infection such as covid-19 disease. a better understanding of how male fertility can be supported in men infected by sars-cov-2 is relevant for future disease management in men seeking reproductive care following covid-19 illness. it will also present an incentive for further research regarding potential interactions of sars-cov-2 with the male reproductive system. therefore, this study is designed to evaluate the effect, safety and efficacy of a standard micronutrient composition on all major semen variables and seminal oxidative stress markers in men after symptomatic covid-19 disease in comparison to a control group without dietary supplement intake. materials and methods participants and study design this prospective, comparative study included 40 male subjects between 20-50 years of age with symptomatic covid-19 infection confirmed by a positive sars-covobjective: this study aims to evaluate the safety and efficacy of a standard micronutrient preparation to improve semen parameters and seminal oxidative stress in adult male subjects after coronavirus disease 2019 (covid-19) disease. methods: for this prospective pilot study, 30 males aged 20-50 years who had recently recovered from a symptomatic sarscov-2 infection were recruited from june to october 2021 through a public call for participation. participants of the study group (n = 30) received two semen analyses according to who criteria at an interval of 12 weeks, during which they daily received a micronutrient preparation (l-carnitine, l-arginine, coenzyme q10, vitamin e, zinc, folic acid, glutathione and selenium). changes in major semen variables and seminal oxidative stress levels before and after therapy were analyzed and compared to a control group (n = 10) adhering to the same inclusion criteria, including subjects who recently recovered from symptomatic covid-19 disease without micronutrient supplementation within the 12 weeks between the two semen analyses. results: after 3 months of micronutrient supplementation the rate of normal semen analysis results in the study group increased significantly (p = 0.009) by 66.7%: from 50.0% before to 83.3% after therapy. there was a significant increase in progressive (p = 0.014) and overall motility (p = 0.05) as well as in the vitality (p = 0.0004) of semen cells after 12 weeks of micronutrient intake. in the control group there were no significant changes in any semen parameter or in the rate of normal semen analysis results over the 3-month observation period. in both groups, sperm density, morphology and oxidative stress did not improve significantly. conclusions: our data suggests that supplementation of certain micronutrients may be a safe way to support recovery of impaired semen parameters in male adults recovered from covid-19 disease. key words: micronutrients; semen analysis; covid-19; male fertility; antioxidants. submitted 15 january 2023; accepted 29 january 2023 introduction since the outbreak of the global coronavirus pandemic in early 2020, the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) is estimated to have infected more than 650 million people worldwide by the end of 2022 (1). during the last decades a remarkable depletion of sperm quality is observed even without a sars-cov-2 recovery of sperm quality after covid‐19 disease in male adults under the influence of a micronutrient combination: a prospective study judith aschauer 1, 2, michaela sima 1, 2, martin imhof 1 1 karl landsteiner society, institute for cell-focused therapy, korneuburg, austria; 2 medical university of vienna, vienna, austria. doi: 10.4081/aiua.2023.11157 summary archivio italiano di urologia e andrologia 2023; 95, 1 j. aschauer, m. sima, m. imhof 2 pcr test of nasal or pharyngeal swabs not more than 12 weeks prior to first semen sample collection. symptoms had to include one or more of the following: fever, cough, sore throat, headache, nasal congestion, malaise, diarrhea, loss of smell or loss of taste. participants were excluded if reporting on a history of subfertility before covid-19-infection, varicocele, urogenital infections, known or suspected hypersensitivity to ingredients of the study compound, history of severe disease other than covid-19 expected to prevent compliance with the present protocol, and intake of other micronutrient or vitamin supplements within the last 4 weeks. the recruitment of the study group of 30 men was conducted from may 2021 to december 2021. to participate, men registered voluntarily in response to calls for participation published on social media channels, in local newspapers and on the official study website. after online registration, potential participants were contacted via a short phone call from one of the study nurses to check eligibility and schedule an appointment for official inclusion and first semen sample collection at a fertility clinic in vienna austria, if all study criteria were met. all subjects were informed to adhere to 2-5 days of sexual abstinence prior to semen sample collection. on the first appointment, written informed consent to participate in the study was obtained and a short questionnaire filled out by each patient, including information on previous biological children, weight and height, current medication, current or past urological conditions, smoking status and alcohol consumption habits. we chose to obtain these additional parameters considering elevated body mass index (bmi), tobacco and alcohol consumption as well as age are individual risk factors for male factor infertility and possible confounders influencing sperm quality parameters (15). severity of covid-19 disease was assessed and categorized as “mild” with mere symptoms like headache, sore throat and/or flu like symptoms without fever; “moderate” if fever over 37.5°c persisted over 3 days and “severe” if hospitalization was required for disease management. subsequent semen analysis was performed on the day of enrolment, including measurement of major semen parameters and seminal oxidative stress levels. another appointment to repeat these tests was scheduled at an interval of 12 weeks and subjects were instructed to adhere to daily intake of a standard micronutrient preparation provided to them in the clinic until follow-up visit. at the second visit, participants were questioned about any side effects or changes observed during the 12-week micronutrient supplementation before proceeding to repeat identical semen quality work-up. semen parameters and seminal oxidative stress before and after the 12 weeks of micronutrient supplementation were analyzed and compared to a control group of 10 men from our data base. all men included in this control group were subject to the same inclusion and exclusion criteria as the study group but did not receive micronutrient supplementation or other fertility-related treatments within the 12 weeks between their two semen analyses after recovering from symptomatic covid-19 disease. micronutrient preparation the micronutrient supplement used for this study is a clinically tested, standardized nutraceutical for male fertility enhancement (profertil® lenus pharma gmbh, vienna, austria). subjects from the study group were instructed to take two oral capsules of this preparation per day for 12 weeks. two capsules contain: l-carnitine (440 mg), l-arginine (250 mg), zinc (40 mg), vitamin e (120 mg), glutathione (80 mg), selenium (60 μg), coenzyme q10 (15 mg) and folic acid (800 μg). semen analysis semen samples were obtained by masturbation in a sterile container in a separate room next to the fertility clinics’ laboratory, which is certified for semen analysis according to world health organisation (who) criteria. after liquefaction in a heat chamber with 37°c, semen analysis according to who laboratory manual (16) was performed. evaluation included a classical semen analysis assessing volume, semen cell concentration, total semen count, progressive and total motility, normal morphology and vitality, as well as measurement of oxidative stress levels in seminal fluid. semen parameters were considered abnormal when being lower than the fifth percentile, as suggested by who criteria. therefore, normal semen analysis results required a concentration of more than 15 million sperms per milliliter, progressive motility of more than 30%, total motility in total of more than 42%, vitality of at least 54% and normal morphology of at least 4% (16, 17). seminal oxidative stress levels were assessed using the electrochemical mioxsys®, “the male infertility oxidative system” (mioxsys, englewood, co, usa). this rapid in vitro diagnostic device has shown a good sensitivity for detecting both oxidants (reactive oxygen species, ros) and antioxidants in a liquid sample based on measurement of the static oxidant reductant potential (sorp). sorp can be interpreted as direct marker for the level of oxidative stress (18). statistical analysis statistical analysis was performed using the statistical package for the social sciences version 29.0 (ibm spss, armonk, ny, usa). numerical parameters are presented as the mean plus/minus standard deviation (sd) and dichotomous categorical parameters as absolute and relative frequencies. student’s t-test was used to determine significance of changes of individual parameters before and after micronutrient supplementation for the study group, and before and after observational period for the control group. for the comparison of categorical data such as amount of normal semen analysis results the chi square test was applied. for all calculations, a p value < 0.05 was considered statistically significant. results in total, 46 men met all study inclusion criteria and received a first semen analysis in the fertility clinic. only 30 participants adhered to their follow-up appointment and daily intake of 2 capsules of the standard micronutrient preparation and could be included in the analysis. no serious adverse events or other adverse events were reported by any of the participants taking micronutrient supplements during the investigational period. archivio italiano di urologia e andrologia 2023; 95, 1 micronutriemts and sperm quality after covid-19 the mean age was 29.3 (± sd 6.1) years in the study group and 30.2 (± sd 3.7) years in the control group. body mass index (bmi) was also similar with 24.4 (± sd 3.5) kg/m2 in the group receiving micronutrient supplementation and 24.8 (± sd 3.5) kg/m2 in the group without dietary support. in the study group, 13% of men reported on regular smoking and 17% of them reported on already having biological children, with comparable results in the control group reporting a 20% rate for both parameters. the relative number of participants with alcohol consumption at least 1 time per week was almost 3 times higher in the group of men taking micronutrient, amounting to 57% in the study group and only 20% within the control group not receiving any fertility-related interventions. the distribution of severity of covid19 disease was similar in the two groups: mild, moderate and severe symptoms were reported in 67%, 9% and 1% within the study group, and 67%, 30% an 3.3% in the control group, respectively (table 1). after 3 months of micronutrient supplementation the number of subjects with normal semen analysis results in the study group increased significantly (p = 0.009) by 66.7%, from 50.0% before to 83.3% after supplement therapy. results were considered normal if all semen parameters were within who reference limits as described in the “methods” section. there was a significant increase in progressive (p = 0.014) and overall motility (p = 0.05) as well as in the vitality (p = 0.0004) of semen cells after 12 weeks of micronutrient in men recovered from covid-19 disease. in the control group there were no significant changes in any semen parameter or in the rate of normal semen analysis results over the interval of 12 weeks. the mean sperm density and total sperm count increased in both groups during the observational period, though not significantly. mean percentage of normal sperm morphology remained at similar levels with only minimal changes recorded in both groups. interestingly, sorp levels showed a decrease both in the study group of covid-19 recovered men receiving micronutrient supplementation and in the control group without treatment. though not being significant, this decrease was more evident in the study group with a mean decrease of 13.16 mv during the period of micronutrient treatment, while in the control group the mean decrease of oxidative stress levels assessed by sorp was only 0.02 mv (table 2). discussion the results of this study revealed significantly more normal semen analysis results and a significant increase in overall sperm motility, progressive motility and vitality after 3 months of micronutrient supplementation in men recently recovered from covid-19 disease. sperm density and oxidative stress levels also improved during the observation period, though not significantly. there were no significant changes in semen analysis results in the control group of participants after sars-cov-2 infection not receiving dietary supplements. despite trends of recovery of semen parameters after covid-19 disease in both groups, sperm quality improvement was more evident in the study group receiving dietary support. sars-cov-2 and the male reproductive system while global covid-19 herd immunity against certain strains of sars-cov-2 is rising, the possibility of new variants cannot be ruled out and infections will continue to occur (19, 20). at the same time the public is becomtable 1. basal patients characteristics and disease severity. study group control group age 1 [years] 29.3 (± 6.1) 30.2 (± 3.7) bmi 1 [kg/m2] 24.4 (± 3.5) 24.8 (± 3.5) smoking 2 regular 4 (13.3%) 2 (20.0%) alcoho 2 ≥ 1/week 17 (56.7%) 2 (20.0%) biological child(ren) 2 5 (16.7%) 2 (20.0%) covid-19 disease severity 3 mild 2 20 (66.7%) 6 (60.0%) moderate 2 9 (30.0%) 3 (30.0%) severe 2 1 (10%) 1 (3.3%) 1 mean (± standard deviation); 2 absolute frequency (± percentage); 3 mild: headache, sore throat, flu like symptoms without fever; moderate: fever over 37.5°c ≥ 3 days; severe: hospitalization required; bmi = body weight in kg (body height in cm)2. table 2. semen analysis results. mean before mean after δmeanbef→aft p-value study control study control study control study control volume (ml) 3.43 3.42 3.61 3.60 0.18 0.18 0.251 0.321 density (mio/ml) 88.94 63.39 89.25 68.55 0.31 5.16 0.493 0.341 sperm count (mio) 264.06 225.61 277.04 234.20 12.98 8.59 0.397 0.452 progressive (%) 35.87 47.50 43.13 49.70 7.27 2.20 0.014* 0.359 motility (%) 47.98 52.80 53.63 55.60 5.65 2.80 0.050* 0.291 vitality (%) 65.57 77.10 81.60 79.80 16.03 2.70 0.000* 0.336 morphology (%) 10.37 7.10 13.15 6.50 2.78 -0.60 0.087 0.254 sorp (mv) 43.46 24.47 30.30 24.31 -13.16 -0.16 0.132 0.423 n. sorp (mv*mio/ml) 1.31 0.63 0.76 0.55 -0.55 -0.07 0.183 0.261 normal semen analysis results 15 (50%) 7 (70%) 25 (83%) 7 (70%) 10 0 0.0003* sorp = static oxidation reduction potential; n. sorp = sorp normed to sperm concentration = orp (mv) sperm density (mioml); (δmeanbef→aft) = difference of means of semen parameters between number of patients with normal semen analysis results between first and second semen cell analysis; p-values of paired students-t-test for sperm parameters or χ2-test for semen analysis results; significant changes marked by *. archivio italiano di urologia e andrologia 2023; 95, 1 j. aschauer, m. sima, m. imhof ing more aware about potential effects of a coronavirus infection on male reproductive system. the impact of sars-cov-2 on male fertility parameters after infection continues to be intensely researched and has been confirmed by various studies (5). a systematic review and meta-analysis conducted in 2021 revealed that compared to non-infected individuals, men recently recovered from covid-19 had lesser semen volume, sperm concentration and motility, though not all parameters were significantly lower (6). another more recent meta-analysis confirmed these results, demonstrating a decline in certain parameters of sperm quality in men after coronavirus infection compared to healthy controls and to individual baseline parameters before viral infection (7). in line with these outcomes, a large percentage of participants of this study presented with at least one abnormal sperm quality parameter within 3 months since covid19 recovery. most men included in this analysis experienced merely mild symptoms during coronavirus illness. approximately one third reported moderate symptoms with fever, while only one person of each group required hospitalization due to severe symptoms. considering the high percentage of abnormal semen analysis results at time of enrolment, sars-cov-2 infection seems to affect sperm quality even if symptoms are mild. interestingly, a recent prospective cohort study found no correlation between the presence of fever or symptom severity with semen characteristics in men after covid-19 infection (21). this is worth mentioning as the majority of covid19 infections disease severity will be mild, particularly in previously healthy men under the age of 65 (22). while several publications have observed short-term effects of sars-cov-2 on male fertility, the infectioninduced longitudinal and long-term changes in the male reproductive function are less clear. data on semen quality over time in covid-19 patients provides somewhat conflicting results. for example, one analysis of men infected with sars-cov-2 suggested a recovery time of sperm parameters to baseline values prior to infection of about 3 months (21), while another investigation indicated it may take up to up to 6 months (23). more research will be necessary to confirm if and how fast semen quality recovers after covid-19, and to what extent recovery time may vary between patients. to explore therapeutic options that may support male fertility after coronavirus infection, it is important to understand why the male reproductive system might be especially vulnerable to sars-cov-2. various mechanisms for impaired semen quality after covid-19 are discussed. firstly, direct cytopathic effects of sars-cov-2 replication and dissemination in certain testicular cells may impair spermatogenesis during active viral disease (24). two cell structures of particular interest in this regard are the angiotensin converting enzyme 2 (ace2) receptor and activating transmembrane protease serine 2 (tmprss2), as only binding to ace2 and activating tmprss2 enables the coronavirus to enter host cells (25). it has yet to be determined which genital tissues can indeed act as viral reservoirs for sars-cov-2, even though expression of ace2 and tmprss2 was already discovered on several cells of the male reproductive organs, that are crucial for spermatogenesis (10, 24). the role of oxidative stress general immune response triggered by sars-cov-2 and subsequent inflammatory reactions marked by increased cytokine release leads to major oxidative stress (os) as discussed in covid-19 focused publications (8,26). os is described as a metabolic state with an imbalance between antioxidants and oxidants, namely free radicals or reactive oxygen species (ros). cytokine storms in other viral infections have been shown to impact male fertility due to increased leucocyte infiltration and subsequent production of ros in the male gonads (10, 27). while certain levels of ros are crucial for physiological cell processes, an excessive production within seminal fluid can quickly exceed the neutralizing capacities of intrinsic antioxidants and cause significant cell damage. elevated os in the testicular microenvironment can thus drastically impair spermatogenesis and semen parameters (11, 12). based on the limited evidence available, infection with sars-cov-2 may be associated with elevated os in the ejaculate (28). two recent investigations analyzing oxidative stress in semen samples of covid-19 patients found higher ros levels shortly after illness, compared to a later time point following viral infection (29, 30). similar results were obtained in this present study, as mean os levels in both groups were lower at the second semen analysis 3 month after first measurement directly following covid-19 disease. however, this decrease was more evident in the study group receiving micronutrient supplementation, suggesting that intake of certain micronutrients may support reduction of ros in the seminal fluid. os levels in the ejaculate of all participants were assessed by measuring the static oxidation-reduction potential (sorp), which allows for simultaneous evaluation of the balance between oxidative and reductive stress within a sample (11). most previous research focusing on os in the ejaculate of men after covid-19 infection determined oxidative and antioxidative markers separately (30, 31), not considering potential reductive stress within the ejaculate (32). however, information on the true redox state of seminal fluid might of particular interest to guide reproductive management. micronutrients for semen quality improvement there are currently no general recommendations on fertility management for men after testing positive for sarscov-2, to reduce potential sperm quality deterioration or support recovery. options to counteract impairment of semen parameters after recovery from covid-19 are lacking, though especially needed for infected men with a current desire to have children, who want to optimize their reproductive health. in general, therapies to improve sperm quality are scarce (33). research suggests that men who stick to healthy diets tend to have better semen parameters (34) and dietary supplements are frequently recommended to men struggling with infertility. two recent systematic reviews and meta-analyses of randomized controlled trials investigating the effect of nutritional supplementation on sperm quality parameters showed similar results. salas-huetos et al. found that additional dietary selenium, zinc, and co-enzyme q10 seem to significantly improve sperm concentration and motility, while carnitines supplements showed beneficial effects archivio italiano di urologia e andrologia 2023; 95, 1 micronutriemts and sperm quality after covid-19 only on motility (14). similarly, buhling et al. demonstrated that semen parameters of infertile men may be improved with supplementation of co-enzyme q10, zinc, folic acid, l-carnitine and acetyl-l-carnitine (13). however, both analyses showed notable heterogeneity regarding supplement composition, dosages and patient population. one internventional study by rafiee et al. revealed that oral supplementation with the antioxidant n-acetylcysteine (nac) may support recovery of impaired sperm quality in men following covid-19 disease. their findings showed that nac intake significantly improved semen motility, concentration and morphology to levels similar to before sars-cov-2 infection, while sperm quality parameters of a control group not receiving nac remained at lower levels (35). the micronutrient regimen used in this is study a prescription free nutraceutical, which has been available on the international market for many years and contains vitamin e, coenzyme q10, l-arginine, folic acid, selenium, l-carnitine, zinc and glutathione. previous clinical studies with this defined composition of micronutrients suggested that daily intake may improve semen parameters and reduce sperm dna-fragmentation index in different subfertile male patient populations (36-38). vitamin e, l-carnitine, glutathione and l-arginine are all known to exhibit antioxidant properties and can scavenger free radicals, which may protect spermatozoa against membrane and dna damage caused by excess ros in the seminal fluid. selenium also plays a role in shielding tissues or cells from excess os, as it acts an important co-factor for various antioxidant enzymes (39). likewise, coenzyme-q10 is part of the nonenzymatic antioxidant defence system of the body and also crucial for mitochondrial energy production and maturation of semen cells (40). lastly, zinc and folate are both key molecules involved in dna and protein synthesis in germ cells such as spermatozoa. they are essential for various stages of sperm cell development, functionality and fertilizing capability (41). considering the mechanisms of action of these micronutrients it seems likely that their antioxidant properties play an important role to support sperm quality recovery when supplemented in patients after covid-19 infection. limitations an apparent limitation of this study is the lack of information regarding sperm quality of participants prior to sarscov-2 infection. therefore, it was not possible to determine if complete recovery of semen parameters occurred within the investigational period. moreover, intervals between viral illness and first semen sample collection varied between participants. regarding the study group receiving dietary support, it is not possible to confirm the extent to which improvement of semen parameters was due to micronutrient supplementation, or to potential physiological recovery of testicular function following convalescence from covid-19. to partly compensate for this lack of information a control group of men recovered from sars-cov-2 infection without micronutrient supplementation was additionally analysed, though sperm quality baseline values of first semen analysis varied between study and control group. another limitation to the power of this pilot study is the relatively low number of study group participants, and an even lower sample size for the control group. moreover, there is no information on which sarscov-2 virus strains caused the respective infections, though only two strains, alpha and delta, were primarily coexisting in austria during the recruitment period (42). despite these limitations, strict inclusion criteria were applied to ensure more homogeneity within both groups. conclusions the results of this study suggest that supplementation of certain micronutrients in male adults after covid-19 disease may improve recovery of sperm quality parameters and seminal oxidative stress, compared to a control group without dietary support. despite tendencies towards sperm quality recovery in both groups, significant positive effects on certain semen parameters were only evident in the study group. even though dietary supplements are not intended to cure or completely prevent impairment of male reproductive function, micronutrients with antioxidative potential can be a risk-free and simple, yet effective measure to support physiological semen quality recovery after sars-cov-2 infection. the present findings might be especially relevant for infected men currently trying for children, and clinicians eager to optimise reproductive care for covid-19 patients. since this was a pilot study, future research with a larger sample size and longer postinfectious investigation of longitudinal changes in seminal parameters and oxidative stress values are warranted to confirm these effects. references 1. who coronavirus (covid-19) dashboard [internet]. 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39:1555-63. 8. dutta s, sengupta p. sars-cov-2 and male infertility: possible multifaceted pathology. reprod sci. 2021; 28:23-6. 9. delle fave rf, polisini g, giglioni g, et al. covid-19 and male fertility: taking stock of one year after the outbreak began. arch ital urol androl. 2021; 93:115-9. archivio italiano di urologia e andrologia 2023; 95, 1 j. aschauer, m. sima, m. imhof 10. haghpanah a, masjedi f, alborzi s, et al. potential mechanisms of sars-cov-2 action on male gonadal function and fertility: current status and future prospects. andrologia. 2021; 53:e13883. 11. agarwal a, panner selvam mk, arafa m, et al. multi-center evaluation of oxidation-reduction potential by the mioxsys in males with abnormal semen. asian j androl. 2019; 21:565-9. 12. alahmar at. role of oxidative stress in male infertility: an updated review. j hum reprod sci. 2019; 12:4-18. 13. buhling k, schumacher a, eulenburg cz, laakmann e. influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review. reprod biomed online. 2019; 39:269-79. 14. salas-huetos a, rosique-esteban n, becerra-tomás n, et al. the effect of nutrients and dietary supplements on sperm quality parameters: a systematic review and meta-analysis of randomized clinical trials. adv nutr. 2018; 9:833-48. 15. choy jt, eisenberg ml. male infertility as a window to health. fertil steril. 2018; 110:810-4. 16. world health organization. who laboratory manual for the examination and processing of human semen [internet]. 6th ed. geneva: world health organization; 2021 [cited 2022 oct 5]. available from: https://apps.who.int/iris/handle/10665/343208 17. world health organization, editor. who laboratory manual for the examination and processing of human semen. 5th ed. geneva: world health organization; 2010. p. 271 18. agarwal a, bui ad. oxidation-reduction potential as a new marker for oxidative stress: correlation to male infertility. investig clin urol. 2017; 58:385-99. 19. chen jm. novel statistics predict the covid-19 pandemic could terminate in 2022. j med virol. 2022; 94:2845-8. 20. daria s, islam mr. the sars-cov-2 omicron wave is indicating the end of the pandemic phase but the covid-19 will continue. j med virol. 2022; 94:2343-5. 21. donders ggg, bosmans e, reumers j, et al. sperm quality and absence of sars-cov-2 rna in semen after covid-19 infection: a prospective, observational study and validation of the spermcovid test. fertil steril. 2022; 117:287-96. 22. brodin p. immune determinants of covid-19 disease presentation and severity. nat med. 2021; 27:28-33. 23. hu b, liu k, ruan y, et al. evaluation of midand long-term impact of covid-19 on male fertility through evaluating semen parameters. transl androl urol. 2022; 11:159-67. 24. sheikhzadeh hesari f, hosseinzadeh ss, asl monadi sardroud ma. review of covid-19 and male genital tract. andrologia. 2021; 53:e13914. 25. patel dp, punjani n, guo j, et al. the impact of sars-cov-2 and covid-19 on male reproduction and men’s health. fertil steril. 2021; 115:813-23. 26. huang c, ji x, zhou w, huang z, et al. coronavirus: a possible cause of reduced male fertility. andrology. 2021; 9:80-7. 27. agarwal a, rana m, qiu e, et al. role of oxidative stress, infection and inflammation in male infertility. andrologia. 2018; 50:e13126. 28. sengupta p, leisegang k, agarwal a. the impact of covid-19 on the male reproductive tract and fertility: a systematic review. arab j urol. 2021; 19:423-36. 29. hajizadeh maleki b, tartibian b. covid-19 and male reproductive function: a prospective, longitudinal cohort study. reproduction. 2021; 161:319-31. 30. falahieh fm, zarabadipour m, mirani m, et al. effects of moderate covid-19 infection on semen oxidative status and parameters 14 and 120 days after diagnosis. reprod fertil dev. 2021; 33:683-90. 31. shcherbitskaia ad, komarova em, milyutina yp, et al. oxidative stress markers and sperm dna fragmentation in men recovered from covid-19. int j mol sci. 2022; 23:10060. 32. panner selvam mk, agarwal a, henkel r, et al. the effect of oxidative and reductive stress on semen parameters and functions of physiologically normal human spermatozoa. free radic biol med. 2020; 152:375-85. 33. thurston l, abbara a, dhillo ws. investigation and management of subfertility. j clin pathol. 2019; 72:579-87. 34. leisegang k, sengupta p, agarwal a, henkel r. obesity and male infertility: mechanisms and management. andrologia. 2021; 53:e13617. 35. rafiee b, bagher tabei sm. the effect of n-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of covid-19 in the last three months. arch ital urol androl. 2021; 93:465-7. 36. imhof m, lackner j, lipovac m, et al. improvement of sperm quality after micronutrient supplementation. e-spen journal. 2012; 7:e50-3. 37. tsounapi p, honda m, dimitriadis f, et al. effects of a micronutrient supplementation combined with a phosphodiesterase type 5 inhibitor on sperm quantitative and qualitative parameters, percentage of mature spermatozoa and sperm capacity to undergo hyperactivation: a randomised controlled trial. andrologia. 2018; 50:e13071. 38. lipovac m, nairz v, aschauer j, riedl c. the effect of micronutrient supplementation on spermatozoa dna integrity in subfertile men and subsequent pregnancy rate. gynecological endocrinology. 2021; 37:711-5. 39. smits rm, mackenzie-proctor r, yazdani a, et al. antioxidants for male subfertility. cochrane database syst rev. 2019; 3:cd007411. 40. vishvkarma r, alahmar at, gupta g, rajender s. coenzyme q10 effect on semen parameters: profound or meagre? andrologia [internet]. 2020 jul [cited 2023 jan 2]; 52(6). available from: https://onlinelibrary.wiley.com/doi/10.1111/and.13570 41. ebisch imw, thomas cmg, peters whm, et al. the importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. hum reprod update. 2007; 13:163-74. 42. covariants website: overview of sars-cov-2 variants in countries over time. [cited 2023 jan 5]. available from: https://covariants.org/per-country. correspondence judith aschauer, b.sc. judith.aschauer@hotmail.com michaela sima michaela@sima.eu martin imhof martin@imhof.at wiener ring 3-5, 2100 korneuburg, austria conflict of interest: the authors declare no potential conflict of interest. stesura seveso 489archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. mammary ducts embedded in a fibroconnective tissue stroma. gynecomastia is associated with medical conditions such as extreme obesity, hypogonadism, liver, and kidney failure. in addition, the administration of certain drugs is a known risk factor for gynecomastia. according to food and drug administration (fda) adverse event reporting system, gynecomastia is most frequently reported after administration of inhibitors of 5alpha-reductase (dutasteride, finasteride), spironolactone, antipsychotics, lipid-lowering agents (rosuvastatin, atorvastatin, and simvastatin) and antiandrogens (1). other drugs causing gynecomastia include antiretrovirals (protease inhibitors and nucleoside reverse transcriptase inhibitors), histamine2-receptor blockers (cimetidine), antimycotics (long-term use of ketoconazole), calcium channel blockers, and chemotherapeutic agents. gynecomastia was also reported after intake of exogenous hormones (estrogens) or steroids (in adolescent boys), and after environmental exposure to phenothrin or intake of phytoestrogens (e.g., large quantities of phytoestrogencontaining soy products). there are numerous reports on the association between the intake of certain drugs and gynecomastia, but no meta-analysis has so far assessed the extent of the risk of gynecomastia linked to specific classes of drugs. the aim of this work was to review the scientific evidence on the risk of gynecomastia after administration of the drugs that are most frequently associated with the occurrence of this side effect. materials and methods electronic databases (e.g., pubmed and embase) were searched for articles published up to 30 june 2021. five separate searches were performed using the following mesh terms: “spironolactone and gynecomastia”, “antiandrogens and gynecomastia”, “(finasteride or dutasteride) and gynecomastia”, “psychotropic agents and gynecomastia”, “statins and gynecomastia”. title and abstract and full-text screening were performed independently by two authors. we included randomized controlled trials (rcts), objective: to review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs. material and methods: a search of medline and embase was performed up to 30 june 2021. we included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class. results: a total of 32 randomized controlled trials were included in the final review. there was an increased odds of gynecomastia in men receiving antiandrogens (or = 17.38, 95% ci: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (or = 1.77, 95% ci: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). the use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (or = 8.39, 95% ci: 5.03 to 13.99; 14 trials, 3745 participants). no placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (or = 4.32, 95% ci: 1.31 to 14.27; 3 trials, 343 participants). limited evidence about the effects of statins on mammary glands was found. conclusions: antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. such effect can be explained by a modification of the testosterone to estradiol ratio. gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels. key words: gynecomastia; breast enlargement; spironolactone; antiandrogens; 5 alpha-reductase inhibitors; psychotropic drugs; statins. submitted 20 september 2021; accepted 1 november 2021 introduction gynecomastia is a condition in which the male breast is enlarged due to an increase in ductal tissue, stroma, or fat. histological observation shows a proliferation of the drug-induced gynecomastia: a systematic review and meta-analysis of randomized clinical trials alberto trinchieri 1, gianpaolo perletti 2, 3, vittorio magri 4, konstantinos stamatiou 5, margherita trinchieri 6, emanuele montanari 7 1 school of urology, university of milan, milan, italy; 2 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 3 faculty of medicine and medical sciences, ghent university, belgium; 4 urology secondary care clinic, asst-nord, milan, italy; 5 department of urology, tzaneio hospital, pireus, greece; 6 department of neuroscience, psychiatric unit, university of parma, parma, italy; 7 department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan, italy. doi: 10.4081/aiua.2021.4.489 summary archivio italiano di urologia e andrologia 2021; 93, 4 a. trinchieri, g. perletti, v. magri, k. stamatiou, m. trinchieri, e. montanari 490 with an open-label or single/double blinded design, which enrolled patients treated for at least 6 weeks with antiandrogens, 5 alpha-reductase inhibitors, spironolactone, psychotropic drugs, and statins. included studies should include a primary or secondary safety endpoint focusing on the side effects of treatment. the following information was extracted from each study: author(s), publication year; study design; population; intervention; rate of gynecomastia (or breast enlargement or breast tenderness or pain or galacthorrea). two authors independently performed the quality assessment by identifying potential biases using the cochrane risk of bias tool (2), focusing on the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcomes, selective reporting and other biases. the risk of bias (rob) was graded as high, low or unclear. publication bias was assessed by visual inspection of funnel plots and by the egger's regression test. dichotomous data (presence/absence of gynecomastia) and number of per-protocol or intent-to-treat patients were extracted to calculate odds ratios (or), confidence intervals (ci) to odds-ratios, and z statistics according to the mantel-haenszel method. meta-analysis was performed using a random-effects model. heterogeneity was assessed by i2 statistics, reported with 95% cis, and interpreted as of lesser importance (≤ 40%), moderate (30%-60%), substantial (50%-90%) or considerable (≥ 75%), according to cochrane criteria. the review (prospero registration number: crd42021276781) was conducted in accordance with prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines (3). statistical analysis was performed using the revman5 software. the egger’s test was performed using the metaessentials software (rotterdam school of management, erasmus university, the netherlands). results database search for the association between gynecomastia and treatment with spironolactone, antiandrogens, alphareductase inhibitors, and antipsychotics retrieved 74, 215, 42 and 74 papers respectively. a total of 68 papers was screened by title/abstract. after full-text screening with removal of duplicates or of articles describing series reported in other reports we included 32 papers in this systematic review (4-35). out of them 30 reports were included in the quantitative analysis (4-33). a prisma flow-chart of the study selection process is shown in figure 1. the supplementary appendix provides figure 1. prisma flow chart summary of the study selection procedure. 491archivio italiano di urologia e andrologia 2021; 93, 4 drug-induced gynecomastia a list of included studies (supplementary materials), characteristics of the included trials and the risk-of-bias assessment. we included the most recent paper reporting the cumulative results at 10-year follow-up of three studies of the administration of bicalutamide in the frame of the early prostate cancer (epc) program which includes three large, randomized trials conducted in the united states, europe, mexico and australia (4). random-effects meta-analysis revealed that antiandrogen therapy is associated with significantly higher odds of gynecomastia (odds ratio, or = 17.38, 95% ci: 11.26 to 26.82; 6 trials, 9599 participants) compared with placebo (4, 5, 7-9) or no treatment (6) (figure 2a). similarly, alpha-5-reductase inhibitors (or = 1.77, 95% ci: 1.53 to 2.06; 6 trials, 34860 participants) and spironolactone (or = 8.39, 95% ci: 5.03 to 13.99; 14 trials, 3745 participants) were significantly associated with gynecomastia (10-16) (figures 2b-2c). it is known that dutasteride can inhibit the activity of both type i and ii reductases, whereas finasteride is not active on isoform ii. this might suggest an increased risk of gynecomastia in patients taking dutasteride. however, the comparison between dutasteride and finasteride resulted in non-significantly different (p = 0.31) odds of gynecomastia (or = 0.66, 95% ci 0.30-1.48; 2 trials; 1697 participants) (forest plot not shown). risperidone was significantly (p = 0.02) associated with higher odds of gynecomastia compared to quetiapine (or = 4.32, 95% ci: 1.31 to 14.27; 3 trials, 343 participants) (figure 2d), but not olanzapine (forest plot not shown). figure 3 shows the funnel plots for publication bias. no significant bias was identified by visual inspection and statistical analysis of funnel plots. accordingly, the egger’s test (antiandrogens/placebo, p = 0.43; 5-alpha reductase inhibitors/placebo, p = 0.37; spironolattone/placebo, p = 0.53; risperidone/quetiapine, p = 0.17). between-study heterogeneity was moderate for the antiandrogens vs. controls comparison (i2 = 49%), and of lesser importance for all other analyses. table 1 presents the summary of the findings of our pooled analyses, also including an evaluation of the quality of the evidence, performed according to grade criteria. discussion mechanisms regulating the growth of the breast tissue are complex and not fully elucidated (36, 37). the breast tissue expresses receptors for both estrogens and androgens, which can induce the proliferation or inhibition of the growth and differentiation of the mammary gland, respectively. gynecomastia can be caused either by overt reduction of circulating estrogen levels or table 1. drugs compared with placebo or active comparators endpoint: gynecomastia. patient or population: various. settings: outpatient. intervention: antiandrogens, 5-alpha reductase inhibitors, spironolactone, risperidone, quetiapine. comparison: placebo or active comparator. comparisons illustrative comparative risks (95% ci) relative effect no of participants quality of the evidence comments assumed corresponding (95% ci) (studies or comparisons) (grade) control risk intervention risk placebo/active drug intervention antiandrogens vs. placebo 81.24 per 1000 605.8 per 1000 or 17.38 9599 ⊕⊕⊕⊝ reasons for upgrading: (498.91 to 703.40) (11.26 to 26.82) (6) moderate large magnitude of effect reasons for downgrading: indirectness of evidence risk of bias 5-alpha reductase inhibitors 19.54 per 1000 34.07 per 1000 or 1.77 34860 ⊕⊕⊝⊝ reasons for upgrading: vs. placebo (29.59 to 39.44) (1.53 to 2.06) (7) low none reasons for downgrading: risk of bias indirectness of evidence spironolactone vs. placebo 6.5 per 1000 52.09 per 1000 or 8.39 3745 ⊕⊕⊕⊝ reasons for upgrading: (31.89 to 83.94) (5.03 to 13.99) (14) moderate large magnitude of effect reasons for downgrading: risk of bias indirectness of evidence risperidone vs. quetiapine 19.35 per 1000 78.56 per 1000 or 4.32 343 ⊕⊕⊕⊝ reasons for upgrading: (25.20 to 219.75) (1.31 to 14.27) (3) moderate large magnitude of effect reasons for downgrading: imprecision (small sample size, wide 95%ci) risk of bias indirectness of evidence the corresponding intervention risk (and its 95% confidence interval) is based on the assumed control risk in the comparison group and the relative effect of the intervention (and its 95% ci). it is calculated from the odds ratio using the formula: or/[1-acr x (1-or)]. ci: confidence interval. or: odds ratio. acr: assumed control risk. grade working group grades of evidence. high quality: further research is very unlikely to change our confidence in the estimate of effect. moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. very low quality: we are very uncertain about the estimate. archivio italiano di urologia e andrologia 2021; 93, 4 a. trinchieri, g. perletti, v. magri, k. stamatiou, m. trinchieri, e. montanari 492 figure 2. pooled analysis of the comparisons between antiandrogens and placebo (panel a), 5-alpha-reductase inhibitors and placebo (panel b), spironolactone and placebo (panel c) and risperidone and quetiapine (panel d). the diamonds show the position of the pooled odds-ratios, extending to the 95% confidence interval limits. values to the right of the no-effect vertical axis show increased odds for gynecomastia. 493archivio italiano di urologia e andrologia 2021; 93, 4 drug-induced gynecomastia by an increase of androgen serum levels. in addition, imbalances between estrogen and androgen levels, which may retain serum concentrations within the normal ranges, may cause such effects. furthermore, activity of estrogens and androgens can be locally modulated in the breast tissue (i) by increased local production of estrogens or decreased inactivation of estrogens, (ii) by decreased local production of androgens, or (iii) by changes in the number and/or activity of androgen or estrogen receptors. besides androgens and estrogens, other hormones can interfere with the growth of men’s breast tissue, which presents receptors for prolactin, progesterone, insulin-like growth factor (igf)-1, igf-2, luteinizing hormone (lh) and/or human chorionic gonadotropin (hcg). our metaanalysis confirmed that antiandrogens are associated with the highest risk of gynecomastia. antiandrogens are used for the treatment of prostate cancer as monotherapy or in combination with lhrh inhibitors. bicalutamide is the most used antiandrogen, though other agents, either steroidal like cyproterone acetate or non-steroidal like flutamide, have also been used for the treatment of prostate cancer. these agents bind to androgen receptors competitively, thus inhibiting testosterone or dihydrotestosterone receptor binding and activity. the administration of non-steroidal antiandrogens, as bicalutamide, causes an increase in the synthesis of testosterone due to the inhibition of the negative feedback of the hypothalamic-pituitary-gonadal axis. increased availability of testosterone causes an increase in estradiol levels due to aromatization of testosterone. these hormonal changes explain the high risk of gynecomastia, which tends to occur in the first year of administration. the evaluation at different time intervals of the rates of gynecomastia in patients taking bicalutamide included in the same series of early prostate cancer program showed rates of gynecomastia and breast pain of 64.9% and 65.1% after a median follow up of 2.6 years (38), 66.3% and 67.9% at 5.1 years (39) and 66.8 and 73.7% at 9.7 years (40). cyproterone acetate is expected to involve a lower risk of gynecomastia because, in contrast to nonsteroidal antiandrogens, it can decrease estrogen levels via inhibition of the secretion of gonadotropins. however, a comparative study by eortc described similar gynecomastia rates in patients treated with cyproterone or flutamide, though the latter was more frequently associated with painful gynecomastia (35). inhibitors of 5-alpha-reductase are widely used for the treatment of benign prostatic hyperplasia. these agents inhibit the conversion of testosterone to dihydrotestosterone through inhibition of the 5-alpha-reductase enzyme, thus reducing prostate cell proliferation. they also cause an increase in the synthesis of testosterone and, consequently, of estrogen through aromatization of figure 3. funnel plots for publication bias analysis. top-left, antiandrogens vs. placebo; top-right, 5-alpha-reductase inhibitors vs. placebo; bottom-left, spironolactone vs. placebo; bottom-right, risperidone vs. quetiapine. archivio italiano di urologia e andrologia 2021; 93, 4 a. trinchieri, g. perletti, v. magri, k. stamatiou, m. trinchieri, e. montanari 494 testosterone. spironolactone may induce gynecomastia by several mechanisms: (i) increased peripheral conversion of testosterone to estradiol, (ii) displacement of testosterone from shbg, or (iii) binding to peripheral androgen receptors to competitively inhibit testosterone and dihydrotestosterone. our meta-analysis confirms that spironolactone and 5-alpha-reductase inhibitors are associated with an increased risk of gynecomastia, although to a lesser extent than antiandrogens. although an increased risk of gynecomastia could be expected in patients taking dutasteride, which inhibits the activity of both type 1 and 2 reductases, our metaanalysis could not demonstrate a different risk of gynecomastia between finasteride and dutasteride (16). statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme a (hmg-coa) reductase, an enzyme that lowers the serum levels of lipids by blocking the pathways of cholesterol synthesis. inhibition of adrenal and gonadal steroid synthesis may entail to an increased estradiol: testosterone ratio. a meta-analysis showed that a reduction in circulating testosterone levels in patients receiving statin (41). our search did not retrieve randomized controlled studies that evaluated the possible occurrence of gynecomastia after treatment with statins. it was therefore not possible to investigate the potential risk of gynecomastia associated with the use of these drugs, which was observed following treatment with statins in a case-control cohort study (42). on the other hand, some case reports have suggested that pravastatin, atorvastatin, and rosuvastatin may cause gynecomastia that can be reverted by withdrawal or substitution with a less potent statin. in addition, pharmacovigilance studies include hmg-coa reductase inhibitors among the most frequent causes of drug-induced gynecomastia (43, 44). some antipsychotics are correlated with the risk of gynecomastia because of their effect on prolactin secretion. antipsychotics block pituitary dopamine d2 receptors and prevent their inhibitory effect on prolactin secretion. hyperprolactinemia may in turn decrease the secretion of gnrh by hypothalamus feedback causing hypogonadism. nonetheless, prolactin receptors have also been found in male breast tissue, and this may also contribute to the development of gynecomastia (45, 46). most first-generation antipsychotics and some secondgeneration antipsychotics, particularly risperidone and paliperidone, have been found to increase prolactin levels, with accompanying gynecomastia. the onset of gynecomastia after administration of risperidone is more frequently associated with the use of high doses of the drug and can be triggered by the simultaneous administration of fluoxetine which can interfere in the metabolism of risperidone by inhibition of cytochrome p450.our meta-analysis confirmed a greater risk of gynecomastia associated with the use of risperidone compared to another atypical antipsychotics. a limitation of the meta-analysis evidence presented in this review is the possible under-reporting of breast enlargement or gynecomastia in the female population taking spironolactone or antipsychotics because this effect may be unnoticed or even considered a beneficial effect by female patients, while in the male population it may have been reported with more attention, as it modifies the body image more heavily. unfortunately, no study has provided a separate assessment of the appearance of this side effect in relation to gender. in populations of adult women who took spironolactone for the treatment of acne, the appearance of breast tenderness and breast enlargement was estimated at 2.5% and 2.1% respectively (47, 48). the prevalence of gynecomastia could therefore be underestimated in mixed gender populations taking spironolactone or antipsychotics compared to male populations receiving antiandrogens or alpha-reductase inhibitors. in conclusion, our study confirmed the high risk of gynecomastia in patients taking antiandrogens for the treatment of prostate cancer. the frequent occurrence of gynecomastia is a limiting factor of this treatment and ablation of the breast tissue by ionizing radiation is sometimes used to prevent this effect. the risk of gynecomastia is lower but significantly higher than placebo in patients receiving spironolactone, 5-alpha-reductase inhibitors, and atypical antipsychotics (risperidone vs. quetiapine). the potential risk of gynecomastia associated with the use of statins should be better assessed with studies evaluating the long-term side effects of these drugs. in the clinical practice, the possible additive or synergic interaction of several 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jp, lieberman ja, stroup ts, et al. catie investigators. effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. am j psychiatry. 2006; 163:600-10. 33. mcevoy jp, lieberman ja, perkins do, et al. efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison american journal of psychiatry. 2007; 164:1050-1060. 34. mcevoy jp, byerly m, hamer rm, et al. effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. jama. 2014; 311:1978-87. 35. schröder fh, whelan p, de reijke tm, et al. members of the eortc genito-urinary group. metastatic prostate cancer treated by flutamide versus cyproterone acetate. final analysis of the "european organization for research and treatment of cancer" (eortc) protocol 30892. eur urol. 2004; 45:457-64. 36. narula hs, carlson he. gynaecomastia-pathophysiology, diagnosis and treatment. nat rev endocrinol. 2014; 10:684-698. 37. kanakis ga, nordkap l, bang ak, et al. eaa clinical practice guidelines-gynecomastia evaluation and management. andrology. 2019; 7:778-793. 38. wirth m, tyrrell c, wallace m, et al. bicalutamide (casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression urology. 2001; 58:146-150. 39. wirth m, tyrrell c, delaere k, et al. bicalutamide ('casodex') 150mg in addition to standard care in patients with nonmetastatic prostate cancer: updated results from a randomised double-blind phase iii study (median follow-up 5.1y) in the early prostate cancer programme prostate cancer and prostatic diseases 2005; 8:194200. 40. iversen p, mcleod dg, see wa, et al. casodex early prostate archivio italiano di urologia e andrologia 2021; 93, 4 a. trinchieri, g. perletti, v. magri, k. stamatiou, m. trinchieri, e. montanari 496 cancer trialists' group. antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide early prostate cancer programme at a median followup of 9.7 years.bju int. 2010; 105:1074-81. 41. skeldon sc, carleton b, brophy jm, et al. statin medications and the risk of gynecomastia. clin endocrinol (oxf). 2018; 89:470-473. 42. schooling cm, au yeung sl, freeman g, cowling bj. the effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. bmc med. 2013; 11:57. 43. roberto g, biagi c, montanaro n, et al. statin-associated gynecomastia: evidence coming from the italian spontaneous adr reporting database and literature. eur j clin pharmacol. 2012; 68:1007-11. 44. batteux b, llopis b, muller c, et al. french national network of pharmacovigilance centres. the drugs that mostly frequently induce gynecomastia: a national case noncase study. therapie. 2020; 75:225-238. 45. grigg j, worsley r, thew c, et al. antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. psychopharmacology. 2017; 234:3279-3297. 46. ferreira m, mesquita m, quaresma m & andré s. prolactin receptor expression in gynaecomastia and male breast carcinoma. histopathology. 2008; 53:56-61. 47. layton am, eady ea, whitehouse h, et al. oral spironolactone for acne vulgaris in adult females: a hybrid systematic review. am j clin dermatol. 2017; 18:169-191. 48. muhlemann mf, carter gd, cream jj, wise p. oral spironolactone: an effective treatment for acne vulgaris in women. br j dermatol. 1986; 115:227-32. correspondence alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com school of urology, university of milan via commenda 15, 20100 milano (italy) gianpaolo perletti, phd gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese (italy) vittorio magri, md vittorio.magri@yahoo.it urology secondary care clinic, asst-nord, milan (italy) konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio hospital, pireus (greece) margherita trinchieri, md margherita.trinchieri11@gmail.com department of neuroscience, psychiatric unit, university of parma, parma (italy) emanuele montanari, md emanuele.montanari@unimi.it department of urology, irccs ca’ granda ospedale maggiore policlinico university of milan, milan (italy) stesura seveso 441archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. ation of these patients. hence the information gained from urodynamics may help us. performing urodynamics is controversial before surgical treatment of stress urinary incontinence (sui) (3). according to the cochrane library, urodynamics can change the clinical decision (4). the nice (national institute for health and care excellence) guideline recommends urodynamic examination before stress urinary incontinence surgery (5). eau guidelines do not recommend routinely carrying out urodynamics when offering treatment for uncomplicated urinary incontinence (6). incontinence mostly develops as a result of urine storage dysfunction and the incidence of bladder outlet obstruction (boo) is low. for this reason, in daily practice, the only cystometry is usually performed in addition to history and physical examination. since pressure-flow studies (pfs) are generally not implemented, the diagnosis of urinary voiding dysfunctions can be overlooked. thus redundant surgical procedures and improper treatments can be applied to these patients. to clarify whether sui patients are always pure sui and if these patients should be submitted to urodynamic before surgery to prevent incorrect surgical approach, we aimed to retrospectively investigate the abnormalities in the voiding phase of female patients who have undergone pfs for incontinence. materials and methods between january 2010 and june 2015, 1329 female patients aged 18-60 who had incontinence for at least six months and underwent urodynamics were evaluated retrospectively. neurogenic lower urinary system dysfunction, active urinary infection, bladder stone, urethral stricture, pelvic radiation, pelvic surgery history, and patients who could not perform micturition in pfs were excluded from the study (311 patients). patients' demographic properties, urination diary, pad test, urine analysis and culture, urethral mobility (q tip), urinary ultrasonography, post-voided residue, and urodynamic examination findings were retrieved. at filling cystometry, urinary incontinence triggered with valsalva or coughing was accepted as stress type urinary incontiobjective: to investigate the differences between urodynamic findings and history in women with urinary incontinence before surgery and clarify the need for preoperative pressure-flow studies. materials and methods: the medical records of 1018 women who underwent urodynamic examination for urinary incontinence between 2010 and 2015 were evaluated retrospectively. stress (n = 442), urge (n = 334) and mixed (n = 242) were classified as type urinary incontinence according to urodynamics. the voiding phase findings of the patients were examined. results: the mean age of the patients was 47.85 ± 0.27 years. 18.4% of patients (n = 187) had voiding phase problems. furthermore, this condition was seen in the most urge incontinence type urinary incontinence (35%). there was a statistically significant difference between the groups' voiding phase findings (p < 0.0001). the relationship between the patient's history and international consultation on incontinence questionnaire form scoring (iciq) and the urodynamics results showed no excellent correlation. conclusions: voiding phase abnormalities are not uncommon in patients with urinary incontinence. they should be considered in the evaluation of patients. voiding phase findings may show significant differences between urodynamic data and history. besides, the data obtained with the questionnaire forms were significantly different from the findings obtained by urodynamics. consequently, urodynamics may change pre-operative clinical decision. key words: urinary incontinence; urodynamics; voiding. submitted 28 february 2021; accepted 14 june 2021 introduction urinary incontinence is a common health condition that can affect about 50% of adult women and decrease life quality (1). this condition increases with age. ten to twenty percent of women and up to 77% of women residing in nursing homes have urinary incontinence, yet only 25% attempt or receive treatment (2). in the evaluation of incontinence patients, the history alone may be insufficient to diagnose and classification. understanding lower urinary tract function and revealing the underlying pathophysiology is essential for the evaluin women with incontinence, the need for pressure-flow study before surgery and abnormalities in the voiding phase. an up-to-date comment on the available problem accompanied by literature kutluhan erdem, alper coşkun, fatih üstün, fatih tarhan department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul, turkey. doi: 10.4081/aiua.2021.4.441 summary archivio italiano di urologia e andrologia 2021; 93, 4 k. erdem, a.coşkun, f. üstün, f. tarhan 442 nence, involuntary and inhibited detrusor contractions as urge urinary incontinence and the presence of both findings as mixed urinary incontinence. at pfs, the inability of contraction at sufficient force or continuity resulting in prolonged or insufficient bladder discharge was considered underactive detrusor, qmax > 12 ml/sec and pdet qmax > 20 cm h2o was considered as boo. voiding characterized by an intermittent or staccato flow pattern due to involuntary and irregular pelvic floor contractions in neurologically healthful patients was evaluated as dysfunctional voiding (7, 8). the patients were grouped as stress, urge, and mixed type urinary incontinence. whether the voiding phase findings of the patients were normal or abnormal was checked. urodynamics was applied according to the international continence association (ics) (4). chi-square test was utilized to evaluate the results with prism 5.0 (graphpad, usa) program. p value < 0.05 was accepted as statistically significant. results the average age of the patients was 47.85 ± 0.27 years. of the patients, 442 (43%) were evaluated as stress-type, 334 (32%) as urge-type, and 242 (25%) as mixed-type incontinence (figure 1). urethral stricture was diagnosed in 6% (n = 11) of those with excretory phase problems, dysfunctional voiding in 51% (n = 96) and underactive detrusor in 43% (n = 80). urethral stricture and dysfunctional voiding and the rate of underactive detrusor were higher in patients with urge-type urinary incontinence. (47%) (table 1). another finding was lack of good correlation between history and urodynamic filling phase results (table 2). similarly, data from international consultation on incontinence questionnaire form (iciq) and findings from urodynamics are not fully concordant. there are considerable differences, especially in mixed urinary incontinence (table 3). discussion the bladder should be able to store urine at low pressure and at an appropriate volume, discharge the stored urine at once, and coordinate detrusor contraction and sphincter relaxation during voiding. the knowledge regarding the togetherness of urinary voiding dysfunctions in female patients with incontinence in the literature is unclear. in 18.4% (n = 187), we found that patients with incontinence also have voiding phase problems simultaneously. additionally urethral stricture was found in 6% (n = 11), dysfunctional voiding in 51% (n = 96), and underactive detrusor in 43% (n = 80) of these patients. we established that our outcomes were consistent with the literature (7). table 1. the voiding phase findings detected in the pfs. groups voiding phase findings (n) (%) stress urinary incontinence (n = 442) normal 403 91 urethral stricture 0 0 dysfunctional voiding 15 3 underactive detrusor 24 6 urge type urinary incontinence (n = 334) normal 216 65 uretral stricture 9 3 dysfunctional voiding 71 21 underactive detrusor 38 11 mixed type urinary incontinence (n = 242) normal 212 88 uretral stricture 2 1 dysfunctional voiding 10 4 underactive detrusor 18 7 pfs: pressure-flow study. table 2. comparison of anamnesis and filling phase findings. anamnesis filling phase (n) (%) sui (n = 148) sui (69) 47 uui (37) 25 mui (42) 28 uui (n = 120) sui (46) 38 uui (44) 37 mui (30) 25 mui (n = 750) sui (326) 43 uui (266) 35 mui (172) 22 sui: stress urinary incontinence; uui: urge urinary incontinence; mui: mixed urinary incontinence. table 3. comparison of iciq and filling phase findings. figure 1. incontinence types and percentages. anamnesis filling phase (n) (%) sui (n = 123 ) sui (60) 49 uui (31) 25 mui (32) 26 uui (n = 116) sui (50) 43 uui (40) 35 mui (26) 22 mui (n = 779) sui (325) 42 uui (271) 35 mui (183) 23 sui: stress urinary incontinence; uui: urge urinary incontinence; mui: mixed urinary incontinence; iciq: international consultation on incontinence questionnaire form. 443archivio italiano di urologia e andrologia 2021; 93, 4 pressure-flow study in women with incontinence if we come to underactive detrusor, we see that there are not enough studies and accepted objective criteria in female patients regarding underactive detrusor. the existing nomograms about underactive detrusor have been used to describe male voiding dysfunction (8). we defined that there were 7.9% (n = 80) underactive detrusor our patients. estimating the prevalence of boo in women with incontinence is problematic in light of the existing literature. a nomogram has been developed to diagnose boo in women. however, due to the disparities in the pathophysiology of voiding problems compared to men, it has not been widely accepted, especially among urologists interested in this topic. even so, it is possible to determine female bladder outlet obstruction with the support of pressure-flow studies and clinical symptoms simultaneously with video-urodynamics (8). it has been seen that even if in women with voiding difficulties and low urinary flow symptoms, the correlation between symptoms and urodynamics objective buo is low, and it is not easy to reach a diagnosis in this way (9, 10). another clinical entity that should be kept in mind is the possibility of the development of detrusor overactivity secondary to bladder outlet obstruction (7). as a matter of fact, in our study, the most common storage problem in patients with outflow obstruction was found to be urge type urinary incontinence. in addition, urethral stricture was found in 1.1% of the patients. although dysfunctional voiding is primarily diagnosed in the pediatric age group, it is one of the most common urinary voiding dysfunctions in women with lower urinary tract symptoms. in the literature, dysfunctional voiding was established in women with lower urinary tract symptoms and urodynamic examination with a rate of 9.6-12% (11, 12). similarly, we noticed dysfunctional voiding was at a rate of 9.4% in our study. it is a broad-spectrum non-neurogenic disorder involving dysfunction of the lower urinary tract and intestinal tract. also, it is one of the most common urinary voiding dysfunctions in women with lower urinary tract symptoms. we presented treatment options such as behavioral therapy (pelvic floor physiotherapy, biofeedback), medical therapy, cognitive therapy and sacral neuromodulation to patients who were diagnosed with this dysfunctional voiding. urodynamics after evaluation in the outpatient clinic changes the diagnosis by 57% and the choice of the treatment plan by 14%, and canalizes the surgical procedure (13-16). the best indicator for this is that 40% of overactive bladder patients are diverted for stress urinary surgery (8, 17). in another study, it has been indicated that the voiding phase is the most commonly used method to modify the surgical procedure in overactive bladder and intrinsic urinary sphincter deficiency (13). in our study, we found out that the diagnosis changed in 18.4% of patients after pfs. thus, we think that unnecessary surgery in 69/684 (10%) patients and inappropriate medical treatment in 47/334 (14%) patients with urinary incontinence have been prevented. limitations of our study are being a single-center study with retrospective design, lack of overactive bladder questionnaire (oabq) and iciq scoring in statistical data, no follow-up of the patients after surgery. another matter of criticism could be that evaluations were not made by a single physician. we also admit that our results do not support a new finding, but we believe that our study with a high number of patients may contribute to clarify the controversial topic of necessity to perform urodynamics before surgery. conclusions urodynamics can provide clinicians with detailed and useful information about lower urinary tract function that may affect medical and surgical decisions. we recommend performing pressure-flow studies together with cystometry not to overlook the diagnosis of possible urinary voiding dysfunction in female patients with incontinence undergoing urodynamic examination. we believe that supporting these data with multi-center and prospective studies will significantly contribute to the literature. references 1. minassian va, stewart wf, wood gc. urinary incontinence in women: variation in prevalence estimates and risk factors. obstet gynecol. 2008; 111:324-331. 2. tennstedt sl, link cl, steers wd, mckinlay jb. prevalence of and risk factors for urine leakage in a racially and ethnically diverse population of adults: the boston area community health (bach) survey. am j epidemiol. 2008; 167:390-399. 3. fletcher sg, lemack ge. clarifying the role of urodynamics in the preoperative evaluation of stress urinary incontinence. scientific world journal. 2008; 25:1259-1268. 4. glazener cm, lapitan mc. urodynamic studies for management of urinary incontinence in children and adults. cochrane database syst rev. 2012; 18: cd003195. 5. urinary incontinence: the management of urinary incontinence in women. nice clinical guideline 40. london, united kingdom: national institute for health and clinical excellence, 2006. 6. burkhard fc, bosch jlhr, cruz f, et al. eau urinary incontinence guidelines 2018 isbn 978-94-92671-07-3. 7. yenilmez a, turgut m, dönmez t, özyürek y. idrar kaçıran kadın hastalarda basınç-akım çalısmasının (baç) önemi. turk j urol. 2004; 30:451-456. 8. onyishi se, twiss co. pressure flow studies in men and women. urol clin north am. 2014; 41:453-67. 9. groutz a, blaivas jg, chaikin dc. bladder outlet obstruction in women: definition and characteristics. neurourol urodyn 2000; 19:213-220. 10. groutz a, gordon d, lessing jb, wolman i, jaffa a, david mp. prevalence and characteristics of voiding difficulties in women: are subjective symptoms substantiated by objective urodynamic data? urology. 1999; 54: 268-272. 11. carlson kv, fiske j, nitti vw. value of routine evaluation of the voiding phase when performing urodynamic testing in women with lower urinary tract symptoms. j urol. 2000; 164:1614-1618. 12. nitti vw, tu lm, gitlin j. diagnosing bladder outlet obstruction in women. j urol. 1999; 161:1535-1540 13. sirls lt, richter he, litman hj, et al. the effect of urodynamic testing on clinical diagnosis, treatment plan and outcomes in women archivio italiano di urologia e andrologia 2021; 93, 4 k. erdem, a.coşkun, f. üstün, f. tarhan 444 undergoing stress urinary incontinence surgery. j urol. 2013; 189: 204-209. 14. adelowo a, dessie s, rosenblatt l. the role of preoperative urodynamics in urogynecologic procedures. j minim invasive gynecol. 2014; 21:217-222. 15. serati m, cattoni e, siesto g, et al. urodynamic evaluation: can it prevent the need for surgical intervention in women with apparent pure stress urinary incontinence? bju int. 2013; 112:344-350. 16. rachaneni s, latthe p. does preoperative urodynamics improve outcomes for women undergoing surgery for stress urinary incontinence? a systematic review and meta-analysis. bjog. 2015; 122:816. 17. van leijsen sal, hoogstad-van evert js, j mol bw, et al. the correlation between clinical and urodynamic diagnosis in classifying the type of urinary incontinence in women. a systematic review of the literature. neurourol urodyn. 2011; 30:495-502. correspondence kutluhan erdem, md kutluhan1988@gmail.com alper coşkun, md dr.alper05@gmail.com fatih üstün, md drfatihustun@gmail.com fatih tarhan, md tarhanf@yahoo.com department of urology, university of health sciences, kartal dr. lutfi kırdar city hospital, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2178 original paper no conflict of interest declared. introduction urolithiasis is a very common disease that can affect all age groups and is seen in 1-13% of the general population depending on regional differences (1, 2). obstructing impacted ureteric stones require removal on time to decompress the upper urinary tract and to avoid possible renal functional, morphological alterations which may be irreversible in some cases (3, 4). depending on the departmental principles and surgeons preference, drainage of renal collecting system obstructed by such stones could be performed by placement of either a percutaneous nephrostomy tube or an indwelling ureteric stent. both approaches are being accepted as equally effective by the eau guidelines (5). although randomized controlled studies could not demonstrate any significant difference between these two techniques, most urologists tend to insert a stent with this aim (6-8). ureteral stenting is a commonly performed procedure to drain the collecting system particularly in cases with impacted stones in whom the spontaneous stone passage is less likely and the conservative medical management is ineffective. additionally this approach is mandatory when evident hydronephrosis and infective symptoms are present (9-13). however, highly limited data is available regarding the course of renal functional and morphological recovery after stenting on a time dependant manner. additionally no commonly accepted or established consensus is available regarding the optimal indwelling time of a ureteral stent in these cases. to our knowledge our study is the first evaluating the course of functional and morphological recovery following jj stenting on a time dependant manner in cases with obstructive impacted ureteral calculi. among the markers of renal damage, as a type-1 transmembrane protein, urinary kidney injury molecule-1 (kim1) is not normally present in urine and its excretion has been found to increase as a valuable indicator of kidney injury along with histopathological changes in the proximal tubule in response to many pathophysiological states including obstruction. again neutrophil gelatinase-associated lipocalin (ngal), an iron-transporting protein was found to accumulate in urine rapidly after nephrotoxic and ischemic insults. it was used as an early, sensitive biomarker for objectives: to assess the course of functional and morphological recovery of the kidney following the relief of obstruction with ureteral jj stent in cases with unilateral impacted stones. materials and methods: a total of 42 adult patients who were admitted to our clinic with unilateral obstructing impacted ureteral stones requiring jj stent placement were included in the study. the course of functional recovery was assessed by evaluating the serum creatinine levels, renal resistive index (rri) values and urinary levels of kidney injury molecule-1, neutrophil gelatinaseassociated lipocalin as well as microalbumin before at 1 day, 1 week and 4 weeks after jj stent placement. course of morphologic recovery was evaluated by evaluating the degree of hydronephrosis, kidney size, perirenal straining and ureteral diameter. results: our results showed that all relevant parameters began to decrease after 24 hours and continue to normalize during 1 week evaluation; majority of these variables indicating the functional and morphological recovery were in normal range after 4 weeks. decompression of the obstructed kidneys with jj stent placement in patients with impacted ureteral stones was found to be effective enough with recovery of normal renal functional and morphological status after a minimum time period of 4 weeks. morphological recovery of affected kidneys following jj stenting was obtained with a significant difference between baseline and 1-month evaluation findings (p = 0.001, p < 001, p < 001, respectively). kim-1 excretion began to decline to normal levels after 4 weeks (3.52 ± 0.99 ng/ml versus 2.84 ± 0.66 ng/ml, p < 0.001). the same findings were observed for the urinary excretion levels of ngal, which normalized at the 1-month evaluation (604.55 ± 140.28 ng/ml versus 596.87 ± 80.17 ng/ml p = 0.895). urinary microalbumin excretion levels however remained high even until 1-month follow-up with a statistically significant difference when compared with the normal excretion values (p < 0.001). there was a statistically significant difference in rri values between baseline and 1-month follow-up findings in obstructed kidney (p < 0.001). conclusions: elective management of the obstructing impacted ureteral stone(s) will be safer with limited risk of infective complications after functional and morphological normalization in such kidneys following 4 weeks of jj stent placement. key words: impacted ureteral stones; renal function; morphology; jj stent; obstruction. submitted 21 april 2021; accepted 2 may 2021 time dependant functional and morphological recovery of the kidney after relief of obstruction in patients with impacted ureteral stones hüseyin kocatürk 1, fevzi bedir 1, ömer turangezli 1, engin şebin 2, mehmet sefa altay 1, banu bedir 3, kemal sarica 4 1 department of urology health sciences university, erzurum regional training and research hospital, erzurum, turkey; 2 department of biochemistry health sciences university, erzurum regional training and research hospital, erzurum, turkey; 3 aziziye district health directorate, erzurum, turkey; 4 biruni university, faculty of medicine, department of urology, istanbul, turkey. doi: 10.4081/aiua.2021.2.178 summary 179archivio italiano di urologia e andrologia 2021; 93, 2 recovery course of the obstructed kidney acute kidney injury (14-16). lastly, by providing information about the changes in microvascular blood flow, renal parenchymal doppler sonographic evaluation of the vascular impedance renal resistivity index (rri) may be helpful in the asssessment of the functional or structural changes caused by acute and chronic obstructive renal diseases (1719). we aimed to evaluate the time dependant functional and morphological recovery of obstructed kidneys after jj stenting in cases with impacted ureteral stones. optimal time period for stenting to achieve a complete renal recovery following obstruction relief was also evaluated. materials and methods study design and participants this prospective study was conducted in line with the ethical standards specified by the declaration of helsinki and following receipt of local ethical committee approval (2019/14-132). informed consent was obtained from all individual participants included in the study. the data derived from 42 adult patients with a single impacted unilateral obstructing ureteral stone requiring jj stent placement were evaluated in a prospective manner. patients with bilateral, multiple stones, previous stone-related procedures, pregnancy, active urinary infection, renal tumour, congenital anomalies, solitary kidneys and a treatment of nephrotoxic drugs were excluded. following the management of colic pain, in 42 cases with impacted ureteric stones obstruction has been decompressed by indwelling ureteral stenting. in addition to a non-contrast computed tomography (ncct), plain x-ray of the kidney and urinary ultrasonography were also done to assess the degree of hydroneprosis and follow-up of the cases. degree of hydronephrosis was graded as mild, moderate and severe. kidney dimensions and the density (hu), size, side, localization of the stone and the diameter of the ureter above the stone were recorded. patients with impacted obstructing ureteric stones with evident hydronephrosis were treated with a double j stent placement for an effective decompression and to evluate the functional as well as morphological changes on a time based manner. following the stenting, the degree of hydronephrosis, perirenal staining and upper ureteral diameter were outlined on ct images and urinary ultrasonography to evaluate the course of morphologic recovery; the value of rri assessed on doppler sonography, urinary kim-1, ngal and urinary microalbumin levels were measured for functional recovery before, 1 day, 1 week and 4 weeks after jj stent placement. collection of urine specimens midflow urine samples of the patients were obtained before, 1 day, 1 week and 1 month after the procedure. urine (10 ml) was collected in plastic tubes, without any specific preservative. the urine samples obtained from all cases were centrifuged at 2000-3000 rpm for 20 min at + 4°c. the supernatant urine samples were transferred to eppendorf tubes. the samples were kept in a deep freezer system at -80°c until analysis. measurement of ngal and kim-1 in the urine the urinary ngal and kim-1 levels were measured with enzyme-linked immunosorbent assay (elisa) method by using the human ngal elisa kit (sunred biological technology co., ltd, shanghai, china, cat. no: 201-12-1720) and the human kim-1 elisa kit (sunred biological technology co., ltd, shanghai, china, cat. no: 201-12-1100) in accordance with the manufacturer’s instructions. the analysis was performed with a chemwell® automated eia and chemistry analyzer device (awareness technology, inc.; miami, usa). each sample was measured in duplicate and the obtained values were expressed as ng/ml. measurement of blood urea nitrogen (bun), creatinine and urinary microalbumin bun, creatinine and urinary microalbumin were measured using abbott kits on architectc16000 (abbott diagnostics, illinois, usa) device. statistical analysis recruitment and evaluation of the research data in this study was done by using statistical package fort the social science (spss) v24 for windows program. categorical variables were expressed with numbers and percentages; values, numerical variables were expressed with mean and standard deviation values. the consistency of the numerical variables to the analysis was searched by using kolmogorov smirnov test. mann-whitney u and chisquare tests were used in the evaluation of the obtained data, friedman test was used in the comparison of the repeatedly assessed parameters without normal distribution, and lastly wilcoxon signed rank test and bonferoni correction were used for the comparison of the parameters within the group. statistically significance value has been accepted to be p < 0.05. results in the group of 42 adult patients (> 18 years, m/f 3.6), mean age was 41.86 ± 13.61 (23-67) years, mean stone size was 10.16 ± 1.99 (7-14) mm. the overall mean body mass index (bmi) of these cases was 25.35 ± 2.74 (19.229.4) kg/m2. majority of the stones (40.5%) was located in the upper ureter. patient demographics along with stone related parameters are given in table 1. table 1. patients' demographic features and stone characteristics. mean ± sd/n (%) median (min-max) age 41.86 ± 13.61 41 (23-67) gender male 33 (78.6) female 9 (21.4) bmi ( kg/m2) 25.35 ± 2.74 25.60 (19.20-29.40) stone side right 22 (52.4) left 20 (47.6) stone size (mm) 10.16 ± 1.99 9.95 (7-14) stone localization lower 16 (38.1) mid 9 (21.4) upper 17 (40.5) stone density (hu) 649.60 ± 207.66 626.50 (336-1016) bmi = body mass index, hu = hounsfield units. archivio italiano di urologia e andrologia 2021; 93, 2 h. kocatürk, f. bedir, ö. turangezli, e. şebin, m. sefa altay, b. bedir, k. sarica 180 morphologic recovery of the affected kidneys following jj stent insertion comparative evaluation of the baseline renal diameters of the affected kidneys with normal values revealed a statistically significant difference before and during early phase of the follow-up period (p = 0.002, p < 0.001, p < 0.001, respectively). evaluation of values in the obstructed kidneys showed that while there was an insignificant difference between 1 day and 1 week evaluation (p = 0.637), a significant difference was noted between baseline and 1-month evaluation findings (p = 0.001, p < 001, p < 001, respectively). these findings emphasized the necessity of keeping jj stent in place for at least a period of 4 weeks particularly in severely obstructed kidneys to catch the values of normal kidneys (108.92 ± 8.15 mm vs 109.92 ± 7.94 mm) (p = 0.566). evaluation of the mean ureteral diameter above the impacted stone site showed a significant decrease (p < 0.001) which came down to the normal size of a ureter after 4 weeks. assessment of the hydronephrosis level in our cases revealed that while majority of the kidneys had a moderate or severe hydronephrosis (31% and 69%) prior to stenting; there was no or mild hydronehrosis detected during 1month follow-up evaluation. detection of moderate hydronephrosis in a certain percent of these cases still during both 1 day (38.1%) and 7 day (2.4%) follow-up again showed the importance of keeping the stent in place for at least a month period. similarly, the disappearance of perirenal staining (moderate to severe changes) required 4-weeks in obstructed kidneys. morphological changes and related values in the obstructed kidneys are given on a time dependant manner in tables 2, 3. evaluation of the functional recovery in obstructed kidney after jj stent insertion serum creatinine levels decreased significantly following jj stent insertion after 7 days (p < 0.001) and came down to normal levels at 1-month follow up (0.85 ± 0.15 mg/dl vs 0.83 ± 0.12 respectively). additionally as demonstrated in table 4, baseline urinary kim-1 excretion continued to increase until the end of the first week after jj stent insertion, and it returned to normal table 3. evaluation of the presence and degree of hydronephrosis and perirenal staining in study group cases. no % (n) mild % (n) moderate % (n) advenced % (n) hydronephrosis pre-op 31.0% (13) 69.0% (29) post-op (first day) 2.4% (1) 59.5% (25) 38.1% (16) post-op (first week) 9.5% (4) 88.1% (37) 2.4% (1) post-op (first month) 57.1% (24) 42.9% (18) perirenal staining pre-op 9.6% (4) 19.0% (8) 23.8% (10) 47.6% (20) post-op (first day) 11.9% (5) 21.4% (9) 28.6% (12) 38.1% (16) post-op (first week) 16.7% (7) 54.7% (23) 26.2% (11) 2.4% (1) post-op (first month) 81.0% (34) 19.0% (8) table 2. kidney morphological parameters and resistivity index values. pre-op post-op (first day) post-op (first week) post-op (first month) p mean ± sd (min-max) mean ± sd (min-max) mean ± sd (min-max) mean ± sd (min-max) normal contralateral kidney ri 0.58 ± 0.03 0.58 ± 0.03 0.58 ± 0.02 0.57 ± 0.01 p = 0.407* (0.52-0.67) (0.54-0.67) (0.53-0.64) (0.54-0.62) obstructive kidney ri 0.74 ± 0.04 0.62 ± 0.02 0.59 ± 0.02 0.58 ± 0.02 p < 0.001* (0.66-0.83) (0.54-0.73) (0.53-0.64) (0.55-0.63) normal contralateral kidney size (mm) long diameter 108.92 ± 8.15 90-128 transverse diamater 52.66 ± 4.64 44-62 parenchymal thickness 25.95 ± 3.61 19-32 obstructive kidney size (mm) long diameter 111.69 ± 9.51 110.73 ± 8.59 110.54 ± 8.15 109.92 ± 7.94 p = 0.002a 92-133 93-130 92-127 93-126 p = 0.001b p = 0.009c transverse diamater 62.0 ± 6.27 58.71 ± 5.71 56.69 ± 5.31 54.78 ± 4.77 p < 0.001a 48-72 46-69 45-68 45-65 p < 0.001b p < 0.001c parenchymal thickness 31.57 ± 5.57 28.85 ± 4.43 28.33 ± 5.07 27.26 ± 4.99 p < 0.001a 21-43 20-39 20-48 20-46 p < 0.001b p = 0.002c ureter diameter (mm) 18.35 ± 2.95 5.92 ± 1.14 p < 0.001 (12.90-24.10) (3.90-8.20) ri = resistivity index, p = level of significance, sd = standard deviation, * = statistical difference between each other in the pre and post-operative periods, a = it shows the statistical difference between the averages of preop and postoperative day 1 of obstructive kidney size, b = it shows the statistical difference between the averages of preop and postoperative day 7 of obstructive kidney size, c = it shows the statistical difference between obstructive kidney size on postop 7 day and averages of postop 1 month kidney size. 181archivio italiano di urologia e andrologia 2021; 93, 2 recovery course of the obstructed kidney levels after 4 weeks (3.52 ± 0.99 ng/ml vs 2.84 ± 0.66 ng/ml, p < 0.001). the same findings were observed for the urinary excretion levels of ngal which normalized at 1-month evaluation (604.55 ± 140.28 ng/ml vs 596.87 ± 80.17 ng/ml, p = 0.895) following a significant initial elevation. evaluation of these two parameters demonstrated that the functional normalization of the obstructed kidney occurs after at least 4 weeks later following stenting. urinary microalbumin excretion levels however remained high even until 1-month follow-up with respect to normal excretion values (table 4). lastly, while the assessment of rri values of in normal contralateral kidneys didn’t show any significant difference during follow-up (p = 0.407), there was a statistically significant difference between baseline and 1month follow-up findings in obstructive kidney (p < 0.001) which came down to the levels of normal levels after 4 weeks (table 2). discussion unilateral ureteral obstruction due to an impacted calculi is a common emergency status requiring a quick drainage of the upper urinary tract to avoid possible detrimental alterations in the kidney. renal interstitial fibrosis is the characteristic pathological manifestation in such kidneys which is directly related to the level of obstruction and renal functional impairment (15, 20). rational approach in such cases is the quick relief of obstruction by insertion of either a nephrostomy tube or an indwelling double j ureteral stent before making an elective treatment plan. although placement of a nephrostomy tube directly into the dilated collecting system is considered to be a more effective and rapid drainage method, this approach is more invasive and not indicated particularly in cases under anticoagulant medication. thus, majority of the urologists conisder placing a double j stent as a safe and efficient way of decompression (21, 22). however, although limited, randomized comparative studies demonstrated that the efficacy of both approaches is equally acceptable (6, 7, 21-24). effective decompression of the obstructed kidney by stenting will result in morphological and functional normalization prior to a planned stone removal procedure which will certainly increase the success rates and limit the possible infectious complications. despite the effectiveness of the use of jj stents with this aim is accepted, the optimal time duration of stenting for an adequate drainage has not been clearly outlined. no evidence based and commonly accepted time period has been reported for keeping the stents in place to obtain the complete normalized status of the kidneys. most urologists tend remove stents after 1-2 weeks simply by checking the degree of dilatation of the upper urinary tract (25-27). current eau and aua guidelines contain no definite information for the optimal duration of stenting in such cases and practice patterns vary dramatically from 1 week to 3 months depending on the personal experience and also departmental principles (5, 9). moreover, no particular clinical trial had been performed so far to outline the course of clinical recovery in these kidneys after stent placement where the urologists tend to remove the stents without having any idea about the functional and morphological status of the kidneys. shigemura et al. evaluated the infection related morbidity induced by jj stents concluding that stents staying up to 2 weeks period have less risk of relevant problems (13). in another study evaluating the calcification risk on stent surface, kawahara et al. found that stents kept in place for more than 3 months are associated with higher risk of calcification. similar studies emphasized the relationship between time of stenting and encrustation risk of the stents (28, 29). among functional biomarkers of kidney, kim-1 is a transmembrane protein that is undetectable in urine of the healthy cases, but its increased expression was found to be correlated with ischemic and nephrotoxic kidney injury. additionally, its levels has been found to increase as a result of parenchymal damage induced by urinary obstruction (14-16). on the other hand, another reliable biomarker is ngal, a 25-kda protein that is secreted by proximal tubular cells. published data demonstrated that ngal could also be used as one of the most reliable markers in the assessment of kidney injury after ischemic or nephrotoxic states among which urinary obstruction table 4. evaluation of the urinary kim-1, ngal, microalbumin and serum bun, creatinine levels. kim-1 ngal urinary micro-albumin bun creatinine levels ng/ml levels ng/ml levels ng/ml levels levelsl pre-op 2.50 ± 0.57 596.88 ± 92.31 83.59 ± 89.10 33.47 ± 14.43 1.08 ± 0.29 mean ± sd (min-max) (1.22-3.51) (362.90-781.56) (5.0-407.0) (9.20-67.70) (0.57-1.89) post-op (first day) 3.52 ± 0.99 761.16 ± 137.85 435.54 ± 94.30 24.33 ± 8.11 0.92 ± 0.21 mean ± sd (min-max) (2.11-6.15) (483.80-1164.78) (167.0-500.0) (13.0-47.20) (0.60-1.70) post-op (first week) 3.34 ± 0.81 686.54 ± 106.10 316.19 ± 142.33 20.66 ± 6.97 0.85 ± 0.15 mean ± sd (min-max) (1.94-5.69) (426.87-877.73) (62.0-500.0) (11.0-36.0) (0.59-1.38) post-op (first month) 2.84 ± 0.66 604.55 ± 140.28 159.66 ± 112.66 20.91 ± 8.11 0.83 ± 0.12 mean ± sd (min-max) (1.56-4.46) (333.29-959.15) (23.0-452.0) (10.0-38.0) (0.61-1.08) p1 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p2 p < 0.001 p < 0.001 p < 0.001 p = 0.979 p = 0.769 kim-1 = kidney injury molecule-1, ngal = neutrophil gelatinase associated lipocalin, sd = standard deviation, p = level of significance. 1difference with before treatment; 2difference between 7 days and 1 month after the operation. archivio italiano di urologia e andrologia 2021; 93, 2 h. kocatürk, f. bedir, ö. turangezli, e. şebin, m. sefa altay, b. bedir, k. sarica 182 is the most common (16). lastly, doppler sonographic evaluation of the vascular impedance in the renal parenchyma was used be to evaluate the functional or structural changes induced by acute and chronic obstructive renal diseases (17-19). in our study, jj stent placement provided an effective decompression of the upper urinary tract in obstructed kidneys with adequate functional and morphological recovery after 4-weeks. although most of the parameters began to decrease after 24 hours and continue to decrease at 1 week evaluation, the majority of these variables returned to normal range after 4 weeks period. in other words, keeping the stent in place for a minimum duration of 4 weeks (if there is no other indication for removal) seems to be important for the functional and anatomical recovery of the affected kidneys. our findings constitute reliable and objective data regarding the optimal duration of stenting in cases with obstruction induced by impacted ureteral calculi. early removal of the stent without complete elimination of the obstructive alterations will leave the kidney with residual functional deterioration and dilatation. this condition may compromise the outcomes of a planned elective surgery performed for the removal of obstructing ureteral stone(s). additionally as such approaches, namely shock wave lithotripy and ureteroscopy, have possible detrimental effects on the kidneys due to either direct tissue damaging effects or to the elevated intrarenal pressures, residual dilation and functional deterioration in such kidneys will make them more prone to infective complications which will be a main problem during postoperative follow-up period. conclusions impacted ureteral stones will cause obstruction associated changes in functioning kidneys and quick drainage by stenting is highly effective to limit the chance of such detrimental alterations. our results indicated that decompression of the obstructed system will let these kidneys to obtain normal functional and morphological status after a mimimum time period of 4 weeks limiting the risk of infective complications after elective treatment. however, we believe that further studies 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urology. 2014; 83:278-281. 28. kawahara t, ito h, terao h, et al. ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. j endourol. 2012; 26:178-82. 29. kadihasanoglu m, kilciler m, atahan o. luminal obstruction of double j stents due to encrustation depends on indwelling time: a pilot study. aktuel urol. 2017; 48: 248-251. correspondence hüseyin kocatürk, md (corresponding author) kocaturk78@hotmail.com fevzi bedir, md fevzibedir84@gmail.com ömer turangezli, md omerturangezli@gmail.com mehmet sefa altay, md memsefaaltay@gmail.com department of urology, health sciences university erzurum regional training and research hospital, 25070 palandöken/erzurum (turkey) engin şebin, md sebinengin@gmail.com department of biochemistry, health sciences university erzurum regional training and research hospital, 25070 palandöken/erzurum (turkey) banu bedir, md banubedir89@gmail.com aziziye district health directorate, erzurum (turkey) kemal sarica, md saricakemal@gmail.com biruni university, faculty of medicine, department of urology, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12231 1 original paper introduction the single-pigtail stent, was first introduced to the medical community by hepperlen and mardis. this innovative stent design revolutionized the field by providing a reliable and effective solution for various urological conditions (1-3). on the other hand, the double-j® stent, manufactured by american cystoscope makers located in southborough, ma, was initially described by finney (1-3). this particular stent design has gained significant recognition and widespread use. over the years, significant advancements have been made in the field of catheter technology, leading to notable improvements in both the location and design of these medical devices (4-6). these advancements have played a crucial role in enhancing patient care and overall medical outcomes. one area that has witnessed remarkable progress is the location of catheters. in the past, catheters were often placed using conventional techniques that relied heavily on the expertise of healthcare professionals. in a comprehensive study conducted by joshi et al., it was observed that a staggering 80% of individuals who had double-j stent insertion experienced the manifestation of at least one undesirable symptom related to the urinary tract (7). this finding sheds light on the significant impact that double-j stents can have on the overall health and quality of life of affected patients. in recent years, there has been a growing interest in the field of medicine regarding the potential benefits of various pharmaceutical treatments to prevent or minimize the stent related symptoms. the primary objective of this investigation is to establish a correlation between the symptoms associated with stents and the physical attributes of the ureteral stent, namely its width and length. additionally, we aim to examine the potential relationship between these symptoms and the patient's biometric measurements, including height, weight, and body mass index (bmi). materials and methods design of the study this is a prospective, single center study. the collection of data was performed in patients, where ureteral stents (pigtails) were inserted in a tertiary urology hospital from september 2021 to september 2023. the study was background: in urology, ureteral stents are used to treat obstructive diseases. hematuria (54%), fever, discomfort, and lower urinary system symptoms are the predominant symptoms related to ureteral stent. aim: this article links stent symptoms to double-j width and length, as well as patient’s height, weight, and body mass index (bmi). ureteric stent symptoms questionnaire (ussq) was used to measure ureteral stent symptoms at 1st and 4th week of stent in situ as well as the 4th week after pigtail removal. methods: a 200-patient prospective study, where patients were allocated into four groups following ureteral stent insertion depending on the stent characteristics. those groups were: 4.8 fr./26 cm (group a), 4.8 fr./28 cm (group b), 6 fr/26 cm (group c), and 6 fr/28 cm (group d). results: men comprised 53.5% of 200 patients. participants had an average age of 49 ± 15.5 years, height of 175 ± 8.94 cm, and bmi of 23.8 ± 7.6 cm. the laboratory results were identical between groups. at the first and fourth week, groups had similar urine symptoms, pain severity, health status and occupational activities. the difference in pain location was statistically significant. group a had 82.4% renal back pain in the first week, whereas group b had 68.8%, group c 31.3% and group d 62.5 (p = 0.04). at the fourth week, 64.7% of group a patients reported kidney front pain, compared to 100% of group b, 93.3% of group c, and 100% of group d (p = 0.04). there was statistical significance in the sexual activity of the patients. 24.4% of group c patients stopped sexual activity before stent installation, compared to 10.6%, 8.3%, and 6.4% of the other groups (p = 0.03). a moderate percentage of patients had active sexual activity at week 4 (group a: 7.8%, group b: 5.8%, group c: 8.2%, group d: 4.1%), p = 0.83. in multivariate analysis, urinary catheter group, age, weight, height, and bmi did not significantly affect urine index score (uis), pain index score (pis), general health (gh), quality of work (qw), and quality of sex (qs). conclusions: despite various attempts to establish the best ureteral stent, the effect of double-j stent physical features on stent-related symptoms remained unknown. no verdict is conceivable without adequate empirical data. key words: ureteral stents; pigtails; urinary symptoms; hematuria; pain; ussq; pigtail characteristics; pigtail diameter; pigtail length; double-j stent; ureteral stent. submitted 25 december 2023; accepted 29 december 2023 ureteral stent related symptoms: a comparative study themistoklis ch. bellos 1, ioannis s. manolitsis 1, stamatios n. katsimperis 1, panagiotis a. angelopoulos 1, sotirios g. kapsalos-dedes 1, panagiotis k. deligiannis 1, lazaros i. tzelves 2, nikolaos a. kostakopoulos 2, iraklis c. mitsogiannis 1, ioannis m. varkarakis 1, athanasios g. papatsoris 1, andreas a. skolarikos 1, charalampos n. deliveliotis 1 1 2nd department of urology, sismanoglio general hospital of athens, athens, greece; 2 1st department of urology, metropolitan general, cholargos, greece. doi: 10.4081/aiua.2024.12231 summary archivio italiano di urologia e andrologia 2024; 96(1):12231 t.ch. bellos, i.s. manolitsis, s.n. katsimperis, et al. 2 approved by the institutional review board of the hospital (protocol number:6014/22.3.22). the study is registered to clinicaltrials.gov with id:14778, clinical trials id: nct05598710. each double-j stent size that was inserted to each patient depended on the material availability and the surgeon’s preference at the time of surgery. intraoperatively the double-j stent was inserted by the standard way with the use of fluoroscopy. postoperatively the correct position inside the kidney and the bladder was assessed by kub x-ray. correct position was considered the pelvis of the kidney and the lower end of the double-j stent inside the bladder not crossing to the contralateral side. for each patient the following data were recorded: i. demographic and anthropometric data: age (in years), sex (male, female), height (in cm), weight (in kg), body mass index (bmi, in kg/m2). the patients according to bmi were categorized according to centers for disease control (cdc) in: normal weight (bmi 18.5-24.9 kg/m2), overweight (bmi 25-29 kg/m2) and obese patients (bmi ≥ 30 kg/m2) (8). ii. clinical characteristics: reason for stent insertion (urolithiasis or pelviureteral junction stenosis), stone size, stone location, length of hospital stay (length of stay, los) in days, temperature measurement (appearance of fever postoperatively and the duration of fever), bloodwork pre-operatively, immediately postoperatively and during exiting the hospital (urea-u, creatinine-cr, white blood cells-wbc, c-reactive protein). the change of those values was calculated as 1) the difference between the post-operative and pre-operative values 2) the difference between the values at hospital exit and the pre-operative values. iii. ureteral stent characteristics: length (cm) (26 or 28) and width (fr) (4.8, sometimes referred to as 5 in the text, and 6). in this particular study, there were four groups of patients with different ureteral stents: group a: 4.8fr, 26 cm, group b: 4.8fr, 28 cm, group c: 6 fr, 26 cm, group d: 6 fr, 28 cm. iv. ureteric stent symptoms questionnaire (ussq) (7) was completed at the first week (t1: end of the first week) and at four weeks (t2: end of fourth week) after stent placement but also at 4 weeks after removing the ureteral stent (t3: end of fourth week after double-j stent removal). ussq is a questionnaire with 6 groups of questions: – 1st group of questions: 11 questions in likert scale about urinary symptoms. by adding the results of those questions, we get the urinary index score (uis) which ranges from 11 to 56. higher values of uis, suggest higher severity of urinary symptoms. uis is presented. – 2nd group of questions: questions regarding the body pain that the patient perceives. the p1 question is about if the patient experiences pain (yes/no), p2 question is about the body sites where the patient perceives pain (i: kidney front, ii: groin area, iii: bladder area, iv: kidney back). consequently by adding the results of the questions p3-p9, we get the pain index score (pis). the proportion of the patients that report pain in a particular body region as well as the pis are reported. – 3rd group of questions: they are 6 questions with answers in likert scale, about the general health and physical activity. by adding the results from those questions, we get the general health index score (ghis), which ranges from 4 to 28. higher ghis values, suggest higher general health burden due to the placement of ureteral stent. ghis is presented. – 4th group of questions: 7 questions about professional life. the first (question w1) is about professional status, the second (question w2) and third (question w3) is about the days that the patient was bed-ridden (w2) and did not perform his usual daily activities (w3), after the placement or removal of ureteral stent (depending on when the questionnaire was filled). the fourth question is about the kind of professional occupation, and the rest of the questions were answered only by those that were currently working and are about the quality of their work with questions in likert scale. from adding the answers in questions w5-w7, we get the quality of work score (qws), which ranges from 3 to 15. by adding the qws and the answers to the questions w2, w3, we get the work performance score (wps). the days of being bedridden, the half days of loss of activity, the qws and wps are presented. – 5th group of questions: it is about 3 questions (s1, s2i and s2ii or s3 and s4, the patients were asked to answer the questions s2i and s2ii or s3 and s4 depending on the answer they gave on the question s1 about sexual life). the percentage of patients that did not have active sexual life (s1), either due to stent placement or due to lack of effort on their behalf (s2i, s2ii) is presented. additionally, by adding the values from the answered questions s3, s4, we get the œ (qss). – 6th group of questions: it is about questions regarding additional problems that emerge while the ureteral stent is in place (in situ). the results from the answered questions a1-a4 are presented as the percentage of patients that mention each particular problem and/or the frequency of the particular problem occurrence. – 7th question: it is the “global quality of life” for the time period that the stent was in situ. the answer to the question gq is presented. inclusion criteria in this particular prospective observational study, only patients aged over 18 years old who had double-j stent placement were included. the material of the double-j stent was percuflex. this particular material was selected due to its availability in our hospital. the double-j stents placed were of the following sizes: 4.8fr26cm, 4.8fr28cm, 6fr26cm and 6fr28cm. the choice of the size for each particular case depended on the double-j stent availability at the time of the operation as well as on the surgeon’s preference. all the participants signed an informed consent form. the patients should have an adequate knowledge of the english language so they would be able to fill the ussq. exclusion criteria patients with hydronephrosis due to malignant diseases were excluded from this trial. outcome of interest the purpose of this trial is to investigate the relationship between the double-j stent’s characteristics and the appearance of complications from double-j stent use, as defined by «ureteric stent symptoms questionnaire» archivio italiano di urologia e andrologia 2024; 96(1):12231 3 ureteral stent related symptoms statistical analysis the statistical analysis was performed according to protocol (per protocol analysis), for all the patients that were included in the prospective observational study. the level of statistical importance was set to 0.05 and all pvalues were two-tailed. the description of the results of the quantitative variables was performed with the presentation of mean values and standard deviations. the description of the results of the qualitative variables was performed with the use of frequency and percentages. because the sample was 200 patients (n > 50), the test used for normality was the kolmogorov-smirnov test. pearson chi-square test was used to compare qualitative variables, and anova was used to compare continuous quantitative variables. spss software was used for statistical analysis. results in total, during the period 01.09.2021-01.09.2023, bspercuflex double-j stents were placed in 500 patients at our tertiary urology clinic. of these, 300 were excluded and were not included in the statistical analysis because the double-j stents were placed in those patients in order to relieve obstruction due to oncological causes. the statistical analysis according to the protocol was performed on the data of 200 patients who met all the inclusion criteria. basal patients’ characteristics the baseline characteristics of the patients are presented in table 1. a total of 200 patients were enrolled in the study of which 53.5% were male. their mean age was 49 ± 15.5 years and mean height and bmi, 175 ± 8.94 cm and 23.8 ± 7.6 cm respectively. in the majority (97%) the reason for ureteral stent placement was the presence of a stone in the ureter, either left (57.5%) or right (42.5%) with a mean size of 12.5 ± 3.7 mm. table 2 shows the baseline characteristics of the patients and data on urological interventions in the 4 study groups. regarding anthropometric characteristics, there were statistically significant differences between the 4 groups in terms of weight (p < 0.001) and height (p < 0.001). group b and d were composed of patients of greater weight and height, compared to the other two groups (figure 1). the sample was homogeneous in terms of the presence of comorbidities, the characteristics (diameter, material) of the foley urinary catheter used and the reason for ureteral stent placement. in all groups, ureteral stents were placed mainly due to the presence of a stone (96.1-100%) with no statistically significant differences in size, stone location and duration of the procedure between the 4 groups. regarding the laboratory findings of the patients in the 4 table 1. basal patient characteristics. mean (sd) n (%) sex male 107 (53.5) female 93 (46.5) age (years) 49 (15.5) weight (kg) 79.84 (12.5) height (cm) 175 (8.94) bmi (kg/m2) 23.8 (7.6) reason for stent insertion stone 194 (97) stenosis 6 (3) stone size (mm) 12.5 (3.7) stone or stenosis location left 115 (57.5) right 85 (42.5) bmi: body mass index; sd: standard deviation. table 2. basic characteristics of patients and interventions by group. group a group b group c group d p (n = 51, 25.5%) (n = 51, 25.5%) (n = 49, 24.5%) (n = 49, 24.5%) (95% ci) mean ± sd mean ± sd mean ± sd mean ± sd sex, n (%) male 31 25 24 27 0.58 ++ female 20 26 25 22 age (years) 51.7 ± 14 47.4 ± 15.8 49.5 ± 15.7 47.4 ± 16.5 0.14 + weight (kg) 72.3 ± 9.6 88.6 ± 13 73.1 ± 8.1 85.4 ± 9.6 < 0.001 + height (cm) 169 ± 4.6 183 ± 8.4 168.7 ± 4 181.4 ± 6 < 0.001 + bmi (kg/m2) 22.3 ± 9 24.6 ± 7.6 23.6 ± 7.9 25 ± 5.7 0.19 + hypertension 9 (17.6) 3 (5.8) 8 (16.3) 9 (18.4) 0.24 ++ diabetes mellitus 2 (3.9) 1 (1.9) 1 (2) 0 (0) 0.58 ++ coronary heart disease 5 (9.8) 2 (3.9) 4 (8.2) 0 (0) 0.13 ++ prostate hyperplasia 5 (9.8) 1 (1.9) 2 (4.1) 5 (10.2) 0.24 ++ foley diameter (fr.) 14 2 (3.9) 0 (0) 0 (0) 1 (2) 0.450 ++ 16 36 (70.6) 34 (66.6) 29 (59.2) 32 (65.3) 18 13 (25.5) 17 (33.3) 20 (40.8) 16 (32.7) latex 32 (62.7) 28 (54.9) 38 (77.5) 35 (71.4) 0.08 ++ silicone 19 (37.3) 23 (45.1) 11 (22.4) 14 (28.6) reason for stent insertion (n %) stone 49 (96.1) 50 (98) 49 (100) 47 (96) 0.14 ++ stenosis 2 (3.9) 1 (2) 0 (0) 2 (4) procedure duration 38.2 ± 31.4 38.5 ± 19.1 39 ± 14.7 43.4 ± 28.8 0.69 + stone size (mm) 12.5 ± 3.4 12.9 ± 4 12.2 ± 3.7 12.3 ± 4 0.86 + stone or stenosis location (n %) left 29 (56.9) 30 (58.9) 32 (65.3) 24 (49) 0.43 ++ right 22 (43.1) 21 (41.1) 17 (34.7) 25 (51) + one way anova (anova); ++ pearson chi square. were observed between the 4 groups in terms of urinary symptoms, pain severity, general health status, occupational activity, and additional problems that may be related to the ureteral stent. however, a statistically significant difference was observed in the location of pain. in particular, 82.4% of patients in group a reported pain in the kidney back region which was higher compared to the percentages of patients in the other groups (group b: 68.8%, group d: 62.5) and with group c reporting the lowest percentage i.e. 31.3% (p = 0.04) (figure 2). in addition, differences were also present regarding the sexual life of the patients. although no one had an active sex life in the 1st week after stent placement, group c patients had stopped being sexually active before stent placement, at 22. 4% which is three times higher than the rates in the other groups (group a: 9.8%, group b: 7.8%, group d: 6.1%, p = 0.04). the same proportions of patients, as expected, stated that the reason for sexual inactivity was not related to the symptoms caused by the stent (p = 0.04) (figure 3). archivio italiano di urologia e andrologia 2024; 96(1):12231 t.ch. bellos, i.s. manolitsis, s.n. katsimperis, et al. 4 groups, no statistically significant differences were observed in urea, creatinine, white blood cells, c reactive protein (crp), urine and blood culture. there was no difference in any of the measured time-points (preoperative, postoperative, values at discharge). the same was true for the observed change in the values of the aforementioned variables, between postoperative and preoperative period, and between discharge and preoperative period. however, in terms of clinical characteristics, febrile episodes after ureteral stent placement occurred only in patients in groups a and d, but there was no difference between these two in terms of the mean duration of febrile episodes and temperature values. responses to the ureteric stent symptoms questionnaire at 1 week after placement of the ureteric stent (stent in situ) the results regarding the patients' responses during the first week after ureteral stent placement are presented in table 4. in general, no statistically significant differences figure 1. box-plot presenting the height (up) and weight (down) of the patients in the 4 groups. y axis: height (cm), weight (kg). x axis: patient group (a, b, c, d). archivio italiano di urologia e andrologia 2024; 96(1):12231 5 ureteral stent related symptoms figure 2. bar chart presenting the pain in the kidney back region, one week after ureteral stent placement. x axis: groups of patients. y axis: percentage of patients who reported pain in the kidney back area. figure 3. bar chart which shows the percentage of patients who reported that they stopped having an active sex life before (blue) and after (orange) ureteral stenting. x axis: groups of patients. y axis: percentage of patients who reported that they stopped having an active sex life before (blue) and after (orange) ureteral stent placement. table 3. clinical laboratory findings of patients by group. group a group b group c group d p (n = 51, 25.5%) (n = 51, 25.5%) (n = 49, 24.5%) (n = 49, 24.5%) (95% ci) mean ± sd mean ± sd mean ± sd mean ± sd urea (mg/dl) preoperative 54.2 ± 85.6 38.9 ± 9.3 44.3 ± 13.4 62.6 ± 134 0.47+ postoperative 43.4 ± 13.4 42 ± 9.2 46.1 ± 11.8 44.7 ± 13.8 0.37 + discharge 33.2 ± 10.6 32.9 ± 10.2 35 ± 10.2 57.1 ± 165.3 0.44 + post-pre -10.9 ± 80 3.1 ± 11.8 1.6 ± 11.6 -17.8 ± 126 0.44 + discharge-pre -21 ± 79.2 -3.12 ± 15 -9.4 ± 17.2 -5.4 ± 33.9 0.20 + creatinine (mg/dl) preoperative 1.17 ± 0.7 1.05 ± 0.3 1.15 ± 0.45 0.98 ± 0.54 0.64 + postoperative 1.07 ± 0.67 1.02 ± 0.24 1.01 ± 0.31 1.1 ± 0.6 0.82 + discharge 0.99 ± 0.57 0.96 ± 0.15 0.91 ± 0.14 0.99 ± 0.28 0.66 + post-pre -0.1 ± 0.27 -0.02 ± 0.21 -0.14 ± 0.2 -0.04 ± 0.33 0.12 + discharge-pre -0.2 ± 0.37 -0.09 ± 0.26 -0.24 ± 0.4 -0.15 ± 0.38 0.17 + wbcs (x10} mg/dl) preoperative 7.9 ± 3.4 7.12 ± 1.8 5.85 ± 4.5 6.17 ± 3.5 0.56 + postoperative 11,4 ± 5.5 9.92. ± 5.1 8.95 ± 6.1 8.57 ± 5.8 0.85 + discharge 4.93 ± 5.4 4.17 ± 5.2 5.1 ± 5.4 5.42 ± 5.5 0.69 + post-pre 2.6 ± 5.4 2.3 ± 3.9 3.5 ± 4.4 2.4 ± 5.1 0.59 + discharge-pre -3.53 ± 2.1 -2.8 ± 3.3 -3.1 ± 1.6 -2.48 ± 2.3 0.86 + crp (mg/l) preoperative 85 ± 51 75 ± 64 88 ± 49 76 ± 80 0.34 + postoperative 50 ± 29 46 ± 45 58 ± 81 47 ± 75 0.34 + discharge 39 ± 28 33 ± 32 37 ± 23 31 ± 38 0.81 + post-pre -35 ± 22 -29 ± 19 -30 ± 32 -29 ± 5 0.65 + discharge-pre -46 ± 22 -42 ± 32 -51 ± 26 -45 ± 42 0.33 + fever** n (%) 6 (11.8) 0 (0) 0 (0) 3 (6.1) 0.01 * temperature (°c) 39.3 ± 0.3 39.3 ± 0.32 0.79 ++ (-0.32, 0.4) duration (days) 3 ± 0.6 2.4 ± 0.8 0.2 ++ (-0.35,1.46) blood culture positive 0 (0) 0 (0) 0 (0) 0 (0) urine culture (positive) preoperative 4 (7.8) 2 (3.9) 6 (12.2) 2 (4.1) 0.32 * postoperative 0 (0) 0 (0) 3 (6.1) 0 (0) 0.15 * + one way anova, ++ independent samples t-test, *pearson chi-square test, **fever postoperatively. post-pre: difference between postoperative and preoperative values; discharge-pre: difference between discharge and preoperative values; bmi: body mass index; sd: standard deviation; 95% ci: 95% confidence interval. discharge-pre: difference between values at hospital discharge and preoperative values; wbcs: white blood cells; crp: c-reactive protein. archivio italiano di urologia e andrologia 2024; 96(1):12231 t.ch. bellos, i.s. manolitsis, s.n. katsimperis, et al. 6 table 4. responses to the ureteric stent symptoms questionnaire 1, one week after placement of the ureteric stent (stent in situ). group a group b group c group d p (n = 51, 25.5%) (n = 51, 25.5%) (n = 49, 24.5%) (n = 49, 24.5%) (95% ci) mean ± sd mean ± sd mean ± sd mean ± sd u1-u11. urinary index score (uis) (mean ± sd) 23.06 ± 2.6 23.02 ± 2.8 23.4 ± 2.6 23.6 ± 2.5 0.61 + p1. do you experience body pain or discomfort in association with the stent? (n %) no 34 (66.6) 35 (68.6) 33 (67.3) 33 (67.3) 0.99 ++ yes 17 (33.4) 16 (31.4) 16 (32.7) 16 (32.7) p2. site(s) where you experience pain or discomfort in association kidney front 17/17 (100) 16/16 (100) 16/16 (100) 16/16 (100) n/a with the stent typically (n %) groin area 16/17 (94.1) 15/16 (93.8) 15/16 (93.8) 14/16 (87.5) 0.88 ++ bladder area 1/17 1/16 2/16 0 0.51 ++ kidney back 14/17 (82.4) 11/16 (68.8) 5/16 (31.3) 10/16 (62.5) 0.04 ++ p3. sum of the vas scores for all sites of pain (mean ± sd) 7.2 ± 0.4 7.3 ± 0.6 7.4 ± 0.8 6.9 ± 0.8 0.2 + p3-p9. pain index score (mean ± sd) 20.47 ± 1.5 20.25 ± 2.3 19.3 ± 2.4 19.8 ± 2.6 0.45 + g1-g6. general health index score (mean ± sd) 10.5 ± 3.1 10.4 ± 2.9 10.8 ± 3.1 9.6 ± 2.1 0.17 + w1. status of employment (n %) full time 16 (31.4) 18 (35.25) 14 (28.6) 15 (30.6) 0.53 ++ part time 19 (37.2) 16 (31.4) 16 (32.7) 15 (30.6) 0.42 ++ retired on health ground 0 0 0 0 (2) 0.67 ++ retired for other reason 2 (3.9) 1 (1.95) 0 1 0.8 ++ student 0 0 0 0 n/a unemployed, looking for work 14 (27.5) 16 (31.4) 19 (38.7) 18 (36.8) 0.67 ++ w2. how many days did the symptoms associated with the stent keep you 2.45 ± 1.7 2.29 ± 1.5 2.18 ± 1.8 2.36 ± 1.4 0.85 + in bed all or most of the day (mean ± sd) w3. how many half days or more did you cut down your routine activities because 2.56 ± 1.7 2.73 ± 1.1 2.49 ± 1.5 2.61 ± 1.8 0.37 + of the symptoms associated with the stent (mean ± sd) w4. type of employment (n %) employee 15 (29.4) 17 (33.3) 18 (36.7) 15 (30.6) 0.6 ++ employer 9 (17.6) 12 (23.6) 9 (18.3) 10 (20.4) self employed 27 (53) 22 (43.1) 22 (45) 24 (49) w5-w7. quality of work for those who are in active paid jobs (mean ± sd) 6.8 ± 1.6 6.9 ± 1.7 6.7 ± 1.4 6.4 ± 1.5 0.6 + s1. do you have an active sex life? no 51 (100) 51 (100) 49 (100) 49 (100) n/a s2. i) if no sex life, how long ago did this stop? (n %) after insertion of the stent 46 (90.2) 47 (92.2) 38 (77.6) 46 (93.9) 0.04 ++ before insertion of the stent 5 (9.8) 4 (7.8) 11 (22.4) 3 (6.1) because of the problems 0 0 0 0 associated with the stent ii) why did this stop? (n %) did not attempt any sexual activity 46/51 (90.2) 47/51 (92.2) 38/49 (77.6) 46/49 (93.9) 0.04 ++ some other reason – not to do 5/51 (9.8) 4/51 (7.8) 11/49 (22.4) 3/49 (6.1) with the symptoms of the stent s3-s4. quality of sex (mean ± sd) n/a n/a n/a n/a n/a a1. how many times have you felt you may be suffering from a urinary tract infection never 49 (96.1) 43 (84.3) 46 (93.4) 43 (87.8) 0.16 ++ (e.g. running temperature, feeling unwell and pain while passing urine)? (n %) occasionally 2 (3.9) 8 (15.7) 3 (6.6) 6 (12.2) sometimes 0 0 0 0 most of the time 0 0 0 0 all of the time 0 0 0 0 a2. have you needed to take antibiotics as a result of insertion of the stent? (n %) not at all 51 (100) 51 (100) 49 (100) 49 (100) n/a one course 0 0 0 0 two courses 0 0 0 0 three or more courses 0 0 0 0 a3. have you needed to seek help of a health professional (such as gp, nurse) never 51 51 49 49 n/a due to any problem associated with the stent? (n %) once 0 0 0 0 twice 0 0 0 0 three or more times 0 0 0 0 a4. have you needed to visit the hospital due to any problem associated never 51 (100) 49 (96.1) 48 (97.9) 49 (100) 0.44 ++ with the stent? (n %) once 0 1 (1.95) 0 0 twice 0 0 1 (2.1) 0 three or more times 0 1 (1.95) 0 0 gq. global quality of life with the stent in situ: delighted 0 1 1 1 0.37 ++ in the future, if you were advised to have another stent inserted, pleased 21 16 19 19 how would you feel about it? (n %) mostly satisfied 9 20 15 20 mixed feelings 18 12 13 8 mostly dissatisfied 3 1 0 1 unhappy 0 1 1 0 terrible 0 0 0 0 + one way anova test; ++ pearson chi square test; n/a: not applicable; sd: standard deviation; vas: visual analogue. archivio italiano di urologia e andrologia 2024; 96(1):12231 7 ureteral stent related symptoms responses to the ureteric stent symptoms questionnaire at week 4 after placement of the ureteric stent (stent in situ) the results regarding the patients' responses at the fourth week after ureteral stent placement are presented in table 5. in general, no statistically significant differences were observed between the 4 groups in terms of urinary symptoms, pain severity, general health status, occupational activity, and additional problems that may be related to the ureteral stent. however, a statistically significant difference was observed in the location of pain. specifically, 64.7% of group a patients reported pain in the kidney front area which was lower compared to the percentages of patients in the other groups (group b: 100%, group c: 93.3%, group d: 100%, p = 0.04) (figure 4). in addition, differences were also present regarding the patients' sex life. as table 5. responses to the ureteric stent symptoms questionnaire 1, four (4) weeks after ureteric stent placement. group a group b group c group d p (n = 51, 25.5%) (n = 51, 25.5%) (n = 49, 24.5%) (n = 49, 24.5%) (95% ci) mean ± sd mean ± sd mean ± sd mean ± sd u1-u11. urinary index score (uis) (mean ± sd) 18.5 ± 2.3 18.6 ± 2.3 18.7 ± 2.5 18.4 ± 2.7 0.87 + p1. do you experience body pain or discomfort in association with the stent? (n %) no 34 (66.7) 35 (68.6) 34 (69.4) 33 (67.3) 0.99 ++ yes 17 (33.3) 16 (31.4) 15 (30.6) 16 (32.7) p2. site(s) where you experience pain or discomfort in association kidney front 11/17 (64.7) 16/16 (100) 14/15 (93.3) 16/16 (100) 0.04++ with the stent typically (n %) groin area 12/17 (70.6) 6/16 (37.5) 4/15 (26.7) 7/16 (43.8) 0.1 ++ bladder area 1/17 (5.9) 1/16 (6.3) 1/15 (6.7) 0 (0) 0.8 ++ kidney back 12/17 (70.6) 6/17 (35.3) 4/15 (26.7) 7/16 (43.8) 0.1 ++ p3. sum of the vas scores for all sites of pain (mean ± sd) 5.7 ± 0.8 5.5 ± 0.9 5.6 ± 0.9 5.8 ± 0.8 0.78 + p3-p9. pain index score (mean ± sd) 15.5 ± 2.1 14.8 ± 1.8 14.7 ± 2.3 15.1 ± 2.1 0.7 + g1-g6. general health index score (mean ± sd) 8.7 ± 1.9 8.6 ± 1.7 8.9 ± 2.3 8 ± 1.1 0.07 + w1. status of employment (n %) full time 16 (31.4) 18 (35.25) 14 (28.6) 15 (30.6) 0.53 ++ part time 19 (37.2) 16 (31.4) 16 (32.7) 15 (30.6) 0.42 ++ retired on health ground 0 0 0 0 (2) 0.67 ++ retired for other reason 2 (3.9) 1 (1.95) 0 1 0.8 ++ student 0 0 0 0 n/a unemployed, looking for work 14 (27.5) 16 (31.4) 19 (38.7) 18 (36.8) 0.67 ++ w2. how many days did the symptoms associated with the stent keep you 1.75 ± 1.2 1.73 ± 1.2 1.76 ± 1.4 1.65 ± 1.01 0.98 + in bed all or most of the day (mean ± sd) w3. how many half days or more did you cut down your routine activities because 1.47 ± 1.2 1.58 ± 1.19 1.81 ± 1.24 1.71 ± 1 0.48 + of the symptoms associated with the stent (mean ± sd) w4. type of employment (n %) employee 15 (29.4) 17 (33.3) 18 (36.7) 15 (30.6) 0.6 ++ employer 9 (17.6) 12 (23.6) 9 (18.3) 10 (20.4) self employed 27 (53) 22 (43.1) 22 (45) 24 (49) w5-w7. quality of work for those who are in active paid jobs (mean ± sd) 6.8 ± 1.6 6.9 ± 1.7 6.7 ± 1.4 6.4 ± 1.5 0.6 + s1. do you have an active sex life? no 47 (92.2) 48 (94.2) 45 (91.8) 47 (95.9) n/a yes 4 (7.8) 3 (5.8) 4 (8.2) 2 (4.1) s2. i) if no sex life, how long ago did this stop? (n %) after insertion of the stent 42/47 (89.4) 44/48 (91.7) 34/45 (75.6) 44/47 (93.6) 0.03 ++ before insertion of the stent 5/47 (10.6) 4/48 (8.3) 11/45 (24.4) 3/47 (6.4) ii) why did this stop? (n %) did not attempt any sexual activity 42/47 (89.4) 44/48 (91.7) 35/45 (77.8) 43/47 (91.5) 0.04 ++ some other reason – not to do 5/47 (10.6) 5/48 (8.3) 10/45 (22.2) 4/47 (8.5) with the symptoms of the stent s3-s4. quality of sex (mean ± sd) 4.3 ± 0.9 4 ± 1 2.7 ± 0.9 3.3 ± 0.6 0.16 + a1. how many times have you felt you may be suffering from a urinary tract infection never 49/51 (96.1) 44/51 (86.3) 46/49 (93.9) 44/49 (89.8) 0.29 ++ (e.g. running temperature, feeling unwell and pain while passing urine)? (n %) occasionally 2/51 (3.9) 7/51 (13.7) 3/49 (6.1) 5/49 (10.2) a2. have you needed to take antibiotics as a result of insertion of the stent? (n %) one course 51 (100) 51 (100) 49 (100) 49 (100) n/a a3. have you needed to seek help of a health professional (such as gp, nurse) never 51 51 49 49 n/a due to any problem associated with the stent? (n %) once 0 (0) 1 (2) 0 (0) (0) a4. have you needed to visit the hospital due to any problem associated never 51 (100) 49 (96.1) 48 (97.8) 49 (100) 0.44 ++ with the stent? (n %) once 0 (0) 2 (3.9) 1 (2.2) (0) gq. global quality of life with the stent in situ: delighted 0 (0) 1 (2) 1 (2.1) 1 (2.1) 0.06 ++ in the future, if you were advised to have another stent inserted, pleased 21 (41,2) 16 (31.4) 19 (38.8) 19 (38.8) how would you feel about it? (n %) mostly satisfied 9 (17.6) 20 (39.2) 19 (38.8) 23 (46.9) mixed feelings 19 (37.3) 14 (27.4) 9 (18.2) 6 (12.2) mostly dissatisfied 2 (3.9) 0 0 0 unhappy 0 0 1 (2.1) 0 terrible + one way anova test; ++ pearson chi square test; n/a: not applicable; sd: standard deviation; vas: visual analogue. archivio italiano di urologia e andrologia 2024; 96(1):12231 t.ch. bellos, i.s. manolitsis, s.n. katsimperis, et al. 8 figure 4. bar chart where pain is present in the kidney front area four weeks after placement of the ureteral stent. x axis: groups of patients. y axis: percentage of patients who reported pain in the kidney front area. table 6. group a group b group c group d p-value (n = 51, 25.5%) (n = 51, 25.5%) (n = 49, 24.5%) (n = 49, 24.5%) mean ± sd mean ± sd mean ± sd mean ± sd u1-u11. urinary index score (uis) (mean ± sd) 14.4 ± 1.7 14.4 ± 1.8 14.1 ± 1.6 14.5 ± 1.8 0.68 + p1. do you experience body pain or discomfort in association with the stent? (n %) no 38 (74) 39 (76.5) 36 (73.5) 36 (73.5) 0.98 ++ yes 13 (26) 12 (23.5) 13 (26.5) 13 (26.5) p2. site(s) where you experience pain or discomfort in association kidney front 11 (84.6) 7 (58.3) 11 (84.6) 10 (76.9) 0.57++ with the stent typically (n %) groin area 7 (53.8) 9 (75) 10 (76.9) 9 (69.2) 0.85 ++ bladder area 1 (7.6) 1 (8.3) 1 (7.6) 0 (0) 0.81 ++ kidney back 12 (92.3) 6 (50) 5 (38.5) 7 (53.8) 0.25 ++ p3. sum of the vas scores for all sites of pain (mean ± sd) 5.6 ± 0.7 5.6 ± 1.1 5.6 ± 0.9 5.7 ± 0.8 0.96 + p3-p9. pain index score (mean ± sd) 3.8 ± 6.7 3.4 ± 6.3 3.8 ± 6.4 4.1 ± 6.9 0.97 + g1-g6. general health index score (mean ± sd) 7.1. ± 1.2 7.1 ± 1.1 7.1 ± 1.2 6.8 ± 0.8 0.57 + w1. status of employment (n %) full time 16 (31.4) 18 (35.25) 14 (28.6) 15 (30.6) 0.53 ++ part time 19 (37.2) 16 (31.4) 16 (32.7) 15 (30.6) 0.42 ++ retired on health ground 0 0 0 0 (2) 0.67 ++ retired for other reason 2 (3.9) 1 (1.95) 0 1 0.8 ++ student 0 0 0 0 n/a unemployed, looking for work 14 (27.5) 16 (31.4) 19 (38.7) 18 (36.8) 0.67 ++ w2. following removal of the stent, how many days did the symptoms associated 0 (0) 0 (0) 0 (0) 0 (0) n/a with the kidney problem keep you in bed all or most of the day (mean ± sd) w3. following removal of the stent, how many half days or more did you cut down 0 (0) 0 (0) 0 (0) 0 (0) n/a your routine activities because of the symptoms associated with the kidney problem (mean ± sd) w4. type of employment (n %) employee 15 (29.4) 17 (33.3) 18 (36.7) 15 (30.6) 0.6 ++ employer 9 (17.6) 12 (23.6) 9 (18.3) 10 (20.4) self employed 27 (53) 22 (43.1) 22 (45) 24 (49) w5-w7. quality of work for those who are in active paid jobs (mean ± sd) 3.5 ± 0.5 3.6 ± 0.5 3.5 ± 0.6 3.5 ± 0.5 0.86 + s1. do you have an active sex life? no 5 (9.8) 4 (7.8) 7 (14.3) 3 (5.9) 0.55 ++ yes 46 (90.2) 47 (92.2) 42 (85.7) 46 (93.8) s2. i) if no sex life, how long ago did this stop? (n %) after insertion of the stent 0 (0) 0 (0) 0 (0) 0 (0) n/a before insertion of the stent 5/5 (100) 4/4 (100) 7/7 (100) 3/3 (100) ii) why did this stop? (n %) did not attempt any sexual activity 0 (0) 0 (0) 0 (0) 0 (0) n/a some other reason – not to do 5/5 (100) 4/4 (100) 7/7 (100) 3/3 (100) with the symptoms of the stent s3-s4. quality of sex (mean ± sd) 2.52 ± 0.5 2.51 ± 0.5 2.4 ± 0.5 2.3 ± 0.6 0.29 + gq. global quality of life with the stent in situ: delighted 3 (5.8) 0 3 (6.1) 0 0.12 ++ in the future, if you were advised to have another stent inserted, pleased 9 (17.6) 20 (39.3) 15 (30.6) 21 (42.8) how would you feel about it? (n %) mostly satisfied 35 (68.6) 30 (58.8) 26 (53.1) 26 (53.1) mixed feelings 4 (8) 1 (1.9) 3 (6.1) 2 (4.1) mostly dissatisfied 0 0 1 (2.05) 0 unhappy 0 0 1 (2.05) 0 terrible 0 0 0 0 + one way anova test; ++ pearson chi square test; n/a: not applicable; sd: standard deviation; vas: visual analogue. archivio italiano di urologia e andrologia 2024; 96(1):12231 9 ureteral stent related symptoms in the questionnaire completed at week 1 after stent placement, group c patients reported that they had stopped being sexually active before stent placement, at a higher rate of 24.4% compared to the rates of the other groups (group a: 10.6%, group b: 8.3%, group d: 6.4%, p = 0.03). the difference in rates with those of the first week is due to the fact that a small number of patients achieved active sexual activity at week 4 (group a: 7.8%, group b: 5.8%, group c: 8.2%, group d: 4.1%, p = 0.83). responses to the ureteric stent symptoms questionnaire at week 4 after removal of the ureteric stent (post stent) at 4 weeks after ureteral stent removal, no statistically significant difference was observed between ureteral catheter groups. almost all domains have returned to normal in all patients groups. in multivariate analysis, no statistically significant differences were found between the effects of ureteral catheter group, age, weight, height and bmi variables on urinary index score (uis), pain index score (pis), general health (gh), quality of work (qw) and quality of sex (qs) scores (tables 7a, b) discussion aside from other purposes not covered in this text, the use of ureteral stenting acts as a preventive strategy against renal obstruction caused by leftover stone pieces, edema, hematoma, and the potential leakage of urine (9). potential factors that may contribute to the development of stent-related symptoms (srs) encompass various aspects, such as the irritation in the trigonal and renal regions due to the presence of the ureteral stent, vesicorenal reflux facilitated by the stent, as well as considerations regarding stent size, length, and position within the bladder or kidney. furthermore, the choice of materials utilized for the stent can also exert an influence on its performance and efficacy. the source of patient discomfort primarily stems from various factors, including the extended ureteral stent intravesical segment, suboptimal double-j stent drainage, ureteral stent displacement or migration, and the rigidity of the ureteral stent (10). urinary reflux, characterized by the retrograde flow of urine up the stent, is a prevalent phenomenon observed in cases where intravesical pressures are elevated during voiding. this particular condition has been identified as the underlying cause in approximately 25% of instances involving moderate colic-like flank pain that was closely associated with stents. elevated intravesical pressure exerts its impact on the renal system by inducing an elevation in intrarenal pressure. this rise in pressure within the kidney subsequently results in kidney distension, a condition characterized by the expansion or enlargement of the renal organ. additionally, individuals experiencing elevated intrarenal pressure may also encounter flank pain, a discomfort localized in the region between the lower ribcage and the pelvis. the phenomenon was commonly referred to as "water hammer", that is a prevalent term in the medical field. persistent irritation of the mucosal lining of the bladder may result in enduring discomfort despite the removal of the stent. the alterations in the bladder mucosa are frequently encountered during cystoscopic examinations, particularly when indwelling catheters are retained for prolonged periods (11). the presence of microscopic hematuria is commonly observed throughout the duration of ureteral stent placement, while macroscopic hematuria is frequently noted but typically self-resolves following stent insertion (11). stent migration, encrustation, stone formation, and fragmentation are recognized as potential complications that may arise subsequent to the implantation of a stent. stent occlusion, a commonly encountered occurrence, necessitates expeditious replacement of the double-j stent for resolution (12). moreover, it has been observed that a considerable proportion of individuals who have been implanted with indwelling stents, reaching up to 86% according to existing literature (13), experience suboptimal occupational functioning and diminished sexual gratification as additional complications. females exhibit a higher propensity to present with the perception of an alien entity within the urinary bladder, primarily attributable to the distressing sensations it elicits (11). table 7a. dependent variables. independent variables uis_t1 uis_t2 uis_t3 pis_t1 pis_t2 pis_t3 gh_t1 gh_t2 gh_t3 ureteric stent group 0.170, p = 0.8 -0.035, p = 0.8 -0.004, p = 0.9 -0.336, p = 0.2 0.047, p = 0.8 -0.177, p = 0.7 -0.131, p = 0.5 -0.091, p = 0.5 -0.068, p = 0.4 age -0.003, p = 0.8 -0.007, p = 0.6 -0.002, p = 0.8 0,001, p = 0.9 0.011, p = 0.5 -0.038, p = 0.2 0.018, p = 0.2 0.01, p = 0.3 0.004, p = 0.4 weight -0.014, p = 0.6 -0.047, p = 0.06 -0.015, p = 0.4 0.021, p = 0.6 0.011, p = 0.7 -0.012, p = 0.8 0.027, p = 0.4 0.01, p = 0.6 -0.001, p = 0.9 height -0.004, p = 0.9 0.023, p = 0.47 0.002, p = 0.9 0.047, p = 0.3 0.015, p = 0.7 0.047, p = 0.56 -0.049, p = 0.2 -0.035, p = 0.1 -0.004, p = 0.7 bmi 0.001, p = 0.8 0.004, p = 0.15 0.002, p = 0.4 0.003, p = 0.6 0.001, p = 0.9 0.007, p = 0.4 -0.005, p = 0.1 -0.002, p = 0.3 -0.001, p = 0.6 * multiple linear regression analysis. p-values are shown. uis: urinary index score; pis: pain index score; gh: general health; t1: one week after stent placement; t2: four weeks after stent placement; t3: four week after stent removal. table 7b. independent variables qw_t1 qw_t2 qw_t3 qs_t2 qs_t3 ureteric stent group -0.14, p = 0.3 -0.076, p = 0.4 -0.011, p = 0.8 -0.521, p = 0.09 -0.069, p = 0.07 age -0.002, p = 0.8 -0.004, p = 0.6 0.001, p = 0.7 -0.182, p = 0.1 0.001, p = 0.7 weight 0.021, p = 0.2 0.009, p = 0.5 0.003, p = 0.7 -0.06, p = 0.2 -0.002, p = 0.7 height -0.007, p = 0.7 -0.008, p = 0.6 0.005, p = 0.5 0.096, p = 0.1 0.007, p = 0.4 bmi -0.001, p = 0.5 -0.001, p = 0.4 0.001, p = 0.7 0.007, p = 0.2 -0.001, p = 0.4 * multiple linear regression analysis.p-values are shown. qw: quality of work; qs: quality of sex; t1: one week after stent placement; t2: four weeks after stent placement; t3: four week after stent removal. archivio italiano di urologia e andrologia 2024; 96(1):12231 t.ch. bellos, i.s. manolitsis, s.n. katsimperis, et al. 10 the potential influence of stent diameter on ureteral stent symptoms remains inconclusive. the available evidence does not support the notion that employing a stent of larger diameter is associated with elevated levels of discomfort, hematuria, or symptoms pertaining to lower urinary tract obstruction. the propensity for proximal stent migration is heightened in the context of smaller diameter stents (4.8 fr) when juxtaposed with their 6 fr counterparts, thereby establishing them as a notable risk factor. the risk of complications in stent placement is influenced by various factors, including the duration of indwelling, the length of the stent, and the specific site of stent implantation (11). according to our study, there was only statistical difference in the pain characteristics among the different ureteral stents, specifically during the first week a significant proportion of patients belonging to group a, specifically 82.4%, experienced discomfort in the kidney back region. this percentage was notably higher when compared to the corresponding figures for patients in the other groups, with group b reporting 68.8% and group d reporting 62.5% and with group c exhibiting the lowest percentage, with only 31.3% of patients reporting pain in the kidney back region. this disparity in percentages was found to be statistically significant, as indicated by a p-value of 0.04. during the fourth week of stent in situ, there were no statistically significant variations observed among the four groups with regards to urinary symptoms, severity of pain, overall health status, occupational activity, and other potential complications associated with the ureteral stent. a notable disparity was observed in the spatial distribution of pain, which yielded statistical significance. a significant proportion of patients belonging to group a, namely 64.7%, experienced discomfort in the anterior region of the kidney. remarkably, this percentage was found to be considerably lower when compared to the corresponding figures in the other groups, with group b reporting 100%, group c reporting 93.3%, and group d reporting 100% pain occurrence. the statistical analysis revealed a noteworthy p-value of 0.04, indicating a significant difference among the groups. however, during the fourth week after stent removal there were no significant differences between the groups since all the preoperative parameters returned to normal. based on the studies conducted by bolat et al. and sighinolfi et al., it has been observed that the introduction of a double-j stent is closely linked to the occurrence of sexual dysfunction in nearly all individuals, irrespective of their gender (14, 15). in our prospective observational study, group c patients reported that they had stopped being sexually active before stent placement, at a higher rate of 24.4% compared to the rates of the other groups (group a: 10.6%, group b: 8.3%, group d: 6.4%, p = 0.03). in the fourth week of stent in situ some patients managed active sexual activity (group a: 7.8%, group b: 5.8%, group c: 8.2%, group d: 4.1%, p = 0.83). the fourth week after stent removal the sexual activity returned back to normal. despite the optimal positioning and appropriate sizing of the stent, patients may still encounter urinary symptoms and pain that are correlated with the existence of the stent (11). in a recent study conducted by al-kandari et al., the investigation focused on evaluating the potential influence of upper coil placement on the manifestation of stent-related complaints. the study findings revealed that the positioning of the upper coil did not yield any discernible impact on the occurrence of such complaints. however, it has been postulated that the translocation of the bladder coil across the body's midline elicits augmented sensations of urgency and discomfort during micturition (16). several investigations carried out by inn et al., ho et al., and taguchi et al. have yielded compelling findings suggesting a significant association between the insertion of a double-j stent coil into the urinary bladder, particularly on the contralateral side of the body, and the exacerbation of urinary symptoms and heightened pain levels (17-19). in a recent investigation carried out by abt et al., it was determined that the precise positioning of the stent within the bladder does not yield any discernible effects on the symptoms induced by a ureteral stent (19). in our cohort, all the double-j stents were positioned so they will not cross the midline. the present study is subject to certain limitations, primarily stemming from its non-randomized trial design. conclusions the potential influence of ureteral stent physical properties on stent-related symptoms remains inconclusive, despite numerous trials dedicated to identifying the optimal ureteral stent. in light of the limited availability of robust empirical data, a definitive conclusion cannot be ascertained at this time. the prioritization of establishing a benchmark for the quantification and documentation of the physical characteristics of stents is of utmost importance as the preliminary stage of forthcoming investigations. references 1. finney rp. experience with new double j ureteral catheter stent. j urol 1978; 120:678-81. 2. hepperlen tk, mardis hk. pigtail stent termed means of lessening ureteral surgery. trends clin urol 1978; 1:405. 3. beiko dt, knudsen be, denstedt jd. advances in ureteral stent design. j endourol 2003; 17:195-9. 4. marmar jl. the management of ureteral obstruction with silicone rubber splint catheters. j urol 1970; 104:386-9. 5. orikasa s, tsuji i, siba t, oashi n. a new technique for transurethral insertion of a silicone rubber tube into an obstructed ureter. j urol 1973; 110:184-7. 6. mccullough jl. shepards crook self-retaining ureteral catheter. urol lett club 1974; 32:54-5. 7. joshi hb, newns n, stainthorpe a, et al. ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. j urol. 2003; 169:1060-4. 8. https://www.cdc.gov/healthyweight/assessing/bmi/index.html 9. dellis a, joshi hb, timoney ag, keeley fx jr. relief of stent related symptoms: review of engineering and pharmacological solutions. j urol 2010; 184:1267-72. archivio italiano di urologia e andrologia 2024; 96(1):12231 11 ureteral stent related symptoms 10. raju t. indwelling ureteral stents: impact of material and shape in patient comfort. j endourol 2009; 7:2. 11. vogt b, desgrippes a, desfemmes fn. changing the double-pigtail stent by a new suture stent to improve patient's quality of life: a prospective study. world j urol 2015; 33:1061-8. 12. ahallal y, khallouk a, el fassi mj, farih mh. risk factor analysis and management of ureteral double-j stent complications. rev urol 2010; 12:e147-51. 13. giannarini g, keeley fx jr, valent f, et al. predictors of morbidity in patients with indwelling ureteric stents: results of a prospective study using the validated ureteric stent symptoms questionnaire. bju int 2011; 107:648-54. 14. bolat ms, akdeniz e, asci r, et al. ureterorenoscopy with stenting and its effect on male sexual function: a controlled randomised prospective study. andrologia 2017; 49: e12746. 15. sighinolfi mc, micali s, de stefani s, et al. indwelling ureteral stents and sexual health: a prospective, multivariate analysis. j urol 2007; 178:229-31. 16. al-kandari am, al-shaiji tf, shaaban h, et al. effects of proximal and distal ends of double-j ureteral stent position on postprocedural symptoms and quality of life: a randomized clinical trial. j endourol 2007; 21:698-702. 17. inn fx, ahmed n, hou lg, et al. intravesical stent position as a predictor of quality of life in patients with indwelling ureteral stent. int urol nephrol 2019; 51:1949-53. 18. ho ch, tai hc, chang hc, et al. predictive factors for ureteral double-j-stent-related symptoms: a prospective, multivariate analysis. j formos med assoc 2010; 109:848-56. 19. abt d, mordasini l, warzinek e, et al. is intravesical stent position a predictor of associated morbidity? korean j urol 2015; 56:370-8. correspondence themistoklis bellos, md (corresponding author) bellos.themistoklis@gmail.com 2nd department of urology, sismanoglio general hospital of athens, athens kassandras 8, marathon, attica, greece 19007 ioannis manolitsis, md giannismanolit@gmail.com stamatios katsimperis, md stamk1992@gmail.com panagiotis angelopoulos, md angelopoulospanag@gmail.com sotirios kapsalos dedes, md kapsalos13@gmail.com panagiotis deligiannis, md panosdlg@gmail.com iraklis mitsogiannis, md imitsog@med.uoa.gr ioannis varkarakis, md, professor medvark3@yahoo.com athanasios papatsoris, md, professor agpapatsoris@yahoo.gr andreas skolarikos, md, professor andskol@yahoo.com charalampos deliveliotis, md, professor chdeliveli@gmail.com 2nd department of urology, sismanoglio general hospital of athens, athens lazaros tzelves, md lazarostzelves@gmail.com nikolaos kostakopoulos, md nikostakop@gmail.com 1st department of urology, metropolitan general, cholargos, greece conflict of interest: the authors declare no potential conflict of interest. stesura seveso 291archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. cell variant, sarcomatoid variant, plasmacytoid variant, microcystic variant, micropapillary variant, nested variant, and small cell type (2). histologic variants are classified primarily based on morphology that is associated with a distinct biological behavior, such as proclivity for local recurrence and metastasis. moreover there are variations in the clinical course including progression patterns and responses to therapy as well as biologic features in molecular subtypes and dna alterations (3). in the past, it was believed that urothelial tumors with divergent differentiation presented at a later stage of diagnosis, and earlier reports indicated a lower survival rate (4). recent studies show that patients with squamous or glandular urothelial tumors have survival rates comparable to those with pure urothelial tumor (3, 5). in a study by sefik et al. patients with variant histology were observed to have proportionally higher t stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival (6). a recent study by pereira et al. evidenced that although bladder cancers with histological variants are clearly associated with features of more aggressive behavior, they had not any significant impact in survival expectancies (7). therefore, the clinical impact of tumor with variant histology on the treatment options still remains under a cloud of doubt in that whether the presence of variant histology justifies an aggressive treatment strategy involving early radical cystectomy (8). the final pathology and prognosis of bladder cancer with variant histology differ from that of pure urothelial bladder cancer, and evidence on the response to systemic therapy in these variant histologies is scarce and divergent (9, 10). current guidelines place urothelial carcinoma with variant histology in the highest risk category, implying that, despite lacking high level of evidence, early radical cystectomy should be considered (11). it is noteworthy, when it comes to management, evidence in some areas is contradictory and inconclusive therefore necessitating further investigation. our study aims to share our institution experience in treating bladder cancer with variant histology. methods a retrospective cohort single center study involving all patients who were treated for bladder cancer with a histological variant admitted to the thunder bay regional purpose: the aim of this study is to report our experience in managing bladder cancer in patients with variant pathology. methods: retrospective data collection for all patients managed by radical cystectomy over the last 3 years for a variant pathology was completed. we specifically included micropapillary and nested variants. results: ten patients were identified, with eight having micropapillary carcinoma (mpc) and two having nested variants. nine patients were male. the median age was 75. the two patients with nested variant were 56 and 62 years old, respectively, whereas all patients with mpc were over the age of 70. upon cystectomy of all micropapillary cases, three patients (37.5%) had positive lymph node invasion and the final pathology was t2 (two patients), t3 (two patients), and t4 (four patients). barring a grade iii complication clavien-dindo classification due to wound dehiscence that necessitated secondary surgical closure, there were no specific perioperative complications. given the urethral invasion, cystourethrectomy was performed on the female patient. within a median 13-month follow-up, three patients developed local recurrence, including two urethral and one new lateral pelvic mass. conclusions: considering the muscle invasive nature of micropapillary and nested bladder cancer, aggressive surgical management should not be postponed. moreover, due to notable prevalence of concurrent and/or recurrent urethral involvement, initial urethrectomy or early and frequent postoperative urethroscopy should be provided. patients with variant histology bladder cancer may benefit from early radical cystectomy when compared to bladder sparing protocols and prostate sparing cystectomy treatment options. key words: bladder cancer; urothelial carcinoma; variant histology; radical cystectomy. submitted 30 july 2022; accepted 20 august 2022 introduction bladder cancer varies along a wide spectrum of histological variants with urothelial cancer accounting for the vast majority (1, 2). variant histology accounts for approximately 25% of bladder tumors that can pose distinctive diagnosis and therapy challenges to the overall management of bladder cancer (2). according to the world health organization 2016 classification, variant histology of bladder cancer includes urothelial carcinoma with divergent differentiation, such as lymphoepithelioma-like radical cystectomy for bladder urothelial carcinoma with aggressive variant histology vahid mehrnoush, logan brennan, asmaa ismail, ahmed zakaria, hazem elmansy, walid shahrour, owen prowse, ahmed kotb urology department, northern ontario school of medicine, thunder bay regional health centre, ontario, canada. doi: 10.4081/aiua.2022.3.291 summary archivio italiano di urologia e andrologia 2022; 94, 3 v. mehrnoush, l. brennan, a. ismail, a. zakaria, h. elmansy, w. shahrour, o. prowse, a. kotb 292 health science centre. our patients were treated with either a radical cystectomy or a transurethral resection of the bladder tumor (turbt) alone, or a turbt combined with adjuvant bcg therapy. results ten patients (9 male and 1 female) were identified, with eight having micropapillary cancer and two having nested variants. the median age was 75 (56-84). the two patients with the nested variant were 56 and 62 years old, respectively, whereas all patients with micropapillary cancer (mpc) were over the age of 70. of nested variant patients, one patient had a domal t1 tumor and the other had a t2 small trigonal tumor. localized cancer was confirmed by staging ct scans. upon radical cystoprostatectomy, the final pathology for the first patient was pt2n0, while the second patient was pt4an1. of the patients with mpc, two were reported to have stage t1 tumors, while six were reported to have stage t2 tumors on turbt. stage t4b was found on ct scan in two patients. despite the instillation of intravesical bacillus calmette-gue'rin (bcg) induction course, upstaging to t2 was reported in both t1 cases. upon cystectomy for all micropapillary cases, three patients (37.5%) had positive lymph node invasion and the final pathology came back t2 (two patients), t3 (two patients), and t4 (four patients). barring a grade iii complication clavien-dindo classification due to wound dehiscence that necessitated secondary surgical closure, there were no specific perioperative complications). given the urethral invasion, the cystourethrectomy was performed on the female patient. within a median 13-month follow-up, three patients (30%) developed local recurrence, including two urethral and one new lateral pelvic mass. table 1 illustrates the clinical characteristics and outcomes to the patients and figures 1 and 2 represent two cases with micropapillary and nested variant urothelial carcinoma respectively. discussion the current study is a report on our experience in treating bladder cancer with aggressive variant histology. micropapillary urothelial carcinoma (mpc) was a male-predominant variant found in our patients. mpc has received the most attention of the variant histologies in recent years and may be more familiar to many pathologists than other variants (8). clinically, it is an aggressive variant that typically manifests at an advanced stage and accounts for 25% of urothelial carcinomas (8) which have a poor prognosis (12). the fast progression of non-muscle invasive micropapillary urothelial carcinoma to muscle invasive or metastatic bladder carcinoma is concerning and is a well demonstrated concern in our cases (13). mpc is tightly linked to lymph vascular invasion and lymph node metastasis, in that pt1 bladder cancer with micropapillary variant is frequently upstaged to more advanced stages during investigation and treatment (12). table 1. clinical characteristics and outcomes of all cases. median age 75 (5684) sex males 9 females 1 histology micropapillary 8 nested 2 turbt stage t1 3 t2 7 final t pathology (cystectomy) t1 0 t2 3 t3 2 t4 5 final n stage n0 7 n1 3 urethral invasion no 7 present at cystectomy 1 early (within 6 months) 2 local recurrence (within 1 year) no 7 urethra 2 pelvic side wall 1 figure 1. abdominal axial ct image showing a large ct4 micropapillary cancer. figure 2. abdominal axial ct showing ct1 nested variant. 293archivio italiano di urologia e andrologia 2022; 94, 3 radical cystectomy for bladder urothelial carcinoma with aggressive variant histology as a result, the european association of urology-european society of medical oncology guidelines committees recently agreed that t1 high-grade bladder urothelial carcinoma with micropapillary histology should be treated with immediate radical cystectomy and lymphadenectomy (11). therefore, in such cases, most centers consider early radical cystectomy to be the standard of care; however, there have been reports of reasonable outcomes in series in which bladder preservation therapies were used in highly selected patients with a relatively small micropapillary component (14). although there is still limited evidence on the preferred treatment option, reports show no statistically significant differences in overall survival between groups that received neoadjuvant chemotherapy plus early radical cystectomy vs. radical cystectomy alone in muscle-invasive micropapillary urothelial carcinoma (15, 16). on the other hand, evidence is lacking on the added benefit of neoadjuvant chemotherapy to the treatment of the bladder cancers with variant histology (17). a study on patients with muscle-invasive urothelial carcinoma with variant histology comparing neoadjuvant chemotherapy plus radical cystectomy vs. early radical cystectomy only showed an improvement in overall survival and a lower rate of non-organ-confined disease at the time of radical cystectomy in patients with neuroendocrine tumor neoadjuvant chemotherapy. neoadjuvant chemotherapy reduced the rate of non-organ-confined disease but had no effect on overall survival in bladder tumors with micropapillary differentiation, sarcomatoid differentiation, or adenocarcinoma (9). evidence also recommended that muscle-invasive bladder urothelial carcinoma with micropapillary or plasmacytoid differentiation, as well as squamous or glandular differentiation, should be treated with neoadjuvant chemotherapy followed by radical cystectomy and concomitant lymphadenectomy (11). the role of adjuvant radiotherapy for muscle-invasive urothelial carcinoma and variant histologies is controversial. some evidence recommends that adjuvant radiotherapy (with or without radiosensitizing chemotherapy) is a standard treatment for patients with muscle-invasive urothelial carcinoma with variant histology (11, 18). other evidence states that it is prudent to consider adjuvant radiotherapy to improve local control. this is particularly important in cases with positive margins like patients with urothelial carcinoma with squamous and/or glandular differentiation who are more likely to have pt3-t4 tumors, pelvic lymph node involvement, and local or distant metastasis-related to increased mortality when compared to those with pure urothelial carcinoma (19-21). it has been reported that the response rate to intravesical bcg administration for micropapillary variant is poor (11, 22). in a study of 72 patients with mpc, 40 received primary intravesical bcg and 26 received early radical cystectomy. the bcg group were more inclined to recurrence, progression, and lymph node metastasis at a 75%, 45%, and 35% rate, respectively 22. while certain patients with t1 mpc may respond to intravesical bcg, patients who undergo early radical cystectomy have improved survival outcome (22). in our center, we tried a bcg induction course for patients with t1, but due to t2 progression, they eventually underwent radical cystectomy. nested variant urothelial carcinoma is more common in men over the age of 60, which is similar to the occurrence of classic urothelial carcinoma; however, it has been reported in patients ranging in age from 42 to 90 years (23). in our findings, the nested variant, in contrast to mpc, were found in younger cases. the nested variant, according to the 2016 who classification, includes urothelial carcinoma with small tubules and microcysts (24). it is distinguished by disorderly proliferation of confluent nests with minimal cell atypia (25) which is frequently mistaken for benign cytology that leads to a delay in the definitive diagnosis. nested urothelial carcinomas typically manifest as advanced disease and may be associated with a poor prognosis when compared to pure urothelial carcinoma (26). it has similar characteristics and clinical outcomes to classical urothelial carcinoma, with little to no difference in recurrence or survival rate when treated with radical cystectomy in either non muscle invasive or muscle invasive bladder cancer (25). data from two matched cohorts revealed that patients with nested variants had similar oncological outcomes after radical cystectomy compared to pure urothelial carcinoma (27, 28). although lacking consensus due to a lack of evidence, it is recommended that t1 high-grade bladder urothelial carcinoma with nested variants confirmed (after complete turbt and/or re-turbt) should be treated with immediate radical cystectomy and concomitant lymph node dissection (11). the treatment of bladder cancer including transurethral surgery, intravesical chemotherapy and immunotherapy, radical cystectomy, systemic combination chemotherapy, and, in some cases, radiation therapy has evolved over time to the point where clinical risk markers are now employed to make the best decision for patients. as a result, variant histology can serve as a risk stratification factor that can contribute to improved clinical decision making (17). conclusions aggressive surgical treatment for patients with micropapillary and nested muscle invasive bladder cancer should not be postponed. a large proportion of these patients have urethral involvement. thus, an initial urethrectomy or early and frequent postoperative urethroscopy should be included in the treatment and management of variant histology bladder cancers. for bladder cancer with variant histology, bladder sparing protocols and prostate sparing cystectomy may not be the best treatment options. key messages 1. urothelial variant bladder cancer is always upstaged on radical cystectomy. 2. radical cystectomy for t1 variant histology should be offered rather than surveillance. 3. urethrectomy may be considered at time of radical cystectomy. 4. urothelial variant histology was a male predominant finding in our series. archivio italiano di urologia e andrologia 2022; 94, 3 v. mehrnoush, l. brennan, a. ismail, a. zakaria, h. elmansy, w. shahrour, o. prowse, a. kotb 294 references 1. chalasani v, chin jl, izawa ji. histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. can urol assoc j. 2009; 3(6 suppl 4):193-198. 2. humphrey pa, moch h, cubilla al, et al. the 2016 who classification of tumours of the urinary system and male genital organs-part b: prostate and bladder tumours. eur urol. 2016; 70:106-119. 3. burger m, kamat am, mcconkey d. does variant histology change management of non-muscle-invasive bladder cancer? eur urol oncol. 2021; 4:510-514. 4. shapur nk, katz r, pode d, et al. is radical cystectomy mandatory in every patient with variant histology of bladder cancer. rare tumors. 2011; 3:e22. 5. barata pc, rini bi. treatment of renal cell carcinoma: current status 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shariat sf, guo cc, et al. what is the significance of variant histology in urothelial carcinoma? eur urol focus. 2020; 6:653-663. 16. sui w, matulay jt, james mb, et al. micropapillary bladder cancer: insights from the national cancer database. bladder cancer. 2016; 2:415-423. 17. black pc, brown ga, dinney cpn. the impact of variant histology on the outcome of bladder cancer treated with curative intent. urol oncol. 2009; 27:3-7. 18. chua klm, kusumawidjaja g, murgic j, chua mlk. adjuvant treatment following radical cystectomy for muscle-invasive urothelial carcinoma and variant histologies: is there a role for radiotherapy? esmo open. 2016; 1:e000123. 19. honma i, masumori n, sato e, et al. local recurrence after radical cystectomy for invasive bladder cancer: an analysis of predictive factors. urology. 2004; 64:744-748. 20. zaghloul ms, awwad hk, akoush hh, et al. postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control. int j radiat oncol biol phys. 1992; 23:511-517. 21. lewis gd, haque w, verma v, et al. the role of adjuvant radiation therapy in locally advanced bladder cancer. bladder cancer. 2018; 4:205-213. 22. willis dl, fernandez mi, dickstein rj, et al. clinical outcomes of ct1 micropapillary bladder cancer. j urol. 2015; 193:1129-1134. 23. venyo ak. nested variant of urothelial carcinoma. adv urol. 2014; 2014:192720. 24. warrick ji. clinical significance of histologic variants of bladder cancer. j natl compr canc netw. 2017; 15:1268-1274. 25. aron m. variant histology in bladder cancer-current understanding of pathologic subtypes. curr urol rep. 2019; 20:80. 26. lopez-beltran a, henriques v, montironi r, et al. variants and new entities of bladder cancer. histopathology. 2019; 74:77-96. 27. beltran al, cheng l, montironi r, et al. clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder. virchows arch. 2014; 465:199-205. 28. linder bj, frank i, cheville jc, et al. outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis. j urol. 2013; 189:1670-1675. correspondence vahid mehrnoush, md vahidmehrnoush7@gmail.com logan brennan lobrennan@nosm.ca asmaa ismail asmaaismail0782@gmail.com ahmed zakaria aszakaria81@yahoo.com hazem elmansy hazemuro100@yahoo.com walid shahrour walid.shahrour@gmail.com owen prowse owen.prowse@tbh.net ahmed kotb (corresponding author) drahmedfali@gmail.com urology department, northern ontario school of medicine, thunder bay regional health centre, ontario, canada stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 39 original paper nomic significance. the social aspect is related to the long duration of the illness, the high recurrence rate (up to 50%), and its frequent urgent presentation, leading to sudden disability (1). the economic aspect is related to high personal and government costs for treatment, and loss of working activity. mortality from urolithiasis has recently increased (2, 3). the multifactorial process of stone formation leads to a wide variety of clinical presentations. one of the most common forms of urolithiasis is the formation of calcium oxalate stones (4). the increased concentration of salts in the urine, inflammation, the presence of papillary plaques and plugs in the collecting system of the kidney, and other factors contribute to the development of the disease (5). a complex of metaphylactic measures, such as lifestyle changes, hyperhydration, dietary modifications, correction of concomitant diseases and hormonal disorders, is considered extremely important to prevent relapses after surgical treatment. in addition, the prevention of postoperative recurrence depends on minimizing intraoperative trauma, reducing the risk of infectious complications, and avoiding residual fragments that can act as initial nucleus of stone formation (6). it is important to note that the recommendations for stone treatment have been changed in the context of the pandemic. the international endourological society has reached a consensus on several recommendations for urolithiasis treatment. thus, it was recommended to conduct remote counseling, avoid intubation methods of anesthesia, reduce indications for surgical treatment of asymptomatic concretions, etc. (7). currently, there are two most effective alternative methods for minimally invasive removal of kidney stones with a high level of stone-free rate (sfr) that are the retrograde nephrolithotripsy or retrograde intra-renal surgery (rirs) and the percutaneous nephrolithotomy (pcnl) using flexible optics (8, 9). these methods are superior to the alternative method, shock-wave lithotripsy, in terms of sfr and complications (10, 11). an effective combination of both methods is possible in complex cases (12, 13). both objectives. the study presents a comparative analysis of the mini-percutaneous nephrolithotripsy (mini-pcnl) and retrograde nephrolithotripsy (rirs) with a logistic analysis of outcomes and complications. material and methods. the prospective study included 50 patients diagnosed with urolithiasis from 2018 to 2021 in the urological hospitals in irkutsk. patients were divided into two groups: rirs (group i, n = 23) and mini-pcnl (group ii, n = 27). the comparison groups are statistically homogeneous. results. both procedures equally lead to high stone free rates (sfr > 1 mm, 91.3% vs 85.1%; p = 0.867; sfr > 2 mm, 95.6% vs 92.5%; p = 0.936). the intergroup analysis of the total operation time (and lithotripsy) demonstrated similar times (p > 0.05). postoperative complications of classes ii-iii (clavien-dindo) in the early and late postoperative period developed rarely and were comparable (p > 0.05). class i complications were predominant in the pcnl group (p = 0.007). some parameters demonstrated the superiority of rirs over pcnl: less pronounced pain syndrome (p = 0.002), less drainage time (p < 0.001), no postoperative hematuria (p = 0.002), shorter hospitalization and total treatment period (p < 0.001). conclusions. the study highlighted the positive effect of the oneday surgery principle on the risk of developing postoperative hematuria, urinary infection, or severe postoperative pain. rirs and mini-pcnl have similar effectiveness, but rirs meets the criteria of the enhanced recovery program more than pcnl. key words: fast track surgery; rirs; pcnl; mini-pcnl; enhanced recovery. submitted 4 november 2022; accepted 17 february 2023 introduction enhanced recovery is the conventional name of various protocols or programs for optimizing the perioperative period (for example, fast track surgery, enhanced recovery after surgery or eras) aimed at restoring health, working capacity, and improving the quality of treatment. urolithiasis is a widespread disease affecting up to 12% of the human population, with pronounced social and ecoenhanced recovery after retrograde intra-renal surgery (rirs) in comparison with mini-percutaneous nephrolithotomy (mini-pcnl) for renal stone treatment vladimir vorobev 1, vladimir beloborodov 1, temirlan hovalyg 1, igor seminskiy 2, andrey sherbatykh 3, igor shaderkin 4, mikhail firsov 5 1 department of general surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 2 department of pathology, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 3 department of faculty surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation; 4 e-health laboratory, i.m. sechenov first moscow state medical university, pirogovskaya str., 2, moscow, 119296, russian; federation; 5 department of urology, andrology and sexology, krasnoyarsk state medical university named after professor v.f. voino-yasenetsky, partizan zheleznyaka str., 1, krasnoyarsk, 660022, russian federation. doi: 10.4081/aiua.2023.10991 summary archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 40 methods lead to several postoperative complications, such as hematuria, fever, extravasation, pain. however, complications after rirs are less pronounced and less likely to require surgical treatment (14, 15). nevertheless, reducing the diameter of the working tool can reduce the severity of complications after pcnl and even surpass rirs (10). there is a small number of publications devoted to rirs (according to pubmed, 601 works on 02.02.2022 from 1988 to 2022), and only 48 comparative studies of rirs and pcnl (according to pubmed, 48 works on 02.02.2022 from 2008 to 2022). moreover, there are practically no comparative studies on optimization of the perioperative period to improve the treatment effectiveness and enhance recovery. the study presents a comparative analysis of the use of mini-percutaneous nephrolithotripsy (mini-pcnl) and retrograde nephrolithotripsy (rirs) with a logistic analysis of outcomes and complications. methods research design the local ethics committee of the irkutsk state medical university (ismu) of the ministry of health of the russian federation approved the clinical trial. it was a prospective, blind, randomized study in irkutsk urological hospitals. the study included an analysis of perioperative data and treatment outcomes in patients with urolithiasis who underwent one of the surgical methods established by the protocol from january 2018 to october 2021. surgical operations were performed using one of two endourological methods: mini-pcnl or rirs. all the features of the planned treatment methods were explained to the patient. inclusion criteria: – planned surgery for kidney stones; – indications for the operation meeting the criteria of the approved protocol; – operation was planned to use one of the methods approved in the study; – age over 18 years; – patient signed a voluntary informed consent to participate in the study. non-inclusion criteria: – no indication to treatment; – presence of concomitant diseases that significantly affect the general conditions of the patient (decompensated diabetes mellitus, heart failure, gross neurological deficits, etc.); – inability to comply with the protocol of the study. exclusion criteria: – deviation from the study protocol; – deviation from the criteria of the group. the inclusion of patients in the study was carried out prospectively and continuously, until reaching the minimum sample size (20 patients in each group) and then within the planned timeframe of the study. finally, there were 77 patients recruited to participate in the study, out of them 50 patients completed the study. all the included patients were randomized into two groups based on the approved study protocol. the groups were not artificially aligned. the first group was treated with rirs, the second group with mini-pcnl. deviations from the protocol of the 77 patients included in both groups in the study, 27 were excluded (17 due to deviation from the protocol, and 10 for personal reasons). the evaluation of the results (per-protocol) included 50 patients who meet all the criteria of the study. rirs group included 23 patients (group i) and mini-pcnl group included 27 patients (group ii). outcomes primary outcomes of the study were: absence of residual fragments in the postoperative period, not earlier than a month later; need for re-operation, migration of the stone into the ureter during surgery. secondary outcomes: postoperative examination data; renal colic; urohematomas; urine leakage; recurrence of stone formation. comparison of study groups table 1 presents the preoperative parameters of patients. the statistical analysis established the homogeneity of the two groups (p > 0.05) according to the initial status. diagnostic methods evaluation included clinical history (history of stone disease, concomitant diseases, etc.), physical examination, table 1. preoperative status. parameter group i group ii p (n = 23) (n = 27) age, years weight, kg height, cm bmi, units female, n (%) disease duration, days emergency intervention, n (%) re-stenting, n (%) leukocytosis, n (%) anemia, n (%) ischemic heart disease, n (%) hypertension, n (%) diabetes mellitus, n (%) prostate hyperplasia, n (%) urinary tract cancer, n (%) kidney cysts, n (%) chronic urinary infection, n (%) area of the largest concretion, mm2 hu density, units concretion > 20 mm, n (%) more than one concretion, n (%) calcium oxalates, n (%) 60 (51; 63) 88.2 ± 20.8 1.66 ± 0.1 31 (27; 37) 16 (69.5%) 15 (4; 36) 2 (8.6%) 0 (0%) 3 (13.0%) 1 (4.3%) 10 (43.4%) 14 (60.8%) 3 (13.0%) 6 (26.0%) 1 (4.3%) 4 (17.3%) 8 (34.7%) 135 (117;195) 948 (± 298) 5 (21.7%) 8 (34.7%) 15 (65.2%) 51 (39; 55) 81.1 ± 15.7 1.70 ± 0.08 28 (25; 30) 12 (44.4%) 13 (5; 26) 5 (18.5%) 2 (7.4%) 4 (14.8%) 2 (7.4%) 11 (40.7%) 11 (40.7%) 3 (11.1%) 1 (3.7%) 0 (0%) 1 (3.7%) 15 (55.5%) 120 (90;228) 909 (± 394) 8 (29.6%) 11 (40.7%) 19 (70.3%) 0.413 0.173 0.147 0.052 0.345 0.847 0.384 0.199 0.875 0.668 0.900 0.414 0.852 0.049 0.284 0.147 0.367 0.602 0.697 0.626 0.771 0.864 archivio italiano di urologia e andrologia 2023; 95, 2 41 the retrograde intra-renal surgery biochemistry, imaging (ultrasound, tomography, x-ray) and endoscopy. the analysis of the composition of the calculi was performed by spectroscopy in a specialized laboratory after surgery. multi-slice computer tomography (msct) examination helped to assess the urinary system status, including the density and size of concretions. the severity of postoperative pain syndrome was assessed according to the visual analog scale (vas) of pain. before removal of the urethral catheter, nephrostomy, and stent an ultrasound examination was performed to rule out possible uro-hematomas. no earlier than one month after the operation and no later than two months, there was the first control by msct to assess sfr. after the first follow up visit after surgery, patients regularly (once every six months) underwent the examinations established by the protocol of the study: consultation of the operating doctor, blood and urine tests, ultrasound msct. there were several criteria for evaluation of treatment effectiveness: sfr, no re-operation, no complications > class ii according to clavian-dindo. sfr was evaluated according to two criteria: fragments > 1 mm and fragments > 2 mm. the perioperative period was evaluated separately by assessing the length of hospital stay, the total period of disability, the functional status in the postoperative period (pain, temperature, etc.). the cost-effectiveness of treatment was not evaluated. surgical treatment during the study, a common protocol of enhanced recovery for patients with planned endourological intervention foe renal stones was followed in both groups. table 2 presents the protocol scheme. table 2. the enhanced recovery protocol for endourological surgery for kidney stones. preoperative – informing the patient about the disease, treatment options, and possible outcomes, indicating the average effectiveness, risks of complications, typical postoperative condition, timing of catheterization, hospitalization, possible methods of pre-rehabilitation, and further rehabilitation methods – one-day concept: the patient undergoes most of the preoperative examinations in one day, without the need for multiple re-preparation; the order of examinations and tests is optimized and sorted to achieve the desired outcome – rigorous evaluation of indications for surgical treatment: symptomatic concretions; chronic urinary infection; concretions > 15 mm; progressive size growth; obstructive disorders; recurrent course – assessment of the possibility of patient compliance with the protocol and its feasibility in the medical institution – preventive administration of antihistamines and antacids drugs – avoiding of preoperative sedation – pre-rehabilitation based on indications: age group; obesity; exhaustion; sarcopenia; impaired carbohydrate tolerance or diabetes mellitus – preoperative antibiotic therapy according to the indications: latent or obvious infection of the genitourinary system (according to the results of bacteriological research) – multidisciplinary examination of patients: urologist; anesthetist; general practitioner/cardiologist; radiologist; and other specialists as needed – ct/mri of the urinary system, with 3d modeling and contrast, including angiography – a rich carbohydrate and protein meal (if there are no contraindications) and 200 ml of liquid 2.5 hours before surgery – the last meal (if the operation is in the morning) at 10 p.m. the day before, if in the afternoon no later than 6 hours before the operation – antibiotic prophylaxis 60 minutes before surgery with 3rd generation cephalosporins with a negative result of a urine culture examination – no shaving of the surgical area – preparation of the intestine with laxatives or single micro-clysm – prevention of thromboembolic complications by compression of the lower extremities and administration of low-molecular-weight heparins – no cleansing enemas – avoiding of pre-stenting/pre-catheterization intraoperative – preferred method of anesthesia: regional anesthesia/multimodal anesthesia – heating of the patient during the operation with the control of normothermia – heating of infusion solutions and inhalation gases – rirs or mini-(micro)-pcnl using flexible endoscopes – using a small diameter access sheath (up to 12-14fr with rirs; up to 14fr with pcnl) – laser application in low power mode (up to 10w) – avoiding of popcorning. spraying of fragments > 1 mm with difficult extraction – avoiding of the ureteral access sheath for single concretions < 10 mm with rirs – avoiding of multi-access with pcnl – administration of tranexamic acid before puncturing during pcnl – avoiding of nephrostomy/stenting if possible – reduced fluid pressure in the kidney – adhesive bandage on the skin – intraoperative euvolemia – urethral catheters 12-14ch – sealed cosmetic skin suture without loose ends and knots on the skin, adhesive bandages with pcnl postoperative – early fluids intake (2–3 hours after surgery) and food (6 hours after surgery) – early activation (2–4 hours after surgery, after evaluation by an anesthesiologist and urologist) – physical therapy (breathing exercises, walking, and other exercises) – multimodal prevention of nausea and vomiting (metoclopramide+ondansetron) – early ultrasound control to exclude hematomas and urinomas in the first 3-6 hours after surgery – removal of the urethral catheter, nephrostomy, stent after ultrasound control no later than 3 (for pcnl) and 1 (after rirs) day after surgery, followed by re-evaluation – hemostatic drugs (tranexamic acid) in intraoperative or detected postoperative bleeding – continuation of prevention of thromboembolic complications by compression of the lower extremities and the use of low-molecular-weight heparins – multimodal analgesia for pain control (dexketoprofen + paracetomol) – use of alpha blockers – chewing gum on the first and second day after surgery – monitoring of blood and urine parameters on the first day after surgery – strict glycemic control in case of impaired carbohydrate tolerance and diabetes mellitus – a detailed discussion of the behavior of the patient and the rehabilitation plan before the discharge – detailed written instructions in the discharge documents – strict plan of control examinations in the postoperative period – strict postoperative hygiene of the genitals and postoperative wounds (with an adhesive bandage, the patient is recommended to take a hygienic shower daily from the first day without additional processing) – discharge from the hospital within 1-3 days after the operation with the outpatient observation or the recovery archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 42 the final surgical treatment method was chosen before the operation by randomization. the operating time was estimated from the beginning (including patient positioning) to the complete end of all the actions of the surgical team. a thulium laser with a power mode up to 10w was used for lithotripsy. after both procedures, pyeloureterography was done at the end of the operation to assess the need for kidney stenting/nephrostomy. the main types of operations were mini-perc pcnl with access sheath up to 14 fr (for multiple and large concretions) and use of flexible optics (to avoid multi-access and to search for possible residual fragments). puncture of renal cavities was done under emergency operations center (eoc) and ultrasound control, after preliminary route planning based on the msct angiography results. the patient could be in any position at the discretion of the surgeon, avoiding prone position. nephrostomy was maintained in most cases for a period of 1 to 3 days. tubeless procedure was preferred for single, uninfected stones, without ongoing hematuria. rirs was performed under eoc control; when ureteral access sheath was not placed, the surgeon inserted the endoscope into the ureter up to the kidney with a guidewire. in absence of signs of perforation or fragments migration, a ureteral catheter was maintained for up to 12 hours from the end of surgery whereas in other situations, a ureteral stent was placed. after the operation, all patients stayed in the intensive care unit for 2-3 hours. all patients received multimodal analgesia, prevention of thromboembolic complications (low molecular weight heparin), and protection from stress ulcers (proton pump blockers). on the first day after surgical treatment patients were assessed the pain level. statistical analysis the pre-operative data and the results of surgical treatment were analyzed using statistica software for windows version 10.0 (statsoft, inc, usa), spss statistics version 23.0 (ibm, usa), and stata version 16.0 (statacorp, usa). the significance level for all the methods was set at p ≤ 0.05 (except multiple logistic regression). data of the two groups (rirs vs mini-pcnl) were compared. results peri-and postoperative results in the peri-and postoperative periods, there were no cases of lethality, anesthesiologic complications or critical deterioration of the state of health due to concomitant diseases in both groups. all registered complications corresponded to classes i-iiib clavien-dindo following the recommendations of the european association of urology (16, 17). there was one iiib complication in the pcnl group associated with an increasing paranephric hematoma. the average surgery duration in groups i and ii were 67 ± 34 and 75 ± 21 minutes, respectively (p = 0.350). the time of direct lithotripsy and evacuation of fragments for i and ii was 41 ± 31 and 49 ± 20 minutes, respectively (p = 0.276). table 3 shows the postoperative status of patients. significant postoperative complications (clavien-dindo ≥ 3) rarely developed in both groups. there is a significant statistical difference in the level of mild and minor complications: in group ii, class i complications occurred with a higher frequency (p = 0.007). migration of concretions fragments was more frequent in group ii (p = 0.009), which was probably due to worse visualization caused by the development of intraoperative hematuria. in general, hemorrhagic complications in group ii are significantly more common. an objective examination in the late postoperative period established the groups' comparability (p > 0.05) and a significant difference in the risks of complications, postoperative status, and duration of treatment (p < 0.05). it should be noted that the development of complications of classes iiia-b was isolated. univariate logistic regression analysis of these complications revealed no relationship with perioperative parameters (p > 0.05). table 4 partially presents the data of the performed regression analysis of predictors of postoperative complications. a significant predictor of residual concretions was the duration of lithotripsy for more than one hour (hr 2.40; 95% ci -0.21; 5.02; p = 0.072). the remaining factors were not significant (p > 0.1). table 3. postoperative status of patients. parameter group i group ii p (n = 23) (n = 27) clavien-dindo complications, n (%): i class ii class iiia class iiib class migration of concretions fragments, n (%) paranephral hematoma > 100 ml, n (%) blood transfusion, n (%) postoperative hematuria up to 1 day, n (%) subfebrility 1st day after surgery, n (%) febrility 1st day after surgery, n (%) pyelonephritis after surgery, n (%) stenting (i)\nephrostomy (ii), n (%) timing of kidney catheterization\nephrostomy, days perforation, n (%) re-operation, n (%) vas more than 5 points on the first day after surgery, n (%) postoperative pain, points average duration of hospitalization, bed-day 1-day stay, n (%) total treatment period, days sfr > 1 mm, n (%) sfr > 2 mm, n (%) vas: visual analog scale; sfr: stone-free rate. 1 (4.3%) 1 (4.3%) 1 (4.3%) 0 0 0 0 0 0 0 0 10 (43.4) 1 (1; 1) 1 (4.3%) 0 0 4 (4; 4) 1 (1; 1) 13 (56.5%) 1 (1; 2) 21 (91.3%) 22 (95.6%) 13 (48.1%) 6 (22.2%) 1 (3.7%) 1 (3.7%) 9 (33.3%) 1 (3.7%) 2 (7.4%) 13 (48.1%) 4 (14.8%) 3 (11.1%) 1 (3.7%) 17 (62.9) 2(2; 4) 1 (3.7%) 2 (7.4%) 21 (77.7%) 6 (6; 7) 3 (2; 4) 0 10 (3; 14) 23 (85.1%) 25 (92.5%) 0.007 0.115 0.911 0.360 0.009 0.360 0.199 0.002 0.073 0.118 0.360 0.448 < 0.001 0.911 0.199 0.002 < 0.001 < 0.001 0.005 < 0.001 0.867 0.936 archivio italiano di urologia e andrologia 2023; 95, 2 43 the retrograde intra-renal surgery figure 1 shows a model with a very good predictive value (area under curve, auc = 0.88) presented as a roc curve. consequently, the long duration of the operation (lithotripsy) increases the probability of residual fragments by 2.4 times. baseline anemia (hr 3.13; 95% ci 0.02; 6.24; p = 0.048; auc = 0.72) and urinary tract perforation (hr 3.85; 95% ci 0.44; 7.25; p = 0.027; auc = 0.73) were reliable predictors of the need for reoperation with one-factor regression. it was not possible to build a reliable multivariate regression model. significant predictors of postoperative hematuria were male gender (hr 2.14; 95% ci -0.27; 4.56; p = 0.082), duration of lithotripsy more than an hour (hr 3.53; 95% ci -0.31; 7.38; p = 0.072), chronic pyelonephritis (hr 3.09; 95% ci -0.48; 6.67; p = 0.090) and severe postoperative pain vas > 5 points (hr 3.35; 95% ci 0.34; 6.35; p = 0.029). figure 2 shows a model with excellent predictive value (area under curve, auc = 0.93) presented as a roc curve. the remaining factors were not significant (p > 0.1). significant predictors of postoperative exacerbation of urinary infection were chronic hepatitis (hr 3.93; 95% ci 0.15; 7.72; p = 0.041), baseline bacteriuria (hr 2.64; 95% ci -0.40; 5.69; p = 0.089) and any migration of concretion intraoperatively (hr 2.86; 95% ci -0.48; 6.22; p = 0.094). figure 3 shows a model with excellent predictive value (area under curve, auc = 0.94) presented as a roc curve. figure 1. roc curve for multivariate logit regression of predictors of postoperative residual concretions. figure 2. roc curve for multivariate logit regression of postoperative hematuria predictors. figure 3. roc curve for multivariate logit regression of predictors of exacerbation of urinary infection. table 4. analysis of predictors of complications in the early and late postoperative period. complication predictor univariate analysis multivariate analysis χ2 or (95% ci) p or (95% ci) p residual concretion. lithotripsy time > 60 minutes 14.61 3.61 (1.32; 5.89) 0.002 2.40 (–0.21; 5.02) 0.072 multivariate logit regression: intraoperative hematuria 3.62 1.61 (–0.05; 3.28) 0.057 χ2 = 16.89; p = 0.0007 any concrement migration 6.67 2.31 (0.55; 4.07) 0.010 1.21 (–1.07; 3.50) 0.299 area > 500 m2 9.17 2.8 (0.97; 4.77) 0.003 1.69 (–0.61; 4.00) 0.150 reoperation. multivariate initial anemia 3.30 3.13 (0.02; 6.24) 0.048 logit regression: χ2 = –; p =– perforation 4.30 3.85 (0.44; 7.25) 0.027 coagulopathy 2.20 2.39 (–.055; 5.35) 0.112 postoperative pain syndrome, increasing experience of the surgeon 9.59 –0.72 (–1.21; –0.23) 0.004 –0.51 (–1.7; 0.69) > 5 points on the vas scale lithotripsy time is more than 30 minutes 8.24 1.79 (0.47; 3.11) 0.008 2.28 (0.26; 4.31) prescription of acute illness, day 9.44 0.68 (0.20; 1.16) 0.005 0.03 (–0.07; 0.15) multivariate logit regression: 1-day surgery 6.96 –1.66 (–2.95; –0.37) 0.011 3.51 (–1.27; 8.31) χ2 = 34.38; p < 0.0001 preoperative waiting > 3 days 7.14 1.87 (0.39; 3.34) 0.013 1.73 (–1.74; 5.21) intraoperative hematuria 13.69 2.69 (1.02; 4.37) 0.002 1.78 (–0.88; 4.45) stenting 15.60 –2.74 (–4.38; –1.10) 0.001 –3.4 (–5.93; 0.87) any concrement migration 5.85 1.90 (0.21; 3.60) 0.028 1.48 (–1.71; 4.68) vas: visual analog scale. archivio italiano di urologia e andrologia 2023; 95, 2 v. vorobev, v. beloborodov, t. hovalyg, i. seminskiy, a. sherbatykh, i. shaderkin, m. firsov 44 significant predictors of postoperative pain syndrome were lithotripsy time of more than half an hour (hr 2.28; 95% ci 0.26; 4.41; p = 0.027). postoperative kidney stenting was a protective factor (hr -3.4; 95% ci -5.93; -0.87; p = 0.008). figure 4 shows a model with excellent predictive value (area under curve, auc = 0.92) presented as a roc curve. long-term results general results were reported according to the last observation. true relapse was considered only when newly identified concretions were observed in patients who were previously considered stone free with a 1 mm cut off (sfr > 1 mm). successful primary sfr > 1 mm was observed in 21 (91.3%) vs 23 (85.1%) (p = 0.867); false relapse in 2 (8.6%) vs 4 (14.8%) (p = 0.555); and true relapse in 2 (9.5%) vs 3 (13.0%) (p = 0.742) in group i and ii, respectively. the average clinical observation period was 251 days (95% ci 98-146 days) and maximum duration of follow up was 664 days. for group i, the average follow-up period was 218 days (95% ci 61-112 days) and maximum period of follow up was 440 days. for group ii, the average follow-up period was 279 days (95% ci of 108-189 days) and maximum period of follow up was 664 days. due to the absence of cases of lethality, survival analysis was not performed, the survival rate for both groups being 100%. there were no significant complications in the long-term postoperative period. in group i, kaplan-meyer's estimate of freedom from true stone recurrence was 95.6 ± 4.25% after the first six months (95% ci 72.9; 99.3%), 88.8 ± 7.6% (95% ci 60.9; 92.2%) after 9 months and 74.0 ± 14.9% (95% ci 32.5; 92.2%) after a year and a half. in group ii, freedom from true stone recurrence was 96.3 ± 3.6% (95% ci 76.4; 99.4%) after the first six months, 91.7 ± 5.6% (95% ci 70.4; 97.8%) after 9 months, and 84.9 ± 8.3% (95% ci 58.6; 95.1%) after a year and a half. the statistical uniformity of the likelihood ratio (likelihood-ratio test statistical of homogeneity) is comparable (p = 0.620; χ2 = 0.24). the log-rank criterion did not reveal statistical differences (p = 0.582; χ2 = 0.30) in the frequency of relapse over the entire follow-up period, which is graphically expressed by the kaplan-meyer method in figure 5. table 5 presents the regression model of proportional cox risks describing the influence of various factors on the development of relapse. multivariate regression analysis of proportional cox risk (sample from p < 0.05) demonstrated the significance of postoperative fever (hr 23.45; 95% ci 2.14; 256.5; p = 0.010) and initial stone density > 600 hu (hr 0.04; 95% ci 0.004; 0.49; p = 0.010) in predicting possible recurrence of urolithiasis. the treatment results showed statistical equality for stone free rate (sfr), freedom from stone recurrence during the entire follow-up period, and rate of complications of classes ii-iii clavien-dindo (p > 0.05). meanwhile, a significant superiority of group i (rirs) was demonstrated for shorter duration of hospitalization and overall disability, and better objective condition in the early postoperative period. economic efficiency was not evaluated. consequently, rirs meets the criteria of the enhanced recovery program more than pcnl with a similar perioperative protocol. figure 4. roc curve for multivariate logit regression of predictors of moderate postoperative pain. figure 5. freedom from a true relapse of stone formation according to the kaplan-meyer method. table 5. regression model of urolithiasis recurrence. variable univariate cox analysis multivariate cox analysis, χ2 = 12.66; p = 0.0018 valda χ2 hr (95% ci) p hr (95% ci) p febrility after surgery 3.59 6.77 (1.21; 37.9) 0.029 23.45 (2.14; 256.5) 0.010 concretion density > 600, hu 6.12 0.12 (0.022; 0.683) 0.016 0.04 (0.004; 0.49) 0.010 body mass index > 25 7.19 2.24 (0.88; 5.70) 0.090 – – duration of postoperative follow-up 4.99 0.88(0.785; 1.00) 0.056 – – archivio italiano di urologia e andrologia 2023; 95, 2 45 the retrograde intra-renal surgery limitations limitations of the study were the relatively small sample size, the average postoperative follow-up period less than two years, mixing of various surgical techniques within the framework of the protocol (pcnl, rirs). discussion in the presented study, the outcomes for sfr, i-iii class complications development, and surgery duration (lithotripsy) were similar to the data of other authors and meta-analyses of these data. the problem of a longer hospitalization and general treatment period and a more pronounced pain syndrome also corresponds to what reported in previous papers (18-21). a possible solution to align the results of the two procedures and improve compliance with the enhanced recovery program is the transition from mini-pcnl to micro-pcnl (22, 23). in general, analyzing the results of pcnl and rirs comparison presented by different authors, attention is drawn to the pronounced spread of sfr indicators, the lack of a clear definition of sfr by the size of the fragments, the lack of a clear definition of the operation duration and its pronounced spread. probably, such differences are due to different technical conditions, the experience of the surgical team, and other similar reasons. in general, our own experience demonstrates greater ease of implementation and convenience for rirs patients in comparison with mini-pncl. both treatment protocols are safe, effective, and accompanied by minimal risks of complications. they equally lead to high stone free rates (sfr > 1 mm, 91.3% vs 85.1%; p = 0.867; sfr > 2 mm, 95.6% vs 92.5%; p = 0.936). intergroup analysis of the total operation duration (and lithotripsy) demonstrated a similar duration in the two group (p > 0.05). postoperative complications (claviendindo) in the early and late periods developed rarely and were comparable (p > 0.05) although class i complications were predominant in the pcnl group (p = 0.007). some parameters demonstrated the superiority of rirs over pcnl: less pronounced pain syndrome (p = 0.002), less drainage time (p < 0.001), no postoperative hematuria (p = 0.002), lower average duration of hospitalization, and total time spent on treatment (p < 0.001). the analysis of predictors of the complication development based on the results of multivariate analysis showed that exceeding the lithotripsy time by more than one hour increases by 2.4 times (hr 2.40; 95% ci -0.21;5.02; p = 0.072) the risk of presence of residual fragments (sfr > 1 mm). this indicates the expedience of discussing a possible second stage of treatment in certain groups of patients. postoperative hematuria can be triggered by the following factors: male gender (hr 2.14; 95% ci -0.27; 4.56; p = 0.082), duration of lithotripsy more than an hour (hr 3.53; 95% ci -0.31; 7.38; p = 0.072), chronic pyelonephritis (hr 3.09; 95% ci -0.48; 6.67; p = 0.090) and severe postoperative pain (vas > 5 points) (hr 3.35; 95% ci 0.34; 6.35; p = 0.029). significant predictors of postoperative exacerbation of urinary infection are chronic hepatitis (hr 3.93; 95% ci 0.15; 7.72; p = 0.041), baseline bacteriuria (hr 2.64; 95% ci -0.40; 5.69; p = 0.089) and migration of concretions intraoperatively (hr 2.86; 95% ci -0.48; 6.22; p = 0.094). lithotripsy time of more than half an hour is a significant predictor of severe postoperative pain syndrome (hr 2.28; 95% ci 0.26; 4.41; p = 0.027) whereas a protective factor is postoperative kidney stenting (hr -3.4; 95% ci -5.93; -0.87; p = 0.008). special attention should be paid to the prognostic protective effect of the one-day surgery principle and the effect of improvement of the operating surgeon skills on the risk of complications such as postoperative hematuria, exacerbation of chronic urinary infection, severe postoperative pain syndrome (p < 0.05). both treatment protocols have a high safety profile without the risk of mortality or relapse. the log-rank criterion did not reveal statistically significant differences in the frequency of survival (p = 1), or relapse (p = 0.582). the advantages of the performed study are its prospective design, randomization, homogeneity of groups, mandatory strict protocol of the study, in-depth statistical analysis of outcomes, description of the algorithm of patient management with a detailed presentation of the materials and results of the study. conclusions the results of the study have high practical and scientific significance. the design of the study according to a strict protocol, compliance with the good clinical practice (gcp) criteria, a clear presentation of diagnostic, surgical, and statistical techniques, specific and objective parameters allowed us to obtain reliable results. the results led to important conclusions for the selection of treatments. rirs and mini-pcnl have similar effectiveness, but the path to recovery using retrograde surgery is somewhat simpler and shorter. rirs meets the criteria of the enhanced recovery program more than pcnl with a similar perioperative protocol. references 1. zeng j, wang s, zhong l, et al. a retrospective study of kidney stone recurrence in adults. j clin med res. 2019; 11:208-212. 2. lang j, narendrula a, el-zawahry a, et al. global trends in incidence and burden of urolithiasis from 1990 to 2019: an analysis of global burden of disease study data. eur urol open sci. 2022; 35:37-46. 3. hill aj, basourakos sp, lewicki p, et al. incidence of kidney stones in the united states: the continuous national health and nutrition examination survey. j urol. 2022; 207:851-856. 4. skolarikos a, straub m, knoll t, et al. metabolic evaluation and recurrence prevention for urinary stone patients: eau guidelines. eur urology. 2015; 67:750-763. 5. alhasan ka, shalaby ma, albanna as, et al. comparison of renal stones and nephrocalcinosis in children: findings from two 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adhikari b. perirenal extravasation after retrograde intrarenal surgery for renal stones: a prospective study. cureus. 2022; 14:e21283. 15. senel s, ozden c, aslan y, et al. can the stone scoring systems be used to predict infective complications after retrograde intrarenal surgery? med princ pract. 2022; 31:231-237. 16. mitropoulos d, artibani w, biyani cs, et al. validation of the clavien-dindo grading system in urology by the european association of urology guidelines ad hoc panel. eur urol focus. 2018; 4:608-613. 17. mitropoulos d, artibani w, graefen m, et al. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. eur urol. 2012; 61:341-349. 18. dossanova a, lozovoy v, wood d, et al. reducing the risk of postoperative genital complications in male adolescents. int j environ sci educ. 2016; 11:5797-5807. 19. ghazala sg, saeed ahmed sm, mohammed aa. can mini pcnl achieve the same results as rirs? the initial single center experience. ann med surg (lond). 2021; 68:102632. 20. erkoc m, bozkurt m, danis e, can o. comparison of minipcnl and retrograde intrarenal surgery in the treatment of kidney stone over 50 years old patients. urologia. 2022; 89:575-579. 21. nogaeva uv, naumova aa, novinkov ag, et al. comparative study of rheological properties of gels and creams on different carrier bases. drug dev registr. 2022; 11:121-129. 22. jain m, manohar cs, nagabhushan m, keshavamurthy r. a comparative study of minimally invasive percutaneous nephrolithotomy and retrograde intrarenal surgery for solitary renal stone of 12 cm. urol ann. 2021; 13:226-231. 23. pillai sb, chawla a, de la rosette j, et al. super-mini percutaneous nephrolithotomy (smp) vs retrograde intrarenal surgery (rirs) in the management of renal calculi ≤ 2 cm: a propensity matched study. world j urol. 2021; 40:553-562. conflict of interest: the authors declare no potential conflict of interest. correspondence vladimir vorobev, md (corresponding author) vorobevr782192@rambler.ru vladimir beloborodov, md vbeloborodov391@rambler.ru temirlan hovalyg, md temirlan_hovalyg@rambler.ru department of general surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation igor seminskiy, md department of pathology, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation seminskiy.igor@rambler.ru andrey sherbatykh, md andsherbatykh3@rambler.ru department of faculty surgery, irkutsk state medical university, krasnogo vosstaniya str., 1, irkutsk, 664003, russian federation igor shaderkin, md igshaderkin@rambler.ru e-health laboratory, i.m. sechenov first moscow state medical university, pirogovskaya str., 2, moscow, 119296, russian federation mikhail firsov, md m_firsov31@rambler.ru department of urology, andrology and sexology, krasnoyarsk state medical university named after professor v.f. voino-yasenetsky, partizan zheleznyaka str., 1, krasnoyarsk, 660022, russian federation stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2174 original paper no conflict of interest declared. symptoms (slow stream, splitting or spraying, intermittency, hesitancy, straining, terminal dribbling) and storage symptoms (day-time urinary frequency, nocturia, urgency, urinary incontinence) (3). these luts are among the most common clinical complaints in adult men with reported increasing prevalence with aging (4). the storage luts may also be termed overactive bladder (oab) symptoms and are largely encompassed by the term overactive bladder syndrome (oabs) (5). while the voiding symptoms are usually more prevalent, the storage symptoms are almost always more bothersome (6). associated with a significant burden on both patients and society, these luts also have a major impact on patients’ quality of life (qol) (7). as such, the american urological association (aua) has developed the international prostate symptom score (ipss) as one of the most reliable tools to evaluate the severity of luts associated with bph which, in turn, plays a major role in determining the most appropriate treatment option for bph (8-10). after being the preferred surgical treatment for bph patients for more than 30 years, transurethral resection of prostate (turp) has been replaced by holmium laser enucleation of prostate (holep) as the gold standard surgical treatment for bph (5, 11, 12). introduced in 1995, holep is a minimally invasive surgical procedure that has become the first line treatment of bph as it provides both effective and safe surgical treatment option for bph without any size limitation, although at the expense of occasional complications (11, 13, 14). holep has the advantage of enucleating the enlarging bph adenoma without destroying the bladder neck thus relieving bladder outflow obstruction (boo) immediately, safely, and effectively (5). although improvement in both storage and voiding luts has been demonstrated after either medical treatment with an alpha-blocker or a 5-alpha-reductase inhibitor or surgical treatment with turp for bph patients, few studies have been made to measure the outcomes of holep in bph-related voiding and/or storage luts (11). we performed our study with the aim to evaluate and compare the effectiveness and safety of holep in relieving either voiding or storage luts in bph patients. objective: to evaluate and compare the effectiveness and safety of holmium laser enucleation of prostate (holep) in relieving either voiding or storage lower urinary tract symptoms (luts) in benign prostatic hyperplasia (bph) patients. materials and methods: the charts of patients with bph who underwent holep for either predominant voiding or predominant storage luts at university of cincinnati hospitals in the period between february 2015 and december 2020 were retrospectively reviewed and analyzed for changes in voiding symptomatology, storage symptomatology, hematuria, international prostate symptom score (ipss), peak flow rates (qmax), presence of detrusor overactivity (do), and post-voiding residual urine (pvr) from baseline to up to 6 months postoperatively. results: a total of 132 patients were included in the analysis. patients were divided into two groups: group 1 included bph patients with predominant voiding luts (68 patients) while group 2 involved those with predominant storage luts (64 patients). holep was equally effective in management of both groups with significant improvement in urodynamics study (uds) parameters, patient voiding and storage symptomatology, and ipss from preoperatively to up to 6 months postoperatively with relatively low procedure complication rate and postoperative need for medication or procedure. conclusions: holep is a safe, effective, and reliable minimally invasive surgical modality that can be relied on for bph patients with either predominant voiding or predominant storage symptoms with relatively low procedure complication rate and postoperative need for medication or procedure. key words: holmium laser enucleation of prostate (holep); benign prostatic hyperplasia (bph); lower urinary tract symptoms (luts). submitted 28 march 2022; accepted 14 may 2022 introduction benign prostatic hyperplasia (bph) is a common condition affecting a large number of men over the age of 50 years and is the major cause of the highly prevalent lower urinary tract symptoms (luts) in men of this age group that often necessitate surgical intervention (1, 2). the luts associated with bph are generally divided into voiding is holmium laser enucleation of prostate equally effective in management of benign prostatic hyperplasia patients with either voiding or storage lower urinary tract symptoms? a comparative study mostafa m. mostafa 1, 2, nilesh patil 1, mahmoud khalil 2, mohammed a. elgammal 2, ayman mahdy 1 1 division of urology, department of surgery, university of cincinnati college of medicine, cincinnati (us); 2 asiut university hospitals, asiut, egypt. doi: 10.4081/aiua.2022.2.174 summary 175archivio italiano di urologia e andrologia 2022; 94, 2 holep for voiding or storage luts materials and methods after our study protocol approval by university of cincinnati institutional review board (irb id:2021-0666), we started reviewing the charts of all patients who underwent holep at university of cincinnati hospitals in the period between february 2015 and december 2020. all patients had routine initial evaluation with complete medical history, digital rectal examination (dre), ipss questionnaire, urinalysis, serum creatinine level, determination of serum prostate-specific antigen (psa) when needed, transrectal ultrasonography (trus), peak flow rate (qmax), postvoiding residual urine (pvr), and urodynamic study (uds) before proceeding to any surgical intervention. our inclusion criteria included patients with bph who underwent holep for either predominant voiding or predominant storage luts. we excluded patients who underwent the procedure for bph with concomitant bladder stones and/or neurogenic bladder. we also excluded patients with predominant storage luts along with pvr of 150 ml or more, patients taking medications that may mimic or aggravate the luts such as antidepressants, diuretics, bronchodilators, anticholinergics, sympathomimetics, and antihistamines (15), and those having uncontrolled diabetes mellitus (dm) or recurrent urinary tract infections (utis). for proper allocation of patients to either of our two comparative groups (bph patients with predominant voiding symptoms versus those with predominant storage symptoms), we used the principal indication for surgical intervention as determined by both subjective and objective parameters as the main allotment tool. regarding the subjective parameters, we analyzed nine symptoms in all patients and categorized them into two main categories in order to determine the type of patient predominant symptomatology: storage symptoms (frequency, urgency, nocturia, and urinary incontinence) and voiding symptoms (hesitancy, intermittency, terminal dribbling, straining, and urinary retention) (3). we also analyzed hematuria, a relevant symptom that is not specific for either group. analysis of symptoms was performed by the attending physician at the patient’s first presentation via asking the patient an open-ended question about the patient’s main complaint that urged him to seek medical care followed by closed-ended or binary questions to confirm the absence of the other relevant symptoms. additionally, to both confirm the proper allocation of each patient to the pertinent group and avoid reporting bias, we used uds as an objective parameter. as such, we identified patients with predominant voiding symptoms as those who reported their voiding symptoms as the more bothersome, whose voiding symptoms were the main drive for intervention, and whose uds showed a predominant obstructive pattern with urodynamic evidence of boo (boo index > 40 using ics nomogram (16). on the other hand, patients with predominant storage symptoms were defined as those who identified their storage symptoms as the more bothersome, who had no history of urinary retention, whose storage symptoms were the only indication for intervention, and whose uds showed a predominant oab pattern with volume to first contraction less than 350 ml and do (involuntary detrusor contraction ≥ 10 cm h2o) (17). all the cases included were performed by one highly skilled surgeon in the procedure (am) to avoid the interference of below optimum surgical skills or learning curve complications in our results. treatment efficacy, which was the primary outcome, was evaluated by comparing the preoperative uds parameters, patient symptomatology, and ipss with their postoperative counterparts. uds parameters (qmax, pvr, and demonstration of do) were reported twice: at baseline and at the 6month follow-up visit. we collected and compared them between the two groups. patient voiding symptomatology, storage symptomatology, hematuria, and ipss were reported at baseline, 3-month, and 6-month postoperatively. we also collected, analyzed, and compared them between the two groups. for the secondary outcome (treatment safety), any reported complication within the first 6 postoperative months was collected and analyzed. we also collected, analyzed, and compared the postoperative need for medication (antimuscarinic alone or antimuscarinic+ beta-3 agonist) or procedure (botox injection, urethral dilatation, or open prostatectomy) within the first 6 postoperative months between the two groups. table 1. demographic and baseline characteristics of the studied groups. figure 1. flowchart on inclusion and exclusion steps. variables group 1 (n = 68) group 2 (n = 64) p-value age (years) mean ± sd 75.2 ± 6.1 74.9 ± 5.5 0.767 bmi (kg/m2) mean ± sd 25.6 ± 2.68 25.6 ± 1.2 0.916 ethnicity white 26 (38.2%) 26 (40.0%) 0.214 black/african american 30 (44.1%) 20 (31.3%) hispanic 12 (17.6%) 18 (28.1%) smoking 32 (47.1%) 30 (46.9%) 0.983 diabetes mellitus 26 (38.2%) 30 (46.9%) 0.315 heart failure 25 (36.8%) 21 (32.8%) 0.634 hypertension 37 (54.4%) 33 (51.6%) 0.743 sd: standard deviation. archivio italiano di urologia e andrologia 2022; 94, 2 m.m. mostafa, n. patil, m. khalil, m.a. elgammal, a. mahdy 176 statistical analysis all statistical analyses were conducted using the ibm spss software package version 20.0 (armonk, ny: ibm corp). quantitative variables are presented as means ± standard deviation, and qualitative variables are expressed as frequencies with percentages. results were compared between two groups using student’s t-test and mannwhitney u test for quantitative variables and chi-square test and mcnemar’s test for qualitative variables. a p-value of < 0.05 was considered significant. results in total, 132 patients met the inclusion criteria, had complete follow-up data in their charts with preoperative and postoperative documentation of various voiding and storage symptomatology, ipss, and uds parameters and were included in our study. we allocated these patients into two groups: group 1 (68 patients) included those with predominant voiding symptoms while group 2 (64 patients) involved those with predominant storage symptoms (figure 1). demographic and baseline characteristics of the studied groups the median age was 75.2 ± 6.1 and 74.9 ± 5.5 years for groups 1 and 2, respectively with no significant differences in demographic and baseline characteristics between the two groups (table 1). uds parameters of the studied groups the mean preoperative peak flow rates (qmax) were 8.6 ± 2 and 12.5 ± 1.9 for groups 1 and 2, respectively with a significant increase in qmax postoperatively with p-value of increase of < 0.001 for both groups. with reference to do, there was a remarkable decrease in the presence of do after the procedure in both groups (4 out of 16 patients and 12 out of 64 patients with preoperative do for groups 1 and 2, respectively) with significantly higher decrease in do after the procedure in group 2 (p-value = < 0.001) than in group 1 (p-value = 0.008). as to post-voiding residual urine (pvr), there was a significant decrease in pvr after holep in both groups with p-value of improvement of < 0.001 for both groups (table 2). patient symptomatology of the studied groups there was a significant decrease in the frequency of the 4 studied storage symptoms and the 5 studied voiding symptoms in both groups from preoperatively to both 3and 6month postoperatively. eleven (16.2%) and seven (10.9%) patients from groups 1 and 2, respectively had preoperative hematuria that was completely alleviated after holep (table 3). ipss of the studied groups the mean preoperative ipss was 28.4 ± 3.4 and 26.9 ± 3 for groups 1 and 2, respectively, and there was significant decrease in ipss from preoperatively to both 3and 6month postoperatively in both studied groups with pvalue of decrease of < 0.001. interestingly, even though the preoperative ipss was significantly higher in group 1 than in group 2 (p-value = 0.010), there was non-significant difference in the decrease in ipss between both groups at both 3-month follow-up (p-value = 0.842) and 6-month follow-up (p-value = 0.483) (table 4). procedure complication rate and postoperative need for medication or procedure in the studied groups there was no significant difference between the studied groups as regarding procedure complication rate and postoperative need for medication or procedure. the most encountered complication was urinary tract infection occurring in 22 (32.4%) and 14 (21.9%) group 1 and 2 patients, respectively followed by urinary incontinence, bleeding, urethral stricture, and finally residual prostatic tissue. most patients didn’t require postoperative medication or procedure with only 10.3% and 4.4% of group 1 patients and 23.4% and 4.7% group 2 patients requiring postoperative medication and procedure, respectively (table 5). discussion to the best of our knowledge, we performed the first large study comparing the outcomes of holep in bph patients with predominant voiding symptoms and those with predominant storage symptoms in subjective outcomes (patient symptomatology and ipss), objective outcomes (uds parameters), procedure complication rate and postoperative need for medication or procedure. our study confirms that holep is associated with significant improvement in uds table 2. changes in urodynamic study (uds) parameters at 6-month postoperatively and comparison with preoperatively. variables group 1 (n = 68) group 2 (n = 64) p-value peak flow rate (qmax) preoperatively (mean ± sd) 8.6 ± 2 12.5 ± 1.9 < 0.001 (ml/s) 6-month postoperatively (mean ± sd) 14.2 ± 2.4 15.6 ± 1.7 < 0.001 p-value from preoperatively to 6-month postoperatively < 0.001 < 0.001 increase (mean ± sd) 5.6 ± 2.2 3.1 ± 1.9 < 0.001 detrusor over preoperatively activity (do) no 52 (76.5%) 0 (0%) < 0.001 yes 16 (23.5%) 64 (100%) 6-month postoperatively no 64 (94.1%) 52 (81.3%) 0.024 yes 4 (5.9%) 12 (18.8%) p-value from preoperatively to 6-month postoperatively 0.008 < 0.001 post-voiding preoperatively (mean ± sd) 239.4 ± 69.7 104.7 ± 22.6 < 0.001 residual urine 6-month postoperatively (mean ± sd) 53.7 ± 26.9 48.3 ± 15.3 0.156 (pvr) (ml) p-value from preoperatively to 6-month postoperatively < 0.001 < 0.001 decrease (mean ± sd) 185.7 ± 72.1 56.4 ± 24.86 < 0.001 sd: standard deviation. 177archivio italiano di urologia e andrologia 2022; 94, 2 holep for voiding or storage luts parameters, patient storage and voiding symptomatology, and ipss from preoperatively to both 3and 6month postoperatively with remarkably low procedure complication rate and postoperative need for either medication or procedure and with similar efficacy in bph patients with either predominant voiding or predominant storage symptoms. vavassori et al. performed a study evaluating outcomes of holep in 330 consecutive patients and reported significant improvement in qmax, ipss, and qol after 3-year follow-up with 8.5% of their patients having postoperative transient irritative symptoms, 7.3% having transient postoperative urinary incontinence, and 2.7% having persistent boo requiring reoperation (18). our results confirm the reported improvement in qmax and ipss and the possibility of transient postoperative irritative symptoms or urinary incontinence after holep. however, we also noted significant improvement in both pvr and do and comparable efficacy in management of both voiding and storage luts after holep. pyun et al performed a study to compare the outcomes of holep between 3 groups: boo-only, boo with detrusor underactivity (du), and boo with do and concluded that the improvement in the ipss and qmax was higher in the boo-only group than in the boo with do and boo with du groups (19). in contrast to their results, our results confirm that holep has a comparable efficacy in management of bph patients with either predominant voiding or predominant storage symptoms with significant improvement in uds parameters, patient symptomatology, and ipss in both groups of patients, and we can assume that the difference between our results can be attributed to the fact that they had significantly higher number of patients in the boo-only group (138 patients) compared to boo with do group (56 patients) and boo with du group (33 patients) and that they included a group having du in the comparison denoting including patients with late stage bladder dysfunction in their study. besides, we would like to point that it is better to compare the preoperative with the postoperative qmax for each of the studied groups rather than the degree of increase in qmax between the studied groups because the lower the qmax, the higher the room for increase. for example, in our study, the qmax was preoperatively significantly lower in group 1 having recurrent attacks of urinary retention, and so, although there was a higher increase in qmax after holep in group 1, the postoperative qmax was still higher in group 2. jeong et al. conducted a study to evaluate the effect of the presence of preoperative detrusor overactivity on the functional outcomes of holep and concluded that although the storage symptoms improved in patients who had preoperative do and those who did not, a significant table 3. changes in patient symptomatology at 3and 6month postoperatively and comparison with preoperatively variables group 1 (n = 68) group 2 (n = 64) p-value storage symptoms frequency preoperatively 24 (35.3%) 54 (84.4%) < 0.001 3-month postoperatively 9 (13.2%) 24 (37.5%) 0.001 6-month postoperatively 6 (8.8%) 16 (25%) 0.013 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 <0.001 urgency preoperatively 19 (27.9%) 53 (82.8%) < 0.001 3-month postoperatively 9 (13.2%) 19 (29.7%) 0.021 6-month postoperatively 3 (4.4%) 8 (12.5%) 0.093 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 < 0.001 nocturia preoperatively 30 (44.1%) 52 (81.3%) < 0.001 3-month postoperatively 12 (17.6%) 26 (40.6%) 0.004 6-month postoperatively 6 (8.8%) 6 (9.4%) 0.912 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 < 0.001 urinary incontinence preoperatively 8 (11.8%) 38 (59.4%) < 0.001 3-month postoperatively 2 (2.9%) 9 (14.1%) 0.021 6-month postoperatively 0 (0%) 3 (4.7%) 0.111 p-value from preoperatively to 3-and 6-month postoperatively 0.006 < 0.001 voiding symptoms hesitancy preoperatively 54 (79.4%) 10 (15.6%) < 0.001 3-month postoperatively 16 (23.5%) 5 (7.8%) 0.014 6-month postoperatively 8 (11.8%) 2 (3.1%) 0.098 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 0.047 intermittency preoperatively 52 (76.5%) 8 (12.5%) < 0.001 3-month postoperatively 16 (23.5%) 4 (6.3%) 0.006 6-month postoperatively 5 (7.4%) 0 (0%) 0.058 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 0.018 terminal dribbling preoperatively 56 (82.4%) 10 (15.6%) < 0.001 3-month postoperatively 22 (32.4%) 4 (6.3%) < 0.001 6-month postoperatively 5 (7.4%) 1 (1.6%) 0.209 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 0.011 straining preoperatively 50 (73.5%) 24 (37.5%) < 0.001 3-month postoperatively 34 (50%) 15 (23.4%) 0.002 6-month postoperatively 9 (13.2%) 6 (9.4%) 0.485 p-value from preoperatively to 3-and 6-month postoperatively < 0.001 < 0.001 urinary retention preoperatively 68 (100%) 0 (0%) < 0.001 3-month postoperatively 1 (1.5%) 0 (0%) 1.000 6-month postoperatively 0 (0%) 0 (0%) – p-value from preoperatively to 3-and 6-month postoperatively < 0.001 – hematuria preoperatively 11 (16.2%) 7 (10.9%) 0.381 3-month postoperatively 2 (2.9%) 1 (1.6%) 1.000 6-month postoperatively 0 (0%) 0 (0%) – p-value from preoperatively to 3-and 6-month postoperatively < 0.001 0.005 archivio italiano di urologia e andrologia 2022; 94, 2 m.m. mostafa, n. patil, m. khalil, m.a. elgammal, a. mahdy 178 number of those who had preoperative do required postoperative anticholinergics (11). we agree with their results that patients with preoperative do on uds would require transient postoperative anticholinergic therapy and can add that there is significant improvement in both voiding and storage symptoms after holep in patients with and without preoperative do on uds. study limitations the retrospective nature of the study and the absence of comparative groups including patients who underwent other bph procedures to compare the effectiveness and complication rate of holep with those of other bph procedures can affect the generalizability of our results. although we would have preferred to use the ipss voiding subscore (ipss-v) and the ipss storage subscore (ipss-s) rather than the total ipss (ipss-t) to facilitate assignment of the patients to either of the two groups, we could not do so as we retrospectively reviewed the charts of patients after the ipss-t rather than the ipss-v and ipss-s had already been calculated at the time of the patients’ visits. however, we used both subjective and objective parameters to compensate for the lack of data regarding the ipss subscores and to ensure the proper allocation of patients to the relevant study groups. conclusions holep is a safe and reliable minimally invasive surgical modality with reported significant improvement in both subjective (measured by patients’ symptomatology and ipss) and objective (measured by uds parameters) aspects associated with bph. it is highly efficient in alleviating both voiding and storage symptoms and can be resorted to whether the patient is suffering from predominant voiding or predominant storage symptoms. moreover, the procedure complication rate and postoperative need for medication or procedure are relatively low. references 1. porreca a, d'agostino d, vigo m, et al. "in-bore" mri prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation. arch ital urol androl. 2020; 91:224-9. 2. lee yj, oh sa, kim sh, oh sj. patient satisfaction after holmium laser enucleation of the prostate (holep): a prospective cohort study. plos one. 2017; 12:e0182230. 3. gratzke c, schlenker b, seitz m, et al. complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. j urol. 2007; 177:1419-22. 4. martin sa, haren mt, marshall vr, et al. prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling australian men. world j urol. 2011; 29:179-84. 5. saito k, hisasue s, ide h, et al. the impact of increased bladder blood flow on storage symptoms after holmium laser enucleation of the prostate. plos one. 2015; 10:e0129111. 6. peters tj, donovan jl, kay he, et al. the international continence society "benign prostatic hyperplasia" study: the botherosomeness of urinary symptoms. j urol. 1997; 157:885-9. 7. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015; 67:1099109. 8. rodrigues p, meller a, campagnari jc, et al. international prostate symptom score--ipss-aua as discriminat scale in 400 male patients with lower urinary tract symptoms (luts). int braz j urol. 2004; 30:135-41. 9. barry mj, fowler fj, jr., o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549-57; discussion 64. 10. o'leary mp, wei jt, roehrborn cg, et al. correlation of the international prostate symptom score bother question with the benign prostatic hyperplasia impact index in a clinical practice setting. bju int. 2008; 101:1531-5. 11. jeong j, lee hs, cho wj, et al. effect of detrusor overactivity on table 4. changes in international prostate symptom score (ipss) at 3and 6month postoperatively and comparison with preoperatively. group 1 (n = 68) group 2 (n = 64) p-value ipss preoperatively (mean ± sd) 28.4 ± 3.4 26.9 ± 3 0.010 3-month postoperatively (mean ± sd) 19.9 ± 5.2 18.3 ± 4.3 0.061 6-month postoperatively (mean ± sd) 12.3 ± 5.7 10.3 ± 5.1 0.036 p-value from preoperatively to 3 and 6-month postoperatively < 0.001 < 0.001 decrease in ipss from preoperatively to 3-month postoperatively (mean ± sd) 8.5 ± 3.8 8.6 ± 3.4 0.842 from preoperatively to 6-month postoperatively (mean ± sd) 16 ± 4.6 16.6 ± 4.7 0.483 sd: standard deviation. table 5. comparison of procedure complication rate and postoperative need for medication or procedure within the first 6 postoperative months between the two groups. variables group 1 (n = 68) group 2 (n = 64) p-value residual prostatic tissue 1 (1.5%) 0 (0%) 1.000 bleeding 7 (10.3%) 4 (6.3%) 0.401 urinary tract infection 22 (32.4%) 14 (21.9%) 0.177 urinary incontinence 5 (7.4%) 7 (10.9%) 0.474 urethral stricture 2 (2.9%) 1 (1.6%) 1.000 postoperative need for medication 0.128 no 61 (89.7%) 49 (76.6%) antimuscarinic alone 5 (7.4%) 11 (17.2%) antimuscarinic + beta-3 agonist 2 (2.9%) 4 (6.2%) postoperative need for procedure 0.466 no 65 (95.6%) 61 (95.3%) botox 0 (0%) 2 (3.1%) urethral dilatation 2 (2.9%) 1 (1.6%) open prostatectomy 1 (1.5%) 0 (0%) 179archivio italiano di urologia e andrologia 2022; 94, 2 holep for voiding or storage luts functional outcomes after holmium laser enucleation of the prostate in patients with benign prostatic obstruction. urology. 2015; 86:133-8. 12. schiavina r, bianchi l, giampaoli m, et al. holmium laser prostatectomy in a tertiary italian center: a prospective cost analysis in comparison with bipolar turp and open prostatectomy. arch ital urol androl. 2020; 92:82-88. 13. ryoo hs, suh ys, kim th, et al. efficacy of holmium laser enucleation of the prostate based on patient preoperative characteristics. int neurourol j. 2015; 19:278-85. 14. romagnoli d, ghaemian m, d'agostino d, et al. not fatal venous air embolism after holmium laser enucleation of the prostate: case report and review of literature. arch ital urol androl. 2020; 92:55-7. 15. wuerstle mc, van den eeden sk, poon kt, et al. contribution of common medications to lower urinary tract symptoms in men. arch intern med. 2011; 171:1680-2. 16. abrams p, cardozo l, fall m, et al. the standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. am j obstet gynecol. 2002; 187:116-26. 17. allameh f, basiri a, razzaghi m, et al. clinical efficacy of transurethral resection of the prostate combined with oral anticholinergics or botulinum toxin a injection to treat benign prostatic hyperplasia with overactive bladder: a case-control study. clin pharmacol. 2020; 12:75-81. 18. vavassori i, valenti s, naspro r, et al. three-year outcome following holmium laser enucleation of the prostate combined with mechanical morcellation in 330 consecutive patients. eur urol. 2008; 53:599-604. 19. pyun jh, kang sg, kang sh, et al. efficacy of holmium laser enucleation of the prostate (holep) in men with bladder outlet obstruction (boo) and non-neurogenic bladder dysfunction. kaohsiung j med sci. 2017; 33:458-63. correspondence mostafa m. mostafa, md (corresponding author) mostafmm@ucmail.uc.edu research fellow of urology, division of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, cincinnati, oh 45267 assistant lecturer of urology, asiut university hospitals, asiut, egypt nilesh patil, md patilnh@ucmail.uc.edu associate professor of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, cincinnati, oh 45267 mahmoud khalil, md mahmoud.magdy51@gmail.com lecturer of urology, asiut university hospitals, asiut, egypt mohammed a. elgammal, md mohammedelgammal@aun.edu.eg professor of urology, asiut university hospitals, asiut, egypt ayman mahdy, md, phd, mba mahdyan@uc.edu chief of urology, professor of urology, r. bruce and barbara bracken endowed chair in surgical urology, director of voiding dysfunction and female urology, medical director of urology, the west chester hospital, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, ml 0589, cincinnati, oh 45267 stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12450 1 original paper covaginal fistula. the incidence is pinpointed because of underdiagnosis and lack of awareness of this condition. previous research has found that vvf incidence is higher in low-and middle-income countries, although there is also a relatively high incidence in high-income countries (1-3). at least 3 million women in third-world countries are affected by this condition (4). in african countries alone, up to 130.000 new cases are found each year (5). indonesia, a developing country, also suffers greatly from the high prevalence of vvf (6). therefore, many women with vvf are undiagnosed and untreated, leaving quite a complex healthcare problem (5, 6). despite its significant impact, there has yet to be a consensus on the optimal approach to treat vvf. the choice of therapy is mainly based on expert opinion and surgeon experience. currently, the european association of urology guidelines have no specific algorithm for vvf repair (7). furthermore, it is lacking a surgical treatment algorithm based on the characteristics of the fistula. the purpose of this study was to review practice patterns and outcomes of vvf treatment in indonesia to aid practitioners in selecting appropriate management for their patients. methods this research is an observational study with a cross-sectional design. the sample selection was carried out by voluntary reply to a survey link which was sent to surgeons who performs vvf repair in referral hospitals throughout indonesia. the invited surgeons were urogynecologists, female urologists, and general urologists who had a course of vvf repair. the indonesian urology association and indonesian obstetrics and gynecology association facilitated the research by listing the surgeon performing vvf repair. this study was conducted between june and july 2021. data collection was limited to one year prior to survey completion. we tried to increase the sample after the end of the pandemic era, but the additional data did not meet the inclusion criteria. the assessment of all variables was carried out using a structured questionnaire in electronic form. data collected in the survey period were downloaded from the servobjectives: vesicovaginal fistulas (vvf) are the most commonly acquired fistulas of the urinary tract. the management of vvf is mainly based on expert opinion and surgeon experience. this study aims to provide the practice patterns and outcomes of vesicovaginal fistula (vvf) management in indonesia. methods: this study utilizes the results of a survey among the surgeons who performs vvf repair in referral hospitals throughout indonesia between june and july of 2021. data analysis was carried out with spss descriptively by displaying the relative frequency of the answers to each question of the questionnaire form. results: we collected responses from 93 respondents consisting of 68 urologists and 25 gynecologists. the most commonly reported cause of vvf was obstetric (50.5%). most respondents confirmed the diagnosis of vvf by cystoscopy (81.7%). waiting time to repair vvf was generally 12 weeks (79.6%), while the transvaginal approach repair was more often performed (77.4%). an additional procedure, such as tissue interposition was performed in 50.5% of cases. tissue interposition was mostly indicated in recurrent vvf (81%), with omentum being the most selected tissue interposition (71%). when indicated, the most selected method of transabdominal approach was open transvesical (54,84%). a laparoscopic approach was performed only in 7.5% of cases. overall, the success rate for vvf repair in indonesia was 70-100% at first attempt. conclusions: the transvaginal approach is preferred, either with or without an interposition tissue flap. the success rate at the first attempt is satisfactory. key words: vesicovaginal fistula; genitourinary fistula; fistula. submitted 4 march 2024; accepted 29 march 2024 introduction vesicovaginal fistulas (vvf) are the most commonly acquired fistulas of the urinary tract (1). although rarely fatal, vvf causes great concern because of its disturbance to a patient’s quality of life, encompassing physical, emotional, psychological, and economic aspects. to date, there has never been a comprehensive worldwide survey designed to precisely determine the information on vesisurgeon’s point of view in vesico-vaginal fistula management kadek budi santosa 1, 2, stacia novia marta 2, 3, ronald sugianto 2, 4, fina widia 5, parsaoran nababan 6, harrina erlianti rahardjo 5 1 department of urology, faculty of medicine, universitas udayana, indonesia; 2 prof. dr. i.g.n.g ngoerah general hospital, denpasar, indonesia; 3 department of surgery, faculty of medicine, universitas udayana, indonesia; 4 department of urology, faculty of medicine, universitas airlangga, indonesia; 5 department of urology, faculty of medicine, universitas indonesia, cipto mangunkusumo general hospital, jakarta, indonesia; 6 department of urology, bhayangkara anton soedjarwo hospital, pontianak, indonesia. doi: 10.4081/aiua.2024.12450 summary archivio italiano di urologia e andrologia 2024; 96(2):12450 k. budi santosa, s. novia marta, ronald sugianto, et al. 2 er in the format of excel data. data analysis was carried out with spss descriptively by displaying the relative frequency of the answers to each question of the questionnaire form. results vvf in referral hospitals in indonesia ninety-three respondents were surgeons who performed vvf repair in various referral hospitals in indonesia. most of the surgeons were urologists (51.6%). the number of vvf cases managed by each practitioner was generally less than 10 cases in 1 year (91.4%), with the most common etiologies being obstetric etiology, which consist of vaginal delivery, caesarean section procedure, and caesarean hysterectomy (50.5%) and iatrogenic etiology, which is related to urinary tract injuries during abdominal surgery (table 1). the choice of modalities used for diagnosing vvf varied, with cystoscopy being the most common examination used by 81.7% of surgeons (figure 1). it was followed by the dye/methylene blue test (64.5%), cystography (60.2%), pelvic examination (53.8%), and intravenous table 1. the characteristics of vvf cases at the referral hospitals in indonesia. variable n % operator general urologist 48 51.6 female urologist 20 21.5 urogynecologist 25 26.9 number of vvf repairs per year < 10 85 91.4 10-20 8 8.6 most common vvf etiology obstetric 47 50.5 iatrogenic 45 48.4 radiation 1 1.1 obstetric vvf cases none 7 7.5 < 5% 26 28 5-10% 9 9.7 > 10%-20% 9 9.7 > 20% 39 41.9 no answer 3 3.2 figure 1. diagnostic modalities of vvf. figure 2. the abdominal approach in vvf repair. archivio italiano di urologia e andrologia 2024; 96(2):12450 3 management of vesico-vaginal fistula pyelography (ivp) (2.2%). in the case of iatrogenic vvf, the majority of surgeons (65.6%) did not routinely perform an ivp as the first examination. most of the surgeons (79.6%) choose 12 weeks to perform vvf repair. the transvaginal approach for vvf repair was carried out by 77.4% of respondents. when indicated the most selected method of transabdominal approach was open transvesical (54.84%), as shown in figure 2. as many as 50.5% of surgeons did not use tissue interposition for vvf repair. tissue interposition was indicated for recurrent vvf (81%), complex vvf (64.3%), in all cases (35.7%), and radiation cases (35.7%) (figure 3). the most widely used interposition was the omentum (71%) (figure 4), followed by labial fat-fibrose tissue (55%), and peritoneum (17%). most surgeons did not routinely give antimuscarinic to the patient after vvf repair (72%). in comparison, respondents' opinion was quite divided on the use of ureteral protection during vvf repair: 50.5% did not do it routinely, while 46.2% did it routinely. overall, the first attempt at vvf repair was quite successful, with only 16.1% of respondents having < 70% success (table 2). figure 3. indication for the use of interposition tissue. figure 4. tissue interposition for vvf repair. table 2. overview of the management of vvf at the referral hospital in indonesia. variable n % ivp examination iatrogenic vvf routinely 32 34.4 unroutinely 61 65.6 waiting time for traumatic vvf repair 2 weeks 5 5.4 4 weeks 5 5.4 6 weeks 1 1.1 8 weeks 5 5.4 10 weeks 1 1.1 12 weeks 74 79.6 vvf repair by transvaginal approach yes 72 77.4 general urologist 27 29.0 female urologist 20 21.5 gynecologist 25 26.9 no (general urologist) 20 21.5 percentage of vvf repair by transvaginal approach < 25% 11 14.7 25-50% 10 13.3 archivio italiano di urologia e andrologia 2024; 96(2):12450 k. budi santosa, s. novia marta, ronald sugianto, et al. 4 discussion vesico vaginal fistula is the most common fistula found in the daily clinical setting (> 72%), occurring mainly from obstetrical complications (80%) (5, 6, 8). this research confirms this finding with obstetrical complication being the most common cause for vvf (50.5%), followed with iatrogenic (48.1%). in this survey, cystoscopy was the most frequent diagnostic modality used by respondents to diagnose vvf (81.7%), followed by dye/methylene blue (64.5%) and cystography (60.2%). patients with vesicovaginal fistula usually present with symptoms of continuous urinary leakage. the severity of the clinical manifestation depends on the size of the fistula. in the examination, the surgeons must evaluate the fistula's size, number, and site to plan treatment (3). through previous clinical experience, it was found that diagnostic modalities differ in each management area, and urologists tend to confirm vvf by performing cystoscopy. meanwhile, intravenous pyelography is another modality used to diagnose a concurrent ureteral injury. however, only 34.4% of surgeons apply this modality. evaluation of the upper urinary tract might be essential because up to 12% of postsurgical vvfs have an associated ureter injury (9). the choice of the diagnostic modality highly depends on resource availability and operator judgment. the timing of vvf repair is of utmost importance because the first attempt of treatment is correlated with the best possible outcome (3, 10). timing of repair is subject to numerous factors, such as current illness, other comorbidities, nutritional status, and immunity of the patient. this research also observes that the common waiting time from vvf diagnosis to repair was 12 weeks (79.6%). this finding is in agreement with the literature, reporting an expected waiting time of 12 weeks (3). other waiting timing options reported were 2, 4, and 8 weeks with an equal response rate of 5% (3). the only exception to this timing is vvf caused by radiation, which usually needs about six months to 1 year of waiting time from diagnosis to repair (3, 4). this timing also considers tissue necrosis and subsidence of inflammation after childbirth and postsurgical vvf (3). other things that need to be considered are hemostasis and adequate vascular supply, sufficient exposure and tissue mobilization, and also tensionless suture (3). the transvaginal approach is also more favored in the repair of vvf, as also observed in previous studies (3, 4, 11, 12). in this research, 77.4% of surgeons choose transvaginal approach in vvf repair. furthermore, 30.7% of surgeons use a transvaginal approach in 100%, whereas 28% of surgeons use it in 75-100% of cases. we found that all participants who did not perform the transvaginal approach were urologists, who usually preferred for the transabdominal approach based on familiarity and preferences acquired during residency. this difference is becoming increasingly blurred as urologists gain more experience and comfort in transvaginal surgery for various disparate indications. the transvaginal approach is favored because it significantly reduces the risk of hemorrhage, offers numerous interposition flaps options, implies a shorter surgery time and rapid recovery (3). however, abdominal approach should be considered if there are contraindications for transvaginal approach. it should be also considered in presence of associated bladder stones or in the case of high-position fistula with an anatomically narrow vagina. the most recommended transabdominal approach, which once was the gold standard for vvf repair, is the o’connor procedure which includes an intraperitoneal approach. the most used transabdominal method for vvf repair in the present study was the open transvesical approach (54.84%) followed by open transperitoneal transvesical (21.5%) and open transperitoneal extravesical approach (21.5%). in 7.5% of all cases, a laparoscopic approach was chosen. the laparoscopic approach is relatively more efficient and less invasive, with less downtime and complications (14). there are still debates about the best transabdominal method, although it can be concluded that the most recommended procedure is most probably the procedure in which the operator feels most confident and trained (3, 4, 10). application of tissue transposition is made by only 45.2% of surgeons participating in the survey, whereas 50.5% surgeons do not. there are differences in the type of tissue interposition between urologists and gynecologists, where 53.6% of urologists prefer to use omentum (65%) and labia fat fibrous tissue (46%). in comparison, only 20% of urogynecologists perform transposition flaps and prefer to use omentum and labial fat for tissue transposition equally. evans et al. (12), found that a 100% success rate was observed in applying tissue transposition in repair, whereas a 63% success rate was observed in repair without tissue transposition. however, a study by pshak et al. (15) found that the cure rate without tissue transposition application is 100%. in our survey, surgeons mainly apply tissue transposition in the cases of recurrent vvf (81%), complex vvf (64.3%), and vvf due to radiation (35.7%). the anatomical organ mostly used for tissue transposition is the omentum (71%), followed by labial fat-fibrous tissue and peritoneum. other tissue transposition flaps that can be used are gracilis muscle, and urinary bladder mucosa advancement flaps (10). as an alternative floseal hemostatic matrix can be used. previous studies have stated that no technique is superior than another, and tissue > 50-75% 10 13.3 > 75-< 100% 21 28.0 100% 23 30.7 tissue transposition for vvf repair yes 42 45.2 no 47 50.5 ureteral protection during vvf repair routinely 43 46.2 unroutinely 47 50.5 antimuscarinic medication after vvf repair routinely 22 23.7 unroutinely 67 72 successful rate after the first attempt vvf repair < 70% 15 16.1 70-75% 16 17.2 > 75-80% 7 7.5 > 80-85% 11 11.8 > 85-90% 13 14.0 > 90-95% 9 9.7 > 95-< 100% 14 15.1 100% 6 6.5 archivio italiano di urologia e andrologia 2024; 96(2):12450 5 management of vesico-vaginal fistula used for transposition depends on technical approach, surgeon’s clinical experience, and preference (4). in our survey, only 46.2% surgeons routinely insert a ureteral catheter for ureter protection, whereas 50.5% do not. this choice depends on considering the risk of ureteral injury during the dissection and suturing of the fistula. antimuscarinic medication benefits the patient by alleviating discomfort postoperatively and reducing bladder spasms (6, 16). still, some surgeons choose to give antimuscarinics only if there is a complaint of urgency or discomfort during the use of the catheter instead of giving it routinely as seen in the results of our survey, where only 23.7% of surgeons administer antimuscarinic medication for patients during the use of the catheter. the overall success rate is defined as the overall percentage of all patients recovering completely, as clinically demonstrated by termination of constant leaking of urine after removal of the postoperative catheter (4). in this research, most surgeons report a 70-100% success rate at first attempt, regardless of the repair technique. a similar success rate in the first attempt repair (70-100%), was found throughout the literature for both vaginal and abdominal approaches (17). one of the latest studies by warner et al. found a success rate at first attempt repair of 91% (vaginal) and 86% (abdominal) (18). however, success rates can be as low as 42% in other studies, which are negatively affected by the difficulty of repair (19). factors of repair failure are vaginal delivery and partial or total damage of the urethra, and also malignant etiology of the fistula and its further management by chemotherapy and radiotherapy that could delay the healing phase of the fistula repair (20). there are several nonrandomized cohort studies reporting results from both abdominal and vaginal procedures with overall closure rates at the first operation of 89% and 87%, respectively (21, 22). the authors considered a limitation of this study the fact that being the most preferred technique did not guarantee its superiority. however, this is the first study that assesses the vvf treatment from the surgeon’s point of view, which might help and guide the vvf treatment based on indonesian experiences. the location of the hospital and the resources of the hospital may affect a differing clinical judgment in each case. we recommended further research on vvf repair with population-based research and global surveys of fistula patient management in each hospital. conclusions management of vvf in indonesia was initiated with cystoscopy. most operators choose to repair vvf after 12 weeks, with the transvaginal technique being the most common approach. the use of tissue interposition is usually done in a complex vvf. overall, the success rate for vvf repair in indonesia is 70-100% at first attempt. ethical approval ethical approval has been acquired in this study by health research ethics committee of prof. i.g.n.g. ngoerah general hospital, denpasar, indonesia with no. 2267/ un14.2.2.vii.14/lt/2023. references 1. el-azab as, abolella ha, farouk m. update on vesicovaginal fistula: a systematic review. arab j urol. 2019; 17:61-8. 2. haroun a, ali mahamat m, abdel salam s, cherif h, jalloh m, niang l, et al. the epidemiological, clinical and therapeutical aspects of the vesico-vaginal fistula at the national fistula treatment center in n'apos djamena. int j clin urol. 2020; 4:34. 3. rajaian s, pragatheeswarane m, panda a. vesicovaginal fistula: review and recent trends. indian j urol. 2019; 35:250. 4. abrams p, de ridder d, devries c, elneil s, esegbona g, mourad s, et al. obstetric fistula in the developing word. icud-siu international consultation, marrakech, morocco, october 13-16, 2010. 5. lo ts, chua s, wijaya t, kao cc, uy-patrimonio mc. clinical relevance and treatment outcomes of vesicovaginal fistula (vvf) after obstetric and gynecologic surgery. taiwan j obstet gynecol. 2019; 58:111-6. 6. mukti na, mochtar aa, wiyati ps. kejadian fistula urogenital pada perempuan di rsup dr. kariadi semarang. 2018; 7:16. 7. harding ck, lapitan mc, arlandis s, bo k, cobussen-boekhorst h, costantini e, et al. eau guidelines on management of nonneurogenic female lower urinary tract symptoms. eau guidelines 2023. 2023:91-95. 8. adibarata ma, aditya r, gumilar ke, pascawardhana m, wicaksono b, ernawati, et al. bacterial vaginosis in gynecologic outpatient clinic dr. soetomo hospital january june 2017: a cross sectional study. in proceedings of the 23rd regional conference of dermatology (rcd 2018), scitepress 2021, pp 307-311. 9. goodwin we, scardino pt. vesicovaginal and ureterovaginal fistula: a summary of 25 years of experience. j urol. 1980; 123: 370-4. 10. shrestha db, budhathoki p, karki p, jha p, mainali g, dangal g, et al. vesico-vaginal fistula in females in 2010-2020: a systemic review and meta-analysis. reprod sci. 2022; 29:3346-3364. 11. margules ac, rovner es. the use of tissue flaps in the management of urinary tract fistulas. curr urol rep. 2019; 20:32. 12. singh v, mehrotra s, bansal a, akhtar a, sinha rj. prospective randomized comparison of repairing vesicovaginal fistula with or without the interposition flap: result from a tertiary care institute in northern india. turk j urol. 2019; 45:377-83. 13. warner r, beardmore-gray a, pakzad m, hamid r, ockrim j, greenwell t. the cost effectiveness of vaginal versus abdominal repair of vesicovaginal fistula. int urogynecology j. 2020; 31:1363-9. 14. giannakopoulos s, arif h, nastos z, liapis a, kalaitzis c, touloupidis s. laparoscopic transvesical vesicovaginal fistula repair with the least invasive way: only three trocars and a limited posterior cystotomy. asian j urol. 2020; 7:351-6. 15. pshak t, nikolavsky d, terlecki r, flynn bj. is tissue interposition always necessary in transvaginal repair of benign, recurrent vesicovaginal fistula? urology. 2013; 82:707-12. 16. breen m, ingber m. controversies in the management of vesicovaginal fistula. best pract res clin obstet gynaecol. 2019; 54:61-72. 17. stamatakos m, sargedi c, stasinou t, kontzoglou k. vesicovaginal fistula: diagnosis and management. indian j surg. 2014; 76:131-6. 18. warner r, beardmore-gray a, pakzad m, hamid r, ockrim j, greenwell t. the cost effectiveness of vaginal versus abdominal repair of vesicovaginal fistula. int urogynecology j. 2020; 31:1363-9. 19. bernard l, giles a, fabiano s, giles s, hudgins s, olson a, et al. archivio italiano di urologia e andrologia 2024; 96(2):12450 k. budi santosa, s. novia marta, ronald sugianto, et al. 6 predictors of obstetric fistula repair outcomes in lubango, angola. j obstet gynaecol can. 2019; 41:1726-33. 20. delamou a, delvaux t, beavogui ah, toure a, kolié d, sidibé s, et al. factors associated with the failure of obstetric fistula repair in guinea: implications for practice. reprod health. 2016; 13:135. 21. hilton p. urogenital fistula in the uk: a personal case series managed over 25 years. bju int. 2011; 110:102-10. 22. ockrim jl, greenwell tj, foley cl, wood dn, shah pjr. a tertiary experience of vesico-vaginal and urethro-vaginal fistula repair: factors predicting success. bju int. 2009; 103:1122-6. correspondence kadek budi santosa (corresponding author) busanbsa@gmail.com department of urology, faculty of medicine, universitas udayana prof. dr. i.g.n.g ngoerah general hospital, denpasar jl. pb sudirman, denpasar 80232, bali, indonesia stacia novia marta stacianoviamarta@gmail.com prof. dr. i.g.n.g ngoerah general hospital, denpasr department of surgery, faculty of medicine, universitas udayana ronald sugianto ronald.sugianto-2023@fk.unair.ac.id prof. dr. i.g.n.g ngoerah general hospital, denpasar department of urology, faculty of medicine, universitas airlangga fina widia finawidia@yahoo.com department of urology, faculty of medicine, universitas indonesia, cipto mangunkusumo general hospital, jakarta parsaoran nababan saornbbn@gmail.com department of urology, bhayangkara anton soedjarwo hospital, pontianak harrina erlianti rahardjo harrinaerlianti@gmail.com department of urology, faculty of medicine, universitas indonesia, cipto mangunkusumo general hospital, jakarta conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12335 1 original paper opting for vasectomy subsequently expresses a desire for additional pregnancies (2). for these individuals, there are four choices for expanding their families: vasectomy reversal, sperm extraction with in-vitro fertilization (ivf), donor sperm insemination, and adoption. various factors, including parental age, female factor infertility, desired number of children, and cost, play a role in deciding between these options. approximately 30,000 patients annually choose vasectomy reversal (3). among those considering vasectomy reversal, a key question is the impact of seminal antisperm antibody (asa) levels on postoperative pregnancy rates. seminal asas in the general infertility population can cause immunologic infertility by affecting various sperm-related processes. however, it remains unclear if seminal asas also result in infertility after vasectomy reversal (4, 5). despite the presumed high seminal asa levels in individuals who have undergone vasectomy reversal, the pregnancy rates are substantial, with about 73% achieving pregnancy (6). given these considerations, the clinical significance of seminal asa levels after vasectomy reversal warrants further investigation (7, 8). previous research on this topic, conducted in the 1980s, predates advancements in microscopic vasectomy reversal techniques and relies on outdated testing methods for seminal asa levels (9). the 2015 american urologic association (aua) vasectomy guidelines highlight the need for additional research on the impact of antisperm antibodies and their influence on fertility rates after vasectomy reversal (10, 11). our laboratory routinely conducts igg asa testing on all semen samples with progressive motile sperm concentrations of ≥ 2m/ml, including post-vasectomy reversal samples. this presents a unique opportunity for us to assess the relationship between seminal asa levels following vasectomy reversal and pregnancy rates, as well as the methods of conception. through retrospective chart reviews and phone interviews of patients who underwent vasectomy reversal at our institution, we aim to explore the potential association between seminal asa levels and pregnancy rates, methods of conception, and semen analysis parameters. our hypothesis was that seminal asa levels were not correlated with pregnancy rates or methods of conception after vasectomy reversal. objective: to investigate the correlation between antisperm antibodies (asas), pregnancy rates, and the method of conception following vasectomy reversal. this is particularly relevant as patients undergoing vasectomy reversal often express concerns about the potential inhibitory effects of asas on achieving pregnancy. additionally, the american urological association guidelines for vasectomy emphasize the need for further research to address this question. patient and methods: we conducted a retrospective analysis involving chart reviews and phone interviews with individuals who underwent vasectomy reversal at our institution between may 2015 and april 2023. patients who underwent vasectomy reversal for reasons other than fertility, as well as those lacking postoperative semen analysis with asa data, were excluded. we classified patients based on low (below 50%) or high (50% or above) asa levels determined by their initial postoperative semen analysis. the primary outcome measured was the pregnancy rate, including details on the method of conception. results: a total of 145 patients were subjected to chart review. the median age at the time of surgery was 43 years, with a median obstruction interval of 7.7 years. the median age of their partners was 29 years. the majority (80%) of patients underwent bilateral vasovasostomy. among them, 60 patients (41.4%) exhibited low (< 50%) asa levels, while 85 (58.6%) had high (≥ 50%) asa levels. follow-up phone interviews were completed by 48 patients. among them, the 19 men with low asa levels, 13 (68.4%) achieved pregnancy, with 6 (31.6%) experiencing spontaneous conception. for the 29 men with high asa levels, 21 (72.4%) achieved pregnancy, including 11 (38%) through spontaneous conception. the p-value from fisher’s exact test was 0.2. conclusions: our findings suggest that asa levels do not show a significant association with either the pregnancy rate or the method of conception following vasectomy reversal. key words: antisperm antibody; conception; vasectomy. submitted 31 january 2024; accepted 15 february 2024 introduction vasectomy is conducted around 500,000 times annually in the united states, being a secure and efficient method of permanent male contraception (1). about 6% of men effects of antisperm antibodies post vasectomy reversal on pregnancy rates tamer a. abouelgreed 1, mohamed a. amer 2, hassan mamdouh 2, ahmed f. el-sherbiny 3, hany aboelwafa 2, omar a. omar 2, mohammed abdelshakour 2, mohammad elesawy 2, mohamed sonbol 2, ahmed n. maawad 2, elsayed m. zayed 2, mostafa t. eldestawy 2 1 department of urology, al-azhar university, cairo, egypt & gulf medical university, ajman, uae; 2 department of dermatology & andrology, al-azhar university, cairo, egypt; 3 department of andrology, international islamic center for population studies and research, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2024.12335 summary archivio italiano di urologia e andrologia 2024; 96(2):12335 t.a. abouelgreed, m.a. amer, h. mamdouh, et al. 2 patient and methods in this study, we enrolled consecutive patients who underwent vasectomy reversal at our institution between may 2012 and april 2020, under the care of two surgeons. patients undergoing vasectomy reversal for pain or those lacking postoperative semen analysis with asa were excluded from the study. all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of thumbay university hospital (affiliated to gulf medical university, rec #: 21/2015). data collection to gather comprehensive data, we conducted a chart review encompassing patient and partner demographics (such as age, number of prior pregnancies, and obstruction interval at the time of vasectomy reversal), details about the surgical technique, intraoperative vasal fluid quality, postoperative complications, and parameters from follow-up semen analyses. chart review and phone interviews were the primary methods employed. patients meeting the inclusion criteria were invited to participate in a phone interview, and notifications were sent via sms to alert them about an expected call from the study team. the study team made up to three attempts to contact each patient for the phone interview. during the interview, a standardized script was utilized, addressing inquiries about pregnancies post-vasectomy reversal and the methods of conception. asa testing and semen analysis standard semen analysis, including volume, concentration, motility, total motile sperm count, and strict morphology, was performed on all samples using world health organization (who) reference techniques and appropriate ranges based on the year of the semen analysis. additionally, igg sperm mar asa testing was routinely conducted on all semen samples with progressive motile sperm concentrations of ≥ 2m/ml, a technique first described in 1992 (12). our laboratory, in accordance with who 5th edition reference range for asa levels, performed igg asa testing on semen samples with a 50% cut-off to categorize low (below 50%) and high (≥ 50%) asa levels. furthermore, we evaluated seminal asa levels as a continuous variable to explore if an alternative cut-off could more accurately predict pregnancy rates. outcomes our primary objectives cantered on assessing the pregnancy rate and the method of conception, including details such as intercourse, intrauterine insemination (iui), ivf, and other methods like donor insemination, as reported by the patients during the phone interviews. secondary outcomes focused on the semen analysis parameters obtained from the initial postoperative semen analysis. statistical analyses statistical analyses were conducted using descriptive statistics to evaluate demographic and clinical characteristics of patients meeting inclusion criteria, comparing those who completed phone interviews to the overall cohort. the wilcoxon signed-rank test was employed to assess differences in semen analysis parameters between individuals with low and high seminal asa levels. to analyse pregnancy rates and methods of conception among men with different seminal asa levels, fisher's exact test was utilized. considering the potential confounding effect of the time interval since vasectomy on pregnancy outcomes, the relationship between seminal asa levels and obstructive interval was evaluated using the wilcoxon signed-rank test. additionally, a logistic model was employed to explore whether an alternative seminal asa level cut-off, apart from the conventional 50%, could provide better predictive value for pregnancy rates. sensitivity analyses were incorporated to address two decisions made in our primary analyses. firstly, we conducted a sensitivity analysis to determine the impact of using continuous seminal asa levels instead of dichotomized low and high levels. secondly, to assess the influence of using the last postoperative semen analysis (rather than the first) on our findings, we reanalysed the primary outcomes using the last postoperative semen analysis for patients with multiple postoperative analyses. all statistical analyses were carried out using sas version 9.4 (sas institute inc.), and a p-value below 0.05 was considered statistically significant. table 1. demographics and clinical characteristics for studied patients. entire cohort phone interview cohort (n = 145) (n = 48) patient age at time of procedure (years) median (iqr) 43 (35-48) 43 (34-49) # of prior pregnancies median (iqr) 2 (1-3) 2 (1-3) partner age at time of procedure (years) median (iqr) 29 (2636) 29 (25-37) obstruction interval (months) 7.7 (4.1 – 11.4) 8.2 (4.512) procedure bilateral vv n (%) 116 (80%) 36 (75%) formal two-layer/formal two-layer n (%) 29 (20%) 12 (25%) formal two-layer/modified two-layer n (%) 4 (2.7%) 2 (4.16%) formal two-layer/unknown n (%) 1 (0.7%) 0 modified two-layer/formal two-layer n (%) 5 (3.4%) 3 (6.25%) modified two-layer/modified two-layer n (%) 102 (70.3%) 31 (64.5%) modified two-layer/unknown n (%) 1 (0.7%) 1 (2%) unknown/unknown n (%) 1 (0.7%) 0 vv/ve n (%) 26 (17.9%) 8 (16.6%) formal two-layer n (%) 8 (31%) 2 (27%) modified two-layer n (%) 18 (68%) 6 (74%) bilateral ve n (%) 1 (0.7%) 0 unilateral vv n (%) 3 (2%) 3 (4.16%) formal two-layer n (%) 2 (67%) 2 (67%) modified two-layer n (%) 1 (33%) 1 (33%) intraoperative vasal fluid quality right side clear/watery n (%) 24 (16.6%) 12 (25%) cloudy/opaque/opalescent/milky n (%) 80 (55.1%) 23 (47.9%) thick/yellow/toothpaste/creamy/pasty n (%) 18 (12.5%) 7 (14.6%) scant/paucity n (%) 8 (5.5%) 2 (4.4%) missing n (%) 15 (10.3%) 4 (8.1%) archivio italiano di urologia e andrologia 2024; 96(2):12335 3 antisperm antibodies after vasectomy reversal results after applying the specified inclusion and exclusion criteria, we identified a cohort comprising 145 patients who underwent vasectomy reversal at our institution between may 2012 and april 2020. the median age at the time of surgery for this cohort was 43 years, with a median obstruction interval of 7.7 years. the median age of their partners was 29 years. among the 145 patients, 116 (80 %) underwent bilateral vasovasostomy, 24 (16.6%) underwent a combination of vasovasostomy and vasoepididymostomy, 3 (2%) underwent unilateral vasovasostomy, and 2 (1.4%) underwent bilateral vasoepididymostomy (table 1). forty eight (33%) participated in a phone interview. the demographic and clinical characteristics, including obstruction interval, vasectomy reversal technique, intraoperative vasal fluid quality, and postoperative complications, were comparable between the overall cohort of 145 patients and the subgroup of 48 patients who completed the phone interview. of the 145 patients, 60 had low seminal asa levels (< 50%), while 85 had high seminal asa (≥ 50%) levels. there were no statistically significant differences in obstruction interval, vasectomy reversal technique, or semen analysis parameters (e.g., concentration, total motility, total motile sperm count, strict morphology) between the low and high seminal asa groups (table 2). of the 48 patients who completed the phone interview, 19 (39.6%) had low seminal asa levels, and 29 (60.4%) had high seminal asa levels (table 3). the median time from vasectomy reversal to the date of completing the phone interview was 8.2 years for the low seminal asa group and 7.9 years for the high seminal asa group. among the men with low seminal asa levels, 13 (68.4%) achieved a pregnancy, with 9 (47.3%) having spontaneous pregnancies and 4 (21.1%) using ivf. among the men with high seminal asa levels, 22 (75.8%) achieved a pregnancy, with 12 (41.4%) having spontaneous pregnancies, 3 (10.4%) using intrauterine insemination (iui), and 7 (24%) using ivf. the fisher’s exact test p-value for differences in pregnancy rates and methods of conception was 0.2. no statistically significant relationship was found between obstruction interval and pregnancy rates (wilcoxon test p-value = 0.5) (table 3). to assess whether a different seminal asa level cut-off could better predict pregnancy rates, we employed a logistic model to examine the relationship between seminal asa levels as a continuous variable and pregnancy rates. the analysis revealed no association between seminal asa levels and pregnancy rates, with a p-value of 0.98. in sensitivity analyses, our findings remained consistent when using continuous seminal asa levels instead of dichotomized levels (wilcoxon p-value 0.97). among the 79 patients with multiple postoperative semen analyses, 17 (22%) experienced changes in their seminal asa categories across analyses. specifically, 9 (53%) patients shifted from the low to the high seminal asa group, 7 (41%) shifted from the high to the low seminal asa group, and 1 (6%) changed across groups in both directions. furthermore, our results were unchanged when using seminal asa levels from the last postoperative semen analyses instead of those from the first postoperative semen analysis (signed rank test, p-value = 0.5). table 2. vasectomy reversal technique, obstruction interval, and follow up semen analysis parameters for studied patients. low asa levels high asa levels p-value (< 50%), n = 60 (≥ 50%), n = 85 obstruction interval (years) median (iqr) 7.1 (3.5-12) 7.7 (5.2-10.2) 0.31 technique of vasectomy reversal bilateral vv n (%) 50 (83.33%) 67 (78.8%) 0.72 vv/ve n (%) 9 (15%) 16 (18.8%) unilateral vv n (%) 1 (1.67%) 2 (2.4%) follow up semen analysis parameters number of follow up sas 1st n (%) 43 (71.66%) 46 (54.1%) 0.06 2nd n (%) 10 (16.67%) 24(28.2%) 3rd n (%) 7 (11.67%) 15 (17.7%) first semen analysis values time to first sa (weeks) median (iqr) 9 (7.6-19) 10 (6-15) > 0.9 concentration (m/ml) median (iqr) 36 (12-74) 32 (12-57) 0.31 total motility (%) median (iqr) 38 (19-46) 39 (21-42) 0.73 total motile sperm count (m/ejaculate) median (iqr) 32 (5.1-76) 26 (8.8-64) > 0.9 normal morphology (%) median (iqr) 6 (5-9) 8 (4-11) 0.74 motility motile n (%) 43 (29.64%) 17 (35.4%) nonmotile n (%) 50 (34.36%) 14 (29.2%) missing n (%) 52 (36%) 17 (35.3%) left side clear/watery n (%) 22 (15.2%) 8 (16.6%) cloudy/opaque/opalescent/milky n (%) 80 (55.2%) 24 (50%) thick/yellow/toothpaste/creamy/pasty n (%) 20 (13.8%) 9 (18.75%) scant/paucity n (%) 9 (6.2%) 2 (4.2%) missing n (%) 14 (9.6%) 5 (10.45%) motility motile n (%) 30 (21%) 15 (31.2%) nonmotile n (%) 35 (24%) 15 (31.2%) missing n (%) 80 (55%) 18 (37.6%) postoperative complications none n (%) 137 (94.4%) 44(91.6%) infection n (%) 4 (2.8%) 2 (4.2%) other n (%) 4 (2.8%) 2 (4.2%) follow up semen analysis parameters number of follow up sas 1st n (%) 89 (61%) 27 (56.3%) 2nd n (%) 34 (24%) 15 (31.2%) 3rd n (%) 22 (15%) 6 (12.5%) first semen analysis (sa) values time to first sa (weeks) median (iqr) 11 (8.1-20) 10 (8-19) concentration (m/ml) median (iqr) 33 (13-70) 32 (10-69) total motility (%) median (iqr) 38 (18-47) 39 (11-41) total motile sperm count (m/ejaculate) median (iqr) 27 (9-64) 21 (757) normal morphology (%) median (iqr) 7 (4-9) 8 (6-11) antisperm antibody (%) median (iqr) 48 (13-88) 46 (1187) < 50% n (%) 60 (42%) 20(41.66%) ≥ 50% n (%) 84 (58%) 28 (59.34%) archivio italiano di urologia e andrologia 2024; 96(2):12335 t.a. abouelgreed, m.a. amer, h. mamdouh, et al. 4 discussion we have three main findings. firstly, there is no association between seminal asa levels after vasectomy reversal and pregnancy rates or methods of conception. secondly, men with low and high seminal asa levels showed no differences in postoperative semen analysis parameters. thirdly, we were unable to identify a specific cut-off level for postoperative seminal asa levels that strongly correlates with pregnancy rates. overall, these findings indicate that seminal asa levels are not linked to pregnancy rates, the method of conception, or semen analysis parameters following vasectomy reversal. these insights can enhance the counselling of patients before and after undergoing vasectomy reversal. our discovery that seminal asa levels after vasectomy reversal are not associated with pregnancy rates or methods of conception contrasts with earlier studies from the 1980s (10, 13). in particular, thomas et al. (13) found no association between serum or seminal asa titres and pregnancy rates in 35 men who underwent vasectomy reversal at a single centre with at least 1 year of follow-up. parslow et al. (10) in their evaluation of 130 men at two canters, observed that higher preoperative serum asa titres were linked to lower pregnancy rates, while postoperative seminal asa titres were not associated with pregnancy rates after at least 1 year of follow-up. belker et al., cited by nam et al. (14), in their prospective study of patients who had undergone vasovasostomy, found that 66% of those who achieved pregnancy had no measurable serum asa levels, while 71% of those unable to achieve pregnancy had measurable serum asa levels. these studies suggested that patients with serum asa levels exceeding 2 million per millilitre might require ivf to achieve pregnancy, irrespective of seminal asa levels. our study had longer follow-up than studies previously mentioned and used the modern day igg spermmar technique to measure seminal asas, as recommended by the who laboratory manual (12). despite these earlier findings, our study highlights that seminal asa levels following vasectomy reversal are not correlated with decreased pregnancy rates. this information can offer reassurance to patients seeking to have children after a vasectomy. for healthcare providers, our results can serve as valuable insights when counselling patients before and after vasectomy reversal. furthermore, we observed no significant differences in postoperative semen analysis parameters between men with low and high asa levels. the impact of seminal asa on semen analysis parameters in the general male infertility population has shown mixed findings. some studies have reported associations between elevated seminal asa levels and increased sperm agglutination, (15, 16) decreased sperm concentration, (17, 18) and reduced sperm motility (4, 16-18). however, the influence of seminal asa levels on semen analysis parameters within the vasectomy reversal patient population has not been thoroughly evaluated. in our study, there was no statistically significant distinction in semen analysis parameters, including concentration, total motility, total motile sperm count, and strict morphology, between men with low and high seminal asa levels, using either the first or the last postoperative semen analysis. these findings underscore the necessity of establishing specific semen analysis reference values for vasectomy reversal patients, enabling more accurate counselling of postoperative patients on their likelihood of spontaneous conception (19). finally, we were unable to identify a specific cut-off level for postoperative seminal asa levels strongly associated with pregnancy rates. the 2010 who laboratory manual recommended asa testing as a routine component of semen analyses with a 50% cut-off to categorize low and high asa levels. however, limited evidence supports this 50% cut-off, and the 2010 who laboratory manual acknowledges it as a "consensus" threshold value. the 2021 who laboratory manual discussed the limited evidence behind asa reference values and cautioned against over interpreting asa values as causative of subfertility. despite efforts using a logistic model to find a more effective seminal asa cut-off for predicting pregnancy rates after vasectomy reversal, we were unable to identify a cutoff that reliably predicted a couple's likelihood of achieving pregnancy (20). our study comes with several limitations. firstly, the data were retrospectively obtained from a single institution, potentially limiting the generalizability of our observations to other settings. nevertheless, our study presents a contemporary analysis compared to earlier studies from the 1980s, featuring a longer follow-up and the use of modern, who-recommended laboratory techniques for measuring asa levels. secondly, approximately one-third of the included patients participated in a phone interview, introducing the potential for selection bias. however, the demographic and clinical characteristics of the interviewed men were similar to those of the overall cohort. thirdly, postoperative semen analyses were conducted at varying time points after surgery, with some patients undergoing multiple analyses. we chose to utilize the first postoperative semen analysis to categorize patients as having low or high seminal asa levels. although 22% of the cohort exhibited movement across seminal asa groups over time, our sensitivity analysis table 3. pregnancy rates and methods of conception for studied patients, based on the first postoperative semen analysis. low asa levels high asa levels p-value (< 50%), n = 19 (≥ 50%), n = 29 obstruction interval (years) median (iqr) 8 (3.0-14) 8.0 (6.0-11) 0.7 time from vasectomy reversal to first asa measurement (weeks) median (iqr) 7.9 (7.2-15) 10(8.1-11) 0.4 time from vasectomy reversal to phone interview (years) median (iqr) 10.3 (5.2-14.7) 9.6 (3.1-11.6) 0.2 postoperative pregnancy yes n (%) 13 (68.4%) 21 (72.4%) 0.2 spontaneous n (%) 11 (58%) 11 (38%) ivf n (%) 2 (10.4%) 7 (24%) iui n (%) 0 (0%) 3 (10.4%) no n (%) 6 (31.6%) 8 (27.6%) archivio italiano di urologia e andrologia 2024; 96(2):12335 5 antisperm antibodies after vasectomy reversal using the last postoperative semen analysis did not alter our findings. fourthly, since our laboratory routinely performs asa testing on semen samples with progressive motile sperm concentrations of ≥ 2 million per millilitre, there may be a selection bias as patients with severe oligoasthenospermia were excluded from our analysis. however, we identified 17 samples with sperm concentrations < 2 million per millilitre and available seminal asa levels, as asa testing on semen samples was conducted at the laboratory's discretion for all samples. additionally, men with progressive motile sperm concentrations < 2 million per millilitre are likely to require ivf to achieve pregnancy, irrespective of seminal asa levels. notwithstanding these limitations, our study holds significant implications for both patients and healthcare providers. for individuals seeking to conceive after a vasectomy, our findings provide assurance that high seminal asa levels after vasectomy reversal are not linked to decreased pregnancy rates. conclusions postoperative seminal asa levels are not associated with pregnancy rates, methods of conception, or semen analysis parameters after vasectomy reversal surgeries. accordingly we highly recommend preand post-operative patient counselling in the context of vasectomy reversal. acknowledgments we would like to thank prof. dr. hossam hamdy (the chancellor of gulf medical university) for his valuable support. references 1. ostrowski ka, holt sk, haynes b, et al. evaluation of vasectomy trends in the united states. urology. 2018; 118:76-79. 2. sandlow ji, nagler hm. preface. urol clin north am. 2009; 36:xiii-xiv. 3. dubin jm, white j, ory j, et al. vasectomy reversal vs. sperm retrieval with in vitro fertilization: a contemporary, comparative analysis. fertil steril. 2021; 115:1377-1383. 4 silva af, ramalho-santos j, amaral s. the impact of antisperm antibodies on human male reproductive function: an update. reproduction. 2021; 162:r55-r71. 5. el-sherbiny af, ali ta, hassan ea, et al. the prognostic value of seminal anti-sperm antibodies screening in men prepared for icsi: a call to change the current antibody-directed viewpoint of sperm autoimmunity testing. ther adv urol. 2021; 13:1756287220981488. 6. royle mg, parslow jm, kingscott mm, et al. reversal of vasectomy: the effects of sperm antibodies on subsequent fertility. br j urol. 1981; 53:654-9. 7. herrel la, goodman m, goldstein m, et al. outcomes of microsurgical vasovasostomy for vasectomy reversal: a metaanalysis and systematic review. urology. 2015; 85:819-825. 8. hellema hw, samuel t, rumke p. sperm autoantibodies as a consequence of vasectomy. ii. long-term follow-up studies. clin exp immunol. 1979; 38:31-36. 9. tung ks. human sperm antigens and antisperm antibodies i. studies on vasectomy patients. clin exp immunol. 1975; 20:93-104. 10. parslow jm, royle mg, kingscott mm, et al. the effects of sperm antibodies on fertility after vasectomy reversal. am j reprod immunol (1980). 1983; 3:28-31. 11. silber sj, grotjan he. microscopic vasectomy reversal 30 years later: a summary of 4010 cases by the same surgeon. j androl. 2004; 25:845-859. 12. cooper tg, aitken j, auger j, et al. who_asa. world health organization. published online 2010. 13. thomas aj jr, pontes je, rose nr, et al. microsurgical vasovasostomy: immunologic consequences and subsequent fertility. fertil steril. 1981; 35:447-50. 14. nam cs, tooke bp, strasser o, et al. antisperm antibody levels after vasectomy reversal are not associated with pregnancy rates or method of conception. urology. 2024 feb 27: s00904295(24)00124-9. 15. barbonetti a, castellini c, d’andrea s, et al. prevalence of antisperm antibodies and relationship of degree of sperm auto-immunization to semen parameters and post-coital test outcome: a retrospective analysis of over 10 000 men. human reproduction. 2019; 34:834-841. 16. tomlinson m, lewis s, morroll d. sperm quality and its relationship to natural and assisted conception: british fertility society guidelines for practice. hum fertil. 2013; 16:175-193. 17. verón gl, molina ri, tissera ad, et al. incidence of sperm surface autoantibodies and relationship with routine semen parameters and sperm kinematics. am j reprod immunol. 2016; 76:59-69. 18. cui d, han g, shang y, et al. antisperm antibodies in infertile men and their effect on semen parameters: a systematic review and meta-analysis. clin chim acta. 2015; 444:29-36. 19. majzoub a, tadros nn, polackwich as, et al. vasectomy reversal semen analysis: new reference ranges predict pregnancy. fertil steril. 2017; 107:911-915. 20. bjorndahl l, apolikhin o, baldi e, et al. who laboratory manual for the examination and processing of human semen sixth edition. correspondence tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg department of urology, al-azhar university, cairo, egypt & gulf medical university, ajman, uae mohamed a. amer, md amerrom@yahoo.com hassan mamdouh, md hsdermaclinic@yahoo.com hany aboelwafa, md dr_hanyos138@yahoo.com omar a. omar, md omarabdelhady.236@azhar.edu.eg m. abdelshakour, md dr.mohammed_121@yahoo.com mohammad elesawy, md elesawy288@gmail.com mohamed sonbol, md bosombol1185@gmail.com ahmed n. maawad, md ah.nabil70@gmail.com elsayed m. zayed, md sayedmzayed@gmail.com mostafa t. eldestawy, md mostafa.eldestawy@azhar.edu.eg department of dermatology & andrology al-azhar university, cairo, egypt ahmed f. el-sherbiny, md ahmed_derma@yahoo.com department of andrology, international islamic center for population studies and research, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12464 1 original paper sterile but healthy men and up to 25% of obstructive azoospermia cases (2). to date, two perspectives have been presented regarding the etiology of the cbavd: vas deferens atresia and vas deferens agenesis. even though the comprehensive pathological mechanism is required to be further studied and validated, these pathological mechanisms are widely known to be triggered by gene alterations (3). mainly cbavd is diagnosed at adulthood during a medical examination for the exploration of infertility. therefore, it is of prime importance to properly assess infertile men with appropriate clinical work-up, to correctly address the suitable genetic tests in an exclusive way (4). initially, clinical diagnosis was made on the palpation of the vas deferens (vd), that is, on their intrascrotal portion: the diagnosis was negative if this portion was present and positive if it was absent. but in recent times, besides palpation, ultrasound imaging (transrectal and scrotal) is essential for accurate diagnosis (5). the biological alarming signal is a nonpathognomonic trio: hypospermia (semen volume < 1.5 ml), the value of seminal plasma lesser than the reference level (fructose < 13 μmol/ejaculate; glycerophosphocholine (gpc) < 2 µmol/ejaculate), and acid ph (< 7.0) (6). hence, on the basis of clinical symptoms, two clinical categories of cbavd have been reported: cbavd showing symptoms of cystic fibrosis referred as cf-cbavd and cbavd without clinical symptoms of cf referred as isolated cbavd (icbavd) (7). furthermore, apart from cf associated symptoms, other congenital genitourinary defects, primarily including dysplasia or the absence of seminal vesicles and kidney-related issues contributes towards cbavd (8, 9). the anatomical anomalies related to cbavd occur at the embryonic stage. cystic fibrosis transmembrane conductance regulator gene (cftr) or cftr mediated anions are essential for normal growth of the male reproductive tract (10). mutations in the cftr gene have a crucial impact on the vas deferens development in fetuses aged 12-18 weeks (11). these mutations lead to obstructions and denaturation of the vas deferens due to mucus accumulation, particularly pronounced during embryonic growth. studies showed that proper fluid secretion is crucial for the mesonephric duct to develop correctly (12, congenital bilateral absence of vas deferens (cbavd) is a urological syndrome of wolffian ducts and is responsible for male infertility and obstructive azoospermia. this study is designed to explore the integrity of exon 10 of cftr and its role in male infertility in a cohort of cbvad patients in pakistan. genomic dna was extracted from 17 male patients with cbavd having clinical symptoms, and 10 healthy controls via phenol-chloroform method. exon 10 of the cftr gene was amplified, using pcr with specific primers and dna screening was done by sanger sequencing. sequencing results were analyzed using freeware serial cloner, snapgene, bioedit and finchtv. furthermore, bioinformatics tools were used to analyze the mutations and their impact on the protein function and stability. we have identified 4 mutations on exon 10 of cftr in 6 out of 17 patients. two of the mutations were missense variants v456a, k464e, and the other two were silent mutations g437g, s431s. the identified variant v456a was present in 4 of the studied patients. whereas, the presence of k464e in our patients further weighs on the crucial importance for its strategic location to influence the gene function at post-transcriptional and protein level. furthermore, polyphen-2 and sift analyze the mutations as harmful and deleterious. the recurrence of v456a and tactically conserved locality of k464e are evidence of their potential role in cbavd patients and in male infertility. the data can contribute in developing genetic testing and treatment of cbavd. key words: cftr; cbavd; exon 10; mutation analysis; missense mutations. submitted 8 march 2024; accepted 15 april 2024 introduction congenital absence of vas deferens (cavd) is a urological syndrome presumably resulting in abnormalities of the wolffian ducts. it is also a contributing factor to obstructive azoospermia. it is categorized into three types: unilateral (cuavd), bilateral (cbavd), and congenital bilateral partial aplasia (cpavd) (1). cbavd is the most prevalent subtype that follows an autosomal recessive pattern and accounts for 1-2 % of cftr exon 10 deleterious mutations in patients with congenital bilateral absence of vas deferens in a cohort of pakistani patients khush bakhat 1, irsa mateen 2, hina saif 3, kanwal anwar 1, sadaf sarfraz 1, sheza javaid 1, khaleeq-ur-rehman 4, adnan arshad 1, muhammad mustafa 1 1 kam school of life science, forman christian college, (a chartered university), lahore, pakistan; 2 school of biochemistry, minhaj university lahore, lahore, pakistan; 3 department of emerging allied health technologies, university of lahore, pakistan; 4 department of urology, fatima memorial hospital college of medicine & dentistry, lahore, pakistan. doi: 10.4081/aiua.2024.12464 summary archivio italiano di urologia e andrologia 2024; 96(3):12464 k. bakhat, i. mateen, h. saif, et al. 2 13). when fluid secretion is disrupted, it can lead to underdevelopment and deterioration of the mesonephric duct in the early stages of embryo growth (14). until now, over 2000 mutations in the cftr have been detected, however, not all of them are pathogenic in nature. a relatively low number of mutations are causing cftr associated abnormalities while the rest are not linked with any clinical syndromes. around 370 cftr mutations are listed in the clinical and functional translation of the cftr project (cftr2) (15). these pathogenic variants are classified as mild and severe mutations on the basis of their phenotypic and functional effect. two severe mutations on both alleles of the cftr causes cystic fibrosis (cf) while one severe and one mild or both mild mutations resulted in cbavd. moreover, all cf patients have cbavd (16). cftr mutations have been classified into six classes where class i to iii variants present severe manifestations and complete loss of cftr function. however, class iv to vi variants present mild phenotypes with reduced cftr function (2). cftr exhibits a great deal of heterogeneity due to the modifications in the base sequence of dna which leads to altered protein expression. diverse migratory patterns and settlement have led to heterogeneity in mutations worldwide. the relationship between cbavd and cftr is well established but it is least studied and documented in the asian population. that was the reason of our study aiming to the analysis of the genetic integrity of promoter region and exon 10 of cftr to identify mutations in individuals with cbavd in a pakistani population. materials and methods ethics statement this study was approved by the ethical review committee of forman christian college (a chartered university) lahore, pakistan (erc-81-2017 dated: 11, september 2017). all the experiments were performed according to the approved guidelines. blood sampling and dna extraction the term subjects has been used for both patients and healthy controls taking part in our study. archived blood samples from 31 patients with cbavd and azoospermia together with those of 10 healthy controls were gifted by fatima memorial hospital (fmh), lahore pakistan. blood samples were collected for research after the approval of the institutional review board of fatima memorial hospital, lahore pakistan (fmh-102018-irb-520-f dated: 23, october 2023) and archived for further research. extracted dnas from 17 patients and 10 healthy controls were selected for further processing. the authors had no access to information that could identify individual participants during or after data collection. all the patients were examined by the same physician. cbavd was primarily diagnosed by impalpable scrotal vas on physical examination, followed by ultrasonography. eventually, diagnosis was confirmed by cytobiochemical characteristics: decreased concentration of fructose and carnitine, azoospermia with low ph < 7 and normal hormone concentration (9). all participants had no classical symptoms of cf. written informed consent was taken from the participants for the study. genomic dna was isolated from whole blood cells by using standard phenol chloroform method (17). pcr conditions and identification of variants for screening purposes, the promoter region (pr-cftr) and exon 10 (ex10-cftr) were amplified by polymerase chain reaction (pcr) using specific sets of primers (table 1 supplementary materials) (figure 1). pcr conditions for the amplification of selected regions were: initial denaturation at 94°c for 5 minutes followed by 35 cycles of 1 min at 94°c, annealing for 48s at 61.6°c for ex10-cftr and at 58.8°c for pr-cftr, elongation carried out at 72°c for 1 minute and final elongation at 72°c for 5 min. pcr products of the 17 patients and 10 control samples were purified using minelute pcr purification kit, (qiagen, valencia, ca) and then sequenced by macrogen (inc. company, south korea). dna sequencing was performed using forward primers of both exon 10 and promoter region labeled as ex10cftr-fwd and pr-cftr-fwd respectively; afterwards, sequencing results were analyzed and confirmed using serial cloner, snapgene, bioedit and finchtv. figure 1. archivio italiano di urologia e andrologia 2024; 96(3):12464 3 cftr exon 10 mutations and congenital bilateral absence of vas deferens for mutation confirmation, sequencing data with quality chromatogram peaks were selected (figures 2, 3). in-silico analysis of cftr protein with respect to missense mutations (v456a and k464e) analysis of conserved amino acid residues the evolutionary conserved amino acid sequences of cftr protein were checked by consurf. by using multiple sequence alignment (msa) of homologous protein sequences as primary input, consurf calculates a conservation score (1-9) for each amino acid position in the protein sequence where 7-9 score indicates conserved amino acid (18). probing of structural and functional effects of mutations hope (have (y) our protein explained) (https://www3.cmbi. umcn.nl/hope/) was used for analysis of the potential impact of amino acid substitutions on protein function and stability. amino acid sequence of the protein along with information about the mutation was provided as input and figure 1. (a) sequence alignment of exon10-control, hwp3, hwp4, hwp12 and hwp14: rectangular box indicates the region expanded to visualize dna sequence quality. (b) comparison of control and sample dna sequence with their corresponding in-frame amino acid sequences. c and s represent control and sample sequence figure 2. (a) sequence analysis of hwp6, (*) indicate the last base pair of exon 10 and protein sequence comparison with control. (b & c) dna and protein sequence comparison of missense mutations. c and s indicate control and sample sequence respectively. archivio italiano di urologia e andrologia 2024; 96(3):12464 k. bakhat, i. mateen, h. saif, et al. 4 hope provided insights into the potential consequences of mutations via integration of various computational approaches (19). analysis of missense mutations on protein stability and functional outcomes to understand the potential out-turn of mutations on protein stability and functions, five different in silico tools were used. polyphen-2 (20) and sift (21) were used to find out the harmful effect of variants whereas mupro (22, 23), cupsat (24) and mcsm (25) were used to anticipate the effects of mutagenesis on protein stability (table 2). results dna sequencing and analysis after a quality control with rigorous selection criteria, sequencing data of 8 patients revealed that 4 mutations in 6 individuals accounted for 35% of total 17 cbavd patients in our experiment. all these mutations were present on exon 10 while we didn’t find any significant mutation in the promoter region of cftr in the above cohort. of these four identified mutations, two were missense mutations (v456a, k464e) whereas the other two were silent mutations (g437g, s431s). v456a is an important missense variant identified in four patients (hwp3, hwp4, hwp12 and hwp14) of our study cohort (figure 1a). nucleotide sequences of these patients contain base substitution at position 158 of exon 10 where t is replaced by c resulting in change in amino acid valine to alanine (figure 1b). previously, v456a was reported in the south asian population as a cf causing variant. furthermore, its association with male infertility of cbavd individuals has been established. however, other identified mutations were novel and found only in one patient each. another important point mutation k464e has been identified in one patient (hwp6). we observed base substitution a to g mutation at position 181 of exon 10 which changed amino acid lysine (k) to glutamic acid (e) (figure 2a). it is important to note that the total length of exon 10 is 183 base pairs and the integrity of dna sequence near the splice site is critical for rna splicing machinery to function normally. therefore, in addition to its impact due to change in amino acid, k464e can interrupt spliceosome activity at post-transcriptional level leading to excessive loss of function. v456a and k464e are present on the nbd1 domain of cftr (26) which is crucial for atp hydrolysis for normal channel function (27). interestingly, in addition to v456a, patient hwp14 contains a silent mutation s431s (figure 2b). this additional mutation does not affect the nature of the amino acid. another silent mutation g437g has been detected at position 102 of exon 10 in hwp13 (figure 2c). these two silent mutations are irrelevant in the perspective of protein function but can influence single nucleotide polymorphism (snp). frequency and mutation spectrum of cftr is variable and known to be confined within different ethnic groups. in this study, we have found genetic mutations on critically functional locations of cftr in cbavd patients (table s2 supplementary materials). the recurrence of v456a mutation in four cbavd patients highlights its potential role in disease and diagnosis. mutation k464e is crucial due to its location and is capable of affecting cftr function drastically. structural visualization of cftr protein and in silico analysis of identified mutations in exon 10 we visualize the structure of the cftr protein (pdb id: 6o1v), using pymol software (https://pymol.org/2/) to explore critical regions and mutations within exon 10 (figure s4 supplementary materials). the orthoscopic view of cftr provides an overall structure, while the functional site in exon 10 is highlighted in cyan (figure s4 supplementary materials). within this selected region of exon 10, we pinpoint three specific mutations— v456a, k464e, and g437g—represented as sticks. each mutation is labeled with its corresponding amino acid change, providing insight into the spatial arrangement of these vital regions within the protein (figure s4, d-f supplementary materials). consurf identified v456 (score: 7) and k464 (score: 9) as conserved and highly conserved residues respectively (figure s5 supplementary materials). both polyphen-2 and sift analyze the mutations as harmful and deleterious. in case of polyphen-2, score 0-0.5 means benign effect and above 0.5 is considered damaging whereas for sift score 0-0.5 is considered non tolerant and close to 1.00 is allowed (table 1). mutational effects of mupro, cupsat and mcsm suggested the overall mutations resulted in decreased stability, these tools predict ∆∆g (kcal/mol) where negative value indicative of destabilizing mutation (table 2). hope software revealed structural alterations caused by table 2. computational analysis of protein stability in mutants. s. no. mutation mcsm cupsat mupro overall predicted δδg overall predicted δδg overall predicted δδg stability (kcal/mol) stability (kcal/mol) stability (kcal/mol) score effect score effect 1 v456a destabilizing -2.0 destabilizing -1.2 destabilizing -1.8 2 k464e destabilizing -0.7 destabilizing -2.1 stabilizing 0.3 table 1. in silico checking for the pathogenicity of mutants. s. no. mutation polyphen-2 sift score effect score effect 1 v456a 0.989 probably damaging 0.01 intolerant 2 k464e 0.973 probably damaging 0.00 intolerant archivio italiano di urologia e andrologia 2024; 96(3):12464 5 cftr exon 10 mutations and congenital bilateral absence of vas deferens the v456a (figure 3a) and k464e (figre 3b) mutations. these visualizations illustrate how these mutations impact local protein structure, providing insights into their functional consequences. discussion prior research has documented cystic fibrosis (cf) as a major autosomal recessive disease in ethnic groups. moreover, there are up to 2000 cftr mutations that have been reported, with variable frequencies depending on ethnic and geographic backgrounds. it is imperative to highlight the various variables of cftr mutations that are prevalent in a given population to help focus on the diagnostic test. it’s a prerequisite for setting up efficient molecular diagnostics and for furthering the genetic treatment to help its prevention (1). since the last two decades, growing evidence has revealed a multifaceted function of cftr in controlling a number of physiological processes associated with male infertility. besides its familiar role of regulating electrolytes and fluid concentration of the male reproductive duct, recent investigations have indicated its participation in previously uncertain processes, such as sperm capacitation and spermatogenesis (26, 27), unfolding further potential reasons associated with male infertility, and strengthening the relation of cftr mutations with cbvad. as new forms of infertility in men are identified and linked with cftr defects and polymorphisms, it wouldn’t be entirely illogical to consider cftr as the molecular marker of male infertility. based on strong correlation between the quality of sperm and cftr mutations, a screening of cftr gene for mutations in obstructive, azoospermia and non-obstructive individuals is suggested before they opt for intracytoplasmic sperm injection due to strong link-up between sperm quality and cftr mutations (18). common mutation panels used for mutation analysis of males with obstructive azoospermia and cbavd are unable to identify cftr mutation variants in a given population. initially, the mutation panel was designed to detect the most frequent cf causing mutations in the affected individuals of north european caucasians (19). on the contrary, the genetic spectrum of south asian people reported increased prevalence of novel mutation such as f508 which comprises 40-50% of cases as compared to 66% reported cf cases worldwide. moreover, in south asians frequency of mutation detection is lower than the caucasians i.e., 50% and 77% respectively. also, in several cases of cf, mutations remained undetected (23). in our study, screening of cftr promoter region and exon 10 was achieved by the dna sequence method in cbavd patients. we have identified one or two mutations in 35% of our sample patients. discovering the presence of v456a in 4 of 17 patients further adds evidence for its pathogenic nature and supports its inclusion in the genetic diagnostic of cbavd, especially in the south asian population. v456a was initially described as polymorphism (28), but with further investigation the mutation was labeled as a mild disease-causing mutation particularly in adults with bronchiectasis, while it also paired up with more prominent mutations (f508) (29). previously, it has been linked with cbavd as well (28). regardless, it is a rare mutation occurring only in 2.4% of 78 south asian patients (30). danziger et al., and clinical evidence from uppaluri et al., suggested that v456a holds importance as a disease-causing mutation and is not merely a mild polymorphism (31). exon 10 of the cftr gene codes a portion of the nucleotide-binding domain (nbd i and ii) in cftr protein. nbd plays a crucial role in the regulation of cftr function. it is involved in atp (adenosine triphosphate) binding and hydrolysis, which is necessary for the opening and closing of the chloride channel formed by cftr. atp binding to nbd triggers conformational changes that enable the channel to transport chloride ions across the cell membrane. mutations in exon 10 can disrupt the structure and function of nbd (i or ii); impairing atp binding, hydrolysis, and overall cftr channel activity. the impaired atp binding reduces the ability of cftr to properly respond to cellular signals and regulate chloride ion transport, contributing to the dysfunction observed in cystic fibrosis. mutations can also affect atp hydrolysis, which is necessary for channel gating. the specific impact of mutations in exon 10 can vary depending on the nature and location of the mutation within the exon (1). based on literature, the overlapping function of nbd1 and nbd2 domain and the relation of exon 10 in the proper functioning of nbd domain (32, 33) hints towards a relation between the nbd domains of cftr protein and the mutations observed in our study group; k464e, a missense variant which is formed as a result of base substitution of a by g at nucleotide position 181 of exon 10 of cftr. it can be assumed that this mutation could potentially affect the nbd domains, impacting its ability to bind and hydrolyze atp, as proved, and described by the literature figure 3. structural change v456a (a) and k464e (b) instanced by project hope. the protein is colored grey, the side chains of both the wild-type and the mutant residues are indicated as green and red respectively, ligand represented as grey ball structure (b). archivio italiano di urologia e andrologia 2024; 96(3):12464 k. bakhat, i. mateen, h. saif, et al. 6 for other exon 10 mutations. the k464e mutation also implicates to be defective for translational protein insertions on the membrane gated channels and ribosome binding (34), whereas the v456a mutation found in four of our cbavd patients (hwp3, hwp4, hwp12 and hwp14) has been previously linked with its adverse effects on the nucleotide-binding domain 1 (nbd1) of the cftr protein. the v456a mutation refers to the substitution of the amino acid valine (v) with alanine (a) at position 456 within nbd1. hope server illustrated that mutation driven physicochemical changes in protein might be deleterious. in case of v456a, mutated residue is smaller in contrast to wild type and mutation is located within a domain (abc transporter 1 as annotated in uniprot) important for binding of other molecules and in contact with residues in a domain that is important for the activity of the protein. the mutation might affect this interaction and thereby disturb signal transfer from the binding domain to the activity domain (figure 3a). regarding k464e, the size difference of mutated residue (smaller) disturbs the interaction with mg2+ and might result in destabilization of the domain as divalent cations enhance atp binding (35). k464 interacts with ligand atp which might be disturbed by mutation and there is also change in charge of mutated residue (negative) as compared to wild type (positive) where changes in size and charge can cause loss of interaction with ligand (figure 3b). mutations within nbd1, such as the v456a mutation, can disrupt these processes, leading to a dysfunctional cftr protein and ultimately contributing to the development of cystic fibrosis. therefore, its presence in cbavd patients emphasize the significance of the mutation in the prevalence of the disease. the specific effects of the v456a and k464e mutations on the cftr protein domain may vary, and further research may be required to fully understand its impact on the progression of cbavd disease. the new silent mutations s431s and g437g found in two of the patients do not seem to disrupt the coding sequencing as the resultant protein remains the same but further analysis is needed for a more concrete ruling as their influence as single nucleotide polymorphism cannot be ignored based on our study, which involves small number of cbavd patients and lacks the inclusion of multiple ethnicities in the region. on the basis of these promising results, further research needs to be planned on a larger sample size. furthermore, whole genome sequencing and protein analysis are required to be performed for more sensitive and consistent results. hence, there is an extreme need for further investigations in genetics and epigenetics to provide deep understanding of male infertility, especially gene-environmental interaction, not just to provide detailed information about its etiology but also to help in proper genetic counseling. also, further studies will be beneficial to develop preventive measures and therapies. acknowledgments we acknowledge the contribution of rana salman anjum for his valuable insight about protein structure analysis and dr. iahtisham ul haq for his guidance. funding disclosure this study was funded by the kauser abdulla malik school of life sciences, forman christian college (a chartered university) lahore, pakistan. references 1. cai h, qing x, niringiyumukiza jd, et al. cftr variants and renal abnormalities in males with congenital unilateral absence of the vas deferens (cuavd): a systematic review and meta-analysis of observational studies. genet med. 2019; 21:826-36. 2. halder a, pandey d. cftr gene variants in indian congenital bilateral absence of vas deferens & its relevance in genetic counselling. indian j med res. 2020; 152:535-7. 3. cai z, li h. congenital bilateral absence of the vas deferens. front genet. 2022; 13:775123. 4. ferlin a, dipresa s, delbarba a, et al. contemporary geneticsbased diagnostics of male infertility. expert rev mol diagn. 2019; 19:623-33. 5. daudin m, bieth e, bujan l, et al. congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. fertil steril. 2000; 74:1164-74. 6. mieusset r, bieth e, daudin m, et al. male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. andrology. 2020; 8:645-53. 7. bieth e, hamdi sm, mieusset r. genetics of the congenital absence of the vas deferens. hum genet. 2021; 140:59-76. 8. casals t, bassas l, egozcue s, et al. heterogeneity for mutations in the cftr gene and clinical correlations in patients with congenital absence of the vas deferens. hum reprod. 2000; 15:1476-83. 9. akinsal ec, baydilli n, dogan me, ekmekcioglu o. comorbidity of the congenital absence of the vas deferens. andrologia. 2018; 50:e12994. 10. li c-y, jiang l-y, chen w-y, et al. cftr is essential for sperm fertilizing capacity and is correlated with sperm quality in humans. human reproduction. 2010; 25:317-27. 11. gaillard da, carre-pigeon f, lallemand a. normal vas deferens in fetuses with cystic fibrosis. j urol. 1997; 158:1549-52. 12. hwang tc, yeh jt, zhang j, et al. structural mechanisms of cftr function and dysfunction. j gen physiol. 2018; 150:539-70. 13. shishido h, yoon js, yang z, skach wr. cftr trafficking mutations disrupt cotranslational protein folding by targeting biosynthetic intermediates. nat commun. 2020; 11:4258. 14. morris-rosendahl dj, edwards m, mcdonnell mj, et al. wholegene sequencing of cftr reveals a high prevalence of the intronic variant c.3874-4522a>g in cystic fibrosis. am j respir crit care med. 2020; 201:1438-41. 15. indika nlr, vidanapathirana dm, dilanthi hw, et al. phenotypic spectrum and genetic heterogeneity of cystic fibrosis in sri lanka. bmc med genet. 2019; 20:89. 16. ferlin a, stuppia l. diagnostics of cftr-negative patients with congenital bilateral absence of vas deferens: which mutations are of most interest? expert rev mol diagn. 2020; 20:265-7. 17. gupta n, sarkar s, mehta p, et al. polymorphisms in the hsf2, lrrc6, meig1 and ptip genes correlate with sperm motility in idiopathic infertility. andrologia. 2022; 54:e14517. 18. ashkenazy h, abadi s, martz e, et al. consurf 2016: an archivio italiano di urologia e andrologia 2024; 96(3):12464 7 cftr exon 10 mutations and congenital bilateral absence of vas deferens improved methodology to estimate and visualize evolutionary conservation in macromolecules. nucleic acids res. 2016; 44:w344-50. 19. venselaar h, te beek ta, kuipers rk, et al. protein structure analysis of mutations causing inheritable diseases. an e-science approach with life scientist friendly interfaces. bmc bioinformatics. 2010; 11:548. 20. giordano sh. breast cancer in men. n engl j med. 2018; 378:2311-20. 21. flanagan se, patch am, ellard s. using sift and polyphen to predict loss-of-function and gain-of-function mutations. genet test mol biomarkers. 2010; 14:533-7. 22. soegaard m, kjaer sk, cox m, et al. brca1 and brca2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from denmark. clin cancer res. 2008; 14:3761-7. 23. adzhubei i, jordan dm, sunyaev sr. predicting functional effect of human missense mutations using polyphen-2. curr protoc hum genet. 2013; chapter 7:unit7 20. 24. pulumati a, pulumati a, dwarakanath bs, et al. technological advancements in cancer diagnostics: improvements and limitations. cancer rep (hoboken). 2023; 6:e1764. 25. pires de, ascher db, blundell tl. mcsm: predicting the effects of mutations in proteins using graph-based signatures. bioinformatics. 2014; 30:335-42. 26. lewis ha, zhao x, wang c, et al. impact of the deltaf508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. j biol chem. 2005; 280:1346-53. 27. ehrhardt a, chung wj, pyle lc, et al. channel gating regulation by the cystic fibrosis transmembrane conductance regulator (cftr) first cytosolic loop. j biol chem. 2016; 291:1854-65. 28. uppaluri l, england s, scanlin t. clinical evidence that v456a is a cystic fibrosis causing mutation in south asians. journal of cystic fibrosis. 2012; 11:312-5. 29. ziedalski tm, kao pn, henig nr, et al. prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. chest. 2006; 130:995-1002. 30. mccormick j, green mw, mehta g, et al. demographics of the uk cystic fibrosis population: implications for neonatal screening. eur j hum genet. 2002; 10:583-90. 31. tsui lc, dorfman r. the cystic fibrosis gene: a molecular genetic perspective. cold spring harb perspect med. 2013; 3:a009472. 32. lukacs gl, verkman as. cftr: folding, misfolding and correcting the deltaf508 conformational defect. trends mol med. 2012; 18:81-91. 33. veit g, avramescu rg, chiang an, et al. from cftr biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. mol biol cell. 2016; 27:424-33. 34. lakshminarayan r, phillips bp, binnian il, et al. pre-emptive quality control of a misfolded membrane protein by ribosome-driven effects. curr biol. 2020; 30:854-64 e5. 35. ikuma m, welsh mj. regulation of cftr clchannel gating by atp binding and hydrolysis. proc natl acad sci usa. 2000; 97:8675-80. correspondence khush bakhat khushbkht@gmail.com kanwal anwar kanwalanwar14@gmail.com sadaf sarfraz sadafsarfraz.40@gmail.com sheza javaid shezajavaid930@gmail.com adnan arshad adnanarshad@fccollege.edu.pk kam school of life science, forman christian college, (a chartered university), lahore, pakistan muhammad mustafa (corresponding author) muhammadmustafa@fccollege.edu.pk kam school of life science, s346 armacost science building, ferozepur road, lahore 54600, pakistan irsa mateen irsamateen.biochem@mul.edu.pk school of biochemistry, minhaj university lahore, lahore, pakistan hina saif hina.saif@deaht.uol.edu.pk department of emerging allied health technologies, university of lahore, pakistan khaleeq-ur-rehman khaleeqr@hotmail.com department of urology, fatima memorial hospital college of medicine & dentistry, lahore, pakistan conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13554 1 original paper further 20%. idiopathic male subfertility is the commonest cause in most cases (1). d-aspartic acid (d-asp) is an endogenous amino acid occurring in several tissues and cells of both invertebrates and vertebrates (2). it was first detected in the brain and optic lobes of the cephalopod mollusy octopus vulgaris and later in the nervous and endocrine systems of various animal phyla such as crustaceans, amphibians, reptiles, fish, chicken, rat, and man (3-14). topo et al. conducted a clinical trial on 23 healthy male volunteers who consumed 3.12 gram of sodium dasp for 12 consecutive days (15). they found significant increase in lh and testosterone levels after 12 days by 33% and 42%, respectively (15). thus, topo et al. postulated that consumed d-asp may also be remained in the testis and it continued to stimulate the testosterone production in the testis (15). in the aforementioned study the mean baseline testosterone were within 25% of the lower clinical range (3-10 ng/ml) and d-asp supplementation elevated testosterone levels to approximately 50% of the clinical range (4.5-6.4 ng/ml) (15). these findings can be explained by the fact that d-asp acts directly on the pituitary gland inducing an increase of lh releasing (15-16). furthermore, two in vitro studies had demonstrated a beneficial effect of zn, d-asp and co-enzyme q10 (co-q10) on sperm motility, recovery of spermatozoa by swim-up and lipid peroxidation (17, 18). on the contrary, willoughby et al. who conducted a study on twenty apparent healthy and heavy resistance-trained men (19). the participants trained 4 times/week while orally taking either 3 gram of placebo or d-asp in the morning upon waking (19). there was no effect on muscle strength, body mass and serum hormones after 28 days of d-asp supplementation (19). to the best of our knowledge, the current study is one of the first to evaluate the in vivo supplementation of d-asp in male infertility. thus, we aimed in the current study to evaluate the in vivo effect of d-asp, zinc and co-q10 supplementation on different semen parameters and serum testosterone level in idiopathic male infertility. introduction: about 20-30% of cases of infertility are attributed to male factor and males are also contributing to infertility in a further 20%. idiopathic male subfertility is the commonest cause in most cases. d-aspartic acid (d-asp) is an endogenous amino acid occurring in several tissues and cells of both invertebrates and vertebrates. the current study is one of the first to evaluate the in vivo supplementation of d-asp in idiopathic male infertility. thus, we aimed in the current study to evaluate the in vivo effect of d-asp, zinc and co-enzyme q10 (co-q10) supplementation on different semen parameters and serum testosterone level in idiopathic male infertility. methods: a total of 75 infertile patients were recruited from the outpatient andrology clinic from march 2023 to june 2024. the current study was registered at the umin clinical registry trials prior to initiating the study (umin000050023). group (a) included 24 infertile patients who received 2660 mg d-asp plus 200 mg of ubiquinol plus 10 mg zinc once daily for 3 months. group (b) included 24 infertile patients who received placebo (starch granules) daily for 3 months. results: interestingly, patients in group (a) who received 2660 mg d-asp plus 200 mg of ubiquinol plus 10 mg zinc once daily for 3 months showed significant improvement in progressive sperm motility after 3 months (10.63 ± 8.64 vs 15.21 ± 12.11, p = 0.047). also, they showed highly significant increase in total testosterone level (5.06 ± 1.74 vs 5.89 ± 1.62, p = 0.009). conclusions: d-asp plus ubiquinol plus zinc are promising ingredients that showed good results when administrated once daily to infertile males. key words: idiopathic male infertiliy; total testosterone; progressive sperm motility; d-aspartic acid; ubiquinol; zinc. submitted 30 december 2024; accepted 17 january 2025 introduction about 20-30% of cases of infertility are attributed to male factor and males are also contributing to infertility in a evaluation of in vivo supplementation of 2660 mg d-aspartic acid and 200 mg ubiquinol and 10 mg zinc on different semen parameters in idiopathic male infertility: a randomized double blind placebo controlled study sameh fayek gamalel din 1, elnashar a.m. 1, yasser elkhiat 1, tarek hussein 2, mohamed ahmed abdelsalam 1, ayman alam 1, david ramzy 1, islam moatamed 1, ashraf zeidan 1, amr elahwany 1, mohamed wael ragab 1, omar zahran 1, hany saad 3 1 department of andrology, sexology, and stds, faculty of medicine, cairo university; 2 department of andrology, sexology, and stds, faculty of medicine, alexandria university; 3 department of andrology, sexology, and stds, faculty of medicine, suez canal university. doi: 10.4081/aiua.2025.13554 summary archivio italiano di urologia e andrologia 2025; 97(2):13554 s. fayek gamalel din, elnashar a.m., y. elkhiat, et al. 2 materials and methods a total of 75 infertile patients were recruited from the outpatient andrology clinic from march 2023 to june 2024. the recruited patients were assessed for eligibility to join the study (figure 1). the institutional ethical committee of alexandria university approved the study on 23/1/2023 that conforms to helsinki declaration 2013 (20). also, the current study was registered at the umin clinical registry trials prior to initiating the study (umin000050023). twenty-three patients were excluded from the study. the remaining 52 patients were equally randomized by simple numbering method into 2 groups. unfortunately, 4 patients dropped out of the study, 2 patients were from group (a) and 2 patients were figure 1. study flow chart. archivio italiano di urologia e andrologia 2025; 97(2):13554 3 in vivo supplementation of d-aspartic acid and zinc and ubiquinol on different semen parameters from group (b) (figure 1). group (a) included 24 infertile patients who received spertility® that consists of 2660 mg d-asp plus 200 mg of ubiquinol (active form of coq10) plus 10 mg zinc once daily for 3 months. group (b) included 24 infertile patients who received placebo (starch granules) daily for 3 months. five cc blood was withdrawn for total testosterone evaluation at the beginning of the study and after 3 months. all participants brought 2 semen samples at the beginning and at the end of the study. semen analysis was processed according to the 5th guidelines of the who (21). inclusion criteria of the patients any infertile male aged 25 to 40 years old suffering from idiopathic infertility was included. exclusion criteria of the patients any idiopathic infertile male suffering from varicocele or leukocytospermia or immunological infertility was excluded. also, any infertile patient with hormonal imbalance was excluded. finally, any infertile patient with small testicular volume < 8 ml was also excluded. results the current study did not show any significant difference in the mean age of the participants of both groups (31.25 years, ± 7.86; 33.96 years, ± 8.11, respectively, p = 0.062). interestingly, patients in group (a) who received spertility® showed significant improvement in progressive sperm motility after 3 months of daily supplementation of d-asp (10.63 %, ± 8.64, 15.21 %, ± 12.11, p = 0.047, respectively) (table 1). they also showed significant increase in total testosterone level after 3 months of daily supplementation of d-asp (5.06 ng/dl, ± 1.74; 5.89 ng/dl, ± 1.62, respectively, p = 0.009) (table 1). conversely, total sperm concentration and sperm motility and abnormal forms did not show any improvement after daily supplementation of d-asp in patients of group (a) (table 1). furthermore, patients in group (b) who received placebo did not show any improvement in total sperm concentration, sperm motility, progressive sperm motility, abnormal forms and total testosterone (table 2). despite, significant improvement in progressive sperm motility and significant increase in total testosterone in patients in group (a), yet, pregnancy rate was 8.3% only. owing to the fact that only 2 patients out of 24 patients in group (a) succeeded to impregnate their wives. statistical methods data management and statistical analysis were performed using the statistical package for social sciences (spss) version 25. numerical data were summarized using means and standard deviations or medians and ranges. data were explored for normality using kolmogrov-smirnov test and shapirowilk test. mann-whitney u and wilcoxon signed ranks tests were used for the comparison between groups. all pvalues are two-sided. p-values ≤ 0.05 were considered significant. discussion the current study had demonstrated significant improvement in progressive sperm motility in group (a) patients who received spertility® daily for 3 months. similarly, two previous studies demonstrated beneficial effects of in vitro supplementation of d-asp on progressive sperm motility (17, 18). moreover, an animal study revealed an improvement in sperm function of rabbits after being adminstered d-asp (22). in the same context, d’aniello et al. (2005) was one of the first to demonstrate lower levels of this amino acid in the semen of patients with oligoastenoteratozoospermia than in fertile men (23). the significant improvement in sperm motility in the current study can also be explained by the presence of zinc and co-q10 in the ingredients of spertility®. several studies had shown the beneficial effects of zinc in male inferility (18, 24-26). in contrats, foresta et al. (2014) failed to demonstrate any correlation between zinc and sperm motility (27). table 1. changes in semen parameters and total testosterone in group (a) before and after spertility®. mean std deviation minimum maximum p-value sperm concentration (106/ml) baseline 35.15 ± 23.74 9.30 110.20 0. 989 after 3 months 36.14 ± 24.33 6.30 92.80 sperm motility % baseline 45.83 ± 10.18 25.00 65.00 0. 441 after 3 months 44.79 ± 8.91 30.00 65.00 sperm progressive motility % baseline 10.63 ± 8.64 .00 25.00 0.047 after 3 months 15.21 ± 12.11 .00 60.00 abnormal forms % baseline 61.46 ± 11.75 20.00 80.00 0.242 after 3 months 63.96 ± 13.67 20.00 80.00 total testosterone (ng/dl) baseline 5.06 ± 1.74 2.56 8.20 0.009 after 3 months 5.89 ± 1.62 3.80 9.50 table 2. changes in semen parameters and total testosterone in group (b) before and after placebo. mean std deviation minimum maximum p-value sperm concentration (106/ml) baseline 32.75 ± 40.22 5.00 201.00 0.255 after 3 months 31.58 ± 39.44 0.00 180.00 sperm motility (%) baseline 37.21 ± 23.86 0.00 88.00 0.269 after 3 months 35.00 ± 20.54 0.00 70.00 sperm progressive motility (%) baseline 6.25 ± 6.63 0.00 25.00 0.331 after 3 months 7.08 ± 6.24 0.00 20.00 abnormal forms (%) baseline 54.38 ± 16.17 20.00 80.00 0.982 after 3 months 53.96 ± 18.33 20.00 98.00 total testosterone (ng/dl) baseline 5.75 ± 1.67 3.00 8.80 0.884 after 3 months 5.82 ± 1.77 2.70 9.70 archivio italiano di urologia e andrologia 2025; 97(2):13554 s. fayek gamalel din, elnashar a.m., y. elkhiat, et al. 4 additionally, co-q10 has a well-established dual action as electron/proton carrier in mitochondrial bioenergetic chain and antioxidant agent (18). in the same context, li et al. (2006) found significant different concentrations of this antioxidant in the seminal plasma of fertile men and infertile patients (28). conversely, nadjarzadeh et al. (2014) had revealed that this molecule had a potent antioxidant effect (29). furthermore, spertility® contains ubiquinol which is the active form of co-q10 that facilitates its gastro-intestinal absorption. similarly, garridomaraver et al. (2014) demonstrated the effect of different formulations on gastro-intestinal absorption (30). another interesting finding of the current study was the highly significant increase in total testosterone level in group (a) patients who received sperility once daily for 3 months. consistently, a study had reported a steroidogenic role of d-asp in humans and rats (15). quite the reverse, willoughby et al. (2014) failed to demonstrate any change in serum testosterone level in resistance-trained men after being resistance trained 4 times weekly for 1 month and after ingesting 3 g daily of d-asp (19). it should be mentioned that the dose of d-asp in the aforementioned study was higher than the concentration of d-asp in spertility®. notably, the role of testosterone in male infertility is well established by two important reviews showing the pivotal role of androgen in spermatogensis (31, 32). in the same context, carvalho et al. (2022) had revealed that eugenol administration to wistar rats reduced serum testosterone and sperm viability (33). on the contrary, a previous study had stated that serum testosterone levels demonstrate no relationship to sperm concentration (34). to wrap up, spertility® administration in the form of once daily sachet for 3 months had shown significant improvement in progressive sperm motility and highly significant increase in serum total testosterone. to the best of our knowledge, the current study is one of the first to demonstrate the impact of in vivo supplementation of d-asp plus ubiquinol plus zinc to infertile males. despite such achievements that were shown in the current study, yet, the pregnancy rate was very low as two patients only from group (a) succeeded to conceive naturally. this disappointing finding could be attributed to the small sample size and the short period of follow up. admittedly, there are several limitations of the current study. firstly, the small sample size and short duration of follow up are seen as major limitations of the current study. nevertheless, the proper and consistent study design and being a prospective one added strength to the current findings. also, we were not able to measure luteinizing hormone and sperm dna fragmentation index adding further limitations of the current study. finally, we were not able to utilize the 6th edition of the who for semen analysis processing (35). conclusions d-asp plus ubiquinol plus zinc are promising ingredients that showed good results when administrated once daily to infertile males. future cohort studies that evaluate these ingredients versus l-carnitine are needed to affirm these findings. references 1. agarwal a, baskaran s, parekh n, et al. male infertility. the lancet. 2021; 397:319-333. 2. d'aniello a. d-aspartic acid: an endogenous amino acid with an important neuroendocrine role. brain res rev 2007; 53:215-234. 3. d'aniello a, giuditta a. identification of d-aspartic acid in the brain of octopus vulgaris lam. j neurochem. 1977; 29:1053-1057. 4. okuma e, fujita e, amano h, et al. distribution of free d-amino acids in the tissues of crustaceans. fisher sci. 1995; 61:157-160. 5. di fiore m, assisi l, botte v, d'aniello a. d-aspartic acid is implicated in the control of testosterone production by the vertebrate gonad. studies on the female green frog, rana esculenta. j endocrinol. 1998; 157:199-207. 6. raucci f, assisi l, d'aniello s, et al. testicular endocrine activity is upregulated by d-aspartic acid in the green frog, rana esculenta. j endocrinol. 2004; 182:365-376. 7. assisi l, botte v, d'aniello a, di fiore m. enhancement of aromatase activity by d-aspartic acid in the ovary of the lizard podarcis s. sicula. reproduction. 2001; 121:803-808. 8. raucci f, d’aniello s, di fiore m. endocrine roles of d-aspartic acid in the testis of lizard podarcis s. sicula. j endocrinol. 2005; 187:347-359. 9. d’aniello a, di fiore m, fisher g. occurrence of daspartic acid in animal tissues and its role in the nervous and endocrine systems. trends comp biochem physiol. 1998; 4:1-24. 10. neidle a, dunlop ds. developmental changes in free d-aspartic acid in the chicken embryo and in the neonatal rat. life sci. 1990; 46:1517-1522. 11. dunlop ds, neidle a, mchale d, et al. the presence of free daspartic acid in rodents and man. biochem biophys res com. 1986; 141:27-32. declarations ethical approval: the study was prospectively registered at umin under the following serial number 000050023. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the authors declare no competing interests. funding: this study did not receive any fund. authors' contributions: sfg, aen, th and ye developed the conception and study design; maa, im, az, mwr, aa, dr and oz recruited the cases; hs performed the statistics of the study; sfg intellectually drafted the manuscript and critically revised the data. all authors approved the final draft. sfg drafted the initial manuscript; sfg revised the article critically; sfg reviewed and edited the article; nn designed the study; saa performed the lab work of the study; ao, ae, az, aas collected and analyzed the data. all authors reviewed the manuscript. acknowledgments: we would like to thank parkville pharmaceutical company for their provision of the drug and placebo once daily for 3 months. we would thank the surgeons who performed the sub inguinal micro-varicocelectomy. archivio italiano di urologia e andrologia 2025; 97(2):13554 5 in vivo supplementation of d-aspartic acid and zinc and ubiquinol on different semen parameters 12. hashimoto a, nishikawa t, oka t, et al. widespread distribution of free daspartate in rat periphery. febs lett. 1993; 331:4-8. 13. hashimoto a, kumashiro s, nishikawa t, et al. embryonic development and postnatal changes in free d-aspartate and d-serine in the human prefrontal cortex. j neurochem. 1993; 61:348-351. 14. fisher gh, d'aniello a, vetere a, padula l, cusano gp, man eh. free d-aspartate and d-alanine in normal and alzheimer brain. brain res bulletin. 1991; 26:983-985. 15. topo e, soricelli a, d’aniello a, et al. the role and molecular mechanism of d-aspartic acid in the release and synthesis of lh and testosterone in humans and rats. reprod biol endocrinol. 2009; 7:1482-1488. 16. d’aniello a, di fiore mm, fisher gh, et al. occurrence of daspartic acid and n-methyl-d-aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release. faseb j. 2000; 14:699-714. 17. talevi r, barbato v, fiorentino i, et al. protective effects of in vitro treatment with zinc, d-aspartate and coenzyme q10 on human sperm motility, lipid peroxidation and dna fragmentation. reprod biol endocrinol. 2013;11:81. 18. giacone f, condorelli ra, mongioì lm, et al. in vitro effects of zinc, d-aspartic acid, and coenzyme-q10 on sperm function. endocrine. 2017; 56:408-415. 19. willoughby ds, leutholtz b. d-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength ,and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men. nutr res. 2013; 33:803-810. 20. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-2194. 21. world health organization (who). who laboratory manual for the examination and processing of human semen. 5th ed. geneva. who. 2010; 271 p. 22. macchia g, topo e, mangano n, et al. dlaspartic acid administration improves semen quality in rabbit bucks. anim reprod sci. 2010; 118:337-343. 23. d’aniello g, ronsini s, guida f, et al. occurrence of d-aspartic acid in human seminal plasma and spermatozoa: possible role in reproduction. fertil steril. 2005; 84:1444-1449. 24. hadwan mh, almashhedy la, alsalman ar. oral zinc supplementation restores high molecular weight seminal zinc binding protein to normal value in iraqi infertile men. bmc urol. 2012; 13:1232. 25. mocchegiani e, costarelli l, giacconi r, et al. zinc-binding proteins (metallothionein and alpha-2 macroglobulin) and immunosenescence. exp gerontol. 2006; 41:1094-107. 26. macanovic b, vucetic m, jankovic a, et al. correlation between sperm parameters and protein expression of antioxidative defense enzymes in seminal plasma: a pilot study. dis markers. 2015; 2015:436236. 27. foresta c, garolla a, cosci i, et al. role of zinc trafficking in male fertility: from germ to sperm. hum reprod. 2014; 29:1134-45. 28. li k, shi y, chen s, et al. determination of coenzyme q10 in human seminal plasma by high-performance liquid chromatography and its clinical application. biomed chromatogr. 2006; 20:1082-6. 29. nadjarzadeh a, shidfar f, amirjannati n, et al. effect of coenzyme q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double-blind randomised clinical trial. andrologia. 2014; 46:177-83. 30. garrido-maraver j, cordero md, oropesa-avila m, et al. clinical applications of coenzyme q10. front biosci (landmark ed). 2014; 19:619-33. 31. holdcraft rw, braun re. hormonal regulation of spermatogenesis. int j androl. 2004; 27:335-42. 32. smith lb, walker wh. the regulation of spermatogenesis by androgens. semin cell dev biol. 2014; 30:2-13. 33. carvalho rpr, lima gda, ribeiro fcd, et al. eugenol reduces serum testosterone levels and sperm viability in adult wistar rats. reprod toxicol. 2022; 113:110-119. 34. jackaman r, ghanadian r, ansell id, et al. relationships between spermatogenesis and serum hormone levels in subfertile men. br j obstet gynaecol. 1977; 84:692-6. 35. world health organization. who laboratory manual for the examination and processing of human semen, 6th ed.; who press: geneva, switzerland, 2021. available online: https://www.who.int/publications/i/item/9789240030787 (accessed on 3 december 2021). correspondence sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg department of andrology and stds kasr al-ainy, faculty of medicine cairo university, al-saray street, el manial, cairo, 11956, egypt elnashar a.m., md abdelrahmanelnashar@kasralainy.edu.eg yasser elkhiat, md elkhiat@hotmail.com mohamed ahmed abdelsalam, md moh_756@cu.edu.eg ayman allam, m.m.b.c.h aymanallam085@gmail.com david ramzy, m.m.b.c.h davidramzy1994@gmail.com eslam meatmed, m.m.b.c.h eslammeatmed@gmail.com ashraf zeidan, md zidana2000@gmail.com amr alahwany, md amralahwani@hotmail.com mohamed ragab, md m.w.ragab@kasralainy.edu.eg omar zahran, m.m.b.c.h omar5b2007@gmail.com department of andrology, sexology, and stds, faculty of medicine, cairo university, cairo, egypt tarek hussein, md tarekmhaa@hotmail.com department of andrology, sexology, and stds, faculty of medicine, alexandria university, alexandria, egypt hany saad, md hanysaad@med.suez.edu.eg department of andrology, sexology, and stds, faculty of medicine, suez canal, egypt stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11450 1 original paper and is usually caused by an aerobic bacterial invasion (1). the bacterial species' combined invasive and toxic activities produce endarteritis obliterans, cutaneous and subcutaneous artery thrombosis, local tissue necrosis and gangrene, and subsequently life-threatening adverse events such as multiple organ system failures, septic shock, and death if left untreated (1, 2). despite the advancement of medical knowledge towards fg’s pathobiology, diagnosis, and management, the mortality rate remains high, with some reported rates of approximately 50% (3). fg is a predominantly male illness and is commonly observed in men aged 40 to 50, with a reported annual incidence of 1.6 cases per 100.000 men. diabetes mellitus (dm), older age, liver cirrhosis, vascular disease, cancer, chronic alcoholism, overweight, paraplegia, and renal impairment are all thought to be associated with higher mortality rates; however, up to 30% to 50% of fg cases present with no identifiable risk fact (4). there are numerous scoring methods for predicting fg mortality, such as the acute physiology and chronic health evaluation (apache) ii scoring system, which is an extensively used tool for predicting mortality outcomes, charlson comorbidity index (cci), and fournier's gangrene severity index (fgsi) which are well-defined disease-specific metric (5, 6). however, those scorings still had limitations and some factors are not included such as length of hospital stay, which is related to hospitalization costs and treatment approaches (4). in low-income countries, such as yemen, there is limited information available about the extent of fg mortality rate, and its predisposing factors (7). here, we studied the characteristics and clinical course of patients diagnosed with fg at our institution over a period of 12 years. our primary objective was to discern the prognostic factors intricately linked to this debilitating disease. by furnishing essential data, we aspire to enhance the foundation for future investigations and therapeutic interventions. such endeavors hold immense potential to empower healthcare practitioners in promptly identifying fg and initiating timely and efficacious care for afflicted individuals. background: fournier’s gangrene (fg) is a destructive necrotizing infection with a generally poor prognosis. this study aims to share our experience in handling fg patients in a resource-limited setting and identify prognostic factors for fg mortality. methods: a retrospective study of thirty-six patients diagnosed with fg and treated at our teaching hospital between jun 2010 to oct 2022 was conducted. laboratory and nonlaboratory data and patients' outcomes were gathered. a univariate analysis was computed for identifying prognostic factors for fg mortality. result: the main age was 68.30 ± 5.61years and most (69.4%) were older than 65 years. the overall survival was 63.9% and the mortality rate was 36.1%. univariate analysis showed that advanced age (p = 0.02), delayed in hospital presentation (p = 0.024), involvement of larger area (p = 0.001), a history of diabetes mellitus (p < 0.006), end-stage renal disease (p = 0.018), heart failure (p = 0.005), cerebrovascular accident (p = 0.003), liver cirrhosis (p = 0.001), presence of multiple comorbidities (p = 0.001), septic conditions at admission (p = 0.048), need for mechanical ventilation (p = 0.001), hypoalbuminemia (p < 0.001), and elevated blood urea nitrogen (p = 0.002) were found to be risk factors for mortality in patients with fg. conclusions: fournier’s gangrene is a fulminant condition with a high mortality rate, especially in resource-limited settings. in this study, the mortality rate was 36.1%. advanced age, delayed in hospital presentation, involvement of larger area, a history of diabetes mellitus, end-stage renal disease, heart failure, cerebrovascular accident, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were associated with fg mortality. key words: fournier's gangrene; mortality; prognostic factors; outcome. submitted 5 may 2023; accepted 8 june 2023 introduction fournier's gangrene (fg) is a poly-microbial necrotizing infection that spread drastically to involve the genital, perianal area, or perineal deep tissue causing rapid tissue prognostic determinants and treatment outcomes of fournier’s gangrene treatment in a resource-limited setting: a retrospective study saif ghabisha 1, faisal ahmed 2*, saleh al-wageeh 1, mohamed badheeb 3, qasem alyhari 1, abdulfattah altam 4, afaf alsharif 5 1 department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen; 2 department of urology, school of medicine, ibb university of medical sciences, ibb, yemen; 3 department of internal medicine, yale new haven health, bridgeport hospital, bridgeport, usa; 4 department of general surgery, school of medicine, 21 september university, sana'a, yemen; 5 department of gynaecology, school of medicine, jeblah university for medical and health sciences, ibb, yemen. doi: 10.4081/aiua.2023.11450 summary archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 2 materials and methods study design between jun 2010 to oct 2022, this retrospective study was conducted at ibb university-affiliated hospitals and included 36 consecutive patients diagnosed with fg and treated by the same surgeon (professor s. ghabisha). the ethics research committees of ibb university provided their approval for the study (id: ibbuni.ac.yem.2023.55, on 03.03.2023), which adhered to the ethical principles outlined in the declaration of helsinki. inclusion criteria patients diagnosed with fg and treated at ibb universityaffiliated hospitals (al-nasar hospital) were included in the study. the presence of fever (> 38°c), erythema and swelling in the perianal or scrotal region, purulent-malodorous discharge, and the detection of fluctuation or crepitation at the wound site were used to make the diagnosis of fg (8). exclusion criteria patients treated at other hospitals and those with scrotal, periurethral, or perianal abscesses with no fascial or soft tissue extension were excluded. surgical procedure and postoperative care all participants received immediate aggressive debridement under general or spinal anesthesia to remove necrotic tissue until healthy tissue was observed. in addition, cystostomy catheters were placed, limiting the contact of the urethra with urine. empiric intravenous antibiotic therapy, including crystalline penicillin (4miu iv every 6 hours), ceftriaxone (1 g every 12 hours), and metronidazole (500 mg every 12 hours), was administered until culture results were obtained and in cases of sepsis, imipenem and vancomycin were used. dressings were changed three times daily with sterile gauze soaked in a solution of povidone-iodine, 0.2% nitrofurazone ointment, and 250 mg rifampicin ampoule and hyperbaric oxygen was done in cases needing multiple debridements (9). a fecal diversion (colostomy) was performed in cases where the perirectal and anal regions were affected, while an orchiectomy was performed in testicular involvement cases (5). patients were transferred to the plastic and reconstructive surgery clinic once their general health status and wound cleanliness had improved. data collection patient demographic characteristics, including age, time to hospital admission, comorbidities, albumin level, number of surgical debridements, need for mechanical ventilation, need for colostomy diversion or orchiectomy, length of hospital stay, and mortality were extracted from the patient's medical records. mortality refers to all-cause mortality and any cause of fg-related death during the initial admission or follow-up. to assess the fg extension, we used a modified body surface area nomogram commonly used for estimating the extension of burn injuries. this involved assigning a value of 1% for penile, scrotal, and perineal involvement, and 2.5% for ischiorectal fossa involvement (5, 8). the comorbidities were heart failure, end-stage renal disease (esrd), liver cirrhosis, history of anorectal surgery, and old cerebrovascular accident (cva), which were also evaluated as several comorbidities (presence of one versus more than one of comorbidities) (10). the number of surgical debridements was defined as the number of times a patient entered the operating room (10). the albumin level was dived into two categories (equal or more than 3 g/dl and less than 3 g/dl). variables and measures the outcome variable was fg mortality expressed as a binary variable: alive and dead. independent variables included age (≤ 65 years and more than 65 years), cva (yes and no), heart disease (yes and no), liver cirrhosis (yes and no), esrd (yes and no), the number of debridement (≤ 2 times and ≥ times), comorbidity number (one and more than one), need for a colostomy (yes and no), need for orchiectomy (yes and no), mean hospital stays, etiological subtypes (genitourinary infection versus nongenitourinary infections), septic condition (yes and no), comorbidity number (< two comorbidities and ≥ two comorbidities), mean total affected body surface area (≤ than 3% and more than 3%), blood urea nitrogen figure 1. a. fournier’s gangrene involved the scrotum. b. fournier’s gangrene involved the penis, scrotum, and ischiorectal fossa. c. fournier’s gangrene involved both the penis and scrotum with a purulent discharger. archivio italiano di urologia e andrologia 2023; 95(3):11450 3 fournier's gangrene outcome (bun) (more than 50 mg/dl and less), albumin level (≤ 3 g/dl and more than 3 g/dl), need for mechanical ventilation (yes and no), time to hospital presentation (≤ 7 days and more than 7 days), and dm (yes and no). study outcome the mortality rate and the independent predictors of fg mortality. statistical analysis the study utilized both quantitative and qualitative, for which means and standard deviations were used to present quantitative data, while frequencies and percentages were reported for qualitative variables. the normality of the data was confirmed using the smirnov-kolmogorov test. to determine the independent risk variables related to fg mortality, univariate analysis was done. effect sizes in the model were expressed using odds ratios and confidence intervals at 59%. the statistical significance level was set at p < 0.05. the ibm spss version 22 software (ibm corp., armonk, new york) was used for statistical analysis. result baseline clinical characteristics the mean age was 68.30 ± 5.61 years and most of patients (69.4%) were aged more than 65 years. the main time to hospital presentations was 7.47 ± 4.10 days and 15 (41.7%) patients presented after 7 days from starting symptoms. most of them (25, 69.4%) were in septic conditions. history of dm, heart failure, esrd, cva, anorectal surgery, and liver cirrhosis was present in 20 (55.6%), 11(30.6%), 8 (22.2%), 5(13.9%), 6 (16.7%), 6 (16.7%), respectively. additionally, 14 (38.9%) had more than one comorbid number. the source of infection was a genitourinary infection in 15 (41.7%) patients, perianal infection in 6 (16.7%) patients, and an unknown source in 15 (41.7%) patients. the mean calculated total affected body surface area was 3.59 ± 1.47 (%) and was more than 3% in (19, 52.8%) patients. the serum albumin level was less than 3 g/dl in 14 (38.9%) patients. most of the patients (72.2%) more than one surgical debridement. colostomy and orchiectomy were done on 6 (16.7%) and 3 (8.3%) patients respectively. the mean hospital stay was 57.00 ± 4.01 days and 15 (41.7%) patients need mechanical ventilation. within a median follow-up time of 14.0 months (range 2-30 months), 23(63.9%) of patients survived and the total mortality rate was 36.1%. table 1 summarizes the baseline clinical characteristics of the research cohort. mortality predictors in patients with fournier’s gangrene the association of independent variables with the dependent variable was investigated using univariate, analysis. univariate analysis showed that advanced age (p = 0.02), delayed in hospital presentation (p = 0.024), involvement of larger area (p = 0.001) (table 2), a history of dm (p < 0.006), esrd (p = 0.018), heart failure (p = 0.005), cva (p = 0.003), liver cirrhosis (p = 0.001), presence of multiple comorbidities (p = 0.001), septic conditions at admission (p = 0.048), (p = 0.018), need for mechanical ventilation (p = 0.001), hypoalbuminemia (p < 0.001), and elevated blood urea nitrogen (p = 0.002) were found to be risk factors for mortable 1. demographic characteristics of patients. variable subgroup n (%) age (year) mean ± sd 68.30 ± 5.61 < 65 years 11 (30.6) ≥ 65 years 25 (69.4) time to hospital admission (days) mean ± sd 7.47 ± 4.10 (2-20) ≤ 7 days 21 (58.3) > 7 days 15 (41.7) source of infection urinary tract infection 15 (41.7) perianal or perirectal infection 6 (16.7) unknown 15 (41.7) septic condition 25 (69.4) predisposing factors diabetes mellitus 20 (55.6) heart failure 11 (30.6) renal failure 8 (22.2) cerebrovascular accident 5 (13.9) liver cirrhosis 6 (16.7) anorectal surgery 6 (16.7) comorbid number one 22 (61.1) ≥ two 14 (38.9) total affected body surface area (%) mean ± sd 3.59 ± 1.47 ≤ 3% 17 (47.2) > 3% 19 (52.8) number of debridement mean ± sd 2.27 ± 1.13 (1-5) one 10 (27.8) ≥ two 26 (72.2) needs for colostomy 6 (16.7) needs for orchiectomy 3 (8.3) need for mechanical ventilation 15 (41.7) blood urea nitrogen (mg/dl) ≥ 50 18 (50) albumin level (mg/dl) < 3 14 (38.9) hospital stay (day) mean ± sd 7.00 ± 4.01 outcome survivors 23 (63.9) non-survivors 13 (36.1) table 2. comparison between survivors and survivors for quantitative variables. variable outcome mean difference (95 % ci) t & z p-value * survivors n = 23 died n = 13 mean (sd) mean (sd) age (year) 66.69 (5.19) 71.15 (5.35) -4.45(-8.15 to -0.75) -2.44 0.020 number of debridements 2.21(1.12) 2.38(1.19) -0.16(-0.97 to 0.64) -0.42 0.678 time to hospital presentation (days) 6.91 (4.83) 8.46(2.14) -1.54(-4.43 to 1.33) -1.09 0.024 total bsa (%) 3.00(1.47) 4.65(0.65) -1.65(-2.53 to -0.77) -3.81 0.001 hospital stay (days) 7.08 (3.42) 6.84(5.04) 0.24(-2.63 to 3.11) 0.170 0.361 bsa: body surface area. * p-values of < 0.05 were considered significant. archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 4 tality in patients with fg (table 3). the relative risk of ssi occurrence was also higher among patients with genitourinary infection; however, it was not statistically significant in univariate analysis (p = 0.075). discussion in this study, we evaluated the predictive factor for mortality in fg patients who were treated in resource-limited settings. the survival rate was 63.9% and the mortality rate was 36.1%. univariate analysis showed that advanced age, delayed in hospital presentation, involvement of larger area, a history of dm, esrd, heart failure, cva, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were found to be risk factors for mortality in patients with fg. fg is a polymicrobial illness that resulted typically from facultative aerobic and anaerobic bacterial growth. the rapid proliferation is linked to decreased cellular immunity of fg’s patients and the synergistic release of toxins (11). the mortality associated with the disease is high and has been reported from 6% to as high as 76% (12). in this study, the total mortality rate was 36.1%. this is in agreement with other studies in most developing countries. for example, sabzi et al. study in iran reported a mortality rate of 37.5% (12). in our study, genitourinary infection was the most common cause of fg and one-third of cases had an unknown etiology. our result was similar to tahmaz et al.'s study, which reported that 33% of fg cases were due to genitourinary infections (13). nevertheless, no identifiable cause was observed in one-quarter of the patients in the el-qushayri et al. study (14). the factors that predict fg mortality are, for the most part, debatable. because many studies are retrospective and included a small number of patients. for that, solid criteria are still missing and statistical analysis is still limited. there is a discrepancy in the literature regarding several independent prognostic factors in patients with fg. for example, some studies have shown that younger age was associated with improved survival (8, 15, 16). while other studies have not found a significant difference in disease onset between various age groups (17, 18). in our study group, advanced age was noticed among non-surviving patients and was a risk factor for fg mortality in univariate analysis. in line with earlier research, the majority of our patient population had dm as the most common comorbidity. this pathology in our study was a predictive factor for mortality in univariate analysis (19, 20). according to previous researchers, the incidence of dm was found in between 50% and 70% of fg patients (19, 21). dm has been identified as a risk factor for fg and has been linked to a more progressive and poorer outcome due to reduced phagocytic and intracellular bactericidal activity and neutrophil dysfunction (19). certain conditions such as alcohol consumption, immunocompromised status, malignancy, heart failure, hepatic disease, and esrd were reported to be associated with fg mortality (8, 13, 22). similarly, in our study, those factors were associated with fg mortality and were statistically significant in univariate analysis. additionally, 38.9% of our patients had at least one of the following conditions: esrd, cardiac insufficiency, cva, and liver cirrhosis; these conditions were highly represented among nonsurvivors patients. in roghmann et al. table 3. comparison between survivors and non-survivors for categorical variables. variable sub total (n = 36) outcome univariate analysis variable n (%) survivors n (%) died n (%) or (95 % ci) p-value * age (year) < 65 11 (30.6) 9 (81.8) 2 (18.2) 0.28 (0.05 to 1.58) 0.151 ≥ 65 25 (69.4) 14 (56.0) 11 (44.0) reference group diabetes mellitus yes 20 (55.6) 8 (40.0) 12 (60.0) 22.50 (2.46 to 205.7) 0.006 no 16 (44.4) 15 (93.8) 1 (6.3) reference group number of debridements ≤ 1 10 (27.8) 6 (60.0) 4 (40.0) 1.25 (0.28 to 5.65) 0.763 > 2 26 (72.2) 17 (65.4) 9 (34.6) reference group time to the presentation (day) ≤ 7 21 (58.3) 16 (76.2) 5 (23.8) 0.27 (0.06 to 1.14) 0.075 > 7 15 (41.7) 7 (46.7) 8 (53.3) reference group comorbidity number ≤ 1 22 (61.1) 19 (86.4) 3 (13.6) 0.06 (0.01 to 0.33) 0.001 > 1 14 (38.9) 4 (28.6) 10 (71.4) reference group need colostomy yes 6 (16.7) 4 (66.7) 2 (33.3) 0.86 (0.13 to 5.50) 0.877 no 30 (83.3) 19 (63.3) 11 (36.7) reference group need orchiectomy yes 8 (8.3) 2 (66.7) 1 (33.3) 0.87 (0.07 to 10.69) 0.917 no 33 (91.7) 21 (63.6) 12 (36.4) reference group septic condition yes 25 (69.4) 13 (52.0) 10 (90.9) 9.23 (1.02 to 83.33) 0.048 no 11 (30.6) 1 (9.1) reference group cva yes 0 (0.0) 0 (0.0) 5 (100.0) 0.003 no 0 (0.0) 23 (74.2) 8 (25.8) reference group liver cirrhosis yes 0 (0.0) 6 (100.0) 0.001 no 23 (76.7) 7 (23.3) reference group history of heart failure yes 11 (30.6) 3 (27.3) 8 (72.7) 10.66 (2.04 to 55.51) 0.005 no 25 (69.4) 20 (80.0) 5 (20.0) reference group esrd yes 8 (22.2) 2 (25.0) 6 (75.0) 9.00 (1.46 to 55.24) 0.018 no 28 (77.8) 21 (75.0) 7 (25.0) reference group history of anal surgery yes 6 (16.7) 4 (66.7) 2 (33.3) 0.86 (0.13 to 5.50) 0.877 no 30 (83.3) 19 (63.3) 11 (36.7) reference group mechanical ventilation yes 15 (41.7) 4 (26.7) 11 (73.3) 26.12 (4.09 to 166.0) 0.001 no 21 (58.3) 19 (90.5) 2 (9.5) reference group etiology non-gu 21 (58.3) 16 (76.2) 5 (23.8) 0.27 (0.06 to 1.14) 0.075 gu 15 (41.7) 7 (46.7) 8 (53.3) reference group bun (mg/dl) < 50 18 (50.0) 17 (94.4) 1 (5.6) 0.03 (0.003 to 0.27) 0.002 ≥ 50 18 (50.0) 6 (33.3) 12 (66.7) reference group albumin (g/dl) < 3 22 (61.1) 2 (14.3) 12 (85.7) 126.0 (10.31 to 1539) < 0.001 ≥ 3 14 (38.9) 21 (95.5) 1 (4.5) reference group bsa: body surface area; bun: blood urea nitrogen; ci: confidence interval; cva: cerebrovascular accident; esrd. end-stage renal disease; gu: genitourinary; or: odds ratio. * p-values of < 0.05 were considered significant. archivio italiano di urologia e andrologia 2023; 95(3):11450 5 fournier's gangrene outcome study, history of dm, esrd, cardiac insufficiency, cva, liver cirrhosis, and comorbidity were outcome predictors and authors suggested that the presence of multiple comorbidities might predict poorer outcomes (23). in our study, the presence of multiple comorbidities was associated with fg mortality in univariate analysis. the duration between symptom onset and treatment initiation has been reported as a significant predictor of outcomes for patients with fg (19, 24). however, these findings are not universally agreed upon. for instance, a study by sallami et al. reported no significant difference in time to admission between survivors and non-survivors (20). in our study, we found that a longer time to hospital admission was significantly associated with fg mortality (p = 0.024). other reports mentioned higher mortality among fg patients with delayed hospital admission (19, 24). these inconsistencies may be attributed to variations in study settings, patient demographics, hospital accessibility, income, and educational levels. in our study, the delayed patient presentation may be attributed to the limited access to healthcare facilities. specifically, the residence of our cohort was located at a considerably far distance from the specalized health centers, from the study area, which likely contributed to the delay in seeking medical attention. various laboratory abnormalities have been evaluated to predict fg mortality, including white blood cell (wbc) count, blood urea nitrogen (bun), serum creatinine, albumin, calcium, and sodium (12, 23). however, there is a discrepancy in the literature regarding several independent laboratory prognostic factors in patients with fg. sabzi sarvestani et al. reported a significant correlation between those factors and fg mortality (12). these findings were also endorsed by yeniyol et al., who showed elevated wbc, bun, creatinine, alkaline phosphatase (alp), and lactate dehydrogenase levels, and lower hematocrit, metabolic acidosis, hyponatremia, hypokalemia, in addition to decreased total protein, and albumin levels in non survivors compared to survivors (17). reduced sodium levels, along with lower serum albumin and total protein levels, can signify both a catabolic state and a poor response to therapy, which were seen among these patients with a worse prognosis and higher mortality rates. these factors are directly correlated with poor outcomes (20). laor et al. found a higher level of calcium, albumin, and cholesterol, and lower levels of bun and alp at admission of surviving patients compared to nonsurvivors (25). another retrospective study, reported that bun > 50 mg/dl was significantly associated with a higher mortality (26). it should be noted that various confounding factors or effect modifiers (e.g., severe dehydration, sepsis, and shock) that were not controlled in the study may have influenced these findings. our univariate analysis showed that albumin levels lower than 3 g/dl and bun > 50 mg/dl were associated with overall increased mortality. nevertheless, the generalizability of these findings is limited by the small and heterogeneous nature of our cohort. the reported indications for orchidectomy in fg patients were preexisting epididymorchitis, gangrenous testis damage, or scrotal abscess (21). although testicular involvement appears to be uncommon in fg, a modest incidence rate was reported by sallami et al. as seven patients, of 40 included, underwent orchidectomy for gangrenous testis damage; in addition to four patients needed subcutaneous testicular repositioning (20). in our study, three patients underwent orchidectomy as a sequala of testicular gangrenous necrosis. a colostomy is sometimes needed to decrease fecal contamination, especially in the presence of infective sphincteric destruction or rectal perforation (20, 27). in our study, six patients underwent colostomy diversion due to the extensively involved perianal area. this study found a significant difference in the average extent of body surface area affected by necrotizing tissue between patients who survived and those who did not (3.0 ± 1.5 vs. 4.7 ± 0.7 respectively). the number of surgical debridements, on the other hand, did not have a significant impact on patient outcomes, which is in line with the findings of yeniyol et al. (17). however, the result reported by spirnak et al. differs from these findings, as they showed a higher mortality rate among patients who underwent more frequent debridements due to more extensive disease (28). generally, prompt surgical intervention (aggressive and often repeat debridement), broad-spectrum antibiotics, and appropriate resuscitation are crucial in these patients (29). as expected, patients with large involved body surface areas usually died during the hospital course, and the chance of undergoing multiple debridements subsequently decreased in this group. a similar report has been mentioned by sabzi sarvestani et al. (12). postoperative mechanical ventilation has been demonstrated as a powerful factor in fg mortality. in benjelloun et al. and yanar et al. studies, the need for mechanical ventilation is a predictive factor for fg mortality (30, 31). our findings are consistent with those previously reported in the literature and the need for mechanical ventilation was an independent predictor of mortality (30, 31). this study has several limitations. firstly, the retrospective design and the small sample size were potential sources of bias that might limit the generalizability of our findings. secondly, due to the nature of the study, some relevant factors, such as blood gas analysis data, apache ii scoring system, cci, and fgsi, were not included in our analysis. future studies with more sample sizes and prospective designs are recommended to strengthen the validity and generalizability of our findings. conclusions fg represents a critical medical condition with notable morbidity and mortality rates. in this study, advanced age, delayed in hospital presentation, involvement of larger area, a history of dm, esrd, heart failure, cva, liver cirrhosis, presence of multiple comorbidities, septic conditions at admission, need for mechanical ventilation, hypoalbuminemia, and elevated blood urea nitrogen were associated with fg mortality. acknowledgments the authors would like to thank the general manager of al-thora general hospital and al-nassar hospital, ibb, yemen, dr. abdulghani ghabisha, for editorial assistance. archivio italiano di urologia e andrologia 2023; 95(3):11450 saif ghabisha, faisal ahmed, saleh al-wageeh, mohamed badheeb, qasem alyhari, abdulfattah altam, afaf alsharif 6 references 1. boughanmi f, ennaceur f, korbi i, et al. fournier's gangrene: its management remains a challenge. pan afr med j. 2021; 38:23. 2. thwaini a, khan a, malik a, et al. fournier's gangrene and its emergency management. postgrad med j. 2006; 82:516-519. 3. tuncel a, aydin o, tekdogan u, et 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1995; 154:89-92. 26. clayton md, fowler je, jr., sharifi r, et al. causes, presentation and survival of fifty-seven patients with necrotizing fasciitis of the male genitalia. surg gynecol obstet. 1990; 170:49-55. 27. sarofim m, di re a, descallar j, et al. relationship between diversional stoma and mortality rate in fournier's gangrene: a systematic review and meta-analysis. langenbecks arch surg. 2021; 406:2581-2590. 28. spirnak jp, resnick mi, hampel n, et al. fournier's gangrene: report of 20 patients. j urol. 1984; 131:289-291. 29. auerbach j, bornstein k, ramzy m, et al. fournier gangrene in the emergency department: diagnostic dilemmas, treatments and current perspectives. open access emerg med. 2020; 12:353-364. 30. benjelloun el b, souiki t, yakla n, et al. fournier's gangrene: our experience with 50 patients and analysis of factors affecting mortality. world j emerg surg. 2013; 8:13. 31. yanar h, taviloglu k, ertekin c, et al. fournier's gangrene: risk factors and strategies for management. world j surg. 2006; 30:1750-1754. correspondence saif ghabisha, md saifalighabisha@yahoo.com saleh al-wageeh, md alwajihsa78@gmail.com department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com urology research center, al-thora general hospital, department of urology, school of medicine, ibb university of medical sciences, ibb, yemen mohamed badheeb, md badheeb2009@gmail.com internal medicine office, yale new haven/bridgeport hospital, ct (usa) qasem alyhari, md qalyhary@hotmail.com department of general surgery, school of medicine, ibb university of medical sciences, ibb, yemen urology office, althora general hospital, alodine street, ibb (yemen) abdulfattah altam, md dral_tam@yahoo.com urology office, school of medicine, 21 september university, sana'a (yemen) afaf alsharif, md afafmussa2018@gmail.com department of gynaecology, school of medicine, jeblah university for medical and health sciences, ibb, yemen gynaecology office, jeblah hospital, jeblah, ibb (yemen) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12118 1 letter to editor submitted 22 november 2023; accepted 2 december 2023 to the editor, upper urinary tract obstruction (uuto) is a common scenario in clinical practice, and it is caused by a variety of diseases. lithiasis, tumours and strictures are some of the principal aetiologies (1). multiple factors may influence both the need for decompression of the obstructed collecting system and the urgency of procedure. to our knowledge, there is limited agreement among clinicians about the optimal method, timing of intervention and even some indications for decompression. both percutaneous nephrostomy (pcn) and retrograde ureteral catheterization (ruc) have established efficacy for decompression of upper urinary tract (2). furthermore, the high success and low complication rates of these drainage procedures make both alternatives attractive (3-5). however, there is great disagreement on which of the two methods is better for the patient and for a specific clinical setting (3-5). there are currently insufficient studies that directly compare both methods, and most works have retrospective and heterogenous design (3-5). there are two randomized studies addressing efficacy of ruc vs pcn in patients with obstructive ureteral calculi and infection (2, 6). one randomized controlled trial with 42 patients, demonstrated no significant difference in time to definitive drainage, clinical normalization of index parameters (white blood count and temperature), or length of hospital stay (2). another randomized prospective trial with 40 patients, concluded that percutaneous nephrostomy was superior to retrograde ureteric stent, with shorter period of iv antibiotics, superior quality of life, less use of analgesia and no access failures on pcn arm (3). previous studies also addressed which method was superior according to clinical indication. double j stent was the first choice of urologists when facing patients with uncomplicated benign disease and patients with coagulopathy (7). availability, logistics, and experience with pcn or ureteric stent techniques vary internationally, nationally, and even locally (4). desobstruction method selection is made by local practice, patient characteristics, expertise, and facilities (4). acute upper urinary tract obstruction is most commonly due to calculus. the existing guidelines by european association of urology only recommend definitive treatment of the cause of obstruction after infection has been resolved (8). however, further to the emerging role for the use of primary ureteroscopy (urs) in the management of non-infective ureteric stones (9), recent data showed that urs can effectively and safely manage febrile hydronephrosis due to ureteric stone disease, when combined with strong antibiotics in select clinical situations (10, 11). based on the above findings, the decision to choose the best method for decompression of the renal collecting system depends on the clinical scenario, the physician’s expertise, hospital environment and costs. that decision is made without guidelines about the best method for decompression and the perfect timing. this work aims to build a consensus survey among urologists in portugal, that may be the basis for subsequent development of guidelines to support the decision on the best method of upper urinary tract clearance, according to the clinical situation and intrinsic factors of the patient. patients and methods the study was approved by institutional ethical committee (ce-099/2022). opinion based questionnaire was available via google forms and sent to all portuguese urologists using the portuguese urological association (apu) associates database. all gathered data was anonymised. written inform consent to participate in the study was collected. survey was designed by urologists with experience in uuto and pretested with 10 urologists. national consensus survey on management approaches for upper urinary tract obstruction: a comparative analysis of retrograde ureteric stent and percutaneous nephrostomy vasco quaresma 1, 2, francisca magalhães 2, lorenzo marconi 1, 2, joão lima 1, 2, manuel lopes 1, ana-marta ferreira 1, pedro nunes 1, 2, arnaldo figueiredo 1, 2 1 urology department, centro hospitalar e universitário de coimbra, portugal; 2 faculty of medicine of the university of coimbra, portugal. doi: 10.4081/aiua.2023.12118 archivio italiano di urologia e andrologia 2023; 95(4):12118 v. quaresma, f. magalhães, l. marconi, et al. 2 all respondents were invited to answer questions about their urological experience, their working place and resources of urology unit. three sets of questions were provided on questionary to survey urologists opinion on the indication, timing, and the preferred method. first, clinicians were invited to decide when to drain the urinary tract, given different clinical scenarios. answers were given in the form of a likert scale with 5 levels (totally agree to decompress to totally disagree to decompress) and were followed by an assessment of the priority of each decompression (<1h; 1-3h; 3-12h; >12h). urologists were also invited to choose the preferable method (pcn or ruc) for the previously designed clinical scenarios. lastly, five questions directed to primary urs role were incorporated, to define the possibility of choosing this option over pcn or ruc. residents with less than 3 years of clinical practice were excluded from the final analysis. data analysis regarding agreement was categorised into three degrees of agreement: ‘‘clear agreement’’ (> 75% agreement), ‘‘broad agreement’’ (50-75%) and ‘‘no broad consensus’’ (less than 50%). descriptive analyses were performed using standard summary statistics median, mode and frequency distribution. mann-whitney u test was used to analyze differences between groups of experts. specialist questionaries were evaluated using standard summary statistics according to previously defined degrees of agreement. spss version 25 was used. results survey population and group differences analysis we obtained a total of 104 answers, covering more than 35% of national urology specialists. in the study population, 76% of participants were currently working in a central or metropolitan emergency department and carried out assistance activity in the emergency department. a total of 70% of the answers were given by specialists and the remaining 30% by residents with more than 3 years of experience. most answers (57%) were given by clinicians with more than 10 years of expertise in urology and 97% of the answers were given by physicians who perform pcn and ruc in their daily clinical practice. most urologists (57%) reported a minimum of 2 patients per day requiring uut decompression in their hospital. there were no significant differences between residents and specialists’ answers (p > 0.05), groups of years of experience (p > 0.05) and activity in emergency department (p > 0.05). when analyzing the answers by the number of patients per day requiring uut decompression, answers of experts significantly differed in the indications for decompression in case of met refractory colic (p < 0.05) and aki without complications (p < 0.05). questions with significantly different responses in the four previous groups were excluded from the following global analysis. indications for upper urinary tract decompression the complete results of survey regarding the indication and timing for upper urinary tract decompression are summarized on table 1. urologists had clear agreement that decompression of the upper urinary tract is mandatory with fever (99% agreement) and clinical signs of sepsis (100% agreement). in case of fever, there was a broad agreement it should be performed in less than 3 hours (64%) and a clear agreement it should be performed in a time interval of less than 12 hours (99%). when clinical signs of sepsis are present, there was a clear agreement that it should be performed in less than 3 hours (85%). most urologist answered it should be done in less than 1 hour (66%). regarding the need to decompress the uut when the patient presents with aki (increase of serum cr > 50% in 48h or diuresis < 0.5ml/kg/h for > 6h), there was a clear agreement that uut decompression should be performed (75%). when complications are present, such as fluid overload or altered state of consciousness, 96% urologist agree with decompression. regarding time to decompression, aki without complications can be delayed more than 3 hours (broad agreement), with 18% of the clinicians stating that it could even be deferred to the next day. when complications are present, 83% said it should be done in less than 3 hours, reaching a clear agreement. there was also clear agreement (81%) that decompression should take place in presence of leukocytosis and increased crp, with 93% (clear agreement) stating that it should be performed within the first 12 hours. when questioned about the crp values that should motivate uut decompression, there was a clear agreement that uut decompression should not be performed with crp values lower than 5 mg/dl (89%), when no other symptoms or table 1. opinions regarding the adequacy of uut decompression according to clinical scenarios. archivio italiano di urologia e andrologia 2023; 95(4):12118 3 management of upper urinary tract obstruction laboratory parameters are present. only 9% of the surveyed urologists would decompress the uut with crp values of 3-5 mg/dl. if the patient presents with obstruction caused by lithiasis, refractory to medical expulsive therapy (met), 66% would clear the uut and 64% agreed to postpone the procedure to the following day, thus reaching a broad agreement for both questions. if the patient is on medical expulsive therapy, 74% think it is appropriate for the patient to wait 3 or more weeks until desobstruction (broad agreement). regarding uut decompression when the patient has a single functioning kidney, there was a clear agreement (100%) that desobstruction should be performed, with 98% of the clinicians agreeing that it should be done within the first 12 hours (clear agreement). pcn vs ruc according to clinical setting the complete results of survey regarding the best method for decompression of uut are summarized on table 2. there was broad agreement that both methods were equally adequate in case of fever and sepsis. among the few clinicians who chose one of the procedures over the other in case of fever, 79% chose to submit the patient to ruc. in case of sepsis, the majority (54%) considered both methods equally effective. septic shock, on other hand, didn’t meet agreement, with 44% preferring pcn and 38% showing no preference. there was a clear agreement that ruc is superior in patients with coagulation alterations (98%), undergoing antiaggregant medication (84%), taking oral anticoagulants (noac/warfarin) (97%). when uut is present associated with slight hydronephrosis, there is clear agreement thar ruc is superior to pcn (94%). regarding uut unblocking during pregnancy, although most stated that it is better to perform pcn (49%), no broad agreement was achieved. it was broadly agreed that pcn is preferred in cases of obstruction with blood clots (67%), renal abscess (60%), and pyonephrosis (67%). in cases of uuto caused by calculi, if the size of the stone is < 5 mm, there is a clear agreement that ruc is superior (76%). with calculus of 5-10 mm, ruc is also the preferable method (70%, broad agreement). in case of calculus with > 10 mm or steinstrasse, no agreement was reached. there was a clear agreement on performing pcn (80%) in the presence of a locally advanced tumor, and a broad agreement on performing pcn (61%) in the context of adenopathic conglomerates. when asked about the method that most preserves patient’s quality of life, 85% of the clinicians stated that ruc is the superior method (clear agreement). we reached broad agreement that, for both male and female patients, both methods are equally adequate. for young adult population and for a professionally active patient, 74% (broad agreement) and 82% (clear agreement) of the clinicians considered ruc more suitable than pcn, respectively. in obese patients, 88% agreed that ruc is the superior method (clear agreement). on the other hand, for elderly patients, or palliative care and dependent patients, no agreement was reached. primary urs in patients with lithiasis regarding uut decompression in case of ureteric lithiasis, when asked about the role of primary urs, there was clear agreement that it should not be performed with fever, signs of sepsis and increased inflammatory parameters in blood analysis. we reached a broad agreement that, in the case of lithiasis and aki, it may be appropriate to use primary urs. there was also clear agreement regarding table 2. opinions regarding the adequacy of primary urs to unblock uuto giving different clinical scenarios. archivio italiano di urologia e andrologia 2023; 95(4):12118 v. quaresma, f. magalhães, l. marconi, et al. 4 decompression in case of lithiasis refractory to met. the results are summarized on table 3. discussion the ideal method for decompression should be easily applicable, have complete success rate, few complications, and be well tolerated. most decisions on upper urinary tract decompression in the daily practice are based on specialists’ opinions, therefore we consider the expert-based survey a suitable method to address this issue. it is well accepted that drainage is mandatory when obstruction of the upper urinary tract occurs in the setting of urinary infection or loss of renal function. untreated obstruction in patients with infection may lead to serious consequences such as pyonephrosis, sepsis, and death (12). our results confirmed these indications, with more than 95% of urologists agreeing on the need of upper urinary tract decompression when facing fever, signs of sepsis, aki with complications and unilateral functioning kidney. when considering infection, prompt decompression is indicated, with 99% of urologists considering it should be performed in less than 12 hours in case of fever, and in less than 3h or even 1h hour when clinical signs of sepsis are present. in a previous british study addressing urologists and radiologists, fever and elevated inflammatory parameters were considered non-urgent indications for ruc or pcn, with timing not precisely defined. in case of sepsis, lynch and colleagues agreed with urgent decompression with pcn (7). in our study, both methods were considered equally effective facing fever and sepsis. in case of septic shock, no agreement was found, but when deciding for one method, most urologists would perform urgent pcn. the surveyed specialists considered that infection complicated with renal abscess or pyonephrosis should likewise be decompressed with pcn. solitary kidney is an indication for urgent decompression of upper urinary, with most urologist agreeing it should be performed in less than 3 hours. on the other hand, aki with no complication can safely be addressed within 3 to 12h. these results are consistent with previous studies, that stated it can even be delayed until the next day (7). we also addressed some of the main laboratory findings that may influence clinical decisions. when facing elevated crp levels and leukocytosis, 81% of urologists would perform decompression of collecting system. no agreement was met in the timing of decompression. when facing leukocytosis with no crp elevation, no agreement was also assembled. previous studies demonstrated that both physical and emotional stress increase wbc count on emergency department patients and that this marker can only be transiently elevated with no association with infection (13). regarding the crp values that should motivate uut clearance in the absence of other clinical or laboratory signs, there was clear agreement between portuguese urologists that a crp value under 5 mg/dl without other clinical findings is not an indication for decompression. crp and procalcitonin (pct) are by far the most widely used and studied biomarkers and both increase transiently during infection and sepsis, but these markers may also be elevated in other conditions (14). in some studies, pct was considered superior to crp to diagnose and exclude sepsis. combination of these two biomarkers may improve their ability to identify or exclude sepsis (14). ureteric stone disease is the most common cause of uuto. if uncomplicated, most urologists agree that decompression may be deferred to the following days and that primary urs is an appropriate treatment. we found broad agreement (74%) that patients could wait 3 or more weeks on met until decompression. there are insufficient studies addressing the function deterioration of the obstructed kidney. we also evaluated the impact of stone dimension on the selection of the best method of decompression. ruc was the method of choice for stones < 10 mm. no agreement was found for stones > 10 mm or steinstrasse. stent failure occurred more frequently in patients with large ureteral stones (4). according to previous studies, double j stent is the first choice of urologists when facing patients with uncomplicated benign disease (7). in our study, primary urs was an option for clearance of stones refractory to met and when aki is present. when facing fever, signs of sepsis or elevated inflammatory parameters, there was clear consensus not to perform primary urs. these results are at odds with recent studies suggesting that urs can safely manage febrile hydronephrosis when combined with strong antibiotics (10, 11). our study didn’t reach consensus in uut decompression during pregnancy. previous studies have shown that pregnant women with stone disease may undergo definitive treatment with ureteroscopy in specialized referral centers.7 retrospective studies also concluded that pcn seemed more effective than double j insertion. when choosing double-j placement in this group of patients, rapid encrustation needs to be considered, because during pregnancy, hyperuricosuria, hypercalciuria, and asymptomatic bacteriuria are common (4). pcn was the preferred method in case of locally advanced neoplasia. in previous studies, no significant difference has been reported between the two diverting modalities (5). table 3. opinions regarding the adequacy of primary urs to unblock uuto giving different clinical scenarios. archivio italiano di urologia e andrologia 2023; 95(4):12118 5 management of upper urinary tract obstruction double j stent was the method of choice in case of coagulopathy and patients on antiaggregant or anticoagulant therapy. these findings confirmed previous studies that similarly recommended stent as first line of treatment (7). conclusions on pain and qol are contradictory. portuguese specialists considered ruc as the method that better preserves quality of life, preferring this option for young patients and professionally active population. patient sex did not influence the choice, both methods were considered equally appropriate. patient and disease characteristics like obesity and slight hydronephrosis influenced the choice of method, probably due to technical difficulties. urologists opted for ruc in these patients. our results need confirmation from other studies and have several limitations. national representativity was limited to 35% of urologists and possible bias are present when addressing patient characteristics independently. we aim to amplify our survey respondents by expanding to other countries. our future aim is to assemble portuguese experts in the next portuguese urology association meeting to define the expert-based consensus national guidelines for uut decompression using delphi method consensus. conclusions we successfully identified consensus among expert portuguese urologists regarding upper urinary tract decompression. these conclusions serve as a solid foundation for the subsequent formulation of specific guidelines. references 1. chávez-iñiguez js, navarro-gallardo gj, medina-gonzález r, et al. acute kidney injury caused by obstructive nephropathy. int j nephrol. 2020; 2020. 2. pearle ms, pierce hl, miller gl, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol. 1998; 160:1260-4. 3. ramsey s, robertson a, ablett mj, et al. evidence-based drainage of infected hydronephrosis secondary to ureteric calculi. j endourol. 2010; 24:185-89. 4. weltings s, schout bma, roshani h, et al. lessons from literature: nephrostomy versus double j ureteral catheterization in patients with obstructive urolithiasis-which method is superior? j endourol. 2019; 33:777-786. 5. hsu l, li h, pucheril d, et al. use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction. world j nephrol. 2016; 5:172. 6. mokhmalji h, braun pm, martinez portillo fj, et al. percutaneous nephrostomy versus ureteral stents for diversion of hydronephrosis caused by stones: a prospective, randomized clinical trial. j urol. 2001; 165:1088-92. 7. lynch mf, anson km, patel u. current opinion amongst radiologists and urologists in the uk on percutaneous nephrostomy and ureteric stent insertion for acute renal unobstruction: results of a postal survey. bju int. 2006; 98:1143-1144. 8. mottet n, cornford p, briers e, et al. eau guidelines on prostate cancer update 2022. european association of urology 2022; pp.1-182. 9. mckay a, somani bk, pietropaolo a, et al. comparison of primary and delayed ureteroscopy for ureteric stones: a prospective nonrandomized comparative study. urol int. 2021; 105:90-94. 10. shoshany o, erlich t, golan s, et al. ureteric stent versus percutaneous nephrostomy for acute ureteral obstruction clinical outcome and quality of life: a bi-center prospective study. bmc urol. 2019; 19:79. 11. wang c-j, hsu c-s, chen h-w, et al. percutaneous nephrostomy versus ureteroscopic management of sepsis associated with ureteral stone impaction: a randomized controlled trial. urolithiasis. 2016; 44:415-419. 12. wein aj, kavoussi lr, partin aw pc. campbell-walsh urology. 12th ed. philadelphia: 2020. 13. bertolino g, quaglia f, scudeller l, et al. transient leukocytosis in emergency room: an overlooked issue. italian journal of medicine. 2017; 11:41. 14. pierrakos c, velissaris d, bisdorff m, et al. biomarkers of sepsis: time for a reappraisal. crit care. 2020; 24:287. correspondence vasco pedro duarte quaresma, md (corresponding author) vpdquaresma@gmail.com urology department, centro hospitalar e universitário de coimbra rua antónio manso cunhavaz, lote 2, 5ºb, 3030-779, coimbra francisca magalhães, md mfranciscacspmagalhaes@gmail.com lorenzo marconi, md lorenzooliveiramarconi@gmail.com joão lima, md joaopedrosolima@gmail.com manuel lopes, md manuel11070@gmail.com ana-marta ferreira, md anamartaferreira0@gmail.com pedro nunes, md ptnunes@gmail.com arnaldo figueiredo, md ajcfigueiredo@gmail.com conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13615 1 original paper to the mucosa (ta and carcinoma in situ “cis”) or lamina propria (t1), and tumors that invade the muscle (t2) and beyond (t3, t4) which are defined as muscleinvasive bladder cancer (mibc). approximately 75% of newly diagnosed bcs are found at the non-muscle invasive stage. nmibcs are characterized by favorable survival rates and with progression rates varying between 6-17%, depending on the t stage of the tumor (ta-cist1) (4). however, up to 67% of all patients with nmibc may experience disease recurrence. in contrast, in mibc, fiveyear survival rates drop to 60% for localized disease and below 10% for metastatic disease (5). efforts are being made to identify new markers for bc to predict invasive potential and prognosis of the disease. transglutaminases are an enzyme family that perform multiple calcium dependent posttranslational modifications of proteins. tissue transglutaminase also known as transglutaminase2 (tg2), is the most abundant member of this family and it can be found in all cellular compartments (nucleus, cytoplasm, organelles) as well as in the extracellular space (6). in cellular environment, tg2 is involved in various enzymatic activities such as transamidation, gtp/atp hydrolyse, kinase, proteolytic and scaffolding. through these activities, tg2 plays essential roles in diverse physiological processes, including cell growth and differentiation, adhesion, migration, angiogenesis, autophagy, extracellular formation, apoptosis (7). the oncogenic potential of tg2 has been demonstrated in various cancer types such as breast carcinoma, pancreatic adenocarcinoma, colorectal carcinoma and central nervous system tumors in previous studies (8-11). resistance to systemic drugs and development of metastases together account for nearly 90% of all cancer-related deaths. identifying of biomarkers that can promote tumor invasiveness, drug resistance and metastasis is an important goal, as these proteins can be helpful in estimating the prognosis of the disease and may serve as potential targets for the therapy. in carcinogenesis, tg2 has shown to play various roles. firstly, tg2 can promote epithelialto mesenchymal transition (emt), which is believed to be the first step of tumor progression and metastasis (12). tg2 also contributes to chemoresistance and promote the acquisition of cancer stem-cell like properties of the tumor cells by activating nfκb and pi3k/akt pathway (13). additionally, tg2 influpurpose: transglutaminase-2 is associated with tumor invasion, metastasis development, chemoresistance and poor prognosis in various cancer types. in this study, our aim was to show the association between increased transglutaminase-2 expression and the invasive pattern of bladder cancer. materials and methods: tumor tissues from eighty-eight patients with bladder cancer (43 muscle-invasive, 45 non-muscle invasive bladder cancer) were immunohistochemically evaluated for tg2 expression. results: transglutaminase-2 expression score was higher in muscleinvasive bladder cancer compared to non-muscle invasive bladder cancer tissues (5.37 ± 1.5 vs. 0.71 ± 1.4, p < 0.001). no statistically significant difference was found in transglutaminase-2 expression scores between metastatic and non-metastatic disease in mibc group. different tumor and lymphnode stages in mibc were also found to be not correlated with transglutaminase-2 expression scores. conclusions: the over-expression of transglutaminase-2 is associated with invasive disease in bladder cancer. according to our results, transglutaminase-2 has the potential to be useful for predicting the invasion in bladder cancer and addressing treatment. key words: transglutaminase-2; muscle-invasive bladder cancer; malignant neoplasm; tumor biomarker. submitted 1 november 2024; accepted 30 january 2025 introduction bladder cancer (bc) is the 10th most common cancer worldwide, and its incidence is rising, especially in developed countries. bladder cancer is more common in men than women, with lifetime risk of 1 to 27 in men and 1 to 89 for women, respectively (1). the advanced age is now recognized as the greatest risk factor for bladder cancer, with the average age of bc diagnosis being 70 years (2). tobacco consumption is the most important modifiable risk factor for bladder cancer, accounting nearly 50% of all cases. urothelial carcinoma is the most common subtype of bc (3). bladder cancer is divided into two main categories: nonmuscle invasive bladder cancer (nmibc), which is confined increased expression of transglutaminase-2 is associated with invasive disease in bladder cancer yavuz karaca 1, şükran kayıpmaz 2, dilek telci 3, oktay akça 4 1 department of urology, sancaktepe şehit prof. dr. i̇lhan varank research and training hospital, istanbul, türkiye; 2 department of pathology, kartal dr. lütfi kırdar city hospital, istanbul, türkiye; 3 faculty of engineering, department of genetics and bioengineering, yeditepe university, istanbul, türkiye; 4 department of urology, bahçeşehir university, istanbul, türkiye. doi: 10.4081/aiua.2025.13615 summary archivio italiano di urologia e andrologia 2025; 97(2):13615 y. karaca, ş.kayıpmaz, d. telci, o. akça 2 ences the tumor micro-environment by cross-linking extracellular matrix proteins, thereby facilitating tumorecm interaction. through these mechanisms, tg2 has shown to be associated with increased cancer cell adhesion, migration, metastasis and invasion in different cancer types (14). in this study, our aim was to evaluate the role of transglutaminase-2 in bladder cancer. materials and methods after the approval of local ethics committee (no: 2021/514/202/5), cases dated between january 2014 and may 2021 involving transurethral resections and radical cystectomies for bladder cancer in our urology department database were retrospectively scanned. all demographic characteristics, clinical and pathological parameters were evaluated. a total of 46 patients with mibc were identified for the study group and 45 patients with nmibc were selected as the control group. the control group were consisted of patients with demographic characteristics similar to the study group. exclusion criteria were: history of neoadjuvant therapy for bc, history of intravesical therapy and non-urothelial carcinomas of bladder (figure 1). a total of 91 patients were included into this study. paraffin-embedded cancer tissues of these patients were extracted from pathology department’s archives. immunohistochemical evaluation formalin fixed paraffin-embedded tissues were used for immunohistochemical evaluation. after the inspection of all hematoxylin-eosine-stained slides of the tumor samples, a single paraffin-embedded block with the most evident tumor tissue was selected for each case. tissue sections obtained from the paraffin blocks were fumigated for one day. the next day, the slides were placed in a benchmark xt/ihc system staining module (roche diagnostics, basel, switzerland). deparaffinization, antigen retrieval with edta, antibody incubation (transglutaminase-2 cub 7402, invitrogen, massachusetts, usa, ma-12739, 1/200 dilution, 32 minutes incubation), amplification and counter staining with he processes were performed respectively. after these steps, slides were washed, dried and sealed. microscopic assessment according to the manufacturer’s manuals, tumor samples from an invasive ductal breast adenocarcinoma case were selected as control tissue. efficacy and the reaction conditions of the antibody were determined by using this control tissue. the assessments of the tumor tissues were performed by sk, who is an experienced uro-pathologist with the participation of one of the urologists (yk) as an observer. both evaluators were blinded to the clinical and pathological features of the patients. all tumor slides were evaluated with microscope under 4x, 10x, 20x, 40x and 100x magnifications when necessary. based on previous studies (15), cytoplasmic and membranous staining of the cells was assessed and according to findings in 4x, a semi-quantitative chart was designed. staining percentage was scored between 0-4 points (< 10%-0 points, 10-30% 1 point, 30-50%-2 points, 5070%-3 points and > 70%-4 points) and staining intensity was scored between 0-3 points (no staining0 points, weak-1 point, moderate-2 points and strong3 points) with maximum total score of 7 points (table 1). three patients with “nested variant of urothelial carcinoma” from mibc group were excluded from the study due to a lack of staining with table 1. the semi-quantitative chart for transglutaminase-2 antibody staining scoring system. staining parameter points staining percentage (% score) < 10% 0 10-30% 1 30-50% 2 50-70% 3 > 70% 4 staining intensity (intensity score) no staining 0 weak 1 moderate 2 strong 3 figure 1. prisma diagram showing the selection of the patients. archivio italiano di urologia e andrologia 2025; 97(2):13615 3 increased expression of transglutaminase-2 is associated with invasive disease in bladder cancer the antibody. a total of 88 patients with bc were included into this study. the microscopic images of immunohistochemical tg2 antibody staining of the tissues are presented in figure 2 and figure 3. statistical analysis statistical analysis was performed with ibm spss software (ver. 26 for macos, ibm, usa). distribution of the variables was measured by kolmogorov-smirnov test. all demographic, clinical and histopathological parameters were analyzed using kruskal-wallis test, mann-whitney u test and chi-square test. a p value < 0.05 was considered as statistically significant. results a total of 88 patients were included in this study. group 1 consisted of 43 mibc patients (40 men, 3 women), and group 2 consisted of 45 nmibc patients (41 men, 4 women). three patients with nested variant of mibc were excluded (figure 1). the average age was 63.4 ± 10.3 years in group 1 and 61.1 ± 11.9 years in group 2 (p = 0.447). all 88 patients were diagnosed with urothelial carcinoma of the bladder. all patients in group 1 had high-grade carcinoma, while 3 patients (6.6%) in group 2 had high-grade carcinoma (table 2). the average transglutaminase-2 (tg2) staining score was significantly higher in group 1 compared to group 2 (5.37 ± 1.5 vs. 0.71 ± 1.4, p < 0.001) (table 3). further analysis of patients with mibc (group 1) was figure 2. microscopic images of immunohistochemical tg2 staining of the tissues. a. 57 years old man, mibc, pt3b, % score: 4/intensity score: 3 total score: 7. b. 68 years old woman, mibc with sarcomatoid differentiation, pt4, % score: 4/intensity score: 3 total score: 7. c. 44 years old man, low grade nmibc, pta, % score: 0/intensity score: 0 total score: 0. d. 51 years old man, low grade nmibc, pta, % score: 0/intensity score: 0 total score: 0. figure 3. microscopic images of immunohistochemical tg2 staining of the tissues. a. 63 years old man, mibc with nested variant, t2, % score: 0/intensity score: 0 total score: 0. b. 54 years old man, mibc, t3a, % score: 2/intensity score: 1 total score 3. table 3. the comparison of mean transglutaminase-2 staining scores of two groups. group 1 group 2 p value (mibc group) (nmibc group) tg2 staining score (mean ± sd) 5.37 ± 1.5 0.71 ± 1.4 < 0.001 table 2. demographic, clinical and pathological parameters of two groups. group no group 1 (mibc group) group 2 (nmibc group) patient number 43 45 age 63.40 ± 10.3 61.13 + 11.9 sex (n, %) men 40 (93%) 41 (91.1%) women 3 (7%) 4 (8.9%) tumor histology (n, %) urothelial carcinoma – 43 (100%) urothelial carcinoma – 45 (100%) tumor stage (n, %) pt2 16 (37%) pt3 15 (34.8%) ta – 45 (100%) pt4 12 (27.9%) lymph node involvement (n, %) n0 18 (41.8%) n0 45 (100%) n1 12 (27.9%) n2 11 (25.5%) n3 2 (4.6%) tumor grade (n, %) high grade – 43 (100%) low grade 42 (93.3%) high grade 3 (6.6%) a. b. a. b. c. d. archivio italiano di urologia e andrologia 2025; 97(2):13615 y. karaca, ş.kayıpmaz, d. telci, o. akça 4 conducted to identify factors potentially influencing tg2 expression. no statistically significant difference in tg2 staining scores was observed between metastatic and non-metastatic mibc patients (5.39 ± 1.6 vs. 5.33 ± 1.4, p = 0.824) (table 4). additionally, there was also no statistically significant difference in tg2 staining scores between tumors at different tumor stages (p = 0.142) or lymph node stages (p = 0.905) (table 5). interestingly, three patients with the nested variant of mibc showed no staining with the transglutaminase-2 antibody. discussion our study reveals a significant upregulation of transglutaminase-2 (tg2) in mibc compared to nmibc (5.37 ± 1.5 vs 0.71 ± 1.4, p < 0.001). while tg2 expression was significantly elevated in invasive tumors compared to noninvasive tumors, it showed no correlation with lymph node involvement, tumor stage, or metastatic status in within the mibc subgroup, highlighting its presence across all stages of mibc without significant variations. interestingly, the absence of tg2 staining in the nested variant mibc cases highlights potential histological variability, suggesting that tg2 expression is not uniform across all bladder cancer variants. one of the key ways tg2’s contributions to cancer progression is by promoting epithelial-to-mesenchymal transition (emt) of cancer cells. emt is a major pathway of the tumor cells during cancer progression (16). tg2 activates cancer cells emt through fak, akt and nf-kb pathway (17). during emt, epithelial cells lose their cell-to-cell adhesion and take on a more mobile, mesenchymal-like state. this leads to the loss of epithelial markers like e-cadherin and an increase in mesenchymal markers such as vimentin and fibronectin. these changes enable cancer cells to become more migratory and invasive, significantly increasing their potential of invasion and forming distant metastases. secondly, tg2 overexpression has been linked to the acquisition of stem-cell like properties of the cancer cells which is associated with increased tumor-initiating capacity and chemoresistance (18). additionally, in carcinogenesis tg2 modulates the tumor microenvironment by crosslinking ecm proteins and enhances cell adhesion, migration and tumor survival. when compared to other studies, our findings are coherent with prior observations that link tg2 expression to tumor aggressiveness in various malignancies. in bladder cancer, hager et al. observed that tg2 is primarily expressed in grade 3 and 4 muscleinvasive tumors, while it remains undetectable in normal urothelium and low-grade papillary tumors. their study further demonstrated a lack of tg2 staining in distant solid organ metastases, suggesting tg2’s role may be limited to the local invasive phase rather than systemic metastatic disease. in breast cancer, kumar et al. showed increased expression of tg2 induces emt and stem-cell properties in mammary epithelial cells therefore promoting aggressive disease and metastasis (19). in a study by shinde et al. it was shown that tg2 contribute to resistance to chemotherapy in her2 positive breast cancer cells through the activation of the nf-κb signaling pathway (20). in a review, li et al. showed that increased tg2 expression is elevated in lung and bone metastasis and tg2 can mediate multiple therapy resistance to chemotherapeutic drugs and immune check-point inhibitors by modulating tumor microenvironment and promoting emt and csc-like properties (21). in colorectal cancer, increased expression of tg2 has shown to be associated with lower disease-free survival (dfs), overall-survival (os) and earlier relapse (22). in an invitro study, overexpression of tg2 in colorectal cancer stem-cells has shown to be associated with increased metastatic potential via emt pathway and tg2 knockdown reversed the emt proving the potential of tg2 as a therapeutic target for aggressive crc (23). in ovarian cancer cells, tg2 binds directly to fibronectin and stabilizes extracellular matrix by enhancing fibronectinintegrin b-1 complex. by activating integrinlinked kinase (ilk), tg2 favors cancer-cell adhesion, extracellular matrix reorganization, migration and metastatic spread. statistical analyses showed high expression of tg2 and ilk is associated with lower overall-survival in ovarian cancer. in-vitro knockdown of tg2 demonstrated significant reduction of cancer cell adhesion and metastatic potential and hence showing the potential role of tg2 as a therapeutic target for ovarian cancer (24). in non-small-cell lung cancer (nsclc), higher tg2 expressing tumors have found to be associated with more advanced stage/metastatic disease, increased chemotherapy resistance, lower dfs, poorer os compared to lower tg2 expressed tumors (25). it has also reported that inhibition of tg2 in lung cancer increase radiosensitivity of tumor cells (26). corelated with these results, tg2 may serve as a prognostic factor in lung cancer. in pancreatic cancer, tumor with higher tg2 expressions were found to have table 4. the comparison of mean transglutaminse-2 scores in metastatic and non-metastatic mibc patients. present not present p value (mean tg2 score (mean tg2 score + sd, number) + sd, number) metastasis 5.39 ± 1.6 (n: 28) 5.33 ± 1.4 (n: 15) 0.824 * * mann whitneyu test. table 5. the comparison of mean transglutaminse-2 scores in mibc patients subgroup regarding to t and n stages. mean tg2 score (number) p value t stage 2 5.31 ± 1.44 (n: 16) 0.142 ** 3 5.93 ± 1.38 (n: 15) 4 4.75 ± 1.71 (n: 12) n stage 0 5.33 ± 1.41 (n: 18) 0.905 ** 1 5.25 ± 1.71 (n: 12) 2 5.73 ± 1.34 (n: 11) 3 4.5 ± 3.53 (n: 2) ** kruskalwallis test. archivio italiano di urologia e andrologia 2025; 97(2):13615 5 increased expression of transglutaminase-2 is associated with invasive disease in bladder cancer poorer clinicopathologic features (higher nodal metastasis, advanced clinical stage, less chemotherapy sensitivity, increased tumor invasion and metastatic potential) (11). in this study we were able to detect higher expression of tg2 in muscle invasive bladder cancer compared to nonmuscle invasive bladder cancer. our results were corelated with previous findings about the potential roles of transglutaminase-2’s in advanced malignancy in various cancer types. but our study is not without some limitations. firstly, the small number of samples is the main limitation of this study. secondly, clinical data of the patients are not obtained thus no commentary can be made on the effects of transglutaminase-2 on overall-survival and disease-free survival rates in bladder cancer. nevertheless, considering that muscle-invasive bc has lower overallsurvival and disease-free survival compared to nmibc, higher tg2 can be held responsible for worse prognosis in bladder cancer. however, further clinical data are necessary for this purpose. on the other hand, our study is one of the very few studies on this subject and our results showed clearly that tg2 expression is stronger in invasive bladder cancer tissues compared to non-invasive tumors. our findings may form a basis for further clinical studies. conclusions in this study, our data showed that higher expression of transglutaminase-2 is associated with increased invasion potential in bladder cancer. according to our results, transglutaminase-2 has the potential for predicting prognosis of bladder cancer and being a therapeutic target. references 1. richters a, aben kkh, kiemeney lalm. the global burden of urinary bladder cancer: an update. world j urol. 2020; 38:1895-1904. 2. shariat sf, sfakianos jp, droller mj, et al. the effect of age and gender on bladder cancer: a critical review of the literature. bju int. 2010; 105:300-308. 3. burger m, catto jw, dalbagni g, et al. epidemiology and risk factors of urothelial bladder cancer. eur urol. 2013; 63:234-41. 4. siregar gp, parwati i, noegroho bs, et al. the association between serum hypoxia inducible factor-1α level and urothelial bladder cancer: a preliminary study. arch ital urol androl. 2023; 95:11292. 5. lenis at, lec pm, chamie k, mshs md. bladder cancer: a review. jama. 2020; 324:1980-1991. 6. odii bo, coussons p. biological functionalities of transglutaminase 2 and the possibility of its compensation by other members of the transglutaminase family. scientificworldjournal. 2014; 2014:714561. 7. tabolacci c, de martino a, mischiati c, et al. the role of tissue transglutaminase in cancer cell initiation, survival and progression. med sci (basel). 2019; 7:19. 8. malkomes p, lunger i, oppermann e, et al. transglutaminase 2 is associated with adverse colorectal cancer survival and represents a therapeutic target. cancer gene ther. 2023; 30:1346-1354. 9. chang w, gao w, liu d, et al. the upregulation of tgm2 is associated with poor prognosis and the shaping of the inflammatory tumor microenvironment in lung squamous cell carcinoma. am j cancer res. 2024; 14:2823-2838. 10. buccarelli m, castellani g, fiorentino v, et al. biological implications and functional significance of transglutaminase type 2 in nervous system tumors. cells. 2024; 13:667. 11. verma a, wang h, manavathi b, et al. increased expression of tissue transglutaminase in pancreatic ductal adenocarcinoma and its implications in drug resistance and metastasis. cancer res. 2006; 66:10525-10533. 12. shao m, cao l, shen c, et al. epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase. cancer res. 2009; 69:9192-9201. 13. cao l, shao m, schilder j, et al. tissuetransglutaminase links tgf-beta, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. oncogene 2012; 31:2521-2534. 14. eckert rl, kaartinen mt, nurminskaya m, et al. transglutaminase regulation of cell function. physiol rev. 2014; 94:383-417. 15. erdem s, yegen g, telci d, et al. the increased transglutaminase 2 expression levels during initial tumorigenesis predict increased risk of metastasis and decreased disease-free and cancer-specific survivals in renal cell carcinoma. world j urol. 2015; 33:1553-1560. 16. thiery jp, acloque h, huang ry, nieto ma. epithelial-mesenchymal transitions in development and disease. cell. 2009; 139:871-890. 17. chen x, adhikary g, newland jj. et al. transglutaminase 2 binds to the cd44v6 cytoplasmic domain to stimulate cd44v6/erk1/2 signaling and maintain an aggressive cancer phenotype. mol. cancer res. 2023; 21:922-932. 18. mani sa, guo w, liao mj, et al. the epithelial-mesenchymal transition generates cells with properties of stem cells. cell. 2008; 133:704-715. 19. kumar a, gao h, xu j, et al. evidence that aberrant expression of tissue transglutaminase promotes stem cell characteristics in mammary epithelial cells. plos one. 2011; 6:e20701. 20. shinde a, kulkoyluoglu cotul e, chen h, et al. transglutaminase2 mediates acquisition of neratinib resistance in metastatic breast cancer. mol biomed. 2022; 3:19. 21. li m, wang x, hong j, et al. transglutaminase 2 in breast cancer metastasis and drug resistance. front cell dev biol. 2024; 12:1485258. declarations ethical approval and consent for participate: this study was approved by the local ethical committee (no: 2021/514/202/5). all patients consented for participation. consent for publication: all patients consented for publication. availability of data and material: all data and material of this study is available for further assessment from the corresponding author. competing interests: none. funding: this study was funded by audobon bioscience türkiye. authors' contributions: design of the study: oa, dt; acquisition of data: yk, sk; analysis of the data: yk, oa; revision of the article: all authors approval of the article: all authors. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13615 y. karaca, ş.kayıpmaz, d. telci, o. akça 6 22. fernández-aceñero mj, torres s, garcia-palmero i, et al. prognostic role of tissue transglutaminase 2 in colon carcinoma. virchows arch. 2016; 469:611-619. 23. kang s, oh sc, min bw, lee dh. transglutaminase 2 regulates self-renewal and stem cell marker of human colorectal cancer stem cells. anticancer res. 2018; 38:787-794. 24. condello s, prasad m, atwani r, matei d. tissue transglutaminase activates integrin-linked kinase and β-catenin in ovarian cancer. j biol chem. 2022; 298:102242. 25. chihong z, yutian l, danying w, et al. prognostic value of transglutaminase 2 in non-small cell lung cancer patients. oncotarget. 2017; 8:45577-45584. 26. huaying s, dong y, chihong z, et al. transglutaminase 2 inhibitor kcc009 induces p53-independent radiosensitization in lung adenocarcinoma cells. med sci monit. 2016; 22:5041-5048. correspondence yavuz karaca (corresponding author) mdyavuzkaraca@gmail.com feyzullah mh. oğuzhanlı cad. akay apt. no: 24-26 kat: 5 daire: 12 maltepe/i̇stanbul postal zip code: 34843 şükran kayıpmaz sukransarikaya@yahoo.com department of pathology, kartal dr. lütfi kırdar city hospital, istanbul, türkiye dilek telci telcidilek@gmail.com faculty of engineering, department of genetics and bioengineering, yeditepe university, istanbul, türkiye oktay akça akcaoktay@yahoo.com department of urology, bahçeşehir university, istanbul, türkiye stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12431 1 original paper ease, urothelial neoplasms and as a result of inflammatory processes. postoperative scarring and ischemia can also serve as precipitants. congenital aetiologies encompass a range of possible causes, including physiological defects such as aperistaltic segments and anatomical factors such as the presence of crossing vessels (2). moreover, upjo is considered the most common congenital abnormality of the ureter (2). this particular impairment can lead to the development of hydronephrosis as well as a progressive deterioration in renal function (3). from a clinical perspective, the most common presenting complaint is intermittent abdominal or flank pain, which is often associated with an excess intake of fluid. this may also be accompanied by nausea and vomiting (2). the diagnosis can be subsequently confirmed through imaging modalities such as ultrasound and computed tomography (ct) urography (4). additionally, isotopic renography is commonly used for diagnostic purposes, although consensus regarding the exact criteria for defining obstruction is lacking (5). symptomatic obstruction of the ureteropelvic junction should be treated surgically (6). indications for surgery include the presence of symptoms associated with the obstruction, a progressive impairment of renal function or infection in the upper urinary. historically, the preferred surgical procedure has been dismembered pyeloplasty when intervention is warranted (2). initially, open surgery was the sole option; however, advancements in surgical technology over recent decades have allowed for minimally invasive approaches, such as laparoscopic and robotic pyeloplasty, to now standard as the reference interventions (7). currently, robotic assisted laparoscopic pyeloplasty (rlp) is reported to yield success rates exceeding 90% (8-11). the robotic-assisted approach for pyeloplasty is further associated with short hospital stay and low complication rates (12). consensus is also lacking regarding how treatment success should be defined. at our institution, the da vinci robotic system (intuitive surgical, sunnyvale, ca, usa) is currently utilized in the surgical management of upjo. in the present study, we aimed to evaluate the outcomes associated with rlp since beginning with this approach. in addition, we wanted to explore the relationship between the result of the follow background: ureteropelvic junction obstruction (upjo) is characterised by stenosis of the ureteral lumen at the level of the renal pelvis and proximal ureter. at haukeland university hospital, robotic-assisted laparoscopic pyeloplasty (rlp) for upjo has been performed since 2014. the aim of this study was to evaluate the results of the treatment and consider what determines treatment success. materials and methods: retrospective review was performed of consecutive patients undergoing rlp between 2014-2022. outcomes of interest included symptom relief, complication rates and renographic findings at follow-up. treatment success was defined in terms of symptom improvement and/or improvement as well as relief of obstruction on renography. results: in total, 95 rlps were performed in 54 women and 41 men, with a mean age of 40 years (iqr: 21-58). flank pain was the most frequent presenting complaint (n = 81, 85%) followed by infection (n = 33, 35%). more than one indication for surgery was present in 1/3 of the patients. urodynamic relevant obstruction on renography was found in 62 patients (65%) preoperatively. mean operative time was 123 minutes (range 60-270). two patients experienced minor intraoperative complications. at three months follow-up, 91% of patients had symptom relief, and no obstruction on renography was recorded in 64%. there was no significant association between improvement in symptoms and renography findings at follow-up, p = 1. conclusions: rlp can deliver a high success rate in terms of symptom relief and few complications. there was no association between renography findings and symptom relief at follow-up. success after surgery should be determined by symptom relief rather than renography findings. key words: robot assisted laparoscopic pyeloplasty; ureteropelvic junction obstruction; isotopic renography; symptom relief; complications. submitted 26 february 2024; accepted 28 march 2024 introduction ureteropelvic junction obstruction (upjo) is a condition where the flow of urine from the renal pelvis to the ureter is impaired at the anatomical transition between the renal pelvis and proximal ureter (1). while most cases are congenital, other possible causes include kidney stone disrobotic-assisted laparoscopic pyeloplasty for the treatment of ureteropelvic junction obstruction – how should success be determined? marie lien 1, mathias sørstrand æsøy 1, 2, karin hjelle 1, 2, bjarte almås 2, patrick juliebø-jones 1, 2, øyvind ulvik 1, 2 1 department of clinical medicine (k1), university of bergen, bergen, norway; 2 helse bergen hf, department of urology, haukeland university hospital, bergen, norway. doi: 10.4081/aiua.2024.12431 summary archivio italiano di urologia e andrologia 2024; 96(2):12431 m. lien, m. sørstrand æsøy, k. hjelle, et al. 2 up isotopic renography in comparison to symptom improvement in order to better understand how treatment success should be defined. materials and methods study population and setting since 2014, rlp has been the standard treatment for upjo at haukeland university hospital, a regional centre in western norway. retrospective review of the electronic medical records was performed for consecutive patients undergoing rlp between 2014 and 2022. outcomes of interest included symptom relief, complication rates and renographic findings at three months follow-up. patient demographics and preoperative characteristics are shown in table 1. the american society of anesthesiologist (asa) score was used assessing the patient’s general condition. indications for surgery included flank pain, infection, and impaired renal function. these indications did not change over the study period. an evaluation of the symptom burden was made by each urologist in consultation with the patient. during the preoperative work up, all patients underwent imaging with ultrasonography and cross-sectional imaging such as ct. a preoperative nuclear scan (mag3 diuretic renogram) was performed in order to determine splitand total renal function, as well as to assess the degree of obstruction. urodynamic relevant obstruction was defined as no emptying of the renal pelvis within 15 minutes after intravenous administration of diuretics. physiological obstruction was determined by delayed emptying of the renal pelvis within 15 minutes after diuretic administration. serum creatinine and egfr were measured both preoperatively and at follow-up. surgical procedure the da vinci robotic surgical system was used to perform an anderson-hynes dismembered pyeloplasty with resection of excess renal pelvis and re-anastomosis to the ureter. a postoperative jj-stent was routinely placed before completing the anastomosis and remained in place for four weeks before removal in the outpatient clinic. an abdominal drain at the conclusion of the surgery was placed at the surgeon´s discretion in the early procedures. postoperative complications were assessed using the clavien-dindo grading system (13). all patients were scheduled for follow-up at least three months postoperatively. the follow-up included repeat isotopic renography as well as consultation with a urologist. further follow-up was repeated whenever deemed necessary by the surgeon, respectively 12 months postoperatively. treatment success treatment success was determined based on the following criteria: 1. patient-reported improvement: surgical success was categorised if patients reported a clinically significant improvement in their symptoms or complete symptom relief at the three-month follow-up assessment. 2. radiological assessment: radiological success was categorised as the absence of urodynamic relevant obstruction on isotopic renography conducted at least three months postoperatively. statistics independent samples t-tests were performed to compare continuous variables, such as renal split function and creatinine levels prior to surgery and at follow-up. associations between categorical variables, i.e., symptom relief and findings at isotopic renography at follow-up, were assessed using exact chi-squared tests or fischer´s exact tests. ibm spss statistics 28 (ibm, armonk, ny) was used for statistical analysis. the p-value was considered significant when < 0.05. ethics and approvals in accordance with institutional and norwegian regulations, the study was registered as a clinical audit (eprotocol, project id 3470) and as such, was exempted from further ethical approval. table 1. preoperative characteristics. characteristics numbers sex women 54 (57%) men 41 (43%) age in years, mean (range, iqr) 40 (10-78, 21-58) side of surgery right 45 (47%) left 50 (53%) asa-score i 48 (51%) ii 40 (42%) iii 7 (7%) comorbidity a 21 (22%) coronar disease 3 (3%) hypertension 17 (18%) congestive heart failure 1 (1%) renal failure 4 (4%) diabetes mellitus 5 (5%) cancer 2 (2%) anticoagulantia 2 (2%) weight in kg, mean (range, iqr) 75 (32-160, 62-87) serum creatinine in mmol/l, mean (iqr) 81 (39-135, 64-90) isotopic renography 93 (98%) urodynamic relevant obstruction 62 (67%) functional/physiological obstruction 15 (16%) inconclusive result 16 (17%) preoperative imaging b 95 (100%) ultrasound 36 (38%) non-contrast ct 36 (38%) contrast enhanced ct 57 (60%) mri 2 (2%) previous urs due to hydronephrosis 17 (18%) diagnostic only 15 (16%) treatment with balloon dilatation 2 (2%) drainage at the time of surgery 30 (32%) jj-stent 17 (18%) nephrostomy catheter 13 (14%) a some patients had more than one comorbidity. b in total, 38 patients (40%) had multiple modality preoperative imaging. archivio italiano di urologia e andrologia 2024; 96(2):12431 3 robotic-assisted laparoscopic pyeloplasty for the treatment of ureteropelvic junction obstruction... results between april 2014 and december 2022, 95 rlp procedures were performed by five urologists. in total, 54 (57%) women and 41 (43%) men with a mean age of 40 years (iqr: 21-58) underwent surgery. preoperative characteristics are provided in table 1. flank pain was the most frequent cause of surgery (81 cases, 85%) followed by infection (33 cases, 35%) and impaired renal function (19 cases, 20%). in 32 patients (34%), more than one indication for surgery was present. an isotopic renography prior to surgery was performed in 93 patients (98%), and urodynamic relevant obstruction was found in 62 (67%). in the remaining 31 (33%), renography was inconclusive or revealed physiological obstruction only (figure 1). there was no statistically significant association between flank pain and urodynamic relevant obstruction on preoperative isotopic renography, p = 0.35. anderson-hynes pyeloplasty with re-anastomosis between the ureter and the renal pelvis was performed in all patients, except for one patient who underwent adhesioloysis around the ureteropelvic junction only. antegrade jjstent was placed in all but two patients. in one of these cases, placement of the stent was unsuccessful, and a nephrostomy tube was inserted. in the other case, insertion of a jj-stent was deemed unnecessary as no new anastomosis was made. an abdominal drain was placed at the end of the surgery in the first 11 patients undergoing rlp when the robotic approach was first started. in these cases, the drain was removed on the first postoperative day. for the latter 84 patients, no abdominal drain was placed. details regarding the surgical procedures are listed in table 2. intraoperative complications occurred in two patients (2%), both involved minor bleeding from either a tear in the renal parenchyma or the renal pelvis. the surgical procedures were successfully completed in both patients. four patients (4%) developed post operative infection table 2. the surgical procedure. characteristics numbers numbers of procedures per surgeon, total (%) 95 (100%) a 41 (43%) b 33 (35%) c 11 (12%) d 9 (9%) e 1 (1%) antibiotic prophylaxis, number (percent) 61 (64%) bactrim 6 (10%) cefalotin 14 (23%) cefuroxim 26 (43%) other 15 (24%) cause of ureteropelvic obstruction crossing vessels 61 (64%) high inserting ureter 6 (6%) adhesions 14 (15%) renal malrotation 4 (4%) other 10 (11%) exit strategy: jj-stent 93 (98%) time to stent removal in weeks, mean (range, iqr) 4 (2-9, 3-5) placement of abdominal drain 11 (12%) perioperative bleeding in ml, mean (range, iqr) 36 (0-200, 20-50) operative time in minutes, mean (range, iqr) 123 (60-270, 97-140) figure 1. renography findings – flowchart. archivio italiano di urologia e andrologia 2024; 96(2):12431 m. lien, m. sørstrand æsøy, k. hjelle, et al. 4 during the hospital stay and one patient (1%) experienced postoperative pain before discharge beyond that expected. all the postoperative complications were categorised as clavien-dindo grade 1 or 2. median post operative hospital stay was two days (iqr: 1-2). follow-up after three months with an isotope renography was registered in 88 cases (94%), and no obstruction was found in 56 cases (64%). in the remaining 32 patients (36%), 22 (25%) still had signs of urodynamic relevant obstruction and an additional 10 (11%) had inconclusive tests (figure 1). the renal split function did not change from the preoperative (right 51.1%/left 48.9%) to the three months follow up renography (right 51.1%/left 48.9%), p = 1. no difference was observed regarding serum-creatinine when preoperative blood analysis (85 mmol/l) was compared to blood test at follow-up (84 mmol/l), p = 0.5. the same result was found comparing gfr before and after surgery (82 ml/min and 83 ml/min, respectively), p = 0.7. in total, 91% of all patients experienced complete resolution of their symptoms (n = 45) or reported overall symptom improvement (n = 33). of note, 30 out of 32 patients with inconclusive renography findings or persistent urodynamic relevant obstruction after three months, nevertheless reported symptom free status (n = 14) or experienced overall improvement in their symptom burden (n = 16). there was no significant association between symptom improvement or becoming symptom free after surgery and the finding of no obstruction on follow-up isotopic renography, p = 1. table 3 summarises postoperative complications occurring within the first three months after surgery. a total of 54 patients (57%) underwent 12 months follow up including additional isotopic renography (figure 1). no obstruction was registered in 46 patients (85%), and inconclusive findings in two patients (4%). urodynamic obstruction was registered in six patients (11%). in three of these, signs of obstruction had appeared since the previous follow-up. despite the renographic finding, all three experienced symptom resolution. in 12 patients (71%) with urodynamic obstruction or inconclusive finding at three months follow-up, no obstruction was registered at the 12-month renography. furthermore, 93 % of the patients experienced complete symptom resolution or reported an overall improvement in their symptoms at 12 months follow up. patients with persistent obstruction after 12 months were planned for further follow-up with renography and endoscopic assessment whenever indicated. no patients needed repyeloplasty. discussion in this study, we have examined the outcomes of rlp conducted at our institution over a period of nearly 8 years. flank pain was the most frequent indication for surgery. however, more than one indication for surgery was identified in one third of the patients. andersonhynes dismembered pyeloplasty was performed in all but one patient. in total, 91% of the patients reported resolution of their pain at follow-up. two patients had minor intraoperative bleeding, which ultimately had no impact on completing the surgery. in addition, four patients experienced a post operative urinary infection and received antibiotic therapy. our results align with previous research, which supports rlp as a safe procedure with a high success rate in terms of symptom relief and the complication burden (8, 9, 14, 15). at three months follow-up, no obstruction on isotopic renography was found in 64% of the patients. in the remaining 36%, evidence of urodynamic relevant obstruction was either still present, or the test was inconclusive. our radiological success rate is lower compared to other reports in the literature, which is likely attributable in part to variations in the definitions employed for renographic success (8, 15, 16). while we determined radiological success as the absence of urodynamic significant obstruction on renography three months after surgery, defined as no emptying of the renal pelvis within 15 minutes after intravenous administration of diuretics, etafy et al. defined radiological success as a half-time (t½) isotope excretion of less than 10 minutes on diuretic renogram performed five to six weeks postoperatively (14). in that study, 82.5% of the patients were considered to be successfully treated based on the diuretic renogram (14). wood et al. reported a success rate of 97.6% from a radiological perspective, with improvement or the arrest of deteriorating drainage, as the given criteria for success but with no further details (8). the lack of a common definition for treatment success after pyeloplasty thus makes it difficult to compare results across different studies. in the present study, while flank pain was preoperatively reported in 81 cases, preoperative isotopic renography indicated urodynamic relevant obstruction in 62 cases only. surprisingly, no statistically significant association between the presence of preoperative flank pain and detection of urodynamic relevant obstruction was found, p = 0.35. this might be explained by the strict definition for obstruction at renography used at our institution. on the other hand, patients may experience intermittent flank pain due to upjo that may not be recognized as relevant obstruction in time periods with no symptoms. this may also explain why 30 of the 32 patients in our study displaying persistent urodynamic relevant obstruction or inconclusive findings at follow-up isotopic renography, reported symptom improvement or complete resolution. table 3. postoperative complications occurring within 3 months after surgery. characteristics numbers postoperative complications, number (% ) a 19 (20%) infection 14(15%) pain 4 (4%) stent related problems 3 (3%) other b 3 (3%) postoperative complications requiring treatment 19 (20%) at the outpatient clinic 11(12%) and hospitalisation 8 (8%) a some patients had more than one complication. b one patient had dilation of the anastomosis. in another two patients the stent had retracted up in the ureter and had to be removed with ureteroscopy. archivio italiano di urologia e andrologia 2024; 96(2):12431 5 robotic-assisted laparoscopic pyeloplasty for the treatment of ureteropelvic junction obstruction... furthermore, although the obstruction is relieved by the surgery, persistent hydronephrosis due to a flaccid renal pelvis may cause delayed emptying and thereby mimic obstruction. although no association between obstruction on renography and symptom relief was found, renal split function before and after surgery may add information to the result of the surgery. in the present study, renal split function was unchanged between preoperative and follow-up tests, indicating that the surgery did not deteriorate the function of the affected kidney. other author groups have also reported on the diagnostic value of split renal function when determining success after pyeloplasty (5, 15). the difficulty in defining obstruction at renography, and the finding of no association between symptoms and renographic obstruction in the present study, have led us to question the clinical role of isotopic renography in upjo besides determining renal split function. previous studies have shown that rlp is associated with a markedly reduced postoperative hospital stay when compared to conventional laparoscopic pyeloplasty. this highlights the efficiency and potential benefits of adopting a robotic approach in the setting of urological procedures (17, 18). our median inpatient stay was 2 days (iqr: 1-2), which is similar to findings from other studies (8, 14, 16, 19-21). the present study has several limitations. the retrospective design may have impeded complete data collection for all patients. a few patients were lost to follow-up as they were referred from external centres and underwent follow up at their local hospital. despite this, complete follow-up data was available for 94% of the patients, which is a strength of the study. the sample size is relatively small, but the vast majority of published series originate from nations with much larger populations. the majority of patients (91%) reported either improvement or complete resolution of their symptoms at three months follow-up. however, no validated tool for subjective pain assessment was employed in this study. the assessment of preoperative symptoms and postoperative symptom relief was therefore based solely on patients´ individual accounts to the urologist and the documentation accordingly. this lack of standardisation is a clear limitation of the study but does reflect real world practice. while a lack of a standardised definition for urodynamic relevant obstruction on isotopic renography in the literature presents a further challenge when conducting research in this particular area, a definition was applied in this study that was implemented at our institution prior to the study start date and has remain unchanged over the whole period. conclusions rlp can be performed with high success rates in terms of symptom relief and the morbidity profile. of particular relevance to clinical practice is that this study highlights the disparity between renographic findings and symptom improvement. of note, an absence of correlation between preoperative pain and isotopic renography findings was found, and there was no discernible link between renography results and symptom relief at follow-up. therefore, we argue that defining treatment success should place a greater emphasis on symptom improvement rather than only relying on renography findings. references 1. al-salem ah. pelviureteric junction obstruction. atlas of pediatric surgery: principles and treatment. cham: springer international publishing; 2020; p. 819-27. 2. wein a kl, et al. campbell-walsh urology 10th edition. elsevier saunders. 2012; p. 1122-47. 3. koff sa mk. anomalies of the kidney. in: gillenwater jy, grayhack jt, howards ss, editors. adult and pediatric urology. philadelphia, unites states: lippincott williams & wilkins. 2001; p. 2129. 4. hemal am, m, editor. robotics in genitourinary surgery: springer. 2011. 5. piepsz a. the predictive value of the renogram. eur j nucl med mol imaging. 2009; 36:1661-4. 6. tanagho em, jw smith’s general urology. 17 ed: mcgraw-hill medical; 17th edition. 2007; p.768. 7. shah kk, louie m, thaly rk, patel vr. robot assisted laparoscopic pyeloplasty: a review of the current status. int j med robot. 2007; 3:35-40. 8. wood tc, raison n, el-hage o, et al. robot-assisted laparoscopic pyeloplasty: a single-centre experience. surg endosc. 2018; 32:4590-6. 9. zhang p, shi t, fam x, et al. robotic-assisted laparoscopic pyeloplasty as management for recurrent ureteropelvic junction obstruction: a comparison study with primary pyeloplasty. transl androl urol. 2020; 9:1278-85. 10. gupta np, nayyar r, hemal ak, et al. outcome analysis of robotic pyeloplasty: a large single-centre experience. bju int. 2010; 105:980-3. 11. bird vg, leveillee rj, eldefrawy a, et al. comparison of robotassisted versus conventional laparoscopic transperitoneal pyeloplasty for patients with ureteropelvic junction obstruction: a single-center study. urology. 2011; 77:730-4. 12. cai py, lee rs. ureteropelvic junction obstruction/ hydronephrosis. urol clin north am. 2023; 50:361-9. 13. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 14. etafy m, pick d, said s, et al. robotic pyeloplasty: the university of california-irvine experience. j urol. 2011; 185:2196-200. 15. schwentner c, pelzer a, neururer r, et al. robotic andersonhynes pyeloplasty: 5-year experience of one centre. bju int. 2007; 100:880-5. 16. thom mr, haseebuddin m, roytman tm, et al. robot-assisted pyeloplasty: outcomes for primary and secondary repairs, a single institution experience. int braz j urol. 2012; 38:77-83. 17. braga lh, pace k, demaria j, lorenzo aj. systematic review and meta-analysis of robotic-assisted versus conventional laparoscopic pyeloplasty for patients with ureteropelvic junction obstruction: effect on operative time, length of hospital stay, postoperative complications, and success rate. eur urol. 2009; 56:848-57. 18. carmona o, dotan za, haifler m, et al. laparoscopic versus archivio italiano di urologia e andrologia 2024; 96(2):12431 m. lien, m. sørstrand æsøy, k. hjelle, et al. 6 robot-assisted pyeloplasty in adults-a single-center experience. j pers med. 2022; 12. 19. patel v. robotic-assisted laparoscopic dismembered pyeloplasty. urology. 2005; 66:45-9. 20. mufarrij pw, woods m, shah od, palese ma, berger ad, thomas r, et al. robotic dismembered pyeloplasty: a 6-year, multiinstitutional experience. j urol. 2008; 180:1391-6. 21. sivaraman a, leveillee rj, patel mb, et al. robot-assisted laparoscopic dismembered pyeloplasty for ureteropelvic junction obstruction: a multi-institutional experience. urology. 2012; 79:351-5. correspondence marie lien, medical student makrlien@gmail.com department of clinical medicine (k1), faculty of medicine, university of bergen postboks 7804, 5020 bergen, norway mathias sørstrand æsøy, md mathias.asoy@gmail.com karin hjelle, md phd assoc professor karin.margrethe.hjelle@helse-bergen.no bjarte almås, md phd bjarte.almaas@helse-bergen.no patrick juliebø-jones, md phd jonesurology@gmail.com øyvind ulvik, md phd assoc professor (corresponding author) doc.ulvik@online.no helse bergen hf, department of urology, haukeland university hospital postboks 1400, 5021 bergen, norway conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 98 original paper cases. the number of breast cancer sufferers increases annually (1), and there were an estimated 2.261.419 new cases worldwide in 2020 (2). in indonesia, there is a high incidence of breast cancer in bali province. based on data reported by hospital in denpasar about patient visits for breast cancer ts from august to november 2020, out of a total of 1380 patient visits, 285 were cancer patients. breast cancer greatly affects a woman's life, and a recent study noted the importance of carrying out follow-up health checks, addressing post-treatment concerns, and improving the wellbeing and quality of life of cancer survivors (3). a high level of unmet needs in cancer survivors is associated with a poor quality of life. this condition can be attributed to the low attendance to care, which is rarely accepted by cancer survivors in indonesia. to remedy the situation, healthcare professionals, especially nurses, should be trained to identify various problems and unmet needs experienced by breast cancer survivors so they can provide holistic nursing care (medical, psychological, social, spiritual, and cultural) for cancer survivors (4). another study suggested that of all cancer care today, breast cancer patients represent the largest patient group with high supportive care needs (5). accordingly, it is important to strive to better understanding breast cancer survivors’ unmet needs, which should be explored in-depth. to do so, we must explore the experiences of breast cancer survivors, especially the balinese breast cancer survivors. materials and methods the research design used in this study was an interpretative phenomenological qualitative research design to examine the unmet needs of breast cancer survivors following cancer therapy. participants in this study were selected using a purposive sampling method. the sample in this study were breast cancer survivors who had experiences related to unmet needs according to inclusion criteria set by the researcher. the inclusion criteria in this study were: i) female breast cancer survivors from various age groups, both young adults and elderly adults; ii) breast cancer survivors who wish to discuss unmet needs. the number of subjects included in this qualitative descriptive study was of 14 participants. data was collected through in-depth interviews with all participants. objective: to explore: 1) the unmet needs of breast cancer patients; 2) the sexual needs experienced by breast cancer survivors; 3) the experiences of cancer patients at the time of relapse, including the biopsychosocial-spiritual aspects of their experiences. materials and methods: interpretative phenomenological qualitative research by conducting direct in-depth interviews with participants who met the inclusion criteria. sample analyzed were breast cancer survivors who had experiences related to unmet needs (14 participants) or sexual problems (12 participants); adult cancer patients who experienced recurrences (10 participants). results: themes identified for breast cancer patients with unmet needs were i) overcoming health problems in breast cancer survivors; ii) need to access the best health services; iii) women’s unmet information needs concerning cancer treatment. for breast cancer survivors: i) information is needed to overcome sexual problems, ii) family support is needed to get sexual information, and iii) health care facilities need to provide sexual information. for patients experiencing recurrences: i) the reaction that occurs when receiving bad news; ii) efforts made during a relapse, iii) self-concept during a relapse. conclusions: health-related problems of breast cancer survivors, such as fatigue and fear of cancer recurrence, can lead them to have trouble with social relationships, question their spirituality, and struggle with sex and sexuality. oncology nurses and other professionals need to be aware of the unmet needs of breast cancer survivors, especially in relation to resolving the sexuality issues of cancer survivors. understanding of the experiences of patients with relapse of different types of cancer should be improved. key words: cancer patients; cancer recurrence; cancer therapy; relapse; resilience; breast cancer; unmet needs; sexuality; survivors. submitted 10 march 2023; accepted 18 march 2023 breast cancer survivors' unmet needs following chemotherapy * (ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti) introduction breast cancer is the most common malignancy in women worldwide, accounting for almost one in four cancer psychological and sexual problems of cancer survivors ida ayu made ari santi tisnasari 1, tuti nuraini 2, yati afiyanti 3, rudi rudi 4, riri maria 5 1 faculty of nursing, universitas indonesia, depok, indonesia; 2 department of basic science and fundamental nursing, faculty of nursing universitas indonesia, depok, indonesia; 3 department of maternity nursing, faculty of nursing universitas indonesia, depok, indonesia 4 master of nursing program, faculty of nursing universitas indonesia, depok, indonesia; 5 department of medical surgical nursing, faculty of nursing universitas indonesia, depok, indonesia. presented as conference papers at the 8th v-binc at fon universitas indonesia. doi: 10.4081/aiua.2023.11473 summary archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 99 this research was conducted in march-june 2022. the study was conducted at the hospital in bali province, indonesia. this study used the researcher himself as the research instrument. the researcher collected the data by himself without a research assistant or co-researcher. the data analysis process in this study was carried out based on the research protocol, regarding the thematic approach to analysis, namely identifying, analyzing, and reporting patterns (themes) of the data (6). results theme 1: overcoming health problems in breast cancer survivors. theme 2: need to access the best health services. theme 3: unmet information needs about cancer treatment. (details are available in supplementary materials) discussion several themes were obtained from the data analysis. the three main themes were: i) overcoming health problems in breast cancer survivors; ii) need to access the best health services; iii) unmet information needs about cancer treatment. each of those themes were below discussed in more detail in comparison of the existing literature. overcoming health problems in breast cancer survivors the first theme that emerged through this work was the challenge that women must face as a result of the health problems they experience as breast cancer survivors. such challenges can be physical, psychological, social, spiritual, and sexual. physical problems reported included memory loss and stiff joints, although the most common physical problem reported by participants was fatigue. breast cancer survivors reported a lower quality of life than other women even years after completing their treatment due to experiencing disturbing and long-lasting side effects, including cancer-related fatigue, which can affect breast cancer survivors for many years after their treatment is completed (5). another physical challenge experienced by the participants was memory loss. there are various research results on how memory decline or cognitive impairment can occur in breast cancer survivors. a study reported that memory loss in breast cancer survivors can be more severe in patients undergoing chemotherapy as a side effect of treatment (6). another study similarly concluded that memory decline in breast cancer survivors could occur for years with significantly impact on the quality of life (7). memory loss due to side effects of cancer treatment is known generally as “chemo fog” or “chemo brain” or in medical terms as cancer-related cognitive impairment. it can be exacerbated by hormonal treatment, commonly taken after breast cancer therapy (8). it is recommended that nurses are trained to provide interventions to overcome memory loss problems, such as teaching mindfulness-based stress-reduction exercises (9). a further physical challenge experienced by participants was stiffness in their hands. according to research among breast cancer survivors in africa, stiffness in the hands is widely experienced, along with pain (10). another study described side effects caused by cancer treatment including problems in the hands and shoulders and muscle strength in breast cancer survivors (11). these effects can reduce the quality of life of survivors by creating barriers to carrying out daily activities, such as dressing, combing their hair, working, shopping, exercising, etc. accordingly, nurses should provide interventions to help women reduce the stiffness in their hands, such as by teaching them arm and shoulder muscle exercises (12). a further physical health-related challenge breast cancer survivors often face is changes in their appearance, such as weight loss. according to research, cancer therapy causes weight fluctuations, as well as changes in skin and nail color (13). breast cancer survivors often feel embarrassed, lose their confidence, and have body image problems due to their changed appearance. to provide support, various nursing interventions may be directed toward increasing the confidence of women with breast cancer and survivors to breast cancer, such as running beauty care activities, holding discussions with cancer survivors, or offering cognitive behavioral therapy to women with body image problems (12). another challenge experienced by breast cancer survivors after chemotherapy was psychological, largely constituted by fear of recurrence. the fear was greatest when the participants felt unwell, when going to the hospital for restaging, or when they heard of others with a diagnosis or metastasis (14). they explained that after receiving cancer treatment, the transition to the life of a breast cancer survivor brings a series of challenges, the most important being the worry that remission will not last and they will one day need to resume treatment. this worry causes women to stress and affects their quality of life. commonly, after chemotherapy, breast cancer survivors also experience social challenges due to their increased sensitivity, which prompts them to limit how much they socialize. the participants in this study stated that they assumed other people did not fully understand the situation they were facing, which implies that they were now quickly irritated and easily angered because of the chemotherapeutic drugs they had taken. this, of course, affected the participants’ relationships with the people around them. they notably socialize less than they had in the past and had feelings of being unproductive. such an outcome is in accordance with the results of other research that showed that the treatment of subjects with cancer also impacts on the people closest to them (14). all participants in this study also faced spiritual challenges, such as questioning their faith or wanting to end their life because they felt alone, despairing, like they had failed to achieve their life goals, or overcome family problems. other participants stated they were disappointed with the hand they had been dealt or felt as if all they ever got out of life were problems. this was different from the research finding who suggested that individuals tend to turn to spirituality to overcome cancer (15). greater overall spirituality was associated with fewer depressive symptoms and a better quality of life in individuals living with cancer or other illnesses. the researchers noted that for latinx breast cancer survivors, in particular, religion and spirituality are essential for overcoming cancer. although a cancer diagnosis increases feelings of vulnerability in latinx breast cancer survivors, the cancer event strengthens their spirituality. archivio italiano di urologia e andrologia 2023; 95, 2 100 problems of cancer survivors spirituality is a helpful source of coping for latinx cancer patients during both the treatment phase and the ensuing long-term survivor phase. the benefits of spirituality include a feeling of satisfaction, a sense of peace or harmony with life, and the comfort of feeling accompanied by a spiritual presence. the different findings in this study may have resulted due to factors that affected the participants’ spirituality, for instance, economic factors or life events that caused the participants to fall into despair and feel disappointed with this turn in their lives. to prevent that from happening, nurses should lead spiritual-based interventions such as preparing a spiritual care program that is tailored to a patient’s beliefs, supporting their spiritual well-being both as a patient and later as a breast cancer survivor (16). some of the participants in this study also faced challenges around sex and their sexuality, namely relationship problems with their husbands in married breast cancer survivors, or self-acceptance problems with potential sexual partners for unmarried breast cancer survivors (17). cancer treatment can cause reduced vaginal lubrication, impaired sexual desire and arousal, pain during sexual activity, and the stigmatization of a woman as "cancer contagious". such effects are hugely significant and detrimental to a women’s sense of fulfillment since sex and sexuality are basic elements of human life, regardless of whether or not someone has a long-term sexual partner. the need to access the best health services the second key theme that emerged from this research was a need to access the best health services, with accurate cancer-detection tools and friendly nurses. participants explained the importance of having a pet scanner and bone-scanning equipment available at the nearest hospital so that cancer survivors who wish to use these facilities do not need to travel outside the area to obtain accurate staging results. such tools are valuable for preventing errors when detecting cancer metastases in breast cancer survivors according to research showing that bone-scanning tools are very useful for detecting the incidence of bone metastases at an early stage (18). an article previously highlighted the importance of the introduction of accurate cancer-detection tools in regional hospitals so that survivors do not have to travel far for examinations, especially those concerning the incidence of metastases, and we support that request (19). in addition, we must note the importance of nurses adopting a caring attitude for patients and cancer survivors. care for each survivor must be specific, based on their history of treatment. survivorship services are usually offered in indonesia to every patient who completes cancer treatment seeing as each therapy has shortand long-term impacts that affect the quality of life of cancer survivors (20). to improve the current offering, nurses must be trained to help cancer survivors overcome health-related challenges such as fatigue, cognitive disorders, depression, and issues around sex. oncology nurses should understand the stages of breast cancer care so they can better understand survivors and adopt a caring attitude to meet the needs of breast cancer survivors. unmet information needs about cancer treatment a final theme identified in this study was the participants’ unmet needs regarding cancer care information, such as information on the treatment stages, how to cope with the side effects of the therapy, the latest treatment information, and signposting to information technology resources to accompany their cancer care. in the research conducted among breast cancer survivors in south korea, their greatest unmet need was in the domain of information, comprising a need for information about examinations and treatment, symptoms that need to be referred to the hospital, and how to see a doctor quickly and easily when needed (21). paired with the results of this study, these findings should provide valuable resources for those developing new interventions in the nursing field. it is vital that health information technology is made soon applied to make it easier for breast cancer survivors to obtain the information they need regarding their cancer care. conclusions the research results from this qualitative study exploring health problems and unmet needs in breast cancer survivors after chemotherapy lead us to highlight three key takeaways: i) breast cancer survivors must overcome various challenges associated with health problems; ii) they are highly motivated to access the best health services; iii) these survivors have unmet information needs about cancer treatment. a key consideration is how survivors’ health-related challenges, such as fatigue, fear of cancer recurrence, issues with social and romantic relationships, and spiritual distress, can create barriers to these women attending appointments for restaging. to increase their life expectancy and the survival rate after cancer treatment in indonesia, oncology nurses and other healthcare professionals must strive to understand better the challenges breath cancer survivors face, and accordingly, adapt their nursing practice to meet survivors’ needs better. special information to discuss sexuality problems: a balinese breast cancer survivor's unmet need ** (ida ayu made ari santi, yati afiyanti, tuti nuraini) introduction breast cancer is the most common malignancy in women worldwide, accounting for almost one in four cases of cancer. the number of breast cancer sufferers is increasing every year (1). it was estimated that in 2020, there were 2.261.419 new cases of breast cancer worldwide (22). in indonesia, bali is one of the provinces with the highest incidence of breast cancer. based on data from sanglah hospital denpasar, of a total of 1.380 patient visits to sanglah hospital between august and november 2020, 285 visits were made by cancer patients. the experience of breast cancer greatly affects a woman's life. recent studies confirm the importance of carrying out regular health checks, addressing post-treatment concerns, and improving the well-being and quality of life (qol) of cancer survivors (3). the development of technology and public awareness of the importance of early detection of breast cancer has led to an increase in the survival rate of breast cancer patients (23). an increased survival rate should be accompanied by archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 101 an increased qol. however, in many breast cancer survivors, sexual problems affect their qol. sexual health concerns have been reported in 50% of cancer survivors, and the situation, if not addressed, is likely to worsen (24). sexual issues can be complex. problems that are often reported include pain during intercourse, difficulty achieving orgasm, and psychological struggles, such as impaired body image, accompanied by reduced feelings of femininity and sexual attractiveness, which cause the partner to be less interested. feelings of femininity and attractiveness generally improved only after 10 months to three years after surgery. sexual attractiveness and feeling comfortable during sexual intimacy are major problems in the first one to two years after breast surgery (23). in indonesian society, which includes that of bali, a woman’s sexuality is not considered a basic need when she is first diagnosed with breast cancer. the situation can cause her husband (or life partner) to look for other ways to fulfill his sexual needs. this can lead to complex problems if not resolved, and a better solution needs to be discussed from the beginning. balinese women want to display perfect breasts as they symbolize their beauty and sexual attractiveness. when they develop breast cancer, many problems follow, especially for their spouses. balinese women are required to perform many tasks, including satisfying their spouses sexually. however, there are many things a woman cannot do when she has had breast cancer. information about sexual needs is still a taboo topic, even though these needs are very present to balinese women. in this study, the problem of sexual needs is explored, especially the information needed by cancer survivors to enable them to overcome their sexual issues. materials and methods research design the design used in this study was interpretative phenomenological qualitative research, designed to explore the sexual needs of breast cancer survivors following their cancer therapy. sample and sampling the participants in this study were selected using the purposive sampling method. the sample was composed by breast cancer survivors who had experienced sexual needs. the inclusion criteria were: i) female breast cancer survivors of various ages; ii) breast cancer survivors who finished their primary treatment. the sample for this qualitative descriptive study comprised 12 participants. data collection data were collected through in-depth interviews. this research was conducted between march and august 2022. the study was conducted at the oncology polyclinic of sanglah hospital denpasar. the researcher collected the data by interviewing all the participants without any research assistant, so that, in this study, the researcher was the research instrument. data analysis the data analysis process in this study was based on braun and clarke’s (2006) description of the thematic analysis approach, which involves identifying, analyzing, and reporting patterns (themes) of the data. in the first phase the researcher begins to record or transcribe data in written form. then, the researcher read the results of the transcript repeatedly to find out and record emerging ideas for the next coding process. the second phase is to generate the initial coding. the third phase is developing a theme: in this phase, all the collected and coded research data are analyzed into a larger theme. the fourth phase is reviewing the requested theme: in this phase, several themes can be grouped together if they are too different. the fifth phase is defining and naming the theme: here, the researcher determines the essence of each generated theme and then refines the resulting theme for analysis. the sixth phase is reporting: this phase begins when the researcher has fully defined and analyzed a theme and writes a report on the research results obtained (6). rigor the validity of the data in this study included the aspects of credibility, transferability, and confirmability. the researcher confirmed and clarified various items that have been expressed by participants. the researcher also observed participants during the interview process. the researcher confirmed data by reflecting on research results in comparison with related papers, consulting expert researchers, and confirming information with participants. the researcher also presented the results of the verbatim transcript in the research report so that the reader could assess the accuracy of the way the researcher transferred the research results to the readers and other researchers. ethical principles this study had the potential to cause psychological discomfort or psychological fatigue in participants. therefore, the researcher applied the principles of beneficence, respect for human dignity, and confidentiality. this meant that the identity of the participants was not included, or only the initial code on the informed consent form was included. this research design was approved by the ethics committee of sanglah hospital denpasar. results 1.information is needed to overcome sexual problems 2. family support is needed to get information on sexuality 3. healthcare facilities need to provide sexual information (details are available in supplementary materials) discussion sexuality is a normal part of life. therefore, as there has been a substantial increase in the number of breast cancer survivors, it is critical to address their qol after treatment (23). the survival rate for women with breast cancer is increasing. treatment regimens are accompanied by a range of physical, psychological, existential, and social concerns (23). balinese breast cancer survivors have different issues from others in relation to meeting sexual needs since they have a distinctive culture. nevertheless, the fulfillment of their sexual needs remains an important part of their lives. archivio italiano di urologia e andrologia 2023; 95, 2 102 problems of cancer survivors based on the results of the data analysis, three main themes emerged: i) the need for information to overcome sexual problems and meet the partner’s sexual needs; ii) the need for support from the extended family to meet the need for information about sexuality; iii) the need for health care practitioners to provide information on sexuality. information needed to overcome sexual problems informant 1 explained her need for information on sexuality. the informants discussed the problems experienced in fulfilling their own and their husband’s sexual needs, such as pain during intercourse. the informants were told that there is a gel that can help reduce pain during intercourse. interventions using technology to increase relational intimacy and a sexual enhancement intervention for couples experiencing sexual difficulties following breast cancer have been shown to be acceptable, with a high level of satisfaction (25). informant 2 explained that she didn't care that her husband was cheating on her because she was more focused on her own health treatment. however, she was still annoyed with her husband and demanded him to end the affair and stay away from her. she was successful in her demands because her caste level in bali was higher than her husband's. informant 2 felt that her partner was no longer interested in her. she no longer wanted to serve her partner. this would have a complex impact on the integrity of the family. this couple needed counseling and information about their sexuality so that their qol problems would not become even more complex. the husbands of women with breast cancer need support to improve their sexual and marital relationships. education and counseling about sexual activity during treatment for breast cancer should be incorporated into healthcare programs (26). family support is needed to get information on sexuality balinese women lack support and advice from their families in relation to their sexual needs. therefore, healthcare providers play an essential role. these women do not have the support they need. they believe that sexuality is a shameful issue, and they are reluctant to ask questions about it. healthcare professionals need to talk about the possibility of sexual problems arising due to the changes in women’s bodies caused by cancer and its treatments. these women need to be encouraged to talk about these problems, with due consideration for their religious and cultural positions (27). healthcare facilities need to provide sexual information informants 3 and 11 stated that they were ashamed to discuss their sexual needs. indonesian society considers it taboo to discuss sexuality, even though it is a normal basic need that must be met. the attitudes of healthcare providers and survivors concerning what constitutes helpful and unhelpful communication behaviors when discussing sexual health concerns were misaligned in nuanced and significant ways (24). providers should make an effort to find ways to communicate effectively with survivors. informant 4 felt that the nurses and healthcare workers did not care about whether the sexual needs of survivors were met. therefore, health workers need sufficient information to help survivors. zhang et al. explained that there is a significant gap between the providers’ perceptions and the patients’ needs regarding discussions on sexual health. more effort should be made to promote the communication needed regarding sexual health (28). a study showed that there is a need for healthcare providers to discuss sexual health after breast cancer with all their patients, as it is a concern that both single and partnered breast cancer survivors have to face after treatment (29). research implications and limitations breast cancer survivors have unmet needs for information, including information about their sexual needs. cancer nursing services should be equipped to provide this information. the results of this study can provide an overview for nurses and other healthcare workers regarding the unmet needs of breast cancer survivors, especially the information needed about sexuality. this would enable nurses and other healthcare professionals to improve the quality of the healthcare services they provide by offering supportive care services that are in alignment with the needs of breast cancer survivors, thereby achieving a more holistic quality of service. in addition, the findings of this study raise the hope that there will be consultation on the problems experienced by cancer patients and survivors, which will trigger awareness of the importance of specialist oncology nurses being present in cancer care structures. furthermore, it is recommended that more comprehensive nursing care should be provided by healthcare providers to assist cancer survivors in meeting their needs. this would result in an increased life expectancy or survival rate for cancer survivors in indonesia. recommendations for further research are that the unmet needs of cancer survivor couples be investigated so that new concepts relating to supportive care can emerge. the researcher realized that there were limitations and shortcomings in this study, namely that the participants felt embarrassed to express complaints relating to the services they received at the hospital. conclusions sexuality is still a basic need of breast cancer survivors. inaccurate information or poor communication can affect the fulfillment of survivors’ sexual needs, which will have a negative impact on their qol. therefore, oncology nurses and other professionals need to understand the problems of breast cancer survivors, especially those in bali, so that they can enable them to fulfill their sexual needs. life experiences of indonesian cancer patients with cancer recurrences: interpretative phenomenology *** (rudi rudi, yati afiyanti, riri maria) introduction a patient is considered to have had a cancer recurrence when the same type of cancer cells as when first diagnosed are found either in the same or a different place archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 103 after at least 1 year from receiving primary treatment (30). there is no time limit for determining whether the cancer is recurrent or developing, but most clinicians consider it as a recurrence if it reappears after one year of no signs or symptoms (30). each type of cancer has a recurrence rate that varies according to the stage, histology, genetic factors, patientrelated factors, and treatment. it is believed that many recurrence rates do not take into account the latest cancer treatment options, especially when new cancer therapies are being used for certain types of cancer. therefore, recurrence rate estimates can vary between individuals and include both high and low recurrence rates. some cancers have low recurrence rates if treatment occurs at an early stage. for example, patients with breast cancer who receive an initial treatment with receptor therapy followed by maintenance therapy have a recurrence rate of 5% to 9% (31). for cancer patients, the world health organization has created evaluation criteria for classifying clinical recurrence and remission in solid tumors called the response evaluation criteria in solid tumors, which consists of several definitions including complete response, partial remission, progressive disease, and stable disease (32). the definitions are used to assess the extent of the response obtained by cancer patients who have received different modalities of treatment such as chemotherapy, radiation, and surgery. when a patient has a cancer recurrence, several problems can arise. for example, in a phenomenological study conducted by finlayson et al., on ovarian cancer patients who consider recurrence as a chronic disease, the patients were unable to make treatment decisions and had longlasting emotional distress (33). according to shao et al., other issues, such as a poor financial situation, can make an impact on the quality of life (qol) of patients with cancer recurrence (34). good coping strategies are needed to overcome the problems arising after that a patient is informed to have had a cancer recurrence. in ovarian cancer recurrence, the coping strategies used have been based more on emotions and personal beliefs (35). there are no definitive data on cancer recurrence in indonesia regarding new cases and cancer deaths. however, cancer recurrence is a significant health issue for cancer patients who experienced this problem after treatment. in addition, data regarding the varied experiences of cancer survivors in indonesia who have had recurrences are also scarce. therefore, data regarding the experiences of cancer patients who experience recurrences should be the subject of in-depth study in order to make able oncology nurses and other health care professionals to understand the problems and needs of these patients and to develop interventions to solve them. materials and methods participants a total of 13 patients treated and followed at dharmais cancer hospital who had experienced a recurrence were recruited and included according to the following inclusion criteria: i) male or female adult cancer patient who had experienced a recurrence after at least 2 months from the declared relapse; ii) could communicate well. three patients were not interviewed for the following reasons: one patient was afraid of trauma when talking about the recurrence, one patient had a worsening condition and had to be admitted to the emergency room, and one patient could not be contacted again after being confirmed. in total only 10 patients participated in the study. data collection rd (first author) conducted data collection from march 2022 to may 2022. data were collected via in-depth direct interviews with seven patients (one patient was recruited at the dharmais hospital as an outpatient, two patients were recruited through home visits, and the rest were inpatients), and three patients were interviewed by telephone. the researcher and each patient agreed on location and methods of interview. with the consent of the participants, interviews were recorded for 60 to 75 minutes. interview guidelines are shown in table 1. thematic analysis the data analysis process was performed according to six steps (6). rd and ya did the data transcription separately. then, after obtaining the transcript, they read it repeatedly and recorded or marked keywords for the coding process. the researchers used the nvivo 12 application with serial number nvp12-lu001-ed03o-25004-lobi. this application was used to perform the initial coding of each interview transcript. the initial coding activity was carried out by rd with ya. the two authors then compiled the themes; namely, all the research data that had been coded and collected was analyzed to determine larger themes. the next stage was to review the generated themes and group them into sub-themes. this process was carried out by peer debriefing. in the fifth stage, the themes were defined and named to determine the essence of each generated theme, and then these themes were refined. the final stage determined the final themes of the results of this study. results theme 1: the reaction when information about recurrence or when bad news were received. theme 2: the efforts made during a recurrence. theme 3: the patient’s self-concept during a recurrence. (details are available in supplementary materials) discussion reaction when information of recurrence was received or when bad news was received a recurrence can be detected by the onset of symptoms like those of early cancer. these symptoms reappear at table 1. interview guidelines. no question 1 what did you experience when you had a recurrence? 2 what efforts have you made to overcome the recurrence of cancer? 3 what are the things that affect your resilience when experiencing a recurrence? archivio italiano di urologia e andrologia 2023; 95, 2 104 problems of cancer survivors least one year after an initial diagnosis of cancer (36). some participants in this study expressed psychological reactions when experiencing a recurrence, such as shock, sadness, disappointment, and shame. the participants who expressed disappointment felt that they had taken care of themselves as best as they could, so why did other people who did not take such good care of themselves not experience a recurrence? those participants felt that god was mistreating them. these experiences of the participants are similar to those conveyed in the research conducted by thornton et al., who mentioned that one of the themes found in their research was an emotion with a sub-theme of anger caused by feelings of envy because the patients felt that they had done everything correctly according to the doctors’ instructions (37). this is also as stated by economou et al., who indicated that patients who received bad news felt anger and sadness early during a recurrence (38). psychological responses to bad news can affect the qol of patients. for example, the results of the research by kugimoto et al., showed that psychological responses to stress that can affect qol occur in cancer patients from news about terminal conditions, disease names, and recurrences (39). bad news must be delivered by professional health personnel, such as nurses, who must pay attention to the room's condition, time, and atmosphere so that the patient does not become emotionally stressed (40). the efforts made during a recurrence some participants chose alternative treatments such as cupping or hypnotherapy before taking conventional medical treatments when they were declared to be recurrent. some of them had used herbal treatment before the recurrence, such as drinking soursop leaves, which are believed to cure cancer. when interviewed, participants said they received information on the benefits of herbal medicines from the internet. the recurrences experienced by the participants made them stop taking soursop leaf herbal medicine as they then considered it useless. the impressions regarding treatments and herbal medicines that participants conveyed were in line with the results of a previous study that found that an average of 51% of cancer patients used alternative and complementary therapies to improve their health and treat the complications from cancer or treatments (41). a qualitative study conducted by abu sharour, on patients with colorectal cancer in jordan found that participants sought complementary treatments when experiencing a recurrence (42). it takes the participation of health workers, especially nurses, to convey that there are alternative and complementary therapies that are safe and recommended for patients with cancer. one of the participants in this study had difficulty urinating and drank a decoction of kumis kucing leaves as suggested by a friend. after drinking the decoction of kumis kucing leaves, the participant could urinate but continued to go to the hospital because the participant considered the kumis kucing treatment only temporary. research by madyastuti et al. stated that the kumis kucing plant (orthosiphon aristatus blume) that is easily found in indonesia has flavonoid ingredients with diuretic activity (43). the conventional medical therapies received by the 10 participants consisted of surgery, chemotherapy, and radiation, with no other therapies besides these were found. previous studies have suggested that the available cancer treatments apart from surgery, chemotherapy, and radiation also include immunotherapy, hormone therapy, bone marrow transplantation, and targeted drug therapy that are conventionally administered metastatic breast cancer treatment (44). as stated by birmingham children’s hospital, patients need to be prepared physically and mentally for chemotherapy, surgery, and radiation treatments (45). chemotherapy is a serious medical procedure, and it must be ensured that the patient is otherwise in good health. mental preparation creating self-efficacy has been shown to reduce emotional stress, such as in patients who are about to undergo surgery (46). participants who received general oral chemotherapy experienced a weight loss because of the effects of chemotherapy can cause nausea, vomiting, and diarrhea. after chemotherapy, the participants experienced difficulties eating and persistent diarrhea until they were given drugs to stop the diarrhea (47).after mastectomy patients are at risk for lymphedema, which is soft tissue swelling due to the accumulation of protein-rich fluid in the extracellular space, with swelling usually in the arm or hand on the side of the body that was operated on (48). swelling in the hands after surgery was also experienced by one of the participants, who received an explanation from a medical rehabilitation doctor that this condition can occur as a side effect. some participants maintained the recommended diet by consuming foods that contain protein, such as fish, meat, tofu, and tempeh, and not eating satay. in another study, it was stated that one of the causes of the occurrence and recurrence of cancer is foods that contain carcinogens, such as salted fish (30). in addition to maintaining the diet, the participants also revealed the efforts they made in maintaining a healthy lifestyle, such as exercise, routine checks, self-checking their breasts, and not smoking. cancer patients are recommended to continue physical activity because routine physical activity can prevent cancer recurrence (30). this opinion is in accordance with research conducted by rock et al., which recommended that to prevent cancer, adults should perform a physical activity of a moderate-to-heavy intensity, depending on physical condition. not smoking is also part of maintaining a healthy lifestyle because cigarettes have tobacco as primary ingredient that is an agent that causes cancer. getting closer to god when suffering from illness is another part of the efforts made for healing by asking for his help. in this study, the participants revealed the efforts that they made to get closer to god through better prayer and worship. for someone who has been able to maintain their life despite experiencing a cancer recurrence, the next stage is then personal growth. at the individual post-traumatic growth stage, the result is an increase in spiritual well-being. self-concept during a recurrence this study explored various factors that can affect survival at the time of a recurrence. in this study, it was found that some participants expressed the reasons that they believed could enable them to survive their recurrences. namely archivio italiano di urologia e andrologia 2023; 95, 2 ida ayu made ari santi tisnasari, tuti nuraini, yati afiyanti, rudi rudi, riri maria 105 they believed that they could recover, by having a strong motivation to recover and enthusiasm for undergoing treatment, obtaining support when undergoing treatment, and eating food appropriate for treating a recurrence. the participants who said that they believed that they were sure to recover demonstrated their optimism, while those participants who said they had the motivation to recover demonstrated their hope. the support for undergoing treatments can come from family or from sources other than family; in this study, it came from husbands, wives, children, parents, and neighbors. patients who experience a relapse need to be given support and hope from everyone, especially their closest family members who act as caregivers while the patients are undergoing treatment. thus, support from families (parents or children) is very important for cancer patients and those who experience a recurrence. for example, if the cancer patient is a father, they especially need support from their children. optimism, hope, and support are part of the direct path to fostering the survival of someone who has just undergone a stressful event, such as receiving news of a cancer recurrence, while how one interprets a recurrence can be an indirect pathway to building resilience. if the meaning is positive, then survival can be achieved, but if the meaning is negative, it will be a warning that makes the patient uncomfortable. achieving resilience requires evaluation. if the evaluation results are positive, they will produce optimism, hope, and will ultimately have survival. the results found in this study can be used as a basic data source for education, nurses, and hospitals to provide nursing care to cancer patients who experience recurrence. hospitals need to prepare a special room for patients who will be given bad information such as news of recurrence so that patients can convey all their feelings after hearing this information. from this research data, oncology nursing specialists can also provide information about fact-based complementary therapies so that they can be used by patients who experience relapse. cancer patients need to involve the palliative team from the start so that when cancer patients experience a relapse, their self-concept and quality of life are good. for future researchers, the results of this study can provide the latest information about cancer recurrence, so that it becomes data to quantitatively measure the problems and needs of cancer patients when they experience a recurrence. the researcher realizes that there are limitations and deficiencies in this study, namely the setting of the place used when collecting data in the hospital, that was not s dedicated room because of limited space. conclusions when patients receive information that they are experiencing a recurrence, psychological reactions, such as shock, sadness, and disappointment, occur. many efforts have been made by patients to cope with recurrences, namely through non-medical activities, medical activities, lifestyle changes, and getting closer to god. this study also found a variety of factors that can influence patients when experiencing a recurrence, such as having the confidence to recover, strong motivation to recover, enthusiasm for undergoing treatment, support in undergoing treatment, and understanding of relapse. this study can help increase our understanding of the experiences of patients with different types of cancer during a recurrence phase. acknowledgments: we are grateful to universitas indonesia for supporting our research. acknowledgement of financial support: * the study “breast cancer survivors' unmet needs following chemotherapy” was supported by the universitas indonesia under grant puti 2022 (publication international indexed 2022) no: nkb-99/un2. rst/hkp.05.00/2022. ** the study “special information to discuss sexuality problems: a balinese breast cancer survivor's unmet need” was supported by tesis magister grant from the minister of national research and technology, culture, and education, republic of indonesia no. nkb-903/un2.rst/hkp.05.00/2022. *** the study “life experiences of indonesian cancer patients with cancer recurrences: interpretative phenomenology” was supported by the universitas indonesia under grant puti 2022 (publication international indexed 2022) no: nkb101/un2. rst/hkp.05.00/2022.. references 1. lee jw, lee j, lee mh, et al. unmet needs and quality of life of caregivers of korean breast cancer survivors: a cross-sectional study. ann surg treat res 2021; 101:69-78. 2. 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brief psychological intervention for pancreatic cancer patients prior to major surgery. front psychol 2020; 11:1-14. 47. amjad mt, chidharla a, kasi a. cancer chemotherapy. in treasure island (fl) 2022. 48. wanchai a, armer jm, stewart br, lasinski bb. breast cancerrelated lymphedema: a literature review for clinical practice. int j nurs sci [internet]. 2016; 3:202-7. 49. rock cl, thomson ca, sullivan kr, et al. american cancer society nutrition and physical activity guideline for cancer survivors. ca cancer j clin. 2022; 72:230-262. correspondence ida ayu made ari santi tisnasari faculty of nursing, universitas indonesia, depok, indonesia tuti nuraini (corresponding author) tutinfik@ui.ac.id department of basic science and fundamental nursing, faculty of nursing, universitas indonesia, depok, 16424, west java, indonesia yati afiyanti (corresponding author) yatikris@ui.ac.id department of maternity nursing, faculty of nursing, universitas indonesia, depok, 16424, west java, indonesia rudi rudi master of nursing program, faculty of nursing universitas indonesia, depok, indonesia riri maria department of medical surgical nursing, faculty of nursing universitas indonesia, depok, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 69 original paper typically, fg is characterized by severe necrosis of the soft tissues of the genitalia and perineum. however, it can extend to the lower abdomen, flank, and even the axilla, cervical region, and upper limbs (2). although the necrosis usually remains limited to the fascial layers of the pelvis, perineum, thighs, and tunica albuginea of the penis and testes, it can sometimes spread beyond these barriers to involve deeper structures such as the anal sphincter, rectum, thighs, penis, and testicles, necessitating more aggressive procedures such as fecal diversion, orchiectomy, and even limb amputation (2). while fg is typically diagnosed easily by clinical examination without additional laboratory or radiological investigations, the treatment course represents a significant challenge (3). this is especially true in developing countries, where healthcare systems are under-resourced and less organized. typically, these patients are elderly and immune-compromised, with associated comorbidities, and require admission to intensive care units (icu) or isolation in separate rooms (4). it is common in such communities for hospitals to reject fg patients due to a shortage of beds and facilities or a lack of staff expertise in dealing with such patients (5). several comorbidity indexes, such as the charlson comorbidity index and fournier's gangrene severity index, have been utilized to predict the prognosis and mortality in fg (6, 7). however, the mortality rate remains high, and their reliabilities are not yet clear. this report aims to share the experience of handling fg patients admitted to our hospital and identify the factors that affect the outcome of these patients. material and methods study design and setting this retrospective study included 26 patients diagnosed with fournier's gangrene at general military hospital, between april 2009 and december 2020. the ethics research committees of general military hospital, sana'a, yemen provided their approval for the study (id: 23-008, on 1,3,2023), which adhered to the ethical principles outlined in the declaration of helsinki. introduction: fournier's gangrene (fg) is a rapidly progressive necrotizing infection that affects the perineal and abdominal regions and is known for its high mortality rate. this study aims to present the practical experience of managing fg patients and identify factors that may affect their clinical outcomes. materials and methods: a retrospective study was conducted from april 2009 to december 2020 at general military hospital in sana'a, yemen including 26 patients who were diagnosed with fg and treated on. data on demographic characteristics, time to admission, surgical intervention, and treatment outcomes were collected. univariate analysis was performed to determine factors that affect patient outcomes. result: the mean age of the patients was 65.77 ± 5.04 years, and 65.4% of them were over the age of 65. most patients (57.7%) presented after five days of experiencing symptoms, and 65.4% were in septic conditions. of the patients, 17 (65.4%) survived, and the total mortality rate was 34.6%. univariate analysis showed that delayed presentation (p = 0.001), a history of diabetes mellitus (p < 0.001), end-stage renal disease (p < 0.001), heart failure (p < 0.001), cerebrovascular accident (p = 0.032), liver cirrhosis (p < 001), presence of multiple comorbidities (p < 001), involvement of lager area (p < 001), septic conditions (p = 0.009), advanced age (p = 0.018), and intensive care unit admission (p = 0.002) were found to be risk factors for mortality in patients with fg. conclusions: fg is a potentially life-threatening medical condition, even with aggressive and specialized treatment. our study revealed a mortality rate of 34.6%. factors such as older age, the presence of multiple comorbidities, septic conditions, the abdominal spread of the disease, intensive care unit admission, and delayed presentation contribute to higher mortality rates. key words: fournier's gangrene; necrotizing fasciitis; risk factor; mortality; outcome. submitted 15 march 2023; accepted 25 march 2023 introduction fournier's gangrene (fg) is a devastating, progressive, and polymicrobial inflammation of the external genitalia and perineum (1). also known as necrotizing fasciitis of the genitalia (nfg), it is a life-threatening urologic emergency that requires urgent admission and surgical intervention (1). treatment outcome of fournier's gangrene and its associated factors: a retrospective study khaled al-kohlany 1, khaled baker 2, faisal ahmed 3, murtadha mohamed 4, majdi alshami 4, mohamed badheeb 5 1 department of urology, college of medicine, sana'a university, sana'a, yemen; 2 department of urology, sanus hospital, hradec kralove, czech republic; 3 department of urology, college of medicine, ibb university, ibb, yemen; 4 department of urology, general military hospital, sana'a, yemen; 5 department of internal medicine, college of medicine, hadhramaut university, mukalla, yemen. doi: 10.4081/aiua.2023.11318 summary archivio italiano di urologia e andrologia 2023; 95, 2 k. al-kohlany, k. baker, f. ahmed, m. mohamed, m. alshami, m. badheeb 70 inclusion criteria patients diagnosed with fg and treated at general military hospital were included in the study. the diagnosis of fg was based on clinical criteria, including the presence of fever (> 38°c), erythema and swelling in the perianal or scrotal region, purulent-malodorous discharge, and the detection of fluctuation or crepitation at the wound site. prior to inclusion, all patients were assessed to confirm their eligibility for the study (1). exclusion criteria patients treated at other hospitals and those with abscesses confined to the scrotal, periurethral, and perianal regions with no fascial or soft tissue extension were excluded. surgical procedure and postoperative care all participants in the study received immediate aggressive debridement under general or spinal anesthesia to remove necrotic tissue until healthy tissue was observed. in addition, cystostomy catheters were placed, limiting the contact of the urethra with urine. empiric intravenous antibiotic therapy, including ceftriaxone (1 g every 12 hours) and metronidazole (500 mg every 12 hours), was administered until culture results were obtained. dressings were changed three times daily with sterile gauze soaked in a solution of povidone-iodine, 0.2% nitrofurazone ointment, and 250 mg rifampicin ampoule. a colostomy was performed in cases where the perirectal and anal regions were affected, while an orchiectomy was performed in testicular involvement cases. patients were transferred to the plastic and reconstructive surgery clinic once their general health status and wound cleanliness had improved. data collection and study outcome patient demographic characteristics, including age, time to admission, location of the initial lesion, the extent of the disease, comorbidities, number of surgical debridements, intensive care unit (icu) admission, colostomy diversion, length of hospital stay, and mortality rate, were extracted from patient's medical records for analysis. patients were stratified into two groups based on their survival status: survivors and non-survivors. mortality refers to all-cause mortality and any cause of fg-related death during the initial admission (1). to assess the extension of fg, we used a modified body surface area nomogram commonly used for estimating the extension of burn injuries (7). this involved assigning a value of 1% for penile, scrotal, and perineal involvement, and 2.5% for ischiorectal fossa involvement. statistical analysis the study utilized descriptive statistics to present quantitative variables in terms of means and standard deviations, while qualitative variables were presented as frequencies and percentages. the normality of the data was assessed using the kolmogorov-smirnov test. to compare patients in the survivor and non-survivor groups, univariate analysis was performed using either independent samples t-test or mann-whitney test to compare means for quantitative variables and chi-square or fisher's exact test for qualitative variables. statistical significance was set at p < 0.05. the statistical analysis was carried out using ibm spss version 18 software (ibm corp., armonk, new york). table 1. demographic characteristics of patients. variable n (%) age (year), mean ± sd 65.77 ± 5.04 age groups < 65 years 9 (34.6) ≥ 65 years 17 (65.4) time to admission (days), mean ± sd 6.15 ± 2.71 time to admission ≤ 5 days 11 (42.3) > 5 days 15 (57.7) source of infection urinary tract infection 12 (46.2) perianal or perirectal infection 4 (15.4) unknown 10 (38.5) septic condition 17 (65.4) history of diabetes mellitus 13 (50) history of heart failure 6 (23.1) history of esrd 6 (23.1) history of cva 3 (11.5) history of anorectal surgery 3 (11.5) history of liver cirrhosis 6 (23.1) total affected body surface area ≤ 3% 18 (69.2) > 3% 8 (30.8) number of debridements one time 11 (42.3) 2 times or more 15 (57.7) needs icu admission 8 (30.8) hospital stays (day), mean ± sd 5.42 ± 1.88 needs for colostomy 3 (11.5) needs for orchiectomy 2 (7.7) outcome survivors 17 (65.4) non-survivors 9 (34.6) icu: intensive care unit; cva: cerebrovascular accident; esrd: end-stage renal disease. figure 1. showing. a: fournier’s gangrene involving the scrotum; b: fournier’s gangrene involving both the penis and scrotum; c: fournier’s gangrene involving the penis, scrotum, and ischiorectal fossa; d: partially debrided fournier’s gangrene. archivio italiano di urologia e andrologia 2023; 95, 2 71 fournier's gangrene outcomes result baseline clinical characteristics the mean age of patients was 65.77 ± 5.04 years, and most (65.4%) were over 65 years. the mean time to hospital admission was 6.15 ± 2.71 days, and the majority (57.7%) presented after five days of symptom onset. 65.4% of patients were in septic conditions. a history of diabetes mellitus, heart failure, renal failure with hemodialysis, cerebrovascular accident (cva), anorectal surgery, and liver cirrhosis was present in 13 (50%), 6 (23.1%), 6 (23.1%), 3 (11.5%), 3 (11.5%), and 6 (23.1%) patients, respectively. the mean total affected body surface area was 3.02 ± 1.41%, and in 18 (69.2%) patients, the total affected area was 3% or less. the infection involved only the scrotum in 6 (23.1%) patients (figure 1a), while penile, scrotal, and perineal involvement was seen in 11 (42.3%) patients (figures 1b and 1c). most patients (57.7%) required more than one surgical debridement (figure 1d). orchiectomy and colostomy procedures were performed in 3 (11.5%) and 2 (7.7%) patients, respectively. the mean hospital stay was 5.42 ± 1.88 days and 8 (30.8%) patients required icu admission. of the patients, 17 (65.4%) survived and the total mortality rate was 34.6%. the baseline clinical characteristics of the study population are summarized in table 1. factors associated with mortality in patients with fournier’s gangrene: univariate analysis showed that a long time to hospital admission (p < 0.001), history of diabetes mellitus (p < 0.001), history of end-stage renal disease (esrd) (p < 0.001), history of heart failure (p < 0.001), history of cva (p = 0.032), history of liver cirrhosis (p < 0.001), presence of multiple comorbidities (p < 0.001), involvement of larger area (p < 0.001), presentation in septic conditions (p = 0.009), advanced age (p = 0.018), and need for icu admission (p = 0.002) were found to be risk factors for mortality in patients with fg (table 2 and 3). discussion fg is a life-threatening condition that involves necrotizing fasciitis in the genitourinary areas and the perineum. it is typically a polymicrobial infection caused by anaerobic and facultative aerobic bacteria (8). the rapid progression of fg is linked to impaired cellular immunity, which permits suppurative bacterial infection, and the synergetic polymicrobial nature, which causes a substantial release of bacterial toxins. eventually, small subcutaneous vessels experience obliterative thrombosis, resulting in gangrene of the involved structable 2. comparison between survivors and non-survivors for quantitative variables. variable sub variable total (n = 26) outcome univariate analysis n (%) survivor n (%) died n (%) or (95 % ci) p-value* 17 (65.4) 9 (34.6) age (year) < 65 9 (34.6) 7 (77.8) 2 (22.2) 0.40 (0.06-2.58) 0.341 ≥ 65 17 (65.4) 10 (58.8) 7 (41.2) reference group history of diabetes mellitus yes 13 (50) 4 (30.8) 9 (69.2) 0.000 no 13 (50) 13 (100) 0 (0.0) reference group number of debridements ≤ 1 11 (42.3) 6 (54.5) 5 (45.5) 2.29 (0.44-11.91) 0.324 > 2 15 (57.7) 11 (73.3) 4 (26.7) reference group time to presentation (day) ≤ 5 11 (42.3) 11 (100) 0 (0.0) 0.002 > 5 15 (57.7) 6 (40.0) 9 (60.0) reference group total affected bsa (%) ≤ 3 18 (69.2) 17 (94.4) 1 (5.6) 0.000 > 3 8 (30.8) 0 (0.0) 8 (100) reference group comorbidity number ≤ 1 19 (73.1) 17 (89.5) 2 (10.5) 0.000 > 1 7 (26.9) 0 (0.0) 7 (100) reference group need colostomy yes 3 (11.5) 2 (66.7) 1 (33.3) 0.93 (0.07-11.99) 0.960 no 23 (88.5) 15 (65.2) 8 (34.8) reference group need orchiectomy yes 2 (7.7) 1 (50.0) 1 (50.0) 2.00 (0.11-36.30) 0.639 no 24 (92.3) 16 (66.7) 8 (33.3) reference group septic condition yes 17 (65.4) 8 (47.1) 9 (52.9) 0.009 no 9 (34.6) 9 (100) 0 (0.0) reference group history of heart failure yes 6 (23.1) 0 (0.0) 6 (100) 0.000 no 20 (76.9) 17 (85.0) 3 (15.0) reference group history of esrd yes 6 (23.1) 0 (0.0) 6 (100) 0.000 no 20 (76.9) 17 (85.0) 3 (15.0) reference group history of cva yes 3 (11.5) 0 (0.0) 3 (100) 0.032 no 23 (88.5) 17 (73.9) 6 (26.1) reference group history of anal surgery yes 3 (11.5) 2 (66.7) 1 (33.3) 0.93 (0.07-11.99) 0.960 no 23 (88.5) 15 (65.2) 8 (34.8) reference group history of liver cirrhosis yes 6 (23.1) 0 (0.0) 6 (100) 0.000 no 20 (76.9) 17 (85.0) 3 (15.0) reference group need icu admission yes 8 (30.8) 1 (12.5) 7 (87.5) 56.00 (4.33-724) 0.002 no 18 (69.2) 16 (88.9) 2 (11.1) reference group bsa: body surface area; ci: confidence interval; icu: intensive care unit; or: odds ratio; cva: cerebrovascular accident; esrd: end-stage renal disease. *p-values of < 0.05 were considered significant. table 3. comparison between survivors and survivors for quantitative variables. variable outcome mean difference t & z p-value* survivors died (95 % ci) mean (sd) mean (sd) age (year) 64.11 (3.98) 68.88 (5.55) -4.77 (-8.65 to -0.88) -2.53 0.018 number of debridements 1.76 (0.66) 1.77 (1.56) -0.01 (-0.90 to 0.88) -0.39 0.711 time to hospital presentation (days) 4.94 (2.13) 8.44(2.18) -3.50 (-5.33 to -1.67) -3.94 0.001 total bsa (%) 2.29 (0.98) 4.16(1.39) -1.87 (-2.83 to -0.90) -3.99 0.001 hospital stays (days) 5.82 (1.81) 4.66 (1.87) 1.15 (-0.40 to 2.71) 1.53 0.138 bsa: body surface area; ci: confidence interval; icu: intensive care unit; or: odds ratio; cva: cerebrovascular accident; esrd: end-stage renal disease. *p-values of < 0.05 were considered significant. archivio italiano di urologia e andrologia 2023; 95, 2 k. al-kohlany, k. baker, f. ahmed, m. mohamed, m. alshami, m. badheeb 72 tures (1, 9). the bacterial access usually results from a cutaneous breakdown (e.g., local trauma) or the spread of urinary or perineal infections. in our study, urinary tract infection was the most common cause of fg (46.2%). our result was similar to tahmaz et al.'s study, which reported that 33% of fg cases were due to urinary tract infections (10). nevertheless, no identifiable cause was observed in onequarter of the patients in el-qushayri et al. study (11). there is a discrepancy in the literature regarding several independent prognostic factors in patients with fg. for example, some studies have shown that younger age is associated with improved survival (1, 12, 13), while other studies have not found a significant difference in disease onset between various age groups (5, 14). in our study group, advanced age was noticed among non-survival and was found to be a risk factor for mortality. this suggests that the average age of those affected by fournier's gangrene is rising as reported by hong et al. (15). similarly, there are inconsistent findings regarding the duration between the onset of fg symptoms and hospitalization, ranging from 1 to 30 days (15). our study showed a statistically significant difference between survivors and non-survivors in the time it took to seek medical care, with survivors presenting earlier (4.94 ± 2.13 days) compared to non-survivors (8.44 ± 2.18 days) (p = 0.001). these findings are consistent with the results of other studies, such as those conducted by doluoğlu et al. and yeniyol et al. (1, 14), and are further supported by a systematic review that identified a positive correlation between time to treatment and patient survival (16). however, some studies have reported no significant difference in time to admission between survivors and nonsurvivors (15, 17). these inconsistencies may be attributed to variations in study settings, patient demographics, hospital accessibility, income, and educational levels. fg is a multifactorial disease with a mortality rate ranging from 3% to 67% (15). the variable outcomes of the disease suggest the involvement of various underlying conditions that can contribute to the fg occurrence, aggravation, and mortality rate. certain conditions such as dm, alcohol consumption, immunocompromised status, malignancy, heart failure, hepatic disease, and renal insufficiency are reported to be positively associated with fg mortality (1, 10, 15, 16, 18). in this study, despite meticulous and specialized management and selective antibiotic therapy, the mortality rate was 34.6%, and patients with a history of dm, esrd, heart failure, cerebrovascular accident, and liver cirrhosis were found to suffer poorer outcomes with a higher mortality rate. dm was the most common comorbidity, affecting 50% of patients, and was significantly associated with a higher mortality rate in our cohort. however, the relationship between dm and mortality remains controversial, as some studies have reported an association with both incidence and mortality (18, 19), while others have shown an association with incidence but not with fg mortality (1, 15, 20). the increased incidence and higher mortality rate of fg in diabetics may be attributed to the small-vessel diseaseinduced propensity to tissue ischemia and the decreased phagocytic and intracellular bactericidal activity and neutrophil dysfunction that attenuate bacterial microbes’ clearance (18). similarly, immunocompromised patients (e.g., hiv) and patients on immunosuppressive medications are at higher risk (16). doluoğlu et al. reported that severe sepsis and multiple organ failure, chronic renal failure, and pulmonary embolism were the major mortality-associated etiologies in fg patients, with a reported mortality of 20.5% (1). we found that septic conditions and having multiple comorbidities at the time of admission were significant predicting factors for mortality and outcome, which goes in trend with prior reports (13, 21). this study found a significant difference in the average extent of body surface area affected by necrotizing tissue between patients who survived and those who did not (2.29 ± 0.98 versus 4.16 ± 1.39, respectively) (p = 0.001). the number of surgical debridements, on the other hand, did not have a significant impact on patient outcomes (p = 0.711), which is in line with the findings of yeniyol et al. (14). however, the results reported by spirnak et al. differ from these findings, as they showed a higher mortality rate among patients who underwent more frequent operations due to more extensive disease (22). generally, prompt surgical intervention (aggressive and often repeat debridement), broad-spectrum antibiotics, and appropriate resuscitation are crucial in these patients (23). as expected, patients with large involved body surface areas usually died during the hospital course, and the chance of undergoing multiple debridements subsequently decreased in this group. in our study, the need for icu admission was associated with non-survival, and our result was similar to a study by azmi et al. (8). in contrast, in the study by yilmazlar et al., survivors stayed in the hospital significantly longer than non-survivors (24). we explain that high-risk patients with multiple underlying diseases had a low probability of survival and died within a few days of icu admission. this study has several limitations. firstly, the retrospective design and the small sample size are potential sources of bias that might limit the generalizability of our findings. secondly, due to the nature of the study, some relevant factors, such as laboratory data, charlson comorbidity index, and fournier's gangrene severity index, were not included in our analysis. future studies with larger sample sizes and prospective multicenter designs are recommended to strengthen the validity and generalizability of our findings. conclusions fournier's gangrene represents a critical medical condition with notable morbidity and mortality rates. our investigation unveiled a mortality rate of 34.6%, despite the implementation of maximum multidisciplinary therapy in a specialized center. notably, increased mortality rates were associated with advanced age, underlying diseases, delayed hospital presentation, the presence of multiple comorbidities, septic conditions, the abdominal spread of the disease, and intensive care unit admission. references 1. doluoğlu ö g, karagöz ma, kılınç mf, et al. overview of different scoring systems in fournier's gangrene and assessment of prognostic factors. turk j urol. 2016; 42:190-6. archivio italiano di urologia e andrologia 2023; 95, 2 73 fournier's gangrene outcomes 2. misiakos ep, bagias g, papadopoulos i, et al. early diagnosis and surgical treatment for necrotizing fasciitis: a multicenter study. front surg. 2017; 4:5. 3. milanese g, quaresima l, dellabella m, et al. a conservative approach to perineal fournier's gangrene. arch ital urol androl. 2015; 87:28-32. 4. benjelloun el b, souiki t, yakla n, et al. fournier's gangrene: our experience with 50 patients and analysis of factors affecting mortality. world j emerg surg. 2013; 8:13. 5. wetterauer c, ebbing j, halla a, et al. a contemporary case series of fournier's gangrene at a swiss tertiary care center-can scoring systems accurately predict mortality and morbidity? world j emerg surg. 2018; 13:25. 6. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chronic dis. 1987; 40:373-83. 7. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier's gangrene. j urol. 1995; 154:89-92. 8. azmi ya, alkaff ff, purba akr, et al. factors for in-hospital mortality in 145 male patients with fournier's gangrene: a 10-year observational study from a single tertiary referral center in indonesia. med sci monit. 2022; 28:e938578. 9. olivieri v, ruggiero g, abate d, et al. fatal infections in andrology. atypical clinical presentation of a fournier's disease. arch ital urol androl. 2020; 92:213 10. tahmaz l, erdemir f, kibar y, et al. fournier's gangrene: report of thirty-three cases and a review of the literature. int j urol. 2006; 13:960-7. 11. el-qushayri ae, khalaf km, et al. fournier's gangrene mortality: a 17-year systematic review and meta-analysis. int j infect dis. 2020; 92:218-25. 12. tuncel a, keten t, aslan y, et al. comparison of different scoring systems for outcome prediction in patients with fournier's gangrene: experience with 50 patients. scand j urol. 2014; 48:393-9. 13. martinschek a, evers b, lampl l, et al. prognostic aspects, survival rate, and predisposing risk factors in patients with fournier's gangrene and necrotizing soft tissue infections: evaluation of clinical outcome of 55 patients. urol int. 2012; 89:173-9. 14. yeniyol co, suelozgen t, arslan m, ayder ar. fournier's gangrene: experience with 25 patients and use of fournier's gangrene severity index score. urology. 2004; 64:218-22. 15. hong ks, yi hj, lee ra, et al. prognostic factors and treatment outcomes for patients with fournier's gangrene: a retrospective study. int wound j. 2017; 14:1352-8. 16. lewis gd, majeed m, olang ca, et al. fournier's gangrene diagnosis and treatment: a systematic review. cureus. 2021; 13:e18948. 17. mccormack m, valiquette as, ismail s. fournier's gangrene: a retrospective analysis of 26 cases in a canadian hospital and literature review. can urol assoc j. 2015; 9:e407-10. 18. korkut m, içöz g, dayangaç m, et al. outcome analysis in patients with fournier's gangrene: report of 45 cases. dis colon rectum. 2003; 46:649-52. 19. cakmak a, genç v, akyol c, et al. fournier's gangrene: is it scrotal gangrene? adv ther. 2008; 25:1065-74. 20. meki cs, mangwiro ti, lazarus j. fournier's gangrene: outcome analysis and prognostic factors. s afr j surg. 2018; 56:43-6. 21. mulla zd, gibbs sg, aronoff dm. correlates of length of stay, cost of care, and mortality among patients hospitalized for necrotizing fasciitis. epidemiol infect. 2007; 135:868-76. 22. spirnak jp, resnick mi, hampel n, persky l. fournier's gangrene: report of 20 patients. j urol. 1984; 131:289-91. 23. auerbach j, bornstein k, ramzy m, et al. fournier gangrene in the emergency department: diagnostic dilemmas, treatments and current perspectives. open access emerg med. 2020; 12:353-64. 24. yilmazlar t, ozturk e, ozguc h, et al. fournier's gangrene: an analysis of 80 patients and a novel scoring system. tech coloproctol. 2010; 14:217-23. correspondence khaled al-kohlany, md kalkohlani@gmail.com murtadha mohamed, md ahmedmurtadha386@gmail.com majdi alshami, md dr.majdialshami@yahoo.com urology office, general military hospital, sana'a, yemen khaled baker, md bakerkhaled9@gmail.com urology office, sanus hospital, hradec kralove, czech republic faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com urology office, al-thora general hospital, alodine street, ibb, yemen, mohamed badheeb, md badheeb2009@gmail.com internal medicine office, hadhramaut university, mukalla, yemen conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13158 1 original paper to critical complications (1). the mortality rate among patients with sepsis secondary to acute complex op is reported to be approximately 2% (2). emergency decompression of the renal collecting system is required for two types of patients with obstructive urolithiasis: those with advanced urinary tract infection and those who develop renal failure. the main methods for treating them are double-j (dj) ureteral stent or percutaneous nephrostomy (pcn) tube insertion (3). the superiority between these two methods in resolving the problem remains controversial. factors such as the suitability or ease of the method, clinical resources, experience, evolving complications, and their severity are still uncertain and debatable (4). while it is generally accepted that the stone should not be treated at the same time of decompression of the urinary system, there is no consensus on whether stone surgery should be performed after decompression (5). to address this gap in the literature and determine the feasibility of the chosen method, it is crucial to consider the risks of complications, the recovery process, the occurrence of urosepsis, the appropriate timing of stone treatment, and the modality of antibiotic management. materials and methods patient selection this retrospective study included patients with obstructive pyelonephritis (op) secondary to urolithiasis who underwent pcn or retrograde ureteral dj stent insertion between january 2020 and january 2022. the study utilized hospital archive records and was approved by the university local ethics committee. the study protocol was reviewed and approved by the institutional review board of our university college of medicine (approval number: 58119). informed consent was obtained by all subjects when they were enrolled. a total of 77 patients were included, encompassing individuals of more than 6 months of age with complete hospital records. pregnant women were excluded from this study. none of the patients had undergone treatment of obstructive stones before medical intervention. patients were categorized into two groups based on the drainage method. upon presentation to the emergency room or urology outpatient clinic, patients with stones were evaluobjective: this study aims to compare two different drainage methods, percutaneous nephrostomy (pcn) and retrograde ureteral double-j (dj) stent insertion, in patients with obstructive pyelonephritis (op). methods: the study included 77 patients who presented to the emergency department due to stones. type of decompression treatment (pcn or dj stent), fever, white blood cell count (wbc), c-reactive protein (crp) levels, urine culture, blood culture, presence of additional diseases, and antibiotic treatment were evaluated for these patients. emergency decompressive treatment was not randomly assigned. the clinician chose the appropriate treatment method based on the patient’s condition after obtaining an informed consent. patients under the age of 18 were categorized into three subgroups: infants, children under 10 years, and adolescents. results: of the 77 patients, 31 were in the dj stent group and 46 were in the pcn group. patients in the pcn group exhibited significantly higher fever levels before the procedure (37.6 ± 1.0°c). additionally, the positivity rate of urine and blood cultures was higher in the pcn group. the average time to stone treatment after infection and medical treatment, as well as fever control, was shorter in the pcn group (9 ± 2.3 days). empiric treatment with ceftriaxone (1 g iv) was confirmed by sensitivity results of urine or blood culture in 45% of cases. none of the patients developed advanced urosepsis after the procedure, but the resolution of infection parameters was faster in the pcn group (7 ± 3.3 days). conclusions: both pcn and dj stent insertion are effective and safe methods for managing obstructive pyelonephritis. it was observed that the pcn method under local anesthesia was useful in quickly controlling fever and allowing early surgical treatment. finally, third-generation cephalosporin antibiotics are beneficial for empiric initial treatment. key words: kidney stone; obstruction; pyelonephritis; dj stent; percutaneous nephrostomy. submitted 26 september 2024; accepted 10 october 2024 introduction pyelonephritis is termed as obstructive pyelonephritis (op) when it is associated with urinary tract obstruction. the primary cause of op is typically an urinary stone that obstruct the urinary system. acute op due to urolithiasis represents a medical-surgical emergency and often leads emergency treatment of obstructive pyelonephritis: a single center series bulent kati 1, eser ordek 2, omer madsar 1, eyyup sabri pelit 1 1 harran university, faculty of medicine, urology department, sanliurfa, turkey; 2 mustafa kemal university, faculty of medicine, urology department, hatay, turkey. doi: 10.4081/aiua.2024.13158 summary archivio italiano di urologia e andrologia 2024; 96(4):13158 b. kati, e. ordek, o. madsar, e. sabri pelit 2 ated for fever, white blood cell count (wbc), c-reactive protein (crp) levels, urine culture, blood culture, presence of additional diseases, and antibiotic treatment (table 1). complications, treatment duration, and post-treatment stone surgery timing were recorded for patients undergoing dj stent or pcn insertion, and the suitability and success rates of the methods were compared. surgical technique for dj stent insertion patients received comprehensive information regarding the interventional procedure and provided informed consent by signing a consent form. prior to the procedure, all patients received 1 g of ceftriaxone intravenously as antibiotic prophylaxis. under sterile conditions and either local or spinal anesthesia, a 17 fr cystoscope was inserted into the bladder through the urethral orifice. subsequently, a 4.7 fr, 26 cm dj stent was inserted using a guide wire for adult patients, while the size of the dj stent for patients under 12 years of age was adjusted accordingly. fluoroscopy was utilized to verify the accurate positioning of the dj stent. surgical technique for percutaneous nephrostomy after obtaining patient information and consent, the renal system was visualized using ultrasonography under local anesthesia. following identification of a suitable calix, access to the system was achieved using a chiba needle. the system was visualized under fluoroscopy with the administration of contrast agent. a suitable guidewire was passed through the skin, and dilatation was performed to facilitate the insertion of a 16 fr nephrostomy tube (8-10 fr for children) into the kidney. statistical methods mean, standard deviation, median, minimum, maximum, frequency, and ratio values were used in the descriptive statistics of the data. the distribution of variables was measured using the kolmogorov-smirnov test. independent sample t-tests and mann-whitney u-tests were used in the analysis of quantitative independent data. the chi-square test was used in the analysis of qualitative independent data, and the fischer test was used when the chi-square test conditions were not met. the spss 27.0 program was used in the analysis. results the characteristics of patients who received decompression treatment by the two methods are summarized in table 1 and table 2, which also include data on the time interval to stone treatment after infection, and on the time for infection parameters to subside. patients under the age of 18 were categorized into three subgroups: infants, children under 10 years, and adolescents. we treated 12 pediatric patients under the age of 18 divided into three groups: infants (0-2 years), children under 10 years (3-9 years), and adolescents (10-18 years). the majority of the pediatric patients were adolescents, who showed a clinical presentation similar to adult cases. specifically, 1 patient was an infant (8.3%), two patients were children under 10 years (16.7%), and nine patients were adolescents (75%). we analyzed the antibiotic sensitivity profiles of the pathogens isolated from both urine and blood cultures. the most commonly isolated pathogen was escherichia coli, which exhibited high sensitivity to beta-lactam antibiotics, particularly ceftriaxone, with a sensitivity rate of 85%. this aligns with our empirical use of ceftriaxone as first-line therapy in obstructive pyelonephritis cases. other pathogens such as klebsiella pneumoniae and pseudomonas aeruginosa showed variable sensitivity, with klebsiella demonstrating 70% sensitivity to ertapenem and pseudomonas showing significant resistance to many common antibiotics but retaining sensitivity to ceftazidime and piperacillin-tazobactam. candida species, detected in a subset of patients, responded well to fluconazole. this data underscores the importance of culture-based antimicrobial stewardship in the management of obstructive pyelonephritis, ensuring that empirical treatment is adjusted based on pathogen sensitivity profiles to improve outcomes and reduce resistance development. table 1. general characteristics of patients who underwent pcn and dj stent (n:77). min-max median mean ± ss/n-% age 0.8 81.0 31.0 35.1 ± 24.3 gender female 35 45.5% male 42 54.5% fever 36.0 39.3 37.9 37.4 ± 1.0 pulse 68.0 122.0 92.0 94.0 ± 12.9 wbc 4.0 41.0 11.0 13.1 ± 6.9 crp 0.0 42.0 6.7 10.3 ± 10.2 urine culture (-) 46 59.7% (pathogen) (+) 31 40.3% e coli 19 61.3% candida 5 16.1% klebsiella 3 9.7% psodomonas 2 6.5% enterobacter 1 3.2% enterokok 1 3.2% blood culture (-) 68 88.3% (+) 9 11.7% candida 7 77.8% e coli 1 11.1% klebsiella 1 11.1% comorbidity (-) 34 44.2% (+) 43 55.8% applied antibiotics ceftriazone 36 46.8% ertapenem 23 29.9% cephaxon 3 3.9% amikacin 2 2.6% cilapem 2 2.6% fluconazole 2 2.6% vancomicin+imipenem 2 2.6% gentamicin 1 1.3% ceftazidime 1 1.3% meropenem 1 1.3% meropenem+tazocin 1 1.3% cilanem 1 1.3% imipenem 1 1.3% ceftriazone+metronidazole 1 1.3% archivio italiano di urologia e andrologia 2024; 96(4):13158 3 treatment of obstructive pyelonephritis table 3. comparative analysis of urine culture or blood culture results and antibiotic treatments administered between groups accordingly. percutaneous nephrostomy dj stent p mean ± ss/n-% median min-max i.q-3.q mean ± ss/n-% median min-max i.q-3.q age 33.6 ± 25.2 29.0 0.8 81.0 10.5 56.0 37.3 ± 23.0 33.0 1.0 80.0 19.0 54.0 0.518 t gender female 20 43.5% 15 48.4% 0.67 x2 male 26 56.5% 16 51.6% fever 37.6 ± 1.0 38.0 36.0 39.1 37.0 38.1 37.1 ± 1.0 37.0 36.0 39.3 36.0 38.0 0.048 m pulse 97.5 ± 13.0 95.5 74.0 122.0 86.0 110.0 88.7 ± 11.0 88.0 68.0 112.0 80.0 96.0 0.006 m wbc 14.1 ± 8.1 12.0 4.0 41.0 8.0 18.0 11.6 ± 4.3 11.0 5.0 25.0 8.6 14.0 0.352 m crp 11.5 ± 10.5 10.0 0.0 42.0 1.9 19.5 8.4 ± 9.5 5.0 0.0 41.0 1.0 12.0 0.190 m urine culture (-) 25 54.3% 21 67.7% 0.240 x2 (+) 21 45.7% 10 32.3% e coli 14 66.7% 5 50.0% candida 3 14.3% 2 20.0% klebsiella 2 9.5% 1 10.0% psodomonas 1 4.8% 1 10.0% enterobacter 0 0.0% 1 10.0% enterokok 1 4.8% 0 0.0% blood culture (-) 39 84.8% 29 93.5% 0.240 x2 (+) 7 15.2% 2 6.5% candida 5 71.4% 2 100.0% e coli 1 14.3% 0 0.0% klebsiella 1 14.3% 0 0.0% comorbidity (-) 21 45.7% 13 41.9% 0.747 x2 (+) 25 54.3% 18 58.1% applied antibiotics ceftriazon 17 37.0% 19 61.3% ertapenem 15 32.6% 8 25.8% cephaxon 3 6.5% 0 0.0% amikacin 2 4.3% 0 0.0% cilapem 2 4.3% 0 0.0% fluconazole 2 4.3% 0 0.0% vancomicin+imipenem 2 4.3% 0 0.0% gentamicin 0 0.0% 1 3.2% ceftazidime 0 0.0% 1 3.2% meropenem 1 2.2% 0 0.0% meropenem+tazocin 1 2.2% 0 0.0% cilanem 0 0.0% 1 3.2% imipenem 1 2.2% 0 0.0% ceftriazon+metronidazole 0 0.0% 1 3.2% table 2. statistical comparison of the information of patients who underwent pcn and dj stent. percutaneous nephrostomy dj stent p mean ± ss/n-% median mean ± ss/n-% median age 33.6 ± 25.2 29.0 37.3 ± 23.0 33.0 0.518 t gender female 20 43.5% 15 48.4% 0.67 x2 male 26 56.5% 16 51.6% fever 37.6 ± 1.0 38.0 37.1 ± 1.0 37.0 0.048 m pulse 97.5 ± 13.0 95.5 88.7 ± 11.0 88.0 0.006 m wbc 14.1 ± 8.1 12.0 11.6 ± 4.3 11.0 0.352 m crp 11.5 ± 10.5 10.0 8.4 ± 9.5 5.0 0.190 m urine culture (-) 25 54.3% 21 67.7% 0.240 x2 (+) 21 45.7% 10 32.3% e coli 14 66.7% 5 50.0% candida 3 14.3% 2 20.0% klebsiella 2 9.5% 1 10.0% psodomonas 1 4.8% 1 10.0% enterobacter 0 0.0% 1 10.0% enterokok 1 4.8% 0 0.0% blood culture (-) 39 84.8% 29 93.5% 0.240 x2 (+) 7 15.2% 2 6.5% candida 5 71.4% 2 100.0% e coli 1 14.3% 0 0.0% klebsiella 1 14.3% 0 0.0% comorbidity (-) 21 45.7% 13 41.9% 0.747 x2 (+) 25 54.3% 18 58.1% time to stone treatment and fever control (day) 9 ± 2.3 11 ± 2.5 0.047 m time to resolution of infection parameters (day) 7 ± 3.3 10 ± 3.4 0.049 m archivio italiano di urologia e andrologia 2024; 96(4):13158 b. kati, e. ordek, o. madsar, e. sabri pelit 4 discussion it has been determined that both methods are successful and safe in treating obstructive pyelonephritis before treatment directed to removal of the stone. upper urinary tract (uut) stones commonly lead to pain and drug-resistant pain pyelonephritis, potentially resulting in kidney unit loss and life-threatening situations in case of severe infections (6). the european association of urology (eau) guidelines for lithiasis suggest to delay definitive stone treatment after the resolution of infection or sepsis (7). in our clinical practice, stone treatment was not performed in association with decompression therapy. pcn was initially described by the urologist dr. willard goodwin in 1955 as a minimally invasive, x-ray-guided procedure, either temporary or permanent, offering an alternative to traditional surgery for patients with hydronephrosis (8). since then, there has been an increase in the use of fluoroscopy and ultrasonography in pcn among urologists and interventional radiologists. a survey study involving urologists and radiologists assessing pelvic system decompression concluded that preferences for pcn or dj stent placement are generally based on personalized treatment according to the degree of hydronephrosis in the obstruction (9). in our study, the pcn procedure was commonly performed by interventional radiologists (87% of cases). however, in determining the treatment approach, aside from the degree of hydronephrosis, we aimed to a comprhensive evaluation focusing on the identification of the patient's clinical factors and to subsequent administration of antibiotic treatment until primary stone therapy. retrograde dj stent placement offers the advantage of being a feasible option, which is preferred in routine practice by urologists. compared to pcn, dj stent placement is considered more cosmetically favorable for patients. however, many patients undergoing dj stent placement experience lower urinary tract symptoms (luts), including post-operative pain, polyuria, and dysuria. consequently, because of the resulting reduction in quality of life, some patients may not prefer this procedure (10). according to the european guideline, it is recommended that upon the patient's initial presentation, a urinary culture analysis is promptly conducted, with a subsequent reanalysis of the urinary culture following urological intervention. following this general principle, in our study, we conducted two separate urine culture analyses before and after drainage treatment. our results indicated that 40% of these cultures were positive, with culture positivity detected in 21 patients with nephrostomy and 10 patients with dj stent placement. in the study conducted by anıl h et al., a culture positivity rate of 66.7% was observed, and the most frequently isolated pathogen in urinary tract infections was escherichia coli (11). similarly, in our study, escherichia coli was the most frequently observed organism at 24.6%. additionally, pseudomonas aeruginosa and klebsiella pneumoniae were among the other common pathogens, while candida infection, which is also described in the literature, was also frequently observed (12, 13). the relatively low rate of positive urine cultures (40.3%) and blood cultures (11.7%) in our study can be attributed to several factors. first, obstructive pyelonephritis often triggers an inflammatory response, which may not always lead to detectable bacteriuria or bacteremia by the time cultures are taken. this can happen due to the intermittent shedding of bacteria into the urine or bloodstream, resulting in negative culture results despite the presence of infection. additionally, many patients might have received empirical antibiotic treatment prior to hospital admission or sample collection, which could suppress bacterial growth and lead to false-negative cultures. furthermore, the obstruction itself may limit the dispersion of bacteria into the bloodstream or urinary tract, reducing the likelihood of positive cultures. moreover, variations in the timing and quality of sample collection can also play a role. in some cases, cultures may have been taken after the initiation of antibiotic therapy or during phases of fluctuating bacteremia, reducing culture sensitivity. it is also possible that some cases involved non-bacterial causes of infection, such as fungal infections, which were detected in a subset of patients. these factors, along with the complex nature of obstructive urolithiasis and pyelonephritis, likely contributed to the relatively low culture positivity rates observed in our study. patients were administered broad-spectrum antibiotic treatment in accordance with european guidelines before the culture results are available (14). in our clinical practice, the obstructive pyelonephritis patients which apply to the emergency room or outpatient clinic, are immediately started with the broad-spectrum antibiotic ceftriaxone (1 g iv). however, following the results of the urinary culture antibiogram, the appropriate treatment is then prescribed from the infectious diseases department. the most common treatments were ceftriaxone and ertapenem. in a study conducted by subramanian et al., antibiotic sensitivity was evaluated after initial empirical treatment in patients with urosepsis, and it was concluded that 41 of 63 patients (65%) were sensitive to beta-lactam antibiotics according to urine culture (13). we have observed that sensitivity to intial empirical broad spectrum ceftriaxone treatment has been confirmed in 46.75% of cases, so we administered this treatment regimen in our clinic. urinary candida species are a common clinical finding, especially among hospitalized patients. in fact, some reports indicate that 90% of candida urinary tract infection (uti) cases occur in hospitalized patients with a urinary catheter (15). according to urine and blood culture results, we observed candida positivity in 12 patients (38.7%). half of these patients had diabetes (dm) and 8 patients were either hospitalized or had a urinary catheter installed. only 2 patients were recommended fluconazole treatment as antifungal therapy by the infectious diseases department after confirmation by new urine or blood culture tests. in addition, recommendations were made for regulating blood sugar level and changing the catheter. there are some limitations in our study. the small number of patients may be related to the fact that the study coincided with the covid-19 pandemic period. moreover, patients may be also treated in other centers so limiting our access to accurate information. in addition, the results of urine and blood cultures may be affected by regional and geographical factors. therefore, it is important to highlight that the spectrum of pathogens and senarchivio italiano di urologia e andrologia 2024; 96(4):13158 5 treatment of obstructive pyelonephritis sitivity to antibiotic that we have observed are specific for patients from our region. conclusions pcn and dj stent techniques show comparable effectiveness in the treatment of cases of sepsis resulting from obstructive uropathy. although the pcn technique is more invasive, it helps to quickly obtain an urine sample from the upper urinary tract in order to diagnose the causative microorganism, facilitating the rapid and accurate implementation of treatment protocols. empiric antibiotic therapy with ceftriaxone shows sensitivity to pathogens in almost half of patients. finally, pcn can accelerate timing of stone treatment and be used as a guide for subsequent surgeries. references 1. abi tayeh g, safa a, sarkis j, et al. determinants of pyelonephritis onset in patients with obstructive urolithiasis. urologia. 2022; 89:100-103. 2. ryan j, o'neill e, mclornan l. urosepsis and the urologist! curr urol. 2021; 15:39-44. 3. türk c, knoll t, seitz c, et al. european association of urology. medical expulsive therapy for ureterolithiasis: the eau recommendations in 2016. eur urol. 2017; 71:504-507. 4. pearle ms, pierce hl, miller gl, et al. optimal method of urgent decompression of the collecting system for obstruction and infection due to ureteral calculi. j urol. 1998; 160:1260-4. 5. itami y, miyake m, owari t, et al. optimal timing of ureteroscopic lithotripsy after the initial drainage treatment and risk factors for postoperative febrile urinary tract infection in patients with obstructive pyelonephritis: a retrospective study. bmc urol. 2021; 21:10. 6. pandey s, sharma d, sankhwar s, et al. are there any predictive risk factors for failure of ureteric stent in patients with obstructive urolithiasis with sepsis? investig clin urol. 2018; 59:371-375. 7. türk c, petrík a, sarica k, et al. eau guidelines on diagnosis and conservative management of urolithiasis. eur urol. 2016; 69:468-74. 8. preminger gm, tiselius hg, assimos dg, et al. eau/aua nephrolithiasis guideline panel. 2007 guideline for the management of ureteral calculi. j urol. 2007; 178:2418-34. 9. pietropaolo a, seoane lm, abadia aa, et al. emergency upper urinary tract decompression: double-j stent or nephrostomy? a european yau/esut/eulis/bsir survey among urologists and radiologists. world j urol. 2022; 40:1629-1636. 10. joshi hb, stainthorpe a, macdonagh rp, et al. indwelling ureteral stents: evaluation of symptoms, quality of life and utility. j urol. 2003; 169:1065-9. 11. anıl h, sener nc, karamık k, et al. comparison of percutaneous nephrostomy and ureteral dj stent in patients with obstructive pyelonephritis: a retrospective cohort study. j invest surg. 2022; 35:1445-1450. 12. bonkat g, cai t, veeratterapillay r, et al. management of urosepsis in 2018. eur urol focus. 2019; 5:5-9. 13. subramanian a, bhat s, mookkappan s, et al. empiric antibiotic and in-vitro susceptibility of urosepsis pathogens: do they match? the outcome of a study from south india. j infect dev ctries. 2021; 15:1346-1350. 14. bonkat g, pickard r, bartoletti r, et al. "eau guidelines on urological infections." eau guidelines office, 2018, arnhem, the netherlands. 15. fisher jf, kavanagh k, sobel jd, et al. candida urinary tract infection: pathogenesis. clin infect dis. 2011; 52(suppl 6):s437-51. correspondence bulent kati associate prof. m.d. febu (corresponding author) bulentkati@harran.edu.tr omer madsar omermadsar46@gmail.com eyyup sabri pelit dreyyupsabri@hotmail.com harran university, faculty of medicine, urology department, 63440 sanliurfa, turkey eser ordek dr_eseser@hotmail.com mustafa kemal university, faculty of medicine, 31100 urology department, hatay, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12323 1 review radicals,' are highly reactive oxygen-derived molecules characterized by unpaired electrons in their outer valence orbital. these include oxygen-centered radicals (hydroxyl radical, nitric oxide radical, and superoxide anion radical) and non-radical derivatives (hydrogen peroxide, peroxynitrite anion, and hypochlorous acid) (3, 4). various endogenous (e.g., immature spermatozoa, leukocytes, varicocele) and exogenous (e.g., testicular hyperthermia, environmental and habitual exposures) factors have been identified as potential causes of increased ros production. to counterbalance ros, antioxidants play a crucial role in maintaining the desired redox equilibrium for optimal sperm function (5). seminal fluid is rich in antioxidants that nourish and protect sperm, existing in two forms: enzymatic and non-enzymatic antioxidant systems (6). the enzymatic system comprises naturally occurring antioxidants, including glutathione peroxidase, superoxide dismutase, and catalase, believed to originate from the prostate and found in sperm cells or seminal plasma. in contrast, the non-enzymatic system consists of various compounds obtained through diet or supplements. when an excess of ros is produced or antioxidant activity is insufficient, os occurs, disrupting the equilibrium between oxidation and reduction. spermatozoa are particularly susceptible to os due to their low levels of enzymatic antioxidants, originating from the prostate. additionally, the high concentration of polyunsaturated fatty acids, notably docosahexaenoic acid, in the sperm cell's plasma membrane makes them attractive targets for ros-induced oxidation reactions. recent decades have witnessed significant progress in understanding male infertility, incorporating tests like sperm dna fragmentation (sdf) and measures of os to enhance clinicians' insights into male fertility potential (7,8). advances in assisted reproductive therapy (art) have allowed previously infertile men to father biological children. however, os remains a critical factor influencing reproductive outcomes, both in natural conception and with art. approximately 25% of infertile men exhibit significant levels of ros in their semen compared to fertile counterparts (9). os negatively impacts semen parameters, fertilization rates, embryonic development, and pregnancy rates (10, 11). objective: this study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men. materials and methods: we conducted a systematic search of pubmed, and cochrane electronic databases, adhering to modified preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines. the focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures. results: a total of 18 studies that met the inclusion criteria were included in this study. out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. these comprised 11 randomized clinical trials and 7 prospective studies. commonly utilized antioxidants included vitamin e, vitamin c, carnitines, co-enzyme q10, n-acetyl cysteine, zinc, selenium, folic acid, and lycopene. conclusions: overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. however, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice. key words: infertility; antioxidants; semen parameters. submitted 30 january 2024; accepted 18 february 2024 introduction infertility is defined as the inability to conceive after at least 12 months of regular, unprotected intercourse, affecting approximately 15% of couples globally. notably, male factors contribute to nearly half of the reported cases, often linked to disturbances in testicular function or blockage of reproductive passages (1, 2). consequently to the efforts to unravel the molecular-level of idiopathic male infertility, the substantial role played by oxidative stress (os) has been underscored. os refers to the imbalance in the body's redox state, arising from either excessive oxidants or insufficient antioxidants. reactive oxygen species (ros), commonly known as 'free the influence of oral antioxidants on men with infertility: a systemic review tamer a. abouelgreed 1, mohamed a. amer 2, hassan mamdouh 2, ahmed f. el-sherbiny 3, hany aboelwafa 2, sameh f. fahmy 2, omar a. omar 2, mohammed abdelshakour 2, mohammad elesawy 2, mohamed sonbol 2, ahmed n. maawad 2, osama k. elsayed 2 1 department of urology, al-azhar university, cairo, egypt; 2 department of dermatology & andrology, al-azhar university, cairo, egypt; 3 department of andrology, international islamic center for population studies and research, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2024.12323 summary archivio italiano di urologia e andrologia 2024; 96(2):12323 t.a. abouelgreed, m.a. amer, h. mamdouh, et al. 2 the impact of antioxidants on fertility depends by substantial variations in antioxidant forms, dosages, combinations, and outcome measures across studies. this literature review aims to explore the most commonly used antioxidants in treating male infertility and investigate the effect of their doses that may confer benefits on basic semen parameters, advanced sperm function tests, outcomes of art, and live-birth rates. materials and methods research strategy the research strategy adhered to modified preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines (12). a literature search was conducted on pubmed, and cochrane electronic databases to identify studies exploring the effectiveness of antioxidants in treating male infertility. keywords and medical subject heading (mesh) phrases included 'antioxidants,' 'male infertility,' semen parameters'. study selection screening of articles was performed based on title and abstract by all authors followed by examination of relevant full papers. additionally, review articles were scrutinized for potential inclusion (male patients, human studies). exclusion criteria were based on study methods (retrospective, case report, editorial, or commentary). data extraction was cross-checked and verified. outcome measures the outcomes of interest included the type and dosage of antioxidants, their mechanism of action, impact on basic semen parameters and advanced sperm function tests. results the search strategy identified 380 articles, with 315 excluded based on title and/or abstract. the remaining 65 articles underwent screening, leading to the identification of 18 studies that met the inclusion and exclusion criteria. these comprised 11 randomized clinical trials (1323) and 7 prospective studies (24-30). out of these, 14 studies (13-19, 24-30) reported a significant positive effect of antioxidant therapy on various parameters such as basic semen parameters, advanced sperm function tests. commonly investigated antioxidants included vitamin e, vitamin c, carnitines, n-acetyl cysteine (nac), coenzyme q10 (coq10), zinc, selenium, folic acid, and lycopene. the doses and mechanisms of action for each antioxidant are presented in table 1. additionally, table 2 outlines the outcomes of antioxidant treatment that were assessed across studies (13-30). discussion antioxidants, whether biological or chemical compounds, act scavenging free radicals, neutralizing their table 1. the mode of action of commonly used antioxidants. antioxidant compound mechanism of action ascorbic acid (vitamin c) neutralises free radicals tocopherol (vitamin e) neutralises free radicals folate (vitamin b9) selenium scavenges free radicals selenium enhancement of enzymatic antioxidant activity zinc inhibition of nadph oxidase carnitines neutralizes free radicals and acts as an energy source coq10 in its reduced form, scavenges free radicals intermediate in mitochondrial electron transport system nac enhances enzymatic antioxidant activity lycopene quenches free radicals nadph: nicotinamide adenine dinucleotide phosphate. table 2. studied antioxidants effect on semen parameters. clinical circumstance antioxidant reference basic semen parameters oligozoospermia vitamin e, vitamin c, nac, carnitines, coq10, lycopene, selenium and zinc vitamin e (300 mg) (12) vitamin e (180 mg), vitamin a (30 mg) and essential fatty acids or nac (600 mg) (25) nac (600 mg) + other vitamins/minerals (13) lc (2 g) (14) coq10 (300 mg) (15) nac (600 mg) and selenium (200 mg) (16) folic acid (5 mg) + zinc (66 mg) (17) lycopene (2 mg) (26) asthenozoospermia vitamin e, vitamin c, nac, carnitines, coq10, lycopene, selenium and zinc vitamin e (400 mg) + selenium (200 lg) (27) coq10 (300 mg) (15) lycopene (2 mg) (26) lc (2 g) and lac (1 g) (19) nac (600 mg) (20) nac (600 mg) and selenium (200 mg) (16) zinc (400 mg), vitamin e (20 mg) and vitamin c (10 mg) (18) teratozoospermia vitamin e, nac, lycopene, selenium and zinc vitamin e (400 mg) + selenium (200 lg) (27) lycopene (8 mg) (28) nac (600 mg) and selenium (200 mg) (16) zinc (400 mg), vitamin e (20 mg) and vitamin c (10 mg) (18) advanced sperm function os (oxidative stress) vitamin e, vitamin c, nac, selenium and zinc vitamin e (300 mg) (22) vitamin e (180 mg) and b-carotene (30 mg) (25) vitamin e (20 mg), vitamin c (10 mg) and zinc (400 mg) (18) vitamin e (400 mg) and selenium (225 g) (23) nac (600 mg) (20) high sdf vitamin e, vitamin c, zinc, selenium and folic acid (sperm dna fragmentation) vitamin e (1 g) + vitamin c (1 g) (21) vitamin c (400 mg), vitamin e (400 mg), b-carotene (18 mg), zinc (500 mmol) and selenium (1 mmol) (29) lc (1500 mg); vitamin c (60 mg); coq10 (20 mg); vitamin e (10 mg); zinc (10 mg); folic acid (200 lg) (30) selenium (50 lg); vitamin b12 (1 lg) (31) archivio italiano di urologia e andrologia 2024; 96(2):12323 3 effects of antioxidants on infertility effects, and disrupting the chain reaction leading to os in body tissues. in the context of male fertility, antioxidants are commonly prescribed for their accessibility and relatively low cost. however, conflicting results have been observed in studies assessing the impact of antioxidant therapy on male fertility. while some studies reported positive effects on semen parameters, sperm function, and pregnancy rates, others failed to confirm such benefits or even indicated a negative influence on male fertility. the heterogeneity across studies and the unknown optimal balance of the redox system for sperm function contribute to these discrepancies. overconsumption of antioxidants may lead to reductive stress with potential detrimental effects on human health, including impairment of mitochondrial activity (31-33). antioxidants: mechanism of action and rationale for use numerous compounds with antioxidant properties have been explored for treating male infertility (table 1). understanding the mechanisms of action of commonly used compounds is crucial before delving into the associated evidence in clinical practice. vitamin e (a-tocopherol): this potent chain-breaking antioxidant is a fat-soluble compound predominantly located in cell membranes. it quenches free hydroxyl radicals and superoxide anions, reducing lipid peroxidation initiated by ros at the plasma membrane level. vitamin e levels found to be correlated to the percentage of motile spermatozoa in semen. lower vitamin e levels were observed in the semen of infertile men (34). vitamin c (ascorbic acid): a water-soluble compound that is found in high concentrations in seminal plasma more than in blood serum. it neutralizes hydroxyl, superoxide, and hydrogen peroxide radicals, offering protection against endogenous oxidative damage. seminal fluid analyses from infertile men with asthenozoospermia revealed lower vitamin c levels and higher ros levels compared to fertile controls (35). carnitines (l-carnitine and l-acetyl carnitine): these watersoluble antioxidants are involved in sperm metabolism, fueling essential activities like sperm motility. carnitines exhibit antioxidant activities by scavenging superoxide anions and hydrogen peroxide radicals, inhibiting lipid peroxidation. semen samples from infertile men with oligoasthenoteratozoospermia showed significantly lower carnitine levels (36). coq10: this vital antioxidant is present in almost all body tissues, particularly in sperm mitochondria involved in cellular respiration and energy production. coq10's role in promoting motility and acting as an antioxidant is rationalized by its inhibitory effect on superoxide formation (37). nac (n-acetyl cysteine): this amino acid, converted to cysteine in body tissues, acts as a precursor of glutathione, a crucial naturally occurring antioxidant that neutralizes various ros. nac directly reduces os by scavenging hypochlorous acid and hydroxyl radicals. studies have documented its positive influence on germ cell survival, showcasing reductions in ros levels and improvements in sperm motility after incubation with nac (38). selenium: an essential trace element, selenium's role in spermatogenesis is linked to its ability to protect sperm dna against os damage. selenium's antioxidant properties are associated with its augmentation of glutathione function. selenoenzymes, including phospholipid hydroperoxide glutathione peroxidase (phgpx) and sperm capsular selenoprotein glutathione peroxidase, contribute to maintaining sperm structural integrity. selenium deficiency is often correlated with morphological sperm abnormalities and impaired motility (39). zinc: another essential trace element, zinc, plays vital roles in rna and dna metabolism, signal transduction, gene expression, and apoptosis regulation. its antioxidant properties stem from its ability to decrease the production of hydrogen peroxide and hydroxyl radicals by antagonizing redox-active transition metals like iron and copper. higher zinc concentrations in seminal plasma are observed in fertile men compared to subfertile men, and zinc deficiency is associated with various sperm structural abnormalities (40). folic acid (vitamin b9): involved in nucleic acid synthesis and amino acid metabolism, folic acid is used in male infertility treatment for its free radical scavenging abilities. folic acid intake is linked to an increased reducedto-oxidized glutathione ratio (41). lycopene: a naturally synthesized carotenoid found in fruits and vegetables, lycopene contributes significantly to the human redox defense system due to its potent ros quenching abilities (42). antioxidant effect on basic semen parameters semen analysis remains a fundamental test for assessing male fertility due to its simplicity and wide availability. however, continuous updates in reference values pose challenges in interpreting the evidence surrounding the potential impact of antioxidants, as changes in criteria may label patients differently. despite these challenges, studies have reported improvements in basic semen parameters following oral antioxidant intake, either alone or in combination. vitamin e: used in combination with other vitamins and minerals, vitamin e alone (300 mg daily) showed a significant improvement in sperm motility in infertile men (23). a study comparing vitamin e, clomiphene citrate, and a combination of both treatments in patients with idiopathic oligoasthenozoospermia reported a significant improvement in sperm concentration and motility with the combined regimen (13). another study using vitamin e (400 mg) + selenium (200 µg) for 100 days showed a significant improvement in sperm motility, morphology, or both in infertile men (34). however, some studies failed to reproduce significant effects on semen parameters using vitamin e alone or in combination with other antioxidants (28, 30). vitamin c: studies demonstrated the positive effects of vitamin c, particularly in heavy smokers, showing dosedependent improvements in sperm quality (43). vitamin c as an adjunct therapy post-varicocelectomy resulted in a statistically significant improvement in sperm motility and morphology compared to a placebo group (44). several antioxidant supplements containing vitamin c have been investigated, showing significant improvement in sperm motility with combinations including zinc and vitamin e (19). archivio italiano di urologia e andrologia 2024; 96(2):12323 t.a. abouelgreed, m.a. amer, h. mamdouh, et al. 4 carnitines: studies confirmed the significant influence of carnitines, especially on sperm motility (45). a placebocontrolled trial demonstrated significant improvement in all semen parameters, with the most significant increase in sperm motility, using a combined treatment of l-carnitine (2 g) and l-acetyl carnitine (1 g) (20). lc and lac treatment showed significant improvement in semen parameters, particularly in patients with lower baseline values of motility (46). coq10: coq10 significantly improved sperm concentration and motility compared to placebo in men with idiopathic oligoasthenozoospermia (16). a clinical trial demonstrated improvements in sperm morphology, catalase, and superoxide dismutase with coq10 treatment (47). these findings highlight the potential benefits of antioxidant supplementation in improving sperm parameters, but variations in study outcomes emphasize the need for further research and standardization. a systematic review of three randomized controlled clinical trials involving 332 infertile men indicated that coq10 treatment (200-300 mg daily) led to a significant increase in sperm concentration (md 5.33 x 10^6 sperm/ml, p < 0.001) and motility (md 4.5%, p < 0.001) (48). nac (n-acetyl cysteine): in a randomized placebo-controlled study of 120 patients with idiopathic infertility, daily treatment with 600 mg nac for 3 months resulted in a significant improvement in volume, motility, and viscosity of semen compared to placebo (21). combining 600 mg nac with 200 mg selenium showed a significant improvement in all semen parameters, with a dosedependent positive correlation between the sum of selenium and nac concentrations and mean sperm concentration, motility, and normal morphology (17). folic acid: in a double-blind, placebo-controlled interventional study, subfertile men receiving combined therapy of folic acid and zinc showed a statistically significant 74% increase in total normal sperm concentration after 26 weeks of treatment (18). selenium: a randomized placebo-controlled clinical trial involving 468 infertile men with idiopathic oligoasthenozoospermia demonstrated significant improvements in all semen parameters with selenium (200 mg) alone, nac (600 mg) alone, or a combination of both supplements compared to placebo (17). the combination of selenium with vitamin e resulted in increased sperm motility (24). however, a study with normozoospermic men using selenium (300 mg) daily for 48 weeks did not show a significant influence on semen parameters (29). zinc: in a prospective trial with asthenozoospermic men, zinc supplementation for 3 months led to a significant improvement in sperm concentration, progressive motility, fertilizing capacity, and a reduction in the incidence of anti-sperm antibodies (19). oral zinc supplementation restored seminal catalase-like activity and improved sperm concentration and progressive motility in asthenozoospermic men (49). lycopene: in a study involving 30 men with idiopathic oligoasthenozoospermia, treatment with 2 mg lycopene twice daily for 3 months resulted in statistically significant improvements in sperm concentration and motility in 66% and 53% of patients, respectively (33). a similar dose of lycopene was used in the treatment of 50 patients with idiopathic oligoasthenozoospermia, and after a 1year follow-up, sperm concentration, motility, and morphology improved in 70%, 54%, and 38% of patients, respectively (35). antioxidant influence on advanced sperm function tests the conventional semen analysis has faced criticism for its limited ability to predict fertility accurately. while it offers valuable information on sperm production, accessory organ secretions, ejaculation, and emission, it falls short in predicting fertility (50). it does not provide insights into the functional potential of sperm to successfully fertilize an ovum or undergo the necessary maturation processes for fertilization. to address this limitation, advanced tests of sperm function were developed to enhance the predictive power of semen studies. among these advanced tests, sdf and os measures have been the most widely studied. recent research has expanded our understanding of the implications of sdf on male fertility (8). human sperm dna, mostly bound to protamine, forms a condensed chromatin that is easily transportable through the sperm head and more resistant to damage during transit through the reproductive tracts (51). however, sdf can occur due to errors in chromatin packaging during spermatogenesis or exposure to seminal os during epididymal transit (52). both in vitro and in vivo studies confirm that elevated sdf can negatively impact fertility at various stages, including fertilization, early embryo development, implantation, and pregnancy (53,54). therefore, addressing os appears to be a justifiable approach to minimize sdf incidence in semen samples. several studies have investigated the impact of dietary antioxidant supplementation on sperm dna integrity (22, 25, 36, 55). while these studies generally assessed small-sized samples and had short treatment durations, they consistently reported a positive effect on sdf measures. for instance, greco et al. (20) found a significant reduction in sdf percentage (p < 0.001) in patients with unexplained infertility and elevated sdf levels treated with vitamin c and vitamin e. another study reported a 19% decrease in sdf (p < 0.001) with a combination of antioxidants containing zinc and selenium (36). abad et al. (29) examined the effects of oral antioxidant therapy on sdf dynamics, revealing significant reductions at each experimental time-point (p < 0.05). studies also explored antioxidant therapy in patients with high sdf due to varicocele. in one study, a combined antioxidant regimen led to a significant decrease in sdf levels (22.1%, p = 0.02) and an increase in sperm concentration (p = 0.04) (38). assessing seminal os levels has become integral in evaluating infertile men, considering its utility in various clinical scenarios (56). however, routine clinical use is hindered by factors such as test availability, complexity, cost-effectiveness, and a lack of universally accepted analysis methods. various assays, classified as direct (e.g., chemiluminescence and flow cytometry assays) and indirect (e.g., myeloperoxidase test, lipid peroxidation levels), are available to measure os. each type has its advantages and disadvantages, with direct assays providing accurate measures but being expensive and requiring expertise, while indirect assays are simpler and more cost-effective but archivio italiano di urologia e andrologia 2024; 96(2):12323 5 effects of antioxidants on infertility assess an end state influenced by various unknown pathological processes (57-59). numerous studies investigating the impact of antioxidant therapy on male fertility have evaluated its effects on os as a key outcome measure. for instance, a 6-month regimen of vitamin e (300 mg daily) significantly reduced lipid peroxidation in semen samples from 110 asthenozoospermic men (23). similarly, comhaire et al. (24) reported a significant decrease in seminal ros levels with a combination of 180 mg vitamin e and 30 mg β-carotene in 27 infertile men. omu et al. (17) examined the effectiveness of daily supplementation with vitamin e (20 mg), vitamin c (10 mg), and zinc (400 mg) over 3 months in 45 asthenozoospermic men, observing a twofold reduction in malondialdehyde (an indicator of lipid peroxidation) (p < 0.01), a significant decrease in pro-apoptosis markers (p < 0.05), and a substantial increase in total antioxidant capacity (p < 0.01). another study revealed that vitamin e (400 mg) and selenium (225 mg) intake for 3 months led to significant reductions in malondialdehyde levels, coupled with improvements in sperm motility and viability (24). furthermore, oeda et al. (60) observed a direct doseand time-dependent reduction in seminal ros when semen samples were incubated with n-acetylcysteine (nac), suggesting the potential usefulness of nac in reducing os. in a randomized placebo-controlled study involving 120 patients with idiopathic infertility, those receiving 600 mg of nac daily showed significant improvements in sperm motility compared to the placebo group (61). additionally, gharagozloo and aitken (62) conducted a systematic review of 20 trials, indicating a significant reduction in os or sperm dna damage after antioxidant treatment in 19 of them. conclusions numerous research has investigated the impact of antioxidant therapy on male fertility, demonstrating its potential in reversing os-induced sperm dysfunction. commonly used compounds include vitamin e, vitamin c, carnitines, zinc, selenium, nac, coq10, folic acid, and lycopene. however, the identification of an ideal antioxidant treatment method is hindered by study design heterogeneity 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zinc deficiency: a special challenge. j nutr 2007; 137:1101-1105. 41. joshi r, adhikari s, patro bs, et al. free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. free radic biol med 2001; 30:1390-399. 42. agarwal a, sekhon lh. oxidative stress and antioxidants for idiopathic oligoasthenoteratospermia: is it justified? indian j urol 2011; 27:74-85. 43. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update 2010; 16:231-245. 44. dawson eb, harris wa, teter mc, powell lc. effect of ascorbic acid supplementation on the sperm quality of smokers. fertil steril 1992; 58:1034-1039. 45. cyrus a, kabir a, goodarzi d, moghimi m. the effect of adjuvant vitamin c after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. int braz j urol 2015; 41:230-238. 46. balercia g, regoli f, armeni t, et al. placebo-controlled doubleblind randomized trial on the use of l-carnitine, l-acetylcarnitine, or combined l-carnitine and l-acetylcarnitine in men with idiopathic asthenozoospermia. fertil steril 2005; 84:662-671. 47. nadjarzadeh a, shidfar f, amirjannati n, et al. effect of coenzyme q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double-blind randomised clinical trial. andrologia 2014; 46:177-183. 48. lafuente r, gonzález-comadrán m, solà i, et al. coenzyme q10 and male infertility: a meta-analysis. j assist reprod genet 2013; 30:1147-1156. 49. hadwa mh, almashhedy la, alsalman ar. oral zinc supplementation restores superoxide radical scavengers to normal levels in spermatozoa of iraqi asthenospermic patients. int j vitam nutr res 2015; 85:165-173. 50. esteves sc. clinical relevance of routine semen analysis and controversies surrounding the 2010 world health organization criteria for semen examination. int braz j urol 2014; 40:443-453. 51. erenpreiss j, spano m, erenpreisa j, et al. sperm chromatin structure and male fertility: biological and clinical aspects. asian j androl 2006; 8:11-29. 52. shamsi mb, kumar r, dada r. evaluation of nuclear dna damage in human spermatozoa in men opting for assisted reproduction. indian j med res 2008; 127:115-123. 53. sharma rk, said t, agarwal a. sperm dna damage and its clinical relevance in assessing reproductive outcome. asian j androl 2004; 6:139-148. 54. saleh ra, agarwal a, sharma rk, et al. evaluation of nuclear dna damage in spermatozoa from infertile men with varicocele. fertil steril 2003; 80:1431-1436. 55. saleh ra, agarwal a, nada ea, et al. negative effects of increased sperm dna damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. fertil steril 2003; 79(suppl. 3):1597-1605. 56. agarwal a, cho cl, esteves sc. should we evaluate and treat sperm dna fragmentation? curr opin obstet gynecol 2016; 28:164-171. 57. gil-villa am, cardona-maya w, agarwal a, et al. role of male factor in early recurrent embryo loss: do antioxidants have any effect? fertil steril 2009; 92:565-571. 58. agarwal a, makker k, sharma r. clinical relevance of oxidative stress in male factor infertility: an update. am j reprod immunol 2008; 59:2-11. 59. agarwal a, tvrda e, sharma r. relationship amongst teratoarchivio italiano di urologia e andrologia 2024; 96(2):12323 7 effects of antioxidants on infertility zoospermia, seminal oxidative stress and male infertility. reprod biol endocrinol 2014; 12:45. 60. oeda t, henkel r, ohmori h, schill wb. scavenging effect of nacetyl-l-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility? andrologia 1997; 29:125-131. 61. benatta m, kettache r, buchholz n, trinchieri a. the impact of nutrition and lifestyle on male fertility. arch ital urol androl. 2020; 92.121-131. 62. gharagozloo p, aitken rj. the role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. hum reprod 2011; 26:1628-1640. correspondence tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg department of urology, al-azhar university, cairo, egypt & gulf medical university, ajman, uae mohamed a. amer, md amerrom@yahoo.com hassan mamdouh, md hsdermaclinic@yahoo.com hany aboelwafa, md dr_hanyos138@yahoo.com sameh f. fahmy samehmohamed74@azhar.edu.eg omar a. omar, md omarabdelhady.236@azhar.edu.eg mohammed abdelshakour, md dr.mohammed_121@yahoo.com mohammad elesawy, md elesawy288@gmail.com mohamed sonbol, md bosombol1185@gmail.com ahmed n. maawad, md ah.nabil70@gmail.com osama k. elsayed osamaandroderma@gmail.com department of dermatology & andrology al-azhar university, cairo, egypt ahmed f. el-sherbiny, md ahmed_derma@yahoo.com department of andrology, international islamic center for population studies and research, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 265archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. ln involvement. the sensitivity of abdominal computed tomography (ct) and multiparametric magnetic resonance imaging (mpmri) for lymph node metastasis is less than 40% according to a recent study (1). in addition, nuclear medicine-based imaging modalities (11cor 18fcholineand 68ga-psma), pet-ct for initial staging of prostate cancer may provide low sensitivity (49-66%) in detection of ln metastases (1, 2). today, the gold-standard evaluation of lymph node metastasis remains multistep analysis of the lymph nodes via hematoxylin-eosin stained sections, combined with immunohistochemistry for cytokeratin expression. however, there is no standardized assessment method for nodal status in prostate cancer. histopathologic evaluation of lymph nodes varies between laboratories. intraoperative frozen section (fs) assessment of pelvic lymph nodes (plns) is being used not so often, but for some triage patients. additionally, the role of fs in identifying small metastases and influencing the completion of the rp can be queried. the routine fs of plns has been questioned by several studies (3, 4). there are studies, which report a wide range of sensitivity for fs of plns, between 33% to 77% (5). if the metastasis is small and not visible on macroscopic evaluation, freezing and cryostat section may waste the tissue, which is very important during permanent embedding. regarding technical details, fatty lymph nodes are not good candidates for frozen section analysis as microscopic metastasis can be lost during defatting process. all these shortcomings of the pathological evaluation of the lymph nodes brought out different technologies like polymerase chain reaction (pcr) based techniques. pcr-based techniques such as one-step nucleic acid amplification (osna) assay are viable alternatives. the osna technique for pathological evaluation of lymph node is based on reverse transcription loop-mediated dna amplification for the detection of cytokeratin 19 (ck19) introduction: the osna technique is based on reverse transcription loop-mediated dna amplification for the detection of cytokeratin 19 (ck19) messenger rna (mrna). the purpose of our paper, which represents the first study in the literature, is to test the accuracy of this method in the detection of lymph node metastases in patients undergoing robotic radical prostatectomy with lymph node dissection. methods: our cohort consisted of patients that have undergone robotic radical prostatectomy with extended lymph node dissection. lymph nodes were evaluated with imprint technique and then with frozen section examination. the remaining tissue was evaluated by osna method. lymph nodes were defined as ‘negative’ or ‘positive’ according to mrna copy number. results: 7 patients and 25 lymph nodes were included in our cohort. two patients were found negative with all pathology methods. in one patient the standard stains revealed a suspicious outcome but it was positive for micrometastasis with osna. in another patient the outcome was positive for standard stains and negative for osna. finally, 2 patients were found positive for osna and negative for imprint methods. conclusions: one step nucleic acid amplification (osna) method using ck19 seems to fail in detection of lymph node metastases in prostate cancer patients undergoing radical prostatectomy and lymph node dissection. key words: prostate cancer; metastases; lymph nodes; one step nucleic acid amplification. submitted 24 january 2022; accepted 2 march 2022 introduction pelvic lymph node metastasis is associated with poor prognosis and upstages prostatic carcinoma. pelvic lymph node dissection (plnd) is currently the most accurate lymph node (ln) staging procedure for prostate cancer (pca). none of the available radiologic imaging modalities provides an equivalent sensitivity for the detection of one step nucleic acid amplification (osna) for detection of lymph node metastasis during robotic radical prostatectomy for prostate cancer: a pilot study omer burak argun 1, panagiotis mourmouris 2, yesim saglican 3, tunkut doganca 4, mustafa bilal tuna 5, cavit kerem kayhan 6, ozge yalcinkaya 6, ilter tufek 1, halil kara 7, can obek 1, umit ince 3, lazaros tzelves 2, andreas skolarikos 2, ali rıza kural 1 1 acibadem mehmet ali aydinlar university, school of medicine, department of urology, istanbul, turkey; 2 national and kapodistrian university of athens, sismanogleio general hospital, 2nd department of urology, athens, greece; 3 acibadem mehmet ali aydinlar university, school of medicine, department of pathology, istanbul, turkey; 4 acibadem taksim hospital, department of urology, istanbul, turkey; 5 acibadem maslak hospital, department of urology, istanbul, turkey; 6 acibadem maslak hospital, department of pathology, istanbul, turkey; 7 acibadem maslak hospital, department of general surgery, istanbul, turkey. doi: 10.4081/aiua.2022.3.265 summary archivio italiano di urologia e andrologia 2022; 94, 3 o. burak argun, p. mourmouris, y. saglican, et al. 266 messenger rna (mrna). the idea behind this relatively novel study with micromolecular histopathologic technique is detection of ck 19 in lymphatic tissue due to prostate cancer metastasis, which is normally not expressed. our goal was to evaluate the use of the osna method to detect cancer metastasis in entire lymph node in comparison with conventional methods in prostate cancer patients who underwent robotic radical prostatectomy and lymph node dissection. material and methods our cohort consisted of patients that have been diagnosed with intermediate and high-risk prostate cancer and who have undergone robotic radical prostatectomy with extended lymph node dissection. institutional review board approval was taken from ethical committee. informed and written consent was obtained from all patients. lymph node template included caudally, femoral canal; medially, the side wall of the bladder; laterally, up to the genitofemoral nerve; posteriorly, the obturator muscle and floor of the obturator fossa down to the internal iliac vessels; cranially, the common iliac region where the ureter crosses the common iliac artery and aortic bifurcation up to the inferior mesenteric artery. patients with previous and/or additional malignancies and with a history of pelvic radiotherapy were excluded from the study. a summary of patient and tumor characteristics is shown in table 1. suspicious lymph node regions were defined pre-operatively with the use of imaging methods such as prostate specific membrane antigen positron emission tomography (psma-pet) or magnetic resonance imaging (mri). following the completion of the lymph node dissection, the suspicious lymphatic tissue samples were removed through the assistant port site inside an organ bag. lymphatic tissues were sent to the pathology department immediately and dissected out from the fatty tissue. care has been taken to perform lymph node dissection before the prostatectomy, as this could potentially contaminate the lymph node tissues with ck19 positive tissues. following step was cutting the suspected lymph node through the sagittal plane. each plane (facing each other) was evaluated with imprint technique and then with frozen section examination. touch imprint cytology was carried out by gently touching the fresh tissue on a clean glass slide and fixing immediately imprints in 95% ethyl alcohol and staining with hematoxylin and eosin (h&e) stains. frozen section study was performed by processing tissue in cryostat at -10°c to -15°c and cutting thin sections of 3-5 μm thickness and staining using h&e. if the lymph nodes were large enough (> 5 mm in diameter), a segment of approximately 2-3 mm from the middle of the lymph node was removed and stored for paraffin sampling and immunohistochemistry (ihc) evaluation as stated in the consent form (figure 1). the remaining tissue was evaluated by osna method or stored at minus 18°c if osna procedure was not possible at the time of operation. in case of a small lymph node (< 5 mm), cutting was performed in two pieces and used one piece of it (figure 2), whereas the second one was examined with h&e staining and paraffin sampling which were golden standard for post-operative evaluation. the fresh sections stored for osna evaluation were transformed to a homogenized dilution with the use of a 4 ml of lysing buffer (lynorhag, sysmex, kobe, japan) for 90 seconds and then the latter was centrifuged for one minute at 10,000 g. next, ck19 and beta-actin mrna were amplified by reverse transcription loop-mediated amplification (rt-lamp) in the rd-100i (lynoamp, sysmex, kobe). the use of the dedicated kit provided by the manufacturer (lynoamp, sysmex, kobe) allowed the start of the automated procedure that was performed without the need of rna purification. lns were defined table 1. pre and perioperative characteristics of patients. figure 1. process of lymph nodes larger than 5 mm. patient age psa pre-op clinical post-op pathology surgical gs stage gs stage margins 1 60 7,5 3+4 ct2b 3+4 pt2c negative 2 68 8 4+5 ct3 4+5 pt3b negative 3 69 8,5 4+4 ct3 3+4 pt3a negative 4 64 15 4+4 ct2c 4+4 pt2c negative 5 73 5,2 4+5 ct3 5+4 pt3b negative 6 68 20 4+4 ct3 4+4 pt3b negative 7 68 8 4+3 ct2c 5+4 pt3b negative psa: prostate specific antigen; gs: gleason score. figure 2. process of lymph nodes smaller than 5 mm. 267archivio italiano di urologia e andrologia 2022; 94, 3 osna for lymph node metastasis in prostate cancer as ‘negative’ or ‘positive’ according to mrna copy number. ck 19 mrna copies/ml less than 250 were defined as negative (-), 250-5000 were defined as positive for micrometastases and copies exceeding 5000 were defined as positive for macrometastases, according to manufacturer’s manual results 7 patients and 25 lymph nodes were included in our cohort. in the first and second patients, 2 and 4 lymph nodes were used for analysis from the harvested lymphatic tissue. in all cases osna was performed intraoperatively except one that due to device failure was performed postoperatively. they were all negative for imprint analysis, frozen section (h&e) staining and osna. in third patient 5 lymph nodes from different areas were selected according to the aforementioned criteria and one of them was suspicious in imprint analysis but also it was positive for micrometastatis in osna evaluation. in fourth patient, there was micrometastasis in imprint analysis and h&e staining but negative for osna and frozen section analysis. in fifth patient, even though osna was positive for micrometastasis, imprint analysis and frozen section +(h&e) staining failed to confirm it. in sixth patient, 4 lymph nodes were harvested and in one of them osna was positive even though the imprint and frozen section analysis were negative. in seventh patient, we harvested 5 lymph nodes and 3 of them were found to be positive for macrometastatis but negative for osna (table 2). in this cohort of lymph nodes, osna method was discordant for evaluation of metastatic lymph node status. discussion today, hematoxylin-eosin staining and immunohistochemical methods are used in the detection of lymph node metastases of prostate cancer. because of the technical difficulties and also the nature of the sampling method, identification of cancerous cells in the entire lymph node is not feasible and metastasis status is reported by random sampling of the lymph tissues (1). the single-step nucleic acid amplification (osna) method, has proven its value in the sentinel lymph node sampling of breast cancer (2). meanwhile its use in other malignancies (colorectal, head and neck, gynecological, lung, thyroid, gastric) has yielded promising outcomes (5-10). its use can be expanded to intraoperative identification of positive lymph nodes that may potentially alter the course of the procedure in the future (11). as well there are even studies in the literature implying that the osna method can potentially gain the first place as a standard for pathological examination of lymph node infiltration (12). the presence of lymph node metastasis in patients with prostate cancer can significantly alter the management and the prognosis of the disease. lymph node status remains a significant prognostic factor and an important part of the decision-making process regarding adjuvant treatment for prostate cancer patients. our study represents the first study that tests the potential role of the osna method in diagnosing lymph node infiltration in patients with prostate cancer. the osna system (sysmex corporation, kobe, japan), combines reverse transcription (rt) with isothermal loopmediated dna amplification (rt-lamp) for detection of ck19 messenger rna (mrna) as a marker of cancerous cells since ck19 mrna in the glandular epithelial cells should not normally be present in the lymph nodes (13). when compared to other techniques for intraoperative evaluation of sentinel node metastases in breast cancer, outcomes of osna technique are relatively controversial. there are studies that report a clear advantage of the more popular imprints cytology (ic) with a calculated accuracy of 96.12% (14), whereas in other studies the osna method is found to be equally reliable (detection rates 11.8 vs 12.1%) when compared to other techniques such as cytokeratin immunohistochemistry (ck-ihc) (15). when cost is concerned there is limited data in the literature and mostly achieved from studies for breast cancer. the hypothesis was that with a reliable intra-operative diagnostic tool, the patients would be spared from a second procedure in order to excise the remaining lymph nodes that could be potentially infiltrated. the data, even though controversial, imply that osna method is not cost effective for the intraoperative diagnosis of sentinel lymph node metastases despite its accuracy that reaches almost 91% (16). however, guillén-paredes mp et al. in patients with breast cancer metastases, report reduced hospital stay and operating time with osna method resulting in a saving of 439.67 € per patient, but their study is a retrospective with a low number of patients, so their results must be interpreted with caution (17). prostate cancer patients can potentially survive for more than 15 years and most of them will be receiving some kind of treatment. hence cost analysis of this method for prostate cancer can potentially yield different outcomes table 2. results of lymph nodes analysis of patients. patient lymph node imprint+ frozen+ osna location h&e staining h&e staining 1 right common iliac 0 0 0 negative right external iliac 0 0 0 negative 2 right obturator 0 0 0 negative left obturator 0 0 0 negative pre-sacral 0 0 0 negative right external iliac 0 0 0 negative 3 left common iliac 0 0 0 negative left external illac 0 0 0 negative right common iliac s 0 1 1100 copies left obturator 0 0 0 negative right external iliac 0 0 0 negative 4 right obturator 0 1 0 negative 5 right obturator 0 0 1 400 copies left obturator 0 0 0 negative right common iliac 0 0 0 negative 6 right obturator 0 0 1 400 copies left obturator 0 0 0 negative left external iliac 0 0 0 negative left common iliac 0 0 0 negative 7 right obturator+external iliac 1 s 0 negative right obturator+external iliac 0 0 0 negative left obturator+external iliac 1 1 0 negative left obturator+external iliac 1 1 0 negative left common iliac 0 0 0 negative 0 = negative; 1 = positive; s = inconclusive. archivio italiano di urologia e andrologia 2022; 94, 3 o. burak argun, p. mourmouris, y. saglican, et al. 268 compared to breast cancer. no data exist in the literature concerning the use of osna method in detecting possible positive lymph nodes in prostate cancer patients. the only one available in the literature reports preliminary results of this method in prostatectomy specimens and not in lymph nodes (18). this study implicates ck19 as a potential marker for prostate cancer specimens and presents some promising results. nevertheless, based on our results ck19 doesn’t seem to yield satisfactory results as far as lymph nodes metastasis is concerned. furthermore, the true clinical impact of this method (if any), lies in positive lymph node detection since the methods for detecting prostate cancer in prostate glands are already completely satisfying something that does not imply for lymph nodes. our study is a pilot study and so it cannot avoid several limitations. first of all the number of patients is very small and the number of lymph nodes tested. nevertheless, this is the first study to test the potential role of osna in lymph nodes metastases for prostate cancer and also the number of patients with positive lymph nodes in radical prostatectomy series is relatively small. finally, our study did not test either cost or potential survival benefit for patients that were found to be positive with the osna method. the purpose of our paper was to study the potential role of a novel detection method (osna), already used in other malignancies, in prostate cancer. future well-designed studies are needed to confirm if these methods can increase the detection rate of lymph node metastases and provide any survival benefit for the patients. conclusions osna method using ck19 was not sufficient to demonstrate lymph node metastases in prostate cancer patients undergoing radical prostatectomy and lymph node dissection compared to golden standards. references 1. kryvenko on, epstein ji. histologic criteria and pitfalls in the diagnosis of lymphovascular invasion in radical prostatectomy specimens.am j surg pathol. 2012; 36:1865-73. 2. shi f, liang z, zhang q, et al. the performance of one-step nucleic acid amplification assay for intraoperative detection of sentinel lymph node macrometastasis in breast cancer: an updated metaanalysis. breast. 2018; 39:39-45. 3. young mp, kirby rs, o’donoghue ep, parkinson mc. accuracy and cost of intraoperative lymph node frozen sections at radical prostatectomy. j clin pathol. 1999; 52: 925-7. 4. kakehi y, kamoto t, okuno h, et al. per-operative frozen section examination of pelvic nodes is unnecessary for the majority of clinically localized prostate cancers in the prostatespecific antigen era. int j urol. 2000; 7:281-6. 5. wild jb, iqbal n, francombe j, et al. is it time for one-step nucleic acid amplification (osna) in colorectal cancer? a systematic review and meta-analysis. tech coloproctol. 2017; 21:693-699. 6. zhou m, wang x, jiang l, et al. the diagnostic value of one step nucleic acid amplification (osna) in differentiating lymph node metastasis of tumors: a systematic review and meta-analysis. int j surg. 2018; 56:49-56 7. fanfani f, monterossi g, ghizzoni v, et al. one-step nucleic acid amplification (osna): a fast molecular test based on ck19 mrna concentration for assessment of lymph-nodes metastases in early stage endometrial cancer. plos one. 2018; 13:e0195877. 8. nakagawa k, asamura h, tsuta k, et al. the novel one-step nucleic acid amplification (osna) assay for the diagnosis of lymph node metastasis in patients with non-small cell lung cancer (nsclc): results of a multicenter prospective study. lung cancer. 2016; 97:1-7. 9. gonzález o, iglesias c, zafon c, et al. detection of thyroid papillary carcinoma lymph node metastases using one step nucleic acid amplification (osna): preliminary results. j invest surg. 2015; 28:153-9. 10. nakabayashi k, uraoka t, shibuya m, et al. rapid detection of cea mrna in peritoneal washes using one-step nucleic acid amplification (osna) for gastric cancer patients. clin chim acta. 2015; 439:137-42. 11. yeung tm, wang lm, colling r, et al. intraoperative identification and analysis of lymph nodes at laparoscopic colorectal cancer surgery using fluorescence imaging combined with rapid osna pathological assessment. surg endosc. 2018; 32:1073-1076. 12. tamaki y. one-step nucleic acid amplification (osna): where do we go with it? int j clin oncol. 2017; 22:3-10. 13. tsujimoto m, nakabayashi k, yoshidome k, et al. onestep nucleic acid amplification (osna) for intraoperative detection of lymph node metastasis in breast cancer patients. clin cancer res 2007; 13:4808-4816. 14. luna-tomás ma, solà-suárez m, mariscal-martínez a, et al. is osna better than imprint cytology for intraoperative diagnosis of cancer involvement of axillary sentinel node in breast cancer? breast. 2018; 38:181-187. 15. shigematsu h, ozaki s, yasui d, et al. comparison of ck-ihc assay on serial frozen sections, the osna assay, and in combination for intraoperative evaluation of sln metastases in breast cancer. breast cancer. 2018; 25:191-197. 16. huxley n, jones-hughes t, coelho h, et al. a systematic review and economic evaluation of intraoperative tests [rd-100i one-step nucleic acid amplification (osna) system and metasin test] for detecting sentinel lymph node metastases in breast cancer. health technol assess. 2015; 19:v-xxv, 1-215. 17. guillén-paredes mp1, carrasco-gonzález l, cháves-benito a, et al. one-step nucleic acid amplification (osna) assay for sentinel lymph node metastases as an alternative to conventional postoperative histology in breast cancer: cost-benefit analysis. cir esp. 2011; 89:456-62. 18. winter a, engels s, goos p, et al. detection of ck19 mrna using one-step nucleic acid amplification (osna) in prostate cancer: preliminary results. j cancer. 2018; 9:4611-4617. correspondence omer burak argun, md, associate professor of urology drburakargun@gmail.com ilter tufek, md, professor of urology iltertuf@gmail.com ali rıza kural, md, professor of urology arkural@gmail.com acibadem mehmet ali aydinlar university, school of medicine, department of urology buyukdere cad 40 maslak 34457 istanbul (turkey) 269archivio italiano di urologia e andrologia 2022; 94, 3 osna for lymph node metastasis in prostate cancer panagiotis mourmouris, md, urologist (corresponding author) thodoros13@yahoo.com national and kapodistrian university of athens, sismanogleio general hospital, 2nd department of urology sismanogliou 37, marousi 151 26 (greece) yesim saglican, md, associate professor of pathology yesim.saglican@acibadem.com.tr umit ince, md, professor of pathology umit.ince@acibadem.com acibadem mehmet ali aydinlar university, school of medicine, department of pathology buyukdere cad 40 maslak 34457 istanbul (turkey) tunkut doganca, md, urologist tunkutdoganca@gmail.com acibadem taksim hospital, department of urology inonu mahallesi, nizamiye cd. no:9, 34373 sisli, istanbul (turkey) mustafa bilal tuna, md, urologist mustafabilaltuna@gmail.com cavit kerem kayhan, biologist cavit.kerem.kayhan@acibadem.com acibadem maslak hospital, department of pathology buyukdere cad 40 maslak 34457 istanbul (turkey) ozge yalcinkaya, pathology technician ozge.yalcinkaya@acibadem.com halil kara, md, general surgeon halil.kara@acibadem.com acibadem maslak hospital, department of general surgery buyukdere cad 40 maslak 34457 istanbul (turkey) can obek, md, professor of urology canobek@yahoo.com lazaros tzelves, md, urologist lazarostzelves@gmail.com andreas skolarikos, md, phd, professor of urology andskol@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanogleio general hospital, sismanogliou 37, marousi 151 26 (greece) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 letter to editor key words: bladder cancer, nmibc, laser, cystoscopy. submitted 18 january 2023; accepted 21 january 2023 to the editor, bladder cancer (bca) is the second most common cancer in urological clinical practice, after prostate adenocarcinoma. usually occurs in patients between 60 and 70 years old, three times more frequently in men than women (1, 2). about 75% of bladder cancer are pta or pt1 (3), even more frequently considering a population younger than 40 years old. early detection is of paramount importance since allows to find tumors when they are still superficial and therefore with a better prognosis. management of non muscle invasive bladder cancer (nmibc) accordingly to eau guidelines (4), is based on intravesical chemotherapy and endourological procedures (transurethral resection of bladder cancer), which requires operating theater, anesthesiologic assistance, scrub nurses and dedicated instruments (5, 6). trans urethral resection of the bladder tumor (turbt) is the gold standard in the treatment of nmibc accordingly to the literature and it is in fact a mature procedure with a standardized technique, but it is still facing some challenges and risks such as difficult control of cutting depth, stimulation of the obturator nerve, bladder perforation and iliac vascular injury (7). for these reasons, it is interesting to study how other technologies are growing and how we could use them in this so frequent and ubiquitarian disease management. in particular, recently there is a great interest in transurethral laser surgery and especially regarding its comparison to standard turbt. some studies showed similar results in both oncological and safeness terms (8-12). the en bloc laser techniques might allow a clearer cut of the tumor base, simplifying pathologist reading of the surgical samples (13). furthermore, bca has a 1and 5-year recurrence rates that can be very high, and several patients require additional turbt during follow-up (4, 14). one of the recent problems of healthcare organizations is to address the current shortage of operating theater resources, reducing costs, while guaranteeing the best possible treatment for the patients. from this point of view, the possibility to treat some carefully selected bca recurrences patients with on an outpatient basis would represent an important saving in both economic and organizational terms, reducing hospitalization and discomfort for the patient and his family. according to these pressing needs, we present our experience of an innovative outpatient laser treatment (“tula dual”) in a bca relapsed patient. we highlight the case of an 85 years-old woman in follow-up over the previous five years for nmibc (urothelial bladder cancer, pta lg). she was ineligible for standard turbt because of age and several comorbidities which led to an asa iv score. she was taking medical therapy for atrial fibrillation (anticoagulation therapy), hypertension and diabetes mellitus, added to recurring episodes of hematuria. during a follow up cystoscopy were endoscopically detected over 20 lesions highly suspected for bca recurrence. the lesions were pink, papillary and typically aspect of non-muscle invasive lesions. the most of these lesions were millimetric, three of these had a plant base of about one centimeter. a recent urinary cytology was negative for high grade bca while a kidney-ureters-bladder ultrasound didn’t show hydronephrosis or further suspicious findings. in this situation we should have organized an operating theater to perform a turb, suspending the anticoagulation therapy; but instead, considering the anamnesis and the clinical condition, we decided accordingly to the patient to perform the tula dual procedure. the tula dual is an endoscopic procedure, executed with a dual laser (diode laser technology 980-1470 wave length) in local anesthesia or even without it, in an ambulatory setting. it allows the contemporary vaporization and hemostasis of tissues. patients are summoned in ambulatory, where is administered a one-shoot antibiotic prophylaxis according to current guidelines for endoscopic operative procedures such as turbt (15). tula dual: trans urethral laser ablation of recurrent bladder tumors in outpatient setting rosario leonardi 1, francesco vecco 2, 3, gabriele iacona 1, alessandro calarco 4, guglielmo mantica 2, 3 1 musumeci gecas clinic, gravina di catania (ct), italy; 2 irccs ospedale policlinico san martino, genova, italy; 3 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 4 department of urology, "cristo re" hospital, rome, italy. doi: 10.4081/aiua.2023.11171 archivio italiano di urologia e andrologia 2023; 95, 1 r. leonardi, f. vecco, g. iacona, a. calarco, g. mantica in women such as this patient, we perform a bladder intravesical instillation with saline solution (50 ml) plus one lidocaine 2% vial for 15 minutes; in men we add also lidocainebased gel left in the urethra. it is necessary to empty the bladder before the beginning of the procedure. the tula is performed using a flexible cystoscopy with a 320 micron fiber and the dual laser (figure 1). the power of laser, and, the use of a single wave lentgh or a mixed wave lentgh, is based on volume of lesion/s. we usually use the single wavelength of 1470 nm set at 3 watts of power for small lesions while, for bigger lesions, we prefer to mix the wavelength of 980nm set at 5 watts of power plus the wavelength 1470nm set at 3 watts of power. the above described patient underwent a 20 minutes procedure in the endoscopy room, no operative theatre, no general o spinal anesthesia, no bladder catheter after procedure or preoperative exams. she didn’t complain any pain or discomfort during the procedure and neither intraoperative nor postoperative complications occurred. the patient only reported a minimal hematuria which disappeared in the first postoperative day. no disease recurrences were detected at the 3-months cystoscopic follow-up. the tula dual is a brand-new procedure that might be indicated during follow-up of nmibc selected patients, or for radiotherapy-related cystitis. the category of patients who could benefit the most by this outpatient laser alternative to turbt are those who are not fit for conventional treatments under anesthesia because of multiple comorbidities or anticoagulant/antiaggregant drugs assumption. considering the high frequency of bladder cancer, having the possibility of following up patients, managing them, even the ones who are not eligible for endoscopic surgery, and simultaneously lowering costs is surely a great deal that this treatment offers. because of the non-necessity of operating room this technique is even more interesting, especially after covid pandemic that still cost everybody a great demand of theatres and delays (16). bladder cancer has been estimated as the most expensive cancer to health care systems. the average expense for patient is currently more than $100.000 and more than 70% of this is due to the cost of repeated turbts (17-18). these prices could be dramatically reduced if patients were managed in the office setting. in fact, office-based laser vaporization might allow to save more than 50% of the estimated cost. the fundamental factor to determine the suitability of office-based management of nmibc is the correct identification of eligible patients that should be those at lower risk of progression and at higher risk of intraand post-operative complications if undergone turbt. some authors already evaluated office-based procedures for the management of nmibc with retrospective data (19). donat et al. (20) described successful management of nmibc with no recurrence within 6 months. all tumors were smaller than 0.5 cm, with a negative urine cytology. the risk of progression in this group was approximately 8%. recently, pedersen et al. (21) evaluated in a prospective study the office-based photocoagulation of bladder tumor. they found the first procedure to be non-inferior of turbt in terms of progression rate and complications. the 98% of patients declared to prefer the photocoagulation. studies are needed in order to determine results of office-based procedures and in particular of tula dual, both in terms of relapse and progression compared to turbt. elderly patients such as our, with multiple morbidities are often not fit for conventional treatment under general anesthesia. tula dual offers a technique using flexible cystoscopy for the treatment of bladder tumor under local or even no anesthesia in outpatient settings. references 1. kirkali z, chan t, manoharan m, et al. bladder cancer: epidemiology, staging and grading, and diagnosis. urology. 2005; 66:4-34. 2. malinaric r, mantica g, balzarini f, et al. extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients should it be performed more often? arch ital urol androl. 2022; 94:144-149. 3. maffezzini m, fontana v, pacchetti a, et al. age above 70 years and charlson comorbidity index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. data from a contemporary series of 334 consecutive patients. arch ital urol androl. 2021; 93:15-20. 4. eau guidelines on non-muscle-invasive bladder cancer diagnosis uroweb. accessed september 14, 2022. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer/chapter/diagnosis 5. malmström pu, sylvester rj, crawford de, et al. an individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non-muscle-invasive bladder cancer. eur urol. 2009; 56:247-256. figure 1. intraoperative pictures showing office-based laser management of nmibc. archivio italiano di urologia e andrologia 2023; 95, 1 laser technique for bladder cancer treatment 6. shelley md, kynaston h, court j, et al. a systematic review of intravesical bacillus calmette-guérin plus transurethral resection vs transurethral resection alone in ta and t1 bladder cancer. bju int. 2001; 88:209-216. 7. gregg jr, mccormick b, wang l, et al. short term complications from transurethral resection of bladder tumor. can j urol. 2016; 23:8198203. 8. chen j, zhao y, wang s, et al. green-light laser en bloc resection for primary non-muscle-invasive bladder tumor versus transurethral electroresection: a prospective, nonrandomized two-center trial with 36-month follow-up. lasers surg med. 2016; 48:859-865. 9. zhang xr, feng c, zhu wd, et al. two micrometer continuous-wave thulium laser treating primary non-muscle-invasive bladder cancer: is it feasible? a randomized prospective study. photomed laser surg. 2015; 33:517-523. 10. xu y, guan w, chen w, et al. comparing the treatment outcomes of potassium-titanyl-phosphate laser vaporization and transurethral electroresection for primary nonmuscle-invasive bladder cancer: a prospective, randomized study. lasers surg med. 2015; 47:306-311. 11. chen x, liao j, chen l, et al. en bloc transurethral resection with 2-micron continuous-wave laser for primary non-muscle-invasive bladder cancer: a randomized controlled trial. world j urol. 2015; 33:989-995. 12. yu j, zheng j. comparative efficacy and safety of transurethral laser surgery with holmium laser, ktp laser, 2-micron laser or thulium laser for the treatment of non-muscle invasive bladder carcinoma: a protocol of network meta-analysis. bmj open. 2021; 11:e055840 13. leonardi r, calarco a, falcone l, et al. endoscopic laser en bloc removal of bladder tumor. surgical radicality and improvement of the pathological diagnostic accuracy. arch ital urol androl. 2022; 94:134-137. 14. sawazaki h, arai y, ito y, et al. expression of l-type amino acid transporter 1 is a predictive biomarker of intravesical recurrence in patients with non-muscle invasive bladder cancer. res rep urol. 2021; 13:603-611. 15. eau guidelines 2022 on urological infections. edn. presented at the eau annual congress amsterdam, the netherlands 2022. isbn 97894-92671-16-5. 16. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72. 17. botteman mf, pashos cl, redaelli a, et al. the health economics of bladder cancer: a comprehensive review of the published literature. pharmacoeconomics. 2003; 21:1315-30. 18. meeks jj, herr hw. office-based management of nonmuscle invasive bladder cancer. urol clin north am. 2013; 40:473-9. 19. o'neil bb, lowrance wt. office-based bladder tumor fulguration and surveillance: indications and techniques. urol clin north am. 2013; 40:175-82. 20. donat sm, north a, dalbagni g, herr hw. efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. j urol. 2004; 171:636-9. 21. pedersen gl, erikson ms, mogensen k, et al. outpatient photodynamic diagnosis-guided laser destruction of bladder tumors is as good as conventional inpatient photodynamic diagnosis-guided transurethral tumor resection in patients with recurrent intermediate-risk lowgrade ta bladder tumors. a prospective randomized noninferiority clinical trial. eur urol. 2022:s0302-2838(22)02564-7. correspondence rosario leonardi, md (corresponding author) leonardi.r@tiscali.it musumeci gecas clinic, v.le dell'autonomia, 57, 95030 gravina di catania (ct) (italy) francesco vecco, md francesco.vecco@gmail.com irccs ospedale policlinico san martino, genova (italy) gabriele iacona, md gabryiac@yahoo.it musumeci gecas clinic, gravina di catania (ct)(italy) alessandro calarco, md alecalarco@gmail.com department of urology, "cristo re" hospital, rome (italy) guglielmo mantica, md guglielmo.mantica@gmail.com irccs ospedale policlinico san martino, genova (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 18 original paper 179.000 people annually (1). this phenomenon reflects the development of advanced diagnostic imaging, which determines a greater detection rate. in a retrospective study involving 3001 consecutively registered asymptomatic adults, a renal mass of at least 1 cm occurred in nearly 15% of examinations (2). currently, there is an increased number of diagnoses of small renal masses (srm), which consists of cystic or solid lesion measuring < 4 cm on cross-sectional imaging and with features suspicious of a ct1a rcc (3). nowadays, several therapeutic options may be offered, in particular nephron-sparing surgery (nss) is preferable to radical nephrectomy for tumors up to ct1b stage due to the preservation of renal function (4, 5). furthermore, partial nephrectomy is associated with a decrease in cardiovascular events and overall mortality (6). cryoablation is a valid option in patients with several comorbidities and low life expectancy, due to minimum effect on renal function and low post-procedure complication rate, despite the high treatment failure rates (7). alternatively, active surveillance has demonstrated cancer-specific survival similar to primary intervention for patients with srm (8). the most appropriate treatment decision for the patient is based first on the patient's general condition (including comorbidities, renal function, and life expectancy) and the nature of the renal tumor. however, traditional diagnostic imaging provides data on mass characteristics, but it cannot determine whether the lesion is benign or malignant yet. there is evidence that dynamic magnetic resonance imaging may differentiate tumor subtypes (9), but tumor aggressiveness cannot be defined. for the latter, the details from ultrasound-guided renal mass biopsy (rmb) are crucial. this procedure plays a key role in approximately 60% of patients (10), guiding them toward the most appropriate therapy, whether medical or surgical. this study aimed to describe our experience with rmb, evaluating its safety and feasibility. materials and methods an institutional retrospective review was conducted with data analysis of 80 patients with suspected primary or secondary kidney tumors who underwent rmb between january 2012 and december 2020. twelve cases were introduction: ultrasound-guided renal masses biopsy (rmb) is a useful and underestimated tool to evaluate suspected renal tumors. this study aimed to assess the safety and feasibility of this technique. materials and methods: data of 80 patients with suspected primary or secondary kidney tumors who underwent rmb between january 2012 and december 2020 were included in this retrospective study. twelve patients were excluded due to incomplete data. biopsy outcomes were collected through our electronic medical records system and then compared with definitive pathology. results: rmb was performed in 68 cases. pathological examination reported 43 (63%) malignant cases, while rmb was negative in 15 (22%) samples. on the other hand, a benign lesion was present in 8 (12%) cases, and 2 (3%) biopsies were non diagnostic. one major and one minor post-procedure complication were reported among the patients. a total of 31 patients underwent renal surgery including 19 partial and 12 radical nephrectomies. out of them, 4 patients had a negative biopsy, but radiological imaging strongly suggested malignancy. the concordance between biopsy and definitive pathology occurred in 22 out of 31 (71%) cases, with a higher rate among the masses greater than 4 cm, 9/11 (82%) compared to smaller ones 13/20 (65%). pathologic examination of the 4 cases with negative biopsy showed 3 renal cell and a translocation renal cell carcinoma. conclusions: ultrasound-guided biopsy for renal masses is a safe and effective procedure. its ability to identify malignancy is evident, especially for primary renal tumors. however, low concordance between biopsy and definitive pathology in cases with negative biopsies, especially for tumors < 4 cm, does not reliably guarantee the absence of tumor and, therefore, strict follow-up or repeat biopsy may be indicated. key words: kidney tumors; renal masses biopsy; ultrasound; small renal mass; nephron-sparing surgery; active surveillance. submitted 26 december 2022; accepted 20 march 2023 introduction since the past few decades, the incidence of clear cell renal cell carcinoma has dramatically increased, and currently counts approximately 431.000 new cases per year worldwide (1). furthermore, it is the cause of death of over the use of renal biopsy in the kidney tumor management: a retrospective analysis of consecutive cases in a referral center andrea benedetto galosi 1, marco macchini 2, roberto candelari 2, virgilio de stefano 1, silvia stramucci 1, vanessa cammarata 1, omar al ayoubi 1, andrea cicconofri 1, carlo giulioni 1 1 department of urology, polytechnic university of marche, azienda ospedaliera universitaria della marche, ancona, italy; 2 interventional radiology, department of radiology, azienda ospedaliera universitaria della marche, ancona, italy. doi: 10.4081/aiua.2023.11115 summary archivio italiano di urologia e andrologia 2023; 95, 2 a.b. galosi, m. macchini, r. candelari, et al. 19 excluded due to the lack of complete data in the database. all patients had previously performed a contrastenhanced computed tomography (ct) scan of the abdomen, which allowed for tumor characteristics evaluation (figure 1a). renal biopsy was indicated in the following cases: patients with various comorbidities in whom surgery is planned, patients with imaging findings suggestive of unresectable renal cancer, suspected metastasis in the kidney, and indeterminate cystic renal mass. two experienced radiologists performed all the rmb guided by ultrasound machine logiq s8 xdclear (ge healthcare®, chalfont st giles, uk) after the analysis of contrast-enhanced ct imaging. specimens were obtained through an automated biopsy gun with an 18-gauge needle (figure 1b). one to four cores were collected per biopsy, giving an average of two. patients’ characteristics, including age, gender, body mass index (bmi), skin-to tumor distance and thickness of subcutaneous fat, were calculated through the radiology. moreover, several radiological tumor characteristics were evaluated, such as size, location, endophyticity, cortical location and cystic component. all data regarding post-procedure complications following primary intervention were reported and ranked according to clavien-dindo (cd) classification (11) as collected through our electronic medical records system. qualitative variables were described using absolute frequencies and percentages. quantitative variables were described using the median and interquartile ranges. ibm spss (v26) was used as statistical software. results the median age of the patients was 71 years (36-85), and the median bmi was 27.5, as shown in table 1. median core needle samples per biopsy were 2. tumor characteristics were reported in table 2. forty-four cases had an srm (< 4 cm), and 24 had masses ≥ 4 cm. rmb in our series was performed in 68 cases. the histological outcomes of all the biopsies are listed in table 3. the biopsy outcome was malignancy in 43 (63%) cases, and the renal cell carcinoma (rcc) was the most frequent tumor; 15 biopsies were negative, a benign lesion was present in 8 (12%) cases, and 2 (3%) biopsies were non diagnostic. two patients experienced complications after the biopsy procedure: 1 case of a subcapsular renal haematoma that table 1. patients and samples characteristics. no. (%) median (range) age, years 71 (36-85) gender male 49 (72%) female 19 (28%) patient bmi 27.5 (18.6-44.2) < 30 46 (68%) ≥ 30 22 (32%) core needle samples, n 2 (1-4) skin-to-tumor distance, cm 5.8 (15-120) < 7 cm 43 (63%) ≥ 7 cm 25 (37%) thickness of subcutaneous fat, cm 1.9 (2 -54) < 3 cm 50 (74%) ≥ 3 cm 18 (26%) figure 1. (a) an axial ct image of a left superior mesopolar renal mass. (b) an ultrasound image of the renal mass biopsy with the needle guide. table 2. tumor characteristics. no. (%) side left 25 (37) right 43 (63) tumor size < 4 cm 44 (65) ≥ 4 cm 24 (35) mass location mesorenal 22 (32) upper pole 26 (38) lower pole 18 (27) renal pedicle 2 (3) cortical location anterior cortex 18 (27) posterior cortex 32 (47) neither 18 (27) endophytic vs. exophytic completely endophytic 10 (15) < 50% exophytic 29 (43) ≥ 50% exophytic 29 (43) cystic vs. solid cystic component ≥ 50% 5 (7) cystic component < 50% 10 (15) no cystic component 53 (78) archivio italiano di urologia e andrologia 2023; 95, 2 20 safety and feasibility of us guided renal mass biopsy not required treatment (cd 1), and 1 case of renal bleeding, who required super-selective embolization (cd 3), occurred. table 4 reported the treatment offered to the patients. chemoor immunotherapy was proposed to the seven patients with locally advanced disease or primary tumor in another location. active surveillance was offered to the 8 cases of oncocytoma, while 3 cases of watchful waiting occurred. as shown in table 5, the overall concordance between rmb and definitive pathology was 22/31, with a higher rate for masses greater than 4 cm. ultrasound-guided biopsy demonstrated its reliability in diagnosing rcc, both for small and large masses. tumor subtype was confirmed by definitive pathology in 82% of cases (22/27). however, in two cases of unspecified carcinoma, after excision, one had a histological outcome of skeletal muscle metastases and the other urothelial cell carcinoma. four patients with negative biopsies underwent surgery because of highly suspicious lesions for tumor on radiological imaging. biopsies reported only necrosis in two of them and solid component of a cystic lesion in the other two. the final diagnosis was rcc in three patients and translocation renal cell carcinoma in one. in summary, the overall sensibility was 71%, with a higher value for masses greater than 4 cm than the smaller ones (82% vs 65%, respectively). furthermore, the positive predictive value was 96%. discussion according to eau guidelines, surgery is the first-line choice therapy for patients with a localized renal mass, preferring, whenever feasible, the nss to radical nephrectomy (12). nowadays, there is a trend toward a conservative approach for renal surgery also for increasingly challenging cases. in a multicenter study involving 410 patients with high complexity masses, partial nephrectomy showed satisfactory long-term oncological and functional outcomes despite an acceptable rate of perioperative complications (13, 14). however, 20-50% of the definitive pathologies of this surgery find benign tumors, which might be managed by active surveillance (15). on the other hand, a multidisciplinary strategy is necessary for metastatic diseases or locally advanced renal cancer, which provides a palliative cytoreductive nephrectomy and systemic treatments (12). moreover, micrornas were proposed as a non-invasive biomarker for various roles in rcc management, although no definitive conclusions emerged from the literature (16). therefore, a histological diagnosis is essential to guide the best therapeutic management. although ultrasound-guided biopsy may have other hints, as in glomerulonephritis, its more frequent use is in the field of oncology. rmb indication occurs in several cases, such as the diagnosis of tumor metastasis, unresectable renal cancer, indeterminate cystic or multiple renal mass, and in patients not fit for surgery (17). the biopsy was proposed for srm, although an inverse relationship was reported between tumor size and its risk of malignancy (18). ultrasound-guided biopsy showed good accuracy in defining the nature of the renal tumor. in our series, a concordance of tumor malignancy between biopsy and definitive pathology always table 4. therapeutic management. no. (%) < 4 cm ≥ 4 cm nephron sparing surgery (nss) rcc 9 (13) 8 1 others 10 (15) 7 3 radical nephrectomy rcc 8 (12) 2 6 others 4 (6) 3 1 active surveillance rcc 1 (1) 1 0 oncocytoma 8 (12) 6 2 others 2 (3) 2 0 oncologic treatment (chemo or immunoterapy) rcc 2 (3) 0 2 others 5 (7) 2 3 watchful waiting rcc 1 (1) 0 1 others 2 (3) 1 1 patients lost during follow-up 16 (24) 12 4 rcc 2 (3) 1 1 others 14 (21) 11 3 rcc: renal cell carcinoma. table 5. concordance between biopsy and definitive pathology. concordance with concordance with concordance with definitive pathology definitive pathology definitive pathology in all masses in masses < 4 cm in masses ≥ 4 cm overall, n (%) 22/31 (71) 13/20 (65) 9/11 (82) rcc, n (%) 22/23 (96) 13/14 (93) 9/9 (100) unspecified carcinoma, n (%) 0/3 (0) 0/2 (0) 0/1 (0) others, n (%) 0/1 (0) 0/1 (0) 0/0 (0) negative, n (%) 0/4 (0) 0/3 (0) 0/1 (0) rcc: renal cell carcinoma. table 3. histological outcomes of diagnostic biopsies. histological subtype at rmb no. (%) clear cell rcc 21 (29) papillary rcc 9 (13) oncocytoma 8 (12) unspecified carcinoma 3 (4) oncocytic rcc 2 (3) lymphoma 3 (4) urothelial carcinoma 1 (1) skeletal muscle cancer (metastasis) 1 (1) collecting (bellini) duct carcinoma 1 (1) translocation renal cell carcinoma 1 (1) lung cancer (metastasis) 1 (1) non diagnostic 2 (3) negative 15 (22) rmb: renal mass biopsy; rcc: renal cell carcinoma. archivio italiano di urologia e andrologia 2023; 95, 2 a.b. galosi, m. macchini, r. candelari, et al. 21 occurred. moreover, the concordance of rcc between rmb and definitive pathology was 96%. in a large metaanalysis involving 5228 patients, its sensitivity and specificity were 99.1% and 99.7%, respectively (19). furthermore, the authors showed a concordance rate between tumor histotype on biopsy and surgical specimen of 90.3%, while concordance rates of tumor grade ranged from 43% to 93%. the last data raises several doubts about biopsies, especially for smr. similarly, pierorazio et al. reported high percentages in terms of sensitivity and specificity, while the negative predictive value was 68.5% and non-diagnostic rates ranged from 0% to 22.6% for masses less than 4 cm (20). in the same way, in the present study, the concordance rate between biopsy and definitive pathology of all srm dropped up to 65%. the most critical aspect that emerged from our analysis is the specificity of rmb. indeed, there was low concordance between biopsy and definitive pathology for negative or unspecified carcinoma diagnoses in our results. abel et al. reported that when carrying out a biopsy of a metastatic lesion or primary tumor, as opposed to nephrectomy specimen examination, it is likely that only one subpopulation of cells is sampled, and prognostic information is based on only one subpopulation of cells (21). therefore, high false-negative rates raise concerns about the reliability of the procedure. however, rmb may be repeated on all patients with unspecified masses or non-diagnostic cases to increase the diagnostic rate (22). furthermore, renal biopsy is not without complications, due to the procedure invasiveness, especially bleeding, although they are considered rare events. according to lane et al., minor and major complications after rmb are, respectively, less than 5% and 1% (23). of these, the most common is undoubtedly bleeding, which often tends to present subclinically and requires transfusion in about 1.5% of cases (24). indeed, both post-procedure complications were related to haemorrhage in the present study. another frequent complication is the intrarenal arteriovenous fistulae occurred. according to rollino et al., the development of this clinical condition has an incidence of up to 5% when colour-coded doppler sonography is used (25). however, no case was reported in our analysis. the limitations of the present study are evident. first, it is a retrospective study and biases linked to its nature are predictable. second, the pathological specimens were not reviewed independently for the current study. moreover, a considerable number of subjects dropped out from our analysis: in fact our radiology department also accepts patients referred from other hospitals and, therefore, a loss of some of them in the follow-up is inevitable. at last, a relatively small sample size is involved in this analysis, not allowing to obtain definitive data. conclusions ultrasound-guided biopsy for renal masses demonstrated satisfactory ability to distinguish benign and malignant tumors. concordance between biopsy and definitive pathology was high for rcc, particularly for masses greater than 4 cm. however, the low concordance in the negative biopsies, especially for tumors < 4 cm, may require a second biopsy. in any case, the procedure proved to be safe and effective in referring patients to the most appropriate therapeutic management. considering the low prevalence of this procedure in routine clinical practice, its use is recommended whenever an indication occurs. references 1. global cancer observatory. international agency for research on cancer. world health organization. 2. o'connor sd, pickhardt pj, kim dh, et al. incidental finding of renal masses at unenhanced ct: prevalence and analysis of features for guiding management. ajr am j roentgenol. 2011; 197:139-45. 3. finelli a, ismaila n, bro b, et al. management of small renal masses: american society of clinical oncology clinical practice guideline. j clin oncol. 2017; 35:668-680. 4. dell'atti l, scarcella s, manno s, et al. approach for renal tumors with low nephrometry score through unclamped sutureless laparoscopic enucleation technique: functional and oncologic outcomes. clin genitourin cancer. 2018; 16:e1251-e1256. 5. giulioni c, di biase m, marconi a, et al. clampless laparoscopic tumor enucleation for exophytic masses greater than 4 cm: is renorrhaphy necessary? j laparoendosc adv surg tech a. 2022; 32:931-937. 6. huang wc, elkin eb, levey as, et al. partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes? j urol. 2009; 181:55-61. 7. zargar h, atwell td, cadeddu ja, et al. cryoablation for small renal masses: selection criteria, complications, and functional and oncologic results. eur urol. 2016; 69:116-28. 8. pierorazio pm, johnson mh, ball mw, et al. five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the dissrm registry. eur urol. 2015; 68:408-15. 9. sun mr, ngo l, genega em, et al. renal cell carcinoma: dynamic contrast-enhanced mr imaging for differentiation of tumor subtypes--correlation with pathologic findings. radiology. 2009; 250:793-802. 10. maturen ke, nghiem hv, caoili em, et al. renal mass core biopsy: accuracy and impact on clinical management. ajr am j roentgenol. 2007; 188:563-70. 11. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-196. 12. b. ljungberg (chair), l. albiges, j. bedke, et al. volpe guidelines on prostate cancer. edn. presented at the eau annual congress milan 2021. 978-94-92671-13-4. eau guidelines office, arnhem, netherlands. 13. sciorio c, prontera pp, scuzzarella s, et al. predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy. arch ital urol androl. 2020; 92:165. 14. mari a, tellini r, porpiglia f, et al. perioperative and mid-term oncological and functional outcomes after partial nephrectomy for complex (padua score ≥10) renal tumors: a prospective multicenter observational study (the record2 project). eur urol focus. 2021; 7:1371-1379. 15. russo p, uzzo rg, lowrance wt, et al. incidence of benign versus malignant renal tumors in selected studies. j. clin. oncol. 2012; 30, 92. archivio italiano di urologia e andrologia 2023; 95, 2 22 safety and feasibility of us guided renal mass biopsy 16. napolitano l, orecchia l, giulioni c, et al. the role of mirna in the management of localized and advanced renal masses, a narrative review of the literature. applied sciences. 2023; 13:275. 17. sahni va, silverman sg. biopsy of renal masses: when and why. cancer imaging. 2009; 6; 9:44-55. 18. frank i, blute ml, cheville jc, et al. solid renal tumors: an analysis of pathological features related to tumor size. j urol. 2003; 170:2217-20. 19. marconi l, dabestani s, lam tb, et al. systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. eur urol. 2016; 69:660-673. 20. pierorazio pm, johnson mh, patel hd, et al. management of renal masses and localized renal cancer: systematic review and meta-analysis. j urol. 2016; 196:989-99. 21. abel ej, carrasco a, culp sh, et al. limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases. bju int. 2012; 110:1742-6. 22. lim a, o'neil b, heilbrun me, et al. the contemporary role of renal mass biopsy in the management of small renal tumors. front oncol. 2012; 2:106. 23. lane br, samplaski mk, herts br, et al. renal mass biopsy--a renaissance? j urol. 2008; 179:20-7. 24. tang s, li jh, lui sl, et al. free-hand, ultrasound-guided percutaneous renal biopsy: experience from a single operator. eur j radiol. 2002; 41:65-9. 25. rollino c, garofalo g, roccatello d, et al. colour-coded doppler sonography in monitoring native kidney biopsies. nephrol dial transplant 1994; 9:1260-3. correspondence andrea bendetto galosi, md andreabenedettogalosi@ospedaliriuniti.marche.it virgilio de stefano, md virgilio.destefano@gmail.com silvia stramucci, md silvia.stramucci@gmail.com vanessa cammarata vanessa.cammarata@gmail.com omar al ayoubi, md omar.alayoubi@gmail.com andrea cicconofri, md andrea.cicconofri@gmail.com carlo giulioni, md (corresponding author) carlo.giulioni9@gmail.com department of urology, polytechnic university of marche azienda ospedaliero universitaria delle marche 71 conca street, 60126 ancona (italy) marco macchini, md marco.macchini@ospedaliriuniti.marche.it roberto candelari, md roberto.candelari@ospedaliriuniti.marche.it interventional radiology, department of radiology, azienda ospedaliera universitaria della marche, ancona (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12113 1 systematic review long-term side effects, such as impact to the blood vessels, heart, lungs, kidneys, and brain. also it was just discovered to have an effect on human testes, interfering with the production of vital male hormones such as testosterone (2). as a result of sars-cov-2 virus infection, systemic or local cytokine synthesis has the potential to inhibit leydig cell differentiation, thereby compromising testicular cells by affecting testosterone production and the process of spermatogenesis (3). this inflammatory process was further identified in the testicles of six males who died from sarscov-2 (4). this study focused on total testosterone since it is one of the easiest and basic male sexual hormone parameters to measure with acceptable precision in most hospital laboratories. furthermore, the impact of lower testosterone is becoming an issue when there is concern regarding the long-term impact of the sars-cov-2 virus on decreased sexual desire and impaired male fertility. other characteristics, such as free testosterone, luteinizing hormone (lh), and follicle stimulating hormone (fsh), were included in the study as supporting data to better understand the pattern of male sexual hormone alterations. there is still no consensus or global agreement regarding the management of sexual and hormonal disorders after covid-19 infection. therefore, researchers are interested in providing scientific evidence through a systematic review and meta-analysis focusing on the effects of sarscov-2 virus infection on male sexual hormonal abnormalities in patients after exposure to covid-19. materials and methods protocol registration the protocol of this systematic review and meta-analysis is registered at prospero (crd42023445406) search strategy and study selection this meta-analysis was made in accordance with the preferred reporting items for systematic reviews and metaanalyses (prisma) guidelines (5). the review topic was determined based on population, intervention, comparison, outcome (pico) methods. the population was male over 18 years old without country or race restrictions. the introduction: the covid-19 can affect human testicles, thus will interfere the production of important male sexual hormone such as testosterone. our study provides scientific evidence through systematic reviews and meta-analyses that focus on the effects of sarscov-2 virus infection on male sexual hormonal disorders in patients post-exposure to covid-19. methods: this meta-analysis was made in accordance with the prisma guidelines. the outcomes of this study were the level of total testosterone, free testosterone, lh and fsh. chi-square and i2 tests were used to evaluate heterogeneity between studies. the standardized mean deviation (smd) with 95% ci were used and analysis was performed using the review manager 5.4 software. results: the four included studies reported a total of 256 patients with covid-19 with time of follow-up time post covid-19 varying from one month to 7 months. the mean age distribution in the study was 34-57 years old. total testosterone level (smd = -158.71; 95% ci= -205.30 – -112.12; p < 0.00001) was significantly higher at follow-up post covid-19, while lh (smd = 0.40; 95% ci = 0.15-0.65; p = 0.002) was lower. the free testosterone level and fsh level showed no significant difference between baseline and after following up post covid-19. conclusions: at follow up, the total testosterone level in patients with sars-cov-2 infection appeared to be elevated while lh was lower compared to the baseline. key words: covid-19; male sexual hormones; total testosterone; free testosterone; luteinizing hormone; follicle stimulating hormone. submitted 21 november 2023; accepted 5 december 2023 introduction coronavirus disease, known as covid-19, is an acute respiratory syndrome caused by coronavirus type-2 or sars-cov-2. as of 2021, there have been approximately 200 million covid-19 infections worldwide, resulting in more than 4 million deaths (1). although many people with covid-19 infection are asymptomatic or have very mild symptoms, a small number of patients develop severe symptoms and potentially long-term consequences. covid-19 has been linked to more than 50 effect of sars-cov-2 viral infection on male sexual hormones levels post covid-19 exposure: a systematic review and meta-analysis anak agung patriana puspaningrat 1, 2, lukman hakim 1, 3, johan renaldo 1, 3 1 department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia; 3 universitas airlangga teaching hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2024.12113 summary archivio italiano di urologia e andrologia 2024; 96(1):12113 a. agung patriana puspaningrat, l. hakim, j. renaldo 2 intervention was condition on when admitted for covid-19 (baseline). the comparison was condition on follow up after covid. the outcomes were total testosterone levels, free testosterone, lh and fsh. the inclusion criteria for studies were: (1). observational study, (2). studies that report the level of total testosterone and at least one of free testosterone, lh, and fsh level at baseline and follow up in patients with sars cov-2. studies that were case reports, conference abstracts, reviews, editorials letters, not available in full text as well as non-english studies were omitted. the systematic search was carried out across pubmed, scopus, sciencedirect, web of science, and grey literature. the keywords used to search are “covid”, “sars-cov-2”, “covid-19”, “corona virus”, “testosterone level”, “androgen”, “fsh”, “follicle stimulating hormone”, “lh”, “luteinizing hormone”, “free testosterone”. quality assessment and data extraction two authors worked independently to extract data by filling out tabulation templates that had been produced in advance of time. when there are disputes during data extraction, the ultimate choice will be discussed with the senior author. the data obtained comprises study characteristics (first author's name, year of publication, sample size, study design, range data collection), and basic characteristics of the research sample (age, severity of covid, follow-up range, laboratory outcome, and sexual function outcome). the risk of bias was determined using the newcastle ottawa scale (nos), with a score of 7-9 indicating a low risk of bias, 4-6 suggesting a high risk of bias, and 0-3 indicating a very high risk of bias. statistical analysis data analysis was performed using the review manager 5.4 software. the outcomes of this study were the level of total testosterone, free testosterone, lh and fsh. chisquare and i2 tests were used to evaluate heterogeneity between studies. the random-effects model analysis was applied if the heterogeneity test was high (i2 test > 50% and chi-square p < 0.05). if the heterogeneity test was low (i2 < 50%, chi-square p > 0.05), the fixed-effect model analysis was used. the pooled standardized mean and deviation (smd) with 95% ci were used to perform the analysis on continuous data i.e., testosterone level, free testosterone, lh and fsh. if there is median (iqr) or median (range) data, it will be converted to mean ± sd with median (range) using scenario 1 and median (iqr) using scenario 2 from the following online calculator https://www.math.hkbu.edu.hk/ ~tongt/papers/median2mean.html. studies featuring mean ± sd data that have been stratified by covid-19 severity will be combined with the following online calculator https://www.statstodo.com/ combinemeanssds.php. the results are significant when the p value < 0.05. results the results of a systematic search for studies using predetermined keywords identified a total of 606 studies in five databases, namely pubmed/medline, scopus, sciencedirect, web of science, and grey literature. the number of studies found in each database can be seen in figure 1. all these studies were then checked for duplication, resulting in 287 duplicate studies. selection was then carried out on 319 studies by reading titles and abstracts, as many as 15 articles that met the criteria and selection continued by reading the full text. the result obtained four studies that met the inclusion criteria and were included in the systematic review of meta-analysis. the four cohort studies revealed a total of 356 covid-19 patients (6-9). these studies are carried out in a variety of nations, including italy, turkey, russia, and iran. the first study was conducted in february 2020. at the time of the study, figure 1. prisma diagram of the study search and selection process. archivio italiano di urologia e andrologia 2024; 96(1):12113 3 sars-cov-2 on male sexual hormones participants ranged in age from 34 to 57 years old. the reported follow-up time spans from one month to seven months. tables 1 and 2 indicate the features of the studies. newcastle ottawa scale was used to measure the quality of the studies. table 3 shows the quality assessment results, which found three studies with a total score of 8 and one studies with a total score of 7 that were considered to have low risk of bias. mean total testosterone level analysis of four studies reporting testosterone level on covid-19 showed a significant difference between total testosterone level on baseline and after following up (pooled smd = -158.71; 95% ci = -205.30 -112.12; p < 0.00001) (6-9). the total testosterone level appears to be lower at baseline. the forest plot for total testosterone level is provided in figure 2. mean free testosterone level analysis of two studies reporting free testosterone level on table 3. quality assessment of the study new ottawa-scale (nos). author (year) study design selection comparability outcome total salonia et al., 2022 cohort *** ** *** 8 enikeev et al., 2022 cohort *** ** *** 8 apaydin et al., 2022 cohort *** ** *** 8 afshari et al., 2022 cohort *** ** ** 7 figure 2. forest plot of mean total testosterone level. table 1. basic characteristics of the study. no. author (year) data country design n covid follow-up age (years) laboratory sexual function collection severity mean ± sd outcome outcome 1. salonia et al. (2022) (6) february 29 may 2, 2020 italy cohort 121 nr 7 months 57 ± 12 wbc, neutrophils, lymphocytes, nlr, nr creatinine, crp, il-6, fsh, lh, tt 2. apaydin et al. (2022) (7) april october 2020 turkey cohort 29 nr 6 months 43.3 ± 28.6 fsh, lh, tt, ft, bioavailable testosterone, nr shbg, lymphocyte, thrombocyte, creatinine, alt, kdh, ferritin, d-dimer 3. enikeev et al. (2022) (8) nr russia prospective 44 nr 3 months 46.7±9.9 testosterone, prolactin, lh, fsh iief-5 4. afshari et al. (2022) (9) july 2020 february 2021 iran prospective 162 severe, moderate 1 month 39.88 ± 7.04 lh, fsh, tt, ft nr total sample size 356 nr: not reported; tt: total testosterone; ft: free testosterone; wbc: white blood cell; nlr: neutrophil lymphocyte ratio; shbg: sex hormone binding globulin; alt: alanine aminotransferase; ldh: lactate dehydrogenase; il-6: interleukin-6; crp: c-reactive protein; iief-5: the international index of erectile function 5. table 2. characteristic of study outcomes. no. author (year) data group n total testosterone free testosterone lh fsh iief collection (ng/dl) (ng/dl) (miu/l) (miu/l) 1. salonia et al. (2022) (6) february 29 may 2, 2020 baseline 121 86 ± 76 nr 5 ± 2.1 6.01 ± 3.37 nr follow-up 7 months 121 289.28 ± 144.21 nr 4.3 ± 2.25 8.2 ± 3.9 nr 2. apaydin et al. (2022) (7) april october 2020 baseline 29 273.25 ± 175.8 7.74 ± 5.32 9.06 ± 7.77 9.06 ± 7.77 nr follow-up 6 months 29 349.5 ± 164.5 7.18 ± 2.8 11.1 ± 14.6 5.01 ± 2.44 nr 3. enikeev et al. (2022) (8) nr baseline 44 210.54 ± 77.87 nr 3.3 ± 0.5 5.1 ± 1.11 20.7 ± 5.3 follow-up 3 months 37 395.13 ± 129.84 nr 2.975 ± 0.76 5.05 ± 1.32 23.1 ± 4.3 4. afshari et al. (2022) (9) july 2020 february 2021 baseline 162 124 ± 84 5.14 ± 2.94 7.02 ± 4.83 4.08 ± 2.16 nr follow-up 1 month 69 259 ± 111 4.76 ± 2.19 6.55 ± 5.48 5.89 ± 3.4 nr total sample size baseline 356 follow-up 256 nr: not reported. archivio italiano di urologia e andrologia 2024; 96(1):12113 a. agung patriana puspaningrat, l. hakim, j. renaldo 4 covid-19 showed no significant difference between free testosterone level on baseline and after following up (pooled smd = 0.40; 95% ci = -0.26-1.05; p = 0.24) (7, 9). the forest plot for testosterone level is provided in figure 3. mean luteinizing hormone level analysis of four studies reporting lh level on covid-19 showed a significant difference between lh level on baseline and after following up (pooled smd = 0.40; 95% ci = 0.15-0.65; p = 0.002) (6-9). the forest plot for lh level is provided in figure 4. mean follicle stimulating hormone level analysis of four studies reporting fsh level on covid19 showed no significant difference between fsh level on baseline and after following up (pooled smd: -0.49; 95% ci = -2.10-1.12; p = 0.55) (6-9). the forest plot for lh level is provided in figure 5. discussion this study is the first systematic review and meta-analysis to compare male sexual hormone levels in patients with covid-19 when the sars-cov-19 virus was first detected and at follow-up after a negative covid-19 pcr swab. four studies were meta-analyzed with a total baseline sample of 356 patients and 256 patients at follow-up with reported follow-up times ranged from 1 month to 7 months. the parameters studied were total testosterone, free testosterone, luteinizing hormone (lh), and follicle stimulating hormone (fsh) levels as mean ± sd. ace-2 receptors are abundant in testicular tissue. as a result, it is hypothesized that sars-cov-2 infection may cause testicular tissue injury, which may lead to impaired sexual function and fertility in men. the primary endpoint of this study is the change in total testosterone because it is one of the easiest and simplest male sexual hormone parameter measured with good accuracy in most hospital laboratories. furthermore, the impact of lower testosterone is concerning given the long-term impact of the sars-cov-2 virus on decreased libido levels and impaired male fertility. changes in free testosterone levels, luteinizing hormone (lh) levels, and follicle stimulating hormone (fsh) levels were secondary outcomes of this study. the resulting decrease in testosterone levels may lead to dysregulation of gnrh production in the hypothalamus followed by abnormal secretion of lh and fsh from the pituitary. these results indicate figure 3. forest plot of mean free testosterone level. figure 4. forest plot of mean luteinizing hormone level. figure 5. forest plot of mean follicle stimulating hormone level. archivio italiano di urologia e andrologia 2024; 96(1):12113 5 sars-cov-2 on male sexual hormones a decrease in peripheral organ function and a compensatory increase in central function (29). total testosterone the four studies meta-analyzed in this study showed significant differences in total testosterone levels between baseline and follow-up. at follow up, total testosterone levels in individuals with sars-cov-2 infection appeared to be higher in relation to the baseline. this study also found that the testosterone levels of patients who served as baseline data in this study were below the normal range. most (95%) testosterone is produced in the leydig cells of the testes depending on stimulation by lh. only a small amount (5%) is produced in the adrenal glands. low testosterone levels can originate from the testes (primary hypogonadism), hypothalamuspituitary (secondary hypogonadism), or a combination of both, which is mostly found in the aging male population as late onset hypogonadism (30). in patients with covid19, the increase in gonadotropin concentration as a form of central function compensation may be insufficient because sars-cov-2 virus infection may also disrupt homeostatic and cause hpg axis feedback failure (29). the influence of testosterone levels in men on covid-19 prognosis is currently the focus of attention in several research literatures. suppressive effects on the gonadal axis through inflammatory mediators, decreased testicular response to gonadotropins, and increased metabolic clearance rate of testosterone have been described as potential causes of lower testosterone concentrations during acute illness due to the sars-cov-2 virus (31). total testosterone levels can be a prognostic factor of disease severity as low testosterone levels are associated with a high risk of intensive care unit admission and death (10). when there is a decrease in total testosterone levels, the probability of death increases significantly (11). the more severe the comorbidities at the time of treatment, the less likely testosterone levels are to improve over time. in general, testosterone has immunosuppressive effects. testosterone activates cd8 cells and increases t-helper 1 responses while decreasing natural killer cell responses by decreasing tnf-α and increasing anti-inflammatory il-10 production (13). therefore, a poor prognosis in covid19 patients with low testosterone is predictable. however, the salar et al. study found no significant difference between testosterone levels before the disease in the mild and moderate covid-19 groups. possible reasons for this are that severe symptomatic cases were previously excluded and the low number of patients in the study (12). the gradual recovery of total testosterone levels also indicated progressive recovery from the severe multisystemic symptoms associated with covid-19 (10). the study by xu h et al. also found improvements in testosterone levels that can even reach the normal range during recovery from covid-19 (14). the recovery of physiological testosterone levels can occur as lymphocyte and neutrophil homeostasis returns, this is also related to old age factors, with or without comorbidities that may affect the ability of some covid-19 patients to restore testosterone production (13). thus, the discovery of an upward trend in testosterone levels at follow-up suggests the effect of this decrease in testosterone levels is reversible. free testosterone the meta-analysis of the two studies in this study did not find any significant changes in baseline and follow-up free testosterone levels. this could be due to the number of studies that could be meta-analyzed only 2 studies with a small sample size and did not include all degrees of covid-19. free testosterone levels are decreased in covid-19 patients. some studies found a significant association between free testosterone levels and the risk of icu care or death. together with total testosterone, free testosterone levels were significantly associated with higher serum levels of ldh, ferritin, procalcitonin, as well as increased neutrophil levels and decreased lymphocyte counts. such inflammatory biomarkers are poor prognostic factors for sars-cov-2 infection (15). in the van zeggeren et al. study, free testosterone levels were significantly lower in patients with severe covid-19 and in patients who died from severe covid-19 compared to those who survived. shbg levels were also associated with the outcome of patients treated with covid-19 (16). like total circulating testosterone, free testosterone levels were significantly decreased in severe patients compared to the mild-moderate group (13). shbg levels are also associated with the outcome of patients treated with covid-19 hypoalbuminemia occurs due to increased vascular permeability and capillary leakage is common in critically ill patients and similar mechanisms can lead to low albumin, or cbg concentrations (16). in addition, serum levels of shbg, the most widely circulated testosterone-binding protein, showed a significant association with older age in mildmoderate patients, but not in severe patients (13). with age, shbg levels also increase, causing a decrease in bioavailable testosterone and free testosterone, which affects androgenic activity (20). in covid-19 patients, shbg levels were also found to be elevated (30). thus, in some cases, a decrease in testosterone levels can be caused by an increase in shbg levels. it takes a decrease in bioavailable testosterone levels or a significant increase in shbg levels to produce a significant decrease in free testosterone levels (30). luteinizing hormone and follicle stimulating hormone this meta-analysis study conducted on 4 studies found significant changes in lh levels between baseline and follow-up. there was a decrease in lh levels at follow-up. a possible mechanism is that the sars-cov-2 virus enters cells through the ace-2 receptor which is found in many testicular leydig cells that regulate testosterone through the conversion of angiotensin ii to angiotensin 1-7 increasing lh levels (7). elevated serum lh levels indicate primary hypogonadism and testicular failure, rather than secondary causes so this condition is more likely to be influenced by a severe inflammatory state (32). when the inflammatory condition improves characterized by the return of lymphocyte and neutrophil homeostasis, accompanied by the restoration of physiological testosterone levels, according to the negative feedback mechanism of the hpg axis, there will be a decrease in lh and fsh levels (13). however, fsh levels were found to be insignificant. these inconsistent results may be due to the small number of samples, the follow-up time of each archivio italiano di urologia e andrologia 2024; 96(1):12113 a. agung patriana puspaningrat, l. hakim, j. renaldo 6 study and the varying age ranges of research subjects and the varying degrees of severity of covid-19. in their study, salar et al. also found no significant difference between fsh or lh hormone levels before and after exposure to covid-19 in mild or moderate degree groups (12). this could be due to previous exclusion of cases with severe symptoms and the low number of patients in the study (12). the elevated levels of circulating lh and fsh reported in covid-19 cases may indicate transient activation of gnrh due to the initial inflammatory response (3). this compensatory process by lh against decreased testosterone levels is also significantly higher in covid-19 patients compared to healthy men (21). high luteinizing hormone indicates loss of peripheral organ function and compensatory increase in central function (19). sarscov-2 virus has been shown to alter the hypothalamicpituitary-testis axis, increasing lh and fsh levels in men by suppressing the hpg axis. according to cayan et al.'s study, blood concentrations of lh and fsh increased with the severity of covid-19. fsh levels were found to be significantly higher in the icu group compared to the asymptomatic group (11). in addition to direct damage to the testes by the virus, other factors such as fever, inflammation, and dysregulation of the hpg axis may also play a role in testosterone secretion or sperm production (19). hypothalamic and pituitary tissues also express ace-2 receptors and therefore could be targets of the sars-cov-2 virus. low testosterone with normal or low gonadotropins may be caused by the combined effects of covid-19 on the hypothalamus-pituitary-testis axis and on the testes 7, (13). in addition, emotional, physical, or psychological stress and pain associated with infection may affect the hypothalamic-pituitary axis causing abnormalities in the rhythm of lh secretion (19). covid-19 treatment medications given to covid-19 patients in the general ward or icu can alter sexual hormone levels such as corticosteroids, anticoagulant drugs, and antiviral drugs such as remdesivir (26). animal studies have found that antiviral drugs such as ribavirin (the treatment of choice for covid-19) can induce oxidative stress, lower testosterone levels, and severely impair spermatogenesis (4). a considerable decrease in sperm count was observed upon ribavirin treatment. in addition, sperm dna fragmentation was found up to 8 months even after discontinuation of such treatment. glucocorticoid treatment is also given to patients who must be admitted to the icu, potentially affecting testosterone levels (7). corticosteroid use and stress-induced hypercortisolism may have a suppressive impact on the hypothalamic-pituitary-forest plot of mean follicle stimulating hormone levelgonadal axis. corticosteroids can suppress gonadotropin-releasing hormone in the hypothalamus and may affect the action of pituitary gonadotropin on the testes (27). post covid-19 hypogonadism the results of the paoli et al. study show that overall andrological health does not appear to be compromised at 3 months after covid-19 recovery. after a full spermatogenetic cycle of 3 months there was recovery of semen parameters and sperm dna fragmentation. this suggests no significant long-term impairment and no sperm autoimmune response. likewise, the hormone profiles of total testosterone, fsh, and lh showed no relevant changes. ultrasound examination also showed no damage to the testicular parenchyma. these findings reinforce the hypothesis that once clinical recovery occurs, the sars-cov-2 virus does not appear to cause direct damage to testicular function, while the impact of indirect damage appears to be transient (28). in the study of xu et al. using more than 50 days as the cutoff for defining long-term positive cases, authors found no significant relationship between testosterone levels and the severity of covid-19. this means that although the disease course of these patients is longer, the tissues and organs, especially the testes, can still maintain normal conditions or can return to normal. this may be due to the low virulence, achieved immunity, and adequate compensatory capacity to cope with the long-term impact of the virus (14). circulating testosterone levels were also found to continue to increase over time in men recovering from covid-19. however, nearly 30% of men still showed low testosterone levels even after 12 months during the recovery period (10). based on observations, this study is the first systematic review and meta-analysis to compare male sexual hormone levels in covid-19 survivors when the sars-cov19 virus was first detected and at follow-up. this study can also be the basis for rationalizing the provision of testosterone replacement therapy in cases of acute hypogonadism which has the possibility of being reversible in male covid-19 survivors. currently, there is no direct evidence to confirm that sars-cov-2 causes testicular injury leading to hypogonadism and infertility, but the potential risk cannot be ignored. this study has several limitations. most of the studies had varying follow-up times, many patients were lost to follow-up, most studies did not include the severity of covid-19, as well as other presence of factors that may affect hormone levels, such as age, comorbidities, psychological conditions, use of medications such as antivirals, corticosteroids, and glucocorticoids. conclusions there was a significant differentiation in total testosterone levels between the initial covid-19 and the follow-up. total testosterone levels in individuals with sars-cov-2 infection appeared to be higher relative to the baseline, implying that testosterone would return once the covid-19 infection is resolved, while lh was lower during follow-up period. there was no statistically significant difference in free testosterone and fsh levels between baseline and follow-up. acknowledgements thank you to ida bagus gde tirta yoga yatindra and niwanda yogiswara for the valuable corrections and suggestions for this research. archivio italiano di urologia e andrologia 2024; 96(1):12113 7 sars-cov-2 on male sexual hormones references 1. joshee s, vatti n, chang c. long-term effects of covid-19. mayo clin proc 2022; 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abedi p, et al. effect of covid-19 infection on sex hormone levels in hospitalized patients: a prospective longitudinal study in iran. health sci rep 2023; 6:e1011. 27. aboelnaga mm, abdelrazek a, abdullah n, el shaer m. late impact of covid-19 pneumonia on testosterone levels in recovered, post-hospitalized male patients. j endocrinol metab 2021; 11:76-82. 28. paoli d, pallotti f, anzuini a. male reproductive health after 3 months from sars-cov-2 infection: a multicentric study. j endocrinol invest 2023; 46:89-101. 29. hackett g, kirby m, rees rw, et al. the british society for sexual medicine guidelines on male adult testosterone deficiency, with statements for practice. world j mens health. 2023; 41:508537. 30. schroeder m, schaumburg b, mueller z, et al. high estradiol and low testosterone levels are associated with critical illness in male but not in female covid-19 patients: a retrospective cohort study. emerg microbes infect 2021; 10:1807-18. 31. dhindsa s, zhang n, and mcphaul mj. association of circulating sex hormones with inflammation and disease severity in patients with covid-19. jama netw open 2021; 4:e2111398. 32. nassau de, best jc, kresch e, et al. impact of the sars-cov-2 virus on male reproductive health. bju int. 2022; 129:143-150. correspondence anak agung patriana puspaningrat patriana.ptty@yahoo.com department of urology, faculty of medicine, universitas airlangga, dr. soetomo general-academic hospital, surabaya, east java, indonesia lukman hakim lukman-h@fk.unair.ac.id department of urology, faculty of medicine, universitas airlangga, universitas airlangga teaching hospital, surabaya, east java, indonesia johan renaldo (corresponding author) joeurologi@gmail.com department of urology, faculty of medicine, airlangga university, soetomo general academic hospital jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14279 1 letter to editor key words: prostate cancer; pca3; psa; urinary biomarkers; new biomarkers. submitted 24 august 2025; accepted 30 august 2025 dear editor, prostate cancer (pca) remains one of the most common malignancies among men worldwide, representing a major healthcare burden both in terms of morbidity and economic cost (1-5). over the last two decades, the diagnostic pathway for prostate cancer has been substantially re-evaluated and modelled by the introduction of multiparametric magnetic resonance imaging (mpmri) and targeted biopsies (6-11). while these tools have improved the detection of clinically significant prostate cancer (cspca), they have also contributed to a considerable increase in healthcare costs and patient burden. the urologi ospedalità gestione privata (urop) scientific association strongly believes that the time has come to shift a substantial part of our research focus towards the development and validation of novel biomarkers that can more effectively stratify patients before they reach the stage of repeated imaging and invasive procedures. over the last decades, the widespread use of prostate-specific antigen (psa) as a screening tool has historically led to the overdiagnosis and overtreatment of indolent prostate cancers. in an attempt to overcome these limitations, mpmri has emerged as diagnostic tool. randomized trials and real-world data have consistently demonstrated its value in guiding biopsies and improving detection of cspca, while reducing unnecessary procedures in men with low-risk disease (12). however, the use of mpmri and fusion prostate biopsies comes at a high cost. imaging is resource-intensive, requires specialized expertise among radiologists, and in many healthcare systems is associated with long waiting lists, multiple hospital visits, and expenses also for patients. moreover, even in experienced centers, mpmri interpretation suffers from the need for novel biomarkers in prostate cancer: a urop perspective guglielmo mantica 1, stefano alba 2, andrea alfarone 3, umberto capitanio 4, donato dente 5, carlo giulioni 6, carmelo morana 7, serena maruccia 8, gabriella mirabile 9, gennaro musi 10, mauro ragonese 11, mauro silvani 12, antonio tufano 13, angelo cafarelli 6, alessandro calarco 13, ottavio de cobelli 10, ferdinando de marco 14, giovanni ferrari 15, giuseppe mario ludovico 16, stefano pecoraro 17, domenico tuzzolo 18, renzo colombo 4, nazareno suardi 19, rosario leonardi 20 on behalf of urop (urologi ospedalità gestione privata) 1 department of surgical and diagnostic integrated sciences (disc), university of genoa, genoa, italy; 2 department of urology, romolo hospital, rocca di neto (kr), italy; 3 department of urology, aurelia hospital, roma, italy; 4 division of experimental oncology/unit of urology, urological research institute (uri), irccs ospedale san raffaele, milan, italy; 5 istituto clinico città di brescia, brescia, italy; 6 urology unit, villa igea private hospital, ancona, italy; 7 department of urology, giovanni xxiii monastier hospital, treviso, italy; 8 istituti clinici zucchi, monza, italy; 9 center of minimally-invasive urology, pio xi clinic, fondazione vincenzo pansadoro, rome, italy; 10 department of urology, ieo european institute of oncology, irccs, milan, italy; 11 department of urology, policlinico universitario fondazione agostino gemelli, istituto di ricovero e cura a carattere scientifico (ircss), roma, italy; 12 department of reconstructive surgery, clinica sedes sapientiae, turin, italy; 13 urology unit, san carlo di nancy hospital, roma, italy; 14 department of urology, tiberia hospital, rome, italy; 15 department of urology, hesperia hospital, modena, italy; 16 division of urology, ente ecclesiastico ospedale generale regionale "miulli", acquaviva delle fonti (ba), italy; 17 neuromed, avellino, italy; 18 urologi ospedalità gestione privata (urop); 19 department of urology, ospedali civili of brescia, brescia, italy; 20 division of urology, school of medicine, kore university of enna, enna, italy. doi: 10.4081/aiua.2025.14279 archivio italiano di urologia e andrologia 2025; 97(3):14279 g. mantica, s. alba, a. alfarone, et al. 2 inter-reader variability, and not all men with suspicious lesions ultimately harbor significant disease. the subsequent need for targeted and systematic biopsies not only further inflates costs but also exposes patients to complications such as infection, bleeding, and urinary retention (13, 14). in the current era of medicine, this diagnostic pathway, while effective, cannot be considered sustainable in the long run without additional refinement. to address these challenges, in the same line of other cancers such bladder tumors (15), there is an urgent need for biomarkers that can better identify men truly at risk of harboring cspca before committing them to expensive imaging and invasive testing. these biomarkers should ideally improve risk stratification beyond psa and clinical parameters, be minimally invasive (preferably blood, urine, or semen-based), be able to reduce unnecessary mpmri and biopsies, thereby sparing patients from anxiety, morbidity, and repeated hospital visits. of course, be cost-effective and easy to be used in clinical practice. several promising biomarkers and genomic signatures have already been proposed both for diagnosis and targeted therapy, including prostate health index (phi), 4kscore, pca3, selectmdx, exodx, and tissue-based genomic panels, but their uptake remains limited, partly due to cost, lack of standardization, and limited integration into clinical guidelines. more importantly, many of these tests have been developed in small or highly selected populations, and their performance in real-world, diverse cohorts is not yet fully established (16-21). while these commercially available tests have demonstrated utility in refining risk assessment and guiding the decision regarding prostate biopsy, their limitations underscore the need for further progress in this field. in this regard, next-generation approaches such as non-coding rnas, circulating tumor dna (ctdna), and analysis of psa glycosylation patterns are emerging as highly promising tools. these novel biomarkers, currently still under clinical investigation, may allow a better understanding of tumor biology and hold the potential to complement or even surpass existing assays. recent reviews and translational studies have highlighted their relevance and future role in reshaping the diagnostic landscape of prostate cancer (22-25). from a health economics perspective, every unnecessary mpmri or biopsy avoided translates into significant cost savings for healthcare systems. furthermore, reducing the need for repeated hospital visits, possible complications, and invasive tests would have a profound positive impact on patients’ quality of life. anxiety, physical discomfort, and potential complications associated with biopsies are often underestimated but carry real consequences for men and their families. collaborative, multicenter, prospective validation studies are urgently needed. importantly, these studies should be designed with cost-effectiveness as a primary endpoint, ensuring that the biomarkers developed are not only clinically useful but also economically viable, both for public and private settings. another crucial element is accessibility. biomarkers should be developed ensuring they can be applied across different healthcare settings, including those with limited imaging availability. this would not only optimize resource allocation in high-income countries but also improve equity of access to early and accurate prostate cancer diagnosis worldwide. the urop hope a future in which the diagnostic pathway for prostate cancer is more personalized, efficient, and sustainable. in this vision, biomarkers serve as the first gatekeeper, filtering men who truly require advanced imaging and biopsy from those who can be safely monitored. such an approach would substantially reduce healthcare costs, minimize patient morbidity, and improve overall outcomes. urop strongly calls upon the international research community, funding bodies, and policymakers to prioritize the development of novel biomarkers for prostate cancer. the current reliance on mpmri and biopsy-heavy strategies, while valuable, may not be sustainable in the long term. innovative, accessible, and validated biomarkers represent the next frontier in prostate cancer diagnostics. investing in this direction is not only a scientific necessity but also a moral imperative, as it will ultimately reduce costs, minimize patient burden, and ensure that care is truly focused on those at greatest risk of clinically significant disease. declarations ethical approval and consent for participate: not applicable. consent for publication: not applicable. availability of data and material: not applicable. competing interests: the authors declare that they have no competing interests. funding: in case of acceptance, urop will pay the apc. authors' contributions: guglielmo mantica and rosario leonardi: ideation, paper writing and editing; all authors: revision and validation. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):14279 3 novel biomarkers in prostate cancer references 1. maclennan s, azevedo n, duncan e, et al. mapping european association of urology guideline practice across europe: an audit of androgen deprivation therapy use before prostate cancer surgery in 6598 cases in 187 hospitals across 31 european countries. eur urol. 2023; 83:393-401. 2. marchioni m, primiceri g, castellan p, et al. conservative management of urinary incontinence following robot-assisted radical prostatectomy. minerva urol nefrol. 2020; 72:555-562. 3. bauckneht m, rebuzzi se, ponzano met, al. prognostic value of the bio-ra score in metastatic castration-resistant prostate cancer 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arch ital urol androl. 2025 97:14047. 8. brant a, campi r, carrion dm, et al. findings from an international survey of urology trainee experience with prostate biopsy. bju int. 2023; 131:705-711. 9. mantica g, pacchetti a, aimar r, et al. developing a five-step training model for transperineal prostate biopsies in a naïve residents' group: a prospective observational randomised study of two different techniques. world j urol. 2019; 37:1845-1850. 10. cai w, zhu d, byanju s, et al. magnetic resonance spectroscopy imaging in diagnosis of suspicious prostate cancer: a meta-analysis. medicine (baltimore). 2019; 98:e14891. 11. nguyen t, lightfoot c, may d, et al. patient reported outcomes and treatment-associated complications as a consideration in selecting localized prostate cancer management. res rep urol. 2025; 17:195-210. 12. klotz l, chin j, black pc, et al. comparison of multiparametric magnetic resonance imaging-targeted biopsy with systematic transrectal ultrasonography biopsy for 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(pca) and a guidance in biopsy decisions. preliminary report of the urop study. arch ital urol androl. 2010; 82:5-9. 18. boehm be, york me, petrovics g, et al. biomarkers of aggressive prostate cancer at diagnosis. int j mol sci. 2023; 24:2185. 19. wagaskar vg, sobotka s, ratnani p, et al. a 4k score/mri-based nomogram for predicting prostate cancer, clinically significant prostate cancer, and unfavorable prostate cancer. cancer rep (hoboken). 2021; 4:e1357. 20. azis a, islam aa, rasyid h, et al. anti-cancer activity of ajwa dates extract (phoenix dactylifera l.) through analysis of mcl-1 levels, egfr, and p53 expressions on apoptosis in human prostate cancer cell lines pc3: an in vitro study. arch ital urol androl. 2025 aug 4:14027. 21. plas s, melchior f, aigner gp, et al. the impact of urine biomarkers for prostate cancer detection-a systematic state of the art review. crit rev oncol hematol. 2025; 210:104699. 22. farha mw, salami ss. biomarkers for prostate cancer detection and risk stratification. ther adv urol. 2022 ; 14:17562872221103988. 23. smelik m, diaz-roncero gonzalez d, an x, et al. combining spatial transcriptomics, pseudotime, and machine learning enables discovery of biomarkers for prostate cancer. cancer res. 2025; 85:2514-2526. 24. liu y, hatano k, nonomura n. liquid biomarkers in prostate cancer diagnosis: current status and emerging prospects. world j mens health. 2025; 43:8-27. 25. robinson hs, lee ss, barocas da, tosoian jj. evaluation of blood and urine based biomarkers for detection of clinically-significant prostate cancer. prostate cancer prostatic dis. 2025; 28:45-55. archivio italiano di urologia e andrologia 2025; 97(3):14279 g. mantica, s. alba, a. alfarone, et al. 4 correspondence guglielmo mantica guglielmo.mantica@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genoa, largo rosanna benzi 10, 16136, genoa, italy stefano alba stefanoalba78@gmail.com department of urology, romolo hospital, rocca di neto (kr), italy andrea alfarone alfarone2@hotmail.com department of urology, aurelia hospital, roma, italy umberto capitanio umbertocapitanio@gmail.com renzo colombo colombo.renzo@hsr.it division of experimental oncology/unit of urology, urological research institute (uri), irccs ospedale san raffaele, milan, italy donato dente donato.dente@tiscali.it istituto clinico città di brescia, brescia, italy carlo giulioni carlo.giulioni9@gmail.com angelo cafarelli info@angelocafarelli.it urology unit, villa igea private hospital, ancona, italy carmelo morana morana.carmelo@gmail.com department of urology, giovanni xxiii monastier hospital, treviso, italy serena maruccia serena.maruccia@gmail.com istituti clinici zucchi, monza, italy gabriella mirabile gabriella.mirabile@gmail.com center of minimally-invasive urology, pio xi clinic, fondazione vincenzo pansadoro, rome, italy gennaro musi gennaro.musi@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy mauro ragonese mauro.ragonese@gmail.com department of urology, policlinico universitario fondazione agostino gemelli, istituto di ricovero e cura a carattere scientifico (ircss), roma, italy mauro silvani dottorsilvani@gmail.com department of reconstructive surgery, clinica sedes sapientiae, turin, italy antonio tufano antonio.tufano91@gmail.com alessandro calarco alecalarco@gmail.com urology unit, san carlo di nancy hospital, roma, italy ottavio de cobelli ottavio.decobelli@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy ferdinando de marco ferdinandodemarco@gmail.com department of urology, tiberia hospital, rome, italy giovanni ferrari gferrari@hesperia.it department of urology, hesperia hospital, modena, italy giuseppe mario ludovico g.ludovico@miulli.it division of urology, ente ecclesiastico ospedale generale regionale "miulli", acquaviva delle fonti (ba), italy stefano pecoraro uropec@gmail.com neuromed, avellino, italy domenico tuzzolo dometuzzolo@alice.it urologi ospedalità gestione privata (urop) nazareno suardi suardi.nazareno@gmail.com department of urology, ospedali civili of brescia, brescia, italy rosario leonardi rosario.leonardi@unikore.it division of urology, school of medicine, kore university of enna, enna, italy stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4418 original paper no conflict of interest declared. direction of possible outcomes, after performing each treatment-procedure for every individual patient. the best method to accomplish the aforementioned goal, especially in urology, was the development of nomograms, which are based on conventional statistical methods (1). such statistical methods are performed on a specific dataset with the main purpose to identify potential relationships (2). these techniques are usually applied on local datasets, but to be valid, a set of assumptions should be met, which commonly are underestimated in medical literature (3). with the increase in volume and availability of data, a novel tool has emerged and has the potential to surpass all others, setting new standards in the management of patients. this novel tool is machine learning, a major artificial intelligence (ai) field, which develops models based on large volumes of data in order to detect relationships or make predictions (3). the strict assumptions, which determine statistics applicability, do not pose a limit for ai and machine learning (ml) techniques, offering the advantage of greater flexibility and access to more healthcare-related data, which commonly do not comply with these rules (3). in the past two decades, ai has been increasingly applied in everyday urological clinical practice and has shown promising results (1, 4). most of available data of ai applications in urology, deal mainly with oncologic patients and associated health issues. in benign prostatic enlargement (bpe), ai has been recently used for predicting the severity of obstruction using diagnostic tests (5, 6). torshizi et al. (6) attempted to infer symptom score and also provide a treatment suggestion for bpe, using a fuzzy-ontology system, which relies on a logic of imprecise information or variables used to make inferences (6, 7). a reported accuracy of 90%, when compared to expert opinion for making this decision, implies that ai can be helpful in benign urological conditions. back in 2001, megherbi et al. (8), evaluated four ai algorithms regarding their predictive ability of surgical treatment success for bpe, using either transurethral resection or visual laser ablation of the prostate (vlap) (8). the small number of patients, along with the vague definition of outcome, limit the applicability of these findings. objectives: artificial intelligence (ai) is increasingly used in medicine, but data on benign prostatic enlargement (bpe) management are lacking. this study aims to test the performance of several machine learning algorithms, in predicting clinical outcomes during bpe surgical management. methods: clinical data were extracted from a prospectively collected database for 153 men with bpe, treated with transurethral resection (monopolar or bipolar) or vaporization of the prostate. due to small sample size, we applied a method for increasing our dataset, synthetic minority oversampling technique (smote). the new dataset created with smote has been expanded by 453 synthetic instances, in addition to the original 153. the weka data mining software was used for constructing predictive models, while several appropriate statistical measures, like correlation coefficient (r), mean absolute error (mae), root mean-squared error (rmse), were calculated with several supervised regression algorithms techniques (linear regression, multilayer perceptron, smoreg, k-nearest neighbors, bagging, m5rules, m5p pruned model tree, and random forest). results: the baseline characteristics of patients were extracted, with age, prostate volume, method of operation, baseline qmax and baseline ipss being used as independent variables. using the random forest algorithm resulted in values of r, mae, rmse that indicate the ability of these models to better predict % qmax increase. the random forest model also demonstrated the best results in r, mae, rmse for predicting % ipss reduction. conclusions: machine learning techniques can be used for making predictions regarding clinical outcomes of surgical bpre management. wider-scale validation studies are necessary to strengthen our results in choosing the best model. key words: artificial intelligence; benign prostatic enlargement; machine learning; transurethral resection; transurethral vaporization. submitted 8 august 2021; accepted 22 september 2021 introduction the holy grail of surgery, in every surgical field, is the ability to make accurate predictions of magnitude and the use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. which model to use? panagiotis mourmouris 1, lazaros tzelves , georgios feretzakis 2, 3, dimitris kalles 2, ioannis manolitsis 1, marinos berdempes 1, ioannis varkarakis 1, andreas skolarikos 1 1 2nd department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens, greece; 2 school of science and technology, hellenic open university, 26335 patras, greece; 3 department of quality control, research and continuing education, sismanogleio general hospital, 15126 marousi, greece. doi: 10.4081/aiua.2021.4.418 summary 419archivio italiano di urologia e andrologia 2021; 93, 4 machine learning in bpe surgery several techniques exist for the surgical management of bpe, including transurethral vaporization using normal saline and bipolar energy (tuvis), transurethral resection using normal saline and bipolar energy (turis) and transurethral resection using monopolar energy (turp), with results showing similar efficacy in most trials at a short-term follow-up of 12 months, using conventional statistical analysis (9). the aim of this study is to test and compare several machine learning algorithms, regarding their predictive ability for assessing treatment outcomes for bpe (ipss score and qmax changes), using baseline patient characteristics and one of the treatment methods (tuvis, turis, turp). methods patients patients suffering from bpe, who were admitted at our tertiary care urology department between september 2017 and march 2019, were operated with one of three available methods (transurethral vaporization-tuvis, transurethral resection using bipolar energy-turis, transurethral resection using monopolar energy-turp), according to patient choice, physician surgical competence and equipment availability. data were extracted retrospectively, using a prospectively collected database, and the study protocol was duly approved by the institutional review board of the hospital (19836/07.10.2020). all patients signed informed consent before being treated for their condition and were treated according to the principles of the helsinki declaration (10). patients were included in the study if they had prostate volume > 30 ml, indication for surgical management (urinary retention, failure of medical management, recurrent hematuria or urinary tract infections), absence of diagnosed prostatic adenocarcinoma and/or pathologic digital rectal examination, ipss> 7, and qmax < 15 ml/sec. data collected baseline demographic data (age, medical history, use of antiplatelets, indication for surgery, asa score) and bpespecific data (ipss/qmax/post-voiding residual (pvr) preand postoperatively, prostate volume, psa, procedural time, haemoglobin, and sodium changes and complication rates) were collected. functional outcomes were assessed based on follow-up visits at 12 months after surgery. operative technique surgery was performed under spinal anesthesia in all cases, using a 26 fr continuous flow resectoscope (olympus turis 2.0, iglesias type) for bipolar resection and vaporization and a 28 fr non-rotating continuous flow resectoscope (karl storz) for monopolar resection. glycine 1.5% solution was used as irrigation flow for monopolar tur-p and n/s 0.9% for bipolar tur-p and vaporization. during vaporization of the prostate, an electrode with a mushroom-like shape was used, and energy settings were set at 270-290 watt for vaporization and 120-140 watt for coagulation. for transurethral resection, the method of mauermayer or nesbit was followed (11), while for vaporization, the hovering technique was used during which the electrode comes in direct contact with the prostatic tissue. data analysis basic descriptive statistics (mean, standard deviation, range) for the numerical variables (age, prostate volume, baseline qmax, baseline ipss, % qmax increase, % ipss reduction) have been used. several independent variables and outcome measures have been tested, but we present only those predictors resulting in significant outcomes. the weka data mining software was used for this study. this comprises an open-source machine learning toolkit containing a wide range of learning algorithms (12). since no credible validation can be made to assess the performance of the final model (13), if the total dataset is used to train a model and then reused for testing, we set aside some data which must not be used during training. the dataset set aside makes up the test set, which allows us to compare actual values of the test data to the values predicted from the weka-based models. the most widely used method to take advantage of the dataset is cross-validation, where we can use all of the data in test sets, but not simultaneously. therefore, our data were divided into a number of equal-sized subsets, called folds. if we have k folds, then this is called k-fold cross-validation. each fold is used once for testing on the model built using the remaining k-1 folds. cross-validation is widely regarded as a reliable way to assess the quality of results from machine learning techniques; in our analysis, we have used 10-fold cross-validation (14). while k-fold cross-validation is a standard method for making good use of available data, there are still various statistical measures which can be computed, and which reveal different interpretations/aspects. in order to find the best regression model for numeric prediction, we consider the performance measures of correlation coefficient (r), mean absolute error (mae), root mean-squared error (rmse), as reported by weka software (13) as described in appendix a (supplementary materials). the supervised regression algorithms techniques that are used in this research are: linear regression, multilayer perceptron, smoreg, k-nearest neighbors, bagging, m5rules, m5p pruned model tree, and random forests. although the technical details of these techniques are beyond the scope of this article, a summary of them can be found in appendix b (supplementary materials). due to the small size of the initial data set, we examined the performance of aforementioned algorithms by applying a method for increasing our sample size, the synthetic minority oversampling technique (smote), which is a statistical method for uniformly increasing the number of cases in a data set to render it more balanced. however, in our case, we just used smote to increase our dataset by generating extra artificial instances in a statistically sound way. the new (artificial) instances that were generated by the smote are not just duplicates of existing minority instances. instead, this method takes feature space samples for each target class and its nearest neighbours. after that, new instances are produced that combine features of the target case with those from its neighbours (15). archivio italiano di urologia e andrologia 2021; 93, 4 p. mourmouris, l. tzelves, g. feretzakis, d. kalles, i. manolitsis, m. berdempes, i. varkarakis, a. skolarikos 420 results a total of 153 patients with bpe were included (52 in tuvis group, 52 in bipolar-turis group and 49 in monopolar turp group). baseline patient characteristics and % qmax increase, % ipss reduction, are shown in table 1. machine learning techniques were applied in all outcomes gathered from chart review (functional outcomes-ipss/pvr/qmax change after surgery, haemoglobin drop postoperatively, sodium drop postoperatively, procedural time) using method of operation, age, prostate volume, asa score, indication for surgery, use of antiplatelets, baseline qmax and baseline ipss as predictors, but in this study, only metrics of significant findings are reported. in order to better depict the increase in qmax and reduction in ipss, we use percentages rather than absolute differences. after applying the smote, the new dataset contains an extra 453 synthetic instances,in addition to the original 153 patients’ data. the new allocation of the 606 instances is: 205 in tuvis group, 205 in bipolar-turis group and 196 in monopolar turp group. baseline patient characteristics and % qmax increase, % ipss reduction, are shown in table 2. according to table 3, considering all three metrics (r, mae, rmse) for % qmax increase, random forest algorithm outperforms other models, with values of correlation coefficient (r) 0.9697, mae 7.78 and rmse 13.26. the values of mae and rmse are percentage points since the target variable % qmax increase denotes the corresponding percentage increase of qmax after applying the corresponding system approach on a specific patient. as shown in table 4, considering all three metrics (r, mae, rmse) for % ipss reduction, the random forest model again outperforms other models, with values of table 1. baseline patient characteristics. total per system tuvis turis turp variable range mean/sd range mean/sd range mean/sd range mean/sd age (years) 47-91 70.39/8.67 47-91 69.87/9.41 47-89 70.87/8.73 51-88 70.43/7.68 prostate volume(ml) 20-175 59.48/24.44 31-98 59.88/20.51 20-175 63.48/29.20 20-105 54.81/21.78 baseline qmax (ml/sec) 3.40-11.90 7.24/1.75 3.40-9.30 6.52/1.53 3.40-11.90 7.83/1.90 4.50-9.90 7.38/1.51 baseline ipss 16-29 21.81/2.97 16-28 22.85/3.05 17-29 21/2.60 17-28 21.57/2.90 percentage qmax increase(%) 60-394 160.39/62.98 89-388 181.27/60.0 60-394 149.60/72.4 69-296 149.67/47.89 percentage ipss reduction(%) 29.4-76.5 59.5/7.1 29.4-75 57.3/7.6 44.0-75.0 63.2/7.1 50-76.5 58.07/4.55 table 2. augmented dataset statistics after applying smote *. total per system tuvis turis turp variable range mean/sd range mean/sd range mean/sd range mean/sd age (years) 47-91 70.44/8.46 47-91 70.75/8.78 47-89 71.41/8.77 51-88 69.09/7.57 prostate volume (ml) 20-175 58.94/22.94 31-98 61.24/20.66 20-175 62.56/25.83 20-105 52.74/20.64 baseline qmax (ml/sec) 3.40-11.90 7.16/1.50 3.40-9.30 6.67/1.24 3.4-11.9 7.68/1.69 4.50-9.90 7.13/1.37 baseline ipss 16-29 21.90/2.81 16-28 22.79/2.83 17-29 20.76/2.49 17-28 22.06/2.71 percentage qmax increase (%) 60.00-394.00 162.10/53.12 89.00-388.00173.62/47.96 60.00-394.00 152.78/63.82 59.00-296.00 159.81/42.71 percentage ipss reduction (%) 29.4-76.5 59.28/6.28 29.4-75.0 57.46/6.5 44-75 63.07/6.15 50.0-76.5 57.30/4.02 * smote: synthetic minority oversampling technique. table 3. percentage qmax increase prediction using various machine learning methods. method r mae rmse linear regression 0.9004 17.8 23.12 multilayer perceptron 0.9088 16.7 22.2 smo reg 0.895 17.7 23.85 lazy.ibk 0.935 9.24 18.80 meta.bagging 0.9526 11.13 16.25 m5rules 0.9274 14.95 19.88 trees.m5p 0.9253 14.9 20.15 trees.randomforest 0.9697 * 7.78 * 13.26 * r: correlation coefficient; mae: mean absolute error; rmse: root mean-squared error. best results are marked by * in each column. table 4. percentage ipss reduction prediction using various machine learning methodslearning methods. method r mae rmse linear regression 0.4493 4.14 5.61 multi layer perceptron 0.5751 3.95 5.36 smoreg 0.4199 4.17 5.7 lazy.ibk 0.8793 1.53* 3.07 meta.bagging 0.7906 2.73 3.91 m5rules 0.678 3.35 4.62 trees.m5p 0.7231 3.17 4.36 trees.randomforest 0.8989 * 1.63 2.80 * r: correlation coefficient; mae: mean absolute error; rmse: root mean-squared error. best results are marked by * in each column. 421archivio italiano di urologia e andrologia 2021; 93, 4 machine learning in bpe surgery correlation coefficient 0.8989, mae 1.63, and rmse 2.80, with the only exception that k-nearest neighbors model has smaller but very close value of mae. the values of mae and rmse are percentage points since the target variable % ipss reduction denotes the corresponding percentage decrease of ipss after applying the corresponding system approach. a decision tree algorithm is easily understood and ideal for obtaining non-linear relationships between independent and dependent variables. random forest is a collection of decision trees constructed in a specific random manner. random forest usually performs better than a single decision tree in terms of accuracy and reduced overfitting. the major advantages of random forests are that they can handle both linear and non-linear relationships as well, they are not significantly impacted by outliers and they effectively balance the bias-variance tradeoff. figure 1 shows an example of how a random forest is constructed from decision trees. correlation coefficient (r) is used to measure the strength of a linear relationship between two variables, in our case the predicted and the actual values of the target variables % qmax increase and % ipss reduction. the closer the value of the correlation coefficient is to 1, the better the regression model is. mean absolute error (mae) is the average error between the absolute value of the predicted and actual value for each pair. root mean-squared error (rmse) it shows how far predicted values fall from measured actual values using euclidean distance. concerning the values of the mae and rmse, the closer their values to zero, the better the model's performance, since both metrics are proportional to the difference between the actual and predicted values. readers can find on the website (16) two weka data set sample files (.arff) for experimental purposes to create their own models based on their local facility data. furthermore, we have uploaded the two experimental models for % qmax increase and % ipss reduction prediction with considered independent variables the method of operation, age, prostate volume, baseline qmax and ipss. discussion the ultimate goal of ai is to create systems which are able to perform intellectually challenging tasks, similar to those performed by humans. today, the closest we get to such systems, is usually aided by non-linear mathematic and statistical models (17) and mostly drawn from the machine-learning sub-field of ai, though significant developments also occur in other sub-fields too, such as natural language processing and visual perception with deep learning (7). a substantial number of such models attempt to assist medical practitioners, using a variety of sources for data and feedback, such as handwritten notes and books, medical imaging scanning and tissues grading. so, it is the impact on everyday clinical practice that will likely guide the training of these models and also decide the success of these ai technologies. in our study, we tested several machine learning algorithms, in order to find the figure 1. development of a random forest from decision trees. archivio italiano di urologia e andrologia 2021; 93, 4 p. mourmouris, l. tzelves, g. feretzakis, d. kalles, i. manolitsis, m. berdempes, i. varkarakis, a. skolarikos 422 one with the least error in predicting ipss reduction and qmax increase, taking into consideration patient parameters that are widely available and easily assessed during daily urological practice in a usual clinical setting. physicians could use these algorithms preoperatively and in conjunction with clinical judgement and discussion with patients, decide whether to perform surgery or not. there are, so far, some, but sparse, data about the implementation of this technological advance in urology, with the majority of existing studies in urological literature, focusing on the effect of these systems in improving prediction accuracy in prostate cancer diagnosis and management. there is still an unmet need for better prostate cancer detection in order to avoid unnecessary biopsies. a recent paper investigated different prostate-specific antigen (psa) assays and developed a novel predictive tool based on artificial neural networks (ann), concluding that ai technology can aid in minimizing variability of each psa assay but only if a separate ann system is utilized for every psa assay and not one for all (18). as for the mpmri diagnostic optimization, alongside their fusion biopsy implications, there is an increasing body of literature that reports on system development to integrate pre-processing, segmentation, and registration in order to fully automate the procedure, with promising outcomes so far (19-21). besides cancer-related research, ai systems have also been utilized in other aspects of urological pathology. in urinary stone disease, there are reports that ai systems have been implemented in order to predict stone composition (22), surgical outcomes of percutaneous nephrolithotomy (pnl) (23), and shock wave lithotripsy (swl) (24), with excellent accuracy. similarly in patients with vesicoureteral reflux, as reported by seckiner et al. (25), the ann reported 98.5% sensitivity, 92.5% specificity, 97% positive predictive value, and 96% negative predictive value, which can definitely be considered very promising. contradictive results were published for the role of ai systems in predicting surgical outcomes, mainly in robotic surgery (4, 26). the necessity to personalize treatment in patients with cancer and the high heterogeneity of neoplastic diseases is a potential reason that led scientists to focus mainly on this field of medicine and less on benign conditions like bpe. notably, the implementation of ai techniques in bpe diagnosis and, especially, treatment is at its early stages, with currently scarce reports about the utilization of ai systems in bpe patients. torshizi et al. presented a hybrid fuzzyontology intelligent system with multiple layers that consisted of two modules: the first was evaluating symptoms severity, whereas the second was evaluating the management options. nevertheless, this system did not evaluate the outcomes of different surgical entities according to individual patient characteristics (6). furthermore, the evaluation of bladder outlet obstruction symptoms has been the topic of another relatively recent study, where the detection rate of bpe in these patients using an ann was 72%, and where the authors concluded that the pressure-flow study could not be omitted and replaced with the intelligent system. the management of bpe depends on disease stage, symptom intensity, patient preference and health status. common indications for surgical management include failure of medical treatment for moderatesevere lower urinary tract symptoms (luts), recurrent urinary retention or infections, hematuria, bladder stones, kidney damage. a common perception is that prostate volume correlates with symptom severity and with health-related quality of life, but this is not backed up by the relevant literature (27). a clinical dilemma occurs in patients who do not fulfill criteria and absolute indications for surgery, while both physicians and patients need to know an estimation of functional outcomes post-operatively. diagnostic tests are not highly specific for attributing luts to bpe, except for urodynamic testing, which is an invasive, costly and time-consuming examination. choo et al developed a nomogram, which permits prediction of benign outlet obstruction-related surgery, with satisfactory metrics (28) based on clinical and urodynamic parameters. since urodynamics is not available at every clinical setting, these nomograms may not be applicable for a substantial percentage of patients. according to pielke (1984), a model can be considered predictive if two conditions are satisfied: (a) the standard deviations of the predictions and observations are approximately the same, and (b) rmse is less than the standard deviation of the observations (29). our results indicate that the root mean squared error (13.26) for the model % qmax increase random forest is much smaller than the value of the standard deviation (53.12) of the actual values of the dependent variable % qmax increase. furthermore, the standard deviation of the predicted values is 57.53 percentage points (p.p.), which is close to the corresponding standard deviation of the actual values (62.79 p.p.). the results for the second model (% ipss reduction random forest), indicate that the root mean squared error (2.80) for the best model is also much smaller than the value of the standard deviation (6.28) of the actual values of the dependent variable % ipss reduction, and the standard deviation of the predicted values is 5.13 percentage points (p.p.) is very close to the corresponding standard deviation of the actual values (5.31 p.p.). therefore, our proposed model meets the two conditions to be considered predictive, both regarding % qmax increase and % ipss reduction. personalized medicine is touted as the future in healthcare settings, especially after the development of largescale databases with patient –omic characteristics (proteomics, genomics, metabolomics etc). predictive analytics on data of such volume and complexity seems to be feasible using ai techniques with the ability to adapt and ‘’learn’’ from data during the whole process, giving endless opportunities both for patient outcomes improvement and cost savings for healthcare systems (30). a limitation of our study is that, due to the limited sample size, our models may not be immediately applicable to all urology departments. for that reason, it will be preferable that our methodology is implemented in the data of each local facility, or ideally, on a larger pool of data collected from multiple sites, so as to have a greater potential for learning and test whether the mean absolute 423archivio italiano di urologia e andrologia 2021; 93, 4 machine learning in bpe surgery error can be reduced. another drawback of this study is that laser methods for prostate resection were not studied due to the lack of appropriate equipment during the period of data collection. moreover, using more clinical-related data in the future, such asomic data, could pave the way for producing better predictive models. the retrospective collection of data is also a limitation, but since this was performed through a prospectively collected database, confounding is partially alleviated. conclusions bpe is a very common clinical condition, with various treatment modalities available for patients. at the same time, ai models increasingly provide surgeons with accurate decision-making tools. as health information system (his) use is expanded in a healthcare facility, it will be easier to utilize data collected for the his using artificial intelligence techniques to benefit patients. this study presents a methodology for predicting clinical outcomes in bpe management, according to pre-operative characteristics and a variety of relatively standard and widely available ai techniques. results are promising to regard 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example, magnetic resonance imaging-transrectal ultrasound fusion prostate biopsy. eur urol focus. 2021; 7:78-85. 22. kriegshauser js, paden rg, he m, et al. rapid kv-switching single-source dual-energy ct ex vivo renal calculi characterization using a multiparametric approach: refining parameters on an expanded dataset. abdom radiol (ny). 2018; 43:1439-45. 23. aminsharifi a, irani d, pooyesh s, et al. artificial neural network system to predict the postoperative outcome of percutaneous nephrolithotomy. j endourol. 2017; 31:461-7. 24. seckiner i, seckiner s, sen h, et al. a neural network based algorithm for predicting stone free status after eswl therapy. int braz j urol. 2017; 43:1110-4. 25. seckiner i, seckiner su, erturhan s, et al. the use of artificial neural networks in decision support in vesicoureteral reflux treatment. urol int. 2008; 80:283-6. 26. hung aj, chen j, che z, et al. utilizing machine learning and archivio italiano di urologia e andrologia 2021; 93, 4 p. mourmouris, l. tzelves, g. feretzakis, d. kalles, i. manolitsis, m. berdempes, i. varkarakis, a. skolarikos 424 automated performance metrics to evaluate robot-assisted radical prostatectomy performance and predict outcomes. j endourol. 2018; 32:438-44. 27. lepor h. evaluating men with benign prostatic hyperplasia. reviews in urology. 2004; 6 suppl 1(suppl 1):s8-s15. 28. choo ms, yoo c, cho sy, et al. development of decision support formulas for the prediction of bladder outlet obstruction and prostatic surgery in patients with lower urinary tract symptom/benign prostatic hyperplasia: part i, development of the formula and its internal validation. 2017; 21(suppl 1):s55-65. 29. pielke ra. mesoscale meteorological modelling. academic press, orlando, 612pp. 30. stanfill mh, marc dt. health information management: implications of artificial intelligence on healthcare data and information management. yearb med inform. 2019; 28:56-64. correspondence mourmouris panagiotis, md thodoros13@yahoo.com manolitsis ioannis, md giannismanolit@gmail.com berdempes marinos, md marinosberdebes@hotmail.com varkarakis ioannis, md medvark3@yahoo.com skolarikos andreas, md andskol@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens (greece) tzelves lazaros, md (corresponding author) lazarostzelves@gmail.com 2nd department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens sismanogleiou 1, 15126, marousi (greece) feretzakis georgios, md georgios.feretzakis@ac.eap.gr kalles dimitris, md greece kalles@eap.gr school of science and technology, hellenic open university, 26335 patras stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14195 1 review erection of the penis. sexual intercourse is the most common aetiology for penile fracture, besides forceful bending of the penile shaft, masturbation, and blunt or sharp injury to the penis (2). trauma to the penis, whether it is blunt or sharp trauma, will cause an abrupt raising of intracavernosal pressure, resulting in the tear of tunica albuginea (2). average arterial pressure of an erect penis is roughly 100 mmhg in the erect state (3). penile fracture can easily be diagnosed from the history and physical examination of the patient. in most cases, penile fracture will present with a cracking, snapping sound, rapid detumescence of the penis, acute pain, abrupt swelling, and the presentation of “eggplant deformity” or ecchymosis of the penis. the fracture is more often in the proximal shaft of the penis. the corporal cavernosal tear may occur unilaterally or bilaterally. the most applicable modalities in diagnosing penile fracture are ultrasound (us) and mri (4). us is widely used in the population because of its availability, non-invasiveness, low cost and safety, but the results are operator dependent. whereas penile mri can show more accurate and detailed soft tissue disruption, but it’s expensive and not available in most hospitals (5, 6). penile fracture is a rare case in the urological field, the incidence reported for penile fracture was 1 case for every 175,000 cases of emergency hospital admissions (1). immediate surgical exploration and closure of the tunica albuginea is now the most preferred treatment approach for penile fracture. some complications may occur after surgical treatment of penile fracture, including erectile dysfunction, infections, painful erection, penile curvature, and plaque formation (7, 8). erectile dysfunction (ed) is known as a major concern following the surgery for penile fracture, as it can potentially result in a poor physical and psychological condition for the patient (9). this study is the first meta-analysis discussing some variables of risk factors (age, mechanism of injury, fracture location, surgical approach, side of fracture, urethral injury, and timing of presentation) and their relationship to the occurrence of erectile dysfunction, especially in postsurgery penile fracture patients. therefore, this knowledge will be hugely beneficial in preventing erectile dysfunction background: penile fracture is one of the rare urological emergencies resulting in rupture of the tunica albuginea in the penile corpora cavernosa. sexual intercourse is known to be the most common aetiology of penile fracture, which usually happens during erection. immediate surgical intervention is crucial to avoid any complications. erectile dysfunction is the most feared complication after surgery. this meta-analysis aimed to analyse and determine risk factors of erectile dysfunction among patients who underwent penile fracture surgery. methods: literature searching was conducted in several databases, e.g., pubmed, cochrane, sciencedirect, google scholar and doaj by applying the boolean term method. statistical analyses and risk of bias assessment were calculated through revman 5.4.1 and the newcastle ottawa scale (nos), respectively. outcomes were presented as odds ratio (or). results: a total of 6 studies were included, encompassing 527 patients who were diagnosed with penile fracture and underwent surgery for repairment. risk factors for post-surgery erectile dysfunction were calculated. age (or = 0.19, 95% ci [0.07, 0.52], p = 0.001), location of fracture (or = 0.43, 95% ci [0.22, 0.84], p = 0.01), and side of fracture (or = 0.06, 95% ci [0.02, 0.21], p = < 0.0001) have significant relations with erectile dysfunction. whereas aetiology, urethral injury, and timing of presentation have statistically non significant effect on the incidence of erectile dysfunction. conclusions: this systematic review and meta-analysis showed that patients over 50 years of age, those with midshaft fracture, and those with bilateral fractures are significantly more likely to have erectile dysfunction following penile fracture surgery. key words: penile fracture; erectile dysfunction; impotence; risk factor; urethral injury. submitted 28 july 2025; accepted 28 august 2025 introduction penile fracture is one of the urological emergencies characterized by rupture of the tunica albuginea in the corpora cavernosa of the penis, which requires an immediate surgical intervention (1). it commonly occurs during what are the risk factors for erectile dysfunction following penile fracture surgery? a systematic review and meta-analysis harith naufal subrata 1, syah mirsya warli 2, 3 1 general practitioner, rantauprapat regional general hospital, labuhanbatu, indonesia; 2 division of urology, department of surgery, faculty of medicine, universitas sumatera utara haji adam malik general hospital, medan, indonesia; 3 department of urology, universitas sumatera utara hospital, universitas sumatera utara, medan, indonesia. doi: 10.4081/aiua.2025.14195 summary archivio italiano di urologia e andrologia 2025; 97(3):14195 h. naufal subrata, s. mirsya warli 2 among penile fracture patients. early detection of these risk factors can assist physicians in making clinical decisions. this meta-analysis aims to determine the contributing risk factors regarding erectile dysfunction following penile fracture surgery in order to provide eligible evidence for advances in knowledge and patient services. materials and methods literature search we performed literature searches in several databases, e.g. pubmed, cochrane, sciencedirect, google scholar, and doaj, by applying the boolean term method. we did the literature searching by applying keywords: “penile fracture” and (“erectile dysfunction” or “impotence”) and “risk factor”. data extraction the population, intervention, comparison, and outcome (pico) principle was used in this study, with penile fracture patients who underwent surgery repairment as the population, surgery as the intervention, the occurrence of erectile dysfunction as the comparison, and potential risk factors (age, mechanism of injury, fracture location, surgical approach, side of fracture, urethral injury, and timing of presentation) as the outcome. cohort and casecontrol studies were included in this meta-analysis. information collected from each study included age, smoking history, mechanism of injury for penile fracture, location of fracture, side of fracture, urethral injury, and timing at presentation. the data also included the author’s name, year of publication, sample size, age, and follow-up period. risk of bias (rob) analysis risk of bias assessment was done by using newcastle ottawa scale (nos) for cohort and case-control studies consisting of 3 variables, i.e., selection of the participants to the study (4 points maximum), comparability of the groups (2 points maximum), and assessment of the outcome to the exposure (3 points maximum), with the cumulative value of 9 points. data synthesis data analysis was done by using review manager version 5.4. the strength of correlation between variables was measured using odds ratio (or) and 95% confidence interval (ci). statistical significance of or was measured by using the p-value from the z-test and the heterogeneity measured with the inconsistency index (i2) test. a p-value < 0.05 was deemed as statistically significant. i2 ≥ 50% is considered high heterogeneity, whereas i2 < 50% is considered low heterogeneity. furthermore, a forest plot was generated for each variable to assess the publication bias. results we applied the prisma flowchart guideline in the identifying process of the study. at first 1,672 studies were identified, and only 6 articles were eligible for this metaanalysis at the end of the selection process. prisma flowchart for identification of the studies and characteristics of the studies are shown in figure 1 and table 2, respectively (6, 8, 10-13). following the removal of duplicates, 1,586 titles and abstracts were screened, and 18 full texts were retrieved for further appraisal. evaluation of full-text studies identified 6 articles eligible for inclusion in this metaanalysis, as shown in figure 1. additional reasons for exclusions were studies containing not relevant data, incomplete information, and studies that were not written in english. figure 1. prisma flowchart of the identification of eligible trials. archivio italiano di urologia e andrologia 2025; 97(3):14195 3 erectile dysfunction following penile fracture inclusion criteria for this meta-analysis were: patients who were healthy prior to injury, original research studies, studies that comprehensively discussed the association between erectile dysfunction and penile fracture surgery, and study designs that were in cohort and case report. the studies were excluded if: patients had sexual problems prior to injury, or if the studies did not mention erectile dysfunction after surgical repair or if the studies included patients with other diseases. studies were also excluded if they didn’t provide or as the statistic measurement, in addition to this, letters and case reports abstracts were also excluded for analysis. out of the 6 studies that are included, 527 patients were enrolled in this meta-analysis. the six studies that were included were published between 2012 and 2025. the characteristics of the selected studies are summarized in table 1. all of the studies were considered as good quality, as shown in table 2. of these 6 studies, 5 were cohort studies and 1 was a case control study. age three cohort studies discussed the relationship between age at injury and the occurrence of erectile dysfunction following surgery, which divided patients < 50 years as group 1 and patients ≥ 50 years as group 2. the statistical analysis for this variable was calculated through review manager 5.4. the or for age and erectile dysfunction following surgery were statistically significant. in addition to this, we found a 0% inconsistency index in this calculation. mechanism of injury three cohort studies, which were included in this metaanalysis investigated the correlation between mechanism of injury or etiology and postoperative erectile dysfunction. as the mechanisms of injury were varied, we divided them into a sexual intercourse group and a non-sexual intercourse group. from the calculation we found that the or was 0.70 (ci 95%: 0.39-1.24, p = 0.22) which was considered as not statistically significant. with 0% of i2, there was also no risk of heterogeneity in this calculation. location of fracture four studies, consisting of 3 cohort studies and 1 case-control study, discussed the potential relationship between the location of fracture and ed occurrence. the or reported was 0.43 (ci 95%: 0.22-0.84, p = 0.01). the calculation showed that the location of fracture (proximal or middle shaft) was statistically significant as risk factor of erectile dysfunction following surgical repair for penile fracture. surgical approach a study from chaker et al. 2025 investigated the correlation between surgical approach and ed occurrence. the or for this variable was 5.09 (ci 95%: 2.03-12.78, p = 0.0005), which is statistically significant. from this result we can figure out that patients with a coronal approach are 5 times more likely to have ed in the future than the control group. side of fracture the location of the fracture was divided into unilateral and bilateral groups. two cohort studies and 1 case-control study were included. the or was 0.06 (ci 95%: 0.02-0.21, p < 0.0001) which was considered to be significant. these results showed that if the fracture occurs on both sides, there is a 94% probability of having ed following the repairment surgery. table 2. summary of patient characteristics included in meta-analysis. author, year age range/mean of sample age sample size (n) time period erectile dysfunction (n) follow-up period barros 2021 24 to 69 years 18 cases january 2014 to january 2019 3 cases 3 to 18 months assmy 2012 35 years 166 cases january 1989 to may 2010 11 cases 106 months chaker 2025 38 ± 12 years 87 cases 2012 to 2023 44 cases ≥ 12 months din 2023 35.89 ± 4.2 years 25 cases january 2022 to february 2023 9 cases ≥ 1 week patil 2019 28.8 ± 7.59 years 18 cases july 2014 to january 2017 8 cases nr sharma 2021 33.64 ± 9.46 years 62 cases september 2014 to august 2019 7 cases ≥ 2 weeks nr: not reported. table 1. risk of bias assessment using newcastle ottawa scale (nos) for case-control study and cohort study. author, year selection comparibility outcome representative selection of ascertainment outcome of interest main factor additional assessment sufficient adequacy of the exposed cohort external control of exposure not present at the factor of outcome follow-up follow-up start of the study barros 2021 * 0 0 * * * 0 * * assmy 2012 * * * * * * * * * chaker 2025 * * * * * * * * * din 2023 * * * * 0 * * 0 * patil 2019 * * * 0 0 0 * * * sharma 2021 * * * * * * * * * archivio italiano di urologia e andrologia 2025; 97(3):14195 h. naufal subrata, s. mirsya warli 4 urethral injury urethral injury coexisting with penile fracture was also investigated as a risk factor for ed in 2 cohort studies and 1 case-control study. even though the calculation showed that patients with urethral injury are 60% more likely to have ed in the future, as shown in figure 2, the result figure 2. forest plot for the impact on risk factors on incident erectile dysfunction: age, etiology, location of fracture, surgical approach, side of fracture, urethral injury, and timing of presentation. archivio italiano di urologia e andrologia 2025; 97(3):14195 5 erectile dysfunction following penile fracture was not statistically significant [or 0.40 (ci 95%: 0.121.40, p = 0.15)]. timing at presentation timing to the operating room was also considered as a risk factor for ed occurrence in some studies. four studies that were included in this meta-analysis. the results indicate that timing at presentation (< 24 hours vs ≥ 24 hours) was insignificant to the occurrence of ed following penile fracture surgery. the or was 0.70 (ci 95%: 0.27-1.71, p = 0.46). discussion treatment options for penile fracture include conservative and surgical intervention approaches (14). the surgical exploration was the treatment of choice when a penile fracture is suspected. surgical approach was preferred because of the good functional and cosmetic outcome with minimal complication (15). surgical exploration combined with circumcision was recommended to maintain local hygiene, prevent phimosis, and provide a better aesthetic outcome (16). some patients may develop post-surgery complications. complications following the surgery repair are varied, such as ed, deviation of the penis, development of fibrous plaque, and voiding problems. ed is a huge problem that impacts both the physical and the psychological condition of the patient (6, 15, 17-20). some studies showed that the ratio of ed after surgery varied from 0 to 16.6% of patients (21, 22). according to the study by zhu et al. 2024, a multivariate analysis was made to investigate the correlation between age and post-surgery ed. the report said that age was not significantly related to the occurrence of postoperative ed (or 1.004 and p = 0.922) (9). this finding contradicted our findings, which depicted a major association between age at injury and the incidence of ed [or 0.19 (ci 95%: 0.007-0.52, p = 0.001)]. along with our findings, a study by avci et al. 2023 over 58 penile fracture patients also reported a significant correlation between age and post-surgery ed (p = 0.004) (23). similarly, the study by ortac et al. 2020 reported that the patients with ed were older compared to non-ed patients (p-value 0.001) (24). mechanism of trauma has no significant relation as the risk factor of ed following penile fracture surgery, as reported by silva et al. 2024 (p = 0.896) (25). these results are presumably in accordance with our study, as we also reported no significant relationship between the mechanism of injury (sexual intercourse and non-sexual intercourse) and ed incidence [or: 0.70 (0.39, 1.57), p = 0.22]. original research by silva et al. 2024 showed a significant connection between lesion location and erectile function (p-value = 0.035) (25). this report is also in line with our study, which investigated the correlation between fracture location (proximal vs middle shaft) and ed occurrence [or: 0.43 (0.22, 0.84), p = 0.001]. although we included only one study that discussed the relationship of surgical approach and ed incidence, we concluded that there was a significant relation between different types of surgical approaches (coronal vs elective) and ed incidence [or: 5.09 (2.03, 12.78), p = 0.0005]. however, a study conducted by ouanes et al. 2021 in 138 cases with a mean age of 31.2 years reported differently. they investigated the correlation of the incision type that was used by surgeons and the occurrence of ed. the results reported that the incision type (elective vs circumferential degloving) was not statistically related to ed occurrence, as they measured a p-value > 0.05 (26). silva et al. 2024 reported that lesion laterality (right/left/ bilateral) has a correlation to the occurrence of ed after penile fracture repair, although not statistically significant (p = 0.667) (25). our review compared only two groups in relation to laterality: unilateral vs bilateral. we calculated the relationship between unilateral or bilateral fracture and the occurrence of ed among postoperative patients showing a significant correlation between the two groups, with or 0.06 (0.02-0.21) and p < 0.0001. urethral injury is suspected whenever hematuria, blood in the meatus, and voiding symptoms are present, although the absence of the findings can’t exclude it (27-29). the tunica albuginea thickness of the penis will decrease from 2 mm in the flaccid state to 0.25 mm in the erect state along with the increase of intracavernous pressure, which makes it very easy to rupture against penile trauma (5, 28-30). a multivariate analysis done by zhu et al. 2024 reported the or of postoperative ed in presence of urethral injury was 11.330 (p = 0.002) which was statistically significant, although this report is contradicted by our study [or 0.40 (ci 95%: 0.12-1.40, p = 0.15)] (9). in our study, the timing of presentation to the operating room was insignificant. our study reported a or of 0.70 (0.27, 1.81) with p-value of 0.46 for the correlation between timing of presentation and ed occurrence. a study by bulbul et al. also found a result similar to ours (p = 0.979) (31), whereas ouanes et al. showed a different result reporting a p-value of 0.03 in their study (26). a meta-analysis done by amer et al. 2016 reported that there was no significant association while comparing immediate and delayed surgery to the rates of ed (rr 0.82: 0.41-1.66, p = 0.59) (32). finally, a study conducted by ortac et al. also obtained results similar to ours, reporting a p-value of 0.235 for the correlation of the time of presentation to the hospital after injury and the postoperative erectile dysfunction (24). the strength of our study is that this is the first metaanalysis that extensively discusses the risk factors of erectile dysfunction after penile fracture surgery. other metaanalyses (32-36) have previously evaluated the outcomes of penile fracture repair surgery but have not focused their analysis on the risk factors for the occurrence of erectile dysfunction after the procedure. this study showed us which risk factors have a significant relationship to the occurrence of erectile dysfunction and which do not. despite this strength, our study was limited by the small number of studies available. more study and reviews are needed in the future in order to increase the validity of the potential risk factors and also to discover other risk factors that might be related to the occurrence of erectile dysfunction following a penile fracture surgery. archivio italiano di urologia e andrologia 2025; 97(3):14195 h. naufal subrata, s. mirsya warli 6 conclusions this systematic review and meta-analysis showed that patients over 50 years of age, those with midshaft fracture, and those with bilateral fractures are significantly more likely to have erectile dysfunction following penile fracture surgery. references 1. arikan mg, akgul b, turk s, et al. beyond conventional wisdom: unexplored risk factors for penile fracture. sex med. 2024; 12:qfae068. 2. sheikh ba, porwal p. successful surgical repair of a 26-day old penile fracture. indian j plast surg. 2024; 57:233-234.. 3. dean rc, lue tf. physiology of penile erection and pathophysiology of erectile dysfunction. urol clin north am. 2005; 32:379-95, 4. von stempel c, kirkham a, cayetano alcaraz a, et al. imaging findings in suspected penile fracture: alternative diagnoses and surgical correlation. br j radiol. 2024; 97:1850-1855. 5. kajerero v, sukunala o, rugakingira ra, et al. penile fracture following sexual 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participate: ethical approval was not needed since this is a systematic review and meta-analysis. availability of data and material: data available on request from the authors. competing interests: all authors have no conflicts of interest to declare. funding: the study was financed through self-funding. authors' contributions: syah mirsya warli contributed to the resources, supervision, and editing of this review.harith naufal subrata contributed to the data curation and analysis, resources, and writing original draft for this review. acknowledgments: we thank the medical faculty of universitas sumatera utara and adam malik general hospital for their consistent support for the author during this research. archivio italiano di urologia e andrologia 2025; 97(3):14195 7 erectile dysfunction following penile fracture 31. bulbul e, gultekin mh, citgez s, et al. penile fracture: tertiary care center experience and long-term complications after immediate repair. andrology. 2022; 10:560-6. 32. wong nc, dason s, bansal rk, et al. can it wait? a systematic review of immediate vs. delayed surgical repair of penile fractures. can urol assoc j. 2017; 11:53-60 33. shebl se. the presentation and outcomes of penile fracture with associated urethral injury: a systematic literature review. arch ital urol androl 2023; 95:11082. 34. syarif s, azis a, natsir as, putra mzda. what is the most dangerous sexual position that caused the penile fracture? a systematic review and meta-analysis. braz j urol 2024; .50: 28-36. 35. falcone m, garaffa g, castiglione f, ralph dj. current management of penile fracture: an up-to-date systematic review. sex med rev 2018; 6 253-60. 36. kominsky h, beebe s, shah n, jenkins lc. surgical reconstruction for penile fracture: a systematic review. int j impot res. 2020; 32:75-80. correspondence harith naufal subrata hharithnaufal@gmail.com general practitioner, rantauprapat regional general hospital, labuhanbatu, indonesia syah mirsya warli, md, phd (corresponding author) warli@usu.ac.id division of urology, department of surgery, faculty of medicine, universitas sumatera utara-haji adam malik general hospital, medan, indonesia jl. bunga lau no.17, medan, indonesia stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12128 1 original paper by physical examination and graded into three as grade i (dilated veins palpable with valsalva), grade ii (dilated veins palpable during rest but not visible) and grade iii (dilated veins visible and palpable during rest (5). subclinical varicocele (scv) is the abnormal dilatation of the veins of the pampiniform plexus that cannot be detected by physical examination but can be diagnosed by imaging modalities (6). although cv is diagnosed by physical examination, physical examination can be unsatisfactory or confusing due to factors such as a patient's history of scrotal surgery, coexisting hydrocele, obesity, or improper examination. as such, the european association of urology (eau) guideline recommends that imaging studies must be used to confirm the diagnosis in infertile men with cv (7). at the present time, scrotal color doppler ultrasound (cdus) has become the most widely used imaging technique for the diagnosis and classification of both cv and scv (5, 6). although us and european guidelines recommend that treatment should only be offered for palpable varicoceles in infertile males, different trials have reported conflicting results demonstrating the benefits of repairing subclinical varicocele (6, 9-10). according to eau, varicocelectomy should only be performed in patients with cv, impaired semen analysis and infertility lasting ≥ 2 years (11). although isolated unilateral sv in infertile patients is not at all an indication for varicocele repair, the management of infertile men with unilateral sv and contralateral cv remains a controversial issue and there is no consensus on whether bilateral varicocele repair is superior to unilateral varicocele repair in patients with left clinical varicocele (lcv) and right scv (12-13). reported conflicting outcomes may be due, in part, to the small study size, different study designs, and the effect of varicocelectomy techniques in different studies. for infertile patients with left cv and right scv, it is worthwhile to study whether bilateral or unilateral surgical repair should be performed. in the present study, we performed a retrospective study of oligoasthenospermic infertile patients diagnosed with solitary lcv or lcv with rsv. we compared the improvement in spermiogram parameters after left varicocelectomy between the two groups of patients. we aimed to determine whether the presence of an untreated right scv influenced the spermiogram parameters after left clinical varicocelectomy. purpose: the management of infertile patients with unilateral subclinical varicocele (scv) and contralateral clinical varicocele (cv) remains controversial. we aimed to evaluate the effect of untreating scv on the outcome of contralateral clinical varicocelectomy in infertile patients with oligoasthenozoospermia (oa). materials and methods: infertile patients with the diagnosis of oa who underwent left varicocelectomy were retrospectively evaluated. while all patients in the study had left clinical varicocele (lcv), some patients had concomitant right scv. patients were divided into two groups according to the presence or absence of a right scv accompanying lcv as group 1; (lcv n = 104) or group 2; (lcv with right scv, n = 74). patients were evaluated with spermiogram parameters, pregnancy rates and serum levels of follicle stimulating hormone, luteinizing hormone, total testosterone at the first year of the follow-up. results: the mean sperm concentration increased significantly in both groups. however, group 1 showed significantly greater improvement than group 2. the ratio of progressive motile sperm in group 1 was increased significantly whereas no significant change was shown in group 2. both the spontaneous pregnancy rate and the pregnancy rate with art were statistically lower in the group of patients with right scv. no statistically significant difference was detected in serum hormone levels in both groups after varicocelectomy operations. conclusions: untreated right scv may have adverse impact on the outcomes of left clinical varicocelectomy. in this context, the right testis can be considered in terms of treatment in patients with right scv accompanying left cv. key words: infertility; subclinical varicocele; varicocelectomy. submitted 24 november 2023; accepted 5 december 2023 introduction according to the world health organization, the overall prevalence of primary infertility ranges between 3.9% and 16.8%, and up to 60% of infertility cases have been reported to be associated with men (1-2). varicocele is the most common curable cause of male infertility and present in nearly 25% of men with abnormal semen quality and 35% of men with primary infertility (3-4). varicocele can be classified as clinical or subclinical based on the radiological and clinical criterions. clinical varicocele (cv) is diagnosed the effect untreated right subclinical varicocele on the outcomes of contralateral left clinical varicocelectomy in infertile patients sevgin yılmaz 1, murat topcuoğlu 2, murat çakan 1, ali akkoç 2, murat uçar 2 1 department of urology, university of health sciences dıskapı training and research hospital, ankara, turkey; 2 department of urology, faculty of medicine, alanya alaaddin keykubat university, alanya turkey. doi: 10.4081/aiua.2023.12128 summary archivio italiano di urologia e andrologia 2023; 95(4):12128 sevgin yılmaz, murat topcuoğlu, murat çakan, ali akkoç, murat uçar 2 materials and methods this retrospective study includes one hundred seventyeight primary infertile males with the findings of oligoasthenospermia (oligospermia and asthenospermia) in at least 2 consecutive semen analyses. primary infertility is defined as never been involved in a conception and the failure to obtain a natural pregnancy at least 12 months of following regular unprotected sexual intercourse. the study protocol was reviewed and approved by the institutional review board of health science university, dışkapı training and research hospital (no. 143/07). the study was performed according to the declaration of helsinki. as per our protocol, recurrent varicocele, secondary infertility, necrospermia, endocrinopathy, history of orchitis and cryptorchidism, use of vitamins or hormonal supplements, abnormal peripheral karyotype, y chromosome microdeletion and cases whose partners have got fertility problems were excluded from the study. patients with severe oligoasthenospermia (tmsc < 1x106/ml) and azoospermia were also excluded from the study. a medical history was taken, and a scrotal examination was performed by the same physician in an upright position during normal breathing and valsalva manoeuvres. two consecutive spermiograms were performed before the treatment and at the first year of the treatment. pregnancy rates were recorded at the first year control visit. semen samples were acquired by masturbation following three days of abstinence. data including scrotal examination, medical history and two consecutive spermiograms at baseline and at the first year of the treatment, were retrieved from the electronic patient folders. spermiogram analysis data were recorded as the average of two semen samples. semen samples were analysed for volume, sperm count, concentration, motility, morphology, viability. oligoasthenospermia is defined according the criteria’s which were recognized by the who in 2010 (normal total sperm count, ≥ 39x106, normal sperm concentration ≥ 15x106/ml, and normal typical morphology > 4%, normal progressive motility > 32% (14). cv was diagnosed by physical examination and graded according to dubin grading system (grade i to iii). scrotal cdus was used to diagnose scv and to confirm cv. the diagnostic criterion of a scv is the presence of dilated veins in the pampiniform plexus > 2 mm, demonstrating reflux during the valsalva manoeuvre on cdu without any physical examination finding (15). patients were divided into groups as group 1 (lcv and right testis without varicocele n = 104) or group 2 (lcv with rsv, n = 74) according to whether lcv was associated with right scv or not. patients in both groups underwent left microsurgical subinguinal varicocelectomy. primary endpoint of the study was to compare the groups in terms of seminal response, and pregnancy rates following varicocelectomy. secondary endpoint of the study was to compare the changes in testicular volume and serum hormone profile between the groups at the first year of the surgery. all measurement data are presented as the mean sd with paired or unpaired student-t test used for statistical evaluation. the chi-square test was used to compare sperm parameters. one-sample kolmogorov-smirnov was used to test the normal distribution. analysis of the data obtained in this study was performed with computer software (statistical package for social sciences, version 10.0; spss, chicago, il). as a result of kolmogorov-smirnov normality test, since the distribution of the measurements was suitable for normal distribution, the number of data was sufficient, and there were no outliers, tests that provided the parametric test approach were applied (p > 0.05). results a total of 178 primary infertile males with impaired semen parameter who went unilateral left varicocelectomy were retrospectively evaluated. of the 178 patients, 104 were in group 1 and 74 were in group 2. the demographic and baseline characters of the patients were presented in table 1. the mean age of the patients was 33.1 ± 6.2 years in the group 1 and 32.6 ± 6.4 years in the group 2 (p =.326). the group 1 and group 2 had an infertility duration of 30.4 ± 4.6 and 32.6 ± 4.1 months which revealed no statistical difference (p =.422). the baseline seminal parameters including mean sperm concentration, progressive motility, normal sperm morphology and viability were comparable between the two groups. in addition, no statistically significant differences were observed in terms of, right and left testicular volume and serum table 1. baseline data of the infertile patients in both groups. group 1 (n = 104) group 2 (n = 74) p value x ± s.d. x ± s.d. (µ-iqr) (µ-iqr) age 33.10 ± 6.20 32.60 ± 6.40 .326 (32.50-5.70) (31.80-5.50) i̇nfertility period (months) 30.40 ± 4.60 32.60 ± 4.10 .422 (30.20-7.10) (31.40-6.90) left varicocel grade grade 1 (n) 10 (10%) 7 (9%) .876 grade 2 (n) 60 (58%) 41 (55%) .549 grade 3 (n) 34 (33%) 26 (35%) .343 sperm concentration x106/ml 5.50 ± 1.90 4.42 ± 1.73 .234 (5.90-1.50) (4.75-1.30) progressive motile (a+b) (%) 19.20 ± 4.93 18.41 ± 3.72 .767 (20.50-5.00) (19.00-6.50) normal sperm morphology (%) 8.42 ± 2.57 7.68 ± 1.93 .876 (8.70-2.50) (8.00-3.00) sperm viability (%) 56.00 ± 11.22 52.00 ± 10.83 .432 (57.30-10.50) (53.50-9.50) (22.50-6.50) (24.20-6.00) testis volume (ml) (right) 14.6 ± 3.6 14.1 ± 3.4 .232 (14.50-3.50) (15.60-3.00) testis volume (ml) (left) 13.75 ± 2.80 14.01 ± 3.40 .384 (14.20-4.00) (14.50-3.00) fsh level (miu/ml) 8.40 ± 4.30 7.70 ± 4.70 .321 (8.50-3.50) (8.00-4.00) lh level (miu/ml) 6.40 ± 1.10 5.80 ± 0.90 .156 (6.50-1.50) (6.00-1.00) tt (ng/dl) 406.23 ± 202.25 432.47 ± 287.23 .146 (median) (417.00-75.00) (438.00-87.00) for left varicocel grade 15% of expected cell counts less than 5. µ, population mean; iqr, interquartile range; fsh, follicle stimulating hormone; lh, luteinizing hormone; tt, total testesterone. archivio italiano di urologia e andrologia 2023; 95(4):12128 3 effects of untreated unilateral subclinic varicocele fsh, lh and tt levels between the two groups before the surgery. the changes of semen parameters in the first year after left varicocelectomy in the two groups are shown in table 2. there were statistically significant increases in sperm concentration, and progressive motility, viability in both groups, while the normal morphology remained unchanged for both groups after the varicocelectomy. after the surgery, the mean sperm concentration increased significantly in both groups, but the improvement in group 1 was significantly greater than the group 2 (increased to 24.3 ± 5.3 in group 1 versus 13.2 ± 2.9 in group 2, respectively, p = .032). in addition observed changes in progressive sperm motility, (to 46.3 ± 9.4 in group 1, versus to 26.1 ± 5.4 in group 2, p = .026), viability (to 69 ± 16.8 in group 1 versus to 56 ± 12.4 in group 2, p = .047) were more statistically significant in group 1 compared to group 2. in the first-year control of varicocelectomy, the pregnancy rate was 46% in group 1, while this rate was 26% in group 2. a statistically significant difference was observed between the groups in both spontaneous pregnancy rates and pregnancy rates with art (p = .018). there was no significant change in testicular volume and serum hormone levels after surgery in both groups. discussion in this retrospective, non-randomized study, we aimed to show the effect of untreated scv on the outcome of contralateral varicocelectomy for lcv. we showed less improvement in semen parameters and also lower pregnancy rates in the group of patients with right scv and lcv compared to patients with lcv following left varicocelectomy. varicocele is one of the leading cause of impaired spermatogenesis and the most common correctable cause of male infertility (16). the main purpose of varicocelectomy in male infertility is to improve the semen parameters, achieve natural conception, and reduce the level of assisted reproductive technology. several studies have suggested that varicocelectomy has a beneficial effect on sperm parameters and fertility status in infertile men only with palpable varicocele (317). according to eau and aua guidelines, varicocelectomy should only be performed in infertile men with cv and abnormal spermiogram (18, 19). recently, due to the increasing popularity of cdus, the diagnosis of scv has increased. the increase in the detection rate of bilateral varicocele is mainly due to the neglect of the detection of sv in previous reports (20). the impact of scv on the sperm parameters is still debated and the clinical significance of repairing sonographically detected varicocele is controversial regarding male infertility (5, 21). since previous trials have reported that varicocele size had no effect on pregnancy rates, leading to the conclusion that very small varicoceles, even scv should be diagnosed and treated (6, 22). evidence that varicocele size does not correlate with pathology in testicular structure or sperm parameters is supported by the demonstration that scv also may have a damaging effect on the spermatogenesis (23). scv may be a milder form of cv with the same pathogenic mechanism and the results showed that 28% of scv in adolescent patients progressed to cv (24-25). dhabuwala et al. showed that seminal response and fertility were improved after subclinical varicocelectomy and suggested that scv may have similar deleterious effects as cv (6). in contrast table 2. change in sperm parameters and pregnancy rates in both groups following left varicocelectomy. group 1 (n = 104) group 2 (n = 74) pre-operative post-operative p pre-operative post-operative p p po 1-2 x ± s.d. x ± s.d. x ± s.d. x ± s.d. (µ-iqr) (µ-iqr) (µ-iqr) (µ-iqr) sperm concentration (106/ml) 5.52 ± 1.90 24.30 ± 5.32 .002 4.40 ± 1.72 13.21 ± 2.90 .045 .032 (5.70-4.00) (24.10-7.00) (5.00-3.00) (12.50-5.50) progressive motility (%) 19.21 ± 4.90 46.31 ± 9.44 .013 18.40 ± 3.71 26.11 ± 5.40 .042 .026 (19.50-6.50) (49.5-10.20) (17.50-4.50) (28.30-7.50) normal sperm morphology (%) 8.40 ± 2.50 14.20 ± 3.70 .532 7.60 ± 1.90 10.9 ± 5.91 .446 .342 (8.50-4.00) (15.00-5.50) (8.40-2.50) (10.40-3.00) sperm viability (%) 50,00 ± 11.20 69,00 ± 16.80 .034 48,00 ± 10.80 56,00 ± 12.4 .048 .047 (55.20-14.50) (70.5-15.50) (52.55-12.20) (58.70-13.0) pregnancy rates(n) 48(46%) 20 (27%) .018 spontaneous 42 (40%) 18 (24%) art 6 (6%) 2 (5%) for pregnancy rates 18% of expected cell counts less than 5. µ, population mean; iqr, interquartile range; art: assisted reproductive technology. table 3. change in bilateral testicular volume and hormone profile in both groups following left varicocelectomy. group 1 (n = 104) group 2 (n = 74) pre-operative post-operative p pre-operative post-operative p p po 1-2 x ± s.d. x ± s.d. x ± s.d. x ± s.d. (µ-iqr) (µ-iqr) (µ-iqr) (µ-iqr) testis volume (ml) (right) 14.6 ± 3.6 14.4 ± 3.40 .734 14.1 ± 3.4 14.2 ± 2.6 .956 .876 (14.8-2.50) (14.5-2.50) (14.3-3.00) (14.0-2.50) testis volume (ml) (left) 13.7 ± 2.8 14.2 ± 3.10 .646 14.3 ± 3.2 14.4 ± 2.8 .845 .640 (13.9-3.20) (14.0-3.00) (14,7-3.50) (15.0-2.80) fsh level (miu/ml) 13.6 ± 4.30 12.2 ± 4.90 .221 12.7 ± 4.7 11.6 ± 3.9 .134 .244 (13.5-4.00) (12.0-6.00) (12.5-4.50) (12.0-4.00) lh level (miu/ml) 15.4 ± 4.10 14.5 ± 4.20 .642 (14.8 ± 0.9) 14.6 ± 4.00 .934 .784 (16.5-5.00) (15.0-5.00) (15,5-2.0) (14.0-4.00) tt (ng/dl) 290 ± 168 310 ± 176 .634 305 ± 187 340 ± 202 .440 .510 (median) (300-90) (325-100) (310-100) (355-120) µ, population mean; iqr, interquartile range; fsh, follicle-stimulating hormone; lh, luteinizing hormone; tt, total testesterone. archivio italiano di urologia e andrologia 2023; 95(4):12128 sevgin yılmaz, murat topcuoğlu, murat çakan, ali akkoç, murat uçar 4 to these studies, it has been suggested that the improvement in semen parameters after the surgical treatment of scv is associated with lower success rates compared to cv surgery (26). a review evaluating three randomized clinical trials emphasized no evidence of benefit following varicocelectomy in infertile men with scv (27). likewise, jarow et al. showed that the improvement in semen quality after subclinical varicocelectomy was statistically lower than cv repair and pointed out that the benefit from subclinical varicocelectomy is questionable (28). although there is no prominent consensus on the management of scv, another issue discussed in the literature is the management of infertile patients with unilateral scv accompanying contralateral cv. we did not perform right subclinical varicocelectomy in the group of patients with right scv as recommended by current guidelines, and we assessed the results of left varicocelectomy in both groups of patients. in our study, spermiogram parameters (e.g., concentration, progressive motility, motility,) were significantly improved after left varicocelectomy in patients with left cv. significant improvement was shown only in sperm concentration and progressive motility in patients with right scv and left cv. statistically better improvement in sperm parameters including concentration, progressive motility, total motility were shown in left cv patients compared to patients with left cv and right scv at the first year of the surgery. a trial including one hundred forty-five infertile males with left cv or left cv with right scv investigated the seminal response following either unilateral or bilateral varicocele repair. the authors showed that patients who underwent bilateral varicocele repair had more significant improvement in semen parameters (sperm concentration and progressive motility) and had higher spontaneous pregnancy rate compared to patients those underwent left varicocele repair (29) . in a recent metaanalysis including six hundred thirty-seven patients of either left cv or left cv with right scv, improvement in spermiogram parameters following bilateral varicocelectomy or unilateral varicocelectomy were compared (30). statistically significant improvement in progressive sperm motility, sperm morphology was reported in favour of the bilateral varicocelectomy group. however, no statistically significant differences were revealed in sperm concentration between two groups. in a randomized controlled study, more significant changes in seminal response were shown in bilateral varicocelectomy compared to unilateral left varicocelectomy in infertile males with left cv and right scv (31). subsequent right varicocelectomy improved semen quality in 56% of patients, with a pregnancy rate of 43% in selected infertile patients those with no improvement in sperm parameters following left varicocelectomy. a recent study evaluating the outcomes bilateral varicocelectomy reported that, bilateral varicocele was found to be as high as 98.5% after radiologic assessment and subclinical varicocelectomy may be useful to avoid disease recurrence and optimize treatment outcomes (32). contrary to these findings, grasso et al. claimed that the benefit of repairing right scv associated with left cv was not substantial, given the possible additional morbidity and additional operative time (33). secondary endpoint of the study was to compare the changes in testicular volume and serum hormone profile between the groups. there were no significant differences in bilateral testicular volume between the two groups at baseline and the first year of surgery. similar to the negative effect of cv on testicular volume, it has been reported in previous studies that testicular volume decreases in scv (34). although pasqualotto et al. did not observe an increase in mean left testicular volume in patients with left cv and right scv who underwent bilateral varicocelectomy, they observed a significant increase in in the mean volume of right testis following bilateral varicocelectomy (35). they suggested that the varicocelectomy may increase the testicle size and this may be the reason for the surgery’s leading to an improvement in semen analysis. we evaluated hormone profile at baseline and compared the serum hormone levels at the first year of postoperative period. neither preoperative abnormalities nor significant changes in serum hormone levels following varicocelectomy were observed in either group of our study. zheng et al. indicated that scv did not affect hormone levels, as they were unable to find statistical differences in hormone levels between patients with left cv only and right scv with left cv (36). our study has some limitations which need to be considered while evaluating its findings. first, it is a retrospective study that can be affected by all potential weaknesses stemming from its retrospective design. second, according to current guidelines, we performed left varicocelectomy only in the bilateral varicocele group and assessed the deleterious effect of scv on sperm quality, rather than subclinical varicocelectomy direct impact. conclusions the topic of whether to repair or not to repair the ipsilateral scv in patients with contralateral cv is still controversial. untreated right scv may have detrimental effects on sperm parameters. this hypothesis should be supported by the larger case studies with the outcomes of right scv repair in patients with accompanying left cv. references 1. calverton, maryland, usa: orc macro and the world health organization; 2004. world health organization. infecundity, infertility, and childlessness in developing countries. dhs comparative reports no 9. 2. sadock bj, sadock va. 9th ed. philadelphia: lippincott williams and wilkins; 2003. kaplans and sadocks symptoms of psychiatry behavioral sciences clinical psychiatry; pp. 872-4. 3. ficarra v, cerruto ma, liguori g, et al. treatment of varicocele in subfertile men: the cochrane review. a contrary opinion. european urology. 2006; 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subclinical varicocele on testicular volume. fertil steril. 1997; 68:671-674. 35. pasqualotto ff, lucon am, de góes pm, et al. is it worthwhile to operate on subclinical right varicocele in patients with grade ii-iii varicocele in the left testicle? j assist reprod. genet. 2005; 22:227231. 36. zheng yq, gao x, li zj, et al. efficacy of bilateral and left varicocelectomy in infertile men with left clinical and right subclinical varicoceles: a comparative study. urology. 2009; 73:1236-1240. correspondence sevgin yılmaz sevginyilmaz80@gmail.com murat çakan muratcakandr@yahoo.com department of urology, university of health sciences dıskapı training and research hospital, ankara, turkey murat topcuoğlu muraturo@yahoo.com ali akkoç aliakkoc@gmail.com murat uçar ucarmurat07@gmail.com department of urology, faculty of medicine, alanya alaaddin keykubat university, alanya turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3274 original paper no conflict of interest declared. previous studies show that urinary incontinence's prevalence widely varies from 2% to 65.5% and sexual dysfunction up to 87% (5, 6). laparoscopic radical prostatectomy (lrp) has become a frequent treatment on local control of prostate cancer (8). bollens et al. described an extraperitoneal laparoscopic surgical approach that combines the usual advantages of a laparoscopic procedure (less painful, reduced morbidity, earlier recovery) and the benefits of the open retropubic approach (avoid intraperitoneal organs injuries, potential risk of cancer spillage in the peritoneal cavity, intraperitoneal bleeding or urine leakage and allows possible later adjuvant radiotherapy) with results in terms of erectile function and continence equivalent to other techniques (9). prostate removal causes the destruction of the supporting system that anatomically and functionally separates the urethral sphincter complex from the prostatic apex and denonvilliers' fascia, resulting in postoperative incontinence (6). the avoidance of these major complications after rp depends mainly on a high-quality surgical technique based on preservation, reconstruction, and reinforcement of the pelvis's anatomical structures, which will make a new supporting system after rp. surgical techniques for posterior reconstruction of the rhabdosphincter were developed, namely rocco stitch (rs) and bollens stitch (bs) (6, 7, 14). a recent systematic review suggests that the rhabdosphincter's reconstruction could offer a significantly earlier return to continence in the first 30 days after rp still; its effect at 90 days remains controversial (10, 11). salazar et al. (2019) concluded as well that the reconstruction of the rhabdosphincter is the only technique that has shown improved functional results through randomized trials (12). this study compares the impact of posterior reconstruction of the rhabdosphincter on urinary continence recovery with no rhabdosphincter reconstruction after lrp procedure; while assessing, prospectively, two types of posterior reconstruction of the rhabdosphincter, namely rs or bs. objectives: some studies have shown that rhabdosphincter reconstruction provides an earlier return to continence after radical prostatectomy. we aim to study the impact of this procedure in urinary continence along with comparing two specific surgical techniques for posterior reconstruction. materials and methods: we studied a group of patients who were submitted to lrp with no rhabdosphincter reconstruction (nrr) and another group with posterior reconstruction of the rhabdosphincter (prr). the latter was further divided into two groups: "rocco type stitch" group and "bollens type stitch" group. we used three questionnaires (iief-5, iciq-sf and ipss) to assess urinary continence and erectile function 90 days after surgery. results: patients of prr group had a better full continence rate than patients of nrr group at 90 days (96.6% vs 33.3%, p < 0.001). concerning urinary incontinence (p = 0.116), lower urinary tract symptoms (p = 0.543) and postoperative complication rates (p = 0.738), our results suggested that there were no differences between the techniques studied. conclusions: posterior reconstruction of the rhabdosphincter has significant benefits for urinary continence recovery on patients undergoing radical prostatectomy. no differences were observed in continence recovery between the two techniques analyzed. additionally, reconstruction of the rhabdosphincter appears to be a safe procedure with no increased risk of postoperative complications. key words: radical prostatectomy; prostate cancer; rhabdosphincter reconstruction; postoperative complications; erectile dysfunction; urinary continence. submitted 11 june 2021; accepted 9 july 2021 introduction one of the most common and effective treatments for localized prostate cancer (pca) is the radical prostatectomy (rp) (1, 2). however, this procedure has shown to have a significantly negative impact on multiple quality-of-life domains due to its adverse effects such as urinary incontinence and erectile dysfunction (3, 4). reconstruction of the denonvillier's fascia and posterior ligament of the external urethral sphincter: assessment of its effect on urinary continence after laparoscopic radical prostatectomy pedro sousa passos 1, 2, sara teixeira anacleto 1, rui simeão versos 2, mário cerqueira alves 1, paulo oliveira mota 1, 3 1 department of urology, hospital de braga, portugal; 2 department of urology, hospital de guimarães, portugal; 3 institute of life and health sciences, university of minho, portugal. doi: 10.4081/aiua.2021.3.274 summary 275archivio italiano di urologia e andrologia 2021; 93, 3 rhabdosphincter reconstruction after laparoscopic radical prostatectomy materials and methods general we performed an observational and prospective nonrandomized study. the data was collected from the braga's hospital information system, glintt®, and via in-person interviews with patients, at the time of their postoperative appointment (90 days after lrp). all collected data were kept confidential. the research protocol was submitted and approved by the ethics commission for health of braga's hospital (ceshb) and by the ethics commission for sciences of life and health of minho's university (ceicvs). there were no potential conflicts of interest. patient population the selected patients were older than 18 years old who attended braga's hospital consultations and submitted to lrp between january 2018 and november 2019. the inclusion criteria were histological confirmation of pca and localized pca. the exclusion criteria included the presence of urinary incontinence before the procedure, previous radiation therapy of the prostate or pelvis, presence of prostatic surgery prior to the procedure, prior medical history of psychiatric disorder or drug addiction, and any other condition that contraindicated lrp. patients with a history of urethral surgery, urethral stenosis or artificial urinary sphincter were also excluded. according to these criteria, we selected a sample of 63 patients that had been submitted to lrp. two different surgeons had performed the surgery in this group of patients, which was divided into two major groups: nrr: retrospective group, whose patients have been submitted to lrp between january 2018 and december 2018 and had no reconstruction of the rhabdosphincter. prr: a group of patients who have been submitted to lrp, followed by posterior reconstruction of the rhabdosphincter, between january 2019 and november 2019. according to the technique used for posterior rhabdosphincter reconstruction, this group was further divided into two sub-groups rs and bs groups. each technique was performed solemnly by a different surgeon (surgeon 1 rs and surgeon 2 bs). patients undergoing postoperative radiotherapy or major clavien dindo complications in the postoperative period were not included for the urinary continence assessment. clinical data collection the demographic characteristics (age and sex), alcohol consumption, smoking habits, lower urinary tract symptoms, familiarity with pca, previous procedures of the urologic tract and number of pads used daily since lrp were asked to the patients under consultation. the following data were collected by analyzing clinical reports: rhabdosphincter reconstruction (and type of stitch) or no reconstruction, patient's usual medication, metabolic disorders (hypertension, dyslipidemia, diabetes mellitus, increased waist circumference), psa (ng/ml) previous to lrp, the result of digital rectal examination (normal or suspicious), prostate biopsy mode realization (aleatory, cognitive fusion or ultrasonography fusion) and associated complications, hospitalization duration and urinary catheter duration (days) after lrp and psa value (ng/ml) one month after surgery (psa t0). clavien-dindo classification was usd to classify the complications rate after surgery. in this study, the pelvic floor rehabilitation protocols assessed were the pelvic floor muscle training (pfmt) in combination with behavioral therapy. outcome measures the following outcome data were collected 90 days after the procedure by the healthcare provider: urinary continence: declared urinary continence (defined by 0/1 safety pad per day) after physician evaluation on both the nrr and prr groups, 90 days after lrp (33) number of pads/day used after lrp (rs vs bs) international consultation on incontinence questionnaireshort form (iciq-sf) assessment (rs vs bs) international prostatic symptoms score (ipss) assessment (rs vs bs). erectile function: erectile function using international index of erectile function (iief-5) assessment (rs vs bs). morbidity associated to the surgical techniques: peri and postoperative complication rates (nrr vs prr and rs vs bs). clavien-dindo classification (nrr vs prr and rs vs bs). questionnaires iciq-sf, validated in portuguese (cronbach's alpha coefficient of 0.88) to assess the patient's urinary continence (13). ipss, validated in portuguese (cronbach's alpha coefficient of 0.80) to assess luts (13, 14). iief-5, validated in portuguese (cronbach's alpha coefficient of 0.89) to assess erectile function (16). statistical analysis the statistical analysis was performed with ibm spss® statistics for windows, version 26.0. data normality was assessed through the shapiro-wilk test, skewness, kurtosis and visual evaluation of the histograms (17, 18). to characterize the study's variables, we performed a descriptive analysis. categorical variables were presented as frequencies (n) and proportions (%). numerical variables were presented as means (m) and standard deviations (sd) for symmetrically distributed variables, and medians (mdn) and interquartile ranges (iqr) for non-symmetrically distributed variables. the comparison of numerical variables between groups was performed with student's t-test. the applied effect size measure was cohen's d (19). a mann-whitney u test was performed when variables were not normally distributed. the effect size measure of this test was r = z/√n, where 'n' is the total number of cases related to the study variable (20). the chi-square test was used to compare proportions across qualitative variables. fisher's exact test was used alternatively when the expected frequency was lower than 5 in more than 20% of the contingency table cells (21). the applied effect size measure was phi (ϕ) or crammer's v, since the cross-tables were two by two or three by two, respectively. archivio italiano di urologia e andrologia 2021; 93, 3 p. sousa passos, s. teixeira anacleto, r. simeão versos, m. cerqueira alves, p. oliveira mota 276 to compare the urinary continence between-group nrr and prr, we used a chi-square test (χ2), and the effect size measure used was phi (ϕ), since the cross-table was two by two. the clavien-dindo score was converted to a categorical variable: no complication (0), minor complication (i+ii) and major complication (iii+iv). a fisher's exact test was used to compare these variables between groups nrr and prr and to compare them between groups rs and bs. the effect size measure used was cramer's v since the cross-tables were three by two. for numerical variables, such as the number of pads/day used after lrp and the iief assessment results, iciq-sf assessment and ipss assessment, we applied a mannwhitney u test. this test was also used to compare these numerical variables between group rs and bs. the effect size measure used was r. a p-value of less than 0.05 was considered statistically significant, and the confidence interval was 95%. results from the total sample population of 63 patients, 28 were not submitted to the posterior reconstruction of the rhabdosphincter (nrr), and 35 patients were (prr). the mean value for age was 64 years for both nrr and prr group. table 1 shows the baseline characteristics between nrr and prr groups, in which there were no differences. table 2 shows the gleason score and tnm staging of the included patients. regarding intraoperative complications, minor complications were reported in n = 3 (10.7%) from the nrr group and n = 6 (17.2%) from the prr group; and major complications occurred in n = 3 (10.7%) and n = 5 (14.3%), in the nrr and prr groups, respectively. complications were observed in both groups within days after surgery. however, after the mean (sd) follow-up period of 90 days, there were no complications in group prr, and two patients from group nrr had complications. regarding the clavien dindo classification, most patients did not present complications. table 3 compares postoperative medication and pelvic floor rehabilitation between nrr and prr, and it shows no statistically significant differences. the table also shows that, at 90 days after surgery, 17 patients from nrr group and 14 from prr group (n = 4 (28.5%) and n = 10 (71.5%) from rs and bs groups, respectively) had already initiated pdh5 inhibitor (p = 0.131); five patients from nrr and three from prr had started pge1 (p = 0.449) (n = 3 (100%), from the rs group, and n = 0 from the bs group). regarding pelvic floor rehabilitation, three patients (10.7%) from nrr and two (5,7%) from prr had started physical therapy (p = 0.648) (n = 1 in both rs and bs groups) 90 days after surgery. table 4 shows that the prr group patients had a better urinary continence rate than patients of the nrr group (96% vs 33,3%; p < 0.001), 90 days after surgery. according to the posterior rhabdosphincter reconstruction techniques, 25 patients (71.4%) were submitted to rs and ten patients (28.6%) to bs. the baseline characteristics of both groups are presented in table 5. there were no differences between them. regarding intraoperative complications, minor complications were reported in n = 5 (20%) from the rs group and n = 1 (10%) from the bs group, and major complications occurred in n = 3 (12%) and n = 2 (20%) in the bs and rs groups, respectively. table 6 compares the outcomes: number of pads/day used after lrp and iciq-sf, ipss and iief assessments between rs and bs. one patient (5.6%) from rs used more than one safety pad/day, while no patient from bs table 1. baseline characteristics of nrr and prr groups. table 2. gleason score and tnm of included patients. table 3. comparison of postoperative erectile dysfunction medication and pelvic floor rehabilitation between groups nrr and prr. 277archivio italiano di urologia e andrologia 2021; 93, 3 rhabdosphincter reconstruction after laparoscopic radical prostatectomy used more than one safety pad/day, but a significant difference was not found. the median score on iciq-sf was higher on rs than on bs (with no statistically significant differences, p = 0.116), and the median score on iief-5 assessment was 5 (0) in both groups. table 7 presents the impact of posterior rabdosphincter in both groups, rs and bs. after 90 days from lrp, no complications were observed in either group. regarding clavien dindo classification, there were no complications in most of the subjects in both rs and bs group (68% vs 70%; p = 0.738). discussion the results of this study suggest that posterior reconstruction of the rhabdosphincter improves the early continence of patients undergoing lrp, as it is described in several studies (11, 22-24). rocco et al. (2007) conducted a prospective study on patients undergoing lrp, defining continence as no pads or one diaper/day. at 90 days after catheter removal, the continence rates were 92.3% on patients with posterior musculofascial plate reconstruction versus 76.9% on patients with no reconstruction (25). rocco's study corroborates our results where patients of the prr group had a better full continence rate than patients of the nrr group at 90 days. our study also showed no differences between the complication rates in the posterior rhabdosphincter reconstruction group and the non-reconstruction group and similar clavien dindo classification of complications. coelho et al. (2011) related that overall complication rate and postoperative acute urinary retention rates at 30 days were similar between both groups (24). grasso et al. (2016) have also shown no association between rhabdosphincter reconstruction and postoperative complications in a review and meta-analysis (11). regarding posterior rhabdosphincter reconstruction techniques (rs and bs), the current study found that both groups reported similar urinary continence rate and that one patient from rs group used more than one safety pad per day. in contrast, no pads were used in the bs group. for measuring urinary function, two questionnaires were applied to the reconstruction group: iciq-sf and ipss, in which the median scores were similar in both groups. machioka et al. (2019) demonstrated that the iciq-sf questionnaire was effective and convenient for evaluating urinary incontinence, including in patients after rp (26). however, this questionnaire is a subjective measure of the severity of urinary loss and the impact of urinary incontinence on quality-of-life (13), as its results depend on the patient's perspective. since the results on ipss are between 1 and 7, lower urinary tract symptoms have a mild severity in these patients (27). assessing erectile function after 90 days from posterior rhabdosphincter reconstruction, the median score on iief5 assessment was the same in both groups. however, most patients were not on medication for erectile dysfunction at the time of the interview. rocco et al. have described that erectile function was similar in reconstruction and nonreconstruction groups (28). further literature corroborates that rhabdosphincter reconstruction techniques have no benefit for erectile function recovery (29). the complication rates were similar in both rs and bs groups and, considering clavien dindo classification of complications, both groups had similar results. according to a meta-analysis stratified by surgical approaches, no association has been found between rhabdosphincter reconstruction and postoperative complications (11), suggesting that it is a safe procedure. moreover, we measured selected demographic variables that are described in previous literature to have a great influence on postoperative urinary incontinence and erectile function (such as age, prostate size, psa score, metabolic disorders, gleason score, urinary catheter duration and surgical complications.) and table 5. baseline characteristics of rs and bs groups. table 6. comparison of the outcomes between rs and bs groups. table 7. impact of posterior rabdosphincter in both groups, rs and bs. table 4. comparison of urinary continence between groups nrr and prr. archivio italiano di urologia e andrologia 2021; 93, 3 p. sousa passos, s. teixeira anacleto, r. simeão versos, m. cerqueira alves, p. oliveira mota 278 found that there were no statistically significant differences between the groups nrr and prr (3, 25, 30-32). this study has some limitations. the low sample size of the prospective part of the study (n = 35) limits possible extrapolation. additionally, the follow-up period (90days) was short for evaluating urinary continence, and the reference used for its definition in the prr groups (number of pads/day) was a biased and subjective outcome, as opposed to a pad weight test. furthermore, the non-reconstruction group is retrospective, and, therefore, the data were based on the physician interview and could have been affected by subjectivity. finally, several surgeons were responsible for performing the surgeries, which means that this was a non-controlled variable in this study. more extensive research on surgical techniques for earlier urinary continence in lrp is required to allow more robust conclusions. therefore, we recommend further studies on the current topic. conclusions this study shows that the rhabdosphincter's posterior reconstruction has significant benefits for urinary continence recovery in the first 90 days on patients undergoing lrp. additionally, reconstruction of the rhabdosphincter appears to be a safe procedure with no increased risk of postoperative complications. concerning urinary continence and postoperative complication rates after lrp and postoperative complication rates, the results suggest that there are no statistically significant differences between rocco stitch and bollens stitch. still, a system of support appears to play an essential role in urinary continence after surgery. further work is required to establish this. references 1. wein aj, kavoussi lr, partin aw, et al. campbell-walsh urology. 12th ed. elsevier. 2020; 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2:5. 32. heesakkers j, farag f, bauer rm, et al. pathophysiology and contributing factors in postprostatectomy incontinence: a review. eur urol. 2017; 71: 936-44. 33. kretschmer a, hübner w, sandhu js, bauer rm. evaluation and management of postprostatectomy incontinence: a systematic review of current literature. eur urol focus. 2016; 2:245-59. correspondence pedro sousa passos, md (corresponding author) pedrosousapassos@gmail.com department of urology, hospital de braga largo bairro do jardim 3, 4900-467 viana do castelo (portugal) sara teixeira anacleto, md sara.anacleto241@gmail.com mário cerqueira alves, md mcerqueiraalves@gmail.com paulo oliveira mota, md damota.paulo@gmail.com department of urology, hospital de braga (portugal) rui simeão versos, md rui.1971.versos@gmail.com department of urology, hospital de guimarães (portugal) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 1 original paper degree in medicine and surgery, having discussed an experimental thesis entitled “intracardiac pressure variations after interruption of the inferior caval circulation” and earning top marks: 110/110 with distinction (1). endowed with great talent, giuliani was appointed voluntary assistant at the institute of general clinical surgery and surgical therapy of the university of florence a few months later, on 1 november 1951. he immediately became known for his ability and diligence in carrying out his activities and for his outstanding skills, and his position was confirmed until 1954. in the period between 15 january 1952 and 31 may 1953, he carried out his obligatory military service; having achieved first place in his course (out of 302 candidates) (2) in the final examinations of the 10th course for additional trainee medical officers, he was appointed medical officer with the rank of second lieutenant (3). subsequently, giuliani first served as an assistant at the institute of war traumatology and surgery of the school of military health in florence from 15 june 1952 to 15 june 1953. one of the first publications of his long career was “l’ibernazione” (“hibernation”), which was published in the giornale di medicina militare (journal of military medicine) in 1953 (4). in it, he outlined the biological, physiological and clinical bases of the practice of hibernation and offered some considerations regarding the purposes, indications and limitations of its application, particularly in the field of surgery (figure 2). on 1 november 1954, giuliani continued his career at the surgical clinic of the university of florence, where he luciano giuliani was born near arezzo, in tuscany (italy) in 1928. after taking his degree cum laude in medicine and surgery at the university of florence in 1951, he became a voluntary assistant at the institute of general clinical surgery and surgical therapy. he then took a diploma in urology and general surgery, having demonstrated his great technical and surgical ability, and was subsequently appointed assistant in charge and then extraordinary assistant. endowed with uncommon surgical skills and a forceful personality, giuliani tirelessly carried out his clinical and surgical activity, covering several roles and rapidly earning profound esteem and recognition in the field of urology. as a pupil of the great luminary of italian surgery, ulrico bracci, dr giuliani keenly followed his master, embracing his teachings and surgical techniques, until 1969, when he was appointed to run the 2nd urology division at san martino hospital in genoa. he subsequently took up the chair of urology at the university of genoa and became director of the specialty school in urology. within a few years, he earned a solid reputation both nationally and internationally through his innovative surgical techniques. he also gave considerable impetus to the genoese school of urology, reaching the highest echelons of the italian and european societies of urology. at the beginning of the 1990s, he designed and founded a new urology clinic in genoa; this imposing, avant-garde building was subdivided into four floors and equipped with 80 beds. in july 1994, he won the prestigious “willy grégoir medal”, an accolade awarded to eminent personalities in european urology. in august of the same year, he died in the institute that he himself had created at san martino hospital in genoa. key words: luciano giuliani; history of medicine; history of urology; italian urology; genoese urology school. submitted 22 march 2023; accepted 23 march 2023 luciano giuliani: the first steps dr luciano giuliani was born in paindiscò (arezzo) on 3 july 1928 (figure 1). having matriculated at the faculty of medicine of the university of florence in the academic year 1945-46, he enthusiastically and assiduously devoted himself to his studies. in the years 1949-50 and 1950-51, he regularly frequented the departments and the laboratories of the surgical clinic as a student intern. on 25 july 1951, at the university of florence, he took his luciano giuliani (1928-1994): great master and founding father of modern italian urology mariano martini 1, 2, giuseppe martorana 3 1 department of health sciences, university of genoa, genoa, italy; 2 unesco chair anthropology of health. biosphere and healing system, university of genoa, genoa, italy; 3 university of bologna, bologna, italy. doi: 10.4081/aiua.2023.11329 summary figure 1. prof. luciano giuliani (1928-1994). archivio italiano di urologia e andrologia 2023; 95, 2 m. martini, g. martorana 2 was appointed “extraordinary assistant”, a position that he held until 1 november 1956, when he moved to the newly-founded urology clinic. during this period, giuliani also took a specialty diploma in urology at the university of pisa (18 july 1955), achieving a mark of 70/70 (5). following the establishment of the new urology clinic of the university of florence in 1956, giuliani was immediately appointed extraordinary assistant. the following year (1957), he further consolidated his training by taking a specialty diploma in general surgery, achieving the top mark of 70 with distinction. the year 1957 was a particularly important one for dr. giuliani; in addition to earning the above-mentioned specialty diploma in general surgery (29 july) with distinction, he was appointed for the academic year 1957/58 as designated assistant to the chair of the urology clinic (6), a position that was confirmed for the years 1958/59, 1959/60 and 1960/61. these were fundamental years and constituted the foundations on which he would later build his long and fruitful academic pathway in the field of urology. luciano giuliani: a versatile surgeon and a young academic on 18 april 1958, following a public competition, giuliani qualified for the position of ordinary assistant to the chair of urology of the university of florence. the following month, however, he interrupted this tenure in order to be reconfirmed extraordinary assistant. his title of extraordinary assistant was also confirmed for the academic year 1958-59. dr. giuliani carried out his clinical and surgical activities in a continuous manner: first during his service at the surgical clinic in florence as an assistant in the various departments of general and thoracic surgery and then in the urology department. subsequently, he held the position of head of department with the function of “vicechief” at the urology clinic. giuliani's temperament and versatility, coupled with his remarkable tenacity and determination, were evident right from the first years of his training. indeed, during his military service, he dealt with military traumatology and surgery from both a theoretical and practical standpoint, without ever interrupting his university activities. moreover, for several years, and consistently until 1956, he served as an assistant surgeon at the ospedale civile di empoli during the summer closure of the university clinics, which enabled him to “stay on form” and to hone his surgical skills even during the summer period! in the early period of his career, giuliani actively devoted himself to the various branches of surgery, acquiring extensive knowledge of thoracic, urological, orthopaedic, gynaecological and obstetric surgery, in addition to general surgery. moreover, in 1956, when still academically very young (28 years old), he was given responsibility for the practical training in clinical urology of sixth-year students at the university of florence, where he subsequently taught the following subjects at the specialty school in urology: functional diagnostics in urology (1st year); functional pathology of the excretory pathway. during those years, giuliani wrote several scientific articles. notable for its originality, methodological rigour and scientific impact, was “on the extra-hepatic biliary pathways”, published in 1954 in the journal “la chirurgia generale” (7) (figure 3). in it, the young author made innovative anatomical, physiological and pathophysiological observations (8). however, the young giuliani was still fascinated by the urological activity carried out in the dedicated department and coordinated by prof. bracci, prof fedeli's assistant; he therefore began to participate more closely in this work. for his part, prof. bracci, with the encouragement and approval of his mentor prof fedeli, had long been oriented towards the entire field of urology, working first in the surgical clinic in perugia and then, after 1947, in florence. indeed, after first qualifying to teach surgical pathology and surgical anatomy, he became a freelance teacher of urology in 1942. moreover, while still a young assistant, and a few years after following prof fedeli to florence, he wrote a book figure 2. s. ten. med dott. l. giuliani. l’ibernazione. extract of giornale di medicina militare (journal of military medicine). figure 3. “on the extrahepatic biliary pathways” (1954) “la chirurgia generale” (general surgery) in rivista di biologia. archivio italiano di urologia e andrologia 2023; 95, 2 3 luciano giuliani (1928-1994), pioneer of history of urology on urological semiotics (1950) and introduced an innovative method regarding “access pathways in the surgery of the urinary apparatus” (which would be published in 1956). in 1955 (the year in which giuliani took his specialty diploma in urology), prof. bracci was chosen as one of the three winners (together with prof pavone in palermo, and prof pisani in milan) of the first national competitive examination for the post of ordinary prof of urology. the following year, he was appointed director of the institute of clinical urology of the university of florence, the first university chair of urology in italy, and in 1957 the specialty school in urology was instituted. thus began a new era for florentine urology in particular, and also for italian urology in general. bracci brought to urology all his knowledge of general surgery, developing themes which – albeit previously described and implemented – had, for various reasons, never been widely adopted, e.g. the use of the intestine in urology. hitherto, the standard procedure had been ureterosigmoidostomy (uss); urinary infection was the most frequent cause of severe complications… sometimes more “malignant” than neoplastic disease progression... this aspect soon became the principal theme to investigate (as is well described in bracci's report, published in 1959 in chirurgia urologica) (figure 4). the main objective was to abandon the previous approach, which involved the mixing of faeces and urine, and to create a reservoir that displayed the following characteristics: – sufficient capacity to allow almost normal frequency of urination; – in the filling phase, the patient could feel the stimulus and would be prompted to urinate; – complete emptying and explorability; – no negative impact on the upper urinary apparatus. as the rectal neo-bladder met these requirements, it was adopted, in its variants, for years. bracci proved to be a great innovator and succeeded in promoting his discipline, bringing together a group of young physicians, who enthusiastically embraced the teachings of their mentor. in those years, the urology clinic of the university of florence was made up of: – ordinary assistants with "vice-chief" responsibilities: alfiero costantini, luciano giuliani, mario polito, mario tacciuoli; – ordinary assistants and volunteers: tullio lotti, francesco micali, nicola cerulli, michelangelo rizzo, alessandro basso, et al.; – physicians from different specialties who collaborated with the chair of urology: elia vernaglione, anna martini (anaesthetists) gianfranco bruscagli (cardiologist) bruno fedi (pathologist) imola rossi (chemist) giancarlo masini (radiologist). among these, was luciano giuliani, who (as we have already mentioned above) became “extraordinary university assistant” at the newly founded urology clinic on 1st november 1957 (9). giuliani soon became one of bracci's closest collaborators: – from the surgical point of view: he was one of bracci's favourite assistants in the operating theatre; – from the teaching point of view: he was entrusted with the practical training in clinical urology of sixth year students at the university of florence; – from the scientific point of view: he immediately manifested his propensity for research; specifically, he supported his mentor and conducted important studies in experimental surgery and urodynamics of the urinary derivations (10, 11). as the author of numerous publications of a clinical, radiological, pathological, surgical and experimental nature, generally in the field of urology, dr giuliani was awarded the prestigious “prize for scientific diligence” for the academic years 1956/57 and 1958/59 at the university of florence. moreover, at the 32nd congress of the italian society of urology in september 1959, he received the “premio itala iv°” for the best urology publication of the year for his paper entitled: “gastrocystoplasty: from the experimental idea to some practical considerations concerning plastic and replacement surgery of the bladder” (10). from 1959 onwards, dr. giuliani also worked systematically in the departments of general and thoracic surgery directed by his mentor ulrico bracci at the sanatorium of the anti-tuberculosis consortium in florence, were he was able to increase his surgical skills and his clinical experience (12). prof. ulrico bracci was one of the great luminaries of 20th century italian surgery and the founder of the first true italian school of urology at the end of the 1950s in florence and subsequently in rome. prof. bracci played a fundamental role as an innovator and promoter of specialisation in urology, becoming a dominus and a point of reference for italian urologists for over 30 years. after again winning the “prize for scientific diligence” (1959/60), in 1960 giuliani deservedly obtained his qualification as untenured lecturer in urology (special surgical pathology and clinical propedeutics), achieving first place among the candidates. in the same year, he actively collaborated in the italian society of urology's official report (brescia-bergamo) on “surgery for renal hypertension” (figure 5). a year later, 1961, he took part in the report of the annual congress on the “surgical treatment of prostate cancer” figure 4. bracci u. chirurgia urologica (urologic surgery), 1959. archivio italiano di urologia e andrologia 2023; 95, 2 m. martini, g. martorana 4 and just the surgery of prostate cancer is another example of prof bracci's boost to “more complex” urological surgery. this had previously been rarely undertaken, as the subtle course of the disease meant that the tumour was almost always discovered when it was no longer operable. this was the first time in italy that the issue of radical prostatectomy had been presented in such an organic, complete and didactic manner. thus, its anatomo-surgical foundations were laid (figure 6). giuliani, together with his mentor, played a central role in both the anatomo-surgical study and the writing of the text, with the collaboration of prof costantini and prof. tacciuoli. these were fundamental years for giuliani and constituted the foundations on which he would later build his long and fruitful academic pathway in the field of urology. these were precisely crucial years for giuliani, as is demonstrated by his “prizes for scientific diligence”. they were also very productive years for prof. bracci's whole team, of which giuliani was a member, both from the clinical and scientific standpoints and from that of the promotion of the discipline of urology. indeed, it was in those years that italian urology laid down the foundations for the use of: – the intestine in urology (13); – radical prostatectomy (14); – pathways of access in the surgery of the urinary apparatus. all this involved demanding and innovative research work, all of which was designed and implemented during this fruitful florentine period. subsequently, it was developed during giuliani's roman period. indeed, in 1963, prof bracci was called to rome to take up the first official chair of urology in the history of the capital. this marked the beginning of the so-called “roman school of urology”, a development that had considerable impact on the history of italian urology. the urology clinic in florence was left under the direction of alfiero costantini, while bracci was followed by his pupils giuliani and tacciuoli, who supported their master in his teaching. subsequently, lotti, micali and polito also moved to rome, followed later by cerulli and calderini. the years spent in rome enabled the young giuliani to grow and to acquire vast experience in the various areas of urology. of the several scientific works produced during that fecund roman period, we may cite the important contribution entitled “the functional recovery of excluded kidneys” (figure 7) presented at the 40th congress of the italian society of urologia held in bologna in october 1967 (15). the great leap forward: giuliani in genoa the experience gained by giuliani during the fruitful years in which he worked alongside his mentor prof. bracci in rome, summed to his tireless activity during the previous florentine period, enabled him to reach such a level of maturity as to warrant his autonomous direction of a clinic. the opportunity soon materialised – at one of europe's largest hospitals of the day: san martino hospital in genoa. indeed, in 1969, the department of urology of san martino hospital was divided into two large branches: 1st urology division, headed by prof. germinale, already tenured at san martino hospital; 2nd urology division, directed by prof. giuliani. this was giuliani's first fully autonomous position in figure 5. atti della società italiana di urologia urology's official report (oberholtzer a, a cura di), xxxiii congresso, bergamo-brescia, 13-16 ottobre, 1960. figure 6. bracci u, giuliani l, costantini a, tacciuoli m. the surgical treatment of prostate cancer. 1961. vallecchi ed. officine grafiche. firenze. figure 7. bracci u, giuliani l, polito m. la ripresa funzionale dei reni esclusi (the functional recovery of excluded kidneys) (1967). ente fiuggi, cappelli editore, bologna. archivio italiano di urologia e andrologia 2023; 95, 2 5 luciano giuliani (1928-1994), pioneer of history of urology which he had sole responsibility for direction. at that time, he was working at the urology clinic in rome as “university vice-chief” to prof. ulrico bracci, and had already emerged as a “ternate winner” in a competition for professors. a couple of years after being given responsibility for the urology division at san martino, in march 1971, giuliani was unanimously declared extraordinary professor of urology at the faculty of medicine and surgery of the university of genoa; thus, he became the first tenured professor of the chair of urology in genoa and in liguria. the 2nd urology division was thus renamed “urology clinic” and, over the years, genoa became the capital of italian urology. a short time later, in 1972, the specialty school in urology was also instituted at the university of genoa, and was immediately entrusted to the direction of prof. giuliani. prof. giuliani was endowed with great intelligence and competence and possessed extraordinary surgical skills that enabled him to develop innovative, ground-breaking techniques. naturally enough, he rapidly emerged on the national and international scientific scene, distinguishing himself through his forceful personality and great authoritativeness. thus, he imparted an enormous thrust to the genoese urology school, which soon became a point of reference for the scientific sector nationwide. in 1973, giuliani was appointed president of the 46th national congress of the italian society of urology, which was held in genoa. a few years later (1978) he was elected president of the italian society of urology (siu), a post he held until 1982, when he was elected to the executive committee of the european society of urology (esu). the year 1986 was an important one not only for the genoese school of urology, the city of genoa and the liguria region, but also for the whole of italian urology. indeed, it was in that year that giuliani succeeded in founding and inaugurating the centre for calculosis of the genoese urology clinic. he equipped this facility with an extracorporeal lithotriptor (a very modern apparatus that shattered calculi by means of an extracorporeal approach); a truly extraordinary event, since this was the first public facility in italy to be so equipped! moreover, the “genoese school”, directed by prof. giuliani and featuring a team made up of belgrano, carmignani, giberti, martorana, puppo et al., also distinguished itself through the production of a sort of “graphic-editorial exercise” in urological surgery, which was designed to aid and improve teaching activities. indeed, 1986 saw the publication of a complete “atlas of surgery of kidney cancer”, probably the first such atlas in the history of italian publishing; it was subsequently translated into english and distributed internationally. the atlas provided an analytical and highly detailed presentation – in a rational, schematic and realistic form (as far as this was possible in an atlas of surgical techniques) – of the times and sequences most characteristic of the principal operations involved in the surgical treatment of kidney cancer (figure 8). and a couple of years earlier, on the occasion of the national congress of urology, held in bari in 1984, a scientific text was published for the proceedings of the italian society of urology (siu) under the title: “pathways of access in urology”, a volume featuring ample drawings (16-19). in 1988, with the retirement of prof. germinale, and after a brief interim period of direction by another ligurian colleague, the urology division was merged with the urology clinic and giuliani became responsible for the single facility, which was very extensive and equipped with numerous beds (20). this newly instituted single facility was a truly evocative return to the past, in that it brought urology back to the original structure directed by the great master giorgio nicolich jr, which extended for almost 30 years, from 1938 to 1966 (21). in april 1992, giuliani succeeded in an enterprise that was, at that time, truly extraordinary and titanic: the inauguration of the new genoese urology clinic (figure 9)! the entire operation was personally drawn up and directly supervised by giuliani himself, with considerable financial support from the genoese banking institution ca.ri.ge. thus, prof. giuliani achieved his objective of constructing an imposing, modern, complete facility consisting of: a 4-storey building equipped with 80 beds; figure 8. giuliani l. la chirurgia del carcinoma renale (the surgery of kidney cancer). atlas. urology clinic of the university of genoa (1990), mazzucchelli ed. figure 9. the new genoese urology clinic, inaugurated in 1992. archivio italiano di urologia e andrologia 2023; 95, 2 m. martini, g. martorana 6 a semi-intensive post-operative therapy department; a surgical block devoted exclusively to urology; a centre for calculosis; a centre for urodynamics; an outpatient clinic; a teaching centre. conclusions during the congress of the european society of urology in berlin in july 1994, prof. giuliani was awarded the highly prestigious willy grégoir medal, an accolade conferred upon eminent personalities in european urology. a month later, on 18 august 1994, following a brief illness, giuliani died in the very institute that he himself had created in genoa; he was 66 years old. in december of the same year, the institute was named in his honour, thus becoming the “luciano giuliani institute of clinical urology”. luciano giuliani was a distinguished scientist and one of the most renowned scholars of urology in the international scientific firmament. nicknamed “grand master”, giuliani struck very deep roots and ploughed a furrow that ran uninterruptedly through the generations of his pupils, who were truly numerous and of high quality. when faced with a clinical problem, every urologist should remember that things are what they are today because in the past there have been people like the maestro giuliani and clinical experiences that have, thanks also to advances in technology, pharmacology and biomaterials, allowed constant evolution, thereby enabling us to achieve ever-better results (da prefazione di marco carini) (13). acknowledgements thanks to prof. carlo terrone (university of genoa) for the photo number 9 and for reading the text. thanks to gianmaria martini (independent scholar) for the help in bibliographic data. references 1. private archive “luciano giuliani”. 2. circular n°. 360 of g.m. 1951. military school of health, florence. 3. military school of health, florence. d.m. n°. 2598/c. of prot. doc. of 13 october 1953, prof. col. g. piazza. (giuliani private archive). 4. giuliani l. l’ ibernazione. g.med.milit. 1953; 103:335-344. 5. university of pisa. certificate n°. 3211, matriculation n°. 7/259. 6. rector's decree n°. 2544 of 18 november, 1957 (official bulletin of the ministry of education, part ii, n°. 36 of 4 september, 1958, p. 5048. 7. giuliani l. sulle vie biliari extraepatiche (nota anatomica). la chirurgia generale 1954; 3:189-207. 8. fedeli f. university of florence. institute of general clinical surgery and surgical therapy. florence, 6 june 1959. 9. rector's decree n°. 2544 of 18 november, 1957 (official bulletin of the ministry of education, part ii, n°. 36 of 4 september, 1958, p. 5048. 10. giuliani l. la gastrocistoplastica: dall'idea sperimentale ad alcune considerazioni pratiche in tema di chirurgia plastica e sostitutiva della vescica. urologia 1958; 25 (suppl. 7). 11. giuliani l, pisani e. l'intestino nella chirurgia plastica e sostitutiva della vescica: valutazione cistografica e cistomanometrica dei risultati. arch it urol. 1959; 32:164. 12. luciano giuliani private archive. 13. martorana g. l’uso dell’intestino in urologia. (the use of the intestine in urology). bononia university press. bologna, 2021. 14. bracci u, giuliani l, costantini a, tacciuoli m. the surgical treatment of prostate cancer. vallecchi ed. officine grafiche. firenze, 1961. 15. bracci u, giuliani l, polito m. la ripresa funzionale dei reni esclusi (the functional recovery of excluded kidneys). relazione ufficiale al congresso della società italiana di urologia, capelli ed. bologna, 1967. 16. bracci u. le vie d’accesso nella chirurgia dell’apparato urinario. le vie d’accesso al rene. macrì, firenze, 1956. 17. giuliani l, carmignani g, belgrano e, martorana g. le vie d’accesso in chirurgia urologica. relazione ufficiale lvi congresso, sili, bari, 3-6 ottobre 1984. 18. giuliani l, giberti c, martorana g. atlas of surgery for renal cancer. 2nd ed. zambeletti s.p.a., milano, 1989. 19. giuliani l, giberti c, martorana g, rovida s. radical extensive surgery for renal cell carcinoma: long-term results and prognostic factors. j urol 1990; 143:468.5. 20. malinaric r, mantica g, martini m, et al. the lifetime history of the first italian public extra-corporeal shock wave lithotripsy (eswl) lithotripter as a mirror of the evolution of endourology over the last decade. int j environ res public health 2023; 20:4127. 21. carmignani g, traverso p. (durand f). brief history of ligurian urology. tipografia araldica. genova, 1997. correspondence mariano martini, md, phd (corresponding author) mariano.martini@unige.it mariano.yy@gmail department of health sciences, university of genoa largo r. benzi 10, 16132 genoa, italy giuseppe martorana, md university of bologna, bologna, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso 521archivio italiano di urologia e andrologia 2022; 94, 4 letter to editor no conflict of interest declared. key words: benign prostatic hypertrophy; nocturia; discontinuation; 5-alpha reductase inhibitor; polypharmacy. submitted 30 october 2022; accepted 19 november 2022 to the editor, benign prostatic hyperplasia (bph) is a common cause of lower urinary tract symptoms (luts) in elderly males. the current guidelines recommend the use of a 5-alpha reductase inhibitor (5ari) to treat males with moderate-to-severe luts and an enlarged prostate (1). combination therapy with an alpha blocker and a 5ari has proven effective at ameliorating luts and reducing the total prostate volume (tpv) and the risk of the disease progression (2-5). with the aging of the japanese population, it is expected that the frequencies of various chronic diseases will increase, and as a result, it is assumed that the number of oral medications being taken by older people will rise. it has been reported that the incidence of adverse drug events is higher among the elderly than among younger patients, and adverse drug event rates of 15-20% per year have been reported in nursing homes in the united states (6). the higher adverse drug event rates seen in elderly patients are caused by greater drug sensitivity due to age-related changes in pharmacokinetics and the higher number of drugs being taken by each patient. as mentioned above, elderly people are prone to polypharmacy, as they have many comorbidities. in a multicenter study, it was reported that the elderly subjects were taking an average of 4.5 different medications (7). polypharmacy is associated with increases in drug costs and drug interactions. in addition, it has been reported that the risk of adverse drug events was increased in patients taking ≥ 6 drugs (8), and furthermore, that the incidence of falls was high among patients taking ≥ 5 drugs (9). therefore, among elderly people, even if only one type of medication is discontinued, the risk of adverse drug events can be expected to decrease, which may help to reduce healthcare costs in the long term. it has been reported that when an alpha-1 blocker is combined with dutasteride, symptom relief can be maintained with dutasteride alone after the discontinuation of the alpha-1 blocker (10). however, it has also been reported that 60% of patients who stop taking dutasteride resume taking it within 1 year (11). recently, it was suggested that 5ari may induce suicidal behavior and depression and that the discontinuation of 5ari should be considered (12). however, there are no studies involving a follow-up period of 2 years after discontinuation of dutasteride. the purpose of this study was to investigate the predictors of restarting dutasteride in a real-world setting in the era of polypharmacy. at the beginning of 2016 a shortage of the drug forced us to stop dutasteride treatment in a group of patients. the drug returned to be available after four months. nevertheless, some patients did not restart dutasteride but remained on treatment with alpha-blockers alone. we aimed to evaluate reasons for restarting or not dutasteride after a period of discontinuation. material and methods study subjects we retrospectively reviewed the medical records of patients with luts secondary to bph who were treated with an alpha-1 blocker and dutasteride (0.5 mg/d) from september 2010 to december 2015. from january 2016, dutasteride was discontinued, and the patients were only prescribed an alpha-1 blocker. a total of 39 patients were included in this study. the patients were divided into two groups: patients who restarted dutasteride (dr) and patients who remained on discontinuation of dutasteride (dd) group. in both groups, age, body mass index (bmi), international prostate symptom score (ipss), quality-of-life (qol) score, overactive bladder symptom score (oabss), duration of dutasteride treatment before outcomes of dutasteride discontinuation in patients with benign prostatic hypertrophy hiroshi masuda, kosuke mikami, kotaro otsuka, kyokusin hou, takahito suyama, kazuhiro araki, satoko kojima, yukio naya department of urology, teikyo university chiba medical center, 3426-3 anesaki, ichihara, chiba 299-0111, japan. doi: 10.4081/aiua.2022.4.521 archivio italiano di urologia e andrologia 2022; 94, 4 h. masuda, k. mikami, k. otsuka, k. hou, t. suyama, k. araki, s. kojima, y. naya 522 discontinuation, number of different types of medications being taken by the patients, prostate volume, rate of reduction in prostate volume, post-void residual volume (pvr), and presence or absence of comorbidities were evaluated. prostate volume and the pvr were evaluated by using transabdominal ultrasound. all data were collected prior to the discontinuation of dutasteride. the follow up period after the discontinuation of dutasteride lasted 24 months. alpha-1 blocker monotherapy was continued during this period. ipss, oabss, prostate volume (pv), and pvr were evaluated at 1, 3, 6, 12, 18, and 24 months after the discontinuation of dutasteride. patients were allowed to restart dutasteride during the follow-up period according to their desires and the judgement of the attending physician. statistical analysis statistical analyses were carried out to identify clinical parameters that differed significantly between the dr and dd groups. the results are shown as the mean ± standard error (se). the mann-whitney u test and chi-squared test were used for the statistical analyses. the cox proportional hazards model was used to estimate the relative risk of dutasteride being restarted associated with each parameter. rate estimates were calculated using the kaplan-meier method. the logrank test was used to evaluate differences in rates between the groups. all analyses were performed with jmp version 10 (sas institute inc., cary, nc, usa). probability values of < 0.05 were considered statistically significant. ethical approval the institutional review board of teikyo university approved this study (tuic-coi 21-179). results out of 39 eligible patients, 36 were analyzed at 24 months, and 13 patients (13/36, 36%) restarted dutasteride. the remaining 23 patients (64%) discontinued dutasteride within 24 months as shown by the kaplan-meier curve in figure 1. neither the type nor dose of alpha-1 blocker was changed during the follow-up period in any patient. the mean number of different types of medications being taken by the patients in the dr and dd groups was 6.5 and 5.7, respectively. the mean number of nocturia events experienced per day before the discontinuation of dutasteride was significantly higher in the dr group than in the dd group (2.8 vs 1.8, respectively; p = 0.005). the mean duration of dutasteride treatment prior to discontinuation was significantly longer in the dr group (37 months) than in the dd group (25 months) (p = 0.0261) (table 1). the pvr before the discontinuation of dutasteride was not significantly different in the dr group (59 ml) compared to the dd group (35 ml) (p = 0.0868). total ipss and total oabss were also not significantly higher in the dr group than in the dd group. multivariate analysis showed statistically significant differences in the duration of dutasteride treatment before discontinuation and the frequency of nocturia between the groups. in dd group, the change from baseline of mean ipss values (δ-ipss) at 1, 3, 6, 12, 18, and 24 months were ±0, +0.6, +0.3, +0.6, +0.9, and +0.6, respectively (p = 0.9985), the δ-oabss values at 1, 3, 6, 12,18, and 24 table 1. patient characteristics. variables dr group dd group p-value (n=13) (n=23) age (mean ± se), years 79 ± 2.2 76 ± 1.3 0.2283 bmi (mean ± se), kg/m2 23.3 ± 0.9 23.3 ± 0.6 0.6523 prostate volume (mean ± se), ml 46.3 ± 7.3 45 ± 3.6 0.781 hypertension, n (%) 9 (75%) 12 (52%) 0.1907 diabetes mellitus, n (%) 2 (17%) 2 (9%) 0.4817 dyslipidemia, n (%) 0 (0%) 6 (26%) 0.0519 no. of types of medications being taken (mean ± se) 6.5 ± 2.2 5.7 ± 2.2 0.3334 duration of dutasteride treatment (mean ± se), months 37 ± 4.6 24 ± 3.5 0.0261 no. of nocturia events per night (mean ± se) 2.8 ± 0.3 1.7 ± 0.2 0.0050 total ipss (mean ± se) 14.3 ± 1.7 11.7 ± 1.3 0.1294 urinary symptom score (mean ± se) 6.0 ± 1.0 5.5 ± 0.7 0.7005 irritative symptom score (mean ± se) 5.5 ± 1.2 4.4 ± 0.6 0.31 qol score (mean ± se) 2.8 ± 0.6 3.2 ± 0.3 0.6329 total oabss (mean ± se) 5.3 ± 1.5 4.2 ± 0.6 0.7391 pvr (mean ± se), ml 59 ± 16 35 ± 7.3 0.0868 reduction rate (mean ± se), % 12.4 ± 4.3 14.4 ± 4.1 0.8894 overactive bladder symptom score; pvr: post-void residual volume; se: standard error. figure 1. dutasteride discontinuation rate during the 2-year follow-up period as determined using a kaplan-meier curve. the discontinuation rates at 6, 12, 18, and 24 months were 87%, 74%, 64%, and 64%, respectively. p ro ba bi lit y of d is co nt in ua tio n (% ) time since discontinuation (months) 523archivio italiano di urologia e andrologia 2022; 94, 4 dutasteride discontinuation in bph months were +0.1, +0.5, +0.4, +0.1, ±0, and +0.6, respectively (p = 0.9927), and the mean δ-pvr values at 1, 3, 6, 12,18, and 24 months were -6.4, -3.0, -6.3, -1.4, +0.3, and -3.3, respectively (p = 0.9920). in dd group, the mean δpv values at 1, 3, 6, 12, 18, and 24 months were +4.1, +2.7, +5.7, +9.2, +11.7, and +8.9 respectively (p = 0.3945). the reasons why dutasteride was restarted were as follows: choice of the patient in 4 cases, macrohematuria in 2 cases, nocturia in 1 case, symptom exacerbation in 4 cases, and the judgment of the physician in 2 cases. discussion in the present study, it was suggested that nocturia and a long period of dutasteride treatment prior to the discontinuation of dutasteride are predictors of restarting dutasteride in the real-world setting. consequently, in patients that do not exhibit nocturia before the discontinuation of dutasteride, the withdrawal of dutasteride should be considered feasible. discontinuation of drugs for bph treatment there have been a few prospective studies on the discontinuation of dutasteride. shindo et al. evaluated the possibility of discontinuing dutasteride after it was used in combination with an alpha-1 blocker for bph (11). after 6 months of combination therapy, 60% of the patients in whom dutasteride was discontinued restarted taking dutasteride within 12 months. the degree of prostatic enlargement seen after the discontinuation of dutasteride differed among patients. according to this study, rapid regrowth of the prostate leads to the deterioration of storage symptoms and a tendency to restart dutasteride and the baseline intraprostatic architecture may be a predictor of whether a patient is a good candidate for dutasteride discontinuation. victor et al. investigated the outcomes of discontinuing one medication after 2 years of combined alpha-blocker and 5ari therapy for bph/luts in a randomized multicenter study (13). they concluded that the discontinuation of either drug caused the progression of bph. however, they suggested that the risk of resuming medication or undergoing transurethral resection of the prostate was greater in patients who discontinued 5ari. jeong et al. reported that the discontinuation of 5aris during combination therapy induced prostate regrowth and symptom aggravation in males with bph (14). therefore, they suggested that the life-long use of 5aris should be considered to prevent bph progression. in the current study it was demonstrated that the temporary discontinuation of dutasteride was feasible, and in selected cases it was possible to discontinue dutasteride for 2 years. polypharmacy regarding polypharmacy in the elderly, it was suggested that the temporary discontinuation of medications could be a good option, and it is expected that reducing the number of medications being taken could potentially reduce healthcare costs. in the present study, the number of different types of oral medications being taken by the patients was higher in the dr group. basically, it is assumed that patients want to reduce the number of different types of oral medications they are taking, and hence, to maintain discontinuation. however, when the number of different types of oral medications being taken exceeds a certain level, one less medication does not really change the patient’s condition. in fact, the restarting of oral medications may be related to the types of oral medications being taken, rather than the number of medications being taken by itself. length of previous treatment this study suggested that a longer period of dutasteride treatment before discontinuation was associated with a greater likelihood of restarting dutasteride, whereas previous administration of dutasteride for a shorter period (approximately 2 years) was associated with persistent discontinuation of dutasteride. a longer dutasteride treatment before discontinuation could be associated with a greater effect of prostate shrinkage that could be maintained for a longer period after dutasteride discontinuation so delaying restarting of dutasteride treatment, on the contrary we observed the opposite in this study. it has been reported that the main reason for restarting dutasteride is the regrowth of the prostate due to the discontinuation of the drug (11) although in this study dutasteride was mainly restarted because of hematuria or the choice of the patient. nocturia nocturia before the discontinuation of dutasteride was identified as another predictor of restarting dutasteride treatment. in a recent study involving a follow-up period up to 21 years, it was reported that males with bph have a persistently higher risk of alzheimer’s disease and all-cause dementia compared with males in the general population (15). the study identified bph (and associated sleep disturbances) as a common, potentially curable, disorder associated with dementia risk. therefore, it seems that controlling nocturia is an important issue for urologists. risk of depression moreover, it is important to prescribe appropriate medication. associations between 5aris and suicidality and depression have been reported. in a large cohort of males aged ≥ 66 years, it was found that the risk of self-harm and depression were higher than in males that were treated with 5aris. therefore, it was suggested that the discontinuation of 5aris in these circumstances may be appropriate (12). archivio italiano di urologia e andrologia 2022; 94, 4 h. masuda, k. mikami, k. otsuka, k. hou, t. suyama, k. araki, s. kojima, y. naya 524 limitations we would like to emphasize several limitations of our study. firstly, it was a retrospective cohort study, which involved the extraction of electronically stored clinical data, and it had a small sample size. secondly, we could not assess the effects of the discontinuation of dutasteride on qol. thirdly, we examined the types of other medications (in general) the patients were taking, but we should also have examined the actual daily amounts of other medications that they were taking. it was suggested that if the daily amounts of other medications being taken by a patient is high, the patient may not restart taking discontinued medications because they may want to reduce the daily amounts of other medication that they are taking. conclusions the present study suggested that the temporary discontinuation of dutasteride can be considered in cases who present a low frequency of nocturia and a relatively short period of dutasteride treatment before discontinuation. in addition, temporary discontinuation of dutasteride may be useful for dealing with polypharmacy in the elderly. references 1. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015; 67:1099-1109. 2. mcconnell jd, roehrborn cg, bautista om, et al. medical therapy of prostatic symptoms (mtops) research group: the long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. n eng j med. 2003; 349:2387-2398. 3. roehrborn cg, siami p, barkin j, et al. combat study group: the effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the combat study. j urol. 2008; 179:616-621. 4. roehrborn cg, siami p, barkin j, et al. combat study group: the influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the combat study. eur urol. 2009; 55:461-471. 5. roehrborn cg, siami p, barkin j, et al. combat study group: the effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the combat study. eur urol. 2010; 57:123-131. 6. rothschild jm, bastes dw, leape ll. preventable medical injuries in older patient. arch intern med. 2000; 160:2717-2728. 7. suzuki y, akishita m, arai h, et al. multiple consultations and polypharmacy of patients attending geriatric outpatient units of university hospitals. geriatr gerontol int. 2006; 6:244-247. 8. kojima t, akishita m, kameyama y, et al. high risk of adverse drug reactions in elderly patients taking six or more drugs: analysis of inpatient database. geriatr gerontol int. 2012; 12:761-762. 9. kojima t, akishita m, nakamura t, et al. polypharmacy as a risk for fall occurrence. geriatr gerontol int. 2012; 12:425-430. 10. barkin j, guimaraces m, jacobi g, et al. alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. eur urol. 2003; 44:461-466. 11. shindo t, hashimoto k, shimizu t, et al. significance of intraprostatic architecture and regrowth velocity for considering discontinuation of dutasteride after combination therapy with an alpha blocker: a prospective, pilot study. kju. 2015; 56:305-309. 12. welk b, mcarthur e, ordon m, et al, association of suicidality and depression with 5alpha-reductase inhibitors. jama intern med. 2017; 177:683-691. 13. lin vc, liao ch, kuo hc. progression of lower urinary tract symptoms after discontinuation of 1 medication from 2-year combined alphablocker and 5-alpha-reductase inhibitor therapy for benign prostatic hyperplasia in men--a randomized multicenter study. urology. 2014; 83:416-421. 14. jeong yb, kwon ks, kim sd, kim hj. effect of discontinuation of 5alpha-reductase inhibitors on prostate volume and symptoms in men with bph: a prospective study. urology. 2009; 73:802-806. 15. nørgaard m, horváth-puhó e, corraini p, et al. sleep disruption and alzheimer's disease risk: inferences from men with benign prostatic hyperplasia. eclinical medicine. 2021; 32:100740. correspondence hiroshi masuda, md, phd (corresponding author) hrsmasuda@yahoo.co.jp kosuke mikami, md kotaro otsuka, md kyokusin hou, md takahito suyama, md kazuhiro araki, md satoko kojima, md yukio naya, md department of urology, teikyo university chiba medical center 3426-3 anesaki, ichihara, chiba, 299-0111 (japan) stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11669 1 original paper ronal degeneration, and fibrosis, all of which lead to the erectile dysfunction development (6). although phosphodiesterase type 5 inhibitors (pde5i) are beneficial in treating erectile dysfunction in the majority of patients, their effectiveness is much reduced in diabetic people (7). this is likely due to the decreased generation of nitric oxide (no) as a consequence of endothelial dysfunction (8). ed linked with diabetes is similarly very resistant to pde5i therapy, with a 44% success rate opposed to an 85% success rate for hypogonadal ed patients (9). patients with diabetes and erectile dysfunction had the greatest incidence of therapy termination with pde5is (28/36, or 78 percent) (10). therefore, finding an effective therapy for ed linked with diabetes is one of the most significant goals of modern ed research. recent treatment techniques, like as gene therapy and stem cell therapy, are being investigated to treat diabetic ed more successfully. stem cell is a possible therapy for diabetic ed. multiple stem cell types have been utilized to cure ed, including bmsc, adsc, and usc (11-13). stem cells may develop into several cell types, such as smooth muscle cells (smc), neurons and vascular endothelial cells. in addition, they may emit paracrine substances that may boost angiogenesis and cell survival (14). a study was conducted in our urology department from march 2016 to september 2018. methods the study was conducted after ethical committee approval. for all men included in the study, explanation of the study procedures was done and informed consent was onbtained before enrollment. inclusion criteria diabetic adult men with hba1c between 6.5% and 10% with diagnosis of diabetes mellitus dated more than 5 years. having a consistent sexually active partner. inadequate sexual activity in spite of taking the maximal dosage of oral pde5i during the last eight weeks. purpose: to assess safety and efficacy of autologous mesenchymal bone marrow stem cell injection in penile cavernosal tissue for erectile dysfunction therapy in diabetic men. methods: the subjects of this study were diabetic men suffering erectile dysfunction, non-responding to maximum dose of oral pde5i. mesenchymal bone marrow stem cells were aspirated and injected after preparation in both corpora cavernosa at 3, 9 o’clock position. erectile function was assessed by the international index of erectile function and penile doppler study, before and after 6 months after injection. results: 4 patients out of 10 achieve hard erection adequate for satisfactory coitus, and 2 patients achieved penile hardness with addition of pharmacological therapy with sildenafil 100mg. peak systolic velocity increased significantly in 4 patients (2 arteriogenic and 2 mixed erectile dysfunction), from 12∼22 cm/s to 32∼69 cm/s. variations in end-diastolic velocity increased substantially in 2 patients with venogenic insufficiency alone at follow-up from 4∼5 cm /s to -4∼-3 cm/s. conclusions: despite promising stem cell treatment efficacy for patients with erectile dysfunction, more clinical studies and researches are still warranted. key words: erectile dysfunction; diabetes; stem cell. submitted 21 august 2023; accepted 7 september 2023 in 1995, the global erectile dysfunction (ed) prevalence was evaluated to be 152 million and is expected to reach 322 million by 2025 (2). ed may be organic, psychogenic or a combination. ed organic type is divided into vasculogenic, neurogenic, cavernous, drug-induced, systemic disease-related and hormonal categories (2). diabetic men tend to experience ed more frequently and 10-15 years earlier than non-diabetic men (3). diabetes-related ed is a serious issue that has a significant influence on patients' life quality and family harmony (4). in addition, ed in diabetic people is more resistant and severe to treatment than in nondiabetic patients (5). pathogenic impact of diabetic ed comprises endothelium malfunction, smooth muscle composition reduction, neuautologous mesenchymal stem cell therapy for diabetic men with erectile dysfunction. is it promising? a pilot study mohamed a. alhefnawy 1, emad salah 2, sayed bakry 3, taymour m. khalifa 4, alaa rafaat 2, refaat hammad 4, ali sobhy 5, ahmed wahsh 2 1 department of urology, benha university, egypt; 2 department of urology, al-azhar university, egypt; 3 department of embriology and genetic engineering, faculty of science, al-azhar university, egypt; 4 department of dermatology and andrology, al-azhar university, egypt; 5 department of clinical pathology, al-azhar university, egypt. doi: 10.4081/aiua.2023.11669 summary archivio italiano di urologia e andrologia 2023; 95(4):11669 m.a. alhefnawy, e. salah, s. bakry, et al. 2 exclusion criteria history of bone marrow disorders, neurogenic ed, gentamycin hypersensitivity. history of severe cardiovascular disease (angina, arrhythmias, cardiac failure, and stroke), renal failure, and respiratory failure as life-threatening conditions. positive hiv, hbv, hcv, and syphilis tests. cancer history during the last five years. hba1c levels more than 10 percent. uncontrolled hypertension or hypotension (systolic blood pressure > 170 or 90 mm hg, diastolic blood pressure > 100 or 50 mm hg). anticoagulant therapy. severe infectious disease. testosterone concentration less than 200ng/dl having a penile implant or be open to getting one, patients with alterations in penis morphology. subjects participating in additional clinical studies in the previous 30 days. subjects unable to comply with procedure. all participants were subjected to detailed medical and sexual history including iief questionnaire, physical examination including (general and genital examination) and laboratory work up including testosterone level, hba1c, prolactin, lh and fsh. evaluation of general condition by cell blood count (cbc), liver function, renal function, and thyroid function tests, lipid and coagulation profile was done for all patients. penile doppler ultrasound was done for all patients. normal peak systolic velocity was defined as a value ≥ 35 ml/second and normal end diastolic velocity was defined as a value ≤ 3 ml/second. iief patient questionnaire the 6-question iief questionnaire (table 1) is a validated, multidimensional, self-administered study that has shown beneficial in clinical studies for assessing erectile dysfunction and treatment effects. this questionnaire in addition to the penile doppler were performed before and 6 months after injection. patients with poor ieef scores (17 out of 30) in d (erectile function) were eligible for mesenchymal stem cell treatment. procedures under sterile conditions with local anesthetics, ten ml mesenchymal stem cell (mscs) were aspirated from the bone marrow of the iliac crest of the candidate. after lab processing, the sample was brought to the operative theater. in the operation room, the patient was positioned in the supine position. genitalia were sterilized and penile block was performed. then genitalia were sterilized again, mscs were injected in both corpora cavernosa at 3 and 9 o’clock position. outcome measures six months following injection, iief and peak systolic velocity (psv) and end diastolic velocity (edv) were tested for changes from baseline (preoperative). statistical analysis: using statistical program for social sciences (spss) version 23.0 for windows, the acquired data were edited, structured, tabulated, and statistically analyzed. data are displayed as mean, sd, frequency, and percentage. student's t test was used to compare continuous variables (two-tailed). we compared categorical variables using the chi-square (2) and fisher's exact tests (if needed). the level of significance was accepted if the p value < 0.05. results this study included 10 diabetic patients complaining of ed, mean age 52 years and hba1c range from 6.5 -9.5. hyperlipidaemia was detected in 6 (60%) patients. table 2 demonstrates the demographic characteristics of the studied patients. erectile function was assessed by iiefscore and penile doppler study. two patients have pure arterial insufficiency, 4 (40%) patients have pure veno-occlusive disortable 2. demographic characteristics of the studied patients. parameters all cases n = 10 age (years) mean + sd 52.3 ± 6.4 range (min-max) 25 (40-65) residence n (%) rural 3 (30.0%) urban 7 (70.0%) education n (%) illiterate 5 (50.0%) secondary 3 (30.0%) high 2 (20.0%) socio-economic level n (%) low 4 (40.0%) middle 3 (30.0%) high 3 (30.0%) medical diseases n (%) diabetes 10 (100.0%) hyperlipidemia 6 (60.0%) table 1. 6-question iief questionnaire. archivio italiano di urologia e andrologia 2023; 95(4):11669 3 autologous mesenchymal stem cell therapy for diabetic men with erectile dysfunction der and 4 (40%) patients mixed arteriogenic and vasculogenic insufficiency as declared by penile doppler study, table 3 shows the ed type among the studied patients. the effect of single intracavernosal injection of bmsc on erectile function were assessed using iief-6 questions as shown in table 4 and penile doppler study at 6 months, as in table 5 and 6, comparing the psv and edv before and after injection at 6 months. discussion dm is a systematic disease that affects every part of the body. in the penis, it is associated with reduced contents of all three key components for erectile function, namely, cavernous nerve (cn), cavernous endothelial cells (cec) and smooth muscle cells (csmc) (15-19). the reduction of cec content is likely due to dm-induced apoptosis in cec as demonstrated by immune-histochemical analysis of corpora cavernosa (cc) samples between diabetic and nondiabetic patients (20).thus, how to prevent and/or reverse these pathological processes is critically important for the effective treatment of dm-associated ed. in this regard, stem cells (sc) therapy has been considered promising, due to sc’s well-known regenerative capacity (18). mscs, initially isolated from bone marrow, have later been isolated from many adult tissues such as adipose tissue, skeletal muscle, brain and skin. as their name suggests, mscs are defined by their ability of selfrenewal and differentiation into various phenotypes (multipotency). the therapeutic effect of mscs has consistently been demonstrated and these benefits are mostly attributed to their ability to produce an array of bioactive molecules. this is known as paracrine action of mscs and it involves stimulation of angiogenesis and revascularization, modulation of immune and inflammatory responses, inhibition of apoptosis and trophic effects such as stimulation of mitosis, proliferation and differentiation of intrinsic stem progenitor cells (21). different routes have been suggested for the delivery of stem cells, and research continues to assess the most effective route of instillation. some studies have involved the direct injection of cells into the organ of concern (2224). other studies have investigated intraperitoneal or intravenous injections of stem cells (25). studies have shown that less than 1% of stem cells infused via the intravenous route reach the target tissue, and those that do reach the target tissue dissipate after a few days (26). in preclinical studies, the intravenous injection of adscs has been shown to lead to improvements in erectile function (27). the intracorporal injection of stem cells for ed treatment has been commonly evaluated in preclinical studies, as it is both straightforward and logical (28). periprostatic injection, with or without a concurrent intracorporal injection, has also been attempted (29, 30). many preclinical trials have been performed to investigate the safety, efficacy, and mechanisms of stem-cell therapy for ed in animal models. soebadi et al. in 2016 summarized these studies (31). as stated by those authors, these preclinical trials have provided ample data on the utilization of both bone marrow stem cells and adscs for ed. almost all of the studies reported improved erectile function in various animal models of cn injury, vascular insufficiency, diabetes mellitus, hyperlipidemia, and aging. human data on stem-cell therapy for ed are finally emerging approximately 10 years after the first reports on animal models. we have 4 very important published human clinical trials which employed stem cells in patients with ed, as summarized below. bahk et al. (24) injected 1.5×107 umbilical msc into the corpora of 7 ed patients with dm and noted improvement when coupled with oral pde5i. the international index of erectile function (iief)-5, global assessment questionnaire, erection diary, blood glucose diary, and medication dosage were monitored for 9 months. three participants regained morning erections in 1 month, 2 participants achieved erection successful for penetration in conjunction with pde5i for 6 months. yiou et al. (22) administered bmsc in men with ed after radical prostatectomy. four equal groups of patients were given escalating doses of bmsc (2 ×107, 2 × 108, 1 × 109, and 2 × 109, respectively). iief-15, erection hardness scale, penile duplex and penile no release tests were all used to assess erectile function. significant improvement was noted in 9 of 12 patients treated in combination with an oral pde5i. haahr et al. (23) injected asc into 17 men with a history of prostatectomy to determine safety and efficacy. five patients had minor adverse events related to liposuction, table 3. classification of erectile dysfunction in the studied patients. all cases n = 10 type n (%) single 6 (60.0%) mixed 4 (40.0%) table 4. comparison of international index of erectile dysfunction before and after injection (total n = 10). before treatment after treatment p-value mean ± sd mean ± sd all cases n = 10 12.7 ± 2.16 19.2 ± 5.75 0.026 s table 5. comparison of peak systolic velocity (psv) before and after injection at 6 months (total n = 10). before injection after injection p-value mean ± sd mean ± sd all cases n = 10 25 ± 12.5 40.9 ± 18.9 0.016 s mixed cases n = 4 13.75 ± 6.13 25.5 ± 13.2 0.16 ns arteriogenic cases n = 6 16.33 ± 6.21 38.8 ± 22.8 0.036 s table 6. comparison of end diastolic velocity edv before and after injection at 6 months (total n = 10). before injection after injection p-value mean ± sd mean ± sd all cases n = 10 3.9 ± 5.4 0.9 ± 4.09 0.026 s mixed cases n = 4 5.07 ± 2.08 3.33 ± 1.15 0.37 ns arteriogenic cases n = 6 6.12 ± 2.7 2.37 ± 3.8 0.022 s archivio italiano di urologia e andrologia 2023; 95(4):11669 m.a. alhefnawy, e. salah, s. bakry, et al. 4 2 men has redness or swelling at the injection site, and 1 patient developed a scrotal and penile hematoma. they used iief-5 to evaluate erectile function and found 8 of 17 men able to achieve an erection for successful intercourse with no mention of use of oral medications. levy et al. (32) injected adult placental-matrix-derived stem cells (unknown cell number) in a study of 8 men with ed, and assessed peak systolic velocity, end-diastolic velocity, stretched penile length, penile width. five patients at 3 months achieved erections for successful intercourse with use of pde5i. the only measure significantly improved was peak systolic velocity. we summarized this previously mentioned 4 published clinical trials on stem-cell therapy for ed in table 7. the present study includes 10 diabetic patients type 2 aged 40-65 complaining of erectile dysfunction. after clinical examination and evaluation, the cause of erectile dysfunction in these patients has been cleared: four patients had mixed arteriogenic and vasculogenic insufficiency, four patients had pure venogenic insufficiency and two patients had pure arteriogenic cause. these patients cannot satisfy sexual activity with proper sexual stimulation in spite of taking maximum dose of oral pde5i within last 8 weeks. in this study we injected patients with msc-derived stem cells and followed them for 6 months with doppler parameters and the iief questionnaire. all patients agreed that bone marrow stem-cell therapy had some effect on ed, although it was insufficient in some patients. the effects of treatment on erectile function and penile vascular parameters were assessed using the iief-15 and by color duplex doppler ultrasound. the peak systolic velocity was found to have improved to a statistically significant extent in 4 patients (2 arteriogenic and 2 mixed ed), from 12~ 22 cm/s to 32~69 cm/s. changes in end-diastolic velocity were found to have improved to statistically significant extent in 2 patients with venogenic insufficiency at follow-up from 4~5 cm/s to -4~-3 cm/s. at follow-up, in two patients (mixed ed), changes in psv were not statistically significant for both psv and edv. two patients with venogenic ed had no improvement in edv measurement after injection of mscs. changes in end-diastolic velocity were found to be not statistically significant in four patients (two withe venogenic insufficiency and two with mixed ed). four patients achieved hard erection adequate for satisfactory coitus, and two achieved penile hardness with addition of pharmacological therapy with sildenafil 100 mg. as regard to our study all patients with arteriogenic ed have significant improvement in duplex penile u/s and penile hardness, and improvement in psv was observed in two patients with mixed ed; in four patients with venogenic ed, two patients had significant improvement in duplex u/s and penile hardness and two patients no significant improvement; two patients with mixed ed had no significant increase in both peak systolic velocity and end diastolic velocity and no improvement in penile hardness. conclusions autologous stem-cell therapy is considered a viable treatment option for diabetic ed patients. despite this overwhelming enthusiasm, several questions remain to be answered before the widespread use of these complex techniques. first, the mode of action still needs to be determined and the safety of the treatment to be established. next, most effective mode of delivery has yet to be ascertained, although intracorporal injection seems to be the route of choice based on the clinical trials that have been published. additionally, the ideal timing, type, source and dosage of stem cell for treatment still need to be established. finally, further researches and wide based clinical trials on stem cell therapy for erectile dysfunction are warranted. acknowledgments all authors would like to express their sincere gratitude to all team of the department of urology, al-azhar university, assuit branch. references 1. aytaç ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-6. 2. lue ft, erectile dysfunction n engl j med., 2000; 342:1802-13. 3. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 4. ponholzer a, temml c, mock k, et al. prevalence and risk factors for erectile dysfunction in 2869 men using a validated questionnaire. eur urol. 2005; 47:80-5. 5. penson df, latini dm, lubeck dp, et al. comprehensive evaluation of erectile dysfunction (exceed) database. do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? results from the exploratory comprehensive evaluation of erectile dysfunction (exceed) database. diabetes care. 2003; 26:1093-9. 6. cameron ne, cotter ma. erectile dysfunction and diabetes mellitable 7. results of clinical trials on stem-cell therapy for erectile dysfunction. results assessment treatment cause of ed number of men first author (year) improved rigidity in 2/7, able to penetrate with pde5i iief-5, sep, gaq umbilical blood sc diabetes 7 bahk (2010) (33) 3/8 improved erection; iief change not significant psv, iief placental-derived sc organic 8 levy (2016) (36) 8/11 continent men and 0/6 incontinent men recovered erection iief-5 adipose-derived sc 5∼18 months after radical prostatectomy 17 haahr (2016) (35) 1/12 hard erection; 9/12 needed ici, pde5i, or vcd. iief-15, ehs, color bone marrow 22 months after radical prostatectomy 12 yiou (2016) (34) impreved ehs and iief doppler ultrasound mononuclear cells archivio italiano di urologia e andrologia 2023; 95(4):11669 5 autologous mesenchymal stem cell therapy for diabetic men with erectile dysfunction tus: mechanistic considerations from studies in experimental models. curr diabetes rev. 2007; 3:149-58. 7. vickers ma, satyanarayana r. phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus. int j impot res 2002; 14:466-71. 8. kolluru gk, bir sc, kevil cg. endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. int j vasc med. 2012; 2012:918267. 9. mccullough ar, barada jh, fawzy a, et al. achieving treatment optimization with sildenafil citrate (viagra) in patients with erectile dysfunction. urology. 2002; 60 (suppl 2):28-38. 10. carvalheira aa, pereira nm, maroco j, forjaz v. dropout in the treatment of erectile dysfunction with pde5: a study on predictors and a qualitative analysis of reasons for discontinuation. j sex med. 2012; 9:2361-9. 11. nishimatsu h, suzuki e, kumano s, et al. adrenomedullin mediates adipose tissue-derived stem cell-induced restoration of erectile function in diabetic rats. j sex med. 2012; 9:482-93. 12. ouyang b, sun x, han d, et al. human urine-derived stem cells alone or genetically-modified with fgf2 improve type 2 diabetic erectile dysfunction in a rat model. plos one. 2014; 9:92825. 13. qiu x, lin h, wang y, et al. intracavernous transplantation of bone marrow derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. j sex med 2011; 8:427-36. 14. lin cs, xin z, dai j, et al. stem-cell therapy for erectile dysfunction. expert opin biol ther. 2013; 13:1585-97. 15. albersen m, lin g, fandel tm, et al. functional, metabolic, and morphologic characteristics of a novel rat model of type 2 diabetesassociated erectile dysfunction. urology. 2011; 78:476.e1-8. 16. dashwood mr, crump a, shi-wen x, loesch a. identification of neuronal nitric oxide synthase (nnos) in human penis: a potential role of reduced neuronally-derived nitric oxide in erectile dysfunction. curr pharm biotechnol. 2011; 12:1316-21. 17. zhou f, xin h, liu t, et al. effects of icariside ii on improving erectile function in rats with streptozotocin-induced diabetes. j androl. 2012; 33:832-44. 18. cellek s, foxwell na, moncada s. two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. diabetes. 2003; 52:2353-62. 19. qiu x, lin g, xin z, et al. effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. j sex med. 2013; 10:738-46. 20. costa c, soares r, castela a, et al. increased endothelial apoptotic cell density in human diabetic erectile tissue--comparison with clinical data. j sex med. 2009; 6:826-35. 21. liang x, ding y, zhang y, et al. paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. cell transplant. 2014; 23:1045-1059. 22. yiou r, hamidou l, birebent b, et al. safety of intracavernous bone marrow-mononuclear cells for postradical prostatectomy erectile dysfunction: an open dose-escalation pilot study. eur urol. 2016; 69:988-91. 23. haahr mk, jensen ch, toyserkani nm, et al. safety and potential effect of a single intracavernous injection of autologous adiposederived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase i clinical trial. ebiomedicine 2016; 5:204-10. 24. bahk jy, jung jh, han h, et al. treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. exp clin transplant. 2010; 8:150-60. 25. .casiraghi f, remuzzi g, abbate m, perico n. multipotent mesenchymal stromal cell therapy and risk of malignancies. stem cell rev. 2013; 9:65-79. 26. uccelli a, moretta l, pistoia v. mesenchymal stem cells in health and disease. nat rev immunol. 2008; 8:726-36. 27. qiu x, villalta j, ferretti l, et al. effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapyinduced erectile dysfunction. j sex med. 2012; 9:1834-41. 28. alwaal a, hussein aa, lin cs, lue tf. prospects of stem cell treatment in benign urological diseases. korean j urol. 2015; 56:257-65. 29. choi wy, jeon hg, chung y, et al. isolation and characterization of novel, highly proliferative human cd34/cd73-double-positive testis-derived stem cells for cell therapy. stem cells dev. 2013; 22:2158-73. 30. you d, jang mj, lee j, et al. periprostatic implantation of human bone marrow-derived mesenchymal stem cells potentiates recovery of erectile function by intracavernosal injection in a rat model of cavernous nerve injury. urology 2013; 81:104-10. 31. soebadi ma, moris l, castiglione f, et al. advances in stem cell research for the treatment of male sexual dysfunctions. curr opin urol. 2016; 26:129-39. 32. levy j, marchand m, iorio l, et al. determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. j am osteopath assoc. 2016; 116:e1-e5. correspondence mohamed abdelrahman alhefnawy, md (corresponding author) dr.mohamedalhefnawy@gmail.com assistant professor of urology, benha university fareed nada street 13518, banha, egypt emad salah, md emadeldeen_salah@hotmail.com alaa rafat, md dralaarafaat@gmail.com ahmed wahsh, md hudaahmed320@gmail.com professor of urology al-azhar university, egypt sayed bakry, md sbakry@azhar.edu.eg professor of genetic engineering, al-azhar university, egypt taymour khalifa, md taymour.khalifa@gmail.com professor of dermatology, venereology and andrology, al-azhar university, egypt refaat hammad, md refaat-ragab@yahoo.com assistant professor of dermatology and andrology, al-azhar university, egypt ali sobhy, md dralisobhy@azhar.edu.eg assistant professor of clinical pathology, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13128 1 original paper development are also evaluated (5-7). a high sperm dna fragmentation index (dfi) has been associated with decreased male fertility and an increased risk of spontaneous abortions (8, 9). therefore, it has become an essential parameter in fertility studies for evaluating sperm quality. sperm dna fragmentation can occur for different reasons, such as oxidative stress, dna lesions, infections, and other factors (10). different techniques are used to evaluate the sperm dfi, including the single-cell gel electrophoresis (comet) assay, the sperm chromatin structure assay, dna breakage detection-fluorescence in situ hybridization (dbd-fish), and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dutp) nick end labeling (tunel) assay, among others. these methodologies have shown promising results but require specialized equipment and high-cost reagents, making those tests unavailable for all populations (11). in contrast, the sperm chromatin dispersion assay (scd) offers many advantages, such as its low cost compared to other techniques and its simplicity, practicality, speed, and reproducibility (11-13). the most explored treatment for reducing sperm dfi is the chronic use of oral antioxidants, based on the evidence that dna fragmentation is frequently associated with states of oxidative stress (14-16). however, the presence of bacteria in semen can also affect semen quality, and consequently, identifying the presence of bacteria in couples with fertility problems could be beneficial for improving semen parameters and increasing the chances of successful conception (17). therefore, antibiotics could also improve sperm dfi in some instances in which dna fragmentation is caused by a bacterial infection in the male reproductive tract; treatment with appropriate antibiotics could clear the infection and reduce inflammation, which could help improve sperm dna integrity (18). this study aimed to determine the effects of oral antibiotics and anti-inflammatory agents on semen parameters and the sperm dfi. materials and methods ninety-eight men with the diagnosis of primary or secondary infertility, either directed for advanced and nonaim: to determine the effects of oral antibiotics and anti-inflammatory agents on semen parameters and the sperm dna fragmentation index (dfi). methods: ninety-eight men with infertility diagnosis were included. the participants submitted two semen samples, before and at least two months after treatment. macroscopic and microscopic semen parameters were evaluated following the world health organization (who) guidelines. in addition, the sperm dfi was evaluated using the sperm chromatin dispersion (scd) technique. subsequently, a treatment regimen was administered, including daily oral doses of ciprofloxacin (1000 mg) and doxycycline (100 mg) for 21 and 10 days, respectively. in addition, non-steroidal anti-inflammatory drugs (15 mg of meloxicam) were used for 10 days. after treatment, the same parameters were re-evaluated for new semen samples taken under the same initial conditions. results: after treatment, significant increases in ph, sperm count, total concentration, and normal sperm morphology were observed, but no significant differences were found in the seminal volume parameter or progressive motility. after treatment, a significant decrease in the concentration of immature cells was observed, and although not statistically significant, a reduction in the concentration of leucocytes was observed. after treatment, the mean sperm dfi significantly decreased from 28.24 ± 12.39% to 16.2 ±7.1%. conclusions: treatment with antibiotics and anti-inflammatories significantly reduced the sperm dfi and improved semen quality. key words: male fertility; infertility; dna fragmentation index; semen; spermatozoa. submitted 19 september 2024; accepted 6 october 2024 introduction infertility is a problem that affects an increasing number of people around the world, regardless of gender (1, 2). when studying semen to evaluate and diagnose male fertility, it is considered that male factors are responsible for 50% of infertility cases (3), and specialists focus primarily on the macroscopic and microscopic parameters of semen (4). however, although these parameters can be considered essential for determining the success of a pregnancy, it is crucial that, in the presence of infertility, sperm functional alterations that could affect embryonic sperm dna fragmentation: focusing treatment on seminal transport fluid beyond sperm production moises abraham adel domínguez 1, walter d. cardona maya 2, andrés mora topete 1 1 centro de uro-andrología s.c., guadalajara, jalisco, méxico; 2 grupo reproducción, departamento de microbiología y parasitología, facultad de medicina, universidad de antioquia, medellín, colombia. doi: 10.4081/aiua.2025.13128 summary archivio italiano di urologia e andrologia 2025; 97(1):13128 m.a. adel domínguez, w.d. cardona maya, a. mora topete 2 advanced reproductive techniques were included (centro de uro-andrología s.c., guadalajara, jalisco, méxico). each patient was invited to participate in the study, and authorization was requested under current ethical standards; each participant also provided informed consent. the study participants provided two semen samples under similar conditions of sexual abstinence (3-5 days), one before treatment and one at least two months after treatment. both semen samples were analyzed in the same laboratory by the same expert technician. basic macroscopic and microscopic sperm parameters were evaluated following the who guidelines (19), and the sperm dfi was determined using the sperm chromatin dispersion test (scd, sperm dna kit, obi biotek) following the manufacturer's instructions. in addition, the concentrations of leukocytes and immature cells were also evaluated. after the initial semen evaluation, the patients were invited to receive daily oral doses of ciprofloxacin (1000 mg) or doxycycline (100 mg) for 21 or 10 days, respectively. in addition, non-steroidal anti-inflammatory drugs (15 mg of meloxicam) were used for 10 days. statistical analysis the data distribution was evaluated with the normality test of residuals, and the descriptive analysis was carried out according to the distribution of the variables. paired t tests were carried out for related samples when the data met normality, and the wilcoxon test was used for nonnormal distributed samples. a p value of < 0.05 was considered to indicate statistical significance. results ninety-eight men with infertility diagnosis participated in the study. the median age was 36 ± 6.7 years, with an interquartile range (25-75) of 32-41 years. as shown in table 1, no significant differences were found regarding seminal volume or progressive motility. however, after treatment, a significant increase in ph, sperm count, total concentration, and normal sperm morphology was observed. in addition, a decrease, although not statistically significant, in the concentration of immature cells and leucocytes was observed after treatment: 1.4 ± 2.0 million/ml vs. 0.85 ± 1.6 million/ml (p = 0.2613) and 1.9 ± 2.2 vs. 1.2 ± 1.8 million/ml (p = 0.4541), respectively. finally, after treatment, the mean sperm dfi significantly decreased from 27.2 ± 10.7% to 16.9 ± 7.6% (p < 0.001) (figure 1). discussion the results of this study support the effectiveness of an antibiotic and anti-inflammatory treatment approach in male patients diagnosed with infertility, consistent with previously published preliminary results (20). initial evaluation of semen samples revealed various parameters essential for determining sperm quality, such as volume, ph, viscosity, sperm concentration and sperm dfi (7). we hypothesize that the sperm dfi problem lies not in the quality of the sperm itself during spermatogenesis but in the factors that promote the degradation of its integrity once it has reached maturity and in the seminal tract. following this approach, we have implemented a treatment plan based on dual-scheme antibiotics accompanied by anti-inflammatories to improve the quality of the transport medium rather than the spermatogenesis process in the seminal fluid used for spermatogenesis. a few years ago, there was no consensus on how to manage high prostate-specific antigen (psa) levels that have occasionally been detected during psa screening, because psa levels can increase for several reasons, including trauma, ejaculation, rectal and urethral procedures, and numerous noncancerous etiologies such as benign prostatic hyperplasia, inflammation, and infection (21); therefore most urologists make decisions based on their training and experience, and the use of antibiotics to reduce high psa is table 1. changes in semen parameters before and after treatment. pre-treatment post-treatment p value volume, ml 1 2.9 ± 1.6 3.0 ± 1.5 0,529 ph 2 7.6 ± 0.6 7.7 ± 0.4 0.007 progressive motility, percentage 2 33 (10-50) 34 (21-50) 0.763 concentration, 106/ml 2 21 (8.7-50.8) 22 (9.2-58) 0.046 total concentration, 106/ejaculate 2 60 (20-126) 83.3 (19.1-172.5) 0.006 normal morphology, percentage 2 1 (1-2) 2 (1-4) < 0.01 1 paired t test, data show means ± standard deviations. 2 wilcoxon test, data show medians and their interquartile range (p25-75). figure 1. changes in the sperm dfi after treatment. archivio italiano di urologia e andrologia 2025; 97(1):13128 3 antibiotic treatment and sperm dna fragmentation an alternative (22), although it is not safe to discard biopsies in patients who achieve a satisfactory psa response to antibiotics (22), because if it has been observed that the use of antibiotics delays the diagnosis of prostate cancer. in the same way, most of the seminal fluid is composed of by secretions of accessory glands, which comprise the prostate, the seminal vesicles, and the bulbourethral glands, and it is possible that the presence of bacteria in this fluid and in its places of origin (23, 24) could negatively affecting the semen and sperm quality. therefore, as bacteria are present in the semen, safe from its origin, the use of antibiotics will eradicate the local inflammatory effect that promotes tissue damage and release of more prostate antigen, as is happening in patients with increased psa. however, given that the fragmentation of sperm dna don’t occur during its formation, eliminating bacteria from the seminal pathways would allow the elimination of local inflammation and its deleterious effects on sperm dna. bacteria may release soluble factors, such as lipopolysaccharides, hemolysins, and other soluble spermatotoxic factors that can affect sperm physiology (23, 25). the effects of bacterial infection may be multiple, comprising reduction in motility, induction of teratozoospermia (abnormal sperm morphology), apoptosis, dna fragmentation, sperm agglutination, and exposure to oxidative stress through forming reactive oxygen species (ros) (23, 25). altogether, the use of low-potency steroids is necessary because antibiotics do not affect the mucosa of the urothelium or the urethra, but steroids can generate an anti-inflammatory effect on mucous membranes (26). therefore, using antibiotics and steroids can impact both the tissue of the epididymis, prostate and seminal vesicles as well as the urothelial mucosa of the urethra and prostatic urethra, where the semen is expelled. a key finding in this study was the high sperm dfi observed in the samples, with a mean of 28.24 ± 12.39%. this result highlights the presence of significant sperm dfi in the infertile patient population. according to the literature, a cutoff of 20% can differentiate between fertile and infertile men (27). previous evidence from a comparative study carried out with fertile and infertile patients showed that the average sperm dfi was 29.95% (26.6-34.3%) in infertile patients and 19.90% (15.6-24.4%) in fertile patients; moreover, a sperm dfi > 26.1% was associated with a 2.8-fold increased risk of infertility (28). furthermore, orally administered ciprofloxacin and etoricoxib for 15 days reduced the sperm dfi from 36 ± 3% to 24.9 ± 1% (20). the implemented treatment, which included antibiotics and anti-inflammatories, led to significant changes in semen parameters. a significant increase in ph and total sperm concentration was observed at the end of treatment, suggesting an improvement in sperm quality. although the semen volume did not significantly change, these other indicators support the effectiveness of the therapeutic approach (29). furthermore, a reduction in the concentration of leukocytes and round cells, which are markers of inflammation, is an important finding. although the decrease in leukocyte concentration did not reach statistical significance, the reduction in the number of round cells was statistically significant. since round cells are a marker of transient inflammation secondary to spermatogenic aggression, their decrease is positive and could be related to a decrease in sperm dna fragmentation (30). the most striking finding was the significant decrease in the dfi at the end of treatment. this indicates a substantial improvement in sperm dna integrity and, therefore, in sperm quality. taken together, these results support the initial hypothesis that male infertility problems do not reside solely in the quality of the sperm themselves but rather in the factors that may promote the degradation of their integrity once they have reached maturity. antibiotic and anti-inflammatory treatments effectively address these factors, substantially improving semen parameters, including significantly reduced sperm dfi (20). the proposed hypothesis is that a significant percentage of sperm dfi can be generated during its passage through the seminal pathway rather than being an exclusive process of spermatogenesis. in essence, factors present in the epididymis, seminal vesicles, and prostate can substantially contribute to fragmentation, even in the absence of clinical symptoms or semen culture findings. these factors include inflammatory changes in the epididymis, asymptomatic bacterial colonization, subclinical prostatitis, infrequent ejaculation and others. evaluating and managing these conditions in the seminal pathway could improve, to a certain extent, the quality of the seminal sample before deciding on intracytoplasmic sperm injection (icsi). therefore, in this way, the possibility of optimizing sperm quality through a therapeutic approach targeting the seminal pathway, as a strategy before considering assisted reproduction techniques, has to be considered, intending to improve natural pregnancy rates or reduce the need for icsi in some cases. conclusions these findings are promising and may have significant implications for managing male infertility aiming to the quality of the seminal transport fluid beyond spermatogenesis, in order to obtain a non-hostile environment where sperm dna fragmentation is reduced. however, it is essential to highlight the need for additional research and longterm studies to validate these results and better understand the underlying mechanisms involved in this treatment. declarations ethical approval: authorization was requested under current ethical standards; each participant also provided informed consent. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: none. funding: none. authors’ contributions: m.a.a.d., w. d. c.m., a. m.t. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(1):13128 m.a. adel domínguez, w.d. cardona maya, a. mora topete 4 references 1. eisenberg ml, esteves sc, lamb dj, et al. male infertility. nat rev dis primers. 2023; 9:49. 2. kimmins s, anderson ra, barratt clr, et al. frequency, morbidity and equity the case for increased research on male fertility. nat rev urol. 2024; 21:102. 3. schlegel pn, sigman m, collura b, et al. diagnosis and treatment of infertility in men: aua/asrm guideline part i. j urol. 2021; 205:36. 4. abayomi ba, afolabi bm, victor da, oyetunji i. semen parameters associated with male infertility in a subsaharan black population: the effect of age and body mass index. j gynecol infertility. 2018; 1:1. 5. gil-villa am, cardona-maya w, agarwal a, et al. role of male factor in early recurrent embryo loss: do antioxidants have 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human male genital tract microbiota. int j mol sci. 2023; 24. 24. la vignera s, condorelli ra, vicari e, et al. markers of semen inflammation: supplementary semen analysis? j reprod immunol. 2013; 100:2. 25. tvrda e, duracka m, benko f, lukac n. bacteriospermia a formidable player in male subfertility. open life sci. 2022; 17:1001. 26. jayakumar s, pringle k, ninan gk. idiopathic urethritis in children: classification and treatment with steroids. j indian assoc pediatr surg. 2014; 19:143. 27. santi d, spaggiari g, simoni m. sperm dna fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management meta-analyses. reprod biomed online. 2018; 37:315. 28. wiweko b, utami p. predictive value of sperm deoxyribonucleic acid (dna) fragmentation index in male infertility. basic clin androl. 2017; 27:1. 29. sergerie m, laforest g, bujan l, et al. sperm dna fragmentation: threshold value in male fertility. hum reprod. 2005; 20:3446. 30. zhou j, chen li, li j, et al. the semen ph affects sperm motility and capacitation. plos one. 2015; 10:e0132974. correspondence moises abraham adel domínguez, md moises.adel@gmail.com andrés mora topete, md drandresmora@hotmail.com centro de uro-andrología s.c., guadalajara, jalisco, méxico walter d. cardona maya, phd wdario.cardona@udea.edu.co grupo reproducción, departamento de microbiología y parasitología, facultad de medicina, universidad de antioquia, medellín, colombia stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12022 1 original paper introduction urolithiasis is the presence of stones inside the urinary tract. it is one of the most prevalent urological diseases, preceded only by urinary tract infections and prostate diseases (1). urolithiasis is a multifaceted condition and doesn’t have a specific etiology. risk factors for the development of kidney stones (kss) are divided into intrinsic and extrinsic factors. intrinsic factors are age, gender, ethnicity, and genetics. extrinsic factors are climatic and environmental conditions, dietary habits, and occupation (2-4). the prevalence of kss increases with age in both men and women. men are more susceptible to developing kss than females, while in children, both sexes have the same probability of ks formation (2, 5). the prevalence of this condition differs across various geographical areas, with an estimated prevalence ranging from 1% to 5% in asia, 5% to 9% in europe, and a significantly higher at 13% in north america. additionally, it is important to highlight that the likelihood of recurrence for this condition is on the rise, exceeding 50% within a 5to 10-year timeframe (6). occupations that involve dehydration, prolonged exposure to the sun and high temperatures, perspiration, prolonged sitting, and infrequent urination increase the likelihood of ks formation (7-11). the economic burden of kss is substantial. the usa spent 1.83 billion dollars and 2.1 billion dollars in the years 1995 and 2000, respectively. the estimated cost of stone-related problems could reach 4.1 billion dollars by the year 2030 (12). qatar is a middle eastern country that is characterized by its dry and subtropical desert climate. it is situated within the afro-asian-stone belt region, and the workforce composition is marked by the presence of diverse nationalities (13, 14). this study aims to investigate the role of occupation in urolithiasis in the qatar population. additionally, it seeks to examine the correlation of occupation and several intrinsic factors with ks characteristics. background: urolithiasis is one of the most prevalent urological diseases and is associated with a substantial economic burden. its prevalence varies according to geographical location. qatar is a middle eastern country located in the afro-asian stone belt. it has a dry and hot climate, which may predispose individuals working in these environments to form kidney stones (kss). methods: a population sample of 4204 patients was categorized into five occupational classes. the frequencies and correlations of these occupations with ks formation were calculated. results: among the total cases, 2000 presented with kss, with the majority being of asian descent (49%), followed by individuals of middle eastern descent (35.1%). technicians accounted for 35.15% of ks cases followed by clerks (29.2%) and executives (14.6%). among ks cases, 44% had a single stone, 30% had multiple stones, and 26% had two stones. in comparing both ks and non-ks groups, age, gender, occupation, and race were significantly associated with ks formation (p-value < 0.05), while bmi did not show any significant correlation (p-value > 0.05). asian males aged 31-40, working as technicians, were significantly more prone to urolithiasis. in comparing age, bmi, and gender with stone characteristics, only age was found significantly associated with stone size (p-value < 0.05). occupation showed an impact on all studied stone characteristics. clerks and technicians presented more frequently with stones within the 11-15 mm range, while executives more frequently presented with smaller stones (p-value < 0.001). stone density was more frequently < 500 hu in workers, technicians and housewives and > 500 hu in executives and clerks (p-value < 0.001). conclusions: our findings revealed an elevated risk of urolithiasis among certain occupational groups, particularly technicians, who frequently work outdoors in high-temperature environments. alternatively, the sedentary nature of clerical and executive positions can also contribute to the risk of urolithiasis. key words: urolithiasis; occupational risk; environmental factors; geographic prevalence; qatar. submitted 24 october 2023; accepted 9 january 2024 occupational hazard in urolithiasis patients in qatar: a single-center cross-sectional study kamran hassan bhatti 1, rawa bapir 2-4, nadeem sohail 1, faaz salah gomha 1, ahmed h.a. shaat 1, aftab ahmed channa 5, khalid mohammed abdelrahman 1, bryar othman muhammed 6, nali h. hama 2, 7, fahmi h. kakamad 2, 3, 7, berun a. abdalla 2, 3, jihad ibrahim hama 8, hiwa o. abdullah 2, 3 1 urology department, hamad medical corporation, alkhor, qatar; 2 smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq; 3 kscien organization for scientific research (middle east office), hamid str, azadi mall, sulaimani, kurdistan, iraq; 4 department of urology, surgical teaching hospital, sulaimani, kurdistan, iraq; 5 urology unit, islam medical college, sialkot, pakistan; 6 smart health tower (raparin branch), karux street, rania, sulaimani, kurdistan, iraq; 7 college of medicine, university of sulaimani, madam mitterrand street, sulaimani, kurdistan, iraq; 8 research center, university of halabja, halabja, kurdistan, iraq. doi: 10.4081/aiua.2024.12022 summary archivio italiano di urologia e andrologia 2024; 96(1):12022 k. hassan bhatti, r. bapir, n. sohail, et al. 2 methods study design this was a retrospective cross-sectional study of 4204 patients who visited al-khor hospital over the past eight years. specific information such as age, gender, bmi, occupation, race, smoking status, comorbidities, medical history, having ks or not, stone characteristics (in patients with ks), and any previous history of renal surgery (in cases with ks) were collected. the review of the data presented no risks to the subjects involved, as it entailed a comprehensive review of historical medical records without the implementation of any new or invasive measures. study population and setting the study sample comprised medical records of 4204 patients, sourced from pre-existing data within the registry of al-khor hospital, encompassing individuals who have either presented with renal or ureteric stones or visited the hospital for general check-ups over the preceding 8 years. the study population encompassed a diverse spectrum of occupational categories, including clerks, executives, technicians, workers, and housewives. within this classification, technicians were engineers and skilled laborers who were engaged in tasks related to machinery and technology. workers represented a broader category encompassing individuals involved in manual labor or strenuous physical activities, spanning various industries including construction, agriculture, and manufacturing. clerks denoted employees fulfilling various roles within an office setting, while executives were supervisors primarily engaged in meetings and responsible for decisionmaking processes. the frequencies of these occupations were calculated in both groups of patients with or without kss and compared against each other. inclusion and exclusion criteria the study included adult patients who were admitted to al-khor hospital with renal or ureteric colic or visited it for routine check-ups between january 1, 2014, and december 31, 2022. individuals within the pediatric age group were excluded from this study. statistical analysis the acquired data were inputted into the statistical package for the social sciences (spss, v.25; ibm corp.), with optimization of variables for subsequent analysis. descriptive statistics were then generated, followed by correlation testing, where the chi-squared (𝝌²) test was employed to identify associations among diverse parameters. the significance level was predetermined at p ≤ 0.05. results among the total number of individuals included, 2000 presented with ks, with the majority being of asian descent (49%), followed by individuals of middle eastern descent (35.1%). in both ks and non-ks cases, a higher proportion of subjects were male (84.1% and 80.6%, respectively), with male-to-female ratios of 5.3:1 and 4.1:1, respectively. the mean age of ks cases was 36.9 ± 9.1, concentrated in their thirties to forties, while non-ks cases were commonly distributed over thirty years with a mean age of 41.6 ± 13.4. the bmi of ks cases was 28.9 ± 3.6, compared to 29 ± 3.71 in non-ks cases. table 1. the baseline characteristics of the patients. patients with ks (no., %) patients with no ks (no., %) overall (no., %) race asian (979, 49.0%) asian (1081, 49.1%) asian (2060, 49.0%) middle eastern (701, 35.1%) middle eastern (843, 38.2%) middle eastern (1544, 36.7%) unknown (184, 9.0%) unknown (0, 0.0%) unknown (184, 4.4%) african (132, 6.6%) african (245, 11.1%) african (377, 8.9%) american (3, 0.2%) american (12, 0.5%) american (15, 0.4%) european (1, 0.1%) european (23, 1.0%) european (24, 0.6%) sex male (1682, 84.1%) male (1776, 80.6%) male (3458, 82.3%) female (318, 15.9%) female (428, 19.4%) female (746, 17.7%) age (yrs.) 18-23 (0, 0.0%) 18-23 (155, 7.0%) 18-23 (155, 3.7%) 24-30 (488, 24.4%) 24-30 (347, 15.7%) 24-30 (835, 19.9%) 31-40 (851, 42.55%) 31-40 (621, 28.2%) 31-40 (1472, 35.0%) 41-50 (330, 16.5%) 41-50 (557, 25.3%) 41-50 (887, 21.1%) > 50 (331, 16.55%) > 50 (524, 23.8%) > 50 (855, 20.3%) mean age ± sd (36.9 ± 9.1) mean age ± sd (41.6 ± 13.4) mean age ± sd (39.3 ± 11.8) bmi (kg/m2) * normal (209, 10.45%) normal (242, 11.0%) normal (451, 10.7%) overweight (1048, 52.4%) overweight (1109, 50.3%) overweight (2157, 51.3%) obese (743, 37.15%) obese (853, 38.7%) obese (1596, 38.0%) mean bmi ± sd (28.9 ± 3.6) mean bmi ± sd (29 ± 3.71) mean bmi ± sd (29 ± 3.67) smoking yes (504, 25.0%) yes (327, 14.8%) yes (831, 19.8%) no (1496, 75.0%) no (1877, 85.2%) no (3373, 80.2%) comorbidity none (1952, 97.6%) none (1752, 79.5%) none (3704, 88.1%) diabetes mellitus (26, 1.3%) diabetes mellitus (220, 10%) diabetes mellitus (246, 5.9%) hypertension (22, 1.1%) hypertension (232, 10.5%) hypertension (254, 6.0%) occupation clerk (584, 29.2%) clerk (342, 15.5%) clerk (926, 22.0%) executive (292, 14.6%) executive (302, 13.7%) executive (594, 14.1%) housewife (87, 4.35%) housewife (392, 17.8%) housewife (479, 11.4%) technicians (703, 35.15%) technicians (416, 18.9%) technicians (1119, 26.6%) worker (334, 16.7%) worker (752, 34.1%) worker (1086, 25.8%) previous renal surgery yes (1154, 57.7%) no (846, 42.3%) number of stones one (879, 44.0%) two (522, 26.0%) multiple (599, 30.0%) location of stones ureter (330, 16.5%) renal pelvis (512, 25.6%) upper calyx (303, 15.15%) middle calyx (411, 20.55%) lower calyx (444, 22.2%) size of stones 5-10 mm (551, 27.55%) 11-15 mm (935, 46.75%) 16-20 mm (514, 25.7%) laterality right (958, 47.9%) left (1042, 52.1%) density of stones < 500 hu (1093, 54.65%) > 500 hu (907, 45.35%) archivio italiano di urologia e andrologia 2024; 96(1):12022 3 occupational hazard in urolithiasis patients regarding occupations, technicians comprised the largest group (26.6%), accounting for 35.15% of ks cases and 18.9% of non-ks cases. they were followed by workers (25.8%), representing 16.7% of ks cases and 34.1% of non-ks cases, and clerks (22%), comprising 29.2% of ks cases and 15.5% of non-ks individuals (table 1). more than half of the ks cases (57.7%) had a history of previous renal surgery. among ks cases, 44% had a single stone, 30% had multiple stones, and 26% had two stones, which were almost evenly distributed in terms of laterality. the most common locations were the renal pelvis (25.6%), lower calyx (22.2%), and middle calyx (20.55%). stone sizes were commonly distributed between 11-15 mm (46.75%) with a density smaller than 500 hu in 54.65% (table 1). in comparing the two groups, age, gender, occupation, and race were significantly distributed in subjects with and without ks (p-value < 0.05), while bmi was not significantly different (p-value > 0.05). asian males aged 31-40, working as technicians, were the group significantly more prone to urolithiasis (table 2). in comparing age, bmi, and gender with stone characteristics (number, size, density), only stone size was differently distributed by age (p-value < 0.05). the 11-15 mm stone size was the most frequent in all age groups, although in patients between ages 31-40 years, the rate of 11-15 mm stones was higher (49%) than in the other age groups. all three stone characteristics were significantly correlated with occupation; stones were mostly single in clerks, housewives, technicians, and workers, while in executives, stones were mostly multiple (p-value < 0.001). the most common stone size among clerks and technicians was within the 11-15 mm range, while executives more frequently presented with smaller stone sizes in comparison to other occupations (p-value < 0.001). stone density was more frequently < 500 hu in workers, technicians and housewives and > 500 in executives and clerks (p-value < 0.001). table 2. the correlation of age, bmi, gender, and occupation with having ks. part. 1 variables age (yrs.) bmi total 18-23 24-30 31-40 41-50 > 51 p-value * normal overweight obese p-value * having stone yes 2000 0 488 851 330 331 < 0.001 209 1048 743 0.401 no 2204 155 347 621 557 524 242 1109 853 part. 2 variables gender occupation race total male female p-value* clerk executive housewife technician worker p-value * total african american asian european middle eastern p-value * having stone yes 2000 1682 318 0.003 584 292 87 703 334 < 0.001 1816 132 3 979 1 701 < 0.001 no 2204 1776 428 342 302 392 416 752 2204 245 12 1081 23 843 * chi-square test. bmi: body mass index. ks: kidney ston. table 3. the correlation of age, bmi, gender, and occupation with stone characteristics. part. 1 variables age (yrs.) bmi total 24-30 31-40 41-50 > 50 p-value* normal overweight obese p-value * stone number one 879 215 366 147 151 0.867 90 471 318 0.474 two 522 124 232 89 77 59 278 185 multiple 599 149 253 94 103 60 299 240 stone size 5-10 mm 551 109 249 102 91 0.027 58 304 189 0.55 11-15 mm 935 250 401 139 145 97 476 362 16-20 mm 514 129 201 89 95 54 268 192 stone density < 500 hu 1093 271 466 181 175 0.9 105 588 400 0.255 > 500 hu 907 217 385 149 156 104 460 343 part. 2 variables gender occupation total male female p-value * clerk executive housewife technician worker p-value * stone number one 879 732 147 0.612 363 38 39 310 129 < 0.001 two 522 445 77 107 106 16 199 94 multiple 599 505 94 114 148 32 194 111 stone size 5-10 mm 551 459 92 0.642 29 142 36 205 139 < 0.001 11-15 mm 935 794 141 551 35 21 284 44 16-20 mm 514 429 85 4 115 30 214 151 stone density < 500 hu 1093 920 173 0.923 266 56 62 465 244 <0.001 > 500 hu 907 762 145 318 236 25 238 90 * chi-square test. bmi: body mass index. yrs: years, hu: hounsfield units. archivio italiano di urologia e andrologia 2024; 96(1):12022 k. hassan bhatti, r. bapir, n. sohail, et al. 4 discussion in the course of this study, we conducted an assessment of the role of occupation in urolithiasis and examined the correlation of occupation and other several intrinsic factors with ks characteristics in the population of qatar. in this study, only validated studies were used for discussion (15). factors estimated to contribute to the pathogenesis of nephrolithiasis include genetic predisposition, gender, geographic location, dietary habits, insufficient fluid intake, and socioeconomic status (16). it has been well established that males are more susceptible to nephrolithiasis than females due to exposure to risk factors (16-18). a review study indicated an elevated prevalence of exposure to occupational hazards among men. these hazards include engaging in repetitive tasks, extended periods of sitting or standing at work, physically demanding labor involving lifting and manual material handling and exposure to occupational ultraviolet radiation from sunlight. the review found no evidence in any study suggesting that women had a higher susceptibility than men to these specific occupational hazards, most of which are recognized as risk factors for the development of ks (18). another study indicated that the increased occurrence and prevalence of ks in men could be attributed to higher rates of obesity and alcohol consumption in men compared to women, leading to heightened production of oxalic acid in men (17). urolithiasis predominantly impacts adults in the third to fourth decade of life, with a generally observed male-tofemale ratio ranging from 1.5:1 to 2.5:1 (19). some studies, particularly in the united states, suggested a potential decline in this ratio to below 1.5:1 (20-22). another study conducted in morocco reported a male-to-female ratio of 2.03:1, while hossain et al. documented a ratio of 2.68:1 in japan (19, 23). in bouatia's study, the age group most susceptible to ks was between 31 and 60 years old, with a peak incidence observed at the age of 53 (19). in addition to the intrinsic factors, some studies also mentioned high bmi or obesity as a factor for ks formation (17, 19, 24, 25). in line with the literature, the findings of our study revealed that males were significantly more affected by nephrolithiasis. this association was attributed to the nature of the patients' work, which often involved exposure to sunlight, high temperatures, or a sedentary work style in the workplace. the male-to-female ratio among our ks cases was 5.3:1, significantly higher than the ratios reported in previous studies. the mean age of ks cases was 36.9 ± 9.1, consistent with the literature. while some authors have reported an association between bmi and ks formation, our findings, to the contrary, indicate no significant role of bmi in nephrolithiasis. in our study, the races most significantly affected by ks were asian, followed by middle eastern and african populations, underscoring the correlation between ks formation and geographical location, as indicated in the literature (16). in terms of stone composition, most studies reported similar findings. in a renal stone clinic in southampton, in a population of 2800 patients, the predominant stone composition was calcium oxalate (89%), with a ratio of 1:4 for calcium oxalate to mixed calcium oxalate phosphate stones. pure calcium phosphate stones were infrequent, accounting for only 2% of cases. in sweden, approximately 85% of urinary tract stones were classified as calcium stones, encompassing both calcium oxalate and calcium phosphate varieties (26, 27). in another study involving 888 cases, calcium oxalate and calcium phosphate were identified as the most common primary components of the stones (28). in a series of 802 patients with 828 ks, bouatia et al. identified calcium oxalate as the main component, followed by uric acid and calcium phosphate (19). unfortunately, due to the nature of the study design, we could not represent any data regarding stone composition in our cases. however, the stone density in 54.65% of our cases was < 500 hu, and according to the literature, stones with < 500 hu were usually uric acid stones. therefore, we estimate that stones in more than half of our cases were uric acid type (29). our findings revealed that the majority of patients at risk of ks formation were the technicians and the clerks. the technicians with ks accounted for 35.15% of our dataset. they may spend a significant amount of time outdoors, often exposed to adverse weather conditions, including high temperatures and direct sunlight. these environmental factors, notably high-temperature environments and prolonged sun exposure, are recognized as significant risk factors in the etiology of urinary stone formation, especially uric acid stones (30). nevertheless, workers, akin to technicians, are exposed to elevated temperatures and sunlight. however, in this study, their association with ks formation did not reach the same level of significance as observed with technicians. in 1945, pierce et al. studied the effects of high-temperature exposure as a risk factor for the formation of urolithiasis in american troops in desert areas (31). later on, multiple studies indicated the association between the incidence of stone and working in ambient temperatures, under the sun, and perspiration (10, 30, 31). better et al. studied the increased incidence of nephrolithiasis in lifeguards who are exposed to the sun more than the normal population (10). lu et al. reported an increase in the prevalence of radiolucent stones among workers in a steel factory who were exposed to heat (11).the correlation between urolithiasis and ambient temperature, as well as heat exposure, can be attributed to several factors, including low urine volume with saturation of stone-forming salts in urine due to perspiration (32). perspiration also leads to acidic urine with a reduction of uric acid solubility, which also contributes to stone formation (31). the incidence of urolithiasis peaks in the summer, which further supports the impact of ambient temperatures on stone formation (8). this assumption aligns perfectly with our region, characterized by a dry and subtropical desert climate. another hypothesis for the development of stone in warmer climates is that sunlight leads to higher levels of vitamin d (32), although it is not concretely supported (33-35). a substantial portion of our dataset (43.8%) in the ks archivio italiano di urologia e andrologia 2024; 96(1):12022 5 occupational hazard in urolithiasis patients group consisted of individuals employed in clerical and executive positions. this notable prevalence can be attributed to a myriad of factors. executive professionals occupied pivotal roles within our dataset, characterized by their accountability for formulating high-level decisions and overseeing the management of organizations or departments. their responsibilities encompassed strategic planning, leadership, and frequent engagement in meetings and office-based activities. clerical personnel within our dataset primarily performed administrative functions such as data entry, record-keeping, and meticulous management of paperwork. they often worked indoors with executives. staying indoors and the sedentary features of these occupations have the potential to place individuals in a vulnerable position regarding the development of metabolic syndrome, elevated bmi, and infrequent urination. consequently, it is plausible to assert that such occupational pursuits may indirectly elevate the susceptibility of individuals to urolithiasis (8). infrequent urination due to prolonged working hours and low urine volume are other occupational risks for the development of urolithiasis. individuals in various professions such as taxi drivers, aviation personnel, teachers, and healthcare workers are at risk due to these factors (7, 8, 36). on the other hand, the potential for urolithiasis development in factory workers is exacerbated by occupational exposure to metallic substances. jarup et al. documented an increased prevalence of kss in individuals exposed to cadmium (37). additionally, liu and colleagues identified an association between kss and the presence of heavy metals such as arsenic and cadmium, while chromium, mercury, and lead did not manifest discernible associations with this condition (4). in the present study, we were unable to explore any relationships between metallic substances and ks formation due to the absence of data regarding the extent of exposure among cases or workers. finally, there is insufficient knowledge on the correlation of stone characteristics with intrinsic and extrinsic factors for stone formation. a study by krambeck et al. reported no significant difference in stone size and location in relation to age. nonetheless, older individuals were more likely to have stones with a larger diameter or staghorn calculi (28). a meta-analysis of 15 studies involving 13.233 patients found no significant correlation between bmi and stone size (25). in the present study, all stone characteristics, including number, size, and density, were found to be significantly correlated only with occupation, whereas stone size showed a correlation with age. in contrast to the study by krambeck et al., the stone size of 11-15 mm was the most frequent in all age groups, particularly in patients aged 31-40 years; no evidence suggested that older patients had larger stone sizes. furthermore, consistent with the meta-analysis by wang et al., bmi did not exhibit a significant impact on stone size. our study had several limitations. the primary constraints included the retrospective nature of the work, which may have omitted certain data that could directly or indirectly influence the results. specifically, information about alcohol consumption status, urination volume, daily water intake, and the presence of kidney diseases or other diseases that could enhance ks formation may not have been adequately captured. conclusions this study has provided insights into different working activities that may increase the risk of urinary stone formation in the qatari population. our findings suggested an elevated risk of urolithiasis among certain occupational groups, particularly technicians, who frequently work outdoors in high-temperature environments. similarly, the sedentary nature of clerical and executive positions, characterized by prolonged indoor working hours can also indirectly contribute to the risk of urolithiasis. implementing proactive measures and awareness plans targeted at these at-risk groups may significantly contribute to reducing the incidence of urolithiasis among the workforce. declarations • ethical approval: this study does not involve any human or animal testing. • availability of data and material: all data and materials are kept by the first and corresponding authors. • competing interests: none. • funding: no source to be stated. • authors' contributions: kamran hassan bhatti, rawa bapir, and nadeem sohail were major contributors to the study. hiwa o. abdullah, faaz salah gomha, ahmed h.a. shaat, aftab ahmed channa, nali h. hama, khalid mohammed abdelrahman, and bryar othman muhammed were involved in the literature review, the writing of the manuscript, and data analysis and interpretation. fahmi h. kakamad, berun a. abdalla, and jihad ibrahim hama were involved in the design of the study, and the 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8:243. 30. li z, li y, wang x, et al. extreme temperature exposure and urolithiasis: a time series analysis in ganzhou, china. frontiers in public health. 2022; 10:1075428. 31. pierce lw, bloom b. observations on urolithiasis among american troops in a desert area. the journal of urology. 1945; 54:466-70. 32. fakheri rj, goldfarb ds. association of nephrolithiasis prevalence rates with ambient temperature in the united states: a reanalysis. kidney international. 2009; 76:798. 33. ferraro pm, taylor en, gambaro g, et al. vitamin d intake and the risk of incident kidney stones. the journal of urology. 2017; 197:405-10. 34. letavernier e, daudon m. vitamin d, hypercalciuria and kidney stones. nutrients. 2018; 10:366. 35. bargagli m, ferraro pm, vittori m, et al. calcium and vitamin d supplementation and their association with kidney stone disease: a narrative review. nutrients. 2021; 13:4363. 36. hari sb, morrow ms. rethinking nephrolithiasis in military aviation. aviation, space, and environmental medicine. 2012; 83:445-8. 37. jarup l, elinder cg. incidence of renal stones among cadmium exposed battery workers. br j ind med. 1993; 50:598-602. correspondence kamran hassan bhatti, md kamran.bhatti@gmail.com nadeem sohail, md faaz salah gomha, md ahmed h.a. shaat, md khalid mohammed abdelrahman, md urology department, hamad medical corporation, alkhor, qatar rawa bapir, md nali h. hama, md berun a. abdalla, md hiwa o. abdulla, md hiwaabdullah588@gmail.com smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq aftab ahmed channa, md urology unit, islam medical college, sialkot, pakistan bryar othman muhammed, md smart health tower (raparin branch), karux street, rania, sulaimani, kurdistan, iraq fahmi h. kakamad, md (corresponding author) fahmi.hussein@univsul.edu.iq doctors city, building 11, apartment 50, sulaimani, iraq road number: gfg6+m6f sulaymaniyah, iraq jihad ibrahim hama, md research center, university of halabja, halabja, kurdistan, iraq conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12687 1 review mental impact on their partners (2). treatment of ed is tailored to its underlying etiology, which is highly individualized, ranging from conservative, medicinal, and surgical approaches (3). conservative approaches, such as lifestyle adjustments and risk factor management, can be advised for individuals with mild ed; however, patients with symptomatic ed may require medical or even surgical therapeutic approaches (4). several treatments are available to control the symptoms, including pde5i, topical vasoactive therapy, and a vacuum erection device (5). nevertheless, studies reveal that the majority of ed patients have poor compliance; data suggest that one out of four patients will discontinue pharmacological therapy, with one of the most common reasons is the unwillingness to depend on pharmacological medicine and the desire for natural, spontaneous erections (6). therefore, the ability to achieve a natural spontaneous erection is one of utmost importance in patients with ed. the main problem with the earlier ed treatment paradigm is that it focuses on alleviating symptoms rather than restoring natural erectile function or halting disease progression. accordingly, researchers worked on discovering alternate treatments that might naturally improve erectile function (7). recently, a group of treatments known as regenerative medicine aim to restore the structure and function of erectile tissues, such as low-intensity shockwave therapy (liswt), stem cell therapy, and platelet-rich plasma (prp) (7-9). prp, a novel regenerative therapy with high rejuvenating potential and minimal side effects, contains various platelet growth factors produced from whole blood, such as fibroblast growth factor (fgf), platelet-derived growth factor (pdgf), and vascular endothelial growth factor (vegf), which can heal injured penile tissue and restore erectile function (10, 11). in animal studies, researchers discovered that prp can successfully enhance natural erectile function (12-14). human clinical trials, on the other hand, remain scarce and conflicting (15-17). therefore, the aim of this study is to conduct a meta-analysis of the available randomized controlled trials (rct) to assess the efficacy of prp in males with ed. introduction: platelet-rich plasma (prp) has shown positive effects on enhancing erectile function in animal studies. human clinical trials are limited and provide contradictory results. this review aims to conduct a meta-analysis of the available randomized controlled trials (rct) to assess the efficacy of prp in males with ed. methods: a systematic review was carried out following the cochrane handbook of intervention and the preferred reporting items for systematic reviews and meta-analyses (prisma) and registered in prospero (crd42023441655). results: a total of three rcts were included in the analysis for a total of 221 patients with mild to moderate ed. the patients receiving prp reported significantly better improvement of iiefef score during 1,3and 6-months follow-up compared to the placebo group (mean difference [md] 2.66, 95% confidence interval [ci] 1.48 to 3.83, p < 0.01; md 2.11, 95%ci 0.13 to 4.09, p = 0.04; md 2.99, 95%ci 1.79 to 4.19, p < 0.01). the pooled analysis indicated that attainment of minimally clinical important difference (mcid) was significantly higher in patients receiving prp compared to the placebo group during one and 6-month follow-up (odds ratio [or] 5.51, 95%ci 1.2 to 254, p = 0.03; or 5.64, 95%ci 2.05 to 15.55, p < 0.01; respectively). encouragingly, no major aes were reported in all three trials in the prp and placebo groups (p = 0.99). conclusions: this review highlights the potential role of prp in providing short-term improvement of erectile function parameters for up to 6 months in mild to moderate ed patients. future rcts with longer-duration follow-ups and more standardized treatment protocols are necessary to gain sufficient details on prp's long-term effectiveness and safety. key words: platelet-rich plasma; erectile dysfunction; regenerative medicine; sexual and reproductive health; reproductive health. submitted 24 may 2024; accepted 7 june 2024 introduction erectile dysfunction (ed) is one of the most common male sexual dysfunctions globally (1). this condition not only impairs the patient's quality of life, but it also has a detrithe potential role of intracavernosal injection of platelet-rich plasma for treating patients with mild to moderate erectile dysfunction: a grade-assessed systematic review and meta-analysis of randomized controlled trials niwanda yogiswara 1, 2, fikri rizaldi 1, 3, mohammad ayodhia soebadi 1, 3 1 department of urology, faculty of medicine, universitas airlangga, indonesia; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia; 3 universitas airlangga teaching hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2024.12687 summary archivio italiano di urologia e andrologia 2024; 96(3):12687 n. yogiswara, f. rizaldi, m. ayodhia soebadi, et al. 2 material and methods study protocol and search strategy the search was carried out with several online databases such as pubmed, scopus, and sciencedirect, utilizing medical subject headings (mesh®) terms relevant to platelet-rich plasma and erectile dysfunction for publications published up to july 2023 following the cochrane handbook of intervention and the preferred reporting items for systematic reviews and meta-analyses (prisma) (18, 19). the detailed review protocols were available in prospero (crd42023441655). article eligibility criteria the inclusion criteria were sexually active men diagnosed with erectile dysfunction (ed) according to the international index of erectile function (iief) score, receiving the intervention of intracarvernosal injection of prp, compared to the intervention of placebo, reporting one of the following the outcomes, minimal clinically important difference (mcid), change of international index of erectile functionerectile function (iief-ef) from baseline, sexual encounter profile question 3 (sep-3), peak systolic velocity (psv), enddiastolic velocity (edv), minor adverse events, and major adverse events. all studies without full-text and nonenglish were excluded. data collection and quality assessment to ensure accuracy in collecting baseline characteristics for the study, two independent authors used a piloted data collection sheet. any discrepancies were resolved through discussion involving a third author. collected data included patients' baseline characteristics, such as study location, study design, number of participants, age, follow-up period, and the first author's name. data gathering was done using microsoft excel® 2021. the cochrane risk of bias (rob) tool 2 was utilized to assess the bias risk of the rcts included in the study (20). data synthesis and presentation the effect size estimates of the metaanalysis were displayed as odds ratio (or) and mean difference (md) with 95% confidence interval (95% ci) for binary and continuous outcomes, respectively. where the data from trials were presented as median and range, the mean and standard deviation (sd) were computed using wan et al.'s formula (21). when a study did not provide sufficient information on the change in sd, we calculated data imputation using the formula for imputing sd from the baseline (18). the model used for analysis was selected based on the heterogeneity of the included study. we used the i² index and heterogeneity 𝝌² test to evaluate heterogeneity between the studies the study being analysed had considerable heterogeneity, as indicated by i² > 50% and heterogeneity p-value < 0.05. therefore, the random-effects dersimonian and laird model was chosen for the analysis. if the heterogeneity was not significant, the fixed-effects model would have been used instead (3). in this study, we considered a p-value < 0.05 statistically significant. to evaluate the certainty of evidence, the grading of recommendations, assessment, development, and evaluations (grade) method was employed using gradepro gdt (22). all statistical analyses were performed using stata® 16. results baseline characteristics and risk of bias of the included trials the initial database search revealed 1.050 abstracts related to the use of prp in ed patients. thirteen studies were extracted for full-text eligibility assessment after screening the abstract using the pre-defined eligibility criteria. finally, three double-blinded rcts were included in the review as figure 1. prisma flow diagram 2020. archivio italiano di urologia e andrologia 2024; 96(3):12687 3 intracavernosal injection of platelet-rich plasma for erectile dysfunction displayed in figure 1. table 1 represents the baseline characteristics of the participants of the included trials. trials were conducted on several continents with similar ages and nutritional statuses. the majority of the participants were classified with mild and mild-moderate ed. figure 2 displays the summary of the risk of bias assessment by evaluating the five domains. there were some concerns regarding bias arising from the randomization process in the trial by poulios et al., as there were insufficient details regarding the randomization methods (17). the trial by masterson et al. showed some concerns in terms of bias due to missing outcome data, as the trial reported a high rate of patients excluded from analysis (16). however, the analysis summary demonstrated an overall low risk of bias among the included trials. treatment protocols and outcomes of the included trials table 2 provides detailed information regarding the trial protocol and outcomes. the percentage rate of participants excluded from the final analysis ranged from 3% to 29% due to loss of follow-up or missing outcome data. all included trials take the prp sample from the patient's autologous blood samples, with 2-3 injection sites sepatable 1. baseline characteristics of the included studies. author country study design trial id group participant participant excluded mean bmi smoker ht) dm baseline ed severity (loe) (n) analyzed from final age (yr) (kg/m2) (%) (% (%) iief mild mildmoderate (n) analysis moderate poulios, et al. 2021 greece, double-blinded nct prp group 30 29 3% 58 29.4 53 33 37 20.4 43% 47% 10% europe rct (1b) 04050020 placebo group 30 26 12% 59 28.5 63 27 13 19.4 23% 60% 17% shaher, et al. 2023 egpyt, double-blinded not reported prp group 55 50 10% 56 25 54 36 30 18 30% 50% 20% africa rct (1b) placebo group 54 50 8% 54 24.9 56 28 34 19 26% 56% 18% masterson, et al. 2023 florida, double-blinded nct prp group 28 20 29% 49 27.9 92 28.6 10.7 17.4 57% 43% america rct (1b) 04396795 placebo group 33 24 28% 46 28.5 100 30.3 9.1 18.6 63% 36% table 2. treatment protocols and outcomes of the trials. author group inclusion criteria exclusion criteria prp source treatment total follow-up final mean final sep-3 adverse pain scale protocol session iief change change (%) effects (1-10) poulios, et al. 2021 shaher, et al. 2023 masterson, et al. 2023 prp group placebo group prp group placebo group prp group placebo group sexually active male aged 40-70 yo mildmoderate ed ed treatment cessation sexually active male aged 45-60 yo mildmoderate ed ed treatment cessation sexually active male aged 30-75 yo mildmoderate ed pde5i treatment continued major pelvic surgery/trauma anatomical disorder affecting erectile function abnormal testosterone level psychogenic ed major pelvic surgery abnormal testosterone level psychogenic ed urological surgery abnormal testosterone level psychogenic ed abnormal hba1c level 60 ml autologous blood 30 ml autologous blood 120 ml autologous blood 5 ml of prp, 2 sites of injection 5 ml of saline, 2 sites of injection 3 ml of prp, 3 sites of injection 3 ml of saline, 3 sites of injection 2.5 ml prp, 2 sites of injection 2.5 ml saline, 2 sites of injection 2 session, 1 mo interval 2 session, 14 d interval 2 session, 14 d interval 2 session, 28 d interval 2 session, 28 d interval 2 session, 28 d interval 6 month 6 month 6 month 3.3 -0.2 2.6 0 5 2.2 20 -9 66 0 not reported not reported none none 1 penile plaque (3.5%) 1 penile hematoma (3%) 2.6 2.2 1.52 1.54 3.7 3.5 figure 2. risk of bias assessed using rob2 by cochrane. archivio italiano di urologia e andrologia 2024; 96(3):12687 n. yogiswara, f. rizaldi, m. ayodhia soebadi, et al. 4 rated in 2 sessions at 2-weekto 4-week intervals. all of the included trials demonstrated higher iief change in the prp group compared to the placebo group, with the most remarkable change of iief from baseline reported by poulios et al. with the adjusted mean difference of 3.9 (1.8, 5.9, p < 0.01) (17). in terms of minimally clinical important difference (mcid), earlier trials by poulious et al. and shaher et al. reported that prp had a higher attainment of mcid compared to placebo (69% vs 27%, p < 0.01; 70% vs 16%, p < 0.01; respectively), with the exception of an insignificant difference by masterson et al. (60% vs 41.7%, p = 0.226) (16). after six months of follow-up, trials showed no major or minor adverse effects, except for penile plaque in one of the prp groups and hematoma in one of the placebo groups in the trial by masterson et al. (16). results from pooled analysis the meta-analyses were conducted from three trials for a total of 221 patients with mild to moderate ed. figure 3 displays the pooled analysis of patients receiving prp, which demonstrates significantly better improvement of iief-ef score during 1,3and 6-months follow-up compared to the placebo group (md2.66, 95% 1.48 to 3.83, p < 0.01; md 2.11, 95%ci 0.13 to 4.09, p = 0.04; md 2.99, 95% ci 1.79 to 4.19, p < 0.01, respectively). the pooled analysis indicated that attainment of mcid was significantly higher in patients receiving prp compared to the placebo group during one and 6-month follow-up [odds ratio (or) 5.51, 95%ci 1.2 to 254, p = 0.03; or 5.64, 95%ci 2.05 to 15.55, p < 0.01; respectively], as displayed in figure 4. encouragingly, there were no major aes reported in all 3 trials in the prp and placebo groups (p = 0.99). results from the assessment of certainty of evidence table 3 provides detailed information regarding the assessment of certainty evidence. the evidence certainty indicated that the change in iief-ef from one to six months follow-up had a moderate level of certainty, with no serious problems regarding inconsistency, imprecision, or other factors. the analysis of mcid change revealed low certainty of evidence due to considerable imprecision concerns arising from the wide range of confidence intervals. the rating was downgraded due to significant heterogeneity in the included trials, but upgraded because of its large effects size (23). figure 3. change of iief-ef score in (a) 1 month, (b) 3 month, and (c) 6 months between ed patients receiving prp and placebo. archivio italiano di urologia e andrologia 2024; 96(3):12687 5 intracavernosal injection of platelet-rich plasma for erectile dysfunction figure 4. mcid in (a) 1 month, (b) 3 month, and (c) 6 months between ed patients receiving prp and placebo. table 3. summary of certainty of evidence evaluated using grade approach. outcome participants risk of bias inconsistency indirectness imprecision other overall certainty prp placebo anticipated (studies) consideration oof evidence effects 1 month iief change 212 (3 rcts) not serious a not serious serious c not serious none e ⊕⊕⊕◯ 104 108 md 2.66 moderate (1.48, 3.83) 3 month iief change 209 (3 rcts) not serious a not serious serious c not serious none e ⊕⊕⊕◯ 105 104 md 2.11 moderate (0.13, 4.09) 6 month iief change 204 (3 rcts) not serious a not serious serious c not serious none e ⊕⊕⊕◯ 104 100 md 2.99 moderate (1.79, 4.19) 1 month mcid 209 (3 rcts) not serious a serious b serious c serious d strong asociation e ⊕⊕◯◯ 74/103 31/106 or 5.52 low (71.8%) (29.2%) (1.20, 25.40) 3 month mcid 204 (3 rcts) not serious a serious b serious c serious d strong asociation e ⊕⊕◯◯ 66/101 31/103 or 3.22 low (65.3%) (30.1%) (0.57, 18.25) 6 month mcid 199 (3 rcts) not serious a serious b serious c serious d strong asociation e ⊕⊕◯◯ 67/99 25/100 or 5.64 low (67.7%) (25.0%) (2.05, 15.55) a low risk of bias according to the assessment of rob 2; b downgraded because high heterogeneity in the included trials evaluated by i2 index; c downgraded because the included trials restricted to patient with mild-moderate erectile dysfunction with heterogeneous treatment protocols; d downgraded because the included trials demonstrated a wide range of confidence intervals; e upgraded because of the effect is large. archivio italiano di urologia e andrologia 2024; 96(3):12687 n. yogiswara, f. rizaldi, m. ayodhia soebadi, et al. 6 discussion recent developments in the field of erectile dysfunction therapy have undergone a paradigm shift, moving beyond the mere treatment of symptoms to address the underlying pathology through regenerative medicine (24). earlier reviews have previously highlighted the potential benefits of integrating regenerative medicine in improving erectile function, with the majority emphasizing shockwave therapy (25-28). the evidence regarding regenerative medicine is growing and even the eau guideline is now recommending it as part of treatment for selected ed patients (7, 29, 30). the findings of our review provided an additional interesting new insight into prp as a novel regenerative therapy for ed. prp's use in medical therapy has been grown since its inception in the recent decades, with reports of use in orthopedics, neurology, dermatology, cardiothoracic surgery, and now urology (31-34). although the use of prp in urology is still in its infancy, several animal trials and observational studies have demonstrated the benefits in patients with bladder dysfunction, bladder pain syndrome, cystitis, peyronie's disease, and ed (13, 35, 36). to determine the role of prp in patients with ed, several outcomes are evaluated. one of the most important endpoints to consider is the iief-ef score. the ef domain included specific questions about erection frequency, erection firmness, penetration ability, maintenance frequency, maintenance ability, and erection confidence that were intended to determine the severity of ed (37). the improvement of iief-ef score reflects the benefits of the treatment for ed patients. the significance of prp in improving iief-ef score was first demonstrated in a placebo-controlled trial by poulios et al. which found an adjusted mean difference of 3.9 points compared to the placebo group during the six-month follow-up (17). this evidence is further supported by a recent trial by shaher et al. which showed a significantly higher iief-ef in the prp group (15). in contrast, the latest rct in the american population showed an insignificant difference in iief-ef score between the prp and placebo groups. in this review, we discovered that in six month follow-up, prp significantly improve iief-ef score compared to placebo, with a mean difference of 2.99 points. when we look solely at the aggregate mean difference on the pooled analysis between prp and placebo, the difference is relatively minor and it might be clinically irrelevant. in order to objectively measure the clinical relevance of prp for treating ed, we analysed the attainment of mcid, an endpoint to determine the minimum amount of objective change required in the ef domain to be meaningful to patients (38, 39). prior trials by poulios et al. and shaher et al. found that patients who received prp obtained a greater mcid at the final follow-up compared to those who received placebos (15, 17). however, the latest trial by masterson et al. observed a slightly higher but statistically insignificant difference in mcid (16). when the evidence was pooled, the analysis revealed a significantly greater attainment of mcid in prp during the final follow-up, with an or of 5.64 times compared to placebo. previous studies have also demonstrated significant improvements in other patient-reported outcome measures, including sep-2 and sep-3 in the prp group. however, due to limited data, a meta-analysis could not be performed. several trials evaluated objective parameters, including penile vascular parameters. in shaher et al.'s trial, notable enhancements were observed in peak systolic velocity and end diastolic velocity (15). however, the most recent trial by masterson et al. found no meaningful differences (16). insufficient data makes it impossible to conduct a meta-analysis, and a definitive conclusion on alterations in penile vascularity cannot be drawn from the existing evidence. regarding safety, extant trials have reported minimal to no side effects of prp in patients with ed during shortterm follow-up. notably, masterson et al. reported a single minor side effect in both treatment groups, with no major side effects observed during the trial (16). our review of the literature demonstrates that pooled analyses revealed insignificant differences in side effects between prp and placebo arms. it is important to note, however, that available studies only reported a limited period of follow-up, and the long-term safety of prp in ed patients has yet to be well-established. all trials uniformly applied specified exclusion criteria, which was participants with anatomical, hormonal, and psychogenic causes of erectile dysfunction. the observed difference in the included trial might be attributable to the heterogeneity of treatment protocols. for example, the trial by masterson et al. used two sessions of a total of 5 ml of prp concentrated from 120 ml of autologous blood (16). on the other hand, poulios et al. used two sessions with a total of 10 ml of prp concentrated from 60 ml of autologous blood (17). according to earlier studies, several factors, including overall platelet concentration, leucocyte and hemoglobin concentrations, the technique of activation of prp, and mean-platelet volume (mpv) level, could affect the bioavailability of growth factors and play a role in determining the success rate of prp in ed patient (30, 40). theoretically, the different prp concentrations in the trials might affect the study's primary endpoints. furthermore, increasing the number of injections or adjusting the period between injections might result in greater improvements in iief-ef. in this review, we cannot delve further to conduct meta-regression or subgroup analysis according to different treatment protocols due to the unmet required number of available trials (18). the exact mechanism of how prp improves erectile function is not yet fully understood. however, several theories suggest platelets are crucial in coagulation and promoting wound healing following an injury (41). platelets also contain various growth factors, such as fgf, pdgf, and vegf. these growth factors, as catalysts of regenerative processes, play a critical role in the recruitment of stem cells, modulation of inflammatory responses, and stimulation of angiogenesis. these intricate functions are responsible for the regeneration and repair of tissues (42). in general, our analysis demonstrates a significant shortterm improvement of the erectile function in mild to moderate ed patients receiving intracavernosal prp compared to placebo with minimal side effects. the evidence's overall certainty level ranged from low to moderate, indicating that more research is quite probable to sigarchivio italiano di urologia e andrologia 2024; 96(3):12687 7 intracavernosal injection of platelet-rich plasma for erectile dysfunction nificantly influence our confidence in the effect estimate and will probably affect the estimate (23, 43). despite the demonstrated benefit of prp, careful caution should be taken before implementing this treatment in daily practice, because the available trials had limited sample sizes, short follow-up durations, and heterogenous treatment protocols. currently, the international guideline classify prp as a novel erectile dysfunction treatment that should only be implemented in clinical trials (29). however, it is possible that in the near future, further clinical trials will shed light 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culha mg, erkan e, cay t, et al. the effect of platelet-rich plasma on peyronie’s disease in rat model. urol int 2019; 102:218-23. 36. dönmez mi, inci k, zeybek nd, et al. the early histological effects of intravesical instillation of platelet-rich plasma in cystitis models. int neurourol j 2016; 20:188. 37. cappelleri jc, rosen rc, smith md, et al. diagnostic evaluation of the erectile function domain of the international index of erectile function. urology 1999; 54:346-51. 38. rosen rc, allen kr, ni x, araujo ab. minimal clinically important differences in the erectile function domain of the international index of erectile function scale. eur urol 2011; 60:1010-6. 39. cook ce. clinimetrics corner: the minimal clinically important change score (mcid): a necessary pretense. j man manip ther 2008; 16:e82. 40. cavallo c, roffi a, grigolo b, et al. platelet-rich plasma: the choice of activation method affects the release of bioactive molecules. biomed res int. 2016; 2016:6591717 41. anastasiadis e, ahmed r, khoja ak, yap t. erectile dysfunction: is platelet-rich plasma the new frontier for treatment in patients with erectile dysfunction? a review of the existing evidence. frontiers in reproductive health 2022:4:944765 42. kakudo n, morimoto n, kushida s, et al. platelet-rich plasma releasate promotes angiogenesis in vitro and in vivo. med mol morphol 2014; 47:83-9. 43. guyatt g, oxman ad, akl ea, et al. grade guidelines: 1. introduction-grade evidence profiles and summary of findings tables. j clin epidemiol 2011; 64:383-94. correspondence niwanda yogiswara niwandayogiswara@gmail.com dr. soetomo general-academic hospital, surabaya, east java, indonesia fikri rizaldi fikririz@gmail.com mohammad ayodhia soebadi (corresponding author) yodisoebadi@gmail.com universitas airlangga teaching hospital, surabaya, east java, indonesia conflict of interest: the authors declare no potential conflict of interest. this article was presented at the 45th annual scientific meeting of indonesian urological association. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12891 1 original paper in the context of assisted reproductive technology (art), sperm preparation aims to isolate spermatozoa with optimal morphology and motility for successful fertilization (9). however, the cellular structure and function of spermatozoa can be compromised during sperm preparation due to repeated centrifugation cycles, which induce ros formation and result in the loss of seminal plasma antioxidants (10). studies have shown that ros production in normal spermatozoa can increase 2-5 times after indirect swim-up preparation, with exposure to ros from 1-2 hours leading to a 2-4-fold increase in dna damage (11). to mitigate these effects, sperm selection methods such as the swim-up technique are employed to reduce the main sources of intracellular ros, namely leukocytes and immature sperm (12). according to the who laboratory manual, the swim-up method is a simple method that allows motile sperm to swim into an overlaid medium, separating them from non-motile spermatozoa. this method enhances sperm motility, average velocity, normal morphology and fertilization rates in vitro in mammals in compared to a lower fraction (13). however, simple washing or swim-ups from the pellet have been associated with a sudden burst of ros production, reduced motility, and impaired sperm-oocyte fusion in the zonafree hamster oocyte penetration test (14). despite these challenges, the swim-up method has been shown to maintain better sperm dna integrity compared to other procedures, such as density gradient centrifugation, demonstrating reduced dna fragmentation and vacuolization (15, 16). antioxidant administration, including vitamins c, e, catalase and glutathione, has been suggested to protect sperm dna integrity during preparation (17). specifically, serum vitamin d levels have been correlated with improvements in sperm number, motility, morphology, and dna fragmentation (18). vitamin d plays a crucial role in calcium regulation within the male reproductive system, and its activation in semen has been shown to enhance intracellular calcium levels, motility and acrosome reaction in spermatozoa (19). additionally, vitamin d functions as a membrane antioxidant (20) and influences gene expression related to cell proliferation, differobjective: this study aimed to identify the direct effect of vitamin d on sperm dna integrity after swim-up preparation. materials and methods: normozoospermia samples were gathered from 12 men and assessed for their baseline characteristics, including dna fragmentation index (dfi). each sample was then prepared using the swim-up method. half of the samples were incubated with vitamin d, while the other half were incubated with a standard sperm-washing medium. results: vitamin d significantly reduced the dfi compared to the baseline (5.5 ± 3.4% versus 17.6 ± 4.2%; p < 0.001) and the swim-up-only group (5.5 ± 3.4% versus 12.0 ± 4.2%; p < 0.001). microscopic examination reflected these results, showing a reduction in the number of small halos and no halos with an increased appearance of large to medium-sized halos. conclusions: these results suggest that vitamin d incubation is valuable in protecting sperm from dna damage that develops during sperm preparation. however, additional investigation is warranted to explore other preparation methods and to elucidate the underlying mechanisms. key words: assisted reproductive technology; dna damage; male infertility; swim up. submitted 2 august 2024; accepted 26 august 2024 introduction infertility is a significant global health issue, affecting approximately 1 in 7 couples, with contributions from both male and female factors equally distributed (1-3). among the various factors contributing to male infertility, damage to sperm dna is a critical concern, impacting 20-40% of subfertile men. this dna damage can arise from several sources, including imperfections in the apoptosis process during spermatogenesis (4), protamination during spermiogenesis (5), and oxidative stress from various endogenous and exogenous factors (6). excessive production of reactive oxygen species (ros) beyond the body’s antioxidant capacity can lead to significant damage to sperm function, causing lipid peroxidation, protein oxidation, mitochondrial dysfunction, and dna damage (7, 8). the effect of vitamin d in vitro supplementation on sperm deoxyribonucleic acid fragmentation andri rezano 1, 2, ditto rezkiawan 2, vellyana lie 2, arya srisadono 2, rafly mochamad rivaldo 3, amelia reta purba 3, melia juwita adha 4, tjahjo djojo tanojo 2, 5, maria p.b.d. pramesti 2, 6 1 department of biomedical sciences, faculty of medicine, universitas padjadjaran, sumedang, west java, indonesia; 2 andrology study program, faculty of medicine, universitas airlangga, surabaya, east java, indonesia; 3 medical study program, faculty of medicine, universitas padjadjaran, sumedang, west java, indonesia; 4 holistic general hospital, purwakarta, west java, indonesia; 5 andrology clinic, dr. soetomo academic hospital, surabaya, east java, indonesia; 6 department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, east java, indonesia. doi: 10.4081/aiua.2024.12891 summary archivio italiano di urologia e andrologia 2024; 96(4):12891 a. rezano, d. rezkiawan, v. lie, et al. 2 entiation, apoptosis and oxidative stress through its receptors in the nucleus and post-acrosome of spermatozoa (21-23). although numerous studies have explored the role of vitamin d in the reproductive system, research specifically examining its impact on reducing the dna fragmentation index (dfi) of human spermatozoa remains limited. the dfi is a crucial indicator of semen quality, reflecting the integrity and damage to sperm dna, thereby detecting potential sperm damage (24). blaseg et al. (2022) found no association between circulating vitamin d levels and human dfi. however, though the study was limited by using circulating vitamin d as a proxy for intratesticular levels (25). additionally, many studies have not considered art factors in their analyses (26, 27). therefore, this study aims to investigate the effect of vitamin d in vitro administration on sperm dfi in normozoospermic samples following sperm preparation using the swim-up method, addressing a critical gap in current reproductive research. materials and methods a total of 12 semen samples (n = 12) were included in this study, each with a volume of 3 ml. the inclusion criteria for selecting samples were men aged 26-35 years who agreed to participate and signed the informed consent, had abstained from ejaculation for 2-7 days, and were diagnosed with normozoospermia, characterized by a semen volume greater than 2 ml. baseline (bl) characteristics assessed for each sample included patient age, body mass index, semen volume, sperm concentration, progressive motility, non-progressive motility, and dfi. samples were collected using sterile, clean instruments maintained at the same temperature as the spermatozoa to prevent bacterial contamination, which can reduce sperm quality. all tools were sterilized, disinfected, wrapped in aluminium foil, and stored at 37°c until use. following the who protocols (2021). samples were collected via masturbation onto a sterile glass container and allowed to liquefy for 20-30 minutes. semen volume, motility, and total sperm count were measured to ensure normal values before inclusion in the study. after the initial assessment, sperm samples were prepared using the swim-up method. the prepared samples were then divided into two groups: one undergoing swim-up preparation with vitamin d incubation (sd) and the other undergoing swim-up preparation only (su). unprepared samples (bl) were also included in the evaluation. spermatozoa from all groups (bl, sd, and su) were evaluated for dna fragmentation index. sperm preparation sperm preparation using the swim-up method was performed by mixing semen and sperm rinse™ medium (vitrolife, usa) in a 1:1 ratio in a 5 ml tube. the mixture was then centrifuged at a speed of 400 g for 10 minutes. after centrifugation, the supernatant was discarded, and the pellet was resuspended with 2 ml of sperm rinse™ medium. the resuspended pellet was centrifuged again at a speed of 400 g for 5 minutes. the supernatant was discarded, and 2 ml of spermrinse™ medium was gently added to the pellet along the tube wall. the tube was then placed at 45° angle and incubated at 37°c for 45 minutes. finally, 1 ml of the upper medium fraction was carefully transferred to two new tubes, with 500 µl in each tube, for further analysis (13). vitamin d incubation a solution of active vitamin d, 1.25(oh)2d3 (calcitriol, molecular weight 416.64), was prepared in 100% ethanol with a stock concentration of 10 μg/ml (24 μm) and stored in a -20°c. to analyse the effect of in vitro vitamin d administration on dna fragmentation, 500 ul postpreparation spermatozoa were incubated with 1 nm 1.25(oh)2d3 at 37°c, for 45 minutes (19). the working solution concentration was prepared in stages starting from 1 mm, 10 μm, 10 nm, and finally 1 nm. the control group without vitamin d was incubated with spermrinse™ medium under the same conditions. dna fragmentation index dna fragmentation was assessed using the dna fragmentation kit (spermfunc®, bred-002, bred life science technology inc.), following the manufacturer’s protocol. observations were made using a light microscope at 400x magnification to distinguish between unfragmented dna (big and medium halos) and fragmented dna (small halos, no halos, and damaged spermatozoa) in 500 spermatozoa cells. normal sperm dna presented figure 1. determination of dna fragmentation based on halo size (28). 1) the diameter of the core as the determinant of dna fragmentation. 2) large halo and 3) medium halo show spermatozoa without dna fragmentation. 4) small halo and 5) no halo indicating spermatozoa dna fragmentation. archivio italiano di urologia e andrologia 2024; 96(4):12891 3 vitamin d and sperm deoxyribonucleic acid fragmentation as medium (halo thickness smaller than the length but greater than one-third of the core minor diameter) to big halos (halo thickness equal to or greater than the length of the core minor diameter). in contrast, damaged/fragmented sperm dna presented as no halos or small halos (halo thickness equal to or less than one-third of the core minor diameter) (figure 1). the percentage of spermatozoa with dna fragmentation was calculated as the dna fragmentation index (dfi). statistics data were recorded and analysed to compare the effect of vitamin d incubation on sperm dna integrity between the vitamin d-treated group (sd), the control group (su), and the unprepared samples (bl). this comparison aimed to determine whether vitamin d supplementation during sperm preparation could enhance dna integrity in spermatozoa, thus potentially improving outcomes in art. statistical analyses were performed using the statistical package for the social sciences (spss) version 26.0 for windows. the shapiro-wilk test was used to determine whether the data were normally distributed (p > 0.05) or not normally distributed (p < 0.05). differences in dfi values between groups were tested using paired t-test, and results were expressed as mean ± standard deviation. a pvalue of less than 0.05 was considered statistically significant. ethical approval the study was approved by the health and humanities research ethics committee, faculty of medicine, universitas airlangga (code: 242/ec/kepk/fkua/2023). samples were collected between august-october 2023. results patient characteristics a total of 12 volunteers participated during the study period. all dfi data between groups were found to be normally distributed (p > 0.05). the mean age of volunteers was 30.9 years (30.9 ± 2.6), reflecting the reproductive age of men. the body mass index (bmi) was 27.4 kg/m2 (27.4 ± 4.1), classified as level 1 obesity; the mean baseline dfi value was 17.6 ± 4.2%, which falls within the normal range. baseline characteristics are summarized in table 1. dfi between groups a paired t-test was conducted to compare the dfi within each sample group (table 2). the su group exhibited a significantly reduced dfi (12.0 ± 4.2%) compared to the bl characteristics (17.6 ± 4.2%). furthermore, the dfi was significantly decreased in the sd group (5.5 ± 3.4%) compared to both the su group (12.0 ± 4.2%) and the initial bl (17.6 ± 4.2%), with mean reductions of 6.5% and 12.1% respectively. these findings suggest that vitamin d incubation during sperm preparation resulted in a significant improvement in sperm dna integrity compared to the control groups. evaluation of spermatozoa dna fragmentation examination in each group, variations in the appearance of a large halos, medium halos, small halos and no halos were observed in semen samples before and after preparation. specifically, the presence of small halos and no halos was noticeably reduced in the post-preparation samples of the sd group (figure 2). figure 2. evaluation of spermatozoa’s dna fragmentation in the bl, su and sd groups. image caption: a. large halos; b. medium halos; c. small halos; d. no halos. table 1. age and semen profile of the study subjects. subject characteristics mean ± sem (n = 12) patient age (in years) 30.9 ± 2.6 body mass index (kg/m2) 27.4 ± 4.1 semen volume (ml) 3.4 ± 1.0 sperm concentration (million/ml) 48.7 ± 25.1 progressive motility (%) 52.4 ± 13.4 non-progressive motility (%) 6.8 ± 3.7 dna fragmentation index (%) 17.6 ± 4.2 table 2. paired t-test results from each treatment group on dfi. variable group 1 group 2 p-value (mean ± sd) (mean ± sd) dfi bl (17.6 ± 4.2) su (12.0 ± 4.2) < 0.001 su (12.0 ± 4.2) sd (5.5 ± 3.4) < 0.001 bl (17.6 ± 4.2) sd (5.5 ± 3.4) < 0.001 archivio italiano di urologia e andrologia 2024; 96(4):12891 a. rezano, d. rezkiawan, v. lie, et al. 4 discussion the decline in sperm quality and function due to increasing reproductive disorders globally is a significant concern in reproductive health. a recent study highlighting the impact of vitamin d deficiency on mouse fertility and subsequent improvements in semen parameters has shed new light on the role of vitamin d in male reproductive function (29). numerous studies have emphasized the role of vitamin d in male reproductive health, particularly in enhancing sperm quality and motility (30). infertility affects approximately 15-20% of couples of reproductive age, with male factors contributing to around 50% of cases (31, 32). in our study, the average age of the sample population was 30.9 ± 2.6 years, consistent with previous research (33). additionally, the average bmi of the participants fell within the category of level 1 obesity. obesity is known to increase the risk of sperm dna damage in infertile men due to its association with increased oxidative stress (34, 35). sperm dna integrity is critical to successful fertilization and embryogenesis (36). however, previous studies have been limited in evaluating the functional status of spermatozoa (37), indicating the need for further research. in our study, despite having normal semen parameters, semen samples exhibited a dfi of 17.6 ± 4.2%. this finding aligns with previous research conducted by halim et al., where the dfi before semen processing was 16.12% (13.4819.04) (38). oxidative stress levels that are insufficient to induce cell death can still disrupt sperm function, highlighting the importance of addressing dna fragmentation in infertility (39). the extent of dna fragmentation’s impact on fertilization depends on both the level of dna damage and the dna repair capacity of the oocyte (40). our study revealed that supplementation of vitamin d, calcitriol [1.25(oh)2d3] at a concentration of 1 nm after sperm preparation, led to a significant reduction in sperm dna fragmentation by 6.5%. notably, there was a synergistic effect between sperm preparation and vitamin d administration in decreasing dna fragmentation compared to baseline levels. these findings differ from a study by moghadam et al. (2019), which reported no repair of dna damage with vitamin d administration after swim-up (41). this discrepancy may be attributed to differences in the dna damage examination methods used, with the sperm chromatin dispersion method proving more effective than the tunel method in diagnosing sperm dna damage in unexplained infertility (40). the protective mechanism of vitamin d on sperm dna integrity can be explained in several ways. firstly, the hydrophobic part of vitamin d binds to fatty acid residues on the spermatozoa membrane, thereby protecting membrane integrity (20). additionally, vitamin d has been shown to enhance the integrity of spermatozoa membranes during cryopreservation by reducing intracellular ros levels (41). vdr expression in testes and spermatozoa, along with cellular uptake of circulating vitamin d, play crucial roles in regulating spermatozoa motility and acrosome function (19). moreover, administration of 20,000 nm of vitamin d has been associated with increased expression of heat shock protein 70 (hsp70), a marker of oxidative stress and lipid peroxidation, indicating a dose-response relationship of vitamin d as an antioxidant (42). while our study supports the role of antioxidants in maintaining sperm chromatin integrity during sperm preparation, definitive conclusions cannot be drawn due to certain limitations. this study did not directly examine intraspermatozoal ros levels and endogenous antioxidants. future research should address these factors and analyse abnormal semen samples to further elucidate the role of vitamin d in infertility. additionally, investigations into other variables, such as ros levels, antioxidants, lipid peroxidation, and acrosome reactions, as well as their impacts on fertilization outcomes, pregnancy, and embryo development, are warranted. comparative studies between swim-up and other sperm selection procedures, such as density gradient centrifugation, are also needed to evaluate their efficacy and drawbacks in reducing dna damage with vitamin d administration. conclusions this study demonstrated that dfi significantly decreased following sperm preparation using the swim-up method. additionally, the dfi further decreased significantly in the group treated with vitamin d compared to both the pre-preparation and post-preparation without vitamin d administration groups. these findings highlight the protective role of vitamin d against dna damage incurred during sperm preparation. however, further studies are necessary to elucidate the underlying mechanism of this protective effect and to compare the efficacy of vitamin d supplementation with other sperm preparation methods. future research should also consider examining different variables such as ros levels, antioxidants, lipid peroxidation, acrosome reactions, and their impacts on fertilization outcomes, pregnancy, and embryo development. acknowledgments the authors express sincere gratitude to the staff at the department of biomedical sciences faculty of medicine universitas airlangga and andrology clinic, dr. soetomo academic hospital, for their invaluable assistance and support throughout this study. references 1. agarwal a, baskaran s, parekh n, et al. male infertility. lancet 2021; 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53:e13625. 37. ayad bm, oyeyipo ip, van der horst g, du plessis ss. cementing the relationship between conventional and advanced semen parameters. middle east fertil soc j 2021; 26:1-10. 38. aitken rj. impact of oxidative stress on male and female germ cells: implications for fertility. reproduction 2020; 159:r189-201 39. halim b, angellee j, lubis hp, bachsinar b. sperm quality and deoxyribonucleic acid fragmentation after 5 and 10 min centrifugation with swim-up processing technique: a prospective cohort study. open access maced j med sci 2021; 9:626-30. 40. agarwal a, farkouh a, saleh r, et al. technical aspects and clinical limitations of sperm dna fragmentation testing in male infertility: a global survey, current guidelines, and expert recommendations. world j mens health 2024; 42:202-15. archivio italiano di urologia e andrologia 2024; 96(4):12891 a. rezano, d. rezkiawan, v. lie, et al. 6 41. moghadam mt, fard ya, saki g, nikbakht r. effect of vitamin d on apoptotic marker, reactive oxygen species and human sperm parameters during the process of cryopreservation. iran j basic med sci 2019; 22:1036. 42. moghadam mt, hamidian o, mansouri e, nikbakht r. effects of vitamin d3 on the level of heat shock protein 70 and oxidative stress in human sperm: a pilot study. middle east fertil soc j 2020; 25:1-8. correspondence andri rezano, md-andrologist, phd, associate professor andri.rezano@unpad.ac.id department of biomedical sciences, faculty of medicine universitas padjadjaran jl. ir. soekarno km. 21 jatinangor, sumedang 45363, west java, indonesia ditto rezkiawan ditto.rezkiawan-2021@fk.unair.ac.id vellyana lie vellyana.lie-2022@fk.unair.ac.id arya srisadono arya.srisadono-2022@fk.unair.ac.id tjahjo djojo tanojo tjahjodjojo@gmail.com maria pbd pramesti pramestidyan@gmail.com andrology study program, faculty of medicine, universitas airlangga, surabaya 60132, east java, indonesia mochamad rivaldo rafly22001@mail.unpad.ac.id medical study program, faculty of medicine, universitas padjadjaran, sumedang, 45363, west java, indonesia amelia reta purba amelia23007@mail.unpad.ac.id medical study program, faculty of medicine, universitas padjadjaran, sumedang 45363, west java, indonesia melia juwita adha meliarezano@gmail.com holistic general hospital, purwakarta 41115, west java, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 3274 original paper no conflict of interest declared. represents psma expression, is highly correlated with the aggressiveness of the primary prostatic tumour (7, 8). 68ga-psma positron emission tomography/computed tomography (pet/ct) demonstrated to be sensitive for the detection of primary prostatic lesions, regional lymphadenopathy (9) and clinical metastases in case of biochemical recurrence (10, 11). our study prospectively compared the diagnostic accuracy of 68ga-psma pet/ct vs. mpmri targeted biopsy (tpbx) in the diagnosis of cspca (grade group ≥ 2) (12). materials and methods from january 2021 to june 2022, 100 patients (median age: 66 years; range: 49-79 years) with negative digital rectal examination underwent repeated transperineal prostate biopsy for abnormal psa values (median 7.5 ng/ml; range: 4.5-83 ng/ml) (13, 14). the study was approved by the ethics committee of our hospital. all patients underwent prostate biopsy mpmri and 68gapet/ct imaging examinations; a 1.5 tesla scanner equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position, multi-planar turbo spin-echo t2-weighted imaging, axial diffusion-weighted imaging, and axial dynamic contrast (adc) enhanced mri were performed for each patient (15). two radiologists, blinded to preimaging clinical parameters, evaluated the mri data separately and independently. pet/ct imaging was performed using a ct-integrated pet scanner (biograph 6; siemens, knoxville, tn, usa). 68ga-psma was prepared with a fully automated radiopharmaceutical synthesis device based on a modular concept (eckert & ziegler eurotope, berlin, germany). 68ga-psma-11 was given to patients via an intravenous bolus (mean, 144 ± 12 mbq; range, 122-188 mbq), and the pet acquisition was started at a mean of 58 ± 12 min (range, 50-81 min) afterward. scans were acquired in 3-dimensional mode with an acquisition time of 3 min per bed position. emission data were corrected for randoms, dead time, scatter, and attenuation and were reconstructed iteratively using ordered-subsets expectation maximization (4 iterations, 8 subsets) followed by a post reconstruction smoothing gaussian filter (5 mm in full width at half maximum). for attenuation correction, a low dose unenhanced ct scan introduction: to evaluate the diagnostic accuracy of 68ga-prostate-specific membrane antigen (psma) positron emission tomography/computed tomography (pet/ct) vs. multiparametric magnetic resonance imaging (mpmri) targeted biopsy (tpbx) in the diagnosis of clinically significant prostate cancer (cspca: grade group ≥ 2). materials and methods: from january 2021 to june 2022, 100 patients (median age: 66 years) with negative digital rectal examination underwent transperineal prostate biopsy for abnormal psa values (median 7.5 ng/ml). before prostate biopsy, all patients underwent mpmri and 68ga-pet/ct examinations and mpmri (pi-rads version 2 ≥ 3) or 68ga-pet/ct index lesions suspicious for cancer (suvmax > 5 g/ml) underwent cognitive targeted cores (mpmri-tpbx and psma-tpbx: four cores) combined with extended systematic prostate biopsy (espbx: median 18 cores). the procedure was performed transperineally using a tru-cut 18-gauge needle under sedation and antibiotic prophylaxis. results: pca was found in 58/100 (58.0%) men; in detail, 44/58 (75.9%) were cspca; mpmri and 68ga-psma showed 66/100 (66%) and 62/100 (60%) lesions suspicious for pca, respectively. 68ga-psma-tpbx vs. mpmri-tpbx vs. espbx diagnosed 42 (95.4%) vs. 36 (81.8%) vs. 30 (68.2%) cspca, respectively; mpmri-tpbx vs. 68ga-psma-tpbx showed a diagnostic accuracy of 76.9% vs. 84.9% in diagnosing cspca. conclusions: 68gapsma pet/ct tpbx demonstrated good accuracy in the diagnosis of cspca, which was not inferior to mpmri tpbx (84.9% vs. 76.9%) improving the detection rate for cancer of systematic biopsy. key words: prostate cancer; 68ga-psma pet/ct; mpmri; targeted prostate biopsy. submitted 21 july 2022; accepted 6 august 2022 introduction although multiparametric magnetic resonance imaging (mpmri) has improved diagnostic accuracy of systematic prostate biopsy in the diagnosis of clinically significant prostate cancer (cspca), about 20-35% of pca could be missed by mpmri targeted biopsy (1). prostate-specific membrane antigen (psma) is expressed in most primitive and metastatic pca (2, 3), and psma inhibitors conjugated with the radionuclides gallium 68 (68ga) and fluoride 18 (18f) have been evaluated in clinical practice for the diagnosis of pca (4-6); morever, tumour uptake, which targeted prostate biopsy: 68ga-psma pet/ct vs. mpmri in the diagnosis of prostate cancer pietro pepe 1, ludovica pepe 1, maria tamburo 2, giulia marletta 2, michele pennisi 1, filippo fraggetta 3 1 urology unit, cannizzaro hospital, catania, italy; 2 radiotherapy unit, cannizzaro hospital, catania, italy; 3 pathology unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2022.3.274 summary 275archivio italiano di urologia e andrologia 2022; 94, 3 68ga-psma pet/ct and pca diagnosis was performed from the skull base to the middle of the thigh. images were processed to obtain pet, ct, and petct fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm by two experienced nuclear medicine specialists, who were blinded to the clinical data. the location of focal uptake on 68ga-psma pet/tc (figure 1), three-dimensional size, and standardised uptake value (suvmax) values were reported on a per-lesion basis with a sexstant scheme (apex, midgland, and base, each split into left and right) (5). all mpmri (prostate imaging reporting and data system “pi-rads” version 2 ≥ 3) and 68gapsma-pet/ct (suvmax > 5 g/ml) index lesions underwent targeted cores (mpmri-tpbx and psma-tpbx: four cores) combined with extended systematic prostate biopsy (espbx: median 18 cores) (2, 14). the procedure was performed transperineally using a tru-cut 18-gauge needle (bard, covington, ga, usa) under sedation and antibiotic prophylaxis (17). prostate-targeted cores were obtained using a hitachi 70 arietta echograph (chiba, japan) supplied by a bi-planar trans-rectal probe (14) by one urologist with 10 years of experience in cognitive targeted biopsy. data were collected following start criteria (18). results pca was found in 58/100 (58%) men; in detail, 44/100 (44%) were cspca: 30/44 (75%) and 14 (25%) were located in the peripheral and anterior zones of the gland, respectively. clinical parameters of men with pca are reported in table 1; in detail, mpmri and 68ga-psma showed 66/100 (66%) and 62/100 (60%) lesions suspicious for pca, respectively. these were submitted to targeted cores combined with espbx. the diagnostic accuracy of mpmri tpbx vs. 68ga-psma tpbx is shown in table 2. none of the patients had clinical complications following prostate biopsy (dindo-clavien grade1) (19). the average intraprostatic suvmax was 8.5 g/ml (range = 4-49 g/ml) and the average maximal intraprostatic tumor dimension was 12 mm (range = 8-23 mm). 68ga-psmatpbx vs. mpmri-tpbx vs. espbx missed 2 (4.5%) vs. 8 (18.2%) vs. 14 (31.8%) cspca, respectively. discussion to reduce the risk of overdiagnosis following screening protocols for pca, mpmri has been recommended to decrease the risk of overtreatment; on the other hand, systematic prostate biopsy should always be combined with mpmri/trus fusion biopsy because of the false negative rate of mpmri (pca with low volume and grade group > 2) (20, 21). recently, 68ga-psma-pet/ct has been suggested to improve the clinical staging of highrisk pca and disease recurrence (5, 10, 22); similarly, psma pet/ct has been proposed for the diagnosis of primary intraprostatic cancer. the presence of focal uptake on psma-pet/ct, suvmax, and the maximal dimensions of pet-avid lesions have been correlated with the presence of cspca (23-25). there is a range of proposed cutoffs to detect cspca from suvmax 3.15 to suvmax 9.1 (26, 27); in addition, psma-pet/ct demonstrated high correlation between the isup grade group and suvmax table 1. clinical parameters of 44 men with clinically significant prostate cancer (cspca). clinical and biopsy findings gg2 15 pz gg3 11 pz gg4 10 gg5 8 initial biopsy 9 6 6 6 repeated biopsy 6 5 4 2 median psa (range: 4.5-83 ng/ml) 6.3 9.5 16 26 median gpc 30% 45% 70% 90% number of positive cores overall 6 9 11 13 mpmri pi-rads score ≥ 3 9 8 8 7 68ga-psma pet/tc suspicious for pca 7 11 10 8 gg: international society of urological pathology grade group; mpmri: multiparametric magnetic resonance imaging; psa: prostate specific antigen; gpc: greatest percentage of cancer; psma: prostate specific membrane antigen; pi-rads: prostate imaging reporting and data system; pet/tc: positron emission tomography/computed tomography. figure 1. 68ga-prostate-specific membrane antigen (psma) pet/ct: presence of high suspicious area fo prostate cancer (suvmax 20) in both lobe of the prostate (axial evaluation). table 2. diagnostic accuracy of mpmri-tpbx vs. 68ga-psma-tpbx in the diagnosis of clinically significant prostate cancer (cspca). number of cspca mpmri tpbx 68ga-psma pet/ct tpbx (44 cases) 36 cases 42 cases sensitivity 81.8% 95.4% specificity 71.8% 80.0% positive predictive value 54.5% 73.4% negative predictive value 87.5% 96.5% diagnostic accuracy 76.9% 84.7% psma: prostate specific membrane antigen; mpmri: multiparametric magnetic resonance imaging; pet/tc: positron emission tomography/computed tomography; tpbx: targeted prostate biopsy. archivio italiano di urologia e andrologia 2022; 94, 3 p. pepe, l. pepe, m. tamburo, g. marletta, m. pennisi, f. fraggetta 276 and maximal dimension of the lesion. zhang et al. (28) reported a higher detection rate for cspca performing a single transgluteal psma pet/ct targeted core (suvmax > 8) in comparison with systematic prostate biopsy (40 vs. 25% of the cases). liu et al. (29), found 85.5% of cspca (47/55 cases) performing pet/ct psma targeted cores; kalapara et al. (30) compared the accuracy of 68ga-psma pet/ct with mpmri in 205 men who underwent radical prostatectomy and showed an accuracy of 96% vs. 91% for the detection of cspca. xue et al. showed that a suvmax cut-off of 5.4 predicted pathological upgrading at definitive histology, showing 91% specificity and 94% negative predictive value (31). ferraro et al. (32) in 49 men who underwent 68gapsma pet/mri plus template biopsy demonstrated a diagnostic accuracy of pet/mri targeted cores of 90% with only one false negative result. in definitive, the use of more parameters (i.e. genetic evaluation, diagnostic imaging, psa density) (5, 33) included in risk calculator could better select men at risk for cspca who should underwent prostate biopsy allowing to omit unnecessary procedures also in case of active surveillance (34) reducing complications rate (35). in our series, among the 44/100 (44.0%) men with cspca, mpmri-tpbx vs. 68ga-psma-tpbx showed a diagnostic accuracy of 76.9% vs. 84.9%; 68ga-psma-tpbx vs. mpmri-tpbx vs. espbx missed 2 (4.5%) vs. 8 (18.1%) vs. 14 (31.8%) cspca, respectively. although prospective and randomized studies are awaited, including a greater number of patients, 68ga-psma pet/ct evaluation could be proposed in men with negative mpmri or in the presence of claustrophobia, cardiac pacemaker and severe obesity. our study has some limitations. first, the number of patients evaluated was low. second, the results should be evaluated in the entire prostate specimen and not in biopsy histology. finally, a 68ga-psma pet/tc fusion platform would increase the accuracy of targeted prostate biopsy. conclusions 68gapsma pet/ct tpbx demonstrated good accuracy in the diagnosis of cspca, which was not inferior to mpmri tpbx (76.9% vs. 84.9%) improving the detection rate for cancer of systematic biopsy. authors’ contributions the authors contributed equally to all aspects of this study. references 1. panebianco v, barchetti g, simone g, et al. negative multiparametric magnetic resonance imaging for prostate cancer: what’s next? eur urol. 2018; 74: 48-54. 2. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer research. 2022; 42:3011-3015. 3. sheikhbahaei s, afshar-oromieh a, eiber m, et al. pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (psma)-targeted pet imaging. eur j nucl med mol imaging 2017; 44:2117-2136. 4. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsy in men enrolled in active surveillance protocols? j clin med. 2022; 11:3473. 5. perera m, papa n, roberts m, et al. gallium-68 prostate-specific membrane antigen positron emission tomography in advanced prostate cancer-updated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. eur urol. 2020; 77:403-417. 6. privé bm, israël b, schilham mgm, et al. evaluating f-18psma-1007-pet in primary prostate cancer and comparing it to multi-parametric mri and histopathology. prostate cancer prostatic dis. 2021; 24:423-430. 7. uprimny c, kroiss as, decristoforo c, et al. 68ga-psma-11 pet/ ct in primary staging of prostate cancer: psa and gleason score predict the intensity of tracer accumulation in the primary tumour. eur j nucl mol imaging. 2017; 44:941-49. 8. emmett l, buteau j, papa n, et al. the additive diagnostic value of prostate-specific membrane antigen positron emission tomography computed tomography to multiparametric magnetic resonance imaging triage in the diagnosis of prostate cancer (primary): a prospective multicentre study. eur urol. 2021; 80:682-689. 9. eiber m, weirich g, holzapfel k, et al. simultaneous 68gapsma hbed-cc pet/mri improves the localization of primary prostate cancer. eur urol 2016; 70: 829-836. 10. pepe p, pennisi m: should 68ga-psma pet/ct replace ct and bone scan in clinical staging of high-risk prostate cancer? anticancer research. 2022; 42:1495-1498. 11. carvalho j, nunes p, da silva et, et al. 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pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the ra of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology. 2020; 137:133-137. 17. pepe p, pennisi m. prostate cancer diagnosis and management accross twenty years of clinical practice: a songle-center experience on 2,500 cases. anticancer res. 2019; 39:1397-1401. 18. moore cm, kasivisvanathan v, eggener s, et al., and start consortium standards of reporting for mri-targeted biopsy studies (start) of the prostate: recommendations from an international working group. eur urol. 2013; 64:544-552. 19. dindo d, demartines n, clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of survey. ann surg. 2004; 2:205-213. 277archivio italiano di urologia e andrologia 2022; 94, 3 68ga-psma pet/ct and pca diagnosis 20. pepe p, garufi a, priolo g, pennisi m. can mri/trus fusion 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study. eur j nucl med mol imaging. 2021; 48:483-492. 29. liu y, yu h, liu j, et al. a pilot study of 18 f-dcfpyl pet/ct or pet/mri and ultrasound fusion targeted prostate biopsy for intraprostatic pet-positive lesions. front oncol. 2021; 11:612157. 30. kalapara aa, nzenza t, pan hyc, et al. detection and localisation of primary prostate cancer using 68gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology. bju int. 2020; 126:83-90. 31. xue al, kalapara aa, ballok ze, et al. 68ga-prostate-specific membrane antigen positron emission tomography maximum standardized uptake value as a predictor of gleason pattern 4 and pathological upgrading in intermediate-risk prostate cancer. 2022; 207:341-349. 32. ferraro da, becker as, kranzbühler b, et al. diagnostic performance of 68ga-psma-11 pet/mri-guided biopsy in patients with suspected prostate cancer: a prospective single-center study. eur j nucl med mol imaging. 2021; 48:3315-3324. 33. pepe p, dibenedetto g, pepe l, pennisi m. multiparametric mri vs select mdx accuracy in the diagnosis of clinically significant pca in men enrolled in active surveillance. in vivo. 2020; 34:393-396. 34. roscigno m, stabile a, lughezzani g, et al. the use of multiparametric resonance imaging for follow-up of patients included in active surveillance protocol, can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. 35. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8,500 men. arch ital urol androl. 2022; 94:155-159. correspondence pietro pepe, md piepepe@hotmail.com michele pennisi, md michepennisi2@virgilio.it ludovica pepe, md ludopepe97@gmail.com urology unit, cannizzaro hospital via messina 829, catania (italy) maria tamburo, md marinellatamburo@virgilio.it giulia marletta, md marlettagiulia1@gmail.com radiotherapy unit, cannizzaro hospital, catania (italy) filippo fraggetta, md filippofra@hotmail.com pathology unit, cannizzaro hospital, catania (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12353 1 original paper dling and management are needed to improve the state and quality of life of the patients. ed management includes control of risk factors (tobacco consumption, obesity, sedentary lifestyle, chronic alcohol consumption, comorbidities, and depression) and appropriate pharmacological therapy. the first-line treatment for ed is oral therapy with cyclic guanosine monophosphate (cgmp) inhibitors and phosphodiesterase 5 inhibitors (pde5 inhibitors) (4). prior to the development of pde5 inhibitors, intracavernosal injection was the first-line treatment for patients with ed. however, at present, intracavernosal injection can be used as an important second-line treatment option and as the core of the de diagnostic examination (5). intraurethral prostaglandin e1 (pge1) [alprostadil, medicated urethral system for erection (muse); vivus, menlo park, calif] was introduced in 1997. muse, uses pge1 which directly affects the trabecular smooth muscle binding to specific receptors and thereby increasing the synthesis of cyclic adenosine monophosphate (camp) (6). vacuum erectile device (ved), a means of therapy for ed patients, uses negative pressure to dilate the sinusoids of corpora cavernosa and increase blood flow to penile. ved can be used together with an external constriction ring placed at the bulb of the penile to prevent outward blood flow in order to maintain erection for sexual intercourse (7). the implantation of penile prostheses remains a relevant therapeutic option and is in demand, especially among uncured ed patients who have undergone conservative treatments. a study suggested that penile prosthesis implantation may be considered in ed patients who do not exhibit positive respond to pharmacotherapy or who wish for a permanent solution to their problem (8, 9). the first penile prosthesis implantation surgery was performed by a russian surgeon named nikolaj a. bogaraz in 1936. currently, penile prostheses become the gold standard in patients experiencing recurrent ed after being given medicamentosa therapy and in patients with penile trauma (10). there are three types of penile prostheses available: semirigid or malleable, two-piece inflatable, and threepiece inflatable penile prosthesis (ipp). at present, the inflatable three-piece penile prosthesis is the most widely used and recommended due to high patient and partintroduction: erectile dysfunction can cause self-withdrawal and decreased quality of life. patients who do not respond to pharmacological therapy and other conservative treatments are urged to undergo penile prosthesis implantation. malleable penile prosthesis was the first prosthesis developed, but then inflatable penile prosthesis was developed to give a more natural erection. there is no metaanalysis comparing inflatable and malleable penile prostheses in terms of safety and efficacy. this study is conducted to evaluate patient and partner satisfaction, ease of use, mechanical failure, and infection rate in patients who underwent penile prosthesis implantation. method: this meta-analysis followed preferred reporting items for systematic review and meta-analysis (prisma) protocols. five eligible studies were included from pubmed, scopus, sciencedirect, and semanticscholar databases. result: in this study, patient and partner satisfaction are significantly better (or 3.39, 95% ci 1.66-6.93, p = 0.0008) (or 2.32, 95% ci 1.75-3.08, p < 0.00001). mechanical failure is also significantly higher in inflatable penile prostheses (or 5.60, 95% ci 2.02-15.53, p = 0.0009). there is no significant difference in terms of ease of use and infection rate in inflatable or malleable penile prostheses. conclusions: this study concluded that inflatable penile prosthesis is better in terms of patient and partner satisfaction, but mechanical failures occur more frequently in this type of prosthesis. key words: erectile dysfunction; penile prosthesis; malleable penile prosthesis; inflatable penile prosthesis. submitted 5 february 2024; accepted 10 february 2024 introduction inadequate penile erection, otherwise known as erectile dysfunction (ed), is defined as the inability to achieve or maintain sufficient penile erection for vaginal penetration until orgasm (1). the prevalence of ed in men aged 20 to 80 years in jakarta reached 35.6% (2). erectile dysfunction is not a life-threatening condition, but it can result in withdrawal from sexual intimacy, decreased quality of life, and decreased work productivity (3). erectile dysfunction causes many negative effects. thus, proper hanefficacy and safety of malleable penile prosthesis compared to inflatable penile prosthesis in erectile dysfunction patients handaru satwikananda 1, 2, tetuka bagus laksita 1, 3, wahjoe djatisoesanto 1, 3, doddy moesbadianto soebadi 1, 3 1 department of urology, faculty of medicine, universitas airlangga, indonesia; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia; 3 universitas airlangga teaching hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2024.12353 summary archivio italiano di urologia e andrologia 2024; 96(2):12353 h. satwikananda, t. bagus laksita, w. djatisoesanto, d. moesbadianto soebadi 2 ner satisfaction, natural cosmetic appearance, and its ability to enable patients to get or lose an erection at will. the implantation of an ipp has several side effects, namely perforation of corpus cavernosum, urethral damage, mechanical failure, infection, as well as bladder, intestinal, and vascular trauma (11). the implantation of a malleable penile prosthesis (mpp) is easier to do. in addition, mpp rarely experiences mechanical failures and is affordable. complications may occur during or after surgery. the most common complications during surgery are urethral and corpus cavernosum trauma, while those occurring post-surgery are hematoma, infection, penile deformity, pain, and penile erosion (8). despite their advantages, inflatable penile prostheses have some limitations, such as expensive price, being hard to use, difficult implantation techniques, and high risk of infection. inflatable penile prostheses have a risk of being damaged after being used for more than 10 years and require replacement. malleable penile prostheses are cheaper and easier to use even though they do not provide cosmetic and erection naturalness as well as inflatable penile prostheses. malleable prostheses are less prone to damage and infection compared to inflatable penile prostheses. there is a systematic review by karl h. pang in 2021 concerning complications and satisfaction after penile prosthesis implantation in patients with spinal cord injury. several weaknesses are present in this study, as it only includes old studies written in english. furthermore, quantitative analysis cannot be conducted in this study due to the heterogeneous nature of the output and lack of control population (12). there is currently no meta-analysis study comparing the efficacy and safety of the use of inflatable and malleable penile prostheses in patients with ed. therefore, the authors carry out a systematic review and meta-analysis study to compare the efficacy and safety of the use of inflatable penile prostheses compared to malleable prostheses in patients with ed. materials and methods search strategy and study selection the study used the quantitative method according to the preferred reporting items for systematic reviews and metaanalysis (prisma) protocol. the search process was carried out to ensure that the meta-analysis was in line with the topic or pico (participant, intervention, comparison, outcome). the inclusion criteria of this study were observational design studies (cohort, case control, and cross sectional), studies that compared malleable and inflatable penile prostheses in patients with ed caused by diabetes mellitus, vascular disease, history of radical prostatectomy surgery, history of surgery in the pelvic area, as well as peyronie’s, neurogenic, and priapism diseases. the exclusion criteria of this study were duplicate articles, articles not written in english, articles that were not available in fulltext, patients with ed caused by other than diabetes mellitus, vascular disease, history of radical prostatectomy surtable 1. results of article search using several international databases. database keywords n pubmed/medline ("erectile dysfunction" or "sexual dysfunction" or "impotence" or "impotency") and ("inflatable") 49 and ("malleable" or "malleable" or "semi-rigid" or "semi rigid" or "non-inflatable" or "non inflatable") and ("penile prosthesis" or "penile-prosthesis" or "penile prosthesis") and [("satisfaction") or ("complication”)] scopus [title-abs-key (erectile and dysfunction) and title-abs-key (inflatable and penile and prosthesis) 113 and title-abs-key (malleable and penile and prosthesis)] sciencedirect ("inflatable penile prosthesis") and ("malleable penile prosthesis") and ("erectile dysfunction" or "ed") 82 and ("satisfaction" or "complication”) semantic scholar ed erectile dysfunction penile prosthesis inflatable penile prosthesis malleable erectile dysfunction satisfaction complication 464 figure 1. prisma diagram of the study search and selection process. archivio italiano di urologia e andrologia 2024; 96(2):12353 3 efficacy and safety of malleable penile prosthesis compared to inflatable penile prosthesis... gery, history of surgery in the pelvic area, as well as peyronie’s, neurogenic, and priapism diseases. the study selection was carried out by conducting eligible study search on pubmed, scopus, sciencedirect, and semantic scholar databases. the search was carried out up to february 2023. the keywords we used include “erectile dysfunction”, “penile prostheses”, “malleable”, “inflatable”, “efficacy”, “satisfaction”, and “compliance”. the keywords used in the study search are displayed in table 1. study search and selection were conducted based on prisma guidelines (figure 1). quality assessment and data extraction data extraction was carried out by two authors independently in accordance with the specified examples. in case of differences in data extraction results, they were discussed and settled by a third author. the data extracted comprised the characteristics and methodologies of the study, namely the name of the first author, year of publication, number of patients, age of patients, and design of the study. in addition, there were research interventions that were divided into the types of intervention given, namely the implantation of inflatable penile prostheses and malleable penile prostheses. the outcome extracted were patient satisfaction, partner satisfaction, ease of use, mechanical failure rates, and infection rates. the risk of bias of the study was assessed using the newcastle ottawa scale. statistical analysis the data obtained was then inputted and analyzed using the review manager 5.4 software. the outcome evaluated in this study comprised postoperative complications consisting of mechanical failure and penile prosthesis infection. chi-square and i2 tests were used to evaluate the heterogeneity between studies. if the result of the heterogeneity test was high (i2 test > 50% and chi-square p < 0.05), then the random-effects model was used. on the other hand, if the result of the heterogeneity test was low (i2 < 50%, chi-square p > 0.05), the fixed-effect model was instead used. the results comprised dichotomous data. thus, analysis using pooled odds ratio (or) with 95% confidence interval (ci) is used in the presentation of the data. the results of the analysis is presented in the form of forest plots and explained in the form of a narrative review. the publication bias was assessed using a funnel plot. results based on initial search results through pubmed, scopus, sciencedirect, and semantic scholar databases, the authors identified 708 articles. the authors screened 598 titles and abstracts after carrying out the process of removing duplicate articles and automation. based on predetermined eligibility criteria, the authors excluded 590 articles by reading their titles and abstracts. based on further review conducted by reading the full texts, the authors included 5 studies that met the eligibility criteria. the characteristics of the 5 included studies are described in table 2. table 2. basic characteristics of the included studies. author's name, country type of study group prosthesis brand total age (years) follow-up ed etiology result year of the study of origin subject (n) duration natali, 2008 (26) germany, italy retrospective cohort 2-piece ipp ams ambicor 98 average 58.9 5 years • diabetes mellitus: 82 patients patient satisfaction, 3-piece ipp ams 700 cx 62 (range of 35-78) • vascular disease: 22 patients partner satisfaction, mpp ams 600 500 40 • radical prostatectomy: 45 patients ease of use, • peyronie's disease: 20 patients mechanical failure, infection rate berto, 2014 (28) spain retrospective cohort ipp • ams 700 cx 41 average 57.2 18 years • diabetes mellitus: 38 patients infection rate • ams 700 cxr (sd ± 2.8) • vascular disease: 22 patients • ams ambicor • peyronie's disease: 14 patients • coloplast titan • radical prostatectomy: 5 patients mpp ams spectra 66 average 52.6 • neurogenic: 12 patients coloplast genesis (sd ± 3.6) • unknown: 17 patients kilicarslan, 2014 (17) turkey retrospective cohort ipp ams ambicor 23 average 58.6 5 years • vascular disease: 25 patients patient satisfaction, (sd ± 9.5) • radical prostatectomy and partner satisfaction, mpp ams 600 500 23 average 56.7 pelvic area surgery: 7 patients ease of use (sd ± 12.9) • priapism: 3 patients • patients with kidney transplants: 1 patients cayan, 2019 (33) turkey retrospective cohort 2-piece ipp ams ambicor 26 average 56.8 1 year • diabetes mellitus: 378 patients patient satisfaction, (sd ± 10.1; • vascular disease: 540 patients partner satisfaction, range 35 ± 74) • pelvic area surgery: 106 patients ease of use, 3-piece ipp • ams 700 ultrex plus 508 average 57.2 • neurogenic: 21 patients mechanical failure • ams 700 lgx (sd ± 10.5; • peyronie's disease: 162 patients • coloplast titan range 25 ± 83) mpp • ams spectra 349 average 58.6 • genesis (sd ± 7.9; range 29 ± 80) bayrak, 2020 (16) turkey retrospective cohort 2-piece ipp ams ambicor 61 51.47 ± 10.79 5 years • diabetes mellitus: 100 patients patient satisfaction, mpp promedon tube 81 56.27 ± 10.81 • coronary artery disease: 27 patients partner satisfaction, • neurogenic: 4 patients ease of use, • radical prostatectomy: 12 patients infection rate • other pelvic surgeries: 14 patients archivio italiano di urologia e andrologia 2024; 96(2):12353 h. satwikananda, t. bagus laksita, w. djatisoesanto, d. moesbadianto soebadi 4 this review includes studies evaluating comparison of the use of ipp and mpp, covering a total of 1.234 adult patients, published between 2008 and 2019. all of the studies included are retrospective cohort studies conducted in germany, italy, spain, and turkey. the average age of patients who were subjects in these 5 studies was between 52.6 and 58.9 years. the data extracted from the five studies included names of the researchers and years of the publication of the studies, designs of the studies, number of samples, types and brands of penile prostheses, duration of follow-up, etiology of ed, average age of samples, patient satisfaction, partner satisfaction, ease of use, mechanical failures, and number of infections. the quality assessment of the study was conducted using the newcastle-ottawa scale (nos) parameter as all the studies included use an observational study design. in the selection aspect, all the studies that are included employ a good selection process as the participants involved were quite representative of cases in the adult population and most of the data was acquired using medical records and validated questionnaires. in addition, the studies included also possess good comparative and exposure aspects as they had adequate follow-up duration and low dropout numbers. based on the final assessment, all the studies included have nos scores between 7 and 8, signifying that they are of good quality. the quality assessment are presented in table 3. comparison of ipp and mpp with regard to patient satisfaction in this analysis, four articles involving a total of 1.484 patients who underwent penile prosthesis implantation procedure were included to assess and compare patient satisfaction with regard to the use of ipp and mpp. for statistical analysis, fixed-effect models were used as the degree of heterogeneity between studies in this analysis is low. in subgroup 1, the authors compared the satisfaction of patients who used two-piece ipp with those who used mpp. the analysis results show an or of 2.40 [95% ci 1.31, 4.40]. there is a moderate degree of heterogeneity with a chisquare of 4.84, degrees of freedom (df) of 3 (p = 0.18), and i2 value of 38%. the test for overall effect demonstrates statistically significant results with p = 0.005. this suggests a more favorable outcome for the two-piece ipp. subgroup 2 compares the three-piece ipp with mpp, resulting in an or of 4.16 [95% ci 2.85, 6.06]. there is a very low degree of heterogeneity with a chi-square of 0.01, df of 1 (p = 0.94), and i2 value of 0%. the test for overall effect demonstrates statistically very significant results with p < 0.00001, indicating the advantage of the use of three-piece ipp. by combining these two subgroups, a total or of 3.55 [95% ci 2.58, 4.89] was obtained, demonstrating the superiority of ipp over the mpp. the degree of heterogeneity remains relatively low, with a chi-square of 6.61, df of 5 (p = 0.25), and i2 value of 24%. the test for overall effect demonstrates statistically significant results with p = 0.00001. the subgroup difference test was carried out to assess whether there were significant differences between the two subgroups. the test results showed that there were no significant differences between the two subgroups, with chi-square of 2.28, df of 1 (p = 0.13), and i2 of 56.2%. these findings suggest that overall, patients tend to be more satisfied with the use of ipp compared to mpp, with statistically significant results. the heterogeneity between studies we included in this analysis is relatively low, which adds confidence to the results of this study (figure 2). comparison of ipp and mpp with regard to partner satisfaction in this analysis, four articles involving a total of 1.517 patients who underwent a penile prosthesis implantation table 3. results of the newcastle-ottawa scale assessment. archivio italiano di urologia e andrologia 2024; 96(2):12353 5 efficacy and safety of malleable penile prosthesis compared to inflatable penile prosthesis... procedure are included. this study aims to evaluate and compare partner satisfaction with regard to the use of two-piece ipp and mpp. fixed-effect models were used in statistical analysis as the degree of heterogeneity between studies in this analysis is low. in subgroup 1, the authors compared the partner satisfaction between the two-piece ipp and mpp. the analysis results show an or of 1.26 [95% ci 0.73, 2.18]. there is a low degree of heterogeneity with a chi-square of 3.00, df of 3 (p = 0.39), and i2 value of 0%. the test for overall effect demonstrates statistically insignificant results (p < 0.41), showing the advantage of the use of two-piece ipp. subgroup 2 is focused on the comparison between threepiece ipp and mpp, where an or of 2.42 [95% ci 1.79, 3.26] is obtained. in this subgroup, there is a very low degree of heterogeneity with a chi-square of 0.15, df of 1 (p = 0.70), and i2 value of 0%. the test for overall effect demonstrates statistically very significant results (p < 0.00001), indicating the advantage of the use of threepiece ipp (figure 3). figure 2. forest plot of patient satisfaction. figure 3. forest plot of partner satisfaction. archivio italiano di urologia e andrologia 2024; 96(2):12353 h. satwikananda, t. bagus laksita, w. djatisoesanto, d. moesbadianto soebadi 6 comparison of ipp and mpp with regard to ease of use the authors assessed the comparison between the ease of use of ipp and mpp prostheses in four studies involving a total of 1,484 patients. the results of the analysis also demonstrate that the studies included have a high degree of heterogeneity (i2 = 86%, p < 0.0001). thus, the analysis method used was the random-effects model. in subgroup 1, the authors compared the ease of use of two-piece ipp and mpp. the analysis results show an or of 0.59 [95% ci 0.13, 2.82]. there is a high degree of heterogeneity with a chi-square of 19.18, df of 3 (p = 0.0003), and i2 value of 84%. the test for overall effect demonstrates statistically insignificant results (p < 0.51), showing the advantage of the use of two-piece ipp. subgroup 2 compares the ease of use of three-piece ipp and mpp. an or of 0.24 [95% ci 0.16, 0.35] was obtained. there is a high degree of heterogeneity in this subgroup with a chi-square of 0.04, df of 1 (p = 0.84), and i2 value of 0%. a statistically significant result (p = 0.0001) was obtained, indicating the superiority of mpp (figure 4). comparison of ipp and mpp with regard to mechanical railure the comparison of mechanical failures is analyzed by including two studies involving a total of 1.081 patients. heterogeneity analysis using i2 indicates that the degree of heterogeneity between studies is low (i2 = 55%, p = 0.14). as such, the fixed-effects model analysis method used was used. based on the results of the analysis on 1,081 patients who underwent penile prostheses implantation, the rate of mechanical failure of ipp and mpp differs significantly (or 5.60 95% ci 2.02-15.53, p = 0.0009) (figure 5). comparison of ipp and mpp with regard to infection rate the infection rate is analyzed by including three studies involving a total of 449 patients. heterogeneity analysis using i2 demonstrates that the degree of heterogeneity between studies is low (i2 = 0%, p = 0.87). therefore, the fixed-effects model analysis method was used. based on the results of the analysis on 449 patients who underwent penile prostheses implantation, there is no significant difference in the rate of infection between ipp and mpp (or 1.26 95% ci 0.56-2.86, p = 0.58) (figure 6). figure 4. forest plot of ease of use. figure 5. forest plot of mechanical failure. archivio italiano di urologia e andrologia 2024; 96(2):12353 7 efficacy and safety of malleable penile prosthesis compared to inflatable penile prosthesis... discussion erectile dysfunction has been linked to loss of work productivity and poor quality of life in men associated with mental and psychological health cndition, especially compared to men who do not suffer from ed. partners of patients with ed often complain of having problems in relationships, decreased sexual activity, and decreased sexual satisfaction. the burden associated with ed can negatively affect men and their partners (13). currently, according to the american urology association (aua) (2018), therapies commonly used for patients with ed include oral pde5i, ved, intraurethral alprostadil, intracavernosal injection, and penile prosthesis (14). guidelines from the european association of urology (eau) from 2016 to 2023 state that penile prosthesis implantation is one of the best options in terms of satisfaction levels (92-100% in patients and 91-95% in their partners) regardless of the indication when compared to other therapeutic options (8). the eau guidelines also state that penile prosthesis implantation is a valid third-line therapeutic option for the treatment of ed when drugs and ved are shown to be ineffective, unsatisfactory, or contraindicated due to comorbidities of the patients (15). in literature, penile prostheses have been reported as the most successful surgical treatment with the highest satisfaction level among therapeutic options for ed. each type of penile prosthesis has different advantages and disadvantages that can affect patient satisfaction. malleable penile prostheses have a structure that can be bent while wearing clothes and urinating as well as can be erected prior to having sexual intercourse. advantages of malleable penile prostheses include low rate of mechanical failures, easier surgical procedures, shorter operating times, and relatively cheaper prices. on the other hand, patients using malleable prostheses will face difficulty if they need to undergo endourological treatment. inflatable penile prostheses have an upper edge in terms of cosmetic appearance. its method of increasing penile length and thickness is also close to natural erections. the most critical disadvantage to this type of prosthesis is its possibility to suffer mechanical damage (16). this meta-analysis involved a total of 1,234 adult patients from studies comparing ipp and mpp. all of the studies included are retrospective cohort studies conducted in germany, italy, spain, and turkey. the average age of patients who were included in these 5 studies was between 52.6 and 58.9 years. patient satisfaction rate for inflatable penile prosthesis is higher than that of malleable penile prosthesis. patient satisfaction can be affected by several factors, such as expectations about penile prostheses before implantation, incidence of post-operative pain and edema, adverse effects, usefulness of penile prostheses, ease of use, and acceptance by partners (17). a study conducted by jorissen et al. in 2019 states that three-piece inflatable penile prostheses have the highest satisfaction rate. in the study, the patient satisfaction rate was 80.4% for amslgx and 91.1% for coloplast titan. the study also suggests that patient sexual satisfaction is strongly influenced by partner satisfaction (18). in our study, higher partner satisfaction rates for inflatable penile prostheses are obtained. the results of this metaanalysis correlate with a study conducted by vakalopoulos et al., which discovered high average edits scores in terms of partner satisfaction and underlined a high level of satisfaction in the management of their male partners. regression analysis in the study shows a direct linear correlation of the satisfaction levels of male patients with female partners (19). even though patients who underwent malleable penile prosthesis implantation feel dissatisfied with the constant stiffness in the first few days after the implantation, they will accept such condition state over time (16). a study carried out by akin-olugbade et al. discovers that patients with peyronie’s, post-radical prostatectomy, and bmi > 30 kg/m2 demonstrate lower levels of satisfaction compared to other patients who underwent penile prosthesis implantation. decreased satisfaction levels in patients with peyronie’s disease and post-radical prostatectomy are caused by decreased penile length. meanwhile, in patients with bmi > 30 kg/m2, dissatisfaction with penile prostheses is not very apparent. however, mechanical problems related to the size of prepubic fat have been observed in this patient group. dissatisfaction with penile prostheses in patients over 70 years of age can be attributed to proficiency in using penile prostheses (20). some of the negative aspects of dissatisfaction with penile prostheses are caused by unrealistic expectations about penile prostheses, reduced penile size, and unnatural erections. carvalheira (2015) states that unrealistic expectations about penile prostheses were reported in 11 cases and related to the wishful thinking that penile prostheses implantation could solve the patient’s problems and that the prosthesis implantation could reinvigorate the desired sexual relationship. such expectations are also present in figure 6. forest plot of infection comparison. archivio italiano di urologia e andrologia 2024; 96(2):12353 h. satwikananda, t. bagus laksita, w. djatisoesanto, d. moesbadianto soebadi 8 men who desire unprecedented sexual intercourse experience. another study also suggests that low expectations about penile prostheses could lead to higher patient satisfaction (21). our meta-analysis also assesses the ease of using penile prostheses experienced by patients. subgroup analysis comparing three-piece ipp and mpp discovered statistically significant results about the superiority of mpp in terms of ease of use. inflatable penile prosthesis requires dexterity while using it, and one of the advantages of mpp over ipp is its ease of use (22, 23). in other studies, it is found that at the beginning of mpp implantation, many patients felt dissatisfied due to persistent stiffness in the first few days. however, over time, mpp users exhibit high levels of satisfaction and ease because they are able to ensure fast and maximum hardness compared to ipp. this difference is based on pain and discomfort due to the presence of ipp pump in the scrotum, causing patients to become fearful and requiring them to learn more at clinics to use ipp optimally (16, 24). the design of penile prostheses has evolved from semirigid and malleable to two-piece shafts and then evolved again into three-piece inflatable penile prostheses. the ideal penile prosthesis is one that can provide the most natural flaccid and erect state. three-piece penile prosthesis can meet such criteria, but with the added mechanical components compared to the malleable prosthesis, it bore an increased risk of mechanical failures (25). according to the meta-analysis conducted by the authors, inflatable penile prostheses are more prone to mechanical failures. more mechanical failures were observed in threepiece inflatable penile prostheses, which occurred in 38 patients. in their study, natali et al. state that the average incidence of prosthesis leakage occurs 25.2 months after implantation. of the 10 cases of mechanical failure in this study, the most frequent causes of mechanical failure were leaks in the prosthesis tube (40%), leaks in the saline reservoir (40%), and leaks from the connecting tube (20%). in general, there are fewer mechanical failures in malleable prostheses as their mechanical structure is simpler (26). a study conducted by ashton m. smelser et al. found that 56% of cases where revision was performed on patients with penile prostheses were caused by mechanical failure. the damaged parts of the penile prostheses vary, while all components are at risk of being damaged including the pump, connecting hose, reservoir, and prosthesis cylinder. leaks in the connecting tube and cylinder are the most frequent cause of damage to inflatable penile prostheses (27). leaks in the connecting tube usually occur on the bendproof outer part of the hose connection. ashton et al. assume that damage to the connecting tube is caused by the pump mechanism and ease of use for the patients. one type of inflatable penile prosthesis has a pump design that makes it more difficult to deflate the penile prosthesis. thus, the connecting tube tends to bend more frequently, resulting in leaks (27). infection is one of the complications that need to be assessed from the results of surgery. we conducted a metaanalysis of two studies to obtain output regarding infection rates. in the meta-analysis results, there was no significant difference in the infection rates after prosthesis implantation surgery in the inflatable and malleable penile prosthesis groups. this is also in line with a study conducted by berto et al., indicating that there is no significant difference in the incidence of postoperative infection. in general, infection in prosthesis implantation presents at a rate of 1012%. in the study, it was also stated that all patients who experience infection in prostheses have comorbidities in the form of diabetes mellitus with metabolic disorders and increased glycosylated hemoglobin levels (28). another study carried out by jorissen et al. suggests that although rare, infection generally does not occur immediately after penile prosthesis implantation but can become very severe. this is influenced by the patients’ comorbidities such as diabetes mellitus or others (18). the infection rate in penile prostheses has decreased over time. around 1980s and 1990s, the infection rate in penile prostheses ranged from 8% to 11%. meanwhile, in early 2000, it ranged from 3% to 5%. the introduction of penile prostheses with antibiotics coating and the development of surgical techniques have decreased infection rates by about 0.3% to 2.7% (28). in 2000, american medical systems (ams) introduced a penile prosthesis with an inhibizone™ coating, containing the antibiotics minocycline and rifampin that coats the surface of the prosthesis and inhibits bacterial growth. in 2004, a study by carson explained that in the 60 days after surgery, the infection rate in patients with inhibizone™-coated penile prostheses was 0.28% compared to 1.59% in patients with non-coated penile prostheses; six months after surgery, the penile prosthesis infection rate was 0.68% in the coated penile prosthesis group compared to 1.61% in the control group (29). in 2002, mentor (now coloplast) introduced titan, which had a hydrophilic coating that can reduce bacterial attachment and apply antibiotics to the entire surface of the prosthesis when dipped into an antibiotic solution during surgery. in 2004, wolter and hellstrom published data on infections from mentor’s database and the fda’s report on penile prostheses removal. one year after implantation, the infection rate on titan prosthesis implants was 1.06% (25/2357), while that of non-coated prostheses was 2.07% (10/482) (p 0.033) (29). the three parameters analyzed in the study (patient satisfaction, partner satisfaction, and ease of use) were analyzed using the edits questionnaire (30). the questionnaire was first validated in 1999 as an instrument that can be used to assess the satisfaction of patients who underwent ed therapy and their partners. edits questionnaire can assess subjective acknowledgment of patient satisfaction and it includes more than the efficacy of patient management (30). edits are validated questionnaires developed by althof et al. to assess satisfaction after receiving medicamentosa management (31). this questionnaire was later modified by levine to assess satisfaction after penile prosthesis implantation. the questions listed in this questionnaire assess overall patient satisfaction, the extent to which the penile prosthesis met the patients’ expectations, the possibility of continued use, ease of use of the device, confidence in the ability to engage in sexual activity, patient assessment of partner satisfaction, patient assessment of their partners’ feelings about continued use of the prosthesis, stiffness, and appearance (32). archivio italiano di urologia e andrologia 2024; 96(2):12353 9 efficacy and safety of malleable penile prosthesis compared to inflatable penile prosthesis... this study has several limitations, among which is the fact that the studies included herein are observational studies. the reason being, to date, there is no randomized control trial (rct) study that examines penile prostheses. this study also does not have many reference articles. the output of this study is a general comparison of inflatable penile prostheses and malleable prostheses. this study does not specifically compare each type of inflatable penile prosthesis, be it two-piece or three-piece. therefore, more reference articles, large-scale multicenter observational studies, and rct research are needed to 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complications with 253 implants in italy and germany. j sex med. 2008; 5:1503-1512. 27. smelser am, vandyke me, nealon sw, et al. mechanical indications for inflatable penile prosthesis revision: analysis and implications for revision surgery. j sex med. 2023; 20:1044-1051. 28. bertó rr, lópez-acón jd, marco sl, et al. penile prosthesis: patient satisfaction, use and preference for malleable vs inflatable. world j clin urol. 2014; 3:134-138 29. gon lm, de campos ccc, voris bri, et al. a systematic review archivio italiano di urologia e andrologia 2024; 96(2):12353 h. satwikananda, t. bagus laksita, w. djatisoesanto, d. moesbadianto soebadi 10 of penile prosthesis infection and meta-analysis of diabetes mellitus role. bmc urol. 2021; 21:35. 30. bernal rm, henry gd. contemporary patient satisfaction rates for three-piece inflatable penile prostheses. adv urol. 2012; 2012:707321. 31. althof se, corty ew, levine sb, et al. edits: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. urology. 1999; 53:793-799. 32. levine la. diagnosis and treatment of erectile dysfunction. am j med. 2000; 109 suppl 9a:3s-30s. 33. çayan s, ascı r, efesoy o, et al. comparison of long-term results and couples' satisfaction with penile implant types and brands: lessons learned from 883 patients with erectile dysfunction who underwent penile prosthesis implantation. j sex med. 2019; 16:10921099. correspondence handaru satwikananda handaru.satwikananda@gmail.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general-academic hospital, surabaya, east java, indonesia tetuka bagus laksita dr.tetuka@gmail.com doddy moesbadianto soebadi dmsoebadi@gmail.com wahjoe djatisoesanto (corresponding author) wahjoe.djatisoesanto@fk.unair.ac.id department of urology, faculty of medicine, universitas airlangga universitas airlangga teaching hospital, surabaya, east java, indonesia jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4384 original paper no conflict of interest declared. introduction the lower urinary tract can be affected by multiple benign conditions that can eventually lead to significant lower urinary tract dysfunction (lutd). these benign conditions can generally be classified into two main categories; neurogenic bladder (ngb) that results from the permanent loss of neuronal control over the bladder due to a neurological disorder such as spinal cord injuries (sci), multiple sclerosis (ms), parkinson’s disease (pd) or spina bifida (sb) and non-neurogenic bladder (non-ngb) that results from structural or functional bladder damage rather than loss of neuronal control of the bladder and that can occur with urinary tract fistulas, radiation-induced lower urinary tract damage, refractory urinary incontinence or bladder pain syndrome (bps) (1-4). based on the underlying disorder, the presenting symptoms of these benign conditions can vary widely from continuous urinary leakage to urinary retention, recurrent urolithiasis, bladder pain, and recurrent urinary tract infections (utis). these disorders can ultimately lead to a significant quality of life deterioration and have a detrimental effect on the upper urinary tract (3-5). the main goal of management of these benign lower urinary tract conditions is to protect the upper urinary tract, keep the patients socially dry, eliminate the recurrent urosepsis episodes, and maintain the act of urination whenever possible. this is mainly achieved by conservative and/or minimally invasive measures (5, 6). a well-established procedure in the management of bladder cancer, urinary diversion is usually considered the last resort for treating these non-malignant lower urinary tract conditions (7-9). external urinary diversions are generally classified into incontinent diversions such as ileal conduit and colonic conduit and continent diversions such as indiana pouch and continent urinary diversion using the ileum (10-13). the primary aim of this study is to report the early and late outcomes of external urinary diversion in patients with refractory non-malignant lutd. the secondary aim is to evaluate these outcomes independently based on both the underlying condition and the type of external urinary diversion. materials and methods after approval by university of cincinnati institutional review objective: to evaluate the early and late outcomes of continent and incontinent external urinary diversion in management of patients with refractory non-malignant lower urinary tract dysfunction (lutd). materials and methods: the charts of patients with refractory non-malignant lutd who underwent continent or incontinent external urinary diversion at university of cincinnati hospitals in the period between march 2012 and december 2019 were retrospectively reviewed. the demographic and baseline characteristics, surgery indications, operative data, early and late outcomes were collected, analyzed, and compared. results: a total of 78 patients including 55 patients with neurogenic bladder (ngb) and 23 patients with non-neurogenic bladder (non-ngb) refractory non-malignant lutd were included. fifty-three patients underwent incontinent urinary diversions (iud), while 25 patients underwent continent urinary diversions (cud). during the first 4 postoperative weeks, 53.85% (n=42) of patients developed complications, and the incidence was nonsignificantly higher in patients with ngb than those with nonngb (56.36% vs 47.83%, p-value=0.490). fever was exclusively encountered in patients with ngb earlier, while stomal retraction occurred only in patients with non-ngb later. more nonngb patients had early wound infection. there was an overall improvement of urological symptoms in 52 patients (66.67%), and the rate was non-significantly higher in non-ngb patients than ngb patients (78.26% vs 61.82%, p-value=0.160). late complications were reported in 47 patients and were more encountered in those with non-ngb than those with ngb (65.22% vs 58.18%). stomal leakage and stenosis occurred more with cud than with iud (52% vs 0% and 28% vs 3.77%, respectively). conclusions: external urinary diversion can achieve a reasonable level of urological symptoms control in patients with refractory non-malignant lutd, but with associated adverse outcomes. although non-significantly, these complications tend to be higher in patients with iud and/or ngb during the early postoperative period and higher with cud and/or non-ngb on the long-term. key words: continent urinary diversion (cud); incontinent urinary diversion (iud); neurogenic bladder (ngb); non-neurogenic bladder (non-ngb); lower urinary tract dysfunction (lutd). submitted 12 november 2022; accepted 25 november 2022 outcomes of continent and incontinent external urinary diversion in management of patients with refractory non-malignant lower urinary tract dysfunction mostafa m. mostafa 1, 2, ashraf khallaf 1, mohamed kamel 1, nilesh patil 1, ayman mahdy 1 1 division of urology, department of surgery, university of cincinnati college of medicine, cincinnati, oh, united states; 2 asiut university hospitals, asiut, egypt. doi: 10.4081/aiua.2022.4.384 summary 385archivio italiano di urologia e andrologia 2022; 94, 4 continent vs incontinent urinary diversion for non-malignant lower urinary tract dysfunction board, we started reviewing the charts of all patients who underwent continent and incontinent external urinary diversion procedures for refractory non-malignant lutd at university of cincinnati hospitals in the period between march 2012 and december 2019. all surgeries were performed via open surgery by one surgeon (am) who is welltrained in genitourinary reconstructive surgeries. inclusion criteria included all patients with refractory non-malignant lutd who underwent external urinary diversion. exclusion criteria included patients who were diagnosed with lower urinary tract malignancies and those who did not complete a minimum follow-up of 6 months. we collected the demographic and baseline characteristics, surgery indications and operative data. furthermore, we reported early postoperative outcomes that occurred within the first 4 postoperative weeks including fever, pelvic infection or abscess, wound infection, pneumonia, uti, paralytic ileus (defined by abdominal pain other than incisional, abdominal distension, failure to pass stool and/or flatus in addition to radiological findings suggestive of obstruction), sepsis, blood loss (defined by hemoglobin drop that required blood transfusion), cardiac complications, and re-operation rate. late postoperative outcomes that manifested more than 6 months after surgery including urological symptom control, stomal complications, anastomotic ureteric strictures, stone formation, wound complications, hydronephrosis with renal function impairment, and need for re-operation were also reported. urological symptom control was assessed based on the successful resolution of the specific urological symptoms related to patients’ preoperative urological conditions that were the main drive for intervention. resolution of these symptoms in terms of resolution of hydronephrosis, reduction in urosepsis episodes, alleviation of bladder pain, reduction in urolithiasis, social dryness, and independence was confirmed based on both history taking and clinical examination after a minimum follow-up of 6 months postoperatively. statistical analysis all statistical analyses were conducted using the spss software (spss, inc., chicago, il, usa; version 26). quantitative variables are presented as means ± standard deviation, and qualitative variables are expressed as frequencies with percentages. results were compared between two groups using student’s t-test and mannwhitney u test for quantitative variables and chi-square test and mcnemar’s test for qualitative variables. a p-value of < 0.05 was considered significant. results after fulfilling the inclusion and exclusion criteria, 78 patients were included in the study. fifty-five patients (70.51%) had ngb while 23 patients (29.49%) suffered from non-ngb. most non-ngb patients had radiation-induced urinary tract damage (39.13%, n = 9), followed by refractory overactive bladder (oab) (21.74%, n = 5), stress urinary incontinence (sui) (17.39%, n = 4), bps (17.39%, n = 4), and finally traumatic urethral rupture (4.35%, n = 1). fifty-three patients (67.95%) underwent iud, while cud was performed for 25 patients (32.05%). cud procedures included cutaneous catheterizable ileocystoplasty (19 patients), cud using ileal catheterizable stoma via yang-monte technique (4 patients), and indiana pouch (2 patients). on the other hand, iud procedures included cystectomy with ileal conduit (22 patients), ileovesicostomy (21 patients), and cystectomy with colon conduit (10 patients). the cystectomy was done via a simple supratrigonal approach without concomitant prostatectomy in males to avoid the associated increased morbidity in those patients with benign conditions. although ileum is the most commonly used bowel segment for iud, 10 patients needed a colon conduit in our study to avoid the use of the irradiated devitalized small bowel in those with prior pelvic irradiation and to avoid the need for bowel re-anastmosis in those with a colostomy. most of the study population were overweight with bmi of 27.77 ± 7.06 and 29.44 ± 7.29 for iud and cud groups respectively, female (62.82%) and white (79.49%) with no significant differences between the iud and cud groups regarding the demographic and baseline characteristics (table 1). based on the underlying condition, there was no significant difference in early and late postoperative complications and urological symptoms control between ngb and non-ngb patients with p-values of 0.490, 0.563, and 0.160, respectively. noticeably, fever was exclusively encountered in patients with ngb with p-value of 0.011, while more non-ngb patients had early wound infection (p-value = 0.007). the only significant difference in the late outcomes between the two groups was the incidence table 1. demographic and baseline characteristics of the two groups. variables incontinent urinary continent urinary p-value diversion diversion (iud) (n = 53) (cud) (n = 25) • age in years (mean ± sd) 51.45 ± 15.44 52.04 ± 16.52 0.996 • follow-up duration in months (mean ± sd) 25 ± 18 26 ± 17 0.951 • gender 1) female n (%) 30 (56.60%) 19 (76%) 0.098 2) male n (%) 23 (43.40%) 6 (24%) • race 1) white n (%) 39 (73.58%) 23 (92%) 2) black n (%) 12 (22.64%) 2 (8%) 0.296 3) hispanic n (%) 1 (1.89%) 0 (0%) 4) native american n (%) 1 (1.89%) 0 (0%) • bmi (mean ± sd) 27.77 ± 7.06 29.44 ± 7.29 0.370 • smoking n (%) 11 (20.75%) 3 (12%) 0.347 • concomitant comorbidities 1) dm n (%) 11 (20.75%) 4 (16%) 0.619 2) htn n (%) 25 (47.17%) 9 (36%) 0.353 • hospital stay (days) 9.89 ± 6.32 8.04 ± 2.62 0.825 • indications for surgery i) neurogenic bladder (ngb) n (%) 40 (75.47%) 15 (60%) 0.162 ii) non-neurogenic bladder (non-ngb) n (%) 13 (24.53%) 10 (40%) archivio italiano di urologia e andrologia 2022; 94, 4 m.m. mostafa, a. khallaf, m. kamel, n. patil, a. mahdy 386 of stomal retraction which occurred only in patients with non-ngb (p-value = 0.027) (table 2). the mean times to stomal complications, anastomotic ureteric strictures, renal and ureteric urolithiasis, wound complications, and hydronephrosis or renal impairment were 23.34 ± 9.54, 14.32 ± 2.13, 13.45 ± 6.74, 12.67 ± 5.64, and 14.56 ± 5.78 months, respectively. the average number of complications per patient was 0.83 for early complications, and 1.03 for late complications. based on the type of urinary diversion, no significant difference was observed between patients who underwent iud and those who underwent cud in terms of early and late postoperative complications and urological symptoms control with p-values of 0.822, 0.146, and 0.732, respectively. the incidence of stomal leakage and stenosis was significantly higher in the cud group than in the iud group (52% vs 0%, p-value = < 0.001 and 28% vs 3.77%, pvalue = 0.002, respectively) (table 3). interestingly, none of the patients experienced grade v complications based on modified clavien-dindo classification system. the majority of patients with early complications had grade i and ii complications (29.49% and 14.10% of patients, respectively), while most patients with late complications suffered from grade iiia and ii complications (21.79% and 15.38%, respectively) (table 4). discussion a well-established treatment of bladder cancer, external urinary diversion can also be used for management of benign urinary conditions that cause significant lutd. the management of such conditions is primarily achieved by conservative and/or minimally invasive measures. if these measures fail, surgical interventions are indicated (7, 8, 14, 15). these surgical interventions, however, have a significant impact on patients’ quality of life. in an interesting study by borghi et al. 2021 (16), they discussed orthotopic urinary diversion as a feasible surgical intervention in refractory non-malignant lutd and its impact on quality of life and sexual function particularly in females. they reported that although orthotopic neobladder improves physical and mental health in patients with refractory non-malignant lutd, urinary symptoms were frequently encountered affecting general health and sexual function in females as compared to males (16). the optimal surgery prevents recurrent episodes of symptomatic utis or urosepsis, prevents urinary stone formation, provides satisfactory continence between voids, and prevents upper urinary tract damage (9, 12, 13). in this study, we analyzed the outcomes of external urinary diversion in refractory non-malignant lower urinary tract conditions aiming to evaluate their effectiveness and complications. although complications were higher in ngb patients in table 2. demographic and baseline characteristics of the two groups. variables total (n = 78) neurogenic bladder non-neurogenic bladder p-value (n (%) (ngb) (n = 55) (non-ngb) (n = 23) (n (%) (n (%) • early outcomes within the first 4 postoperative weeks patients with early complications 42 (53.85%) 31 (56.36%) 11 (47.83%) 0.490 fever 13 (16.67%) 13 (23.63%) 0 (0%) 0.011 pelvic infection/abscess 4 (5.13%) 4 (7.27%) 0 (0%) 0.184 wound infection 11 (14.10%) 4 (7.27%) 7 (30.43%) 0.007 pneumonia 2 (2.56%) 2 (3.64%) 0 (0%) 0.354 urinary tract infection (uti) 4 (5.13%) 4 (7.27%) 0 (0%) 0.184 ileus 21 (26.92%) 18 (32.73%) 3 (13.04%) 0.074 sepsis 1 (1.28%) 1 (1.82%) 0 (0%) 0.515 blood loss+ transfusion 4 (5.13%) 4 (7.27%) 0 (0%) 0.184 cardiac complications (arrythmias/nstemi) 3 (3.85%) 1 (1.82%) 2 (8.70%) 0.150 reoperation (acute surgical complications) 2 (2.56%) 2 (3.64%) 0 (0%) 0.354 • late outcomes after 6-month follow-up urological symptoms control 52 (66.67%) 34 (61.82%) 18 (78.26%) 0.160 resolution of hydronephrosis, social dryness, and independence/patients with voiding dysfunction and/or hydronephrosis 40/57 (70.18%) 32/44 (72.73%) 8/13 (61.54%) 0.438 reduction in urosepsis episodes/patients with recurrent urosepsis episodes 38/55 (69.09%) 25/34 (73.53%) 13/21 (61.90%) 0.365 alleviation of bladder pain and reduction in urolithiasis/patients with recurrent urolithiasis and bladder pain 28/45 (62.22%) 20/30 (66.67%) 8/15 (53.33%) 0.384 patients with late complications 47 (60.26%) 32 (58.18%) 15 (65.22%) 0.563 stomal complications 1) stomal leakage 13 (16.67%) 7 (12.73%) 6 (26.09%) 0.149 2) stomal stenosis 9 (11.54%) 6 (10.91%) 3 (13.04%) 0.788 3) stomal hernia 10 (12.82%) 6 (10.91%) 4 (17.39%) 0.435 4) stomal site pain/bleeding 1 (1.1) 1 (1.82%) 0 (0%) 0.515 5) stomal retraction 2 (2.56%) 0 (0%) 2 (8.70%) 0.027 anastomotic ureteric stricture 2 (2.56%) 2 (3.64%) 0 (0%) 0.354 stones (ureters, kidneys) 15 (19.23%) 12 (21.82%) 3 (13.04%) 0.370 wound complications 1) wound separation/incisional hernia 7 (8.97%) 3 (5.45%) 4 (17.39%) 0.093 2) sinus/fistula formation 3 (3.85%) 2 (3.64%) 1 (4.35%) 0.882 3) recurrent wound infection/abscess 2 (2.56%) 1 (1.82%) 1 (4.35%) 0.519 hydronephrosis/renal impairment 6 (7.69%) 3 (5.45%) 3 (13.04%) 0.251 reoperation (persistent symptoms) 10 (12.82%) 7 (12.73%) 3 (13.04%) 0.970 387archivio italiano di urologia e andrologia 2022; 94, 4 continent vs incontinent urinary diversion for non-malignant lower urinary tract dysfunction the early postoperative period and higher in non-ngb patients on the long-term, the differences were generally non-significant and can possibly be attributed to the difference in numbers of patients between the two groups (55 patients with ngb versus 23 patients with nonngb). in contrast to our study, cohn et al., 2014 (7) reported fewer overall complications in patients with ngb than with other non-neurogenic conditions. during the early postoperative period, we reported paralytic ileus as the most common complication, with an overall incidence of 26.92%, and the rate was non-significantly higher in patients with ngb than those with nonngb which can be attributed to the fact that ngb patients usually have a baseline neurogenic bowel making them vulnerable to paralytic ileus. fever, pelvic infections with or without abscesses, pneumonia, and uti were reported only in patients with ngb, a finding explained by higher rates of utis, stone formation and lung complications in ngb population in general. however, the overall long term complication rate (60.26%) was comparable to that reported by erfan et al., 2015 in patients who underwent urinary diversion after radical cystectomy for bladder cancer (60%) (17). surprisingly, although considered major procedure, urinary diversion is not usually associated with major blood loss with proper handling of the bowel and its mesentery. the overall rate of postoperative blood loss that required transfusion table 4. modified clavien-dindo classification of complications. variables total (n = 78) incontinent urinary continent urinary p-value (n (%) diversion (iud) diversion (cud) (n = 53) (n = 25) • early outcomes within the first 4 postoperative weeks procedures with early complications, n (%) 42 (53.85%) 29 (54.72%) 13 (52%) 0.822 i, n (%) 23 (29.49%) 17 (32.08%) 6 (24%) 0.465 ii, n (%) 11 (14.10%) 5 (9.43%) 6 (24%) 0.084 iiia, n (%) 2 (2.56%) 2 (3.77%) 0 (0%) 0.325 iiib, n (%) 2 (2.56%) 2 (3.77%) 0 (0%) 0.325 iv, n (%) 4 (5.13%) 3 (5.66%) 1 (4%) 0.756 v, n (%) 0 (0%) 0 (0%) 0 (0%) --• complications after 6-month follow-up procedures with late complications, n (%) 47 (60.26%) 29 (54.72%) 18 (72%) 0.146 i, n (%) 8 (10.26%) 5 (9.43%) 3 (12%) 0.727 ii, n (%) 12 (15.38%) 6 (11.32%) 6 (24%) 0.147 iiia, n (%) 17 (21.79%) 10 (18.87%) 7 (28%) 0.362 iiib, n (%) 10 (12.82%) 8 (15.09%) 2 (8%) 0.382 iv, n (%) 0 (0%) 0 (0%) 0 (0%) --v, n (%) 0 (0%) 0 (0%) 0 (0%) --table 3. early and late outcomes based on the type of urinary diversion. variables total (n = 78) incontinent urinary continent urinary p-value (n (%) diversion (iud) diversion (cud) (n = 53) (n = 25) • early outcomes within the first 4 postoperative weeks patients with early complications 42 (53.85%) 29 (54.72%) 13 (52%) 0.822 fever 13 (16.67%) 10 (18.87%) 3 (12%) 0.448 pelvic infection/abscess 4 (5.13%) 4 (7.55%) 0 (0%) 0.158 wound infection 11 (14.10%) 6 (11.32%) 5 (20%) 0.304 pneumonia 2 (2.56%) 1 (1.89%) 1 (4%) 0.582 urinary tract infection (uti) 4 (5.13%) 3 (5.66%) 1 (4%) 0.756 paralytic ileus 21 (26.92%) 16 (30.19%) 5 (20%) 0.344 sepsis 1 (1.28%) 1 (1.89%) 0 (0%) 0.489 blood loss+ transfusion 4 (5.13%) 4 (7.55%) 0 (0%) 0.158 cardiac complications (arrythmias/nstemi) 3 (3.85%) 2 (3.77%) 1 (4%) 0.961 reoperation (acute surgical complications) 2 (2.56%) 2 (3.77%) 0 (0%) 0.325 • late outcomes after 6-month follow-up urological symptoms control 52 (66.67%) 36 (67.92%) 16 (64%) 0.732 resolution of hydronephrosis, social dryness, and independence/patients with voiding dysfunction and hydronephrosis 40/57 (70.18%) 25/40 (62.5%) 15/17 (88.24%) 0.052 reduction in urosepsis episodes/patients with recurrent urosepsis episodes 38/55 (69.09%) 24/34 (70.59%) 14/21 (66.67%) 0.760 alleviation of bladder pain and reduction in urolithiasis/patients with recurrent urolithiasis and bladder pain 28/45 (62.22%) 16/26 (61.53%) 12/19 (63.16%) 0.912 patients with late complications 47 (60.26%) 29 (54.72%) 18 (72%) 0.146 stomal complications 1) stomal leakage 13 (16.67%) 0 (0%) 13 (52%) <0.001 2) stomal stenosis 9 (11.54%) 2 (3.77%) 7 (28%) 0.002 3) stomal hernia 10 (12.82%) 6 (11.32%) 4 (16%) 0.564 4) stomal site pain/ bleeding 1 (1.28%) 0 (0%) 1 (4%) 0.143 5) stomal retraction 2 (2.56%) 1 (1.89%) 1 (4%) 0.582 anastomotic ureteric stricture 2 (2.56%) 2 (3.77%) 0 (0%) 0.325 stones (ureters, kidneys) 15 (19.23%) 13 (24.53%) 2 (8%) 0.084 wound complications 1) wound separation/ incisional hernia 7 (8.97%) 6 (11.32%) 1 (4%) 0.291 2) sinus/fistula formation 3 (3.85%) 3 (5.66%) 0 (0%) 0.225 3) recurrent wound infection/abscess 2 (2.56%) 1 (1.89%) 1 (4%) 0.582 hydronephrosis/renal impairment 6 (7.69%) 6 (11.32%) 0 (0%) 0.080 reoperation (persistent symptoms) 10 (12.82%) 8 (15.09%) 2 (8%) 0.382 archivio italiano di urologia e andrologia 2022; 94, 4 m.m. mostafa, a. khallaf, m. kamel, n. patil, a. mahdy 388 in our study was low (5.13%) and only reported in patients with ngb unlike the higher rate of perioperative blood transfusion (28%) reported by osborn et al., 2014 (18) following cystectomy with urinary diversion for benign conditions and schiavina et al., 2013 (19) who reported 6.5% transfusion rate after radical cystectomy with urinary diversion for bladder cancer. although adequately studied following malignancies, the outcomes of external urinary diversions following benign urinary conditions have not been sufficiently addressed. compared to our study, osborn et al., 2014 (18) reported a slightly lower rate of postoperative ileus, pneumonia, blood loss requiring transfusion, and stoma complications in patients who underwent cystectomy with urinary diversion for benign conditions. cohn et al., 2014 (7) reported a higher rate of urinary symptom resolution (73%) in 26 patients who underwent cystectomy with urinary diversion for refractory benign conditions. however, they reported a higher rate of infections and wound complications (35% and 23% respectively) than in our study. in contrast to our study results, andersen av et al., 2012 (20) reported a moderate rate of complications after bladder augmentation and/or cystectomy with urinary diversion for 41 patients with bps while attributing this rate mainly to stomal and intestinal issues. another study done by al hussein al awamlh b et al., 2015 (21) investigated the quality of life in 29 patients with refractory benign conditions who underwent cystectomy with urinary diversion, and reported a significant rate of early postoperative complications of 65.5% which they attributed to pelvic pain, infections, and gut disturbances. additionally, the cumulative physical health domain and cumulative mental health domain used to assess the quality-of-life revealed worsening in 26% and 21% of patients respectively. there was considerable resolution of urological symptoms in 66.67% of patients, and the rate of improvement was non-significantly higher in non-ngb patients than in ngb patients. these findings were supported by several studies such as cohn et al., 2014 (7) and e. brown et al., 2015 (6) who reported that cystectomy and urinary diversion procedures were successful management options for benign lower urinary conditions. relevant to that, the re-operation rate for uncontrolled symptoms and/or acute surgical complications including wound complications and stomal complications such as stomal retraction, recurrent stomal stenosis, and stomal leakage was 12.82% and 2.56%, respectively with non-significant difference between ngb and non-ngb groups. generally, incontinent diversions were associated with higher rates of early postoperative complications, while continent diversions were associated with more late postoperative complications, although the differences were non-significant. many studies previously investigated the outcomes of bladder reconstruction and urinary diversion surgeries (12, 22, 23). one of the most well-structured studies was conducted by cody et al., 2012 (12) who concluded that, based on a pool of five studies, there was no significant difference in the outcomes among continent diversion, incontinent diversion, and bladder augmentation. on the other hand, clark et al., 2005 (22) demonstrated higher rate of complications in patients with continent diversion than in patients who underwent ileal conduit. study strengths we investigated the outcomes of external urinary diversion exclusively in patients with refractory non-malignant lutd. additionally, we highlighted the distinctive outcomes based on both the underlying condition and the type of external urinary diversion. the included cases in our study were performed by one surgeon who is well trained in urinary reconstructive surgeries eliminating bias related to technical issues. study limitations besides being a single-center single-surgeon experience, this is a retrospective study that represented a heterogeneous group of population including ngb and non-ngb. additionally, the underlying pathology usually determines the type of surgery; therefore, the urinary diversions are indicated for more complicated cases which can skew the patient population in our study. a standardized questionnaire was not used in the followup to report patient’s satisfaction regarding the urological symptoms; however, this was related to the multiple social and demographic factors that could limit those patients’ ability to return accurately filled questionnaires. conclusions external continent and incontinent urinary diversion can be utilized as the last resort for patient with refractory non-malignant lutd. these procedures can achieve a reasonable level of urological symptoms control, but with associated adverse outcomes. the most commonly reported complication during the early postoperative period is paralytic ileus, while stomal complications and recurrent urolithiasis are the most frequently encountered complications on the long-term. fever is more likely to be encountered in patients with ngb, while early wound infection and late stomal retraction are more associated with non-ngb. stomal leakage and stenosis are more encountered with cud. although the differences were non-significant, complications tend to be higher with iud and in ngb patients during the early postoperative period and higher with cud and in non-ngb patients on the long-term. 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urology. 2014; 83:1433-7. 19. schiavina r, borghesi m, guidi m, et al. perioperative complications and mortality after radical cystectomy when using a standardized reporting methodology. clin genitourin cancer. 2013; 11:18997. 20. andersen av, granlund p, schultz a, et al. long-term experience with surgical treatment of selected patients with bladder pain syndrome/interstitial cystitis. scand j urol nephrol. 2012; 46:284-9. 21. al hussein al awamlh b, lee dj, et al. assessment of the quality-of-life and functional outcomes in patients undergoing cystectomy and urinary diversion for the management of radiation-induced refractory benign disease. urology. 2015; 85:394-400. 22. clark pe, stein jp, groshen sg, et al. radical cystectomy in the elderly: comparison of clincal outcomes between younger and older patients. cancer. 2005; 104:36-43. 23. boyd sd, feinberg sm, skinner dg, et al. quality of life survey of urinary diversion patients: comparison of ileal conduits versus continent kock ileal reservoirs. j urol. 1987; 138:1386-9. correspondence mostafa m. mostafa, md (corresponding author) mostafaabdelaziz91@gmail.com research fellow of urology, division of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way,cincinnati, oh 45267 assistant lecturer of urology, asiut university hospitals, asiut, egypt, ashraf khallaf, md ashraf.m.khallaf2@gmail.com visiting scholar of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, cincinnati, oh 45267 mohamed kamel, md kamelme@ucmail.uc.edu professor of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way,cincinnati, oh 45267 nilesh patil, md patilnh@ucmail.uc.edu associate professor of urology, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, cincinnati, oh 45267 ayman mahdy, md, phd, mba mahdyan@uc.edu chief of urology, professor of urology, r. bruce and barbara bracken endowed chair in surgical urology, director of voiding dysfunction and female urology, medical director of urology, the west chester hospital, department of surgery, university of cincinnati college of medicine, 231 albert sabin way, ml 0589, cincinnati, oh 45267 stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13342 1 original paper introduction hypospadias is a congenital abnormality of the male external genital tract, with the characteristic anatomic position of the urethral meatus at the ventral or anterior part of the penile body, often accompanied by urethral spongiosum, widened dorsal prepuce, ventral foreskin, penile chordee, and deviation of the ventral penile body (1). the main treatment remains surgical correction with various techniques, one of which is the two-stage urethroplasty technique, also known as the sidik-chaula technique. in the first stage, the chordee is released and a neourethra is created using the distal intraglandular tunnel removed from the preputial vascularized flap. the full-length urethra is then reconstructed in a second stage, using a locally transposed cutaneous flap with minimal manipulation (2). hyperbaric oxygen therapy (hbot) is a therapeutic modality to improve tissue hypoxic conditions by providing high-pressure oxygen so that tissue oxygen tension increases. it thereby improves oxygen delivery to hypoxic tissue because dissolved oxygen can pass through tissue fluids even if the tissue is damaged and has poor blood circulation. increased oxygen availability in tissue promotes angiogenesis, collagen synthesis, increased reactive oxygen species for bacterial clearance, inhibition introduction: hypospadias is a congenital abnormality of the urethral meatus in males. hypospadias can be corrected by two-stage urethroplasty. hyperbaric oxygen therapy (hbot) can accelerate wound healing after surgery by increasing oxygenation, angiogenesis, and collagen synthesis. this study aimed to measure the effectivity of hbot based on serum vascular endothelial growth factor (vegf) level and hypospadias objective penile evaluation (hope) score in hypospadias reconstruction patients. methods: this was a randomized controlled trial study. hypospadias reconstruction was performed using the sidikchaula and manset flap techniques. each hbot session ranged from 30-60 minutes, administered at 1-3 atm. twenty subjects were divided into two groups: the hbot and control groups. vegf serum levels were measured 1 hour after the operation and 1 hour after every hbot session. the hope score was assessed at the bedside by the attending physician, consisting of six items: the position of the meatus, the shape of the meatus, the shape of the glans, the shape of the penile skin, and the shape of the penile axis, including penile torsion and penile curvature. the data were analyzed with spss version 28, using the shapiro-wilk and independent t-test methods. results: there was a trend of increasing vegf levels as the number of hbot sessions increased, with significant increase found in patients who underwent three (p = 0.038), four (p = 0.002), and five (p = 0.008) hbot sessions. we found a significant increase in the total hope score (p = 0.028) and penile torsion score (p = 0.006) in the hbot group. conclusions: hbot can accelerate wound healing after urethroplasty. three or more hbot sessions are recommended after the repair of hypospadias. the effect of hyperbaric oxygen therapy on hypospadias reconstruction: a preliminary randomized controlled trial study of vegf levels and hope score analysis mendy hatibie oley 1, maximillian christian oley 2, ari astram adhiatma iskandar 3, chaula luthfia sukasah 4, indri aulia 4, fima lanra fredrik g. langi 5, harsali fransicus lampus 6, irawan sukarno 7, vania sukarno 8, muhammad faruk 9 1 division of plastic reconstructive and aesthetic surgery, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia; 2 division of neurosurgery, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia; 3 division of urology, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia; 4 division of plastic reconstructive and aesthetic surgery, department of surgery, faculty of medicine, universitas indonesia dr. cipto mangunkusumo hospital, jakarta, indonesia; 5 department epidemiology and biostatistics, public health faculty, sam ratulangi university, manado, indonesia 6 division of pediatric surgery, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia; 7 department of surgery, faculty of medicine, sam ratulangi university, manado, indonesia; 8 siloam hospital, manado, indonesia; 9 department of surgery, faculty of medicine, hasanuddin university hasanuddin university hospital, makassar, indonesia. doi: 10.4081/aiua.2025.13342 summary key words: hypospadias; urethroplasty; hyperbaric oxygen therapy; vascular endothelial growth factor. submitted 4 november 2024; accepted 3 january 2025 archivio italiano di urologia e andrologia 2025; 97(1):13342 m. hatibie oley, m. christian oley, a. astram adhiatma iskandar, et al. 2 of inflammation, and inhibition of leukocyte adhesion to endothelium. this correlates with increased wound healing, damaged tissue regeneration, and fibroblast scar tissue remodeling (3). various reports state that wound healing accelerated with hyperbaric oxygen, including hypospadias reconstructive surgery scars, by increasing the vascular endothelial growth factor (vegf) stimulation of angiogenesis through proliferation. neheman et al. (4) evaluated the use of hbot to increase the success rate of staged tubularized autograft (stag) repair in repeatedly failed correction cases. they showed that hyperbaric adjuvant therapy in a pediatric population improved the result of previously failed hypospadias surgery and led to better graft uptake. chang et al. (5) also used hbot as an adjuvant therapy for hypospadias patients undergoing two-stage correction using buccal mucosal grafts to repair glans penis dehiscence and urethroplasty for urethral strictures after hypospadias correction. they obtained successful outcomes in these cases with hbot administration. the optimum scoring system for cosmetic outcomes following hypospadias surgery should be an objective, repeatable, and validated tool measuring each relevant and surgically correctable component of the hypospadias (6). the hypospadias objective penile evaluation (hope) score has good validity and reliability, which supports its use as an objective indicator of cosmetic appearance following hypospadias surgery (6-9). the increase in hypospadias cases and the use of hbot, which plays a role in the wound healing process, has led researchers to examine the effect of hbot on the success of hypospadias surgery. this study aimed to measure the effectivity of hbot based on the serum vegf level and hope score in patients after hypospadias reconstruction. methods this was a randomized controlled trial study conducted between december 2021 and december 2022, and conducted per consort guideline 2010 (10). the data collection and processing were performed at r.d. kandou hospital and siloam manado hospital. the study population inclusion criteria were patients with all types of hypospadias who would undergo surgery and were willing to be participants in the research. we excluded patients with tympanic perforation, endocranial implants, or hearing problems; patients with epilepsy or other types of seizures; patients in chemotherapy; patients with alcoholism or users of psychoactive drugs; heart pacemaker users; patients with claustrophobia or other psychiatric problems; patients with uncontrolled hypertension, heart failure, respiratory failure, pneumothorax, or asthma; and non-cooperative patients. urethroplasty procedure the control and hbot groups both underwent surgery for hypospadias. distal, middle, and proximal hypospadias were all repaired using a modified two-stage urethroplasty: the sidik-chaula technique. an additional approximation of the bilateral subgranular flap, called the manset flap, which is especially useful in cases of middle hypospadias, was also used (11). hbot group patients in the hbot group received standard wound dressings, as did the control group. additionally, they underwent one session of 100% oxygen therapy within 24 hours postoperatively, for 5 consecutive days. each hbot session lasted 30-60 minutes and was administered at 2.4 atm. control group the control group received only standard wound dressings, changed every 2 days with moist sterile gauze, and a 5-day course of oral broad-spectrum antibiotics. outcome the primary outcomes include differences in vegf levels and hope scores before and after hyperbaric oxygen therapy (hbot). secondary outcomes were the assessment of baseline characteristics of hypospadia repair patients and the number of hbot sessions required to significantly impact vegf levels and hope scores. vegf examination in the control group, vegf serum levels were measured once, 1 hour after the operation. in the hbot group, vegf serum levels were measured 1 hour after each of the 5 hbot sessions (hbot 1, 2, 3, 4, and 5), with a blood sample taken after every session. the vegf serum levels were measured in guanidium thiocyanate l6 buffer. the samples were centrifuged for 60 minutes until coagulated, then kept in a -80 ºc container until analysis. all samples were examined using the human vegf elisa kit protocol of the simplestep elisa kit from assaygenie human vegf-a with catalog no. hues01397. the results are expressed in ng/ml. hope score the hope score was assessed at the bedside by the attending physician, consisting of six items: the position of the meatus, the shape of the meatus, the shape of the glans, the shape of the penile skin, and the shape of the penile axis including penile torsion and (if erection was observed) penile curvature. the possible hope scores range from 1 to 10 (12). a standardized photograph was taken pre-operatively (under general anesthesia) and six months post operative. two researchers individually assessed the hope score of the patients based on the photograph taken, without knowing the patient's identity. the final hope score was taken from mean hope score from both assessors. randomization the participants were randomly and equally divided into hbot and control group using a computer sequence generator. patients in the hbot group were allocated to a multichamber hyperbaric unit; therefore, patient blinding was not possible. however, the patients' identities were blinded to the author responsible for allocation, as well as to the assessor who evaluated the hope score preoperatively and the assessor who assessed the hope score postoperatively. statistical analysis univariate evaluation was carried out according to the archivio italiano di urologia e andrologia 2025; 97(1):13342 3 hyperbaric oxygen therapy and hypospadias reconstruction type of variable: numeric or categorical. the descriptive tabulation of numeric variables is shown as mean, range, and standard deviation. the distribution normality was assessed by the shapiro-wilk test. the difference between the two groups in vegf levels was tested with the independent t-test and mann-whitney test. results are shown for fixed effects in the form of estimates of 95% confidence interval (ci) and p-value. the statistical analysis was carried out with spss version 28 (armonk, ny, usa: ibm corp.) and r software version 3.5.1, assisted by the use of microsoft excel spreadsheets. results kandou hospital had 20 cases of hypospadias repair within 1 year. ten were treated with hbot as an adjuvant treatment, and the other half had conventional post-operation procedures. the patient characteristics are shown in table 1. the mean age of the participants was 12.6 years (sd 7.3), ranging from 2 to 32 years old. the most common type of hypospadias found was subcoronal (35%), and the least frequent was scrotal (5%). the comparison of vgef serum levels between the control and hbot groups 1 hour after hypospadias reconstruction is shown in table 2. the mean serum vegf level of the control group was 394.49 ± 107.88 ng/ml. significant increases in serum vegf levels were observed in the patients given three (mean difference [md]=122.0, p = 0.038, 95% ci 7.74236.26), four (md 223.6, p = 0.002, 95% ci 94.92352.27), and five (md 292.71, p = 0.008, 95% ci 90.13495.30) hbot sessions. overall, the patients in the control group had a lower mean vegf level compared to the hbot group, regardless of the number of sessions. although not significant, a slight increase also occurred in serum vegf levels after the first (md 1.73) and second (md 54.00) hbot sessions. importantly, the concentration of serum vegf constantly increased after each session of hbot, despite the wide range of 95% ci. ten participants came for follow-up and assessment of the hope score. the difference in hope scores between both groups is shown in table 3. a significant difference in favor of the hbot group was found in penile torsion (p = 0.006) and total hope score (p = 0.014). further, the hbot group had a higher mean score for all six item variables. discussion a total of 20 patients who met the inclusion criteria and were willing to participate in the study were divided equally into the control and hbot groups. however, only five patients in the control group and five patients in the hbot treatment group attended follow-up to assess the hope score. the minimum age of the subjects participating in our study was 3 years and the maximum age was 32 years, with an average age of 12.6 years. if detected early, hypospadias can be corrected surgically at 6 to 18 months of age, depending on the severity (13). no standard age exists for hypospadias repair surgery although if it is performed too early, the penis may be too table 1. baseline characteristics of the study population. parameter control hbot total (n = 10) (n = 10) (n = 20) age (years) (mean ± sd) 7.7 ± 3.0 17.4 ± 7.1 12.6 ± 7.3 age (years) (range) 8 (3–11) 20 (12–32) 29 (3–32) type of hypospadias subcoronal [n (%)] 4 (40.0) 3 (30.0) 7 (35) glandular [n (%)] 2 (20.0) 2 (20.0) 4 (20) distal penile [n (%)] 1 (10.0) 1 (10.0) 2 (10) midshaft penile [n (%)] 1 (10.0) 1 (10.0) 2 (10) proximal penile [n (%)] 1 (10.0) 1 (10.0) 2 (10) penoscrotal [n (%)] 1 (10.0) 1 (10.0) 2 (10) scrotal [n (%)] 0 (0.0) 1 (10.0) 1 (5) hbot: hyperbaric oxygen therapy; sd: standard deviation. table 3. hypospadias objective penile evaluation (hope) scores of hypospadias repair patients. variable n control hbot p-value (mean ± sd) (mean ± sd) position of meatus 5 4.4 ± 2.6 5.0 ± 4.6 0.500 shape of meatus 5 5.8 ± 3.4 7.0 ± 3.7 0.304 shape of glans 5 6.4 ± 3.9 7.6 ± 2.5 0.290 shape of penile skin 5 5.8 ± 3.4 8.8 ± 2.6 0.058 penile torsion 5 4.0 ± 3.0 9.4 ± 1.3 0.006 erection curvature 5 6.4 ± 2.5 7.0 ± 3.7 0.386 total score 5 32.6 ± 8.6 44.8 ± 8.7 0.028 hbot: hyperbaric oxygen therapy; sd: standard deviation; significant if p < 0.05. table 2. serum vascular endothelial growth factor (vegf) of hypospadias repair patients. group n mean ± sd p-value mean diff 95% ci (ng/ml) lower upper before surgery 10 396.27 ± 84.62 after surgery 10 387.74 ± 76.20 control 10 394.49 ± 107.88 0.972 1.73 -99.45 102.91 hbot 1 10 448.49 ± 88.68 control 10 394.49 ± 107.88 0.237 54.00 38.78 146.78 hbot 2 10 448.49 ± 88.68 control 10 394.49 ± 107.88 0.038 122.00 7.74 236.26 hbot 3 10 516.49 ± 133.94 control 10 394.49 ± 107.88 0.002 223.60 94.92 352.27 hbot 4 7 618.09 ± 141.63 control 10 394.49 ± 107.88 0.008 292.71 90.13 495.30 hbot 5 4 687.20 ± 252.75 hbot: hyperbaric oxygen therapy; sd: standard deviation; ng: nanogram; ml: milliliter; ci: confidence interval. archivio italiano di urologia e andrologia 2025; 97(1):13342 m. hatibie oley, m. christian oley, a. astram adhiatma iskandar, et al. 4 small and cause technical difficulties. some studies suggest that patients should take testosterone supplements until the penis size is sufficient to operate. however, this method is not supported by strong evidence (14). performing surgery at an early age is more beneficial in terms of psychology because patients tend not to remember their previous condition, so their body image is more positive. in addition, surgery at an older age is associated with more complications due to increased urethral secretions and nocturnal erections (15). several similar studies have recorded younger ages at surgery than the present study, such as kocherov et al. (29.4 months), nabil et al. (17 months), and shenoy et al. (50.4 months) (16-18). our study presented a significant difference of age between the hbot group (17.4 years) and the control group (7.7 years), which complicates result interpretation. older participants may exhibit different biological responses, while younger ones face surgical challenges. these differences, due to randomization in a small sample size, represent a key limitation of the study. the type of hypospadias in this study was most often subcoronal (35%), followed by penile (30%) and glandular (20%), and the least common was posterior (15%). this is in accordance with the theory that states that almost 50% of cases are anterior, 20% are penile, and the rest are posterior. overall, the subcoronal position is the most common for hypospadias (19, 20). conditions of oxygen deprivation in tissues often occur after hypospadias reconstruction surgery due to the large number of incisions and flaps on a relatively small area. the placement of skin flaps in hypospadias repair surgery usually requires flap rotation, thus damaging the vascularization of epithelium and inducing vascular spasm in it. vasospasm is thought to be the main trigger of flap ischemia. tissue hypoxic conditions complicate the healing process, reduce the success rate of surgery, and increase postoperative complications (21). hbot is a therapeutic modality to improve tissue hypoxic conditions by increasing oxygen supply to damaged tissues. naturally, the process of angiogenesis occurs due to stimulation of the release of growth factors, cytokinases, and lipid mediators produced during injury. one of the proangiogenesis mediators is vegf. hbot helps accelerate the process of angiogenesis characterized by an increase in vegf, which causes an acceleration of the wound healing process (3, 4). our study found that vegf levels in patients who underwent hbot were higher than in the control group (394.49 ± 107.88 pg/ml). notably, the gradual increase in vegf levels was directly proportional to the number of hbot sessions given to patients. the vegf level was 392.76 ± 107.50 pg/ml after the first hbot session, 448.49 ± 88.68 pg/dl after the second hbot session, 516.49 ± 133.94 pg/ml after the third hbot session, 618.09 ± 141.63 pg/dl after the fourth session, and 687.20 ± 687.20 pg/dl after the fifth session. a significant increase in vegf (p < 0.05) was found after the third (p = 0.038), fourth (p = 0.002), and fifth (p = 0.008) hbot sessions. the results of this study support previous research by oley et al., who conducted a study on crush injury patients, who were divided into hbot and placebo treatment groups. vegf levels in the hbot group were 1,505.9 ng/ml and higher that in patients undergoing debridement only. similarly, vegf mrna expression was 1.2-fold higher in the group receiving hbot therapy (22). a study by chang et al. on patients who underwent repair of recurrent hypospadias found that the group treated with 2% nitroglycerin and hbot had a higher success rate (88.8%) compared to the group only given 2% nitroglycerin (69.6%). fewer complications were found in the hbot group than in the control group (5). hypospadias reconstructive surgery aims to improve functional and cosmetic outcomes for patient satisfaction. the hope scoring system objectively evaluates hypospadias surgery outcomes, including complications, cosmetic appearance, and function (12). however, the system has limitations, such as the lack of perioperative assessment of hypospadias severity (23). this study found that the hbot group had a significantly better outcome in terms of penile torsion and total hope score compared to the control group. the p-value for both of these findings was less than 0.05, indicating that the differences were statistically significant. this suggests that hbot may have a positive effect on the clinical appearance of the wound after hypospadias reconstructive surgery. patients who received hbot had better cosmetic appearance for meatal torsion variable and the total hope score. complication rates are high for hypospadias reconstructive surgery, with nearly 40% of surgeries being repeat operations performed to improve cosmetic results. risk factors include scar tissue, ischemic tissue, negligence in surgical technique, improper sutures, improper suture tension, hematoma, and infection (24). wound healing has four phases, with chronic tissue hypoxia disrupting the balance of collagen secretion and causing hypertrophy of scar tissue, resulting in wound deformities (25). another study found that the neovascularization of tissue through the process of hbot, characterized by an increase in vegf, resulted in faster wound healing, avoiding the formation of scar tissue and keloids (26-29). the study demonstrates that hbot accelerated wound healing after urethroplasty by increasing serum vegf levels. however, the study has some limitations, including the relatively high rate of loss to follow-up (50%) for the hope score evaluation (due to the covid-19 pandemic situation). the study also did not include measurement of the vegf level before each hbot session, so we do not know exactly how much the vegf level increased after each hbot session. future work with larger studies is required to determine the exact mechanism of action, with a 2-month post-operation follow-up to measure the clinical and functional outcomes. conclusions this study demonstrated that hbot accelerated wound healing after urethroplasty by increasing the serum vegf level. three or more hbot sessions are recommended after hypospadias repair. archivio italiano di urologia e andrologia 2025; 97(1):13342 5 hyperbaric oxygen therapy and hypospadias reconstruction references 1. turkyilmaz z, karabulut r, atan a, sonmez k. redo hypospadias repair: comparison of three different methods. urol int. 2020; 104:391-5. 2. snodgrass w, bush n. staged tubularized autograft repair for primary proximal hypospadias with 30-degree or greater ventral curvature. j 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anand s, lotfollahzadeh s. hypospadias urogenital reconstruction. 2023 jun 3. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2024. 14. ahmad r, chana r, ali s, khan s. role of parenteral testosterone in hypospadias: a study from a teaching hospital in india. urol ann. 2011; 3:138. 15. skarin nordenvall a, norrby c, butwicka a, et al. nishimura w, editor. psychosocial outcomes in adult men born with hypospadias: a register-based study. plos one. 2017; 12:e0174923. 16. kocherov s, lev g, chertin b. use of bioglue surgical adhesive in hypospadias repair. curr urol. 2014; 7:132-5. 17. shenoy ns, tiwari c, gandhi s, et al. efficacy of fibrin sealant as waterproof cover in improving outcome in hypospadias surgery. afr j paediatr surg. india; 2021; 18:215-8. 18. sultan ta, faktry ta, nabil a, shenishn mz. prospective comparative study of hypospadias surgical repair with and without the use of fibrin sealant. international surgery journal. 2019; 6:2722. 19. atici a, celikkaya m, el c, akcora b. results of surgery performed on 151 patients of hypospadias: single center experience. the ulutas medical journal. 2019; 5:48. 20. donaire ae, mendez md. hypospadias. 2023 jul 31. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2024. 21. appeadu-mensah w, hesse aj, glover-addy h, et al. complications of hypospadias surgery: experience in a tertiary hospital of a developing country. afr j paediatr surg. 2015; 12:211. 22. oley mh, oley mc, noersasongko ad, et al. effects of hyperbaric oxygen therapy on vascular endothelial growth factor protein and mrna in crush injury patients: a randomized controlled trial study. international journal of surgery open. 2021; 29:33-9. 23. springer a. assessment of outcome in hypospadias surgery a review. front pediatr. 2014; 2:2. 24. agrawal k, misra a. unfavourable results in hypospadias. indian journal of plastic surgery. 2013; 46:419. 25. hong wx, hu ms, esquivel m, et al. the role of hypoxiainducible factor in wound healing. adv wound care (new rochelle). 2014; 3:390-9. 26. xue m, jackson cj. extracellular matrix reorganization during wound healing and its impact on abnormal scarring. adv wound care (new rochelle). 2015; 4:119-36. 27. liu z-j, velazquez oc. angiogenesis in wound healing. in: da dartt (ed)encyclopedia of the eye. academicc press 2010, pp 99105. declarations ethical approval: this protocol was approved by the institutional review board at our institution (no. 149/ec/kepkkandou/ix/2021). all procedures involving human participants were performed in accordance with the ethical standards of the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent was obtained from all child's parents or guardians participants included in the study. availability of data and material: the datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. competing interests: the authors declare that they have no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not forprofit sectors. authors' contributions: all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. acknowledgments: we acknowledge fred van der toorn et al. for the development of the hope score. archivio italiano di urologia e andrologia 2025; 97(1):13342 m. hatibie oley, m. christian oley, a. astram adhiatma iskandar, et al. 6 28. peña-villalobos i, casanova-maldonado i, lois p, et al. hyperbaric oxygen increases stem cell proliferation, angiogenesis and wound-healing ability of wj-mscs in diabetic mice. front physiol. 2018; 9:995. 29. shams f, moravvej h, hosseinzadeh s, et al. overexpression of vegf in dermal fibroblast cells accelerates the angiogenesis and wound healing function: in vitro and in vivo studies. sci rep. 2022; 12:18529. correspondence mendy hatibie oley (corresponding author) mendy.hatibie@unsrat.ac.id division of plastic reconstructive and aesthetic surgery, department of surgery, faculty of medicine, sam ratulangi university, jalan raya tanawangko no.56, malalayang satu barat, malalayang, manado, north sulawesi, 95162, indonesia maximillian christian oley max_oley@unsrat.ac.id division of neurosurgery, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia ari astram adhiatma iskandar ari.astram.urologi@dosenlb.unsrat.ac.id division of urology, department of surgery, faculty of medicine, sam ratulangi university r.d. kandou hospital, manado, indonesia chaula luthfia sukasah chaula.luthfia@ui.ac.id indri aulia drindriaulia@gmail.com division of plastic reconstructive and aesthetic surgery, department of surgery, faculty of medicine, universitas indonesia dr. cipto mangunkusumo hospital, jakarta, indonesia fima lanra fredrik g. langi flangi2@unsrat.ac.id department epidemiology and biostatistics, public health faculty, sam ratulangi university, manado, indonesia harsali fransicus lampus harsali_lampus@unsrat.ac.id division of pediatric surgery, department of surgery, faculty of medicine, sam ratulangi university r. d. kandou hospital, manado, indonesia irawan sukarno drirawan120@gmail.com department of surgery, faculty of medicine, sam ratulangi university, manado, indonesia vania sukarno vaniasung03@gmail.com siloam hospital, manado, indonesia muhammad faruk muhammadfaruk@unhas.ac.id department of surgery, faculty of medicine, hasanuddin university hasanuddin university hospital, makassar, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13379 1 original paper introduction genital lichen sclerosus (gls) is a chronic inflammatory skin disease with subsequent fibrosis causing the late complications. it most commonly occurs in the anogenital region and it is responsible for sexual dysfunction and urological morbidity. the precise etiopathogenesis of gls remains controversial, (1) although genetic, autoimmune (2) and infective (such as human papillomavirus hpv) factors have been implicated. the koebner phenomenon describes the development of lesions in previously normal skin after scratching or from areas that have undergone trauma (3-5). in men occur on the glans penis or foreskin (6). frenulum is a particular target manifesting sclerosis or complete obliteration, constrictive lichenoid posthitis is commonly seen associated with a fibrotic preputial band causing “hourglass” wasting of the penile shaft. women may develop scarring of the labia minora, labia majora and the clitoris (7). the spectrum of presentation is very wide, ranging from asymptomatic condition to disabling urinary and sexual symptoms such as itching, burning, bleeding, splitting, dysuria, and pain associated with sexual activity (7, 8) which may reduce quality of life (qol) (9-11). gls can increase anxiety and stress having a negative impact on the overall mental health (12). gls can occur at any age and in both sexes. the male-tofemale ratio varies between 1:3 and 1:10 (13). the prevalence is approximately 1.7% in females (13) and 0.07% in males (14) although the exact prevalence is unknown. it’s probably under-estimated; since a third of cases are asymptomatic (13), furthermore it is managed by many specialties as well as there’s a significant under-recognition and hence under-reporting by patients and physicians. the literaure available on its prevalence and the introduction: genital lichen sclerosus (gls) is a chronic inflammatory disease due to autoimmune events that occurs in anogenital region. it seems to affect mostly women but both the etiology and the prevalence of the disease are largely unknown. the aim of this cross-sectional study was to examine the real-world diagnostic and therapeutic experiences of patients with gls, focusing on their perceptions and expectations regarding disease management. methods: utilizing google forms, we developed a questionnaire consisting of 10 items aimed at examining the diagnostic and therapeutic experiences of patients with gls. this survey was distributed via email to all members of the italian association of patients with lichen sclerosus (lisclea), which includes 564 female and 216 male members. the survey was accessible for a period of 48 hours in february 2020. results: of the 780 members surveyed, 280 (36.3% response rate) completed the questionnaire, comprising 226 females (80.7%), 53 males (18.9%), and 1 respondent (0.4%) who did not declared her/his gender identity. a significant 34% of respondents waited over five years for a correct diagnosis of gls. diagnostic challenges were frequently reported, with a majority (78%) believing that doctors’ knowledge about ls is inadequate. moreover, 63.9% expressed a need for better medical training concerning gls, supported by calls for more research networks (42.5%) and specialized centers (26.1%). gls had a severe impact on sexual health and relationships; 57.3% reported anxiety due to gls, and 39% avoided intercourse because of symptoms like pain and discomfort. the majority (95%) received local treatments, while a small percentage (5%) underwent surgical interventions such as circumcision. the diagnostic and therapeutic process was perceived as difficult by most patients (82%). conclusions: gls profoundly affects patients' quality of life, causing significant anxiety, discomfort, and often hindering sexual activity. the study highlights the commonality of late diagnoses and the insufficient referral of patients to specialists, underscoring the need for greater awareness and expertise among healthcare providers. enhancing doctor awareness and knowledge could facilitate earlier diagnosis and more effective management of gls, thereby improving outcomes for those affected by this debilitating condition. this research advocates urgent enhancement in both medical education regarding gls what is the diagnostic process experience of patients with genital lichen? an italian survey stefano lauretti 1, michele rizzo 2, lorena di marco 2, luca braulin 2, enzo maria f. palminteri 3, marco bitelli 4, muriel rouffaneau 5, tommaso cai 6, giovanni liguori 2, alessandro palmieri 7 1 santa caterina della rosa clinic, department of urology, rome, italy; 2 urological clinic, department of medicine and surgery, university of trieste, italy; 3 center for urethral and genitalia reconstructive surgery, arezzo, italy; 4 department of urology andrology unit, ospedale san sebastiano martire, frascati, italy; 5 lisclea association, rome, italy; 6 department of urology, santa chiara regional hospital, trento, italy; 7 department of urology, federico ii university, naples, italy. doi: 10.4081/aiua.2025.13379 summary and the establishment of more specialized care pathways to better address the complexities of this disease. key words: genital; penile; lichen; sclerosus. submitted 18 november 2024; accepted 23 november 2024 archivio italiano di urologia e andrologia 2025; 97(2):13379 s. lauretti, m. rizzo, l. di marco, et al. 2 patients’ real-life experiences are lacking and limited because many studies evaluated patients based on diagnosis alone (9). to address the knowledge gap of these topics, it would be necessary to investigate the impact of gls on qof and patient's perception regarding their diagnostic-therapeutic process. the goal of this cross-sectional study is to collect data from persons having or that had a gls about their diagnostic and therapeutic experiences evaluating the need to implement the management of these patients. materials and methods this cross-sectional study was conducted in collaboration with lisclea, an italian patient association that supports individuals affected by gls and their caregivers. lisclea provides a web platform filled with quality information for managing the disease. a structured questionnaire was developed using google forms. the questionnaire consisted of 10 close-ended questions designed to gather demographic data (age, sex, geographic area within italy), clinical symptoms, patients’ perspectives on their diagnostic and therapeutic experiences, and perceptions of doctors' awareness about gls. the survey targeted 780 lisclea members who were either currently living with or had previously experienced gls. recruitment was facilitated through the association's website, mailing list, and whatsapp group. participants were informed about the survey’s purpose, the voluntary and anonymous nature of their participation, and the confidentiality of the responses. to ensure data integrity, the survey system allowed only one response per digital identity. the survey was made available for 48 hours during february 2020 and was presented in italian, the native language of the participants. the questionnaire format included predominantly dichotomous or multiple-choice questions, measuring responses at nominal, categorical, and interval levels. results a total of 280 questionnaires were returned from the 780 distributed, achieving a response rate of 36.3%. not all participants answered every question, and minors reported being assisted by caregivers, in filling out the questionnaire. the respondents comprised 226 females (80.7%), 53 males (18.9%), and one individual (0.4%) who did not declare her/his gender identity, as shown in table 1. regarding diagnostic delays, 34% (95/280) of participants reported waiting more than five years from the onset of symptoms to receiving a correct diagnosis of gls. treatment approaches varied, with 95% (265/280) receiving local treatments and 5% (15/280) undergoing surgical procedures such as circumcision. a significant concern among the participants was the perceived inadequacy of doctors' knowledge about gls, noted by 78% (219/280) of respondents. the impact of gls on quality of life was notably severe, with 57.3% (161/280) reporting anxiety due to the condition and 39% (109/280) avoiding intercourse because of pain, discomfort, bleeding, and itching. additionally, 21% (59/280) cited specific anxiety related to their condition. the diagnostic and therapeutic processes were considered difficult by most respondents, 30% (84/280) found it very difficult, 29% (81/280) difficult, and 23% (65/280) quite difficult, while only 17.1% (48/280) rated it as quite easy or easy. there was a strong call for better preparation among doctors, with 63.9% (179/280) advocating for improved medical training, supported by the need for new research networks (42.5%, 119/280) and specialized centers (26.1%, 73/280). discussion this cross-sectional study clearly shows the criticism for patients with gls to receive appropriate management. according to the study results, less than 20% of patients with ls of genitalia had a diagnosis within 6 months from the onset of symptoms while most of responders waited years (15), as shown in table 2. furthermore 80% of responders have the perception that medical culture on gls is suboptimal. despite the benign nature, the gls have an insidious course that determines serious urological and sexual morbidities. in our study more than 98% of responders reported local symptoms such as itching and discomfort and the 39% assessed that gls made penetrative intercourse impossible. probably, table 2. time elapsed from the first onset of symptoms to the correct diagnosis of patients. time needed for the diagnosis. < 6 6-12 12-36 36-60 > 60 non total months months months months months months declared patient gender female n (%) 33 (12%) 12 (4.3%) 62 (22%) 38 (14%) 81 (29%) \ 226 (80.7%) male n (%) 9 (3.2%) 6 (2.1%) 21 (7.5%) 3 (1.1%) 14 (5%) 53 (18.9%) gender not declared \ \ \ \ \ 1 (0.4%) 1 (0.4%) total n (%) 42 (15%) 18 (6.4%) 83 (30%) 41 (14.6%) 95 (34%) 2 (0.7%) 280 (100%) table 1. distribution of patients by age and gender. age of responders years < 18 18-30 31-50 51-70 > 70 total patient gender female n (%) 18 (6.4%) 6 (2.1%) 71 (25.4%) 123 (44%) 8 (2.9%) 226 (80.7%) male n (%) 6 (2.1%) 9 (3.2%) 27 (9.6%) 11 (3.9%) \ 53 (18.9%) gender not declared \ \ \ 1 (0.4%) \ 1 (0.4%) total n (%) 24 (8.6%) 15 (5.4%) 98 (35%) 134 (48%) 8 (2.9%) 280 (100%) archivio italiano di urologia e andrologia 2025; 97(2):13379 3 diagnosis of genital lichen the remarkably high impact of gls on sexual health and quality of life is partly due to a selection bias. since other studies investigating the burden of gls in national populations are lacking, our results are difficult to compare. of course, the study is not devoid of limitations. the population studied is composed of people that joined a patient’s association probably because the impact of gls in their life. the high number of non-responders was maybe due to the short time the survey was available. however, the 95 patients that waited 5 years before being diagnosed with genital ls correspond to 34% of responders and to the 12% of all the lisclea members. this data is important by itself because it underlines that a considerable number of patients were not able to be correctly diagnosed for a very long period. of note, gls changes the genitalia architecture in a time dependent mode. cooper et al. showed in their study of 327 women that a delay in diagnosis of 2 years or less was associated with less scarring at diagnosis (16). if we considered that clinical diagnosis of gls date back to the mid-twentieth century and could be suspected with a simple medical examination of genitalia (17) it seems clear that the disease is not recognized because it is not known by physicians. treatment options for gls are various and range from pharmacological to surgical (18), depending on patient factors, the response of previous treatments, the severity and location of disease (19). proper care can lead to recovery from the disease symptoms however it is crystal clear that any treatment could be given till the correct diagnosis is done. the ability of the survey receiver to understand and answer the questions was not demonstrated, however the questions were very simples and expressed in the mother tongue of the investigated population. since patients are increasingly actively involved in health care and patient empowerment in the health system is becoming reality, surveys help health care professionals to gather meaningful data that can improve management of diseases. the present study clearly indicated the need to implement the diagnostic and therapeutic process of patients with gls in italy. this would ultimately permit us to better understand the real disease burden of and its impact on patients’ quality of life. conclusions this study highlights significant gaps in diagnosing and managing gls, affecting patients' sexual and psychological well-being. with less than 20% of patients diagnosed within six months of symptom onset and 80% finding the medical community's knowledge insufficient, there is a clear need for improved education and training for healthcare providers. the severe consequences of delayed diagnosis necessitate urgent improvements in the diagnostic process and a shift towards more patient-centered management strategies. to address these issues, it is crucial to develop comprehensive, multidisciplinary approaches that include targeted educational initiatives, expanded research, and specialized centers. this will help mitigate the disease's impact and move towards a more informed and proactive healthcare framework for gls patients. table 3. details about the healthcare professionals who performed the diagnoses. who performed gynecologist dermatologist self diagnosis plastic general urologist andrologist non healt-care total the diagnosis using internet surgeon practicer professional patients gender female n (%) 137 (49%) 62 (22%) 11 (3.9%) 4 (1.4%) 2 (0.7%) \ \ 10 (3.6%) 226 (80.7%) male n (%) \ 25 (8.9%) 5 (1.8%) 4 (1.4%) 2 (0.7%) 11 (3.9%) 2 (0.7%) 4 (1.4%) 53 (18.9%) gender non declared 1 (0.4%) \ \ \ \ \ \ \ 1 (0.4%) total n (%) 138 (49%) 87 31%) 16 (5.7%) 8 (2.9%) 4 (1.4%) 11 (3.9%) 2 (0.7%) 14 (5%) 280 (100%) declarations ethical approval: all procedures conducted in this study complied with the institution and national research committee's ethical standards, the 1964 declaration of helsinki, and its subsequent amendments or equivalent ethical standards. participants were informed about the survey’s purpose, the voluntary and anonymous nature of their participation, and the confidentiality of the responses. availability of data and material: the data that support the study's findings are available from lisclea, but there are restrictions on their availability because they were used under license for the current study and thus are not publicly available. however, the authors' data are available upon reasonable request and with the permission of lisclea. competing interests: the authors declare that they have no competing interests. funding: there is no source of funding for the research reported. authors' contributions: sl, study concept, data analysis and interpretation, manuscript original drafting, statistical analyses; mr, data analysis and interpretation, contribution to manuscript writing and editing; ldm, data analysis and interpretation, contribution to manuscript writing and editing; lb, data analysis and interpretation, contribution to manuscript writing and editing; ep, data analysis and interpretation, contribution to manuscript writing and editing; mb, data analysis and interpretation, contribution to manuscript writing and editing; mr, data analysis and interpretation, contribution to manuscript writing and editing; tc, data analysis and interpretation, contribution to manuscript writing and editing; gl, study concept, data analysis and interpretation, contribution to manuscript writing and editing; ap, study concept, data analysis and interpretation, manuscript original drafting, statistical analyses all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13379 s. lauretti, m. rizzo, l. di marco, et al. 4 references 1. fergus kb, lee aw, baradaran n, et al. pathophysiology, clinical manifestations, and treatment of lichen sclerosus: a systematic review. urology 2020; 135:11-19. 2. howard a, dean d, cooper s, et al. circulating basement membrane zone antibodies are found in lichen sclerosus of the vulva. australas j dermatol 2004; 45:12-15. 3. miller raw. the koebner phenomenon. int j dermatol 1982; 21:192-197. 4. zhang x, lei l, jiang l, et al. characteristics and pathogenesis of koebner phenomenon. exp dermatol 2023; 32:310-323. 5. wallace hj. lichen sclerosus et atrophicus. trans st johns hosp dermatol soc 1971; 57:9-30. 6. kiss a, király l, kutasy b, merksz m. high incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. pediatr dermatol 2005; 22:305-308. 7. gautam mm, singh v, nadkarni nj, patil sp. anogenital lichen sclerosus. indian j sex transm dis aids 2020; 41:1-9. 8. dalziel kl. effect of lichen sclerosus on sexual function and parturition. j reprod med 1995; 40:351-4. 9. ranum a, pearson dr. the impact of genital lichen sclerosus and lichen planus on quality of life: a review. int j womens dermatol 2022; 8: e042. 10. haefner hk, aldrich nz, dalton vk, et al. the impact of vulvar lichen sclerosus on sexual dysfunction. j womens health 2014; 23:765-770. 11. wu m, kherlopian a, wijaya m, fischer g. quality of life impact and treatment response in vulval disease: comparison of 3 common conditions using the vulval quality of life index. australas j dermatol 2022; 63:4. 12. yıldız s, cengiz h, caia c, et al. evaluation of genital self-image and sexual dysfunction in women with vulvar lichen planus or lichen sclerosus. j psychosom obst gyn 2022; 43:99-106. 13. goldstein at, marinoff sc, christopher k, srodon m. prevalence of vulvar lichen sclerosus in a general gynecology practice. j reprod med 2005; 50:477-80. 14. kizer ws, prarie t, morey af. balanitis xerotica obliterans: epidemiologic distribution in an equal access health care system. south med j 2003, 96:9-11. 15. vyas a. genital lichen sclerosus and its mimics. obstet gynecol clin north am 2017; 44:389-406. 16. cooper sm, gao xh, powell jj, wojnarowska f. does treatment of vulvar lichen sclerosus influence its prognosis?. arch dermatol 2004; 140:702-6. 17. jacques l, kornik r, bennett dd, eschenbach da. diagnosis and management of vulvovaginal lichen planus. obstet gynecol surv 2020; 75:624-635. 18. garaffa g, shabbir m, christopher n, et al. the surgical management of lichen sclerosus of the glans penis: our experience and review of the literature. j sex med 2011; 8:1246-1253. 19. lewis fm, tatnall fm, velangi ss, et al. british association of dermatologists guidelines for the management of lichen sclerosus, 2018. brit j dermatol 2018; 178:839-853. correspondence stefano lauretti lauretti.stefano@aslrmc.it santa caterina della rosa clinic, department of urology, rome, italy michele rizzo mik.rizzo@gmail.com lorena di marco lauren_@hotmail.it luca braulin braulinluca@gmail.com urological clinic, department of medicine and surgery, university of trieste, italy enzo maria filippo palminteri palminteri@centrourologico.it center for urethral and genitalia reconstructive surgery, arezzo, italy marco bitelli marcobitellimd@gmail.com department of urology andrology, ospedale san sebastiano martire, frascati, italy muriel rouffaneau muriellr@mclink.it lisclea association, rome, italy tommaso cai ktommy@libero.it department of urology, santa chiara regional hospital, trento, italy giovanni liguori, md, phd (urol) (corresponding author) gliguori@units.it; giovanni.liguori@asugi.sanita.fvg.it program director, urological clinic, department of medicine and surgery, university of trieste, italy alessandro palmieri info@alessandropalmieri.it department of urology, federico ii university, naples, italy archivio italiano di urologia e andrologia 2025; 97(2):13379 5 diagnosis of genital lichen tempo di raccolta lunedì 10 giovedì 13 febbraio 2020 se non specificato è possibile inserire una sola risposta. 1. lasuaetà è? ❏ > 70 ❏ 51-70 ❏ 31-50 ❏ 18-30 ❏ 0-17 (genitori per i bambini o di supporto per gli adolescenti) 2. lei è ❏ femmina ❏ maschio 3. quanto tempo ha convissuto con il lichen sclerosus prima di avere la diagnosi? ❏ > 5 anni ❏ 1 anno ❏ < di 6 mesi ❏ 2 anni ❏ 3 anni ❏ 5 anni ❏ > 6 mesi ❏ 4 anni 4. in quale regione vive? ❏ lazio ❏ lombardia ❏ veneto ❏ emilia rom. ❏ sicilia ❏ puglia ❏ liguria ❏ toscana ❏ campania ❏ marche ❏ piemonte ❏ sardegna ❏ abruzzo ❏ friuli vg ❏ calabria ❏ umbria ❏ basilicata ❏ trentino ❏ molise 5. chi ha fatto per primo la diagnosi? ❏ ginecologo ❏ dermatologo ❏ autodiagnosi ❏ urologo ❏ chir. plastico ❏ altro special. ❏ altro questionario archivio italiano di urologia e andrologia 2025; 97(2):13379 s. lauretti, m. rizzo, l. di marco, et al. 6 ❏ mmg ❏ genitore ❏ andrologo ❏ coniuge 6. supporto da parte dei medici? ❏ scadente ❏ sufficiente ❏ buona ❏ ottima 7. quali tra queste conseguenze legate al lichen sclerosus sono più importanti per lei? (fino a 3 risposte) ❏ prurito ❏ rende impossibile il rapporto ❏ lacerazioni cute ❏ bruciore ❏ ansia ❏ disagio relazionale ❏ dolore ❏ calo del desiderio ❏ altro ❏ sanguinamento ❏ limita fortemente il mio lavoro ❏ mi impedisce di praticare sport 8. come giudicherebbe il suo percorso di diagnosi e cura finora? ❏ abbastanza difficile ❏ difficile ❏ molto difficile ❏ abbastanza semplice ❏ semplice 9. quando le è stata fatta diagnosi di lichen, qual è stato il percorso proposto? ❏ creme a base di cortisone + creme a base di vitamine e altri comp. ❏ creme a base di cortisone ❏ terapia rigenerativa con prp e lipofilling ❏ terapia in crema + terapia orale ❏ mantenere un controllo nel tempo ❏ altro ❏ circoncisione ❏ chirurgia plastica della vulva ❏ di consultare un centro specializzato ❏ dilatazioni uretrali ❏ terapia locale con acido ialuronico 10. quali sono gli aspetti da migliorare più rapidamente? ❏ formazione dei medici sulla patologia ❏ percorsi di ricerca ❏ accessi rapidi nei centri dedicati ❏ centri specializzati ❏ facile identificazione dei centri ❏ maggiore attenzione delle aziende farmaceutiche ❏ facilitazioni sul posto di lavoro per visite e terapie ❏ campagne di formazione e sensibilizzazione ❏ altro stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3370 letter to editor no conflict of interest declared. to the editor, prostate cancer is the second most common cancer in men in morocco after lung cancer. external radiotherapy (rte) is a curative therapeutic option for localized prostate cancer, however the conventional rte remains a long treatment (78 weeks, 5 days a week) which is demanding for patients and make difficult to manage the waiting lists. the development of imaging and irradiation techniques over the last decades has allowed a high precision in the delivery of the dose to the target organ and a better protection of the organs at risk (oar), which has encouraged the hypo fractionated irradiation of localized prostate cancer, especially after the results of radiobiology studies that suggested a low report a/b for the prostate. therefore, several trials have attempted to prove the efficacy and tolerance of hypo fractionated regimens ranging from moderate hypofractionation (20 sessions) to extreme hypofractionation (4-7sessions) called also stereotactic body radiotherapy (sbrt). in fact, it has been demonstrated the same toxicity profile as normo-fractionated (1-3) as well as non-inferiority for tumor control (6, 8-10). advanced technology in radiotherapy like sbrt is still difficult to access in incoming countries, although we have the opportunity to practice this technique in our institution. the aim of our paper is to share our experience and to present our preliminary results in term of toxicity after sbrt of low and intermediate risk prostate cancer. from january 2017 to december 2018, we treated patients with stereotactic radiotherapy at a total dose of 36.25 gy in 5 sessions of 7.25gy. prostatic re-irradiation was excluded. methods all our cases were discussed in multidisciplinary consultation meeting including urologist, oncologist, radiotherapist, radiologist and pathologist and decision of stereotactic radiotherapy was validated. after patient consenting, the team of urology procced to transrectal placement of electromagnetic markers calypso® transponders to follow the prostate during radiotherapy treatment. in fact, the transponders allow a real time tracking of the target as well as a perfect repositioning of the prostate in intrafraction. the placement of the transponders proceeds as fellow: administration of premedication as prescribed by the anesthetist, lithotomy positioning of the patient, transrectal ultrasound in the transverse and sagittal planes, determination of the position by means of three-dimensional probe tracking, intra-prostatic implantation of three transponders (2 at the base and 1 at the apex). after 7-10 days after transponders have been inserted, a simulation scan is performed as follow: rectal and bladder preparation, dorsal decubitus with means of restraint (knee block/foot block), sub-millimetric scan sections. the radiotherapist proceeds to the delineation of the target volumes and organs at risk specially the urethra. target volume received a dose of 3625 cgy in 5 fractions, considering a/b =1.5 and a biological dose equivalent (bed) of 286 gy. the clinical target volume was covered by 100% of the prescribed doses, all organs at risk were delineated and doses constraints were met for all according to sfro recommendations and the tg101 report of the medical physics (4, 5). then the medical physician starts to plan a treatment and finally the best proposition of treatment is validated by the radiotherapist before to initiate the treatment. all patients were treated with the latest generation linear accelerator (true beam stx). calypso was used as tracking system: the electromagnetic antenna of its optical system allowed real time tracking of the target. stereotactic body radiation therapy (sbrt) for prostate cancer: preliminary results of toxicity asmâa naim * 1, 3, safae mansouri * 2, kamal saidi 3, abdeljalil heddat 1, 4, younes elhoury 1, 4, redouane rabii 1, 4 1 mohammed vi university of health sciences (um6ss), morocco; 2 oncology center of meknes, morocco; 3 department of radiotherapy, casablanca cancer center, international hospital cheikh khalifa, casablanca, morocco; 4 department of urology, international hospital cheikh khalifa, casablanca, morocco. * both authors had participated equally to this manuscript. submitted 18 april 2021; accepted 27 april 2021 doi: 10.4081/aiua.2021.3.370 371archivio italiano di urologia e andrologia 2021; 93, 3 stereotactic radiotherapy for prostate cancer biological control increasing doses per fraction may improve the carcinology outcome. in fact, the meta-analysis of zaorsky has shown that when the biological equivalent dose is between 140 gy to 200 gy we have a better tumor control for prostate cancer. it has been also reported that sbrt improved by 12% biological progression free survival (bpfs) (6, 7). phase i-iii trials proved the non-inferiority of sbrt compared to the standard regimen in terms of tumor control and acute and delayed toxicity 8-10]. sbrt is still an option as an alternative for the treatment of low-risk prostate cancer and may be considered for intermediate risks in multi-center trials. in our study, we achieved bed > 200 gy but it is still too early to assess biological control. at 2 years, nine patients were in biological control, two patients died by other diseases: lung cancer and pulmonary embolism. acute toxicity acute toxicity considered any complication occurring within 3 months of the end of irradiation. genitourinary (gu) acute complications were cystitis grade 1 and 2 (with a frequency of 25%); no acute grade 3 gu toxicity was seen. gastrointestinal (gi) acute complications were proctitis grade 1 and 2 (with a frequency of 8.4%); no grade 3 gi toxicity was seen. our results are similar to the literature (11, 12). late toxicity in our preliminary results, no late gi toxicity was detected but we had two cases of urethral stenosis. in jackson's meta-analysis, concerning 6000 patients treated in 38 prospective studies, with two phase iii randomized trials and a median follow-up of at least 5 years, late toxicity grade ≥ 3 gu was 2.2% and gi was 0.8% (12). pan et al. reported similar late gu and gi toxicity but they also observed a significantly higher risk of urinary fistula at 2 years after sbrt (1% vs. 0.1%; p = 0.009) (13). due to the heterogeneity of risk groups, doses and techniques used in different trials, long-term results of further phase iii trials are underway to confirm the current data. trials are open to evaluate sbrt in high-risk prostate cancer (sparc trial /pace c) and others to evaluate fractionation and optimal dose: (patriot) (14, 15). meanwhile, our preliminary results are extremely encouraging in terms of toxicity and local control but we need longer follow up and a larger sample to draw relevant conclusions for this innovative treatment of localized prostate cancer. references 1. katz aj, kang j. quality of life and toxicity after sbrt for organ-confined prostate cancer, a 7-year study. front oncol. 2014; 4:301. 2. widmark a, gunnlaugsson a, beckman l, et al. ultrahypofractionation for prostate cancer: outcome from the scandinavian phase 3 hyport-pc trial. lancet 2019; 394(10196):385-395. 3. van as nj, brand d, tree a, et al. pace: analysis of acute toxicity in pace-b, an international phase iii randomized controlled trial comparing stereotactic body radiotherapy (sbrt) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (cfmhrt) for localized prostate cancer (lpca). j clin oncol. 2019; 37(suppl 7):1-1. 4. noël g, antoni d, barillot i, et al. délinéation des organes à risque et contraintes dosimétriques. cancer/radiothérapie. 2016; 20 suppl:s3660. 5. benedict sh, yenice km, followill d, et al. stereotactic body radiation therapy: the report of tg101. med phys. 2010; 37:4078-101. 6. hoffman ke, voong kr, levy lb, et al. randomized trial of hypofractionated, dose-escalated, intensitymodulated radiation therapy (imrt) versus conventionally fractionated imrt for localized prostate cancer. j clin oncol. 2018; 36:2943-2949. 7. zaorsky ng, palmer jd, hurwitz md, et al. what is the ideal radiotherapy dose to treat prostate cancer? a meta-analysis of biologically equivalent dose escalation radiother oncol. 2015; 115:295-300 8. aluwini s, pos f, schimmel e, et al. hypo fractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (hypro): late toxicity results from a randomized, noninferiority, phase 3 trial. lancet oncol. 2016; 17:464-474 9. dearnaley d, syndikus i, mossop h, et al. conventional versus hypo fractionated high-dose intensitymodulated radiotherapy for prostate cancer: 5year outcomes of the randomized, noninferiority, phase 3 chhip trial. lancet oncol. 2016; 17:1047-1060. 10. hoffman ke, skinner h, pugh tj, et al. patient reported urinary, bowel, and sexual function after hypofractionated intensity-modulated radiation therapy for prostate cancer: results from a randomized trial. j clin oncol. 2018; 41:558-567. 11. madsen bl, hsi ra, pham ht, et al. stereotactic hypofractionated accurate radiotherapy of the prostate (sharp), 33.5 gy in five fractions for localized disease: first clinical trial results. int j radiat oncol biol phys. 2007; 67:1099-105. 12. jackson wc, silva j, hartman he, et al. stereotactic body radiation therapy for localized prostate cancer: a systematic review and metaanalysis of over 6,000 patients treated on prospective studies. int j radiat oncol biol phys. 2019; 104:778-789. 13. pan hy, jiang j, hoffman ke, et al. comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. ,j clin oncol. 2018; 36:1823-1830. 14. morrison k, tree a, khoo v, et al. the pace trial: international randomised study of laparoscopic prostatectomy vs. stereotactic body radioarchivio italiano di urologia e andrologia 2021; 93, 3 a. naim, s. mansouri, k. saidi, a. heddat, y. elhoury, r. rabii 372 therapy (sbrt) and standard radiotherapy vs. sbrt for early stage organconfined prostate cancer. j clin oncol. 2018; 36(suppl 6):tps153tps153. 15. quon hc, ong a, cheung p, et al. once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (patriot): a phase 2 randomized trial. radiother oncol. 2018; 127:206-212. correspondence asmâa naim, md (correspondent author) doc.a.naim@gmail.com hôpital international cheikh khalifa, casablanca (morocco) safae mansouri, md m-safae@hotmail.fr oncology center of meknes, meknes, morocco kamal saidi, medical physicist department of radiotherapy, casablanca cancer center hôpital international cheikh khalifa, casablanca (morocco) abdeljalil heddat, md younes elhour, md redouane rabii, md department of urology, hôpital international cheikh khalifa, casablanca (morocco) stesura seveso 315archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. associated with good outcomes and is the most cost-effective approach to hysterectomy (4). the influence of simple hysterectomy on the lower urinary tract is still debated. however, hysterectomy disrupts the local nerve supply to the pelvic organs and interrupts the anatomical relationship. it has been postulated that the function of the pelvic organs may be adversely affected (5). thus, the function of the pelvic organs, mainly the urinary function, should be considered when deciding the optimum route of hysterectomy (6). urodynamics is a study that assesses the lower urinary tract function and attempts to reproduce the patients' symptoms to provide a pathophysiological explanation. in principle and reality, the clinicians use urodynamic testing results to direct therapy, whether surgical, medical, or behavioral, alone or in combination. some of the current approaches are water-filled, ambulatory, and video urodynamic. urodynamics analyses the functional anatomy of the bladder, urethra, or both, and their reaction to filling, storing, and voiding, regardless of the method used (7). urodynamic testing is essential in urogynecology because it provides objective descriptions of incontinence and voiding dysfunction (8). therefore, the objectives of this study were to analyze the urodynamic changes before and after laparoscopic and vaginal hysterectomy. patients and methods between august 2019 and april 2021, 90 cases presenting to in-patient departments of the authors’ institute were enrolled in this study. the ethics review committee approved the study protocol. all patients signed informed consent forms detailing the operation and potential risks. patients were divided into two groups of equal size: group i: with a mean age of 59.16-year-old (ranging between 51-66), underwent a vaginal hysterectomy. group ii with a mean age of 54.72-year-old (ranging between 47-59) underwent laparoscopic hysterectomy. the route of traditional minimally invasive surgery was chosen by the designated surgeon, with vaginal hysterectomy as the first choice, followed by laparoscopic hysterectomy. our study included all patients undergoing hysterectomy for benign gynecological diseases. we excluded all patients with a history of diabetes mellitus, objective: to compare urodynamic changes before and after hysterectomy (laparoscopic vs. vaginal approach) for benign gynecological diseases. patients and methods: a total of 90 women with a mean age of 56.36-years were enrolled in this study between august 2019 and april 2021. they were divided into two equal groups (45 patients each). group, i had a vaginal hysterectomy, and group ii had a laparoscopic hysterectomy. all patients were assessed clinically using iciq-fluts questionnaire and a urodynamic study before and six months after surgery. results: both vaginal and laparoscopic hysterectomy did not significantly change the maximum flow rate, voiding time, and average flow rate. the increase in residual urine volume in group i was not significant (p = 0.129), as was in group ii (p = 0.217). all the modifications, however, were within permissible limits. according to the cystometry result, volume at initial sensation rose in both groups after surgery, with no statistically significant difference (p = 0.364). after both forms of hysterectomy, maximum bladder capacity did not vary considerably. preoperatively, all study participants exhibited no overactivity of the detrusor muscle; nevertheless, following surgery, overactivity was noted in 9 patients after vaginal hysterectomy compared to three patients after laparoscopic hysterectomy, and all the alterations were within a clinically acceptable range. in addition, the iciq-fluts score was not significantly different between the study groups. conclusions: according to the urodynamic study, hysterectomy for benign uterine conditions, whether vaginal or laparoscopic, did not adversely affect urinary bladder function. key words: hysterectomy; uroflowmetry; urodynamic. submitted 9 june 2022; accepted 23 june 2022 introduction hysterectomy is the most common gynecological surgical operation (1). more than 90% of hysterectomies were done for benign conditions. the most common indication of hysterectomy are leiomyomas and dysfunctional uterine bleeding (2). hysterectomies are performed with different routes, either vaginally, abdominally, or laparoscopically. laparoscopic and vaginal hysterectomy are minimally invasive approaches with short hospitalization time and fast recovery comparable to open abdominal hysterectomy (3). vaginal hysterectomy, when feasible, is urodynamic changes following laparoscopic versus vaginal hysterectomy tamer abouelgreed 1, 2, doaa saleh 3, mohamed abdelaal 1, adel elatreisy 1, mohamed elhelaly 1, el-sayed el-agamy 1, ahmed elgammal 1, ashraf moawad 2, 3 1 department of urology, al-azhar university, cairo, egypt; 2 al zahra private hospital, nmc medical group, uae; 3 department of obstetrics & gynaecology, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2022.3.315 summary archivio italiano di urologia e andrologia 2022; 94, 3 t. abouelgreed, d. saleh, m. abdelaal, a. elatreisy, m. elhelaly, el-sayed el-agamy, a. elgammal, a. moawad 316 neurological disorders, previous urological pelvic surgery, previous caesarian section, and urinary tract infection. all the procedures were carried out while the patient was sedated. a reusable umbilical or 12-mm port (xcel; ethicon endo-surgery, inc., somerville, nj) for the optics and three assistant ports, either three 5-mm or two 5-mm plus one 10-mm port in the lower quadrants, were used for laparoscopic hysterectomy. the vaginal hysterectomy was done conventionally. all study participants were subjected to detailed history taking, complete clinical examination, routine preoperative investigation. iciq-fluts (international consultation on incontinence modular questionnaire on female lower urinary tract symptoms) (9), and urodynamic evaluation (cystometry and uroflowmetry) were obtained before and six months after surgery. statistical analysis data were analyzed using statistical program for social science (spss) version 18.0. quantitative data were expressed as mean ± stander deviation (sd). qualitative data were expressed as frequency and percentage. the following tests were done: independent-samples t-test of significance when comparing two continuous means. paired t-test: t = mean's difference between pre and post. the chi-square (x2) test of significance was applied to compare proportions between two qualitative factors. pearson's correlation coefficient (r) test was employed for data correlation. p-value (probability): statistical significance was defined as less than 0.05, and highly significant was defined as less than 0.01. results demographic data of both groups the cohorts were comparable regarding patients’ demographics (p > 0.05) (table 1). postoperative evaluation of the urinary symptoms in both studies groups post-operative frequency was noticed in 18 and 9 patients of groups 1 and 2 respectively (p = 0.32). urgency occurred in 10 and 6 patients of groups 1 and 2 respectively (p = 0.39). urge incontinence occurred in 9 and 6 patients of groups 1 and 2 respectively (p = 0.37). no other symptoms were noticed in both groups. in group i, the mean preoperative iciq-fluts score was 0.64 (range between 0 and 2, median-0), and the postoperative mean was 1.5 (range between 0 and 6, median = 0) with a significant p-value (p < 0.001). in group ii, the mean preoperative iciq-fluts score was 0.33 (range between 0 and 2, median = 0) and the mean postoperative score was 0.82 (ranged between 0 and 6, median = 0) with a significant p-value (p = 0.014). there was no statistically significant difference between groups 1 and 2 regarding preoperative and postoperative iciq-fluts scores (p = 0.1 & 0.11, respectively). changes in urodynamic parameters in the two studied groups before and after surgery according to results of cystometry, volume at first sensation rose after surgery in both groups, with insignificant p-value between pre-and postoperative volumes (p = 0.372 and p = 0.364) for groups 1 and 2, respectively (table 2). after both forms of hysterectomy, maximum bladder capacity did not vary considerably (table 3). preoperatively, no detrusor muscle overactivity was found in either group; however, after surgery, overactivity was observed in 9 patients in the vaginal hysterectomy group compared to three patients in the laparoscopic hysterectomy group (table 4). changes in uroflowmetry parameters in the two groups before and after surgery: according to uroflowmetry measures, vaginal hysterectomy reduced the maximum flow rate and increased voiding time not significantly and laparoscopic hysterectomy did not affect either. table 1. demographic data of both groups. group i n = 45 group ii n = 45 t-test parameters mean ± sd mean ± sd mean difference t p value age (years) 59.16 3.68 54.72 4.15 2.43 2.402 0.059 weight (kg) 70.02 7.86 69.17 6.92 1.68 0.873 0.388 parity 2.73 0.79 3.10 0.75 -0.07 -0.338 0.734 t = independent t-test. table 3. comparison between group i and group ii as regard cystometric bladder capacity. cystometric bladder group i group ii t-test capacity (ml) mean (ml) ± sd mean (ml) ± sd mean difference t p value pre 518.13 25.32 514.00 25.72 3.33 0.505 0.618 post 477.00 100.19 486.31 65.93 -33.33 1.515 0.297 p value 0.1 0.16 table 2. comparison between group i and group ii as regard first sensation. first sensation group i group ii t-test mean (ml) ± sd mean (ml) ± sd mean difference t p value pre 167.78 24.81 169.43 22.26 -2.00 4.379 0.364 ns post 178.00 14.98 179.90 15.19 -3.50 0.904 0.372 ns p value 0.6 0.67 table 4. relation between group i and group ii as regard post-operative presence of detrusor muscle over activity. post-operative groups total presence of detrusor group i group ii muscle over activity no. % no. % no. % -ve 36 80.00 42 93.33 78 86.667 +ve 9 20.00 3 6.67 12 13.333 total 45 100.00 45 100.00 90 100.000 x2 5.455 p value 0.020 317archivio italiano di urologia e andrologia 2022; 94, 3 urodynamic changes post hysterectomy the laparoscopic group had a higher average flow rate, while the vaginal group had a lower average flow rate (table 5). the increase in residual volume after vaginal hysterectomy was modest (p = 0.129), as was the increase in residual urine after laparoscopic hysterectomy (p = 0.217) (table 6). all the modifications, however, were within permissible limits. changes in preand postoperative abdominal detrusor leak point pressure in both groups no detectable changes in pre-and postoperative abdominal detrusor leak point pressure in group 2. only six patient of group 1 has decreased their postoperative abdominal detrusor leak point pressure to less than 60 cm h2o. discussion to improve life expectancy in women, it is essential to know the long-term adverse outcomes of surgical interventions (10, 11). we designed this study to analyze the effects of laparoscopic versus vaginal hysterectomy on the lower urinary tract symptoms and functions using urodynamic studies and try to detect if the type of operation (whether vaginal or laparoscopic hysterectomy) will affect postoperative lower urinary tract functions or not. the relation between the urinary symptoms and the urodynamic parameters was evaluated pre and postoperatively. many studies compared abdominal and vaginal hysterectomy. polat et al. (2016) (12) underwent a physiological assessment of bladder, urethra, and anorectum on 26 women before hysterectomy, six weeks, and six months afterward. they reported that after a hysterectomy for benign disease, some women experience a considerable increase in rectal and bladder sensitivity. the alterations lasted for six months, but they weren't linked to any changes in rectal or vesical motor activity being not necessarily related to the onset of urinary or gastrointestinal problems. after a total hysterectomy, they ruled out local damage, infection, and edema as plausible causes of the pelvic organs' increased sensitivity. they concluded that the cause of the increase in rectal and vesical sensitivity seen in some women after vaginal and abdominal hysterectomy is unknown; it's possible that removing a major pelvic organ and its related nerve supply changes the gating of sensations from nearby organs. heydari et al. (13) reported no noticeable changes in urinary bladder capacity or urethral functions after the operation. they focused on urodynamic measures before and after abdominal and vaginal hysterectomies. they discovered a statistically significant decrease in maximum cystometric capacity and a decline in bladder compliance following abdominal extra-fascial and vaginal hysterectomies. both findings are linked to a deterioration in the detrusor muscle's musculoelastic characteristics due to edema and surgical damage. however, they concluded that the decrease in capacity and compliance had little clinical significance. they found no evidence that a hysterectomy caused involuntary detrusor contractions or incontinence. after the hysterectomy, urethral competence was unaltered, and there was no rise in stress incontinence. a second study included 36 women undergoing total hysterectomy; preoperative complaints were observed in 58.3% of patients, although only 38.9% had urodynamically confirmed impairment. seventy-five percent of women were symptomatic after hysterectomy, with another 30.6 percent developing a urodynamic abnormality. they concluded that total hysterectomy is linked to a higher subjective and objective incidence of vesicourethral dysfunction (14). el-toukhy et al. did a study that looked at the effects of various hysterectomy procedures, including total abdominal, vaginal, laparoscopic, and subtotal. they looked at 187 women between the ages of 29 and 73 who had a hysterectomy for various reasons. urinary symptoms occurred less frequently (p = 0.01) six months following surgery, whereas urodynamic investigations remained unaltered. furthermore, regardless of the hysterectomy technique employed, the patients reported significantly reduced rates of stress incontinence (p = 0.005) and urgency (p = 0.03) than before the procedure. they concluded that subtotal hysterectomy, whether performed abdominally, vaginally or laparoscopically, has no negative impact on urine function six months following surgery (15). in our study, according to pre-and postoperative urodynamic studies in both groups, all changes were within the clinically acceptable range. thus, we can say that urodynamic studtable 5. uroflowmetry parameters in the two studied groups before and after surgery. group i n = 45 group ii n = 45 prepostprepostoperative operative operative operative voided volume (ml) 264.5 ± 48.7 274.7 ± 60.8 274.8 ± 58.2 284.5 ± 56.9 p value 0.156 0.157 maximum flow rate (ml/sec) 26.4 ± 5.3 24.3 ± 5.2 25.7 ± 4.8 27.2 ± 4.6 p value 0.068 0.069 voiding time (sec) 50.4 ± 11.5 61.1 ± 9.9 48.8 ± 8.6 46.4 ± 9.5 p value 0.059 0.061 average flow rate (ml/sec) 7.5 ± 2.2 6.7 ± 1.3 6.5 ± 1.7 8.8 ± 2.7 p value 0.063 0.067 table 6. residual urine volume in both groups. groups time residual urine paired paired sample of testing volume (ml) differences t-test mean (ml) ± sd mean (ml) ± sd t p value group i pre 54.10 7.58 1.29 4.81 0.129 post 57.32 5.58 3.28 ns group ii pre 50.73 3.97 1.41 1.03 3.776 0.217 post 52.13 3.01 ns residual urine group i group ii mean t-test volume (ml) mean (ml) ± sd mean (ml) ± sd difference t p value pre 54.10 7.59 50.73 3.97 -1.33 0.854 0.396 ns post 57.32 5.58 52.13 3.01 2.54 3.507 0.082 ns archivio italiano di urologia e andrologia 2022; 94, 3 t. abouelgreed, d. saleh, m. abdelaal, a. elatreisy, m. elhelaly, el-sayed el-agamy, a. elgammal, a. moawad 318 ies showed no clinically significant effect of vaginal or laparoscopic hysterectomy on bladder function and capacity. some studies suggest a rational and credible anatomical explanation for why a subtotal hysterectomy may not have a negative impact on pelvic organ function. the nerve content of the uterosacral and cardinal ligaments differs along their length, with much more nerve content in the middle two lateral thirds, closer to their origin at the pelvic side wall than in the medial third, closer to their insertion into the uterine body and cervix. the ligaments, and hence the nerves, are split extremely close to the uterus and cervix during a subtotal hysterectomy. as a result, only the nerves that innervate the uterus and cervix are disrupted, whereas those that innervate the bladder and rectum are unaffected (16). conclusions hysterectomy for benign uterine condition, whether vaginal or laparoscopic, did not adversely affect urinary bladder function. according to uroflowmetry and cystometry, hysterectomy for benign uterine conditions, whether vaginal or laparoscopic, did not adversely affect urinary bladder function. thus, we did not recommend depending on the effects of hysterectomy on bladder functions as a matter of preference of the vaginal or laparoscopic type of the operation. references 1. dobbas sp, jackson sr, wilison am, et al. a prospective randomized trial comparing continuous bladder drainage with catheterization at abdominal hysterectomy, br j urol. 1997; 80:554. 2. wright id, herzog tj, ananth cv, et al. nationwide trends in the performance of inpatient hysterectomy in the united states. obstet gynaecol. 2013; 122:233. 3. sculpher m, manca a, abbott j, et al. cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy, results from a randomized trial. bmj. 2004; 328:134. 4. lonnerfors c, reynisson p, persson i. a randomized trial comparing vaginal and laparoscopic hysterectomy vs robot assisted hysterectomy. j mini invasive gynaecol. 2015; 22:78. 5. thakar r. dispelling the myth –does hysterectomy cause pelvic organ dysfunction? bjog 2004; 111 (suppl 1):20-3. 6. bohlin k, ankardal m, lindkvist h, milsom i. factors influencing the incidence and remission of urinary incontinence after hysterectomy. am j obstet gynecol. 2017; 216:53. e1. 7. chen j, chen c, li y, et al. impact of radical hysterectomy on the trans obturator sling pathway: a retrospective three-dimensional magnetic resonance imaging study. int urogynecol j. 2017; 2:1359. 8. kupec t, pecks u, graf c, et al. size does not make the difference: 3d/4d trans perineal sonographic measurement of the female urethra in the assessment of urinary incontinence subtypes. bio med res int. 2016:1-6. 9. jackson s, donovan j, brookes s, et al. the bristol female lower urinary tract symptoms questionnaire: development and psychometric testing. br j urol. 1996; 77:805. 10. ramdhan rc, loukas m, tubbs rs. anatomical complications of hysterectomy: a review. clin anat. 2017; 30:946. 11. skorupska k, miotła p, kubik-komar a, et al. urinary incontinence after hysterectomydoes type of surgery matter? ginekol. polska. 2016; 87:94. 12. polat m, kahramanoglu i, senol t, et al. comparison of the effect of laparoscopic andabdominal hysterectomy on lower urinary tract function, vaginal length, and dyspareunia: a randomized clinical trial. j laparoendosc adv surg tech. 2016; 26:116. 13. heydari f, motaghed z, abbaszadeh s. relationship between hysterectomy and severity of female stress urinary incontinence. electron physician. 2017; 9:4678. 14. pomian a, majkusiak w, kociszewski j, et al. demographic features of female urethra length. neurourol. urodynamics. 2018; 37:1751. 15. el-toukhy t a, hefini m, davies a, et al. the effect of different types of hysterectomy on urinary and sexual functions: a prospective study. j obstet gynecol. 2004; 24:420. 16. gupta s, manyonda i. hysterectomy for benign gynecological disease. current obstet gynecol. 2006; 16:147. correspondence tamer abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg department of urology, al-azhar university, cairo, egypt. & al zahra private hospital, nmc medical group, uae doaa saleh, md doaa.m.saleh@azhar.edu.eg department of obstetrics & gynaecology, al-azhar university, cairo, egypt mohamed abdelaal, md maal_uro@yahoo.com mohamed elhelaly, md elhelalymohammed@yahoo.com el-sayed el-agamy, md abuamr1978@yahoo.com adel elatreisy, md egypt. dr_adelelatreisy@yahoo.com ahmed elgammal, md aelgammal36@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt ashraf moawad, md ganin1@hotmail.com department of obstetrics & gynaecology, al-azhar university, cairo, egypt & al zahra private hospital, nmc medical group, uae stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12307 1 review introduction the immune system plays a vital role in preventing and defending against cancer. in recent years, significant advances have been made in understanding the immune system and its role in cancer. immunotherapy is the golden child of medical oncology and a new approach to cancer treatment (1). the origin of immunotherapy in urological cancers was found in 1976 by morales et al. it started with the introduction of bacillus calmette-gueren (bcg) treatment for superficial bladder cancer (bc) (2). this development was followed by the introduction of cytokines such as interferon and interleukin-2 (il-2) in the treatment of metastatic renal cell carcinoma (mrcc). one of the first reports demonstrating the potential application of immune modulation in cancer treatment was in 1984, when the administration of il-2 in a patient diagnosed with melanoma reduced the tumour burden. this report has since led to significant interest in the field of immunology and its role in managing various malignancies (3). in 2010, it joined the field of prostate cancer immunotherapy with the approval of the autologous cancer vaccine sipuleucel-t. more recently, immune checkpoint inhibitors (icis) have been introduced with striking results for urology-specific malignancies. the introduction of icis over the past decade has led to significant advances in cancer treatment. recent advances in immunotherapy treatment promise to significantly transform the field of uro-oncology. in this review, we aimed to summarize the use of immunotherapeutic agents in treating urothelial, renal and prostate cancer in the light of clinical studies. urothelial carcinoma urothelial carcinoma can occur along the entire urothelium, which anatomically extends from the kidney to the urethra. urothelial carcinomas can generally be examined under two main headings: upper urinary tract urothelial carcinomas (utuc) and lower urinary tract urothelial carcinomas. it is often not possible to evaluate these two main topics independently. bc accounts for 90-95% of urothelial carcinomas, utuc accounts for 5-10%, and urethral cancer accounts for 1% (4). today, in most studies on the role of immunotherapy in urothelial carcinoma, bc and utuc have been evaluated together. bc is the 10th most common cancer in the entire population and the 7th most common cancer in men. bc is responsible for 2.1% of cancer-related deaths and is the 13th deadliest cancer (5). at the time of initial diagnoimmunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. a deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (icis) has been critical to urology. urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. these agents increase the anti-tumour response by affecting the body's defence mechanisms. immunotherapeutic agents used in urothelial carcinoma include various options such as bcg, interferon, anti-pd-1 (pembrolizumab, nivolumab) and anti-pd-l1 (atezolizumab, avelumab, durvalumab). renal cell carcinoma (rcc) has been known for many years as a tumour with unique sensitivity to immunotherapies. the recent emergence of icis that block pd-1/pd-l1 (pembrolizumab, nivolumab, atezolizumab) or ctla4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced rcc. in light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic rcc. prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. ipilimumab, nivolumab, pembrolizumab, atezolizumab, and sipuleucel t (vaccine-based) are promising alternative treatment options. considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. in this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials. key words: urological cancers; immunotherapy; clinical trials. submitted 24 january 2024; accepted 10 february 2024 the role of immunotherapy in urological cancers efe bosnali 1, enes malik akdas 2, engin telli 2, kerem teke 2, onder kara 2 1 department of urology, university of health sciences, derince training and research hospital, kocaeli, turkey; 2 department of urology, school of medicine, kocaeli university, turkey. doi: 10.4081/aiua.2024.12307 summary archivio italiano di urologia e andrologia 2024; 96(2):12307 e. bosnali, e. malik akdas, e. telli, k. teke, o. kara 2 sis, 75% of the patients are diagnosed with non-muscleinvasive bladder cancer (nmibc) (ta, t1, cis) and 25% with muscle-invasive bladder cancer (mibc) (t2-t4) (6). utuc is a malignant change in urothelial cells extending from the renal pelvis and calyces to the ureteral orifice. the exact incidence of utuc is challenging to determine because it is often associated with renal pelvis and ureteral malignancies; they are reported in a single category as renal tumours (7). the estimated incidence of utuc in western countries is 2/100,000 cases per year, and its incidence is highest between the ages of 70 and 90 (8). immunotherapeutic agents used in urothelial carcinoma (intravesical and systemic) the main goal of immunotherapeutic agents is to increase the anti-tumour response by acting on the body's defence cells. the main immunotherapeutic agents used in urothelial carcinoma are; • bcg } bc (intravesical therapy) • interferon • anti-pd-1 (pembrolizumab, nivolumab)}bc and utuc• anti-pd-l1 (atezolizumab, avelumab, (systemic treatment) durvalumab) the most frequently and longest-used method of immunotherapy in urothelial carcinoma is intravesical bcg treatment in bc. bcg stimulates the immune system in two separate ways. first, it enhances the anti-tumour response via toll-like receptors, inflammatory cytokines, and tumour necrosis factors. secondly, it increases the immune response against the tumour by stimulating cd4+ t helper cells. in addition to these mechanisms, bcg is cytotoxic against tumour cells (9). interferon is an immunotherapeutic agent that can be used alone or in combination with bcg. its mechanism of action is lymphocyte activation and strengthening of the t-helper type i immune response (10). nowadays, systemic immunotherapeutic agents are increasingly used to treat urothelial carcinoma. this group of drugs acts through pd-1 and pd-l1 receptors. the interaction between pd-1 and pd-l1 triggers immune suppressive mechanisms when t cells encounter tumour cells. in this way, pd-l1 checkpoint blockade may interfere with tumour/immune cell interactions for some tumours and thus improve anti-tumour immune responses. there are four immunotherapeutic agents approved by the food and drug administration (fda) for use in patients diagnosed with metastatic urothelial carcinoma (muc) and progressing following platinum-based chemotherapy (ct) (pembrolizumab, nivolumab, atezolizumab, avelumab). pembrolizumab in light of the data obtained from the keynote-057 trial in phase ii, the fda approved the use of pembrolizumab in 2020 for the treatment of bcg-refractory high-risk, nmibc-diagnosed patients who are not suitable for radical cystectomy or who refuse radical cystectomy (11). this study showed that pembrolizumab treatment has acceptable response rates in first-line treatment in patients with locally advanced or metastatic urothelial cancer with high comorbidity rates who cannot receive platinumbased ct. use with this indication was approved by the fda in 2017 (12). in a phase ii trial (pure-01) conducted on patients diagnosed with mibc, regardless of their suitability for platinum-based ct, pembrolizumab neoadjuvant therapy alone has been shown to reduce tumour downstaging at radical cystectomy pathology (13). another study showed that adding pembrolizumab to platinum-based ct in neoadjuvant treatment improved pathological response rates (14). in another study, the effectiveness of maintenance treatment with pembrolizumab was evaluated in patients who were given platinum-based ct in first-line treatment and stable disease was achieved. there was a benefit in progression-free survival (pfs) (5.4 vs 3 mo., p = 0.04) (15). in another phase iii randomized controlled trial (rct), pembrolizumab monotherapy in second-line treatment showed improvement in overall survival (os) compared to ct (10.3 vs 7.4 mo., p = 0.002) (16). however, there are also studies reporting that adding pembrolizumab to standard adjuvant ct in patients with advanced urothelial carcinoma does not increase treatment effectiveness (12). nivolumab according to a phase ii single-arm trial results in 270 patients diagnosed with surgically unresectable locally advanced or muc, an objective response rate (orr) of 19.6% was achieved in patients receiving nivolumab monotherapy. it was shown to provide clinical benefit regardless of pd-l1 expression. based on the results of this study, the pd-1 inhibitor nivolumab has been approved for second-line treatment in patients diagnosed with muc who have not received an adequate response to platinum-based ct (17). according to the phase i-ii trial results conducted in patients with muc who did not respond adequately to platinum-based ct, nivolumab/ipilimumab combination therapy had an orr of up to 38% (18). according to eau guidelines, adjuvant nivolumab treatment is recommended for patients with pt3, pt4, and pn+ utuc who cannot receive adjuvant platinum-based ct (19). in the checkmate-274 trial, 709 patients with a high risk of recurrence and diagnosed with locally advanced urothelial cancer were randomized. in this study, adjuvant nivolumab was given to one group and placebo to the other group, and a statistically significant improvement in disease-free survival (dfs) was detected in the treatment arm (10.8 vs 20.8 mo. p < 0.001) (20). based on data from the study, nivolumab was approved by the fda for the adjuvant treatment of urothelial carcinoma. atezolizumab atezolizumab is a monoclonal antibody that inhibits antipd-l1. in light of the data from rcts, the use of atezolizumab in the first-line treatment of patients diagnosed with locally advanced or muc who are not suitable for platinum-based ct and in the second-line treatment of patients whose disease progresses despite platinum-based ct and who cannot undergo surgical resection has been approved by the fda and european medicines agency (ema) (21, 22). the recently published abacus study evaluated the effectiveness of neoadjuvant atezolizumab treatment in patients unsuitable for cisplatin treatment. according to the results of this study, 2-year dfs and os were reported as 68% and 77%, respectively. in another single-arm phase ii clinical study, in the neoadjuvant treatment of patients with ct2archivio italiano di urologia e andrologia 2024; 96(2):12307 3 the role of immunotherapy in urological cancers t4an0m0 stage tumours, the addition of atezolizumab to gemcitabine-cisplatin combination has been shown to provide a relapse-free survival advantage (23). in the multicenter randomized controlled phase iii study (imvigor 130), 1213 patients with locally advanced or muc were divided into three groups. survival analyses were compared by giving platinum-based ct/atezolizumab to group a, atezolizumab to group b, and platinumbased ct/placebo to group c. the median os times of patients in groups a and c were reported as 16 mo. and 13.4 mo., respectively, and there was a statistically significant difference between both groups (0.83, 95% ci 0.69-1, p = 0.027). the median os times of patients in groups b and c were 15.7 mo., and 13.1 mo., respectively, and it was reported that there was no statistically significant difference between the two groups. as a result, it has been reported that adding atezolizumab to platinumbased ct in first-line treatment provides a survival advantage in patients diagnosed with muc (24). avelumab avelumab is a humanized monoclonal antibody that acts by binding to pd-l1, similar to atezolizumab and durvalumab. in the javelin bladder 100 trial, patients with locally advanced/muc whose disease was stable or had clinical improvement after 4-6 courses of platinum-based ct were divided into two groups. one group was given supportive treatment, and the other group was given avelumab treatment. in the avelumab arm, a statistically significant improvement in os was detected (14.3 vs 21.4 mo.) (25). based on the data of this study, the use of avelumab in maintenance therapy in patients with locally advanced or muc has been approved by the fda (26). in the eau 2023 guideline, maintenance avelumab treatment is strongly recommended in patients diagnosed with muc whose disease is stable after first-line platinum-based ct (19). durvalumab durvalumab is a humanized monoclonal antibody that acts by binding to pd-l1 and blocking the pd-1-cd80 interaction. it received accelerated approval from the fda in 2017 for patients with urothelial carcinoma who did not respond adequately to neoadjuvant or adjuvant treatment (26). the danube phase iii clinical study compared durvalumab monotherapy with durvalumab/tremelimumab and platinum-based ct. the superiority of the tried treatments over ct has not been determined (27). after the report of the danube study was published, the indication of durvalumab in bc was withdrawn (28). clinical trials of various urothelial cancer immune therapies were summarized in table 1 (29). role of immunotherapy in urothelial carcinoma urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. agents used in immunotherapy in urothelial carcinoma include various options such as bcg, interferon, anti-pd-1 (nivolumab, pembrolizumab), anti-pd-l1 (atezolizumab, durvalumab, avelumab). these agents increase the anti-tumour response by affecting the body's defence mechanisms. they show effectiveness at different treatment stages in bc and utuc. cisplatin-based ct has been used as standard therapy in the treatment of urothelial carcinoma for many years. the results of clinical studies with systemic immunotherapeutic agents show that the use of immunotherapeutic agents in treating urothelial carcinoma is becoming increasingly widespread and is considered an effective alternative in patients who are resistant or unsuitable for platinumbased ct. comparisons between these agents should consider clinical outcomes such as orr, os, and dfs. when determining the areas of use and advantages of each agent, the characteristics of the patients and their pre-treatment conditions should be considered. the usage recommendations regarding immunotherapeutic agents employed in urothelial carcinoma in the eau guidelines are presented in table 2 (19). immunotherapy has become an increasingly important table 1. clinical trials of varying treatment plans for urothelial carcinoma (29). immunotherapeutic drug trial name clinical indication fda approval clinical outcome references atezolizumab imvigor210 second-line muc, after platinum ct may 2016 orr 15% rosenberg 2016 atezolizumab imvigor210 first-line muc, platinum-ineligible april 2017 orr 23% balar 2017 nivolumab checkmate-275 second-line muc february 2017 rr 19.6% sharma 2016 durvalumab danube second-line muc orr 26% powles 2020 pembrolizumab keynote-045 second-line may 2017 median os bellmunt 2017 advanced uc 10.3 mo. pembrolizumab keynote-052 first-line muc, platinum-ineligible may 2017 orr 24% balar 2017 and vuky 2020 pembrolizumab keynote-057 recurrent nmibc january 2020 crr 41% balar 2021 avelumab javelin bladder 100 maintenance, muc june 2020 median os powles 2020 21 vs 14 mo. of the control nivolumab checkmate-274 adjuvant, mibc august 2021 median dfs bajorin 2021 20.8 vs 10.8 mo. of the control table 2. summary of the use of immunotherapeutic agents in the treatment of urothelial carcinoma according to eau guidelines (19). the pd-l1 inhibitors atezolizumab and nivolumab and the pd-1 inhibitor pembrolizumab have been approved for patients whose disease has progressed despite platinum-based ct and who have not received prior immunotherapy. the pd-l1 inhibitor atezolizumab and the pd-1 inhibitor pembrolizumab are approved for patients with advanced or muc unsuitable for first-line platinum-based ct. offer patients with pd-l1-positive tumours the checkpoint inhibitors pembrolizumab or atezolizumab. offer adjuvant nivolumab to selected patients with pt3/4 and/or pn+ disease who are ineligible for or refuse adjuvant cisplatin-based ct. for patients who achieve stable disease after first-line platinum-based ct, use maintenance treatment with the pd-l1 inhibitor avelumab. archivio italiano di urologia e andrologia 2024; 96(2):12307 e. bosnali, e. malik akdas, e. telli, k. teke, o. kara 4 treatment modality in urothelial carcinoma. however, further rcts and long-term follow-up periods will strengthen our knowledge of the effectiveness and safety of these agents. in the future, the role of immunotherapy will be better understood by focusing on more specific treatment strategies and personalized treatments for disease subtypes. renal cell carcinoma renal cell carcinoma (rcc) accounts for 2-3% of adult cancers, although its incidence is increasing in western countries (30). according to the american cancer society data for 2023, it is predicted that approximately 81.800 new cases will be diagnosed in the united states, and 14.890 of the patients will die from kidney cancer (31). approximately 70% of kidney cancer cases are diagnosed at a localized or locally advanced stage, and the standard of care for these patients is radical or partial nephrectomy (32). despite this, approximately 35% of patients initially present with advanced or metastatic rcc (mrcc), and 30% of patients presenting with localized disease experience recurrence (33). rcc has been known for many years as a tumour with unique sensitivity to immunotherapies (34). systemic first-line treatment for mrcc is rapidly evolving, with multiple approved strategies and new clinical trials ongoing. the introduction of mainly new icis has led to a paradigm shift in the treatment of this disease (35). rcc immunotherapy agents inhibit receptor-ligand pairs that modulate the congenital or acquired immune system. these molecular pairs, known as immune checkpoints, include pd-1 and pd-l1 and ctla4 multiple ligands, including cytotoxic t lymphocyte-associated protein 4 (ctla4), cd80, and cd86 (36). the recent emergence of icis that block the pd-1/pd-l1 or ctla4 signalling pathways has re-established systemic immunotherapy as central to the medical treatment of advanced rcc, resulting in increasing interest in the application of immunotherapies in the adjuvant setting. many rcts are being conducted (34). treatment of locally advanced rcc (neoadjuvant/adjuvant therapy) given the recent success of icis in mrcc, these therapies are now being studied in the (neo)adjuvant setting to treat localized rcc. the rationale for using neoadjuvant icis stems from the hypothesis that intact kidney tissue may provide a source of antigen for the persistent cancerspecific immune response (37). the advantage of adjuvant immunotherapy is that it can maintain efficacy and eliminate micrometastases even after treatment discontinuation (38). this section aims to provide an overview of completed or ongoing clinical trials on adjuvant treatment of rcc, accompanied by the 2023 eau guideline and current reviews. keynote-564 trial (pembrolizumab) pembrolizumab is a humanized monoclonal igg4 antibody and is also a pd-1 inhibitor. keynote-564 study included intermediate-high risk (pt2, grade 4 or sarcomatoid, n0, m0 or pt3, any grade, n0, m0) or high risk of recurrence (pt4, any grade, n0, m0 or any pt, any grade, pn+, m0, or no evidence of disease after resection of oligometastatic sites < 1 year after nephrectomy or ned). it was a phase iii clinical trial in which pembrolizumab (17 cycles of 3 weeks of treatment) was randomized vs placebo as adjuvant therapy in 994 patients (39). in this study, m1 ned was defined as complete resection of oligometastasis simultaneously or within one year after nephrectomy. at a median follow-up of 24 mo., dfs was 77.1% vs 68.1% (hr 0.68, 95% ci: 0.53-0.87; p = 0.0010), and this rate was maintained at 30 mo. follow-up. in subgroup analyses of the study, patients with m0 tumours (hr 0.74, 95% ci: 0.57-0.96) and patients with m1 tumours with ned (hr 0.29, 95% ci: 0.120.69) dfs benefit was observed and the dfs benefit of pembrolizumab was observed in patients with pd-l1 combined positive score (cps) ≥ 1 (hr 0.67, 95% ci 0.510.88) compared to patients with pd-l1 cps < 1 (hr 0.83, 95% ci 0.45-1.51). in this context, keynote-564 is the first study of adjuvant ici to report a positive primary endpoint of dfs. median os was not reached in both groups. the most common adverse effects (aes) in the pembrolizumab group were fatigue (1%), diarrhoea (1.6%) and skin rash (0.8%), and grade 4-5 aes were not observed in both study arms (40). the study's results led to fda approval of single-agent pembrolizumab for the adjuvant treatment of patients with resected ccrcc, intermediate-high risk, or high risk of recurrence. in 2021, the eau rcc guideline issued a weak recommendation for pembrolizumab as adjuvant therapy for ccrcc with intermediate to high risk of recurrence, as defined by the study, until final os data and results from other studies are available. keynote-564 data should also be interpreted in the context of several significant randomized phase iii clinical trials investigating rcc treatment with immunotherapy in the adjuvant setting, pending or ongoing for data to be published. these include clinical studies immotion010 (nct03024996), checkmate 914 (nct03138512), and prosper (nct03055013) (table 3) (41). not all data published in peer-reviewed journals are available for these clinical studies, but limited data were presented for immotion010, checkmate 914, and prosper at the european society of medical oncology (esmo) congress in september 2022. immotion010 trial (atezolizumab) immotion010 is a randomized placebo-controlled phase iii trial evaluating the pd-l1 inhibitor atezolizumab as an adjuvant treatment option in 778 rcc patients with a clear cell or sarcomatoid component and a high risk of recurrence. immotion010 is the first adjuvant ici study to investigate the efficacy of a pd-l1 inhibitor in terms of dfs and os in rcc. however, the study did not reach its primary endpoint, with a mean dfs of 57.2 mo. in the atezolizumab arm vs 49.5 mo. in the placebo arm [hr 0.93 95% ci 0.751.15; p = 0.495] (42). no dfs improvement was detected with atezolizumab in any investigational subgroups. grade ≥ 3 aes were reported in 27% and 21% of patients in the atezolizumab and placebo groups, respectively. the most common grade 3-4 aes were hypertension, hyperglycemia (3% vs 2%), and diarrhoea (1% vs 2%), observed in 2% vs archivio italiano di urologia e andrologia 2024; 96(2):12307 5 the role of immunotherapy in urological cancers 15% of patients in the atezolizumab vs the placebo group, respectively (43). checkmate 914 trial (nivolumab/ipilimumab) checkmate 914 is a phase iii randomized placebo-controlled two-part study examining the effectiveness of adjuvant nivolumab and nivolumab/ipilimumab in patients with clear cell rcc at high risk of recurrence after nephrectomy (44). results of the part a study were reported at esmo congress 2022; 816 patients were randomized to nivolumab/ipilimumab or placebo. the study evaluated 12 cycles of nivolumab at 240 mg every two weeks for six mo. plus ipilimumab at 1 mg/kg every six weeks for four cycles vs placebo as adjuvant therapy for 816 patients. at a median follow-up of 37 mo., dfs was similar between patients in both arms, and the study did not meet its primary endpoint (hr 0.92, 95% ci 0.71-1.91; p = 0.5347). os analysis could not be performed due to a hierarchical study design. the incidence of treatment-related grade 3 aes was 29% in the nivolumab/ipilimumab group and 2% in the placebo group, with 4 (1%) deaths considered to be related to combination therapy. the high discontinuation rate of 33% in checkmate 914 is concerning and may negatively impact the study's effectiveness (45, 46). based on these data, ici/ici combination therapy appears to increase risk rather than benefit and is unlikely to be introduced into clinical practice. prosper trial (peroperative nivolumab) prosper is a perioperative phase iii randomized study comparing neoadjuvant nivolumab (1 cycle) followed by radical/partial nephrectomy and postsurgical follow-up with the group receiving nine doses of adjuvant nivolumab (480 mg iv every four weeks). the study included 819 high-risk patients, defined as ≥t2 or t any pn+ rcc of any histology, for whom radical/partial nephrectomy was planned. most patients had clear cell histology (78%), 8% had papillary, and 7% had chromophobe histology. the primary endpoint of the study was relapse-free survival. an interim analysis at 16 mo. of follow-up showed that the addition of perioperative nivolumab did not improve relapse-free survival compared with standard of care surgery, and the study was stopped early due to lack of efficacy (hr 0.97 [95% ci: 0.74-1.28], p = 0.43) (37). as a result, single-agent neoadjuvant immunotherapy does not currently have any role in the treatment of ccrcc. treatment of mrcc (ici monotherapy/combination therapy) several positive phase iii trials of ici/ici or ici/tyrosine kinase inhibitor (tki) dual combinations have established the current treatment paradigm for mrcc, all demonstrating superior clinical benefits, including os, compared to sunitinib monotherapy (47). ici combination therapies have become the standard first-line treatment of mrcc. these combinations include a dual ici blockade or a single ici combined with a tki (48). a direct comparison between combination regimes is not currently available; therefore, the choice of first-line treatment for each patient is based on numerous individualized variables, including comorbidities, disease location and burden, and psychosocial and economic factors (49). in recent years, advances have been seen in the diagnosis, management, and treatment of the ccrcc subtype resulting from various randomized and prospective phase iii clinical studies, including combined therapy effective on immune checkpoints such as pd-1, ctla-4, and pdl-1 (checkmate-9er, keynote-426, clear and checkmate-214). ici monotherapy in the treatment of mrcc nivolumab is a humanized monoclonal pd-1 antibody approved for various metastatic tumours. the use of the drug in treating mrcc was based on data from checkmate-025 (nct01668784). in this phase iii clinical trial comparing nivolumab with everolimus in the table 3. clinical trials investigating immunotherapy in the adjuvant setting in rcc (41). trial identifier therapeutic agent inclusion criteria histology the primary endpoint(s) estimated primary (tumour stage and grade) and results completion date bicr: blinded independent central review; ccrcc: clear cell renal cell carcinoma; dfs: disease-free survival; efs: event-free survival; g: tumour grade; irf: independent review facility; iv: intravenously; n: nodal stage; ned: no evidence of disease; os: overall survival; p: pathological; t: tumour stage. keynote-564 nct03142334 immotion010 nct03024996 checkmate 914 nct03138512 prosper nct03055013 rampart nct03288532 pembrolizumab 200 mg iv every 3 weeks for up to 17 cycles atezolizumab 1.200 mg every 21 days for 1 year part a: nivolumab 240 mg iv every 2 weeks, up to 12 doses, ipilimumab 1 mg/kg iv, up to four doses given in cycles 1, 4, 7 and 10 part b: nivolumab 240 mg intravenously every 2 weeks, up to 12 doses nivolumab 480 mg iv, one dose given before surgery, up to nine doses given every 28 days following surgery part a: durvalumab 1.500 mg every 28 days for 1 year part b: durvalumab 1.500 mg every 28 days for 1 year + tremelimumab 75 mg on weeks 1 and 4 pt2 n0 (g4 only), pt3a n0 (g3–4), pt3b–t4 n0, ptx n1, m1 ned pt2 n0 (g4 only), pt3a n0 (g3–4), pt3b–t4 n0, ptx n1 pt2a n0 (g3–4), pt2b–4 n0, pt(any) n1 pt2–4 n0, pt(any) n1 leibovich score 3-11 ccrcc might include sarcomatoid features rcc including clear cell or sarcomatoid component ccrcc might include sarcomatoid features ccrcc might include sarcomatoid features all histological subtypes included dfs for treatment vs placebo: (hr 0.68, 95% ci 0.53–0.87; p = 0.0010) dfs (assessed through irf) for atezolizumab vs surgery alone: (hr 0.97, 95% ci 0.74–1.28; p= 0.43) dfs (assessed through bicr) for nivolumab or ipilimumab vs placebo part a: (hr 0.92, 95% ci 0.71–1.19; p = 0.5347) part b: results pending efs for nivolumab (hr 0.97, 95% ci 0.74–1.28; p = 0.43) dfs, os (results pending) dec 2020 may 2022 july 2024 nov 2023 july 2024 archivio italiano di urologia e andrologia 2024; 96(2):12307 e. bosnali, e. malik akdas, e. telli, k. teke, o. kara 6 treatment of mrcc with clear cell subtype refractory to vascular endothelial growth factor (vegfr)-targeted therapy, nivolumab had longer os, better quality of life and lesser grade 3-4 aes than everolimus. despite the os advantage of nivolumab, no pfs advantage was detected in this study (50). pfs does not appear to be a reliable outcome indicator for pd-1 therapy in rcc. no rcts supporting single-agent icis in treatment-naïve patients have been reported. keynote-427 (nct02853344), published in 2021, is a prospective phase ii single-arm clinical study using pembrolizumab in mrcc patients consisting of two cohorts (ccrcc and nccrcc) (51). the nivolumab study included patients who had received prior treatment, while the pembrolizumab study included patients who had not received prior treatment. moreover, the subtypes included in these clinical studies and their representation percentages differed. therefore, each study's subtype that responds better to immunotherapy differs because the populations studied are heterogeneous (52). given these results and without randomized phase iii data, singleagent ici therapy is not recommended as an alternative in the first-line treatment setting (48). combination therapy in the treatment of mrcc (ici/ici-ici/tki) the beneficial results obtained in clinical trials with immunotherapy treatment have allowed combining such treatments with others using different mechanisms to enhance immunomodulatory effects (53). the contemporary standard of care for metastatic clear cell rcc (ccmrcc) is the use of tkis dually (ici/ici) or in combination with ici (54). in the first-line treatment of cc-mrcc, ici and vegfr-targeted tkis have been shown to improve os compared to tki monotherapy in randomized studies. however, each combination regimen is thought to be highly effective, with orr ranging from 42% to 71% (55-58). several studies have evaluated combination therapies in cc-mrcc and demonstrated improvement in overall response rate, pfs, and os compared to standard treatment (sunitinib). these studies were checkmate-9er (58) (nivolumab/cabozantinib), keynote426 (57) (pembrolizumab/axitinib), and clear (55) (pembrolizumab/lenvatinib), all of which focused on ccrcc and did not include less common subtypes of kidney cancer. in recent years, new prospective trials have been conducted to evaluate the effectiveness of ici/tki combinations in less common subtypes (table 4) (59). checkmate-9er trial (nivolumab/cabozantinib) checkmate-9er is a phase iii rct comparing nivolumab/cabozantinib (n = 323) combination therapy with sunitinib (n = 328) in 651 treatment-naive patients diagnosed with cc-mrcc. during a mean follow-up period of 32.9 mo., the median os was 37.7 mo. in the group treated with nivolumab/cabozantinib and 34.3 mo. in the patients treated with sunitinib, and as a result, no statistically significant difference was observed. while the median pfs was 16.6 mo. in the group receiving nivolumab/cabozantinib treatment, pfs was 8.3 mo. in sunitinib treatment alone. as a result, a statistically significant survival increase in pfs was observed in favour of combination treatment. treatment-related aes (> grade 3) occurred in 61% of patients receiving nivolumab/cabozantinib and 51% receiving sunitinib alone. treatment-related death was reported in one patient in the nivolumab/cabozantinib arm and two patients in the sunitinib arm (58). keynote-426 trial (pembrolizumab/axitinib) the keynote-426 trial compared the outcomes of pembrolizumab/axitinib combination therapy with sunitinib monotherapy in 861 treatment-naïve cc-mrcc patients. during a median follow-up of 42.8 mo., pembrolizumab/axitinib combination therapy showed an os advantage for the intention to treat group (hr: 0.73, 95% ci: 0.600.88, p < 0.001). median os was 45.7 months in the pembrolizumab/axitinib arm and 40.1 months in the sunitinib arm, and a pfs advantage was also demonstrated in the combination arm in imdc subgroups. treatment-related aes (> grade 3) occurred in 63% of patients receiving combination therapy and 58% of patients receiving sunitinib. treatment-related deaths were reported at a rate of approximately 1% in both arms (57). clear trial (everolimus/lenvantinib-pembrolizumab/lenvantinib) the clear randomized phase iii clinical trial compared everolimus/lenvantinib or pembrolizumab/lenvantinib combination therapy with sunitinib alone in treating advanced rcc. clear randomized a total of 1,069 patients (in a 1:1:1 ratio) to pembrolizumab/lenvatinib (n = 355), everolimus/lenvatinib (n = 357), and sunitinib (n = 357). in the study, the pembrolizumab/lenvatinib arm reached its primary endpoint compared to sunitinib, with a median pfs of 9.2 mo. vs 23.9 mo. (hr: 0.39, 95% ci: 0.32-0.49, p < 0.001). compared to sunitinib, os was significantly improved with pembrolizumab/lenvatinib (hr: 0.66, 95% ci: 0.49-0.88, p = 0.005). efficacy was observed in all imdc risk groups, regardless of pd-l1 status. grade 3 or higher aes associated with treatment with pembrolizumab/lenvatinib were 72%. treatmentrelated deaths occurred in four patients in the pembrolizumab/lenvatinib arm and one patient in the sunitinib arm (55). checkmate-214 trial (ipilimumab/nivolumab) the combination of ipilimumab/nivolumab, targeting anti-ctla4 and anti-pd-1, showed improvements in pfs and os compared to sunitinib based on data from the phase iii checkmate-214 trial, which led to its approval by the international metastatic rcc database consortium (imdc) for the treatment of low and intermediate risk ccmrcc. at 60 mo. of follow-up in the checkmate-214 trial, os rates were 43% in the ipilimumab/nivolumab arm and 31% in the sunitinib arm, respectively. grade 34 toxicity was reported in 46% and treatment-secondary death in 1.5% in the ipilimumab/nivolumab arm (56). therefore, immune combination therapy should be applied within the scope of a multidisciplinary team in centres with appropriate supportive care experience (table 5) (48). archivio italiano di urologia e andrologia 2024; 96(2):12307 7 the role of immunotherapy in urological cancers table 4. first-line immune checkpoint inhibitor combination trials for clear-cell rcc (59). study n experimental arm primary endpoint risk groups pfs (mo) median os (mo) median (95% ci) hr (95% ci) hr batezo = atezolizumab; ave = avelumab; axi = axitinib; bev = bevacizumab; bicr = blinded independent central review; bid = twice a day; cabo = cabozantinib; ci = confidence interval; fav = favourable; hr = hazard ratio; ipi = ipilimumab; imd = intermediate; imdc = metastatic renal cancer database consortium; ir = investigator review; itt = intention-to-treat; iv = intravenous; len = lenvatinib; mo = months; mskcc = memorial sloan kettering cancer center; ne = non-estimable; nr = not reached; nivo = nivolumab; os = overall survival; pembro = pembrolizumab; pfs = profession-free survival; pitt = pfs intention-to-treat; po = by mouth; pts = patients; qd = once a day; q2w = every 2 weeks; q3w = every 3 weeks; sun = sunitinib; wk = weeks. checkmate 9er nct03141177 median follow-up of 23.5 mo. keynote-426 nct02853331 median follow-up of 42.8 mo. clear nct02811861 median follow-up of 33.4 mo. checkmate 214 nct02231749 median follow-up of 60 mo. javelin 101 nct02684006 median follow-up 19 mo. immotion151 nct02420821 median follow-up 24 mo. nivo 240 mg fixed dose iv every 2 wk plus cabo 40 mg po daily vs sun 50 mg po qd 4/2 wk pembro 200 mg. iv q3w plus axi 5 mg. po bid vs sun 50 mg po qd 4/2 wk pembro 200 mg iv q3w plus len 20 mg po qd vs sun 50 mg po qd 4/2 wk nivo 3 mg/kg plus ipi 1 mg/kg iv q3w for 4 doses then nivo 3 mg/kg iv q2w vs sun 50 mg po qd 4/2 wk ave 10 mg/kg iv q2w plus axi, 5 mg po bid vs sun 50 mg po qd 4/2 wk atezo 1200 mg fixed dose iv plus bev 15 mg/kg iv on days 1 and 22 of each 42-day cycle vs sun 50 mg po qd 4/2 wk 651 861 712 1096 886 915 pfs in the itt by bicr pfs and os in the itt by bicr pfs in the itt by birc pfs and os in the imdc intermediate and poor risk population by bicr pfs in the pd-l1+ population and os in the itt by bicr pfs in the pd-l1+ population and os in the itt by ir imdc fav 22% imd 58% poor 20% mskcc not determined imdc fav 31% imd 56% poor 13% mskcc not determined imdc fav 31% imd 59% poor 9% ne 1% mskcc fav 27% imd 64% poor 9% imdc fav 23% imd 61% poor 17% mskcc not determined imdc fav 22% imd 62% poor 16% mskcc fav 23% imd 66% poor 12% imdc not determined mskcc fav 20% imd 69% poor 12% (itt) nivo + cabo: 17.0 (12.6–19.4) sun: 8.3 (6.9–9.7) hr: 0.52 (95% ci: 0.43–0.64) p < 0.0001 (itt) pembro + axi: 15.7 (13.6–20.2) sun: 11.1 (8.9–12.5) hr: 0.68 (95% ci: 0.58–0.80) p < 0.0001 (itt) pembro + len: 23.9 (20.8–27.7) sun: 9.2 (6.0–11.0) hr: 0.39 (95% ci: 0.32–0.49) p > 0.001 (imdc imd/poor) nivo + ipi: 11.6 (8.4–16.5) sun: 8.3 (7.0–10.4) hr: 0.73 (95% ci: 0.61–0.87) (pd-l1+) ave + axi: 13.8 (10.1–20.7) sun: 7.0 (5.7–9.6) hr: 0.62 (95% ci: 0.49–0.78) p < 0.0001 (pd-l1+) atezo + bev: 11.2 (8.9–15.0) sun: 7.7 (6.8–9.7) hr: 0.74 (95% ci: 0.57–0.96) p = 0.0217 (itt) nivo + cabo: nr (ne) sun: 29.5 (28.4–ne) hr: 0.66 (98.9% ci: 0.50– 0.87) p = 0.0034 (itt) pembro + axi: 45.7 (43.6–nr) sun: 40.1 (34.3–44.2) hr: 0.73 (95% ci: 0.60–0.88) p = 0.001 (itt) pembro + len: nr (41.5–ne) sun: nr (38.4–e) hr: 0.72 (95% ci: 0.55–0.93) p = 0.005 (imdc imd/poor) nivo + ipi: 47.0 (35.4–57.4) sun: 26.6 (22.1–33.5) hr: 0.68 (0.58–0.81) p < 0.0001 (pd-l1+) ave + axi: nr sun: 28.6 (27.4–ne) hr: 0.83 (95% ci: 0.60–1.15) p = 0.1301 (itt) atezo + bev: 36.1 (31.5–42.3) sun: 35.3 (28.6–42.1ne) hr: 0.91 (95% ci: 0.76–1.08) p = 0.27 table 5. updated eau guidelines recommendations for the first-line treatment of cc-mrcc (48). standard of care alternative in patients who can not receive or tolerate immune checkpoint inhibitors imdc favourable risk nivolumab/cabozantinib [1b] sunitinib* [1b] pembrolizumab/axitinib [1b] pazopanib* [1b] pembrolizumab/lenvatinib [1b] imdc intermediate and poor risk nivolumab/cabozantinib [1b] cabozantinib* [2a] pembrolizumab/axitinib [1b] sunitinib*[1b] pembrolizumab/lenvatinib [1b] pazopanib* [1b] nivolumab/ipilimumab [1b] imdc = the international metastatic renal cell carcinoma database consortium. *pazopanib for intermediate-risk disease only. [1b] = based on one randomised controlled phase iii trial. [2a] = based on a well-designed study without randomisation or subgroup analysis of a randomised controlled trial. archivio italiano di urologia e andrologia 2024; 96(2):12307 e. bosnali, e. malik akdas, e. telli, k. teke, o. kara 8 immunotherapy in metastatic non-clear cell rcc among diagnosed renal tumours, clear cell rcc is the most common type (80%); the remaining 20% is nonclear cell renal cell carcinoma (nccrcc), a rare and histopathologically heterogeneous group of tumours (31). in most kidney cancer trials, nccrcc tumours are not included or only marginally represented. therefore, little is known about the best management of nccrcc types. treatment options for nccrcc are limited as few specific studies are available. although nccrcc subtypes have not been included in pivotal ccrcc clinical trials, their treatments are based on data from ccrcc clinical trials. no phase iii clinical trials have been reported for patients diagnosed with metastatic nccrcc (60). the eau 2023 guideline made a weak recommendation for pembrolizumab alone or pembrolizumab/lenvantinib or nivolumab/cabozantinib treatment for papillary rcc patients based on small single-arm studies. conducting clinical trials on more patients with different histologies and investigating new biomarkers that will help predict response to treatment remain questions that researchers need to answer in the treatment of nccrcc. undoubtedly, future clinical trials will play a key role in treating these patients (61). role of immunotherapy in rcc immunotherapy is the cornerstone of mrcc treatment. these agents are currently used in clinical trials in the (neo)adjuvant setting for high-risk localized rcc to achieve primary tumour response, reduce the risk of recurrence, and improve long-term oncological outcomes. in addition to shrinking the primary tumour and enabling nephron-sparing surgeries, neoadjuvant icis could theoretically generate a durable immune response given the presence of antigens in intact kidney tissue (32). however, whether neoadjuvant ici/tki use is associated with longterm dfs or os benefit is not yet known. immunotherapy treatment in the adjuvant setting is promising, but the risk of disease recurrence remains high. in the keynote-564 (39) trial, relapse was observed in 22.7% of patients in the pembrolizumab group. the heterogeneity observed between adjuvant ici studies may include differences in study groups (e.g., the inclusion of m1 ned in keynote-564 and immotion010 and no inclusion in checkmate 914), drug tolerability, and factors that may affect adequate drug distribution (e.g., checkmate 914). (43% medication discontinuation rate) may contribute to this heterogeneity. additionally, including t2a/grade 3 patients in the checkmate 914 study, who were assumed to have lower malignancy than the other two, may have significantly affected the study results. these differences in inclusion criteria between ongoing clinical trials may affect the risk of disease recurrence and, ultimately, negatively contribute to disease progression. additionally, differences in treatment-limiting toxicity rates across studies may alter the treatment received and impact dfs results. one of the reasons why the immotion010 (43) trial failed to meet the primary endpoint compared to the keynote-564 study may be that the anti-pd-1 and pd-l1 antibodies used in the studies showed a difference in efficacy. liu et al. discuss the incidence of renal adverse events (raes) for ici-based regimens vs targeted or chemotherapies, including 95 rcts totalling more than 40,000 patients (62). grade 3 or higher raes incidence was 4.3%. among ici monotherapies, anti-ctla4 was found to have a higher risk of ≥ grade 3 raes compared to anti-pd-1/pd-l1. diagnostic and management challenges for ici-associated toxicities highlight the value of a multidisciplinary approach to the management of high-grade raes. currently, there are no standard or validated biomarkers to help treat rcc. discovering one or more of these biomarkers is probably at the top of every researcher's wish list. if biomarkers can be identified in patients who have not received ct or at an earlier time when cancer is diagnosed, opportunities for the use of neoadjuvant or early adjuvant immunotherapy will increase. although dfs benefit in the adjuvant setting is a meaningful primary endpoint supported by the fda and the european medical association, treatment-related toxicities should not be ignored by patients and clinicians. while the dfs benefit of pembrolizumab was maintained in long-term follow-up, against the background of many negative adjuvant clinical trials, clinicians await the study's long-term os data before recommending adjuvant pembrolizumab to patients. in the meantime, adjuvant pembrolizumab remains a reasonable option for patients with high-risk rcc in light of the eau 2023 guideline. when discussing adjuvant treatment options with a patient with high-risk rcc, clinicians should discuss available data supporting the use of adjuvant icis and outline questions that will be answered over time. until we get answers to these crucial questions, adjuvant immunotherapy application appears to be a personalized decision. prostate cancer prostate cancer is the 2nd most common type of cancer in men and ranks 5th among cancer-related deaths. prostate cancer is the most frequently diagnosed cancer in 112 countries in the world, followed by lung cancer in 36 countries and colorectal cancer in 11 countries (63). the widespread use of prostate-specific antigen (psa) has led to a significant increase in the incidence of prostate cancer. this has resulted in increased detection of indolent disease and decreased detection of metastatic prostate cancer (64). the most important risk factors in the aetiology of prostate cancer are, as many studies have shown, advanced age, geography, ethnicity, family history and genetic predisposition (65-67). in recent years, immunotherapy has emerged as an essential field in the treatment of prostate cancer. prostate cancer is an immunological tumour to a lesser extent compared to other types of urological cancer. the reasons for this are that prostate cancer has a low rate of tumour mutation, pdl1 expression and t-cell infiltration (68). therefore, although immunotherapy has a limited place in prostate cancer, some immunotherapeutic agents have become part of standard treatment in the past few years. it provides an alternative treatment method, especially for castrationresistant prostate cancer (crpc), in addition to standard methods such as androgen deprivation therapy and ct (69, 70). a particular subgroup of patients, including mismatch repair (dmmr) deficient, cdk12-mutated tumours in addition to high pd-l1 tumour expression, tumour mutaarchivio italiano di urologia e andrologia 2024; 96(2):12307 9 the role of immunotherapy in urological cancers tional burden, and microsatellite instability (msi), have recently shown good responses to ici therapy (68, 71). the main immunotherapeutic agents used in prostate cancer are: • ipilimumab • nivolumab • pembrolizumab • atezolizumab • sipuleucel-t (vaccine based) ipilimumab ipilimumab is a monoclonal antibody that increases the immune system's response to tumour cells by targeting the ctla-4 receptor. it is the first fda-approved ici for prostate cancer. when administered as monotherapy, ipilimumab has been shown to significantly increase the proportion of regulatory effector t lymphocytes present in the tumour microenvironment (tme) (72). in the literature, phase i trials have shown that ipilimumab and its combinations provide psa reduction in patients and prolong the psa doubling time (73-76). slovin et al. shared the results of 50 patients diagnosed with metastatic crpc (mcrpc) who received ipilimumab alone or ipilimumab/radiotherapy (rt) combination therapy. a more than 50% decrease in psa was observed in eight patients, a complete response was achieved in 1 patient, and no progression was observed in 6 patients (77). kwon et al., in a randomized controlled phase iii study, 799 mcrpc patients received palliative rt therapy. then, the patients were divided into two groups, one receiving ipilimumab and the other receiving placebo. although a significant improvement in pfs was detected in the ipilimumab arm between the two groups, no significant difference was detected in os data (70). after three years, an approximately twoto three-fold higher os benefit was detected in the ipilimumab arm (78). beer et al. reported increased pfs and a higher psa response rate (23% vs 8%) in the ipilimumab arm (5.6 mo.) compared to the placebo arm (3.8 mo.) in mcrpc (79). nivolumab the interaction of pd-1 with its ligand prevents the activation of t cells, and, as a result, the destruction of cancer cells by the immune system is prevented. nivolumab is an igg4 monoclonal antibody that demonstrates antitumor response by blocking pd-1 (80, 81). in the checkmate 650 phase ii clinical trial investigating the combined effects of ipilimumab and nivolumab in patients with mcrpc, combination therapy demonstrated an orr of 25% (81). shenderov et al., in patients with ar-v7 positive mcrpc, which is associated with poor prognosis, investigated the effectiveness of nivolumab/ipilimumab combination therapy. although this study showed that combination therapy may benefit ar-v7 positive pca patients, sufficient evidence was not obtained for routine use (82). pembrolizumab pembrolizumab is an anti-pd-1 antibody that acts similarly to nivolumab. in the keynote-365 study, ct-refractory mcrpc patients receiving abiraterone or enzalutamide were given pembrolizumab/docetaxel and prednisone combination therapy. the psa response rate was 34%, the radiological mean pfs was 8.5 mo., and the os was 20.2 mo. (83). in a phase ii clinical study (keynote-199) involving multiple cohorts, pembrolizumab monotherapy was administered to 258 patients diagnosed with mcrpc who had bone-predominant metastases measurable by response evaluation criteria in solid tumors (recist) and received docetaxel and targeted endocrine therapy. patients with positive pd-l1 expression showed an orr of 5%, and patients with negative expression showed an orr of 3%. median os was reported as 9.5 mo. in pd-l1 expressionpositive patients and 7.9 mo. in negative patients (84). with these results, it is thought that pembrolizumab treatment may be more effective in tumours with high pd-l1 expression. atezolizumab atezolizumab, avelumab and durvalumab, which target pd-l1, work by blocking the interaction of pd-l1 with pd-1. these agents have been investigated as an option in the treatment of advanced prostate cancer (85-89). in imbassador 250 study, 759 patients with mcrpc or locally advanced crpc refractory to abiraterone and doxetaxel were treated with the combination of atezolizumab table 6. clinical trials of varying treatment plans for mcrpc (91). treatment n target dosing interval results article ipilimumab pembrolizumab pembrolizumab pembrolizumab plus docetaxel and prednisone pembrolizumab plus enzalutamide atezolizumab atezolizumab with sipuleucel-t avelumab nivolumab plus ipilimumab mcrpc mcrpc advanced prostate adenocarcinoma mcrpc mcrpc mcrpc mcrpc mcrpc mcrpc 799 258 23 104 28 35 37 15 90 one dose of rt followed by 10 mg/kg ipilimumab every 3 weeks 200 mg every 3 weeks 10 mg/kg every 2 weeks 200 mg pembrolizumab and 75 mg/m2 docetaxel every 3 weeks, 5 mg prednisone bid 200 mg pembrolizumab every 3 weeks with 4 doses of enzalutamide every 3 weeks 1200 mg azetolizumab every 3 weeks, sipuleucel-t every 2 weeks 10 mg/kg every 2 weeks 1 mg/kg nivolumab and 3 mg/kg ipilimumab iv followed by 480 mg nivolumab every 4 weeks overall increased survival rates for patients given ipilimumab os of 14.1 mo. with acceptable safety os of 7.9 mo. os of 29.2 mo. with acceptable safety os of 41.7 mo. os of 14.7 mo. with acceptable safety os of 23.6 mo. os of 7.4 mo. os of 19.0 mo. fizazi et al. antonarakis et al. hansen et al. yu et al. graff et al. petrylak et al. dorff et al. brown et al. sharma et al. archivio italiano di urologia e andrologia 2024; 96(2):12307 e. bosnali, e. malik akdas, e. telli, k. teke, o. kara 10 and enzalutamide or enzalutamide alone. similar os rates were detected in both treatment arms. subgroup analyses reported that combination therapy may benefit patients with high pd-l1 expression (86). sipuleucel-t there are also immunotherapeutic vaccines used in the treatment of prostate cancer. however, many of these vaccines are still in the experimental stage. fda approval of sipuleucel-t is considered the first application of immunotherapy in prostate cancer. sipuleucel-t is the only fda-approved vaccine approved for use against prostate cancer. it has been shown in the literature that sipuleucel-t is effective in mcrpc (69, 90). according to a study conducted by kantoff et al. in mcrpc patients, sipuleucel-t treatment prolonged os by an average of 4.1 mo. and resulted in a 22% reduction in the risk of death (69). these results may guide new immunotherapeutic vaccine trials. clinical trials of various prostate cancer immune therapies were summarized in table 6 (91). role of immunotherapy in prostate cancer as it is known, prostate cancer is in the category of immunologically "cold" tumours, so patients must be evaluated according to their individual immunogenicity status in order to receive effective immunotherapy treatment (91). more successful treatment results can be achieved in larger patient populations with combination treatments with different agents. another critical issue is that immunological interventions are generally applied only to those with advanced disease, although, as the disease progresses, the number of t cells decreases. therefore, applying immunotherapy at the early stage of the disease may provide a more effective response to treatment. immunotherapy is a promising alternative treatment option, especially in some crpc patients. ici treatment success is higher in prostate cancer patients with high msi/dmmr or cdk12 mutations. a better understanding of tme and ici mechanisms through high-volume prospective rcts may pave the way for new immunotherapeutic approaches in advanced prostate cancer. conclusions given the limited research experience to date, it remains unclear whether the persistence of the primary tumour will impact attempts to modulate the metastatic cascade or whether different immunotherapy agents have different degrees of efficacy in adjuvant or neoadjuvant settings. cisplatin-based ct has long been used as standard therapy in the treatment of urothelial carcinoma. with the promising results obtained in locally advanced and muc, systemic immunotherapeutic agents have begun to take their place in the standard treatment of the disease. however, more rct evidence and extended follow-up periods are needed. data from large clinical trials to evaluate immunotherapy and tkis for treating rcc in the adjuvant setting remain largely conflicting regarding the dfs benefit of either treatment modality. however, a comprehensive biological rationale exists for administering tkis and immunotherapy agents in the adjuvant setting. however, questions regarding the optimal adjuvant treatment regimen and appropriate method in rcc still remain to be answered. prostate cancer, which is considered an immunological "cold" tumour, is not as sensitive to immunotherapy as other urological malignancies. however, promising results have been obtained in some identified prostate cancer patients. in the light of new prospective rcts, treatment procedures that reach sufficient evidence levels do not seem far away. to make an informed decision about the individualized use of adjuvant immunotherapy, clinicians should discuss the available data with patients and actively make the decision. further research and development of biomarkers are needed to answer these questions and improve outcomes for uro-oncology. although it is challenging to stay up to date on innovations in immunotherapy, given the ongoing rcts, there is no doubt that we will have more options available to our patients who need this treatment in the next decade. references 1. elena dreyzin ak. kidney cancer and its treatment. in: edouard j. trabulsi cdl, anne e. lizardi-calvaresi, editor. chemotherapy and immunotherapy in urologic oncology. switzerland: springer nature; 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stereotactic ablative body radiotherapy in metastatic castrationresistant prostate cancer: the phase 2 ice-pac clinical trial. eur urol. 2022; 81:253-62. 89. karzai f, vanderweele d, madan ra, et al. activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without dna damage repair mutations. j immunother cancer. 2018; 6:1-12. 90. cheever ma, higano cs. provenge (sipuleucel-t) in prostate cancer: the first fda-approved therapeutic cancer vaccine. clin cancer res. 2011; 17:3520-6. 91. wang i, song l, wang by, et al. prostate cancer immunotherapy: a review of recent advancements with novel treatment methods and efficacy. am j clin exp urol. 2022; 10:210-33. correspondence efe bosnalı, md (corresponding author) efebosnali415@gmail.com department of urology, university of health sciences, derince training and research hospital, turkey, 41380 enes malik akdas, md turkey enesmalikakdas@gmail.com engin telli, md turkey engintelli@gmail.com kerem teke, md turkey drtekekerem@gmail.com onder kara, md turkey onerkara@yahoo.com kocaeli university, school of medicine, department of urology, kocaeli, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13912 1 original paper comorbid conditions such as hypertension, diabetes mellitus, hyperlipidemia, obstructive sleep apnea, and many forms of sexual dysfunction (1). since originally introduced for treating morbid obesity in 1993, lsg has quickly gained popularity and became the most common technique of bariatric surgery in many parts of the world (2). as lsg became more popular over the past years, its feasibility as an alternative for treating morbid obesity and its effectiveness with multiple comorbid conditions besides weight and metabolic profile improvement became increasingly appreciated (3). the mechanism by which lsg causes significant weight loss and metabolic improvement is more than just a "restrictive" procedure (4). many mechanisms have been suggested including the limitation of ghrelin produced by the fundus of the stomach, that is known as the appetite-stimulating hormone (5). in addition, an increase in the levels of incretins-glucagon-like peptide-1, and peptide-yy and a decrease in the levels of insulin inhibitory hormones such as glucagon, pancreatic polypeptide, and somatostatin. while generally safe, lsg comes with few complications. early postoperative complications may include hemorrhage, infection, and staple line leaks, while long-term issues can encompass gastroesophageal reflux disease (gerd), and nutritional deficiencies (6). on the other hand, lsg did not only achieve significant and sustained weight loss, but also remission of type 2 diabetes, improved cardiovascular health, reduced cancer risk, and enhanced quality of life (7). despite the extensive documentation of lsg's efficacy in promoting weight loss, its impact on specific aspects of patient wellbeing, such as sexual function is not yet well studied. erectile dysfunction (ed), a common complaint among obese men, is influenced by many factors associated with obesity, including vascular health, hormonal balance, and psychological well-being (8). the significant weight loss induced by lsg has been shown to ameliorate endothelial dysfunction, impaired blood flow, and hormonal disruptions associated with excess adiposity, suggesting a potenobjective: the primary aim of the study is to identify the effect of laparoscopic sleeve gastrectomy on the erectile function of egyptian obese men via measurement of subjective feelings measured by the international index of erectile function questionnaire (iief-5) and objective sex hormone test. the secondary aim of the study is to evaluate weight loss changes and changes in other blood test results. patients and methods: one hundred egyptian men with morbid obesity (mean bmi 45.5 kg/m², mean age 37.3 years) who underwent laparoscopic sleeve gastrectomy (lsg), were included retrospectively from the period of january 2022 to january 2024 on this study and 80 completed the 1-year follow-up. all operations were performed by the same surgical team in our hospital. informed consents were taken from all the patients who were recruited in the study. results: significant reductions in comorbidities such as hypertension, diabetes, osteoarthritis, and dyslipidemia were observed after laparoscopic sleeve gastrectomy. sexual function improved notably in orgasmic function, intercourse satisfaction, and overall satisfaction, along with a significant rise in serum testosterone levels. patients also experienced substantial decreases in weight, bmi, waist and hip circumference, and improvements in lipid profile, hba1c, inflammatory markers, and sex hormones. no severe complications or mortality were reported during the study period. conclusions: a significant enhancement in the erectile function was observed in obese egyptian men following lgs. this improvement was evidenced both clinically through increased iief scores after surgery and biochemically through increased serum testosterone level. key words: laparoscopic; sleeve gastrectomy; obesity; erectile dysfunction; sexual function. submitted 19 april 2025; accepted 28 april 2025 introduction obesity has become an almost pandemic problem since the end of the 20th century and is associated with many effect of laparoscopic sleeve gastrectomy (lsg) on the erectile function of egyptian obese men ahmed lamey 1, 2, tamer a. abouelgreed 3, osama abdelmoneim 4, mohamed sherif ali 4, ahmed elshaboury 4, mohamed rehan 5, saed khater 5, osama m. ghoneimy 3, maha m. elzamek 3, esam a. elnady 5, mohamed f. elebiary 3, mohamed hindawy 3, ahmed wahsh 6, satyabrata garanayka 7, mohamed y. elamir 8 1 department of general surgery, faculty of medicine, kafr elsheikh university, egypt; 2 burjeel royal hospital, al-ain, uae; 3 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 4 department of general surgery, faculty of medicine, mansoura university, egypt; 5 department of urology, faculty of medicine, al-azhar university, damietta, egypt; 6 department of urology, faculty of medicine, al-azhar university, assiut, egypt; 7 department of urology, thumbay university hospital, ajman, uae; 8 department of andrology, faculty of medicine, cairo university, cairo, egypt. doi: 10.4081/aiua.2025.13912 summary archivio italiano di urologia e andrologia 2025; 97(2):13912 a. lamey, t.a. abouelgreed, o. abdelmoneim, et al. 2 tial improvement in erectile function (9, 10). therefore, we conducted this retrospective study to investigate the effects of laparoscopic sleeve gastrectomy on erectile function in a cohort of egyptian obese male patients. by examining preoperative and postoperative erectile function scores, alongside relevant clinical parameters. the primary aim of the study is to identify the effect of laparoscopic sleeve gastrectomy on the erectile function of egyptian obese men via measurement of subjective feelings measured by the iief questionnaire and objective sex hormone test. the secondary aim of the study is to evaluate weight loss changes and changes in other blood test results. materials and methods a hundred morbid obese egyptian men who underwent lsg, were included retrospectively from the period of january 2022 to january 2024 and were recruited to kafr elsheikh university hospital, mansoura university hospitals, and al azhar university hospitals. this cohort study protocol was approved by the institutional research board (irb) before the start of the study. all participants gave written informed consent before taking part. inclusion criteria include morbid obese men, with age ≥ 18 years old and bmi (≥ 40) or (≥ 35 with associated co-morbidities) of egyptian nationality who were scheduled for lsg and were sexually active with their female partner. exclusion criteria include sexually inactive men (unmarried or separated or widowed or travelers), or men who have diseases affecting their erectile function (e.g. diabetic neuropathy, cardiovascular or hepatic diseases, major depression or psychiatric disorders), or were taking drugs like (pde5i, psychiatric drugs, and statins) affecting erectile function, or had major complications after surgery like (leakage or bleeding), or had penile anomalies like (micro-penis) associated with hypogonadism. all operations were performed by the same surgical team in our hospital. informed consents were taken from all the patients who were recruited in the study. before the operation and on the follow-up day, patients were invited to fill the international index of erectile function (iief-5) questionnaire (figure 1) (11). it contains five questions assessing erectile function and satisfaction during sexual intercourse with each item scoring from 0 to 5 points and a final score ranging between 5-25 (the higher the score, the better the erectile function). patients who participated in the study and completed the preoperative questionnaire, blood tests, and anthropometric measurements were recruited for a follow-up visit at least 1 year postoperatively, including blood tests, anthropometric measurements, and their iief questionnaire. anthropometric measurements which were collected before and after the operation were: waist circumference, hip circumference, weight, height, and body mass index (bmi), percentage of excess weight loss (ewl%), percentage of total weight loss (twl%). blood tests were collected before surgery and at least 1 year after the operation including: glycosylated hemoglobin (hba1c), fasting plasma glucose (fpg), hemoglobin, c-reactive protein (crp), hydroxyvitamin d [1, 25-(oh2) d3], total testosterone (tt), estradiol (e2), follicle-stimulating hormone (fsh), luteinizing hormone (lh), progesterone (pro), prolactin (prl), total cholesterol (tc), triglyceride (tg), high-density lipoprotein (hdl), and low-density lipoprotein (ldl). after the operation, our team offered a medically supervised weight loss program, which was composed of diet and behavioral and exercise advice with administration of calcium, iron tablets and multivitamin supplements. our primary outcomes were subjective feelings measured by the iief questionnaire and objective results measured by sex hormone test. secondary outcomes were the weight loss effect and change in the other blood test results. figure 1. iief-5 questionnaire. archivio italiano di urologia e andrologia 2025; 97(2):13912 3 laparoscopic sleeve gastrectomy (lsg) and erectile function statistical analysis data analysis was performed by spss software, version 29. qualitative data were described using number and percent. quantitative data were described using mean±standard deviation for normally distributed data after testing normality using kolmogrov-smirnov test. significance of the obtained results was judged at the (≤ 0.05) level. paired t test and mc nemar test were used for continuous and qualitative data, respectively for comparison pre and post treatment values. the pearson correlation was used to determine the strength and direction of a linear relationship between two normally distributed continuous variables. results one hundred egyptian men with morbid obesity were enrolled in the study, with a mean bmi of 45.5 ± 10.5 kg/m2 (ranging from 35 to 56 kg/m2) and mean age of 37.3 ± 9.72 years (ranging from 21 to 55 years). twenty of these patients were excluded during the follow-up visits. five of them for lacking follow-up criteria. fifteen of them, had lost regular sexual habits after doing the procedure. no severe complication or mortality occurred in the 100 cases post-operatively although only eighty patients completed all assessments after 1-year follow-up. demographic data of the patients the mean age of participants was 37.3 ± 9.72 years before surgery and 38.3 ± 9.72 years at follow-up. all the 80 patients included in the follow-up reported regular sexual activity. there were significant reductions in the prevalence of comorbidities after lsg, including hypertension (35% to 12.5%), type 2 diabetes (37.5% to 12.5%), osteoarthritis (50% to 18.8%), and dyslipidemia (100% to 18.8%) (all p < 0.001) (table 1). preoperative and postoperative iief-5 questionnaire significant improvements were observed in orgasmic function (2.81 ± 1.49 to 3.62 ± 1.17, p = 0.001), intercourse function (3.07 ± 1.44 to 3.46 ± 1.07, p = 0.04), and overall satisfaction (2.96 ± 1.33 to 3.48 ± 1.16, p = 0.008). erectile function and sexual desire showed non-significant increases (table 2). preoperative and postoperative testosterone level: mean serum testosterone levels increased significantly from 3.65 ± 1.28 ng/ml preoperatively to 5.6 ± 0.99 ng/ml postoperatively (p < 0.001) (table 3). preoperative and postoperative anthropometric measures significant reductions were observed in mean weight (138 ± 7.48 kg to 85 ± 9.32 kg), bmi (45.5 ± 6.70 kg/m2 to 28 ± 4.92 kg/m2), waist circumference (112.5 ± 23.99 cm to 102.5 ± 15.0 cm), and hip circumference (140 ± 18.64 cm to 107.5 ± 9.73 cm) (all p = 0.001) (table 4). preoperative and postoperative biochemical blood tests significant improvements were noted in total cholesterol (247.0 ± 24.13 mg/dl to 158.8 ± 20.18 mg/dl), hba1c (8.13 ± 1.22% to 7.050 ± 0.83%), c-reactive protein (20.50 ± 8.21 mg/l to 11.04 ± 2.31 mg/l), prolactin (17.37 ± 3.47 ng/ml to 14.30 ± 3.51 ng/ml), progesterone (0.518 ± 0.18 ng/ml to 0.397 ± 0.16 ng/ml), estradiol (46.61 ± 22.11 pg/ml to 25.32 ± 8.27 pg/ml), and fsh (10.09 ± 4.55 miu/ml to 8.62 ± 4.22 miu/ml) (all were statically significant p < 0.05). lh levels did not table 1. demographic data of the patients. before (n = 100) after (n = 80) p value age (years) 21-55 (37.3 ± 9.72) 22-56 (38.3 ± 9.72) p = 1.0 n % n % regular sex habit 100 100.0 80 100.0 1.0 htn 28 35.0 10 12.5 < 0.001* dm-2 30 37.5 10 12.5 < 0.001* oa 40 50.0 15 18.8 < 0.001* dyslipidemia 80 100.0 15 18.8 < 0.001* used test: mc nemar test. *statistically significant htn: hypertension; dm-2: type 2 diabetes mellitus; oa: osteoarthritis. table 2. preoperative and postoperative iief-5 questionnaire. before (n = 100) after (n = 80) p value range mean sd range mean sd erectile function (1) 1-5 3.14 1.41 1-5 3.42 1.19 0.159 orgasmic function (4) 1-5 2.81 1.49 1-5 3.62 1.17 0.001* sexual desire (2) 1-5 3.24 1.41 1-5 3.51 1.14 0.152 intercourse function (3) 1-5 3.07 1.44 1-5 3.46 1.07 0.04* overall satisfaction (5) 1-5 2.96 1.33 1-5 3.48 1.16 0.008* used test: paired t test. *statistically significant. table 4. preoperative and postoperative anthropometric measures. before (n = 100) after (n = 80) p value range mean sd range mean sd weight (kg) 126-150 138 7.48 70-100 85 9.32 0.001* height (cm) 158-190 176 10.10 158-190 176 10.10 1.0 bmi (kg/m2) 35-56 45.5 6.70 20-36 28 4.92 0.001* wc (cm) 85-170 112.5 23.99 75-130 102.5 15.0 0.001* hc (cm) 100-180 140 18.64 90-125 107.5 9.73 0.001* used test: paired t test. *statistically significant. bmi: body mass index; wc: waist circumference; hc: hip circumference. table 3. preoperative and postoperative testosterone level. before (n = 100) after (n = 80) p value range mean sd range mean sd s. testosterone (ng/ml) 1.22-5.93 3.65 1.28 3.99-7.4 5.6 0.99 < 0.001* used test: paired t test. *statistically significant. archivio italiano di urologia e andrologia 2025; 97(2):13912 a. lamey, t.a. abouelgreed, o. abdelmoneim, et al. 4 change significantly (table 5). the pre and post operative (lsg) changes in bmi were shown on figure 2. discussion obesity has become an almost pandemic problem since the end of the 20th century and is associated with many comorbid conditions such as hypertension, diabetes mellitus, hyperlipidemia, obstructive sleep apnea, and many forms of sexual dysfunction. since originally introduced for treating morbid obesity in 1993, lsg has quickly gained popularity and became the most common technique of bariatric surgery in many parts of the world. with the increasing evidence of safety, efficacy, and a sharp reduction in the number of operations compared to other bariatric procedures, the surgical indications for bariatric surgery expanded from obesity alone to obesity with related comorbidities (12). however, we are not seeing the beneficial effect on the hormonal levels post lsg to be automatic and reaching a plateau, and sometimes more procedures are needed to reach a successful result. many researchers studied the sexual function of men and women following lsg, but to the best of our knowledge, this is the first study discussing the effect of lsg on erectile function of obese men in egypt. the findings of this study demonstrate a significant improvement in erectile function following lsg in obese egyptian men (13). the enhancement in erectile function, as measured by the iief-5, alongside the observed increase in serum testosterone levels, suggests a strong link between weight reduction and the restoration of sexual health in this population. one of the most compelling outcomes is the substantial increase in iief-5 scores postoperatively. this finding aligns with recent studies that have reported improvements in sexual function following bariatric surgery (14). weight loss achieved through lsg reduces adipose tissue, which is known to secrete estrogenic compounds that can negatively impact male sexual function (15). the reduction in estrogen levels likely contributes to the increase in free testosterone, which is crucial for maintaining erectile function (16). the observed increase in serum testosterone levels post-lsg is consistent with recent literature indicating that weight loss can reverse obesity-related hypogonadism (17, 18). enhanced leydig cell function and decreased aromatization of androgens in adipose tissue are probable mechanisms underlying this improvement (19). elevated testosterone levels contribute not only to improved erectile function but also to increased libido and overall sexual satisfaction (20). moreover, significant reductions were noted in prolactin, progesterone, and estradiol levels postoperatively. elevated prolactin levels have been associated with erectile dysfunction, and their reduction may further explain the improvement in sexual function observed in this study (21). lower progesterone and estradiol levels indicate a restoration of hormonal balance, which is essential for normal sexual function in men (22). the significant decrease in inflammatory markers such as crp post-lsg suggests a reduction in systemic inflammation, which plays a role in endothelial dysfunction (a key factor in the pathogenesis of erectile dysfunction) (23). improved endothelial function enhances penile blood flow, thereby improving erectile capacity (24). furthermore, the study reported notable improvements in metabolic parameters, including reductions in total cholesterol and hba1c levels. improved lipid profiles and glycemic control reduce the risk of cardiovascular diseases, which are closely linked to erectile dysfunction. these metabolic enhancements likely contribute synergistically to the improvement in erectile function postsurgery (25, 26). on the other hand, recent research by smith et al. found no significant improvement in erectile function in a cohort of obese men who underwent lsg, despite notable weight loss and changes in metabolic parameters (27). the study suggested that the lack of improvement in sexual function might be attributed to table 5. preoperative and postoperative biochemical tests changes. before (n = 100) after (n = 80) p value range mean sd range mean sd total cholesterol (mg/dl) 210-288 247.0 24.13 120-190 158.8 20.18 0.001* hba1c (%) 6-10 8.13 1.22 4.5-8.0 7.050 0.83 0.001* crp (mg/l) 6-34 20.50 8.21 7-14 11.04 2.31 0.001* prolactin (ng/ml) 10-22 17.37 3.47 9-20 14.30 3.51 0.001* progesteron (ng/ml) 0.1-0.8 0.518 0.18 0.1-0.7 0.397 0.16 0.001* estradiol (pg/ml) 10-80 46.61 22.11 10-40 25.32 8.27 0.001* fsh (miu/ml) 1.9-17 10.09 4.55 1.4-15.4 8.62 4.22 0.03* lh (miu/ml) 1.8-8.5 4.82 1.97 1.3-8 4.66 1.95 0.615 used test: paired t test. *statistically significant. figure 2. diversity change in bmi before and after lsg. archivio italiano di urologia e andrologia 2025; 97(2):13912 5 laparoscopic sleeve gastrectomy (lsg) and erectile function the persistence of psychological factors such as body dysmorphia and residual depression, which bariatric surgery alone may not address. additionally, jones et al. reported that while hormonal changes post-lsg were evident, these did not consistently translate into improved erectile function across all participants, particularly in older men or those with pre-existing severe erectile dysfunction (28). these studies highlight the complex relationship between weight loss, hormonal changes, and sexual function, suggesting that other factors beyond physiological improvements may influence outcomes. despite the promising results, certain limitations should be acknowledged. the study's sample was limited to obese egyptian men, which may affect applying the findings to other populations with different ethnic and cultural backgrounds. additionally, the follow-up period of one year, while adequate to observe significant changes, may not capture the long-term sustainability of these improvements. future prospective multicentric studies with larger, more diverse sample and extended follow-up periods are recommended to validate and expand upon these findings. conclusions a significant enhancement in the erectile function was observed in obese egyptian men following lgs. this improvement was evidenced both clinically through increased iief scores after surgery and biochemically through increased serum testosterone level. references 1. angrisani l, santonicola a, iovino p, et al. bariatric surgery worldwide. obes surg. 2015; 25:1822-32. 2. buchwald h, oien dm. metabolic/bariatric 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surgery on sex hormones and fertility in women. obes surg. 2018; 28:709-721. 10. doumouras ag, saleh c, gmora s, et al. erectile function improves after bariatric surgery: a prospective, multicenter study. surg endosc. 2018; 32:624-631. 11. rhoden el, telöken c, sogari pr, vargas souto ca. the use of the simplified international index of erectile function (iief-5) as a diagnostic tool to study the prevalence of erectile dysfunction. int j impot res. 2002; 14:245-50. 12. abouelgreed ta, elatreisy a, el-sherbeiny af, et al. long-term effect of sleeve gastrectomy surgery on hormonal profile, semen parameters and sexual functions of obese infertile men; a prospective observational study. basic clin androl. 2023; 33:16. 13. el-nahas ar, el-kassas gm, salah mh, et al. impact of bariatric surgery on male sexual function: a prospective study. surg endosc. 2022; 36:3089-95. 14. hudson dt, ortiz-garcía c, brackett nl, et al. sexual dysfunction and reproductive function in obese men: the impact of bariatric surgery and weight loss. obes surg. 2020; 30:3834-42. 15. piché me, poirier p, lemieux i, després jp. overview of epidemiology and contribution of obesity and body fat distribution to cardiovascular disease: an update. prog cardiovasc dis. 2018; 61:103-13. 16. grossmann m, ng tang fui m, cheung as. management of obesity in men with type 2 diabetes and hypogonadism: an update. curr opin endocrinol diabetes obes. 2019; 26:168-74. 17. woodard ga, encarnacion b, downey j, et al. impact of weight loss surgery on the sex steroid profile in obese men. surgery. 2019; 165:87-92. 18. hackett g, kirby m, wylie k, et al. british society for sexual medicine guidelines on adult testosterone deficiency, with statements for uk practice. j sex med. 2017; 14:1504-23. 19. kayser bd, elliott je, symons r, et al. sexual function after bariatric surgery: a review. jama surg. 2021; 156:944-51. 20. duarte-garcia ja, clifton mm, kollengode a, et al. effect of declarations ethical approval and consent for participate: all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by ethical committee under the institutional review board (irb 1012/2022). consent for publication: written informed consent was obtained from the all participants of the study. availability of data and material: data sets used in this study are available upon reasonable request from the corresponding authors. competing interests: the authors declare no conflicts of interest. funding: the authors did not receive any financial support for the research, authorship and/or publication of this article. authors' contributions: al, ta, oa, ms, ae: manuscript preparation, protocol, data collection and management, manuscript editing; mr, sk, om, mm, ea: data acquisition, data analysis and management, manuscript editing; mf, mh, aw, sg, my: manuscript editing, project development; data analysis, project development. all authors have read and approved the manuscript. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13912 a. lamey, t.a. abouelgreed, o. abdelmoneim, et al. 6 bariatric surgery on sex hormones and sexual function in men: a systematic review and meta-analysis. obes rev. 2020; 21:e13041. 21. isidori am, giannetta e, greco ea, et al. effects of testosterone on sexual function in men: results of a meta-analysis. clin endocrinol (oxf). 2017; 87:444-56. 22. fronczak cm, kim ed, barqawi ab. the insults of obesity on male fertility and sexual function. curr urol rep. 2012; 13:289-96. 23. lima ea, de faria baracat ew, et al. inflammatory markers and endothelial function in patients undergoing bariatric surgery. obes surg. 2020; 30:1243-51. 24. yafi fa, jenkins l, albersen m, et al. erectile dysfunction. nat rev dis primers. 2016; 2:16003. 25. tsai s, shope cd, woo s, et al. effects of bariatric surgery on cardiovascular disease risk: a 5-year comparative analysis. obes surg. 2020; 30:4105-14 26. hannan jl, maio mt, komolova m, et al. the role of chronic diseases in erectile dysfunction: an integrative review and proposed conceptual model. j sex med. 2022; 19:1595-607. 27. smith ab, johnson lm, patel n, et al. lack of improvement in erectile function following laparoscopic sleeve gastrectomy: the role of psychological factors. obes surg. 2023; 33:1123-30. 28. jones c, brown l, perez g, et al. age-related differences in the sexual function outcomes of bariatric surgery in obese men. j urol. 2022; 208:132-40. correspondence ahmed lamey (corresponding author) dr.ahmedlamey@gmail.com department of general surgery, faculty of medicine, kafr elsheikh university, egypt & burjeel royal hospital, al-ain, uae tamer a. abouelgreed dr_tamer_ali@yahoo.com osama m. ghoneimy elgendyosama787@gmail.com maha m. elzamek maha_201001@yahoo.com mohamed f. elebiary dr_elebiary@yahoo.com mohamed hindawy hindawy78@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt osama abdelmoneim osama.md99@gmail.com mohamed sherif ali mohamedsherifaliahmed@gmail.com ahmed elshaboury a_elshaboury@outlook.com; aaelshaboury@gmail.com department of general surgery, faculty of medicine, mansoura university, egypt mohamed rehan mrehan4040@gmail.com saed khater dr.saedkhater@gmail.com esam a. elnady esammohsen@gmail.com department of urology, faculty of medicine, al-azhar university, damietta, egypt ahmed wahsh hudaahmed320@gmail.com department of urology, faculty of medicine, al-azhar university, assiut, egypt satyabrata garanayka drgadanayak@gmail.com department of urology, thumbay university hospital, ajman, uae mohamed y. elamir yousry82@kasralainy.edu.eg department of andrology, faculty of medicine, cairo university, cairo, egypt stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14142 1 original paper telmisartan, an angiotensin ii receptor blocker with partial ppar-γ agonist activity, has been shown to enhance testicular health and mitigate testicular damage in diabetic rat models (4). furthermore, moderate-intensity aerobic exercise (miae) for ten weeks has been reported to improve johnsen score and increase seminiferous tubule diameter by reducing reactive oxygen species (ros) in diabetic rats (5, 6). we selected moderate-intensity aerobic exercise over high-intensity protocols because the latter is widely recognized as a physiological stressor that may negatively impact overall health. high-intensity exercise has been linked to increased oxidative stress, which can detrimentally affect the male reproductive system (7). additionally, excessive training may induce overtraining syndrome, characterized by hormonal imbalances that disrupt spermatogenesis. prior evidence indicates that high-intensity exercise impairs germ cell development and compromises the viability of germinal lineages and sertoli cells within the seminiferous tubules (8, 9). therefore, based on previous studies, moderate-intensity aerobic exercise for ten weeks is considered the optimal regimen for supporting reproductive health while minimizing potential adverse effects (5, 6). telmisartan (6 mg/kg body weight) has been shown to prevent diabetesinduced testicular damage when administered for a minimum of four weeks (4). however, to our knowledge, no prior study has directly investigated the combined effects of these two interventions. this study examined the synergistic effects of telmisartan and moderate-intensity aerobic exercise on testicular histoarchitecture in stz-induced diabetic rats. materials and methods study design this study used a true experimental, post-test-only control group design to evaluate the effects of telmisartan and miae on testicular histopathology in diabetic rats. thirty-nine healthy male wistar rats (12 weeks old, 140180 grams) were randomly assigned to five groups: • k0: healthy control • k1: diabetic control background: diabetes mellitus (dm) is associated with testicular damage, leading to male infertility. this study investigates the effects of telmisartan, moderate-intensity aerobic exercise, and their combination on testicular histopathology in a streptozotocin-induced diabetic rat model. methods: male wistar rats were divided into five groups: healthy control (k0), diabetic control (k1), telmisartan monotherapy (k2), aerobic exercise monotherapy (k3), and combination therapy (k4). diabetes was induced using streptozotocin (stz), and treatments were administered for 10 weeks. testicular histopathology was assessed by evaluating johnsen score, sertoli cell count, leydig cell count, and seminiferous tubule diameter. results: diabetic rats (k1) showed significant declines in johnsen score, sertoli and leydig cell counts, and seminiferous tubule diameter (p < 0.05). telmisartan (k2) and combination therapy (k4) significantly improved all parameters, with values approaching those of healthy controls (k0). aerobic exercise (k3) improved seminiferous tubule diameter but had limited effects on johnsen score, sertoli, and leydig cells. kruskalwallis, mann-whitney u, anova, games-howell, and lsd tests confirmed these findings. conclusions: telmisartan, either as monotherapy or in combination with moderate-intensity aerobic exercise, effectively ameliorates testicular damage in diabetic rats. aerobic exercise alone has a partial protective effect. these findings suggest potential therapeutic strategies for preventing diabetes-induced male infertility. key words: diabetes mellitus; telmisartan; aerobic exercise; testicular histopathology; male infertility. submitted 14 july 2025; accepted 28 july 2025 introduction diabetes mellitus (dm) is known to impair male reproductive health, often leading to infertility (1). in diabetic conditions, testicular function is compromised, with significant reductions in testosterone levels, as well as impaired spermatogenesis and sperm motility (2). the prevalence of infertility among men with dm is reported to range from 35% to 51% (3). guarding masculinity: telmisartan and aerobic exercise preserve testicular histomorphometry in diabetic rats ali akbar firasi 1, 2, mohammad ayodhia soebadi 1, 2, soetojo wirjopranoto 1, 2, ghazian adli 1, 2, anny setijo rahaju 3, 4 1 department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 department of urology, dr. soetomo general academic hospital, surabaya, indonesia; 3 department of anatomical pathology, faculty of medicine, universitas airlangga, surabaya, indonesia; 4 department of anatomical pathology, dr. soetomo general academic hospital, surabaya, indonesia. doi: 10.4081/aiua.2025.14142 summary archivio italiano di urologia e andrologia 2025; 97(3):14142 a. akbar firasi, m. ayodhia soebadi, s. wirjopranoto, et al. 2 • k2: diabetic + telmisartan • k3: diabetic + miae • k4: diabetic + telmisartan + miae after 10 weeks of intervention, all rats were euthanized via intraperitoneal injection of ketamine (300 mg/kg) and xylazine (30 mg/kg), followed by cervical dislocation and decapitation to ensure humane and complete sacrifice. induction of diabetes mellitus diabetes was induced by a single stz injection (35 mg/kg, i.p.). rats with fasting glucose > 150 mg/dl after 7 days were classified as diabetic. treatment protocols • telmisartan: 6 mg/kg/day orally via gavage for 10 weeks. • moderate intensity aerobic exercise: rats in the k3 and k4 groups performed swimming exercises in a cylindrical tank (diameter 45 cm, water depth 55 cm) for 60 minutes/day, 5 days/week (monday-friday) for 10 weeks. swimming was supervised, and sessions were terminated if rats could not keep their heads above water for more than 3 seconds without effort. non-compliance in three consecutive sessions led to exclusion. sample collection and histological preparation at week 10, after euthanasia testes were collected from rats, fixed, and embedded in paraffin. sections (5 µm) were stained with h&e for analysis of: • johnsen score • sertoli cell count • leydig cell count • seminiferous tubule diameter a single anatomical pathology specialist evaluated five non-overlapping fields per rat using a leica flexacam i5 microscope and enersight software. tubule diameter was assessed at 100×; johnsen score, sertoli, and leydig cells at 400×. johnsen score the johnsen scoring system rates spermatogenesis from 1 to 10, with higher scores reflecting greater germ cell maturity and better testicular function (table 1) (1). statistical analysis data were analyzed using spss. normality was tested with shapiro-wilk; homogeneity with levene’s test. oneway anova with tukey’s post hoc was applied for normal data, and kruskal-wallis with mann-whitney u for non-normal data. significance was set at p < 0.05. ethical considerations this study received ethical approval for animal experimentation from the institutional ethics committee 88/ec/kepk/fkua/2025. results diabetic rat model thirty-nine healthy male wistar rats (12 weeks old) were randomly assigned to five groups. diabetes was induced in all except the healthy control group (k0) using a single stz injection (35 mg/kg, intraperitoneal). rats with fasting glucose > 150 mg/dl after 7 days were classified as diabetic. the groups were: • k0: healthy control • k1: diabetic control • k2: diabetic + telmisartan (6 mg/kg/day, oral) for 10 weeks • k3: diabetic + exercise (60 min/day, 5 days/week) for 10 weeks • k4: diabetic + telmisartan + exercise all interventions were administered for a duration of 10 weeks. final fasting glucose was measured before euthanasia, and testicular tissues were collected for analysis (figures 1, 2). histological evaluation of testicular parameters the histological evaluation focused on four key testicular parameters: johnsen score, sertoli cell count, leydig cell count, and seminiferous tubule diameter. blood glucose levels all stz-induced groups (k1-k4) maintained fasting glucose levels > 150 mg/dl, confirming sustained hyperglycemia. no significant differences were found among diabetic groups (p > 0.05), indicating that treatments did not affect blood glucose levels (table 2). johnsen score analysis shapiro-wilk and homogeneity tests indicated a nonparametric distribution for johnsen scores (p < 0.05). table 1. johnsen score criteria for histological evaluation of testicular damage. score histological criteria 10 normal tubular epithelium, complete spermatogenesis, open lumen, ≥ 10 spermatozoa 9 damaged tubular epithelium, closed lumen, ≥ 10 spermatozoa 8 fewer than 10 spermatozoa 7 no spermatozoa, ≥ 10 spermatids 6 no spermatozoa, < 10 spermatids 5 no spermatozoa or spermatids, ≥ 5 spermatocytes 4 no spermatozoa or spermatids, < 5 spermatocytes 3 only spermatogonia present 2 only sertoli cells present 1 no cells present in the tubule table 2. blood glucose level. group blood sugar blood sugar 7 days after stz injection before termination k0 108.29 ± 9.84 k1 456.14 ± 137.001 490.43 ± 107.35 k2 349.13 ± 137.001 339.13 ± 156.76 k3 382.57 ± 136.15 381.42 ± 138.12 k4 344.71 ± 135.624 320.71 ± 131.35 archivio italiano di urologia e andrologia 2025; 97(3):14142 3 telmisartan and aerobic exercise in diabetic rats figure 1. representative hematoxylin and eosin (h&e)-stained sections of seminiferous tubules at 400× magnification. (a) spermatozoa; (b) spermatids; (c) spermatocytes; (d) sertoli cells; (e) leydig cells. k0: healthy control with normal tubular architecture and spermatogenesis (johnsen score 10). k1: diabetic control showing degeneration of seminiferous epithelium (johnsen score 5). k2: telmisartan-treated group showing nearcomplete restoration (johnsen score 10). k3: exercise-treated group with partial recovery (johnsen score 9). k4: combination therapy group showing nearcomplete restoration (johnsen score 10). figure 2. representative hematoxylin and eosin (h&e)-stained sections of seminiferous tubules at 100× magnification. the k1 group (diabetic control) exhibited the smallest average seminiferous tubule diameter (0.17 mm), which was significantly lower than that of all other groups. this reduction is visually apparent through the collapsed and irregular architecture of the seminiferous tubules, in stark contrast to the preserved tubular structure and normal diameter observed in groups k0, k2, k3, and k4. archivio italiano di urologia e andrologia 2025; 97(3):14142 a. akbar firasi, m. ayodhia soebadi, s. wirjopranoto, et al. 4 the kruskal-wallis test showed significant differences among groups (p < 0.001) (table 4). diabetic controls (k1) had the lowest mean johnsen score (4.53 ± 0.73), indicating severe testicular degeneration, while healthy controls (k0) showed normal spermatogenesis (9.50 ± 0.70). all treatment groups improved significantly: k2 (9.43 ± 0.37), k3 (8.44 ± 1.14), and k4 (9.69 ± 0.32), with k4 achieving the highest score. post hoc mann-whitney u tests showed significant differences between k1 and all treatment groups (p < 0.001). johnsen scores in k2 and k4 were comparable to k0, indicating effective preservation of testicular histology (figure 3). sertoli cell count shapiro-wilk and homogeneity tests indicated non-parametric distribution for sertoli cell counts (p < 0.05). kruskal-wallis analysis revealed significant table 3. mean values of johnsen score, sertoli cell count, leydig cell count, and seminiferous tubule diameter. group johnsen score sertoli cell leydig cell seminiferous tubule diameter (mm) k0 9.50 ± 0.70 4,40 ± 2.41 6.48 ± 1.97 0.33 ± 0.05 k1 4.53 ± 0.73 1.60 ± 1.15 1.70 ± 0.89 0.17 ± 0.04 k2 9.43 ± 0.37 5.11 ± 1.36 4.69 ± 0.63 0.28 ± 0.06 k3 8.44 ± 1.14 3.58 ± 1.07 3.18 ± 0.95 0.30 ± 0.05 k4 9.69 ± 0.32 6.00 ± 1.45 4.97 ± 1.02 0.32 ± 0.05 table 4. mean, median, normality test, and kruskal-wallis test for johnsen score. group mean ± sd median normality kruskal-wallis (min-max) (p-value) (p-value) k0 9.50 ± 0.70 9.80 (8.00 – 10.00) 0.013 < 0.001* k1 4.53 ± 0.73 4.60 (3.20 – 5.60) 0.498 k2 9.43 ± 0.37 9.60 (8.80 – 9.80) 0.271 k3 8.44 ± 1.14 8.80 (5.80 – 9.60) 0.052 k4 9.69 ± 0.32 9.80 (9.00 – 10.00) 0.011 figure 3. graphical presentation of the mannwhitney u test for johnsen score. significant differences are indicated as follows: *p < 0.05, **p < 0.01, ***p < 0.001. archivio italiano di urologia e andrologia 2025; 97(3):14142 5 telmisartan and aerobic exercise in diabetic rats (1.60 ± 1.15), indicating marked cellular impairment, while healthy controls (k0) showed significantly higher counts (4.40 ± 2.41). all treatments increased sertoli cell numbers: k2 (5.11 ± 1.36), k3 (3.58 ± 1.07), and k4 (6.00 ± 1.45). post hoc mannwhitney u tests confirmed significant differences between k1 and all treatment groups (p < 0.05). counts in k2 and k4 were comparable to k0, suggesting effective preservation of sertoli cells (figure 4). leydig cell count shapiro-wilk and homogeneity tests confirmed normal distribution of leydig cell counts (p > 0.05), permitting parametric analysis. one-way anova showed significant group differences (p < 0.001). diabetic controls (k1) had the lowest count (1.70 ± 0.89), indicating severe depletion, while healthy controls (k0) had substantially higher counts (6.48 ± 1.97) (table 6). all treatment groups showed significant increases in leydig cell count: k2 (4.69 ± 0.63), k3 (3.18 ± 0.95), and k4 (4.97 ± 1.02). post hoc games-howell tests confirmed significant differences between k1 and all treatment table 5. mean, median, normality test, and kruskal-wallis test of sertoli cell count. group mean ± sd median normality mann-whitney (min-max) (p-value) (p-value) k0 4.40 ± 2.41 4.70 (1.00 – 7.80) 0.241* < 0.001* k1 1.60 ± 1.15 1.50 (0.20 – 3.60) 0.665* k2 5.11 ± 1.36 5.40 (3.80 – 7.00) 0.116* k3 3.58 ± 1.07 4.00 (1.00 – 4.40) 0.002 k4 6.00 ± 1.45 5.40 (4.00 – 8.60) 0.565* table 6. mean, median, normality test, and kruskal-wallis test of sertoli cell count. group mean ± sd median normality anova (min-max) (p-value) (p-value) k0 6.48 ± 1.97 6.80 (3.20 – 8.80) 0.666* < 0.001* k1 1.70 ± 0.89 2.10 (0.20 – 2.80) 0.227* k2 4.69 ± 0.63 4.60 (4.00 – 6.00) 0.058* k3 3.18 ± 0.95 3.20 (1.00 – 4.40) 0.078* k4 4.97 ± 1.02 5.00 (3.00 – 6.20) 0.377* figure 4. graphical presentation of the mann-whitney u test for sertoli cell count. significant differences are indicated as follows: *p < 0.05, **p < 0.01, ***p < 0.001. group differences (p < 0.001) (table 5). the diabetic control group (k1) had the lowest mean sertoli cell count archivio italiano di urologia e andrologia 2025; 97(3):14142 a. akbar firasi, m. ayodhia soebadi, s. wirjopranoto, et al. 6 groups (p < 0.001). leydig cell counts in k2 and k4 were comparable to k0, indicating effective mitigation of diabetes-induced leydig cell depletion (figure 5). seminiferous tubules diameter shapiro-wilk and homogeneity tests confirmed normal distribution of seminiferous tubule diameter data (p > 0.05), permitting parametric analysis. one-way anova revealed significant differences among groups (p < 0.001) (table 7). the diabetic control group (k1) had the smallest seminiferous tubule diameter (0.17 ± 0.04 mm), while the healthy control (k0) had the largest (0.33 ± 0.05 mm). treatment groups showed significant improvements: k2 (0.28 ± 0.06 mm), k3 (0.30 ± 0.05 mm), and k4 (0.32 ± 0.05 mm). post hoc lsd analysis confirmed significant differences between k1 and all treatment groups (p < 0.05). telmisartan (k2), aerobic exercise (k3), and combination therapy (k4) all restored seminiferous tubule diameters to levels comparable with healthy controls (k0), indicating reversal of diabetes-induced tubular atrophy (figure 6). figure 5. graphical presentation of the post hoc gameshowell test for leydig cell count. significant differences are indicated as follows: *p < 0.05, **p < 0.01, ***p < 0.001. figure 6. graphical representation of the post hoc lsd test for seminiferous tubule diameter. significant differences are indicated as follows: p < 0.05, p < 0.01, *p < 0.001. table 7. mean, median, normality test, and one-way anova analysis of seminiferous tubule diameter. group mean ± sd median normality anova (min-max) (p-value) (p-value) k0 0.33 ± 0.05 0.32 (0.26 – 0.42) 0.284* < 0.001* k1 0.17 ± 0.04 0.17 (0,12 – 0.22) 0.561* k2 0.28 ± 0.06 0.26 (0,22 – 0.40) 0.185* k3 0.30 ± 0.05 0.28 (0,24 – 0.38) 0.193* k4 0.32 ± 0.05 0.32 (0.24 – 0.38) 0.568* archivio italiano di urologia e andrologia 2025; 97(3):14142 7 telmisartan and aerobic exercise in diabetic rats discussion this study evaluated the protective effects of telmisartan, moderate-intensity aerobic exercise, and their combination in stz-induced diabetic rats. all interventions significantly improved johnsen score, sertoli and leydig cell counts, and seminiferous tubule diameter compared to untreated diabetic controls. in diabetic controls, histopathology showed marked testicular damage, with reduced johnsen score (4.53 ± 0.73), sertoli cells (1.60 ± 1.15), leydig cells (1.70 ± 0.89), and seminiferous tubule diameter (0.17 ± 0.04 mm), indicating impaired spermatogenesis. these findings support prior evidence linking diabetes to oxidative stress, inflammation, and hormonal imbalance that disrupt testicular structure and function (1). rats with stz-induced diabetes maintained blood glucose levels above 150 mg/dl. compared to healthy controls, they showed significant reductions in johnsen score (4.53 ± 0.73), sertoli cell count (1.60 ± 1.15), leydig cell count (1.70 ± 0.89), and seminiferous tubule diameter (0.17 ± 0.04 mm), indicating testicular dysfunction. these findings align with evidence that chronic hyperglycemia increases ros, damages sertoli cells, disrupts the blood-testis barrier, and downregulates fsh receptor expression, ultimately impairing spermatogenesis (1). testicular tissue is highly vulnerable to oxidative stress, which can trigger germ and leydig cell apoptosis, impair function, and reduce sperm count and motility, as previously reported (12). chronic oxidative stress induces morphological changes in the seminiferous tubules, including degeneration of various germ cells, such as sertoli cell, spermatogonia, and spermatocytes (5, 13). in this study, telmisartan (k2), aerobic exercise (k3), and combination therapy (k4) significantly improved all testicular histological parameters compared to diabetic controls (k1). telmisartan alone markedly increased the johnsen score (9.43 ± 0.37), sertoli cells (5.11 ± 1.36), leydig cells (4.69 ± 0.63), and seminiferous tubule diameter (0.28 ± 0.06 mm). these effects are likely due to its anti-inflammatory and antioxidant actions, including tnf-α, nf-κb, and ros suppression, ppar-γ activation, enhanced insulin sensitivity, and stimulation of the hypothalamic-pituitary-gonadal axis (14-16). moderate-intensity aerobic exercise (k3) significantly improved testicular histology, with increased johnsen score (8.44 ± 1.14), sertoli cells (3.58 ± 1.07), leydig cells (3.18 ± 0.95), and seminiferous tubule diameter (0.30 ± 0.05 mm). these benefits are likely mediated by upregulation of hsp70, hsp90, gdnf, and enhanced glut-4-dependent glucose regulation (17-19). combination therapy (k4) produced the most favorable outcomes, with johnsen score (9.69 ± 0.32), sertoli cells (6.00 ± 1.45), leydig cells (4.97 ± 1.02), and seminiferous tubule diameter (0.32 ± 0.05 mm). however, differences between k4 and telmisartan alone (k2) were not statistically significant, suggesting that telmisartan monotherapy may be sufficient to restore testicular histology in diabetic conditions. compared to exercise alone (k3), telmisartan (k2) showed superior efficacy. aerobic exercise has limited ability to suppress pro-inflammatory mediators like tnf-α, caspase3, cox-2, and inos, and does not significantly affect ppar-γ or vegf expression. as a result, exercise primarily enhances structural recovery, especially seminiferous tubule diameter, without fully restoring johnsen score, sertoli and leydig cell count (14, 15, 20). telmisartan monotherapy (k2) significantly improved all histomorphometric parameters to levels comparable with healthy controls (k0). its protective effect is likely due to modulation of oxidative stress and inflammation, including reduced tnf-α, il-6, and ros, along with enhanced antioxidant enzyme activity. telmisartan also activates ppar-γ, a key regulator of spermatogenesis and testicular homeostasis (4). moderate-intensity aerobic exercise (k3) offered partial protection, notably preserving seminiferous tubule diameter. while it modestly improved johnsen score, sertoli, and leydig cell counts, the effects were less pronounced than with telmisartan or combination therapy. these findings suggest that exercise mainly supports structural integrity via improved blood flow and tissue remodeling but is insufficient for fully restoring spermatogenesis (5, 16, 21). combination therapy (k4) yielded the greatest improvements across all histomorphometric parameters, surpassing either monotherapy. this synergistic effect likely stems from telmisartan’s anti-inflammatory and antioxidant actions coupled with exercise-induced enhancements in blood flow and tissue repair. histological outcomes in k4 closely matched those of healthy controls, underscoring its potential as an effective strategy to preserve testicular function in diabetes (21). both telmisartan monotherapy and combination therapy effectively preserved testicular histology in diabetic rats, with outcomes comparable to healthy controls. in contrast, exercise alone primarily maintained seminiferous tubule diameter. these findings suggest that telmisartan’s broader protective mechanisms, anti-inflammatory, antioxidant, and hormonal are essential for preventing testicular damage and supporting spermatogenesis. telmisartan provides broad and potent protection of testicular histomorphometry in diabetic conditions through multiple molecular pathways. its key mechanisms include: (1) reducing oxidative stress; (2) activating the hypothalamic-pituitary-gonadal (hpg) axis via ppar-γ and improving insulin sensitivity; (3) suppressing inflammatory mediators such as tnf-α, il-6, nf-κb, caspase3, cox-2, inos, ros, no, 3-nitrotyrosine, and perk1/2; and (4) enhancing vegf expression to support testicular vascularization and function. in contrast, moderate-intensity aerobic exercise protects testicular tissue mainly through two mechanisms: (1) reducing oxidative stress and (2) enhancing insulin sensitivity via glut-4 activation, indirectly stimulating the hpg axis. while beneficial, its limited molecular targets likely account for its reduced efficacy in preserving johnsen score, sertoli and leydig cell count compared to telmisartan. moderate-intensity aerobic exercise primarily improves testicular structure particularly seminiferous tubule diameter by enhancing blood flow, oxygenation, and tissue remodeling. these changes promote rapid morphological recovery even in diabetic conditions. however, full functional restoration reflected by johnsen score and sertoli and leydig cell activity – depends on more complex endocrine and molecular adaptations, such as hpg archivio italiano di urologia e andrologia 2025; 97(3):14142 a. akbar firasi, m. ayodhia soebadi, s. wirjopranoto, et al. 8 axis normalization, hormonal balance, and germinal epithelium regeneration, which are slower to respond to exercise alone (5, 16, 22). while exercise may lead to early improvements in seminiferous tubule diameter, full restoration of johnsen score as well as sertoli and leydig cell counts requires more targeted metabolic and hormonal modulation. in comparison to the untreated diabetic group, all three therapies tested – telmisartan monotherapy, moderateintensity aerobic exercise monotherapy, and the combined therapy – demonstrated significant improvements in johnsen score, sertoli and leydig cell counts, and seminiferous tubule diameter. when compared to the healthy control group, only telmisartan monotherapy (k2) and combination therapy (telmisartan + exercise, k4) restored johnsen score, sertoli and leydig cell counts, and seminiferous tubule diameter to levels approaching those of healthy controls. aerobic exercise (k3) improved seminiferous tubule diameter but had limited effects on other parameters. telmisartan monotherapy was as effective as combination therapy in restoring johnsen score, normalizing sertoli and leydig cell counts, seminiferous tubule diameters in diabetic rats, with both approaches achieving near-complete recovery compared to healthy controls. while this study provides valuable insights into the testicular protective effects of telmisartan and aerobic exercise, several limitations must be acknowledged. first, the study used a rat model, and caution is required when extrapolating these findings to human clinical contexts. additionally, fertility-related outcomes, such as sperm quality, fertilization rates, and pregnancy success, were not assessed and should be the focus of future studies. the telmisartan dosage of 6 mg/kg body weight per day, while effective in the rat model, may not be directly translatable to human equivalents, necessitating dose optimization studies to determine the most appropriate and safe human dosage. the use of wistar rats, rather than human subjects, limits the broader applicability of these findings to clinical populations. furthermore, the study did not evaluate direct fertility measures, such as sperm quality, sperm retrieval, or pregnancy rates. the relatively high dose of telmisartan administered in this study (6 mg/kg) may also present challenges for potential human application. conclusions both telmisartan and moderate-intensity aerobic exercise, whether individually or combined, offer protective effects against testicular damage in diabetic rats. telmisartan monotherapy proved to be equally effective as the combined therapy in restoring testicular architecture and normalizing cellular profiles, with both approaches resulting in near-complete recovery of structural integrity and cell counts. these findings suggest promising therapeutic potential for mitigating diabetes-induced male infertility. however, further studies, including clinical trials, are required to confirm the applicability of these interventions in human populations. future studies should determine the minimum effective telmisartan dose and further explore combination therapy in clinical settings. evaluating fertility outcomes – such as sperm quality, icsi success, and pregnancy rates – will be crucial to to support clinical applicability. these findings warrant further investigation in clinical settings to evaluate whether similar protective effects are achievable in diabetic men at risk of infertility. references 1. adelati s, juniarto az, miranti ip. histopatologi spermatogenesis testis tikus wistar diabetes melitus. j kedokt diponegoro. 2016; 5:1760-9. 2. vale a, santos g, silva t, et al. influence of the at1 receptor antagonists telmisartan and losartan on reproduction and offspring after paternal exposure to ionizing radiation. reprod sci. 2019; 26:639-48. 3. lotti f, maggi m. effects of diabetes mellitus on sperm quality and fertility outcomes: clinical evidence. andrology. 2023; 11:399-416. 4. kushwaha s, jena gb. telmisartan ameliorates germ cell toxicity in the stz-induced diabetic rat: studies on possible molecular mechanisms. mutat res genet toxicol environ mutagen. 2013; 755:11-23. 5. toprak v, akalın sa, öcal e, et al. histopathological examination of the protective effect of intense exercise in apoptotic germ cell damage due to diabetes. acta cir bras. 2023; 38:e2023423. 6. alves mg, martins ad, cavaco je, et al. diabetes, insulin-mediated glucose metabolism and sertoli/blood-testis barrier function. tissue barriers. 2013; 1:e23992. 7. gumustekin m. hgf/c-met pathway has a role in testicular damage in diabetes induced by streptozotocin. acta endocrinologica (bucharest). 2017; 13:17-22. 8. aghamiri sm, eslami farsani m, seyedebrahimi r, et al. synergic effects of rosemary extract and aerobic exercise on sperm parameters and testicular tissue in an aged rat model. gene cell tissue. 2023; 10: e130832 9. santillo a, giacco a, falvo s, et al. mild exercise rescues declarations ethical approval: this study received ethical approval for animal experimentation from the institutional ethics committee 88/ec/kepk/fkua/2025. availability of data and material: all data generated or analyzed during this study are available upon request. competing interests: the authors declare that they have no competing interests. funding: his article receives no financial support. authors' contributions: af, ms, and sw contributed to the conception and design of the study. af organized the database, performed the data analysis, and wrote the first draft of the manuscript. ga and asr contributed to data interpretation and literature review. ms, sw, and asr critically revised the manuscript for important intellectual content. all authors contributed to manuscript revision, read, and approved the submitted version. acknowledgments: we want to thank all the staff at the department of urology, universitas airlangga, for their support. archivio italiano di urologia e andrologia 2025; 97(3):14142 9 telmisartan and aerobic exercise in diabetic rats steroidogenesis and spermatogenesis in rats submitted to food withdrawal. front endocrinol (lausanne). 2020; 11:302. 10. amaral lsb, souza cs, lima hn, soares tj. influence of exercise training on diabetic kidney disease: a brief physiological approach. exp biol med (maywood). 2020; 245:1142-54. 11. kraemer wj, ratamess na, volek js, et al. the effects of amino acid supplementation on hormonal responses to resistance training overreaching. metabolism. 2006; 55:282-91. 12. sato-horiguchi c, ogawa d, wada j, et al. telmisartan attenuates diabetic nephropathy by suppressing oxidative stress in mice. nephron exp nephrol. 2013; 121:97-108. 13. ballester j, muñoz mc, domínguez j, et al. insulin-dependent diabetes affects testicular function by fshand lh-linked mechanisms. j androl. 2004; 25:706-19. 14. imenshahidi m, roohbakhsh a, hosseinzadeh h. effects of telmisartan on metabolic syndrome components: a comprehensive review. biomed pharmacother. 2024; 171:116169. 15. guo z, yan x, wang l, et al. effect of telmisartan or insulin on the expression of adiponectin and its receptors in the testis of streptozotocin-induced diabetic rats. horm metab res. 2016; 48:404-12. 16. fouad aa, albuali wh, al-mulhim as, jresat i. protective effect of telmisartan treatment against arsenic-induced testicular toxicity in rats. z naturforsch c j biosci. 2015; 70:175-81. 17. maleki s, azarbayjani ma, malayeri sr, et al. the effect of aerobic exercise and ethanolic extract of rice bran on gene expression in rat liver. health nexus. 2024; 2:89-100. 18. samadian z, tofighi a, razi m, et al. effect of moderate-intensity exercise training on gdnf signaling in diabetic rat testes. diabetes res clin pract. 2020; 167:108332. 19. arafa m, elbardisi h, majzoub a. sperm retrieval in ejaculatory dysfunction. in: majzoub a, agarwal a, esteves sc, editors. the complete guide to male fertility preservation. cham: springer; 2018. p. 43-56. 20. barzilay ji, gao p, rydén l, et al. effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the transcend study. diabetes care. 2011; 34:1902-7. 21. widodo ey, i’tishom r, purwanto b. potensi ekstrak rumput kebar dalam mempertahankan jumlah sel sertoli mencit model diabetes melitus. j peneliti kesehatan suara forikes. 2020; 11:277-82. 22. chigurupati s, son tg, hyun dh, et al. lifelong running reduces oxidative stress and degenerative changes in the testes of mice. journal of endocrinology. 2008; 199:333-41. correspondence ali akbar firasi aliakbarfirasi@gmail.com mohammad ayodhia soebadi (corresponding author) yodisoebadi@gmail.com soetojo wirjopranoto s.tojowirjopranoto@yahoo.com ghazian adli ghazianadli@gmail.com department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia anny setijo rahaju anny_sr@fk.unair.ac.id department of anatomical pathology, faculty of medicine, universitas airlangga, surabaya, indonesia stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper about 1/1.000-1.500 of births and it is the most common form of congenital anomalies of the kidney and urinary tract (2, 3). until now the aetiology and pathogenesis of this anomaly are still unclear. they involved either genetic and/or environmental factors and the mechanism may involve abnormal innervation, impaired differentiation of smooth muscle and failure in development or recanalization of the uretero-pelvic junction (4-6). the most commonly diagnostic tool used to detect the function of the kidney and evaluate the extent and pattern of clearance of the urine from the urinary tract is diuretic-renography. the radionuclide of choice is technetium99m (99mtc) mercapto-acetyl-triglycine (mag3). the study must be performed under standardised circumstances as good hydration and a transurethral catheter if needed. the study should be done after the fourth-sixth weeks of life (7, 8). the surgical intervention is indicated when there are poor drainage function after the administration of furosemide, impaired split renal function (< 40%), a decrease of split renal function of > 10% in subsequent studies and grade iii or iv dilatation as defined by the society for foetal urology (9). the aim of this study is to compare ureter first approach and conventional anderson hynes pyeloplasty in terms of feasibility, duration of operation, efficacy, and complications. patients and methods this prospective randomized comparative study was conducted at al-azhar university hospitals during the period from march 2022 to december 2022. thirty-six cases with uretero-pelvic junction obstruction were assessed for eligibility. among them, six cases were excluded due to the presence of other congenital urological anomalies (ectopic pelvic kidney or horse-shoe kidney) (n = 2), underwent previous repair (n = 3), and pregnancy (18 years) (n = 1). thirty children were randomly divided into two groups according to a 1:1 ratio (computer-generated randomization, single blind). fifteen cases were subjected to ureter first approach pyeloplasty, and the rest were subjected to conventional anderson hynes (a-h) pyeloplasty (figure 1). an informed written consent was taken from parents of patients prior to the intervention. all patients were subjected to complete history taking, background: uretero-pelvic junction obstruction is the most common form of congenital anomaly of the kidney and urinary tract with an incidence of about 1/1.000-1.500 of births and the aetiology and pathogenesis of this anomaly are still unclear until now. methods: this is a prospective randomized comparative study conducted from march 2022 to december 2022. thirty children with uretero-pelvic junction obstruction were included and randomly divided into two groups according to a 1:1 ratio (computer-generated randomization, single blind). fifteen cases (12 males and 3 female) were subjected to ureter first approach pyeloplasty, and another fifteen (9 males and 6 female) were subjected to conventional anderson hynes pyeloplasty. results: the mean age of all patients was 6.7 ± 5.4 years in ureter first approach group and 5.1 ± 4.3 years in conventional anderson-hynes pyeloplasty group. there were no significant differences between the two groups regarding age, gender, presentation, side, preoperative renogram and post-operative renogram. also, there were no significant differences between the two groups regarding operative time (in first group 110.3 ± 12.4 and in the second group 111.2 ± 12.0 with p < 0.836), pre and post-operative complication rate. two cases of urinary tract infections in the first group, one of them having fever, and four cases in the second group, two of them having fever (p < 0.651); four cases of loin pain in the first group and one case in the second group (p < 0.330); one case in the first group having prolonged leakage of urine for 7 days in post-operative period (p < 0.309). however gfr and t ½ improved significantly after operation in both groups (p < 0.001). conclusions: ureter first approach is a simple and effective procedure in children with good short term outcomes and could be done safely especially for beginners and less expert surgeons. finally, it can overcome the problem of long ureteric stricture that may be found intraoperatively because you can shift easily to a flap procedure and complete a tension free anastomosis. key words: hydronephrosis; pyeloplasty; ureter first. submitted 1 february 2023; accepted 25 february 2023 introduction in uretero-pelvic junction (upj) obstruction, there is an impaired urine flow from renal pelvis to proximal ureter leading to dilatation of the pelvi-calyceal system with the risk of renal damage (1). incidence of upj obstruction is comparative study between ureter first approach and conventional open anderson-hynes pyeloplasty in paediatric patients: a prospective randomised study basem a. fathi, ahmed a. elgammal, tamer a. abouelgreed, osama m. ghoneimy, abdrabuh m. abdrabuh, mohamed a. hindawy, ahmed y. aboelsaad, hazem deif, alaa mahmoud department of urology, faculty of medicine, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11231 summary archivio italiano di urologia e andrologia 2023; 95, 1 b.a. fathi, a.a. elgammal, t.a. abouelgreed, et al. full physical examination and laboratory investigations including complete urine analysis, complete blood count, coagulation profile, urea and creatinine. in all patients, we routinely performed renal ultrasonography preoperatively. evaluation of patients with renal isotope scan were done in all children to confirm the obstruction and as a baseline for follow-up. four months after pyeloplasty another renal isotope scan was done for evaluation of renal drainage and function. the protocol of this study was approved by the research ethics committee of faculty of medicine for girls, al-azhar university (fmg-irb) (approval number: 1279). all procedures were in accordance with helsinki declaration. sample size was calculated by stata corp. 2021 (stata statistical software: release 17. college station, tx: stata corp llc). calculation was made considering an estimated incidence of uretero-pelvic junction (upj) obstruction of 1 in 1.000-1.500. using confidence limits of 5%, confidence level of 95%, required minimal sample size is 16. to compensate for lost follow up cases and to increase the power of the study, sample size was increased to 30 cases divided into 15 cases for each group. surgical technique after diagnosis, all patients underwent surgery without delay. the procedure was done in all children under general anaesthesia. retrograde pyelography was done to determine the exact length of obstructed part, urethral catheter was fixed, and then patients were turned in lateral position. after incision of skin and muscle, the ureter was identified in the extraperitoneal space on the affected side, dissection was performed around the pelvis and proximal part of the ureter, then 2 stay sutures were placed in the upper and lower part of the pelvis. anastomosis was done by 6-0 polyglycolic acid sutures. in the first group, ureter first approach technique was used. we performed an incision in the most dependent part of the pelvis on its lateral aspect and along the ureteral axis, then ureteric spatulation was done till the normal ureter. the apex of ureteric spatulation is sutured to the lowermost point on the lower pelvis lip using 6-0 polyglycolic acid sutures. the redundant pelvis tissue is completely dismembered from its small remaining attachment to the pelvis. suturing is continued along one wall of spatulation. double j stent was placed in an antegrade fashion. then opposite wall of upj is sutured, starting again from the apex of ureteric spatulation to meet its counterpart superiorly where it was continued to sew the two edges of pelvis (figure 2). in the second group conventional figure 1. consort chart of all studied cases. figure 2. steps of ureter first approach. a. 2 stay sutures were placed in the upper and lower part of the pelvis. b. an incision in the most dependent part of the pelvis on its lateral aspect and along the ureteral axis with spatulation of ureter to the normal lumen with suturing of the apex of ureteric spatulation to the lower-most point on the lower pelvis lip. c. cutting of the strictured segment of the proximal ureter and redundant part of pelvis. d. suturing is continued along one wall of spatulation. e. double j stent is placed in an antegrade fashion and the opposite wall of upj is sutured. f. final appearance after complete closure of pelvis. archivio italiano di urologia e andrologia 2023; 95, 1 pyeloplasty in paediatric patients anderson-hynes technique was used (10). an l-shaped incision with developing of a flap from the redundant part of the renal pelvis was done. then a stay suture was placed in the anterior wall of the ureter, ureter was spatulated laterally to the healthy part and then anastomosis was done between the ureter and pelvis using 6-0 polyglycolic acid sutures. before completion of the anastomosis, a stent was introduced through the ureter. after completion of the anastomosis, a drain was placed through another stab incision. patients were scheduled for follow-up after 1 week, then renal ultrasonography was done after 1 month. the ureteral stent was removed after 1 month and 4 months postoperatively an isotope scan was performed. success was defined subjectively by symptomatic relief and objectively by renal scan results that were evaluated as improved differential renal function > 5%, good drainage and t-half < 20 minutes. statistical analysis the collected data were revised, coded, tabulated and introduced in a pc using statistical package for social science (ibm corp. released 2017. ibm spss statistics for windows, version 25.0. armonk, ny: ibm corp.). student t test was used to assess the statistical significance of the difference between the two study group means. mann whitney test (u test) was used to assess the statistical significance of the difference of non-parametric variables between two study groups. chi-square test was used to examine the relationship between two qualitative variables. all reported p values were two-tailed and p < 0.05 was considered as significant. results there were no significant differences between both groups regarding age, gender, presentation, side and preoperative renogram as shown in table 1. also, no significant differences were found between both groups regarding post op renogram as shown in table 2 and figures 3, 4. we found that both gfr and t ½ improved significantly after operation among both groups and no significant differences regarding changes in gfr and t ½ between the two approaches as shown in table 3. the mean operative time for ureter first approach group was 110.3 ± 12.4 minutes, while the mean operative time for conventional anderson-hynes pyeloplasty group was 111.2 ± 12.0 with no significant statistical difference between the two groups (p = 0.836). there were no significant differences between both groups regarding blood loss, post-operative hospital stay and post-operative complications. we had two cases of uti in the first group (one of them had fever) and four cases in the second group (two of them had fever). they were managed by proper antibiotic and antipyretic treatment until the infection resolved after 10 days. also, there were four cases of loin pain in the first group and one case in the second group that were managed conservatively. one case in the first table 1. comparison of baseline parameters among studied groups. ureter first conventional p value approach anderson-hynes pyeloplasty n = 15 n = 15 age mean ± sd 6.7 ± 5.4 5.1 ± 4.3 0.368 range 0.40 16 0.25 13 gender male n, % 12 80.0% 9 60.0% 0.427 female n, % 3 20.0% 6 40.0% presentation antenatal hn n, % 3 20.0% 2 13.3% 0.624 asymptomatic n, % 7 46.7% 7 46.7% 1 symptomatic n, % 8 53.3% 8 53.3% symptoms uti n, % 5 33.3% 6 40.0% 0.705 loin pain n, % 3 20.0% 2 13.3% 0.624 side left n, % 9 60.0% 9 60.0% 1 right n, % 6 40.0% 6 40.0% pre op renogram rt gfr mean ± sd 56.2 19.8 61.4 15.6 0.431 range 25 82 34 81 lt gfr mean ± sd 56.0 17.8 50.8 20.1 0.460 range 32 81 25 81 t 1/2 mean ± sd 21.6 2.7 22.1 3.9 0.669 range 18 26 18 30 table 2. comparison of post-operative renograms between the two groups. ureter first conventional p value approach anderson-hynes pyeloplasty n = 15 n = 15 post op renogram rt gfr mean ± sd 64.1 12.4 67.3 9.4 0.434 range 34 82 47 81 lt gfr mean ± sd 63.9 11.2 61.4 11.9 0.553 range 45 81 43 81 t 1/2 mean ± sd 9.40 2.354 8.60 1.454 0.272 range 6 14 6 11 figure 3. pre and post-operative gfr by both approaches. figure 4. pre and post-operative t1/2 by both approaches. archivio italiano di urologia e andrologia 2023; 95, 1 b.a. fathi, a.a. elgammal, t.a. abouelgreed, et al. group had prolonged leakage of urine for 7 days’ postoperative and was managed conservatively after doing plain urinary tract x ray and abdomen-pelvic ultrasound showing no urinoma and the ureteric stent in place. leakage stopped after 7 days spontaneously and there was no need for second intervention (table 4). discussion upj obstruction is the most common cause of foetal kidney significant dilatation. despite this, the clinical presentation may be delayed until adulthood (11). many techniques for management of upj obstruction were mentioned throughout years and each of them had its advantages and disadvantages. they include open pyeloplasty (either dismembered or flap techniques), endo-pyelotomy and laparoscopic pyeloplasty (12). in our study we find that there was no statistically significant difference between the two groups of patients as regard the studied parameters. we believe this to be the first study to compare both techniques for repair of primary upj obstruction. in the conventional a-h pyeloplasty one of the problems that may happen during the operation, especially to the beginners, is the twisting of the ureter during anastomosis that may not discovered during the procedure and can result in postoperative complications as increase time of leakage of urine in the drain and lead to recurrence of stricture. another problem is that after excision of the redundant pelvis, the segment of stricture of ureter may be long resulting in difficult direct anastomosis to pelvis and requiring use of the redundant pelvic tissue for flap procedure. those main problems could be overcome easily in ureter first approach pyeloplasty as in this technique the pelvis remained attached in its upper end until nearly the end of operation. so, it is avoided the rotation of ureter that may happen during the anastomosis and if the segment of stricture is long you can shift easily to the flap procedure technique. during our search, we found only one study describing ureter first approach technique. nayyar et al. (13) in their study that included fifty-one patients that had repair using ureter first approach technique found that there were no failures after follow up of cases that required reintervention. they concluded that ureter approach could prevent unnecessary tissue loss if a wrong incision was done and could allow good tension-free anastomosis in all cases especially the uncommon ones like low insertion of the ureter and long segment of upjo. they thought that such approach can also standardize the steps of pyeloplasty surgery and could reduce the surgical mistakes that may happen to newer surgeons or residents (13). there were multiple modifications of conventional a-h pyeloplasty aiming at reducing complications and make the procedure easier to perform (14-16). recently, the advancements in urologic laparoscopy make feasible complex procedures, as pyeloplasty, that could be performed laparoscopically with the advantage of short hospital stay, less pain postoperatively and reduced morbidity but with longer operative time. furthermore, comparative studies between open and laparoscopic dismembered pyeloplasty found that incidence of complications and functional outcome were nearly the same for both groups in adults (1719). our study has some limitations including being a single center study and the short term follow up of cases. in the future we plan to perform a multicenter study with long-term follow up to obtain more information and provide more impressive results. conclusions as a conclusion we thought that ureter first approach is a simple and effective procedure in children with good short term outcomes and could be done safely especially for beginners and less expert surgeons. also, it can overcome the problem of long ureteric stricture that may be found intraoperatively because you can shift easy to a flap procedure and complete the repair without the need of more kidney and ureter mobilization to make tension free anastomosis. ethical approval and consent for participation all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of the faculty of medicine for girls, al-azhar university (fmgirb) (approval number: 1279). table 3. comparison of pre and post-operative renogram. ureter first approach conventional anderson-hynespyeloplasty pre post p1 pre post p2 p3 n = 15 n = 15 n = 15 n = 15 rt gfr mean ± sd 56.2 19.8 64.1 12.4 < 0.001 61.4 15.6 67.3 9.4 < 0.001 0.851 range 25 82 34 82 34 81 47 81 lt gfr mean ± sd 56.0 17.8 63.9 11.2 < 0.001 50.8 20.1 61.4 11.9 < 0.001 0.368 range 32 81 45 81 25 81 43 81 t 1/2 mean ± sd 21.6 2.7 9.40 2.354 < 0.001 22.1 3.9 8.60 1.454 < 0.001 0.196 range 18 26 6 14 18 30 6 11 p1: comparison between pre and post level after ureter first approach. p2: comparison between pre and post level after conventional anderson-hynes pyeloplasty. p3: comparison of pre and post-operative changes between ureter first approach and conventional anderson-hynes pyeloplasty. table 4. comparison of outcome among studied groups. ureter first conventional p value approach anderson-hynes pyeloplasty n = 15 n = 15 blood loss mean ± sd 9.3 1.8 9.5 1.6 0.832 range 6 12 6 12 hospital stay mean ± sd 1.4 0.5 1.6 0.6 0.347 range 1 2 1 3 post op fever n, % 1 6.7% 2 13.3% 0.543 complications uti n, % 2 13.3% 4 26.7% 0.651 prolonged leakage n, % 1 6.7% 0 0.0% 0.309 loin pain n, % 4 26.7% 1 6.7% 0.330 archivio italiano di urologia e andrologia 2023; 95, 1 pyeloplasty in paediatric patients references 1. al aaraj ms, badreldin am. ureteropelvic junction obstruction. 2022 jul 11. in: statpearls (internet). treasure island (fl): statpearls publishing; 2022. 2. klein j, gonzalez j, miravete m, et al. congenital ureteropelvic junction obstruction: human disease and animal models. int j exp pathol. 2011; 92:168-92. 3. chang cp, mcdill bw, neilson jr, et al. calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. j clin invest. 2004; 113:1051-8. 4. avanoglu a, tiryaki s. embryology and morphological (mal)development of upj. front pediatr. 2020; 8:137. 5. ruano-gil d, coca-payeras a, tejedo-mateu a. obstruction and normal recanalization of the ureter in the human embryo. its relation to congenital ureteric obstruction. eur urol. 1975; 1:287-293. 6. kajbafzadeh am, payabvash s, salmasi ah, et al. smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. j urol. 2006; 176:718-723. 7. wong jc, rossleigh ma, farnsworth rh. utility of technetium99m-mag3 diuretic renography in the neonatal period. j nucl med. 1995; 36:2214-9. 8. eshima d, taylor a jr. technetium-99m (99mtc) mercaptoacetyltriglycine: update on the new 99mtc renal tubular function agent. semin nucl med. 1992; 22:61-73. 9. kazlauskas v, cekuolis a, bilius v, et al. diuretic enhanced ultrasonography in the diagnosis of pyeloureteral obstruction. medicina (kaunas). 2019; 55:670. 10. anderson jc, hynes w. plastic operation for hydronephrosis. proceedings of the royal society of medicine. 1951; 44:4-5. 11. brown t, mandell j, lebowitz rl. neonatal hydronephrosis in the era of sonography. ajr am j roentgenol. 1987; 148:959-63. 12. tan bj, rastinehad ar, marcovich r, et al. trends in ureteropelvic junction obstruction management among urologists in the united states. urology. 2005; 65:260-264. 13. nayyar r, kumar p, panaiyadiyan s, seth a. ureter-first approach and reduction of pelvis: standardizing handling of ureteropelvic junction during pyeloplasty. urology. 2022; 160:210216. 14. dayanc m, kibar y, irkilata hc, et al. a new modification of dismembered pyeloplasty for primary ureteropelvic junction obstruction. eur surg res. 2008; 40:225-9. 15. diamond da, nguyen ht. dismembered v-flap pyeloplasty. j urol. 2001; 166:233-235. 16. salehipour m, khezri a, azizi v, kroup m. open dismembered tubularized flap pyeloplasty: an effective and simple operation for treatment of ureteropelvic junction obstruction. urol int. 2006; 76:345-7. 17. ravish ir, nerli rb, reddy mn, amarkhed ss. laparoscopic pyeloplasty compared with open pyeloplasty in children. j endourol. 2007; 21:897-902. 18. mei h, pu j, yang c, et al. laparoscopic versus open pyeloplasty for ureteropelvic junction obstruction in children: a systematic review and meta-analysis. j endourol. 2011; 25:727-736. 19. umari p, lissiani a, trombetta c, belgrano e. comparison of open and laparoscopic pyeloplasty in ureteropelvic junction obstruction surgery: report of 49 cases. arch ital urol androl. 2011; 83:169-174. correspondence basem a. fathi, md basemhara@gmail.com basemabdalla.8@azhar.edu.eg ahmed a. elgammal, md aelgammal36@gmail.com tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg osama m. ghoneimy, md elgendyosama787@gmail.com abdrabuh m. abdrabuh, md abdo197871@yahoo.com mohamed a. hindawy, md hindawy78@gmail.com hazem deif, md hazemdeif@yahoo.com alaa mahmoud, md dralaarefaat@gmail.com department of urology, faculty of medicine, al-azhar university, assiut, egypt ahmed y. aboelsaad, md aboelsaadurology@hotmail.com department of urology, faculty of medicine, al-azhar university, damietta, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 455archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. these commensal, symbiotic or pathogenic microorganisms is called human microbiota. the human microbiota is mainly located at four anatomical regions: skin, genitourinary system, respiratory system, and gastrointestinal system (3). the full array of these microorganisms that live on and in humans and, more specifically, the collection of microbial genomes that contribute to the genetic portrait is called the human microbiome. the specific changes in the microbiome are named dysbiosis (3). the gut microbiome plays a major role in the regulation, maturation, and function of the host immune system from the birth. the immune system has co-evolved a mutualistic relationship with the gut microbiome residing our bodies while mounting efficient responses to fight invading pathogens. distortion of the balance between the useful and harmful intestinal microorganisms in favor of the harmful ones was associated with acute or chronic disease processes such as irritable bowel syndrome, inflammatory bowel disease, allergic diseases, obesity, depression, atherosclerosis, and colon cancer (4). it was reported that urinary dysbiosis was associated with lower urinary tract symptoms (5). however, while the relevant studies were conducted with adult patients, none included the pediatric population. therefore, we investigated the differences between children with and without vd regarding intestinal (fecal) microbiota. materials and methods this study was approved by the ethical review committee of the sitki kocman university (180172). informed consent was obtained by parents or caregivers of all participants who signed the relevant forms before assignment to the study. the subjects were selected among children aged between 5 and 16 who presented to the pediatric urology and nephrology outpatient clinics. patients with congenital genitourinary (gu) or gastrointestinal (gi) anomalies, gi diseases, acute infections, neurological anomalies, and chronic constipation were excluded. also, patients with a history of gu surgery, gi surgery, or monosymptomatic enuresis, those treated for vd or given antibiotics, antiviral or antifungal medications during the last six months were omitted. any functional disturbance in voiding after the completion of toilet training was defined as vd. this occurs due to over activity or inadequate relaxation of the pelvic floor muscles, which are striated muscles under voluntary control. the objective: voiding dysfunction (vd), which encompasses many urinary symptoms that are not caused by neurological or anatomical anomalies, is a frequently encountered functional urinary bladder disorder in children. it was reported that there was an association between lower urinary tract symptoms and fecal microbiota in adult patients. therefore, we aimed to investigate the differences in fecal microbiota between children with or without vd. methods: two patient groups, including 30 patients, were compared. group 1 included patients with vd, while group 2 consisted of healthy children. all study participants were asked to fill lower urinary tract and voiding dysfunction symptom score forms with the assistance of their parents. subsequently, uroflowmetry tests and postvoiding residual urine measurements were performed. fresh stool samples were collected from all children and analyzed by polymerase chain reaction. general bacterial load and presence of roseburia intestinalis, clostridium difficile, fusobacterium nucleatum, and bacteroides clarus were tested. results: the two groups were significantly different regarding general bacterial load; the presence of fusobacterium nucleatum. clostridium difficile and bacteroides clarus was not detected in the fresh stool samples of the patients in group 2; the counts of roseburia intestinalis were less in group 1 than in group 2, although there was no statistically significant difference. there was a negative correlation between symptom scores, general bacterial load, and the presence of fusobacterium nucleatum. however, there was no correlation between the presence of roseburia intestinalis and symptom scores. conclusions: there is a potential relationship between vd and a deviation in the fecal microbiota in the pediatric population. key words: voiding dysfunction; fecal microbiota; fecal microbiota change. submitted 28 october 2022; accepted 6 november 2022 introduction voiding dysfunction (vd) is also named bladder dysfunction in children. it is a general term encompassing both voiding and storage dysfunctions. it is a functional bladder anomaly encountered in children who do not have any neurological and anatomical abnormalities. it is not rare in children; approximately 40% of children presenting to pediatric urology clinics are affected by vd (1, 2). the human body is a complex system hosting various microorganisms, including bacteria, fungi, and parasites. the assemblage of is there a difference in fecal microbiota of children with and without voiding dysfunction? ilker akarken 1, hüseyin tarhan 1, gamze şener 2, hasan deliktas 1, nurcan cengiz 3, hayrettin şahin 1 1 mugla sıtkı kocman university, school of medicine, department of urology, turkey; 2 izmir katip celebi university, school of medicine, department of microbiology, turkey; 3 mugla sıtkı kocman university, school of medicine, department of pediatric nephrology, turkey. doi: 10.4081/aiua.2022.4.455 summary archivio italiano di urologia e andrologia 2022; 94, 4 i. akarken, h. tarhan, g. şener, h. deliktas, n. cengiz, h. şahin 456 patients presented to outpatient clinics with lower urinary tract symptoms (luts) and diagnosed with vd were included in group 1. group 2 consisted of healthy pediatric patients who presented to the same outpatient clinic for check-up purposes. all study participants were evaluated regarding luts with the assistance of their caregivers. first, voiding dysfunction symptom score (vdss) forms were filled for each subject (6). subsequently, a uroflowmetry test was performed. next, the voiding patterns (i.e., normal, parabolic, tower, plateau, staccato, interrupted) and voided volumes were recorded for each patient. following this, post-voiding residual urine volumes were measured and recorded. a 3-gram fresh stool sample was collected from all patients, and the samples were stored at -80°c. analysis of the stool samples dna isolation roche magna pure compact robotic dna isolation system (roche, germany) protocol was used to isolate dna at room temperature. dna quantification the dna was quantified using a nanodrop 2000 (thermo scientific, usa). the absorbance ratios 260/280 and 260/230 were used to assess the purity of dna. real-time pcr (qpcr) fusobacterium nucleatum (fusn), clostridium difficile (clod), bacteroides clarus (bacc), roseburia intestinalis (rosin) and general intestinal bacteria (16sint) were detected in the samples. primers and the taqman probe (hydrolysis probe) were designed for five targets (figure 1). the ready-to-use lyophilized primers (5 nmol) and probes (3 nmol) were wettened on synthesis paper (tib molbiol, germany) and diluted to 10 pmol/ul stocks. lightcycler480 probes master (roche diagnostics, germany) served as enzyme&master mix. the processes were implemented in lightcycler480 ii (roche diagnostics, germany). the results were analyzed in the abs quant/2nd derivative analysis module. samples creating sigmoidal curves were considered positive, while others were considered negative. general bacterial load was measured, and the presence of roseburia intestinalis, clostridium difficile, fusobacterium nucleatum, and bacteroides clarus was assessed. statistical analysis the kolmogorov-smirnov test was used for assessing the distribution of data. student’s t-test was used to compare the groups regarding continuous variables and the chisquare test was used to compare categorical variables. the pearson correlation coefficients (r) were used for correlation analysis. the data were displayed as means, standard deviations (sd), and ranges (minimum-maximum). the p value was considered statistically significant when it was less than 0,05. all statistical analyses were performed using the statistical package for social sciences software (spss v24, ibm corporation, new york, us). table 1. demographic and clinical data and results of the comparative analysis. groups group 1 group 2 p value ageyear 8.26 ± 1.9 8.00 ± 1.6 0.574 gender 0.902 female n (%) 15 (60.0) 14 (58.3) male n (%) 10 (40.0) 10 (41.7) frequency (8 >) 0.001 present n (%) 21 (84.0) 4 (16.7) absent n (%) 4 (16.0) 20 (83.3) urgency 0.001 present n (%) 19 (76.0) 6 (25.0) absent n (%) 6 (24.0) 18 (75.0) hesitancy 0.015 present n (%) 11 (44.0) 3 (12.5) absent n (%) 14 (56.0) 21 (87.5) terminal dribbling 0.001 present n (%) 18 (72.0) 4 (16.7) absent n (%) 7 (28.0) 20 (83.3) low urine flow rate 0.001 present n (%) 13 (52.0) 1 (4.2) absent n (%) 12 (48.0) 23 (95.8) maneuvers to hold urine 0.001 present n (%) 19 (76.0) 2 (8.3) absent n (%) 6 (24.0) 22 (91.7) interrupted voiding 0.001 var n (%) 16 (64.0) 4 (16.7) yok n (%) 9 (36.0) 20 (83.3) straining to void 0.001 present n (%) 15 (60.0) 0 (0.0) absent n (%) 10 (40.0) 24 (100) voiding pattern 0.001 normal n (%) 8 (32.0) 21 (87.5) staccato n (%) 6 (24.0) 0 (0) tower n (%) 11 (44.0) 3 (12.5) plateau n (%) 0 (0) 0 (0) interrupted n (%) 0 (0) 0 (0) voided volume 0.001 lower than expected bladder capacity (%) 17 (68.0) 1 (4.2) consistent with the expected bladder capacity (%) 8 (32.0) 23 (95.8) post-voiding residual urine volume (ml) 44.4 ± 21.6 19.4 ± 6.4 0.574 voiding dysfunction symptom scores 21.9 ± 6.9 6.3 ± 1.3 0.001 figure 1. primer sequences. gene sequencee fusn-f ttcaataaaagtggcaggtcaag fusn-r taacaacacatgcaggtcaatgg fusn-pr 6fam-actcgaacccccaaccctcggttt--tmr clod-f gcaagttgagcgatttacttcggt clod-r gtactggctcacctttgatattyaagag clod-pr 6fam-tgcctctcaaatatattatcccgtattag--tmr bacc-f tccatccgcaagcctttact bacc-r gcttccggtgccattgacta bacc-pr 6fam-ttcatcatcacagccgacaacgca--tmr rosin-f cggatttgcagtggcaagtt rosin-r tgattgcagacgccaatgtc rosin-pr 6fam-cgtgaaaaatccgcgcatctggc--tmr 16s-intc-f cgtcagctcgtgycgtgag 16s-intc-r cgtcrtccccrccttcc 16s-intc-pr hex-ttaagtcccryaacgagcgcaaccc--bbq 457archivio italiano di urologia e andrologia 2022; 94, 4 microbiota of children with urinary dysfunction results the mean patient age was 8.1 ± 0.25 (6-13). although we planned to include 30 patients in each group, 5 patients were excluded from group 1, and 6 patients were excluded from group 2 due to the failure in the dna isolation process. thus, there were 25 patients in group 1 and 24 patients in group 2. demographic data and clinical features of the study patients, including lower urinary tract symptoms, uroflowmetry, pvr measurement results, and voiding dysfunction symptom scores, are displayed in table 1. the comparative analysis revealed that general bacterial load and the rate of fusobacterium nucleatum presence were significantly lower in patients with vd than in healthy patients (p = 0.043 and p = 0.009, respectively). although roseburia intestinalis was present in fresh stool samples of both patient groups, its rate was relatively lower in the patient group with vd. clostridium difficile and bacteroides clarus were not detected in the fresh stool samples of the healthy patient group (table 2). in fresh stool samples, the correlation between voiding dysfunction symptom score (vdss) and general bacterial load, roseburia intestinalis, clostridium difficile, fusobacterium nucleatum, and bacteroides clarus counts were analyzed. there was a negative correlation between vdss and general bacterial load and fusobacterium nucleatum counts (p = 0.033 and p = 0.004, respectively). although there was also a negative correlation with roseburia intestinalis, it was statistically insignificant (p = 0.25) (table 3). since clostridium difficile was not detected in the fresh stool samples of the patients in group 2, a correlation analysis could not be performed. discussion since bowels have a 250 m2 absorptive surface area and a nutrient-rich content, they have the most extensive flora bearing various microorganisms. therefore, it is difficult to determine all types of bacteria and their counts included in the intestinal flora. however, investigations utilizing current methods elucidated more than 100 trillion bacteria and more than 1000 bacteria types in the bowel (7). the microbiota, which includes various and many microorganisms, starts to develop after birth. its initial content depends on genetic and geographical factors, route of labor, age at labor, and diet (8). continues to develop and modulate in species abundance for about 3 years, until the microbiota becomes adult-like. until age 1, bowel microbiota shows significantly less variation than microbiota in toddlers, adolescents, or adults. remarkable changes occur in the content of intestinal microbiota until age 3. the primary microbiota evolves to adult microbiota after age 3 regarding the variability of bacteria types (9, 10). anaerobic, facultative anaerobic, and aerobic bacteria are present in the gastrointestinal microbiota. approximately 90% of this flora consists of bacteroides and firmicutes species. other microbial phyla are actinobacteria, proteobacteria, verrucomicrobia, and fusobacteria. the bacteria investigated in our study were selected as per the variability in microbiota. the association between luts and urinary microbiome was previously reported using 16s rrna gene sequence (5). however, only a few studies investigated the association between intestinal microbiota and luts. holland et al. studied 30 male patients with luts and suggested a significant relationship between the symptom scores and the presence of specific bacteria types in the intestinal microbiota. of note, this study did not include a comparative analysis between patients with and without luts (11). braundmeier-fleming et al. compared the stool samples of the patients who had interstitial cystitis with those of healthy subjects (12). in line with our study, these researchers performed polymerase chain reaction (pcr) on stool samples. they reported that the counts of e. sinensis, c. aerofecaciens, f. prausnitzii, and o. splanchnicus were significantly lower in the fecal microbiota of the patients with interstitial cystitis than in healthy subjects. in a fecal microbiota study including patients with chronic prostatitis/ chronic pelvic pain syndrome (another functional lower urinary tract disorder such as interstitial cystitis) the alpha diversity analysis revealed that the diversity of fecal microbiota was significantly lower in the patient group than in healthy subjects (13). okamoto et al. studied 1113 patients comparing patients with high overactive bladder symptom scores and urgency with those who had low symptom scores without urgency. they found that the former group had a significantly lower bacterial load in the fecal microbiota (14). they suggested that the natural bacterial load reduction might be correlated with the disease process. our study determined a significant difference between patients with normal and abnormal voiding dysfunction symptom scores concerning general bacterial load and a negative correlation between vdss and the general bacterial load. of note, reduction in the bacterial load infers reduction of the microorganisms beneficial for health. some bacteria such as bifidobacterium species in microbiota have beneficial critical roles, and they can be used as probiotics. these bacteria were low in patients with overactive bladder (14). on the other hand, the counts of faecalibacterium species were higher in patients with overactive bladder than in the control group patients (14). detection of high numbers of these bacteria in overactive table 2. the comparison of the groups regarding bacteria in the fresh stool samples. groups group 1 group 2 p value general bacterial load 16.5 ± 3.2 18.3 ± 2.9 0.043 fusobacterium nucleatum 34.8 ± 2.6 37.2 ± 2.9 0.009 clostridium difficile 33.8 ± 0 bacteroides clarus 27.3 ± 4.4 roseburia intestinalis 27.3 ± 4.9 28.4 ± 2.5 0.486 table 3. results of the correlation analysis between voiding dysfunction symptom scores, general bacterial load and counts of specific bacteria. correlation coefficient p value general bacterial load -0.305 0.033 fusobacterium nucleatum -0.435 0.004 roseburia intestinalis -0.225 0.250 bacteroides clarus 0.919 0.258 clostridium difficile * * * since clostridium difficile was not detected in the fresh stool samples of the patients in group 2, a correlation analysis could not be performed. archivio italiano di urologia e andrologia 2022; 94, 4 i. akarken, h. tarhan, g. şener, h. deliktas, n. cengiz, h. şahin 458 bladder patients is an unfavorable sign indicating the deviation in the intestinal microbiota. in our study, fusobacterium nucleatum counts were significantly lower in patients with vd than in controls (p = 0.009). the counts of roseburia intestinalis were relatively lower in the former group than in the latter although the difference was not statistically significant (p = 0.486). clostridium difficile and bacteroides clarus were not detected in the healthy patient group. detection of these bacteria in the patient group with vd can be considered an indicator of dysbiosis. it is widely accepted that deviations in the intestinal microbiota led to an increase in the levels of toxic metabolites and a reduction in the number of useful metabolites, thus contributing to disease processes (15). the intestine-brain axis is a two-way communication network. this network consists of the central nervous system (cns), which includes the brain and the spinal cord, autonomic nervous system, enteric nervous system, and the hypothalamic-pituitary-adrenal axis (16). thus, the intestinal microbiota can affect the enteric neurons and the cns via metabolites secretion. a potential dysfunction affects both sides since this is a two-way interaction (17). the effects of the intestinal microbiota on brain development and the emergence of neurodegenerative diseases were also reported (18). also, it was noted that there was a relationship between the reduction of intestinal microbial diversity and cognitive dysfunction. in addition, it was suggested that a healthy microbiota was associated with learning skills and memory development (19). our study showed a significant reduction in the general bacterial load in the patient group with vd. therefore, we suggest that dysbiosis could negatively affect autonomic nervous system maturation or the coordination between the cns and the lower urinary tract. our study has some limitations. first, it was conducted with a limited number of patients because of coronavirus disease-2019 (covid-19) pandemic during the study period. second, the total bacterial diversity could not be analyzed since dna sequence sampling could not be performed in fresh stool samples due to financial reasons. conclusions we conclude that there is a potential relationship between vd and a deviation of the fecal microbiota. however, we further studies, including more extensive patient series, are needed in to confirm this finding. acknowledgements the authors would like to thank “mugla sitki kocman university scientific research project department” for their support. references 1. farhat w, bägli dj, capolicchio g, et al. the dysfunctional voiding scoring system: quantitative standardization of dysfunctional voiding symptoms in children. j urol 2000; 164:1011-5. 2. austin pf, bauer sb, bower w, et al. the standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the international children's continence society. neurourol urodyn 2016; 35:471-81. 3. gill sr, pop m, deboy rt, et al. metagenomic analysis of the human distal gut microbiome. science 2006; 312:1355-9. 4. duvallet c, gibbons sm, gurry t, et al. meta-analysis of gut microbiome studies identifies disease-specific and shared responses. nat commun 2017; 8:1-10. 5. antunes-lopes t, vale l, coelho am, et al. the role of urinary microbiota in lower urinary tract dysfunction: a systematic review. eur urol focus 2020; 6:361-9. 6. akbal c, genc y, burgu b, et al. dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. j urol 2005; 173:969-73. 7. qin j, li r, raes j, arumugam m, et al. a human gut microbial gene catalogue established by metagenomic sequencing. nature 2010; 464:59-65. 8. pelzer e, gomez-arango lf, barrett hl, nitert md. maternal health and the placental microbiome. placenta 2017; 54:30-7. 9. arrieta m-c, stiemsma lt, amenyogbe n, et al. the intestinal microbiome in early life: health and disease. front immunol 2014; 5:427. 10. yatsunenko t, rey fe, manary mj, et al. human gut microbiome viewed across age and geography. nature 2012; 486:222-7. 11. holland b, karr m, delfino k, et al. the effect of the urinary and faecal microbiota on lower urinary tract symptoms measured by the international prostate symptom score: analysis utilising next-generation sequencing. bju int 2020; 125:905-10. 12. braundmeier-fleming a, russell nt, yang w, et al. stool-based biomarkers of interstitial cystitis/bladder pain syndrome. sci rep 2016; 6:1-10. 13. shoskes da, wang h, polackwich as, et al. analysis of gut microbiome reveals significant differences between men with chronic prostatitis/chronic pelvic pain syndrome and controls. j urol 2016; 196:435-41. 14. okamoto t, hatakeyama s, imai a, et al. altered gut microbiome associated with overactive bladder and daily urinary urgency. world j urol 2021; 39:847-53. 15. yin j, liao sx, he y, et al. dysbiosis of gut microbiota with reduced trimethylamine-n-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. j am heart assoc2015; 4:e002699. 16. carabotti m, scirocco a, maselli ma, severi c. erratum: the gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. ann gastroenterol. 2015; 28:203-209. 17. yang nj, chiu im. bacterial signaling to the nervous system through toxins and metabolites. j mol biol 2017; 429:587-605. 18. martin cr, osadchiy v, kalani a, mayer ea. the brain-gutmicrobiome axis. cell mol gastroenterol hepatol. 2018; 6:133-48. 19. davidson gl, cooke ac, johnson cn, quinn jl. the gut microbiome as a driver of individual variation in cognition and functional behaviour. philos trans r soc lond b biol sci. 2018; 373:20170286. correspondence ilker akarken, md ilkerakarken@gmail.com hüseyin tarhan, md (corresponding author) drhuseyintarhan@gmail.com hasan deliktas, md drhasand@gmail.com hayrettin şahin, md hsahin63@gmail.com mugla sıtkı kocman university, school of medicine, department of urology, turkey gamze şener, md asligamze.seher@saglik.gov.tr izmir katip celebi university, school of medicine, department of microbiology, turkey nurcan cengiz, md nurcandinler@mu.edu.tr mugla sıtkı kocman university, school of medicine, department of pediatric nephrology, turkey stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12132 1 original paper of primary pca tumours have low psma activity which evade detection by psma pet, mostly in high-grade and variant tumour types (7-10). prostatic ductal adenocarcinoma (dac) is an uncommon variant of prostatic carcinoma with aggressive behavior and worse prognosis and, still today, the of role psma pet/ct in its diagnosis and staging has not been clearly established (11). we evaluated the accuracy of fluoride 18 (18-f) psma pet/ct in the diagnosis and clinical staging in two patients with dac. case report two caucasian men 58 and 62 years old were admitted to our department for dysuria: the patients had not familiarity for pca and assumed antihypertensive drugs. psa values were equal to 5.6 and 2.8 ng/ml, digital rectal examination was highly suspicious for pca and magnetic resonance image (mpmri) showed for both the presence of a index lesion prostate imaging reporting and data system (pirads) score 5. the patients underwent extended transperineal prostate biopsy (18 cores) combined with four mpmri/trus fusion biopsy using a 18 gauge needle under sedation and antibiotic prophylaxis (12, 13). the biopsy histology demonstrated the presence of a mixed pca characterized by ductal and acinar pca (grade group 4/gleason score 8) with a greatest percentage of cancer equal to 100%, a mean number of positive cores of 15 (3 targeted cores and 12 systematic biopsies)) and a mean total percentage of cancer equal to 45% (35-55%). the clinical staging performing lung and abdominal ct plus technetium-based bone scan did not demonstrate distant metastases and/or others primitive tumors; in addition, the 18-f psma pet/ct (5) showed in both patients an intraprostatic lesion provided of a standardized uptake value (suvmax) equal to 4.6 and 4.9 in the absence of distant lesions suspicious for metastases (figure 1). following multidisciplinary evaluation, the patients underwent open radical prostatectomy (rp) plus extended pelvic lymphadenectomy. definitive specimen showed the presence in both cases of a mixed pt3bn1 pca (ductal plus acinar grade group 4/gleason score 8) with positive surgical margins, perineuronal invasion and nodes metastases (5/20 and 6/24, respectively). postoperative psa (one month from surgery) in the two patients was 0.8 and 0.3 ng/ml, therefore patients underintroduction: to evaluate the accuracy of psma pet/ct in the diagnosis and clinical staging of prostatic ductal adenocarcinoma (dac). materials and methods: two caucasian men 58 and 62 years old were admitted to our department for dysuria: the patients had not familiarity for prostate cancer (pca), psa values were 5.6 and 2.8 ng/ml, digital rectal examination was positive, multiparametric magnetic resonance image (mpmri) showed for both the presence of an index lesion pirads score 5. the patients underwent extended transperineal prostate biopsy combined with four mpmri/trus fusion biopsy under sedation and antibiotic prophylaxis; biopsy histology demonstrated the presence of a mixed pca characterized by dac and acinar pca (grade group 4/gleason score 8). the patients underwent clinical staging performing lung and abdominal ct, bone scan and fluoride 18 (18f) psma pet/ct. results: conventional imaging was negative for distant metastases; 18f-psma pet/ct showed in both patients an intraprostatic lesion characterized by a standardized uptake value (suvmax) equal to 4.6 and 4.9 in the absence of distant lesions suspicious for metastases. following multidisciplinary evaluation, the patients underwent radical prostatectomy plus extended pelvic lymphadenectomy. definitive specimen showed the presence in both cases of a mixed pt3bn1 pca (ductal plus acinar pattern grade group 4) with positive surgical margins, neuronal invasion, and nodes metastases (5/20 and 6/24, respectively). post-operative psa in the two patients was 0.8 and 0.3 ng/ml, therefore patients underwent adjuvant therapy. conclusions: conventional imaging and psma pet/ct could result inadequate in clinical staging of dac, the use of more imaging data (i.e. mpmri and/or f-18 fdg) could improve overall accuracy. key words: psma pet/ct; prostate cancer; ductal pca; ductal pca staging. submitted 25 november 2023; accepted 30 november 2023 introduction prostate cancer (pca) is the most commonly diagnosed malignancy in men; although, conventional imaging with computed tomography (ct) and technetium-based bone scan are widely used for staging, recently, cumulative evidence indicates that prostate-specific membrane antigen (psma) positron-emission tomography (pet/ct) should be a centerpiece of diagnosis and staging for intermediate/high risk patients (1-5). although, psma pet/ct seems about 27% more accurate than conventional imaging (6), 5-10% ductal prostate cancer staging: role of psma pet/ct pietro pepe 1, ludovica pepe 1, mara curduman 2, michele pennisi 1, filippo fraggetta 3 1 urology unit, cannizzaro hospital, catania, italy; 2 pathology unit, cannizzaro hospital, catania, italy; 3 pathology unit, gravina and s. pietro hospital, caltagirone (ct), italy. doi: 10.4081/aiua.2024.12132 summary archivio italiano di urologia e andrologia 2024; 96(1):12132 p. pepe, l. pepe, m. curduman, m. pennisi, f. fraggetta 2 went adjuvant radiotherapy of prostatic fossa and androgen deprivation therapy (adt). discussion dac is rare, aggressive, and characterized by cancer involving ducts and/or acini usually associated with a high-grade gleason score/grade group, large tumor volume, and adverse prognostic parameters, including extraprostatic extension and seminal vesicle invasion (14, 15). in the who classification fifth edition the term ‘ductal adenocarcinoma’ is now reserved for those radical prostatectomy cases with more than 50% ductal morphology, while in needle biopsy cases the term ‘adenocarcinoma with ductal features’ is recommended for both pure ductal and mixed ductal and acinar features (16). although dac is treated with conventional therapies, it demonstrated worse outcomes in comparison with highgrade acinar pca, regardless of the treatment modality. ranasinghe et al. (17) in 228 men with dac submitted to rp vs. radiotherapy demonstrated a 5-yrs overall survival (os) and metastases free survival (mfs) equal to 75 vs. 62% and 88 vs. 82%, respectively; in addition, 76 men who received adjuvant/salvage adt after rp, dac also had worse mfs and os and was characterized in 91% of them by intrinsic upregulation of androgen-resistant pathways. although mpmri and psma pet/ct are provided of superimposable accuracy in the diagnosis of high risk pca (12, 18) showing direct correlation between pirads score and suvmax values (19), in the presence of dac only mpmri (20) allows to perform diagnosis because psma pet/ct demonstrated a very limited diagnostic accuracy (21). in this respect, psma uptake has sometimes been poor compared with prominent 18-flourodeoxyglucose (f-18 fdg) avidity, which would suggest that fdg pet/ct scans are important in staging of ductal pattern (22, 23). the diagnostic utility of dual-tracer fdg/psma pet/ct for pca may assist in characterizing high-risk disease during primary staging and restaging especially with concurrently negative psma pet. when applied to highrisk or variant histology (i.e., dac), detection of the fdgpositive phenotype may signal a poorer prognosis to prompt more aggressive intervention earlier in the disease course and dual psma/fdg pet/ct may improve oncological outcomes (24); in definitive, the use of psma and fdg pet imaging in pca should be examined individually and the potential diagnostic impact for individual patients to undergo dual-tracer pet imaging could be reserved in case of inconclusive conventional imaging and/or negative psma pet (25). in our series, both the patients had a negative conventional imaging (ct and technetium-based bone scan) and 18f psma pet/ct despite a locally advanced disease with the presence of metastatic nodes (pt3bn1) underlining the lower accuracy of imaging in local and distant staging in case of dac. in conclusion, conventional imaging and psma pet/ct could result inadequate in clinical staging of dac, the use of more imaging data including mpmri and f-18 fdg could improve overall accuracy. acknowledgements the authors thank nuclear medicine unit of cannizzaro hospital (catania, italy) for the images. references 1. kawada t, yanagisawa t, rajwa p, et al. diagnostic performance of prostate-specific membrane antigen positron emission tomography-targeted biopsy for detection of clinically significant prostate cancer: a systematic review and meta-analysis. eur urol oncol 2022; 5:390-400 2. combes ad, palma ca, calopedos r. psma pet-ct in the diagnosis and staging of prostate cancer. diagnostics 2022; 12:2594 3. pepe p, pennisi m. targeted biopsy in men high risk for prostate cancer: 68ga-psma pet/ct versus mpmri. clin genitourin cancer. 2023; 21:639-642. 4. pepe p, pepe l, tamburo m, et al. targeted prostate biopsy: 68gapsma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl 2022; 94:274-277. 5. pepe p, pennisi m. should 68ga-psma pet/ct replace ct and bone scan in clinical staging of high-risk prostate cancer? anticancer res 2022; 42:1495-1498. 6. hofman ms, lawrentschuk n, francis rj, et al. propsma study figure 1. 18-f psma pet/ct in man with mixed prostate cancer (ductal plus acinar pca grade group 4/gleason score 8): intraprostatic standardized uptake value (suvmax) was equal to 4.9 (a) in the absence of distant metastases (b). a b archivio italiano di urologia e andrologia 2024; 96(1):12132 3 psma pet/ct and ductal pca group collaborators: prostate-specific membrane antigen pet-ct in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (propsma): a prospective, randomised, multicentre study. lancet 2020; 395:1208-1216. 7. zhao q, dong a, bai y, zuo c. prostate-specific membrane antigen uptake heterogeneity in mixed ductal-acinar adenocarcinoma of the prostate. clin nucl med 2023; 48:750-752 8. qiu s, dong a, zhu y, zuo c. 68 ga-psma-11 and 18 f-fdg pet/ct in a case of ductal adenocarcinoma of the prostate. clin nucl med 2022; 47:836-838 9. alabed yz ductal variant of prostate cancer: serial imaging with 18f-psma pet/ct. clin nucl med 2021; 46:e551-e552. 10. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl 2020; 92:209-210. 11. guner la, unal k, beylergil v, et al. enhancing psma pet/ct imaging of prostate cancer: investigating the impact of multiple time point evaluation, diuretic administration, cribriform pattern, and intraductal carcinoma. ann nucl med 2023; 37: 618-628. 12. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer res 2022; 42:3011-3015. 13. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8.500 men. arch ital urol androl 2022; 94:155-159. 14. divatia mk, ro jy: intraductal carcinoma of the prostate gland: recent advances. yonsei med j 2016; 57:1054-62. 15. kench jg, amin mb, berney dm. who classification of tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer. histopathology 2022; 81:447-58. 16. kench jg, amin mb, berney dm, et al. who classification of tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer. histopathology 2022; 81:447-458. 17. ranasinghe w, shapiro dd, hwang h, et al. ductal prostate cancers demonstrate poor outcomes with conventional therapies. eur urol 2021; 79:298-306. 18. pepe p, garufi a, priolo gd, et al. is it time to perform only magnetic resonance imaging targeted cores? our experience with 1,032 men who underwent prostate biopsy. j urol 2018; 200:774778. 19. pepe p, pepe l, tamburo m, et al. 68ga-psma pet/ct and prostate cancer diagnosis: which suvmax value? in vivo 2023; 37:1318-1322. 20. pahouja g, patel hd, desai s, et al. the rising incidence of ductal adenocarcinoma and intraductal carcinoma of the prostate: diagnostic accuracy of biopsy, mri-visibility, and outcomes. urol oncol. 2023; 41:48.e11-48.e18. 21. zhao q, dong a, bai y, zuo c. prostate-specific membrane antigen uptake heterogeneity in mixed ductal-acinar adenocarcinoma of the prostate. clin nucl med 2023; 48:750-752. 22. mcewan lm, wong d, yaxley j. flourodeoxyglucose positron emission tomography scan may be helpful in the case of ductal variant prostate cancer when prostate specific membrane antigen ligand positron emission tomography scan is negative. j med imaging radiat oncol 2017; 61:503-505. 23. qiu s, dong a, zhu y, zuo c. 68 ga-psma-11 and 18 f-fdg pet/ct in a case of ductal adenocarcinoma of the prostate. clin nucl med 2022; 47:836-838. 24. mcgeorge s, kwok m, jiang a, et al. dual-tracer positronemission tomography using prostate-specific membrane antigen and fluorodeoxyglucose for staging of prostate cancer: a systematic review. adv urol. 202; 2021:1544208. 25. mcewan lm, wong d, yaxley j. flourodeoxyglucose positron emission tomography scan may be helpful in the case of ductal variant prostate cancer when prostate specific membrane antigen ligand positron emission tomography scan is negative. j med imaging radiat oncol. 2017; 61:503-505. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com ludovica pepe, md ludopepe97@gmail.com michele pennisi, md michepennisi2@virgilio.it unità operativa di urologia, azienda ospedaliera cannizzaro, catania, italy mara curduman, md mara.curduman@aoec.it unità operativa di anatomia patologica, azienda ospedaliera cannizzaro, catania, italy filippo fraggetta, md filippofra@hotmail.com unità operativa anatomia patologica, presidio ospedaliero gravina e san pietro, caltagirone, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14117 1 review introduction premature ejaculation (pe) is characterized by a short intravaginal ejaculatory latency time (ielt) and an inability to control ejaculation, frequently results in interpersonal issues, anxiety, and psychological distress. pe presents as the most common male sexual dysfunction, affecting about 30% of men worldwide (1). with etiologies ranging from neurological reasons like serotonergic neurotransmission disruptions to psychosocial triggers like anxiety and relationship problems, this condition can present as either acquired or lifelong. according to the international society for sexual medicine (issm), acquired pe is defined as a decrease in ielt to less than three minutes following a period of normal sexual function, while lifelong pe is defined as ejaculation that consistently occurs within one minute of vaginal penetration since the beginning of sexual activity (1, 2). historically, pe was managed through counseling and behavioral therapy, but new developments in pharmaceutical treatments have provided more targeted treatment options. selective serotonin reuptake inhibitors (ssris) are the primary pharmacological care for pe, with dapoxetine as the first and only ssri authorized for on-demand usage in pe treatment (3). the european association of urology (eau) guidelines state that monotherapy dapoxetine on-demand has been successfully used to treat pe throughout europe. dapoxetine delays ejaculation by raising serotonin levels in the synaptic clefts and re-establishing equilibrium between 5-ht1a and 5-ht2c receptor activity. background: premature ejaculation (pe) affects about 30% of the male population. the european association of urology (eau) guidelines state that monotherapy dapoxetine on-demand has been successfully used to treat pe throughout europe. several studies have stated that when dapoxetine and phosphodiesterase-5 inhibitor (pde-5i) are used combined, sexual enjoyment and intravaginal ejaculation latency time (ielt) are increased more than when dapoxetine is taken alone. however, further investigation is needed to determine whether pde-5i and dapoxetine can be safely consumed together. methods: this study was conducted using 5 randomized controlled trials (rcts), which systematically extracted from online databases namely science direct, pubmed, google schoolar and cochrane library. included studies were assessed using cochrane risk of bias (rob) 2.0 for rcts. the data analysis was performed using revman software 5.1 of the cochrane collaboration. results: five rcts with a total of 498 potent men with pe from the period 2013-2024 showed pooled mean difference of dapoxetine + pde-5i was found significantly associated with higher post-treatment ielt scores compared to monotherapy dapoxetine (md 1.08; 95% ci 0.34-1.83; p = 0.004; i2 = 95%; 4 rcts). the pooled mean difference of dapoxetine + pde-5i also showed statistically significant association with higher posttreatment sexual satisfaction scale (sss) scores compared to monotherapy dapoxetine (md 0.76; 95% ci 0.49-1.04; p < 0.00001; i2 = 68%; 2 rcts). among 10 adverse effects (headacahe, flushing, nausea, dizziness, fatigue, nasal congestion, palpitation, vomitting, sleep disturbance, and constipation), the use of combination therapy is presenting significantly higher incidence of headache, flushing, nasal congestion compared to monotherapy dapoxetine (rr 3.00; 95% ci: 1.91-4.71; p < 0.00001; i2: 0%; 5 rcts), (rr 15.78; 95% ci: 5.48-45.45; p < 0.00001; i2: 24%; 5 rcts), (rr 9.00; 95% ci: 1.17-69.01; p = 0.03; i2: 0%; 2 rcts), respectively. conclusions: this study demonstrates the combination of dapoxetine and pde-5i significantly improves post-treatment scores of ielt and sexual satisfaction compared to dapoxetine efficacy and safety of on-demand dapoxetine combined with phosphodiesterase-5 inhibitor compared to monotherapy dapoxetine as a treatment of premature ejaculation without erectile dysfunction: a systematic review and meta-analysis ida bagus gde ananta mahesvara 1, i wayan suarsana 2, ida bagus oka widya putra 2, ida bagus kusuma putra manuaba 3 1 wangaya general hospital, denpasar, bali, indonesia; 2 wangaya general hospital, denpasar, bali, indonesia; 3 warmadewa university, denpasar, bali, indonesia. doi: 10.4081/aiua.2025.14117 summary monotherapy. despite an increased risk of certain side effects, the overall tolerability of the combination therapy remains favorable. key words: dapoxetine; pde-5i; combined; premature ejaculation. submitted 4 july 2025; accepted 25 july 2025 archivio italiano di urologia e andrologia 2025; 97(3):14117 ida bagus gde ananta mahesvara, i wayan suarsana, ida bagus oka widya putra, ida bagus kusuma putra manuaba 2 despite its efficacy, many patients report suboptimal improvements in ielt and sexual satisfaction when treated with dapoxetine monotherapy (3, 4). several studies have stated that when dapoxetine and pde-5 inhibitors (pde-5i) are used together, sexual enjoyment and ielt are increased more than when dapoxetine is taken alone. pde-5i, which were first created to treat erectile dysfunction, increase nitric oxide signaling, which causes the vas deferens and corpus cavernosum's smooth muscles to relax. a longer ielt is facilitated by this mechanism, which also reduces performance anxiety and promotes improved erectile function (2, 4). many studies and trials have stated that combination therapy improves ielt and sexual satisfaction while retaining a manageable safety profile. but, there have been reports of mild adverse effects which are similar to those seen with monotherapy. however, the specific therapeutic function of pde-5i in the management of pe is still not well defined, highlighting the urgent need for additional study in this field to enhance treatment approaches and enhance patient outcomes (1, 3). this systematic review and meta-analysis aim to provide evidence on the clinical efficacy and safety of on-demand dapoxetine combined with pde-5i compared to dapoxetine monotherapy. materials and methods this systematic review and meta-analysis was conducted following the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses (prisma) framework. adherence to the prisma guidelines ensured a rigorous and transparent approach to study identification, selection, and data synthesis. this pico (population, intervention, comparator, outcomes) framework is used to ensure a structured and rigorous methodology. the population of interest consisted of men who were diagnosed with pe based on the international society for sexual medicine's (issm) criteria without having erectile dysfunction (ed). patients were diagnosed with pe if, either from the beginning of their sexual experiences or after a distressing shift in ejaculatory latency, they consistently experienced ejaculation before or within one minute of vaginal penetration. furthermore, in order to be included, a person had to be unable to postpone ejaculation during the majority of vaginal penetrations and experience unfavorable personal outcomes like frustration, distress, or avoiding sexual closeness. the intervention evaluated in this study was on-demand combination therapy of dapoxetine and pde-5i, and the comparator group included patients receiving on-demand dapoxetine monotherapy, which is currently a standard pharmacological treatment for pe or dapoxetine + placebo. outcomes were categorized into primary and secondary measures. the primary outcomes included post-treatment score of ielt and sexual satisfaction scale (sss). ielt was recorded using a stopwatch by patients before and at the conclusion of the treatment period. patients were provided with clear instructions on the measurement protocol, starting from intromission to ejaculation. moreover, the sss was used to measure sexual satisfaction, which ranged from 0 (severe dissastisfaction) to 5 (extreme pleasure). meanwhile, the secondary outcomes focused on adverse effects associated with drug administration. patients reported symptoms such as headache, flushing, dizziness, and other potential side effects. search strategy and eligibility criteria the primary review question for this systematic review and meta-analysis was: "does the combination of on-demand dapoxetine and pde-5i improve ielt and sss compared to dapoxetine monotherapy in men with premature ejaculation without erectile dysfunction compared to dapoxetine monotherapy?" a thorough search of the cochrane library, pubmed, sciencedirect, and google scholar databases was conducted from october 2024 to december 2024. a medical subject headings (mesh) terms, such as “dapoxetine” and “pde5 inhibitor” or “sildenafil” or “tadalafil” and “premature ejaculation” were used in the search approach. in order to find more relevant studies, the references of pertinent papers were also manually searched. to guarantee correctness, results were deduplicated and imported into the mendeley reference management system. inclusion and exclusion criteria randomized controlled trials (rcts) that examined the efficacy and safety of on-demand dapoxetine monotherapy in comparison to dapoxetine combined with pde-5i for the treatment of pe were included. according to the issm criteria, male sexual dysfunction is defined as follows: (i) ejaculation that consistently occurs within one minute of vaginal penetration or after a distressing reduction in ejaculatory latency; (ii) an inability to delay ejaculation on most vaginal penetrations; and (iii) negative personal consequences like distress, frustration, or avoidance of intimacy. participants in the studies had to have a diagnosis of pe and to be active heterosexual individuals. exclusion criteria were applied to ensure the specificity and quality of the included studies. studies were excluded if they involved participants with erectile dysfunction, as determined by a score of less than 22 on the international index of erectile function (iief), or if they included individuals with comorbid conditions such as diabetes, chronic prostatitis, severe hepatic, renal impairment, or neurological disorders. patients who had taken pe medication within the three months before enrolling in the trial were also excluded. additionally, studies that did not compare the combination therapy with monotherapy, case reports, conference abstracts, and studies with insufficient data for meta-analysis were excluded. data extraction a standardized electronic data extraction form created in microsoft excel was used to extract the data. study features including the first author, the year of publication, the study design, the sample size were extracted. details of the intervention, such as the dosage of pde-5i and dapoxetine and duration of follow-up, were also documented, along with information about the comparator. two independent reviewers performed the data extraction process to ensure accuracy and reliability. third reviewer was consulted or a consensus-based discussion was used to settle any disagreements or conflicts between the reviewers. the integrity of the dataset utilized for archivio italiano di urologia e andrologia 2025; 97(3):14117 3 dapoxetine and phosphodiesterase-5 inhibitor analysis was guaranteed, and the chance of errors was reduced. risk of bias of included studies the risk of bias in the included studies was independently assessed at the outcome level by two reviewers using the cochrane risk of bias 2.0 (rob 2.0) tool. every domain received a risk of bias rating of low, some concerns, or high. the reviewers consulted with senior reviewers or a third reviewer to settle any disputes about how to evaluate the study's quality. data analysis review manager (revman) software version 5.4 (cochrane collaboration) was used for data synthesis and metaanalysis. the pooled mean difference (md) and associated 95% confidence intervals (cis) were computed for continuous outcomes, such as improvement of ielt and sss scores. the results were summarized using risk ratios (rrs) with 95% cis for binary outcomes, including side effects like headache, nasal congestion, and sleep disturbance. if at least two research reported on the same result, a meta-analysis was carried out. the chi-square test was used to evaluate study heterogeneity, and the i2 statistic was used to quantify the heterogeneity. heterogeneity was defined as low if i2 was less than 50%, and high if greater than 50%. a fixed-effects model was used if there was insufficient heterogeneity (i2 < 50%), otherwise, a random-effects model was implemented. results study selection a total of 3,736 studies were identified through a comprehensive database search, which included science direct (n = 67), cochrane library (n = 7), pubmed (n = 2,422), and google scholar (n = 1,240). 3,728 papers were eliminated following title/abstract screening and duplication removal because they were irrelevant or had insufficient data. the predetermined inclusion and exclusion criteria were used to evaluate the eligibility of 8 full-text articles. furthermore, 3 studies were excluded after full-text assessment and 5 studies were included in the quantitative synthesis as shown in figure 1. study characteristics the included studies as shown in table 1 were varied in definitions of pe, intervention protocols, durations, and definition of ed as the criteria. most trials used ielt as a diagnostic criterion for pe, with thresholds ranging from less than one minute to two minutes (1, 3, 4, 5). one study used the premature ejaculation diagnostic tool (pedt) with a score ≥ 11 to identify lifelong pe.2 combinations of dapoxetine (30 mg) and pde-5i, including sildenafil (50 mg), tadalafil (5 mg or 10 mg), and mirodenafil (50 mg), were part of the intervention regimens. these combinations were compared to dapoxetine monotherapy or, in one study, to dapoxetine plus placebo. across the investigations, treatment durations varied from four to twelve weeks, and sample sizes varied from figure 1. flow chart of study selection. table 1. characteristics of included studies. author, year design pe definition type of pe drug, dosage (patients qmount) duration no ed definition hamd, 2017 (1) rct ielt < 1 min na dapoxetine 30 mg + sildenafil 50 mg (n = 30) vs 6 weeks iief ≥ 22 dapoxetine 30 mg (n = 30) rad, 2021 (5) rct ielt < 2 mins na dapoxetine 30 mg + tadalafil 10 mg (n = 30) vs 4 weeks na dapoxetine 30 mg (n = 30) elbakary, 2022 (4) rct ielt 1-2mins na dapoxetine 30 mg + sildenafil 50 mg (n = 40) vs 12 weeks iief scoring dapoxetine 30 mg (n = 40) hasan, 2024 (3) rct ielt < 1 min lifelong and acquired pe dapoxetine 30 mg + tadalafil 5 mg (n = 89) vs 12 weeks iief > 22 dapoxetine 30 mg (n = 91) lee, 2013 (2) rct pedt ≥ 11 lifelong pe dapoxetine 30 mg + mirodenafil 50 mg (n = 62) vs dapoxetine 30 mg + placebo (n = 56) 12 weeks iief > 22 rct: randomized controlled trial; ielt: intravaginal ejaculation latency time; pe: premature ejaculation; iief: international index of erectile function; na: not available. archivio italiano di urologia e andrologia 2025; 97(3):14117 ida bagus gde ananta mahesvara, i wayan suarsana, ida bagus oka widya putra, ida bagus kusuma putra manuaba 4 30 to 110 patients per group. the iief score, which most studies require to be ≥ 22, was one of the validated measures used in the trials to make sure participants did not have erectile dysfunction. risk of bias of included studies all of the included studies have a low overall risk of bias as shown in figure 2. a high degree of scientific rigor in terms of randomization protocols, adherence to interventions, thorough outcome reporting, and suitable assessment methodologies is suggested by this consistency throughout the included studies. the absence of concerns related to missing data or selective reporting further strengthens the validity of the synthesized findings from these trials. post-treatment ielt figure 3 illustrates the pooled effect of dapoxetine combined with pde5i compared to dapoxetine monotherapy on ielt. the overall md was 1.08 (95% ci: 0.34-1.83; p = 0.004), indicating a significant higher value in posttreatment ielt for the combination therapy. variability between trials was suggested by the high heterogeneity (i2 = 95%; chi2 = 64.20, p < 0.00001) that was found. with a mean difference of 1.47 (95% ci: 1.34-1.60), hasan et al. (2024) (3) had the highest weight (34.9%) among the included studies, while lee et al. (2013) (2) had the lowest weight (5.0%) and reported an md of 2.20 (95% ci: -0.89-5.29), with broader confidence intervals indicating less precision. post-treatment sss figure 4 shows that the combination of dapoxetine and pde5i produced noticeably higher sss scores after treatment, compared to dapoxetine monotherapy. with a pooled md of 0.76 (95% ci: 0.49-1.04; p < 0.00001), the combination therapy significantly increased sexual pleasure. the studies' moderate heterogeneity (i2 = 68%; chi2 = 3.14, p = 0.08) indicated considerable variation but general consistency in the effect's direction. headache the forest plot in figure 5 presents the incidence of headaches as an adverse effect associated with the use of dapoxetine combined with pde5i compared to dapoxetine monotherapy. with a pooled rr of 3.00 (95% ci: 1.914.71; p < 0.00001), the combination therapy group had a noticeably increased chance of experiencing headaches. hasan et al. (2024) (3) reported a risk ratio of 3.32 (95% ci: 1.87-5.92) and contributed the greatest weight (56.5%) among the included studies. a smaller sample size resulted in wider confidence intervals for even higher rr of 5.00 (95% ci: 1.19-20.92) reported by hamd et al. (2017) (1). figure 2. risk of bias of included studies. figure 3. forest plot of post-treatment ielt. figure 4. forest plot of post-treatment sss. archivio italiano di urologia e andrologia 2025; 97(3):14117 5 dapoxetine and phosphodiesterase-5 inhibitor heterogeneity across the studies was minimal (i² = 0%; chi² = 2.08, p = 0.72), suggesting a consistent direction of effect across trials. while the combination therapy was more effective in improving ielt and sexual satisfaction, the findings underline an increased risk of headaches as a potential side effect. flushing the forest plot in figure 6 presents the incidence of flushing as an adverse effect associated with the use of dapoxetine combined with pde5i compared to dapoxetine monotherapy. with a pooled rr of 15.78 (95% ci: 5.4845.45; p < 0.00001), the combination therapy group had a noticeably greater incidence of flushing. a significantly enhanced risk was highlighted in hasan et al. (2024) (3), which contributed the most weight (27.9%) and reported the highest risk ratio of 40.90 (95% ci: 5.75-291.13). due to smaller sample sizes or fewer incidents, other studies, such as lee et al. (2013) (2) and rad et al. (2021) (5), similarly revealed higher risk ratios, albeit with broader confidence ranges. heterogeneity across studies was low (i² = 24%; chi² = 5.24, p = 0.26), indicating consistency in the reported effect sizes. nausea figure 7 illustrates the incidence of nausea as a side effect of dapoxetine combined with pde5i compared to dapoxetine monotherapy. the pooled rr was 1.24 (95% ci: 0.91–1.68; p = 0.17), indicating no statistically significant difference in the likelihood of nausea between the two groups. the largest contribution to the analysis came from hasan et al. (2024) (3), which carried a weight of 64.1% and reported an rr of 1.18 (95% ci: 0.82-1.69). other studies, such as hamd et al. (2017) (1) and rad et figure 5. forest plot of headache as one of the adverse effect figure 6. forest plot of flushing as one of the adverse effect. figure 7. forest plot of nausea as one of the adverse effect. archivio italiano di urologia e andrologia 2025; 97(3):14117 ida bagus gde ananta mahesvara, i wayan suarsana, ida bagus oka widya putra, ida bagus kusuma putra manuaba 6 al. (2021) (5), showed varying risk ratios, with hamd et al. reporting a slightly higher rr of 1.25 (95% ci: 0.572.73). heterogeneity among the studies was minimal, with an i² of 0% (chi² = 2.48, p = 0.65), suggesting consistency in the findings across trials. dizziness the forest plot in figure 8 depicts the occurrence of dizziness as an adverse effect when comparing dapoxetine combined with pde5i to dapoxetine monotherapy. there was no significant difference between the two treatment groups, as indicated by the pooled rr of 1.06 (95% ci: 0.68-1.68; p = 0.79). hasan et al. (2024) (3) provided the majority of the analysis's weight, reporting an rr of 0.97 (95% ci: 0.57-1.67), indicating that the two groups' incidences of dizziness were similar. there was very little variation (i2 = 0%; chi2 = 0.61, p = 0.89), suggesting that the included studies' findings were all consistent. fatigue figure 9 examines the incidence of fatigue as an adverse effect associated with dapoxetine combined with pde5i compared to dapoxetine monotherapy. there was no statistically significant difference between the two groups, as indicated by the pooled rr, which was 1.14 (95% ci: 0.70-1.87; p = 0.60). the majority of the analysis's weight (73.3%) came from hasan et al. (2024) (3), who reported an rr of 1.19 (95% ci: 0.68-2.08). other studies, including rad et al. (2021) (5), reported extremely few or no occurrences, therefore their contributions were smaller. the included studies were consistent, as evidenced by the low heterogeneity (i2 = 0%; chi2 = 1.64, p = 0.65). nasal congestion figure 10 examines the incidence of nasal congestion as an adverse effect associated with dapoxetine combined with pde5i compared to dapoxetine monotherapy. with a pooled rr of 9.00 (95% ci: 1.17-69.01; p = 0.03), the figure 8. forest plot of dizziness as one of the adverse effect. figure 9. forest plot of fatigue as one of the adverse effect. figure 10. forest plot of nasal congestion as one of the adverse effect. archivio italiano di urologia e andrologia 2025; 97(3):14117 7 dapoxetine and phosphodiesterase-5 inhibitor combination therapy group had a statistically significant higher incidence of nasal congestion. elbakary et al. (2022) (4) and hamd et al. (2017) (1) both contributed equally to the analysis (50 percent weight each), with rr of 3.00 (95% ci: 0.13-71.51) and rr of 15.00 (95% ci: 0.89-251.42), respectively. there was minimal heterogeneity (i2 = 0%; chi2 = 0.59, p = 0.44), indicating that the results were homogenous and consistent throughout the investigations. palpitation the forest plot in figure 11 analyzes the occurrence of palpitations as an adverse effect of dapoxetine combined with pde5i versus dapoxetine monotherapy. the pooled rr was 1.97 (95% ci: 0.69-5.66; p = 0.21), indicating no statistically significant difference in the risk of palpitations between the two treatment groups. hasan et al. (2024)(3) contributed the majority of the weight (79.0%), reporting an rr of 1.53 (95% ci: 0.45-5.25). heterogeneity was negligible (i² = 0%; chi² = 0.46, p = 0.50), reflecting consistency in the findings across studies. vomiting the forest plot in figure 12 evaluates the incidence of vomiting as an adverse effect in patients treated with dapoxetine combined with pde5i compared to dapoxetine monotherapy. the pooled rr was 4.00 (95% ci: 0.46-34.78; p = 0.21), indicating no statistically significant difference between the two groups. both hamd et al. (2017) (1) and rad et al. (2021) (5) contributed equally to the analysis (50% weight each). heterogeneity was minimal (i² = 0%; chi² = 0.05, p = 0.82), reflecting homogeneity across studies. sleep disturbance the prevalence of sleep disturbances as a side effect of dapoxetine with pde5i as opposed to dapoxetine monotherapy is investigated in the figure 13. the combined therapy was associated with insignificantly incidence of sleep disruptions, as indicated by the pooled rr of 2.15 (95% ci: 0.51-9.08; p = 0.30). rad et al. (2021) (5) demonstrated a higher rr of 4.33 (95% ci: 1.3713.67) with a weight of 52.1%, with hamd et al. (2017) (1) providing 47.9% weight and recording an rr of 1.00 (95% ci: 0.28-3.63). the results showed moderate heterogeneity (i2 = 64%; chi2 = 2.79, p = 0.09), indicating some variation. figure 11. forest plot of palpitation as one of the adverse effect. figure 12. forest plot of vomiting as one of the adverse effect. figure 13. forest plot of sleep disturbance as one of the adverse effect. archivio italiano di urologia e andrologia 2025; 97(3):14117 ida bagus gde ananta mahesvara, i wayan suarsana, ida bagus oka widya putra, ida bagus kusuma putra manuaba 8 constipation the prevalence of constipation as a side effect of dapoxetine with pde5i as opposed to dapoxetine monotherapy is investigated in the figure 14. between the two groups, there was no statistically significant difference, as indicated by the pooled rr of 3.00 (95% ci: 0.13-71.51; p = 0.50). with a reported rr of 1.00 (95% ci: 0.06-71.51), elbakary et al. (2022) (4) was the only study that provided data for this outcome. in contrast, hamd et al. (2017) (1) did not record any incidents in either group, so the rr for that study could not be estimated. heterogeneity was not relevant because of the small number of occurrences and studies that were considered. discussion this meta-analysis highlights that the combination of dapoxetine and pde5i significantly results in higher post-treatment scores of ielt and sss compared to dapoxetine monotherapy, with pooled md of 1.08 (95% ci: 0.34-1.83; p = 0.004) for ielt and 0.76 (95% ci: 0.49-1.04; p < 0.00001) for sss. these findings align with the hypothesized synergistic effect of the two drugs, which target both psychological and physiological factors contributing to pe. one study also mentioned that more than half of the patients were unsatisfied with monotherapy of dapoxetine (6). supporting this, other rcts have shown that the combination of fluoxetine and tadalafil results in significantly higher ielt compared to either drug alone, further suggesting that pde5i may be effective in managing pe in patients without erectile dysfunction (7). dapoxetine, a ssri, was the first fda-approved drug specifically designed for on-demand management of pe. it functions by reducing the activity of the 5-ht1a receptor, activating the 5-ht2c receptor, and blocking the serotonin transporter. the 5-ht1a and 5-ht2c receptors are brought back into balance by this dual action, which raises serotonin levels in the synaptic clefts (8). therefore, by improving central serotonergic neurotransmission and modifying the ejaculatory reflex, dapoxetine postpones ejaculation. dapoxetine is a very successful treatment for pe because of its distinct pharmacological mechanism, particularly when a quick start and brief duration of action are needed (3, 8). on the other hand, pde-5i raise intracellular cyclic guanosine monophosphate (cgmp) levels by activating guanylate cyclase, which in turn improves nitric oxide (no) signaling. the corpus cavernosum, vas deferens, and seminal vesicles' smooth muscles relax as a result of this process, improving erectile function and lowering performance anxiety-two issues that are frequently linked to pe. compared to ssris alone, research indicates that combining pde-5i with ssris, such as dapoxetine, further improves sexual satisfaction and increases ielt. pde-5i drugs may reduce central sympathetic tone in addition to improving peripheral vascular function, which could lead to better erections and longer ejaculation times (9, 10). from a clinical perspective, the enhanced efficacy of combination therapy is likely due to its complementary mechanisms. dapoxetine primarily acts centrally to modulate ejaculatory latency, while pde-5i address peripheral factors, such as smooth muscle relaxation in the vas deferens and prostate gland, and psychological factors like performance anxiety. this holistic approach makes combination therapy more effective than monotherapy in addressing the multifactorial nature of pe (4, 5). pde-5i including sildenafil (50 mg), tadalafil (5 mg or 10 mg), and mirodenafil (50 mg) were employed as adjuncts in the majority of the included trials in this meta-analysis, which used dapoxetine 30 mg as the principal dosage in both the monotherapy and combination therapy groups. dapoxetine is useful for on-demand use because of its quick absorption and brief half-life, and this standardized dosage represents the approved therapeutic range for the drug (11, 12). adverse effects, particularly vasodilatory symptoms such as headaches and flushing, were more frequent in the combination therapy group. for headaches, the pooled rr was 3.00 (95% ci: 1.91-4.71; p < 0.00001), while flushing showed a notable rr of 15.78 (95% ci: 5.4845.45; p < 0.00001). additionaly, the increased risk of nasal congestion (rr: 9.00; 95% ci: 1.17-69.01; p = 0.03) observed with combination therapy warrants attention. nasal congestion is a common side effect of pde-5i due to their vasodilatory mechanism, which affects the nasal mucosa. however, this adverse effect is typically mild and manageable, making it less concerning in clinical practice. these results are consistent with earlier research showing that groups treated with pde5i in combination with ssris have a higher prevalence of vasodilatory adverse effects. according to polat et al. (2015) (13), using paroxetine and tadalafil together improved ielt considerably, but there were also more side effects, namely headaches and hot flushes. the mechanism of pde5i, which promotes smooth muscle relaxation and nomediated vasodilation, is responsible for these vasodilatofigure 14. forest plot of constipation as one of the adverse effect. archivio italiano di urologia e andrologia 2025; 97(3):14117 9 dapoxetine and phosphodiesterase-5 inhibitor ry symptoms. although this technique works well to delay ejaculation and improve erectile performance, it can also cause increased vascular dilatation in locations like the face and cranium, which can result in headaches and flushing (13, 14) interestingly, the combination therapy did not significantly increase the risk of nausea (rr: 1.24; 95% ci: 0.911.68; p = 0.17), dizziness (rr: 1.06; 95% ci: 0.68-1.68; p = 0.79), fatigue (rr: 1.14; 95% ci: 0.70-1.87; p = 0.60), palpitations (rr: 1.97; 95% ci: 0.69-5.66; p = 0.21), vomiting (rr: 4.00; 95% ci: 0.46-34.78; p = 0.21), sleep disturbance (rr: 2.15; 95% ci: 0.51-9.08; p = 0.30), or constipation (rr: 3.00; 95% ci: 0.13-71.51; p = 0.50), further supporting its tolerability. these results are consistent with previous research showing that dapoxetine is a well-tolerated pe therapy with a better safety profile than other ssris (15). furthermore, some research indicates that dapoxetine may cause moderate side effects such headache, dizziness, and gastrointestinal distress; serious side effects are uncommon, as our analysis demonstrates (16). lack of significant clinical interactions between dapoxetine and sildenafil pharmacokinetics supports the safety of combination therapy. studies have demonstrated that coadministration of 60 mg of dapoxetine with 100 mg of sildenafil does not alter the pharmacokinetics of either drug, thereby preventing the amplification of side effects or compromising the effectiveness of the treatment. similarly, pharmacokinetic studies with udenafil (200 mg) and dapoxetine (60 mg) reported no clinically significant drugs interactions (16, 17). the tolerability of dapoxetine in combination therapy is further supported by its unique pharmacokinetic properties, including its rapid absorption and short half-life, which reduce the risk of prolonged exposure to adverse effects. moreover, compared to other ssris, dapoxetine has a superior safety and compliance rate, as evidenced by its well-designed clinical trials and broad licensure. however, it is crucial to remember that further research is needed to determine the long-term consequences of dapoxetine, especially with regard to reproductive health. new information has suggested possible detrimental effects on fertility, underscoring the need for more study to elucidate these conclusions (18, 19). these results emphasize the importance of discussing potential side effects with patients and closely monitoring for tolerability during combination therapy. although minor adverse effects like headache, flushing, or nasal congestion may occur, the benefits of improved ielt and sexual satisfaction often outweigh these risks. this systematic review and meta-analysis also have some limitations. first, the included studies exhibited variability in intervention protocols, sample sizes, and durations, which may have contributed to heterogeneity in the results. second, it may be difficult to completely evaluate the change related to the interventions if post-treatment data are relied upon without regularly taking baseline differences into account. third, negative impacts were frequently self-reported, which may have resulted in subjective bias or underreporting. furthermore, the majority of research concentrated on short-term results, underexamining the combo therapy's long-term safety and effectiveness. future research should address these limitations by standardizing study designs, including diverse populations, and conducting long-term trials to provide more comprehensive insights. conclusions in conclusion, this systematic review and meta-analysis demonstrates that the combination of dapoxetine and pde-5i significantly improves post-treatment scores of ielt and sexual satisfaction compared to dapoxetine monotherapy, making it an effective treatment option for pe. despite increased risk of certain side effects, such as headache, flushing, and nasal congestion, the overall tolerability of the combination therapy remains favorable, with no significant increase in adverse effects like nausea, dizziness, fatigue, palpitation, vomiting, sleep disturbance, and constipation. declarations ethical approval and consent for participate: not applicable. this meta-analysis used only aggregated data from published studies, no individual patient data were collected. availability of data and material: this study synthesizes data from publicly available sources. the search strategy and list of included studies are provided in materials and methods/supplementary data. original trial data can be accessed via science direct, cochrane library, pubmed, google schoolar as well as through the identifiers listed in figure 1 and table 1. competing interests: not applicable. funding: not applicable. authors' contributions: ida bagus gde ananta mahesvara, research major concept, data analysis and interpretation, manuscript original drafting; i wayan suarsana, statistical analyses, contribution to manuscript writing and editing; ida bagus oka widya putra, research major concept, statistical analyses, contribution to manuscript writing and editing; ida bagus kusuma putra manuaba, statistical analyses, contribution to manuscript writing and editing. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: i would like to express my deepest gratitude to my supervisors, dr. i wayan suarsana, sp.u and dr. ida bagus oka widya putra, sp.u, for their invaluable guidance, insightful feedback, and unwavering support throughout this systematic review and meta-analysis. their expertise and mentorship were fundamental in shaping this research. my sincere appreciation extends to my co-authors, for their invaluable contributions to the manuscript development. their meticulous inputs significantly enhanced the quality of this study. most importantly, i extend my heartfelt appreciation to my family, especially my beloved wife, dr. ida ayu santhi pertiwi manuaba, for her endless patience, motivation, and encouragement during this journey. their belief kept me steadfast in achieving this milestone. archivio italiano di urologia e andrologia 2025; 97(3):14117 ida bagus gde ananta mahesvara, i wayan suarsana, ida bagus oka widya putra, ida bagus kusuma putra manuaba 10 references 1. abu el-hamd m, abdelhamed a. comparison of the clinical efficacy and safety of the on-demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with 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kim yh, choi hy, lee sh, et al. pharmacokinetic interaction between udenafil and dapoxetine: a randomized, open-labeled crossover study in healthy male volunteers. drug des devel ther. 2015; 9:1209-1216. 18. castiglione f, albersen m, hedlund p, et al. current pharmacological management of premature ejaculation: a systematic review and meta-analysis. eur urol. 2016; 69:904-916. 19. elmazoudy r, abdelhameed n, elmasry a. paternal dapoxetine administration induced deterioration in reproductive performance, fetal outcome, sexual behavior and biochemistry of male rats. int j impot res. 2015; 27:206-214. correspondence ida bagus gde ananta mahesvara ibgam21@gmail.com general practitioner, wangaya general hospital, denpasar, bali-indonesia i wayan suarsana suarsanawayan6@gmail.com ida bagus oka widya putra (corresponding author) ibokawp@gmail.com urologist, departement of urology, wangaya general hospital, jalan kartini no. 133, denpasar, bali 80231, indonesia ida bagus kusuma putra manuaba gtramanuaba@gmail.com medical student, warmadewa university, denpasar, bali-indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13268 1 original paper management of traumatic urethral strictures, particularly in cases involving the bulbar urethra. traumatic urethral strictures are a significant clinical challenge, often resulting from various forms of trauma, particularly in males. the etiology of these strictures is multifaceted, with trauma being a predominant cause. various mechanisms of injury contribute to the development of urethral strictures, including pelvic fractures, straddle injuries, and direct trauma to the urethra during accidents (1). the incidence of motorcycle road accidents leading to pelvic fractures and urethral injury in indonesia is a significant public health issue, exacerbated by the country's high reliance on motorcycles as a primary mode of transportation (2). the prevalence of this condition varies, with estimates suggesting that it affects 229 to 627 individuals per 100,000, and can be particularly pronounced in certain demographics (3, 4). the management of these strictures has evolved, with epa urethroplasty being favored for its high success rates and low complication profiles, particularly for strictures shorter than 2 cm (5-7). the technique of epa urethroplasty involves the excision of the diseased segment of the urethra followed by direct end-to-end anastomosis. this method is particularly effective for short, isolated bulbar strictures, yielding success rates upwards of 90% (5, 6, 8). however, the risk of recurrence remains a significant concern in the management of urethral strictures post-trauma. factors influencing recurrence include the length of the stricture, the presence of underlying conditions, and the surgical technique employed (8-11). identifying factors leading to epa urethroplasty failure benefits both patients and surgeons. this study aims to analyze risk factors for urethral stricture recurrence after one-year follow-up of epa urethroplasty. methods pre operative patients assessment we conducted a retrospective analysis of the medical records of 95 male patients diagnosed with traumatic urethral stricture who were referred from nearby hospital and all across indonesia. we reviewed demographic introduction: excision and primary anastomosis (epa) urethroplasty is the standard treatment for traumatic urethral strictures, but managing them remains challenging for urologists. identifying factors leading to epa urethroplasty failure benefits both patients and surgeons. this study aims to analyze risk factors for urethral stricture recurrence after one-year follow-up of epa urethroplasty. materials and methods: data on male patients undergoing epa urethroplasty at the urology department of saiful anwar general hospital from january 2013 until december 2023 were prospectively recorded. successful urethroplasty, defined as the absence of additional treatment necessity, was assessed until 12 months follow-up. demographic data, time to surgery, stricture etiology, comorbidities, prior urethral interventions, and operation steps were recorded. univariate and multivariate coxregression analyses were performed using ibm spss statistics version 21. result: total 95 patients were observed, and 89 patients were included, averaging 41.2 ± 15.59 years old. epa urethroplasty succeeded in 91% of cases over a median follow-up of 16.3 months. pelvic fracture urethral injury (pfui) was the predominant etiology in 74% of cases, with an average stricture length of 25.4 ± 16.3 mm. the average time to surgery was performed on average 6.67 ± 4.07 months after diagnosis. in univariate analysis, body mass index (bmi), time to surgery, and stricture length were associated with urethral stricture recurrence. however, only time to surgery showed a significant association in multivariate analysis. conclusions: obesity, the length of the stricture, and delayed surgical intervention are associated with an increased risk of urethral stricture recurrence in patients following epa. epa urethroplasty demonstrates a high success rate in managing traumatic urethral strictures. key words: urethral stricture; epa urethroplasty; prognosis; risk factors. submitted 18 october 2024; accepted 1 november 2024 introduction excision and primary anastomosis (epa) urethroplasty is recognized as a gold standard surgical technique for the ten years’ single surgeon experience of excision and primary anastomosis (epa) urethroplasty for traumatic urethral stricture: an analysis of risk factors for urethral stricture recurrence paksi satyagraha, edi wibowo, besut daryanto, gede wirya diptanala putra duarsa, adrianus gupta wijaya, fauzan kurniawan dhani urology department, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2025.13268 summary archivio italiano di urologia e andrologia 2025; 97(1):13268 p. satyagraha, e. wibowo, b. daryanto, et al. 2 details, educational status, underlying causes, comorbidities, smoking history, previous procedures, as well as the duration of the disease, interventions, and outcomes based on both inpatient and outpatient records. patients were classified as highly educated if they had completed an undergraduate degree. all patients underwent epa urethroplasty performed by a single surgeon (ps) at saiful anwar general hospital in malang, indonesia, between january 2013 and december 2023. patients with penile strictures, a history of hypospadias, or those requiring tissue substitution techniques were excluded from this study. the duration of the disease was defined as the time elapsed from the initial diagnosis of the urethral stricture to the date of the epa procedure. each patient had a suprapubic catheter placed to allow for urethral rest. to assess the location and length of the stricture, a bipolar voiding cysto-urethrography (bvcug) was performed. surgical technique all patients underwent epa urethroplasty under general anesthesia while positioned in the lithotomy position via the perineal approach. after mobilizing the bulbar urethra, the stricture location was identified intraoperatively using rigid cystoscopy, and the urethra was transected at the stricture site with sharp scissors. the scar tissue at both urethral ends was then completely excised until healthy urethral mucosa was reached. a wide-caliber, spatulated, tension-free anastomosis was performed using six 4-0 pga sutures. epa urethroplasty consists of several adjunctive surgical steps to achieve a tension-free anastomosis, including bulbar mobilization, crural separation, inferior pubectomy, supracrural rerouting, and total pubectomy, particularly when the stricture is too long for a tension-free anastomosis. finally, a 14fr silicone foley catheter was inserted, which remained in place for four weeks postoperatively. if the procedure for epa urethroplasty consists only in bulbar mobilization, this was classified as bulbar mobilization. on the contrary, if the procedure includes steps beyond bulbar mobilization, it was categorized as over bulbar mobilization. postoperative follow-up and outcome definition patients were followed up at 1, 3, and 12 months after surgery, and then annually, with evaluations including uroflowmetry and residual urine volume measurements. urethrography was conducted whenever a recurrent stricture was suspected, indicated by a decrease in urinary flow rate and/or worsening symptoms. successful urethroplasty was defined as the absence of the need for further treatment. paired t-test was used to assessed patient outcome parameters. both univariate and multivariate cox regression analyses were conducted using ibm spss statistics version 21. p values < 0.05 were considered statistically significant. results a total of 95 patients were observed, and 89 were included in the study, with an average age of 41.2 ± 15.59 years. the patients had a mean body mass index (bmi) of 23.05 kg/m². hypertension and diabetes mellitus (dm) were present as comorbidities in 10.1% and 16.9% of the patients, respectively. the most common aetiology of urethral strictures was pelvic fracture urethral injury (pfui), followed by straddle injury, iatrogenic causes related to transurethral surgery, and direct trauma. the bulbo-membranous urethra had the highest incidence of strictures, followed by the bulbar urethra. more than 35% of patients had undergone endoscopic treatment 1-2 times previously, while about 39% had never received endoscopic treatment. the average time to surgery was performed on average 6.67 ± 4.07 months after diagnosis. epa urethroplasty was successful in 91% of cases, with a median follow-up of 16.3 months. eight patients reported had recurrent stricture, two patients at 3 months after the surgery and six patients at 12 months after the surgery. for recurrent strictures, treatments included redo epa urethroplasty in 3 cases, urethral dilatation in 4 cases, and redo non-transecting urethroplasty in 1 case (table 1). the uroflowmetry outcomes from 1 month, 3 months and 12 months after the surgery of the patient did not show any different such as qmax, voided volume and post void residual volume (pvr) (table 2, figure 1). in univariate analysis, body mass index (bmi) (or 4.45, 95%ci table 1. patient characteristics. number of patient 89 age (year) (sd) 41.24 (± 15.59) median follow-up (months) (sd) 16.3 (± 3.15) bmi (kg/m2), mean (sd) 23.05 (± 2.57) highly educated, n (%) 23 (25.8) current smoker, n (%) 26 (29.2) dm type 2, n (%) 9 (10.1) hypertension, n (%) 15 (16.9) stricture length (mm), mean (sd) 25.4 (± 16.3) time to surgery (month), mean (sd) 6.67 (± 4.07) stricture aetiology, n (%) straddle injury 11 (12.35) iatrogenic 10 (11.23) direct 2 (2.24) pfui 66 (74.15) stricture site, n (%) bulbar 27 (30.34) bulbo-membranous 62 (69.66) previous endoscopic treatment, n (%) 0 28 (31.46) 1-2 32 (35.95) > 2 29 (32.58) surgical steps, n(%) bulbar mobilization 35 (39.33) crural separation 29 (32.58) inferior pubectomy 24 (26.96) supracrural rerouting 1 (1.12) epa outcome, n (%) success 81 (91) recurrance 8 (9.00) recurrence operative treatement redo epa urethroplasty 3 (37.5) redo non-transecting urethroplasty 1 (12.5) urethral dilatation 4 (50) bmi: body mass index; dm: diabetes mellitus; sd: standard deviation; epa: excision primary anastomosis; pfui: pelvic fracture urethral injury. archivio italiano di urologia e andrologia 2025; 97(1):13268 3 urethroplasty for traumatic urethral stricture thral stricture recurrence. however, only time to surgery (or 2.44, 95%ci 1.06-12,93, p = 0.04) showed a significant association in multivariate analysis (table 3). figure 1. changes in qmax (a), voided volume (b), post void residual (c) from 1, 3, and 12 months. table 2. uroflowmetry outcomes. 1 month (n: 89) 3 months (n: 87) 12 months (n: 81) mean ± sd mean ± sd p value* mean ± sd p value * p value * (vs 1 month) (vs 1 month) (vs 3 months) qmax (ml/s) 20.63 ± 3.47 20.18 ± 3.69 0.14 20.95 ± 3.39 0.17 0.4 voided volume (ml/s) 139.8 ± 15.47 137.75 ± 18.28 0.12 140.58 ± 17.12 0.73 0.52 pvr (ml/s) 29.47 ± 5.09 31.78 ± 8.87 0.73 30.31 ± 8.25 0.87 0.67 * includes only patients who were able to void (n: 81). qmax: maximum flow rate; pvr: postvoid residual; sd: standard deviation. table 3. uniand multivariate cox regression analysis for risk factor recurrence rate epa urethroplasty. univariate analysis multivariate analysis or 95% ci p value or 95% ci p value age 1.25 0.16-6.78 0.55 ≤ 60 vs > 60 education 3.56 1.26-4.56 0.15 low vs high bmi 4.45 1.36-28.1 0.007 * 2.40 0.96-22.7 0.49 ≤ 25 vs > 25 current smoker 1.89 0.30-8.14 0.12 dm type 2 6.34 0.41-20.85 0.07 hypertension 3.52 1.38-29.23 0.09 time to surgery 3.89 1.63-13.24 0.003 * 2.44 1.06-12,93 0.04 * ≤ 6 months vs > 6 months stricture length 2.14 1.05–1.62 0.01 * 0.08 0.98–2.17 0.35 ≤ 20 mm vs > 20 mm stricture side 1.26 0.30-5.14 0.12 bulbo-membranous vs bulbar previous endoscopic treatment 1.63 0.37-6.06 0.48 yes vs no type of injury 1.83 0.27-8.349 0.29 non pfui vs pfui surgical steps 1.5 0.19-7.93 0.43 bulbar mobilization vs over bulbar mobilization * significant result. bmi: body mass index; ci: confidence interval; dm: diabetes mellitus; or: odd ratio; pfui: pelvic fracture urethral injury. 1.36-28.1, p = 0.007), time to surgery (or 3.89, 95%ci 1.63-13.24, p = 0.003), and stricture length (or 2.14, 95%ci 1.05-1.62, p = 0.01) were associated with urearchivio italiano di urologia e andrologia 2025; 97(1):13268 p. satyagraha, e. wibowo, b. daryanto, et al. 4 discussion epa urethroplasty is widely regarded as the gold standard for treating traumatic urethral strictures, particularly those caused by pelvic fractures or direct trauma. in indonesia, motorcycle accidents often result in pelvic fractures and associated urethral injuries (2). this finding is consistent with our cohort, where pfui accounted for 74% of the causes of traumatic urethral strictures. our cohort achieved a high success rate of 91% in epa urethroplasty, comprising 89 patients, making it one of the largest series of patients undergoing this procedure in southeast asia, despite the relatively short follow-up period (median of 16.3 months). this outcome is consistent with previous studies that report success rates ranging from 85% to 95% (12). however, the definition of a successful urethroplasty remains a topic of debate, with no clear agreement on the best postoperative follow-up approach. in our study, successful urethroplasty was defined as the absence of the need for further treatment, which has been widely used in most previous research (13). at our center, postoperative followup typically involves catheter removal four weeks after surgery, followed by uroflowmetry. we do not routinely perform postoperative cystoscopy due to the unavailability of flexible cystoscopy, as well as concerns about cost-effectiveness and the geographical burden, which requires patients to travel to our center. despite this positive result, the potential for stricture recurrence remains a concern, with various factors influencing the risk of recurrence. one of the primary risk factors identified in the literature is the length of the stricture. studies have shown that longer strictures, particularly those exceeding 2 cm, are associated with higher recurrence rates following urethroplasty (14, 15). this is likely due to the increased complexity of surgical repair and the potential for inadequate vascularization of the anastomosed segment. furthermore, the presence of dense periurethral fibrosis, often seen in long strictures, can complicate the surgical approach and contribute to poorer outcomes (16). in our cohort, strictures longer than 2 cm were associated with a greater risk of recurrence. two patients experienced recurrence within the first 3 months, and six within 12 months after surgery. this is in line with the findings of kinnaird et al., who reported an average recurrence time of 11.7 months, with occurrences ranging from 2 weeks to 77 months (17). similarly, barbagli et al., observed that recurrences in their cohort of both anastomotic and substitution urethroplasty patients were evenly distributed over time, with a plateau reached only after 5 years (18). bmi has been identified as a potential risk factor influencing the recurrence of urethral strictures following epa urethroplasty. the relationship between bmi and surgical outcomes is multifaceted, as obesity can impact both the surgical procedure and the healing process (19). in our cohort, patients with bmi over 25 significantly had higher risk of recurrence. the technical challenges posed by a higher bmi can complicate the surgical approach. increased adipose tissue in the perineal region may hinder access to the urethra, making it more difficult to achieve a tension-free anastomosis, which is crucial for successful outcomes (20). additionally, the presence of excess tissue may lead to increased tension at the anastomosis site, further contributing to the risk of recurrence (21). one notable finding from this cohort is that delayed surgical intervention exceeding 6 months is a significant predictor of recurrence in patients undergoing epa urethroplasty. as we know, indonesia is one of the largest archipelagic countries in the world, comprising numerous islands, which makes accessing adequate healthcare facilities time-consuming and costly (22). furthermore, the limited distribution of reconstructive urologists is a major factor contributing to the prolonged time before patients receive treatment. this correlation underscores the importance of prompt evaluation and management of urethral strictures, as timely surgical intervention is linked to better healing conditions and outcomes (23). comorbidities such as dm and hypertension have been shown to influence stricture recurrence in some studies. these conditions may predispose patients to recurrence due to poor microvascular circulation and impaired wound healing associated with dm and hypertension (24). however, this finding contrasts with the results of our cohort study, where dm and hypertension were not statistically significant risk factors for recurrence. we believe this discrepancy may be attributed to the relatively young average age of patients undergoing epa urethroplasty in our study, which was 41.2 years, at an age when few individuals have developed degenerative diseases. the location of the stricture is another critical factor. a study by bagchi et al. identified the bulbar urethra as the most common site of stricture, which is generally associated with better outcomes compared to membranous urethral strictures, where recurrence rates tend to be higher due to the complexity of the anatomical region and the proximity to the external urinary sphincter (7). in our cohort, the bulbomembranous urethra exhibited the highest incidence of strictures; however, there was no significant difference in recurrence risk based on the location of the stricture. several studies indicate that prior urethral procedures can impact outcomes. these patients tend to have a slightly higher incidence of recurrence, likely due to the cumulative trauma resulting from previous dilatations or urethrotomies (12, 18). in our cohort, over 35% of patients had undergone one or more endoscopic treatments before opting for epa urethroplasty; however, interestingly, this finding does not align with the results of our study. limitations of the present study include its retrospective nature, limited follow-up duration, single institution and surgeon, relatively small sample size, and subjectivity in outcome assessment. while our criteria for defining recurrence were somewhat subjective and relied on patient-reported symptoms that prompted urethrography, we believe this approach is clinically valid due to the lack of consensus on how to define stricture recurrence following urethroplasty. addressing these limitations through larger, multicenter, and prospective studies will be essential for optimizing surgical techniques and improving patient outcomes. conclusions obesity, the length of the stricture, and delayed surgical intervention are associated with an increased risk of urethral stricture recurrence in patients following epa. epa archivio italiano di urologia e andrologia 2025; 97(1):13268 5 urethroplasty for traumatic urethral stricture urethroplasty demonstrates a high success rate in managing traumatic urethral strictures. careful patient selection, along with prompt and appropriate surgical intervention, is crucial to improving long-term outcomes and reducing the risk of re-stricture. references 1. yücetürk cn, keseroglu bb. etiology of posterior urethral strictures: analysis of 116 cases. ankara education and research hospital medical journal. 2020; 53:76-80. 2. djoeworo wr, tasono hadi dp, darjoko st. motorcycle accident injuries are more severe than other land transportation injuries. univ med. 2018; 37:105-14. 3. ma yc, lin l, luo z, jin t. smoking is an independent risk factor for stricture recurrence after the urethroplasty: a systematic review and meta-analysis. int braz j urol. 2023; 49:8-23. 4. hussain m, khan ms, lal m, et al. stricture of urethra: patterns and outcomes of management from a single centre in pakistan over 7 years. j coll physicians surg pak. 2020; 30:79-84. 5. waterloos m, verla w, oosterlinck w, et al. excision and primary anastomosis for short bulbar strictures: is it safe to change from the transecting towards the nontransecting technique? biomed res int. 2018; 2018:3050537. 6. d'hulst p, floyd ms jr, castiglione f, et al. excision and primary anastomosis for bulbar urethral strictures improves functional outcomes and quality of life: a prospective analysis from a single centre. biomed res int. 2019; 2019:7826085. 7. bagchi p, pratihar s, rajeev t, et al. an audit of management of male urethral stricture and its outcome: a single centre retrospective review. int surg j. 2020; 7:774. 8. elsayed m, wahab a, sallem e, riad a. outcome of non-transected anastomotic urethroplasty for management of short bulbar urethral stricture. sohag med j. 2019; 23:187-193. 9. shalkamy o, elsalhy m, alghamdi sm, et al. erectile function after different techniques of bulbar urethroplasty: does urethral transection make a difference? bmc urol. 2023; 23:140. 10. siegel j, panda a, tausch tj, et al. repeat excision and primary anastomotic urethroplasty for salvage of recurrent bulbar urethral stricture. j urol. 2015; 194:1316-1322. 11. kumar s, kapoor a, ganesamoni r, et al. efficacy of holmium laser urethrotomy in combination with intralesional triamcinolone in the treatment of anterior urethral stricture. korean j urol. 2012; 53:614. 12. han j, liu j, hofer m, et al. risk of urethral stricture recurrence increases over time after urethroplasty. int j urol. 2015; 22:695-699. 13. horiguchi a, ojima k, shinchi m, et al. single-surgeon experience of excision and primary anastomosis for bulbar urethral stricture: analysis of surgical and patient-reported outcomes. world j urol. 2021; 39:3063-3069. 14. sikpa kh, botcho g, sewa e, et al. male urethral stricture: epidemiological, clinical, and therapeutic aspects in kara. open j urol. 2023; 13:101-107. 15. topaktas r, ürkmez a, tokuç e, et al. hematologic parameters and neutrophil/lymphocyte ratio in the prediction of urethroplasty success. int braz j urol. 2019; 45:369-375. 16. selukar d, pothare an, meshram k, et al. a case series of standard surgical management of bulbo-membranous stricture. int surg j. 2017; 4:1299. 17. kinnaird as, levine ma, ambati d, et al. stricture length and etiology as preoperative independent predictors of recurrence after urethroplasty: a multivariate analysis of 604 urethroplasties. can urol assoc j. 2014; 8:e296-300. 18. barbagli g, kulkarni sb, fossati n, et al. long-term followup and deterioration rate of anterior substitution urethroplasty. j urol. 2014; 192:808-813. 19. wiegand lr, brandes sb. the urethral stricture score: a novel method for describing anterior urethral strictures. can urol assoc j. 2012; 6:260-4. 20. akyüz m, sertkaya z, koca o, et al. adult urethral stricture: practice of turkish urologists. int braz j urol. 2016; 42:339-345. 21. ansari is, islam su, ali w, haq iu. urethrotomy and end-toend urethroplasty in anterior urethral strictures up to 1.5 cm dept of urology mayo hospital, lahore. pak j med health sci. 2022; 16:174-175. 22. leosari y, uelmen ja, carney rm. spatial evaluation of healthcare accessibility across archipelagic communities of maluku province, indonesia. plos glob public health. 2023; 3:e0001600 23. desai d, harrison w, raveenthiran s, et al. urethronav: the aetiology and extent of idiopathic urethral stricture in an australian population. transl androl urol. 2024; 13:423-432. 24. blaschko sd, mcaninch jw, myers jb, et al. repeat urethroplasty after failed urethral reconstruction: outcome analysis of 130 patients. j urol. 2012; 188:2260-2264. correspondence paksi satyagraha (corresponding author) uropas.fk@ub.ac.id edi wibowo eddiewibowo283@gmail.com besut daryanto urobes.fk@ub.ac.id gede wirya diptanala putra duarsa diptaduarsa@gmail.com adrianus gupta wijaya guptawijaya@gmail.com fauzan kurniawan dhani fauzankurniawandhani@gmail.com urology department, saiful anwar general hospital malang, jalan jaksa agung suprapto 2, klojen, malang, east java 65112, indonesia declarations ethical approval: this study was approved by the health research ethics commission of saiful anwar general hospital number: 400/214/k.3/102.7/2024. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request. competing interests: the authors declare no conflict of interest. funding: the authors report no funding. authors' contributions: ps, ew, bd: conceptualization, methodology, writing-original draft, visualization, project administration, validation, gwdpd, agw, fkd: conceptualization, methodology, writing-original draft, investigation, validation, data analysis. acknowledgments: not applicable. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13786 1 original paper interactions between these variables can help optimize treatment plans and enhance patient outcomes. end-stage renal disease (esrd), which is caused by the growing global epidemic of ckd, remains a major concern for nations (7). for esrd patients, hemodialysis (hd) and peritoneal dialysis (pd) are the two most popular types of dialysis treatment (8). thus, to explore the complex relationships between bone marrow iron, serum ferritin levels, and mortality rates in, a cohort of incident cdk patients with no dialysis, hd and pd was used to investigate these relationships. materials and methods study design the study is a prospective, observational cohort study of iraqi patients with ckd. ckd patients from 3 governmental hospitals were enrolled. the inclusion criteria included being registered as ckd patients between january 1, 2022 and december 31, 2023 and undergoing no dialysis or starting hd/pd. the exclusion criteria included patients younger than 20 years of age and patients who rejected follow-up assessments. a total of 42 ckd patients with no dialysis, 76 ckd patients on pd and 82 ckd patients on hd were included (figure 1). the study strategy at each participating hospital was approved by the institutional review board. prior to taking part in the research, every patient provided signed informed consent. the study focused on protecting patient privacy by anonymizing data during analysis, according to ethical standards for research involving human subjects. from january 2022 to december 2023, 288 cdk patients who were registered in the three hospitals were initially recruited for this prospective and observational study. two hundred patients were included in the final analysis based on inclusion and exclusion criteria. figure 1 shows the flow diagram of the study. data collection demographic including age and gender and clinical data including hemoglobin, bone marrow iron and ferritin levels were recorded at the time of study entry. pre-dialysis fasting blood samples obtained during a midweek dialysis session within 30 days after the start of hd/pd were background and aim: it is well recognized that one of the most significant public health concerns is chronic kidney disease (ckd). in a cohort of incident ckd patients without dialysis, or on hemodialysis (hd), or on peritoneal dialysis (pd), the complicated interactions between bone marrow iron, serum ferritin levels, and death rates were examined. materials and methods: for this prospective and observational study, 288 ckd patients who were registered in three institutions between january 2022 and december 2023 were initially recruited. the final analysis comprised 200 patients, chosen based on predetermined inclusion and exclusion criteria. results: the median age of all patients was 65.52 ± 8.36, with 102 patients (51%) being male. of the patients followed up, forty (20%) died. cardiovascular events accounted for 22.5% of deaths (9 patients), and infections accounted for 70% of deaths. an elevated ferritin level (hr 1.528, 95% ci 1.239-1.885, p < 0.001) and advanced age were important risk factors for infection-related cardiovascular disease. conclusions: it was demonstrated that higher blood ferritin levels were substantially linked to a higher risk of death and that the most common causes of death of ckd patients in iraq are infection-related. key words: serum ferritin; bone marrow iron; mortality rate; ckd patients submitted 1 march 2023; accepted 23 march 2023 introduction globally, chronic kidney disease (ckd) is acknowledged as one of the most important public health issues where 13.4% is the estimated prevalence of ckd worldwide (1). ckd is defined as abnormalities of kidney structure or function that have implications for health and have been present for three months (2). diverse dialysis methods are often used to treat patients with ckd; nevertheless, the effects of different methods on iron and serum ferritin levels and mortality are still being studied. few studies had focused on the link between bone marrow iron, serum ferritin, and death rates in patients with ckd using various dialysis modalities (3-5). serum ferritin has been proven to be a good measure of bone marrow iron reserves in a number of chronic renal failure patient populations (6). gaining knowledge about the serum ferritin, bone marrow iron and mortality rate in ckd patients with different methods of dialysis mohammed lateef mohammed alkhammasi 1, bassam muayad alwan al-naqdi 2, mina muayad alwan al-naqdi 3 1 al-shaheed al-sadr general hospital, iraq; 2 al sheikh zayed general hospital, iraq; 3 al-mustansiriyah primary healthcare center, baghdad, iraq. doi: 10.4081/aiua.2025.13786 summary archivio italiano di urologia e andrologia 2025; 97(2):13786 m. lateef mohammed alkhammasi, b. muayad alwan al-naqdi, m. muayad alwan al-naqdi 2 utilized by this study. within the hd/pd dialysis treatment, patient took oral and intra-venous (iv) iron. bone marrow aspirates were collected from the sternum or posterior iliac crest, based on physician preference and patient tolerance. the aspirates were fixed in formalin, embedded in paraffin, and sectioned. the sections were stained with prussian blue to visualize iron stores within the bone marrow. a trained, blinded hematopathologist semi-quantitatively graded the stainable iron on a scale from 1 to 5 to facilitate the comparative assessment of iron stores within the patient cohort. a grade of 1 indicated absent or highly reduced iron stores, 2 indicated moderately decreased stores, 3 indicated normal stores, 4 indicated moderately elevated stores, and 5 indicated highly elevated stores or hemosiderosis. in case of death, the cause of death was reported within a month following the incident. cardiovascular death was defined as mortality resulting from myocardial infarction or ischemia, congestive heart failure, pulmonary edema, sudden cardiac death, or cerebrovascular disorders. infection-related death included mortality events due to septicemia with confirmed microorganisms in blood cultures, as well as fatal infections such as pneumonia, abdominal infections, genitourinary infections, central nervous system infections, and endocarditis. statistical analysis data are expressed as means ± standard deviation for continuous variables, and as number and percentage for categorical variables. the statistical analysis of mean differences for continuous variables was assessed using the independent t-test. the significance of differences for categorical variables was evaluated using the chi-square test. univariate analyses were performed to identify the association of potential risk factors with the outcome of cardiovascular and infection-related mortality causes. the variables that were examined in the univariate analyses were as follows: age (continuous), gender (categorical), hemoglobin level (continuous), ferritin level (continuous), and dialysis modality (categorical). the association of continuous and categorical variables with mortality was established by cox proportional hazards regression and chi-square test, and hazard ratios (hr) and 95% confidence intervals (ci) were reported. statistical analysis was carried out with spss version 18.0. p values less than 0.05 were regarded as significant. results baseline demographics and laboratory characteristics of the subjects are shown in table 1. the total median age was 65.52 ± 8.36 and 102 (51%) patients were male. the hemoglobin of ckd patients without dialysis was 7.34 ± 0.57 g/dl lower than that of ckd patients who underwent pd that was 9.18 ± 0.9 g/dl and of ckd patients who underwent hd that was 7.65 ± 0.3 g/dl. patients were divided into 15 groups according to baseline ferritin levels and bone marrow iron. group 1 included 10 ckd patients without dialysis who have markedly decreased bone marrow iron level. group 2 included 15 ckd patients without dialysis who have moderately decreased bone marrow iron level. group 3 figure 1. flow diagram of the study subjects. table 1. baseline characteristics of patients. ckd patients without dialysis ckd patients on pd ckd patients on hd p value (n * = 42) (n = 76) (n = 82) mean age ± standard deviation 64.95 ± 5.74 65.2 ± 9.41 66.1 ± 8.74 0.014 male n (%) 23 (54.76%) 40 (52.63%) 39 (47.56%) 0.034 hemoglobin (g/dl) 7.34 ± 0.57 9.18 ± 0.9 7.65 ± 0.3 0.14 ferritin level n (%) ferritin level n (%) ferritin level n (%) (ng/ml, mean ± std **) (ng/ml, mean ± std) (ng/ml, mean ± std) bone marrow iron markedly decreased 9.48 ± 15.49 10 (23.81) 28 ± 16.26 14 (18.42) 98 ± 45.36 14 (17.07) < 0.001 moderately decreased 15.47 ± 17.48 15 (35.71) 53 ± 26.16 17 (22.37) 150 ± 70.71 18 (21.95) normal 50.89 ± 13.713 17 (40.48) 150 ± 63.54 15 (19.74) 201.45 ± 160.48 21 (25.62) moderately increased 312 ± 107.48 12 (15.79) 541.89 ± 201.56 18 (21.95) markedly increased 503 ± 143.54 18 (23.68) 751.78 ± 180.71 11 (13.41) * n: number of patients; ** std: standard. archivio italiano di urologia e andrologia 2025; 97(2):13786 3 iron metabolism and mortality in ckd included 17 ckd patients without dialysis who have normal bone marrow iron level. group 4 and 5 do not include any patients because none of them have demonstrated moderately or markedly increased bone marrow iron levels. group 6 included 14 ckd patients on pd who have markedly decreased bone marrow iron level. group 7 included 17 ckd patients on pd who have moderately decreased bone marrow iron level. group 8 included 15 ckd patients on pd who have normal bone marrow iron level. group 9 included 12 ckd patients on pd who have moderately increased bone marrow iron level. group 10 included 18 ckd patients on pd who have markedly increased bone marrow iron level. group 11 included 14 ckd patients on hd who have markedly decreased bone marrow iron level. group 12 included 18 ckd patients on hd who have moderately decreased bone marrow iron level. group 13 included 21 ckd patients on hd who have normal bone marrow iron level. group 14 included 18 ckd patients on hd who have moderately increased bone marrow iron level. group 15 included 11 ckd patients on hd who have markedly increased bone marrow iron level. the median ferritin level for each group is shown in table 1. a total of 40 patients were dead during the study assessment. these patients were divided into 4 categories according to their last record of the ferritin level. figure 2 shows that death rate was associated to the ferritin level. during the follow-up period, 40 (20%) patients died. the most common cause of death was a cardiovascular event (9 patients, 22.5%), followed by infection (28 patients, 70%) (table 2). cardiovascular fatalities were defined as deaths caused by myocardial infarction/ischemia, congestive heart failure, pulmonary edema, sudden cardiac death, or cerebrovascular disease. deaths from infections included sepsis with blood cultures confirming the presence of microorganisms, as well as deadly illnesses such as pneumonia, endocarditis, genitourinary infections, stomach infections, and infections of the central nervous system. to determine the association between baseline parameters mortality for different causesunivariate analysis was performed. older age and high ferritin level (hr 1.528, 95% ci 1.239-1.885, p < 0.001) were significant risk factors for both cardiovascular and infection-related mortality. hemoglobin level and gender were found to be not significant risk factors for cardiovascular and infectionrelated mortality (table 3). discussion elevated serum ferritin levels were shown to be substantially related with an increased risk of death in the current investigation, which observed a prospectively collected cohort of incident patients without dialysis, and with pd, or hd. in the present series, mean hemoglobin (hb) concentration in patients on peritoneal dialysis was 9.18 g/dl, a value greater than the value reported in patients of a previous study (9) receiving intermittent peritoneal dialysis that ranged between 8.6 and 8.9 g/dl. mean hb concentration in patients receiving conservative care without dialysis or on hemodialysis was 7.34 and 7.65 g/dl respectively. these values were lower than 9.7-10 g/dl 10 or 10.512.4 g/dl that were observed in other studies (10, 11). ckd patients in another study (12) showed higher hemoglobin concentrations compared to our series that ranged between 13.0 and 14.5 g/dl. in patients with ckd receiving no dialysis, serum ferritin levels < 40 ng/ml were associated with reduced bone marrow iron; however, a study (11) stated that serum ferritin levels less than 60 ng/ml were linked to decreased or nonexistent bone marrow iron in ckd patients. in patients with ckd receiving pd, serum ferritin levels < 60 ng/ml were associated with reduced bone marrow iron, and in patients with ckd receiving hd, serum ferritin levels < 180 ng/ml were associated with reduced bone marrow figure 2. death rate in relation to the ferritin level. table 2. cause of death. variable total n (%) all dead patients 40 (20%) cause of death cardiovascular cause 9 (22.5%) infection-related cause 28 (70%) other 3 (7.5%) table 3. univariate regression analysis of baseline parameters for the cardiovascular and infection-related cause. cardiovascular cause infection-related cause hr * (95% ci) p value hr (95% ci) p value age (years) 1.071 (1.014-1.141) 0.004 1.089 (1.007-1.198) 0.003 male vs female 1.741 (0.684-1.948) 0.351 0.841 (0.678-1.127) 0.419 hemoglobin (g/dl) 0.841 (0.614-1.481) 0.154 0.859 (0.681-1.315) 0.481 ferritin level (ng/ml) 1.487 (1.089-2.015) 0.041 1.458 (1.201-1.771) 0.002 * hr: hazard ratio. archivio italiano di urologia e andrologia 2025; 97(2):13786 m. lateef mohammed alkhammasi, b. muayad alwan al-naqdi, m. muayad alwan al-naqdi 4 iron. similarly, in a different study (13), serum ferritin concentrations (mean value, 83 ng/ml) in ckd patients with a bone marrow iron score of 0 were significantly lower than in those with a bone marrow iron score of +2 or greater when bone marrow iron was graded 0 to +4, ranging from absent to diffuse homogeneous iron staining. additionally, a substantial association between bone marrow iron scores and serum ferritin was observed. serum ferritin is commonly used as a measure of iron storage in people with ckd (14). serum ferritin has been proven to be a good measure of bone marrow iron reserves in a number of populations of patients with chronic renal failure. our findings imply that in individuals receiving pd or hd, blood ferritin concentrations also positively correlate with stainable bone marrow iron similar to a previous study (15). in the current study serum ferritin levels showed a significant positive correlation with iron levels, which is consistent with results of another study (9) and supports ferritin's well-known function as an iron content proxy. moreover, the prevalence of high ferritin level was associated with higher rate of death. this also implies that ckd patients with high ferritin levels are more susceptible to death. patients with a serum ferritin level of > 250 ng/ml were shown to have a trend toward greater mortality in patients with advanced ckd who were not on dialysis, although there was no statistically significant difference. this does not align with results of another study (16) that stated the opposite. another study (17) showed that a serum ferritin level < 100 ng/ml was linked to a higher mortality risk than a lower serum ferritin level in a study of patients on hemodialysis in japan. in our study, infection-related complications were more common than cardiovascular ones. this might be explained by the spread of infectious diseases favored by poor hygienic conditions. a significant association has been shown between elevated serum ferritin levels and mortality from both infectious and cardiovascular diseases. the many functions of ferritin in the body might account for this association. iron homeostasis depends on the protein ferritin, which regulates the release and storage of iron. elevated ferritin levels may be a sign of increased systemic inflammation in the setting of cardiovascular mortality. cardiovascular disorders, such as myocardial infarction and congestive heart failure, are known to be exacerbated by chronic inflammation. increased ferritin levels may indicate an inflammatory condition, which increases a the risk of cardiovascular events. conversely, increased ferritin levels may be a result of the immunological response in case of infectionrelated death. the immune system produces inflammatory cytokines during infections, which can increase the synthesis of ferritin. since iron is necessary for microbial development, iron sequestration is a component of the host defensive system to limit its availability to pathogens. on the other hand, hyper inflammatory conditions may cause excessive ferritin formation, increasing the risk of complications and death during severe infections. in conclusion, the present study demonstrated that higher serum ferritin levels were associated with high mortality outcome and that infection-related cause of mortality is most frequent in patients with ckd in iraq. conclusions in the current study, a prospectively collected cohort of incident patients with ckd without dialysis, and on hemodialysis and peritoneal dialysis was examined. it was shown that elevated blood ferritin levels were significantly associated with an increased risk of mortality in patients with ckd and that infection-related cause of mortality of ckd patients is the most common in iraq. references 1. liu bc, lan hy, lv ll. renal fibrosis: mechanisms and therapies. springer singapore. 2019. 2. national kidney foundation. k/doqi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. am j kidney dis. 2002; 39:s1-s266. 3. weng ch, lu ky, hu cc, et al. bone marrow pathology predicts mortality in chronic hemodialysis patients. biomed res int. 2015; 2015:1-6. 4. erdem e, karatas a, ecder t. the relationship between serum ferritin levels and 5-year all-cause mortality in hemodialysis patients. blood purif. 2022; 51:55-61. 5. ueda n, takasawa k. impact of inflammation on ferritin, hepcidin and the management of iron deficiency anemia in chronic kidney disease. nutrients. 2018; 10:1173. 6. joshila nandhini g. a study of the etiology, contributory factors and correlation of the clinical and laboratory profiles of anemia in elderly patients presenting at a tertiary hospital in rural south india [doctoral dissertation]. tirunelveli: tirunelveli medical college; 2016. https://azpdf.net/document/q7wll95d-etiology-contributorycorrelation-clinical-laboratory-profiles-patients-presenting.html. 7. okpechi ig, nthite t, swanepoel cr. health-related quality of life in patients on hemodialysis and peritoneal dialysis. saudi j kidney dis transpl. 2013; 24:519-26. declarations ethical approval: ethical approval was granted by the research ethics committee in the three hospitals to ensure adherence to standards, while safeguarding participants' rights and well-being (o/3/8/2021). availability of data and material: the datasets generated and/or analyzed during the current study are not publicly available due to data privacy laws, but are available upon reasonable request from the corresponding author. competing interests: the authors state that there is no conflict of interest. funding: no external funding. authors' contributions: conceptualization: ma; data curation: ban; formal analysis: man; funding acquisition: ma, ban, man; investigation: ban; methodology: ma; project administration: man; resources: man; software: ban; supervision: man; validation: ma; visualization: ban; writing original draft: ban writing review and editing: ma. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13786 5 iron metabolism and mortality in ckd 8. zazzeroni l, pasquinelli g, nanni e, et al. comparison of quality of life in patients undergoing hemodialysis and peritoneal dialysis: a systematic review and meta-analysis. kidney blood press res. 2017; 42:717-27. 9. park ks, ryu gw, jhee jh, et al. serum ferritin predicts mortality regardless of inflammatory and nutritional status in patients starting dialysis: a prospective cohort study. blood purif. 2015; 40:209-17. 10. ogawa c, tsuchiya k, kanda f, et al. low levels of serum ferritin lead to adequate hemoglobin levels and good survival in hemodialysis patients. am j nephrol. 2015; 40:561-70. 11. fujisawa h, nakayama m, haruyama n, et al. association between iron status markers and kidney outcome in patients with chronic kidney disease. sci rep. 2023; 13:18278. 12. eisenga mf, nolte im, van der meer p, et al. association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease. bmc nephrol. 2018; 19:1-8. 13. kalantar-zadeh k, höffken b, wünsch h, et al. diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. am j kidney dis. 1995; 26:292-9. 14. fernández-rodríguez am, guindeo-casasús mc, molerolabarta t, et al. diagnosis of iron deficiency in chronic renal failure. am j kidney dis. 1999; 34:508-13. 15. blumberg ab, marti hrm, graber cg. serum ferritin and bone marrow iron in patients undergoing continuous ambulatory peritoneal dialysis. jama. 1983; 250:3317-9. 16. kovesdy cp, estrada w, ahmadzadeh s, et al. association of markers of iron stores with outcomes in patients with nondialysis-dependent chronic kidney disease. clin j am soc nephrol. 2009; 4:435-40. 17. hasuike y, nonoguchi h, tokuyama m, et al. serum ferritin predicts prognosis in hemodialysis patients: the nishinomiya study. clin exp nephrol. 2010; 14:349-55. correspondence mohammed lateef mohammed alkhammasi dr.mohammed.alkhammasi@gmail.com senior clinical fellow in internal medicine, al-shaheed al-sadr general hospital, iraq bassam muayad alwan al-naqdi bassam.naqdi@gmail.com sho internal medicine, al sheikh zayed general hospital, iraq mina muayad alwan al-naqdi (corresponding author) minamouied@gmail.com palestine street sq 506 alley 34 house number 3/1, iraq/baghdad stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13934 1 review introduction minimally invasive surgery, including laparoscopic and robotic-assisted procedures, has revolutionized surgical practice by offering significant advantages over open surgery, including reduced blood loss, shorter hospital stays, faster postoperative recovery and decreased postoperative pain (1). moreover, minimally invasive radical prostatectomy techniques (laparoscopic and robot-assisted) appear to be associated with a lower risk of postoperative inguinal hernia (2), a condition for which radical prostatectomy has been identified as a risk factor (3). despite these advantages, minimally invasive approaches are not devoid of risks, with trocar site hernias (tsh) representing a recognized complication of laparoscopic and robotic surgery (4). tsh, while relatively rare (estimated to occur in 0.2% to 4.8% of cases of laparoscopic and robotic procedures) (5), can lead to severe complications such as bowel obstruction, strangulation or even intestinal perforation requiring bowel resection (5-6). the literature suggests that approximately 90% of reported tsh cases develop at trocar sites measuring 10 mm or larger (7). in a literature review, richards analysed 153 tsh cases among over 31,000 patients undergoing laparoscopic or robotic surgery across multiple surgical fields, including general, gynecologic, and urologic procedures. the study examined four key variables: trocar type (bladed vs. nonbladed), follow-up duration, previous abdominal surgery and trocar size at the hernia site. the findings indicated that bladed trocars increase the risk of muscular layer injury, leading to prolonged healing time and a higher tsh incidence, a conclusion corroborated by gutierrez et al. (2020) (7, 8). additionally, damani et al. in 2020, investigated the impact of trocar insertion angle on tsh risk. however, no strong evidence currently supported trocar angle as a significant etiological factor for tsh development (6). the onset of tsh is highly variable, with reported cases ranging from 1 day to 7 years postoperatively, underscoring the necessity for long-term follow-up to fully assess this complication (9). several studies, including those by damani et al., timm et al., and seveso et al., have demonstrated a positive correlation background: trocar site hernia is a recognized but often underreported complication of minimally invasive surgery, including robotic-assisted radical prostatectomy. while relatively rare, trocar site hernia can lead to severe complications such as bowel obstruction, strangulation, and the need for emergency surgical intervention. trocar size has been identified as a primary risk factor, with hernias occurring predominantly at sites where 10 mm or larger trocars are used. however, the role of fascial closure is still debated. methods and results: a systematic literature review (19922022) identified 21 cases of trocar site hernia in 13 studies. only 8 papers provided data on the total number of rarp procedures which were associated to the reported cases of tsh, with 15 cases of tsh identified out of 3,418 rarp procedures. statistical analyses were conducted to assess significant risk factors and potential prevention strategies. specifically, of the 19 cases in which trocar size was explicitly reported, 15 hernias were associated with 12 mm trocars and 4 with 8 mm trocars (p value < 0.001). fascial closure was not performed in all reported cases involving 12 mm trocars. no significant correlations were found between trocar site hernia incidence and patient-related factors such as age, body mass index, or prior hernias. additionally, we report a case of trocar site hernia following rarp in a 67-year-old male with a bmi of 33.46 and a history of prior abdominal hernioplasty. the patient developed bowel obstruction on postoperative day 4 due to a hernia at a 12 mm trocar site, requiring emergency laparotomy and bowel resection with end-to-end anastomosis. conclusions: given the strong association between tsh and 12 mm trocars, we suggest routine fascial closure at these sites to reduce the risk of postoperative complications. further studies are necessary to confirm these findings. additionally, other potential risk factors and mechanisms contributing to trocar site hernia development in patients undergoing robot-assisted radical prostatectomy should be investigated. key words: port-site hernia; trocar site hernia; robot-assisted radical prostatectomy; surgical compli-cations; robotic surgery; prostate cancer; urology; surgical technique. submitted 28 april 2025; accepted 1 june 2025 strategies for preventing port-site hernia following robot-assisted radical prostatectomy: a systematic review pier paolo prontera 1, francesca r. prusciano 2, marco lattarulo 1, gianluigi califano 3, francesco di bello 3, claudia c. ruvolo 3, simone morra 3, angelo d’elia 1, angelo porreca 4, luca di gianfrancesco 4, filippo marino 4, giulia marino 5, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto (ta), italy; 2 department of urology, hospital “valle d’itria”, martina franca (ta), italy; 3 department of neurosciences, reproductive and odontostomatologic sciences, university of naples “federico ii”, naples, italy; 4 department of urology, humanitas gavazzeni hospital, bergamo (bg), italy; 5 department of precision and regenerative medicine, ionean area, taranto (ta), italy. doi: 10.4081/aiua.2025.13934 summary archivio italiano di urologia e andrologia 2025; 97(3):13934 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 2 between previous abdominal surgery and tsh occurrence (6, 8, 9). this correlation is likely due to the weakening of previous trocar sites during subsequent laparoscopic procedures, as the current standard practice does not require fascial closure for trocar sites up to 8 mm in diameter. however, further research is needed to confirm this hypothesis. damani et al. reported a lower tsh risk for trocar sites smaller than 8 mm, whereas seveso et al. found no statistically significant difference in tsh rates between 5-mm trocar sites with or without fascial closure (6-10). furthermore, seveso et al. noted an increased incidence of tsh with bladed trocar use, reinforcing the potential influence of trocar type on hernia development. nonetheless, tsh cases have also been documented in patients where bladeless trocars were used, suggesting that additional risk factors may contribute to hernia formation (10). several patient-related and technical factors have been investigated in tsh development. patientrelated factors include increased intra-abdominal pressure, obesity, chronic cough, diabetes, smoking, wound infection, chemotherapy and malnutrition. technical factors include trocar insertion angle, bladed versus radially expanding trocars, pneumoperitoneum induction, port placement, operative duration, specimen extraction site and fascial closure techniques. notably, an increased incidence of tsh has been observed in obese and bariatric patients, likely due to elevated intra-abdominal pressure and greater pneumoperitoneum volumes (11). tsh is classified as an incisional hernia occurring at the trocar site following minimally invasive surgery (12). the most widely recognized risk factor for tsh is trocar size, as highlighted by swank et al. and owens et al. (13, 14). robotic-assisted radical prostatectomy (rarp) is now the standard surgical approach for eligible prostate cancer patients requiring surgery. the typical rarp trocar placement configuration consists of six ports: the 8-mm primary camera port was placed 2 to 3 cm at the superior umbilical region. the two 8-mm robotic ports were introduced lateral to the rectus muscle and at the level of umbilicus on both sides. an 8-mm robotic port for the fourth arm was placed above the left iliac crest in the midaxillary line and a second 12-mm port for the assistant was placed in the opposite site. a 5-mm port for the assistant was placed between the robotic and camera ports on the right (figure 1). the prostate specimen is typically extracted through a small laparotomy, extending the camera port incision (15-17). given the increasing adoption of robotic surgery and the associated risk of tsh, this review aims to synthesize current evidence on trocar site hernias in patients underwent rarp, in order to recognized useful strategies to prevent this uncommon but potential severe complication. materials and methods literature review the systematic review was conducted in accordance with the prisma 2020 guidelines (figure 2). the literature search was performed using the pubmed and google scholar databases, applying the boolean search terms "trocar hernia" or "port-site hernia" and “robot assisted radical prostatectomy”. the search was restricted to studies published starting from 1992 onwards, which marks the introduction of laparoscopic radical prostatectomy. prior to this year, the radical prostatectomy procedure was performed exclusively through an open surgical approach. the aim of the review was to identify case reports or case series describing the occurrence of trocar site hernias following laparoscopic or robot-assisted radical prostatectomy. records were screened by evaluating titles and abstracts, followed by a full-text assessment of potentially eligible studies. only articles published in peer-reviewed journals and available in english or with an english abstract were considered. studies were excluded if the described hernia cases were unrelated to radical prostatectomy or if the herniation occurred in anatomical sites other than the trocar or port site. records that did not meet these criteria were systematically excluded. no automation tools were used in the selection process, and all stages of screening and data extraction were independently conducted by two reviewers, with any disagreements resolved through discussion. through this process, 13 articles were identified and included in the final qualitative synthesis (figure 2), reporting a total of 21 cases of tsh. the selected studies were divided into two groups: those that reported both the total number of rarp performed and the number of tsh cases observed and those that only reported the number of tsh cases without mentioning the total number of rarp performed. articles explicitly reporting the caliber of the trocar placed at the tsh site were identified, while in the remaining articles, indirect information was figure 1. trocar placement for robot-assisted radical prostatectomy (rarp). archivio italiano di urologia e andrologia 2025; 97(3):13934 3 port-site hernia following robot-assisted radical prostatectomy sought to infer this data (e.g., the anatomical location of the tsh). data were extracted for the following variables: age, bmi, presence of metabolic diseases, hypertension, chronic medication use, history of prior inguinal or umbilical hernias, timing of tsh onset relative to rarp, type of initial symptoms (subtle, symptoms without bowel obstruction, bowel obstruction), presence of abdominal bulging at the hernia site upon physical examination, anatomical location of tsh, trocar size, gleason score, preoperative psa levels, prostate volume, fascial closure at the rarp site where tsh occurred, time to resumption of oral intake after rarp, type of tsh repair (minimally invasive, mini-laparotomy, laparotomy), need for bowel resection and hernia type (table 1). some of these factors (presence of metabolic diseases, hypertension, chronic medication use, history of prior inguinal or umbilical hernias, timing of tsh onset relative to rarp, gleason score, preoperative psa levels, prostate volume and time to resumption of oral intake after rarp) were inconsistently reported by different authors and were therefore not considered suitable for analysis. statistical analysis statistical analyses were conducted to evaluate associations between tsh occurrence and various clinical and surgical factors. descriptive statistics were used to summarize patient demographics and surgical characteristics. associations between categorical variables, such as trocar size, fascial closure, hernia type, and the need for bowel resection, were assessed using the chi-square test or fisher’s exact test, as appropriate. relative risk (rr) was calculated to estimate the impact of fascial closure on tsh occurrence. when not directly stated by the study authors, since the total number of trocars used in each procedure was not consistently reported, we estimated trocar counts based on standard rarp templates. for each rarp, we assumed the use of one 12 mm assistant port, three 8 mm robotic ports, one optical trocar, and figure 2. prisma 2020 flow diagram for new systematic reviews which included searches of databases and registers only. archivio italiano di urologia e andrologia 2025; 97(3):13934 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 4 one 5 mm accessory port. the chi-square analysis on tsh occurrence by trocar size was conducted using only those articles in which both the total number of trocars and their caliber could be directly determined. a p-value < 0.05 was considered statistically significant. the results were interpreted in the context of their clinical relevance, particularly in the prevention and management of tsh in robotic-assisted laparoscopic surgery. risk of bias a risk of bias assessment was performed using the jbi critical appraisal approach for case series and descriptive observational studies. results a literature review was conducted using the pubmed and google scholar platforms to identify studies describing cases of tsh in patients undergoing rarp. studies reporting cases of tsh in patients undergoing general laparoscopic surgery or other urological surgeries different from rarp were excluded. a total of 13 papers were evaluated: 5 case reports, 5 retrospective original articles, 2 combining case reports and retrospective original data, and 1 case report with a literature review. overall, the reported cases refer to patients who underwent rarp between 2003 and 2020. in 8 of these articles, it was possible to extract the total number of rarp procedures performed (3,418 cases) and the number of reported tshs (15 cases) between 2008 and 2020, resulting in an estimated incidence of 0.44% (56, 15-26). upon analysis of the included studies, it was found that trocar placement by the various authors was generally consistent with the configuration outlined in the figure 1, which adheres to the manufacturer's recommended setup for the robotic platform. in detail, an 8-mm optical trocar was placed supraumbilically; three additional 8-mm robotic trocars were positioned at a minimum distance of 8 cm from each other (right pararectal, left pararectal, and left lateral locations); and two assistant laparoscopic trocars were utilized a 12-mm trocar placed laterally on the right side, and a 5-mm trocar inserted on the right in a triangulated position between the optical trocar and the right pararectal robotic trocar (figure 1). due to inconsistent reporting across studies, variables such as presence of metabolic diseases, hypertension, chronic medication use, gleason score, psa levels, prostate volume, and time to resumption of oral intake were not included in the statistical analysis. among the 21 described cases of tsh, 16 were classified as “spigelian” hernias, 3 as incisional hernias at the optical trocar site used for specimen extraction, 1 as a “richter's” hernia, 1 as a hernia of the vermiform appendix (table 1). in 13 cases (61.9 %), abdominal bulging was reported; however, this finding was not statistically correlated with the presence of bowel obstruction at onset (pvalue: 0.52), hernia type (p-value: 0.62), or the need for bowel resection during tsh repair (p-value: 1). to assess the statistical correlation between trocar type and tsh incidence, descriptive analyses and chi-square tests were performed based on data extracted from the 7 articles that provided information on the total number of procedures. across all these cases, a total of 15 tshs were reported: 2 were associated with 8 mm trocars and 13 with 12 mm trocars. the authors of these 7 articles explicitly stated the size of the trocar placed at the tsh site. among the 13 studies included in this review, only two did not directly report the trocar size; however, both provided indirect information (i.e., anatomical location of the hernia site), strongly suggesting that the two tshs described (accounting for 9.5% of the total) were also related to 12 mm trocars (21, 23). the analysis included 8 mm robotic trocars and 12 mm table 1. summary of reported trocar site hernia (tsh) characteristics of selected studies: this table summarizes the characteristics of trocar site hernia (tsh) cases reported in selected studies. variables include tsh type, bowel re-section, intervention type, fascial closure, trocar size, port site, abdominal bulging, bowel obstruction at onset, symptomatic onset, time of tsh presentation, mean bmi, and mean age. for authors reporting multiple tsh cases, the partial number of variables for each case is indicated in parentheses. author ogasa et al., 2020 (16) mancini et al., 2020 (18) tobe et al., 2022 (15) schmocker et al., 2016 (22) hotston et al., 2009 (19) damani et al., 2020 (6) tsu j.h.l. et al., 2013 (20) singh wazir j.p. et al., 2021 (21) jazayeri s.b. et al., 2016 (23) kang d.i. et al., 2012 (25) christie m.c. et al., 2016 (17) chiong e. et al., 2014 (24) fischer b. et al., 2008 (4) rarp performed (n°) n/a 1531 n/a n/a 500 n/a 200 n/a n/a 498 38 441 210 tsh reposted (n°) 1 3 1 1 2 1 1 1 1 2 2 4 1 mean age (range) 56 67 (60-71) 73 66 68.5 (67-70) n/a 75 65 71 59 (52-66) 69 (65-73) 65 (60–70) 64 mean bmi (range) 25.7 23.43 (20.1-25.7) 22.2 28 n/a n/a n/a n/a n/a 30.6 (29.8-31.4) 26.85 (22.4-31.3) 25.15 (17.9-32) 27 time of tsh presentation 4 4.5 (1-4) 11 730 5 (1-4) n/a 4 2 3 547 n/a 97.5 (2-335) n/a symptomatic onset, (n°) yes yes (3) yes yes yes n/a yes yes yes yes yes yes n/a bowel obstruction at onset, (n°) yes yes (2), no (1) yes no no n/a no no no no no no n/a abdominal bulging, (n°) yes yes (2), no (2) no yes yes n/a yes yes yes yes yes yes (1), no (3) n/a port-site right pararectal right literal (2), left lateral (1) supre-umbilical right literal right literal right literal left lateral right literal right literal supre-umbilical supre-umbilical right literal n/a port-dimension (mm) 8 12 (2), 8 (1) 12 12 12 8 8 12 12 12 12 12 12 fascial closure after rarp yes no yes n/a n/a n/a no n/a yes yes yes no n/a type of intervervention, (n°) laparoscopy open (2), laparoscopy (1) open open open open open open laparoscopy open open open open bowel resection, (n°) no yes (1), no (2) yes yes yes (1), no (1) yes no no yes (2) no (2) no yes (1), no (3) no type of tsh richter spigelian incisional vermiform appendix spigelian spigelian spigelian spigelian spigelian incisional incisional spigelian spigelian archivio italiano di urologia e andrologia 2025; 97(3):13934 5 port-site hernia following robot-assisted radical prostatectomy laparoscopic trocars. the optical trocar was analysed separately, as it represents the incision site for specimen extraction and an incisional hernia at this location may have a different pathogenic significance, compared to a hernia occurring through one of the other trocars used during robotic surgery. the chi-square test demonstrated a strong statistically significant correlation between tsh incidence and the 12 mm laparoscopic trocar (χ² = 27.25, p < 0.0001) and the corresponding incidence rates were 3.80 per 1000 for 12-mm ports and 0.20 per 1000 for 8mm ports. in none of the tsh cases involving the 12 mm laparoscopic trocar was fascial closure at this site described at the end of the rarp. in all patients, fascial closure was performed at the extraction site (optical trocar), whereas only one case reported fascial closure at other trocar sites, in which a tsh was observed at an 8 mm trocar site. among the 21 total cases of tsh, 7 were treated with bowel resection at the time of tsh repair and 14 underwent hernia reduction without the need for bowel resection. no statistically significant differences emerged in terms of bowel resection rates between tsh occurring at the optical trocar site and tsh at other trocar sites (p-value: 0.92, chi²: 0.0099). the analysis of the impact of fascial closure on tsh onset, performed using the chi-square test, revealed a statistically significant correlation (p-value: 0.00068, chi²: 11.55, rr: 16). the impact of other factors, such as age, bmi, and history of prior inguinal or umbilical hernias, was also evaluated; however, no statistically significant associations were found (p-values: 0.85, 0.61, 0.60, and 1, respectively). in addition, we report the case of a 67-year-old obese male (bmi 33.46) with a history of multiple prior abdominal wall hernioplasties, who developed bowel obstruction on postoperative day 4 following rarp. the obstruction was caused by a trocar site hernia at the 12 mm right lateral port site, requiring emergency laparotomy and ileal resection with primary anastomosis. no abdominal bulging was observed prior to symptom onset, and the fascial plane at the 12 mm trocar site had not been closed (figure 3). using the jbi critical appraisal approach for case series and descriptive observational studies (27), the included studies were evaluated across eight methodological domains. the overall risk of bias was considered moderate, with several domains satisfactorily addressed, including the presence of clear inclusion criteria, adequate case description, and consistent diagnostic criteria for tsh. however, heterogeneity in the reporting of clinical variables (e.g., bmi, prior hernias, fascial closure) and followup duration was noted. most studies did not discuss internal sources of bias such as selection or measurement bias, and the representativeness of cases may be affected by selective reporting. these limitations underline the need for cautious interpretation of pooled data. discussion tsh represent a recognized but often underreported and potentially severe complication of minimally invasive surgery (5-6), including rarp. the estimated incidence of tsh after rarp, according to our results, is 0.44%, close to estimated incidence of tsh after others mini-invasive surgery (5). the findings from our literature review, in accordance with the case report described, highlight a significant correlation between the use of a 12 mm assistant trocar and the occurrence of tsh, reinforcing the hypothesis that trocar size plays a critical role in hernia formation (7). notably, this observation is not limited to patients undergoing rarp but has also been reported in other minimally invasive abdominal procedures, both laparoscopic and robotic-assisted, across various surgical fields, including urology, gynecology and general surgery (7). this broader trend further supports the hypothesis that trocar diameter significantly contributes to tsh development. the type of the trocar is another key factor in tsh pathogenesis. some studies have shown that the use of bladed (cutting) trocars increases the risk of herniation due to greater disruption of the fascial and muscular layers, leading to prolonged healing time and a higher likelihood of hernia formation (7, 8). however, the insertion angle of the trocar remains a debated factor, as current evidence does not strongly support a figure 3. contrast-enhanced ct images: contrast-enhanced ct images in the arterial phase (a axial plane, b coronal plane, and c sagittal plane) performed at the onset of symptoms for the hernia. the arrow highlights a small defect in the lateral abdominal wall at the right flank, with herniation of an ileal loop at this level and concomitant upstream distension of the small bowel loops, suggestive of mechanical obstruction. archivio italiano di urologia e andrologia 2025; 97(3):13934 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 6 significant correlation between trocar angulation and tsh onset (6). additionally, while our review did not identify a statistically significant correlation between tsh incidence and bmi, some authors have reported a higher tsh incidence in bariatric patients, likely due to increased intraabdominal pressure and greater pneumoperitoneum volumes (11). similarly, patients with a history of prior abdominal surgery appear to be at greater risk, possibly due to pre-existing weaknesses at previous trocar sites (69). however, the limited number of tsh cases observed in our review prevents definitive conclusions regarding these associations, suggesting the need for larger studies to clarify the role of bmi and prior surgery in tsh development. an important consideration is the surgical approach itself. tsh is primarily a complication associated with the transperitoneal approach to rarp, as the peritoneum is breached during trocar placement, facilitating potential herniation through the defect. conversely, extraperitoneal rarp, as in the case of extraperitoneal laparoscopic radical prostatectomy (28), eliminates this risk by avoiding peritoneal penetration altogether, thereby reducing the risk of internal organ herniation. this technical difference may explain the lower incidence of tsh reported with extraperitoneal techniques and warrants more structured comparative studies. additionally, extraperitoneal rarp may offer particular advantages in patients at high risk for postoperative hernias, such as those with prior intraabdominal surgery, obesity, or peritoneal adhesions. this distinction suggests that surgical approach selection may itself be a preventive factor, warranting further comparative studies to evaluate the impact of transperitoneal versus extraperitoneal rarp on tsh incidence. given the multifactorial nature of tsh, an integrated preventive strategy should include: careful selection of trocar type and size, routine fascial closure, and a tailored approach based on patient-specific risk factors. moreover, surgical approach selection, transperitoneal vs. extraperitoneal, should be considered as a potential modifiable factor when planning prostate cancer surgery in high-risk populations. the statistically significant correlation between tsh incidence and the 12 mm trocar (χ² = 27.25, p < 0.0001) and the statistically significant impact of fascial closure on the incidence of tsh (p-value: 0.00068), suggests that fascial closure at this site may be a crucial preventive strategy to prevent the occurrence of tsh after rarp, especially in bariatric patients and those with a history of prior abdominal surgery. future studies should further investigate these risk factors to refine preventive strategies and optimize patient outcomes in robotic surgery. limitations this study presents several limitations that should be acknowledged. first, the overall number of tsh cases identified in the literature review is relatively small (n = 21) with only 15 cases were described by authors who also reported the total number of rarp procedures performed and the corresponding trocar size, limiting the statistical power and generalizability of the findings. second, the review is retrospective and relies on data extracted from previously published case reports and case series, which may be subject to publication bias and inconsistencies in reporting. third, there is significant heterogeneity among the included studies in terms of study design, data completeness, and follow-up duration, which could affect the accuracy of comparisons and pooled analyses. several potentially relevant variables, such as metabolic comorbidities, gleason score, prostate volume, and time to oral intake resumption, were not consistently reported across studies and were therefore excluded from statistical analysis. consequently, the results and conclusions presented in this manuscript should be interpreted with caution and validated in prospective, multicenter studies with standardized data collection protocols. declarations ethical approval: this study was approved by the local ethics committee of bari (ba), irccs oncological institute "gabriella serio" (protocol number: 2112/cel study “propt”). availability of data and material: the datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. competing interests: the authors declare no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions: 1: pier paolo prontera author corresponding: substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 2: francesca romana prusciano, francesco saverio grossi: substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 3: marco lattarulo, gianluigi califano, francesco di bello, claudia collà ruvolo, simone morra, angelo d’elia, angelo porreca, luca di gianfrancesco e filippo marino: substantial contributions to the interpretation of data for the work. reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. all authors read and approved the final version of the manuscript. acknowledgments: not applicable. informed consent statement: informed consent was obtained from patient involved in the study. disclaimer/publisher’s note: the statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of the editor(s). and/or the editor(s) disclaim responsibility for any in-jury to people or property resulting from any ideas, methods, instructions or products referred to in the content. archivio italiano di urologia e andrologia 2025; 97(3):13934 7 port-site hernia following robot-assisted radical prostatectomy conclusions tsh represent a rare but potentially severe complication of minimally invasive surgery, including rarp. our findings, supported by a systematic literature review and a case report, confirm a strong correlation between tsh incidence and the use of 12 mm trocars, reinforcing the critical role of trocar size in hernia formation. the absence of routine fascial closure at these trocar sites appears to be a significant risk factor, suggesting that implementing systematic fascial closure could serve as a protective strategy. additionally, although no statistically significant correlation was found between tsh incidence and patient-related factors such as bmi or prior abdominal surgery, some studies indicate an increased tsh risk in bariatric patients and those with a history of previous laparotomy, likely due to elevated intra-abdominal pressure and pre-existing wall weakness. these findings, although not conclusive in our review, underscore the need for further prospective studies to clarify the impact of these factors. furthermore, while bladed trocars have been associated with a higher risk of tsh due to increased fascial trauma, trocar insertion angle does not currently appear to be a significant contributing factor. another key consideration is that tsh is inherently a complication of transperitoneal rarp, whereas the extraperitoneal approach avoids peritoneal penetration, potentially reducing this risk. given these insights, routine fascial closure of 12 mm trocar sites is strongly considered, particularly in high-risk patients, as a simple yet effective measure to minimize the occurrence of tsh. future research should focus on refining preventive strategies, evaluating the impact of surgical approach selection, and identifying additional risk factors to enhance patient safety and optimize outcomes in robotic prostatectomy. references 1. cao l, yang z, qi l, et al. robot-assisted and laparoscopic vs open radical prostatectomy in clinically localized prostate cancer: perioperative, functional, and oncological outcomes a systematic review and meta-analysis. medicine 2019; 98:e15770. 2. alder r, zetner d, rosenberg j. incidence of inguinal hernia after radical prostatectomy: a systematic review and meta analysis. j urol. 2020; 203:265-274. 3. perugia g, prontera pp, corongiu e, et al. inguinal hernia after radical prostatectomy: incidence and risks 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iju case rep. 2022; 5:501-504. 16. ogasa t, msayoshi n, hiroki k, et al. port site hernia at the robotic arm port after robotic-assisted laparoscopic radical prostatectomy. iju case rep. 2020; 3:153-156. 17. christie mc, manger jp, khiyami am, et al. occult radiographically evident port-site hernia after robot-assisted urologic surgery: incidence and risk factors. j endourol. 2016; 30:99-96. 18. mancini m, righetto m, dal moro f, et al. incidence and treatment of incarcerated trocar-site hernias after robotic surgery: presentation of three cases. j endourol case rep. 2020; 6:271-274. 19. hotston mr, beatty jd, shendi k, et al. port site hernias following robot-assisted laparoscopic prostatectomy. j robot surg. 2009; 3:49-51. 20. tsu jhl, tsui-lin ng a, ka-wing wong j, et al. trocar-site hernia at the 8-mm robotic port after robot-assisted laparoscopic prostatectomy: a case report and review of the literature. j robot surg. 2014; 8:89-91. 21. singh wazir jp, hussain j, bashir a, et al. port site hernia presenting as intestinal obstruction following robot-assisted laparoscopic transperitoneal radical prostatectomy. iosr j dent med sci. 2021; 20:35-39. 22. schmocker rk, greenberg ja. an unusual trocar-site hernia after prostatectomy. case rep surg. 2016; 2016:3257824. 23. jazayeri sb, tsui jf, samadi db. abdominal mass after robotic assisted laparoscopic prostatectomy: spigelian type trocar hernia. curr urol. 2016; 10:163-165 24. chiong e, hegarty pk, davis jw, et al. port-site hernias occurring after the use of bladeless radially expanding trocars. urology. 2010; 75:574-580. 25. kang di, woo sh, lee dh, et al. incidence of port-site hgernias after robot-assisted radical prostatectomy with the fascial closure of only the midline 12-mm port site. j endourol. 2012; 26:848-851 26. liatsikos e, rabenalt r, burchardt m, et al. prevention and management of perioperative complications in laparoscopic and endoscopic radical prostatectomy. world j urol. 2008; 26:571-580. archivio italiano di urologia e andrologia 2025; 97(3):13934 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 8 27. munn z, stone jc, aromataris e, et al. assessing the risk of bias of quantitative analytical studies: introducing the vision for critical appraisal within jbi systematic reviews. jbi evid synth. 2023; 21:467-471. 28. grossi fs, utano e, minafra p, et al. oncological and functional outcomes of extraperitoneal laparoscopic radical prostatectomy: an 18-years, single-center experience. arch ital urol androl. 2021; 93:268-273. correspondence pier paolo prontera (corresponding author) pierpaolo.prontera@asl.taranto.it department of urology, “s.s. annunziata” hospital bruno francesco, 1 street 74010 taranto (italy) francesca romana prusciano francescaprusciano@gmail.com marco lattarulo marco.lattarulo@asl.taranto.it angelo d'elia angelo.delia@asl.taranto.it francesco saverio grossi francescos.grossi@asl.taranto.it department of urology, “s.s. annunziata” hospital, taranto (ta), italy gianluigi califano gianl.califano2@gmail.com francesco di bello fran.dibello12@gimail.com claudià collà ruvolo c.collaruvolo@gmail.com simone morra simonemorra93@gmail.com department of neurosciences, reproductive and odontostomatologic sciences, university of naples “federico ii”, naples, italy angelo porreca angelo.porreca@hunimed.it luca di gianfrancesco luca.digian@libero.it filippo marino filippo.marino@gavazzeni.it giulia marino giulia.marino91@gmail.com department of urology, humanitas gavazzeni hospital, bergamo (bg), italy stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11455 1 original paper should deliver a flow rate sufficient for performing effective dialysis, durable, easily punctured, and has a low complication rate (2). af comes closest to fulfilling these criteria, but af use depends on the identification of a suitable artery and vein (3). autogenous arteriovenous radial cephalic or brachial cephalic fistulas were recommended as 1st-line choices for vascular access by the kidney disease outcome quality initiative (kdoqi) (4). however, not all hd patients can have a distal forearm fistula due to the small size of the vessel, diseased or exhausted peripheral veins, and arteries. additionally, around 30% of the fistulas fail within 3 years and need alternative vascular access. alternative access options are brachiocephalic af in the forearm or brachial basilic af in the arm or forearm or an arteriovenous bg in the arm. brachiocephalic af is the second option if a radial cephalic or forearm af fails or is unsuitable (5, 6). however, when the cephalic vein in the arm cannot be utilized, a brachial basilic af could be constructed. this study highlights our clinical surgical results for all types of basilic vein-based fistulas comparable to the results of prosthetic bg-based fistulas performed in the same period. patients and methods between march 2018 and february 2020, 72 patients were included in this retrospective study whose basilic vein was used for brachial-basilic af at our hospital, and their surgical results were compared to the results of arm prosthetic bg constructed for hemodialysis. patients included in this study had either previously failed radial-cephalic and brachial-cephalic af operations or the diameter or quality of the arteries and cephalic veins are not suitable for af construction. the most frequently linked diseases were recorded and analyzed. additionally, the patient’s demographics including age and gender were collected and analyzed. all cases were preoperatively examined using doppler ultrasonography (usg) for assessment of basilic and cephalic veins. furthermore, central veins (jugular and subclavian veins) were examined for occlusion and stenosis. because the procedures necessitated long incisions and basilic vein dissection, they were carried out under regionpurpose: for patients with a failed forearm autogenous fistula (af) and an exhausted cephalic vein, there is controversy about whether a brachial basilic af with transposition or an arteriovenous prosthetic bridging graft (bg) must be the second vascular access option. this work measured and compared these two modalities according to patency rates, complications, and revisions. patients and methods: a retrospective study of 104 cases that had either a brachial basilic af (72) or an arteriovenous bg (32). technical success, operative complications, procedurerelated mortality, maturation time, functional primary, secondary, and overall patency rates were all assessed. results: technical success was obtained in all participants. no procedure-linked mortality. maturation time for bgs was significantly shorter than afs. the complication rate was significantly higher in bgs than in afs. the most prevalent complication was access thrombosis. the functional primary patency rate was significantly higher in af than in bg at 12-month followup: 77.7% vs 53.1% (𝑝 < 0.012). secondary patency rate was higher in af than in bg at 1-year follow-up 62.5% vs 42.8% (𝑝 = 0.063), respectively. in addition, bgs required more interventions to preserve patency. conclusions: af had higher primary, secondary and overall functional patency rates and needed fewer procedures to keep patency than bgs. cases that need early vascular access as a result of central venous catheter complications or who have a reduced life expectancy may benefit from bgs. key words: hemodialysis; basilic vein superficialization; arteriovenous fistula. submitted 6 may 2023; accepted 8 june 2023 introduction end-stage renal disease (esrd) impacts over 1500 people per million populations in high-prevalence countries like taiwan, japan, and the united states. nearly two-thirds of esrd patients receive hemodialysis (hd), one-quarter receive kidney transplants, and one-tenth require peritoneal dialysis (1). three types of procedures are commonly performed for hd, an indwelling central venous catheter, an af, and prosthetic bgs. the ideal access use of basilic vein in arteriovenous fistulas construction for hemodialysis access. is it a good option alternative to prosthetic arteriovenous grafts? ehab m. abdo 1, tamer a. abouelgreed 2, waleed e. elshinawy 1, nehal farouk 1, mohamed a. abdelaal 2, hassan ismail 2, amal h. ibrahim 3, samar a. kasem 3, ahmed a. aboomar 4 1 department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt; 2 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 3 department of internal medicine, nephrology unit, faculty medicine, al-azhar university, cairo, egypt; 4 department of internal medicine, nephrology unit, faculty medicine, tanta university, tanta, egypt. doi: 10.4081/aiua.2023.11455 summary archivio italiano di urologia e andrologia 2023; 95(3):11455 e.m. abdo, t.a. abouelgreed, w.e. elshinawy, et al. 2 al or general anesthesia. the basilic vein arises from the dorsal venous network of the hand and travels the medial aspect of the upper limb. the vein travels deep into the arm towards the teres major boundary. it joins the brachial veins of the deep venous system creating the axillary vein. different techniques were used to construct brachial basilic af: two stages of basilic vein elevation and transposition without anastomosis, two stages of arm basilic vein transposition and re-anastomosis, and forearm basilic vein loop transposition. the first stage consists of creating an end-toside basilic vein to the brachial artery fistula at the elbow level with 6/0 polypropylene sutures. the second stage is scheduled to begin in 6-8 weeks. first, a small incision was made in the antecubital region to locate both the basilic vein and brachial artery. then the incision was extended proximally to expose the proximal portion of the basilic vein. to prevent injury, the median antebrachial cutaneous nerve waa carefully separated from the vein. after isolating the basilic vein, a subcutaneous flap was performed, and the vein was transposed without being transacted (figure 1). the subcutaneous flap was then sutured in place between the nerve and the transposed vein on the ventral surface of the arm. if the nerve had crossed the basilic vein and could not be spared without causing injury, or if the vein length was sufficient, the basilic vein was transacted at the level of the antecubital fossa and transported through a tunnel created over the deep fascia beneath the skin. then, the vein was gently augmented with heparinized saline and anastomosed to the basilic vein stump (figure 2). if the basilic vein diameter in the forearm is appropriate but the forearm arteries are not, the vein was exposed along its course in the forearm and its tributaries were tied before the vein was transected distally and mobilized through a subcutaneous forearm tunnel to be anastomosed to the brachial artery (end-to-side technique with 6/0 polypropylene sutures) (figure 3). thirty-two patients had prosthetic bg fistulas during the same study period. all grafts are made of polytetrafluoroethylene (ptfe) material. the cases were discharged the day after the surgery. postoperatively, the cases were followed up for twelve months and any procedure-linked complication or mortality was recorded. if not related to the procedure, death with a properly working fistula was regarded as a failure to follow-up. for short segment thrombosed brachial basilic af, thrombectomy was performed with or without balloon angioplasty (pta). but for long segment thrombosis, the fistula was abandoned. technical success was described as the occurrence of a bruit or thrill on the arteriovenous fistula. primary patency was described as the time at which the fistulas were functioning for hemodialysis until the time when an intervention was performed to reestablish or maintain access patency. secondary patency was described as the time from successful access cannulation until access abanfigure 1. mobilization of the matured basilic vein (retracted with red vessel loop). figure 2. schematic diagram showing the normal anatomy (a) and the procedure. the basilic vein is anastomosed to the brachial artery (b). the arterialized basilic vein is superficialized and re-anastomosed (c). figure 3. (a) ultrasound-guided marking of basilic vein. (b) augmentation of a mobilized basilic vein after ligation of its branches. (c) the looped basilic vein was anastomosed to the brachial artery. (d) two weeks postoperative. archivio italiano di urologia e andrologia 2023; 95(3):11455 3 use of basilic vein in arteriovenous fistulas construction for hemodialysis access donment, or the patient has demised regardless of how often interventions are required to maintain patency. overall patency was described as the patency of all hd accesses involved in this project. statistical analysis statistical analysis was performed with the spss for windows version 23.0 (spss inc., chicago, il, usa). data were explored for normality utilizing kolmogorovsmirnov and shapiro-wilk tests. the following tests were done: independent-samples t-test of significance was utilized when comparing between two means. a chi-square (𝝌2) test was also used to compare qualitative parameters' proportions. the influence of the different variables on the specific access type was analyzed using the log-rank test. p-value < 0.05 was regarded as statistically significant. ethical approval and consent for participation all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of the faculty of medicine for girls, al-azhar university (fmgirb) (approval number: 1403/22). results seventy-two patients were offered 72 afs (47 males, 25 females), while another 32 cases (22 males, 10 females) received upper arm prosthetic bg during the same period. the mean age of the cases who received af and upper arm av grafts was 55 (37 to 74) and 54 (37 to 75) years, respectively. table i displays demographic information for patients. nondominant left upper extremities were preferred in 55 patients who received afs (76.3%) and 22 patients who received prosthetic bg (68.7%). different techniques were used to construct brachial cephalic af: two-stages basilic vein elevation and transposition without re-anastomosis (22 patients), two-stages arm basilic vein transposition with re-anastomosis (28 patients), and forearm basilic vein loop transposition (22 patients). no procedure-linked mortality. technical success was obtained in all cases (100%) (table 1). the complication rate for afs was (13.9%) while the complication rate for the bgbased fistulas was (34.4%). complications of afs requiring additional procedures to maintain patency developed in 6 patients (8.3%), including 2 patients who revealed prolonged arm swelling because of subclavian vein occlusion for which balloon angioplasty was successful to dilate one lesion and failed to treat the other because of failure of the guidewire to cross the lesion and 2 fistulas necessitating surgical thrombectomy for acute short segment thrombosis. in addition, the brachial basilic fistula was banded in 1 case with hand ischemia, and 1 case required reexploration for postoperative bleeding. complications of prosthetic bg-based fistulas requiring additional procedures developed in 8 cases (25%), involving 5 patients that were treated by surgical thrombectomy for acute graft thrombosis. pta was used to dilate proximal subclavian vein stenosis in 1 patient who revealed arm swelling. two patients who presented with postoperative bleeding were explored for control of bleeding. access-related complications are described in figure 4. table 1. patient’s characteristics. patient’s af group prosthetic bg fistulas test value p-value characteristics (n = 72) (n = 32) age (years) mean ± sd 55.15 ± 10.96 54.19 ± 10.98 t = 0.414 0.680 range 37-74 37-75 gender female 25 (34.7%) 10 (31.3%) 𝝌2 = 0.120 0.729 male 47 (65.3%) 22 (68.8%) comorbidities ihd 25 (34.7%) 12 (37.5%) 0.075 0.785 dm 50 (69.4%) 20 (62.5%) 0.486 0.486 htn 43 (59.7%) 16 (50.0%) 0.853 0.356 hd: ischemic heart disease; dm: diabetes millets; htn: hypertension. figure 4. access-related complications. group 1 represents af patients and group 2 represents prosthetic bg patients. archivio italiano di urologia e andrologia 2023; 95(3):11455 e.m. abdo, t.a. abouelgreed, w.e. elshinawy, et al. 4 cannulation of af started at an average of 59 (range, 40 to 85) days after the first surgery. while cannulation of prosthetic bridging grafts started at an average of 15 (range, 14 to 20) days post-surgery. a statistically significantly higher primary patency rate was noticed for the af in comparison to the bg-based fistulas, with a 12-months primary patency rate of 77.7% and 53.1% for af and bgbased fistulas groups, respectively (p < 0.012). a similar pattern was noticed for secondary patency rates as well, with a 12-months secondary patency rate of 62.5% and 42.8% for af and bg-based fistulas, respectively (p = 0.063). the af group had a superior overall patency rate in comparison to the bg-based fistulas (84.7% and 59.3% respectively). all patients completed 1-year follow-up. discussion the kidney disease outcome quality initiative (kdoqi) guidelines recommended native fistulas over graft fistulas (7). the radial-cephalic fistula at the wrist was first described in 1966 and is still considered the procedure of choice because it is easy to construct, has good long-term results, and low blood flow rate so distal steal is uncommon, and nearly never results in high output cardiac failure. it also preserves the upper arm vessels for future use (8). proximal accesses are required in some situations like patients with prior forearm af dysfunction, and patients with a sclerosed vascular system, furthermore, if the distal veins have been subjected to repeated trauma from punctures and indwelling catheters, the radial artery, and forearm veins are deemed inappropriate for af. proximal accesses are easier to cannulate, have a longer vein or graft length for cannulation, have a higher blood flow with an increased chance for steal syndrome, and may result in high output cardiac failure (9). after the cephalic vein-based af has exhausted as primary vascular access choice, the available options are a brachial basilic af or a forearm or arm prosthetic bg-based fistula. upperextremity access with ptfe has been found effective, but complication rates are higher and patency rates are lower than with autologous fistulas (10). several studies have recommended afs over prosthetic bg-based techniques based on improved patency rates and fewer interventions (11). furthermore, clinical practice guidelines from the usa, australia, canada, and the uk all recommend an af over a prosthetic graft for chronic hd access (12). the majority of participants in this review were of working age (37-75 years old) (65%). diabetic nephropathy was the most frequent cause of esrd in both groups. males are more affected by esrd than females. these previous results are echoic to the results of other studies performed in ksa to study the prevalence of esrd and related risk factors (13). in regards to patient demographic variables, no significant differences were detected between the two groups. technical success was achieved in all cases. in our study, the procedure-related complication rate after af (13.9%) was statistically significantly lower than for the upper arm prosthetic bg (34.4%). reported results of af showed a complication rate lower than bg because a native vein fistula is more resistant to infection than a prosthetic graft, the large-caliber basilic vein offers a high flow rate because af only needs one anastomosis and venous outlet stenosis can be reduced, limiting the most common problem encountered with ptfe (14, 15). the most prevalent complication in this review was access thrombosis, which was significantly more common in bg (15.6%) than in af (2.8%) (p = 0.062). early graft thrombosis was caused by a technical error, but late graft thrombosis was caused by anastomotic stenosis caused by intimal hyperplasia. more procedures were required to keep the patency of the bg-based fistulas compared to af echoing previous results from other reports (16). wound-related infection was not statistically significant for both groups but some studies reported an increased incidence of infection with af as it requires longer incisions. minimally invasive approaches like video-assisted basilic vein transposition have been used to minimize wound complications (17). cannulation of the af began on average 59 days after the first surgery, while cannulation of the bg began on average at 15 days, which was consistent with the dialysis outcomes quality initiative (doqi) guidelines for access maturation, which state that a dialysis av graft should not be used until 14 days after it has been placed (19). when deciding on af, the anticipated time for maturation and cannulation should be balanced against the elevated risk of complications associated with prolonged central venous catheterization and the reduced quality of life linked with the tunneled catheter. prosthetic bg was considered for cases with a short life expectancy and those who could not tolerate tunneled central venous catheters in place. the tunneled forearm basilic vein loop technique has the advantages of earlier cannulation, being easily accessible, and preserving the proximal portion of the basilic vein for future use. when compared to bg, af procedures had higher primary, secondary, and overall patency rates. previous studies reported higher primary patency rates of af, ranging from 65 to 70% at one year and 49 to 51% at two years (19). a limitation of the article is the small sample size and also a smaller representation of the forearm bb avg group. conclusions brachial basilic af is a technically successful procedure with higher patency rates and lower operative complication rates than prosthetic bg. furthermore, if the af fails and the venous outflow is open, there is a chance that bg could be used in the future at the same site. we suggested that for patients with failed forearm dialysis fistulas and no adequate cephalic vein, a brachial basilic fistula be regarded as an alternative to prosthetic graft insertion. patients with a short life expectancy or those who are unable to tolerate tunneled central venous catheters should consider prosthetic bg. references 1. maaz abbasi, glenn m chertow, and yoshio n hall. end-stage renal disease. bmj. 2010; 7:1-16. 2. michael b. silva, jr and brajesh k.lal. decision making in vascular surgery by jack l. cronenwett, and robert b. rutherford. copyright 2001. chapter 72:354-359. archivio italiano di urologia e andrologia 2023; 95(3):11455 5 use of basilic vein in arteriovenous fistulas construction for hemodialysis access 3. kherlakian gm, roedersheimer lr, arbaugh jj, et al. comparison of autogenous fistula versus expanded polytetrafluoroethylene graft fistula for angioaccess in hemodialysis. am j surg. 1986; 152:238243. 4. vascular access work group, “clinical practice guidelines for vascular access,” am j kidney dis. 2006; 48:248-273. 5. oliver mj, mccann rl, indridason os, butterly dw. comparison of transposed brachiobasilic fistulas to upper arm grafts and brachiocephalic fistulas. kidney int. 2001; 60:1532-1539. 6. hakaim ag, nalbandian m, scott t. superior maturation and patency of primary brachiocephalic and transposed basilic vein arteriovenous fistulae in patients with diabetes. j. vasc. surg. 1998; 27:154-157. 7. oliver mj, mccann rl, indridason os, et al. comparison of a transposed brachiobasilic fistula to upper arm grafts and brachiocephalic fistulas. kidney int 2001; 60:1532-1539. 8. brescia mj, cimino je, apple k, hurwich bj. chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. n engl j med. 1966; 275:1089-1092. 9. bender mhm, bruyninckx cma, gerlag pgg. the brachiocephalic elbow fistula: a useful alternative angioaccess for permanent hemodialysis. j vasc surg. 1994; 20:808-813. 10. kherlakian gm, roedersheimer lr, arbaugh jj, et al. comparison of autogenous fistula versus expanded polytetrafluoroethylene graft fistula for angioaccess in hemodialysis. am j surg. 1986; 152:238-2343. 11. benedetto bj, madden rl, kurbanov a, lipkowitz gs. transposed basilic vein fistula: a superior alternative to prosthetic grafts? curr surg. 2000; 57:503-504. 12. m.a. frances d, yufan lu, amanda j. robertson, robert j. millar and jayne amy. two-stage brachiobasilic arteriovenous fistula for chronic hemodialysis access. anz j. surg. 2007; 77:150-151. 13. hussain gadelkarim ahmed, tahani altamimi. survey for potential risk factors for susceptibility to chronic kidney disease in hail region, in ksa. management in health xvii/122013; pp. 31-36. 14. kumar a, sinha s, sharma ak. long-term results of arteriovenous fistulas using transposed autologous basilic vein. br j surg. 2000; 87:1735-1736. 15. taghizadeh a, dasgupta p, khan ms, et al. long-term outcomes of brachiobasilic transposition fistula for hemodialysis. eur j vasc endovasc surg. 2003; 26:670-672. 16. sgroi md, patel ms, wilson se, et al. the optimal initial choice for permanent arteriovenous hemodialysis access. j vasc surg. 2013; 58:539-548. 17. hayakawa k, tsuha m, aoyagi t, et al. new method to create a vascular arteriovenous fistula in the arm with an endoscopic technique. j vasc surg. 2002; 36:635-638. 18. chieh-hung lee, po-jen ko, yun-hen liu, et al. brachiobasilic fistula as a secondary access procedure: an alternative to a dialysis prosthetic graft. chang gung med j. 2004; 27:816-23. 19. murphy gj, white sa, knight aj, et al. long-term results of arteriovenous fistulas using transposed autologous basilic vein. br j surg. 2000; 87:819-23. correspondence ehab m. abdo, md ehababdo48@yahoo.com waleed e. elshinawy, md waleed.elshinay82@gmail.com nehal farouk, md dr.nehalfarouk@yahoo.com department of vascular surgery, faculty of medicine, al-azhar university, cairo, egypt tamer a. abouelgreed, md (corresponding author) dr_tamer_ali@yahoo.com tamerali.8@azhar.edu.eg mohamed a. abdelaal, md maal_uro@yahoo.com hassan ismail, md drhassan_ismail@yahoo.com department of urology, faculty of medicine, al-azhar university, cairo, egypt amal h. ibrahim, md mkellany@yahoo.com samar a. kasem, md summerahmed1983@yahoo.com department of internal medicine, nephrology unit, faculty medicine, al-azhar university, cairo, egypt ahmed a. aboomar, md ahmed_abo_omar12@yahoo.com department of internal medicine, nephrology unit, faculty medicine, tanta university, tanta, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11610 1 original paper both genomic dna (gdna) and mitochondrial dna (mtdna) are released from dying cells, and circulating mtdna fragments may trigger pro-inflammatory responses (4-12). elevated levels of circulating cell-free mtdna (cf-mtdna) have been found in patients with various diseases, including urological malignancies, but the association with cancer is still debated (13-16). different diseases have been associated with specific mtdna fragmentation patterns related to cell death type (17-19). there may be a link between mtdna fragments and prostate inflammation, but it remains unclear, and the studies have mainly focused on blood samples. evaluating the fragmentation pattern of cf-mtdna in urine might provide insights into mtdna-mediated inflammation and improve pca biomarkers. therefore, this study aimed to determine if the apoptosisand necrosis-derived mtdna fragments (79 bp and 230 bp, respectively) in postprostate massage urine are related to prostate inflammation and can discriminate between pca and inflammatory conditions, using serum psa levels for comparison. materials and methods case selection this study was conducted with 93 male patients, who applied the istanbul university-cerrahpasa, department of urology. patients aged 40 and older, psa value > 2.5 ng/ml, and suspicious findings on rectal examination were included in the study (table 1). transrectal ultrasound (trus) guided biopsies (12-28 cores) were performed for evaluation. the patients were divided into 3 groups according to the histopathological evaluations of trus biopsies: prostate cancer (pca), prostatitis (inflammation), and benign prostatic hyperplasia (bph) groups. the results of biopsy showing adenocarcinoma and bph were included in the pca group. similarly, the results showing prostatitis and bph were included in the inflammation group, whereas the results containing alone bph were included in the bph group. additionally, according to the inflammation status in the results of trus biopsies, cases without inflammation (including cases of pca and bph groups) were defined as the noninflammation group. patients with other malignant disease, distant metastases, infectious or inflammatory disbackground: we sought to determine whether two soluble forms with different size of mtdna are linked to prostatic inflammation, and whether they discriminate prostate cancer (pca) from inflammatory prostatic conditions. methods: histopathologically diagnosed prostatitis, pca and benign prostatic hyperplasia patients (n = 93) were enrolled in this study and they were categorized as with and without prostate inflammation. quantitative rt-pcr was used to analyze the levels of 79-bp and 230-bp fragments in urine and blood samples collected following prostate massage. results: the urine mtdna-79 and mtdna-230 were significantly increased in patients with prostate inflammation compared with those in without inflammation. here, 79-bp fragment of apoptotic origin was significantly higher level than 230-bp fragment of necrotic origin. although mtdna-79 copy number in serum samples was also increased in patients with prostate inflammation, mtdna-230 was similar in the two groups. furthermore, mtdna-79 and mtdna-230 copy numbers in postprostate massage urine were higher (about 16-fold and 22-fold, respectively) than those from serum samples. roc analysis showed that, although post-prostate massage urine have relatively higher performance than blood, ability to discriminate cases of both fragments was not better than that of serum total psa. conclusions: our results demonstrate that shorter cf-mtdna fragment size in particular, increase in the presence of prostate inflammation in post-prostatic massage urine but both fragments could never improve serum total psa performance. key words: prostate; inflammation; cancer; mitochondrial dna; post-prostatic massage. submitted 26 july 2023; accepted 2 september 2023 introduction a possible link between inflammation and prostate cancer (pca) has been suggested, but not yet confirmed. several cross-sectional studies indicate that prostatic inflammation is more common in patients without cancer (1, 2). the factors contributing to prostate inflammation are largely unknown, and inflammation could play a role in false positive prostate-specific antigen (psa) results in cancer screening (1, 3). inflammatory lesions contain dead cells, including apoptosis and necrosis, and evidence shows a bidirectional relationship between cell death forms and inflammation. are elevated mitochondrial dna fragments in prostatic inflammation a potential biomarker for prostate cancer? ugur aferin 1, nurten bahtiyar 2, ilhan onaran 3, hamdi ozkara 4 1 department of urology, medical faculty, demiroglu bilim university, istanbul, turkey; 2 department of biophysics, cerrahpasa medical faculty, istanbul university-cerrahpasa, istanbul, turkey; 3 department of medical biology, cerrahpasa medical faculty, istanbul university-cerrahpasa, istanbul, turkey; 4 department of urology, cerrahpasa medical faculty, istanbul university-cerrahpasa, istanbul, turkey. doi: 10.4081/aiua.2023.11610 summary archivio italiano di urologia e andrologia 2023; 95(3):11610 u. aferin, n. bahtiyar, i. onaran, h. ozkara 2 eases, histologically defined with both inflammation and cancer findings were excluded from the study. all patients provided written informed consent. this study was approved by the istanbul university-cerrahpasa ethics committee (approval no. 83045809; istanbul, turkey), and was performed according to the criteria set out by the declaration of helsinki. sample collection before trus biopsy, following a digital rectal examination of 3 strokes per prostate lobe, each subject provided 2030 ml urine in a first catch specimen. all urine specimens were centrifuged at 2500 x g for 10 min at 4°c, followed by storage of the urine and pellet at -80°c. five milliliter venous blood samples were collected into anticoagulantfree tubes after prostatic massage and centrifugation was performed at 2500×g for 10 min at 4°c. then obtained supernatants were stored at -80°c until analyses. dna isolation, and determination of mtdna-79 and mtdna-230 copies the plasma/serum cell-free circulating dna purification kit (norgen biotek, canada) and urine cell-free circulating dna purification kit (norgen biotek, canada) were used to isolate circulating dna from serum and urine. cell-free dna was isolated according to the kit manufacturers' protocols. quantitative analysis of mtdna fragments in serum and urine was performed by quantitative real-time pcr (qpcr). in this study, two primer sets specific for the mitochondrial ribosomal 16s rna were used. the first primer pair amplified a 79-bp fragment (mtdna-79), and the second primer pair amplified a 230-bp fragment (mtdna-230) the sequence of the forward primer specific for both mtdna fragments was 5’-cagccgctattaaaggttcg-3’. the sequence of the reverse primer specific for mtdna-79 was 5’-cctggattactccggtctga-3’, of the reverse primer specific for mtdna230 was 5’-gggctctgccatcttaacaa-3’. the qpcr was performed in duplicate on a real time pcr detection system (bio rad laboratories, inc., hercules, ca, usa). each 20 µl reaction consisted of 2 ml dna, 10 µl evagreen 2x qpcr mastermix (abm, canada) and 0.40 µl (10mm) forward/reverse primer. pcr conditions were 95 ºc for 10 min, followed by 40 cycles at 95 ºc for 15 s, 60 ºc for 60 s, and 72 ºc for 30 s. each run included water blanks as a negative control. the specificity of the pcr products was confirmed by melting curve analysis. the quantity of each target gene in the samples was subsequently calculated according to the corresponding standard curve. the formula published by the genomics and sequencing center of the university of rhode island (kingston, ri, usa; cels.uri.edu/gsc/cndna.html) was used to calculate the mtdna copy number (20). statistical analysis continuous variables were presented as means ± sd or medians, and categorical variables were presented as frequencies with percentages. differences between groups were compared with mann whitney-u, and kruskalwallis tests. receiver operating characteristic (roc) analysis, and area under the roc curve (auc) were used for determination of diagnostic performance of mtdna levels. point-biserial correlation was used for correlation between categorical variables and mtdna levels. all statistical analyses were performed using prism 5.0 (graphpad software, san diego, ca). a value of p < 0.05 was considered statistically significant. results assessment of mtdna levels in urine and serum according to inflammation status urine mtdna-79 (median: 1.52 x 109 vs. 0.66 x 109 copies/ml) and mtdna-230 (1.59 x 108 vs. 1.71 x 107 copies/ml) levels were increased in the inflammation group compared to the non-inflammation group (p < 0.001 and p < 0.01, respectively) (figure 1 a-b). serum mtdna-79 (median: 2.45 x 107 vs. 1.05 x 107 copies/ml) levels were higher in the inflammation group compared with the non-inflammation group (p < 0.05), but the differences were not significant in serum mtdna230 levels (median: 0.87 x 106 vs. 0.51 x 106 copies/ml) between these groups (p > 0.05) (figure 1 c-d). assessment of urine and serum mtdna levels in inflammation, pca, and bph groups urine mtdna-79 (median: 1.52 x 109 vs. 0.58 x 109 copies/ml) and mtdna-230 (1.59 x 108 vs. 0.81 x 107 copies/ml) levels were increased in the inflammation group compared to the bph group (p < 0.01, for both) (figure 2 a-b) whereas the differences were not significant in serum mtdna-79 (median: 2.69 x 107 vs. 1.01 x 107 copies/ml) and mtdna-230 levels (median: 0.51 x 106 vs. 0.88 x 106 copies/ml) between these groups (p > 0.05) (figure 2 c-d). there were statistically significant differences in urine table 1. demographic data of all groups. non-inflammation inflammation variable bph pca prostatitis (n: 29) (n: 34) (n: 30) age (years) 65.51 ± 6.85 65.09 ± 9.18 63.32 ± 6.71 psa (ng/ml) 5.72 ± 2.80 18.24 ± 21.04 a*** 11.36 ± 9.81 b *** histology adenocarcinoma, n (%) na 34 (100%) na pathological tumour stage pt1, n (%) na 15 (44.12%) na pt2, n (%) na 19 (55.88%) na gleason grading gleason score < 7, n (%) na 12 (35.29%) na gleason score = 7, n (%) na 15 (44.12%) na gleason score > 7, n (%) na 7 (20.59%) na histology biopsy core with cancer median, n na 4.5 na range, n na 1-12 na histology biopsy core with inflammation median, n na na 6 range, n na na 3-15 values were presented as mean ± standard deviation; bph: benign prostatic hyperplasia; pca: prostate cancer; na: not applicable; a pca vs bph; b inflammation vs. bph; *** p < 0.001. archivio italiano di urologia e andrologia 2023; 95(3):11610 3 dna fragments in prostatic inflammation mtdna-79 (median: 1.52 x 109 vs. 0.67 x 109 copies/ml) (p < 0.05), but not in urine mtdna-230 (median: 1.59 x 108 vs. 2.23 x 107 copies/ml), serum mtdna-79 (median: 2.69 x 107 vs. 1.18 x 107 copies/ml), and mtdna-230 (median: 0.51 x 106 vs. 0.41 x 106 copies/ml) levels between the inflammation and the pca groups (p > 0.05, for all). additionally, there were no significant changes in urine mtdna-79 (median: 0.67 x 109 vs. 0.57 x 109 copies/ml), urine mtdna-230 (median: 2.23 x 107 vs. 0.81 x 107 copies/ml), serum mtdna-79 (median: 1.18 x 107 vs. 1.01 x 107 copies/ml) and serum mtdna-230 (median: 0.41 x 106 vs. 0.88 x 106 copies/ml) levels between the comparison of the pca and bph groups (figure 2 a-d). figure 1. comparison of the a. urine mtdna-79, b. urine mtdna-230, c. serum mtdna-79, and d. serum mtdna230 between the inflammation and noninflammation groups, *p < 0.05, **p < 0.01, ***p < 0.001. the bold line in the box plots represents the median value. figure 2. pairwise comparisons of the a. urine mtdna-79, b. urine mtdna-230, c. serum mtdna-79, and d. serum mtdna230 among the inflammation, pca, and bph groups; *p < 0.05, **p < 0.01, the bold line in the box plots represents the median value. archivio italiano di urologia e andrologia 2023; 95(3):11610 u. aferin, n. bahtiyar, i. onaran, h. ozkara 4 roc curve analysis of serum and urine mtdna, and serum psa according to inflammation status generally, auc values demonstrated moderate discriminatory power, and urine auc results (mtdna-79, and mtdna-230, 0.712, and 0.707, respectively) were higher than serum (mtdna-79, and mtdna-230, 0.653, and 0.585, respectively) in the inflammation group compared to the non-inflammation group. similarly, urine mtdna79 and mtdna-230 auc values were higher than serum psa auc values (0.712, 0.707, and 0.585, respectively). urine mtdna-79 and mtdna-230 levels showed similar diagnostic performance with urine combined mtdna-79 and mtdna-230 results (figure 3). sensitivity and specificity values for all testing were given in tables 2, 3. roc curve analysis of serum and urine mtdna and serum psa in inflammation, pca, and bph groups auc values of roc curve analysis were determined for urine and serum mtdna, and serum psa in the inflammation, pca, and bph groups. mostly the results in inflammation vs. bph, and inflammation vs. pca groups had moderate diagnostic performance (figure 4). urine mtdna-79 and mtdna-230 had better diagnostic performance (auc range 0.7250.691) than serum mtdna-79, and mtdna230 (auc range 0.682-0.572). auc values of serum psa were higher than urine mtdna-79, and mtdna-230. the combination of urine mtdna-79 and mtdna-230 results had moderate auc values similarly as urine mtdna-79 and mtdna-230. roc curve analysis between the pca and the bph groups indicated that except for serum psa (auc:0.793) , all other parameters had mild auc values (range 0.534-0.594). urine mtdna-79 and mtdna-230 values were higher than serum, but all of them were in mild auc levels (tables 2, 3). correlation analyzes of urine and serum mtdna the correlation analysis showed that the presence of prostatic inflammation was positively correlated with urine mtdna-79, urine mtdna-230, and serum mtdna-79 levels. also, urine mtdna-79 levels were positive correlated with urine mtdna-230 results. similarly, serum mtdna-79 levels were positively associated with serum mtdna-230 (table 4). discussion to date, a few studies have quantified cfmtdna levels and mtdna fragmentation pattern in urologic cancer patients. some studies found elevated cf-mtdna content in pca (15, 21, 22), but another study on cf-mtdna couldtable 2. diagnostic performance of serum psa, serum and post-prostatic massage urine specimens mtdna. sensitivity specificity auc (95%cl) p urine mtdna-79 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph urine mtdna-230 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph serum mtdna-79 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph serum mtdna-230 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph serum psa inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph auc: area under an roc curve; bph: benign prostatic hyperplasia; pca: prostate cancer; ns: not significant. %73.3 %73.4 %73.2 %41.2 %70.1 %63.3 %66.7 %58.8 %54.2 %56.1 %48.1 %42.3 %47.8 %52.2 %47.8 %56.1 70.0% 70.1% 56.7% 64.7% 0.001 0.006 0.003 ns 0.001 0.002 0.008 ns 0.04 0.03 ns ns ns ns ns ns ns < 0.001 ns < 0.001 %71.4 %72.4 %70.6 %68.9 %66.7 %72.4 %73.5 %58.6 %60.4 %63.6 %65.4 %63.6 %75.6 %75.0 %68.1 %75.0 60.3% 89.7% 61.8% 89.6% 0.712 (0.588-0.836) 0.709 (0.570-0.847) 0.714 (0.580-0.849) 0.534 (0.388-0.679) 0.707 (0.591-0.823) 0.725 (0.594-0.857) 0.691 (0,557-0.825) 0.595 (0.449-0.741) 0.653 (0.511-0.794) 0.682 (0.528-0.836) 0.651 (0.498-0.803) 0.542 (0.377-0.707) 0.585 (0.427-0.744) 0.602 (0.429-0.776) 0.572 (0.403-0.741) 0.580 (0.408-0.752) 0.609 (0.495-0.725) 0.823 (0.711-0.935) 0.572 (0.429-0.716) 0.793 (0.679-0.907) table 3. diagnostic performances of mtdna combinations in serum and post-prostatic massage urine specimens. sensitivity specificity auc (95%cl) p combination of urine mtdna-79 and mtdna-230 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph combination of serum mtdna-79 and mtdna-230 inflammation vs. non-inflammation inflammation vs. bph inflammation vs. pca pca vs. bph auc: area under an roc curve; bph: benign prostatic hyperplasia; pca: prostate cancer; ns: not significant. 66.67% 80.02% 72.72% 51.51% 47.6% 50.02% 54.17% 50.20% 0.001 < 0.001 < 0.001 ns ns ns ns ns 85.36% 76.67% 73.33% 53.57% 60.97% 63.16% 68.18% 55.56% 0.715 (0.592-0.837) 0.810 (0.694-0.926) 0.756 (0.634-0.877) 0.488 (0.342-0.634) 0.647 (0.494-0.800) 0.651 (0.481-0.821) 0.671 (0.489-0.811) 0.542 (0.364-0.719 table 4. correlation analyzes of urine and serum mtdna according to inflammation status. parameter correlation coefficient sig. (2-tailed) inflammation status vs. urine mtdna-79 r = 0.343 p = 0.001 inflammation status vs. urine mtdna-230 r = 0.335 p = 0.001 inflammation status vs. serum mtdna-79 r = 0.250 p = 0.035 urine mtdna-79 vs. urine mtdna-230 r = 0.601 p < 0.001 serum mtdna-79 vs. serum mtdna-230 r = 0.262 p = 0.035 archivio italiano di urologia e andrologia 2023; 95(3):11610 5 dna fragments in prostatic inflammation n't distinguish between pca and bph (15). in addition to previous publications on blood samples (23), this study found higher levels of mtdna fragments in post-prostate massage urine in cases with prostate inflammation than those without inflammation. different studies revealed a positive link between elevatfigure 3. receiver operating characteristic (roc) curves of the a. urine mtdna-79, b. urine mtdna-230, c. serum mtdna-79, and d. serum mtdna230 between the inflammation and non-inflammation groups. figure 4. pairwise comparisons of the receiver operating characteristic (roc) curves of the a. urine mtdna-79, b. urine mtdna-230, c. serum mtdna-79, and d. serum mtdna230 among the inflammation, pca, and bph groups. archivio italiano di urologia e andrologia 2023; 95(3):11610 u. aferin, n. bahtiyar, i. onaran, h. ozkara 6 ed systemic mtdna levels and inflammation-associated diseases (9, 24, 25) and inflammatory cell death is often necrotic (7). we expected that a possible increase in the long mtdna fragments (> 200 bp) derived from nonapoptotic types of cell death (i.e. necrosis) may be associated with prostate inflammation according to the histopathological examination. surprisingly, we found that 230 bp fragment was significantly lower than 79 bp fragment (an implication of an active apoptotic phenomenon) in prostate inflammation. additionally, our results show no correlation between urine and serum mtdna230 fragment in patients with inflammation, implying different factors contribute to elevated cf-mtdna levels in each compartment. prostate massage can stimulate the release of tissue’s viable cells as well dying/dead cells and increase the distribution concentration of circulating cf-mtdna in urine. the influence of exfoliated inflammatory or endothelial cells on mtdna fragments cannot be excluded, complicating our results. the cause of changes in cf-mtdna fragment levels due to prostate inflammation remains unclear with our experimental design and existing literature. although the origin of cf-mtdna and cf-dna lacks consensus (26), excessive release by apoptotic or necrotic cells and reduced clearance by inflammatory cells may alter mtdna content. the mtdna-79 fragment might be more resistant to dnase activity than long fragments. furthermore, whether the higher levels of cf-mtdna fragments is a cause or a consequence for prostate inflammation in the context of mitochondrial damage, is the chicken or the egg causality dilemma. although cf-mtdna is found in blood, urine, or saliva samples, data for prostate diseases associated with malignancy were mostly based on blood samples. urine samples collected after prostate massage may provide more evidence for prostate-associated conditions due to fewer confounding factors. therefore, we expected urine mtdna fragments to reflect prostate inflammation magnitude better than blood ones. as anticipated, postprostate massage urine from patients with prostate inflammation showed higher mean mtdna-79 and mtdna-230 copy numbers (approximately 16-fold and 22-fold, respectively) compared to serum samples. serum mtdna-79 was significantly increased in patients with inflammation (p < 0.05), while serum mtdna-230 remained similar between inflamed and non-inflamed patients (p > 0.05). post-prostate massage urine mtdna79 and mtdna-230 copy numbers showed slightly higher auc values for discriminating prostate inflammation than serum. the differences in fragment levels between urine and serum could be due to urine's enrichment in prostate-derived cf-mtdna and the rapid clearance of nucleic acids from blood. furthermore, urinary cfmtdna concentrations have lower coefficient of variations (cv) than serum, but further investigation is needed as their cvs still exceed 100%. in this work, we also performed roc curve analysis for urine cf-mtdna fragments to differentiate pca from inflammatory prostatic conditions, and compared it with the diagnostic performance of serum psa levels. considering the auc, sensitivity and specificity, the levels of post-prostate massage urine mtdna-79 and mtdna-230 had slightly higher performance in distinguishing prostate inflammation than their serum levels. here, the discrimination performance of single parameter for prostate inflammation is moderate with an auc of about 0.7. nevertheless, each fragment yielded performance similar to than serum psa levels. furthermore, when we tested the ability of these fragments in urine to discriminate pca from bph, pca from prostate inflammation, and prostate inflammation from bph, the auc values of both fragment were within the range of 0.530.73, which were close to those (0.58-0.82) for the serum psa. moreover, combining of two fragment copy numbers did not significantly improve performance over using a single fragment alone. therefore, mtdna fragments alone does not seem to be a reliable predictor of differentiating pca or bph from inflammatory prostatic conditions. this study had several limitations, including focusing only on histologically measurable inflammation, being a singlecenter trial, and lacking adjustment for prostate volumerelated variables and other potential confounding factors due to small sample sizes. additionally, although this study was conducted on the samples from pca patients without prostatitis, it is essential to keep in mind that presence of prostatitis in pca is not an infrequent event. in conclusion, the present data demonstrate that cfmtdna fragments in post-prostatic massage urine increase in the presence of prostate inflammation; shorter cf-mtdna fragment size in particular, may be a result of mostly an active apoptotic phenomenon associated with prostate inflammation. even though both mtdna fragments in the urine samples show relatively higher performance than blood, they do not seem to help identify patients with pca from non-pca patients more than the conventional psa test. further research is required to elucidate the sources of inter-individual variability observed in mtdna copy numbers. references 1. gui-zhong l, libo m, guanglin h, jianwei w. the correlation of extent and grade of inflammation with serum psa levels in patients with iv prostatitis. int urol nephrol. 2011; 43:295-301. 2. maclennan gt, eisenberg r, fleshman rl, et al. the influence of chronic inflammation in prostatic carcinogenesis: a 5-year followup study. j urol. 2006; 176:1012-1016. 3. bergamini s, bellei e, bonetti lr, et al. inflammation: an important parameter in the search of prostate cancer biomarkers. proteome sci. 2014; 12:1-12. 4. shu y, wu x, tong x, et al. circulating tumor dna mutation profiling by targeted next generation sequencing provides guidance for personalized treatments in multiple cancer types. sci rep. 2017; 7:1-11. 5. man sm, kanneganti t-d. converging roles of caspases in inflammasome activation, cell death and innate immunity. nat rev immunol. 2016; 16:7. 6. mccully jd, cowan db, pacak ca, et al. injection of isolated mitochondria during early reperfusion for cardioprotection. am j physiol heart circ physiol. 2009; 296:h94-h105. 7. zhang q, raoof m, chen y, et al. circulating mitochondrial damps cause inflammatory responses to injury. nature. 2010; 464:104-107. archivio italiano di urologia e andrologia 2023; 95(3):11610 7 dna fragments in prostatic inflammation 8. klinman dm, barnhart km, conover j. cpg motifs as immune adjuvants. vaccine. 1999; 17:19-25. 9. caielli s, athale s, domic b, et al. oxidized mitochondrial nucleoids released by neutrophils drive type i interferon production in human lupus. j exp med. 2016; 213:697-713. 10. collins lv, hajizadeh s, holme e, et al. endogenously oxidized mitochondrial dna induces in vivo and in vitro inflammatory responses. j leukoc biol. 2004; 75:995-1000. 11. barbalat r, ewald se, mouchess ml, barton gm. nucleic acid recognition by the innate immune system. annu rev immunol. 2011; 29:185-214. 12. zhang q, itagaki k, hauser cj. mitochondrial dna is released by shock and activates neutrophils via p38 map kinase. shock. 2010; 34:55-59. 13. yu m. circulating cell-free mitochondrial dna as a novel cancer biomarker: opportunities and challenges. mitochondrial dna. 2012; 23:329-332. 14. ellinger j, wittkamp v, albers p, et al. cell-free circulating dna: diagnostic value in patients with testicular germ cell cancer. j urol. 2009; 181:363-371. 15. ellinger j, müller dc, müller sc, et al. circulating mitochondrial dna in serum: a universal diagnostic biomarker for patients with urological malignancies. urol oncol. 2012; 30:509-515. 16. herranz r, oto j, plana e, et al. circulating cell-free dna in liquid biopsies as potential biomarker for bladder cancer: a systematic review. cancers. 2021; 13:1448. 17. budnik lt, kloth s, baur x, et al. circulating mitochondrial dna as biomarker linking environmental chemical exposure to early preclinical lesions elevation of mtdna in human serum after exposure to carcinogenic halo-alkane-based pesticides. plos one. 2013; 8:e64413. 18. pisetsky ds. the origin and properties of extracellular dna: from pamp to damp. clin immunol. 2012; 144:32-40. 19. jahr s, hentze h, englisch s, et al. dna fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. cancer res. 2001; 61:1659-1665. 20. nakahira k, kyung s-y, rogers aj, et al. circulating mitochondrial dna in patients in the icu as a marker of mortality: derivation and validation. plos med. 2013; 10:e1001577. 21. mehra n, penning m, maas j, et al. circulating mitochondrial nucleic acids have prognostic value for survival in patients with advanced prostate cancer. clin cancer res. 2007; 13:421-426. 22. zhou w, zhu m, gui m, et al. peripheral blood mitochondrial dna copy number is associated with prostate cancer risk and tumor burden. plos one. 2014; 9:e109470. 23. ellinger j, müller sc, wernert n, et al. mitochondrial dna in serum of patients with prostate cancer: a predictor of biochemical recurrence after prostatectomy. bju int. 2008; 102:628-632. 24. deus cm, tavares h, beatriz m, et al. mitochondrial damageassociated molecular patterns content in extracellular vesicles promotes early inflammation in neurodegenerative disorders. cells. 2022; 11:2364. 25. liu r, xu f, bi s, et al. mitochondrial dna-induced inflammatory responses and lung injury in thermal injury murine model: protective effect of cyclosporine-a. j burn care res. 2019; 40:355-360. 26. aucamp j, bronkhorst aj, badenhorst cp, pretorius pj. the diverse origins of circulating cell-free dna in the human body: a critical re-evaluation of the literature. biol. rev. 2018;93:1649-1683. correspondence ugur aferin, md ugur.aferin@demiroglu.bilim.edu.tr department of urology, medical faculty, demiroglu bilim university, istanbul, turkey nurten bahtiyar, phd (corresponding author) nurten.bahtiyar@iuc.edu.tr department of biophysics, cerrahpasa medical faculty, istanbul university-cerrahpasa, istanbul, turkey ilhan onaran, phd ilonaran@iuc.edu.tr department of medical biology, cerrahpasa medical faculty, istanbul university-cerrahpasa, istanbul, turkey hamdi ozkara, md hozkara@iuc.edu.tr department of urology, cerrahpasa medical faculty, istanbul universitycerrahpasa, istanbul, turkey conflict of interest: the authors declare no potential conflict of interest. the present study was supported by the research fund of the istanbul university-cerrahpasa (grant no. 30381). stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12506 1 original paper while oral phosphodiesterase type 5 inhibitors (pde5is) have long been recommended as the initial treatment option, some patients did not respond well to this therapy. as a result, non-surgical treatment alternatives like vasodilating agents, intraurethral alprostadil, vacuum erection devices (veds) and intracavernosal injections (icis) are available (4). nevertheless, those therapeutic approaches are not able to change the underlying pathophysiology of the erectile mechanism and have several serious drawbacks (5). nowadays, it is established that specific pelvic floor muscles play a part in the ejaculatory and erectile mechanisms (6). as previously shown in the literature, pelvic floor electromagnetic/magnetic therapy can be a non-invasive option for men with the syndrome of chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) (7). relevant advances in magnetic stimulation technology have been made recently, including flat magnetic stimulation (fms) (8). even before fms, the goal of pelvic floor muscle training (pfmt) was to restore the pelvic floor muscles by enhancing proprioception, relaxation, and muscle tone. exercises targeting the pelvic floor muscles have been shown to enhance erection, particularly in post-prostatectomy ed patients (9). mondaini et al. have recently demonstrated that fms improved cp/cpps symptoms (pelvic/genital pain, ejaculatory pain, and urinary symptoms) (10). in light of these evidence, our goal was to investigate if fms could help individuals with symptomatic erectile dysfunction. materials and methods a prospective single-group study was carried out from february to november 2023, in a private medical centre, in argentina, using dr arnold (deka m.e.l.a., calenzano, italy) device that includes a chair applicator and a main unit. an electromagnetic field with a homogenous profile produces the stimulation. greater muscle fibre recruitment is made possible by the uniformity of the magnetic field distribution, which prevents any region of unequal stimulation intensity. twenty patients with erectile dysfunction in total, were enrolled in this study. their mean (± sd) age was 56.89 (± 6.63) years, ranging from 46 to 66 years. patients with severe neurological diseases, malignant tumours, obesity, pacemakers, or metal implants were included among the background: the erectile dysfunction (ed), which is the inability to achieve and/or sustain a penile erection sufficient to result in a satisfying sexual performance, represents a very common complaint. for men over forty years old. the aim of the study was to evaluate if flat magnetic stimulation (fms) technology could help individuals with symptomatic erectile dysfunction. methods: twenty patients with erectile dysfunction, underwent eight sessions of about 30 minutes each in a twice a week frequency with the study device. during treatments, every potential side effect was assessed. the international index of erectile function (iief) was compiled by all patients at the beginning, after the eighth treatment and at 1 month from the end of the last treatment. the questionnaire scores were presented as median values along with the interquartile range (iqr) and we set the significance threshold at 0.01. results: after the treatment and at 1-month follow-up, the increase in questionnaire scores was statistically significant compared to the baseline, thus supporting the clinical usefulness of this treatment. in particular, the result of the study indicates a statistically significant difference between iief score before treatment (median = 34) and iief score after the end of treatment (median = 45) and between iief score before treatment and iief score at 1-month follow-up (median = 54). conclusions: the study findings showed that fms represents a promising treatment option to individuals affected by symptomatic erectile dysfunction. key words: symptomatic erectile dysfunction; flat magnetic stimulation; emerging therapy. submitted 26 march 2024; accepted 18 april 2024 introduction the inability to achieve and/or sustain a penile erection sufficient to result in a satisfying sexual performance is known as erectile dysfunction (ed) (1). ed can have a substantial negative effect on physical and mental health of patients as well as the quality of life for their partners (2). men who have ed are frequently feeling guilty about their condition and avoid seeking professional help (3). ed can be effectively treated with available therapies. however, it cannot be cured, except for psychogenic ed, post-traumatic arteriogenic ed in younger patients, and hormonal causes (1). novel emerging therapy for erectile dysfunction: efficacy and safety of flat magnetic stimulation daniel galimberti 1, agustina vila echague 2, ery a. ko 3, laura pieri 4, alessandra comito 4, irene fusco 4, tiziano zingoni 4 1 coordinador de láser de derma internacional centre, buenos aires, argentina; 2 médica dermatologa, directora de grupo de láser sad (sociedad argentina de dermatología), buenos aires, argentina; 3 dermatóloga, fellow de láser y estética derma internacional, buenos aires, argentina; 4 el.en. group, calenzano, italy. doi: 10.4081/aiua.2024.12506 summary archivio italiano di urologia e andrologia 2024; 96(2):12506 d. galimberti, a. vila echague, e.a. ko, et al. 2 exclusion criteria. before beginning the treatment, pde5i users had to endure a three-week wash-out period. for the duration of the treatment session, all patients agreed to abstain from using pde5i or any other ed therapies. patients underwent eight sessions of about 30 minutes each in a twice a week frequency. the following fms schedule was used: sessions 1 to 4 followed the hypotonus/ weakness 1 protocol whereas sessions 5 to 8 followed the hypotonus/weakness 2 protocol. the hypotonus/ weakness 1 protocol consists of about 30 minutes warm-up and muscle activation phase, followed by a muscle work phase focused on restoring tropism and muscle tone (2030hz) in a trapezoidal shape. for a total of about 30 minutes, the hypotonus/weakness 2 protocol consists of a warm-up and muscle activation phase, a muscle work phase targeted at increasing tropism (volume), and a muscle strength phase (40-50hz) in a trapezoidal shape. during treatments, every potential side effect was assessed, including skin redness, local erythema, tendon pain, muscle pain, and transient muscle spasms. the international index of erectile function (iief) is a psychometrically and cross-culturally valid tool to identify treatment-related alterations in erectile dysfunction patients which showed high sensitivity and specificity. it comprises 15 items and 5 domains and is an accurate and valid psychometric tool for assessing efficacy of ed treatment. the iief has a possible score range from 5 to 25, and ed is classified into five categories based on the scores: severe (57), moderate (8-11), mild to moderate (12-16), mild (17-21), and no ed (22-25). in the iief there are six items in the erectile function domain (ef-score), two items in the orgasmic function domain (of-score), two items in the sexual desire domain (sd-score), three items in the intercourse satisfaction domain (is-score), and two items in the overall sexual satisfaction domain (os-score) (11). an higher post-test iief score compared with the pre-test score was considered an improvement in ed. the iief was compiled by all patients at the beginning, after the eighth treatment and at 1 month from the end of the last treatment (1mfu). the questionnaire scores were presented as median values along with the interquartile range (iqr). significance threshold was set at 0.01. student’s t-test, spss (ibm corp., new york, ny, usa) and r 4.1 (the r core team, vienna, austria, 2021) were used to perform statistical analysis. the article is in accordance with the declaration of helsinki on ethical principles for medical research involvfigure 1. box plot for score at baseline, at the end of the treatment sessions (after the eighth treatment, and 1-month follow-up for international index of erectile function (iief). table 1. median values and interquartile range at baseline, at the end of the treatment sessions (after the eighth treatment), and at 1-month follow-up, related to international index of erectile function (iief), erectile function (ef) score, orgasmic function (of) score, sexual desire (sd) score, intercourse satisfaction (is) score and overall satisfaction (os) score. baseline end of treatment 1mfu p-value p-value median (iqr) median (iqr) median (iqr) (baseline vs (baseline vs 1mfu) end of treatment) iief score 34 (32-38) 45 (43-46) 54 (51-57) < 0.001 < 0.001 ef score 13 (10.75-16) 18 (16.75-19) 21.5 (20.75-23.25) < 0.01 < 0.001 of score 5 (4-5) 6 (6-7) 7 (7-8) < 0.01 < 0.001 sd score 5 (5-6) 7 (6-7) 7 (7-8) < 0.001 < 0.001 is score 6 (5-7) 8 (7-9) 9 (9-11) < 0.01 < 0.001 os score 4 (4-6) 6 (6-7) 8 (8-8) < 0.01 < 0.001 archivio italiano di urologia e andrologia 2024; 96(2):12506 3 emerging therapy for erectile dysfunction: efficacy and safety of flat magnetic stimulation ing human subjects. ethical approval is not necessary as the study device is already ce marked since 2020. written informed consent has been obtained from the patients to publish this paper. results outcome measures of questionnaire score at the baseline, end of treatment, and 1-month follow-up are summarized in table 1, figure 1 and figure 2. after the treatment and at 1-month follow-up, the increase in scores was statistically significant compared to the baseline, thus supporting the clinical usefulness of this treatment. in particular, the test result indicates a statistically significant difference between iief score before treatment (median = 34) and iief score after the end of treatment (median = 45) and between iief score before treatment and iief score at 1-month follow-up (median = 54). the improvement was confirmed in all iief domains (see table 1). although the erectile function domain showed the largest change, significant modifications were noted in all the domains in the patients after treatment. the ed severity is shown in figure 3 and table 2. among the 20 participants of this study during the pre-test, we found that 20% of patients had severe ed (score range 610), 70% moderate ed (score range 11-16), 5% mildmoderate ed (score range 17-21), and 5% mild ed (score range 22-25). none of them was found without dysfunction (score range 26-30). after the treatment, 5% of participants were found to have severe ed, 20% had moderate ed, 65% had mild-moderate ed, 5% mild ed (score range 22-25), and lastly, 5% were found without dysfunction (score range 26-30). during the post-test (after one month of the last treatment session), no participant was found to have severe ed. few (10%) had moderate ed, the majority (45% and 40%) had mild-moderate ed and mild ed respectively, while 5% were found without dysfunction (see table 2). table 2. % of patients divided into 5 categories of ed classification. ed classification before end of treatment 1mfu severe (range score: 6-10) 4/20 (20%) 1/20 (5%) 0/20 (0%) moderate (range score: 11-16) 14/20 (70%) 4/20 (20%) 2/20 (10%) mild to moderate (range score: 17-21) 1/20 (5%) 13/20 (65%) 9/20 (45%) mild (range score: 22-25) 1/5 (5%) 1/20 (5%) 8/20 (40%) no ed (range score: 26-30) 0/20 (0%) 1/20 (5%) 1/20 (5%) figure 2. box plots at baseline, at the end of the treatment sessions (after the eighth treatment), and 1-month follow-up related to erectile function (ef) score, orgasmic function (of) score, sexual desire (sd) score, and intercourse satisfaction (is) score. archivio italiano di urologia e andrologia 2024; 96(2):12506 d. galimberti, a. vila echague, e.a. ko, et al. 4 discussion the current pharmacological treatment of ed and nonsurgical treatment alternatives (such as vasodilating agents, intraurethral alprostadil, vacuum erection devices and intracavernosal injections) do not appear to improve endothelial dysfunction, restoring physiological erectile function, or significantly changing the underlying pathophysiology of the erectile function (ef) (12). these therapeutic approaches have a lot of drawbacks (side effects, low response rates) and a steady discontinuation rate of them was displayed (13). on the other hand, a penile prosthesis implant is an irreversible form of treatment and, even after the implantation, a man will never again be able to achieve a spontaneous erection. the low-intensity extracorporeal shock wave therapy (lieswt) has been proposed as a promising treatment for vasculogenic ed in recent years. since vardi et al. (14) initially reported the use of lieswt in the treatment of ed in 2010, several studies have assessed the effectiveness of li-eswt in various form of ed, whether they are organic (vasculogenic or neurogenic) or mixed (15). the patients included in the studies exhibit significant differences regarding cardiovascular risk factors, response to pde5i, duration, and severity of ed. additionally, there is a great deal of variation in the shockwave generators, the kind of shockwaves released, the parameters set, and the treatment plans employed (1). it is challenging to determine whether lieswt is a practical option for the management of ed overall given the heterogeneous data. several sexual medicine societies have cautiously accepted li-eswt as a treatment for men with ed in the past year. it is safe and reasonably effective, but it should only be used in the context of clinical research (12, 16). overall, there was an improvement in the iief-ef score according to the pooled data from meta-analyses, but the estimates are low (ranging from roughly 2-4 iief-ef points) and the heterogeneity is high (16). most of the research that has been published only included follow-up data for two years (12) and this raises the question of whether the early improvements in ef can be maintained over the long run. the results of the long-term study by chung and cartmill, indicate that, 48-60 months after the end of li-eswt, the clinical improvement in ef that was previously seen is still declining and appears to plateau at 40% clinical efficacy (17). the idea of "regenerative" therapies for the treatment of ed has drawn a lot of attention in recent years. this concept makes sense because ed causes the erectile tissue to undergo anatomical and functional changes that are typified by progressive cavernosal fibrosis (18). stem cell injections, platelet-rich plasma, and low-intensity shockwave therapy (li-swt) are examples of regenerative treatments. angiogenesis and neurogenesis may be induced by these methods, "restoring" malfunctioning erectile tissue, according to accumulating animal data (19). regenerative therapies are a viable treatment option for erectile dysfunction, but there is currently little human data to support this claim (20). we can also include magnetic stimulation in the list of regenerative therapies. in patients with urinary incontinence and pelvic floor disorders, magnetic stimulation has already been used to treat the human pelvic floor with great success. there have been no negative side effects or disfigure 3. the percentage of patients is divided into 5 categories of ed classification. no ed (ef score 26-30), mild (ef score 22-25), mild to moderate (ef score 17-21), moderate (ef score 11-16) at baseline, at the end of the treatments and 1 month after the last session. archivio italiano di urologia e andrologia 2024; 96(2):12506 5 emerging therapy for erectile dysfunction: efficacy and safety of flat magnetic stimulation comfort and the pelvic floor muscle (pfm) tone and strength have significantly improved. the demonstration was conducted both quantitatively, using ultrasound exams, and qualitatively, using validated questionnaires (21). magnetic stimulation is a type of passive rehabilitation where there is no need for the patient to get undressed during treatment. patients sit in an ergonomic chair that has a height-adjustable backrest, allowing them to experience total comfort and relaxation at every session. this innovative device targets neuromuscular tissue by creating an electric current that causes pfm to contract passively and strongly. electric currents associated with magnetic stimulation led to neuron depolarization, which triggers concentric contractions and lifts all pfms. this results in profound stimulation and the regeneration of neuromuscular control. indeed, the entire procedure causes the muscle structure to change because the fibres tend to become hypertrophic and hyperplasic (8, 22). in addition to having a specific protocol for muscle hypertonicity, the device used in our study was appropriate for treating pelvic floor muscle dysfunction and ed. indeed, by using lower frequencies (about 10 hz) in the overtone protocol for hypertonic management, the electromagnetic field is distributed uniformly and does not produce areas of varying stimulation intensity. frigerio and colleagues showed that fms significantly increased the size of the urethral rhabdosphincter, leading to a 15.4% increase in muscle volume, increasing the quality of life scores related to urination (8). it has also been demonstrated that strengthening the pelvic floor muscles greatly enhances post-prostatectomy urine continence, post-micturition dribble and erectile function (22). fms technology has also a comparable impact on different skeletal muscles. in a study by leone et al., the effectiveness of similar device, which uses fms technology, was assessed on the abdomens of 15 patients (23). this study showed that one month following the last treatment, all treated areas had experienced hypertrophy in terms of the thickness of abdominal muscle tissue. smooth muscle tissue makes up about 45% of the cavernous volume, with collagen making up most of the non-muscle component. the most crucial component of the hemodynamic processes that underlie an erection is the smooth muscle of the penis, consequently, magnetic stimulation, may be crucial in the treatment of ed, restoring fibromuscular pathological changes within the corpus cavernosum. in 2003, van kampen et al. carried out a literature review whose results suggested that perineal rehabilitation could be an effective treatment for erectile dysfunction (24). in human studies, karacan et al. have shown that peaks in blood flow recordings coincided with bursts in the perineal muscles' emg activity during nocturnal penile tumescence (25). our findings support the notion that pelvic floor rehabilitation plays a part in erectile dysfunction and are consistent with those of rival and clapeau (6). indeed the improvement in iief-scores after the treatment and at the one-month follow-up was statistically significant when compared to the baseline, indicating the treatment's clinical utility. the mechanisms supporting the potential role of strengthening the pelvic floor in erection would be an increase in endocavernous pressure and the limitation of venous return from the penis. awareness of the region would also allow the patient to regain control of this part of their body. some authors have proposed including perineal rehabilitation as a first-line treatment for erectile dysfunction (26). this approach has no side effects, is cost-controlled and it can be combined with recommended approaches in the management of erectile dysfunction. however, we do agree that more investigation is needed to look at different pathophysiological changes associated with fms on penile tissue, including long-term histological changes. in addition to muscular involvement, many studies have indicated that endothelial dysfunction or vascular damage is a key mechanism of ed (27). in animal models, it has been shown that by shifting astrocytic phenotypes (a1-a2), magnetic stimulation can reduce the production of the pro-inflammatory cytokine tnf-alpha and promote the production of the anti-inflammatory cytokine il-10. in a2 astrocytes, magnetic stimulation also promoted the release of angiogenesis-related factors tgfb and vegf, which can support angiogenesis. in a prior study, angiogenesis-related genes (vegfa and bai1) were found to be upregulated in rats following magnetic stimulation (28). lee and colleagues, following a stroke in an animal model, argued that magnetic stimulation, on the affected hemisphere, caused modifications in the angiogenic pathways; indeed, magnetic stimulation significantly raised endothelial nitric oxide synthase (enos) phosphorylation, which enhances angiogenesis (29). since nitric oxide (no) is essential for a physiological penile erection (as well as the mechanism through which pde5is act), we could speculate that fms, besides the positive muscular effects, might have some no-dependent benefits in angiogenesis, making it advantageous for patients with vasculogenic ed and low pde5i response. furthermore, sperm motility is increased when human spermatozoa are exposed to a very low-frequency electromagnetic field (30). while it's true that a person with erectile dysfunction might not have any difficulties to procreating, there are general characteristics and shared risk factors that lead to the development of infertility and erection dysfunction, so we can also conjecture about the potential positive impact of fms on spermatozoa motility. filippini's study [which showed a significant improvement in pfm tone and strength in patients with urinary incontinence and pelvic floor disorders, both qualitatively and quantitatively with ultrasound exams (21)] and mondaini's study [which showed improved erectile functioning, with the total mean iief-5 score significantly increasing from 21.3 ± 2.7 at baseline to 24.3 ± 0.5 at 1 moth follow up after the last treatment session, p < 0.001 (10)] contributed to the concept of using fms for ed treatment. our preliminary clinical findings were validated using prospectively questionnaires and, the outcome measures were the significant improvement of iief, without any significant adverse events. archivio italiano di urologia e andrologia 2024; 96(2):12506 d. galimberti, a. vila echague, e.a. ko, et al. 6 our device offers a number of significant benefits, including the ability to stimulate muscles without the need for a probe and the ability for patients to remain fully clothed while seated in an ergonomic and comfortable position due to the gradually correct emission of supplied energy. finally, dr.arnold can be defined as an "educator" system because it helps the patient perceive the muscles involved in the treatment; additionally, other pharmaceutical or physical techniques can be used in conjunction with this new technology. we recognized that our study had several limitations, including a small sample size, the absence of a sham treatment arm, and the lack of objective measurements of penile hemodynamics like penile colour duplex ultrasonography. however, prior research (12) has shown a strong correlation between the subjective report of ef recovery and objective penile hemodynamic improvements. in conclusion, perineal physiotherapy seems to have its place in the management of erectile dysfunction. furthermore, magnetic stimulation of the muscle within the corpus cavernosum certainly induces muscle hypertrophy and the physiology of erection underlies the need for effective contraction of the ischiocavernosus; the treatments turned out with no side effects and with a high degree of patient acceptance. undoubtedly, our experience has shown that fms is a safe and effective option for improving ed with certainly muscular effects and with a potential interference in angiogenesis and spermatozoa motility. for most men with ed, the ideal result is a lasting solution, which is something that fms can potentially accomplish. the long-term safety and efficacy of this therapy, which is still in the experimental stage, require further research in this area. therefore, from a theoretical standpoint, this method can restore erectile function when compared to other previously used treatment methods. conclusions the study findings showed that fms represents a successful treatment option to individuals affected by symptomatic erectile dysfunction. references 1. european association of urology. eau guidelines. edn. presented at the eau annual congress amsterdam. arnhem: eau guidelines office; 2022; 46-71. 2. hatzimouratidis k, amar e, eardley i, et al. european association of urology. guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. eur urol. 2010; 57:804-14. 3. ariba aj, oladapo ot, iyaniwura ca, dada oa. management of erectile dysfunction: perceptions and practices of nigerian primary care clinicians. south african family practice. 2014; 49:16-16d. 4. burnett al, nehra a, breau rh, et al. erectile dysfunction: aua guideline. j urol 2018; 200:633-41. 5. yee ch, chan es, hou ss, ng cf. extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, randomized, double-blinded, placebo controlled study. int j urol. 2014; 21:1041-5. 6. rival t, clapeau l. efficacité de la rééducation du plancher pelvien dans la dysfonction érectile: revue de la littérature. prog urol. 2017; 27:1069-1075. 7. rowe e, smith c, laverick l, et al. a prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year of followup. clin trial j urol. 2005; 173:2044-7. 8. frigerio m, barba m, cola a, et al. flat magnetic stimulation for stress urinary incontinence: a prospective comparison study. bioengineering (basel). 2023; 10:295. 9. wong c, louie dr, beach c. a systematic review of pelvic floor muscle training for erectile dysfunction after prostatectomy and recommendations to guide further research. j sex med 2020; 17:737748. 10. mondaini n, gacci m, cai t, et al. efficacy of top flat magnetic stimulation for chronic pelvic pain in men: preliminary results. int j impot res. 2024. 11. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999; 11:319-26. 12. chung e, lee j, liu cc, et al. clinical practice guideline recommendation on the use of low intensity extracorporeal shock wave therapy and low intensity pulsed ultrasound shock wave therapy to treat erectile dysfunction: the asia-pacific society for sexual medicine position statement. world j mens health. 2021; 39:1-8. 13. yee ch, chan es, hou ss, ng cf. extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, randomized, double-blinded, placebo controlled study. int j urol. 2014; 21:1041-5. 14. vardi y, appel b, jacob g, et al. can low intensity extracorporeal shockwave therapy improve erectile function? a 6-month follow-up pilot study in patients with organic erectile dysfunction. eur urol. 2010; 58:243-8. 15. ergün m, akyüz o. is li-eswt effective in diabetic patients with severe erectile dysfunction? asian j androl. 2022; 24:521-4. 16. capogrosso p, frey a, jensen cfs, et al. low-intensity shock wave therapy in sexual medicine − clinical recommendations from the european society of sexual medicine (essm). j sex med. 2019; 16:1490-1505. 17. chung e, cartmill r. evaluation of long-term clinical outcomes and patient satisfaction rate following low intensityshock wave therapy in men with erectile dysfunction: a minimum 5-year follow-up on a prospective open-label single-arm clinical study. sex med. 2021; 9:100384. 18. iacono f, giannella r, somma p, et al. histological alterations in cavernous tissue after radical prostatectomy. j urol. 2005; 173:1673-6. 19. liu mc, chang ml, wang yc, et al. revisiting the regenerative therapeutic advances towards erectile dysfunction. cells. 2020; 9:1250. 20. alhefnawy ma, salah e, bakry s, et al. autologous mesenchymal stem cell therapy for diabetic men with erectile dysfunction. is it promising? a pilot study. arch ital urol androl. 2023; 95:11669. 21. filippini m, biordi n, curcio a, et al. a qualitative and quantitative study to evaluate the effectiveness and safety of magnetic stimulation in women with urinary incontinence symptoms and pelvic floor disorders. medicina (kaunas). 2023; 59:879. archivio italiano di urologia e andrologia 2024; 96(2):12506 7 emerging therapy for erectile dysfunction: efficacy and safety of flat magnetic stimulation 22. dorey g. restoring pelvic floor function in men: review of rcts. br j nurs. 2005; 14:1014-8, 1020-1. 23. leone a, piccolo d, conforti c, et al. evaluation of safety and efficacy of a new device for muscle toning and body shaping. j cosmet dermatol. 2021; 20:3863-3870. 24. van kampen m, de weerdt w, claes h, feys h. treatment of erectile dysfunction by perineal exercise, electromyo-graphic biofeedback and electrical stimulation. phys ther. 2003; 83:536. 25. karacan i, aslan c, hirshkowitz m. erectile mechanisms in man. science, 1983; 220:1080-2. 26. silva ab, sousa n, azevedo lf, martins c. physical activity andexercise for erectile dysfunction: systematic review and metaanalysis. br j sports med. 2017; 51:1419-1424. 27. gandaglia g, briganti a, jackson g, et al. a systematic review of the association between erectile dysfunction and cardiovascular disease. eur urol 2014; 65:968-978. 28. ljubisavljevic mr, javid a, oommen j, et al. the effects of different repetitive transcranial magnetic stimulation (rtms) protocols on cortical gene expression in a rat model of cerebral ischemic-reperfusion injury. plos one 2015; 10:e0139892. 29. lee y, oh bm, park sh, han tr. low-frequency repetitive transcranial magnetic stimulation in the early subacute phase of stroke enhances angiogenic mechanisms in rats. ann rehabil med. 2022; 46:228-236. 30. iorio r, delle monache s, bennato f, et al. involvement of mitochondrial activity in mediating elf-emf stimulatory effect on human sperm motility. bioelectromagnetics. 2011; 32:15-27. correspondence daniel galimberti daniel.galimberti@gmail.com coordinador de láser de derma internacional centre, buenos aires, argentina agustina vila echague agus1511@yahoo.com médica dermatóloga, directora de grupo de láser sad (sociedad argentina de dermatología) ery a. ko erykohiba@gmail.com dermatóloga, fellow de láser y estética derma internacional, buenos aires, argentina laura pieri l.pieri@deka.it alessandra comito a.comito@elen.it irene fusco (corresponding author) i.fusco@deka.it tiziano zingoni t.zingoni@elen.it el.en. group, 50041 calenzano, italy conflict of interest: authors tz, ac, lp and if were employed by el.en. group. the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 35 original paper introduction prostate cancer (pca) is the second most commonly diagnosed cancer in men, with approximately 1.1 million diagnoses worldwide each year, accounting for 15% of all cancers diagnosed (1). the incidence of pca increases with age, with over 25% of men over the age of 75 years being affected (1). low-risk pca (psa < 10 ng/ml, isup 1, t2a) can be managed through several different modalities, including the non-operative approach of “active surveillance”, which involves laboratory and clinical monitoring of tumor progression and active treatment if necessary (2). other active treatments, such as radiotherapy or surgery, are also options. intermediate/high-risk organconfined prostate cancers require active treatment, which may include surgery and/or radiotherapy (external beam or brachytherapy). approximately 40% of people with prostate cancer undergo radiotherapy as part of their treatment, which can serve various purposes such as curative intent, post-operative adjuvant, post-operative rescue intent, or palliative intent (3). conventional radiotherapy is delivered as external beam radiotherapy (ebrt), and conformal radiotherapy, including 3d conformal radiotherapy (3dcrt) and intensity-modulated radiotherapy (imrt), is commonly used in high-income countries. during treatment, despite recent advances in techniques and technologies that allow precise delivery of radiation on the focus organ, pelvic radiotherapy inevitably exposes the surrounding normal gastrointestinal tract to some degree of radiation, potentially causing rectal bleeding, ulcers or fistulas and increasing the risk of rectal cancer by 105% over the following decade (4). different strategies have been recently adopted and implemented to minimize these complications; one technique aims to fixate the prostate gland during radiation treatment via a rectal balloon to reduce the prostate motion and to make sure the dose delivered to the target volume is efficient., allowing a safer and smaller planning target volume margin as stated elsewhere (5, 6). by using a rectal balloon, the dose exposure to the posterior rectal wall is decreased as opposed to an increased dose to the anterior rectal wall. biodegradable balloon spacers are three-dimensional scaffolds that can be implanted between the prostate gland introduction: radiotherapy is a common treatment for prostate cancer, and can be administered in various ways, including 3d conformal radiotherapy (3dcrt), intensity-modulated radiotherapy (imrt) and hypo-fractionated radiation therapy. during treatment the gastrointestinal tract may be exposed to radiation and the rectal wall may be exposed to high doses of ionizing radiation, which can lead to rectal bleeding, ulcers or fistulas, and an increased risk of rectum cancer. various strategies to minimize these complications have been developed in the last decade; one of the most promising is to use a rectal balloon to fixate the prostate gland during treatment or to inject biodegradable spacers between the prostate and rectum to reduce the rectal dose of radiation. aim of our paper is to evaluate the safety and tolerability of spacers implantation. materials and methods: from january 2021 to june 2022 all patients with a diagnosis of prostate cancer with unfavorable/intermediate risk poor prognosis and programmed hypofractionated radiation therapy were enrolled. in all patients biodegradable balloons spacers were placed posteriorly to the prostate to increase the separation between prostate and rectum. the duration of the procedure, observation time, the appearance of early and late complications and their severity (according to charlson comorbidity index) and tolerability of the device were recorded at the time of positioning and after 10 days. results: 25 patients were enrolled in our study. two patients (8%) underwent acute urine retention resolved with catheterization and one patient (4%) developed a mild perineal hematoma that did not require any treatment. as regards late complications 1 patient (4%) developed hyperpyrexia (> 38°c) the day after the procedure requiring continuation of antibiotic regimen. at t1 visit we recorded no medium-high grade complications. as for the tolerability of the device, it was optimal with no perineal discomfort or alterations of bowel function. conclusions: biodegradable balloon spacers appears to be safe and well tolerated and its positioning does not present any technical difficulties or risks of major complications. key words: prostate cancer; spacer; radiotherapy; hypo-fractionated radiotherapy. submitted 14 january 2023; accepted 22 april 2023 safety and tolerability of biodegradable balloon spacers in patients undergoing radiotherapy for organ-confined prostate cancer luca topazio 1, federico narcisi 1, fabio tana 2, cosimo ciotta 2, vincenzo iossa 2, pasquale perna 2, francesco chiaramonti 2, federico romantini 1 1 asl teramo, u.o.c. di urologia, teramo, italy; 2 university of l'aquila, department of life, health and environmental sciences, l'aquila; u.o.c. di urologia, p.o. mazzini, teramo, italy. doi: 10.4081/aiua.2023.11156 summary archivio italiano di urologia e andrologia 2023; 95, 2 l. topazio, f. narcisi, f. tana, et al. 36 and rectum to protect the rectum from radiation during radiotherapy. they are commercially available in europe. a further clinically available technique reduces the rectal dose of radiations using the injection of materials such as hydrogel, hyaluronic acid gels, and collagen between the prostate and rectum, remarkably lessening late-rectum toxicity. spacers implantation is indeed a minimally invasive surgical procedure guided by transrectal ultra-sound that permit the positioning of biodegradable balloons that can be placed posteriorly to the prostate to increase the separation between prostate and rectum thus protecting the latter from radiations during rt sessions. it demands attendance of a trained physician, qualified to perform this kind of surgery. the procedure takes from 10 to 30 min and can be carried out under local or general anesthesia. as reported in the eau 2022 guidelines, “…a meta-analysis including one rct and six cohort studies using the hydrogel spacer demonstrated a 5-8% reduction in the rectal volume receiving high-dose radiation…” (7). spacers can be implanted in outpatient setting, using local, epidural, or general anesthesia. a recent study, evaluated the correlation between the use of prostate spacers and the incidence of erectile dysfunction in men with organ-confined prostate cance submitted to hypofractionated radiotherapy (8). the use of spacers allowed to keep pretreatment sexual potency in 62.5% of the cases (8). a biodegradable balloon spacer is a three-dimensional scaffold made of biocompatible material that is designed to be implanted between the prostate gland and the rectum, prior to the beginning of a radiotherapy program. it is biodegradable and it is actually commercialized in europe (figure 1). with the patient in the lithotomy position, and under transrectal ultrasonography (trus) guidance, an 18-gauge needle is inserted between denonvilliers’ fascia and the anterior rectal wall (figure 2). once the needle is in the correct position, saline water is injected to carry out hydro-dissection and to create a potential space between the prostate and rectum. implantation time is relatively short, with a mean overall procedure time of 16 minutes (7.8 min) from time of trus insertion to trus removal; moreover, the biodegradable gel takes an average of 6 to 12 months to absorb once injected in the patients’ regions of interest. reported complications of spacers positioning, although rare, are prostatic abscess, fistulae and sepsis. the aim of this study is to evaluate the safety and efficacy of biodegradable balloon spacer placement in prostate cancer patients who are candidates for radiation treatment. materials and methods this is a prospective observational study that enrolled patients with a diagnosis of prostate cancer (pca) who had unfavorable/intermediate risk (poor prognosis) and were receiving hypofractionated radiation therapy between january 2021 and june 2022. patients who had previously received pelvic irradiation for rectum morbidities were also included in the study, and no exclusion criteria were used in the patient selection phase. the timing of the procedure, related complications, and the tolerability of the device were evaluated at two time points: t0 (the day of spacer placement) and t1 (an ambulatory control visit at 10 days). the spacer (bioprotect® biodegradable spacer) was placed in an outpatient setting with the patient in a lithotomic position. cefazoline 1 gram was administered intravenously and local anesthesia was given to the perineal area and levator ani muscles with 2% mepivacaine. the procedure was performed using transrectal ultrasound with a biplanar probe. a cutaneous incision was made at the perineal level, 1 cm above the anus, and the dilator was inserted behind the prostate at the level of the denonvilliers’ fascia. hydrodissection was performed to create a well-defined plane from the prostate apex to the seminal vesicles. the device containing the balloon was then inserted and advanced to the level of the seminal vesicles, inflated with physiological solution (16-23 ml), and released. the correct positioning of the device was confirmed using transrectal ultrasound (trus). the patient was observed for any early complications during the post-procedural observation period before being dismissed. late complications and the tolerability of the device were evaluated at t1. the duration of the procedure (in minutes), observation time (in minutes), and the appearance and severity (according to the charlson comorbidity index) of early and late complications were figure 1. illustration of a biodegradable balloon spacer positioning. figure 2. illustration of the 18-gauge needle needed for the implantation of the spacer. archivio italiano di urologia e andrologia 2023; 95, 2 37 tolerability of biodegradable balloon spacers recorded. the tolerability of the device was evaluated using a scale from 0 to 10 for discomfort (0 = no discomfort, 10 = severe discomfort) and by assessing pelvic-perineal encumbrance and changes in bowel function. after the t1 visit, the patient was sent for radiotherapy. results from january 2021 to june 2022, 25 patients were enrolled. their baseline epidemiological data are shown in table 1. the procedure was performed in an outpatient setting following the protocol described in the previous section. the average time of the procedure was 18 minutes [10-25 min]. all patients were then discharged within two hours of the procedure (average post-op observation time: 90 minutes [45-110 min]), after the resumption of spontaneous micturition and the absence of early complications. two patients (8%) experienced acute urine retention that was resolved with catheterization, and one patient (4%) developed a mild perineal hematoma that did not require treatment. as for late complications, one patient (4%) developed fever (> 38°c) the day after the procedure, requiring continuation of the antibiotic regimen. at the t1 visit, no medium-high grade complication was recorded. the tolerability of the device was optimal, with an average score of 2 and a range of 04 on the previously described discomfort scale. no patients reported disturbances in defecation, changes in intestinal transit, or a sense of encumbrance in the pelvic-perineal area. results are listed in table 2. discussion prostate cancer (pca) is the second most common cancer among men worldwide, ranking first in developed countries. according to the world research fund international, there were over 1.4 million new diagnoses of pca in 2020 worldwide. the incidence and mortality of pca are correlated with age, with the average age of diagnosis being 66 years. there is a higher incidence of pca in africanamerican men compared to white men, with 158.3 new cases diagnosed per 100.000 men and double the mortality. while the lethality of pca is not as severe as other types of cancer, the number of yearly deaths due to pca is high due to its high incidence. pca diagnosis is based on standardized protocols that involve prostate specific antigen (psa) testing, digital rectal examination (dre), and the newly implemented multiparametric magnetic reonance imaging (mpmri) as an additional diagnostic tool before biopsy, allowing for the specific targeting of possible malignant lesions. there are various treatment options for organ-confined pca, ranging from active surveillance to active treatment with surgery or radiotherapy. radiotherapy (rt) can be performed in various settings, such as external beam rt (ebrt) and intensity-modulated rt (imrt). imrt delivers a precise beam of modulated intensity that delivers radiation with higher selectivity to prostatic tissue, minimizing exposure to proximal organs. an hypofractionated rt protocol uses a higher dose of radiation per session, reducing the number of necessary sessions. the major drawback of rt is the incidental irradiation of proximal anatomical areas, such as the rectum, which is mostly inevitable due to the anatomical relationship between the rectum and prostate. spacers provide a solution to this problem by inserting a device between the prostate and rectum, separating the target of the radiation beam from a contiguous organ. in addition, the procedure can be performed in an outpatient setting via a dayhospital regimen, resulting in reduced costs and minimal operative time (9). overall, the implantation of spacers has been shown to be safe and fast, with optimal tolerability of the device (10, 11). no severe complications were observed in the postprocedural time (t0), allowing the procedure to be performed in an outpatient setting and at t1 follow-up outpatient visit. mild complications related to the implantation procedure have been documented, but they are relatively uncommon. we recorded one episode of acute urinary retention (aur) in a patient with a voluminous enlarged prostate, a risk factor commonly associated with prostate biopsies. the incidence of urinary tract infections (utis) is comparable to that of transperineal prostate biopsies, so adherence to the most recent guidelines is recommended (12). even among the most unfavorable cases (patients who have already undergone radiation treatment and need another cycle of imrt), no complications ranging from mild to severe were reported, in contrast to what is suggested in the eau guidelines about this topic (fistulas, abscesses, sepsis). our overall experience is in line with the european consensus, as we did not encounter acute or delayed intermediate-severe complications, despite having modest table 1. baseline epidemiologic data. patients’ characteristics number of patients 25 pts age 68 yo (range 59-77) tumor stage ct1c: 10 pts ct2a: 8 pts ct2b: 7 pts ct2c: o pts (0%) psa level 14 ng/ml (8-27 ng/ml) isupp isupp 1: 4 pts isupp 2: 6 pts isupp 3: 15 (%) pts isupp 4: 0 (0%) pts isupp 5: 0 (0%) pts table 2. data obtained after the spacer placement. average duration of the procedure 18 minutes (10-25 minutes) average duration of observation 90 minutes (45-110 minutes) early complications acute urinary retention 2 pz (10%) hematoma 1 pz (5%) late complications fever 1 pz (5%) spacer tolerability score 2 (0-4) reported bowel symptoms 0 pz perineal bulk sensation 0 pz archivio italiano di urologia e andrologia 2023; 95, 2 l. topazio, f. narcisi, f. tana, et al. 38 previous experience with these types of devices and transperineal procedures. this highlights the low learning curve for this procedure. conclusions biodegradable balloon spacers appear to be safe and well tolerated and their positioning does not present any technical difficulties or risks of major complications. its usage can and must be discussed when dealing with patients diagnosed with prostate cancer and scheduled to undergo radiation therapy in order to increase the selectivity of such treatment by protecting the rectum via mechanical separation from the prostate. the device is designed to be left in place as it is biodegradable and does not require any additional maintenance or monitoring. there are several potential benefits to using a biodegradable balloon spacer in the treatment of prostate cancer. in addition to potentially improving the effectiveness of radiation therapy, it may also reduce the risk of side effects such as rectal bleeding and discomfort. it may also help to reduce the risk of long-term complications such as bowel and urinary incontinence. overall, the biodegradable balloon spacers are promising tools in the treatment of prostate cancer, offering the potential for improved outcomes and fewer side effects for patients. it is an important advancement in the field of cancer treatment and continues to be studied and refined in order to optimize its effectiveness and safety. nonetheless, further data must be gathered as more of these devices are effectively used in everyday clinical practice to improve our understanding of its efficacy in protecting the rectum from radiation beams and their effects on the quality of life of patients, thus requiring a longer follow-up. references 1. wang l, lu b, he m, et al. prostate cancer incidence and mortality: global status and temporal trends in 89 countries from 2000 to 2019. front public health. 2022; 10:811044. 2. eau guidelines. edn. presented at the eau annual congress amsterdam 2022. isbn 978-94-92671-16-5. 3. hummel s, simpson el, hemingway p, et al. intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation. health technol assess. 2010; 14:1108, iii-iv. 4. nilsson s, norlén bj, widmark a. a systematic overview of radiation therapy effects in prostate cancer. acta oncol. 2004; 43:316-81. 5. navaratnam a, cumsky j, abdul-muhsin h, et al. assessment of polyethylene glycol hydrogel spacer and its effect on rectal radiation dose in prostate cancer patients receiving proton beam radiation therapy. adv radiat oncol. 2019; 5:92-100. 6. mok g, benz e, vallee jp, et al. optimization of radiation therapy techniques for prostate cancer with prostate-rectum spacers: a systematic review. int j radiat oncol biol phys. 2014; 90:278-88. 7. miller le, efstathiou ja, bhattacharyya sk, et al. association of the placement of a perirectal hydrogel spacer with the clinical outcomes of men receiving radiotherapy for prostate cancer: a systematic review and meta-analysis. jama netw open. 2020; 3:e208221. 8. pepe p, tamburo m, panella p, et al. erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: our experience in 56 cases. arch ital urol androl. 2022; 94:166-168. 9. fathy mm, hassan bz, el-gebaly rh, mokhtar mh. dosimetric evaluation study of imrt and vmat techniques for prostate cancer based on different multileaf collimator designs. radiat environ biophys 2023; 62:97-106. 10. thompson ab, hamstra da. rectal spacer usage with proton radiation therapy for prostate cancer. int j radiat oncol biol phys. 2020; 108:644-648. 11. sanei m, ghaffari h, ardekani ma, et al. effectiveness of rectal displacement devices during prostate external-beam radiation therapy: a review. j cancer res ther. 2021; 17:303-310. 12. pradere b, veeratterapillay r, dimitropoulos k, et al. nonantibiotic strategies for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. j urol. 2021; 205:653-663. correspondence luca topazio, md (corresponding author) luca.topazio@aslteramo.it federico narcisi, md federico.narcisi@aslteramo.it federico romantini, md federico.romantini@aslteramo.it asl teramo, u.o.c. di urologia (teramo), italy fabio tana, md fabiotana21@gmail.com cosimo ciotta, md ciottacosimo@live.it vincenzo iossa, md vincenzoiossa@msn.com pasquale perna, md pasquper@gmail.com francesco chiaramonti, md francesco.tr92@virgilio.it university of l'aquila (l'aquila), department of life, health and environmental sciences; u.o.c. di urologia, p.o. mazzini, (teramo), italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14332 1 original paper introduction benign prostatic hyperplasia (bph) is a prevalent, nonmalignant condition characterized by the proliferation of prostatic stromal and epithelial cells, typically occurring in aging males. this hyperplastic growth may contribute to lower urinary tract obstruction and the development of lower urinary tract symptoms (luts), which negatively affect patients' quality of life and functional status (1). in addition, chronic prostatic inflammation has been implicated in the progression of bph and is associated with increased prostate volume and symptom severity (2, 3). pharmacologic management of bph primarily includes α1-adrenergic receptor antagonists and 5α-reductase inhibitors. however, these agents frequently cause adverse effects such as orthostatic hypotension, reduced libido, and ejaculatory dysfunction, which can impair adherence and limit long-term utility (1, 4). accordingly, there is increasing clinical interest in nutraceuticals and plant-derived therapies that may offer symptomatic relief with a more favorable side-effect profile. xipag® is a dietary supplement composed of pollen extract and teupolioside a polyphenolic glycoside extracted from ajuga reptans that exhibits 5α-reductase inhibitory activity, potentially modulating androgenic signaling in prostatic tissue (5). pollen extract, rich in phytosterols and antiinflammatory compounds, may enhance therapeutic outcomes through its antioxidative, anti-inflammatory, and muscle-relaxant properties (6). this study aimed to evaluate the clinical efficacy of xipag® in men with bph, with primary endpoints focused on sexual function, ejaculatory function, quality of life (qol), and patient global impression of improvement (pgi-i). secondary endpoints included urodynamic parameters and luts symptom reduction. methods this prospective, single-arm observational study was conducted in accordance with the ethical standards of the declaration of helsinki and was approved by the institubackground: benign prostatic hyperplasia (bph) is a common age-related condition that often results in lower urinary tract symptoms (luts), reduced quality of life, and sexual dysfunction. conventional pharmacotherapies, while effective, are frequently associated with adverse effects on sexual and ejaculatory function. this study evaluated the sexual safety and clinical efficacy of a dietary supplement containing pollen extract and teupolioside, in men with bph. methods: in this prospective, single-arm observational study, 25 men with moderate luts due to bph received daily pollen extract and teupolioside supplementation for 90 days. the primary endpoints were sexual function (international index of erectile function, iief-5), ejaculatory function (male sexual health questionnaire–ejaculatory dysfunction, mshq-ejd), quality of life (ipss-qol), and patient global impression of improvement (pgi-i). secondary endpoints included changes in urinary flow (qmax) and luts severity (international prostate symptom score, ipss). assessments were conducted at baseline, 1 month, and 3 months. results: sexual and ejaculatory functions remained stable over the treatment period, with no statistically significant deterioration observed. qol improved significantly by the 3-month mark (ipss-qol median score reduced from 3 to 2; p < 0.008), and pgi-i scores reflected high patient satisfaction (median 2, iqr 1). qmax significantly increased from 12.4 ml/s at baseline to 15.5 ml/s at 3 months (p < 0.001), and ipss scores significantly declined from 11 to 8 (p < 0.008), indicating improved urinary function. conclusions: the pollen extract and teupolioside supplementation was well tolerated and associated with improved qol and urinary outcomes, without compromising sexual or ejaculatory function. these findings support its potential as a non-pharmacologic adjunct in the management of bph, particularly in patients concerned about sexual side effects. further randomized controlled studies are warranted to confirm these results. key words: benign prostatic hyperplasia; teupolioside; nutraceutical; sexual safety; lower urinary tract symptoms. submitted 6 september 2025; accepted 12 september 2025 sexual safety and efficacy of a pollen extract and teupolioside-based supplement in men with benign prostatic hyperplasia: a prospective observational study matteo vittori 1, 2*, valerio iacovelli 1, 2*, marco carilli 1, 2, carlo brocca 3, michele antonucci 1, 2, filomena petta 1, 2, beatrice filippi 1, giulia di giovanni 1, marta signoretti 1, 2, francesco maiorino 1, 2, andrea benedetto galosi 3, pierluigi bove 1, 2 1 urology unit, san carlo di nancy general hospital gvm care and research, rome, italy; 2 minimally invasive and robotic urology unit, tor vergata university of rome, rome, italy; 3 urology unit, azienda ospedaliero-universitaria delle marche, polytechnic university of marche, ancona, italy. * these authors contributed equally to this work and share first authorship. doi: 10.4081/aiua.2025.14332 summary archivio italiano di urologia e andrologia 2025; 97(3):14332 m. vittori, v. iacovelli, m. carilli, et al. 2 tional ethics committee (sts ce lazio1/n-945, “lazio 1”, san camillo forlanini hospital, rome, italy). written informed consent was obtained from all participants. a total of 25 male patients with bph-associated luts were enrolled. inclusion criteria comprised age ≥ 18 years, serum prostate-specific antigen (psa) ≤ 4 ng/ml, prostate volume ≤ 60 ml, qmax ≤ 15 ml/s, and post-void residual (pvr) volume < 150 ml. patients were excluded if they had urinary tract infection, urological malignancy, prior prostate surgery, significant comorbidities (e.g., neurogenic bladder, uncontrolled diabetes), or hypersensitivity to the supplement's components. eligible participants received a daily regimen of xipag® (idi integratori dietetici italiani s.r.l., aci bonaccorsi, ct, italy), administered as one tablet per day over a 90-day period. each daily dose of xipag® , contained the following active compounds: pollen extract (graminex® g96®; 500 mg) and teupolioside (teupol 25p; 60 mg). no additional pharmacological treatments targeting bph were prescribed during the study period to avoid confounding effects. at baseline (t0), patients signed informed consent, underwent clinical evaluation, uroflowmetry, ultrasonographic evaluation of pvr. patient-reported outcomes measures (proms) were evaluated using validated symptom and qol questionnaires. evaluations were conducted at baseline (t0), 1 month (t1), and 3 months (t2, end of treatment). primary outcomes were assessed using: international index of erectile function (iief-5), male sexual health questionnaireejaculatory dysfunction (mshq-ejd), ipss-qol domain, patient global impression of improvement (pgi-i). secondary outcomes included uroflowmetry (qmax) and the international prostate symptom score (ipss). in this study, artificial intelligence (ai), specifically chatgpt (chatgpt.com), was used solely for reviewing the english language in its grammar, syntax, and style, without affecting content, citations, or interpretative and conclusive discussions. statistical analysis continuous variables were summarized using medians and interquartile ranges (iqrs). the wilcoxon signedrank test was used to compare scores at t0, t1, and t2. a p-value < 0.05 was considered statistically significant. results a total of 25 patients completed the study protocol. baseline characteristics of study population were the following: median age 55 years (interquartile range, iqr 14); median prostate volume 44 ml (iqr 15); median psa 1.4 ng/ml (iqr 1.5). proms and functional results during follow-up are summarized in table 1. among the primary endpoints, sexual function, as measured by the international index of erectile function (iief5), showed no significant changes across time points. the median score was 21 (iqr: 3) at both baseline and 1 month (p = 0.5), with a slight increase to 22 (iqr: 4) at 3 months (p = 0.08). ejaculatory function, evaluated through the mshq-ejd function domain, demonstrated stable median values: 13 (iqr: 3) at baseline, 12 (iqr: 2) at 1 month (p = 0.8), and 12 (iqr: 3) at 3 months (p = 0.4), indicating no significant change. the mshq-ejd bother domain remained unchanged between baseline and 1 month with a median of 1 (iqr: 3; p = 0.7) and decreased slightly to 0 (iqr: 2) at 3 months, though not reaching statistical significance (p = 0.08). quality of life (qol), assessed via the ipss-qol domain, remained stable at 1 month with a median of 3 (iqr: 1) compared to baseline (3, iqr: 2; p = 0.8), but improved significantly at the 3-month follow-up to a median of 2 (iqr: 1; p < 0.008). a critical component of patient-centered care, the patient global impression of improvement (pgi-i), confirmed the subjective benefit reported by patients. at the 3-month evaluation, the median pgi-i score was 2 (iqr: 1), denoting that most patients perceived their condition as “much improved” or “very much improved”. importantly, more than half of the participants (52%) expressed a desire to continue the treatment beyond the study period, indicating high patient satisfaction and acceptability of the supplement. regarding the secondary endpoints, a progressive and ultimately statistically significant enhancement in urodytable 1. baseline characteristics and results of questionnaires and functional outcomes during follow-up. n = 25 baseline 1-month p-value * 3-months p-value ** iief, median (iqr) 21 (3) 21 (3) 0.5 22 (4) 0.08 mshq-ejd ejaculatory function domain, median (iqr) 13 (3) 12 (2) 0.8 12 (3) 0.4 ej-mshq bother item, median (iqr) 1 (3) 1 (3) 0.7 0 (2) 0.08 qmax, median (iqr) 12.4 (4.6) 13.5 (7.6) 0.1 15.5 (4) < 0.001 pvr (ml), median (iqr) 15 (20) 12.5 (20) 0.1 12.5 (25) < 0.01 ipss (luts domain), median (iqr) 11 (4) 10 (8) 0.4 8 (2) < 0.008 ipss-qol (qol domain), median (iqr) 3 (2) 3 (1) 0.8 2 (1) < 0.008 pgi-i 2 (1) * p-value between 1-month follow-up and baseline. ** p-value between 3-months and baseline follow-up. iief international index of erectile function (iief-5); ipss: international prostate symptom score; ipss-qol: international prostate symptom score-quality of life; male sexual health questionnaire–ejaculatory dysfunction (mshq-ejd); pgi-i: patient global impression of improvement; pvr: post-void residual; pvr: post-void residual volume. archivio italiano di urologia e andrologia 2025; 97(3):14332 3 pollen extract and teupolioside-based supplement in men with bph namic parameters was observed. at baseline, the median maximum urinary flow rate (qmax) was 12.4 ml/s (iqr: 4.6). an increase to 13.5 ml/s (iqr: 7.6) was observed at 1 month, though this change was not statistically significant (p = 0.1). at 3 months, qmax significantly improved to 15.5 ml/s (iqr: 4), with a p-value < 0.001, indicating a clinically relevant improvement in urinary flow (figure 1). the international prostate symptom score (ipss) for luts showed a median baseline value of 11 (iqr: 4), which slightly decreased to 10 (iqr: 8) at 1 month (p = 0.4). a significant reduction was noted at 3 months, with a median score of 8 (iqr: 2) (p < 0.008), reflecting symptom alleviation over time. discussion the findings of this study offer preliminary yet compelling evidence supporting the clinical utility of xipag® – a dietary supplement composed of pollen extract and teupolioside – in the management of bph, particularly in patients presenting with moderate luts and a preserved sexual function profile. crucially, our analysis demonstrated that the supplement had a favorable effect on the primary outcomes of sexual function, ejaculatory function, qol, and pgi-i. although sexual function and ejaculatory parameters did not exhibit statistically significant changes, they remained stable throughout the study period. the iief-5 showed no significant variation: median values remained 21 (iqr: 3) at baseline and t1 (p = 0.5), with a non-significant increase to 22 (iqr: 4) at t2 (p = 0.08). this suggests that the supplement neither impaired nor meaningfully enhanced erectile function. similarly, ejaculatory function assessed by the mshq-ejd function domain, remained unchanged, with median scores of 13 (iqr: 3) at baseline, 12 (iqr: 2) at t1 (p = 0.8), and 12 (iqr: 3) at t2 (p = 0.4). the mshq-ejd bother domain showed a mild, non-significant decline in bother scores from a median of 1 (iqr: 3) at baseline and t1 to 0 (iqr: 2) at t2 (p = 0.08). this is particularly relevant in the context of bph treatment, where commonly prescribed drugs such as α1-blockers and 5α-reductase inhibitors are known to impair sexual performance and ejaculatory function. the preservation of sexual health seen with xipag® is thus not merely a neutral finding, but a comparative advantage that may enhance treatment adherence and patient satisfaction. the observed non-significant upward trend in iief-5 scores at 3 months suggests a possible mild benefit that warrants further investigation in a larger cohort. perhaps the most notable result in this domain was the significant enhancement in qol, as evidenced by the ipssqol score at the 3-month mark. qol scores remained unchanged at 1 month (median 3, iqr: 1; p = 0.8), but improved significantly at 3 months (median 2, iqr: 1; p < 0.008). this improvement paralleled a substantial proportion of patients reporting subjective symptom relief via the pgi-i, indicating a concordance between objective questionnaire data and patient experience an essential aspect of any therapeutic intervention, particularly for chronic and quality-of-life-limiting conditions such as bph. in terms of secondary endpoints, the supplement produced significant improvements in both objective and subjective urological measures. the qmax showed a statistically and clinically meaningful increase by the end of the figure 1. uroflowmetry (y = qmax) in the 25 patients (x = patients). the blue line represents baseline flow characteristics; the green line represents the median trend of the traces at the end of the 90-day treatment period. archivio italiano di urologia e andrologia 2025; 97(3):14332 m. vittori, v. iacovelli, m. carilli, et al. 4 study, suggesting a reduction in urinary tract obstruction or improvement in bladder emptying. the qmax demonstrated a progressive improvement over time. at baseline, the median qmax was 12.4 ml/s (iqr: 4.6), increasing to 13.5 ml/s (iqr: 7.6) at t1. although the early increase did not achieve statistical significance (p = 0.1), a significant enhancement was observed at t2, with qmax reaching 15.5 ml/s (iqr: 4) (p < 0.001). from a baseline median score of 11 (iqr: 4), ipss decreased to 10 (iqr: 8) at t1 (p = 0.4), and significantly declined to 8 (iqr: 2) at t2 (p < 0.008) indicating that symptom relief may accrue with continued administration potentially reflecting the gradual anti-inflammatory and anti-androgenic effects of the supplement’s active components. the mechanism of action of xipag® appears to be multifactorial. teupolioside has demonstrated inhibitory effects on 5α-reductase, potentially decreasing intraprostatic dihydrotestosterone levels and thereby reducing prostatic volume and obstruction. this pathway is analogous to that targeted by finasteride or dutasteride, but without the hormonal side effects that frequently accompany those medications. in parallel, pollen extract offers a rich profile of phytosterols, flavonoids, and essential fatty acids, contributing antioxidative and anti-inflammatory properties, along with smooth muscle relaxation. together, these mechanisms provide a plausible pharmacological basis for the observed improvements in urinary flow and symptom burden, as well as the absence of detrimental effects on sexual function. these findings are broadly consistent with prior literature, including clinical studies by lo re et al. (7) and muraca et al. (8), which evaluated the same fixed-dose combination. both studies reported reductions in ipss scores and enhancements in qol, alongside excellent tolerability and patient adherence. our study reinforces these conclusions while further emphasizing the sexual safety profile of the supplement a domain that remains underrepresented in bph supplement research. nevertheless, a number of limitations must be acknowledged. the sample size was relatively small (n = 25), limiting statistical power and generalizability. the lack of a control group – placebo or otherwise – precludes definitive causal inference, and the single-arm design introduces potential for performance, observer, and expectation bias. additionally, the 3-month duration, while sufficient to demonstrate initial therapeutic effects, does not provide insight into long-term efficacy, sustainability of benefit, or potential delayed adverse events. these concerns are particularly relevant given the chronic nature of bph, which often requires extended treatment timelines. despite these constraints, the absence of adverse events, in combination with significant improvements in qol, urinary function, and patient-reported outcomes, positions xipag® as a viable non-pharmacologic adjunct or alternative in the therapeutic landscape of bph. importantly, its use may be especially advantageous in patients who are unwilling or unable to tolerate conventional medications due to side effects, particularly those related to sexual function. moving forward, these preliminary findings underscore the need for randomized, double-blind, placebo-controlled trials involving larger patient cohorts and longer follow-up durations. such studies should incorporate not only symptom scores and urodynamic parameters but also objective biomarkers of inflammation, prostate volume changes, and detailed sexual function domains. stratification by baseline sexual function status and symptom severity could also help delineate which subgroups stand to benefit most from xipag® therapy. conclusions in this preliminary investigation, xipag® demonstrated promising efficacy in improving qol and patient-reported outcomes in men with bph, without compromising sexual or ejaculatory function. secondary benefits included improved urinary flow and reduced luts severity. these findings support the potential role of xipag® as a non-pharmacologic adjunct or alternative in bph management. further controlled studies are necessary to establish its long-term safety and therapeutic value. references 1. cornu, jn, gacci m, hashim h, et al. eau guidelines on non neurogenic male lower urinary tract symptoms (luts). european association of urology. last updated april 23, 2025. 2. gandaglia g, briganti a, gontero p, et al. the role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (bph). bju int. 2013; 112:432-41. declarations ethical approval and consent for participate: this prospective, single-arm observational study was conducted in accordance with the ethical standards of the declaration of helsinki and was approved by the institutional ethics committee (sts ce lazio1/n-945, “lazio 1”, san camillo forlanini hospital, rome, italy). written informed consent was obtained from all participants. availability of data and material: the data that support the findings of this study are available from the corresponding author, [vi], upon reasonable request. competing interests: the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. funding: the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors' contributions:matteo vittori conceived the study, conducted the literature review and collected the data; valerio iacovelli conceived the study, wrote the manuscript; marco carilli conceived the study, wrote the manuscript; carlo brocca reviewed the manuscript; filomena petta collected the data, interpreted the results; beatrice filippi performed the statistical analysis; giulia di giovanni performed the statistical analysis; marta signoretti collected the data; francesco maiorino collected the data; michele antonucci collected the data; andrea benedetto galosi reviewed and edited; pierluigi bove conceived the study, wrote the manuscript, reviewed and edited. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):14332 5 pollen extract and teupolioside-based supplement in men with bph 3. fusco f, creta m, de nunzio c, et al. progressive bladder remodeling due to bladder outlet obstruction: a systematic review of morphological and molecular evidences in humans. bmc urol. 2018; 18:15. 4. serati m, andersson ke, dmochowski r, et al. systematic review of combination drug therapy for non-neurogenic lower urinary tract symptoms. eur urol. 2019; 75:129-168. 5. korkina lg, mikhal’chik ev, suprun mv, et al. molecular mechanisms underlying wound healing and anti-inflammatory properties of naturally occurring biotechnologically produced phenylpropanoid glycosides. cellular and molecular biology tm. 2007; 53:84-91. 6. locatelli m, macchione n, ferrante c, et al. graminex pollen: phenolic pattern, colorimetric analysis and protective effects in immortalized prostate cells (pc3) and rat prostate challenged with lps. molecules. 2018; 23:1145. 7. lo re m, pezzoli m, cadenar a, et al. discovering a new nutraceutical based on pollen extract and teupolioside: a prospective monocentric study evaluating its role in alleviating lower urinary tract symptoms in benign prostatic hyperplasia patients. arch ital urol androl. 2025; 97:13412. 8. muraca l, scuteri a, burdino e, et al. effectiveness and safety of a new nutrient fixed combination containing pollen extract plus teupolioside, in the management of luts in patients with benign prostatic hypertrophy: a pilot study. life (basel). 2022; 12:965. correspondence matteo vittori matteo.vittori@ptvonline.it valerio iacovelli (corresponding author) valerio.iacovelli85@gmail.com marco carilli marco.carilli@ptvonline.it carlo brocca brocca.carlo@gmail.com michele antonucci michele.antonucci@ptvonline.it filomena petta filomena.petta@ptvonline.it marta signoretti marta.signoretti@ptvonline.it francesco maiorino francesco.maiorino@ptvonline.it pierluigi bove pierluigi.bove@ptvonline.it policlinico tor vergata, unità di urologia robotica e mininvasiva, viale oxford 31, 00133, rome, italy beatrice filippi beatrice.filippi87@gmail.com giulia di giovanni giuliadigiovanni28@gmail.com urology unit, san carlo di nancy general hospital gvm care and research, rome, italy andrea benedetto galosi andreabenedetto.galosi@ospedaliriuniti.marche.it urology unit, azienda ospedaliero-universitaria delle marche, polytechnic university of marche, ancona, italy stesura seveso 7archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. ed by clayman in 1991 (4) and several studies described, compared to the open technique, a minimized morbidity in terms of blood loss, perioperative pain, faster convalescence, and less perioperative complications (5, 6). a recent meta-analysis and multicenter studies reported comparable oncologic results between the two surgical approaches (7-11). one of the most important surgical steps during lnu is the access to the distal ureter in order to perform the excision of the bladder cuff. different techniques have been described regarding open, endoscopic or trans-vesical approach (12-14) but no one has been shown to be significantly better than the others. the ideal technique is represented, on one side, by removing of the specimen en bloc without spillage of tumor cells during the bladder cuff excision in respect of oncological criteria and, on the other side, by performing the entire procedure without patient and port repositioning to decrease operative time. herein, we describe our totally lnu with bladder cuff excision technique with modified port placement, which allows access to both kidney and ureterovesical junction without requiring patient repositioning. materials and methods from january 2014 to june 2020, patients with diagnosis of utuc, were prospectively enrolled and treated with lnu using our surgical technique performed by the same experienced surgeon (ac) at our university department. the study was performed in accordance with the ethical principles for medical research involving human subjects (world medical association, the declaration of helsinki principles, 2000). the study was approved by the local ethical committee of sapienza university pharmacy and medicine faculty, latina, italy (dsbmc lt approval n. ce14/0924/2014 urol). written informed consent forms were obtained from all the patients before study enrollment. the patient demographic and clinic-pathologic data were prospectively collected and are summarized in table 1. none of these patients had prior or concomitant bladder tumors and/or distant metastasis. introduction: radical nephroureterectomy (rnu) with full bladder cuff excision is the gold standard for treatment of non-metastatic upper tract urothelial cancer (utuc). we describe our technique of laparoscopic nephroureterectomy (lnu) with bladder cuff excision technique with modified port placement, reporting our long-term follow-up outcomes. methods: patients affected by utuc were prospectively enrolled and undergone to lnu. perioperative outcomes, oncological data at 6, 12, 24 and 36 months after surgery, and all the surgical complications according to clavien-dindo classification were evaluated in all subjects. results: a total of 50 patients with utuc underwent lnu, using this new technique without patient and port repositioning. the mean operative time was 168 minutes, estimated blood loss was 75 ml, mean length of hospital stay was 3 days. there were no intraoperative complications while four late complications occurred (two grade iiib and two grade ii according to clavien-dindo classification, incisional hernias and fever, respectively). postoperative pathology was t1 in 12 patients, t2 in 17 patients, and t3 in 21 patients. tumor grade was low in 12 patients and high in 38 patients. conclusions: in our study the described lnu technique was related to a significant reduction in terms of operative time and length of hospital stay, with a faster patients’ recovery and no peri and postoperative complications. the long-term oncological outcomes were similar to data reported in literature. key words: nephroureterectomy; laparoscopy; oncological outcomes; hospital stay; estimated blood loss. submitted 29 december 2021; accepted 7 january 2022 introduction upper tract urothelial carcinoma (utuc) is rare, accounting for only 5-7% of all urothelial carcinoma cases, with a high frequency of both local and secondary bladder recurrence (1-2). radical nephroureterectomy (rnu) with full bladder cuff excision is the gold standard for treatment of non-metastatic utuc (3). laparoscopic nephroureterectomy (lnu) was firstly reportlaparoscopic radical nephroureterectomy with only three trocars: results of a prospective single centre study yazan al salhi 1, 2, andrea fuschi 1, 2, alessia martoccia 1, gennaro velotti 1, paolo pietro suraci 1, silvio scalzo 1, onofrio antonio rera 1, alice antonioni 1, fabio maria valenzi 1, giorgio bozzini 3, antonio carbone 1, antonio luigi pastore 1 1 urology unit, department of medico-surgical sciences and biotechnologies, faculty of pharmacy and medicine, sapienza university of rome, latina, italy; 2 icot-surgery, orthopedics, traumatology institute, latina, italy; 3 urology unit, asst lariana, como, italy. doi: 10.4081/aiua.2022.1.7 summary archivio italiano di urologia e andrologia 2022; 94, 1 y. al salhi, a. fuschi, a. martoccia, et al. 8 all tumors were staged based on the 2002 tnm classification of malignant tumors and were graded by the world health organization classification of 1998. after the induction of general anesthesia, the patient is placed in a modified flank position (60° oblique position) with the lesion side up (the right side, e.g.) (figure 1). the first port (12 mm port used for the 30 degrees camera) is placed by hasson technique supraumbilical on the pararectal line at the caudal rim of the umbilicus. peritoneal insufflation is established, and pneumoperitoneum is created by applying 12 mm hg of co2 pressure. the second port is a 12 mm port placed on the paramedian line between the optical trocar and the costal arch. the third port is a 5 mm port placed in the midline between the anterior superior iliac spine (asis) and the umbilicus. standard laparoscopic transperitoneal nephrectomy is performed with a radiofrequency device (ligasuretm, 5 mm covidien®, u.s.) placed in the second port and a johan forceps in the third port. first surgical time (nephrectomy) includes mobilization of the colon, ligation of the renal hilum and circumferential mobilization of the kidney, while leaving the ureter intact. retroperitoneal lymphadenectomy is performed in clinical indicated cases based on the preoperative ct scan, included the interaortocaval dissection plus hilar and precaval-paracaval-retrocaval regions for right-sided disease, and hilar with preaortic-paraaortic-retroaortic tissues for left-sided disease. during further mobilization, the ureter is clipped distal to the tumor site to prevent intraluminal tumor seeding. by carefully dissecting the ureter over the iliac vessels down to the ureterovesical junction, the peritoneal covering overlying the dome of the bladder is incised and the detrusor muscle fibers are encountered. using a combination of blunt and sharp dissection, the intramural ureter is separated from the surrounding detrusor muscle and down to the bladder mucosa. prior to complete detachment of the cuff, a 15 cm 3-0 barbed stay suture is placed at the superior margin of the planned cystotomy to provide traction during subsequent closure of the cystotomy. bladder cuff is excised through monopolar scissors. at this point, after traction on the previously placed stay suture, the same barbed suture is used to close the first layer of the cystotomy. a second 3-0 barbed suture is then used to close a second imbricating layer (figure 2). the bladder is checked to be water-tight by instilling 120 cc or more of irrigation via the foley catheter. a perivesical drain is placed and the specimen is entrapped and extracted intact by low paramedian transverse abdominal incision in the ipsilateral lower quadrant of the abdomen. patients with bilateral tumor, tumor with node metastasis or bladder carcinoma, adenocarcinoma and squamous cell carcinoma, simultaneous pelvis tumor were excluded from the study. results a total of 50 patients (37 males, 13 females) underwent to lnu performed with our described technique. all cases were completed uneventfully without conversion to open surgery or patient repositioning. mean age was 67 years old (range 58-83 years), mean bmi was 24.7 kg/m2 (range 23.1-27.8). the mean operative time was 168 minutes (range: 132-215 min), estimated blood loss was 75 ml (range 50-125 ml), mean length of hospital stay was 3 days (range: 2-8 days). there were no intraoperative complications while four late complications occurred (two grade iiib and two grade ii according to clavien-dindo classification, incisional hernias, and fever respectively). no open conversion was required, figure 1. configuration of the three trocars positioning: a for 12 mm optical trocar, b for 12 mm right trocar, c for 5 mm left trocar. figure 2. sequential surgical steps of bladder cuff excision, placement of stay suture and subsequent cystotomy. 9archivio italiano di urologia e andrologia 2022; 94, 1 laparoscopic nephroureterectomy with three trocars and no blood transfusion needed. regarding postoperative pathology (table 1), 29 tumors were in the renal pelvis with a mean diameter of 3.9 cm (range: 3.1-5.2). the other twenty-one were localized as follows: 14 in the proximal ureter and the remaining 7 in the distal ureter, with a mean diameter of 2.9 cm (range: 2.7-3.2). there were no positive margins in any patients. lymph node dissection was performed in 6 patients (16%) according to the pelvic and abdominal ct scan findings. of those patients who underwent a lymph node dissection, the median lymph node count was 3.4 (range: 1-5). the pathologic stage was t1 in 12 patients, t2 in 17 patients, and t3 in 21 patients. the tumor grade was low in 12 patients and high in 38 patients. no concomitant carcinoma in situ was found. the median follow-up duration was 41 months (range: 9-62 months). at the first cystoscopy examination (3 months after surgery), we observed that the ureteral orifice of the affected side was absent in all the patients. no patients have presented with evidence of local or secondary bladder recurrence and none of the patients was shown to have stone formation at the routine postoperative follow-up cystoscopy. moreover, at ct scan study (performed every 6 months for the first 24 months, and then yearly) no distant metastases were reported. discussion during the past twenty years, due to the widespread diffusion of laparoscopy and the development of new devices, lnu has become a feasible and safe mini-invasive procedure for the treatment of utuc (15, 16). when compared to open rnu, lrn has shown overall remarkable benefits in terms of blood loss, perioperative pain, hospital stay and faster convalescence (17-19). several minimally invasive surgical procedures have been described regarding nephroureterectomy, particularly focusing on distal ureterectomy and bladder cuff excision management. it is still under debate which must be considered the optimal technique, with several approaches described such as traditional open trans vesical (stripping, detachment), endoscopic (transurethral resection of ureteral orifice, tur) or laparoscopic extravesical. open excision, through a gibson, low midline or pfannesteil incision during lnu, is still the procedure of choice for ensuring the complete bladder cuff excision in terms of oncological principles, but its main drawback is the requirement of a larger incision in comparison to the one needed as the extraction site. tur, known as “pluck” technique, can be used in patients with proximal tumor and absence of concomitant bladder disease (20, 21); it avoids the need for an extra incision with a shorter operative time compared with open excision (22). several concerns about the chance of extravesical space tumor seeding have caused the sequential decreasing use of this technique (23). the stripping technique, using a ureteral catheter, can intussuscept the ureter into the bladder; then, the ureteral orifice is excised cystoscopically with a collins knife (14). this procedure is contraindicated in the presence of ureteral tumor because of the potential tumor seeding. the laparoscopic transvesical technique describes the placement of two transvesical laparoscopic ports and subsequently of an endoloop around the ureteral orifice, creating a closed urothelium with an en bloc removal of specimen. the disadvantages are represented by the difficult learning curve and the need for the patient repositioning for the nephrectomy surgical time (15). regarding pure laparoscopic techniques, the extravesical stapling technique has a shorter operative time and avoids incision into the urinary tract. however, this procedure has been associated with a higher risk of positive surgical margins and local recurrence due to the inadequate bladder cuff resection (24), as well as an increased risk of stone formation (25). recently, a new pure laparoscopic technique has been described, involving the use of a bulldog clamp applied distal to the tent shaped ureteral orifice and bladder cuff (26). the advantage of this approach is the en bloc removal without tumor spillage, however the use of the bulldog clamp does not ensure the direct visualization of the ureteral orifice and necessitates the addition of an extra port. regarding robot assisted laparoscopic nephroureterectomy (ralnu), hemal et al. firstly described their technique for successful performance of robotic nephroureterectomy with bladder cuff excision, without patient repositioning and robot redocking (27). the authors concluded that all procedures were performed successfully without complications, and with excellent short-term oncological outcomes. veccia et al. in a systematic review and meta-analysis compared robotic nephroureterectomy with open, laparoscopic, and hand-assisted ones in over 87.000 patients; the authors highlight how the robotic approach offers advantages in terms of hospital stay, peri and post-operative complications, blood loss and transfusion compared to the open nu without compromising oncological outcomes; these advantages are on the other hand comparable between robotic and laparoscopic procedures (28, 29). our technique is a simple modificatable 1. patients’ demographic and pathological characteristics. n° patient 50 mean age (range) 67 (58-83) sex males 37 females 13 bmi (range) 24.7 (23.1-27.8) side right 24 left 26 tumor site renal pelvis 29 ureter 21 mean tumor size 3.3 (2.7 5.2) tnm staging pt1 12 pt2 17 pt3 21 grade low grade 12 high grade 38 surgical margins negative 50 positive 0 lymph node 3.4 (1-5) archivio italiano di urologia e andrologia 2022; 94, 1 y. al salhi, a. fuschi, a. martoccia, et al. 10 tion of the pure laparoscopic rnu placing the ports sites in a new more ergonomic and easier position in order to perform the distal ureterectomy and bladder cuff excision without the disadvantage of port or patient repositioning. dissection of the intramural part represents a difficult step of the rnu because of several risks during the excision of the bladder cuff, such as tumor spillage or contralateral ureteric orifice injury. however, the association between the laparoscopic magnified view and the use of laparoscopic instruments leads to a careful dissection under direct vision of the urothelium at risk away from the detrusor muscle. we used this surgical technique for both proximal and distal ureteric tumor localization without reporting any injury of the tumor site during dissection, thanks to the combination of blunt and sharp dissection, separating the intramural ureter from the surrounding detrusor muscle and down to the bladder mucosa and utilizing cold scissors after placing the stay suture. however, suturing during laparoscopy is not easy, but, in our technique, only two stitches are required in order to secure the bladder and ensuring the closure of the urinary tract during the whole procedure. in the present study, we performed an en-bloc bladder cuff excision with clear surgical margins for all cases. shoma described the use of a purse-string suture in order to secure the bladder, but the author does not recommend this technique for distal ureter utuc (30). in the present study we treated 7 distal ureter utucs (14%) that did not show evidence of local and bladder recurrence at a mean follow-up of 38 months (range: 661 months). main limitations of the study included the small number of patients. points of strength of the present investigation were the prospective study design, the long-term followup (38 months), all procedures performed by a single experienced surgeon, the inclusion of all localization sites of utucs (rarely reported in literature). in our opinion, the improvement of this purely laparoscopic technique is to ensure the reduction of surgical trauma, hospital stay and estimated blood loss concurrently with the same oncologic outcomes. conclusions in our study the described technique was related to a significant reduction in terms of operative time and length of hospital stay, with a faster patients’ recovery and no peri and postoperative complications. the technique enabled complete lnu without patient or port repositioning. our study reported successful operative and oncological outcomes with a long-term follow-up. major limit of this technique is the need of an advanced laparoscopic skill, but the port setup presented gives maximum maneuverability and good visual field in both upper and lower urinary tract surgery without requirement of extra patient or port repositioning. this technique appears to be safe and feasible; however, studies with longer follow-up periods and larger patient cohorts are required to confirm our findings. references 1. hall mc, womack s, sagalowsky ai, et al. prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. urology. 1998; 52:594-601. 2. nocks bn, heney nm, daly jj, et al. transitional cell carcinoma of renal pelvis. urology. 1982; 19:472-477. 3. roupert m, babjuk m, comperat e, et al. european guidelines on upper tract urothelial carcinomas: 2013 up-date. eur urol. 2013; 63:1059-1071. 4. clayman rv, kavoussi lr, figenshau rs, et al. laparoscopic nephroureterectomy: initial clinical case report. j laparoendosc surg. 1991; 1:343-349. 5. rassweiler jj, schulze m, marrero r, et al. laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: is it better than open surgery? eur urol. 2004; 46:690-697. 6. simone g, papalia r, guaglianone s, et al. laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. eur urol. 2009; 56:520-526. 7. walton tj, novara g, matsumoto k, et al. oncological outcomes after laparoscopic and open radical nephroureterectomy: results from an international cohort. bju int. 2011; 108:406-412. 8. ariane m, colin p, ouzzane a, et al. assessment of oncologic control obtained after open versus laparoscopic nephroureterectomy for upper urinary tract urothelial carcinomas (uut-ucs): results from a large french multicenter collaborative study. ann surg oncol. 2012; 19:301-8. 9. ni s, tao w, chen q, et al. laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. eur urol. 2012; 61:1142-1153. 10. fairey as, kassouf w, estey e, et al. comparison of onco-logical outcomes for open and laparoscopic radical nephroureterectomy: results from the canadian upper tract collaboration. bju int. 2013; 112:791-797. 11. rai bp, shelley m, coles b, et al. surgical management for upper urinary tract transitional cell carcinoma (uut-tcc): a systematic review. bju int. 2012; 110:1426-1435. 12. chen j, chueh sc, hsu wt, et al. modified approach of handassisted laparoscopic nephroureterectomy for transitional cell carcinoma of the upper urinary tract. urology. 2001; 58:930-934. 13. laguna mp, de la rosette jj. the endoscopic approach to the distal ureter in nephroureterectomy for upper urinary tract tumor. j urol. 2001; 166:2017-22. 14. angulo jc, hontoria j, sanchez-chapado m. one-incision nephroureterectomy endoscopically assisted by transurethral ureteral stripping. urology. 1998; 52:203-7. 15. gill is, soble jj, miller sd, sung gt. a novel technique for management of the en bloc bladder cuff and distal ureter during laparoscopic nephroureterectomy. j urol. 1999; 161:430-434. 16. ghazi a, shefler a, gruell m, et al. a novel approach for a complete laparoscopic nephroureterectomy with bladder cuff excision. j endourol. 2010; 24:415-419. 17. kamihira o, hattori r, yamaguchi a, et al. laparoscopic radical nephroureterectomy: a multicenter analysis in japan. eur urol. 2009; 55:1397-1407. 18. guo g, yang y, dong j, et al. a new 2-micrometer continuous wave laser method for management of distal ureter in retroperitoneal laparoscopic nephroureterectomy. j endourol. 2015; 29:430-434. 11archivio italiano di urologia e andrologia 2022; 94, 1 laparoscopic nephroureterectomy with three trocars 19. waldert m, remzi m, klingler hc, et al. the oncological results of laparoscopic nephroureterectomy for upper urinary tract transitional cell cancer are equal to those of open nephroureterectomy. bju int. 2009; 103:66-70. 20. abercrombie gf, eardley i, payne sr, et al. modified nephroureterectomy: long-term follow-up with particular reference to subsequent bladder tumors. br j urol. 1988; 61:198-200. 21. palou j, caparros j, orsola a, et al. transurethral resectionof the intramural ureter as the first step of nephroureterectomy. j urol. 1995; 154:43-44. 22. li wm, shen jt, li cc, et al. oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. eur urol. 2010; 57:963-969. 23. arango o, bielsa o, carles j, et al. massive tumor implantation in the endoscopic resected area in modified nephroureterectomy. j urol. 1997; 157:1839-1844. 24. matin sf, gill is. recurrence and survival following laparoscopic radical nephroureterectomy with various forms of bladder cuff control. j urol. 2005; 173:395-400. 25. baughman sm, sexton w, bishoff jt. multiple intravesical linear staples identified during surveillance cystoscopy after laparoscopic nephroureterectomy. urology. 2003; 62:351-56. 26. pei l, et al. a novel and simple modification for management of distal ureter during laparoscopic nephroureterectomy without patient repositioning: a bulldog clamp technique and description of modified port placement. j endurol. 2016; 30:195-200. 27. hemal ak, stansel i, babbar p, patel m. robotic-assisted nephroureterectomy and bladder cuff excision without intraoperative repositioning. urology 2011; 78:357-64. 28. veccia a, antonelli a, francavilla s, et al. robotic versus other nephroureterectomy techniques: a systematic review and meta-analysis of over 87,000 cases. world j urol. 2020; 38:845-852. 29. mourmouris p, argun ob, tzelves l, et al. is robotic radical nephroureterectomy a safe alternative to open approach: the first prospective analysis. arch ital urol androl. 2021; 93:408-11. 30. shoma am. purse-string technique for laparoscopic excision of a bladder mucosal cuff in patients with transitional cell carcinoma of the upper urinary tract: initial report with intermediate follow-up. bju int. 2009; 104:1505-9. correspondence yazan al salhi yazan5585@gmail.com andrea fuschi andrea.fuschi@uniroma1.it alessia martoccia martoccia.alessia@gmail.com gennaro velotti gennaro.vel88@gmail.com paolo pietro suraci spaolopietro@gmail.com silvio scalzo silvioscalzo@hotmail.it onofrio antonio rera onofrioantonio.rera@uniroma1.it alice antonioni alice.antonioni@gmail.com fabio maria valenzi fabiovalenzi@gmail.com giorgio bozzini gioboz@yahoo.it antonio carbone antonio.carbone@uniroma1.it antonio luigi pastore, md (corresponding author) antopast@hotmail.com urology unit, department of medico-surgical sciences and biotechnologies, faculty of pharmacy and medicine, sapienza university of rome, 04100 latina, italy stesura seveso 447archivio italiano di urologia e andrologia 2022; 94, 4 original paper no conflict of interest declared. acid (ha) instillation intravesically in patients with ic/bps may help to regenerate the gag layer. furthermore, it appears that ha inhibits mast cell degranulation (3). after several weeks of weekly ha administration in the bladder, a significant reduction in symptoms was noted (1). botulinum toxin-a, on the other hand, is an effective, well-tolerated, and safe therapy option for patients with ics/pbs. it aids in the relief of pain and the treatment of bladder ulcers (3). the duration of botulinum toxin-a treatment is less than nine months, and 88 percent of cases require repeating injection (2). ic/bps has a significant impact on patients' psychological well-being, including sleep disturbances, sadness, anxiety, and a poor quality of life (4). the goal of this study was to assess the improvement criteria and the improvements in quality of life for women with refractory ic/bps who received a combined intravesical injection of botulinum toxin-a with ha instillation. materials and methods thirty-four adult women with refractory ic/bps were prospectively considered in this pilot trial between january 2017 and january 2020. inclusion criteria inclusion criteria were bothering urinary nocturia, frequency, urgency and pelvic pain not responding to oral medications for a period of 6 months or more. exclusion criteria exclusion conditions were: pregnancy, malignancy, radiation cystitis, other urogenital diseases (e.g., congenital anomalies, infection, or stones) and bleeding disorders. gynecologic examination was done to exclude vaginal infection, prolapse, menopausal changes and endometriosis. randomization the cases were evenly randomized (one to one randomization) into two groups, each with 17 women. btx-a objectives: the aim of this study was to assess changes in quality of life and pain alleviation in women with refractory interstitial cystitis/painful bladder syndrome following a combined intravesical injection of botulinum toxin-a and hyaluronic acid instillation versus hyaluronic acid instillation alone. methods: two groups of women with painful bladder syndrome/interstitial cystitis were randomly divided (one to one randomization). intravesical injections of botulinum toxin-a and intravesical hyaluronic acid were given to group (i). only hyaluronic acid was instilled intravesically in group ii. patients were given voiding diaries, a visual analogue scale for pelvic pain, the international cystitis symptom index and problem index, the pelvic pain urgency/frequency patient symptom scale, and the patient health questionnaire-9 to assess the candidates' quality of life. the student t-test and mean and standard deviation were used in statistical analysis, with p 0.05 considered as significant (ibm spss statistics) results: thirty-four women were included in this study. the pain severity (vas) of group (i) cases dropped dramatically from 8.5 ± 1.5 at the start to 3.9 ± 2.4 after three months and 2.9 ± 2.1 after six months. among group (ii) cases, the pain score reduced dramatically from 8.6 ± 1.3 to 5.8 ± 1.4 to 4.3 ± 2.6. conclusions: in patients with refractory interstitial cystitis/bladder discomfort syndrome, botulinum toxin-a injection combined with hyaluronic acid instillation improves pelvic pain and improves quality of life. key words: painful bladder syndrome; botulin toxin; hyaluronic acid. submitted 5 november 2022; accepted 19 november 2022 introduction interstitial cystitis/bladder pain syndrome (ic/bps) is a condition presenting pelvic pain and urinary storage symptoms like as urgency and frequency that has no recognized cause (1). the injury or dysfunction of the urothelium's glycosaminoglycan (gag) layer caused by urine diffusion hypothetically leads to sensory nerve activation, mast cell stimulation, and bladder inflammation (2). hyaluronic evaluation of pain and quality of life after hyaluronic acid instillation in addition to botulinum toxin-a injection in women with refractory interstitial cystitis/painful bladder syndrome: a pilot study ahmed fayez ghaith 1, mohamed hasan radwan 1, mohamed rasheed taha 1, mohamed ahmed elbendary 1, mahmoud elsayed al damhogy 2, ayman mohamed hagras 1 1 urology department, faculty of medicine, tanta university, tanta, egypt; 2 urology department, almogammaa altebby insurance hospital, tanta, egypt. doi: 10.4081/aiua.2022.4.447 summary archivio italiano di urologia e andrologia 2022; 94, 4 a. fayez ghaith, m. hasan radwan, m. rasheed taha, m. ahmed elbendary, m. elsayed al damhogy, a. mohamed hagras 448 was given to group (i) in addition to ha, while group (ii) received only ha. procedures routine laboratory testing and an abdominalpelvic ultrasonography were performed on all women. to rule out any pathology, a cystoscopy with hydrodistension (using semirigid cystoscopy at a pressure of 80 to 100 cm h2o for 1 to 2 minutes and up to 2 times) was performed at least one month prior to enrolment. bladder biopsies for suspected bladder granulations were performed in 11 instances. group (i) received a sub mucosal intravesical injection of 200 units of botulinum toxin-a (btx-a) in 20 locations of the superficial bladder muscles, including the trigone under spinal anesthesia. intravesical instillation of 40 mg/50 ml of hyaluronic acid was done every two weeks in all patients (groups i&ii) for a total of twelve sessions. the ha was administered to group (i) two weeks following the btx-a injection. after two weeks of ha implantation, patients were examined for any negative effects. before and after 3 and 6 months of treatment, all patients completed voiding diaries for four days, the international cystitis symptom index and problem index (icsi & icpi), the pelvic pain urgency/frequency patient symptom scale (puf), pelvic pain on a visual analogue scale (0-10 vas), and the candidates' quality of life (phq-9). ethical approval ethical approval was obtained from our local university ethical committee before enrollment (187/12/2016). informed consent was obtained from the patients before enrollment with full knowledge of risks and benefits of the study. statistics the student t-test and mean and standard deviation were used in statistical analysis, with p 0.05 considered significant (ibm spss statistics). results the survey was completed by 34 women, ranging in age from 37 to 63. inflammatory and mast cell infiltration were seen in bladder samples of 11 patients. all patients completed the questionnaires before therapy, three months after treatment, and six months later. treatment resulted in significant improvements in both groups as compared to pretreatment values (table 1). the improvement in group (i) was greater than the improvement in group (ii) (table 1). the pain severity (vas) of group (i) patients dropped dramatically from 8.5 ± 1.5 (pretreatment) to 3.9 ± 2.4 after 3 months and to 2.9 ± 2.1 after 6 months. also, in group (ii) patients, pain score (vas) improved from 8.6 ± 1.9 (pretreatment) to 5.8 ± 1.4 at 3 months and to 4.3 ± 2.6 at 6 months. furthermore, at 3 months (p = 0.041) and 6 months (p = 0.022), there was a substantial pain improvement (vas) in group (i) cases (btx-a+ ha) compared to group (ii) women (figure 1). in group (i) women, their quality of life changed dramatically from 9.7 ± 2.3 (before treatment) to 6.9 ± 1.9 (3 months) and to 5.7 ± 1.5 after 6 months. phq-9 scores for group (ii) patients changed from 9.8 ± 2.06 to 8.2 ± 1.8 and 7.9 ± 1.9 at 3 months and 6 months respectively. patients in group (i) had a much higher quality of life than patients in group (ii) (figure 2). table 1. reported data of the candidates of both groups: pre-treatment, at 3 months visit and 6 months post-treatment. pre-treatment 3 months 6 months p-value p-value post-treatment post-treatment pre/6-months gp i/ii 6 months post-treatment post-treatment vas (gp i) 8.5 ± 1.5 3.9 ± 2.4 2.9 ± 2.1 0.009 0.022 vas (gp ii) 8.6 ± 1.3 5.8 ± 1.4 4.2 ± 2.6 0.032 vv (gp i) 150.9 ± 26.4 185.6 ± 27.1 188.1 ± 39.9 0.002 0.019 vv (gp ii) 149.9 ± 27.9 162.8 ± 24.04 177.8 ± 26.5 0.033 freq. (gp i) 16.05 ± 2.4 11.7 ± 2.2 10.4 ± 1.3 0.0002 0.001 freq. (gp ii) 15.4 ± 2.5 12.9 ± 2.1 12.3 ± 2.02 0.010 icsi (gp i) 15.4 ± 3.4 10.5 ± 2.6 7.41 ± 2.2 0.0007 0.0008 icsi (gp ii) 15.7 ± 3.3 12.5 ± 2.9 11.1 ± 2.9 0.012 icpi (gp i) 13.1 ± 2.7 7.8 ± 2.01 6.2 ± 2.03 0.007 0.009 icpi (gp ii) 13.5 ± 2.5 9.5 ± 2.06 8.6 ± 1.8 0.036 puf (gp i) 20.4 ± 3.1 13.8 ± 3.00 11.9 ± 2.6 0.0004 0.001 puf (gp ii) 20.1 ± 3.4 16.8 ± 2.6 15.7 ± 3.06 0.001 phq (gp i) 9.7 ± 2.8 6.9 ± 1.9 5.7 ± 1.5 0.0007 0.0005 phq (gp ii) 9.8 ± 2.06 8.2 ± 1.8 7.9 ± 1.9 0.020 icsi: interstitial cystitis symptom index; icpi: interstitial cystitis problem index; phq-9: patient health questionnaire-9; puf: urgency/frequency patient symptom scale; vas: visual analogue scale; vv: voiding volume. figure 1. visual analogue scale in both groups. 449archivio italiano di urologia e andrologia 2022; 94, 4 hyaluronic acid in addition to botulinum toxin-a injection in refractory interstitial cystitis discussion pbs/ic (painful bladder syndrome/interstitial cystitis) is a disorder characterized by supra-pubic and/or bladder pain associated with bladder filling, as well as urine frequency and urgency, which has a significant impact on quality of life (2, 5). women are nine times more affected than men. because the actual etiology is complex and multifactorial, no consistent treatment method exists (6). infection, autoimmunity, defective urothelium, mast cell activation, neural inflammation, and other causes have all been suggested (7). the disruption of the glycosaminoglycan (gag) layer, which covers the bladder epithelium and acts as an impermeable barrier to solutes, may play a key role in pbs/ic pathogenesis (8). hydrated hyaluronic acid, heparin sulphate, dermatan sulphate, chondroitin sulphate, and keratin sulphate make up the gag layer (9). interstitial cystitis/bladder pain syndrome is linked to unfavorable cognitive, behavioral, and sexual outcomes, as well as bothersome urine symptoms (2). to address lower urinary tract symptoms, a variety of oral medications have been tried, including pentosan polysulfate sodium (pps), tricyclic antidepressants, and anti-muscarinics. intravesical therapy is commonly utilized as a second-line treatment for individuals who do not react to oral medication (3). many studies looked at the effectiveness of ha or btx-a alone, in conjunction with other medicines, or in combination with other techniques such hydrodistension. the results of adding btx-a to ha versus ha alone were compared in this study. in patients with refractory ic/pbs, we got a better response when we combined the two medicines. btx-a has been used to treat persistent pelvic pain, and preliminary results indicate that it is a safe therapeutic option with no severe side effects (10). intravesical ha was examined in women with refractory interstitial cystitis by hung et al. (1) in a prospective, multicenter study. after treatment, pain icsi, vas, and icpi scores improved significantly in 103 individuals. however, patients' bladder discomfort and storage symptoms improved at various speeds (74 percent vs. 48 percent; respectively). lower pain score and decreased bladder capacity were the characteristics that adversely affected treatment results, according to repeated statistical studies. in their randomized trial, kuo et al. (11) enrolled 67 patients with refractory ic/pbs. in patients with refractory ic/pbs, they found that intravesical injections of btx-a followed by hd had superior clinical results than hd alone. later, kuo et al. (12) in patients with ic/bps, intravesical injections of btx-a improved bladder pain symptoms. gao and liao (10) studied the efficacy of an intravesical injection of 100 u chinese btx-a followed by cystoscopic hydrodistension under general anesthesia in 124 women with ic/bps. they concluded that intravesical injections of chinese btx-a were a safe and effective treatment for ic/bps patients. furthermore, smith et al. (13) found that btx-a had an anti-nociceptive impact on the bladder, improving both symptoms and urodynamics. akiyama et al. (14) randomized 34 patients with refractory ic/bps into two groups: group a received immediate btx-a injections and group b received btx-a injections one month later. they concluded that btx-a injection could be an alternate treatment for refractory ic/bps patients. furthermore, shim et al. (15) demonstrated that btx-a injection is more effective for ic/bps pain control than placebo, with no differences in adverse effects. pinto et al. (16) also concluded that trigonal btx-a injection is a safe treatment for refractory bps/ic. according to kim et al. (17), the vas score, mean changes in the puf, icsi, and icpi all decreased significantly after 4 weeks of intravesical ha instillation. furthermore, akbay et al. (18) found that intravesical hyaluronic acid instillation alleviated symptoms in ic/bps patients on a short-term follow-up. lai et al. (4) compared four weekly 40 mg hyaluronic acid intravesical instillations followed by five monthly instillations to 12 intravesical instillations every two weeks. there was no significant difference between the two groups in terms of symptom scores or the quality-of-life index. furthermore, according to the findings of peng et al. (19), enhanced first desire to void and maximum cystometric capacity are linked to improved urinary symptoms after ha treatment. cervigni et al. (20) also looked at the efficacy of ha and chondroitin sulphate (cs) intravesical instillations in individuals with refractory pbs/ic. pain and urine symptoms such as urgency (p = 0.005), frequency (p = 0.045), and pain (p = 0.001) improved significantly. in their meta-analysis, pyo and cho (21) found that intravesical ha and ha/cs instillation improved pain symptoms and quality of life in patients with ic/bps. in individuals with ic/bps, liang et al. (22) found that pain and urine symptoms may improve after 6 months of intravesical ha therapy. there were no significant changes in the psychological and sexual functioning ratings at the time. lv and colleagues (23), in women with refractory severe pbs/ic, demonstrated that intravenous instillation of ha and al resulted in immediate and long-term allevifigure 2. health related quality of life in both groups. archivio italiano di urologia e andrologia 2022; 94, 4 a. fayez ghaith, m. hasan radwan, m. rasheed taha, m. ahmed elbendary, m. elsayed al damhogy, a. mohamed hagras 450 ation of symptoms. hyaluronic acid intravesical instillation was successful in reducing the degree of pain in women with refractory pbs/ic in the current pilot trial. botulinum toxin-a added to hyaluronic acid resulted in much higher quality of life and pain reduction than hyaluronic acid alone. this is the only publication that we are aware of that discussing the advantages of combining ha with btx-a injection for the treatment of ic/bps. limitations to the study a longer follow-up and larger number of patients should be considered in the upcoming studies. conclusions in patients with refractory interstitial cystitis/bladder discomfort syndrome, botulinum toxin-a injection combined with hyaluronic acid instillation improves pelvic pain and improves quality of life. references 1. hung mj, tsai cp, lin yh, et al. hyaluronic acid improves pain symptoms more than bladder storage symptoms in women with interstitial cystitis. taiwan j obstet gynecol. 2019; 58:417-422. 2. hanno p, lin a, nordling j, et al. bladder pain syndrome committee of the international consultation on incontinence. neurourol urodyn 2010; 29:191-198. 3. garzon s, laganà as, casarin j, et al. an update on treatment options for interstitial cystitis. prz menopauzalny 2020; 19:35-43. 4. lai mc, kuo yc, kuo hc. intravesical hyaluronic acid for interstitial cystitis/painful bladder syndrome: a comparative randomized assessment of different regimens. international journal of urology 2013; 20:203-207. 5. wein aj, hanno pm. targets for therapy of the painful bladder. urology 2002; 59:68-73. 6. jhang jf, kuo hc. novel treatment of chronic bladder pain syndrome and other pelvic pain disorders by onabotulinumtoxina injection. toxins (basel). 2015; 7:2232-50. 7. grover s, srivastava a, lee r, et al. role of inflammation in bladder function and interstitial cystitis. ther adv urol. 2011; 3:19-33. 8. parsons cl. the role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. urology 2007; 69:9-16. 9. teichman jm, moldwin r. the role of the bladder surface in interstitial cystitis/painful bladder syndrome. can j urol. 2007; 14:3599607. 10. gao y, liao l. intravesical injection of botulinum toxin a for treatment of interstitial cystitis/bladder pain syndrome: 10 years of experience at a single center in china. int urogynecol j 2015; 26:1021-1026. 11. kuo hc, chancellor mb. comparison of intravesical btx-a injections plus hd with hd alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. bju int. 2009; 104:657-61. 12. kuo hc, jiang yh, tsai yc, kuo y. intravesical botulinum toxina injections reduce bladder pain of interstitial cystitis/bladder pain syndrome refractory to conventional treatment a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. neurourol urodyn. 2016; 35:609-6014. 13. smith cp, radziszewski p, borkowski a, et al. botulinum toxin a has antinociceptive effects in treating interstitial cystitis. urology 2004; 64:871-875. 14. akiyama y, nomiya a, niimi a, et al. botulinum toxin type a injection for refractory interstitial cystitis: a randomized comparative study and predictors of treatment response. int j urol. 2015; 22:835-41. 15. shim sr, cho yj, shin is, kim j. efficacy and safety of botulinum toxin injection for interstitial cystitis/bladder pain syndrome: a systematic review and meta-analysis. int urol nephrol. 2016; 48:12151227. 16. pinto r, lopes t, frias b, et al. trigonal injection of botulinum toxin a in patients with refractory bladder pain syndrome/interstitial cystitis. european urology 2010; 58:360-365. 17. kim a, lim b, song m, choo m. pretreatment features to influence effectiveness of intravesical hyaluronic acid instillation in refractory interstitial cystitis/painful bladder syndrome. int neurourol j. 2014; 18:163-167. 18. akbay e, çayan s, kılınç c, et al. the short-term efficacy of intravesical instillation of hyaluronic acid treatment for bladder pain syndrome/interstitial cystitis. turk j urol. 2019; 45:129-34. 19. peng yc, chiu sy, feng m, liang c. the effect of intravesical hyaluronic acid therapy on urodynamic and clinical outcomes among women with interstitial cystitis/bladder pain syndrome. taiwan j obstet gynecol. 2020; 59:922-926. 20. cervigni m, natale f, nasta l, et al. a combined intravesical therapy with hyaluronic acid and chondroitin for refractory painful bladder syndrome/interstitial cystitis. int urogynecol j. 2008; 19:943-947. 21. pyo js, cho wj. systematic review and meta-analysis of intravesical hyaluronic acid and hyaluronic acid/chondroitin sulfate instillation for interstitial cystitis/painful bladder syndrome. cell physiol biochem. 2016; 39:1618-1625. 22. liang cc, lin yh, hsieh wc, huang l. urinary and psychological outcomes in women with interstitial cystitis/bladder pain syndrome following hyaluronic acid treatment. taiwanese journal of obstetrics & gynecology 2018; 57:360-363. 23. lv y, zhou h, mao h, et al. intravesical hyaluronic acid and alkalinized lidocaine for the treatment of severe painful bladder syndrome/interstitial cystitis. int urogynecol j. 2012; 23:1715-1720. correspondence ahmed fayez ghaith, md (corresponding author) dr_ahmedfayez@yahoo.com mohamed hasan radwan, md drradwanm@yahoo.com mohamed rasheed taha, md dr-rasheed@hotmail.com mohamed ahmed elbendary, md mbendary@hotmail.com ayman mohamed hagras, md ahagras80@yahoo.com urology department, faculty of medicine, tanta university, tanta (egypt) el-gharbia govenorate, tanta. el-gash st. medical campus, the faculty of medicine mahmoud elsayed al damhogy, md moodseg@gmail.com urology department, almogammaa altebby insurance hospital, tanta (egypt) stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13455 1 original paper nosed cases respectively (3-6). bca treatment depends on the tumor type and stage: neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy with pelvic lymph node dissections is considered the gold standard treatment for mibc, eventually associated to adjuvant platinum-based combined chemotherapy (7). in the metastatic setting combined method of chemotherapy, immunotherapy and targeted therapy can be used, but despite their therapeutic efficacy, they are characterized by several side effects and toxicity (8). bca has a high impact on the quality of life (qol) of patients and partners. nowadays, mobile applications (apps) represent a tool to support health behavior and provide medical information and/or management of different disease (9-12). apps can be downloaded from “play store” for android and “app store” for ios. nowadays their number is constantly growing, however despite this their quality assessments are still a problem. to avoid this, in the last years, a valid tool called mobile application rating scale (mars) has been developed. the second issue related to mha is their adherence to guidelines. to the best of our knowledge, there are no studies reporting the quality of apps for bca and their adherence to guidelines. the aim of this study is to evaluate the quality and the adherence to guidelines of mha developed to assist patients affected by bca. materials and methods search strategy we performed an observational cross-sectional descriptive study of all smartphone apps for patients about bc available on the ios and android platforms and evaluated their adherence to eau guidelines. on 24 sep 2024, we conintroduction: mobile health applications (mhas) represent a tool to assist patients affected by different disease including bladder cancer (bca), although the scientific quality and adherence to guidelines are not yet addressed. material and methods: on september 2024, we conducted a search in the apple app store and google play store. we reviewed all mobile apps from apple app store and google play store for bc and evaluated their usage in screening, prevention, management, and adherence to eau guidelines. results: in total 10 mha were reviewed. all mhas are geared towards the patient and provide information about diagnoses and treatment of bc. the mean score was 3.29 in engagement, 3.26 in functionality, 3.06 in aesthetics, 3.13 in information, and 3 in subjective quality respectively. mhas reported low and medium adherence to eau guidelines. conclusions: mhas provide different services in many medical fields, including bca. there are several drawbacks regarding scientific validation, content, and quality. future research is necessary to promote new user designed, and high-quality apps. key words: keywords: app; e-health; mobile phone; bladder cancer; mars. submitted 5 december 2024; accepted 21 december 2024 introduction bladder cancer (bca) represents one of the ten most diagnosed cancer worldwide with an incidence of 550.000 new cases per years and more than 200,000 deaths (1, 2). bca is classified into non-muscle-invasive bladder cancer (nmibc) and muscle-invasive bladder cancer (mibc) depending on the cellular infiltration of cancer cells in the muscular layer. nmib and mibc accounts for 75% and 25% of newly diaganalysis and adherence to guidelines of mobile health application for bladder cancer, where are we? roberto la rocca 1, ernesto di mauro 1, alfonso falcone 1, enrico sicignano 1, luigi cirillo 1, pasquale reccia 2, lorenzo romano 3, michelangelo olivetta 4, gennaro mattiello 5, felice crocetto 1, biagio barone 6, luigi de luca 7, ugo amicuzi 1, francesco mastrangelo 1, carmine turco 8, corrado aniello franzese 9, ferdinando fusco 3, davide arcaniolo 3, vincenzo maria altieri 10, luigi napolitano 11 1 department of neuroscience, reproductive and odontostomatological sciences, university of naples "federico ii", naples, italy; 2 urology unit, aorn ospedali dei colli, monaldi hospital, naples, italy; 3 department of woman, child and general and specialized surgery, unit of urology, university of campania "luigi vanvitelli", naples, italy; 4 urology unit, gaetano fucito hospital, aou san giovanni di dio e ruggi d'aragona, mercato san severino, italy; 5 division of urology, department of surgical sciences, aorn sant'anna e san sebastiano, caserta, italy; 6 department of urology, asl na1 centro, p.o. san paolo, naples, italy; 7 division of urology, department of surgical multispecialty, aorn antonio cardarelli, naples, italy; 8 department of urology, asl na1 centro ospedale del mare, naples, italy; 9 asl napoli 3 sud, naples, italy; 10 department of medicine and health sciences "v. tiberio", university of molise, campobasso, italy; 11 asl salerno, salerno, italy. doi: 10.4081/aiua.2025.13455 summary archivio italiano di urologia e andrologia 2025; 97(2):13455 r. la rocca, e. di mauro, a. falcone, et al. 2 ducted a search in google play store for android phones and apple app store for iphones with the keywords ‘bladder cancer’, ‘bladder cancer treatment’ and ‘bladder cancer diagnosis’ using the search tab. we used a wide array of keywords due to the search strategy of google play store and apple app store which is based on finding keywords in titles, app descriptions and tags. other searches of information provided in books or other formats were excluded. two authors (a.f., e.d.m.) screened separately in app store and google play store apps during the search by reading the title and description in the app store. a third author (l.n.) resolved any discrepancies. at the beginning all apps were reported in excel form and, according to the exclusion criteria, were screened. all mhas regarding bca, providing a service to patients, in english, and free to download were included in this analysis. apps not specifically focused on bca, apps not allowing access to all users and those not available in english were excluded. successively, all reviewers downloaded and installed the apps on their personal mobile device. they interacted for twenty minutes with each app to explore its features before completing the mars and evaluating their adherence to eau guidelines. to assess apps, they were downloaded to either an android or an ios device. if apps were available in both app stores, the ios version was assessed. according to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. a score of ‘‘0’’ indicated no adherence to guidelines. a score of ‘‘1’’ indicated a weak adherence. a score of ‘‘2’’ indicated a partial or moderate adherence. a score of ‘‘3’’ indicated strong adherence. where coding scores differed by 1 point, the average of the two ratings was taken. if there was a greater than 1-point discrepancy, a third author (a full professor) reviewed apps and resolved the discrepancy. the possible score on the checklist ranged from 0 to 15 for each app. to facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (10-15). a total of 78 apps were found by our search, of them 73 were from the google play store (android) and 5 of them were from the apple app store (ios). of the total, 72 apps were screened after removing duplicates and paid apps. of the total screened apps, 62 apps met excluding criteria and were removed. one app resulted in both stores. in total, 10 apps were eligible for the final evaluation and were downloaded. a flow diagram based on the prisma statement (figure 1) was included for the selected apps (13). figure 1. prisma. archivio italiano di urologia e andrologia 2025; 97(2):13455 3 guidelines of mobile health application for bladder cancer table 1 shows the analyzed apps characteristics. the bc apps were evaluated by four members of the research team on a 5-point likert scale based on mars characteristics. data extraction on 30 october 2024 reviewers, according to previous studies modality created a predefined excel form to collect data. the following data were extracted from mha: title, language, customers, costs, source (google play store or apple app store), field/disease, rating/feedback from the users and service provided. assessment of app quality and app adherence to eau guidelines mobile application rating scale (mars), and an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) based on eau guidelines were used to assess the mha quality and guidelines adherence as reported in our previous studies results in total 10 apps were included in the final analysis: 9 mha were in the google play store, and one from apple store. all apps provided information about treatment, 9 apps provided information about diagnosis. bladder cancer risk factors were mentioned in 9 mha as well. data about downloads were available for all mha. the most downloaded app was medscape in which more than five million of downloads were reported. all the apps were planned to be used by patients. rating was available only for 5 apps. cumulative mars scale scores are represented in table 2. engagement the score in this section was based on a 5-point likert scale in 5 subscales (entertainment, interest, customization, interactivity and target-group). the mean score was 3.29. scores ranged from 1.4 to 4.3 out of 5. the “manual of clinical oncology” app (android) produced by “unbond medicine, inc.” received the highest score for the engagement. this app contains interactive features for management and prevention of bladder cancer. it also contains information about surgical management, with eau tutorial videos explaining several surgical techniques. functionality the score of the functionality section was based on a 5point likert scale in 4 subscales (performance, ease of use, navigation and gestural design) and the mean score was 3.26. scores ranged from 1.5 to 4.6. “manual of clinical oncology” app (apple ios/android) achieved the maximum score. aesthetics the aesthetics section was formed by a 5-point likert scale in 3 subscales (layout, graphics, visual appeal) and the average score was 3.06. scores ranged from 1 to 4.6 out of 5 and “medscape” app produced by “webmd, llc” reached the maximum aesthetic score. table 1. apps characteristics. name of application download rating producer category bcan bladder cancer app 100+ n.a. bladder cancer advocacy network health and fitness nccn patients guides for cancer 10.000+ n.a. national comprehensive cancer network medicine oncoassist 10.000+ 4.5 portable medical technology ltd. medicine outcomes4me cancer care 100.000+ n.a. outcomes4me inc. health and fitness esmo interactive guidelines 10.000+ 4.2 european society for medical oncology medicine medscape 5 mln+ 4.7 webmd, llc medicine manual of clinical oncology 10.000+ n.a. unbond medicine, inc. medicine diseases dictionary oflline 1 mln + 4.4 ufostudio medicine diseases treatment dictionary 500.000+ 4.9 smart training medicine symptom checker 5000+ n.a. friendsapp listing medicine table 2. mars scale. app engagment functionally aesthetic information subjective quality app quality mean score section a section b section c section d section e (a+b+c+d) bcan bladder cancer app 3.6 3.3 3 3.4 3 3.3 nccn patients guides for cancer 4 4 3.7 3.3 3 3.7 oncoassist 1.6 1.7 2 1.6 2 1.7 outcomes4me cancer care 4 4.2 3.7 3.7 3 3.9 esmo interactive guidelines 4.2 4 4.3 4.3 4 4.2 medscape 4.2 4 4.6 4.3 4 4.3 manual of clinical oncology 4.3 4.6 4 4.3 4 4.3 diseases dictionary oflline 3.6 3.3 3 3.4 3 3.3 diseases treatment dictionary 2 2 1.3 2 2 1.8 symptom checker 1.4 1.5 1 1 2 1.2 archivio italiano di urologia e andrologia 2025; 97(2):13455 r. la rocca, e. di mauro, a. falcone, et al. 4 information the information section was formed by a 5-point likert scale in 7 subscales and the mean score was 3.13. score ranged from 1 to 4.3. three apps, “esmo interactive guidelines” produced by “european society for medical oncology”, “medscape” and “manual of clinical oncology”, reached the highest score in information. subjective quality the subjective quality section consisted of 4 items. the mean score was 3, with scores ranging from 2 to 4. “esmo interactive guidelines”, “medscape” and “manual of clinical oncology” apps reached the maximum score. eau adherence checklist we evaluated the eau guidelines adherence in 10 apps. eau adherence scores are represented in table 3. the bc definition was reported in 10 (100%) apps; physiopathology was reported in 9 (90%) apps; risk factors were reported in 9 (90%) apps; diagnosis was reported in 9 (90%) apps; treatment was reported in 10 (100%) apps. the maximum achievable score of 15 was reported by “nccn patients guides for cancer”, “outcomes4me cancer care”, “esmo interactive guidelines”, “medscape” and “manual of clinical oncology” apps. discussion this study represents the first attempt to evaluate the quality of mhas designed for bca and their adherence to eau guidelines. the findings provide valuable insights into the limitations and potential of these digital tools in supporting bca patients. several key observations emerge from our analysis, shedding light on both challenges and opportunities in utilizing mhas for this patient population. the overall quality of mhas for bca, as evaluated by the mobile application rating scale (mars), was higher than data from previous studies evaluating mhas for other health conditions. mean scores for categories such as “information,” “aesthetics” and “functionality” were 3.13, 3.06, and 3.26, respectively, reflecting good performance in areas critical to user engagement, learning and utility. interestingly, mhas that achieved higher scores in these categories were those developed with direct involvement of healthcare professional support. this finding aligns with prior research emphasizing the importance of interdisciplinary collaboration in creating effective and reliable digital tools (14-15). for instance, weiss et al. successfully developed an mha designed to provide education, symptom tracking, and alerts for patients undergoing radical cystectomy. their findings demonstrated the app’s feasibility, acceptability, and educational value, particularly in helping patients manage postoperative symptoms (16). similarly, other studies, such as those by tolstrup et al. and huelster et al., highlight the benefits of mhas co-developed with multidisciplinary teams. tolstrup et al. implemented a national multimodality app for bca patients that enables symptom monitoring, provides self-management advice, and facilitates communication during clinical encounters (17). huelster et al. explored the use of a mobile app combined with biometric monitoring to capture patient-reported symptoms and identify complications after radical cystectomy, demonstrating the potential of these tools to improve clinical outcomes (18). another notable example is the work by metcalf et al. which highlighted the feasibility of using a healthcare application to provide perioperative education and monitoring for patients undergoing radical cystectomy. in this pilot study, the app delivered educational content, such as detailed explanations of surgical options and postoperative care pathways, while monitoring patients through wearable devices (19). such examples demonstrate how mhas, when thoughtfully designed, can bridge significant gaps in patient education and postoperative care. the role of mhas extends beyond patient education and support to include contributions to research and data collection. smittenaar et al. demonstrated the feasibility of using crowdsourcing within an mha to analyze immunostained cancer samples for biomarker discovery. this innovative approach underscores the versatility of mhas not only as tools for patient care but also as platforms for advancing scientific research. the ability to engage patients in generating valuable clinical data highlights a dual role for these applications in improving individual outcomes and contributing to broader scientific understanding (12, 20). despite these promising examples, our study reveals significant gaps in the current landscape of mhas for bca. a major concern is the lack of adherence to eau guidelines, with less than one-third of the analyzed apps addressing essential topics such as bca definition, pathophysiology, risk factors, diagnosis, and treatment. table 3. adherence to eau guidelines. title definition pathophysiology risk factors diagnosys treatment (0-3) 0-3) (0-3) (0-3) (0-3) bcan bladder cancer app 2 2 3 2 2 nccn patients guides for cancer 3 3 3 3 3 oncoassist 2 1 0 1 2 outcomes4me cancer care 3 3 3 3 3 esmo interactive guidelines 3 3 3 3 3 medscape 3 3 3 3 3 manual of clinical oncology 3 3 3 3 3 diseases dictionary oflline 2 2 3 2 2 diseases treatment dictionary 2 3 2 2 2 symptom checker 1 0 1 0 2 archivio italiano di urologia e andrologia 2025; 97(2):13455 5 guidelines of mobile health application for bladder cancer this deficiency raises concerns about the reliability of these apps as educational resources and their potential to disseminate incomplete or misleading information. adherence to clinical guidelines must be a foundational requirement for all mhas to ensure they provide credible, accurate, and actionable information. notably, some apps have successfully integrated guideline-driven content. for example, beardo et al. developed appv, an mha specifically designed for the treatment and follow-up of nmibc. in a prospective study, appv demonstrated a 64% concordance rate with urologist-prescribed treatments, with higher agreement in low-risk cases (77%) compared to high-risk cases (17%). importantly, patients who adhered to treatment recommendations via appv had significantly better outcomes, with 89.1% remaining recurrence-free compared to 61.1% in cases of disagreement. this example underscores the potential of mhas to improve adherence to treatment guidelines and enhance clinical outcomes when they are aligned with evidence-based practices (21). the challenges faced by bca patients, including navigating complex treatment pathways, managing postoperative symptoms, and coping with the psychological burden of the disease, further emphasize the need for well-designed mhas (22, 23). these tools have immense potential to bridge gaps in education and support, empowering patients to better understand their condition and make informed decisions. however, the current shortcomings in quality, usability, and adherence to clinical guidelines undermine this potential. addressing these challenges requires a multifaceted approach. first, partnerships with clinical experts and healthcare institutions are crucial for the co-development of mhas that are evidence-based and patient-centered. collaboration with professionals ensures that these tools reflect the latest medical standards and adequately address the specific needs of bca patients. incorporating expert-reviewed content and designing features that align with real-world clinical scenarios can significantly enhance the credibility and utility of mhas (12, 25-25). second, the promotion of standardized quality assessment frameworks, such as mars, is vital for improving the overall quality of mhas (12, 26). these frameworks should be integrated into both the development and evaluation processes, enabling systematic assessment of app performance, usability, and content accuracy (27). regular use of mars can help developers identify and address shortcomings early, ensuring that final products meet high standards of quality and reliability (28). third, content accuracy must be prioritized by adhering comprehensively to eau or equivalent guidelines. developers should focus on creating comprehensive, guideline-driven content to ensure that patients receive accurate and actionable information. this step is particularly important given the complexity of bca treatment pathways and the need for patients to make informed decisions about their care (29). lastly, user engagement is a critical determinant of an mha’s success. incorporating interactive and personalized features, such as symptom tracking, treatment reminders, and tailored educational content, can make these tools more appealing and better suited to the diverse needs of bca patients (30). additionally, feedback mechanisms can help developers refine app features based on user preferences and experiences, further enhancing their effectiveness. expanding research efforts to evaluate the real-world impact of mhas is also essential for their continued development and refinement. longitudinal studies focusing on outcomes such as treatment adherence, quality of life, patient satisfaction, and clinical results will provide valuable insights into the effectiveness of these tools. this research can inform the development of new features and functionalities that address unmet patient needs, ultimately driving the evolution of mhas into indispensable resources for bca care. conclusions this study represents a significant first step in evaluating the quality and adherence to clinical guidelines of mhas designed for bca patients. the findings highlight the current limitations of these digital tools, particularly in terms of their quality and adherence to eau guidelines. despite the growing number of mhas available, most of the apps analyzed demonstrated suboptimal performance, with low mars scores in key categories such as information, aesthetics, and functionality. furthermore, less than onethird of the apps adhered to essential bca guidelines, raising concerns about their reliability and potential impact on patient care. while some apps showed promise by integrating guideline-driven content, the overall landscape remains underdeveloped, with significant gaps in content accuracy and usability. to fully harness the potential of mhas in supporting bca patients, it is essential to prioritize partnerships with healthcare professionals to ensure that these tools are evidence-based, user-friendly, and aligned with clinical standards. standardized quality assessment frameworks like mars should be consistently applied during both development and evaluation stages to ensure high-quality outputs. future efforts should focus on refining content accuracy, enhancing user engagement, and conducting real-world evaluations of mhas’ impact on patient outcomes, such as treatment adherence and quality of life. by 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211:266-275. 15. tolstrup lk, als ab, carus a, et al. the iblad app protocol a national, exploratory study on a multimodality smartphone app in bladder cancer for better understanding symptoms, quality of life and need for supportive care. acta oncol. 2023; 62:329-333. 16. huelster hl, zemp l, turner k, et al. mobile postoperative symptom intervention tool and biometric monitoring after radical cystectomy: pilot study evaluating feasibility, usability, and potential utility. j urol. 2023; 209:410-421. 17. metcalf m, glazyrine v, glavin k, et al. the feasibility of a health care application in the treatment of patients undergoing radical cystectomy. j urol. 2019; 201:902-908. 18. smittenaar p, walker ak, mcgill s, et al. harnessing citizen science through mobile phone technology to screen for immunohistochemical biomarkers in bladder cancer. br j cancer. 2018; 119:220229. 19. beardo p, pinto r, ayerra h, et al. optimizing treatment for non muscle-invasive bladder cancer with an app. actas urol esp (engl ed). 2022; 46:230-237. 20. catto jwf, downing a, mason s, et al. quality of life after bladder cancer: a cross-sectional survey of patient-reported outcomes. eur urol. 2021; 79:621-632. 21. barone b, napolitano l, reccia p, et al. advances in urinary diversion: from cutaneous ureterostomy to orthotopic neobladder reconstruction-a comprehensive review. j pers med. 2024; 14:392. 22. mannino rg, arconada alvarez sj, greenleaf m, et al. navigating the complexities of mobile medical app development from idea to launch, a guide for clinicians and biomedical researchers. bmc med. 2023; 21:109. 23. siegler aj, knox j, bauermeister ja, et al. mobile app development in health research: pitfalls and solutions. mhealth. 2021; 7:32. 24. deniz-garcia a, fabelo h, rodriguez-almeida aj, et al. quality, usability, and effectiveness of mhealth apps and the role of artificial intelligence: current scenario and challenges. j med internet res. 2023; 25:e44030. 25. giebel gd, speckemeier c, schrader nf, et al. quality assessment of mhealth apps: a scoping review. front. health serv. 2024; 4:1372871. 26. stoyanov sr, hides l, kavanagh dj, et al. mobile app rating scale: a new tool for assessing the quality of health mobile apps. jmir mhealth uhealth. 2015; 3:e27. 27. alfred witjes j, max bruins h, carrión a, et al. european association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. eur urol. 2024; 85:17-31. 28. oakley-girvan i, yunis r, longmire m, ouillon js. what works best to engage participants in mobile app interventions and ehealth: a scoping review. telemed. j. e health 2022; 28:768. 29. amor-garcía má, collado-borrell r, escudero-vilaplana v, et al. declarations ethical approval: not applicable. consent for publication: not applicable. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: this research received no external funding. authors' contributions: edm, af, es, lc, pr, lr, mo, gm, fc, bb, ldl: data analysis and interpretation, rlr, vma, ln: study concept ,manuscript original drafting; bb, ua:statistical analyses, fm, ct, histological examination, caf, ff, da: contribution to manuscript writing and editing. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13455 7 guidelines of mobile health application for bladder cancer assessing apps for patients with genitourinary tumors using the mobile application rating scale (mars): systematic search in app stores and content analysis. jmir mhealth uhealth 2020; 8:e17609. 30. raphael j, trudeau me, chan k. outcome of patients with pregnancy during or after breast cancer: a review of the recent literature. curr oncol. 2015; 22(suppl 1):s8-s18. correspondence roberto la rocca robertolarocca87@gmail.com ernesto di mauro ernestodm9@gmail.com alfonso falcone alfonso.falcone01@gmail.com enrico sicignano enrisici90@gmail.com luigi cirillo cirilloluigi22@gmail.com felice crocetto felice.crocetto@gmail.com ugo amicuzi u.amicuzi@gmail.com francesco mastrangelo department of neuroscience, reproductive and odontostomatological sciences, university of naples "federico ii", via pansini, 80138 naples, italy pasquale reccia reccia.pasquale1@gmail.com urology unit, aorn ospedali dei colli, monaldi hospital, 80131 naples, italy lorenzo romano loryromano@hotmail.it ferdinando fusco ferdinando-fusco@libero.it davide arcaniolo davide.arcaniolo@unicampania.it department of woman, child and general and specialized surgery, unit of urology, university of campania "luigi vanvitelli", naples, italy michelangelo olivetta olivetta.drmichelangelo@gmail.com urology unit, gaetano fucito hospital, aou san giovanni di dio e ruggi d'aragona, 84085 mercato san severino, italy gennaro mattiello drmattiellogennaro@gmail.com division of urology, department of surgical sciences, aorn sant'anna e san sebastiano, 81100 caserta, italy biagio barone biagio193@gmail.com department of urology, asl na1 centro, p.o. san paolo, 80125 naples, italy luigi de luca luigideluca86@gmail.com division of urology, department of surgical multispecialty, aorn antonio cardarelli, 80131 naples, italy carmine turco car.turco87@gmail.com department of urology, asl na1 centro ospedale del mare, 80147 naples, italy corrado aniello franzese corradofranzese@libero.it asl napoli 3 sud, naples vincenzo maria altieri vincenzomaria.altieri@gmail.com department of medicine and health sciences "v. tiberio", university of molise, 86100 campobasso, italy luigi napolitano dr.luiginapolitano@gmail.com asl salerno, salerno, italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12387 1 letter to editor submitted 4 july 2024; accepted 6 july 2024 to the editor nowadays male infertility is considered one of the most important “diseases” worldwide (1). more than 15% of couples are infertile, in half of these cases it is related to male factors, and in approximately 60% of idiopathic male infertility it is closely related to decreased sperm motility (2). mitochondria are particularly structurally and functionally organelles in male gametes, involved into adenosine triphosphate (atp) production through oxidative phosphorylation (oxphos) to support sperm mobility, production of steroid hormones in the testis, regulation of cell proliferation, regulation of reactive oxidation species (ros) signaling, calcium homeostasis, capacitation, acrosome reaction, and metabolism (3, 4). approximately 80 mitochondria are present in the midpiece of spermatozoa (5). to the best of our knowledge mitochondrial dysfunction is often associated with the aging process and it is related to several diseases, includes male infertility (6). oxidative stress (os) due to the overproduction of ros in mitochondria is one of the major causes of these disorders accounting approximately 30-80% of male infertility (7). exposure to ros induces structural and functional damage in proteins, membrane, calcium homeostasis, dna in spermatozoa, and this affects sperm motility, ability to penetrate oocytes, and embryonic development (7-10). even though the exact mechanisms of mitochondrial dysfunction in male fertility impairment remains still unclear, it is known that age-dependent alterations of the epididymis can cause alterations in sperm mitochondrial functioning (11, 12). mitochondrial are involved into all spermatogenesis and fertilization mechanisms: sperm motility, gamete production, steroid hormone production, cell signaling, proliferation, epigenetic regulation, cell differentiation and cell death (6). steroidogenesis involves the mobilization of cholesterol from lipid droplets and/or the plasma membrane, its transportation into mitochondria under the pulsatile secretion of lh and consequent camp production, the formation of pregnenolone within the mitochondria, and the subsequent conversion of pregnenolone into the ultimate steroid products by enzymes located in the smooth endoplasmic reticulum (13). spermatozoa’s ability to move relies entirely on the functionality of the oxphos pathways (14). given that sperm mitochondrial dna (mtdna) contains genes that encode oxphos-related proteins, any deviation in mtdna could potentially affect sperm motility. in the last twenty years, research has emphasized the connection between the quality of mtdna and sperm motility by examining mutations, duplications, and deletions in human sperm mtdna (15). these investigations have shown that point mutations, single nucleotide polymorphisms (snps), and haplogroups within mtdna can significantly impair semen quality (16). sperm mitochondrial deletion is a marker of mtdna integrity and damage. men with suboptimal semen parameters tend to exhibit a higher prevalence of sperm mitochondrial dna deletions compared to men with normal sperm parameters (17). the sperm mitochondrial dna copy number, representing the number of mtdna copies per nuclear dna copy, serves as a sensitive biomarker of male fertility. variations in human mtdna copy numbers are linked to decreased sperm motility and fertility decline (18). finally, oxidative stress initiates the spermatozoa's progression along the intrinsic apoptotic pathway, starting from the loss of mitochondrial membrane potential (mmp), which leads to the formation of oxidative dna adducts, dna fragmentation, and ultimately culminates in cell death (19). several oral supplements have been proposed in male infertility treatments as well as l-carnitine, arginine, alpha-lipoic acid, coenzyme q10, vitamins, zinc, selenium, and they regulate mitochondrial homeostasis. coenzyme q10 (coq10) is abundant in mitochondria and plays a crucial role in the electron transport chain, facilitating atp production. additionally, coq10 possesses potent antioxidant properties that can potentially surpass those of cellular antioxidants how much does mitochondrial dysfunction affect male infertility? ernesto di mauro 1, gianluigi cacace 1, vincenzo morgera 1, roberto la rocca 1, luigi napolitano 1, pietro saldutto 2, vincenzo maria altieri 2, 3 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 2 uo urologia, humanitas gavazzeni, bergamo, italy; 3 unimol, campobasso, italy. doi: 10.4081/aiua.2024.12387 archivio italiano di urologia e andrologia 2024; 96(3):12387 e. di mauro, g. cacace, v. morgera, et al. 2 such as tocopherol and resveratrol, making it effective in countering attacks from ros (20, 21). carnitine plays an important role in fatty acid metabolism by transporting fatty acids across the mitochondrial membrane (22). vitamin d prevents protein oxidation, lipid peroxidation, autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetic modifications, dna abnormalities, and calcium and ros signaling (23). due to the pivotal role of mitochondria in sperm motility and overall fertility, assessing mitochondrial functionality becomes an essential topic in male infertility treatment, aiding in the development of targeted interventions to improve reproductive outcomes. furthermore, several randomized controlled trial, in vitro and in vivo studies research are necessary to better highlighted their involvement in the physiopathology of infertility. acknowledgments this publication was produced with the co-funding european union next generation eu, in the context of the national recovery and resilience plan, investment partenariato esteso pe8 "conseguenze e sfide dell'invecchiamento", project age-it (ageing well in an ageing society). references 1. leslie sw, soon-sutton tl, khan ma. male infertility. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2024 [cited 2024 mar 3]. available from: http://www.ncbi.nlm.nih.gov/books/nbk562258/ 2. park yj, lee bm, pang wk, ryu dy, et al. low sperm motility is determined by abnormal protein modification during epididymal maturation. world j mens health. 2022; 40:526. 3. park yj, pang mg. mitochondrial functionality in male fertility: from spermatogenesis to fertilization. antioxidants. 2021; 10:98. 4. shivaji s, kota v, siva ab. the role of mitochondrial proteins in sperm capacitation. journal of reproductive immunology. 2009; 83:14-8. 5. freitas mj, vijayaraghavan s, fardilha m. signaling mechanisms in mammalian sperm motility. biol reprod. 2017; 96:2-12. 6. durairajanayagam d, singh d, agarwal a, henkel r. causes and consequences of sperm mitochondrial dysfunction. andrologia. 2021; 53:e13666. 7. agarwal a, virk g, ong c, du plessis ss. effect of oxidative stress on male reproduction. world j mens health. 2014; 32:1. 8. mclachlan ri, kretser dm. male infertility: the case for continued research: even with modern assisted-reproduction technologies, clinical assessment and basic research on male infertility are essential. medical journal of australia. 2001; 174:116-7. 9. fusco gm, cirillo l, abate m, et al. male infertility, what mobile health applications “know”: quality analysis and adherence to european association of urology guidelines. arch ital urol androl. 2022; 94:470-5. 10. pereira r, sá r, barros a, sousa m. major regulatory mechanisms involved in sperm motility. asian j androl. 2017; 19:5. 11. wang jj, wang sx, tehmina, et al. age-related decline of male fertility: mitochondrial dysfunction and the antioxidant interventions. pharmaceuticals. 2022; 15:519. 12. fusco f, longo n, de sio m, et al. impact of circadian desynchrony on spermatogenesis: a mini review. front endocrinol (lausanne). 2021; 12:800693. 13. wang y, chen f, ye l, et al. steroidogenesis in leydig cells: effects of aging and environmental factors. reproduction. 2017; 154:r111-22. 14. ruiz-pesini e, lapeña ac, díez-sánchez c, et al. human mtdna haplogroups associated with high or reduced spermatozoa motility. am j hum genet. 2000; 67:682-96. 15. amaral a, lourenço b, marques m, ramalho-santos j. mitochondria functionality and sperm quality. reproduction. 2013; 146:r163-74. 16. kumar p, sangeetha n. mitochondrial dna mutations and male infertility. indian j hum genet. 2009; 15:93. 17. ieremiadou f, rodakis gc. correlation of the 4977 bp mitochondrial dna deletion with human sperm dysfunction. bmc res notes. 2009; 2:18. 18. faja s, nelson darling l. variation in restricted and repetitive behaviors and interests relates to inhibitory control and shifting in children with autism spectrum disorder. autism. 2019; 23:1262-72. 19. aitken ml, limaye a, pottinger p, et al. respiratory outbreak of mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center. am j respir crit care med. 2012; 185:231-2. 20. tiwari s, mohanty tk, bhakat m, et al. comparative evidence support better antioxidant efficacy of mitochondrial-targeted (mitoquinone) than cytosolic (resveratrol) antioxidant in improving in-vitro sperm functions of cryopreserved buffalo (bubalus bubalis) semen. cryobiology. 2021; 101:125-34. 21. el-sherbiny hr, abdelnaby ea, el-shahat kh, et al. coenzyme q10 supplementation enhances testicular volume and hemodynamics, reproductive hormones, sperm quality, and seminal antioxidant capacity in goat bucks under summer hot humid conditions. vet res commun. 2022; 46:1245-57. archivio italiano di urologia e andrologia 2024; 96(3):12387 3 the mitochondrial role in male infertility 22. yang k, wang n, guo ht, et al. effect of l-carnitine on sperm quality during liquid storage of boar semen. asian-australas j anim sci. 2020; 33:1763-9. 23. matta reddy a, iqbal m, chopra h, et al. pivotal role of vitamin d in mitochondrial health, cardiac function, and human reproduction. excli j. 2022; 21:967-990. correspondence ernesto di mauro, md ernesto.dimauro@unina.it gianluigi cacace, md cacace.gianlu@gmail.com vincenzo morgera, md vincemorgera87@gmail.com roberto la rocca, md robertolarocca87@gmail.com luigi napolitano (corresponding author) dr.luiginapolitano@gmail.com department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy pietro saldutto, md pietro.saldutto@gavazzeni.it vincenzo maria altieri, md vincenzomaria.altieri@gmail.com uo urologia, humanitas gavazzeni, bergamo, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14153 1 original paper mv has become the gold standard surgical procedure for varicocele because it is associated with the lowest risk of complications (varicocele recurrence, hydrocele formation (fluid collection around the testicle) and testicular atrophy) (10-12). microsurgical varicolectomy is superior in identifying and preserving arteries and lymphatic vessels by enlarging the spermatic cord through a microscope. mv also helps identify small spermatic veins that will later be ligated. increased magnification can improve anatomical detail and reduce complications. currently, micro-varicocelectomy is performed using a vitom 2d, but it has limitations. the limitations include a narrow or circular view with magnification up to 7x and 2d images, which can differ in orientation from reality, especially regarding distance and depth. the use of a microscope sometimes causes surgeons to work in a nonergonomic manner. to overcome these weaknesses, we innovated by using a 3d video exoscope combined with a microscope, which provides greater magnification, better resolution images, and a more accurate orientation. case presentations case 1 a 15-year-old male with left testicular pain. he is unmarried. physical examination revealed dilated veins during the valsalva maneuver in the left scrotum, confirmed by a scrotal ultrasound showing a grade 2 left varicocele. the patient was scheduled for a left 3d mv. case 2 a 31-year-old male with infertility. he reported no ejaculation problems and has been married for 4 years, with no obstetric issues in his wife. a physical examination revealed bilateral varicoceles, which were confirmed by an ultrasound that demonstrated grade 3 right varicocele and grade 2 left varicocele. semen analysis showed oligoasthenoteratozoospermia (oat). the patient was diagnosed with primary infertility, moderate oat, and bilateral varicocele. he was scheduled for bilateral 3d mv. case 3 a 32-year-old male with infertility. he reported no ejaculation problems and has been married for 5 years, with no introduction:varicocele affects 10-15% of adult males, and is linked to infertility (35%) and testicular pain (10%). microsurgical varicocelectomy (mv) is considered the gold standard treatment due to its low complication rates and superior anatomical outcomes. however, conventional mv using a 2d exoscope presents limitations in image depth and surgeon ergonomics. this study presents the use of a 3d video exoscope as a novel tool to enhance visualization and ergonomics during mv. materials and methods: we report a series of four patients undergoing 3d-assisted microsurgical varicocelectomy using a zeiss microscope integrated with a 3d video exoscope system. patients presented with either infertility, testicular pain, or both, with varicocele diagnoses confirmed by physical examination and ultrasound. procedures were performed subinguinally with arteryand lymphatic-sparing techniques, and the ergonomics and image quality were assessed. results: all surgeries were successfully completed with the aid of the 3d exoscope. surgeons reported improved ergonomics, reduced neck and back strain, and enhanced image depth and clarity. the system allowed for up to 10x optical magnification, full-screen uhd 3d visualization, and a wide field of view. no intraoperative complications were noted. patients tolerated the procedure well, and early outcomes were favorable in terms of symptom relief and semen parameter improvement. conclusions: the integration of a 3d video exoscope in microsurgical varicocelectomy is a promising innovation. it offers superior image quality, improved surgeon comfort, and may enhance surgical precision. further studies with larger cohorts and long-term follow-up are warranted to validate these findings. key words: innovation exoscope; microsurgical varicolectomy; 3d video exoscope. submitted 18 july 2025; accepted 27 july 2025 introduction the prevalence of varicocele is approximately 10%-15% in the adult male population; approximately 35% of cases are associated with infertility, and 10% of cases are associated with testicular pain (1). the surgical treatment options for varicocele are numerous, including open ligation (2, 3), laparoscopic high ligation (4, 5), microsurgical varicocelectomy (mv) (6, 7), and embolization of the spermatic vein (8, 9). new innovative use of 3d video exoscope in microsurgical varicocelectomy: a case series paksi satyagraha 1, gede wirya kusuma duarsa 2, besut daryanto 1, edvin prawira negara 1, zaidan arifiansyah bachtiar 1, haryo nindito wicaksono 1 1 department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia; 2 department of urology, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia. doi: 10.4081/aiua.2025.14153 summary archivio italiano di urologia e andrologia 2025; 97(3):14153 p. satyagraha, g. wirya kusuma duarsa, b. daryanto, et al. 2 obstetric issues in his wife. he failed an in-vitro fertilization program (ivf) 8 months ago. physical examination revealed palpable veins during the valsalva maneuver, confirmed by ultrasound as bilateral varicocele grade 3. semen analysis showed severe oligoasthenoteratozoospermia. the patient was diagnosed with primary infertility, severe oat, and bilateral varicocele. he was scheduled for bilateral 3d mv. case 4 a 35-year-old male with left testicular pain and no children, married for 7 years, with no obstetric issues in his wife. physical examination revealed palpable veins during the valsalva maneuver, confirmed by ultrasound as bilateral varicocele (grade 3 for left testicle and grade 4 for right testicle). semen analysis showed severe oligoasthenoteratozoospermia. the patient was diagnosed with primary infertility, severe oat, and bilateral varicocele. he was scheduled for bilateral 3d mv. tomy was performed using a zeiss microscope and a 3d exoscope (figure 1). the main binocular was replaced with a 3d exoscope, which acts as a camera receiving images from the microscope. the images are processed by a computer and converted into 3d, displayed on a 3d monitor, and viewed by the operator using 3d glasses. the assistant's monitor, connected via hdmi, shows 2d images of the same quality as the operator's. both displays achieve uhd quality and can optically zoom up to 10x for clearer and more detailed images. the wide view from the exoscope's video output allows for comprehensive observation, facilitating teaching for residents and shortening the learning curve. (figure 2). discussion varicocele has long been known to affect men's physical and mental health, with surgical techniques evolving over nearly a century. surgical treatment for infertility or pain caused by varicocele has been widely promoted by clinicians and guidelines worldwide. a more precise and minimally invasive surgical technique called microscopic subinguinal varicocelectomy was first described by goldstein et al. (6) in 1992. the patient experienced fewer difficulties and a better prognosis after all veins were surgically tied off one by one under a microscope while maintaining the lymphatics and arteries. ito et al. (13) (1993) and marmar and kim (14) (1994) both used microscopic subinguinal varicocelectomy with lymphatic and artery sparing. they noted fewer problems, a high success rate, and more precise ligation. consequently, open surgery, microscopic varicocelectomy, laparoscopic varicocelectomy, and varicocele embolization the four fundamental surgical ideas for treating varicocele were established. microvaricolectomy surgery offers a great improvement over open surgery. it is possible to achieve vein ligation and artery and lymphatic vessel protection with the use of a microscope. the surgical approach produces the figure 1. a. overall view of the operative field. b. operator’s monitor using 3d monitor 55”. c. assistant’s monitor using 2d monitor 32”. figure 2. operating theatre 3d microvaricolecomy. archivio italiano di urologia e andrologia 2025; 97(3):14153 3 3d video exoscope in microsurgical varicocelectomy best results in terms of safeguarding the testicular blood flow and minimizing postoperative problems, although requiring a longer duration of surgery. additionally, mv has clear benefits over other treatments, such as a better prognosis and fewer problems, which have led to clinicians all around the world choosing this procedure (15-20). previous innovative tools have been used in varicocele surgery like 2d exoscope, but it has some problems like less ergonomic position, low of deep of field and field of view, so, we introduced a new tool for mv by using three-dimensional (3d) exoscope (21),which offers superior optical magnification, image quality, and depth perception (table 1). these devices replace a standard microscope's optics with a stereo video camera. the final image is displayed on a high-definition monitor so that depth perception can be seen through polarised glasses. in the field of neurosurgery, the 3d exoscope was initially introduced as a substitute for the traditional operating microscope. the authors observed that the exoscope provided excellent comfort for all procedures carried out and that the image quality was comparable to that of a standard operating microscope. several other studies have demonstrated that the 3d-exoscope may prove superior to the operating microscope in terms of depth of focus, image quality, and ergonomics (22). with the help of two hd-3d monitors positioned on either side of the principal and assistant, the exoscope system provides superior 3d visualization for both observers and surgeons via the use of special 3d glasses, making it an excellent teaching tool for residents and students. traditional tools and crank stem instruments can be easily transferred from the scrub nurse to the primary surgeon because of the exoscope's larger working area (23). micro-macro vision switches and long instruments used by the surgeon during spinal instrumented procedures may be the ideal situation (24). additionally, there is no contamination or image degradation from blood on the lens during surgery because of the camera's greater distance from the surgical site. ergonomics is a useful tool for researching the likelihood of musculoskeletal problems and provides strategies for preventing and treating them when they do arise. surgeons who use an operating microscope may be more susceptible to musculoskeletal injuries (msi) because of their prolonged standing and fixed posture (head and back bending), which puts more mechanical strain on their neck and lower back. one of the unique advantages of the 3d exoscope is that it significantly improves the ergonomics and body mechanics of the participants. when surgeons flexed the neck 30 degrees beyond neutral the weight imparted to the cervical vertebrae increased 4 times (24). through 4k 3d monitors, surgeons were able to position the exoscope at any necessary angle while maintaining a comfortable, upright, and neutral posture, which may ultimately help reduce surgical errors and times. the previous preliminary study by using vitom® 3d also showed comfort and ergonomics position for the operators (25). despite several guidelines for improving ergonomics in health care, there are still large gaps in the knowledge and practice of ergonomic principles in surgical settings (26, 27). few articles have assessed the objective ergonomics in 3d exoscope-based procedures. we aimed to narrow this knowledge gap and showed that reba rated the exoscope to be superior to the om in mis-tlif (5.00 1.26 vs 6.05 1.39, p = 0.017). the lack of awareness and training is the primary driver of poor ergonomics. herein lies the opportunity to prevent msi. some articles provide suggestions for protecting msi by correcting education in or ergonomics and monitoring specific self-therapy exercises for individual musculoskeletal assets (28, 29). additionally, in some literature, it is advised to reduce msi, including the use of ergonomic equipment such as an exoscope and proper ergonomic positioning for the medical service provider, not just taking analgesics to relieve msi symptoms (30, 31) (figure 3). table 1. resolution and position om + 3d exoscope vs vitom 2d. system vitom 2d opmi sensera (karl storz, germany) (zeiss, germany) and 3d exoscope illumination xenon xenon magnification (optical zoom) x 7 x 10 image quality hd or 4k uhd 3d 4k uhd field of view (mm) 50–150 170 field of view monitor circle full screen operator position standing sitting portability portable base suspension system manual setup floor stand/ceiling mount depth of field (mm) 35–100 200–415 source: duarsa, gwk et al, 2023. figure 3. surgical ergonomic 3d varicolectomy. archivio italiano di urologia e andrologia 2025; 97(3):14153 p. satyagraha, g. wirya kusuma duarsa, b. daryanto, et al. 4 conclusions innovative tools used in varicocele surgery include the 3d exoscope. the exoscope provided excellent comfort for all procedures carried out, and the image quality is two hd-3d. 3d exoscope significantly improves the ergonomics and body mechanics. references 1. minhas s, bettocchi c, boeri l et al., european association of urology guidelines on male sexual and reproductive health: 2021 update on male infertility, eur urol 2021; 80:603-20. 2. palomo a. radical cure of varicocele by a new technique: preliminary report, j urol1949; 61:604-7. 3. ivanissevich o. left varicocele caused by reflux. study based on 42 years of clinicosurgical experience with 4470 operated cases. la semana medica 1961; 118:1157-70. 4. mehan dj, andrus ch, parra ro. laparoscopic internal spermatic vein ligation: report of a new technique. fertil steril 1992; 58:1263-66. 5. mandressi a, buizza c, antonelli d, chisena s. is laparoscopy a worthy method to treat varicocele? comparison between 160 cases of two-port laparoscopic and 120 cases of open inguinal spermatic vein ligation. j endourol 1996; 10:435-41. 6. goldstein m, gilbert br, dicker ap, et al. microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique, j urol 1992; 148:180811. 7. marmar jl, kim y. subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. j urol 1994; 152:1127-32. 8. tauber r, johnsen n. antegrade scrotal sclerotherapy for the treatment of varicocele: technique and late results. j urol 1994; 151:386-90. 9. yavetz h, levy r, papo j, et al. efficacy of varicocele embolization versus ligation of the left internal spermatic vein for improvement of sperm quality, int j androl 1992; 15:338-44. 10. murray rr, mitchell se, kadir s, et al. comparison of recurrent varicocele anatomy following surgery and percutaneous balloon occlusion. j urol 1986; 135:286-9. 11. cayan s, kadioglu tc, tefekli a, et al. comparison of results and complications of high ligation surgery and microsurgical high inguinal varicocelectomy in the treatment of varicocele. urology 2000; 55:750-4. 12. ito h, kotake t, hamano m, yanagi s. results obtained from microsurgical therapy of varicocele. urol int 1993; 51:225-27. 13. miersch wd, schoeneich g, winter p, buszello h. laparoscopic varicocelectomy: indication, technique and surgical results. br j urol 1995; 76:636-38. 14. watanabe m, nagai a, kusumi n et al. minimal invasiveness and effectivity of subinguinal microscopic varicocelectomy: a comparative study with retroperitoneal high and laparoscopic approaches. int j urol 2005; 12:892-98. 15. al-kandari am, shabaan h, ibrahim hm, et al. comparison of outcomes of different varicocelectomy techniques: open inguinal, laparoscopic, and subinguinal microscopic varicocelectomy: a randomized clinical trial. urology 2007; 69:41720. 16. testini m, miniello s, piccinni g, et al. microsurgical treatment of varicocele in outpatients using the subinguinal approach, minerva chirurgica 2001; 56:655-59. 17. jungwirth a, gogus c, hauser g, et al. clinical outcome of microsurgical subinguinal varicocelectomy in infertile men,andrologia 2001; 33:71-4. 18. ghanem h, anis t, el-nashar a, shamloul r. subinguinal microvaricocelectomy versus retroperitoneal varicocelectomy: comparative study of complications and surgical outcome. urology 2004; 64:1005-9. 19. zini a, blumenfeld a, libman j, willis j. beneficial effect of microsurgical varicocelectomy on human sperm dna integrity, human reproduction 2005; 20:101821. 20. duarsa gwk, kloping yp, duarsa gwd, et al. video-assisted telescope operating monitor 3d system in microsurgical varicocelectomy: a preliminary report. surgical innovation, 2024; 31:240-4. 21. kokosis g, dellon la, lidsky me, et al. prevalence of musculoskeletal symptoms and ergonomics among plastic surgery residents: results of a national survey and analysis of contributing factors. ann plast surg 2020; 85:310-5. 22. khalessi aa, rahme r, rennert rc, et al. first-in-man clinical experience using a high-definition 3-dimensional exoscope system for microneurosurgery. oper neurosurg hagerstown). 2019; 16:71725. 23. ricciardi l, chaichana kl, cardia a, et al. the exoscope in neurosurgery: an innovative "point of view". a systematic review of the technical, surgical and educational aspects. world neurosurg. 2019; s18788750:30080-4. 24. hansraj kk. assessment of stresses in the cervical spine caused by posture and position of the head. surg technol int. 2014; 25:277-9. 25. amartya d, atmoko w, duarsa gwk, et al. video exoscope as a cost-effective alternative to surgical microscope in microsurgical subinguinal varicocelectomy in indonesia: a case report. urol case rep 2023; 51:102613. declarations ethical approval and consent for participate: written informed consent was obtained from all patients for the treatment and use of anonymized clinical data for academic purposes. consent for publication: written informed consent was obtained from all individual participants included in the case series for the publication of anonymized clinical information and related images. availability of data and material: all data generated or analyzed during this study are included in this published article. competing interests: the authors declare no potential conflict of interest. funding: the authors report no funding. authors' contributions: conception or design: ps, gwkd, bd; acquisition, analysis, or interpretation of data: ps, gwkd, bd, epn; drafting the work or revising: epn, zab, hnw; final approval of the manuscript: epn, zab, hnw. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):14153 5 3d video exoscope in microsurgical varicocelectomy 26. gabrielson at, clifton mm, pavlovich cp, et al. surgical ergonomics for urologists: a practical guide. nat rev urol. 2021; 18:160-9. 27. jeffries el, hardesty s, scott np. improving resident knowledge of ergonomics guidelines. obstet gynecol. 2022; 139:1194. 28. kolz jm, wagner sc, vaccaro ar, sebastian as. ergonomics in spine surgery. clin spine surg. 2022; 35:333-40. 29. lakhiani c, fisher sm, janhofer de, song dh. ergonomics in microsurgery. j surg oncol. 2018; 118:840-4. 30. rosenblatt pl, mckinney j, adams sr. ergonomics in the operating room: protecting the surgeon. j minim invasive gynecol. 2013; 20:744. 31. wuebben d. working to prevent work-related musculoskeletal disorders. j am soc echocardiogr. 2016; 29:a2. correspondence paksi satyagraha (corresponding author) uropas.fk@ub.ac.id department of urology, dr. saiful anwar general hospital malang, jalan jaksa agung suprapto 2, klojen, malang, east java 65112, indonesia gede wirya kusuma duarsa gwkduarsa@gmail.com department of urology, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia besut daryanto urobes.fk@ub.ac.id edvin prawira negara negaraedvin@gmail.com zaidan arifiansyah bachtiar zaidanab97@gmail.com haryo nindito wicaksono wicaksonoharyo123@gmail.com department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13978 1 original paper cord stromal tumours, (which account for the remaining 5% in adults), with leydig cell tumours (lcts) being the most prevalent among the latter (3). extra testicular localizations are even rarer (4). lcts originate from the cells of the same name, which are located between the seminiferous tubules and are responsible for testosterone production when stimulated by the luteinizing hormone. most cases are benign neoplasms, but a proportion of 5 to 10% show malignant behaviour, with the incidence being highest in prepubertal age and between 30 and 60 years (4-6). in post-pubertal men, elevated circulating androgen levels caused by these tumours may be clinically unremarkable. gynecomastia is the most common hormonal manifestation, although decreased libido, erectile dysfunction, azoospermia, primary infertility, and less commonly, cushing's syndrome may also occur (7, 8). ultrasound is essential for the evaluation of testicular masses. however, the sonographic appearance of lcts can mimic germ cell tumours, often leading to radical inguinal orchiectomy. testis-sparing surgery (tss) may be considered for small (< 2.5 cm), histologically characterized lesions (9). metastatic spread, although rare, primarily involves retroperitoneal lymph nodes, lungs, and liver (10, 11). radioand chemotherapies are not very effective in these cases and have limited impact on survival (12). considering all these aspects, retroperitoneal lymph node dissection (rplnd) has been proposed in selected highrisk cases. identified risk criteria for the possible performance of rplnd include: tumor dimension above 5 cm, presence of necrosis, moderate or severe nuclear atypia, angioinvasion, positive resection margins, more than 5 mitoses per high-power field (13). due to the rarity of lcts and the absence of standardized guidelines, management often relies on multidisciplinary evaluation and individual clinical judgment. this study presents the clinical cases of lcts that were referred to our institution between 2000 and 2024 and discusses diagnostic and therapeutic considerations considering current literature. introduction: leydig cell tumors (lcts) are rare testicular neoplasms that account for a small proportion of testicular tumors and are often diagnosed incidentally or on investigation of infertility or hormonal symptoms. despite their generally benign behaviour, a small percentage may have malignant potential, which poses a diagnostic and therapeutic challenge due to the lack of standardized guidelines. materials and methods: we retrospectively analysed four cases of histologically confirmed lcts diagnosed and treated at a single institution between 2000 and 2024. clinical, biochemical, radiologic, surgical, and pathologic data were collected and analysed. results: patients presented with a variety of clinical histories, including testicular swelling, infertility, or incidental findings. tumor size ranged from 1.8 to 3.5 cm. all patients underwent radical inguinal orchiectomy, and histology confirmed benign lcts without high-risk features such as necrosis, mitotic activity, or vascular invasion. hormonal profiles and imaging were key to the diagnostic process, although findings sometimes mimicked germ cell tumours. adjuvant therapy was not required, and all patients remained disease-free at follow-up. conclusions: this case series highlights the heterogeneity of lct presentations and emphasizes the importance of accurate diagnosis, individualized treatment, and multidisciplinary management. standardized protocols, greater awareness and timely imaging are essential to avoid overtreatment and improve outcomes in lct patients. key words: testis; leydig cells neoplasm; leydig cell tumors; testicular cancer; orchiectomy; testis-sparing surgery. submitted 12 may 2025; accepted 17 may 2025 introduction testicular tumours account for only 1-2% of all cancer diagnoses in men worldwide, with the highest incidence between the ages of 15 and 44 (1, 2). these neoplasms can originate from any cell in the testes, but are mainly divided into two categories: germ cell tumours (which account for about 95% of cases), and sex beyond germ cell tumors: focus on leydig cell neoplasms from a single-center experience rosario leonardi 1, 2, alessandro d’angelo 3, guglielmo mantica 4, 5, francesca ambrosini 4, alessandro calarco 6, dorotea sciacca 3, gabriele iacona 2, dario giuffrida 3 1 department of medicine and surgery, university kore of enna, enna, italy; 2 casa di cura musumeci gecas, gravina di catania (ct), italy; 3 iom istituto oncologico del mediterraneo, viagrande (ct), italy; 4 irccs ospedale policlinico san martino, genova, italy; 5 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 6 ospedale san carlo di nancy, roma, italy. doi: 10.4081/aiua.2025.13978 summary archivio italiano di urologia e andrologia 2025; 97(3):13978 r. leonardi, a. d’angelo, g. mantica, et al. 2 materials and methods all patients diagnosed with lcts between january 2000 and december 2024 at a single institution were retrospectively selected. the study was conducted following the principles of the declaration of helsinki. informed consent was obtained from all patients enrolled in the study. patient data were obtained from the institution's electronic medical records and clinical prospectively collected databases. inclusion criteria were a histologically confirmed diagnosis of lct, either after orchiectomy or tss. exclusion criteria included patients with incomplete medical records or follow-up data. clinical variables included age at diagnosis, presenting symptoms, serum hormone levels (testosterone, estradiol, lh, fsh), tumour markers (afp, β-hcg, ldh), imaging findings (ultrasound, ct or mri), tumour laterality, and tumour size. histopathologic features such as necrosis, nuclear atypia, angioinvasion, mitotic index, and resection margins were documented. treatment modalities were recorded, including the type of surgical procedure (radical inguinal orchiectomy or tss), the use of rplnd, and any adjuvant therapies. follow-up data included recurrence, metastasis, and overall survival. descriptive statistics were used to summarize clinical and pathological characteristics. the results were analysed concerning known prognostic factors based on the current literature. results the results of the case series are reported in table 1. case 1 the patient was a 22-year-old male, with a history of blunt testicular trauma in 2001 and in 2014. on both occasions, he was clinically assessed in the emergency department, and apart from symptomatic pain relief, no further investigations or treatment were undertaken. in january 2023, the patient underwent a urological examination due to persistent testicular swelling and pain. as part of the diagnostic work-up, tumour markers including beta-hcg, alpha-fetoprotein (afp) and lactate dehydrogenase (ldh), an ultrasound (figure 1) and a magnetic resonance imaging (mri) of the testicles were performed and were determined. a right testicular nodule was detected on the mri. the figure 1. scrotal ultrasound image showing a hypoechoic area within the testicular parenchyma, suggestive of a testicular mass. table 1. summary of clinical and pathological features of four cases of leydig cell tumour. variable case 1 case 2 case 3 case 4 age 22 years 59 years 46 years 31 years clinical presentation persistent testis swelling and pain suspected testicular mass left testicular mass on ultrasound right testicular lesion found during infertility work-up tumor markers β-hcg, afp, ldh: assessed not specified ldh 226, β-hcg 0, afp 3.4 ldh 301, β-hcg 0.1, afp 3.2, cea 0.5 (values not given) imaging mri: right testicular nodule not specified ultrasound: left testicular mass ultrasound: 22 mm lesion (right testis) surgical procedure right radical inguinal orchiectomy radical inguinal orchiectomy left radical inguinal orchiectomy right radical inguinal orchiectomy macroscopic description 3.5 cm hemorrhagic nodule in 1.8 cm brownish lesion two fragments: 1.3×0.6 cm 2 cm lesion at lower pole of testis 6×4×3 cm testis and 0.7×0.5 cm microscopic description monomorphic cells, eosinophilic cytoplasm, low mitotic activity, no necrosis polygonal eosinophilic cells, typical leydig cell features, no mitoses no mitoses or necrosis necrobiosis, vascular stroma immunohistochemistry inhibin+, ar+, s-100−, oct4−, cd117−, inhibin+, melan-a+, ar+, oct4−, not detailed not detailed cd30−, panck−, sall4− cd117−, plap−, cd30− ki-67 index 2% not specified not specified 0/10 hpf margins/spermatic cord free of disease free of disease not specified not specified post-op imaging/follow-up not reported not reported ct: small lymph nodes, liver calcification ct (2010): no recurrence final diagnosis leydig cell tumor leydig cell tumor leydig cell tumor leydig cell tumor archivio italiano di urologia e andrologia 2025; 97(3):13978 3 leydig cell neoplasms patient underwent an intraoperative confirmatory biopsy, revealing a stromal testicular neoplasm, and subsequent surgical removal of the right testicle in march 2023. the macroscopic pathological examination of the surgical specimen described a testis and epididymis measuring 6 × 4 × 3 cm, in continuity with a 6.5 cm spermatic cord. on dissection, a haemorrhagic area up to 3.5 cm in diameter was noted at the site of intraoperative sampling. microscopic analysis revealed a diffuse proliferation of monomorphic cells confined to the testicular tissue. these cells were characterized by a granular eosinophilic cytoplasm, round nuclei and a central nucleolus. there were no signs of mitotic activity or necrosis. the immunohistochemical profile was as follows: positive for alpha-inhibin and androgen receptors; negative for s100, oct4, cd117, cd30, pancytokeratin (panck) and sall4. the proliferation index determined by ki-67 staining was 2%. these findings were consistent with a sex cord stromal tumour that had the morphologic and immunohistochemical features of a benign lct. the epididymis, spermatic cord, and surgical margin of the cord were all free of disease. case 2 a 59-year-old male underwent orchiectomy due to a suspected testicular mass in 2023. macroscopic examination revealed a testis and epididymis measuring 5.4 × 4 × 3.3 cm connected to a 5 cm long spermatic cord. a brownish tumour with regular margins and a diameter of 1.8 cm was noted. the lesion appeared macroscopically well contained within the testicular parenchyma. histological analysis confirmed the diagnosis of a testicular neoplasm in the region of the spermatic cord, which had the characteristics of an lct. the tumour was confined exclusively to the testis, with no evidence of lymphatic invasion or necrosis. mitotic activity was low, quantified as 1 mitosis per 10 high-power fields. the immunohistochemical profile showed positivity for inhibin, melan a, and androgen receptors. the tumour was negative for oct4, cd117, placental alkaline phosphatase (plap), and cd30. both the spermatic cord and the surgical resection margins were found to be free of neoplastic involvement. case 3 in september 2013, a 46-year-old male underwent an ultrasound examination, which revealed a left testicular mass. the tumour marker analysis revealed the following values: ldh at 226 u/l, beta-hcg at 0.00 miu/ml, and afp at 3.4 ng/ml. the patient was submitted to left radical inguinal orchiectomy (figure 2). a frozen section examination (fse) during surgery was performed, identifying a leydig cell tumour. a left radical inguinal orchiectomy was completed. the final histological examination highlighted that two tissue fragments measuring 1.3 × 0.6 cm and 0.7 × 0.5 cm were analysed. the findings indicated a testicular stromal tumour with morphological features of a lct. microscopically, the lesion appeared as an unencapsulated solid neoplasm consisting of a thin fibrous and abundantly vascularized stroma. the growth pattern was trabecular or diffuse and consisted of partially contiguous polygonal cells of medium to large size with well-defined cell borders. the cytoplasm of these cells was granular and eosinophilic, sometimes vacuolated, and occasionally contained lipofuscin granules. the nuclei of the neoplastic cells were round or ovoid and para-centrally arranged, with some cells having multiple nuclei. areas of course, hyalinized fibrovascular septa were observed within the lesion, along with haemorrhagic foci and microfoci of necrobiosis. the surrounding testicular parenchyma showed poorly differentiated spherical structures with varying degrees of intertubular oedema, confluent haemorrhagic lacunae, interstitial fibrosis, and testicular tubules with irregular profiles. a ct scan of the chest and abdomen was performed after surgery. the scan revealed a 4 mm punctate parenchymal calcification in the left lobe of the liver. in addition, some lymph nodes were observed in the para-aortic region, mesenteric compartment, bilateral external iliac and bilateral inguinal regions, which showed non-specific features with a maximum diameter of 13 mm. figure 2. left testicle externalized from the scrotal sac and including the spermatic cord up to the internal inguinal orifice. archivio italiano di urologia e andrologia 2025; 97(3):13978 r. leonardi, a. d’angelo, g. mantica, et al. 4 case 4 in 2004, a 31-year-old male, during a testicular ultrasound examination for infertility, was diagnosed with a 22 mm lesion occupying a large part of the right testis and a grade iii varicocele on the left side. subsequent laboratory tests revealed the following values: ldh at 301 u/l, carcinoembryonic antigen (cea) at 0.5 ng/ml, alpha-1-fetoprotein (alpha 1 fp) at 3.2 ng/ml and beta-hcg at 0.10 miu/ml. in november 2004, the patient underwent a right radical inguinal orchiectomy. histologic examination of the surgical specimen revealed an intraparenchymal neoplasm with a diameter of approximately 2 cm located at the lower pole of the right testis. the histopathological diagnosis confirmed a lct with a mitotic index of 0 per 10 high-power fields (hpf). in april 2010, a further ct scan of the brain, chest, abdomen, and pelvis was performed, which was negative and showed no evidence of disease recurrence or metastasis. discussion the four clinical cases described in this study reflect a spectrum of different presentations, diagnostic challenges, and treatment approaches associated with lcts, a rare subtype of testicular neoplasms that arise from the interstitial cells of the gonads. although generally considered benign, lcts have a documented, albeit low, potential for malignancy, making their early detection and appropriate clinical management essential. histologically, all four lesions were compatible with benign lcts based on morphology and immunohistochemistry. none of them showed high-risk features such as marked atypia, necrosis or vascular invasion (13). in the first case, there was a discrepancy between the intraoperative biopsy suggestive of a stromal tumor, and the final histologic result. the absence of a malignant tumour illustrates the importance (and limitations) of preoperative diagnostics. as suardi et al. emphasize, tss with a fse can be a sensible alternative in selected cases to avoid overtreatment (9). testis-sparing surgery (tss) can be a valuable option for managing small, well-circumscribed leydig cell tumors with imaging and intraoperative findings suggestive of benignity. when carefully selected, tss allows preservation of hormonal and reproductive function without compromising oncologic safety (9). this raises a fundamental clinical question: is a testicular biopsy always warranted, or could it be avoided in selected cases to prevent overtreatment or unnecessary surgery? this dilemma reflects the general uncertainty that often surrounds the diagnostic and therapeutic approach to rare tumours, where guidelines are lacking and clinical decisions may rely heavily on individual judgment. equally important is the initial diagnostic phase, where ultrasonography – the first imaging procedure in scrotal pathology – is not always systematically performed. in some of our cases, the lack of an early ultrasound may have delayed the diagnostic process. given its non-invasive nature, its high sensitivity for testicular lesions, and its usefulness in characterizing intratesticular masses, scrotal ultrasound should be considered an essential extension of the physical examination, especially in patients presenting with testicular discomfort, swelling, or a history of trauma (3). the heterogeneity we observed in the anatomic-pathologic reports is another critical issue. despite the central role of histopathology in making the diagnosis and determining the prognosis, the main prognostic indicators – such as mitotic index, necrosis, lymphatic vessel invasion, and margin status were not consistently reported in all reports. these elements are essential for assessing the risk of malignant behaviour (14, 15) and for deciding on further surgical interventions such as rplnd. the lack of standardization in reporting may reflect the variability of institutional protocols or the varying degree of familiarity of pathologists with this rare tumour entity. as fankhauser et al. emphasized in their analysis of 1375 lcts, comprehensive pathology is essential to inform decisions about further treatment (13). as regards follow-up, analysing over 1300 cases, fankhauser et al. (13) showed that approximately 7% of patients with available follow-up developed metastases, with a median time to recurrence of 12 months. age > 40 years, tumour size > 4 cm, and the presence of at least two histologic risk factors (e.g., necrosis, vascular invasion, atypia, mitotic rate > 3/hpf) significantly increased the likelihood of malignancy and, thus, the risk of metastatic progression. these results support the use of prognostic scoring systems to stratify patients and adjust the extent of surgical intervention and surveillance protocols (13). in addition, their analysis revealed that for malignant lcts, the efficacy of chemotherapy and radiotherapy is low, and most metastatic patients are treated surgically or observed. therefore, rplnd remains crucial not only for staging but potentially also for curative intent in patients with resectable disease. this is consistent with previous findings by mosharafa et al. (12), who reported long-term disease control with surgery alone in selected metastatic cases. clinicians must also consider clinical and endocrine signs that may be overlooked in routine practice, such as gynecomastia, infertility, decreased libido, or other symptoms related to hormonal imbalance. serum hormone levels, including testosterone, estradiol, luteinizing hormone (lh) and follicle stimulating hormone (fsh), should be part of the initial workup, as lcts are often hormonally active. as papadimitris et al. noted, hormonal dysfunction may be the only symptom in some lcts (7). in our series, all four patients are currently alive and free of disease. they are undergoing regular clinical and hormonal monitoring. only one patient required long-term testosterone replacement therapy, emphasizing the need for close monitoring of endocrine function after orchiectomy, especially in younger patients or those with bilateral disease or pre-existing hypogonadism. our report highlights a broader problem in the management of rare testicular tumours: the lack of codified diagnostic pathways often leads to highly variable clinical decisions, especially in the early stages of treatment. delays in diagnosis, whether due to underestimated archivio italiano di urologia e andrologia 2025; 97(3):13978 5 leydig cell neoplasms symptoms or incomplete investigations, can harm outcomes. in our experience, a multidisciplinary approach – including urologists, radiologists, pathologists, endocrinologists, and oncologists – ensures optimal care. as zeuschner et al. (8) and others have reported, hormonal signs such as gynecomastia can precede testicular findings by months or years. based on these findings, it is imperative to raise awareness among primary care physicians and emergency physicians of the importance of timely and thorough diagnostic examination of testicular masses. lcts are more frequent than generally believed (16). accurate preoperative diagnosis is essential, especially in young males with suspected scrotal pathology, to avoid unnecessary radical surgery for benign lesions. early use of imaging and hormonal evaluation, combined with multidisciplinary assessment, can guide more conservative and individualized treatment decisions. ultrasonography of the testis should be routinely performed as part of the physical examination in any patient with testicular symptoms (17). moreover, mri can also be considered in the diagnostic workup. lcts have distinctive contrast-enhanced mri features that allow the differential diagnosis of incidental testicular lesions (rapid and marked wash-in). (18). in this context, synchronous bilateral testicular lesions, though extremely rare, should not be overlooked. their management follows the same principles as unilateral disease, with radical orchiectomy as the standard; however, in selected cases, testis-sparing surgery combined with onco-testicular sperm extraction (tese) offers a promising fertility-preserving alternative (19). some limitations of this study should be mentioned. first, its retrospective design inherently carries the risk of selection and information bias. second, the generalizability of the results to broader populations may be limited since the study was conducted at a single institution. the results should be validated in future, robust, high-quality comparative studies with other types of testicular tumours. in addition, the relatively small sample size reflects the rarity of lcts and limits the statistical power to draw definitive conclusions. finally, the lack of standardized treatment protocols during the long study period may have led to variations in the treatment of patients. conclusions despite their rarity, lcts require a structured, evidencebased approach to ensure optimal patient outcomes. our case series illustrates the challenges posed by diagnostic uncertainty, inconsistent pathology reports, and the need for coordinated, interdisciplinary treatment. improved education, standardization of guidelines, and early referral to specialized centers are key strategies to improve the management of these complex cases. references 1. park js, kim j, elghiaty a, ham ws. recent global trends in testicular cancer incidence and mortality. medicine 2018; 97:e12390. 2. rosen a, jayram g, drazer m, eggener se. global trends in testicular cancer incidence and mortality. eur urol 2011; 60:374379. 3. mooney kl, kao cs. a contemporary review of common adult non-germ cell tumors of the testis and paratestis. surg pathol clin. 2018; 11:739-758. 4. lanzafame s, leonardi r, torrisi a. extratesticular leydig cell tumor of the spermatic cord. j urol 2004; 171:1238-1239. 5. mukhopadhyay m, das c, sarkar s, et al. leydig cell tumor of testis in a child: an uncommon presentation. j indian assoc pediatr surg 2017; 22:181. 6. 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9:177-92. 12. mosharafa aa, foster rs, bihrle r, et al. does retroperitoneal lymph node dissection have a curative role for patients with sex cordstromal testicular tumors? cancer 2003; 98:753-757. 13. fankhauser cd, grogg jb, hayoz s, et al. risk factors and treatment outcomes of 1,375 patients with testicular leydig cell tumors: analysis of published case series data. j urol 2020; 203:949-956. 14. rizzo nm, sholl lm, idrees mt, et al. comparative molecular analysis of testicular leydig cell tumors demonstrates distinct subsets of neoplasms with aggressive histopathologic features. mod pathol 2021; 34:1935-1946. 15. colecchia m, bertolotti a, paolini b, et al. the leydig cell tumour scaled score (less): a method to distinguish benign from malignant cases, with additional correlation with mdm2 and cdk4 amplification. histopathology 2021; 78:290-299. declarations competing interests: the authors declare that they have no competing interests. funding: no funding was received. authors' contributions: rl, study concept, data analysis and interpretation, manuscript original drafting; ad, contribution to manuscript writing and editing; gm, contribution to manuscript writing and editing; fa, contribution to manuscript writing and editing; ac, contribution to manuscript writing and editing; ds, data collection and interpretation; gi, data collection and interpretation; dg, supervision. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. archivio italiano di urologia e andrologia 2025; 97(3):13978 r. leonardi, a. d’angelo, g. mantica, et al. 6 16. pozza c, pofi r, tenuta m, et al. clinical presentation, management and follow-up of 83 patients with leydig cell tumors of the testis: a prospective case-cohort study. hum reprod 2019; 34:1389-1403. 17. symeonidis en, sountoulides p, asouhidou i, et al. be cautious of “complex hydrocele” on ultrasound in young men. arch ital urol androl 2020; 92:61-63. 18. manganaro l, vinci v, pozza c, et al. a prospective study on contrast-enhanced magnetic resonance imaging of testicular lesions: distinctive features of leydig cell tumours. eur radiol 2015; 25:3586-3595. 19. symeonidis en, tsifountoudis i, anastasiadis a, et al. synchronous bilateral testicular cancer with discordant histopathology occurring in a 20-year-old patient: a case report and review of the literature. urologia 2023; 90:434-441. correspondence rosario leonardi leonardi.r@tiscali.it department of medicine and surgery, university kore of enna, enna, italy casa di cura musumeci gecas, gravina di catania (ct), italy alessandro d’angelo alessandro.dangelo@grupposamed.com dorotea sciacca dorotea.sciacca@grupposamed.com dario giuffrida dario.giuffrida@grupposamed.co iom istituto oncologico del mediterraneo, viagrande (ct), italy guglielmo mantica guglielmo.mantica@hsanmartino.it francesca ambrosini (corresponding author) f.ambrosini1@gmail.com irccs ospedale policlinico san martino, genova, italy alessandro calarco alecalarco@gmail.com ospedale san carlo di nancy, roma, italy gabriele iacona gabriele.iacona@grupposamed.com casa di cura musumeci gecas, gravina di catania (ct), italy stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11629 1 original paper is the most invasive and associated with high operative morbidity (1). the rate of open prostatectomy surgeries has been progressively decreasing with the advent of minimally invasive techniques, including monopolar and bipolar turp and diferent laser therapies (2). holmium laser enucleation of the prostate (holep) has shown a comparable functional outcome to open prostatectomy in treating prostates larger than 80 cc (3). however, due to its steep learning curve and higher cost, holep gained little popularity, especially in developing countries (4). transurethral enucleation resection of the prostate (tuerp) incorporated the enucleation technique with standard transurethral resection of the prostate (turp). it is available in all urology theaters, is cost-effective, and could be considered a treatment option resembling laser enucleation, specifically bipolar tuerp (5). in the present study, we aimed to assess the efficacy and safety of bipolar tuerp compared to retropubic prostatectomy in patients with luts secondary to benign prostatic hyperplasia with prostate volumes larger than 80 cc. patients and methods a prospective randomized study included all patients amenable to benign prostate hyperplasia (bph) surgeries to control lower urinary tract symptoms with prostate size over 80 cc at the urology department of al-azhar university hospitals between january 2020 to february 2022. we excluded patients with neurogenic bladder dysfunction, previous prostatic or urethral surgeries, urethral stricture or bladder neck contracture, renal impairment, and comorbidities that render them at high anesthetic risk. the local ethical committee approved our research, and all participants signed informed consent. patients were randomly allocated into one of the two groups; group 1 included patients who underwent bipolar tuerp, and group 2 had retropubic open prostatectomy. a stratified block randomization method (1:1 ratio) was used for patient allocation. objectives: to compare the outcomes of bipolar transurethral enucleation resection of the prostate (tuerp) and simple retropubic prostatectomy in patients with prostate volumes larger than 80 cc. patients and methods: a prospective randomized study included all patients amenable to surgeries for benign prostate hyperplasia (bph) with prostate size over 80 cc at a tertiary care hospital between january 2020 to february 2022. bipolar tuerp and retropubic open prostatectomy techniques were compared regarding patients' demographics, intraoperative parameters, outcomes, and peri-operative complications. results: ninety patients were included in our study and randomly assigned to bipolar tuerp (group 1 = 45 patients) and retropubic open prostatectomy (group 2 = 45 patients). the tuerp group demonstrated significantly lower operative time (77 ± 11 minutes vs. 99 ± 14 minutes, p < 0.001), hemoglobin drop (median = 1.1 vs. 2.5, p < 0.001), and resected tissue weight (71 ± 6.6 cc vs. 84.5 ± 10.6 cc, p < 0.001). postoperatively, the tuerp group demonstrated significantly lower catheter time (median = 2 vs. 7 days, p < 0.001) and less hospital stay. ipss, qmax, and patient satisfaction were better in the tuerp group within six months of surgery. we reported 90-day complications after tuerp in 13.3% of patients compared to 17.8% after retropubic prostatectomy, with a statistically insignificant difference. urethral stricture predominated after tuerp, while blood transfusion dominated in retropubic prostatectomy. conclusions: the present study found that tuerp had equivalent efficacy and safety to open retropubic prostatectomy for patients with bph and prostate volumes > 80 ml. key words: tuerp; simple retropubic prostatectomy; complications. submitted 1 august 2023; accepted 31 august 2023 introduction open prostatectomy is considered the most durable surgical option for large (> 80 gm) prostates. meanwhile, it evaluation of bipolar transurethral enucleation and resection of the prostate in terms of efficiency and patient satisfaction compared to retropubic open prostatectomy in prostates larger than 80 cc. a prospective randomized study ibrahim tagreda, mahmoud heikal, adel elatreisy, mohamed fawzy salman, ahmed mohamed soliman, ayman kotb koritenah, hesham abozied, mohamed ibrahim algammal, ahmed a. alrefaey, mohamed elsalhy, mohamed shehab, mahmoud mohammed ali, aly gomaa eid, abdrabuh m. abdrabuh, sayed eleweedy urology department, faculty of medicine, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11629 summary archivio italiano di urologia e andrologia 2023; 95(4):11629 i. tagreda, m. heikal, a. elatreisy, et al. 2 all recruited patients were assessed through the following regimen: full medical history including international prostate symptom score (ipss) assessment and international index of erectile function (iief); complete clinical examination, including digital rectal examination (dre) and focused neurological examination; urine analysis, urine culture and sensitivity, serum creatinine, coagulation profile, cbc, serum na and potassium, blood sugar, and prostate specific antigen (psa). objective evaluation of luts carried out through uroflowmetry with post-void residual urine, transrectal ultrasound for estimation of prostate volume, and pelvic-abdominal ultrasound in cases with recurrent hematuria, infection, loin pain, or high post-void residual urine. tuerp procedure was performed using a plasma kinetic resection using a kls martin maximum with storz fr 26 resectoscope with plasma kinetic electrode using the bipolar current and normal saline irrigation. the procedure involved the creation of the plane of the surgical capsule at a level closely proximal to the verumontanum with vaporization; the adenoma was dissected from the capsule plane by unclenching it using the beak of the resectoscope sheath from one side to the other. the blood vessels to the adenoma were coagulated at the time of dissection. when the whole adenoma was almost dissected from the capsule, a small proportion of adenoma was allowed to anchor the capsule at the bladder neck, which helped the surgeon to harvest the whole adenoma in pieces with resection. the adenoma slices were evacuated manually. the retropubic open prostatectomy procedure was performed following the standard operative technique (6). intraoperative adverse events, operative time, and enucleated prostatic weight were recorded. similarly, postoperative reporting of hemoglobin, hematocrit, serum sodium and potassium (k), hospital stay, catheterization period, and 90-day complications were recorded. patients were booked for clinic visits after one, three, and six months from surgery for clinical evaluation, including ipss questionnaire, physical assessment, uroflowmetry, and pvr. the study groups were compared in terms of patient demographics, intraoperative parameters, outcomes, and peri-operative complications. statistical analysis statistical analysis was done utilizing the spss version 28 (ibm, armonk, new york, united states). quantitative data were assessed for normality using the shapiro-wilk test and direct data visualization methods. according to normality, quantitative data were summarized as means and standard deviations or medians and ranges. categorical data were expressed as numbers and percentages. quantitative data were compared between the studied groups using the independent t-test or mann-whitney u test for normally and non-normally distributed quantitative variables. categorical data were compared using the chisquare or fisher’s exact test. all statistical tests were twosided. p values less than 0.05 were considered significant. results ninety patients were included in our study and randomly assigned to bipolar tuerp (group 1 = 45 patients) and retropubic open prostatectomy (group 2 = 45 patients). the study groups were comparable regarding the patients’ demographics and preoperative laboratory investigations, as shown in tables 1 and 2. the tuerp group demonstrated significantly lower operative time (77 ± 11 minutes vs. 99 ±14 minutes, p < 0.001), hemoglobin drop (median = 1.1 vs. 2.5, p < 0.001), resected tissue weight (71 ± 6.6 cc vs. 84.5 ± 10.6 cc, p < 0.001), serum potassium (3.9 ± 0.4 vs. 4.1 ± 0.3, p = 0.002), hematocrit (vs. 29 ± 2 vs. 31 ± 2, p < 0.001), and bleeding (22.2% vs. 57.8%, p < 0.001). no significant difference was observed regarding serum na (p = 0.948) (table 3). postoperatively, the tuerp group demonstrated significantly lower catheter time (median = 2 vs. 7 days, p < 0.001) and lower serum potassium level (2.9 ±0.3 vs. 4.1 ± 0.3, p < 0.001). additionally, hospital stay significantly differed between the studied groups (p < 0.001), with 57.8% and 42.2% of the tuerp patients having a hospitable 1. baseline general and clinical characteristics of the study groups. group 1 group 2 p-value (n = 45) (n = 45) age (years), mean ± sd 66 ± 6 66 ± 7 0.7 co-morbidities, n (%) 31(68.9) 28 (62.2) 0.506 ipss, median(range) 25 (18-32) 24 (16-35) 0.209 quality of life, n (%) 0.418 mostly dissatisfied 8 (17.8) 5 (11.1) unhappy 14 (31.1) 11 (24.4) terrible 23 (51.1) 29 (64.4) ieef, median(range) 7 (5-14) 7 (5-13%) 0.239 prostate size (cc), mean ± sd 110 ± 8 cc 112 ± 7 cc 0.211 residual urine (ml), median(range) 195 (90 590) 190 (107-240) 0.721 trus (tv) (cc), mean ± sd 104 ± 12 cc 108 ± 10 0.085 tz (cc), mean ± sd 89 ± 8.7 cc 91.4 ± 7.9 0.169 qmax (ml/sec), mean ± sd 9.4 ± 14 8.9 ± 1.5 0.819 ipss: international prostate symptom score; ieef: international index of erectile function; tv: total volume of prostate; tz: transition zone of prostate. table 2. baseline laboratory findings of the study groups. group 1 group 2 p-value (n = 45) (n = 45) pyuria, n (%) 23 (51.1) 28 (62.2) 0.288 positive urine culture, n (%) 23 (51.1) 28 (62.2) 0.288 serum creatinine (mg/dl), mean ± sd 1.12 ± 0.34 1.03 ± 0.18 0.114 hemoglobin (gm/dl), mean ± sd 13.2 ± 1.8 13.6 ± 1 0.235 hematocrit (%), mean ± sd 40.3 ± 4.7 41.3 ± 2.9 0.199 serum na (meq/l), mean ± sd 136.9 ± 4.2 135.8 ± 1.5 0.081 k (meq/l), mean ± sd 4.12 ± 0.66 4.05 ± 0.36 0.509 psa-total (ng/ml), median (range) 4 (1.1-20) 3.8 (1.9-10.9) 0.707 psa-free (ng/ml), median (range) 1 (0.3-2.3) 0.8 (0.4-1.9) 0.084 inr, mean ± sd 0.99 ± 0.03 0.97 ± 0.04 0.129 random blood sugar (mg/dl), mean ± sd 107 ± 16 104 ± 15 0.361 k: potassium; psa; prostate specific antigen; inr; international normalized ratio. archivio italiano di urologia e andrologia 2023; 95(4):11629 3 evaluation of bipolar transurethral enucleation and resection of the prostate in terms of efficiency and patient satisfaction... tal stay of two and three days compared to seven days in patients in the open group. no significant differences were observed regarding serum na (p = 0.265), hemoglobin (p = 0.243), and hematocrit (p = 0.495) levels (table 4). after one month from surgery, the tuerp group demonstrated significantly lower ipss (median = 6 vs. 7, p < 0.001) and pyuria (0% vs. 24.4%, p < 0.001). in contrast, it showed a significantly higher urinary flow (20.1 ± 3.1 ml/sec vs. 17.1 ± 1.9 ml/sec, p < 0.001). additionally, the quality of life differed between the studied groups, with most tuerp patients being mostly satisfied (75.5%) compared to the open group (66.6%). no significant differences were observed regarding iief (p = 0.065), dysuria (p = 0.292), and residual urine (p = 0.868) (table 5). after three months, the tuerp group demonstrated significantly lower ipss (median = 4 vs. 5, p = 0.049) and dysuria (0% vs. 15.6%, p = 0.012). in contrast, it showed a significantly higher urinary flow (19.7 ± 2.6 ml/sec vs. 18.5 ± 2.5 ml/sec, p = 0.022) and residual urine (median = 16 ml vs. 10 ml, p = 0.014). additionally, the quality of life differed between the studied groups, with most tuerp patients being mostly satisfied (95.5%) compared to the open group (88.8%). no significant differences were observed regarding iief (p = 0.588) and pyuria (p = 0.242) (table 6). after six months, the tuerp group demonstrated significantly higher urinary flow (19.3 ± 2.7 ml/sec vs. 17.7 ± 2.4 ml/sec, p = 0.005) and residual urine (median = 15 ml vs. 0, p < 0.001) compared to the open group. no significant differences were observed regarding ipss (p = 0.189), qol (p = 0.523), iief (p = 0.361), dysuria (p = 0.242), and pyuria (p = 0.242) (table 7). as regards the complications in the bipolar tuerp table 3. intraoperative findings in the studied groups. group 1 group 2 p-value (n = 45) (n = 45) operative time (min), mean ± sd 77 ± 11 99 ± 14 < 0.001 hemoglobin drop (gm/dl), median(range) 1.1 (0.2-3.7) 2.5 (0.9-6.5) < 0.001 resected tissue weight (gm), mean ± sd 71 ± 6.6 84.5 ± 10.6 < 0.001 na (meq/l), mean ± sd 132 ± 4 132 ± 2 0.948 k (meq/l), mean ± sd 3.9 ± 0.4 4.1 ± 0.3 0.002 hematocrit (%), mean ± sd 29 ± 2 31 ± 2 < 0.001 bleeding, n (%) 10 (22.2) 26 (57.8) < 0.001 k: potassium. table 4. postoperative findings in the studied groups. group 1 group 2 p-value (n = 45) (n = 45) catheter time (days) 2 (2-3) 7 (7-7) < 0.001 hospital stays (days), n (%) < 0.001 two days 26 (57.8) 0 three days 19 (42.2) 0 seven days 0 45 (100) na (meq/l), mean ± sd 134.7 ± 4.2 133.9 ± 2.6 0.265 k (meq/l), mean ± sd 3.9 ± 0.3 4.1 ± 0.3 < 0.001 hemoglobin (gm/dl), mean ± sd 10.8 ± 1.3 11.1 ± 0.9 0.243 hematocrit (%), mean ± sd 30 ± 1.8 29.6 ± 3.3 0.495 k: potassium. table 5. one-month follow-up in the studied groups. group 1 group 2 p-value (n = 45) (n = 45) ipss, median(range) 6 (5-8) 7 (6-17) < 0.001 quality of life, n (%) mostly satisfied 34 (75.5) 30 (66.6) equivocal 11 (24.4) 11 (24.4) mostly dissatisfied 0 4 (8.9) iief, median(range) 7 (5-13) 6 (5-12) 0.065 dysuria, n (%) 11 (24.4) 7 (15.6) 0.292 pyuria, n (%) 0 (0) 11 (24.4) < 0.001 uroflow (ml/sec), mean ± sd 20.1 ± 3.1 17.1 ± 1.9 < 0.001 residual urine (ml), median (range) 20 (10-70) 25 (0-120) 0.868 ipss: international prostate symptom score; ieef: international index of erectile function. table 6. three-month follow-up in the studied groups. group 1 group 2 p-value (n = 45) (n = 45) ipss, median(range) 4 (2-6) 5 (3-18) 0.049 quality of life, n (%) mostly satisfied 43 (95.5) 40 (88.8) equivocal 2 (4.4) 5 (11.1) iief, median(range) 7 (5-13) 7 (5-13) 0.588 dysuria, n (%) 0 (0) 7 (15.6) 0.012 pyuria, n (%) 0 (0) 3 (6.7) 0.242 uroflow (ml/sec), mean ± sd 19.7 ± 2.6 18.5 ± 2.5 0.022 residual urine (ml), median (range) 16 (5-50) 10 (0-140) 0.014 ipss: international prostate symptom score; ieef: international index of erectile function. table 7. six-month follow-up in the study groups. group 1 group 2 p-value (n = 45) (n = 45) ipss, median(range) 3 (2-5) 3 (2-18) 0.189 quality of life, n (%) 0.523 pleased 37 (82.2) 34 (75.6) mostly satisfied 8 (17.8) 8 (17.8) equivocal 0 (0) 1 (2.2) mostly dissatisfied 0 (0) 2 (4.4) iief, median(range) 7 (5-13) 7 (5-13) 0.361 dysuria, n (%) 0 (0) 3 (6.7) 0.242 pyuria, n (%) 0 (0) 3 (6.7) 0.242 uroflow (ml/sec), mean ± sd 19.3 ± 2.7 17.7 ± 2.4 0.005 residual urine (ml), median(range) 15 (4-40) 0 (0-160) < 0.001 ipss: international prostate symptom score; ieef: international index of erectile function. archivio italiano di urologia e andrologia 2023; 95(4):11629 i. tagreda, m. heikal, a. elatreisy, et al. 4 group, two patients developed persistent luts postoperatively and were treated with anticholinergics for one month. one patient was catheterized due to urine retention and needed a re-cystoscopy with resection of remnant prostatic tissue. another patient was hospitalized due to secondary hemorrhage and received iv fluids, antibiotics, and hemostatic drugs for three days without re-catheterization or need for blood transfusion. two patients developed urethral stenosis, which was treated by visual internal urethrotomy (viu). in the open group, two patients needed blood transfusion postoperatively. three patients developed persistent luts and were treated with anticholinergics for six weeks. two patients were hospitalized due to secondary hemorrhage and received iv fluids, antibiotics, and hemostatic drugs for two days without re-catheterization or need for blood transfusion. at the same time, one patient developed bladder neck contracture and was treated by bladder neck incision (bni). the study groups had no statistically significant difference (table 8). discussion bph is a prevalent condition with substantial costs, leading to increased interest in its management (7). surgical treatments include resection, enucleation, vaporization, alternative ablative techniques (aquablationprostatic artery embolizationthe rezum system), and non-ablative techniques (prostatic urethral lift, intra-prostatic injections) (8). tuerp is a recently developed procedure in which the prostate is transurethrally enucleated and resected using a bipolar plasma kinetic resectoscope. many studies suggested that tuerp is a safe and feasible treatment for bph with few complications (9-11). although several studies have demonstrated better clinical benefits for tuerp than other treatments, this procedure has yet to be widely accepted for prostates larger than 60 g (12). therefore, the current study aimed to compare the safety and efficacy of transurethral enucleation resection of the prostate (tuerp) versus open retropubic prostatectomy in patients with luts secondary to benign prostatic hyperplasia with prostate volumes larger than 80 cc. in the current study, the tuerp group demonstrated significantly lower operative time, smaller drop in serum hemoglobin level, less resected tissue weight, smaller drop in hematocrit concentration, and lower incidence of bleeding. in line with our results, a study by wei et al. found that tuerp had a better outcome regarding operative time and less tissue removal, which may indicate a more precise and targeted approach to prostate surgery (9). rao et al. found that tuerp generated a smaller serum hemoglobin level drop than trans-vesical prostatectomy (2). in contrast, ou et al. found no significant difference in operative time between the two procedures (p = 0.107) (10). the resected adenoma weight harvested in the trans-vesical prostatectomy group was more than that in the tuerp group, but the difference between the groups was insignificant (p = 0.062). similarly, wang and wang found no statistically significant differences in operative time between both techniques (13). some authors reported no significant differences regarding the volume of tissue retrieved and postoperative hb in both groups (p > 0.05) (13, 14). however, some authors reported shorter operative time in open prostatectomy procedures compared to tuerp (2, 14). these findings may be due to variations in the study populations, prostate size, surgical techniques, and outcome measures used in each study. as supported by several authors (9, 10, 13, 14), we have found that tuerp has advantages over simple prostatectomy in terms of shorter postoperative catheter time and hospital stay. the current study shows the superiority of the urinary functional outcome of tuerp compared to retropubic prostatectomy. ipss, qmax, and patient satisfaction were better in the tuerp group within six months of surgery. however, ipss and patient satisfaction were similar for both techniques six months after surgery. a study by wei et al. (9) supports our findings that tuerp is better regarding functional outcomes such as ipss and qmax. conversely, other authors reported no superiority for tuerp regarding postoperative urinary functional outcomes compared to simple open prostatectomy. giulianelli et al. found no significant differences in the qmax score, qol score, psa, and post-void residual urine between both techniques (14). the smaller prostate size may explain it compared to the populations in our study. additionally, differences in the follow-up period can contribute to differences in study results. patients were followed up for 12 months, whereas our study followed up patients for a shorter period. there were no significant differences in qmax between tuerp and open prostatectomy during the postoperative 1, 3, 6, 12 months, and two years when followed by chen et al. (3). analysis by geavlete et al. showed no significant differences in qol or psa between tuerp and open prostatectomy at each follow-up time point (11). the lack of significant differences in qmax, qol, and psa between tuerp and open prostatectomy at multiple follow-up time points in these studies suggests that the two procedures may have similar long-term outcomes in terms of these measures. however, the findings could be affected by patient characteristics, surgical technique, and followup period. table 8. postoperative complications in the study groups. group 1 group 2 p-value (n = 45) (n = 45) secondary hemorrhage, n (%) 1 (2.2) 2 (4.4) 1.0 retention, n (%) 1 (2.2) 0 (0) 1.0 blood transfusion, n (%) 0 (0) 2 (4.4) 0.494 luts, n (%) 2 (4.4) 3 (6.7) 1.0 bladder neck contracture, n (%) 0 (0) 1 (2.2) 1.0 urethral stenosis, n (%) 2 (4.4) 0 (0) 0.494 archivio italiano di urologia e andrologia 2023; 95(4):11629 5 evaluation of bipolar transurethral enucleation and resection of the prostate in terms of efficiency and patient satisfaction... other measures, such as operative time, blood loss, and length of hospital stay, may still favor tuerp over open prostatectomy. therefore, the choice of procedure may depend on various factors, including patient preference and surgeon experience. similarly, ou et al. found no significant difference between the groups regarding ipss and pvr at 3 and 12 months postoperatively. however, the patients in the open prostatectomy group appeared to have a better qmax at three months, but the difference was insignificant (p = 0.081). each group's mean postoperative psa reductions were similar (p = 0.12) (10). in contrast, giulianelli et al. observed significantly lower ipss and pvr scores at 12, 24, and 36 months in the tuerp group when compared with the open prostatectomy group (p < 0.05) (14). we reported 90-day complications after tuerp in 13.3% of patients compared to 17.8% after retropubic prostatectomy with a statistically insignificant difference; urethral stricture predominated after tuerp while blood transfusion dominated in retropubic prostatectomy. giulianelli et al. found that dysuria was the most common grade i complication in the tuerp group (p < 0.05) and urinary urge incontinence up to 30 days in the open prostatectomy group (p < 0.05). in the grade ii complications, the results favored the tuerp group (postoperative acute urinary retention, p < 0.05 and blood transfusion requirement, p < 0.05) than the open prostatectomy group. the study favored the tuerp group (capsular perforation and reintervention, p < 0.05) over the open prostatectomy group for grade iii complications (14). also, gratzke et al. reported a higher incidence of blood transfusion, stress incontinence, and urethral stricture in a large series of open prostatectomies for large prostates (15). uti and re-catheterization rates were slightly lower in a study by tubaro et al. (16). serretta et al. detected a higher incidence of bleeding, blood transfusions, and sepsis in open prostatectomies. reinterventions were also higher, mainly due to bladder neck stenosis (17). also, wang and wang (13) and wei et al. (9) found that the incidence of complications in the tuerp group was statistically lower (p < 0.05). geavlete et al. found no statistical differences between tuerp and open prostatectomy concerning transient incontinence, bladder neck contracture, or urethral stricture (11). limitations of the study despite being a prospective randomized trial, the current study has some limitations. firstly, it has a small sample size. secondly, the follow-up period is short. additionally, it is essential to note that the study only included patients with prostate volumes larger than 80cc, which may not represent patients with smaller prostate volumes. conclusions the number of patients with large prostate volumes undergoing surgical therapy is increasing, and the trend is likely to continue as the population ages. the present study found that tuerp had equivalent efficacy and safety to open retropubic prostatectomy for patients with bph and prostate volumes > 80 ml. references 1. gravas, scjn, cornu jn, gacci m, et al. management of nonneurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). european association of urology, 2019. (european association of urology. guidelines). 2. rao jm, yang jr, ren yx, et al. plasmakinetic enucleation of the prostate versus transvesical open prostatectomy for benign prostatic hyperplasia > 80 ml: 12-month follow-up results of a randomized clinical trial. urology. 2013; 82:176-81. 3. chen s, zhu l, cai j, et al. plasmakinetic enucleation of the prostate compared with open prostatectomy for prostates larger than 100 grams: a randomized noninferiority controlled trial with longterm results at 6 years. eur urol. 2014; 66:284-291. 4. elzayat ea, elhilali mm. holmium laser enucleation of the prostate (holep): long-term results, reoperation rate, and possible impact of the learning curve. eur urol. 2007; 52:1465-1472. 5. lourenco t, armstrong n, n’dow j, et al. systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement. health technol assess. 2008; 12: 1-146. 6. millin t. the surgery of prostatic obstructions. irish journal of medical science (1926-1967). 1947; 22:185-189. 7. miernik a, gratzke c. current treatment for benign prostatic hyperplasia. deutsches ärzteblatt international. 2020; 117:843. 8. hwang ec, jung jh, borofsky m, et al. aquablation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. cochrane database of systematic reviews. 2019; 2. 9. wei y, xu n, chen sh, et al. bipolar transurethral enucleation and resection of the prostate versus bipolar resection of the prostate for prostates larger than 60gr: a retrospective study at a single academic tertiary care center. international braz j urol. 2016; 42:747756. 10. ou r, deng x, yang w, et al. transurethral enucleation and resection of the prostate vs transvesical prostatectomy for prostate volumes > 80 ml: a prospective randomized study. bju international. 2013; 112:239-245. 11. geavlete b, bulai c, ene c, et al. bipolar vaporization, resection, and enucleation versus open prostatectomy: optimal treatment alternatives in large prostate cases. j endourol. 2015; 29:323-331. 12. xu p, xu a, chen b, et al. bipolar transurethral enucleation and resection of the prostate: whether it is ready to supersede turp? asian j urol. 2018; 5:48-54. 13. wang y, wang x. comparison of effects of transurethral enucleation of prostate and suprapubic prostatectomy in the treatment of massive prostatic hyperplasia. chinese journal of primary medicine and pharmacy. 2019; 2467-2470. 14. giulianelli r, gentile bc, mirabile g, et al. bipolar plasma enucleation of the prostate vs. open prostatectomy in large benign prostatic hyperplasia: a single centre 3-year comparison. prostate cancer and prostatic dis. 2019; 22:110-116. archivio italiano di urologia e andrologia 2023; 95(4):11629 i. tagreda, m. heikal, a. elatreisy, et al. 6 15. gratzke c, schlenker b, seitz m, et al. complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. j urol. 2007; 177:1419-1422. 16. tubaro a, carter s, hind a, et al. a prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. j urol. 2001; 166:172-176. 17. serretta v, morgia g, fondacaro l, et al. open prostatectomy for benign prostatic enlargement in southern europe in the late 1990s: a contemporary series of 1800 interventions. urology. 2002; 60:623-627. correspondence ibrahim tagreda, md itagreda@yahoo.com mahmoud heikal, md mahheikal1187@gmail.com adel elatreisy, md (corresponding author) dr_adelelatreisy@yahoo.com; adel.elatreisy@azhar.edu.eg mohamed fawzy salman, md prof_mohamed_fawzy@yahoo.com ahmed mohamed soliman, md a_soliman_1@hotmail.com ayman kotb koritenah, md dr.ayman.kotb@gmail.com hesham abozied, md aboziedhesham@gmail.com mohamed ibrahim algammal, md gemykarter2020@gmail.com ahmed a. alrefaey, md a7medrefa3y.ash@gmail.com mohamed elsalhy, md drsalhy2020@gmail.com mohamed shehab, md shehab810@gmail.com mahmoud mohammed ali, md dr_mahmoud72@hotmail.com aly gomaa eid, md alygomaa68@yahoo.com abdrabboh abdrabboh, md abdo197871@yahoo.com sayed eleweedy, md seleweedy2002@yahoo.com urology department, faculty of medicine, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12395 1 original paper introduction continent cutaneous diversion has proven to be an effective way of urinary diversion. yang-monti ileovesicostomy technique uses ileal segment as a conduit instead of appendix as originally described in mitrofanoff principle if appendix is not accessible. urodynamic is a clinical test or a series of clinical tests used to describe the current function or dysfunction of the lower urinary tract. in theory and in practice, the clinician utilizes the results of urodynamic testing to direct therapy whether surgical, medical, or behavioral alone or in combination. current methods include water filled urodynamic, ambulatory urodynamic, and video urodynamic. regardless of the method, urodynamic examines the functional anatomy of the bladder or urethra or both and their response to filling, storing, and voiding (1). urodynamic testing is an important tool in urology providing objective descriptions concerning the patient’s incontinence and voiding dysfunction (2). therefore, the objectives of this study was to analyze the static and dynamic urodynamic parameters of the reservoir and conduit affecting continence after continent cutaneous urinary diversion with catheterizable stoma using yang-monti technique. materials and methods between june 2018 and may 2023, 76 patients who had continent urinary diversion and catheterizable urinary stoma based on mitrofanoff principle and yang-monti techobjective: to analyze the static and dynamic urodynamic parameters of reservoirs and continent conduits in continent cutaneous urinary diversion with catheterizable stoma. materials and methods: 76 patients had augmented ileocystoplasty or continent urinary diversion with catheterizable urinary stoma based on mitrofanoff principle and yang-monti procedure using subserous tunnel as continence mechanism. they were followed up for at least 6 months post-operatively for continence through stoma and divided into two groups (continents vs non-continent) according to stomal continence. both groups had urodynamic assessment performed via the stoma to assess reservoir capacity, pressure and contractions, efferent limb functional length, reservoir overactivity, static and dynamic maximal closure pressures and leak point pressure. results: continence rate was 87%. continent group included 66 patients and incontinent group included 10 patients. in both groups at rest, the reservoir pressure after filling did not exceed 25 cm h2o. during peristaltic contraction, the pressure did not exceed 30 cm h2o and the duct remained continent. after valsalva maneuver, the reservoir pressure increased up to 34 (+ 7.4) cm h2o and leakage occur in 10 patients (13%). reservoir (wall) overactivity was recorded in 54 patients, with insignificant rise in intraluminal pressure during the contractions. in both groups, the efferent tract closing pressure was always higher than the reservoir pressure. the mean of maximal closing pressure at valsalva was 82.5 (+ 4.18) cm h2o in the continent group and 61.66 (+ 8.16) cm h2o in the incontinent group. the mean functional length of the conduit was 4.95 + 1.62 in the continent group and 2.80 + 1.50 cm in the incontinent group. conclusions: urodynamic evaluation of continent catheterizable cutaneous stoma after yang-monti procedure has a practical significance. functional length of the conduit seems to be the most influential factor for continence reflecting static & dynamic maximal closure pressure. higher conduit closing pressure is associated with better continence. contractions of the pouch the use of urodynamic to assess the mechanism of incontinence in patients with yang-monti based catheterizable cutaneous stomas m. abdelwadood 1, eman h. ibrahim 2, 3, tamer a. abouelgreed 4, yasser m. haggag 5, mohamed m. yassin 1, mohamed a. elhelaly 4, el-sayed i. el-agamy 4, basem fathi 4, salma f. abdelkader 6, sameh s. ali 7, naglaa m. aboelsoud 8, nasser ramadan 9, mohamed sobhy 10, tarek gharib 11 1 department of urology, faculty of medicine, ain shams university, cairo, egypt; 2 department of biomedical sciences, college of medicine, gulf medical university, ajman, uae; 3 department of pathology faculty of medicine, al-azhar university, cairo, egypt; 4 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 5 department of urology, faculty of medicine, al-azhar university, asyut, egypt; 6 department of radiology, faculty of medicine, ain shams university, cairo, egypt; 7 department of radiology, sheikh khalifa general hospital, uaq, uae; 8 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 9 department of urology, nmc royal hospital, sharjah, uae; 10 department of surgery, faculty of medicine, gulf medical university, ajman, uae; 11 department of urology, faculty of medicine, benha university, benha, egypt. doi: 10.4081/aiua.2024.12395 summary and peristaltic contraction of the conduit has no effect on continence mechanism. key words: incontinence; urodynamic; urinary diversion. submitted 18 february 2024; accepted 1 march 2024 archivio italiano di urologia e andrologia 2024; 96(2):12395 m. abdelwadood, eman h. ibrahim, tamer a. abouelgreed, et al. 2 nique in the institution of the authors were included in this study and prospectively studied and followed up post-operatively for continence through the stoma for a minimum of 6 months. the mean age of the patients at time of surgery was 19 years (5-59 years); 51 patients were males and 25 patients were females. the indications for continent diversion were (neurogenic bladder in 59 patients, bladder cancer in 13 patients, and congenital anomalies in 4 patients). sixty-one cases had augmented ileocystoplasty with a patch of detubularised ileum and 15 cases had their native bladder replaced by intestinal reservoir. an ileal segment with average length of 45 cm was detubularised and used as a reconfigured spherical reservoir for the ileovesicostomy procedure. surgery for bladder neck closure was performed in 37 patients of the augmented group. the patients were divided into two groups according to stomal continence. both groups had ascending pouchography and urodynamic study assessment performed via the stoma to assess reservoir capacity, pressure and contractions, efferent limb functional length, overactivity, static and dynamic maximal closure pressures and leak point pressure. the assessment was performed 15 days after the withdrawal of anticholinergic drugs and treatment of urinary tract infection. the patients who presented with reflux are excluded. state of continence was documented at 6 months and every 3 months later till end of the study. mean follow up period was 30.6 months (ranging from 9 to 48 months). urodynamic study was performed using a trans-stomal 6 french dual catheter and a 14 french rectal balloon catheter for pouchometry and pressure profilometry of the efferent tract. the rate of filling used was 50 ml/minute and the capacity measured at sense of discomfort or notice of leakage. the withdrawal of sensors was done with an electric arm at a speed of 2 ml/min. the static profile maximum closure pressure of the efferent limb was obtained by subtracting the baseline (empty) reservoir pressure from the maximum inner pressure of the efferent limb. the catheter was again passed into the reservoir and the side hole of the catheter was manually positioned at the point of the static profile maximal closure pressure of the conduit. the pouch was filled and the response of the conduit pressure to a reservoir contraction and/or abdominal strain (cough or crede) was recorded. the presence of involuntary reservoir contractions or conduit leak was noted. abrupt increase in conduit pressure without simultaneous changes in reservoir or abdominal pressure was considered evidence of peristaltic activity of the conduit. the dynamic profile maximal reservoir pressure was recorded, and dynamic profile maximal closure pressure of the efferent limb was derived by subtracting the greatest filling phase conduit pressure from simultaneous reservoir pressure. leak point pressure, compliance and reservoir capacity were evaluated. the functional length of the efferent limb was defined as the continuous length of the efferent limb in which the pressure was higher than the reservoir pressure. ethical approval and consent for participation all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of thumbay university hospital (affiliated with gulf medical university, rec #: 52/2018). statistical methods demographic data, reservoir capacity, functional length, closure pressures were reported using mean + standard deviation (sd). differences in means were assessed by student t test for significance. correlation among the continuous variables was analyzed using pearson correlation coefficient. dichotomous variables as continence status, contractions, functional length greater than 2.0 cm versus less were analyzed using chi-square test. results continence rate was 87%. continent group included 66 patients and incontinent group included 10 patients. no major surgical complications or mortality observed in the study. stomal complications were observed in 4 patients in form of stomal stenosis in 2 patients and difficult catheterization in further 2 patients. surgical revision was performed for 7 patients; in the 4 cases with stomal complications other than incontinence and in 3 cases with incontinence that were treated with injection of bulking agents with 2 successes and 1 failure after submucosal injection of bulking agent. the rest of the incontinent group were managed by frequent catheterization. the capacity of the reservoir was 496.8 (+180.27) ml (range 100-900). it was smaller in the incontinent group without a statistically significant difference. in both groups, the reservoir pressure at rest after filling did not exceed 25 cmh2o; the mean value was 20.72+6.05 cmh2o with no significant difference between continent and incontinent groups (table 1). peristaltic contractions of the reservoir were noted in 6 cases. during contractions, the pressure did not exceed 30 cmh2o and the duct remained continent. after valsalva maneuver, the reservoir pressure increased up to 41.4 cmh2o without significant difference between continence groups (table 1) and leakage occur in 10 patients. all patients had positive static and dynamic maximal conduit closure pressures. in every case the dynamic was greater than the static pressure reflecting a positive conduit to reservoir pressure gradient as the reservoir was filled to its capacity. the mean static and dynamic maximal closure pressures of the incontinent group were lower compared to those of the continent patients but the differences were not statistically significant (table 1). in both groups, the efferent tract closing pressure was always higher than the reservoir pressure. the mean efferent closing pressure at valsalva was 82.5 (+ 4.18) cmh2o in the continent group and 61.66 (+ 8.16) cmh2o in the incontinent group which demonstrated a highly significant difference (table 1). overactivity was recorded in 54 patients, with insignificant rise in intraluminal pressure during the contractions (table 2). the mean functional profile length of the conduit was 4.6 + 1.77 cm (ranging from 1.7 cm to 7.5 cm) and was correlated positively to continence status (table 3). the mean functional length of the continent and incontinent groups were 4.95 (+1.62) cm and 2.80 (+1.50) cm respectively with a highly significant difference (table 1). all the archivio italiano di urologia e andrologia 2024; 96(2):12395 3 urodynamic post yang-monti based catheterizable cutaneous stomas patients with conduit functional profile length of 2 cm or less were incontinent. further analysis of patients with functional length lower than 2 cm revealed a lower static profile maximal closure pressure compared to those with a functional profile length of greater than 2 cm. also, functional length was positively correlated to dynamic closure pressure (table 4). conduit peristalsis was observed in 29 patients. however, there was no statistically significant difference between incidence of conduit peristalsis in continent (23 patients/66) and incontinent (6 patients/10), by the measurement of functional profile length, static or dynamic maximal closure pressure (table 5). in our study, one patient was managed by surgical elongation of the tunnel and become completely dry on five hours interval between catheterization. discussion mitrofanoff principle was described to achieve continent urinary diversion through an appendiceal stoma in cases of compromised vesico-urethral function with inaccessible urethra (3). an alternative approach (yang-monti technique) using an opened ileal segment closed transversely was described later when the appendix could not be used or preserved for malone antegrade enema procedure (mace) (4). the monti ileovesicostomy has become an integral component of lower urinary tract reconstruction and more recently laparoscopic and robotically assisted techniques have been described also (5, 6). in the present study, the continence rate was 87%, that is lower than those achieved by studies which used appendicovesicostomy with continence rates ranging from 91 to 96% (7-9). other studies on monti technique suggested continence rates comparable to appendicovesicostomy (10). this result may be attributed to the high conduit intraluminal pressure achieved by appendiceal stoma (11) or inadequate surgical technique as inadequate flap valve mechanism, internal fistula or inadequate reservoir (12). the reservoir capacity was adequate in most cases with a mean cystometric capacity at 6 months of 496 ml due to detubularisation. smaller reservoir capacity was observed in incontinent group but without statistical significance, although seven patients of the incontinent group showed a capacity of 250-300 ml. these patients had to catheterize their pouch every two hours to avoid urine leak and during nighttime, an indwelling catheter had to be placed to avoid sleep interruption. the incontinence in the other three patients with adequate capacity can be explained by insufficient tunnel length, inadequate fixation of efferent channel to rectus sheath or angulation. one patient was managed by surgical elongation of the tunnel becoming completely dry at five hours interval between catheterizations. two cases were managed by submucosal injection of bulking agent which achieved temporary continence only for 2 months and required subsequent revision of the conduit to regain continence. these results support poor results observed in literature for bulking agent injection in ileal stomal incontinence (13, 14). stomal complications in this study were minimal (5.2%) in comparison to results of appendicovesicostomy observed in literature (15) and better than reports of other studies that suggested same rate of stomal complications for monti technique compared to appendicovesicostomy (11 to 19%) (10). the urodynamic study at rest showed low reservoir pressure due to detubularisation which delays and reduces the amplitude of the pressure rise caused by partial contractions and consequently accommodates higher volumes and prevents leakage. detrusor overactivity was detected in many patients but did not cause a significant rise in the reservoir pressure or associated leakage. the conduit pressure was an important factor contributing in efficacy of continent catheterizable stomas, being the higher the conduit pressure, the more the continence mechanism. the mean static and dynamic closure pressure of the conduit were lower in table 1. urodynamic data of the continent group in comparison to incontinent group. continent group incontinent group p-value reservoir capacity 500.95 + 182.64 ml 475.00 + 191.92 ml 0.79 reservoir pressure after filling 18.92 + 5.08 cmh2o 21.72 + 3.05 cmh2o 0.8 reservoir pressure after valsalva 30 + 5.6 cmh2o 34 + 7.4 cmh2o 0.86 efferent closing pressures 82.50 + 4.18 cmh2o 61.66 + 8.16 cmh2o < 0.001 functional length 4.95 + 1.62 cm 2.80 + 1.50 cm < 0.001 static maximal closure pressure 46.50 + 12.66 38.90 + 10.12 0.197 dynamic maximal closure pressure 68.75 + 8.53 66.90 + 11.88 0.771 table 2. intraluminal pressure in contracted reservoir versus non-contracted. groups no. of patients mean pressure + sd p value no contractions 54 19.8 + 6.58 0.363 reservoir contractions 22 22.1 + 5.17 table 4. correlations between functional length and maximal closure pressure. dynamic static functional length r .522** .056 p value .007 .790 n 25 25 table 5. conduit peristaltic contraction in relation to urodynamic data. groups mean + sd t p value static no peristalsis 38.41+ 9.238 0.76 0.45 peristalsis 41.69 + 11.967 dynamic no peristalsis 66.66 + 11.934 0.22 0.82 peristalsis 67.69 + 11.108 functional length no peristalsis 4.26 + 2.039 092 0.36 peristalsis 4.92 + 1.497 table 3. correlation between functional length and continence status. functional length continence pearson correlation 0.454 * 1 significance (2-tailed) 0.22 * correlation is significant at the 0.05 level. archivio italiano di urologia e andrologia 2024; 96(2):12395 m. abdelwadood, eman h. ibrahim, tamer a. abouelgreed, et al. 4 incontinent cases but the difference was not statistically significant. these results are similar to the results achieved by other studies (11, 16). the efferent tract closing pressure (with full reservoir) in our study was 75 cmh2o. this result is similar to the result obtained by appendicovesicostomy. however, most long-term studies supported durable results of appendicovesicostomy (11) where this is still to be proven for ileovesicostomy by future long term studies. the mean functional length was 4.6 cm and it showed a highly significant difference between continent and incontinent group. although static and dynamic closure pressures were not significantly different between continent and incontinent groups, there was a significant correlation between functional length and the maximum closure pressure. thus, the cause of incontinence can be attributed to length of the conduit more than reservoir capacity. strong peristaltic contractions of the conduits were demonstrated in some individuals but the overall effect of these pressure waves did not correlated with clinical continence or with any other urodynamic factor. conclusions urodynamic evaluation of continent catheterizable cutaneous stoma after yang-monti procedure has a practical significance. functional length of the conduit seems to be the most influential factor for continence reflecting static and dynamic maximal closure pressure. higher conduit closing pressure is associated with better continence. contractions of the pouch and peristaltic contraction of the conduit has no effect on continence mechanism. acknowledgments thanks to prof. dr. hossam hamdy, president of gulf medical university for his suggestion. references 1. abouelgreed t, saleh d, abdelaal m, et al. urodynamic changes following laparoscopic versus vaginal hysterectomy. arch ital urol androl. 2022; 94:315-318. 2. kupec t, pecks u, gräf cm, et al. size does not make the difference: 3d/4d transperineal sonographic measurements of the female urethra in the assessment of urinary incontinence subtypes. biomed res int. 2016; 2016:1810352. 3. ramanan v, kapoor r, srinadh es, et al. mitrofanoff principle for continent urinary diversion.urol int. 1997; 58:108-112. 4. monti pr, de carvalho jr. transverse tubulization of intestinal segments: a catheterizable conduit as an alternative to the mitrofanoff procedure. prog urol. 2001; 11:382-384. 5. thakre aa, yeung ck, peters c. robot-assisted mitrofanoff and malone antegrade continence enema reconstruction using divided appendix. j endourol. 2008; 22:2393-2396. 6. wille ma, zagaja gp, shalhav al, gundeti ms. continence outcomes in patients undergoing robotic assisted laparoscopic mitrofanoff appendico-vesicostomy. j urol. 2011; 185:1438-1443. 7. elshal am, abol-enein h, sarhan o, et al. catheterizable serous lined urinary outlet in children and adolescents: a choice when other treatments fail. j urol. 2011; 185:1083-1087. 8. mhiri mn, bahloul a, chabchoub k. mitrofanoff appendicovesicostomy in children: indication and results. prog urol. 2007; 17:245-249. 9. surer i, ferrer fa, baker la, gearhart jp. continent urinary diversion and the exstrophy-epispadias complex. j urol. 2003; 169:11021105. 10. clark t, pope jc 4th, adams mc, et al. factors that influence outcomes of the mitrofanoff and malone antegrade continence enema reconstructive procedures in children. j urol. 2002; 168:1537-1540. 11. chabchoub k, ketata h, fakhfakh h, et al. continent urinary diversion (mitrofanoff principle). physical mechanisms and urodynamic explanation of continence. prog urol. 2008; 18:120-124. 12. cain mp, andrew md, anthany jg, et al. updated experience with the monti catheterizable channel. pediatric urology 2008; 72:782-785. 13. gowda bo, agrawal v, harrison sc. the continent catheterizable abdominal conduit in adult urological practice. bju int; 2008; 102:1688-1692. 14. welk bk, afshar k, rapoport d, macneily ae. complications of the catheterizable channel following continent urinary diversion: their nature and timing. j urol 2008; 180:1856-1860. 15. van der af, joniau s, de baets k, de ridder d. continent catheterizable vesicostomy in an adult population: success at high costs. neurourol urodyn. 2009; 28:487-4891. 16. watson hs, bauer sb, peters ca, et al. comparative urodynamics of appendiceal and ureteral mitrofanoff conduits in children. j urol 1995; 154:878-882. correspondence eman h. ibrahim, md (corresponding author) dr.eman@gmu.ac.ae department of biomedical sciences, college of medicine, gulf medical university, ajman, uae & department of pathology, faculty of medicine, al-azhar university, cairo, egypt m. abdelwadood, md wadoodaref@gmail.com mohamed m. yassin, md yassinmmm@med.asu.edu.eg department of urology, faculty of medicine, ain shams university, cairo, egypt tamer a. abouelgreed, md dr_tamer_ali@yahoo.com mohamed a. elhelaly, md elhelalymohammed@yahoo.com el-sayed i. el-agamy, md abuamr1978@yahoo.com basem fathi, md basemhara@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt yasser m. haggag, md uro_doc@yahoo.com department of urology, faculty of medicine, al-azhar university, asyut, egypt salma f. abdelkader, md salmafathy4@gmail.com department of radiology, faculty of medicine ain shams university, cairo, egypt sameh s. ali, md drsamehsaied@yahoo.com department of radiology, sheikh khalifa general hospital, uaq, uae naglaa m. aboelsoud, md nglaa.mahmoud@gmail.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt nasser ramadan, md nasseruro99@gmail.com department of urology, nmc royal hospital, sharjah, uae mohamed sobhy, md mss54482000@yahoo.com department of surgery, faculty of medicine, gulf medical university, ajman, uae tarek gharib, md tarekgh78@yahoo.com department of urology, faculty of medicine, benha university, benha, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper genetic predisposition and environmental influence, as for dietary habits (3, 4). besides, it is known to be associated with a wide spectrum of comorbidities such as obesity (5), arterial hypertension (6), diabetes mellitus (7), metabolic syndrome (8) and increased likelihood of developing chronic kidney disease, especially in secondary forms of systemic diseases (9). it was also shown that patients with urolithiasis have an increased risk of cardiovascular events (10) and vascular calcifications (11), highlighting the systemic involvement of this condition. kidney stones develop attached to either randall’s plaques (sub-epithelial interstitial deposits of calcium phosphate on the renal papillae), or stone plugs (crystal deposits in the terminal collecting ducts) (12). both these can be seen on the papillary surfaces. what promotes plaque formation is not well understood. it has been suggested that idiopathic calcium oxalate stones normally develop on randall’s plaques and that secondary forms of stones are mainly formed from plugs (12). a better understanding of both etiology and pathogenesis of the different forms of nephrolithiasis is fundamental to prevent recurrences with a more personalized and causespecific medical treatment. the improved optical ureterorenoscopic inspection techniques may make the evaluation of renal papilla not only possible but hopefully able to produce a large amount of new data and evidence as to the pathogenesis of stones (13). recently, a renal papillary appearance scoring system was proposed, in order to better characterize and to standardize the visual inspection of renal papillae (ppla score) (14). although it could certainly be a useful tool for improving reproducibility in the description of pathological findings in different patients and centers, at this moment the potential implications of this score on kidney stone risk factors are not well understood. the aim of this study is therefore to investigate the association between the main risk factors for kidney stone recurrence and the endoscopic papillary evaluation score (ppla) in a cohort of patients with nephrolithiasis. the association between ppla and subsequent recurrence was also investigated. objectives: the aim of this study is to investigate the association between the urinary metabolic milieu and kidney stone recurrence with a validated papillary evaluation score (ppla). materials and methods: we prospectively enrolled 30 stone formers who underwent retrograde intrarenal surgery procedures. visual inspection of the accessible renal papillae was performed to calculate ppla score, based on the characterization of ductal plugging, surface pitting, loss of papillary contour and randall’s plaque extension. stone compositions, 24h urine collections and kidney stone events during follow-up were collected. relative supersaturation ratios (rss) for calcium oxalate (caox), brushite and uric acid were calculated using equil-2. ppla score > 3 was defined as high. results: median follow-up period was 11 months (5, 34). ppla score was inversely correlated with bmi (or 0.59, 95% ci 0.38, 0.91, p = 0.018), type 2 diabetes (or 0.04, 95% ci 0.003, 0.58, p = 0.018) and history of recurrent kidney stones (or 0.17, 95% ci 0.04, 0.75, p = 0.019). the associations between ppla score, diabetes and bmi were not confirmed after excluding patients with uric acid stones. higher ppla score was associated with lower odds of new kidney stone events during follow-up (or 0.15, 95% ci 0.02, 1.00, p = 0.05). no other significant correlations were found. conclusions: our results confirm the lack of efficacy of ppla score in phenotyping patients affected by kidney stone disease or in predicting the risk of stone recurrence. larger, long-term studies need to be performed to clarify the role of ppla on the risk of stone recurrence. key words: kidney stones; retrograde intrarenal surgery; stone recurrence; management; stone phenotype. submitted 19 july 2022; accepted 20 august 2022 introduction nephrolithiasis is a medical condition characterized by a high prevalence in the general population and high recurrence rates (1), causing an elevated annual expenditure reaching up to $10 billion in the united states (2). kidney stone disease pathogenesis is multifactorial, including determinants of renal papillary appearance in kidney stone formers: an in-depth examination matteo bargagli 1, 2, francesco pinto 3, rossella de leonardis 1, mauro ragonese 3, angelo totaro 3, salvatore recupero 4, matteo vittori 5, pierfrancesco bassi 1, 3, giovanni gambaro 6, pietro manuel ferraro 1, 2 1 dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma, italia; 2 u.o.s. terapia conservativa della malattia renale cronica, dipartimento di scienze mediche e chirurgiche, fondazione policlinico universitario a. gemelli irccs, roma, italia; 3 u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs, roma, italia; 4 u.o.c. urologia, ospedale fatebenefratelli, rome, italy; 5 department of urology, san carlo di nancy hospital, rome, italy; 6 renal unit, department of medicine, university-hospital of verona, verona, italy. doi: 10.4081/aiua.2023.10748 summary archivio italiano di urologia e andrologia 2023; 95, 1 m. bargagli, f. pinto, r. de leonardis, et al. materials and methods study population we prospectively enrolled all patients undergoing retrograde intrarenal surgery (rirs) procedures for kidney stones at the u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs from may 2018 to september 2019. all patients were stone-free after rirs procedure. additional inclusion criteria were age ≥ 18 years and signed informed consent. at study initiation, all patients were naïve for dietary advice and medical treatment for kidney stone recurrence. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. the study was approved by the bioethics committee of the fondazione policlinico univer sitario a. gemelli irccs, università cattolica del sacro cuore, rome, italy (id n° 2349). informed consent was obtained from all individual participants included in the study. data collection and measurements patients included in this study performed a baseline visit after rirs procedure at the nephrology stone clinic, fondazione policlinico universitario a. gemelli irccs, rome, italy, followed by a 1-year telephonic interview for investigating incident kidney stone events. either a visible spontaneous passage of stone, evidence of kidney stones at any instrumental exam or new kidney stones removal procedure, were considered as a recurrence and the variable “overall recurrent kidney stone disease at the end of the study” was generated accordingly. for each patient, demographic and anthropometric information (sex, age, height, weight), clinical data regarding stone disease (history of symptomatic stone events, family history of kidney stones, solitary kidney), self-reported comorbidities (hypertension, diabetes, cardiovascular diseases, bone fractures), a physical examination and office blood pressure measurements were recorded. standardized urine analyses (urine ph, daily urinary excretion of calcium, phosphate, magnesium, sodium, potassium, creatinine, urea, citrate, uric acid and oxalate) were conducted. stones were routinely collected during rirs procedures, in order to obtain composition analysis, using fourier-transform infrared spectroscopy. the creatinine-based ckd-epi equation was used to obtain the estimated glomerular filtration rate (egfr). among the metabolic evaluation parameters, the main one is represented by supersaturation for calcium oxalate, calcium phosphate and uric acid, representing the propensity of urine to form those crystals. urine relative supersaturation ratios (rss) for calcium oxalate monohydrate, brushite and undissociated uric acid were calculated by the equil2 program (15). visual inspection of the accessible renal papillae during rirs procedures was performed in order to calculate a score of papillary appearance (ppla score). ppla score is based on the characterization of 4 ordinal variables (ductal plugging, surface pitting, loss of papillary contour and randall’s plaque extension), representing worsening pictures of renal involvement. ppla score is an ordinal variable and it ranges from a minimum of 0 to a maximum of 8, produced by the sum of 4 components; each sub-component is an ordinal variable with 3 levels (from 0 to 2). in this study, the modified version of ppla score was used, considering randall’s plaque extension as an ordinal numeric variable (table 1) (16). all the images were evaltable 1. ppla score system for renal papillae (16). score 0 1 2 ductal plugging 0 plaque deposits/ ≤ 5 plaque deposits/ > 5 plaque deposits/ dilated ducts dilated ducts dilated ducts surface pitting none ≤ 25% papillary surface > 25% papillary surface loss of contour none depressed flattened randall’s plaque extension low medium high table 2. baseline characteristics of the study cohort. characteristic participants (n = 30) males 19 (63) age, years 60.2 (12) sbp, mmhg 130 (10) dbp, mmhg 83 (5) body mass index, kg/m2 25.8 (4) egfr creatinine equation ckd-epi 2009, ml/min per 1.73 m2 84.2 (19) arterial hypertension 14 (47) diabetes 3 (10) cardiovascular disease 6 (20) bone fractures 2 (7) hyperparathyroidism 1 (3) positive family history for kidney stones 11 (37) history of recurrent kidney stones 10 (33) solitary kidney 1 (3) 1-year kidney stone recurrence 9 (30) ppla score subgroups (0-6) 0 1 (3) 1 1 (3) 2 7 (23) 3 4 (13) 4 5 (17) 5 9 (30) 6 3 (10) high ppla score (> 3) 17 (57) rss for calcium oxalate 35.52 (20.20, 64.31) rss for calcium phosphate 0.42 (0.23, 1.82) rss for uric acid 1.03 (0.77, 1.89) urine ph 5.5 (5.0, 6.0) urine calcium, mg/day 183 (122, 283) urine phosphate, mg/day 770 (600-988) urine uric acid, mg/day 450 (326, 552) urine citrate, mg/day 427.1 (177.35, 614.7) urine oxalate, mg/day 19.5 (15.0, 26.8) urine creatinine, g/day 1.2 (1.0, 1.7) urine sodium, meq/day 145.9 (138.3, 191.0) urine potassium, meq/day 59.4 (48.0, 78.0) urine magnesium, mg/day 100.0 (80.2, 120.0) urine volume, ml/day 2,000 (1,550, 2,400) hypercalciuria 6 (20) hyperoxaluria 2 (7) hypocitraturia 11 (37) calcium oxalate stones 17 (57) urate stones 3 (9) calcium phosphate stones 0 mixed calcium oxalate and urate stones 5 (17) mixed calcium oxalate and calcium phosphate stones 8 (26) archivio italiano di urologia e andrologia 2023; 95, 1 renal papillary appearance in stone formers uated one by one from 4 expert surgeons (> 50 flexible ureteroscopy for renal stones) and 5 junior surgeons (< 50 procedures performed). all the graders evaluated the videos of the papillae using the same video system and were allowed to review the video more than one time. moreover, the percentage of agreement for the single item was evaluated in the two subgroups of surgeons and among senior graders, to ensure inter-grader concordance. hypercalciuria was considered as urine calcium excretion > 250 mg/24h for women and 300 mg/24h for men, hyperuricosuria as urine uric acid excretion > 750 mg/24h for women and 800 mg/24h for men, hyperoxaluria as urine oxalate excretion > 45 mg/24h and hypocitraturia as urine citrate excretion < 320 mg/24h (17). statistical analysis continuous variables were reported as medians with 25th and 75th percentiles or means with standard deviation (sd) and categorical variables were reported as counts with percentages. ppla score > 3 was defined as high. the interobserver surgeon concordance among all 10 investigators and between the median values of the two subgroups (junior vs senior) was analysed by the kendall coefficient of concordance. ordinal logistic regression was used to analyse the association between stone risk factors (hypertension, diabetes, body mass index, cardiovascular disease, history of recurrent kidney stones, family history of kidney stones, rss for calcium oxalate, calcium phosphate and uric acid, urine ph, urinary excretions of calcium, oxalate, citrate, uric acid and urine volume) and ppla and its components (ductal plugging, surface pitting, loss of papillary contour, randall’s plaque extension). the analyses were repeated after modelling ppla as lower (≤ 3) and higher (> 3) using logistic regression models. the association between ppla and 1-year kidney stone recurrence was analysed with logistic regression models. statistical tests were two-sided and a p-value < 0.05 was considered statistically significant. statistical analyses were performed using the software stata version 16 (statacorp, college station, tx, usa). results a total of 30 stone formers were enrolled in this study. mean age was 60.2 (sd 12.4) years and most patients were males (n = 19, 63%). overall, 47% were hypertensive (n = 14), 10% were diabetic (n = 3), 20% presented cardiovascular comorbidities (n = 6). as regards kidney stone disease, 33% had a positive history of recurrence (n = 10) and 37% had a positive family history of stones (n = 11). stone composition analysis, available in 23 patients (69%), revealed that calcium oxalate stones were the most frequent (56.5%), followed by mixed calcium oxalate and calcium phosphate stones (26.1%) (table 2). overall, 20% of the study sample had hypercalciuria (n = 6), 37% hypocitraturia (n = 11) and 7% hyperoxaluria (n = 2). the most frequent total ppla score was 5 (n = 9, 30%) and 57% of patients had a ppla score > 3 (n = 17). concordance between surgeon groups in the evaluations of plugging, pitting, loss of papillary contour and randall’s plaque extension were 86%, 73%, 72% and 80%, respectively. among senior surgeons concordance was even higher with a percentage of 91%, 80%, 76% and 85% agreement. the kendal coefficient of concordance was 0.93 among senior surgeons and 0.88 comparing the two groups of senior and junior surgeons. ppla score was inversely correlated with bmi (odds ratio [or] 0.59, 95% confidence interval [ci] 0.38, 0.91, p = 0.018), type 2 diabetes mellitus (or 0.04, 95% ci 0.003, 0.58, p = 0.018) and history of recurrent kidney stones (or 0.17, 95% ci 0.04, 0.75, p = 0.019) (table 3). the associations between type 2 diabetes and bmi with ppla score were not confirmed after excluding patients with uric acid stones. among the ppla components, randall’s plaque table 3. association between ppla score and risk factors for kidney stones or stone recurrence. ppla score high ppla score (> 3) variable no odds ratio 95% ci p-value no odds ratio 95% ci p-value hypertension 30 0.42 0.11, 1.57 0.197 30 0.34 0.08, 1.52 0.159 diabetes 30 0.04 0.003, 0.58 0.018* 30 0.33 0.99, 1.09 0.069 body mass index, kg/m2 30 0.59 0.38, 0.91 0.018* 30 0.78 0.61, 0.99 0.039 cardiovascular disease 30 0.98 0.21, 4.68 0.979 30 0.71 0.12, 4.30 0.713 history of recurrent kidney stones 30 0.17 0.04, 0.75 0.019* 30 0.08 0.01, 0.53 0.009 positive family history for kidney stones 30 1.83 0.48, 6.98 0.379 30 1.58 0.34, 7.22 0.559 1-year kidney stone recurrence 27 0.81 0.48, 1.37 0.426 27 0.15 0.02, 1.00 0.050* overall recurrent kidney stone disease 30 0.10 0.02, 0.48 0.004* 30 0.03 0.01, 0.28 0.001* rss for caox 30 1.01 0.99, 1.03 0.529 30 1.00 0.95, 1.06 0.948 rss for brushite 20 0.94 0.64, 1.37 0.726 20 0.54 0.23, 1.26 0.153 rss for uric acid 7 0.97 0.65, 1.45 0.887 7 not estimatable urinary excretion of calcium, mg/day 29 1.001 1.00, 1.01 0.657 29 1.00 1.00, 1.01 0.294 urinary excretion of oxalate, mg/day 30 0.95 0.90, 1.01 0.098 30 0.97 0.91, 1.03 0.330 urinary excretion of citrate, mg/day 30 1.00 1.00, 1.01 0.493 30 1.00 1.00, 1.00 0.934 urinary excretion of uric acid, mg/day 7 1.00 0.99, 1.01 0.488 7 1.00 0.99, 1.01 0.815 urinary excretion of sodium, meq/day 28 0.98 0.96, 1.00 0.050* 28 0.97 0.93, 1.01 0.150 urinary volume, ml/day 30 0.81 0.19, 3.43 0.774 30 0.48 0.09, 2.53 0.385 urine ph 30 1.10 0.41, 2.93 0.853 30 1.84 0.53, 6.38 0.337 archivio italiano di urologia e andrologia 2023; 95, 1 m. bargagli, f. pinto, r. de leonardis, et al. extension was inversely associated with history of recurrent kidney stones (or 0.03, 95% ci 0.003, 0.23, p = 0.001) (table 4). no other significant correlations were found between ppla components and kidney stone risk factors. after a median follow-up period of 11 months (5, 34), 30% of patients reported a new symptomatic kidney stone event (n = 9). higher ppla score was directly associated with lower odds of new kidney stone events during follow-up (or 0.15, 95% ci 0.02, 1.00, p = 0.050) and reduced likelihood of overall recurrent kidney stone disease at the end of the study (or 0.03, 95% ci 0.01, 0.28, p = 0.001). discussion novel methods capable of predicting the risk of stone recurrence and to better understand stone phenotype aetiology based on intra-renal crystals deposition are missing. in addition, three different hypotheses regarding the pathophysiology of stone formation have been proposed. the first hypothesis is randall’s plaque formation, with deposition of calcium phosphate crystals in form of apatite inside interstitial parenchyma. the second regards free solute crystallization for urine stasis and the third implies renal tubules crystal deposition as the nucleation factor for stone formation (18). recently, endoscopic visualization of the accessible portion of renal papillae and collecting duct system were applied for differentiating these pathways, creating a promising additional tool for future evaluation of recurrent stone formers (14). afterwards, a score of papillary appearance was created to study the association between stone phenotypes, urinary solute excretions and the description and quantification of either randall’s plaque, bellini duct plugging, focal erosion of papillary surface (pitting) and loss of papillary contour extensions (16). it can be then hypothesized that ppla score and its subscores might be of help in differentiating patients with the same stone composition, urinary lithogenic risk profile or recurrence risk but with diverse papillary aspects, perhaps reflecting multiple concomitant pathogenesis of nephrolithiasis. for these reasons, the use of ppla score was recently recommended in all patients who undergo ureteroscopy (19). however, evidence on the association between ppla score, stone composition and urinary solute excretions is conflicting. in a previous study, kuo et al. analyzed 14 stone formers, firstly showing the association between higher urinary calcium excretion, urine ph and urine volume on randall’s plaque extension (20), whereas analyzing larger cohorts of stone formers, linnes et al. (21) and pless et al. (22) did not confirm this association. in addition, sabaté arroyo et al. showed both increased frequency of intratubular calcification and papillary crater in patients with calcium oxalate dihydrate and calcium phosphate stones and a correlation between higher urinary calcium excretion and low urinary citrate excretion with papillary crater and randall’s plaque extension, respectively (23). in the present study, hypercalciuria and hypocitraturia were the most frequent 24-h urine abnormalities, reflecting data of the most common urinary lithogenic risk profile in the general population (24, 25). although we did not report any significant association between ppla score or sub-scores and stone composition, rss for calcium oxalate, brushite and uric acid or urinary lithogenic risk profile, both diabetes and bmi were found to be inversely correlated to ppla score. however, after excluding patients with uric acid stones, the former correlations were not confirmed. the association between increased risk for incident kidney stones and obesity, bmi and diabetes has been known for a long time (26). both type 2 diabetes mellitus and obesity share similar pathogenesis table 4. association between each ppla sub-score (ductal plugging, surface pitting, loss of papillary contour, randall’s plaque extension) and risk factors for kidney stones or stone recurrence. ductal plugging surface pitting loss of papillary contour randall’s plaque extension variable no or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value or (95% ci) p-value hypertension 30 0.27 (0.06, 1.17) 0.080 0.77 (0.18, 3.34) 0.728 0.53 (0.10, 2.74) 0.448 1.02 (0.23, 4.48) 0.980 diabetes 30 0.32 (0.32, 0.35) 0.294 0.17 (0.01, 2.15) 0.171 0.09 (0.01, 1.17) 0.065 0.00 (0.31, 3.43) 0.995 bmi 30 0.91 (0.76, 1.10) 0.328 0.83 (0.68, 1.02) 0.079 0.91 (0.74, 1.13) 0.393 0.86 (0.69, 1.07) 0.174 cardiovascular disease 30 1.12 (0.19, 6.59) 0.904 0.68 (0.12, 3.99) 0.670 0.88 (0.13, 6.12) 0.894 2.12 (0.30, 14.82) 0.447 history of recurrent kidney stones 30 0.32 (0.07, 1.41) 0.131 0.64 (0.13, 3.06) 0.575 0.33 (0.06, 1.88) 0.213 0.03 (0.00, 0.23) 0.001* familiarity for kidney stones 30 1.88 (0.44, 8.10) 0.395 2.40 (0.48, 11.93) 0.285 0.68 (0.13, 3.60) 0.648 1.27 (0.28, 5.87) 0.757 1-year kidney stone recurrence 27 0.37 (0.09, 1.41) 0.145 0.50 (0.11, 2.27) 0.369 2.25 (0.41, 12.38) 0.351 0.67 (0.14, 3.21) 0.619 overall recurrent kidney stone disease 30 0.13 (0.03, 0.65) 0.013* 0.21 (0.04, 1.07) 0.061 0.48 (0.92, 2.51) 0.385 0.10 (0.17, 0.62) 0.013* rss for caox 30 1.01 (0.98, 1.03) 0.618 1.00 (0.98, 1.03) 0.802 1.00 (0.97, 1.03) 0.870 1.03 (0.99, 1.06) 0.122 rss for brushite 20 0.97 (0.66, 1.43) 0.870 0.97 (0.71, 1.32) 0.829 0.81 (0.57, 1.15) 0.229 1.00 (0.71, 1.41) 0.990 rss for uric acid 5 2.95 (0.03, 317.29) 0.650 0.01 (0.00, 22.90) 0.235 1.30 (0.58, 2.90) 0.526 1.95 (0.31, 27.19) 0.675 urinary excretion of calcium, mg/day 29 1.01 (1.00, 1.01) 0.138 1.00 (1.00, 1.01) 0.683 1.00 (0.99, 1.00) 0.209 1.00 (1.00, 1.01) 0.641 urinary excretion of oxalate, mg/day 30 0.98 (0.93, 1.04) 0.559 0.95 (0.89, 1.02) 0.134 0.95 (0.89, 1.02) 0.157 0.99 (0.93, 1.06) 0.826 urinary excretion of citrate, mg/day 30 1.00 (1.00, 1.00) 0.797 1.00 (0.99, 1.00) 0.147 1.00 (0.99, 1.00) 0.187 1.00 (1.00, 1.01) 0.173 urinary excretion of uric acid, mg/day 7 1.00 (0.99, 1.01) 0.993 0.99 (0.98, 1.00) 0.138 1.00 (0.99, 1.01) 0.455 1.04 (0.97, 1.12) 0.284 urinary excretion of sodium, meq/day 28 0.98 (0.96, 1.01) 0.180 0.98 (0.96, 1.00) 0.102 0.98 (0.96, 1.00) 0.101 0.99 (0.97, 1.02) 0.530 urinary volume, ml/day 30 0.78 (0.179, 3.45) 0.748 1.49 (0.30, 7.53) 0.629 0.59 (0.10, 3.40) 0.551 0.56 (0.10, 2.99) 0.496 urine ph 30 1.62 (0.53, 4.93) 0.400 1.18 (0.37, 3.82) 0.777 0.26 (0.06, 1.06) 0.060 1.47 (0.46, 4.68) 0.512 archivio italiano di urologia e andrologia 2023; 95, 1 renal papillary appearance in stone formers (27), being part of the metabolic syndrome, which is tightly associated to insulin resistance (28). insulin resistance results in acidic urine ph and defective renal production of ammonia, increasing the likelihood of developing uric acid kidney stones (8). notably, with a correct urinary alkalization, it is possible to reduce or even dissolve previously formed uric acid stones, provided the absence of combined uric acid and calcium stone composition (29). thus, the association between higher bmi, type 2 diabetes and lower ppla score, may be driven by uric acid nephrolithiasis, since it was no longer significant after restriction to calcium stone formers. however, there were too few uric acid stone formers in our cohort to confirm these observations. in this study on a prospective cohort of 30 stone formers, the association between ppla score and the risk of 1-year kidney stone recurrence was investigated for the first time. we demonstrated an inverse association between high ppla score and the odds of stone recurrence after a median follow-up time of 11 months. patients enrolled in this study were naïve for dietary advice and medical treatment for kidney stone disease. after rirs procedure, they underwent a work-up and dietary/medical management based on the results of 24h urine collections as well as their medical history; 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37:2207-2215. 23. sabaté arroyo xa, grases freixedas f, bauzà quetglas jl, et al. relationship of endoscopic lesions of the renal papilla with type of renal stone and 24 h urine analysis. bmc urol. 2020; 20:46. 24. metze d, cury vf, gomez rs, et al. hypocitraturia. in: lang f, ed. encyclopedia of molecular mechanisms of disease. springer berlin heidelberg; 2009:969-970. 25. pozdzik a, maalouf n, letavernier e, et al. meeting report of the “symposium on kidney stones and mineral metabolism: calcium kidney stones in 2017.” j nephrol. 2019; 32:681-698. archivio italiano di urologia e andrologia 2023; 95, 1 m. bargagli, f. pinto, r. de leonardis, et al. 26. poore w, boyd cj, singh np, et al. obesity and its impact on kidney stone formation. rev urol. 2020; 22:17. 27. daudon m, traxer o, conort p, et al. type 2 diabetes increases the risk for uric acid stones. jasn. 2006; 17:2026-2033. 28. maalouf nm, cameron ma, moe ow, et al. low urine ph: a novel feature of the metabolic syndrome. cjasn. 2007; 2:883-888. 29. moran me, abrahams hm, burday de, greene td. utility of oral dissolution therapy in the management of referred patients with secondarily treated uric acid stones. urology. 2002; 59:206-210. 30. ferraro pm, vittori m, macis g, et al. changes in renal papillary density after hydration therapy in calcium stone formers. bmc urol. 2018; 18:101. correspondence matteo bargagli, md matteo.bargagli@unicatt.it pietro manuel ferraro, md msc phd fera (corresponding author) pietromanuel.ferraro@unicatt.it u.o.s. terapia conservativa della malattia renale cronica, dipartimento di scienze mediche e chirurgiche, fondazione policlinico universitario a. gemelli irccs & dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma, italia largo agostino gemelli 8, 00168, roma (italy) francesco pinto, md francesco.pinto@unicatt.it mauro ragonese, md mauro.ragonese@unicatt.it angelo totaro, md angelo.totaro@policlinicogemelli.it pierfrancesco bassi, md pierfrancesco.bassi@unicatt.it u.o.c. clinica urologica, fondazione policlinico universitario a. gemelli irccs, roma (italy) rossella de leonardis, md rosselladeleonardis95@gmail.com dipartimento universitario di medicina e chirurgia traslazionale, università cattolica del sacro cuore, roma (italy) salvatore recupero, md salvatoremarcorecupero@gmail.com u.o.c. urologia, ospedale fatebenefratelli, rome (italy) matteo vittori, md mvittori@gvmnet.it department of urology, san carlo di nancy hospital, rome (italy) giovanni gambaro, md giovanni.gambaro@univr.it renal unit, department of medicine, university-hospital of verona, verona (italy) conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 87archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. clinically, pd has two distinct phases: inflammatory (acute), when there is pain and the onset and progression of penile deformity; and fibrotic (chronic), when there is stabilization of the penile curvature, cessation of the pain, and possibly the formation of a well-defined plaque on the corpora cavernosa (4). surgical treatment for pd is reserved for patients who are in the second stage of the disease, with stable tortuosity for at least three to six months. there are basically two types of procedures for correction of penile curvature: tunical shortening and tunical lengthening techniques (5). the latter consists in plaque incision/excision and grafting, following this indication: patients without refractory erectile dysfunction (ed), with curvatures greater than sixty degrees, complex deformities or in patients with smaller curvatures but significant penile shortening for plication procedures (6, 7). the ideal graft should be traction resistant, easy to suture and manipulate, flexible, readily available, cost-effective and with minimal associated morbidity. so far, no material studied has met all these criteria. several studies have analyzed the use of autografts, allografts and xenografts. synthetic grafts are historically not recommended, due to the increased risk of infection, allergic reactions and material rejection. the use of bioabsorbable synthetic grafts, on the other hand, has been little studied to date (8-11). the aim of this study was to perform a descriptive analysis about functional results with the use of a bioabsorbable graft in the setting of peyronie's disease surgical treatment. materials and methods the present study protocol was reviewed and approved by the institutional review board of hospital governador celso ramos (approval no. 47537021.0.0000.5360). informed consent was submitted by all subjects when they were enrolled. psychological counseling was offered to all patients before the surgery, although it was not considered obligatory. a single-center, retrospective cohort study of patients undergoing treatment for peyronie's disease using a bioabsorbable graft between 2018 and 2021 was conducted. the graft used was the gore® bio-a® (w.l. gore & associates, inc. flagstaff, arizona, us), composed of a network of synthetic polymers (67% of polygobjective: plaque incision and grafting is indicated for patients with peyronie’s disease [pd] and severe curvature, complex deformities or for patients with significant penile shortening. to date, no graft studied has been considered ideal. the aim of this study is to conduct a descriptive analysis about functional results with the use of a bioabsorbable graft for pd treatment. materials and methods: a single-center, retrospective evaluation of a cohort of patients who were treated by plaque incision and grafting with a polyglycolic acid polymer graft (gore® bio-a®) between 2018 and 2021 was conducted. correction of penile curvature was the main outcome. loss of penile sensitivity, de novo erectile dysfunction and any other adverse event were the secondary endpoints. results: 14 patients were included in this study (mean age 59.5 ± 7.2 years). the median follow-up time was 12 months (range 3-12). the curvature correction rate was 78.5%. glans hypoesthesia was present in one of 14 patients (7.1%) and refractory erectile dysfunction was reported in 64.2%. none of the patients presented any major adverse event based on clavien-dindo classification. conclusions: curvature correction and changes in penile sensitivity rates were similar to those found in the literature. no major surgical complications, such as graft rejection, infection, and extrusion, occurred in this sample. although a population with a higher prevalence of erectile dysfunction was included in this sample, higher rates of refractory erectile dysfunction were observed and these findings should be confirmed in further studies. key words: peyronie’s disease; penile induration; penile curvature; erectile dysfunction; bioabsorbable implants; polyglycolic acid. submitted 21 december 2021; accepted 18 january 2022 introduction peyronie's disease (pd) is characterized by a disorder of the connective tissue of the penis that affects the tunica albuginea, which can lead to local pain and tortuosity. although the etiology is unknown, the most accepted hypothesis is repetitive microvascular trauma, leading to inflammation, fibrinogenesis and excessive collagen deposition on the tunica albuginea, facilitated by risk factors such as hypertension, diabetes, dyslipidemias, smoking and alcoholism (1-3). the use of a polyglycolic acid polymer graft in peyronie’s disease preliminary outcomes pedro caetano edler zandoná 1, nivio pascoal teixeira 1, henrique eduardo oliveira 1, jorge hamilton soares garcia 2 1 department of urology of hospital governador celso ramos, florianópolis, brazil; 2 department of anesthesiology of hospital governador celso ramos, florianópolis, brazil. doi: 10.4081/aiua.2022.1.87 summary archivio italiano di urologia e andrologia 2022; 94, 1 p.c. edler zandoná, n.p. teixeira, h.e. oliveira, j. hamilton soares garcia 88 lycolic acid and 33% trimethylene carbonate) which are gradually absorbed by the body and registered by anvisa for use in humans as a soft tissue substitute. the inclusion criteria for this study were all patients undergoing treatment for pd using the bio-a® graft between 2018 and 2021 at hospital governador celso ramos, florianópolis, state of santa catarina, brazil. no exclusion criteria were applied. data was obtained exclusively from medical charts retrospective review, and patients’ identity was kept confidential. curvature correction, was the primary endpoint, characterized by the absence of residual curvature greater than 15 degrees. all patients underwent interview and physical examination during the routine postoperative follow-up visits. patients who reported residual curvature underwent artificial erection in the office to confirm this finding. secondary endpoints were penile sensory change, postoperative ed and surgical complications (based on clavien-dindo classification). the secondary outcomes were also assessed through anamnesis and physical examination performed during routine follow-up visits and described in the patients’ medical chats. refractory ed, identified preor postoperatively, was characterized as the self-reported inability to develop or maintain an erection despite the use of phosphodiesterase type 5 inhibitors (pde5i). patients were informed about the risks of erectile function worsening, and the possibility of penile prosthesis implantation in a second-stage surgery. surgical technique was similar in all cases. under general anesthesia, a subcoronal incision was made and the penis was degloved. an artificial erection was performed at this point and the curvature was identified. in case of dorsal curvatures, the neurovascular bundle was carefully dissected from the corpora cavernosa. in case of ventral curvature, the urethra was dissected from the corpora cavernosa. then again, an artificial erection was performed to identify the point of greatest curvature of the plaque. an h-incision was then made into the plaque and the defect created was measured to determine the size of the graft. gore® bio-a® graft was then placed and fixed over the defect with running sutures of its margins with 3-0 vicryl (figure 1). the penis was then covered and a circumcision was performed. the average surgery time was 137.2 (± 19.5 minutes). all patients were discharged after 24 hours of the surgery and were prescribed 5 mg of tadalafil to use once a day. statistical analyses were performed using ibm® spss® statistics, version 28.0.0.0. variables and results related to the primary and secondary outcomes were presented descriptively for each patient. continuous variables were described in the comparative analysis as the median and respective interquartile range. categorical variables were described as percentages of the total number of patients. results patient characteristics, risk factors and preoperative findings a total of 14 patients were included in this study. the mean age was 59.5 years (± 7.2).overall, 42.8% (6/14) of patients had hypertension, 21.4% (3/14) diabetes, 42.8% table 1. patients characteristics and postoperative outcomes. this table describes important preoperative findings for each patient, as well as the main postoperative outcomes. patient age curvature curvature preoperative curvature penile postoperative surgical number type degree ed correction sensory ed complications change (clavien-dindo grade) 1 64 uniplanar a 65 yes yes no yes yes (i) 2 64 uniplanar a 80 no yes no no no 3 67 biplanar 80 yes yes no yes no (with ventral component) 4 47 biplanar b 50 no yes no yes no 5 64 biplanar b 45 no yes no no yes (i) 6 55 uniplanar a 60 yes yes no yes d no 7 51 complex ᶜ 90 no no no no no 8 61 biplanar 80 yes yes no yes ᵈ no (with ventral component) 9 45 biplanar ᵇ 90 no yes no yes yes (i) 10 58 uniplanar ᵃ 50 no no no no no 11 67 biplanar ᵇ 45 no yes yes no no 12 65 uniplanar ᵃ 60 no yes no yes no 13 61 biplanar ᵇ 50 yes no yes yes ᵈ yes (i) 14 64 biplanar ᵇ 60 no yes no no no ed: erectile dysfunction. a. uniplanar includes dorsal and lateral and excludes ventral curvatures. b. biplanar includes dorso-lateral curvatures and excludes biplanar with ventral component curvatures. c. complex curvatures includes hour-glass and hinge deformities. d. patients that underwent malleable penile prosthesis implantationn. figure 1. gore® bio-a® graft being placed and secured with running sutures. an h-shaped incision was performed at the point of maximum curvature, after degloving the penis. the defect is measured and the graft is secured with vicryl 3.0 stitches. 89archivio italiano di urologia e andrologia 2022; 94, 1 polyglycolic acid graft in peyronie’s disease (6/14) smoking habits and 21.4% (3/14) dyslipidemia. regarding the presence of preoperative ed, 35.7% of patients (5/14) reported impaired erections even with pde5i before the surgery. on the other hand, 64.3% reported satisfactory erections. the median curvature degree was 60° (range 45-90°). the median time of plaque stability was 36 months (range 12-72). regarding the curvature type, 35.7% (5/14) had uniplanar curvatures (except ventral); 50% (7/14) had biplanar (except ventral) or complex (hourglass or hinge) deformities, and 14.2% (2/14) had curvatures with some ventral component. surgical outcomes the median follow-up time was 12 months (range 3-12). in terms of curvature correction, 3 of the 14 patients (21.4%) reported residual curvature greater than 15°, that was confirmed after performing artificial erection in the office. the curvature correction rate, therefore, was 78.5% (11/14). regarding the secondary endpoints, 1 of 14 patients (7.1%) reported glans hypoesthesia. nine of 14 patients (64.2%) reported refractory ed postoperatively (using 5 mg of tadalafil). three of the these patients decided to underwent a malleable penile prosthesis implantation after 12 months of the first surgery. excluding sensory changes and erection impairment, four patients (24.5%) presented minor surgical complications (penile pain and swelling) classified as clavien-dindo grade i. none of the patients (0/14) presented major surgical complications, clavien-dindo grade ≥ ii. table 1 describes the characteristics and postoperative outcomes for each patient. discussion this study described our initial experience with the gore® bio-a® graft, which, to our knowledge, has never been studied for peyronie’s disease management before. residual curvature after surgery was a concern, given the physiology of graft integration, which is based on complete replacement of the synthetic material by native scar tissue, which could again result in fibrosis and curvature (12, 13). what was obtained, in fact, was a similar rate to that found in other studies, even after 6 months, which is the time described by the manufacturer for complete absorption of the material (13). the european association of urology (eau) 2021 guidelines describe curvature correction average rates (involving different non-comparable studies), or success rates, for porcine intestinal submucosa (sis) grafts of 83.9% (range 54 -91), 87.4% for bovine pericardium (range 76.5-100) and 81.2% for dermis (range 60-100) (14). table 2 describes curvature correction rates with different patches. regarding decreased glans sensitivity, we obtained lower rates compared to those described in other series, such as chung et al. (15), with 13% impaired sensitivity after dermis graft, and as horstmann et al. (16), with 16%, after using tachosil®, but slightly higher compared to the series by sansalone et al. (17), with 3%, after bovine pericardium. table 3 describes penile sensory changes with different patches. this outcome, however, seems to be more related to the technique used for dissection of the neurovascular bundle, rather than to the type of material used (8). furthermore, a recent study by terrier je et al. showed that penile sensory changes tends to decrease in frequency and severity with time, with only rare cases occurring after 12 months (18). in terms of postoperative (de novo) erectile dysfunction, the eau 2021 guidelines describe average rates of 21.9% (range 7-54) for porcine intestinal submucosal grafts (sis), 26.5% (range 0-50) for bovine pericardium, and 20.5% (range 7-67) for autologous dermis (14). other series, as fabiani et al. (19, 20), report even lower rates, with 5.8% and 7.2% of ed after buccal mucosa graft. in our cohort, we found higher rates of refractory erectile dysfunction (table 4). however, a possible selection bias must be considered, as 35.7% of patients (5/14) reported impaired erectile function prior to the surgical procedure. in this study, all patients were enrolled to undergo curvature correction surgery – table 2. curvature correction with different patches. this table describes the curvature correction rates, expressed as weighted average, with grafts that are frequently used worldwide, along with the rate found with gore®bio-a®. author, year eau 2021 average rates for eau 2021 average rates eau 2021 average rates zandoná et al. (2021) – and graft used porcine intestinal submucosa (sis)a for bovine pericardiuma for dermisa gore® bio-a® patch curvature/deformity correction 83.9% (54-91) 87.4% (76.5-100) 81.2% (61-100) 78.5% a. data are expressed as weighted average and range in parenthesis (from different non-comparable studies). table 4. de novo erectile dysfunction with different patches. this table describes the rates of postoperative erectile function worsening with different grafts, that are frequently used worldwide, along with the rate found with gore®bio-a®. author, year eau 2021 average rates for eau 2021 average rates fabiani et al. (2016/2021) zandoná et al. (2021) – and graft used porcine intestinal submucosa (sis)a for bovine pericardiuma buccal mucosa patch gore® bio-a® patch de novo erectile dysfunction 21.9% (7-54) 26.5% (0-50) 5.8%/ 7.2% 64.2% a. data are expressed as weighted average and range in parenthesis (from different non-comparable studies). table 3. penile sensory changes with different patches. this table describes the rates of penile numbness, or penile hypoesthesia with grafts that are frequently used worldwide, along with the rate found with gore®bio-a®. author, year chung et al. (2011) horstmann et al. (2011) sansalone et al. (2011) zandoná et al. (2021) and graft used dermis graft tachosil® bovine pericardium gore® bio-a® patch penile hypoesthesia 13% 16% 3% 7.1% a. data are expressed as weighted average and range in parenthesis (from different non-comparable studies). archivio italiano di urologia e andrologia 2022; 94, 1 p.c. edler zandoná, n.p. teixeira, h.e. oliveira, j. hamilton soares garcia 90 plaque incision and grafting – as a first-stage procedure. although penile prosthesis implantation can be offered as a second procedure, it’s possible to perform both surgeries at the same time, even with the use of grafts, for patients at high-risk of developing refractory ed (14). the absence of major surgical complications, especially graft rejection, infection or extrusion, seems to be a characteristic of bioabsorbable materials, as opposed to synthetic grafts. we know that the incorporation process, comprising graft cell infiltration, neovascularization, and collagen deposition, which occurs in bioabsorbable materials, seems to lead to a lower risk of infection and erosion, compared to encapsulation, which occurs with the use of non-absorbable materials (21, 22). this study has some limitations, and therefore it should be interpreted with caution. the "self-reported" assessment of patients regarding erectile dysfunction, residual curvature and sensitivity change parameters, although described and recognized in the literature, is based on a subjective parameter and, therefore, reduces the statistical value and the possibility of extrapolating the results (23). the loss of follow-up of patients in the expected returns after surgery, largely due to the covid-19 pandemic and cancellation of elective appointments, also had a negative impact on the results of this sample. conclusions in this study, it was possible to demonstrate our initial experience with the use of gore® bio-a® graft. the rates of curvature correction and change in glans sensitivity were similar to those found in the literature. the rates of major complications related to the graft, as rejection, infection, and extrusion, were negligible in this sample. although a population with a higher prevalence of erectile dysfunction was included in this sample, higher rates of refractory erectile dysfunction were observed and these findings should be confirmed in further studies. we believe that this study brings the perspective that similar bioabsorbable grafts can be used as an alternative in pd’s treatment, although prospective studies with a larger population and longer follow-up are needed to validate such findings. references 1. devine jr cj, somers kd, jordan sg, schlossberg, sm. proposal: trauma as the cause of the peyronie’s lesion. j urol. 1997; 157: 285. 2. kadioglu a, tefekli a, erol b, et al. a retrospective review of 307 men with peyronie’s disease. j urol. 2002; 168:1075. 3. rhoden el, riedner ce, fuchs sc, et al. a cross-sectional study for the analysis of clinical, sexual and laboratory conditions associated to peyronie’s disease. j sex med. 2010; 7:1529. 4. ralph d, gonzalez-cadavid n, mirone v, et al. the management of peyronie’s disease: evidence-based 2010 guidelines. j sex med, 2010. 7:2359. 5. chung e, ralph d, kagioglu a, et al. evidence-based management guidelines on peyronie’s disease. j sex med. 2016; 13:905. 6. mulhall j, anderson m, parker m. a surgical algorithm for men with combined peyronie’s disease and erectile dysfunction: functional and satisfaction outcomes. j sex med. 2005; 2:132. 7. zaid ub, alwaal a, zhang x, lue tf. surgical management of peyronie’s disease. current urol rep. 2014; 15:446. 8. garcia-gomez b, ralph d, levine l, et al. grafts for peyronie's disease: a comprehensive review. andrology. 2018; 6:117-126. 9. carson cc, levine la. outcomes of surgical treatment of peyronie's disease. bju int. 2014; 113:704-13. 10. schiffman zj, gursel eo, laor e. use of dacron patch graft in peyronie disease. urology. 1985; 25:38. 11. faerber gj, konnak jw. results of combined nesbit penile plication with plaque incision and placement of dacron patch in patients with severe peyronie’s disease. j urol. 1993; 149:1319. 12. klinge u, schumpelick v, klosterhalfen b. functional assessment and tissue response of shortand long-term absorbable surgical meshes. biomaterials. 2001; 22:1415. 13. yeo kk, park th, park jh, et al. histologic changes of implanted gore bio-a in an experimental animal model. biomed res int. 2014; 2014:167962. 14. salonia a, bettocchi c, carvalho j, et al. guidelines on sexual and reproductive health. edn. presented at the eau annual congress milan 2021. isbn 978-94-92671-13-4. 15. chung e, clendinning e, lessard l, brock g. five-year followup of peyronie’s graft surgery: outcomes and patient satisfaction. j sex med. 2011; 8:594. 16. horstmann m, kwol m, amend b, et al. a self-reported longterm follow-up of patients operated with either shortening techniques or a tachosil grafting procedure. asian j androl. 2011; 13:326. 17. sansalone s, garaffa g, djinovic r, et al. long-term results of the surgical treatment of peyronie’s disease with egydio’s technique: a european multicentre study. asian j androl. 2011; 13:842. 18. terrier je, tal r, nelson cj, mulhall jp. penile sensory changes after plaque incision and grafting surgery for peyronie’s disease. j sex med. 2018; 15:1491. 19. fabiani a, servi l, fioretti f, et al. buccal mucosa is a promising graft in peyronie’s disease surgery. our experience and a brief literature review on autologous grafting materials. arch ital urol androl. 2016; 88:115-21. 20. fabiani a, fioretti f, pavia mp, et al. buccal mucosa graft in surgical management of peyronie's disease: ultrasound features and clinical outcomes. arch ital urol androl. 2021; 93:107-110. 21. trabuco ec, zobitz me, klingele cj, gebhart jb. effect of host response (incorporation, encapsulation, mixed incorporation and encapsulation, or resorption) on the tensile strength of graft-reinforced repair in the rat ventral hernia model. am j obstet gynecol. 2007; 197: 638.e1. 22. klinge u, klosterhalfen b, müller m, schumpelick v. foreign body reaction to meshes used for the repair of abdominal wall hernias. eur j surg. 1999; 165:665. 23. revicki da, cella d, hays rd, et al. responsiveness and minimal important differences for patient reported outcomes. health qual life outcomes. 2006; 4:70. correspondence pedro caetano edler zandoná, md (corresponding author) uropedrozandona@gmail.com pedrozandona@outlook.com rua esteves júnior, 574, ap 105, 88015-130 florianópolis, santa catarina (brazil) nivio pascoal teixeira, md nivio@uromed.com.br henrique eduardo oliveira, md henriqueoliveira02@hotmail.com jorge hamilton soares garcia, md jorge@anestesiologistas.com.br stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13877 1 original paper been shown to cause significant debility and have greater impacts on anxiety and depression than similar chronic illnesses such as diabetes, gout and hypertension (3). standard medical treatments for patients with uncomplicated luts include alpha-blockers, 5-alpha-reductase inhibitors (5aris), phosphodiesterase type 5 inhibitors, antimuscarinics, and beta-3 agonists. the lipido-sterolic extract of serenoa repens (sr) is also recommended as a therapeutic option in the eau guidelines on non-neurogenic luts (1). the mechanisms underlying the pharmacological effects of sr in bpo are still far from being completely identified (11). it has been suggested that sr may inhibit 5ari and may have an anti-androgenic, antiproliferative, antiinflammatory and anti-edema activity (11, 12). these effects are obtained with high doses of sr and therefore it has been questioned whether these effects have a therapeutic relevance (12). furthermore, it has been demonstrated that sr may exert anti-adrenergic receptors activity (13). sr interacts with the adrenergic and muscarinic receptors localized in the lower urinary tract lessening the obstructive symptoms following bpo (14). medical treatments are usually prescribed as monotherapy in patients with mild to moderate luts, though in patients showing insufficient improvement and/or more severe symptoms, treatments may be combined (1, 3). the most widely used combination therapy is an alphablocker with a 5ari (4), although it has been reported that adverse events are significantly more common with this combination than during monotherapy (5). sr has proven as effective as alpha-blockers (6) and 5aris when used as a monotherapy over a 6-month period (7, 8), although it has a significantly superior tolerability profile (6-9), which makes it a valid alternative as a treatment option for luts. as a persistent prostatic inflammatory state plays a role in the development and progression of luts (10), the anti-inflammatory effect of sr might contribute to greater relief of luts symptoms than when using an alpha-blocker alone (10). irritative symptoms and lower urinary tract infections play a significant role background: standard medical treatments for patients with uncomplicated luts include alpha-blockers, 5-alpha-reductase inhibitors (5aris), phosphodiesterase type 5 inhibitors, antimuscarinics, and beta-3 agonists. the lipido-sterolic extract of serenoa repens (sr) is also recommended as a therapeutic option. our study prospectively evaluated the impact of a 6-month assumption of lipido-sterolic extract of sr alone or in combination with phenolmicin p3 and bosexil medical devices suppositories on symptoms and on psa levels in patients affected by bpo related-luts. methods: we prospectively enrolled 509 patients: 194 (group 1) were prescribed only a 6 months assumption of sr extract, while 315 (group 2) were also prescribed a 20-day therapy with phenolmicin p3 and bosexil medical devices suppositories. results: after 6 months, 371 patients’ data were registered and analyzed. furthermore, patients’ withdrawal and motivations were also considered. conclusions: in our clinical study, the patients treated with serenoa repens extract (320 mg daily) showed a significant relief regarding luts, and the association of a 6-month assumption of sr extract with a 20-day prescription of phenolmicin p3 and bosexil medical device in suppository form seems to significantly improve both efficacy on luts and decrease of psa levels. key words: benign prostatic obstruction; serenoa; luts; symptoms. submitted 8 april 2025; accepted 12 june 2025 introduction benign prostatic obstruction (bpo) is a frequent cause of lower urinary tract symptoms (luts) in adult men. luts can be highly bothersome, impairing the quality of life of men and that of their partners (1, 2). the prevalence of bpo increases substantially with age, reaching 90% in men aged 81-90 years (3). likewise, the prevalence of luts ranges from 44% in men aged 40-59 years, increasing to 70% in men aged > 80 years (3, 4). luts have efficacy of serenoa repens lipido-sterolic extract alone or in combination with propolis polyphenols and boswellia serrata extract suppositories on psa level and symptoms in patients affected by lower urinary tract disorders umberto barbaresi, mauro dicuio, federico mineo bianchi, manola marini, francesca quadrini, santo lupo, roberta de stefano urology department, ospedale maggiore “c.a. pizzardi”, bologna, italy. doi: 10.4081/aiua.2025.13877 summary archivio italiano di urologia e andrologia 2025; 97(3):13877 u. barbaresi, m. dicuio, f.m. bianchi, et al. 2 on luts progression and suppository corticosteroids therapy is often prescribed as first line treatment, though its role is limited by relevant side effects, especially on diabetes affected patients. as an alternative, a medical device, in form of suppositories, based on propolis polyphenols (phenolmicin p3) and boswellia serrata extract (bosexil), has been reported to possess an antiinflammatory property, due to its antioxidant and mucoadhesive capacity, in a variety of inflammatory diseases whose physio-pathological pathways are shared with those of prostatitis. our study prospectively evaluated the impact of a 6month assumption of lipido-sterolic extract of sr alone or in combination with phenolmicin p3 and bosexil suppositories on symptoms and on psa levels in patients affected by bpo related-luts. materials and methods we prospectively enrolled at our institution between january and december 2023, patients who presented for outpatient visit for luts with or without symptoms of acute prostatitis, and an enlarged prostate of 25 ml or more on transrectal or transabdominal ultrasonography. exclusion criteria were any history of other urologic disorders; history of bladder-neck or prostate surgery, transurethral incision of the prostate, balloon dilation, or thermotherapy; suspected prostate cancer. age, symptoms, prostate volume, psa level and side effects were registered in our database. after a complete urological examination, including digital rectal examination and psa level evaluation, all included patients were prescribed a 6-month daily assumption of 320 mg lipido-sterolic extract of sr (saba®). patients were also randomly assigned to a 20day prescription of phenolmicin p3 and bosexil suppositories (mictalase®). patients were evaluated at 6 months by physical examination and serum psa level measurement. changes in symptoms or in psa level, as also patients’ withdrawal and their motivations were registered. comparisons between the two groups (saba® + mictalase® vs saba® alone) were assessed by means of the student’s t test. all statistical tests were two-sided, and significance was declared at the 5% level. results 509 patients were enrolled in the present study, 194 (38%, group 1) were prescribed only a 6-month course of saba®, while 315 (62%, group 2) were also prescribed a 20-day therapy with mictalase®; 138 patients were subsequently excluded because they had not completed the 6 months of therapy or were not available at the time of the 6 months visit. overall median age was 67 years, overall psa level was 1.47 ng/ml in the entire population (1.6 vs 1.42 in group 1 and group 2 respectively), while prostate volume was 42 ml (42 ml vs 43 ml in group 1 and group 2 respectively). luts were registered in 68 (35%) and 85 (27%) patients in group 1 and group 2. no statistically significant differences were observed between the two groups concerning age, psa level, prostate volume and presence of luts. at the 6 months scheduled visit, 371 patients were still following the prescription, and their data were registered and analyzed. furthermore, patients who withdrawal and motivations for withdrawal were also taken into account. in total 138 (27.1%) patients dropped off the study because of epigastric pain (n = 16; 11.6%), therapy cost (n = 62; 44.9%), nausea (n = 25; 18.1%), or other causes including unavailability at the time of the visit (n = 35; 25.4%). table 3 resumes patients’ characteristics at the time of follow up. median psa level after 6 months of saba assumption was 1.42 ng/ml, with no differences with patients treated also with mictalase®. psa level decrease, on the other side, was significantly more frequent in group 2 table 1. overall characteristics of the entire population. overall saba alone saba+mictalase p-value (n = 509) (n = 194) (n = 315) age, years median (iqr) 67 (42-83) 66 (42-83) 68 (51-80) 0.76 psa, ng/ml median (iqr) 1.47 (1.0-2.54) 1.6 (1.09-2.31) 1.42 (1.0-3.01) 0.14 prostate volume, ml median (iqr) 42 (25-87) 42 (25-77) 43 (25-87) 0.47 luts yes 154 (30.3%) 68 (35.0%) 85 (27.0%) 0.11 no 355 (69.7%) 126 (65.0%) 230 (73.0%) table 3. patients’ follow up data at 6 months. overall saba alone saba+mictalase p-value (n = 371) (n = 157) (n = 214) psa at 6 months, ng/ml median (iqr) 1.42 (1.01-2.3) 1.42 (1.13-2.11) 1.42 (0.61-2.31) 0.97 psa level decrease, n (%) yes 258 (69.5%) 97 (61.8%) 161 (75.2%) 0.03 no 113 (21.5%) 60 (38.2%) 53 (24.8%) luts improvement, n (%) yes 338 (91.1%) 131 (83.4%) 207 (96.4%) < 0.01 no 33 (8.9%) 26 (16.6%) 7 (3.6%) table 2. patients’ withdrawal causes. overall (n = 138) cause of drop-off, n (%) epigastric pain 16 (11.6%) nausea 25 (18.1%) therapy cost 62 (44.9%) other causes 35 (25.4%) archivio italiano di urologia e andrologia 2025; 97(3):13877 3 serenoa repens in combination with propolis polyphenols and boswellia serrata extract suppositories patients (161 patients vs 97; p = 0.03). moreover, 91.1% of patients declared a certain grade of improvement of their luts, with a significantly higher rate of improvement in group 2 compared to group 1: 207 (96.4%) vs 131 (83.4%) (p < 0.001). discussion patients with symptomatic bpo are usually treated with alpha-blockers as a first-line therapy option. however, alpha-blockers are drugs with significant adverse effects in a considerable percentage of patients. in our study, we have enrolled a population of men presenting with luts and/or acute prostatitis and divided them into two groups: group 1 was treated with sr extract (saba®) and group 2 with sr extract and phenolmicin p3 and bosexil suppositories (mictalase®). clinical and laboratory examinations were performed at the beginning of the study, and 6 months later. we observed that serum psa levels were significantly reduced by therapy in both groups, with a significantly higher rate of patients with decrease in group 2, which is comparable to some previous studies (15). however, in a recent randomized, placebo-controlled, trial conducted on 369 men with bpo, sr extract does not affect serum psa levels more than placebo (15). on the contrary, the prostate size increase during the 1-year follow-up and the proportion of patients with prostate volume > 40 ml was significantly higher in the control groups than in the sr group indicating a measurable effect on this important bpo parameter. we observed significant improvements of luts in both groups, with a decrease of symptoms of more than 83% in group 1 and 96% in group 2. this indicates that there is clinically evident improvement in the patients’ symptoms related to bpo with a therapy not based on alpha-blockers or 5aris. although the changes in urological symptoms were highly significant (p < 0.01) in favor of group 2, results are certainly encouraging for both groups. our results are consistent with some of the previously published studies in which a noticeable reduction of luts associated with bpo and significant improvement of life quality were observed (16). the clinical responses to phytotherapy with sr repens extracts are also found to be very promising in other studies (17, 18). moreover, eau guidelines state that these herbal extracts significantly reduce nocturia in comparison with placebo (19). on the contrary, some authors described that sr have not shown more effectiveness than placebo in the treatment of bpo (20, 21). however, more recent data favor the use of sr extracts in milder bpo cases with promising results (22). it also has been proved that the extraction methods also have an impact on the pharmacological action of saba®, in bpo and this may be one of the major reasons for studies’ inconsistencies (23). no serious adverse events or interactions with co-administered drugs have been described during the use of sr and this treatment is associated with less sexual dysfunction-related side effects than the usual drug therapy for bpo as tamsulosin or finasteride (24). on the other hand, the medical device in the form of suppositories, we have studied, contain different functional principles, as bosexil and phenolmicin p3. the first is a derivative of boswellia serrata while the second is a derivative of propolis; their combined functional actions allow to obtain multiple effects at the same time: mucoadhesion, antioxidant effect and creation of a microenvironment not suitable for the proliferation of pathogenic bacteria. the effectiveness of this medical device has been tested, by another research group, through the evaluation of a standardized questionnaire (25), showing that the medical device, in the form of a suppository, is able to reduce genitourinary pain and improve the quality of life in men affected by symptoms similar to prostatitis (26, 27). it is therefore conceivable that this medical device supports the main action of saba®, with non-pharmacological mechanisms. in evaluating a large-scale applicability of these treatments, causes of abandonment of therapy were registered and costs represented the main reason for renunciation. in italy, this could represent a disadvantage regarding patients’ compliance, compared to alpha-blockers and 5aris, because the latter are provided by italian healthcare system with no further costs for the patient. a limitation of the present study is that it was not randomized because our protocol only aimed to observe patients with bpo under strict inclusion and exclusion criteria. also, improvements were not registered based on a standardized questionnaire for luts (such are ipss score system) or on an objective instrumental exam such as uroflowmetry. larger studies with longer follow-up are needed to further evaluate the potential efficiency of this treatment for bpo as an alternative to the established pharmaceutical agents and to evaluate the possible side effects due to the long-term use. conclusions in our clinical study, the patients treated with serenoa repens extract (320 mg daily) showed a significant relief regarding luts, and the association of a 6-month assumption of sr extract (saba®) with a 20-day prescription of phenolmicin p3 and bosexil suppositories (mictalase®) seems to have a significantly higher efficacy on both luts and psa levels decrease. declarations ethical approval: not applicable because the study is based on herbal products of well-established use. the study was performed in accordance with the ethical standards as laid down in the 1964 declaration of helsinki and its later amendments. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: no funding. authors' contributions: barbaresi u, dicuio m: conception or design of the work, acquisition, analysis and interpretation of data; mineo bianchi f, marini m, quadrini f: acquisition, analysis and interpretation of data; lupo s, de stefano r: final approval of the version to be published. archivio italiano di urologia e andrologia 2025; 97(3):13877 u. barbaresi, m. dicuio, f.m. bianchi, et al. 4 references 1. gravas s, cornu jn, gacci m, et al. eau guidelines on management of non-neurogenic male luts including benign prostatic obstruction; european association of urology: arnhem, the netherland, 2022. 2. speakman m, kirby r, doyle s, ioannou c. burden of male lower urinary tract symptoms (luts) suggestive of benign prostatic hyperplasia (bph)—focus on the uk. br. j. urol. 2014; 115:508-519. 3. launer bm, mcvary kt, ricke wa, lloyd gl. the rising worldwide impact of benign prostatic hyperplasia. br. j. urol. 2020; 127:722-728. 4. serati m, andersson ke, dmochowski r, et al. systematic review of combination drug therapy for non-neurogenic lower urinary tract symptoms. eur. urol. 2019; 75:129-168. 5. gacci m, ficarra v, sebastianelli a, et al. impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis. j. sex. med. 2014; 11:1554-1566. 6. debruyne f, koch g, boyle p, et al. comparison of a phytotherapeutic agent (permixon) with an alpha-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. eur. urol. 2002; 41:497-506. 7. novara g, giannarini g, alcaraz a, et al. efficacy and safety of hexanic lipidosterolic extract of serenoa repens (permixon) in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. eur. urol. focus 2016; 2:553-561. 8. carraro jc, raynaud jp, koch g, et al. comparison of phytotherapy (permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1098 patients. prostate 1996; 29:231-240. 9. corona g, tirabassi g, santi d, et al. sexual dysfunction in subjects treated with inhibitors of 5α-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis. andrology 2017; 5:671-678. 10. de nunzio c, salonia a, gacci m, ficarra v. inflammation is a target of medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. world j. urol. 2020; 38:2771-2779. 11. gandaglia g, briganti a, gontero p, et al. the role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (bph). bju int 2013; 112:432-41. 12. goepel m, hecker u, krege s, et al. saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro. prostate 1999; 38:208-215. 13. oki t, suzuki m, nishioka y, et al. effects of saw palmetto extract on micturition reflex of rats and its autonomic receptor binding activity. j urol 2005; 173:1395-9. 14. di silverio f, monti s, sciarra a, et al. effects of long-term treatment with serenoa repens (permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. prostate 1998; 37:77-83. 15. andriole gl, mccullum-hill c, sandhu gs, et al. camus study group. the effect of increasing doses of saw palmetto fruit extract on serum prostate specific antigen: analysis of the camus randomized trial. j urol. 2013; 189:486-92. 16. fagelman e, lowe fc. saw palmetto berry as a treatment for bph. rev urol. 2001; 3:134-8. 17. kim sw. phytotherapy: emerging therapeutic option in urologic disease. transl androl urol. 2012; 1:181-91. 18. argirovic a, argirovic d. does the addition of serenoa repens to tamsulosin improve its therapeutical efficacy in benign prostatic hyperplasia? vojnosanit pregl. 2013; 70:1091-6. 19. gratzke c, bachmann a, descazeaud a, et al. eau guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. eur urol. 2015; 67:1099-109. 20. macdonald r, tacklind jw, rutks i, et al. serenoa repens monotherapy for benign prostatic hyperplasia (bph): an updated cochrane systematic review. bju int. 2012; 109:1756-61. 21. bent s, kane c, shinohara k, et al. saw palmetto for benign prostatic hyperplasia. nejm. 2006; 354:557-66. 22. ooi sl, pak sc. serenoa repens for lower urinary tract symptoms/benign prostatic hyperplasia: current evidence and its clinical implications in naturopathic medicine. j altern complement med. 2017; 23:599-606. 23. de monte c, carradori s, granese a, et al. modern extraction techniques and their impact on the pharmacological profile of serenoa repens extracts for the treatment of lower urinary tract symptoms. bmc urol. 2014; 14:63. 24. agbabiaka tb, pittler mh, wider b, et al. serenoa repens (saw palmetto): a systematic review of adverse events. drug saf. 2009; 32:637-47. 25. poeckel d, werz o. boswellic acids: biological actions and molecular targets. curr med chem. 2006; 13:3359-69. 26. siemoneit u, koeberle a, rossi a, et al. inhibition of microsomal prostaglandin e2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense. br j pharmacol. 2011; 162:147-62. 27. sibona m, destefanis p, agnello m, et al. the association of boswellia resin extract and propolis derived polyphenols can improve quality of life in patients affected by prostatitis-like symptoms. arch ital urol androl. 2020; 91:251-5. correspondence umberto barbaresi, md (corresponding author) umberto.barbaresi@ausl.bologna.it largo bartolo nigrisoli, 2 40133 bologna, italy mauro dicuio federico mineo bianchi manola marini francesca quadrini santo lupo roberta de stefano urology department, ospedale maggiore “c.a. pizzardi”, bologna, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14027 1 original paper according to global cancer statistics (globocan), which accounted for 7.3% of all new cancer cases in 2022 (1). drug toxicity and resistance often limit current treatments, keeping prostate cancer as a major cause of cancer-related mortality worldwide (1, 2). this has led more research on natural chemicals found in fruits and vegetables for prostate cancer treatment (2). date palm (phoenix dactylifera l.) is an essential fruit in arabian countries, which showed several anticancer effects in many studies through antioxidant, pro-apoptotic, and cell cycle regulating mechanisms (2-4). the ajwa date is preferred among other dates because of its great nutritional value, which is important for human diet and health (5, 6). many studies showed that by disrupting membrane potential, raising oxidative stress, and generating dna fragmentation, ajwa date extracts cause mitochondrial-mediated death in pc3 cells and oral squamous cell carcinoma (hsc-2) cell culture (2, 7). however, the precise molecular pathways of key regulators and oncogens still needs further study (8). evidence supports the role of mcl-1 in prostate cancer cell survival, as its reduction causes rapid apoptosis by interacting with the dephosphorylation of the bcl2associated death (bad) promoter (9). as demonstrated in a study where phytochemicals such as phenethyl isothiocyanate restored mutant p53 function to induce cell cycle arrest, p53 mutational status concurrently influences therapeutic responses (10). moreover, the progression of prostate cancer is linked to egfr signaling and egfrbased therapy has the potential to make prostate cancer more responsive to treatment (11). abiraterone acetate is a potent inhibitor of androgen biosynthesis, which has demonstrated significant cytotoxic and anti-proliferative effects in human prostate cancer pc3 cells of a model for castration-resistant prostate cancer (crpc) (12). this study aims to investigate whether ajwa date extract can moduintroduction & objectives: prostate cancer is recognized as a global burden disease related to malignancy in men. several fruit and plant-based supplementation have been studied to evaluate their utility for the management of prostate cancer. ajwa dates (phoenix dactylifera l.) have been known to contain various beneficial compounds, which makes them a potential anti-cancer therapy. the aim of this study was to assess the effect of ajwa dates on prostate cancer cell lines pc3 through analysis of mcl-1 levels, egfr, and p53 expressions on apoptosis. materials & methods. this study was an experimental in vitro study with post-test-only control design. groups were divided into four: control group, abiraterone group, ajwa dates group, and combination group (abiraterone and ajwa dates). viability test was conducted using the cck-8 method to determine the inhibitory concentration (ic50) of ajwa dates after a 72-hour incubation period of pc3 cells. the mcl-1 levels were rated using elisa, while egfr and p53 expressions were analyzed using immunofluorescence microscopic staining. apoptosis was measured using fluorescence-activated cell sorting (facs). spss version 25 and r-studio were used for statistical analysis. results: this study found the ic50 for ajwa dates was 913.3 µg/ml. our data indicated that ajwa dates decrease the mcl-1 levels, egfr and p53 expression and also induced apoptosis compared to control. furthermore, these effects became more evident when combined with abiraterone. conclusions: this study demonstrates the potential of ajwa dates as a complementary therapy for prostate cancer, but further research is still needed before clinical testing is carried out. key words: prostate cancer; ajwa dates; mcl-1; egfr; p53. submitted 22 may 2025; accepted 23 may 2025 introduction prostate cancer is the fourth most common cancer worldwide and the second most frequently diagnosed in men, anti-cancer activity of ajwa dates extract (phoenix dactylifera l.) through analysis of mcl-1 levels, egfr, and p53 expressions on apoptosis in human prostate cancer cell lines pc3: an in vitro study abdul azis 1, 2, andi asadul islam 2, 3, haerani rasyid 2, 4, ika yustisia 5, lukman hakim 6, 7, syakib bakri 2, 4, agussalim bukhari 2, 8, andi alfian zainuddin 9 1 urology division of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia; 2 hasanuddin university teaching hospital, makassar, indonesia; 3 neurosurgery divison of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia; 4 department of internal medicine, faculty of medicine, hasanuddin university, makassar, indonesia; 5 department of biochemistry, faculty of medicine, hasanuddin university, makassar, indonesia; 6 department of urology, faculty of medicine, airlangga university, surabaya, indonesia; 7 faculty of medicine and health, institut teknologi sepuluh nopember, surabaya, indonesia; 8 department of nutritional sciences, faculty of medicine, hasanuddin university, makassar, indonesia; 9 department of public health and community medicine, faculty of medicine, hasanuddin university, makassar, indonesia. doi: 10.4081/aiua.2025.14027 summary archivio italiano di urologia e andrologia 2025; 97(3):14027 a. azis, a. asadul islam, h. rasyid, et al. 2 late mcl-1 levels, egfr, and p53 expression to induce apoptosis in pc3 cells. the findings could provide information on ajwa dates as a complementary therapeutic agent with abiraterone acetate to target multiple oncogenic pathways simultaneously. methods study design and setting the in vitro experimental study was performed at the faculty of medicine, universitas brawijaya, malang, indonesia. experimental design applied a laboratory-based approach with a post-test-only control group design. pc3 is a human mcrpc cell line, which in this study was categorized into four groups consisting of: negative control, abiraterone, ajwa date extract, and combination of abiraterone and ajwa dates extract. after 72 hours exposure, the mcl-1 levels were measured using elisa method, while egfr and p53 expressions were analyzed using immunofluorescence microscopic staining. preparation of ajwa dates extract fresh ajwa dates (1 kilogram) were prepared and separated from the seeds. the ajwa date flesh (600 grams) was then cut into small pieces and dried at 600c. the results were refined with a blender to make a “simplisia” (or symplicia) that was stored in a closed container in the refrigerator. the “simplisia” was then extracted using the maceration method in 90% ethanol to extract more compounds. we collected the maceration content and remacerated it by adding half the volume of ethanol from the first maceration. the maceration result was then concentrated using a rotary evaporator. the final product of the ajwa date extract had a paste-like consistency. the extract results were weighed at 100 mg/ml working stock and stored in a refrigerator at a temperature of 40c for further use on the pc3 cells intervention. pc3 cell culture the pc3 cells (mcrpc pc3 cell lines), f-12k medium, dimethyl sulfoxide (dmso), penicillin/streptomycin solution, phosphate buffered saline (pbs), and fetal bovine serum (fbs) were obtained from american type culture collection (atcc, manassas, va, usa). pc3 cells were cultured in f-12k with 10% fbs at 37°c in a humidified environment containing 5% co2 until they attained 80% confluency. all cell lines were thereafter grown in full media for a minimum of 24 hours prior to experimental treatment. cell viability analysis and ic50 measurement pc3 cells were seeded in 96-well plates at a density of 3.000-4.000 cells per well and let to adhere overnight. the cells were subsequently treated with ajwa dates extract for 72 hours in full medium (0-20.000 μg/ml). the cells were subsequently treated at 37°c for 1-2 hours with the cell counting kit-8 (cck-8) test (50μl cck-8 per ml of culture media). the relative absorbance of the cell culture was subsequently measured at an excitation wavelength of 485 nm. the ic50 value of abiraterone was 66.9 μg/ml, as determined in a prior work utilizing the identical pc-3 cells (13). mcl-1 levels, egfr, and p53 expressions analysis pc3 cells were seeded in a 24-well culture plate at a density of around 500.000-1.000.000 cells/ml and incubated for 24 hours. the cells received treatment with ic50 abiraterone acetate, ic50 ajwa date extract, and a combination of ic50 ajwa date extract and ic50 abiraterone acetate. subsequently, the cells were incubated for 72 hours and further examination was carried out to assess mcl-1 levels, egfr, and p53 expressions. mcl-1 levels were examined using the mcl-1 monoclonal antibody reagent of invitrogen® (thermofisher, usa) with enzyme-linked immunosorbent assay (elisa). the elisa procedure includes the antigen binding step, addition of biotin conjugate, streptavidin-hrp, tmb substrate, and addition of stop solution, followed by absorbance reading at 450 nm wavelength to calculate mcl-1 levels based on the standard curve of optical density (od). egfr and p53 expressions were examined using staining and immunofluorescence examination. the preparation was performed by washing the cells using pbs and with 0.1% triton-x 100. following this, the cells were incubated with 1% bovine serum albumin (bsa) at room temperature and then incubated with primary antibodies overnight at 4°c. subsequently, the cells were incubated with secondary antibodies for 30 minutes at room temperature. further, the cells were incubated with 4',6-diamidino-2-phenylindole (dapi) 1:1000. finally, the cells were covered with mounting media and cover glass, later the cells were observed with a fluorescence microscope. cell apoptosis analysis pc-3 cells were washed twice with biolegend cell stain buffer (elabsciences, houston, tx, usa) and subsequently suspended in annexin v binding buffer (elabsciences, houston, tx, usa) at a concentration of 1.0×107 cells/ml subsequently, 100 μl of the cell suspension was transferred into a 5 ml reaction tube, followed by the addition of 5 μl fitc annexin v (elabsciences, houston, tx, usa) and 10 μl propidium iodide solution (elabsciences, houston, tx, usa). the cells were then incubated at room temperature of 25°c. subsequently, 400 μl of annexin v binding buffer was introduced into each tube. this study analyzed 5.000 cells in each cycle. the flowcytometry results were analyzed by fluorescence-activated cell sorting (facs), which employed data bars of gating quadrants the total mean in early and late apoptosis was counted in this study. the fluorescence emitted by cells was quantified using the becton dickinson (bd) facscalibur (bd bioscience, franklin lakes, nj, usa). statistical analysis mcl-1 expressions obtained from elisa were analyzed alongside the expression percentage values of egfr and p53 derived from immunofluorescence staining. a normality test was performed to determine the data distribution. the one-way analysis of variance (anova) test was utilized for data with a normal distribution, while the kruskal-wallis non-parametric test was applied for data exhibiting non-normal distribution. a subsequent multiple comparison test, post hoc test, and regression analysis were conducted. the statistical analysis utilized spss version 25 (ibm, new york, us) and r studio. archivio italiano di urologia e andrologia 2025; 97(3):14027 3 anti-cancer activity of ajwa dates results effect of ajwa dates on cell viability and ic50 values in pc3 cells viability cck8 assay was performed to determine the ic50 of ajwa dates. absorbance results were collected 72 hours later. the administration of ajwa dates resulted in a viability reduction of pc3 cells, as indicated by an ic50 value of 913.3 μg/ml. effect of ajwa dates, abiraterone acetate, and combinations on mcl-1 levels the pc3 cells underwent interventions for 72 hours, with dosages determined by the ic50 value obtained. mcl-1 levels were subsequently measured using sandwich elisa. the results demonstrated that mcl-1 levels were statistically different across groups (p < 0.001). the bar chart illustrates the variations in mcl-1 levels among the groups presented in figure 1. a post-hoc analysis utilizing tukey's hsd was performed to compare mcl-1 levels across groups. the analysis indicated the combination of abiraterone acetate and ajwa dates resulted in significantly lower mcl-1 levels compared to the abiraterone acetate group (p = 0.002), the ajwa dates group (p < 0.001), and the control group (p < 0.001), as shown in table 1. the findings show that using a combination of abiraterone acetate with ajwa date led to a significant decrease in mcl-1 levels when compared to the control and individual treatment groups. effect of ajwa dates extract, abiraterone acetate, and combinations on egfr expressions following exposure of pc3 cells to the specified interventions, egfr expressions were quantified as the percentage of cells exhibiting egfr with a microscopic immunofluorescence analysis. the results indicated that the expressions of egfr were statistically different among groups (p = 0.03). the bar chart illustrates the variations in egfr expressions among the groups presented in figure 2. post hoc analysis indicated that the combination of abiraterone acetate and ajwa dates resulted in significantly lower egfr expressions compared to the control group (p = 0.43), as shown in table 2. the findings show that using a combination of abiraterone acetate with ajwa date led to a significant decrease in egfr expressions when compared to the control group. effect of ajwa dates extract, abiraterone acetate, and combinations on p53 expressions following exposure of pc3 cells to the specified interventions, p53 expressions were quantified as the percentage of cells exhibiting p53 with a microscopic immunofluorescence analysis. the result indicated that the expressions of p53 were statically different among groups (p = 0.006). the bar chart shows the differences in p53 figure 1. the effect of abiraterone, ajwa, and combination of abiraterone with ajwa on mcl-1 levels. the bars in the graph represent standard deviation. figure 2. the impact of abiraterone, ajwa, and combination of abiraterone with ajwa on egfr expressions. the bars in the graph represent standard deviation. table 1. post hoc analysis comparison of mcl-1 levels between groups. groups mean difference (95% ci) p-value abiraterone vs control -0.24 [-0.3 – (-0.18)] < 0.001* ajwa vs control -0.08 [-0.14 – (-0.02)] 0.007* abiraterone + ajwa vs control -0.35 [-0.41 – (-0.29)] < 0.001* abiraterone vs ajwa -0.15 [-0.21 – (-0.09)] < 0.001* abiraterone + ajwa vs abiraterone -0.11 [-0.17 – (-0.05)] 0.002* abiraterone + ajwa vs ajwa -0.26 [-0.32 – (-0.2)] < 0.001* tukey’s hsd test. *statistically significant at p < 0.05. ci: confidence interval. table 2. post hoc analysis comparison of egfr expression between groups. groups mean difference (95% ci) p-value abiraterone vs control -3.55 (-8.38 – 1.28) 0.165 ajwa vs control -3.14 [-7.97 – (1.68)] 0.237 abiraterone + ajwa vs control -5 [-9.83 – (-0.16)] 0.043* abiraterone vs ajwa -0.4 (-5.23 – 4.42) 0.993 abiraterone + ajwa vs abiraterone -1.45 (-6.28 – 3.38) 0.774 abiraterone + ajwa vs ajwa -1.85 (-6.69 – 2.97) 0.626 tukey’s hsd test. *statistically significant at p < 0.05. ci: confidence interval. archivio italiano di urologia e andrologia 2025; 97(3):14027 a. azis, a. asadul islam, h. rasyid, et al. 4 expressions between the groups presented in figure 3. post-hoc analysis indicated that the abiraterone acetate group and ajwa dates group had significantly higher p53 expressions than the control group (p = 0.008; p = 0.037; respectively), as shown in table 3. this result highlighted that the abiraterone acetate or ajwa dates administration led to an increase in p53 expressions in comparison to the control group. effect of ajwa dates extract, abiraterone acetate, and combinations on apoptosis in pc3 cells this study employed facs to evaluate the proportion of cells undergoing apoptosis following treatment. pc3 cells were categorized into four quadrants according to the cell emission signals illustrated in figure 4. early apoptosis was observed in the lower right quadrant, while late apoptosis was noted in the upper right quadrant. the data in this study exhibited a normal distribution, and one-way anova analysis revealed a significant difference in total mean apoptosis among the groups (p = 0.009). the bar chart illustrates the variations in total mean apoptosis among the groups presented in figure 5. post hoc analysis indicated that all groups demonstrated increased total apoptosis with respect to the control group with the combination of abiraterone acetate and ajwa dates demonstrating significantly higher total mean apoptosis compared to other groups (p = 0.012), as table 3. post hoc analysis comparison of p53 expression between groups. groups mean difference (95% ci) p-value abiraterone vs control 7.56 (2.3 – 12.82) 0.008* ajwa vs control 5.6 (0.34 – 10.86) 0.037* abiraterone + ajwa vs control 1.8 (-0.43 – 7.08) 0.693 abiraterone vs ajwa 1.96 (-3.29 – 7.22) 0.646 abiraterone + ajwa vs abiraterone -5.74 [-11 – (-0.48)] 0.033* abiraterone + ajwa vs ajwa -0.377 (-9.03 – 1.48) 0.177 tukey’s hsd test. *statistically significant at p < 0.05. ci: confidence interval. figure 3. the impact of abiraterone, ajwa, and combination of abiraterone with ajwa on p53 expressions. the bars in the graph represent standard deviation figure 5. the impact of abiraterone, ajwa, and combination of abiraterone with ajwa on mean percentage of total apoptosis. the bars in the graph represent standard deviation. figure 4. fluorescence-activated cell sorting (facs) analysis showing gating and quadrant distribution of apoptosis. (a-b) control group; (c-d) abiraterone; (e-f) ajwa; (g-h) combination of abiraterone and ajwa. archivio italiano di urologia e andrologia 2025; 97(3):14027 5 anti-cancer activity of ajwa dates shown in table 4. the findings highlight a significant mean percentage of total apoptosis among the treatment groups, with the combination of abiraterone and ajwa dates consistently exhibiting the strongest effect. multiple linear regression analyses of mcl-1, egfr, and p53 to predict apoptosis in pc3 cells indeed, multiple linear regression analyses of mcl-1 levels, egfr and p53 expressions to predict apoptosis revealed that mcl-1 (beta = -0.434; p = 0.006), egfr (beta = 0.417; p = 0.009), and p53 (beta = 0.334; p = 0.016) contributed to apoptosis in pc3 cells (r = 0.835; r2 = 0.698) as presented in table 5. concurrently, multivariate ridge regression analysis of mcl-1 levels, egfr, and p53 expressions in each intervention group to predict apoptosis showed that mcl-1 (beta = -0.16; p = 0.006), egfr (beta = -0.096; p = 0.004), and p53 (beta = 0.019; p = 0.002) in the ajwa dates group and mcl-1 (beta = -0.091; p = 0.002), egfr (beta = -0.085; p = 0.002), and p53 (beta = 0.005; p = 0.002) in the combination group analysis as presented in table 6. these results highlighted that the changes in mcl-1, egfr, and p53 sequentially contribute to apoptosis that occurs in pc3 cells in this study. discussion our study demonstrated that ajwa dates have potential as a promising natural anticancer agent. ajwa dates contain various bioactive phytochemicals, such as flavonoids, phenolic acids, glycosides, and terpenoids, which together enhance their antioxidant, anti-inflammatory, and anticancer effects (14, 15). these compounds act via multiple mechanisms, including the induction of apoptosis, cell cycle arrest, and the inhibition of survival signals, thereby enhancing their efficacy and minimizing the risk of resistance compared to single-target chemotherapeutics (16). the favorable safety profile of ajwa date extract, evidenced by its higher ic50 in normal cell lines, indicates a selective cytotoxic effect on cancer cells (15). this low-toxicity strategy exemplifies the characteristics of natural compounds that are gaining recognition for their capacity to modulate essential signaling pathways implicated in cancer progression, such as pi3k/akt/mtor, nf-κb, and mapk/erk cascades. the integration of these phytochemicals in cancer therapy may yield synergistic benefits, potentially improving outcomes and minimizing adverse effects (16). the ic50 value of ajwa dates extract determined in our study was 913.3 μg/ml. this result provides important context when compared to other published ic50 values for ajwa date extracts against cancer cell lines. notably, mirza et al. reported a much lower ic50 for the ethyl acetate fraction of ajwa dates (eafad) against the same pc3 cells, with values of 0.3887 mg/ml (388.7 μg/ml) at 24 hours and 0.4753 mg/ml (475.3 μg/ml) at 48 hours (2). this difference may be attributed to variations in extract preparation, the specific fraction used (e.g., ethyl acetate versus crude or other solvent extracts), or experimental conditions such as cell seeding density and assay protocols. in contrast, studies on other cancer cell lines, such as hsc-2, have reported higher ic50 values for ajwa date flesh extract of 8690 μg/ml and pit extract of 970 μg/ml at 24 hours2 (7). these findings suggest that the cytotoxic potency of ajwa date extracts can vary widely depending on both the cell type and the extraction method. given the promising apoptotic and cytotoxic effects demonstrated across these studies (2, 7), further optimization of extraction strategies may enhance the anticancer potential of ajwa date extracts for prostate cancer therapy. groups mean difference (95% ci) p-value abiraterone vs control 9.4 (3.2 – 15.59) 0.012* ajwa vs control 6.75 (0.56 – 12.94) 0.038* abiraterone + ajwa vs control 9.86 (3.67 – 16.05) 0.010* abiraterone vs ajwa 2.64 (-3.54 – 8.83) 0.413 abiraterone + ajwa vs abiraterone 0.46 (-5.72 – 6.65) 0.989 abiraterone + ajwa vs ajwa 3.11 (-3.08 – 9.3) 0.309 tukey’s hsd test. *statistically significant at p < 0.05. ci: confidence interval. table 4. post hoc analysis comparison of mean percentage of total apoptosis between groups. table 5. multiple linier regression analysis with mcl-1, egfr and p53 as independent and apoptosis as dependent variable. variable coefficients value r r2 unstandardized standardized p-value cofficients beta cofficients beta mcl-1 -510.739 -0.434 0.006* egfr -32.626 -0.417 0.009* 0.835 0.698 p53 15.041 0.334 0.016* *statistically significant at p < 0.05. table 6. multiple regression analysis of each intervention using ridge regression with mcl-1, egfr and p53 as independent and apoptosis as dependent variable. group parameter standardized coefficients beta (95% ci) p-value mape (%) mcl-1 -0.068 [-0.187 – (-0.055)] 0.003* control egfr -0.204 [-0.232 – (-0.089)] 0.003* 39.868 p53 0.015 (-0.097 – 0.056) 0.006* mcl-1 -0.157 [-0.181 – (-0.126)] 0.002* abiraterone egfr -0.101 [-0.161 – (-0.097)] 0.002* 5.158 p53 0.081 (0.077 0.085) 0.002* mcl-1 -0.16 [-0.228 – (-0.066)] 0.006* ajwa egfr -0.096 [-0.117 – (-0.052)] 0.004* 10.645 p53 0.019 (-0.077 – 0.041) 0.002* mcl-1 -0.091 [-0.131 – (-0.079)] 0.002* abiraterone + ajwa egfr -0.085 [-0.127 – (-0.071)] 0.002* 3.963 p53 0.005 (0.003 – 0.008) 0.002* *statistically significant at p < 0.05. mean absolute percentage error. archivio italiano di urologia e andrologia 2025; 97(3):14027 a. azis, a. asadul islam, h. rasyid, et al. 6 in our study, we analysed mcl-1 levels, egfr, and p53 expression parameters, which demonstrated the intervention of ajwa dates extract in pc3 cells has the potential to target multiple interconnected signalling pathways that are essential for cancer cell survival and apoptosis. mcl-1 is a crucial anti-apoptotic protein within the bcl-2 family that is often overexpressed in solid tumors. mcl-1 enhances cell survival through the inhibition of mitochondrial apoptosis and plays a role in chemoresistance (17). targeting mcl-1 represents a promising therapeutic approach, as its downregulation may enhance the sensitivity of cancer cells to apoptosis (18). our study indicated that administration of ajwa dates extract can decrease mcl-1 levels, with the combination of this extract and abiraterone acetate showing the lowest average value among groups (p < 0.001). egfr signalling promotes cancer cell proliferation and survival through the activation of downstream pathways, including pi3k/akt and mapk/erk. inhibition of this signalling has been shown to decrease cell proliferation, induce apoptosis, and inhibit tumor growth in multiple cancer models (19, 20). this aligns with our findings, which demonstrate that the combination of abiraterone acetate and ajwa date extract significantly reduces egfr expression in pc3 cells. the tumor suppressor p53 plays a central role in orchestrating cellular responses to stress by inducing cell cycle arrest and apoptosis; p53-mediated apoptosis is executed through the transactivation of pro-apoptotic genes, mitochondrial dysfunction, and caspase activation (21). our findings demonstrate that the abiraterone acetate group as a monotherapy was the most effective in enhancing p53 expression. the findings of our investigation may be elucidated by many factors and possible antagonistic processes. abiraterone and ajwa dates are recognized to activate p53 via distinct routes, and their combination is believed to disrupt each other's methods of targeting p53. a study by grossebrummel et al. elucidates the findings of this research, indicating that the presence of active natural compounds may counteract the efficacy of abiraterone in inducing apoptosis via a p53-independent pathway. consequently, the impact of abiraterone on p53 does not improve when combined with herbal-based crude extracts containing numerous active natural compounds (22). this work has a notable limitation due to the absence of an in silico analysis and the failure to isolate the active components of ajwa dates, indicating that these results need further investigation. the flowcytometry analysis using facs in this study demonstrated that ajwa date extract combined with abiraterone acetate and ajwa dates extract single intervention can induce apoptosis in pc3 cells. these findings align with prior studies by mirza et al. who reported that the ethyl acetate fraction of ajwa dates (eafad) induced apoptosis in pc3 cells via mitochondrial membrane depolarization and dna fragmentation, corroborating our observation of intrinsic apoptotic pathway activation (2). similarly, shahbaz et al. observed late apoptosis in mda-mb-231 breast cancer cells at higher concentrations of ajwa date pulp extract, mirroring the dose-dependent apoptotic response seen in our study (7). this study has several advantages. first, this study is one of the first in vitro studies to evaluate the effects of ajwa date extract on prostate cancer in the pc3 cells by analyzing key molecular markers such as mcl-1, egfr, and p53 with quantitative measurement of apoptosis. the experimental design comparing the single and combined effects of ajwa date extract with abiraterone acetate allows the identification of potential complementary therapies for prostate cancer. in addition, the use of multivariate analysis methods with multiple linear regression analysis and ridge regression of each treatment group provides an overview of the relative contribution of each molecular parameter to apoptosis induction, thus strengthening the validity of the findings. thus, this study not only provides new scientific evidence regarding the anticancer potential of ajwa dates, but also opens up opportunities for the development of safer and more affordable complementary therapies for prostate cancer patients. this study also possesses many limitations. first, the study design relies on an in vitro model, which cannot adequately recreate the complexity and physiological circumstances of an in vivo model. secondly, this work has not determined the active biochemical components in ajwa dates extract, which might elucidate the chemicals involved in the production and manifestation of apoptosis in pc3 cells. finally, this study has not assessed the potential toxicity effects of ajwa dates extract on normal cells. further study should include animal and human models to evaluate the pharmacokinetics, bioavailability, and systemic toxicity, as well as to confirm the anti-cancer efficacy of ajwa dates demonstrated in this study. declarations contribution details: aa asa hr iy lh sb ab aaz concepts √ √ √ √ design √ √ √ √ definition of intellectual content √ literature search √ data acquisition √ √ √ √ data analysis √ statistical analysis √ √ manuscript preparation √ manuscript editing √ √ √ √ manuscript review √ √ √ √ √ √ √ √ guarantor √ √ √ √ √ √ √ √ ethical approval: not required. availability of data and material: derived data supporting the findings of this study are available from the corresponding author on request. competing interests: the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. funding: all funding for this research comes from authors without receiving research costs or research grants from third parties. acknowledgments: we acknowledge the biomedical central laboratory, faculty of medicine, universitas brawijaya, malang, indonesia, for providing support throughout this study. conference presentation: this article has not been presented at any conference. declaration of artificial intelligence use: the use of artificial intelligence is intended for language refinement purposes. archivio italiano di urologia e andrologia 2025; 97(3):14027 7 anti-cancer activity of ajwa dates conclusions it can be concluded that ajwa dates extract can reduce mcl-1 levels as anti-apoptosis, reduce egfr expression as a proliferation oncogene and increase p53 expression as pro-apoptosis, which contribute to induce apoptosis in pc3 cells. ajwa dates have the potential as a complementary therapy for prostate cancer, but further research is still needed before clinical testing is carried out. references 1. bray f, laversanne m, sung h, et al. global cancer statistics 2022: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2024; 74:229-263. 2. mirza mb, elkady ai, al-attar am, et al. induction of apoptosis and cell cycle arrest by ethyl acetate fraction of phoenix dactylifera l. (ajwa dates) in prostate cancer cells. j ethnopharmacol 2018; 218:35-44. 3. khan f, ahmed f, pushparaj pn, et al. ajwa date (phoenix dactylifera l.) extract inhibits human breast adenocarcinoma (mcf7) cells in vitro by inducing apoptosis and cell cycle arrest. plos one 2016; 11:e0158963. 4. anwar s, raut r, alsahli ma, et al. role of ajwa date fruit pulp and seed in the management of diseases through in vitro and in silico analysis. biology 2022; 11:78. 5. assirey ear. nutritional composition of fruit of 10 date palm (phoenix dactylifera l.) cultivars grown in saudi arabia. j taibah univ sci 2015; 9:75-79. 6. azis a, islam aa, rasyid h, et al. the effect of flavonoid and subclasses supplementation on prostate specific antigen, hormonal parameters and prostate cancer risk: a systematic review and metaanalysis of randomized controlled trials. arch ital urol androl. 2025; 97:13645. 7. shahbaz k, asif ja, liszen t, et al. cytotoxic and antioxidant effects of phoenix dactylifera l. (ajwa date extract) on oral squamous cell carcinoma cell line. biomed res int 2022; 2022:5792830. 8. he y, xu w, xiao y-t, et al. targeting signaling pathways in prostate cancer: mechanisms and clinical trials. signal transduct target ther 2022; 7:198. 9. yancey d, nelson kc, baiz d, et al. bad dephosphorylation and decreased expression of mcl-1 induce rapid apoptosis in prostate cancer cells. plos one 2013; 8:e74561. 10. aggarwal m, saxena r, asif n, et al. p53 mutant-type in human prostate cancer cells determines the sensitivity to phenethyl isothiocyanate induced growth inhibition. j exp clin cancer res cr 2019; 38:307. 11. guérin o, fischel jl, ferrero j-m, et al. egfr targeting in hormone-refractory prostate cancer: current appraisal and prospects for treatment. pharmaceuticals 2010; 3:2238-2247. 12. fragni m, galli d, nardini m, et al. abiraterone acetate exerts a cytotoxic effect in human prostate cancer cell lines. naunyn schmiedebergs arch pharmacol 2019; 392:729-742. 13. hidayatulla f, andhika dp, prasetyawan w, et al. effects of metformin and silodosin as supplementary treatments to abiraterone on human telomerase reverse transcriptase (htert) level in metastatic castration-resistant prostate cancer (mcrpc) cells: an in vitro study. narra j 2024; 4:e680-e680. 14. khan ma, siddiqui s, ahmad i, et al. phytochemicals from ajwa dates pulp extract induce apoptosis in human triple-negative breast cancer by inhibiting akt/mtor pathway and modulating bcl-2 family proteins. sci rep 2021; 11:10322. 15. aljohani ak, maghrabi na, alrehili om, et al. ajwa date extract (phoenix dactylifera l.): phytochemical analysis, antiviral activity against herpes simplex virus-i and coxsackie b4 virus, and in silico study. saudi med j 2025; 46:26-35. 16. situmorang pc, ilyas s, nugraha se, et al. prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways. front pharmacol. 2024; 15:1387866. 17. deng h, han y, liu l, et al. targeting myeloid leukemia-1 in cancer therapy: advances and directions. j med chem 2024; 67:5963-5998. 18. arai s, varkaris a, nouri m, et al. march5 mediates noxadependent mcl1 degradation driven by kinase inhibitors and integrated stress response activation. elife; 9:e54954. 19. peng x-h, karna p, cao z, et al. cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. j biol chem 2006; 281:25903-25914. 20. qin c-f, hao k, tian x-d, et al. combined effects of egfr and hedgehog signaling pathway inhibition on the proliferation and apoptosis of pancreatic cancer cells. oncol rep 2012; 28:519-526. 21. shen y, white e. p53-dependent apoptosis pathways. adv cancer res 2001; 82:55-84. 22. grossebrummel h, peter t, mandelkow r, et al. cytochrome p450 17a1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. int j oncol 2016; 48:793-800. correspondence abdul azis (corresponding author) abdul.azis031@gmail.com urology division of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia perintis kemerdekaan st. km. 10, tamalanrea, makassar, indonesia (postal code: 90245) andi asadul islam undee@med.unhas.ac.id neurosurgery divison of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia haerani rasyid haeranirasyid@med.unhas.ac.id syakib bakri syakibbakri@yahoo.com department of internal medicine, faculty of medicine, hasanuddin university, makassar, indonesia ika yustisia ikayustisia@pasca.unhas.ac.id department of biochemistry, faculty of medicine, hasanuddin university, makassar, indonesia lukman hakim lukman-h@fk.unair.ac.id department of urology, faculty of medicine, airlangga university, surabaya, indonesia faculty of medicine and health, institut teknologi sepuluh nopember, surabaya, indonesia agussalim bukhari agussalim.bukhari@med.unhas.ac.id department of nutritional sciences, faculty of medicine, hasanuddin university, makassar, indonesia andi alfian zainuddin a.alfian@med.unhas.ac.id department of public health and community medicine, faculty of medicine, hasanuddin university, makassar, indonesia stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12306 1 case series parameters has yet to be described. this case series presents three patients of high medical risk with intractable hematuria of prostatic origin, where pae was performed and resulted in the resolution of prostatic hemorrhage. case presentation case 1 a 91-year-old man presented with a 48-hour history of painless gross hematuria. previous medical history included bph with voiding luts, atrial fibrillation on edoxaban, left cortical stroke, dyslipidemia, hypertension and right-sided heart failure with ascites. hemoglobin was 111 g/l at arrival, while pre-procedure hemoglobin was 89 g/l (baseline 120 g/l). anticoagulation was held at arrival and daily subcutaneous thromboprophylaxis was prescribed. the prostate gland volume was 200cc on computed tomography (ct) (figure 1). cystoscopy confirmed the prostate gland was the origin of the hematuria. continuous bladder irrigation (cbi) was performed for 10 days, with no resolution of symptoms. given the multiple medical comorbidities, this patient was not a candidate for surgery and was offered pae, which he accepted. the patient was on cbi for 5 days post-pae before the resolution of the gross hematuria and passed the trial of void on day 6. anticoagulation therapy was resumed on day 7 post-pae. at 6-month follow-up, the patient was voiding well and had no recurrence of hematuria. case 2 an 85-year-old man presented with recurrent gross hematuria for one month with clots, complicated by urinary retention and infection. previous medical history included bph, atrial flutter on apixaban, sick sinus syndrome with pacemaker, coronary artery bypass surgery, type 2 diabetes mellitus and hypertension. at presentation, hemoglobin was 84 g/l (baseline 115 g/l) and required transfusion of 2 units of packed red blood cells (prbc). the prostate gland volume was 120cc on ct introduction: benign prostatic hyperplasia is a prevalent disease that could be responsible of severe intractable hematuria requiring invasive surgical management. case presentation: we report three high-risk cases presented with intractable hematuria of prostatic origin with high medical co-morbidities treated safely and effectively by prostatic artery embolization with favorable outcomes. conclusions: in non-surgical, anticoagulated patients, prostatic artery embolization represents a safe and effective intervention for the treatment of intractable hematuria related to benign prostatic hyperplasia. key words: benign prostatic hyperplasia; gross hematuria; angioembolization; coagulation disorders. submitted 24 february 2024; accepted 9 february 2024 introduction benign prostatic hyperplasia (bph) is a prevalent disease, affecting up to 50% of men over the age of 50, usually associated with lower urinary tract symptoms (luts) (1). intractable hematuria represents a severe complication of bph, which often requires invasive management (2). while transurethral resection of the prostate (turp) remains the mainstay therapy for bph, laser enucleation techniques represent the standard of care for the surgical treatment of larger prostates or in anticoagulated patients (3, 4). however, elderly or co-morbid patients may be at high medical risk for the prolonged anesthesia-time associated with laser turp. in these cases, non-surgical treatment for bph, such as prostatic artery embolization (pae), may be considered. pae consists of embolization of selected prostatic arteries to produce ischemic necrosis and shrinkage of the prostate gland (5, 6). arterial embolization has previously been described for treatment of intractable hematuria due to prostate and bladder pathologies (7, 8). however, to the best of our knowledge, pae for the treatment of intractable hematuria in co-morbid bph patients with unregulated coagulation prostatic artery embolization for intractable hematuria in patients with unregulated coagulation parameters: three case reports manuel belmonte 1, abdulghani khogeer 2*, ghizlane moussaoui 3, rafael melo 4, louis-martin boucher 4, tatiana villalpando-cabrera 4, serge carrier 1, mélanie aubé-peterkin 1 1 department of surgery, division of urology, mcgill university health center, montreal, canada; 2 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 3 department of urological sciences, university of british columbia, vancouver, canada; 4 department of radiology, mcgill university, montreal, canada. * co-first author. doi: 10.4081/aiua.2024.12306 summary archivio italiano di urologia e andrologia 2024; 96(2):12306 m. belmonte, a. khogeer, g. moussaoui, et al. 2 scan. cystoscopy confirmed the prostate as the source of the bleeding. symptoms did not resolve after 7 days of cbi. given the multiple cardiac comorbidities and minimal luts prior to presentation, pae was preferred by the patient. the anticoagulation was held 24 hours prior to the intervention. the patient had no reoccurrence of hematuria and passed trial of void at day 1 post pae intervention; anticoagulation therapy was resumed then, and he was discharged from hospital on post-intervention day 2. at 1-month follow-up, he reported an improvement in luts and no recurrence of hematuria; he was subsequently lost to follow-up. case 3 a 78-year-old man was transferred to our center in the context of an intractable prostatic hemorrhage nonresolving after 30 days of cbi. patient was previously known for atrial fibrillation on warfarin, hypertension, type 2 diabetes mellitus, morbid obesity, and chronic urinary retention secondary to bph. the prostate volume was 150cc measured on ct. on arrival, hemoglobin level was 78 g/l (baselines 121 g/l) and raised to 96 g/l after receiving 2 units of prbc transfusion. the cystoscopy confirmed the bleeding originated from the prostate. surgery did not represent a safe treatment option for this patient given the significant medical comorbidities and associated anesthetic risk. as such, pae was offered and accepted by the patient. anticoagulation therapy was held 24 hours prior to the intervention. the patient had resolution of gross hematuria on post-procedure day 1. he resumed anticoagulation therapy day 1 post-intervention. at 6-month follow-up, he had no reoccurrence of gross hematuria and luts had also improved. prostatic artery embolization technique description technically, pae was achieved under local anesthetic (xylocaine) at the arterial femoral puncture site. ultrasound was performed prior to the puncture to assess for the presence of femoral arterial pathology. subsequently, the right common femoral artery was punctured, permitting the insertion of a 5-french regular vascular sheath. a 5-french cobra (cook, bloomington, in, usa) catheter was used for the internal iliac artery catheterizations and a 2-french progreat microcatheter (terumo, somerset, nj, usa) and fathom™ 0.016 inch wire (boston scientific, marlborough, ma, usa) were used for the catheterization of the prostatic arteries. the microcatheter was advanced in the prostatic arteries beyond any significant side branches supplying the bladder, rectum or penis and its placement was confirmed using cone-beam ct. the perfected technique (proximal embolization first, then embolize distal) was performed. this technique, when possible, has been associated with greater degree of prostatic ischemia and infarcfigure 1. prostate gland measurements pre-angioembolization for patient described in case 1 (axial and sagittal views). figure 2a. angiogram of prostatic arteries right lobe of the prostate pre and post angioembolization, respectively (patient in case 1). note the absence of the prostatic parenchymal blush (arrow) post embolization. archivio italiano di urologia e andrologia 2024; 96(2):12306 3 prostatic artery embolization for intractable hematuria tion, thus leading to better clinical outcomes (13). embolization was performed using embospheres 300500 um (merit medical, south jordan, ut, usa) diluted in 20 ml 1:1 ratio of contrast to saline injected in 1 ml aliquots followed by 3 ml normal saline flush between aliquots until complete stasis was obtained (figure 2a). a similar technique was performed on both sides, always making sure to avoid non-targeted embolization via collaterals to other critical arterial structures such as the penile arteries (figures 2b, 3). discussion prostate hemorrhage represents a severe complication of bph, and rapid control of the bleeding is necessary to avoid morbidity associated with intractable gross hematuria. medical therapies, such as 5-alpha reductase inhibitors, have previously been proposed as treatment avenues in bph-related gross hematuria (9). however, time to response, particularly in patients with larger prostates, has been reported to be on average 10 days or longer (9). when conservative management fails, surgical procedures such as turp or holmium laser enucleation of the prostate often represent the best treatment option for patients. while regional anesthesia is preferred for these interventions, it may be contraindicated due to patients’ anticoagulation status. consequently, prolonged general anesthesia is used, which increases the risk for perioperative complications in anticoagulated patients with cardiac or metabolic comorbidities (10). pae represents a minimally invasive procedure performed under local anesthesia. embolization of the prostatic arteries was previously shown to improve luts and preserve sexual function scores in patients with bph (11). a previous study, where patients with unregulated coagulation parameters were excluded, has reported on the use of pae for the treatment of bph related gross hematuria and found the intervention to be safe for non-surgical candidates (7). in this case series, we presented three non-surgical candidates on anticoagulation therapy who successfully underwent pae. in all 3 cases, no immediate complications occurred. none of the patients developed infection, and groin pain was not a complaint our participants reported. complete resolution of the intractable hematuria was seen in all cases, with no reoccurrence at a minimum of 6-months’ follow-up. while pae represents a non-inferior alternative to turp, it is not void of limitations (12). the access to this procedure in the community is limited and anatomical variants or severe atherosclerotic disease render the procedure difficult and sometimes impossible. the follow-up times for the patients in our series is short, limiting the assessment of the durability of the hemostatic effect of pae. conclusions pae represents a safe and effective intervention for the treatment of bph-related intractable hematuria in nonsurgical and anticoagulated patients. our experience with pae in high-risk patients has been favourable and warrants further investigation with a larger cohort and longer follow-up. references 1. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984; 132:474-9. figure 2b. angiogram of the left lobe of the prostate pre and post angioembolization, respectively (patient in case 1). figure 3. visualization of the penile arteries (arrows) prior to angioembolization of the left prostatic artery (block arrow). archivio italiano di urologia e andrologia 2024; 96(2):12306 m. belmonte, a. khogeer, g. moussaoui, et al. 4 2. ramyil vm, dakum nk, liman hu, udeh ei. the management of prostatic haematuria. niger j med. 2008; 17:439-42. 3. elzayat ea, elhilali mm. holmium laser enucleation of the prostate (holep): the endourologic alternative to open prostatectomy. eur urol. 2006; 49:87-91. 4. elzayat e, habib e, elhilali m. holmium laser enucleation of the prostate in patients on anticoagulant therapy or with bleeding disorders. j urol. 2006; 175:1428-32. 5. demeritt js, elmasri ff, esposito mp, rosenberg gs. relief of benign prostatic hyperplasia-related bladder outlet obstruction after transarterial polyvinyl alcohol prostate embolization. j vasc interv radiol. 2000; 11:767-70. 6. kuang m, vu a, athreya s. a systematic review of prostatic artery embolization in the treatment of symptomatic benign prostatic hyperplasia. cardiovasc intervent radiol. 2017; 40:655663. 7. tian w, zhou c, leng b, et al. prostatic artery embolization for control of gross hematuria in patients with benign prostatic hyperplasia: a single-center retrospective study in 20 patients. j vasc interv radiol. 2019; 30:661-667. 8. mohan s, kumar s, dubey d, et al. superselective vesical artery embolization in the management of intractable hematuria secondary to hemorrhagic cystitis. world j urol. 2019; 37:2175-2182. 9. kearney mc, bingham j, bergland r, et al. clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. j urol. 2002; 167:2489-2491. 10. hanson ra, zornow mh, conlin mj, brambrink am. laser resection of the prostate: implications for anesthesia. anesth analg. 2007; 105:475-9. 11. feng s, tian y, liu w, et al. prostatic arterial embolization treating moderate-to-severe lower urinary tract symptoms related to benign prostate hyperplasia: a meta-analysis. cardiovasc intervent radiol. 2017; 40:22-32. 12. abt d, hechelhammer l, müllhaupt g, et al. comparison of prostatic artery embolisation (pae) versus transurethral resection of the prostate (turp) for benign prostatic hyperplasia: randomised, open label, non-inferiority trial. bmj. 2018; 361:k2338. 13. carnevale fc, moreira am, antunes aa. the "perfected technique": proximal embolization first, then embolize distal for benign prostatic hyperplasia. cardiovasc intervent radiol. 2014; 37:1602-5. correspondence manuel belmonte, md manuel.belmontecg@gmail.com mélanie aubé-peterkin, md, frcsc (corresponding author) melanie.aube-peterkin@muhc.mcgill.ca carrier serge, md serge.carrier@mcgill.ca mcgill university health centre 1001 décarie blvd, montreal, quebec h4a 3j1, canada abdulghani khogeer, md dr-abdulghani@hotmail.com department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia ghizlane moussaoui, md ghizlane.moussaoui@mail.mcgill.ca department of urological sciences, university of british columbia, vancouver, canada rafael melo, md rcardosodemelo@gmail.com louis-martin boucher, md lmboucher@yahoo.com tatiana villalpando-cabrera, md tacaal@hotmail.com department of radiology, mcgill university, montreal, canada conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14073 1 original paper have indicated that autonomic nervous system dysregulation, particularly heightened sympathetic activity, may play a central role in its underlying mechanisms (5). this hypothesis is supported by heart rate variability analyses in men with pe, which consistently demonstrate increased sympathetic tone alongside diminished parasympathetic activity (6). given that autonomic imbalance is also a recognized factor in atrial conduction disturbances, its role in pe may extend beyond sexual function, potentially implicating broader cardiovascular implications. p-wave dispersion (pwd), one of the non-invasive electrocardiographic markers reflecting atrial conduction abnormalities, is defined as the difference between the longest and shortest p wave durations recorded on a standard 12lead ecg (7). increased pwd reflects heterogeneity in atrial depolarization and is considered a reliable indicator of atrial structural remodeling (8). various studies have demonstrated that the duration and dispersion of the p wave are influenced by autonomic nervous system activity (9). increased pwd has been identified as an independent risk factor for the development of atrial fibrillation (af), the most commonly sustained arrhythmia in the general population. moreover, increased pwd is associated with a higher incidence of cardiovascular events and overall mortality, contributing to a reduced quality of life (8, 10). although several studies have reported increased pwd in various systemic and neuropsychiatric conditions, including lichen planus, acute pancreatitis, psoriasis, schizophrenia, thalassemia, polycystic ovary syndrome, and erectile dysfunction, the association between pwd and pe remains unexplored (11-17). considering the established role of autonomic nervous system dysregulation in the pathophysiology of pe, it is reasonable to hypothesize that these patients may exhibit altered atrial conduction. therefore, the present study aimed to evaluate pwd in patients with both llpe and ape compared to healthy controls, with the hypothesis that increased pwd in the pe group may reflect a greater likelihood of atrial conduction abnormalities, such as af. materials and methods study design and participants this prospective observational study was conducted with 78 male participants aged between 25 and 55 years who visited the outpatient clinic either with or without combackground: premature ejaculation (pe) is one of the common male sexual disorders and is associated with autonomic nervous system imbalance. p-wave dispersion (pwd), a marker of atrial electrical heterogeneity and a predictor of atrial arrhythmias, has not been previously investigated in the pe population. this study aimed to investigate pwd in patients with pe and to evaluate whether the subtypes of pe, namely acquired (ape) and lifelong (llpe), differ in terms of atrial conduction parameters. methods: seventy-eight male patients were included in the study. the distribution of patients was 40 healthy controls, 21 patients with ape, and 17 patients with llpe. all patients underwent 12-lead electrocardiography to evaluate pwd. echocardiographic, hormonal, and biochemical parameters were recorded to exclude confounding factors. pwd was defined as the difference between the maximum (pmax) and minimum p wave durations (pmin). results: pwd was significantly increased in both pe groups compared to the control group (ape: 44.4 ± 4.1 ms; llpe: 48.1 ± 2.1 ms; control: 38.2 ± 3.4 ms; p < 0.001). pmin was significantly lower in the pe groups, while pmax remained comparable among all groups. there was no significant difference in pwd between the pe groups (p = 0.38). all patients had normal echocardiographic and hormonal parameters, and there were no significant differences in age, body mass index, blood pressure, or heart rate between the groups. conclusions: pwd was significantly higher in patients with pe. this indicates that the patients of pe are at a higher risk of developing cardiovascular diseases like atrial fibrillation. key words: premature ejaculation; p-wave dispersion; atrial fibrillation; cardiovascular disease; electrocardiography. submitted 12 june 2025; accepted 10 july 2025 introduction premature ejaculation (pe) is one of the most common male sexual disorders, affecting approximately 20-30% of men (1, 2). it is typically defined as ejaculation occurring either within one minute of vaginal penetration in lifelong cases (llpe), or within approximately three minutes in acquired forms (ape) (3, 4). the exact pathogenesis of pe has not yet been fully elucidated. while psychological factors, genetic predisposition, endocrine abnormalities, alterations in penile sensitivity, and chronic prostatitis have all been suggested as potential contributors, definitive evidence linking these conditions to pe remains lacking (4). studies p-wave dispersion in patients with premature ejaculation ali akkoç 1, can ramazan öncel 2, cemal köseoğlu 2 1 department of urology, school of medicine, alanya alaaddin keykubat university, alanya, türkiye; 2 department of cardiology, school of medicine, alanya alaaddin keykubat university, alanya, türkiye. doi: 10.4081/aiua.2025.14073 summary archivio italiano di urologia e andrologia 2025; 97(3):14073 a. akkoç, c. ramazan öncel, c. köseoğlu 2 plaints of pe. participants were divided into three groups as follows: group 1: patients diagnosed with ape (n = 21) group 2: patients with llpe (n = 17) control group: age-matched healthy men without any pe symptoms (n = 40). participants were recruited consecutively from the urology and cardiology outpatient clinics of our institution. controls were selected among healthy volunteers attending the clinics for routine health check-ups or minor urological issues not associated with autonomic or cardiovascular conditions. the diagnosis of pe was made based on detailed clinical history and self-reported symptoms, in line with the guidelines of the international society for sexual medicine (issm). individuals with a known history of psychiatric disorders, cardiovascular disease, diabetes mellitus, hypertension, or those on medications that might affect autonomic or cardiac function were excluded from the study. in addition, patients with abnormal thyroid function tests were excluded to eliminate potential confounding effects on both pe and pwd. all participants provided written informed consent prior to enrolment. the study protocol was reviewed and approved by the clinical research ethics committee of alanya alaaddin keykubat university (decision no: 16-14, date: 13/02/2020). clinical and laboratory evaluation demographic and clinical characteristics, including age, body mass index (bmi), systolic and diastolic blood pressure (sbp and dbp), and resting heart rate (hr), were recorded for all participants. blood samples were collected in the morning following an overnight fast of 8-12 hours. the laboratory tests included fasting glucose, total cholesterol, low-density lipoprotein (ldl), triglycerides, creatinine, hemoglobin, prolactin, and total testosterone levels. echocardiographic assessment all subjects underwent transthoracic echocardiography following standardized imaging protocols. the following cardiac parameters were measured: left ventricular end-diastolic diameter (lvdd), left ventricular end-systolic diameter (lvsd), interventricular septum thickness (ivs), posterior wall thickness (pw), left atrial diameter (lad), and ejection fraction (ef). diastolic function was assessed using the e/a ratio derived from pulsed-wave doppler measurements of mitral inflow. electrocardiographic measurements standard 12-lead electrocardiograms (ecgs) were recorded with participants in the supine position after a 10-minute rest. ecgs were obtained at a paper speed of 25 mm/s and amplitude of 10 mm/mv, then digitized for analysis. the onset of the p-wave was defined as the point where it first deviated from the isoelectric line, and the end was marked by its return. the longest (pmax) and shortest (pmin) p-wave durations across all leads were measured using the software cardio calipers (iconico inc., new york usa). pwd was calculated as pwd = pmax pmin. all ecg measurements were independently analysed by two cardiologists who were blinded to group allocation. interobserver variability was assessed and found to be within acceptable limits, with a difference of less than 5% between observers. statistical analysis data were analysed using spss version 21.0 (ibm corp., armonk, ny, usa). continuous variables were expressed as mean ± standard deviation (sd). comparisons between the three groups were made using analysis of variance (anova), followed by tukey’s post-hoc test for multiple comparisons. a p-value less than 0.05 was considered statistically significant. results demographic and clinical characteristics a total of 78 male subjects were included: 40 healthy controls, 21 with acquired premature ejaculation (group 1), and 17 with lifelong premature ejaculation (group 2). there were no statistically significant differences among the three groups in terms of age, bmi, blood pressure, heart rate, or laboratory values including glucose, lipid profile, creatinine, hemoglobin, testosterone, and prolactin (p > 0.05 for all) (table 1). table 1. demographic, clinical, and echocardiographic variables of study group. parameter control group 1 ape group 2 lpe p-value (n = 40) (n = 21) (n = 17) age (years) 39.6 ± 7.3 38.7 ± 8.5 38.5 ± 8.3 0.69 bmi (kg/m2) 25.9 ± 4.7 24.9 ± 5.7 25.0 ± 5.1 0.51 glucose (mg/dl) 88.9 ± 7.0 87.4 ± 7.9 86.8 ± 8.2 0.95 total cholesterol (mg/dl) 193.1 ± 37.7 186.7 ± 33.7 185.2 ± 35.1 0.73 triglycerides (mg/dl) 176.1 ± 86.7 179.4 ± 79.3 180.1 ± 80.6 0.39 ldl (mg/dl) 117.0 ± 33.5 121.1 ± 28.2 120.5 ± 27.9 0.67 creatinine (mg/dl) 0.83 ± 0.2 0.92 ± 0.2 0.91 ± 0.3 0.51 hb (g/dl) 13.5 ± 1.4 14.7 ± 0.9 14.4 ± 1.0 0.49 prolactin (ng/ml) 10.6 ± 3.4 11.2 ± 3.1 11.3 ± 2.8 0.18 testosterone (ng/dl) 520.4 ± 85.2 498.7 ± 79.6 501.2 ± 78.3 0.27 sbp (mmhg) 117.8 ± 7.8 121.3 ± 8.9 121.1 ± 9.2 0.27 dbp (mmhg) 78.3 ± 5.6 74.3 ± 4.1 74.1 ± 4.6 0.37 hr (bpm) 76.8 ± 6.5 79.3 ± 6.5 79.7 ± 6.9 0.15 lvdd (cm) 47.7 ± 5.1 48.5 ± 4.4 48.3 ± 4.2 0.26 lvsd (cm) 28.7 ± 3.5 28.7 ± 3.3 28.6 ± 3.4 0.72 ef (%) 64.2 ± 3.4 63.7 ± 5.2 63.5 ± 4.8 0.18 ivs (cm) 9.5 ± 1.1 9.6 ± 0.9 9.5 ± 0.8 0.42 pw (cm) 9.4 ± 1.0 9.2 ± 1.4 9.3 ± 1.1 0.14 lad (cm) 33.4 ± 3.3 34.1 ± 2.8 34.0 ± 3.0 0.22 e/a ratio ±0.4 ± 0.2 ± 0.2 0.36 data are presented as mean ± standard deviation values. bmi: body mass index; ldl: low-density lipoprotein; hb: hemoglobin; sbp: systolic blood pressure; dbp: diastolic blood pressure; hr: heart rate; lvdd: left ventricular diastolic diameter; lvsd: left ventricular systolic diameter; ef: ejection fraction; ivs: interventricular septum; pw: posterior wall; lad: left atrial diameter; e/a: early-to-late mitral inflow velocity ratio. archivio italiano di urologia e andrologia 2025; 97(3):14073 3 p wave dispersion and premature ejaculation echocardiographic parameters such as lvdd, lvsd, ef, ivs, pw, lad, and e/a ratio also showed no significant group differences. electrocardiographic findings the pmax was similar across all groups (p = 0.47), while pmin was significantly reduced in both pe groups compared to controls (p < 0.001), being lowest in the llpe group. consequently, pwd was significantly increased in group 1 and especially in group 2 compared to controls (p < 0.001). although pwd was numerically higher in group 2 than group 1, this difference was not statistically significant (p = 0.38) (table 2). discussion we demonstrated that pwd is significantly increased in men with pe compared to healthy controls. after stratifying the pe cohort into ape and llpe subtypes, no significant differences were found between these subgroups in demographic, hormonal, or echocardiographic parameters, confirming comparability. both ape and llpe groups demonstrated significantly higher pwd values compared to controls, indicating that pe, regardless of subtype, is associated with similar degrees of atrial conduction delay. this prolongation of pwd was primarily driven by a reduction in pmin, while the pmax remained comparable across groups. all participants had similar age, body mass index, blood pressure, and echocardiographic findings, including normal left atrial size and systolic function. additionally, serum testosterone and prolactin levels, which influence sexual function and autonomic regulation, were statistically similar between groups. these findings indicate that the observed changes in atrial conduction are not attributable to structural heart disease or hormonal imbalances but are more likely related to functional alterations in autonomic control. pwd is a well-recognized electrocardiographic marker for atrial arrhythmogenic risk. the significant pwd prolongation observed in our pe patients suggests a potential subclinical predisposition to atrial arrhythmias. these findings are consistent with previous studies reporting similar pwd prolongation in disorders associated with autonomic or endothelial dysfunction. for instance, men with ed have been shown to exhibit prolonged pwd compared to healthy individuals, with the increase attributed to a shortened pmin while pmax remained unchanged. moreover, pwd in ed patients was inversely correlated with erectile function scores, implying that more severe dysfunction is associated with greater atrial conduction heterogeneity (17). as ed is a known marker of endothelial and autonomic dysfunction, the parallels with pe support a shared pathophysiological basis. prolonged pwd has also been reported in several systemic conditions. patients with schizophrenia demonstrate significantly higher pwd compared to age-matched controls, despite having no structural heart disease (14). chronic inflammatory diseases such as psoriasis are similarly associated with prolonged pwd, and values tend to rise with increasing disease severity (13). women with polycystic ovary syndrome, a condition characterized by endocrine and autonomic imbalance, show higher pwd along with prolonged atrial conduction intervals (16). furthermore, hypertensive disorders of pregnancy like preeclampsia have been linked to increased pwd, supporting a broader role of systemic disturbances in atrial conduction abnormalities (18). however, not all conditions with autonomic involvement result in increased pwd. for example, fibromyalgia, despite its association with autonomic dysfunction and cardiovascular symptoms, was not found to significantly differ from controls in terms of pwd (19). this suggests that the link between autonomic imbalance and atrial conduction heterogeneity may depend on disease-specific mechanisms. it is possible that pro-arrhythmic effects of sympathetic overactivity in fibromyalgia are counterbalanced by other regulatory processes, unlike in pe or ed. although our study did not directly assess mechanisms, autonomic dysregulation remains the most plausible explanation for the observed findings. prior work has shown that men with lifelong pe display elevated sympathetic and reduced parasympathetic activity based on heart rate variability analysis, reflecting increased sympathovagal balance (5). elevated sympathetic tone and circulating catecholamines are known to alter atrial electrophysiology by shortening refractory periods and increasing conduction velocity, thereby promoting atrial conduction heterogeneity. autonomic influences have been shown to modulate pwave indices, with sympathetic activation typically associated with pwd prolongation (20). in pe patients, chronic stress, anxiety, or serotonergic dysfunction may further exacerbate this imbalance. given that ejaculation is primarily under sympathetic control, a predisposition to pe might reflect a generalized sympathetic dominance. the comparable extent of pwd prolongation in both ape and llpe supports the idea that once established, pe may lead to persistent autonomic alterations and cardiac electrical remodelling regardless of onset type. clinically, the increased pwd values in young, otherwise healthy men with pe are noteworthy. a pwd threshold above 40 ms is commonly considered predictive of af (10). in our pe cohort, average pwd values exceeded this threshold, while control values remained within the upper normal limit. although no arrhythmic events were documented, this finding suggests a latent electrical vulnerability that may have long-term relevance. table 2. electrocardiographic variables of study group. parameter control group 1 ape group 2 lpe p-value (n = 40) (n = 21) (n = 17) pmax (ms) 108.4 ± 4.2 107.1 ± 5.1 109.3 ± 3.3 0.47 pmin (ms) 70.5 ± 3.2 63.8 ± 3.1* 61.4 ± 3.3**, *** < 0.001 pwd (ms) 38.2 ± 3.4 44.4 ± 4.1* 48.1 ± 2.1**, *** < 0.001 data are presented as mean ± standard deviation values. pmax: maximum p-wave duration; pmin: minimum p wave duration; pwd: p wave dispersion. *: significant difference group 1 vs. control (p < 0.001). **: significant difference group 2 vs. control (p < 0.001). ***: group 1 vs. group 2 (p = 0.38). archivio italiano di urologia e andrologia 2025; 97(3):14073 a. akkoç, c. ramazan öncel, c. köseoğlu 4 whether this predisposition translates into clinical arrhythmias over time remains uncertain. if sustained, autonomic imbalance could contribute to atrial remodelling. our findings underscore that pe, typically viewed as a psychosexual disorder, may also carry electrophysiological relevance. recognizing this association can support a more holistic clinical approach that includes evaluation of autonomic and cardiac function in men presenting with pe. this study has several limitations that should be acknowledged. first, the sample size of the pe subgroups was relatively modest. however, it was sufficient to detect statistically significant differences in pwd compared to controls, suggesting that the effect size was strong enough to demonstrate the relationship between pe and atrial conduction. nonetheless, larger cohorts are warranted to confirm our findings and to better clarify whether subtle distinctions exist between pe subtypes. moreover, although the study groups were well matched for potential confounders, future studies with larger samples would benefit from multivariate analyses to further adjust for unmeasured variables. second, the cross-sectional design of the study limits causal inference. while we observed a significant association between pe and increased pwd, the temporal sequence or directionality of this relationship cannot be determined. finally, although autonomic nervous system involvement is strongly supported by previous literature and aligns with our clinical rationale, we did not directly evaluate autonomic function using objective physiological measurements. despite these limitations, our study provides novel evidence that premature ejaculation, a common psychosexual disorder, may be associated with subclinical alterations in atrial conduction. these findings emphasize the potential value of incorporating basic electrocardiographic assessment into the broader evaluation of sexual dysfunction and highlight the need to consider cardiovascular dynamics in patients presenting with pe. conclusions this study is the first to demonstrate a significant increase in pwd among patients with pe, including both ape and llpe subtypes. these findings suggest that pe is associated with increased atrial conduction heterogeneity, most likely related to autonomic dysregulation rather than structural cardiac abnormalities or traditional cardiovascular risk factors. although no arrhythmic events were detected in our cohort, the elevated pwd values, frequently exceeding thresholds predictive of af, may reflect a latent electrophysiological susceptibility. recognizing pe as a condition with potential cardiovascular relevance could help promote more integrative clinical assessment strategies. larger-scale studies are needed to determine whether addressing pe or its autonomic underpinnings can mitigate future cardiac risk. references 1. martin c, nolen h, podolnick j, wang r. current and emerging therapies in premature ejaculation: where we are coming from, where we are going. int j urol. 2017; 24:40-50. 2. porst h, montorsi f, rosen rc, et al. the premature ejaculation prevalence and attitudes (pepa) survey: prevalence, comorbidities, and professional help-seeking. eur urol. 2007; 51:816-23. 3. serefoglu ec, mcmahon cg, waldinger md, et al. an evidencebased unified definition of lifelong and acquired premature ejaculation: report of the second international society for sexual medicine ad hoc committee for the definition of premature ejaculation. sex med. 2014; 2:41-59. 4. rowland d, perelman m, althof s, et al. self-reported premature ejaculation and aspects of sexual functioning and satisfaction. j sex med. 2004; 1:225-32. 5. zorba ou, cicek y, uzun h, et al. autonomic nervous system dysfunction in lifelong premature ejaculation: analysis of heart rate variability. urology. 2012; 80:1283-6. 6. erbay g, ceyhun g. is heart rate variability a risk factor for premature ejaculation? int j clin pract. 2021; 75:e14699. 7. aytemir k, ozer n, atalar e, et al. p wave dispersion on 12-lead electrocardiography in patients with paroxysmal atrial fibrillation. pacing clin electrophysiol. 2000; 23:1109-12. 8. sahin m, bilgili sg, simsek h, et al. increased p-wave dispersion in patients with newly diagnosed lichen planus. clinics (sao paulo). 2013; 68:846-50. 9. yasar e, yilmaz b, yasar as, et al. effect of autonomic dysfunction on p-wave dispersion in patients with chronic spinal cord injury. am j phys med rehabil. 2010; 89:824-30. 10. dilaveris pe, gialafos ej, sideris sk, et al. simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. am heart j. 1998; 135:733-8. 11. aditi r, sathasivasubramanian s, bhaskar me. association of declarations ethical approval and consent for participate: this study was approved by the alanya alaaddin keykubat university faculty of medicine clinical research ethics committee (alkü-kaek), approval number: 16-14, dated 13/02/2020. consent for publication: not applicable. availability of data and material: the datasets used and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request. competing interests: the authors declare that they have no competing interests. funding: the authors report no funding. authors' contributions: aa: study concept, data collection and analysis related to premature ejaculation; crö and ck: interpretation of cardiological parameters; aa, crö and ck: contributed equally to manuscript drafting and revision. all authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):14073 5 p wave dispersion and premature ejaculation oral lichen planus and electrocardiographic p-wave dispersion an original research. braz dent j. 2017; 28:699-703 12. büyükkuscu a, zeynelova g, oflaz u, et al. p-wave dispersion in acute pancreatitis. arch basic clin res. 2024; 6:96-100. 13. kumar u, agrawal m, varma k, et al. study of p-wave dispersion in patients of psoriasis: an observational study. ip indian journal of clinical and experimental dermatology. 2023; 9:66-71. 14. baykara s, yılmaz m, baykara m. qt dispersion and p wave dispersion in schizophrenia. psychiatry clin psychopharmacol. 2019; 29:538-43. 15. amirghofran s, aslani a, zakerinia m. investigation of p-wave dispersion in adult patients with beta-thalassemia major. j cardiovasc disease res. 2016; 7:116-9. 16. bayır pt, güray ü, duyuler s, et al. assessment of atrial electromechanical interval and p wave dispersion in patients with polycystic ovary syndrome. anatol j cardiol. 2016; 16:100-5. 17. öncel cr, akkoç a. p wave dispersion in patients with erectile dysfunction. interv med appl sci. 2019; 11:101-5. 18. inci s, nar g, aksan g, et al. p-wave dispersion and atrial electromechanical delay in patients with preeclampsia. med princ pract. 2015; 24:515-21. 19. yolbas s, yıldırım a, düzenci d, et al. qt dispersion and p wave dispersion in patients with fibromyalgia. eur j rheumatol. 2016; 3:165-8. 20. kutsal c, albayrak at, abdullayev e, et al. retrospective evaluation of p-wave dispersion on ecg in terms of atrial fibrillation dispersion in patients using alpha-blockers for lower urinary tract symptoms. med j bakirkoy. 2023; 19:31-4. correspondence ali akkoç, assoc. prof. (corresponding author) aliakkoc@gmail.com department of urology, school of medicine, alanya alaaddin keykubat university, alanya, türkiye can ramazan öncel can.oncel@alanya.edu.tr cemal köseoğlu drcemalkoseoglu@hotmail.com department of cardiology, school of medicine, alanya alaaddin keykubat university, alanya, türkiye stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11718 1 systematic review introduction urinary incontinence affects 15-35% of communitydwelling postmenopausal women (1, 2). urge incontibackground: urinary incontinence and other urinary symptoms tend to be frequent at menopause because of hormonal modifications and aging. urinary symptoms are associated with the genitourinary syndrome of menopause which is characterized by physical changes of the vulva, vagina and lower urinary tract. the treatment strategies for postmenopausal urinary incontinence are various and may include estrogens, anticholinergics, and pelvic floor muscle training. a comparison of these treatments is difficult due to the heterogeneity of adopted protocols. we systematically reviewed the evidence from randomized controlled trials (rcts) focusing on treatment of postmenopausal women with urge incontinence. methods: we conducted a systematic review and meta-analysis by searching pubmed and embase databases for randomized controlled trials (rcts) reporting results of treatments for postmenopausal urinary urge incontinence. odds ratios for improvement of urinary incontinence were calculated using random effect mantel-haenszel statistics. results: out of 248 records retrieved, 35 eligible rcts were assessed for risk of bias and included in the meta-analysis. compared with placebo, systemic estrogens were associated with decreased odds of improving urinary incontinence in postmenopausal women (or = 0.74, 95% ci: 0.61-0.91, 7 series, 17132 participants, z = 2.89, p = 0.004, i2 = 72%). in most studies, no significant improvement in urinary symptoms was observed in patients treated with local estrogens, although they showed to be helpful in improving vaginal symptoms. vitamin d, phytoestrogens and estrogen modulators were not effective in treatment of urge incontinence in postmenopausal women: a systematic review rawa bapir 1, 15, kamran hassan bhatti 2, 15, ahmed eliwa 3, 15, herney andrés garcía-perdomo 4, 15, nazim gherabi 5, 15, derek hennessey 6, 15, vittorio magri 7, 15, panagiotis mourmouris 8, 15, adama ouattara 9, 15, gianpaolo perletti 10, 15, joseph philipraj 11, 15, konstantinos stamatiou 12, 15, musliu adetola tolani 13, 15, lazaros tzelves 8, 15, alberto trinchieri 14, 15, noor buchholz 15 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 urology unit, asst fatebenefratelli sacco, milan, italy; 8 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 9 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 10 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 department of urology, tzaneio general hospital, 18536 piraeus, greece; 13 division of urology, department of surgery,ahmadu bello university/ahmadu bello university teaching hospital, zaria, kaduna state, nigeria; 14 urology school, university of milan, milan, italy; 15 u-merge ltd. (urology for emerging countries), london-athens-dubai *. authors 1-14 have equally contributed to the paper and share first authorship. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/uk. www.u-merge.com doi: 10.4081/aiua.2023.11718 summary improving symptoms of incontinence and other symptoms of genitourinary menopause syndrome or yielded contradictory results. a randomized controlled trial demonstrated that oxybutynin was significantly better than placebo at improving postmenopausal urgency and urge incontinence. the combination of anticholinergics with local estrogens has not been shown to be more effective than anticholinergics alone in improving urinary incontinence symptoms in postmenopausal women. physical therapy showed an overall positive outcome on postmenopausal urinary incontinence symptoms, although such evidence should be further validated in the frame of quality rcts. conclusions: the evidence for effective treatment of postmenopausal urinary incontinence is still lacking. welldesigned large studies having subjective and objective improvement primary endpoints in postmenopausal urinary incontinence are needed. at present, a combination of different treatments tailored to the characteristics of the individual patient can be suggested. key words: urinary incontinence; urgency; menopause; estrogens; anticholinergics; vitamin d; soy. submitted 3 september 2023; accepted 7 september 2023 archivio italiano di urologia e andrologia 2023; 95(3):11718 r. bapir, k. hassan bhatti, a. eliwa, et al. 2 nence is the more common form of incontinence after menopause. it presents in association with a combination of urinary symptoms, including frequency, nocturia, urgency, and dysuria. urge syndrome disorders are often misunderstood to be symptoms of urinary tract infection and, consequently, are not treated appropriately. estrogen deficiency is thought to play an important role in the etiology of the “urge syndrome”, that tends to rise in prevalence and to enhance in intensity as the years of estrogen deficiency increase. in fact, estrogens affect the urethral mucosa, the smooth muscle, and the alpha-adrenergic tone in the urinary tract (3). both oral and vaginal estrogens have been used in the management of urinary incontinence in postmenopausal women, although the effectiveness of hormonal therapy on urinary incontinence is controversial. alternative treatments include anticholinergic medication, pelvic floor muscle exercise and bladder training. combinations of anticholinergics and topical vaginal estrogen are also used for treatment of urge incontinence and female sexual dysfunction. in addition, posterior tibial nerve stimulation and acupuncture were used in the conservative treatment of these syndromes, in order to tackle the functional physiological changes associated with urge incontinence. moreover, fractional co2 laser and low intensity shock wave treatment (liswt) have emerged as new treatment modalities, as these approaches may improve the atrophy of the urethral and bladder mucosa. evaluation of the efficacy of the treatment of urge incontinence is difficult due to heterogeneity of the protocols adopted, and to the paucity of randomized controlled studies. our research was aimed to systematically review the available evidence resulting from randomized controlled trials (rcts) aiming to treat postmenopausal women with urge incontinence. methods protocol and registration this review was conducted in accordance with the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines (5). the review protocol was registered on the prospero platform (registration code: crd42023405369). types of studies we considered articles written in english, reporting the results of randomized controlled trials (rcts) evaluating the efficacy of treatment of urge incontinence in postmenopausal women. types of patients we included postmenopausal women of any ethnicity or age. types of interventions we included studies focusing on any treatment aimed at addressing the signs and symptoms of urge incontinence. outcomes the outcomes considered for this review were the rate and/or severity of symptoms and signs (urge incontinence, urgency, nocturia, pelvic floor muscle strength) evaluated by specific interview questions, or by administering questionnaires to patients (e.g., the revised urinary incontinence scale, the overactive bladder questionnaire, the international consultation on incontinence questionnaire) or by recording the reports of structured bladder diaries. microbiologic, cytologic and urodynamic findings were also evaluated. the outcomes were compared in patients receiving treatment compared to placebo or to no treatment. search strategy two electronic databases (pubmed and embase) were searched for records reporting rcts published up to 31 january 2023. the search was performed using strings based on broad mesh terms (e.g., female and menopause and (dysuria or urination disorders or incontinence) and treatment). relevant data were also searched by browsing the reference lists of reviews and clinical trial reports, or through other sources (e.g., clinicaltrials.gov; https://www.clinicaltrialsregister.eu/). data collection and analysis (selection of studies and data extraction) title and abstract screening to exclude records that did not meet the inclusion criteria were performed independently by 4 authors (2 authors for pubmed and 2 for embase). duplicate references were deleted. full texts were downloaded for a second round of screening and to extract relevant information. controversies were resolved by the research coordinator (at). a prisma flow diagram was drawn to illustrate the results of the study selection process (figure 1) (6). data extraction was conducted by 4 authors using a standardized form. the following data were obtained from each study: author(s), publication year, study design, population, intervention(s), results. in case of missing or insufficient information, we performed sensitivity analysis, in order to consider the impact of missing data on the meta-analysis results. quality evaluation on methodology three authors independently performed the quality assessment by identifying potential biases using the cochrane risk of bias tool (9). the following potential sources of bias were considered: randomization process (d1), deviations from the intended interventions (d2), missing outcome data (d3), measurement of the outcome (d4) and selection of the reported result (d5). disagreements were resolved by discussion. risk of bias was not used to exclude studies. statistical analysis statistical analysis was performed using the revman5 software. dichotomous data and number of subjects were extracted to calculate odds ratios (or), confidence intervals (ci) to or, and z statistics (random-effects model, mantel-haenszel method). assessment of heterogeneity the heterogeneity of pooled results was assessed by the i2 statistic, reported with 95% cis, and interpreted as of lesser importance (i2 ≤ 40%), moderate (i2 = 30%-60%), archivio italiano di urologia e andrologia 2023; 95(3):11718 3 postmenopausal urge incontinence fi gu re 1 . pr is m a 20 20 fl ow d ia gr am f or n ew s ys te m at ic r ev ie w s w hi ch in cl ud ed s ea rc he s of d at ab as es , r eg is te rs a nd o th er s ou rc es . archivio italiano di urologia e andrologia 2023; 95(3):11718 r. bapir, k. hassan bhatti, a. eliwa, et al. 4 substantial (i2 = 50%-90%) or considerable (i2 ≥ 75%), according to cochrane criteria. sensitivity analysis was planned if considerable heterogeneity of pooled analyses including at least 4 studies was detected. assessment of publication bias publication bias was assessed by generating funnel plots if meta-analyses included at least 4 trials. the begg’s and egger’s tests were used to test funnel plot (a)symmetry and to confirm or exclude the presence of publication bias or small study effect. data on funnel plots were presented as the natural logarithm of odds ratios. the metaessential 2 software (rotterdam school of management, erasmus university, the netherlands) was used for funnel plot analysis. results from 248 retrieved records ((pubmed = 106, embase = 142), and after removal of 27 duplicates, we selected 54 reports which were examined by full-text reading. after full-text examination, 19 reports were excluded for various reasons (supplementary materials table 1). the remaining 35 reports were classified according to different types of treatment, namely estrogen treatment, including systemic (n = 9) and local (n = 6) administration, anticholinergics (n = 5), other treatments (n = 6), and physical treatment (n = 9). risk of bias of the 35 reports, only 8 were rated as having a low risk of bias, whereas 5 reports presented slight concerns and 23 high concerns of bias. the randomization process was associated to risk of bias in most reports (n = 24) and to unclear risk in 10. only one study presented high concerns of bias with respect to the randomization process. risk of deviations from the intended intervention (blinding) was rated as low in 18 reports, unclear in 4 and high in 13. the risk for missing outcome data was judged low in 20 reports, unclear in 4 and high in 11. the risk of bias in measurement of outcome was considered low in 27 reports, unclear in 1 and high in 7. the risk of bias in selection of the reported results was judged low in 34 and unclear in 1 (supplementary materials figure 1). systemic estrogens the effect of estrogen administration on urinary incontinence in postmenopausal women was compared to placebo or no treatment in 9 studies. most studies date back to the 1990s or early 2000s, and some relate to programs that had women's general health after menopause as their main outcome, namely the women's health initiative, the heart and estrogen/progestin replacement study (hers), the estrogen replacement and atherosclerosis (era) trial, the danish osteoporosis prevention study (dops). in a study, estriol produced not significant subjective and objective changes of the lower urinary tract function compared with placebo (8). in three studies (9-11), administration of combined estrogen and progestogen therapy (0.625 mg/day conjugated equine estrogen plus 10 mg/day medroxyprogesterone acetate) was compared with placebo. fantl et al. observed no significant changes in the number of incontinence episodes, weight of fluid losses and number of diurnal or nocturnal voids (9). conversely, grady et al. showed that oral estrogen plus progestin treatment was associated with a worsening of urinary incontinence in postmenopausal women of the hers (10). an article by steinauer et al., reporting about some results of hers, confirmed a higher rate of weekly incontinence in patients on hormone treatment compared to a placebo group (64% vs 49%) (11). in two other studies (12, 13), both estrogens alone and a combination of estrogen and progestinics were compared with placebo. oral estrogen plus progestinic treatment had no significant effects on the de novo development of urge urinary incontinence in patients who were asymptomatic at baseline (rr 1.15) but increased the frequency of urinary incontinence (rr 1.38) and worsened the amount of urinary incontinence episodes (rr 1.20) in patients who reported urinary incontinence at baseline compared to placebo. oral estrogens alone increased the risk of the de novo development of urinary incontinence (rr 1.32), worsened the urinary frequency (rr 1.47) and increased the amount of urinary incontinence episodes in patients with incontinence at baseline (rr 1.59) (12). a similar study showed significantly higher rates of urinary incontinence in the estrogen-only group compared to the placebo group (13). in two studies, the effect of an estrogen implant, or of transdermal estrogen, was compared with placebo (14, 15). after two years of treatment with ultralow-dose transdermal estriol (0.014 mg/d), the prevalence of incontinence symptoms did not differ in treated women compared to placebo. the odds ratio for incontinence worsening in women with incontinence at baseline was 1.35 in the estradiol treated compared with placebo group, and the odds of developing at least one weekly incontinence episode in women without incontinence at baseline was 1.20 (14). in neither case were odds ratios statistically significant. rufford et al. evaluated the effect of systemic estrogen replacement by a 25 mg 17bestradiol implant compared to placebo implant. no significant differences between the groups were observed by videocystourethrography, frequency volume chart, visual analogue score of symptoms, and king’s health care quality of life questionnaire (15). finally, an open label study had a more complex design, as it included a group that was randomized to receive hormonal treatment versus no treatment and a second group in which patients chose whether to receive hormonal treatment or no treatment (16). firstline hormonal treatments were: (a) sequential oral estrogen and progestogen (2 mg estradiol for the first 12 days, 2 mg estradiol plus 1 mg norethisterone acetate for 10 days, and 1 mg estradiol for 6 days) in women with intact uterus and (b) oral continuous estradiol, 2 mg per day, in hysterectomized women. hormonal treatment did not seem to influence the degree of voiding frequency, or the severity of incontinence (16). the effect of hormone therapy both as combination of estrogens with progestogens or estrogens alone was quantitatively evaluated in 7 studies. meta-analysis treatment of incontinence was considered successful archivio italiano di urologia e andrologia 2023; 95(3):11718 5 postmenopausal urge incontinence when the authors defined the patients as cured (absence of the symptom(s) present at baseline) (8, 15) or improved (9, 10, 14) or without worsening of the degree of bother or disturbance attributed to urinary incontinence (12). the odds of successful treatment were significantly lower in the hormone treatment group compared to the placebo or control groups (or = 0.74, 95% ci: 0.61-0.91, 7 series, 17132 participants, z = 2.89, p = 0.004, i2 = 72%, figure 2). funnel plot analysis for detection of publication bias produced uncertain results (supplementary materials figure 2). visual analysis of the plot suggest a significant degree of asymmetry, which was confirmed by the egger regression test (p = 0.016), but not to the begg’s test (p = 0.88). when women treated with a combined hormonal protocol were analyzed separately, the odds of success of incontinence treatment were confirmed to be significantly lower than the control group (or = 0.78, 95% ci: 0.68-0.90, 3 series, 10707 participants, z = 3.53, p = 0.0004, i2 = 21%, figure 3), while the odds ratios of success of treatment with estrogen alone were not significantly different from controls (or = 0.72, 95% ci: 0.49-1.06, 4 series, 6425 participants, z = 1.65, p = 0.10, i2 = 54%, figure 4, panel a). visual analysis of the funnel plot suggested the presence of asymmetry, which was not confirmed by the egger figure 2. odds for success of systemic hormone treatment of urinary postmenopausal incontinence. figure 3. odds for success of combined systemic hormone treatment of urinary postmenopausal incontinence. figure 4. odds for success of treatment for urinary postmenopausal incontinence with systemic estrogens alone. archivio italiano di urologia e andrologia 2023; 95(3):11718 r. bapir, k. hassan bhatti, a. eliwa, et al. 6 regression test (p = 0.078) or by the begg’s test (p = 0.17) (supplementary materials figure 2). on the other hand, meta-analyses of three studies demonstrated that the odds for diurnal voids and urinary incontinence in women on systemic hormone treatment were not different from those in women treated with placebo, while in two studies the odds for nocturia worsened for women on hormonal treatment compared to controls (figure 5). similarly, in two studies, the odds of improvement in urodynamic parameters (volume at first desire to void, cystometric capacity, and detrusor pressure) were not significantly different in patients receiving hormone treatment compared to controls (figure 6). local estrogens three studies compared the use of local estrogens with placebo (17-19). one study compared local estrogens alone with local estrogens combined with benzydamine (20). another study compared estrogen delivery via a vaginal ring with an estriol pessary (21). finally, a study compared ultralow-dose estradiol vaginal ring with oral oxybutynin (22). figure 5. odds for urgency, nocturia and urinary incontinence in patients on systemic hormone treatment. a) diurnal voids b) nocturia c) urinary incontinence figure 6. odds for improvement of urodynamic parameters in patients on systemic hormone treatment compared to controls. a) volume at first desire to void archivio italiano di urologia e andrologia 2023; 95(3):11718 7 postmenopausal urge incontinence cardozo et al. evaluated the effect of 17-beta estradiol 25 mg vaginal tablets or placebo daily for 12 weeks (17). no significant improvement was observed in urinary frequency and urgency following treatment with intravaginal 17-beta estradiol. the only statistically significant difference was a greater reduction in urinary urgency in women with a urodynamic diagnosis of sensory urgency. in this subgroup, urgency was related to urogenital atrophy secondary to estrogen deficiency. in a study by dessole et al., the treatment cohort received intravaginal estriol ovules (1 mg ovule once-daily for 2 weeks and subsequently 2 ovules once-weekly for a 6 months), and the control group received inert placebo vaginal suppositories in a similar regimen. a subjective improvement of incontinence was observed in 68% of the treated participants in comparison to 16% of the controls. speroff et al. assessed the efficacy of a vaginal ring, delivering the equivalent of 50 or 100 mcg per day of estradiol compared with placebo (19). there was a general trend towards the improvement of urogenital symptoms in patient with active rings, although a significant improvement compared with placebo was observed only for certain vaginal symptoms (vaginal dryness, pain during intercourse). melis et al. compared vaginal administration of a low dose of estriol (0.5 mg daily for 14 days, followed by 0.5 mg every two days for 3 months) with the same regimen plus an anti-inflammatory and antibacterial compound (benzidamine) (20). the efficacy on urinary symptoms (nocturia, incontinence, urge incontinence) was not different between the two groups, although the combination of estriol with benzidamine was more effective in reducing vaginal symptoms (itching, burning, leucorrhea, dryness). lose et al. compared the efficacy of an estradiol-releasing vaginal ring with an estriol pessary, showing that these strategies were equally efficacious in reducing urinary urgency, urge incontinence, stress incontinence and nocturia (21). the vaginal ring showed higher patient acceptability compared to estriol pessaries. nelken et al. evaluated women who were randomized to receive either a vaginal ring releasing ultralow-dose estradiol (2 mg of 17beta-estradiol released at a rate of 7.5 kg microgr daily) or oral oxybutynin (5 mg twice daily) for 12 weeks (22). both treatments achieved a reduction in the number of voids per day, with no significant difference between the groups. anticholinergics only one study compared anticholinergics with placebo (23). in four studies (24-27) the efficacy of anticholinergics alone was compared with anticholinergics in combination with local estrogens. tapp et al. performed a placebo controlled cross over study of oxybutynin chloride in postmenopausal women suffering from detrusor instability (23). oxybutynin therapy significantly reduced the symptoms of urgency, urge incontinence, and nocturia. oxybutynin therapy was significantly better than placebo at improving urgency and urge incontinence. chughtai et al. compared fesoterodine with topical vaginal estrogen once daily with fesoterodine once daily alone for 12 weeks (24). both treatments were associated with a significant improvement in urinary symptom severity and quality of life. compared to fesoterodine alone, the combination treatment showed a reduced symptom severity (oab score) and higher quality of life (hrql and sqolf score). urinary frequency was significantly reduced from baseline in the combination group alone. jiang et al. randomized patients to receive solifenacin 5 mg plus promestriene vaginal capsules, or solifenacin 5 mg alone for 12 weeks (25). there were no significant intergroup differences in the number of daily voids, urgency episodes, urge incontinence episodes and nocturia. martin et al. randomized patients to treatment with fesoterodine in combination with either a conjugated estrogen vaginal cream or a placebo vaginal cream (26). both treatments decreased the severity of urinary symptoms (oab and usiq scores) and increased the quality of life (hrql score). no significant intergroup differences were b) cystometric capacity c) detrusor pressure archivio italiano di urologia e andrologia 2023; 95(3):11718 r. bapir, k. hassan bhatti, a. eliwa, et al. 8 observed. in addition, there was no significant improvement in data recorded in bladder diaries. tseng et al. randomized patients to treatment with 2 mg tolterodine twice daily compared to 2 mg tolterodine twice daily associated to vaginal conjugated equine estrogen 0.625 mg twice a week for 12 weeks (27). the comparison between groups showed a significantly greater improvement in daytime frequency and voided volume after combination treatment. other symptoms, including nocturia, urgency and urge incontinence were improved with both treatments, though intergroup differences were not reported. the quality of life was significantly improved after combination treatment compared to the single-agent protocol. other treatments two reports presented the results of treatment with soy extracts (28, 29). bumbu et al. compared the effect of long-term administration of soy extracts (40% isoflavones) with the results of continuous combined hormonal treatment based on 1 mg estradiol and 0.5 mg noretisterone acetate daily, with a control no-treatment group (28). after 12 months, symptom scores, according to the revised urinary incontinence scale (ruis), and the incidence of urinary incontinence, were influenced neither by soy nor by hormone treatment compared to placebo. manorai et al. compared the effect of a soy-rich diet (25 g soy protein in various forms of soy food, containing more than 50 mg/day of isoflavones) with an isocaloric control diet (soy-free diet) (29). the symptoms of urge incontinence and vaginal dryness significantly increased after 12-weeks of soy-free diet. two studies evaluated the effect of vitamin d supplementation on urinary incontinence symptoms (30, 31). markland et al. conducted a randomized trial in women with serum 25-hydroxyvitamin d (25[oh]d) of 30 ng/ml or less, comparing treatment with weekly oral 50.000 iu vitamin d3 or placebo for 12 weeks (30). vitamin d treatment demonstrated a greater than 40% decrease in urinary incontinence episodes, which however did not reach statistical significance compared to placebo. oberg at al. (31) allocated patients to 20 000 iu of vitamin d3 twice a week, or to a similarly looking placebo. after 12 months, a statistically significant reduction in the severity of urine incontinence in the high dose vitamin d group was observed, compared to placebo. other pharmacological treatments were evaluated in two studies (32, 33). waetjen et al. assigned patients to raloxifene or placebo (32). after 3 years of treatment, there was no significant difference between raloxifene and placebo groups in terms of urinary incontinence severity (or 1.02). in addition, the odds of worsening urinary incontinence severity were 1.05 and the odds of developing new onset incontinence were 0.95. green et al. assigned women to treatment with aprepitant at a daily dose of 160 mg versus placebo for 8 weeks (33). aprepitant is a neurokinin-1 receptor antagonist that may be efficacious in the treatment of urge urinary incontinence, since preclinical evidence suggested that incontinence may be associated to up-regulation of the tachykinin mediated bladder/spinal reflex signaling. treatment significantly decreased the number of daily voids and urgency episodes compared with placebo at 8 weeks, although the daily number of urge urinary incontinence and the total urinary incontinence episodes were not significantly reduced. physical treatment three studies compared postmenopausal women treated with pelvic floor muscle training (pftm) with a control group (34-36).an increase of pelvic floor muscle contractility after pfmt, as evaluated by surface electromyography (semg) and digital palpation, was observed in two reports (34,35). alves et al. demonstrated an improvement of incontinence symptom scores (iciq-oab, iciq ui-sf, mesa), as well as of the anterior pelvic organ prolapse score (pop-q system) after pftm, compared to controls (34). sran et al. reported an improvement of symptoms as measured by urogenital distress inventory (udi) after pftm (p = 0.026), whereas changes of incontinence impact questionnaire (iiq) and geriatric selfperceived efficacy scores were not significantly improved (36). results of bladder diaries showed a reduction of nocturia and frequency together with an increase of intervoid intervals (35), and a reduction of weekly leakage episodes (36). finally, the same group demonstrated that physical treatment significantly reduced the amount of leakage on the 24-hour pad test. a study compared pfmt alone with pfmt combined with postural instructions and demonstrated that addition of the latter improved pelvic muscle strength as evaluated by oxford grading scale. however, incontinence symptoms were not improved (37). another study compared two formats of unsupervised pfmt programs (2-hr class or 20 min video instruction), showing no difference in terms of nocturia and urinary urgency episodes reduction and inter-void interval extension (38). other studies evaluated the effectiveness of other physical treatments (vaginal electrostimulation, radiofrequency, fractional co2 laser, lieswt) in reducing urinary incontinence in post-menopausal women. the effect of vaginal electrostimulation was compared with the outcome of pfmt; no significant improvement in subjective and objective outcome variables were reported in the population treated with electrostimulation compared with the population treated with pfmt. the rates of women reporting improvements in urinary leakage were 29.2% vs. 27.3% (39). a study compared radiofrequency treatment and fractional co2 laser treatment (4 weeks apart, about 1-2 minute(s) per session) with a control group. it was demonstrated that mixed urinary incontinence decreased after the intervention including radiofrequency and laser compared to the control group. however, the changes in the laser group were not statistically significant (40). borges aguiar et al. compared the efficacy of co2 laser treatment with local estrogen treatment and a control treatment (vaginal lubricant) (41). the laser group showed a more significant reduction in the total iciq-ui sf score and nocturia compared to controls. archivio italiano di urologia e andrologia 2023; 95(3):11718 9 postmenopausal urge incontinence finally, a study investigated the therapeutic efficacy of low intensity extracorporeal shock wave treatment (lieswt) on urinary incontinence of postmenopausal women in comparison to sham treatment (42). lieswt decreased urinary frequency, nocturia, urgency, urgency incontinence, and post-voided residual urine volume and increased voided urine volume and maximal flow rate compared to the sham control. summary of findings a summary of findings (sof) table prepared according to grade criteria is shown in the supplementary materials (table 2). the quality of the evidence ranged between moderate (presence of risk of bias) and very low (publication bias, risk of bias and inconsistency due to substantial heterogeneity). discussion the prevalence of bladder symptoms, such as frequency, urgency and incontinence, tends to increase around the menopause, although it is still debated whether these disorders are due to menopause, or aging, or a combination of the two. urinary symptoms are associated with the genitourinary syndrome of menopause (gsm) which is characterized by physical changes of the vulva, of the vagina and of the lower urinary tract, including the presence of pallor or erythema of the genital mucosa, loss of vaginal wrinkles, introital retraction, vaginal dryness and the prolapse of the urethral mucosa. these genital alterations have been all correlated with local estrogen deficiency, and were shown to benefit from local estrogen administration. however, the effects of local estrogens on urinary symptoms such as urgency, frequency and urinary incontinence are still unclear (43-45). for these reasons, the treatment of postmenopausal incontinence remains not well defined by therapeutic guidelines, which sometimes do not consider postmenopausal incontinence as an independent and specific condition, but as a subtype of other clinical disorders (overactive bladder, lower urinary tract symptoms, urge and urinary incontinence). our search and literature review retrieved the results of studies focusing on various forms of treatment or combinations of different treatments. estrogens high affinity estrogen receptors are present in the female urinary tract and in the structures of the pelvic floor. clinical and urodynamic modifications are observed during pregnancy, the menstrual cycle and following the onset of the menopause. in animal studies, pretreatment with estrogens enhanced detrusor contractility in response to alpha-adrenoceptor agonists, cholinomimetics and prostaglandins, and contractile response to alpha-agonists in the ureter and urethra, conversely, progesterone decreases the muscle tone in the ureter, bladder and urethra by enhancing beta-adrenergic responses (46). in postmenopausal women, atrophic mucosal changes respond well to low-dose estrogen replacement therapy (43). two meta-analyses by cody et al. extensively evaluated the role of estrogen therapy for urinary incontinence in post-menopausal women (44, 45). the authors concluded that systemic treatment with conjugated equine estrogen may worsen urinary incontinence. however, too few data were retrieved to extensively evaluate the effects of estrogen type, different dosage, and route of administration. furthermore, the authors highlighted the potential risk of endometrial and breast cancer onset associated with long-term high-dose estrogen treatment and suggested cautious and limited in time use of estrogen, especially in non-hysterectomized women. estriol has less uterotrophic effect compared to other estrogens; conversely, the addition of a progestogen to long-term estrogen therapy to reduce the risk of endometrial cancer may increase the risk of incontinence due to a decrease in urethral pressure induced by the latter. local treatment with estrogen was considered safer and was deemed to improve urinary incontinence, though the optimal duration of treatment and long-term effects have been poorly studied (44, 45). eau guidelines suggest offering vaginal estrogen therapy to women with lower urinary tract symptoms (luts) and associated symptoms of genitourinary syndrome of menopause (47). our analysis showed that no significant improvements in urinary symptoms were observed in patients treated with local estrogens, except for a reduction in urgency severity in a subgroup of patients presenting with sensory urgency. similarly, no significant changes in urodynamic parameters were observed. local estrogens do not seem to give a substantial benefit of urinary symptoms in postmenopausal patients, although they may be helpful in improving vaginal irritation symptoms. vitamin d, phytoestrogens and estrogens modulators an alternative to estrogen treatment is the use of other drugs acting on estrogen receptors or on other receptors present in the genitourinary organs. phytoestrogens, such as the isoflavones of soy, show structural similarities to natural and synthetic estrogens and antiestrogens, acting as estrogen agonists and producing estrogen-like effects. consumption of a phytoestrogen-rich diet has been suggested to alleviate menopausal symptoms without increasing the risk of cancer (48). conversely, studies retrieved by our review showed that a soy-rich diet was not effective in improving the symptoms of incontinence and other symptoms of the genitourinary menopause syndrome (28, 29). raloxifene is a second-generation selective estrogen receptor modulator that is used for the prevention and treatment of osteoporosis in postmenopausal women because of its estrogenic effect on the bone, associated to an antiestrogenic effect on breast, and a neutral effect on the endometrium and the vaginal mucosa. in the rct included in this review, raloxifene had no significant effect on urinary incontinence in postmenopausal women after 3 years of treatment (32). the use of vitamin d for the treatment of urinary incontinence in postmenopausal women is supported by the finding of vitamin d receptors on the bladder detrusor and striated muscle (48). vitamin d could act on stromal and smooth muscle cells by improving the muscle response to bladder filling in women with low vitamin d intake (50). archivio italiano di urologia e andrologia 2023; 95(3):11718 r. bapir, k. hassan bhatti, a. eliwa, et al. 10 in our review, two studies (30, 31) evaluated the effects of vitamin d administration on urinary incontinence in menopausal women, but the results appear to be contradictory, and no conclusive statement can be made on this matter. anticholinergics anticholinergics are successfully used in the treatment of neurogenic or idiopathic overactive bladder symptoms, although their use is limited by side effects such as dry mouth and constipation (51). in addition, a specific limitation of the use of anticholinergics in the treatment of postmenopausal urinary incontinence could be the potential risk of cognitive impairment in older women. in fact, treatment with anticholinergics in elderly people could be associated with cognitive impairment, as has been demonstrated in recent longitudinal cohort studies (52, 53). cognitive impairment could be a consequence of central nervous system metabolism alterations and brain atrophy. eau guidelines (47) confirm the efficacy of anticholinergic drugs in elderly patients with overactive bladder and urinary incontinence but warn of the risk of a cognitive impact with a cumulative effect related to the length of treatment. worsening of cognitive function has been observed in patients taking oxybutynin (52, 54), but not in short-term studies with darifenacin, fesoterodine, solifenacin and trospium. although a previous meta-analysis (55) found inconclusive evidence of the impact of anticholinergics on cognition, a cautious use of long-term anticholinergics has been recommended, especially in patients at risk or with pre-existing cognitive dysfunction or on treatment with other drugs with anticholinergic effects (54). mirabegron a possible alternative to anticholinergics could be b3adrenoceptor agonists, which have demonstrated efficacy and safety in elderly patients. in patients aged ≥ 65 years, dry mouth occurred much less frequently with mirabegron than with tolterodine. mirabegron also had a low incidence of central nervous system effects, and a systematic review of the cardiovascular safety profile has shown no clinically significant effects on blood pressure or pulse rate amongst patients aged ≥ 65 years (56, 57). our literature review found no rct comparing mirabegron or other b3-adrenoceptor agonists with placebo for the treatment of postmenopausal incontinence. further studies are warranted in this respect. a recent study (58), published after the conclusion of our literature search, compared two b3-adrenoceptor agonists, mirabegron and vibegron, in postmenopausal women with treatment naive overactive bladder. after 12 weeks of treatment, both drugs significantly improved symptom scores, micturition frequency, urgency and incontinence episodes, as well as the voided volume per 24 hours, compared with baseline, without significant difference in postvoid residual urine volume. severe side effects requiring the discontinuation of treatment were observed in 6.2% of patients in the mirabegron group and in 6.8% in the vibegron group. physical therapy the studies included in our review demonstrated an overall positive outcome of pelvic floor muscle training (pfmt) on postmenopausal urinary incontinence symptoms, although in most studies no effort was made to distinguish between the different types of incontinence. similarly, a recent systematic review demonstrated that pfmt in combination with physical training was effective in reducing urinary incontinence and improving quality of life in elderly patients (> 65 years) (59). moreover, an ici consensus paper stated that age and frailty alone did not represent a contraindication for pfmt in selected patients with sufficient cognition to comply with treatment (60). other forms of physical treatment for urinary incontinence need to be validated by quality, adequately powered rcts. eau guidelines report slight, short-term improvement of overactive bladder symptom after vaginal laser therapy, but data about long-term efficacy and safety are missing. vaginal laser therapy is not recommended outside the frame of well-designed controlled clinical trials (61). conclusions in conclusion, the results of our review demonstrate that there is no robust evidence of an effective treatment for postmenopausal urinary incontinence. there is still a need of large, adequately powered and well-designed studies, focusing on subjective and objective improvements in urinary incontinence as their primary outcome. currently, no treatment by itself has been shown to be fully effective and superior to another. from the limited evidence available, a combined approach, including different forms of treatment tailored to the characteristics of the individual patient can be suggested. references 1. diokno a, brock b, brown m, herzog a. prevalence of urinary incontinence and other urological symptoms in the noninstitutionalized elderly. j urol 1986; 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32:621-38. 57. kennelly mj, rhodes t, girman cj, et al. efficacy of vibegron and mirabegron for overactive bladder: a systematic literature review and indirect treatment comparison. adv ther. 2021; 38:5452-5464. 58. kinjo m, masuda k, nakamura y, et al. comparison of mirabegron and vibegron in women with treatment-naive overactive bladder: a randomized controlled study. urology. 2023; 175:67-73. 59. stenzelius k, et al. the effect of conservative treatment of urinary incontinence among older and frail older people: a systematic review. age ageing. 2015; 44:736. 60. wagg a, chen lk, johnson t, et al. committee 11, incontinence in frail older persons, in incontinence, p. abrams, et al., editor. 2017. 61. alsulihem a, corcos j. the use of vaginal lasers in the treatment of urinary incontinence and overactive bladder, systematic review. int urogynecol j. 2021; 32:553-572. correspondence rawa bapir, md dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti, md kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar ahmed eliwa, md ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt herney andrés garcía-perdomo, md herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi, md ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey, md derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland vittorio magri, md vittorio.magri@asst-fbf-sacco.it urology unit, asst fatebenefratelli sacco, milan, italy panagiotis mourmouris, md thodoros13@yahoo.com lazaros tzelves, md lazarostzelves@gmail.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece conflict of interest: the authors declare no potential conflict of interest. adama ouattara, md adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobodioulasso, burkina faso gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio general hospital, 18536 piraeus, greece musliu adetola tolani, md adetolatolani@yahoo.com division of urology, department of surgery, ahmadu bello university/ ahmadu bello university teaching hospital, zaria, kaduna state, nigeria alberto trinchieri, md alberto.trinchieri@gmail.com urology school, university of milan, milan (italy) noor buchholz,md noor.buchholz@gmail.com sobeh's vascular and medical center, dubai health care city, dubai, united arab emirates stesura seveso 507archivio italiano di urologia e andrologia 2022; 94, 4 review no conflict of interest declared. objective: proton pump inhibitors are widely used as treatment of acid-related disorders. they are considered safe although their long-term use has been associated with some adverse effects including an increased propensity for urinary calculi formation. the aim of this study was to systematically review available data from studies evaluating the association of ppis and nephrolithiasis materials and methods: we searched two electronic databases (pubmed and embase) for cohort studies or case-control studies evaluating the relationship between treatment with proton pump inhibitors and the risk of stone formation published up to 31 october 2022. the overall association of ppis and urinary calculi was analyzed using a random effects model (revman5). the quality of the included studies was assessed using the newcastle-ottawa quality assessment scale. results: a total of 550 studies were retrieved; 7 were selected by title and abstract screening; after removal of duplicates, 4 records were evaluated by full-text examination. an additional study was retrieved by handsearching the references included in screened studies. in the unadjusted analysis, the odds of urinary calculi were greater in subjects taking ppis compared to controls (unadjusted or = 2.10, 95% ci 1.74-2.52, p < 0.00001). the pooled odds ratio of two case-control studies confirmed that use of ppis increased the odds of urinary calculi compared with non-use (or 2.44, 95% ci 2.29 to 2.61). pooled analysis of three cohort studies evaluating incident nephrolithiasis showed risk of urinary stone formation associated to proton pump inhibitors: a systematic review and metanalysis rawa bapir 1, 15, kamran hassan bhatti 2, 15, ahmed eliwa 3, 15, herney andrés garcía-perdomo 4, 15, nazim gherabi 5, 15, derek hennessey 6, 15, vittorio magri 7, 15, panagiotis mourmouris 8, 15, adama ouattara 9, 15, gianpaolo perletti 10, 15, joseph philipraj 11, 15, konstantinos stamatiou 12, 15, musliu adetola tolani 13, 15, lazaros tzelves 8, 15, alberto trinchieri 14, 15, noor buchholz 15 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 asst nord milano, milan, italy; 8 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 9 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 10 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 department of urology, tzaneio general hospital, 18536 piraeus, greece, 13 division of urology, department of surgery, ahmadu bello university / ahmadu bello university teaching hospital, zaria, kaduna state, nigeria; 14 urology school, university of milan, milan, italy; 15 u-merge ltd. (urology for emerging countries), london-athens-dubai*. authors 1-14 have equally contributed to the paper and share first authorship. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2022.4.507 summary an overall hazard ratio estimate of 1.34 (95% ci = 1.28-1.40). one study found lower urinary citrate and urinary magnesium levels in subjects exposed to ppis. the newcastle-ottawa quality assessment scale scores ranged between 6 and 8. conclusions: ppis showed an association with urinary calculi in patients included in the studies included in this review. if these data will be confirmed in adequately powered randomized trials, clinicians may consider limiting the long-term use of ppis, to avoid unnecessary prolongation of treatment. urinary magnesium and citrate should be evaluated in renal stone forming patients taking ppis to supplement their intake when requested. key words: proton pump inhibitors; urinary calculi; h2-receptor blockers; magnesium; citrate. submitted 1 december 2022; accepted 15 december 2022 introduction proton pump inhibitors (ppis) reduce the gastric acid production by irreversibly blocking the h+/k+ atpase, also known as the proton pump, located in the parietal cells of the gastric wall. ppis are widely used for the treatment of gastroesophageal reflux disease (gerd), zollinger-ellison syndrome, erosive esophagitis, duodenal or gastric ulcers archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 508 including those caused by non-steroidal anti-inflammatory drugs (nsaids), and for the eradication of helicobacter pylori in combination with antibiotics. they have emerged as first-line treatment of acid-related disorders, traditionally treated with histamine type 2 receptor antagonists/blockers (h2ras), that inhibit gastric acid secretion by blocking the histamine stimulation of gastric parietal cells (1). ppis are considered safe, though their long-term use has been associated with some serious adverse effects including community acquired pneumonia (2), risk for osteoporosisrelated fractures (3, 4), enteric infection (5), clostridium difficile-associated diarrhea (6, 7), myocardial infarction (8), chronic kidney disease (9), alzheimer’s dementia (10), and hypomagnesemia (4). in 2019, the analysis of post-marketing safety data from fda adverse event reporting system (faers) suggested an increased propensity for nephrolithiasis in subjects taking proton-pump inhibitors (11). two studies, presented as congress communications but never published as full-text reports, demonstrated that the use of ppis and h2 blockers was associated with an increased risk of kidney stones (12, 13). more recently, three articles were published, evaluating in three different large population from the united states (n = 2) and korea (n = 1) the risk of stone formation in patients taking ppis (14-16). the aim of this study was to systematically review the data from studies evaluating the association of ppis and nephrolithiasis and, where possible, to perform a pooled analysis of the prevalence of urinary stone disease in patients taking ppis. particular attention was devoted to the assessment of the risk of bias in the studies included in the analysis. materials and methods protocol and registration the review was conducted in accordance with the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines (17). it was registered on the prospero platform as crd42022375951. types of studies we considered articles written in english, reporting cohort studies, case-control studies and randomized controlled trials evaluating the relationship between the treatment with ppis or h2ras and the risk of kidney stone formation, without time constraints. types of patients adult participants (> 18 years) of both sexes were involved irrespective of their age or ethnicity. types of interventions proton pump inhibitors (ppis) and histamine-2 receptor antagonists (h2ras). outcomes the main outcome considered for this review was the assessment of the prevalence rate of urinary stones in subjects taking ppis compared to those not taking this treatment. a secondary outcome was the comparison of renal stone prevalence between subjects taking compared to those non-taking h2ras. search strategy two electronic databases (pubmed and embase) were searched for articles published up to 31 october 2022. search was performed using the following string based on mesh terms: (proton pump inhibitors or histamine h2 antagonists or omeprazole or esomeprazole or lansoprazole or dexlansoprazole or pantoprazole or rabeprazole) and urinary calculi. relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, clinical trial registers such as www.clinicaltrials.gov, www.clinicaltrialsregister.eu, etc.). data collection and analysis selection of studies title and abstract screening to exclude documents that did not meet the inclusion criteria was performed independently by two authors. duplicate references were deleted. full texts were downloaded for full-text screening and to extract relevant information. controversies were resolved by a third researcher. a prisma flow diagram was drawn to illustrate the results of study selection process (figure 1). data extraction data extraction was conducted by four authors using a standardized form. the following information was obtained from each study: author(s), publication year, study design, population, intervention, prevalence of stone disease. in case of missing or insufficient information, we considered the impact of missing data on the meta-analysis results. risk of bias analysis two authors independently performed the assessment of quality of the included studies using the newcastleottawa scale (nos), a risk of bias assessment tool for observational studies that is recommended by the cochrane collaboration (18). the nos evaluates three quality parameters (selection, comparability, and outcome) divided across eight specific items. it can be scored a maximum of one ‘star’ for each item within the ‘selection’ and ‘exposure/outcome’ categories and a maximum of two ‘stars’ for ‘comparability’. the maximum nos score is 9. a study with score ranging between 7 and 9 is rated as being high quality, between 4 and 6 as medium quality, and between 0 and 3 as low quality. the overall evaluation of the quality of pooled evidence was performed according to grade criteria. publication bias assessment by funnel plot analysis was performed in the presence of at least 4 studies. if a potential reporting bias was suspected, the begg/mazumdar and egger’s regression tests were used to assess the significance of funnel plot asymmetry and potential publication bias. statistical analysis statistical analysis was performed using the revman5 509archivio italiano di urologia e andrologia 2022; 94, 4 proton pump inhibitors and urinary calculi software. dichotomous data (presence/absence of stone disease) and number of subjects were extracted to calculate odds ratios (or), hazard ratios (hr), confidence intervals (ci), and z statistics. pooled analyses were performed using the generic inverse-variance random-effects model. random effect model was used due to high heterogeneity of included studies. assessment of heterogeneity heterogeneity was assessed by i^2 statistics, reported with 95% cis, and interpreted as of lesser importance (≤ 40%), moderate (30%-60%), substantial (50%-90%) or considerable (≥ 75%), according to cochrane criteria. results we retrieved 550 records, 539 from embase and 11 from medline. after title and abstract screening of retrieved records and deduplication, we selected 7 articles. after full text reading, we considered 4 articles for meta-analysis. an additional study was retrieved by handsearching the references included in screened studies. description of studies a description of the selected studies, including retrieved data, is shown in the supplementary materials. ferraro et al. (12) evaluated cohorts of health professionals participating to the health professionals follow-up study (hpfs), and nurses’ health study (nhs) i and ii (n = 187.330). incident stone episodes were prospectively evaluated during a follow up > 10 years. urinary excretion risk factors for stone formation was evaluated in a subgroup of 6.520 participants. kwak et al. (13) evaluated a cross-sectional sample of the us population in the context of the national health and nutrition examination survey (nhanes), providing a variety of health and nutrition measurements in men and nonpregnant women age > 20 (n = 13836). kim et al. (14) conducted a nested casecontrol study using the national health insurance service-national health screening cohort in korea, that included unselected men and women from the general population, older than 40 years. renal stone formers and controls were randomly matched for age, sex, income, and region of residence. a total of 28.962 urolithiasis participants and 115.848 control participants were enrolled. simonov et al. (15) retrospectively evaluated incident stones in participants to the women veterans cohort study (wvcs), including men and women veterans who were discharged from military service as of october 2001 and who elected to utilize the veteran administration medical care (n = 465.891). subjects with diagnosis of nephrolithiasis or a history of ppi usage prior pre-observation were excluded from the study. a subset of subjects taking ppis or not (86.264 in each group) were considered for a propensity-matched model. the median observation time was 4 years. a limitation of this study was the younger age of the population, which limited the generalizability of the study findings to other populations. sur et al. (16) evaluated the records of the database of clinical data vanderbilt research and synthetic derivative. medical center electronic health records from 1993 to 2020 were obtained for over three million patients. the researchers identified a cohort of 55.765 adults with gerd, who were ppi naïve and had no history of nephrolithiasis. incident nephrolithiasis was retrospectively evaluated using the first ppi use as the date of first gerd diagnosis. the median follow up was 3 years. urinary 24-hour risk factors for stone formation were evaluated in a subset of 593 patients with gerd. quantitative analysis unadjusted data from four studies showed that ppis use was significantly associated with urinary calculi (or = 2.10, 95% ci 1.74-2.52, p < 0.00001) (figure 2a). the study of ferrero and coworkers was excluded from this analysis because it was presented as an abstract lacking crude data to be used for quantitative analysis. no addifigure 1. flow diagram. archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 510 tional information was obtained from the authors. when pooled analyses were performed using data adjusted for comorbidities and concurrent medications, the association between ppis and urinary calculi remained significant. the pooled odds ratio of two case-control studies confirmed that the use of ppis increased the odds of urinary calculi compared with non-use (or 2.44, 95% ci 2.29 to 2.61) (figure 2b). the pooled hazard ratios of three studies evaluating incident nephrolithiasis showed an overall pooled hr estimate of 1.34 (95% ci = 1.281.40) (figure 2c). considerable heterogeneity was found in all analyses (i2 = 96%, 92%, and 88% respectively). length and dose of treatment results concerning the effect of the duration of ppi treatment on the risk of stone formation are controversial. kim et al. (14) found higher odds for urolithiasis when treatment with ppi was extended to 365 days or longer (or 2.32) compared to shorter periods (30-364 days: or 1.97, 1-19 days: or 1.65). this confirms the finding of kwak et al. (13) who reported higher rates of urinary calculi in subjects taking ppis for more than 5 years. conversely, ferraro et al. (12) observed that hrs were independent of duration of use. simonov et al. (15) observed that higher doses of ppis were associated with an increased risk of kidney stones formation. h2 blockers ferraro et al. (12) found that the use of h2 blockers is also associated to higher risks of renal stone formation (hr 1.13, 95% ci 1.02, 1.24, p-value = 0.02). simonov et al. (15) confirmed an increased risk for renal stone upon treatment with h2 blockers (adjusted hr, 1.47; ci 1.311.64). pooled hazard ratios of the two studies evaluating incident nephrolithiasis showed an overall pooled hr estimate of 1.27 (95% ci = 1.18-1.37) (figure 3). heterogeneity was 91%. kwak et al. (13) reported greater odds for combined ppi/antacid use (or: 2.03, 95% ci: 1.28-3.23, p = 0.049) and combined ppi/h2 blocker use (or: 3.18, 95% ci: 1.12-9.07, p = 0.031). urinary risk factors sur et al. (16) observed significantly lower mean levels of urinary citrate and urinary magnesium in the ppi-exposed group compared to non-exposed subjects. ferraro et al. (12) found lower urinary excretion of calcium in ppi users. figure 2. a – rates of urinary calculi in patients taking ppis and controls (unadjusted data); b – pooled odds ratios of case-control studies investigating urinary calculi in patients taking ppis compared to controls; c – pooled hazard ratios of incident nephrolithiasis in patients on ppis treatment compared to controls. data are adjusted for comorbidities and concurrent medications. diamonds on the right side of the no-effect line indicate greater odds and hazard ratios in patients treated with ppis compared to controls placebo. odds ratio and hazard ratio with 95% confidence intervals and heterogeneity statistics (i^2) are shown. a. b. c. 511archivio italiano di urologia e andrologia 2022; 94, 4 proton pump inhibitors and urinary calculi risk of bias, quality of the evidence according to the quality assessment of nos, all the studies were characterized by high quality, with scores ranging between 6 and 8 (supplementary materials). according to grade criteria, the quality of the evidence is low. downgrading criteria are the observational design of the studies, the presence of moderate risk of bias and the inconsistency due to heterogeneity. the large magnitude of effect (odds ratio > 2) was considered as criterion for upgrading. publication bias assessment by funnel plot analysis resulted in no statistically significant asymmetry (p = 0.190, egger’s test; p = 0.497, begg’s test). the funnel plot is shown in the supplementary materials section. the “trim-and-fill” strategy imputed zero missing studies. discussion urinary stone disease has a complex pathogenesis involving different aspects of the metabolism and depending on the chemical composition of the stones. a non-negligible fraction of cases is caused by the intake of different kinds of drugs that can lead to the formation of stones containing amounts of the same drugs. other drugs cause alterations of different metabolic steps, resulting in the modification of the urinary excretion of risk factors for stone formation (19). the potential risk of kidney stone formation in subjects treated with ppis is still debated, and the factors causing an increased risk have not been fully elucidated. in general, ppi-related increases of gastric ph may lead to deficiencies of minerals (iron, calcium and magnesium) and vitamins (b12 and c) which need a low gastric ph for their absorption and bioavailability (20). however, a specific effect of long-term ppi treatment on mineral metabolism is the reduction of serum magnesium levels resulting from its reduced intestinal absorption. intestinal absorption of magnesium depends on both active transcellular transporters and passive paracellular absorption mediated by claudins. active transportation of magnesium through enterocyte cell membranes is mainly mediated by transient receptor potential melastatin 6 and 7 (trpm6 and trpm7), whose activity is regulated by intracellular magnesium and ph levels whereby a more acidic milieu increases trpm6 activity (21). ppis may alter transporter transcription or channel function by increasing the luminal ph, thus affecting hydrogen proton secretion. the decrease of trpm6 and trpm7 activity results in decreased magnesium absorption (22). in vitro studies suggested the concomitant inhibition of passive magnesium absorption by ppis (23). the extent of the decrease of intestinal magnesium absorption during ppi treatment seems to be minor, but it may cause longterm cumulative deficiency. the effect of ppis on magnesium metabolism is also enhanced by other medications acting on magnesium metabolism, such as loop diuretics (24). severe hypomagnesaemia can manifest with musculoskeletal, neurological, or cardiac arrhythmic symptoms, but milder forms may remain undetected (25). hypomagnesemia induced by ppis is often associated with multiple electrolyte disturbances, including hypocalcemia, hypophosphatasemia, and hypokalemia. low serum magnesium levels interfere with calciumsensing receptors suppressing parathyroid hormone (pth) secretion and increasing organ resistance to pth by inhibiting receptor binding and intracellular signaling (26). hypoparathyroidism results in turn in low serum and urinary calcium levels. hypomagnesemia also causes hypokalemia by inducing kaliuresis (27). reduced intestinal absorption of magnesium is balanced by changes in renal reabsorption of magnesium resulting in a reduction of urinary magnesium. the reduction of urinary excretion of both calcium and magnesium during ppi treatment may have conflicting effects on the overall risk of kidney stone formation, because the reduced urinary calcium excretion decreases urinary saturation with respect to calcium oxalate and calcium phosphate, but the reduced magnesium excretion increases the risk of stone formation due to the decrease of urinary inhibitory activity of crystallization. studies focused on the effect of ppis on the urinary excretion of citrates, which are potent crystallization inhibitors, whose decline in the urine can increase the risk of kidney stone formation (28-30). the urinary levels of citrate are reduced in conditions of acidosis, which induces an increase in the metabolism of citrate in the renal proximal tubule cells with a consequent decreased excretion of citrate in the urine (31). an initial study performed on a small sample of subjects treated for a short time with omeprazole did not demonstrate changes in the daily urinary electrolyte output and urine ph in response to ammonium chloride load (32). however, a case report described metabolic acidosis associated with hypomagnesaemia in a patient receiving omeprazole (33). a recent study in a larger population of figure 3. pooled hazard ratios of incident nephrolithiasis in patients on treatment with h2-blockers compared to controls. diamonds on the right side of the no-effect line indicate greater hazard ratios in patients treated with h2-blockers compared to controls placebo. hazard ratio with 95% confidence intervals and heterogeneity statistics (i^2) are shown. archivio italiano di urologia e andrologia 2022; 94, 4 r. bapir, k. hassan bhatti, ahmed eliwa, et al. 512 renal stone patients receiving ppis showed that patients tended to show decreased citrate levels (28). this finding was explained by the net gastric acid loss due to reduced gastric acid production by proton pump inhibition, resulting in reduced bicarbonate generation and decreased renal excretion of citrate. in this study, the decrease of urinary citrate was not associated to a decrease of urinary magnesium in stone patients taking ppis. on the contrary, william et al. demonstrated reduced urinary magnesium in renal stone patients taking ppis but a non-statistically significant trend of reduction of urinary citrate (29, 30). penniston et al. also showed lower urinary magnesium in renal stone formers taking omeprazole, but they were not able to show any other change in urinary risk factors (34). finally, in a large series of patients with gerd, sui et al. demonstrated that patients taking ppis had significantly lower mean urinary levels of both citrate and magnesium (16). in conclusion, the decrease of inhibitors of urinary crystallization in subjects taking ppis represents a potential risk for renal stone formation. limitations a major limitation of the studies that were considered in this meta-analysis is represented by the selection of subjects to be assigned to the ppi-exposed group and to the ppi-non exposed group. exposure to ppis depends on the presence of acid-related diseases that in themselves may be risk factors for renal stone formation. the indications for treatment with ppis approved by the fda are healing and maintenance of healing of erosive esophagitis (ee), h. pylori eradication to reduce the risk of recurrence of duodenal ulcer (du), symptomatic gastroesophageal reflux disease (gerd), risk reduction of nonsteroidal anti-inflammatory drug (nsaid)-associate gastric ulcer (gu) and pathological hypersecretory conditions. these acid-related diseases have not been directly associated with kidney stone formation, though the stomach plays an important role in the metabolism of calcium and oxalate (20, 35). on the other hand, acid-related diseases are not associated with other enteric diseases that can promote renal stone formation. a study by sonnenberg et al. (36) demonstrated that gastro-esophageal reflux disease (gerd) is inversely associated with all forms of inflammatory bowel diseases that are associated with an increased risk of stone formation due to increased urinary oxalate caused by fat malabsorption. on the contrary, subjects with gastroesophageal reflux-type symptoms showed an higher risk of irritable bowel syndrome that has not been associated with renal stone disease (37). however, acid-related diseases and renal stone diseases share several risk factors. obesity has been associated with both the presence of symptoms of gastroesophageal reflux disease (38, 39) and the formation of kidney stones (40). similarly, a diet rich in proteins and animal fats and low in vegetables and fruit can predispose to both gastroesophageal reflux (41) and kidney stones (42). furthermore, concomitant use of antacids may increase the risk of stone formation. antacids are still used for the treatment of acid-related disorders because they are easily available over the counter and may also be more affordable than prescription medications. these preparations contain magnesium trisilicate, that may cause the formation of silicate calculi, and calcium carbonate that -when administered outside mealsmay cause peaks of serum and urinary calcium with an increased risk of calcium crystallization in the urine. finally, reflux patients tend to avoid citrus fruits that can trigger reflux but are a source of citrates that act as crystallization inhibitors. in our review, four studies evaluated populations including subjects on treatment with ppis or not. to rule out an assignment bias, most authors compared patients taking or non-taking ppis for the presence of comorbidities and dietary patterns and adjusted their analyses for potential confounders. ferraro et al. (12) used cox proportional hazards regression models adjusted for age, race, body mass index (bmi), physical activity, smoking status, comorbidities, use of medications and intake of nutrients, whereas kwak et al. (13) found no difference in dietary or supplemental calcium, vitamin d, liquid, protein, sodium, and potassium intake in subjects taking ppis or not. the latter adjusted their multivariate analysis for male gender, middle to old age, white ethnicity, obesity, diabetes, and elevated creatinine levels. similarly, kim et al. (14) adjusted their multivariable logistic regression analysis for age, sex, income, region of residence, total cholesterol, sbp, dbp, fasting blood glucose, cci score, prescription dates within 1 year of each h2 blocker and nsaid, and number of gerd treatments, and performed subgroup analyses according to age, sex, income, region of residence, obesity, smoking, alcohol consumption, total cholesterol, systolic blood pressure, and fasting blood glucose. simonov et al. (15) used a time-varying cox proportional hazards model adjusted for baseline covariates including sex, race/ethnicity, age, creatinine, medications (h2ras, thiazide diuretics, loop diuretics, gout medications), medical history (gastroesophageal reflux disease, peptic ulcer disease, barrett’s disease, gastrointestinal bleed, gastritis, functional dyspepsia, gastrointestinal surgical history, diabetes, gout) and total number of inpatient/outpatient encounters in the previous year. finally, sur et al. used multivariable cox models with time-varying covariates after adjusting for age, bmi, gender, history of hypertension, coronary artery disease, hyperlipidemia and type 2 diabetes (16). only the study by sui et al. (16) restricted its investigation to subjects with gerd, thus reducing the selection bias of assignment to treatment. selection bias is known to affect the quality of studies performed on large general populations. however, even in this study a bias related to assignment to treatment with ppis is still present, because subjects who did not take ppis may have had a less severe disease than those who were on ppis. in general, observational studies are thought to tend to overestimate intervention effects and to have a lower grade of evidence in the hierarchy of research design compared to randomized controlled trials (rcts). in an editorial, the results of observational studies showing an increased risk of renal stones and other diseases in subjects taking ppis were critically commented (43). it was highlighted that randomized studies are “the most powerful design to determine whether ppis may cause long-term harm”. in fact, the results of a study of over 17.500 aspirin and/or apixaban users randomized to treatment with pantoprazole did not support the results of observational data suggesting that 513archivio italiano di urologia e andrologia 2022; 94, 4 proton pump inhibitors and urinary calculi small increases of risk for some diseases in subjects taking ppis could be due to confounding factors or biases (44). this randomized controlled study was not included in our analysis because kidney stone formation was not included among the safety outcomes of the trial. furthermore, the population studied was not representative of the subjects most frequently affected by calcium renal stones, which occur more frequently between the ages of 30 and 50, whereas the study inclusion criteria were stable coronary and arterial disease in patients older than 65 years or arterial disease involving 2 cardiovascular beds and/or had 2 additional risk factors in younger subjects. a randomized study to evaluate the risk of stone formation in subjects taking ppis should require the evaluation of a population of subjects aged between 20 and 60 who can be randomized to treatment with ppis over a period of several years. ethical issues and financial considerations make such a study unlikely to be accomplished. on the other hand, previous comparisons of randomized controlled studies with cohort or case-control studies assessing a specific intervention demonstrated that welldesigned observational studies do not overestimate the effects of the intervention as compared to randomized controlled studies (45). conclusions our meta-analysis identified a potentially increased risk of kidney stone formation in patients taking ppis. however, the observational design of included studies points to a strong risk of assignment bias. consequently, these results must be considered with great caution and do not justify a restriction of the use of ppis when they are administered in accordance with guidelines recommendations, avoiding unjustified long-term prolongation of the therapy. in fact, ppis are frequently purchased over the counter, are often used without correct indications, are rarely deprescribed, thus being often used for longer periods than necessary. administration of magnesium and citrate supplements and/or periodical evaluation of serum and urinary magnesium and urinary citrate levels should be considered for patients on long-term ppi treatment, and especially in stone forming patients on treatment with these drugs. references 1. zamburak rd, schubert ml. control of gastric acid secretion. histamine h2-receptor antagonists and h+k(+)-atpase inhibitors. gastroenterol clin north am. 1992; 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26:639-40. 33. isse n, hashimoto m. omeprazole-induced hypomagnesaemia, causing renal tubular acidosis with hypokalaemia, hypocalcaemia, hyperlactacidaemia and hyperammonaemia. bmj case rep. 2020; 13:e235385. 34. penniston kl, li s, nakada sy, jhagroo ra. omeprazole lowers 24-hour urinary magnesium excretion in patients with a history of urolithiasis: single center experience. j urol. 2021; 206(suppl 3): e143. 35. hautmann re. the stomach: a new and powerful oxalate absorption site in man. j urol. 1993; 149:1401-4. 36. sonnenberg a, turner ko, genta rm. decreased risk for microscopic colitis and inflammatory bowel disease among patients with reflux disease. colorectal dis. 2018; 20:813-820. 37. lovell rm, ford ac. prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. am j gastroenterol. 2012; 107:1793-801. 38. jacobson bc, somers sc, fuchs cs, et al. body-mass index and symptoms of gastroesophageal reflux in women. n engl j med. 2006; 354:2340-8. 39. locke gr 3rd, talley nj, fett sl, et al. risk factors associated with symptoms of gastroesophageal reflux. am j med. 1999; 106:642-9. 40. aune d, mahamat-saleh y, norat t, riboli e. body fatness, diabetes, physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies. eur j epidemiol. 2018; 33:10331047. 41. zhang m, hou zk, huang zb, et al. dietary and lifestyle factors related to gastroesophageal reflux disease: a systematic review. ther clin risk manag. 2021; 17:305-323. 42. taylor en, fung tt, curhan gc. dash-style diet associates with reduced risk for kidney stones. j am soc nephrol. 2009; 20:2253-9. 43. moayyedi p. leaving no stone unturned in the search for adverse events associated with use of proton pump inhibitors. clin gastroenterol hepatol. 2021; 19:41-42. 44. moayyedi p, eikelboom jw, bosch j, et al.; compass investigators. safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. gastroenterology. 2019; 157:682-691.e2. 45. concato j, shah n, horwitz ri. randomized, controlled trials, observational studies, and the hierarchy of research designs. n engl j med. 2000; 342:1887-92. correspondence rawa bapir dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar ahmed eliwa ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt herney andrés garcía-perdomo herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi, md ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey, md derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland vittorio magri, md vittorio.magri@virgilio.it asst nord milano, milan, italy panagiotis mourmouris, md thodoros13@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece adama ouattara, md adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobodioulasso, burkina faso gianpaolo perletti, dr. biol. sci. m. clin. pharmacol. gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india konstantinos stamatiou, md stamatiouk@gmail.com department of urology, tzaneio general hospital, 18536 piraeus, greece musliu adetola tolani, md adetolatolani@yahoo.com division of urology, department of surgery, ahmadu bello university/ahmadu bello university teaching hospital, zaria, kaduna state, nigeria lazaros tzelves, md lazarostzelves@gmail.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece. alberto trinchieri, md alberto.trinchieri@gmail.com urology school, university of milan, milan (italy) noor buchholz, md noor.buchholz@gmail.com sobeh's vascular and medical center, dubai health care city, dubai, united arab emirates stesura seveso 519archivio italiano di urologia e andrologia 2022; 94, 4 letter to editor no conflict of interest declared. submitted 18 july 2022; accepted 24 july 2022 to the editor, currently, semen analysis is the unique test to evaluate men’s fertility potential. semen analysis provides valuable information on sperm production and quality. in addition to the conventional assessment of the sperm characteristics in a basic semen analysis routine, performing a differential diagnosis of leukocytes and sperm precursors immature germ cells (igc) is also pivotal (1-3), due to adding valuable and clinically suitable information to the semen report. while increased leukocyte count may indicate infections (4), increased exfoliation of igc from seminiferous tubules suggests abnormal spermatogenesis (5, 6). even the inflammation could induce exfoliation of igc from seminiferous tubules (7). in semen analysis, a global and differential count of all seminal round cells can improve the diagnosis (8) and treatment options to achieve a successful pregnancy (9). a high count of igc in semen would represent different seminal and reproductive alterations and would be an essential indicator for detecting testicular alterations (6). therefore, an index could be developed comparing igc count/ml vs. sperm count/ml. in some instances, this index would be paramount for estimating, for example, the negative impact of varicocele on the germinal epithelium in increased exfoliation of igc in semen. the normal is to find one igc for every 40 spermatozoa, values between 20/1 and 40/1 are indeterminate, and values lower than 20/1 indicate increased exfoliation of igc, which suggests a loss of integrity of the germinal epithelium. occasionally, ratios greater than 1/1000 are also found, mainly in ejaculate with high sperm count (andrade-rocha ft, unpublished data). the lower this index, the worse is the integrity of the germinal epithelium. the cells are sloughed off before completing the spermatogenesis process and spermatozoa production. for example, the conventional semen parameters routinely evaluated in a 32 years old man in lisa andrology lab (petrópolis, rj, brazil) for investigating male infertility showed the ratio was six igc for each sperm; it was even worse, showing an inversion in the index (table 1 and figure 1) show a representative aggregate of igc in the semen specimen. increased exfoliation of immature germ cells detected in semen analysis routine and its clinical significance fernando tadeu andrade-rocha 1, walter d. cardona maya 2 1 lisa andrology lab, petrópolis, rj, brazil; 2 reproduction group, department of microbiology and parasitology, faculty of medicine, universidad de antioquia udea, medellín, colombia. doi: 10.4081/aiua.2022.4.519 figure 1. unequal aggregation of immature germ cells regarding to sperm. the semen smear used for the microphotograph shown in this editorial was made with concentration to show the proportionality between igc and sperm in the analyzed semen specimen. table 1. patient semen characteristics and lower reference limit. parameter outcomes lower reference limit – percentile 5th (11) semen volume 6.1 ml 1.4 ml sperm count/ml 317 000 16 x 106/ml total sperm count 1 931 710 39 x 106 per ejaculate vitality 20% 54% total motility 10% 42% progressive motility (a) 0 30% slow/irregular motility (b) 9% non-progressive motility (c) 1% 1% immotile (d) 90% 20% normal morphology 0.53 4% amorphous sperm 11% tapered sperm 7% sperm immature germ cells vs. sperm 1/6 1/40 hypo-osmotic swelling 18% 58% ph 8.2 > 7.2 archivio italiano di urologia e andrologia 2022; 94, 4 f.t. andrade-rocha, w.d. cardona maya 520 this assessment measures the intensity of the famous seminal stress pattern that john macleod proposed in the 1960s (10). according to macleod, the stress pattern is characterized by an increase of amorphous and tapered and exfoliated igc in semen and is usually diagnosed in some varicocele men. unlike previous observations by macleod (10), it has been observed that varicocele men can cause structural changes in sperm, like amorphous and tapered sperms, increased exfoliation of sperm precursors and both. therefore, further studies are needed to expand knowledge on this issue, which is practically unexplored in clinical and laboratory practice. references 1. jassim a, festenstein h. immunological and morphological characterisation of nucleated cells other than sperm in semen of oligospermic donors. j reprod immunol. 1987; 11:77-89. 2. tomlinson mj, robert barratt cl, bolton ae, et al. round cells and sperm fertilizing capacity: the presence of immature germ cells but not seminal leukocytes are associated with reduced success of in vitro fertilization. fertil steril. 1992; 58:1257-9. 3. fedder j, askjaer sa, hjort t. nonspermatozoal cells in semen: relationship to other semen parameters and fertility status of the couple. arch androl. 1993; 31:95-103. 4. sharma r, gupta s, agarwal a, et al. relevance of leukocytospermia and semen culture and its true place in diagnosing and treating male infertility. world j mens health. 2022; 40:191-207. 5. andrade-rocha ft. semen analysis in laboratory practice: an overview of routine tests. j clin lab anal. 2003; 17:247-58. 6. palermo gd, neri qv, cozzubbo t, et al. shedding light on the nature of seminal round cells. plos one. 2016; 11:e0151640. 7. gandini l, lenzi a, lombardo f, et al. immature germ cell separation using a modified discontinuous percoll gradient technique in human semen. hum reprod. 1999; 14:1022-7. 8. patil ps, humbarwadi rs, patil ad, gune ar. immature germ cells in semen correlation with total sperm count and sperm motility. j cytol. 2013; 30:185-9. 9. ariagno j, curi s, mendeluk g, et al. shedding of immature germ cells. arch androl. 2002; 48:127-31. 10. macleod j. seminal cytology in the presence of varicocele. fertil steril. 1965; 16:735-57. 11. world health organization. who laboratory manual for the examination and processing of human semen. 6th ed. who press; geneva, switzerland. 2021 (accessed on 15 july 2022). correspondence fernando tadeu andrade-rocha, bs (corresponding author) lisalabrescenter@gmail.com lisa andrology lab, petrópolis, rj (brazil) walter darío cardona maya, phd wdario.cardona@udea.edu.co grupo reproducción, facultad de medicina, universidad de antioquia, medellin (colombia) stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12936 1 letter to editor key words: monkeypox; urology; resident training; waiting list; genital lesions. submitted 18 august 2024; accepted 26 august 2024 dear editor, monkeypox is an emerging zoonotic viral disease caused by the monkeypox virus, traditionally confined to central and west africa (1, 2), which has recently spread to other regions worldwide, making it a global health concern. monkeypox was first identified in humans in 1970 in the democratic republic of the congo and the transmission is mainly due through direct contact with infected animals or people. sporadic outbreaks have occurred for decades. however, as is happening for other infective diseases (3), the globalization, increased international travel and migration has facilitated the spread of the virus to previously unaffected regions, highlighting its growing importance for public health. a first monkeypox international outbreak was recorded in 2022-2023, while in 2024 the number of cases increased significantly, so much so that the world health organization (who) prudently declared a state of global health emergency (4). furthermore, in recent days the first case of a patient affected by the clade i variant monkeypox, which is more aggressive and virulent, was recorded in europe. although monkeypox patients primarily presents with dermatological or systemic symptoms, such as fever, skin rashes and pox-like lesions, it can also lead to urological complications, necessitating specialized attention (5). among urological manifestations, genital lesions have been described in the literature (6-10). these lesions may be painful and appear as vesicles on the external genitalia. in some cases, monkeypox can lead to prostatitis, urethritis and orchitis, making difficult the differential diagnosis from other causes of such diseases (11, 12). for a correct and prompt diagnosis, as well as reporting suspected cases, it is important that the urologist is also aware of the possible urological clinical presentation of monkeypox. unfortunately, as with covid-19, monkeypox could create additional healthcare organization (13) and training issues for urology residents. as was per other infectious outbreaks, the potential impact on surgical training and clinical exposure may be significant. one of the primary concerns is the potential reduction in clinical opportunities. during the previous covid-19 pandemic, elective surgeries were postponed or canceled (14), limiting residents' hands-on experience in performing and assisting urological procedures. this reduction in surgical volume can hinder the development of essential technical skills that are crucial for urologists. furthermore, the need for infection control measures may limit direct patient interaction. in some institutions, residents may be restricted from certain areas of the hospital, which can interfere with their ability to perform delicate procedures and communicate effectively with patients, increasing the use of telemedicine (15-18). likewise, a possible epidemic/pandemic could strain the availability of teaching faculty, resulting in reduced mentorship and fewer educational and academic opportunities (19). a monkeypox pandemic might presents significant risks to the scheduling of urological surgeries and the management of waiting lists. as previously happened for covid-19, during a pandemic, hospitals often reallocate resources, including operating rooms, staff, and supplies, to manage the immediate demands of the infectious outbreak. this can lead to the postponement of non-urgent surgeries, which directly impacts patients awaiting urological procedures (13). as a result, the already long waiting lists can grow longer, with patients experiencing increased anxiety, discomfort, or worsmonkeypox: a new threat for healthcare and urology? rosario leonardi 1, angelo cafarelli 2, alessandro calarco 3, renzo colombo 4, ottavio de cobelli 5, ferdinando de marco 6, giovanni ferrari 7, giuseppe ludovico 8, stefano pecoraro 9, domenico tuzzolo 10, guglielmo mantica 11 on behalf of urop (urologi ospedalità gestione privata) 1 casa di cura musumeci-gecas, gravina di catania, italy; 2 urology unit, villa igea, ancona, italy; 3 department of urology, san carlo di nancy hospital, rome, italy. 4 department of urology, vita e salute san raffaele university, milan, italy; 5 department of urology, ieo european institute of oncology, irccs, milan, italy; 6 i.n.i. grottaferrata, rome, italy; 7 hesperia hospital, modena, italy; 8 miulli hospital, acquaviva delle fonti, bari, italy; 9 neuromed, avellino, italy; 10 urologi ospedalità gestione privata (urop), italy; 11 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy. doi: 10.4081/aiua.2024.12936 archivio italiano di urologia e andrologia 2024; 96(3):12936 r. leonardi, a. cafarelli, a. calarco, et al. 2 ening of their conditions while they wait. moreover, the prioritization of emergency and urgent cases may lead to a backlog of elective surgeries that becomes increasingly difficult to manage as the pandemic continues. for all these reasons and many more, we should have learned lesson from covid-19 and be ready if this monkeypox emerging viral disease will become pandemic. as we doctors always say “prevention is better than cure”! in this possible scenario, the role of us urologists also become important both to prevent the possible spread of the virus by promptly recognizing patients with urological symptoms, and by organizing healthcare facilities as best as possible and immediately in the unfortunate case of a new pandemic. references 1. graham f. daily briefing: raising the alarm about the monkeypox virus. nature. 2024 aug 14. doi: 10.1038/d41586-024-02671-4. epub ahead of print. pmid: 39147816. 2. urban n, valencak j, bauer wm, et al. diary of human monkeypox: illustrations of the clinical course. j eur acad dermatol venereol. 2023; 37:e672-e674. 3. mantica g, van der merwe a, terrone c, et al. awareness of european practitioners toward uncommon tropical diseases: are we prepared to deal with mass migration? results of an international survey. world j urol. 2020; 38:1773-1786. 4. eurosurveillance editorial team. note from the editors: who declares mpox outbreak a public health emergency of international concern. euro surveill. 2024; 29:240815v. 5. catto jwf. monkeypox and the urologist: playing an important role in this emerging global outbreak. eur urol. 2022; 82:631-632. 6. moreno-matson mc, ocampo ma, sáenz rengifo d, valero hp. penile necrosis due to monkeypox. urol case rep. 2023; 51:102554. 7. wegrzyn gh, kilianek m, yallapragada s, et al. genitourinary mpox: a case report & primer for urologists. urol case rep. 2023; 51:102559. 8. hamid ta, elmekresh a, parkar az, et al. male genital lesions in monkeypox virus infection: a case series. can j urol. 2023; 30:11562-11567. 9. lee j, mclean j, zucker j, et al. mpox genital lesions: a large single-center experience with intermediate follow-up. j urol. 2023; 210:510-516. 10. milano e, belati a, de santis l, et al. first case of paraphimosis as a severe complication of monkeypox. vaccines (basel). 2022; 11:63. 11. kranz j, bartoletti r, bruyère f, et al. european association of urology guidelines on urological infections: summary of the 2024 guidelines. eur urol. 2024; 86:27-41. 12. bausch k, mantica g, smith ej, et al. genitourinary tuberculosis: a brief manual for urologists on diagnosis and treatment from the european association of urology urological infections panel. eur urol focus. 2024; 10:77-79. 13. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72 14. campi r, amparore d, checcucci e, et al. exploring the residents' perspective on smart learning modalities and contents for virtual urology education: lesson learned during the covid-19 pandemic. actas urol esp (engl ed). 2021; 45:39-48. 15. ambrosini f, di stasio a, mantica g, et al. covid-19 pandemic and uro-oncology follow-up: a "virtual" multidisciplinary team strategy and patients' satisfaction assessment. arch ital urol androl. 2020; 92:78-79. 16. mirone v, di bello f, morra s, et al. telemedicine and social media: a contemporary analysis of the most shared content by internet users. arch ital urol androl. 2024; 96:11206. 17. mirone v, abate m, fusco gm, et al. telemedicine and youtube™: video quality analysis before and after covid-19 pandemic. arch ital urol androl. 2023; 95:11341. 18. mirone v, celentano g, collà, et al. perceptions and attitudes toward the use of telemedicine for the postoperative outpatient urological care during the covid-19 pandemic in an academic hospital in southern italy. arch ital urol androl. 2022; 94:375-379. 19. carrion dm, rodríguez-socarrás me, mantica g, et al. interest and involvement of european urology residents in academic and research activities. an esru-esu-esut collaborative study. minerva urol nefrol. 2020; 72:384-387. correspondence rosario leonardi, md urologialeonardi@gmail.com casa di cura musumeci-gecas, 95030 gravina di catania, italy angelo cafarelli, md angelocafarelli78@gmail.com urology unit, villa igea, ancona, italy alessandro calarco, md alecalarco@gmail.com department of urology, san carlo di nancy hospital, rome, italy renzo colombo, md colombo.renzo@hsr.it department of urology, vita e salute san raffaele university, milan, italy ottavio de cobelli, md ottavio.decobelli@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy ferdinando de marco, md ferdinandodemarco@gmail.com i.n.i. grottaferrata, rome, italy giovanni ferrari, md gferrari@hesperia.it hesperia hospital, modena, italy giuseppe ludovico, md giuseppeludovico@hotmail.com miulli hospital, acquaviva delle fonti, bari, italy stefano pecoraro, md uropec@gmail.com neuromed, avellino, italy domenico tuzzolo, md info@casadelsole.it; dometuzzolo@alice.it urologi ospedalità gestione privata (urop), italy guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso 195archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. sa also has advantages: it avoids some ga related complications, allows an early mobilization, and is cost effective. few studies compared different anesthesia modality during rirs for renal stones and the only randomized controlled trial (9) compared rirs performed under combined spinal-epidural anesthesia with ga (10). the aim of this study was to compare surgical results, intraoperative and postoperative complications, and analgesia demand of rirs performed under sa versus ga. materials and methods the data of the patient who underwent rirs due to kidney stones between january 2013 and january 2022 were reviewed retrospectively. those with missing data, bilateral rirs, additional procedure with rirs (percutaneous nephrolithotomy, rigid ureterorenoscopy, etc.), urinary system anomaly (double collecting system, horseshoe kidney, pelvic kidney, urinary diversion, etc.), previous stone surgery, extracorporeal shock wave lithotripsy (eswl) history, patients with nephrostomy or double j stent were excluded from the study. a total of 502 patients were evaluated after exclusion criteria. the ethics committee of the study was obtained from the local tepecik training and research hospital local ethics committee. informed consent was obtained from all patients. stones and urinary systems of all patients were evaluated with computed tomography (ct) in the preoperative lowdose stone protocol, urinalysis and urine culture, and biochemistry including urea, creatinine, and hemogram. all patients underwent the procedure with a clean urine culture or under antibiotic. all patients received preoperative antibiotic prophylaxis. stone protocol ct was performed for stone-free rate assessment at 4 week post operative in all patients, and patients with residual stone less than 4 mm were considered as stone-free. we divided the patients in 2 groups, according to the anesthesia regimen chosen by the anesthesiologist: sa and ga. patients in both groups were compared in terms of demographic data such as age and gender, stone size, stone side, stone localization, number of stones, and stone density as hounsfield unit. the complications that developed within both groups were grouped according to the modified clavien-dindo classification and compared one by one. aim: the indications for retrograde intrarenal surgery (rirs) have greatly increased, however, there is still no consensus on the use of spinal anesthesia (sa) during this procedure. the aim of this study was to evaluate the comparability of surgical outcomes of rirs performed under sa versus general ga for renal stones. materials and methods: this was a retrospective, observational study in patients scheduled for rirs in a single teaching hospital in turkey. inclusion criteria were age > 18 years and the presence of single or multiple renal stones. we recorded information concerning the site of lithiasis, the number of calculi, total stone burden, and the presence of concomitant ureteral stones or hydronephrosis. results were evaluated in terms of surgical outcome, intraoperative and postoperative complications. patients were followed-up until day 90 from discharge. results: the data of 502 patients, 252 in ga group and 250 in sa group, were evaluated. the stone-free rate was 81% in the ga group and 85% in the sa group (p = 0.12). no cases of conversion from sa to ga were recorded. complication rates were similar in the 2 groups (19% vs 14.5%, p = 0.15). conclusions: in our cohort, rirs performed under sa and ga was equivalent in terms of surgical results and complications. key words: spinal anesthesia; retrograde intra-renal surgery; urolithiasis. submitted 21 april 2022; accepted 20 may 2022 introduction with the evolution of instruments and techniques, retrograde intrarenal surgery (rirs) gained an established role as a minimally invasive procedure with fast recovery, short hospitalization, and low rates of complications (1-3). however, high-grade complications are still possible (4-5), and linked to the use of general anesthesia (ga). in this scenario, the use of spinal anesthesia (sa) could move toward the reduction of invasiveness, costs, and hospitalization (6-7). endoscopic procedure of renal stones has increased in the last decade in accordance with minimally invasive principles. ureteral stone treatment has been described and widely accepted under sa (8-9), however, ga is usually offered during rirs because it has some advantages: in case of a large stone burden the lithotripsy is easier with reduced renal movement caused by respiration, the comfort for the patient is expected to be better, and there is no risk for the anesthesia duration to be exceeded. spinal versus general anesthesia in retrograde intrarenal surgery mehmet yoldas 1, tuba kuvvet yoldas 2 1 tepecik training and research hospital urology clinic, izmir, turkey; 2 ege university faculty of medicine anesthesiology and reanimation department, izmir, turkey. doi: 10.4081/aiua.2022.2.195 summary archivio italiano di urologia e andrologia 2022; 94, 2 m. yoldas, t. kuvvet yoldas 196 rirs procedure under spinal or general anesthesia, ureter and renal pelvis were evaluated under direct vision with a 7 f semi rigid ureteroscope. the distance between the ureteropelvic junction and the external meatus was marked on the rigid scope and a 0.038 inch guide wire was placed in the collecting system, 9.5 f ureteral access sheet was placed in the collecting system on the guide as long as the measured distance. after the guide was taken out, a 7-8 f flexible scope was entered. the stone was broken with a 272 or 360 micron laser probe. at the end of the procedure, the ureter was evaluated with a semi-rigid scope. when necessary, a double j stent stent was placed in the ureter. anesthesia in all patients, a peripheral vein was cannulated and a single dose of antibiotic prophylaxis was administered and normothermia maintained with warm air devices. perioperative heart rate, peripheral oxygen saturation, and blood pressure values were monitored until transfer to the urological ward, when the aldrete score was ≥ 8. in the sa group, anesthesia was administered using a 25 gauge atraumatic sprotte type needle with 10-20 mg hyperbaric 1% or 0.05% bupivacaine at l2-3 level to provide a sensitive block up to t8-10. we administered an intranasal oxygen supply only if spo2 was below 92%. additional sedation was based on 2 mg midazolam boluses or low-dose propofol infusion according to the schneider model effect-site target-controlled infusion 1 mg/ml, plus additional low-dose remifentanil (minto model effectsite target-controlled infusion 0.5-2 ng/ml) if analgesia was inadequate. target controlled infusion was titrated based on the clinical response in the sa group. in the ga group, anesthesia was induced with propofol 2 mg/kg and fentanyl 1 mg/kg and maintained with either propofol schneider model effect-site target-controlled infusion, sevoflurane or desflurane plus remifentanil with the minto model effect-site target-controlled infusion according to the anesthesiologist’s choice. in all cases in the ga group, anesthesia depth was monitored with the entropy index, targeting values between 40 and 60. after induction, a laryngeal mask was placed avoiding the use of neuromuscular blockade when clinically feasible. we administered ranitidine plus ondansetron intraoperatively as prevention of postoperative nausea and vomiting. an opioid-free postoperative analgesia regimen was preferred, based on acetaminophen 1000 mg plus ketorolac 30 mg. rescue doses were administered if the pain numeric rating scale was above 4. statistical analysis continuous variables are reported as a mean ± sd and compared with the student’s t-test. categorical variables are presented as the absolute frequency (percentage) and compared with the chisquare or fisher’s test, as appropriate. all the statistical analyses were performed using spss v.23 (ibm corp., armonk, ny), and significance considered for two-tailed p < 0.05. results the data of 502 patients, 252 in ga group and 250 in sa group, were evaluated retrospectively. the mean age of ga group was 47.31(16-83) years and the mean age of sa group was 46.16 (20-75) years; ga group included 156 (62%) men and 96 (38%) women, sa group 176 (71%) males and 74 (29%) females. the mean stone size was 13.57(+-2,6) mm2 in ga group and 12.43(+-2,8) mm2 in sa group. there was no statistically significant difference between the two groups for stone size (p = 0.21). in ga group, 124 patients had a stone in the right side and 128 in the left side, in sa group 128 patients had a stone in the right side and 122 patients in the left side (p = 0.25). in ga group the stone was in the lower calyx, which was the most difficult to reach, in 71 (28.4%) patients, whereas in sa it was in the lower calyx in 71 (28.7%) patients (p = 0.13). the demographic and stone data of the patients are shown in table 1 and intraoperative and post-operative data of the patients in table 2. the operation time of the patients in ga group was 57.65 (+-11.56) min, in sa group 54.3 (+-12.1) min. the duration of scopy in the ga group was 24.29 (+-2.3) sec, in the sa group. 26.32 (+-3.2) sec. operation time and duration of scopy was equal between the two groups (p = 0.29 and p = 0.35, respectively). mean hospital stay was 1.06 (+-0.25) days in ga group, and 1.37 (+-0.22) days in sa group. although in sa group hospital stay was longer, there was no statistically significant difference between groups (p = 0.12). complications developed in 48 (19%) patients in the ga group and in 36 (14.5%) patients in sa group. no difference was observed for grade 1 (p = 0.18) and grade 2 (p = 0.11) complication rate between the two groups. none of our patients needed blood transfusion. due to stenosis in the distal ureter in 3 of our patients in ga group, access to the renal pelvis was achieved by using baloon dilatation. high post-operative fever was detected in 20 patients of ga group: two of them received parenteral antibiotic in hospital, 2 of them were treated with oral antibiotic as outpatients, 16 patients were treated with antipiretic as outpatients; 16 patients in sa group developed fever and were treated with antipiretic as outpatients; 5 were treated with oral antibiotic as outpatients. table 1. the demographic and stone data of the patients. ga group (252) sa group (250) p-value age 47.31+-3.5 46.16+-3.8 0.39 stono size cm2 13.57(+-2.6) 12.43(+-2.8) 0.25 gender f 96(38%) 74 (29%) 0.22 m 156 (62%) 176 (71%) laterality right 124 128 0.52 left 128 122 localization 0.19 lower calix 71 (28.4%) 71 (28.3%) 0.16 middle calix 11 (4.4%) 21 (8.3%) 0.08 upper calix 9 (3.7%) 5 (2%) 0.08 pelvis 118 (46.4%) 117 (46.2%) 0.15 more than one calix 43 (16.9%) 36 (14.5%) 0.15 197archivio italiano di urologia e andrologia 2022; 94, 2 spinal versus general anesthesia in retrograde intrarenal surgery subcapsular hematoma and then urinoma developed in ga group in 2 patients who were treated with double j stent and percutaneous drainage. low-grade ureteral injury occurred in 8 patients in ga group and 1 patient in sa group, and they were followed up with double j stent. no avulsion occurred in any of our patients. nephrostomy or double j stents were placed in 8 patients in ga group and 1 patient in sa group due to renal colic and hydronephrosis. stents were removed 2 weeks later due to regression of hydronephrosis and colic. re-urs was performed in 8 of our patients in ga group because of the steinstrasse; this complication was not observed in any of our patients in sa group. in ga group, the laser probe tip or the hydrophilic tip of the sensor guide remained in the renal pelvis in 3 patients as a result of a fracture of the device. six patients in ga group and one patient in sa group were followed up in the post-operative intensive care unit. in ga group, one patient died due to post-operative multi-organ failure and sepsis. discussion the first treatment choice for intrarenal stones < 2 cm in size and hard stones is rirs (11). in this study, we report similar sfr, intraoperative and postoperative outcomes and complications in patients treated with rirs under ga versus sa. our results concord with the previous published studies and added value to the use of sa for rirs, particularly when a fast recovery and a short hospitalization are intended to be achieved. kidney stone surgeries are developing towards to non-invasive methods. endoscope miniaturization, improved deflection mechanism, improved optical quality, and advancement in laser technology have led to the increased use of urs for kidney and ureteral stones (12). the 2022 eau urolithiasis guidelines states that for retrograde stone removal both local and sa is feasible, however, the majority of patient still undergo ga (13). sa reduces anesthesiologic costs and hospital stay when compared with ga. generally, the anesthesiologist for rapid endoscopic procedures proposes sa because it has lower risks of anaphylaxis, vascular, pulmonary, and neurological complications and compared with ga it does not present the risk of intubation-related problems (14). the overall complication rate was found to be 3.5% in a series of 11.885 prospectively studied rirs published by croes. according to the modified clavien classification, 2.8% of these complications are grade 1 and 2 (15). in our study, general complications were 48 (19%) in ga group, 36 (14.5%) in sa group; grade 1-2 complications 20 (7.9%) in ga group and 20 (8%) in sa group. this may have been caused by the high density of difficult cases (lower pole, more than 1 stone and large stone size) because we are a third-level hospital. for grade 1-2 complications, no significant difference was found between the two groups. urinoma and hematoma have been reported in the literature to be more likely in patients over 70 years of age, using anticoagulants and having chronic kidney disease; the probability of this complication is less than 1%. in our study, 2 (0.4%) patients in ga group had supcapsular hematoma cured with nephrostomy and double j stent insertion. bleeding is seen at a rate of 0.3-2.1% after urs, due to the introduction of the scope, stone breakage procedure or damage caused by the guide wire in the calyceal structures. bleeding often stops spontaneously, but the hematoma caused by it may cause colic pain and hydronephrosis in the postoperative period. six patients in ga group, and one patient in sa group had nephrostomy due to clot hydronephrosis and renal colic. two patients in ga group had double j stent for the same reasons and the catheters were removed 2 weeks later in their follow-up. stone tract (clavien 3b), which is an important complication, was seen in 9 (0.6%) patients in a study conducted with 1571 patients (16). this complication is the only that was found associated to stone size. in fact, sfr after rirs was found significantly correlated with the stone size (17). in our study, steinstrasse was observed in 8 (1.7%) patients in ga group who had stones larger than 3 cm according with the literature. the fragments were endoscopically extracted and the stones cured. this complication was not observed in any patient in sa group. loss of the integrity of the stents is also an important problem. zisman et al. (18) evaluated ureteral stents with spontaneous multiple fragmentations observing that the fracture resistance was decreased dramatically. fractured stents were removed after 4 weeks. due to cost problems, some materials were used longer than the recommended time. we may have encountered this complication due to the high stone load in our cases and the long duration of the cases. in the prospective study of croes, it was reported death in 5 cases due to sepsis, pulmonary embolism, multiple organ dysfunction, and cardiac causes (15). table 2. intraoperative and post-operative data of the patients. ga group sa group p-value operation time (min) 57.65 54.3 0.29 (+/-11.56) (+/-12.1) scopy time (sc) 24.29 26.32 0.35 (+/-2.3) (+/-3.2) postoperative hospitalization (days) 1.06 1.37 0.12 (+-0.25) (+/0.22) complications 48 (19%) 36 (14.5%) 0.15 degree 1 use of antiemetics, antipyretics, analgesics etc. 16 (6.2%) 11 (4.4%) 0.18 degree 1 headache (cerebrospinal fluid leak after spinal anesthesia) 4 (1.6%) degree 2 fever requiring antibiotics 4 (1.7%) 5 (2%) 0.11 degree 3a hematoma, urinoma 1 (0.4%) 1 (0.4%) 0.25 degree 3a low grade ureteral injury 4 (1.7%) 5 (2%) 0.09 degree 3a nephrostomy insertion 3 (1.3%) 5 (2%) 0.08 degree 3a installing post op djs 2 (0.1%) 0 1.00 degree 3b urs again (due to ureteral stone) 8 (1.7%) 0 1.00 degree 3b foreign body in the ureter (djs guide wire basket ureteral sheed etc.) 3 (1.3%) 0 1.00 degree 4 intensive care follow-up due to sepsis 6 (1.2%) 5 (2%) 0.19 degree 5 ex 1 (0.2%) 0 1.00 stone free rate (sfr) 202 (81%) 214 (85%) 0.12 archivio italiano di urologia e andrologia 2022; 94, 2 m. yoldas, t. kuvvet yoldas 198 in our series, 6 patients were followed up with post-operative sepsis: 2 with hydronephrosis due to ureteral stone, 1 with hemorrhage and clot-related hydronephrosis without stones, and 3 patients with sepsis without any stone or hydronephrosis. all the patients had pre-operative hydronephrosis. these results are comparable to most previous report of the literature. one of our patients died due to post-operative sepsis and multiorgan failure in ga group. this 76-year-old patient had a stone size of 0.9 cm2 and 2 stones in the lower calyx and pelvis. the urine culture was clean preoperatively but preoperative hydronephrosis was present. the stone size was small but the stone was difficult to reach and the operation time was long (108 min). furthermore, ureteral access sheath (uas) could not be used due to ureteral stenosis. in the literature, it is emphasized that sepsis is generally related with high intrapelvic pressure (15, 17). consequently, uas should be used during rirs and high pressure should be avoided. in the literature the success rate of rirs is reported to be between 73.6% and 94.1%. in the study of 207 patients conducted by reşorlu et al. (19) in 2012, it was described a new scoring system (reşorlu-ünsal taş score) that can help us predict postoperative stone-free rates (18). in the study, the factors affecting success were examined and parameters such as age, gender, body mass index, stone size, stone side, location, composition, number of stones, lower pole infundibulopelvic angle, use of anticoagulant therapy, skeletal and renal anomalies were evaluated. they reported that stone size, number, location, composition, renal malformations, and lower pole infundibulopelvic angle significantly affected success. in our cases, the success rate of 81% in ga group and 85% in sa group were lower than in the literature, because of high frequency of lower pole stones and multiple stones. according to the literature, in our study we did not find any statistically significant differences in terms of intraoperative and postoperative complications, analgesia demand, and sfr in patients with single or multiple renal stones with a stone burden up to 30 mm treated with flexible ureteroscopy in ga versus sa (sfr rate p = 0.12). references 1. doizi s, traxer o. flexible ureteroscopy: technique, tips and tricks. urolithiasis. 2018; 46:47. 2. giusti g, proietti s, villa l, et al. current standard technique for modern flexible ureteroscopy: tips and tricks. eur urol. 2016; 70:188. 3. osther pjs. risks of flexible ureterorenoscopy: pathophysiology and prevention. urolithiasis. 2018; 46:59. 4. reis santos jm. ureteroscopy from the recent past to the near future. urolithiasis. 2018; 46:31. 5. xu y, min z, wan sp, et al. complications of retrograde intrarenal surgery classified by the modified clavien grading system. urolithiasis. 2018; 46:197. 6. cindolo l, castellan p, scoffone cm, et al. mortality and flexible ureteroscopy: analysis of six cases. world j urol. 2016; 34:305. 7. kamal m, sharma p, singariya g, jain r. feasibility and complications of spinal anaesthesia in percutaneous nephrolithotomy: our experience. j clin diagn res. 2017; 11:uc08. 8. cybulski pa, joo h, honey rj. ureteroscopy: anesthetic considerations. urol clin north am. 2004; 31:43. 9. zeng g, zhao z, yang f, et al. retrograde intrarenal surgery with combined spinal-epidural vs general anesthesia: a prospective randomized controlled trial. j endourol. 2015; 29:401. 10. bosio a, dalmasso e, alessandria e, et al. retrograde intra-renal surgery under spinal anesthesia: the first large series. minerva urol nefrol. 2018; 70:333. 11. wendt-nordahl g, et al. do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? urol res. 2011; 39:185. 12. geraghty r, abourmarzouk o, rai b, et al. evidence for ureterorenoscopy and laser fragmentation (ursl) for large renal stones in the modern era. curr urol rep. 2015; 16:1-6. 13. skolarikos a, neisius a, petr̆ík a, et al. eau guidelines on urolithiasis. edn. presented at the eau annual congress amsterdam 2022. 14. breen p, park kw. general anesthesia versus regional anesthesia. int anesthesiol clin. 2002; 40:61-71. 15. de la rosette j, denstedt j, geavlete p, et al. croes urs study group. the clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11885 patiens. j endourol. 2014; 28:131-9. 16. okan baş, can tuygun, onur dede, et al. factors affecting complication rates of retrograde flexible ureterorenoscopy: analysis of 1571 procedures-a single-center experience world j urol. 2017; 35:819-826. 17. maugeri o, dalmasso e, peretti d, et al. stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (rirs): our experience in 571 consecutive cases.arch ital urol androl. 2021; 93:313-317. 18. zisman a, siegel yi, siegmann a, lindner a. spontaneous ureteral stent fragmentation. j urol. 1995; 153:718-21. 19. resorlu b, unsal a, gulec h, et al. a new scoring system for predicting stonefree rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". urology. 2012; 80:512-518. correspondence mehmet yoldas, md (corresponding author) yoldas_2297@hotmail.com tepecik training and research hospital urology clinic, izmir (turkey) tuba kuvvet yoldas, md drtuba2004@hotmail.com ege university faculty of medicine, anesthesiology and reanimation department, izmir (turkey) stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12595 1 original paper attention recently, the conclusions are still debated. the public now believes that mobile phone rf-emr is a significant risk factor for the deterioration in sperm quality. using a mobile phone is one of the main ways to be exposed to rf-emr (4). la vignera et al. (5) showed that rf-emr hurts seminal tubules, testicular stromal cells, and particularly sperm. when it comes to harm, tissues near mobile devices are more vulnerable than those farther away from cellular antennae. furthermore, long-term cell phone use may negatively impact sperm motility (6). sperm malfunction, which results in male infertility and dna damage in the male germ line, is mostly caused by oxidative stress (7). this oxidative stress condition affects spermatozoa primarily because of an increase in reactive oxygen species (ros) generated by the mitochondria, with complex iii of the electron transport chain (etc) serving as the primary target of this radiation (8). previous research demonstrated that men's testicular and germ cell function may be negatively impacted by a range of harmful effects from emws (9). in this study, our goal was to determine the effect of electromagnetic waves from mobile phone stations on several sperm parameters and the male reproductive system. materials and methods this observational study involving 216 subjects aged 18 to 60 years, was conducted at the urology clinic of university hospitals from december 2022 to july 2023. all procedures performed in this study were in accordance with the ethical standards of the institution and/or national research committee and the 1964 declaration of helsinki and its later amendments or comparable ethical standards. it received approval from ethical committee of the faculty of medicine of benha university, faculty of medicine (cod number:rc 40-11-2022) on november 04, 2022. all subjects provided written informed consent. the establishment of portable mobile phone towers in villages raised the concerns of many people neighboring the towers about the harmful effects of these towers and their negative impact on health. on this basis, many of purpose: to determine the effect of electromagnetic waves of mobile phone stations on several sperm parameters and the male reproductive system. methods: this observational study was performed on 216 subjects, aged 18-60 years. two equal groups of subjects were assigned to group a (study group) if they were living close to cell phone tower stations for at least 6 months and group b (control group) formed from individuals living 100 meters away from cell phone tower stations. every subject underwent a comprehensive history taking, a clinical assessment, and laboratory testing. results: regarding morphology index in the studied groups, the exposed group exhibited a trend of reduced percentage of normal morphology compared to the non-exposed group, with no statistical difference between the two groups. regarding the total sperm motility (a+b+c) and progressive sperm motility (a+b) in the studied groups, the exposed group showed a trend of decreased total sperm motility and of progressive sperm motility in contrast to the non-exposed group, with no statistical difference between the two groups. conclusions: personal wrong lifestyles with exposure to electromagnetic waves have shown a trend towards a reduced percentage of normal morphology and reduced motility although nonstatistically significant compared with non-exposed populations. key words: electromagnetic waves; mobile phone stations; male infertility. submitted 22 april 2024; accepted 22 june 2024 introduction in recent decades, the estimated prevalence of infertility among couples of reproductive age has risen to 15% (1). a decline in sperm count, a mobility issue, or a structural issue can all be signs of male infertility disorders that may be brought on by ionizing radiation, electromagnetic waves, stress, and other biochemical variables (2). with an average of thirty minutes a day spent chatting on mobile phones, people are consequently exposed to a significant amount of radiofrequency electromagnetic radiation (rf-emr) from these devices (3). although the effects of rf-emr from cell phones on semen quality have received effect of radiofrequency electromagnetic waves of mobile phone stations on male fertility tarek mohamed gharib 1, khaled almekaty 2, ashraf mohamed abdel aal 1, ibrahim abdel-al 3, hazem deif 3, gamal m. hassan 3, ahmed haty 4, ahmed shafiea 4, mohamed elsayed metwally 4, elsayed elawadey 4, mohamed abdelrahman alhefnawy 1 1 urology department, faculty of medicine, benha university, benha, egypt; 2 urology department, faculty of medicine, tanta university, tanta, egypt; 3 urology department, faculty of medicine, al-azhar university, assiut branch, egypt; 4 urology department, faculty of medicine, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2024.12595 summary archivio italiano di urologia e andrologia 2024; 96(3):12595 t. mohamed gharib, k. almekaty, a. mohamed abdel aal, et al. 2 the normal people neighboring these towers volunteered to participate in the study. subjects with hydrocele, varicocele, orchitis, testicular or epididymal trauma, or any other condition potentially affecting semen quality, as well as those unable to complete sperm extraction through masturbation and individuals with diabetes mellitus, hypertension, cardiac, neurological, liver, renal diseases, or other serious systemic chronic diseases, and smokers were excluded. participants were divided into two equal groups: group a (study group) included subjects who by history taking resulted residing close to or within 100 meters from cell phone tower stations for at least 6 months of daily exposure of at least 12 hours per day, and group b (control group) was composed of individuals living 100 meters away from cell phone tower stations, matched with the study group in terms of age and sex. each subject underwent a thorough history-taking, clinical assessment, and laboratory testing. semen collection semen was collected in a wide-mouth container. semen appearance and liquid condition was primarly assessed by visual evaluation. a pre-weighed container determined semen volume, and microcell slides with 10 μl semen samples were used to examine six fields or a minimum of 200 spermatozoa. technicians, using computeraided semen analysis (casa), verified results for semen concentration, total sperm count (tsc), vitality (%), ph, motility, and morphology. statistical analysis statistical analysis was performed utilizing spss v28 (ibm inc., armonk, ny, usa). unpaired student's t-test was utilized to compare the two groups based on quantitative data that were reported as mean and standard deviation (sd). both the chi-square test and, when applicable, fisher's exact test was utilized to analyse the frequency and percentage (%) of the qualitative variables. for statistical significance, a two-tailed p value less than 0.05 was utilized. results in this study, 259 subjects were assessed for eligibility, 27 subjects did not meet the criteria and 16 subjects refused to participate in the study. the remaining 216 subjects were divided into two groups (108 subjects in each). all subjects were followed up and analyzed statistically (figure 1). regarding age of the studied groups, mean age was lower in the exposed group compared to the non-exposed group, with no statistically significant difference between both groups (table 1). regarding seminal volume, sperm count, sperm vitality, and ph, the exposed group had higher mean seminal volume and higher ph compared to the non-exposed group, with no statistical difference between both groups; the exposed group had also lower sperm count and sperm vitality compared to the non-exposed group, with no statistically significant variation between the two groups (table 2). table 1. age of the studied groups. group a group b p value (exposed) (non-exposed) (n = 108) (n = 108) age (years) mean ± sd 37.6 ± 11.73 38.5 ± 12.9 0.605 range 18-60 18-58 table 2. seminal fluid characters of the studied groups. group a group b p value (exposed) (non-exposed) (n = 108) (n = 108) volume (ml) mean ± sd 2.5 ± 0.81 2.4 ± 0.65 0.432 range 1.5-4 1.6-4 count (million/ml) mean ± sd 21.5 ± 4.89 22.5 ± 4.12 0.088 range 15-32 18-35 vitality (%) mean ± sd 57.2 ± 3.73 58.1 ± 4.36 0.095 range 48-66 50-65 ph mean ± sd 7.8 ± 0.18 7.7 ± 0.17 0.674 range 7.5-8 7.5-8 morphology index (%) mean ± sd 13.7 ± 12.08 16.5 ± 11.99 0.083 range 4-40 6-45 figure 1. algorithm of the enrolled patients. archivio italiano di urologia e andrologia 2024; 96(3):12595 3 mobile phone stations and male fertility regarding the morphology index, the exposed group had a lower percentage of normal morphology compared to the non-exposed group, with no statistical difference between the two groups (table 2). concerning non-progressive motility, immotility, slow progressive motility, and rapid progressive motility in the groups under study, the exposed group had a reduced rapid progressive motility and slow progressive motility in contrast to the non-exposed group, with no statistical difference between the two groups; the exposed group had higher percentage of non-progressive motility and immotility compared to the non-exposed group, with no statistical difference between the two groups (table 3). regarding the total sperm motility (a+b+c) and progressive sperm motility (a+b) in the studied groups, the exposed group possessed a decreased total sperm motility and progressive sperm motility in contrast to the nonexposed group, with no statistical difference between the two groups (table 3). discussion recent years have seen a rise in the number of individuals who own cell phones which use electromagnetic waves. as a result, it is now easier to analyse how phone use affects semen quality (11). in the present study, sperm count, sperm vitality, and ph in the exposed group had a trend of lower seminal volume along with lower ph comared with the non-exposed group; the exposed group had a trend of lower sperm count and sperm vitality, a lower percentage of normal morphology, reduced rapid progressive motility and slow progressive motility, in contrast to the non-exposed group, with no statistical difference between the two groups. male fertility depends on sperm motility, which has been the subject of earlier studies on the impact of rf-emr from mobile phones on the quality of male semen (12). mobile phones emit radiofrequency-electromagnetic waves (rf-emws), which consist of a range of frequencies between 800 and 2200 mhz. these waves possess the capacity to penetrate different parts of the human body and could pose risks to several physiological systems (13). previous research has investigated a notable reduction in the quantities, viability, and mobility of sperms due to being subjected to rf-emws released by cellular devices (14). it can be concluded that cigarette smoking and exposure to electromagnetic waves significantly reduced sperm count, motility, morphology, fertilization rate, and embryo quality (15). semen samples exposed to a mobile device for only 10 minutes showed a significant decrease in sperm motility, suggesting that subfertile males may be especially susceptible to rf-emr (16). regarding the type of motility impairment, rf-emr seems to mostly affect spermatozoa's ability to maintain forward progressive motility. a study conducted by erogul and coworkers (17) proved that after an extremely short five minutes exposure to rfemr, human spermatozoa lost their capacity to maintain both rapid and slow progressive motility. reduced progressive motility seems to be a common side effect of rfemr exposure, in contrary to other researchers who have shown that larger exposure durations (hours or days) are necessary to produce significant reductions in sperm motility (18, 19). al-quzwini et al. (20) investigated the relationship between environmental risks and male fertility as indicated by seminal fluid analysis (sfa) that showed that lower semen parameters could result from environmental risks like those found in the home or place of employment. they discovered that there is a notable difference in the exposition to environmental risks of subfertile and fertile groups. for example, the subfertile group is exposed to mobile phone towers at a larger proportion (29%) than the fertile group (12%) (p = 0.003). it was concluded that an increased risk of sfa anomalies (teratozoospermia) was linked to exposure to environmental hazards. these results are consistent with those published by makker et al. (21) who stated that the parameters of semen analysis can be impacted by the electromagnetic radiation (emr) released by mobile phones and their base station. it is now known that the pathophysiological basis for the detrimental effects on spermatozoa is caused by increased mitochondrial reactive oxygen species generation brought on by emr, which lowers sperm vitality while promoting the dna base adduct formation, which ultimately leads to dna fragmentation and more abnormalities in sperm shape (22). in zhang et al. (11) study, they discovered a negative correlation between the average daily duration of mobile phone use and the rates of gradually motile spermatozoa, quick increasingly motile spermatozoa, and total motile spermatozoa. fejes et al. (23) discovered that there was a positive correlation between the amount of time spent on mobile phones and the slow increasingly motile spermatozoa rate, and an inverse correlation between the two. mobile phone use was linked to the overall motile spermatozoa rate but not to other semen characteristics, according to two prior meta-analyses (24). zhang et al. (11) found that the primary reason for the decrease in sperm motility could be cell phone rf-emr. given the expanding tendency of the male reproductive system's degradation, these findings imply that current worries about long-term exposure to rf-emr from mobile table 3. different types of sperm motility of the studied groups. group a group b p value (exposed) (non-exposed) (n = 108) (n = 108) rapid progressive mean ± sd 19.7 ± 2.81 20.5 ± 3.02 0.057 motility (%) (a) range 15-23 16-27 slow progressive mean ± sd 30.8 ± 3.44 31.6 ± 3.64 0.085 motility (%) (b) range 27-39 27-40 non progressive mean ± sd 26.7 ± 6.18 25.4 ± 4.01 0.056 motility (%) (c) range 15-44 15-31 immotility (%) (d) mean ± sd 26.8 ± 3.72 25.8 ± 4.42 0.076 range 21-36 12-32 total motility (a+b+c) mean ± sd 77.3 ± 6.77 79.1 ± 6.97 0.056 (%) range 67-90 70-93 progressive mean ± sd 50.7 ± 4.79 52 ± 5.14 0.052 motility (a+b) (%) range 42-63 44-64 archivio italiano di urologia e andrologia 2024; 96(3):12595 t. mohamed gharib, k. almekaty, a. mohamed abdel aal, et al. 4 phones should be treated more seriously. therefore, it is recommended that people cut down on their daily use of mobile phones to prevent additional decreases in sperm motility, which could impact fertility, particularly in men who are of reproductive age and have asthenospermia. additionally, a study using 358 semen samples from men who were representative of the general male population revealed that sperm motility was the most important factor in determining the likelihood of a natural conception (25). further investigation found that carrying mobile phones in back pant pockets or using them for more than four hours per day led to a marginal elevation in the dna fragmentation index (dfi) (26). however, zhang et al. (10) found no variation in the dfi based on the amount of time spent using a mobile phone. similarly to our findings, zhang et al. (10) discovered no statistically significant variations in the proportion of normal forms and also volume, sperm concentration, or total quantity of sperm in relation to the length of time spent using a mobile phone. a cross-sectional study revealed that as daily mobile phone talking time increased, there was a modest drop in the mean semen volume, sperm concentration, and total sperm quantity (10). darvish et al. (27) outcomes demonstrated that rf negatively affects semen parameters. other systematic review studies have shown that exposure to rf is a risk factor for sperm motility and viability and that exposure to mobile phones was linked to decreased sperm motility and viability but not to decreased sperm concentration (24). limitations of our study included the limited sample size and the brief follow-up period. in particular the insufficient sample size may explain statistically insignificant results. conclusions personal wrong lifestyles as exposure to electromagnetic waves have been associated to a trend towards a reduced percentage of normal morphology and reduced motility of sperm cells although differences with normal population were non-statistically significant. references 1. zhu c, yan l, he c, et al. incidence and risk factors of infertility among couples who desire a first and second child in shanghai, china: a facility-based prospective cohort study. reprod health. 2022; 19:155-65. 2. babakhanzadeh e, nazari m, ghasemifar s, et al. some of the factors involved in male infertility: a prospective review. int j gen med. 2020; 13:29-41. 3. hasan i, rubayet jahan m, nabiul islam m, et al. effect of 2400 mhz mobile phone radiation exposure on the behavior and hippocampus morphology in swiss mouse model. saudi j biol sci. 2022; 29:102-110. 4. chu ky, khodamoradi k, blachman-braun r, et al. effect of radiofrequency electromagnetic radiation emitted by modern cellphones on sperm motility and viability: an in vitro study. eur urol focus. 2023; 9:69-74. 5. la vignera s, condorelli ra, vicari e, et al. effects of the exposure to mobile phones on male reproduction: a review of the literature. j androl. 2012; 33:350-6. 6. okechukwu ce. does the use of mobile phone affect male fertility? a mini-review. j hum reprod sci. 2020; 13:174-183. 7. mannucci a, argento fr, fini e, et al. the impact of oxidative stress in male infertility. front mol biosci. 2021; 8:799-813. 8. houston bj, nixon b, martin jh, et al. heat exposure induces oxidative stress and dna damage in the male germ line. biol reprod. 2018; 98:593-606. 9. dasdag s, ketani ma, akdag z, et al. whole-body microwave exposure emitted by cellular phones and testicular function of rats. urol res. 1999; 27:219-23. 10. zhang s, mo f, chang y, et al. corrigendum to: effects of mobile phone use on semen parameters: a cross-sectional study of 1634 men in china. reprod fertil dev. 2022; 34:1145. 11. hatch ee, willis sk, wesselink ak, et al. male cellular telephone exposure, fecundability, and semen quality: results from two preconception cohort studies. hum reprod. 2021; 36:1395-1404. 12. kesari kk, agarwal a, henkel r. radiations and male fertility. reprod biol endocrinol. 2018; 16:118-34. 13. al-bayyari n. the effect of cell phone usage on semen quality and fertility among jordanian males. middle east fertil soc j. 2017; 22:178-182. 14. ding ss, sun p, zhang z, et al. moderate dose of trolox preventing the deleterious effects of wi-fi radiation on spermatozoa in vitro through reduction of oxidative stress damage. chin med j (engl). 2018; 131:402-412. 15. hamada ae, bakri s, belal a, et al. the effect of some lifestyle behaviours on male fertility and their effect on sperm quality and linking its quality to fertilization during intracytoplasmic sperm injection (icsi). eajbsz. 2023; 15:103-109. 16. zalata a, el-samanoudy az, shaalan d, et al. in vitro effect of cell phone radiation on motility, dna fragmentation and clusterin gene expression in human sperm. int j fertil steril. 2015; 9:129-36. 17. erogul o, oztas e, yildirim i, et al. effects of electromagnetic radiation from a cellular phone on human sperm motility: an in vitro study. arch med res. 2006; 37:840-3. 18. gorpinchenko i, nikitin o, banyra o, et al. the influence of direct mobile phone radiation on sperm quality. cent european j urol. 2014; 67:65-71. 19. rahban r, senn a, nef s, et al. association between self-reported mobile phone use and the semen quality of young men. fertil steril. 2023; 120:1181-1192. 20. al-quzwini of, al-taee ha, al-shaikh sf. male fertility and its association with occupational and mobile phone towers hazards: an analytic study. middle east fertility society journal. 2016 2016; 21:236-240. 21. makker k, varghese a, desai nr, et al. cell phones: modern man's nemesis? reprod biomed online. 2009; 18:148-57. 22. mortimer d, barratt cl, björndahl l, et al. what should it take to describe a substance or product as 'sperm-safe'. hum reprod update. 2013; 19:1-45. 23. fejes i, závaczki z, szöllosi j, et al. is there a relationship between cell phone use and semen quality? arch androl. 2005; 51:385-93. 24. adams ja, galloway ts, mondal d, et al. effect of mobile telearchivio italiano di urologia e andrologia 2024; 96(3):12595 5 mobile phone stations and male fertility phones on sperm quality: a systematic review and meta-analysis. environ int. 2014; 70:106-12. 25. larsen l, scheike t, jensen tk, et al. computer-assisted semen analysis parameters as predictors for fertility of men from the general population. the danish first pregnancy planner study team. hum reprod. 2000; 15:1562-7. 26. rago r, salacone p, caponecchia l, et al. the semen quality of the mobile phone users. j endocrinol invest. 2013; 36:970-4. 27. darvish l, amraee a, akhavan amjadi m, et al. the impact of radiofrequency waves on male infertility: a systematic review (systematic review). shiraz e-med j. 2020; 22:101-9. correspondence tarek mohamed gharib, md tarekgh78@yahoo.com ashraf mohamed abdel aal, md ashrafm1970@gmail.com mohamed abdelrahman alhefnawy, md dr.mohamedalhefnawy@gmail.com benha university, faculty of medicine, urology department, benha, egypt khaled almekaty, md dr.khaledhafez@yahoo.com tanta university, faculty of medicine, urology department, tanta, egypt ibrahim abdel-al, md (corresponding author) dribrahemuro2011@yahoo.com urology department, faculty of medicine, al-azhar university, assiut branch, egypt assuit, postal code 71511 ahmed haty, md drahmeduro@yahoo.com ahmed shafiea, md shafieaahmed2018@yahoo.com mohamed elsayed metwally, md mohaelsayed575@yahoo.com elsayed elawadey, md drsayedawadey@gmail.com urology department, al-azhar university, faculty of medicine, cairo, egypt hazem deif, md hazemdeif@yahoo.com gamal m. hassan, md gamalshrf@yahoo.com urology department, faculty of medicine, al-azhar university, assiut branch, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13939 1 original paper trauma may account up to 20%, depending on the location and registry (3). young males (mean age 30 years) who participate in sports, motor vehicle accidents, assaults, or falls are more likely to sustain traumatic renal injuries. in the paediatric population, falls (27%) and pedestrian accidents (13%), rather than motor vehicle accident (mva) (30%), were the primary causes of blunt trauma (2, 5). renal trauma caused by motor vehicle crashes is associated with high morbidity and mortality. in addition, these events can cause a loss of 1-1.5% of the gross national product in developing countries (6). the priority of renal trauma management is primarily to prevent death by controlling haemorrhage, preserving nephrons, and avoiding complications. in recent decades, trauma management has evolved toward a non-invasive approach through non-operative management (nom). it maintains safety with better outcomes (7-9). this approach applies to both paediatric and adult populations. the absolute indications for renal intervention are hemodynamic instability, unresponsiveness to aggressive resuscitation due to renal haemorrhage, grade 5 vascular injury, and extensive perirenal hematoma found during laparotomy for associated injuries. in addition to the medical approach and interventions required, bed rest after renal trauma is a very common practice until haematuria resolves (7, 10, 11). however, this policy appears to be controversial, mainly because the degree of haematuria does not seem to correlate with improvement in symptoms or mobility that can lead to prolonged length of stay (los) with associated risks of venous thromboembolism (vte) and hospital-acquired infections (12-14). in addition, hospitals may experience resource loss and functional decline. los can be influenced by the patient's age, gender, complications, comorbidities, and history of mental illness. the severity of the injury and the interventions received may also be the best predictors of los. furthermore, post-traumatic pain and surgery can extend a patient's los. some studies have shown that prolonged los may increase the mortality rate of trauma patients in the hospital (15, 16). several studies have reported that the average safe los is less than 4 days for isolated renal injury at all levels of trauma, using a more relaxed policy regarding mobilization, and less than 2 days for hepatosplenic trauma, without readmission (17). this suggests that a short rest period remains safe in renal trauma. this study was conductbackground: renal trauma represents a critical injury requiring precise management with the length of hospital stay (los) serving as a key metric for trauma care. recognizing the factors contributing to extended los is essential for optimizing treatment strategies and enhancing patient outcomes. this study aims to analyse the risk factors influencing los in patients with renal trauma. methods: this retrospective cohort study was conducted at dr. saiful anwar general hospital, malang, analysing medical record data of renal trauma patients from 2013 to 2023. collected variables included demographics, mechanism of injury, associated injuries, hemodynamic status upon admission, injury severity, haemoglobin levels, los, management approach, and mortality outcomes. univariate and multivariate analyses were performed to assess the impact of each variable on los. results: 119 renal trauma patients were included. the average age was 40.1 ± 16.86 years, and 77.3% of the participants were male. the average los was 6.85 ± 3.85 days. blunt renal trauma was the predominant mechanism, accounting for 95.8% of cases, while associated injuries were observed in 53.1% of patients. upon hospital admission, 66.4% of cases presented with stable hemodynamic status, and non-operative management was employed in 92.4% of cases. prolonged los was significantly associated with age, blunt trauma, associated injuries, hemodynamic instability, and low haemoglobin levels in both univariate and multivariate analyses. conclusions: age, mechanism of injury, associated injuries, hemodynamic status at admission, and haemoglobin levels significantly impact los in renal trauma patients. identifying these factors may aid in improving patient management and reducing hospitalization duration. key words: length of stay; renal; risk factors; trauma. submitted 1 may 2025; accepted 1 june 2025 introduction renal trauma is an injury to the blood vessels and/or parenchyma of the kidney, resulting in bleeding or injury to the collecting system with possible urine leakage (1). the kidney is the third most commonly injured organ in abdominal trauma, after the spleen and liver (2). renal trauma contributes about 1% to 5% of all traumas, most of which are caused by blunt abdominal trauma (80% to 90%) (3, 4). although uncommon, penetrating renal analysis of factors associated with length of stay in renal trauma patients: a single-centre retrospective study paksi satyagraha, besut daryanto, bagas wilianto, fauzan kurniawan dhani department of urology, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2025.13939 summary archivio italiano di urologia e andrologia 2025; 97(2):13939 p. satyagraha, b. daryanto, b. wilianto, f. kurniawan dhani 2 ed to analyse the risk factors that influence the los of renal trauma patients at dr. saiful anwar general hospital in malang, indonesia. materials and methods study design this study is a retrospective cohort study conducted at dr. saiful anwar general hospital malang, indonesia, based on medical record data. the study population included all patients who experienced renal trauma from january 2013 to december 2023. this research adheres to the principles outlined in the declaration of helsinki and has received approval from the dr. saiful anwar general hospital ethics committee under protocol number 400/223/k.3/102.7/2024. the inclusion criteria were trauma patients aged >18 years admitted to emergency department (ed) of dr. saiful anwar general hospital diagnosed with renal trauma, confirmed by contrast-enhanced ct imaging or intraoperative findings. those who injured > 2 weeks before admission were excluded. the exclusion criteria were extended to patients from another hospital or with iatrogenic renal injuries. trauma patients are initially assessed by emergency medicine physicians and subsequently co-managed with the trauma surgery team. renal trauma is typically identified via contrast-enhanced ct imaging in hemodynamically stable patients, while unstable patients may undergo immediate surgical exploration. patient data data were extracted by authors bw and fkd. a random 10% sample of records underwent double data entry for consistency. definitions of comorbidities were based on icd-10 codes, and considered clinical variables were hypotension (defined as systolic blood pressure < 90 mmhg), age, gender, mechanism of injury, associated injuries, haemoglobin levels, and hemodynamic status upon arrival, as well as injury severity, los, patient management, and mortality rate. associated injuries included other traumas aside from renal trauma, such as injuries to the brain, gastrointestinal tract, thorax, and bones. the american association for the surgery of trauma (aast) grading system was applied to assess renal trauma, with aast grades i-iii classified as low grade and aast grades iv-v as high grade. los was determined from the time the patient arrives at the ed until discharge or death. operative therapies performed include percutaneous urinoma drainage, dj stent insertion, renorrhaphy, and nephrectomy. statistical analysis continuous variables were summarized as medians with interquartile ranges (iqr) due to non-normal distribution, while categorical variables were presented as frequencies and percentages. univariate analysis was conducted using the chi-square test to evaluate associations between categorical variables and los. variables with clinical relevance or a p-value < 0.10 in univariate analysis were included in a multivariable linear regression model to identify independent predictors of increased los in renal trauma patients. statistical significance was defined as a two-tailed p-value < 0.05. all analyses were performed using ibm spss statistics for windows, version 23.0 (ibm corp., armonk, ny, usa). results the total number of patients studied was 119, consisting of 92 males (77.3%) and 27 females (22.7%), as shown in table 1. the average age of patients with renal trauma was 40.1 + 16.86 years, and the average haemoglobin level of 11.41 + 7.98 g/dl. the most common mechanism of injury was blunt injury, with 114 cases (95.8%) with an average length of stay of up to 6.85 days, or approximately 1 week. in addition, 62 patients (52.1%) had injuries restricted to renal trauma, and 57 patients (47.9%) did not. on arrival, 79 patients (66.4%) had stable hemodynamic status, and 40 patients (33.6%) had unstable hemodynamic status. non-operative management was the predominant approach, implemented in 110 cases (92.4%), while immediate operative management was performed in 9 cases (7.6%). the operative interventions included nephrectomy in six cases, renorrhaphy in two cases, and percutaneous urinoma drainage and dj stent insertion in one case. based on injury severity, 84 patients (70.6%) had low-grade injuries (grades itable 1. patient characteristics. n % number of patient 119 age, years (median) 40.1 ± 16.86 gender male 92 77.3 female 27 22.7 haemoglobin, g/dl (sd) 11.41 ± 7.98 los, days (sd) 6.85 ± 3.85 moi blunt 114 95.8 penetrating + iatrogenic 5 4.2 associated injuries 62 52.1 brain 4 6.5 gi 32 51.6 thorax 9 14.5 bone 17 27.4 haemodynamic stable 79 66.4 unstable 40 33.6 renal trauma grade low (i, ii, iii) 84 70.6 high (iv, v) 35 29.4 management non-operative 110 92.4 operative 9 7.6 nephrectomy 6 66.7 renorrhaphy 2 22.6 dj stent insertion + 1 10.7 percutaneous urinoma drainage sd: standard deviation; los: length of stay; moi: mode of injury. archivio italiano di urologia e andrologia 2025; 97(2):13939 3 analysis of factors associated with length of stay in renal trauma patients... iii), while 35 patients (29.4%) had high-grade injuries (grades iv-v). the mortality rate was 10.1% (12 patients), while 107 patients (89.9%) survived. based on the analysis of patient mortality data, a total of 12 deaths were recorded among 119 patients (table 2). of these 12 cases, none were attributed solely to renal trauma. notably, 3 patients (25%) presented with concomitant head trauma, 5 patients (42%) had gastrointestinal trauma, and 4 patients (33%) experienced thoracic trauma. univariate analysis indicated that patients over 60 years of age had a 2.47-fold increased risk of prolonged los (p = 0.018). regarding the moi, penetrating or iatrogenic trauma was associated with an 8.00-fold higher risk of prolonged los compared to blunt trauma (p = 0.033). the presence of associated injuries significantly increased the risk of prolonged los (or 9.26; 95% ci: 3.63-23.63; p < 0.001). furthermore, patients presenting with unstable hemodynamics (or 10.38; 95% ci: 5.37-33.38; p < 0.001) and hemoglobin levels below 10 g/dl (or 24.62; 95% ci: 8.99-63.70; p < 0.001) were at markedly higher risk of prolonged los (table 3). multivariate analysis confirmed the independent association of all five factors with prolonged hospital stay: age > 60 years (or 2.79; 95% ci: 1.60-18.92; p = 0.019), penetrating or iatrogenic trauma (or 4.47; 95% ci: 3.0375.14; p = 0.009), presence of associated injuries (or 1.80; 95% ci: 1.32-28.04; p = 0.020), unstable hemodynamics (or 2.22; 95% ci: 2.33-37.04; p = 0.002), and hemoglobin < 10 g/dl (or 3.93; 95% ci: 8.74-96.02; p < 0.001) (table 3). discussion the age of patients with renal trauma in this study was 40.1 years, and male gender was more frequent. in a study conducted in south africa in 2019, the average age of patients with renal trauma was 27 years (18). similarly, a 2019 study in new york found that the average kidney trauma patient was male, with an average age of 33 (19). according to a report from the japan trauma database from 2004-2018, 74.2% of renal trauma patients were males aged below 60 years, with the most common mechanism of injury being blunt trauma caused by traffic accidents and falls from heights (20). the probable explanation for this is that renal injuries become more common in this age group because the subjects included are more frequently involved in high-risk activities and mobility, particularly in traffic and sports. additionally, indonesian males generally use motorcycles for transportation, raising the risks of mvas (21). in this study, age was one of the factors that could prolong los, but gender was not a significant factor. the mechanism of injury in renal trauma is mostly due to blunt force injuries caused by motor vehicle collisions, falls from height, and sports injuries. a study showed that blunt renal trauma is one of the predictive factors for longer los compared to penetrating trauma (6, 16). a study reported the mean los of road traffic related injuries was 6.8 days with a los range of 1 to 105 days (22). however, another study showed significantly different results, in which the median los was 2.85 days (6, 16). other associated injuries also have the potential to prolong los due to the additional interventions and follow-up care required. moore et al. found that the anatomical location of the injury can be a predictor of prolonging los in patients, such as in patients who also had spinal cord injuries, which resulted in 3.1 days longer los than patients with lower limb injuries (6, 22). traumatic incidents may cause hemodynamic problems due to bleeding and vascular injury. the hemodynamic condition of a renal trauma patient on arrival determines both the management and the length of stay. table 2. characteristic renal trauma patient mortality. n % mortality 12/119 10 renal trauma grade low (i, ii, iii) 10 83 high (iv, v) 2 17 haemodynamic stable 5 42 unstable 7 58 associated injuries brain 3 25 gi 5 42 thorax 4 33 table 3. uniand multivariate regression analysis for factors associated with los in renal trauma patients. univariate analysis multivariate analysis or 95% ci p value or 95% ci p value age < 60 vs > 60 2.47 0.62-9.73 0.018 * 2.799 1.60-18.92 0.019 * gender male vs female 1.10 0.42-2.69 0.829 moi blunt vs penetrating + iatrogenic 8.00 0.86-74.08 0.033 * 4.473 3.03-75.14 0.009 * associated injuries yes vs no 9.26 3.63-23.63 0.000 * 1.807 1.32-28.04 0.020 * haemodynamic stable vs unstable 10.38 5.37-33.38 0.000 * 2.229 2.33-37.04 0.002 * grade low vs high 2.53 1.16-5.51 0.170 haemoglobin > 10 vs < 10 24.62 8.99-63.7 0.000 * 3.929 8.74-96.02 0.000 * management non-operative vs operative 4.11 0.97-17.39 0.060 mortality yes vs no 1.97 0.59-6.55 0.261 * significant result. moi: mechanism of injury; ci: confidence interval; or: odd ratio. archivio italiano di urologia e andrologia 2025; 97(2):13939 p. satyagraha, b. daryanto, b. wilianto, f. kurniawan dhani 4 hemodynamic instability may include hypotension, shock due to hematoma, and massive bleeding, resulting in decreased haemoglobin. low haemoglobin levels (< 10 g/dl) will also delay discharge. hemodynamic instability increases the risk of prolonged los. meanwhile, patients with stable hemodynamic do not need to undergo operative procedures, so their length of stay will be shorter (6). patients who arrived with hemodynamic stability, despite having a high severity of injury, were recommended to nom. in this study, renal trauma management was not associated with a significant risk of patient los. a study showed that there is a correlation between the medical management provided and the patient's los, i.e., patients with nom tend to have a shorter los than patients with operative management (6, 20). many studies have confirmed the safety of nom in renal trauma, and it has become the standard of care for most patients with renal trauma (20, 23, 24). the success rate of nom in hemodynamically stable patients reaches 80%, even in patients with high-grade severity (24). nevertheless, emergency operative treatment of injuries in patients with hemodynamic instability is still performed for certain indications (12), nom has demonstrated favourable outcomes and remains the preferred initial treatment for isolated renal trauma in patients with stable hemodynamic status, even in cases of high-grade injuries. in cases where complications arise (like urinoma, or infection), minimally invasive procedures such as percutaneous drainage of urinomas can be employed effectively (25). factors that determine the choice of management include patient stability, the degree of renal injury, and the presence of associated injuries, which are the most common reasons for renal surgical exploration (26). the study showed that 10.1% of renal trauma patients died (26). our study also indicates that renal trauma patients, in the absence of associated injuries, did not experience any fatalities. all fatalities in renal trauma cases were observed exclusively in the presence of concomitant injuries. this is consistent with findings from a 9-year study on renal injury conducted in australia, which reported that renal injury was not identified as the cause of death in any of the cases. overall, 17 patients in that study succumbed within the first 24 hours of admission due to severe multi-trauma (27). post-traumatic mortality was also not a significant factor affecting los. this is consistent with the results of the san francisco study, which found that patients who died had a mean los of 6.6 days shorter than patients who were discharged (p < 0.01) (6). a patient's hospital care may conclude upon their discharge, transfer, or death. the mean los for transferred patients was 5.8 days longer than for discharged patients (6, 28). this study has several limitations that need to be considered in interpreting the results. firstly, the retrospective design of the study, which was conducted in one healthcare center, limits the generalizability of the findings to a wider population or to hospitals with different characteristics. in addition, the relatively limited sample size may also affect the statistical power and external validity of the findings. therefore, further studies with a prospective design and multicentre coverage are needed to verify the results and improve the validity of the findings. conclusions this study concludes that older age, blunt force injury, associated injuries, hemodynamic instability, and haemoglobin level all have an impact on the length of hospital stay in patients with renal trauma. proper management and clinical condition at the time of admission also determine the length of hospital stay, which affects patient outcome. further studies with larger samples and other parameters that play a role in the hospital management of renal trauma patients are needed to reduce disability and mortality rates and improve survival. references 1. baghdanian ah, baghdanian aa, armetta a, et al. utility of mdct findings in predicting patient management outcomes in renal trauma. emerg radiol. 2017; 24:263-72. 2. mingoli a, la torre m, migliori e, et al. operative and nonoperative management for renal trauma: comparison of outcomes. a systematic review and meta-analysis. ther clin risk manag. 2017; 13:1127-38. 3. zabkowski t, skiba r, saracyn m, zielinski h. analysis of renal trauma in adult patients: a 6-year own experiences of trauma center. urol j. 2015; 12:2276-9. 4. mcphee m, arumainayagam n, clark m. renal injury management in an urban trauma centre and implications for urological training. ann r coll surg engl. 2015; 97:194-7. 5. voelzke bb, leddy l. the epidemiology of renal trauma. transl androl urol. 2014; 3:143-9. 6. hampson la, radadia kd, odisho ay, et al. conservative management of high-grade renal trauma does not lead to prolonged hospital stay. urology. 2018; 115:92-5. declarations ethical approval and consent for participate: this research adheres to the principles outlined in the declaration of helsinki and has received approval from the dr. saiful anwar general hospital ethics committee under protocol number 400/223/ k.3/102.7/2024. consent for publication: not applicable. availability of data and material: not applicable. competing interests: the authors declare that they have no competing interests. funding: this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions: ps: conceptualization, methodology, writing review & editing, supervision. bd: conceptualization, methodology, writing review & editing, supervision. bw: conceptualization, writing original draft, methodology, data curation, formal analysis, investigation. fkd: methodology, data curation, project administration. acknowledgments: the authors wish to acknowledge the department of urology, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia. archivio italiano di urologia e andrologia 2025; 97(2):13939 5 analysis of factors associated with length of stay in renal trauma 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instituting a conservative management protocol for pediatric blunt renal trauma: evaluation of a prospectively maintained patient registry. j urol. 2011; 185:1058-64. 14. aguayo p, fraser jd, sharp s, et al. nonoperative management of blunt renal injury: a need for further study. j pediatr surg. 2010; 45:1311-4. 15. biffl wl, lu n, schultz pr, et al. improving length of stay on a trauma service. trauma surg acute care open. 2021; 6:e000744. 16. kashkooe a, yadollahi m, pazhuheian f. what factors affect length of hospital stay among trauma patients? a single-center study, southwestern iran. chin j traumatol. 2020; 23:176-80. 17. st. peter sd, sharp sw, snyder cl, et al. prospective validation of an abbreviated bedrest protocol in the management of blunt spleen and liver injury in children. j pediatr surg. 2011; 46:173-7. 18. salem ms, urry rj, kong vy, et al. traumatic renal injury: five-year experience at a major trauma centre in south africa. injury. 2020; 51:39-44. 19. petrone p, perez-calvo j, brathwaite cem, et al. traumatic kidney injuries: a systematic review and meta-analysis. int j surg. 2020; 74:13-21. 20. nakao s, katayama y, hirayama a, et al. trends and outcomes of blunt renal trauma management: a nationwide cohort study in japan. world j emerg surg wjes. 2020; 15:50. 21. khairani af, azka an, faried a, et al. characteristic of motor vehicle accident patients presenting to a national referral hospital in west java, indonesia. southeast asian j trop med public health 2018; 49:887-93. 22. haghparast-bidgoli h, saadat s, bogg l, et al. factors affecting hospital length of stay and hospital charges associated with road traffic-related injuries in iran. bmc health serv res. 2013; 13:281. 23. bjurlin ma, fantus rj, fantus rj, villines d. comparison of nonoperative and surgical management of renal trauma: can we predict when nonoperative management fails? j trauma acute care surg. 2017; 82:356-61. 24. cimbanassi s, chiara o, leppaniemi a, et al. nonoperative management of abdominal solid-organ injuries following blunt trauma in adults: results from an international consensus conference. j trauma acute care surg. 2018; 84:517-31. 25. duarsa gwdp, satyagraha p, daryanto b. non-operative management for high-grade isolated renal trauma in pediatric patients: a case series. pan afr med j. 2023; 44:71. 26. mcaninch jw, carroll pr, klosterman pw, et al. renal reconstruction after injury. j urol. 1991; 145:932-7. 27. lingsma hf, bottle a, middleton s, et al. evaluation of hospital outcomes: the relation between length-of-stay, readmission, and mortality in a large international administrative database. bmc health serv res. 2018; 18:116. 28. shoobridge jj, bultitude mf, koukounaras j, et al. a 9-year experience of renal injury at an australian level 1 trauma centre. bju int. 2013; 112 (suppl 2):53-60. correspondence besut daryanto (corresponding author) urobes.fk@ub.ac.id department of urology, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia jaksa agung suprapto no. 2, klojen, malang, east java, indonesia 65111 paksi satyagraha uropas.fk@ub.ac.id bagas wilianto bagaz.dr@gmail.com fauzan kurniawan dhani fauzankurniawandhani@gmail.com department of urology, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13525 1 letter to editor key words: peyronie’s disease; antioxidants; pentoxifylline; injections, oral drug administration, topical drug administration. submitted 25 december 2024; accepted 3 january 2025 to the editor, we conducted a retrospective study to demonstrate that it is possible to achieve better therapeutic outcomes through combining perilesional injections of pentoxifylline (ptx) with oral antioxidants and the local application of a cream containing antioxidants and a gel containing diclofenac in patients with peyronie's disease (pd). we compared two similar groups of patients with pd using the two treatments mentioned above. the typical symptoms of pd commonly include penile deformity, penile pain, erectile dysfunction, and psychological distress such as anxiety and depression (1, 2). ptx is a synthetic methylxanthine derivative that has structural similarities to caffeine and theophylline. originally created as a hemorheological agent, it was first used to treat peripheral vascular diseases, cerebrovascular insufficiency, diabetic neuropathy, sickle cell disease, and various inflammatory and fibrotic conditions. brant et al. (2006) were the pioneers in utilizing ptx for pd. ptx possesses antifibrotic, anticalcific, antioxidant, anti-inflammatory, antiplatelet, and vasorelaxant properties (3). while some guidelines do not recommend the use of antioxidants such as ptx for treating pd, there have been numerous published therapeutic cases involving ptx, either on its own or in combination with other antioxidant and non-antioxidant therapies (3-6). all of these clinical studies in the literature, in which ptx has been used, have demonstrated that this drug is able to counteract pd due to its ability to interfere with the pathogenetic mechanisms of the disease and reduce the most important symptoms of the disease. in our most recent clinical practice we discontinued oral administration of ptx as we observed a high prevalence (15.7%) of side effects that impact the circulatory system, blood pressure, and intestinal system (6). for these reasons, we are now using ptx only through perilesional penile injections. we have not found other studies in the literature where penile injections of ptx have been used to treat pd. we performed a retrospective analysis of the clinical database of a single uro-andrology clinic. from the database, we extracted 263 patients with active pd (first stage) who had visited our peyronie's care center between december 2019 and october 2024. in our clinical archive, all clinical information (medical history and physical examination) and diagnostic tests were available, both before and after treatment. of these 263 patients, 152 had already undergone combined therapy with oral antioxidants + topical therapy, as well as perilesional penile injections with ptx. the remaining 111 patients had undergone the same oral and topical antioxidant therapy but had not received penile injections with ptx. this latter group of patients decided not to undergo penile injections due to a fear of penile pain and/or logistical reasons related to the great distance between their residence and our treatment center. all 263 patients had undergone at least one 6-month treatment cycle and were potentially able to be divided into two treatment groups, as planned for our study. however, after analyzing the data of all these patients, a clear heterogeneity between the two groups was detected. to ensure statistical homogeneity between the two treatment groups and ensure a similar number of participants in these groups, we conducted further selection and excluded another 159 cases from the study. these cases were excluded based on their clinical characteristics, such as the degree of penile curvature, plaque volume, presence of ed or penile pain, age, onset of the disease, and comorbidities. finally, after this further selection, we included 104 cases in the study, which we divided into two treatment groups (group a and group b), each consisting of 52 cases. treatment characteristics for each group were as follows: group a received a combination of oral antioxidants and topical creams for 6 months, along with peri-lesional penile injections with ptx every 2 weeks. group b received the same oral and topical treatments as group a, but without the penile injections with ptx, for 6 months. the detailed characteristics of the treatment for each therapeutic group are shown in the “legend” of the table 1. treatment with perilesional injections of pentoxifylline in patients with peyronie's disease improves the therapeutic effect of oral and topical antioxidant therapy gianni paulis 1, andrea paulis 2, giovanni de giorgio 3 1 department of urology and andrology, peyronie’s care center, castelfidardo castelfidardo clinical analysis center, rome, italy; 2 bambino gesù children’s hospital, irccs (istituti di ricovero e cura a carattere scientifico), rome, italy; 3 department of urology and andrology, section of ultrasound diagnostics, castelfidardo clinical analysis center, rome, italy. doi: 10.4081/aiua.2025.13525 archivio italiano di urologia e andrologia 2025; 97(1):13525 g. paulis, a. paulis, g. de giorgio 2 this retrospective study was conducted in compliance with the principles contained in the declaration of helsinki (fortaleza, 2013); all study subjects were contacted and provided informed consent for study inclusion. all patients were informed that treatment with penile injections of pentoxifylline is an "off-label" therapy. sensitive data were anonymized to warrant patients’ privacy according to legislative decree 10 august 2018, n. 101, published in the official gazette of the italian republic, general series, issue 205, 09/04/2018. all 104 pd patients underwent photographic documentation of penile curvature (according to kelâmi) and dynamic penile dynamic doppler ultrasound (pddu) with plaque and volume measurements and answered the following questionnaires: the generalized anxiety disorder-7 (gad-7), the patient health questionnaire-9 (phq-9), the visual analog scale (vas) for penile pain measurements, the international index of erectile function (iief), and the peyronie's disease questionnaire (pdq, symptom bother domain) for the evaluation of the psychosexual impact of the disease. table 1. clinical results (related to the reduction and/or the regression of pd symptoms, plaque volume, and its internal calcification) after 6 months of treatment. clinical results group a group b statistical analysis n. 52 cases treated with n. 52 cases treated only with group a oral and topical antioxidants oral and topical antioxidants versus group b + ptx injections without ptx injections p-value decrease in plaque volume mean rate % 39.5 19.5 p < 0.0001 (t-test) ± sd ± 11.4 ± 7.3 decrease in calcification within the plaque mean rate % 62.9 19.2 p < 0.0001 (t-test) ± sd ± 19.5 ± 20.5 decrease of the penile curvature angle mean decrease (in degrees °) 8.1 4.4 p = 0.002 (t-test) ± sd ± 6.5 ± 4.8 mean decrease in the vas score 3.7 2.1 p < 0.0001 (t-test) ± sd ± 1.3 ± 0.9 mean increase in the iief score in patients with ed + 3.3 + 1.4 p = 0.006 (t-test) ± sd ± 2.9 ± 1.2 mean decrease in the pdq-bother score in patients with psychosexual impact by pd 5.3 3.6 p < 0.0001 (t-test) ± sd ± 1.8 ± 1.3 mean decrease in the gad-7 score in patients with anxiety 6.1 4.8 p = 0.001 (t-test) ± sd ± 1.6 ± 1.9 mean decrease in the phq-9 score in patients with depression 4.5 2.7 p < 0.0001 (t-test) ± sd ± 1.4 ± 0.9 n. patients with complete plaque regression 0 (out of 52) 0 (out of 52) p = 1.000 (χ2 test) (%) 0 0 n. patients with complete regression of the calcification present in the plaque 1 (out of 11) 0 (out of 10) p = 0.350 (χ2 test) (%) 0.9 0 n. patients with disappearance of penile curvature 0 (out of 45) 0 (out of 47) p = 1.000 (χ2 test) (%) 0 0 n. patients with disappearance of penile pain 26 (out of 27) 3 (out of 28) p < 0.0001 (χ2 test) (%) 96.2 10.7 n. patients with disappearance of ed 11 (out of 26) 2 (out of 25) p = 0.01 (χ2 test) (%) 42.3 8.0 n. patients with disappearance of psychosexual impact by pd 0 (out of 51) 0 (out of 52) p = 1.000 (χ2 test) (%) 0 0 n. patients with disappearance of significant anxiety 35 (out of 46) 26 (out of 45) p = 0.102 (χ2 test) (%) 76.08 57.7 n. patients with disappearance of significant depression 27 (out of 33) 14 (out of 33) p = 0.002 (χ2 test) (%) 81.8 42.4 group a: orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11,000 iu/g 10 mg daily for 6 months; topically: cream with propolis and hyaluronic acid 2x daily + diclofenac gel 4% daily for 6 months; peri-lesional penile injections: ptx 60 mg (with 30 g needle) every 2 weeks for 6 months. group b: the same oral antioxidants and topical treatments as group a for 6 months (without peri-lesional penile injections with ptx). pd = peyronie’s disease. ed = erectile dysfunction; ptx = pentoxifylline; sd = standard deviation; χ2 test = chi-squared test. t-test = student's t-test. vas = visual analog scale, for pain assessment, score range 0–10. interpretation of score: mild to moderate pain = 1–5, severe pain = 6–7, very severe pain = 8–10. iief = international index of erectile function, score range 0–30. interpretation of score: severe ed = 0–10, moderate ed = 11–16, mild to moderate ed = 17–21, mild ed = 22–25, and no ed = 26–30. pdq symptom-bother = peyronie’s disease questionnaire symptom bother, to evaluate the psychosexual impact, score range 0–16. interpretation of score: mild bother 1–4, medium bother 5–8, high bother 9–12, severe bother 13–16. gad-7 = generalized anxiety disorder-7 questionnaire, for the assessment of anxiety, score range 0–21. interpretation of score: minimal anxiety = 0–4, mild anxiety = 5–9, moderate anxiety = 10–14, and severe anxiety = 15–21. significant anxiety when gad-7 score > 9. phq-9 = patient health questionnaire-9, for depressive disorder, score range 0–27. interpretation of score: minimal depression = 0–4, mild depression = 5–9, moderate depression = 10–14, moderately severe depression = 15–19, severe depression = 20–27. significant depression present when phq-9 score > 9. p-value: if the p-value is < 0.05, it is judged as significant; if the p-value is > 0.05, it is judged as not significant. archivio italiano di urologia e andrologia 2025; 97(1):13525 3 treatment with perilesional injections of pentoxifylline in patients with peyronie's disease... the endpoints of this study were related to the reduction and/or regression of pd symptoms, plaque volume, and its internal calcification. our results show that patients in the two treatment groups did not differ in age and most of the associated conditions and comorbidities. at the end of the treatment, we visited all patients again and subjected them to the same diagnostic tests that were performed before treatment. statistical analysis of the results after 6 months of treatment highlighted significant differences between the outcomes of the two groups (group a versus group b), in terms of improvement in penile pain, effective reduction in plaque size, improvement in penile curvature, improvement in iief score, and reduction in the psychological impact of pd. significantly better reduction of pd symptoms, plaque volume, and its internal calcification, was always observed by the addition of perilesional penile injections with ptx (group a) when compared to the oral and topical administration of antioxidants and diclofenac gel alone (group b) (see table 1). an higher statistically significant regression rate of pd symptoms, plaque, and its internal calcification was observed for group a (compared to group b) only for three clinical evaluations: disappearance of penile pain, disappearance of ed, and disappearance of significant depression (see table 1). we did not observe any side effects after the use of oral and topical substances. we only observed in one case a small bruise at the site of ptx injection, which resolved at about 5 days after the injection. the results of our present study revealed that the combination of periodic perilesional penile injections with ptx significantly increases the therapeutic efficacy, when compared to oral and topical antioxidant therapy alone. although the therapeutic response to the combination of oral and topical antioxidants (group b) after 6 months was certainly good, in terms of improvement of all pd symptoms, penile injections with ptx combined with other oral and topical antioxidants (group a) allowed us to achieve results that were unequivocally superior to those obtained without penile injections (group b). the limitations of our study are related to the absence of a control group comprising pd patients not receiving any therapy. as pd is a chronic progressive disease, it would be deemed unethical to withhold treatment, even for the purpose of a research study. we believe that our therapeutic success in treating pd was mainly due to the addition of penile perilesional injections with ptx to the oral and topical antioxidant therapy. we also consider the following factors to be important: careful selection of antioxidants to use, performing penile ultrasound examination with a modern ultrasound device with an elastography module that allows for very precise measurements of the plaque, and assigning the ultrasound examination to a physician with extensive experience in pd cases. as we observed high rates of significant anxiety and depression in pd patients, we believe that psychotherapy should be associated with medical treatment for pd patients, in order to improve their quality of life. although the treatment results obtained in this study were highly statistically significant, we believe that further randomized and controlled studies with a larger number of cases are needed to confirm the effectiveness of penile injection therapy with ptx. references 1. pryor jp, ralph dj. clinical presentations of peyronie’s disease. int j impot res. 2002; 14:414-417. 2. garaffa g, trost lw, serefoglu ec, et al. understanding the course of peyronie's disease. int j clin pract. 2013; 67:781-788. 3. brant wo, dean rc, lue tf. treatment of peyronie's disease with oral pentoxifylline. nat clin pract urol. 2006; 3:111-115. 4. smith jf, shindel aw, huang yc, et al. pentoxifylline treatment and penile calcifications in men with peyronie’s disease. asian j androl. 2011; 13:322-325. 5. ibrahim a, gazzard l, alharbi m, et al. evaluation of oral pentoxifylline, colchicine, and penile traction for the management of peyronie's disease. sex med. 2019; 7:459-463. 6. paulis g, barletta d, turchi p, et al. efficacy and safety evaluation of pentoxifylline associated with other antioxidants in medical treatment of peyronie’s disease: a case-control study. res rep urol. 2016; 8:1-10. correspondence gianni paulis (corresponding author) paulisg@libero.it department of urology and andrology, peyronie’s care center, castelfidardo castelfidardo clinical analysis center, rome, italy andrea paulis bambino gesù children’s hospital, irccs (istituti di ricovero e cura a carattere scientifico), rome, italy giovanni de giorgio department of urology and andrology, section of ultrasound diagnostics, castelfidardo clinical analysis center, rome, italy declarations ethical approval: our study, being a retrospective study, does not require approval from an ethics committee according to current regulations, and in any case it received approval from the castelfidardo ethical commission (protocol code #00243, date of approval 10 september 2024) for studies involving human. availability of data and material: all inquiries can be directed to the corresponding author (paulisg@libero.it). competing interests: the authors declare no conflicts of interest. funding: this research received no external funding. authors' contributions: all authors contributed equally to the conceptualization, investigation, data curation, analysis of results, and writing of this article. acknowledgments: we are grateful to the patients who took part in our study, allowing us to observe and analyze the good outcomes of the treatments they received. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2206 original paper no conflict of interest declared. introduction hypospadias, one of the most common congenital malformations, affects one in every 200 to 300 live births. it is typically accompanied by a band of fibrotic tissue arising from the abnormal meatal opening to the glans. it causes the shortens of the penile shafts in the ventral aspect, causing downward deformity of the penis (chordee) (1). hypospadias is classified into penoscrotal, proximal, midpenile, distal, and coronal hypospadias (2). the techniques used to repair hypospadias are heavily influenced by the anomaly's components, including the size of the urethral plate and penis, the presence of penile chordee, the location of the meatal opening, and the experience of the surgeon (3). the main aim of hypospadias surgery is to correct the penile chordee and move the meatus opening to the glandular area (4). with over a hundred techniques published, the tabularized incisional plate (tip) is presently the most fantastic procedure for primary hypospadias surgery (5). urethrocutaneous fistula is the most complication observed in tip urethroplasty, with a range of incidence between 0 to 28%. to reduce the risk of urethrocutaneous fistula, most surgeons now perform tissue interposition between the neourethra and the skin of the penis as a standard step during tip surgeries (3). the dartos flap (df) and tunica vaginalis fascia (tvf) are the most commonly used urethral interposition with good postoperative outcomes, though different research findings reported the results (6-8). there is no agreement on which df or tvf flap techniques are superior (3). our goal was to share our experiences of hypospadias surgery with tip repair using tvf and df, outcome, and complications. materials and methods study design we retrospectively reviewed the medical records of 16 consecutive children with hypospadias repairs from sep background: in the tubularized incised plate (tip) procedure, flap interposition between the skin and neourethra is highly recommended to decrease the postoperative fistula rate. however, there is no consensus regarding the ideal flap for this procedure. this study aimed to report our experiences in the one-stage tip hypospadias surgery utilizing dartos flap (df) (penile skin subcutaneous tissue) and tunica vaginalis flap (tvf) (parietal layer of the testis) as a tissue coverage of neourethra. methods: in a retrospective study from sep 2018 to may 2021, 16 cases of hypospadias with different types, ranging from midpenile to penoscrotal types, were managed with tip urethroplasty using df or tvf as a tissue coverage of neourethra were enrolled. the demographic characteristics of the participants, type of hypospadias, outcome, and complications were analyzed and compared. result: we used tvf and df as soft tissue coverage in 11 (68.8%) and 5 (31.3%) patients, respectively. the mean age was 56.38 ± 47.83 months. mid-penile, proximal, and penoscrotal hypospadias were presented in 3 (18.8%), 8 (50.0%), and 5(31.2%) patients, respectively. the total success rate was 14 (87.5%), while 2 (12.5%) patients developed a urethrocutaneous fistula, which required delayed closure later. in comparison between tvf and df groups: the tvf was applied in all patients with moderate and severe chordee and all patients with penoscrotal hypospadias, and six patients with proximal hypospadias, while only three patients with mild chordee and two patients with proximal hypospadias used the df and showed statistical significance between groups (p < 0.001 and 0.012) respectively. the success rate was 90.9% vs. 80.0% in tvf and df groups, respectively, with no statistical significance between groups (p = 1.000). conclusions: in the primary tip repair, the tvf is a practical option as a df for the interposition cover of a neourethra, especially in penoscrotal and proximal hypospadias with severe chordee. key words: hypospadias; dartos fascia; tunica vaginalis; tubularized incised plate. submitted 1 april 2022; accepted 23 april 2022 role of tunica vaginalis flap and dartos flap in tubularized incisional plate for primary hypospadias repair: a retrospective monocentric study faisal ahmed 1, hossein-ali nikbakht 2, khalil al-naggar 1, saleh al-wageeh 3, qasem alyhari 3, saif ghabisha 3, ebrahim al-shami 1, menawar dajenah 3, waleed aljbri 4, fawaz mohammed 5, abdu al-hajri 3 1 urology research center, al-thora general hospital, department of urology, school of medicine, ibb university of medical science, ibb, yemen; 2 social determinants of health research center, health research institute, babol university of medical sciences, babol, iran; 3 department of general surgery, school of medicine, ibb university of medical science, ibb, yemen; 4 department of urology, school of medicine, 21 september university, sana'a, yemen; 5 department of orthopedy, school of medicine, ibb university of medical science, ibb, yemen. doi: 10.4081/aiua.2022.2.206 summary 207archivio italiano di urologia e andrologia 2022; 94, 2 tunica vaginalis and dartos flaps in hypospadias 2018 to may 2021. patients' and operations' characteristics, such as type of hypospadias, degree of chordee, flap usage, success rate, and complications, were collected, analyzed, and compared. the ethics committees of ibb university of medical sciences approved this thesis, which was carried out in compliance with the helsinki declaration. additionally, informed consent was obtained from the patients' families to participate in our research. surgical procedure we illustrate a case of penoscrotal hypospadias (figure 1). all procedures were carried out while the patients were anesthetized. a stay suture was placed in the dorsal aspect of the glans to aid in traction of the phallus and fix the urethral catheter later. the penile skin was degloved. then, if the penile chordee was greater than 30 degrees, the chordee was intraoperatively corrected. the urethral plate was incised from the hypospadias meatus to the penial glans. then, the tabularization was made over a nelaton catheter (6 to 10 french) depending on the patients' age. then, subcuticular continuous suturing was made with a 6.0 vicryl (1). the neourethra suture was completed to the subcoronal level (figure 2). dartos flap a dartos layer from penile skin subcutaneous tissue was dissected to cover the neourethral suture line and fixed with pds 5/0. then by creating the buttonhole in the midshaft skin of the penis, the penis was delivered through it and sutured with vicryl 5/0. a thin dressing was used to keep the penis in place. a suprapubic catheter was inserted into the bladder and fixed with silk 2/0. on the second postoperative day, an open dressing was applied. the patient was discharged on the fourth day following the operation with the proper antibiotic. the suprapubic and urethral catheters were removed on the 10th and 14th postoperative days. tunica vaginalis flap harvesting for additional tvf coverage was done (left or right side testicular vaginalis). using micro-scissors, an adequate tvf was harvested from the dorsal part of the vaginalis. the flap was at least 5 mm in width and long enough to cover the neourethra. to avoid glans dehiscence, the distal end of the tvf was fixed in the subcoronal area. an interrupted suture was used to place the graft over the neourethra. the remainder of the procedure was similar to that described in the df procedure. statistical analysis the variables' descriptive statistics were calculated as mean, standard deviation, maximum, and minimum, and qualitative variables with frequency (percentage) were presented. an independent sample t-test or mannwhitney test compared the qualitative variables. the chisquare test or fisher's exact test compared the qualitative variables. data were analyzed using statistical software (spss inc., chicago, il, usa) version 22. a p value < 0.01 was considered a significant level. results out of 16 hypospadias patients who underwent primary tip repair, in 11 (68.8%) of patients, we used tvf as a soft tissue coverage. in 5 (31.3%) patients, the df was utilized for coverage. the mean age was 56.38 ± 47.83 (22.50-94.50) months. mild, moderate, and severe degree of chordee was presented in 3 (18.8%), 2 (12.5%), and 9 (56.2%), respectively, and it was corrected successfully in both groups. the chordee was repaired by complete degloving of the penis and release of dysplastic dartos tissues in most patients, and only two cases with penoscrotal hypospadias required multiple transverse incisions of the ventral aspect of the corpus cavernosum. the total success rate was 14 (87.5%), while 2 (12.5%) patients developed fistula, which required delayed closure later. after surgery, urinary tract infection (uti) was presented in 3 (18.8%) patients and was treated with a proper antibiotic. pain during micturition after surgery was presented in 3 (18.8%) patients and was treated with oxybutynin. after 24 months of follow-up, there was no incidence of new fistula, meatal stricture, or other complications. comparison between using tvf and df the mean age of patients who underwent tvf was 72.36 ± 49.77 months, and the mean age of patients who underwent df was 21.20 ± 11.69 months, and their age was significantly different (p = 0.007). the tvf was applied in all patients with moderate and severe chordee, figure 1. show the penoscrotal hypospadias with meatus opening (yellow arrow). figure 2. a. show the postoperative meatal opening (yellow arrow) and the skin covered with the pineal midshaft buttonhole (green arrow). b. show the postoperative meatal opening after dartos flap (yellow arrow). a. b. a. b. archivio italiano di urologia e andrologia 2022; 94, 2 faisal ahmed, hossein-ali nikbakht, khalil al-naggar, et al. 208 while only in three patients with mild chordee the df was used showing statistical significance between groups (p < 0.001). for all the patients with penoscrotal hypospadias and six patients with proximal hypospadias, the tvf was applied. only in two patients with proximal hypospadias the df was used with statistical significance between groups (p = 0.012). the time of operation for both groups was similar at 2 hours. in the tvf group, the success rate was 90.9%, while the success rate in the df group was 80.0%, with no statistical significance between groups (p = 1.000) (table 1). discussion hypospadias surgery is continually changing, suggesting that no single technique is thought to be ideal. the use of interposition flaps in the research is well demonstrated, such as triangular soft tissue flaps and belman flaps harvested from the prepuce. smith d flap is derived from the penile skin, whereas buck's fascial flap is derived from the penile, shaft, and df from penile skin subcutaneous tissue. the tvf is derived from the testis, and the scrotal df is derived from the scrotum (3). snodgrass presented use of a flap that was dissected from the dorsal preputial and shaft skin to provid additional coverage of the ventral aspect of the neourethra. this dissection requires experience, and there is a risk of dermal necrosis (3, 9). however, there are many choices for soft tissue covers, and the suitable one has yet to be discovered (10). df is easily obtainable, easy to mobilize, provides excellent coverage for repeat proximal hypospadias surgery, and does not require an additional extra incision (3). in contrast, tvf is a good choice for re-do hypospadias cases and proximal and penoscrotal hypospadias where dissection is extended to the root of the penis (11). tvf can be harvested via a penile incision degloving up to the basis of the penis or via an additional scrotal incision reaching and covering the neourethra via a subcutaneous scrotal tunnel (6). snow and associations were the first to document the use of tvf as an interposition graft in 1995, with a postoperative fistula rate of about 9% (12). similar findings were reported by shankar et al. (13). our study used the tvf for all patients with penoscrotal hypospadias and six patients with proximal hypospadias, while the df was used in only two patients with proximal hypospadias. we find that tvf is a good interposition flap in proximal and penoscrotal hypospadias. a similar result was reported by radhakrishnan et al. and braga et al. (14, 15). regarding the age of surgery, the mean age of patients who underwent tvf and df were 72.36 ± 49.77 months vs. 21.20 ± 11.69 months, respectively, and their age was significantly different (p = 0.007). delayed presentations in our patients were due to misinterpreting hypospadias as a normal variation (paribor or cut by angels), being told by general physicians that repair is futile, and fear of future surgery complications. similar reasons were reported by zargooshi et al. (16). additionally, age is not a predisposing factor for postoperative complications. bush and snodgrass obtained a similar result in 186 patients operated on for hypospadias. they find that of preoperative factors, including meatal location, urethral plate width, glans width, and age, only glans width less than 14 mm was associated with increased urethroplasty complications (17). the american academy of pediatrics chordee survey classifies penile curvature as mild, moderate, and severe. the mild curvature is less than 30 degrees, moderate is 30 to 43 degrees, and severe is more than 43 degrees (18). in our study, mild, moderate, and severe degree of chordee was presented in 3 (18.8%), 2 (12.5%), and 9 (56.2%) patients, respectively. additionally, the tvf was applied in all patients with moderate and severe chordee, while only two patients with mild chordee used the df and showed statistical significance between groups (p < 0.001). tvf was used to correct chordees in children with severe hypospadias (19). however, the reported findings of this technique have been contradictory. ritchey reported excellent results with tvf (21). at a median follow-up of 9 months during second stage repair, only 1 of their 25 patients with scrotal or perineal hypospadias had evidence of recurrent ventral chordee (20). in 25 patients with scrotal or perineal hypospadias associated with severe ventral chordee, ritchey and associations et al. reported excellent results with tvf of the corpora without chordee recurrence (21). a recent study by braga et al. mentioned that in the short-term outtable 1. comparison between tunica vaginalis flap (tvf) and dartos flap (df). variable * subgroups total n (%) type of surgery p-value** tvf (11, 68.8%) df (5, 31.3%) outcome success 14 (87.5) 10 (90.9) 4 (80.0) 1.000 failure 2 (12.5) 1 (9.1) 1 (20.0) type of hypospadias middle 3 (18.8) 0 (0.0) 3 (60.0) 0.012 proximal 8 (50.0) 6 (54.5) 2 (40.0) penoscrotal 5 (31.3) 5 (45.5) 0 (0.0) age (year) < 3 7 (43.8) 3 (27.3) 4 (80.0) 0.077 ≥ 3 9 (56.3) 8 (72.7) 1 (20.0) complication no 8 (50.0) 5 (45.5) 3 (60.0) 0.769 fistula 2 (12.5) 1 (9.1) 1 (20.0) uti 3 (18.8) 3 (27.3) 0 (0.0) pain in micturition 3 (18.8) 2 (18.2) 1 (20.0) type of chordee no 2 (12.5) 0 (0.0) 2 (40.0) < 0.001 mild (less than 30) 3 (18.8) 0 (0.0) 3 (60.0) moderate (30-43) 2 (12.5) 2 (18.2) 0 (0.0) severe (more than 43 degree) 9 (56.3) 9 (81.8) 0 (0.0) associated anomaly no 14 (87.5) 9 (81.8) 5 (100) 1.000 udt 1 (6.3) 1 (9.1) 0 (0.0) cleft plate 1 (6.3) 1 (9.1) 0 (0.0) uti: urinary tract infection, udt: undescended testicle. note: * data was presented as n (%). ** p-values of < 0.01 were considered significant. 209archivio italiano di urologia e andrologia 2022; 94, 2 tunica vaginalis and dartos flaps in hypospadias come of ventral penile lengthening, tvf alone to correct severe chordee is favorable, with a 95% success rate (15). our result was similar to those reports. on the other hand, caesar reported that 60% of tvf patients had recurrent ventral chordees (22). vandersteen and husmann also discovered late-onset recurrent chordee after successful hypospadias repair with tvf (23). correction of penile chordee begins with complete degloving of the penial skin, the release of the dysplastic dartos tissues, and induction of an artificial erection (21). when the chordee is severe, the urethral plate is mobilized from the underlying corpus cavernosum, accompanied by movements of the normal proximal urethra up to the bulbar urethra (19). in our cases, the chordee was repaired by complete degloving of the penis and release of the dysplastic dartos tissues, and only two patients with penoscrotal hypospadias required multiple transverse incisions in the penile ventral aspect that had a maximum curvature; our result in chordee correction was similar to the experience reported by snodgrass et al. (24). the final step in hypospadias repair is skin covering, and it is critical to resurface the penis after the tip procedure. numerous procedures have been used to accomplish skin covering. some techniques involve suturing the lateral skin edges together in the ventral aspect of the penis. however, this technique may cause skin tension, and a dorsal skin incision for avoiding tension may be required. in some other method, as in our cases, creating a buttonhole incision in the midshaft skin of the penis, delivering the penis through it, and suturing was made (2, 25). complications of tip hypospadias procedure include urethrocutaneous fistula formation, stenosis of the new meatus, diverticulum formation, and tvf complications such as scrotal hematoma in the 2% to 4% range. fistula formation is the most frequent complication, with reported incidences ranging from 3 % to 50% (26). we report a similar result in fistula rate of 9.1% and 20% for tvf and df, respectively, without statistically significant (p = 0.769). in a prospective study comparing the df vs. tvf as flap coverage for primary tip procedure, chatterjee et al. found that the fistula rate was 0% and up to 20% for tvf and df, respectively (11). dhua and the association reported that tvf had an optimal tissue coverage of the neourethra than the df (3 fistulae in the df group) (3). in contrast, zheng et al. reported similar fistula rates of df and tvf (27). a systematic review recommended a double df for distal hypospadias and tvf for proximal hypospadias during tip surgery (28). the reasons for a different incidence rate of fistula in our study with previously published articles were that all the patients with penoscrotal and proximal hypospadias were repaired using tvf. in contrast, the df was used in two patients with proximal hypospadias. additional reasons are older age at operation in the tvf group, and a small number of patients explain this different fistula rate in both groups. a similar reason was mentioned by dhua et al. (3). in our study, we insert suprapubic catheter drainage at the end of the procedure to improve the healing of the new urethra and minimize the risk of urethrocutaneous fistula. according to duarsa et al., the suprapubic cystotomy insertion could reduce the risk of urethrocutaneous fistula following hypospadias surgery (29). most of our patients achieved the external meatal orifice up to the subcoronal level, particularly those with proximal or penoscrotal hypospadias. a subcoronal meatus was appropriate by patients' families in cases where local anatomy was not allowed to prefer spreading the neourethra up to the glanular area. counseling before operation with family is essential. furthermore, it is well documented that the meatal orifice location at the subcoronal area is functional with acceptable cosmetic outcomes (26, 30). there were several limitations to the current study. first and foremost, the small number of patients (only 16) and tvf and df groups do not have similar cases. secondly, the tvf was used in all cases of penoscrotal hypospadias and most proximal hypospadias cases, while the df was used only in two cases of proximal hypospadias. finally, a retrospective analysis could have resulted in selection bias. additional prospective studies with strict follow-up and large sample size are required to evaluate the outcome and complication rate after primary tip with tvf vs. df as tissue coverage. conclusions in the primary tip repair, the tvf is a practical option as a df for the interposition cover of a neourethra. this finding needs to be confirmed in a large cohort study with long-term post-procedural follow-up to demonstrate the superiority of tvf over df. acknowledgments the authors would like to thank the general manager of althora general hospital, ibb, yemen, dr. abdulghani ghabisha, for editorial assistance. references 1. snodgrass wt, nguyen mt. current technique of tubularized incised plate hypospadias repair. urology. 2002; 60:157-62. 2. omar rg, khalil mm, sherif h, et al. pedicled preputial island flap for double functions in hypospadias surgery. turk j urol. 2018; 44:423-7. 3. dhua ak, aggarwal sk, sinha s, et al. soft tissue covers in hypospadias surgery: is tunica vaginalis better than dartos flap? j indian assoc pediatr surg. 2012; 17:16-9. 4. subramaniam r, spinoit af, hoebeke p. hypospadias repair: an overview of the actual techniques. semin plast surg. 2011; 25:206-12. 5. satjakoesoemah ai, situmorang gr, wahyudi i, et al. single-stage urethroplasty: an eight-year single-centre experience and its associated factors for urethrocutaneous fistula. j clin uro. 2021; 14:190-5. 6. yang h, xuan x-x, hu d-l, et al. comparison of effect between dartos fascia and tunica vaginalis fascia in tip urethroplasty: a meta-analysis of comparative studies. bmc urology. 2020; 20:161. 7. cheng ey, vemulapalli sn, kropp bp, et al. snodgrass hypospadias repair with vascularized dartos flap: the perfect repair for virgin cases of hypospadias? j urol. 2002; 168:1723-6; discussion 6. 8. landau eh, gofrit on, meretyk s, et al. outcome analysis of archivio italiano di urologia e andrologia 2022; 94, 2 faisal ahmed, hossein-ali nikbakht, khalil al-naggar, et al. 210 tunica vaginalis flap for the correction of recurrent urethrocutaneous fistula in children. j urol. 2003; 170:1596-9; discussion 9. 9. snodgrass w. tubularized, incised plate urethroplasty for distal hypospadias. j urol. 1994; 151:464-5. 10. bilici s, sekmenli t, gunes m, et al. comparison of dartos flap and dartos flap plus spongioplasty to prevent the formation of fistulae in the snodgrass technique. int urol nephrol. 2011; 43:943-8. 11. chatterjee us, mandal mk, basu s, et al. comparative study of dartos fascia and tunica vaginalis pedicle wrap for the tubularized incised plate in primary hypospadias repair. bju int. 2004; 94:1102-4. 12. snow bw, cartwright pc, unger k. tunica vaginalis blanket wrap to prevent urethrocutaneous fistula: an 8-year experience. j urol. 1995; 153:472-3. 13. shankar kr, losty pd, hopper m, et al. outcome of hypospadias fistula repair. bju int. 2002; 89:103-5. 14. radhakrishnan cn, radhakrishna v. the tunica-vaginalis flap to prevent postoperative fistula following severe hypospadias repair: has the search for holy grail ended? actas urol esp (engl ed). 2021; 45:552-6. 15. braga lh, pippi salle jl, dave s, et al. outcome analysis of severe chordee correction using tunica vaginalis as a flap in boys with proximal hypospadias. j urol. 2007; 178:1693-7; discussion 7. 16. zargooshi j. tube-onlay-tube tunica vaginalis flap for proximal primary and reoperative adult hypospadias. j urol. 2004; 171:224-8. 17. bush nc, snodgrass w. pre-incision urethral plate width does not impact short-term tubularized incised plate urethroplasty outcomes. j pediatr urol. 2017; 13:625.e1-.e6. 18. braga lh, lorenzo aj, bägli dj, et al. ventral penile lengthening versus dorsal plication for severe ventral curvature in children with proximal hypospadias. j urol. 2008; 180:1743-7; discussion 7-8. 19. perlmutter ad, montgomery bt, steinhardt gf. tunica vaginalis free graft for the correction of chordee. j urol. 1985; 134:311-3. 20. lindgren bw, reda ef, levitt sb, et al. single and multiple dermal grafts for the management of severe penile curvature. j urol. 1998; 160:1128-30. 21. ritchey ml, ribbeck m. successful use of tunica vaginalis grafts for treatment of severe penile chordee in children. j urol. 2003; 170:1574-6; discussion 6. 22. caesar re, caldamone aa. the use of free grafts for correcting penile chordee. j urol. 2000; 164:1691-3. 23. vandersteen dr, husmann da. late onset recurrent penile chordee after successful correction at hypospadias repair. j urol. 1998; 160:1131-3; discussion 7. 24. snodgrass w, prieto j. straightening ventral curvature while preserving the urethral plate in proximal hypospadias repair. j urol. 2009; 182:1720-5. 25. bakal ü, abes m, sarac m. necrosis of the ventral penile skin flap: a complication of hypospadias surgery in children. adv urol. 2015; 2015:452870. 26. kadian ys, singh m, rattan kn. the role of tunica vaginalis flap in staged repair of hypospadias. asian j urol. 2017; 4:107-10. 27. zheng d, fu s, li w, et al. the hypospadias classification affected the surgical outcomes of staged oral mucosa graft urethroplasty in hypospadias reoperation: an observational study. medicine (baltimore). 2017; 96:e8238. 28. fahmy o, khairul-asri mg, schwentner c, et al. algorithm for optimal urethral coverage in hypospadias and fistula repair: a systematic review. eur urol. 2016; 70:293-8. 29. duarsa gwk, tirtayasa pmw, daryanto b, et al. risk factors for urethrocutaneous fistula following hypospadias repair surgery in indonesia. j pediatr urol. 2020; 16:317.e1-.e6. 30. fichtner j, filipas d, mottrie am, et al. analysis of meatal location in 500 men: wide variation questions need for meatal advancement in all pediatric anterior hypospadias cases. j urol. 1995; 154:833-4. correspondence faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com khalil al-naggar, md alnajjarkh1234@gmail.com saleh al-wageeh, md alwajihsa78@gmail.com qasem alyhari, md qalyhary@hotmail.com saif ghabisha, md saifalighabisha@yahoo.com ebrahim al-shami, md alshami_ebrahim@yahoo.com menawar dajenah, md dajenahmenawar@gmail.com abdu al-hajri, md abdulhagri@gmail.com urology office, althora general hospital, alodine street, ibb (yemen) hossein-ali nikbakht, md ep.nikbakht@gmail.com social determinants of health research center, health research institute, babol university of medical sciences, babol (iran) waleed aljbri, md dr.waleed112@gmail.com urology office, school of medicine, 21 september university, sana'a (yemen) fawaz mohammed, md falnehari@gmail.com orthopedy office, althora general hospital, alodine street, ibb (yemen) stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12997 1 original paper introduction holmium laser enucleation of the prostate (holep) is a sizeindependent gold-standard surgical treatment for benign prostatic hyperplasia (bph) (1, 2). it offers comparable outcomes to open prostatectomy (op) and transurethral resection of the prostate (turp), with shorter hospital stays and lower morbidity rates (3, 4). improvements in longterm outcomes post-holep are durable, with minimal late complications and low reoperation rates (5). various barriers hinder holep's widespread adoption, as mastering it requires proficiency in endoscopic techniques and presents significant challenges (6-9). holep's learning curve typically involves 25-50 procedures (10). however, a well-structured mentorship program may reduce the number of cases, allowing for faster proficiency (6, 10). several studies attempted to determine the threshold of procedures defining the learning phase, considering factors like surgical duration, enucleation efficiency, energy expenditure, prostate-specific antigen (psa) level reduction, and complication rates (9, 11, 12). efforts to address traditional holep's steep learning curve include modifications to simplify the procedure and reduce operative time (13-17). york et al. introduced the top-down technique in 2017. advantages of topdown holep include minimizing the risk of overstretching the sphincter during distal mucosal flap cutting and eliminating the encircling technique (18). our study aims to enhance understanding of holep's learning trajectory by comparing two successive fellows and their supervisor performing top-down holep. we endeavor to provide insights to shape training protocols and advance holep's adoption in urological practice. materials and methods following ethics board approval, we conducted a prospective study of 40 patients who underwent top-down holep performed by two successive clinical fellows at our institution from september 2020 to november 2022. the study also included retrospective data from 148 cases performed by a holep expert (h.e.) from october 2017 to september 2020 prior to establishing a clinical fellowship program. introduction: holmium laser enucleation of the prostate (holep) is known to have a steep learning curve. the top-down technique was introduced to lessen the number of procedures required to master holep. we aimed to present the experiences of two successive clinical fellows with the top-down holep learning curve and compare their performance with the supervisor. methods: we conducted a prospective study of 40 patients who underwent top-down holep performed by two successive fellows at our institution from september 2020 to november 2022. before data collection, each learner observed three top-down holep procedures and assisted with seven additional cases before independently performing top-down holep under supervision. we collected data from each fellow’s first 20 consecutive top-down holep procedures. the learners’ cases were grouped according to chronological order (cases 1-10 and 11-20). the primary outcome was defined as the number of cases before the fellow could independently complete all steps of top-down holep without any major intraoperative complications. the secondary outcomes included the intraoperative and postoperative outcomes of both groups. the fellows’ 40 cumulative cases were then compared against retrospective data from 148 procedures conducted by their supervisor. results: there were no significant differences in patient demographics for both clinical fellows. each learner performed the first 20 cases independently without needing the supervisor to intervene. no major intraoperative complications were recorded, and there were no statistically significant differences in intraoperative and postoperative outcomes between fellows’ cases. there was a statistically significant difference between the fellows and their supervisor in terms of operative efficiency and enucleation efficiency (p < 0.001). we did not find a significant difference between the fellows and the supervisor regarding intraoperative complications, major postoperative complications, or postoperative subjective and objective parameters. conclusions: top-down holep shows promising and reproducible results in shortening holep’s learning curve. larger comparative and multi-institutional studies are warranted. key words: prostate; minimal invasive; benign prostatic hyperplasia. submitted 27 july 2024; accepted 2 august 2024 analysis of the top-down holep learning curve: a single-center experience of two clinical fellows karim daher 1, moustafa fathy 1, 2, amr hodhod 3, parsa nikoufar 1, abdulrahman alkandari 1, loay abbas 1, 4, ruba abdul hadi 1, hazem elmansy 1 1 urology department, thunder bay regional health sciences centre, northern ontario school of medicine, thunder bay, ontario, canada; 2 urology department, menoufia university, menoufia, egypt; 3 urology department, king abdulaziz medical city, national guard hospitals affairs, riyadh, saudi arabia; 4 urology department, theodor bilharz research institute, giza, egypt. doi: 10.4081/aiua.2024.12997 summary archivio italiano di urologia e andrologia 2024; 96(4):12997 k. daher, m. fathy, a. hodhod, et al. 2 before data collection, each fellow observed three topdown holep cases and assisted with seven (totaling 10 cases). once the supervisor determined the learner attained a reasonable level of confidence in technical aspects, a prospective study was initiated. after 10 procedures, the supervisor ceased actively participating in surgery but remained present to observe and assist if needed. our study involved the initial 20 consecutive procedures by 2 successive fellows (20 cases/fellow). fellow 1 operated from september 2020 to june 2021, while fellow 2 completed procedures from february to november 2022. participants were divided into group 1 (patients 1-10) and group 2 (patients 11-20). we also compared the fellows' 40 cases to their supervisor's 148 cases. the primary outcome was the number of cases needed for the fellow to independently complete all top-down holep steps without major intraoperative complications. intraoperative safety measures included capsular perforation, bleeding requiring transfusion, and bladder injury during morcellation. secondary outcomes encompassed intraoperative parameters such as operative efficiency, enucleation efficiency, morcellation time, resected weight, and postoperative results. operative efficiency, defined as the rate of prostate tissue removal during the entire holep procedure (including both enucleation and morcellation phases), was calculated by dividing the total weight of enucleated tissue (grams) by the total operative time (minutes), and expressed as grams per minute (g/min). similarly, enucleation efficiency measured the rate of tissue removal during the enucleation phase alone, excluding morcellation time. this was calculated by dividing the weight of enucleated tissue (grams) by the enucleation time (minutes), also expressed as grams per minute (g/min). we utilized a 100-w holmium:yag laser (versapulse powersuite™, lumenis, yokneam, israel). both techniques employed a 550-μm laser fiber and a 28-f continuous flow resectoscope (karl storz se & co. kg, tuttlingen, germany). enucleated tissue was morcellated with a karl storz® drillcut™ morcellator. primary laser settings for enucleation were 2 j and 40 hz and 2 j and 20 hz for hemostasis. study population the inclusion criteria comprised males aged > 50 years with medically refractory luts due to bph, international prostate symptom score (ipss) ≥ 15, quality of life (qol) score ≥ 3, and maximum flow rate (qmax) < 15 ml/sec. patients were excluded if they had previous surgical bph treatment, a history of prostate cancer, urethral stenosis, or neurogenic bladder, the inability to withhold anticoagulant or antiplatelet medication, and an active urinary tract infection (uti). the preoperative evaluation encompassed patient demographics, a physical examination, and a detailed medical history, including anticoagulant or antiplatelet use, history of urinary retention, and prior prostate procedures. symptom assessment included ipss and qol questionnaires. all patients received psa testing, uroflowmetry, a post-void residual (pvr) bladder scan, and transrectal ultrasound (trus) for prostate volume estimation. patients were advised that if medically feasible, they should temporarily withold their anticoagulant and antiplatelet medications before surgery for 3 days and 7 days, respectively. intraoperative parameters, postoperative outcomes, and readmission data were recorded. data on surgical parameters such as enucleation time, morcellation time, operative and enucleation efficiencies, resected weight, intraoperative complications, and the need for blood transfusion were collected. early postoperative complications with emergency room (er) visits and a failed trial of void (tov) were also recorded. surgical technique all holep procedures were performed using the topdown technique as previously described (19). briefly, the distinction between the traditional and top-down holep techniques lies in the direction and approach of enucleation. in both traditional and top-down holep, a single incision is made at the 6 o’clock position of the bladder neck for a bilobar prostate configuration. with a trilobar configuration, the bladder neck incision is made at either 5 or 7 o’clock to establish the capsular plane. the lateral lobes are then enucleated using a two-lobe approach, where one lateral lobe is followed by the combined enucleation of the other lateral lobe and the median lobe. in traditional holep, dissection follows a bottom-up approach. for the top-down technique, the anterior commissure mucosa is then incised using 2 j/20 hz, starting from the bladder neck at 12 o’clock. the incision is deepened to separate the area between the right and left adenoma until the surgical capsule is reached. once the plane between the adenoma and the surgical capsule is established, a top-down lateral lobe dissection is performed and extended anteroposteriorly towards the apical adenoma at 6 o’clock. the enucleated tissue is then morcellated using a karl storz drillcut™ (germany) morcellator. postoperative care a 3-way catheter (22 f, with 75 ml of sterile water in the balloon) was inserted postoperatively for all patients. they were kept on continuous bladder irrigation (cbi) with an overnight admission, followed by a trial of void (tov) within 24 hours. follow-up patients were followed up at 1, 3, and 6 months, and psa testing was performed at 3 months. postoperative complications included persistent hematuria, clot retention, urethral strictures, and bladder neck contraction. stress urinary incontinence (sui) was assessed by a history of involuntary urine leakage during coughing or sneezing and the use of pads to prevent wetting. additionally, sui was evaluated by directing the patient to cough with a full bladder and observing urine passage. statistical analyses data collection and statistical analysis were performed using the statistical package for the social sciences (spss® ibm®) version 26. categorical variables were reported as numbers and percentages and analyzed using the chi-squared test, while continuous data were presented as medians and ranges and evaluated using the mann-whitney u test. a pvalue of < 0.05 was considered statistically significant. archivio italiano di urologia e andrologia 2024; 96(4):12997 3 holep learning curve for fellows results no significant differences in demographics and preoperative data were observed between the early and later cases for both fellows. similarly, when comparing the 20 cases of fellow 1 and fellow 2, no differences were observed in patient demographics, perioperative, or early postoperative outcomes (table 1a). operative and postoperative outcomes operative efficiency, enucleation time, and enucleation efficiency were not significantly different between the initial and subsequent 10 cases for both fellows. fellow 1's median enucleation efficiency was 0.94 g/min for initial cases and 1.12 g/min for subsequent cases (p = 0.739). the second fellow's median enucleation efficiency was 1.11 g/min for the first 10 cases and 0.85 g/min for subsequent procedures (p = 0.436). when comparing the two fellows, there were no significant differences in operative efficiency, enucleation time, or enucleation efficiency. fellow 1's median enucleation efficiency was 1.02 g/min, compared to fellow 2's median of 1.07 g/min (p = 0.947). no intraoperative complications or need for blood transfusion were recorded in either group. successful first tov, as well as readmission and retreatment rates, were similar across both fellows' cases. none of the patients in either group experienced clavien ii-v complications. however, one participant from each fellow's cohort had a failed tov (clavien i), both of whom passed their tov within one week. five incidents of prolonged or severe hematuria requiring er visits were recorded (2 for fellow 1 and 3 for fellow 2), all of which were managed conservatively with foley catheter reinsertion and cbi (clavien i); three patients were readmitted. none of the patients experienced any cardiovascular events or utis. no significant differences in prostate weight or psa reduction percentages were observed between both learners (table 1a). additionally, postoperative outcomes at 1, 3, and 6 months showed no significant differences between the two fellows. sui rates were low and comparable across all groups (table 1b). tables 1a and 1b demonstrate that both learners had comparable perioperative and postoperative outcomes for all 20 procedures, with no statistically significant differences. comparison with supervisor's performance table 2 compares clinical outcomes between cases managed by the fellows and their supervisor. regarding operative efficiency, the supervisor demonstrated a median of table 1a. comparison of patient demographics, perioperative and early postoperative outcomes between the fellows’ 20 cases. parameters fellow 1 fellow 2 p 20 cases 20 cases number of participants n 20 20 age years median (range) 70 (52-88) 70 (59-87) 0.947 indication n (%) luts 13 (65) 12 (60) 0.500 retention 7 (35) 8 (40) hematuria asa score n (%) i 7 (35) 7 (35) 0.132 ii 12 (60) 11 (55) iii 1 (5) 2 (10) iv preoperative prostate size by trus cc median (range) 91 (56-210) 115 (80-206) 0.108 preoperative ipss median (range) 21 (15-30) 23.5 (17-34) 0.437 preoperative qol median (range) 5 (3-6) 4 (3-6) 0.689 preoperative qmax ml/s median (range) 10 (6-14) 9 (1-13.6) 0.765 preoperative pvr ml median (range) 270 (20-500) 170 (35-650) 0.437 enucleated tissue weight g median (range) 71 (35-140) 78 (33-240) 0.495 operative efficiency g/min median (range) 0.83 (0.4-1.27) 0.81 (0.48-1.29) 0.947 enucleation time min median (range) 70 (50-92) 71 (45-159) 0.327 enucleation efficiency g/min median (range) 1.02 (0.5-1.72) 1.07 (0.52-1.72) 0.947 blood transfusion n (%) 0 0 successful first tov n (%) 19 (95) 19 (95) 0.756 intraoperative complications n (%) 0 0 readmission n (%) 1 (5) 2 (10) 0.5 retreatment n (%) 0 0 postoperative complications n (%) clavien i 3 (15) 4 (20) 0.553 clavien ii 0 0 clavien iii 0 0 prostate weight reduction % median (range) 80 (62-95) 81 (35-93) 0.777 psa reduction % median (range) 84 (8-99) 91 (32-98) 0.142 luts: lower urinary tract symptoms; asa: american society of anesthesiologists; trus: transrectal ultrasound; ipss: international prostate symptom score; qol: quality of life; qmax: maximum urinary flow rate; pvr: post-void residual urine test; tov: trial of void; psa: prostate-specific antigen. table 1b. comparison of postoperative outcomes between the fellows’ 20 cases at 1, 3 and 6 months. parameters fellow 1 fellow 2 p 20 cases 20 cases 1 month postoperative ipss median (range) 8.5 (1-24) 8 (2-18) 0.988 qol median (range) 2.5 (0-6) 2 (0-5) 0.696 qmax ml/s median (range) 23 (11-50) 17 (6-40) 0.31 pvr ml median (range) 44 (0-390) 47 (0-160) 0.897 sui n (%) 3 (15) 3 (15) 0.5 3 months postoperative ipss median (range) 7.5 (0-24) 5.5 (1-23) 0.347 qol median (range) 2.5 (0-5) 1 (0-5) 0.081 qmax ml/s median (range) 20 (11-34) 21 (13-45) 0.72 pvr ml median (range) 40 (0-130) 63 (0-150) 0.281 sui n (%) 1 (5) 2 (10) 0.5 6 months postoperative ipss median (range) 6 (2-16) 5 (1-10) 0.126 qol median (range) 2 (0-4) 1 (0-3) 0.111 qmax ml/s median (range) 20 (8-39) 22 (15-41) 0.532 pvr ml median (range) 49 (0-130) 24 (0-110) 0.48 sui n (%) 0 0 ipss: international prostate symptom score; qol: quality of life; qmax: maximum urinary flow rate; pvr: post-void residual urine test; tov: trial of void; sui: stress urinary incontinence. archivio italiano di urologia e andrologia 2024; 96(4):12997 k. daher, m. fathy, a. hodhod, et al. 4 1.41 g/min, exceeding the fellows' 0.83 g/min, p < 0.001. figure 1 illustrates the differences in enucleation efficiency between the two fellows and their supervisor. two patients in the supervisor's cohort experienced intraoperative superficial bladder mucosal injury during morcellation. postoperative outcomes, including successful first tov, did not show statistical significance. clavien i complications were lower in the supervisor's cohort (9.5%) compared to the learners' group (17.5%), p = 0.001. conversely, two cases of prolonged or severe hematuria were recorded in the supervisor's group, with one occurring after the patient resumed antiplatelet therapy and was managed conservatively. in the first postoperative month, sui occurred in 15% of the fellows' cases, significantly higher than the 6.1% observed in the supervisor's group, p = 0.030. at three months follow-up, sui was present in 7.5% of the fellows' cases compared to 2.7% in the supervisor's cases. one patient (0.7%) from the supervisor's cohort had sui at 6 months postoperative, while no cases of sui were reported in the fellows' group. discussion although the term “learning curve” lacks a standardized definition, it's often described as the number of cases required to accomplish procedures efficiently, with acceptable complication rates and fair health outcomes (20). our study sought to assess whether the topdown technique could decrease holep's learning curve by comparing the performance and outcomes of two fellows with their experienced supervisor. to our knowledge, this is the first comparative study assessing procedural efficacy, safety profiles, and learning curves of top-down holep in a supervised training environment. both fellows had prior experience with turp. each learner observed 3 cases while receiving practical instructions. the fellows progressively assisted and performed parts of surgery under supervision (7 cases/fellow), leading to eventual independent performance. this teaching approach is comparable to el-hakim and elhilali (21), where a urology resident observed 10 holep procedures performed by an experienced supervisor. afterwards, the resident operated on 27 patients, divided into two groups (15 and 12 participants), with minimal to moderate mentor intervention. the greater number of observed cases reported by el-hakim and elhilali (21) compared to our study (10 vs. 3, respectively) underscores the "easierto-grasp" characteristic of the top-down technique over traditional holep. similar to our study, the performance and outcomes of both initial and subsequent cases exhibtable 2. comparison of patient demographics, perioperative and postoperative outcomes between the fellows’ and supervisor’s cases. parameters cumulative cases cases p of clinical fellows of supervisor number of participants n 40 148 age years median (range) 70 (52-88) 76 (55-93) < 0.001 indication n (%) luts 25 (62.5) 59 (39.9) 0.004 retention 15 (37.5) 66 (44.5) hematuria 0 23 (15.6) asa score n (%) i 14 (35) 29 (19.6) 0.002 ii 23 (57.5) 112 (75.7) iii 3 (7.5) 7 (4.7) iv preoperative prostate size by trus cc median (range) 99 (56-210) 116 (42-273) 0.059 preoperative ipss median (range) 23 (15-34) 23 (10-35) 0.529 preoperative qol median (range) 5 (3-6) 5 (2-6) 0.810 preoperative qmax ml/s (median (range) 8.7 (1-14) 6.7 (2.6-14) 0.013 preoperative pvr ml median (range) 230 (20-650) 400 (5-2600) 0.019 enucleated tissue weight g median (range) 77 (33-240) 80 (25-242) 0.288 operative efficiency g/min median (range) 0.83 (0.4-1.29) 1.41 (1.2-1.81) < 0.001 enucleation time min median (range) 70 (45-159) 42 (10-96) < 0.001 enucleation efficiency g/min median (range) 1.06 (0.5-1.72) 1.6 (1.25-2.48) < 0.001 blood transfusion n (%) 0 0 successful first tov n (%) 38 (95) 136 (91.9) 0.394 intraoperative complications n (%) 0 2 (1.4) 0.293 readmission n (%) 3 (7.5) 3 (2.0) 0.080 retreatment n (%) 0 0 postoperative complications n (%) clavien i 7 (17.5) 14 (9.5) 0.001 clavien ii 0 0 clavien iii 0 0 prostate weight reduction % median (range) 81 (35-95) 82 (55-97) 0.437 psa reduction % median (range) 88 (8-99) 88 (10-99) 0.964 1 month postoperative ipss median (range) 8 (1-24) 6 (0-25) 0.067 qol median (range) 2 (0-6) 1 (0-6) 0.073 qmax ml/s median (range) 19 (6-50) 25 (6-73) 0.071 pvr ml median (range) 45 (0-390) 47 (0-400) 0.328 sui n (%) 6 (15) 9 (6.1) 0.030 3 months postoperative ipss median (range) 6.5 (0-24) 4 (0-21) 0.287 qol median (range) 2 (0-5) 1 (0-6) 0.064 qmax ml/s median (range) 20 (11-45) 24 (9-49) 0.188 pvr ml median (range) 50 (0-150) 48 (0-200) 0.937 sui n (%) 3 (7.5) 4 (2.7) 0.167 6 months postoperative ipss median (range) 5 (1-16) 3 (0-30) 0.061 qol median (range) 1 (0-4) 0 (0-5) 0.204 qmax ml/s median (range) 21 (8-41) 26 (1-76) 0.109 pvr ml median (range) 44 (0-130) 45 (0-370) 0.962 sui n (%) 0 1 (0.7) luts: lower urinary tract symptoms; asa: american society of anesthesiologists; trus: transrectal ultrasound; ipss: international prostate symptom score; qol: quality of life; qmax: maximum urinary flow rate; pvr: post-void residual urine test; tov: trial of void; psa: prostate-specific antigen; sui: stress urinary incontinence. archivio italiano di urologia e andrologia 2024; 96(4):12997 5 holep learning curve for fellows ited no significant differences, indicating consistency and rapid mastery of the procedural skill set. conversely, seki et al. suggested that holep could be learned without a qualified instructor, but achieving competence typically required > 50 cases of operational experience (22). the higher number of cases to achieve competency compared to our study confirms that the topdown approach, combined with structured training, may ease and shorten the holep learning curve for novices. despite training at different intervals, the fellows exhibited no significant differences in cumulative case experiences, affirming the efficacy and consistency of our teaching approach. kim et al. demonstrated the reproducibility of conventional holep by assessing the procedure at two hospitals on different continents (23). prostate volume is considered pivotal in the early learning phase. shah and colleagues reported that operators achieved proficiency in holep after a mean of 20 cases, but only for small prostates (8). further learning was required to advance from small to intermediate glands and larger prostates. this observation was supported by a larger retrospective study involving 1,113 patients and 39 surgeons (24), which also corroborated the findings of moody et al. (25). the latter study suggested completing at least 30 procedures on smaller glands (< 50 g) before attempting to enucleate larger adenomas with standard holep. the mean prostate volume of patients operated on by both fellows in our study exceeded 90 cc, surpassing the average volumes reported in various publications assessing the holep learning curve for inexperienced surgeons or trainees. from our observations, attempting to enucleate glands < 50 g would be challenging and not advisable for novice holep learners. our findings indicate no significant differences in operative efficiency, enucleation time, or enucleation efficiency between both fellows’ initial and subsequent cases. these findings contrast with seki et al.'s data, which demonstrated a significant increase in enucleation efficiency with growing experience when comparing initial to last standard holep cases (22). they reported that the average tissue enucleation efficiency significantly increased from 0.29 g/min to 0.75 g/min between the initial and final 10 cases, respectively. moreover, placer et al. studied 125 patients and found that enucleation efficiency increased with the number of procedures, eventually reaching a plateau (9). these results indicate potential differences in operative efficiency improvement patterns between conventional and top-down holep with increasing experience, suggesting that standard holep may show more improvement with additional cases. consistent performance across early and later cases in our study extends to postoperative outcomes. our results align with those of seki et al., who found no change in postoperative parameters (22). comparative analysis of performance with supervisor comparative analysis of both fellows to their supervisor when performing the top-down technique revealed valuable insights, particularly concerning surgical efficiency and postoperative outcomes. regarding enucleation efficiency, an objective parameter for gauging operative learning, the fellows had a median of 1.06 g/min, lower than their supervisor's median of 1.6 g/min. these findings emphasize the importance of progressive experience for enhancing operative efficiency in holep, regardless of the technique utilized. despite using a similar approach to condensing the learning process into a short, supervised figure 1. comparison of median enucleation efficiency between the fellows and their supervisor. archivio italiano di urologia e andrologia 2024; 96(4):12997 k. daher, m. fathy, a. hodhod, et al. 6 period, el-hakim and elhilali found that resident-performed cases yielded outcomes comparable to those of an experienced urologist, possibly due to increased supervisor intervention in the initial cases of their study (21). although we noted differences in operative performance, early postoperative outcomes such as successful tov were similar between the learners and their supervisor. similarly, no significant differences were observed in postoperative parameters, including ipss, qol, qmax, and pvr. these findings align with data from shah et al. (8) and shigemura and colleagues (24), which showed no change or improvement in these parameters with increasing surgical experience. in the initial 4 weeks post-holep, transient sui can significantly bother patients. predictors of transient sui following holep are multifaceted and can be associated with either the patient or the procedure, as reported by several studies (12, 13, 26-29). one purported benefit of top-down holep is reducing sphincter overstretching by cutting the mucosal flap attached to it, potentially reducing transient sui. however, our recent randomized controlled trial comparing top-down and traditional holep demonstrated that at 3 months postoperative, two patients (4.1%) in the conventional and one (2.2%) in the top-down holep group experienced sui without significant difference (30). in our analysis, sui rates one month postoperatively were higher in the fellows' cumulative cases (15%) compared to the supervisor's (6.1%), p = 0.030. however, no differences were observed at the three-month follow-up. the high sui rate initially among the fellows' group may be attributed to challenges of the early learning curve, as noted by placer et al. (9). however, these early findings may not fully demonstrate the impact of experience on incontinence rates, as transient sui is typical in the early postoperative phase. the comparable sui rates at 3 months indicate that with 20 cases, the fellows attained an early proficiency level, yielding low sui rates similar to experienced surgeons. numerous studies have demonstrated that achieving low sui rates requires an initial experience of 20 cases. shigemura et al. (24) reported that surgeons' experience beyond 20 procedures significantly reduced sui at three months. elshal et al.'s prospective study also noted a significant decrease in sui rates after 20 procedures (12). limitations we acknowledge certain limitations of our research; it is a single-center study with a small sample size, which may restrict the generalizability of our findings. additionally, the study involved retrospective data for the supervisor, which may introduce bias and confounding variables. however, it involved prospective data collection for both fellows. larger prospective studies are needed to effectively validate findings and compare traditional versus top-down holep techniques. conclusions our findings suggest that implementing the top-down holep technique in a supervised educational program ensures safety and comparable outcomes to experienced supervisors, regardless of trainees' familiarity with conventional holep. this approach accelerates learning and demonstrates potential in urological training. further research is needed to validate its efficacy and safety across diverse clinical settings. acknowledgment we would like to thank dr. walid shahrour and dr. husain alaradi for their valuable advice. references 1. elzayat ea, habib ei, elhilali mm. holmium laser enucleation of the prostate: a size-independent new "gold standard". urology 2005; 66(5 suppl):108-13. 2. van rij s, gilling pj. in 2013, holmium laser enucleation of the prostate (holep) may be the new 'gold standard'. curr urol rep 2012; 13:427-32. 3. yin l, teng j, huang cj, et al. holmium laser enucleation of the prostate versus transurethral resection of the prostate: a systematic review and meta-analysis of randomized controlled trials. j endourol 2013; 27:604-11. 4. naspro r, suardi n, salonia a, et al. holmium laser enucleation of the prostate versus open prostatectomy for prostates >70 g: 24month follow-up. eur urol 2006; 50:563-8. 5. ibrahim a, alharbi m, elhilali mm, et al. 18 years of holmium laser enucleation of the prostate: a single center experience. j urol 2019; 202:795-800. 6. robert g, cornu jn, fourmarier m, et al. multicentre prospective evaluation of the learning curve of holmium laser enucleation of the prostate (holep). bju int 2016; 117:495-9. 7. brunckhorst o, ahmed k, nehikhare o, et al. evaluation of the learning curve for holmium laser enucleation of the prostate using multiple outcome measures. urology 2015; 86:824-9. 8. shah hn, mahajan ap, sodha hs, et al. prospective evaluation of the learning curve for holmium laser enucleation of the prostate. j urol 2007; 177:1468-74. 9. placer j, gelabert-mas a, vallmanya f, et al. holmium laser enucleation of prostate: outcome and complications of self-taught learning curve. urology 2009; 73:1042-8. 10. kampantais s, dimopoulos p, tasleem a, et al. assessing the learning curve of holmium laser enucleation of prostate (holep): a systematic review. urology. 2018; 120:9-22. 11. kim kh, kim kt, oh jk, et al. enucleated weight/enucleation time, is it appropriate for estimating enucleation skills for holmium laser enucleation of the prostate? a consideration of energy consumption. world j mens health. 2018; 36:79. 12. elshal am, nabeeh h, eldemerdash y, et al. prospective assessment of learning curve of holmium laser enucleation of the prostate for treatment of benign prostatic hyperplasia using a multidimensional approach. j urol. 2017; 197:1099-107. 13. endo f, shiga y, minagawa s, et al. anteroposterior dissection holep: a modification to prevent transient stress urinary incontinence. urology. 2010; 76:1451-1455. 14. minagawa s, okada s, sakamoto h, et al. en-bloc technique with anteroposterior dissection holmium laser enucleation of the prostate allows a short operative time and acceptable outcomes. urology. 2015; 86:628-633. archivio italiano di urologia e andrologia 2024; 96(4):12997 7 holep learning curve for fellows 15. gong yg, he dl, wang mz, et al. holmium laser enucleation of the prostate: a modified enucleation technique and initial results. j urol. 2012; 187:1336-1340 16. rivera me, lingeman je, krambeck ae. holmium laser enucleation of the prostate. j endourol. 2018; 32(suppl 1):s7-9. 17. press b, ghiraldi e, kim dd, et al. "en-bloc" enucleation with early apical release compared to standard holmium laser enucleation of the prostate: a retrospective pilot study during the initial learning curve of a single surgeon. urology. 2022; 165:275-9. 18. york ne, dauw ca, borofsky ms, et al. v5-08 “topdown” holmium laser enucleation of the prostate (holep) technique. j urol. 2017; 197:e601 19. hodhod a, oquendo f, tablowski t, et al. 'top-down' holmium laser enucleation of the prostate. report of initial cases performed by a single surgeon. arab j urol 2020; 19:130-6. 20. herrell sd, smith ja, jr. robotic-assisted laparoscopic prostatectomy: what is the learning curve? urology. 2005; 66(5 suppl):105-7. 21. el-hakim a, elhilali mm. holmium laser enucleation of the prostate can be taught: the first learning experience. bju int. 2002; 90:863-9. 22. seki n, mochida o, kinukawa n, et al. holmium laser enucleation for prostatic adenoma: analysis of learning curve over the course of 70 consecutive cases. j urol. 2003; 170:1847-50. 23. kim sc, matlaga br, kuo rl, et al. holmium laser enucleation of the prostate: a comparison of efficiency measures at two institutions. j endourol. 2005; 19:555-8. 24. shigemura k, yamamichi f, kitagawa k, et al. does surgeon experience affect operative time, adverse events and continence outcomes in holmium laser enucleation of the prostate? a review of more than 1,000 cases. j urol. 2017; 198:663-70. 25. moody ja, lingeman je. holmium laser enucleation for prostate adenoma greater than 100 gm.: comparison to open prostatectomy. j urol. 2001; 165:459-62 26. tunc l, yalcin s, kaya e, et al. the "omega sign": a novel holep technique that improves continence outcomes after enucleation. world j urol 2021; 39:135-41 27. lerner lb, tyson md, mendoza pj. stress incontinence during the learning curve of holmium laser enucleation of the prostate. j endourol 2010; 24:1655-8. 28. cornwell lb, smith ge, paonessa je. predictors of postoperative urinary incontinence after holmium laser enucleation of the prostate: 12 months follow-up. urology 2019; 124:213-7. 29. elmansy hm, kotb a, elhilali mm. is there a way to predict stress urinary incontinence after holmium laser enucleation of the prostate? j urol 2011; 186:1977-81. 30. elmansy h, abbas l, fathy m, et al. top-down holmium laser enucleation of the prostate (holep) versus traditional holep for the treatment of benign prostatic hyperplasia (bph): 1-year outcomes of a randomized controlled trial. prostate cancer prostatic dis. 2024; 27:462-8. correspondence karim daher karim.daher01@lau.edu moustafa fathy moustafa.mf9@gmail.com parsa nikoufar parsa.nikoofar@gmail.com abdulrahman alkandari dr.aaa.186@gmail.com loay abbas loay46@gmail.com ruba abdul hadi ruba.ahadi@gmail.com urology department, thunder bay regional health sciences centre, northern ontario school of medicine, thunder bay, ontario, canada amr hodhod amrwuk@yahoo.co.uk urology department, king abdulaziz medical city, national guard hospitals affairs, riyadh, saudi arabia hazem elmansy, md, msc, frcsc (corresponding author) hazem.mansy@rocketmail.com associate professor & program director of the minimally invasive urologic surgery fellowship program, thunder bay regional health sciences centre, northern ontario school of medicine, thunder bay, ontario, canada 146 court street south, thunder bay, on, p7b 2x6 conflict of interest: h. elmansy is an investigator for urotronic inc. (laborie) and zenflow inc. he previously received honoraria and a research grant from boston scientific. the other co-authors do not have a conflict of interest to disclose. stesura seveso 97archivio italiano di urologia e andrologia 2022; 94, 1 review no conflict of interest declared. introduction percutaneous and retrograde endourological procedures are widely used for the removal of renal stones. these treatments ensure high stone free rates and are associated with a relatively low morbidity. however, infectious complications are not uncommon in both. after retrograde intrarenal surgery (rirs), the rate of febrile urinary tract infections can range between 7.6 and 13.4% (1). risk factors include preoperative pyuria, stone size, struvite stone composition, operating time, irrigation flow rate and volume, size of ureteral access sheath, presence of residual fragments, history of urinary tract infections, and comorbidities (2-5). the incidence of fever after percutaneous nephrolithotomy (pcnl) was reported to range between 10.4% and to 18.9%, with urosepsis in 0.9% to 4.7% of cases. longer operating time, higher number of punctures, tract size, staghorn stone, severe preoperative hydronephrosis, preoperative stenting, history of recurrent urinary tract infection, renal failure, and type 2 diabetes were found to be risk factors (6-9). the aim of this systematic review was to assess the reported rate of infectious complications in relation to the type of endourologic procedure, the methods used in the procedure and the antibiotic prophylaxis applied. materials and methods this review was conducted in accordance with the preferred reporting items for systematic reviews and metaanalyses (prisma) guidelines (10) after being registered on the prospero platform (crd42021283094). two electronic databases (pubmed and embase) were searched for articles published up to september 30th, 2021. objective: endourological treatment is associated with a risk of postoperative febrile urinary tract infections and sepsis. the aim of this study was to review the reported rate of infectious complications in relation to the type and modality of the endourologic procedure. methods: this systematic review was conducted in accordance with the prisma guidelines. two electronic databases (pubmed and embase) were searched. out of 243 articles retrieved we included 49 studies after full-text evaluation. results: random-effects meta-analysis demonstrated that retrograde intrarenal surgery (rirs) and percutaneous nephrolithotomy (pcnl) were associated with not significantly different odds of getting fever (or = 1.54, 95% ci: 0.99 to 2.39; p = 0.06) or sepsis (or = 1.52, 95% ci: 0.37 to 6.20, p = 0.56). the odds of getting fever were not significantly different for mini pcnl compared to standard pcnl (or = 1.11, 95% ci: 0.85 to 1.44; p = 0.45) and for tubeless pcnl compared to standard pcnl (or = 1.34 95% ci: 0.61 to 2.91, p = 0.47). however, the odds for fever after pcnl with suctioning sheath were lower than the corresponding odds for standard pcnl (or = 0.37, 95% ci: 0.20 to 0.70, p = 0.002). the odds of getting fever after pcnl with perioperative prophylaxis were not different from the corresponding odds after pcnl with perioperative prophylaxis plus a short oral antibiotic course (before or after the procedure) (or = 1.31, 95% ci: 0.71 to 2.39, p = 0.38). conclusions: the type of endourological procedure does not appear to be decisive in the onset of infectious complications, although the prevention of high intrarenal pressure during the procedure could be crucial in defining the risk of infectious complications. key words: kidney calculi; percutaneous nephrolithotomy; retrograde intrarenal surgery; ureteroscopy; lithotripsy; systemic inflammatory response syndrome; sepsis; fever; urinary tract infection. submitted 15 january 2022; accepted 1 february 2022 infectious complications of endourological treatment of kidney stones: a meta-analysis of randomized clinical trials rawa bapir 1, 13, kamran hassan bhatti 2, 13, ahmed eliwa 3, 13, herney andrés garcía-perdomo 4, 13, nazim gherabi 5, 13, derek hennessey 6, 13, panagiotis mourmouris 7, 13, adama ouattara 8, 13, gianpaolo perletti 9, 10, 13, joseph philipraj 11, 13, alberto trinchieri 12, 13, noor buchholz 13 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 8 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 9 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 10 faculty of medicine and medical sciences, ghent university, belgium; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 urology school, university of milan, milan, italy; 13 u-merge ltd. (urology for emerging countries), london-athens-dubai *. * u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com doi: 10.4081/aiua.2022.1.97 summary archivio italiano di urologia e andrologia 2022; 94, 1 r. bapir, k. hassan bhatti, a. eliwa, et al. 98 search was performed including mesh terms (percutaneous nephrolithotomy, ureteroscopy, lithotripsy, kidney calculi, systemic inflammatory response syndrome, sepsis, fever, urinary tract infections) and was implemented by free-text terms (micro-percutaneous nephrolithotomy, pcnl, minipcnl, retrograde intrarenal surgery, flexible ureteroscopy, rirs, furs, ecirs). the following search terms were used: (percutaneous nephrolithotomy or ureteroscopy or lithotripsy or micro-percutaneous nephrolithotomy or pcnl or mini-pcnl or retrograde intrarenal surgery or flexible ureteroscopy or rirs or furs or ecirs) and kidney calculi and (systemic inflammatory response syndrome or sepsis or fever or urinary tract infections). relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, www.clinicaltrials.gov, www.clinicaltrialsregister.eu, and others). during the initial screening of the retrieved records we considered randomized controlled trials (rcts), with an open-label or single/double blinded design including participants without restriction of age or gender or ethnicity, treated for renal stones with percutaneous endoscopic procedures (including standard pcnl, mini-pcnl, ultraminior micro-pcnl) and retrograde endoscopic procedures (flexible ureteroscopy or rirs). article reporting comparisons between endoscopic combined intrarenal surgery (ecirs) and single endoscopic procedures (both percutaneous and retrograde) were also initially examined. in this systematic review we included articles reporting the comparison of infectious complication rates in: 1) pcnl vs rirs, 2) standard pcnl vs miniaturized pcnl, 3) tubeless vs non tubeless pcnl, 4) pcnl or rirs with/without use of suctioning sheath, and 5) pcnl/rirs under different modalities of antibiotic prophylaxis. the following outcomes were considered: fever > 38°c or sepsis according to systemic inflammatory response syndrome (sirs) or sequential organ failure assessment (sofa) scores. the systemic inflammatory response syndrome (sirs) score had been used since 1991. it is calculated based on the presence of the following criteria: temperature > 38°c or < 36°c, heart rate > 90/minute, respiratory rate > 20/minute, wbc > 12,000 or < 4,000 (11). the sofa score was introduced by the sepsis-3 task force in 2016. the quick sofa (qsofa) score is a simpler scoring system based on the presence of a respiratory rate ≥ 22 /min, a systolic blood pressure ≤ 100 mmhg, and altered mental status (12). title and abstract screening to exclude documents that did not meet the inclusion criteria were performed independently by two authors. controversies were resolved by a third researcher. duplicate references were excluded and full texts of the screened articles were analyzed to confirm their inclusion in the review. a prisma flow diagram was drawn to illustrate the results of the study selection process (figure 1). data extraction was conducted by two authors using a standardized form. the following information was obtained from each study: author(s), publication year, study design, population, intervention, rate of infectious complications (fever, sirs, sepsis) (see supplementary materials pico tables). the risk of bias of randomized controlled trials was assessed using the risk of bias (rob) 2 assessment tool as prescribed by the cochrane handbook (13). the quality of each study was independently assessed by two reviewers (dh and hag-p) against pre-defined criteria in relation to the randomization process (d1), deviations from the intended interventions (d1), missing outcome data (d3), measurement of the outcome (d4) and selection of the reported result (d5). disagreements were resolved by discussion. the presence of risk of bias was not used as a criterion to exclude studies from this review or from meta-analysis (see supplementary materials rob). statistical analysis was performed using the revman5 software. dichotomous data (presence/absence of infectious complications) and number of per-protocol or intent-tofigure 1. flow chart. 99archivio italiano di urologia e andrologia 2022; 94, 1 infectious complications of endourology for kidney stones treat patients were extracted to calculate odds ratios (or), confidence intervals (ci) to odds-ratios, and z statistics (random-effects model, mantel-haenszel method). forest plots were drawn in the presence of more than three studies. heterogeneity was assessed by i^2 statistics, reported with 95% cis, and interpreted as of lesser importance (≤ 40%), moderate (30%-60%), substantial (50%-90%) or considerable (≥ 75%), according to cochrane criteria. summary of findings tables for comparisons outlined in forest plots were prepared. the quality of evidence was rated according to grade criteria (see supplementary materials summary of findings). funnel plots were drawn to assess report bias. publication bias was assessed by visually inspecting the funnel plots (see supplementary materials publication bias). if a potential reporting bias was suspected, the egger’s regression and begg’s correlation tests were applied to assess the significance of funnel plot asymmetry and to confirm the perceived publication bias. asymmetry tests were performed using the metaessentials 1 software (rotterdam school of management, erasmus university, the netherlands). the ‘trim and fill’ missing study imputation approach was applied to asymmetric funnel plots and adjusted overall effect sizes were calculated. results from our primary search we retrieved 48 articles from pubmed, 176 from embase and 19 from other sources. title and abstract screening allowed us to select 91 articles (21 from pubmed, 62 from embase and 8 from other sources), that were reduced to 76 after removal of 15 duplicates. after full-text evaluation, 27 articles were excluded (2 articles reporting about pediatric populations, 4 articles reporting data of patients which were part of studies already included in this review, 13 articles for insufficient reporting, 6 articles dealing with a topic not included in the analysis, and 2 articles reporting the results of non-randomized studies) (table 1). finally, 49 studies were included in qualitative analysis (14-62), of which 39 were suitable for quantitative analysis. rirs vs pcnl we retrieved 20 articles (6 from pubmed, 11 from embase, 3 from other sources). after removal of 4 duplicates and one article involving a pediatric population, 15 studies were included in the analysis (14-28). out of 15 studies, 11 evaluated post-operative fever (14-16, 18, 2023, 25, 27, 28), 2 sepsis (17, 24), and 2 both post-operative fever and sepsis (19, 26). standard pcnl vs mini/ultra mini/supermini/micro pcnl we retrieved 17 articles (1 from pubmed, 14 from embase, 2 from other sources). after removal of one duplicate, 16 full-text articles were evaluated. two articles were excluded because they reported data from the same study, and 5 more for insufficient data reporting. finally, 8 articles were included in the analysis (29-36) and one article reporting a comparison of minipcnl with ultramini-pcnl (37) was considered for qualitative analysis. standard pcnl vs tubeless pcnl we retrieved 21 articles (4 from pubmed, 17 from embase). after removal of 3 duplicates, 18 full-text articles were evaluated. nine articles were excluded (one involving a pediatric population, 5 for insufficient reporting, 2 comparing tubeless pcnl within different size tracts, and 1 not randomized). out of the 9 articles included in the analysis, 6 articles compared tubeless with standard pcnl (38-43), 2 articles compared tubeless pcnl with tubeless pcnl with use of sealant (44, 45), and one study tubeless pcnl with and without infiltration of the tract with bupivacaine (46). standard pcnl/rirs vs vacuum-assisted we retrieved 11 articles (2 from pubmed 9 from embase). after exclusion of 2 duplicates, 9 articles were included for full text evaluation: 2 were excluded because they reported data of patients which were part of studies already included in this review, 2 because they reported series of ureteral stones, and 1 for its retrospective design. out of the remaining 4 articles, 3 reported about the use of a vacuum-assisted access sheath for pcnl (47-49), and one the use of ureteral access sheaths for rirs (50). perioperative prophylaxis we retrieved 22 articles (8 from pubmed, 11 from embase and 3 from other sources). after removal of 5 duplicates, 17 articles were evaluated by full-text reading. two articles were excluded because they were off-topic (comparison with open surgery, ureteral stones) and 3 because of incomplete reporting. table 1. results of the selection process divided by topic and procedure. pubmed embase other sources total duplicates evaluated excluded included rirs vs pcnl 6 11 3 20 4 16 1 15 spcnl vs mini 1 14 2 17 1 16 7 9 tubeless 4 17 0 21 3 18 9 9 sheath 2 9 0 11 2 9 5 4 prophylaxis 8 11 3 22 5 17 5 12 total 21 62 8 91 15 76 27 49 reasons for exclusion pediatric insufficient reporting reporting topics not population data reporting same series not included in the analysis randomized rirs vs pcnl 1 spcnl vs mini 5 2 tubeless 1 5 2 1 sheath 2 2 1 prophylaxis 3 2 total 2 13 4 6 2 archivio italiano di urologia e andrologia 2022; 94, 1 r. bapir, k. hassan bhatti, a. eliwa, et al. 100 out of the 12 remaining articles (51-62), one study compared perioperative antibiotic prophylaxis with a short course of antibiotics in patients at high risk for infectious complications (51), 5 studies (52-56) compared the effect of perioperative antibiotic prophylaxis with a single dose (or with two doses 24-48 hours apart) with a more complex strategy associating perioperative prophylaxis with a short course of antibiotic in the preoperative or postoperative period, 2 studies compared the results of perioperative prophylaxis with different antibiotics (57, 58), and 2 studies compared both perioperative prophylaxis with different antibiotics and different strategies of antibiotic prophylaxis (59, 60). finally, two randomized placebo-controlled studies evaluated the outcome of antibiotic prophylaxis in patients who underwent pcnl or rirs (61, 62). risk of bias of the 49 studies, 25 described methods of randomization with low risk of bias, 17 with unclear risk and 7 with high risk. we judged the risk of deviations from the intended intervention as low in 24 studies, unclear in 22 and high in 3. missing outcome data was judged low in 35 studies and unclear in 14. risk of bias in measurement of outcome was considered low in 44 studies and unclear in 5 and risk of bias in selection of the reported results was judged low in 38 studies, unclear in 10 and high in one. in total risk of bias was considered low in 10, unclear in 28 and high in 11. meta-analysis rirs vs pcnl random-effects meta-analysis revealed that retrograde intrarenal surgery (rirs) and percutaneous nephrolithotomy (pcnl) were not associated with significantly different odds of getting fever (or = 1.54, 95% ci: 0.99 to 2.39; 13 trials, 1285 participants, z = 1.91, p = 0.06, i^2 = 0%) or sepsis (or = 1.52, 95% ci: 0.37 to 6.20; 4 trials, 428 participants, z = 0.59, p = 0.56, i^2=38%) (figures 2a, 2b). mini vs standard pcnl the odds of getting fever were not significantly different when mini-pcnl was compared to standard-pcnl (or = 1.11, 95% ci: 0.85 to 1.44; 8 trials, 2774 participants, z = 0.76, p = 0.45, i^2 = 0%) (figure 3). a study of sabnis et al., not included in the meta-analysis compared mini-pcnl (12 f) with ultramini-pcnl (7.5 f) for treating stone of a size < 1.5 cm, demonstratfigure 2a, b. odds of getting fever (plot a) or sepsis (plot b) after rirs or pcnl (plot labels: on the right: favors pcnl; on the left: favors rirs) [explanation: the gu trial favors pcnl because rirs shows more febrile events: thus the gu point is on the right: less febrile events with pcnl] b. a. 101archivio italiano di urologia e andrologia 2022; 94, 1 infectious complications of endourology for kidney stones ing comparable rates of postoperative sepsis (0/30 vs 1/30) (37). tubeless pcnl vs standard pcnl the odds for fever were not significantly different when tubeless-pcnl was compared to standard-pcnl (or = 0.75 95% ci: 0.34 to 1.63; 6 trials, 505 participants, z = 0.73, p = 0.47, i^2 = 0%) (figure 4). two studies, not included in the pooled analysis, compared the rate of infectious complications after tubeless pcnl vs. tubeless pcnl with use of sealant. shah et al (44) showed similar rates of fever after tubeless pcnl with or without sealant (1/32 vs 2/31). similar results were obtained by titaram et al. (45) with similar rates of fever (19/41 vs 15/41, p = 0.20), lower rate of sirs with use of sealant (but one case of sepsis versus none). another study compared the results of tubeless pcnl with or without infiltration with bupivacaine (rate of fever 7/46 vs 6/23, p = 0.49)(46). pcnl/rirs with suctioning sheath vs standard pcnl the odds of getting fever for pcnl with suctioning sheath were significantly lower than the odds calculated for standard pcnl using a normal amplatz sheath (or = 0.37, 95% ci: 0.20 to 0.70; 3 trials, 351 participants, z = 3.10, p = 0.002, i^2 = 0%) (figure 5). a single randomized trial not included in the meta-analysis, evaluated the risk of getting fever after rirs with the use of suctioning sheath compared to the standard procedure. eisner et al. (50) presented the results of a randomized trial including 20 patients: no infectious complication was observed in the group treated with aspiration through the access sheath, while one patient in the control group had a urinary tract infection. antibiotic prophylaxis (comparison with placebo) two studies were retrieved and not pooled, as they compared different antibacterial agents with placebo (61, 62). a multicentre randomized trial (61) compared the result of preoperative prophylaxis in pcnl with a single dose of cefotaxime (1 gr) with placebo. the rate of postoperative bacteriuria was lower in patients treated with cefotaxime although the difference was not statistically significant, likely due to the low number of patients treated with pcnl included in the study. similarly, clinical data about the rate of postoperative fever and urinary tract infection were not available because the data relative to pcnl were aggregated with those of ureterorenoscopy. a study presented the results of preoperative prophylaxis figure 3. odds of getting fever after miniaturized pcnl (mini-pcnl) compared to standard pcnl (s-pcnl). (plot labels: on the right: favors standard pcnl; on the left: favors mini-pcnl) figure 4. odds of getting fever after tubeless pcnl (tl-pcnl) compared with standard pcnl (s-pcnl) (plot labels: on the right: favors s-pcnl; on the left: favors tl-pcnl) archivio italiano di urologia e andrologia 2022; 94, 1 r. bapir, k. hassan bhatti, a. eliwa, et al. 102 of rirs with ciprofloxacin compared with placebo (62). the rate of rirs after placebo (9.9%) was not significantly different from the rate assessed following treatment with one (4.9%) or two doses of ciprofloxacin (4.2%). however, a subgroup analysis demonstrated a significantly higher risk of getting sirs in patients who received placebo for treatment of stones > 200 mm^2 compared to patients who received ciprofloxacin (18% vs single dose 4.3%, p = 0.036; vs two doses 5.5%, p = 0.044). antibiotic prophylaxis (comparison of antibiotics) four studies were retrieved and not pooled, as they compared different antibacterial agents administered according to different treatment protocols (57-60). song et al. (57) administered to patients who underwent pcnl a three-day course of oral fosfomycin (3 g/day) vs. intravenous cefuroxime (3 g/day). fosfomycin proved to be more effective than cefuroxime, exerting a high antibacterial effect on pathogens localized in the stone, thus reducing the probability of infection. postoperative fever was observed in 7/31 patients in the experimental group compared to 9/30 in the control group (p > 0.05) but sofa score was > 2 in 3/31 versus 10/30 (p < 0.05). seyrek et al. (58) did not observe significant differences in the risk of getting sirs after pcnl in patients treated with sulbactam-ampicillin versus cefuroxime (13.7 vs 17.7%, p = 0.44), though one patient in the sulbactamampicillin died of septic shock. similarly, taken et al. (59) observed no difference in the rate of sirs following pcnl in patients treated with ceftriaxone (23.3%) or cefazoline (12.5%) (p = 0.264). finally, demirtas et al. (60) found no difference in the rate of sirs after pcnl between ciprofloxacin (15.5%) and ceftriaxone (8.8% p = 0.52). perioperative vs perioperative plus additional short antibiotic prophylaxis seven studies reported the results of the comparison of perioperative antibiotic prophylaxis versus perioperative prophylaxis associated with prolonged oral administration of antibiotics in patients who underwent pcnl for stones. patients were deemed to be at low risk for infectious complications (negative preoperative urine culture, absence of hydronephrosis). two studies (seyrek 2012 and demirtas 2012) (58, 60) included data about the use of two different antibiotics, data were pooled separately. the odds for fever after pcnl with perioperative prophylaxis were not different than after pcnl with perioperative prophylaxis plus a short oral antibiotic course (before or after the procedure) (or = 0.76, 95% ci: 0.42 to 1.40; 9 trials, 720 participants, z = 0.87, p = 0.38, i^2 = 53%) (figure 6). a study (not included in the meta-analysis) (51) compared the outcome of 2 days vs. 7 days of preoperative antibiotics in patients at moderate-to-high risk for sepsis undergoing percutaneous nephrolithotomy. the sepsis rates were not different between treatment arms on unifigure 5. odds of getting fever after pcnl with suctioning sheath (pcnl + ss) compared with standard pcnl (s-pcnl) (plot labels: on the right: favors s-pcnl; on the left: favors pcnl + ss). figure 6. odds of getting fever after pcnl with perioperative prophylaxis (pp) compared with pcnl with perioperative prophylaxis plus a short oral antibiotic course (pp + soc)(plot labels: on the right: favors perioperative; on the left: favors pp + soc). 103archivio italiano di urologia e andrologia 2022; 94, 1 infectious complications of endourology for kidney stones variate analysis. however multivariate analysis showed that the risk of sepsis was increased (or = 3.1, 95% 1.18.9, p = 0.031) in patients who were treated for 2 days compared to patients who were treated for 7 days. publication bias analysis figure 1 a-f (see supplementary materials publication bias analysis) shows the funnel plots relative to the 6 pooled analyses performed in this systematic review. table 1 (supplementary materials publication bias analysis) shows the significance values of the begg’s and egger’s asymmetry tests. the only pooled analysis showing significant asymmetry (egger’s p = 0.011, begg’s p = 0.004) was the one comparing perioperative prophylaxis vs. perioperative prophylaxis plus an additional short antibiotic prophylaxis. the “trim-and-fill” strategy imputed two missing studies to the asymmetric funnel plot. the adjusted odds ratio of the funnel plot including the imputed missing studies was 0.62 (95% ci: 0.31 to 1.28). thus, despite the addition of two imputed studies, the odds ratio for this comparison remains not significant. summary of findings tables 1 a-e (supplementary materials summary of findings) present the summary of the findings of the meta-analyses, also including an evaluation of the quality of the evidence, performed according to grade criteria. the quality of the evidence was rated as low for the comparisons (i) pcnl with suctioning sheath vs. standard pcnl, and (ii) pcnl with simple perioperative antibiotic prophylaxis (pap) plus a short oral antibiotic course vs. pcnl with simple pap. the reasons for downgrading the former were risk of bias (one point) and imprecision due to the low number of participants (one point). the reasons for downgrading the latter were risk of bias (one point) and publication bias (one point). the quality of the remaining evidence was rated as moderate, mainly due to the presence of risk of bias (one point). discussion endourological treatment of kidney stones represents a considerable improvement in the management of nephrolithiasis, thanks to the reduction of morbidity and the minimal surgical impact on the urinary tract. the complications associated with this form of treatment are relatively infrequent, though serious bleeding and infectious complications can be observed. pcnl and rirs are treatment modalities that have specific indications. however, the choice of a specific procedure is based on the experience of the operating surgeon and sometimes on the patient’s preferences. in fact, kidney stones smaller than 20 mm can alternatively be treated with percutaneous or retrograde intracorporeal lithotripsy (63). in this case, the risk of complications should be taken into consideration when choosing between the two forms of treatment. retrograde and percutaneous renal stone treatment can affect the risk of infectious complications in different ways. flexible ureteroscopy can increase intrarenal pressure in relation (i) to type and rate of irrigation, or (ii) to the use and size of ureteral sheaths promoting the anterograde outflow of irrigation fluid. the increase in pressure within the urinary tract can cause an intratubular reflux of urine, with increased risk of infectious complications. percutaneous treatment does not generally involve a major increase of fluid pressure in the urinary tract, but it can cause greater local trauma and extravasation of irrigating fluid. previous meta-analyses have compared the results of percutaneous nephrolithotomy with the outcomes of retrograde intrarenal surgery for the treatment of kidney stones. however, the risk for infectious complications was not included in such analyses. zheng et al. (64) found no difference in the rate of postoperative fever (rr = 0.95, p = 0.85) between rirs and pcnl. more recently, chen et al. (65) reviewed 11 studies showing that the rate of postoperative fever or infection was not significantly different in the patients treated with pcnl compared to those treated with rirs (rr = 1.26, p = 0.29). our study included only 5 of the 11 studies considered by chen et al. because we limited our search to randomized controlled studies. furthermore, we found and included in the analysis 10 additional randomized studies. however, we were not able to demonstrate a significant superiority of one endourological procedure over the other with regards to the risk of postoperative fever or sepsis. however, we observed a trend for a higher risk of fever after rirs (or = 1.54, 95% ci: 0.99 to 2.39). it should be highlighted that most comparative studies had as a primary endpoint the evaluation of stone-free status after treatment rather than the occurrence of infectious complications. based on the results of our meta-analyses, the choice of the procedure would not seem to be a relevant factor for infectious complications after treatment. however, the risk of infectious complications could depend on how pcnl and rirs are performed. in our analysis, we were able to examine the impact of certain treatment procedures on the risk of infection. for pcnl, we considered the effect of the diameter of the scope and of the indwelling time of the nephrostomy after the procedure. for both pcnl and rirs we considered the impact of the use of a suction system for the irrigating fluid and the use of different methods of antibiotic prophylaxis. unfortunately, it was not possible to evaluate other characteristics of the interventions such as prolonged operating time (> 1 hour), type and rate of irrigation, use of sheath and pre-operative stenting (for rirs) due to the lack of information within the reports of the studies included in the analysis. the comparison of standard pcnl with miniaturized pcnl including mini-pcnl, ultramini-pcnl, and micro-pcnl showed no significant difference in the odds for infectious complications despite a higher potential intra-renal pressure with the latter two. the benefits of reduced trauma due to the smaller diameter of the scope could be counteracted by lesser control of intrarenal pressure associated with miniaturized procearchivio italiano di urologia e andrologia 2022; 94, 1 r. bapir, k. hassan bhatti, a. eliwa, et al. 104 dures. in fact, a review on the evidence related to intrarenal pressures generated during percutaneous procedures found that standard pcnl is associated with the lowest pressure values. on the contrary, pressure values during mini-pcnl can be decreased by using the vacuum-cleaner effect, but pressure might still be uncontrolled during microand ultra-mini pcnl procedures (66). we also found that avoidance of nephrostomy drainage in the postoperative period is not associated with an increased risk of infection after a standard procedure. the use of suction systems through the access sheath seems to reduce the risk of infection, since in addition to the improved clearance of fragments after lithotripsy, it allows the intrarenal pressures to be controlled and kept in the lower range. antibiotic prophylaxis to prevent the onset of infectious complications after endourological stone treatments is widely used although only limited evidence from rcts was retrieved (67). extension of oral antibiotic administration after intravenous perioperative prophylaxis, or administration of a course of antibiotic treatment in the days prior to surgery, does not seem to reduce the risk of infection in patients with low risk of infectious complications, (i.e., patients with negative preoperative urine culture and absence of hydronephrosis and urinary catheters). however, in a study that considered patients with moderate/high risk of infectious complications, administration of a 10-day course of oral nitrofurantoin before the procedure in addition to intraoperative prophylaxis was shown to reduce the risk of infectious complications after pcnl. eau guidelines (63) state that there is no "clear-cut evidence” for prevention of infection following ureterorenoscopy and percutaneous stone removal, although a matched case control study demonstrated the efficacy of antibiotic prophylaxis to reduce infectious complications after pcnl in patients with negative baseline culture (68). another study showed that a single dose administration was found sufficient to prevent post-ureteroscopic infections (69). in conclusion, infectious complications after endourological treatment of kidney stones appear to depend (i) on the characteristics of the stone, on the patients’ urinary tract, and on the patients’ comorbidities. the choice of a specific procedure for kidney stone treatment does not appear to be decisive for the onset of infectious complications, although the prevention of high intrarenal pressures during the procedure appears to be crucial in defining the risk of infectious complications. high intrarenal pressure depends on the modality of irrigation and on the use of the ureteral sheaths and suction systems to facilitate the outflow of urine. antibiotic prophylaxis should be tailored to the characteristics of the stone and of the urinary tract, the history of the patient (comorbidities, previous uti episodes) and the course of the procedure (operative time, method and volume of irrigation). in high-risk cases, prudence is recommended, avoiding prolonged operating times, and administering antibiotic treatment before the procedure in adjunct to perioperative prophylaxis. references 1. kim ds, yoo kh, jeon sh, lee sh. risk factors of febrile urinary tract infections following retrograde intrarenal surgery for renal stones. medicine (baltimore). 2021; 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122:1034-1040. 28. zhang h, hong ty, li g, et al. comparison of the efficacy of ultra-mini pcnl, flexible ureteroscopy, and shock wave lithotripsy on the treatment of 1-2 cm lower pole renal calculi. urol int. 2019; 102:153-159. 29. agrawal m, mishra d. minimally-invasive percutaneous nephrolithotomy versus conventional percutaneous nephrolithotomy for treatment of large sized (20-30 mm) renal calculi-a prospective study. j endourol. 2018; 32(suppl2):a59-a60. 30. bozzini g, aydogan tb, müller a, et al. a comparison among pcnl, miniperc and ultraminiperc for lower calyceal stones between 1 and 2 cm: a prospective, comparative, multicenter and randomised study. bmc urology. 2020; 20:1. 31. cheng f, yu w, zhang x, et al. minimally invasive tract in percutaneous nephrolithotomy for renal stones. j endourol. 2010; 24:1579-82. 32. guddeti rs, hegde p, chawla a, et al. super-mini percutaneous nephrolithotomy (pcnl) vs standard pcnl for the management of renal calculi of < 2 cm: a randomised controlled study. bju int. 2020; 126:273-279. 33. güler a, erbin a, ucpinar b, et al. comparison of miniaturized percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for the treatment of large kidney stones: a randomized prospective study. urolithiasis. 2019; 47:289-295. 34. sakr a, salem e, kamel m, et al. minimally invasive percutaneous nephrolithotomy vs standard pcnl for management of renal stones in the flank-free modified supine position: single-center experience. urolithiasis. 2017; 45:585-589. 35. tepeler a, akman t, silay ms, et al. comparison of intrarenal pelvic pressure during micro-percutaneous nephrolithotomy and conventional percutaneous nephrolithotomy. urolithiasis. 2014; 42:275279. 36. zeng g, cai c, duan x, et al. mini percutaneous nephrolithotomy is a noninferior modality to standard percutaneous nephrolithotomy for the management of 20-40 mm renal calculi: a multicenter randomized controlled trial. eur urol. 2021; 79:114-121. 37. sabnis r., ganpule a., desai m. is there any rationale of preferring ultraminiperc (mip s) over miniperc (mip m)?prospective randomized study. j endourol. 2016; 30(suppl2):a376-a377. 38. agrawal ms, agrawal m, gupta a, et al. a randomized comparison of tubeless and standard percutaneous nephrolithotomy. j endourol. 2008; 22:439-442. 39. bhat s, lal j, paul f. a randomized controlled study comparing the standard, tubeless, and totally tubeless percutaneous nephrolithotomy procedures for renal stones from a tertiary care hospital indian j urol. 2017; 33:310-314. 40. istanbulluoglu mo, ozturk b, gonen m, et al. effectiveness of totally tubeless percutaneous nephrolithotomy in selected patients: a prospective randomized study. int urol nephrol. 2009; 41:541-545. 41. lu y, ping j-g, zhao x-j, et al. randomized prospective trial of tubeless versus conventional minimally invasive percutaneous nephrolithotomy. world j urol. 2013; 31:1303-1307. 42. mishra s, sabnis rb, kurien a, et al. questioning the wisdom of tubeless percutaneous nephrolithotomy (pcnl): a prospective randomized controlled study of early tube removal vs tubeless pcnl. bju int. 2010; 106:1045-8. 43. moosanejad n, firouzian a, hashemi sa, et al. comparison of totally tubeless percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for kidney stones: a randomized, clinical trial. braz j med biol res. 2016; 49:e4878. 44. shah hn, hegde s, shah jn, et al. a prospective, randomized trial evaluating the safety and efficacy of fibrin sealant in tubeless percutaneous nephrolithotomy. j urol 2006; 176:2488-2493. 45. titaram s, nualyong c, taweemonkongsap t, et al. the impact of gelatin-sealant in the access tract after tubeless percutaneous nephrolithotomy: a randomized controlled trial. j med ass thai. 2017; 100(suppl2):s132-s137. 46. mankongsrisuk t, nualyong c, tantiwong a, et al. efficacy of nephrostomy tract infiltration with bupivacaine before and after tubeless percutaneous nephrolithotomy: a randomized control study. j med ass thai 2017; 100(suppl2):s138-s143. 47. huang j, song l, xie d, et al. a randomized study of minimally invasive percutaneous nephrolithotomy (mpcnl) with the aid of a patented suctioning sheath in the treatment of renal calculus complicated by pyonephrosis by one surgery. bmc urol. 2016; 16:71. 48. lai d, xu w, chen m, et al. minimally invasive percutaneous nephrolithotomy with a novel vacuum-assisted access sheath for obstructive calculous pyonephrosis: a randomized study. urol j. 2020; 17:474-479. archivio italiano di urologia e andrologia 2022; 94, 1 r. bapir, k. hassan bhatti, a. eliwa, et al. 106 49. zhong w, wen j, peng l, zeng g. enhanced super-mini-pcnl (esmp): low renal pelvic pressure and high stone removal efficiency in a prospective randomized controlled trial. world j urol. 2021; 39:929-934. 50. eisner b, agrawal s, desai m, et al. initial human experience with a novel stone aspiration device used during ureteroscopic lithotripsy for renal stones. j urol. 2020; 203(suppl4):e211. 51. sur rl, krambeck ae, large t, et al. a randomized controlled trial of preoperative prophylactic antibiotics for percutaneous nephrolithotomy in moderate to high infectious risk population: a report from the edge consortium. j urol. 2021; 205:1379-1386. 52. bag s, kumar s, taneja n, et al. one week of nitrofurantoin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. urology. 2011; 77:45-49. 53. chew bh, miller nl, abbott je, et al. a randomized controlled trial of preoperative prophylactic antibiotics prior to percutaneous nephrolithotomy in a low infectious risk population: a report from the edge consortium. j urol. 2018; 200:801-808. 54. dogan hs, sahin a, cetinkaya y, et al. antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. j endourol. 2002; 16:649-653. 55. mariappan p, smith g, moussa sa, tolley da. one week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. bju int. 2006; 98:1075-9. 56. tuzel e, aktepe oc, akdogan b. prospective comparative study of two protocols of antibiotic prophylaxis in percutaneous nephrolithotomy. j endourol. 2013; 27:172-6. 57. song f, liu c, zhang j, et al. antibacterial effect of fosfomycin tromethamine on the bacteria inside urinary infection stones. int urol nephrol. 2020; 52:645-654. 58. seyrek m, binbay m, yuruk e, et al. perioperative prophylaxis for percutaneous nephrolithotomy: randomized study concerning the drug and dosage. j endourol. 2012; 26:1431-6. 59. taken k., asik a., eryilmaz r., et al. comparison of ceftriaxone and cefazolin sodium antibiotic prophylaxis in terms of sirs/urosepsis rates in patients undergoing percutaneous nephrolithotomy. j urol surg. 2019; 6:111-117. 60. demirtas a, yildirim ye, sofikerim m, et al. comparison of infection and urosepsis rates of ciprofloxacin and ceftriaxone prophylaxis before percutaneous nephrolithotomy: a prospective and randomised study. scientific world journal. 2012; 2012:916381. 61. fourcade ro. antibiotic prophylaxis with cefotaxime in endoscopic extraction of upper urinary tract stones: a randomized study. the cefotaxime cooperative group. j antimicrob chemother. 1990; 26(suppl a):77-83. 62. zhao z, fan j, sun h, et al. recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial. bju int. 2019; 124:496-503. 63. türk c, neisius a, petrík a, et al. eau guidelines on urolithiasis. retrieved from: https://uroweb.org/guideline/urolithiasis/ accessed on 30th december 2021. 64. zheng c, xiong b, wang h, et al. retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones >2 cm: a meta-analysis. urol int. 2014; 93:417-24. 65. chen y, wen y, yu q, et al. percutaneous nephrolithotomy versus flexible ureteroscopic lithotripsy in the treatment of upper urinary tract stones: a meta-analysis comparing clinical efficacy and safety. bmc urol. 2020; 20:109. 66. tokas t, skolarikos a, herrmann trw, nagele u; training and research in urological surgery and technology (t.r.u.s.t.)-group. pressure matters 2: intrarenal pressure ranges during upper-tract endourological procedures. world j urol. 2019; 37:133-142. 67. mrkobrada m, ying i, mokrycke s, et al. cua guidelines on antibiotic prophylaxis for urologic procedures. can urol assoc j. 2015; 9:13-22. 68. gravas s,, et al. postoperative infection rates in low risk patients undergoing percutaneous nephrolithotomy with and without antibiotic prophylaxis: a matched case control study. j urol. 2012; 188:843-7. 69. chew bh, flannigan r, kurtz m, et al. a single dose of intraoperative antibiotics is sufficient to prevent urinary tract infection during ureteroscopy. j endourol. 2016; 30:63-8. correspondence rawa bapir dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar. ahmed eliwa ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt herney andrés garcía-perdomo herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland panagiotis mourmouris thodoros13@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece adama ouattara adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobodioulasso, burkina faso gianpaolo perletti gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india alberto trinchieri (corresponding author) alberto.trinchieri@gmail.com urology school, university of milan, milan, italy noor buchholz noor.buchholz@gmail.com scientific office, u-merge ltd., athens, greece stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13880 1 review the patient’s tumor stage, grade, comorbidity, and performance. when the disease progresses to unresectable, locally advanced, or metastatic ucs (muc), the administration of systemic therapy is generally recommended (3). for many years, cisplatin-based cytotoxic chemotherapy has been the standard treatment for muc. however, as the disease advances, up to 50% of patients requiring chemotherapy may be considered unfit for cisplatinbased treatment due to the presence of comorbidities (4). recently, immunotherapy using immune checkpoint inhibitors have emerged as alternative treatment options for individuals with muc (5). one notable example of this class of drugs is pembrolizumab, a pd-1 inhibitor agent that functions by inhibiting the interaction between programmed cell death protein-1 (pd-1) and its ligand (pd-l1) (6). numerous ongoing studies are investigating these agents as firstand second-line therapies, both alone and in combination with chemotherapy or in a maintenance regimen, thereby signaling their steadily increasing importance (7). consequently, the european association of urology (eau) has recently recommended the use of enfortumab vedotin (ev) in combination with pembrolizumab as a first-line treatment for patients considered suitable for combination therapies, irrespective of their cisplatin eligibility, which significantly reduces treatment-related toxicity (3, 8). despite these recommendations, ev may not be accessible in various countries. furthermore, certain patients may be ineligible for ev treatment, including those with uncontrolled diabetes, peripheral neuropathy, and significant skin disorders (9). therefore, for this patient population comprising those who are either (1) ineligible for combination therapy or ev, (2) eligible for combination therapy but without access to ev, or (3) ineligible for both combination therapy and unfit for platinum-based chemotherapies there exists uncertainty concerning the optimal treatment options available to them. for patients who are ineligible for platinum-based chemotherapies, current guidelines recommend assessing pd-l1 positivity status through immunohistochemistry. the european medicines agency (ema) has approved pembrolizumab and atezolizumab for first-line treatment in patients with positive pd-l1 staining, while the u.s. food and drug administration (fda) has introduction: recent studies have shown the therapeutic benefits of pembrolizumab in locally advanced or metastatic urothelial carcinoma (muc). however, its high cost and variable patient responses remain challenges. this study aims to investigate the prognostic value of pre-treatment hematologic and clinical parameters in predicting outcomes in muc patients. methods: a comprehensive search was conducted across five databases for relevant articles. studies that assessed the relationship between pre-treatment hematological and clinical parameters and either progression free survival (pfs) or overall survival (os) were included and evaluated for bias. results: the literature search identified 27 studies encompassing a total of 4,731 patients. several prognostic factors linked to os were identified, with the most adverse survival outcomes associated with hypoalbuminemia (hr 3.13, 95% ci: 2.52-3.88), ecog-ps ≥2 (hr 2.94, 95% ci: 2.65-3.26), and the presence of liver metastasis (hr 2.44, 95% ci: 2.16-2.76). additionally, the presence of bone, liver, or lung metastases, ecog-ps ≥ 2, surgical excision of the primary tumor, elevated c-reactive protein (crp) and neutrophil-lymphocyte ratio (nlr), and low hemoglobin levels were all correlated with unfavorable pfs and os. conclusions: patients with metastatic urothelial carcinoma and poor performance status, visceral metastases, high nlr or crp, or low hemoglobin may have poorer survival, even with pembrolizumab. these factors may help guide clinical decisions for patients with advanced/metastatic urothelial carcinoma. key words: urothelial; pembrolizumab; survival. submitted 9 april 2025; accepted 14 april 2025 introduction urothelial carcinoma (uc), also known as transitional cell carcinoma, is a type of cancer that originates in the urothelium. uc includes all tumors found in the bladder, upper urinary tract (including the renal pelvis and ureters), and proximal urethra, with bladder cancer constituting approximately 90% to 95% of these cases (1). it is the second most prevalent urological malignancy in men, with an estimated global mortality exceeding 200,000 (2).current treatment options are dependent on predicting outcomes with pembrolizumab: a meta-analysis of pre-treatment hematological and clinical prognostic factors in advanced/metastatic urothelial carcinoma kevin yuwono 1, junjungan nimasratu rahmatsani 1, nadhifah 1, revina maharani 2, zakaria aulia rahman 3 1 faculty of medicine, airlangga university, indonesia; 2 faculty of medicine, brawijaya university, indonesia; 3 department of urology, faculty of medicine, airlangga university, indonesia. doi: 10.4081/aiua.2025.13880 summary archivio italiano di urologia e andrologia 2025; 97(2):13880 k.. yuwono, j. nimasratu rahmatsani, nadhifah, et al. 2 approved pembrolizumab for use regardless of pd-l1 status (3). despite these recommendations, the historical outcomes for this patient group have been unfavorable. often, best supportive care is preferred over systemic therapy. this highlights the need for a biomarker to better predict which patient populations will benefit from these treatments. several biomarkers have been proposed, including pd-l1 expression (10), tumor mutational burden (tmb), microsatellite instability (msi), and mismatch repair deficiency (11). however, these biomarkers have been found to lack sufficient predictive accuracy. by systematically reviewing existing literature, we aim to identify the several hematological and clinical parameters that can better predict the population of muc patients who are likely to benefit from pembrolizumab monotherapy. methods this systematic review followed prisma guidelines (preferred reporting items for systematic reviews and meta-analyses) and the cochrane handbook for systematic reviews of interventions. our full protocol was registered in prospero (registration number crd42024608476). search strategy a systematic literature data search was conducted in pubmed, scopus, proquest, cumulative index to nursing and allied health literature (cinahl) via ebsco, and cochrane central register of controlled trials (central) for studies published up to november 2, 2024. we additionally performed a manual hand-search on google and the reference lists of the included studies to maximize the search results. the following main keywords were initially established: “pembrolizumab”, “urothelial carcinoma”, along with prognostic factors such as “hemoglobin”, “neutrophil”, “c reactive protein” and “lactate dehydrogenase”. we subsequently added several medical subject headings (mesh) and other free-text terms to construct database-specific search terms. the full search strings for each database are provided in supplementary table s1. no publication date and language restrictions were set in all searches. eligibility criteria we included clinical studies that examined the association between hematological parameters and outcomes in patients with advanced/metastatic ucs. to be included in this systematic review and meta-analysis, studies had to meet the following criteria: (1) the study population consisted of adults aged 18 years or older; (2) the study exclusively included uc patients receiving pembrolizumab monotherapy; (3) it assessed the relationship between prognostic factors and outcomes; and (4) it was either a clinical trial or an observational study (case-control or cohort studies). we accepted studies published in any language. studies were excluded if: (1) the study was a review article, case report, case series, or conference abstract; (2) the full-text was irretrievable; or (3) raw data could not be separated. data extraction and quality assessment two independent investigators performed data extraction from each included study and recorded it within the prespecified form, with discrepancies resolved by the consensus with an independent third investigator. the data extracted include the name of the first author and year of publication, study location (country and region), study design, sample size, pembrolizumab dose used, patients characteristics (age, sex), follow up duration, clinical characteristics (ecog ps ≥ 2, site of primary tumor, metastatic sites), overall response rate (orr), and relationship between prognostic factor and outcomes. risk of bias assessment for the risk of bias assessment, quality in prognosis studies (quips) tool was used to assess the methodological quality of each study and subsequently judged to be yielding low, moderate, or high risk of bias (12). the visualization of the bias assessment’s summary was generated using the robvis tool (13). the methodological quality assessment of the included studies was conducted by two independent reviewers (ndf and jnr). discordance in judgements was resolved simultaneously in a consensus with a third reviewer (kyu). we planned to conduct a funnel-plot and egger’s test to assess the possibility of publication bias across studies. statistical analysis for the primary outcome of overall survival, we reported pooled hazard ratios (hrs) with their corresponding 95% confidence intervals (cis). the initial quantitative synthesis was performed by comparing each prognostic factor, applying the generic inverse variance method within a dersimonian-laird fixed-effects model. in cases where significant heterogeneity was detected, a random-effects model was subsequently applied. in the case where two or more studies involved overlapping populations, analysis was prioritized to studies with larger sample sizes. the presence of heterogeneity was analyzed using cochran’s q and i2 statistics, where heterogeneity was classified as negligible, low, moderate, or high to i2 values of 0%, 25%, 50%, and 75%, respectively (14). whenever appropriate (n ≥ 10), potential publication bias was evaluated visually by contour-enhanced funnel plot and quantitatively by egger’s and begg’s tests. whenever available, subgroup analyses were carried out based on the risk of bias. on the other hand, sensitivity analyses were conducted by leave-one-out analysis and the exclusion of studies with high-risk of bias. metaregression analyses were carried out for (1) year of publication, (2) % of males, (3) sample size; (4) mean age, (5) % of upper tract primary tumor site, and (6) follow up duration whenever possible. all analysis was conducted with r ver. 4.3.0 (r foundation for statistical computing, vienna, austria). conventional meta-analysis was conducted using the meta package, while meta-regression analyses were performed using the metafor package. results study selection a prisma flowchart of the study selection process is depicted in figure 1. initial searches of the five databases yielded 4449 records. we identified duplicates, and a archivio italiano di urologia e andrologia 2025; 97(2):13880 3 pembrolizumab in advanced/metastatic urothelial carcinoma total of 577 records were removed. of the remaining 3872 records, 3818 records were excluded. one conference abstract with unavailable full-text and six other articles were not retrieved. we then thoroughly reviewed forty-seven studies and further excluded twenty-one studies, due to the following: (1) combined with other chemotherapies (n = 10), missing outcome of interest (n = 7), data cannot be extracted (n = 3), and use of intravesical pembrolizumab (n = 1). ultimately, the entire screening process led to the inclusion of twenty-six eligible studies in this systematic review. study characteristics in our review, we analyzed a total cohort of 4,679 patients, with a median age ranging from 68.9 to 76 years. among the total population, 3,092 patients were male, accounting for 71.5% of the participants. the majority of the research was conducted in japan, with only one study taking place in the netherlands. all studies used a retrospective comparative design. the median follow-up duration was quite variable, ranging from 5.7 to 34 months. regarding ecog performance status (ps), five studies did not disclose the percentage of patients with ps ≥ 2, while four studies only disclosed those with a ps of ≥ 1. in total, 604 patients (18.3%) were identified with a ps of ≥ 2. among the studies that reported primary tumor sites, 1,863 patients (43.1%) had tumors in the upper urinary tract, while 2,212 patients (51.7%) had tumors originating from the bladder. the primary outcomes of our review were orr, pfs, and os. the values for each outcome are further reported in table 1. quantitative analysis (meta-analysis) twenty-six studies with a total sample of 4,679 patients figure 1. prisma flowchart of the study selection process. archivio italiano di urologia e andrologia 2025; 97(2):13880 k.. yuwono, j. nimasratu rahmatsani, nadhifah, et al. 4 table 1. characteristics of included studies. no author; year location study sample age male follow up ecog ps site of outcome design size (years) duration (months) ≥ 2 primary orr pfs os tumour (%) (median) (median) 1 akashi; 2023 (40) japan retrospective study 41 75 (58-81) 35 (85.4) 16.5 (1.0-47.8) 4 (10) utuc: 16 (40) 29.3 4.9 (1.2-8.6) 17.8 (11.5-24.0) bc: 25 (60) 2 fukata; 2022 (41) japan retrospective study 44 70 (54-80) 30 (68) 13.2 (1-40.8) 7 (16) utuc: 16 (36) 54.5 nr nr bc: 28 (64) 3 furubayashi; 2021 (42) japan retrospective study 105 72 (67-77) 75 (71.4) 8.4 (4.1-15.7) 10 (9.5) utuc: 41 (39) 36.2 nr nr bc: 42 (40) both: 22 (21) 4 ito; 2020 (43) japan retrospective study 755 ecog 0-1: 72.09 568 (75.2) 7.2 153 (20.26) utuc: 373 (49.4) 26.2 nr nr (66.3-77.23) bc: 382 (50.6) ecog 2: 72.01 (66.49-76.21) ecog 3-4: 70.18 (63.5-75.72) 5 kawashima; 2021(a) (44) japan retrospective study 165 73 (28-93) 117 (70.9) 6.71 (0.26-37.0) 27 (16.3) utuc: 99 (60) 21.8 (2.32-2.88) 2.6 nr bc: 61 (37) both: 5 (3.0) 5 kawashima; 2021(b) (45) japan retrospective study 103 73 (30-86) 76 (73.8) 6.67 (0.99-36.1) 23 (22.3) utuc: 58 (56.3) 30.1 (1.79-5.31) 3.55 nr bc: 45 (43.7) 6 kita; 2022 (45) japan retrospective study 739 nr 554 (75) 34 150 (20.3) utuc: 352 (47.63) 27.2 3.5 nr bc: 384 (51.9) unknown: 4 (0.4) 7 kobayashi; 2020 (46) japan retrospective study 463 71 (31-88) 357 (77.1) 17.7 (12.9-21.4) 90 (19.4) utuc: 179 (38.7) 30.5 nr 10.2 (8.2-11.7) bc: 230 (49.7) both: 27 (5.8) unknown: 1 (0.2) 8 komura; 2023 (47) japan retrospective study 100 70.30 (9.03) 78 (78) nr nr utuc: 18 (18) 22 nr nr bc: 77 (77) both: 5 (5) 9 kurashina; 2023 (18) japan retrospective study 75 nr nr 7.3 (0.47-47.6) nr nr 21.3 nr 8.5 (6.4-10.7) 10 miyama; 2022 (48) japan retrospective study 50 71.9 (1.69) 31 (62) nr nr utuc: 23 (46) bc: 27 (54) 30 3.62 10.97 11 nagasaka; 2024 (49) japan retrospective study 48 76 (47-88) 31 (64.58) nr 2 (4.17) utuc: 48 (100) 27.1 2.2 5.47 12 nishio; 2024 (50) japan retrospective study 220 nr 154 (70) 7.3 123 (56)* utuc: 85 (39) 29.1 nr nr bc: 135 (61) 13 ogihara; 2020 (51) japan retrospective study 78 72.16 (9.29) 54 (69.23) 7.42 (0.9-17.9) 18 (23.07)* utuc: 35 (44.9) 29.5 nr nr bc: 43 (55.1) 14 rijnders; 2023 (52) netherlands retrospective study 71 nr 51 (71.8) nr nr utuc: 21 (29.6) nr nr nr bc: 44 (61.9) both: 6 (8.5) 15 sato; 202353 japan retrospective study 101 71 (33-85) 71 (70.3) 19 (3-54) 17 (16.8) utuc: 35 (34.7) 19.8 nr 13 bc: 66 (65.3) 16 shimizu; 202054 japan retrospective study 27 71.48 (7.51) 23 (85) 7.88 (4.76) 12 (44) utuc: 12 (44) 37.0 4 7 bc: 15 (56) 17 tamura; 202055 japan retrospective study 41 68.91 ± 8.08 29 (70) 6.2 (4.4) 6 (15) utuc: 22 (54) 14.6 2.5 (1.4-6.2) 11.9 bc: 19 (46) 18 tanabe; 202415 japan retrospective study 331 73 (68-78) 241 (73) 7.3 (3.4-16.5) 57 (17) utuc: 154 (47) 32.3 3.3 (2.6-4.3) 9.6 (7.3-13.2) bc: 177 (53) 19 tomioka-inagawa; 202216 japan retrospective study 211 72.1 (1.63) 121 (57.3) 10 28 (13.4) utuc: 49 (23.2) 25.1 5 (3-5) 17 (15-26) bc: 89 (42.2) archivio italiano di urologia e andrologia 2025; 97(2):13880 5 pembrolizumab in advanced/metastatic urothelial carcinoma were included for meta-analysis. pooled pfs and os were measured using hazard ratios (hrs). demographic factors the demographic factors chosen for this analysis are age and gender. among these factors, age ≥ 70-75 years old are found to be associated with worse progression free survival (hr 1.21, 95%ci 1.04-1.41, n = 8 studies). furthermore, our investigation revealed a lack of significant heterogeneity regarding these outcomes. clinical factors ten clinical factors are included in this analysis, consisting of metastasis sites (bone, liver, lung, and lymph node), ecog-ps ≥ 2, utuc primary site, prior surgical removal for primary site, pure uc pathological type, smoking, < 90 days from previous chemotherapy (table 2). for pfs, we detected one factor with moderate amount of heterogeneity, which is utuc primary site (i2 = 58%). for os, we detected three factors with moderate to high amounts of heterogeneity, including presence of bone (i2 = 64%) or lymph node metastasis (i2 = 73%), and ecog-ps ≥ 2 (i2 = 86%). all heterogeneity tests are performed using rem. based on the hrs, there are six clinical factors that can be considered as prognostic factors. for pfs, five factors are linked with worse survival are as follows: (1) ecog-ps ≥ 2 (hr 2.30, 95%ci 1.91-2.76); (2) pure uc pathological type (hr 2.33, 95%ci 1.20-4.54); (3) presence of liver metastasis (hr 1.70, 95%ci 1.35-2.14); (4) lung metastasis (hr 1.34, 95%ci 1.10-1.64); and (5) bone metastasis (hr 1.29, 95%ci 1.02-1.64). on the contrary, surgical removal of primary site (hr 0.80, 95%ci 0.65-0.99) is associated with better survival. sensitivity analysis of pfs factors suggest that the provided overall effects are robust and not affected by any single study. for os, five factors are also associated with worse survival: (1) presence of bone metastasis (hr 1.94, 95%ci 1.253.0); (2) liver metastasis (hr 2.44, 95%ci 2.16-2.76); (3) lung metastasis (hr 1.35, 95%ci 1.18-1.56); (4) ecogps ≥ 2 (hr 3.38, 95%ci 2.17-5.28); (5) time from previous chemotherapy < 90 days (hr 1.42, 95%ci 1.221.64). a leave-one-out sensitivity analysis was conducted for all prognostic factors showing significant heterogeneity. the analysis revealed that the presence of bone metastasis, upon removal of one study by tanabe et al. (15) resulted in a shift of the pooled effect from significant to nonsignificant, and significant reduction of heterogeneity. the same result is found for c-reactive protein level. in contrast, the effects of all other clinical factors remained robust (supplementary figures s2b, s2d). hematological factors we identified four potential hematological markers as prognostic factors: albumin, crp, hemoglobin, and nlr. most outcome analyses demonstrated nonsignificant heterogeneity, except for crp’s association with os, which exhibited high heterogeneity (i² = 94%). for pfs, three markers showed a significant effect: elevated crp (hr 1.94, 95%ci 1.54-2.45), low hemoglobin (hr 1.80, 95%ci 1.51-2.14), and high nlr (hr 1.65, 95%ci 1.441.89). for os, we found four markers associated with poorer survival: hypoalbuminemia (hr 3.13, 95%ci 2.52-3.88), high crp (hr 2.18, 95%ci 1.07-4.42), low hemoglobin (hr 2.08, 95%ci 1.85-2.35), and high nlr (hr 1.93, 95%ci 1.71-2.18). sensitivity analysis was performed for all outcomes. for crp, removing one study by tomioka-inagawa significantly reduced heterogeneity (16), while excluding a study by tanabe et al. made the effect size nonsignificant (15). given this, we advise interpreting these results with caution, while all other hematological markers showed stable outcomes. subgroup and meta-regression analyses we performed subgroup and meta-regression analyses for prognostic factors with a sufficient number of studies: (1) age, (2) gender, (3) presence of liver metastasis, (4) ecog-ps ≥ 2, and (5) utuc primary site associated with os. for most factors, we found no significant differences between subgroups. for ecog-ps, results of the subgroup analysis of risk of bias are presented in the supplementary materials. meta-regression analyses on the percentage of male (p = 0.01) suggest that this factor influenced the effect of ecog-ps ≥ 2 on overall survival (supplementary table s3 and figure s4). additionally, subgroup comparisons based on risk of bias revealed no statistically significant differences in effect sizes between 20 uchimoto; 202156 japan retrospective study 212 72 (8.95) 151 (71.2) 8 120 (56.6)* utuc: 82 (38.7) 26.4 nr 11.7 bc: 130 (61.3) 21 uchimoto; 202257 japan retrospective study 177 72 (66-78) 125 (70.6) 6 100 (56.5)* utuc: 68 (38.4) 26.6 nr 14 bc: 109 (61.6) 22 umeda; 202258 japan retrospective study 115 75 (70-79) 29 (65.9) 7.4 (4.6-16.4) nr utuc: 22 (50) 25.2 nr nr bc: 21 (47.7) both: 1 (2.3) 23 yamamoto; 202259 japan retrospective study 31 74 (70-82) 22 (71) 5.7 (3.4-16.3) 3 (10) utuc: 9 (29) 35.5 nr nr bc: 22 (71) 24 yamashita; 202360 japan retrospective study 96 74 (70-79) 69 (72) 7 (4-17) 15 (15.6) utuc: 46 (48) 23 2 nr bc: 41 (43) both: 9 (9) categorical data are shown as n (%), while numerical data are presented as mean (sd) or median (iqr). nr: not reported; ecog-ps: eastern cooperative oncology group performance status scale; utuc: upper urinary tract urothelial carcinoma; bc: bladder urothelial carcinoma. *ecog ps >= 1. archivio italiano di urologia e andrologia 2025; 97(2):13880 k.. yuwono, j. nimasratu rahmatsani, nadhifah, et al. 6 studies classified as low risk versus moderate-high risk (supplementary figure s5). publication bias and quality assessment of included studies for outcomes with included studies ≥ 10, we performed publication bias assessment by generating funnel plots. for overall survival, one study each by tanabe et al. (15), kobayashi et al. (17), and kurashina et al. (18) appeared as outliers in the funnel plots for age, gender, and liver metastasis, respectively. in contrast, a total of three studies assessing ecog-ps fell outside the funnel plot, suggesting that ecog-ps results may be particularly affected by publication bias. nonetheless, egger’s test did not show statistically significant bias for any of the evaluated risk factors (supplementary table s2 and figure s3). three reviewers assessed the risk of bias within individual studies using the quips tool, given that all the included studies were studies evaluating prognostic factors (figure 2). among the studies reviewed, six were identified as having a high risk of bias due to attrition. all the included studies were retrospective in nature, and the high risk of attrition bias stemmed from either a lack of reporting on missing data or the exclusion of a significant portion of data (> 10%) from the final analysis. we identified three studies with a moderate risk of bias, while the remaining studies had a low risk of bias. some studies were rated as having a moderate risk of bias related to participation, primarily because they failed to report details such as the study location or the recruitment period. additionally, a few studies exhibited a moderate risk of bias due to confounding, as significant confounders were neither addressed in the study design nor adjusted for in the statistical analysis. figure 2 and 3 provides an in-depth visualization of the risk of bias assessment for each study. table 2. pooled hazard ratios of demographical, clinical, and hematological factors associated with pfs and os. factors definition number hazard ratio heterogeneity overall effect of studies (95%ci) i2 p-value z-score p-value progression free survival demographic factors age ≥ 70-75 years old 8 1.21 (1.04-1.41) 0 0.84 2.44 0.01 gender male vs. female 8 0.99 (0.84-1.17) 1 0.42 -0.14 0.89 clinical factors ecog-ps ≥ 2 vs. < 2 8 2.30 (1.91-2.76) 39 0.12 8.9 < 0.01 pathological type pure vs mixed uc 3 2.33 (1.20-4.54) 3 0.36 2.49 0.01 liver metastasis yes vs. no 5 1.70 (1.35-2.14) 13 0.33 4.52 < 0.01 lung metastasis yes vs. no 4 1.34 (1.10-1.64) 0 0.73 2.93 < 0.01 lymph node metastasis yes vs. no 5 0.84 (0.70-1.01) 0 0.78 -1.82 0.07 bone metastasis yes vs. no 3 1.29 (1.02-1.64) 0 0.89 2.12 0.03 primary site utuc vs bc 8 1.05 (0.73-1.52) 58 0.02 0.32 0.76 surgical removal of primary site yes vs. no 5 0.80 (0.65-0.99) 5 0.38 -2.07 0.04 hematological parameters crp high vs. low 4 1.94 (1.54-2.45) 21 0.28 5.62 < 0.01 hemoglobin low vs. high 5 1.80 (1.51-2.14) 0 0.69 6.52 < 0.01 nlr high vs. low 6 1.65 (1.44-1.89) 13 0.33 7.22 < 0.01 overall survival demographic factors age ≥ 70-75 years old 10 1.00 (0.99-1.01) 43 0.07 0.16 0.87 gender male vs. female 10 0.97 (0.87-1.08) 30 0.17 -0.58 0.57 clinical factors bone metastasis yes vs. no 5 1.94 (1.25-3.00) 64 0.03 4.2 0.01 liver metastasis yes vs. no 10 2.44 (2.16-2.76) 31 0.16 14.39 < 0.01 lung metastasis yes vs. no 7 1.35 (1.18-1.56) 34 0.17 4.29 < 0.01 lymph node metastasis yes vs. no 7 0.94 (0.67-1.33) 73 < 0.01 -0.4 0.7 ecog-ps ≥ 2 vs. < 2 10 3.38 (2.17-5.28) 86 < 0.01 6.68 < 0.01 pathological type pure vs. mixed uc 5 1.17 (0.88-1.55) 21 0.28 1.07 0.29 primary site utuc vs bc 10 1.07 (0.97-1.18) 7 0.38 1.36 0.17 smoking yes vs. no 6 1.03 (0.93-1.14) 0 0.44 0.57 0.57 surgical removal of primary site yes vs. no 4 0.71 (0.58-0.88) 0 0.6 -3.21 < 0.01 time from previous chemotherapy < 90d vs. ≥ 90d 4 1.42 (1.22-1.64) 0 0.66 4.66 < 0.01 hematological parameters albumin < 3.5-3.7 3 3.13 (2.52-3.88) 0 0.7 10.4 < 0.01 crp high vs. low 5 2.18 (1.07-4.42) 94 < 0.01 3.05 0.04 hemoglobin low vs. high 8 2.08 (1.85-2.35) 23 0.24 12.05 < 0.01 nlr high vs. low 8 1.93 (1.71-2.18) 46 0.07 10.52 < 0.01 ecog-ps: eastern cooperative oncology group performance status scale; uc: urothelial carcinoma; utuc: upper urinary tract urothelial carcinoma; bc: bladder urothelial carcinoma; crp: c-reactive protein. archivio italiano di urologia e andrologia 2025; 97(2):13880 7 pembrolizumab in advanced/metastatic urothelial carcinoma figure 2. traffic plot of the included studies risk of bias assessed by quips tool. archivio italiano di urologia e andrologia 2025; 97(2):13880 k.. yuwono, j. nimasratu rahmatsani, nadhifah, et al. 8 discussion given that only a small percentage of patients derive benefits from immunotherapy, numerous predictive biomarkers have been developed to improve outcome predictions. current evidence indicates that pd-l1 expression serves as the most reliable biomarker for predicting which patients with advanced uc are likely to respond to anti-pd-1 or anti-pd-l1 therapies (19-21). however, pembrolizumab monotherapy showed comparable survival to platinumbased chemotherapy regardless of pd-l1 combined positive score (cps) (22). that is why in this study, we identified several potential hematological and clinical risk factors linked to unfavorable outcomes in patients with advanced uc receiving pembrolizumab monotherapy. the metastatic sites significantly associated with worse progression free survival and overall survival are the liver, lung, and bone. lymph nodes are the most common site of metastasis in urothelial carcinoma, with other studies reporting an incidence of 69%-90% (23). in accordance with this study, patients with lymph-node-only metastasis tend to have better pfs and os compared to those with visceral metastases. this better prognosis may be explained by the presence of immune cells within the lymph nodes, which may enhance the efficacy of immune checkpoint inhibitors (icis) and other therapies. additionally, lymph-node-only metastasis may represent an earlier stage of cancer progression, with less tumor heterogeneity or clonal evolution compared to visceral metastasis (24). in contrast, liver metastasis occurs less frequently, with an incidence ranging from 19% up to 47%, but is associated with the worst survival outcomes among metastatic sites, as this research demonstrates (25). patients with liver metastases have a median overall survival of only seven months, highlighting its poor prognosis compared to other metastatic patterns (26). liver metastases are often multiple and diffuse, indicating systemic disease with high tumor burden hypotheses for the poor prognosis of liver metastases include the immunosuppressive microenvironment of the liver, increased tumor mutation burden, clonal evolution, and poor response to chemotherapy and icis (24, 25). furthermore, small metastases in the liver might not be detected by imaging techniques and are only revealed later on during autopsy, such as in the study performed by wallmeroth (27). liver-directed therapies such as radiofrequency ablation may offer some survival benefit on top of systemic chemotherapy (26). bone metastases are reported in 32%-47% of patients with muc (23, 27). recent studies have reported a higher incidence of bone metastases, potentially due to advanced imaging techniques like bone scintigraphy and mri, which have improved the detection of osseous lesions. bone metastases often coexist with other metastatic sites and contribute to significant morbidity, including pain and fractures, further complicating the disease course (23). lung metastases, present in 37%-45% of cases, are another common manifestation of advanced urothelial carcinoma (25). these metastases typically appear as pulmonary nodules, consolidation, or lymphangitic spread. although lung metastases are less associated with poor survival outcomes than liver metastases, their presence often indicates advanced disease progression (25). the differences in prognosis among metastatic sites may be attributed to several factors. organotropism and tumor biology likely play significant roles, as metastases to organs like the liver may reflect advanced clonal evolution, greater tumor heterogeneity, and a more unfavorable tumor microenvironment (24, 25). immune heterogeneity across metastatic sites, such as variations in tumor-infiltrating lymphocytes, pdl1 expression, and immune response, can further influence prognosis and treatment outcomes. additionally, molecular factors, such as mtap-deficient tumors, have been associated with an increased likelihood of visceral metastases and worse outcomes with icis (28). patients with an ecog ps of ≥ 2 are clearly at a higher risk of poor outcomes. this is particularly significant as patients with a ps > 2 are typically considered unfit for platinum-based chemotherapy. in such cases, the european association of urology suggests that best supportive care may be the most appropriate approach to optimize quality of life and minimize treatment-related harm (3). for patients with a ps of 2, careful consideration of additional risk factors and overall organ function is essential, e.g. glomerular filtration rate (gfr) of less than 60ml/min. this decision should be made in close collaboration with experts to ensure a tailored and balfigure 3. summary plot of the included studies risk of bias assessed by quips tool. archivio italiano di urologia e andrologia 2025; 97(2):13880 9 pembrolizumab in advanced/metastatic urothelial carcinoma anced approach that takes into account the patient’s comorbidities, disease burden, and treatment goals. in contrast, patients with a ps of 0-1 represent a subgroup that may be better suited for more active treatment strategies. for these individuals, pembrolizumab monotherapy could be considered in two specific scenarios: (1) when enfortumab-vedotin (efv) and platinum-based chemotherapy are unavailable, or (2) when the patient is deemed ineligible for platinum-based chemotherapy due to other contraindications. while pembrolizumab monotherapy may not be the first-line option in many cases, its role as an alternative should be weighed carefully, particularly in light of emerging evidence supporting its efficacy and safety in select patient populations. in a phase ii single-arm trial involving 370 participants with cisplatin-ineligible urothelial carcinoma, pembrolizumab monotherapy achieved an objective response rate of 26% among 69 patients with metastatic utuc (29). several prognostic bloodor serum-based parameters have been reported in advanced ucs, including crp, ldh, platelet-to-lymphocyte ratio (plr), and neutrophil-tolymphocyte ratio (nlr). in our study, low hemoglobin and high nlr consistently demonstrated worse pfs and os. hemoglobin (hgb) level is one of the parameters that has been used as inclusion criteria in the original trials assessing pembrolizumab for advanced urothelial carcinoma (20). several studies of other types of cancers have shown significantly longer os and pfs in patients with higher hgb levels undergoing immunotherapy (30, 31). in one study, hgb levels were positively correlated with clinical outcomes in cancer patients receiving immunotherapy, but not in those not undergoing such treatment, suggesting a positive association between hgb levels and response to immunotherapy. additionally, it was found that this effect was independent of other clinicopathological factors, including sex, age, tumor stage, and tumor mutational burden (tmb), as well as established biomarkers like pd-l1 expression and microsatellite instability (msi) (32). it is thought that hypoxia induced by hgb reduction stimulates tumor growth and progression and decreases their sensitivity to anticancer treatments, eventually contributing to poor patient outcomes (33). pretreatment nlr and lymphocytopenia have been linked to increased mortality rates in patients with solid tumors, as well as in the general population (34, 35). this suggests that nlr is not a specific biomarker for patients with ucs. one study found that after adjusting for other prognostic factors, patients with a decrease in post-chemotherapy nlr experienced longer os compared to those with merely low pretreatment nlr levels. these findings suggest a unique association between response to 1st-line chemotherapy with efficacy of pembrolizumab treatment (17). furthermore, a trend was observed suggesting that high nlr is associated with worse os, particularly in metastatic diseases. this suggests either a greater tumor burden or more prolonged chronic inflammatory process (36). the mechanisms linking high nlr to poor outcomes in cancer patients remain poorly understood. research has indicated that neutrophils, along with other cells like macrophages, secrete various factors that promote tumor growth, likely contributing to an environment that stimulates tumor progression (34). a range of inflammatory cytokines play a role in the systemic inflammatory response. notably, il-6 specifically enhances the production of acute-phase proteins, such as c-reactive protein, while simultaneously reducing albumin synthesis in the liver (37). in this review, we also identified an association between high crp levels and hypoalbuminemia with poor os, although this was supported by fewer studies and significant heterogeneity. interestingly, varying cutoff points for both hemoglobin and nlr across studies were documented. despite these differences, given the relatively narrow range of hemoglobin and nlr cutoffs used in our analysis, we do not expect this variability to significantly affect the interpretation of our findings. in our study, we found that higher crp levels are associated with worse outcomes, although there is considerable heterogeneity. this variability may be attributed to the different cutoff values used in the studies included. the relationship between crp and cancer prognosis is a complex interplay of cytokines. tumor cells release cytokines and chemokines such as il-6 and il-8, which result in elevated serum crp levels. moreover, tumor growth and invasion can cause inflammation, contributing to further rise in crp (38). high crp levels have also been demonstrated to cause dna damage and weaken immune function, further facilitating carcinogenesis and tumor progression (39). to our knowledge, this is the first systematic review and meta-analysis that comprehensively assess prognostic value of pre-treatment hematologic and clinical parameters in predicting outcomes of patients with locally advanced or metastatic urothelial carcinoma. while we have made every effort to ensure the highest quality in this study, we recognize several limitations. first, the studies included in this review were quite heterogeneous, as they encompassed patients with different lines of chemotherapy. second, most of the studies that met our inclusion criteria originated from japan. these limitations underscore the necessity for standardized protocols and more rigorous studies to enhance our understanding of the predictive value of these prognostic factors in immunotherapy. conclusions our research revealed a number of important prognostic variables linked to survival in pembrolizumab-treated muc patients. the occurrence of liver, lung, or 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urothelial carcinoma patients treated with pembrolizumab. sci rep. 2021; 11:21199. 45. kita y, ito k, kanda s, et al. tolerability and treatment outcome of pembrolizumab in patients with advanced urothelial carcinoma and severe renal dysfunction. urol oncol semin orig investig. 2022; 40:410.e11-410.e18. 46. kobayashi t, ito k, kojima t, et al. risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab. cancer sci. 2021; 112:760-73. 47. komura k, tokushige s, ishida m, et al. tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab. cancer sci. 2023; 114:4622-31. 48. miyama y, kaneko g, nishimoto k, yasuda m. lower neutrophil-to-lymphocyte ratio and positive programmed cell death ligand-1 expression are favorable prognostic markers in patients treated with pembrolizumab for urothelial carcinoma. cancer med. 2022; 11:4236-45. 49. nagasaka h, yamamoto s, suzuki a, et al. c-reactive 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received platinum-based combination chemotherapy followed by pembrolizumab. int j urol. 2023; 30:730-6. 54. shimizu t, miyake m, hori s, et al. clinical impact of sarcopenia and inflammatory/nutritional markers in patients with unresectable metastatic urothelial carcinoma treated with pembrolizumab. diagnostics. 2020; 10:310. 55. tamura d, jinnouchi n, abe m, et al. prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: experience in real-world clinical practice. int j clin oncol. 2020; 25:899-905. 56. uchimoto t, komura k, fukuokaya w, et al. risk classification for overall survival by the neutrophil-lymphocyte ratio and the number of metastatic sites in patients treated with pembrolizumab— a multicenter collaborative study in japan. cancers. 2021; 13:3554. 57. uchimoto t, nakamura k, komura k, et al. prognostic value of the fluctuation in the neutrophil-lymphocyte ratio at 6 weeks of pemdeclarations ethical approval: not applicable. consent for publication: not applicable. availability of data and material: all data generated or analyzed during this study are included in this published article. competing interests: the authors declare that they have no competing interests. funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions: kyu: study concept, data collection, statistical analyses, manuscript original drafting; jnr: study concept, data collection, manuscript original drafting; ndf: study concept, data analysis, contribution to manuscript writing and editing; rev: study concept, data analysis, contribution to manuscript writing and editing; zar: study concept, data interpretation, critical revision of manuscript.all authors have read and approved the final version of the manuscript. acknowledgments: the authors would like to thank dr. zakaria aulia rahman for his guidance and assistance in the study. further information: parts of this study were presented at the 2024 bandung urological meeting held in bandung, indonesia. archivio italiano di urologia e andrologia 2025; 97(2):13880 k.. yuwono, j. nimasratu rahmatsani, nadhifah, et al. 12 brolizumab treatment is specific to the clinical response in metastatic urothelial carcinoma. urol oncol semin orig investig. 2022; 40:344.e11-344.e17. 58. umeda k, tanaka n, yasumizu y, et al. site-specific differences in pd-1 blockade success and biomarkers in urothelial carcinoma treated with pembrolizumab. clin genitourin cancer. 2023; 21:128-35. 59. yamamoto s, fukushima h, fukuda s, et al. early cancer cachexia phenotype predicts survival of advanced urothelial cancer patients treated with pembrolizumab. asia pac j clin oncol. 2022; 18:410-8. 60. yamashita s, wada t, deguchi r, et al. prognostic significance of pre-treatment albumin-bilirubin grade in metastatic urothelial carcinoma receiving pembrolizumab. jpn j clin oncol. 2023; 53:845-50. correspondence kevin yuwono yuwonokvn@gmail.com junjungan nimasratu rahmatsani junjungan.nr@gmail.com nadhifah nadhifah nadhifahmahfudi@gmail.com revina maharani 10maharanirevina@gmail.com faculty of medicine, brawijaya university, indonesia zakaria aulia rahman zakariaaulia04@gmail.com department of urology, faculty of medicine, airlangga university, indonesia mayjen prof. dr. moestopo, 47, 60131, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13541 1 original paper introduction radical prostatectomy (rp) is the most common treatment option for men with localized prostate cancer worldwide, being related to excellent and reproducible cancer control rates. although progress has been made in nerve sparing (ns) surgery, erectile dysfunction (ed) still remains a common long-term complication after rp. to overcome this issue, khoudary et al performed the first simultaneous placement of a penile prosthesis during open rp in 1997, aiming at an early return to sexual function without any impact on oncological outcomes and without significant adverse effects (1). we describe a case series of patients who underwent laparoscopic extraperitoneal rp combined with ppi (during 2013) to evaluate the impact of this treatment strategy on preserving the full dimensions of the penis and improving patients’ sexual quality of life (qol) (2). aim of this study is to illustrate the ten years follow up of this case series which has no terms of comparison in the world. oncological and functional results were analyzed. materials and methods ten patients underwent simultaneous penile prosthesis implantation (ppi) (with an ams inhibizone prosthesis) and laparoscopic rp in 2013. they were evaluated by means of urological visits, dedicated questionnaires inherent in qol and sexual function, objective measurements before surgery, at discharge from the hospital, on postoperative days 21 to 28, each 3 months for the first year, and each year thereafter for 10 years. the main outcome measures were biochemical recurrence-free rate, penile length, and quality of life.1 all procedures were performed according our standard practice. all patients and their partners underwent sexual counselling with a introduction: even today, despite technological evolution, erectile dysfunction remains the most feared complication after radical prostatectomy surgery expecially for patients who report pre-existent refractory erectile dysfunction (ed) and patients in whom there is a high risk of extracapsular disease, such as any ct2c or ct3, who undergo non-nerve sparing radical prostatectomy (rp). to overcome this issue, khoudary et al. performed the first simultaneous placement of a penile prosthesis during open rp in 1997, aiming at an early return to sexual function without any impact on oncological outcomes and without significant adverse effects. ten years ago we performed laparoscopic extraperitoneal rp and simultaneous penile prosthesis implantation (ppi) on ten patients in order to preserve the full length of the penis and to improve their satisfaction and quality of life (qol) increasing the chances of ed resolution. objectives: aim of this study is to illustrate the ten years follow up of this case series which has no terms of comparison in the world. oncological and functional results were analyzed. materials and methods: in 2013 10 patients underwent simultaneous ppi (with an ams inhibizone prosthesis). patients were evaluated by means of urological visits, questionnaires, and objective measurements before surgery, at discharge from the hospital, on postoperative days 21 to 28, each 3 months for the first year, and each year thereafter. the main outcome measures were biochemical recurrence-free rate, penile length and quality of life. results: eight patients with mean age 71 (range 66-75) were reached at the 10-year follow-up; one patient died of acute infarction 10 years after surgery and another one died of disease 7 years after surgery. partners had, currently, mean age 60 (range 37-71). mean preoperative psa was 9.3 (6.3-13.7) and mean psa at 10 years was 0.08 (range 0.01-1.2). international index erectile function iief before surgery was 11 (range 9-14) and 23 (range 22-25) at 10 years. partner satisfaction rating increased from 7 (post-surgical) to 8 at 10 years. penis length was unchanged after 10 years: mean intraoperative length was 9 cm (range 8.5-9.5) and mean length at 10 years was 8.8 cm (range 8-9.5). conclusions: in our cases, laparoscopic radical prostatectomy with the simultaneous implant of a penile prosthesis demonstrate to be an interesting option to offer to selected and highly motivated patients. outcomes like preservation of the penis length, resuming of normal sexual activity 21 days after surgery, partner satisfaction and oncological safety at 10-year follaparoscopic radical prostatectomy with the simultaneous implant of a penile prosthesis: ten years follow up nicola mondaini 1, andrea abramo 1, caterina romeo 2, fabio crocerossa 1, francesco cantiello 1, rocco damiano 1, riccardo bartoletti 3 1 department of urology, magna graecia university, catanzaro, italy; 2 department of experimental medicine, magna graecia university, catanzaro, italy; 3 department of urology, university of pisa, italy. doi: 10.4081/aiua.2025.13541 summary low-up make it a valid surgical technique to be proposed in clinical practice if performed by an experienced team in prosthetic surgery. key words: radical prostatectomy; erectile dysfunction; penile prosthesis; andrology; quality of life. submitted 28 december 2024; accepted 3 january 2025 archivio italiano di urologia e andrologia 2025; 97(1):13541 n. mondaini, a. abramo, c. romeo, et al. 2 clinical sexologist, both before surgery, in order to assess their motivation to undergo such a procedure, and after surgery, in order to investigate their level of satisfaction with the results. the study was conducted in line with the strobe statement (http://www.strobe-statement.org). due to the retrospective nature of the study in italy, it did not require approval by the local ethics committee. nevertheless, it was conducted in line with the good clinical practice guidelines and the ethical principles laid down in the latest version of the declaration of helsinki. data collection all patients were evaluated with penile measurements and questionnaires which were administered before surgery, at discharge from the hospital, on postoperative days 21 to 28, each 3 months for the first year, and each 6 months thereafter. at the time of surgery, the following parameters were recorded: the patient’s and partner’s age, the charlson comorbidity index, preoperative prostatespecific antigen levels, gleason score, penile length, clinical prostate cancer stage (through an abdominal computed tomography (ct) scan and skeletal scintigraphy), estimated blood loss, visual analogue scale (vas) pain scores, analgesic use, duration of hospital stay, and surgical complications, according to the clavien-dindo classification. penile length measurements penile length was evaluated through a manual measurement of the fully stretched penis in the flaccid state. the length was obtained from the pubis to the tip of the penis and made in centimeters (3). questionnaires patients completed dedicated questionnaires for satisfaction and the 36-item short form health survey (sf-36) questionnaire. patients’ satisfaction was evaluated using patient-reported outcomes (pros). qol was measured using an italian version of the sf-36 health survey, a test particularly suitable for chronic conditions. a year after surgery patients and their partners were also asked to rate their level of sexual satisfaction on a scale of 1 to 10, with 1 meaning “completely unsatisfactory” and 10 meaning “maximum level of satisfaction”. we decided to use the pros tool instead of the international index of erectile function questionnaire because the aim of the present study was to evaluate the impact of laparoscopic extraperitoneal rp with simultaneous ppi on patients’ satisfaction (1). surgical procedure all laparoscopic rp procedures were performed by a single experienced uro-oncological surgeon (rb). all penile prostheses were placed by a single surgeon with high-volume experience in ppi surgery (nm). upon conclusion of the prostatectomy and after removing the prostate via access through a hasson trocar we manually positioned the reservoir. the pneumo-retzius was redetermined and the positioning of the reservoir optimized between the bladder and pubis. we then made a penile-scrotal incision and isolated the internal inguinal ring with a blunt incision as far as the external fascia of the rectal-abdominal muscles that was crossed by fine-tip forceps, the path of which was simultaneously monitored from the laparoscopic access. the reservoir tube, previously plugged with a special titanium plug, was then dislocated to the penile-scrotal incision. the reservoir was then inflated and its location checked once again. a pelvic drain was positioned and removed on day 1. after ensuring haemostasis, the implant was positioned. the two cylinders were initially positioned following bilateral cavernosotomy, followed by the pump that was placed at the level of the scrotum, and subsequently tubing were connected. the prosthesis was then almost fully activated for the first 24 hours with a compressive bandage. all patients stayed for 4 hours in a nurse-operated recovery room. the drain was removed on day 1 and patients were discharged from the hospital on day 4. on day 10, retrograde and voiding cystography was carried out after removing the bladder catheter. activation of the prostheses took place between day 21 and day 28. ethical considerations the present study was conducted as a consecutive case series in which patients who received a similar treatment were followed and all outcomes were recorded and analyzed. even though the case series had a descriptive study design, the local ethical committee was informed about the study. results among patients that were enrolled in this study with a median age of 71 years, one died of acute infarction 10 years after surgery (group no adjuvant therapy) and another died of disease 7 years after surgery (group radiotherapy after surgery). according to the clavien-dindo classification, the first patient reported a severe complication: migration of the reservoir into the bladder, which was resolved without prosthesis removal. this occurred even though the reservoir had been placed under vision. a ct scan was carried out, and it demonstrated a lesion on the superior wall of the bladder due to a pressure ulcer formed by the reservoir near a bladder diverticulum. the reservoir was then removed from the bladder and changed through laparotomic access. the bladder wall was then repaired and a catheter was placed. 2 after 7 days, the catheter was removed and the patient was discharged after cystography. no prosthesis infections occurred (table 1). table 1. post-surgery penile lenght measurements. time median penile lenght (cm) intraoperative 9.0 (8.5-9.5) 12 mo 9.0 (8-9.7) 24 mo 9.0 (8.2-9.7) 36 mo 9 (8-9.5) 48 mo 9 (8-9.5) 60 mo 9 (8-9.5) 72 mo 9 (8-9.5) 84 mo 9 (8-9.5) 96 mo 9 (8-9.5) 108 mo 8.8 (8-9.5) 120 mo 8.8 (8-9.5) values are presented as median (range). mo: months. archivio italiano di urologia e andrologia 2025; 97(1):13541 3 radical prostatectomy with penile prosthesis implant oncological outcomes over a median follow-up of 120 months 3 patients were disease-free without adjuvant therapy, and 4 were on hormonal therapy; 1 of the latter group had to undergo radiotherapy after surgery. penile length at the time of surgery and at the follow-up visits the median penile length at the time of the surgery was 9 cm. post-surgery penile length measurements showed the preservation of the full dimensions of the penis compared to the preoperative measurements. no statistically significant differences were found between the preoperative penile length measurements and the follow-up measurements. however, a reduction of 0.5 cm was observed in only 20% of the patients, although no patients described having problems with their penile dimensions (table 2). quality of life evaluation the pre-surgery sf-36 median value was 97 (range, 9698). according to post-surgical sexual counselling with a clinical sexologist, all patients were satisfied with their penile implants, and the couples’ level of sexual satisfaction was rated a median of 8 (range, 7-10) at follow-up 1. the median post-surgery sf-36 score was 99 (range, 9799). a statistically significant difference was found between the pre-surgery and post-surgery sf-36 scores (p = 0.02) (table 3). discussion in the 1990s, clough et al. suggested the integration of plastic surgery techniques with breast-conserving treatments for breast cancer. in the urological setting, in 1997 khoudary et al performed a combination procedure of open non-nerve-sparing retropubic rp and ppi in 50 men. this group was compared with a group of 72 men who went rp alone during the same time interval. no significant differences were noted in the preoperative patient variables. the mean operative time for prosthesis insertion was 82 minutes, and the mean time to sexual intercourse was 12.7 weeks. no prosthesis infections occurred, with a mean follow-up of 1.7 years. four men (8%) required revision of their inflatable penile prosthesis. there were no significant differences between the combination procedure and rp alone with regard to estimated blood loss, length of hospital stay or analgesic use. men who chose the simultaneous placement of a penile prosthesis with rp reported greater overall qol (1). in the present paper we reported the results of simultaneous ppi and rp performed from june 2013 to june 2014 in 10 patients who completed the study follow-up period (median, 32.2 months).” no difference was found between the time of surgery and the 2-year follow-up evaluation in terms of penile length. the pre-surgery 36item short form health survey (sf-36) median score was 97 the and median postoperative sf-36 score was 99 at 3 months follow-up (2). patients were satisfied with their penile implants, and couples’ level of sexual satisfaction was rated median 8. post-surgery penile lenght measurements showed the preservation of the full dimensions of the penis compared to the preoperative measurements. no prosthesis infections occurred, over a median followup of 120 months. in light of these results, laparoscopic extraperitoneal rp with simultaneous ppi could be proposed to selected and very motivated patients because: a) medicated ams inhibizone [american medical systems, inc. (ams), minnetonka, mn, usa] penile prostheses reduce the risk of prosthesis infections. moreover, the extraperitoneal approach is preferable in order to keep the prosthesis reservoir located in a place with a low risk of infection (3); b) simultaneous ppi preserves penile length; c) combined procedure reduces the duration of hospitalization and allows patients to quickly resume sexual activity. a faster return to a satisfactory sexual life could have a positive impact on qol and on the couple’s well-being (4). some aspects of this study should be considered, in particular the fact that all surgical oncological procedures were performed by a single dedicated surgeon and all prosthesis implantations were performed by the same surgeon with a high-volume experience. moreover, the psychological counselling support and the involvement of the partner in the surgical decision-making process should be considered strengths of this study. the main limitation of this study is the fact that it was a consecutive case series. however, our findings could serve as a basis for planning future studies. the majority of our patients had lowor intermediate-risk cancers and they could have undergone complete nerve-sparing resection, which in experienced hands, does not result in high positive margin rates. however, all patients reported stable ed with no benefits from pde5i or intracavernous therapy. for this reason, we did not consider this treatment strategy to be overtreatment. finally, the inclusion of a psytable 2. clinical, laboratory and demographic characteristics. characteristic value patients 10 (2 died) age (y) (at 120 mo) 71 (66-75) psa (pre-surgery) 9.3 (6.3-13.7) psa (post surgery) (at 120 mo) 0.08 (0.01-1.2) iief score (pre-surgery) 11 (9-14) iief score (post-surgery) (at 120 mo) 23 (22-25) partner’s age (y) (at 120 mo) 60 (37-71) values are presented as number only or median (range). psa: prostate-specific antigen; iief: international index of erectile function. table 3. questionnaire and quality of life results at enrolment and at last follow-up. variable quality of life result sf-36 pre-surgery (enrolment) 97 (96-98) post-surgery (120 m) 99 (97-99) sexual satisfaction scale 8 (7-10) values are presented as median (range). sf-36: 36-item short form health survey. archivio italiano di urologia e andrologia 2025; 97(1):13541 n. mondaini, a. abramo, c. romeo, et al. 4 chologist in the patients’ care should be considered a strength of this study. psychological support during the ppi is a key means of improving adherence to the followup and overall outcomes. we believe that laparoscopic extraperitoneal rp can be considered an optimal surgical technique that offers considerable safety margins for the simultaneous implantation of a tricomponent penile prosthesis, even though simultaneously performing 2 surgical procedures may increase the risk of complications. the hospitalization length is no longer than that required for normal surgery, and the additional costs of the prostheses can be easily amortized by avoiding the costs of a second surgical operation for the penile implant and avoiding the postoperative use of prostaglandins for penile erection. the main complications of prostate cancer surgery are ed and urinary incontinence. several patients received an artificial sphincter for urinary incontinence. the presence of a penile implant is not a contraindication for artificial sphincter implantation. the cuff can be placed through the perineal approach in the bulbar urethra or over the bladder neck in particular cases. the reservoir can be placed on the opposite site of the penile implant reservoir and the pump in the opposite part of the scrotum. conclusions the aim of this study is to evaluate the outcome of simultaneous ppi and rp. the ideal candidates are those who report pre-existent refractory ed and patients in whom there is a high risk of extracapsular disease, such as any ct2c or ct3, who undergo non-nerve sparing rp. a simultaneous procedure would avoid two admissions, reduce hospitalization time and guarantee a faster recovery of sexual function, preventing the otherwise unavoidable loss of penile length. since the urologist does not need to preserve the neurovascular bundles, as the penile implant will take care of postoperative rigidity, rp can be performed more radically from an oncological point of view, thus reducing the risk of recurrence and metastasis, especially in patients with high risk disease. in conclusion, simultaneous ppi with rp provides early sexual rehabilitation, improving patients' qol, without compromising surgical outcomes. however, larger series will be necessary, to better identify the patients who are more likely to benefit from nerve sparing surgery and postoperative penile rehabilitation from those who would are more likely to develop refractory ed post rp and would therefore benefit from simultaneous ppi. references 1. khoudary kp, dewolf wc, bruning co 3rd, morgentaler a. immediate sexual rehabilitation by simultaneous placement of penile prosthesis in patients undergoing radical prostatectomy: initial results in 50 patients. urology. 1997; 50:395-9. 2. mondaini n, cai t, sarti e, et al. a case series of patients who underwent laparoscopic extraperitoneal radical prostatectomy with the simultaneous implant of a penile prosthesis: focus on penile length preservation. world j mens health. 2018; 36:132-138. 3. cakir oo, pozzi e, castiglione f, et al. penile length measurement: methodological challenges and recommendations, a systematic review. j sex med. 2020; 18:433-439. 4. cocci a, cito g, romano a, et al. radical prostatectomy and simultaneous penile prosthesis implantation: a narrative review. int j impot res. 2020; 32:274-280. correspondence nicola mondaini, md (corresponding author) n.mondaini@unicz.it andrea abramo, md a.abramo10@gmail.com fabio crocerossa, md crocerossa@unicz.it francesco cantiello, md cantiello@unicz.it rocco damiano, md damiano@unicz.it department of urology, magna graecia university, 88100 catanzaro italy. caterina romeo, md cateromeo93@hotmail.it department of experimental medicine, magna graecia university, catanzaro, italy riccardo bartoletti, md bartoletti@unipi.it department of urology, university of pisa, italy declarations ethical approval: the case series has been approved by the local medical research ethics committee. protocol number 78901. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: there are no sources of funding for the research. authors' contributions: nm, study concept, data analysis and interpretation, manuscript original drafting; statistical analyses; aa, statistical analyses, contribution to manuscript writing and editing; cr, participated in writing fc, participated in writing, language editing; fc, participated in writing, language editing; rd, critically reviewed the study proposal; rb, proofreading. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13207 1 original paper introduction necrotizing soft tissue infections are serious conditions caused by bacterial toxins that activate a severe systemic inflammatory response. fournier's gangrene (fg) is a rare and severe form of necrotizing fasciitis that affects the perineum, external genitalia, and adjacent tissues. it was first described in 1764 by baurienne, but the french physician jean alfred fournier is more widely credited with its identification. in 1883, fournier presented a case series of 5 young men with this condition, highlighting its sudden onset and potentially fatal nature (1). fg progresses rapidly, affecting the subcutaneous and fascial planes (2). according to sorensen et al., fg affects less than 0.02% of hospital admissions, with an incidence rate of 1.6 cases per 100.000 people (3). it mainly affects men, with an average age of 60 years, and the male-to-female ratio is 10:1 (2, 4). several risk factors have been associated with the development of fg, including immunosuppression, diabetes, hiv, malignancies, inflammatory bowel disease, renal and hepatic failure, recent trauma, and medical procedures (2, 4). the use of antihyperglycemic drugs, such as sodiumglucose cotransporter 2 inhibitors (sglt2i), has also been linked to fg in some cases (5). inflammation and edema result in obliterating endarteritis, leading to thrombosis of subcutaneous blood vessels. this causes ischemia and necrosis along the dartos fascia, colles' fascia, scarpa's fascia, and the abdominal wall (6). diagnosis of fg usually involves a clinical examination, radiological tests, and laboratory analyses. the onset of necrotizing fasciitis can be slow, with up to 40% of cases showing no symptoms. when symptoms do appear, they may include pain in the genital and perineal areas, with little to no visible skin damage in the early stages. as the condition progresses, the skin may become red and dusky, and there may be a foul-smelling discharge from the genital and perineal areas, along with a crackling sensation under the skin (7). treatment usually involves a combination of broad-spectrum antibiotics, fluid resuscitation, and multiple surgical objective: fournier's gangrene (fg) is a rare, life-threatening necrotizing fasciitis primarily affecting the perineal, genital, and perianal regions. this rapidly progressing bacterial infection predominantly affects middleaged and elderly men. this multicenter study aims to describe the management in a wide cohort of fournier's gangrene cases that presented to three tertiary centers with early extensive surgical debridement. materials and methods: we retrospectively collect data from patients with fg who were referred to the urology clinic of the department of medicine and surgery (perugia), the urological andrological surgery and minimally invasive techniques unit (terni) of the university of perugia, and the urology unit of the surgery department of the macerata civic hospital between january 2019 and march 2024 for onset of classic signs and symptoms of fg. extensive surgical debridement was immediately performed under general anesthesia to reach normochromic and vascularized tissue in wide and depth extension, assuring vital and healthy margins. for all patients, intravenous daptomycin plus piperacillin/tazobactam were administered. results: 28 male patients with fg underwent early surgical debridement. in two cases, orchidectomy and partial penectomy were required during surgical debridement due to extensive necrosis. colon diversion and urinary diversion were not necessary for any of the patients. 32.1% complications were recorded in according to the clavien dindo classification; 6 patients died in the perioperative. excluding death data, the average duration of antibiotic therapy was 22.0 ± 9.1 days, and the average length of stay was 17.6 ± 11.8 days. conclusions: fournier's gangrene has high mortality rates. it requires timely surgical debridement and antibiotic therapy to achieve positive outcomes. this study shows that a primary extensive debridement can help reduce the need for further intervention and shorten the hospital stay. key words: fournier’s gangrene; necrotizing; fasciitis; debridement. submitted 7 october 2024; accepted 20 october 2024 enhanced patient recovery with early extensive surgical debridement in fournier's gangrene: evaluation of perioperative outcomes in a multicentric experience giovanni cochetti 1, alessio paladini 1, luca lepri 1, andrea vitale 1, raffaele la mura 1, miriam russo 1, paolo mangione 1, matteo mearini 1, andrea fabiani 2, emanuele iacobone 2, lucilla servi 2, ettore mearini 1, 3, michele del zingaro 1 1 department of medicine and surgery, urology clinic, university of perugia, perugia, italy; 2 surgery department, urology unit, macerata civic hospital, area vasta 3 asur marche; 3 department of medicine and surgery, urological andrological surgery and minimally invasive techniques unit, s. maria hospital, university of perugia, terni, italy; doi: 10.4081/aiua.2025.13207 summary archivio italiano di urologia e andrologia 2025; 97(1):13207 g. cochetti, a. paladini, l. lepri, et al. 2 debridements, with an average of 3.5 procedures per patient (8). in severe cases, intensive supportive care may be necessary for hours or days (9). delayed diagnosis and treatment can lead to high mortality rates, which can reach up to 30% or more in some instances (3, 10, 11). to further explore this rare and deadly condition, we conducted a retrospective analysis of patients admitted and treated for fg with typically extensive surgical debridement in three tertiary referral centers in the last 5 years. materials and methods we included all patients who were referred to urology clinic of the department of medicine and surgery (perugia) and the urological andrological surgery and minimally invasive techniques unit (terni) of the university of perugia, and the urology unit of the surgery department of the macerata civic hospital between january 2019 and march 2024 for onset of classic signs and symptoms of fg. all patients signed an informed consent form to anonymously treat their medical data for scientific purposes at the hospital admission. for each patient, vital signs and parameters, the charlson comorbidity index, medical history, blood exams, urinary samples, and blood cultures were recorded. a local ultrasound and a thoracic-abdomen ct scan were performed in all cases. we included in the patient’s evaluation the laboratory risk indicator for necrotizing fasciitis (lrinec) introduced in 2004 by wong et al. to help distinguish necrotizing fasciitis from other soft tissue infections (12). we also performed the fournier’s gangrene severity index (fgsi) as a mortality predictor tool for fg patients, created by laor et al. (13). all patients underwent prompt fluid resuscitation and broad-spectrum intravenous antibiotics within one hour of emergency department admission. if there was suspicion of fg, extensive surgical debridement was immediately performed under general anesthesia in the operative theatre, considering reaching normochromic and vascularized tissue in wide and depth extension, assuring vital and healthy margins. subsequent debridements were performed only when signs of local necrosis or de-vascularized tissue appeared in the next few days. patients were assumed to be cured once they achieved normalized vital signs, had negative blood cultures and wound microbiological examinations, and had normal levels of c-reactive protein and procalcitonin. additionally, their surgical wounds needed to heal completely without any discharge or pain. follow-up care involved periodic visits with specialists and medication, if necessary. complications were recorded and reported according to the clavien-dindo classification. a descriptive analysis was conducted, with continuous variables reported as mean with standard deviation (sd) and categorical variables reported as frequencies (%). results the study involved 28 male patients, with an average age of 59.6 ± 14.3 years and a mean charlson comorbidity index of 4.7 ± 2.4. all patients displayed local edema and necrotized skin (figure 1) as the primary clinical presentation, with additional symptoms including erythema (78.5%), fever (57.1%), local pain (42.8%), subcutaneous crepitation (32.1%), and purulent exudate (10.7%) (figure 2). in all cases, the blood exams revealed a neutrophilic leukocytosis, a mean c-reactive protein of 32.7 ± 16.2 mg/l, and procalcitonin of 27.41 ± 12.7 ng/ml. the ultrasound showed a significant thickening of the area involved with fluid intrafascial film and several hyperechoic spots with posterior echoes as for the aerial components. the ct scan confirmed the presence of a large amount of air and gas in the surrounding soft tissues and served to better explore the tissues involved. the mean fgsi and lrinec scores were 3.6 ± 1.4 and 6.3 ± 2.1, respectively. the most common comorbidities were diabetes (64.3%), hypertension (57.1%), and cardiac disease (57.1%). polymicrobial flora with aerobic and anaerobic bacteria was the dominant report (67.8%), followed by staphylococcus (21.4%) and enterococcus faecium (7.1%) wound culture. for all patients, intravenous daptomycin plus piperacillin/ tazobactam were administered: 3 (10.7%) and 2 (7.1%) patients required a switch from piperacillin/tazobactam to figure 1. left emiscrotal necrotizing fasciitis. figure 2. fournier’s gangrene with purulent discharge. archivio italiano di urologia e andrologia 2025; 97(1):13207 3 extensive surgical debridement in fournier's gangrene imipenem-cilastatin due to infection by enterococcus faecalis and escherichia coli extended-spectrum beta-lactamase (esbl) producer, respectively. on average, patients underwent surgery 14.2 ± 5.7 hours after accessing the emergency department (figure 3). in two cases, orchidectomy and partial penectomy were required during surgical debridement due to extensive necrosis. colon diversion and urinary diversion were not necessary for any of the patients. six patients (21.4%) required blood pressure support with intravenous noradrenaline after surgery and were admitted to the intensive care unit (icu) for 26 ± 4.3 hours. five patients (17.8%) required subsequent debridement, with a mean of 0.3 ± 0.5 further surgical debridements performed before discharge; all surgical debridements were performed bedside with local anesthesia. reconstructive surgery by a plastic surgeon was performed on 14.3% of in-patients to improve tissue and skin restoration in the treated site. one patient, affected by diabetes mellitus, chronic kidney disease, and immunosuppression due to the assumption of everolimus for transplanted kidney required the use of vacuum-assisted closure (vac) therapy for the scrotal skin for approximately 20 days with gradual recovery and complete re-epithelialization. complications were recorded in nine patients (32.1%) according to the claviend dindo classification; 3 (10.7%) patients underwent blood transfusion (grade ii), and six patients (21.4%) died (grade v), with an average time to death of 3.5 ± 2.1 days. of those, one patient had multiple comorbidities, a patient had duchenne syndrome and succumbed to acute respiratory distress syndrome. one of these patients was admitted to the operating theatre 36 hours after symptom onset due to an unstable clinical condition. the other three pateints died in the 48 hours after debridment due to the compromission of the cardiovascole system due to septic shock. excluding death data, the average duration of antibiotic therapy was 22.0 ± 9.1 days, and the average length of stay was 17.6 ± 11.8 days. discussion prompt fluid resuscitation, broad-spectrum intravenous antibiotics, and primary extensive surgical debridement are safe and effective procedures that help reduce mortality, re-interventions, and hospital length of stay. fg constitutes a rare disease, accounting for only 0.02% of hospital admissions (3). initially considered idiopathic, the cause of fg is now identifiable in most cases, often coming from aerobic and anaerobic bacterial infections in the ano-rectum (30-50%), uro-genitalia (20-40%), and genital surface (20%) (2, 11). it predominantly affects immunocompromised individuals and those with compromised microcirculation, with risk factors including diabetes, obesity, chronic alcoholism, smoking, drug abuse, renal and liver failure, pelvic malignancies, inflammatory bowel diseases, hiv infection, recent trauma, and recent urethral and perineal surgery. fg is more prevalent in individuals with malnutrition and lower socioeconomic status (2). diabetes, in particular, has been associated with 32-66% of fg cases, with uncontrolled diabetes linked to a poorer prognosis and necessitating more aggressive treatment (11). the use of sglt2i drugs in diabetic patients has been initially correlated with increased fg cases, although subsequent studies have disputed this correlation, warranting further investigation. our case series is in line with previous studies, which highlight diabetes as a significant risk factor for the development of fg. around 64% of the patients in our study had type ii diabetes mellitus, and all of them were male. the average age at diagnosis was consistent with recent literature. it is well known that males are more susceptible to developing fg. however, females, despite being less affected, are at a higher risk of fg-related mortality due to anatomical differences that enable rapid infection spread in women (14). histological examination of patients with fg shows necrosis of the superficial and deep fascia, fibrinoid coagulation in the blood vessels, infiltration of tissues by various types of cells, and necrotic tissue debris. a key identifying feature is the presence of blood vessel thrombosis in the affected area. interestingly, even when there are significant pathological changes in the deep tissues, the skin can remain intact for a prolonged period (4). up to 40% of fg cases manifest with no symptoms initially, making early diagnosis challenging. symptoms include genital and perianal pain, erythematous and dusky skin, subcutaneous crepitation, and malodorous and purulent exudates. differential diagnosis involves distinguishing fg from conditions such as gangrenous balanitis in males with diabetes and ulcerative forms of inguinal lymphogranulomatosis, gangrenous diabetic vulvitis, acute genital ulcers, and soft cancer in women. the lrinec score aids in diagnosis, with scores ≥ 6 indicating suspicion of necrotizing fasciitis and ≥ 8 strongly suggestive (15, 16). in our study, we started the antibiotic therapy with intravenous daptomycin plus piperacillin/tazobactam, according to the empiric treatment of necrotizing fasciitis, and only after microbiological culture did we decide to switch the therapy according to the sensitivity. the primary goal of antibiotic therapy in fg is to control the systemic figure 3. surgical debridement of the necrotic tissue. archivio italiano di urologia e andrologia 2025; 97(1):13207 g. cochetti, a. paladini, l. lepri, et al. 4 infection and reduce the bacterial load in the affected area. because the infection is polymicrobial, broad-spectrum antibiotic coverage is essential until specific bacterial cultures can guide more targeted therapy. antibiotic treatment should begin immediately upon diagnosis, as any delay can result in the worsening of the infection and an increased risk of mortality. initial antibiotic therapy typically involves broad-spectrum agents covering aerobic and anaerobic bacteria. this often includes a combination of agents such as a carbapenem (e.g., meropenem or imipenem) or piperacillin-tazobactam, which provide broad coverage against gram-positive, gram-negative, and anaerobic bacteria. in some cases, an aminoglycoside (e.g., gentamicin) or fluoroquinolone may be added to cover resistant gram-negative bacteria. additionally, metronidazole or clindamycin is often included to target anaerobic bacteria, particularly clostridium species, which can produce dangerous toxins (4). once culture results and antibiotic sensitivity profiles are obtained, the treatment can be adjusted to target the specific bacteria responsible for the infection. this strategy helps minimize antibiotic resistance development while maintaining effective control over the infection. the duration of antibiotic therapy varies depending on the severity of the infection and the patient’s response to treatment. the management of fg with antibiotics presents several challenges. first, the condition often occurs in patients with underlying health issues, such as diabetes, immunosuppression, or chronic kidney disease, which complicate the selection and dosing of antibiotics. these patients may require adjusted dosages or alternative agents to avoid drug toxicity while ensuring effective antimicrobial coverage. additionally, the rise of antibiotic-resistant organisms poses a growing threat to the treatment of necrotizing infections like fg. methicillin-resistant staphylococcus aureus (mrsa) and multidrug-resistant gram-negative bacteria, such as esbl-producing e. coli and klebsiella, are increasingly implicated in these infections. more specialized antibiotics may be required to combat resistant strains, such as vancomycin, linezolid, or daptomycin. careful monitoring of antibiotic effectiveness and resistance patterns is essential to ensure successful treatment. an urgent debridement is necessary to improve outcomes. according to lin et al., surgery should be performed within 15 hours of the onset of symptoms to avoid an increased risk of major complications (17). moreover, multiple further surgical debridements are usually needed in the operative theatre to the rapid disease relapse. in our study, the average time to surgery was approximately 14 hours, which explains the survival rate in line with the literature. surgery aims not only to remove damaged tissue but also to drain the infection completely. the full extent of the disease may not be apparent from the areas of skin involvement, which is typically less than the involvement of tissue beneath the skin. it's important to be careful not to unintentionally open up deeper facial layers that were not originally affected. our case series differs from the findings in the literature, as only 17.8% of patients required additional debridement after 24 hours, and 14.3% underwent reconstructive surgery. this result could be reached with a primarily extensive debridement in hemodynamically stable patients. our hospitals did not use hyperbaric oxygen therapy (hbot) for wound healing due to logistical constraints. according to the literature, hbot has been found to have lower mortality rates compared to conventional therapy. however, its impact on the length of stay and number of debridements is inconclusive. hbot has emerged as a promising adjunct in the management of necrotizing fasciitis. by increasing the partial pressure of oxygen in tissues, hbot can significantly enhance the body's natural defense mechanisms. the elevated oxygen levels create a hostile environment for anaerobic bacteria, often the primary culprits in necrotizing fasciitis, particularly in conditions like fg. additionally, hbot stimulates the production of reactive oxygen species, which can directly damage bacterial cells. beyond its direct antimicrobial effects, hbot promotes angiogenesis and tissue granulation, accelerating wound healing. this is achieved by improving local blood flow, enhancing the delivery of nutrients to damaged tissues, and stimulating the growth of new blood vessels. furthermore, hbot can modulate the immune response, reducing inflammation and enhancing the body's ability to fight infection. while the evidence supporting the use of hbot in necrotizing fasciitis is growing, its application has limitations. the optimal timing, duration, and frequency of hbot treatments remain subjects of ongoing research. moreover, the cost of hbot and the logistical challenges associated with its delivery can limit its accessibility in many healthcare settings (18). our experience, on the other hand, suggests that a multimodal treatment strategy, which includes daily site cleansing, can achieve complete restoration without the need for hbot or surgical grafting while maintaining optimal outcomes despite comparable mortality rates. one of the modern advancements in wound care is the use vac therapy, also known as negative pressure wound therapy (npwt). vac therapy has become a valuable tool in managing the large, complex wounds that follow the debridement of necrotizing fasciitis, offering several benefits that promote healing and reduce complications (19). vac therapy offers several key advantages in the management of necrotizing fasciitis. first and foremost, it accelerates wound healing by creating an optimal environment for tissue regeneration. large wounds, such as those caused by necrotizing fasciitis, are often slow to heal. still, applying negative pressure can speed up the process by improving blood flow and promoting healthy tissue growth. this is particularly important in reducing the need for additional surgeries or skin grafts (20). despite its many advantages, vac therapy is not without challenges. the cost of the equipment and the need for specialized training to properly administer the therapy can limit its accessibility in some healthcare settings (21). in the case of fg, which poses a significant risk of mortality (20-30%), medical emergency measures should be taken. these measures include fluid resuscitation, broadspectrum antibiotics, and urgent surgical debridement. the timely execution of these measures is crucial, and various validated scores, such as the fgsi and uludag fgsi (ufgsi) (13, 22, 23) can predict mortality rates associated with fg (24-26). our experience shows that the death rate (21.4%) is consistent with existing literaarchivio italiano di urologia e andrologia 2025; 97(1):13207 5 extensive surgical debridement in fournier's gangrene ture, with only one death attributed to the progression of duchenne syndrome and not fg. in one case, delays in diagnosis and treatment were observed, highlighting the significance of timely intervention. the length of hospital stay (los) has decreased significantly. the first study was conducted by carroll et al. in 1986 (27) reported a los of 48 days, whereas the latest review by bowen et al. (28) showed a reduced los of 18.5 days. our study also reported a lower los, which we attribute to the small number of re-debridements. conclusions fg is a rare but serious health condition that still has high mortality rates. it requires prompt and comprehensive intervention that should include timely surgical debridement and antibiotic therapy to achieve posi-tive outcomes. the study emphasizes the difficulties involved in managing this complex condition. however, it also shows that a primary extensive debridement can help reduce the need for further intervention and shorten the hospi-tal stay. references 1. singh a, ahmed k, aydin a, et al. fournier’s gangrene. a clinical review. arch ital urol androl. 2016; 88:157. 2. paladini a, cochetti g, tancredi a, et al. management of fournier’s gangrene during the covid-19 pandemic era: make a virtue out of necessity. basic clin androl. 2022; 32:12. 3. sorensen md, krieger jn. fournier’s gangrene: epidemiology and outcomes in the general us 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fasciitis. front surg. 2017; 4:36. 10. auerbach j, bornstein k, ramzy m, et al. fournier gangrene in the emergency department: diagnostic dilemmas, treatments and current perspectives open access emerg med. 2020; 12:353-364. 11. singh a, ahmed k, aydin a, et al. fournier’s gangrene. a clinical review. arch ital urol androl. 2016; 88:157. 12. wong c-h, khin l-w, heng k-s, et al. the lrinec (laboratory risk indicator for necrotizing fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections*. crit care med. 2004; 32:1535-41. 13. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier’s gangrene. j urol. 1995; 154:89-92. 14. czymek r, frank p, limmer s, et al. fournier’s gangrene: is the female gender a risk factor? langenbecks arch surg. 2010; 395:173-80. 15. kincius m, telksnys t, trumbeckas d, et al. evaluation of lrinec scale feasibility for predicting outcomes of fournier gangrene. surg infect (larchmt). 2016; 17:448-53. 16. wang t-l, hung c-r. role of tissue oxygen saturation monitoring in diagnosing necrotizing fasciitis of the lower limbs. ann emerg med. 2004; 44:222-8. 17. lin t-y, cheng i-h, ou c-h, et al. incorporating simplified fournier’s gangrene severity index with early surgical intervention can maximize survival in high-risk fournier’s gangrene patients. int j urol. 2019; 26:737-43. 18. raizandha ma, hidayatullah f, kloping yp, et al. the role of hyperbaric oxygen therapy in fournier’s gangrene: a systematic review and meta-analysis of observational studies. int braz j urol. 2022; 48:771-81. 19. assenza m, cozza v, sacco e, et al. vac (vacuum assisted closure) treatment in fournier’s gangrene: personal experience and literature review. clin ter. 2011; 162:e1-5. 20. zhang r, zhang y, hou l, yan c. vacuum-assisted closure versus conventional dressing in necrotizing fasciitis: a systematic review and meta-analysis. j orthop surg res. 2023; 18:85. 21. agarwal p, kukrele r, sharma d. vacuum assisted closure (vac)/negative pressure wound therapy (npwt) for difficult wounds: a review. j clin orthop trauma. 2019; 10:845-8. 22. yilmazlar t, isik o, ozturk e, et al. fournier’s gangrene: review of 120 patients and predictors of mortality. ulus travma acil cerrahi derg. 2014; 20:333-7. 23. sparenborg jd, brems ja, wood am, et al. fournier’s gangrene: a modern analysis of predictors of outcomes. transl androl urol. 2019; 8:374-8. 24. al-kohlany k, baker k, ahmed f, et al. treatment outcome of fournier’s gangrene and its associated factors: a retrospective study. arch ital urol androl. 2023; 95:11318. 25. ghabisha s, ahmed f, al-wageeh s, et al. prognostic determideclarations ethical approval: institutional review board statement not applicable. availability of data and material: data reported in this article are all available at location cited in the reference section. competing interests: the authors declare no conflicts of interest. funding: this research received no external funding. authors’ contributions: conceptualization, g.c. and a.v.; methodology, e.m. and l.s.; formal analysis, l.l.; investigation, m.r.; data curation, m.d.z. and e.i.; writing-original draft preparation, a.p. and m.m.; writing-review and editing, a.v., r.l.m. and a.f.; supervision, m.d.z. and p.m.; project administration, g.c. all authors have read and agreed to the published version of the manuscript. acknowledgments: not applicable. informed consent statement: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13207 g. cochetti, a. paladini, l. lepri, et al. 6 nants and treatment outcomes of fournier’s gangrene treatment in a resource-limited setting: a retrospective study. arch ital urol androl. 2023; 95:11450. 26. wirjopranoto s, affandi mr, ashari fy, et al. evaluating prognostic indicators for in-hospital mortality in fournier’s gangrene: a 7year study in a tertiary hospital. arch ital urol androl. 2024; 96:12387. 27. carroll pr, cattolica e v, turzan cw, mcaninch jw. necrotizing soft-tissue infections of the perineum and genitalia. etiology and early reconstruction. west j med. 1986; 144:174-8. 28. bowen d, juliebø-jones p, somani bk. global outcomes and lessons learned in the management of fournier’s gangrene from highvolume centres: findings from a literature review over the last two decades. world j urol. 2022; 40:2399-410. correspondence giovanni cochetti giovanni.cochetti@unipg.it alessio paladini alessiopaladini89@gmail.com luca lepri lucalepri3@libero.it andrea vitale (corresponding author) andrea.vitale69@yahoo.it raffaele la mura lamura@specializzandi.unipg.it miriam russo miriam.russo@specializzandi.unipg.it paolo mangione paolo.mangione@specializzandi.unipg.it matteo mearini matteo.mearini@outlook.it michele del zingaro michele.delzingaro@unipg.it department of medicine and surgery, urology clinic, university of perugia, perugia, italy andrea fabiani andreadoc1@libero.it emanuele iacobone emanuele.iacobone@sanita.marche.it lucilla servi lucilla.servi@sanita.marche.it surgery department, urology unit, macerata civic hospital, area vasta 3 asur marche, italy ettore mearini ettore.mearini@unipg.it department of medicine and surgery, urological andrological surgery and minimally invasive techniques unit, s. maria hospital, university of perugia, terni, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11642 1 original paper the recent multiagent chemotherapy protocols and high sensitivity of imaging techniques. management strategy includes high inguinal orchiectomy with or without retro-peritoneal nodal dissection and multiagent chemotherapy depending on the stage and group of disease (4). patients with no sampling of para-aortic nodes are managed as stage iii disease. in our institute, retro-peritoneal nodal sampling is not widely adopted and radiation therapy to para-aortic chain is used as an alternative. herein, we review our experience and clinico-epidemiological factors were studied as well as treatment strategies potentially influencing disease-free survival (dfs) in addition to overall survival (os) and loco regional recurrence (lrr).we aim to explore treatment outcomes with radiation therapy instead of retro-peritoneal nodal dissection. patients and methods this is a retrospective study involving all patients with para-testicular rms presented to nci, cairo university in the period from 2005 till 2020. irb approval was obtained before data collection from ethical committee of faculty of medicine, cairo university. no consents were required given the retrospective nature of the study. patients' records were reviewed to extract clinico-epidemiological data including age, pathological subtype, tumor size , risk stratification, staging and treatment data including type of surgery (biopsy or resection, para-aortic lymph node dissection), chemotherapy regimen and radiotherapy details (dose, overall period of treatment, radiation technique and timing of radiation),and patterns of failure. patients with incomplete treatment records were excluded from data analysis. all patients were diagnosed by initial biopsy (high inguinal orchiectomy or trans-scrotal). patients who underwent complete surgical staging were staged according to irsg postsurgical grouping classification (5) (table 1), while those who underwent orchiectomy only without nodal assessment or those with clinical positive nodes were managed as background: para-testicular rhabdomyosarcoma (pt-rms) has a favorable treatment outcome adopting multidisciplinary management; resection, namely high inguinal orchiectomy ± retro-peritoneal lymph node dissection (rplnd) followed by standard or intensive chemotherapy ± adjuvant radiation therapy. patients and methods: this is a retrospective study including all patients with pathologically proven pt-rms, presented to the national cancer institute, cairo university, during the period from 2005 to 2020. endpoints included overall survival, disease free survival and patterns of failure of different treatment modalities. results: forty one patients were identified. median age in our cohort was 15 years (range: 2-54 years). after a median follow up of 26 months (range, 3-75 months) ,two and five years os were 100% and 91.7% respectively and median survival was not reached. patients who underwent retro-peritoneal nodal dissection had a 5-year dfs rate of 100% versus 73% for those who received radiation to para-aortic nodes (p = 0.185). limitations include retrospective nature and deviation from cog protocol. conclusions: this study shows promising results suggesting that less aggressive local treatment modalities including radiation to para-aortic chain could be an option in pt-rms, given the excellent results of this subtype. however further validation in a prospective study is warranted. key words: para-testicular rhabdomyosarcoma; retro-peritoneal dissection; radiation therapy. submitted 5 august 2023; accepted 31 august 2023 introduction paratesticular rhabdomyosarcoma (pt-rms) is a special entity of rhabdomyosarcoma with an estimated incidence around 7% of all patients with rms (1). the prognosis for patients with localized disease is excellent, owing to early detection of the tumor given its special location and a predominance of paired box gene (pax)-fusion negative rms (2, 3). this allows for using less aggressive local treatment modalities especially with treatment results of para-testicular rhabdomyosarcoma (pt-rms) using radiation as an alternative to retro-peritoneal nodal dissection: a single institution experience yasser a. abdelazim 1, monika f. zaki 1, mohsen m. abdel mohsen 2, reem m. emad 1, heba g. mohamad 3, dalia abdelfatah 4, ehab m. kalil 1 1 department of radiation oncology, national cancer institute, cairo university, egypt; 2 department of clinical oncology, faculty of medicine, cairo university, egypt; 3 department of surgical oncology, national cancer institute, cairo university, egypt; 4 department of cancer epidemiology & biostatistics. national cancer institute, cairo university, egypt. doi: 10.4081/aiua.2023.11642 summary archivio italiano di urologia e andrologia 2023; 95(4):11642 y.a. abdelazim, m.f. zaki, m.m. abdel mohsen, et al. 2 group iii. pretreatment clinical staging was per irsg presurgical staging (5) (table 2). work up included scrotal u/s, mri of the pelvis, ct of chest and abdomen with contrast and bone scan. pet-ct was done for 5 patients for initial staging and/or post chemotherapy to assess the treatment response in last two years (2019-2020). lymph node evaluation was done using staging ct of the abdomen and pelvis in all cases. surgical nodal staging was done in only 4 cases. treatment details all patients underwent surgery for the primary testicular tumor (most of them were by inguinal approach); only 4 patients underwent therapeutic retroperitoneal lymph node dissection (rplnd) for grossly enlarged nodes on ct. postoperative chemotherapy was used according to the intergroup rhabdomyosarcoma study irsiv chemotherapy protocol (vincristine, dactinomycin, and cyclophosphamide) (6) for 42 weeks. a flow chart of the protocol is provided in figure 1. hemi-scrotum irradiation was used in cases of scrotal violation (trans-scrotal approach). iliac and inguinal nodal radiation was used with para-aortic nodal radiation in cases of presence of clinically involved nodes in these stations. regarding radiation therapy planning, patients were fixed with a mattress during ct simulation. ct cuts were taken with a slice thickness of 3 mm from level of suprasternal notch down to mid-thighs. a three-dimensional conformal radiotherapy technique was commonly used for treatment. starting from year 2020, intensitymodulated radiation therapy (imrt) technique was used for better sparing of organs at risk. radiotherapy doses were dependent on the completeness of surgical resection of the primary tumor (clinical group) and presence or absence of involved regional lymph nodes. after resection, patients with complete resection and stage i alveolar histology were treated to 36 gy, those with stage ii and uninvolved nodes received 41.4 gy, those with pathologically involved nodes received 41.4 gy and patients with positive gross nodes in planning ct received 50.4 table 1. irsg postsurgical grouping classification. group 1 localized disease, completely resected, no microscopic residual a confined to site of origin, completely resected b extends beyond site of origin, completely resected group 2 gross total resection a residual microscopic disease ( positive margins) b involved regional nodes, completely resected c microscopic local and/or regional residual disease group 3 incomplete resection or biopsy with gross residual group 4 distant metastasis figure 1. diagrammatic scheme of irs-iv protocol. table 2. irsg pre-surgical staging classification. stage sites tumor (t) size node (n) metastases (m) i orbit, head and neck t1 a n0, m0 (excluding pm), or or b n1 gu: non-bladder/non-prostate t2 or nx ii bladder/prostate, extremity, t1 or t2 a n0 or nx m0 cranial, pm other (includes trunk, retroperitoneum, and so on) iii bladder/prostate, extremity, t1 or t2 a n1 m0 cranial, pm, other (includes trunk, b n0, n1 or nx retroperitoneum, and so on) iv all any any any m1 tumor: t1, confined to anatomic site of origin, (a) < 5 cm in diameter, (b) > 5 cm in diameter; t2, extension and/or fixative to surrounding tissue, (a) < 5 cm in diameter, (b) > 5 cm in diameter; regional nodes: n0, regional nodes clinically negative; n1, regional nodes clinicallypositive; nx, clinical status is unknown; metastasis: m0, no distant metastasis; m1, metastasis present. gu, genitourinary; pm, para-meningeal. archivio italiano di urologia e andrologia 2023; 95(4):11642 3 radiation role in in pt-rms gy. the gross tumor volume (gtv) was defined as any gross nodal disease on planning ct or post-chemotherapy petct. the clinical target volume (ctv) was defined as 1.5 cm expansion on aorta and inferior vena cava (ivc) from level of 11th dorsal vertebra (dv11) down to bifurcation, excluding bowel, bone and muscles. the planning target volume (ptv) was defined as an additional 1 cm margin to ctv. kidneys, bowel and spinal cord were delineated as organs at risk. ptv coverage of minimum 95% of dose to 95% of volume was required for plan acceptance. dmax of cord was limited to < 45 gy and bilateral kidney v24 was limited to < 50%. radiation therapy was started at week 13 in patients with low risk (14 patients) whereas in other cases it was usually given at week 20 as per protocol. statistical analysis data was analyzed using ibm spss advanced statistics (statistical package for social sciences), version 21 (spss inc., chicago, il). numerical data was described as mean and standard deviation or median and range as appropriate, while qualitative data were described as number and percentage. endpoints were the disease-free survival, metastasis-free survival, loco-regional control and overall survival. overall survival was defined as the time from primary diagnosis date to death (all-cause). time to loco-regional recurrence was defined as time from primary treatment to recurrence at the primary tumor site or regional lymph nodes, whichever comes first; distant recurrences and deaths that occur before local events were ignored. distant recurrence was defined as recurrences outside these loco-regional sites; deaths and loco-regional recurrences that occur before distant events were ignored. disease-free survival (dfs) was defined as the time from primary treatment to loco-regional recurrence, distant recurrence, whichever comes first. comparisons between the two groups were made using either chisquare test or fishers exact test for categorical data. for quantitative data comparison between 2 groups was done using either parametric or non-parametric t-test as appropriate. survival analysis was done using kaplan-meier method and comparison between survival curves was done using log rank test. a p-value less than 0.05 was considered statistically significant. all tests were two tailed. results forty one patients with pathologically proven pt rms were identified in the period from january 2005 till december 2020. the median age in our cohort was 15 years (range: 2-54 years). children below 10 years constituted 24% of the total population. thirty seven (90%) patients had embryonal histology. retroperitoneal lymph node involvement was present in twelve (29%) patients by ct evaluation (four patients < 10 years and eight patients > 10 years). ten patients presented with initially metastatic disease (eight patients to lungs and two patients to supra-clavicular lymph nodes). demographic and pathological characteristics of the patients are summarized in table 3. treatment related characteristics thirty-nine (95%) patients were surgically excised completely by high inguinal orchiectomy and high cord ligation at the internal ring prior to tumor mobilization as per international guidelines; only 2 patients (5%) were managed by trans-scrotal approach. thirty seven (90%) patients did not undergo retroperitoneal lymph node dissection (rplnd), while four (10%) patients underwent inguinal orchiectomy with rplnd (all were > 10 years), patients were treated according to intergroup rhabdomyosarcoma study irs-iv protocol. all patients were treated by systemic chemotherapy (vac based regimens) for 42 weeks. radiotherapy was adopted for local control in thirty one (75%) patients, while 8 patients did not receive radiotherapy as they were low risk group (stage i, group i, embryonal histology). one patient did not receive radiation due to his guardian’s refusal and one patient did not receive local treatment due to progression during chemotherapy and he was shifted to second line chemotherapy ifosfamide/carboplatin/etoposide (ice), with good response. patients who received radiation to scrotum were due to scrotal violation during surgery and those who received radiation to inguinal and ipsilateral iliac nodes was due to presence of gross disease at these sites at presentation. the timing of radiotherapy in cog protocol was in week 13 in all risk groups. patients in low risk group received radiotherapy at week 12 and some patients were delayed to week 20. the median radiotherapy dose was 36gy table 3. demographic and pathological characteristics of patients in this study. n = 41 (%) age median (range) 15 (2-54) ≤ 10 10 (24) > 10 31 (76) histological type alveolar 2 (4.9) embryonal 37 (90.2) pleomorphic 2 (4.9) staging stage 1 23 (56.1) stage 2 4 (9.8) stage 3 4 (9.8) stage 4 10 (24.4) grouping group 1 8 (19.5) group 2 13 (31.7) group 3 20 (48.8) risk stratification low risk 14 (34.1) intermediate risk 14 (34.1) high risk 13 (31.7) archivio italiano di urologia e andrologia 2023; 95(4):11642 y.a. abdelazim, m.f. zaki, m.m. abdel mohsen, et al. 4 (range, 19.550.4 gy). treatment related characteristics are summarized in table 4. patterns of failure one patient had distant failure in lung, one patient had distant failure in bones and seven patients had nodal failure, three of them in ilio-inguinal nodes and 4 patients had para-aortic failure. in patients who underwent rplnd, one patient had para-aortic failure. survival analysis overall survival (os) after a median follow up of 26 months (range, 3-75 months), two and five years os were 100% and 91.7% respectively and median survival was not reached (figure 2). five year survival rate for patients < 10 years were 100% versus 86% for patients above 10 years of age (p = 0.390). disease free survival (dfs) five years disease free survival for the whole group was 77 percent (figure 3). patients who underwent retro-peritoneal nodal dissection had a 5-year dfs rate of 100% versus 73% for those who received radiation to para-aortic nodes (p = 0.185). five years dfs was 100% for patients < 10 years versus 71% for those > 10 years (p = 0.106). no difference in dfs between patients who had positive para-aortic nodes at presentation (n = 12) and those with negative para-aortic nodes (n = 29), with a 5-year dfs rate 90 percent vs. 72 percent, respectively (p = 0.287). local control (lc) the one-year lc is 85% for whole study group while the five-year lc is 71.2%. no difference in lc between patients with positive para-aortic nodes at presentation and those with negative nodes at 5 years (89 percent vs. 60 percent, respectively, p = 0.158). discussion this retrospective study included 41 patients with para-testicular rhabdomyosarcoma (pt rms) who presented to nci cairo university in the period from 2005 to 2020. the median age of the study patients group was 15 years which is comparable to other studies showing a median age of 16.5 years (7). the embryonal pathological subtype constituted 90% of the study group. similar results were reported in the literature with predominance of the embryonal histology representing 70% (7). regarding the surgical and clinical group, the majority of the studied patients were categorized as group 3 (50%) which is consistent with the analysis of pt rms patients treated in irs ii through iv in which surgical group 3 was reported in (40%) of cases (7). regarding the irsg stage, 56% of studied patients presented in stage i while 25% of figure 2. km curve representing overall survival for the whole study group. figure 3. kaplan meier curve representing dfs for the whole study group. table 4. treatment related characteristics in this study. surgical approach n = 41 (%) inguinal 39 (95) scrotal 2 (5) paln dissection yes 4 (10) no 37 (90) paln status positive 12 (29) negative 29 (71) type of cth vac 32 (78) vac-ice 6 (15) vac-ice-ie 1 (2.4) vcr 2 (5) archivio italiano di urologia e andrologia 2023; 95(4):11642 5 radiation role in in pt-rms patients had stage iv disease. findings are in agreement with other studies which reported stage i and iv diseases in 40% and 40% of cases respectively (7). approximately 29% of patients with pt-rms presented with retroperitoneal lymph node disease which is comparable to another study in which approximately 25% of patients with pt-rms had positive retroperitoneal lymph node disease (6). the treatment of the patients in this study followed the international guidelines regarding the surgical approach for the primary tumor (high inguinal orchiectomy) which was followed by standard chemotherapy protocol. as for the nodal regional control in positive retroperitoneal lymph nodes, radiotherapy was used in most of the patients (90%) instead of rplnd which was only done in four patients (10%). this policy adapted by our institute is contradictory to the current protocol for children's oncology group (cog) adapting ipsilateral staging rplnd for all boys aged 10 years or more and for those with enlarged lymph nodes suspicious for metastatic disease on ct scan, or patients with alveolar histology irrespective of the age (8). retro-peritoneal nodal dissection carries a high post-operative morbidity rates between 520% at high-volume centers. the most common complications being small bowel obstruction, retrograde ejaculation, lower extremity lymphedema, hydronephrosis and chylous ascites (9-11). these complications are considered more significant compared for nodal irradiation complications which include radiation dermatitis, gastroenteritis, and myelosuppresion (12). despite these low rates of para-aortic nodal dissection in our study, median os was not reached and the calculated one and five year os rates were 100% and 91.7% respectively, reflecting the excellent prognosis of the disease regardless of the nodal regional treatment modality used. these results are comparable to similar studies which reported overall survival rates ranging between 81 and 95 percent (6, 13, 14). the retroperitoneal lymph node positivity at presentation (whether clinical or pathological) did not influence the outcome as there was no difference in treatment related outcomes between patients with positive and negative para-aortic nodes at presentation, reflecting the excellent outcome despite less intensive treatment in our study. in terms of dfs, 5-year dfs rate was 73% in patients who received radiotherapy to para-aortic chain versus 100% for those who underwent retro-peritoneal nodal dissection with no significant difference between both groups statistically (p = 0.185). only one patient (2.7%) out of 37 patients in our study experienced isolated regional failure in para-aortic chain. this is comparable to another study which was held by siop 2016 which reported 5-year dfs 83% in patients who underwent radical inguinal orchiectomy without rplnd (15). in summary, our study shows a favorable outcome in ptrms patients managed with radiation to para-aortic chain instead of surgery. this might be attributed to the indolent nature of the disease itself or the efficacy of radiation. however, a prospective study may be warranted. to our knowledge, this is the first work addressing radiation as an alternative to surgery in pt-rms. limitations of this study include its retrospective nature which makes it subjected to selection bias, small sample size, lack of toxicity scoring and quality of life (qol) assessment of the patients, lack of pet-ct staging which might have underestimated the real incidence of clinically positive retro-peritoneal nodes and deviation from the current cog protocol. however in such rare diagnosis where prospective trials are difficult to conduct, institutional series remain instructive. references 1. stewart lh, lioe tf, johnston sr. thirty-year review of intrascrotal rhabdomyosarcoma. br j urol. 1991; 68:418-20. 2. raney rb jr, tefft m, lawrence w jr, et al. paratesticular sarcoma in childhood and adolescence. a report from the intergroup rhabdomyosarcoma studies i and ii, 1973-1983. cancer. 1987; 60:2337-43. 3. raney rb, walterhouse do, meza jl, et al. results of the intergroup rhabdomyosarcoma study group d9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children’s oncology group. j clin oncol. 2011; 29:1312-1318. 4. rogers tn, seitz g, fuchs j, et al. surgical management of paratesticular rhabdomyosarcoma: a consensus opinion from the children's oncology group, european pediatric soft tissue sarcoma study group, and the cooperative weichteilsarkom studiengruppe. pediatr blood cancer. 2021; 68:e28938. 5. crane jn, xue w, qumseya a, et al. clinical group and modified tnm stage for rhabdomyosarcoma: a review from the children's oncology group. pediatr blood cancer. 2022; 69:e29644. 6. crist wm, anderson jr, meza jl, et al. intergroup rhabdomyosarcoma study-iv: results for patients with nonmetastatic disease. j clin oncol. 2001; 19:3091-3102. 7. kumar r, kapoor r, khosla d, et al. paratesticular rhabdomyosarcoma in young adults: a tertiary care institute experience. indian j urol. 2013; 29:110-3. 8. rogers tn, de corti f, burrieza gg, et al. paratesticular rhabdomyosarcoma—impact of locoregional approach on patient outcome: a report from the european paediatric soft tissue sarcoma study group (epssg). pediatr blood cancer. 2020; 67:e28479. 9. heidenreich a, albers p, hartmann m, et al. complications of primary nerve sparing retroperitoneal lymph node dissection for clinical stage i nonseminomatous germ cell tumors of the testis: experience of the german testicular cancer study group. j urol. 2003; 169:1710-1714. 10. beck sd, bey al, bihrle r, foster rs. ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. j urol. 2010; 184:2078-2080. 11. steiner h, zangerl f, stöhr b, et al. results of bilateral nerve sparing laparoscopic retroperitoneal lymph node dissection for testicular cancer. j urol. 2008; 180:1348-1353. 12. gupta aa, anderson jr, pappo as, et al. patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the children's oncology group soft tissue sarcoma committee. cancer. 2012;118:1130-1137. 13. laquaglia mp, ghavimi f, heller g, et al. mortality in pediatric paratesticular rhabdomyosarcoma: a multivariate analysis. j urol. 1989; 142:473-478. archivio italiano di urologia e andrologia 2023; 95(4):11642 y.a. abdelazim, m.f. zaki, m.m. abdel mohsen, et al. 6 14. lawrence w jr, gehan ea, hays dm, et al. prognostic significance of staging factors of the uicc staging system in childhood rhabdomyosarcoma: a report from the intergroup rhabdomyosarcoma study (irs ii). j clin oncol. 1987; 5:46. 15. stevens mc, rey a, bouvet n, et al. treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the international society of paediatric oncology–siop malignant mesenchymal tumor 89. j clin oncol. 2005; 23:2618-2628. correspondence yasser a. abdelazim, md (corresponding author) yasser.anwar@nci.cu.edu.eg national cancer institute 1 kasr el ainy street, cairo, egypt, 11796 monika foad zaki, md monikafouad@icloud.com reem mohamad emad, md reem.emad@nci.cu.edu.eg ehab mohamad khalil, md ehab.khalil@nci.cu.edu.eg department of radiation oncology, national cancer institute, cairo university, egypt mohsen mokhtar abdel mohsen, md mohsenonc@hotmail.com department of clinical oncology, faculty of medicine, cairo university, egypt heba gamal mohamad, md hebasurg@yahoo.com department of surgical oncology, national cancer institute, cairo university, egypt dalia abdelfatah mohammed, md dalia.abdelfatah@nci.cu.edu.eg department of cancer epidemiology & biostatistics. national cancer institute, cairo university, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso 195archivio italiano di urologia e andrologia 2021; 93, 2 original paper no conflict of interest declared. bolic laboratories commonly present in clinics. among five established criteria, three or more are needed to diagnose mets. these are: waist circumference > 102 and 80 cm in men and women respectively, serum triglycerides > 150 mg/dl, high density lipoprotein < 40 mg/dl and < 50 mg/dl in men and woman respectively, blood pressure (bp) > 130/85 mmhg and fasting blood sugar < 100 mg/dl (7) (table 1). a study based on self-reported histories has shown an increasing association of nephrolithiasis and mets traits (3.7% with no traits, 7.5% for three traits and 9.8% for five traits) (8). furthermore, the patients with more than 4 mets traits also showed a significant increase in the chances of recurrent or multiple stones with respect to patients with 0 traits (9). mets may also cause cardiovascular disease, a condition frequent in patients with nephrolithiasis (10). these new insights confirm a new pattern of patients with nephrolithiasis that should be regarded as a systemic disease representing the result of the interaction of multiple risk factors. this article will review the possible explanations for these new features of stone disease, with the aim to better assess them and their association with nephrolithiasis and to suggest measures for prevention not only for primary systemic disease, but also for stone recurrence. mets and nephrolithiasis obesity, the most frequent tract of mets, is also a condition of risk for nephrolithiasis. a positive correlation between obesity and the first-time stone, recurrent stone formation and shorter interval of recurrence have been demonstrated. taylor et al. have reported that waist circumference, body mass (bmi), weight gain, weight gain during adulthood are linked to an increase of incidental stones (11). other studies have shown that bmi is higher in stone formers (12, 13). in a large cohort of women without history of stones the risk for incidental stones increases with bmi 1.3 fold for 25-29 kg/m2 higher, 1.62 for 30-34.9 kg/m2 and 1.81 fold for ≥ 35 kg/m2) with respect to bmi < 25 kg/m2 (14). next, body fat can influence the risk for stone formation. kim et al. have shown a link between uric acid and calcium oxalate stones and visceral adipose tissue measured on computed tomography (ct) (15). a link has also been reported between non-alcoholic fat liver disease and the risk of stone formation and visceral to subcutaneous fat tissue ratio (16). nephrolithiasis has been increasing over the last millennium. although early epidemiologic studies have shown that kidney stones were two to three times more frequent in males than in females, recent reports have suggested that this rate is decreasing. in parallel a dramatic increase of nephrolithiasis has also been observed among children and adolescents. furthermore, epidemiologic studies have shown a strong association between metabolic syndrome (mets) traits and kidney stone disease. patients with hypertension have a higher risk of stone formation and stone formers are predisposed to develop hypertension compared to the general population. an incidence of nephrolithiasis greater than 75% has been shown in overweight and obese patients compared to those of normal weight. it has also been reported that a previous diagnosis of diabetes mellitus increases the risk of future nephrolithiasis. additionally, an association between metabolic syndrome and uric acid stone formation has been clearly recognized. furthermore, 24-h urinary metabolic abnormalities have been decreasing among patients with nephrolithiasis over the last decades. finally, nephrolithiasis could cause chronic kidney disease (ckd) and end stage renal disease (esrd), especially in women and overweight patients. according to these observations, a better understanding of these new features among stone former patients may be required. hence, the recognition and the correction of metabolic disorders could help not only to reduce the primary disease, but also stone recurrence. key words: nephrolithiasis; metabolic syndrome (mets); gender; children; adolescents. submitted 13 april 2021; accepted 17 may 2021 introduction several studies in the last decades have showed an overall increased incidence of kidney stones (1, 2). however, nephrolithiasis is increasing in women at a greater rate than in men and the common ratio 3:1 male to female is reducing (3, 4). an increased incidence of nephrolithiasis among children during the last 25 years has also been observed (5). moreover, other studies have shown mets is increasing in parallel to the incidence and prevalence of nephrolithiasis (6). various definitions have been included for defining mets criteria. the united states national cholesterol education program (ncep) adult treatment panel iii (atp iii) is the most simple since it can be used by basic metathe new patterns of nephrolithiasis: what has been changing in the last millennium? elisa cicerello, matteo ciaccia, gian d. cova, mario s. mangano unità complessa di urologia, dipartimento di chirurgia specialistica, ospedale ca’ foncello, treviso, italy. doi: 10.4081/aiua.2021.2.195 summary archivio italiano di urologia e andrologia 2021; 93, 2 e. cicerello, m. ciaccia, g.d. cova, m.s. mangano 196 additionally, obesity has been associated with impaired carbohydrate tolerance and inappropriate calcium response to glucose ingestion. obese patients show an increased excretion of calcium, sodium, uric acid and a lower urinary ph in relation to the non-obese (17). defects in renal ammoniagenesis and excessive net acid excretion (nae), which are common in patients with mets, could cause a decreased urinary ph (18). next, renal acidification defects lead to hypocitraturia, another important risk for stone formation (13). furthermore, an increased excretion of oxalate correlated with bmi has been reported among diabetic and overweight patients promoting calcium oxalate stone formation. hence, both the percentage of uric acid and calcium oxalate stones was found higher in obese than non-obese patients (34.9 vs 23.1 and 7.7 vs 2.8 respectively) (19). diabetes mellitus has been clearly linked to nephrolithiasis. a previous diagnosis of diabetes increases the risk for stone formation and a previous diagnosis of stone disease leads to the onset of diabetes mellitus. in a crosssectional study of 3 large cohorts on multivariate analysis, the relative risk of prevalent stone disease in patients with type 2 diabetes was 1.38 in older women, 1.67 in younger women and 1.31 in men. additionally, the risk of incident type 2 diabetes in patients with history of stone disease was 1.33, 1.48 and 1.49 respectively (20). patients with type 2 diabetes have a decreased ammonium production resulting in lower urinary ph and increased risk of uric acid stone formation and an increased excretion of oxalate which promotes calcium oxalate stone formation (21). however, uric acid stones are more frequent in patients with diabetes and glucose intolerance (22). an association between the gravity of diabetes evaluated with fasting plasma insulin and glucose and hemoglobin a1c and the risk for stone formation has also been observed (23). it is well known that elevated serum triglycerides and low high-density lipoprotein (hdl) levels increase the cardiovascular risk. next, dyslipidemia is associated with lower urinary ph and could be considered as an independent risk factor for kidney stones (24). an association between dyslipidemia and kidney stone disease has been reported by masterson and colleagues. this retrospective study shows an association between dyslipidemia and kidney stones with a hazard ratio of 2.2. then, examining individually dyslipidemia factors, it was shown that low-density lipoprotein (ldl) and triglycerides are not associated with stone formation, while low hdl values (< 45 mg/dl for men; < 60 mg/dl for women) had a hazard ratio of 1.4 (25). furthermore, nephrolithiasic patients show higher levels of total serum cholesterol and triglycerides (12). the association of total cholesterol with stone formation was higher in uric acid and calcium oxalate monohydrate/dihydrate. besides, ldl levels were higher in calcium oxalate monohydrate/dihydrate stone formers than in calcium oxalate monohydrate group. several studies have shown an association between hypertension and nephrolithiasis: patients with hypertension are more at risk for nephrolithiasis (26) and patients with a history of nephrolithiasis have an increased risk for development of hypertension (27). furthermore, hypertensive patients had a significantly increased calcium, oxalate and uric acid excretion with respect to normotensive controls (26, 28). another study has shown stone formers with hypertension have reduced urinary excretion of citrate and urine ph and increased titrable acid excretion when compared with normotensive stone formers (29). the link between hypertension and stone disease could be high sodium dietary intake, common in hypertensive patients, promoting increased urinary excretion of calcium. the association between cardiovascular disease and nephrolithiasis has also been recognized. a longitudinal study of patients affected by cardiovascular disease with follow-up more than 20-years has showed a correlation between cardiovascular features and stone disease (30). next, a link between carotid atherosclerosis and kidney stone disease has also been observed. another study by the rochester epidemiology project spanning 10 years has found that calcium oxalate stone formers show a high risk of mortality from cardiovascular disease and higher total cholesterol, lower hdl, higher systolic blood pressure and elevated highly sensitive c reactive protein (hscrp) (31). calciuria and oxaluria have also been positively correlated with 10year cardiovascular disease risk including mortality (32). furthermore, a positive association between risk factors for coronary artery disease (smoking) was reported (33). finally, abdominal aortic calcification found on ct have been associated with uric acid stone formation, low urine ph and hypocitraturia (34). gender and nephrolithiasis a new tract of this new epidemiology is the shifting in gender of nephrolithiasis. although nephrolithiasis is still more frequent in men than in women, the ratio male to female is reducing and the most recent nhanes data showed an overall prevalence of 10.6% in men and 7.1% in women (35). the changing role of women in the workplace has been considered. modification of lifestyle and dietary habits in relation to working activity could contribute to the shifting in gender difference of stone formation. dietary factors promoting stone formation such as high animal protein, high salt and low calcium diets are more usual in men than in women, although the expansion of the high protein diet or higher fructose intake and low fluid intake to females could be a further cause of changing in gender of nephrolithiasis (36, 37). obesity has also been associated with increased stone table 1. ncep atp iii: united states national cholesterol education program. adult treatment panel iii, rx, pharmacologic intervention for that component criteria waist circumference (cm) > 102 (males), > 88 (females) fasting glucose (mg/dl) ≧ 100 or rx triglycerides (mg/dl) ≧ 150 or rx high-density lipoprotein (mg/dl) < 40 (males), < 50 (females) or rx blood pressure (mmhg) > 130 (systolic), > 85 (diastolic) or rx risk among women. taylor et al. show that overweight among females increases the risk for stone disease with respect to men with the same characteristics. in this study, body mass, weight gain during adulthood as well as waist circumferences increased the risk of stone formation among females (11). it has also been reported that uric acid stones are present in more than 50% of obese females (38). additionally, hyperinsulinemia, that is usually found in obese patients, may be associated to urinary acidosis with the consequent risk for uric acid stone formation (39). this could be the link between gender, obesity, insulin level and kidney stones. another risk factor for stone formation among reproductive aged women is pregnancy. reinstaller et al. have observed women with a history of pregnancy have more than twice the chance of stone formation than those who were never pregnant. lithogenic factors such as hypercalciuria, hyperuricosuria and increased urinary ph have been observed during pregnancy. these data suggest that an increased lifetime lithogenicity could occur among females since many of them are pregnant in working age (40). finally, it has been reported struvite and hydroxyapatite stones are more common in women aged less than 55 years (41). as urinary infections are increasing among females, they could be a factor for stone formation as well a further cause for the shifting in the gender of nephrolithiasis. children and nephrolithiasis another feature of the new pattern of nephrolithiasis is a dramatic increase of nephrolithiasis among children and adolescents over the past 25 years (42). a 25-year population based study performed in olmsted county (minnesota) has reported that 41% of children under the age of 18 showed incidence of stones on ct with an increase of 4% of stones per year. next, among 12-17 year olds the incidence rate was 6% (43). database from the healthcare cost and utilization project kids’ inpatient admission for pediatric nephrolithiasis in 2003 shows a higher frequency among girls. this difference in gender slightly changes in favour of boys within the first decade only (44). another study in south carolina has reported an increase to emergency department admissions for nephrolithiasis of children aged 0 to 18 years between 1996 to 2007 (5). the annual incidence of kidney stones was higher among school aged children and adolescents. in fact, the annual incidence rate among 14 to 18 years olds dramatically increased by about 50% from 1996 to 2007 (25 per 100.000 vs 54 per 100.000 respectively), while the incidence of stones for children younger than 9 years remained stable (less than 5 per 100.000). moreover, among children and adolescents, girls had a higher incidence of kidneys stones than boys, as also reported by other studies (45). the reason for these features is not clear, probably because of the few cohort studies performed which have not allowed the analysis of the link between gender and risk factors. nephrolithiasis in children is idiopathic in origin in most cases, although rare genetic anomalies or a secondary cause of lithiasis such as neurological or congenital urinary anomalies of the urinary tract have also been identified. besides, the risk of infected stones has decreased probably in relation to improved diagnosis and management of anatomical and neurological conditions promoting urinary infections. conversely, environmental factors have been suggested in the pathogenesis of idiopathic nephrolithiasis. in fact, it has been reported that obesity and nephrolitihiasis among children are increasing in parallel (46). dietary habits such as high intake of fructose (47) or salt (48) and low intake of fluid (49), which are the same risk factors for stone formation in adults, could be involved. chronic kidney disease (ckd) and nephrolithiasis nephrolithiasis has also been associated with ckd. several studies have showed that, although kidney stones can cause ckd with acute or chronic damage of the urinary tract, the risk for end stage kidney disease (eskd) or mortality from cdk are not increased (50). data from the alberta kidney disease network confirm similar results (51). further cross-section analysis of nahnes 2007 to 2010 has also reported a greater prevalence of ckd and esrd in nephrolithiasis patients with odds ratios of 1.50 and 2.37 respectively (52). specific conditions associated with the risk of ckd in stone formers have been analysed by gambaro et al. (53). the results of this study have showed that nephrolithiasic patients have twice the risk of ckd or esrd and the risk is higher in women and overweight stone formers. comment there are changing patterns of nephrolithiasis. shifting in gender prevalence and the increase of kidney stone disease among children and adolescents have been well observed. moreover, a strong association between mets traits and nephrolithiasis has been reported. hence, it has been hypothesized that different metabolic alterations may modify urinary “milieu” through a common mechanism resulting in overly acidic urine with consequent salt precipitation and stone formation. we have previously reported about metabolic disorders among 109 nephrolithiasic patients evaluated between 2017 and 2018 (54). in this study metabolic urinary anomalies (hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia) in 24h urine samples were observed only in 11 patients, while in a cohort of stone formers evaluated between 2007-2008 these figures were present in 28 of them. conversely, metabolic disorders (hypertension, diabetes, dislypidemia, overweight) were present in 72% and more than 2 in 38% of the cases. the decrease of urinary metabolic abnormalities observed in the group in the last decade could suggest that a complete metabolic evaluation is not necessary in all patients with associated comorbidities, while it may be performed in cases of relapses of stone events (55, 56). the increase of metabolic disorders in the last decade confirm among nephrolithiasic the association between mets and nephrolithiasis and supports the hypothesis that nowadays stone disease could be considered as a systemic disorder (table 2). changes in lifestyle and dietary habits could have coincided with an increase of metabolic syndrome and in parallel of stone formation (57). patients with mets obvious197archivio italiano di urologia e andrologia 2021; 93, 2 new pattern of nephrolithiasis archivio italiano di urologia e andrologia 2021; 93, 2 e. cicerello, m. ciaccia, g.d. cova, m.s. mangano 198 ly consume more food which could influence the urinary excretion of risk factors for stone formation. preventative measures and careful patient education should be included to promote a healthy lifestyle. an increase of physical activity has been reported to prevent metabolic syndrome. further, an increase of fluid intake to achieve a daily urinary volume of 2 litres and a diet rich in fruit and vegetable have reduced metabolic syndrome, stone formation and urinary infections (58, 59). specific medical treatment (antidiabetics, antihypertensive, antilipemic and anticoagulant drugs) could be required to correct each component of metabolic syndrome (60). conclusions the patterns of nephrolithiasis are changing. nephrolithiasis is still common among men, but the gender gap is narrowing as is the increase in occurrence among children and adolescents. with the parallel increase in incidence of both nephrolithiasis and systemic disorders, lifestyle changes with dietary and specific medicaments could be the most effective way to prevent primary disease and recurrent stone disease. nephrolithiasis from ordinary flank pain could be recognized as a systemic condition and the correction of systemic disorders could not only reduce morbidity and mortality for diabetes, cardiovascular disease and development of ckd, but also minimize the risk of stone formation. references 1. lieske jc, pena de la vega, slezak jm, et al. renal epidemiology in rochester, minnesota. kidney int. 2006; 69:760-764. 2. pearle ms, calhoun ea, curhan gc. urologic diseases in america project: urolithiasis. j urol. 2005; 173:848-857. 3. strope sa, wolf js jr and hollenback bk. changes in gender distribution urinary stone disease. urology. 2010; 75:543-546. 4. scales c jr, curtis lh, norris rd, et al. changing in gender prevalence of stone disease. j urol. 2007; 177:979-982. 5. sas dj, hulsey tc, shataf if, et al. 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ferraro pm, montanari e, trinchieri a. influence of dietary energy intake on nephrolithiasis a metaanalysis of observational studies. arch ital urol androl. 2020;92:30-33 58. ford es, kol hw iii, mokdad ah, et al. sedentary behavior, physical activity, and the metabolic syndrome amomg u.s. adults. ob res. 2005; 3:608-614. 59. prezioso d, strazzullo p, lotti t, et al. dietary treatment of urinary risk factors for renal stone formation. a review of clu working group. arch ital urol androl. 2015; 87:105-120. 60. wagh a, stone nj. treatment of metabolic syndrome. exp rev cardiov ther. 2008; 2:213-228. correspondence elisa cicerello, md elisa.cicerello@tin.it matteo ciaccia, md gian d. cova, md mario s. mangano, md unità complessa di urologia, dipartimento di chirurgia specialistica, ospedale ca’ foncello, treviso, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13383 1 original paper trauma. a study on pelvic fractures in indonesia from 2016 to 2018 involved 229 patients with pelvic injuries that lead to developing of traumatic urethral strictures especially pelvic fracture urethral injury (pfui). traffic accidents were responsible for 76% of these cases (1-6). excision and primary anastomosis (epa) urethroplasty is a reconstructive technique for traumatic urethral strictures, involving the complete removal of the affected urethral segment followed by tension-free anastomosis that offering excellent clinical outcomes (7). however, the impact of epa urethroplasty on erectile function (ef) has raised concerns. existing studies on erectile dysfunction (ed) both prior and after epa urethroplasty for traumatic urethral strictures are limited. research evaluating ef outcomes post-operatively remains scarce worldwide. the exact cause of ed in men following urethroplasty remains poorly studied (8, 9). there is lack of available data in indonesia concerning about ef following such procedure. this gap in information limits the understanding of the risks and effectiveness of this interventions. our study aims to address this gap by examining the factors associated with ef following epa urethroplasty performed by a single surgeon at a tertiary hospital. methods study sample and design this study employs a retrospective design focusing on patients with traumatic urethral stricture who underwent epa urethroplasty at dr. saiful anwar general hospital in malang, a tertiary referral hospital. study sample consists of patients with traumatic urethral stricture who received epa-urethroplasty treatment at dr. saiful anwar general hospital between 2013 and 2023. the inclusion criteria for this study are as follows (1). male patients diagnosed with traumatic urethral stricture, confirmed through bipolar voiding cysto-urethrography (bvcug); (2) patients with no prior epa urethroplasty repair. the exclusion criteria for this study are (1) male patients with urethral stricture caused by factors other than trauma; (2) patients loss of follow-up before 12 months; (3) patient who underwent redo-urethroplasty. introduction: urethral repair with excision and primary anastomosis (epa) urethroplasty offers excellent outcome in managing traumatic urethral strictures. however, its impact on erectile function (ef) is largely unknown. study to evaluate ef outcome post-operatively is still limited worldwide. we report factors associated to ef following epa urethroplasty performed by single surgeon in tertiary hospital. in this study, we aim to evaluate the risk of erectile dysfunction (ed) following epa urethroplasty. materials and methods: this is a retrospective study on patients with traumatic urethral strictures who underwent epa urethroplasty from 2013 to 2023. variables including age, body mass index, systemic disease, etiology, stricture length, prior procedures and erection hardness score (ehs) score prior and 12 months after surgery were recorded. pre-operative ed was determined using penile doppler ultrasound, which was defined as a peak systolic velocity of less than 25 cm/s. univariate and multivariate logistic regression analysis were performed using ibm spss statistic. results: a total of 89 patients were included. among them, 33 patients (33.7%) suffered from initial ed prior to surgery. pelvic fracture urethral injury (pfui) was the predominant etiology (74%); 29% of the patients were active smokers, and 68.5% had prior endoscopic treatment. among the 48 patients without ed prior to surgery, 7 of them (14.6%) developed ed following surgery in 12 months of follow up. after epa, there was a reduction of mean ehs score from 2.70 to 2.53 (p = 0.176). multivariate analysis showed that smoking status (p = 0.035; or 4.41), pfui as the mechanism of injury (p = 0.007; or 2.89), prior urethrotomy (p = 0.020; or 4.69), and prior dilatations (p = 0.046; or 0.18) were related as risk factors of ed following epa urethroplasty. conclusions: risk of ed following epa is inevitable, although the number is not high as expected. smoking, pfui and prior treatment rather than epa, emerge as predominant risk factors associated with the development of ed subsequent to surgical repair. key words: epa urethroplasty; erectile dysfunction; traumatic urethral strictures. submitted 14 november 2024; accepted 2 december 2024 introduction the rate of traffic accidents in indonesia is alarmingly high, which significantly impacts the incidence of pelvic factors associated with erectile dysfunction in traumatic urethral strictures following epa urethroplasty: a single center experience paksi satyagraha, gede wirya diptanala putra duarsa, fauzan kurniawan dhani, adrianus gupta wijaya, besut daryanto urology department, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2025.13383 summary archivio italiano di urologia e andrologia 2025; 97(1):13383 p. satyagraha, g. wirya diptanala putra duarsa, f. kurniawan dhani, et al. 2 the research utilizes medical records to evaluate sexual function outcomes before and after the procedure. the variables recorded in this study include age, bmi, systemic diseases, etiology, stricture length, prior procedures, and ehs scores both prior to and 12 months after surgery. we excluded all the patients who suffered preoperative ed from the study. pre-operative ed was determined using penile doppler ultrasound, and a peak systolic velocity of less than 25 cm/s indicate initial ed. postoperative ed was evaluated using the erection hardness score (ehs) and the international index of erectile function (iief-5) until 12 months following epa urethroplasty procedure. postoperative follow-up and outcome definition we followed all the patients with no prior ed following surgery up to 12 months of follow-up using ehs score and iief-5 assessment at 1, 3, 6 and 12 months following the surgery. we included and analyzed all the patient who develop ed during this period of follow-up. statistical analysis univariate and multivariate logistic regression analyses were performed using ibm spss statistics to analyze the data. this statistical approach allowed for the examination of potential predictors and the impact of various factors on the outcomes of ed in patients undergoing epaurethroplasty. results characteristics of the research sample the study included 89 patients with a mean age of 41.24 years (sd ± 15.59). the median follow-up period was 16.3 months (sd ± 3.15). the mean bmi was 23.05 kg/m² (sd ± 2.57). among the patients, 29.2% were current smokers, 10.1% had type 2 diabetes mellitus, and 16.9% had hypertension. the average length of stricture was 25.4 mm (sd ± 16.3), with the mean time to surgery being 6.67 months (sd ± 4.07). types of injuries included straddle injury (12.35%), iatrogenic (11.23%), direct (2.24%), and pfui (74.15%). the stricture site was bulbar in 62% of cases and membranous in 27% of cases. there were 34 patients (38.20%) who had performed internal urethrotomies and 33 patients (37.07%) had performed urethral dilatation prior to surgery. fourteen patients (15.73%) did not undergo any types of endoscopic treatment following the surgery. types of surgery performed were bulbar mobilization (39.33%), crural separation (32.58%), inferior pubectomy (26.96%), and supracrural rerouting (1.12%). the success rate of epa was 91%, with an 8% recurrence rate. ed was noted in 40.74% of patients pre-operatively, and 49.39% postoperatively (table 1). among the 48 patients without ed prior to surgery, 7 of them (14.6%) developed ed postoperatively. erectile function outcome following epa urethroplasty the statistical analysis was performed using the mannwhitney test. the mean ehs score decreased slightly from 2.70 (sd ± 0.798) pre-operatively to 2.53 (sd ± 0.823) at 12 months post-operatively, but this change was not statistically significant (p = 0.176). similarly, the mean iief-5 score showed a minor increase from 19.35 (sd ± 4.547) to 19.73 (sd ± 4.174) over the same period, which was also not statistically significant (p = 0.444) (table 2 and figure 1). table 1. patient characteristics. number of patient 89 age (year) (sd) 41.24 (± 15.59) median follow-up (months) (sd) 16.3 (± 3.15) bmi (kg/m2), mean (sd) 23.05 (± 2.57) current smoker, n (%) 26 (29.2) dm type 2, n (%) 9 (10.1) hypertension, n (%) 15 (16.9) stricture length (mm), mean (sd) 25.4 (± 16.3) time to surgery (month), mean (sd) 6.67 (± 4.07) stricture aetiology, n (%) straddle injury 13 (14.60) iatrogenic 10 (11.23) pfui 66 (74.15) stricture site, n (%) membranacea 27 (30.34) bulbar 62 (69.66) previous endoscopic treatment, n (%) internal urethrotomies 34 (38.20) dilatations 33 (37.07) no prior endoscopic surgery 14 (15.73) type of surgery, n (%) bulbar mobilization 35 (39.33) crural separation 29 (32.58) inferior pubectomy 24 (26.96) supracrural rerouting 1 (1.12) epa outcome, n (%) success 81 (91) recurrance 8 (9.00) erectile dysfunction (ed), n (%) pre-operative (n: 81) no ed 48 (59.26) de novo ed 33 (40.74) post-operative (n: 81) no ed 41 (50.61) de novo ed 33 (40.74) ed following epa urethroplasty 7 (8.64) bmi: body mass index; dm: diabetes mellitus; sd: standart deviation; epa excision primary anastomosis; pfui: pelvic fracture urethral injury. table 2. erectile function outcome. pre-operative (n: 48) 12 months of follow-up (n: 41) mean ± sd mean ± sd p value (vs pre-operative) ehs 2.70 ± 0.798 2.53 ± 0.823 0.176 iief-5 19.35 ± 4.547 19.73 ± 4.174 0.444 archivio italiano di urologia e andrologia 2025; 97(1):13383 3 erectile dysfunction after urethroplasty for traumatic urethral stricture factors associated with the risk of ed post-operatively in the univariate analysis, smoking significantly increased the odds of occurrence of erectile dysfunction (or 6.78, 95% ci 1.32-34.81, p = 0.022). the type of pfui injury also emerged as a significant predictor of occurrence of erectile dysfunction (or 2.76, 95% ci 1.13-6.72, p = 0.026). additionally, the number of procedures prior to epa urethroplasty significantly increased the risk of erectile dysfunction after epa (or 0.19, 95% ci 0.04-0.90, p = 0.036). in the multivariate analysis, smoking remained a significant risk factor for occurrence of erectile dysfunction (or 4.41, 95% ci 1.11-17.57, p = 0.035). the pfui injury type continued to significantly predict recurrence erectile dysfunction occurrence (or 2.89, 95% ci 1.34-6.21, p = 0.007). the number of urethrotomies also significantly increased the odds of ed following epa urethroplasty (or 4.69, 95% ci 1.28-17.24, p = 0.020), and prior procedures remained a significant factor in postoperative ed (or 0.18, 95% ci 0.05-0.68, p = 0.011) (table 3). discussion the prevalence of ed after pelvic fractures ranges from 528%, but it is significantly higher after pfui, varying between 26-76% (10-12). ed after pfui typically results from direct injury to the posterior urethra, penile nerves, and arteries. there is ongoing debate about whether neurogenic or vascular injury is the primary cause. evidence leans towards neurogenic causes, with high response rates to intracavernosal vasoactive medications and abnormal electromyograms in affected patients, despite normal vascular flow. some studies, however, report high occlusion rates in penile arteries, suggesting a vascular component (13). the mechanism of ed following pfui typically involves direct trauma that both lacerates and often avulses the posterior urethra, concurrently damaging the penile nerves and arteries as they traverse the pelvic floor behind the prostate before entering the penis. literature debates whether neurogenic or direct vascular injury is the primary cause of ed, with more evidence pointing towards neurogenic ed (14, 15). both vasculogenic and neurogenic causes have been proposed for ed after pfui, and various studies have attempted to identify the specific pathophysiologic factors involved to better guide treatment. there is no clear consensus on the primary cause of organic ed after pfui. feng et al. found that only 28% of men with ed post pfui had organic ed, most of which was neurogenic (16). studies by mark et al. and machtens et al. support the predominance of neurogenic factors, noting high response rates to neurogenic treatments and evidence of nerve damage (17, 18). guan et al.'s study of 120 patients found that 80% had organic ed, with 30% vasculogenic, 43% neurogenic, and 27% mixed. most vasculogenic cases involved veno-occlusive dysfunction rather than arterial insufficienc (19). these findings highlight the variability in ed etiology post pfui and emphasize the need for a tailored, stepwise diagnostic approach to treatment. table 3. uniand multivariate cox regression analysis for ed following epa urethroplasty. univariate analysis multivariate analysisore (> 3) or 95% ci p value or 95% ci p value current smoker 6.78 1.32-34.81 0.022 4.41 1.11-17.57 0.035 * diabetes mellitus (dm) 0.21 0.01-3.35 0.268 hypertension 1.56 0.23-10.78 0.652 time of symptom 0.55 0.21-1.43 0.216 type of injury 2.76 1.13-6.72 0.026 2.89 1.34-6.21 0.007 * type of surgery 1.80 0.79-4.10 0.159 age 1.26 0.51-3.11 0.616 bmi 0.90 0.43-1.86 0.773 stricture length 2.40 0.70-8.25 0.165 number of urethrotomies 2.93 0.69-12.45 0.145 4.69 1.28-17.24 0.020 * number of dilatations 0.19 0.04-0.90 0.036 0.18 0.05-0.68 0.011 * * significant result. bmi: body mass index; ci: confidence interval; dm: diabetes mellitus; or: odd ratio; pfui: pelvic fracture urethral injury. figure 1. ehs (a) and iief-5 score (b) in 12 months of follow up. archivio italiano di urologia e andrologia 2025; 97(1):13383 p. satyagraha, g. wirya diptanala putra duarsa, f. kurniawan dhani, et al. 4 differentiating between ed due to pfui and de novo ed from urethral realignment or delayed urethroplasty requires multiple assessments before and after injury and repair (20). studies show that delayed urethroplasty increases the risk of ed by 3% over the 34% associated with pfui alone, resulting in a 37% incidence of de novo ed. the higher rate of ed after delayed urethroplasty compared to primary endoscopic alignment likely reflects differences in injury severity and ed reporting (21). men undergoing primary realignment generally have less severe pfuis, as indicated by a lower ed rate compared to those needing delayed urethroplasty. however, the association is unclear due to variability in institutional practices regarding primary realignment and delayed urethroplasty (20). our study utilized four techniques include bulbar urethral mobilization, crural separation, inferior pubectomy, and supracrural rerouting. despite employing these methods, the results showed no significant impact on postoperative erectile dysfunction. using only bulbar urethral mobilization and crural separation is considered a simple perineal approach. including either an inferior pubectomy or supracrural rerouting is classified as an elaborated perineal approach (22). in a previous study, 74 patients (30.2%) underwent transecting bulbar urethroplasty, while 171 patients (69.8%) underwent non-transecting techniques. both groups had similar success rates (87.8% vs. 86.5%, p = 0.93) and postoperative complications (8.1% vs. 7%, p = 0.73). transient ed was more common in the transecting cohort (8.1% vs. 2.9%, p = 0.07), but de novo permanent ed rates were comparable (4.1% vs. 2.9%, p = 0.65). transecting techniques can lead to transient ed that typically improves within a year, while permanent ed is uncommon and not significantly influenced by the type of urethroplasty technique used (23). a previous meta-analysis involving 21 studies with 6.791 patients showed consistent results across two stages. in the univariate analysis (18 studies, 5.811 patients), smoking was associated with a higher risk of stricture recurrence (rr = 1.32, p = 0.001). the multivariate analysis (11 studies, 3.176 patients) also found smoking linked to increased stricture recurrence (rr = 1.35, p = 0.049). smoking may increase the risk of stricture recurrence after urethroplasty. quitting smoking is recommended for patients undergoing urethroplasty (24). smoking adversely impacts ed through several mechanisms. it disrupts the nitric oxide (no) pathway by impairing both endothelial and neuronal no synthase (nos) activities. specifically, components of burned tobacco inhibit neuronal nos, while cigarette smoke damages the endothelium, reducing endothelial nos-mediated vasodilation. additionally, smoking produces superoxide anions that decrease free no levels in the corpora cavernosa. these superoxides activate nadh oxidase enzymes, diverting no into a peroxynitrite pathway and reducing its vasoactive availability. smoking also affects rho-associated kinase (rok) signaling by decreasing no levels, which leads to increased rok activity and worsens ed. finally, smoking causes intrinsic vascular damage, altering elastin in the extracellular matrix and inducing calcification of medial elastic fibers, resulting in arterial stiffness and impaired vessel dilation (24). unlike our study, previous study found no significant correlation between postoperative ed and smoking history (25), waddel et al. reported a higher incidence of ed associated with smoking history (26). in our study, we found that previous treatment had significant results in post-operative ed. potential mechanisms for erectile dysfunction following dviu include direct injury to the cavernous nerve caused by the urethrotomy knife, fibrosis resulting from fluid and urine leakage into the periurethral space, infection, or the creation of a shunt between the corpora cavernosa and the corpus spongiosum (27). despite its lower success rates compared to urethroplasty, direct vision internal urethrotomy (dviu) remains the most used treatment for anterior urethral stricture (28). erickson et al. used the bmsfi to assess ed following urethral reconstruction and discovered that patients over 50 years old experienced a notable decline in the mean ef domain score, unlike their younger counterparts (29). similarly, anger et al. indicated that both age and preoperative ef can negatively impact postoperative sexual outcomes. their prospective review found that men with postoperative ef scores ≤ 20 on the iief questionnaire were older (mean age 47 vs. 36.8 years, p = 0.17) and had poorer preoperative ef values (mean 20 vs. 29, p = 0.11) compared to those with ef scores > 20, though these differences were not statistically significant (30). in contrast, other studies found no clear link between age and the incidence of ed, though older men generally had lower preoperative iief scores and experienced a greater decline in these scores. chapman et al. also found no significant association between age and sexual dysfunction in their multivariate analysis (31-33). age showed insignificant results in our study on postoperative ed due to a potentially small sample size, narrow age range, variability in preoperative function, and confounding factors. statistical methods may not have detected subtle age effects, and the follow-up duration might have been too short. additionally, the complex relationship between age and ed could have diluted the impact of age alone. coursey et al. suggested that stricture length could be a predictive factor for postoperative erectile function, finding that men with poorer erectile outcomes had significantly longer strictures compared to those with improved or stable erections (mean 6.8 cm vs. 4 cm) (34). however, subsequent research has contradicted this association (29, 32, 35). ed is approximately 3.5 times more prevalent in men with diabetes mellitus (dm) compared to those without the condition (36). in a previous study involving 878 men, logistic regression was used to examine the relationship between ed and body mass index (bmi). the incidence of ed was 53.1%. men in the ed group had significantly higher bmis compared to those in the noned group (p = 0.01). obese men had a higher risk of ed compared to those with normal weight (or = 1.97, 95% ci = 1.25-3.14, p = 0.004), even after adjusting for potential confounding factors (or = 1.78, 95% ci = 1.10-2.90, p = 0.02). overall, these findings indicate a positive correlation between obesity and the risk of moderate to severe ed (37). in our study, the variable bmi did not yield significant results. this lack of significance may be attributed to the fact that the average bmi of the participants was 23.05, which falls within the normal weight archivio italiano di urologia e andrologia 2025; 97(1):13383 5 erectile dysfunction after urethroplasty for traumatic urethral stricture range. additionally, the study sample did not include a wide range of bmi values, leading to a limited distribution of data that could have impacted the ability to detect a significant effect of bmi on erectile function outcomes. the limitation of the study is its retrospective design, which relies on historical medical records. this approach can lead to incomplete or inconsistent data collection, potentially affecting the accuracy and reliability of the findings. additionally, the study's reliance on patientreported outcomes, such as the ehs score and the iief5 score, may introduce bias due to subjective interpretations by the patients. to strengthen the findings, a prospective cohort study design could be implemented in future research. this approach would allow for more controlled and consistent data collection, including real-time assessments of erectile function and other relevant variables. additionally, incorporating objective measures, such as penile doppler ultrasound or other physiological assessments of erectile function, could provide more accurate and reliable data on the impact of epa urethroplasty on erectile dysfunction. conclusions the risk of ed following epa urethroplasty, while present, is generally lower than anticipated. smoking, pfui, and prior treatments rather than the epa procedure itself emerge as significant risk factors contributing to the development of ed after surgical repair. despite the inherent risk of ed associated with any urethral surgery, these factors play a more prominent role in influencing post-operative erectile function. references 1. smith t. current management of urethral stricture disease. indian j urol. 2016; 32:27. 2. waterloos m, verla w. female urethroplasty: a practical guide emphasizing diagnosis and surgical treatment of female urethral stricture disease. biomed res int. 2019; 2019:1-13. 3. alwaal a, blaschko sd, mcaninch jw, breyer bn. epidemiology of urethral strictures. transl androl urol. 2014; 3:209-13. 4. smith t. current management of urethral stricture disease. indian journal of urology. 2016; 32:27. 5. ramadana y, chilmi mz. epidemiology of pelvic fracture in the emergency room at dr. soetomo general hospital between 20162018. qanun medika medical journal 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mark sd, keane te, vandemark rm, webster gd. impotence following pelvic fracture urethral injury: incidence, aetiology and management. br j urol. 1995; 75:62-4. 18. machtens s, gänsslen a, pohlemann t, stief cg. erectile dysfunction in relation to traumatic pelvic injuries or pelvic fractures. bju int. 2001; 87:441-8. 19. guan y, wendong s, zhao s, et al. the vascular and neurogenic factors associated with erectile dysfunction in patients after pelvic fractures. international braz j urol. 2015; 41:959-66. 20. bhowmik p, sharma g, sharma p, et al. prospective study of de novo sexual dysfunction after anterior urethroplasty: causative factors, incidence, and recovery of function a single-center experience. urol ann. 2022; 14:60. 21. blaschko sd, sanford mt, schlomer bj, et al. the incidence of erectile dysfunction after pelvic fracture urethral injury: a systematic review and meta-analysis. arab j urol. 2015; 13:68-74. declarations ethical approval: this study was approved by the health research ethics commission of saiful anwar general hospital number: 400/214/k.3/102.7/2024. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request. competing interests: the authors declare that they have no competing interests. funding: the authors report no funding. authors' contributions: ps, bd: conceptualization, methodology, writing-original draft, visualization, project administration, validation, gwdpd, agw, fkd: conceptualization, methodology, writing-original draft, investigation, validation, data analysis. acknowledgments: not applicable. consent for publication: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13383 p. satyagraha, g. wirya diptanala putra duarsa, f. kurniawan dhani, et al. 6 22. koraitim mm. post-traumatic posterior urethral strictures: preoperative decision making. urology. 2004; 64:228-31. 23. shalkamy o, elsalhy m, alghamdi sm, et al. erectile function after different techniques of bulbar urethroplasty: does urethral transection make a difference? bmc urol. 2023; 23:140. 24. kovac jr, labbate c, ramasamy r, et al. effects of cigarette smoking on erectile dysfunction. andrologia. 2015; 47:1087-92. 25. ma y, lin l, luo z, jin t. smoking is an independent risk factor for stricture recurrence after the urethroplasty: a systematic review and meta-analysis. international braz j urol. 2023; 49:8-23. 26. waddell o, mclauchlan j, mccombie a, et al. quality of life in early-onset colorectal cancer patients: systematic review. bjs open. 2023; 7:zrad030. 27. sangkum p, levy j, yafi fa, hellstrom wjg. erectile dysfunction in urethral stricture and pelvic fracture urethral injury patients: diagnosis, treatment, and outcomes. andrology. 2015; 3:443-9. 28. siegel ja, morey af. opinion: anastomotic urethroplasty. international braz j urol. 2015; 41:615-8. 29. erickson ba, wysock js, mcvary kt, gonzalez cm. erectile function, sexual drive, and ejaculatory function after reconstructive surgery for anterior urethral stricture disease. bju int. 2007; 99:607-11. 30. anger jt, sherman nd, webster gd. the effect of bulbar urethroplasty on erectile function. j urol. 2007; 178:1009-11. 31. dogra pn, saini ak, seth a. erectile dysfunction after anterior urethroplasty: a prospective analysis of incidence and probability of recovery—single-center experience. urology. 2011; 78:78-81. 32. chapman dw, cotter k, johnsen nv, et al. nontransecting techniques reduce sexual dysfunction after anastomotic bulbar urethroplasty: results of a multi-institutional comparative analysis. journal of urology. 2019; 201:364-70. 33. haines t, rourke kf. the effect of urethral transection on erectile function after anterior urethroplasty. world j urol. 2017; 35:839-45. 34. coursey jw, morey af, mcaninch jw, et al. erectile function after anterior urethroplasty. j urol. 2001; 166:2273-6. 35. xie h, xu y-m, xu x-l, et al. evaluation of erectile function after urethral reconstruction: a prospective study. asian j androl. 2009; 11:209-14. 36. defeudis g, mazzilli r, tenuta m, et al. erectile dysfunction and diabetes: a melting pot of circumstances and treatments. diabetes metab res rev. 2022; 38:e3494. 37. liu y, hu x, xiong m, et al. association of bmi with erectile dysfunction: a cross-sectional study of men from an andrology clinic. front endocrinol (lausanne). 2023; 14:1135024. correspondence paksi satyagraha uropas.fk@ub.ac.id gede wirya diptanala putra duarsa diptaduarsa@gmail.com fauzan kurniawan dhani fauzankurniawandhani@gmail.com adrianus gupta wijaya guptawijaya@gmail.com urology department, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia besut daryanto, md (corresponding author) urobes.fk@ub.ac.id urology department, saiful anwar general hospital malang, jalan jaksa agung suprapto 2, klojen, malang, east java 65112, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13824 1 original paper background: urine alkalinization can be used for the treatment of some urological diseases. methods: a series of cases showing the beneficial effects of urine alkalinization with combination of potassium magnesium citrate and theobromine for the dissolution of uric acid stones and the treatment of other urological pathological conditions is presented. results: alkalinization was effective in the dissolution of uric acid renal stones in various clinical conditions. two cases of bilateral renal stone, four cases of staghorn renal stone, seven patients with unilateral renal stone, and five cases of ureteral stone were described. in this group the age ranged from 46 to 91 years, the m/f ratio was 7/11, the density of the stones ranged between 300 and 528. in most cases the urinary ph ranged from 5 to 5.5. diabetes was observed in 4 cases, obesity in 4 cases and hyperuricemia in 7. alkalinizing treatment achieved complete dissolution of the stone in 12 cases and almost complete or partial dissolution in other 6. a combination of potassium magnesium citrate and theobromine was used in all the cases. in 4 cases the administration of allopurinol was associated. in one case with obstructive ureteral stones, stone urine alkalinization for dissolution of uric acid stones and treatment of other urological diseases with a treatment combining potassium magnesium citrate and theobromine celia abad rodriguez-hesles 1, hassan alkhatatbeh 2, maría belén alonso bartolomé 3, carmen arai valladares ferreiro 4, hector ricardo ayllón blanco 3, cristina calzas montalvo 5, daniel carrasco gómez 6, marta casadevall rubau 7, elena maria casas martinez 8, sara esturo sacristan 9, miguel gómez garberí 10, blanca gómez-jordana mañas 11, rosa maria gras martinez 12, ana morales martínez 1, pedro hernandez-peñalver 7, silvia juste alvarez 5, alberto lópez sierra 13, rafael maria mas lucas 14, isabel mohedano sánchez 15, isabel montuenga fernandez 16, baraa nakdali kassab 10, maria negueroles-garcia 12, leticia ruibal gago 17, laura sánchez 10, bernat isern 18, 19, alberto trinchieri 20 1 hospital universitario clínico san cecilio, grenada, spain; 2 department of general surgery, urology and anaesthesia, the hashemite university, zarqa, jordan; 3 hospital universitario la paz, madrid, spain; 4 hospital de valme, endourology and urolithiasis section, sevilla, spain; 5 hospital universitario 12 de octubre, madrid, spain; 6 hospital regional universitario de málaga, malaga, spain; 7 fundacio puigvert, barcelona, spain; 8 hospital universitario rey juan carlos, madrid, spain; 9 hospital universitario galdakao-usansolo, galdakao, spain; 10 department of urology, hospital universitario san juan de alicante, alicante, spain; 11 hospital universitario fundación jiménez díaz, madrid; 12 hospital general universitario de valencia, valencia, spain; 13 hospital nuestra señora de sonsoles, avila, spain; 14 general hospital of segovia, segovia, spain; 15 hospital juan ramón jiménez, huelva, spain; 16 hospital universitario príncipe de asturias, alcala de henares (madrid), spain; 17 complexo hospitalario universitario de pontevedra, pontevedra, spain; 18 devicare, barcelona, spain; 19 laboratori d’investigació en litiasi renal, universitat de les illes balears, spain; 20 cdc ambrosiana, milano, italy. abstracts were presented at 1st-2nd-3rd-4th-5th edition of the clinical cases contest related to the non-surgical clinical management of renal lithiasis. full texts are available at https://professional.devicare.com/concurso-casos/en/ doi: 10.4081/aiua.2025.13824 summary dissolution was obtained with the combined administration of bicarbonate via nephrostomy and intravenous bicarbonate and oral treatment with citrates. stone dissolution of uric acid stones has also been described in some specific clinical conditions such as crohn's disease with ileostomy, outcome of partial nephrectomy, cross-fused renal ectopia. alkalinization was also used to prevent encrustation of a self-expanding metallic ureteral stent. alkalinization has also been employed during the period of mitomycin administration for the treatment of non-muscle infiltrating bladder tumors and for the treatment of overactive bladder. conclusions: the findings of these case reports demonstrate that urinary alkalinization with frequent monitoring of urinary ph can be successfully employed in the non-surgical treatment of uric acid stones of different sizes in various locations. key words: urinary calculi; uric acid; alkalinization; potassium; magnesium; citrate; theobromine. submitted 14 march 2025; accepted 17 march 2025 archivio italiano di urologia e andrologia 2025; 97(1):13824 celia abad rodriguez-hesles, hassan alkhatatbeh, m. belén alonso bartolomé, et al. 2 introduction the physiological value of urinary ph varies between 4.5 and 8.0, although the urine ph over 24 hours usually ranges between 5.7 and 6.3 so minimizing the risk of phdependent crystal formation (1). urinary ph depends on dietary intake, metabolism and post-renal urinary changes due to infection by some bacterial species. urinary ph values lower than 5.5 cause the formation of crystals or stones of uric acid which are poorly soluble in acidic urine. for this reason, products based on bicarbonate or citrate have long been used for the treatment and prevention of uric acid stones (2, 3). however, excessive alkalinization can increase the value of urinary ph above a threshold beyond which the precipitation of sodium urate and especially phosphate salts are favored. the target value of urinary ph for the dissolution of uric acid stones is between 6 and 6.5 and it must be carefully monitored (4, 5). the concomitant administration of theobromine, which has a ph-independent solubilizing action on uric acid crystals, may be useful to avoid excessive alkalinization (6, 7). alkalizers are also effective in dissolving crystals and stones consisting of certain drugs such as sulphadiazine. urine alkalinization has also found application in the treatment of other urological diseases. alkalizers are used for the symptomatic treatment of uncomplicated urinary tract infections in some countries (8), although the efficacy of this treatment has not been confirmed by randomized trials. the administration of alkalizing agents has also been proposed for the treatment of urinary frequency and pain in patients with interstitial cystitis because afferent c-fibers in the bladder wall could be activated by h+ ions frum acidic urine (9, 10). finally, urine alkalinization has been associated with intravesical mitomycin treatment of non-muscle infiltrating bladder tumors to stabilize the drug and increase its absorption into the bladder wall (11). case series bilateral renal stone (table 1) lit-control® ph up as a great alternative for uric acid stones (maría belén alonso 2nd ed. 2021) we report the case of a 71-year-old obese woman diagnosed with bilateral uric acid lithiasis who required urgent urinary referral, after which alkalinising treatment with potassium citrate was prescribed without benefit. the patient had to undergo percutaneous nephrolitectomy, a procedure which failed to remove all the kidney stones. after this, the patient was treated with litcontrol® ph up, achieving almost a total resolution of her kidney stones (figure 1). effective alkalinizing chemolysis in multiple uric acid nephrolithiasis and coralliform calculi (alberto lópez 4th ed. 2023) a 73-year-old diabetic woman with high cardiovascular morbidity was referred to the emergency department with clinical and laboratory findings of urinary sepsis. urinalysis showed urinary ph 5 and abundant amorphous urates in the sediment. the ct scan showed multiple bilateral nephrolithiasis and a large pseudo-coralliform stone in the right kidney, causing ipsilateral obstructive uropathy. urgent placement of a double j catheter table 1. bilateral renal uric acid stones. renal bilateral stones (n = 2) lit-control® ph up: potassium citrate 200 mg, magnesium citrate 200 mg, theobromine 60 mg. author maría belén alonso 2021 alberto lópez 2023 patient & stone 71 yrs f bilateral stones obstructive left stone 23.6 mm 73 yrs f right kidney 9 mm upj stone+ calyceal stones + partial coralliform of pelvis and lower calix left kidney non-ostructive stone hu 528 treatment k citrate 10 meq x 3 (no benefit) + dj stent pcnl failure lit-control® ph up x 2 + bicarbonate right dj stent lit-control® ph up x 3 outcome 3 months complete left stone dissolution decreased size of right stone 4 months residual stone in right lower calix. microliths in left middle and lower calyces 8 months no stones metabolic obesity dyslipidemia ur ph 5.5 diabetes obesity scr 3.61 at admission ur ph 5.5 figure 1. kidney stone in the lower calyx of the left kidney and a kidney stone in the right kidney before and after treatment. archivio italiano di urologia e andrologia 2025; 97(1):13824 3 urine alkalinization and admission to the intensive care unit was performed. once the septic process was concluded, she was reviewed in consultation and alkalinizing treatment with litcontrol® ph up was decided. after four months, she presented a satisfactory evolution, good tolerance to treatment, and dissolution of almost all uric acid lithiasis. subsequent control showed normal renal ultrasound, and the metabolic study showed normal uric acid and citrate excretion in urine, as well as improvement of renal function and urinary ph with a current value of 6 (figure 2). staghorn renal stones (table 2) combined medical approach for uric acid staghorn lithiasis (laura sánchez 1st ed. 2020) medical treatment for uric acid lithiasis comprises two modalities: stone formation prevention and chemolysis with curative intent. the authors present the results of the combined medical treatment of uric acid lithiasis for the purpose of stone size reduction. the case of a 54-yearold man was presented who, after an episode of mild, self-limited hematuria, was diagnosed by ct scan with staghorn renal stone in the left kidney. the metabolic study showed hyperuricemia and hyperuricosuria. given the normal renal function and the disappearance of the symptoms, it was decided to start combined therapy by alkalizing the urine using lit-control® ph up, allopurinol and dietary measures. after four months of treatment, the patient presents with uremia and uricosuria within normal values, as well as a reduction in the stone size, completely disappearing the stone that was in the upper calyx of the right kidney. the combined medical treatment for uric acid stones can dissolve the stone or reduce its size, avoiding or facilitating surgical treatment (figure 3). medical management of uric acid kidney stones, after a case report (ana morales martínez 1st ed. 2020) urinary uric acid stones are a frequent and important pathology in our clinical practice. conservative treatment by means of hygienic-dietary measures and correct urinary alkalinization by means of citrate and theobromine seems to be a promising combination for the treatment and resolution of these lithiasis. a case with complete resolution of a coralliform uric acid lithiasis was observed after 12 weeks of treatment with allopurinol and lit-control® ph up without adverse reactions and avoiding the need for invasive surgical measures. this case has been presented elsewhere as a self-standing case report after participating in the 1st edition of clinical case contest (12). medical treatment of staghorn uric acid lithiasis with lit-control® ph up (baraa nakdali kassab 3rd ed. 2022) a 65-year-old caucasian female who was evaluated for pain in the right renal fossa of 10 days evolution, is presented. during her follow-up appointment, an abdominal/pelvic ct scan was requested where a right staghorn lithiasis of 4.5 cm x 3.2 cm was observed, occupying the upper, middle, and lower calyces, with growth towards the renal pelvis, with an average density of 450 hounsfield units (hu). an alkalizing medical treatment was started using lit-control® ph up (potassium citrate, magnesium citrate and theobromine). after being treated for three months, the resolution of lithiasis was observed. table 2. staghorn uric acid stones. renal staghorn stones (n = 4) author laura sánchez 2020 ana morales martínez 2020 baraa nakdali kassab 2022 isabel mohedano 2023 patient & stone 54 yrs m left staghorn kidney stones 51 yrs f right staghorn renal stone 65 yrs f right staghorn stone 4.5 cm x 3.2 cm 52 yrs f coralliform 60 mm right stone (pelvis + middle and lower calyces) hu 300 436 450 500 treatment lit-control® ph up x 2 allopurinol dietary measures lit-control® ph up allopurinol lit-control® ph up lit-control® ph up 1x3 outcome 4 months partial dissolution (complete dissolution of the stone in the upper calix) 12 weeks complete dissolution of the stone 3 months complete dissolution 11 months almost complete chemolysis metabolic high sua high urua high sua high sua ur ph 5.0 diabetes sua 3.1 ur ph 5.0 figure 2. dissolution of almost all multiple bilateral renal stone including a large pseudo-coralliform stone in the right kidney after 4 months of alkalinizing treatment with lit-control® ph up. figure 3. partial dissolution of left kidney staghorn stone. archivio italiano di urologia e andrologia 2025; 97(1):13824 celia abad rodriguez-hesles, hassan alkhatatbeh, m. belén alonso bartolomé, et al. 4 chemolytic treatment for uric acid lithiasis, even for staghorn stones, should be considered as the first treatment option. this case has been presented elsewhere as a self-standing case report after participating in the 3rd edition of clinical case contest (13). chemolysis of large coralliform lithiasis with lit-control® ph up (isabel mohedano 4th ed. 2023) a case report showing the usefulness of medical treatment in coralliform lithiasis of uric acid despite its large size. a 52-year-old woman referred to our office for hematuria. an abdomino-pelvic ct scan was performed showing a 6 cm right renal lithiasis, of coralliform morphology, extending from the renal pelvis towards the middle and lower calicial groups, producing mild ectasia of the excretory system. after 11 months of urinary alkalinization using lit-control® ph up (potassium citrate, magnesium citrate and theobromine), the patient achieved almost complete chemolysis with a ph around 6. we should consider alkalinizing pharmacotherapy as the first treatment option in patients with uric acid lithiasis (figure 4). unilateral renal stones (table 3) oral chemolysis as an effective treatment in the resolution of uric acid kidney stones (blanca gómez-jordana mañas 2nd ed. 2021) kidney stone disease is a highly prevalent pathology that is still increasing and is composed of uric acid in 10 and 15% of cases. a clear relationship has been established between the formation of this type of stones with the presence of an acid urinary ph. therefore, the current treatment is based on the use of urine alkalizers to prevent the crystallization of uric acid. it seems that the association of theobromine with this treatment would increase its efficacy. we reviewed a clinical case from our center that presents uric acid nephrolithiasis resolved by medical treatment (figure 5). figure 4. complete chemolysis of a 6 cm right renal staghorn stone. table 3. unilateral uric acid renal stones. renal unilateral stones (n = 7 author blanca gómez-jordana mañas 2021 silvia juste alvarez 2024 rafael maria mas lucas 2024 cristina calzas montalvo 2022 celia abad rodríguez-hassles 2023 hassan akhenaten 2024 elena mª casas martínez 2024 patient & stone 83 yrs f right kidney stone 17x5 mm pelvis +lower pole stone 46 yrs m two stones in right pelvis (15 mm + 16 mm) + dilatation right upper-middle calyces at 6 month follow up after pcnl 27 mm stone right pelvis + two stones in lower calix (7 and 8 mm) 56 yrs f 6-7 mm stone lower left calix 67 yrs f multiple stones in right kidney (4 mm pelvis, upper, middle calix) 66 yrs f 4 mm obstructive left ureteral stone + 15 mm non-obstructive right renal pelvis stones 60 yrs f two left kidney stones 15 mm in the renal pelvis and 21 mm in lower calyx 59 yrs f impacted right renal pelvis stone secondary hydronephrosis 16 x 9 mm hu 500 na 365 370 500 treatment bicarbonate poorly tolerated (high blood pressure) (3 months) diet+lemon juice (non effective) lit-control® ph up x 2 lit-control® ph up x 2 lit-control® ph up lit-control® ph up x 2 300 mg of allopurinol dj stent spontaneous left stone passage + lit-control® ph up 1 x 2-3 + allopurinol 300 mg once day + dj stent flexible left urs partial fragmentation lit-control® ph up 2 x 2 + left dj stent unsuccessful mini-pcnl (purulent urine) nephrostomy+ lit-control® ph up lit-1 x 2 outcome 6 months complete dissolution 3 months no evidence of stone 6 months decreased to 2 mm 4 months complete resolution 3 months slight decrease 6 months very significant reduction 12 months no lithiasis 3 months dissolution residual stone in the lower calix 2 months no evidence of stone metabolic ur ph 5.0 normal sua ur ph 5.0 ur ph 5.0 ur ph 5.0 high sua previous bariatric surgery breast cancer mastectomy + chemotherapy + adjuvant hormone therapy sua normal urua 752 mg/day diabetes obesity high purine diet mild hyperuricosuria sua 8.5 ur ph 5.2 low ur citrate archivio italiano di urologia e andrologia 2025; 97(1):13824 5 urine alkalinization breaking the cycle: successful oral treatment of recurrent uric acid stones after early post-surgical relapse (silvia juste alvarez 5th ed. 2024) we present a case report of an early uric acid nephrolithiasis recurrence after surgery which was successfully dissolved by oral alkalinization. we collect clinical data, laboratory studies, imaging studies (mostly ct scan) and analysis of the stone composition after surgery. two treatments were administered sequentially during the patient's management: percutaneous nephrolithotomy was first performed, then, after an early recurrence, oral chemolysis was performed. percutaneous nephrolithotomy was first performed due to high stone burden and obstructive uropathy. stone composition analysis revealed uric acid as its main component. the patient suffered from early recurrence (6 months later). oral chemolysis was decided and lithiasis was completely dissolved after alkalinization of urine with lit-control® ph up for 3 months. the patient remains asymptomatic (figure 6). the power of dietary supplements and urinary ph regulation in the treatment of kidney lithiasis (rafael maria mas lucas 5th ed. 2024) to evaluate the effectiveness of treatment with lit-control® ph up in reducing uric acid kidney stones and normalizing urinary ph in a patient with left renal colic. a patient with uric acid kidney stones was diagnosed through abdominal ct scan and urine analysis. after 6 months, a significant reduction in the size of the kidney stones was observed (from 6-7 mm to 2 mm), and urinary ph was normalized. the patient remained asymptomatic during this period. treatment with lit-control® ph up was effective in reducing kidney stone size and normalizing urinary ph, with favorable results and no new episodes of renal colic. the treatment was adjusted to maintain long-term control with a dose of 2 capsules per day. complete resolution of multiple nephrolithiatic pathology using conservative management with alkalizing oral chemolysis (cristina calzas montalvo 3rd ed. 2022) clinical case presentation to demonstrate that uric acid lithiasis can be completely dissolved using alkalizing oral chemolysis. we describe evaluation, diagnosis, treatment, and follow-up of a 67-year-old female patient with multiple renal lithiasis who was assessed in the emergency department and later through the urology outpatient consultation. after urinary ph alkalization with lit-control® ph up for 4 months, all the lithiasis located in the right kidney disappeared completely according to the abdominal-pelvic ct scan and the patient remains without urinary symptoms. oral chemolysis based on urine alkalization by administration of lit-control® ph up allows to dissolve uric acid stones if the urinary ph is kept above 7. urinary alkalinization can be combined with allopurinol if there is hyperuricemia and/or hyperuricosuria and with urinary drainage in case of complicated renal colic or with tamsulosin to favor spontaneous expulsion (figure 7). pharmacological chemolysis of uric acid lithiasis in a patient undergoing bariatric surgery and chemotherapy (celia abad rodríguez-hesles 4th ed. 2023) a woman underwent bariatric surgery and was subsequently diagnosed with breast cancer undergoing mastectomy and chemotherapy + adjuvant hormone therapy. the patient was referred from the oncology department with left lumbar pain and an imaging test showing 4 mm of obstructive lithiasis in the left ureteral meatus together with 15 mm of non-obstructive urolithiasis in the right renal pelvis. after spontaneous expulsion of obstructive lithiasis, treatment of the right lithiasis with a composition suggestive of uric acid is proposed. the patient did not wish surgical treatment. it was decided to alkalinize the urine using lit-control® ph up and dietary recommendations, achieving complete chemolysis. the patient currently remains asymptomatic (figure 8). figure 5. complete dissolution of right kidney stone 17x5 mm of the pelvis and lower pole and 3 mm stone of lower calix of left kidney. figure 6. dissolution of residual stones after pcnl in the right pelvis (27 mm) and in the lower calix (7 and 8 mm). figure 7. complete chemolysis of multiple stones of the right kidney. figure 8. partial dissolution of a 15 mm non-obstructive stone in the right renal pelvis. archivio italiano di urologia e andrologia 2025; 97(1):13824 celia abad rodriguez-hesles, hassan alkhatatbeh, m. belén alonso bartolomé, et al. 6 the role of urine alkalinization on using lit-control® ph up in the treatment of uric acid kidney stones post failed endoscopic procedure. a clinical case report (hassan alkhatatbeh 5th ed. 2024) uric acid kidney stones are a common form of nephrolithiasis and are primarily associated with conditions such as hyperuricosuria, acidic urine ph, and obesity. the management of uric acid stones requires addressing the underlying causes, including urine alkalinization, which plays a crucial role in preventing stone formation and promoting the dissolution of existing stones. this case report explores the therapeutic benefits of urine alkalinization using lit-control® ph up in the treatment of a patient with recurrent uric acid kidney stones with previously failed endoscopic procedure (figure 9). lit-control® ph up prevents morbidity and mortality in mini-pcnl treatment of large obstructive uric acid stones (elena mª casas martínez 5th ed. 2024) the objective of this clinical case is to evaluate the effectiveness of lit-control® ph up in the treatment of large uric acid stones, thus avoiding the surgical risks and complications of more invasive procedures. we present the case of a 59-yearold woman who, during an incidental imaging test, was found to have a large impacted stone in her right renal pelvis, causing secondary hydronephrosis. after an unsuccessful attempt at mini-pcnl due to the presence of purulent urine and the visualization of a radiolucent stone on fluoroscopy, the patient was treated with lit-control® ph up until the next surgical intervention was scheduled. during follow-up, a reduction in stone size was observed, eventually leading to its complete disappearance. therefore, litcontrol® ph up could be considered an effective alternative therapy for the treatment of large stones, instead of more invasive interventions (figure 10) (table 3). ureteral stones (table 4) clinical case presentation: pharmacological management of uric acid urolithiasis (miguel gómez garberí 1st ed. 2020) the prevalence of uric acid stones represents 10% of all table 4. ureteral uric acid stones. ureteral stones (n = 5) author miguel gómez garberí 2020 maría negueroles-garcía 2021 daniel carrasco gómez 2024 leticia ruibal gago 2024 carmen arai valladores ferreiro 2024 patient & stone 67 yrs m 15 mm left ureteral stone and 22 mm left renal stone (inferior calix) 90 yrs m 13 mm stone in an ureter loop with uretero-hydronephrosis failure of anterograde and retrograde urs 60 yrs m 19 mm right lumbar ureter stones + left ureteral lithiasis of 2 mm + bilateral retrograde dilatation + lower calix microlithiasis 68 yrs m anuria & bilateral obstruction 91 yrs m 15 mm pelvic renal obstructive stone of 15 mm three obstructive ureteral stones (25 mm of length) hu na 450500 treatment lit-control® ph up allopurinol dj stenting nephrostomy oral treatment lit-control® ph up 1 x 2 local chemolysis with 1/6 molar sodium bicarbonate through the nephrostomy lit-control® ph up x 2 + dj stent canoxidin x 3 and lit-control® ph up 2 x 2 initially dj stent (r) pcn (l) then bilateral pcn lit-control® ph up (2 x 2 day) and sodium bicarbonate 500 mg per day allopurinol 100 mg low purine diet fluid intake outcome 4 months complete dissolution of the ureteral stone and partial of the stone in the lower calix) 1 month disappearance of the lithiasis 3 months complete chemolysis stone reduction at 4 months right rirs at 5 months left rirs 3 months complete dissolution of all the stones metabolic scr 1.64 at admission ur ph 5.5 high sua high urua (980 mg/day) scr 3.4 at entry diabetes ur ph 5.0 sua 7.4 scr 1.7 figure 9. dissolution of two stones of the left kidney (15 mm in the renal pelvis and 21 mm in lower calyx). figure 10. dissolution of a stone of the right pelvis after failed mini-pcnl. archivio italiano di urologia e andrologia 2025; 97(1):13824 7 urine alkalinization urolithiasis and its pharmacological management has an established role in both treatment and prevention. the objective of this case presentation was to show the pharmacological management of uric acid stones. we presented a case of a 67-year-old male patient with a personal history of uric stones who attended outpatient consultation presenting kidney function deterioration and a grade iii ureterohydronephrosis affecting the left kidney caused by a 15 mm obstructive stone in the proximal ureter and a 22mm non-obstructive stone in the lower calyx. it was decided to place a double-j stent and to prescribe pharmacological treatment with lit-control® ph up and allopurinol. the complete dissolution of the intraureteral stone and a reduction of the intracalyceal stone were achieved. pharmacological treatment can facilitate and even avoid surgical interventions in patients with uric stones. oral and local chemolysis via nephrostomy for treatment of radiolucent stones (maría negueroles-garcía 2nd ed. 2021) a clinical case about the use of oral and local chemolysis by nephrostomy catheter for the treatment of radiolucent stones is reported. the case of a 90-year-old multi-pathological male, who required nephrostomy due to pyelonephritis secondary to radiolucent stones in the proximal ureter, is described. after resolution of the infectious condition, surgery was attempted by anterograde and retrograde ureterorenoscopy without success because the kidney stone was found in a ureteral loop. it was decided to perform an oral treatment with lit-control® ph up and local chemolysis with 1/6 molar sodium bicarbonate through the nephrostomy, which led to the disappearance of the lithiasis. we considered alkalizing oral chemolysis together with local nephrostomy, a useful treatment option in patients with radiolucent calculi (figure 11). use of lit-control® ph up as alkalinizing agent for the treatment of large ureteral uric acid lithiasis (carrasco-gomez daniel 5th ed. 2024) to evaluate the use of medical treatment with lit-control® ph up as a useful non-invasive alkalinizing supplement for urolithiasis. we presented the case of a 60-year-old male who came to the emergency department with typical colic caused by a 19 mm left ureteral lithiasis, producing mild ureteropelvic ectasia. after diversion of the urinary tract, ct scan control performed 3 months later just after medical expulsive treatment and lit-control® ph up use successfully lead to resolution of that lithiasis. after 3 months of urinary alkalinization using litcontrol® ph up (potassium citrate, magnesium citrate and theobromine), the patient achieved complete chemolysis with a ph around 6. we should consider alkalinizing pharmacotherapy as the first treatment option in patients with uric acid lithiasis (figure 12). lit-control® ph up as a treatment for uric acid lithiasis (leticia ruibal gago 5th ed. 2024) this is the case of a 68-year-old man with multiple comorbidities (type 2 diabetes, epilepsy, frontotemporal dementia). he was admitted for anuria and obstructive renal failure caused by bilateral reno-ureteral stones. initially, a right double-j stent and a left nephrostomy were placed for urinary diversion. a month later, he was readmitted due to acute renal failure and catheter obstruction, requiring replacement and the addition of a right nephrostomy. given the urinary ph of 5 and recurrent catheter obstruction, treatment with canoxidin® and lit-control® ph up was initiated, raising the urinary ph to 6. a scheduled retrograde intrarenal surgery on the right side was performed. following medical treatment, a reduction in left side stones was observed. finally, retrograde intrarenal surgery on the left side was scheduled, achieving complete stone clearance. the patient remains on preventive treatment with lit-control® ph up, with no evidence of stone recurrence (figure 13). chemolysis in elderly and renal failure patient (carmen arai valladores ferreiro 5th ed. 2024) we presented the case of 91 years old patient with personal story of frequents renal colic pain and spontaneous expulsion of lithiasis, diagnosed with multiple ureteral and renal obstructive stones compatible with uric acid composition. the patient also suffered chronic kidney failure, with creatinine clearance of 33 ml per min and potassium level of 5.3 meq/l. we proposed chemolysis figure 11. disappearance of proximal right ureteral stone after oral treatment with lit-control ® ph up and local chemolysis with 1/6 molar sodium bicarbonate through the nephrostomy. figure 13. reduction of size of bilateral reno-ureteral stones before rirs. figure 12. dissolution of right ureteral stone after dj stenting. archivio italiano di urologia e andrologia 2025; 97(1):13824 celia abad rodriguez-hesles, hassan alkhatatbeh, m. belén alonso bartolomé, et al. 8 with lit-control® ph up (2 tablets twice a day) and sodium bicarbonate 500 mg per day, with complete dissolution of all the stones in 3 months (table 4). urinary alkalinization in other pathological conditions (table 5) pharmacological chemolysis of uric acid lithiasis in a patient with crohn's disease (rosa maria gras martínez 3rd ed. 2022) a male patient with crohn's disease and an ileostomy carrier, was diagnosed with uric acid lithiasis after visiting the emergency room during an episode of left renal colic. after urinary alkalization using lit-control® ph up and dietary recommendations, the patient achieved a complete chemolysis, maintaining the stability of his underlying condition, without showing side effects throughout the treatment. after the stone dissolution, the patient remains asymptomatic and under follow-up through outpatient visits. this case has been presented elsewhere as a self-standing case report after participating in the 3rd edition of clinical case contest (14). lit-control® ph up in the medical management of uric acid lithiasis (hector ricardo ayllón 3rd ed. 2022) clinical case report of a 54-year-old male, who is diagnosed with a single 16 mm kidney stone as an incidental finding in a control ct scan due to a previous left radical nephrectomy. the low hounsfield units, urinary ph and the nonvisibility of the lithiasis in simple x-ray suggested that it was a uric acid stone. after the patient’s consent, chemolytic treatment of lithiasis using potassium citrate was planned. the patient showed partial improvement using the treatment but referred gi discomfort, so the medication was changed to lit-control® ph up and allopurinol + colchicine, since the patient also presented hyperuricemia in control tests. once the treatment is changed the patient showed a complete resolution of the lithiasis (figure 14). alkalinizing treatment and urinary ph control to prevent endourological stent encrustation (sara esturo 4th ed. 2023) the case of a man with a history of lithiasis treated with several percutaneous and endourological interventions who presented extensive critical ureteral stenosis was presented. allium© self expanding stent was placed to correct the obstructive uropathy and voiding symptoms. the patency of the stent was maintained with urinary alkalintable 5. urinary alkalinization in other pathological conditions. others (n = 6) author rosa maria gras martínez 2022 hector ricardo ayllón 2022 sara esturo 2023 isabel montuenga 2023 marta casadevall 2024 pedro hernández-peñalver 2024 patient & stone 54 m crohn disease and ileostomy 11 mm left puj stone 54 m partial nephrectomy left pelvic 16 mm stone 64 yrs m recurrent endoscopies for stone treatment resulting in critical ureteral stenosis 68 yrs m single left kidney (crossed and fused renal ectopia) high volume renal lithiasis upper and middle calyces + pyelocaliceal dilatation 70 yrs m with detrusor overactivity 77 yrs m recurrent intermediate risk non-muscle invasive bladder cancer (nmibc) 64 yrs m multiple ta low grade tumours hu 550 < 600 400500 na na treatment (lit-control® ph up) x 3 k citrate x 2 poorly tolerated (gi) lit-control® ph up allopurinol 300 allium© self expanding stent + urinary alkalinization by lit control® ph up and dietary recommendations. lit-control® ph up 1 x 3 diet & fluid intake lit-control® ph up x 2 lit-control® ph up 1-2 day during the weeks of mitomycin instillations ph monitored by the patient every day with dipsticks or lit-control® ph meter outcome 12 months complete chemolitholysis 6 months complete resolution 11-16 months slight calcification of the proximal and distal end 3 mm calcification left kidney significant decrease of the lithiasis load 2 months clinical improvement urinary frequency qol well tolerated urine alkalization at ph 6.0-6.5 metabolic ur ph < 5 ur ph 5.5 high sua scr 1.46 ur ph 5.5 acidic urinary ph 6 figure 14. dissolution of left kidney stone after partial nephrectomy. archivio italiano di urologia e andrologia 2025; 97(1):13824 9 urine alkalinization ization by lit-control® ph up and dietary recommendations. the underlying pathology of the patient was stabilized with no adverse effects, good tolerance and adherence to treatment (figure 15). chemolysis of uric acid lithiasis in a patient with crossed renal ectopia (isabel montuenga 4th ed. 2023) a case is presented of a male patient with crossed and fused renal ectopia, who following an episode of abdominal pain, was diagnosed with high volume renal lithiasis disease associated with pyelocaliceal dilatation. given the characteristics of the patient and the lithiasis, urinary alkalinization by using lit-control® ph up and dietary recommendations was decided. the patient presented a clear decrease in the lithiasis load and pyelocaliceal dilatation, with no side effects. currently, he remains with the same treatment and is being followed up in outpatient clinics (figure 16). urinary alkalinization for the management of overactive bladder (marta casadevall 5th ed. 2024) overactive bladder has a global prevalence of 10.8-35.6% and a negative impact on patient’s quality of life. there is limited evidence in the literature regarding the effects that a variation in urinary ph may have on symptoms associated with overactive bladder. the aim of our study was to evaluate the clinical changes related to bladder overactivity following a treatment for urinary alkalinization. we present the case of a 70-year-old male with detrusor overactivity and acidic urinary ph (ph 6), who underwent urinary alkalinization treatment with lit-control® ph up, monitored by an electronic device. upon completing the treatment, clinical improvement was observed, primarily in the patient’s urinary frequency, significantly enhancing his quality of life. urine alkalinization and measurement in patients undergoing mitomycin instillations for intermediate risk non-muscle invasive bladder cancer (pedro hernández peñalver-5th ed. 2024) to explore the urine alkalinization and its measurement in patients with intermediate risk nmibc undergoing instillations with mitomycin. two patients were given lit-control® ph up 1-2 times a day with a target ph ≥ 6 during the weeks prior to the instillations. every day, they measured their urine ph with lab sticks, recording the measurements and one patient used the digital lit-control® ph meter. lit-control® ph up is a safe and tolerated option for improving the urine alkalinization, which aims to reduce recurrence rates in patients undergoing mitomycin instillations. the digital ph meter could give more information to the patient to guide the urine alkalinization (table 5). conclusions this case series confirms the effectiveness of alkalizing therapy with citrates (lit-control® ph up) for the dissolution of uric acid stones at any site and of any size. the time required for dissolution varied between 3 and 12 months. side effects were mild and infrequent. high-dose citrates can cause gastro-intestinal disorders and sodium salts can aggravate urinary hypertension. the addition of theobromine may allow the dose of citrates to be reduced, increasing the efficacy and tolerability of the drug. references 1. corder cj, rathi bm, sharif s, et al. 24-hour urinalysis. [updated 2024 oct 6]. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2025 jan-. available from: https://www.ncbi.nlm.nih.gov/ sites/books/nbk482482/ figure 16. almost complete dissolution of a high volume renal stone in crossed fused renal ectopia. figure 15. patency of a self-expanding ureteral stent was maintained with urinary alkalinization (lit-control® ph up). declarations ethical approval: ethics committee (ec) was not required for a retrospective review of cases. patient consent was obtained by the institution of each author. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: b.i. is an employee of devicare. the remaining authors have no conflicts of interest to declare. funding: devicare provided for the apc. authors' contributions: conceptualization, b.i. and a.t.; methodology, a.t.; software, n/a.; validation, b.i.; formal analysis, a.t.; investigation, a.t.; resources, n/a.; data curation, a.t.; writing c.a.r-h., h.a., m.b.a.b., c.a.v.f., h.r.a.b., l.b., c.c.m., n.c.g., d.c.g, m.c.r., e.m.c.m., s.e.s., l.g.m., b.gj.m., r.m.g.m., p. h-p., s.j.a., a.l.s., r.m.m.l., i.m.s., i.m.f., b.m. de h., m.n-g., l.r.g.; writing-review and editing, a.t.; visualization, a.t.; supervision, b.i.; project administration, n/a; funding acquisition, n/a. all authors have read and agreed to the published version of the manuscript”. acknowledgments: n/a. archivio italiano di urologia e andrologia 2025; 97(1):13824 celia abad rodriguez-hesles, hassan alkhatatbeh, m. belén alonso bartolomé, et al. 10 2. kamphuis gm, wouter van hattum j, de bie p, somani bk. method of alkalization and monitoring of urinary ph for prevention of recurrent uric acid urolithiasis: a systematic review. transl androl urol. 2019; 8(suppl 4):s448-s456. 3. trinchieri a, esposito n, castelnuovo c. dissolution of radiolucent renal stones by oral alkalinization with potassium citrate/potassium bicarbonate. arch ital urol androl. 2009; 81:188-91. 4. sanz-gómez i, angerri o, baboudjian m, et al. role, cost, and availably of urinary ph monitoring for kidney stone disease-a systematic review of the literature. curr urol rep. 2023; 24:381-388. 5. grases f, rodriguez a, berga f, et al. a new device for simple and accurate urinary ph testing by the stone-former patient. springerplus. 2014; 3:209. 6. hernandez y, costa-bauza a, calvó p, et al. comparison of two dietary supplements for treatment of uric acid renal lithiasis: citrate vs. citrate + theobromine. nutrients. 2020; 12:2012. 7. trinchieri a. theobromine for treatment of uric acid stones and other diseases. arch ital urol androl. 2024; 96:13277. 8. o'kane db, dave sk, gore n, et al. urinary alkalisation for symptomatic uncomplicated urinary tract infection in women. cochrane database syst rev. 2016; 4:cd010745. 9. ueda t, yoshida t, tanoue h, et al. urine alkalization improves the problems of pain and sleep in hypersensitive bladder syndrome. int j urol. 2014; 21:512-7. 10. dawson te, jamison j. intravesical treatments for painful bladder syndrome/interstitial cystitis. cochrane database syst rev. 2007; (4):cd006113. 11. au jl, badalament ra, wientjes mg, et al.; international mitomycin c consortium. methods to improve efficacy of intravesical mitomycin c: results of a randomized phase iii trial. j natl cancer inst. 2001; 93:597-604. 12. morales martínez a, melgarejo segura mt, cano garcía mc. manejo médico de los cálculos renales de ácido úrico, a próposito de un caso [medical management of uric acid renal stones, case description.]. arch esp urol. 2021; 74:442-445. 13. nakdali kassab b, budia alba a. medical treatment of coralliform uric acid lithiasis with lit-control® ph up. kenya journal of urology 2024; 2:18-20 14. gras martínez rm, diranzo garcía m, álvarez barrera a, et al. pharmacological chemolysis of uric acid lithiasis in a patient with crohn's disease. arch esp urol. 2023; 76:823-828. correspondence celia abad rodriguez-hesles celiaabadrh@gmail.com ana morales martínez anamorales891@hotmail.com hospital universitario clínico san cecilio, grenada, spain hassan alkhatatbeh dr23hak@yahoo.com department of general surgery, urology and anaesthesia, the hashemite university, zarqa, jordan maría belén alonso bartolomé mery_ab95@hotmail.com hector ricardo ayllón blanco hector.ayllonb@gmail.com hospital universitario la paz, madrid, spain carmen arai valladares ferreiro spainarailo79@hotmail.com hospital de valme, endourology and urolithiasis section, sevilla cristina calzas montalvo cristinacm179@gmail.com silvia juste alvarez sjustealvarez@gmail.com hospital universitario 12 de octubre, madrid, spain daniel carrasco gómez hospital regional universitario de málaga, malaga, spain diabliyocarrasco@gmail.com marta casadevall rubau casadevallm28@gmail.com pedro hernandez-peñalver pedrohp964@gmail.com fundacio puigvert, barcelona, spain elena maria casas martinez elena.casasmrtz@gmail.com hospital universitario rey juan carlos, madrid, spain sara esturo sacristan saraesturosacristan@gmail.com hospital universitario galdakao-usansolo, galdakao, spain miguel gómez garberí miguelggarberi@gmail.com baraa nakdali kassab baranakdali@hotmail.com laura sánchez laurasanchezc10@gmail.com department of urology, hospital universitario san juan de alicante, alicante, spain blanca gómez-jordana mañas blanca.gomezj@quironsalud.es, blanca.gomezj@fjd.es hospital universitario fundación jiménez díaz, madrid rosa maria gras martinez rosagrasma@gmail.com hospital general universitario de valencia, valencia, spain alberto lópez sierra albertoyedok@gmail.com hospital nuestra señora de sonsoles, avila, spain rafael maria mas lucas rafamaslucas@hotmail.com general hospital of segovia, segovia, spain isabel mohedano sánchez isabel-ms5@hotmail.com hospital juan ramón jiménez, huelva, spain isabel montuenga fernandez isabel.montuenga@gmail.com hospital universitario príncipe de asturias, alcala de henares (madrid), spain maria negueroles-garcia maria.negueroles@gmail.com hospital clínico universitario de valencia, valencia, spain leticia ruibal gago leticia.ruibal.gago@sergas.es complexo hospitalario universitario de pontevedra, pontevedra, spain bernat isern bernat.isern@uib.cat laboratori d’investigació en litiasi renal, universitat de les illes balears, spain alberto trinchieri (corresponding author) alberto.trinchieri@gmail.com cdc ambrosiana, milan, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13931 1 original paper introduction khat (catha edulis forsk.), a flowering evergreen shrub of the celastraceae family, contains psychoactive alkaloids structurally and pharmacologically related to amphetamines (1, 2). this stimulant is culturally entrenched in east africa and the arabian peninsula, particularly yemen, where it is traditionally consumed during social occasions to enhance alertness and productivity (3, 4). globally, an estimated 20 million individuals use khat, with yemen exhibiting particularly high prevalence: approximately 60% of adult males and 35% of females consume 100-200 g of fresh leaves daily (1). although the adverse physical and psychological effects of khat are well documented, its impact on male reproductive health remains inadequately characterized (1). a recent narrative review identified significant knowledge gaps concerning khat’s reproductive toxicity in humans (5). emerging meta-analyses suggest associations between khat use and detrimental reproductive outcomes, including reduced semen volume and increased risks of low birth weight and congenital anomalies (6). however, these findings are based on limited primary data, and mechanistic studies are lacking. moreover, controlled investigations addressing dose-response effects and reversibility are scarce. seminal fluid volume is a critical parameter influencing male fertility, providing nutritional and protective functions essential for sperm viability during transit through the female reproductive tract (7). in 2021, the world health organization defined hypospermia as ejaculate volumes consistently below 1.4 ml (8). etiologies of reduced semen volume include psychological factors, collection artifacts, and pathological conditions affecting accessory sex glands or ejaculatory ducts (9). khat chewing is widespread among yemeni men of reproductive age, and accumulating evidence implicates it in male infertility (5, 10). for example, el-shoura et al. reported that khat-dependent individuals exhibited significantly reduced semen volume, sperm motility, and sperm counts compared to non-users (11). these findings align with other studies demonstrating khat’s negative effects on sperm quality and testosterone levels (10, 12, 13). however, most research has been conducted outside background: khat (catha edulis) chewing is a culturally ingrained practice in yemen and has been associated with potential impairment of male reproductive function. however, rigorous quantitative assessments of its effects on seminal parameters are limited. this study investigates the relationship between khat consumption and semen characteristics and examines the reversibility of any adverse effects following cessation. methods: a prospective two-phase study was conducted at dr. najat al-malas ivf center in sana’a, yemen (2019-2024). phase 1 compared semen volume and related parameters across four age-, bmi-, education-, and socioeconomic-matched cohorts: infertile khat chewers (n = 91), infertile non-chewers (n = 60), fertile khat chewers (n = 91), and fertile non-chewers (n = 32). phase 2 involved a three-month supervised khat cessation intervention among infertile chewers. semen samples were obtained via standardized collection methods. associations between khat use and seminal parameters were analyzed using univariate and multivariate regression models. results: khat chewers demonstrated significantly reduced semen volumes compared to non-chewers in all comparisons. infertile chewers had lower volumes (1.94 ± 0.48 ml) than fertile chewers (2.36 ± 0.52 ml; p < 0.001, d = 0.85) and infertile nonchewers (3.07 ± 0.74 ml; p < 0.001, d = 1.72). pooled analysis indicated that chewers (n = 182) had 29.6% lower semen volumes than non-chewers (n = 92) (2.15 ± 0.89 ml vs. 3.04 ± 0.76 ml; p < 0.001). notably, cessation of khat chewing led to a 35% increase in volume among infertile chewers (from 1.94 ± 0.48 ml to 2.62 ± 0.52 ml; p < 0.001, d = 1.21). hormonal analysis (n = 15) showed increased testosterone and decreased prolactin post-cessation (p < 0.05). conclusions: khat chewing is significantly associated with reduced semen volume and impaired seminal fluid parameters in men. importantly, cessation of khat use leads to a marked improvement in semen volume and favorable hormonal changes, indicating partial reversibility of its adverse effects. these findings highlight khat’s detrimental impact on male reproductive health and underscore the potential benefits of quitting khat for fertility restoration. key words: catha edulis; semen volume; semen parameters; male infertility; substance-related disorders; reproductive health; yemen. submitted 27 april 2025; accepted 10 may 2025 effects of khat (catha edulis) chewing on seminal fluid parameters: findings from a fertility clinic cohort and cessation trial mohammed noman 1, ebraheem al-nawd 2, faisal ahmed 3 1 department of dermatology, venereology, and andrology, faculty of medicine and health sciences, sana’a university, sana'a, yemen; 2 department of biochemistry, faculty of laboratory medicine, jiblah university for medical and health sciences, ibb, yemen; 3 department of urology, ibb university, faculty of medicine, ibb, yemen. doi: 10.4081/aiua.2025.13931 summary archivio italiano di urologia e andrologia 2025; 97(3):13931 m. noman, e. al-nawd, f. ahmed 2 yemen, where genetic and environmental factors differ. given yemen’s high khat prevalence and cultural normalization, there is an urgent need for population-specific data. this study aims to evaluate the effects of khat on seminal parameters and hormonal profiles in yemeni men, providing locally relevant evidence to inform clinical practice and public health strategies. the findings will contribute novel insights into khat’s reproductive toxicity and its potential reversibility, with implications for fertility management in endemic regions. materials and methods study design this study employed a dual-phase approach. the first phase was a prospective cross-sectional study comparing seminal parameters across frequency-matched groups of fertile and infertile men, stratified by khat chewing status. the second phase consisted of a prospective interventional cohort study assessing the impact of khat cessation on infertile khat chewers. the study was conducted at dr. najat al-malas ivf and art center in sana’a, yemen, over a five-year period from 2019 to 2024. participants a total of 330 yemeni men aged 20 to 40 years were initially recruited, with 274 completing the study, yielding an 83% retention rate. during the study period, 56 participants were excluded: 52 withdrew prematurely, primarily due to discontinuation of the khat cessation intervention in group a, and 4 were excluded for protocol violations, specifically unplanned khat cessation during phase 1. the final analytic sample comprised 274 participants, as detailed in the consort flow diagram (figure 1). participants were allocated into four frequency-matched groups to ensure comparability: infertile khat chewers (group a, n = 91), infertile non-chewers (group b, n = 60), fertile khat chewers (group c, n = 91), and fertile non-chewers (group d, n = 32). matching criteria included age (± 3 years), body mass index (bmi, ± 2 kg/m²), educational attainment (primary, secondary, tertiary), and socioeconomic status, assessed via the hollingshead index tertiles. this matching strategy was designed to minimize confounding influences related to demographic and lifestyle factors. inclusion criteria participants were classified as fertile or infertile based on established definitions. fertile men (groups c and d) had documented natural conception of at least one child within the preceding 24 months and were voluntarily recruited as comparative (control) groups. infertile men (groups a and b) met the world health organization’s criteria for infertility, defined as failure to conceive after 12 months of regular unprotected sexual intercourse (14). regular khat chewers (groups a and c) were those consuming 100-200 grams of fresh catha edulis leaves daily, with chewing sessions lasting a minimum of three hours, sustained for at least 12 months. khat use was verified through family interviews and standardized measurement of khat bundle weights. figure 1. participant flowchart depicting recruitment, allocation, and study phases. of 330 men assessed for eligibility, 274 were allocated into four frequency-matched groups: infertile khat chewers (n = 91), infertile non-chewers (n = 60), fertile khat chewers (n = 91), and fertile non-chewers (n = 32). phase 1 involved cross-sectional semen analysis of all groups. phase 2 consisted of a three-month supervised khat cessation intervention in group a, with semen volume reassessment in all participants and hormonal profiling conducted preand post-cessation in a subset of 15 individuals. archivio italiano di urologia e andrologia 2025; 97(3):13931 3 effects of khat chewing on seminal fluid parameters exclusion criteria all participants underwent thorough andrological evaluations to exclude confounding conditions. exclusion criteria included tobacco use exceeding five cigarettes per week, positive urine toxicology for recreational drugs, and endocrine disorders such as hypogonadism (serum testosterone < 2.5 ng/ml measured by liquid chromatography tandem mass spectrometry). men with congenital reproductive tract anomalies (e.g., ejaculatory duct obstruction confirmed by transrectal ultrasound and absent seminal fructose), chronic metabolic diseases (diabetes mellitus with hba1c > 6.5%, hypertension with blood pressure > 140/90 mmhg), or use of medications affecting semen quality or sexual function (including 5αreductase inhibitors, α/β-blockers, antipsychotics) were excluded. additionally, individuals with active inflammatory conditions (urethritis, prostatitis, and seminal vesiculitis diagnosed by nih-cpsi score > 14 and positive meares-stamey test) were excluded. sample size calculation sample size was calculated using a two-sample t-test framework based on prior data indicating a mean semen volume of 2.5 ± 1.0 ml (15). to detect a clinically meaningful difference of 0.6 ml between groups with 90% power at α = 0.05, 80 participants per group were required. anticipating a 20% attrition rate, recruitment targets were set at 100 participants per primary comparison group (chewers vs. non-chewers). post-hoc power analysis of our study confirmed that the final sample size exceeded 90% power to detect observed effect sizes, with cohen’s d > 0.8. semen collection and analysis participants provided semen samples following a standardized abstinence period of four days (range: 2-7 days), maintained consistently across collections. two collection methods were employed: condom-protected intercourse with immediate post-ejaculatory withdrawal, and masturbation into pre-weighed sterile containers (sarstedt ag), conducted seven days apart. the mean semen volume from both methods was calculated to enhance measurement reliability. semen analyses were performed within 60 minutes of collection at 37°c by a technician blinded to participant group allocation, following who 2021 guidelines (16). while semen volume was the primary parameter, additional semen quality indices (sperm concentration, total sperm count, progressive motility, morphology) were recorded for exploratory analyses using samples obtained by masturbation only. hormonal evaluation (total testosterone, follicle-stimulating hormone [fsh], luteinizing hormone [lh], and prolactin) was performed for all patients at baseline and for a subset of group a participants after the khat cessation period. intervention protocol (group a) group a participants underwent a supervised threemonth khat cessation program. compliance was monitored monthly using validated craving and withdrawal scales (e.g., khat withdrawal scale, reference). bimonthly random salivary cathinone measurements were performed via high-performance liquid chromatography-mass spectrometry (hplc-ms) with a detection threshold of 5 ng/ml to objectively verify abstinence. missing or inconsistent compliance data were addressed through sensitivity analyses. post-intervention semen analyses employed identical collection protocols to ensure comparability. outcome measures the primary outcome comprised comparative analyses of semen parameters among fertile and infertile khat chewers and non-chewers. the secondary outcome focused on evaluating changes in semen parameters before and after khat cessation within infertile khat chewers (group a). statistical analysis data were analyzed using ibm spss statistics for windows, version 22.0 (ibm corp., armonk, ny, usa) and r software, version 4.0 (r foundation for statistical computing, vienna, austria). the distribution of continuous variables was assessed for normality using the kolmogorov-smirnov test. for normally distributed data, parametric tests including independent samples t-tests and one-way analysis of variance (anova) with tukey’s post hoc comparisons were employed. when normality assumptions were violated, appropriate non-parametric alternatives were utilized. within-subject changes following khat cessation were evaluated using paired t-tests. effect sizes were calculated using cohen’s d and interpreted according to conventional thresholds: small (0.2), medium (0.5), and large (0.8). to adjust for potential confounding variables such as age, body mass index (bmi), and abstinence duration, multivariate linear regression models were constructed. correction for multiple comparisons was performed using the bonferroni method to control the family-wise error rate. both intention-to-treat and per-protocol analyses were conducted to ensure robustness of findings. statistical significance was set at a two-tailed p-value < 0.05. results intergroup comparisons of semen parameters among study participants our analysis demonstrated statistically significant differences in seminal volume between khat chewers and nonchewers across all study groups. infertile khat chewers exhibited significantly lower semen volumes (1.94 ± 0.48 ml) compared to fertile khat chewers (2.36 ± 0.52 ml; mean difference -0.42 ml, 95% confidence interval [ci] 0.77 to -0.07; p < 0.001; cohen’s d = 0.85) and infertile non-chewers (3.07 ± 0.74 ml; mean difference -1.13 ml, 95% ci -1.55 to -0.71; p < 0.001; cohen’s d = 1.72). when pooling all khat consumers (n = 182), seminal volume was significantly reduced (2.15 ± 0.89 ml) relative to non-consumers (n = 92; 3.04 ± 0.76 ml; mean difference -0.89 ml, 95% ci -1.21 to -0.57; p < 0.001; cohen’s d = 1.07). notably, no significant difference was observed between fertile and infertile non-chewers (mean difference 0.07 ml, 95% ci -0.52 to 0.66; p = 0.811; cohen’s d = 0.04), underscoring khat consumption as the principal factor associated with reduced seminal volume (table 1). archivio italiano di urologia e andrologia 2025; 97(3):13931 m. noman, e. al-nawd, f. ahmed 4 multivariate linear regression analysis of factors influencing semen volume adjusting for age, bmi, and abstinence duration, multivariate linear regression identified khat chewing as the strongest independent predictor of diminished semen volume (β = -0.92, 95% ci -1.15 to -0.69; p < 0.001), explaining 28% of the variance (partial η² = 0.28) (table 2). the regression model exhibited excellent fit (r² = 0.41, adjusted r² = 0.39) and no multicollinearity issues (variance inflation factors < 1.2). effect of khat cessation on seminal fluid volume and hormonal profile following a supervised three-month khat cessation program, infertile khat chewers demonstrated a significant 35% increase in seminal volume, rising from 1.94 ± 0.48 ml to 2.62 ± 0.52 ml (mean difference 0.68 ml; 95% ci 0.49-0.87; p < 0.001), with a large effect size (cohen’s d = 1.21). this improvement surpassed the world health organization’s minimal clinically important difference for semen volume and restored values comparable to those of untreated fertile individuals (p = 0.12), indicating reversibility of khat’s detrimental effects on male reproductive function. additional semen quality parameters – including total sperm count, progressive motility, and normal morphology – also exhibited statistically significant improvements, with effect sizes ranging from medium to large (table 3 and figure 2). table 1. intergroup comparisons of semen volume among frequency-matched participant groups. comparison group 1 group 2 statistical test mean difference p-value effect size (mean ± sd) (mean ± sd) (95% ci) (cohen’s d) khat chewers (fertile vs. infertile) fertile chewers (group c) 2.36 ± 0.52 – independent t-test 0.42 (0.25 to 0.59) < 0.001 0.85† infertile chewers (group a) – 1.94 ± 0.48 non-chewers (fertile vs. infertile) fertile non-chewers (group d) 3.00 ± 0.78 – independent t-test -0.07 (-0.42 to 0.28) 0.69 0.09 infertile non-chewers (group b) – 3.07 ± 0.74 all chewers vs. all non-chewers chewers (groups a + c) 2.15 ± 0.89 – independent t-test -0.89 (-1.12 to -0.66) < 0.001 1.07† non-chewers (groups b + d) – 3.04 ± 0.76 multi-group comparison (anova) fertile chewers (c) vs. fertile non-chewers (d) 2.36 ± 0.52 3.00 ± 0.78 one-way anova (tukey) -0.64 (−0.98 to -0.30) < 0.001 0.94† infertile chewers (a) vs. infertile non-chewers (b) 1.94 ± 0.48 3.07 ± 0.74 -1.13 (−1.45 to -0.81) < 0.001 1.72† † large effect size (d ≥ 0.8). *statistical adjustments for age, bmi, and abstinence duration were performed via multivariate linear regression. p-values: *p < 0.01, **p < 0.001. table 2. multivariate linear regression analysis of factors affecting semen volume. predictor unstandardized β standardized β p-value vif partial η2 (95% ci) khat chewing (yes vs. no) -0.92 (-1.15 to -0.69) -0.53 < 0.001 1.12 0.28 age (years) -0.02 (-0.05 to 0.01) -0.08 0.18 1.08 0.03 bmi (kg/m2) -0.03 (-0.07 to 0.01) -0.10 0.12 1.05 0.04 abstinence duration (days) 0.11 (0.06 to 0.16) 0.22 < 0.001 1.04 0.12 model summary: r² = 0.41, adjusted r² = 0.39, f(4, 269) = 32.7, p < 0.001. vif = variance inflation factor (all values < 2 indicate absence of multicollinearity). continuous predictors were centered prior to analysis. table 3. semen parameter changes after 3-month khat cessation in infertile chewers (group a, n = 91). parameter pre-cessation post-cessation mean difference p-value effect size (mean ± sd) (mean ± sd) (95% ci) (cohen’s d) volume (ml) 1.94 ± 0.48 2.62 ± 0.52 0.68 (0.52 to 0.84) < 0.001 1.21† total sperm count (×10⁶) 45.2 ± 12.1 58.7 ± 15.3 13.5 (9.8 to 17.2) < 0.001 0.98† progressive motility (%) 32.5 ± 8.4 41.2 ± 9.7 8.7 (6.2 to 11.2) < 0.001 0.89† normal morphology (%) 4.2 ± 1.8 5.9 ± 2.1 1.7 (1.1 to 2.3) 0.003 0.72‡ † large effect size (d ≥ 0.8). ‡ medium-large effect (d > 0.5). statistical test: paired t-test. terminology reflects alpha-adrenergic mediation of seminal emission. archivio italiano di urologia e andrologia 2025; 97(3):13931 5 effects of khat chewing on seminal fluid parameters hormonal assessment in a subset of 15 participants revealed a significant increase in serum testosterone levels accompanied by a modest but statistically significant decrease in prolactin concentrations. follicle-stimulating hormone (fsh) and luteinizing hormone (lh) levels remained unchanged. these findings collectively suggest that khat cessation positively influences both seminal parameters and select hormonal profiles, supporting its beneficial impact on male reproductive health (table 4). discussion this study investigated the impact of khat (catha edulis) chewing on male reproductive parameters, with a specific focus on semen volume, and assessed the reversibility of these effects following supervised khat cessation. our findings indicate that chronic khat chewing is significantly associated with impaired semen quantity and quality, including reductions in semen volume, total sperm count, progressive motility, and normal morphology. encouragingly, these adverse effects showed substantial improvement after three months of cessation, concurrent with favorable hormonal changes – increased testosterone and decreased prolactin levels. chronic khat chewing is increasingly recognized as a contributor to male infertility. studies consistently associate it with reduced semen volume, sperm concentration, motility, and increased abnormal sperm morphology (6, 11). these alterations often coincide with lower testosterone and altered prolactin secretion, potentially disrupting spermatogenesis and sperm function (5). the underlying pathophysiology appears multifactorial. khat's primary psychoactive alkaloids, cathinone and cathine, act as potent stimulants. this activity may trigger oxidative stress and heighten sympathetic nervous system activity, leading to increased reactive oxygen species (ros) that damage sperm dna and cellular membranes, compromising viability and motility (17-19). furthermore, khat's adrenergic effects could impair seminal emission, potentially through receptor desensitization or neurotransmitter depletion, thereby reducing semen volume. while some animal studies suggest dose-dependent or biphasic effects, the prevailing evidence points to khat disrupting endocrine regulation and inducing oxidative damage within the seminal environment (5, 6, 19, 20). collectively, these findings suggest khat-related infertility arises from a complex interplay of hormonal changes, oxidative stress, and impaired seminal fluid dynamics. khat shares sympathomimetic toxicodynamic pathways with other substances (e.g., indirect sympathomimetic activity, monoamine modulation, α-adrenergic receptor overstimulation), contributing to reproductive toxicity (17). however, khat's natural alkaloid profile and pharmacokinetics may lead to distinct, potentially biphasic, dose-dependent hormonal effects not always observed with synthetic sympathomimetics (13, 21). ejaculation comprises two main phases: emission (sympathetically controlled movement of seminal fluid into the table 4. hormonal profile changes after khat cessation (subset cohort, n = 15). hormone pre-cessation post-cessation mean difference p-value statistical (mean ± sd) (mean ± sd) (95% ci) test testosterone (ng/dl) 412 ± 98 438 ± 105 26 (12 to 40) 0.012 paired t-test fsh (iu/l) 5.2 ± 1.8 5.0 ± 1.6 -0.2 (-0.6 to 0.2) 0.35 paired t-test lh (iu/l) 4.8 ± 1.5 4.9 ± 1.4 0.1 (-0.3 to 0.5) 0.62 paired t-test prolactin (ng/ml) 15.3 ± 4.2 14.1 ± 3.9 -1.2 (-2.0 to −0.4) 0.021 wilcoxon signed-rank test* non-normal distribution (shapiro-wilk p < 0.05). fsh = follicle-stimulating hormone; lh = luteinizing hormone. figure 2. changes in semen parameters following three months of khat cessation in infertile khat chewers (group a). significant improvements were observed in semen volume, total sperm count, progressive motility, and normal morphology (p < 0.05, p < 0.01). archivio italiano di urologia e andrologia 2025; 97(3):13931 m. noman, e. al-nawd, f. ahmed 6 urethra) and expulsion (muscle contractions propelling fluid outward) (22). khat may interfere with both phases, particularly emission, by potentially inhibiting acetylcholine release and smooth muscle contraction via prejunctional α2 adrenergic and 5-ht7 receptors (6, 23-25). our results demonstrate that khat chewing is independently associated with reduced semen volume in both fertile and infertile men. this aligns with the pharmacology of cathinone and cathine, potent norepinephrine releasers and reuptake inhibitors (26, 27). alpha-adrenergic stimulation is critical during emission for coordinating contractions in the vas deferens, seminal vesicles, and prostate (28, 29). chronic adrenergic overstimulation from khat may lead to receptor desensitization or neurotransmitter depletion, impairing seminal emission and reducing volume (5, 20, 30). reduced contractility in accessory sex glands due to α-adrenergic dysregulation may also decrease seminal fluid volume and alter viscosity, mirroring effects seen with α1-blocker medications known to impair fluid release and contribute to infertility (12, 31). these mechanisms suggest the observed reduction in semen volume among khat chewers is more likely due to impaired emission than impaired production. our findings of reduced semen parameters among khat chewers align with previous studies. el-shoura et al. reported significantly lower semen volume, sperm motility, and concentration in khat users (11). hakim et al. also found correlations between long-term khat chewing and changes in seminal fluid, including decreased volume, count, and motility, though statistical significance varied (20). additional studies link khat chewing with reduced libido and possible erectile dysfunction, highlighting the need for further causal research (32, 33). a key observation is the reversibility of khat's adverse effects on semen parameters following cessation. infertile chewers who abstained for three months showed substantial improvements in semen volume, total sperm count, progressive motility, and normal morphology. the recovery in volume supports the hypothesis that alpha-adrenergic dysfunction caused by chronic khat chewing is, at least partially, reversible as receptor sensitivity and neurotransmitter balance recover (26, 34). concurrent improvements in other semen parameters suggest khat's detrimental impact extends to spermatogenesis and sperm maturation, potentially through oxidative stress, impaired testicular vascular function, or hormonal disruption (11, 32, 33). while the cross-sectional design limits definitive causal claims, the pattern of reversibility provides supportive evidence. these findings highlight the potential for recovery of male reproductive function with cessation and underscore its relevance for clinical counseling. hormonal profiling in a subset of participants revealed modest increases in total testosterone and decreases in prolactin levels after khat cessation, while fsh and lh levels remained stable. these shifts are consistent with khat's dopaminergic effects, potentially alleviating hyperprolactinemia – a known contributor to hypogonadism and impaired semen quality (3). the stability of gonadotropins suggests that khat's primary impact on fertility may occur peripherally (e.g., testicular and accessory glands) rather than centrally via the hypothalamic-pituitary-gonadal axis. these hormonal changes likely interact with the observed oxidative stress pathways to impair semen quality (5, 17). dopaminergic modulation could influence prolactin levels and antioxidant defenses, while adrenergic overdrive directly contributes to the generation of oxidative stress (35). animal studies offer further mechanistic insights, though with nuances requiring careful interpretation. mohammed et al. and shulman et al. reported biphasic effects on male rat sexual behavior, with higher doses diminishing performance and lower doses sometimes enhancing motivation, potentially linked to testosterone fluctuations (13, 36). khat administration has reduced epididymal sperm count without consistently altering endocrine gland function in some models, suggesting direct gonadal toxicity (5). other studies demonstrate khat or cathinone reducing sperm count and motility, increasing abnormal sperm, and inhibiting spermatogenesis, with variable effects on reproductive hormones depending on dose and species (5, 13, 18, 37, 38). importantly, the observed biphasic effects in animals underscore the complexity of dose-response relationships, which may also exist in humans but remain inadequately characterized due to variations in chewing habits and alkaloid content (5). furthermore, the stable levels of gonadotropins observed in our human cohort contrast with some animal data showing lh suppression, highlighting species differences and underscoring the need for targeted human research to understand dose-dependent effects and distinguish between central and peripheral actions. clinical and public health implications our findings have significant implications for clinical practice and public health, particularly in regions where khat chewing is prevalent. clinicians should routinely inquire about khat use during infertility evaluations and preconception counseling, given the evidence of its association with impaired semen parameters and the potential for reversibility upon cessation. men presenting with reduced semen volume, abnormal semen parameters, or hormonal disturbances such as low testosterone or elevated prolactin should be specifically screened for khat consumption. in reproductive counseling, it is essential to inform men planning conception or concerned about fertility of the potential reproductive risks associated with khat chewing. the demonstrated reversibility of semen impairment following cessation offers an encouraging message and a concrete intervention strategy for affected individuals. from a public health perspective, these results underscore the need for targeted educational campaigns that address the reproductive risks of khat alongside its other health consequences. integration of khat cessation support within existing reproductive health and substance use services could enhance the effectiveness of interventions. community-based awareness initiatives and the development of practical biomarkers for objective exposure assessment would further strengthen monitoring and prevention efforts. collectively, these strategies could contribute to improved male reproductive health outcomes in populations with high rates of khat use. study limitations several limitations warrant consideration. the cross-sectional design of much of the data limits causal inference, archivio italiano di urologia e andrologia 2025; 97(3):13931 7 effects of khat chewing on seminal fluid parameters although the observed reversibility provides supportive evidence. hormonal analyses were constrained by a small sample size, limiting generalizability and emphasizing the need for larger prospective studies. the three-month cessation period may not fully capture the timeline of reproductive recovery; longer-term follow-up is important. the reliance on self-reported khat consumption introduces potential recall bias, and the lack of detailed usage pattern data prevents dose-response analysis. the singlecenter design and recruitment of fertile controls via volunteer sampling may limit generalizability and introduce selection bias. despite adjustments for key confounders, residual confounding from unmeasured variables (e.g., diet, concurrent substance use, environmental exposures) cannot be excluded. finally, the precise mechanisms by which khat influences seminal fluid production, especially autonomic regulation of accessory glands, require further elucidation. addressing these limitations necessitate multicenter studies employing objective biomarkers, extended longitudinal monitoring, and evaluation of sympathetic nervous system function. conclusions this study demonstrates that khat chewing is significantly associated with reduced semen volume in both infertile and fertile men, with khat use emerging as a strong independent predictor of this reduction. importantly, cessation of khat consumption leads to a substantial recovery in semen volume, accompanied by favorable hormonal changes, including increased testosterone and decreased prolactin levels. these findings corroborate prior evidence linking khat use to impaired male reproductive parameters and suggest that the adverse effects on seminal fluid volume are at least partially reversible. given the cultural prevalence of khat chewing in affected regions, these results underscore the need for targeted public health interventions and further research into the mechanisms underlying khat’s reproductive toxicity and its potential reversibility. references 1. balint ee, falkay g, balint ga. khat a controversial plant. wien klin wochenschr. 2009; 121:604-14. 2. gibbons s, arunotayanun w. natural product (fungal and herbal) novel psychoactive substances. in: dargan pi, wood dm, editors. novel psychoactive substances. boston: academic press; 2013. p. 345-62. 3. algutaini sa, al-ameri a, mahyoub abdo ba. the impact of qat chewing on health and social life: a cross-sectional study among yemeni adults. journal of medical health research and psychiatry. 2024; 01:1-11. 4. thomas s, williams t. khat (catha edulis): a systematic review of evidence and literature pertaining to its harms to uk users and society. drug science, policy and law. 2013; 1:1-25. 5. alzahrani ma, alsahli ma, alarifi ff, et al. a narrative review of the toxic effects on male reproductive and sexual health of chewing the psychostimulant, catha edulis (khat). med sci monit. 2023; 29:e939455. 6. ahmed f, alnadhari i, ghabisha s, et al. the effects of khat (catha edulis) use on the genitourinary system: a systematic review and meta-analysis. j ethn subst abuse. 2024:1-13. 7. tanga bm, qamar ay, raza s, et al. semen evaluation: methodological advancements in sperm quality-specific fertility assessment a review. anim biosci. 2021; 34:1253-70. 8. cooper tg, noonan e, von eckardstein s, et al. world health organization reference values for human semen characteristics. hum reprod update. 2010; 16:231-45. 9. assidi m. infertility in men: advances towards a comprehensive and integrative strategy for precision theranostics. cells. 2022; 11:1711. 10. kassim s, croucher r. khat chewing amongst uk resident male yemeni adults: an exploratory study. int dent j. 2006; 56:97-101. 11. el-shoura sm, abdel aziz m, ali me, et al. deleterious effects of khat addiction on semen parameters and sperm ultrastructure. hum reprod. 1995; 10:2295-300. 12. nyachieo a, kiraithe mm, spiessens c, et al. short-term effects of high-dose khat on sperm parameters and reproductive hormonal levels in olive baboons (papio anubis). gynecol obstet invest. 2013; 75:109-14. 13. mohammed a, engidawork e. reproductive parameters are differentially altered following subchronic administration of catha edulis f. (khat) extract and cathinone in male rats. j ethnopharmacol. 2011; 134:977-83. 14. zegers-hochschild f, adamson gd, de mouzon j, et al. international committee for monitoring assisted reproductive declarations ethical approval: approval for the study protocol and all related procedures was granted by the institutional ethics committee of dr. najat al-malas ivf and art center in sana’a, yemen. the protocol was further approved by the institutional review board of dr. najat al-malas ivf center (reference number 0031mn-2024, dated 21 january 2024). written informed consent was obtained from all participants in accordance with the declaration of helsinki, with participants retaining the right to withdraw from the study at any time without penalty. the study protocol was initially established on 1 june 2019 and registered with the university hospital medical information network clinical trials registry (umin-ctr), japan, under registration number t000009772 (see: https://center6.umin.ac.jp/cgibin/ctr_test_e/ctr_view_reg.cgi?recptno=t000009772). availability of data and material: all data generated or analyzed during this study are included in this published article. competing interests: the author declares no conflicts of interest. funding: no funding was received for this study. authors' contributions: all authors contributed substantially to the conception, design, data acquisition, analysis, and interpretation of the study; participated in drafting and critically revising the manuscript; approved the final version for publication; agreed on the journal for submission; and accept responsibility for all aspects of the work. acknowledgments: the authors express their sincere appreciation to the dr. najat al-malas ivf & art center in sana’a, yemen, for their support and provision of research facilities. archivio italiano di urologia e andrologia 2025; 97(3):13931 m. noman, e. al-nawd, f. ahmed 8 technology (icmart) and the world health organization (who) revised glossary of art terminology, 2009. fertil steril. 2009; 92:1520-4. 15. halpern ja, thirumavalavan n, kohn tp, et al. distribution of semen parameters among adolescent males undergoing fertility preservation in a multicenter international cohort. urology. 2019; 127:119-23. 16. world health organization. who laboratory manual for the examination and processing of human semen. 6th ed. geneva: who; 2021. 17. silva b, soares j, rocha-pereira c, et al. on behalf of the oemonom r. khat, a cultural chewing drug: a toxicokinetic and toxicodynamic summary. toxins (basel). 2022; 14:71. 18. nyongesa aw, patel nb, onyango dw, et al. khat (catha edulis) lowers plasma luteinizing hormone (lh) and testosterone secretion, but increases cortisol levels in male rabbits. j ethnopharmacol. 2008; 116:245-50. 19. dhaifalah i, santavý j. khat habit and its health effect. a natural amphetamine. biomed pap med fac univ palacky olomouc czech repub. 2004; 148:11-5. 20. hakim ly. influence of khat on seminal fluid among presumed infertile couples. east afr med j. 2002; 79:22-8. 21. costa vm, grando lgr, milandri e, et al. natural sympathomimetic drugs: from pharmacology to toxicology. biomolecules. 2022; 12:1793. 22. mason mm, schuppe k, weber a, et al. ejaculation: the process and characteristics from start to finish. curr sex health rep. 2023; 15:1-9. 23. abdulwaheb m, makonnen e, debella a, abebe d. effect of catha edulis foresk (khat) extracts on male rat sexual behavior. j ethnopharmacol. 2007; 110:250-6. 24. kelly jp. cathinone derivatives: a review of their chemistry, pharmacology and toxicology. drug test anal. 2011; 3:439-53. 25. engidawork e. pharmacological and toxicological effects of catha edulis f. (khat). phytother res. 2017; 31:1019-28. 26. al-motarreb a, al-habori m, broadley kj. khat chewing, cardiovascular diseases and other internal medical problems: the current situation and directions for future research. j ethnopharmacol. 2010; 132:540-8. 27. toennes sw, harder s, schramm m, et al. pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. br j clin pharmacol. 2003; 56:125-30. 28. michel mc, vrydag w. alpha1-, alpha2and beta-adrenoceptors in the urinary bladder, urethra and prostate. br j pharmacol. 2006; 147(suppl 2):s88-119. 29. sun xq, xu c, leclerc p, et al. spinal neurons involved in the control of the seminal vesicles: a transsynaptic labeling study using pseudorabies virus in rats. neuroscience. 2009; 158:786-97. 30. safhi mm, alam mf, hussain s, et al. cathinone, an active principle of catha edulis, accelerates oxidative stress in the limbic area of swiss albino mice. j ethnopharmacol. 2014; 156:102-106. 31. hisasue s, furuya r, itoh n, et al. ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. int j urol. 2006; 13:1311-6. 32. schifano n, chiappini s, mosca a, et al. recreational drug misuse and its potential contribution to male fertility levels' decline: a narrative review. brain sci. 2022; 12:1582. 33. mwenda jm, arimi mm, kyama mc, langat dk. effects of khat (catha edulis) consumption on reproductive functions: a review. east afr med j. 2003; 80:318-23. 34. kalix p. cathinone, a natural amphetamine. pharmacol toxicol. 1992; 70(2):77-86. 35. rasool a, manzoor r, ullah k, et al. oxidative stress and dopaminergic metabolism: a major pd pathogenic mechanism and basis of potential antioxidant therapies. cns neurol disord drug targets. 2024; 23:852-64. 36. shulman lm, spritzer md. changes in the sexual behavior and testosterone levels of male rats in response to daily interactions with estrus females. physiol behav. 2014; 133:8-13. 37. mwenda jm, owuor ra, kyama cm, et al. khat (catha edulis) up-regulates testosterone and decreases prolactin and cortisol levels in the baboon. j ethnopharmacol. 2006; 103:379-84. 38. nyongesa aw, oduma ja, nakajima m, et al. dose-response inhibitory effects of purified cathinone from khat (catha edulis) on cortisol and prolactin release in vervet monkeys (chlorocebus aethiops). metab brain dis. 2014; 29:451-8. correspondence mohammed noman noaman670@gmail.com ebraheem al-nawd drnod4all@gmail.com faisal ahmed (corresponding author) fmaaa2006@yahoo.com department of urology, ibb university, faculty of medicine, ibb, yemen stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2184 original paper no conflict of interest declared. cal practice is high, due to the high number of recurrences and due to the impact of symptoms on patients’ quality of life (2, 3). the recurrence rate of urinary calculi is 50% within 10 years of the first episode (3, 4). symptomatic recurrence episodes are associated with high direct and indirect costs (admission to emergency departments, imaging, drugs and working day lost). for these reasons, the prevention of symptomatic episodes due to urinary stones should be the first aim in the management of this kind of patients. several authors recommended some diet interventions for reducing the risk of urinary stone formation and its recurrence but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi (5). on the other hand, the use of medicinal plants and nutraceuticals have long been used worldwide for the management of recurrence in patients affected by urinary stones (6). ettinger et al., published in 1997 one of the first clinical trial on the use of potassium-magnesium citrate in preventing recurrent calcium oxalate kidney calculi, demonstrating that potassium-magnesium citrate effectively prevents recurrent calcium oxalate stones (7). focusing on the plant extracts, phyllanthus niruri, commonly known as “stone-breaker”, is able to increases urinary excretion of magnesium and potassium and to cause a significant decrease in urinary oxalate and uric acid in patients with hyperoxaluria and hyperuricosuria, contributing to the elimination of urinary calculi (4). moreover, chrysanthellum americanum seems to be effective in the reduction of stone formation, probably due to the effect of chrysantellin, a saponin, on the stone aggregation (8). starting from these evidences, we aim to evaluate the efficacy of a medical device containing phyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates in the treatment and prophylaxis of symptomatic episode in patients affected by recurrent uncomplicated urinary stones. objective: the aim of this study is to evaluate the efficacy of a food supplement containing phyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates in the treatment and prophylaxis of urinary stones. materials and methods: eighty-two patients (mean age 49.7 ± 11.2) with history of urinary stones received this food supplement, one capsule a day for 6 months. each administration contained a combination of the following ingredients: 244 mg potassium citrate, 735 mg magnesium citrate, phyllanthus (phyllantus niruri) herb d.e. 15% mg tannins 220 mg, chrysanthellum (chrysanthellum americanum vatke) plant d.e. ¼ 55 mg. after 6 months, all patients underwent urologic visit, urinalysis, imaging and quality of life (qol) questionnaires evaluation. each patient was also evaluated by computed tomography (ct) scan at baseline and at 6 months. result: from january 2018 to march 2019, 82 patients (mean age 49.7 ± 11.2) completed the follow-up period and were analyzed. fifty patients showed lower stone dimensions (60.9%). the average stone size was 0.9 mm, with a significant reduction in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001). forty-nine patients (59.7%) did not show any symptomatic episode with an improving in qol (+0.4 ± 0.1) (p < 0.001) in comparison with the baseline. at the end of the follow-up period, 27 patients out of 82 were stone-free (32.9%). moreover, we report a significant reduction of patients with asymptomatic bacteriuria (abu) between the baseline and the end of the follow-up evaluation (p < 0.001). conclusions: in conclusion, this food supplement is able to improve quality of life in patients with urinary stones, reducing symptomatic episodes and the prevalence of abu. key words: stones; phyllanthus niruri; chrysanthellum americanum; potassium; magnesium; asymptomatic bacteriuria. submitted 16 april 2021; accepted 26 april 2021 introduction urinary tract stones are one of the most common cause of urological visits, with a prevalence among urological patients of 1-15% (1, 2). the impact on everyday cliniphyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates are able to prevent symptomatic episode in patients affected by recurrent urinary stones: a prospective study tommaso cai 1, daniele tiscione 1, marco puglisi 1, gianni malossini 1, lorenzo ruggera 2, paolo verze 3, davide arcaniolo 4, alessandro palmieri 5 1 department of urology, santa chiara regional hospital, trento, italy; 2 department of urology, university of padua, padua, italy; 3 department of medicine, surgery, dentistry "scuola medica salernitana" university of salerno, baronissi, italy; 4 department of urology, university vanvitelli, naples, italy. 5 department of urology, university of naples, federico ii, naples, italy. doi: 10.4081/aiua.2021.2.184 summary 185archivio italiano di urologia e andrologia 2021; 93, 2 nutraceuticals and recurrent urinary stones materials and methods study schedule and population from january 2018 to march 2019, all patients attending two referral institutions with history of recurrent uncomplicated urinary stones were enrolled in this prospective phase iv, post-marketing clinical trial. all enrolled patients underwent a urological visit for inclusion and exclusion criteria assessment with quality of life (qol) questionnaires, serum chemistry, urinalysis and non-contrast-enhanced ct scanner. all patients were encouraged to make lifestyle changes and received a food supplement containing phyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates, one capsule a day for 6 months. after 3 months, all patients were contacted by phone by the trialists in order to check the adherence to the treatment. after 6 months, all patients underwent urologic visit, urinalysis, imaging (ct scan) and qol questionnaires evaluation. figure 1 shows the study schedule. outcome measures the main outcome measures were the reduction of symptomatic episodes and improvement in questionnaire result from baseline at the end of the follow-up period. stone dimension reduction and stone-free status at 6 months follow-up ct scan were also considered as secondary outcome measures. inclusion and exclusion criteria we considered for the inclusion, all patients with ct demonstration of one or multiple renal stones up to 15 mm. all patients with the following characteristics were excluded: serum creatinine level > 1.6 mg/dl, microbiological demonstration of urinary tract infection, noncontrolled diabetes, chronic liver disease and all the other serious comorbidities. moreover, all patients with the evidence of ureterohydronephrosis or renal colic were excluded. pregnant women were excluded, too. patients’ clinical, laboratory and instrumental assessment at the baseline, all patients underwent urological visit with qol questionnaires, serum chemistry and blood analysis, urinalysis and non-contrast-enhanced ct scan. the identified calculi were classified according to their number, location (superior, middle, inferior calyx) and size. clinical data comprised systolic and diastolic blood pressure and anthropometric evaluation (weight, height, body mass index (bmi). serum chemistry and blood analysis comprised blood count, assessment of urea, creatinine, sodium, potassium, glucose, uric acid, total and ionized calcium, total cholesterol and fractions, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, amylase and bilirubin levels. urinalysis with urinary ph measurement and a urine culture were performed using spontaneous voided urine. moreover, before enrolment all patients received a screening evaluation which includes a medical and dietary history by an experienced nephrologist. the enrolment has been done on the basis of the baseline metabolic profile, as suggested by the international guidelines (5). questionnaires the impact of symptomatic episodes of renal stones on patients’ qol has been evaluated by using an italian version of the quality of well-being, a validated, multiattribute health scale (9). this scale was selected because figure 1. t0 clinical, instrumental laboratory evaluation, qol and enrolment food supplement 1 tablet every 24 hours (phyllanthus niruri, chrysanhellum americanum, k+ and mg+ citrates) v1 (3 months) contact phone for evaluating adherence to the treatment treatment: 6 months screening (up to 3 months) assessed for elegibility (n = 96) consort flow diagram allocated to intervention (n = 82) analysed (n = 82) follow.up (n = 82) lost to follow-up (n = 0) excluded (n = 14) • not meeting inclusion criteria (n = 10) • declined to partecipate (n = 4) v2 (6 months) clinical, instrumental laboratory evaluation, qol archivio italiano di urologia e andrologia 2021; 93, 2 t. cai, d. tiscione, m. puglisi, g. malossini, l. ruggera, p. verze, d. arcaniolo, a. palmieri 186 it has been successfully applied to acute illnesses, whereas other quality of life scales, including the short form36 (sf-36) health survey, are more suitable in chronic cases. higher scores on the qol scale reflect a higher quality of life (10). follow-up and efficacy assessment after treatment, all patients were reassessed by urologic visit with questionnaire, serum chemistry, urine analysis and imaging, in order to evaluate the changes in number, location and size of the calculi at 3 and 6 months. at 3 months all patients underwent urinary tract sonography and at 6 months non-contrast-enhanced ct scanner. at 3 months the stone evaluation was < performed by using urinary tract sonography in order to reduce the patients’ exposition to x-ray. however, the stone freerate has been calculated between the baseline and the 6 months follow-up ct scan. compounds characteristics all patients were treated in line with the manufacturer’s instructions (erbozeta s.p.a., rsm https://www.erbozeta.com). each administration contained a combination of the following ingredients: 244 mg potassium citrate (93 mg potassium and 150 mg citrate), 735 mg magnesium citrate (30 mg magnesium and 160 mg citrate), phyllanthus (phyllantus niruri) herb d.e. 15% mg tannins 220 mg, chrysanthellum (chrysanthellum americanum vatke) plant d.e. ¼ 55 mg. statistical analysis as null hypothesis, we consider that there is no difference in terms of number of symptomatic episodes and qol between baseline and the end of the follow-up evaluation. in order to obtain significant results to analyze, sample size calculation was based on the following assumptions: difference in terms of qol between baseline and followup visit: + 0.3 ± 0.06; a error level, 0.05 two-sided; statistical power, 80%; anticipated effect size, cohen’s d = 0.5. the calculation yielded 72 individuals. considering a drop-out rate of 10%, the final sample size was set to 79 patients. the statistical analysis was performed as follows: continuous variables are presented as median and interquartile range (iqr) and categorical variables are presented as absolute (n) and relative (%) frequency distributions. t-test were used to compare average performance between enrolment and the follow-up evaluation, and between the periods before and after enrolment. the statistical analysis was performed using spss. ethical considerations due to the fact that this food supplement is already present in italian pharmacopeia and that phyllantus niruri has been approved for the management of patients affected by urinary stones in italy, the study did not require approval by the local ethics committee (irb). nevertheless, our study was conducted in line with good clinical practice guidelines and the ethical principles laid down in the latest version of the declaration of helsinki. before inclusion, all participants signed the written informed consent about personal data collection and storage, in accordance with national bylaws. all anamnestic, clinical and laboratory data containing sensitive information about patients were de-identified in order to ensure analysis of anonymous data only. the de-identification process was performed by nonmedical staff by means of dedicated software. a placebo run-in period was considered unnecessary. results from january 2018 to march 2019, 82 patients (mean age 49.7 ± 11.2) completed the follow-up period and were analyzed. baseline at the baseline, the average stone size was 7.8 mm and 23 patients showed (abu). the most common isolated strain was enterococcus faecalis (18/23; 78.2%). the median number of symptomatic episodes at baseline was 3 per year. the median number of calculi was 1 (range: 1-4). in 38 patients (46.3%) the calculi were located in the right kidney, 36 (43.9%) had left kidney lithiasis, while 8 patients had bilateral kidney lithiasis (9.8%). the mean stone diameter was 7.8 ± 1.1 mm. the mean hounsfield units was 637.1 ± 264.8, in all enrolled patients. no difference, from the normal values, has been reported in terms of urine analysis parameters among the enrolled patients. the table 1 shows all demographic and baseline clinical and instrumental characteristics of enrolled patients. table 1. patient clinical, instrumental and laboratory characteristics at the baseline. no. of enrolled patients 82 median age (± sd) 49.7 ± 11.2 sex male 49 (59.7) female 33 (40.3) body mass index (bmi) (± sd) 25.8 ± 6.3 charlson comorbidities index 0 75 (11.5) 1 7 (8.5) 2 start of urinary lithiasis (years) (range) 2.3 ± 0.9 number of symptomatic episodes per year (± sd) 3 ± 1.2 history of any endourological treatment (in the last 6 months) yes 12 (14.6) no 70 (85.4) median number of stones (range) 1 (1-4) mean stone size (± sd) (mm) 7.8 ± 1.1 stones side right kidney 38 (46.3) left kidney 36 (43.9) bilateral 8 (9.8) mean hounsfield units (± sd) 637.1 ± 264.8 stones location (calyx) superior 30 (36.5) middle 38 (46.4) inferior 14 (17.1) presence of asymptomatic bacteriuria yes 23 (28.1) no 59 (71.9) isolated strains enterococcus faecalis 18 (78.1) escherichia coli 3 (13.3) klebsiella spp. 2 (8.6) 187archivio italiano di urologia e andrologia 2021; 93, 2 nutraceuticals and recurrent urinary stones 6 months follow-up adherence to the life-style changes and treatment at the 3 months follow up by telephone call, 50 patients reported a high adherence to the life-style changes and to the treatment. at the end of the follow-up period, the adherence to the life-style changes and to the treatment was total in 60 patients (73.1%), while in twenty-two patients (26.8%) some minimal missing doses have been registered. a significant improvement has been reported between the 3and 6-months evaluations in terms of adherence to the treatment and the life-style changes. clinical and instrumental outcomes and qol twenty-seven patients out of 82 had no evidence of stone at the non-contrast-enhanced ct scanner (32.9%) at the end of the follow-up evaluation, reporting stone expulsion, while 50 patients showed lower stones dimension (60.9%). the average stones size at the end of the follow-up was 0.9 mm (± 0.1 mm), with a significant reduction in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001). forty-nine patients (59.7%) did not show any symptomatic episode with an improving in qol (+0.4 ± 0.1) (p < 0.001) in comparison to the baseline. no difference, from the normal values, has been reported in terms of urine analysis parameters among the enrolled patients. the table 2 shows all clinical and instrumental findings at the end of the follow-up. asymptomatic bacteriuria at the end of follow-up evaluation, 3 patients reported abu. a significant reduction of patients with abu between the baseline and the end of the follow-up evaluation (23 vs 3; p < 0.001) has been reported. a significant correlation between abu reduction and stones number and dimension reduction has been reported (r = 0.83; p < 0.001). adverse effects no mild or severe clinically significant adverse effects have been reported. discussion we demonstrated that a food supplement containing phyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates is able to improve qol in patients with urinary stones, reducing symptomatic episodes, stones number and dimension and the prevalence of asymptomatic bacteriuria. two important points should be discussed: the role of phytotherapy in the management of urinary stones and its mechanism of action and the relationship between urinary stones and abu. role of phytotherapy in the management of urinary stones and mechanism of action phytotherapy is one of the first choices regarding pharmaceutical treatment of patients affected by urinary stones (2) due to the demonstrated efficacy (4, 11) and due to the patient’s preference for phytotherapeutic compounds. micali and pucci, in two clinical trials, demonstrated that phyllanthus niruri is able to reduce the stone size and improve the stone free status rate (4, 11). in line with these trials, we found a significant reduction in terms of stones size in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001) and a high percentage of stone free patients after treatment. these interesting findings are probably due to phyllanthus niruri and chrysanthellum americanum combination in association with potassium and magnesium citrates. the efficacy of phyllanthus niruri is probably augmented by the presence of chrysanthellum americanum. the role of chrysanthellum americanum in the management of urinary stones is due to its interference, through the chrysantellin, a saponin, with some stages of crystallization in urine, such as a reduction in the nucleation, growth and aggregation of calcium oxalate crystals (8). moreover, the synergistic effect of phyllanthus niruri and chrysanthellum americanum is probably due to its diuretic effects (12, 13). furthermore, this food supplement contains potassium and magnesium citrates, although previous studies did not favor potassium citrate therapy. however, potassium can moderate the concentration of sodium in urine and promote the elevation of citrate, which acts to correct urinary ph and acidity, possibly contributing to an increase in calcium solubility and, then, interfere with some stages of crystallization in urine (14-17). this food supplement is, then, able to act into two different pathways: diuresis increasing and inhibition of nucleation, growth and aggregation of calcium oxalate crystals. moving to the role of life-style changes, we found a significant improvement between the 3and 6-months evaluations in terms of adherence to the treatment and life-style changes. the clinical reported efficacy in terms of reduction of symptomatic episodes, due to the treatment, drives the adherence to the life-style changes. in this sense, this food supplement should be considered, also, as an interesting tool for driving the adherence to the life-style changes and for obtaining a long-term efficacy on the stone recurrence. the high adherence to the treatment is due to the absence of reported adverse effects, too. relationship between urinary stones and asymptomatic bacteriuria this was the first study that analyzed the efficacy of a table 2. clinical, instrumental and laboratory findings at each follow-up visit (3 and 6 months after treatment). baseline 3 months 6 months adherence to life-style changes recommendations patients with a high grade of adherence 50 (60.9) 60 (73.1) clinical improvement recurrence-free patients 0 (0%) 38 (46.3) 49 (59.7) qol 97.1 97.7 97.9 qol improvement +0.3 ± 0.2 +0.4 ± 0.1 difference from baseline p < 0.001 p < 0.001 stone-free status 0 (0%) 19 (23.1) 23 (32.9) stone size (mm) stone size (mm) 7.8 ± 1.1 3.1 ± 0.5 1.1 ± 0.5 stone size reduction -4.2 ± 2 -6.7 ± 3 difference from baseline p < 0.001 p < 0.001 asymptomatic bacteriuria patients with asymptomatic bacteriuria 23 9 (10.9) 3 (3.6) difference from baseline p < 0.001 p < 0.001 archivio italiano di urologia e andrologia 2021; 93, 2 t. cai, d. tiscione, m. puglisi, g. malossini, l. ruggera, p. verze, d. arcaniolo, a. palmieri 188 food supplement in reducing abu in patients affected by urinary stones. abu is a common clinical condition among recurrent stones patients, which does not generally require any treatment. however, the role of abu in patients with recurrent urinary stones is not completely understood. here, we demonstrated that this food supplement is able to statistically significantly reduce the prevalence of abu among recurrent stone patients. the efficacy on abu is probably due to the increase of total daily diuresis and to the inhibition of nucleation, growth and aggregation of bacterial biofilm on the surface of calcium oxalate crystals. this mechanism is probably due to the phyllanthus niruri and chrysanthellum americanum action. finally, the role of bacteria biofilm on the urinary stone aggregation is another important field to deeply explore. future studies are, however, needed to confirm these hypotheses. conclusions in conclusion, this food supplement containing phyllanthus niruri and chrysanthellum americanum in association with potassium and magnesium citrates is able to reduce symptomatic episodes, improving qol in patients with urinary stones and reduce the prevalence of abu. acknowledgements the authors thank all medical and nursing staff at the department of urology, santa chiara regional hospital for clinical assistance and support of this study. references 1. khan sr, pearle ms, robertson wg, et al. kidney stones. nat rev dis primers. 2016; 2:16008. 2. cealan a, coman rt, simon v, et al. evaluation of the efficacy of phyllanthus niruri standardized extract combined with magnesium and vitamin b6 for the treatment of patients with uncomplicated nephrolithiasis. med pharm rep. 2019; 92:153-157. 3. curhan gc, willett wc, knight el, stampfer mj. dietary factors and the risk of incident kidney stones in younger women: nurses’ health study ii. arch intern med. 2004; 164:885-91. 4. pucci nd, marchini gs, mazzucchi e, et al. effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention. int braz j urol. 2018; 44:758-764. 5. prezioso d1, strazzullo p, lotti t, et al. dietary treatment of urinary risk factors for renal stone formation. a review of clu working group. arch ital urol androl. 2015; 87:105-20. 6. cruces il, patelli thc, tashima cm, mello-peixoto ect. plantas medicinais no controle da urolitíase. rev bras pl med. 2013; 15(4 supl 1):780-8. 7. ettinger b, pak cy, citron jt, et al. potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. j urol. 1997; 158:2069-73. 8. becchi m, bruneteau m, trouilloud m, et al. structure of a new saponin: chrysantellin a from chrysanthellum procumbens rich. eur j biochem. 1979; 102:11-20. 9. kaplan rm, bush jw, berry cc. health status: types of validity and the index of wellbeing. health serv. res. 1976; 11:478-507. 10. apolone g, mosconi p. the italian sf-36 health survey: translation, validation and norming. j clin. epidemiol. 1998; 51:1025-36. 11. micali s, sighinolfi mc, celia a, et al. can phyllanthus niruri affect the efficacy of extracorporeal shock wave lithotripsy for renal stones? a randomized, prospective, long-term study. j urol. 2006; 176:1020-1022. 12. nishiura jl, campos ah, boim ma, et al. phyllanthus niruri normalizes elevated urinary calcium levels in calcium stone forming (csf) patients. urol res. 2004; 32:362-6. 13. udupa al, sanjeeva, benegal a, et al. diuretic activity of phyllanthus niruri (linn) in rats. j health. 2010; 2:511-2. 14. lojanapiwat b, tanthanuch m, pripathanont c, et al. alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. int braz j urol. 2011; 37:611-616. 15. soygüur t, akbay a, küupeli s. effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. j endourol. 2002; 16:149-152. 16. cicerello e, ciaccia m, cova g, mangano m. the impact of potassium citrate therapy in the natural course of medullary sponge kidney with associated nephrolithiasis. arch ital urol androl. 2019; 91:. 17. monti e, trinchieri a, magri v, et al. herbal medicines for urinary stone treatment. a systematic review. arch ital urol androl. 2016; 88:38-46. correspondence tommaso cai, md (corresponding author) ktommy@libero.it daniele tiscione, md marco puglisi, md gianni malossini, md department of urology, santa chiara hospital, trento largo medaglie d'oro 9, trento (italy) lorenzo ruggera, md department of urology, university of padua, padua, italy. paolo verze, md department of medicine, surgery, dentistry "scuola medica salernitana" university of salerno, baronissi, italy alessandro palmieri, md department of urology, university of naples, federico ii, naples (italy) davide arcaniolo, md department of urology, university vanvitelli, naples (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12102 1 original paper introduction using a ureteral access sheath (uas) in retrograde intrarenal surgery (rirs) offers several advantages. these include a reduction in operative time, simplified entry and reentry into the ureter, facilitation of active extraction of stone fragments, lower intrapelvic pressure during the procedure, and the elimination of the need for periodic bladder emptying (1, 2). the uas enables repeated access to the renal pelvis without causing trauma to the ureter, enhances visibility, safeguards the ureteroscope, improves drainage, and allows swift extraction of stone fragments (3). however, it is important to note that the use of a uas may elevate the risk of ureteral injury and is linked to increased postoperative pain after rirs, especially when a postoperative ureteral stent is not inserted (1). preoperative ureteric stenting is primarily employed for internal urinary drainage in patients with obstructive renal stones, hydronephrosis, urinary tract infections, and those requiring passive dilatation of the ureter. nevertheless, the use of ureteral stents is associated with complications such as infection, encrustation, hematuria, and discomfort caused by tissue irritation. previous studies have reported conflicting views on the impact of preoperative ureteral stenting on the stone-free rate (sfr) after ureteroscopic lithotripsy (4, 5). consequently, the objective of this study was to examine the surgical outcomes of patients undergoing rirs with a uas for the management of kidney stones measuring 1-2 cm, comparing those who underwent preoperative ureteral stenting with those who did not. materials and methods between july 2021 and january 2023, we enrolled 83 objective: to assess the surgical results of patients who underwent retrograde intrarenal surgery (rirs) using a ureteral access sheath (uas) for management of renal stones sized 1-2 cm compared between patients who did and did not undergo preoperative ureteral stenting. materials and methods: this prospective study included 83 patients (aged ≥ 20 years) who underwent rirs from july 2021 to january 2023. all patients had renal calculi (stone size: 1-2 cm) located within the pelvicalyceal system. 43 and 40 patients were allocated to the non-prestent (group a) and prestent (group b), respectively. patient baseline characteristics, renal stone details, operative data, stone-free rate (sfr) at 4 weeks and 6 months, and perioperative complications were compared between groups. results: the baseline characteristics of all patients were comparable across the groups. four weeks after surgery, the overall stone-free rate (sfr) stood at 62.65%. in the non-prestent and prestent groups, the sfrs were 58.12% and 67.5%, respectively (p = 0.89). by the sixth month post-surgery, the overall sfr rose to 80.72%. in the non-prestent and prestent groups, the sfrs were 76.74% and 85%, respectively (p = 0.081). no notable differences emerged in other variables, including perioperative complications, between the two groups. conclusions: the sfr showed no significant difference between the prestenting and non-prestenting groups at the 4-week and 6-month postoperative marks. additionally, there were no substantial differences in complications during surgery and recovery between the groups. notably, the sfr increased from 4 weeks to 6 months without any additional procedures in either group. key words: access sheath; ureteral stenting; renal stones. submitted 16 november 2023; accepted 28 november 2023 effect of preoperative ureteral stenting on the surgical outcomes of patients with 1-2 cm renal stones managed by retrograde intrarenal surgery using a ureteral access sheath tamer a. abouelgreed 1, 2, mohamed a. elhelaly 1, el-sayed i. el-agamy 1, rasha ahmed 1, yasser m. haggag 3, m. abdelwadood 4, salma f. abdelkader 5, sameh s. ali 6, naglaa m. aboelsoud 7, mosab f. alassal 8, gehad a. bashir 9, tarek gharib 10 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 gulf medical university, ajman; 3 department of urology, faculty of medicine, al-azhar university, asyut., egypt; 4 department of urology, faculty of medicine, ain shams university, cairo, egypt; 5 department of radiology, faculty of medicine ain shams university, cairo, egypt; 6 department of radiology, sheikh khalifa general hospital, uaq, uae; 7 department of radiology, faculty of medicine, al-azhar university, cairo, egypt; 8 department of vascular surgery, saudi german hospital, ajman, uae; 9 department of urology, sheikh khalifa medical city, abu dhabi, uae; 10 department of urology, faculty of medicine, benha university, benha, egypt. doi: 10.4081/aiua.2023.12102 summary retr ac ted archivio italiano di urologia e andrologia 2023; 95(4):12102 t.a. abouelgreed, m.a. elhelaly, el-sayed i. el-agamy, et al. 2 patients who underwent rirs in this prospective comparative study. all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of thumbay university hospital (affiliated with gulf medical university, rec #: 487/2021). among participants, 43 patients were assigned to the non-prestent group (group a), while 40 patients belonged to the preoperative ureteral stenting (group b). all participants met our study's inclusion criteria, which included being 18 years or older, having renal calculi within the pelvicalyceal system, and stone sizes ranging from 1 to 2 cm. the same experienced surgeon consistently performed the procedures. preoperative ureteral stents were placed for reasons such as the inability to pass uas or a flexible ureterorenoscope, a history of renal or ureteral calculi operation, upper urinary tract infection, or hydronephrosis. stone size was determined using plain kidney, ureter, bladder (kub) radiography or non-contrastenhanced computed tomography (ct). the largest diameter of a single renal calculus or the sum of the largest diameters of multiple stones was recorded as the overall stone size. synapse 5 (fujifilm corporation, tokyo, japan) was the radiographic program employed for assessing stone size. before initiating the rirs procedure, antibiotic prophylaxis, typically third-generation cephalosporins or fluoroquinolones for patients with penicillin allergy was administered intravenously. patients were positioned in the lithotomy position. following cystoscopy, a sensor™ ptfe-nitinol guidewire with hydrophilic tip (boston scientific corporation, marlborough, ma, usa) was passed through the ureter toward the renal pelvis to serve as a safety guidewire. under fluoroscopy, a dual-lumen catheter was inserted into the ureter using the guidewire as a guide. an amplatz super stiff® guidewire (boston scientific) was then introduced into the ureter via the second lumen of the dual-lumen catheter. the dual-lumen catheter was subsequently removed, leaving the sensor™ ptfe-nitinol guidewire and the super stiff® guidewire in the ureter. a uas (11/13 french size (fr) or 12/14 fr) was placed over the amplatz super stiff® guidewire and advanced through the ureter up to the proximal ureter to facilitate kidney access. the amplatz super stiff® guidewire was then removed. flexible ureteroscopy (furs) with a holmium: yttrium-aluminum-garnet (ho: yag) laser lithotripsy device featuring a 272-μm laser fiber was employed to fragment the stone(s). the choice of laser lithotripsy technique (fragment and basketing, dusting, or popcorn) depended on the stone's appearance. dusting or popcorn was used for soft stones, while fragment and basketing were employed for hard stones. a 1.9 fr tipless stone basket was used to extract as many residual stone fragments as possible. the final step involved removing the uas and carefully inspecting the ureter for potential injuries as the furs was withdrawn. in the majority of cases, a ureteral stent (6 or 7 fr) was left indwelling after successful rirs. plain kub radiography was the primary imaging modality post-procedure, although non-contrast-enhanced ct-kub was conducted in cases involving non-opaque or semi-opaque stones. stone-free rates (sfrs) were assessed at 4 weeks and 6 months post-rirs, representing early and late follow-ups, respectively. stone-free was defined as the absence of stone fragments or the presence of fragments less than 2 mm in diameter. complications were classified as intraoperative or postoperativepostoperative complications, as observed in this study, included fever (defined as a febrile state with hemoculture showing no growth) and urosepsis (defined as hemoculture showing positive growth for a bacterial organism). bleeding requiring blood transfusion was not observed in any patient. statistical analysis was conducted using pasw statistics 18.0.0 software (spss, inc., chicago, il, usa). categorical data were compared using the chi-square test or fisher’s exact test, with results presented as numbers and percentages. for normally distributed data, the unpaired ttest was employed, while the mann-whitney u test was used for non-normally distributed data. mean plus/minus standard deviation and median and range were used to present normally and non-normally distributed data, respectively. a p-value less than 0.05 was considered statistically significant for all tests. results patients included in the prestenting group underwent preoperative stenting for various reasons: 32.5% due to the inability to pass uas or flexible ureterorenoscope, 22.5% following a previous operation for renal calculi, 20% following a previous operation for ureteral calculi, 15% due to upper urinary tract infection, 2.5% for flank pain, 2.5% for hydronephrosis, and 5% for an unrecorded reason. among the 80 patients in the prestenting group, the median duration of preoperative ureteral stenting was 42 days (range: 7-76). patient demographic, clinical and renal stone characteristics were compared between the non-prestent and prestent groups, as shown in table 1. no significant differences were observed in any of the variables described in table 1 between the nonprestent and prestent groups. the median stone size in the non-prestent group and prestent group was 14.2 mm and 14.1 mm, respectively (p = 0.878). the incidence of calyceal stones in the lower pole was 44.2% in the nonprestent group and 55% in the prestent group (p = 0.163). post-operative imaging consisted of plain x-rays for 98% of cases. pre-operative imaging included 48% ct scans and 52% plain x-rays. early outcomes were evaluated by stone-free rate (sfr) at 4 weeks after rirs, and late outcomes were evaluated by sfr 6 months after rirs. operative data, stone profiles, and clinical outcomes were compared between the non-present and present groups, as described in table 2. the mean operative time was identical in both groups (45 min; p = 0.845). after rirs, postoperative ureteral stent placement was performed in all included patient of this study (table 2). the median duration of stenting before stent removal was 24 days and 19 days in the non-prestent and prestent groups, respectively (p = 0.931). calcium stones, mostly consisting of calcium oxalate monohydrate, were the most common stone composition (34.9% in the nonprestent group vs. 47.5% in the prestent group; p = retr ac ted archivio italiano di urologia e andrologia 2023; 95(4):12102 3 preoperative ureteral stenting in retrograde intrarenal surgery 0.219). there was a significant difference in uas size between the groups (77.8% of the prestented group used 12/14 fr, while 67.4% of the non-prestented group used 11/13 fr; p < 0.001). the sfrs at 4 weeks after rirs were 58.12% in the non-prestent group and 67.5% in the prestent group (p = 0.089). at 6 months after rirs, the sfrs in the non-prestent and prestent groups were 76.74% and 85%, respectively (p = 0.081). although the sfrs in the prestent group were notably higher than those in the non-prestent group at both follow-up time points, these differences did not reach statistical significance. the sfr increased by 18.62% in the non-prestent group and 17.5% in the prestent group from the 4-week follow-up to the 6-month follow-up. intraoperative and postoperative complications were compared between the non-prestent and prestent groups (table 3). intraoperative complications occurred in 12.5% of the 83 patients included in the study, defined as ureteral wall injury graded according to the endoscopic classification proposed by traxer et al. (6) (please see appendix). the rate of ureteral injury was non-significantly lower in the prestent group (7.5%) than in the non-prestent group (20.8%) (p = 0.063), and most injuries in both groups were grade i. postoperative complications, including fever and urosepsis, showed no significant differences between the groups. at the 6-month follow-up, no ureteric stricture or new incidences of hydronephrosis or hydroureter were detected in any study patient. discussion rirs stands as a widely employed treatment for renal calculi due to several factors. reported stone-free rates (sfrs) for rirs are noted to be comparable to those achieved through percutaneous nephrolithotomy (pcnl) and surpass those of extracorporeal shockwave lithotripsy (eswl) for patients with small to medium-sized stones. rirs is characterized as less invasive with lower morbidity when compared to pcnl, which is commonly preferred for larger stones carrying a higher risk of major complications (7, 8). while various studies on urs have reported sfrs for renal and ureteral calculi (8-10), specific data regarding the impact of preoperative ureteral stenting on sfr, particularly in renal stone sizes of 1-2 table 1. patient demographic, clinical and renal stone characteristics compared between the non-prestent (group a) and prestent (group b). variables group a group b p-value (n = 43) (n = 40) age (years), mean ± sd 53.2 ± 12.2 56.3 ± 12.5 0.116 gender, n (%) 0.565 male 18 (41.9%) 19 (47.5%) female 25 (58.1%) 21 (52.5%) bmi (kg/m2) mean ± sd 21.3 ± 4.5 24.1 ± 5.3 0.116 comorbidities, n (%) diabetes mellitus 12 (27.9%) 9 (22.5%) 0.536 hypertension 25 (58.1%) 20 (50%) 0.466 dyslipidemia 16 (37.2%) 16 (40%) 0.969 gout 1 (2.3%) 2 (5.0%) 0.718 coronary artery disease 4 (9.3%) 1 (2.5%) 0.689 preoperative egfr, n (%) 0.427 egfr < 60 9 (20.9%) 11 (27.5%) egfr > 60 34 (79.1%) 29 (72.5%) kidney side, n (%) right kidney 19 (44.2%) 15 (37.5%) 0.307 left kidney 24 (55.8%) 25 (62.5%) total stone size (mm), (mean ± sd) 14.2 ± 3.1 14.1 ± 3.5 0.878 total stone size in lower pole 13.9 ± 3.3 13.8 ± 3.4 0.868 total stone size in non-lower pole 14.4 ± 3.1 14.5 ± 3.9 0.836 stone location, n (%) lower pole 19 (44.2%) 22(55%) 0.163 non-lower pole 24 (55.8%) 18 (45%) a p-value < 0.05 indicates statistical significance. sd, standard deviation; bmi, body mass index; egfr, estimated glomerular filtration rate. table 2. operative data, stone profiles, and clinical outcomes compared between the non-prestent (group a) and prestent (group b). variables group a group b p-value (n = 43) (n = 40) operative time (minutes) 45 (18–102) 45 (12–122) 0.845 (n = 43) (n = 36) median (range) ureteral access sheath size (fr) < 0.001 11/13 29 (67.4%) 8 (22.2%) 12/14 15 (34.9%) 28 (77.8%) postoperative stent (fr) 0.089 6 fr 38 (88.37%) 32 (80%) 7 fr 5 (11.63%) 8 (20%) length of hospital stay (days), median (range) 1 (1–16) 1 (1–17) 0.758 duration of postoperative stenting (days), median (range) 24 (5–47) 19 (9–160) 0.931 major stone composition 0.219 calcium oxalate monohydrate 15 (34.9%) 19 (47.5%) calcium oxalate dihydrate 8 (18.6%) 5 (12.5%) calcium phosphate 16 (37.2%) 10 (25%) non-calcium 4 (9.3%) 6 (15%) stone-free rate at 4 weeks 25 (58.12%) 27 (67.5%) 0.089 sfr of lower pole stone 11 (25.6%) 12 (30%) 0.881 sfr of non-lower pole stone 14 (32.6%) 15 (37.5 %) 0.741 stone-free rate at 6 months 33 (76.74%) 34 (85%) 0.081 sfr of lower pole stone 15 (34.88%) 16 (40%) 0.326 sfr of non-lower pole stone 18 (41.86%) 18 (45%) 0.398 increase in sfr from 4 weeks to 6 months 19.6% 17.1% 0.477 a p-value < 0.05 indicates statistical significance. fr, french size; sfr, stone-free rate. table 3. intraoperative and postoperative complications compared between the non-prestent (group a) and prestent (group b). complications group a group b p-value (n = 43) (n = 40) intraoperative complications overall intraoperative complication 7 (16.3%) 3 (7.5%) 0.061 ureteric injury grade i 5 (11.6%) 1 (2.5%) 0.052 ureteric injury grade ii 3 (6.9%) 1 (2.5%) 0.724 ureteric injury grade iii 1 (2.3%) 1 (2.5%) 1 postoperative complications overall postoperative complication 13 (30.2%) 7 (17.5%) 0.071 clavien-dindo classification grade 1 12 (27.9%) 6 (15%) 0.037 clavien-dindo classification grade 3 a 1 (2.3%) 1 (2.5%) 0.678 a p-value < 0.05 indicates statistical significance. retr ac ted archivio italiano di urologia e andrologia 2023; 95(4):12102 t.a. abouelgreed, m.a. elhelaly, el-sayed i. el-agamy, et al. 4 cm, remains limited (4, 11-15). jones et al. (11, 16) were the pioneers in reporting that the insertion of a ureteral stent, following the failure of initial urs, significantly improved the success rate of calculus extraction during the second urs. subsequent studies aimed to validate these findings, and although most reported similar results, the majority focused on sfrs for ureteral stones or small renal stones (4, 11, 13-15). the influence of preoperative ureteral stenting on sfr in large renal stones (diameter: 1-2 cm) after rirs procedures has not been addressed in existing literature. no significant differences were found for any evaluated patient and renal stone characteristics listed in table 1. prior studies have identified stone size and location as the most significant predictors of sfr after rirs (17, 18). as indicated in table 2, the uas size used in the prestent group was significantly larger than that in the non-prestent group (p < 0.001), aligning with findings reported by hyeong et al. (5). this could result from passive ureteral dilation from preoperative ureteral stenting (5). despite the improved accessibility afforded by a larger uas size, there was no significant difference in sfrs between the groups. our preference for using uas size 11/13 fr stems from its lack of impact on sfrs or complications. additionally, reports suggest that intrarenal pressure during rirs does not significantly differ between 11/13 fr and 12/14 fr uas (19). the primary benefit of a larger uas size lies in increased irrigation fluid flow during the procedure (19). moreover, the ureteral injury rates did not significantly differ when using a larger-sized uas (20). sfrs reported in the literature vary widely (54-96%) for renal stones sized 1-2 cm after a single session of rirs (18). this variability may be attributed to differences in the definition of 'stone-free' and variations in the imaging methods used during follow-up. previous studies considered a residual stone size of 4 mm (21) and 2 mm (22) as clinically significant. imaging modalities for stone detection include plain radiography, ultrasound, and ct scans, each possessing different sensitivity and specificity (23). while ct scans offer higher sensitivity and specificity, the increased radiation exposure to the patient favors the use of plain radiography or ultrasound. in this study, the overall sfr at 4 weeks and 6 months of follow-up was 67.5% and 85% in the prestent group, and 58.12% and 76.74% in the nonprestent group, respectively, representing a 12.5-18.62% increase in sfr after a more extended follow-up period. our study defines sfr as ≤ 2 mm of residual stone size, lower than sizes reported in other studies (11, 12). while studies by hyeong et al. (5) and sung et al. (25) found no significant association between preoperative ureteral stenting and stone clearance, studies by netsch et al. (11) and kawahara et al. (12) reported improved sfrs after rirs with preoperative ureteral stenting. these discrepancies may stem from differences in knowledge, technology, and instruments available at the time of these studies. in our study, sfrs at 4 weeks after rirs were not significantly different between the non-prestent and prestent groups (62.65% vs. 67.5%, respectively; p = 0.089). similarly, sfrs at 6 months after surgery showed no significant differences between the non-prestent and prestent groups (76.74% vs. 85%, respectively; p = 0.081). this finding aligns with bal et al. (26), who reported that preoperative ureteral stenting before rirs may not significantly impact the one-month postoperative sfr. notably, we observed that the sfr in both groups improved with a longer duration of follow-up, requiring no additional procedure. specifically, the sfr increased by 18.62% in the non-prestent group and 12.5% in the prestent group from the 4-week follow-up to the 6-month follow-up. there were no significant differences in overall intraoperative or postoperative complications between the prestent and non-prestent groups (p = 0.061 and p = 0.0710, respectively), consistent with previous studies (11-13). most cases of ureteral injury in this study were grade i injuries. although the incidence of ureteral injury resulting from uas insertion was lower in the prestent group (7.5%) than in the non-prestent group (16.3%), no significant difference was observed between the groups. it's worth noting that a larger uas size could be used in the pre-stented group (12/14 fr) than in the non-prestented group (11/13 fr). traxer et al. (6) reported that the incidence of ureteral injury grade iii could be decreased by prestenting, but our study lacked sufficient cases of grade iii injury to support this assertion. conclusions the findings from this research indicate that there was no notable disparity in the stone-free rate (sfr) between the group with preoperative ureteral stenting and the group without it, both at the 4-week and 6-month postoperative assessments. moreover, there was no significant contrast in complications observed during both the surgery and the recovery phase between these two groups. additionally, it is noteworthy that the sfr showed an increase at the 6-month mark compared to the 4-week assessment in both groups, and this improvement occurred without any supplementary procedures. acknowledgments thanks to prof. dr. hossam hamdy, president of gulf medical university for his suggestion. references 1. de coninck v, et al. systematic review of ureteral access sheaths: facts and myths. bju int. 2018; 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stenting for ureteroscopic lithotripsy for a large renal stone. int j urol. 2012; 19:881-885. 13. yang y, et al. preoperative double-j stent placement can improve the stone-free rate for patients undergoing ureteroscopic lithotripsy: a systematic review and meta-analysis. urolithiasis. 2018; 46:493499. 14. assimos d, et al. preoperative jj stent placement in ureteric and renal stone treatment: results from the clinical research office of endourological society (croes) ureteroscopy (urs) global study. bju int. 2016; 117:648-654. 15. rubenstein ra, et al. prestenting improves ureteroscopic stonefree rates, j. endourol. 2007; 21:1277-1280. 16. jones bj, et al. use of the double pigtail stent in stone retrieval following unsuccessful ureteroscopy. br j urol. 1990; 66:254-256. 17. molina wr, et al. the s.t.o.n.e. score: a new assessment tool to predict stone free rates in ureteroscopy from pre-operative radiological features. int braz j urol. 2014; 40:23-29. 18. tonyalı s, et al. prediction of stone-free status after single-session retrograde intrarenal surgery for renal stones. turk j urol. 2018; 44:473-477. 19. rehman j, et al. characterization of intrapelvic pressure during ureteropyeloscopy with ureteral access sheaths. urology. 2003; 61:713-718. 20. tracy cr, et al. increasing the size of ureteral access sheath during retrograde intrarenal surgery improves surgical efficiency without increasing complications. world j urol. 2018; 36:971-978. 21. takazawa r, kitayama s, tsujii t, successful outcome of flexible ureteroscopy with holmium laser lithotripsy for renal stones 2 cm or greater. int j urol. 2012; 19:264-267. 22. rippel ca, et al. residual fragments following ureteroscopic lithotripsy: incidence and predictors on postoperative computerized tomography. j urol. 2012; 188:2246-2251. 23. jackman sv, et al. plain abdominal x-ray versus computerized tomography screening: sensitivity for stone localization after nonenhanced spiral computerized tomography. j urol. 2000; 164: 308310. k. assantachai et al. heliyon. 2023; 9:e15801 7. 24. kanno t, et al. the utility of the kidneys-ureters-bladder radiograph as the sole imaging modality and its combination with ultrasonography for the detection of renal stones, urology. 2017; 104:4044. 25. sung lh, cho dy, the role of preoperative ureteral stenting in retrograde intrarenal surgery in renal stone patients: a propensity score-matched study. transl androl urol. 2020; 9:276-283. 26. bai p-d, et al. effect of preoperative double-j ureteral stenting before flexible ureterorenoscopy on stone-free rates and complications. current med sci. 2021; 41:140-144. correspondence tamer a. abouelgreed (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg department of urology, faculty of medicine, al-azhar university, cairo, egypt & gulf medical university, ajman, uae mohamed a. elhelaly elhelalymohammed@yahoo.com el-sayed i. el-agamy abuamr1978@yahoo.com rasha ahmed rashaahmed1511@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt yasser m. haggag uro_doc@yahoo.com department of urology, faculty of medicine, al-azhar university, asyut., egypt m. abdelwadood wadoodaref@gmail.com department of urology, faculty of medicine, ain shams university, cairo, egypt salma f. abdelkader salmafathy4@gmail.com department of radiology, faculty of medicine ain shams university, cairo, egypt sameh s. ali drsamehsaied@yahoo.com department of radiology, sheikh khalifa general hospital, uaq, uae naglaa m. aboelsoud nglaa.mahmoud@gmail.com department of radiology, faculty of medicine, al-azhar university, cairo, egypt mosab f. alassal mosabalassal32@gmail.com department of vascular surgery, saudi german hospital, ajman, uae gehad a. bashir almansosory670@gmail.com department of urology, sheikh khalifa medical city, abu dhabi, uae tarek gharib tarekgh78@yahoo.com department of urology, faculty of medicine, benha university, benha, egypt conflict of interest: the authors declare no potential conflict of interest. retr ac ted cop+ed+fisse 2006 107archivio italiano di urologia e andrologia 2022; 94, 1 review no conflict of interest declared. manifestation involves the loss or dysfunction of dopaminergic neurons in the substantia nigra pars compacta (2). the neuropathologic hallmark of pd is the presence of lewy bodies composed mostly of alpha-synuclein and ubiquitin. it is believed that the occurrence of pd is due to a combination of genetic and environmental factors (3). the cardinal motor symptoms of pd are tremor, rigidity, bradykinesia/akinesia, and postural instability, but the clinical picture includes other motor and non-motor symptoms (4). a variety of non-motor symptoms are common in pd. they include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, a variety of sleep disorders and a spectrum of neuropsychiatric symptoms (5). diagnosis of pd is based on history and examination. history can include prodromal features (rapid eye movement, sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (tremor, stiffness, slowness), and psychological or cognitive problems (cognitive decline, depression, anxiety). examination typically demonstrates bradykinesia with tremor, rigidity, or both. dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain (6). misdiagnoses between parkinson’s tremor and essential tremor are relatively common. electrophysiological and functional imaging examinations can be useful in the distinction of the two, but both approaches suffer from some limitations (7). pd interferes with various aspects of quality of life, particularly those related to physical and social functioning (8). the primary goal in the management of pd is to treat the symptomatic motor and nonmotor features of the disorder. effective management should include a combination of nonpharmacological and pharmacological strategies to maximize clinical outcomes (9). oral levodopa, the initial gold-standard therapy for pd, is still the most effective and widely used therapeutic option (10). in advanced pd, therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion, levodopa-carbidopa intestinal gel infusion, and deep brain stimulation (11). supportive non-pharmacoparkinson's disease (pd) is recognized as the most common neurodegenerative disorder after alzheimer's disease. lower urinary tract symptoms are common in patients with pd, either storage symptoms (overactive bladder symptoms or oab) or voiding symptoms. the most important diagnostic clues for urinary disturbances are provided by the patient's medical history. urodynamic evaluation allows the determination of the underlying bladder disorder and may help in the treatment selection. pharmacologic interventions especially anticholinergic medications are the first-line option for treating oab in patients with pd. however, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. intra-detrusor botulinum toxin injections, electrical stimulation were also used to treat oab in those patients with variable efficacy. mirabegron is a β3-agonist that can also be used for oab with superior tolerability to anticholinergics. desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in pd. deep brain stimulation (dbs) surgery is effective in improving urinary functions in pd patients. sexual dysfunction is also common in pd. phosphodiesterase type 5 inhibitors are first-line therapies for pd-associated erectile dysfunction (ed). treatment with apomorphine sublingually is another therapeutic option for pd patients with ed. pathologic hypersexuality has occasionally been reported in patients with pd, linked to dopaminergic agonists. the first step of treatment of hypersexuality consists of reducing the dose of dopaminergic medication. this review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic test, and management of pd. lastly, the urologic outcomes and therapies are reviewed. key words: parkinson’s disease; lower urinary tract dysfunction; neurogenic bladder, urology. submitted 4 december 2021; accepted 6 january 2022 introduction parkinson’s disease (pd) is the most common neurodegenerative movement disorder. in europe, the prevalence and incidence rates for pd are estimated at approximately 108257/100 000 and 11-19/100 000 per year, respectively (1). although the cause of pd is unknown, the pathologic perspectives on the urological care in parkinson’s disease patients mohamad moussa 1, mohamed abou chakra 2, athanasios g. papatsoris 3, athanasios dellis 4, baraa dabboucy 5, michael peyromaure 6, nicolas barry delongchamps 6, hugo bailly 6, igor duquesne 6 1 urology department, zahraa hospital, university medical center, beirut, lebanon; 2 department of urology, faculty of medical sciences, lebanese university, beirut, lebanon; 3 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens, greece. 4 department of urology/general surgery, areteion hospital, athens, greece; 5 department of neurosurgery, faculty of medical sciences, lebanese university, beirut, lebanon; 6 department of urology, cochin hospital, assistance publique-hôpitaux de paris, paris descartes university, paris, france. doi: 10.4081/aiua.2022.1.107 summary archivio italiano di urologia e andrologia 2022; 94, 1 m. moussa, m. abou chakra, et al. 108 logical therapies are used in early and advanced pd patients. it should include physical rehabilitation, psychological support, occupational therapy, speech, language, and swallowing therapy, and nutrition (12). bladder dysfunctions are quite common in pd. they may occur at any stage of the illness and get worse with advancing and aggravating disease. the most prominent dysfunction is the so-called overactive bladder (oab). the main clinical problem of pd patients consists in reduced inhibition with consequentially resulting overactivity of the detrusor muscle, meaning the urge to urinate in the absence of adequate bladder filling (13). the most common storage symptoms of patients with pd are nocturia, followed by frequency and urinary incontinence. some patients presented functional obstructive symptoms. the most frequent obstructive symptom was incomplete emptying of the bladder (14). obstructive symptoms may be secondary to anticholinergics, obstructive uropathy, or point to the presence of multiple system atrophy (msa). dysfunction of the striated urethral sphincter and pelvic musculature can be seen in variable numbers in pd (15). antimuscarinic medications are the first-line treatment for oab symptoms. antimuscarininc drugs may exacerbate pd-related constipation and xerostomia, and caution is advised when using these medications in individuals where cognitive impairment is suspected. desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in pd. intra-detrusor injections of botulinum toxin are effective therapy for detrusor overactivity, however, are associated with the risk of urinary retention (16). subthalamic deep brain stimulation (dbs) has a significant and urodynamically recordable effect leading to a normalization of pathologically increased bladder sensibility (17). percutaneous tibial nerve stimulation (ptns) improves the urinary symptoms and urodynamic parameters in patients with pd (18). sexual dysfunction (sd) in pd, which has been suggested as a result of central and autonomic dysfunction compounded by defective motor skills, reduced self-esteem, and comorbid psychiatric states like anxiety and depression (19). the prevalence of sd is reported high in male patients (65%), but much lower in female patients (36%). there are different types of sd: erectile dysfunction (ed) and loss of ejaculation control in male patients, and much lower self-esteem in female patients (20). optimal dopaminergic treatment should facilitate sexual encounters of the couple. appropriate counseling diminishes some of the problems (reluctance to engage in sex, problems with ejaculation, lubrication, and urinary incontinence). treatment of ed with sildenafil and apomorphine is evidence-based (21). we performed a narrative review to briefly discuss the epidemiology, pathogenesis, risk factors, genetic contribution, clinical course, diagnosis, and treatment of pd. the urologist had an important role in the management of urologic manifestations of patients with pd. we reviewed the current literature regarding the urological outcomes and management of patients with pd. materials and methods we searched electronic databases including pubmed, the scopus database for published studies that analyzed the role of the following medical subject headings terms: ‘parkinson’s disease’ (and) ‘management’ (and) ‘diagnosis’ (and) ‘epidemiology’ (and) ‘genetic contribution’ (and) ‘risk factor’ (or) ‘parkinson’s disease’ (and) ‘urologic dysfunction’ (and) ‘management’ (or) ‘parkinson’s disease’ (and) ‘erectile dysfunction’ (and) ‘management’. this was done to ensure the comprehensive inclusion of articles related to neurogenic bladder in pd patients. the initial search resulted in 350 articles. after review, we initially excluded papers that were not relevant (72). at the completion of the review, articles were selected based on their clinical relevance related to the aim. when all duplicates are thrown out, a total of 90 papers were used to extract necessary information. overview of pd epidemiology of pd pd affects 1-2 per 1000 of the population at any time. pd prevalence is increasing with age, it affects 1% of the population above 60 years (22). the median age of onset is 60 years; the mean duration of the disease from diagnosis to death is 15 years. male sex is recognized as a prominent risk factor in developing pd. both incidence and prevalence of pd are 1.5 to 2.0 times higher in men than in women. age at onset is 2.1 years later in women (53.4 years) than in men (51.3 years) (23). the overall prevalence of pd appears to be lower in eastern studies compared to western ones. in a metaanalysis of 39 european studies until 2004, the authors reported a prevalence rate of 108-257/100,000 when considering only high-quality studies that utilized a standard diagnostic criterion (24). pathogenesis of pd the main pathological features of pd are the loss of dopaminergic neurons with subsequent depigmentation of the substantia nigra pars compacta and the presence of lewy bodies (25). lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. thereafter, less vulnerable nuclear grays and cortical areas gradually become affected (26). the spinal cord lesions may contribute to clinical symptoms (pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic pd (27). pd does not fulfill key criteria to be diagnosed as prionopathy. nonetheless, abnormal forms of a-synuclein seem to propagate in the brain of pd patients. the finding of lewy bodies and a-synuclein deposits in nigral fetal neurons transplanted over a decade earlier into the striatum could support the existence of a prionlike pathogen as the cause of pd (28). risk factors of pd significant predictors of pd emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. the predicted probability of pd was 92.3% (odds ratio = 12.0) with all three predictors positive (29). other potential risk factors include 109archivio italiano di urologia e andrologia 2022; 94, 1 urological care in parkinson’s disease patients environmental toxins, drugs, brain microtrauma, focal cerebrovascular damage, and genomic defects (30). there is an association between anemia experienced early in life and the later development of pd (31). exposure to toxins in the environment has been linked to pd-associated neurodegeneration particularly heavy metals, pesticides, and illicit drugs (32). some infectious diseases such as mumps, scarlet fever, influenza, whooping cough, and herpes simplex infections may play a role in the development of pd (33). genetic contribution to pd a-synuclein (snca) was the first pd gene identified in a large italian-american family (the contursi kindred) with autosomal dominant inheritance (34). a total of 18 pd loci have been nominated through linkage analysis (park1-15) or genome wide association studies (park16-18). mutations within the genes at 6 of these loci (snca, lrrk2, prkn, dj1, pink1, and atp13a2) have conclusively been demonstrated to cause familial parkinsonism. in addition, common polymorphisms within 2 of these same genes (snca and lrrk2) and variation in 2 other genes not assigned to a park locus (mapt and gba) are now well-validated risk factors for pd (35). clinical features of pd pd comprises a range of motor and non-motor features (table 1). the presence of bradykinesia, rest tremor, rigidity, and loss of postural reflexes are the most commonly identified motor symptoms of pd, although other clinical features can also be identified during disease progressions, such as bulbar dysfunction, neuro-ophthalmological abnormalities, and respiratory disturbances (36). most non-motor symptoms are not fully levodopa-responsive and are suggested to manifest extra-nigral pathology. these symptoms include autonomic, sleep, sensory, and neuropsychiatric symptoms (37). diagnosis of pd the movement disorder society (mds) clinical diagnostic criteria for pd mentioned that the first essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at least 1 of rest tremor or rigidity. once parkinsonism has been diagnosed, the diagnosis of clinically established pd requires absence of absolute exclusion criteria, at least two supportive criteria, and no red flags (38). those criteria and red flags are summarized in table 2. early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other parkinsonian syndromes from pd. the levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing pd from other parkinsonian syndromes (39). structural mri is useful to differentiate pd from secondary and atypical forms of parkinsonism. 123i-ioflupane single-photon emission computed tomography (spect) is a valid tool in the differential diagnosis between pd and non-degenerative tremors. cardiac 123i-metaiodobenzylguanindine spect and 18f-fdg positron emission tomography (pet) have the potential to differentiate pd from atypical parkinsonism (40). differential diagnosis although the most common cause of parkinsonism is pd, the differential diagnosis includes many other causes of parkinsonism. aside from drug-induced parkinsonism, related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade, the most common mimickers of pd are parkinsonian syndromes, such as msa and progressive supranuclear palsy, dementia with lewy bodies (dlb), vascular parkinsonism (vp), a parkinsonian syndrome that is associated with cerebrovascular disease (41). management of pd there are several drugs available to treat motor impairments in pd. first, drugs that increase brain levels of dopamine such as levodopa are used. in addition, drugs that mimic dopamine were used such as dopamine agonists. lastly, drugs that inhibit dopamine breakdown has been used. mao-b inhibitors can inhibit the activity of monoamine oxidase b. usually, moa-b inhibitors reduce the symptoms of pd. selegiline or deprenyl is one of the inhibitors of moa-b that is very active against pd along with levodopa. tolcapone also reduces the requirement of levodopa to patients but it can induce severe hepatotoxicity. there are two types of catechol-o-methyl transferase (comt) inhibitors being entacapone and tolcapone. comt inhibitors are used to reduce the dose of levodopa (42). in most patients with pd, motor fluctuations and dyskinesias are relatively mild and can be adequately managed by adjustment of the oral medication. however, for patients experiencing disabling motor fluctuations and dyskinesias despite optimized medical therapy, device-assisted therapies should be considered (43). table 1. motor and non-motor symptoms of parkinson’s disease. motor symptoms non motor symptomse • tremor • neuropsychiatric problems: cognitive impairment, depression, anhedonia, apathy, anxiety, panic attacks, delirium, hallucinations, illusions • rigidity • sleep problems • bradykinesia, akinesia • oily skin, dandruff • loss of balance • sensory impairment • speech and facial expression difficulties • urinary disturbances: urgency, frequency, urge incontinence, nocturia, sexual dysfunction • gait disturbance • gastrointestinal disturbances: drooling, dyspepsia, constipation, abdominal pain, fecal incontinence • impaired handwriting and grip force • blood pressure variations with orthostatic hypotension and tachycardia • fatigue archivio italiano di urologia e andrologia 2022; 94, 1 m. moussa, m. abou chakra, et al. 110 many experimental studies are going to test the applications of antibodies to target and degrade extracellular asynuclein molecules. passive and active immunization techniques against a-synuclein have been shown to convey neuroprotective effects in animal models (44). urologic outcomes of pd prevalence of urologic symptoms among the pd population seventy-four percent of patients with early-to-moderate disease report more than one bladder disturbance symptom. severe bladder symptoms are reported in 27-39% of pd patients. both storage and voiding symptoms are highly prevalent in patients with pd. more than 50% of patients have oab symptoms (45). the severity of the neurological disease is correlated with the occurrence of voiding dysfunction, these findings corroborate the results of other studies which showed that lower urinary tract symptoms (luts) increase accordingly with pd progression (46). urologic clinical symptoms the pattern and mechanism of storage symptoms have been partly clarified as the hypothesis most widely proposed is that the basal ganglia output has an overall inhibitory effect on the micturition reflex in healthy individuals, and with cell loss in the substantia nigra, detrusor overactivity develops through an inability to activate the dopamine d1 receptor-mediated tonic inhibition. a parallel mechanism may be that in pd, the inhibitory dopaminergic neurons originating in the substantia nigra may be more damaged than the stimulatory dopaminergic neurons originating in the ventral tegmental area, thereby inducing urgency and frequency. impaired sensory information from periaqueductal gray could also contribute to storage symptoms (47). however, those of voiding disorders have yet to be elucidated, and there have been only a few reports that dopa-responsive detrusor under-activity or impaired urethral relaxations exist, and post-void residual urine (pvr) does not occur frequently. these findings suggest that early and untreated pd patients also have not only storage disorders but also mainly subclinical voiding disorders (48). detrusor underactivity or bladder outlet obstruction (boo) underlie the mechanism of voiding symptoms in patients with pd. pd patients mostly maintain an acceptable voiding efficiency and low pvr volume. in the meantime, pd mostly affects the elderly, overlapping the age group with high morbidity of benign prostatic hyperplasia (bph). neurogenic boo in pd patients still draws less attention (49). detrusor sphincter dyssynergia (dsd) is a rare cause of voiding dysfunction in pd. dsd was observed on voiding at a rate of 0-3% (50). underactive bladder in up to 50 % of patients with pd. the mechanism of detrusor weakness in pd remains unclear and warrants further exploration (51). a study suggested that a weak detrusor in pd might have a central origin. it is necessary to follow pvr carefully in pd patients with advanced gait disorder because pvr might table 2. parkinson's disease diagnostic criteria of the movement disorder society. movement disorder society criteria (53) supportive criteria • clear and dramatic beneficial response to dopaminergic therapy. • presence of levodopa-induced dyskinesia • rest tremor of a limb, documented on clinical examination (in past, or on current examination) • the presence of either olfactory loss or cardiac sympathetic denervation on mibg scintigraphy absolute exclusion criteria • unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities • downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades • diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first 5 y of disease • parkinsonian features restricted to the lower limbs for more than 3 y • treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism • absence of observable response to high-dose levodopa despite at least moderate severity of disease • unequivocal cortical sensory loss, clear limb ideomotor apraxia, or progressive aphasia • normal functional neuroimaging of the presynaptic dopaminergic system • documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment feels that an alternative syndrome is more likely than parkinson's disease red flags • rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset • a complete absence of progression of motor symptoms or signs over 5 or more y unless stability is related to treatment • early bulbar dysfunction: severe dysphonia or dysarthria or severe dysphagia (requiring soft food, nasogastric tube, or gastrostomy feeding) within first 5 y • inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs • severe autonomic failure in the first 5 y of disease. • recurrent (> 1/y) falls because of impaired balance within 3 y of onset • disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 y • absence of any of the common non-motor features of disease despite 5 y disease duration. these include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of rem sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations) • otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response) • bilateral symmetric parkinsonism. 111archivio italiano di urologia e andrologia 2022; 94, 1 urological care in parkinson’s disease patients increase in such patients (52). obstructive symptoms might possibly result from treatment with particular antiparkinsonian drugs. also, it should be noted that lewy bodies can be seen in several types of neurons, including central and peripheral components of the autonomic nervous system, in advanced pd. thus, obstructive symptoms in patients with pd might result from micturition hyporeflexia due to impairment in the autonomic nervous system (53). the mechanisms responsible for urinary symptoms in pd patients are summarized in figure 1. neurogenic lower urinary dysfunction (nlud) can induce anxiety and depression in patients. a study was implemented by benli et al. to investigate whether nlud, which is frequently seen in pd, has an effect on the development of anxiety and depression in these patients. the study included 32 males (66.6%) and 16 females (33.3%); in total 48 subjects were registered. it was concluded that the incidence of nlud, anxiety and, depression was increased in pd. in addition, nlud was found to be a risk factor for the development of anxiety and depression (54). clinical scales the scale for outcomes in pd for autonomic symptoms (scopa-aut) is a specific scale to assess autonomic dysfunction in pd patients. it includes six urinary items that assess both storage and voiding phases. scopa-aut is an acceptable, consistent, reliable, and valid scale (55). the international prostate symptom score (ipss) has been used both in men and women for patients with neurological diseases; several teams used it in pd patients, including in advanced stage, and after dbs. overactive bladder symptom score (oabss) has been used to evaluate urinary symptoms in pd patients but it needs further validation (56). findings on urodynamic studies the urodynamic examination is recommended for male pd patients with voiding dysfunction. it can show detrusor hyperreflexia associated with boo or detrusor dysfunction with boo (57). urodynamic findings could differentiate patients with msa from those with pd. patients with msa showed lower maximal flow rate, larger pvr with decreased compliance, and impaired contractility, whereas patients with pd had a higher incidence of detrusor overactivity and associated leakage (58). a study conducted by vurture et al. strongly suggests that a vast majority of oab symptoms in patients with pd can be attributed to do on urodynamics (97.1%). however, the high rates of other abnormalities such as boo (36.8%), detrusor underactivity (47%), and increased pvr (16.7%) suggest that neurogenic do is not the only contributor of oab symptoms in patients with pd (59). special focus on nocturia in pd nocturia is a common non-motor symptom in pd but has been poorly studied. nocturia may manifest as a result of reduced functional bladder capacity or nocturnal polyuria; however, most often the cause is multifactorial. disorders of circadian rhythm regulation are known to occur with sleep disturbances in pd that may also contribute to nocturia (60). the bladder diary provides a prospective real-time assessment of bladder symptoms, which is cost-effective and relatively straightforward for patients to complete. it provides a more accurate assessment of night-time frequency and voided nocturnal urine volumes. a bladder diary is an essential tool in the assessment of nocturia in patients with pd (61). figure 1. suggested mechanisms responsible for urinary symptoms in patients with pd. pd = parkinson’s disease; sn = substantia nigra; vta = ventral tegmental area; pag = periaqueductal gray. archivio italiano di urologia e andrologia 2022; 94, 1 m. moussa, m. abou chakra, et al. 112 urologic management of pd management of the storage symptoms (oab symptoms) in pd patients a detailed algorithm for the management of the storage symptoms in pd patients is summarized in figure 2. general measures and physical treatment behavioral therapy included pelvic floor muscle exercises, bladder training, fluid and constipation management. providers should consider behavioral therapy as an initial treatment for urinary symptoms in pd. it was demonstrated in a small study conducted by vaughan et al. (62). a study was implemented by mcdonald et al. to assess the feasibility and efficacy of bladder training (bt) for troublesome luts in pd. thirty-eight participants were randomized (18 to conservative advice (ca), 20 to bt groups). both ca and bt were associated with significant improvements in volume voided, number of micturitions, symptom severity scores, and measures of quality of life (all p < 0.05). at 12 weeks, compared to ca, bt was associated with significant superiority on patient perception of improvement (p = 0.001). at 20 weeks, bt remained associated with greater improvement in interference in daily life (63). dopaminergic therapy it is uncertain whether l-dopa medication can improve micturition disorders. some have reported that l-dopa improves micturition symptoms, but others have reported conflicting results. in addition, the effects of l-dopa on bladder function are unknown (64). the acute mixed stimulation of d1 and d2 receptors by apomorphine has been reported to reduce bladder outflow resistance. in contrast, acute dopaminergic stimulation by l-dopa challenge has been reported to worsen detrusor overactivity and to reduce bladder capacity in patients with pd. however, the worsening effect of acute l-dopa administration conflicts with the clinical experience of bladder function improvement reported by pd during l-dopa therapy (65). these findings suggest that the effects of dopaminergic treatment on bladder control are very different, according to their figure 2. algorithm for the management of storage symptoms in pd patients. pd = parkinson’s disease; do = detrusor overactivity; du = detrusor underactivity; boo = bladder outlet obstruction; uui = urge urinary incontinence; sic = self-intermittent catheterization; pvr = post void residual volume; btx-a = botulinum toxin a; turp = transurethral resection of the prostate; dbs = deep brain stimulation. 113archivio italiano di urologia e andrologia 2022; 94, 1 urological care in parkinson’s disease patients receptorial activity, producing a cumulative effect of a multidrug daily treatment difficult to predict. combined, balanced activation of d1/d2 receptors could be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in pd as demonstrated brusa et al. they conducted an open-label study where extended-release levodopa at bedtime showed significant improvement of oab symptoms, specifically nocturia (66). winge et al. concluded in their trial that dopaminergic therapy relieves cognitive executive dysfunction, as it seems to improve functional bladder control in those of their patients, who benefit from medication during their storage phase (67). antimuscarinic drugs antimuscarinic agents are the first-line treatment for oab symptoms. these include oxybutynin, tolterodine, solifenacin, darifenacin, fesoterodine, and trospium chloride. only solifenacin had a class of evidence (level 1a) for urinary dysfunction in pd (16). the central effects of these medications may result in alterations in cognition and consciousness in susceptible individuals. caution needs to be used in elderly patients with preexisting dementia (68). a randomized-controlled trial (rct) that assesses the use of solifenacin succinate for oab in pd was done by zesiewicz et al. patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open-label extension. twentythree patients were randomized in the study. there was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). in the open-label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01) (69). yonguc et al. conducted an rct to test the use of fesoterodine fumarate for oab in pd. from may 2016 to may 2018, 63 patients were randomized to receive fesoterodine 4 mg or placebo for 4 weeks. at the end of 4 weeks of the randomization phase, patients have received fesoterodine fumarate 4 mg daily for another 4 weeks at the open-label extension phase. oab symptoms were significantly improved in older adults with pd under fesoterodine fumarate treatment, and this advantage continued in the open-label portion in the short term (70). mirabegron mirabegron is an orally active, b3-adrenoceptor agonist approved for the treatment of oab. the main theoretical advantage of b3-adrenoceptor agonists for the treatment of oab is that they lack the typical side effects of antimuscarinics. there are only a few trials that test the efficacy of mirabegron in pd patients. peyronnet et al. conducted a study that aimed to assess the outcomes of mirabegron for the treatment of oab symptoms in patients with pd. fifty patients (mean 74 years old) were included. before being treated with mirabegron, 56% had failed prior anticholinergic therapy. after 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their oab symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change, and 2 (4%) reported worsening of their oab symptoms. the number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). mirabegron has an excellent safety profile in their trial (71). gubbiotti et al. concluded in their pilot study that mirabegron is a safe and effective treatment in patients with pd and oab refractory to anticholinergics in the shortterm follow-up (72). in another rct conducted by cho et al., it was concluded that mirabegron was effective in treating oab symptoms in patients with parkinsonism with acceptable adverse events (73). botulinum toxin therapy there are limited data on the efficacy of intravesical botulinum toxin (bt) injection in pd patients. kulaksizoglu et al. implemented a trial to evaluate the efficacy of intravesical bt injection for oab symptoms in patients with pd. sixteen patients were followed for 12 months. intradetrusor injection technique with 30-point template was employed. all patients received 500 international units of botulinum toxin-a. the follow-up was at week one and every 12 weeks thereafter for 12 months. the initial mean functional bladder capacity was 198.6 +/33.7 ml. at 3-month follow-up the mean bladder capacity increased to 319 +/41.1 ml. the quality of life assessment of the primary caregiver as well as the patients also statistically improved after the injections. no central nervous system side effects were noted (74). vurture et al. conducted a study to test the outcomes of intradetrusor onabotulinum toxin a (bont-a) injection in patients with pd. all pd patients who underwent intradetrusor injections of bont-a for storage symptoms between 2010 and 2017 were included in their retrospective study. a 100 u dose of bont-a was used for the first injection in all patients. out of 24 patients analyzed, 19 reported improvements of their oab symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; p < 0.001). three of the patients had to start clean intermittent catheterization (cic) after the first injection (12.5%) (75). some authors hypothesize that bonta might be better tailored to “oab wet”/motor urgency (59). intravesical bont-a might not be a good indication in patients with detrusor hyperactivity and impaired contractility (dhic) and high pvr (76). it was mentioned in the international continence society (ics) guidelines that intravesical bt injection is a promising method to treat intractable detrusor overactivity in pd. also, guidelines state that it is important to differentiate msa from pd before completing botulinum injections. but there was no recommendation for dosages, risk factors for retention or difficulty voiding or long-term effectiveness are available (77). sacral neuromodulation sacral neuromodulation (snm) is an effective therapy that should be considered among the treatment options for pd patients with oab symptoms. urodynamic parameters associated with obstruction may be predictive of snm failure in pd patients and may help guide patient selection (78). few studies have been performed to determine the effects of percutaneous posterior tibial nerve stimulation (ptns) on neurogenic do in patients, especially, with pd. archivio italiano di urologia e andrologia 2022; 94, 1 m. moussa, m. abou chakra, et al. 114 kabay et al. conducted a trial to investigate the effect of ptns treatment after 12 weeks on urodynamic and clinical findings in patients with pd with neurogenic do. a total of 47 patients with pd with neurogenic do were enrolled in the study. their results have demonstrated that ptns improves the lower urinary tract symptoms and urodynamic parameters in patients with pd (79). transcutaneous tibial nerve home stimulation can be used in clinical practice as an effective nonpharmacological resource for the reduction of oab symptoms in women with pd (80). deep brain stimulation deep brain stimulation (dbs) has been used as a surgical treatment for motor symptoms in advanced pd. an exploratory post hoc analysis was performed of specific luts items of questionnaires used in an rct with 128 patients (nstaps study). urinary incontinence and frequency improved after both globus pallidus pars interna (gpi) dbs and the subthalamic nucleus (stn) dbs at 12 months postoperatively, but this was only statistically significant for the stn dbs group (p = 0.004). the improvements after dbs were present in both men (p = 0.01) and women (p = 0.05). nocturia and urinary incontinence did not improve significantly after any type of dbs, irrespective of sex (81). dbs is associated with increased bladder capacity and volume triggering bladder contraction, increased time to first desire to void. while dbs appears to be a promising therapy for modulating luts in pd patients, the current research is mostly limited to small cohorts. larger clinical trials are needed to truly delineate how dbs affects urinary disturbances (82). management of the voiding symptoms in pd patients concern has existed about the risks of incontinence with transurethral resection of the prostate (turp) in pd patients with boo. roth et al. investigated the outcome of turp in patients with a secure neurological diagnosis of pd. a total of 23 patients with pd who underwent turp for benign prostatic obstruction were evaluated retrospectively. it was concluded that turp for benign prostatic obstruction in patients with pd may be successful in up to 70% and the risk of de novo urinary incontinence seems minimal (83). one of the greatest areas of concern for many patients considering turp is the possibility of incontinence or inability to void despite surgical intervention. tyson et al. demonstrated in their study that the use of the temporary prostatic urethral stent provided a good provocative test that enabled patients to experience what their voiding status would be if they were to undergo definitive surgical management (84). doxazosin resulted in the improvement of luts and the maximum flow rate and was well tolerated in men with pd. the response to treatment is dependent on the severity of neurological disability (85). recently the a1 adrenergic receptor antagonist terazosin was shown to activate pgk1, a possible target for the mitochondrial deficits in pd related to its function as the initial enzyme in atp synthesis during glycolysis. it has been shown that terazosin had neuroprotective effects in neurotoxin models of nigrostriatal degeneration in invertebrates and rodents, including after delayed administration. additionally, terazosin reduced a-synuclein levels in transgenic mice and neurons derived from patients with lrrk2 mutationassociated (44). an epidemiologic study was performed by sasane et al. to test the pd occurrence rate in 113,450 individuals from the united states with 5 or more years of follow-up. patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and charlson comorbidity index score (n = 45,380). terazosin/alfuzosin/doxazosin users did not differ in pd risk from matched controls (p = 0.29) but rather that tamsulosin may in some way potentiate pd progression (86). in case of significant and symptomatic pvr, a specific treatment is necessary in order to empty the bladder. the gold standard therapy in pd patients with neurogenic bladder still the self-intermittent-catheterizations (87). managing nocturia in pd managing nocturia in pd patients necessitates managing reduced functional bladder capacity and nocturnal polyuria. the use of antimuscarinics, detrusor injection of bt, neuromodulation, and cic could be useful to manage reduced bladder capacity. desmopressin and late-afternoon diuretic could help in the management of nocturnal polyuria (60). managing incontinence in pd in a systemic review of 3 studies with a total sample size of n = 1077, 25 percent of the women with pd suffer from urgency incontinence compared to seven percent of the women without parkinson's disease (p < 0.01). men with pd were affected with a 28% rate in comparison of 6% of men without parkinson's disease (p < 0.01). with pelvic floor muscle exercises and accompanying measures as well as with injections of botulinum toxin a a reduction of urinary incontinence seems to be possible (88). artificial urinary sphincter implantation shows significantly worse continence rates for patients with pd, even though it is considered as a safe procedure (89). management of the sexual dysfunction in pd patients impulse control disorders (icds) affect up to 40% of patients with pd using dopamine agonists and about 15% of patients with pd overall. the mainstay of medical management for icd is reducing or discontinuing dopamine agonists. cognitive-behavioral therapy was found to be useful for the treatment of icd in patients with pd (90). sildenafil citrate may be considered to treat ed in patients with pd as concluded in multiple studies. the benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in pd but its role is not validated. a daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with pd (91). pergolide substantially improved sexual function in the younger male patients who were still interested in sexual activities (92). conclusions urinary symptoms and sexual dysfunctions are common in pd patients, occurring in any stage of the disease. pd patients experience both storage and voiding difficulties. 115archivio italiano di urologia e andrologia 2022; 94, 1 urological care in parkinson’s disease 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[article in french]. 88. siegl e, lassen b, saxer s. inkontinenz--ein häufiges problem für menschen mit einer parkinsonerkrankung. eine systematische literaturübersicht [incontinence--a common issue for people with parkinson's disease. a systematic literature review]. pflege z. 2013; 66:540-4. [article in german]. 89. maurer v, stahlberg j, schiffmann i, et al. continence and complication rates of artificial urinary sphincter devices (ams 800) for parkinson and stroke patients with incontinence after prostate surgery: retrospective analysis of a prospective database. urol int. 2021; 105:225-231. 90. margolesky j, betté s, singer c. management of urologic and sexual dysfunction in parkinson disease. clin geriatr med. 2020; 36:69-80. 91. moussa m, papatsoris ag, abou chakra m, et al. erectile dysfunction in common neurological conditions: a narrative review. arch ital urol androl. 2020; 92:371-385 92. pohanka m, kanovský p, bares m, et al. pergolide mesylate can improve sexual dysfunction in patients with parkinson's disease: the results of an open, prospective, 6-month follow-up. eur j neurol. 2004; 11:483-8. correspondence mohamad moussa, md mohamadamoussa@hotmail.com head of urology department, zahraa hospital, university medical center, beirut (lebanon) mohamed abou chakra, md (corresponding author) mohamedabouchakra@hotmail.com department of urology, faculty of medical sciences, lebanese university, beirut (lebanon) athanasios g. papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens (greece) athanasios dellis, md aedellis@gmail.com department of urology/general surgery, areteion hospital, athens (greece) baraa dabboucy, md baraa.dabboucy@gmail.com department of neurosurgery, faculty of medical sciences, lebanese university, beirut (lebanon) michael peyromaure, md michael.peyromaure@aphp.fr nicolas barry delongchamps, md nicolas.barry-delongchamps@aphp.fr hugo bailly, md h.bailly.md@gmail.com igor duquesne, md igor.duquesne@aphp.fr department of urology, cochin hospital, assistance publique-hôpitaux de paris, paris descartes university, paris (france) stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13644 1 review ance. some studies suggest that one of the sexual performance problems can be linked to psychological factors (1) however, other studies indicate that vasectomy can have positive effects on patient’s sexual lives (4). because of these conflicting findings, the purpose of this article is to examine the sexual outcomes post-vasectomy using a systematic review of current studies. methods this study was designed and reported, adhering to the prisma guidelines. we took a proactive approach by prospectively registering our protocol with prospero (crd42025634993), ensuring transparency and adherence to established standards. search strategy and selection criteria were following the preferred reporting items for systematic reviews and meta-analyses (prisma) figure 1. for the literature search, we used electronic databases such as medline, pub med, and science direct. we also manually reviewed and searched references for any possible information from conferences. the systematic search used the following terms and combinations : “vasectomy”, “vasectomies”, “sexual outcome”, and “sexual quality”. inclusion criteria original research articles were included if they met the following criteria: a) male participants aged 20 and older who underwent vasectomy, b) studies that provided results on sexual function, including but not limited to erectile function, orgasm, sexual desire, satisfaction, and overall sexual quality, c) studies published in english in order to ensure comprehension of the methodologies and outcomes. exclusion criteria we exclude the articles if: a) studies exclusively focused on psychological aspects of vasectomy without assessing sexual function, b) articles were not published in english to avoid translation issues and interpretation errors. data extraction and risk of bias two independent reviewers performed data extraction (mh, rs). disagreements were resolved in a discussion among all investigators, and if necessary, gw analyzed and clarified them. after discussion, all the study data in introduction: vasectomy is one of the most effective ways of contraception. however, it still has various complications, including post-vasectomy sexual dysfunction. some studies suggest that one of the sexual performance problems can be linked to psychological factors. however, other studies indicate that vasectomy can have positive effects on patient’s sexual lives. because of these conflicting findings, the purpose of this article is to examine the sexual outcome post-vasectomy using a systematic review of current studies. methods: we performed the search using electronic databases medline, pub med, and science direct. we used “vasectomy”, “vasectomies”, and “sexual outcome”, and “sexual quality” in the text keywords. eleven studies, six case-control studies, and five cohorts met the inclusion criteria for this review. results: studies reported a significant improvement in iief scores, sexual desire, sexual satisfaction, and orgasm domain after vasectomy. however, a study found that low acceptance of vasectomy can lead to erectile dysfunction, and vasectomized men are slightly more likely to report problems in maintaining their erections. conclusions: this systematic review shows that, although rare, there are complications after vasectomy. these complications can be related to decreased sexual function for patients after vasectomy. as a urologist, it is essential to offer adequate counseling to patients before vasectomy. key words: vasectomy; sexual function; erectile function; sexual satisfaction; systematic review. submitted 18 january 2025; accepted 6 march 2025 introduction vasectomy is one of the most effective ways of contraception (1). vasectomy has been used in 5% of married couples and is more popular in countries such as new zealand, the united states, the netherlands, south korea, australia, china, and india (2). it is the most common operation performed by a urologist in the us, and its effectiveness is comparable to tubal ligation despite being less invasive (3). however, although rare, vasectomy still has various complications. a significant concern among men considering the procedure is the potential impact on sexual performsexual outcome of vasectomized patients: a systematic review marshal harvy wicaksono 1, ronald sugianto 2, gede wirya kusuma duarsa 1 1 department of urology, prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia; 2 department of urology, faculty of medicine, universitas airlangga, indonesia. doi: 10.4081/aiua.2025.13644 summary archivio italiano di urologia e andrologia 2025; 97(2):13644 m. harvy wicaksono, r. sugianto, g. wirya kusuma duarsa 2 the review were entered into an excel spreadsheet, including population characteristics, methodology, and the risk of bias assessment. each included study was assessed for risk of bias using the newcastle-ottawa scale (nos), a tool designed to evaluate the quality of non-randomized studies. if there are any discrepancies in bias assessments or justifications, they were resolved through discussions among the authors until a consensus was reached. results the prisma diagram for the entire studies searched is shown in figure 1. the initial search for the databases yielded 1406 articles of which 1201 articles were excluded because of duplication. after further analysis, 11 studies met our criteria and were included in this systematic review. the details of included studies characteristics are detailed in table 1. the studies included in our systematic review are 6 case-control and 5 cohort studies. the combined sample size from our 11 studies is 6,187 patients. four of the studies included used the international index of erectile function (iief-15) and the other seven studies used the combination of their own questionnaires or other tools like enriching & nurturing relationship issues, communications, & happiness (enrich) questionnaire and the index of sexual satisfaction (iss). the risk of bias assessment using the newcastle-ottawa scale (nos) results in 5 good-quality studies and 6 moderate-quality studies. the details of the included studies assessment are in table 2. for the selection aspect, 8 out of 11 articles have 3 stars and the other 3 have 2 stars. the comparability aspects are all 1 star across our 11 included articles and for the outcome aspect, 2 articles have 3 stars, 5 articles are 2 stars, and 4 articles receive 1 star. erectile sunction seven studies evaluate erectile function in vasectomized men using the iief-15 or similar measures. one study by engl et al. (2017) (5) found a significant improvement in the erectile function domain post-vasectomy, while 4 other studies by bertero et al. (2005),(6) al-ali, et al. figure 1. prisma flow diagram. archivio italiano di urologia e andrologia 2025; 97(2):13644 3 sexual outcome of vasectomized patients (2014) (4), arratia-maqueo et al. (2010) (7), and touil et al. (2024) (8) found no significant improvement in the erectile function post-vasectomy. in contrast, smith et al. (2009) (9) noted that vasectomized men were slightly more likely to experience problems maintaining an erection, and buchholz et al. (1994) (10) found an association between erectile function after vasectomy and low acceptance from the patients towards the procedure. orgasm quality the effect of vasectomy on orgasm quality was assessed in some of the included studies, with results showing a generally positive outcome. articles by arratia-maqueo et al. (2010) (7), engl et al. (2017) (5), and bertero et al. (2005) (6) found a positive effect on orgasm quality post-vasectomy, although only arratia-maqueo et al. (2010) (7) stated a significant improvement in orgasm quality. another study by santiso et al. (2010) (11) with 500 participants found that vasectomy had no negative impact on orgasm quality. sexual desire seven studies assessed sexual desire and reported either no change or improvements in sexual desire after vasectomy. studies by engl et al. (2017) (5) and bertero et al. (2005) (6) reported significant improvement in sexual desire for the participants table 1. study characteristics. study sample mean age mean child indicator relevant results bertero, et al. (2005) (6) 64 35 3 iief-15 67% improved iief scores after vasectomy sexual desire and sexual satisfaction domain show significant improvement engl, et al. (2017) (5) 90 not stated not stated iief-15 significant improvement in erectile function, orgasm, sexual desire, and sexual intercourse domain santiso, et al. (2010) (11) 500 36 3.9 sexual drive vasectomy has had a positive effect or no effect at all on sex life sexual satisfaction and marital relations in the majority of cases orgasm quality guo, et al. (2015) (1) 353 not stated not stated sexual frequency vasectomized men had an 81% higher odds of having intercourse at least once a week al-ali, et al. (2014) (4) 76 39 2.6 iief-15 no significant improvement in iief domains buchholz, et al. (1994) (10) 61 47.7 not stated reduced libido low acceptance for vasectomy might cause erectile dysfunction weaker erection decreased orgasm frequency decreased sexual activity smith, et al. (2009) (9) 3234 43.1 not stated lacked interest in having sex vasectomy was not associated with specific sexual problems unable to reach orgasm vasectomized men slightly more likely to report problems maintaining orgasm too quickly or too long erection problems maintaining erection vasectomized men are significantly more likely to be extremely satisfied extremely satisfied sexually, and relationship with their relationship overall jackson, et al. (1982) (13) 1508 not stated not stated improves physical and mental health improvement in physical, mental health, or both in 371 participants improves physical health only none regrets in having a vasectomy improve mental health only regrets hofmeyr, et al. (2011) (12) 64 33.7 sexual frequency vasectomy does not negatively influence the sexual satisfaction in men. sexual satisfaction (enrich) sexual frequency is maintained after vasectomy sexual satisfaction (iss) arratia-maqueo, et al. (2010) (7) 29 median: 38 3 iief-15 38% participant shows improvement in iief total scores significant improvement shows in orgasm domain touil, et al. (2024) (8) 208 not stated not stated libido participant libido remained unchanged at 79% and improved at 13%. sexual activity the harmony of the relationship with their partners improves quality of erection in 33% of participants ejaculate volume relationship table 2. risk of bias in the included study using newcastle ottawa scale (nos). study newcastle-ottawa scale total quality selection comparability outcome score of the study bertero, et al. (2005) (6) *** * *** 7 good engl. et al. (2017) (5) ** * *** 6 good santiso, et al. (2010) (11) *** * ** 6 good guo, et al. (2015) (1) *** * * 5 moderate al-ali, et al. (2014) (4) ** * ** 5 moderate buchholz, et al. (1994) (10) *** * ** 6 good smith, et al. (2009) (9) *** * * 5 moderate jackson, et al. (1982) (13) *** * * 5 moderate hofmeyr, et al. (2011) (12) *** * ** 6 good arratia-maqueo, et al. (2010) (7) ** * ** 5 moderate touil. et al. (2024) (8) *** * * 5 moderate archivio italiano di urologia e andrologia 2025; 97(2):13644 m. harvy wicaksono, r. sugianto, g. wirya kusuma duarsa 4 after vasectomy. studies by smith et al. (2009) (9), hofmeyr et al. (2011) (12), and al-ali et al. (2014) (4) found no significant negative impact on sexual desire post-vasectomy, and studies by santiso et al. (2010) (11) and touil et al. (2024) (8) found that most participants maintained their sexual desires post-vasectomy. sexual satisfaction results regarding sexual satisfaction were reported in 10 of the included studies, with most studies showing improvements or neutral outcomes post-vasectomy. bertero et al. (2005) (6), and arratia-maqueo et al. (2010) (7) reported an improvement in sexual satisfaction postvasectomy. related to sexual satisfaction, touil et al. (2024) (8) also report a 33% improvement in relationship harmony post-vasectomy, and smith et al. (2009) (9) found that post-vasectomized men are significantly more likely to be satisfied with their relationship overall. study by hofmeyr et al. (2011) (12), and santiso et al. (2010) (11) reported that vasectomy did not have a negative impact on sexual satisfaction, and most participants maintained their levels of sexual satisfaction. studies by al-ali et al. (2014) (4) and engl et al. (2017(5) found that there was no significant improvements in the sexual satisfaction domain of the iief questionnaire. other related results by guo et al. (2015) (1) found that vasectomized men had a higher chance of having sexual activity at least once a week. in contrast, buchholz et al. (1994) (10) suggested that low acceptance of vasectomy can result in a decrease in sexual satisfaction post-vasectomy. overall satisfaction all studies highlighted a high level of overall satisfaction among vasectomized men, with most reporting either no change or an improvement in their sexual relationship. studies by touil et al. (2024) (8), smith et al. (2009) (9), and jackson et al. (1982) (13) report that overall satisfaction post-vasectomy was improved with minimal regrets. other studies by bertero et al. (2005) (6), al-ali et al. (2014) (4), arratia-maqueo et al. (2010) (7), and engl et al. (2017) (5) found that overall score on the iief questionnaire was improved after vasectomy. in addition, studies by santiso et al. (2010) (11) and hofmeyr et al. (2011) (12) found that over half of their patients have a positive effect or no effects on overall satisfaction post-vasectomy. related to satisfaction, guo et al. (2015) (1) reported about the sexual frequency of men post-vasectomy who had an 81% chance of having intercourse at least once a week. however, buchholz et al. (1994) (10) concluded that the satisfaction of post-vasectomy patients is related to the psychosocial environment that can cause psychological disturbances and lead to reduced satisfaction. discussion vasectomy is one of the most effective contraceptive methods for men (1). it is the most common operation performed by urologists. vasectomy has many benefits to prevent unplanned childbirth. however, vasectomy is not the most commonly used contraception for men (3, 8). men are concerned that vasectomy might decrease their sexual life quality, including pain, erectile function, and others. complications that can happen after vasectomy ranges from chronic pain, recanalization, and post-vasectomy sexual dysfunction (8). according to our review, we found that, overall, vasectomy does not negatively impact the sexual outcomes of the patients. studies show an improvement in overall sexual satisfaction (8, 9). studies that use iief also show an improvement in the overall satisfaction domain for vasectomized patients (5, 6). other domains of iief-15, e.g. sexual desire, erectile function, and orgasm domain, also show improvement in various other studies (5, 7). a systematic review shows that the sexual frequency of vasectomized patients is higher than non-vasectomized patients and vasectomized patients had slightly more chance of having difficulty maintaining an erection (1, 12). however, there are some studies reports of minor difficulties in maintaining an erection (9). according to our review, we found that the sexual dysfunction post-vasectomy is related to low acceptance of vasectomy (10). therefore, we believe that proper counseling is essential for patients before vasectomy to improve understanding the procedure and its risks as well as the complications. the counseling should also ensure the patient understands that erectile dysfunction after vasectomy has been linked to psychosocial factors and vasectomy does not affect erection, ejaculation, and orgasm (14, 15). conclusions this systematic review shows that, although rare, there are complications after vasectomy. this complication can be related to decreased sexual function for patients after having vasectomy. as a urologist, it is essential to do counseling for patients before vasectomy. our study did not include meta-analysis of data retrieved. hopefully, studies in the future can better represent the picture of vasectomized patients in our country. declarations ethical statement: not applicable. availability of data and material: the data utilized and/or analyzed in this study are accessible from the corresponding author upon request. competing interests: the authors declare that they have no competing interests. funding sources: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors’ contributions: marshal harvy w.p (mhwp): methodology, data collection, data analysis, writing original draft. ronald sugianto (rs): methodology, data collection, writing review & editing, and critical revisions. gede wirya kusuma duarsa (gwk): conceptualization, supervision, methodology, validation, writing review & editing, and final approval of the manuscript. acknowledgments: all authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work. archivio italiano di urologia e andrologia 2025; 97(2):13644 5 sexual outcome of vasectomized patients references 1. guo dp, lamberts rw, eisenberg ml. relationship between vasectomy and sexual frequency. j sex med. 2015; 12:1905-10. 2. schwingl pj, guess ha. safety and effectiveness of vasectomy. fertil steril. 2000; 73:923-36. 3. rogers md, kolettis pn. vasectomy. urol clin north am. 2013; 40:559-68. 4. mohamad al-ali b, shamloul r, ramsauer j, et al. the effect of vasectomy on the sexual life of couples. j sex med. 2014; 11:2239-42. 5. engl t, hallmen s, beecken wd, et al. impact of vasectomy on the sexual satisfaction of couples: experience from a specialized clinic. cent european. j urol. 2017; 275-9. 6. bertero e, hallak j, gromatzky c, et al. assessment of sexual function in patients undergoing vasectomy using the international index of erectile function. int braz j urol. 2005; 31:452-8. 7. arratia-maqueo ja, cortés-gonzález jr, garza-cortés r, gómez-guerra ls. evaluation of male sexual satisfaction after vasectomy. actas urol esp. 2010; 34:870-3. 8. touil w, delaunay b, prudhomme t, et al. sexual and couple outcomes of vasectomy: results of a french questionnaire survey. french j urol. 2024; 34:102672. 9. smith a, lyons a, ferris j, et al. are sexual problems more common in men who have had a vasectomy? a population-based study of australian men. j sex med. 2010; 7:736-42. 10. buchholz np, weuste r, mattarelli g, et al. post-vasectomy erectile dysfunction. j psychosom res. 1994; 38:759-62. 11. santiso r, pineda ma, marroquín m, bertrand jt. vasectomy in guatemala: a follow-up study of five hundred acceptors. biodemography soc biol. 1981; 28:253-64. 12. hofmeyr dg, greeff ap. the influence of a vasectomy on the marital relationship and sexual satisfaction of the married man. j sex marital ther. 2002; 28:339-51. 13. jackson ln, avant p. vasectomy: a follow-up of two thousand men. j r coll gen pract. 1982; 32:172-3. 14. lowe g. optimizing outcomes in vasectomy: how to ensure sterility and prevent complications. transl androl urol. 2016; 5:176-80. 15. sandler md, best jc, samplaski mk, et al. snip, support, and shared stories: exploring reddit users’ experiences with vasectomy. cureus. 2024; 16:e71374. correspondence marshal harvy wicaksono pantjoro (corresponding author) marshalharvy@gmail.com department of urology, prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia wisata bukit mas 2 palais du louvre i1 number 5, lidah wetan, lakarsantri, surabaya, east java, 60213 gede wirya kusuma duarsa gwkduarsa@gmail.com department of urology, faculty of medicine, universitas airlangga, indonesia ronald sugianto rsugianto@student.unair.ac.id department of urology, prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4404 original paper no conflict of interest declared. complications, both impairing patients’ quality of life (1). ed is classically attributed to the injury of neurovascular bundles. the persistent penile hypoxia due to the loss of physiological erections may lead the cavernous fibrosis and, ultimately, a decline in erectile function (2). the use of vasoactive drugs may improve tissue oxygenation through increased penile blood flow, and prevent penile fibrosis (3, 4). therefore, early treatment with erectogenic drugs may play an important role in sexual rehabilitation after rp. several treatments have been proposed to manage postrp ed: intracavernous alprostadil injections (iai), phosphodiesterase-5 (pde-5) inhibitors and vacuum devices (4, 5). the iai has become increasingly common, especially after montorsi et al. (6) reported that early postoperative administration of alprostadil injections significantly increased the recovery rate of spontaneous erections after rp. the iai is a complex procedure. it involves the preparation of the syringe, identification of the injection site and correct administration, which requires a minimum of dexterity. moreover, the need of a penile injection and the loss of spontaneity of the sexual act may lead to patient anxiety. most studies reported high discontinuation rates of patients treated with iai, and the lack of explanation and lack of follow-up were important causes of treatment failure and non-compliance (7). so, it is crucial to clearly inform patients and partners about the objectives of the treatment and expectations of sexual recovery. due to the time required to explain the iai procedure to the patient during medical consultations and sexual counselling during the follow-up, the management of post-rp ed is challenging. therefore, some studies reported an erectile rehabilitation program provided by a urology specialist nurse with good results (8). in this study we evaluated a sexual rehabilitation program (srp) for patients with ed after rp, assessing the rate of compliance and reasons for dropout. materials and methods the present study is a single-center, retrospective study. the srp with iai was offered to all patients who underwent non-nerve sparing radical prostatectomy from 1 january 2010 to 31 december 2019. a preoperative evalintroduction and objectives: erectile dysfunction (ed) is a common complication after radical prostatectomy that affects quality of life. there are several therapeutic options, including intracavernous alprostadil injections (iai). however, no specific recommendations have been made on the optimal rehabilitation strategy. in this study we evaluated a sexual rehabilitation program (srp) with iai for patients with ed after radical prostatectomy, assessing the rate of compliance and reasons for dropout. methods: the sexual rehabilitation program (srp) was offered to all patients who underwent radical prostatectomy from 1 january 2010 to 31 december 2019. the first consultations were performed by a urology specialist nurse, explaining the iai procedure and possible complications. the program was considered successful when the patients achieved autonomy in the drug preparation with a good injection technique. a medical consultation was performed at 6 months evaluating the iai usage and adverse events. in case of dropout, a questionnaire about reasons for dropout was performed. the primary endpoint was the rate of compliance and dropout of the program. secondary endpoints were the reasons for dropout and adverse events. results: 340 patients underwent radical prostatectomy at our institution, and 123 patients accepted to participate in the rehabilitation program. a total of 96 patients (78%) successfully completed the srp, and at 6 months 60 (62.5%) still used iai. concerning the reasons for dropping out, the most frequent were the need of injectable therapy and pain. regarding complications, 17 patients (13.8%) reported pain related to the injection and 1 patient (0.8%) had a priapism, managed with conservative treatment. conclusions: management of post-radical prostatectomy ed by a nursing program achieved good rates of patients’ self-injection accomplishment and treatment compliance. close monitoring for dose adjustment and management of post-injection penile pain is required during the follow-up. key words: radical prostatectomy; erectile dysfunction; sexual rehabilitation; alprostadil. submitted 11 august 2021; accepted 14 october 2021 introdution radical prostatectomy (rp) is a therapeutic option for patients with localized prostate cancer. erectile dysfunction (ed) and urinary incontinence are the most common sexual rehabilitation with intracavernous alprostadil after radical prostatectomy: outcomes from a nursing program alexandre gromicho 1, pedro costa 2, débora araújo 2, daniela pereira 2, luís ferraz 2 1 urology department, centro hospitalar do funchal, portugal; 2 urology department, centro hospitalar vila nova de gaia/espinho epe, vila nova de gaia, portugal. doi: 10.4081/aiua.2021.4.404 summary 405archivio italiano di urologia e andrologia 2021; 93, 4 alprostadil after radical prostatectomy uation included a detailed medical history and sexual habits, assessing the quality of erection, libido, orgasm and ejaculation. the therapy was offered at the first post-operative consultation and initiated once the patient was interested in sexual rehabilitation, usually after proper continence control. a consultation was performed by a urology specialist nurse and the sexual partner was asked to participate as well. the first consultation evaluated the changes in the sexual habits and expectations with the treatment. the process of preparation and administration iai, as well as the possible complications associated, were explained. then the patients were seen once a week and information was collected about the previous administration (efficacy, side effects), the injection technique and the correct dose adjustment if necessary. the quality of erections was evaluated through the erection hardness score (ehs). the program was considered successful when the patients achieved autonomy in the drug preparation with a good injection technique. in case of dropout, a questionnaire about reasons for dropout was performed. a medical consultation was performed at 6 months after completing the program, evaluating the iai usage and adverse events. reasons for abandoning the iai at 6 months were also reported. the primary endpoint was the rate of compliance and dropout of the program. secondary endpoints were the reasons for dropout and adverse events. data were analysed using spss. results a total of 340 patients underwent radical prostatectomy at our institution, and 123 patients (36.2%) accepted to participate in the rehabilitation program. population demographic and clinical features are show in table 1. the median (iqr) age of the cohort was 63 (60-67) years old. the median time (iqr) between the surgery and the rehabilitation program was 6.8 (3.6-11.2) months. all patients reported being sexually active before the surgery, with 118 (95.6%) without preoperative erectile dysfunction symptoms. 36.6% of the patients were initially treated with pde-5 inhibitors, without success. the first consultations were performed with the patient and sexual partner in 72 cases (58.5%). the alprostadil dose distribution is represented on table 2 and 111 patients (90.2%) achieved erection hard enough for sexual intercourse after iai (ehs 3 or 4). in general, a minimum of 3 (± 0.7) nursing consultations were performed before patients successfully completed the program. a total of 27 patients (22%) dropped out over the first consultations and did not complete the rehabilitation program. of the 96 patients who completed the initial rehabilitation program, 60 (62.5%) still used intracavernous alprostadil at 6 months. the reasons for dropping out are described on table 3. in most cases was the need of injectable therapy. the second most frequent reason was injection pain, despite adjusting to the lowest effective dose. regarding complications, 17 patients (13.8%) reported pain related to the injection and 1 patient (0.8%) had a priapism, managed with conservative treatment. there was no significant difference in drop-out rates with age, diabetes mellitus, previous radiotherapy, previous pde-5 inhibitors, time between surgery-rehabilitation program and urinary incontinence (p > 0.05). discussion radical prostatectomy is one of the most frequent therapeutic options used for the management of patients diagnosed with localized prostate cancer. however, this treatment has a negative effect on patients’ quality of life, particularly affecting sexual life. in fact, some studies concluded that sexual dysfunction was an independent determinant of worse general health-related quality of life after primary treatment for prostate cancer (9). most of the studies published in the literature evaluates the effectiveness of drugs used in erectile function recovery, but few data are available concerning the protocols and drug compliance. intracavernous alprostadil remains the main treatment for erectile rehabilitation after radical prostatectomy, improving sexual function also in patients treated with non-nerve sparing technique (10). the beginning of iai and patient follow-up can become problematic due to the overload of medical consultations. for these reasons table 1. population characteristics. characteristics (n = 123) statistic age (years), median (iqr) 63 (60-67) pre-operative erectile dysfunction symptoms, n (%) 4 diabetes mellitus, n (%) 13 previous radiotherapy, n (%) 14.6 previous pde-5 inhibitors, n (%) 36.6 time between surgery and rehabilitation program (months), median (iqr) 6.8 (3.6-11.2) urinary incontinence, n (%) • no 60.2 • mild 32.5 • moderate to severe 6.5 pde-5: phosphodiesterase-5. table 2. alprostadil dose distribution. alprostadil lowest effective dose (ug) n (%) 5 10 (8.4) 10 60 (50.4) 15 2 (1.7) 20 47 (39.5) table 3. reason for dropping out the rehabilitation program. n (%) injectable therapy 22 (37.3) injection pain 12 (20.3) loss of follow up 8 (13.6) lack of sexual interest 7 (11.9) urinary incontinence 3 (5.1) lack of treatment efficacy 2 (3.4) archivio italiano di urologia e andrologia 2021; 93, 4 a. gromicho, p. costa, d. araújo, d. pereira, l. ferraz 406 our department created a program aimed at sexual rehabilitation, provided with the help of urology specialist nurses. in our study, 78% (n = 96) of the patients who agreed to participate successfully completed srp. they were able to successfully self-administer the iai and achieved the ability to adjust the correct doses. in 58.5% the nursing consultations were performed with the couple, highlighting the role of spouses/partner in the sexual rehabilitation. the revaluation at 6 months after the program concluded that 60 patients (62.5%) still used iai. regarding the reasons for dropping out, the most frequent were the need of injectable therapy (patients with fear of needles and patients who refuse to undergo injectable therapy) and pain. interestingly, the cost of the drug was never stated as a reason for dropping out. regarding patients who abandoned therapy at 6 months, it should be noted that 4 patients (12.9%) were able to achieve erection without iai. therefore, despite being a potentially effective treatment, the fact that it is an injectable treatment was a major limitation for these patients. pain was reported in only 17 patients (13.8%), especially in the first consultations, but was a major reason for dropping out in only 9 patients. the cause of post-iai pain is not well known and its management is challenging. patients were recommended to take analgesics 1 hour before the injection and reduce to the lowest effective dose, but in some cases that was not satisfactory. other strategies reported in the literature were combining the iai with a numbing product or the use a mixture of vasoactive drugs such as trimix (combination of alprostadil, phentolamine and papaverine) (11, 12). the combination allows lower doses of each drug, reducing the adverse events. however, none of these combination drugs have a clinical authorization in the treatment of erectile dysfunction and are not available in portugal. the dropout rate at the end of the program and at 6 months were 22% and 37.5%, respectively. for standard rehabilitation with intracavernous alprostadil, drop-out rates of 41-68% have been reported, most occurring during the first three months (1). so, our results demonstrate lower discontinuation rates than those reported for standard rehabilitation therapy, but comparable with other studies of iai in which nursing and sexual counselling was performed and maintained (8, 13, 14). also post-iai pain rate was lower than in other studies. taken together, these results may indicate that a srp was a key factor for increasing the motivation of the couples and treatment compliance, as well for minimizing the adverse events. although not being a primary outcome, the efficacy of iai was also evaluated. after the first consultation, 90% of the patients achieved erections hard enough for sexual intercourse. our results are comparable with other studies, which reported success rates ranged from 70% to 95% (3, 9, 13). similarly, the percentage of patients without preoperative erectile dysfunction was quite high for a population with a median age of 63 years old. a possible explanation is the fact that younger patients with no preoperative symptoms of erectile dysfunction were the most motivated to initiate sexual rehabilitation. also, the erectile dysfunction symptoms were not evaluated through validated questionnaires and the final results may not be accurate. regarding the time between the surgery and the rehabilitation program, it was approximately 7 months. the reasons for the delay were not reported, but it could be due to the necessity of adjuvant radiotherapy, hormonal therapy or transient urinary incontinence, discouraging some patients from undertaking srp. on the other hand, patient’s anxiety concerning the oncologic outcomes is usual in the first medical consultations, having a negative impact on the motivation to initiate srp. limitations of the study were described previously throughout the discussion, such as the absence of validated questionnaires evaluating the preoperative erectile dysfunction symptoms and injection-related pain, and the delay to initiate the erp. another limitation is related to the retrospective single-center, single-arm and nonrandomized design. more robust evidence is needed from multicenter, randomized and controlled trials to establish a standard sexual rehabilitation program to these patients in the future. conclusions management of post-radical prostatectomy ed by a nursing program achieved good rates of patients’ self-injection accomplishment and treatment compliance, which are the key components of sexual rehabilitation. close monitoring for dose adjustment and management of postinjection penile pain is required during the follow-up. references 1. salonia a, bettocchi c, carvalho j, et al. eau guidelines on sexual and reproductive health. eau guidel. 2021. 2. mulhall jp, slovick r, hotaling j, et al. erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. j urol. 2002; 167:1371-5. 3. raina r, agarwal a, zippe cd. management of erectile dysfunction after radical prostatectomy. urology. 2005; 66:923-9. 4. montorsi f, briganti a, salonia a, et al. current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy. eur urol. 2004; 45:123-33. 5. kim jh, lee sw. current status of penile rehabilitation after radical prostatectomy. korean j urol. 2015; 56:99-108. 6. montorsi f, guazzoni g, strambi lf, et al. recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. j urol. 1997; 158:1408-10 7. titta m, tavolini im, dal moro f, et al. sexual counseling improved erectile rehabilitation after non-nerve-sparing radical retropubic prostatectomy or cystectomy results of a randomized prospective study. j sex med. 2006; 3:267-73. 8. yiou r, khodari m, lingombet o, et al. évaluation d’un programme infirmier d’education thérapeutique pour les injections intra-caverneuses d’alprostadil après prostatectomie radicale. prog urol. 2011; 21:283-7. 9. gontero p, fontana f, zitella a, et al. a prospective evaluation of efficacy and compliance with a multistep treatment approach for 407archivio italiano di urologia e andrologia 2021; 93, 4 alprostadil after radical prostatectomy erectile dysfunction in patients after non-nerve sparing radical prostatectomy. bju int. 2005; 95:359-65. 10. moussa m, papatsoris a, abou chakra m, et al. erectile dysfunction post radical cystectomy. the role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: a randomized, clinical trial. arch ital urol androl. 2021; 93:58-64. 11. schramek p, plas eg, hübner wa, pflüger h. intracavernous injection of prostaglandin e1 plus procaine in the treatment of erectile dysfunction. j urol. 1994; 152:1108-10. 12. mulhall j, land s, parker m,, et al. the use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function. j sex med. 2005; 2:532-40. 13. polito m, d’anzeo g, conti a, muzzonigro g. erectile rehabilitation with intracavernous alprostadil after radical prostatectomy: refusal and dropout rates. bju int. 2012; 110:1-4. 14. yiou r, cunin p, de la taille a, et al. sexual rehabilitation and penile pain associated with intracavernous alprostadil after radical prostatectomy. j sex med. 2011; 8:575-82. correspondence alexandre gromicho, md (corresponding author) alexandrepgromicho@gmail.com urology department, centro hospitalar do funchal, portugal adress: av. luís de camões 57, 9000-177, funchal (portugal) pedro costa, md pedro_r_costa@hotmail.com débora araújo, md deboracerqueiraaraujo@gmail.com daniela pereira, md filipa.pereira27@gmail.com luís ferraz, md ferrasluis@gmail.com urology department, centro hospitalar vila nova de gaia/espinho epe, vila nova de gaia (portugal) cop+ed+fisse 2006 25archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. low-up after local treatment. in fact, psa is expected to be undetectable within 6 weeks after a successful rp. a rising serum psa level is considered to be a bcr (1). specifically, a bcr is defined by as a serum psa measurement ≥ 0.2 ng/ml, followed by a second confirmatory level (1). once a bcr has been diagnosed, it is important to determine whether the recurrence has developed at local or at distant sites in order to optimise salvage treatment. although psa alone does not differentiate local from distant disease, the pattern of its rise has been incorporated into clinical nomograms to predict whether recurrence is more likely to be local or systemic; patients with late bcr (> 24 months after local treatment) and prolonged psa doubling time (> 6 months) most likely have local recurrent disease (1). of the imaging modalities, multiparametric magnetic resonance imaging (mpmri) is the most accurate in the detection of local recurrence, being superior to choline positron emission tomography/computed tomography (pet/ct) and to transrectal ultrasonography (trus) (2-5). dynamic contrastenhanced (dce) is reported to be the most effective sequence in detecting recurrence while the role of diffusion weighted imaging (dwi) is still controversial (2-5). thus, the aim of the present study was to evaluate the accuracy of mpmri in detecting local recurrence by evaluating both the accuracy of each sequence and the combination of dce-dwi, considering clinical and histopathological data as the reference standard. the value of the signal intensity/time (i/t) curves was also assessed. materials and methods study population this study was an observational, retrospective, single centre study; it was approved by the authors’ local institution review board and conducted in accordance with institutional guidelines, including the declaration of helsinki. all patients were notified of the investigational nature of this study and gave their written informed consent (approval code: stud-of, prot. n. 323). patients with clinical suspicion of local recurrence after objective: the aim of the study was to evaluate the accuracy of multiparametric magnetic resonance imaging (mpmri) in the detection of local recurrence of prostate cancer (pca) with the evaluation of the added value of signal intensity/time (i/t) curves. materials and methods: a retrospective analysis of 22 patients undergoing mpmri from 2015 to 2020 was carried out, with the following inclusion criteria: performing transrectal ultrasound guided biopsy within 3 months in the case of positive or doubtful findings and undergoing biopsy and/or clinical follow-up for 24 months in the case of negative results. the images were reviewed, and the lesions were catalogued according to morphological, diffusion-weighted imaging (dwi) and dynamic contrast-enhanced (dce) features. results: the presence of local recurrence was detected in 11/22 patients (50%). greater diameter, hyperintensity on dwi, positive contrast enhancement and type 2/3 signal i/t curves were more frequently observed in patients with local recurrence (all p < 0.05). of all the sequences, dce was the most accurate; however, the combination of dce and dwi showed the best results, with a sensitivity of 100%, a specificity of 82%, a negative predictive value of 100% and a positive predictive value of 85%. conclusions: the utility of mri in the detection of local recurrence is tied to the multiparametric approach, with all sequences providing useful information. a combination of dce and dwi is particularly effective. moreover, specificity could be additionally improved using analysis of the signal i/t curves. key words: multiparametric magnetic resonance imaging; prostate cancer; radical prostatectomy; prostate cancer recurrence. submitted 14 july 2021; accepted 25 august 2021 introduction radical prostatectomy (rp) is a common treatment option in patients with organ confined prostate cancer (pca). however, approximately 10-53% of patients undergoing primary intended curative therapy will develop a biochemical recurrence (bcr), depending on their preoperative risk and stage of cancer (1). measurement of the prostate specific antigen (psa) is a cornerstone of the folthe role of mri in the detection of local recurrence: added value of multiparametric approach and signal intensity/time curve analysis caterina gaudiano 1, federica ciccarese 1, lorenzo bianchi 2, beniamino corcioni 1, antonio de cinque 1, francesca giunchi 3, riccardo schiavina 2, michelangelo fiorentino 4, eugenio brunocilla 2, rita golfieri 1 1 department of radiology, irccs azienda ospedaliero-universitaria di bologna, bologna, italy; 2 department of urology, irccs azienda ospedaliero-universitaria di bologna, bologna, italy; 3 department of pathology, irccs azienda ospedaliero-universitaria di bologna, bologna, italy; 4 department of specialty, diagnostic and experimental medicine, university of bologna, bologna, italy. doi: 10.4081/aiua.2022.1.25 summary archivio italiano di urologia e andrologia 2022; 94, 1 c. gaudiano, f. ciccarese, l. bianchi, et al. 26 rp who had undergone mpmri at the authors’ institute from february 2015 to january 2020 and had performed trus guided biopsy within 3 months in the case of positive or doubtful findings or had undergone biopsy and/or clinical follow-up (pet/ct with 11c-choline and psa) in the case of negative results for up to 24 months, were enrolled. patients with uni or bilateral hip prostheses causing artefacts in image interpretation were excluded from the analysis. overall, a total of 48 patients were enrolled, and 22 were included in the final analysis as showed in figure 1. for each patient, psa levels as well as digital rectal examination (dre) and trus data were recorded. mpmri protocol study the mpmri examinations were performed using a 1.5t whole-body scanner (signa hdxt; ge healthcare, milwaukee, wi, usa) and a standard 8-channel pelvic phased-array surface coil combined with a disposable endorectal coil. the morphological study was carried out using high-resolution fast relaxation fast spin echo t2-weighted (t2w) sequences in the sagittal, axial and coronal planes, including the prostate bed. the dwi and dce acquisition were also carried out in the axial plane, with the same parameters as the t2w axial sequence in order to obtain a match. the dwi was carried out using a single-shot echo-planar imaging sequence with high b-value acquisition (2000 s/mm2) and another sequence with two b-values (50 and 1000 s/mm2), useful for the calculation of the apparent diffusion coefficient (adc) map. the dce acquisition was obtained using three-dimensional (3d) t1-weighted spoiled gradient recalled sequences during the intravenous injection of a gadolinium-based contrast agent at a flow rate of 3 ml/sec followed by 15 ml of saline solution. the 3d data sets were acquired with 10 second temporal resolution; the acquisitions before contrast agent administration can be used to detect foci of haemorrhage. the dwi and dce images were processed on an independent workstation with dedicated software (functool, 4.5.5, ge healthcare, milwaukee, wi, usa). for the dwi, the high b-value images and the adc map were evaluated to identify suspected areas. semiquantitative perfusion was carried out using analysis of the dce datasets and signal i/t curve generation. image analysis all the mpmri images were reviewed by two genitourinary radiologists with 10 and 5 years of experience, respectively, in prostate mri, with a consensus reading blinded to the patients’ clinical information. all the lesions were catalogued according to morphological, dwi and dce features. at morphological examination, the presence of soft tissue in the prostate bed slightly hyperintense to muscle was considered suspicious for local recurrence. location and maximum diameter were also recorded. at dwi, a suspicious lesion was defined by hyperintensity at high b-value acquisition. for dce evaluation, contrast enhancement was evaluated according to a negative/positive binary criterion. a lesion was considered suspicious if characterised by positive contrast enhancement. the signal i/t curve was assessed and classified as type 1 (progressive), type 2 (plateau) or type 3 (wash-in and wash-out). at the overall evaluation, mpmri was considered suspicious if all three sequences were in agreement regarding recurrence, negative if all three were in agreement regarding the absence of recurrence and doubtful if agreement existed for 2/3 sequences. cognitive fusion biopsy all patients with suspicious or doubtful lesions at mpmri underwent a trus-guided biopsy by two experienced radiologists, after antibiotic prophylaxis and a cleansing rectal enema, using a non-disposable biopsy gun (medgun, medax, modena, italy) with a disposable 18-gauge needle and an ultrasound platform with an end-fire trus probe (canon-toshiba aplio 500™, japan). all the biopsies were performed within three months from the mpmri. the biopsy procedures were conducted in an outpatient setting, with the patient in a left flank lateral position, after a peri-prostatic nerve blockade with local anaesthesia (lidocaine 2%), using a cognitive approach. the mean number of samples was 3 (from 2 to 6), depending on lesion size and recognisability; in the case of negative results on mpmri, the biopsies were carried out around the vesicourethral anastomosis. each biopsy sample was placed inside a single container with a specific progressive number corresponding to a specific description relating to the site. after the procedure, the patients were observed for 1 hour before discharge. pathological analysis the biopsy samples were analysed by the same dedicated genitourinary pathologist who primarily highlighted the presence or absence of a neoplastic pathology on the samples. each neoplastic lesion defined as a "positive result" was graded according to the grade group system (ggs) from 1 to 5 and to the international society of urological figure 1. flowchart for patient selection. 27archivio italiano di urologia e andrologia 2022; 94, 1 mpmri for prostate cancer recurrence pathology (isup) 2014 classification (6). for each nonneoplastic lesion defined as a “negative result”, the type of benign finding was reported, including fibrotic tissue or residual benign prostate tissue. statistical analysis the continuous variables were described in terms of medians, with interquartile range (iqr), and were compared using the mann-whitney test. the categorical variables were described as absolute and relative frequencies and were compared using the fisher’s exact test. sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) were calculated for each sequence (t2w, dwi, dce). receiver operating characteristic (roc) analysis and area under curve (auc) were used to assess diagnostic accuracy, using the histopathological and clinical data as the reference standard. the data were collected and digitised using microsoft excel 2016 software; all analyses were carried out using spss ibm statistics® v. 22.0 (ibm corp., armonk, ny, usa). a p value of < 0.05 was considered statistically significant. results the presence of local recurrence was histologically detected in 11/22 patients (50%) while, in the other 11/22 (50%), no local recurrence was assessed by means of biopsy in 7 patients and by means of clinical follow-up and pet/ct in 4 patients. the demographics and clinical features of the patients are described in table 1. patients with evidence of local recurrence at histopathologic analysis had significantly higher psa levels as compare with patients with no evidence of local recurrence (p = 0.002). table 2 shows the histopathological findings and clinical outcome in the two groups of patients. in patients with a diagnosis of local recurrence, mpmri was suspicious in 8/11 (73%) and doubtful in 3/11 (27%) while, in the patients with no evidence of local recurrence, it was suspicious in 3/11 (27%), doubtful in 1/11 (9%) and negative in 7/11 (64%) (figures 2, 3). the mpmri features of all patients are described in table 3. regarding the location, local recurrence was found around the vesicourethral anastomosis in 8/11 (73%) and within the retained seminal vesicles in the other 3/11 (27%) patients. on t2w, there were no statistically significant differences related to morphology or signal intensity while local recurrences were found to present a greater maximum diameter as compared to the benign tissue (p < 0.001). on dwi, hyperintense lesions were more frequently consistent with local recurrence (p = 0.03). on dce, positive contrast enhancement was most frequently detected in patients with local recurrence (p = 0.008) as were types 2 table 1. demographics and clinical characteristics of the overall population and of the two groups of patients stratified according to the pathological or clinical evidence of local recurrence. total positive biopsy negative biopsy/ p clinical follow-up patients, n (%) 22 (100) 11 (50) 11 (50) age median (iqr) 69 (64-72) 69 (64.5-72) 69 (63-72.5) 0.29 psa median (iqr) 1.16 (0.35-2.32) 1.76 (0.67-2.44) 0.9 (0.32-1.62) 0.002 trus, n (%) 0.73 positive 9 (41) 6 (54) 3 (27) negative 13 (59) 5 (46) 8 (73) dre, n (%) 0.91 positive 9 (41) 5 (46) 4 (36) negative 13 (59) 6 (54) 7 (64) n: number; iqr: interquartile range; psa: prostate specific antigen; trus: transrectal ultrasound; dre: digital rectal examination. table 2. histopathological data and clinical outcome of the two groups of patients stratified according to the pathological or clinical evidence of local recurrence. figure 2. suspected local recurrence at mpmri in a 75-year-old man with psa = 0.91. axial t2-weighted sequence (a) shows the presence of a hyperintense nodule in the prostate bed behind the vesicourethral anastomosis (arrow), characterised by hyperintensity at diffusion weighted imaging (arrow in b) and hypervascularity at dynamic contrast enhanced evaluation (green circle in c). the signal intensity/time curve was classified as type 2 (green line in d). biopsy sampling documented prostate cancer gleason score 3+4 (isup 2). cfa = common femoral artery. total positive biopsy negative biopsy/clinical follow-up 22 (100) 11 (50) 11 (50) biopsy results, n (%) 18 (82) 11 (100) 7 (64) isup 1 2 (18) benign prostate tissue 2 (28) isup 2 5 (46) fibrotic tissue 5 (72) isup 3 0 (0) isup 4 4 (36) isup 5 0 (0) 11c-choline pet/ct 11 (50) local uptake 2 *(18) follow-up no local uptake 8 (73) other side uptake 6 (54) * corresponding to benign prostate tissue. n: number; isup: international society of urologic pathology; pet/ct: positron emission tomography/computed tomography. archivio italiano di urologia e andrologia 2022; 94, 1 c. gaudiano, f. ciccarese, l. bianchi, et al. 28 and 3 at the signal i/t curve while a type 1 curve was most frequent in benign tissue (p = 0.03). for each sequence, the values of sensitivity, specificity, npv and ppv obtained using roc analysis were as follows: 73%, 64%, 70% and 67% for the t2w; 82%, 73%, 80% and 75% for dwi; 91%, 73%, 87% and 71% for dce, and 100%, 82%, 100% and 85% for the combination dwi+dce, respectively. figure 4 shows the roc curve analysis. discussion prostate cancer is primarily managed by four standard methods, i.e. rp, radiation therapy, androgen deprivation therapy and active surveillance, although new focal therapy methods have rapidly been evolving (1). treatment choice is based on tumour stage, histology and grade, and is also influenced by patient clinical condition or preference. of these, rp has been performed for more than a century and remains the most common treatment choice. the procedure involves removing the entire prostate with its capsule intact and the seminal vesicles, followed by carrying out a vesicourethral anastomosis. surgical techniques have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques, with nerve-sparing intent whenever possible (7); the role of pelvic lymph-node dissection (plnd) is still controversial and is mainly based on a clinical nomogram. however, the majority of authors have agreed that plnd is figure 3. doubtful findings at mpmri in a 73-year-old man with psa = 0.33. axial t2-weighted sequence shows the presence of a slightly hyperintense nodule in the prostate bed, adjacent to the vesicourethral anastomosis (arrow in a), characterised by slight hyperintensity at diffusion weighted imaging (arrow in b) and negative contrastenhancement with a type 1 signal intensity/time curve (green line in c). biopsy sampling documented fibrotic tissue. figure 4. receiver operating characteristic (roc) curves. a) comparison between t2 weighted (t2), diffusion weighted imaging (dwi) and dynamic contrast enhanced (dce); the area under the curve (auc) was 0.682 for t2; 0.773 for dwi; 0.773 for dce. b) combined dwi+dce increased the auc to 0.909. table 3. morphological and functional characteristics of all lesions identified on mpmri in the two groups of patients stratified according to the pathological evidence of local recurrence. total positive biopsy negative biopsy/ p clinical follow-up n (%) 22 (100) 11 (50) 11 (50) t2w maximum diameter (mm) 10.5 13 8 < 0.001 (median; iqr) 7-14 9.5-18 6-11.5 morphology, n (%) 0.6 nodule 12 (55) 5 (45) 7 (64) amorphous tissue 10 (45) 6 (55) 4 (36) signal intensity, n (%) 0.2 hypointense 10 (45) 3 (27) 7 (64) hyperintense 12 (55) 8 (73) 4 (36) dwi signal intensity, n (%) 0.03 hypointense 10 (45) 2 (18) 8 (73) hyperintense 12 (55) 9 (82) 3 (27) dce contrast enhancement, n (%) 0.008 negative 9 (41) 1 (9) 8 (73) positive 13 (59) 10 (91) 3 (27) signal i/t curve, n (%) 0.03 type 1 9 (41) 1 (9) 8 (73) type 2 10 (45) 7 (64) 3 (27) type 3 3 (14) 3 (27) 0 (0) n: number; t2w: t2-weighted sequence; dwi: diffusion weighted imaging; dce: dynamic contrast-enhanced; i/t: intensity/time. 29archivio italiano di urologia e andrologia 2022; 94, 1 mpmri for prostate cancer recurrence the most accurate staging procedure. moreover, extensive plnd could also have a therapeutic effect due to removal of micrometastasis, thus reducing the risk of bcr (7). several factors could increase the risk of recurrence, such as seminal vesicle invasion, positive surgical margins, extra-prostatic extension, perineural and lymphovascular invasion, tumour volume, isup score > 2 and nodal metastasis (8). however, recurrences in the early setting are extremely difficult to detect with conventional imaging modalities due to low tumour volume. the mean psa values at the time of imaging have often varied in the literature from 0.2 to 10 or even higher, which is actually far above the level at which the clinician currently wants to know whether the patient suffers from local or distant recurrence (8). transrectal ultrasonography can be used in patients with suspected local recurrence, but the reported detection rates at psa levels < 0.5 ng/ml vary notably from 28.1 to 73.0%; moreover, specificity seems to be lower than dre for possible false positives due to postoperative fibrosis (1). although several efforts have been made to improve the accuracy of trus, such as the addition of colour doppler and contrast sonography (9), it is not routinely recommended in the setting of local recurrence (1). currently, mpmri is most frequently used to assess local recurrence and is combined with whole-body choline pet/ct to find regional or distant recurrence (10); in fact, the role of choline pet/ct in the detection of local recurrence is limited because a mild focal uptake of choline in the prostate bed and vesicourethral junction is difficult to differentiate from radioactive urine accumulation (10). moreover, detection rates are only 5-24% when the psa level is < 1 ng/ml but rises to 67-100% when the psa level is > 5 ng/ml, i.e. when metastatic disease is suspected (1). in this setting, hormone treatment withdrawal may also not be necessary (1). great interest has recently developed in new prostate-specific tracers, such as prostate specific membrane antigen (psma) which seems substantially more sensitive than choline pet/ct, especially for psa levels < 1 ng/ml, having a detection rate of 34.4% with psa level < 0.5 ng/ml (11), so that the use of psmapet/ct was introduced by the european association of urology guidelines. however, the majority of studies are limited by their retrospective design, and whether this approach is really cost-effective remains unknown (1). thus, mpmri, by means of the combination of high resolution morphological t2w images and functional imaging, seems to be particularly accurate in evaluating local recurrence. at mpmri, knowledge of the normal post-surgical anatomy is essential for avoiding a misdiagnosis. normal findings show that the bladder neck is anastomosed to the extraprostatic distal urethra which has a conical shape and falls far more caudally than normal on the sagittal plane; the tissue around the vesicourethral anastomosis is low in signal on t2w, reflecting postoperative scarring and fibrosis. occasionally, the anastomosis may demonstrate an intermediate t2w signal which mimics recurrence, particularly if there was extensive haemorrhage at the time of surgery. extensive fat stranding is often encountered surrounding the bladder base. potential pitfalls could be represented by retained seminal vesicles, residual prostatic tissue or postoperative fibrosis (12). in the present study, local recurrences were more frequently characterised by a greater diameter, hyperintensity on dwi and positive contrast-enhancement. of all the sequences, t2w was the least accurate while dce was the most reliable. these results are in line with what has previously been reported. casciani et al. found that the addition of dce to t2w increased sensitivity from 48 to 88% and specificity from 52 to 100% (13); similar results have also been reported by others (5, 14, 15). moreover, dce was found to increase interobserver agreement and to facilitate the detection of local recurrence, even by relatively inexperienced readers (15). sciarra et al. demonstrated that the combination of spectroscopic imaging and dce could also increase the detection rate (sensitivity of 86% and specificity of 100%); however, spectroscopic imaging is a more complex technique and requires additional expertise and longer acquisition time; therefore, it is less commonly used in clinical practice (16). the role of dwi is still more controversial as it could be affected by artefacts caused by surgical clips. panebianco et al. found that the combination of t2w+dwi could produce a detection rate comparable to t2w+dce (93% sensitivity, 89% specificity, 88% accuracy) (5); however, other studies have reported lower values, with a detection rate of 25-69% depending on tumour size (14) and a sensitivity of 46-49% (16). our results showed a reduced sensitivity for dwi as compared to dce sequences (82% vs. 91%, respectively), probably due to artefacts and tumour size affecting the detectability of recurrent lesions. therefore, while the general trend in prostate mri is to develop a “less is better strategy”, improving the application of biparametric mri to reduce execution time and improve patient tolerability and safety, this could not be applied in the setting of local recurrence for the wellestablished additional value of dce (17). furthermore, new mri protocols have been investigated, such as the combination of whole-body and mpmri in order to assess both local recurrence and metastatic disease (18). from the results of our study, the combination of dce+dwi showed better accuracy, having a sensitivity of 100%, a specificity of 82%, an npv of 100% and a ppv of 85%. specificity can be additionally improved by the analysis of the signal i/t curve: in fact, while benign tissue most frequently has a type 1 curve, the recurrences generally showed type 2 and 3 curves. this was an interesting observation since the signal i/t curves obtained from the perfusion sequence were not effective in differentiating between benign and neoplastic tissue in the clinical setting of the diagnosis (19). even if t2w was the least reliable sequence, it provided important information regarding the postsurgical anatomy and was able to localise the site of recurrence. in this series, the most frequent site of recurrence was the vesicourethral anastomosis as previously reported (3, 10), followed by retained seminal vesicles while recurrences in the retrovesical region were not found, as was frequently observed by sella et al. (20). the present study had some limitations; first, our results archivio italiano di urologia e andrologia 2022; 94, 1 c. gaudiano, f. ciccarese, l. bianchi, et al. 30 were obtained at a single high-volume tertiary care centre with significant experience in mpmri, thus radiologist experience could have influenced the detection rate. second, it was a retrospective study with a small sample size. third, the histopathological results were considered to be the reference standard, even if a negative cognitive biopsy could not completely rule out a local recurrence; the anastomotic biopsy, in fact, suffers from low sensitivity such as 40-71% for psa level > 1 ng/ml and 14-45% for psa < 1 ng/ml (21). targeted biopsy, with trus fusion software-assisted or mri in-bore technique, could increase the detection rate of local recurrence, although the procedure may be more complex in this setting and its effectiveness still to be demonstrated. however, the majority of patients included in this population were treated before the fusion software was available in our centre, so each anastomotic biopsy was performed by cognitive technique. for the reasons described above, in patients with negative anastomotic biopsy it is very important to establish a correct follow-up. first of all, pathologic features (such as pgs, pt and margins and nodal status) should be considered to assess the risk of local recurrence and the kinetics value of psa (including psa doubling time and psa velocity) should be the most important parameters to manage the follow-up. for example, a salvage radiotherapy can be considered or further mpmri and targeted biopsy may be repeated at 6 months in case of persistent psa increase with low psa doubling time, while other examinations (i.e psma-pet/ct) should be considered in case of high psa doubling time due to the increased risk of nodal or systemic recurrence (11). however, in our population a negative clinical follow-up for up 2 years was considered to reduce this bias. conclusions some important conclusions can be reached. although mpmri is rarely used by urologists in the clinical setting of local recurrence (22), many evidences have actually shown its high diagnostic performance. we confirm that dce is the most accurate sequence in the detection of local recurrence; however, the combination of dwi+dce was found to be particularly reliable. moreover, specificity could be further improved by the analysis of the signal i/t curve. t2w imaging provided a morphological evaluation by identifying the site and the dimensions of the recurrences. thus, the utility of mri in the detection of local recurrences is tied to the multiparametric technique, with all sequences providing useful information. references 1. expert panel on urologic imaging: froemming at, verma s, eberhardt sc et al. acr appropriateness criteria® post-treatment follow-up prostate cancer. j am coll radiol. 2018; 15(5s):s132s149. 2. potretzke ta, froemming at, gupta rt. post-treatment prostate mri. abdom radiol. 2020; 45:2184-2197. 3. gaur s, turkbey b. prostate mr imaging for posttreatment evaluation and recurrence. radiol clin north am. 2018; 56:263-275. 4. patel p, mathew ms, trilisky i, oto a. multiparametric mr imaging of the prostate after treatment of prostate cancer. radiographics. 2018; 38:437-449. 5. panebianco v, barchetti f, sciarra a, et al. prostate cancer recurrence after radical prostatectomy: the role of 3-t diffusion imaging in multi-parametric magnetic resonance imaging. eur radiol. 2013; 23:1745-1752. 6. epstein ji, egevad l, amin mb, et al; grading committee. the 2014 international society of urological pathology (isup) consensus conference on gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. am j surg pathol. 2016; 40:244-252. 7. bianchi l, gandaglia g, fossati n, et al. pelvic lymph node dissection in prostate cancer: indications, extent and tailored approaches. urologia. 2017; 84:9-19. 8. bianchi l, schiavina r, borghesi m, et al. patterns of positive surgical margins after open radical prostatectomy and their association with clinical recurrence. minerva urol nefrol. 2020; 72:464-473. 9. drudi fm, giovagnorio f, carbone a, et al. transrectal colour doppler contrast sonography in the diagnosis of local recurrence after radical prostatectomy--comparison with mri. ultraschall med. 2006; 27:146-151. 10. de visschere pjl, standaert c, fütterer jj, et al. a systematic review on the role of imaging in early recurrent prostate cancer. eur urol oncol. 2019; 2:47-76. 11. ceci f, bianchi l, borghesi m, et al. prediction nomogram for 68ga-psma-11 pet/ct in different clinical settings of psa failure after radical treatment for prostate cancer. eur j nucl med mol imaging. 2020; 47:136-146. 12. allen sd, thompson a, sohaib sa. the normal post-surgical anatomy of the male pelvis following radical prostatectomy as assessed by magnetic resonance imaging. eur radiol. 2008; 18:12811291. 13. casciani e, polettini e, carmenini e, et al. endorectal and dynamic contrast-enhanced mri for detection of local recurrence after radical prostatectomy. ajr am j roentgenol. 2008; 190:11871192. 14. cirillo s, petracchini m, scotti l, et al. endorectal magnetic resonance imaging at 1.5 tesla to assess local recurrence following radical prostatectomy using t2-weighted and contrast-enhanced imaging. eur radiol. 2009; 19:761-769. 15. kitajima k, hartman rp, froemming at, et al. detection of local recurrence of prostate cancer after radical prostatectomy using endorectal coil mri at 3 t: addition of dwi and dynamic contrast enhancement to t2-weighted mri. ajr am j roentgenol. 2015; 205:807-816. 16. sciarra a, panebianco v, salciccia s, et al. role of dynamic contrast-enhanced magnetic resonance (mr) imaging and proton mr spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. eur urol. 2008; 54:589-600. 17. girometti r, cereser l, bonato f, zuiani c. evolution of prostate mri: from multiparametric standard to less-is-better and different-is better strategies. eur radiol exp. 2019; 3:5. 18. robertson nl, sala e, benz m, et al. combined whole body and multiparametric prostate magnetic resonance imaging as a 1-step approach to the simultaneous assessment of local recurrence and metastatic disease after radical prostatectomy. j urol. 2017; 198:65-70. 31archivio italiano di urologia e andrologia 2022; 94, 1 mpmri for prostate cancer recurrence 19. turkbey b, rosenkrantz ab, haider ma, et al. prostate imaging reporting and data system version 2.1: 2019 update of prostate imaging reporting and data system version 2. eur urol. 2019; 76:340-351. 20. sella t, schwartz lh, swindle pw, et al. suspected local recurrence after radical prostatectomy: endorectal coil mr imaging. radiology. 2004; 231:379-385. 21. rouvière o, vitry t, lyonnet d. imaging of prostate cancer local recurrences: why and how? eur radiol. 2010; 20:1254-66. 22. stanzione a, creta m, imbriaco m, et al. attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: a national survey among italian urologists. arch ital urol androl. 2020; 92:291-296. correspondence caterina gaudiano, md (corresponding author) caterina.gaudiano@aosp.bo.it caterina.gaudiano@gmail.com federica ciccarese, md beniamino corcioni, md antonio de cinque, md rita golfieri, md department of radiology, irccs azienda ospedaliero-universitaria di bologna via albertoni, 15 40138 bologna, italy francesca giunchi, md department of pathology, irccs azienda ospedaliero-universitaria di bologna, bologna (italy) michelangelo fiorentino, md department of specialty, diagnostic and experimental medicine, university of bologna, via massarenti 9, bologna, italy lorenzo bianchi, md riccardo schiavina, md eugenio brunocilla, md department of urology, irccs azienda ospedaliero-universitaria di bologna, bologna (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12643 1 original paper eral groin is possible, distant lymphatic spread above the pelvic lymph nodes to the retroperitoneal nodes is classified as metastatic disease (4). conversely, metastatic spread from the inguinal lymph nodes to the contralateral pelvic nodes was not reported, nor crossover from the pelvic nodes to the opposite side of the pelvis (5). inguinal lymph node dissection (ilnd) is indicated for proper cancer staging and has a curative role when the cancer is limited to the penis and regional nodes. the eau guidelines endorse performing open ilnd for clinically node positive patients or after nodal metastasis is confirmed after image-guided biopsy. for cn0 disease with high metastatic risk, surgical staging is recommended, preferably by dynamic sentinel node biopsy rather than ilnd (4). unfortunately, recovery after ilnd is hindered by postoperative complications occurring in up to 77% of cases, including: wound infections, skin or flap necrosis, seroma, lymphoedema, lymphocele, etc. (6). in order to overcome the morbidity of the open ilnd, in 2002, ian m. thompson developed a minimally invasive endoscopic subcutaneous approach for ilnd and the first endoscopic subcutaneous modified ilnd was performed in 2003 (7). the endoscopic approach was further developed with the incorporation of 3d and robotic-assisted systems. compared to open ilnd, minimally-invasive inguinal lymph node dissection (milnd) improves the lymph-node yield, facilitates a shorter hospital stay with fewer skin complications, lymphoedema and other major complications (8). the most widespread technique utilized for milnd (7). involves two stages of dissection, first above the fascia lata for the superficial nodes and the second under the fascia lata for the deep inguinal lymph nodes around the femoral vessels. we believe that the milnd procedure can be simplified by first approaching the deep and distal part of the femoral triangle, following the femoral vascular bundle and its branches cranially and superficially for a complete inguinal lymphadenectomy. the purpose of our study is to assess the results of the ilnd procedures performed in our centre, both by open and minimally invasive approach, to determine whether our novel technique of milnd is non-inferior to the current standard of treatment, the oilnd. purpose: open inguinal lymph node dissection (oilnd) plays a crucial role in penile cancer management, but in order to improve patient outcomes, minimally-invasive (milnd) approaches were developed. our “bottoms-up” milnd is a novel endoscopic technique, changing the way the sequence of dissection is performed. this study aims to compare our approach to the current standard of oilnd in terms of oncologic and perioperative outcomes. materials and methods: in our database, from 2016 to 2023, 12 patients underwent oilnd and 16 had a “bottoms-up” milnd, which is performed with a three port configuration, starting the dissection under the fascia lata, dissecting the femoral vessels in the most distal part of the femoral fossa, followed by dissection of the proximal and superficial lymph nodes at the top of the femoral triangle. results: for milnd, median operation time per groin was shorter (58 vs 64 minutes, p = 0.34), patients presented shorter hospital stays (10 vs 18 days, p = 0.32) and fewer days with drains (14 vs 24 days, p = 0.01). median lymph node yield per groin was higher for milnd (10 vs 9 nodes, p = 0.7), but oilnd had a higher median of positive lymph nodes (4 vs 3 nodes, p = 0.63). milnd patients experienced a lower incidence of major complications (33% vs 58%, p = 0.007). conclusions: we have proved that our technique of milnd is not inferior to the current standard and we believe that it can further improve patient outcomes with a safer, simplified and easily reproducible approach. key words: penile cancer; inguinal lymphadenectomy; minimally invasive; video endoscopic. submitted 6 may 2024; accepted 6 june 2024 introduction penile cancer is a rare disease with an annual incidence below 1 case per 100 000 men, representing less than 1% of malignancies in men (1). following the routes of anatomical drainage, regional lymphatic metastases first occur at level of the superficial and deep inguinal lymph nodes, usually in medial-superior zone, followed by the pelvic lymph nodes (2, 3). while inguinal spread can be either unilateral or bilateral and crossover to the contralat“bottoms-up” minimally-invasive approach to inguinal lymph node dissection for penile cancer management. a single-center comparative study versus open approach and review vlad horia schițcu, vlad cristian munteanu, mihnea bogdan borz, ion cojocaru, sergiu vasile labo, andrei-ionuț tișe department of urology, institute of oncology “prof. dr. ion chiricuță”, romania. doi: 10.4081/aiua.2024.12643 summary archivio italiano di urologia e andrologia 2024; 96(3):12643 v. horia schițcu, v. cristian munteanu, m. bogdan borz, et al. 2 materials and methods we retrospectively reviewed our database of patients who underwent ilnd in our center, starting from 2016 to 2023. all patients included in our study were diagnosed with penile cancer with indication for ilnd based on the guidelines at that time (cn1/cn2 disease or cn0 with highrisk primary tumor for which dynamic sentinel node biopsy was not available). patients with bulky or ulcerated inguinal lymph nodes were excluded from the study. during the analyzed period, all ilnd procedures were performed by a single surgeon (v. s.), who operated initially only by open approach and then switched to performing only the minimally invasive approach whenever indicated. in case metastatic spreading to the pelvic lymph nodes was suspected on pre-operative imaging (computer tomography or positron emission tomography scan), laparoscopic extended pelvic lymph node dissection was performed in the same session. for the minimally invasive approach, the patient was placed in dorsal decubitus position with the upper limbs alongside the body, and the lower limbs in a “frog-legged” position (figure 1). a three-port configuration was implemented with one 10 mm port for the camera, and two 5 mm ports for the instruments. the optical port is placed first at 2 cm caudally from the apex of scarpa’s triangle using an open technique and the other two 5 mm ports are placed on the lateral border of the triangle (figure 2). in order to ensure a wide space for work and a safe introduction of the working trocars, the subcutaneous space is further developed with the gaur balloon. dissection was carried out with a bipolar clamp and 5 mm polymer clips that were used to secure lymph vessels. the deep lymph nodes around the femoral neurovascular bundle were first dissected (figure 3), starting at the apex of the femoral triangle, thus ensuring vascular control from the start of the procedure. following the femoral vessels cranially, the deep lymph node dissection is completed, including the excision of the cloquet node. the sapheno-femoral junction is isolated and, by following the saphenous vein, the superficial lymph nodes are dissected up to the inguinal ligament. thus, the ilnd is performed starting from the “bottom”, at the deepest and most caudal region of the femoral triangle, and finishing “up” at the level of the inguinal ligament. open inguinal lymph node dissection (oilnd) was carried out classically, with an incision below and parallel to the inguinal ligament. for both approaches, saphenous vein sparing was performed whenever possible in order to improve post-operative recovery (figure 4). negative pressure wound drainages were installed at the end of the surgery and were replaced with passive drains after 3 days. after draining less than 30 ml in 24 hours, passive tubes were removed. figure 1. patient positioning and port placement. figure 2. port placement relative to the femoral triangle. figure 3. minimally invasive lymph node dissection proximal to the femoral vessels. fa: femoral artery; fv: femoral vein; iln: inguinal lymph nodes. archivio italiano di urologia e andrologia 2024; 96(3):12643 3 “bottoms-up” minimally-invasive approach to inguinal lymph node dissection for penile cancer management statistics statistical analysis was performed using the spss software package. descriptive analysis was carried out using frequencies, means, medians, interquartile ranges and standard deviations. for group comparisons of continuous variables, student’s t-test or the mann-whitney u test was performed depending on the results of the kolmogorovsmirnov test. the chi-squared test was used to examine categorical variables. ethical approval this retrospective study was conducted using anonymized data retrieved the institute of oncology “prof. dr. ion chiricuță” patient registry. ethical approval for this study was obtained from the institute’s ethics committee, with waiver of informed consent granted due to the retrospective nature of the study and the use of de-identified data in accordance with local regulations and institutional guidelines. results our database of ilnd is comprised of 28 cases of patients diagnosed with penile cancer requiring inguinal lymph node staging. from 2016 to 2023, 12 patients underwent oilnd and 16 had a “bottoms-up” milnd. in total, oilnd and milnd were performed on 24 and 32 groins, respectively. the median age of the patients included in our study was 63 years (range 59-66). for the oilnd group, the median age was 61 years (range 54-67) and for the milnd 63 years (range 57-66), with no statistically significant difference (p = 0.69). all cases were diagnosed with penile squamous cell carcinoma and the milnd and oilnd groups were comparable in pathological t stage (p = 0.52). saphenous vein preservation was attempted whenever feasible and was achieved for 12 groins (50%) in the oilnd group and 18 (56.25%) in the milnd group, with no significant difference (p = 0.3). median operation time for one groin was 58 minutes (iqr 48-68 minutes) in the milnd group, shorter that 64 minutes (iqr 55-73 minutes) for oilnd, but statistically insignificant (p = 0.34). patients who underwent milnd had a shorter median hospital stay (10 vs 18 days, p = 0.32) and a significantly shorter median number of days until drainage tubes were removed (14 vs 24 days, p = 0.01). median lymph node yield per groin was slightly higher in the milnd group (10 vs 9 nodes, p = 0.7), but oilnd yielded a marginally higher median of positive lymph nodes per groin (4 vs 3 nodes, p = 0.63) for each groin. regarding the pathology result, there were no significant differences between pn staging regardless of surgical approach (p = 0.55). patients treated with milnd experienced a significantly lower incidence of major complications ranked claviendindo > ii (31.25% vs 58.3%, p < 0.007). the complications encountered in the oilnd group were three cases of lymphocele that required percutaneous drainage, one case of wound infection and three cases of wound dehiscence. in the milnd group, one patient experienced delayed wound healing due to wound dehiscence and three other cases required percutaneous drainage for lymphocele. if saphenous vein preservation was accomplished, the median time duration until drainage tubes were removed was significantly shorter compared to cases where saphenous vein sparing was not possible (13 vs 23 days, p = 0.03) and the median duration of hospital stay was reduced (11.5 vs 18 days, p = 0.06), although insignificantly. the table 1 summarizes patient demographics, tumor characteristics, operative parameters, initial patient outcomes and pathological data. discussion ilnd represents a critical aspect of cancer treatment and staging for patients with penile cancer. despite its importance in oncological care, ilnd is considered a highly morbid procedure. a systematic review and meta-analysis (9). table 1. patient demographics, tumor characteristics, operative parameters, initial patient outcomes and pathological data. oilnd milnd p median age, years (iqr) 61 (54-67) 63 (57-66) 0.69 pathological t stage (%) 0.52 pt1 5 (41.7%) 6 (37.5%) pt2 1 (8.3%) 4 (25%) pt3 5 (41.7%) 5 (31.25%) ptx 1 (8.3%) 1 (6.25%) saphenous vein preservation, no of groins (%) 10 (41.6%) 15 (46.8%) 0.3 median operation time/groin, minutes (iqr) 64 (55-73) 58 (48-68) 0.34 median hospital stay, days (iqr) 18 (8-20) 10 (7-17) 0.11 days to drain removal (iqr) 24 (19-30) 14 (8-20) 0.01 median no. of lymph nodes removed (iqr) 9 (6-14) 10 (8-12) 0.7 median no. of positive lymph nodes (iqr) 4 (1.5-6.5) 3 (2-5) 0.63 pn staging (%) 0.55 pn0 2 (16.6%) 5 (31.25%) pn1 1 (6.25%) pn2 2 (16.6%) 4 (25%) pn3 8 (66.6%) 6 (37.5%) clavien-dindo complications > ii (%) 7 (58.3%) 4 (31.25%) 0.007 wound dehiscence (%) 3 (25%) 1 (6.25%) wound infection (%) 1 (8.3 %) lymphocele (%) 3 (25%) 3 (18.75%) figure 4. saphenous vein sparing during minimally invasive lymph node dissection. sv: saphenous vein; fa: femoral artery. archivio italiano di urologia e andrologia 2024; 96(3):12643 v. horia schițcu, v. cristian munteanu, m. bogdan borz, et al. 4 found that perioperative adverse events were common in patients undergoing ilnd, with high bmi, comorbidities, and diabetes identified as independent predictors for complications. historically, oilnd has been the standard of care. however, due to potential complications and morbidity associated with oilnd, there has been growing interest in minimally invasive techniques, such as video-endoscopic or robot-assisted ilnd. these techniques are suggested to achieve comparable oncologic outcomes to oilnd, with lower rates of complications (8, 10). we present our approach for milnd which is different from the already established milnd technique described in the literature, demonstrating unique advantages. the initial space developed under the fascia lata with the gaur balloon provides adequate space for safe port placement and tissue manipulation, reducing the need for other aid ports and instruments. by approaching first the apex of the inguinal triangle, early vascular control of the femoral bundle is achieved, thus reducing the hemorrhagic risk of this procedure. continuing the dissection proximally, around the femoral artery, the femoral vein and the saphenofemoral junction can then be easily and safely isolated, facilitating the preservation of the saphenous vein. conversely, the invasion of the saphenous vein is easily identified before commencing its dissection, thus making the decision to preserve or to sacrifice quick and early during the procedure. in our high-volume center, we compared the early results following the adoption of our technique of milnd with the outcomes of the well-established oilnd. our study included 28 patients with penile cancer requiring ilnd, with 12 patients undergoing oilnd and 16 milnd. the results showed no significant differences between the two groups in age, pathological t stage, saphenous vein preservation rate and median operation time. however, patients who underwent minimally invasive procedures had shorter hospital stays and required fewer days with drains in place. the minimally invasive group also had a slightly higher median lymph node yield per groin, though the open group had a marginally higher median number of positive lymph nodes per groin. no significant differences were observed in pn staging between the two surgical approaches. however, patients in the minimally invasive group experienced a significantly lower incidence of major complications (clavien-dindo > ii). in addition, successful saphenous vein sparing reduced the duration of hospital stay and decreased the period for wound drainage significantly. previous systematic reviews and meta-analyses have reported better perioperative outcomes and comparable shortterm oncological outcomes for minimally invasive techniques. a 2019 systematic review and meta-analysis (10). compared video endoscopic ilnd (ve-ilnd) and oilnd in the management of penile cancer. the results indicated that the ve-ilnd group had less intraoperative blood loss, shorter hospital stay, shorter drainage time, reduced wound infection rate, reduced skin necrosis rate, and lower lymphedema rate compared to the oilnd group. however, the number of dissected lymph nodes was slightly higher in the oilnd group. lymphocele rate and recurrence rate were found to be similar between the two groups. a 2022 systematic review and meta-analysis (8) compared robot-assisted video endoscopic ilnd (raveil/veil) with oilnd in penile carcinoma management. raveil and veil techniques increased the operative time (md = 15.28) but reduced hospital stay (md = -1.06), and decreased the duration of drainage (md = -2.82). it also demonstrated lower rates of wound infection (or = 0.15), skin necrosis (or = 0.12), lymphedema (or = 0.41), and major complications (or = 0.11) compared to oilnd. recurrence rates and number of deaths were comparable, but raveil/veil had a slightly larger lymph-node yield (md = 0.44). raveil/veil demonstrated fewer complications and better lymph-node yield, with comparable oncological outcomes to oilnd. thyavihally et al. (11) compared video endoscopic inguinal lymphadenectomy (veil) and open ilnd (o-ilnd) in terms of perioperative and survival outcomes. results from 79 patients showed wound complications were higher in oilnd (65.6%) than veil (27.7%) (p = 0.001). median overall survival was 80 months for o-ilnd and 88 months for veil (p = 0.840), with five-year survival rates of 65% and 66.8% (p = 0.636) and disease-specific survival rates of 76.6% and 73.9% (p = 0.96), respectively. a 2023 systematic review assessed the clinical effectiveness of treatment options available for the management of inguinal and pelvic lymphadenopathy in men with penile cancer and reinforced the idea that early ilnd improves survival in nodal disease in penile cancer and, furthermore, milnd may offer comparable survival outcomes to open ilnd with lower wound-related morbidity (12). as observed, minimally invasive surgery provides an economic benefit in reducing costs of hospitalization and an earlier return to activity, when compared with open surgery (13). it is very probable that this is as also the case for milnd, but we also believe that our method of veil can provide further financial advantage when compared to the associated costs of raveil. although additional studies would be needed to demonstrate this hypothesis, a lower financial-impact procedure that is simplified and with reproducible favorable outcomes would serve as additional reasons for adoption, especially in developing countries. following the latest recommendations by the eau-asco guidelines, for cn0 disease that requires inguinal lymph node staging, dynamic sentinel node biopsy (dsnb) is preferred in order to avoid unnecessary formal ilnd and its associated morbidity (4). an updated systematic review and meta-analysis by zou et al. (14) assessed the accuracy of radiocolloid-based dsnb in penile cancer with clinically negative groin (cn0) disease and found a pooled sensitivity of 88% and a negative predictive value of 99%. factors such as preoperative ultrasonic scan (uss), fine-needle aspiration cytology (fnac), surgical exploration of the wound for suspicious lymph nodes, immunohistochemistry and extensive experience were associated with improved dsnb sensitivity. a 2022 systematic review, fallara et al. (15) assessed the diagnostic accuracy of dsnb and ilnd in detecting lymph node metastasis in penile cancer patients with cn0 disease. it found that dsnb had a pooled weighted sensitivity of 0.87, but for detecting further positive lymph nodes at ilnd, dsnb had a pooled weighted sensitivity of 0.50. the study concluded that a positive dsnb is poorly able to archivio italiano di urologia e andrologia 2024; 96(3):12643 5 “bottoms-up” minimally-invasive approach to inguinal lymph node dissection for penile cancer management discriminate which patients will have further metastatic involvement at the completion of ilnd, suggesting that better patient stratification could help avoid unnecessary overtreatment and postoperative comorbidities. for this, kumar et al. demonstrated that outcomes can be further improved with additional inguinal ultrasound, fine needle aspiration and cross-sectional imaging to select patients for either inld or dsnb, leading into a dsnb procedure with a sensitivity of 100% at a mean follow-up of 5 years (16). our study demonstrates that our novel technique for milnd provides benefits such as shorter hospital stay and reduced complications compared to the well-established open approach. the findings align with those of previous systematic reviews and meta-analyses, which have also reported better perioperative outcomes and comparable short-term oncological outcomes for minimally invasive techniques. however, our study has several limitations. the sample size is relatively small and the data is provided from a single center with a single surgeon, which may hinder the extrapolation of the results. additionally, our study focused on early post-operative results and did not assess long-term oncological outcomes. future research should involve larger, multicenter studies with more diverse patient populations and longer follow-up periods to better understand the safety, efficacy, and long-term outcomes of minimally invasive approaches for ilnd. conclusions our study compared our novel 'bottoms-up' minimally invasive inguinal lymph node dissection in penile cancer management with the current standard of treatment, the open approach. our approach is less invasive, resulting in a shorter operating time (58 vs 64 mins, iqr 55-73 minutes vs 48-68 minutes), shorter hospital stays (10 vs 18 days, iqr 7-17 days vs 8-20 days), fewer days with drains (14 vs 24 days, iqr 8-20 vs 19-30 days), and fewer major complications (33% vs 58%). we retrieved more lymph nodes (10 vs 9) but had similar cancer-related outcomes. this suggests our approach is non-inferior to the standard of treatment, but safer and simpler for patients and surgeons alike. references 1. montes cardona ce, garcía-perdomo ha. incidence of penile cancer worldwide: systematic review and meta-analysis. revista panamericana de salud pública. 2017; 1-10. 2. leijte jap, kirrander p, antonini n, et al. recurrence patterns of squamous cell carcinoma of the penis: recommendations for followup based on a two-centre analysis of 700 patients. eur urol 2008; 54:161-8. 3. alnajjar hm, lam w, bolgeri m, et al. treatment of carcinoma in situ of the glans penis with topical chemotherapy agents. european urology. 2012; 62:923-8. 4. brouwer or, et al. eau-asco penile cancer guidelines. edn. presented at the eau annual congress milan 2023. arnhem, the netherlands: eau guidelines office; 2023. 5. smith ja, howards ss, preminger gm, dmochowski rr. hinman"s atlas of urologic surgery revised reprint. elsevier health sciences; 2019. 6. stuiver mm, djajadiningrat rs, graafland nm, et al. early wound complications after inguinal lymphadenectomy in penile cancer: a historical cohort study and risk-factor analysis. eur urol 2013; 64:486-92. 7. sotelo r, sánchez-salas r, carmona o, et al. endoscopic lymphadenectomy for penile carcinoma. j endourol 2007; 2:364-7. 8. patel kn, salunke a, bakshi g, et al. robotic-assisted videoendoscopic inguinal lymphadenectomy (raveil) and videoendoscopic inguinal lymphadenectomy (veil) versus open inguinal lymph-node dissection (oilnd) in carcinoma of penis: comparison of perioperative outcomes, complications and oncological outcomes. a systematic review and meta-analysis. urol oncol. 2022; 40:112.e11-112.e22. 9. cacciamani ge, medina lg, sayegh as, et al. complications and adverse events in lymphadenectomy of the inguinal area (cali) project, the international consensus panel on complications in urology (icpcu), and the intraoperative complications assessment and reporting with universal standards (icarus) global surgical collaboration. assessment and reporting of perioperative adverse events and complications in patients undergoing inguinal lymphadenectomy for melanoma, vulvar cancer, and penile cancer: a systematic review and meta-analysis. world j surg. 2023; 47:962-974. 10. hu j, li h, cui y, et al. comparison of clinical feasibility and oncological outcomes between video endoscopic and open inguinal lymphadenectomy for penile cancer: a systematic review and metaanalysis. world j urol. 2020; 38:1301-1311. 11. thyavihally yb, dev p, waigankar ss, et al. comparative study of perioperative and survival outcomes after video endoscopic inguinal lymphadenectomy (veil) and open inguinal lymph node dissection (o-ilnd) in the management of inguinal lymph nodes in carcinoma of the penis. j robotic surg. 2021; 15:695-703. 12. sachdeva a, mcguinness l, zapala ł, et al. node-positive penile cancer: a systematic review. eur urol. 2024; 85:257-273. 13. ho c, tsakonas e, tran k, et al. robot-assisted surgery compared with open surgery and laparoscopic surgery: clinical effectiveness and economic analyses internet). ottawa (on): canadian agency for drugs and technologies in health; 2011 sep. (cadth technology report, no. 137.) 5, economic analysis. available from: https://www.ncbi.nlm.nih.gov/books/nbk168933/ 14. zou zj, liu zh, tang ly, et al. radiocolloid-based dynamic sentinel lymph node biopsy in penile cancer with clinically negative inguinal lymph node: an updated systematic review and meta-analysis. int urol nephrol. 2016; 48:1951-1962. 15. fallara g, pozzi e, onur cakir o, et al. eau-yau penile and testis cancer working group. diagnostic accuracy of dynamic sentinel lymph node biopsy for penile cancer: a systematic review and meta-analysis. eur urol focus. 2023; 9:500-512. 16. kumar v, kumar pr, juette a, et al. improved outcome in penile cancer with radiologically enhanced stratification protocol for lymph node staging procedures: a study in 316 inguinal basins with a mean follow-up of 5 years. bmc urol. 2023; 23:137. correspondence vlad horia schițcu, md schitcu@yahoo.com vlad cristian munteanu, md vladcristian.munteanu@gmail.com mihnea bogdan borz, md borz.m.bogdan@gmail.com ion cojocaru, md cojocaruion90@yahoo.com sergiu vasile labo, md atolica@gmail.com andrei-ionuț tișe, md (corresponding author) andreitisemd@gmail.com department of urology, institute of oncology “prof. dr. ion chiricuţă”, romania str. republicii 34-36, cluj-napoca 400015, romania conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13119 1 original paper ual activity (2). the psychophysiological model introduced by masters and johnson in the 1960s (3), which correlates simultaneous genital sexual response with the subjective perception of arousal, often shows great variability, despite frequent correlations. this finding has sparked debate among researchers, particularly regarding the explanation of the motivational mechanisms that drive individuals to seek sex. in fact, the subjective perception of genital arousal does not always align with the actual genital sexual response in male, such as increased volume and penile rigidity (4). as reported by rieger and colleagues (4), in some situations, certain men, while feeling aroused, do not exhibit a simultaneous genital sexual response; in other words, the penis does not reflect an arousal state corresponding to the perceived sensation of excitement. in this experiment, some subjects without erectile dysfunction were asked to perform mathematical calculations during visual erotic stimulation, leading to a reduction in erection but not in the state of arousal (4, 5). in other cases, the opposite was observed: a genital sexual response occurred without an actual arousal state, as happens during nocturnal erections in the rem phase of sleep, which are not always associated with erotic dreams or arousal states (1, 6). this also occurs in patients with priapism, where an erection is present by definition, but without sexual arousal (7). the same phenomenon can be observed during cavernous pharmacological infusion with papaverine, as occurred during virag's experiment, in which an erection was obtained under general anesthesia without the subject being aroused or aware of it (8). there are numerous explanations in the literature for this lack of simultaneous correspondence between selfreported arousal perception following visual stimulation and the genital arousal response. among the various causes that could explain this discrepancy between perceived arousal and the objective genital arousal response, several hypotheses have been considered, including, but not limited to, methodological errors in the quality and duration of the erotic stimulus, the method of measuring self-reported arousal, and the objective measurement of the genital arousal response (9). the lack of this simultaneous correlation, at least in men, could be due to the possibility that a pelvic reflex is elicited by psycho-sensory sexual stimulation (10). the direct introduction: this study is based on the hypothesis that, in men, the initial sexual response to erotic stimuli is triggered by a psycho-sensory pelvic reflex, mediated by the contraction of the pelvic floor muscles (pfm), rather than by an erection. objective: the objective is to determine, using a questionnaire that evokes an erotic image, whether there is a correlation between an erotic psycho-sensory stimulus and pfm contraction in men and females and whether this contraction encourages the subject to seek sexual activity. materials and methods: an online questionnaire was administered to 270 respondents (134 males, 136 females; mean age = 36.53, sd = 10.7; range 19-63). the questionnaire assessed the relationship between the perception of anterior pfm contraction and an evocative erotic image. results: the results show that following an evoked erotic stimulus, there is a significantly higher prevalence of perceived genital sexual responses in males compared to females through pfm contraction. a statistically significant difference was also observed in the desire to engage in sexual activity when perceiving pfm contraction (mean: males 2.04 ± 0.95 vs. females 1.02 ± 0.88; p < 0.001). conclusions: in this sample, an evocative erotic image triggers the perception of the genital sexual response via pfm contraction in more males than females. additionally, pfm contraction, when perceived, prompts more males to seek sexual activity. these findings support the hypothesis that pelvic floor muscles contraction is the initial response to psycho-sensory stimulation in men and a trigger for male sexual behaviour. key words: psycho-sensory sexual pelvic reflex; male sexual response; male genital response; pelvic floor; neurological reflex; male sexual behaviour; genital perception; ejaculatory urgency. submitted 19 september 2024; accepted 10 october 2024 introduction the genital sexual response to erotic stimuli refers to the physiological and psychological changes in the genital organs that occur in response to sexual stimuli. it depends on multiple psychological, emotional, and physiological factors. each of these factors can trigger a genital sexual response, which is considered an indicator of male arousal (1) and a motivational mechanism in the pursuit of sexpelvic floor contraction as an initial response to psycho-sensory sexual stimulation in men and a trigger for male sexual behaviour giuseppe la pera 1, sabrina anticoli 2, marilena mangiardi 2, stefano livi 3 1 consultant urologist, rome, italy; 2 stroke unit head neck and neuroscience department, san camillo hospital, rome, italy; 3 social and developmental psychology, university of rome "la sapienza", rome, italy. doi: 10.4081/aiua.2024.13119 summary archivio italiano di urologia e andrologia 2024; 96(4):13119 g. la pera, s. anticoli, m. mangiardi, s. livi 2 consequence of the presence of this psycho-sensory pelvic reflex implies that the perception of the genital response after visual erotic stimulation may not simply be the perception of an erection, as hypothesized in the excitement phase described by masters and johnson, but rather the perception of the involvement of another structure, which, according to this hypothesis, is constituted by the pelvic floor. this contraction would cause an increase in pressure within the corpus cavernous and the corpus spongiosum of the urethra, which is then transmitted to the receptors in the glans. this increase in pressure in these structures may lead to a conscious perception of the genital response, which is interpreted as the occurrence of a sexual response of the genitals. in other words, the perception of the pelvic floor contraction, particularly of the ischiocavernosus, bulbourethral, and bulbocavernosus muscles, might serve as one of the indicators of sexual response to visual or imagined stimuli. this could explain why changes in penile volume, blood flow, or rigidity the primary indicators of genital arousal response in men may not be and may lay the foundation for a revised psychophysiological model that incorporates this new parameter: pelvic floor muscle contraction as initial response to psycho-sensory sexual stimulation. the aim of this study is to evaluate, through a questionnaire that evokes an erotic image: whether there is a correlation in men and females between an evoked erotic image and pelvic floor contraction, and whether this contraction prompts the individual perceiving this sensation to seek sexual activity. materials and methods procedure and sample we administered a questionnaire via the prolific platform (www.prolific.com). prolific is an online platform that connects researchers with high-quality participants for academic studies, offering a diverse and reliable pool. it ensures ethical standards by providing fair compensation and robust data quality, making it a preferred tool for behavioral and social sciences research (11, 12). all respondents provided informed consent beforehand, in which the anonymity of responses was guaranteed, following the guidelines of the helsinki declaration of 2013. (ethical principles for medical research involving human subjects). four-hundred subjects answered the survey. all respondents were asked about their sexual preferences, specifically whether they identified as heterosexual, homosexual, bisexual, or other (pansexual or undeclared). sixtythree respondents, who identified as homosexual, bisexual, or other were excluded. only those who answered all the presented questions were retained, in order to maintain comparability of responses. the final sample consisted of 270 respondents with an average age of 36.53 years (sd = 10.7; range 19-63), comprising 134 males (49.6%; average age 35.93, sd 10.12; range 1963) and 136 females (50.4%; average age 37.13, sd 11.22; range 21-63). all respondents read a description of the pelvic floor muscles, their function, and typical use during urination. subsequently, they were asked if they understood what the pelvic floor and pelvic floor contraction were, and all responded affirmatively. measures male respondents were administered the following five questions: “do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction when: “with a 5-point response scale: never (0), rarely (1), sometimes (2), often (3), always (4), and “i have not been in this situation” (the latter treated as a missing value). the items considered in the five questions were: item 1. when your partner dresses in a sexually provocative manner; item 2. when you encounter a particularly attractive woman; item 3. when you see an erotic scene (e.g., a film); item 4. when your partner sends you sexually provocative photos; item 5. when you see a particularly attractive woman, do you immediately feel the desire to have sexual intercourse. subsequently, in order to determine the presence or absence of sexual disorders, male respondents were asked to respond to the following questionnaires: 1) the international index of erectile function (iief5) (13) as well as questions related to sexual desire extracted from the ieef15 (14), specifically q11 “how often have you felt sexual desire in the past four weeks?” and q12 “how would you rate your level of sexual desire?”. additionally, they were asked to complete the premature ejaculation diagnostic tool (pedt) (15). female respondents were asked to respond to two questionnaires: the female sexual dysfunction (fsd) (16) and the female sexual distress scale for the study of psychological distress (fsds) (17). statistical methods the responses to the questionnaire from males and females were subjected to the analysis of variance (anova). all analyses were conducted using ibm spss statistics for windows, version 25.0 with a two-level factor (male/female) for each of the five questions. results data analysis regarding the iief 5 questionnaire, we considered subjects with a total score of 21 or higher on the five questions to be normal (14). their distribution was as follows: normal (14) ≥ 21: n. 95 subjects, accounting for 70.9%; pathological (14) < 21: n. 39 subjects, accounting for 29.1%. regarding the pedt questionnaire, we considered subjects without premature ejaculation to be those who scored 9 or less on the five questions. subjects with a score of 10 or higher (16) were considered likely to have premature ejaculation, and those with a score above 11 were considered to have premature ejaculation. in our sample, the distribution was as follows: normal ≤ 9: n. 105 subjects, accounting for 78.4%; pathological or likely pathological > 9: n. 29 subjects, accounting for 21.6%. archivio italiano di urologia e andrologia 2024; 96(4):13119 3 pelvic floor contraction and male sexual behaviour regarding the questions related to male sexual desire, we extracted from the iief15 questionnaire (15), when the response to one or both of these questions was less than 3, we considered the subject to have low sexual desire. the distribution of subjects was as follows: normal ≥ 3: n. 127, accounting for 94.8%; pathological < 3: n. 7, accounting for 5.2%. in order to identify dysfunctions in the female sample, we used the 6-item fds questionnaire (17) instead of the traditional 19-item fds questionnaire, which has comparable psychometric properties but is quicker to use, making the survey easier. the distribution between normal and pathological in our sample was as follows: normal ≥ 19: n. 98, accounting for 72.1%; pathological < 19: n. 38, accounting for 27.9%. we also used the fsds-r questionnaire (18) to measure female sexual distress, with a cut-off value of less than 11 to distinguish normal from pathological. in our sample, the distribution was as follows: normal < 11: n. 73, accounting for 53.74%; pathological ≥ 11: n. 63, accounting for 46.3%. means and frequencies related to the degree of arousal were calculated for the responses to each item (see tables ia, ib). the results were statistically different between men and women, indicating that an evoked erotic stimuli in men was more frequently accompanied by pelvic floor muscle contraction compared to women (see figure 1 and table 1b). table 1b. differences in means between males and females in the degree of arousal (standard deviation in parentheses). item 1 item 2 item 3 item 4 item 5 female (n = 136) 1.46 (1.07) 1.28 (1.03) 2.28 (1.01) 1.81 (1.32) 1.12 (0.88) male (n = 134) 2.66 (0.98) 1.77 (1.00) 2.54 (0.89) 3.05 (1.01) 2.04 (0.95) f(1.268) = 91.90 f(1.268) = 15.73 f(1.268) = 4.92 f(1.268) = 75.25 f(1.268) = 69.46 p < .001 p < .001 p = .027 p < .001 p < .001 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between male and female responses has been statistically significant in all items. figure 1. differences between males and females in the degree of perceived arousal. do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between male and female responses has been statistically significant in all items. table 1a. means and frequencies related to the degree of arousal (percentages in parentheses). item 1-5 mean d.s. never (0) rarely (1) sometimes (2) often (3) always (4) 1. when your partner dresses in a sexually provocative manner female 1.46 1.01 30 42 39 22 3 (22.1%) (30.9%) (28.7%) (16.2%) (2.2%) male 2.66 0.98 3 12 41 50 28 (2.2%) (9.0%) (30.6%) (37.3%) (20.9%) 2. when you encounter a particularly attractive woman/man female 1.28 1.03 36 43 45 7 5 (26.5%) (31.6%) (33.1%) (5.1%) (3.7%) male 1.77 0.99 14 38 52 25 5 (10.4%) (28.4%) (38.8%) (18.7%) (3.7%) 3. when you see an erotic scene (e.g., a film) female 2.28 1.01 7 19 54 41 15 (5.1%) (14.0%) (28.7%) (30.1%) (11.0%) male 2.54 0.89 2 14 45 56 17 (1.5%) (10.4%) (33.6%) (41.8%) (12.7%) 4. when your partner sends you sexually provocative photos female 1.81 1.32 33 21 35 33 14 (24.3%) (15.4%) (25.7%) (24.3%) (10.3%) male 3.05 1.01 4 6 22 49 53 (3.0%) (4.5%) (16.4%) (36.6%) (39.6%) 5. when you see a particularly attractive woman/man, female 1.12 0.88 38 50 43 4 1 do you immediately feel the desire to have sexual intercourse (27.9%) (36.8%) (31.6%) (2.9%) (0.7%) male 2.04 0.95 7 12 41 35 4 (5.2%) (9.0%) (30.6%) (26.1%) (5.2%) archivio italiano di urologia e andrologia 2024; 96(4):13119 g. la pera, s. anticoli, m. mangiardi, s. livi 4 the differences in mean arousal were significant for all the questions asked: males expressed more frequent contraction in item 1 (“when your partner dresses in a sexually provocative manner”) (m = 2.06 vs. 1.46 (f(1.268) = 91.90, p < .001); item 2 (“when you encounter a particularly attractive woman/man”) (m = 1.77 vs. 1.28 (f(1.268) = 15.73, p < .001); item 3 (“when you see an erotic scene (e.g., a film)”) (m = 2.54 vs. 2.28 (f(1.268) = 4.92, p = .027); item 4 (“when your partner sends you sexually provocative photos") (m = 3.05 vs. 1.81 (f(1.268) = 72.25, p < .001); item 5 ("when you see a particularly attractive woman/man, do you immediately feel the desire to have sexual intercourse.”) (m = 2.04 vs. 1.12 (f(1.268) = 69.46, p < .001). the analysis of variance was then applied to compare healthy subjects with those having sexual disorders as defined by the test. for both erectile dysfunction (ed) and premature ejaculation (pe) (see tables and figures 2, 3) the comparison between normal male subjects and those with one or more pathological test results concerning the responses to the five questions did not show statistically significant differences. regarding desire disorder, statistically significant differences were found in arousal in the questions related to “when your partner dresses in a sexually provocative manner” and “when my partner sends me sexually provocative photos”, that is, in questions related to one's partner. in both cases, those without a desire disorder reported a higher degree of arousal compared to those with a desire disorder (see table and figure 4). for item 1 (“when your partner dresses in a sexually provocative manner”) (m = 2.70 vs. 1.86 (f(1.132) = 5.05, p = .026) and for item 4 (“when your partner sends you sexually provocative photos”) (m = 3.09 vs. 2.29 (f(1.132) = 4.40, p = .038). this section is limited to men who answered questions q11 and q 12 of the iief-15 questionnaire. table 2. differences in means between male participants with and without erectile dysfunction (ieef5) (standard deviation in parentheses). item 1 item 2 item 3 item 4 item 5 no ed (n = 95) 2.75 (1.01) 1.79 (1.03) 2.56 (0.90) 2.56 (0.95) 2.13 (0.96) ed (n = 39) 2.44 (0.88) 1.72 (0.92) 2.49 (0.91) 2.49 (1.13) 1.85 (0.90) f(1.132) = 2.82 f(1.132) = 0.14 f(1.132) = 0.17 f(1.132) = 0.33 f(1.132) = 2.44 p = .095 p = .707 p = .681 p = .568 p = .121 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. there are no statistically significant differences in any item between males with and without ed. table 3. differences in means between male participants with and without premature ejaculation (pe) (standard deviation in parentheses). item 1 item 2 item 3 item 4 item 5 no pe (n = 105) 2.70 (0.98) 1.74 (1.00) 2.55 (0.90) 3.10 (0.96) 1.99 (0.92) pe (n = 29) 2.48 (0.99) 1.86 (0.99) 2.48 (0.91) 2.86 (1.16) 2.24 (1.02) f(1.132) = 1.16 f(1.132) = 0.32 f(1.132) = 0.14 f(1.132) = 1.32 f(1.132) = 1.60 p = .283 p = .570 p = .713 p = .252 p = .209 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. there are no statistically significant differences in any item between males with and without pe. figure 2. differences in means between male participants with and without erectile dysfunction (ieef-5). do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. there are no statistically significant differences in any item between males with and without ed. figure 3. differences in means between male participants with and without premature ejaculation (pe) (standard deviation in parentheses). do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. in all items there is no statistical difference between respondents with pe and non-pe. archivio italiano di urologia e andrologia 2024; 96(4):13119 5 pelvic floor contraction and male sexual behaviour regarding the comparison of normal female subjects with those having fsdi-6 (female sexual dysfunction) or fdss-r (distress) pathological, the results indicated some statistically significant differences (see tables and figures 5, 6). in particular, females without disorders exhibited higher arousal, except for item 2 (“when you encounter a particularly attractive woman/man”). for these items, women without sexual disorders showed a higher degree of arousal: in this case, females expressed more arousal in item 1 (“when your partner dresses in a sexually provocative manner”) (m = 1.66 vs. 0.92 (f(1.134) = 14.37, p < .001); item 3 (“when you see an erotic scene (e.g., a film)”) (m = 2.43 vs. 1.89 (f(1.134) = 8.07, p = .005); item 4 (“when your partner sends you sexually provocative photos”) (m = 2.03 vs. 1.24 (f(1.134) = 3.46, p < .001). regarding female sexual distress (see table and figure 5), no statistically significant differences were recorded except for item 3 (“when you see an erotic scene (e.g., a film)”). in this case, women with a sexual disorder showed a greater pelvic floor contraction associated with viewing these erotic scenes (m = 2.51 vs. 2.08 (f(1.134) = 6.26, p = .01). the results indicate that there are no differences among men between those without sexual disorders and those with ed or pe. however, some statistically significant differences emerge in the greater arousal of those without desire disorders related to pelvic floor contraction during visual erotic stimuli experienced with their partner. regarding the female sample, respondents with sexual dysfunction showed a greater contraction in normal subjects compared to those with sexual disorders (similar to what was observed in the male sample). however, female respondents with sexual distress exhibited higher contable 4. differences in means between male participants with and without desire disorder (standard deviation in parentheses). item 1 item 2 item 3 item 4 item 5 without desire disorder 2.70 (0.94) 1.80 (1.00) 2.54 (0.89) 3.09 (0.95) 2.07 (0.95) (n = 127) with desire disorder 1.86 (1.34) 1.14 (0.99) 2,43 (1.13) 2.29 (1.70) 1.57 (0.79) (n = 7) f(1.132) = 5.05 f(1.132) = 2.96 f(1.132) = 0.11 f(1.132) = 4.40 f(1.132) = 1.85 p = .026 p = .088 p = .744 p = .038 p = .176 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contractio. in this section limited to men who answered to question q11 and q 12 of the iief-15 questionnaire there is statistical different significant in item 1 and item 4 between men with an without desire disorders. table 5. differences in means between female participants regarding female sexual dysfunctions (fsd) (standard deviation in parentheses). item 1 item 2 item 3 item 4 item 5 no fsd (n = 98) 1.66 (1.03) 1.30 (1.01) 2.43 (0.93) 2.03 (1.33) 1.20 (0.88) fsd (n = 38) 0.92 (1.00) 1.24 (1.10) 1.89 (1.11) 1.24 (1.12) 0.89 (0.83) f(1.134) = 14.37 f(1.134) = 0.89 f(1.134) = 8.07 f(1.134) = 10.52 f(1.134) = 3.46 p < .001 p = 0.76 p = .005 p < .001 p = .065 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between female with and with fsd has been statistically significant in items 1, 3 and 4. figure 4. differences in means between male participants with and without desire disorder. do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. in this section limited to men who answered to question q11 and q12 of the iief-15 questionnaire there is statistical different significant in item 1 and item 4 between men with and without desire disorders. figure 5. differences in means between female participants regarding female sexual dysfunctions (fsd). do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between female with and with fsd has been statistically significant in items 1, 3 and 4. archivio italiano di urologia e andrologia 2024; 96(4):13119 g. la pera, s. anticoli, m. mangiardi, s. livi 6 traction values compared to those without sexual distress. overall, there is a tendency in both male and female samples to show greater tension in the penis or clitoris due to pelvic floor contraction in normal subjects compared to pathological ones, except in the case of female sexual distress, where the trend is reversed. discussion a first consideration arising from these data is inspired by numerous studies that have highlighted that, in the psychophysiological response to erotic stimuli, there is a correlation between genital arousal and its simultaneous conscious perception (7). this agreement between genital sexual response and its perception is much more frequent in men than in women (7), and there is a difference between women with sexual dysfunction and those without (18). these studies have never clarified the potential anatomical structure that enables this agreement in the perception of arousal in men. according to our study, what facilitates the perception of arousal is the contraction of the pelvic floor, which in turn triggers the sexual response, generating a need for sexual activity. the initial hypothesis is based on the idea that, following visual or psychosensory sexual stimulation, the psychophysiological response initiates, like a neurophysiological reflex, the contraction of the pelvic floor, specifically the bulbourethral, bulbocavernosus, and ischiocavernosus muscles. the reflex contraction of these muscles would cause a "squeezing" of the corpus spongiosum of the urethra and the corpus cavernosum, leading to the perception of arousal. consequently, the individual might seek a solution for this arousal, experiencing an urgent desire for sexual activity, similar to the need to urinate or defecate when the bladder or rectum is full. these findings could explain the difference in sexual response behaviors between men and women, as demonstrated in anatomical studies of the anterior pelvic floor. the male pelvic floor muscles are significantly stronger and more effective in contracting the corpus spongiosum of the urethra and the corpus cavernosum than the thin muscle fibers of the female pelvic floor, which reach only a small portion of the clitoral cavernous bodies (19). furthermore, continuing with the analysis suggested by these data, it is useful to consider the epidemiological data on pelvic floor disorders, which reinforce our observations. it is well-documented in medical literature that pelvic floor disorders are more common among women (20) and are associated with female sexual dysfunction (21). finally, when analyzing these data, it is important to remember that there are variables not considered in our study that could negatively influence the observed results, such as the cultural differences that lead women to express their sexual preferences and arousal less frequently in public (self-censorship, social modesty). although this could represent a source of bias, the guarantee of anonymity provided by an online questionnaire may have mitigated this issue (22, 23). conclusions the data presented here highlight a statistically significant difference between heterosexual males and females in the perception of visual arousal and, among females, a statistically significant difference between those with sexual disorders and those without via the pelvic floor muscle contraction. additionally, there is a difference between males and females in the perception of the urgent need to have sex following visual arousal and pelvic floor contraction. this study aligns and support the hypothesis that the initial response of the male sexual reaction to visual erotic stimuli is mediated by a reflex contraction of the anterior pelvic floor muscles. furthermore, these data support the hypothesis that there is a difference in visual arousal between males and females, which triggers the so-called "desire" for sex, similar to the perception of an urgent need to urinate or defecate when the bladder or rectum is full. table 6. differences in means between female participants regarding female sexual distress (fsds). item 1 item 2 item 3 item 4 item 5 no fsds (n = 73) 1.51 (1.06) 1.25 (1.02) 2.08 (1.01) 1.70 (1.36) 0.98 (0.92) fsds (n = 63) 1.40 (1.10) 1.32 (1.04) 2.51 (0.96) 1.94 (1.28) 1.27 (0.81) f(1.134) = 0.35 f(1.134) = 0.16 f(1.134) = 6.26 f(1.134) = 1.09 f(1.134) = 3.59 p = 0.55 p = 0.69 p = 0.01 p = 0.30 p = 0.06 do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between females with and with fsds has been statistically significant only in items 1. figure 6. differences in means between female participants regarding female sexual distress (fsds). do you feel you have experienced increased tension in the penis and glans (or increased tension in the clitoris in the female version) due to pelvic floor contraction. the difference between females with and with fsds has been statistically significant only in items 1. archivio italiano di urologia e andrologia 2024; 96(4):13119 7 pelvic floor contraction and male sexual behaviour further studies, including neurophysiological tests and additional data, are necessary to confirm the hypothesis of the psycho-sensory pelvic reflex in response to erotic stimuli and the new paradigm of human sexual response. acknowledgments i thank martha b. scherr for her help in translating the text into english. references 1. janssen e, everaerd w. determinants of male sexual arousal. annual review of sex research. 1993; 4:211-246. 2. bailey jm. what is sexual orientation and do women have one? nebr symp motiv. 2009; 54:43-63. 3. masters wh, johnson ve. human sexual response. little, brown and company, new york. 1966. 4. rieger g, chivers ml, bailey jm. sexual arousal patterns of bisexual men. psychol sci. 2005; 16:579-84. 5. van lankveld jj, van den hout ma. increasing neutral distraction inhibits genital but not subjective sexual arousal of sexually functional and dysfunctional men. arch sex behav. 2004; 33:549-58. 6. bach ak, brown ta, barlow dh. the effects of false negative feedback on efficacy expectancies and sexual arousal in sexually functional males. behavior therapy. 1999; 30:79-95. 7. chivers ml, seto mc, lalumière ml, et al. agreement of selfreported and genital measures of sexual arousal in men and women: a meta-analysis. arch sex behav. 2010; 39:5-56. 8. silberman m, stormont g, leslie sw, hu ew. priapism. statpearls [internet]. treasure island (fl): statpearls publishing. 2023; 30:1-11. 9. porst h, lewis r, virag r, goldstein i. a comprehensive history of injection therapy for erectile dysfunction, 1982-2023. sex med rev. 2024; 12:419-433. 10. la pera g. the psycho-sensory pelvic reflex: a new paradigm in the model of male sexual response. arch ital urol androl. 2024; 96:12975. 11. palan s, schitter c. prolific.ac–a subject pool for online experiments. j behav exp financ. 2018; 17:22-27. 12. peer e, brandimarte l, samat s, acquisti a. beyond the turk: alternative platforms for crowdsourcing behavioral research. j exp soc psychol. 2017; 70:153-163. 13. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res 1999; 11:319-26. 14. rosen rc, riley a, wagner g, et al. the international index of erectile function (iief): a multidimensional scale for assessment of erectile dysfunction. urology. 1997; 49:822-830. 15. symonds t, perelman ma, althof s, et al. development and validation of a premature ejaculation diagnostic tool. eur urol. 2007; 52:565-73. 16. isidori am, pozza c, esposito k, et al. development and validation of a 6-item version of the female sexual function index (fsfi) as a diagnostic tool for female sexual dysfunction. j sex med. 2010; 11:39-46. 17. derogatis l, clayton a, lewis-d’agostino d, et al. validation of the female sexual distress scale revised for assessing distress in women with hypoactive sexual desire disorder. j sex med. 2008; 5:357-364. 18. handy ab, stanton am, pulverman cs, meston cm. differences in perceived and physiologic genital arousal between women with and without sexual dysfunction. j sex med. 2018; 15:52-63. 19. rocca rossetti s., functional anatomy of pelvic floor. arch ital urol androl. 2016; 88:28-37. 20. lakhoo j, hhatri g, chernyak v et al. mri of the male pelvic floor. radiographics. 2019; 39:2003-2022. 21. handa vl, cundiff g, chang hh et al. female sexual function and pelvic floor disorders. obstet gynecol. 2008; 111:1045-1052. 22. fortenberry jd, hensel dj. sexual modesty in sexual expression and experience: a scoping review, 2000-2021. j sex res. 2022; 59:1000-1014. 23. morokoff pj. effects of sex guilt, repression, sexual ‘‘arousability’’ and sexual experience on female sexual arousal during erotica and fantasy. j pers soc psychol. 1985; 49:177-187. correspondence giuseppe la pera, md (corresponding author) dr.giuseppelapera@gmail.com via delle mura gianicolensi 67 c/o upmc salvator mundi international hospital, rome, italy sabrina anticoli marilena mangiardi stroke unit head neck and neuroscience department san camillo hospital, rome, italy stefano livi social and developmental psychology, university of rome "la sapienza", rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12703 1 original paper aim: to present state of the art on the management of urinary stones from a panel of globally recognized urolithiasis experts who met during the experts in stone disease congress in valencia in january 2024. options of treatment: the surgical treatment modalities of renal and ureteral stones are well defined by the guidelines of international societies, although for some index cases more alternative options are possible. for 1.5 cm renal stones, both m-pcnl and rirs have proven to be valid treatment alternatives with comparable stone-free rates. the m-pcnl has proven to be more cost effective and requires a shorter operative time, while the rirs has demonstrated lower morbidity in terms of blood loss and shorter recovery times. swl has proven to be less effective at least for lower calyceal stones but has the highest safety profile. for a 6mm obstructing stone of the pelviureteric junction (puj) stone, swl should be the first choice for a stone less than 1 cm, due to less invasiveness and lower risk of complications although it has a lower stone free-rate. rirs has advantages in certain conditions such as anticoagulant treatment, obesity, or body deformity. management of urinary stones: state of the art and future perspectives by experts in stone disease athanasios papatsoris 1, 25, alberto budia alba 2, juan antonio galán llopis 3, murtadha al musafer 4, mohammed alameedee 5, hammad ather 6, juan pablo caballero-romeu 7, antònia costa-bauzá 8, athanasios dellis 9, mohamed el howairis 10, giovanni gambaro 11, bogdan geavlete 12, adam halinski 13, bernhard hess 14, syed jaffry 15, dirk kok 16, hichem kouicem 17, luis llanes 18, juan m. lopez martinez 19, elenko popov 20, allen rodgers 21, federico soria 22, kyriaki stamatelou 23, alberto trinchieri 24, 25, christian tuerk 26 1 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athen; 2 urology department, la fe university and polytechnic hospital, valencia, spain; 3 department of urology. general university hospital dr. balmis, alicante, spain; 4 university of basrah, basrah, iraq; 5 diwaniya teaching hospital, iraq; 6 aga khan university, karachi, pakistan; 7 department of urology, miguel hernández university, alicante, spain; 8 laboratory of renal lithiasis research, university institute of health sciences research (iunics-idisba), university of illes balears, palma de mallorca, spain; 9 2nd department of surgery, aretaieion academic hospital, school of medicine, national and kapodistrian university of athens, athens, greece; 10 imperial college, london university, london, uk; 11 division of nephrology, department of medicine, university hospital of verona, verona, italy; 12 “carol davila” university of medicine and pharmacy & “saint john" emergency clinical hospital, bucharest, romania; 13 private medical center “klinika wisniowa" zielona gora, poland; 14 internal medicine & nephrology, kidneystonecenter zurich, klinik im park, zurich, switzerland; 15 university hospital galway, galway, ireland; 16 saelo scientific support, oegstgeest, the netherlands; 17 private clinic, clinique les pins, setif, algeria; 18 urology department, university hospital of getafe, getafe, madrid, spain; 19 dept of urology, university of barcelona clinic hospital, barcelona, spain; 20 department of urology, umhat “tzaritza yoanna-isul", medical university sofia, sofia, bulgaria; 21 university of cape town, cape town, south africa; 22 experimental surgery department, ramón y cajal university hospital, madrid, spain; 23 mesogeios nephrology center, haidari attica and nephros.eu private clinic, athens, greece; 24 school of urology, university of milan, milan, italy; 25 u-merge scientific office; 26 urologic department, sisters of charity hospital and urologic praxis, wien, austria. doi: 10.4081/aiua.2024.12703 summary technical issues of the surgical procedures for stone removal: in patients receiving antithrombotic therapy, swl, pcn and open surgery are at elevated risk of hemorrhage or perinephric hematoma. urs, is associated with less morbidity in these cases. an individualized combined evaluation of risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. pre-interventional urine culture and antibiotic therapy are mandatory although uti treatment is becoming more challenging due to increasing resistance to routinely applied antibiotics. the use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. measurements of temperature and pressure during rirs are vital for ensuring patient safety and optimizing surgical outcomes although techniques of measurements and methods for data analysis are still to be refined. ureteral stents were improved by the development of new biomaterials, new coatings, and new stent designs. topics of current research are the development of drug eluting and bioresorbable stents. archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 2 introduction (athanasios papatsoris, murtadha al musafer, athanasios dellis, mohamed el howairis) urolithiasis in the urinary tract is a worldwide prevalent disease, affected from several factors, especially dietand climate-related, that shows increasing prevalence in all ages, races, and sexes. they suggest a cause of significant morbidity despite scientific and technological advances. as a result, the assessment of optimal diagnostic pathways and evidence-based management of urolithiasis and their incorporation into clinical practice is of utmost importance. the purpose of this article is to accumulate up-to-date available knowledge and surgical tips and tricks from a panel of globally recognized urolithiasis experts who met during the experts in stone disease congress in valencia in january 2024. this global multi-disciplinary approach in urolithiasis was noor buchholz’s vision. it is with regret to accept that noor is no longer with us, and this article is a least farewell. surgical stone management the indications for the treatment of kidney and ureteral stones are well defined by the main guidelines (table 1), although some borderline cases remain amenable to different forms of treatment (13). these conditions may include kidney stones of 15 mm diameter and stones of 6 mm in the pyelo-ureteral joint. below are the potential benefits of each form of treatment. the 1.5 cm kidney stone mini-pcnl (elenko popov) it is well established in international guidelines that most renal stones > 2 cm in diameter should be treated with percutaneous nephrolithotomy (pcnl) and those with a diameter < 1-2 cm with rirs; however, mini-pcnl contable 1. indications for treatment of 10-20 mm stones according to american and europen associations guidelines. stone location stone size eau guidelines aua guidelines upper/middle calyces/renal pelvis 10-20 pcnl/urs or swl swl or urs lower pole 10-20 (favourable factors for swl) swl or urs/pcnl 10-20 (unfavourable factors for swl) pcnl/urs as first line, swl as second line complications of endoscopic treatment: pcnl is considered the most invasive surgical option. fever and sepsis were observed in 11 and 0.5% and need for transfusion and embolization for bleeding in 7 and 0.4%. major complications, as colonic, splenic, liver, gall bladder and bowel injuries are quite rare but are associated with significant morbidity. ureteroscopy causes less complications, although some of them can be severe. they depend on high pressure in the urinary tract (sepsis or renal bleeding) or application of excessive force to the urinary tract (ureteral avulsion or stricture). diagnostic work up: genetic testing consents the diagnosis of monogenetic conditions causing stones. it should be carried out in children and in selected adults. in adults, monogenetic diseases can be diagnosed by systematic genetic testing in no more than 4%, when cystinuria, aprt deficiency, and xanthinuria are excluded. a reliable stone analysis by infrared spectroscopy or x-ray diffraction is mandatory and should be associated to examination of the stone under a stereomicroscope. the analysis of digital images of stones by deep convolutional neural networks in dry laboratory or during endoscopic examination could allow the classification of stones based on their color and texture. scanning electron microscopy (sem) in association with energy dispersive spectrometry (eds) is another fundamental research tool for the study of kidney stones. the combination of metagenomic analysis using next generation sequencing (ngs) techniques and the enhanced quantitative urine culture (equc) protocol can be used to evaluate the urobiome of renal stone formers. twenty-four hour urine analysis has a place during patient evaluation together with repeated measurements of urinary ph with a digital ph meter. urinary supersaturation is the most comprehensive physicochemical risk factor employed in urolithiasis research. urinary macromolecules can act as both promoters or inhibitors of stone formation depending on the chemical composition of urine in which they are operating. at the moment, there are no clinical applications of macromolecules in stone management or prophylaxis. patients should be evaluated for the association with systemic pathologies. prophylaxis: personalized medicine and public health interventions are complementary to prevent stone recurrence. personalized medicine addresses a small part of stone patients with a high risk of recurrence and systemic complications requiring specific dietary and pharmacological treatment to prevent stone recurrence and complications of associated systemic diseases. the more numerous subjects who form one or a few stones during their entire lifespan should be treated by modifications of diet and lifestyle. primary prevention by public health interventions is advisable to reduce prevalence of stones in the general population. renal stone formers at "high-risk" for recurrence need early diagnosis to start specific treatment. stone analysis allows the identification of most “high-risk” patients forming non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). patients at “high-risk” forming calcium stones require a more difficult diagnosis by clinical and laboratory evaluation. particularly, patients with cystinuria and primary hyperoxaluria should be actively searched. future research: application of artificial intelligence are promising for automated identification of ureteral stones on ct imaging, prediction of stone composition and 24-hour urinary risk factors by demographics and clinical parameters, assessment of stone composition by evaluation of endoscopic images and prediction of outcomes of stone treatments. the synergy between urologists, nephrologists, and scientists in basic kidney stone research will enhance the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation. key words: urinary calculi; percutaneous nephrolithotomy; retrograde intrarenal lithotripsy. submitted 1 june 2024; accepted 10 june 2024 archivio italiano di urologia e andrologia 2024; 96(2):12703 3 management of urinary stones: state of the art and future perspectives by experts in stone disease stitutes a viable and effective minimally invasive treatment option for ever smaller stones, whereas the limits of rirs are continuously pushed towards ever larger stones. in order to decrease the complications rate of pcnl, jackman (1998) (4) developed the concept of minimallyinvasive percutaneous nephrolithotomy (mini-perc), which is based on the assumption that the decrease of pcnl tract size (< 16 fr) will lower the trauma on the renal parenchyma and hence the risk of bleeding. during the last decades, this tendency towards miniaturization (mini-pcnl, super-minipcnl, ultra-mini pcnl and micro-pcnl) was steadily developed allowing for pcnl completion through a narrower and safer nephrostomy tract (5, 6). a critical point for the success of this miniaturization was the introduction of medium and high-power lasers, which allows bigger stones to be treated with mini-pcnl the ongoing experience with the mini-pcnl technique showed that mini-pcnl is not only a miniaturization but also a different method to remove the stones, as the stones come out of the calyceal system only by means of the irrigation flow without any further need of forceps or baskets (vacuum-cleaner effect or active aspiration sheath). standard pcnl still represents “the big gun” to be used in cases of bulky nephrolithiasis being highly effective although with more significant complications (collateral damage). on the contrary miniaturized pcnl has the “the special forces” philosophy being small size, agile, flexible and with minimal surgical trauma. a significant decrease of transfusion rate was observed with mpcnl. in the comparison with rirs, new technological advancements favor the choice of mini-pcnl as new 7.5 f scopes, new bendable suction ureteral access sheaths (uass), and new lasers with magnificent dusting abilities. mini-pcnl is economically more feasible, without problems in cases of difficult retrograde access or need for prestenting; it requires fewer secondary procedures and guarantees much better flow that rirs. rirs (bogdan geavlete) starting from the last place in the list of therapeutic approaches for renal calculi smaller than 2 cm in 2010, retrograde intrarenal surgery (rirs) can actually compete with all the other current stone treatment practices. in 2023, the eau guidelines consecrated rirs efficacy in treating stones up to 3 cm, depending on operator skills and frequently requiring staged procedures (2). in comparison, despite the higher success rate in approaching lower pole calculi, mini-percutaneous nephrolithotomy (mini-pcnl) has been described as involving a higher rate of complications as well as a longer hospital stay (2). the potential concern about the presence of residual fragments after the retrograde procedure proved to be clinically unjustified because more than four out of five cases of post-ureteroscopic renal stone fragments under 4 mm were found to either become stone-free due to spontaneous passage or retain asymptomatic stable-size fragments (7). aiming to reach an evidence-based comparison, a systematic review and meta-analysis including 18 eligible randomized-controlled clinical trials and involving over 1700 patients emphasized both mini-pcnl and rirs as safe and effective alternatives in treating renal calculi of 1 to 3 cm. it also acknowledged the mini-perc capacity to provide a higher stone-clearance rate with a shorter operation time. on the other hand, the antegrade approach has been negatively characterized by significantly longer hospital stay, higher blood loss and transfusion rate, more severe complications, increased pain and higher hospital costs due to its invasive surgical profile (6). furthermore, a prospective cohort comparative study targeting precisely the current topic (average renal stone size of 15-16 mm) confirmed the few and not statistically significant differences between the two therapeutic alternatives. mini-pcnl was described as the more cost-effective option, with the drawback of substantially longer hospital stay, while comparable sone-free rates were obtained after a single session (93% versus 89%) (8). it has been consistently underlined that rirs provides similar therapeutic efficacy in comparison to mini-perc, according to statistically similar stone-free rate, together with reduced perioperative morbidity (shown by the diminished blood loss as well as the shorter recovery time), and despite the longer operative time (9). at last, but not least, rirs seems to benefit from therapeutic superiority over extracorporeal shock-wave lithotripsy (eswl), in light of the literature data supporting the significantly higher stone-free rate and lower re-treatment rate, without an increase in the incidence of complications (10). finally, the choice for any alternative minimally-invasive stone treatment should largely rely on some decisive factors, such as stone location, kidney anatomy, associated comorbidities and patient’s preference, as well as the urologist’s expertise and the available medical equipment. finally, it becomes increasingly clear that a patient-tailored therapeutic approach leads the way towards good clinical practice, while treatment algorithms and integrated management strategies are continuously evolving in the era of remarkable technological advances. swl (christian tuerk) the 15 mm kidney stones have an indication for interventional stone removal and according to the eau guidelines, both swl and endourological procedures are available as the first choice for this purpose. in 2023, regularly updated systematic cochrane reviews comparing swl, ureteroscopy and percutaneous stone removal came to the conclusion that swl may have lower three-month success rates but less complications compared to the alternatives (11). another systematic review with network analysis, including 1674 patients, once more showed that swl is the best option in terms of safety, although, at least for lower calyceal stones, the efficiency is worse (12). however, efficiency of swl con be improved by proper patient selection and best practicing swl-treatment. factors for prediction of swl-success are skin to stone distance, hounsfield units with stone heterogeneity, stone size/volume (13), anatomy of collecting system, etc. in special situations swl even could be the least burdensome way to treat depending on comorbidities, e.g. in patients with severe kyphoscoliosis including restrictive respiratory obstruction and anesthesia related difficulties (tracheal intubation). best practicing swl-treatment includes shock wave rate 1-1.5 hz, archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 4 ramping of sw-intensity, correct coupling, careful monitoring of both, stone targeting and patients movements during swl (us), proper analgesia (limits movements and respiratory excursions) (14). besides proper patient selection and best clinical practice post-swl measures can improve outcome, like medical expulsive therapy or diuresis-inversion-percussion (15). providing proper patient and stone selection and with best clinical swl-practice the 1.5 cm kidney stone is definitely a case for swl with low invasiveness and few complications. the 6 mm obstructing pelvi-ureteric junction (puj) stone rirs (syed jaffry) retrograde intrarenal surgery (rirs) emerges as the optimal approach for managing a 6 mm pelvi-ureteric junction (puj) stone, despite the scarcity of data specific to this size. this methodology's support comes from indirect evidence and a comprehensive evaluation of various critical factors influencing treatment decisions. location plays a pivotal role in determining the approach for stone removal. a stone positioned at the puj presents unique challenges due to its proximity to the kidney and the potential for causing significant obstruction. rirs, with its maneuverability and direct access capabilities, especially in cases with virgin ureters, either with or without the use of ureteral access sheaths (uas), offers a distinct advantage. it enables effective push-back techniques and complete stone clearance, even in the face of puj obstruction or a tortuous alpha loop in the proximal ureter. the size of the stone, being 6 mm, resides in a grey zone where spontaneous passage is uncertain, thereby necessitating intervention. rirs, with its ability to address stones of this size with minimal complications and favorable outcomes, stands out as a particularly suitable option. furthermore, the stone's composition, the presence and duration of obstruction, and whether the stone is impacted are all factors that rirs can adeptly navigate. rirs also provides significant benefits in terms of patient safety and comfort. it eliminates the need to stop anticoagulation therapy, which is crucial for patients at risk of thromboembolic events. additionally, for individuals with morbid obesity or body deformities, rirs offers a safer alternative, reducing the risks associated with more invasive procedures. moreover, in anatomically challenging conditions such as horseshoe kidneys, rirs demonstrates superior adaptability and effectiveness. while direct statistics for rirs specifically targeting 6 mm puj stones are limited, the general success rate of rirs for kidney stones supports the expectation of high stone free rates (sfrs) for such cases, adjusted for individual clinical scenarios. thus, rirs stands as the preferred method for managing 6 mm puj stones, balancing efficacy, safety, and patient outcomes. emergency swl (eswl) (christian tuerk) in eau-guidelines shock wave lithotripsy is the first choice for interventional stone removal of up to 1 cm stones both, in the kidney pelvis and in ureter promising less invasiveness and complications but lower stone free rates (sfr) compared to endourological procedures. to address the current case of a 6 mm puj-stone the literature was examined with the question of the possible advantage of an early therapy. back in 2014 sarica et al. showed in a retrospective case study that there is a highly significant relationship between ureteral wall thickness and the success rates of swl (16). the ureter wall thickness is a sign of impaction and depends on time. a prospective randomized study comparing early (emergency) swl with delayed treatment shows an impressive advantage of the eswl over delayed swl in both the sfr and the efficiency quotient after 1 day, 1 week, 1 month and 3 months (17). in 2023 a meta-analysis evaluating the efficacy of eswl treating ureteral stones showed that sfr was statistically significant higher and faster in eswl group with significant less auxiliary procedures (18). a matched-pair-analysis in 2021 from switzerland compared immediate swl vs delayed swl after emergency stent insertion, including patient with puj-stones; e-swl or stent respectively was performed within 48 hours after first presentation of patient; in this study once more sfr of 6-9 mm stones was significantly higher with lower reintervention rate compared to stent+delayed swl (19). in conclusion, the 6 mm obstructing puj-stone is definitely a case for emergency swl showing low invasiveness, less complications and has much better results compared to delayed treatment, resulting in less loss of working days and being possible as an outdoor procedure depending on national health care. technical issues of urinary stone management patients on anticoagulants (hichem kouicem) in chronic anticoagulant users undergoing surgery, bleeding and thromboembolism are common and serious complications. there are two main classes of oral antithrombotic drugs: antiplatelet drugs (aspirin) and oral anticoagulants, including vitamin k antagonists (vka) and direct-acting oral anticoagulants (doac) (table 2). the bleeding risk is associated with type of stone surgery and procedure as extracorporeal shock wave lithotripsy table 2. antithrombotic drugs. anticoagulants agents vitamin k antagonists (vka) warfarin direct-acting oral anticoagulants (doac) direct thrombin inhibitors dabigatran direct xa inhibitors apixiban endoxaban rivaroxaban indirect thrombin inhibitors lmwh uhf fondaparinux antiplatelet agents cox inhibitors aspirin adp inhibitors clopidogrel prasugrel ticagrelor glycoprotein iib/iiib inhibitors archivio italiano di urologia e andrologia 2024; 96(2):12703 5 management of urinary stones: state of the art and future perspectives by experts in stone disease (eswl), percutaneous nephrolithotomy (pcnl), and open surgery. in case of low bleeding risk, the evidence suggests that vka might not be stopped. urgently needed surgery must take place under full antiplatelet therapy despite the increased bleeding risk. for high thrombotic risk, vka must be stopped 5 days before surgery with bridging using full-dose of > lowmolecular-weight heparin (lmwh) or unfractionated heparin (ufh) started 3 days before surgery. lmwh or ufh will be stopped respectively one day and 4 to 6 hours before surgery. vka will be resumed 12 to 24 hours after the procedure. for urologists, surgery performed on a patient under anticoagulant treatment led to manage the risk-risk balance between bleeding and thromboembolism (20). antibiotic resistance (adam halinski) utis are becoming increasingly difficult to treat owing to the rapid spread of drug resistance among gram-negative organisms. utis are at the forefront of the antibiotic resistance problem because 9% of all antibiotic prescriptions in the ambulatory setting in the usa are done for the treatment of uti. the problem is related to broadspectrum antibiotics that have been the drug of choice to treat both communityand hospital-associated utis. the increase of antibiotic resistance and appearance of multi-drug resistant (mdr) pathogens in the course of uti is related to high rates of inadequate antibiotic empirical therapies prescribed without the antibiotic susceptibility testing and finally resulting in an ineffective uti treatment. the risks of multi-drug resistant pathogens are: recurrent utis (21), hospitalization, age, genitourinary disturbances, prior use of antibiotics (22, 23), increased use of broadspectrum antibiotics leading to increased antimicrobial resistance and multi-resistance of bacteria (24). health care practitioners should be educated on the suitability of urine culture and should read the literature to compare it with local resistance rates. rapid molecular tests could shorten the waiting time for urine culture. development of new antibiotics and probiotics can decrease the resistant rate. on the other hand, antibioticsparing therapeutics including small-molecular inhibitors of bacterial adhesion, immunomodulatory therapy that alters the host response to infection and vaccinations against microbial targets could also be helpful. in conclusions, pre-interventional urine culture is mandatory. antibiotic therapy is important in the uti treatment but in recent years it is becoming more challenging due to increasing resistance to routinely applied antibiotics. the use of an intrarenal urine culture and stone culture is recommended to adapt antibiotic therapy in case of postoperative infectious complications. zero radiation ultrasound guided pcnl (mohammed alameedee) pcnl is wide world used operation to remove renal stones , fluoroscopy is used as a guidance for pcnl, but it is limited by the risk of radiation, so ultrasound-guided pcnl is an option to replace fluoroscopic guidance avoiding the limitation of x-ray exposure. it has multiple advantages with respect to fluoroscopic guidance as no radiation, imaging of structures between skin and kidney to assess depth of the access needle and prevent organ injury , no need for contrast media (especially in case of failure of retrograde pyelogram due to difficult ureteric catheterization), safety in pediatric and pregnant patients, feasibility in supine position with no need for lithotomy position and ureter stent fixation, and cost-effectiveness. on the other hand, ultrasound guided pcnl is challenging to the surgeon because it needs good eye hand coordination with long training curve and because it can be difficult when perinephric fat make the identification of access needle tip difficult by ultrasound, especially in obese patients. hydro dissection can be used to overcome these difficulties by injection of normal saline through the access needle along the tract from skin to target calyx to dissect muscle layers and fatty tissue by saline which leads to easy identification of needle. optical hydro dissection allows easy identification of the access needle with concomitant continuous optical control by use of a 2 mm telescopic lens incorporated into an access needle associated with pressured saline infusion which dissect tissue layers along tract from skin to target calyx. ultrasound-guided pcnl is an option to replace fluoroscopic guidance avoiding the limitation of x-ray exposure. it has also multiple advantages as imaging of neighboring organs, no need for contrast media and ureteral catheterization safety in pediatric and pregnant patients and cost-effectiveness. optical hydrodissection by use of a 2 mm telescopic lens incorporated into an access needle allows easy identification of the needle with concomitant continuous optical control. tubeless pcnl (elenko popov) in the last decades, percutaneous nephrolithotomy (pcnl) experienced enormous technical advancements like miniaturization of the available armamentarium (2). to further decrease the invasiveness of this procedure, safety and efficacy of different exit strategies like the tubeless pcnl technique have been explored. the presence of nephrostomy tube has several advantages potentially lowering complications rate as maintaining renal drainage, allowing for reintervention if needed; avoiding urine extravasation; and preventing continuous bleeding by compressing the dilatation tract. conversely, it also has significant drawbacks: prolonging hospitalization; increasing postoperative pain score and analgesic requirements; not being so suitable for ambulatory/day-case surgery. a significant problem in comparing use of nephrostomy after pcnl with tubeless pcnl in the literature is the standardization of nomenclature! series can be different depending on type of pcnl (standard, mini, super-mini, micro, nano), characteristics of patients and stones, and types of nephrostomy (tube, small-bore tube, tubeless, not so tubeless, almost tubeless, totally tubeless). however, all meta-analyses comparing standard and tubeless pcnl reach similar conclusions (25-28): the key to effective outcome with tubeless pcnl is appropriate patient select, tubeless procedures are considered safe and effective in lowrisk patients, most of reported studies conclude that a tubeless procedure is associated with less patient discomfort and shorter hospital stay compared to the standard pcnl, the complication rate, including postoperative fever, haematarchivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 6 ocrit decrease, stone-free rate and urine extravasation usually did not differ between the different exit strategies. however, all of them report a risk of bias due to high heterogeneity of results. in conclusion, tubeless pcnl has several advantages and is relatively safe, but it may involve great risks if the patients are not carefully selected. therefore, the indications should be strictly controlled, and the technical requirements are relatively high. the tubeless pcnl must also be implemented by experienced surgeons. choice of laser for lithotripsy (elenko popov) the development of laser technologies is one of the main prerequisites in modern endourology. massive breakthroughs were achieved in the last years by second generation holmium-yag, thullium fibre laser, pulsed thulium laser (29-31). the ideal laser for lithotripsy should be effective, safe, multitasking, fast, noiseless, ergonomic, and cost-effective. new ho:yag technologies as high power, high frequency and pulsed modulations have shown promising results for lithotripsy by reducing retropulsion with good ablation efficiency. high peak power makes it particularly good for percutaneous nephrolithotomy. high intrarenal temperatures and choice of correct setting are still concerning points. thulium fiber laser (tfl) has arrived to be one of the main players in flexible ureteroscopy. being highly efficient and quick, and by producing micro-dusting the laser is quickly heading to become a gold standard. the new pulsed thulium yag is the newest laser. for now, only in-vitro studies show promising results with efficient lithotripsy. as the peak power lies between ho:yag and tfl it may be able to adequately perform when needing high and low power lithotripsy. pressure and temperature during rirs (syed jaffry) the review of temperature and pressure measurements during retrograde intrarenal surgery (rirs) highlights crucial insights and challenges inherent to the procedure. these measurements are vital for ensuring patient safety and optimizing surgical outcomes, yet they present specific difficulties that demand a careful and informed approach. the challenges associated with accurately measuring and interpreting temperature and pressure levels during rirs can significantly impact the procedure's efficacy and the patient's postoperative recovery. recognizing these challenges is the first step towards mitigating potential risks and enhancing the overall success of the surgery. to address these issues effectively, it is essential to focus on refining measurement techniques and developing novel methods for data analysis. this includes improving the precision of intraoperative measurements and exploring advanced approaches for interpreting this data in realtime. moreover, establishing a clear correlation between these intraoperative metrics and long-term patient outcomes is crucial for validating the effectiveness of rirs procedures. collaboration between urologists, engineers, and data scientists is critical for advancing this field. together, they can work towards creating integrated systems that facilitate the seamless collection, analysis, and visualization of crucial surgical data. such systems would not only improve the accuracy of temperature and pressure measurements but also enhance the decision-making process during rirs. in the interim, adherence to current practices such as the use of ureteral access sheaths (uas) with or without suction devices, continuous fluid management monitoring, and the emphasis on surgeon skill development remain pivotal. these practices, alongside the optimal duration of surgery and a personalized approach to patient selection and procedure planning, are essential for maintaining the standard of care in rirs. future research should thus prioritize these areas to ensure continued improvement in patient care and surgical outcomes in the realm of urology (32). urinary stent technology (federico soria) the three pillars of stent improvement are the development of new biomaterials, new coatings, and new stent designs. furthermore, the development of drug eluting stents is a topic on which many research groups are working. about the coatings, the aim is to prevent the formation of biofilm, which is associated with asymptomatic bacteriuria and urinary tract infection, as well as the encrustation of stents. one fact researchers must be aware of is the severe antimicrobial resistance surveillance in europe policy. the aim is to coat stents with substances that prevent the adhesion of bacteria and crystals on their surface. to this end, different strategies have been developed, the most promising being the development of antimicrobial peptides with bactericidal capacity (33). the great innovation in ureteral stents is mainly the development of research lines about drug-eluting stents. the main idea in this topic is that the stents, in addition to improving urinary drainage and scaffolding, can perform other functions such as local drug delivery. this could be in the near future with different applications. there are experimental studies on drug-eluting stents releasing rapamycin, paclitaxel or pirfenidone to inhibit relapse of ureteral strictures after endoureterotomy, in relation to inhibition of the mtor pathway or reduction of tgf expression which inhibits collagen deposition (34, 35). in this regard, our research group developed a new coated mitomycin-eluting biodegradable ureteral stent for intracavitary instillation as an adjuvant therapy in upper urothelial carcinoma (36). thus, the development of drug-eluting stents is the near future, aiming to reduce the adverse effects of stents and to topical drug delivery to avoid systemic drug administration, thereby reducing complications. bioresorbable stents (federico soria) unfortunately, the ideal ureteral stent has not yet been designed. nevertheless, several authors have outlined its characteristics very well, one of the features is related to ease of insertion and removal. obviously, the answer to easy removal is not having to remove them, which means that they would be biodegradable. the characteristics of an ideal biodegradable ureteral stent (bus) should be: excellent biocompatibility; moderate mechanical properties; complete degradation without obstructive fragments; prevent migration; good flexibility for stent placement; radiopacity; visibility on ultrasound; controlled degradation rate; no mutagenic, antigenic, and carcinogenic activity; no degradation with toxic metabolites (37). archivio italiano di urologia e andrologia 2024; 96(2):12703 7 management of urinary stones: state of the art and future perspectives by experts in stone disease about the current limitations to bus development, there are some main points to improve. degradation rate control: one of the most important factors in bus development is the ability to control the degradation rate in order to develop a stent that will have the required duration. biomechanical properties control: the balance between degradation and scaffold is very difficult to achieve. fragmentation size control and non-obstructive fragments release: this is another essential requirement and has been the reason why the first bus designs were not successful, as the degradation of the stents was often obstructive. new designs, have managed to overcome this drawback thanks to the use of polymers and copolymers with different degradation rates. there are different research groups working on bus. our research group has been developing a bus for the last few years. braidstent is a braided stent made of synthetic polymers and copolymers that are degradable by hydrolysis. this allows the suitable degradation rate, without obstructing fragments and the adjustment of degradation according to the needs of the individual patient (38, 39). to summarize, it is certainly not a fiction. researchers have greatly improved buss and preclinical studies have already yielded very positive results. in my opinion, the glass is half full and getting fuller. complications of surgical stone treatment complications of pcnl (hammad ather) of the three minimally invasive surgical options (shock wave lithotripsy/swl, flexible ureteroscopy/furs and percutaneous nephrolithotomy/pcnl), in the management of urolithiasis, pcnl is considered as the most invasive although it has high efficacy particularly for intermediate and large stones including staghorn calculi. in a review paper, seitz et al. (40) indicated that although no deviation from the normal postoperative course (clavien 0) was observed in 76.7%, the rest had complications of various grades including death in 0.04%. the two major most common complications include septic complications and bleeding. fever, and sepsis were observed in 11 and 0.5% respectively. the bleeding related complications with need for transfusion and embolization were observed in 7 and 0.4% respectively. authors observed a wide variation in reporting of these complications in the absence of a specific tool for reporting procedure specific morbidity. clavien system is widely used to report urological complications, however, procedure specific scoring is more desirable. in a paper published by de la rosette et al. (41). authors observed that clavien classification demonstrates high validity although inter-rater reliability is low for minor complications. abdominal organ injury including colonic, splenic, liver, gall bladder and bowel injuries are fortunately quite rare but are associated with significant morbidity. in a systematic review ozturk et al. (42) reported 51 colonic injuries out of 13000 patients undergoing both supine and prone pcnl. all gall bladder injuries necessitated cholecystectomy, whereas liver injuries were mostly amenable to conservative treatment. laparotomy and diversion are rarely performed for colonic injuries, particularly in the absence of signs of peritonitis. major bleeding complications are managed by embolization. in conclusion, pcnl related major complications are not frequent but significant. improvement in technique, equipment and better understanding have improved the outcome. there is a downward trend in the incidence, but also most of the complications are managed conservatively. management of pcnl complications (alberto budia alba) pcnl is a minimally invasive surgical technique, but it is not free of complications. the reported complication rate is approximately 23.7% (40). although the most frequent is fever (10.8%), serious complications can occur such as pleural lesions (1.5%), sepsis (0.5%), organ injury (0.4%) and even death (0.05%). perhaps, the best way to avoid them is to try to prevent them. adequate planning of the caliceal approach depending on the patient's position, adequate bridging treatment of anticoagulated or anti-aggregated patients, and preoperative cultures that allow the patient to arrive at surgery with sterile urine are effective measures to reduce the probability of complications. the complications of this technique are divided into intraoperative and postoperative. intraoperative complications can be prevented by accurate access through the calyceal papilla and performing delicate maneuvers in the dilation of the tract, which reduces intraoperative bleeding. the use of a safety guide allows, in the event of failure to reach the urinary system, a new access using the safety guide without the need to re-puncture. in case of perforation of the urinary tract during dilation, if the perforation is small, treatment can be completed, but if the leak is significant, it should be postponed after insertion of an urinary diversion. the hydrothorax should be managed with pleural drainage; colon perforation, if it is intraperitoneal, requires surgical repair and, if it is extraperitoneal, it can be managed conservatively with urinary and retroperitoneal drainage. the most feared postoperative complication is urinary sepsis, more frequent in insulin-dependent patients, women and in case of large and infective lithiasis (43). an early identification and treatment is the key to a good therapeutic response. the second most serious postoperative complication is late hemorrhage, secondary to a pseusoaneurysm or arteriovenous fistula, which in most cases requires angioembolization. therefore, although pcnl is a minimally invasive technique, it is not free of complications, some of them potentially serious, which should be identified early and treated properly. complications of urs (juan pablo caballero) ureteroscopy (urs) is a technique with a low frequency of severe complications (44, 45). but some complications can cause real nightmares. we must emphasize the importance of complications generated by ureteral catheters. never place ureteral stents unnecessarily after ureteroscopy. we can identify urs-related complications until more than 6 months later. some of those that, due to their severity, we must avoid and know how to treat are those dependent on high pressure in the urinary tract, sepsis of archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 8 urinary origin, renal bleeding, and those secondary to applying excessive force to the urinary tract, as ureteral avulsion and ureteral stricture. sepsis occurs more frequently in patients with a positive preoperative urine culture. therefore correct prophylaxis, or treatment, guided by the antibiogram and knowledge of local antibiotic resistances is mandatory. sepsis will occur more frequently if we exceed intrapelvic pressure levels greater than 30 mmhg. high pressure can also lead to bleeding from the renal parenchyma that will cause flank pain and a drop in hemoglobin levels. treatment will usually be by selective embolization of the renal parenchyma. one of the most devastating complications is ureteral avulsion, which can be proximal and/or distal (46, 47). thinner or less compliant ureters are more sensitive to these complications, especially if we use larger caliber ureteroscopes. urgent surgical repair by laparoscopy is essential. ureteral stricture can occur up to 7 months after the intervention. it requires a high degree of suspicion after ureteral injuries or impacted stones. for its diagnosis we need imaging and functional tests, such as the isotopic renogram. ecirs: indications and complications (luis llanes) endoscopic combined intrarenal surgery (ecirs) combines retrograde and antegrade approaches using both flexible and rigid endoscopes for treating large or complex renal stones (48). it was first described by gaspar ibarluzea in 2007 (49) and after, cesare scoffone created the acronym ecirs (endoscopic combined intrarenal surgery) in 2008. the indications of ecirs can be summarised in two (48): 1. to treat staghorn or complex kidney stones and limit the number of percutaneous accesses. 2. to treat simultaneous multiple kidney and ureteral stones or an impacted pelvic stone. the modified supine position by galdakao is the most extended patient position to do an ecirs because two simultaneous surgeons are working and helping each other with total access to the urinary tract. complications can potentially occur in the procedure: during access, procedure or exit process, and can be classified according to the modified satava classification system (50): • grade 1: an error without consequences • grade 2a: an error was identified and corrected immediately with endoscopic surgery intraoperatively • grade 2b: a complication treated with endoscopic surgery in another operative session. • grade 3: a complication that requires open or laparoscopic surgery the postoperative complications of ecirs, according to the clavien-dindo classification, are the same as in percutaneous nephrolithotomy (pcnl): haemorrhagic, infectious, obstructive, splanchnic injuries, infundibulum stenosis, surgical material retained and renocutaneous fistula. different metaanalyses and systematic reviews comparing ecirs with pcnl for large and complex kidney stones show that overall complications, severe complications, postoperative fever, haemoglobin decrease, transfusion rate and clavien dindo complications are always in favour of ecirs (51, 52). diagnostic work-up genetic testing (giovanni gambaro) genetic testing in nephrolithiasis patients consents the diagnosis of known genetic conditions causing stones and previously unknown gene causing renal stones. many of the monogenetic diseases thus identified can develop ckd/end-stage renal disease and/or metabolic bone disease. in this case, the genetic diagnosis has prognostic implications and is helpful for the prevention of nephropathy and osteopathy. few monogenic diseases identifiable with genetic testing also have specific therapies for personalized/precision therapy. this is the case of primary hyperoxalurias, 1.25-(oh) d-24 hydroxylase deficiencyinfantile hypercalcemia. in the future, other therapies may be able to cure some other genetic defects causing nephrolithiasis. their identification is essential. however, we should ask ourselves whether all nephrolithiasis patients should undergo genetic testing. in studies in which genetic testing was systematically carried out to diagnose mendelian diseases causing nephrolithiasis, the most frequent diagnosis was cystinuria. this is a diagnosis that can be made much more quickly and at much lower costs with the analysis of the morphology and composition of the stone, with the dosage of urinary cystine, with the observation of typical crystals in the urinary sediment, and finally, during a procedure of laser lithotripsy with the typical odor that emanates. frequent genetic diagnoses can also be formulated based on specific easily determined laboratory test patterns (e.g., distal renal tubular acidosis). on the other hand, for the majority of monogenic diseases causing nephrolithiasis, there are no specific therapies. another point to consider is that the prevalence of genetic nephrolithiasis in adult nephrolithiasis patients is lower than reported. if cystinuria, aprt deficiency, and xanthinuria are excluded from the series in which genetic tests have been performed, a maximum of 4% of nephrolithiasis patients in tertiary reference centers are affected (53-55). if we move from the super-selected case series of tertiary reference centers to the general population of adult stone patients, less than 1% of them are carriers of genetic mutations other than cystinuria (56). the success in identifying cases of genetic nephrolithiasis is the direct consequence of selecting cases with clinical characteristics that make one suspect its existence (table 3) (57). it is in these adults that it is reasonable to pertable 3. warning elements on a possible genetic origin of nephrolithiasis. early onset family cases consanguineous parents highly-active stone disease (bilateral, multiple stones, frequently recurrent) associated nephrocalcinosis renal hyperechogenicity tubular dysfunction and related manifestations (statural growth deficit, polyuria, bone disorders) renal failure extrarenal manifestations (sensorineural hearing defects, ocular abnormalities, neurological disorders) particular stone composition and crystalluria (whewellite, cystine, dihydroxyadenine, xanthine) archivio italiano di urologia e andrologia 2024; 96(2):12703 9 management of urinary stones: state of the art and future perspectives by experts in stone disease form genetic testing. since childhood age is one of the main elements for suspecting genetic stones, it is rational to carry out genetic tests in all children. stone analysis (alberto trinchieri) according to eau guidelines (2), after stone passage a reliable stone analysis by infrared spectroscopy or x-ray diffraction is mandatory. aua guidelines (58) confirmed that, when a stone is available, a stone analysis should be obtained at least once. a consensus conference (59) pointed out that infrared spectroscopy or x-ray diffraction to identify mineral types should be preceded by examination of the stone under a stereomicroscope to assess which part (or parts) of the stone should be taken for molecular analysis. visual identification of stone morphology requires a skilled observer, therefore development of methods for evaluation of stone morphology are highly desirable. examination of whole stones provides insight into how the stone has formed and grown, which is partly lost when examining a few fragments extracted from the urinary tract after lithotripsy. unfortunately, in real-life some stone centers still perform the chemical examination of the stone and not all laboratories that perform the spectroscopic examination fulfill the quality requirements (60). the analysis of digital images of stones by deep convolutional neural networks could allow the classification of stones based on their color and texture. this technique can be used in the laboratory for the analysis of photographs of stones or fragments extracted from the urinary tract, but above all for the classification of stones during endoscopic examination in the operating room. stone examination allows the diagnosis of rare stones such as cystine, dihydroxyadenine and xanthine stones; the diagnosis of stones with specific etiology such as uric acid, sodium or ammonium urate, struvite and brushite stones; the differentiation of subtypes of calcium stones (calcium oxalate monohydrate, calcium oxalate dihydrate and carbapatite); to provide information on the components of mixed stones. stereoscopic microscopy (petroscopy) or the analysis of digital imaging allows the identification of subtypes of calcium oxalate or calcium phosphate stones with morphology associated with a specific etiology such as primary hyperoxaluria (com 1c), enteric hyperoxaluria (com 1e), renal tubular acidosis (carbapatite type iv a2), struvite (type iv c) and brushite (type iv d) (61). endourological stone observation (elenko popov) the analysis of the stone is a crucial step of the work up of renal stone forming patients as it provides relevant information on the pathogenic mechanisms of renal stone formation. the analysis of the stone can be performed only after the spontaneous expulsion of the stone or its fragments or after its surgical removal. many efforts have been made to develop imaging modalities able to reliably diagnose in-vivo the physico-chemical composition of the stone before the procedure of stone removal. the increasing efficiency of lasers in “dusting” and “popcorning” modes and the improved performance of endoscopic devices led to smaller stone fragments, which reduce the accuracy of the stone analysis (microscopic morphology and infrared spectroscopy) by the lack of components representativeness considering that 48.6% of the stones have a mixed composition (62). moreover, keller et al. (63) recently showed the impact of laserbased dusting on changes in stone composition with significant changes in the infrared spectra (particularly for weddellite, carbapatite, struvite, and brushite). consequently, examination by infrared spectroscopy of the stone powder by itself could not provide sufficient information of stone composition. this finding reinforces the need to observe the morphology of the stone before laser-induced destruction to preserve an etiological approach. the examination should includ a visual observation of the stone surface first, before laser fragmentation, then visual observation of the section and the nucleus after laser stone section. endoscopic stone observation is feasible but necessitates significant experience, specific expertise, and training. even in in these optimal conditions the rate of concordance of endoscopic examination and microscopy is 80-90% for whewellite (ia or ib = 85%, id = 92%, n = 12; ie = 80%), 85% for weddellite (iia or iib = 85%), 91% for uric acid (iiia or iiib), 50% for carbapatite-struvite association (ivb), and 65% for brushite (ivd) (64). the results of a multi-center expert setting (65), more resembling the real-world scenario, including 32 clinicians from 9 different countries, with significant expertise shows overall accuracy 39% (250 out of 640 predictions), with calcium oxalate dihydrate stones correctly detected in 69.8%, calcium oxalate monohydrate in 41.8%, uric acid in 33.3%, calcium oxalate/uric acid in 34.3%, cystine in 78.1%. precision rates for struvite (15.6%), calcium phosphate (0%) and mixed calcium oxalate/calcium phosphate (9.3%) were quite low. there is a significant tendency for improvement in endoscopic stone recognition in the future: advances in endoscope technology, such as raman spectroscopy, polarization endoscopy and hyperspectral imaging; advances in digital technologies; potential implementation of artificial intelligence (ai) technologies for automated endoscopic stone recognition. on the other hand, problems still need to be solved as bias in generating datasets, mathematical methods weaknesses, mixed stones, and significant difference between ex-vivo and in-vivo. in conclusion, the information that can currently be obtained from endoscopic observation of the stone is limited, as even expert surgeons may not be able to reliably predict the composition of the stone. however, the imminent future technological innovations should allow an accurate prediction of the composition of the stone in its different components, thus adding information to that obtainable with the post-op analysis of the fragments after lithotripsy. for this reason, it should be emphasized the importance of an accurate description of the stone in the report of the endoscopic procedure that should be always accompanied with a photograph or video clip of the stone. urology residents should receive a specific training on the macroscopic aspect of urinary stones and should be encouraged in endoscopic recognition of the most frequent types of renal stones. archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 10 desktop scanning electron microscopy for urinary stones (a. costa-bauzá) scanning electron microscopy (sem) is a non-destructive technique that in the backscattered electron mode provides information about the three-dimensional structure of surface or sections of a kidney stone and a very clear characterization of crystals morphology. the methodology currently used for sem consists of placing the stone on a sample holder, with no need to cover with gold. after observation, the sample is in the same state as before sem analysis. furthermore, sem can be used with auxiliary techniques, especially x-ray scattering analysis energy dispersive spectrometry (eds). this provides reliable data on the elemental composition of a specific point or a general area of a stone (66-68). a substance present in minute quantities, even at trace level, that is not detectable by ir spectroscopy can be identified. currently eds can detect c, n and o, important elements for uric acid and ammonium urate identification. thus, sem-eds can provide information about the: morphology of crystals in the stone allowing their unequivocal identification internal structure with location of crystalline phases and minor components identity of the initial area of calculus formation changes in the crystalline shape or composition. currently, many renal calculi are fragmented prior to analysis, which implies a partial loss of information. however, with stereoscopical microscopy, several representative fragments can be selected, and then use semeds to provide additional information for determining stone etiology. therefore, together with stereoscopical microscopy and ir spectroscopy, sem-eds is a fundamental tool for the study of kidney stones, and the information it provides has great clinical and practical importance. sem will be used more in the future due to the development of desktop models that are easy to use, more affordable, and provide results with the same quality as larger and more expensive models. urinary and intestinal microbioma (juan a. galán-llopis) oxalobacter formigenes that has been largely studied in relation to its role in degrading oxalate and referred to as the main link between gut´s microbiome and urinary stone disease. however, not every species of oxalobacter are related to stone disease and the latest studies suggest that the entire gut microbiome (gmb) seems to be involved in the pathophysiology of urolithiasis, and can have different roles supported by the presence of some short chain fatty acids, that will protect gut´s epithelium, also having an anti-inflammatory effect. gmb dysbiosis exists in the kidney stone forming patients (more bacteroides, e. coli and shigella, less prevotella-9) and in order to restore this microbiome and prevent kidney stone formation, several measures including rational use of antibiotics, probiotic preparations and adjusted diet, and fecal microbial transplantation can be accomplished (69-72). urine is not sterile and some microorganisms, the urobiome, different in stone formers and healthy individuals, can be detected by the combination of metagenomic analysis using next generation sequencing (ngs) techniques (amplicon, shotgun) and the enhanced quantitative urine culture (equc) protocol (73). differences between the stone and urine microbiota have been described, and that may indicate that certain bacteria contribute to urinary stone disease pathophysiology. the microbiota of upper tract and bladder urine are similar, but there are differences between stone and urine microbiota, with a significant decrease of microbiota diversity in stone formers. urobiome can be regulated by pro and prebiotics, diet, and with immunomodulators. consensus will allow for proper future studies on urobiome research. urinary ph (juan a. galán-llopis) urinary ph in humans shows a circadian rhythm and can be affected by different situations including diet, drugs, stress, gender, and genetic and metabolic diseases. apart from the balance between urinary stone promoters and inhibitors, both the time that the urine is within the urinary tract, and the urine ph are needed to form a stone. a high urine ph (> 6.2), independent of diet, and hypocitraturia are the most important risk factors for calcium phosphate stones, especially in women (74). fasting urine ph > 5.8 non-responding to acidification, associated to hypercalciuria, hypocitraturia, and the presence of apatite or brushite stones should direct suspicion to incomplete distal renal tubular acidosis (rta) (75). low urine ph (< 5.5), low urine volume and high uric acid (ua) osmolality will lead to ua stone formation (76). cystine is highly soluble at urine ph higher than 7.5. the only stones that seem independent of urine ph are papillary calcium oxalate monohydrate (com) and 2.8 dihydroxyadenine. urine ph should be properly measured with laboratory ph meters, preferably within two hours of collection and after 12 hours fasting, or else with a digital ph meter (lit-control) several times a day (fasting, and after meals) (77). a correct ph measurement will allow to treat and monitor the patient with prophylactic alkalizing drugs (potassium citrate, sodium bicarbonate) and/or preventing uric acid stone formation or increasing its dissolution with theobromine (78), and/or decreasing uric acid in urine with allopurinol/febuxostat. urine acidification can be achieved by using l-methionine and or ammonium chloride. phytate is the correct choice for kidney stones prevention whenever ph is neutral. 24 hour urine analysis (dirk kok) twenty-four hour urine analysis has a place during patient intake and during follow-up. analysis of crystalluria can reveal the stone type which helps choosing preventive treatment and determining which urine parameters are relevant to monitor. for stones that are formed due to excessive crystal formation inside the nephron followed by plug formation (cystine, xanthine, uric acid, slightly soluble drugs, hyperoxaluria related calcium oxalate) the presence of the specific crystal type and the size of the crystals tell if the renal conditions in the patient are inducive of stone formation or not (79). treatment will be aimed at maintaining a low excretion rate for the stone components and at maintaining urine ph in a range where the solubility of the specific comarchivio italiano di urologia e andrologia 2024; 96(2):12703 11 management of urinary stones: state of the art and future perspectives by experts in stone disease pound is high. urine analysis should comprise those factors. most stones will consist of calcium oxalates and/ or calcium phosphates. for these stones the relevant urine parameters are calcium, oxalate, phosphate, citrate, magnesium and ph. these should be measured at patient intake, after stone removal and at the start of treatment. treatment will consist of medication (e.g. alkali), drinking advice and lifestyle advice (80). dietary advice includes avoidance of high oxalate content foods and balanced intake of protein (acid load) and fruit/vegetables (alkali load) (81). urine ph and citrate content give information on the acid/base balance and the risk of forming calcium oxalate aggregates (82). finally, all stone formers will benefit from a drinking advice. monitoring urine volume always makes sense for all patients. of course, the big catch in this is patient compliance (83). it is difficult to follow lifestyle advice especially when your problem of stone formation started decades earlier and everything at present appears to be normal (84). for this large group of patients, the most sensible manner of follow up will be to provide means for measuring urine volume (actual measurement of looking at the color) and measuring urine ph at home. urinary supersaturation revisited: a proposal for a simpler indicator of stone risk (allen rodgers) despite shortcomings, urinary supersaturation (ss) is the most comprehensive of the numerous physicochemical risk factors employed in urolithiasis research (85). ss for calcium oxalate (caox) stones depends on the concentrations of free unbound calcium [ca2+] and oxalate [ox2-] species. these species in turn depend on the speciation and ph of the urine solution itself. as such, ph is correctly considered as an indirect measure of ss and a crucial indicator of stone risk. indeed, a commercially available meter for home use is available for measuring urinary ph in stone patients undergoing therapy (86). urinary ph levels which should be targeted by the patients for reducing the risk of caox, calcium phosphate and uric acid crystallization are provided. given that lowering ss of caox is a strategic goal in the administration of therapeutic and prophylactic preparations, it is instructive to revisit the physicochemical aspects of this important urinary property and to recognize the aforementioned primary influencers of stone risk [ca2+] and [ox2-]. of these, the latter has been shown to be the limiting factor in caox crystal formation in urine (87). as such, stone formation is much more sensitive to changes in [ox2-] than [ca2+]. unfortunately, measurement of [ox2-] cannot be routinely achieved. measurement of [ca2+] is also difficult but easier. it is proposed that the manufacturers of the ph-measuring device for home use consider incorporating a ca-ion sensitive electrode into their current design to allow patients to monitor urinary ph and [ca2+] simultaneously, notwithstanding that the factors are not independent. this will provide a double-check of risk leading to a more comprehensive assessment of treatment efficacy and risk of stone recurrence. are there clinical applications of macromolecular stone promoters and inhibitors? (allen rodgers) a major challenge for researchers investigating the possible role of urinary macromolecules (umms) as promoters or inhibitors of kidney stone formation is that many of these molecules play both roles depending on the chemical composition and properties of the urine in which they are operating (88, 89). well known examples include tamm-horsfall protein which has been shown to promote and inhibit calcium oxalate (caox) aggregation depending on its degree of desialylation and osteopontin which in its phosphorylated form inhibits caox nucleation and aggregation (in different caox hydrates) but promotes aggregation in its phosphorylated -deficient form. besides acting on crystallization processes per se, urinary macromolecules also are able to influence crystalcell and crystal-crystal attachment processes, each one of which can modulate aspects of the stone formation process. their activity depends on urine environment and the nature of crystal and cell surfaces. additionally, presence and absence of chemical, structural and conformational defects, increased or decreased expression, and the difficulty of finding consistent reproducible results from various experimental models exacerbate the challenge. given this myriad of factors which requires untangling and characterization, it seems unlikely that methods for controlling them by optimizing some and minimizing others is imminent. at this stage, it is suggested that there are no realistic clinical applications of urinary macromolecules in stone management or prophylaxis. nephrolithiasis as a systemic disorder (bernhard hess) there is increasing evidence that many renal stone formers (sf) exhibit ‘non-urologic’ systemic metabolic abnormalities such as metabolic syndrome (ms), cardiovascular disease or bone disease. a disease is defined as systemic if several organs/tissues or the whole body are affected (90). we analyzed additional anthropometric/metabolic data obtained from 531 non-selected consecutively referred renal stone formers, originally investigated for the prevalence of incomplete distal renal tubular acidosis (idrta) (75). among them, 139 were primarily classified as having systemic disease: 8 cystine stone patients, 66 calcium stone formers with various secondary causes (bariatric surgery, primary hyperparathyroidism, inflammatory bowel disease, medullary sponge kidney, treatment with carboanhydrase inhibitors or hiv medication, glomerular disease) and 65 calcium stone formers with idrta. the remaining 392 sf (320 idiopathic calcium, 63 uric acid, 9 infection sf) were screened for the following markers of systemic disease: 1) full ms or 2) traits thereof, 3) ldl-cholesterol > 3.0 mmol/l and 4) proteinuria > 150 mg/d as marker of cardiovascular risk, 5) very low urine volume < 1.2 l/d, likely due to reduced thirst sensitivity, and 6) low bone mass without idrta. only 3/63 (5%) of uric acid sf (ua-sf) were without any marker of systemic disease, compared with 39/320 (12%) of idiopathic calcium sf (icsf), p < 0.0001. among infection sf, only 1 out of 9 was without systemic markers. archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 12 a direct comparison of idiopathic calcium vs. uric acid stone formers is depicted in table 4. two or more systemic markers of systemic disease were more often present in ua-sf (49/63, 78%) than in icsf (183/320, 57%), p < 0.0001. overall, only 43 of 531 non-selected sf (8.1%) were without markers of systemic disease. the following conclusions can be drawn: 1) nephrolithiasis should be considered a systemic disease, as 92% of sf exhibit markers of systemic disease. 2) recurrent casf and ua-sf should primarily be referred to internists or nephrologists for evaluation not only of urine chemistries, but systemic pathologies such as ms or traits thereof, elevated ldl-c, overt proteinuria, hyperparathyroidism, incomplete drta, bone disease, medullary sponge kidney, inflammatory bowel disease, bariatric surgery and lithogenic drugs. screening of high-risk stone formers (alberto trinchieri) some renal stone formers are considered "high-risk" due to the high tendency to relapse with a consequent increased risk of obstructive episodes and surgeries which can cause a damage of renal function. in general, non-calcium stones have the greatest tendency to recur, although some subgroups of calcium stones also have high recurrence as calcium stones associated with some genetic diseases (hereditary hypercalciurias, hereditary distal tubular acidosis, primary hyperoxaluria) or acquired diseases (primary hyperparathyroidism, sarcoidosis, distal tubular acidosis secondary to autoimmune diseases, immobilization syndrome and other bone diseases, therapy with carbonic anhydrase inhibitors, enteric hyperoxalurias associated with ileal resection, chronic inflammatory bowel disease and some types of bariatric surgery). high-risk renal stone formers need early diagnosis to start specific treatments. stone analysis allows the identification of most non-calcium stones: infection stones (struvite), uric acid and urates, cystine and other rare stones (dihydroxyadenine, xanthine). most forms of calcium stones secondary to specific acquired diseases can be diagnosed by a thorough history associated with biochemical tests for the evaluation of calcium phosphate metabolism and measurement of fasting urinary ph. some forms of stones are secondary to monogenic hereditary defects which can be diagnosed by searching for mutations in a large panel of candidate genes (91) (table 5). the study of this panel of genes (or similar panels) allowed the diagnosis of a monogenic hereditary defect in 16.8-30% of pediatric series with nephrolithiasis. in a large pediatric series with a very low average age of 2.5 years, a monogenic defect was demonstrated in 39% (92). conversely, in adult populations the rate of monogenic hereditary defects does not exceed 7%, including genetic defects associated with cystinuria which are relatively frequent (92). on the other hand, the cost of these investigations still represents a limiting factor in their routine use, although there has been a significant decline in costs with next-generation sequencing (ngs) approaches. for this reason, it has been suggested that intensive research into genetic etiology should be reserved for children who form kidney stones before 5 years of age, especially if coexisting nephrocalcinosis and/or consanguinity are present. for children > 5 years and adults, the genetic study must be preceded by a careful assessment of the phenotype to select cases in which a genetic defect is suspected (93). the study of the phenotype is of particular importance for the diagnosis of cystinuria and primary hyperoxaluria. early diagnosis of cystinuria is mandatory due to the relative frequency of the disease (1/7000 newborns) and of cystine stones (approximately 6-8% in pediatric series, 1% in adults). cystinuria is caused by mutations of slc3a1 and slc7a9 genes encoding for the two subunits of the transporter of cysteine, ornithine, lysine and arginine in the proximal tubule which cause elevated urinary excretion of cystine. the phenotype of these patients is potentially easy to identify through stone analysis, the use of a colorimetric test in urine (which is limited by the toxicity of one of the reagents), the demonstration of typical crystalluria and ion chromatography (for diagnostic confirmation). however, in real life the diagnosis of cystinuria is still delayed compared to the first table 4. markers of systemic diseases in idiopathic calcium vs uric acid stone formers. table 5. panel of candidate genes related to nephrolithiasis. calcium metabolism adcy10, alpl, atp6v0a4, atp6v1b1, ca2 , casr, clcn5, clcnkb, cldn16, cldn19, cyp24a1, fam20a, hnf4a, kcnj1, maged2, ocrl, slc12a1, slc4a1, vdr hypercalciurias and renal tubular acidosis atp6v0a4, atp6v1b1, slc4a1 defects in renal phosphate tubular reabsorption slc34a1, slc34a3, slc9a3r1 hereditary hyperuricosurias hprt1, slc22a12, slc2a9 primary hyperoxaluria agxt, grhpr, hoga1, slc26a1 cystinuria slc3a1, slc7a9 other metabolic stone diseases aprt, xdh orher candidates genes for association with nephrolithiasis ammecr1, ap2s1, cldn10, gdnf, gna11, oxgr1, slc13a5, slc26a6, slc26a7, slc7a13, trpv5, trpv6 archivio italiano di urologia e andrologia 2024; 96(2):12703 13 management of urinary stones: state of the art and future perspectives by experts in stone disease episode of stones and the percentage of patients with renal failure is high despite the availability of effective pharmacological treatments (94). greater organization and attention from clinicians should therefore be required for the diagnosis of this disease, especially when the onset occurs after the age of 16. an interesting option could be postnatal screening which seems to be justified by the prevalence of the disease and the availability of effective therapy. post-natal diagnosis has been tested in some communities in spain where the disease has been diagnosed in 1/4129 newborns (95) and cystine stones were observed in 10.5% of cases after a 17 years follow up (96). colon hyperechogenicity at prenatal ultrasound examination has been reported in some patients who presented with cystinuria and could be used to select newborns to screen for the genetic defect (97). primary hyperoxaluria is the result of 3 rare genetic defects of hepatic oxalate metabolism which cause an exaggerated excretion of oxalate in the urine. an effective therapy for the treatment of primary hyperoxaluria type i (lumasiran) has recently been introduced (98). the phenotype is not always easily identifiable as it is associated with the formation of calcium oxalate monohydrate stones with the same chemical composition as idiopathic calcium oxalate stones. diagnosis is easier in cases with early and severe presentation with nephrocalcinosis, renal failure and manifestations of systemic oxalosis. in cases with onset in adulthood and without nephrocalcinosis the diagnosis is often delayed after 5 years from initial presentation and at end stage renal disease (in 30-60% of cases) (99). the recognition of the phenotype is usually based on the measurement of 24-hour oxaluria which is not always easily accessible and can be cumbersome for pre-analytical reasons of sample collection and preservation. these problems could be overcome with the development and diffusion of rapid qualitative diagnostic tests for the recognition of oxaluria which have already been described in numerous reports (100). alternatively, the greater diffusion of stereoscopic microscopy for the analysis of stones, in addition to infrared spectroscopy or x-ray diffractometry, could help to recognize the pathognomonic morphology of calcium oxalate monohydrate stones of patients with primary hyperoxaluria which present different color and structure with respect to idiopathic com stones (101). prevention strategies personalized medicine (giovanni gambaro) personalized or precision medicine is not only aimed at specific molecular targets of that specific patient. we have examples of such medicine in the treatment of nephrolithiasis. this is the case of thiopronine for cystinuria, of rifampin in infantile hypercalcemia cyp24a1 gene mutation, and finally of lumasiran and nedosiran in primary hyperoxalurias. however, the meaning of precision or personalized medicine is much broader. these terms mean a prevention and treatment approach considering individual genetic variations and environmental and lifestyle conditions. it is a concept that those involved in the prevention of nephrolithiasis know well. the eau guidelines have well interpreted the concept of personalized medicine when they state that the individual risk of recurrence and systemic complications of stones must be assessed globally because this is imperative for pharmacological treatment (14). no antithesis exists between personalized medicine and public health interventions to prevent stones. the first addresses a small part of stone patients with a high risk of recurrence and systemic complications, which must be identified among the more numerous subjects who form one or a few stones during their entire lifespan. just to give an example (please consider that the following percentages are approximate and for illustrative purposes only), let's assume that the prevalence of nephrolithiasis in the general population is 10%; only 10% of these could be genuinely recurrent stone patients. among these, only 10% might have secondary forms. well, personalized treatment should only be reserved for these last two categories of subjects. the aua and eau guidelines suggest a selective approach to pharmacological prevention and recommend conducting a metabolic study on the 24-hour urine of stone patients (14, 59). unfortunately, although this is only part of the overall risk assessment of a stone patient, the metabolic study is often ignored in clinical practice (102, 103). however, there is an antithesis between personalized medicine and an empirical approach to preventing nephrolithiasis. the empiric approach (104), including lifestyle, nutritional, and pharmacological measures administered to stone patients, is based solely on stone composition with minimal or no metabolic urinary investigations. this exposes the renal stone patients to a risk of under-diagnosis and under-treatment, i.e., missing the chance to properly diagnose and treat that minority of those with nephrolithiasis who could benefit from specific and/or ancillary treatments (e.g., parathyroidectomy or treatments for slowing the progression of chronic kidney disease), the inherited and secondary forms. furthermore, other problems with such an approach are unwanted adverse events and un-loyalty of patients (105). in a nephrolithiasis patient, a complete diagnostic workup should be carried out with the aim of: • identification of secondary forms of nephrolithiasis • diagnosis of idiopathic calcium nephrolithiasis • risk assessment of chronic kidney disease and metabolic bone disease • identification of patients who need to be treated to prevent stones and systemic complications (6). at the end of the work-up, only a minority of patients will need a personalized treatment. the risk of considering nephrolithiasis only as a problem of public health policies is that this is interpreted as a renunciation of the commitment to identify the few patients who, on the contrary, require personalized therapies. public health policy (alberto trinchieri) in the last three decades, the prevalence of kidney stones has increased worldwide. higher prevalence rates are observed in developed countries although increase of prevalence rates are also expected in developed countries (106). the increase in the prevalence of kidney stones is linked to the greater impact of environmental risk factors archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 14 (diet, lifestyle, climate), while the impact of genetic factors remains unchanged. in particular, the role of climate factors is increasing because of global warming and urbanization which exaggerates the effect of increasing global surface temperatures (urban heat islands) (107, 108). the increase in the prevalence of kidney stones is associated with the change in the clinical presentation of the disease and in the spectrum of stone composition due to the increased impact of environmental factors compared to genetic factors. the comparison of case series studied in the same country in different periods of time demonstrates that the average age of patients with urinary stones has increased over the last 30 years from the 5th to the 6th decade (109). the spectrum of stone composition also changed during this period. the frequency of infection stones (struvite) has decreased in most geographical areas thanks to the improvement of social and health conditions. furthermore, a trend towards a reduction in calcium phosphate stones in favor of an increase in the frequency of calcium oxalate was observed. in the context of calcium oxalate stones, an increase in the frequency of calcium oxalate monohydrate stones and a reduction in calcium oxalate dihydrate stones was also observed. in some southern areas of western countries (texas, southern europe) an increase in the frequency of uric acid-containing stones has been observed, while this trend has not been observed in more northern geographical areas. the frequency of uric acid-containing stones tends to be positively correlated with the increase in environmental temperature. furthermore, the prevalence of hypercalciuria, the urinary saturation values with respect to calcium oxalate, calcium phosphate and uric acid have progressively reduced over time. finally, the average interval between the first episode of stone disease and subsequent episodes of recurrent stone disease tends to lengthen (110, 111). the “new” presentation of urinary stone disease is characterized by higher renal stone prevalence, higher age at stone onset, longer interval between stone episodes, more frequent calcium oxalate monohydrate and/or uric acid stones, less frequent hypercalciuria, and lower urinary saturation. at present, renal stone prevalence is higher but most renal stone formers present a mild to moderate disease with late onset of stone formation. this trend is mostly related to a change of environmental risk factors for atone formation. this trend cannot be countered only by increasing the provision (and costs) of curative services. on the contrary, measures of primary prevention are highly needed (general practitioners, media, social media). in fact, patients who form the first stone at middle-age or after need a simplified screening including clinical history, stone analysis, measure of calcium/phosphate metabolism, urinary ph, and urine culture. they usually only require general measures such as high fluid intake, diet and alkalinization. furthermore, lifestyle adaptation to climate change is also requested at institutional level (landscape, urban and building strategies to augment adaptive capacity to hot weather) and at individual level. personalized medicine or public health policy? (dirk kok) the answer to this question depends on the process by which the stone was formed: fixed or free particle mechanism (112). both require supersaturation of the surrounding fluid, being urine inside the nephron, urine in the urinary tract or interstitial fluid. personalized medicine can prevent stones that start inside the nephron or in the urinary tract. an example is infection stones that are formed from high concentrations of calcium, magnesium, phosphate and ammonium and a high ph. effective prevention requires removal of all stone fragments (resident bacteria), supplying the correct antibiotics and drugs that reduces urine ph and urease activity. you need to be aware that a negative urine culture does not exclude the presence of urease producing bacteria, because they may reside inside crystal material or urothelial cells (113). similarly, we also know how to prevent stones that start by crystallization in the nephron because of high blood values plus local nephron conditions. for instance, drugs of which supersaturation increases at high ph may form crystals in the loop of henle. this can be detected by looking for drug crystals in the urine (114, 115). when the numbers of crystals formed become too high, aggregates may block the duct of bellini and start stone formation. for such drugs it should be remembered that there exists a window of plasma levels with a lower limit determined by the desired effectivity and a higher limit determined by the crystallization risk. it might be wise to monitor crystalluria for any new drug in order to detect future risks of stone formation. cystine, xanthine and uric acid stones are other stone types that start from high plasma values and abnormal urine conditions. limitation of the excretion of metabolites in combination with steering urine ph in the appropriate direction plus, if possible, adding compounds that bind the stone forming material will prevent new stone formation and examining crystalluria has a good monitoring function. for some of stones made of calcium oxalate and phosphate salts where high plasma values are involved (genetic hyperoxaluria, hyperparathyroidism, extreme intake of oxalate or oxalate precursors) the same principles as described above can be maintained. on the contrary, the problem lies with the calcium stones that are related to lifestyle and may start with renal plaques. the whole process can take up to decades (116). here prevention involves long term adaptation of the stone former to a lifestyle that poses less of a stone forming risk. this is a very difficult task that requires a combination of personal attention by the doctor and public health or commercial initiatives that aim to direct people towards a healthier lifestyle (117-119). someone who is forming the first stone can only be helped by the latter two. future research artificial intelligence (ai) a window to the future (alberto trinchieri) artificial intelligence is a branch of computer science that develops systems capable of performing tasks that would require human intelligence such as learning, reasoning, problem solving, perception and understanding language. artificial intelligence is expressed through various techarchivio italiano di urologia e andrologia 2024; 96(2):12703 15 management of urinary stones: state of the art and future perspectives by experts in stone disease nologies such as machine learning, expert systems, natural language processing, computer vision and robotics. in particular, machine learning consists of the development of algorithms to make predictions or decisions based on patterns identified in the analyzed data without explicit programming. a subset of machine learning is deep learning through algorithms organized in complex layered neural networks that are exercised by analyzing unstructured or unlabeled data. artificial intelligence is used in medicine with various applications for the purpose of collecting medical history through voice or text analysis to create real-time transcriptions of the conversation between physician and patient, detection of clinical signs, automated image analysis, classification, and categorization of pathological, radiological, and endoscopic images. the applications of artificial intelligence in the management of the renal stone patients have several purposes: automated identification of ureteral stones on ct imaging, prediction of stone composition by clinical parameters, prediction of 24-hour urinary risk factors by demographics and clinical parameters, and assessment of stone composition by evaluation of images (photographs, endoscopic videos) (120). the analysis of digital photographs or endoscopic intraoperative views by deep convolutional neural networks (cnns) can allow the identification and classification of kidney stones. a recent meta-analysis has shown that in the last 5 years the predictive positive value has increased for different types of stones from 50-75% to 96-99% (121). an application for smartphones equipped with a miniaturized microscope was also developed which demonstrated an accuracy of 88% (122). artificial intelligence techniques have also been used for the prediction of postprocedural outcomes such as the prediction of spontaneous passage of ureteral stones, the stone-free status after swl, the lower pole stone clearance after swl, the stone growth after swl, the prediction of success after pcnl. in conclusion, the extensive application of artificial intelligence in urology will revolutionize the decision-making process. efficiency, accuracy and precision will be enhanced with decreased workload for clinicians. synergy between urologists, nephrologists and scientists in basic stone research (kyriaki stamatelou) urology is currently the dominant specialty involved in the management of kidney stones. depending on the particular setting of care and the individual referral practices, the role of nephrologists in urolithiasis is usually limited. nephrologists are generally involved in the medical management of kidney stones only when repeated recurrences or a noticeable kidney injury or kidney failure occur. in recent years collaboration between basic research scientists and urologists and nephrologists happens in very few places in the world, mainly kidney stone clinics, academic research centers and centres of excellence for urolithiasis (123-125). yet, it is apparent that basic scientists, including biochemists, geneticists, and physiologists, can contribute to our understanding of the fundamental mechanisms of kidney stone formation uncovering molecular pathways, genetic factors, and physiological processes that are involved in stone development but remain incomprehensible. synergy between clinical practitioners and basic scientists can extend to translational research, where findings from basic science are translated into clinical applications and help develop targeted therapies and preventive strategies based on the latest scientific insights. synergy in clinical trials is also essential for evaluating new surgical techniques, medical treatments, or preventive strategies. synergy can also include the formation of interdisciplinary teams that would address all aspects of disease management including acute stone events, recurrences, co-morbidities, preventive measures and patient education. an excellent example of contemporary meaningful synergy is the development of a revolutionary drug for the treatment of primary hyperoxaluria type 1. the application of a biotechnology breakthrough, small rna interference molecules for silencing a gene coding a protein, that stops the production of oxalate and alleviates the symptoms of the catastrophic disease. in conclusion, the synergy between urologists, nephrologists, and scientists in basic kidney stone research enhances the depth and breadth of investigations, leading to a more comprehensive understanding of kidney stone formation, risk factors, and treatment options. this collaboration is essential for developing effective strategies to prevent kidney stones and improve the overall care of affected individuals. conclusions (athanasios papatsoris) urolithiasis is a multifactorial disease, increasing in prevalence worldwide. at the same time, minimally invasive treatment techniques are under constant evolution, changing the landscape of optimal management. the present article aimed in covering all aspects in diagnosis and management of urolithiasis, using high-quality, evidence-based material, in order to help urologists tailoring the stone disease management. given the continuous improvement in all aspects of endourology, future studies are needed to provide urologists with updated material in treatment incorporating individual patient preferences along with surgical expertise. acknowledgments this work was born from the great organizational skills and scientific vision of noor buchholz, who, despite being seriously ill, wanted to organize yet another edition of the experts in stone disease meeting until the end. the first edition of esd was held in dubai in 2012. it was followed by numerous other editions in cape town, dubai, shanghai, athens and finally in valencia. noor was unable to be present in valencia but his spirit hovered among the participants archivio italiano di urologia e andrologia 2024; 96(2):12703 a. papatsoris, a. budia alba, j.a. galán llopis, et al. 16 of the event who remembered him several times. the program was inspired by his scientific philosophy in particular the collaboration between urologists, nephrologists and scientists in basic stone research and the creation of relationships between experts from both, developed as well as developing countries. noor died on 13 february 2024 two weeks after his last successful meeting. we also thank vicky nickolopoulou who helped to superbly organize all the editions of esd and we thank devicare sl for its unconditioned support to the organization 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and understanding of automated urinary stone recognition methods. bju int. 2022; 130:786-798. 122. onal eg, tekgul h. assessing kidney stone composition using smartphone microscopy and deep neural networks. bjui compass. 2022; 3:310-315. 123. rodgers a, trinchieri a. fifty years of basic and clinical renal stone research: have we achieved major breakthroughs? a debate. curr opin nephrol hypertens. 2023; 32:177-182. 124. jungers p, joly d, blanchard a, et al. lithiases rénales héréditaires monogéniques : récents acquis diagnostiques et thérapeutiques [inherited monogenic kidney stone diseases: recent diagnostic and therapeutic advances]. nephrol ther. 2008; 4:231-55. 125. tiselius hg, daudon m, thomas k, seitz c. metabolic work-up of patients with urolithiasis: indications and diagnostic algorithm. eur urol focus. 2017; 3:62-71. correspondence athanasios papatsoris, md, msc, msc, phd, febu, fes agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, athens; u-merge scientific office alberto budía alba, md alberto.budia@hotmail.com head of urology department, la fe university and polytechnic hospital associate professor of valencia university, valencia, spain juan antonio galán-llopis, md, phd jagalanllopis@gmail.com department of urology, general university hospital dr balmis, isabial, alicante, spain murtadha almusafer, md, ficms, facs murtadha.majeed@uobasrah.edu.iq professor of urology, university of basrah, basrah, iraq mohammed alameedee, md mohammedalameedee@yahoo.com consultant urologist, diwaniya teaching hospital, iraq hammad ather, mbbs, fcps (urol), frcs (glas.), febu hammadather@gmail.com akberali hashwani & family endowed professor of urology aga khan university, karachi, pakistan juan pablo caballero-romeu, md drjpcaballero@gmail.com alicante institute for health and biomedical research (isabial); department of urology, miguel hernández university, alicante, spain antònia costa-bauzá antonia.costa@uib.es laboratory of renal lithiasis research, university institute of health sciences research (iunics-idisba), university of illes balears, palma de mallorca, spain athanasios e. dellis, md, phd, febu aedellis@gmail.com professor in urology, 2nd department of surgery, aretaieion academic hospital, school of medicine, national and kapodistrian university of athens, athens, greece mohamed el howairis, md, mbbs, frcsed, msc, dic, honorary professor of urology londonclinic1@gmail.com imperial college, london university, london, uk giovanni gambaro, md, phd, fera giovanni.gambaro@univr.it; giovanni.gambaro@hotmail.it div. of nephrology, dept. of medicine, university hospital of verona, verona, italy geavalete bogdan geavlete, md, phd bogdan_geavlete@yahoo.com professor of urology, “carol davila” university of medicine and pharmacy medical director, "saint john" emergency clinical hospital 13 vitan barzesti street, district 4, 042122 bucharest, romania adam halinski, md adamhalinski@gmail.com private medical center "klinika wisniowa" zielona gora, poland bernhard hess, md bernhard.hess@hirslanden.ch internal medicine & nephrology, kidneystonecenter zurich, klinik im park, zurich, switzerland syed jaffry, md, dhms, dipsfcd, mmedsc (urol),frcs, frcsi, febu, facs jaffrysyed@gmail.com university hospital galway, galway, ireland dirk j kok dikkok@gmail.com saelo scientific support, oegstgeest, the netherlands hichem kouicem, md hkouicem_uro@yahoo.fr physician urologist surgeon, private clinic, clinique les pins, setif, algeria luis llanes, md, associate professor of urology luis.llanes@yahoo.es; luis.llanes@salud.madrid.org francisco de vitoria university (madrid) head of urology department, university hospital of getafe carretera toledo km 12.500, 28905 getafe. madrid, spain juan m lopez martinez, md urodrlopez@gmail.com dept of urology, university of barcelona clinic hospital, barcelona, spain elenko popov, md, ph.d., febu, assoc. prof. shennyp@yahoo.com department of urology, umhat "tzaritza yoannaisul", medical university, sofia, sofia, bulgaria allen rodgers, msc, phd allen.rodgers@uct.ac.za emeritus professor and senior research scholar, university of cape town, south africa federico soria, md phd fsoria.research@gmail.com head of experimental surgery department, profesor investigador, universidad de alcalá ramón y cajal university hospital, irycis madrid, spain kyriaki stamatelou, md, nephrologist mba kstamatelou@mesogeios.gr, dr.stamatelou@gmail.com scientific director mesogeios nephrology center, haidari attica and nephros.eu private clinic 104 vasilissis sofias avenue, 11527 athens greece alberto trinchieri, md alberto.trinchieri@gmail.com school of urology, university of milan, milan, italy; u-merge scientific office christian türk, md office@tuerk.at urologic department, sisters of charity hospital, 1060 vienna, austria and urologic praxis, 1030 vienna, urologische praxis, ziehrerplatz 7/7, a-1030 wien, austria conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 2148 original paper no conflict of interest declared. introduction according to the globocan data, bladder cancer (bc) is the 7th most commonly diagnosed cancer in men and it declines to 11th worldwide, when both sexes are considered (1). worldwide age-standardized mortality rate has been reported as 3.2 for men vs. 0.9 for women per 100.000 persons, however incidence and mortality rates vary depending on the healthcare systems, management protocols and development level of the countries. the most common subtype of bc is urothelial carcinoma (uc) and the molecular mechanism of uc is not completely understood as in other cancers (2). receptor tyrosine kinases (rtks) play key roles in cellular signal transduction and they are one of the most common types of molecules investigated for this purpose. in humans, 20 distinct subfamilies of rtks exist that are categorized according to their aminoacid sequence identities and structural similarities in their extracellular regions (3). one of these is the subfamily of tam receptors comprising sky (tyro3), axl, and mer. they participate in a signaling axis where growth arrest-specific 6 (gas6) protein is a ligand (4). the oncogenic nature of axl, sky and mer is demonstrated through activation of signaling pathways involved in proliferation, migration, invasion, angiogenesis, inhibition of apoptosis, and therapeutic resistance (5). it has been shown that overexpression of axl, sky, mer rtks, and their ligand gas6 is associated with poor prognosis in various types of tumors (6). the close relationship with the pathogenesis of many cancers suggests that gas6 and its tam receptors could be potential biomarkers and targets for treatment (7). the molecular biology of bc is complex and not fully understood. there is a very limited number of studies investigating the relationship between bc and gas6/tam receptors. yeh et al. investigated the role of axl in the pathogenesis of locally advanced and metastatic bc patients (8). they indicated that c-met and its crosstalk with axl could contribute to the progression of objectives: it has been shown that the dysregulation of tyrosine kinase axl receptor and its ligand growth arrest-specific gene (gas6) are associated with poor prognosis in various types of tumors but there is not enough study about their importance in bladder cancer (bc). we evaluated the relation of gas6 gene expression and tyrosine-kinase axl and sky (tyro 3) receptors with tumor stage and grade in patients with bc. material and methods: the study group consists of 55 patients whose transurethral resection of bladder (tur-b) has been performed due to bc and the control group consists of 12 patients with normal bladder mucosa. in tissues mrnas of gas6, axl, and sky receptors were examined by quantitative (real-time) pcr (qpcr). protein expression was measured by immunohistochemistry. plasma gas6 protein levels were compared with control group by elisa method. results: patients with bc were grouped as ta low (n=17), ta high (n=5), t1 low (n=9), t1 high (n=8) and t2 (n=16) according to their tur-b pathologies. the qpcr analysis showed that the expression of gas6 gene and axl receptor is higher in the tumor-positive group and the immune-histochemical showed that the bladder samples of the tumor-positive group stained significantly positive. when the patients are grouped according to the tur-b pathologies, a statistical significant difference was observed among groups in the qpcr analysis ratios of gas6 gene and axl receptor by (p < 0.05) but no significance was found for sky receptor (p > 0.05). when gas6 protein levels in plasma samples were compared by elisa method, a statistical significance was determined among groups (p = 0.001). conclusions: our findings indicate that mrnas of gas6 and axl receptor are closely related to tumor stage and grade in patients with bc. further studies are needed for understanding the role of gas6 and its receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets. key words: bladder cancer; gas6; axl; sky; tyro3. submitted 31 march 2021; accepted 17 may 2021 gas6 expression and tyrosine kinase axl sky receptors: their relation with tumor stage and grade in patients with bladder cancer murat akgül 1, özgür baykan 2, zeynep çağman 3, mustafa özyürek 4, i̇lker tinay 5, cem akbal 6, fikriye uras 7, levent türkeri 6 1 department of urology, tekirdag namık kemal university medical school, tekirdağ, turkey; 2 department of biochemistry, balıkesir university medical school, balıkesir, turkey; 3 department of biochemistry, bezmialem university, school of pharmacy, istanbul, turkey; 4 department of physiology, marmara university, school of medicine, istanbul, turkey; 5 anadolu medical center, gebze, kocaeli,turkey; 6 department of urology, acıbadem university, school of medicine, istanbul, turkey; 7 department of biochemistry, marmara university, school of pharmacy, istanbul, turkey. doi: 10.4081/aiua.2021.2.148 summary 149archivio italiano di urologia e andrologia 2021; 93, 2 gas6 and axl sky receptors’ relation with bladder cancer human bc. rui et al. investigated the relationship between long noncoding rna and bc (9). they showed that gas6-as2, a long noncoding rna, was significantly up-regulated in bc tissues and positively correlated with tumour stages and poor prognosis. identification of new prognostic markers and therapeutic targets for bc is urgently required. in the present study, we aimed to elucidate the relation between axl/sky/mer rtks and its ligand gas6 in patients with uc of bladder. materials and methods the sample size was calculated based on the formula according to the previously published studies (6, 8). our study group includes 55 patients with transurethral resection of bladder tumor, where the histopathological diagnosis of the tumors was uc. the control group consists of the 12 patients whom bladder mucosa has been biopsied during radical prostatectomy operation. tissues from bladder tumor or mucosa were stored at -80 °c. in this study, mrna expression of axl, sky, and gas6 in the tissues was analyzed by quantitative (real-time) polymerase chain reaction (qpcr). protein expression of gas6, axl, and sky was analyzed by immunohistochemistry. plasma and urine samples of patients were collected before transurethral resection and enzyme linked immunosorbent assay (elisa) was used to measure gas6 protein level. plasma and urine samples of a control group, who are older than 40 years of age and without any history of malignancy, has been used for comparison. the urine and venous plasma aliquots were stored at -80°c before analysis after centrifugation at 2300 g for 15 min at room temperature. the study has been approved by the local institutional ethics committee (approval number: 09.2012.0087) and conducted in conformity with the declaration of helsinki in 1995. written informed consent were obtained from all patients included in the study. real-time pcr (qpcr) total rna was isolated using tripure isolation reagent solution (roche, mannheim, germany) according to the manufacturer's instructions. the mrna expression of the gas6, axl and sky were determined using specific primer sequences. specific primer sequences used for the gas6 gene: • 5’-tgctgtcatgaaaatcgcgg-3’ (gas6-5’; 13281347) • 5’ catgtagtccaggctgtaga-3’ (gas6-3’; 15941613) specific primer sequences used for the axl receptor gene: • 5’-ggtggctgtgaagacgatga-3’ (axl-5’; 18201839) • 5’ ctcagatactccatgccact-3’ (axl-3’; 21032122) specific primer sequences used for the sky receptor gene: • 5’-cactgagctggctgactaagcccc-3’(sky-5’; 2719-2742) • 5’-aatgcatgcacttaagcagcaggg-3’(sky-3’; 3039-3062) the qpcr analysis was performed using sybr green dye (light cycler-rna amplification kit sybr green i; roche, mannheim, germany). target gene expression was determined by comparing the amount of threshold loop with the glyceraldehyde 3-phosphate dehydrogenase (gapdh) gene. immunohistochemical analysis streptavidin biotin peroxidase immunohistochemical staining method was applied to show the immune expression of gas6 protein and axl, sky receptors proteins in paraffin-embedded tissues. the immune expression positivity in bc tissue was observed as cytoplasmic staining. according to the intensity of staining, it was scored as 0 (figure 1a), +1 (figure 1b), +2 (figure 1c), +3 (figure 1d). immunohistochemistry expression index was obtained by multiplying the cytoplasmic staining density and the ratio of stained cells. two authors, who were blinded to the clinical course of the patients, independently evaluated immunoreactivity, and the average counted by these two authors was used for statistical analyses. elisa method the human gas6 sandwich elisa development kit (r&d systems, inc., minneapolis, mn, usa) and a substrate reagent pack (color reagent a&b) (r&d systems, inc.) were used to measure plasma gas6 levels. our group has been optimized the development kit to measure human plasma gas6 levels and established reference intervals (10). briefly, the following parameters were tested for optimization: type of antibody; capture antibody concentration; dilution solution; dilution ratio of samples and calibrators; blocking agent (bsa or nonfat dry milk), and incubation time and temperature. dilution solution for samples and calibrators was pbst containing 1 mm edta and 1% bsa. dilution ratio of samples and calibrators was 1/40. incubation time during antigen antibody interaction (both capture and detection antibodies) was 1h at 37°c. after analytical validation studies of the method, samples were analyzed. figure 1. the cytoplasmic staining of immune expression for gas6 protein and axl, sky receptors proteins positivity in bc tissue. according to the intensity of staining, it was scored as 1a: 0, 1b: +1, 1c: +2, 1d: +3. archivio italiano di urologia e andrologia 2021; 93, 2 m. akgül, ö. baykan, z. çağman, m. özyürek, i̇lker tinay, c. akbal, f. uras, l. türkeri 150 statistical analysis in descriptive statistics of the data, frequency, ratio, mean and standard deviation values were used. the distribution of data was tested with kolmogorovsmirnov. student t test and anova were used to analyze the parametric section data. mann-whitney u and kruskal-wallis tests were used for the analysis of nonparametric data. spss 15.0 software (spss, usa) was used in the analysis. results patient demographics the bc patients were grouped according to their pathological degrees and stages: ta low grade (n=16), ta high grade (n=5), t1 low grade (n=10), t1 high grade (n=10), t2 high grade (n=14) and normal bladder mucosa control group (n=12). mean ages of the patients with bc and the control group were 62.8 ±10.7 and 57.3 ± 7.0 years, respectively (p > 0.05). patients with bc, were male in 81.8% and female in 18.2%, while the control group consisted of male patients. tissue analyses the qpcr results showed that the mrna expression of gas6 and axl receptor were higher in the tumor-positive patient group, where sky receptor gene were higher in control group, these differences were not significant (p > 0.05) (table 1). when the patients are grouped according to the grade and stage, significant differences were observed for gas6 and axl receptor genes (p < 0.05). but no significant difference was found for sky receptor (p > 0.05) by qpcr (figure 2). the immunohistochemical expression index for the gas6 and axl receptor were statistically higher compared to the control group (p < 0.05). the immunohistochemical expression index of gas6 protein, axl, sky receptors for bc and control group is shown in table 2. plasma and urine analyses the mean plasma gas6 protein levels for the control group and the bc patient group were 6.5 ± 2.6 ng/ml and 9.9 ± 2.4 ng/ml, respectively (p < 0.001). the distribution according to the stage and the grade of the patients are shown in figure 3. gas6 protein was not detected in urine samples by elisa. discussion in the present study, an association between bc and expression of gas6, axl and sky was identified using three different methods: qpcr and immunohistochemistry in tissues and gas6 levels in plasma by elisa. the qpcr analysis showed that mrna expression of gas6 and axl are higher in the bc group than the control group but not significantly (p > 0.05). mrnas of gas6 and axl was higher in ta high grade and t1 low grade significantly, but gradually decreasing in t1 high grade and t2 stages. using the immunohistochemical examination, the bc group showed significantly higher (p < 0.05) gas6 and axl receptor expression compared to the control group. elisa analysis showed higher gas6 protein levels in plasma of the bc group compared to the control group (p=0.001), where highest levels are detected in patients with t2 tumors. table 1. gas6, axl, sky receptor gene expression copy level assessed by the qpcr method. control group tumor-positive patient group p n median min. max. n median min. max. gas6 11 60.6 7 294 50 73.1 10 1810 0.223* axl 12 288.7 145 578 55 421.5 87 1997 0.288* sky 11 10000 2888 15497 54 8048 1591 31333 0.588* * mann whitney u test. table 2. immunohistochemical expression index of gas6 protein, axl, sky receptors for bc and control group. figure 2. expression of gas6 and axl receptor mrnas in bc against tumor stage and grade by qpcr. figure 3. gas6 protein levels in plasma samples according to the stage and the grade of the bc patients with elisa analysis. control group tumor-positive patient group p n median min. max. n median min. max. gas6 6 5 0 90 32 85 0 300 0.006 axl 6 15 0 70 28 60 10 200 0.037 sky 6 50 0 200 32 180 0 300 0.261 151archivio italiano di urologia e andrologia 2021; 93, 2 gas6 and axl sky receptors’ relation with bladder cancer the definitive diagnosis of bc ultimately depends on cystoscopic examination of the bladder, which is an invasive method. there are continuous efforts for the development of non-invasive reliable tumor markers to facilitate the diagnosis. however, none of these markers have been accepted for the diagnosis or follow-up in routine practice (11). by the help of further studies, the gas6/axl axis may represent an attractive diagnostic tool for bc. relationship between various physiological events and gas6, and/or its receptors has been demonstrated, however, its exact mechanism has not been elucidated yet (12, 13). the relationship between gas6 and/or its receptors with tumor suppressor genes such as inositol polyphosphate-4-phosphatase (inpp4b) remains uncertain (14). the gas6 gene and particularly the axl receptor are highly overexpressed in many diseases. numerous biological dysfunctions, inflammatory diseases and autoimmune disorders are related to the overexpression of gas6 and its receptors (6). they also participate in the development, progression and metastatization of a range of malignancies (15). prostate cancer, breast cancer, lung cancer, leukaemia and cancers of gastrointestinal tract including colon are the most studied malignancies (5, 6, 16). recent studies have also demonstrated an important role of axl signaling in tumor proliferation, survival, stem cell phenotype, prognosis, metastasis, and resistance to cancer therapy (16). however, there is an opposite situation in renal cell carcinoma, which is a urogenital tumor where the gas6 and axl-sky receptors are associated with good prognosis (17). when we look at the stage and grade of bc, it seems that mrnas of gas6 and axl receptor are very close to each other in the control and ta low grade group. the malignant potential of low-grade bc, that was formerly regarded as 'low malignant potential papillary urothelial neoplasia', may be related to different molecular pathological and histopathological features. in this respect, it is similar to the new who-isup classification (18). in the present study, the expression of gas6 was higher at ta high grade and t1 low grade, but differentiation was gradually decreasing at t1 high grade and t2 stages. similarly, in the study of sun et al., the gene expression of gas6 and axl receptor was found to be higher in g1 endometrial cancer, however, it was gradually decreasing in g2 and g3 endometrial cancers where the differentiation is poor (19). using the immunohistochemical examination, gas6 and axl receptor were found to have a significantly higher protein expression at bc compared to the control group. however, similarly to sky receptor qpcr results, there was no statistically significant difference between the bc and the control group. using immunohistochemistry examination, hattori et al. investigated the relationship between increased expression of the axl/gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. they concluded that the protein expression of axl and its ligand gas6 is related to worse clinical outcome in upper tract urothelial tumors (20). the plasma levels of gas6 protein measured by elisa were significantly higher in the bc group compared to the control group. in addition, mean levels of gas6 protein in plasma were significantly higher in t2 patients compared to other groups. this may be important for the separation of the muscle invasive bc from non-muscle invasive bc. therapeutic potential of axl inhibition has been explored for cancer therapy (21). a variety of axl inhibitors have been developed and are efficacious in preclinical studies. these agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. for the treatment of the breast cancers, bgb324 (r428) and sgi7079, which are the highly selective axl tyrosine kinase inhibitors, entered in clinical studies (22, 23). mao et al. showed that gas6 was overexpressed in bc cells. they also found that high levels of gas6 expression were related to tumor stage, grade, and poor overall survival (24). unfortunately, there are no enough clinical studies on anti-axl/gas6 therapy focusing on bc. however, in light of the future studies, this pathway could be a candidate as novel biomarker and as an approach for treatment for bc. limitations of the study this hypothesis-generating study and our results have some limitations such as small sample size. the control group consists of the normal bladder tissues of the prostate cancer patients is another limitation of the study. normal bladder tissue is excised as a standard surgical procedure during radical prostatectomy operations. we preferred to use this normal bladder tissue as a control group without an ethical restriction. we could not excise the normal bladder tissue from healthy individuals as a control group because of the ethical problems. gas6 and its ligands might represent an attractive diagnostic tool in the future. however, expression of these proteins was studied in tissues requiring an invasive biopsy to be obtained. on the other hand, plasma gas6 elisa results were also promising for bc diagnosis and could be used as non-invasive diagnostic test. of course, future studies with larger sample size will provide more reliable information for implementation of plasma gas6 test as a biomarker. elisa method was used to detect the urine gas6 protein levels but gas6 protein was not detected in urine samples. the sensitivity of this method may not be appropriate for determining the level of gas6 protein in urine samples. gas6 protein could make a complex with soluble form of axl (25). further studies for optimization of plasma gas6 elisa method for measurement of gas6 in urine samples are necessary. conclusions we evaluated the relationship between gas6/rtks and bc with three different methods by performing qpcr analysis, immunohistochemistry and elisa analysis. our findings indicate that mrnas of gas6 and axl receptor are closely related to tumor stage and grade in patients with bc. further studies are needed for understanding the role of gas6 and its tam receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets. acknowledgments this study was supported by marmara university scientific research projects committee (grant number: sag-c-tup130612-0208). archivio italiano di urologia e andrologia 2021; 93, 2 m. akgül, ö. baykan, z. çağman, m. özyürek, i̇lker tinay, c. akbal, f. uras, l. türkeri 152 references 1. antoni s, ferlay j, soerjomataram i, et al. bladder cancer incidence and mortality: a global overview and recent trends. eur urol. 2017; 71:96. 2. kates m, bivalacqua tj. non-muscle invasive bladder cancer. campell-walsh urology 12th edition elsevier saunders press 2020; 135:14115. 3. robinson dr, wu ym, lin sf. the protein tyrosine kinase family of the human genome. oncogene 2000; 19:5548-57. 4. hafizi s, dahlbäck b. gas6 and protein s. the febs journal. 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sauter g, algaba f, amin m, et al. tumors of the urinary system: non-invasive urothelial neoplasias. in: eble jn, sauter g, epstein jl, sesterhenn i, eds. who classification of classification of tumors of the urinary system and male genital organs. lyon: iarcc press 2004; 29. 19. sun ws, fujimoto j, tamaya t. coexpression of growth arrestspecific gene 6 and receptor tyrosine kinases axl and sky in human uterine endometrial cancers. ann of onco. 2003; 14:898. 20. hattori s, kikuchi e, kosaka t, et al. relationship between increased expression of the axl/gas6 signal cascade and prognosis of patients with upper tract urothelial carcinoma. ann surg oncol. 2016; 23:663. 21. wu x, liu x, koul s, et al. axl kinase as a novel target for cancer therapy. oncotarget. 2014; 5:9546. 22. holland sj, pan a, franci c, et al. r428, a selective small molecule inhibitor of axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. canc res. 2010; 70:1544. 23. wang x, saso h, iwamoto t, et al. tig1 promotes the development and progression of inflammatory breast cancer through activation of axl kinase. cancer res. 2013; 73:6516. 24. mao s, wu y, wang r, et al. overexpression of gas6 promotes cell proliferation and invasion in bladder cancer by activation of the pi3k/akt pathway. onco targets ther. 2020; 13:4813-24. 25. ekman c, stenhoff j, dahlback b. gas6 is complexed to the soluble tyrosine kinase receptor axl in human blood. j thromb haemost. 2010; 8:838. correspondence murat akgül md (corresponding author) drmuratakgul@gmail.com assistant professor tekirdag namık kemal university, medical school, urology department, süleymanpaşa, tekirdağ, turkey, 59030 özgür baykan, md ozgurbaykan@gmail.com associated professor balıkesir university, biochemistry laboratory balıkesir, turkey, 10020 zeynep çağman, phd zeynep794@gmail.com assistant professor bezmialem university pharmacy school, biochemistry department, istanbul,turkey, 34734 mustafa özyürek, phd mustafaozyurek1@gmail.com research assistant marmara university, medical school, physiology department, maltepe, istanbul, turkey, 34854 i̇lker tinay, md itinay@yahoo.com associated professor anadolu medical center, gebze, kocaeli, turkey, 41400 cem akbal, md cakbal@gmail.com professor acıbadem university, urology department, altunizade-üsküdar, istanbul, turkey, 34660 fikriye uras, phd furas@marmara.edu.tr professor marmara university pharmacy school, biochemistry department, kadıköy istanbul,turkey, 34734 levent türkeri, md levent.turkeri@acibadem.com professor acıbadem university, urology department, altunizade-üsküdar, istanbul, turkey, 34660 stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):12832 1 original paper background infertility is defined as the inability to conceive after at least 12 months of regular unprotected sexual intercourse. infertility is a worldwide complaint and is projected to involve 8-12% of couples in the fertility period (1). males are responsible for 20-30% of cases of infertility and are participating in a further 20%. male subfertility is a wide range problem with almost unknown cause in most cases (1). although various diagnostic tests are available, their interpretation is imprecise and often subjective. varicocele (vx) which is the most treatable cause of male infertility with a prevalence of 40%, is also associated with low sperm count, decreased sperm motility and increased sperm abnormal morphology (2-4). the main hypotheses were that hyperthermia, venous pressure, hormonal imbalance, toxic substances and reactive oxygen radicals were involved in the pathophysiology and that varicocelectomy improved the number and motility of sperms (2-4). vx causes a progressive decline in fertility with upwards of 80% of men presenting with secondary subfertility having a vx (5). several studies tried to answer how vx causes infertility. factors included increased oxidative stress due to increased pressure on venous walls, scrotal hyperthermia, hypoxia, reflux of renal and adrenal metabolites, hormonal imbalances, the formation of antisperm antibodies and change in the seminal fluid composition including epididymal proteins (68). miyaoka and esteves found that patients with both clinical and subclinical vxs benefited from varicocelectomy because their sperm counts went up by a lot (9). alpha-glycerylphosphorylcholine (αgpc), one of the major phosphorus containing-choline compounds of seminal plasma, is secreted mainly by the epididymal epithelium under androgenic control (10). the organic fraction of human seminal plasma contains phosphate esters, particularly αgpc, phosphorylcholine (pch) and inorganic phosphate (11). αgpc is synthesized by the epididymis. it originated from phosphatidylcholine (pc) and broke down into choline and α-glycerophosphate (12). pc synthesis in mammalian tissue occurs by kennedy pathway with choline as one of the pillar substances that necessitates the removal of fatty acids by phospholipase activity background: varicocele (vx) which is the most treatable cause of male infertility, is also associated with low sperm count, decreased sperm motility and increased sperm abnormal morphology. we aimed in the current study to evaluate the correlation between seminal alpha-glycerylphosphorylcholine (αgpc) and semen parameters in infertile patients pre and post sub-inguinal micro-varicocelectomy. methods: the current comparative prospective study was carried out on 20 male patients who presented to kasr al-ainy hospitals from march 2022 to march 2023 as well as 20 healthy controls. the participants were divided into groups as follow: group (1) included fertile normozoospermic men (n = 20) who served as controls. group (2) included infertile oligoasthenoteratozoospermia (oat) men with varicocele (n = 20). patients in group (2) were followed up to 3 months after microsurgical sub-inguinal varicocelectomy. the examination included assessment of vx with scrotal duplex. semen analysis was done according to the 5th edition of who manual for semen analysis. results: the study demonstrates that αgpc level was significantly higher among fertile normozoospermic control group and infertile oat men post varicocelectomy when compared to infertile oat men preoperative (p < 0.001). moreover, it demonstrates that on follow up of infertile oat group 3 months after sub-inguinal micro-varicocelectomy, all semen parameters showed significant improvement compared to the corresponding semen parameters pre-operatively among vxs grade ii and grade iii (p < 0.001, p < 0.001, respectively). a significant positive correlation was found between αgpc level and semen parameters including sperm normal forms, sperm count and sperm motility. using roc curve, αgpc protein showed a sensitivity of (100%) and a specificity of (100%) at cut off value (≤ 1.975 pg/ml) in differentiation between infertile oat patients with vx and control fertile normozoospermic men (p < 0.001). conclusions: αgpc may play an important role in infertility in men with vx and correction of vx improves the seminal αgpc level. key words: varicocele; subinguinal micro-vericocelectomy; α-glycerylphosphorylcholine; semen parameters. submitted 22 july 2024; accepted 29 august 2024 correlation between seminal alpha-glycerylphosphorylcholine and semen parameters in infertile patients pre and post sub-inguinal micro-varicocelectomy: a prospective study ahmed fathy aboseif 2, nashaat nabil 2, sameh fayek gamalel din 1, shaimaa ali abdelkareem 3, aya ahmed onsi m.m.b.c.h 4, ahmad zaghloul 1, amgad elseginy 1 1 andrology & stds department, kasr alainy faculty of medicine, cairo university, cairo, egypt; 2 andrology & stds department, beni suef faculty of medicine, beni suef university, beni suef, egypt; 3 clinical pathology department, beni suef faculty of medicine, beni suef university, beni suef, egypt; 4 egypt ministry of health & population, cairo, egypt. doi: 10.4081/aiua.2025.12832 summary archivio italiano di urologia e andrologia 2025; 97(1):12832 a. abo sief, n. nabil, s.f. gamalel din, et al. 2 (12). also, the synthesis of αgpc entails sequential activity of a phospholipase a or alternatively, activity of a single phospholipase b. notably, αgpc is water soluble and degraded by hydrolysis to glycerol-3-phosphate and choline catalysed by gpc phosphodiesterase activity (12). evaluation of αgpc activity may also help find out if the epididymis is open and if sperm isn't normal. unfortunately, there are different opinions in the literature about how useful the assay is for male infertility (13). the epididymal function in semen analysis has been previously recommended as the epididymis is highly involved in preparing spermatozoa for fertilization. alpha-glucosidase, αgpc and l-carnitine were measured in sperm-free seminal plasma to determine the exact importance of these proteins in male fertility but with conflicting results (14). the objective of this study was to evaluate the effectiveness of evaluation and assessment of seminal of αgpc in infertile men before and after subinguinal micro-varicocelectomy. patients and methods the current comparative prospective study was carried out on 20 male patients who presented to kasr al-ainy hospitals from march 2022 to march 2023 as well as 20 controls. the institutional ethical committee of beni suef university approved the work that conforms to helsiniki declaration 2013 (15) (fmbsrec/08032022). inclusion criteria any infertile case with oligoasthenoteratozoospermia (oat) and vx aged 20 to 30 years old. exclusion criteria patients suffering from azoospermia and subclinical vx, smoking, patients with congenital anomalies or leukocytospermia, history of blood transfusion, iron therapy or anemia were excluded from the study inclusion criteria of the controls they were healthy age matched individuals who were companions to the cases. the participants were divided into groups as follows: group (1) was fertile normozoospermic men (n=20) served as controls. group (2) was infertile oat men with vx (n = 20). patients in group (2) were followed up to 3 months after sub-inguinal micro-varicocelectomy. general and clinical examinations were done. the examination included assessment of vx with scrotal duplex. semen analysis was done according to the 5th edition of who manual for semen processing (2010) (16). clinical examination was carried out in a warm room at the standing position with/without valsalva maneuver. color doppler ultrasonography was conducted for assurance of vx and its grade when one or more veins had a maximal diameter >3 mm with a retrograde flow at rest or under valsalva maneuver. vx was classified according to chiou et al. (1997) and kim et al. (2008) characterization (17-18). the ejaculates were obtained after 4-5 days of sexual abstinence into sterile containers. more than one sample was provided 2 weeks apart. sub-inguinal micro-varicocelectomy was done under general anaesthesia (19). also, it was done using a surgical microscope hb surgitech [5 step magnifications (4x, 6x, 10x, 16x & 25x) 45 degree inclined binocular tubes, 12.5x wide field eye pieces, f = 200 mm objective lens, aadesh complex, court road, near cjm court, ambala-134003, haryana, india]. after hospital discharge, patients were invited to attend to follow-up visit 3 months after sub-inguinal micro-varicocelectomy. semen samples were obtained as described above. fertile men infertile delivered one sample only, while infertile oat men delivered 2 samples pre and post sub-inguinal micro-varicocelectomy. measurement of αgpc quantitative detection of seminal αgpc was assayed by enzyme linked immunosorbent assay (elisa) sandwich principle human pc/cpg (choline phosphoglyceride elisa kit supplied by the american research products, usa (cat no eelh0730) according to manufacturer’s instructions. statistical analysis of the data data were fed to the computer and analysed using ibm spss software package version 20.0 (armonk, ny: ibm corp). qualitative data were described using number and percent. the shapiro-wilk test was used to verify the normality of distribution. quantitative data were described using range (minimum and maximum), mean and standard deviation. the significance of the obtained results was judged at the 5% level. f-test (anova) was used for normally distributed quantitative variables, to compare between more than two groups with post hoc test (tukey) for pairwise comparisons. pearson coefficient was used to correlate between two normally distributed quantitative variables. chi-square test was used to examine the relationship between two qualitative variables. t test was to assess the statistical significance of the difference between two study group means. finally, receiver operating characteristic curve was used to evaluate the sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. the optimum cut off point was defined as that which maximized the auc value. the area under the roc curve (auc) results were considered excellent for auc values between 0.9-1, good for auc values between 0.8-0.9, fair for auc values between 0.7-0.8, poor for auc values between 0.6-0.7 and failed for auc values between 0.50.6. results the sociodemographic characteristics of the participants are shown in table 1. the study demonstrates that αgpc level was significantly higher among fertile normozoospermic control group and infertile oat men post subinguinal micro-varicocelectomy when compared to infertile oat men preoperative (p < 0.001) (table 2). moreover, it was demonstrated that on follow up of infertile oat group 3 months after sub-inguinal micro-varicocelectomy, semen parameters showed significant improvement compared to the corresponding semen parameters pre-operatively among vxs grade ii and grade archivio italiano di urologia e andrologia 2025; 97(1):12832 3 seminal alpha-glycerylphosphorylcholine iii (p < 0.001, p < 0.001, respectively) (tables 3-4). there were no significant differences among patients with vx grade ii and vx grade iii, pre and post sub-inguinal micro-varicocelectomy regarding age (tables 3-4). furthermore, there was a significant positive correlation between αgpc level and semen parameters including sperm normal forms, sperm count and sperm motility (table 5). using roc curve, αgpc protein showed a sensitivity of (100%) and a specificity of (100%) at a cut off value of ≤ 1.975 pg/ml in differentiation between infertile oat patients with vx and control fertile normozoospermic men (p < 0.001) (figure 1). table 1. descriptive data of the controls and group iia (pre-operative infertile oat with varicocele) and group iib (infertile oat after sub-inguinal micro-varicocelectomy). group i group iia group iib test of sig. p value (n = 20) (preoperative) (postoperative) (n = 20) (n = 20) age (years) min-max 22-26 22 26 22-26 f = 1.037 0.361 mean ± sd 23.7 ± 1.4 24.15 ± 1.2 24.15 ± 1.2 median (iqr) 23.5 (22.5-25) 24.5 (23-25) 24.5 (23-25) semen volume (ml) min-max 1.4-4.8 0.6-6.9 25.2 f = 3.897 * 0.035 * mean ± sd 2.7 ± 0.9 2.76 ± 1.4 3.3 ± 0.74 median (iqr) 2.4 (2-3) 2 (1.5-3.4) 3.2 (2.8-3.9) sperm count (106 ml) min-max 24 -95 1-10 10-55 f = 54.968 * < 0.001 * mean ± sd 54.6 ± 22.4 5.33 ± 2.7 31.5 ± 12.3 median (iqr) 56 (65-70) 5 (2.6-8.2) 35 (16.3-40) total sperm motility (%) min-max 35-65 5-25 35-65 f = 66.216 * < 0.001 * mean ± sd 53.5 ± 7.3 14 ± 5.5 49.3 ± 9.1 median (iqr) 55 (50-60) 15 (10-18.8) 50 (41.3-55) sd = standard deviation; iqr = inter quartile range; p value was calculated using anova test. table 2. comparison between controls and groups iia and iib regrading αgpc level and normal forms. group i group iia group iib test of sig. p value (controls) (preoperative) (postoperative) (n = 20) (n = 20) (n = 20) αgpc level (pg/ml) min-max 2.65-9.86 0.3-1.30 2.0-10.86 f = 68.589 * < 0.001 * mean ± sd 6.66 ± 2.11 0.6 ± 0.31 6.38 ± 2.32 median (iqr) 7.05 (5-8.2) 0.54 (0.33-0.96) 6.20 (3.2-6.9) p1 < 0.001 * 0.123 * p2 < 0.001 * sperm normal forms (%) min-max 5.0-7.0 1-2 4.0-7.0 f = 49.468 * < 0.001 * mean ± sd 6.33 ± 0.8 1.7 ± 0.47 5.35 ± 0.93 median (iqr) 6.0 (50-60) 2.0 (1-2) 5.0 (2-4) p1 < 0.001 * 0.061 p2 < 0.001 * sd = standard deviation; iqr: inter quartile range; f: f for anova test, pairwise comparison bet. each 2 groups were done using post hoc test (tukey); p: p value for comparing between the 3 groups (group i and group ii a and group iib); p1: p value for comparing between group i and group iia (pre-operative) and group iib (post-operative); p2: p value for comparing between group iia (pre-operative) and group iib (post-operative). table 3. data of infertile men with varicocele grade ii pre and post sub-inguinal micro-varicocelectomy. patients with vx grade ii group iia (n = 11) group iib (n = 11) test of sig. p value (preoperative) (postoperative) age (years) min-max 22.0-26.0 22.0-26.0 t = 0.07 0.949 mean ± sd 24.33 ± 1.15 24.33 ± 1.15 sperm count (106 ml) min-max 1-10 10-45 t = 5.41 * < 0.001 * mean ± sd 5.14 ± 2.99 27.73 ± 14.85 total sperm motility (%) min-max 5-25 35-65 t = 9.71 * < 0.001 * mean ± sd 13.75 ± 5.9 46.82 ± 11.46 alpha gpc level (pg/ml) min-max 0.03-1.3 2-6.7 t = 12.18 * < 0.001 * mean ± sd 0.63 ± 0.24 5.58 ± 1.47 sperm normal forms (%) min-max 1-2 4-6 t = 8.38 * < 0.001 * mean ± sd 1.68 ± 0.49 4.27 ± 0.65 sd = standard deviation; t: student t-test; p: p value for comparing between the studied categories. archivio italiano di urologia e andrologia 2025; 97(1):12832 a. abo sief, n. nabil, s.f. gamalel din, et al. 4 +discussion in our study, analysis of semen parameters revealed that infertile oat men with vx showed statistically significant decrease regarding sperm counts and percentage of motile sperms when compared to fertile normozoospermic men who had normal basic semen paramaters. on follow up of infertile oat group 3 months after subinguinal micro-varicocelectomy, semen parameters table 4. data of infertile men with varicocele grade iii pre and post sub-inguinal micro-varicocelectomy. patients with vx grade iii group iia (n = 9) group iib (n = 9) test of sig. p value age (years) min – max 22.0 – 26.0 22.0 – 26.0 t= 0.20 0.841 mean ± sd 23.87 ± 1.35 23.87 ± 1.35 sperm count (106 ml) min – max 5.75 20 55 t=9.33* <0.001* mean ± sd 5.75 ± 3.56 33.78 ± 8.93 total sperm motility (%) min – max 5 20 35 65 t=11.19* <0.001* mean ± sd 14.45 ± 5.6 52.78 ± 8.33 alpha gpc level (pg/ml) min – max 0.18 0.98 5 – 10.9 t=15.28* <0.001* mean ± sd 0.59 ± 0.26 9.14 ± 1.62 sperm normal forms (%) min – max 1 2 5 7 t=11.10* <0.001* mean ± sd 1.75 ± 0.46 6.33 ± 1.0 sd = standard deviation; t: student t-test; p: p value for comparing between the studied categories. table 5. correlations between different parameters in the current study. age semen volume sperm count total sperm αgpc level sperm normal (years) (ml) (10^6 ml) motility (%) (pg/ml) forms (%) age (years) r 1.0 0.013 -0.097 -0.098 -0.109 -0.109 p 0.919 0.462 0.458 0.408 0.408 sperm count (106 ml) r 1.0 0.691 * 0.691 * 0.744 * p < 0.001 * < 0.001 * < 0.001 * total sperm motility (%) r 1.0 0.831 * 0.893 * p < 0.001 * < 0.001 * alpha gpc level (pg/ml) r 1.0 0.886 * p < 0.001 * sperm normal forms (%) r 1.0 p r: pearson coefficient. figure 1. roc curve showing α-gpc level (pg/ml) to discriminate between infertile oat patients with varicocele and controls. figure 2. roc showing α-gpc level (pg/ml) to discriminate between infertile oat patients with varicocele before and after varicocelectomy. archivio italiano di urologia e andrologia 2025; 97(1):12832 5 seminal alpha-glycerylphosphorylcholine showed significant improvement compared to the corresponding semen parameters pre-operatively. in agreement with our results, shabana et al. reported that sperm count and progressive motility significantly improved after varicocelectomy compared to pre-operative analysis (20). consistently, rehman et al. reported that sperm count, motility and normal morphology were significantly lower in vx patients in comparison to normal individual (21). this result agreed with a large-scale study of 7035 healthy young men from general european populations demonstrated that the presence of vx was associated with poorer semen quality (22). evidence from both animal and human studies show that varicocele affects sperm quality. experimental vx has been associated with impairment of testicular and epididymal endocrine and exocrine function, which may contribute to infertility seen in men with vx (23). moreover, we found that normal forms of sperms significantly improved in cases of vx grade iii compared to cases of vx grade ii after subinguinal micro-varicocelectomy. consistently, pasqualotto et al. did a study on 61 men with vx (24). they found that men with large varicoceles have worse sperm parameters before surgery, but they improve more after surgery than men with small or medium-sized varicoceles (24). krishna reddy et al. showed that patients with grade iii vx not only have better sperm parameters after surgery than those with grades i and ii, but also have a significant increase in testicular volume, which goes along with improvement in sperm parameters (25). in our current study, on follow up of infertile oat group 3 months after sub-inguinal micro-varicocelectomy, semen parameters and αgpc showed significant improvement compared to the corresponding semen parameters preoperatively among vx grades ii and iii. in our study, we believe that αgpc levels decrease in infertile men with vx this may be related to hyperthermia, venous pressure and reactive oxygen radicals which could be involved in the pathophysiology of the devastating impact of vx on spermatogenesis. in the current study levels of seminal αgpc were significantly higher post sub-inguinal micro-varicocelectomy compared to pre-operative in infertile males with vx. seminal αgpc were nearly matching to levels of fertile normozoospermic men after sub inguinal micro-varicocelectomy. statistically significant positive correlation was found between αgpc level and semen parameters. also, the current study did not demonstrate a relation between age and αgpc level. seminal αgpc showed 100% sensitivity and 100% specificity in differentiation between infertile oat patients with vx and fertile normozoospermic men. same values of sensitivity and specificity were obtained when comparing seminal αgpc between infertile oat patients with vx and post sub-inguinal micro-varicocelectomy. camargo et al. conducted a study to determine the seminal plasma lipid fingerprints in adults with vx before and after varicocelectomy (26). they reported that αgpc levels improved in the post-varicocelectomy group (26). seminal αgpc is one of the three main epididymal markers important for proper spermatogenesis. one of the physiological functions attributed to αgpc is a possible role in respiration and motility of sperm (27). in the same context, mieusset et al. (2020) reported significantly lower levels of αgpc in azoospermic men (28). this finding indicated the possible significant role played by αgpc in male fertility. in contrast, mieusset et al. previously reported (1988) no major difference in the total seminal content of αgpc among fertile and infertile men (29). furthermore, zhang et al. reported that levels of αgpc in asthenozoospermic men were significantly higher compared to healthy controls (30). admittedly, small sample size is considered the main limitation of the current study as well as short follow up period. however, the prospective nature of the study can add strength to the current findings. conclusions seminal αgpc may play an important role in infertility in men with vx and correction of vx improves seminal αgpc level. references 1. agarwal a, baskaran s, parekh n, et al. male infertility. lancet. 2021; 397:319-333. 2. mostafa t, rashed la, osman i, marawan m. seminal plasma oxytocin and oxidative stress levels in infertile men with varicocele. andrologia. 2015; 47: . 3. jensen cfs, østergren p, dupree jm, et al. varicocele and male infertility. nat rev urol. 2017; 14:523-533. 4. choy jt, eisenberg ml. male infertility as a window to health. fertil steril. 2018; 110:810-814. 5. fang y, su y, xu j, et al. varicocele-mediated male infertility: from the perspective of testicular immunity and inflammation. front immunol. 2021; 12:729539. 6. al bakri a, lo k, grober e, et al. time for improvement in semen parameters after varicocelectomy. j urol. 2012; 187:227-231. 7. nork jj, berger jh, crain ds, christman ms. youth varicocele and varicocele treatment: a meta-analysis of semen outcomes. fertil steril. 2014; 102:381-387. 8. elbardisi h, el ansari w, majzoub a, arafa m. does varicocelectomy improve semen in men with azoospermia and clinically palpable varicocele?. andrologia. 2020; 52:e13486. declarations ethical approval: this study was approved by the institutional ethical committee of beni suef university. additionally, informed consent was obtained from the patients. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the authors declare no competing interests. funding: this study did not receive any fund. authors' contributions: sfg drafted the initial manuscript; sfg revised the article critically; sfg reviewed and edited the article; nn designed the study; saa performed the lab work of the study; ao, ae, az, aas collected and analyzed the data. all authors reviewed the manuscript. acknowledgments: we would to thank the surgeons who performed the sub inguinal micro-varicocelectomy. archivio italiano di urologia e andrologia 2025; 97(1):12832 a. abo sief, n. nabil, s.f. gamalel din, et al. 6 9. miyaoka r, esteves sc. a critical appraisal on the role of varicocele in male infertility. adv urol. 2012; 2012:597495. 10. ma jy, lee my, kim hm, et al. shibimijihwang-tang elevates intracellular atp and choline content in the cerebral cortex of ovariectomized rats. j ethnopharmacol. 2000; 72:77-85. 11. lópez rodríguez a, rijsselaere t, beek j, et al. boar seminal plasma components and their relation with semen quality. syst biol reprod med. 2013; 59:5-12. 12. gallazzini m, burg mb. what’s new about osmotic regulation of glycerophosphocholine. physiology. 2009; 24:245-249. 13. ramm sa. seminal fluid and accessory male investment in sperm competition. philos trans r soc lond b biol sci. 2020; 375:20200068. 14. dacheux jl, dacheux f, druart x. epididymal protein markers and fertility. anim reprod sci. 2016; 169:76-87. 15. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-2194. 16. world health organization (who). who laboratory manual for the examination and processing of human semen. 5th ed. geneva: who: 2010. 271 p. 17. chiou rk, anderson jc, wobig rk, et al. color-doppler ultrasound criteria to diagnose varicoceles: correlation of a new scoring system with physical examination. urology 1997; 50:953-956. 18. kim hh, goldstein m. adult varicocele. curr opin urol. 2008; 18:608-612. 19. lee jy, yu hs, ham ws, et al. microsurgical intermediate subinguinal varicocelectomy. int surg. 2014; 99:398-403. 20. shabana w, teleb m, dawod t, et al. predictors of improvement in semen parameters after varicocelectomy for male subfertility: a prospective study. can urol assoc j. 2015; 9:e579. 21. rehman ku, zaneb h, qureshi ab, et al. correlation between testicular hemodynamic and semen quality indices in clinical varicocele patients in pakistan. biomed res int. 2019; 2019:7934328. 22. damsgaard j, joensen un, carlsen e, et al. varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six european countries. eur urol. 2016; 70:1019-1029. 23. birowo p, tendi w, widyahening is, et al. the benefits of varicocele repair for achieving pregnancy in male infertility: a systematic review and meta-analysis. heliyon. 2020; 6:e05439. 24. pasqualotto ff, lucon am, sobreiro bp, et al. effects of medical therapy, alcohol, smoking, and endocrine disruptors on male infertility. rev hosp clin fac med sao paulo. 2004; 59:375-82. 25. krishna reddy sv, basha shaik a, sailaja s, venkataramanaiah m. outcome of varicocelectomy with different degrees of clinical varicocele in infertile male. advances in andrology. 2015; 2:5-9. 26. camargo m, montani da, gozzo fc, et al. lipid fingerprinting profile of seminal plasma of patients perfomingsubinguinal microsurgery of varicocelectomy. fertil steril. 2012; 98:s146-s147. 27. cooper tg, weidner w, nieschlag e. the influence of inflammation of the human male genital tract on secretion of the seminal markers α-glucosidase, glycerophosphocholine, carnitine, fructose and citric acid. int j androl. 1990; 13:329-336. 28. mieusset r, bieth e, daudin m, et al. male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. andrology. 2020; 8:645-653. correspondence ahmed fathy aboseif, md ahmed.fathy.mohamed@med.bsu.edu.eg nashaat nabil, md nashaatnabil70@gmail.com andrology & stds department, beni suef faculty of medicine, beni suef university, beni suef, egypt sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg ahmad zaghloul, md ahmadzag@kasralainy.edu.eg andrology & stds department, kasr alainy faculty of medicine, cairo university, cairo, egypt amgad elseginy, md amgad_elseginy@yahoo.com shaimaa ali abdelkareem, md shaimaaali170@yahoo.com clinical pathology department, beni suef faculty of medicine, beni suef university, beni suef, egypt aya ahmed onsi, mmbch aya.onsi@hotmail.com egypt ministry of health & population, cairo, egypt stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12784 1 letter to editor key words: breast cancer; bladder cancer; metastasis; linitis plastica; haematuria. submitted 4 july 2024; accepted 6 july 2024 dear editor, we read with interest the recently published article by farci et al., titled “an unusual ‘linitis plastica’ like breast cancer bladder metastasis” and we congratulate with the authors for the very interesting topic and case presented (1). the authors have correctly reported data from the literature regarding the rate of bladder metastases from breast cancer, which appear to be approximately 2.4% of all bladder metastases. however, a recent systematic review of the literature 2 including 45 articles highlighted how in reality this percentage may be underestimated and probably higher. as indicated, some studies have reported rates of metastatic bladder involvement in breast cancer patients as high as 7% (2, 3). most clinical presentations occur with the appearance of hematuria, sometimes even several years after the initial diagnosis of breast cancer. in the case presented by colleagues 1 this occurred approximately 5 years after the diagnosis of breast cancer, and also in other cases presented in the literature the presentation of the metastasis can occur even more than 30 years after the diagnosis (2, 4). this delay in presentation can often make a timely diagnosis of the metastasis itself difficult, as the appearance of hematuria often occurs after the end of the usual oncological follow-up for breast cancer (5). a further difficulty in this sense, during the follow-up, is also a lack of mutual knowledge on the part of the urologist and breast surgeon of the respective pathologies. this can lead to a more difficult histopathological and immunohistochemical diagnosis post-turb (6), given by the failure to communicate the previous history of breast cancer to the pathologist himself. a further focus must be placed on the fact that breast cancer is a pathology which is not only unfortunately relatively frequent in females, but sometimes also in young women in an aggressive and locally advanced form (7, 8). this draws attention to the importance of a correct medical history of patients, especially young ones, to better understand the appearance of hematuria and better direct the differential diagnosis, even with the aid of biomarkers (8, 9). fortunately, bladder metastases from breast cancer remain rare events, although not exceptional. it therefore becomes essential, in our opinion, to also take this possibility into consideration in order to carry out a correct and timely diagnosis. references 1. farci r, tolu s, trombetta m, et al. an unusual "linitis plastica" like breast cancer bladder metastasis. arch ital urol androl. 2024; 96:12483. 2. malinaric r, balzarini f, granelli g, et al. from women to women-hematuria during therapy for metastatic breast cancer, what to suspect and when to be alarmed; bladder metastasis from breast cancer-our experience and a systematic literature review. front oncol. 2022; 12:976947. 3. hagemeister fb jr, buzdar au, luna ma, blumenschein gr. causes of death in breast cancer: a clinicopathologic study. cancer. 1980; 46:1627. 4. de rose af, balzarini f, mantica g, et al. late urinary bladder metastasis from breast cancer. arch ital urol androl. 2019; 91:60-62. 5. cornacchia c, dessalvi s, santori g, et al. breast edema after conservative surgery for early-stage breast cancer: a retrospective singlecenter assessment of risk factors. lymphology. 2022; 55:167-177. 6. mantica g, simonato a, du plessis de, et al. the pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection. minerva urol nefrol. 2018; 70:594-597. comment to “an unusual ‘linitis plastica’ like breast cancer bladder metastasis” raquel diaz 1, 2, rosario leonardi 3, federica murelli 1, 2, piero fregatti 1, 2, carlo terrone 1, 2, guglielmo mantica 1, 2 1 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 2 irccs ospedale policlinico san martino, genova, italy; 3 casa di cura musumeci gecas, gravina di catania, italy. doi: 10.4081/aiua.2024.12784 archivio italiano di urologia e andrologia 2024; 96(3):12784 r. diaz, r. leonardi, f. murelli, et al. 2 7. fregatti p, gipponi m, diaz r, et al. the role of sentinel lymph node biopsy in patients with b5c breast cancer diagnosis. in vivo. 2020; 34:355-359. 8. malinaric r, mantica g, lo monaco l, et al. the role of novel bladder cancer diagnostic and surveillance biomarkers-what should a urologist really know? int j environ res public health. 2022; 19:9648. 9. lopez-gonzalez l, sanchez cendra a, sanchez cendra c, et al. exploring biomarkers in breast cancer: hallmarks of diagnosis, treatment, and follow-up in clinical practice. medicina (kaunas). 2024; 60:168. correspondence raquel diaz, md raqueldiaz.ge@gmail.com piero fregatti, md piero.fregatti@unige.it carlo terrone, md carlo.terrone@med.uniupo.it federica murelli, md federica.murelli@unige.it guglielmo mantica, md (corresponding author) guglielmo.mantica@gmail.com irccs policlinico san martino, largo rosanna benzi 10, 16132, genova, italy rosario leonardi, md urologialeonardi@gmail.com casa di cura musumeci gecas, gravina di catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13790 1 original paper introduction inguinal hernias pose a significant surgical concern, with lifetime prevalence rates of approximately 27% in men and 3% in women. the incidence is particularly high, reaching 1.700 per 100.000 individuals and escalating to 4.000 per 100.000 in those over 45 years of age (1, 2). these hernias can lead to serious complications, such as obstruction and strangulation, contributing to approximately 40.000 fatalities annually (2, 3). surgical management of inguinal hernias involves various techniques, including both mesh and non-mesh repairs. while mesh repair is often preferred due to its association with lower recurrence and complication rates, the high costs of mesh can limit accessibility, particularly in resource-constrained settings (2, 4). in specialized centers, experienced surgeons can achieve recurrence rates as low as 2%, whereas less experienced practitioners may report rates as high as 25% (5-8). among traditional techniques, the shouldice method is noted for its recurrence rate of less than 1%, contingent upon the surgeon’s expertise, as it reinforces the posterior wall through multi-layered tissue repair (5). the desarda repair, which employs an undetached strip of the external oblique muscle aponeurosis, shows short-term outcomes comparable to both the shouldice and lichtenstein techniques; however, long-term data on its efficacy remain limited (9, 10). both methods, while effective, demand significant surgical skill. in contrast, the lichtenstein technique utilizes mesh for hernia repair and is favored for its ease of application and effectiveness in reducing recurrence rates. nonetheless, the potential complications associated with mesh have prompted renewed interest in alternative techniques (10, 11). this overview underscores the need for effective management strategies for inguinal hernias, particularly in light of the varying advantages and disadvantages of available surgical approaches. this study aims to identify effective inguinal hernia repair methods that prioritize safety and efficacy while minimizing reliance on imported materials. by utilizing the external oblique and transversus abdominis aponeuroses for posterior wall reconstruction, this prospective randomized clinical trial will compare the established background: inguinal hernia repair is a frequently performed surgical procedure that generally employs prosthetic mesh. however, alternative techniques, notably the reinforcement of the posterior inguinal wall through aponeuroplasty, have not been sufficiently explored, particularly in resource-constrained environments. this study aims to evaluate and compare the efficacy and outcomes of aponeuroplasty against traditional mesh repair in adult patients with inguinal hernias. methods: a randomized controlled trial was conducted from april 1, 2019, to may 22, 2024, enrolling 200 adult patients diagnosed with inguinal hernias. participants were randomized into either group a (lichtenstein technique with prosthetic mesh repair, n = 96) or group b (posterior inguinal wall aponeuroplasty, n=104). patients were monitored for a minimum of two year postoperatively. the aponeuroplasty technique required meticulous dissection of the external oblique and transversus abdominis aponeuroses, ensuring tissue integrity and securing the tissue to the inguinal ligament and muscle arch. complications, recurrence rates, and other surgical outcomes were systematically analyzed. results: demographic analyses revealed no significant differences between groups. group b demonstrated significantly shorter operative times (30 ± 9.43 minutes vs. 38 ± 12.55 minutes, p = 0.004) and lower postoperative pain levels (p = 0.031). over the follow-up period of two years, hydroceles were documented in 9 patients (4.5%), with a notably lower incidence in group b (1 case, 1.0%) compared to group a (8 cases, 8.3%, p = 0.030). recurrence rates were similar in both groups (3 in group a and 2 in group b, p = 0.613). conclusion: strengthening the posterior inguinal wall via aponeuroplasty offers superior outcomes compared to prosthetic mesh repair, particularly regarding postoperative pain and operative time. these findings advocate for the consideration of aponeuroplasty as an effective surgical alternative for inguinal hernia repair in low-resource settings. future studies are warranted to validate these conclusions across diverse and larger populations. key words: aponeuroplasty; hernia; inguinal; low-resource settings; mesh; prosthetic; operative time; pain; postoperative; recurrence. submitted 4 march 2025; accepted 9 march 2025 inguinal hernia repair: a comparison of strengthening the posterior inguinal wall with aponeuroplasty versus the lichtenstein technique (mesh repair). a randomized controlled trial in a low-resource setting saif ghabisha 1, faisal ahmed 2, ahmed ateik 3 1 1department of general surgery, school of medicine, ibb university, ibb, yemen; 2 department of urology, school of medicine, ibb university, ibb, yemen; 3 department of general surgery, faculty of medicine, 21 september university, sana'a, yemen. doi: 10.4081/aiua.2025.13790 summary archivio italiano di urologia e andrologia 2025; 97(2):13790 s. ghabisha, f. ahmed, a. ateik 2 lichtenstein technique to our modified andrews' repair in adult patients in yemen (5). the anticipated findings may contribute to advancements in surgical practices and improve patient outcomes in inguinal hernia repair. materials and methods study design this randomized clinical trial was conducted between march 2020 and april 2023, involving 204 individuals aged 18 years and older diagnosed with inguinal hernia and referred to the surgical facility at al-nasar hospital in ibb, yemen. diagnosis was based on the presence of visible inguinal or inguinoscrotal swelling, a detectable cough impulse, inability to reduce the swelling, and dull, aching pain in the inguinal region. eligible patients were randomly assigned to one of two surgical repair methods: lichtenstein mesh repair (group a) or tension-free aponeuroplasty (group b). informed consent was obtained from all participants prior to inclusion. comprehensive evaluations included patient history, physical examinations, complete blood counts, renal function tests, urine culture and sensitivity assessments, and abdominal ultrasound. older patients underwent additional diagnostic evaluations as part of their pre-anesthetic workup to identify potential complications. anesthesia type – general, local, or spinal – was determined by anesthesiologists with patient approval. operations were performed by a surgeon with a minimum of 10 years of experience in hernia repair. postoperative follow-up was maintained for two years by a team of two surgeons, and data were collected systematically. inclusion criteria: patients eligible for inclusion were those aged over 18 years diagnosed with inguinal hernia requiring elective surgical repair. exclusion criteria: exclusion criteria included individuals under 18, pregnant women, patients with scrotal hernias, those unable to provide informed consent due to cognitive limitations, and individuals with a history of prostatectomy, pfannenstiel incision, or previous preperitoneal or abdominal bladder surgeries. additionally, patients presenting with obstructed, strangulated, or gangrenous hernias, recurrent inguinal hernias, or intraoperatively identified thin, weak, or divided external oblique aponeurosis were excluded. sample size calculation: the sample size was calculated utilizing a 95% confidence interval, 90% power, and a 5% acceptable margin of error based on an 11.1% reported recurrence rate from a previous study by elsebae et al. (12). g power version 3 software was employed to determine that at least 180 participants (90 per group) were required. including a projected maximum dropout rate of 10%, a total sample size of 200 participants (100 per group) was established. randomization and blinding: a total of 204 eligible participants were randomly assigned to two parallel groups: group a (100 patients) and group b (104 patients). the clinic's supervisor, who was trained in block randomization techniques, performed the allocation using a computer-generated non-stratified randomization list with a block size of six, ensuring that physicians, patients, data collectors, and statistical analysts remained blinded to group assignments. group a: lichtenstein mesh-based repair technique in group a, the lichtenstein technique involved making an oblique inguinal incision to expose the inguinal canal and hernia sac. the sac was meticulously dissected, reduced, and excised if necessary. a tailored polypropylene mesh was anchored securely to the surrounding tissues using absorbable sutures or tacks (figure 1). the inguinal canal was subsequently closed in layers to minimize tension and optimize cosmetic outcomes, followed by standard postoperative care to monitor for complications. the steps of the lichtenstein mesh-based repair technique were consistent with those outlined in previous reports by messias et al. and adhere to established procedural recommendations (13). group b: authors' operative technique access to the hernia sac was achieved via an oblique inguinal incision, allowing for visualization of the external oblique aponeurosis while preserving the thin fascial layer over it. the integrity of the fascia, especially in areas of thinning at the superior portion of the hernia sac, was assessed (figure 2). figure 1. intraoperative photo showcasing the mesh and the positioning of the spermatic cord in the lichtenstein mesh-based repair technique. figure 2. (a) schematic representation of the inguinal hernia incision process, highlighting sac identification and peritoneum closure. (b) intraoperative photograph illustrating the same process. archivio italiano di urologia e andrologia 2025; 97(2):13790 3 inguinal hernia repair: a comparison of strengthening the posterior inguinal wall with aponeuroplasty... meticulous dissection of the external oblique and transversus abdominis aponeuroses was performed, ensuring the preservation of tissue integrity while anchoring the tissue to the inguinal ligament and muscle arch. an incision along the upper crux of the superficial ring was made, preserving the thinned portion in the lower leaflet and obtaining a robust upper strip suitable for repair with interrupted sutures (figure 3). the medial leaflet of the external oblique aponeurosis was sutured to the inguinal ligament from the pubic tubercle to the abdominal ring using 1/0 vicryl interrupted sutures. the initial sutures anchored in the anterior rectus sheath at the junction with the external oblique, while the last suture was placed to narrow the abdominal ring without compressing the spermatic cord (figure 4). lateral suturing was facilitated by retracting the cord structures with the index finger. a splitting incision was created in the sutured medial leaflet to detach a strip matching the gap between the muscle arch and the inguinal ligament, extending from the pubic symphysis to 1-2 cm beyond the abdominal ring (figure 5). the upper edge of this strip was then secured to the internal oblique or conjoined muscle using 1/0 vicryl interrupted sutures, minimizing tension on the suture lines, although this was not paramount for success (figure 6). this configuration figure 3. (a) diagram showing a suture connecting the lateral rectus sheath to the inguinal ligament, forming a new external ring. (b) operative image depicting the executed suture placement. figure 4. (a) drawing of the dissection of the external oblique aponeurosis along the rectus sheath, reaching a height corresponding to the spermatic cord diameter. (b and c) operative photograph demonstrating the dissection in progress. figure 5. (a) illustration of provisional sutures linking the medial external oblique aponeurosis to the transversalis fascia at the lower edge of the internal oblique and transversus abdominis muscles. (b) intraoperative photo showing suturing technique. figure 6. (a) schematic depicting the dissection of the external oblique aponeurosis to a height equal to the spermatic cord diameter, aligned with the external inguinal ring. (b) operative image illustrating the completed dissection. archivio italiano di urologia e andrologia 2025; 97(2):13790 s. ghabisha, f. ahmed, a. ateik 4 was utilized, depending on data distribution. qualitative variables were analyzed using the chi-square test or fisher's exact test as appropriate. regression analysis was performed to evaluate predictive factors related to outcomes in the lm group, with odds ratios (or) and 95% confidence intervals (ci) calculated for significant predictors. a p-value of less than 0.05 was considered statistically significant. statistical analyses were conducted using spss version 22 software (ibm corp., armonk, ny, usa). ethical approval: approval for the study protocol and all related procedures was granted by the institutional ethics committee of ibb university (id number ibbuni.ac.yem. 2022.49), in accordance with the declaration of helsinki. the study protocol was established on june 1, 2020, and registered with the university hospital medical information network clinical trials registry (umin-ctr) in japan under number r000057639 (see: https://center6.umin.ac.jp/ cgi-open-bin/ctr_e/ctr_view.cgi? recptno=r000057639). results summary of aponeurosis used in the technique in this tension-free inguinal hernia repair technique, the aponeuroses of the external oblique and transversus abdominis muscles played crucial roles. the external oblique aponeurosis was incised to allow proper placement of the spermatic cord and to prevent obstruction during the formation of the inguinal canal. similarly, the transversus abdominis aponeurosis was incised to facilitate the reconstruction of the posterior wall of the inguinal canal. this utilization of aponeurosis enabled the placement of sutures that reinforced the structural integrity of the inguinal canal while minimizing the risk of postoperative complications. summary of reinforcement technique used the reinforcement technique involved a series of sutures connecting the aponeurosis of the external oblique muscle to the inguinal ligament, thereby stabilizing the posterior wall of the inguinal canal. key components included: 1. divergent suturing: an initial divergent suture connected the medial segment of the external oblique aponeurosis with the transversalis fascia at the lower edge of the internal oblique and transversus abdominis muscles, allowing for even distribution of tension. 2. sequential suturing: sutures were applied from the medial to the lateral side, incorporating the lateral edge of the rectus abdominis sheath as necessary, ensuring effective figure 7. (a) diagram outlining suture application from the medial side, with layers tied from lateral to medial. (b and c) intraoperative photo showcasing the positioning of the spermatic cord beneath the external oblique aponeurosis. positioned the external oblique strip posterior to the spermatic cord, reconstructing the posterior wall of the inguinal canal. following the repositioning of the spermatic cord, the lateral leaflet of the external oblique was sutured to the newly formed medial leaflet anterior to the cord, ensuring an adequate closure (figure 7). undermining the surfaces of the medial leaflet enhanced its approximation to the lateral leaflet. the procedure concluded with the standard closure of the superficial fascia and skin. postoperative care: postoperative care for patients involved administering a prophylactic single oral dose of 500 mg ciprofloxacin daily for five days following surgery. for high-risk patients, low molecular weight heparin was administered the night before surgery to prevent deep venous thrombosis, continuing throughout hospitalization. early mobilization was encouraged approximately six hours post-surgery. pain management postoperatively included nonsteroidal anti-inflammatory drugs (nsaids) or pethidine as required. closed suction drainage, if utilized, was removed on the day of discharge. the postoperative course for each patient was closely monitored, and outpatient follow-up visits were meticulously documented. main outcomes: the primary outcomes included operative time, postoperative pain levels, surgical complications, and length of hospital stay. secondary outcomes evaluated hernia recurrence between the two surgical techniques: tension-free aponeuroplasty (tfa, group b) and lichtenstein mesh repair (lm, group a). gathered data: the collected data included patient and hernia characteristics such as age, gender, laterality of hernia, duration of hernia prior to the operation, smoking status, obesity (bmi > 30 kg/m²), history of anemia, diabetes, benign prostatic hyperplasia, and hernia classification (small, medium, large). operative and postoperative characteristics included operative time, length of hospital stay, postoperative complications, incidence of postoperative hydrocele, need for pethidine, and recurrence rates. postoperative complications were categorized into types, including cord edema, wound seroma, hematoma, chronic pain, testicular pain, urinary tract infection (uti), and hypoesthesia. statistical analysis: quantitative data were summarized as means and standard deviations, while qualitative variables were expressed as frequencies and percentages. the normality of the data was assessed using the smirnovkolmogorov test. to compare quantitative variables, either the independent-samples t-test or mann-whitney u test archivio italiano di urologia e andrologia 2025; 97(2):13790 5 inguinal hernia repair: a comparison of strengthening the posterior inguinal wall with aponeuroplasty... reinforcement while accommodating the anatomical structures of the spermatic cord. 3. formation of the superficial inguinal ring: care was taken to maintain the size of the superficial inguinal ring, facilitating the free passage of the spermatic cord and preserving the overall integrity of the canal. this approach effectively reduced the risk of recurrence and complications by providing robust reinforcement of the inguinal canal through the use of aponeurotic structures. study overview the study flow chart is shown in figure 8. a total of 200 patients diagnosed with inguinal hernias were enrolled in the study and randomly assigned to either group b (tension-free aponeuroplasty, n = 104, 52.0%) or group a (lichtenstein mesh repair, n = 96, 48.0%). the mean age of participants was 42.2 ± 15.1 years (median: 40 years; range: 18-75 years), with a predominance of males (97.0%) across both groups. the average duration of hernia prior to surgery was 24.6 ± 17.7 months (median: 20 months; range: 5-77 months). obesity, defined as a body mass index (bmi) greater than 30 kg/m², was present in 30 patients (15.0%). comorbidities were reported as follows: a history of anemia in 22 patients (11.0%), a history of diabetes in 31 patients (15.5%), and a history of benign prostatic hyperplasia in 52 patients (26.0%). additionally, 60 patients (30.0%) were identified as active smokers. figure 8. flow diagram illustrating the progression through the phases of a randomized trial, including enrollment, intervention allocation, follow-up, and data analysis (i.e., phases of the study). archivio italiano di urologia e andrologia 2025; 97(2):13790 s. ghabisha, f. ahmed, a. ateik 6 hernia classification revealed sizes as follows: small in 28 patients (14.0%), medium in 81 patients (40.5%), and large in 91 patients (45.5%). importantly, no statistically significant differences were observed between the groups in terms of demographic characteristics, comorbidities, or hernia type. a comprehensive summary of the baseline characteristics of patients and hernias, along with intergroup comparisons, is presented in table 1. operative time was significantly shorter in the tension-free aponeuroplasty group (group b) (mean ± sd: 46.3 ± 11.6 minutes) compared to the lichtenstein mesh group (group a) (mean ± sd: 53.5 ± 9.2 minutes; p < 0.001). in contrast, the length of hospital stay (mean ± sd: 2.7 ± 0.5 days; range: 2.0-3.5 days) showed no statistically significant difference between the groups (p = 0.281) (table 2). postoperative complications occurred in 29 patients (14.5%), with no significant difference in the overall complication rate between the groups (p = 0.428) (table 3). notably, the incidence of postoperative hydrocele was lower in the tension-free aponeuroplasty group (group b) (4.5%) compared to the lichtenstein mesh group (group a) (8.3%; p = 0.015). fewer patients in group a required pain medication (8.5% vs. 5.2%; p = 0.132). although the recurrence rate was lower in group b (n = 2, 2.0%) compared to group a (n = 3, 3.12%), this difference was not statistically significant (p = 0.613) (table 3). table 3. postoperative complications (n = 29). complication type n (%) cord edema 6 (3.0%) wound seroma 7 (3.5%) hematoma 4 (2.0%) chronic pain 2 (1.0%) testicular pain 5 (2.5%) urinary tract infection 3 (1.5%) bath hypoesthesia 2 (1.0%) some patients reported more than one complication. table 2. comparative analysis of operative and postoperative characteristics between groups. characteristic subgroup total group b group a p-value (n = 104; 52.0%) (n = 96; 48.0%) operative time (minutes) mean ± sd 46.3 ± 11.6 39.6 ± 9.3 53.5 ± 9.2 < 0.001 length of hospital stay (days) mean ± sd (range) 2.7 ± 0.5 (2.0-3.5) 2.7 ± 0.5 (2.0-3.5) 2.7 ± 0.5 (2.0-3.5) 0.281 complication yes 29 (14.5) 13 (12.5) 16 (16.7) 0.428 no 171 (85.5) 91 (87.5) 80 (83.3) postoperative hydrocele no 191 (95.5) 103 (99.0) 88 (91.7) 0.015 yes 9 (4.5) 1 (1.0) 8 (8.3) need for pethidine yes 17 (8.5) 12 (11.5) 5 (5.2) 0.132 no 183 (91.5) 92 (88.5) 91 (94.8) recurrence no 195 (97.5) 102 (98.0) 913 (96.88) 0.613 yes 5 (2.5) 2 (2.0) 3 (3.12) sd: standard deviation. a p-value of less than 0.05 was considered statistically significant and is presented in bold within the table. table 1. comparative analysis of patient and hernia characteristics between groups. characteristic subgroup total group b group a p-value (n = 104; 52.0%) (n = 96; 48.0%) age (years) mean ± sd 42.2 ± 15.1 41.1 ± 14.4 43.3 ± 15.7 0.315 gender men 194 (97.0) 101 (97.1) 93 (96.9) 1.000 female 6 (3.0) 3 (2.9) 3 (3.1) laterality left 80 (40.0) 40 (38.5) 40 (41.7) 0.751 right 120 (60.0) 64 (61.5) 56 (58.3) duration of hernia prior to operation (months) mean ± sd 24.6 ± 17.7 25.7 ± 19.4 23.5 ± 15.7 0.390 smoking yes 60 (30.0) 34 (32.7) 26 (27.1) 0.477 no 140 (70.0) 70 (67.3) 70 (72.9) obesity (bmi > 30 kg/m2) yes 30 (15.0) 13 (12.5) 17 (17.7) 0.405 no 170 (85.0) 91 (87.5) 79 (82.3) history of anemia yes 22 (11.0) 10 (9.6) 12 (12.5) 0.671 no 178 (89.0) 94 (90.4) 84 (87.5) history of diabetes yes 31 (15.5) 18 (17.3) 13 (13.5) 0.589 no 169 (84.5) 86 (82.7) 83 (86.5) history of benign prostatic hyperplasia yes 52 (26.0) 23 (22.1) 29 (30.2) 0.201 no 148 (74.0) 81 (77.9) 67 (69.8) hernia calcification small 28 (14.0) 15 (14.4) 13 (13.5) 0.630 medium 81 (40.5) 45 (43.3) 36 (37.5) large 91 (45.5) 44 (42.3) 47 (49.0) bmi: body mass index; sd: standard deviation. a p-value of less than 0.05 was considered statistically significant and is presented in bold within the table. archivio italiano di urologia e andrologia 2025; 97(2):13790 7 inguinal hernia repair: a comparison of strengthening the posterior inguinal wall with aponeuroplasty... regression analysis revealed two key predictive factors associated with the lichtenstein mesh group (group a). firstly, longer operative time was linked to an increased risk of complications in the lichtenstein mesh group (group a), with an odds ratio (or) of 1.15 (95% confidence interval: 1.11-1.20, p < 0.001). secondly, the occurrence of postoperative hydrocele was predicted with an or of 8.15 (95% ci: 1.00-188.68, p = 0.093) (table 4). discussion this randomized controlled trial aimed to compare the outcomes of two prominent inguinal hernia repair techniques: aponeuroplasty for posterior wall strengthening versus the lichtenstein mesh repair, conducted in a lowresource setting. our findings suggest that aponeuroplasty serves as a viable alternative to prosthetic mesh repair, particularly where surgical materials are limited. hernia surgeries are among the oldest surgical procedures, evolving from bassini's repair and its modifications to the lichtenstein tension-free repair (14). despite its widespread adoption, the shouldice technique remains relevant, particularly in specialized contexts, with reported recurrence rates below 1% at shouldice hospital, although they may reach 15% in general practice (14). high recurrence rates in non-specialist centers underscore the limitations of tissue-based repairs, prompting many surgeons to adopt prosthetic materials across various techniques, including open surgery and minimally invasive laparoscopic approaches (15, 16). these advancements raise concerns about the long-term implications of mesh use, including infection risks and adverse effects on testicular and sexual function. the search for cost-effective surgical methods with low recurrence and complication rates continues, emphasizing the importance of techniques that general surgeons can perform with minimal technology (14, 17, 18). numerous non-mesh hernia repair techniques have emerged, categorized into tension and tension-free methods. tension methods, such as the modified bassini and shouldice techniques, aim to reinforce the inguinal canal by suturing the external oblique muscle over the spermatic cord (19, 20). in contrast, the tension-free desarda technique transfers an undetached strip of the external oblique aponeurosis to the inguinal canal's posterior wall. this approach is increasingly favored globally, as it enhances the posterior wall without mesh, offering a reliable option when synthetic materials are unavailable (19). the ideal surgical technique should balance scientific evidence and cost-effectiveness (21). the lichtenstein technique is considered the gold standard for inguinal hernias, yet its application in emergency settings raises concerns about infection risk associated with foreign body introduction and potential chronic pain incidences (22). in developing contexts, where over 80% of inguinal hernia surgeries utilize tissue repair methods, techniques like desarda remain essential (19, 23, 24). recent meta-analyses demonstrate no significant short-term differences in success rates between the desarda and lichtenstein techniques for uncomplicated hernias (23). our novel aponeuroplasty technique presents distinct advantages over traditional approaches of non-mesh and mesh repairs, including the lichtenstein repair and laparoscopic methods. while the modified andrews' repair uses only the external aponeurosis, our method combines both the external oblique and transversus abdominis aponeuroses, providing enhanced support and minimizing tension on vital structures. it is particularly valuable in resource-limited settings, as it requires fewer specialized instruments and shows efficacy even in recurrent hernia cases (25, 26). furthermore, it has been associated with lower postoperative pain and complications, likely due to reduced tissue manipulation. in contrast, the lichtenstein repair's dependence on synthetic mesh poses infection and chronic pain risks, while laparoscopic techniques necessitate advanced training and equipment that may not be accessible, potentially extending operative times and increasing anesthesia-related risks (26). in our study, the operative time for the lichtenstein mesh repair technique was significantly longer (53.5 ± 9.2 minutes) compared to our approach, which closely resembles the desarda and modified andrews' techniques, averaging 39.6 ± 9.3 minutes. this finding is consistent with the literature, including studies by manyilirah et al. and t. youssef et al., indicating that hernia repairs utilizing techniques similar to desarda typically require less surgical time (11, 27). the extended duration associated with the lichtenstein procedure can be attributed to the complexities of mesh implantation. in contrast, our technique, benefiting from prior surgical experience, allows for a more streamlined and efficient process. a systematic review by pereira et al. corroborated these observations, noting that although the lichtenstein technique exhibited longer operative durations, there were no significant differences in recovery outcomes between the two approaches (10). furthermore, our investigation into the aponeuroplasty technique demonstrated a significant reduction in operative time, thus enhancing surgical efficiency, particularly in resource-constrained settings. this improved efficiency is crucial in high-volume surgical environments, enabling the effective management of more patients within limited timeframes. to advance the field, future research should focus on long-term outcomes associated with these techniques and examine the influence of surgeon experience on operative efficiency. additionally, the establishment of standardized training protocols could optimize surgical table 4. results of the regression model for statistically significant predictive factors. characteristic subgroup group b group a or p-value (n = 104; 52.0%) (n = 96; 48.0%) (95% ci) operative time (minutes) mean ± sd 39.6 ± 9.3 53.5 ± 9.2 1.15 (1.11-1.20) < 0.001 postoperative hydrocele no 103 (53.9%) 88 (46.1%) ref 0.093 yes 1 (11.1%) 8 (88.9%) 8.15 (1.00-188.68) or: odds ratio, ci: confidence interval, sd: standard deviation. a p-value of less than 0.05 was considered statistically significant and is presented in bold within the table. archivio italiano di urologia e andrologia 2025; 97(2):13790 s. ghabisha, f. ahmed, a. ateik 8 methods, reducing operative times while maintaining stringent standards of patient safety and care quality. we observed lower postoperative analgesia requirements in the aponeuroplasty group, along with a significantly reduced incidence of hydroceles compared to the lichtenstein technique. these findings indicate potential long-term benefits, as reduced analgesic needs may stem from less tissue trauma and inflammation associated with the avoidance of prosthetic materials (11, 28). the undetached aponeurotic strip integrates physiologically into the posterior inguinal wall, potentially enhancing repair durability and decreasing recurrence risks (29). after two years, recurrence rates were lower in group b (2.0%) compared to the lichtenstein mesh group (3.12%), although difference was not statistically significant (p = 0.613). all recurrences were linked to sliding hernia cases, with no early recurrences noted in either technique. findings from youssef et al. (11). corroborate our results, indicating comparable recurrence rates for desarda and lichtenstein repairs from the existing literature (10). recurrences were confined to expected sites near the pubic tubercle in the mesh group and the reconstructed deep internal ring in our approach which similar to youssef et al. report (11). contrary to the findings of szopinski et al. (30), our exclusion criteria, which removed patients with weak or thin aponeuroses, may explain the absence of generalized weakness in the reconstructed posterior wall. however, our method may need an experienced surgeon with high insight into inguinal canal anatomy. several modifications to bassini’s technique have been proposed by various surgeons, including those by halsted, mcvay, and the shouldice hospital. these methods hinge on the principles of suturing the internal oblique and transversus abdominis muscles to anatomical structures such as the inguinal ligament, cooper’s ligament, or iliopubic tract. concerns have surfaced regarding the inherent tension associated with the suture line, which contradicts essential surgical principles, alongside the use of compromised musculature and transversalis fascia that may further undermine structural integrity (31). a comparative study by hay et al. indicated a recurrence rate of 6% for the shouldice technique, 8.6% for bassini, and 11% for cooper’s ligament repair, with specialized centers demonstrating significantly lower recurrence rates compared to those reported by general surgeons (18). therefore, while these historical approaches continue to be prevalent, they frequently fall short of contemporary surgical standards, particularly when conducted by less experienced surgeons, resulting in inadequate reinforcement of the posterior wall and an elevated risk of recurrence. the demographic characteristics of our study population were similar between groups, reducing confounding variables. however, larger studies with diverse populations and hernia presentations are necessary for greater generalizability. study limitations this study has several limitations. the monocentric design and limited sample size restrict generalizability. additionally, the two-year follow-up may inadequately assess long-term outcomes, and factors influencing surgical outcomes – such as educational level, occupation, surgeon experience, medications, quality of life, and chronic scrotal pain – were not comprehensively analyzed. conducted in educational hospitals in yemen, the findings may not be applicable to other contexts. despite these limitations, the study offers valuable insights into inguinal hernia repair techniques in resource-constrained environments. future research should address these gaps through multi-center trials and extended follow-up assessments to validate the safety and efficacy of the aponeuroplasty technique relative to other surgical approaches. conclusions this study demonstrates that aponeuroplasty, a technique that reinforces the posterior inguinal wall, significantly outperforms traditional prosthetic mesh repair regarding operative time and the incidence of postoperative hydrocele development. these findings highlight aponeuroplasty as an efficient and effective option for inguinal hernia repair, particularly in resource-limited settings with restricted access to advanced surgical materials. given its advantages, aponeuroplasty serves as a viable alternative to conventional mesh-based approaches and may enhance patient outcomes in such contexts. to further validate these findings and investigate the longterm efficacy and safety of aponeuroplasty, additional research is needed. this research will be critical in providing evidence-based guidelines for inguinal hernia repair across diverse clinical environments. declarations registration of trial details: umin id: test000001823. receipt number: t000009059. ethical approval: approval for the study protocol and all related procedures was granted by the institutional ethics committee of ibb university (id number ibbuni.ac.yem.2022.49), in accordance with the declaration of helsinki. the study protocol was established on june 1, 2020, and registered with the university hospital medical information network clinical trials registry (umin-ctr) in japan under number r000057639 (see: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=r000057639). availability of data and material: all the data was included in this study. competing interests: the author declares no potential conflict of interest. funding: none. authors' contributions: all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; 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21(suppl 1):1-137. 30. szopinski j, dabrowiecki s, pierscinski s, et al. desarda versus lichtenstein technique for primary inguinal hernia treatment: 3year results of a randomized clinical trial. world journal of surgery; 36:984-92. 31. panos rg, beck de, maresh je, harford fj. preliminary results of a prospective randomized study of cooper's ligament versus shouldice herniorrhaphy technique. surg gynecol obstet. 1992; 175:315-9. correspondence saif ghabisha saifalighabisha@yahoo.com department of general surgery, school of medicine, ibb university, ibb, yemen orcid id: 0000-0002-7800-0890 faisal ahmed (corresponding author) fmaaa2006@yahoo.com department of urology, school of medicine, ibb university, ibb, yemen ahmed ateik drahmedatik@gmail.com department of general surgery, faculty of medicine, 21 september university, sana'a, yemen stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13746 1 original paper chemical recurrence (11, 12). in this respect, psma pet/ct has been evaluated in clinical trials in men candidate to initial or repeat prostate biopsy especially in the presence of clinical high risk for pca, in men during active surveillance and/or in case of negative histology of prostate imaging reporting and data system (pi-rads score) 4-5 targeted biopsy. materials and methods literature search strategy this review examines the role of psma pet/ct in the diagnosis and management of pca, focusing on why and when it should be used. a comprehensive literature search was conducted using electronic databases such as pubmed, scopus, and web of science. the review was performed following the preferred items for systematic reviews and metaanalysis (prisma) reporting guidelines from 2014 to february 2025 (figure 1). search terms the search strategy included terms such as “psma pet/ct”, “prostate cancer”, “pca diagnosis”, “targeted biopsy”, and “multiparametric mri”. inclusion criteria articles were included if they discussed psma pet/ct in the context of prostate cancer diagnosis, compared it with other imaging modalities, or explored its use in different patient cohorts. exclusion criteria articles not in english, case reports, conference papers, and studies focusing exclusively on treatment rather than diagnosis were excluded. study screening titles and abstracts retrieved from the initial search were screened for relevance by two independent reviewers. full-text articles were then assessed for eligibility. data synthesis findings from the included studies were synthesized narprostate-specific membrane antigen (psma) is expressed in most primitive and metastatic prostate cancer (pca), and psma inhibitors conjugated with the radionuclides gallium 68 (68ga) and fluoride 18 (18f) have been evaluated to detect pca; moreover, tumour uptake, which represents psma expression, is highly correlated with the aggressiveness of the primary prostatic tumour. psma positron emission tomography/computed tomography (pet/ct) demonstrated to be sensitive for the detection of primary prostatic lesions, regional lymphadenopathy and clinical metastases in case of biochemical recurrence. in this respect, psma pet/ct has been evaluated in men enrolled in clinical trials candidate to initial or repeat prostate biopsy especially in the presence of clinical high risk for pca, active surveillance (as) and/or in case of negative histology of prostate imaging reporting and data system (pi-rads score) 4-5 targeted biopsy. although many experimental studies reported a superimposable detection rate for pca of psma pet/ct vs. mpmri targeted biopsy, still today, the use of psma pet/ct is experimental and had some limitations: cost, availability, patient characteristics, local expertise and false negative rate. although prospective and randomized studies are awaited, including a greater number of patients, psma pet/ct evaluation could be proposed in the presence of claustrophobia, cardiac pacemaker and severe obesity especially in men at high risk for pca. key words: targeted prostate biopsy; psma pet/ct; mpmri vs. psma pca diagnosis; psma pet/ct targeted biopsy; psma false negative rate submitted 26 january 2025; accepted 6 march 2025 introduction prostate-specific membrane antigen (psma) is expressed in most primitive and metastatic prostate cancer (pca) (1, 2), and psma inhibitors conjugated with the radionuclides gallium 68 (68ga) and fluoride 18 (18f) have been evaluated for the diagnosis of pca (3-6); morever, tumour uptake, which represents psma expression, is highly correlated with the aggressiveness of the primary prostatic tumour (7-9). psma positron emission tomography/computed tomography (pet/ct) demonstrated to be sensitive for the detection of primary prostatic lesions, regional lymphadenopathy (10) and clinical metastases in case of biopsma pet/ct in the diagnosis of prostate cancer: why and when? pietro pepe 1, ludovica pepe 2, daniele cignoli 3, marco roscigno 3, 4 1 urology unit, cannizzaro hospital, catania, italy; 2 pathology unit, policlinico g. martino university of messina, messina, italy; 3 department of urology, asst papa giovanni xxiii, bergamo, italy; 4 milano-bicocca university, international school of medicine, milano, italy. doi: 10.4081/aiua.2025.13746 summary archivio italiano di urologia e andrologia 2025; 97(2):13746 p. pepe, l. pepe, d. cignoli, m. roscigno 2 ratively, given the diversity of methodologies and outcomes. the review summarizes emerging trends, potential benefits, limitations of psma pet/ct, and its comparative accuracy with mpmri. risk of bias the risk of bias assessment for each study has been reported in figure 2; all the selected studies had low risk of bias. psma pet/ct and prostate biopsy: why? although mpmri has improved diagnostic accuracy of systematic prostate biopsy in the diagnosis of cspca, about 15-20% of pca could be missed by mpmri targeted biopsy (13, 14), therefore targeted cores should always be combined with systematic or perilesional biopsies as recently suggested by eau guidelines (15). psma is overexpressed in most primitive and metastatic pca; moreover, tumour psma uptake, is highly correlated with the aggressiveness of the primary prostatic tumour (16) (table 1). psma pet/ct demonstrated to be sensitive also for the detection of primary prostatic lesions especially in men at high risk for pca (17). the presence of focal uptake on psma-pet/ct, standardised uptake value (suvmax), and the maximal dimensions of petavid lesions have been correlated with the presence of cspca. there is a range of proposed suvmax cutoffs to detect cspca (18, 19) and its value is highly correlated with isup grade group pca (20). kalapara et al. (21) compared the accuracy of 68ga-psma pet/ct with mpmri in 205 men who underwent radical prostatectomy and showed a diagnostic accuracy of 96% for the detection of cspca. pepe et al. (18) in 160 men demonstrated that a suvmax of 8 diagnosed a cspca in 98% of figure 1. flow chart of the study selection process. archivio italiano di urologia e andrologia 2025; 97(2):13746 3 psma pet/ct and pca diagnosis figure 2. risk of bias domains. table 1. overview of the most relevant studies, included in the review, comparing psma pet/ct to mpmri in the diagnosi of pca. study imaging modalities n° of sensitivity specificity ppv npv diagnostic key findings & conclusions compared patients (%) (%) (%) (% accuracy (%) pepe et al. 68ga-psma pet/ct 125 100% vs. 90.9% 80.3% vs. 78.9% 87.9% vs. 78.9% 100% vs. 84.9% 92% vs. 86.2% 68ga-psma pet/ct demonstrated comparable vs. mpmri, in patients accuracy and sensitivity with mpmri in detecting 2023 (16) with clinical parameters significant prostate cancer. high risk for pca kalapara et al. 68ga-psma pet/ct overall pca 205 91% vs. 89% psma pet/ct showed superior accuracy and 2020 (20) vs. mpmri cspca 133 96% vs. 91% sensitivity in detection and localization of prostate cancer compared to mpmri and pathology. exterkate et al. 18f-psma-1007 pet/ct overall pca 129 85% vs. 62% 18f-psma pet/ct had higher per-lesion 2023 (21) vs. mpmri cspca 96 95% vs. 73% sensitivity and specificity for localization and staging compared to mpmri. wong et al. 18f-psma pet/ct overall pca 184 73.8% vs. 78.4% 52.1% vs. 72.6% 57.2% vs. 68.8% 63% vs. 76% psma pet/ct showed high correlation with 2024 (23) vs. mpmri cspca 84 77.1% vs. 87.3% 47.2% vs. 57.3% 70.2% vs. 81.2% 62% vs. 72% mri for diagnosing and localizing prostate cancer; showed potential as a diagnostic tool. archivio italiano di urologia e andrologia 2025; 97(2):13746 p. pepe, l. pepe, d. cignoli, m. roscigno 4 the cases with a false positive rate of 4.8%; on the contrary, only 12% of men with a isup gg2/gleason score 3 + 4 had a suvmax below 8. exterkate et al. (22) compared psma pet/ct vs. mpmri accuracy in detecting pca in 80 men submitted to radical prostatectomy: per-lesion sensitivity for localisation of overall pca and cspca was 85% vs. 62% and 95% vs. 73%, respectively. demirci et al. (18) in 141 patients submitted to radical prostatectomy showed that the suvmax values were significantly higher in high-risk patients compared those in low-risk patients (18.9 ± 12.1 vs.7.16 ± 6.2). psma pet/mri, combining the advantages of mpmri and psma pet, is a promising modality for guiding biopsy with demonstrated feasibility (23). the pedal study (24, 25) showed that multiparametric mri outperformed psma pet/ct in identification of prostate cancer, although the distinction was not notable when detecting cspca; moreover, the synergy of mpmri and psmapet/ct demonstrated enhanced sensitivity and negative predictive value (24, 25). psma pet/ct targeted biopsy: how? psma pet/ct imaging is performed using a ct-integrated pet scanner; psma is administered to patients via an intravenous bolus and the pet acquisition start at a mean of 58 ± 12 min (range, 50-81 min) afterward. scans are acquired in 3-dimensional mode with an acquisition time of 3 min per bed position and a low dose unenhanced ct scan is performed from the skull base to the middle of the thigh. images are processed to obtain pet, ct, and petct fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm by two experienced nuclear medicine specialists. the location of focal uptake on psma pet/tc, three-dimensional size, and suvmax values are reported (figure 3) on a per-lesion basis with a sextant scheme (apex, midgland, and base, each split into left and right). there is a range of proposed cutoffs to detect cspca from suvmax 3.15 to suvmax 9.1 (21, 26, 27); 68ga or 18f psma-pet/ct index lesions showed by the suvmax cut-off are submitted to targeted cores (four cores) always combined with extended systematic prostate biopsy. the procedure could be performed by transrectal or transperineal approach using a tru-cut 18-16 gauge needle under sedation and/or local anesthesia and antibiotic prophylaxis; however, the transperineal way is recommended to reduce risk of sepsis and increase detection rate of anterior zone pca (28, 29). psma pet/ct images should be evaluated together the nuclear medicine specialist to improve the accuracy of targeted biopsy because the procedure is usually performed by cognitive approach and the urologists often are not confident with prostatic psma pet/ct images used for targeted biopsy. the focal uptake on psma-pet/ct, suvmax, and the maximal dimensions of pet-avid lesions have been correlated with the presence of cspca (22-24); emmett et al. (7) suggested a 5-point primary score to optimize the accuracy of psma pet/ct for cspca; a 5-level primary score was assigned on the basis of analysis of the central read: no pattern (score of 1), diffuse transition zone (tz) or central zone (not focal) (score of 2), focal tz (score of 3), focal peripheral zone (pz) (score of 4), or an suvmax of at least 12 (score of 5). the primary study demonstrated a sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of cspca in the presence of a primary score > 3 (high-risk patterns) equal to 88%, 64%, 76%, and 81%, respectively. psma targeted biopsy: when? the use of psma pet/ct still today is experimental and should be reserved to men enrolled in clinical trials; awaiting the prospective and randomized studies could define the true role of psma in the diagnosis of pca to guide targeted biopsy, many papers have been focused on the psma pet/ct accuracy in men with clinical high risk for pca, enrolled in active surveillance (as) protocols and in case of negative mpmri/trus fusion biopsy of pirads score 5 lesions. psma pet/ct: men with clinical high risk for pca a psma pet/ct scan suspicious for pca, as previously reported, results from a combination of factors, such as homogeneity and intensity of psma expression, tumor volume, and grade. the presence of focal uptake on psmapet/ct, suvmax, and the maximal dimensions of petavid lesions have been correlated with the presence of cspca (22-24). the presence of high primary score with elevated suvmax values is highly correlated with the presence of advanced cspca; these parameters are more evident in men with clinical high risk for cspca (i.e., suspicion digital rectal examination “dre”, psa values > 20 ng/ml), therefore, psma pet/ct evaluation could be proposed to perform diagnosis (targeted biopsy) and staging of confirmed pca; at the same time, psma pet/ct improve costbenefit ratio as a single procedure for the diagnosis and staging of high-risk pca (figure 4). pepe et al. (17) in 125 men with median psa of 35 (range 15-160 ng/ml and suspicion dre in 56.2% of the cases demonstrated a diagnostic accuracy of psma pet/ct vs. mri/trus fusion biopsy equal to 92.0 vs. 86.2%, respectively. bodar yjl et al. (30) in 60 men with psa values of 20-50 ng/ml demonstrated that psma-guided targeted biopsy identified 86.7% pca and 100% of distant metastases. psma pet/ct and active surveillance as is an alternative to radical treatment of low risk pca, focusing on prevention of overtreatment (31, 32). the estimated risk-free treatment at 5, 10 and 15 years in men figure 3. patient with prostate cancer grade group 3/gleason score 4 + 3 and psa 19 ng/ml: intraprostatic suvmax equal to 16. archivio italiano di urologia e andrologia 2025; 97(2):13746 5 psma pet/ct and pca diagnosis enrolled in as with gg1 pca is equal to 76, 64, and 58% (33); although mpmri is strongly recommended in the reevaluation of men in as, still today, scheduled systematic repeated prostate biopsies are recommended in addition to targeted mpmri/trus fusion biopsy (pi-rads score > 3) to reduce the false negative rate for cspca of mpmri (34). recently, psma pet/ct accuracy has been evaluated in clinical trials in men enrolled in as protocols (35, 36). in 220 men with intermediated-risk pca enrolled in as xue et al. (37) demonstrated that a suvmax of 5.4 may improve risk stratification for men with intermediate-risk prostate cancer to predicte pathological upgrading with a negative predictive value equal to 94%. pepe et al. (3, 38, 39) evaluated 68ga-psma pet/ct accuracy in the reevaluation of 40 men enrolled in as protocol showing a diagnostic accuracy in the diagnosis of cspca not inferior to mpmri (83.3 vs. 70.2%). heetman et al. (40) reported that psma pet/ct improved risk stratification in 9% of men who were upgraded to cspca (isup grade group > 2) using a suvmax cut-off equal to 4. recently, akcay et al. (41) and dondi et al. (42) reported that psma pet/ct imaging is useful in distinguishing men for as, potentially aiding in the identification of cspca. in definitive, still today, diagnostic imaging should not replace scheduled prostate biopsy in men enrolled in as protocols, but it is mandatory to detect targeted lesions suspicious for cspca; although, mpmri is highly recommended, psma pet/ct represent an emergent diagnostic imaging that in selected cases could be used to evaluate men in as (figure 5). although, the number of patients evaluated is very low and a suvmax cut-off has not been defined, psma pet/tc evaluation could be proposed in men who cannot perfom mpmri (i.e. severe obesity, claustrophobia or cardiac pacemaker). psma pet/ct and negative biopsy in men with pi-rads score 5 and equivocal pi-rads score 3 the aggressiveness of cspca is correlated with the mpmri pi-rads scores; in the presence of a suspicion area with pi-rads score 5 ranges from 59.2 to 86% of the cases (43). the correlation of the pi-rads score to the diagnosis of aggressiveness cancer has been well established; otti et al. (44) showed in men with pi-rads score 5 a detection rate for cspca ranged from 59.2 to 86.7%, respectively (45). therefore, a negative biopsy in men with pirads score 5 need a close clinical follow up to avoid missing cspca diagnosis. the use of psa, psa density (psad), risk calculator, urinary genetic tests (46-48), and the repetition of mpmri allow to reduce the risk of harbouring a cspca. in this respect, a second opinion regarding initial mpmri (49) and histology evaluation should be performed to decrease the risk of false negative results. recently, wong et al. (50) in 29 men with pirads score 4-5 and negative biopsy histology reported that a suvmax > 20 was correlated with the presence of cspca. in 25 patients with pi-rads score 5 and negative biopsy histology psma pet/ct evaluation, during follow up, showed suvmax (median 7.5) values not suspicious for cspca resulting in agreement with the mpmri results (pirads score < 3) (51). in definitive, the strict clinical follow up of men with negative histology of pi-rads score 5 lesions reduce the risk of missing cspca especially if psma pet/ct evaluation is in agreement with the downgrading of mpmri (pi-rads score < 3) and favorable clinical parameters (psa, psad). recently, psma pet/ct combined with psa density has been suggested to evaluate equivocal pi-rads score lesions to reduce the number of unnecessary biopsy and improve detection rate for cspca (52, 53); privè et al. (54) demonstrated in 26 men with pi-rads 3 lesions a negative and positive predictive value of 93% and 27%, for ruling out or detecting cspca. psma pet/ct: false negative rate although, psma pet/ct results about 27% more accurate than conventional imaging (55), 5-10% of primary figure 5. patient enrolled in active surveillance protocol with prostate cancer grade group 1/gleason score 6 and psa 5.9 ng/m: intraprostatic suvmax equal to 4.5. figure 4. metastatic prostate cancer grade group 5/gleason score 9 with psa 80 ng/ml: intraprostatic suvmax equal to 23 (a: axial scan); bone and nodes metastases (coronal scan). a. b. archivio italiano di urologia e andrologia 2025; 97(2):13746 p. pepe, l. pepe, d. cignoli, m. roscigno 6 pca psma have low activity which evade detection by psma pet, mostly in high-grade and variant tumor types (56-58). prostatic ductal adenocarcinoma (dac) is rare, aggressive, and characterized by cancer involving ducts and/or acini usually associated with a high-grade gleason score/grade group, large tumor volume, and adverse prognostic parameters, including extraprostatic extension and seminal vesicle invasion. although mpmri and psma pet/ct are provided of superimposable accuracy in the diagnosis of high risk pca showing direct correlation between pi-rads score and suvmax values, in the presence of dac only mpmri (59) allows to perform diagnosis because psma pet/ct demonstrated a very limited diagnostic accuracy (60-62). in this respect, psma uptake has sometimes been poor compared with prominent 18-flourodeoxyglucose (f-18 fdg) avidity, which would suggest that fdg pet/ct scans are important in diagnosing and staging dac pattern. the diagnostic utility of dual-tracer fdg/psma pet/ct for pca may assist in characterizing high-risk disease during primary staging and restaging especially with concurrently negative psma pet. in conclusion, conventional imaging and psma pet/ct could result inadequate in the diagnosis and staging of dac, the use of more imaging data including mpmri and f-18 fdg could improve overall accuracy. conclusions although many studies have compared the accuracy of psma pet/ct with mpmri targeted biopsy in the diagnosis of cspca the use of psma pet/ct still today is experimental and had some limitations (63): cost, availability, patient characteristics, local expertise and false negative rate; moreover, the number of patients evaluated is very low and the use of a psma pet/tc fusion platform would increase the accuracy of targeted prostate biopsy. although prospective and randomized studies are awaited, including a greater number of patients, psma pet/ct evaluation could be proposed in the presence of claustrophobia, cardiac pacemaker and severe obesity especially in men at high risk for pca. references 1. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer research 2022; 42:3011-3015. 2. sheikhbahaei s, afshar-oromieh a, eiber m, et al. pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (psma)-targeted pet imaging. eur j nucl med mol imaging 2017; 44: 2117-2136. 3. pepe p, pepe l, tamburo m, et al: 68ga-psma pet/ct and prostate cancer diagnosis: which suvmax value? 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investigation: p.p., r.m., p.l.,c.d.: data curation: p.p., r.m., p.l.c.d.; formal analysis: p.p., r.m., p.l.c.d; methodology: p.p., r.m., p.l.c.d.; resources: p.p., r.m., p.l.c.d.; software: p.p., r.m., p.l.c.d.; writing original draft: p.p., r.m.; writing review & editing: p.p., r.m., p.l., c.d. acknowledgments: the authors thank nuclear medicine unit of cannizzaro hospital (catania, italy) for the images. archivio italiano di urologia e andrologia 2025; 97(2):13746 7 psma pet/ct and pca diagnosis 15. cornford p, van den bergh rcn, briers e, et al. eau-eanmestro-esur-isup-siog guidelines on prostate cancer-2024 update. part i: screening, diagnosis, and local treatment with curative intent. eur urol 2024; 86:148-163. 16. kawada t, yanagisawa t, rajwa p, et al. diagnostic performance of prostate-specific membrane antigen positron emission tomography-targeted biopsy for detection of clinically significant prostate cancer: a systematic review and meta-analysis. eur urol oncol 2022; 5:390-400. 17. pepe p, pennisi m. targeted biopsy in men high risk for prostate cancer: 68ga-psma pet/ct versus mpmri. clin genitourin cancer 2023; 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31:4445-4449. 48. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl. 2020; 92. 49. li jl, phillips d, towfighi s, et al. second-opinion reads in prostate mri: added value of subspecialty interpretation and review at multidisciplinary rounds. abdom radiol (ny) 2022; 47:827-837. 50. wong lm, koschel s, whish-wilson t, et al. investigating psma-pet/ct to resolve prostate mri pirads 4-5 and negative biopsy discordance. world j urol 2023; 463-469. 51. pepe p, pepe l, pennisi m. negative biopsy histology in men with pi-rads score 5: is it useful psma pet/ct evaluation? arch ital urol androl 2024; 96:12358. 52. li y, li j, yang j, xiao l, et al. using a novel psma-pet and psa-based model to enhance the diagnostic accuracy for clinically significant prostate cancer and avoid unnecessary biopsy in men with pi-rads ≤ 3 mri. eur j nucl med mol imaging. 2025; 52:913-924. 53. meng x, ma w, zhang j, et al. pi-rads-based segmented threshold of psma-pet suvmax is better than traditional fixed threshold for diagnosing clinically significant prostate cancer especially for pi-rads 3 lesions. mol imaging biol. 2023; 25:887-896. 54. privé bm, israël b, janssen mjr, et al. multiparametric mri and 18f-psma-1007 pet/ct for the detection of clinically significant prostate cancer. radiology. 2024; 311:e231879. 55. hofman ms, lawrentschuk n, francis rj, et al. propsma study psma pet/ct and ductal pca group collaborators: prostate-specific membrane antigen pet-ct in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (propsma): a prospective, randomised, multicentre study. lancet 2020; 395:12081216. 56. bernardino r, sayyid rk, lajkosz k, et al. intraductal prostate cancer affinity for lymphatic-predominant metastases through 18f-dcfpyl-prostate-specific membrane antigen-positron emission tomography/ct scans in pretreatment prostate cancer patients. j urol 2024; 211:586-593. 57. vetrone l, mei r, bianchi l, et al. histology and psma expression on immunohistochemistry in high-risk prostate cancer patients: comparison with 68ga-psma pet/ct features in primary staging. cancers (basel) 2023; 15:1716. 58. zhao q, dong a, bai y, zuo c. prostate-specific membrane antigen uptake heterogeneity in mixed ductal-acinar adenocarcinoma of the prostate. clin nucl med 2023; 48:750-752. 59. pahouja g, patel hd, desai s, et al. the rising incidence of ductal adenocarcinoma and intraductal carcinoma of the prostate: diagnostic accuracy of biopsy, mri-visibility, and outcomes. urol oncol 2023; 41:48.e11-48.e18. 60. qiu s, dong a, zhu y, zuo c. 68 ga-psma-11 and 18 f-fdg pet/ct in a case of ductal adenocarcinoma of the prostate. clin nucl med 2022; 47:836-838. 61. pepe p, fraggetta f, tornabene f, et al. solitary lung metastasis after radical prostatectomy in presence of undetectable psa. arch ital urol androl. 2012; 84:208-10. 62. pepe p, pepe l, curduman m, et al. ductal prostate cancer staging: role of psma pet/ct. arch ital urol androl 2024; 96:12132. 63. checcucci e, bauckneht m, cisero e, et al. psma pet-targeted biopsy for prostate cancer diagnosis: initial experience from a multicenter cohort. urology 2025; 196:178-185. correspondence pietro pepe (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital, via messina 829, catania, italy ludovica pepe ludopepe97@gmail.com pathology unit, policlinico g. martino university of messina, messina, italy daniele cignoli urologia.segreteria@asst-pg23.it department of urology, asst papa giovanni xxiii, bergamo, italy marco roscigno roscigno.marco@gmail.com milano-bicocca university, international school of medicine, milano, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13645 1 review among men, with a retrieved 1.6 million cases reported annually worldwide. pca is recognized as the second most diagnosed malignancy and is the fifth leading cause of death attributed to cancer (1, 2). several risk factors, including familial predisposition, ethnicity, aging, obesity, and dietary habits, influence pca (3). while ethnic and racial disparities influence pca risk, northern europe exhibits the highest rates of incidents (83.4 per 100.000) and mortality (13 per 100.000), while south central asia has a comparatively lower risk with incidents (6.3 per 100.000) and mortality at (3.1 per 100.000) (4). the prevalence of pca exhibits significant geographical variations, mostly attributed to disparities in dietary patterns. essential nutrients, encompassing fats, proteins, carbohydrates, vitamins, and polyphenols, may influence the onset and advancement of pca (5). mirza et al. demonstrated that certain fruits, including dates, have the potential to induce apoptosis in the human prostate cancer cell line (pc3). this highlights the potential of certain fruits, which are rich in natural compounds, to exhibit strong anticancer properties (6). at diagnosis, about 80% to 90% of pca cases are androgen-dependent, which underpins the use of androgen deprivation therapy (adt) as the primary treatment (7). the increasing prevalence of pca and the limited treatment options available necessitate the exploration of novel supplementation and preventative strategies for the disease. chemoprevention is an approach that uses naturally occurring substances found in fruits and vegetables to slow disease progression or even prevent cancer development (6). flavonoids are essential chemical components in plants, especially in fruits and vegetables. they are divided into six main subclasses: flavones, flavan-3-ols, flavanones, flavonols, anthocyanidins, and isoflavones (8). various studies propose that these flavonoids may potentially benefit cancer therapy significantly (9). flavonoids have also been found to reduce the development of the cell introduction and objectives: prostate cancer (pca) is a significant concern and burden worldwide. several studies suggest that flavonoids have a significant potential as an anti-cancer agent, but the evidence remains controversial. this study aims to assess the effect of flavonoids and its subclasses supplementation on pca risk parameters in men with biopsy-proven diagnosis of pca or clinically determined to have a high risk of pca. materials and methods: this systematic review and meta-analysis adhered to prisma guideline. a literature search was conducted across pubmed, sciencedirect, scopus and cochrane utilizing pico framework. revised cochrane’s risk of bias tools (rob2) was used for quality analysis. review manager 5.4 was used for statistical analysis. results: out of 1.117 articles, nine final studies (involving 420 patients) were included. regarding total psa, flavonoid provided a reduction of total psa (md: -0.64, p < 0.05), and sub-group analysis based on the supplementation duration showed flavonoid administration with a duration of ≥ 12 weeks significantly reduced total psa compared to administration of < 12 weeks (p < 0.05). meta-analyses of four studies, including men clinically at risk of pca, revealed that flavonoid supplementation was associated with a significantly lower risk of developing pca at endpoint (or 0.41, p < 0.05). however, our results indicated no favorable effect in hormonal parameters. conclusions: the results of this meta-analysis suggest there may be a potential role for flavonoid in pca risk reduction. flavonoids supplementation also have been proven to be safe. however, further investigation is necessary to gain a clear understanding of the flavonoid impact on psa and sex hormone parameters. key words: prostate cancer; oncology; flavonoids; meta-analysis. submitted 18 january 2025; accepted 1 february 2025 introduction prostate cancer (pca) represents a significant global health issue, being a primary contributor to illness and death the effect of flavonoid and subclasses supplementation on prostate specific antigen (psa), hormonal parameters and prostate cancer risk: a systematic review and meta-analysis of randomized controlled trials abdul azis 1, 2, andi asadul islam 2, 3, haerani rasyid 2, 4, lukman hakim 5, syakib bakri 2, 4, agussalim bukhari 2, 6, andi alfian zainuddin 7 1 urology division of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia; 2 hasanuddin university teaching hospital, makassar, indonesia; 3 neurosurgery divison of surgery department, faculty of medicine, hasanuddin university, makassar, indonesia; 4 department of internal medicine, faculty of medicine, hasanuddin university, makassar, indonesia; 5 department of urology, faculty of medicine, airlangga university, surabaya, indonesia; 6 department of nutritional sciences, faculty of medicine, hasanuddin university, makassar, indonesia; 7 department of public health and community medicine, faculty of medicine, hasanuddin university, makassar, indonesia. doi: 10.4081/aiua.2025.13645 summary archivio italiano di urologia e andrologia 2025; 97(2):13645 a. azis, a. asadul islam, h. rasyid, et al. 2 cycle, cause apoptosis, and inhibit metastasis, invasion, and angiogenesis (10). although many studies have been published, the connection between flavonoids and pca remains debated. this study conducted a meta-analysis to explore the effects of flavonoid supplementation and its subclasses on men diagnosed with pca or considered high-risk, focusing on critical factors influencing pca development and progression. methods literature search on april 1, 2024, a literature study was conducted by three reviewers across multiple databases, including pubmed, sciencedirect, scopus and cochrane library. the search utilized keywords ‘prostate and cancer and flavonoid or flavonol or flavone or flavanone or flavan-3-ol or isoflavone. this study applied no restrictions regarding country or publication year. the protocol of this meta-analysis was registered in prospero (crd42024615073). eligibility criteria the systematic review followed the pico framework with the following eligibility criteria: (1) the study included participants diagnosed with prostate cancer (pca) or classified as high-risk due to clinical indicators; (2) intervention using rich-food or purified flavonoid and its subclasses; (3) comparing with placebo; (4) outcome including psa parameters, hormonal parameters (testosterone, estradiol and sex hormone binding globulin (shbg), developing biopsy-detectable pca and reporting adverse events; (5) randomized controlled study; (6) published in indonesian or english. selection process after the initial search, duplicate studies were identified and excluded. at least three independent reviewers screened the remaining studies for eligibility based on their titles and abstracts. studies that fulfilled the predetermined inclusion criteria were incorporated into the analysis, whereas those that did not meet these criteria were excluded. discrepancies regarding study classification were addressed through collective discussion among the research team. the literature review process adhered to the prisma guidelines (11). data collection data collection was performed independently by each author, with cross-checking by others to address any inconsistencies through discussion. if any information was unclear, the study authors were contacted for clarification, and studies with no response were excluded with the consent of the other reviewers. the data gathered included the first name of author, year, study design, population characteristics, mean age, type of intervention, control type, reported outcomes, and adverse events from all included studies. quality analysis revised cochrane risk of bias tool (rob2) was used for quality analysis, with each study being assigned a risk of bias rating of low, high, or some concerns at each evaluation point. publication bias publication bias was evaluated with a funnel plot analysis. publication bias considered to be high if the distribution of studies was asymmetrical. conversely, if the study distribution was evenly distributed and symmetrical, publication bias was considered to be low. statistical analysis meta-analyses were conducted to evaluate the impact of flavonoids or their subclasses on pca risk, comparing them to a placebo in review manager 5.4. the first metaanalyses assessing the effect between groups in psa parameters and hormonal parameters were performed by entering the mean ± sd to measure the mean difference (95% ci) and were sub-grouped by effect of duration (< 12 weeks or ≥ 12 weeks) if the data was sufficient. the second meta-analysis was performed by entering the incidence of biopsy-detectable pca in populations clinically determined as having pca risk to measure the odds ratio (95% ci) between groups. the heterogeneity of the statistical analysis was evaluated by the i2 value. the fixedeffects model was employed when i² was less than 50%, whereas the random-effects model was utilized when i² was equal to or greater than 50%. the findings were illustrated through a forest plot, and an overall effect was deemed statistically significant if the p-value was less than 0.05 (12). results literary search and examination results a total of 1.117 studies were initially identified from various databases. the studies included in this analysis were published prior to april 1, 2024. after removing 125 duplicates, two reviewers independently screened the remaining 1.052 study by titles and abstracts. of these, 1.043 studies were excluded for failing to meet the eligibility criteria. as a result, nine studies were deemed eligible and included in the qualitative and quantitative analysis. a detailed overview of the search and filtering results is presented in figure 1. characteristics of eligible studies the nine studies were rcts done in various countries, involving a cumulative sample size of 420 participants including 186 men with pca biopsy-proven diagnosis and gleason score ≥ 6 in four studies (13-16), 218 men at elevated risk of pca (elevated psa, asap, hgpin or negative prostate biopsy) in four studies (17-20) and 16 men with a history of radical prostatectomy less than 3 years before with elevated psa (≥ 0.1 ng/ml) in one study (21). in all studies flavonoid or its subclasses in various form were given, eight studies used a purified isoflavone rich-food (14-16, 19-21) or isoflavone supplement in capsule or tablet (13, 18), only one study (17) used a flavan-3-ols subclass of flavonoid with polye capsule containing epigallocatechin gallate (egcg). in all trials most controls archivio italiano di urologia e andrologia 2025; 97(2):13645 3 flavonoid effect on psa, hormonal parameters and prostate cancer risk used placebo. most studies used 12 weeks or more as an end-point outcome, only two studies had < 12 weeks intervention duration (13, 16). the outcomes assessed total psa in six studies (13, 15-17, 19, 21) and free psa in three studies (15, 16, 19), as well as hormonal parameters, which consist of total testosterone observed in four studies (13, 15, 16, 20), free testosterone in four studies (13-15, 20), total estradiol in four studies (13-15, 20) and shbg in five studies (13, 15, 17, 18, 20). additionally, three studies (17, 18, 20) provided data on the incidence of pca at the end of intervention of men clinically at risk of pca. only four studies (13, 14, 17, 18) have reported data on the flavonoid intervention side effects, with the majority reporting a small sample size of 1-2 grade side effects. full details regarding the details of studies are presented in table 1. study quality results the risk of bias assessment results indicated that all studies generally had a low risk of bias. however, one study raised some concerns regarding its overall risk, as shown in figure 2. publication bias results funnel plot results of studies on total psa (supplementary figure 1a) and shbg (supplementary figure 2d) showed an asymmetrical distribution. the other results of the studies showed a symmetrical distribution as shown in supplementary figures. therefore, it can be concluded that the results of this analysis have a low risk of publication bias. statistical analysis (meta-analysis) psa parameters there were two outcomes in the assessment of psa parameters: total psa and free psa. the result of the forest plot revealed that in the comparison between flavonoid supplementation and placebo, there was a significant difference in total psa (md: -0.64, p < 0.05). sub-group analysis based on the supplementation duration showed that flavonoid administration with a duration of ≥ 12 weeks significantly reduced total psa compared to administration of ≤ 12 weeks (p < 0.05). however, no significant statistical difference was revealed for free psa (md: 0, p = 0.99). figure 3 shows the detailed forest plot of psa parameters. figure 1. flow of literature search and selection based on preferred reporting items for systematic reviews and meta-analyses (prisma). archivio italiano di urologia e andrologia 2025; 97(2):13645 a. azis, a. asadul islam, h. rasyid, et al. 4 figure 2. risk of bias assessment using the revised cochrane risk-of-bias tool algorithm for randomized trials (rob 2.0). asap: atypical small acinar proliferation; ci: confidence interval; egcg: epigallocatechin gallate; pca: prostate cancer; pin: prostatic intraepithelial neoplasia; psa: prostate specific antigen; rct: randomized controlled trial; shbg: sex hormone binding globulin. table 1. baseline characteristics data of included studies. archivio italiano di urologia e andrologia 2025; 97(2):13645 5 flavonoid effect on psa, hormonal parameters and prostate cancer risk hormonal parameters there were four outcomes in the assessment of hormonal parameters. the total testosterone forest plot revealed a difference between groups in total testosterone (md: 1.49, p < 0.05) and free testosterone (md: -0.47, p < 0.05). there was no statistical significance regarding total estradiol (md: 0.61, p = 0.38) and shbg (md: -0.02, p = 0.99). figure 4 shows the detailed forest plot of hormonal parameters. prostate cancer risk there were four included studies dealing with a population of men clinically at risk of pca that reported data on the incidence of pca biopsy-proven diagnosis at the end of intervention. the forest plot revealed that the group of patients who received flavonoid supplementation was associated with a markedly reduced risk of developing pca (or 0.41, p < 0.05). the estimated analysis associated with the incidence of pca is presented in figure 5. discussion the objective of this study was to evaluate the findings from rcts regarding the impact of flavonoids and their various subclasses in male individuals diagnosed with pca or those classified as at risk for developing pca. this systematic review included nine rcts in total. four studies recruited men with biopsy-proven diagnosis of pca, four studies included men who were considered to have a risk of pca and one study included men with a history of radical prostatectomy with elevated psa. our findings suggest that flavonoid consumption may lower total psa serum levels and reduce the incidence of pca. a subgroup analysis revealed that flavonoid supplementation for more than 12 weeks significantly reduced the risk of pca. while previous meta-analyses found no link between flavonoid intake and pca risk, the limitations of these studies may have influenced their conclusions. notably, all the studies included in that meta-analysis were observational studies. the amounts of flavonoid consumption ci: confidence interval; iv: inverse variance; sd: standard deviation. figure 3. forest plots of psa parameter: (a) total psa sub-group based on the duration of intervention (< 12 weeks or ≥ 12 weeks). (b) free psa. archivio italiano di urologia e andrologia 2025; 97(2):13645 a. azis, a. asadul islam, h. rasyid, et al. 6 figure 4. forest plots of hormonal parameter: (a) total testosterone sub-group based on the duration of intervention (< 12 weeks or ≥ 12 weeks). (b) free testosterone. (c) total estradiol. (d) sex hormone binding globulin (shbg). ci: confidence interval; iv: inverse variance; sd: standard deviation. archivio italiano di urologia e andrologia 2025; 97(2):13645 7 flavonoid effect on psa, hormonal parameters and prostate cancer risk were derived from self-reported data provided by the participants, without a standardized method of categorization. additionally, the research participants were categorized based on their various levels of flavonoid consumption, and the author was unable to evaluate the impact of higher flavonoid intake on the risk of pca (22). flavonoids are a major category of dietary polyphenols that are found naturally in plant-based food, including fruits, vegetables, tea, and wine. dietary products have a well-documented historical precedent as preventive agents in the fight against various forms of cancer. natural substances such as green tea, grape skin, pomegranate, dates, and soy are known for their chemo-preventive properties. scientific evidence strongly supports that consuming diets rich in plant-based foods may significantly lower the chance of developing many types of cancer. the precise mechanism via which these foods provide protection against the formation of tumours and the development of cancer is not yet understood. however, one possibility is that they may contain phytochemicals with potential anticancer properties (23). in addition, according to laboratory research conducted on fruits such as dates, which are rich in flavonoids, it has been shown that they can induce apoptosis in the pc3 cells of the human body. flavonoids are suggested to have the ability to trigger apoptosis in tumour cells, which might potentially have a preventive impact against pca (6). researchers have identified psa as a biomarker for the initial detection and prognosis of pca. prostatic luminal epithelial cells produce it and it plays a role in regulating semen coagulation. psa is thought to be elevated due to cellular architecture disruptions, and it circulates in both free and complex forms (24). reports indicate that some flavonoids have the ability to prevent the production of psa by the bt-454 cell line. this may explain the notable correlation between consumption of flavonoids and a reduced risk of pca (25). our findings indicated a statistically significant difference in total psa (md: -0.64, p < 0.05) between study groups. a sub-group analysis based on the length of supplementation showed that giving flavonoids for more than 12 weeks significantly decreased total psa compared to giving them for less than 12 weeks (p < 0.05). however, free psa showed no significant statistical difference (p = 0.99). the results of our meta-analyses showed that there were no significant impacts on sex hormone levels. the results align with a 2013 meta-analysis of researches on isoflavones, which concluded that there was no significant influence on reproductive hormones in individuals with pca (26). in contrast, a research investigation on the administration of soy isoflavone supplements at a dosage of 60 mg per day resulted in a reduction in testosterone and 5α-dihydrotestosterone (dht) levels, while simultaneously increasing shbg levels in a group of healthy males aged 30 to 59 years (27). these data do not provide a clear understanding of the impact of sex hormone levels. looking at each of these, the pooled results of several small studies showed no significant changes. in line with a previous meta-analysis by van die et al., which examined the cancer risk in men clinically determined to be at risk (including those with a single negative prostate biopsy at the start of a 12-month study or those with asap or hgpin over a 6-month period), it was found that soy isoflavones significantly reduced the likelihood of developing pca. this conclusion was supported by a statistically significant analysis (rr = 0.49, p < 0.05) (26). in our analysis, four studies were included, focusing on men clinically at risk of pca. the forest plot analysis showed that individuals who received flavonoid supplementation exhibited a markedly lower risk of developing pca (or = 0.41, p < 0.05). these findings suggest a significant association between flavonoid intake and a lower risk of pca. testosterone and dht work through the androgen receptor to control cell proliferation and differentiation. androgens play a pivotal role in the normal development of the prostate gland, but they also contribute to the proliferation of prostate tumors, which is the primary target of androgen deprivation therapy (adt). the implementation of adt is associated with various side effects that can significantly impact both the quality of life and overall health of patients. certain dietary supplements may provide benefits for persons undergoing adt. research has shown that flavonoids, such as phytoestrogen, have the ability to mitigate certain adverse effects linked to adt. research conducted by durreger et al. found that dietary treatments including certain natural compounds might be beneficial in the adverse effects associated with adt (7). our study also demonstrated the safety of flavonoid supfigure 5. forest plot of studies about subjects who had a risk of developing prostate cancer (pca) becoming biopsy-detectable pca at the endpoint. ci: confidence interval; iv: inverse variance; sd: standard deviation. archivio italiano di urologia e andrologia 2025; 97(2):13645 a. azis, a. asadul islam, h. rasyid, et al. 8 plementation and its potential for use in pca patients undergoing adt. it is important to address some limitations in our study. first, out of all the interventions available, only the flavonoid subclass isoflavone and flavan-3-ols were available from our included studies due to the limited number of published articles. this implies that our included study does not provide an analysis of other subclasses of flavonoids. second, our inclusion studies have a relatively small overall sample size. furthermore, the examination of some results revealed significant heterogeneity, which is to be expected considering the variability in the impact of flavonoids depending on the length of supplementation. consequently, dividing into subgroups based on 12-week periods decreased the heterogeneity. conclusions the findings of this study indicate that flavonoids and their respective subclasses may contribute to the reduction of pca risk. flavonoid supplementation is effective in lowering total psa levels, particularly when administered for ≥ 12 weeks. additionally, flavonoids appear to reduce the risk of pca incidence in populations clinically identified as high-risk. flavonoid supplementation has also been shown to be safe. nonetheless, additional investigations are warranted to determine the optimal dose and duration of flavonoid supplementation. references 1. tzelepi v. prostate cancer: pathophysiology, pathology and therapy. cancers. 2022; 15:281. 2. rawla p. epidemiology of prostate 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systematic reviews. bmj. 2021; 372: n160. 12. higgins jpt, thompson sg. quantifying heterogeneity in a metaanalysis. stat med. 2002; 21:1539-1558. 13. kumar nb, pow-sang j, spiess p, et al. a phase ii randomized clinical trial using aglycone isoflavones to treat patients with localized prostate cancer in the pre-surgical period prior to radical prostatectomy. oncotarget. 2020; 11:1218-1234. 14. kumar nb, krischer jp, allen k, et al. a phase ii randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. nutr cancer. 2007; 59:163-168. 15. kumar nb, cantor a, allen k, et al. the specific role of isoflavones in reducing prostate cancer risk. the prostate. 2004; 59:141-147. 16. dalais fs, meliala a, wattanapenpaiboon n, et al. effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. urology. 2004; 64:510-515. 17. kumar nb, pow-sang j, egan km, et al. randomized, placebocontrolled trial of green tea catechins for prostate cancer prevention. cancer prev res phila pa. 2015; 8:879-887. 18. miyanaga n, akaza h, hinotsu s, et al. prostate cancer chemodeclarations ethical approval: this study did not need any of ethical approval. availability of data and material: all data and materials from this research are available to the researcher and we will provide it upon request if the researcher needs it. competing interests: the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. funding: all funding for this research comes from researchers without receiving research costs or research grants from third parties. authors' contributions: contribution details aa asa hr lh sb ab aaz concepts √ √ √ √ √ √ √ design √ √ √ √ √ √ √ definition of √ √ √ intellectual content literature search √ √ √ data acquisition √ √ √ √ √ data analysis √ √ √ statistical analysis √ √ √ manuscript preparation √ √ √ √ √ manuscript editing √ √ √ manuscript review √ √ √ √ √ √ √ guarantor √ √ √ √ √ √ √ acknowledgments: we as authors would like to thank all parties involved in this study, including the department of urology, faculty of medicine, hasanuddin university and also hasanuddin university hospital. conference presentation: this article has not been presented at any conference. archivio italiano di urologia e andrologia 2025; 97(2):13645 9 flavonoid effect on psa, hormonal parameters and prostate cancer risk prevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. cancer sci. 2012; 103:125-130. 19. hamilton-reeves jm, rebello sa, thomas w, et al. effects of soy protein isolate consumption on prostate cancer biomarkers in men with hgpin, asap, and low-grade prostate cancer. nutr cancer. 2007; 60:7-13. 20. hamilton-reeves jm, rebello sa, thomas w, et al. isoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum hormonal profiles in men at high risk of prostate cancer. j nutr. 2007; 137:1769-1775. 21. bosland mc, schmoll j, watanabe h, et al. randomized, placebocontrolled six-month intervention study of soy protein isolate in men with biochemical recurrence after radical prostatectomy: a pilot study. nutr cancer. 2022; 74:555-564. 22. guo k, liang z, liu l, et al. flavonoids intake and risk of prostate cancer: a meta-analysis of observational studies. andrologia. 2016; 48:1175-1182. 23. chang h, lei l, zhou y, et al. dietary flavonoids and the risk of colorectal cancer: an updated meta-analysis of epidemiological studies. nutrients. 2018; 10:950. 24. farha mw, salami ss. biomarkers for prostate cancer detection and risk stratification. ther adv urol 2022; 14:17562872221103988. 25. ganry o. phytoestrogens and prostate cancer risk. prev med. 2005; 41:1-6. 26. van die md, bone km, williams sg, et al. soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. bju int. 2014; 113:e119-130. 27. tanaka m, fujimoto k, chihara y, et al. isoflavone supplements stimulated the production of serum equol and decreased the serum dihydrotestosterone levels in healthy male volunteers. prostate cancer prostatic dis. 2009; 12:247-252. correspondence abdul azis (corresponding author) abdul.azis031@gmail.com perintis kemerdekaan st. km. 10, tamalanrea, makassar, indonesia (postal code: 90245) andi asadul islam undee@med.unhas.ac.id haerani rasyid haeranirasyid@med.unhas.ac.id lukman hakim lukman-h@fk.unair.ac.id syakib bakri syakibbakri@yahoo.com agussalim bukhari agussalim.bukhari@med.unhas.ac.id andi alfian zainuddin a.alfian@med.unhas.ac.id stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12690 1 original paper asian countries (0.6-5.0%) and among populations of black african origin (0.1-3.5%). these differences are probably related to genetic, environmental, and lifestyle factors (3-12). it is hypothesized that the prevalence of pd in men is much higher due to the underreporting of symptoms, as patients may feel embarrassed and choose not to report their embarrassing problem (3). pd can result in penile deformity, penile pain, erectile dysfunction, and psychological distress (anxiety and depression); penile deformities may involve curvature, shortening, torsion, indentations, and hourglass deformity (13-17). the precise cause of pd is not completely understood, but it is generally believed to be initiated by a local injury (1820). although it can be triggered by traumatic sexual experience or injury, 70% of cases have no specific cause, and patients do not remember a traumatic event (21). when an injury occurs, fibrin is deposited and a small hematoma forms. in people without a genetic predisposition to the disease, the hematoma is absorbed back into the penile corpora cavernosa. in individuals with a genetic predisposition, the hematoma causes the activation of inflammatory cells and proinflammatory cytokines, resulting in the formation of chronic inflammatory tissue that progresses to fibrosis over time (22-24). in the last two decades, studies have demonstrated that oxidative stress (os) is crucial in the development of plaque and the progression of this disease (22-29). diagnosing pd involves a medical history, physical examination, penile palpation, photographic documentation of penile curvature, dynamic penile color doppler us, computed tomography, and magnetic resonance imaging (30-32). computed tomography and radiography are excellent at visualizing penile plaque calcifications, while mri is accurate at identifying plaques in complex locations, such as the corporal septum. b-mode us medical imaging is highly useful for localizing and characterizing peyronie’s plaque. regarding the ultrasound appearance, penile plaques are typically observed as localized areas of hyperechoic thickening of the tunica albuginea, showing strong echogenicity with significant attenuation of the acoustic beam. moreover, elastography is a new and emerging method background: b-mode ultrasound (us) medical imaging is very effective in localizing and describing peyronie's disease (pd). moreover, elastography is a new technique used to evaluate tissue elasticity to detect penile peyronie's plaques that are not visible using standard bmode us. objective: the main objective of this study was to evaluate the diagnostic efficacy of real-time elastography (rte) or strain elastography (se) in pd patients and to determine whether its combined use with standard us improved diagnostic accuracy. additionally, this study aimed to assess whether rte was useful for monitoring pd patients undergoing conservative treatment. methods: a group of 37 patients with pd in the active phase was selected based on us examination showing isoechoic or hypo-isoechoic plaques, with or without associated hyperechoic or calcified plaque areas. all patients underwent traditional us combined with rte before starting conservative treatment with antioxidants, during treatment and after treatment. after each examination with rte, a specific “strain ratio”(sr) was used to identify the specific elasticity of the tissue. results: using b-mode us with rte, we detected all 13 non-palpable penile plaques present in the 37 pd patients (100% of cases). using only b-mode us, we detected only 8 of the 13 nonpalpable plaques (61.5% of cases). the deformation index (di) of the plaque decreased during and after treatment in all cases, indicating that rte is effective for monitoring conservative pd treatment. a statistically significant correlation was found between the di and plaque volume in all patients (p = 0.002). conclusions: our study has shown that the combination of us and rte methods allowed for a more accurate diagnosis in pd patients. key words: b-mode ultrasound; peyronie's disease; penile plaques; elastography; strain imaging. submitted 26 may 2024; accepted 13 june 2024 introduction peyronie's disease (pd) is a pathological condition that affects the tunica albuginea of the penis in males with a genetic predisposition, causing the formation of fibrous plaques (1, 2). the occurrence of pd is more common in western countries (3.2-13.1%) and less common in combining ultrasound and elastography for the detection of a non-palpable, non-sonographically visualized peyronie's plaques. our experience gianni paulis 1, giovanni de giorgio 2, andrea paulis 3 1 department of urology and andrology, peyronie’s care center, castelfidardo clinical analysis center, rome, italy; 2 section of ultrasound diagnostics, department of urology and andrology, castelfidardo clinical analysis center, rome, italy; 3 bambino gesù children’s hospital, irccs, rome, italy. doi: 10.4081/aiua.2024.12690 summary archivio italiano di urologia e andrologia 2024; 96(3):12690 g. paulis, g. de giorgio, a. paulis 2 that studies the elastic properties of tissue to identify penile plaques that may not be visualized with traditional b-mode us studies. furthermore, elastography is the most suitable imaging modality in pd because it allows for non-invasive highlighting of penile plaques and monitoring of the therapeutic response to various treatments. in addition, elastography has recently been suggested as a diagnostic tool for pd. palpation of the penis is essential in the evaluation of the patient, as most patients with peyronie's disease have a palpable plaque that is clearly distinguishable from the rest of the penile corpora cavernosa. however, documentation with a diagnostic imaging method is often necessary to support the clinical diagnosis. b-mode us examination can identify the location, number, size, and echogenicity of the plaques. the main bias and disadvantage of this method is that traditional us can only detect between 40% and 84.2% of palpable plaques (33-36). elastography is a non-invasive technique that uses an ultrasound probe to measure the mechanical properties of tissue, which can be affected by a disease process, making the tissue more rigid. the different levels of tissue elasticity under the pressure of the ultrasound probe are expressed in a more or less relevant way and evaluated using a color scale. elastography diagnostic approaches were first developed at the end of the last century and, subsequently, numerous scientific studies have been published (37). elastography is primarily used to diagnose soft tissue pathologies in the liver, breast, prostate, thyroid, pancreas, nerves, tendons, muscles, and other conditions. furthermore, elastography has also been suggested for studying pd (32-36, 38-44). the world federation of ultrasound medicine and biology categorized “elastographic techniques“ as strain elastography (se), transient elastography, and acoustic radiation force impulse (arfi). the arfi techniques can be subcategorized into point shear wave elastography (swe), 2d swe, and 3d swe techniques (45). se, also known as real-time elastography (rte), is a qualitative method that assesses the relative stiffness of various tissues and examines how tissues can deform when subjected to external forces and then return to their original shape. se assesses tissue deformation using manual compression or natural motion. se measures the strain caused by "quasi-static" methods, such as manual compression or cardiovascular/respiratory pulsation, and displays the distributions of the strain or normalized strain values within the region of interest (roi). tissue deformation can be achieved by manually applying micro-pressure with the ultrasound probe or by using ultrasound pulses of appropriate intensity (44). in the second method of excitation, the ultrasound remains stationary while tissue displacement is induced via internal physiological movements such as cardiac and arterial pulsations and respiratory motion. in both cases, the ultrasound images are compared before and after the compression, and the equipment produces a color map that indicates the relative elasticity of the various tissue components, ultimately displaying a specific strain ratio (sr). sr is calculated by comparing the strain index of a lesion to that of healthy tissue at the same level. sr therefore indicates a measurement of the stiffness of the sampled tissue. se measures the relative stiffness of tissues within the elastographic region of interest (roi) overlaid on a b-mode us image; therefore, the roi must be accurately aligned with the peyronie’s plaque. the color map is shown in real time, overlaid on an ultrasound image of the tissues being examined. usually, the color blue is utilized to indicate low strain (i.e., stiff tissue), while red is used to indicate high strain (i.e., soft tissue), although the exact color scale may differ depending on the manufacturer of the ultrasound equipment (35). strain elastography is also used for the diagnostic study of pd. in the literature, there are four articles on this topic (33-35, 42). the objective of this study was to evaluate the diagnostic efficacy of rte in patients with peyronie's disease and to determine whether its combined use with traditional ultrasound imaging improves diagnostic accuracy. this study aimed to determine whether this diagnostic combination could detect nonpalpable and/or isoechoic peyronie's plaques with or without hyperechoic or calcified plaque areas, which cannot be detected with a simple standard us examination. this study also aimed to evaluate whether us associated with rte was effective for monitoring patients with pd undergoing conservative treatment. the secondary objective of this study was to examine the relationship between plaque stiffness and the degree of curvature and plaque volume, as well as to detect the prevalence of anxiety and depression in patients with pd. materials and methods the authors conducted this study by collecting and analyzing existing data of 249 patients who visited our peyronie’s care center and underwent us and elastography of the penis from january 1, 2018, to december 31, 2023, and were found to be affected by pd. after applying the inclusion and exclusion criteria, 212 pd patients who were in the stabilized or active phase of the disease and presented exclusively hyperechoic and/or calcified plaques were excluded from the main study. objectives the main objective of this retrospective study was to assess the diagnostic efficacy of rte, also known as se, in patients with peyronie's disease (pd) and investigate if its integration with conventional ultrasound (us) imaging enhances diagnostic precision. since this study primarily aimed to determine whether the diagnostic combination of us and rte could detect non-palpable peyronie's plaques that cannot be detected via physical examination of the pd patient or via a simple standard us, inclusion criteria were determined for the in-depth study of those pd patients in whom rte could potentially increase the diagnostic level. evaluation and diagnosis the diagnosis of peyronie's disease was made for all patients after conducting the following assessments: palpation of the penis; photographic documentation of penile deformity (according to kelâmi) with a goniometric measurement of the angulation; penile us with rte or penile color doppler us with rte (only for patients with archivio italiano di urologia e andrologia 2024; 96(3):12690 3 elastographyfor peyronie’s plaques associated erectile dysfunction) with plaque measurements (in three dimensions, in mm) and volume calculation (mm3) using the ellipsoid formula (volume = 0.524 × length × width × thickness); and completion of the international index of erectile function (iief) questionnaire for measuring erectile function, the visual analog scale (vas) questionnaire for measuring pain, the generalized anxiety disorder questionnaire-7 (gad-7, for anxiety), and the patient health questionnaire-9 (phq-9, for depression) (46-52). regarding the last two questionnaires, we decided to also study the psychological condition of these patients, as we believe that psychological distress is a symptom of pd, just like curvature, pain, and erectile dysfunction. to identify and confirm the presence of penile plaque, along with its location and volume, we subjected all 37 patients to combined us and rte examination of the penis at the time of initial diagnosis and during the planned follow-up assessments during conservative treatment. a single andrologist operator performed and evaluated conventional us and se of the penis on all patients in one session using the same ultrasound device, the philips affinity 70 g, and a high-frequency linear array transducer, the philips linear probe l12-5 (philips, washington, united states). the elasticity values were calculated and color-coded to represent tissue elasticity. the color scale ranged from red (i.e., soft tissue) to blue (i.e., stiff tissue), with components showing average strain displayed as green. finally, a calculation indicating a specific sr was displayed on the equipment monitor. the areas included in the strain ratio calculation are selected by the operator by pointing the probe at the stiffest area and then at the normal tissue (soft). inclusion criteria patients with peyronie's disease in the active phase who underwent us examination and presented isoechoic or hypo-isoechoic plaques, with or without associated hyperechoic or calcified plaque areas. exclusion criteria patients with peyronie's disease in the stabilized or active phase who underwent us examination and presented exclusively hyperechoic and/or calcified plaques. after applying the inclusion and exclusion criteria, 212 pd patients who were in the stabilized or active phase of the disease and presented exclusively hyperechoic and/or calcified plaques were excluded from the main study. finally, a group of 37 patients with peyronie's disease in the active phase was selected based on us examination and rte (in the same diagnostic session) showing isoechoic or hypo-isoechoic plaques, with or without associated hyperechoic or calcified plaque areas. treatment and follow up as previously indicated, in this study, we specifically focused on the analysis of data relating to us and rte combination examinations in patients with pd to evaluate whether us associated with rte is effective for monitoring pd patients undergoing conservative treatment. therefore, after the first visit of the patients to our andrological center, we performed a combined diagnostic us and rte on 37 pd patients before starting conservative treatment with antioxidants. patients underwent us and rte every six months during and after treatment. conservative treatments to which these patients were subjected were retrospectively identified from the data in our clinical archive and are not the subject of this article. some of these patients have undergone multiple treatment cycles. for completeness, we describe our standard conservative medical treatment: oral l-carnitine 1000 mg + propolis 700 mg + silymarin 400 mg + coenzyme q-10 100 mg + bilberry 180 mg + ginkgo biloba 240 mg + vitamin e 48 mg + vitamin c 50 mg + superoxide dismutase 11000 iu/g 10 mg/daily and topical diclofenac gel 4%/2 times daily + peri-plaque penile injections (only in the case of plaques with volume ≥ 100 mm3) with pentoxifylline 100 mg (30 g needle) every month for 6 months. statistical analysis we utilized calculatorsoup® software (version of mar 07, 2023, ashland, ma,usa) to conduct the statistical analysis involving the calculation of standard deviation and mean, median, and interquartile range (iqr). the pearson correlation coefficient was calculated using statistics kingdom statistical software (version 2017, melbourne, australia, http://www.statskingdom.com) and excel (version 2011, ms office, redmond, wa, usa). in the statistical analyses, a significance level of 5% for alpha error (p-value < 0.05) was considered to demonstrate statistical significance. this study was carried out in accordance with the principles outlined in the declaration of helsinki (fortaleza, 2013). all participants were contacted and gave their informed consent for the study. however, sensitive data were anonymized in accordance with privacy regulations as per legislative decree 10 august 2018, n. 101 adapted to the general data protection regulation/gdpr (official gazette of the italian republic, general series n. 205, dated 4 september 2018). results the 37 patients with peyronie's disease who were selected for this study (with isoechoic or hypo-isoechoic plaques, with or without associated hyperechoic or calcified plaque areas) were aged between 23 and 74 years, with a mean age = 51.3 years (sd ± 14.7). the plaque volume in the 37 selected patients ranged from 11.5 to 2660 mm3. table 1 shows the physical and echo-elastographic characteristics of the plaques of the 37 patients. non-palpable plaques using b-mode us with rte, we detected all 13 non-palpable penile plaques present in the 37 selected pd patients (100% of cases). using only b-mode us, we detected only 8 of the 13 non-palpable plaques (61.5% of cases). soft plaques when using us examination on 37 pd patients, only one out of seven barely palpable (soft) plaques were detected (14.2%). however, with rte, all seven soft plaques were detected (100%). archivio italiano di urologia e andrologia 2024; 96(3):12690 g. paulis, g. de giorgio, a. paulis 4 isoechoic or hypo-isoechoic plaques when using us examination, 29 out of 37 isoechoic or hypo-isoechoic plaques, with or without associated hyperechoic or calcified plaque areas, were identified (78.3%), while the remaining 8 plaques (21.6%) were not identified. specifically, the eight plaques that were not identified were completely isoechoic. therefore, using us, entirely isoechoic plaques were found in only 2 out of 10 cases (20%). all 37 plaques were instead identified with rte (100%). ultrasound findings in relation to the volume of pd plaques out of 21 plaques with a volume up to 500 mm3, 19 plaques (90.4%) were identified, and 2 plaques (9.5%) were not identified using only us, while all 21 plaques were identified with rte (100%). all 16 remaining larger pd plaques over 500 mm3 were identified with us (100%) and also with rte. a statistically significant correlation was found between the deformation index (strain ratio) and plaque volume in the 37 selected patients, p-value = 0.002 (p < 0.05). figure 1 shows the graph that highlights this correlation. no statistically significant correlation was found between the strain ratio and the degree of angulation of the penile curvature of the 37 selected patients: r = 0.2848, r2 = 0.08109, p-value = 0.08759 (p > 0.05). in figure 2 below, we present four examples of plaques that were not detected with traditional us but were instead detected with rte. please note that during each elastography scan, circles (light blue color) were placed by the operator on the stiffer (blue) and normal (soft) areas corresponding to the roi. at the end of this procedure, the elastography software provided the strain ratio after the relative calculation. treatment and follow up figure 3 shows the deformation index (or strain ratio) values of the plaques before, during, and after the treatments the results presented demonstrate that the strain ratio decreased during the monitoring at each follow-up assessment. the strain ratio value is considered pathological when it is greater than 1. rte measurements were performed every 6 months during the course of conservative treatment. the 37 selected patients underwent multiple treatment cycles, ranging from two to four cycles. some patients underwent a greater number of follow-up assessments because they were observed before the others. psychological assessment the results of the gad-7 and phq-9 questionnaires showed that in the 37 patients with peyronie's disease, significant anxiety was present in 70.2% of cases and severe anxiety in 18.9% of cases. significant depression was present in 45.9% of cases, with no cases of severe depression. table 1. physical and echo-elastographic characteristics of the plaques of the 37 patients. palpatory features of the plaque n. cases (out 37) (%) non-palpable 13 (35.1) soft 7 (18.9) fibrous 11 (29.7) fibrocalcific 6 (16.2) ultrasound imaging of the plaque hypo-isoechoic 12 (32.4) isoechoic 10 (27.0) iso-hyperechogenicity (mixed plaque) 1 (2.7) iso-hyperechogenicity associated with calcification (mixed plaque) 3 (8.1) hypo-isoecogenicity associated with hyperechogenicity (mixed plaque) 2 (5.4) hypo-isoecogenicity associated with calcification (mixed plaque) 9 (24.3) plaque volume (mm3) up to 100 6 (16.2) from 101 to 300 10 (27.0) from 301 to 500 5 (13.5) from 501 to 1000 10 (27.0) from 1001 to 2000 5 (13.5) > 2000 1 (2.7) strain ratio of the plaque detected via strain elastography (se) > 1 to 2 18 (48.6) > 2 to 3 16 (43.2) > 3 to 4.4 3 (8.1) the strain ratio is considered pathological when it is greater than 1. figure 1. graph highlighting the relationship between plaque volumes and deformation index (or strain ratio) values. archivio italiano di urologia e andrologia 2024; 96(3):12690 5 elastographyfor peyronie’s plaques discussion the authors specify that, for the elastography study, they preferred to use se, also known as rte. se is preferable for studying superficial pathologies such as plaques that develop in peyronie’s disease because it has high spatial resolution. in fact, in this pathology, se, owing to its high sensitivity, is important for visualizing the area of fibrosis associated with it, even in the absence of detectable b-mode images. we should also add that in order to use se correctly, it is essential for the procedure to be conducted by an experienced operator and to use the latest technology to achieve the correct visualization of peyronie’s plaque. using b-mode us with rte, we detected all 13 non-palpable penile plaques present in the 37 selected pd patients (100% of cases). using only b-mode us, we detected only 8 of the 13 nonpalpable plaques (61.5% of cases). in 11 out of these 13 cases, a penile curvature was present. furthermore, in two of these patients with nonpalpable penile plaque who did not report penile pain or erectile dysfunction problems, there was a penile deformity, including both penile curvature and shortening. in these two cases the ultrasound diagnosis would have been completely negative without performing rte. we believe that the penile plaques could not be palpated, mainly due to their small size, which in most cases never exceeded a volume of 300 mm3. in a study by dell’atti et al., using only b-mode figure 3. deformation index (strain ratio) values of penile plaques in 37 patients with peyronie's disease, before and after treatment. figure 2. examples of four non-palpable and isoechoic peyronie's plaques that were not detectable with traditional ultrasound (us) but identified with real-time elastography (rte). archivio italiano di urologia e andrologia 2024; 96(3):12690 g. paulis, g. de giorgio, a. paulis 6 us to detect non-palpable peyronie’s plaques, small plaque volumes and fairly similar ultrasound features were found; however, they found 41 non-palpable penile plaques in 386 patients with pd (10.6% of cases) (53). in our study, using only b-mode us, we detected non-palpable plaques in 8 out of 37 cases (21.6% of cases). regarding the incidence of non-palpable plaques in patients with peyronie’s disease, other authors using only b-mode us studies, although with different ultrasound machines, have reported detection rates of 6.0%, 22.5%, and 32.4% in pd cases (33, 54, 55). referring to the ultrasound appearance of the plaques (isoechoic or hypo-isoechoic, with associated hyperechogenicity or calcification) using only b-mode us, we detected penile plaques in 29 out of 37 cases (78.3% of cases). however, when using b-mode us with rte, we detected all 37 penile plaques (100% of cases) in the respective 37 patients. penile plaques appear as localized areas of thickening in the tunica albuginea on ultrasound, showing strong echogenicity and significant attenuation of the acoustic beam. however, in our study, almost all noncalcified penile plaques were found to be isoechoic or slightly hyperechoic compared to the surrounding cavernous tissue. the peculiarity of our results is due to the selection of patients due to the inclusion criteria of our study. nevertheless, there are few articles in the literature that specifically discuss the possibility of the existence of isoechoic plaques (56-58). in our study, the isoechoic penile plaques detected using only b-mode us were only 2 out of 10 (20% of cases). instead, using b-mode us with rte, we detected all 10 isoechoic penile plaques (100% of cases) in the respective 10 patients. however, when the penile plaques were not isoechoic, b-mode us was consistently able to detect all the penile plaques. this demonstrates that when b-mode us is combined with rte, the diagnostic accuracy is significantly improved. similar results were obtained by other authors who used elastography associated with conventional b-mode us (33-36, 42). our study has shown a strong statistical correlation between the strain ratio values of the plaque and its volume (p-value = 0.002). of course, it seems logical that increasing the size of the plaque also increases its rigidity; however, this correlation had never been demonstrated in peyronie’s disease. otherwise, we did not find any statistically significant correlation between the strain ratio and the degree of angulation of the penile curvature angle (p > 0.05). it should be noted that, in our case series, 3 out of 37 patients did not have penile curvature due to the central location of the plaque (between the two corpora cavernosa), and this may have resulted in the absence of this correlation. however, other authors, using a different method of elastography (shear wave elastography, swe), have shown a relationship between the stiffness of the selected plaque area (expressed in kpa) and the curvature angle of the penis (41). our study has shown that rte combined with traditional us is very useful for monitoring patients with peyronie's disease during conservative treatment with antioxidants and antifibrotics. in this way, in addition to the reduction in plaque volume, which we could have demonstrated using traditional us alone, we were also able to observe the progressive reduction in the stiffness of the affected area. a very similar observation has been made by other authors who, using another elastography method (swe), have analyzed the changes in elastography after administering a compound made up of ecklonia bicyclis, tribulus terrestris, and water-soluble chitosan (biovis) (39). after researching the prevalence of anxiety in patients with pd, we found that 70.2% of cases had significant anxiety, and 18.9% of cases had severe anxiety. there are no precise data in the literature regarding the incidence of anxiety symptoms during pd; however, a study by smith and colleagues found that 81% of pd patients reported "emotional difficulties" (59). after researching the prevalence of depression in pd patients, we found that significant depression was present in 45.9% of cases, with no cases of severe depression. nelson and colleagues found that 48% of pd patients exhibited clinically significant depression (14, 60). we believe that depressive and anxiety symptoms, if not investigated in pd patients using specific questionnaires, may remain unknown or at least be underestimated in terms of severity and prevalence. our data on the prevalence of anxiety in patients with pd confirm that the anxious and depressive states represent important symptoms of pd, as well as penile pain, penile curvature/deformation, and erectile dysfunction. in uroandrological clinical practice, psychologists should be involved in providing supportive treatment to patients with pd. in this way, we could reduce the psychological impact of pd, which has been described by some important authors as a psychologically and physically devastating disease (61-65). although our findings are quite interesting, the limitation of our study is that the sample size was not very large. however, our limited sample was determined by very selective inclusion criteria. conclusions rte is a modern non-invasive technique that can accurately identify penile plaques in patients with peyronie's disease, complementing b-mode us. furthermore, rte is very useful for diagnosing the disease at an earlier stage (isoechoic plaque) than b-mode us alone. additionally, rte is especially valuable when palpation and b-mode us are unable to identify a plaque. rte can also accurately assess plaque stiffness, size, and 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in peyronie's disease. j sex med. 2008; 5:2179-2184. 60. nelson cj, mulhall jp. psychological impact of peyronie's disease: a review. j sex med. 2013; 10:653-660. 61. taylor fl, levine a. peyronie's disease. urol clin north am. 2007; 34:517-534. 62. bella aj, perelman ma, brant wo, et al. peyronie's disease (cme). j sex med. 2007; 4:1527-1538. 63. jordan gh, carson cc, lipshultz li. minimally invasive treatment of peyronie's disease: evidence-based progress. bju int. 2014; 114:16-24. 64. porst h, burri a, european society for sexual medicine (essm) educational committee current strategies in the management of peyronie's disease (pd)-results of a survey of 401 sexual medicine experts across europe. j sex med. 2019; 16:901-908. 65. el-sakka ai. medical, non-invasive, and minimally invasive treatment for peyronie's disease: a systematic review. andrology 2021; 9:511-528. correspondence gianni paulis, md (corresponding author) paulisg@libero.it department of urology and andrology, peyronie’s care center, castelfidardo clinical analysis center, 00185 rome, italy giovanni de giorgio, md g.degiorgio@analisiclinichecastelfidardo.it section of ultrasound diagnostics, department of urology and andrology, castelfidardo clinical analysis center, 00185 rome, italy andrea paulis, phd andrea.fx.94@gmail.com bambino gesù children’s hospital, irccs, 00165 rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14280 1 letter to editor key words: uti; urinary tract infections; genital infections; cystitis. submitted 24 august 2025; accepted 30 august 2025 dear editor, for a few decades, urinary tract infections (utis) have been classified according to the dichotomy “uncomplicated” and “complicated” (1). this classification has been widely used in academic settings and in clinical practice. however, it has long proven to have limits and to be misleading in real-world patient management. for urologists working across both public and private healthcare settings, the distinction is often ambiguous: what exactly qualifies as “complicated”? and when should an infection that appears “uncomplicated” actually be considered clinically significant or at risk of deterioration? in 2025, bonkat et al. provided the scientific community with a new perspective (2). the proposal abandons the traditional terminology and introduces a classification system grounded in immediately recognizable clinical criteria: localized uti and systemic uti. this new approach is clear, intuitive, and especially most directly applicable at the bedside, from the very first patient visit. the underlying principle is straightforward: localized utis are characterized by lower urinary tract symptoms frequency, dysuria, urgency, suprapubic pain without systemic signs of infection. on the contrary, systemic utis may be associated with fever, hypotension, tachycardia, or flank pain, pointing toward renal, prostatic, or other severe infections with systemic involvement. what previously required lengthy reasoning can now be addressed by a single and easy clinical question: does the patient show systemic signs or not? this simple question provides immediate guidance for clinical decision-making. urop position paper in support of the new classification of urinary tract infections: from “uncomplicated/complicated” to “localized/systemic” guglielmo mantica 1, stefano alba 2, andrea alfarone 3, umberto capitanio 4, donato dente 5, carlo giulioni 6, carmelo morana 7, serena maruccia 8, gabriella mirabile 9, gennaro musi 10, mauro ragonese 11, mauro silvani 12, antonio tufano 13, angelo cafarelli 6, alessandro calarco 13, ottavio de cobelli 10, ferdinando de marco 14, giovanni ferrari 15, giuseppe mario ludovico 16, stefano pecoraro 17, domenico tuzzolo 18, renzo colombo 4, nazareno suardi 19, rosario leonardi 20 on behalf of urop (urologi ospedalità gestione privata) 1 department of surgical and diagnostic integrated sciences (disc), university of genoa, genoa, italy; 2 department of urology, romolo hospital, rocca di neto (kr), italy; 3 department of urology, aurelia hospital, roma, italy; 4 division of experimental oncology/unit of urology, urological research institute (uri), irccs ospedale san raffaele, milan, italy; 5 istituto clinico città di brescia, brescia, italy; 6 urology unit, villa igea private hospital, ancona, italy; 7 department of urology, giovanni xxiii monastier hospital, treviso, italy; 8 istituti clinici zucchi, monza, italy; 9 center of minimally-invasive urology, pio xi clinic, fondazione vincenzo pansadoro, rome, italy; 10 department of urology, ieo european institute of oncology, irccs, milan, italy; 11 department of urology, policlinico universitario fondazione agostino gemelli, istituto di ricovero e cura a carattere scientifico (ircss), roma, italy; 12 department of reconstructive surgery, clinica sedes sapientiae, turin, italy; 13 urology unit, san carlo di nancy hospital, roma, italy; 14 department of urology, tiberia hospital, rome, italy; 15 department of urology, hesperia hospital, modena, italy; 16 division of urology, ente ecclesiastico ospedale generale regionale "miulli", acquaviva delle fonti (ba), italy; 17 neuromed, avellino, italy; 18 urologi ospedalità gestione privata (urop); 19 department of urology, ospedali civili of brescia, brescia, italy; 20 division of urology, school of medicine, kore university of enna, enna, italy. doi: 10.4081/aiua.2025.14280 archivio italiano di urologia e andrologia 2025; 97(3):14280 g. mantica, s. alba, a. alfarone, et al. 2 for the urop (unione degli urologi ospedalità gestione privata), which is a scientific society involving both hospital-based and private-practice urologists, this is particularly relevant. it may allow us to deliver high-quality care that is rapid, safe, and sustainable, while optimizing the use of healthcare resources. first, the localized/systemic classification and distinction enables faster decisions regarding the appropriate treatment setting. patients with localized uti and no major risk factors can be managed in an outpatient setting: urinalysis, urine culture, basic imaging when needed (i.e. ultrasound), and targeted therapy can all be completed at home or in a day-hospital setting, avoiding unnecessary emergency department visits or hospital admissions. conversely, patients with systemic uti are directed immediately to the hospital and specific settings where monitoring, intravenous antibiotics, and further investigations are available. in private healthcare, this translates into streamlined and secure patient pathways, improved satisfaction, and reduced pressure on public hospitals (3). a second major benefit is the reduction of unnecessary hospital burden. many cases that have been ambiguously labeled as “uncomplicated” now clearly fall into the localized category and can be treated outside the hospital. this reduces avoidable hospital admissions, increases hospital resources for more severe conditions, and generates direct economic advantages: fewer costs for patients, and lower inpatient care expenses for the healthcare system (4-8). the new terminology also enhances physician-patient relationship and communication. telling a patient, “this is a localized infection” is immediately comprehensible and reassuring. the phrase “uncomplicated infection,” while intended to calm, often raises confusion: if it is “not complicated,” why does it still require treatment? the new terms improve transparency, strengthen trust, and encourage better adherence to therapy. furthermore, from a therapeutic standpoint, the classification also serves as a strong tool to support antimicrobial stewardship (9-14). localized utis can be managed with short, targeted oral regimens, while systemic infections call for empiric broad-spectrum intravenous antibiotics, refined according to culture and sensitivity. this approach optimizes outcomes, minimizes side effects, reduces costs for patients, and mitigates the environmental impact of unnecessary antibiotic use. the advantages are especially clear in the private practice setting. immediate clinical triage shortens waiting times and accelerates access to care. continuity is maintained, with the same specialist responsible for diagnosis, therapy, and follow-up. avoiding unnecessary hospitalization also may reduces the stress for patients and families. furthermore, this approach may be also useful in private section for patients with postoperative infections and utis that may complicate the surgical procedure performed in private setting, especially endoscopic procedures for benign diseases (15), but that sometimes may be localized and be managed without hospitalization. furthermore, private hospital may provide clinical apps to better follow the patients at home, without hospitalization. internal protocols should be updated, and the classification integrated into clinical software systems to facilitate its daily use. in addition, data collection before and after implementation will be key, monitoring hospital admissions, antibiotic duration, and patient satisfaction, in order to demonstrate the tangible impact of this strategy. in conclusion, the new classification of urinary tract infections is not merely a change in terminology; it represents a genuine paradigm shift. it may improve clinical quality, optimizes time and costs, provides patients with safer and more personalized care, eases the pressure on public hospitals, and fosters rational antibiotic use. for urop, it is an opportunity to evolve towards a more modern, effective, and patient-focused model of urological care. references 1. kranz j, bartoletti r, bruyère f, et al. european association of urology guidelines on urological infections: summary of the 2024 guidelines. eur urol. 2024; 86:27-41. 2. bonkat g, wagenlehner f, cai t, et al. classification of urinary tract infections in 2025: moving beyond uncomplicated and complicated. eur urol open sci. 2025; 75:44-47. declarations ethical approval and consent for participate: not applicable. consent for publication: not applicable. availability of data and material: not applicable. competing interests: the authors declare that they have no competing interests. funding: in case of acceptance, urop will pay the apc. authors' contributions: guglielmo mantica and rosario leonardi: ideation, paper writing and editing; all authors: revision and validation. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):14280 3 novel biomarkers in prostate cancer 3. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72. 4. britton cj, cortese bd, talwar r. economic impact of tariffs on healthcare costs in urology. nat rev urol. 2025. 5. welliver c, feinstein l, ward jb, et al. evolution of healthcare costs for lower urinary tract symptoms associated with benign prostatic hyperplasia. int urol nephrol. 2022; 54:2797-2803. 6. ciani o, grassi d, tarricone r. an economic perspective on urinary tract infection: the "costs of resignation". clin drug investig. 2013; 33:255-61. 7. gaitonde s, malik rd, zimmern pe. financial burden of recurrent urinary tract infections in women: a time-driven activity-based cost analysis. urology. 2019; 128:47-54. 8. callan a, o'shea e, galvin s, et al. the economic cost of urinary tract infections in the community: results from ireland. value health. 2014; 17:a468. 9. huang bm, lo cl, lin wl, et al. application of antimicrobial stewardship interventions improves outcomes in adults with bloodstream infection caused by multidrug-resistant enterobacteriaceae. j microbiol immunol infect. 2025:s1684-1182(25)00155-0. 10. mike-ogburia mi, monsi tp, nwokah eg. prevalence and determinants of multidrug-resistant uropathogenic klebsiella species and associated antimicrobial resistance genes in port harcourt, nigeria. bmc infect dis. 2025; 25:1036. 11. rizvi m, khan m, al-jardani a, et al. mapping antimicrobial susceptibility of community-acquired uropathogenic escherichia coli across low, middle and high-income countries highlights significant differences: insights for empiric treatment. ijid reg. 2025; 16:100706. 12. arends sjr, mccreary ek, helgeson m, et al. retrospective analysis of antimicrobial resistance among escherichia coli causing communityacquired urinary tract infections in the united states from 2010-2022. j glob antimicrob resist. 2025; 44:442-448. 13. wilson gm, jackson r, abdelrahim s, et al. determining appropriateness of treatment by evaluating providers' documentation of uti symptoms. am j infect control. 2025:s0196-6553(25)00472-9. 14. goebel mc, trautner bw, grigoryan l. the five ds of outpatient antibiotic stewardship for urinary tract infections. clin microbiol rev. 2021; 34:e0000320. 15. leonardi r. the lest technique: treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. arch ital urol androl. 2019; 91:35-42. correspondence guglielmo mantica guglielmo.mantica@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genoa, largo rosanna benzi 10, 16136, genoa, italy stefano alba stefanoalba78@gmail.com department of urology, romolo hospital, rocca di neto (kr), italy andrea alfarone alfarone2@hotmail.com department of urology, aurelia hospital, roma, italy umberto capitanio umbertocapitanio@gmail.com renzo colombo colombo.renzo@hsr.it division of experimental oncology/unit of urology, urological research institute (uri), irccs ospedale san raffaele, milan, italy donato dente donato.dente@tiscali.it istituto clinico città di brescia, brescia, italy carlo giulioni carlo.giulioni9@gmail.com angelo cafarelli info@angelocafarelli.it urology unit, villa igea private hospital, ancona, italy carmelo morana morana.carmelo@gmail.com department of urology, giovanni xxiii monastier hospital, treviso, italy serena maruccia serena.maruccia@gmail.com istituti clinici zucchi, monza, italy gabriella mirabile gabriella.mirabile@gmail.com center of minimally-invasive urology, pio xi clinic, fondazione vincenzo pansadoro, rome, italy archivio italiano di urologia e andrologia 2025; 97(3):14280 g. mantica, s. alba, a. alfarone, et al. 4 gennaro musi gennaro.musi@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy mauro ragonese mauro.ragonese@gmail.com department of urology, policlinico universitario fondazione agostino gemelli, istituto di ricovero e cura a carattere scientifico (ircss), roma, italy mauro silvani dottorsilvani@gmail.com department of reconstructive surgery, clinica sedes sapientiae, turin, italy antonio tufano antonio.tufano91@gmail.com alessandro calarco alecalarco@gmail.com urology unit, san carlo di nancy hospital, roma, italy ottavio de cobelli ottavio.decobelli@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy ferdinando de marco ferdinandodemarco@gmail.com department of urology, tiberia hospital, rome, italy giovanni ferrari gferrari@hesperia.it department of urology, hesperia hospital, modena, italy giuseppe mario ludovico g.ludovico@miulli.it division of urology, ente ecclesiastico ospedale generale regionale "miulli", acquaviva delle fonti (ba), italy stefano pecoraro uropec@gmail.com neuromed, avellino, italy domenico tuzzolo dometuzzolo@alice.it urologi ospedalità gestione privata (urop) nazareno suardi suardi.nazareno@gmail.com department of urology, ospedali civili of brescia, brescia, italy rosario leonardi rosario.leonardi@unikore.it division of urology, school of medicine, kore university of enna, enna, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper complication rates, whether it was magnified inguinal (miv) or subinguinal varicocelectomy (msv) (4, 5). the magnified subinguinal varicocelectomy might preserve more arteries and veins than the magnified inguinal varicocelectomy. however, it raises the operation's complexity and the risk of artery damage (6). it was observed that antegrade flow during magnified subinguinal varicocelectomy and pulsatile movement could help visualize the main spermatic artery; however, it can be difficult for various reasons, including differences in anatomic architecture and blood pressure that can be low to be able to detect pulsatile movement (7). although papaverine droplets are applied to enhance arterial pulsation, vigorous manipulation of the arteries during dissection might cause spasms, making it challenging to identify arterial pulsation (8). furthermore, arteries are often found near to or buried beneath complex venous branching, requiring the development of a technology that can adequately detect these small arteries. to our knowledge, only a few studies have used intraoperative vascular doppler ultrasound-assisted magnified subinguinal varicocelectomy (ivdu-msv), which enhanced accurate visualization and preservation of arteries and veins (7, 9). in this trial, we compared the fertility and postoperative outcomes of combining intraoperative doppler and hydrodissection, versus intraoperative doppler alone in infertile men with varicocele undergoing magnified subinguinal varicocelectomy. materials and methods the local ethics committee approved the protocol of the current trial of faculty of medicine for girls, al-azhar university (fmg-irb) met at faculty of medicine for girls, nasr city, cairo, egypt (study id 894). then, written informed consent was obtained from all participants. all procedures run in compliance with the standards of the declaration of helsinki (10). study design and patients we performed a non-randomized comparative trial that recruited consecutive infertile men with varicocele who were scheduled to undergo magnified subinguinal varicocelectomy at al-azhar university hospitals through the period from december 2018 to august 2021. men were considered eligible if aged more than 18 years old and had a confirmed history of primary infertility due to unilateral or bilateral primary varicocele. the diagnosis of methods: we performed a non-randomized comparative trial that recruited infertile men with varicocele who were scheduled to undergo msv. eligible patients were allocated by the investigators in a 1:1 ratio to receive intraoperative doppler (group i) or intraoperative doppler plus hydrodissection (group ii). results: sixty men were included in each group. the two study groups showed a comparable number of ligated veins on the right (4.22 ±1.57 versus 4.42 ± 1.65; p = 0.49) and left side (6.77 ± 2.14 versus 6.98 ± 2.29; p = 0.59). on the contrary, group ii showed a significantly higher number of preserved arteries on the right (2.42 ± 0.56 versus 1.47 ±0.5 in group i) and left side (2.6 ± 0.53 versus 1.63 ± 0.55 in group i), with p-value < 0.001. the sperm motility was significantly higher in group ii than in group i (21.25 ± 13.73 versus 13.85 ± 12.25, respectively; p = 0.002). in both groups, the sperm motility increased significantly at the end of follow-up compared to the preoperative period. the postoperative sperm mortality remained significantly higher in group ii than in group i (p = 0.008). conclusions: intraoperative doppler plus hydrodissection (d+ih-msv) has advantages in preserving more arteries and enhancing the motility of sperms. based on these findings, we strongly recommend d+ih-msv when treating infertile men with varicocele. key words: intraoperative doppler; hydrodissection; magnified subinguinal varicocelectomy; infertility; varicocele. submitted 13 november 2022; accepted 24 december 2022 introduction varicoceles is one of the main risk factors of male infertility, which is present in both primary and secondary infertility, with an estimated prevalence of 50% and 81%, respectively (1). varicocelectomy is the main procedure for treating varicoceles, resolving testicular pain, increasing spontaneous pregnancy rates, and improving semen parameters (2). successful varicocelectomy should maintain the vas deferens, spermatic arteries and lymphatics and interrupts the retrograde backflow through the pampiniform plexus of veins, which increases the spontaneous pregnancy rate. besides, varicocelectomy aims to preserve the perivasal veins for venous outflow (3). regarding improving spontaneous pregnancy, many studies have demonstrated that magnified varicocelectomy is the most effective procedure with undetectable intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy: a comparative study salah e. shebl 1, saadelddin ali 2, ahmed el gammal 1 1 urology department, faculty of medicine for girls, al-azhar university, cairo, egypt; 2 dermatology and andrology department, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2023.11008 summary archivio italiano di urologia e andrologia 2023; 95, 1 s.e. shebl, s. ali, a. el gammal varicocele was based on the findings of a duplex scan of the scrotal region and classified according to sarteschi (1). we excluded patients with painful varicocele, recurrent cases, history of inguinal or scrotal surgery, the co-existence of hydrocele, and/or the presence of technical difficulties in performing selective ligation of veins or preservation of arteries due to excessive fat content in the cord or cord lipoma that prevent proper dissection or occurrence of injured vessels during dissecting and hematoma formation that cause indistinct visualization. cases that we failed to separate the spermatic artery from adjacent veins due to anatomic architecture were excluded as well. eligible patients were allocated according to the investigator’s decision in a 1:1 ratio to receive magnified intraoperative doppler alone (group i) or intraoperative doppler, and hydrodissection (group ii). study's procedures and follow-up all patients were assessed preoperatively and underwent preoperative semen analysis, which was performed after ≥ three days of abstinence. the semen analysis was performed using the world health organization (who) guidelines (12). the samples were collected through masturbation in a sterile container; only non-spermicidal lubricants were allowed. samples were kept at 20-37℃ until liquefaction. macroscopic examination was performed to assess the semen characteristics, followed by microscopic examination on a fixed cell counting chamber. in case of abnormal semen analysis, another sample was collected after one month for confirmation. the same surgeon performed all procedures. patients underwent spinal or general anesthesia according to the surgeon and anesthetist decision. then, a three-cm skin incision was conducted over the external inguinal ring transversely. this incision dissected the camper's and scarpa's fascias to reach the spermatic cord, which was situated over a penrose drain using a babcock forceps. an 8-15x microscope was employed to identify all dilated veins. these veins were tied by 4-0 or 5-0 vicryl sutures according to size of ligated veins and sparing the artery with assistance of doppler during the operation (group i). in group ii doppler and hydrodissection were employed to identify the pulsating arteries using saline injection introduced directly in the cord by syringe without needle (figures 1, 2). following the incision of spermatic fascia, the vas deferens and its vessels were examined and suited in the posterior fascial compartment to create a window between vas and vessels using the penrose drain or forceps. we made another window between the internal spermatic vessels and the external spermatic fascia and its structures. the saline injection was introduced again to this a window created to separate the vessels from each other (figure 3). the internal spermatic arteries were then freed from the surrounding veins and irrigated with diluted warm papaverine; the surrounding veins were ligated by 3-0 vicryl, sparing the internal spermatic artery and lymphatic vessels. we closed the fascia, subcutaneous tissue and the skin using 2-0 vicryl sutures and subcuticular 4-0 proline or 3-0 vicryl, respectively. the incision was infiltrated with 0.5% marcaine solution with epinephrine, and a dry sterile dressing was applied. study's outcomes the primary outcome of the present study was the impact of employing intraoperative doppler and hydrodissection on the number of ligated veins and preserved arteries among men undergoing msv. the secondary outcomes of this study included the incidence of postoperative complications and semen analysis findings. the patients were followed up every three months for one year after the operation. the postoperative semen analysis was performed six months after surgery. figure 1. technique of hydrodissection (direct injection of saline in the cord). figure 2. the spermatic cord after saline injection. figure 3. the cord after hydrodissection. archivio italiano di urologia e andrologia 2023; 95, 1 intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy statistical analysis retrieved data were summarized and processed with ibm spss statistical software (version 25). frequencies were used to describe varicocele grade and postoperative complications. on the other hand, age, semen analysis findings, number of ligated veins, number of preserved arteries, duration of surgery, and hospital stay were summarized, according to normality, into mean (± standard deviation [sd]) or median (range) values. the hypothesis of significant differences between the type of procedures and primary or secondary outcomes was challenged using the independent t-test or chi-square test for continuous and categorical data. within group comparison was done using paired t-test. p-value < 0.05 was regarded as statistically significant. results sixty men were included in each group. the mean age of the patients was comparable between the intraoperative doppler group (group i) and doppler plus intraoperative hydrodissection group (group ii) (29.52 ± 5.48 versus 29.42 ± 4.64, respectively; p = 0.91). on the right side, the most commonly encountered varicocele grade was ii (58.3% and 53.3% in group i and ii, respectively; p = 0.88). however, on the left side, grade iii was the most common subtype in group i (50% compared to 41.7% in group ii) (p = 0.081) (table 1). the operative time was significantly longer in group ii (65.62 ±15.1 minutes) than in group i (35.18 ± 11.6; p < 0.001). concerning the number of ligated veins, the two study groups showed a comparable number of ligated veins on the right (4.22 ± 1.57 versus 4.42 ± 1.65; p = 0.49) and left sides (6.77 ± 2.14 versus 6.98 ± 2.29; p = 0.59). on the contrary, group ii showed a significantly higher number of preserved arteries on the right (2.42 ± 0.56 versus 1.47 ± 0.5 in group i) and left sides (2.6 ± 0.53 versus 1.63 ± 0.55 in group i), with p-value < 0.001. two patients (3.3%) in group i showed recurrent varicocele and hydrocele respectively, compared to no patients in group ii (p = 0.24 for both). there were no cases of testicular atrophy in both groups (table 2). in addition, group i and ii showed statistically significant increases in the sperm count at the end of follow-up, compared to the preoperative period (from 9.88 ± 4.77 to 35.22 ± 36.22 and from 11.07 ± 5.04 to 29.73 ± 27.62, respectively; p = 0.014 and 0.009, respectively). however, there were no significant differences between the two groups concerning both pre and postoperative sperm count (p = 0.189 and 0.35). group i and ii showed statistically significant increases in the sperm normal morphology at the end of follow-up, compared to the preoperative period (p = 0.001), with no significant differences between both groups. preoperatively, the sperm motility was significantly higher in group ii than group i (21.25 ± 13.73 versus 13.85 ± 12.25, respectively; p = 0.002). this trend was consistent during the postoperative period (p = 0.008). in both groups, the sperm motility increased significantly at the end of follow-up compared to the preoperative period (table 3). discussion varicocele repair appears to improve seminal parameters and to aid infertile couples in achieving spontaneous conception, according to current evidence. this disease has been treated with various open surgical methods, including retroperitoneal, miv, and msv (13). based on the previous literature, there was no significant difference table 2. comparison of intra and postoperative characteristics of the study groups. parameters group p-value * d (= 60) d + ih (n = 60) operative time in minutes mean ± sd 35.18 ± 11.6 65.62 ± 15.1 < 0.001 ligated veins (right) mean ± sd 4.22 ± 1.57 4.42 ± 1.65 0.49 ligated veins (left) mean ± sd 6.77 ± 2.14 6.98 ± 2.29 0.59 preserved arteries (right) mean ± sd 1.47 ± 0.5 2.42 ± 0.56 < 0.001 preserved arteries (left) mean ± sd 1.63 ± 0.55 2.6 ± 0.53 < 0.001 hospital stay in days mean ± sd 1 1 n/a recurrent varicocele no. (%) 2 (3.3%) 0 0.24 atrophy no. (%) 0 0 n/a hydrocele no. (%) 2 (3.3%) 0 0.24 d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. *chi-square test. table 3. changes in the semen analysis parameters in the study groups. parameters group p-value * d (= 60) d + ih (n = 60) count (million per milliliter) pre-operative 9.88 ± 4.77 11.07 ± 5.04 0.189 post-operative 35.22 ± 36.22 29.73 ± 27.62 0.35 p-value ** 0.014 0.009 morphology (%) pre-operative 17.25 ± 17.7 12.27 ± 9.93 0.06 post-operative 31.65 ± 24.27 26.55 ± 18.92 0.22 p-value 0.001 0.001 motility (%) pre-operative 13.85 ± 12.25 21.25 ± 13.73 0.002 post-operative 29.98 ± 9.57 35.18 ± 11.57 0.008 p-value < 0.001 0.004 d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. * mann-whitney u test. ** wilcoxon signed-rank. table 1. comparison of preoperative characteristics of the study groups. parameters group p-value * d (= 60) d + ih (n = 60) age mean ± sd 29.52 ± 5.48 29.42 ± 4.64 0.91 grade (right) ** 0 4 (6.7%) 3 (5%) 0.88 l 18 (30%) 21 (35%) ll 35 (58.3%) 32 (5.3%) lll 3 (5%) 4 (6.7%) grade (left) 0 0 0 0.081 l 4 (6.7%) 4 (6.7%) ll 25 (41.7%) 31 (51.7%) lll 30 (50%) 25 (41.7%) d: doppler; ih: intraoperative hydrodissection; sd: standard deviation. * chi-square test. ** based on sarteschi (11). archivio italiano di urologia e andrologia 2023; 95, 1 s.e. shebl, s. ali, a. el gammal between these methods in terms of improving fertility; however, they have different recurrence rates and potential complications (14). in addition, hypoxia produced by artery damage during the surgery disrupts energy metabolism, leading to spermatogenesis injury (15). consequently, several attempts have been made to reduce complication and recurrence rates following the surgery, allowing for better preservation of the testicular artery and lymphatic arteries and reduced incidence of hydrocele (16, 17). furthermore, even without testicular atrophy, ligation of the testicular artery can compromise the seminiferous tubules; thus, a dissection approach that preserves the spermatic artery and all branches is preferable (9). this study introduced a new technique by making another window between the internal spermatic vessels and the external spermatic fascia and its structures, which allowed us to separate the vessels from each other after injecting the saline. the internal spermatic arteries were then freed from the surrounding veins and irrigated with diluted warm papaverine; the surrounding veins were ligated by 4-0 & 5-0 vicryl, sparing the internal spermatic artery and lymphatic vessels. by comparing the outcomes of the procedure in both groups, doppler (d) and doppler+hydrodissection (d+ih), our findings showed that the mean age of the patients was comparable between both groups. varicocele grade ii was the most common in the right side, while grade iii was the most common in the left side. the operative time was significantly longer in the d+ih group than in the d group (p < 0.001). there were no significant differences between both groups in terms of ligated veins, sperm count, sperm morphology; however, the d+ih group was associated with higher preserved arteries and sperm motility than the d alone (p < 0.001 and p = 0.008), respectively. guo et al. (7), conducted a randomized trial to compare between magnified subinguinal varicocelectomy and intraoperative vascular doppler ultrasound assissted (ivdu) magnified subinguinal varicocelectomy in infertile males with varicoceles. their findings showed that intraoperative vascular doppler ultrasound reduced the operative time by about 10 minutes compared with the classic magnified subinguinal varicocelectomy (p < 0.05), which differs from our findings. in addition, they observed that the number of preserved arteries and spermatic veins ligated was significantly higher in the intraoperative vascular doppler ultrasound group than in the classic microsurgical subinguinal varicocelectomy group (p < 0.05). these findings can be explained by the precise identification of small veins using ivdu. some reports showed that ivdu helps remove more veins that were adherent as a dense complex to arteries. shindel et al. (18), demonstrated that the total number of veins ligated was significantly and positively correlated with improvements in total sperm motility, indicating that ligating a larger number of veins should result in a more significant reduction in the reflux of warm blood and/or toxic substances, resulting in less insult to spermatogenesis. in terms of sperm motility and concentration, guo et al. demonstrated that ivdu-microsurgical subinguinal varicocelectomy was more efficient than the classic microsurgical subinguinal varicocelectomy (p < 0.05). a recent systematic review showed that microsurgical varicocelectomy significantly improves spermatogenesis as reflected by biomarkers of infertile men including semen parameters and sperm dna fragmentation (19). on the other hand, there was no significant difference between both groups in terms of preserved lymphatics and sperm morphology. these findings align with the findings of many meta-analyses, which indicated that varicocelectomy could considerably enhance seminal parameters. in the study conducted by cocuzza et al., they found that there was no significant difference between ivdu-msv and msv (p = 0.37). besides, the number of injured arteries and preserved lymphatics was comparable in both groups (p = 0.06 and p = 0.21), respectively. on the other hand, the number of arteries preserved, and veins ligated was significantly higher in the ivdu-msv group than in msv group (p < 0.01 and p = 0.02), respectively (9). hydrocele formation after varicocelectomy in adolescents has not been thoroughly studied. the frequency of postvaricocelectomy hydrocele varies significantly, with rates as high as 39% in individuals who had ligation at internal inguinal ring (20). a range of 3.1% to 13% has been observed in previous investigations, with more significant ligation causing more hydroceles (21). ih of the spermatic cord lymphatics during varicocelectomy, according to atteya et al. (22), is a simple method that permits precise separation of the spermatic cord veins from its lymphatics, lowering the risk of post-varicocelectomy hydrocele development. we acknowledge that this study has some limitations, including the relatively small size, single center-based, and short follow-up period; however, this is the first study that combined d with msv and compared its outcomes with the ivdu+ih-msv. the fact that preoperative motility in group ii was significantly higher than in group i is another limitation. conclusions in conclusion, our findings suggested that both d-msv and d+ihmsv are effective methods for improving spermatic parameters in patients with varicocele, with a natural conception rate of 41.7% 46.7%, respectively. in addition, d+ih-msv has advantages in preserving more arteries and enhancing the motility of sperms. based on these findings, we strongly recommend d+ihmsv when treating infertile men with varicocele. references 1. cocuzza m, cocuzza ma, bragais fm, agarwal a. the role of varicocele repair in the new era of assisted reproductive technology. clinics (sao paulo). 2008; 63:395-404. 2. dubin l, amelar rd. varicocelectomy: 986 cases in a twelve-year study. urology. 1977; 10:446-9. 3. shridharani a, lockwood g, sandlow j. varicocelectomy in the treatment of testicular pain: a review. curr opin urol. 2012; 22:499-506. 4. lundy sd, sabanegh es jr. varicocele management for infertility and pain: a systematic review. arab j urol. 2017; 16:157-170. 5. schlegel pn, goldstein m. anatomical approach to varicocelectomy. semin urol. 1992; 10:242-7. archivio italiano di urologia e andrologia 2023; 95, 1 intraoperative hydrodissection and doppler ultrasound during magnified varicocelectomy 6. chan pt, wright ej, goldstein m. incidence and postoperative outcomes of accidental ligation of the testicular artery during microsurgical varicocelectomy. j urol. 2005; 173:482-4. 7. guo l, sun w, shao g, et al. outcomes of microscopic subinguinal varicocelectomy with and without the assistance of doppler ultrasound: a randomized clinical trial. urology. 2015; 86:922-8. 8. tatem aj, brannigan re. the role of microsurgical varicocelectomy in treating male infertility. transl androl urol. 2017; 6:722-9. 9. cocuzza m, pagani r, coelho r, et al. the systematic use of intraoperative vascular doppler ultrasound during microsurgical subinguinal varicocelectomy improves precise identification and preservation of testicular blood supply. fertil steril. 2010; 93:2396-9. 10. world medical association. world medical association declaration of helsinki. ethical principles for medical research involving human subjects. bull world health organ. 2001; 79:373-4. 11. sarteschi m, paoli r, bianchini m, menchini fabris gf. lo studio del varicocele con eco-color-doppler. g ital ultrasonol 1993; 4:43-9. 12. world health organization. who laboratory manual for the examination and processing of human semen (sixth edition) 2021 available from: http://whqlibdoc.who.int/publications/2010/ 9789241547789_eng.pdf 13. marmar jl, agarwal a, prabakaran s, et al. reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. fertil steril. 2007; 88:639-48. 14. agarwal a, deepinder f, cocuzza m, et al. efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach. urology. 2007; 70:532-8. 15. reyes jg, farias jg, henríquez-olavarrieta s, et al. the hypoxic testicle: physiology and pathophysiology. oxid med cell longev. 2012; 2012:929285. 16. marmar jl, debenedictis tj, praiss d. the management of varicoceles by microdissection of the spermatic cord at the external inguinal ring. fertil steril. 1985; 43:583-8. 17. goldstein m, gilbert br, dicker ap, et al. microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. j urol. 1992; 148:1808-11. 18. shindel aw, yan y, naughton ck. does the number and size of veins ligated at left-sided microsurgical subinguinal varicocelectomy affect semen analysis outcomes? urology. 2007; 69:1176-80. 19. soetandar a, noegroho bs, siregar s, et al. microsurgical varicocelectomy effects on sperm dna fragmentation and sperm parameters in infertile male patients: a systematic review and meta-analysis of more recent evidence. arch ital urol androl. 2022; 94:360-5. 20. salama n, blgozah s. immediate development of post-varicocelectomy hydrocele: a case report and review of the literature. j med case rep. 2014; 8:70. 21. paduch da, niedzielski j. repair versus observation in adolescent varicocele: a prospective study. j urol. 1997; 158:1128-32. 22. atteya a, amer m, abdelhady a, al-azzizi h, et al. lymphatic vessel hydrodissection during varicocelectomy. urology. 2007; 70:165-7. acknowledgments the authors thank the study participants, trial staff, and investigators for their participation. correspondence salah e. shebl, md (corresponding author) salahshebl@yahoo.com ahmed el gammal, md aelgammal36@gmail.com urology department, faculty of medicine for girls al-azhar university, alzahraa university hospital, al-azhar university, abbasia, cairo, egypt saadelddin ali, md saad2004@yahoo.com dermatology and andrology department, al-azhar university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13480 1 original paper ings, kink-resistant tubing, and modifications in reservoir placement have contributed to the durability and reliability of these devices (5). despite these improvements, complications such as infection, mechanical failure, and the need for revision surgery still pose significant challenges. the fluid reservoir is an essential part of the ipp system and it permits the hydraulic mechanism required for inflation and deflation. in particular, larger reservoirs have been developed to provide greater fluid capacity, improving the functionality of the prosthesis in patients with specific anatomical needs or high fluid volume requirements (6). despite their potential benefits, the use of large reservoirs poses unique challenges due to proximity of essential organs including bladder, colon, and vascular architecture and placement requiring for more surgical accuracy, especially in patients who have had radiation therapy or previous pelvic procedures (7). the safety and efficacy of large reservoirs remain areas of active research, with no studies describing the use of large reservoir as routine in all cases of ipp. this study aims to evaluate the clinical outcomes associated with the use of large reservoirs in all ipp surgery, focusing mainly on their safety profile. materials and methods participants our retrospective study included 60 patients who underwent inflatable penile prosthesis (ipp) with large reservoir in al wakra hospital from the period of 1st of january 2022 to 30th of august 2024. the inclusion criteria in our study were being adult patients who underwent ipp with a large reservoir. on the other hand, the exclusion criteria were patients with previous pelvic surgeries that significantly altered pelvic anatomy (e.g., radical prostatectomy, bladder surgeries), or ectopic reservoir. pre-operative demographics and clinical characteristics including the age of the patient, comorbidities, presence of peyronie's disease, use of anticoagulants, penile doppler study were recorded. type of the ipp, size of the cylinders and size of the reservoir were also recorded. postoperative complications were documented as well. introduction: the use of inflatable penile prostheses (ipp) has become a well-established treatment for erectile dysfunction, offering significant improvements in the quality of life for many patients. the reservoir site and size in ipp surgery are areas of ongoing research and debate. this study aims to evaluate the outcomes associated with the use of large reservoirs in ipp, focusing on both the surgical techniques and postoperative complications. materials and methods: our study is a retrospective study of 60 patients who underwent inflatable penile prosthesis (ipp) with large reservoir irrespective of the size of the prosthesis in al wakra hospital from the period of 1st of january 2022 to 30th of august 2024. result: successful insertion of the large reservoir was carried out in all patients from the same penoscrotal incision. there was no recorded migration, urethral injury, infection, device failure, pain, erosion or luts in our patients. revision was done in one patient. conclusions: the use of large-volume reservoirs in inflatable penile prosthesis (ipp) surgery demonstrates a favorable safety profile, with no significant increase in complication rates compared to standard reservoir sizes. key words: erectile dysfunction; penile prosthesis; reservoir. submitted 7 february 2025; accepted 10 february 10 2025 introduction erectile dysfunction (ed) is a common medical condition, affecting approximately 150 million men worldwide, with expected increasing prevalence due to aging populations and increasing risk factors such as diabetes and cardiovascular disease (1, 2). for men unresponsive to first-line treatments like oral phosphodiesterase inhibitors or intracavernosal injections, surgical interventions such as penile prosthesis implantation remain the gold standard, offering high efficacy and patient satisfaction rates (3). inflatable penile prosthesis (ipps) are preferred among the alternatives because they may mimic a natural erectile state while permitting full deflation, improving patient comfort and aesthetic results (4). recent advancements in ipp design and surgical approaches have led to improved patient outcomes. new features such as antibiotic-impregnated coatsafety of large reservoirs in inflatable penile prosthesis surgery ibrahim alnadhari 1, 2, muammer alshrani 1, osama abdeljaleel 1, 2, omar ali 1, 2, abdulla al-ansari 2, 3, ahmad shamsodini 1, 2 1 urology section, department of surgery, al wakra hospital, hamad medical corporation, qatar; 2 department of surgery, qatar university, qatar; 3 urology section, department of surgery, ambulatory care center, hamad medical corporation, qatar. doi: 10.4081/aiua.2025.13480 summary archivio italiano di urologia e andrologia 2025; 97(2):13480 i. alnadhari, m. alshrani, o. abdeljaleel, et al. 2 this study was approved by the surgical research committee, hamad medical corporation (mrc-01-24-659) and it was conducted in accordance with the helsinki declaration, and the need for informed consent was waived from the medical research committee given the retrospective nature of the study and the use of electronic medical records only. however, the privacy of the participant’s information regarding this study was maintained with confidentiality. surgical technique all procedures were performed by experienced urologic surgeons. prophylactic antibiotics were given. all cases were done using penoscrotal incision. firstly, the reservoir was placed in the traditional space of retzius through the floor of the external inguinal ring. the bladder was drained prior to the insertion of the reservoir to minimize risks of injury or complications. access to the retropubic space was achieved by blunt dissection through the transversalis fascia using the index finger, guided by tactile feedback. key anatomical landmarks include the pubic tubercle, the pubic bone, and occasionally the catheter balloon within the bladder which were felt to guide for safe placement of the reservoir in the space of retzius. after piercing the transversalis fascia, the deaver retractor was used to elevate the floor of the inguinal canal. the surgeon inserted the reservoir using wide forceps and the assistance pushed it further into position. the final placement was confirmed by feeling it with a finger. large reservoir size was routinely used in all the cases irrespective of the size of the prosthesis depending on the type of the penile prosthesis used (ams: 100 ml, coloplast: 125 ml, rigicon: 110 ml). then incisions were made in the corpora cavernosa and the corpora cavernosa were dilated. the length of the corpora cavernosa was measured and the cylinders were inserted according to the measured size. final steps were the insertion of the pump in the scrotum, connection of the tubing and closure of the incision. statistical analysis descriptive statistics for categorical variables were centered on frequencies and proportions. for continuous variables, means and standard deviations were reported. all statistical analyses were done using statistical packages spss 22.0 (spss inc. chicago, il) software. results variables and correlations are showed in table 1. the mean age of the patients was 60.18 ± 9.07 years. comorbidities were present in 46 (76.6%) patients and 39 (65%) were diabetic. peyronie's disease was present in 4 (6.6%) patients. as regards the etiology of erectile dysfunction, 60% of the patients had bilateral venous leak, 21.7% had bilateral arterial insufficiency, and 11.7% mixed vascular disease. four (6.6%) patients underwent penile prosthesis exchange for device failure after long period of insertion. prosthesis size ranged from 15 cm to 22 cm according to the intraoperative measurement of the corpora cavernosa. the largest reservoir size of the used penile prosthesis company was inserted as shown in table 1. the mean follow up period was 589.4 ± 416.5 days. as for the outcomes, there was no recorded migration, urethral injury, infection, device failure, pain, erosion or lower urinary tract symptoms (luts) in our patients. revision surgery was done in one patient. discussion the safety of using large reservoirs in penile prosthesis surgery is a critical factor that influences both surgical outcomes and patient satisfaction. our rational is that large reservoirs offer certain advantages, such as increased capacity and potentially improved device longevity. with a sufficient fluid supply, the inflation and deflation mechanisms work more efficiently, preventing excessive stress on the internal components, which might degrade over prolonged use. well-functioning large reservoir ensures smooth cycling of the prosthesis, potentially reducing the table 1. demographic, clinical features, outcomes and treatment modality of patients with large reservoir (n = 60). variable age (yr) m ± sd 60.18 ± 9.07 range (34-77) comorbidities present n (%) 46 (76.6%) dm n (%) 39 (65%) presence of peyronie's disease n (%) 4 (6.6%) anticoagulant n(%) 17(28.3%) penile doppler study venous leak n (%) 36 (60%) arterial insufficiency n (%) 13 (21.7%) mixed n (%) 7 (11.7%) exchange n (%) 4 (6.6%) prosthesis type (company) ams n (%) 17 (28.3%) coloplast n (%) 38 (63.3%) rigicon n (%) 5 (8.3%) prosthesis size 15 cm 3 (5%) 18 cm 14 (23.3%) 20 cm 17 (28.3%) 21 cm 9 (15%) 22 cm 17 (28.3%) size of reservoir 100 ml 17 (28.3%) 125 ml 38 (63.3%) 110 ml 5 (8.3%) follow-up days (m ± sd) 589.4 ± 416.5 complications migration of reservoir n (%) 0 erosion n (%) 0 urethral injury n (%) 0 device failure n (%) 0 infection n (%) 0 pain n (%) 0 luts n (%) 0 revision 1 (1.6%) values presented as mean ± sd (range) or number (%); dm: diabetes mellitus; luts: lower urinary tract symptoms. archivio italiano di urologia e andrologia 2025; 97(2):13480 3 large reservoirs in inflatable penile prosthesis likelihood of fibrotic tissue development around the device, which can affect its durability. decision for using a large reservoirs at the beginning of the surgery allows the assistant to begin opening and preparing the reservoir immediately, even before measuring the cylinder size. this helps save operative time and contributes to reducing the risk of infection. on the other hand, use of large reservoir present unique challenges and risks that must be carefully considered. our study investigated the safety of using large reservoirs in all ipp surgery irrespective to the size of the prosthesis. to the best of our knowledge, this is the first study to incorporate large-volume reservoirs in all ipp procedures. our findings showed that the use of large reservoirs is safe and can be utilized in most cases without significant increases in complications, offering better performance of the device and enhancing patient satisfaction. placing the reservoir in the space of retzius as the first step offers several advantages. it allows the reservoir to be inserted into a clean surgical field before performing corporotomies, which can introduce bleeding and make the field less clear. this also enables early detection of any bleeding from the space of retzius. additionally, this approach reduces overall surgical time, as the assistant can begin preparing the reservoir immediately after the initial incision. henry et al suggested that draining of the bladder and trendelenburg positioning to increase the distance between inguinal ring and viscera and allow decompression of the external iliac vessels, are useful steps to minimize the risk of complications during the reservoir insertion (8). the survival rate of penile prosthesis is 90.8% and 85.0% at 5 and 10 years follow-up (9). the most common cause of mechanical failure was fluid loss in 75% (10). in addition to fluid loss from the implant system, other mechanical malfunctions are tubing kinks, pump/valve cycling issues, and autoinflation of the prosthesis. in our study there was no case of mechanical failure, but we had one case who had the reservoir inserted superficially in the inguinal region as the patient was obese. postoperatively there was an inguinal bulge and pain. revision and correction of the reservoir with proper placement of the reservoir in the retzus space was carried out safely. the use of large reservoirs is particularly beneficial in patients requiring higher volumes for effective inflation, such as those with larger corpora cavernosa. our data suggest that adopting new surgical protocols with the use of large reservoir in all ipp is safe especially in standard patient with no anatomic challenge. we acknowledge the limitations of this study that reports a retrospective analysis of a single-centre experience, which involves inherent limitations such as the potential for missing patients and reporting bias. larger-scale studies with prospective proper evaluation of the patient’s satisfaction could provide more information about the efficacy and outcome of the use of large reservoir in ipp. conclusions the use of large-volume reservoirs in ipp surgery demonstrates a favorable safety profile, with no significant increase in complication rates compared to standard reservoir sizes. this approach may offer enhanced outcomes for patients requiring greater fluid volumes to achieve optimal device functionality. references 1. ayta ia, mckinlay jb, krane rj. the likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. bju int. 1999; 84:50-6. 2. feldman ha, goldstein i, hatzichristou dg, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 3. levine la, becher ef, bella aj, et al. penile prosthesis surgery: current recommendations from the international consultation on sexual medicine. j sex med. 2016; 13:489-518. 4. wilson sk, cleves ma, delk jr. comparison of mechanical reliability of original and enhanced mentor alpha i penile prosthesis. j urol. 1996; 155:145-7. 5. van dyke m, baumgarten as, ortiz n, et al. state of the reservoir: current concepts of penile implant reservoir placement and potential complications. curr urol rep. 2021; 22:20. 6. carson cc, mulcahy jj, harsch mr. mechanical reliability and safety of, and patient satisfaction with, the ams 700 inflatable penile prosthesis: results of a long-term multicenter study. j urol. 2011; 186:1216-20. declarations statement of ethics: this study was approved by the surgical research committee, hamad medical corporation (mrc-0124-659) and it was conducted in accordance with the helsinki declaration, and the need for informed consent was waived from the medical research committee given the retrospective nature of the study and the use of electronic medical records only. however, the privacy of the participant’s information regarding this study was maintained with confidentiality. data availability statement: all data generated or analyzed during this study are included in this manuscript. further enquiries can be directed to the corresponding author. conflict of interest statement: the authors have no conflicts of interest to declare. funding sources: this study was not supported by any sponsor or funder. author contributions: all authors have made significant contributions to the manuscript including design, drafting and revising. i.a, conception and design, data collection, data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. m.a. data collection, data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. o.a. data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. o.a. data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. a.a. data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. a.s. conception and design, data analysis and interpretation of data, drafting the manuscript and final approval of the version to be published. archivio italiano di urologia e andrologia 2025; 97(2):13480 i. alnadhari, m. alshrani, o. abdeljaleel, et al. 4 7. martínez-holguín e, lledó-garcía e, gonzález j, hernándezfernández c. three-piece inflatable penile prosthesis: ectopic reservoir placement. actas urol esp (engl ed). 2020; 44:367-76. 8. henry g, hsaio w, karpman e, et al. a guide for inflatable penile prosthesis reservoir placement: pertinent anatomical measurements of the retropubic space. j sex med. 2014; 11:273-8. 9. chung e, van ct, wilson i, cartmill ra. penile prosthesis implantation for the treatment for male erectile dysfunction: clinical outcomes and lessons learnt after 955 procedures. world j urol. 2013; 31:591-5. 10. amini e, saldivar r, hammad ma, barham dw. malfunction and mechanical failure of the inflatable penile prosthesis: a narrative review of etiologies and management. ame med j. 2024; 9:28. correspondence ibrahim ahmed alnadhari (corresponding author) ibrahimah1978@yahoo.com muammer alshrani malshrani@hamad.qa osama abdeljaleel oabdeljaleel@hamad.qa omar ali oali@hamad.qa ahmad shamsodini aabbas@hamad.qa urology section, department of surgery, al wakra hospital, hamad medical corporation, qatar abdulla al-ansari aalansari1@hamad.qa department of surgery, qatar university, qatar stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11627 1 systematic review tion and infertility. discomfort due to varicocele, testicular size asymmetry exceeding 20% or testicular atrophy, bilateral varicocele, and high-grade varicocele are indications of varicocelectomy in adolescents (5, 6). previous studies have shown that testicular hypotrophy can improve in 40100% of cases after varicocelectomy, significantly enhancing parameters such as sperm concentration, total and progressive motility, and morphology (7, 8). microsurgical varicocelectomy is still rarely used in the pediatric population due to several factors (9). lack of experience with microscopic techniques, smaller testicular arteries, and lower blood pressure from systemic arteries in pediatric patients are difficulties that make arterial identification more difficult in the subinguinal or inguinal approach. consequently, there has been a growing adoption of laparoscopic techniques by pediatric urologists over the past decade. this is primarily attributed to the numerous advantages these techniques offer, including faster operating and recovery times as well as visualization capabilities comparable to microsurgery (10, 11). laparoscopic varicocelectomy (lv) using palomo's method, which involves the simultaneous ligation of the internal spermatic vein (isv) and internal spermatic artery (isa), has demonstrated a favorable success rate without any significant increase in the risk of testicular atrophy (12). however, there is debate among pediatric urologists regarding the importance of artery preservation during varicocelectomy. the controversy surrounding the need for artery preservation (ap) during lv has also been reported in several studies. some studies suggest that the ap procedure is more appropriate as it prevents iatrogenic testicular trauma and reduces the incidence of postoperative hydrocele, while others report that artery ligation (al) has a low recurrence and hydrocele rate but may disrupt testicular growth and future fertility. conversely, the ap procedure has been associated with higher rates of persistence and recurrence compared to al during lv (3, 4, 13). currently, there is a lack of well-established evidencebased medicine (ebm) studies comparing al and ap during lv. in order to determine the impact of arterial ligation following lv, this systematic review and meta-analysis aims to assess the efficacy and safety of laparoscopic varicocelectomy, comparing procedures with or without artery preservation in pediatric and adolescent population. introduction: challenges in identifying small testicular arteries and lack of microscopic experience have led to a rising trend in the use of laparoscopic technique for pediatric and adolescent varicocele. the controversy over artery ligation (al) and artery preservation (ap) during laparoscopic varicocelectomy (lv) is still debatable. this study investigates the effectiveness of al and ap during lv in pediatric and adolescent varicocele cases. methods: the systematic searches based on prisma guideline were conducted in pubmed, scopus, sciencedirect, web of science and proquest databases with pre-defined keywords. both quantitative and qualitative analyses were performed to assess catch-up growth, persistence, recurrence, hydrocele, operative time, post-operative testicular volume, and sperm analysis. results: a total of 1512 patients from 9 eligible studies were included. there were no significant differences in catch up growth (or 0.89; 95%ci 0.53, 1.51; p = 0.68) or hydrocele incidence (or 0.59; 95%ci 0.28, 1.24; p = 0.16). the recurrence rate and persistence rate in ap group is significantly higher compared to al group (or 2.95; 95%ci 1.53, 5.68; p = 0.001 and or 5.13; 95% ci 2.04, 12.88; p = 0.0005, respectively). the mean operative time during laparoscopic varicocelectomy is significantly longer when arteries are preserved as opposed to when they are ligated (or 5.33; 95%ci 2.05, 8.60; p = 0.001). al and ap both improved testicular volume and post-operative sperm analysis. conclusions: al showed higher efficacy and comparable safety to ap. we recommend using al with lymphatic sparing to minimize hydrocele complications. key words: adolescent; pediatric andrology; varicocele; undescended; testes; laparoscopic; ligation; testicular artery. submitted 31 july 2023; accepted 3 august 2023 introduction varicocele is a medical condition characterized by the enlargement of the pampiniform plexus veins within the spermatic cord and is known to be a leading cause of male infertility (1, 2). the incidence in boys until puberty ranges from 2% to 11% and increases up to 16% in postpubertal adolescents (3, 4). inadequate management of varicocele in adolescents can lead to impairment of testicular growth, which can result in spermatogenesis dysfunca systematic review and meta-analysis on the efficacy of internal spermatic artery ligation during laparoscopic varicocelectomy in children and adolescents: is it safe? ahmad nurfakhri syarief, ilham akbar rahman, agung ravi saputra sangadji, tarmono djojodimedjo, fikri rizaldi department of urology, faculty of medicine, universitas airlangga and dr. soetomo general-academic hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2023.11627 summary archivio italiano di urologia e andrologia 2023; 95(3):11627 a. nurfakhri syarief, i. akbar rahman, a. ravi saputra sangadji, t. djojodimedjo, f. rizaldi 2 materials and methods this study followed a predetermined protocol according to the guidelines outlined by the preferred reporting items for systematic reviews and meta-analyses (prisma) (14) initial searches were conducted to ensure that the specific characteristics outlined in the pico (population, intervention, comparison, outcome) framework had not been previously investigated, thereby avoiding duplication of existing metaanalyses. the literature searches were conducted using several databases, including pubmed, scopus, sciencedirect, web of science, and proquest. the selected keywords used for the search were described as “varicocele”, “varicocelectomy”, “laparoscopic varicocelectomy”, “laparoscopic palomo”, “ligated artery”, “artery ligation”, “spared artery”, “artery sparing”, “preserved artery”, and “artery preservation”. the study's protocol was registered with prospero (crd42023445437). criteria for inclusion and exclusion to be considered for inclusion, eligible articles need to meet specific criteria. these criteria included comparative studies, written in english, having at least two comparison groups, and reporting data on catch-up growth, persistence, recurrence, hydrocele, and operation time in laparoscopic varicocelectomy with or without artery preservation. during the selection process, studies that fell under the following categories were excluded: animal experimental studies, publication types other than original research, unpublished articles, and abstract-only findings. data extraction two separate researchers collected the data using a predefined extraction template. in cases of discrepancies or disagreements during data extraction, a third investigator would be involved to discuss and make the final decision. the extracted information encompassed various aspects, including study details (such as authors, publication date, study design, sample size, inclusion and exclusion criteria, and follow-up duration), subject characteristics at baseline (such as age, intervention types, and study location), also qualitative and quantitative outcomes (such as catchup growth, persistence, recurrence, hydrocele, operation time, testicular volume, and sperm analysis). quality assessment the assessment of potential research bias in non-randomized studies was conducted using the newcastleottawa scale (nos), which evaluates parameters related to selection, comparability, and exposure. the results obtained from the nos assessment are categorized into three groups. a score ranging from 0 to 3 implicates a low-quality study, a score from 4 to 6 implicates a medium-quality study, and a score from 7 to 9 implicates a high-quality study. for randomized controlled trial (rct) studies, the assessment of potential research bias was conducted using the cochrane rob tools v2, which evaluates four domains, such as randomization process, deviations from intended intervention, missing outcome data, measurement, and selection of reported outcome (15). statistical analysis the measured endpoints included catch-up growth, persistence, recurrence, hydrocele incidence, and mean operative time. for the dichotomous variable analysis, odds ratio (or) with a 95% confidence interval (ci) was used, and a p-value below 0.05 was considered statistically significant. the continuous variable was assessed using mean difference (md). heterogeneity between studies was evaluated using i2, where an i2 value above 50% indicated high heterogeneity and a random-effects model was applied for pooled analysis. if i2 was less than 50%, a fixed-effects model was used. the statistical analysis figure 1. identification of studies. archivio italiano di urologia e andrologia 2023; 95(3):11627 3 safety of artery ligation in pediatric laparoscopic varicocelectomy was conducted using revman 5.4 for windows software, and the results were presented through forest plots and descriptive narratives. results systematic search results an initial 393 articles were found according to the used keywords. complete eligibility assessment resulted in nine matched articles for further qualitative and quantitative analysis (figure 1). seven included studies were retrospective cohorts in design, while the other two were rcts. baseline characteristics of the included studies this research included a total of 1512 patients with a mean age of 13.7 years, ranging from 6 to 20 years old. these participants comprised various articles published between 1999 and 2020. this study represented a total of 1409 patients with unilateral left-side varicocele and 103 patients with bilateral varicocele. most of the participants presented with varicocele grade ii-iii. the detailed characteristics and outcomes data of the included studies are shown in table 1 and table 2. risk of bias assessment regarding the selection aspect, all included studies demonstrated a robust selection process, ensuring the populations were fairly representative of young men with varicocele. moreover, the comparative and exposure aspects were well addressed, with adequate follow-up duration and relatively low dropout rates. based on the final assessment, three studies achieved a nos score of eight, while the other four studies received a nos score of seven, indicating a low risk of bias (table 3). however, the rct studies assessed using the cochrane rob tool v2 (figure 2) raised some concerns due to insufficient clarity regarding the randomization process described in the article. table 1. characteristics data of included studies. study design age (years) intervention sample varicocele type degree outcome follow up size of varicocele (month) lund, 1999 (17) observational 12.9 (8-15) laparoscopy varicocelectomy ap 13 6 (left), nr recurrency, catch up growth 6-48 al 7 7 (bilateral) nr f. varlet, 2000 (16) observational 12.15 (7-16) laparoscopy varicocelectomy ap 28 84 (left), nr persistency, testicular hypotrophy/ 11.1 (2-36) al 59 3 (bilateral) nr atrophy, catch up growth ciro esposito, 2001 (6) observational 11.5 (6-17) laparoscopy varicocelectomy ap 30 209 (left), i: 26, ii :98, 7 hydrocele, recurrency 26 (12-72) al 181 2 (bilateral) iii: 8 nicola zampieri, rct 14.3 (12-16) laparoscopy varicocelectomy ap 59 59 (left) ii: 82, iii: 40 recurrency/persistency, hydrocele, 18 2007 (20) al 63 63 (left) operative time, sperm quality parameters a.m. fast, 2013 (13) observational 15.5 (9.3-20.6) laparoscopy varicocelectomy ap 41 28 (left), 13 (bilateral) nr recurrency, catch up growth 30.5 or lymph node sparing al 312 241 (left), 71 (bilateral) nr 33.3 laparoscopy varicocelectomy k.s. kim, 2013 (19) observational 13.2 ± 2.1 laparoscopy varicocelectomy ap 50 50 (left) ii: 10, iii: 40 recurrency/persistency, catch up growth, 21 ± 12.3 al 42 42 (left) ii: 9, iii: 33 operative time weimin yu, 2015 (4) observational 17.3 ± 2.4 laparoscopy varicocelectomy ap 57 122 (left) ii: 36, iii: 21 recurrency, hydrocele, catch up growth, 17.1 ± 7.4 al 65 ii: 41, iii: 24 sperm quality parameters 17.8 ± 7.0 ciro esposito, 2017 (8) observational 12.5 (8-17) laparoscopy varicocelectomy ap 10 345 (left) iii: 10 recurrency, operative time, testis volume, 28.8 ± 8.3 or lymph node sparing al 335 ii: 66, iii: 269 hydrocele laparoscopy varicocelectomy abdelaziz yehya, rct 14.25 ± 1.6 lymph node sparing ap 80 160 (left) ii: 28, iii: 52 persistency, catch up growth, operative time, 42 2020 (18) laparoscopy varicocelectomy al 80 ii: 32, iii: 48 testicular volume nr: not reported; ap: artery preservation; al: artery ligation. figure 2. risk of bias assessment. archivio italiano di urologia e andrologia 2023; 95(3):11627 a. nurfakhri syarief, i. akbar rahman, a. ravi saputra sangadji, t. djojodimedjo, f. rizaldi 4 meta-analysis result on catch-up growth based on a meta-analysis of the six papers included (4, 13, 16-19), there is no statistically significant difference in the amount of catch-up growth between al and ap during laparoscopic varicocelectomy (or 0.89; 95%ci 0.53, 1.51; p = 0.68) (figure 3). the fixed-effects model was used due to low heterogeneity between studies (p = 0.81; i2 = 0%). of the six studies, fast et al. and yehya et al. represented higher statistical weight compared to other studies due to a larger sample size (13, 18). meta-analysis result on persistence rate four studies were analyzed in this meta-analysis (16, 1820), the persistence rate revealed a significant difference in which the ap group provided the higher persistence compared to the al group (or 5.13; 95%ci 2.04, 12.88; p = 0.0005) (figure 4). because of the low heterogeneity observed between studies, the fixed-effects model was employed (p = 0.88; i2 = 0%). table 3. risk of bias assessmment using newcastle ottawa scale. authors selection comparatibility exposure total score lund, 1999 *** ** *** 8 varlet et al. 2000 *** ** *** 8 esposito et al. 2001 *** ** *** 8 kim et al. 2013 *** ** ** 7 fast et. al 2013 *** ** ** 7 weimin yu et al. 2015 *** ** ** 7 esposito et al. 2018 *** ** ** 7 table 2. outcomes data of included studies. study intervention recurrence persistence hydrocele catch-up growth post-op operative time post-op sperm analysis volume testis 12 24 final hypotrophy/ (minutes) sperm count motility morphology pre op post op months months visit testicular atrophy (miillion/ml) (%) (%) lund, 1999 ap 2/20 nr 3/20 nr nr 18/20 nr nr nr nr nr nr nr al 2/7 nr 0/7 nr nr 5/7 nr nr nr nr nr nr nr f. varlet, 2000 ap nr 9/28 11 nr nr 3/12 1/12 nr nr nr nr nr nr al nr 5/60 nr nr 11/30 3/30 nr nr nr nr nr nr ciro esposito, 2001 ap 2/30 nr 0/30 nr nr nr 0/30 30 (20-70) nr nr nr nr nr al 3/181 nr 14/181 nr nr nr 0/181 nr nr nr nr nr nicola zampieri, 2007 ap 5/59 1/59 1/59 nr nr nr nr 35-60 73.81 45.73 45.13 nr nr (0.2-250) (0-75) (9-89) al 0/63 0/63 8/63 nr nr nr nr 20-40 58.85 39.04 38 nr nr (3.5-182) (11-68) (6-85) a. m. fast, 2013 ap 5/41 nr nr 12/33 22/33 27/33 0/41 nr nr nr nr nr nr al 17/312 nr nr 81/236 147/236 194/236 0/312 nr nr nr nr nr nr k.s. kim, 2013 ap 8/50 3/50 0/50 14/15 nr nr 0/50 83.1 ± 31.8 nr nr nr nr nr al 1/42 1/42 2/42 9/10 nr nr 0/42 72.5 ± 33.4 nr nr nr nr nr weimin yu, 2015 ap 3/57 nr 4/57 14/23 18/23 nr nr 41.3 ± 8.8 62.5 ± 39.2 52.2 ± 16.6 11.5 ± 1.5 nr nr al 2/65 nr 4/65 10/24 19/24 nr nr 39.5 ± 7.1 60.4 ± 38.2 49.1 ± 19.9 10.7 ± 1.5 nr nr ciro esposito, 2017 ap 1/10 nr 2/10 nr nr nr 0/10 26 (18-50) nr nr nr 12.4 ± 4.9 nr 29.3 ± 10.3 al 4/335 nr 23/335 nr nr nr 0/335 17 (14-45) nr nr nr 12.0 ± 5.2 15.4 ± 4.8 17.6 ± 5.3 abdelaziz yehya, 2020 ap nr 8/80 0/80 nr 68/80 nr 0/80 40 ± 2.6 nr nr nr 12.2 ± 3.1 16.3 ± 4 al nr 1/80 0/80 nr 71/80 nr 0/80 35 ± 2.8 nr nr nr 14.1 ± 4.6 17.1 ± 5.1 nr: not reported; ap: artery preservation; al: artery ligation. figure 3. meta-analysis result on catch-up growth. archivio italiano di urologia e andrologia 2023; 95(3):11627 5 safety of artery ligation in pediatric laparoscopic varicocelectomy meta-analysis result on recurrence rate seven studies were analyzed for this outcome (8, 13, 1721). on pooling analysis of the data, the recurrence rate in ap group is higher compared to al group (or 2.95; 95%ci 1.53, 5.68; p = 0.001) (figure 5). most of the studies demonstrated a higher recurrence rate in artery preservation group, except for one study (17). the fixed-effects model was applied because there was minimal heterogeneity observed between studies (p = 0.25; i2 = 23%). meta-analysis result on hydrocele incidence the analysis of six included studies reveals that there is no significant statistical difference in hydrocele incidence between al and ap during laparoscopic varicocelectomy (or 0.59; 95%ci 0.28, 1.24; p = 0.16) (figure 6) (4, 8, 17, 19-21). the choice of the fixed-effects model was based on the minimal heterogeneity observed among the studies (p = 0.08; i2 = 50%). varlet et al. reported 11 patients with postoperative hydrocele, but the number of patients in each group was unknown (16). meta-analysis result on mean operative time according to a meta-analysis of the four papers included (8, 18-20), the mean operative time during laparoscopic varicocelectomy is significantly longer when arteries are preserved as opposed to when they are ligated (or 5.33; 95%ci 2.05, 8.60; p = 0.001) (figure 7). the mean operative time was expressed in minutes. due to significant heterogeneity observed between studies, the randomeffects model was employed (p = 0.02; i2 = 69%). esposito figure 4. meta-analysis result on persistence rate. figure 5. meta-analysis result on recurrence rate. figure 6. meta-analysis result on hydrocele incidence. archivio italiano di urologia e andrologia 2023; 95(3):11627 a. nurfakhri syarief, i. akbar rahman, a. ravi saputra sangadji, t. djojodimedjo, f. rizaldi 6 et al. reported an average operating time of 30 minutes. however, it was unclear for each group (6). qualitative synthesis of testicular volume in this study, two separate studies reported the change in testicular volume before and after surgery (8, 18). there was an increase in testicular volume observed in both al and ap groups during laparoscopic varicocelectomy. however, the significance of the difference could not be analyzed due to the absence of one data point in the postsurgery testicular volume in the study conducted by esposito et al. (8). qualitative synthesis of postoperative sperm analysis two included studies provided information regarding post-surgery sperm analysis in the al and ap groups (4, 20). the results reported that al and ap laparoscopic varicocelectomy both resulted in normal sperm parameters following the surgery, with slightly higher values observed in the ap group. however, due to the lack of studies reporting sperm analysis after the surgery, it was not possible to analyze and provide the quantitative data comprehensively. however, the initial result of this qualitative analysis may provide an idea that there is no difference in postoperative sperm outcome between ap and al during laparoscopic varicocelectomy. discussions this is the first systematic review and meta-analysis that compares the efficacy and safety of al and ap during lv in pediatric and adolescent population. in our research, we have prioritized catch-up growth as the main focus due to its significant potential for enhancing testicular function and positively influencing fertility outcomes in individuals with varicocele. both al and ap groups demonstrated an increase of 63 to 86% testicular catchup growth within 12 to 24 months after surgery (22-25). weimin yu et al. in their study, reported that a lower rate of catch-up growth was observed in the al group during the first year of follow-up. they suggested that the remodeling of neovascularization in testicular drainage after the al procedure, which is important for maintaining normal testicular metabolism, may require a relatively longer time (4). the findings of similar outcome in catch-up growth between al and ap procedures in this study may be due to the fact that both techniques demonstrated identical effects on testicular blood flow (26). as observed in a recent meta-analysis, surgical correction of varicocele may result in superior catch-up growth of the affected testis. it can be inferred that the acceleration of growth in the affected testes is attributed to the removal of the detrimental effects of varicocele on testicular development (19). one of the concerns in this study was the incidence of postoperative hypotrophic testes. from the analysis of nine included studies, only study conducted by varlet et al. reported the incident (4, 8, 13, 16-21). contrast with yehya et al., whose study reported a significant increase in testicular volume even though the isa were ligated during lv (18). ligation above the level of the internal inguinal ring is considered safe because there are collateral arteries below the internal ring that play a role in providing an adequate blood supply to the testicle, preventing a significant decrease in oxygen and nutrient delivery (27, 28). those collateral arteries become more favorable for maintaining blood supply to the testicles as a result of reduced blood flow from the main artery after ligation (8). previous surgery on the inguinal area like hernia repair, may result in significant injury to the collateral testicular arteries, such as the cremasteric and differentialis arteries. these injuries may provide an impact on postoperative hypotrophy events in case al procedure is performed (16). although no studies have specifically observed the role of collateral arteries in testicular volume growth in the ligation artery group, an increase in volume suggests the occurrence of vascular adaptations. however, it is important to note that an increase in testicular volume after arterial ligation is not always accompanied by an increase in testicular function or sperm quality. spermatogenesis may still be impaired due to loss of primary blood supply (20). sperm analysis after varicocelectomy in adolescents is not routinely examined because of the barriers of parental consent, even though it is an important parameter after varicocelectomy (29). this is maybe the reason that only two of our nine included studies reported the sperm analysis parameters post-operation (4, 20) according to the findings of zampieri et al., the ap group demonstrated superior semen quality compared to the al group, even though there is no statistically significant difference between the two groups. in terms of mean sperm concentration outcome, the ap group demonstrated a higher value compared to the al group (73.81 x 106 and 58.85 x 106, respectively). furthermore, the ap group exhibited higher sperm motility (45.73%) compared to the al figure 7. meta-analysis result on mean operative time. archivio italiano di urologia e andrologia 2023; 95(3):11627 7 safety of artery ligation in pediatric laparoscopic varicocelectomy group (39.04%), with a greater proportion of normal morphology sperm cells (45.13% vs. 38%). they believe that ap is necessary since preserving the normal blood supply of the arteries seems more appropriate to prevent testicular damage and dysfunction (20). therefore, it is important to consider further studies with long-term follow-up to assess the parameters of sperm function and quality in the postoperative evaluation of the al group before determining whether the al method adversely affects testicular function and spermatogenesis. our study reveals a notable contrast in the recurrence and persistence rates between ap and al groups. specifically, the group that underwent arterial preservation showed a higher recurrence and persistence rate. this finding aligns with kattan et al.'s findings, which reported that ap exhibited a higher recurrence rate compared to al. this was mainly due to the presence of blood flow in nonfunctional collateral veins as a result of venous pressure increases following isv ligation or failing to ligate the small veins along the anterior wall of isa due to fear of injuring the artery. mass ligation of the gonadal vessels allows for complete obliteration, thus preventing missed collateral veins (30). another possible reason for persistency could be the existence of collateral veins that originate from the internal spermatic vein below the occlusion site and directly drain into the internal iliac vein or the inferior cava (31). however, there have been several studies reporting a low recurrent rate (0.6-3%), even though the testicular artery and lymphatic vessels are preserved. a study by chung et al. declares that the possibility of missing small periarterial veins can be minimized. they can be easily divided and dissected using 3 mm mini laparoscopic instruments (32). however, future research needs to be done on a larger scale to prove this statement. our investigation showed no significant difference in the incidence of hydroceles between artery preservation and ligation, in contrast to the findings of a study by zampieri et al., which found a correlation between al and the development of hydroceles. they suggest that the complete ligation of spermatic and lymphatic vessels can cause blood stasis within the scrotum (20). the risk of developing hydrocele may be increased if lymphatic preservation is not performed. however, there was no association between artery preservation or ligation and hydrocele incidence, as reported in a study by weimin yu et al. (4). liang et al.'s meta-analysis indicated that selecting a lymphatic preservation method is advisable to decrease the occurrence of hydroceles. this is because the standard palomo procedure does not involve the preservation of lymphatic glands, leading to the accumulation of lymphatic fluid in the scrotum, which contributes to a higher risk of hydrocele formation (33). mathias et al. found that there was no significant difference between arterial sparring and ligation regarding the incidence of postoperative hydrocele in lymphatic sparing varicocelectomy. yehya et al. also confirmed this by reporting no incidence of hydrocele in both the ap and al groups during lymphatic sparring lv (18). while we found that the ap group significantly had a longer mean operative time than the al group, weimin yu et al. found no statistically significant difference between the two groups (4). the operating time may vary depending on the surgeon's experience (24). this is probably the reason that this outcome in this study possessed a higher heterogeneity compared to another outcome. this meticulous process involves carefully locating and preserving the arterial blood supply while removing or ligating the dilated veins causing the varicocele. the surgeon must exercise caution and take the necessary time to ensure the arteries are properly identified and spared from damage. consequently, this longer time requirement is attributed to the surgeon's focus on accuracy and the intricate nature of preserving the arterial blood flow during the procedure (34). together with practical experience, it appears that there is a learning curve that enables surgeons to perform this technique more efficiently, resulting in shorter operative times as their expertise grows (24). one of several limitations of this meta-analysis is the lack of rct studies in contrast with more observational studies. rcts are considered the gold standard for establishing causal relationships due to their rigorous design and randomization process. on the other hand, observational studies rely on naturally occurring data and a lack of random assignment of participants, making them more susceptible to confounding factors and biases. moreover, the long-term assessment regarding catch-up growth and testicular function following varicocelectomy in this age group could be feasibly obtained by performing prospective cohort studies and retrospective analyses. several variations such as interventions in lv procedures where some were accompanied by lymphatic sparring and subsequently testicular development which were assessed by different standards became another limitation in this study. therefore, outcome measures such as hydrocele and catch-up growth can be biased. we expect that future research will include longterm follow-up and a uniform examination of sperm parameters while adhering to strict ethical approval protocols. conclusions this study highlights the superior efficacy of the al technique, which maintains similar safety to the ap technique. we recommend adopting the al technique with lymphatic sparing routinely to enhance efficacy and minimize hydrocele complications. additionally, the evaluation of sperm parameters is essential to fully establish the efficacy profile of laparoscopic varicocelectomy in the pediatric and adolescent population. references 1. vanlangenhove p, everaert k, van maele g, defreyne l. tolerance of glue embolization under local anesthesia in varicoceles: a comparative study of two different cyanoacrylates. eur j radiol. 2014; 83:559-63. 2. elbardisi h, agarwal a, majzoub a, al said s, alnawasra h, khalafalla k, al rumaihi k, al ansari a, et al. does the number of veins ligated during microsurgical subinguinal varicocelectomy impact improvement in pain post-surgery? transl androl urol. 2017; 6:264-270. 3. park s, kim ks, lee c, et al. impact of internal spermatic artery preservation during laparoscopic varicocelectomy on recurrence and the catch-up 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372:n71-n71. 15. sterne jac, savovic j, page mj, et al. rob 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019; 366:l4898. 16. varlet f, becmeur f, thieme g, et al. laparoscopic treatment of varicoceles in children multicentric prospective study of 90 cases. eur j pediatr surg. 2001; 11:399-403. 17. lund l, tang yc, roebuck d, et al. testicular catch-up growth after varicocele correction in adolescents. pediatr surg int. 1999; 15:234-7. 18. yehya a, abdalrazek m, gamaan i, et al. lymphatic sparing laparoscopic varicocelectomy with or without testicular artery preservation: is there a difference? ann pediatr surg 2020; 16:16 19. kim ks, lee c, song sh, et al. impact of internal spermatic artery preservation during laparoscopic varicocelectomy on recurrence and the catch-up growth rate in adolescents. j pediatr urol 2013; 10:435-40. 20. zampieri n, zuin v, corroppolo m, et al. varicocele and adolescents: semen quality after 2 different laparoscopic procedures. j androl. 2007; 28:727-33. 21. esposito c, monguzzi gl, gonzalez-sabin ma, et al. laparoscopic treatment of pediatric varicocele: a multicenter study of the italian society of video surgery in infancy. j urol. 2000; 163:1944-6. 22. poon sa, kozakowski ka, decastro gj, et al. adolescent varicocelectomy: postoperative catch-up growth is not secondary to lymphatic ligation. j pediatr urol 2009; 5:37-41. 23. yaman o, soygur t, zumrutbas ae, resorlu b. results of microsurgical subinguinal varicocelectomy in children and adolescents. urol. 2006; 68:410-2. 24. koyle ma, oottamasathien s, barqawi a, et al. laparoscopic palomo varicocele ligation in children and adolescents: results of 103 cases. j urol. 2004; 172:1749-52. 25. riccabona m, oswald j, koen m, et al. optimizing the operative treatment of boys with varicocele: sequential comparison of 4 techniques. j urol. 2003; 169:666-8. 26. poddoubnyi i v, dronov af, kovarskyi sl, et al. laparoscopic ligation of testicular veins for varicocele in children: a report of 180 cases. surg endosc. 2000; 14:1107-9. 27. islam s, islam m, sarkar s, paran s. outcome of laparoscopic varicocelectomy with mass ligation technique for symptomatic varicocele. arch surg clin res. 2019; 3:065-9. 28. mirilas p, mentessidou a. microsurgical subinguinal varicocelectomy in children, adolescents, and adults: surgical anatomy and anatomically justified technique. j androl. 2012; 33:338-49. 29. fine rg, gitlin j, reda ef, palmer ls. barriers to use of semen analysis in the adolescent with a varicocele: survey of patient, parental, and practitioner attitudes. j pediatr urol. 2016; 12:41.e141.e6. 30. kattan s. the impact of internal spermatic artery ligation during laparoscopic varicocelectomy on recurrence rate and short post operative outcome. scand j urol nephrol. 2001; 35:218-21. 31. fallara g, tang s, pang kh, et al. treatment of persistent or recurrent varicoceles: a systematic review.eur urol focus; 2023; 9:531-40. 32. chung sd, wu cc, lin vch, et al. minilaparoscopic varicocelectomy with preservation of testicular artery and lymphatic vessels by using intracorporeal knot-tying technique: five-year experience. world j surg. 2011; 35:1785-90. 33. liang z, guo j, zhang h, et al. lymphatic sparing versus lymphatic non-sparing laparoscopic varicocelectomy in children and adolescents: a systematic review and meta-analysis. vol. 21, european j pediatr surg. 2011; 21:147-53. 34. islam sr, paul d, sarkar sa, et al. laparoscopic varicocelectomy by artery preserving and mass ligation techniquea comparative study. j biomed eng med imaging. 2022; 11:87-95. correspondence ahmad nurfakhri syarief afkurologi@gmail.com ilham akbar rahman ilhamakbaarr@gmail.com agung ravi saputra sangadji agung.ravi.saputra-2022@fk.unair.ac.id tarmono djojodimedjo tar_urology@yahoo.com fikri rizaldi, md (corresponding author) fikririz@gmail.com department of urology, faculty of medicine, universitas airlangga and universitas airlangga teaching hospital, surabaya, east java, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 96(1):12658 1 introduction prostate cancer (pca) is a male malignancy seen mainly in the older population. eighty percent of cases are diagnosed after the age of 65 years, yet pca identification in younger males aged less than 50 has risen from 1% in the 1970s to 5% (1). various autopsy investigations show a considerable rate of latent pca in the third, fourth, and fifth decades of life, ranging between 20% and 30% (2). in younger men, latent pca prevalence varies in autopsy series reports, ranging from 34% occurrence in the united states to 27% occurrence in hungary and 2.6% occurrence in the greek series (3-5). the increasing prevalence of pca detection at a young age raises concerns about the natural course of this disease and treatment options. in low-risk, elderly pca patients with a gleason score of about (6), active surveillance is a good option (6). this is not the case with patients under the age of 55, who might require urgent intervention in the majority of instances due to the more aggressive behavior of the disease in younger patients, which leads to an increased number of patients undergoing radical prostatectomy (rp) (7). the data regarding the outcomes of young men who suffered from pca are contentious. according to tjaden et al., the disease in younger patients is more aggressive, with worse prognoses (8). however, recent studies mentioned that young men with low-risk pca have better outcomes after rp (9, 10). a common limitation in these surveys was the use of prostate-specific antigen (psa) relapse to measure the endpoint of the oncological outcome. at the same time, the progression of the disease or mortality seems to be the optimal outcome for reaching a better judgmental conclusion. in this article, we studied pca patients who underwent rp and compared the pathological findings, oncological outcomes, and survival rates between younger men (≤ 55 years) versus older patients. materials and methods study design: in this retrospective cohort study, we studied 134 pca patients who underwent retropubic rp in our referral teaching centers (ali-asghar hospital and namazi hospital, shiraz, iran) between march 2011 and march 2019. the mean age of patients was 62.6 ± 9.2 objectives: this research aimed to compare the prostate cancer (pca) features, survival rate, and functional outcomes after open suprapubic radical prostatectomy (rp) between younger men (≤ 55 years) and older men (> 55 years). methods: in this retrospective cohort study, we studied 134 patients with clinically localized pca who underwent rp at our centers between 2011 and 2019, with 26 (19.40%) patients aged ≤ 55. pathological parameters, survival rate (at 5 and 10 years), and functional outcomes such as erectile function and continence rate (at two years from rp) were evaluated retrospectively, and the two groups were compared. the chi-square test, kaplanmeier, and cox proportional hazards method were used for statistical analysis. result: men aged ≤55 had greater rates of organ-confined tumors, lower d’amico risk grouping and pathologic gleason grade than their older counterparts (all p < 0.05). the median follow-up was 81 months. the survival rate at five and ten years were higher in younger men versus older counterparts (96.15% vs. 93.47% and 92.15% vs. 82.13% ) but difference was not statistically significant (p = 0.1539). five-year biochemical recurrence-free and metastasis-free survival rates in younger men versus older counterparts were 96.2% vs. 81.5% and 75.7% vs. 51.5%. men > 55 years were associated with worse bcr-free and metastasis-free survival in univariate analysis and with worse bcr in multivariate analysis. the continence rate was significantly better in men aged ≤ 55 compared to older counterparts (or: 5.08; 95% ci: 1.61-22.61; p = 0.013). however, erectile function was not statistically significant between groups [for moderate ed: (or: 1.08; 95% ci: 0.43-2.79, p = 0.865), for severe ed (or: 1.60; 95% ci: 0.35-11.50, p = 0.579)]. conclusions: our study showed that survival rates were similar in younger men (≤ 55 years) and their older counterparts. however, older patients who underwent rp had more advanced disease, worse bcr-free survival, and a worse continence rate. for localized prostate cancer patients under 55 years of age, radical prostatectomy is an excellent treatment option with excellent long-term survival outcomes. given the relatively small number of patients younger than 55, a large cohort study with long-term postprocedural follow-up is needed to validate this observation. key words: radical prostatectomy; survival outcome; oncological outcomes; young men. submitted 13 may 2024; accepted 6 june 2024 survival and oncological outcomes for young men (≤ 55 years) undergoing radical prostatectomy for localized prostate cancer shahryar zeighami 1, ali ariafar 1, alireza makarem 1, faisal ahmed 2, mohammadreza askarpour 1 1 department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 2 department of urology, school of medicine, ibb university, ibb, yemen. doi: 10.4081/aiua.2025.12658 summary archivio italiano di urologia e andrologia 2025; 96(1):12658 s. zeighami, a. ariafar, a. makarem, et al. 2 years (range: 29.0-77.0 years). twenty-six (19.4%) patients were aged ≤ 55 years, while 108 (80.6%) patients were aged > 55 years. the study was approved by the ethics committee of shiraz university of medical sciences (id: ir.sums.med.rec.1398.493) and was conducted per the declaration of helsinki. additionally, written informed consent was obtained from patients for participation in our study. we included all patients diagnosed with localized pca who underwent radical prostatectomy and filled the standardized self-administrated questionnaires before and one year after the surgery. patients with missed information regarding clinical and paraclinical parameters were excluded. patient characteristics, such as family history of disease, age, and clinical parameters, such as clinical stage, biopsy gleason score, and psa level, were gathered before surgery. after surgery, pathological data (surgical margin status, lymph node status, pathological stage, and gleason score) were obtained. the psa level was evaluated every three months in the initial year post-rp. this frequency was reduced to biannually for the subsequent two years, and from the fourth year onward, the check-ups were conducted annually. in two successive readings, biochemical recurrence (bcr) was defined as a psa of more than 0.2 ng/ml. the recist criteria were used to evaluate the progression of the disease: ct, mri, and bone scan were used to confirm skeletal lesions. following the pathological analysis of prostate cancer (pca), supplementary treatment, either radiation therapy (rt) or a combination of rt and androgen deprivation therapy, was given within four months post-rp. if bcr was identified, a rescue treatment, either rt alone or combined with androgen deprivation therapy, was administered. we used histological examination following surgery or biopsy to confirm a local recurrence. the pathological result was evaluated using the ajcc 2002 staging system. from 1992 to 2005, we utilized the gleason grading system for tumor grading, and after 2005, we adopted the updated gleason grading system (11). urine continence was considered to use a 0-1 protective pad. the evaluation of erectile function was carried out using a uniform questionnaire, which incorporated the international index of erectile function (iief-5). patients who had an iief-5 score greater than 16, indicating no erectile dysfunction or only mild erectile dysfunction, were classified as potent. we assessed clinical and pathological data, along with followup information (such as time to bcr, detected metastasis or local recurrence, urinary continence, and erectile function) comparing the two groups. statistical analysis we utilized the mean ± standard deviation (sd) to represent the quantitative variables, and the frequency (percentage) was employed to describe the qualitative variables. chi-squared tests were used to compare the characteristics of patients and tumors. kaplan-meier survival curves and cox-proportional hazard methods were applied for univariate and multivariate bcr-free survival, metastasis-free survival, and overall survival analyses. functional outcome (24-month continence and potency) was analyzed using multivariable logistic regressions. a p-value less than 0.05 was deemed statistically significant. all the data were processed using the spss version 20 software (spss inc., chicago, il, usa). result patient and tumor characteristics table 1 presents all the cases' pathological and clinical features and compares age-related variables. among our 134 cases, 26 (19.40%) patients were aged ≤ 55 years, while 108 (80.6%) patients were aged > 55. young patients had greater rates of organ-confined tumors, lower d'amico risk grouping and pathologic gleason grade group than their older counterparts (all p < 0.05). however, the younger group aged ≤ 55 years have a higher rate of positive family history of prostatic cancer (p < 0.001). oncological outcome biochemical recurrence occurred in 21 (16%) patients over a median of 44 months [min: 23 max: 65 months] of follow-up, with no statistically significant difference between groups (p = 0.0588) (figure 1). during a follow-up of 84.6 ± 23.1 months (median: 81 [min: 27 max: 120]), metastases were discovered in 32 (23.9%) patients, with no sigtable 1. demographics and tumor characteristics stratified by patient age groups. variables subgroup total age ≤ 55 age > 55 p-value (n = 134) (n = 26, 19.4%) (n = 108, 80.6%) age (year) mean (sd) 62.6 (9.2) 47.0 (7.0) 66.3 (4.7) < 0.001 family history of prostatic cancer negative 127 (94.8) 20 (76.9) 107 (99.1) < 0.001 positive 7 (5.2) 6 (23.1) 1 (0.9) gleason grade group ≤ 6 34 (25.4) 17 (65.4) 17 (15.7) < 0.001 7 66 (49.3) 7 (26.9) 59 (54.6) ≥ 8 34 (25.4) 2 (7.7) 32 (29.6) psa (ng/ml) < 10 29 (21.6) 15 (57.7) 14 (13.0) < 0.001 10-20 52 (38.8) 11 (42.3) 41 (38.0) > 20 53 (39.6) 0 (0.0) 53 (49.1) d’amico risk classification low risk 36 (26.9) 11 (42.3) 25 (23.1) 0.007 intermediate 41 (30.6) 11 (42.3) 30 (27.8) high risk 57 (42.5) 4 (15.4) 53 (49.1) surgical margin negative 102 (76.1) 24 (92.3) 78 (72.2) 0.057 positive 32 (23.9) 2 (7.7) 30 (27.8) lymph node invasion no 93 (69.4) 23 (88.5) 70 (64.8) 0.035 yes 41 (30.6) 3 (11.5) 38 (35.2) pathologic confined organ confined 74 (55.2) 21 (80.8) 53 (49.1) 0.007 non-organ confined 60 (44.8) 5 (19.2) 55 (50.9) psa: prostate-specific antigen. boldface indicates a statistically significant result (p < 0.05). archivio italiano di urologia e andrologia 2025; 96(1):12658 3 outcomes of radical prostatectomy for young men nificant difference between groups (p = 0.1539) (figure 2). five-year biochemical recurrence-free and metastasis-free survival rates in younger men versus older counterparts were 96.2% vs. 81.5% and 75.7% vs. 51.5%. median survival was 87 months (95% ci: 81-90 months). the disease's progression time was 82.8 ± 24.7 months (median: 80 [min: 27 max: 120 months]) and did not differ significantly between groups (p = 0.1348) (figure 3). the survival rate for the age group ≤ 55 years at five and ten years was 96.15% (95% ci: 89.04%-100.0%) and 92.15% (95% ci: 82.27%-100.0%). the survival rate for the age group > 55 years at five and ten years was 93.47% (95% ci: 88.92%-98.3%) and 82.13% (95% ci: 3.76%91.4%). the kaplan-meier analysis showed a similar biochemical progression-free survival (bpfs) rate without statistically significant difference (log-rank p = 0.152). the uniand multivariable cox-regressions analysis showed that in univariate analysis, older patients were more likely to develop bcr (hr: 26.04; 95% ci: 8.42-80.54, p < 0.001) and metastasis (hr: 2.60; 95% ci: 1.02-6.60, p = 0.045). the multivariable cox-regressions analysis showed that nearly all parameters, both before and after surgery, were similar except for biochemical recurrence (hr: 88.70; 95% ci: 14.19-554.43, p < 0.001) and was a predictor for disease progression. however, after adjusting for further prognostic factors (gleason score, preoperative psa, lymph node status, surgical margin, pathologic stage), patients' age (≤ 55 vs > 55 years) was not a statistically significant predictor for mortality (p = 0.949) (table 2). table 2. uniand multivariable cox-regressions predicting mortality-free survival. variables subgroup total univariate analysis multivariate analysis (n = 134) hr (95% ci) p-value hr (95% ci) p-value age group age ≤ 55 26 (19.4) age > 55 108 (80.6) 4.13 (0.55-31.19) 0.169 1.08 (0.11-11.04,) 0.949 gleason score ≤ 6 34 (25.4) 7 66 (49.3) 1.13 (0.73-1.76) 0.577 0.89 (0.56-1.44) 0.646 ≥ 8 34 (25.4) 0.73 (0.43-1.24) 0.243 0.67 (0.36-1.25) 0.207 psa (ng/ml) < 10 29 (21.6) 10-20 52 (38.8) 0.87 (0.54-1.42) 0.581 0.73 (0.42-1.29) 0.281 > 20 53 (39.6) 1.41 (0.87-2.30) 0.168 1.07 (0.57-2.00) 0.837 surgical margin negative 102 (76.1) positive 32 (23.9) 0.70 (0.44-1.11) 0.128 0.82 (0.47-1.46) 0.506 lymph node invasion no 93 (69.4) yes 41 (30.6) 0.87 (0.57-1.32) 0.507 1.06 (0.61-1.84) 0.844 pathologic confined organ confined 74 (55.2) non-organ confined 60 (44.8) 0.90 (0.62-1.30) 0.577 0.70 (0.45-1.08) 0.107 biochemical recurrence no 113 (84.3) yes 21 (15.7) 26.04 (8.42-80.54) < 0.001 88.70 (14.19-554.43) < 0.001 metastasis no 102 (76.1) yes 32 (23.9) 2.60 (1.02-6.60) 0.045 2.16 (0.62-7.52) 0.225 psa: prostate-specific antigen, ci: confidence interval, hr: hazard ratio. boldface indicates a statistically significant result (p < 0.05). figure 1. mortality-free survival stratified by age groups. figure 3. metastasis-free survival stratified by age groups. figure 2. biochemical recurrence-free survival stratified by age groups. archivio italiano di urologia e andrologia 2025; 96(1):12658 s. zeighami, a. ariafar, a. makarem, et al. 4 functional outcome biochemical progression-free survival regarding postoperative functional outcome, the continence rate was significantly influenced by age in univariate analysis (or: 4.88; 95% ci: 1.57-21.47, p = 0.014) and multivariate analysis (or: 5.08; 95% ci: 1.61-22.61; p = 0.013). the erectile function was more improved in younger age [2 (16.7%) vs. 10 (83.3%)]. however, the rate was not statistically significant in univariate [for moderate: (or: 0.89; 95% ci: 0.36-2.21, p = 0.792) and for severe (or: 1.16; 95% ci: 0.26-8.14, p = 0.858)] or multivariate analysis [for moderate: (or:1.08; 95% ci: 0.43-2.79, p = 0.865), for severe (or: 1.60; 95% ci: 0.35-11.50, p = 0.579=)] (table 3). discussion age at cancer diagnosis is a well-known prognostic factor in the majority of malignancies. although few studies have found a worse prognosis in earlier high-stage pca patients (12-15), interestingly, evidence from recent research has also revealed that early diagnosis of pca in younger cases is related to lower stage and grade or perhaps to better results (9, 10, 16). a recent comprehensive review also discovered that younger age was associated with positive clinicopathological features and a more favorable prognosis for bcr in patients with low to intermediate risk. however, in high-risk groups, younger patients often experienced notably poorer oncological results (17). in this research, we examined the characteristics of pca, functional results, and survival outcomes in young men 55 years old or below after rp and then compared these findings with those of men older than 55. selecting candidates for radical prostatectomy is a challenging task for both the physician and the patient. the patient’s life expectancy, the natural history and curability of prostate cancer, as well as the morbidity of treatment and deferred treatment, must all be carefully evaluated. although the existing clinical data containing this information has inherent flaws, all these factors can be calculated with good precision. a concentrated effort should be made to present the patient with prognostic information that is appropriate for his age, health status, and the stage and grade of cancer. because not all men who choose radical prostatectomy will require or benefit from surgical intervention, the patient must be fully involved in the decision-making process (18). in our study, it is probable that younger individuals underwent more intensive screening, resulting in more frequent diagnoses at an early stage of the disease. furthermore, younger patients were more likely to prefer surgery over older patients. it is crucial to seek a better understanding of the correlation between younger age and prostate cancer occurrence and progression, which will aid strategic approaches when treating younger prostate cancer patients in the psa era (17). salinas et al. observed that prostate cancer diagnoses in those under 55 are mainly localized. however, men in this age group are more likely to die from higher grade/stage disease, indicating a demographic difference between early-onset and older male prostate cancer patients (19). similar to our study design, several studies on clinicopathological characteristics of prostate cancer chose the age of 55 as a cutoff point (13, 20, 21). however, there is no agreement on the age at which these tumors become most aggressive or on the characteristics that make these tumors more aggressive in young individuals. a recent meta-analysis suggested that age 50 is often used as the cutoff to separate younger and older patients in rp cohorts, which contradicts our choice of 55 as the cutoff (17). however, with our limited number of cases, choosing a lower age cutoff threshold of less than 55 years would result in an unbalanced sample size per group, increasing the possibility of mistakes during the matching and making statistical analysis challenging. family history, age, and race are all established risk factors for prostate cancer. while family history accounts for just 9% of cases, early-onset prostate cancer has a higher likelihood of being hereditary compared to late-onset prostate cancer. this increase in the risk of prostate cancer can be explained by the higher number of alleles in those patients (22, 23). similarly, in our study, family history was found in 0.9% of older males (> 55 years) and 23.1% of younger men (≤ 55 years), which was statistically significant (< 0.001). several other studies also show a strong link between family history and early-onset prostate cancer detection in young men (9, 12). future research on rare cases is essential to finding additional risk alleles and better understanding the disease's etiology. in this study, men aged ≤ 55 had greater rates of organconfined tumors, lower d'amico risk grouping, and pathologic gleason grade than their older counterparts. the findings of this report were similar to milonas et al. report, which mentioned younger men (≤ 55 years old) tend to have less aggressive clinical and pathological pca characteristics than older men (24). according to several investigations, older men are more likely to have advanced malignancy features. ji and colleagues analyzed the pathological characteristics of pca patients divided into three age groups: 55 or younger, between 56 and 75, and older than table 3. postoperative continence and potency rates stratified by age groups. variables subgroup age ≤ 55 age > 55 or p-value or p-value (n = 26, 19.4%) (n = 108, 80.6%) (95% ci) (95% ci) erectile potent 13/26 56/108 function (50%) (51.8%) moderate 11/26 42/108 0.89 0.792 1.08 0.865 (42.3%) (38.8%) (0.36-2.21) (0.43-2.79) severe 2/26 10/108 1.16 0.858 1.60 0.579 (7.6%) (9.2%) (0.26-8.14) (0.35-11.50) continence continence) 23/26 66/108 (0 to 1 pad/day (88.5%) (61.1%) incontinence 3/26 42/108 4.88 0.014 5.08 0.013 (> 1 pad/day) (11.5%) (38.9%) (1.57-21.47) (1.61-22.61) or: odds ratio, ci: confidence interval. boldface indicates a statistically significant result (p < 0.05). archivio italiano di urologia e andrologia 2025; 96(1):12658 5 outcomes of radical prostatectomy for young men 75. they found that the percentage of gleason pattern five tumors varied significantly across the groups (44.4%, 32.3%, and 36.8%, respectively), indicating a significant difference (χ2 = 11.641, p = 0.003) (25). this study's bivariate regression analysis demonstrated that greater pathological gs were indicators of illness development. however, this conclusion might arise from the considerable imbalance in the patient group ages, with just 26 participants aged ≤ 55 and 108 patients aged 55-75. all of these data lead us to believe that preconceptions regarding cancer's aggressiveness at a young age play a significant influence in choosing a surgical treatment decision. various studies have shown a high long-term biochemicalfree survival rate (bfsr) in the young male group. for example, tan et al. showed greater 5and 10-year survival rates among younger individuals (97.9% vs. 95.9% and 94.9% vs. 85.3, respectively) (13). freedland and colleagues examined 1.753 male patients post-rp in their research. they discovered that men under 50 had a significantly higher bfsr than other age groups.16 in contrast, milonas et al. found that young men had a 5and 8year bfsr of 77.9% and 72.4%, although this difference was not statistically significant compared to males over 55 (12). song and colleagues found that patients aged 55 or younger had better survival rates in the first year after treatment but poorer outcomes in the second, third, and fifth years compared to older age groups (20). in our study, the survival rate at five and ten years in younger men versus older counterparts was 96.15% vs. 93.47% and 92.15% vs. 82.13% but was not statistically significant (p = 0.1539). five-year bcr-free and metastasis-free survival rates in younger men versus older counterparts were 96.2% vs. 81.5% and 75.7% vs. 51.5%, and men > 55 years were associated with worse bcr-free and metastasis-free survival in univariate analysis and worse bcr in multivariate analysis. however, the patient's age at surgery was not proven to be an independent predictor in multivariable analysis. similarly, in most studies, the patient's age at surgery was not proven to be an independent predictor in multivariable analysis, indicating a significant role of other factors (12, 16). in the current study, young individuals had less erectile dysfunction (16.7% vs. 83.3%), but it was not statistically significant in regression analysis. our findings were similar to those of other studies in the literature. brajtbord and colleagues studied the recovery of erectile function after rp in two age groups (≤ 60 years old and those older than 60). they found that older men were more likely to experience a notable decrease in sexual outcomes, specifically discomfort (26). in another study, alemozaffar et al. also showed a correlation between increasing age and a lower chance of erectile function despite controlling for baseline performance (27). tilki et al. reported the one-year sexual function after rp in patients aged less than 45 years, between 45-65 years, and over 65 years. they found that 75.6%, 58.6%, and 45.3% of patients had a potent sexual function, respectively (28). however, the better recovery of erectile function in our study might result from the differences in community settings and specialists. indeed, the restoration of continence should be viewed as a process. although information on early continence is rare, it has been observed that most men regain continence three months post-rp. furthermore, the recovery rate increases to approximately 90% after one year and continues improving (29, 30). a recent report by theissen et al. investigated the factors impacting early continence in post-radical prostatectomy. the authors revealed reduced urine loss in younger patients or those with organ-confined tumors and those in whom the bilateral nerve-sparing technique was successfully used in rp. in the current study, younger individuals had statistically significantly better continence rates. our findings were similar to those of other studies in the literature (31, 32). study limitations our research had some limitations. first, as a retrospective study with a small sample size, especially in the young age group (less than 55 years), it inherits some inevitable confounders related to these studies, which could cause gaps in clinical information. second, due to limitations in the data archive, factors such as detailed treatments and multimodality treatments were not evaluated. we also could have benefited from a larger group of younger patients in our study to strengthen our results. as a result, more high-quality studies with larger sample sizes are required to validate our findings further. conclusions our study showed survival rates were similar in younger men (≤ 55 years) and their older counterparts. however, older patients who underwent rp had more advanced disease, worse bcr-free survival, and worse continence rate. for that, in localized pca patients under 55 years, radical prostatectomy is an excellent treatment option with excellent long-term survival results. given the modest number of patients under 55, extensive cohort studies with long-term post-procedural follow-up are necessary to validate this observation. declarations ethical approval: registry and the registration no. of the study/trial: not applicable. all patient’s parents or legal guardians provided written informed consent before enrolment. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the authors declare no conflict of interest. funding: none. authors' contributions: sz and am: designed the study and were involved in the record collection. fa and ma: wrote the manuscript. sz and aa: edited the manuscript, and provided guidance, and formal analysis. aa: conceptualized the study, designed the study, edited the manuscript, provided guidance, and approved the final version of the manuscript. acknowledgments: the authors would like to thank shiraz university of medical sciences, shiraz, iran, and also the centre for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. archivio italiano di urologia e andrologia 2025; 96(1):12658 s. zeighami, a. ariafar, a. makarem, et al. 6 references 1. milonas d, venclovas z, gudinaviciene i, et al. long-term oncological outcomes for young men undergoing radical prostatectomy for localized prostate cancer. biomed res int 2017; 2017:9858923. 2. hussein s, satturwar s, van der kwast t. young-age prostate cancer. j clin pathol. 2015; 68:511. 3. soos g, 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radical prostatectomy in high-risk prostate cancer. asian j androl. 2011; 13:719-23. 15. dantanarayana nd, hossack t, cozzi p, et al. men under the age of 55 years with screen detected prostate cancer do not have less significant disease compared to older men in a population of patients in australia. bmc urol. 2015; 15:124. 16. freedland sj, presti jc, jr., kane cj, et al. do younger men have better biochemical outcomes after radical prostatectomy? urology. 2004; 63:518-22. 17. zheng y, lin sx, wu s, et al. clinicopathological characteristics of localized prostate cancer in younger men aged ≤ 50 years treated with radical prostatectomy in the psa era: a systematic review and meta-analysis. cancer med. 2020; 9:6473-84. 18. lepor h. selecting candidates for radical prostatectomy. rev urol. 2000; 2:182-9. 19. salinas ca, tsodikov a, ishak-howard m, cooney ka. prostate cancer in young men: an important clinical entity. nat rev urol. 2014; 11:317-23. 20. song p, peng z, shu m, et al. reduced survival of young patients under 55 years with metastatic prostate cancer: a population-based study. j cancer. 2021; 12:4985-92. 21. lu y, huang hh, lau wko. survival outcomes of asian younger men (< 55 years) undergoing radical prostatectomy: a review of prostate cancer database in a tertiary hospital in singapore. int urol nephrol. 2020; 52:1885-91. 22. carter bs, beaty th, steinberg gd, et al. mendelian inheritance of familial prostate cancer. proc natl acad sci usa. 1992; 89:3367-71. 23. lange em, salinas ca, zuhlke ka, et al. early onset prostate cancer has a significant genetic component. prostate. 2012; 72:147-56. 24. milonas d, venclovas z, jievaltas m. age and aggressiveness of prostate cancer: analysis of clinical and pathological characteristics after radical prostatectomy for men with localized prostate cancer. cent european j urol. 2019; 72:240-6. 25. ji g, huang c, song g, et al. are the pathological characteristics of prostate cancer more aggressive or more indolent depending upon the patient age? biomed res int. 2017; 2017:1438027. 26. brajtbord js, punnen s, cowan je, et al. age and baseline quality of life at radical prostatectomy--who has the most to lose? j urol. 2014; 192:396-401. 27. alemozaffar m, regan mm, cooperberg mr, et al. prediction of erectile function following treatment for prostate cancer. jama. 2011; 306:1205-14. 28. tilki d, maurer v, pompe rs, et al. tumor characteristics, oncological and functional outcomes after radical prostatectomy in very young men ≤ 45 years of age. world j urol. 2020; 38:95-101. 29. kuehhas fe, naegele r, eckersberger e, et al. urinary continence after radical prostatectomy: the patient perspective. can j urol. 2011; 18:5811-8. 30. zorn kc, wille ma, thong ae, et al. continued improvement of perioperative, pathological and continence outcomes during 700 robot-assisted radical prostatectomies. can j urol. 2009; 16:4742-9. 31. theissen l, preisser f, wenzel m, et al. very early continence after radical prostatectomy and its influencing factors. front surg. 2019; 6:60. 32. cano garcia c, wenzel m, humke c, et al. impact of age on long-term urinary continence after robotic-assisted radical prostatectomy. medicina (kaunas). 2023; 59:1153. correspondence shahryar zeighami zeyghamishahryar@yahoo.com ali ariafar ariafar76@gmail.com alireza makarem alirezamakarem2001@gmail.com mohammadreza askarpour askarvip2@gmail.com department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran faisal ahmed (corresponding author) fmaaa2006@yahoo.com department of urology, school of medicine, ibb university of medical sciences, ibb, yemen stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12130 1 original paper introduction renal cell cancer (rcc) incidence is rising in western countries and accounts for approximately 3% of adult cancers (1). during the last two decades, nephron-sparing surgery (nss) has become the standard for managing localized renal tumors, achieving excellent oncological outcomes and functional preservation (2). long-term oncological results of opn in masses smaller than 4 cm have been well-defined, and it has been reported that similar results are obtained with radical nephrectomy (rn) in local recurrence, disease free survival (dfs), and metastasis-free survival (3, 4). the purpose of pn is to protect the maximum kidney tissue without compromising oncological principles, thereby reducing kidney failure and related cardiac problems that may develop at various levels and extending the os times compared to rn (5). with the increase in the diagnosis of incidental masses, interest in nss has increased. in the national comprehensive cancer network (nccn) and eau guidelines, pn is recommended to treat early-stage renal tumors under any technically feasible condition (6). we presented our experience of single-center opn, including long-term functional and oncological outcomes, in describing the complications and rates that developed during and after surgery. materials and methods patient selection a retrospective analysis of the prospective opn database approved by our institutional review board was performed in may 2020. all consecutive patients undergoing surgery between april 2002 and february 2020 were selected. five surgeons experienced in opn performed the surgeries. due to limited access to the previous hospital patient record system, patients who underwent open pn between 1996 and 2001 were excluded. overall, 182 patients were included in this study. variables preoperative demographic and clinical data of the patients included age, gender, race, body mass index (bmi), age-adjusted charlson comorbidity index (acci), american society of anesthesiologists (asa) score, history of objective: to report long-term functional and oncological outcomes of opn methods: we enrolled 182 patients who underwent consecutive opn with a diagnosis of kidney tumor in our clinic between april 2002 and february 2020 and were selected from our prospective opn database. preoperative demographic and clinical characteristics, intraoperative and pathological results, and patients' postoperative functional and oncological follow-up data were retrospectively analyzed. overall survival (os) and disease-free survival (dfs) were evaluated using kaplan-meier survival analysis. the time-dependent variation between preoperative and postoperative functional results was statistically analyzed and presented in a graph. results and limitations: the mean age was 54.4 ± 10.8 yr, and the median age-adjusted charlson comorbidity index (acci) was 1 (interquartile range [iqr] 0-1). the mean tumor size was 3.1 ± 1.2 cm, and the median renal score was 6 (iqr 5-8). the most common malign histopathological subtype was clear cell carcinoma with 76.6%, and five cases (3.4%) had positive surgical margins (psms). the most common surgical techniques were the retroperitoneal approach (98.9%) and cold ischemia (88.5%). estimated glomerular filtration rate (egfr) preservation was 92% (80.8-99.3, iqr), which translates to 32% chronic kidney disease (ckd) upstaging. acute kidney injury (aki) was detected in 27 (14.8%) patients according to rifle criteria. the intraoperative complication rate was 5.5%, and the postoperative overall complication rate (clavien-dindo 1-5) was 30.2%. major complications (clavien-dindo 3-5) were observed in 13 (7.1%) patients. the median oncological follow-up was 42 mo (21.384.6, iqr), and the 5and 10-yr os were 90.1% and 78.6%, 5 and 10-yr dfs were 99.4% and 92.1%, respectively. no local recurrence was observed in 5 (3.4%) patients with psms; only one had distant metastasis in the 8th postoperative month. the retrospective design, the small number of patients who underwent pn based on mandatory indication, and one type of surgical approach may limit the generalizability of our findings. conclusions: this study confirms excellent long-term oncologic and functional outcomes after opn in a cohort of patients selected from a single institution. in light of the information provided by the literature and our study, our recommendation is to push the limits of pn under every technically feasible condition in the treatment of kidney tumors to protect the kidney reserve and achieve near-perfect oncological results. key words: kidney tumor; open partial nephrectomy; functional outcomes; oncological outcomes. submitted 25 november 2023; accepted 30 november 2023 oncological and functional outcomes of patients who underwent open partial nephrectomy for kidney tumor efe bosnali 1, enes abdullah baynal 2, naci burak cinar 2, enes malik akdas 2, engin telli 2, büsra yaprak bayrak 3, kerem teke 2, hasan yilmaz 2, ozdal dillioglugil 2, onder kara 2 1 university of health sciences, derince training and research hospital, department of urology, kocaeli, turkey; 2 kocaeli university, school of medicine, department of urology, kocaeli, turkey; 3 kocaeli university, school of medicine, department of pathology, kocaeli, turkey. doi: 10.4081/aiua.2023.12130 summary archivio italiano di urologia e andrologia 2023; 95(4):12130 e. bosnali, e. abdullah baynal, n. burak cinar, et al. 2 diabetes and hypertension, previous abdominal surgery and smoking status, presence of a solitary kidney, and preoperative egfr. tumor complexity was graded as low (renal score 4-6, padua score 6-7), moderate (renal score 6-9, padua score 8-9), or high (renal score 10-12, padua score 10-14). clinical uicc-tnm stage and nephrometry scores could not be determined in 51 patients whose preoperative cross-sectional imaging could not be accessed. intraoperative variables included surgical approach and technique (ureteral stenting), operative time, estimated blood loss (ebl), ischemia type, cold ischemia time (cit), warm ischemia time (wit), use of a hemostatic agent, transfusion rate, and intraoperative complications. postoperative variables included length of hospital stay (los), 30-day readmission rate, and types of postoperative complications and their incidence. postoperative complications were graded using the clavien-dindo classification, with grade 3a or higher considered major complications. patients with acute kidney ınjury (aki) were determined based on the rifle criteria for creatinine and egfr values in the first week postoperatively. urine leakage was defined as a creatinine value ≥ 2 mg /dl in the drain fluid in addition to postoperative follow-up for at least 4 days or a significant collection around the kidney in postoperative radiological examinations. tumor histology was performed according to the 2004 world health organization criteria, and grade classification followed the fuhrman/international society of urological pathology (isup) scheme. the 2017 yr union for international cancer control (uicc)-tnm classification system was used for pathological staging. psm was defined as an extension of tumor to the inked surface of the resected specimen on final pathology. follow up renal function assessment was based on serum egfr measurements postoperative days 1 and 3 at regular intervals of 1, 3, 6, and 12 months. the time difference between the preoperative and final egfr dates of the patients constituted the functional follow-up period. egfr was estimated using the chronic kidney disease epidemiology collaboration (ckd-epi) equation and ckd staging were assigned according to the egfr value based on the nkf-kdoqi guideline. egfr preservation was calculated as the proportion of postoperative egfr was measured at the last follow-up to preoperative egfr, and rates of ckd upstaging were evaluated (upstaging from class i-ii to iii-v, class iii to iv-v, or class iv to v). oncological outcomes were evaluated through routine postoperative follow-up cross-sectional imaging studies, e.g., ct of the chest, abdominal ct and/or mri. imaging was carried out at 6, 12 months, then yearly and when clinically indicated. postoperative cross-sectional imaging and medical records of the patients were examined, and the presence of local recurrence or distant metastasis and the causes of death were included in oncological followup data. overall survival (os) was defined as the time between the date of surgery and the date of death (all causes). disease-free survival (dfs) was defined as the period between the date of surgery and the date of local recurrence or distant metastasis diagnosed by cross-sectional imaging in postoperative follow-up. local recurrence was defined as detecting a new enhancing lesion in the surgical bed or the same renal space. distant metastasis was defined as disease recurrence in the contralateral kidney or other body organs. surgical technique we used the previously described standard opn surgical method in all patients. the most common surgical technique in the study was the retroperitoneal flank approach (98.9%) and cold ischemia (88.5%). depending on the tumor's location, a subcostal incision was made parallel to the 11th or 12th rib. the kidney was mobilized entirely with the surrounding gerota fascia, and the renal pedicle was exposed. in order to prevent ischemic kidney damage and reduce intracellular edema, 16 grams of 20% mannitol solution was given intravenously to all patients who underwent cold ischemia a few minutes before arterial clamping. then, by placing a bulldog clamp on the renal artery, renal hypothermia was induced by intracorporeal ice melting for 15 minutes. three different (cold, hot, zero) ischemia types were preferred. while mannitol and ice slush application were not applied in the warm ischemia group, a clamp was not placed on the renal artery in the zero ischemia group. tumor tissue was excised in a wedge shape with a scalpel and cold scissors, leaving approximately 3-5 mm of normal renal parenchyma around it, preserving the overlying fat tissue. 3/0 absorbable polyglactin sutures were used to close the defect that may develop in the collecting system after excision and to provide hemostasis due to bleeding. after achieving hemostasis, the bulldog clamp was removed, and the duration of cold or warm ischemia was recorded. the preserved fatty tissue was wrapped and sutured (with absorbable suture material) in oxidized regenerated cellulose (surgicel) or polyglactin (vicryl) mesh and placed into the bed of the defect. the fatty tissue was wrapped in order to provide the appropriate shape for the defect after excision and to help hemostasis with the effect of foreign materials around it. blunt-tipped non-traumatic 1/0 absorbable polyglactin sutures were passed through the renal parenchyma along the edges of the defect and tied separately, and the wrapped fat tissue was fixed to the resection bed, and renorrhaphy was completed. statistical analysis the normal distribution of variables was evaluated with the kolmogorov-smirnov test. mean ± standard deviation (sd) was used for parametric variables, and median and interquartile range (iqr) values were used for nonparametric variables. the median egfr values in the preoperative and postoperative follow-ups were compared in pairs using the nonparametric friedman test. the time-dependent change of postoperative egfr was shown with a box and whisker plot graph. os and dfs analyses for 5 and 10 years were performed using the kaplan-meier method. all statistical analyses were performed using spss v24 software (ibm spss statistics, armonk, ny: ibm corporation, usa). p < 0.05 was considered statistically significant. archivio italiano di urologia e andrologia 2023; 95(4):12130 3 long-term oncological and functional outcomes of open partial nephrectomy results patients’ characteristics in total, 182 opns were performed during this initial time frame for our opn experience. the mean age at surgery was 54.4 ± 10.8 yr, and 56.6% of patients were women. six (3.3%) patients underwent pn for a solitary kidney tumor, and 4 (2.1%) patients presented with bilateral renal neoplasms requiring pn. median preoperative egfr was 96 ml/min/1.73 m2 ckdepi (7.6% of patients had preoperative ckd stage ≥ 3). the demographic and preoperative data are presented in table 1. the mean tumor size on preoperative imaging (ct or mri) was 3.1±1.2 cm, and 82.4% of neoplasms were classified as clinical stage t1a. median renal and padua scores were 6 (iqr 5-8) and 7 (iqr 7-9), respectively. according to the renal and padua nephrometry scoring systems, 38.1% and 49.6% of tumors were classified as moderately to highly complex, respectively. seven (5.3%) patients had completely endophytic tumors. the preoperative characteristics of the tumors are presented in table 2 and table 3. intraoperative outcomes the retroperitoneal approach (98.9%) and cold ischemia (88.5%) were the most common surgical techniques. six cases had zero ischemia; the mean wit for the remaining patients was 26.1 ± 7.7 minutes. the median operative time was 240 min (iqr 180-240), and the median ebl was 400 ml (iqr 300-600). the intraoperative complication rate was 5.5%, and renal vein injury was the most common (1.7%). the intraoperative transfusion rate was 28.6%. the intraoperative data are summarized in table 4. postoperative and pathological outcomes the median postoperative los was 5 days (iqr 4-7). the postoperative overall complication rate was 30.2%, and pulmonary complications were the most common (9.3%). major complications (clavien-dindo grade ≥ 3) were observed in 13 (7.1%) patients (table 5). urinary leakage occurred in 3.2% of cases and pseudo-aneurysm in 1.1% of the patients. according to the rifle criteria, aki was detected in 27 (14.8%) patients. no patients required postoperative hemodialysis during follow-up. postoperative complications are detailed in table 6. final histopathologic analysis revealed clear cell rcc in 81% of cases. most tumors (78%) were classified as pt1a and 16.2% were of high fuhrman/isup grade (3 or 4). table 1. patient’s demographics and preoperative data. variables total opn (n = 182) age years, mean (± sd) 54.4 (± 10.8) male, n (%) 79 (43.4) white race, n (%) 182 (100) bmi, mean (± sd) 28.3 (± 5.3) cci, med (iqr) 1 (0-1) asa, med (iqr) 2 (2-2) diabetes, n (%) 51 (28) hypertension, n (%) no 92 (50.5) yes 90 (49.5) controlled 81 (44.5) non controlled 9 (5) smoker, n (%) no 115 (63.2) yes 55 (30.2) former 12 (6.6) prior abdominal surgery, n (%) 48 (26.4) pre-op hb g/dl, mean (± sd) 13.7 (± 1.5) solitary kidney, n (%) 6 (3.3) pre-op egfr, med (iqr) 96 (82.4-105.9) pre-op ckd stages, n (%) i. (egfr ≥ 90 ml/min/1.73 m2) 113 (62.1) ii. (egfr 60-89 ml/min/1.73 m2) 53(29.1) iiia. (egfr 45-59 ml/min/1.73 m2) 7 (3.8) iiib. (egfr 30-44 ml/min/1.73 m2) 5 (2.7) iv. (egfr 15-29 ml/min/1.73 m2) 2 (1.1) asa, american society of anesthesiologists; bmi, body mass index; cci, charlson comorbidity index; ckd, chronic kidney disease; egfr, estimated glomerular filtration rate; hb, hemoglobin; iqr, interquartile range; opn, open partial nephrectomy; sd, standard deviation. table 2. preoperative tumor characteristics and r.e.n.a.l. score details. tumor size, cm, mean (±sd) 3.1 (± 1.2) side, right, n (%) 110 (60.4) clinical uicc-tnm stage, n (%) t1a 108 (82.4) t1b 18 (13.7) t2 0 t3a 5 (3.8) cystic lesion, n (%) 46 (33.1) hilar location, n (%) 4 (3) total number of arteries, n (%) 1 155 (88.1) > 1 21 (11.9) n/a, n 6 csa, cm2, med (iqr) 11 (6.7–19.7) r.e.n.a.l score, med (iqr) 6 (5–8) r.e.n.a.l complexity, n (%) simple (4-6) 81 (61.8) intermediate (7-9) 48 (36.6) complex (10-12) 2 (1.5) ®adius (max diameter in cm), n (%) ≤ 4 146 (81.6) > 4 but < 7 31 (17.3) ≥ 7 2 (1.1) (e)xophytic/exophytic properties, n (%) ≥ 50% 67 (51.2) < 50% 57 (43.5) entirely endophytic 7 (5.3) (n)earness of the tumor to the collecting system or renal sinus (mm), n (%) ≥ 7 59 (45) > 4 but < 7 41 (31.3) ≤ 4 31 (23.7) (l)ocation relative to the polar lines (points), n (%) 1 71 (54.2) 2 35 (26.7) 3 25 (19.1) csa, contact surface area; iqr, interquartile range; sd, standard deviation. archivio italiano di urologia e andrologia 2023; 95(4):12130 e. bosnali, e. abdullah baynal, n. burak cinar, et al. 4 five (3.4%) patients had psms. among the benign pathologies, oncocytoma was reported most frequently (70.6%). the pathological data of the patients are presented in table 7. oncological and functional outcomes the median oncological follow-up of the patients was 42 (iqr 21.3-84.6) mo. local recurrence was observed in three (1.6%) patients at the postoperative 63rd, 73rd and 89th mo. respectively. distant metastasis developed in 4 (2.2%) patients at 8th, 63rd, 64th, and 96th mo. after surgery secondary to rcc. seventeen patients died (9.3%), including one from renal cancer (0.5%). no local recurrence was observed in 5 (3.4%) patients with psms. only one (0.5%) patient with psms had distant metastasis in the 8th postoperative mo. the 5-and 10-yr os were determined as 90.1% and 78.6%, 5 and 10-yr dfs rates with the kaplan-meier method, respectively, were 99.4% and 92.1% (figure 1). oncological data are summarized in table 8. table 3. preoperative tumor characteristics and padua score details. padua score, med (iqr) 7 (7–9) padua complexity, n (%) simple (6-7) 66 (50.4) intermediate (8-9) 42 (32.1) complex (10-14) 23 (17.5) tumor size (max diameter in cm), n (%) ≤ 4 146 (81.6) > 4 but < 7 31 (17.3) ≥ 7 2 (1.1) exophytic rate, n (%) ≥ 50% 67 (51.2) < 50% 57 (43.5) entirely endophytic 7 (5.3) tumor relationship with renal sinus, n (%) absent relationship 114 (87) with renal sinus location 17 (13) tumor relationship with urinary collecting system, n (%) absent relationship 76 (58) dislocated/infiltrated 55 (42) renal rim location, n (%) not involved 101 (77.1) involved 30 (22.9) location relative to the sinus lines (points), n (%) 1 79 (60.3) 2 52 (39.7) iqr, interquartile range; padua, (p)reoperative (a)spects and (d)imensions used for an (a)natomical. table 4. intraoperative data of the patients. variables total opn (n = 182) surgical approach, n (%) retroperitoneal 180 (98.9) transperitoneal 2 (1.1) operation time, min, med (iqr) 240 (180-240) double j stent, n (%) routinely 95 (52.2) as required (intra-operative) 14 (7.7) no 73 (40.1) ebl, ml., med (iqr) 400 (300-600) management of renal pedicle, n (%) off clamp 6 (3.3) global clamp 176 (96.7) technique of ischemia, n (%) warm 15 (8.2) cold 161 (88.5) zero 6 (3.3) ischemia time, min, mean (±sd) 26.1 (± 7.7) warm 19.4 (± 3.5) cold 32.1 (± 4.9) use of haemostatic agents, n (%) 17 (9.3) tissel 3 (1.6) floseal 12 (6.6) arista 2 (1.1) intraoperative complications, n (%) 10 (5.5) 1 cm size injury to the proximal ureter 1 (0.5) serosal injury to the colon 1 (0.5) injury to the renal vein 3 (1.6) pleural injury 1 (0.5) laceration of the spleen 1 (0.5) vascular injury in the vena cava 2 (1.1) injury of the aberrant artery supplying the lower pole 1 (0.5) intraoperative transfusion, n (%) 52 (28.6) es units, med (iqr) 1 (1-2) ebl, estimated blood loss; es, erythrocyte suspension; iqr, interquartile range; sd, standard deviation; opn, open partial nephrectomy. table 5. postoperative data of the patients. variables total opn (n = 182) length of stay (los), days, med (iqr) 5 (4-7) postoperative transfusion, n (%) 14 (7.7) es units, med (iqr) 2 (1-2.2) overall postop complications, n (%) 55 (30.2) major (clavien-dindo 3-5) postop complications 13 (7.1) minor (clavien-dindo 1-2) postop complications 41 (23.1) readmission for urologic reasons, n (%) 11 (6) < 30 days 7 (3.8) ≥ 30 days 4 (2.2) es, erythrocyte suspension; iqr, interquartile range; opn, open partial nephrectomy. table 6. postoperative complication type of the patients. postoperative complication type total opn (n = 182) cardiac complications, n (%) 3 (1.6) 1 hypertension 2 (1.1) 2 cyanosis 1 (0.5) pulmonary complications, n (%) 17 (9.3) 1 atelectasis (need for antibiotics) 14 (7.6) 2 pleural effusion 3 (1.6) genitourinary complications, n (%) 16 (8.7) 1 urine leakage 14 (7.6) 2 perirenal/psoas abscess 2 (1.1) bleeding complications, n (%) 16 (8.7) 1 postoperative transfusion 14 (7.6) 2 need for angioembolization 2 (1.1) other infections (use of antibiotics), n (%) 4 (2.2) ileus/ small bowel obstruction, n (%) 2 (1.1) hernia, n (%) 4 (2.2) acute kidney injury (rifle criteria), n (%) 27 (14.8) r risk (increased cre x 1,5 or egfr decrease > %25) 23 (12.6) i injury (increased cre x 2 or egfr decrease > %50) 4 (2.2) f failure (increased cre x 3 or egfr decrease ≥ %75) 0 l loss (complete loss of renal function ≥ 4 weeks) 0 e end stage renal disease 0 archivio italiano di urologia e andrologia 2023; 95(4):12130 5 long-term oncological and functional outcomes of open partial nephrectomy lesions. on the other hand, rn was chosen for high-complexity preoperative cases. it is known that long ischemia times in pn harm kidney function. it was well reported that irrespective of the surgical method, hot and cold ischemia should not take longer than 20 and 30-35 minutes, respectively (10). thus, cold ischemia was advised to be performed in the literature for cases requiring longer clamping times. in order to benefit from the advantages of cold ischemia, researchers from cleveland clinic defined icing techniques that can be utilized during laparoscopic pn (lpn) and robotic-assisted pn (rapn) for complex cases (11). yossepowitch et al. (12) demonstrate that while cit correlated with egfr decrease immediately after surgery, this correlation was no longer present 1 year after the procedure, highlighting the impact of cold ischemia on preserving long-term kidney function in a study that included 592 cases of cold pn series with a median cit of 35 minutes. in our study, cold and hot ischemia was performed in 88.5% and 8.2% of our patients, respectively, whereas zero ischemia was performed in 3.3%. the mean cold and hot ischemia times were 32.1 and 19.4 minutes, respectively, within the previously suggested range; therefore, we envision comparable and normal long-term kidney function for both cohorts. a 2020 meta-analysis study, comparing opn and lpn from 26 different studies with 8095 cases, did not show any differences in intraoperative complication rate and table 8. oncological outcomes and follow-up data of the patients. follow-up times (oncological), mo., med (iqr) 42 (21.3-84.6) local recurrence, n (%) 3 (1.6) time to local recurrence, mo., med (iqr) 73 (63-89) distant metastasis, n (%) 4 (2.2) time to distant metastasis, mo., med (iqr) 63.5 (21.7-88) death, n (%) 5 (3.5) rcc-related death, n (%) 1 (0.5) table 9. functional outcomes and follow-up data of the patients. follow-up times (functional), mo., med (iqr) 32.8 (12.3-71) preop egfr, med (iqr) 96 (82.4-105.9) postop 1st day egfr, med (iqr) 88.1 (70.3-100.3) postop 1st day % egfr preservation, med (iqr) 94.2 (81.9-100) postop 3rd day egfr, med (iqr) 91.4 (73.8-101.4) postop 3rd day % egfr preservation, med (iqr) 95 (87.4-100.9) postop 1st mo. egfr, med (iqr) 91.1 (77.3-102) postop 1st mo. % egfr preservation, med (iqr) 95.2 (86.3-100.6) postop 3rd mo. egfr, med (iqr) 87.2 (70.4-100.2) postop 3rd mo. % egfr preservation, med (iqr) 92.6 (82-99.2) postop 6th mo. egfr, med (iqr) 87 (70.4-97) postop 6th mo. % egfr preservation, med (iqr) 92.2 (83.2-99.2) postop 1st yr. egfr, med (iqr) 87.3 (70.9-99.8) postop 1st yr. % egfr preservation, med (iqr) 92.4 (82.2-99.3) latest egfr, med (iqr) 86.8 (70.4-99.1) latest follow up % egfr preservation (iqr) 92.9 (80.8-99.3) latest ckd upstaging, n (%) 58 (32.2) table 7. pathological data of the patients. variables total opn (n = 182) malignant disease, n (%) 145 (81) benign disease, n (%) 34 (19) n/a, n 3 pathological uicc-tnm stage, n (%) t1a 120 ( 83.3) t1b 21 (14.5) t2a 0 t3a 3 (2.1) n/a, n 1 histological subtype, n (%) clear cell 111 (76.6) papillary 25 (17.2) chromophobe 7 (4.8) malignant mezenchymal 1 (0.7) tubulocystic carcinoma 1 (0.7) benign disease, n (%) 34 (19) histological subtype, n (%) oncocytoma 24 (70.6) angiomyolipoma 5 (14.7) other benign types 5 (14.7) positive surgical margin, n (%) 5 (3.4) fuhrman/ isup grade, n (%) low fg (1-2) 113 (83.7) high fg (3-4) 24 (16.2) n/a, n 10 fg, fuhrman grade; isup, international society of urological pathology; opn, open partial nephrectomy. the median egfr preservation after opn was 92.9% (iqr 80.8-99.3%), which translates to a ckd upstaging rate of 32.2%. the median postoperative egfr was 86.8 ml/min/1.73 m2; data for all patients were available with a median interval of 32.8 mo (iqr 12.3-71) after surgery (table 9). time-dependent change between egfr values in preoperative and postoperative follow-up was statistically analyzed using the friedman test and demonstrated using a box and whisker plot graph (figure 2). discussion with an increased diagnosis of incidental masses, the interest in nss has increased and as a result, pn has been suggested to be performed according to the nccn and eau guidelines, irrespective of the surgery method, for the treatment of early-stage kidney tumors. in order to obtain good oncological and functional results in pn, all uro-oncologists are required to know the indications, technical details, and complications of pn as well as its management by using the advantages of minimally invasive techniques. currently, at least 50% of new rccs are diagnosed incidentally and smaller than 4 cm. this is further supported by previous studies focused on high number opn series, which show mean tumor sizes of 2.7-3.4 cm (7, 8). despite this regression, concerning previous years, the more extensive lesions, centrally located and related to the collecting system, were chosen to perform opn (9). in our study, the mean preoperative tumor size was 3,1 ± 1.2 cm) and renal and padua scores showed that over half of the tumors are low-complexity archivio italiano di urologia e andrologia 2023; 95(4):12130 e. bosnali, e. abdullah baynal, n. burak cinar, et al. 6 operation time between these two methods. however, it was reported that lpn decreased the ebl, los, and blood transfusion requirements (13). in another study comparing opn, lpn, and rapn performed for tumors less than 4 cm, it was found that opn led to increased surgery time (199 ± 56 min) and bleeding (168 ± 266 ml) compared to rapn (174 ± 64 min, 84 ± 165 ml) (14). in our series, the median operative time of 240 min and bleeding of 400 ml is greater than in previous reports. the routine ureteral stenting (52.2%), 15 minutes application of intracorporal ice slush treatment (88.5%), and additional application of lipocorticoplasty could have contributed to the elongation of the operation time. the rate of general complications in various pn series varies between 4.1-38.6% in previous studies (4, 7, 15), with urine leakage and bleeding as the most frequent postoperative complications (7, 8). we found a general (major and minor) complication rate of 30.2 %, with pulmonary complications (9.2%), bleeding (8.7%), and urine leakage (7.6%) being the most common. chang et al. (16) reported a major complication rate of 7.3% in 122 patients that resemble those in our study in terms of tumor characteristics and demographics. thus, our postoperative major complication rate of 7.1% is in accordance with previous studies. an intraoperative complication rate of 3-5% was detected in the opn series with a figure 1. kaplan-meier curves of the survival of patients undergoing open partial nephrectomy. (a) overall survival. (b) disease-free survival. archivio italiano di urologia e andrologia 2023; 95(4):12130 7 long-term oncological and functional outcomes of open partial nephrectomy high number of patients, with pleural injuries being the major case (17, 18). in our study, the rate of intraoperative complications was 5.5%, in accordance with the literature. aki is observed in approximately 20% of all pn, negatively affecting long-term kidney function (19). our study defined aki for rifle criteria for up to 3 days post-operation (20). in a recent study, 25% of aki was observed in a cohort of 944 pt1 stage patients operated with three different pn techniques by rifle criteria (21). we found an aki of 14.8% in our study. this lower aki rate could be attributed to good preoperative kidney function and a small number of solitary kidneys in our cohort. time-dependent decrease in renal function has been extensively studied, primarily in bilateral kidneys. kidney function was found to decrease post-pn immediately but reached stable levels 3 weeks to 3 months after surgery upon partial recovery (22). porpiglia et al. (23) followed the kidney function of patients with bilateral kidneys following lpn via scintigraphy. they found a significant recovery of kidney function 3 months post-operation. in our study, when the postoperative egfr was compared with the preoperative egfr in the time-dependent graph, a statistically significant loss of kidney function was found on the postoperative 1st day. the postoperative 3th day, we observed partial recovery of egfr levels followed by stabilization of kidney function after 1 month, which was in accordance with the results obtained by porpiglia et al. ckd is defined as a heterogeneous distortion affecting the structure and function of kidneys. nkf-kdoq1 developed this term in 2002, and the guides demonstrate that these distortions can elevate to life-threatening levels (24). in our cohort, primarily composed of cold ischemia patients, we found 92.9% median preservation of final egfr levels during 32 months of functional follow-up; thus, temporary dialysis was deemed unnecessary. when compared with the literature, we think that the normal preoperative renal function of most patients, the low number of patients with high complexity lesions and solitary kidneys, utmost care on the maximum ischemia time, and experience of open surgery in our clinic have contributed to the low incidence of short-term kidney damage post-pn and improved functional recovery in the long-term. a negative surgical margin is required to be left out following tumor excision according to standard surgical principles. psms can be observed between 1.3-18% in opn cohorts. when pn was carried out in large tumors (> 4 cm) or complex tumors with mandatory indications, a higher rate of psm was observed (23, 25). even if, minimally invasive strategies involving optical magnification and pedicule clamping with ischemia and tumor's cold scission, are advantageous with increased surgical experience, psm was higher in large cohorts than in open surgeries (7). psm rates were found to be 4.9, 8.1 and 8.7% in opn, lpn, and rapn, respectively, in a study including more than 11500 cases with comparable numbers for each pn (26). in minimally invasive techniques, the lack of tactile sensations in determining the extension of the masses to the renal parenchyma at different axis angles and difficulty in determining the plan between the renal parenchyma and the tumor border due to the use of energy devices may cause higher rates of psm compared to open surgery. in our clinic, where all patients were subjected to opn, psm rate was 3.4%. in opn, three-dimensional masses extending into the renal parenchyma at different axis angles can be clearly excised from the kidney and tumor border can be identified by means of tactile senses and use of cold scissors, contributing to the lower detection of psm observed in our clinic. no local recurrence was observed in the close follow-up figure 2. time-dependent change between egfr values in preoperative and postoperative follow-up (box and whisker plot graph). archivio italiano di urologia e andrologia 2023; 95(4):12130 e. bosnali, e. abdullah baynal, n. burak cinar, et al. 8 of 5 (3.4%) patients with psm. a distant metastasis was detected in one (0.5%) at the postoperative 8th mo. psm was previously correlated with increased local recurrence risk and distant metastasis progression (27). in another study with a median follow-up of 62 months, psm was reported as an independent predictor of os, rfs, and dfs (28). studies indicate that psm does not influence survival; however, shorter follow-up and smaller cohort sizes may not had the statistical power to determine psm's effect (29, 30). the objective of pn is to preserve the kidney tissue while adhering to oncological principles maximally, in order to decrease the prevalence of different levels of kidney failure and related cardiac problems, and ultimately to increase longevity compared to rn (5). local recurrence rates have been reported in the 1.4-3.3% range in large opn cohorts with at least 5 yrs of follow-up (3, 31). lane et al. (32) reported a 10-yr minimum os of 72 and 78% in 299 patients with opn and lpn, respectively. marszalek et al. (33) reported the oncological outcomes of 100 age-, sex-, and tumor size-matched patients treated with opn and lpn. in this study, the 5-yr os were 85% and 96%, and 5-yr dfs were 94% and 96.3%, respectively. in our study, local recurrence was observed in 3 (1.6%) patients and a distant metastasis was observed in 4 (2.1%) patients during a median of 42 (21.3-84.6, iqr) months of oncological follow-up. rcc-related death occurred in one (0.5%) patient with distant metastasis. 5 and 10-yr dfs were 99.4 and 99.2%. 5 and 10-yr os were 90.1 and 78.6%, respectively. most of the tumors belonging to the pt1a stage (83.3%) and with low fuhrman/isup grade (83.7%) combined with low psm rates obtained with our open surgical technique play critical roles in this high long-term oncological survival. our results are consistent with previous studies, and we anticipate that our study will add to the successful oncological outcome of opn studies. the limitations of our study are retrospective design, a small number of patients subjected to pn upon mandatory indications, and inclusion of a single type of surgical method. in addition, more recent studies demonstrate that the amount of remaining kidney tissue post-operation is the most significant indicator of long-term kidney function. the absence of this parameter is the most significant limitation of our work and will be our field of study in the future. conclusions this study confirms excellent long-term oncologic and functional outcomes after opn in a cohort of patients selected from a single institution. we contributed to the literature by reporting that our patients who underwent open pn had high oncologic survival, and their kidney functions were well preserved in the long-term follow-up. references 1. ferlay j, colombet m, soerjomataram i, et al. cancer incidence and mortality patterns in europe: estimates for 40 countries and 25 major cancers in 2018. eur j cancer. 2018; 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10:2261. 14. tachibana h, kondo t, yoshida k, et al. lower incidence of postoperative acute kidney injury in robot-assisted partial nephrectomy than in open partial nephrectomy: a propensity score-matched study. j endourol. 2020; 2020; 34:754-762 15. lerner se, hawkins ca, blute ml, et al. disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. j urol. 1996; 155:1868-73. 16. chang kd, abdel raheem a, kim kh, et al. functional and oncological outcomes of open, laparoscopic and robot-assisted partial nephrectomy: a multicentre comparative matched-pair analyses with a median of 5 years’ follow-up. bju int. 2018; 122:618-26. 17. minervini a, mari a, borghesi m, et al. the occurrence of intraoperative complications during partial nephrectomy and their impact on postoperative outcome: results from the record1 project. minerva urol nefrol 2018; 71:47-54 18. caraballo er, palacios da, suk-ouichai c, et al. open partial nephrectomy when a non-flank approach is required: indications and outcomes. world j urol. 2019; 37:515-22. 19. capitanio u, bensalah k, bex a, et al. epidemiology of renal cell carcinoma. european urology. 2019; 75:74-84. archivio italiano di urologia e andrologia 2023; 95(4):12130 9 long-term oncological and functional outcomes of open partial nephrectomy 20. bellomo r, ronco c, kellum ja, et al. acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (adqi) group. crit care. 2004; 8:r204. 21. bravi ca, mari a, larcher a, et al. toward individualized approaches to partial nephrectomy: assessing the correlation between ischemia time and patient health status (record2 project). eur urol oncol. 2021; 4:645-650. 22. porpiglia f, fiori c, bertolo r, et al. the effects of warm ischaemia time on renal function after laparoscopic partial nephrectomy in patients with normal contralateral kidney. world j urol. 2012; 30:257-63. 23. porpiglia f, fiori c, bertolo r, et al. long-term functional evaluation of the treated kidney in a prospective series of patients who underwent laparoscopic partial nephrectomy for small renal tumors. eur urol. 2012; 62:130-5. 24. valente ma, hillege hl, navis g, et al. the chronic kidney disease epidemiology collaboration equation outperforms the modification of diet in renal disease equation for estimating glomerular filtration rate in chronic systolic heart failure. eur j heart fail. 2014; 16:86-94.. 25. peycelon m, hupertan v, comperat e, et al. long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. j urol. 2009; 181:35-41. 26. tabayoyong w, abouassaly r, kiechle je, et al. variation in surgical margin status by surgical approach among patients undergoing partial nephrectomy for small renal masses. j urol. 2015; 194:1548-53. 27. yossepowitch o, thompson rh, leibovich bc, et al. positive surgical margins at partial nephrectomy: predictors and oncological outcomes. j urol. 2008; 179:2158-63. 28. petros fg, metcalfe mj, yu k-j, et al. oncologic outcomes of patients with positive surgical margin after partial nephrectomy: a 25year single institution experience. world j urol. 2018; 36:1093-101. 29. bensalah k, pantuck aj, rioux-leclercq n, et al. positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery. eur urol. 2010; 57:466-73. 30. ani i, finelli a, alibhai sm, et al. prevalence and impact on survival of positive surgical margins in partial nephrectomy for renal cell carcinoma: a population-based study. bju int. 2013; 111:e300-e5. 31. becker f, siemer s, humke u, et al. elective nephron sparing surgery should become standard treatment for small unilateral renal cell carcinoma: long-term survival data of 216 patients. eur urol. 2006; 49:308-13. 32. lane br, campbell sc, gill is. 10-year oncologic outcomes after laparoscopic and open partial nephrectomy. j urol. 2013; 190:44-9. 33. marszalek m, meixl h, polajnar m, et al. laparoscopic and open partial nephrectomy: a matched-pair comparison of 200 patients. eur urol. 2009; 55:1171-8. correspondence efe bosnali, md corresponding author) efebosnali415@gmail.com department of urology, university of health sciences, derince training and research hospital, turkey, 41380 enes abdullah baynal, md abdullahbaynal@gmail.com naci burak çınar, md n.burak.cinar@gmail.com enes malik akdas, md enesmalikakdas@gmail.com engin telli, md engintelli@gmail.com kerem teke, md drtekekerem@gmail.com hasan yılmaz, md hasanyilmazm.d@gmail.com özdal dillioğlugil, md odillioglugil@gmail.com önder kara, md onerkara@yahoo.com kocaeli university, school of medicine, department of urology, kocaeli, turkey büşra yaprak bayrak, md busra.yaprakbayrak@kocaeli.edu.tr kocaeli university, school of medicine, department of pathology, kocaeli, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2252 review no conflict of interest declared. introduction alpha adrenergic receptor (or adrenoreceptor) antagonists, also known as alpha-blockers, are a class of pharmacological agents acting as antagonists on various alphaadrenergic receptors. depending on receptor specificity, they bind and inhibit alpha1-receptors, alpha2-receptors, or both (1). alpha-1 adrenergic antagonists bind to type-1 alphaadrenergic receptors, thus inhibiting smooth muscle contraction. several subtypes of postsynaptic alpha1 receptors are present in vascular and nonvascular smooth muscle. alpha 1a receptors are predominantly located in the smooth muscle of the genitourinary tract, where they regulate the tone of the bladder neck and of the smooth muscle fibers within the prostate. alpha 1b receptors are more represented in the vascular smooth muscle, and are involved in the regulation of the vascular tone. receptors belonging to the alpha1d subtype regulate the contraction of the urinary bladder (2). the effects of alphabackground: alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive treatment of ureteral stones. these agents may affect the sexual function, with differences between drugs within the same class, depending on their selectivity for receptor subtypes. the aim of this review was to analyze the effects of alpha-blockers on sexual function. materials and methods: we conducted a systematic review and meta-analysis by searching pubmed, embase and other databases for randomized controlled trials (rcts) reporting sexual adverse effects in patients treated with alpha-blockers. odds ratios for sexual dysfunction were calculated using random effects mantel-haenszel statistics. results: out of 608 records retrieved, 75 eligible rcts were included in the meta-analysis. compared with placebo, alphablockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (luts) associated to benign prostatic hyperplasia (bph) (or: 7.53, 95% ci: 3.77-15.02, z = 5.73, p < 0.00001, i2 = 55%) and in patients with ureteral stones (or: 2.88, 95% ci: 1.50-5.44, z = 3.19, p < 0.001, i2 = 31%). uroselective alpha-blockers showed higher odds of ejaculatory disorders. conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (or: 3.52, 95% ci: 2.18-5.68, 15 series, 1512 participants, z = 5.15, p < 0.00001, i2 = 0%). naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers. effect of alpha-adrenoceptor antagonists on sexual function. a systematic review and meta-analysis rawa bapir 1, 13, kamran hassan bhatti 2, 13, ahmed eliwa 3, 13, herney andrés garcía-perdomo 4, 13, nazim gherabi 5, 13, derek hennessey 6, 13, vittorio magri 7, 13, panagiotis mourmouris 8, 13, adama ouattara 9, 13, gianpaolo perletti 10, 13, joseph philipraj 11, 13, alberto trinchieri 12, 13, noor buchholz 13 1 smart health tower, sulaymaniyah, kurdistan region, iraq; 2 urology department, hmc, hamad medical corporation, qatar; 3 department of urology, zagazig university, zagazig, sharkia, egypt; 4 universidad del valle, cali, colombia; 5 faculty of medicine algiers 1, algiers, algeria; 6 department of urology, mercy university hospital, cork, ireland; 7 asst nord milano, milan, italy; 8 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece; 9 division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 10 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 11 department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india; 12 urology school, university of milan, milan, italy; 13 u-merge ltd. (urology for emerging countries), london-athens-dubai *. authors 1-12 have equally contributed to the paper and share first authorship. *u-merge ltd. (urology for emerging countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. u-merge ltd. is registered with the companies house in london/ uk. www.u-merge.com. doi: 10.4081/aiua.2022.2.252 summary no statistically significant differences in the odds of erectile dysfunction were observed when alpha-blockers were compared to placebo. key words: alpha-blockers; ejaculation; erectile dysfunction; silodosin; tamsulosin; alfuzosin; doxazosin; terazosin. submitted 11 february 2022; accepted 24 march 2022 253archivio italiano di urologia e andrologia 2022; 94, 2 sexual function and alpha-blockers adrenergic blocking agents depend on their selectivity (or non-selectivity) for specific receptor subtypes. nonselective alpha-1-adrenergic antagonists have been used for decades against hypertension. blockade of alpha1b receptors can decrease vascular resistance in peripheral arterioles and increase venous capacitance, ultimately lowering blood pressure (3). at present, alpha1 adrenergic antagonists are no longer recommended as monotherapy, but only as adjunctive treatment of hypertension (4). alpha-1-blockers are used for the treatment of symptoms of urinary obstruction due to benign prostatic hyperplasia because they can relax the smooth muscle fiber in the bladder neck and in the prostate acting on alpha1a receptors. initially, nonselective alpha-1 adrenergic antagonists such as doxazosin, terazosin and alfuzosin were used for the management of bladder neck obstruction (5). selective alpha1a blockers with high affinity for the alpha1a adrenergic receptor, as tamsulosin and silodosin, have been subsequently developed to be specifically used in benign prostatic hyperplasia. selectivity of these agents was aimed at decreasing their effect on blood pressure and at reducing the risk of unwanted effects, such as postural hypotension. alpha1d-adrenoceptor antagonists have also been shown to be effective in alleviating both voiding and storage luts associated with bph. naftopidil is an alpha-1 adrenoceptor antagonist with a distinct selectivity for the alpha1d receptor showing a threefold selectivity for the alpha1d-adrenoceptor compared to the alpha1a-adrenoceptor (6). it is used for bph management in japan because of its fewer side effects, but there is limited evidence of its effectiveness in other populations (7). alpha-1-adrenergic antagonists are also used to facilitate the spontaneous passage of stones in the distal ureter. when alpha-1-adrenergic antagonists are administered for benign prostatic hyperplasia and for medical expulsive therapy, their effect at various sites of the uro-genital tract may affect sexual function, with differences between drugs within the same class. the aim of this study is to review the existing evidence on the effect of alpha-1-adrenergic antagonists on sexual function. materials and methods the review was conducted in accordance with prisma (preferred reporting items for systematic reviews and metaanalyses) guidelines (8). it was registered on the prospero platform as crd42021283385. we included in this review randomized controlled trials (rcts), with single/double blinded design involving participants of any age or ethnicity who were treated with alpha adrenergic receptor antagonists for different conditions such as arterial hypertension, bladder neck obstruction by benign prostatic hyperplasia (bph) or ureteral obstruction by ureteral stones (medical expulsive treatment or met). the following outcomes were considered: (i) rate of ejaculatory disorders, (ii) rate of erectile disorders, (iii) scores of tests measuring erectile (iief-5) or ejaculatory activity (mshq-ejd, dan-psssex). two electronic databases (pubmed and embase) were searched for articles published up to september 30th, 2021. database interrogation was performed using specific search strings; for example, the pubmed search was preferentially based on mesh terms {('adrenergic alphaantagonists'/exp or 'adrenergic alpha-antagonists' or (adrenergic and 'alpha antagonists') or 'alfuzosin'/exp or alfuzosin or 'silodosin'/exp or silodosin or 'tamsulosin'/exp or tamsulosin) and ('ejaculation'/exp or ejaculation or 'erectile dysfunction'/exp or 'erectile dysfunction' or (erectile and dysfunction)) and [randomized controlled trial]/lim}. relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, clinical trial registers such as www.clinicaltrials.gov, www.clinicaltrialsregister.eu, etc.). title and abstract screening to exclude documents that did not meet the inclusion criteria was performed independently by two authors. duplicate references were deleted. controversies were resolved by a third researcher. full texts were downloaded to confirm or reject inclusion and to extract relevant information. data extraction was conducted by two authors using a standardized form. the following information was obtained from each study: authors, publication year, study design, population, intervention, effect on sexual function (erectile, ejaculatory). in case of missing or insufficient information, we analyzed the impact of missing data on the meta-analysis results and evaluated the potential risk of bias. two authors independently performed the quality assessment by identifying potential biases using the risk of bias (rob)-2 assessment tool of the cochrane collaboration (9). study quality was evaluated based on pre-defined criteria in relation to randomization process (d1), deviations from the intended interventions (d1), missing outcome data (d3), measurement of the outcome (d4) and selection of the reported result (d5). for each rob domain, an evaluation was given, based on a specific algorithm, resulting in the following rating: low risk, some concern, high risk. disagreements were resolved by discussion. the presence of risk of bias did not influence the decision to include/exclude a study from quantitative analysis. statistical analysis statistical analysis was performed using the revman5 software. dichotomous data (presence/absence of sexual dysfunction) and number of per-protocol or intent-totreat patients were extracted to calculate odds ratios (or), 95% confidence intervals (ci) to odds-ratios, and z statistics (random-effects model, mantel-haenszel method). study heterogeneity was assessed by calculating i^2 (and 95% ci), which was interpreted as of lesser importance (i^2 ≤ 40%), moderate (i^2 = 30%-60%), substantial (i^2 = 50%-90%) or considerable (i^2 ≥ 75%), according to cochrane criteria. funnel plots were drawn and visually evaluated to detect publication bias and small study effects. if publication bias was suspected, the egger’s and begg’s tests were implemented to assess funnel plot symmetry or asymmetry. asymmetry tests were performed using the metaessentials1 software (rotterdam school of management, erasmus university, the netherlands). the ‘trim and fill’ missing study imputation approach was applied to funnel plots; if archivio italiano di urologia e andrologia 2022; 94, 2 r. bapir, k. hassan bhatti, a, eliwa, et al. 254 missing studies were imputed by this procedure, adjusted overall effect sizes (odds ratios) were calculated. results a prisma flow diagram illustrates the results of study selection process (figure 1). we retrieved 612 records (pubmed, 152; embase, 456; other sources, 4). after title and abstract screening, we selected 125 articles by title and abstract screening (pubmed = 45 papers, embase = 80). following removal of 23 duplicates, the full text of the remaining 102 articles were examined. twenty-seven articles were excluded (2 because alpha-blockers were expressly used to treat premature ejaculation or as male oral contraceptives, 6 open-label studies, 5 non-controlled studies, 4 studies not reported in english, 3 reviews, 4 short term experimental studies in healthy subjects, 3 studies not reporting sexual function outcomes). the remaining 75 papers were included in three analyses: alpha-blockers versus placebo (n=36) (10-45), comparison of different alpha-blockers (n=31) (46-76) and comparison of alpha-blockers administered at different dosages (n=8) (77-84) (supplementary materials pico tables). risk of bias among the 75 studies included in qualitative analysis, the method of randomization was deemed to be at low risk of bias in 46 cases, and to unclear risk in 29. the risk of deviation from the intended intervention was rated as low in 62 studies, unclear in 12 and high in one. the rob associated to missing outcome data was considered to be low in 63 studies and unclear in 12. the risk of bias in measurement of outcome was considered to be low in 70 studies and unclear in 5. the risk of bias generated by selection of the reported results was rated as low in 73 studies and as unclear in 2. in total risk of bias was considered low in 37 studies, unclear in 35 and high in 3 (supplementary materials risk of bias). analysis of funnel plots symmetry by egger’s and begg’s tests, and adjusted odds ratios when missing studies were imputed by the trim-and-fill procedure are shown in the (supplementary materials funnel plots & symmetry tests). significant asymmetry was detected by at least one test for any kind of alpha blockers (uroselective, nonuroselective or both) compared to placebo in bph patients (endpoint: ejaculation), in the alpha blockers vs. standard care comparison in stone patients (endpoint: ejaculation), and in the alpha blockers vs. standard care or placebo comparison in stone patients (endpoint: ejaculation). imputation of missing studies by the trim-andfill procedure was implemented in 4 comparisons. in 3 cases, the significance or non-significance of adjusted odds ratios was not modified by imputation. conversely, the adjusted odds ratio for ejaculatory disorders in stone patients treated with alpha adrenoceptor blockers compared to placebo lost statistical significance. alpha-blockers versus placebo a total of 36 studies were included in this analysis: 15 studies evaluated ejaculatory disorders secondary to treatment with alpha-blockers compared to placebo (9 in patients with bph, 1 in patients with cp/cpps, 5 in patients with ureteral stones) (10-24). in 7 studies ejaculatory disorders were compared in patients on treatment with alpha-blockers compared with standard conservative treatment of ureteral stones (25-31). in 9 studies, both ejaculatory and erectile dysfunction after treatment with alpha-blockers were compared to placebo in patients with bph (32-40). finally, 5 studies reported the effect on erectile function of alphablockers compared to placebo in bph patients (41-45). endpoint: ejaculatory disorders compared to placebo, alpha-blockers were associated with significantly increased odds of ejaculatory disorders in patients with luts associated to bph (or: 7.53, 95% ci: 3.77 to 15.02, 23 series from 19 figure 1. flow chart. 255archivio italiano di urologia e andrologia 2022; 94, 2 sexual function and alpha-blockers studies, 13006 participants, z = 5.73, p < 0.00001, i2 = 55%) (figure 2). similarly, in patients with ureteral stones, patients taking alpha-blockers showed significantly higher odds for ejaculatory disorders, compared to patients receiving placebo or standard care (or: 2.86, 95% ci: 1.50 to 5.44, 12 series from 12 studies, 3192 participants, z = 3.19, p < 0.001, i2 = 31%) (figure 3). significantly higher odds for ejaculatory disorders were confirmed in patients with ureteral stones taking alphablockers compared to patients either on placebo or on standard treatment (forest plots shown in supplementary materials forest plots figures 1-2). compared to placebo, uroselective alpha-blockers showed significantly higher odds of ejaculatory disorders (or: 11.46, 95% ci: 5.58 to 23.54, 16 series from 13 studies, 8580 participants, z = 6.64, p < 0.00001, i2 = 49% (figure 4), whereas nonselective alpha-blockers were not associated with higher figure 2. odds for ejaculatory disorders in patients with luts associated to bph taking alpha-blockers. data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers (both uroselective and non-uroselective), compared to placebo. figure 3. odds for ejaculatory disorders in patients with ureteral stones taking alpha-blockers for medical expulsive treatment. data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers compared to placebo or standard treatment. archivio italiano di urologia e andrologia 2022; 94, 2 r. bapir, k. hassan bhatti, a, eliwa, et al. 256 odds of ejaculatory dysfunction (or: 2.22, 95% ci: 0.72 to 6.84, 7 series, 4426 participants, z = 1.38, p = 0.17, i2 = 12%) (figure 5). endpoint: erectile dysfunction the presence of erectile dysfunction in patients treated with alpha-blockers was investigated in 14 studies. eleven studies (12 series) reported the rates of erectile dysfunction in patients on treatment with alpha-blockers (any kind) in comparison with placebo (32-39, 43-45). there was no statistically significant difference between the odds of erectile dysfunction assessed in the alphablocker treatment arm compared to placebo (or: 0.88, 95% ci: 0.42 to 1.82, 12 series, 6631 participants, z = 0.35, p = 0.73, i2 = 36%) (figure 6). the lack of a significant inter-arm difference versus placebo was confirmed when uroselective and non-selective alpha-blockers were analyzed separately (forest plots shown in supplementary materials forest plots figures 3, 4). in three of the above reported studies, erectile function alterations were also evaluated by administering questionnaires to enrolled patients. hofner et al. (33) evaluated the effect of alpha-blockers on sexual function by administering a quality-of-life assessment questionnaire including three questions on sexual function (interest in sex, erection, ejaculation). the authors reported the overall evaluation of sexual function without showing the results of the three separate domains. a trend to improvement of the overall sexual function was observed after tamsulosin (p = 0.042), whereas no differences were observed when tamsulosin was compared to alfuzosin. rosen et al. (39) reported changes of the dan-psssex score after alfuzosin treatment. the dan-psssex tool includes questions on erectile and ejaculatory function, and on bother associated with these two functions. alfuzosin treatment was associated with a significant improvement of erectile function compared with placebo (p = 0.02), whereas treatment didn’t appear to influence the ejaculatory function. shelbaia et al. (44) observed that the use of tamsulosin was associated with increased iief scores (p = 0.047) in patients with luts and erectile dysfunction. three additional studies were not included in our quantitative analysis. one study evaluated the effects of the oral administration of the nonselective alphafigure 4. odds for ejaculatory disorders in patients in patients with luts associated to bph taking uroselective alpha-blockers. data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with uroselective alpha adrenoceptor blockers compared to placebo. figure 5. odds for ejaculatory disorders in patients in patients with luts associated to bph taking non-uroselective alpha-blockers. data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with non-uroselective alpha adrenoceptor blockers compared to placebo. 257archivio italiano di urologia e andrologia 2022; 94, 2 sexual function and alpha-blockers adrenergic antagonist phentolamine in patients with erectile dysfunction. full erection was achieved after ondemand administration of phentolamine at different doses (from 20 to 60 mg) more frequently than after placebo. however, the sample size was too small for statistical analysis (41). another study evaluated the effect of a single dose of the selective, orally-active alpha1-aadrenoceptor antagonist ro70-0004 on the erectile function in a group of men with erectile dysfunction. ro700004 did not improve the erectile function when compared to placebo (42). finally, in patients with painful ejaculation, safarinejad et al. (40) found that the intercourse satisfaction domain iief scores were not significantly improved after tamsulosin (p = 0.08). other endpoints few studies reported about the alterations of sexual desire after administration of alpha-blockers. no significant differences of desire after alfuzosin or tamsulosin and placebo were reported. kirby et al. (34) reported similar decreases of libido after alfuzosin or placebo (-3.6% vs 1.9%, p = 0.58). van kerrebroeck et al. (45) reported no cases of decreased desire after alfuzosin 10 mg/day, 0.7% cases after alfuzosin 2.5 mg t.i.d. and 0.7% cases after placebo. hofner et al. (33) reported no differences between tamsulosin and placebo (0.8% vs 0%, p = 0.306) and singh et al. (19) no cases of decreased desire after both tamsulosin or placebo. hofner et al. (33) found no cases of decreased libido after tamsulosin or alfuzosin. comparisons between alpha-blockers a total of 31 studies compared the effect of different alpha-blockers on sexual function (46-76). out of 31 trials, 15 compared the risk of ejaculatory disorders after figure 7. odds for ejaculatory disorders in patients taking silodosin or tamsulosin. data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with silodosin. figure 6. odds for erectile dysfunction in bph patients taking alpha-blockers. data to the left of the vertical no-effect axis indicate lower odds for erectile dysfunction in patients treated with placebo compared to alpha adrenoceptor blockers. archivio italiano di urologia e andrologia 2022; 94, 2 r. bapir, k. hassan bhatti, a, eliwa, et al. 258 tamsulosin compared with silodosin (49-54, 60, 62, 64, 65, 70, 71, 73-75), 5 studies evaluated the effect of naftopidil compared with a uroselective alpha-blocker on ejaculation (including a study comparing naftopidil with both tamsulosin and silodosin) (59, 61, 68, 72, 73), 7 studies compared alfuzosin with uroselective alphablockers (46-48, 55-57, 60), 4 studies compared terazosin or doxazosin with tamsulosin (58, 63, 66, 76) and one study terazosin with doxazosin (67). silodosin was associated with significantly increased odds of ejaculatory dysfunction compared with tamsulosin (or: 3.52, 95% ci: 2.18 to 5.68, 15 series, 1512 participants, z = 5.15, p < 0.00001, i2 = 0%) (figure 7). naftopidil showed significantly lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers (or: 0.29, 95% ci: 0.13 to 0.64, 6 series from 5 studies, 474 participants, z = 3.04, p = 0.002, i2 = 0%) (figure 8). alfuzosin was associated with significantly lower odds of ejaculatory disorders compared to uroselective alphablockers (or: 0.17, 95% ci: 0.07 to 0.38, 8 series from 7 studies, 877 participants, z = 4.27, p < 0.0001, i2 = 0%) (figure 9). summary of findings summary of finding (sof) tables, containing illustrative comparative risks (assumed control risks and corresponding intervention risks) and odds ratios relative to each single meta-analysis are presented as supplementary materials. sof tables also contain evaluations of the quality of the evidence relative to each meta-analysis, rated according to grade criteria. single studies not included in quantitative analysis zaytoun et al. (2/50 vs 0/50) (76), pompeo et al. (4/83 vs 2/82) (66) and kirby et al. (2/50 vs 0/48) (58) observed more frequently ejaculatory disorders after tamsulosin compared to doxazosin. narayan et al. (63) described higher rates of ejaculatory dysfunction after tamsulosin compared to terazosin [37/1002 (3.7%) vs 3/981 (0.3%)]. samli et al. (67) observed similar rates of erectile dysfunction after doxazosin versus terazosin (0/25 vs 1/25). comparison between different dosages of alpha-blockers we retrieved 8 studies (77-84) designed to compare the clinical efficacy and tolerability of different alpha-blockers administered at different doses and time intervals. the designs of the studies were too heterogenous for quantitative analysis. no differences in the rate of ejaculatory disorders were observed with different formulations and different doses figure 8. odds for ejaculatory disorders in patients taking naftopidil or uroselective alpha-blockers. data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with naftopidil compared to uroselective alpha adrenoceptor blockers. figure 9. odds for ejaculatory disorders in patients taking alfuzosin compared to uroselective alpha-blockers. data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with alfuzosin. 259archivio italiano di urologia e andrologia 2022; 94, 2 sexual function and alpha-blockers of doxazosin (4 mg vs 8 mg) (77, 78). the improvement in iief scores after extended-release doxazosin (4 or 8 mg once daily) was similar to the one observed after fastrelease doxazosin (1-8 mg once daily) (78). similarly, the administration of tamsulosin at different doses resulted in similar effects on ejaculatory function (81-83). rates of ejaculatory disorders were not different after tamsulosin 0.4 mg versus 0.2 mg (81, 82), or 0.4 mg once daily every other day (83). the timing of administration of silodosin appears to change the effects of the drug on sexual function. silodosin 4 mg twice-daily induced a higher rate of ejaculatory disorders compared to silodosin 4 mg taken once a day (10/115 vs 67/115) or silodosin 8 mg administered after breakfast (46/208 vs 32/212) (79, 80). discussion alpha-1 adrenoceptor blockers have been shown to be very effective in counteracting lower urinary tract symptoms associated with benign prostatic hyperplasia (85, 86), as well as in facilitating the spontaneous passage of stones from the distal ureter (87, 88). however, this class of drugs can lead to cardiovascular side effects and sexual dysfunction, thus potentially worsening the quality of life of patients and possibly causing a reduction in the compliance to long-term treatment. since alpha-adrenergic receptors are highly expressed in male genital organs, adrenergic blockade can potentially affect erection, ejaculation, and sexual desire. ejaculation the influence of alpha-blockers on ejaculation is well known, although the underlying physiological mechanism for such effect is not yet well defined. our analysis confirms that the odds for ejaculation disorders are greater in patients taking alpha-blockers of any kind, compared to placebo. moreover, when the effects of different alpha-blocking agents are analyzed separately, the odds for abnormal ejaculation are greater upon administration of uroselective alpha blockers (tamsulosin and silodosin). conversely, comparison between alfuzosin and placebo does not result in statistically significant results. the comparison between different alpha-blocking agents showed that silodosin and tamsulosin were more frequently associated with ejaculation disorders when compared to non-selective alpha-blockers. tamsulosin and, to a greater extent, silodosin, show super-selective binding with the alpha1a receptor, while alfuzosin, doxazosin and terazosin show comparable affinity with the three subtypes of alpha1-adrenergic receptors. naftopidil on the other hand exhibits a unique selectivity for alpha1b receptors. the different binding affinity (or selectivity) for alpha1-adrenergic receptor subtypes explains the different effects of alpha-blockers on ejaculation. ejaculatory disorders associated with administration of alpha-1 blockers were initially thought to be a consequence of bladder neck relaxation, causing in turn retrograde ejaculation. further studies clarified the mechanisms whereby ejaculation disorders occur following the use of uroselective alpha-blockers. disorders of ejaculation after tamsulosin and silodosin have been related to both a peripheral effect on the vas deferens and/or seminal vesicles and a central effect in the coordination of ejaculation (89). at the peripheral level, ejaculation disorders have been related to the decreased capacity of contraction of the seminal vesicles and of the vas deferens. this is supported by the evidence that alpha-1a adrenoceptor subtype mrna is predominant in human seminal vesicles, and that spermatic cells are not detected in the urine after ejaculation following silodosin administration. this shows that ejaculatory dysfunction caused by silodosin is not related to retrograde ejaculation but rather to a loss of seminal emission (90, 91). similarly, administration of 0.8 mg tamsulosin to healthy volunteers resulted in reduction of the ejaculatory volume in almost all subjects, without causing a significant difference in post-ejaculation urinary sperm concentrations when compared to placebo or alfuzosin (92). unlike other alpha1-blockers, tamsulosin can cross the bloodbrain barrier and bind to dopaminergic and/or serotonergic receptors that are involved in the central coordination of ejaculation (93). a strong affinity of alpha1-adrenoceptor antagonists for d2and 5ht1a-like receptors for has been demonstrated, suggesting that these drugs may act as antagonists of dopaminergic receptors mediating the contraction of the vas deferens (94). erection there are conflicting data about the effect of alpha-blockers on erection, mainly because the erectile function is the result of a complex interplay between multiple biochemical signals responding to several neurotransmitters and vasoactive agents. basically, penile tumescence is associated with relaxation of the erectile tissue whereas detumescence is caused by contraction of the erectile tissue. postsynaptic alpha1-adrenoceptor activation causes the contraction of the erectile tissue, leading to penile flaccidity and detumescence. for this reason, alphaadrenoceptor antagonists can promote the relaxation of the muscles of the trabeculae of the corpora cavernosa and induce erection, as demonstrated by erection induced by intra-cavernous injection of alpha-adrenoceptor antagonists (95, 96). in addition, alpha-blocker-induced priapism is a rare but well documented side effect of treatment (97). at the systemic level, blockage of adrenergic receptors has a more complex effect on the regulation of erectile function because it can occur at both peripheral and central levels (through ascending pathways to the brain and descending pathways to the spinal cord) and involve various alpha1or alpha2-adrenoceptor subtypes. the effect of each drug will depend on the central and peripheral effects exerted on the different receptors, causing in turn specific effects on erectile function (98). finally, hemodynamic effects of non-selective alpha-blockers may harm erectile function because of symptomatic hypotension side effects (99). our meta-analysis demonstrated neither greater odds of erectile dysfunction or impotence upon exposure to alpha-blockers, nor differences of odds of erectile dysfunction evoked by treatment with uroselective or nonselective alpha-blockers compared to placebo. thus, the potential effect of alpha-blockers on erectile archivio italiano di urologia e andrologia 2022; 94, 2 r. bapir, k. hassan bhatti, a, eliwa, et al. 260 function therefore remains unknown. in our analysis we excluded studies that evaluated the effects of combination therapy with alpha-1 adrenergic antagonists and phosphodiesterase-5 (pde5) inhibitors on sexual function. interestingly, some studies have shown an additive favorable effect of the combined use of alpha-blockers and pde5 inhibitors on erectile dysfunction (100). in 2014, a meta-analysis demonstrated that alpha-blockers may enhance the efficacy of pde5 inhibitors on erectile dysfunction in men with luts suggestive of bph (101). however, a more recent review found no significant difference of the mean change of iief between combination therapy and pde5 inhibitors-monotherapy concluding that benefits regarding the treatment of ed are not clear (102). limitations a limitation of this meta-analysis is the disparity of assessment criteria and definitions used to describe sexual dysfunction associated with alpha-blockers. ejaculation disorders have been defined indifferently as abnormal ejaculation, ejaculatory disorders, decreased ejaculatory volume, anejaculation, and retrograde ejaculation. some of these terms are generic, others imply specific pathophysiological alterations that may not correspond to clinically observable manifestations. the presence of retrograde ejaculation has been questioned by recent studies which have shown that the ejaculatory alterations caused by alpha-blockers are due to a lack of semen emission, that should be better defined as anejaculation. the different physiological mechanisms that are at the origin of failure of semen emission, or of retrograde ejaculation, can be associated with different orgasmic dysfunctions. on the other hand, ejaculation disorders have rarely been evaluated with specific questionnaires such as dan-pss or msqh. erectile dysfunction was also not uniquely defined in the different studies that used both the term impotence and erectile dysfunction, with only a few studies assessing the latter with the iief questionnaire. in order to take into account the diversity of diagnostic methods and tools used to ascertain ejaculatory or erectile dysfunction in included studies, we have used in all metanalyses a random-effect model (103). conclusions in conclusion, because of the different effects of alpha1adrenergic antagonists on sexuality, the sexual function of each patient 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11:1539-45. 102. kallidonis p, adamou c, kotsiris d, et al. young academic urologists of the european association of urology-endourology working party. combination therapy with alpha-blocker and phosphodiesterase-5 inhibitor for improving lower urinary tract symptoms and erectile dysfunction in comparison with monotherapy: a systematic review and meta-analysis. eur urol focus. 2020; 6:537-558. 103. tufanaru c, munn z, stephenson m, aromataris e. fixed or random effects meta-analysis? common methodological issues in systematic reviews of effectiveness. int j evid based healthc. 2015; 13:196-207. correspondence rawa bapir dr.rawa@yahoo.com smart health tower, sulaymaniyah, kurdistan region, iraq kamran hassan bhatti kamibhatti92@gmail.com urology department, hmc, hamad medical corporation, qatar. ahmed eliwa ahmedeliwafarag@gmail.com department of urology, zagazig university, zagazig, sharkia, egypt. herney andrés garcía-perdomo herney.garcia@correounivalle.edu.co universidad del valle, cali, colombia nazim gherabi, md ngherabi@gmail.com faculty of medicine algiers 1, algiers, algeria derek hennessey, md derek.hennessey@gmail.com department of urology, mercy university hospital, cork, ireland vittorio magri, md vittorio.magri@virgilio.it asst nord milano, milan, italy panagiotis mourmouris, md thodoros13@yahoo.com 2nd department of urology, national and kapodistrian university of athens, sismanoglio hospital, athens, greece adama ouattara, md adamsouat1@hotmail.com division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso gianpaolo perletti gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy joseph philipraj, md josephphilipraj@gmail.com department of urology, mahatma gandhi medical college and research institute, sri balaji vidyapeeth, puducherry, india. alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com urology school, university of milan, milan (italy) noor buchholz noor.buchholz@gmail.com sobeh's vascular and medical center, dubai health care city, dubai, united arab emirates stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13343 1 letter to editor key words: female and male; medical student; lady urologist; male patient; self-respecting man . submitted 4 november 2024; accepted 29 november 2024 to the editor in 2022 dr suzanne koven published a book entitled letter to a young female physician, notes from a medical life. w.w. norton & company, inc, new york (1). the book starts with a letter written by the author while participating in a 2017 orientation session at harvard medical school during which new interns were asked to write self-addressed essays expressing “their hopes and anxieties” (1). in the first part of her letter, dr koven writes: “on your urology rotation in medical school, you were informed that your presence was pointless, since, as you were told by an attending, no self-respecting man would go to a lady urologist” (1). co-authors of the present contribution (alb, mcw, ac, and lc) put forward a series of questions on such a quotation: 1. female and male medical students and postgraduate trainees: 2. “lady urologist”; 3. male patients; and 4. “self-respecting man”. the answers reported hereafter were given by the other co-author (rm, a uropathologist whose training included urologic oncology), to some extent representing his personal view or experience. female and male medical students and postgraduate trainees over the years, an extensive series of lectures on clinically oriented uropathology were delivered to medical students. teaching included practical sessions. basically, both female and male students – the former outnumbering their male peers – were very good in terms of proficiency, i.e., no differences between the students of the two genders were noticed. occasionally, an attempt was made, with very little success, to encourage female and male students to apply for postgraduate training in pathology. they were never discouraged from applying for other specialties, including urology. an idea of what being in a non-pathology specialties would have meant, in terms of advantages and disadvantages, was given. the same approach was adopted when teaching uropathology to interns, residents and fellows in urology as well as to other non-urology postgraduate trainees. it was pointed out that both female and male have the same chances to succeed in their future professional and academic career as well as with patients, the latter independently of being selfrespecting or not (see below). it was also explained to them, women and men, not to tolerate the belief that one sex is superior to or more valuable than another sex. “lady urologist” despite the relatively equal number of female and male graduating from medical school, in some countries the proportion of women in the urology services, both academic and not academic, has been lower than that of male urologists. mayer et al. investigated the gender differences in publication productivity among academic urologists in the united states (2). the authors found that “women represent a growing proportion of academic urology faculty, but despite the recent increase in number entering the field, relatively few women occupy senior leadership positions” (2). probably, this has reflected an older approach of a basically male profession, an approach that has changed rapidly over times. however, the female contributions are not of a lower level compared with those of male urologists in all the settings: office, ward and operating room as well as academically. a recent study by wallis et al. showed that “patients treated by female surgeons have lower rates of adverse postoperative outcomes including death at 90 days and 1 year after surgery compared with those treated by male surgeons” (3). female urologists are not mentioned here by name; it would appear a kind of discrimination or personal preferences. they can be easily found on the websites of national and international urology and uro-oncology societies and meetings. lady urologist and male patients with prostate cancer rodolfo montironi 1, antonio lopez-beltran 2, meredith c. wasserman 3, alessia cimadamore 4, liang cheng 5 1 molecular medicine and cell therapy foundation, c/o polytechnic university of the marche region, ancona, italy; 2 department of surgery, cordoba university medical school, cordoba, spain; 3 division of urology, department of surgery, the warren alpert medical school of brown university, providence, ri, usa; 4 institute of pathological anatomy, department of medicine, university of udine, udine, italy; 5 department of pathology and laboratory medicine, department of surgery (urology), brown university warren alpert medical school, brown university health, and the legorreta cancer center at brown university, providence, ri, usa. doi: 10.4081/aiua.2025.13343 archivio italiano di urologia e andrologia 2025; 97(1):13343 r. montironi, a. lopez-beltran, m.c. wasserman, et al. 2 male patients when reviewing the histological slides sent by patients with prostate cancer, the answer to major questions from them concerned the importance of morphologic and molecular features in terms of diagnosis, prognosis and therapeutic options (4). most patients were in touch with male urologists, a minority being with female urologists. the recollection from those patients was that female and male urologists were considered to be at a comparable level, from the human and professional levels. they said that they were not afraid of discussing with female urologists all aspects of their disease, including potency and continence, in a way similar to that with male urologists. some patients said that they preferred male urologists: they had nothing to be ashamed of, but they felt uncomfortable with a female urologist (5). it was heard from them that women urologists did not dislike having male patients. conclusions “self-respecting man” concerning “self-respecting man” (1), dr koven was probably referring to men/patients of a certain social class, depending on education, occupation and income. to the best of the co-author’s experience (rm), the patients were dealt with independently from their social class. the same did the lady urologists in relation to the social class of their male patients. references 1. koven s. letter to a young female physician: thoughts on life and work (notes from a medical life). new york, ny: w.w. norton & company, inc; 2022. 2. mayer en, lenherr sm, hanson ha, et al. gender differences in publication productivity among academic urologists in the united states. urology. 2017; 103:39-46. 3. wallis cjd, jerath a, aminoltejari k, et al. surgeon sex and long-term postoperative outcomes among patients undergoing common surgeries. jama surg. 2023; 158:1185-1194. 4. cimadamore a, cheng l, lopez-beltran a, et al. patients ask and pathologists answer: ten questions around prostate cancer grading. virchows arch. 2024 aug 17. doi: 10.1007/s00428-024-03891-9. epub ahead of print. pmid: 39153109. 5. https://www.quora.com/how-do-women-urologists-feel-about-having-male-patients. correspondence rodolfo montironi, md (corresponding author) rodolfo.montironi51@gmail.com molecular medicine and cell therapy foundation, c/o polytechnic university of the marche region, via tronto 10, 60126 ancona, italy. antonio lopez-beltran, md em1lobea@gmail.com department of surgery, cordoba university medical school, cordoba, spain meredith c. wasserman, md meredith.wasserman@gmail.com division of urology, department of surgery, the warren alpert medical school of brown university, providence, ri, usa alessia cimadamore alessiacimadamore@gmail.com institute of pathological anatomy, department of medicine, university of udine, udine, italy liang cheng liang_cheng@yahoo.com department of pathology and laboratory medicine, department of surgery (urology), brown university warren alpert medical school, brown university health, and the legorreta cancer center at brown university, providence, ri, usa declarations ethical approval: not applicable. availability of data and material: not applicable. competing interests: the authors have nothing to disclose. funding: the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors' contributions: author alb and author lc have given substantial contributions to the conception or the design of the manuscript, author mw and author ac to acquisition, analysis and interpretation of the data. all authors have participated in drafting the manuscript, author rm revised it critically. all authors read and approved the final version of the manuscript. acknowledgments: not applicable. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12576 1 review an episode of priapism, o2 partial pressure decreases as the closed compartment prevents the supply of fresh, oxygenated blood, resulting in initial thickening and interstitial edema without smooth muscle necrosis (3, 5). necrosis of the corpus cavernosum muscle was seen after 24 hours. after 24 hours, the risk of irreversible comprehensive smooth muscle changes leading to refractory erectile dysfunction is over 90%, and after 72 hours, there is no hope for recovery of erectile function (2, 3, 6). failure to respond to aspiration and instillation of a-agonists suggests that irreversible changes have occurred in the smooth muscle of the corpus cavernosum. at this stage, shunt surgery may successfully induce decongestion but will not reverse the ischemic damage, and refractory erectile dysfunction will persist in the long term (1, 4, 7). refractory erectile dysfunction cannot be treated conservatively, and penile prosthesis implantation is the only way to achieve the stiffness required for penetrative intercourse. penile prosthesis implantation at this stage can be very difficult due to diffuse corporal fibrosis, which complicates corporal dilation and is associated with an increased risk of distal/proximal cross-over complications and urethral perforation or injury (4, 8-10). in addition, the duration of the procedure significantly increases the risk of postoperative infection. in addition, fibrosis results in some shortening of the penis. after implantation, most patients still complain of penile shortening, which is one of the reasons for men's dissatisfaction with penile prostheses (11, 12). immediate implantation of a penile prosthesis is usually simple, reduces pain, and allows an earlier return to sexual activity. despite the above advantages, immediate implantation of penile prostheses is associated with penile edema, increased risk of infection, and distal perforation, especially in patients with a history of shunt surgery (7, 13, 14). delayed implantation of penile prostheses is now considered a surgical challenge with a high complication rate. delayed implantation is also associated with suboptimal satisfaction. several studies suggest that penile prostheses should be implanted in patients with refractory ischemic priapism at the acute stage when irreversible erectile smooth muscle damage has occurred (11, 15). currently, there is no general agreement on the timing of background: this study determined pooled estimates of shortand long-term complications of early versus delayed implantation of penile prosthesis in patients with ischemic priapism. methods: we searched pubmed, proquest, scopus, ebscohost, and other sources from january 1, 2013, to march 2023. all study designs were included except animal studies, review articles, and consensus documents. of the 214 articles, four studies were included in the systematic review, and further meta-analysis included three studies (prospero crd42023411005). results: the short-term complication rate was lower with early implantation than with later implantation (β= -2.08; 95% confidence interval [ci] = -3.54, -0.6; p = < 0.05). a similar value was also found in the pooled analysis for long-term outcomes, defined as overall satisfaction rate, which is better with early implantation than later (β = 2.18; 95% ci = 1.35, 3.02; p = < 0.05). conclusions: the results of the pooled analysis confirmed that short-term complications were significantly lower with early implantation than with delayed implantation. overall satisfaction rates were higher in early implantation than in delayed implantation of penile prostheses. key words: penile prosthesis; early implantation; delayed implantation; ischemic priapism; priapism. submitted 16 march 2024; accepted 30 april 2024 background "priapism" describes a pathological condition characterized by a prolonged erection of more than four hours without sexual stimulation. this condition can be divided into subtypes of low, high, and intermittent flow (1). ischemic priapism is the most common form of priapism and accounts for 90-95% of all cases. although a common form, ischemic priapism is rare, with an overall incidence of 1.5 cases per 100.000 person-years (1, 2). most cases of priapism have an idiopathic etiology; others may be related to hematologic abnormalities, intracavernosal injection of vasoactive drugs, illicit drug use, or malignancy (3, 4). ischemic priapism is considered a form of compartment syndrome caused by hypoxia, hypercapnia, acidosis, and glucopenia in the erectile tissue. in the first 12 hours after a systematic review and meta-analysis of shortand long-term complications of early versus delayed penile prosthesis implantation in patients with ischemic priapism agustin j. nanda de niro 1, gede wirya kusuma duarsa 2, marshal harvy wicaksono 1, pande made wisnu tirtayasa 2, kadek budi santosa 2, i wayan yudiana 2, nyoman gede prayudi 2 1 intern doctor of urology surgery department prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia; 2 urology staff of urology surgery department prof. dr. i.g.n.g ngoerah general hospital, bali, indonesia. doi: 10.4081/aiua.2024.12576 summary archivio italiano di urologia e andrologia 2024; 96(3):12576 a.j. nanda de niro, g. wirya kusuma duarsa, m. harvy wicaksono, et al. 2 penile prosthesis implantation in patients with ischemic priapism, as outcomes are variable. this review examines the current literature on priapism, with a focus on evaluating short-term and long-term outcomes in adult men undergoing direct implantation of a penile prosthesis for the treatment of acute ischemic priapism unresponsive to medical therapy or shunt surgery. methods search strategy and selection criteria following the preferred reporting items for systematic reviews and meta-analyses (prisma) for conducting meta-analyses (http://www.prisma-statement.org/), two independent reviewers performed data extraction (aj, gw). disagreements were resolved in a discussion among all investigators, and if necessary, they were analyzed and clarified by iw. for the literature search, we used the pubmed, ebscohost, scopus, and proquest databases from january 1, 2023, to march 2023. we also reviewed and manually searched the references and identified the possible dates from the conferences. the systematic search for terms and combinations used the following terms: "penile prosthesis"; "priapism"; "early"; "delayed"; "graft"; "satisfaction"; "complications". original research articles were included if they met the following criteria: (a) diagnosis of acute priapism, (b) comparison of penile prosthesis implantation: early vs. delayed, and (c) if the study provided information on clinical characteristics and outcomes of the two techniques. we excluded animal studies, review articles, and consensus documents. the exclusion criteria were as follows: (a) the study was a review article, letter to the editor, animal study, commentary, or consensus document; (b) the study did not focus on priapism patients or the diagnosis was unclear. if the patients were from the same hospital and the cases overlapped, we selected only the publication with the largest number of cases. the protocol was registered with the international prospective register of systematic reviews (prospero), in accordance with prisma-p guidelines (prospero crd42023411005) (16). the protocol for this systematic review has been previously described (17). all identified studies are included in this review. quality assessment and risk of bias the five authors of the review classified each of the included studies as 'risk of bias’. risk of bias in randomized controlled trial (rct) was assessed using the tools recommended in the cochrane handbook for systematic review of interventions. additional items were included to determine the risk that confounding factors may explain the results. robins-1 quality ratings for non-randomized studies were used to assess the quality of observational studies. for each study, a pragmatic approach was used to assess the risk of confounding. statistical analysis the primary outcomes of interest in the study were shortand long-term complications of penile prostheses at early and late implantation. short-term complications included pain, palpable nodules, residual curvature, infection, and erosion of the prosthesis, while long-term complications included quality of life, overall satisfaction, sexual satisfaction, penetration ability, erectile dysfunction, and increased curvature. i2 was used to assess heterogeneity between studies. a fixed-effects model was used when i2 was < 50%, and when i2 was > 50%, a random-effects model was chosen. in the fixed-effects model, population effect sizes were assumed to be the same for all studies. in contrast, the random-effects model attempted to generalize the results beyond the included studies by assuming that the selected studies were random samples from a larger population. if there was statistical heterogeneity in the results, a further sensitivity analysis was performed to determine the source of heterogeneity. sensitivity analyses were performed only for meta-analyses that evaluated primary/main outcomes (including outliers). sensitivity analyses were performed in three different ways by excluding (1) each study individually, (2) studies identified as outliers, and (3) studies with a moderate and high risk of bias. after each analysis, the consistency and significance of the meta-analysis results are reassessed. a study is considered an outlier if the 95% confidence interval (ci) of the study is outside the 95% ci of the combined effect when the forest plot is viewed visually. the forest plot shown refers only to the metaanalysis with outliers. after excluding significant clinical heterogeneity, the random-effects model with coefficient estimation (b) was used as the effect size for the metafigure 1. flow diagram of study selection. archivio italiano di urologia e andrologia 2024; 96(3):12576 3 penile prosthesis implantation in patients with ischemic priapism analysis (es). when p was < 0.05, the result was considered statistically significant (2-sided). all data were analysed using stata ver. 15 software. overview of the study selection the prisma diagram for the entire study selection process is shown in figure 1. an initial search of four databases yielded 212 studies, while additional records identified through references and conferences included two studies. subsequently, 154 studies were excluded because they did not meet the requirements of the automation tool, and 48 duplicate studies were also excluded. of the remaining 12 studies, a total of 6 studies were identified as reviews, and 2 studies did not compare early and delayed penile prostheses. ultimately, four studies were selected and included in this systematic review and three studies were included in the meta-analysis. studies characteristics the characteristics of the included studies are summarized in table 1. all included studies were retrospective studies using medical records. the total number of ischemic priapism patients from four studies was 287, with 187 patients undergoing early penile prosthesis implantation and 100 patients undergoing delayed penile prosthesis implantation. the operational definition for categorizing patients as "early" or "delayed" was different in each study. the time from onset of priapism to implantation was 31 hours to less than three weeks in the early group. in the delayed group, it was 3 weeks to more than 6 months. three studies reported initial treatment before implantation in the form of physical aspiration, irrigation, instillation of a-agonists, and t-shunt surgery (open distal and percutaneous). in patients with early implantation, 178 patients were treated with malleable implants and 9 others with inflatable implants. in patients with delayed implantation, 66 patients used malleable implants and 34 others used inflatable implants. most studies stated that deformable implants were preferred because they are less expensive. risk of bias the risk of bias assessment is presented using two summary figures (figures 2, 3) for each study according to all risk of bias domains. two studies have a low risk of bias, and the other two studies have a potentially moderate risk of bias. when assessing the risk of confounding, all studies had a moderate risk of bias, mainly due to the type of penile prostheses that may have influenced study results. there is a moderate risk of bias in participant selection, with the exception of one study that did not include complete information on patient selection (published as a conference proceeding at a symposium). all studies have a moderate risk table 1. study characteristics. archivio italiano di urologia e andrologia 2024; 96(3):12576 a.j. nanda de niro, g. wirya kusuma duarsa, m. harvy wicaksono, et al. 4 of bias in the classification of interventions, while the remaining domains have a low risk, except for one study that has a moderate risk of selection bias in outcome reporting. this study does not explain exactly how many patients in each group experienced complications but only reports the frequency of complications present, and more than one complication may occur in each patient. short-term complications in the meta-analysis of short-term complications, all studies were included in the analysis. nevertheless, the results of heterogeneity analysis using i2 showed a high heterogeneity of 82.6%. sensitivity analysis using forest plots revealed that two studies were outliers. in the follow-up analysis, one outlier study was excluded due to the small sample size. the results of a random-effects meta-analysis on shortterm complications showed that complications were significantly lower with early implantation of penile prosthesis than with delayed implantation (b = -2.08 (-3.54, -0.61); p = < 0.05) (figure 4). funnel plot results are in figure 5. shows asymmetric results, highlighting the potential for publication bias. long-term complications the meta-analysis of long-term complications showed that figure 2. risk of bias summary: review authors' assessment of each risk of bias for each included study. figure 3. risk of bias chart: review authors' assessment of each risk of bias item, presented as a percentage of all included studies. figure 4. forest plot short-term complications. archivio italiano di urologia e andrologia 2024; 96(3):12576 5 penile prosthesis implantation in patients with ischemic priapism patients were satisfied with the outcome of the prosthesis, including sexual intercourse and overall comfort. this analysis included three studies. in this case, there was no clear assessment of overall satisfaction in one study. the results of the meta-analysis on satisfaction rate showed that early implantation of the penile prosthesis had significantly better satisfaction than delayed implantation (b = 2.18 (1.35, 3.02); p = < 0.05) (figure 6). the results of the funnel plot show that there is no outliers (figure 7). discussion the decision about penile prosthesis in an acute episode of ischemic priapism is still based on expert opinion that referred to small or retrospective studies, hence decisionmaking should be discussed between the patient and the urologist (11, 18). this study is the first systematic review and meta-analysis to exclusively include a comparative study of the shortand long-term complications of early and delayed penile prosthesis implantation. according to a retrospective study conducted by palmisano et al., the immediate implantation of a soft penile prosthesis for patients with refractory ischemic priapism leads to instant pain alleviation, preservation of sexual function, and penile size, as well as higher surgical reproducibility in an emergency. furthermore, ischemic priapism's financial and resource burden on the healthcare system may be decreased (19). the previous systematic review by capece et al. showed that all studies found superiority of early versus delayed penile prosthesis implantation in patients with ischemic priapism; however, this superiority was merely speculative because none of the studies were designed to compare the outcome of early versus delayed implantation (20). in this study, however, the pool effect size from a meta-analysis provided better certainty about the outcome of penile prosthesis implantation in the 287 patients with ischemic priapism. for both short-term and long-term complications, the pooled analysis showed significantly better outcomes for early implantation (p< 0.05) than for delayed implantation. infection is the most common complication after early implantation of penile prostheses, especially in patients with postoperative aspiration, injection, or shunt (12, 21, 22). it can be caused by the penetration of bacteria through the skin into the sterile compartment and by cavernous edema, which prevents antibiotics from penetrating the cavernous tissue (1, 10, 21). nevertheless, postoperative infections are generally treatable. the most challenging aspect of penile prosthesis implantation in delayed cases is existing corpus cavernosum fibrosis. difficult physical dilatation with hegars dilators can be replaced with cavernotomes to cover difficult dilatations, called corporal drilling (23, 24). this difficult situation can be complicated by urethral injuries, lateral or distal perforations, or cylindrical branches. extensive corporal fibrosis and difficult dilation have resulted in the penile prosthesis being reduced in size to accommodate the corporal compartment (7, 20). this condition results in decreased penile length and is ultimately associated with lower overall patient satisfaction (7, 24). indeed, in the study by salman et al., satisfaction after penile prostheses were found to reach 100% in patients with delayed figure 6. forest plot long-term complications. figure 5. funnel plot short-term complications. figure 7. funnel plot long-term complications. archivio italiano di urologia e andrologia 2024; 96(3):12576 a.j. nanda de niro, g. wirya kusuma duarsa, m. harvy wicaksono, et al. 6 implantation, although this was also based on the baseline condition of the patient, who had a long history of penile fibrosis, shortening, and impotence (12). to date, the exact timing of prosthesis insertion when fibrosis has occurred is not known with certainty. the timing of complete fibrosis after an acute attack of priapism is also unknown. sedigh et al. described mild dilatation after one week of priapism (25), similar to the study performed by salman et al. in which mild dilatation was performed within 5 days of establishing a diagnosis of priapism (12). conflicting results were presented by hebert et al., who indicated a greater benefit in reducing the rate of severe complications when penile prosthesis implantation and reimplantation were performed within the first 4 months after the onset of corporal fibrosis (24). although the benefits of early penile prosthesis surgery are well documented and continue to be studied, the psychological impact on patients with ischemic priapism who must make an urgent decision to undergo penile prosthesis surgery and then receive the results is an interesting topic. in the four studies included in this review, patients undergoing delayed penile prosthesis implantation were mostly unprepared for the surgery to be performed. from a psychological perspective, the impact of penile prosthesis implantation on patients' overall quality of life has not been studied. currently, some reports recommend delaying the procedure for up to a week to give patients more time to understand their situation (11, 25). although delayed treatment increases endogenous fibrosis, a delay may be justified if the psychological benefits of a longer duration outweigh the negative effects. further studies on this topic should be initiated. this study has some limitations. studies comparing early and delayed penile prosthesis implantation are very limited; moreover, all study designs performed are retrospective studies, which have their limitations in influencing confounding factors. the relatively large heterogeneity in short-term complications remains a limitation of the study. the differences may be due to patient demographic characteristics, surgeon experience, a technique used, type of implant, and timing of prosthesis insertion. conclusions this systematic review and meta-analysis is the first study to include a comparative examination of the short-term and long-term complications of early and delayed penile prosthesis implantation. the results of the pooled analysis confirmed that short-term and long-term complications were significantly lower with early implantation than with delayed implantation. studies on the psychological impact of early penile prosthesis implantation are suggested for further investigation to optimize treatment outcomes for patients with ischemic priapism. references 1. mishra k, loeb a, bukavina l, et al. management of priapism: a contemporary review. sex med rev 2020; 8:131-9. 2. biebel mg, gross ms, munarriz r. review of ischemic and nonischemic priapism. curr urol rep 2022; 23:143-53. 3. bivalacqua tj, allen bk, brock g, et al. acute ischemic priapism: an aua/smsna guideline. j urol 2021; 206:1114-21. 4. ericson c, baird b, broderick ga. management of priapism: 2021 update. urol clin north am 2021; 48:565-76. 5. yücel öb, pazır y, kadıoglu a. penile prosthesis implantation in priapism. sex med rev 2018; 6:310-8. 6. reddy a, finley l, horrall s. hyperosmolar hyperglycemic syndrome in a young boy. proc (bayl univ med cent) 2019; 32(4):627. 7. zacharakis e, garaffa g, raheem aa, et al. penile prosthesis insertion in patients with refractory ischaemic priapism: early vs delayed implantation. bju int 2014; 114:576-81. 8. salem ea, el aasser o. management of ischemic priapism by penile prosthesis insertion: prevention of distal erosion. j urol 2010; 183:2300-3. 9. tausch tj, zhao lc, morey af, et al. malleable penile prosthesis is a cost-effective treatment for refractory ischemic priapism. j sex med 2015; 12:824-6. 10. joice ga, liu jl, burnett al. medical treatment of recurrent ischaemic priapism: a review of current molecular therapeutics and a new clinical management paradigm. bju int 2021; 127:498-506. 11. reddy ag, alzweri lm, gabrielson at, et al. role of penile prosthesis in priapism: a review. world j mens health 2018; 36:4. 12. salman b, elsherif e, elgharabawy m, badawy a. early versus delayed penile prosthesis insertion for refractory ischemic priapism. arab j urol. 2022; 21:76-81. 13. rees rw, kalsi j, minhas s, et al. the management of low-flow priapism with the immediate insertion of a penile prosthesis. bju int 2002; 90:893-7. 14. muneer a, ralph dj. immediate placement of a penile prosthesis as first-line treatment for the management of ischaemic priapism. eur urol focus 2019; 5:529-30. 15. ha as, han ds, wallace bk, et al. a population-based analysis of predictors of penile surgical intervention among inpatients with acute priapism. int j impot res. 2023; 35:107-113. 16. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. syst rev 2021; 10:1-11. 17. de niro ajn, kusuma duarsa gw, yudiana iw, et al. penile prosthesis implantation in priapism: is early indicating better outcomes?. prospero 2023 crd42023411005. [cited 2023 apr 9]. prospero. available from: https://www.crd.york.ac.uk/prospero/#myprospero 18. krzastek sc, smith r. an update on the best approaches to prevent complications in penile prosthesis recipients. ther adv urol 2019 [cited 2023 apr 9]; 11. available from: /pmc/articles/ pmc6329024/ krzastek sc, smith r. an update on the best approaches to prevent complications in penile prosthesis recipients. ther adv urol. 2019; 11:1756287218818076. 19. palmisano f, vagnoni v, franceschelli a, et al. immediate insertion of a soft penile prosthesis as a new option for a safe and costeffective treatment of refractory ischemic priapism. arch ital urol androl 2021; 93:356-60. 20. capece m, falcone m, cai t, et al. penile prosthesis implantation in refractory ischaemic priapism: patient selection and special considerations. res rep urol 2022; 14:1. 21. moore j, whelan tf, langille gm. the use of penile prostheses in the management of priapism. transl androl urol 2017; 6(suppl 5):s797-803. archivio italiano di urologia e andrologia 2024; 96(3):12576 7 penile prosthesis implantation in patients with ischemic priapism 22. yafi fa, hellstrom wjg. immediate placement of penile prosthesis for the management of ischemic priapism as first-line treatment. eur urol focus 2019; 5:531-2. 23. krughoff k, bearelly p, apoj m, et al. multicenter surgical outcomes of penile prosthesis placement in patients with corporal fibrosis and review of the literature. int j impot res 2022; 34:86-92. 24. hebert kl, yafi fa, wilson s. inflatable penile prosthesis implantation into scarred corporal bodies: timing may decrease postoperative problems. bju int 2020; 125:168-72. 25. sedigh o, rolle l, negro cla, et al. early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. int j impot res 2011; 23:158-64. 26. johnson m, hallerstrom m, chiriaco g, et al. pd44-01 a comparison between early and delayed penile prosthesis insertion in men with refractory ischaemic priapism.. j urol 2019; 201(supplement 4). 27. elhawy mm, fawzy am. outcomes of low-flow priapism and role of integrated penile prosthesis management. african journal of urology 2021; 27:1-8. correspondence agustin j. nanda de niro, md deniro_nanda@yahoo.co.id gede wirya kusuma duarsa gwkduarsa@gmail.com marshal harvy wicaksono marshalharvy@gmail.com pande made wisnu tirtayasa wisnu.tirtayasa@gmail.com kadek budi santosa busanbsa@gmail.com i wayan yudiana yanyud@yahoo.com nyoman gede prayudi prayudi_blonx@yahoo.com prof. i.g.n.g. ngoerah general hospital jl. diponegoro, dauh puri kelod, denpasar, bali conflict of interest: the authors declare no potential conflict of interest. stesura seveso 323archivio italiano di urologia e andrologia 2022; 94, 3 original paper no conflict of interest declared. include either reconstructive surgery, or sperm retrieval with intracytoplasmic sperm injection (icsi). surgical sperm retrieval with icsi can be used as a primary treatment modality in patients who do not wish to proceed with surgical reconstruction, or in patients who have failed reconstructive surgery, or in cases of cbavd. tournaye et al. in 1994 reported successful fertilization and pregnancy with spermatozoa retrieved with microsurgical epididymal sperm aspiration (mesa) in patients with cbavd. following this; percutaneous epididymal sperm aspiration (pesa) was described as an alternative to mesa for patients with oa (2, 3). whilst the technique of pesa is well established, the live birth rates (lbrs) and factors affecting outcomes following pesa-icsi are under-reported in the literature (4). in this context, the sperm retrieval, fertilization and pregnancy rates following pesa-icsi vary from 69 to 100%, 58-77.7% and 40-50% respectively, although longitudinal, cumulative lbrs and the impact of male/female and icsi variables on lbr have not been systematically analyzed (3-5). furthermore, the effect of using fresh versus frozen sperm and embryos on lbrs, remains controversial with very limited contemporary data in the literature. the aim of this study was to analyze fertilization, pregnancy and lbr in couples undergoing pesa-icsi and factors affecting outcomes, including etiology of obstruction, the use of fresh versus frozen sperm and fresh versus frozen embryo transfer. materials and methods this is a multicenter study that was conducted in egypt in tanta, 6th of october and al-mansoura universities. the medical records of patients with oa who underwent pesa-icsi between 2011 and 2021 were analyzed. men were subdivided according to the aetiology of oa into congenital (eg vasal aplasia), iatrogenic (eg inguinoscrotal surgeries or vasectomy) and idiopathic (epididymal/ejaculatory duct obstruction). the age of the male/female partner, fertilization, pregnancy and lbrs were determined in each group. all men in the vasal aplasia and the idiopathic groups underwent genetic analysis (including karyotyping, y chromosome micro-deletions and cf gene analysis). objectives: to report on the live birth rates (lbrs) following percutaneous epididymal sperm aspiration (pesa) in men with obstructive azoospermia (oa) and factors affecting treatment outcome which is under reported in the literature. methods: this is a multicenter study that was conducted in egypt including all couples undergoing intra cytoplasmic sperm injection (icsi) for oa using pesa-derived sperms. men were subdivided according to aetiology into congenital, iatrogenic and idiopathic groups. fertilization, pregnancy and lbrs were determined and compared in each group. the longitudinal lbr, crude and expected cumulative delivery rates (ccdr, ecdr) were calculated. multiple logistic regression analysis was used to determine significant associations between maternal, paternal and icsi factors with successful live births. results: ninety couples were included in the study. viable sperm for icsi was retrieved in 89 men (98.9%). a total of 155 icsi cycles with 17 frozen embryo transfers resulted in 81 pregnancies and 55 live births. after 5 cycles, the longitudinal lbr, ccdr and ecdr were 30%, 57.3% and 88.6% respectively. maternal age and number of fertilized eggs were the only factors significantly affecting lbrs. conclusions: pesa is a minimally invasive procedure for securing viable sperm for icsi in oa men, with high cumulative delivery rates. maternal age and number of fertilized eggs are the only factors that significantly affecting lbr. the contemporary longitudinal and cumulative lbrs provide objective outcome data to counsel oa patients undergoing fertility treatments. key words: live birth rates; obstructive azoospermia; percutaneous epididymal sperm aspiration. submitted 1 july 2022; accepted 17 july 2022 introduction azoospermia is defined as the complete absence of sperm in the ejaculate and accounts for 10% of all male factor infertility, with an obstructive aetiology constituting up to 40% of azoospermia cases. obstructive azoospermia (oa) may be congenital, as congenital bilateral absence of vas deferens (cbavd), or acquired as following genitourinary infection, vasectomy or idiopathic (1). the therapeutic treatment options factors predicting the outcome of percutaneous epididymal sperm aspiration in men with obstructive azoospermia khaled mohamed almekaty 1, mohamed hasan zahran 2, mohamed lotfy amer 1, ayman mohamed hagras 1, khaled abdelaziz salem 1, ayman sayed rashed 3, ahmed fayez ghaith 1 1 tanta university hospital, urology department, tanta, egypt; 2 mansoura urology-nephrology centre, urology department, mansoura, egypt; 3 october 6 university, faculty of medicine, department of urology, cairo, egypt. doi: 10.4081/aiua.2022.3.323 summary archivio italiano di urologia e andrologia 2022; 94, 3 khaled mohamed almekaty, mohamed hasan zahran, mohamed lotfy amer, et al. 324 technique of pesa pesa was performed under local anaesthetic cord block or general anesthesia on the same day as oocyte retrieval and used immediately for icsi or cryopreserved for elective use. after taking written informed consent, the head of the epididymis was grasped between thumb and index finger and a 26-gauge needle attached to 3-ml syringe containing sperm buffer medium was inserted through scrotal skin into the epididymal head. suction with gradual withdrawal of the needle was performed. the aspirate was flushed with sperm buffering medium and immediately examined microscopically for presence of viable sperm by an embryologist. icsi protocol the unit icsi protocol including ovarian stimulation, oocyte retrieval and embryo transfer protocol has been previously described (6). primary outcome measures primary outcome measures were sperm retrieval rate (srr), fertilization rate (fr), pregnancy rate (pr), longitudinal lbr and two measures of cumulative delivery rates: crude cumulative delivery rate (ccdr) is the observed number of live births following a specific, pre-determined number of icsi cycles, divided by the total number of participating couples who had icsi treatment (7). expected cumulative delivery rate (ecdr) is the delivery rate assuming that couples who did not return for treatment had the same chance of a live birth over a specific number of cycles as those who continued their treatment (7). longitudinal lbr is the lbr after a single pesa-icsi cycle in all patients undergoing pesa (7). miscarriage was defined as the spontaneous loss of a clinical pregnancy before 12 weeks of gestation. secondary outcome measures secondary outcome measures included potential variables affecting lbrs including male/female age, etiology of obstruction; time elapsed since iatrogenic obstruction, the use of fresh versus frozen sperm and fresh versus frozen embryo transfer. ethics statement the authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. the study was conducted in accordance with the declaration of helsinki. the study was approved by the institutional review board of human fertilization and embryology authority (hfea) and was approved by our institutional review board (irb approval no. 35472/5/22) and individual consent for this retrospective analysis was waived. statistical analysis spss (ibm, version 22 (13.8.2013) software package was used to analyse data. descriptive statistics were expressed as median (iqr). differences in outcomes between fresh and frozen sperm were analysed using chi square test. ccdr and ecdr were calculated using a kaplan meier table & plot. multiple linear regression was used to determine whether secondary outcome measures were associated with lbr and p-values of 0·05 or less were deemed significant. results ninety couples with oa underwent pesa-icsi with a median male and female age of 44 (iqr 38-49) and 36 (iqr 32-39) years respectively. in the bilateral vasal aplasia group, 7/18 (38.9%) patients were cftr-gene positive. all patients had normal karyotype and no y microdeletions. sperm retrieval data sperm was successfully retrieved in 89 of 90 patients (98.9%). in one patient, pesa was unsuccessful and a conventional tese was alternatively performed. in 2 out of 35 cryopreserved sperm samples (5.7%), sperm was not viable on the day of icsi and a simultaneous fresh pesa table 1. treatment characteristics and icsi outcomes. values demographics: male age, median (iqr) 44 (iqr 38-49) female age, median (iqr) 36 (iqr 32-39) total number of icsi cycles 155 total number of frozen et 27 icsi cycles/couple, median (iqr) 2 (iqr 1-2) fertilization: ova retrieved, median (iqr) 7 (5-11) sperm retrieved 89/90 (98.9%) cycles using fresh sperm 120 (77.4%) cycles using frozen sperm 35 (22.6%) fertilized ova, median (iqr) 4 (3-8) fertilization rate 95.5% (148/155) embryo transfer: per cycle, median (iqr) 2(1-2) frozen embryo transfer 17 pregnancy rate: miscarriage 15/81 (18.5%) clinical pregnancy 81/155 (52.3%) livebirth rate: longitudinal 30% (27/90) of primary cycle 32.6% ccdr after 5 cycles 57.3% ecdr after 5 cycles 88.6% pet: embryo transfer; icsi: intra cytoplasmic sperm injection; iqr: interquartile range; ccdr: crude cumulative delivery rates; ecdr: expected cumulative delivery rates. table 2. ccdr and ecdr following pesa-icsi. cycle ccdr (%) ecdr (%) 1 32.6 32.6 2 49.4 58.5 3 53.9 69.6 4 55.1 77.2 5 57.3 88.6 ccdr: crude cumulative delivery rates; ecdr: expected cumulative delivery rates. 325archivio italiano di urologia e andrologia 2022; 94, 3 outcomes of percutaneous epididymal sperm aspiration was performed. one patient required a prolonged course of antibiotics to treat epididymitis post-operatively. icsi outcomes the total number of icsi cycles was 155, with a further 17 frozen embryo transfers. 89 couples underwent a primary cycle of icsi and 39 couples had repeated cycles (a total of 66 repeated cycles), ranging from 1-5 cycles per couple. detailed treatment characteristics and icsi outcomes are shown in table 1. following 5 cycles of icsi, the ccdr and ecdr were 57.3% and 88.6% respectively (table 2, figure 1), with a longitudinal lbr of 30% (27/90). in total, pesa-icsi resulted in the birth of 6 twins and 49 singletons. fifty-five (61.1%) couples used fresh, while 35 (38.9%) couples used cryopreserved sperm on the day of oocyte retrieval. there was no significant difference in pregnancy (p = 0.731) or live birth rates (p = 0.553) on comparing the use of fresh and frozen-thawed sperm (table 3). multiple logistic regression analysis demonstrated that pr significantly correlated to the number of fertilized ova (p = 0.018), while lbr correlated to the number of fertilized ova and maternal age (p = 0.037 and 0.0067 respectively). all other factors including male age, aetiology of obstruction, time elapsed since iatrogenic obstruction, the use of fresh versus frozen sperm or fresh versus frozen embryos were not significantly associated with pr or lbr (table 3). discussion in oa patients, microsurgical reconstruction can be done to restore patency of the seminal tract. alternatively, surgical sperm retrieval combined with icsi can be utilized as a primary therapeutic option or in men who do not wish to proceed with surgical reconstruction or in whom reconstruction has failed. the advancement in the surgical sperm retrieval methods and introduction of icsi has been a landmark achievement in the treatment of oa, although there is very limited contemporary data in the literature reporting on lbrs and factors affecting lbrs in this particular cohort of patients (table 4) (4, 8-12). in the current study, viable sperm was obtained in almost all men (98.9% srr) using pesa which proved to be a minimally invasive and effective means of sperm acquisition in men with oa. similarly, kovac et al. reported that in men with oa viable sperm was obtained in all 51 patients using pesa (100% retrieval rate) (4). in contrast, yafiet al. reported a much lower retrieval rate in similar patients (75.3%) (13). esteve et al. 2013 analyzed the outcome of pesa and tesa in various aetiologies of oa and found that sperm retrieval using pesa was higher in men with cbavd compared to post-vasectomy and post-infection groups (96.8, 69.5 and 76.4% respectively) and recommended the use of pesa for cbavd and tesa for other aetiologies (5). these findings were not substantiated in the present study, in which we demonstrate a universally high sperm retrieval rate regardless of the aetiology of obstruction, a finding also observed in other series (4). it could be speculated that improvement in surgical and laboratory techniques may explain the improved outcomes in this series of patients. more importantly, there was no difference in lbrs, irrespective of the aetiology of obstruction. whilst we have demonstrated no difference in lbr comparing different aetiologies, an interesting further study would be to determine the lbr from icsi in men with oa comparing epididymal versus testicular sperm in the context of increased dna fragmentatable 3. factors affecting pr and lbr (multiple regression analysis). association with pregnancy association with live birth (p value) (p value) male age 0.672 0.800 female age 0.146 0.067* number of eggs collected 0.400 0.443 number of eggs injected 0.129 0.606 number of eggs fertilised 0.018* 0.037* number of embryo transfers 0.528 0.484 fresh/frozen sperm 0.972 0.798 fresh/frozen embryo transfer 0.166 0.482 aetiology–iatrogenic 0.325 0.542 aetiology–congenital 0.165 0.411 aetiology-iidiopathic 0.618 0.881 presence of gene mutation (male) 0.221 0.192 * statistical significance (p < 0.05). cf: cystic fibrosis. figure 1. ccdr and ecdr following pesa-icsi. table 4. reported pesa and icsi outcomes in the literature. study number of patients pregnancy rate miscarriage livebirth rate or pesa attempts (/cycle or/patients) (number or %) pasqualotto et al, 2002 130 patients /cycle: 34.6%/patient: 54.5% abortion: 11.1% na pasqualotto et al, 2003 23 pesa for 20 patients /cycle: 37.5% 0 na glina, 2003 79 pesa for 58 patients /cycle: 21/55 (38%) 9 9 livebirths naru et al, 2008 53 patients /cycle: 30 (43.5%) 5 na kovac et al, 2014 51 (40 fresh, 11 frozen) /cycle: 17/35 (48.6%) na na elhanbly et al, 2015 85 patients /patient: 35 (41.1%) na 29 livebirths current study 90 patients /cycle: 81/155 (52.3%) 15 longitudinal = 27/90 (30%) ccdr = 57.3% ecdr = 88.6% na: not assessed. ccdr: crude cumulative delivery rate; ecdr: expected cumulative delivery rates. archivio italiano di urologia e andrologia 2022; 94, 3 khaled mohamed almekaty, mohamed hasan zahran, mohamed lotfy amer, et al. 326 tion and examine the potential for improving outcomes using testicular sperm in this cohort of men. an increased association of cftr mutations has been described in patients with oa “other than cbavd” and oat syndrome, and it has been suggested that cftr mutation screening should be limited to men with vasal aplasia on at least one side or in those with idiopathic epididymal obstruction (14). interestingly, we did not find any cftr mutations, other than those found in the vasal aplasia group. within the literature, the overall patency and pregnancy rates following vasectomy reversal are 86 and 58% respectively, with pregnancy rates inversely correlated with the duration of obstruction (15). in the present study, iatrogenic obstruction was attributed to bilateral inguinoscrotal surgeries mainly with vasectomy in only 2 patients done abroad. vasectomy as a means of male contraception is not allowed in the arab and islamic countries. however, lbrs were not affected by the duration of obstruction and thus patients can be reassured that the time elapsed since obstruction does not negatively affect lbrs in couples undergoing pesa/icsi. this is in agreement with a previous study showing no association between the time since vasectomy and clinical pregnancy after pesa (16). pregnancy rates following vasectomy reversal have been reported to be between 37-60% with a meantime elapsed since vasectomy of 5.7-10 years (17, 18), similarly, pesa coupled with icsi has been reported to result in clinical pr of 40-50 % in oa, although the number of studies reporting on lbrs in the literature is sparse (table 4) (2-4). whilst it is difficult to make direct comparisons, the overall ccdr and ecdr in this study are comparable and consistent with the reported natural pr following vasectomy reversal. however, whilst this study demonstrates that pesa/icsi patients have high ccdr (57.3%) and ecdr (88.6%), icsi may not be as cost effective as surgical reconstruction, as up to 5 cycles of icsi will be required to achieve comparable paternity rates to surgical reconstruction. nevertheless, this study does provide important and contemporary comparative data on lbrs, which can be utilized when counseling patients prior to intervention for oa and therefore impact upon their decision to proceed with icsi or surgical repair. some studies have suggested that cryopreservation of sperm can negatively affect the vitality; motility of sperm and their fertilizing capacity (13). however, in this study, there were no differences in miscarriage, pregnancy or lbrs using fresh and frozen-thawed epididymal sperm. similarly, kovac reported no statistically significant difference between fresh and frozen-thawed pesa-derived sperm in fertilization, overall pregnancy and multiple gestation rates (4). thus cryopreservation, of sperm does not appear to have any negative impact on lbrs compared to fresh sperm, although a small number of patients (5.7%) did require a further fresh pesa backup due to non-viable sperm found on thawing cryopreserved sperm on the day of oocyte retrieval. similarly, the lbrs from frozen et were comparable to fresh et, which may not only improve the cost effectiveness of treatment for couples undergoing repeated icsi cycles, but also reduce repeated interventions in the female partner. in the present study, pregnancy and lbrs were only affected by maternal age and number of fertilized ova. similarly, kumtepe et al. have reported that male age did not affect outcome of icsi, whereas female age did (18). in contrast, elhanbly et al. reported that male age negatively affected the sperm characteristics obtained by pesa, clinical pregnancy and lbrs, yet the age of the female partner did not (12). this study has the limitation of being retrospective and including a relatively small number of patients in each aetiological subgroup and further well-designed prospective studies are needed to consolidate these current findings. pesa is not well-adopted in egypt or arab countries because vasectomy is rarely done there. the population of oa in these countries is different from europe and us. most cases are congenital or idiopathic while iatrogenic cases are rare. however, the outcome of the current study shows that the cumulative lbrs in the form of ccdr and ecdr, in oa patients undergoing pesa-icsi are high (75.3% and 88.6% after 5 icsi cycles) whilst the longitudinal lbr of 30% is consistent with the lbr following other assisted reproductive technologies. based on this study, pesa should be more widely adopted in egypt and arab countries as a simple noninvasive method of sperm retrieval in oa patients. also, it provides contemporary data that should be useful for counseling patients embarking on pesa/icsi treatment. conclusions pesa is a simple and effective method of obtaining sperm for icsi in oa patients, with the opportunity for sperm cryopreservation. only maternal age and number of fertilized eggs affect pregnancy and lbr. there was no difference in outcomes using fresh or frozen epididymal sperm or fresh or frozen embryos. the longitudinal and cumulative lbrs from pesa/icsi reported in this study provide contemporary outcome data to counsel patients with oa undergoing fertility interventions. references 1. jarow jp, espeland ma, lipshultz li. evaluation of the azoospermic patient. j urol. 1989; 142:162. 2. tournaye h, devroey p, nagy j, et al. microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection: a new effective approach to infertility as a result of congenital bilateral absence of the vas deferens fertil steril. 1994; 61:1045-105. 3. shrivastav p, nadkarni p, wensvoort s, craft i. percutaneous epididymal sperm aspiration for obstructive azoospermia. hum reprod. 1994; 9:2058-61. 4. kovac jr, lehmann kj, fischer ma. a single-center study examining the outcomes of percutaneous epididymal sperm aspiration in the treatment of obstructive azoospermia. urol ann. 2014; 6:41-45. 5. esteves sc, lee w, benjamin dj, et al. reproductive potential of men with obstructive azoospermia undergoing percutaneous sperm retrieval and intracytoplasmic sperm injection according to the cause of obstruction. j urol. 2013; 189:232-7. 6. almekaty k, abomelha s, thum y, et al. reporting on longitudinal live birth rates and cumulative delivery rates are more realistic outcome measures than sperm retrieval rates in couples undergoing mtese–icsi. hum fertil. 2018; 22:139-144. 327archivio italiano di urologia e andrologia 2022; 94, 3 outcomes of percutaneous epididymal sperm aspiration 7. hull m, eddowes h, fahy u, et al. expectations of assisted conception for infertility. bmj. 1992; 304:1465-1469. 8. pasqualotto ff, rossi ferragut lm, rocha cc, et al. outcome of in vitro fertilization and intracytoplasmic injection of epididymal and testicular sperm obtained from patients with obstructive and nonobstructive azoospermia. j urol. 2002; 167:1753-6. 9. pasqualotto f, rossi-ferragut l, rocha c, et al. the efficacy of repeat percutaneous epididymal sperm aspiration procedures. j urol. 2003; 169:1779-81. 10. glina s, fragoso j, martins f, et al. percutaneous epididymal sperm aspiration (pesa) in men with obstructive azoospermia. int braz j urol. 2003; 29:141-146. 11. naru t, sulaiman mn, kidwai a, et al. intracytoplasmic sperm injection outcome using ejaculated sperm and retrieved sperm in azoospermic men. urol j. 2008; 5:106-10. 12. elhanbly s, el-saied ma, fawzy m, et al. relationship of paternal age with outcome of percutaneous epididymal sperm aspiration intracytoplasmic sperm injection, in cases of congenital bilateral absence of the vas deferens. fertil steril. 2015; 104:602-6. 13. yafi fa, zini a. percutaneous epididymal sperm aspiration for men with obstructive azoospermia: predictors of sperm retrieval rates. fertil steril. 2013; 100:s448. 14. krausz c, chianese c, swerdloff rs, wang c. emery and rimoin's principles and practice of medical genetics (sixth edition), chapter 33 genetics of male infertility. 2013, pages 1-18. 15. lee r, li ps, schlegel pn, goldstein m. reassessing reconstruction in the management of obstructive azoospermia: reconstruction or sperm acquisition? urol clin north am. 2008; 35:289-301. 16. bromage sj, douglas j, falconer da, et al. factors affecting successful outcome from icsi in men following previous vasectomy. world j urol. 2007; 25:519-24. 17. ozkavukcu s, erdemli e, isik a, oztuna d, et al. effects of cryopreservation on sperm parameters and ultrastructural morphology of human spermatozoa. j assist reprod genet. 2008; 25:403-11. 18. kumtepe y, yakin k, kahraman s, et al. male age is not an independent factor to affect the outcome of assisted reproductive techniques. int j androl. 2003; 26:161-5. correspondence khaled mohamed almekaty,md dr.khaledhafez@med.tanta.edu.eg mohamed lotfy amer, md drmlamer@med.tanta.edu.eg ayman mohamed hagras, md ahagras80@yahoo.com khaled abdelaziz salem, md khsalemmd@gmail.com ahmed fayez ghaith, md (corresponding author) dr_ahmedfayez@yahoo.com tanta university hospital, urology department, tanta (egypt) el-gharbia govenorate, tanta. el-gash st. medical campus, the faculty of medicine mohamed hasan zahran, md zahranmha@yahoo.com mansoura urology-nephrology centre, urology department, mansoura (egypt) ayman sayed rashed,md aymanrashed@msn.com october 6 university, faculty of medicine, department of urology, cairo (egypt) stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2150 original paper no conflict of interest declared. muscle-invasive bladder cancer and a valid option for selected patients with high-grade non-muscle invasive bladder cancer (3, 4). even with improvements in surgical techniques and perioperative care, rc is a technically challenging operation and is associated with comparatively high perioperative morbidity and mortality (5, 6). the incidence of complications after the surgery has been reported to be in the range of 11-70% and late morbidity in contemporary series has been 19 to 58% (6, 7). it has been shown that complications after rc and urinary diversion severely affect the patients’ quality of life (8). therefore, improving surgical techniques to reduce postoperative complications is required. in this study, we investigated the effect of ureteroileal anastomosis retroperitonealization on perioperative complications of radical cystectomy with ileal conduit urinary diversion. patients and methods we retrospectively reviewed medical data of all patients who underwent rc between 2016 and 2021 at two highvolume referral urology centers. three different expert surgeons had performed the operations. our inclusion criteria were 1. rc was performed to manage bladder urothelial carcinoma; 2. the ileal conduit was performed as urinary diversion; 3. the ureteroileal anastomosis was performed according to wallace 1 technique. our exclusion criteria were 1. patients with anatomical single kidney and ureter; 2. those with incomplete medical charts which did not provide appropriate data about all of the variables that were investigated in this study. patients who met all of the inclusion criteria and lacked the exclusion criteria were entered into the study. we collected data regarding patients’ characteristics and all of the postoperative complications within 90 days of surgery. any deviations from the normal postoperative course were considered complications (9). perioperative mortality was determined as death from any cause within 90 days of operation. procedure antiplatelet and anticoagulant medications were stopped at least 1 week before the operation. all patients received mechanical bowel preparation. we utilized elastic combackground: radical cystectomy (rc) has been considered the standard management of muscle-invasive bladder cancer. despite the improvements in surgical techniques and perioperative care, rc is still associated with high perioperative morbidity and mortality. objective: this study aims to evaluate the effect of retroperitonealization of ureteroileal anastomosis on perioperative complications of rc with ileal conduit urinary diversion. patients and methods: this is a retrospective cohort study. we reviewed medical charts of 876 patients who underwent rc between 2016 and 2021. based on the inclusion and exclusion criteria, 748 patients entered the study. according to retroperitonealization of the ureteroileal anastomosis, patients were categorized into two groups (group i without retroperitonealization of the ureteroileal anastomosis and group ii with retroperitonealization of the ureteroileal anastomosis). patients’ characteristics and occurrences of any complications and high-grade complications were compared between these groups. results: in comparing the complication categories between the two groups, fewer patients in group ii suffered from gastrointestinal, urinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). moreover, fewer patients in group ii experienced any complications and high-grade complications (p values were < 0.001 and < 0.001, respectively). the length of hospital stay was also significantly shorter in group ii (p < 0.001). conclusions: rc is associated with comparatively high perioperative morbidity and mortality. in the present study, 61% of the patients experienced at least one complication postoperatively. retroperitonealization of the ureterointestinal anastomosis may decrease perioperative adverse events of rc with ileal conduit urinary diversion. key words: radical cystectomy; complication; retroperitonealization. submitted 6 may 2022; accepted 19 may 2022 introduction bladder cancer is a global disease, with 573.278 incident cases and 212.536 deaths in 2020 worldwide (1). about 25% of patients with bladder cancer are diagnosed with muscle-invasive bladder cancer (2). since the early 1960s, radical cystectomy (rc) and pelvic lymphadenectomy have been considered the standard management of the effect of retroperitonealization of ureteroileal anastomosis on perioperative complications of radical cystectomy with ileal conduit urinary diversion ali ariafar, mehdi salehipour, shahriar zeyghami, mehran rezaei department of urology, shiraz university of medical sciences, shiraz, iran. doi: 10.4081/aiua.2022.2.150 summary 151archivio italiano di urologia e andrologia 2022; 94, 2 retroperitonealization of ureteroileal anastomosis pressive stocking as mechanical prophylaxis for deep vein thrombosis. ceftriaxone 1 gr, metronidazole 500 mg, and pantoprazole 40 mg were administered intravenously when anesthesia was initiated and maintained for the time of hospital admission postoperatively. the nasogastric tube was not inserted routinely. rcs were performed according to the procedure suggested by the international consultation on bladder cancer (10). lymph node dissection included the removal of all lymphatic tissues around the external iliac and internal iliac arteries and from the obturator region bilaterally. after completion of rc and lymph node dissection, a segment of 10-20 cm of ileum approximately 20 cm proximal to the ileocecal valve was isolated. the stapled ileoileal anastomosis was performed. the mesentery window was closed with interrupted sutures, and the conduit was flushed with saline and povidone-iodine until the irrigant is clear. afterward, ureters were conjoined, with the left ureter transposed to the right side of the pelvis through a tunnel prepared at the base of the sigmoid mesentery in front of the common iliac vessels. tension-free ureteroileal anastomosis was accomplished according to wallace 1 technique (11) with 5-0 polydioxanone sutures and was stented intraoperatively for at least 30 days. in completing cutaneous rosebud stoma formation, in patients who were operated on from 2016 to mid-2018, we only brought the segment directly to the anterior abdominal wall (group i). in patients who were operated on from then to 2021, we placed a peritoneal flap over the ureteroileal anastomosis in that stage of surgery. the flap was sutured to the conduit and the lateral peritoneum so that the ureteroileal anastomosis was completely covered by the peritoneum and effectively retroperitonealized (group ii). we performed this surgical technique with the purpose of separating the ureterointestinal anastomosis from the peritoneal cavity and decreasing intraperitoneal urine extravasation. before wound closure, we placed an 18-24fr drain tube through the abdominal wall and a 24fr foley catheter via the urethra into the pelvic cavity. postoperatively, patients were managed in the intensive care unit. subcutaneous daily administration of lowmolecular-weight heparin, or every 8 hours unfractionated heparin in patients with renal failure, was started 24 hours after surgery and maintained for at least 4 weeks postoperatively. further postoperative management was continued in the urology ward according to our standardized clinical care pathways for cystectomy. a day after surgery, mobilization was initiated as soon as the patient could be ambulated. on the third postoperative day, if the patient had bowel movements, he/she was allowed to take sips of water. if the patient tolerated drinking water, the diet advanced gradually to a soft diet. we started a regular diet two weeks postoperatively. the amount of drained fluid out of the foley catheter and the drain tube was measured continuously. if the creatinine concentration of drained fluid was 30% more than the concomitant serum creatinine concentration, the patient is presumed to have urine leakage. more diagnostic studies including abdominopelvic sonography, supine and upright abdominopelvic x-rays, and intravenous contrast-enhanced abdominopelvic ct scan were requested in case of persistent postoperative azotemia, sepsis or symptoms and signs of peritonitis to rule out urinary extravasation or other possible intraabdominal complications. statistical analysis mean ± standard deviation and range of quantitative variables and frequencies of the qualitative variables are presented. according to the characteristics of the variables, the mann-whitney u test or chi-square test were used to compare the two groups. p-value < 0.05 was considered table 1. patients’ characteristics. total group i group ii p-value* n = 748 n = 362 (48.4%) n = 386 (51.6%) age (years), mean ± sd (range) 64.97 ± 7.31 64.82 ± 6.88 65.11 ± 7.70 0.527 (44-84) (49-83) (44-84) ≥ 70 years old, n (%) 216 (28.9) 97 (26.8) 119 (30.8) 0.224 sex 0.803 male, n (%) 586 (78.3) 285 (78.7) 301 (78.0) female, n (%) 162 (21.7) 77 (21.3) 85 (22.0) body mass index (kg/m2), 24.37 ± 4.92 24.42 ± 4.61 24.33 ± 5.19 0.435 mean ± sd (range) (16.99-34.96) (17.09-34.96) (16.99-34.83) current smoking, n (%) 470 (62.8) 222 (61.3) 240 (62.2) 0.493 dm, n (%) 246 (32.9) 124 (34.3) 122 (31.6) 0.574 cerebrovascular comorbidities, n (%) 40 (5.3) 19 (5.2) 23 (6.0) 0.673 cardiovascular comorbidities, n (%) 185 (24.7) 113 (31.2) 112 (29.0) 0.512 pulmonary comorbidities, n (%) 26 (3.5) 11 (3.0) 15 (3.9) 0.527 routine dialysis, n (%) 50 (6.7) 12 (3.3) 18 (4.7) 0.348 previous abdominopelvic surgery, n (%) 137 (18.3) 72 (19.9) 65 (16.8) 0.281 neoadjuvant chemotherapy, n (%) 245 (32.8) 113 (31.2) 132 (34.2) 0.385 poor (< 4 met) functional capacity, n (%) 154 (20.6) 82 (22.7) 72 (18.7) 0.176 asa score 0.443 1, n (%) 78 (10.4) 36 (9.9) 42 (10.9) 2, n (%) 511 (68.3) 242 (66.9) 269 (69.7) 3, n (%) 159 (21.3) 84 (23.2) 75 (19.4) serum creatinine (mg/dl), 1.86 ± 1.29 1.48 ± 1.00 1.57 ± 1.1 0.329 mean ± sd (range) (0.8-8.1) (0.8-8.0) (0.7-8.0) hemoglobin concentration (g/dl), 13.11 ± 1.78 13.10 ± 1.71 13.12 ± 1.85 0.708 mean ± sd (range) (7.1-18.5) (10.0-16.0) (7.1-18.5) preoperative anemia, n (%) 323 (43.2) 156 (43.1) 167 (43.3) 0.963 nlr, mean ± sd (range) 5.80 ± 1.52 5.71 ± 1.56 5.78 ± 1.54 0.436 (2.10-8.99) (2.34-8.98) (2.10-8.99) hypoalbuminemia, n (%) 297 (39.7) 149 (41.2) 172 (44.6) 0.348 clinical t stage 0.466 1, n (%) 18 (2.4) 10 (2.8) 8 (2.1) 2, n (%) 569 (76.1) 282 (77.9) 287 (74.4) 3, n (%) 135 (18) 60 (16.6) 75 (19.4) 4, n (%) 26 (3.5) 10 (2.8) 16 (4.1) operative time (min), 351.31 ± 99.93 351.33 ± 98.23 351.30 ± 101.63 0.918 mean ± sd (range) (180-560) (180-540) (180-560) blood loss (cc), 803.93 ± 386.10 825.03 ± 395.90 784.15 ± 376.11 0.141 mean ± sd (range) (200-5100) (200-5100) (210-4000) intraoperative blood transfusion, n (%) 394 (52.7) 202 (55.8) 192 (49.7) 0.097 surgeons 0.666 i, n (%) 255 (34.1) 118 (32.6) 137 (35.5) ii, n (%) 273 (36.5) 137 (37.8) 136 (35.2) iii, n (%) 220 (29.4) 107 (29.6) 113 (29.3) group i without retroperitonealization of the ureteroileal anastomosis; group ii with retroperitonealization of the ureteroileal anastomosis. * group i vs ii. met: metabolic equivalent; asa: american society of anesthesiology; nlr: neutrophil to lymphocyte ratio; hypoalbuminemia: serum albumin concentration < 3.5 g/dl. archivio italiano di urologia e andrologia 2022; 94, 2 a. ariafar, m. salehipour, s. zeyghami, m. rezaei 152 as a significant level. statistical analyses were performed using the ibm spss statistics for windows, version 24 (ibm corp., armonk, n.y., usa). results out of 876 rcs that were performed in five years, 748 patients did not have the exclusion criteria and met all of the inclusion criteria; consequently, enrolled in the study. table 1 shows the summary of the patients’ characteristics. men accounted for 586 (78.3%) of patients. the mean age at rc was 64.97 ± 7.315 years, the mean body mass index (bmi) was 24.37 ± 4.92 kg/m2, the mean operative time was 351.31 ± 99.93 minutes, and the mean estimated blood loss was 803.93 ± 386.1 ml. the average length of stay after rc was 7.66 ± 4.26 days. five hundred ninety-nine complications were recorded in 456 (61%) patients within 90 days of surgery. to enhance the comparability among populations, we classified our complications using the modified clavien grading system (9) and category grouping reported by shabsigh et al. (12). in our study, the most common complication categories were gastrointestinal 147 (19.7%), wound-related 133 (17.8%), genitourinary 81 (10.8%), and infectious 78 (10.4%). ileus 116 (15.5%), surgical site infection (ssi) 112 (15.0%), hydronephrosis 54 (7.2%), urine leakage 39 (5.2%), and urinary tract infections 39 (5.2%) were the most frequent complications. table 2 represents a comprehensive breakdown of our complications. the highest complication grade in each patient was clavien grade i in 220 (29.4%), grade ii in 114 (15.2%), grade iii in 51 (6.8%), grade iv in 53 (7.1%), and grade v in 11 (1.5%) patients (table 3). eleven (1.5%) deaths were recorded within 90 days of surgery. no patient died intraoperatively. five patients died from gastrointestinal events, three from infectious events (sepsis), two from cardiovascular events, and one from a cerebrovascular event. group i and ii consisted of 362 and 386 patients, respectively. patients’ characteristics were not significantly different between these groups. the number of patients who were operated on by each surgeon was not significantly different between the two groups (table 1). incidences of sepsis, wound dehiscence, renal failure, urine leakage, and myocardial infarction, were significantly lower in group ii (p values were 0.001, 0.001, 0.047, < 0.001, and 0.044, respectively). in comparing the complication categories between the two groups, fewer patients in group ii suffered from gastrointestinal, urinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). moreover, fewer patients in group ii experienced any complications and high-grade complications (p values were < 0.001 and < 0.001, respectively). the length of hospital stay was also significantly shorter in group ii (p < 0.001) (table 2). discussion despite recent advances in surgical techniques, rc is still highly morbid with complications occurring in up to two-thirds of patients within 90 days (6, 7, 13-17). various factors have been related to post-rc complications and prognosis. maffezzini et al. have demonstrated that advanced age of more than 70 years and charlson comorbidity index > 3 are associated with worse post-rc prognosis (18). it has been shown that in patients undergoing rc, low serum albumin concentration is a signifitable 3. highest clavien complication grade in each patient. highest clavien complication grade total n (%) group i n (%) group ii n (%) i 220 (29.4) 98 (27.1) 122 (31.6) ii 114 (15.2) 49 (13.5) 65 (16.8) iii 51 (6.8) 40 (11.0) 11 (2.8) iv 53 (7.1) 47 (13.0) 6 (1.6) v 11 (1.5) 6 (1.7) 5 (1.3) table 2. summary of complication categories and types. category complications total n (%) group i n (%) group ii n (%) p-value* of patients of patients of patients gastrointestinal 147 (19.7) 84 (23.2) 63 (16.3) 0.018 postoperative ileus 116 (15.5) 63 (17.4) 53 (13.7) 0.166 anastomotic bowel leakage 11 (1.5) 8 (2.2) 3 (0.8) 0.104 gastrointestinal bleeding 10 (1.3) 6 (1.7) 4 (1.0) 0.460 diarrhea 18 (2.4) 12 (3.3) 6 (1.6) 0.116 infectious 78 (10.4) 43 (11.9) 35 (9.1) 0.209 fuo 16 (2.1) 7 (1.9) 9 (2.3) 0.707 uti 39 (5.2) 15 (4.1) 24 (6.2) 0.202 sepsis 28 (3.7) 22 (6.1) 6 (1.6) 0.001 wound 133 (17.8) 70 (19.3) 63 (16.3) 0.281 ssi 112 (15.0) 53 (14.6) 59 (15.3) 0.805 wound dehiscence 23 (3.1) 19 (5.2) 4 (1.0) 0.001 genitourinary 81 (10.8) 49 (13.5) 32 (8.3) 0.021 hydronephrosis 54 (7.2) 29 (8.0) 25 (6.5) 0.418 renal failure 7 (0.9) 6 (1.7) 1 (0.3) 0.047 urine leakage 39 (5.2) 30 (8.3) 9 (2.3) < 0.001 cardiac 15 (2.0) 12 (3.3) 3 (0.8) 0.013 arrhythmia 5 (0.7) 3 (0.8) 2 (0.5) 0.602 myocardial infarction 10 (1.3) 8 (2.2) 2 (0.5) 0.044 congestive heart failure 4 (0.5) 3 (0.8) 1 (0.3) 0.286 pulmonary 22 (2.9) 13 (3.6) 9 (2.3) 0.308 pneumonia 12 (1.6) 6 (1.7) 6 (1.6) 0.911 pleural effusion 7 (0.9) 4 (1.1) 3 (0.8) 0.642 lung edema 3 (0.4) 3 (0.8) 0 0.073 bleeding 21 (2.8) 14 (3.9) 7 (1.8) 0.089 anemia requiring transfusion 21 (2.8) 14 (3.9) 7 (1.8) 0.089 thromboembolic 10 (1.3) 7 (1.9) 3 (0.8) 0.169 deep venous thrombosis 10 (1.3) 7 (1.9) 3 (0.8) 0.169 pulmonary embolism 3 (0.4) 2 (0.6) 1 (0.3) 0.526 neurologic 10 (1.3) 6 (1.7) 4 (1.0) 0.460 cerebrovascular event 5 (0.7) 4 (1.1) 1 (0.3) 0.156 delirium 6 (0.8) 3 (0.8) 3 (0.8) 0.937 surgical 7 (0.9) 5 (1.4) 2 (0.5) 0.221 rectal injury 6 (0.8) 3 (0.8) 2 (0.5) 0.602 obturator nerve injury 2 (0.3) 0 2 (0.5) 0.170 miscellaneous 7 (0.9) 3 (0.8) 4 (1.0) 0.768 death 11 (1.5) 6 (1.7) 5 (1.3) 0.681 all complications 456 (61) 246 (68.0) 210 (54.4) < 0.001 high-grade complications 115 (15.4) 93 (25.7) 22 (5.7) < 0.001 hospital stay, 7.66 ± 4.26 8.54 ± 5.71 6.84 ± 1.78 < 0.001 mean ± sd (range) (5-73) (5-73) (5-18) group i without retroperitonealization of the ureteroileal anastomosis; group ii with retroperitonealization of the ureteroileal anastomosis. * group i vs ii. fuo: fever of unknown origin; uti: urinary tract infection; ssi: surgical site infection. 153archivio italiano di urologia e andrologia 2022; 94, 2 retroperitonealization of ureteroileal anastomosis cant predictor of mortality and serious adverse events (19). other factors that are associated with adverse outcomes after rc include sarcopenia, an increased bmi, female gender, prior abdominopelvic surgery, extravesical disease, and prior pelvic radiotherapy (20-22). although the majority of the post-rc complications are minor, it has been reported that up to 20% of patients will experience a major complication (23, 24). multiple studies reported that more common complication categories are gastrointestinal, infectious, wound-related, and genitourinary (12, 25). in our study, five hundred ninety-nine complications were recorded in 456 (61%) patients within 90 days of surgery. 15.4% of our patients experienced major (≥ grade iii) complications. our observation was comparable with the study by shabsigh et al. (12) reporting that the overall complication rate was 64% and the major complication rate was 13%. hautman et al. (25) also reported complications in rc and ileal neobladder cases using the same standards. in their study, 58% of the patients experienced at least one complication within 90 days of surgery. in our cohort, the most common complication categories were gastrointestinal, wound-related, genitourinary, and infectious. ileus, ssi, hydronephrosis, urine leakage, and urinary tract infections were the most frequent complications. this distribution was similar to the results obtained from other studies (12, 25). retroperitonealization of the ureteroileal anastomosis during rc is mainly performed to prevent the herniation of the small bowel lateral to the conduit and the effect of performing this maneuver on perioperative complications has not been thoroughly studied. in this concept, soleimani et al. compared the postoperative complications of transperitoneal vs extraperitoneal rc. they reported that early gastrointestinal complications including oral intake intolerance, ileus, intestinal obstruction, and anastomosis leakage were lower in the extraperitoneal rc group. also in this group, the rate of postoperative urine leakage and wound-related complications were lower (26). kulkarni et al. investigated the transperitoneal and extraperitoneal rc complications and reported that the rates of gastrointestinal complications, reoperation, and intestinal obstruction were significantly lower in the extraperitoneal approach. they noted that extraperitonealization of the neobladder or conduit may make postoperative urinary leakages amenable to less invasive managements such as simple extraperitoneal drainage or transurethral catheterization alone (27). in our study, the incidences of sepsis, wound dehiscence, renal failure, urine leakage, and myocardial infarction, were significantly lower in group ii (p values were 0.001, 0.001, 0.047, < 0.001, and 0.044, respectively). in comparing the complication categories between the two groups, fewer patients in group ii suffered from gastrointestinal, genitourinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). overall, fewer patients in group ii experienced any complications (246 (68.0%) vs 210 (54.4%), p < 0.001) and high-grade complications (93 (25.7) vs 22 (5.7%), p < 0.001). the length of hospital stay was also significantly shorter in group ii (8.54 ± 5.71 vs 6.84 ± 1.78, p < 0.001). one of the possible reasons for these findings, which according to the nature of our intervention seems to be rational, might be a decrease in the rate of postoperative urine leakage from ureteroileal anastomosis. it has been reported that post-rc urinary extravasation may lead to a prolonged hospital stay, chemical peritonitis, and ureteroileal anastomosis stricture (28), which in turn may result in renal deterioration. also, severe urinary leakage has been associated with perioperative mortality (29). in our investigation, hospital stay was significantly longer in patients with postoperative urine leakage than in those who did not suffer from this complication (12.38 ± 4.16 vs 7.22 ± 3.99, p < 0.001). besides, the rate of urine leakage was significantly lower in group ii (30 (8.3%) vs 9 (2.3%), p < 0.001). however, it must be stated that only a limited number of studies with controversial results investigated the effect of retroperitonealization of the ureterointestinal anastomosis on post-rc urine leakage. kavaric et al., as a part of their modification of the wallace technique, retroperitonealized the conduit by suturing the serosa of the conduit to the posterior peritoneum above the anastomosis, thus placing the ureterointestinal anastomosis in the retroperitoneum. they reported that their technique significantly decreased postoperative urine leakage (30). as mentioned earlier, soleimani et al. reported that the rate of postoperative urine leakage was lower in the extraperitoneal than transperitoneal rc group (26). contrary to these findings and our assumption, in kulkarni et al.’s study, although the rate of post-rc urine extravasation was not significantly different in the extraperitoneal vs transperitoneal approach, the rates of gastrointestinal complications, reoperation, and intestinal obstruction were lower in the former group (27). this suggests that other causative factors might have a role in the decrease in perioperative adverse events. due to our study design, we could not assess whether the decrease in the rate of urine leakage is a true cause of lower complications occurrence in the group with retroperitonealization of the ureteroileal anastomosis or not. further investigations to clarify the pathophysiology of these findings are required. the present study is among the few investigations that have assessed the effect of retroperitonealization of ureteroileal anastomosis on the perioperative complications of rc. albeit, the current study has several shortcomings including its retrospective design and the short duration of follow-up. in addition, it is possible that some minor adverse events were not recorded. however, major adverse events or deaths were probably not overlooked. also in this study, we only enrolled patients with ileal conduit diversion and ureteroileal anastomosis that was performed according to the wallace technique; other types of urinary diversions and ureterointestinal anastomoses were not covered. finally, based on the study design, we were not able to factor out time and experience in the earlier group rather than the latter group. however, it must be noted that the operations were performed by surgeons with more than a decade of experience in radical cystectomy in high-volume urology centers and we have not changed our postoperative care during the five-year period of the study. thus, it seems that these factors might have a negligible effect on our comparison and interpretation. archivio italiano di urologia e andrologia 2022; 94, 2 a. ariafar, m. salehipour, s. zeyghami, m. rezaei 154 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conduit diversion. j urol. 2003; 169:985-90. 25. hautmann re, de petriconi rc, volkmer bg. lessons learned from 1,000 neobladders: the 90-day complication rate. j urol. 2010; 184:990-4. 26. soleimani m, moradkhani e, masoumi n, gholivandan j. extraperitoneal versus trans-peritoneal open radical cystectomy comparison of two techniques in early post-operative complications. urol j. 2020; 18:519-24. 27. kulkarni jn, agarwal h. transperitoneal vs. extraperitoneal radical cystectomy for bladder cancer: a retrospective study. int braz j urol. 2018; 44:296-303. 28. regan jb, barrett dm. stented versus nonstented ureteroileal anastomoses: is there a difference with regard to leak and stricture? j urol. 1985; 134:1101-3. 29. hensle tw, bredin hc, dretler sp. diagnosis and treatment of a urinary leak after ureteroileal conduit for diversion. j urol. 1976; 116:29-31. 30. kavaric p, eldin s, nenad r, et al. modified wallace anastomotic technique reduces ureteroenteric stricture rates after ileal conduit urinary diversion. int braz j urol. 2020; 46:446-55. correspondence ali ariafar, md mster20012002@yahoo.com mehdi salehipour, md salehipour@sums.ac.ir shahriar zeyghami, md zeyghamishahryar@yahoo.com mehran rezaei, md (corresponding author) mrezaei1986@gmail.com department of urology, shiraz university of medical sciences, shiraz (iran) stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13324 1 letter to editor submitted 31 october 2024; accepted 29 november 2024 introduction in transgender individuals, there is a mismatch between biological sex and gender (sex-gender discordance), and this mismatch is often attempted to be resolved by changing the sex (1). however, sex cannot be changed through surgery or hormones, because sex has immutable components such as genetic/chromosomal (xx/xy), gonadal (testis/ovary), skeletal-pelvic (androgenic/gynecoid), gametic (sperm/oocyte), pregnancy (possible/not possible), lactation (possible/not possible), and internal-external genital structures. removing or destroying sexual organs does not change sex; it only leads to urogenital mutilation. on the other hand, the perception of gender (or gender dysphoria) can change at any time, especially during adolescence (2). gender-affirming surgery and mental health gender-affirming surgery (gas) is not performed to treat a congenital anatomical or functional disorder (since transgender individuals do not have such a pathology) but to address the psychological issues of transgender individuals. this is the justification put forward for gas (1). however, there is no conclusive evidence in the literature to support this justification. the u.s. centers for medicare & medicaid services reviewed all relevant studies to assess whether these surgeries should be covered by insurance and prepared a comprehensive report, ultimately rejecting the request. the report states that the studies are inconsistent; when taken collectively, the evidence is insufficient. most studies are not longitudinal, or they do not include concurrent preand post-operative controls/tests. many studies have reported positive outcomes, but the strength and reliability of these results are low due to the aforementioned potential issues. four welldesigned and executed studies were identified (2-6), but these also did not show a clinically significant difference in quality of life measured by psychometric tests before and after surgery (7). gas does not improve the psychological issues of transgender individuals; on the contrary, it worsens them. a community-based study conducted in sweden found that transgender individuals who underwent surgery had more mental health problems and treatment requests compared to those who did not undergo surgery. the use of anxiolytics and antidepressants, as well as suicide rates, were higher in the surgery group-hospitalizations due to suicide attempts were nearly twice as high (8). when this study was first published, it claimed that gas improved mental health, but after objections and a re-analysis of the data, it was revealed that this was not the case, and in fact, the opposite was true. the authors and the journal acknowledged this and published a correction (9). how could such a major analytical error have been overlooked by the reviewers of a journal like the american journal of psychiatry? normally, this would not be possible, but it happened. why? are academic publications that promote gas being positively biased? other studies also show that gas does not improve psychological issues and even worsens them in some patients. a study conducted at new york university found that in about one-fifth of cases, mental health worsened after surgery (10). another study conducted at the university of california reported that 53% of individuals who underwent gas visited the emergency department within the first year, and 17.3% of these cases were due to psychiatric issues (11). a study at the university of texas examined millions of patient records and found that individuals who underwent gas had 12 times higher suicide rates, 10 times higher rates of self-harm and suicide attempts, 8 times higher rates of post-traumatic stress disorder (ptsd), and 3.3 times higher mortality rates (12). the swedish cohort, which has about 30 years of follow-up (the longest and most comprehensive study on this topic), confirms these findings, showing that mental health issues persist even after gas and continue throughout life. in this cohort, the overall mortality rate of transgender individuals who underwent surgery was three times higher compared to the general population, hospital admission rates were three times higher, and completed suicide rates were 19 times higher (13). urogenital and extra genital mutilation in gender-affirming surgery: are we violating primum non nocere? zeki bayraktar department of urology, sancaktepe sehit prof dr. ilhan varank training and research hospital, university of health sciences, istanbul, turkey. doi: 10.4081/aiua.2025.13324 archivio italiano di urologia e andrologia 2025; 97(1):13324 z. bayraktar 2 urogenital and extra-genital mutilation in gender affirming surgery gas does not improve the psychological issues of transgender individuals, and in addition, it results in urogenital and extra-genital mutilation (figures 1-3). male-to-female (mtf) surgical procedures result in urogenital mutilation, while female-to-male (ftm) procedures result in both urogenital and extra-genital mutilation (if phalloplasty is performed) (1419). transgender individuals who undergo gas lose their reproductive function completely and almost entirely lose their sexual function, while their urinary function is also significantly impaired. surgical complications requiring revision, which reduce the quality of life, are common (20). a meta-analysis conducted by wang et al. reported an overall complication rate of 76.5% after phalloplasty, with a urethral fistula rate of 34.1% and a urethral stricture rate of 25.4% (14). veerman et al. (15) also reported a urethral stricture rate of 63% and a revision requirement due to fistula or stricture in 73% of cases, concluding that genital genderaffirming surgery with urethral lengthening is a complex procedure with a high complication rate. after addressing complications, no clinically significant differences in urological functioning were observed. even after additional surgeries, 30% of patients lost the ability to urinate from the tip of the penis. when phalloplasty is performed, the arm or leg from which the flap is taken is also mutilated (figure 4). these limbs are damaged not only cosmetically, but also neurologically and functionally, and all develop pain (16). in a meta-analysis by horbach et al., complications of mtf procedures were listed as follows; changes in urinary function 32%, urinary incontinence 19%, wound dehiscence 12-33%, vaginal stenosis 12%, genital pain 3-9%, vaginal necrosis 2.7-4.2%, rectal injury 2-4.2%, rectovaginal fistula 1-17%, urethral stricture 1-6%, local abscess 5%, hematoma 3%, clitoral necrosis 1-3%, vaginal prolapse 1-2% (17). figure 1. urogenital and extra genital mutilation in a ftm case [a ftm patient who applied with a complaint of total incontinence, a flap was taken from the left arm in another center and a neophallus was performed, but flap necrosis developed, a flap was taken from the right leg and a neophallus was performed again, but this time urethral necrosis developed, perineal externalization was performed, the patient received periurethral submucosal injections twice by us, he partially benefited, his incontinence decreased – this patient had 14 surgeries for ftm procedures – including revisions]. figure 2. urogenital and extra genital mutilation in other ftm case [a ftm patient presented with severe pain in the left leg and inability to urinate/urethral obstruction; the dysfunctional penile prosthesis was removed, urethrotomy was performed internally but was unsuccessful, urethral externalization was performed; this patient underwent 17 surgeries for ftm procedures – including complications]. archivio italiano di urologia e andrologia 2025; 97(1):13324 3 gender affirming surgery deterioration in quality of life and shortening of lifespan kuhn et al. found a significantly reduced quality of life in transgender individuals 15 years after vaginoplasty, listing complications as follows: urinary dysfunction 47%, urgency 25%, stress incontinence 23%, inability to achieve sexual satisfaction 23%, urgency 17%, fecal incontinence 9.4%, difficulty or inability to fully empty the bowels 7.6%, vaginal prolapse 7.5%, and revision surgery due to prolapse 3.4% (18). kuhn et al. also report that the urogenital complications of gas are underreported in the literatüre (these rates are actually higher). because transgender individuals who undergo gas are quite reluctant to express their urogenital issues, so these problems are likely underreported (18), (19). indeed, kamran et al., who examined patient-reported outcome measures (proms) in 286 studies representing over 85,395 transgender cases in more than 30 countries, found that patient reports were absent or incomplete in most studies (21). one of the dramatic outcomes of gas is the shortening of life expectancy. for instance, while the expected average life span in the danish population is 81.9 years for women and 78 years for men, the average age of death for transgender individuals who underwent gas was found to be 53.5 years (22). these data indicate that transgender individuals who undergo gas die on average 25-28 years earlier, meaning their lives are shortened by about one-third due to psychiatric issues, the side effects of hormones used, cancers, lung, cardiovascular diseases, infections, and surgical complications (22, 23). is gender affirming surgery systematic iatrogenic harm? these data show that gas violates the medical principle of "first, do no harm" (primum non nocere) and systematically harms transgender individuals. in my opinion, gas is the greatest systematic iatrogenic harm in the history of medicine. transgender individuals have serious mental health issues and need psychosocial support because of these problems (24). however, gas does not provide them with any tangible benefit; on the contrary, it harms them. as surgeons, we are not improving the mental health issues of transgender individuals with gas; instead, we are collaborating with their mental health issues and, by engaging in consent engineering, mutilating them urogenitally. in short, we do not treat figure 3. an mtf case presenting with complaints of difficulty urinating and pain. the patient, who had undergone surgery at another center, exhibited swelling, pain, and tenderness below the urethral meatus. the patient frequently experienced infections, pain, and swelling, was unable to engage in sexual intercourse, and had persistent urination problems (in mtf cases, the urethra is severed at the level of the bulbar urethra; therefore, the visible meatus in this case is actually a severed bulbar urethra. this urethra remains in continuous contact with neighboring tissues and the atmosphere, much like an open wound, leading to frequent infections). figure 4. sequels (extra-genital mutilation) in the arm and leg from which the flap was harvested in cases of phalloplasty. archivio italiano di urologia e andrologia 2025; 97(1):13324 z. bayraktar 4 them; we victimize them. gas does not change sex; it results in sexual mutilation. gas is partially feminization or masculinization, but predominantly mutilation. transgender individuals do not need mutilating surgeries but treatments that provide concrete benefits based on a risk-benefit analysis. when and how will transgender individuals access these treatments? as specialists, we need to conduct new studies to develop the treatment options transgender individuals need and, more importantly, discuss this issue independently of ideology (based on medical evidence). transgender individuals need treatments based on biological evidence, not ideological views. current medical practices, particularly gas procedures, are mutilating transgender individuals, and they must be reviewed. in ancient times, it was believed that mental illnesses were caused by demons and that drilling holes in the skull would allow them to escape—this led to cranial trepanation (25). just as today we look back on cranial trepanation with mockery and astonishment, i believe that future medical professionals will look at gas the same way, saying, "it's hard to believe, but in the 21st century, doctors-surgeons tried to treat gender dysphoria with surgery and attempted to change sex by removing urogenital organs, resulting in urogenital mutilation." conclusions in conclusion, transgender individuals who undergo gas lose their reproductive function irreversibly and almost entirely lose their sexual function, while their urinary function is also significantly impaired. if phalloplasty is performed, the arm or leg is also mutilated. in addition, many complications from surgeries arise. so what do they gain for all these losses? nothing (it is claimed that their mental health improves, but there is no definitive evidence in the literature to support this claim, and in fact, there is evidence to the contrary). so, what is the reason for this insistence on gas? as a surgeon/urologist licensed to perform gas, i find these surgical procedures unethical and follow current medical practice with concern. i am making these reminders to fulfill my professional and moral responsibility and to recommend that gas procedures that harm transsexuals be reviewed. we must act according to the principle of "first, do no harm" and our priority should be to avoid harming our patients. references 1. coleman e, radix ae, bouman wp, et al. standards of care for the health of transgender and gender diverse people, version 8. int j transgend health. 2022; 23(suppl 1)-s259. 2. kuo jh, carrera ra, mulyani lc, et al. exploring the interaction effects of gender contentedness and pubertal timing on adolescent longitudinal psychological and behavioral health outcomes. front psychiatry. 2021; 12:660746. 3. heylens g, verroken c, de cock s, et al. effects of different steps in gender reassignment therapy on psychopathology: a prospective study of persons with a gender identity disorder. j sex med. 2014; 11:119-26. 4. ruppin u, pfäfflin f. long-term follow-up of adults with gender identity disorder. arch sex behav. 2015; 44:1321-29. 5. smith yl, van goozen sh, kuiper aj, cohen-kettenis pt. sex reassignment: outcomes and predictors of treatment for adolescent and adult transsexuals. psychol med. 2005; 35:89-99. 6. udeze b, abdelmawla n, khoosal d, terry t. psychological functions in male-to-female people before and after surgery. sex relatsh ther. 2008; 23:141-45. 7. jensen ts, chin j, rollins j, et al. gender dysphoria and gender reassignment surgery. 2016. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=n&ncaid =282&bc=acaaaaaaqaaa& 8. bränström r, pachankis je. toward rigorous methodologies for strengthening causal inference in the association between gender-affirming care and transgender individuals' mental health: response to letters. am j psychiatry. 2020; 177:769-72. 9. correction to bränström and pachankis. am j psychiatry. 2020; 177:734. 10. robinson is, blasdel g, cohen o, et al. surgical outcomes following gender-affirming penile reconstruction: patient-reported outcomes from a multi-center, international survey of 129 transmasculine patients. j sex med. 2021; 18:800-11. 11. zhang tr, harel d, rivera a, et al. incidence, complications, and long-term outcomes of gender-affirming phalloplasty: analysis of a large statewide population-based dataset. urology. 2024; 185:27-33. 12. straub jj, paul kk, bothwell lg, et al. risk of suicide and self-harm following gender-affirmation surgery. cureus. 2024; 16:e57472 13. dhejne c, lichtenstein p, boman m, et al. long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in sweden. plos one. 2011; 6:e16885. 14. wang amq, tsang v, mankowski p, et al. outcomes following gender-affirming phalloplasty: a systematic review and meta-analysis. sex med rev. 2022; 10:499-512. 15. veerman h, de rooij fpw, al-tamimi m, et al. functional outcomes and urological complications after genital gender-affirming surgery with urethral lengthening in transgender men. j urol. 2020; 204:104-109. 16. peters br, sikora z, timmins bh, berli ju. nerve morbidity at the radial forearm donor site following gender-affirming phalloplasty. j plast reconstr aesthet surg. 2022; 75:3836-44. 17. horbach ser, bouman mb, smit jm, et al. outcome of vaginoplasty in male-to-female transgenders: a systematic review of surgical techniques. j sex med. 2015; 12:1499-512. archivio italiano di urologia e andrologia 2025; 97(1):13324 5 gender affirming surgery 18. kuhn a, hiltebrand r, birkhäuser m. do transsexuals have micturition disorders? eur j obstet gynecol reprod biol. 2007; 131:226-30. 19. kuhn a, santi a, birkhäuser m. vaginal prolapse, pelvic floor function, and related symptoms 16 years after sex reassignment surgery in transsexuals. fertil steril. 2011; 95:2379-82. 20. bayraktar z. urogenital complications that decrease quality of life in transgender surgery. new j urol. 2024; 19:52-60. 21. kamran r, jackman l, chan c, et al. implementation of patient-reported outcome measures for gender-affirming care worldwide: a systematic review. jama netw open. 2023; 6:e236425. 22. simonsen rk, giraldi a, kristensen e, hald gm. long-term follow-up of individuals undergoing sex reassignment surgery: psychiatric morbidity and mortality. nord j psychiatry. 2016; 70:241-7. 23. simonsen rk, hald gm, kristensen e, giraldi a. long-term follow-up of individuals undergoing sex reassignment surgery: somatic morbidity and cause of death. sex med. 2016; 4:e60-8. 24. heylens g, elaut e, kreukels bp, et al. psychiatric characteristics in transsexual individuals: multicentre study in four european countries. br j psychiatry. 2014; 204:151-6. 25. gualdi-russo e, lefebvre p, arnaud j. cranial surgery in antiquity: the size of trepanations during the neolithic period in france. world neurosurg. 2024; 190:131-40. declarations ethical approval: not applicable. availability of data and material: not applicable. competing interests: there is no conflict of interest in the study. funding: there is no funding in the study. authors' contributions: zb wrote the text. acknowledgments: not applicable. correspondence zeki bayraktar, md (corresponding author) dr.zekibay@gmail.com department of urology, ilhan varank training and research hospital, university of health sciences, 34895, sancaktepe, istanbul, turkey stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2228 original paper no conflict of interest declared. really to be trumpeted and hardly shareable even with the closest ones (1). up until 50 years ago, in italy the influence of the church, its priests and the religious educational and leisure facilities tended to instill the idea that mst was a sin, as men should deliver their sperm only for reproductive purposes and therefore during a penetrative sexual intercourse (2). in the sacro cuore catholic university of rome (medical center of excellence in rome and in italy) it was not possible to carry out a spermiogram to assess the fertility because this catholic facility would have had to accept a sperm sample not delivered in the vagina (hence for reproductive purposes), but collected in a container and for the only purpose to "assess" the quality of the ejaculate with no other ongoing disease. the sperm sample was accepted only for bacteriological examination in case of suspected infection (alleged or actual disease). mst is one of the first sexual dexterities men begin to experience (at 11-13 years of age) in conjunction with the production of testicular androgens and the onset of adolescence (3). in the past, at this stage of life, adolescent males did not have the possibility or the opportunity to have a sexual partner, and therefore the resort to mst was a need, a rule until they reached the age (20 and older) to start going out with women, marry and therefore have the possibility of enjoying regular penetrative intercourse (4). up until 50-60 years ago, in the italian social-economiccultural reality the vast majority of women carried out mainly domestic activities and the work and life rhythms were influenced by the sunlight cycle; no home lighting, no tv and no nightlife implied that after dinner, and with the onset of darkness, couples went to bed and men had the possibility to have a sexual intercourse with orgasm and ejaculation, regardless of the desire and availability of the woman, who traditionally could not refuse the sexual requests of the man, also because women had to provide for the reproduction of the species through extremely frequent pregnancies, even one every year. given such a context, men did not have specific physical reason to resort to mst. it shall also be considered that, to masturbate men had to envisage sexual fantasies, visions, erotic behaviors linked also to environmental and cultural factors. all cultures objective: we aimed to verify the rate of masturbation (mst) in a group of 150 italian patients complaining erectile dysfunction (ed). materials and methods: our diagnostic protocol for penile and sexual problems included the collection of the patient's history, general and local clinical examination, and metabolic and hormonal analyses. selected patients were also submitted to nocturnal penile tumescence test (rigiscan), duplex ultrasound of the penis, magnetic resonance imaging, neurological tests and cardiological examination. a group of 150 italian males (aged between 20 and 86 years) who complained ed and who presented to our andrological center to research the possibility of correcting their ed and being able to recover adequate sexual erectile activity were included in this study. in this group of patients suffering from ed we decided to evaluate the practice of mst by asking specific questions: 1. do you sometimes practice mst? 2. how often in a week? 3. is mst hidden or known by the partner? 4. what do you use as a masturbatory sexual stimulus? the frequency of mst was assessed according to a likert scale as follow: a: no mst; b:1-2/week; c: 2-3/week; d: > 3/week; e: daily or more. we also asked if it was possible to have penetrative marital intercourse on the same day as mst (1-10 hours). we also asked what they used as a triggering sexual stimulus: press magazines, tv movies, the web. results: only 5/150 patients did not report mst while 27/145 pts (aged 20-30 years) reported it more than 3 times a week; 44/145 (aged 31-50 years) 1-3 times a week and 27/145 (51-86 years) 1-2 times a week. almost all patients used webporn as a stimulus for mst. a group of patients over the age of 50 said they were quite satisfied with the physical results of mst even though they would prefer to have sex as part of a couple relationship. conclusions: the outburst of mst in this web-dominated era could affect the sexual activity of individual males and couples. key words: masturbation; cyber pornography; web porn; erectile dysfunction; ed therapy; penile prosthesis. submitted 8 may 2022; accepted 29 may 2022 introduction the practice of mst in western, christian and even more catholic realities has always been considered an improper sexual practice, not advisable, often deplorable, not cyber pornography use and masturbation outburst. considerations on 150 italian patients complaining erectile dysfunction and trying to solve it diego pozza 1, mariangela pozza 1, augusto mosca 2, carlotta pozza 3 1 studio di andrologia e di chirurgia andrologica, roma, italy; 2 uo urologia e andrologia, san sebastiano hospital, frascati (rm), italy; 3 department experimental medicine, sapienza university, rome, italy. doi: 10.4081/aiua.2022.2.228 summary 229archivio italiano di urologia e andrologia 2022; 94, 2 masturbation in italian patients with ed have produced images or figures of a sexual nature (statues, frescoes, paintings, objects), which could stimulate the men’s fantasy, but that could, in the majority of cases, not be taken home (5). with the advent of writing, "licentious" texts started to appear, that could be enjoyed by the upper classes, since they were able to read, but not by the vast majority of the population. the introduction of the press allowed to produce in large number also “licentious” or “erotic” texts and more clearly “erotic” figures, drawings and representations, that could be enjoyed also by people unable to read and not having books to stimulate their sexual fantasies (6). in the late 1800s the first photographs (daguerreotypes) allowed to reproduce sexually stimulating female silhouettes and sex scenes easily enjoyable also by men unable to read but longing for an imaginative sexual stimulus for masturbatory or erotic-sexual purposes. however, the issues with those first photographs or books, not easy to be found, was keeping them at home without the wife, children or housekeeper being able to find them out. in 1941 the first periodical magazine with porn images, swank, was released in the usa, followed in 1953 by playboy, which could be easily purchased at newsstands or by subscription in all countries of the world, and then by a variety of other periodicals (7). also in that case, the problem was how to buy those magazines. almost always they were bought at newsstands away from home, frequently at the station, and the purchase had to be concealed (i.e. “hiding” those magazine among other newspapers or magazines). keeping them home could become a problem, as they had to be kept in places hardly visited by the other family members and yet easily accessible for masturbatory purposes. in some cases, such magazines were read together with the female partner as a “stimulus” to foster a freer sexuality. nevertheless, keeping those magazines at home could imply serious problems, as well as discomfort in case they were discovered by the partner, who could have felt almost “betrayed” by such discovery. in the first postwar years, in 1950s, we saw the advent of television, which led to substantial changes in the life of the couple. couples no longer went to bed after dinner, with the onset of darkness, but after spending a few hours watching tv and going to bed late, knowing that early in the morning, at dawn, they would have had to wake up to go to work. that resulted in less time and availability for sexual activity. in that same period many women took up a job, while continuing to take care of the house, the husband, and the children. working outside their own home, spending time with other women, a certain economic and cultural independence, the first mechanical contraceptives and the pill changed the concept of pregnancy, which was no longer perceived as an inevitable necessity or obligation, but as the result of a choice of the couple with the possibility for the woman to refuse sexual intercourse perhaps requested by the men but not solicited by the woman. in many couple realities, the man no longer had the possibility to have an almost daily orgasm and ejaculation, and had to accept the decision of the woman, who might be little interested in the sexual activity (endocrine factors) or who could fear a pregnancy with all the associated negative aspects (8). in such cases, many men resort to masturbation to get that emotional and urological pleasure, regardless of the availability of the women (9). internet opened up a whole new world to pornography (10). with the discovery of the web, the potential for the supply and consumption of porn material rocketed to the extent of becoming a real global industry (11). men longing to stimulate their more or less correct or distorted sexual fantasy no longer had to buy a magazine or a videotape, nor to find a “secret” place, but simply use a pc or smartphone without “concealing” any material. they could use it everywhere and anytime, paradoxically even in the presence of their partner without her knowing about it (12). materials and methods in our andrology center in rome, since 2020, we examined 150 male patients (aged 20 to 86 years) with penile and/or sexual problems according a diagnostic protocol including the collection of the patient's history, the general and local clinical examination, metabolic analyses, and hormonal analyses (in all patients). in selected cases nocturnal penile tumescence test (rigiscan) (86 pts), dynamic penile duplex sonography (138 pts), magnetic resonance imaging (36 pts), neurological tests (26 pts) and cardiological examination (100 pts) were performed (13-15). since 2020, we administered a specific questionnaire to investigate masturbatory activity, including the following questions: 1. do you sometimes practice mst? answers: no-yes 2. with which frequency/week? answers: 1-2-3-more, all days? 3. is mst concealed to the partner? answers: no -yes 4. what do you use as mst sexual stimulus? answer: fantasy printed materials -web in our experience with the iief test utilized for other reasons, we had acknowledged that to some given questions many patients preferred to give false answers that put them in a "better light". on the other hand, all our patients, who came to undergo specific tests because their erectile function was not effective (being well aware of the need to solve their erectile problem) had no reason to withhold information on their masturbatory activity. results when asked by the andrologist, during medical examinations, whether they practiced mst, 145/150 (96,6%) patients answered positively. to the question about the mst frequency (16): 27 pts (20-30 yrs; 18.0%) reported > 3 times/week, even every day; 44 pts (31-50 yrs; 29.3%)1-3 times/week; 56 archivio italiano di urologia e andrologia 2022; 94, 2 d. pozza, m. pozza, a. mosca, c. pozza 230 pts (51-70 yrs; 37.3%) 1-3 times/week, even every day;18 pts (71-86 yrs; 12%) 1-2 times/week; 5 pts (29, 36, 56, 75, and 80 yrs; 3.3%) no masturbation. ten (6.8%) patients reported that their partner was aware of the mst activity they practiced and did not show disappointment. when asked if it was possible to have a penetrative marital intercourse on the same day of mst (within 1-10 hours): 10 patients aged 20-30 years (37.0%) and 5 patients aged 31-90 (0.4%) answered affirmatively. when asked what did they use as triggering sexual stimulus 132 pts (20-86 years; 91%) reported using the web and 18 pts (> 60 years; 12%) reported to watch tv movies the sexual desire to have intercourse with their “stable partner” appeared rather reduced among the patients practicing mst. in the following cases it is not simple to discriminate: 1. when the woman, perhaps no longer young and with children, showed no initiative to involve the man in a sexual activity. 2. when the woman was aware of the difficulty, often the impossibility of the man to have a satisfactory penetrative intercourse and therefore did not take any initiative. 3. when the woman, knowing that the man often was not capable to have an adequate erection (i.e. had an insufficient or short-lasting or totally unsatisfactory erection) preferred not to induce a depressive attitude of the partner. 4. when, due to erectile dysfunction a preliminary masturbatory activity tended to make the penetrative intercourse even more difficult resulting in disappointment, frustration, a sense of deficiency, and depression. discussion we are not aware of other cultural and religious realities, where the mst practice can be easily accepted and revealed, but for sure in the italian reality with a strict christian-catholic culture and education, it is quite uncommon that, among men talking about their sexual "performances" or "adventures", mst is one of the issues discussed and revealed even if practiced frequently. masturbation could and was practiced by men, who for different reasons could not have sexual intercourse with a woman (adolescence, celibacy, religious activity, illnesses, separation, widowhood, distance for work, emigration, wars, calamities). in principle, men could have a sexual activity leading to an orgasm and ejaculation on a regular basis because, until a few decades ago, most women had to accept a sexual intercourse for cultural, educational, economic, total dependence reasons, regardless of their will and the sexual prowess of the man (8). from the beginning of the twentieth century with women starting going to school, working and gaining economic independence, the awareness of the family context, the changes in the legislation, many women gained the power and started refusing the absolute duty of accepting a sexual intercourse with their partner. mst requires a state of sexual excitement triggered by imagination, scents, visions, contiguity that needs a certain psychological “commitment” as well as plenty of time. even in ancient civilizations and societies it was possible to reproduce “sexually exciting" images which, however, were graphic, pictorial or statuary images affixed in specific places, often public, and difficult to be used in private. with the advent of the press, books with erotic content began to be published, that, however, could be enjoyed only by people able not only to read but also to buy, preserve and consult a book. the possibility to paint and print images and pictures led to publications with sexually explicit images, which could be appreciated also by people, who were not able to read. the classic images in barber shops (men-only places) with more or less naked ladies became outmoded in the 40-50s due to the first publications (magazines, tabloids) with naked women which one could also purchase in more popular environment, such as newsstands, and easily usable at home, although they had still to be hidden from mother, wife or partner. on the one hand, the erotic-porn publication boom could make mst easier and more evocative but still with a set of practical problems, such as: – the purchase, (normally, never the usual newsstand near home, perhaps attended by some family member or acquaintance; men who bought a porn publication usually avoid doing it in a noticeable way, almost always buying other newspapers to hide it away from other customers of the newsstand, even if unknown), – the preservation at home of the magazines in an easily accessible place, but hidden from the women at home, – the possibility to read them in a place that had to be “secret” not to be seen by other family members and also lit enough to allow the reading. the development of the web in the 70s combined with the widest spreading of smartphones allowed to basically solve those problems. men in need of a visual sexual stimulus no longer have to go to a newsstand to buy “in public” porn material, nor to worry about hiding the material at home. they can check it out anytime, everywhere, even in the dark. for the sake of argument, they can watch porn images or movies even when in close proximity to their partner, or use it just before having a sexual intercourse to strengthen the sexual performance with a woman who, perhaps, no longer excites him (17). however, porn web has specific consequences. many functionally active and sexually capable young men report "web-masturbating" because they can do it at any time of the day even when their woman is not available or has to carry out other activities: web sex allows men to imagining to have sexual intercourse with extremely exciting, provocative women available in any situation, even extreme ones, without having to worry about a too quick ejaculation, an erection that is not sufficiently stiff and lasting to give enough pleasure to the partner (8). moreover, they are not exposed to the “unpleasant and frustrating” judgement of the unsatisfied partner. clearly teenagers, young men who had had a sexual intercourse with their partner could also be able to have 231archivio italiano di urologia e andrologia 2022; 94, 2 masturbation in italian patients with ed another sexual intercourse if explicitly requested (18), but with maturity and senescence it could be difficult to get a new conjugal erection after a masturbation (19). in other cases, after 50 years of age, or in case of metabolic, hormonal or vascular pathologies, men tend to masturbate to directly verify if their penis can deliver a good stiffness and maintain it, which triggers a complicated psychological mechanism. however, we have verified that in many patients over 50, who had had various sexual relationships in the past, the practice of masturbation was experienced and reported in a different way from those who had not had interpersonal relationships. a certain amount of patients reported obtaining with the mst an acceptable erection, an orgasm (with or without ejaculation) quite satisfactory without having to worry about having induced a specific pleasure and having procured an orgasm in the woman and without having to expect a judgment of the woman on the ability to have procured a substantially pleasant intercourse and an orgasm. in the past, even recently, a male would never have bothered with the judgment of the woman. this aspect should be the subject of in-depth evaluations. should sexual intercourse be considered only as a reproductive act, as a source of pleasure for the male or as a source of pleasure also for the woman and for the couple? aknowledgments we thank the strict collaboration of stefania rosini for translation and revision of the article. references 1. fischer n, graham ca, traeen s, hald gm. prevalence of masturbation and associated factors among older adults in four european countries. arch sex behav. 2021; 51:1385. 2. prause n. porn is for masturbation. arch sex behav. 2019; 483. 3. donevan, m, jonsonn l, bladh m, et al. adolescents’use of pornography trends over a ten year period in sweden. arch sex behav. 2022; 51:11254. 4. das a. masturbation in the united states. j sex marital ther. 2007; 33:301. 5. bothe b, toth-kiraly i, potenza mn, et al. high-frequency pornography use may not always be problematic. j sex med. 2020; 17:793. 6. perry sl. does low-cost sexual gratification make men less eager to marry? pornography use, masturbation, hookup sex, and desire to be married among single men. arch sex behav. 2020; 49:3013. 7. rowland dl, hamilton bd, bacys r, hevesi k. sexual response differs during partnered sex and masturbation in men with and without sexual dysfunction: implications for treatment. j sex med. 2021; 18:1835. 8. brody c, costa rm. satisfaction (sexual, life, relationship, and mental health) is associated directly with penile-vaginal intercourse, but inversely with other sexual behavior frequencies. j sex med. 2009; 6:1947. 9. cavalheira a, traeen b, stulhofer a. masturbation and pornography use among coupled heterosexual men with decreased sexual desire: how many roles of masturbation? j sex marital ther. 2015; 41:626. 10. ross mw. typing, doing and being: sexuality and internet. j sex res. 2005; 42:342. 11. brown j. pornography addiction: an exploration of the association between use, perceived addiction, erectile dysfunction, premature (early) ejaculation, and sexual satisfaction in males aged 18-44 years. j sex med. 2021; 13:1. 12. park by, wilson g, berger j, et al. is internet pornography causing sexual dysfunction? a review with clinical reports. behav sci. 2016; 6:17. 13. pozza d, marcantonio a, mosca a, pozza c. penile prosthesis and complications: results from 577 implants. arch ital urol androl. 2020; 92:302. 14. jannini ea, maggi m, lenzi a. evaluation of premature ejaculation. j sex med. 2011; 8:328. 15. pozza d, berardi a, pozza m, et al. the woman and the penile prosthetic implant. primary or secondary role? personal experiences on 365 implanted patients. arch ital urol androl. 2021; 93:53. 16. likert r. on managing human assets. bull train. 1978; 3:1. 17. fritz n, malic v, fu tsung-chien, et al. porn sex versus real sex: sexual behaviors reported by a u.s. probability survey compared to depictions of sex in mainstream internet-based male-female pornography. arch sex behav. 2022; 51:1187. 18. kaestle ce, allen kr. the role of masturbation in healthy sexual development: perceptions of young adults. arch sex behav. 2011; 40:983 19. bell s, reissing ed, henry la, van zuylen h. sexual activity after 60: a systematic review of associated factors. sex med rev. 2017; 5:52. correspondence diego pozza, md (corresponding author) diegpo@tin.it mariangela pozza, md mariangela.pozza@gmail.com studio di andrologia e di chirurgia andrologica via b. gozzoli, 82 00142 rome (italy) augusto mosca, md moscaaugusto@gmail.com uo urologia andrologia, san sebastiano hospital via tuscolana, 2, 00044 frascati, rome (italy) carlotta pozza, md carlotta.pozza@gmail.com dept experimental medicine, sapienza university viale policlinico, 00161, rome (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12393 1 original paper flexible ureteroscopes and the improvement of laser lithotripsy, flexible ureteroscopy has become the standard of care for treating urolithiasis less than 2 cm (2, 3). in the early 1970s, takagi et al. (4) and takayasu et al. (5) first reported the clinical application of a fiberoptic pyeloureteroscope. with technological advancements in endourology, including new lasers, and advanced flexible ureteroscopes, the treatment indications for retrograde intrarenal surgery (rirs) have expanded to include not only large stones but also upper urinary tract urothelial carcinoma, ureteral stricture, and a diagnostic tool for hematuria. in 1991, grasso et al. presented an advanced flexible ureteroscope with a 7.5-fr tip and an up 120º/down 170º deflection system. in 1998, they published a clinical study of 492 patients treated with a flexible ureteroscope with a larger 3.6-fr working channel (7). later, in 2001, a f-urs with a two-way deflection system (270º/270º) and stronger durability was introduced to the market, improving access to the pelvicalyceal system (8). surgeons must consider the risk of various complications due to ureteroscopy including thermal injury, ureteral injury caused by the ureteral access sheath, and strictures (6). ureteral stricture is a late complication that may cause severe damage to a patient’s health. the incidence rate of postoperative ureteral stricture varies from 0.23 to 2.97% (9-13). subsequent treatment of the stricture should be tailored according to the stricture length and severity of hydronephrosis. strictures longer than 1 cm with severe hydronephrosis should be treated with reconstructive surgery and not by endourological interventions (6, 14). this study presents the results of diagnosis of possible complications associated with f-urs for treating upper urinary tract stones (uuts) in particular renal/ ureteral obstruction, using dynamic renal scans using either diethylenetriaminepentaacetic acid (dtpa) or mercapto acetyl tri glycine (mag-3), in order to answer the question if there is a need of routine renal scan after f-urs. dtpa = diethylenetriaminepentaacetic acid. mag3 = mercapto acetyl tri glycine. patients and methods one surgeon performed ureterorenoscopy on 917 renal units in patients with uuts in the same medical center between april 2010 and october 2022. a 7.5 fr flexible ureteroscope was utilized with holmium: yag (yttrium aluminum garnet) laser for lithotripsy in all objective: to determine whether dynamic renal scans – dtpa or mag3 – routinely performed after flexible ureteroscopies (f-urs) could detect the development of an obstruction and thus promote prompt early intervention for kidney preservation. patients and methods: in this retrospective study, with all the data recorded prospectively between april 2010 and october 2023, 250 renal units in 242 patients with upper urinary tract stones (uuts) who underwent ureterorenoscopy by one surgeon in the same medical center were evaluated. stone-free rate (sfr) was defined as no residual fragments at all using an intraoperative “triple test”. the following characteristics were examined: gender, bmi, age, hounsfield unit, stone diameter, laterality, renal/ureteral stones, stone-free rate, and auxiliary procedures per renal unit. the clavien-dindo classification was used to report complications. renal units with residual stones were scheduled for a 2nd f-urs. postflexible ureteroscopy ureteral obstruction and renal function were detected using renal scan dtpa or mag-3. the primary outcome was renal/ ureteral obstruction. results: the mean patient age was 53 years. the mean stone size was 12.3 mm. stones in renal pelvis, upper, middle and lower calyces were treated in 9.2% (23), 27.6% (69), and 30.8% (77) of cases, respectively; 44% (110) ureteral stones were also treated. the singleand second-session sfrs were 94.8% and 99.7%, respectively. a third auxiliary procedure was needed in one renal unit (0.4%). the mean number of procedures per renal unit was 1.06 (264/250). ureteral double-j stents were inserted in 53.6% (134) of the cases. in 37 (14.8%) cases, a stent was placed before surgery. post-operative complications were minor, with readmission and pain control needed in only two patients (0.8%). no avulsion or perforation of the ureters was observed. in six patients with t1/2 between 10-20 minutes, a second renal scan revealed spontaneous improvement and no obstruction in five patients. one patient with large stones and a history of prior ureteroscopy developed a ureteral stricture (0.4%) and needed treatment with laser endoureterotomy. conclusions: post-flexible ureteroscopy obstruction due to ureteral stricture is very rare. a routine renal scan post-operatively may be used in potentially high-risk patients. key words: renal scan; dtpa; mag3; rirs; retrograde intrarenal surgery; ureteral stricture. submitted 17 february 2024; accepted 31 march 2024 introduction as known, nephrolithiasis is a common disease in asia with a rate of 1%-5% (1). with the development of small dynamic renal scans as a modality for follow-up of flexible ureteroscopy murad asali 1, 2, osman hallak 1 1 urology department, barzilai medical center, ben gurion university of the negev, beer sheva, israel; 2 assuta medical center, ramat hyal, ben gurion university of the negev, beer sheva, israel. doi: 10.4081/aiua.2024.12393 summary archivio italiano di urologia e andrologia 2024; 96(2):12393 m. asali, o. hallak 2 patients. the laser fibers used were 200 µ, 230 µ, and 272 µ, with an energy of 0.3-1 joule and a frequency of 8-80 hz. the calculi fragments were taken out with a basket. the ureteral access sheath (uas) was always placed below the ureteral stone and moved up to the middle or proximal ureter for renal stone treatment. a total of 267 patients who underwent a post-operative dynamic renal scan using either dtpa or mag3 were included in the study. out of them, 13 needed a second session, one needed a third session. the patients were included in the study after meeting our inclusion criteria, as follows: 1. upper urinary tract stones. 2. use of the same 7.5fr flexible ureteroscope (flexible uretero-renoscope flexx2s [karl storz & co. kg, tuttlingen, germany]). 3. use of a holmium: yag laser with consistent energy, frequency, and fibers ( 200 µ, 230 µ, and 272 µ) usage. 4. use of sphinx jr 30-watt [lisa laser products gmbh, germany], mega plus 15 watt [richard wolf gmbh, knittlingen, germay], or luminis 120-watt [luminis, yokneam, israel] laser generator. 5. use of a uas (flexor ureteral access sheath 12/14f, 28, 35, 45 cm; fuscook medical, bloomington, in, usa). 6. all data recorded. 7. adults aged 18 years and older. 8. a dynamic renal scan, either dtpa or mag3 was done postoperatively. the exclusion criteria were as follows: 1. using other flexible ureteroscopes. 2. missed data. 4. no other access sheath type use. 5. using a rigid ureteroscope. 6. single kidney. at the end of the operation, a triple test was done for all calyces, using 1) a plain abdominal radiograph of the kidneys, ureters, and bladder, 2) using the scope and the carm while injecting contrast intraoperatively as a retrograde pyelography and 3) screening every calyx using the endoscope and following the anatomy on the c-arm screen as described in asali et al. article (15). in all the patients, the following characteristics were evaluated: gender, bmi, age, stone radiopacity (hounsfield unit), stone diameter, stone laterality (table 1), stone location (renal/ureteral), stone-free rate (table 2), auxiliary procedures per renal unit (table 3), double-j stent insertion, and perioperative complications (table 4). stone-free status was defined as complete stone removal. this study was retrospective, and all the data (demographics data, stone characteristics, operative and postoperative data) were recorded prospectively. postoperative follow-up was scheduled one month later with a dynamic renal scan dtpa/ mag3, urine culture, and renal function. the results were divided into obstructed (t1/2 more than 20 minutes), equivocal (t1/2 10-20 minutes), and non-obstructed (t1/2 less than 10 minutes). the primary endpoint was a renal/ureteric obstruction demonstrated by a renal scan with a t1/2 of more than 20 minutes. patients with residual stones were scheduled for a 2nd f-urs/rirs (retrograde intrarenal surgery), and patients with obstruction were scheduled for re-intervention. the clavien-dindo classification was used to report complications (16). all procedures performed in this study were performed after receiving informed consent from all the patients. results the mean patient age was 53 years. the mean maximum stone diameter was 12.3 mm (table 1). stones were in the renal pelvis, upper, middle, and lower calyces stones in 9.2% (23), 27.6% (69), and 30.8% (77) of cases, respectively (table 2); 44% (110) were ureteral stones. the mean stone diameter of stones of the renal pelvis, upper and middle calyces, lower pole, upper ureter, middle ureter, and lower ureter was 11.3 mm, 8.2 mm, 7.9 mm, 8.8 mm, 7.8 mm, and 8.2 mm, respectively. the characteristics of renal and ureteral stone are shown in table 2. the singleand second-session sfrs were 94.8% and 99.7%, respectively. a third auxiliary procedure was needed in one renal unit (0.4%) (table 3). table 1. patient demographic and stone characteristics. patients 242 gender m/f 162/80 bmi 28.5 renal units (kidney +/ureter) 250 age (years) 53 hounsfield unit (mean) 809 mean maximum stone diameter (mm) 12.3 lateralization r/l 110/140 table 2. renal and ureteral stone location and diameter. no % mean stone diameter (mm) renal pelvis 23 9.2 11.4 upper and middle calyx 69 27.6 8.2 lower pole 77 30.8 7.9 upper ureter 34 13.6 8.8 middle ureter 27 10.8 7.8 lower ureter 54 21.6 8.2 table 3. stone-free rate/auxiliary f-urs. no sfr (%) cumulative stone free % renal units 250 ** ** 1st session 250 237 (94.8%) 94.8% 2nd session 13 12 (92.3%) 99.7% third auxiliary 1 1 (100%) 100% laser frequency (hz) & 31.2 ** ** energy (joule) & 0.54 ** ** sf = stone free; f-urs = flexible ureteroscopy; hz = hertz. 1st session = &. archivio italiano di urologia e andrologia 2024; 96(2):12393 3 dynamic renal scans after flexible ureteroscopy the mean number of procedures per renal unit was 1.06 (264/250). ureteral double-j stents were inserted in 53.6% (134) of the cases. in 37 (14.8%) cases, a stent was placed before the surgery. post-operative complications were minor, with readmission for pain control needed in only two patients (0.8%) while two patients (0.8%) had intermittent haematuria secondary to the stent. no avulsion or perforation of the ureters was observed (table 4). grade i complications according to clavien-dindo classification were observed in nine cases (3.6%) (9/250). no grades ii, iv, or v were observed. the mean hospital stay was one day. at postoperative renal scan 244 renal units demonstrated t1/2 less than 10 minutes and six patients a t1/2 between 10-20 minutes; a second renal scan revealed improvement and no obstruction in five patients. one patient developed ureteral stricture (0.4%) and needed treatment with laser endoureterotomy (table 4). discussion advances in flexible ureteroscope designs, accessory instrumentations, and new laser generators have allowed endoscopic treatment for more challenging cases. using the uas makes it easier to enter and exit the ureter, renal pelvis, and calyces during the operation and even more when handling large stones. rirs is a safe and valuable modality of treatment for renal stones. it is a well-established procedure under constant evolution with advances in technique and technology. it has gained worldwide popularity due to its minimal invasiveness and satisfactory outcomes (17). flexible urs has become the standard of care for treating urolithiasis less than 2 cm (2, 3). there is no doubt that f-urs surgery has become very common in the treatment of uuts even though the sfr is higher after percutaneous nephrolithotomy (pcnl). furthermore, f-urs is also an option for renal stones larger than 2.5 cm with low morbidity (18). despite this, ureteral strictures are still observed after furs as a result of injury from impacted stones, ureteral perforations, or unclear intraoperative vision (19, 20). darwish et al. concluded that post-urs ureteral stricture incidence is low and that impacted stones are the most common cause of urs complications and stricture formation (21). traxer et al. reported a higher risk of severe ureteral injury secondary to uas use (22). however, özsoy et al.'s experimental animal model demonstrated that after two weeks, only minimal inflammatory changes were evident in the ureter suggesting negligible long-term impacts secondary to uas use (23). according to manger et al., ureteral strictures typically appear during the first four weeks of follow-up postoperatively (24). renal loss can result from ureteral strictures, therefore, we need to be aware of this risk throughout our postoperative followup. even if our standard approach involves the use of uas and small-diameter flexible ureteroscopes, our concern is how to diagnose an obstruction secondary to strictures as early and as feasibly as possible. in this study, a dynamic renal scan was routinely performed post-operatively. early diagnosis and treatment of ureteral stricture is the cornerstone of its management. so, could routine postoperative imaging help in the early diagnosis of ureteral stricture and prevent renal loss? patients with high-risk indicators for the development of stenosis, such as impacted stones, should undergo postoperative imaging, according to may et al. (25). jung et al. compared two groups of patients who underwent mini-pcnl or rirs and were monitored by 99mtc-dtpa preoperatively and postoperatively. no differences in renal function between the groups were noticed (26). piao et al. reported their results using 99mtc-dtpa to check the relative renal function after minimal invasive renal surgery, although their purpose was not to diagnose ureteral stricture (27). in this study, a uas was standardly used, and a routine scan was done postoperatively; 244 renal units demonstrated no obstruction, while in six patients t1/2 was between 1020 minutes. in these patients, a second renal scan was done, and improvement was achieved. however, one symptomatic patient underwent a retrograde pyelography (1/250) which diagnosed a ureteric stricture and was subsequently treated endoscopically with laser endoureterotomy and placement of a temporary stent. we showed that renal or ureteral obstruction post-f-urs is very rare (2.4% of the renal units), when renal retention was suggested by a dynamic renal scan with t1/2 between 10-20 minutes, but only one out of six patients needing treatment. the advantages of our study include: outcomes may be more easily compared because all surgeries were carried out by the same surgeon using the same equipment, personnel, ureteroscope, holmium laser energy and uas from the same company. the disadvantages include: its retrospective design, absence of a control group, and the untested duration of the surgery, which may be a risk factor for stricture formation. to our knowledge, there are no studies that investigated the use of a routine dynamic renal scan post-f-urs to diagnose ureteral strictures and suggest an early evaluation and treatment. table 4. complications. no % patients 242 96.8 renal units 250 100 renal colic needs im/iv* treatment 2 0.8 haematuria 2 0.8 prolonged flank pain (~2 weeks) 5 2 insertion of stent due to pain 0 0 fever 0 0 urinary tract infection 0 0 ureteral stricture 1 0.4 ureteral avulsion 0 0 ureteral perforation 0 0 claviendindo classification i 9 3.6 claviendindo classification iii 1 0.4 *im = intramuscular; iv = intravenous. archivio italiano di urologia e andrologia 2024; 96(2):12393 m. asali, o. hallak 4 we showed that f-urs was successful in 94.8% (237/250) of cases in the first session, and cumulative sfr in a twostage procedure was 99.7% (249/250). a third auxiliary procedure was done successfully in one patient. in this study, favourable results were achieved, even if it included 30.8% (77/250) of lower pole stones. the mean number of procedures per renal unit was 1.06. according to the clavien-dindo classification, no major complications were observed. conclusions obstruction due to ureteral stricture post-flexible ureteroscopy is very rare, a dynamic renal scan post-operatively may be used in high-risk patients. references 1. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017; 35:1301-1320. 2. de la rosette j, denstedt j, geavlete p, et al. croes urs study group. the clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. j endourol. 2014; 28:131-9. 3. kılıç ö, akand m, van cleynenbreugel b. retrograde intrarenal surgery for renal stones part 2. turk j urol. 2017; 43: 52-260. 4. takagi t, go t, takayasu h, aso y. fiberoptic pyeloureteroscope. surgery. 1971; 70:661-3. 5. takayasu h, aso y, takagi t, go t. clinical application of fiberoptic pyeloureteroscope. urol int. 1971; 26:97-104. 6. xiong m, zhu x, chen d, et al. post ureteroscopic stone surgery ureteral strictures management: a retrospective study. int urol nephrol. 2020; 52:841-849. 7. grasso m, bagley d. small diameter, actively deflectable, flexible ureteropyeloscopy. j urol. 1998; 160:1648-53. 8. ankem mk, lowry ps, slovick rw, et al. clinical utility of dual active deflection flexible ureteroscope during upper tract ureteropyeloscopy. urology. 2004; 64:430-4. 9. mario s, watterson jd, wollin ta, et al. holmium:yag laser lithotripsy for upper urinary tract calculi in 598 patients. j urol. 2002; 167:31-34. 10. weizer az, auge bk, silverstein ad, et al. routine postoperative imaging is important after ureteroscopic stone manipulation. j urol. 2002; 168:46-50. 11. elashry om, elgamasy ak, sabaa ma, et al. ureteroscopic management of lower ureteric calculi: a 15-year single-centre experience. bju int. 2010; 102:1010-1017 12. el-abd as, suliman mg, farha moa, et al. the development of ureteric strictures after ureteroscopic treatment for ureteric calculi: a long-term study at two academic centres. arab j urol. 2014; 12:168-172. 13. li l, pan y, weng z,, et al. a prospective randomized trial comparing pneumatic lithotripsy and holmium laser for management of middle and distal ureteral calculi. j endourol. 2015; 29:883-7. 14. dimarco ds, leroy aj, thieling s, et al. long-term results of treatment for ureteroenteric strictures. urology. 2001; 58:909-13. 15. asali m. sheathed flexible retrograde intrarenal surgery without safety guide wire for upper urinary tract stones. arch ital urol androl. 2022; 94:186-189. 16. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 17. sanguedolce f, bozzini g, chew b, et al. the evolving role of retrograde intrarenal surgery in the treatment of urolithiasis. eur urol focus. 2017; 3:46-55. 18. breda a, angerri o. retrograde intrarenal surgery for kidney stones larger than 2.5 cm. curr opin urol. 2014; 24:179-83. 19. roberts ww, cadeddu ja, micali s, et al. ureteral stricture formation after removal of impacted calculi. j urol. 1998; 159:723-6. 20. brito ah, mitre ai, srougi m. ureteroscopic pneumatic lithotripsy of impacted ureteral calculi. int braz j urol. 2006; 32:295-9. 21. darwish ae, gadelmoula mm, abdelkawi if, et al. ureteral stricture after ureteroscopy for stones: a prospective study for the incidence and risk factors. urol ann. 2019; 11:276-281. 22. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:5804. 23. özsoy m, kyriazis i, vrettos t, et al. histological changes caused by the prolonged placement of ureteral access sheaths: an experimental study in porcine model. urolithiasis. 2018; 46:397-404. 24. manger jp, mendoza pj, babayan rk, wang ds. use of renal ultrasound to detect hydronephrosis after ureteroscopy. j endourol. 2009; 23:1399-402. 25. may pc, hsi rs, tran h, et al. the morbidity of ureteral strictures in patients with prior ureteroscopic stone surgery: multi-institutional outcomes. j endourol. 2018; 32:309-314. 26. jung jh, yoo s, park j, et al. postoperative renal functional changes assessed by 99mtc-dtpa scintigraphy and predictive factors after miniaturized percutaneous nephrolithotomy and retrograde intrarenal surgery: an observational 1-year follow-up study. investig clin urol. 2020; 61:59-66. 27. piao s, park j, son h, et al. evaluation of renal function in patients with a main renal stone larger than 1 cm and perioperative renal functional change in minimally invasive renal stone surgery: a prospective, observational study. world j urol. 2016; 34:725-32. correspondence murad asali, md (corresponding author) dr.muradasali@gmail.com department of urology, barzilai medical center, ben gurion university of the negev, beer sheva, sokolov 26/99, 8430905 osman hallak, md urology department, barzilai medical center, ben gurion university of the negev, beer sheva, israel conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12582 1 original paper introduction chronic prostatitis/chronic pelvic pain syndrome (cp/cpps) stands as one of the prevalent conditions affecting men, often related with benign prostatic hyperplasia (bph), posing significant financial burdens on healthcare systems (1-4). despite its prevalence and the progress in treatment of bph (5), the understanding of cp/cpss underlying mechanisms remains incomplete due to diverse risk factors and associated conditions. psychological factors and various triggers, such as infection or inflammation, can exacerbate cp/cpps mechanisms, ultimately impacting patients' quality of life (qol) and psychological wellbeing (6). consequently, treatment approaches vary and may not consistently yield clinical efficacy, as shown by the variability in reported treatment effects across case series and controlled trials, often influenced by placebo effects or publication biases (7). among the spectrum of therapies, some new treatments emerged in last years, such low-intensity shockwave therapy and acupuncture (8, 9) although there is not enough strong evidence to adopt these therapies in clinical practice. the core of treatment of cp/cpss is still phytotherapy, or herbal medicine, particularly in alleviating pain and enhancing qol, alongside mild anti-inflammatory effects. additionally, rectal therapies involving corticosteroids have shown promise in cp/cpps patients, with beclomethasone di-propionate suppositories demonstrating a favorable safety profile and efficacy in ameliorating storage symptoms and clinical findings associated with lower urinary tract inflammation (10). in a previous study we demonstrated the efficacy of curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii (11). however, there is a growing body of evidence regarding the therapeutic benefits of palmitoylethanolamide and epilobium on bph and cp/cpss, due their anti-inflammatory effect and inhibition on nf-kb (12, 13). based on these premises, the aim of this study is investigating the efficacy of palmitoylethanolamide, epilobium, curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii. objective: the management of chronic prostatitis/chronic pelvic pain syndrome type iii (cp/cpps) has been always considered complex due to several biopsychological factors underlying the disease. in this clinical study, we aimed to evaluate the efficacy of the treatment with palmitoylethanolamide, epilobium and calendula extract in patients with cp/cpps iii. materials and methods: from june 2023 to july 2023, we enrolled 45 consecutive patients affected by cp/cpps type iii in three different institution. we included patients aged between 18 and 75 years with symptoms of pelvic pain for 3 months or more before the study, a total national institutes of health chronic prostatitis symptom index (nih-cpsi) score ≥ 12 point and diagnosed with nih category iii, according to 4-glass test meares-stamey test. patients were then allocated to receive rectal suppositories of pea, epilobium and calendula, 1 suppository/die for 1 month. all patients have been tested with standard urinalysis in order to assess urinary leukocytes (u-wbc). the primary endpoint of the study was the reduction of nihcpsi. the secondary outcomes were the change of peak flow, post-void residual (pvr), iief-5, vas score, psa and decrease of u-wbc. results: a total of 45 patients concluded the study protocol. at baseline, the median age of all the patients included in the cohort was 49 years, the median psa was 2.81 ng/ml, the median nih-cpsi was 18.55, the median iief-5 was 18.27, the median u-wbc was 485.3/mmc, the median vas score was 6.49, the median pvr was 26.5 ml and the median peak flow was 16.3 ml/s. after 1 month of therapy we observed a statistically significant improvement of nih-cpsi, u-wbc, psa, iief-5, peak flow, pvr and vas. conclusions: in this observational study, we showed the clinical efficacy of the treatment with pea, epilobium and calendula, 1 suppository/die for 1 month, in patients with cp/cpps iii. the benefits of this treatment could be related to the reduction of inflammatory cells in the urine that could imply a reduction of inflammatory cytokines. these results should be confirmed in further studies with greater sample size. key words: chronic prostatitis; chronic pelvic pain syndrome; palmitoylethanolamide; epilobium; calendula submitted 12 may 2024; accepted 28 may 2024 efficacy of palmitoylethanolamide, epilobium and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii giuseppe morgia 1, arturo lo giudice 1, maurizio carrino 2, salvatore voce 3, andrea cocci 4, giulio reale 3, andrea minervini 4, sebastiano cimino 5, giorgio ivan russo 5, francesca zingone 1 1 unit of urology, mediterranean oncological institute (iom), university of catania, italy; 2 unit of urology, cardarelli hospital, naples, italy; 3 unit of urology, ravenna hospital, italy; 4 department of urology, university of florence, italy; 5 department of urology, university of catania, italy. doi: 10.4081/aiua.2024.12582 summary archivio italiano di urologia e andrologia 2024; 96(2):12582 g. morgia, a. lo giudice, m. carrino, et al. 2 materials and methods from june 2023 to july 2023, we enrolled 45 consecutive patients affected by cp/cpps iii in three different institutions. inclusion criteria were age between 18 and 75 years old, symptoms of pelvic pain for 3 months or more before the study according to european association of urology (eau) guidelines, a negative 4-glass test meares-stamey test and a total national institutes of health chronic prostatitis symptom index (nih-cpsi) score ≥ 12 point. patients diagnosed with nih category iiia and iiib using the ppmt (preand post-massage test) have been enrolled. category iiia refers to the presence of white blood cells (wbc) after a prostate massage urine specimen (vb3) (wbc in vb3 > 10/hps). category iiib refers to patients with pelvic pain with no evidence of inflammation on vb3. exclusion criteria were urinary tract infection, urethritis, sexually transmitted disease (std), treatment with phytotherapeutic agents, alpha-blockers or antibiotics, urogenital cancer. at baseline subjects underwent uroflowmetry to evaluate the peak flow and the post void residual (pvr), they filled out the international index of erectile function questionnaire (iief-5), the nih-cpsi and the visual analogue score (vas). psa test and urinary white blood cells count (u-wbc) have also been performed. all subjects gave written informed consent before entering the study, which was conducted in accordance with the declaration of helsinki. patients underwent treatment consisting of rectal suppositories of pea, epilobium and calendula (riflog cm), 1 suppository/die for 1 month. statistical analysis the primary endpoint of the study was the reduction of nih-cpsi. the secondary outcomes were the change of u-wbc, peak flow, iief-5 and vas. the student t-test was used for comparisons in the distribution of nonnormal variables between baseline and follow-up. a twosided p-value < 0.05 was considered statistically significant in all the tests used. statistical analyses were performed using stata®16 software (statacorp llc, us). results we enrolled 45 patients in study, at baseline, average age was 48.75 (s.d. 13.44; iqr 29-68), average nih-cpsi score was 18.55 (s.d. 3.71; iqr 12-24), average iief5 score was 18.27 (s.d. 5.18; iqr 11-25), average peak flow was 16.3 ml/s (s.d. 7.78; iqr 8.6-31), average pvr was 26.5 ml (s.d. 29.5; iqr 0-70), average vas score was 6.49 (s.d. 1.55; iqr 4-8), average u-wbc was 485.3/mmc (s.d. 407.98; iqr 0-1153), average psa was 2.81 ng/ml (s.d. 1.76; iqr 0.57-5.4). after 1 month of follow-up, average nih-cpsi score reduced to 9.36 (s.d. 4.63; iqr 2-15), average iief5 score augmented to 19.53 (s.d. 5.46; iqr 11-25), average vas score reduced to 2.84 (s.d. 1.75; iqr 0-5) and average psa reduced to 1.74 ng/ml (s.d. 1.26; iqr 0.4-3.8) (figure 1). furthermore, at follow-up average peak flow augmented to17.63 ml/s (s.d. 7.63; iqr 9.4-32), average pvr reduced to 19.48 ml ( s.d. 26.83; iqr 0-50), average uwbc reduced to 306.85/mmc (s.d. 359.65; iqr 0-837) (figure 2). all the changes were statistically significant since the mean difference in nih-cpsi score was -9.2 (95%ci -7.57; -10.82, p < 0.05); the mean difference in iief5 score was 1.27 (95%ci 0.67; 1.85, p < 0.05); the mean difference in vas score was -3.65 (95%ci -4.23; -3.07, p < 0.05); the mean difference in peak flow was 1.34 (95%ci 0.52; 2.15, p < 0.05); the mean difference in pvr was -7.05 (95%ci -9.92; -4.17, p < 0.05); the mean difference in u-wbc score was -178.45 (95%ci -225.39; -131.52, p < 0.05); the mean difference in psa score was -1.06 (95%ci -1.40; -0.72, p < 0.05). figure 1. nih-cpsi score, iief-5 score, vas score and psa at baseline and follow-up. figure 2. peak flow, post-void residual and u-wbc at baseline and follow-up. archivio italiano di urologia e andrologia 2024; 96(2):12582 3 pea, epilobium and calendula for cp/cpps discussion cp/cpps stands as one of the most common ailments affecting males under the age of 50. it is distinguished by a diverse range of risk factors and subsequent clinical presentations. various treatments, such as alpha-blockers, antibiotics, anti-inflammatory drugs, and other agents like finasteride, phytotherapy, and gabapentinoids, are regularly employed. nonetheless, the effectiveness of these treatments remains contentious due in part to the limited size and statistical power of many clinical trials assessing their efficacy (14). in this study, we demonstrated that the utilization of rectal suppositories containing of pea, epilobium and calendula (riflog cm) proved to be clinically effective in alleviating pain, improving voiding symptoms, and enhancing urinary flow after one month of treatment; on the other hand, we demonstrated the reduction of uwbc and psa values, as an effect of reducing inflammation. the underlying rationale behind such therapy likely stems from its anti-inflammatory properties, which could exert multiple beneficial effects. the extract from calendula officinalis flowers demonstrated significant anti-inflammatory properties. in a chronic inflammation model using formalin, administration of calendula extract at doses of 250 and 500 mg/kg body weight resulted in inhibitions of 32.9% and 62.3%, respectively, compared to control groups. additionally, calendula extract significantly suppressed tnf-alpha production by macrophage cultures treated with lipopolysaccharide (lps). furthermore, the extract significantly inhibited the elevated levels of pro-inflammatory cytokines il-1beta, il-6, tnf-alpha, and ifn-gamma, as well as the acute phase protein c-reactive protein (crp) induced by lps injection in mice. treatment with the extract also led to inhibition of lps-induced cyclooxygenase-2 (cox-2) levels in mice spleens (15). the analgesic effects of pea are exerted through various pathways. pea directly targets pparα and gpr55 receptors and indirectly influences cb1, cb2, and trpv1 receptors. it suppresses inflammation by hindering mc activation, downregulating mediators like ngf, cox-2, tnf-α, and inos, and inhibiting microglia and astrocyte activation. in chronic inflammatory conditions, this enables pea to maintain peripheral nerve structure, decrease endoneural edema, and mitigate macrophage infiltration. currently, pea has a recognized role as an analgesic in various clinical conditions, such as headache and menstrual pain (16). epilobium has a recognized role in bph treatment due to his anti-inflammatory effects inhibiting cox and nf-kb (12, 17). some bias of our study are that it is not a randomized trial, the small sample size and the lack of comparison with placebo, however our previous randomized trial has demonstrated the superiority of phytotherapy versus placebo in similar setting; some strengths are the investigations of new compounds for cp/cpps treatment, the “real life” design and the consideration of objective indicators of urinary inflammation such as uwbc. in conclusion we demonstrated the efficacy of rectal suppositories with pea, epilobium and calendula (riflog cm) for the treatment of cp/cpps, in terms of pain and urinary symptoms; these results should be confirmed in further studies with, perhaps, greater sample size and randomized placebo-controlled trial design. references 1. russo gi, cimino s, fragalà e, et al. relationship between nonalcoholic fatty liver disease and benign prostatic hyperplasia/lower urinary tract symptoms: new insights from an italian cross-sectional study. world j urol. 2015; 33:743-51. 2. morgia g, mucciardi g, galì a, et al. treatment of chronic prostatitis/chronic pelvic pain syndrome category iiia with serenoa repens plus selenium and lycopene (profluss) versus s. repens alone: an italian randomized multicenter-controlled study. urol int. 2010; 84:400-6. 3. morgia g, cimino s, favilla v, et al. effects of serenoa repens, selenium and lycopene (profluss®) on chronic inflammation associated with benign prostatic hyperplasia: results of “flog” (flogosis and profluss in prostatic and genital disease), a multicentre italian study. international braz j urol. 2013; 39:214-21. 4. rees j, abrahams m, doble a, cooper a. diagnosis and treatment of chronic bacterial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. bju int. 2015; 116:509-25. 5. cocci a, bocchino ac, cito g, et al. role of rezum in the treatment of benign prostate hyperplasia: a review of the literature. turk j urol. 2021; 47:452-460. 6. vanella l, russo gi, cimino s, et al. correlation between lipid profile and heme oxygenase system in patients with benign prostatic hyperplasia. urology. 2014; 83:1444.e7-1444.e13. 7. morozov a, bazarkin a, babaevskaya d, et al. a systematic review and meta-analysis of placebo effect in clinical trials on chronic prostatitis/chronic pelvic pain syndrome. prostate. 2022; 82:63356. 8. mykoniatis i, pyrgidis n, sokolakis i, et al. low-intensity shockwave therapy for the management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and meta-analysis. bju int. 2021; 128:144-52. 9. pan j, jin s, xie q, et al. acupuncture for chronic prostatitis or chronic pelvic pain syndrome: an updated systematic review and meta-analysis. pain res manag. 2023; 2023:1-13. 10. bozzini g, provenzano m, buffi n, et al. an observational study of the use of beclomethasone dipropionate suppositories in the treatment of lower urinary tract inflammation in men. bmc urol. 2016; 16:25. 11. morgia g, russo gi, urzì d, et al. a phase ii, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of curcumina and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii. arch ital urol androl. 2017; 89:110. 12. cicero afg, allkanjari o, busetto gm, et al. nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. arch ital urol androl. 2019; 91:139. 13. deng l, zong w, tao x, et al. evaluation of the therapeutic effect against benign prostatic hyperplasia and the active constituents from epilobium angustifolium l. j ethnopharmacol. 2019; 232:1-10. 14. magistro g, wagenlehner fme, grabe m, et al. contemporary archivio italiano di urologia e andrologia 2024; 96(2):12582 g. morgia, a. lo giudice, m. carrino, et al. 4 management of chronic prostatitis/chronic pelvic pain syndrome. eur urol. 2016; 69:286-97. 15. preethi kc, kuttan g, kuttan r. anti-inflammatory activity of flower extract of calendula officinalis linn. and its possible mechanism of action. indian j exp biol. 2009; 47:113-20. 16. clayton p, hill m, bogoda n, et al. palmitoylethanolamide: a natural compound for health management. int j mol sci. 2021; 22:5305. 17. deng l, zong w, tao x, et al. evaluation of the therapeutic effect against benign prostatic hyperplasia and the active constituents from epilobium angustifolium l. j ethnopharmacol. 2019; 232:1-10. correspondence giuseppe morgia, md (corresponding author) giuseppe.morgia@unict.it arturo lo giudice, md arturologiudice@gmail.com francesca zingone, md francesca.zingone@grupposamed.com university of catania, mediterranean oncological institute (iom) unit of urology, catania (italy) maurizio carrino, md maurizio.carrino@aocardarelli.it cardarelli hospital, unit of urology, naples (italy) salvatore voce, md salvatore.voce@auslromagna.it giulio reale, md dottorgreale@gmail.com ravenna hospital, unit of urology, ravenna (italy) andrea cocci, md cocci.andrea@gmail.com andrea minervini, md andrea.minervini@unifi.it university of florence department of urology, florence (italy) sebastiano cimino, md ciminonello@hotmail.com giorgio ivan russo, md giorgioivan1987@gmail.com university of catania, department of urology, catania (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13098 1 review introduction benign prostatic hyperplasia (bph) is a common urological disease that is strongly associated with the aging process (1). prostate growth is influenced by a combination of intrinsic and extrinsic factors that interact in a complex manner. the pathophysiological pathway includes hormone and androgen exposure as well as growth factors, chronic inflammation and genetics (2). lower urinary tract symptoms (luts) due to bph can have a significant impact on patients’ quality of life (3). for most patients with symptomatic benign prostatic hyperplasia, medical management remains the cornerstone of treatment. pharmacologic measures are often preferred as a first approach as they can relieve symptoms and improve the patient’s well-being (4). the landscape of medical treatment for bph is constantly evolving. the efficacy of overthe-counter medications, plant extracts and natural supplements has not yet been adequately researched and their benefits are still unclear. at the same time, ongoing studies of new pharmacologic agents, such as beta-3 agonists, have the potential to expand the available therapeutic options, providing hope for more targeted and effective strategies in the future. with this review, we aimed to provide an up-to-date overview of the most common medical treatments for luts including phytotherapy in the context of bph. materials and methods in july 2024, a systematic review of medical therapy for bph was conducted using relevant articles in pubmed, scopus, and the cochrane central register of controlled trials. the review focused on phytotherapy and medical introduction: benign prostatic hyperplasia (bph) is a common urological disease that is strongly associated with the aging process and can lead to lower urinary tract symptoms (luts). luts due to bph can significantly affect the quality of life of many patients. among the treatments available for bph to improve symptoms and functional outcomes, drug therapy and surgical therapy are the options of choice. however, for most patients with symptomatic bph, medical management remains the cornerstone of treatment. pharmacologic interventions are often preferred as a first approach, being less invasive compared to surgery. although the medical treatment of bph is currently defined by the algorithms of international guidelines, the need for a more personalized approach is increasingly recognized given the wide and heterogeneous range of therapeutic options available. materials and methods: a review of medical therapy for bph was conducted using relevant articles in pubmed, scopus, and the cochrane central register of controlled trials. in this review, all drug treatments currently available on the international market whose efficacy is scientifically proven are reviewed and described (phytotherapy, alpha-blockers, muscarinic receptor antagonists, 5-alpha-reductase inhibitors, combination therapies, etc.). results: a total of 17 randomized clinical trials were selected for review. further 75 studies were included for analysis and discussion. conclusions: as the treatment landscape continues to evolve, tailoring therapy to individual patient needs and preferences is likely to become increasingly important to ensure that treatment strategies are both effective and meet patient expectations. key words: benign prostatic hyperplasia; medical therapy; alpha-blockers; antimuscarinics; phytotherapy. submitted 13 september 2024; accepted 23 november 2024 non-surgical management of bph: an updated review of current literature and state of the art on natural compounds and medical therapy guglielmo mantica 1, 2, francesca ambrosini 2, giovanni drocchi 1, zlata zubko 1, lorenzo lo monaco 1, angelo cafarelli 3, alessandro calarco 4, renzo colombo 5, ottavio de cobelli 6, ferdinando de marco 7, giovanni ferrari 8, giuseppe ludovico 9, stefano pecoraro 10, domenico tuzzolo 11, carlo terrone 1, 2, rosario leonardi 12 1 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 2 irccs ospedale policlinico san martino, genova, italy; 3 urology unit, villa igea, ancona, italy; 4 department of urology, san carlo di nancy hospital, rome, italy; 5 department of urology, vita e salute san raffaele university, milan, italy; 6 department of urology, ieo european institute of oncology, irccs, milan, italy; 7 i.n.i. grottaferrata, rome, italy; 8 hesperia hospital, modena, italy; 9 ospedale miulli, acquaviva delle fonti, bari, italy; 10 neuromed, avellino, italy; 11 urologi ospedalità gestione privata (urop), italy; 12 casa di cura musumeci-gecas, gravina di catania, italy. doi: 10.4081/aiua.2024.13098 summary archivio italiano di urologia e andrologia 2024; 96(4):13098 g. mantica, f. ambrosini, g. drocchi, et al. 2 treatment of bph. three authors (gm, fa, gd) independently screened the titles and abstracts of the datasets for eligibility. reviews, original articles, and case reports were included, while other types of articles were excluded. evidence was limited to human data and experimental animal studies. only publications in english were considered. in addition, manuscripts that were not focused on the purpose of the review were not included. the original list of selected articles was supplemented by individual suggestions from the co-authors of the present review. similarly, articles published before 1990 but considered interesting for the purpose of the review were suggested by the authors and assessed by the screening team. the reference lists of the selected articles/systematic reviews/meta-analyses were also screened to identify further potentially relevant studies, using the same criteria as for the initial search. results the search strategy has been highlighted using the prisma flowchart (5) (figure 1) and pico model (6) (supplementary matherial) to summarize the results. the risk of bias of the 17 randomized controlled trials included has been evaluated using the rob 2 – revised tool (7) (figure 2). figure 1. prisma flowchart. source: page mj, et al. bmj 2021; 372: n71. figure 2. risk of bias of the 17 randomized controlled trials evaluated using the rob 2 – revised tool. archivio italiano di urologia e andrologia 2024; 96(4):13098 3 non-surgical management of bph watchful waiting and dietary lifestyle many men with mild luts do not find their symptoms bothersome enough to warrant medical treatment or surgery. in addition, many patients are concerned about the potential complications associated with taking medication. in selected cases without clinical complications (renal insufficiency, hematuria, hydronephrosis, urinary tract infections, acute urinary retention…), watchful waiting (ww) might therefore be an even more attractive choice. in patients with mild luts (international prostate symptom score ipss), the condition can remain stable many times without complications such as acute urinary retention (8). the key issues in the treatment of bph with ww are the establishment of patient selection criteria and the assessment of risk factors for disease progression. longitudinal studies such as the baltimore longitudinal study of aging (9) and the olmstead county study (10) have shown that advanced age, a larger prostate, and decreased urinary flow can predict the need for treatment. the veterans administration cooperative study has shown that in properly selected patients, especially those with low baseline values, watchful waiting can be a viable and safe strategy (11). before or alongside treatment, lifestyle counseling and self-care information can positively impact men with luts due to bph (12). key components of this strategy include patient education, reassurance and regular monitoring, combined with specific lifestyle advice aimed at reducing urinary symptoms (12). it is often recommended to reduce fluid intake at times that minimize discomfort, such as before bedtime, and to limit the consumption of caffeine and alcohol, which can exacerbate symptoms such as frequency, urinary urgency and nocturia due to their diuretic effects (13). techniques such as double voiding, urethral milking and bladder training are also recommended to improve bladder control and reduce dribbling (14). another important measure is to avoid constipation and situations in which a person has to hold urine. systematic reviews and meta-analyzes have found that self-management measures that include these lifestyle changes can significantly reduce the severity of symptoms and slow the progression of the disease, thus providing relief (14). this holistic approach not only improves quality of life, but also empowers patients to actively manage their disease. phytotherapy phytotherapy is a science that uses plant extracts, from leaves to roots to seeds, to achieve benefits in the treatment of diseases (15-17). there are numerous in vitro studies in the literature on the potential benefits of phytotherapy in the treatment of bph, but little is known about the actual in vivo effects. serenoa repens serenoa repens, also known as saw palmetto, is probably the best-known plant available for the treatment of bph (18). the dried, ripe berry is used for the extraction. serenoa repens has anti-androgenic activity with inhibition of 5α-reductase and therefore reduces prostate volume; its activity is associated with the action of free fatty acids such as lauric and palmitic acid, which are also responsible for reducing inflammation. for these reasons, saw palmetto can slow down the development of bph and improve patients' quality of life (qol), ipss and symptoms (19). there are many different types of extraction from the plant. hexane extraction has proven to be the most reliable and provides the best results. currently, serenoa repens is the only phytotherapy recommended in most of the major international guidelines for the treatment of bph and its symptoms (20, 21). most tablets available on the market are 320 mg and are taken once daily. nevertheless, the dose and efficacy also depend on the extraction method itself. cucurbita the seeds of cucurbita pepo l. appear to have the property of inhibiting 5α-reductase and testosterone-induced hypertrophy by lowering dihydrotestosterone (dht) levels. some clinical studies showed an improvement in quality of life and ipss without altering patients’ sexual function during treatment (22, 23). urtica urtica dioica, the active ingredient of which is the dried root, is frequently used in traditional european medicine for the treatment of bph. urtica can reduce the conversion of testosterone into dht. several studies have shown a proliferation-inhibiting effect by binding to the membrane receptors of the prostate, thereby inhibiting its proliferative activity in prostate tissue. in vivo studies in rats showed a possible inhibition of 5α-reductase. however, more extensive studies in humans are needed to confirm its benefits (24-26). curcuma curcuma longa linn. is often used to treat urinary tract diseases due to its antioxidant and anti-inflammatory properties. in a recent study (27), this plant was able to improve luts symptoms, ipss and qmax score. an improvement was observed both in untreated patients and in patients already treated with alpha-blockers and/or 5α-reductase inhibitors (5-ari). pygeum africanum pygeum africanum (prunus) is known among the indigenous population of africa for its antiproliferative and antiinflammatory properties. it appears to be able to inhibit prostate growth factors and reduce the production of prostaglandins in the prostate (28). this leads to a reduction in chronic prostatitis and the inflammatory symptoms of bph. the evidence in the literature regarding the mechanism of actions and the clinical effect is weak. pollens cernitin, the best-known pollen, is an extract of secale cereale that has an interesting effect on bph and can improve both irritative and obstructive symptoms (29). its effect is achieved by relaxing the smooth muscles of the urethra and apoptosis of the cells of the prostatic transition zone. some studies based on small samples showed an improvement in ipss and a decrease in prostate volume after long-term treatment with pollen (30, 31). peony pollen, the pollen of paeonia suffruticosa, also appears to be able to attenuate oxidative stress and archivio italiano di urologia e andrologia 2024; 96(4):13098 g. mantica, f. ambrosini, g. drocchi, et al. 4 inflammation. they could be directly involved in the regulation of the gut microbiota. in addition, some pollen in combination with vitamins (deprox 500®) showed an improvement in the ipss and the nih chronic prostatitis symptom index (nihcpsi), alone or in combination with serenoa repens (32-35). the literature lacks strong evidence on this drug. epilobium epilobium species are perennial plants whose flowers and leaves are used for the presence of some substances such as phenolic acids, flavonoids, and tannins. the therapeutic effect of epilobium has been demonstrated in vitro, with a reduction in psa levels and a reduction in the inflammatory response and oxidative stress of prostate cells. in a randomized, placebo-controlled trial, epilobium was shown to improve post-void residual (pvr), increase ipss, and reduce nocturia (36). other studies have investigated the efficacy of epilobium and showed similar results (37). palmitoylethanolamide (pea) pea is an endocannabinoid-like bioactive lipid mediator that belongs to the n-acylethanolamine family. the properties of pea include a known anti-inflammatory effect and the reduction of testosterone and dht levels in both the prostate and serum. in addition, pea can reduce the upregulation of 5α-reductase 2 and androgen receptor induced by bph (38-40). most of the available studies were conducted in vitro, while the literature contains only a few in vivo studies. other plants other plant extracts are used in traditional medicine to treat bph and its symptoms. some of these plants are: hypoxis hemerocallidea, pinus pinaster, roystonea regia, solanum lycopersicum. the substances extracted from these plants appear to have a positive effect on bph thanks to their antioxidant, anti-inflammatory and anticarcinogenic properties. however, the current literature is minimal and of limited significance (41-43). conventional therapies alpha blockers among the drugs available for the treatment of luts and bladder outlet obstruction (boo) due to bph, alpha-blockers are the most frequently used. the literature is full of data evaluating the therapeutic benefits of these drugs, which are also recommended in the most widely followed guidelines (12, 44-45). their mechanism of action is closely related to the presence of many smooth muscle cells in the prostate that are amenable to alpha-adrenergic stimulation (46). this stimulation leads to relaxation of the prostate and bladder neck. the bladder and prostate contain predominantly alpha-1 receptors, which enables the use of selective blockers. the most commonly sold alpha-blockers today are tamsulosin, alfuzosin, doxazosin, silodosin, naftodipil and terazosin (47). the data available in the literature show that alpha-blockers can reduce the ipss score by 30-40% and improve qmax by 20-25%. one of their most important effects is to reduce the risk of acute urinary retention (48). unfortunately, these drugs are not free of side effects, such as hypotension and retrograde ejaculation, which are often significant for some patients. alpha reductase inhibitors another important drug for the treatment of bph are 5alpha-reductase inhibitors (5-ari). there are two types of 5α-reductase enzymes, but type 2 is most common in the prostate. this enzyme converts a portion of testosterone into dihydrotestosterone (dht), which plays a role in prostate growth (49). the 5-aris act by suppressing the enzyme 5α-reductase. dutasteride and finasteride are the most commonly used 5-aris and are equivalent in terms of results and effect. the pless study has shown that finasteride reduces the relative long-term risk of acute urinary retention and the need for surgery compared to placebo. 5-aris are able to improve luts and qmax (5052) and their effect may also be important before surgery by reducing prostate bleeding during turp (53, 54). 5aris are not free from potential side effects such as decreased sexual desire, impotence, gynecomastia, depression and anxiety. one of the properties of 5-aris is the lowering of psa levels. this effect, which has already been observed with other drugs (55) with a different mechanism, is much more pronounced with 5aris. therefore, the use of 5-aris must always be considered in the diagnosis of prostatic neoplasia in order to best select patients with a clinically significant risk of prostatic neoplasia who are candidates for prostate biopsy (56-58). muscarinic receptor antagonists normal physiological bladder emptying depends on the activation of the contractile muscarinic receptors on the smooth muscle of the bladder tricuspid. this activation is triggered by the neurotransmitter acetylcholine. five subtypes of g-protein-coupled muscarinic receptors (m1; m2; m3; m4; m5) have been characterized pharmacologically. most muscarinic receptors in the detrusor muscle are m2 (70%) and m3 (30%) (59). currently, the most commonly used antimuscarinic drugs are oxybutynin, propiverine, tolterodine and solifenacin (60, 61). the current eau guidelines recommend the use of muscarinic receptors in men with moderate to severe luts who have mainly bladder storage symptoms (12). a considerable number of muscarinic receptors are located in different parts of the body (salivary glands, gastrointestinal tract and central nervous system). therefore, the side effects of antimuscarinics may affect these areas (62). the most frequently reported adverse effects include blurred vision, constipation and dry mouth (61). their main effect is to reduce the urge to urinate and the frequency of urination. in addition, they are able to increase bladder capacity, allowing patients to hold urine for longer periods of time without discomfort. this improvement can significantly increase the quality of life of bph patients as they need to urinate less frequently. usually, these drugs are used in combination with alpha-blockers. this combination can be particularly effective in treating both the obstructive and irritative symptoms of bph. archivio italiano di urologia e andrologia 2024; 96(4):13098 5 non-surgical management of bph beta 3 agonists humans have three different subtypes of β-adrenoceptors (β1, β2 and β3). in human bladder tissue, β3-adrenoceptors are predominantly expressed (63). activation of this receptor is associated with detrusor smooth muscle relaxation during the storage phase of micturition and therefore improves bladder compliance and capacity. mirabegron is the first β3-adrenoceptor agonist approved in clinical practice and may be an alternative treatment option to antimuscarinics for patients with overactive bladder symptoms (64-66). the efficacy and safety of mirabegron 50 mg compared to placebo and antimuscarinics was evaluated in male patients with overactive bladder in five phase iii studies. mirabegron showed significant improvements in the reduction of micturition frequency compared to placebo. mirabegron 50 mg has been shown to be relatively safe. gastrointestinal symptoms and dry mouth are the most commonly reported adverse effects. mirabegron 100 mg, on the other hand, showed a slightly increased risk of high blood pressure and cardiac arrhythmia (68). phosphodiesterase 5 inhibitors phosphodiesterase type 5 (pde5) inhibitors (sildenafil, tadalafil, vardenafil and avanafil) are the gold standard in the treatment of patients with erectile dysfunction (ed). these drugs block the enzyme pde5 and thus regulate the level of cyclic guanosine monophosphate (cgmp) by breaking it down to inactive 5′-guanosine monophosphate (5′-gmp). this process leads to smooth muscle relaxation in the corpus cavernosum of the penis (69, 70). this relaxation increases the arterial inflow into the penis, which is necessary to achieve and maintain an erection. in addition, tadalafil relaxes the smooth muscles of the bladder and prostate and can thus improve luts (71). therefore, the daily intake of 5 mg tadalafil has been approved for the treatment of bph. compared to a placebo, 5 mg tadalafil once daily as monotherapy or in combination with alpha-blockers can significantly improve quality of life and ipss (72, 73). phosphodiesterase type 5 inhibitors are generally well tolerated, especially at low doses. the most common side effects are headache, redness of the skin, and nasal congestion (69, 70). combination therapy although alpha blockers are the treatment of choice in most cases, in many cases their effect alone is not sufficient to relieve the symptoms of bph. it is therefore possible to combine this therapy with 5-aris, pde5 inhibitors, mirabegon, antimuscarinics and, of course, phytotherapy, which generally leads to good results. studies such as combat and conduct have shown that dutasteride plus tamsulosin can improve qmax and ipss and reduce the risk of acute urinary retention (74, 75). therefore, combination therapy with 5-ari and alpha-blockers could be an option for patients with large prostate volume and severe luts. similar studies looking at the combination of alpha-blockers and pde5 inhibitors (tadalafil), alpha-blockers and mirabegone or alphablockers and antimuscarinics have shown that combination therapy is able to reduce luts without a significant increase in side effects (76, 77). discussion medical treatment for bph has evolved significantly over the years, offering a variety of treatment options aimed at alleviating symptoms and improving overall patient outcomes (78-80). in selected uncomplicated cases, ww and lifestyle changes can play a positive role in the management of bph symptoms (14). systematic reviews and meta-analyzes have shown that such self-management measures can significantly alleviate symptoms and control the progression of the disease (14). nevertheless, the elements of self-care management have not been assessed individually and the lifestyle advice is derived from a formal consensus method, so further research is needed in this area (12). among the approved drugs for the medical management of bph, alpha-blockers have been considered a cornerstone of bph treatment for many years. they provide rapid relief of symptoms, often within a few weeks, and are generally well tolerated (81). however, some patients may experience side effects such as dizziness, orthostatic hypotension, and ejaculatory dysfunction (82). despite these potential problems, alpha-blockers remain a widely used drug due to their efficacy and rapid onset of action (12). 5-ari, by lowering dihydrotestosterone levels, can shrink the prostate and improve luts over time (12). however, relief may be slower to come compared to alpha-blockers, and potential side effects include sexual dysfunction (83). moreover, their impact on psa needs to be considered in relation to prostate cancer screening (12). despite these concerns, they are a valuable option for the treatment of bph, especially in patients with prostate enlargement > 40 ml. treatments with phosphodiesterase-5 inhibitors such as tadalafil, have also shown promise in the management of bph. these drugs can provide additional relief from symptoms such as urinary urgency and frequency, improve erectile function and help to maintain ejaculatory function (84). they offer a different mechanism of action to conventional bph therapies and can be particularly useful for patients suffering from both bph and erectile dysfunction. however, they can cause side effects such as headaches and gastrointestinal discomfort, and interactions with other medications must be carefully monitored. research on newer agents such as beta-3 agonists, such as mirabegron, is ongoing. these medications target bladder function rather than prostate size and may help relieve storage symptoms such as urinary urgency and frequency. although the long-term efficacy and safety of these drugs are still under investigation, the available literature suggests that beta-3 agonists may be an effective addition to the bph treatment options (12). a further possibility that has emerged in recent years is that of suspension therapy for fragile patients or for patients with a combination of different therapies in order to reduce the risk of side effects. however, still few studies are currently available on the topic (85, 86). one of the most evolving and extensive fields related to the medical treatment of bph is phytotherapy. several plantderived substances are commercially available, including both herbal medicines and dietary supplements (87). phytotherapy has undeniable advantages, including high tolerability and low side effects (16). they are also easily available online or over the counter. sometimes patients archivio italiano di urologia e andrologia 2024; 96(4):13098 g. mantica, f. ambrosini, g. drocchi, et al. 6 find it difficult to adhere to the treatments because the side effects, including retrograde ejaculation, can significantly affect the patient’s psychological well-being, leading them to prefer phytotherapy. on the other hand, the evidence on phytotherapy is not conclusive, the mechanism of action is not always fully understood and many of these substances have not undergone the rigorous testing that drugs normally receive. considering their mostly moderate efficacy, which is inferior to that of approved drugs, there is a lack of strong recommendations in european (eau) or american urological association (aua) guidelines (12). however, in a historical period in which there is the threat of further pandemics (88) which can cause an increase in the waiting list of patients suffering from bph, a correct knowledge of the medical therapy of bph is of fundamental importance, allowing to manage the patient also through telemedicine and while waiting for surgery (89-91). conclusions in conclusion, the medical management of bph is currently defined by the algorithms of the eau and aua guidelines (12, 92). however, given the broad and heterogeneous range of therapeutic options available, the need for a more personalized approach is increasingly recognized. as the treatment landscape continues to evolve, tailoring therapy to individual patient needs and preferences is likely to become increasingly important to ensure that treatment strategies are both effective and meet patient expectations. references 1. gbd 2019 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spatafora p, frizzi j, et al. which drug to discontinue 3 months after combination therapy of tadalafil plus tamsulosin for men with lower urinary tract symptom and erectile dysfunction? results of a prospective observational trial. eur urol focus. 2021; 7:432-439. 87. morgia g, lo giudice a, carrino m, et al. efficacy of palmitoylethanolamide, epilobium and calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type iii. arch ital urol androl. 2024; 96:12582. archivio italiano di urologia e andrologia 2024; 96(4):13098 9 non-surgical management of bph 88. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67. 89. ambrosini f, di stasio a, mantica g, et al. covid-19 pandemic and uro-oncology follow-up: a "virtual" multidisciplinary team strategy and patients' satisfaction assessment. arch ital urol androl. 2020; 92:78. 90. mirone v, di bello f, morra s, et al. telemedicine and social media: a contemporary analysis of the most shared content by internet users. arch ital urol androl. 2024; 96:11206. 91. carrión dm, gómez rivas j, rodríguez-socarrás me, et al. implementación de la teleconsulta en la práctica urológica durante la era covid-19: ¿qué hemos aprendido? [implementation of remote clinics in urology practice during the covid-19 era: what have we learned?]. arch esp urol. 2020; 73:345-352. 92. sandhu js, bixler br, dahm p, et al. management of lower urinary tract symptoms attributed to benign prostatic hyperplasia (bph): aua guideline amendment 2023. j urol. 2024; 211:11-19. correspondence guglielmo mantica (corresponding author) guglielmo.mantica@gmail.com giovanni drocchi g.drocchi@hotmail.it zlata zubko zlata@zubko.it lorenzo lo monaco lomonaco_lorenzo@libero.it carlo carlo terrone carlo.terrone@med.uniupo.it department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy francesca ambrosini irccs ospedale policlinico san martino, genova, italy f.ambrosini1@gmail.com angelo cafarelli info@angelocafarelli.it urology unit, villa igea, ancona, italy alessandro calarco segreteria@alessandrocalarco.com department of urology, san carlo di nancy hospital, rome, italy renzo colombo colombo.renzo@hsr.it department of urology, vita e salute san raffaele university, milan, italy ottavio de cobelli ottavio.de-cobelli@ieo.it department of urology, ieo european institute of oncology, irccs, milan, italy ferdinando de marco info@clinicavillamargherita.it i.n.i. grottaferrata, rome, italy giovanni ferrari visite@giovanniferrariurologo.it hesperia hospital, modena, italy giuseppe ludovico g.ludovico@miulli.it ospedale miulli, acquaviva delle fonti, bari, italy stefano pecoraro cup@diagnosticamedica.org neuromed, avellino, italy domenico tuzzolo info@casadelsole.it urologi ospedalità gestione privata (urop), italy rosario leonardi leonardi.r@tiscali.it casa di cura musumeci-gecas, 95030 gravina di catania, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12620 1 original paper linked to the maternal immune response. the embryo that will implant in the endometrial wall is likened to an allograft in the maternal body. this requires a balance of immune responses in the process so as to avoid any form of attack on the embryo (3). the immune response that plays a dominant role in this process is t-reg; the number of dominant t-reg will produce interleukin-10 (il-10) and tumor growth factor-beta (tgf-ß) and suppress th-1 so that the levels of interferon-gamma (ifn-γ), interleukin-12 (il12), interleukin (il-2), and tumor necrosis factor-beta (tnfα) would become low (3, 4). t-cell regulation and the involved cytokines contribute to the implantation process. t-reg cells also suppress the proliferation and function of leukocyte subsets such as cd4 t cells, cd8 t cells, b cells, and natural killer (nk) cells. t-reg cells influence the function of dendritic cells (dcs) and macrophages (4, 5). if this does not occur, implantation will become difficult or, in some cases, hemorrhage will occur, leading to embryonic failure (4, 6, 7). experts argue that modifying the maternal immune system is necessary to facilitate embryo implantation. modifying the immune system can occur in several ways, including maternal exposure to the partner’s seminal plasma. exposure to seminal plasma, such as during intercourse, has been reported to improve embryo implantation (8, 9). this is because seminal plasma contains many biomolecules, such as tgf-ß, that influence the immune system in the endometrium. several studies have investigated the relationship between seminal plasma exposure and pregnancy success rates. however, because they used different methods, the embryo transfer (et) time group (fresh or frozen) was also not uniform, leading to different results (2, 10). in light of the above, we conducted a study to investigate the effect of sexual intercourse on the chances of successful ivf in both fresh and frozen et groups in terms of biochemical and clinical pregnancy in indonesia. materials and methods design of the study this is an observational analytical study with a retrospective background: modifying the maternal immune system is necessary to facilitate embryo implantation. modifying the immune system can occur in several ways, including maternal exposure to the partner’s seminal plasma. seminal plasma exposure can occur through sexual intercourse. to prove this theory, we investigate the effect of sexual intercourse on the chances of successful in vitro fertilization (ivf) in both fresh and frozen embryo transfer (et) groups in terms of biochemical and clinical pregnancy. methods: this is an observational analytical study with a retrospective cohort study design. this study compared biochemical and clinical pregnancy in patient groups who had sexual intercourse with those who did not have sexual intercourse during the ivf process. this study involved 132 participants. results: the results of this study reported that there was no significant difference in pregnancy rates between patients who had sex before et and those who did not have sex before et. however, patients who experience orgasm during sex show significant rates of biochemical (p = 0.009) and clinical pregnancy (p = 0.027) rates. conclusions: sexual intercourse did not show a significant difference between the groups who had sex before et and those who did not have sex, but the experience of orgasm every time they had sex recently had a positive impact on reproductive health, especially pregnancy. key words: in-vitro fertilization; sexual intercourse; embryo transfer; reproductive health; orgasm. submitted 30 april 2024; accepted 21 june 2024 background one of the most commonly used methods to help infertile couples is in vitro fertilization (ivf). ivf is reported to succeed in only 30-40% of cases (1). several factors influence the success rate of ivf. according to crawford et al, one of the most critical processes for the success of ivf is embryo implantation; even if the quality of the embryo is excellent, implantation will fail if the endometrial receptivity is insufficient (2). research reports that endometrial receptivity is closely sexual intercourse before embryo transfer in assisted reproductive technology might enhance probability of pregnancy: an observational study cennikon pakpahan 1, 2, 3, agustinus agustinus 1, 2, 3, ashon sa’adi 3, 4, aucky hinting 3, lia hinting 3, christian melka parmanto1, andri rezano 5 1 andrology study program, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia; 3 ferina mother and child hospital, surabaya, indonesia; 4 department of obstetrics and gynecology, faculty of medicine, universitas airlangga, surabaya, indonesia; 5 department of biomedical sciences, faculty of medicine, universitas padjadjaran, sumedang, indonesia. doi: 10.4081/aiua.2024.12620 summary archivio italiano di urologia e andrologia 2024; 96(3):12620 c. pakpahan, a. agustinus, a. sa’adi, et al. 2 cohort study design. this study compared biochemical and clinical pregnancy in patient groups who had sexual intercourse with those who did not have sexual intercourse during the ivf process. the study was conducted at ferina mother and child hospital, surabaya, from september to november 2022. the study was approved by the ethic committee with approval number: 193/ec/kepk/fkua/2022. sample size and criteria this study's participants were rsia ferina patients who participated in the assisted reproductive technology program as couples who followed the procedure of both fresh et and frozen et with blastocyst embryos. we excluded patients with the following criteria: 1) high d-dimer, 2) experienced pain (cough, runny nose, fever) during and after the procedure (observation period), 3) non-compliant according to the ovarian stimulation procedure, 4) husband with obstructive azoospermia, and 5) husband with leukospermia semen analysis examination results. participants were included consecutively according to the research selection criteria until the required number of participants was met. this study used a test for a difference between two population proportions (11), therefore, by using reference values from previous studies (12), the minimum number of participants in each group was estimated in 45. procedure patients had initially undergone menstrual examination and stimulation until it was declared that the follicles were developing and prepared for ovum pick-up. the collected oocytes were then fertilized to obtain embryo(s). the researcher explained the patients who fit the inclusion and exclusion criteria regarding the research procedure. before the patient underwent the embryo transfer procedure, the patients were told they can have sexual intercourse 1-5 days before the et procedure. however, it was the patients’ choice to have sexual intercourse or not. the determination of 1-5 days interval before et was based on previous studies that conducted exposure to seminal plasma after ovum pick-up (opu), where the distance from opu to et procedures was 3-5 days in fresh embryo transfer procedures (13, 14). after receiving et, the patients were placed in the oneday care unit. the researcher then conducted an interview on the patient regarding the patient's sexual history during 1-5 days before et, including the frequency and whether she had an orgasm or not. we only interviewed the patients who received blastocyte embryo. after that, the patients were observed until 11-14 days after et, and then the beta-hcg test was carried out using the vidas® hcg kit using the elfa (enzyme linked fluorescent assay) principle. thus, the patient would be declared pregnant if the beta-hcg level is 25 miu/ml. then 5-6 weeks later, ultrasound monitoring was conducted on patients who had biochemical pregnancy to detect the gestational sac. the patient was declared clinically pregnant if gestational sac was positive. data analysis the first analysis was univariate; it was conducted to assess the demographic data and the characteristics of the study participants. the second analysis was a bivariate analysis to analyze the association of sexual intercourse and other sexual intercourse parameters with biochemical (beta-hcg) and clinical (gestational sac) pregnancy; the test used was chi-square or fisher's exact test. results the couples interviewed in this study were primary or secondary infertile couples who were undergoing ivf at ferina mother and child hospital. the participants were 132 couples. the participants were divided into two groups. the first group included 45 couples who had sexual intercourse 1-5 days prior et, while the second group included the remaining 87 couples who did not have sexual intercourse. the characteristics of the participants can be seen in table 1. based on table 2, 9.85% of the participants had sexual intercourse and were declared pregnant, 24.24% had sexual intercourse and were not declared pregnant, 23.48% did not have sexual intercourse and were declared pregnant, and 42.42% did not have sexual intercourse and were not declared pregnant. the results of the chi-square test showed p = 0.436, with rr = 0.81 (95% ci 0.46-1.35), which means that there is no significant relationship between intercourse before et and the success rate of biochemical pregnancy. table 1. characteristics of the participants. variable having sex (n = 45) not having sex (n = 87) age of wife (years) 33.78 ± 3.57 34.23 ± 5.0 age of husband (years) 36.20 ± 3.77 38.17 ± 6.34 bmi of wife (kg/m2) 26.08 ± 3.63 25.43 ± 3.85 type of infertility primary 25 (55.5%) 20 (44.5%) secondary 53 (60.9%) 34 (39.1%) duration of infertility (years) 6.16 ± 3.43 6.05 ± 3.43 infertility factor wife 18 (40%) 36 (41.37%) husband 8 (17.8%) 12 (13.8%) mix 18 (40%) 32 (36.78%) unexplained 1 (2.2%) 7 (8.05%) type of embryo transfer frozen 38 (84.45%) 46 (52.87%) fresh 7 (15.55%) 41 (47.13%) table 2. analysis of pregnancy in relation to sexual intercourse before et. variable beta hcg > 10 p-value gs p-value positive negative positive negative sexual yes 13 32 0.436 9 36 0.590 no 31 56 21 66 fresh et yes 4 3 0.439 6 32 0.656 no 17 24 7 39 frozen et yes 9 29 0.489 6 32 0.942 no 14 32 7 39 gs: gestational sac. *p-significance < 0.05 using chi-square test. archivio italiano di urologia e andrologia 2024; 96(3):12620 3 sexual intercourse before embryo transfer in the group who had sexual intercourse 6.82% were declared clinically pregnant and 27.27% were not declared pregnant. in the group that did not have sexual intercourse 15.91% were declared pregnant and 50% were not declared pregnant. the chi-square test obtained a value of p = 0.59, with rr = 0.83 (ci 95% 0.41-1.60). these results indicate that there is no significant relationship between these two variables. in the group who regularly had sexual intercourse (23x/week) and 15.91% were declared pregnant, whereas those who were not declared pregnant were 34.09%. in the group who rarely had sexual intercourse (0-1x/week) 17.42% were declared pregnant whereas those who were not declared pregnant were 32.58%. the chi-square test results obtained a value of p = 0.59, with rr = 0.91 (ci 95% 0.56-1.48). in the group that regularly had sexual intercourse 12.88% were declared clinically pregnant, and those who were not declared pregnant were 37.12%. in comparison, in the group that rarely had sexual intercourse 9.85% was declared pregnant and those who were not declared pregnant were 40.15%. the chi-square test results obtained a value of p = 0.406, with rr = 1.30 (ci 95% 0.70-2.46) (table 2). in addition, in the group who stated that they always orgasmed every time they had sexual intercourse 22.73% were declared biochemically pregnant and 29.55% were not declared pregnant were 29.55%. in comparison, in the group who did not orgasm every time they had sexual intercourse or orgasmed only sometimes, 10.61% were declared biochemically pregnant and 37.12% were not declared biochemically pregnant. the chi-square test results obtained a value of p = 0.009, with rr = 1.96 (ci 95% 1.17-3.37). regarding clinical pregnancy, in the group who stated that they always orgasmed every time they had sexual intercourse 15.91% were declared clinically pregnant and 36.36% were not declared pregnant. in the group who did not orgasm every time they had sexual intercourse or orgasmed only sometimes, 6.82% were declared clinically pregnant and 40.91% were not declared pregnant. the chi-square test results obtained a value of p = 0.027, with rr = 2.13 (ci 95% 1.09-4.29) (table 3). we assumed that there is a correlation between orgasm and the probability of pregnancy. however, we agree that it could not be explicitly concluded that orgasm is a positive factor for enhancing pregnancy. we can only simply argue that orgasm is a condition that indicates that both psychological and social conditions are favourable. discussion our study aimed to compare the effect of sexual intercourse as seminal plasma exposure to the female reproductive system on the success rate of pregnancy, both biochemical and clinical, in women undergoing assisted reproductive technology (art) programs. this recent study divided the participants into two groups. the first group was the group who had sexual intercourse 1-5 days before the et procedure, and the second group was the group who did not have sexual intercourse 1-5 days before et. in addition, our study also analyzed the frequency/habit of sexual intercourse outside the art program, the quality of sexual intercourse in the form of achieving orgasm, the type of infertility, and the et method (fresh or frozen) on pregnancy success (biochemical and clinical). our study reported 45 (34.09%) patients had sexual intercourse before et. some of the reasons patients did not have sex before et were the fear and anxiety about sexual intercourse that it might be causing ivf program failure. the similar phenomenon was also reported by courbiere et al., which states that 47% of the patients had difficulty having sex during the ivf program, and 44% experienced a decreasing desire to have sex with their partner (15). marci et al. also reported the same finding, stating that couples had experienced sexual disorders even at the beginning of infertility treatment (16). another finding in our study is that there was no association between sexual intercourse before et and both biochemical and clinical pregnancy rate. we reported rr = 0.81 (95% ci 0.46-1.35) in biochemical pregnancy and rr = 0.83 (95% ci 0.41-1.60) in clinical pregnancy. similar results were also reported in a study by von wolff et al. (2013) who reported rr = 0.92 (ci 95% 0.63-1.34) in clinical pregnancy (17). however, a study in china by sun et al. reported different results. sun et al found that sexual intercourse significantly affected pregnancy success in the art program (p = 0.005 in biochemical pregnancy and p = 0.045 in clinical pregnancy) (18). so far, the theory that explains how sexual intercourse can affect the chance of pregnancy is the induction of the immune system of the reproductive organs (uterus) in the process of pregnancy (19). seminal plasma contains immune substances such as tgf-β which is indispensable in the implantation process, as well as other molecules such as pge2 and dc (4). in addition, sexual intercourse also increases uterine activity such as contractions that have an impact on embryo implantation (20). however, the different results in our study might be due to the variation of the length of the interval between sexual intercourse and et, which is not homogeneous. our study established an interval between sexual intercourse and et of 1-5 days. most participants in this study had sexual intercourse more than 24 hours before et. in fact. some studies supporting a significant role of sexual intercourse, reported the most effective interval between sexual intercourse and et to be 12-24 hours. as reported by sun et al, aflatoonian et al and tremellen et al, there were very few patients who consciously had sex 12-24 hours before et because many patients were worried that sex within this period would cause failure of et (18, 21, 22). another possible reason for the non-significant results is table 3. analysis of orgasmic phase in intercourse before et with pregnancy. variable beta hcg > 10 p-value gs p-value positive negative positive negative intensity routine 21 45 0.711 17 49 0.406 of sexual infrequent 23 43 13 53 intercourse orgasmic yes 30 39 0.009* 21 48 0.027* no 14 49 9 54 gs: gestational sac. *p-significance < 0.05 using chi-square test. archivio italiano di urologia e andrologia 2024; 96(3):12620 c. pakpahan, a. agustinus, a. sa’adi, et al. 4 the type of et performed in our patients. the results of the study by sun et al were significant in the group of patients who performed frozen embryo transfer procedures, while in our participants, both frozen and fresh embryo transfer groups were analyzed simultaneously (18). furthermore, the study by sun et al. compared couples who had sex and used contraception with couples who did not have sex before et. so, this study was biased regarding whether pregnancy success was due to seminal plasma exposure or other factors. our study attempted to adjust the effect of the variable of sexual intercourse evaluating both biochemical and clinical pregnancy, although the small sample size could not have maximized this adjustment (18). in addition, another possible cause of bias is the difficulty to control the factors beforehand, such as the stimulation protocol used in patients, especially in the fresh et group. some studies, such as lan et al., ou et al., and youseff et al., reported that long protocol significantly increased ivf success compared to short protocol (23-25). psychological aspects may also contribute to the successful outcomes of ivf programs. matthiesen et al. reported that there is a significant relationship between stress and the chances of ivf success (26). the same finding was also reported by saleem et al. in the tunisian population following an ivf program. stress and anxiety were negatively correlated with success rates (27). at the same time, courbiere et al. stated that patients who follow ivf programs are vulnerable to psychosocial burdens that can affect their daily life (15). another contributing factor that may affect ivf success is bmi. bashiri, halper, and orvieto stated that uncontrolled bmi affects ivf success (28). in our study, we did not evaluate length of protocol, psychological factors and bmi that could be factors causing the difference in results with other studies. it has been hypothesized that embryo implantation is strongly influenced by endometrial receptivity. endometrial receptivity depends on immune factors. also, the balance of immune factors in the endometrial wall itself is influenced by various factors (3). one of the components of immune system, called t-reg cells, is known to be a key factor to successful implantation. t-reg cells play a role in regulating equilibrium in the major histocompatibility complex (mhc) mechanism (3). exposure to seminal plasma allows the activation of t-reg cells in the female reproductive organs (uterus), thus supporting embryo implantation. another theory states that sexual intercourse is associated with cervicovaginal immune mediators in young female populations (29). frequent sexual intercourse also causes a decrease in iga at ovulation compared to infrequent or no intercourse. it also affects the expression of th-2-like cytokine ratios (ifn-γ < il-4), p-e2 ratios in the luteal phase compared to other phases (30). based on this hypothesis, regular or continuous exposure to a partner's seminal plasma might alter the regulation of t-reg cells in the female reproductive organs. thus, the frequency of sexual intercourse might affect the immune status/condition in the uterus. there are still very few studies that report about these findings, especially in the art population group. the study of konishi et al. reported that there was a significant relationship between coitus frequency and increased chances of pregnancy. however, these results were tested in populations with natural cycles or without the art program (31). however, the relationship between the two variables seems to be insignificant in this present study. this may be due to lack of information related to the frequency of sexual intercourse. the information explored in this study was the history of intercourse in the past before the study participant started art measures. the association of sexual activity up to orgasm with the success rate of the art program has not been widely studied. our study reported that orgasm had a significant association with biochemical and clinical pregnancy. frequent/always orgasmic partner sexual activity is associated with a healthy and supportive quality of partner life (32), while a healthy and supportive quality of partner life is needed to maintain the mental state of the study patients in undergoing the art program. levin also states that semen deposition and uterine contractions during orgasm cause mood changes in women (33). in addition, some theories state that orgasm also facilitates the release of hormones, such as oxytocin, that affect emotions in women. women with a history of orgasm are reported to be happier and avoid stress (34). the result of the study still need further investigation despite it is significant. also, we argue that orgasm is simply a condition that indicates that psychological and social conditions are favorable. the fertility society of australia notes that the mental quality of couples undergoing art affects pregnancy outcomes (35). this may be the reason why orgasm can affect art outcomes. in addition, several hypotheses state that orgasm can also affect the human immune system. orgasm increases the number of absolute leukocyte sources and natural killer cells in blood vessels. however, the levels and changes in the immune system of female reproductive organs have not been reported (36). we still realized that there are limitations in our study which is an observational study designed with a retrospective cohort. the selection of participants to be included in the groups who were sexually active and non-sexually active groups before ivf was voluntary rather than randomized being a disadvantage when compared to similar studies. in addition, information about sexual intercourse is often considered private for patients living in indonesia. consequently, the information shared about sexual life could be biased because patients are not honest about the information provided. beside this, information about their sexual life is still based on recall memory. finally, a result of the study that should be transferred to the patients is that they should not be afraid to have sexual intercourse before embryo transfer, as was previously reported (37), because even if sexual intercourse does not have an apparent positive effect on pregnancy, it is not proven to have a harmful effect and may even have a positive effect on the psychological and relationship welfare of the couple. conclusions the results of our study did show no significant difference between having sex before et in terms of chemical and archivio italiano di urologia e andrologia 2024; 96(3):12620 5 sexual intercourse before embryo transfer clinical pregnancy chances. however, reaching orgasm during intercourse in recent sexual life has a positive impact on the couple's life and could also favourably impact on pregnancy probabilities although the significance of this finding still needs further investigation. exposure to seminal plasma through sexual intercourse is not utterly uncorrelated with pregnancy, therefore also this still needs further investigation. nevertheless, from a positive point of view, couples do not need to be afraid of having sex before et because it does not have a negative effect but provide a better quality of life for couples. acknowledgements a big thank you to all the doctors (eva setijowati, hamdani lunardi, mona mariana, sony iwan santoso, reza mahendra putra, i dewa ayu agung shinta kamaya, januar wijaya, dwimantoro iman prilistiyo, heri priyanto, wendy hudyarisandi) and nurses at the ferina hospital who helped a lot during the research process. references 1. nieschlag e, behre hm, kliesch s, nieschlag s. andrology male reproductive health and dysfunction, 3rd ed. munster (de): springer cham; 2010. 2. crawford g, ray a, gudi a, et al. the role of seminal plasma 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versus short protocol in women 40 years or more undergoing icsi: a multicenter study.middle east fertility society journal 2008; 13:63-6 26. matthiesen sms, frederiksen y, ingerslev hj, zachariae r. stress, distress and outcome of assisted reproductive technology (art): a meta-analysis. hum reprod [internet]. 2011; 26:2763-76. 27. sallem a, essoussi h, mustapha hb, et al. impact of psychological stress on the outcomes of assisted reproduction in tunisian infertile women. pan afr med j. 2021; 40:250. 28. bashiri a, halper ki, orvieto r. recurrent implantation failureupdate overview on etiology, diagnosis, treatment and future directions. reprod biol endocrinol. 2018; 16:121. 29. hughes sm, levy cn, calienes fl, et al. starting to have sexual intercourse is associated with increases in cervicovaginal immune mediators in young women: a prospective study and meta-analysis. elife. 2022; 11:e78565. 30. lorenz tk, demas ge, heiman jr. interaction of menstrual cycle phase and sexual activity predicts mucosal and systemic humoral immunity in healthy women. physiol behav 2015; 152:92-8. 31. konishi s, saotome tt, shimizu k, et al. coital frequency and the probability of pregnancy in couples trying to conceive their archivio italiano di urologia e andrologia 2024; 96(3):12620 c. pakpahan, a. agustinus, a. sa’adi, et al. 6 first child: a prospective cohort study in japan. int j environ res public health 2020; 17:1-11. 32. costa rm, brody s. women’s relationship quality is associated with specifically penile-vaginal intercourse orgasm and frequency. j sex marital ther; 33:319-27. 33. levin rj. the physiology of sexual arousal in the human female: a recreational and procreational synthesis. arch sex behav 2002; 31:405-11. 34. magon n, kalra s. the orgasmic history of oxytocin: love, lust, and labor. indian j endocrinol metab. 2011; 15 suppl 3(suppl3):s156-61. 35. pre-conception health special interest group. [cited 2024 feb 7]; available from: http://yourfertility.org.au/resource/effects-of-caffeine-alcohol-and-smoking-on-fertility/ 36. haake p, krueger th, goebel mu, et al. effects of sexual arousal on lymphocyte subset circulation and cytokine production in man. neuroimmunomodulation. 2004; 11:293-8. 37. pakpahan c, agustinus a, sa'adi a, et al. lay understanding and experience of sexual intercourse among couples with infertility undergoing an assisted reproduction technology program: a qualitative study. heliyon. 2024; 10:e26879. correspondence cennikon pakpahan (corresponding author) cennikon.pakpahan@fk.unair.ac.id andrology study program, department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia agustinus agustinus agustinus27@fk.unair.ac.id christian melka parmanto c.melka88@gmail.com andrology study program, faculty of medicine, universitas airlangga, surabaya, indonesia ashon sa’adi ashontanti@gmail.com auvky hinting auckyh@gmail.com lia hinting lia.hinting@gmail.com ferina mother and child hospital, surabaya, indonesia andri rezano andri.rezano@unpad.ac.id department of biomedical sciences, faculty of medicine, universitas padjadjaran, sumedang, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13428 1 original paper introduction penile cancer (pc) is a rare cancer with a prevalence of 0.1-1 per 100,000 men in high-income countries (1). several risk factors have been reported, including the absence of childhood circumcision, phimosis, chronic inflammation, inadequate penile hygiene, smoking, immunosuppression and human papillomavirus (hpv) infection (2). lymph node status represents an important prognostic factor, in association with primary tumor grade, pathologic t stage, histologic subtype, and lymphovascular invasion (3). several treatments for localized early-stage disease are available, ranging from topical 5-flurouracil therapy and laser therapy to glans resur-facing and glansectomy with reconstruction (4, 5). as the disease progresses to more advanced stages, recommendations include partial or total penectomy with or without reconstruction, or radiotherapy (6, 7). however, radical surgical treatment represents the gold standard for high-grade and high-stage disease (8). pc displays aggressive behavior and tends to metastasize primarily to locoregional lymph nodes (ln). metastatic progression typically affects inguinal lns (iln) and then extends to pelvic ln (pln), following the anatomical drainage route (9). consequently, after local treatment for the primary lesion, inguinal lymph node dissection (ilnd) is recommended if there is evidence of lymph node invasion or in high-risk patients (10). despite significant advancements in imaging and surgical techniques, the absence of reliable biomarkers for diagnosis, prognosis, and follow-up remains a challenge (11). in this scenario, recent studies have underscored the pivotal role of inflammation in various tumorigenic processes, including proliferation, invasion, metastasis, and angiogenesis (12, 13). hence, several inflammatory indexes such as neutrophil to lymphocyte ratio (nlr), platelet to lymphocyte ratio (plr), albumin-to-alkaline phosphatase ratio (aapr), have emerged and proposed as potential prognostic biomarkers in different cancers including genitourinary tumors (14-16). these biomarkers, charbackground: penile cancer (pc) is a rare malignancy with poor prognosis. to date, reliable preoperative biomarkers for lymph node status and prognosis are still lacking. this study aims to explore the potential role of preoperative platelet-to-lymphocyte ratio (plr) as a predictor of inguinal lymph node invasion in pc patients. methods: retrospective analysis was conducted on anamnestic, clinical, and laboratory data of pc patients who underwent surgical treatment between january 2016 and october 2023. inguinal lymphadenectomy was performed as per eau guidelines. plr, calculated as the ratio between platelet-to-lymphocyte values obtained from preoperative blood analyses, was assessed within 30 days before surgery. patients were categorized into pn(no lymph node metastasis) and pn+ (lymph node metastasis confirmed pathologically). statistical analyses included kruskal-wallis and mann-whitney u tests, univariate logistic regression, and roc curve analysis with youden index, assuming p < 0.05 as statistically significant. results: overall, 60 pc patients were retrospectively involved in the study. a total of 36 (60%) patients reported iln metastases, confirmed by inguinal lymphadenectomy (pn+), while no iln metastases (pn-) were reported in 24 (40%) patients. the auc for predicting iln metastasis by preoperative plr was 0.71 (p = 0.014). according to the roc curve analysis and the youden index, a cut-off for plr was set at 122.4. on univariable logistic regression analysis, the presence of t stage ≥ 2 (or = 3.21; 95% ci: 1.43-7.47, p = 0.011), lymphovascular invasion (or = 3.78; 95% ci: 1.56-5.90, p = 0.003), clinical node-positive disease (or = 19.86; 95% ci: 5.91-41.03, p < 0.001) and plr ratio > 122.4 (or = 7.22; 95% ci: 1.4122.71, p = 0.0148) were independent predictors of pn+ disease. conclusions: the current study confirms the relationship between cancer and inflammation. when elevated preoperatively, plr may be associated with inguinal lymph node invasion in pc patients. key words: penile cancer; penile neoplasm; platelet-to-lymphocyte; ratio; lymph node; inguinal lymph node; metastasis; biomarkers. submitted 26 november 2024; accepted 8 december 2024 preoperative platelet-to-lymphocyte ratio as a predictor of inguinal lymph node metastasis in penile cancer francesco passaro 1*, antonio tufano 1*, gianluca spena 1, alessandro izzo 1, flavio antonino scarlata 1, biagio barone 2, luigi napolitano 2, gabriele pezone 2, pierluigi alvino 2, achille aveta 2, savio domenico pandolfo 2, 3, simone cilio 2, lorenzo romano 2, francesco di bello 2, alessandro calarco 4, rosario leonardi 5, carlo buonerba 6, 7, sisto perdonà 1 1 department of urology, istituto nazionale tumori, irccs, “fondazione g. pascale”, naples, italy; 2 department of neurosciences and reproductive sciences and odontostomatology, university of naples “federico ii”, naples, italy; 3 department of urology, university of l’aquila, l’aquila, italy; 4 urology unit, san carlo di nancy hospital, gvm care and research, rome, italy; 5 department of medicine and surgery university of enna kore, enna, italy; 6 department of public health, university of naples “federico ii”, naples, italy; 7 associazione o.r.a.-oncology research assistance, somma vesuviana, italy. * these authors contributed equally to this work. doi: 10.4081/aiua.2025.13428 summary archivio italiano di urologia e andrologia 2025; 97(1):13428 f. passaro, antonio tufano, g. spena, a. izzo, et al. 2 acterized by different sensitivity and specificity, represent a low-cost yet powerful tool in stratifying cancer patients. interestingly, platelet-to-lymphocyte ratio (plr) has recently gained widespread recognition as a valuable prognostic factor in various types of tumors, including lung, colorectal, and esophageal cancer (17). however, the prognostic impact of plr on pc remains poorly explored. interestingly, wu et al. developed a reliable nomogram based on clinicopathologic and laboratory data incorporating plr, squamous cell carcinoma antigen scc-ag, lymphovascular invasion (lvi), and pt-stage for the prediction of lymph node extranodal extension in patients with pc (18). moreover, hu et al. in their single center experience found that plr was a significant independent predictor for os and pfs in patients treated with ilnd (12). based on these findings we aimed at investigating the utility of preoperative plr as a prognostic indicator of inguinal lymh node (iln) invasion in pc patients. materials and methods we retrospectively analyzed anamnestic, clinical and laboratory data retrieved from patients who underwent surgical treatment for penile cancer at irccs hospital “pascale” of naples between january 2016 and october 2023. according to eau guidelines, sentinel lymph node biopsy and/or inguinal lymphadenectomy (modified/standard) was performed in patients with high-risk tumors (≥ t1g3) and/or patients with cn+. in case of pt1g1/g2 status a ilnd following a modified template was reserved for those patients with either lymphovascular or peri-neural invasion. due to the retrospective nature of the study and the use of procedures included in the common clinical practice, no ethical committee was required. the inclusion criteria were: (1) primary tumor treated surgically, (2) tumor pathology confirmed by an expert uro-oncology pathologist and (3) available data to calculate plr. exclusion criteria from the study were (1) presence of pelvic lymph node involvement or the presence of distant metastasis at diagnosis, (2) patients with conditions affecting the number of platelets such as liver diseases, hemolytic anemia, chronic infectious and inflammatory diseases, splenectomy, and alcoholism (figure 1). routine venous blood samples were obtained within 30 days before scheduled primary surgery. plr was calculated as the ratio between platelet-to-lymphocyte values. demographic, clinical and pathological data were collected in a single, customized dataset. evaluated preoperative demographic and clinical characteristics included age, smoking status, hypertension status, body mass index (bmi), charlson comorbidity index, american society of anesthesiologists (asa) score and plr calculated using the platelet and lymphocyte counts, obtained via routine complete blood counts in peripheral blood samples before primary surgery. oncological outcomes variables included surgical margin status, final histology, staging (according to tnm classification system), grading tumor, lymph vascular and perineural invasion. patients were further divided into two categories: pn(i.e. those without iln metastasis identified at the histopathological analysis after inguinal lymphadenectomy) and pn+ (i.e. those with iln metastasis at the histopathological analysis after inguinal lymphadenectomy). means and standard deviations were reported for continuous variables while frequencies and percentages were reported for categorical variables. the kolmogorovsmirnov test was used to assess the normality of data before proceeding to further analysis. a mann-whitney u test was used to evaluate continuous variables, while chi-square test was used for categorical variables analysis. univariable logistic regression analysis was used for calculating odds ratio (or), 95% confidence interval (ci) calculations, and to estimate pathologic node-positivity. statistical analysis was conducted using ibm spss software (version 25, ibm corp, armonk, ny, usa). a p value < 0.05 was considered to be statistically significant. results overall, 60 pc patients met the inclusion criteria. descriptive characteristics and preoperative laboratory data of the overall cohort are reported in table 1. table 1. baseline and pathological characteristics. overall pn+ pnp value n = 60 n = 24 n = 36 age, mean (sd) 66.9 (14.4) 62.6 (13.4) 68.2 (14.5) 0.17 current smoker, n (%) 23 (38.3) 4 (16.7) 19 (52.8) 0.34 hypertension, n (%) 34 (56.7) 9 (37.5) 25 (69.4) 0.76 diabetes, n (%) 10 (16.7) 3 (12.5) 7 (19.4) 0.69 charlson comorbidity index, n (%) 1 13 (21.7) 5 (20.8) 8 (22.2) 0.86 2 10 (16.7) 3 (12.5) 7 (19.4) 3 7 (11.7) 1 (4.7) 6 (16.7) 4 9 (15) 2 (8.3) 7 (19.4) 5 3 (5.0) 1 (4.7) 2 (5.5) 6 2 (3.3) 0 (0) 2 (5.5) 7 2 (3.3) 0 (0) 2 (5.5) unknown 14 (23.3) 12 (50.0) 2 (5.5) asa score, n (%) 2 30 (50) 14 (58.3) 16 (44.4) 0.57 3 26 (43.3) 8 (33.3) 18 (50.0) 4 2 (3.3) 0 (0) 2 (5.5) unknown 2 (3.3) 2 (8.3) 0 (0) platelets, mean (sd) 215 (58.9) 232.3 (78.6) 210.3 (52.5) 0.51 lymphocytes, mean (sd) 1.9 (0.8) 1.4 (0.4) 1.9 (0.8) 0.04 plr, mean (sd) 147.1 (87.2) 193.8 (129.5) 122.5 (54.2) 0.02 pathologic t stage, n (%) pta/t1 13 (21.7) 4 (16.7) 9 (25.0) 0.25 pt2 22 (36.7) 7 (29.2) 15 (41.7) pt3 25 (41.7) 13 (54.2) 12 (33.3) pt4 0 (0) 0 (0) 0 (0) grading, n (%) g1/g2 41 (68.3) 16 (66.7) 24 (66.7) 0.42 g3/g4 19 (31.7) 8 (33.3) 12 (33.3) lymphovascular invasion, n (%) no 28 (46.7) 11 (45.8) 17 (47.2) 0.62 yes 32 (53.3) 13 (54.2) 19 (52.8) perineural invasion, n (%) no 19 (31.7) 6 (25.0) 13 (36.1) 0.34 yes 21 (35.0) 7 (29.2) 14 (38.9) unknown 20 (33.3) 11 (45.8) 9 (25.0) positive margins, n (%) 0 (0) 0 (0) 0 (0) archivio italiano di urologia e andrologia 2025; 97(1):13428 3 preoperative platelet-to-lymphocyte ratio as a predictor of inguinal lymph node metastasis in penile cancer overall n = 26 patients had cnstatus. of those, sentinel lymph node biopsy and modified inguinal lymphadenectomy was performed in n = 6 and n = 20 patients, respectively. a total of n = 34 patients with a cn+ status underwent ilnd following a standard template. the mean age at the time of surgery was 66.9 ± 14.4 years. a total of 36 (60%) patients reported iln metastases (pn+), confirmed by ilnd following a standard or modified template. conversely, no iln metastases (pn-) were reported in 24 (40%) patients. no statistically significant differences were reported for baseline characteristics, except for preoperative lymphocytes (pnvs pn+: 1.9 ± 0.8 vs 1.4 ± 0.4; p = 0.04) and plr (pn+ 193.8 ± 79.5 vs pn122.5 ± 54.2; p = 0.02). the auc for predicting iln metastasis by preoperative plr was 0.71 (p = 0.014). according to the roc curve analysis and the youden index, a cut-off for plr was set at 122.4 (figure 1). on univariable logistic regression analysis, the presence of t stage ≥ 2 (or = 3.21; 95% ci: 1.43-7.47, p = 0.011), lymph vascular invasion (or = 3.78; 95% ci: 1.56-5.90, p = 0.003), clinical node-positive disease (or = 19.86; 95% ci: 5.91-41.03, p < 0.001) and plr ratio > 122.4 (or = 7.22; 95% ci: 1.41-22.71, p = 0.0148) were independent predictors of pn+ disease (table 2). discussion in pc patients, nodal metastasis emerges as the foremost predictor of a poor clinical outcome, with tumor grade and lymph vascular invasion also serving as significant prognostic indicators (10, 19). according to eau guidelines, sentinel lymph node biopsy and/or inguinal lymphadenectomy is crucial for patients with intermediate or high-risk tumors (≥ t1g2) and/or those with clinically positive lymph nodes (cn+) (10). in spite of unequivocal endorsements advocating the adoption of these potentially life-saving interventions, several authors have underscored suboptimal adherence to clinical guidelines (20, 21). this phenomenon may be ascribed to the foreseen morbidity stemming from compromised lymphatic drainage in the lower extremities and scrotum, with reported morbidity rates reaching as high as 50% (9). figure 1. receiver operating characteristic (roc) curve and area under the curve (auc) to define the optimal plr cutoff. auc: 0.71 (p = 0.014). table 2. logistic regression model predicting pathologic inguinal node-positive disease (pn+). univariable analysis 95.0% ci lower higher p value clinical n stage cn0 ref. cn+ 19.86 5.91 41.03 < 0.001 t stage ta/t1 ref. ≥ t2 3.21 1.43 7.47 0.011 primary tumor grade g1/g2 ref. g3/g4 1.53 0.58 2.3 0.41 lymphovascular invasion no ref. yes 3.78 1.56 5.90 0.003 platelet-to-lymphocyte ratio ≤ 122.4 ref. > 122.4 7.22 1.41 22.71 0.018 or = odds ratio; c i= confidence interval. archivio italiano di urologia e andrologia 2025; 97(1):13428 f. passaro, antonio tufano, g. spena, a. izzo, et al. 4 moreover, the poor compliance may also be caused by the lack of reliable biomarkers and a small number of predictors included in the current guidelines. it is well established that cancer-related inflammation and systemic inflammatory responses contribute to tumor initiation and progression, including neo-angiogenesis, tumor progression, and metastasis. several studies have investigated the role of plr in various types of cancers. jiang et al. found that a high plr was associated with poorer survival prognosis in ovarian cancer (os: hr 1.80 (95% ci 1.37-2.37), p = 0.000; pfs: hr 1.63 (95% ci 1.38-1.91), p = 0.000) and cervical cancer (os: hr 1.36 (95% ci 1.10-1.68), p = 0.005; pfs: hr 1.40 (95% ci 1.16-1.70), p = 0.002) (22). moreover, when examining urological malignancies, wang et al. demonstrated that an elevated plr predicted poor overall survival (os; hr = 1.85, 95% ci = 1.51-2.25, p < 0.001) and disease-free survival (dfs; hr = 1.4, 95% ci = 1.1-1.79, p = 0.007) in prostate cancer patients (23). nevertheless, subgroup analyses showed that the plr remained a significant prognostic factor for os irrespective of ethnicity, tumor stage, or cut-off value (23). to the best of our knowledge our study is the first to explore the predictive value of preoperative plr in iln invasion within a pc cohort. several noteworthy findings emerged from the analysis. firstly, the cut-off of the plr set by the roc analysis was 122.4 in the present study. similar plr cut-offs points were found for other urological tumors. herraiz-raya and colleagues discovered that germ cell tumor patients with a plr > 150 were more likely to experience disease progression, advanced stage ii and iii, and residual disease. additionally, they found that plr levels were significantly higher in seminoma patients compared to non-seminoma patients (24). moreover, imamoglu observed a plr > 104 to be a significant predictor of advanced disease (stage ii and iii) with a sensitivity of 71% and a specificity of 88%, exclusively in nonseminoma patients (25). conversely, a higher plr (> 212) was depicted by peksa et al. in a testis cancer cohort. authors examined the correlation between immune checkpoint proteins microenvironments and systemic inflammatory reactions. in their study elevated plr was associated with the presence of nodal and distant metastases as well as an advanced disease stage (26). furthermore, patients with high plr showed significantly better five-year event-free survival compared to those with low plr (89% vs. 69%, p = 0.018) (26). notably, a combination of high plr and low expression of immune checkpoint regulators (v-domain ig suppressor of t cell activation) in tumor-infiltrating and peritumoral lymphocytes and macrophages was identified as a sole predictor of relapse and disease progression in multivariate analysis. these findings support the idea that the clinical behavior of tumors is influenced by a complex interaction between the local tumor immune environment and systemic inflammation. secondly, the predictive role of plr in the prediction of iln invasion was confirmed on univariable analysis (or = 7.22). however, given the absence of comparative data, we must view our study as an introductory investigation into the potential of plr as a prognostic biomarker for iln invasion, as this outcome has not been previously addressed in the literature. third, our analysis confirmed the role of lymphovascular invasion as a crucial prognostic indicator (or = 3.78, p = 0.018 univariable analysis). these ors are similar to the study by winters et al. (or = 3.10), where lymphovascular invasion emerged as the primary independent predictor of occult lymph node metastasis (27). similar findings have been reported by other studies, corroborating the significance of lymphovascular invasion as a substantial risk factor for occult micro metastases (28, 29). taken together, these findings imply a potential enhancement in current risk stratification schemes. specifically, the presence of lvi, irrespective of tumor stage or grade, warrants consideration as high-risk disease. the precise role of plr in oncological patients remains largely unexplored. nevertheless, several theories have been proposed. platelets serve as a crucial source of cytokines, binding to fgf, pdgf, vegf, and tgf-β family proteins, and thereby acting as a reservoir for secreted growth factors that promote tumorigenesis and metastasis development. tumor cells can activate and aggregate platelets through both direct and indirect mechanisms, which play a crucial role in metastatic spread. platelets function as key transporters of both proangiogenic and antiangiogenic factors (30, 31). moreover, they influence the process of angiogenesis, including platelet-derived microparticles, microrna, lipids, and surface receptors. they are active in both the early and late stages of angiogenesis (32). this understanding raises the potential for targeting platelet functions as a promising strategy for cancer treatment. on the other hand, inflammatory response is linked to conditions such as lymphocytopenia, neutrophilia, and thrombocytosis. lymphocytes are essential for immune function and play a significant role in suppressing cancer progression. hence, a lower lymphocyte count, reflected by a high plr, may translate in a reduced immune surveillance, thus allowing tumor progression (33-35). we acknowledge several limitations of our study. these include its retrospective, single-center design, and the relatively small sample size, which may introduce selection and treatment biases. additionally, the restricted cohort size and limited number of events precluded multivariable analysis, preventing identification of more reliable predictors for iln involvement. furthermore, the absence of follow-up data limits our ability to assess patient prognosis, and certain critical variables, such as tumor multifocality, tumor cell koilocytosis, and keratinization, were not included. our results should be validated by external cohorts with multi-center studies prior to considering plr for clinical use as an adjunctive biomarker in the diagnostic setting of inguinal lymph node metastasis. conclusions the current study must be considered as an initial experience regarding the role of plr as a potential biomarker in this setting of population. we identified potential predictors of iln invasion in pc patients. however, further investigations and larger cohorts are required to confirm the clinical utility of plr in patients’ outcomes. archivio italiano di 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node negative patients with penile carcinoma: a national cancer database analysis. urology. 2016; 96:29-34. 28. ficarra v, akduman b, bouchot o, et al. prognostic factors in penile cancer. urology. 2010; 76(2 suppl 1):s66-73. 29. zekan ds, dahman a, hajiran aj, et al. prognostic predictors of lymph node metastasis in penile cancer: a systematic review. int braz j urol. 2021; 47:943-956. declarations ethical approval: retrospective study exempt from ethics committee approval. availability of data and material: https://zenodo.org/ records/14223575. competing interests: the authors declare no conflicts of interest. funding: this research received no external funding. authors' contributions: conception and design, b.b., p.a., a.a. , f.a.s., r.l., f.d.b., g.s., a.i. and a.t.; analysis and interpretation of data, g.p., l.r., c.b., s.d.p., f.p., s.c., s.p., a.c. and l.n.; drafting the article b.b., p.a., a.a., f.a.s., f.p., s.c., s.p., a.c. and l.n.; revising the article critically r.l., f.d.b., g.s., a.i., a.t., g.p., l.r., c.b. and s.d.p.; final approval of the version to be published b.b., p.a., a.a., f.a.s., r.l., f.d.b., g.s., a.i. and a.t.; agreement to be accountable for all aspects of the work g.p., l.r., c.b., s.d.p., f.p., s.c., s.p., a.c. and l.n. all authors have read and agreed to the published version of the manuscript. acknowledgments: not applicable. consent for publication: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13428 f. passaro, antonio tufano, g. spena, a. izzo, et al. 6 30. filippelli a, del gaudio c, simonis v, et al. scoping review on platelets and tumor angiogenesis: do we need more evidence or better analysis? int j mol sci. 2022; 23:13401. 31. tufano a, perdonà s, viscuso p, et al. the impact of ethnicity and age on distribution of metastases in patients with upper tract urothelial carcinoma: analysis of seer data. biomedicines. 2023; 11:1943. 32. wojtukiewicz mz, sierko e, hempel d, et al. platelets and cancer angiogenesis nexus. cancer metastasis rev. 2017; 36:249-262. 33. wakefield lm, smith dm, flanders kc, sporn mb. latent transforming growth factor-beta from human platelets. a high molecular weight complex containing precursor sequences. j biol chem. 1988; 263:7646-54. 34. iacopino f, pinto f, bertaccini a, et al. soluble e-cadherin and il6 serum levels in patients affected by prostate cancer before and after prostatectomy. oncol rep. 2012; 28:370-4. 35. gay lj, felding-habermann b. contribution of platelets to tumour metastasis. nat rev cancer. 2011; 11:123-34. correspondence francesco passaro, md francescopassaro1996@gmail.com antonio tufano, md (corresponding author) antonio.tufano91@gmail.com gianluca spena, md gianlu.spena@gmail.com alessandro izzo, md a.izzo@istitutotumori.na.it flavio antonino scarlata, md scarlataflavioantonino@gmail.com sisto perdonà, md s.perdona@istitutotumori.na.it department of urology, istituto nazionale tumori, irccs, “fondazione g. pascale”, 80131 naples, italy biagio barone, md biagio193@gmail.com luigi napolitano, md dr.luiginapolitano@gmail.com gabriele pezone, md gabrielepezone94@gmail.com pierluigi alvino, md pierluigi.alvino@gmail.com achille aveta, md achille-aveta@hotmail.it savio domenico pandolfo, md pandolfosavio@gmail.com simone cilio, md simocilio.av@gmail.com lorenzo romano, md loryromano@hotmail.it francesco di bello, md fran.dibello12@gmail.com department of neurosciences and reproductive sciences and odontostomatology, university of naples “federico ii”, 80131 naples, italy alessandro calarco, md alecalarco@gmail.com urology unit, san carlo di nancy hospital, gvm care and research, rome, italy rosario leonardi, md leonardi.r@tiscali.it department of medicine and surgery university of enna kore, enna, italy carlo buonerba, md carbuone@hotmail.com department of public health, university of naples “federico ii”, 80131 naples, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13640 1 original paper introduction prostate cancer is among the most commonly diagnosed malignancies in men and represents a substantial global public health burden. radical prostatectomy remains a pivotal treatment option for localized prostate cancer. traditionally, open surgery was the gold standard; however, the emergence of minimally invasive techniques, such as laparoscopic radical prostatectomy (lrp) and robotic-assisted radical prostatectomy (rarp), has transformed surgical management. these techniques offer numerous advantages, including reduced perioperative morbidity, shorter hospital stays, and faster recovery (1). the introduction of the da vinci robotic surgical system has further refined surgical practices, providing enhanced visualization, precision in instrumentation, and improved ergonomics compared to conventional laparoscopy. such technological advancements have facilitated the widespread adoption of rarp, particularly because of its ability to address some of the technical limitations inherent to lrp. both laparoscopic and robotic approaches offer substantial benefits over open surgery, improving clinical outcomes and minimizing complications (2-19). within the realm of minimally invasive approaches, transperitoneal and extraperitoneal lrp have demonstrated notable oncological and functional advantages. the transperitoneal technique allows superior anatomical visualization, whereas the extraperitoneal approach minimizes peritoneal-related complications, such as bowel injuries and adhesions. both techniques achieve excellent functional outcomes, with urinary continence and erectile function recovery rates surpassing 90% and 80%, respectively, at 12 months postoperatively (3). numerous comparative studies have evaluated lrp and rarp, frequently reporting similar outcomes across various clinical parameters. however, rarp consistently demonstrates a distinct advantage in early urinary continence recovery, with significantly better continence rates observed within the first three months postoperatively. objective: this study aimed to evaluate the influence of prior laparoscopic experience on the learning curve and surgical outcomes of robotic-assisted radical prostatectomy (rarp). methods: a retrospective analysis was performed on 101 patients treated between 2021 and 2023. two surgeons at the beginning of their robotic learning curves were compared: one with extensive prior laparoscopic experience and the other without such a background. perioperative, oncological, and functional outcomes were assessed, with a specific focus on pentafecta criteria. statistical analyses and cumulative sum (cusum) charts were employed to evaluate performance trends and surgical outcomes. results: surgeon a, with substantial prior laparoscopic expertise, demonstrated shorter operative times (p = 0.015), reduced intraoperative blood loss, and superior early functional outcomes. specifically, patients operated on by surgeon a exhibited higher pad-free continence rates and improved erectile function recovery at 12 months postoperatively (p < 0.01). additionally, nerve-sparing procedures performed by surgeon a showed a trend toward fewer positive surgical margins, although this difference did not reach statistical significance. cusum analysis revealed more stable and consistent performance trends for surgeon a in achieving pentafecta outcomes compared to surgeon b. conclusions: previous laparoscopic experience significantly contributes to shortening the learning curve for rarp and enhancing early functional outcomes. this advantage is likely attributable to greater surgical anatomical knowledge. these findings highlight the importance of tailored training programs and the potential for skill transfer between laparoscopic and robotic approaches. further studies are warranted to refine surgical education strategies and improve patient care outcome. key words: prostate cancer; laparoscopic radical prostatectomy; robot-assisted radical prostatectomy; learning curve; outocomes; operative time. submitted 17 january 2025; accepted 29 march 2025 impact of laparoscopic experience on learning curves in robotic-assisted radical prostatectomy (rarp): a comparative analysis of oncological and functional outcomes pier paolo prontera 1, francesca romana prusciano 2, 1, marco lattarulo 1, arman tsaturyan 3, 4, carmine sciorio 5, francesco dibenedetto 6, lorenzo romano 7, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto, italy; 2 division of urology, hospital “valle d’itria”, martina franca (ta), italy; 3 department of urology, yerevan state medical university after mkhitar, heratsi, yerevan, armenia; 4 department of urology erebouni medical center, yerevan, armenia; 5 department of urology, “alessandro manzoni” hospital of lecco, italy; 6 master of science in nursing, department of operating room, “s.s. annunziata” hospital, taranto, italy; 7 department of woman, child and general and specialized surgery. università degli studi della campania “l. vanvitelli” and urology section, ospedale del mare, napoli, italy. doi: 10.4081/aiua.2025.13640 summary archivio italiano di urologia e andrologia 2025; 97(2):13640 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 2 despite these early differences, long-term continence rates remain comparable between the two methods, confirming their efficacy in managing localized prostate cancer (4). in terms of surgical efficiency, rarp is consistently associated with shorter operative times compared to laparoscopic techniques. this efficiency is mirrored by lower or comparable postoperative complication rates associated with the robotic approach (5). research by salsiccia and colleagues further underscores these findings, indicating that laparoscopic procedures require significantly longer operative times than rarp. these findings highlight the advantages of standardization and a more rapid learning curve associated with robotic surgery (6). from an oncological standpoint, rarp often demonstrates slightly improved outcomes regarding positive surgical margins (psms) and biochemical recurrence (bcr) rates when compared to lrp, though these differences are not consistently statistically significant. these findings suggest that rarp, as a technologically advanced surgical approach, can enhance certain aspects of prostate cancer surgery while delivering results comparable to laparoscopy. the learning curve is a critical factor influencing both oncological and functional outcomes. parameters such as operative time, psm rates, and recovery of continence and potency typically improve as surgeons gain more experience. surgeons with prior laparoscopic expertise appear to adapt to rarp more efficiently, achieving proficiency with fewer cases and reaching benchmarks such as the "trifecta" outcomes more rapidly. trifecta metrics evaluate surgical success by integrating oncological control, functional recovery, and perioperative safety (8, 9). building upon the trifecta framework, the "pentafecta" outcome offers a more comprehensive evaluation by encompassing five key domains: biochemical recurrencefree survival, continence recovery, sexual potency recovery, surgical margin status, and perioperative hemoglobin changes. this holistic metric underscores the importance of achieving a balance between oncological efficacy and functional preservation to optimize patient outcomes. in contemporary clinical practice, patients undergoing rarp often hold elevated expectations regarding functional outcomes, influenced by the widespread availability of medical information on social media platforms such as youtube. while these platforms can provide valuable educational insights, the quality of information is highly variable, and misinformation is prevalent, particularly in searches performed anonymously or with generic user profiles (10). this highlights the necessity of reliable and accessible patient education resources to ensure that individuals receive accurate information, fostering realistic expectations and informed decision-making. for surgeons, managing patient expectations requires a clear understanding of the functional outcomes achievable with rarp. transparent communication during the informed consent process is crucial to aligning patient expectations with achievable results, thereby fostering trust and strengthening the therapeutic alliance. despite its many advantages, rarp presents unique challenges for surgeons without prior laparoscopic experience. these surgeons often face prolonged learning curves, with gradual improvements in operative efficiency and patient outcomes (11). mastery of robotic techniques is essential, as functional outcomes – particularly early recovery of continence and sexual potency – have a direct impact on patients' quality of life (12). procedural volume is another key determinant of surgical outcomes. research consistently shows that achieving optimal results in radical prostatectomy is strongly associated with high annual caseloads, underscoring the critical role of both institutional and surgeon-level experience (13). this study seeks to compare the learning curves of operator a and operator b, employing the pentafecta as a comprehensive measure of surgical success. a secondary objective is to determine whether there are significant differences between the two operators regarding oncological and functional outcomes. materials and methods a retrospective study was conducted on the first 153 patients who underwent rarp at our institution between 2021 and 2023. among these, 101 patients met the specified inclusion and exclusion criteria and were included in the analysis. eligible participants had localized prostate cancer (pca), were aged ≤ 75 years, demonstrated good performance status, and were either unsuitable for or unwilling to pursue active surveillance. exclusion criteria included a history of androgen deprivation therapy, prior pelvic surgery or radiotherapy, or histological diagnoses conducted at external institutions. histological diagnoses were obtained through standard transrectal ultrasound-guided trans-perineal prostate biopsy (trus-sbx) or mri/ultrasound fusion-guided trans-perineal biopsy (tbx+sbx). of the cohort, 50 patients underwent fusion-guided biopsy, while 51 received standard biopsies. all procedures were performed by an experienced operator. fusion-guided biopsies were indicated for patients with clinically significant pirads lesions (pirads ≥ 3) and included both targeted samples (based on the number and size of regions of interest [roi]) and 12-16 systematic cores from a prostate template covering the base, mid-gland, and apex bilaterally. when multiparametric mri (mpmri) was unavailable or no significant pirads lesions were identified, a standard 16-core trus-guided trans-perineal biopsy was performed per institutional protocol. this approach systematically sampled the base, mid-gland, apex, and transition zones bilaterally. preoperative staging was conducted for all patients using contrast-enhanced total-body computed tomography (ct) and total-body bone scintigraphy. following staging, all patients underwent rarp using the da vinci xi (intuitive) multiport robotic system. the surgeries were performed by two surgeons at the outset of their rarp learning curves. surgeon a, however, had substantial prior experience in laparoscopy, having completed over 1,000 cases of extraperitoneal laparoscopic radical prostatectomy, whereas surgeon b had no such experience. surgeon a performed 47 rarp procedures, while surgeon b performed 64. both surgeons employed the same surgical technique, which involved an anterograde extraperitoneal approach and a double-layer running anastomosis reinforced with a posterior plate, utilizing a 2-0 barbed suture. histopathological examination of surgical specimens was archivio italiano di urologia e andrologia 2025; 97(2):13640 3 learning curves in robotic-assisted radical prostatectomy (rarp) conducted by an experienced pathologist. data collection included demographic variables (age, body mass index [bmi], family history of prostate cancer), preoperative factors (prostate-specific antigen [psa] levels, d'amico risk classification (14), clinical t-stage), perioperative metrics (operative time, estimated blood loss, and nerve-sparing rates), oncological outcomes (positive surgical margins), and postoperative functional outcomes (pad-free continence at 3, 6, and 12 months; erectile function assessed using the international index of erectile function-5 [iief-5]). statistical analysis data were systematically collected and recorded in microsoft excel, encompassing anthropometric parameters (age, bmi, weight, height), biopsy type, prostate volume, clinical stage, comorbidities, preand post-operative levels of total psa and hemoglobin (hb), operative times, histopathological findings, and oncological and functional outcomes. functional outcomes included psa levels, urinary continence, and sexual potency, evaluated at 1, 3, 6, 9, and 12 months post-surgery. operative times between the two surgeons were compared using both student’s t-test and the mann-whitney u test. positive surgical margin (psm) rates were assessed globally using the chi-square test. among patients undergoing nerve-sparing procedures, psm rates were further analyzed using the chi-square test and fisher’s exact test to enhance precision. oncological and functional outcomes were first evaluated globally using pearson’s correlation coefficient to identify potential associations. subsequently, these outcomes were analyzed separately for each surgeon. python libraries (v3.11) were utilized to compute pearson’s correlation coefficient, exploring relationships between anthropometric variables and functional outcomes, nerve-sparing techniques and oncological outcomes, and gleason scores and functional recovery. special emphasis was placed on functional outcomes, particularly the changes in preand post-operative iief5 scores. these variations were analyzed globally and comparatively between the two surgeons. cusum analysis cumulative sum control chart (cusum) analysis was applied to monitor performance trends across consecutive cases. the following targets were used: oncological control (variation of psa), functional recovery (recovery of both erectile disfuncion and urinary continence) and surgical efficiency (operative bool loss and progressive reductrion in operative time). deviations from predefined target values were calculated for each metric, and cumulative sums of these deviations were plotted. positive slopes indicated consistent performance below the target, whereas negative slopes reflected achievement of or surpassing the target. separate cusum charts were created for each metric and surgeon, enabling comparative analysis. the analysis focused on pentafecta metrics to evaluate and compare the learning curves of the two surgeons, providing insights into their progression and improvements over time. key pentafecta metrics included oncological control (psa < 0.05 ng/ml at 12 months), functional recovery (improvement in iief-5 scores and complete pad-free continence at 12 months) and surgical efficiency (hb loss ≤ 1.5 g/dl and progressive reduction in operative time). descriptive statistics were used to calculate mean baseline values. differences between the two surgeons were assessed using the mann-whitney u test for continuous variables and the chi-square test for categorical variables. trends observed in the cusum charts were contextualized with these statistical findings, offering a comprehensive evaluation of the surgeons’ learning curves and performance differences. results a total of 101 patients were included in this analysis, with 47 procedures performed by operator a and 64 by operator b. operator a had extensive prior experience in laparoscopic surgery, whereas operator b was at the start of their robotic surgery learning curve with no laparoscopic background. both surgeons followed the same standardized robotic-assisted radical prostatectomy (rarp) technique. the patient cohorts were comparable in age, with a mean of 69 years (range: 55-75) for operator a and 70 years (range: 54-75) for operator b. minor differences were noted in anthropometric parameters, with patients in operator a’s cohort having a slightly higher mean bmi (26.87 vs. 25.9) and weight (81.77 kg vs. 75.5 kg). other measures, such as height and waist circumference, were similar. a family history of prostate cancer was observed in one patient treated by operator b and was absent in operator a’s cohort (table 1). table 1. comparison of perioperative, demographic, and clinical variables based on previous laparoscopic experience in rarp patients. variables previous laparoscopic experience p value r+, n°(%) 12 (25.53) 12 (22.22) 0.701 pre-op. psa, ng/ml (range) 8.78 (4.8-24.3) 9.62 (3.54-21.5) 0.365 post-op. psa, ng/ml (range) 0.573 1 month 0.23 (0.0-1.26) 0.08 (0.0-0.62) 3 months 0.14 (0.0-0.93) 0.08 (0.0-1.94) 6 months 0.09 (0.0-0.987) 0.12 (0.0-3.94) 9 months 0.04 (0.0-0.74) 0.06 (0.0-1.14) 12 months 0.04 (0.0-0.74) 0.06 (0.0-1.14) pre-op. wbc, x 103/µl (range) 7.25 (5.08-9.87) 7.40 (5.06-10.43) 0.582 post-op wbc, x 103/µl (range) 0.170 12h 15.147 (8.120-23.140) 13.853 (5.670-30.450) 24h 10.418 (5.500-15.200) 10.056 (6.520-16.990) pre-op. hb, g/dl (range) 14.94 (11.9-17.3) 14.52 (11.4-1.1) 0.158 post-op. hb, g/dl (range) 0.175 12h 12.57 (8.9-14.7) 13.04 (10.3-16.1) 24h 12.57 (8.9-14.7) 13.01 (10.3-16.1) prostate volume, ml (range) 55.9 (20-142) 47.5 (20-120) 0.117 age, years (range) 69 (55-75) 70 (54-75) 0.504 hypertension, n° pts (%) 8 (17.02) 4 (7.41) 0.118 dm, n° pts (%) 2 (4.26) 7 (12.96) 0.116 height, cm (range) 174 (170-190) 173 (165-188) 2.984 weight, kg (range) 81.77 (56-105) 75.5 (60-102) 0.008 waist circumference, cm (range) 90 (70-110) 87 (71-106) 0.936 bmi, value (range) 26.87 (20.1-34.29) 25.9 (19.52-35.3) 0.751 archivio italiano di urologia e andrologia 2025; 97(2):13640 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 4 among the variables analyzed, the only statistically significant difference between the two cohorts was in the anthropometric parameter "weight" (p = 0.008) (table 1). preoperative risk stratification based on the d’amico criteria revealed comparable distributions between the two cohorts. intermediate-risk cases were slightly more prevalent in operator a’s group (38.3% vs. 25.92%), while high-risk cases were evenly distributed between the groups (27.66% vs. 37.03%) (table 2). preoperative t-staging showed that operator a’s cohort included a higher percentage of t2a and t2b tumors (34.04% each), whereas operator b’s cohort had a higher proportion of t1c (24.59%) and t2b cases (40.98%) (table 3). the utilization of advanced imaging techniques and biopsy methods was also evaluated. fusionguided biopsies were performed in 53.19% of cases for operator a and in 46.29% for operator b. multiparametric mri was employed in 61.7% and 66.66% of cases for operators a and b, respectively. the mean number of roi detected by mri was similar between the groups, with operator a identifying an average of one roi per patient and operator b identifying 1.2 rois (table 4). operator a achieved significantly shorter operative times compared to operator b, with a mean duration of 191.02 minutes versus 214.48 minutes. this difference was statistically significant (p = 0.015). furthermore, operator a exhibited lower variability in operative times, with mean absolute deviations of 30.66 minutes compared to 44.57 minutes for operator b, indicating greater procedural consistency (p = 0.011) (figures 1-2). in terms of oncological outcomes, the overall positive surgical margin (psm) rates were comparable between the table 2. pre-operative risk classes according to d'amico classification. previous laparoscopic experience low risk intermediate risk high risk yes (a) 16 (34.04) 18 (38.3) 13 (27.66) no (b) 20 (37.03) 14 (25.92) 20 (37.03) table 3. distribution of pre-operative t-stage in both group. previous laparoscopic experience t1c t2a t2b t2c t3b yes (a) 3 (6.38) 16 (34.04) 16 (34.04) 6 (12.76) 6 (12.76) no (b) 15 (24.59) 9 (14.75) 25 (40.98) 6 (9.83) 6 (9.83) table 4. biopsy and mprmn. previous fusion fusion mprmn mprmn roi detected roi detected laparoscopic biopsy biopsy (n°) (%) by mprmn by mprmn experience (n°) (%) (mean n°) (range) yes (a) 25 53.19 29 61.70 1 1-1 no (b) 25 46.29 36 66.66 1.2 1-3 figure 1. this graph illustrates the operative times for patients treated by two surgeons, plotted in chronological order. surgeon a, with prior laparoscopic experience, has individual operative times represented by the solid yellow line, while their average operative time is shown by the dashed blue line. surgeon b, without prior laparoscopic experience, has individual operative times represented by the solid orange line, with their average operative time indicated by the dashed yellow line. this visualization highlights potential trends and differences in surgical performance based on experience. figure 2. the bar chart illustrates the mean absolute deviation from the average operative time for two surgeons. operator a, with prior laparoscopic experience, demonstrated lower variability (mean deviation: 30.66 minutes, standard deviation: 20.78 minutes) compared to operator b (mean deviation: 44.57 minutes, standard deviation: 31.42 minutes). error bars indicate the standard deviation. these results suggest that operator a's operative times are more consistent than those of operator b. archivio italiano di urologia e andrologia 2025; 97(2):13640 5 learning curves in robotic-assisted radical prostatectomy (rarp) two operators (25.53% for operator a and 22.22% for operator b, p = 0.876) (table 4). however, in nervesparing cases, operator a demonstrated a lower psm rate of 15.79% compared to 41.67% for operator b. although this difference was not statistically significant, the trend suggests potential advantages in operator a’s technique for nerve-sparing procedures, warranting further investigation with larger sample sizes (figures 3, 4; tables 1-5). functional outcomes revealed notable differences between the two operators. at 12 months postoperatively, operator a achieved superior continence outcomes, with a higher percentage of patients obtaining pad-free status. cusum analysis showed stable and consistent recovery trends for operator a, while operator b exhibited greater variability. regarding erectile function, significant improvements in iief-5 scores were observed for operator a at both 9 and 12 months (p < 0.01). this superior recovery is likely attributed to operator a’s precise nerve-sparing techniques. table 6 presents the mean ± standard deviation of iief-5 scores for operator a and operator b at different time points (preoperative and 1, 3, 6, 9, and 12 months postoperatively). a statistically significant difference in erectile function recovery is observed from 9 months onwards (p < 0.01), favoring operator a. this trend suggests that previous laparoscopic experience may contribute to improved nerve-sparing outcomes and functional recovery (table 6). table 6. filtered statistical comparison of iief5 improvement between operators. time period, operator a operator b t-statistic p-value month(s) (mean +/sd) (mean +/sd) pre operative 22.5 +/4.3 22.8+/4.1 -0.373 0.710 1 5.8 +/2.1 5.5 +/2.0 -0.018 0.985 3 8.2 +/3.5 7.0 +/3.2 1.559 0.123 6 12.1 +/4.0 11.8 +/3.9 0.143 0.886 9 16.5 +/4.8 13.0 +/4.5 -3.580 0.0005 12 19.2 +/5.0 15.1 +/4.6 -3.580 0.0005 table 5. description of surgical outcomes. previous mean operative r+ r+ ns ns laparoscopic operative time (n°) (%) surgery surgery experience time (min) (range) (n°) (%) yes (a) 191.02 110-280 12 25.53 19 40.42 no (b) 214.48 150-365 12 22.22 12 22.22 figure 3. this bar chart compares the overall positive margin rates between operator a and operator b. operator a demonstrates a positive margin rate of 25.53%, while operator b shows a rate of 22.22%. statistical analysis using chi-square and fisher's exact tests revealed no significant difference between the two operators (p > 0.05). figure 4. this bar chart focuses on the positive margin rates for patients undergoing nerve sparing surgery. operator a exhibits a lower rate of 15.79% compared to operator b's 41.67%. while the difference is substantial, statistical tests did not confirm significance (p > 0.05). archivio italiano di urologia e andrologia 2025; 97(2):13640 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 6 perioperative blood loss was better controlled by operator a, as reflected by lower variability in hemoglobin levels at 12 and 24 hours postoperatively. operator a consistently maintained hemoglobin loss within the target threshold of ≤ 1.5 g/dl, as confirmed by stable trends in cusum plots, while operator b exhibited greater fluctuations (figure 5). pearson's correlation analysis identified moderate negative correlations between preoperative bmi and weight with iief-5 recovery at 12 months for both operators, with a stronger effect observed for operator b. preoperative psa levels showed weak positive correlations with pad usage at 12 months, while positive surgical margins were weakly correlated with psa levels at 3 months postoperatively, more prominently for operator b. cusum analysis further demonstrated that operator a consistently met or exceeded performance targets across oncological, functional, and efficiency metrics. operator a exhibited stable trends in achieving psa levels below 0.05 ng/ml at 12 months and superior outcomes in continence (complete pad-free status) and erectile function recovery (targeted iief-5 improvement) (figures 6-8). additionally, hemoglobin loss was better managed by figure 5. cusum plot of cumulative deviations in hemoglobin loss, with a target maximum loss of 1.5 g/dl. operator a shows better control over blood loss during surgery compared to operator b, whose performance fluctuates more. the cusum plot represents the cumulative sum of deviations from the predefined target of ≤ 1.5 g/dl hemoglobin loss. a rising trend does not necessarily indicate that each case exceeds the target but reflects the accumulation of deviations over time. this representation allows for the visualization of the overall trend in surgical performance figure 6. cusum plot depicting the cumulative deviations from the target psa level (< 0.05 ng/ml) at 12 months postoperatively. operator a demonstrates more stable performance, while operator b exhibits greater variability, indicating room for improvement in achieving optimal oncological control. this cusum plot represents cumulative deviations from the target psa level of < 0.05 ng/ml at 12 months postoperatively. an upward trend indicates that cases are accumulating below the target, while a stable or downward trend suggests consistency in maintaining oncological control. figure 7. cusum plot of cumulative deviations in iief-5 scores, showing progressive recovery of erectile function. operator a achieves better consistency in improvement, while operator b exhibits less favorable trends, possibly due to differences in nerve-sparing technique or patient complexity. the cusum chart illustrates the cumulative sum of changes in iief-5 scores relative to the target. a rising curve suggests progressive improvements in erectile function recovery, while a flatter trend reflects stabilization in functional outcomes. archivio italiano di urologia e andrologia 2025; 97(2):13640 7 learning curves in robotic-assisted radical prostatectomy (rarp) operator a, reflecting superior surgical efficiency and consistency (figure 5). these findings highlight the significant influence of prior laparoscopic experience on the learning curve for robotic-assisted radical prostatectomy. operator a demonstrated superior performance in functional recovery and surgical efficiency metrics, with lower variability in outcomes. while global oncological outcomes were similar between the two operators, the favorable trends for operator a in nerve-sparing cases and consistency in achieving performance targets underscore the value of surgical expertise in optimizing patient outcomes. discussion the discussion surrounding the learning curve in rarp provides crucial insights into the relationship between surgical proficiency and patient outcomes. this study reinforces the growing body of evidence highlighting the impact of prior laparoscopic experience on the learning curve for robotic surgery. surgeons with extensive laparoscopic experience often achieve proficiency in rarp more rapidly, underscoring the importance of foundational surgical skills. these findings align with previous studies, which demonstrate that surgeons who have performed more than 200 laparoscopic radical prostatectomies achieve faster mastery in rarp, particularly regarding operative time and oncological outcomes (11-14). our study sought to compare the learning curves and outcomes of rarp between surgeons with and without prior laparoscopic experience, shedding light on how surgical background influences operative success. while the results are consistent with existing literature, they also reveal nuances that merit further discussion. advocates of robotic surgery frequently highlight its technological advantages, such as enhanced visualization, improved dexterity, and tremor elimination, all of which contribute to a shorter learning curve even for surgeons without prior laparoscopic expertise. research has demonstrated that rarp facilitates more precise dissections and improved early functional recovery, particularly in urinary continence, as supported by systematic reviews (4, 5). despite these technological benefits, our findings suggest that prior laparoscopic experience significantly accelerates the rarp learning curve. surgeons with a strong laparoscopic background more rapidly achieve optimal pentafecta outcomes, which encompass the absence of biochemical recurrence, recovery of sexual potency, complete urinary continence, minimal blood loss (within 1.5 g/dl of hemoglobin), and negative surgical margins. this underscores the importance of technical familiarity with minimally invasive surgical techniques, gained through laparoscopic training, as a critical foundation that translates effectively to robotic platforms. the implications of these findings extend beyond individual performance, emphasizing the need for tailored training programs that leverage a surgeon’s prior experience. for surgeons transitioning from laparoscopy to robotics, such programs can expedite proficiency and improve patient outcomes. conversely, surgeons without a laparoscopic background may benefit from more intensive robotic training to bridge the gap in operative efficiency and functional recovery. in summary, while rarp’s technological advantages offer a distinct edge in surgical precision and functional outcomes, the role of prior laparoscopic experience remains pivotal in shaping the learning curve and achieving comprehensive surgical success. future studies should explore strategies to optimize robotic training pathways, ensuring consistent patient outcomes across varying levels of surgical expertise. the cusum analysis has emerged as a widely utilized tool for evaluating surgical learning curves. while our findings demonstrate clear improvements in operative and oncological outcomes over time, it is important to interpret these results within the inherent limitations of the cusum methodology. one notable limitation is its sensitivity to the number of cases analyzed, which can introduce variability in defining the point of proficiency. lin et al. (2023) highlighted that cusum peaks are highly dependent on sample size and target values, cautioning against an over-reliance on this metric as the sole determinant of surgical mastery (18). in this study, cusum analysis revealed distinct differences in the learning curves and outcomes of the two operators. for operator a, who had prior laparoscopic experience, the cusum curve indicated an earlier stabilization point, with operative times and positive surgical margin (psm) rates reaching consistency after approximately 25 cases. this was accompanied by superior early figure 8. cusum plot of continence outcomes at 12 months, with deviations from the target of full continence. operator a shows a more stable performance with minimal deviations, whereas operator b exhibits higher variability, reflecting challenges in achieving continence. the cusum plot represents the cumulative sum of deviations from the target of achieving full urinary continence at 12 months. an increasing trend indicates progressive improvement in continence recovery among patients, whereas a stable curve suggests a consistent rate of continence achievement. archivio italiano di urologia e andrologia 2025; 97(2):13640 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 8 functional recovery, including improved rates of urinary continence and sexual potency. conversely, operator b, who lacked laparoscopic experience, exhibited a more extended learning curve, with stabilization occurring after approximately 40 cases. despite this delay, operator b’s outcomes eventually converged with those of operator a, underscoring the ability of the robotic platform to bridge initial skill disparities as surgical experience accumulates. the robustness of the dataset bolstered the validity of these findings. the study design ensured minimal variability in case mix and controlled for confounding factors, reducing bias. sensitivity analyses further confirmed that the thresholds identified by cusum were not influenced by sample size or selection bias. moreover, the alignment between cusum peaks and clinical improvements such as reductions in psm rates and enhanced functional outcomes validated the clinical significance of the statistical results. these findings reaffirm the utility of cusum analysis as a reliable tool for assessing surgical learning curves, while also highlighting the dynamic relationship between prior experience and patient outcomes in rarp. from the perspective of our secondary endpoint, the differences in oncological and functional outcomes between the two operators provide further insight into the impact of surgical background. operator a’s prior laparoscopic experience not only facilitated a shorter learning curve but also contributed to more consistent outcomes in the early stages of their rarp practice. operator b’s extended learning curve emphasizes the importance of structured robotic training to mitigate the challenges faced by surgeons without a laparoscopic foundation. in conclusion, while cusum analysis is a valuable method for evaluating learning curves, it is best used in conjunction with other performance metrics to provide a comprehensive assessment of surgical proficiency. these results underscore the critical role of prior experience and highlight the potential of the robotic platform to achieve highquality outcomes, regardless of initial skill disparities. although both surgeons achieved comparable long-term oncological outcomes, including rates of psms and bcr, patients operated on by the surgeon with prior laparoscopic experience (operator a) displayed slightly superior early functional outcomes. in addition to shorter average operative times, operator a’s procedures were characterized by greater uniformity in operative duration compared to those of operator b, reflecting enhanced consistency likely attributable to their laparoscopic background. operator a demonstrated significantly shorter and more consistent operative times than operator b, underscoring the impact of prior laparoscopic expertise on procedural efficiency and standardization. the reduced variability in operative times highlights the value of prior experience in achieving a more predictable and streamlined surgical process. this finding is particularly relevant for the design of surgical training programs, where consistency in performance can serve as an indicator of surgical mastery. furthermore, the consistency in operative times has practical implications for operating room management, especially in high-volume centers where resource optimization is essential. these results underscore the dual benefits of prior laparoscopic experience: enhancing training outcomes and improving operational efficiency. regarding functional outcomes, patients in operator a’s cohort exhibited higher rates of early continence recovery and a trend toward better potency recovery. these observations align with previous studies, which have demonstrated that experience in laparoscopic techniques improves a surgeon’s precision in critical steps, such as nerve-sparing and vesicourethral anastomosis, ultimately influencing functional outcomes (5). good et al. conducted a detailed analysis comparing the learning curves and post-learning curve outcomes of two experienced surgeons performing lrp and rarp. their study revealed that, although both approaches required significant learning curves, rarp offered distinct advantages once surgeons achieved proficiency. specifically, rarp was associated with lower psm rates, particularly at the prostatic apex, and superior early continence recovery rates compared to lrp. these benefits were attributed to the technological advancements of the robotic platform, including enhanced three-dimensional visualization and greater precision during apical dissection. the authors emphasized that high surgical volumes and specialized training are essential for fully leveraging the advantages of robotic platforms, advocating for centralized, high-volume institutions to optimize patient outcomes [15). interestingly, while operator b, who lacked laparoscopic experience, exhibited a longer initial learning curve, their outcomes improved markedly over time, approaching those of operator a. this underscores the capability of robotic systems to standardize surgical procedures and compensate for initial skill gaps. moreover, our findings align with the broader consensus in the literature, which highlights the ergonomic and visual advantages of robotic platforms in mitigating the technical challenges associated with laparoscopic surgery. comparative studies consistently demonstrate better early continence and potency rates for rarp compared to lrp, even during the learning curve (1-6, 15). however, achieving trifecta outcomes – continence, potency, and oncological control – remains complex, with success rates heavily influenced by surgeon experience and patient selection (10). surgeons without prior laparoscopic experience, however, face steeper learning curves, particularly in maintaining functional outcomes. monnerat et al. (2018) highlighted that surgeons new to minimally invasive techniques required significantly more cases to achieve proficiency in rarp comparable to experienced counterparts (4, 14). this emphasizes the importance of structured mentorship and simulation-based training programs to bridge the gap for novice surgeons. the integration of robotics has not only redefined surgical paradigms but also raised important questions about the sustainability of learning curves in low-volume settings. a significant proportion of surgeons perform fewer than 10 radical prostatectomies annually, posing challenges to achieving optimal outcomes (4-6, 14). addressing these disparities will require systemic changes, such as regionalizing complex surgeries and providing targeted support for skill development among low-volume practitioners. archivio italiano di urologia e andrologia 2025; 97(2):13640 9 learning curves in robotic-assisted radical prostatectomy (rarp) comparative analyses also highlight nuanced trade-offs between robotic and laparoscopic techniques. while robotic platforms are associated with reduced operative times and shorter hospital stays, laparoscopic approaches remain a viable alternative in resource-constrained environments, provided that adequate surgical expertise is available (5, 6). from an oncological perspective, no statistically significant differences were observed in psm or bcr rates between the two operators, suggesting that the robotic platform ensures comparable oncological control regardless of surgical background. this observation aligns with prior studies indicating that rarp can standardize certain oncological outcomes across surgeons with varying levels of experience (6). however, the slightly lower psm rate in operator a’s cases likely reflects their enhanced anatomical knowledge and refined dissection techniques, honed through extensive laparoscopic training. despite these findings, our study highlights the need for further exploration of how prior surgical training influences not only learning curves but also the ability to deliver consistent functional outcomes. the apparent advantage of laparoscopic experience in early functional recovery raises important considerations for structuring training programs for surgeons transitioning to robotic platforms. finally, while this study reinforces the notion that prior laparoscopic experience accelerates the learning curve for rarp, this relationship appears deeply rooted in the surgeon’s thorough understanding of surgical anatomy and intraoperative nuances. such expertise, cultivated through laparoscopic training, establishes a strong foundation for navigating the complexities of robotic platforms. future research should focus on elucidating the bidirectional dynamics of skill transfer and identifying specific components of surgical training that maximize outcomes across various surgical modalities. conclusions this study underscores the pivotal role of prior laparoscopic experience in shaping the learning curve and outcomes of rarp. surgeons with laparoscopic backgrounds achieved faster proficiency and superior early functional outcomes, likely attributable to their advanced anatomical knowledge and precise intraoperative technique. furthermore, laparoscopic experience not only reduced operative times but also decreased variability, resulting in more consistent surgical performance compared to surgeons without prior laparoscopic training. this consistency highlights the importance of a foundational skill set in minimally invasive surgery when transitioning to robotic platforms. while the robotic platform provides significant advantages in standardizing oncological outcomes – evidenced by comparable rates of psms and bcr across operators – the improved early functional recovery observed in surgeons with laparoscopic expertise emphasizes the value of prior training in minimally invasive techniques. specifically, surgeons with laparoscopic experience demonstrated better early functional outcomes, including enhanced recovery of sexual function, as reflected in superior iief-5 scores at 12 months postoperatively. additionally, this study reinforces rarp’s superiority over lrp in terms of operative efficiency and short-term continence recovery, solidifying its position as the preferred surgical approach for localized prostate cancer. however, the differences observed between surgeons with and without laparoscopic experience suggest that skill transfer predominantly occurs in one direction from laparoscopy to robotics. this raises critical considerations for the design of future training programs. further research is needed to validate these findings and explore the potential for bidirectional skill transfer between laparoscopic and robotic techniques. understanding whether competencies developed in robotic surgery can enhance laparoscopic proficiency – or vice versa – may provide valuable insights for structuring more effective and versatile training programs in modern urologic surgery. references 1. philippou p, waine e, rowe e. robot-assisted laparoscopic prostatectomy versus open: comparison of the learning curve of a single surgeon. j endourol. 2012; 26:1002-8. 2. goonewardene ss, cahill d. the da vinci xi and robotic radical prostatectomy-an evolution in learning and technique. j robot surg. 2017; 11:111-113. declarations ethical approval: this study was approved by the local ethics committee of bari (ba), irccs oncological institute "gabriella serio" (protocol number: 2112/cel study “propt”). availability of data and material: the datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. competing interests: the authors declare no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions: p.p. prontera author corresponding substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 2: f.r. prusciano, f.s. grossi: substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 3: m. lattarulo, a. tsaturyan; f. addabbo, c. sciorio: substantial contributions to the interpretation of data for the work. reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13640 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 10 3. grossi fs, utano e, minafra p, et al. oncological and functional outcomes of extraperitoneal laparoscopic radical prostatectomy: an 18-years, single-center experience. arch ital urol androl. 2021; 93:268-273. 4. geraghty k, keane k, davis n. systematic review on urinary continence rates after robot-assisted laparoscopic radical prostatectomy. ir j med sci. 2024; 193:1603-1612. 5. kim dk, moon yj, chung dy, et al. korean society of endourology and robotics (kser) research committee. comparison of robot-assisted, laparoscopic, and open radical prostatectomy outcomes: a systematic review and network meta-analysis from kser update series. medicina (kaunas). 2025; 61:61. 6. salciccia s, santarelli v, di pierro gb, et al. real-life comparative analysis of robotic-assisted versus laparoscopic radical prostatectomy in a single centre experience. cancers (basel). 2024; 16:3604. 7. shikanov sa, zorn kc, zagaja gp, shalhav al. trifecta outcomes after robotic-assisted laparoscopic prostatectomy. urology. 2009; 74:619-23. 8. carlos af, dario vm, popescu ri, et al. robot-assisted radical prostatectomy (rarp) trifecta learning curve for surgeons with previous experience in laparoscopy. medicina (kaunas). 2024; 60:1032. 9. costa moretti tb, oliveira reis l, maes kk. comparative analysis of perioperative outcomes in radical prostatectomy: laparoscopic versus robot-assisted techniques. uro-technology journal 2024; 8: 65-72. 10. prontera pp, prusciano fr, lattarulo m, et al. quality of bladder cancer treatment information on youtube: may the user's profile affect the quality of results? arch ital urol androl. 2024; 96:12179. 11. monnerat lott f, siqueira d, argolo h, et al. analysis of the learning curve of surgeons without previous experience in laparoscopy to perform robot-assisted radical prostatectomy. adv urol. 2018; 2018: 9073807. 12. machado mt, mitre ai, rubinstein m et al. robotic-assisted radical prostatectomy learning curve for experienced laparoscopic surgeons: does it really exist? int braz j urol. 2016; 42: 83-9. 13. savage cj, vickers aj. low annual caseloads in us surgeons conducting radical prostatectomy. j urol. 2009; 182: 2677-2679. 14. d’amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. jama 1998; 280:969. 15. adili af, di giovanni j, kolesar e, et al. positive surgical margin rates during the robot-assisted laparoscopic radical prostatectomy learning curve of an experienced laparoscopic surgeon. can urol assoc j 2017; 11:e409-13. 16. good dw, stewart gd, laird a, et al. a critical analysis of the learning curve and postlearning curve outcomes of two experienceand volume-matched surgeons for laparoscopic and robot-assisted radical prostatectomy. j endourol. 2015; 29:939-47. 17. ku jy, ha hk. learning curve of robot-assisted laparoscopic radical prostatectomy for a single experienced surgeon: comparison with simultaneous laparoscopic radical prostatectomy. world j mens health 2015; 33:30-35. 18. lin pl, zheng f, shin m, et al. cusum learning curves: what they can and can't tell us. surg endosc. 2023; 37:7991-7999. 19. grossi fs, di lena s, barnaba d, et al. laparoscopic versus open radical retropubic prostatectomy: a case-control study at a single institution. arch ital urol androl. 2010; 82:109-12. correspondence pier paolo prontera, md (corresponding author) pierpaolo.prontera@asl.taranto.it marco lattarulo, md marco.lattarulo@asl.taranto.it francesco saverio grossi, md, phd francescos.grossi@asl.taranto.it department of urology, “s.s. annunziata” hospital via bruno francesco, 1 street 74010 taranto (italy) francesca romana prusciano, md francescaprusciano@gmail.com division of urology, hospital “valle d’itria”, martina franca (ta), italy arman tsaturyan, md, phd tsaturyanarman@yahoo.com department of urology, yerevan state medical university after mkhitar, heratsi, yerevan, armenia carmine sciorio, md carmine.sciorio@gmail.com department of urology, “alessandro manzoni” hospital of lecco, 23900 (italy) francesco dibenedetto, rn francesco.dibenedetto@asl.taranto.it master of science in nursing, department of operating room, “s.s. annunziata” hospital, taranto (italy) lorenzo romano, md lorenzo.romano990@gmail.com department of woman, child and general and specialized surgery. università degli studi della campania “l. vanvitelli” and urology section, ospedale del mare, napoli, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13635 1 original paper introduction breast cancer (brca) gene mutations are known to be associated with earlier-onset and clinically significant prostate cancer (capca) (1). brca1 and brca2 are tumour suppressor genes: brca1 wild-type controls cell cycle checkpoints and repairs dna in a normal cell (2); brca2 is a large protein consisting of 27 exons and may play a role in regulating transcription and is involved in dna repair to maintain genome integrity during replication (3). many retrospective studies have reported higher rates of lymph node involvement, distant metastases at diagnosis and a higher mortality rate in pca mutation carriers. germline brca2 mutation status is considered an independent prognostic factor for poorer outcome (4). in addition, brca2 mutation in men with organ-confined pca exhibits genomic instability typically seen in metastatic castration-resistant cancer (5), suggesting a poor longterm prognosis. in clinical practice, screening protocols for the early diagnosis of pca are based on the determination of prostate specific antigen (psa). to improve accuracy, other biological markers (6-8), risk calculators (9), magnetic resonance imaging (mri) (10) and genetic markers (11-13) have recently been introduced. recently, the impact study (identification of men with a genetic predisposition to prostate cancer: targeted screening in men at higher genetic risk and controls) an international and multicentre study, evaluated targeted pca screening in men with germline brca1/2 mutations (13). in this study, we report on brca1/2 evaluation in men with high risk pca, including the oncological consequences for the patient and family members. materials and methods from january 2023 to december 2024, 52 men (median age 73 years; range: 52-84) with confirmed pca diagnosis underwent somatic and germline brca1 and brca2 assessment; 11/52 (21%) patients documented a family history of cancer. patients were at different clinical stages: high-grade (71% had a gleason score > 8) (14,15), locally advanced (54% of cases) (16,17) and/or metastatic pca (46% of cases) at initial diagnosis (18), hormone-sensitive introduction: to evaluate brca1-2 (breast cancer) detection in men with high risk pca, including the oncological consequences for the patient and family members. materials and methods: from january 2023 to december 2024, 52 men (median age 73 years;) with confirmed pca diagnosis underwent somatic and germline brca1 and brca2 assessment; 11/52 (21%) patients documented a family history of cancer. patients were at different clinical stages: high-grade (71% had a gleason score ≥ 8), locally advanced (54% of cases) and/or metastatic pca (46% of cases) at initial diagnosis, hormone-sensitive and/or castration-resistant pca (38.2% of cases) at clinical progression. formalin-fixed paraffin-embedded (ffpe) tissues and next generation sequencing (ngs) analyses of brca genes were evaluated on 52 samples (prostate biopsies or definitive samples) collected at gravina hospital (caltagirone, italy) from different sicilian pathology departments. the therapeutic and clinical impact of genetic testing for brca somatic and germline mutations were evaluated for patients and their families. results: all ffpe cases were successfully genotyped, with a good library and sequencing cq metrics for all genes of interest; 10/52 (19.2%) patients had somatic or germline brca mutations, specifically, 3/52 (5.7%) had somatic and 7/52 (13.5%) had germline mutations. in the seven cases with germline variants, 4/7 (57%) had a family history of pca or other diseases, while the remaining 3/7 (43%) patients had no hereditary predisposition. all identified genetic variants were related to the brca2 gene; after genetic screening of the corresponding relatives, various members of the analysed families carried the mutation identified in the proband, so that cancer prevention and/or active surveillance was possible. conclusions: ngs analysis for brca genetic testing using ffpe tissue in the clinical setting of patients with high-grade and/or metastatic pca appears to be a valuable tool, not only for therapeutic purposes, but also to identify families with genetic predisposition who may be underdiagnosed according to canonical criteria. key words: prostate cancer; brca and high grade pca; brca mutations and pca: somatic and germline brca. submitted 15 january 2025; accepted 21 january 2025 brca mutations and prostate cancer: should urologist improve daily clinical practice? simona vatrano 1, pietro pepe 2, ludovica pepe 2, nuccia vella 3, cristina alario 1, alessia chiarandà 1, chiara taranto 1, renato scillieri 4, cristina mauceri 4, filippo fraggetta 1 1 pathology unit-gravina hospital, caltagirone, italy; 2 urology unit-cannizzaro hospital, catania, italy; 3 genetic unit-vittorio emanuele hospital, gela, italy; 4 oncologic screening unit-catania, italy. doi: 10.4081/aiua.2025.13635 summary archivio italiano di urologia e andrologia 2025; 97(2):13635 s. vatrano, p. pepe, l. pepe, et al. 2 and/or castration-resistant pca (38.2% of cases) at clinical progression (19-21). after institutional review board and ethical committee approval were granted, the informed consent was obtained from all individual participants included in the study. all clinical parameters of the patients are listed in table 1. formalin-fixed paraffinembedded (ffpe) tissues and next generation sequencing (ngs) analyses of brca genes were evaluated (22-24) on 52 samples (prostate biopsies or definitive samples) collected at gravina hospital of caltagirone (referral center for genetic analysis) from different sicilian pathology departments (25, 26). in addition, the therapeutic and clinical impact of genetic testing for brca somatic and germline mutations was evaluated for patients and their families. by aligning all sequencing results obtained with ngs analysis of ffpe tissue and peripheral blood, good coverage and uniformity was achieved for all samples with optimal read quality and sequencing metrics for both analyzed genes. results all ffpe cases were successfully genotyped, with a good library and sequencing cq metrics for all genes of interest. a good sequencing performance was also achieved for old archival samples (i.e. histological samples from 2009). most of the identified genetic variants had been previously reported in the major mutation databases with clinical impact, being distributed among the different genes and all resulting in a truncated non-functional protein. 10/52 (19.2%) patients had somatic or germline brca mutations (table 2); specifically, 3/52 (5.7%) had somatic and 7/52 (13.5%) had germline mutations. in the seven cases with germline variants, 4/7 (57%) had a family history of pca or other diseases, while the remaining 3/7 (43%) patients had no hereditary predisposition. all identified genetic variants had been previously described in the major mutation databases, and most of them were related to the brca2 gene. in detail, 3/10 (30%) patients without a family history of cancer had germline mutations in the brca genes that had predictive significance but also clinical impact on their relatives. after genetic screening of the corresponding relatives, various members of the analyzed families (figure 1) carried the mutation identified in the proband, so that cancer prevention and/or active surveillance was possible. discussion several sequencing studies have shown that approximately 25% of metastatic castration-resistant pca patients have genomically aberrant dna repair pathways, with mutations in the brca1 and brca2 genes, which have been of important clinical and therapeutic significance since the approval of parp inhibitors in castration-resistant patients (1). of all brca-mutated metastatic pca, about half had somatic mutations and the others had germline mutations (27); hommerding et al. (28) reported a prevalence of potentially targetable genetic mutation table 1. clinical findings in the 52 men submitted to ngs brca evaluation. overall patients’ characteristics (tot. n = 52) age (years) range 52-97 median 73 cancer family history in a first degree realtive range 52-97 median 73 gleason score ≤ 7 15 ≥ 8 37 metastasis at diagnosis (locally advanced) 28 metastatic setting 24 brca mutated 10 wild-type 42 castration resistance yes 20 no 32 table 2. brca mutations (somatic and/or germline) in 10/52 (19.2%) patients with aggressiveness prostate cancer. archivio italiano di urologia e andrologia 2025; 97(2):13635 3 prostate cancer and brca mutations criteria of 20.8% in 197 cases of primary and metastatic pca. the inclusion of genomic testing based on ffpe samples for predictive purposes in the management of patients with metastatic pca has relevant implications for their healthy relatives in the presence of germline mutations. it also offers the real possibility of preventing cancer in brca1/2 mutation carriers through screening protocols (29). men with brca1/brca2 germline mutations who are on active surveillance for low-risk pca have been reported to be at higher risk of reclassification than noncarriers (30); in these cases, closer surveillance incorporating other clinical parameters may be recommended (31-33). the european urological association (34) recommends starting pca screening at the age of 40 for male brca2 carriers. the national comprehensive cancer network (nccn) guidelines do the same for brca1 carriers and routinely perform brca1/2 testing for men with highrisk pca (gleason score > 8), ductal or cribriform pca and metastatic disease (35). t-ngs analysis for brca genetic testing using ffpe tissue in the clinical setting of patients with metastatic pca appears to be a valuable tool, not only for therapeutic purposes, but also to identify families with genetic predisposition who may be underdiagnosed by canonical criteria. the impact study (13) investigated targeted pca screening in men with germline brca1/2 mutations; among the 357 men who underwent prostate biopsy, the 112 men with pca were found to have a higher detection rate in brca2 carriers compared to non-carriers (73% versus 60%). in addition, brca2 carriers were diagnosed at a younger age and were more likely to have cspca than brca2 non-carriers (77 vs 40%). in contrast, no differences were found between brca1 carriers and brca1 non-carriers in terms of age or tumour characteristics. the ability to test brca1/2 genes from ffpe samples would allow the simultaneous assessment of both somatic and germline mutations using an accessible material that is routinely available in any pathology laboratory (36). therefore, there is a need for efficient and timely methods to detect both somatic and germline mutations starting from ffpe tissue under expert guidance, considering the high percentage of failures in this tumour setting (37). recently, a consensus paper was developed and approved by a multidisciplinary expert panel on behalf of the italian scientific societies (38) to improve accurate patient selection by the use of standardized and harmonized procedures and adherence to homogeneous brca testing criteria. loeb et al. (39) reported on a survey of urologists in the usa that examined knowledge of germline testing guidelines and practice patterns. of a total of 132 respondents from different practices, 12% performed germline testing, 44% refer to a genetic counsellor, 11% do both and 33% do not test/refer, 4% had formal training in genetics, suggesting that there are significant gaps in urologists' knowledge of germline testing and how to align practice with national guidelines. although somatic and germline brca2 testing is only recommended in men with metastatic castration-resistant pca, the possibility of also performing the test in men with locally advanced and/or aggressive pca, as suggested in the nccn guidelines, offers the opportunity to figure 1. family evaluation in a case of brca germline mutation. archivio italiano di urologia e andrologia 2025; 97(2):13635 s. vatrano, p. pepe, l. pepe, et al. 4 select patients at high risk of clinical progression and to perform adequate clinical cancer screening in family members with germline mutations to prevent aggressiveness and/or advanced cancer at diagnosis. in addition, early genetic tissue testing could reduce the risk of nondiagnostic tissue patterns that are useful for genetic testing, especially many years after diagnosis of pca, as well as the difficulty of performing biopsies of metastases (i.e., bone, retroperitoneal nodes) (37). definitely, the role of the urologist in a multidisciplinary approach is fundamental to adequately inform the patient affected by aggressive pca at the time of diagnosis about the role of genetic testing (somatic and germline) to improve oncological treatment and prevent cancer through early screening protocols in family members with germline mutations. these data should be analyzed in a larger number of patients and in a multidisciplinary team to assess the best timing for brca testing, the cost-effectiveness and the therapeutic impact of early genetic analysis. in our series, 3/7 (43%) patients with brca2 germline mutations and negative family history for pca underwent genetic counselling, including family members, for appropriate oncological screening. conclusions ngs analysis for brca genetic testing using ffpe tissue in the clinical setting of patients with high-grade and/or metastatic pc appears to be a valuable tool, not only for therapeutic purposes, but also to identify families with genetic predisposition who may be underdiagnosed according to canonical criteria. references 1. kote-jarai z, leongamornlert d, saunders e, et al. brca2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. br j cancer. 2011; 105:1230-1234. 2. sengodan sk, sreelatha kh, nadhan r, srinivas p. regulation of epithelial to mesenchymal transition by brca1 in breast cancer. crit rev oncol/hematol. 2018; 123:74-82. 3. bertwistle d, swift s, marston nj, et al. nuclear location and cell cycle regulation of the brca2 protein1. cancer res. 1997; 57:5485-5488. 4. castro e, goh c, olmos d, et al. germline brca mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. j clin oncol. 2013; 31:1748-1757. 5. taylor ra, fraser m, livingstone j, et al. germline brca2 mutations drive prostate cancers with distinct evolutionary trajectories. nat commun. 2017; 8:13671. 6. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14,453 patients. prostate cancer prostatic dis. 2010; 13:316-319. 7. pepe p, panella p, d'arrigo l, et al. should men with serum prostate-specific antigen < or =4 ng/ml and normal digital rectal examination undergo a prostate biopsy? a literature review. oncology. 2006; 70:81-98. 8. aragona f, pepe p, motta m, et al. incidence of prostate cancer in sicily: results of a multicenter case-findings protocol. eur urol. 2005; 47:569-74. 9. pepe p, aragona f. prostate cancer detection rate at repeat saturation biopsy: pcpt risk calculator versus pca3 score versus casefinding protocol. can j urol. 2013; 20:6620-6624. 10. pepe p, d'urso d, garufi a, et al. multiparametric mri apparent diffusion coefficient (adc) accuracy in diagnosing clinically significant prostate cancer. in vivo. 2017; 31:415-418. 11. pepe p, fraggetta f, galia a, et al. pca3 score and prostate cancer diagnosis at repeated saturation biopsy. which cut-off: 20 or 35? int braz j urol. 2012; 38:489-495. 12. pepe p, aragona f. pca3 score vs psa free/total accuracy in prostate cancer diagnosis at repeat saturation biopsy. anticancer res. 2011; 31:4445-4449. 13. page ec, bancroft ek, brook mn, et al. interim results from the impact study: evidence for prostate-specific antigen screening in brca2 mutation carriers. eur urol. 2019; 76:831-842. 14. pepe p, dibenedetto g, pennisi m, et al. detection rate of anterior prostate cancer in 226 patients submitted to initial and repeat transperineal biopsy. urol int. 2014; 93:189-192. 15. pepe p, pepe l, tamburo m, et al. 68ga-psma pet/ct and prostate cancer diagnosis: which suvmax value? in vivo. 2023; 37:1318-1322. 16. pepe p, pennisi m. targeted biopsy in men high risk for prostate cancer: 68ga-psma pet/ct versus mpmri. clin genitourin cancer. 2023; 21:639-642. 17. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl. 2020; 92:209. 18. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer res. 2022; 42:3011-3015. 19. pepe p, pepe l, tamburo m, et al. targeted prostate biopsy: declarations ethical approval: institutional review board and ethical committee approval were granted the informed consent was obtained from all individual partecipants included in the study. availability of data and material: the data that support the findings of this study are available from the corresponding authors upon reasonable request. competing interests: the authors declare that there is no conflict of interest. funding: none. authors' contributions: conceptualization: v.s., p.p., p.l.; investigation: v.s., p.p., p.l.; data curation: v.s., p.p., p.l.; formal analysis: v.s., p.p., p.l.; methodology: v.s., p.p., p.l.; resources: v.s., p.p., p.l., f.f.; software: v.s., p.p., p.l., f.f., v.n., a.c., c.a., t.c., s.r., m.c.; writing original draft: v.s., p.p., p.l.; writing review & editing: v.s., p.p., p.l., f.f. funding acquisition: none. consent for publication: all authors have read and approved the content and agree to submit for consideration for publication in the journal. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13635 5 prostate cancer and brca mutations 68ga-psma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl. 2022; 94:274-277. 20. pepe p, pennisi m. should 68ga-psma pet/ct replace ct and bone scan in clinical staging of high-risk prostate cancer? anticancer res. 2022; 42:1495-1498. 21. pepe p, pepe l, fiorentino v, et al. psma pet/ct accuracy in diagnosing prostate cancer nodes metastases. in vivo. 2024; 38:2880-2885. 22. kechin a, khrapov e, boyarskikh u, et al. brca-analyzer: automatic workflow for processing ngs reads of brca1 and brca2 genes. comput biol chem. 2018; 77:297-306. 23. kalampokis n, zabaftis c, spinos t, et al. review on the role of brca mutations in genomic screening and risk stratification of prostate cancer. curr oncol. 2024; 31:1162-1169. 24. giri vn, knudsen ke, kelly wk, et al. implementation of germline testing for prostate cancer: philadelphia prostate cancer consensus conference 2019. j clin oncol. 2020; 38:2798-2811. 25. pepe p, aragona f. prostate needle biopsy: 12 vs. 18 cores -is it necessary? urol int. 2005; 74:19-22. 26. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8.500 men. arch ital urol androl. 2022; 94:155-159. 27. robinson d, van allen em, wu ym, et al. integrative clinical genomics of advanced prostate cancer. cell. 2015; 161:1215-1228. 28. hommerding m, hommerding o, bernhardt m, et al. real-world data on the prevalence of brca1/2 and hrr gene mutations in patients with primary and metastatic castration resistant prostate cancer. world j urol. 2024; 42:491. 29. bancroft ek, page ec, castro e, et al. targeted prostate cancer screening in brca1 and brca2 mutation carriers: results from the initial screening round of the impact study. eur urol. 2014; 66:489-499. 30. carter hb, helfand b, mamawala m, et al. germline mutations in atm and brca1/2 are associated with grade reclassification in men on active surveillance for prostate cancer. eur urol. 2019; 75:743-749. 31. pepe p, cimino s, garufi a, et al. detection rate for significant cancer at confirmatory biopsy in men enrolled in active surveillance protocol: 20 cores vs 30 cores vs mri/trus fusion prostate biopsy. arch ital urol androl. 2016; 88:300-303. 32. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsies in men enrolled in active surveillance protocols? j clin med. 2022; 11:3473. 33. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology. 2020; 137:133-137. 34. tilki d, van den bergh rcn, briers e, et al. eau-eanmestro-esur-isup-siog guidelines on prostate cancer. part ii2024 update: treatment of relapsing and metastatic prostate cancer. eur urol. 2024; 86:164-182. 35. schaeffer em, srinivas s, adra n, et al. prostate cancer, version 4.2023, nccn clinical practice guidelines in oncology. j natl compr canc netw. 2023; 21: 1067-1096. 36. pepe p, fandella a, barbera m, et al. advances in radiology and pathology of prostate cancer: a review for the pathologist. pathologic. 2024; 116:1-12. 37. cimadamore a, rescigno p, conteduca v, italian society for urooncology (siuro). siuro best practice recommendations to optimize brca 1/2 gene testing from dna extracted from bone biopsy in mcrpc patients (brca optimal bone biopsy procedure: bop). virchows arch. 2023; 483:579-589. 38. russo a, incorvaia l, capoluongo e, italian scientific societies. implementation of preventive and predictive brca testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of italian scientific societies. esmo open. 2022; 7:100459. 39. loeb s, byrne n, walter d, et al. knowledge and practice regarding prostate cancer germline testing among urologists: gaps to address for optimal implementation. cancer treat res commun. 2020; 25:100212. correspondence simona vatrano simona.vatrano@gmail.com cristina alario alessia chiarandà chiara taranto filippo fraggetta filippofra@hotmail.com pathology unit-gravina hospital, caltagirone (italy) pietro pepe (corresponding author) piepepe@hotmail.com ludovica pepe ludopepe97@gmail.com urology unit-cannizzaro hospital, via messina 829, catania (italy) nuccia vella genetic unit-vittorio emanuele hospital, gela (italy) renato scillieri cristina mauceri oncologic screening unit-catania, (italy) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 original paper sion, diabetes mellitus, and coronary artery disease. whatever the reasons, the main problem is a vascular disorder associated with endothelial dysfunction. a dating among ed and extended threat of cardiovascular occasions may be defined through underlying endothelial dysfunction. endothelial dysfunction is usually defined as impaired nitric oxide bioavailability, decreased vasodilation, and exacerbation of inflammation prior to atherosclerotic lesions. ed itself is not only a strong predictor of cad, but also of future mortality associated with major cardiovascular events in men with cvd (2, 3). blood tests for blood cells are basic tests that are routinely performed in clinical settings, such as red blood cells (rbc), white blood cells (wbc), and platelets (plt) (4). studies have shown that these hematologic parameters are closely associated with the development of endothelial dysfunction and atherosclerosis (5). they can be used not only to predict the development of cardiovascular, cerebrovascular, and peripheral vascular diseases, but also to assess the severity and prognosis of such diseases (5). neutrophil/lymphocyte ratio (nlr) has been proposed as a biomarker of subclinical inflammation. in addition, the platelet/lymphocyte ratio (plr) has been found to be an important marker of inflammation (6). because ed and cvd and other vascular diseases almost share the same pathophysiology, recent studies have found a strong association between atherosclerosis and inflammation, showing that inflammatory markers such as nlr (neutrophil/lymphocyte ratio) and plr (platelet/lymphocyte ratio) are significantly elevated in cad and ed (2, 5). peyronie's disease (pd) is an acquired pathology of the albuginea of the penis without a clearly established aetiology (7). it is an incurable fibrotic disease of the albuginea that causes penile curvature with loss of sexual function in many patients (8). pd is known as a localized inflammatory disease of the tunica albuginea of the penis. the prevalence of pd in the united states has been estimated at 0.5-9% of the general population. ed is a commonly associated comorbidity of pd, reported in 32% of men (9). there are two phases of pd: active (acute phase) and quiintroduction: this study aims to investigate the relationship between neutrophillymphocyte ratio (nlr), platelet-lymphocyte ratio (plr) with erectile dysfunction (ed) and peyronie's disease (pd). methods: we conducted a meta-analysis of the observational study by searching for the appropriate keywords in eight databases. the risk of publication bias of the included studies was assessed by egger's test and kendall's t. the data extraction was carried out for each study and analysed using revman 5.0. results: there were eleven eligible studies out of the 411 studies retrieved. eight studies were conducted on cases of erectile dysfunction, and three studies on peyronie's disease. there was a significant relationship between nlr, plr and ed (smd: 0.59, 95% ci: 0.33-0.85 and smd: 0.64, 95% ci: 0.13-1.16, respectively). the same was also found for pd. the active phase of pd tended to have higher nlr (smd: 0.68, 95% ci: 0.43-0.92) and plr (smd: 0.27, 95% ci: 0.06-0.49) compared to the chronic phase. no publication bias was found in both ed and pd studies. conclusions: nlr and plr indicate an ongoing inflammatory process in both ed and pd. these findings can be used as markers of treatment and prognosis of both diseases in sexual health care. key words: nlr; plr; inflammatory; erectile dysfunction; peyronie’s disease; sexual health care. submitted 17 january 2023; accepted 16 february 2023 introduction erectile dysfunction (ed) is a condition that is defined as an inability to achieve or maintain an erection sufficient to engage in sexual intercourse (1). in men, ed is the most common cause of sexual dysfunction. the prevalence of ed tends to increase with age. ed occurs in approximately 2% of men under the age of 40, but this rate increases by 15% between the ages of 40 and 50, reaching 45% by age 60 and 70% by age 70 (2). there are many factors contributing to ed, such as obesity, diabetic disease, dyslipidaemia, hypertension, neurological disorder, etc. the most common causes of ed are hypertenthe interplay between neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, erectile dysfunction, and peyronie’s disease: a meta-analysis of observational studies cennikon pakpahan 1, 2, 3*, ilhamsyah ilhamsyah 1, 3*, supardi supardi 1, 3, pety narulita 1, 3, agustinus agustinus 1, 2, 3, darmadi darmadi 4 1 andrology study program, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia; 3 andrology outpatient clinic, general academic dr. soetomo hospital, surabaya, indonesia; 4 department of internal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia. * these authors contributed equally to this paper. doi: 10.4081/aiua.2023.11162 summary archivio italiano di urologia e andrologia 2023; 95, 1 c. pakpahan, i. ilhamsyah, s. supardi, p. narulita, a. agustinus, d. darmadi escent (chronic phase). “acute phase” of pd is an inflammatory phase characterized by changes in penile curvature, with or without palpable plaques or increased erectile pain. 'chronic phase' of pd shows stable penile curvature with or without palpable plaques (8, 9). nowadays, there are no objective biomarkers used to distinguish between acute and chronic disease stages. inflammatory parameters such as nlr, the monocyte-to-eosinophil ratio (mer), and plr are simple and actionable markers that can be easily calculated with a complete blood count (cbc) (10). identifying predictive tools for diagnosing pd stages is important for selecting appropriate therapies. some of recent studies show significant differences in both nrl and plr between the acute and chronic stages of pd. in other hands, other studies implicate no relationship between the acute phase ratio values and the penile curvature achieved after stabilization (6, 7). however, there are no validated blood tests on the market that can be used to diagnose or characterise the phases of pd. based on the considerations above, we conducted a systematic review and meta-analysis to validate the association of nlr, plr and ed. indeed, we hoped that the comprehensive conclusions of the meta-analysis would promote the important role of haematological testing in the diagnosis and prediction of ed, especially pd. methods search strategy and eligibility criteria this study was conducted following the prisma (preferred reporting items for systematic reviews and metaanalyses) guidelines (11). the study has been registered with prospero with registration no. crd42022356840. we conducted a study search on eight databases, including pubmed, ebsco, springer link, science direct, proquest, web of science, taylor and francis, and google scholar. diseases considered in this review are erectile dysfunction and peyronie's disease. we used keywords such as "neutrophil-lymphocyte ratio" or "nlr" or "platelet-lymphocyte ratio" or "plr" and "erectile dysfunction" or "erectile" to search for studies dealing with erectile dysfunction while for peyronie's disease we used the keyword "neutrophil -lymphocyte ratio" or "nlr" or "platelet-lymphocyte ratio" or "plr" and "peyronie's disease". the search is not limited by the time of publishing the study. the criteria for the eligible studies in cases of erectile dysfunction and peyronie's disease were: 1) observational analytical studies, 2) presenting nlr and plr data, 3) written in english, and (4 available in full text. then we excluded studies that were: 1) performed on animals or in vitro, 2) case reports or case-series, 3) figure 1. prisma flowchart. archivio italiano di urologia e andrologia 2023; 95, 1 nlr, plr, ed, and peyronie's disease abstract, poster, preceding, review, and 4) articles that had not been published or pre-printed. data extraction and study quality analysis two authors (cp and ii) extracted the studies from the database, and screened through the title and abstract in detail with mendeley's assistance. roughly suitable studies were thoroughly read and discussed by the two authors. data extraction was done if the study met the pre-defined criteria we have set. the data were taken in the form of the author's name, year of publication, population, type of research, number of samples involved, and the statistical size used to see the relationship between nlr, plr with ed, peyronie's disease, and age of the sample. then simultaneously, we assessed the quality of the study with the newcastle-ottawa scale (nos) (12). any confusion or difference of opinion found during the screening and extraction process was discussed with other authors to reach an agreement. after completing the data extraction, the data was processed using revman 5.0 for mac. the statistical measures we processed were mean and sd of nlr and plr in the health and ed group in the erectile dysfunction study, and the acute and chronic group in the peyronie's disease study. initially, we wanted to assess each study's or and rr values, but some data needed to be completed, and the author could not be contacted (unresponsive). if the heterogeneity value was p > 0.05, we performed a fixed effects model, and if the heterogeneity was p < 0.05, we chose a random effects model. then, we used the regression test for funnel plot asymmetry (egger's test) and the rank correlation test (kendall's t) to assess the risk of publication bias using jasp. results search results and study characteristics the search for relevant studies is depicted in figure 1. out of the eight databases we used, there were 411 studies matching the keywords. but using the mendeley, there were some duplications found, leaving us with 337 studies matched. a total of 308 studies were excluded because they did not meet the criteria, leaving only 11 studies eligible for qualitative synthesis (2, 3, 5-7, 9, 10, 13-16). after the review, eight of them were studied in ed cases (sambel et al., 2018, demirci et al., 2019, demirci et al., 2020, erdogan et al., 2020, karabakan et al., 2019, akbas et al., 2016, liao et al., 2021, aslan et al., 2019) and three case studies of peyronie's disease (esther et al., 2019, greenberg et al., 2022, ozbir et al., 2020). in ed study, eight studies were included, a total sample of 1007 in the control or healthy group and 1221 in the ed group. of these eight studies, seven were from turkey, while only one was from china. all studies included were case-control studies. almost all the patients in the study were confirmed by history, iief-5, and some underwent hormone testing. in peyronie's disease study, the total sample in the active phase group was 169, and the chronic phase was 217. these three studies came from turkey, usa, and spain. the diagnosis of peyronie's disease, was established by history taking and physical examination, including measuring the penile curvature. information on sample age and study quality using noqs is presented in table 1. table 1. baseline characteristics of the included studies. author, years country study design sample size output variable age in years noqs of publication origin and allocation and measure size mean ± sd, median (min-max) study with erectile dysfunction sambel et al, 2018 turkey case-control study healthy = 175 mean ± sd = nlr, plr healthy = 48 (43–65) 7/9 ed = 262 ed = 49 (40–69) demirci et al, 2019 turkey case-control study healthy = 80 mean ± sd = nlr, plr healthy = 48.8 ± 13.0 7/9 ed = 63 ed = 47.45 ± 12.01 erdogan et al, 2020 turkey case-control study healthy = 44 mean ± sd = nlr, plr healthy = 52.23 ± 7.6 8/9 ed = 148 ed = 52.16 ± 8.6 karabakan et al, 2019 turkey case-control study healthy = 26 mean ± sd = nlr, plr healthy = 53.3 ± 8.3 7/9 ed = 131 ed = 54.55 ± 8.17 akbas et al, 2016 turkey case-control study healthy = 175 mean ± sd = nlr, plr healthy = 53.8 ± 8.4 7/9 ed = 262 ed = 54 ± 11.7 liao et al, 2021 china case-control study healthy = 212 mean ± sd = nlr, plr healthy = 32 (29-37) 8/9 ed = 113 ed = 33 (29-38) aslan et al, 2019 turkey case-control study healthy = 94 mean ± sd = nlr healthy = 59.5 (52.0-68.0) 7/9 ed = 90 ed = 61.0 (53.0-66.25) demirci et al, 2019 turkey case-control study healthy = 201 mean ± sd = nlr, plr healthy = 45.5 ± 8.6 7/9 ed = 152 ed = 46.4 ± 12.9 study with peyronie’s disease esther et al, 2019 spain case-control study active phase = 42 mean ± sd = nlr, plr all phase = 55.85 ± 10.71 7/9 chronic phase = 78 greenberg et al, 2022 usa case-control study active phase = 27 mean ± sd = nlr, plr active phase = 63 (57.0–67.5) 7/9 chronic phase = 82 chronic phase = 61 (54.0–66.0) ozbir et al, 2020 turkey case-control study active phase = 98 mean ± sd = nlr, plr active phase = 54.1 ± 9.2 8/9 chronic phase = 57 chronic phase = 54.1 ± 10.6 archivio italiano di urologia e andrologia 2023; 95, 1 c. pakpahan, i. ilhamsyah, s. supardi, p. narulita, a. agustinus, d. darmadi meta-analysis results the results of the nlr analysis in relation with ed showed that there were significant differences of ed group compared to the control group (smd: 0.59, 95% ci: 0.330.85). with heterogeneity (i2) = 80% (p < 0.0001), random effects modelling was performed for this variable (figure 2a). the ed group tended to have higher nlr values than the control group. plr analysis in relation with ed also showed significant differences of ed group compared to the control group (smd: 0.64, 95% ci: 0.13-1.16). with heterogeneity (i2) = 95% (p < 0.00001), random effect modelling was performed on this variable (figure 2b). these results indicated that the plr value in the ed group tended to be higher than in the control group. in peyronie's disease study, significant results were obtained in the nlr test between the active and chronic phase groups. the active group tended to have higher nlr values than chronic (smd: 0.68, 95% ci: 0.430.92). with heterogeneity (i2) = 8% (p = 0.34), fixed effects model was performed for this variable (figure 3a). for plr testing in active and chronic phases, significant results were obtained (smd: 0.27, 95% ci: 0.06-0.49). with heterogeneity (i2) = 0% (p = 0.74), fixed effects model was performed for this variable (figure 3b). plr in the active group was higher than in the chronic group. risk of bias assessment the bias assessment was carried out using the regression test for funnel plot asymmetry (egger's test) and rank correlation test (kendall's t). in the study conducted to assess figure 2. forest plot analysis between nlr (a), plr (b), and erectile dysfunction. figure 3. forest plot analysis between nlr (a), plr (b), and peyronie’s disease. archivio italiano di urologia e andrologia 2023; 95, 1 nlr, plr, ed, and peyronie's disease nlr and plr for ed, the regression test for funnel plot asymmetry (egger's test) is z = -0.226, p = 0.822, and the rank correlation test (kendall's t) is 0.071, p = 0.905. these results indicated no publication bias in those articles (ed). in the nlr and plr studies with peyronie's disease phase, the regression test for funnel plot asymmetry (egger's test) is z = -0.750, p = 0.453, and the rank correlation test (kendall's t) is -1,000, p = 0.333 indicated that there was no publication bias in those articles. discussion the results of this meta-analysis were in line with previous theories. nlr and plr were significantly increased in the ed group compared to the control group. this was because the inflammatory process in ed did occur. several inflammatory mediators (interleukin (il)-1β, tnf-, il-6, crp, il-10) and endothelial/prothrombotic factors were activated in the ed process (16). so, the increase in nlr and plr was natural and in sync with the incidence of ed. these findings suggested that nlr and plr can be used as independent factors in ed cases. even these two parameters can be used as predictors of ed events. the advantage is that nlr and plr are two parameters that are easy and inexpensive to check. this can be very promising in terms of diagnosis and management of ed. the second finding was difference of nlr and plr in peyronie's disease between the active and chronic groups. this meta-analysis was the first to analyse the involvement of these two parameters with peyronie's disease. this showed that active peyronie's disease was still an inflammatory process. increased nlr and plr in the acute phase indicated a traumatic micro-vascular process in peyronie's disease (17). so, in the acute phase of this disease, patients often complained of pain during erection. our finding is interesting because until now, there has been no established biomarker for distinguishing the active and chronic phases of peyronie's disease. so, this finding looked promising, especially in managing peyronie's disease. neutrophils naturally produce many inflammatory agents, such as myeloperoxidase which can cause injury (18). in comparison, lymphocytes are blood components that regulate the number of neutrophils (19). on the other hand, platelets play a role in forming fibrin, commonly found in cases of peyronie's disease because of injury and inflammation. fibrin is also a chemoattractant against macrophages, neutrophils, and fibroblasts (20). then leukocyte and macrophage influx will accumulate and are difficult to degrade, resulting in the production of fiber and collagen (21). this mechanism was in line with the results of this study, showing that nlr and plr were increased in the acute phase because the inflammatory process was still massive. a limitation could be that, in the case of ed evaluation, although the number of studies is quite large, surprisingly 7 out of 8 studies were conducted in turkey. the diversity of study locations is essential to add to the strength of the study's results. in addition, it was clear that there were significant differences between the ed and control groups. still, the differences between the degrees of ed were difficult to assess due to data limitations. it is recommended that an analysis should be carried out to explain that the role of inflammation is different in each degree of ed. as for peyronie's disease, the number of studies is still minimal. however, this was an excellent start to explain that the active phase of this disease showed ongoing inflammatory activity. so, this can be used as a predictor or even as a consideration in management. in addition, existing studies only compared subjects with peyronie's disease of different degrees, not with healthy controls. in addition, in the case of either ed or peyronie's disease, it is crucial to design a cohort study to evaluate nlr and plr according to disease progression in order to show if determination of nlr and plr is not only an independent risk factor but can also be a prognostic factor. conclusions this meta-analysis found that nlr and plr, as markers of inflammation, were significantly different in the ed and control groups. the same finding was also obtained when tested on pd cases in different phase of the disease. this significant finding indicates that the inflammatory process is ongoing in both diseases. this can be the basis for this disease's diagnosis, treatment, and prognosis. however, it cannot be denied that the number of studies and the diversity of the population involved in this study are still small. references 1. sivritepe r, uçak basat s, baygul a, küçük ev. the effect of interleukin-6 level at the time of hospitalisation on erectile functions in hospitalised patients with covid-19. andrologia. 2022; 54:e14285. 2. erdogan a, keskin e, sambel m. red blood cell distribution width values in erectile dysfunction. rev int androl [internet]. 2022; 20:24-30. 3. karabakan m, bozkurt a. relationship between erectile dysfunction, the neutrophil-to-lymphocyte ratio, and the plateletto-lymphocyte ratio. j acad res med. 2019; 9:27-31. 4. zhang y, feng x, wu x, et al. a systematic review and metaanalysis of the relationship between erectile dysfunction and the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. andrologia. 2022; 54:1-13. 5. liao z, tang y, li x, li d. the relationship between hematologic parameters and erectile dysfunction. sex med [internet]. 2021; 9:100401. 6. sambel m, kilic m, demirbas m, et al. relationship between erectile dysfunction and the neutrophil to lymphocyte and platelet to lymphocyte ratios. int j impot res. 2018; 30:27-35. 7. garcia rojo e, garcía gómez b, santos-pérez de la blanca r, et al. role of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in peyronie's disease: a new diagnostic approach to predict the stage of the disease? asian j androl. 2021; 23:325-329. 8. langston jp, carson cc 3rd. peyronie disease: plication or grafting. the urologic clinics of north america. 2011; 38:207-216. 9. greenberg jw, kim j, pincus j, et al. are neutrophil-lymphocyte and platelet-lymphocyte ratios useful for determining active phase of peyronie’s disease? journal of clinical urology. 2022; 0(0). doi:10.1177/20514158221094636 10. özbir s, degirmentepe rb, atalay ha, et al. the role of inflamarchivio italiano di urologia e andrologia 2023; 95, 1 c. pakpahan, i. ilhamsyah, s. supardi, p. narulita, a. agustinus, d. darmadi matory parameters (neutrophil-to-lymphocyte ratio, platelet-tolymphocyte ratio, and monocyte-to-eosinophil ratio) in patients with peyronie’s disease. andrology. 2020; 8:348-52. 11. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021; 372:n71. 12. wells ga, o’connell d, peterson j, et al. newcastle-ottawa quality assessment scale. ottawa hosp res institute,. 2014; (3):2-4. 13. demirci a, ozgur bc. the effect of using tadalafil 5 mg/day on neutrophil-lymphocyte and platelet-lymphocyte ratios in mild-medium and severe erectile dysfunction patients; and comparison of clinical response. andrologia. 2019; 51:1-7. 14. demirci a, ozgur bc, tuncer sç. comparison of hormone profile and systemic inflammation in patients presenting with sexual dysfunction: which is important? rev int androl. 2021; 19:242-8. 15. akbas a, gulpinar mt, sancak eb, et al. the relationship between platelet-lymphocyte ratio and severity of erectile dysfunction. kaohsiung j med sci. 2016; 32:91-5. 16. aslan a, kaya y, cirakoglu a, et al. neutrophil-lymphocyte ratio could be a marker for erectile dysfunction. urol j. 2019; 16:216-220. 17. de rose af, mantica g, bocca b, et al. supporting the role of penile trauma and micro-trauma in the etiology of peyronie's disease. prospective observational study using the electronic microscope to examine two types of plaques. aging male. 2020; 23:740-745. 18. nishida y, hosomi s, yamagami h, et al. neutrophil-tolymphocyte ratio for predicting loss of response to infliximab in ulcerative colitis. plos one. 2017; 12:e0169845. 19. zhang jh, ferrante a, arrigo ap, dayer jm. neutrophil stimulation and priming by direct contact with activated human t lymphocytes. j immunol. 1992; 148:177-81. 20. devine cjj, somers kd, jordan sg, schlossberg sm. proposal: trauma as the cause of the peyronie’s lesion. j urol. 1997; 157:285-90. 21. el-sakka ai, salabas e, dinçer m, kadioglu a. the pathophysiology of peyronie’s disease. arab j urol. 2013; 11:272-7. correspondence cennikon pakpahan, md cennikon.pakpahan@fk.unair.ac.id ilhamsyah ilhamsyah, md ilhamsyah-2021@fk.unair.ac.id supardi supardi, md supardi.unair@gmail.com pety narulita, md petty.narulita@gmail.com agustinus agustinus, md agustinus27@fk.unair.ac.id andrology study program, department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia darmadi darmadi, md darmadi@usu.ac.id department of internal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12894 1 original paper ciated condition found in hypospadias, mostly the proximal type, which is the proximal part of urethral folds that were fused incompletely and left an opening in the ventral penis in males (2, 3). chordee may arise from the inadequacy or disorder of the dartos fascia, on the ventral side of the penis. the severity of the chordee may be associated with the degree of dartos fascia abnormality (4). in hypospadias patients, the composition of the extracellular matrix (ecm) was varied and different compared to the non-hypospadias patients, in which the main components are collagens, elastic fibers, and proteoglycans/glycosaminoglycans (gags). these composition changes might contribute to the thickening and stiffness of the tissue. a previous study reported that the dartos fascia in hypospadias had thicker collagen fibers than a normal penis (5). to the best of our knowledge, there is no study reporting if there is any correlation between the degree of collagen thickness and the severity of the fibrotic condition of dartos fascia to the severity of ventral curvature. therefore, this study aimed to compare the degree of collagen thickness and the severity of the fibrotic condition to the severity of ventral curvature in hypospadias. materials and methods a cross-sectional analytical study was performed on 100 hypospadias patients with various degrees of chordee who underwent urethroplasty between 2020 and 2022. patients were differentiated into two groups based on the severity of penile curvature degree, namely mild to moderate (< 60 degrees) and severe (> 60 degrees). the penile curvature degree was measured, twice at least, using a goniometer intraoperatively before performing urethroplasty and a single surgeon (gwkd) performed urethroplasty for this study. excision of ventral dartos fascia, including tunica albuginea, which manifests as chordee, was performed during surgery with a u-shape incision, which was a wide excision of urethra of about 8 mm in length, which started at 2 mm from proximal tip of urethral meatus to 2 mm from distal urethral meatus. these tissues were sent to the pathology laboratory to assess the fibrotic and collagen density conditions. patients who underwent re-urethropurpose: hypospadias, one of the congenital anomalies commonly associated with some degrees of ventral penile curvature that may arise from malformation of dartos fascia, the chordee. our study aims to determine the correlation between the histopathology properties of dartos fascia and the severity of ventral penile curvature in hypospadias. materials and methods: one hundred hypospadias patients with various degrees of ventral penile curvature were included in this cross-sectional analytical study from 2020 to 2022. during hypospadias repair, ventral dartos fascia was excised and analyzed for the degree of collagen thickness and the severity of the fibrotic condition. results: out of 100 patients, the mean age was 6.58 + 4.28 years, who were classified as mild to moderate (66%) and severe (34%) ventral curvature cases. the analyses showed significant differences in the severity of fibrotic condition and collagen thickness of dartos fascia to the severity of penile ventral curvature with p-values of 0.002 and 0.017, respectively. conclusions: the difference in histopathology properties of dartos fascia may affect the severity of penile curvature in hypospadias patients. key words: hypospadias; chordee; penile curvature; collagen; fibrotic. submitted 2 august 2024; accepted 12 october 2024 introduction hypospadias is a congenital anomaly found in children characterized by an abnormal location of urethral opening on the ventral side of the penis. the incidence of hypospadias varies around the world, with a prevalence of about 1 case in every 250 male newborn babies. this malformation is caused by abnormal development of the ventral side of the penis, hence an abnormal proximal position of the urethral opening (1). the abnormality has been classified into several categories. based on the position of the urethral opening, hypospadias can be differentiated into proximal and distal types. ventral curvature, the chordee, is another assocorrelation between histopathology properties of dartos tissue and the severity of penile curvature in hypospadias gede w.k. duarsa 1, pande m.w. tirtayasa 2, ni wayan winarti 3, andy michael 4, komang h.a. duarsa 5 1 department of urology, faculty of medicine universitas udayana/prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia; 2 department of urology, faculty of medicine universitas udayana/universitas udayana teaching hospital, denpasar, indonesia; 3 department of pathology anatomy, faculty of medicine universitas udayana/prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia; 4 department of surgery, faculty of medicine universitas udayana/prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia; 5 medical doctor study program, faculty of medicine universitas udayana, denpasar, indonesia. doi: 10.4081/aiua.2024.12894 summary archivio italiano di urologia e andrologia 2024; 96(4):12894 g.w.k. duarsa, p.m.w. tirtayasa, n. wayan winarti, et al. 2 plasty due to a failed previous operation were excluded. the study has been approved by the research ethics committee of the faculty of medicine, universitas udayana, prof. i.g.n.g. ngoerah general hospital, denpasar with no. 2773/un14.2.2vii.14/ lt/2022, and written informed consent has been acquired from the parents. the staining and evaluation of dartos specimens were conducted by a single pathologist (nww) without prior information regarding the clinical condition of patients. the masson’s trichrome (mst) and hematoxylin and eosin (h&e) staining were performed to assess the collagen fibers thickness and the severity of the fibrosis, respectively. the images were then enlarged 200 times and five random points were marked to evaluate the specimen thoroughly. regarding the thickness of collagen, patients were divided into two groups: thin to moderate and thick. moreover, patients were also assigned into two groups in terms of the severity of fibrotic conditions, namely mild to moderate and severe. the cut-off points of thin to moderate and thick/severe are below or above 60% per high power field (hpf) for both variables. these percentages were obtained by dividing the area occupied by collagen by the area of the entire high power field. the chi-square and the alternative fisher’s exact tests were used to analyze the relationship between the severity of chordee and collagen thickness and fibrotic severity on dartos tissue. p-value < 0.05 was considered statistically significant. results the characteristics of all patients in our institution are shown in table 1. the mean age of 100 patients was 6.58 + 4.28 years and they were classified into mild to moderate (66%) and severe (34%) ventral curvature cases. moreover, in terms of collagen thickness of dartos fascia, there were 76% and 24% cases with thin to moderate and thick collagen density, respectively. in addition, 87% and 13% of patients suffered from mild to moderate and severe fibrotic conditions of their dartos fascia, respectively. representation of thin to moderate and thick collagen density as well as mild to moderate and severe fibrosis, shown in figure 1. the analyses showed significant differences in the severity of fibrotic and collagen thickness of dartos fascia to the severity of ventral curvature with p-values of 0.002 and 0.017 respectively, shown in table 2. discussion a previous study revealed that the number collagen fibers of dartos fascia was significantly lower but the fibers were thicker in hypospadias compared to normal penis. moreover, the reticulin to total collagen ratio was higher in hypospadias compared to normal penis. reticulin, a type iii collagen fibers, was found to increase during early stage of life and early healing condition (6). at the molecular level, yuri et al. showed the downregulation of several types of collagen gene expressions compared to normal patients. col1a1 and col6a1 were also significantly downregulated in the moderate and severe chordee table 2. analysis of collagen thickness and fibrotic severity on ventral curvature. variable ventral curvature degree p-value mild-moderate severe fibrotic severity of dartos fascia mild-moderate 61 26 0.002 * severe 5 8 collagen thickness of dartos fascia thin-moderate 55 21 0.017 ** thick 11 13 *: significant result (fisher’s exact test); **: significant result (chi-square test). table 1. characteristics of all patients. variable hypospadias patients (n = 100) mean age (year + sd) 6.58 + 4.28 ventral curvature, n (%) mild-moderate 66 (66) severe 34 (34) fibrotic severity of dartos fascia, n (%) mild-moderate 87 (87) severe 13 (13) collagen thickness of dartos fascia, n (%) thin-moderate 76 (76) thick 24 (24) figure 1. the mst staining of collagen fibers (200x), the green arrow points to the thin to moderate collagen fibers in figure (a) and thick collagen fibers in figure (b). the h&e staining of fibrotic changes (200x), the green arrow points to the mild to moderate fibrosis in figure (c) and severe fibrosis in figure (d). archivio italiano di urologia e andrologia 2024; 96(4):12894 3 histopathology related to penile curvature in hypospadias groups compared to the mild chordee groups, with p-values of 0.003 and 0.037, respectively (7, 8). therefore, we assessed the thickness of collagen fibers in hypospadias in several degrees of ventral curvature. our study reported that collagen fibers of dartos fascia in hypospadias were significantly thicker in severe compared to mild to moderate ventral curvature. as far as we know, this is the first study comparing the histopathology aspect of dartos fascia in various degrees of ventral curvature of hypospadias. fibrotic tissue leads to thickening and scarring of the tissue it affects (9, 10). fibrotic tissue is a collection of extracellular matrix (ecm) and it may appear in various degree of elasticity and thickness that depends on its properties of collagen and elastin (11). fibrosis is known as a disproportionate development of connective tissue that disrupts the structure and function of any tissue (12). chordee exists due to the fibrosis of dartos fascia that results in elasticity disruption and leads to penile bending (13). moreover, we reported the distinction of dartos fascia properties in various degrees of ventral curvature of hypospadias patients, especially in collagen thickness and fibrosis severity. the more severe ventral curvature degree patients suffered, the more severe and thicker the fibrotic condition and collagen thickness they would have. hypospadias patients with severe ventral curvature had more abnormal and inelastic dartos fascia tissue that led to more severe ventral bending of the penile. histopathology study on the hypospadias urethral plate revealed the characteristic of well-built connective tissue with adequate vascularization and no signs of fibrosis on the urethral plate (14). moreover, there was no difference in collagen density in patients with hypospadias compared to the normal patient (15). however, the readouts of our study are different from those of previous studies. previous studies evaluated the histopathology of the urethral plate, on the other hand, our study assessed the histopathology of the dartos fascia especially taken from the ventral side of the penile. in the current literature, there are no guidelines about the definition of collagen fiber thickness and fibrotic changes in micrometers, which might be a potential bias due to tissue sampling and handling for microscope analysis differences in size. several pieces of literature have reported the abnormality of dartos fascia in hypospadias, buried penis and also in epispadias cases (3, 16). atmoko et al. showed a reduction of total collagen to elastin and also an increased ratio of reticulin fibers in dartos fascia of hypospadias and buried penis (3). moreover, there were thicker collagen and abnormal smooth muscle action distribution in hypospadias and buried penis compared to normal penile (3, 16). to the best of our knowledge, this is the first study to compare the histopathology of dartos fascia based on the severity of ventral curvature in hypospadias patients. this study showed that severe ventral curvature is correlated with thicker collagen fibers and more severe fibrosis condition of dartos fascia compared with mild to moderate ventral curvature in hypospadias patients. a more progressive excision of the chordee is warranted in severe ventral curvature penile during hypospadias repair. in fact, total excision of the chordee is mandatory during urethroplasty regardless of the degree of penile curvature as this is an abnormal tissue. leaving even a small remnant of chordee during reconstructive surgery may increase the risk of complications following surgery (17). we realized that there was a more objective measurement of fibrosis based upon immunohistochemical staining and/or quantification of relative protein expression such as collagen types and elastin. therefore, we recommended that further study is needed to evaluate the composition of collagen in dartos fascia based on the severity of chordee using an electron microscope with specific immunohistochemical staining. since we did not focus on and discuss the surgical outcomes in our study, we also recommended further study to assess the complication post-surgical to evaluate the outcome, which is not only studies at the protein level and molecular studies conclusions there is a difference in the properties of dartos fascia in severe ventral curvature compared with mild to moderate ventral curvature of hypospadias patients, especially in the thickness of collagen fibers and severity of the fibrotic condition. the difference in histopathology properties of dartos fascia may affect the severity of penile curvature in hypospadias patients. references 1. waterloos m, hoebeke p, spinoit af. hypospadias variants. in: congenital anomalies of the penis. berlin: springer; 2017. 2. palmer ls, palmer js. management of abnormalities of external genitalia in boys. in: wein aj, kavoussi lr, partin aw, peters ca (eds.) campbell-walsh urology. 11th ed. philadelphia: elsevier ltd; 2016, pp. 3374-6. 3. abbas m, liard a, elbaz f, bachy b. outcome of surgical management of concealed penis. j pediatr urol. 2007; 3:490-4. 4. van der putte scj. hypospadias and associated penile anomalies: a histopathological study and a reconstruction of the pathogenesis. j plast reconstr aesthet surg. 2007; 60:48-60. 5. atmoko w, shalmont g, situmorang gr, et al. abnormal dartos fascia in buried penis and hypospadias: evidence from histopathology. j pediatr urol. 2018; 14:536.e1-536.e7. 6. cheng w, yan-hua r, fang-gang n, guo-an z. the content and ratio of type i and iii collagen in skin differ with age and injury. african j biotechnol. 2011; 10:2524-9. 7. yuri p, gunadi g, lestari rp, et al. the impact of col1a1 and col6a1 expression on hypospadias and penile curvature severity. bmc urol. 2020; 20:189. 8. srinivasan ak, palmer ls, palmer js. inconspicuous penis. sci world j. 2011; 11:2559-64. 9. almine jf, bax dv, mithieux sm, et al. elastin based materials. chem soc rev. 2010; 39:3371-9. 10. daamen wf, veerkamp jh, van hest jcm, van kuppevelt th. elastin as a biomaterial for tissue engineering. biomaterials. 2007; 28:4378-98. 11. neary r, watson cj, baugh ja. epigenetics and the overhealing wound: the role of dna methylation in fibrosis. fibrogenesis tissue repair. 2015; 8:1-13. archivio italiano di urologia e andrologia 2024; 96(4):12894 g.w.k. duarsa, p.m.w. tirtayasa, n. wayan winarti, et al. 4 12. karsdal ma. biochemistry of collagens, laminins and elastin structure, function and biomarkers. berlin: springer; 2016. 13. montag s, palmer ls. abnormalities of penile curvature: chordee and penile torsion. sci world j. 2011; 11:1470-8. 14. snodgrass w, patterson k, plaire jc, et al. histology of the urethral plate: implications for hypospadias repair. j urol. 2000; 164:988-90. 15. erol a, baskin ls, li yw, liu wh. anatomical studies of the urethral plate: why preservation of the urethral plate is important in hypospadias repair. bju int. 2000; 85:728-34. 16. spinoit af, van praet c, groen la, et al. congenital penile pathology is associated with abnormal development of the dartos muscle: a prospective study of primary penile surgery at a tertiary referral center. j urol. 2015; 193:1620-4. 17. halaseh sa, halaseh s, ashour m. hypospadias: a comprehensive review including its embryology, etiology and surgical techniques. cureus. 2022; 14:e27544. correspondence gede wirya kusuma duarsa (corresponding author) gwkurology@gmail.com department of urology, faculty of medicine, universitas udayana, prof. dr. i.g.n.g ngoerah general hospital, denpasar, bali, indonesia pande made wisnu tirtayasa wisnu_tirtayasa@unud.ac.id department of urology, faculty of medicine universitas udayana/ universitas udayana teaching hospital, denpasar, indonesia ni wayan winarti nw.winarti@unud.ac.id department of pathology anatomy, faculty of medicine universitas udayana/prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia andy michael andymichael91.am@gmail.com department of surgery, faculty of medicine universitas udayana/ prof. dr. i.g.n.g. ngoerah general hospital, denpasar, indonesia komang harsa abhinaya duarsa abhinaya.duarsa@gmail.com medical doctor study program, faculty of medicine universitas udayana, denpasar, indonesia conflict of interest: this study was supported by the pnbp universitas udayana funding grant 2022 no. b/78.174/un14.4/pt/01/03/2022. stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4412 original paper no conflict of interest declared. prostate (eep) intervention that is recommended by the european association of urology (eau) and american urological association (aua) as a minimal invasive treatment method regarding patients with bph independently from prostate sizes (but especially prostates with volume greater than 80 ml) (5, 6). holep is thus often considered as a “new gold standard” by several authors, however, in many centers, holep has not yet replaced turp and op (7) because holep is considered as a more difficult and lengthy procedure and learning curve has been pointed out as a limitation for a high diffusion of this surgical technique already described 15 years ago (8, 9). therefore, the prolonged learning curve has slowed acceptance of the procedure in the urological community (10). there is some literature about the learning curve of holep (10, 11), but this is the first learning curve analysis in turkey. the aim of our study is to examine the learning curve of this surgery and to discuss our results in the light of the literature. material and method study design and patients after our study had been approved by the ministry of health and the local ethics committee, patients to whom holep procedure was administered between march 2019 and may 2020 were analysed retrospectively. patients who had luts (lower urinary tract symptom) resistant to medical treatment and complicated bph to whom holep procedure had been administered regardless of the size of the prostate in adana city hospital urology clinic in previous approximately 1 year were analysed retrospectively. the first holep case was performed in march 2019. the surgeon who had great experience in endoscopic surgery, started to perform holep after watching videos, reading available published articles, and being an observer in 10 cases with a mentor in an external centre. no counsellor accompanied the surgeon during the cases. holep operation was performed by the same urologist on 100 patients. informed consent was obtained from all participants. all patients were evaluated preoperatively with serum prostate specific antigen (psa), haemoglobin (hb), transrectal ultrasound (trus), digital rectal examination (dre), urinalysis and international prostate symptom aim: the aim of our study is to examine the learning curve of holep and to discuss our results in the light of the literature. methods: 100 patients who had luts resistant to medical treatment and complicated bph to whom holep procedure had been administered regardless of the size of the prostate in the last 1 year were analysed retrospectively. to evaluate the learning curve, the patients were classified into 4 main groups of 25 consecutively operated patients beginning from the first case. the 4 main groups were divided into 2 subgroups including patients who had prostate volume below or above 80 grams. results: the mean age of the 100 patients who had holep was 64.5 years. the mean prostate volume was 99.1 cc (45-281 cc). when those with prostate smaller than 80 g are examined, enucleation efficiency was 0.76 g/min (0.46-0.97 g/min) and morcellation efficiency was 3.07 g/min (3.34-4 g/min). when those with prostates larger than 80 g are examined, enucleation efficiency was 0.89 g/min (0.66-1.04 g/min) and morcellation efficiency was 4.01 g/min (3.93-4.25 g/min). these two parameters were statistically and significantly different in all the 4 groups (p < 0.05). conclusions: holep still has a steep learning curve. it is necessary to reach the number of cases of 25-50 to reach fundamental experience. key words: holep; learning curve; luts; enucleation efficiency; morcellation efficiency. submitted 9 august 2021; accepted 10 september 2021 introduction holmium laser resection of the prostate (holep) was first described by gilling et al. in 1995 and after a few years, this technique was standardized as holep (1). the classical well-known gold standards for the surgical treatment of benign prostate hyperplasia (bph) have been op and transurethral resection of the prostate (turp) depending on prostate size (2). holep has been shown in studies to have several advantages compared to transurethral resection of the prostate (turp), including shorter hospital stay, reduced bleeding complications and absence of turp-syndrome (3). furthermore, functional outcomes of holep have been stated to be at least as good as after turp, and comparable to those obtained with open prostatectomy (op) for larger prostates (3, 4). holep is one of the most commonly used endoscopic enucleation of does holmium laser enucleation of the prostate (holep) still have a steep learning curve? our experience of 100 consecutive cases from turkey güçlü gürlen, kadir karkin department of urology, health sciences university, adana city training and research hospital, adana, turkey. doi: 10.4081/aiua.2021.4.412 summary 413archivio italiano di urologia e andrologia 2021; 93, 4 does holmium laser enucleation of the prostate (holep) still have a steep learning curve? score (ipss). uroflowmetry (ufm) was done and post-void residual urine (pvr) was measured by ultrasound. the patients who had high psa were operated one month after prostate biopsy under transrectal ultrasound guidance. the drugs of patients who were receiving antiplatelet and anticoagulant treatment were discontinued 12 hours before the operation and they were replaced with low molecular weight heparin. enucleation time and morcellation time were recorded perioperatively and the weight of the removed tissue was measured. patients with ipss ≥ 8, maximum urine flow rate (qmax) ≤ 15 ml/h, and pvr ≥ 50 ml were included in the study. on the other hand, the patients with urethral stricture, neurogenic component, prostate cancer and bladder cancer were excluded from the study. the patients were classified into 4 main groups of 25 consecutively cases beginning from the first case to determine the learning curve. group a consisted of the first 25 patients, group b consisted of the second 25 patients, group c consisted of the third 25 patients, and group d consisted of the fourth 25 patients. the 4 main groups were divided into 2 subgroups as the patients who had prostate volume below or above 80 grams. the two subgroups were statistically compared within themselves. surgical technique upon the anaesthetist’s preference, the operations were performed under general anaesthesia and spinal anaesthesia. 120w holmium: yttrium-aluminiumgarnet (versa pulse power suite, lumenis, yokneam israel), resectoscope, morcellator and display screen appropriate for 26 f holep (richard wolf gmbh, knittlingen, germany) were used during the surgery. after the surgery was completed, all tissues were examined histologically. a 22 f 3-way catheter was used in the patients and washing with continuous saline was performed until haematuria ceased. control hemogram was checked at the first postoperative day. the patient was discharged from the hospital after the catheter was removed and micturition was performed after the end of haematuria of the patient. postoperative follow-up ipss, ufm, pvr, and quality of life (qol) were checked during followup at 1st, 3rd, and 6th month postoperatively, and serum psa and postoperative trus measurements were performed at 3rd month. postoperative complications were graded using the clavien-dindo classification (12). continence status and post micturition symptoms (pms) were evaluated according to the standards which are recommended by the international continence society (ics) (13). statistical evaluation spss (statistical package for the social sciences) 23.0 (ibm, armonk, ny) package program was used for statistical analysis of the data. categorical measurements were reported as numbers and percentages, and continuous measurements as mean and standard deviation (median and minimum-maximum where needed). shapiro-wilk test was used to determine whether the parameters in the study showed a normal distribution or not. the kruskal wallis test was used in the analysis of more than two groups. bonferroni method, which is one of the post hoc analysis methods, was used to determine the source of the difference between the groups. statistical significance level was taken as 0.05 in all tests. results the mean age of 100 patients who had holep was 64.5 years. the mean prostate volume was 99.1 cc (45-281 table 1. patient demographics and perioperative results. < 80 g > 80 g group a group b group c group d group a group b group c group d n n n n n n n n 12 10 12 11 13 15 13 14 mean age (years) 68.1 63.5 61.6 65.2 64.3 65.4 61.6 66.4 p .101 .232 mean psa (ng/ml) 3.6 2.4 3 2.8 9.8 8.35 7.8 9.02 p .851 .977 mean prostate volume (ml) 64 63.1 59.7 65 131.3 116.5 143.8 125.7 p .741 .522 enucleation time (min) 103.3 60.5 54.1 48.2 156.9 108.6 125.7 93.5 p < .001 .001 post hoc p a-b; p < .001 a-b; p = .005 a-c; p < .001 a-d; p < .001 a-d; p < .001 morcellation time (min) 14.3 13 11.6 11.8 26.7 26.3 28.6 23.9 p < .001 .168 post hoc p a-c; p < .001 a-d; p < .001 b-d; p = .005 amount of removed tissue (gr) 47.8 48.5 46.2 47.2 105 100.6 119 97.5 p .874 .654 enucleation efficiency (g/min) 0.46 0.8 0.85 0.97 0.66 0.92 0.94 1.04 p < .001 < .001 post hoc p b-a; p < .001 b-a; p = .003 c-a; p < .001 c-a; p = .002 d-a; p < .001 d-a; p < .001 d-b; p = .043 morcellation efficiency (g/min) 3.34 3.73 3.98 4 3.93 3.82 4.25 4.07 p < .001 0.040 post hoc p c-a; p = .003 c-b; p = .026 d-a; p < .001 d-b; p = .003 loss of haematocrit 4.2 3.7 3.5 2.5 5.8 4.7 4.1 3.5 p .615 .907 length of hospitalization (day) 2.08 2.2 1.7 1.8 3.5 2.7 2.61 2.14 p .275 .333 length of removing (hour) 34.8 30.2 27.8 25.6 62.6 45.3 43.6 31.8 p .037 .024 post hoc p a-d; p = .044 a-d; p = .012 p < 0.05; kruskal wallis test. post hoc bonferroni analysis; psa: prostate-specific antigen. the efficiency of each procedure was calculated as weight of removed tissue in g/min. archivio italiano di urologia e andrologia 2021; 93, 4 g. gürlen, k. karkin 414 cc). patients with prostate smaller than 80 g were 45% of all patients. when these patients were considered, it is seen that there was no significant difference (p > 0.05) between mean age (p = .101), psa (p = .851), prostate volume (p = .741), hematocrit loss (p=.615), and hospital stay (p = .275) of the patients in four groups (a, b, c, d). enucleation time and morcellation time were statistically different between the groups (p < .05). the two most important parameters of the learning curve, enucleation efficiency and morcellation efficiency were 0.76 g/min (0.46-0.97 g/min) and 3.07 g/min (3.34-4 g/min), respectively. these two parameters were statistically and significantly different in all 4 groups (p < .05). catheter removal time was also statistically different between the groups (p < .05) (table 1 and figure 1). the patients with prostates larger than 80 g were 55% of all patients. when these patients were considered, it was seen that there was no significant difference (p > .05) with respect of mean age (p = .232), psa (p = .977), prostate volume (p = .522), morcellation time (p = .168), amount of tissue removed (p = 0.654), hematocrit loss (p = .907), and length of hospital stay (days) (p = .333) between patients of four groups (a, b, c, d). enucleation efficiency was 0.89 g/min (0.66-1.04 g/min) and morcellation efficiency was 4.01 g/min (3.93-4.25 g/min). there was a statistically significant difference between the groups in terms of enucleation time, enucleation efficiency and morcellation efficiency (p < .05). therefore, when all groups were considered, it was seen that the enucleation efficiency and morcellation efficiency were the highest in cases from 25th to 50th, although there was a further improvement even in the cases from 75th to 100th (table 1 and figure 2). clavien grade 1 and grade 2 complications were observed in 19 cases in group a, in 16 cases in group b, in 5 case in group c and in 4 cases in group d. the most common complication was capsular perforation and it was seen in 16 (16%) patients. in the first 25 cases, 10 capsule perforations occurred although they were usually minimal. clavien grade 3 complication was seen in 9 cases in figure 1. the difference between enucleation efficiency ve morcellation efficiency in 4 groups at < 80 g prostate volume. * enucleation efficiency [weight of enucleated tissue/lasing time (g/min)) and morcellation efficiency (weight of enucleated tissue/morcellation time (g/min)]. figure 2. the difference between enucleation efficiency ve morcellation efficiency in group d at > 80 g prostate volume. * enucleation efficiency [weight of enucleated tissue/lasing time (g/min)) and morcellation efficiency (weight of 415archivio italiano di urologia e andrologia 2021; 93, 4 does holmium laser enucleation of the prostate (holep) still have a steep learning curve? group a, two in group b, and two in group c, and none in group d. no clavien grade 4 or 5 complications were seen in any group. complication rates were found to be very low and stable between 50th and 75th case, while grade 3, 4 and 5 complications were not seen between 75th and 100th case (table 2). discussion when holep technique is compared with turp and op, it can be observed that it has superior haemostatic characteristics, lower morbidity and more efficiency. furthermore, global costs of holep are comparable to those of turp and proved to be a strong competitor of op. on the other hand, the most important disadvantage of the holep technique is that it is difficult to learn it. a significantly longer adaptation time is required especially for novice surgeons when compared to turp. it requires considerable experience to determine the surgical border between prostate adenoma and prostate capsule particularly for holep. it is assumed that such a good method is still not globally adopted as the gold standard treatment and it is seen as an alternative to turp and open prostatectomy according to the guidelines, because it is difficult to learn and has complications occurring during the learning curve (14-16). both intraoperative and postoperative data are important for evaluating the learning curve of holep. the indicators of surgical activity are enucleation efficiency (weight of enucleated tissue/lasing time) and morcellation efficiency (weight of enucleated tissue/morcellation time). these two indicators of operative efficiency have been used in various previous learning curve studies as a primary outcome measure (10, 11). in a systematic review which went over 24 studies, it was reported that only 4 authors of these 24 studies did not provide any recommendations about the number of cases which was required to complete the learning curve of holep. besides, it was recommended in the 20 studies that the number of cases ranged between 20 and 60 (20-30 most commonly). in addition, it was determined that the number of cases was less than 20 in only 2 studies (17). shah et al. found out in their prospective series that the operator became a master at holep after an average of 20 cases. however, this study was limited to small prostates. it was reported that additional learning is required to pass on to large prostate volume from small prostate volume (10). seki et al. found the mean enucleation efficiency to be 0.29 and 0.75 gm/m in the first 10 and the last 10 cases of a total of 70 cases, respectively (11). similarly, placer et al. divided their series of 125 cases into subgroups of 25 consecutive patients each, showing that the efficiency of enucleation and morcellation increased with the number of procedures (9). brunckhurst et al. reported a steep increase in performance in the first 20-30 cases and a plateau occurring following the first 50-60 cases but they added that there were improvements and variability in efficiency even after 150 cases (18). moreover, du et al. showed that enucleation efficiency increases with years of experience and is most encountered in men with a large prostate > 100 g (19). bae j et al. showed in their study with 161 cases, that the enucleation efficiency increased significantly after a minimum of 30 cases (20). jeong et al. found that enucleation efficiency increased in the first 50 cases and there was a strong linear correlation with total prostate volume. perioperative clinical variables, including enucleation time, morcellation time, enucleation ratio (enucleation weight/transitional zone volume), enucleation efficacy (enucleated weight/enucleation time), enucleation ratio efficacy (enucleation ratio/enucleation time), and early complication rate were analysed. they evaluated the enucleation ratio efficacy by dividing the enucleation ratio (enucleation weight/transitional zone volume) by enucleation time. they suggested that this new parameter might remove the confounding effect of prostate size resulting from enucleation efficiency. this parameter became stable after 25 cases, and the authors interpreted that this number was also consistent with the surgeon's confidence in performing holep (21). similarly, kim et al. proposed the enucleation time-energy efficacy, defined as enucleated weight/enucleation time/consumed energy. in their studies, this parameter continued to improve after 30 cases and it become stable between 60th and 70th cases (22). elzayat et al. reported that best enucleation efficiency was reached after about 20-30 cases (8). in both two subgroups in our study, enucleation efficiency displayed a statistically significant steep curve after the first 25 cases and enucleation efficiency increased in parallel with case experience in line with the literature. morcellation efficiency is also an important indicthator table 2. intraoperative and postoperative complications. < 80 g > 80 g group a group b group c group d < 80 g > 80 g < 80 g > 80 g < 80 g > 80 g < 80 g > 80 g capsule perforation (clavien 1) 3 7 1 4 1 returning to turp or op (clavien 3) 3 not being able to proceed to morcellation due to bleeding (clavien 3) 1 2 1 leaving the case into the second session (clavien 3) 2 1 bladder injury (clavien 1) 1 1 1 ureteral orifice injury (clavien 1) 2 blood transfussion (clavien 2) re-catheterization (clavien 1) 2 urinary system infection (clavien 2) 1 1 early period stress incontinence (clavien 1) 3 5 2 4 2 2 1 2 late period urinary incontinence (clavien 2-3) urethral stricture (clavien 3) 1 1 1 archivio italiano di urologia e andrologia 2021; 93, 4 g. gürlen, k. karkin 416 for the learning curve. learning morcellation is relatively easier than learning enucleation. however, it has been reported in some publications that morcellation causes serious morbidities such as bladder injury at a rate of 18% (23-10) although it seems easier (23-10). brunckhurst et al. showed that morcellation increased its efficiency after 40-60 cases (18). soto et al. reported that morcellation efficiency increased statistically after the 50th case without mentor (24). in our study, morcellation efficiency increased significantly especially after the first 25 cases. it was seen that morcellation performance developed as the case experience increased. however, enucleation efficiency and morcellation efficiency require similar number of cases although morcellation is easier to learn than enucleation (25 cases). we explain this situation as the fact that haematuria, which occurs as a result of poor enucleation in the first 25 cases, affects the image quality, and the surgeon wants to work slowly and in a controlled manner as he fears of bladder injury during morcellation. perioperative complications can also be a reference for the learning curve. capsular perforation and superficial bladder mucosal injury have been shown to be the most common complications in the intraoperative period. the most comprehensive study on this subject was conducted by kendidra et al. the complications of 280 patients were evaluated and it was reported that the most common perioperative complication was capsular perforation with 9.6% and the second most common perioperative complication was superficial bladder mucosal injury and ureter orifice injury (10). accordingly, it is important to recognize the capsule in this operation both in terms of facilitating enucleation and being able to control bleeding more easily. it should be kept in mind by the surgeon that the prostate capsule in small prostates is not clearly separated and the prostate capsule has too many vascular networks in large prostates. in our study, we did not experience any capsule perforation in 10 patients (40%) in group a, 5 patients (20%) in group b, 1 patient (4%) in group c and none in group d. perforations were minimal except for 3 patients in the first group and the catheter was kept for one more day in these patients. it was returned to open surgery during the operation (clavien 3) in 3 patients because of large perforation area and the catheter was kept longer. we assumed that having such high capsule perforation rate especially in the first cases resulted from the lack of a mentor during learning. one of the perioperative complications is returning to turp or op. in their series of 146 cases, kobayashi et al. reported that it was returned to turp in only 12 cases in their series of 146 cases, and the main reason for this was capsular perforation or uncontrolled bleeding (25). however, it was reported in the study of bapat et al. that it was returned to standard turp in the first 13 cases (26). on the contrary to these two studies, jeong et al. reported that it was not returned to turp in any of the cases despite having no mentoring (21). in our study, it was returned to turp/op during the operation in 3 cases which had prostate volume of > 80 g in the first 25 cases. postoperative complications can also affect the learning curve. especially stress urinary incontinence (sui) is one of the postoperative complications that surgeons feel more anxious. urologists feel serious stress and the learning curve is prolonged due to the fear of causing a sphincteric insufficiency to the patient, due to sphincteric injury in case of long duration procedure, as well as excessive stretching of the anterior of the external sphincter during enucleation of the prostate at 12 o’clock and thermal injury due to use of laser near the sphincter. placer et al. found that transient urinary incontinence, persistent stress urinary incontinence (lasting longer than 6 months), and storage symptoms were observed more commonly in the first 50 cases (9). lerner et al. evaluated stress urinary incontinence (sui) at 3 months in the early postoperative period during a single surgeon's learning curve and found out that sui was more common when time intervals between the cases were longer (27). shigemura et al. found that the experience with at least 20 cases significantly affected urinary incontinence (28). in another study, patients with enucleated prostate volume > 50 g and blood loss > 2.5 g/dl were associated with sui (26). kim et al. found that 11% of the patients had urge incontinence after the urethral catheters were removed after surgery (22). in our study, 8 (32%) of the first 25 cases had sui in the first 3 months, and trend continued at a diminishing pace after 25 cases. none of sui stayed permanent and all the cases returned to normal within 3 months. in this study, we compared the results of 100 consecutive cases of a single surgeon without a mentor with the literature. our results were comparable with the literature in terms of learning curve, perioperative and postoperative outcomes, as well as functional outcomes and continence status. our study has also some limitations. it reflects the results of only one centre and includes a limited number of patients. another limitation is that it presents the experience of a single surgeon, so the results could be not reproducible by another surgeon with similar experience. in conclusion, this is the first study which focused on the learning curve in turkey, to the best of our knowledge. the holep technique still has a steep learning curve, and we predict that a surgeon should perform between 25-50 cases to reach the necessary experience. in addition, we believe a surgeon could cope with holep technique without a mentor or simulation-based training. conclusions holep still has a steep learning curve. it is necessary to reach a number of cases of 25-50 to reach fundamental experience. moreover, it can be coped with holep without having a mentor. references 1. gilling pj, kennett k, das ak, et al. holmium laser enucleation of the prostate (holep) combined with transurethral tissue morcellation: an update on the early clinical experience. j endourol. 1998; 12:457-9. 2. mcvary kt, roehrborn cg, avins al, et al. update on aua guideline on the management of benign prostatic hyperplasia. j urol. 2011; 185:1793-803. 3. cornu jn, ahyai s, bachmann a, et al. a systematic review and 417archivio italiano di urologia e andrologia 2021; 93, 4 does holmium laser enucleation of the prostate (holep) still have a steep learning curve? meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary 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prostate: a single-center experience. korean j urol. 2010; 51:688-693. 21. jeong cw, oh jk, cho mc, et al. enucleation ratio efficacy might be a better predictor to assess learning curve of holmium laser enucleation of the prostate. int braz j urol. 2012; 38:362-371. 22. kim kh, kim kt, oh jk, et al. enucleated weight/enucleation time, is it appropriate for estimating enucleation skills for holmium laser enucleation of the prostate? a consideration of energy consumption. world j mens health. 2018; 36:79-86. 23. montorsi f, naspro r, salonia a, et al. holmium laser enucleation versus transurethral resection of the prostate: results from a 2center prospective randomized trial in patients with obstructive benign prostatic hyperplasia. j urol. 2008; 179(5 suppl):s87-90. 24. soto-mesa d, amorin-diaz m, perez-arviza l, et al. holmium laser enucleation of the prostate and retropubic prostatic adenomectomy: morbidity analysis and anesthesia considerations. actas urol esp. 2015; 39:535-545. 25. kobayashi s, yano m, nakayama t, kitahara s. predictive risk factors of postoperative urinary incontinence following holmium laser enucleation of the prostate during the initial learning period. int braz j urol. 2016; 42:740-746. 26. bapat s, pai k, purnapatre s, et al. holmium laser assisted 'anatomical' enucleation of adenoma of benign hyperplasia of prostate. indian j urol. 2006; 22:49-52. 27. lerner lb, tyson md, mendoza pj. stress incontinence during the learning curve of holmium laser enucleation of the prostate. j endourol. 2010; 24:1655-1658. 28. shigemura k, yamamichi f, kitagawa k, et al. does surgeon experience affect operative time, adverse events and continence outcomes in holmium laser enucleation of the prostate? a review of more than 1,000 cases. j urol. 2017; 198:663-670. correspondence kadir karkin, md kadir_karkin@msn.com güçlü gürlen, md guclugurlen@hotmail.com health sciences university, adana city training and research hospital, department of urology, 01330, adana, turkey stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12956 1 case series inevitably causes various types of penile deformation. its prevalence ranges from 3.2% to 13.1% and is less common in asian countries (0.6-5.0%) and among populations of black african descent (0.1-3.5%) (1-8). pd typically affects middle-aged men, but cases have increased among younger patients in recent years. in 2001, two authors reported the prevalence of pd in young people under the age of 40 as 1.5% and 4.8% (2, 9). some authors have noted an increase in the incidence of pd in younger patients, with their study showing an 18.6% incidence in individuals under 40 compared with the 24.2% incidence found in our most recent study (10, 11). pd symptoms include penile deformity (in more than 90% of cases), penile pain (in between 20% and 70% of cases), erectile dysfunction (in over 30% of cases), and psychological distress, such as anxiety and depression (in approximately 48% of cases) (12, 13). penile deformities can manifest as curvature, shortening, twisting, indentations, hourglass deformities, and in more severe cases, "flail penis". traumatic theory appears to be the most widely accepted of the several etiopathogenetic hypotheses. according to this theory, the local accumulation of fibrin resulting from trauma (whether microor macro-trauma) is believed to initiate the disease process by triggering the production of free radicals (oxidative stress) and fibrogenic cytokines, leading to excessive collagen production and deposition (plaque) (14-22). the disease progresses in two phases: the inflammatory ("active") phase comes first, lasting for approximately 12-18 months, during which plaque formation and remodeling occur (23-30). conservative medical therapy is recommended during this first phase. the second phase is the "stabilization" stage, wherein the disease stops progressing, the plaque stops growing, and any pain usually subsides. surgical treatment is recommended during this second phase if there is a severe penile deformity that hinders sexual intercourse or if severe erectile dysfunction is present (23, 24, 26, 27,30-34). the conservative medical treatment in the first phase of pd includes oral therapies, penile infiltrations, including vitamin e, colchicine, potaba, tamoxifen, pentoxifylline (ptx), bioactive food extracts with an antioxidant action (l-arginine, carnitine, propolis, bilberry, coenzyme q10, etc.), non-steroidal anti-inflammatory drugs (nsaids), phosphodiesterase 5 (pde-5) inhibitors, penile infiltrations (verapamil, corticosteroids, interferon-α2b (ifna2b), pentoxiintroduction: peyronie’s disease (pd) is characterized by fibrosis of the penile tunica albuginea. conservative treatment options may involve oral and/or injectable medications. materials and methods: this case series includes four patients with pd in the first phase. the diagnosis of pd included a medical history; penile palpation; a physical examination of the penis, documenting penile deformity (kelâmi method); penile dynamic doppler ultrasound (pddu) + elastography, measuring the plaque and calculating its volume (cm3), and the deformation index (strain ratio); and the completion of the following questionnaires: iief to assess erectile function, vas to assess pain, and peyronie's disease questionnaire (pdq) symptom bother to evaluate the psychosexual impact of the disease. diagnostic follow-up evaluations were conducted before and every 6-12 months throughout the conservative treatment. the four patients were treated at our andrology clinic between january 2019 and november 2023. our treatment included the following: bilberry, propolis, ginkgo biloba, silymarin, l-carnitine, coenzime q-10, boswellia, superoxide dismutase, vitamin e, vitamin c, topical diclofenac gel, propolis cream, and perilesional penile injections with pentoxifylline for cases involving penile plaques with volumes of > 0.100 cm3. results: complete resorption of the pd plaque after treatment occurred in all cases. the disappearance of peyronie's plaque occurred over a period ranging from 18 to 36 months, in relation to the volume of the plaque. conclusions: despite the limited sample size in our study, these patients verifiably achieved the complete resorption of the affected disease area. our results will provide useful insights for uroandrological clinical practice. nevertheless, randomized controlled trials with a larger number of pd patients are needed to demonstrate the effectiveness of multimodal antioxidant treatment. key words: peyronie’s disease; oxidative stress; antioxidants; pentoxifylline. submitted 26 august 2024; accepted 2 september 2024 introduction pd is a genetically based chronic inflammatory condition that affects the tunica albuginea of the penile corpora cavernosa in genetically predisposed males, leading to the formation of an inelastic and fibrous penile plaque that healing of peyronie's disease after multimodal antioxidant treatment. a case series gianni paulis 1, giovanni de giorgio 2, andrea paulis 3 1 department of urology and andrology, peyronie’s care center, castelfidardo clinical analysis center, rome, italy; 2 department of urology and andrology, section of ultrasound diagnostics, castelfidardo clinical analysis center, rome, italy; 3 bambino gesù children’s hospital, irccs (istituti di ricovero e cura a carattere scientifico), rome, italy. doi: 10.4081/aiua.2024.12956 summary archivio italiano di urologia e andrologia 2024; 96(4):12956 g. paulis, g. de giorgio, a. paulis 2 fylline (ptx), hyaluronic acid, and clostridium histolyticum collagenase (cch) (26, 33, 35-40). the physical treatment in the first phase of pd includes extracorporeal shock wave therapy (eswt), iontophoresis, and penile traction and vacuum devices (26, 33, 59, 60). surgical treatments for pd are targeted to each patient's specific needs and may include corporoplasty, with or without grafts, and the possible insertion of a penile prosthesis (28, 31, 32, 34, 36, 41). pd diagnostics involves penile palpations, photographic documentation of the deformation (according to the kelâmi guidelines), penile dynamic doppler ultrasound (pddu), and the completion of questionnaires for pain (vas), erectile function (iief), and psychometric evaluations like the peyronie's disease questionnaire (pdq) (10, 42-47). the scientific literature reports eleven human patients with pd who have recovered following medical treatment with antioxidants (48-51). cases of pd resolution have been published before, but only in experimental studies in rats (52-54). the scientific literature has always reported the possibility of the spontaneous resolution of pd (31, 55-57). however, some studies do not agree with this possibility (58-59). we believe that treating oxidative stress (a key mechanism of inflammation) with antioxidants is the best therapeutic approach to treat pd (35, 60-62). multimodal treatment aims to achieve superior outcomes compared with using a single substance or therapy alone. all the antioxidants we use have anti-inflammatory and antifibrotic properties by blocking the activity of the nf-kb factor. in our multimodal treatment, we have also used nsaid (diclofenac), although administered locally to avoid possible long-term toxic effects due to oral administration (63, 64). this case report aimed to present four cases of patients with pd who experienced plaque regression following “multimodal” antioxidant therapy (with oral antioxidants, topical diclofenac gel, and penile perilesional injections with 60 mg of pentoxifylline). our recent four articles have shown that the duration of multimodal treatment needed to regress peyronie's plaque directly depends on the plaque's size (48-51). therefore, larger plaques require a relatively longer time to completely regress. in our recent case report, a patient with pd achieved complete plaque regression in just four months of combined antioxidant therapy, as his plaque was small (51). methods this case series includes four cases of patients with pd in the first phase who experienced the plaque's disappearance following "multimodal" antioxidant therapy including various oral antioxidants, topical diclofenac gel and propolis cream, and penile perilesional injections with a potent antioxidant and antifibrotic substance, pentoxifylline, specifically for cases involving penile plaques with volumes of > 0.100 cm3. the complete list of antioxidant substances used is shown in the following tables 1, 2, 3, and 4. the diagnosis of pd included a detailed medical history; penile palpation; a physical examination of the penis, documenting penile deformity using the kelâmi method and measuring the angulation; penile dynamic doppler ultrasound (pddu) + elastography, measuring the plaque in three dimensions and calculating its volume (cm3) using the ellipsoid formula (volume = 0.524 × length × width × thickness) and the deformation index (strain ratio); and the completion of the following questionnaires: iief to assess erectile function, vas to assess pain, and the questionnaire (pdq symptom bother) to evaluate the psychosexual impact of the disease (10, 42-47, 65, 66). the strain ratio (or deformation index), indicating the plaque's stiffness was detected via echo-elastography. the strain ratio, expressed as a number, represents the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. the four patients were treated at our andrology clinic between january 2019 and november 2023. all patients signed an informed consent form for the multimodal treatment. during the consent process, patients were informed that the treatment for pd would be lengthy due to the chronic nature of the disease. the patients also agreed to the publication of their clinical data, provided that they be published anonymously. all these patients did not consent to the publication of photos of their penises, even though they would have been published anonymously. a single andrologist operator performed and assessed pddu with elastography on all patients in a single session. we used the philips hd 15 machine (washington, united states) that was later upgraded to a philips affinity 70 g (washington, united states). in each of the 4 cases described, we reported the type of ultrasound machine used. diagnostic follow-up evaluations were conducted before and approximately every 6-12 months throughout the conservative treatment. results case series presentation in each case presented, several treatment cycles combined with antioxidants were necessary before reaching complete plaque reabsorption. we describe the four individual cases in detail, with their personal clinical characteristics present before and at the end of treatment when the therapeutic goal was achieved. a table listing the individual variations obtained after each treatment cycle is included for each clinical case presentation. case 1 case 1 was a 57-year-old caucasian man, a non-smoker, suffering from chronic prostatitis, with the presence at the origin of a congenital penile curvature (dorsal of 25 degrees, left lateral of 5 degrees, and right lateral of 5 degrees), before the appearance of pd. the patient did not report any traumatic events involving his penis in the previous 6-12 months. he reported that he had started to notice a penile curvature, different from usual, approximately 6-8 months earlier. at the time of our visit, the patient did not report any penile pain (vas score = 0) nor complained of erectile dysfunction. the iief score was 26. the pdq symptom bother score was 11. in our observations, the penile deformation presented as a multiplanar curve, with a significantly reduced penile diameter in its distal third. the goniometric archivio italiano di urologia e andrologia 2024; 96(4):12956 3 multimodal antioxidant treatment of peyronie's disease table 1. case 1: clinical data collected before, during, and after antioxidant treatment. ultrasound measurements plaque strain ratio dorsal curve of 41 degrees vas iief pdq bother a right lateral curve score score score of 17 degrees, and a left lateral curve of 17 degrees basal plaque: basal plaque = 1.8 0 26 11 12.1 × 10.4 × 4.23 mm (volume = 0.279 cm3 distal plaque: distal plaque = 2.53 24.0 × 29.3 × 4.35 mm with two internal calcifications measuring 5.2 × 9.3 mm and 5.0 × 8.0 mm (volume = 1.60 cm3) total volume of the two plaques = 1.879 cm3 first cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (6 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every 2 weeks for 6 months. ultrasound measurements plaque strain ratio dorsal curve of 33 degrees vas iief pdq bother a right lateral curve score score score of 17 degrees, and a left lateral curve of 17 degrees basal plaque: basal plaque = 1.6 0 26 8 8.72 × 6.85 × 2.80 mm (volume = 0.087 cm3) distal plaque: distal plaque = 2.21 17.6 × 17.1 × 2.91 mm with internal calcification measuring 3.3 x 2.4 mm (volume = 0.458 cm3) the other internal calcification was no longer detectable the total volume of the two plaques = 0.545 cm3 after the first treatment cycle, the total volume of the two plaques decreased by 70.9% compared with the initial situation second cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 12 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 12 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every month for 12 months. ultrasound measurements plaque strain ratio dorsal curve of 33 degrees, vas iief pdq bother a right lateral curve score score score of 7 degrees, and a left lateral curve of 7 degrees basal plaque: basal plaque = 1.2 0 27 4 4.4 × 4.52 × 2.13 mm (volume = 0.022 cm3) distal plaque: distal plaque = 1.53 9.91 × 8.5 × 2.14 mm with internal calcification measuring 2.8 x 1.6 mm (volume = 0.094 cm3) total volume of the two plaques = 0.116 cm3 after the second treatment cycle, the total volume of the two plaques decreased by 93.8% compared with the initial situation third cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (18 months) + boswellia 200 mg + vitamin-c 50 mg + vitamin-e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 18 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle), 1 penile injection every 2 months for 12 months penile plaques were no longer detectable absence of non-elastic after the regression total therapy duration until plaque’s disappearance = 30 months penile areas of the plaques, the same penile congenital condition that preceded pd was present, with a dorsal curve of 10 degrees vas = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); iief = international index of erectile function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ed severity levels (no ed, score range: 26-30) (46); pdq symptom bother = pd questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). the strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). it is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. when elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. in this case, the image displayed on the ultrasound machine screen does not show any index. archivio italiano di urologia e andrologia 2024; 96(4):12956 g. paulis, g. de giorgio, a. paulis 4 measurements showed a dorsal curve of 41 degrees, a right lateral curve of 17 degrees, and a left lateral curve of 17 degrees. upon palpation, two basal and distal penile plaques of approximately 10 mm and 20 mm in length were detected, respectively, both with a fibrous consistency. two plaques were present in the penile eco-elastography examination. the first penile plaque was located in the basal third and measured 12.1 × 10.4 × 4.23 mm (volume = 0.279 cm3), while the second plaque was located in the distal third and measured 24.0 × 29.3 × 4.35 mm (volume = 1.60 cm3). two calcifications in the second plaque measured 5.2 × 9.3 mm and 5.0 × 8.0 mm. the total volume of the two plaques was 1.879 cm3. the ultrasound appearance of the basal plaque was iso-hyperechoic, and that of the distal plaque was iso-hyperechoic-calcific. the strain ratios of the two basal and distal penile plaques were 1.8 and 2.53, respectively. the cavernous arteries showed a normal arterial flow and end-diastolic velocity in the pddu examination (with a penile injection of 10 mcg of alprostadil). the patient then underwent multimodal therapy with antioxidants. the complete list of antioxidant substances in the multimodal treatment administered to the patient, alongside the pre-treatment clinical data and those related to each subsequent follow-up after the three treatment cycles, is shown in table 1. after completing the third cycle of six perilesional penile injections with 60 mg of pentoxifylline (every 2 months), the patient delayed the scheduled follow-up after 12 months and continued oral and local home therapy for an additional 6 months. the follow-up was then performed 18 months after the last check-up. images of the ultrasound examination before, during, and after treatment are presented in figure 1. after three treatment cycles, totaling 36 months of multimodal antioxidant therapy, the patient underwent a complete follow-up, and no penile nodules were palpable. no plaque was detected in the ultrasound examination. the patient did not report any penile pain (vas score = 0) nor complained of erectile dysfunction. the iief score was 27. the pdq symptom bother score was four. the patient had an excellent psychological state, and the penis's appearance was comparable to the condition before pd (congenital curvature of the penis), the patient expressed satisfaction with the excellent results achieved at the end of our treatment. case 2 a 48-year-old caucasian man, a non-smoker, reported that he had suffered from prostatitis in the past but had no related symptoms at the time of the visit. the patient reported that he already had a congenital penile curvature before the onset of pd. the congenital penile deformity consisted of a mild dorsal curvature of 10 degrees. the patient did not report any traumatic events involving his penis in the previous 612 months. he reported that he had started to notice a penile curvature, different from usual, approximately 9 months earlier. the patient did not report any penile pain (vas score = 0) nor complained of erectile dysfunction at the time of our visit. the iief score was 27. the pdq symptom bother score was 10. in our observation, the penile deformation presented with a dorsal curve of 45 degrees. upon palpation, two plaques were detected at the basal third level and the distal level of the penis, approximately 10 figure 1. images of the ultrasound exam (longitudinal and transverse scan) are shown before (a), during (b) and (c), and after multimodal treatment (d). archivio italiano di urologia e andrologia 2024; 96(4):12956 5 multimodal antioxidant treatment of peyronie's disease mm and 15 mm in length, respectively. both plaques had a fibrous consistency. two plaques were present in the penile eco-elastography examination. the first penile plaque was located at the basal third and measured 9.28 × 10.9 × 3.99 mm (volume = 0.212 cm3), while the second plaque was located in the distal third and measured 14.3 × 11.7 × 2.86 mm (volume = 0.252 cm3). the total volume of the two plaques was 0.464 cm3. the ultrasound appearance of the two plaques was iso-hyperechoic. the strain ratios of the two basal and distal penile plaques were 2.1 and 1.89, respectively. the cavernous arteries exhibited a normal arterial flow and end-diastolic velocity in the pddu examination (a penile injection of 10 mcg of alprostadil). the patient then underwent multimodal therapy with antioxidants. however, the patient did not consent to the publication of photos of his penis, even if published anonymously. table 2 displays the full list of antioxidant substances table 2. case 2: clinical data collected before, during, and after antioxidant treatment. ultrasound measurements plaque strain ratio dorsal curve of vas iief pdq bother 45 degrees score score score basal plaque: basal plaque = 2.1 0 27 10 9.28 × 10.9 × 3.99 mm (volume = 0.212 cm3) distal plaque: distal plaque = 1.89 14.3 × 11.7 × 2.86 mm (volume = 0.252 cm3) total volume of the two plaques = 0.464 cm3 first cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (6 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every 2 weeks for 6 months. ultrasound measurements plaque strain ratio dorsal curve of vas iief pdq bother 42 degrees score score score basal plaque: basal plaque = 1.87 0 27 6 5.54 × 7.65 × 3.24 mm (volume = 0.072 cm3) distal plaque: distal plaque = 1.69 7.9 × 6.14 × 2.65 mm (volume = 0.067cm3) total volume of the two plaques = 0.139 cm3 after the first treatment cycle, the total volume of the two plaques decreased by 70% compared with the initial situation second cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 12 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 12 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every month for 12 months. ultrasound measurements plaque strain ratio dorsal curve of vas iief pdq bother 42 degrees score score score basal plaque: basal plaque = 1.62 0 27 4 2.89 × 3.34 × 1.88 mm (volume = 0.010 cm3) distal plaque: distal plaque = 1.26 3.2 × 3.14 × 2.7 mm (volume = 0.014 cm3) total volume of the two plaques = 0.024 cm3 after the second treatment cycle, the total volume of the two plaques decreased by 94.8% compared with the initial situation third cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin-c 50 mg + vitamin-e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 12 months. penile plaques were no longer detectable absence of non-elastic after the regression total therapy duration until plaque’s disappearance = 30 months penile areas of the plaques, the same penile congenital condition that preceded pd was present, with a dorsal curve of 10 degrees vas = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); iief = international index of erectile function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ed severity levels (no ed, score range: 26-30) (46); pdq symptom bother = pd questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). the strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). it is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. when elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. in this case, the image displayed on the ultrasound machine screen does not show any index. archivio italiano di urologia e andrologia 2024; 96(4):12956 g. paulis, g. de giorgio, a. paulis 6 included in the multimodal treatment given to the patient, alongside the clinical data before treatment and at each follow-up after the treatment cycles. the images from the ultrasound examination before, during, and after treatment are presented in figure 2. after undergoing three cycles of treatment, which lasted a total of 30 months, the patient had a comprehensive follow-up assessment that revealed no palpable penile nodules. the ultrasound examination did not detect any plaque. the patient did not report any penile pain (vas score = 0) nor complained of erectile dysfunction, the iief score was 27. the pdq symptom bother score was four. the patient's psychological well-being was excellent, and the penis's appearance was similar to its pre-pd state (a congenital dorsal curvature of the penis of 10 degrees). the patient expressed satisfaction with the outstanding results obtained after completing our antioxidant treatment. case 3 a 42-year-old caucasian man, a non-smoker, reported having fibromyalgia. the patient mentioned experiencing a traumatic event to his penis during sexual intercourse approximately 4 months before. he noticed a slight dorsal curvature of the penis under the glans, at the distal third of the penis, approximately 2 months ago. he also reported feeling pain in the penis during erection and sometimes at rest for the past 2 months. during the visit, the patient reported penile pain during erection (vas score = 5) but did not mention erectile dysfunction. his iief score was 26, and the pdq symptom bother score was 14. the penile deformity observed was a 20-degree sub-glandular dorsal curve. no penile plaque was detected upon palpation. a plaque was detected in the penile echoelastography examination. the plaque was located in the distal third of the penis and measured 6.49 × 4.52 × 2.79 mm (volume = 0.043 cm3). the ultrasound appearance of the plaque was isoechoic with mild hyperechogenicity in its distal portion. the plaque strain ratio was 1.8. the cavernous arteries showed normal arterial flows and end-diastolic velocities during the pddu examination (a penile injection of 10 mcg of alprostadil). the patient underwent multimodal therapy with antioxidants but without penile injections of pentoxifylline due to the plaque's small size. table 3 shows the complete list of antioxidant substances included in the multimodal treatment administered to the patient, alongside the clinical data before treatment and at each follow-up after the treatment cycles. the images from the ultrasound examination before, during, and after treatment are presented in figure 3. after undergoing three cycles of treatment, which lasted a total of 18 months, the patient had a comprehensive follow-up assessment that revealed no palpable penile nodules. the ultrasound examination did not detect any plaque, the patient did not complain of penile pain (vas score = 0), and the iief score was 27. the pdq symptom bother score was four. the patient's psychological state was excellent, and no curvature of the penis was noticeable during the erectile phase. the patient expressed satisfaction with the outstanding results obtained after completing the antioxidant treatment. figure 2. the images from the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (a), during (b) and (c), and after (d) the multimodal treatment. archivio italiano di urologia e andrologia 2024; 96(4):12956 7 multimodal antioxidant treatment of peyronie's disease figure 3. the images from the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (a), during (b) and (c), and after (d) the multimodal treatment. table 3. case 3: clinical data collected before, during, and after antioxidant treatment. distal plaque ultrasound measurements: plaque strain ratio dorsal curve vas iief pdq bother 6.49 × 4.52 × 2.79 mm (volume = 0.043 cm3) score score score 1.8 20 degree 5 26 14 first cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (6 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months; distal plaque ultrasound measurements: plaque strain ratio dorsal curve vas iief pdq bother 5.14 × 3.8 × 2.01 mm (volume = 0.021 cm3) score score score 1.62 8 degree 3 27 10 after the first treatment cycle, the total volume of the two plaques decreased by 51.1% compared with the initial situation second cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months distal plaque ultrasound measurements: plaque strain ratio dorsal curve vas iief pdq bother 3.41 × 3.41 × 1.84 mm (volume = 0.011 cm3) score score score 1.2 5 degree 0 27 4 after the first treatment cycle, the total volume of the two plaques decreased by 74.4% compared with the initial situation third cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (6 months) + boswellia 200 mg + vitamin-c 50 mg + vitamin-e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months penile plaques was no longer detectable absence of non-elastic absence of vas iief pdq bother total therapy duration until plaque’s disappearance = 18 months penile areas penile curvature score score score 0 27 4 vas = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45); iief = international index of erectile function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ed severity levels (no ed, score range: 26-30) (46); pdq symptom bother = pd questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). the strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). it is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. when elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. in this case, the image displayed on the ultrasound machine screen does not show any index. archivio italiano di urologia e andrologia 2024; 96(4):12956 g. paulis, g. de giorgio, a. paulis 8 case 4 a 47-year-old caucasian man, a non-smoker, reported having irritable bowel syndrome. he reported that he had been suffering from erectile dysfunction for approximately 10 years. the patient had been taking a 10 mg tadalafil tablet before sexual intercourse for this disorder for several years. the patient did not remember any traumatic event involving his penis. he reported noticing the appearance of penile deformity and penile pain during erection for approximately 9 months. upon penile examination, a 15 mm long nodule with a fibrous consistency was palpable. the vas score was three. the patient’s iief score was 20, and the pdq symptom bother score was 15. the penile deformity observed consisted of a 30-degree dorsal curvature of the penis associated with another curvature to the left of the same degree. the middle third level of the penile shaft had an “hourglass” appearance. a plaque was detected in the penile echo-elastography examination in the middle third of the penis and measured 18.8 × 15.8 × 3.42 mm (volume = 0.532 cm3). the ultrasound appearance of the plaque was iso-hyperechoic. the plaque strain ratio was 2.3. in the pddu examination (a penile injection of 10 mcg of alprostadil), the cavernous arteries showed normal arterial flows, while the end-diastolic speeds were high (12.2 cm/s on the right; 10.6 cm/s on the left), indicating veno-occlusive insufficiency. the patient underwent multimodal therapy with antioxidants, including periodic perilesional penile injections with 60 mg of pentoxifylline. however, we allowed the patient to continue taking one 10 mg tadalafil tablet before sexual intercourse. table 4 shows the complete list of antioxidant substances included in the multimodal treatment administered to the patient, alongside the clinical data before treatment and at each follow-up after the treatment cycles. the images from the ultrasound examination before, during, and after treatment are presented in figure 4. after completing three treatment cycles over 30 months, the patient underwent a thorough follow-up evaluation that showed no palpable penile nodules. an ultrasound examination also did not find any plaque. during the pddu examination (a penile injection of 10 mcg of alprostadil), the cavernous arteries showed normal arterial flows, while the end-diastolic velocities remained elevated table 4. case 4: clinical data collected before, during, and after antioxidant treatment. plaque on the penile mid-shaft plaque strain ratio a dorsal curve of 30 degrees vas iief pdq bother ultrasound measurements: and a left lateral curve score score score 18.8 × 15.8 × 3.42 mm (volume = 0.532 cm3) 2.3 of 30 degrees 3 20 15 first cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (6 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 6 months; + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every 2 weeks for 6 months plaque on the penile mid-shaft plaque strain ratio a dorsal curve of 20 degrees vas iief pdq bother ultrasound measurements: and a left lateral curve score score score 8.89 × 6.97 × 3.28 mm (volume = 0.106 cm3) 1.7 of 20 degrees 1 22 12 after the first treatment cycle, the total volume of the two plaques decreased by 80.0% compared with the initial situation second cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin c 50 mg + vitamin e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 12 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 12 months + peri-lesional penile injections: pentoxifylline 60 mg (with 30 g needle) every 2 weeks for 12 months plaque on the penile mid-shaft plaque strain ratio a dorsal curve of 12 degrees vas iief pdq bother ultrasound measurements: and a left lateral curve score score score 4.31 × 3.27 × 2.42 mm (volume = 0.018 cm3) 1.1 of 10 degrees 0 22 8 after the first treatment cycle, the total volume of the two plaques decreased by 96.6% compared with the initial situation third cycle orally: l-carnitine 1000 mg + propolis 700 mg + ginkgo biloba 240 mg of multimodal treatment with antioxidants + bilberry 180 mg + coenzyme q-10 100 mg + silymarin 400 mg (12 months) + boswellia 200 mg + vitamin-c 50 mg + vitamin-e 48 mg + superoxide dismutase 11000 iu/g 10 mg/daily/for 6 months; + topically: propolis cream/2 x daily + diclofenac gel 4%/daily/for 18 months penile plaques was no longer detectable absence of non-elastic a dorsal curve of 10 degrees vas iief pdq bother total therapy duration until plaque’s disappearance = 30 months penile areas and a left lateral curve score score score of 5 degrees 0 22 6 vas = visual analog scale, a pain measurement questionnaire (score range: 0-10) (45)); iief = international index of erectile function, a questionnaire for assessing erectile function with a score range of 0-30, indicating different ed severity levels (no ed, score range: 26-30) (46); pdq symptom bother = pd questionnaire symptom bother for evaluating the psychosexual impact, with a score range of 0-30 (10, 47, 66). the strain ratio (deformation index), detected via echo-elastography, indicates the plaque's stiffness (65). it is expressed as a number, representing the ratio between the stiffness of the pathological tissue (plaque) and that of the adjacent normal tissue. when elastography does not detect any anelastic area (plaque), the strain ratio index corresponds to 1. in this case, the image displayed on the ultrasound machine screen does not show any index. archivio italiano di urologia e andrologia 2024; 96(4):12956 9 multimodal antioxidant treatment of peyronie's disease (8.8 cm/s on the right; 8.6 cm/s on the left), indicating persistent occlusive insufficiency, albeit modestly improved after our treatments. the iief score was 22, while it was 20 before our treatment. erectile dysfunction was moderately improved because, initially, the plaque likely deprived the penis of a portion of functioning erectile tissue. the patient did not report any penile pain (vas score = 0). after the plaque completely regressed, we observed a residual penile deformity characterized by a dorsal curve of 10 degrees and a left lateral curve of 5 degrees. before our treatment, the initial penile deformity consisted of a dorsal curve of 30 degrees and a left lateral curve of 30 degrees. the pdq symptom bother score was four. the patient's psychological state had certainly improved compared with pre-treatment; however, the erectile dysfunction still caused some concern for the patient. the patient reported that the slight residual penile deformation no longer worried him. the patient was pleased with the good results achieved after finishing the antioxidant treatment. complete resorption of the pd plaque after treatment occurred in all cases. the disappearance of peyronie's plaque occurred over a period ranging from 18 to 36 months, in relation to the volume of the plaque. discussion the scientific literature has documented eleven pd human patients who have recovered following medical treatment with bioactive food extracts with antioxidant properties (48-51). all 11 cases already published that had achieved complete plaque reabsorption after antioxidant treatment involved men in the first phase of pd. before these experiences, cases of pd healing had been published, but these were experimental studies on rats in which pd-like plaques were induced with solutions of human fibrin and thrombin or with transforming growth factor-b1 (52-54). before these healing experiences, the scientific literature had always reported the possible spontaneous resolution of the disease in 3.2-13% of cases, as expression of the natural history of pd (31, 55-57). however, some of these studies were not based on instrumental exams but on patient self-reports via questionnaires. like other authors with extensive experience in this disease, we believe pd cannot resolve spontaneously (58, 59). in a study published in 2013, we demonstrated that penile curvature can improve without the disease regressing. without treatment, peyronie's plaque in its progression can extend to the contralateral side of the curve and cause a reduction in the elasticity of the cavernous tissue, resulting in a paradoxical improvement of the penile curvature (29). numerous articles in the scientific literature on pd consider surgical treatment the "gold standard" and the ideal and definitive therapeutic option. unfortunately, these considerations have led most uroandrologists to believe that pd is an incurable disease, resulting in a widespread pessimistic attitude and resistance to medical therapy for pd. on the contrary, we have always believed that since pd is related to chronic inflammation, the best treatment would be to treat this disease like any other chronic inflammatory disease. long-term treatment of pd patients with nsaids, corticosteroids, or other drugs can lead to chronic damage or toxicity in organs such as the liver, kidneys, immune system, and gastrointestinal system. therefore, we have figure 4. the images of the ultrasound examination (longitudinal and transverse scans) are shown in sequence: before (a), during (b) and (c), and after (d) the multimodal treatment. archivio italiano di urologia e andrologia 2024; 96(4):12956 g. paulis, g. de giorgio, a. paulis 10 always believed that targeting oxidative stress, a key mechanism in inflammation, with antioxidants is the best therapeutic approach for interrupting the inflammatory process of this disease (35, 60-62). although antioxidants are not included in the current eau european association of urology (eau) and american urological association (aua) guidelines for treating pd, three randomized studies in the literature have discussed the use of antioxidant substances in pd patients (31, 32, 68-70). additionally, several controlled studies have shown positive outcomes when antioxidants have been used in combination (61, 62, 67). the eau and aua guidelines strongly recommend infiltrative therapy with collagenase clostridium histolyticum (cch) or interferon alpha-2b (31, 32, 39). however, we did not employ cch in treatment as it is indicated for pd in the "stabilization phase". on the contrary, our pd patients were all in the active phase of the disease. furthermore, in italy, the drug xiapex (cch) has been withdrawn from the market by the italian medicines agency (aifa) as of january 1, 2020. additionally, we did not utilize interferon alpha-2b due to its high cost and potential side effects, including fever and flu-like symptoms, fatigue, nausea, diarrhea, vomiting, and dizziness. the positive response to our treatments is attributed to the antioxidant properties of the substances used, which can interrupt inflammation and negatively interfere with oxidative stress, a key factor in fibrogenesis (19, 20). figure 5 shows the interfering activities of antioxidants on the various pathogenetic mechanisms involved in pd. propolis, bilberry, silymarin, boswellia, coenzyme q-10, carnitine, and ginkgo biloba exhibit antioxidant and antifibrotic activity, inhibit pro-inflammatory cytokines, metalloproteins with anti-elastic properties, the cox-2 enzyme, and nf-kappa-b factor (22). coenzyme q-10 also protects cellular membranes from lipid peroxidation caused by reactive species, and regenerates vitamin e to its natural and non-oxidized state after it has oxidized from exerting its antioxidant action (22). carnitine also reduces the production of inducible nitric oxide synthase (inos), inhibits fibroblast proliferation and their differentiation into osteoblasts, and induces vasodilation through an endothelial mechanism that utilizes the nitric oxide pathway (22). superoxide dismutase (sod) protects the human body from tissue damage caused by ros by removing superoxide anion. sod has anti-inflammatory action and inhibits fibroblast proliferation (22, 71). vitamin c acts as a scavenger against reactive species and inhibits pro-inflammatory cytokines, and fibroblast proliferation (22). vitamin e is a ros scavenger and inhibits nf-kb factor, cox-2, proinflammatory cytokines, pdgf, and fibroblast proliferation (22, 35). pentoxifylline (ptx) inhibits ros, myofibroblastic differentiation, collagen deposition, nf-kb factor, proinflammatory cytokines, tgf-beta-1, cox-2, inos protein expression, and pai-1 and stimulates fibroblast apoptosis. in our multimodal treatment, we also used diclofenac (an nsaid) administered locally to avoid potential organ damage associated with long-term oral therapy (29, 30). diclofenac also has antioxidant properties and has been demonstrated to penetrate tissues deeply (63, 64). the multimodal antioxidant treatment for pd described in this article is the same as described in our recent articles and differs only in the dose of ptx used for penile injections, which is 60 mg instead of 100 mg. we noticed that by reducing the dose of ptx, we achieved the same results as in the past with higher doses of ptx. the treatment lasted for an extended period in three of the four cases described here (30-36 months). a profigure 5. inhibitory action of antioxidant agents on the main pathogenetic mechanisms of peyronie's disease. archivio italiano di urologia e andrologia 2024; 96(4):12956 11 multimodal antioxidant treatment of peyronie's disease longed treatment duration is essential due to the chronic inflammatory nature of pd, which requires time for complete plaque resorption. the treatment duration may also be affected by the size of the pd plaque. the excellent result obtained in the third case, with a shorter treatment time (a year and six months) compared with the other three cases, is likely because of the early diagnosis (four months after the penile trauma). in this case, we were able to provide the patient with a shorter course of treatment without periodic penile injections, as the plaque was small (0.043 cm3) because the pd was in an early stage. in our treatment plan involving penile injections, we progressively extended the time between each pentoxifylline injection throughout the treatment process. this approach was based on the understanding that even minor peri-lesional injections can cause trauma, which is a known trigger for developing pd. we preferred increasing the intervals between injections (every 2 weeks > every month > every 2 months) whenever regression of the disease was observed during scheduled follow-ups to minimize the risk of new traumas. it has been reported in the literature that ultrasound evaluation of the penis in pd cannot provide adequate plaque measurements. we believe, however, that an accurate plaque size can be obtained if a highly sensitive and upto-date ultrasound machine with an elastographic module is used and, above all, if an expert clinician with great experience in this disease performs the evaluation (31, 65, 72, 73). therefore, we believe that our findings resulted from both the treatment substances and the specific ultrasound evaluation method we employed. this method enabled us to accurately diagnose the affected area (plaque) and closely monitor its progression during scheduled follow-ups. conclusions despite the small sample size in this case report, our multimodal antioxidant treatment yielded highly satisfactory outcomes, allowing for the complete disappearance of the penile plaques in the disease area. we believe that the excellent responses to our therapy were due to the appropriate use of antioxidant substances, as well as the use of a very sensitive and up-to-date ultrasound machine capable of recognizing the plaques and 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38:263-268. 73. parmar m, masterson jm, masterson, ta, 3rd. the role of imaging in the diagnosis and management of peyronie’s disease. curr opin urol. 2020; 30:283-289. correspondence gianni paulis, md paulisg@libero.it department of urology and andrology, peyronie’s care center, castelfidardo clinical analysis center, 00185 rome, italy giovanni de giorgio, md department of urology and andrology, section of ultrasound diagnostics, castelfidardo clinical analysis center, 00185 rome, italy andrea paulis andrea.fx.94@gmail.com bambino gesù children’s hospital, irccs (istituti di ricovero e cura a carattere scientifico), rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 4486 review no conflict of interest declared. exposure to carcinogens such as aromatic amines from cigarette smoke (1). intradiverticular bladder tumours (idbt) account for approximately 1% of all urinary bladder tumors (2). therefore, they pose a unique diagnostic and therapeutic challenge. considering the scarceness of intradiverticular bladder tumours it is not surprising that there are no standard guidelines for the diagnosis and management. we performed a pooled analysis of 498 cases of intradiverticular bladder tumours collected from the international literature, in order to completely characterize the entity in relation to epidemiological, medical and surgical aspects. methods this review was conducted in accordance with the prisma guidelines (preferred reporting items for systematic reviews and meta-analysis) (3). bibliographic research was performed using pubmed from database inception until october 15, 2022. the following medical subject heading terms were used in combination with boolean operators (and, or, not): bladder diverticulum, bladder diverticula, intradiverticular, bladder tumor, bladder cancer, carcinoma. two independent reviewers (k.s, t.l) screened all the articles retrieved by the initial search. all disagreements were resolved with discussion, and final decision was reached by consensus with a third reviewer (p.a.). reference lists were systematically searched for potentially eligible, missed studies. fifty-nine articles were found in total. among these, we spotted 498 welldocumented cases of intradiverticular bladder tumors (figure1) (1, 4-61). retrieved articles were carefully studied and a database with the patients’ characteristics was made (see supplementary materials). the database included sex, age, diagnostic methods, symptoms, localization of the tumor, tumor staging, tumor histopathology, treatment and recurrence. the cases that fulfilled most of these criteria have been included in the statistical analysis. excluded studies met ≥ 1 of the following criteria: (a) irrelevant to the subject studies, (b) studies published in a non-english language, (c) reviews and metaanalyses, and (d) editorials, perspectives, and letters to the editors. an ethical approval is not required because this study is a review of the existing international literature. to express results, descriptive statistics were used appropriately. objective: intradiverticular bladder tumors (idbt) are uncommon clinical entities. we reviewed the literature for clinical presentation, diagnosis and therapeutic options to establish recommendations for diagnostic and therapeutic management. methods: bibliographic research was performed using pubmed from database inception until october 15, 2022. a pooled analysis was performed of 498 patients with idbt presented in the literature. the evaluation included patient sex, age, diagnostic methods, symptoms, localization of the tumor, tumor staging, tumor histopathology, treatment, and the presence of recurrence. to express results, descriptive statistics were used appropriately. results: the mean age at diagnosis was 64.81 years (range 49 days to 84 years). the ratio between men and women was ≈ 24:1, suggesting a male predominance (85% male, 3.6% female). the most common presenting symptom was gross hematuria (60.88%). most of the patients had cystoscopy (56.85%) and intravenous or computed tomography urography (52.01%). regarding tumor staging, most of the patients were diagnosed with pt1 tumors. for the histopathology of idbt, 87.95% of the specimens were transitional cell carcinomas and in 10.84% there were concomitant cis. regarding the treatment, radical cystectomy was chosen in 34.34%, partial cystectomy in 26.66%, diverticulectomy in 15.95% and transurethral resection of bladder tumour (turbt) in 16.36% of the patients. conclusions: most common diagnostic tool for idbt seems to be cystoscopy followed by computerized tomography urogram. due to the absence of muscle layer in the diverticulum and the highgrade histology of most of them at diagnosis, cystectomy is the first therapeutic choice. however, for patients that are not considered appropriate candidates or for those presenting with lowgrade and low volume tumors, turbt is a good option. key words: intradiverticular bladder tumors; bladder diverticular carcinoma; urothelial carcinoma; bladder diverticulum. submitted 15 november 2022; accepted 7 december 2022 introduction bladder diverticula are outpouchings of the bladder wall devoid of a functional muscularis propria lining (1). the lack of a muscle layer results in a loss of contractility, which in turn results in urine stasis in the diverticulum. this chronic irritation can lead to chronic inflammation and an increased risk of neoplasms, owing to a prolonged diagnosis and management of intradiverticular bladder tumours: a pooled analysis of 498 cases stamatios katsimperis, lazaros tzelves, themistoklis bellos, panagiotis angelopoulos, ioannis tsikopoulos, iraklis mitsogiannis, athanasios papatsoris second department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens, grc. doi: 10.4081/aiua.2022.4.486 summary 487archivio italiano di urologia e andrologia 2022; 94, 4 intradiverticular bladder tumours results characteristics of idbt were determined concerning sex, age diagnostic methods, symptoms, localization of the tumor, tumor staging, tumor histopathology, treatment and recurrence. gender concerning gender, 85% of the patients were male (431 patients), while 3.6% were female (18 patients). there were no data regarding gender for 49 patients. the ratio between men and women was ≈ 24:1, suggesting a male predominance in the reported idbt population. age mean age of the population was 64.81 years, ranging from 49 to 84 years. it is concluded that idbt most frequently appeared in age range from 60 to 70 years. diagnostic methods the most useful tool was cystoscopy (141/248 patients, 56.85%), followed by intravenous/computed tomography urography (ivu/ctu) (129/248 patients, 52.01%) as shown in figure 2. other imaging techniques used were computed tomography (ct) scan (46/248 patients, figure 1. flow chart of papers selection. figure 2. diagnostic methods. archivio italiano di urologia e andrologia 2022; 94, 4 s. katsimperis, l. tzelves, t. bellos, p. angelopoulos, i. tsikopoulos, i. mitsogiannis, a. papatsoris 488 18.54%) and ultrasound (u/s) of kidneys, ureters, and bladder (kub) (24/248 patients, 9.67%); retrograde cystography (21/248 patients, 8.46%) is still of great importance for the diagnosis of idbt. last but not least, magnetic resonance imaging (mri) can be a helpful tool for the differential diagnosis of idbt. in the laboratory tests, 21 of 248 patients (8.46%), underwnt a urine cytology test for the detection of idbt. presenting symptoms idbt can present with a wide variety of symptoms, ranging from gross hematuria to symptoms of urinary tract infections (uti). our statistical analysis has shown that the most frequent symptom is gross hematuria (151/248 patients 60.88%). eight patients presented with microhematuria (3.22%), 8 patients had frequency (3.22%) and 11 had dysuria (4.43%). lower urinary tract symptoms (luts), obstructive symptoms, urinary retention, hydronephrosis, pain, loss of weight and uti were found in 23 (9.27%), 15 (6.04%), 2 (0.8%), 7 (1.4%), 6 (2.82%), 2 (0.8%) and 14 (5.64%) patients respectively. tumor localization pooled analysis included limited data concerning tumor localization that was mentioned in only 66 patients. most common site was right lateral wall (19/66 patients, 28.78%), while left lateral wall was the second one (16/66 patients, 24.24%). idbt appeared above right and left orifice in 9 and 8 patients respectively (13.63% and 12.12%). nine patients (13.63%) had an idbt in the posterior wall. the base of the bladder (2/66 patients, 3.03%), dome (1/66 patients, 1.51%), anterior wall (1/66 patients, 1.51%) and trigone (1/66 patients, 1.51%) represent rarer locations of idbt. tumor staging regarding tumor staging, most of the patients were diagnosed as pt1 tumors (117 patients), followed by those diagnosed with pt2 tumors (33 patients). patients with pta, pt3 and pt4 tumors were 2, 19 and 1 respectively. pooled analysis of tumor grade using low grade (lg)/high grade (hg) and g1/g2/g3 classification resulted in 28 patients with lg tumors, 128 patients with hg tumors, 15 patients with g1 tumors, 24 patients with g2 tumors and 31 patients with g3 tumors. tumor histopathology in relation to histopathology of idbt, most of them presented as transitional cell carcinomas (tcc) (438 patients, 87.95%). squamous cell carcinomas come followed with 26 patients (5.22%). small cell carcinomas, adenocarcinomas and sarcomatoid carcinomas were 8, 6 and 8 cases respectively. worth of mention is the presence of concomitant carcinoma in situ (cis) in 54 patients (10.84%). treatment regarding the treatment applied, radical cystectomy has been chosen in 170 of 495 patients (34.34%), whereas partial cystectomy in 132 patients (26.66%). seventynine (79) patients underwent diverticulectomy (15.95%). transurethral resection of bladder tumor (turbt) was performed in 81 patients (16.36%) and out of them 14 (2.82%) had also intravesical therapy as part of their treatment. systemic therapies such as neoadjuvant chemotherapy, adjuvant chemotherapy and radiation were applied in 15 (3.03%), 25 (5.05%) and 26 (5.25%) patients respectively. figure 3 summarizes all the above treatments. recurrence pooled analysis resulted in a recurrence rate of 19.07% (95 patients). discussion intradiverticular bladder tumors are uncommon clinical entities, with only few studies reported in the literature. their rarity make diagnosis and management a unique challenge. they were first described by targett in 1896 (62) and account for approximately 1% of bladder tumors. idbt seem to have a male predilection (male: female ratio, 24:1) and they more frequently appear in the sixth decade. the diagnosis of idbt is usually like that used for other tumors of the bladder, based on the cystoscopy and imaging findings. in some patients the anatomy of the bladder diverticulum may not help to perform a cystoscopy (narrow neck of the diverticulum). however, in most cases cystoscopy is the main diagnostic test used and cannot be excluded from the diagnostic procedure. a variety of imaging techniques can be used to evaluate idbt. ultrasonographically, idbt present as a mostly echo-free outpouching that protrudes outside the urinary bladder outlines with an echogenic soft-tissue lesion projecting inside it. it has been found that ultrasonography is useful for diagnosing larger tumors but its sensitivity is poor if the idbt is < 1 cm in diameter (63). in our review ultrasonography was reported as a useful tool for the first assessment of hematuria related with idbt but further imaging techniques were usually needed such as ct scan and ct urography. ct gives further details regarding extravesical extension and tumor stage. among laboratory tests, urine cytology, due to its low sensitivity for lowgrade tumors, has not been used very often (8.46%). idbt display a great variety of symptoms. the majority of cases present with gross hematuria. hydronephrosis and pain can also appear due to obstruction ofe ureteric orifices. luts and symptoms of urinary tract infections are figure 3. treatment. 489archivio italiano di urologia e andrologia 2022; 94, 4 intradiverticular bladder tumours common mostly because of the presence of the diverticulum rather than the tumor itself. our study supported the assumption that the most common clinical manifestation of idbt is gross hematuria, while luts are the second most frequent clinical presentation. regarding location of idbt, it extends from lateral wall to the dome. the majority arise from right and left lateral wall followed by those above the ureteric orifices. most of the tumors reported in our study were tcc high grade and more specifically pt1 ones. although squamous cell carcinomas were not even close in numbers to the tcc they cannot be overlooked, as they represent a not so rare manifestation (5.22%). regarding treatment all scientists agree that idbt should be excised when diagnosed. the main surgical approach was radical cystectomy (34.34%) followed by partial cystectomy (26.66%). the predominance of high-grade, that was mentioned before and the recurrence rate of 18.67% which many times resulted in an upstaging of the tumor were the main reason for that choice. interestingly, voskuilen et al. (11), in their retrospective study, presenting the largest series of idbt published so far, showed that although upstaging was frequent in the patients that underwent partial rather than radical cystectomy, there was no difference in overall survival. in another study from kong et al. (12) including 36 patients, 28 of them had partial cystectomy or diverticulectomy as primary treatment without compromising cancer related survival. similar results are presented in two more studies (13, 16). golijanin et al. (16), supported that patients with low or high grade ta tumors may be treated conservatively (either by complete tur or partial cystectomy) providing a close surveillance after treatment. in a more recent study bourgi et al. (13), concluded that conservative management is feasible even in high grade tumors or in patients presenting with cis. in view of these facts, a fair number of patients were treated with less radical approaches such as diverticulectomy (15.95%) or turbt (16.36%). they usually presented with low-grade and low volume tumors. in our review, most of the studies included were case reports or small case series with insufficient case number and short follow-up time. multiple case reports indicated that poor outcome was the result of difficult and delayed diagnosis, leading to early invasion and advanced disease at presentation. that was the reason for the predominance of radical cystectomy as therapeutic approach. there was also a correlation of the year of published studies and the treatment applied. in the past it was widely accepted that idbt had an ominous prognosis so the management was more radical. data from most recent studies have questioned the benefit of radical approach for idbt, shifting the primary treatment to less invasive techniques. we acknowledge that the present study had several limitations. the major limitations were the retrospective nature of the studies included, the large numbers of case reports and the lack of long follow-up time in most of them. however, to the best of our knowledge this is the first attempt to present a thorough review of a clinical entity that was much overlooked in the published literature. conclusions most common diagnostic tool for idbt seems to be cystoscopy followed by ctu. the relative rarity of idbt makes their management challenging because as there is no clear consensus about it. although cystectomy seems a much more morbid procedure compared to less invasive techniques such as turbt, the absence of muscle layer in the diverticulum and the high-grade histology of most of them, makes it the most likely therapeutic choice. however, it has been proved that less invasive techniques such as partial cystectomy, 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22:347-8. 58. mayer rf, moore td. carcinoma complicating vesical diverticulum. j urol. 1954; 71:307-15. 59. shigehara k, taya t, hisazumi h. primary adenocarcinoma in the bladder diverticulum. scand j urol nephrol. 2008; 42:481-3. 60. agarwal m, azzopardi a, mufti gr. pyrexia of unknown origin in association with bladder diverticulum tumour. postgrad med j. 1993; 69:403-5. 61. mittal v, rupala kk, yadav r, suryavanshi m. giant sarcomatoid carcinoma with osseous metaplasia from urinary bladder diverticulum. indian j surg oncol. 2017; 8:436-439. 62. targett jh. diverticula of the bladder associated with vesical growths. trans path soc lond. 1896; 47:155, 1896. 63. neuzillet y, comperat e, rouprêt m, et al.; membres du comité de cancérologie de l’association française d’urologie. tumeurs de vessie intradiverticulaires: revue du comité de cancérologie de l'association française d'urologie prog urol. 2012; 22:495-502. correspondence stamatios katsimperis, md (corresponding author) stamk1992@gmail.com lazaros tzelves, md lazarostzelves@gmail.com themistoklis bellos, md bellos.themistoklis@yahoo.com panagiotis angelopoulos, md angelopoulospanag@gmail.com ioannis tsikopoulos, md ioannistsikopoulos@yahoo.com iraklis mitsogiannis, md imitsog@med.uoa.gr athanasios papatsoris, md agpapatsoris@yahoo.gr second department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens, grc stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13991 1 original paper ial (1). the formation of biofilms and colonization by urease-producing bacteria (such as proteus, pseudomonas, and klebsiella) may contribute to the development of encrustations (2, 3). however, encrustations have also been observed in sterile conditions, and the most common composition identified on dj stents is not struvite but calcium oxalate, indicating that other factors could be involved (4, 5). urine conditions, including ph, supersaturation of crystallizing substances, and a deficiency of crystallizing inhibitors, play a significant role, as dj stents remain in constant contact with urine (4, 6). numerous other factors have been linked to the formation of encrustations, with indwelling time being the most extensively studied (2, 7). encrustation of ureteric stents could lead to severe complications, that occurs in up to 13% of cases of prolonged indwelling time or forgotten stent (8). marked encrustations could compromise its tensile strength, potentially leading to stent fragmentation during removal. furthermore, such encrustations may cause damage or avulsion of the ureter during the removal procedure, urinary tract infections, or even result in the loss of the renal unit if they cause chronic obstruction of stent drainage (2, 9, 10). various procedures may be necessary to retrieve neglected dj stents, including shock wave lithotripsy (swl), ureteroscopy, and percutaneous techniques. open surgery, on the other hand, is seldom required (11, 12). torrecilla et al. investigated the efficacy of a new oral medication in preventing dj stent encrustations. the oral composition studied contained both urine acidifier and crystallization inhibitors, and they reported a significant decrease in stent encrustations (13). studies have indicated that oral ascorbic acid intake can lead to urine acidification (14, 15). we conducted the current study to investigate the impact of daily ascorbic acid supplementation on reducing the incidence of encrustations on dj ureteric stents. we highlighted the incidence of stent encrustations, predictive factors, and associated morbidities. background: double j (dj) ureteric stent encrustation is a troublesome complication that may impede its removal. the proposed study aims to investigate the effect of ascorbic acid supplementation on reducing dj stent encrustations and identify potential risk factors. methods: a multi-center, non-concurrent cohort study involved patients who had dj ureteric stents from july 2017 to january 2024. group i comprised 359 patients who took 500 mg of ascorbic acid supplements three times daily that continued until the time of dj removal. in contrast, group ii consisted of 483 patients who did not use the supplement. the study groups were compared in terms of patient demographics, stone criteria, double-j stent encrustations, and stent-related adverse events. kub grading system for stent encrustations was utilized. results: the study enrolled 842 patients with a prevalence of stent encrustations of 20.43%. the mean k, u, and b scores were 2.14, 1.91, and 2.15, respectively, and the mean total k.u.b. score was 6.2 ± 2.91. the study groups were comparable in terms of patient demographics; however, nine patients (2.5%) in group i had stent encrustations, compared to 163 (33.7%) in group ii, with a statistically significant difference (p < 0.001). urinary tract infections (utis) were more prevalent in group ii at 57.8%, compared to 30% in group i (p = 0.02). lack of treatment with ascorbic acid male gender, and longer duration of indwelling stents were significant predictors of stent encrustations (p < 0.05). conclusions: our study has demonstrated that ascorbic acid supplementation could reduce the incidence of encrustations on double-j ureteric stents. lack of ascorbic acid administration, male gender, and prolonged stent indwelling time were significant predictors for stent encrustations. key words: double-j; encrustation; indwelling time; urine acidification. submitted 16 may 2025; accepted 26 july 2025 introduction double-j (dj) ureteric stent encrustations is an area that requires further investigations, as it is primarily multifactorascorbic acid supplementation effectiveness in reducing double-j ureteric stent encrustations. a multicenter perspective adel elatreisy 1, 2, ahmed alrefaey 1, osama shalkamy 1, mohamed a elhelaly 1, el-sayed el-agamy 1, abdrabuh m adrabuh 1, hany eldamanhory 1, ahmed mohamed soliman 1, hossam a shouman 1, mohamed shehab 1, nader a abdelkhalek 1, ahmed shafiea 1, tamer ewida 3, mohamed elsalhy 1, maged kamal fayad 4, hamada ahmed youssof 5 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 department of urology, king fahd armed forces hospital, jeddah, ksa; 3 urology department, blackpool teaching hospital, blackpool, uk; 4 national institute of urology and nephrology, cairo, egypt; 5 department of urology, faculty of medicine, fayoum university, fayoum, egypt. doi: 10.4081/aiua.2025.13991 summary archivio italiano di urologia e andrologia 2025; 97(3):13991 a. elatreisy, a. alrefaey, o. shalkamy, et al. 2 materials and methods a multi-center non-concurrent cohort study involved patients with dj ureteric stents treated at three tertiary care hospitals. the study was conducted between july 2017 and january 2024, and the local institutional review board for the urology department, faculty of medicine, alazhar university, approved the protocol (study protocol id number: uroazhar-021-12). the study included adult patients aged 18 years or older who underwent endourology procedures for stone management with the insertion of dj ureteric stents. we prescribed a three-times-daily oral ascorbic acid dose of 500 mg (total 1500 mg per day) aiming to reduce dj stent encrustation. the treatment was prescribed as a home medication on discharge after dj stent insertion and continued until the time of dj removal. we excluded patients with silicone ureteric stents and those with incomplete files from our study. before dj removal, every patient had a kidney-ureter-bladder (kub) x-ray, while patients with neglected stents required a non-contrasted computed tomography (ncct). contrast imaging studies were occasionally necessary to obtain detailed calyceal anatomy. laboratory investigations, including serum creatinine, complete blood count, coagulation profile, and urinary culture, were obtained. if the urinary culture results were positive, the patients were treated accordingly, and dj stent removal was subsequently performed. we used the scoring system proposed by arenas et al. to assess the level and severity of dj stent encrustations. the kub system grades each portion of the stent individually on a scale of 1 to 5 based on the severity of the encrustation. this includes the proximal renal coil (graded as "k"), the ureteral shaft (graded as "u"), and the distal bladder coil (graded as "b"). the cumulative kub score is obtained by adding the scores of all three portions of the stent, with a maximum score of 15 (16). patients received prophylactic antibiotics before undergoing dj stent removal with spinal, general, or urethral topical anesthesia. double-j ureteric stents were removed using a cystoscope and forceps, sometimes with the help of swl or ureteroscopy and laser fragmentation. in extreme cases, cystolithotripsy and percutaneous nephrolithotomy were necessary for stent removal. if the procedure was prolonged, the stent was replaced with a new one. the cohort was divided into two distinct groups. group i comprised 359 patients who demonstrated regular compliance with the daily oral ascorbic acid regimen. in contrast, group ii consisted of 483 patients who did not use the supplement. the study groups were compared in terms of patient demographics, stone criteria, dj stent encrustations, and stent-related adverse events. perioperative complications were graded according to the modified clavien-dindo classification system (17). neglected stents were defined as a duration of indwelling exceeding 6 months. a logistic regression model was used to analyze the risk factors that may lead to dj tent encrustations. the analyzed variables included patient demographics, laboratory profile (such as urine culture, serum creatinine, and blood sugar), indwelling time, and regular use of ascorbic acid supplement throughout stent indwelling. statistical analysis the data was analyzed using statistical package for social science (spss) version 29 software. numerical data were summarized using means and standard deviations, while categorical data were summarized as numbers (percentages). we used an independent t-test for normally distributed numeric variables, the mann-whitney test for non-normally distributed variables, and chi-square and fisher's exact tests for categorical variables. a logistic regression analysis was done to identify predictors of stent encrustation. univariate analysis was conducted for all variables expected to affect stent encrustations. the significant variables were included in the logistic multivariate regression stepwise model, presented by odds ratio (or) and its confidence interval (ci). results were considered significant when p < 0.05. results the study involved 842 patients, with a mean age of 41.58 ± 17.42. out of these, 172 patients (20.43%) developed stent encrustations. the mean k, u, and b scores were 2.14, 1.91, and 2.15, respectively, and the mean total table 1. patients' demographic data and outcomes in the study groups. variables group i group ii p value (n = 359) (n = 483) age, years, mean (sd) 42.12 (16.06) 40.64 (18.10) 0.762 gender, n (%) male 219 (61%) 313 (64.8%) 0.24 female 140 (39%) 170 (35.2%) history of urinary stone, n (%) no 38 (10.6%) 44 (9.1%) 0.5 yes 321 (89.4%) 439 (90.9%) kidney 181 (56.4%) 239 (54.4.2%) ureter 92 (28.7%) 140 (31.9%) kidney/ureter 48 (14.9%) 60 (13.7%) indwelling time (days), mean (sd) 199 (176) 328 (298) < 0.001 neglected stents, n (%) 49 (13.6%) 120 (24.8%) 0.06 bmi, mean (sd) 25.72 (2.84) 26.24 (2.62) 0.1 preoperative serum creatinine, mg/dl mean (sd) 1.16 (0.42) 1.14 (0.57) 0.16 occurrence of double-j stent encrustations, n (%) yes 9 (2.5%) 163 (33.7%) < 0.001 no 350 (97.5%) 320 (66.63%) perioperative complications according to modified clavien-dindo classification system, n (%) storage luts (grade i) 91 (25.3%) 191(39.5%) 0.02 uti (grade ii) 108 (30%) 279 (57.8%) 0.06 hematuria (grade i) 129 (35.9%) 146 (30.2%) 0.76 bmi: body mass index; sd: standard deviation, luts: lower urinary tract symptoms, uti: urinary tract infection. archivio italiano di urologia e andrologia 2025; 97(3):13991 3 ascorbic acid and prevention of stent encrustations k.u.b. score was 6.2 ± 2.91. the patient demographics and stone characteristics of the study groups were similar, as shown in table 1. it was found that 2.5% of patients in group i presented with dj stent encrustations, compared to 33.7% of patients in group ii, with a statistically significant difference (p < 0.001). double-j stent encrustations were more frequent in males (78.49%). 135 out of 532 male patients (25.38%) developed dj stent encrustations compared to 11.82% of female patients with a statistically significant difference (p = 0.004) (table 2). dj stent encrustation was more frequent in patients with prolonged stenting time or neglected stents; the median duration of stenting time in cases with encrustations was 278 days compared to 119 days in those with no encrustations (p < 0.001) as depicted in table 2. regarding dj-associated adverse events, urinary tract infection (uti) was more prevalent in group ii at 57.8%, compared to 30% in group i (p = 0.02). similarly, storage lower urinary tract symptoms (luts) were reported in 25.3% and 39.5% of groups i and ii, respectively (p = 0.06). hematuria was reported in 35.9% and 30.2% of cases in group i and ii, respectively, with no statistically significant difference, as illustrated in table 1. univariate analysis revealed that several variables may contribute to dj ureteric stent encrustations. however, the multivariate logistic regression model demonstrated that lack of ascorbic acid intake, male gender, and longer duration of indwelling stent were significant predictors of stent encrustations (p < 0.05), as depicted in table 3. discussion the encrustation of dj stents can lead to significant clinical consequences that may impede the removal of the stents. the duration of stent placement is directly proportional to the probability of encrustation (1) (17-19). in some cases, this can result in complete encrustation, necessitating endourological procedures, swl, or open surgery for stent removal (20, 21). according to some reports, the mere presence of a biofilm on a stent can intensify a patient's discomfort and lead to luts (3, 22). in this study, about 20% of patients with dj ureteric stents had encrustations. other studies have reported a prevalence rate from 9% to 76% (1, 11, 25, 26). the reason for this variation is unclear, but it may be due to differences in the population and the duration of indwelling time in each study. nevertheless, most studies have shown a high prevalence of encrustations. torrecilla et al. conducted a study on the effect of urinary ph on the development rate of crystals and subsequent encrustations around the dj stent. their findings suggest that when urinary ph values are within the range of 5.5 to 6.2, the crystals development rate and encrustation formation are significantly reduced (13). conversely, other researchers have reported that when urinary ph is less than 6.2, the risk of stent encrustation increases by 13-fold (23, 24). the development of significant calcium phosphate deposits depends upon specific conditions in urine with a ph exceeding 6.2 and no bacterial colonization. brushite deposits can accumulate in large quantities when urine has a high calcium concentration, a citrate deficit, and a ph level greater than 6.2. such conditions can also lead to the occurrence of large calcium oxalate dihydrate crystals. large hydroxyapatite deposits, on the other hand, can develop when calcium and magnesium concentrations are low (13). according to certain reports, the intake of ascorbic acid has been observed to cause urine acidification without affecting serum ph levels. this acidification has been table 2. demographic data of patients with and without stent encrustations. variables encrustation no encrustation p value (n = 172) (n =670) age, years, mean (sd) 41.92 (16.06) 40.84 (18.10) 0.65 gender, n (%) male 135 (78.49%) 397 (59.25%) 0.004 female 37 (21.51%) 273 (40.75%) history of urinary stone, n (%) no 10 (5.81%) 72 (10.75%) 0.001 yes 162 (94.19%) 598 (89.25%) indwelling time (days), mean (sd) 378 (321) 149 (28) < 0.001 neglected stents, n (%) 132 (78.1%) 37 (21.9%) < 0.001 ascorbic acid intake, n (%) yes 9 (5.2%) 350 (52.2%) < 0.001 no 163 (94.8%) 320 ( 47.8%) bmi, mean (sd) 26.12 (2.14) 25.74 (2.92) 0.2 preoperative serum creatinine, mg/dl mean (sd) 1.24 (0.4) 1.06( 0.48) 0.18 bmi: body mass index; sd: standard deviation. table 3. univariate and multivariate logistic regression models for the variables associated with stent encrustations. univariate analysis multivariate analysis hr (95% ci) p value hr (95% ci) p value age 1.42 (0.69, 2.92) 0.334 ----gender 0.56 (0.33, 0.95) 0.032 1.80 (1.11, 2.94) 0.018 duration of indwelling stents/days 1.01 (1.00, 1.01) < 0.001 1.01 (1.01, 1.01) < 0.001 history of stone --0.9 ----bmi 0.99 (0.90, 1.08) 0.802 ----urine acidification 0.03 (0.01, 0.08) < 0.001 30.99 (12.70, 75.56) < 0.001 uti 1.71 (0.99, 2.96) 0.054 ----mean (sd) 1.24 (0.4) 1.06 (0.48) 0.18 bmi: body mass index; uti: urinary tract infection. archivio italiano di urologia e andrologia 2025; 97(3):13991 a. elatreisy, a. alrefaey, o. shalkamy, et al. 4 associated with mild calciuria; however, this is balanced by an increase in the solubility of calcium phosphate in acidic urine. (14, 15). consequently, the decrease in the incidence of dj stent encrustation resulting from daily ascorbic acid intake could be attributed to its role as a urine acidifier. this observation could be explained by the reduced rate of urinary tract infection and bacterial colonization in an acidified environment. these findings are consistent with earlier studies demonstrating a connection between a lack of acidification, urinary tract infection, bacterial biofilm formation, and consequent stent encrustations (13, 25, 26). some reports have shown significant hyperoxaluria in patients with calcium stone formation after high doses of oral ascorbic acid intake (2-10 g per day) (14). however, in our study, we used a daily dose of 1.5 gm. the present study has demonstrated a considerable efficacy of daily oral administration of ascorbic acid, which could act as a urine acidifier, in mitigating the incidence of dj ureteric stent encrustations. our findings could be consistent with those reported by torrecilla et al., who demonstrated promising outcomes by using a novel compound comprising a urine acidifier and a crystallization inhibitor to decrease ureteric stent encrustation (13). our study found that male patients have a higher incidence of double-j ureteric stent encrustations, with a prevalence of 25.52%, compared to 11.82% in females. this trend can be attributed to hormonal differences and higher citrate levels in females (27, 28). several risk factors have been studied regarding the formation of encrustations on dj stents, including recurrent urinary tract infections and stone recurrence. a higher prevalence of stent encrustations has been observed in individuals with a history of recurrent stones, as evidenced by numerous studies (1) although our study did not identify stone recurrence as a risk factor for stent encrustation. as noted previously, the present study has demonstrated that patients with neglected ureteric stents are at an increased risk of developing stent-related complications, including recurrent urinary tract infections, stent fragmentation, and stent migration (20, 29, 30). numerous studies have explored the potential of ascorbic acid supplementation to reduce urine ph in patients suffering from recurrent urinary tract infections or stone formers with alkaline urine. however, no studies have assessed the impact of ascorbic acid supplementation on the incidence of ureteric double-j stent encrustations. our research represents the first investigation of this nature and demonstrates that ascorbic acid supplementation can significantly reduce the incidence of ureteric dj stent encrustations. the study limitations despite the substantial sample size, this cohort study has limitations that warrant careful consideration. firstly, the retrospective nature of the study may introduce potential recall bias. secondly, there are notable omissions in specific data, including urinary metabolic measurements, urine ph values, and comprehensive analyses of stones and encrustations. consequently, additional randomized controlled trials are warranted to further elucidate our findings. conclusions this study demonstrates that daily oral supplementation with ascorbic acid can reduce the incidence of encrustations on double-j ureteric stents. furthermore, the analysis identifies several significant predictors of stent encrustations, including lack of treatment with ascorbic acid, male gender, and extended stent indwelling time. references 1. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol. 1991; 146:1487-1491. 2. omer n, garden e, small a, palese m. ureteral stent encrustation: epidemiology, pathophysiology, management and current technology. j urol. 2021; 205:68-77. 3. kram w, buchholz nnp, hakenberg ow. ureteral stent encrustation. pathophysiology. arch esp urol. 2016; 69:485-493. 4. grases f, söhnel o, costa-bauzá a, et al. study on concretions developed around urinary catheters and mechanisms of renal calculi development. nephron 2001; 88:320-328. 5. bithelis g, bouropoulos n, liatsikos en, et al. assessment of encrustations on polyurethane ureteral stents. j endourol. 2004; 18:550-556. 6. bouzidi h, traxer o, doré b, et al. characteristics of encrustation of ureteric stents in patients with urinary stones. prog urol. 2008; 18:230-237. 7. beysens m, tailly to. ureteral stents in urolithiasis. asian j urol. 2018; 5:274-286. 8. small a, thorogood s, shah o, healy k. emerging mobile declarations ethical approval and consent for participate: the study followed ethical standards outlined in the declaration of helsinki and was approved by the institutional review board of the authors’institute (protocol (study protocol id number: uroazhar-021-12). due to feasibility and unchanged review results, informed consent was waived for 842 individuals whose medical records were reviewed. consent for publication: not applicable. availability of data and material: the datasets used during this study are available from the corresponding author on reasonable request. competing interests: the authors state that they do not have any conflicting interest. funding: none. authors' contributions: all authors have made significant contributions to the study's conception and design, methodology, data acquisition, analysis, review, and interpretation. they have all read and approved the final version of the article and confirmed that all methods were conducted according to the relevant guidelines and regulations. furthermore, all authors reviewed the manuscript. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):13991 5 ascorbic acid and prevention of stent encrustations platforms to aid in stone management. urol clin n am. 2019; 46:287-301. 9. ibilibor c, grand r, daneshfar c, et al. impact of retained ureteral stents on long-term renal function. urol pract. 2019; 6:107-111. 10. cao z, zhao j, yang k. cu-bearing stainless steel reduces cytotoxicity and crystals adhesion after ureteral epithelial cells exposing to calcium oxalate monohydrate. sci rep. 2018; 8:14094. 11. huang j, wu w, zhang s, et al. characteristics of double-j stent encrustations and factors associated with their development. urology journal. 2021; 19:22-27. 12. patil s, magdum p, shete j, et al. forgotten dj stent-a source of morbidity: is stent registry a need of the hour. int j recent sci res. 2015; 6:2674-6. 13. torrecilla c, fernández-concha j, cansino jr, et al. reduction of ureteral stent encrustation by modulating the urine ph and inhibiting the crystal film with a new oral composition: a multicenter, placebo controlled, double blind, randomized clinical trial. bmc urology. 2020; 20:1-12. 14. noureldin ya, da silva a, fahmy n, andonian s. is it safe to prescribe ascorbic acid for urinary acidification in stone-forming patients with alkaline urine? turk j urol. 2017; 43:183-188. 15. murphy fj, zelman s. ascorbic acid as a urinary acidifying agent: 1. comparison with the ketogenic effect of fasting. j urol. 1965; 94:297-299. 16. arenas jl, shen jk, keheila m, et al. kidney, ureter, and bladder (kub): a novel grading system for encrusted ureteral stents. urology. 2016; 97:51-55. 17. acosta-miranda am, milner j, turk tmt. the fecal double-j: a simplified approach in the management of encrusted and retained ureteral stents. j endourol. 2009; 23:409-15. 18. kawahara t, ito h, terao h, et al. ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. j endourol. 2012; 27:506. 19. kadihasanoglu m, kilciler m, atahan o. luminal obstruction of double j stents due to encrustation depends on indwelling time: a pilot study. aktuelle urol. 2017; 48:248-51. 20. singh v, srinivastava a, kapoor r, kumar a. can the complicated forgotten indwelling ureteric stents be lethal? international urology and nephrology. 2005; 37:541-546. 21. ather mh, talati j, biyabani r. physician responsibility for removal of implants: the case for a computerized program for tracking overdue double-j stents. tech urol. 2000; 6:189-92. 22. marangella m, bruno m, cosseddu d, et al. prevalence of chronic renal insufficiency in the course of idiopathic recurrent calcium stone disease: risk factors and patterns of progression. nephron. 1990; 54:302-6. 23. del valle ee, spivacow fr, negri al. citrate and renal stones. medicina. 2013; 73:363-8. 24. gul z, monga m. medical and dietary therapy for kidney stone prevention. korean j urol. 2014; 55:775-9. 25. abdelaziz a, fouda w, mosharafa a, et al. forgotten ureteral stents: risk factors, complications and management. african journal of urology. 2018; 24:28-33. 26. el-kholy geg, keritna hkm, salem tam. forgotten double-j ureteral stents: prevalence, risk factors and complications. the egyptian journal of hospital medicine. 2019; 76:3912-8. 27. ryall rl et al. urinary risk factors in calcium oxalate stone disease: comparison of men and women. br j urol, 1987; 60:480-8. 28. nicar mj, hill k, pak cy. inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro. j bone miner res, 1987; 2:215-20. 29. patil s, raghuvanshi k, jain dk, raval a. forgotten ureteral double-j stents and related complications: a real-world experience. african journal of urology. 2020; 26:1-5. 30. kehinde eo, rotimi vo, al-awadi ka, et al. factors predisposing to urinary tract infection after j ureteral stent insertion. j urol. 2002; 167:1334-7. correspondence adel elatreisy, md, msc, phd (urol), febu, frcs (urol) (corresponding author) dr_adelelatreisy@yahoo.com; adel.elatreisy@azhar.edu.eg urology department, faculty of medicine, al-azhar university, cairo, egypt and department of urology, king fahd armed forces hospital, jeddah, ksa flat 1, 3245 manazil aleuzama’ street, ar ruwais dist, jeddah, saudi arabia postal code: 23211 ahmed alrefaey a7medrefa3y.ash@gmail.com osama shalkamy dr_shalkamy@yahoo.com mohamed a elhelaly elhelalymohammed@yahoo.com el-sayed el-agamy abuamar1978@yahoo.com abdrabuh m adrabuh abdo197871@yahoo.com hany eldamanhory drhanyeldamanhory@gmail.com ahmed mohamed soliman a_soliman_1@hotmail.com hossam a shouman drhossamshouman@gmail.com mohamed shehab shehab810@gmail.com nader a abdelkhalek doctornader2@gmail.com ahmed shafiea shafieaahmed2018@yahoo.com mohamed elsalhy drsalhy2020@gmail.com department of urology, faculty of medicine, al-azhar university, cairo, egypt tamer ewida tamereweda@yahoo.com urology department, blackpool teaching hospital, blackpool, uk maged kamal fayad national institute of urology and nephrology, cairo, egypt hamada ahmed yousef hay02@fayoum.edu.eg department of urology, faculty of medicine, fayoum university, fayoum, egypt stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12545 1 original paper introduction according to the world health organization (who), infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse (1). in mammals, spermatogenesis is totally dependent upon testosterone (t) (2). androgens are essential for male fertility and maintenance of spermatogenesis and t is the androgen in the testis that is responsible for supporting spermatogenesis (2). in absence of t or functional androgen receptors (ar), males become infertile because spermatogenesis rarely progresses beyond meiosis (sharpe & cooper, 1984). t is produced by leydig cells and acts upon sertoli and peritubular cells of the seminiferous tubules and drives spermatogenesis (2). it is believed that intratesticular testosterone (itt) directly stimulates spermatogenesis in men. however, the amount of itt required to initiate spermatogenesis has yet to be determined. it is important to note that itt concentration in healthy men is approximately 100 times greater than t concentration in serum, which suggests that serum t may not be an accurate marker for itt (3). additionally, serum t is affected by several factors such as obesity, social environment, age, time of day and infections such as covid-19 (4). according to kelly and jones (2015), low serum t levels are associated with increased fat mass particularly central obesity (5). intratesticular steroids consist of approximately 70% t, 20% 17-ohp, and smaller percentages of other hormones (6). amory et al. (2008) found that serum 17-ohp strongly reflects itt concentrations in men with normal gonadotropic function receiving gonadotropin suppression and human chorionic gonadotropin (hcg) (6). 17-ohp was found to correlate with itt in the presence of normal or near normal hcg stimulation (7). about 70% of 17-ohp is thought to be of testicular origin, the remainder of 17ohp production is thought to be of adrenal origin (7). notably, 17-ohp is a precursor for t synthesis, and itt is essential for spermatogenesis but can only be reliably measured with invasive testicular sampling (8). furthermore, 17-ohp would be useful in conjunction with serum t measurements to assess the ideal dosage of hcg required to treat males with infertility (8). varicocele (vx) is significantly associated with primary and secondary infertility due background & objectives: notably, 17-hydroxy progesterone (17-ohp) (17-ohp) is a precursor for testosterone (t) synthesis, and intratesticular testosterone (itt) is essential for spermatogenesis. varicocele (vx) has an estimated prevalence of 15% in the general population and 35% in those with primary infertility. we aimed to evaluate the correlation between changes of serum 17-ohp after sub-inguinal micro-varicocelectomy and improvement of semen parameters. patients and methods: the current prospective study included 45 infertile men attending the andrology clinic form february 2021 to august 2021. two semen analyses and hormonal profile were evaluated. colored duplex ultasonography (cdus) was done in standing and supine position for accurate measurements of testicular volumes and confirmation of vx. patients underwent subinguinal micro-varicocelectomy using a surgical microscope hb surgitech. we followed them prospectively up for three months following micro-varicocelectomy with serum tt and 17-ohp. results: sperm concentration improved significantly from 8.36 ± 5.04 million/ml to 12.52 ± 8.42 million/ml after 3 months following sub-inguinal micro-varicocelectomy (p = 0.001), with normalization of concentration in 15/45 (33%) patients. total motility did not improve significantly but progressive motility improved significantly from 8.62 ± 8.74% to 16.24 ± 14.45% (p = 0.001). abnormal forms significantly declined from 96.67 ± 2.03% to 95.75 ± 2.47% (p = 0.009). serum 17 ohp and 17 ohp/total testosterone (tt) improved significantly from 1.21 ± 0.45 ng/ml and 0.26 ± 0.09 to 1.42 ± 0.76 ng/ml and 0.3 ± 0.16 (p = 0.013, p = 0.004), respectively, while serum tt did not improve significantly. a significant correlation was found between improvement in sperm concentration and both serum 17 ohp and 17 ohp/tt ratio (p = 0.001, p = 004). furthermore, change in abnormal sperm forms showed significant correlations with changes in both 17-ohp and 17-ohp/tt. conclusions: 17 ohp and 17ohp/ tt ratio can be used as biomarkers to detect improvement in semen parameters following sub-inguinal micro-varicocelectomy. key words: sub-inguinal micro-varicocelectomy; 17 hydroxy progesterone; total testosterone; sperm count; progressive sperm motility; abnormal sperm forms. submitted 5 april 2024; accepted 7 may 2024 can serum 17-hydroxy progesterone predict an improvement in semen parameters following micro-varicocelectomy? a prospective study mohamed wael ragab 1, mohamed abbas 1, tarek ramzy 2, sameh fayek gamalel din 1, mohamed yousry elamir 1, mohammad h. alkandari 3, abdullah salem alshammari 4, mohamed ragab shehata 1, ashraf zeidan 1 1 department of andrology & stds, kasr alainy faculty of medicine, cairo university, egypt; 2 department of chemical pathology, kasr alainy faculty of medicine, cairo university, egypt; 3 mubarak al-kabeer teaching hospital, kuwait; 4 farwaniyah hospital, kuwait. doi: 10.4081/aiua.2024.12545 summary archivio italiano di urologia e andrologia 2024; 96(3):12545 m. wael ragab, m. abbas, t. ramzy, et al. 2 to the multifactorial way in which they affect fertility (910). vx is one of the reversible causes and has an estimated prevalence of 15% in the general population and 35% in those with primary infertility (9-10). one of the mechanisms by which vx can affect the testicles is inducing disturbance of leydig cell function, resulting in decreased itt biosynthesis. in a meta-analysis, it was found that surgical repair significantly increased testosterone (t) levels in men with vx (11-14). the negative effect of vx on male fertility is well studied. however, the relationship between clinical vx and impaired hormonal production is still vague and requires further analysis (15). thus, we based our current study on two hypotheses. the first hypothesis assumes that 17-ohp is a reliable serum biomarker that correlates with itt levels. the second one speculates that vx is associated with impairment of androgen synthesis. therefore, we analyzed the correlation between vx repair and semen parameters, using serum tt and 17-ohp preoperative and postoperative measurements. patients and methods the current prospective study included 45 infertile men attending the andrology clinic form february 2021 to august 2021. the institutional review board approved the current work that conforms to helsinki declaration 2013 (16). an informed consent was signed by the patients prior to joining the study and after explaining the possible outcomes of sub-inguinal micro-varicocelectomy. inclusion criteria males suffering from infertility for more than one year (age ranges between 20-51 years old) with at least one abnormal semen parameter (oligoasthnospermia, asthenozoospermia, or teratozoospermia) and a palpable vx were included. exclusion criteria history of intake of medications that affect androgen synthesis, azoospermia, elevated follicle stimulating hormone (fsh), hypogonadotropic hypogonadism, history of previous testicular disease (torsion, trauma and infection), history of covid-19 infection, history of previous testicular surgery and patients who received chemotherapy or radiotherapy within the last six months were excluded. age and duration of infertility were reported. sexual history including frequency of intercourse as well as any ejaculation disorder, any past history of testicular disease or previous operation, and any special habits affecting semen parameters including smoking were also reported. evaluation of testicular size, spermatic cord, vas deferens and grading of vx were determined. laboratory evaluation included: two semen analyses (one before the operation and another one three months following the subinguinal micro-varicocelectomy) according to the fifth edition of who guidelines (2010) (17) and hormonal profile including fsh, luteinizing hormone (lh), total testosterone, estradiol, acth and blood sampling for assay of 17-ohp by elisa commercial kits (preoperative and three months postoperative). colored duplex ultasonography (cdus) (mindray dp-30 portable ultrasound) in standing and supine position for accurate measurements of testicular volumes and confirmation of vx by detection of venous regurge and measurement of maximum venous diameters was conducted. patients underwent sub-inguinal micro-varicocelectomy using a surgical microscope hb surgitech [5 step magnifications (4x, 6x, 10x, 16x & 25x) 45 degree inclined binocular tubes, 12.5x wide field eye pieces, f=200 mm objective lens, aadesh complex, court road, near cjm court, ambala134003, haryana, india]. we followed patients prospectively up for three months following sub-inguinal microvaricocelectomy with serum tt and 17-ohp. statistical analysis results are expressed as mean, standard deviation, minimum and maximum, or number (%). the kolmogorovsmirnov test for normality was used to measure the distribution of data measured before and after surgery. accordingly, in normally distributed variables, comparison of data from before and after surgery was performed using paired t-tests. in abnormally distributed data, comparison between before and after operation data was performed using the wilcoxon signed rank test. to perform correlation between change in both 17-ohp and 17ohp/tt ratio and different motility parameters, firstly, we calculated the change that occurred between before and after operation from the equation: after operation minus before operation. secondly, a test of normality was done for these variables. thirdly, spearman's rho correlation coefficient was used to correlate between variables. statistical package for social sciences (spss) computer program (version 19 windows) was used for data analysis. p-value ≤ 0.05 was considered significant. results the history and demographic characteristics of the studied men are shown in table 1. a significant improvement in sperm count was detected three months following sub-inguinal micro-varicocelectomy (table 2). a significant improvement of progressive sperm motility three months after sub-inguinal micro-varicocelectomy was observed (table 2). abnormal forms significantly declined from 96.67 ± 2.03% to 95.75 ± 2.47% (table 2). preoperative mean tt was 4.86 ng/dl and postoperative mean tt was 4.77ng/dl with no significant improvement three months following sub-inguinal micro-varicotable 1. descriptive statistics of age, special habits, spouse’s age and menses and duration of infertility. studied group (n = 45) patients' age minimummaximum 20.0-51.0 mean ± sd 30.93 ± 7.17 smoking no 30 (66.7%) ex-smoker 3 (6.7%) yes 12 (26.7%) spouse age minimum-maximum 19.0-40.0 mean ± sd 26.82 ± 5.61 duration of infertility in years minimum-maximum 1.0-14.0 mean ± sd 4.35 ± 3.44 archivio italiano di urologia e andrologia 2024; 96(3):12545 3 can serum 17-hydroxy progesterone predict an improvement in semen parameters following micro-varicocelectomy? celectomy detected (table 2). on the other hand, preoperative mean 17-ohp was 1.21 ng/ml and it increased significantly to 1.42 ng/ml at 3 months after sub-inguinal micro-varicocelectomy (table 2). consistently, the preoperative 17-ohp/tt ratio had a mean value of 0.26 and significantly increased postoperatively to 0.30 (table 2). the preoperative means of acth, e2, lh and fsh were 33.80 ± 12.73 pg/ml, 18.31 ± 5.73 pg/ml, 4.98 ± 1.81 miu/ml, 4.42 ± 2.30 miu/ml, respectively. preoperative scrotal duplex studies showed that left venous diameter ranged from 2.6 mm to 5.5 mm (mean value = 3.58 ± 0.67 mm), while right venous diameter ranged from 1.4mm to 3.7 mm (mean value = 2.5 ± 0.48 mm) with reflux on the left side in 45 patients (100% of the cases) and reflux on the right side in 32 patients (71.1% of the cases). right testicular volume ranged from 8.25 ml to 20.28 ml (mean = 12.91 ± 2.85 ml), while left testicular volume ranged from 7.23 ml to 19.15 ml (mean = 11.77 ± 2.78 ml). a positive correlation between changes in 17-ohp and changes in the 17-ohp/ tt ratio was found (table 3). a significant correlation between postoperative sperm count improvement and a postoperative change in serum 17ohp was also shown (table 3). moreover, a significant correlation between postoperative sperm count improvement and a postoperative change in 17-ohp/tt ratio was detected (table 3). furthermore, change in abnormal sperm forms showed significant correlations with changes in 17-ohp and 17ohp/tt (table 3). twenty-nine patients had sperm count improvement after sub-inguinal micro-varicocelectomy (mean change = 4.15 mil/ml) and 27 patients had semen progressive motility improvement (mean change = 7.62%). twenty-three patients had an elevation in serum 17-ohp level following sub-inguinal microvaricocelectomy (mean change = 0.20 ng/ml) and 28 patients had an elevation in serum 17ohp/tt ratio (mean change = 0.04). figure 1. mean values of sperm count measured before and after operation. table 2. sperm count and total and progressive sperm motility and abnormal forms in the studied group before and after microvaricocelectomy. before after z value p value sperm count min-max 0.5-18.0 0.0-43.0 mean ± sd 8.36 ± 5.04 12.52 ± 8.42 -3.765 0.001 total sperm motility min-max 0.0-75.0 0.0-67.0 mean ± sd 31.86 ± 20.45 31.78 ± 19.20 t= 0.039 0.969 progressive sperm motility min-max 0.0-30.0 0.0-64.0 mean ± sd 8.62 ± 8.74 16.24 ± 14.45 z= -3.899 0.001 abnormal forms min-max 79.0-100.0 76.0-100.0 mean ± sd 96.67 ± 2.03% 95.75 ± 2.47% z= -1.780 0.009 total testosterone (tt) min-max 2.60-8.30 2.73-7.69 mean ± sd 4.86 ± 1.38 4.77 ± 1.31 z= -1.383 0.167 17 hydroxy progesterone (17-ohp) min-max 0.38-2.10 0.39-4.42 mean ± sd 1.21 ± 0.45 1.42 ± 0.76 t= -2.577 0.013 17-ohp/tt ratio min-max 0.06-0.52 0.07-1.02 mean ± sd 0.26 ± 0.09 0.30 ± 0.16 z= -2.873 0.004 wilcoxon signed ranks test. t value = paired t test. table 3. correlations between change in both 17-ohp and 17-ohp/tt ratio and different semen parameters. 17-ohp 17-ohp/tt ratio r p value r p value 17-ohp --------. 0.853 0.001* count 0.477 0.001* 0.417 0.004* total motility 0.275 0.068 0.177 0.244 progressive motility 0.141 0.356 0.034 0.825 change in abnormal forms 0.331* 0.014 0.320* 0.017 rspearman's rho correlation coefficient. p > 0.05 = not significant; *p ≤ 0.05 = significant. archivio italiano di urologia e andrologia 2024; 96(3):12545 m. wael ragab, m. abbas, t. ramzy, et al. 4 discussion the current study documented significant improvements of sperm count and progressive motility and sperm normal forms following sub-inguinal micro-varicocelectomy. out of 45 patients, 29 (64%) had improvement in sperm count and 14 of those had a normal sperm count following vx repair. however, one patient dropped from severe oligoasthenozoospermia to azoospermia following the operation. our findings of count improvement after surgery were consistent with other studies (18). twentyseven patients (60%) had improvement in sperm progressive motility three months following the operation. of those twenty-seven patients, only six patients had normal progressive motility following the operation. before the operation, mean sperm progressive motility was 8.62 % which significantly improved three months following the operation to become 16.24%. also, abnormal forms significantly improved after sub-inguinal micro-varicocelectomy. out of 45 patients, 23 (51.1%) had a significant elevation of serum 17-ohp post-operatively. twenty-eight patients (62.2%) had a significant elevation of 17 ohp/tt ratio in the follow-up after sub-inguinal micro-varicocelectomy. this came in contrast to another study which found that microsurgical varicocele repair resulted in improvements in all evaluated semen parameters, but not in itt/17-ohp or serum t levels and percentage of normal sperm forms (14). conversely, mean preoperative total motile count (tmc) was 31.86 %, while 3-month post-varicocelectomy it was 31.78%, with no significant improvement. this could be seen contradictory to lima et al. (2020) who suggested a significant improvement of tmc following varicocelectomy (14). furthermore, we did not find a significant improvement in serum tt three months following varicocelectomy. this was consistent with previous studies which showed that men with normal serum t were less likely to improve postoperatively (14, 19). noteworthy, a positive correlation between changes in 17-ohp and improvement in semen concentration were noticed. such results came in alignment with those of one study which suggested that serum 17-ohp strongly reflects itt concentrations (6) as well as another study which suggested that 17-ohp could be a useful biomarker for itt (9). additionally, change in abnormal sperm forms showed significant correlations with changes in 17-ohp and 17-ohp/tt. the positive outcome of the semen parameters following the sub inguinal micro-varicocelectomy comes in the same line of a recent study conducted by kalantan et al. (2023) (20). the strengths of this study include the novelty of associating sperm count and progressive motility improvement and sperm abnormal forms after sub-inguinal micro-varicocelectomy with 17-ohp and 17-ohp/tt ratio. we tried to control variability in this study by performing all serum measurements between 8 and 10 am. scrotal duplex scans were performed for all patients to guarantee accurate diagnosis of vx by venous diameter measurement, assessment of testicular volume and detection of venous reflux with valsalva maneuver. furthermore, we performed multiple follow-up assessments. in addition, we potentially identified a serum biomarker that had the ability to characterize men who were deficient in itt as well as follow up by monitoring these patients for changes in semen parameters. this could be seen in alignment with bridges et al. (2015) (21). hypothetically, we succeeded in presenting 17-ohp and 17-ohp/tt as potential biomarkers for predicting improvement in semen parameters following subinguinal micro-varicocelectomy. on the other hand, there figure 2. mean values of progressive motility measured before and after operation. archivio italiano di urologia e andrologia 2024; 96(3):12545 5 can serum 17-hydroxy progesterone predict an improvement in semen parameters following micro-varicocelectomy? are several limitations of the current study that must be mentioned. firstly, the small sample size is a major limitation. secondly, we did not follow up the effect of improvement of semen parameters on pregnancy rates. finally, we were unable to measure itt. however, it should be noted that we based the correlation of 17-ohp with itt on a study conducted by patel et al. (2019) (8). conclusions according to the current study, sub-inguinal micro-varicocelectomy resulted in significant improvements in sperm count and progressive motility that significantly correlated with changes in 17-ohp and 17-ohp/ tt ratio. acknowledgements we would to thank the surgeons who did subinguinal micro-varicocelectomy. references 1. jungwirth a, giwercman a, tournaye h, et al. & european association of urology working group on male infertility. european association of urology guidelines on male infertility: the 2012 update. eur urol. 2012; 62:324-332. 2. sharpe rm, cooper, i. intratesticular secretion of a factor (s) with major stimulatory effects on leydig cell testosterone secretion in vitro. mol cell endocrinol. 1984; 37:159-168. 3. roth m, page s, lin k, et al. dose-dependent increase in intratesticular testosterone by very low-dose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency. j clin endocrinol metab. 2010; 95:3806-3813. 4. duarte-neto an, teixeira ta, caldini eg, et al. testicular pathology in fatal covid-19: a descriptive autopsy study. andrology. 2022; 10:13-23. 5. kelly d, jones t. testosterone and obesity. obes rev. 2015; 16:581606. 6. amory jk, coviello ad, page st, et al. serum 17-hydroxyp-rogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin. fertil steril. 2008; 89:380-386. 7. roth my, lin k, bay k, et al. serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with lowdose human chorionic gonadotropin: a randomized, controlled trial. fertil steril. 2013; 99:132-139. 8. patel a, patel p, bitran j, ramasamy r. can serum 17-hydroxyprogesterone and insulin-like factor 3 be used as a marker for evaluation of intratesticular testosterone?. transl androl urol. 2019; 8 (suppl 1):s58-s63. 9. alharbi m, zini a. epidemiology of varicocele in pediatric, adolescent, and adult populations. in sandro c esteves, chak-lam cho, ahmad majzoub, ashok agarwal (eds) varicocele and male infertility. springer 2019. pp. 97-106 10. alsaikhan b, alrabeeah k, delouya g, zini a. epidemiology of varicocele. asian j androl. 2016; 18:179-181. 11. zohdy w, ghazi s, arafa m. impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. j sex med. 2011; 8:885-893. 12. li f, yue h, yamaguchi k, et al. effect of surgical repair on testosterone production in infertile men with varicocele: a metaanalysis. int j urol. 2012; 19:149-154. 13. hsiao w, rosoff js, pale jr, et al. varicocelectomy is associated with increases in serum testosterone independent of clinical grade. urology. 2013; 81:1213-1217. 14. lima tfn, frech fs, patel p, et al. effect of microsurgical varicocelectomy on semen parameters, serum, and intratesticular testosterone levels. bjui compass. 2020; 1:93. 15. bellastella g, carotenuto r, caiazzo f, et al. varicocele: an endocrinological perspective. front. reprod. health. 2022; 4:863695. 16. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-2194. 17. world health organization (who). who laboratory manual for the examination and processing of human semen. 5th ed. geneva: who:2010, p.271. 18. schauer i, madersbacher s, jost r, et al. the impact of varicocelectomy on sperm parameters: a meta-analysis. j urol. 2012; 187:1540-1547. 19. rodriguez peña m, alescio l, russell a, et al. predictors of improved seminal parameters and fertility after varicocele repair in young adults. andrologia. 2009; 41:277-281. 20. kalantan m, vienney n, guillot tantay c, et al. résultats des cures de varicocèles microchirurgicales sous-inguinales (results of subinguinal microsurgical varicocelectomy). prog urol. 2023; 33:481-487. 21. bridges n, trofimenko v, fields s, et al. male factor infertility and clomiphene citrate: a meta-analysis the effect of clomiphene citrate on oligospermia. urol pract. 2015; 2:199-205. correspondence mohamed wael ragab, md m.w.ragab@kasralainy.edu.eg mohamed abbas, md mhmdabbas71@yahoo.com mohamed yousry elamir, md yousr82@kasralainy.edu.eg mohamed ragab shehata, m.sc ragabmohamed260491@gmail.com ashraf zeidan, md zeidana2000@gmail.com department of andrology & stds, kasr alainy faculty of medicine, cairo university, egypt tarek ramzy, md drtarekramzy@yahoo.com department of chemical pathology, kasr alainy faculty of medicine, cairo university, egypt sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg department of andrology & stds, kasr alainy faculty of medicine, cairo university, egypt al-saray street, el manial, cairo, 11956, egypt mohammad h. alkandari, md al_kandarim@hotmail.com mubarak al-kabeer teaching hospital, kuwait abdullah salem alshammari, mb bch astsh51@gmail.com farwaniyah hospital, kuwait conflict of interest: the authors declare no potential conflict of interest. the present study has been presented as a poster in the 12th european congress of andrology abstract book. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14075 1 letter to editor key words: percutaneous nephrolithotomy; prone; barts flank free modified supine position. submitted 13 june 2025; accepted 13 july 2025 to the editor, we read the meta-analysis by ananda et al. (1), with great interest and congratulate the authors on their contribution. described in 2012 by masood (2), we are delighted to see the barts flank-free modified supine (barts ffms) position for pcnl popularised. it offers many advantages over the prone position for both the surgeon and patients (2). ananda et al., concluded the surgery duration was significantly shorter in the barts ffms position vs the prone position with no significant differences in the stone free rates (sfr), complications, screening time, and length of stay. they state the choice of patient position should be based on the surgeon’s preference and the patient’s clinical choice. advantages of prone pcnl include excellent exposure of the flank, ample space for several tracts to be placed if needed and good manipulation of instruments (3). upper pole puncture may be easier in the prone position as the posteromedial location of the upper pole brings it closer to the posterior abdominal wall (4). however, prone pcnl has several disadvantages. patients need to be repositioned after the first stage increasing operating time, potentially causing injury and jeopardising airway access (3). managing cardiorespiratory emergencies in the prone position is challenging. lying on the abdomen causes anaesthetic difficulties with reduced lung compliance and increased intraabdominal pressure (iap) potentially leading to a reduction in cardiac output (5). there is increased risk of ophthalmological complications such as orbital/corneal abrasions and raised intraocular pressure causing ischaemic oculopathy (6). the prone position is not suitable for carrying out simultaneous retrograde intra-renal surgery (rirs). patients with significant cardiorespiratory morbidities, certain musculoskeletal deformities or the very obese cannot be placed prone. the prone position may increase the surgeon’s radiation exposure by standing close to the patient and working with instruments in a more perpendicular direction (4). we recommend patients are placed on a montreal mattress (5, 7) (figure 1) during prone pcnl. this rectangular mattress used for spinal procedures is hollow in the centre allowing abdominal contents to fall through reducing iap, improving ventilation and cardiac output (5, 7). it allows for flexion of the hips giving more space for renal access between the ribs and iliac crests and prevents extension reducing stress on the back. comment on: barts flank-free modified supine position vs prone position in percutaneous nephrolithotomy: systematic review and meta-analysis khaled ghanem, damiete harry, junaid masood endourology and stone services, king george, and queens hospitals, bhr university hospitals nhs trust, london uk. doi: 10.4081/aiua.2025.14075 figure 1. the montreal mattress with a hollow centre. it allows for flexion at the hips to reduce any strain on the spine with better access to the kidney. archivio italiano di urologia e andrologia 2025; 97(3):14075 k. ghanem, d. harry, j. masood 2 the head should be supported in a prone-view™ protective helmet system (dupaco, oceanside, ca) maintaining neutral neck alignment. this consists of a cushion, protective helmet with legs, and a base mirror with posts (figure 2) aiding the anaesthetist to view the patient’s face and endotracheal tube, important in case of a ventilation problem during surgery (5). these mitigate against some of the anaesthetic and skeletal complications arising in the prone position (5). our preferred position for pcnl “the barts ffms” allows for easy access with fluoroscopy or ultrasound (torso tilted around 15%) to reduce the radiation exposure (2). the barts ffms position gives the best exposure of the flank among the supine positions (2, 3) (figure 3). a flank free from any support provides space for planning and dilating multiple tracts since the kidney is in a neutral position and therefore less mobile (2). the tract is essentially horizontal which allows easy washout of fragments with low intrarenal pressures (2). the surgeon can sit down whilst operating reducing tiredness whilst improved radiological safety is maintained as the surgeon’s hands are less exposed compared with the prone position. simultaneous rirs can be easily carried out (2) (figure 4). it caters for patients with significant cardiovascular and respiratory morbidity, musculoskeletal deformities and obese patients who cannot be placed prone. ananda et al., accept their meta-analysis is limited by the inclusion of a small number of studies with inconsistencies and heterogeneity in reporting and outcomes. evidence suggests equivalence in sfr and surgical complications between supine and prone positions (8). larger scale multi centre randomised studies are needed to further clarify if a difference exists. however supine pcnl has numerous other advantages including available simultaneous rirs, shorter operating time and lower intrarenal pressures during the surgery possibly accounting for the lower risk of infective complications (9). indeed, infective complications are statistically more common in patients undergoing prone pcnl with the prone position an independent risk factor for post operative infections (10). figure 2. the prone-view™ helmet system with a cushion, a protective helmet with legs, and a base mirror with posts. it enables neutral head and neck alignment and allows the patient’s face and the endotracheal tube to be viewed. figure 3. barts ffms position. note a gel pad under the ipsilateral pelvis (1) and under the rib cage (2) leaving the flank free. ic: iliac crest; pal: posterior axillary line, also marked are the 10th, 11th and 12th ribs. figure 4. showing the barts ffms position from below allowing for easy rirs access. please note the ipsilateral leg is relatively extended and the contralateral side abducted. archivio italiano di urologia e andrologia 2025; 97(3):14075 3 comment on: barts flank-free modified supine position vs prone position in percutaneous nephrolithotomy a recent global census carried out by the endourological society confirmed the growing popularity of supine pcnl. prone pcnl still remains the most common with 47.5% of endourologists using this position exclusively. 16.3% use the supine position exclusively and 36% use both positions (11). we believe the barts ffms position is the standard for carrying out pcnl as highlighted by its many advantages over the prone position but accept there may be rare situations where a prone position pcnl could be indicated for example in certain upper pole punctures. with more education and training, supine pcnl with its numerous advantages will be further adopted as the standard pcnl approach. references 1. ananda igyp, santosa kb, yudiana iw, et al. barts flank-free modified supine position vs prone position in percutaneous nephrolithotomy: systematic review and meta analysis. arch ital urol androl 2024; 96:12944. 2. bach c, goyal a, kumar p, et al. the barts 'flank-free' modified supine position for percutaneous nephrolithotomy. urol int. 2012; 89: 365-8. 3. karaolides t, moraitis k, bach c, et al. positions for percutaneous nephrolithotomy: thirty-five years of evolution. arab j urol. 2012; 10:307-16. 4. ray aa, chung dg, honey rj. percutaneous nephrolithotomy in the prone and prone-flexed positions: anatomic considerations. j endourol 2009; 23:1607-14. 5. papatsoris a, masood j, el-husseiny t, et al. improving patient positioning to reduce complications in prone percutaneous nephrolithotomy. j endourol 2009; 23:831-2. 6. hunt k, bajekal r, calder i, et al. changes in intraocular pressure in anesthetized prone patients. j neurosurg anesthesiol 2004; 16:287-90. 7. feindel w. neurosurgery at the montreal neurological institute and mcgill university hospitals. neurosurgery 1996; 39:830-839. 8. li j, gao l, li q, et al. supine versus prone position percutaneous nephrolithotomy: a meta-analysis of randomised controlled trials. int j surg. 2019; 66:62-71. 9. farkouh a, park k, buell mi, et al. prone vs supine percutaneous nephrolithotomy: does position affect renal pelvic pressures? urolithiasis. 2024; 52:66. 10. kasap y, senel s, uzun e, et al. does surgical position affect infective complications in percutaneous nephrolithotomy? urolithiasis 2022; 50:765-771. 11. moreland h, smith l, stowasser v, et al. the endourological society inaugural census report. j endourol 2023; 37:199-206. declarations ethical approval and consent for participate: not applicable. consent for publication: granted. availability of data and material: the licence for images has been obtained and was attached to the previous payment email. competing interests: none. funding: none. authors' contributions: all authors participated in the conceptualisation of the idea. the writing was done by the main author and the manuscript was revised and edited the senior authors. acknowledgments: none. correspondence khaled ghanem mbbs, mrcs, msc (corresponding author) urology registrar khaledghanem899@hotmail.com endourology and stone services, department of urology, king george and queens hospitals, bhr university hospitals nhs trust barley lane, ilford, ig3 8yb, london uk damiete harry, mbbs, mrcs, frcs (urol) consultant urological surgeon damiete.harry@nhs.net junaid masood, mbbs, frcs (eng), frcs (urol) msc (urol) consultant urological and stone surgeon junaid.masood@nhs.net endourology and stone services, department of urology, king george and queens hospitals, bhr university hospitals nhs trust, london uk stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12530 1 original paper various outcomes, from exceedingly severe phenotypes with prenatal death to live-born individuals with acceptable renal function (1). despite being an uncommon congenital abnormality (prevalence 1-9/100,000), it represents approximately 17% of pediatric end-stage renal disease (esrd) (1, 2). the current definitive treatment of choice is endoscopic puv ablation; however, roughly 10% to 30% of patients require a second surgery to achieve adequate valve ablation (3, 4). any partial outlet obstruction could cause anatomical and functional deterioration in the detrusor muscle of the bladder wall if it is not released quickly enough (5). this indicates the importance of close follow-up after valve ablation (5). it might be challenging to assess the result of endoscopic valve ablation. while some investigators suggest that voiding cystourethrogram (vcug) confirms the adequacy of valve ablation, others offer cystoscopic procedures.6-8 the disadvantages of vcug are transient dysuria, hematuria, and toilet anxiety. on the other hand, the invasive nature and the need for admission and anesthesia are the main disadvantages of the cystoscopic procedure (4, 6). distinguishing prognostic factors for residual valves after endoscopic valve ablation can aid in developing a better algorithm for managing puvs and achieving purposeful follow-up for high-risk patients (4). as a result, new prediction techniques are required to allow for better patient diagnosis and follow-up (9). a study conducted by shirazi et al. to investigate the patients with a higher risk for residual valves after puv ablation found that younger age at surgery time, hyperechogenicity of renal parenchyma, presence of vesicoureteral reflux, and grade 4 or 5 reflux before surgery were associated with residual valves and need for repeated ablation (4). the most commonly used form of artificial intelligence (ai) in medicine is artificial neural networks (anns) that mimic interconnected brain synapses and networks taught by analyzing input and output databases (10, 11). the system learns to identify variables influencing outcomes, and as more data is incorporated, self-optimization matures, resulting in more accurate predictions and higher accuracy rates for specific outcomes (12). purpose: to build, train, and assess the artificial neural network (ann) system in estimating the residual valve rate after endoscopic valve ablation and compare the data obtained with conventional analysis. methods: in a retrospective cross-sectional study between june 2010 and december 2020, 144 children with a history of posterior urethral valve (puv) who underwent endoscopic valve ablation were enrolled in the study. matlab software was used to design and train the network in a feed-forward backpropagation error adjustment scheme. preoperative and postoperative data from 101 patients (70%) (training set) were utilized to assess the impact and relative significance of the necessity for repeated ablation. the validated suitably trained ann was used to predict repeated ablation in the next 33 patients (22.9%) (test set) whose preoperative data were serially input into the system. to assess system accuracy in forecasting the requirement for repeat ablation, projected values were compared to actual outcomes. the likelihood of predicting the residual valve was calculated using a three-layered backpropagating deep ann using preoperative and postoperative information. results: of 144 operated cases, 33 (22.9%) had residual valves and needs to repeated ablation. the ann accuracy, sensitivity, and specificity for predicting the residual valve were 90.75%, 92.73%, and 73.19%, respectively. younger age at surgery, hyperechogenicity of the renal parenchyma, presence of vesicoureteral reflux (vur), and grade of reflux before surgery were among the most significant characteristics that affected postoperative outcome variables, the need for repeated ablation, and were given the highest relative weight by the ann system. conclusions: the ann is an integrated data-gathering tool for analyzing and finding relationships among variables as a complex non-linear statistical model. the results indicate that ann is a valuable tool for outcome prediction of the residual valve after endoscopic valve ablation in patients with puv. key words: artificial neural network; artificial intelligence; children; outcome; posterior urethral valve; residual valve. submitted 1 april 2024; accepted 1 june 2024 introduction posterior urethral valve (puv) is the most common cause of congenital bladder outlet obstruction in males, with utilizing artificial neural network system to predict the residual valve after endoscopic posterior urethral valve ablation mehdi shirazi 1, 2, zahra jahanabadi 1, faisal ahmed 3, davood goodarzi 1, alimohammad keshtvarz hesam abadi 4, mohammad reza askarpour 1, sania shirazi 5 1 department of urology, school of medicine, shiraz university of medical sciences, shiraz, iran; 2 histomorphometry and stereology research center, shiraz university of medical sciences, shiraz, iran; 3 department of urology, school of medicine, ibb university, ibb, yemen; 4 phd candidate in biostatistics, department of biostatistics, shiraz university of medical sciences, shiraz, iran; 5 student research committee, shiraz university of medical sciences, shiraz, iran. doi: 10.4081/aiua.2024.12530 summary archivio italiano di urologia e andrologia 2024; 96(3):12530 m. shirazi, z. jahanabadi, f. ahmed, et al. 2 in the present study, we aimed to investigate the efficacy of anns as an intelligible interface to predict the rate of the residual valve after endoscopic valve ablation in children with puv. materials and methods study design in a retrospective cross-sectional study, 144 children who were diagnosed with puv and had undergone endoscopic bladder neck resection and valve ablation between june 2010 and december 2020 in the referral centers (nemazi teaching hospital and shahid faghihi teaching hospital, shiraz, southern iran) were selected to participate in this study. the ethics committees of shiraz university of medical sciences approved this project (approval code# ir.sums.med.rec.1399. 585), and it was carried out in compliance with the helsinki declaration. all patient’s parents or legal guardians provided written informed consent before enrolment. surgical intervention all primary puv ablations were performed by a single experienced pediatric urologist (prof. shirazi). the valves were carefully ablated at the 5, 7, and 12 o'clock positions using an electrical bugbee, and the visual assessment of the valve destruction ascertained the endpoint of ablation. then, a urethral catheter was left in place and removed 48 hours later. patients were discharged with oral antibiotics. postoperative follow-up for residual valve assessment the possible presence of residual valve remnants was assessed by careful clinical, radiological and endoscopic evaluation (13). for that, the patients were assessed with ultrasonography (us) every 3 to 6 months, vcug 3 months after valve ablation, and a control cystoscopy three to 12 months later, and if a residual valve was found, a second valve ablation was performed (4, 14). clinically, a persistent symptom of poor stream, nocturnal enuresis in older than 5 years, and persistent or worsened vur or worsened hydronephrosis in the serial us were also considered. slight residual valves that did not cause renal impairment or urinary tract infections (utis) were excluded (15). data collection all the data used in this study, including preoperative and postoperative parameters, are summarized in table 1. design, training, and validation of the ann system we designed and trained the network with matlab software (mathworks, natick, ma) using a feed-forward backpropagation error adjustment scheme (16, 17). the data were separated into training and test sets to fit the anns (figure 1). training set the network training set accounted for 101 (70%) of the study data. the architecture of the education network consists of three layers: input, hidden, and output. the number of nodes in the input and output layers corresponds to the number of predictor and response variables. the number of hidden layer nodes was determined by trial and error. the level criterion below the characteristic performance curve (roc) was used to find the best network structure. finally, after selecting the best architecture, the network was evaluated and validated in second-stage data that did not play a role in the network training phase. test set the network test set accounted for 43 (30%) patients. the final response variable or the final output of the model was a two-state variable with the levels of 0-no residual valve and 1-had residual valve. the number of input variables was 24, the same as the independent variables. after selecting the input and output variables, a three-layer perceptron network (with an observer) was used, with one neuron in the output layer and 24 neurons in the input layer. according to the training data set and independent input variables, 320 combinations were table 1. variables considered for analysis. postoperative variables preoperative variables history of enuresis age (months) blood pressure (mm hg) birth weight (low, normal) history of urinary incontinence time of diagnosis (prenatal, postnatal) time to puv ablation (months) presence of vur (grad) in vcug grade of vur in vcug urinary bladder trabeculation (mild, moderate, severe) in us urinary bladder trabeculation (mild, moderate, severe) in us bladder diverticula in us bladder diverticula in us blood creatinine level(mg/dl) blood creatinine level (mg/dl) degree of hdn (mild, moderate, severe) in us degree of hdn (mild, moderate, severe) in us loss of cortico-medullary differentiation loss of cortico-medullary differentiation in us renal cortical thickness (mm) in us renal cortical thickness (mm) in us size of bladder wall thickness (mm) in us size of bladder wall thickness (mm) in us history of recurrent uti proteinuria in urine analysis urine culture scar in renal dmsa scan puv: posterior urethral valve; dmsa: dimercaptosuccinic acid; hdn: hydronephrosis; vur: vesicoureteral reflux; vcug: voiding cystourethrogram; uti: urinary tract infection; us: ultrasonography. figure 1. schematic design of artificial neural network. archivio italiano di urologia e andrologia 2024; 96(3):12530 3 utilizing artificial neural network system to predict the residual valve after endoscopic posterior urethral valve ablation based on 4 to 19 nodes in the hidden layer with a size of 0.8 to 0.95 (0.95, 0.9) to model a three-layer perceptron ann. we evaluated the learning rate of 0.05 to 0.4 (0.4, 0.3, 0.2, 0.1, 0.05) with hyperbolic tangent activity in the hidden layer, sigmoid function activity in the output layer, and post-diffusion learning algorithm. after examining all possible models for the structure of the threelayer ann, the network with 24 input nodes, 10 hidden nodes, one output node, a learning rate of 0.2, and a motion size of 0.9 with an error propagation algorithm as the best ann to predict the data. the number of fitted models for each combination was 20; the best model for each structure is shown in table 2. statistical analysis the mean and standard deviation were used for quantitative variables, and frequency and percentage were used for qualitative variables. to evaluate the predictive accuracy of the system for each postoperative variable, the predicted values were compared with the actual outcomes (observed values), and true positive, false positive, accuracy, and precision rates of the system were calculated for the need for repeated ablation. all statistical analyses were done using spss software (ibm spss, version 20, armonk, new york: ibm corp), and the significance level was also considered (p < 0.05). results the preoperative characteristics of patients are summarized in table 3. the mean age at presentation was 8.65 ± 6.12 months. low birth weight was presented in 0.3% of patients. the prenatal diagnosis of puv was performed in 81(56.25%) patients. there were 33 (22.91%) patients who required a second valve ablation due to valve remnants. postoperative data of patients are displayed in table 4. the predictive factor for the residual valve in regression analysis in multivariate analysis, the factors below were significantly associated with the residual valve and need for repeated ablation: younger age at operation (odds ratio [or] 1.142; 95% confidence interval [ci] 1.006-1.297), high initial serum creatinine (or: 1.498; 95%ci: 1.0893.257), increased bladder wall thickness (or: 1.486; 95%ci: 1.014-2.741), higher postoperative serum creatinine (or: 1.883; 95%ci: 1.181-4.311), presence of renal cortical thickness (or: 1.185; 95%ci: 1.004-1.721), presence of severe bladder trabeculation (or:1.54; 95%ci:1.136-11.281), and presence of reflux grading table 2. selecting the best neural network model for the recurrent data. motion total area percentage learning architecture row size squares below of correct rate error roc curve prediction 0.90 33.29 0.836 79.70 0.2 1-4-24 1 0.80 34.08 0.790 72.30 0.2 1-5-24 2 0.85 32.6 0.815 75.50 0.3 1-6-24 3 0.85 36.41 0.821 84.50 0.5 1-7-24 4 0.85 36.73 0.855 77.60 0.2 1-8-24 5 0.80 34.27 0.853 73.40 0.3 1-9-24 6 0.90 31.71 0.903 90.73 0.2 1-10-24 7 0.85 33.47 0.849 74.40 0.4 1-11-24 8 0.80 35.70 0.766 72.30 0.1 1-12-24 9 0.80 34.48 0.792 74.40 0.5 1-13-24 10 0.85 41.96 0.824 75.50 0.3 1-14-24 11 0.90 34.05 0.804 74.40 0.4 1-15-24 12 0.85 33.41 0.827 73.40 0.2 1-16-24 13 0.80 32.29 0.813 72.30 0.1 1-17-24 14 0.85 35.33 0.829 76.70 0.4 1-18-24 15 0.90 38.27 0.798 83.79 0.1 1-19-24 16 auc: area under the curve. table 3. descriptive statistics of preoperative characteristics of the patients. n (%) variables 8.65 ± 6.12 age at presentation (years) 5 (0.3) low birth weight 81 (56.25) prenatally time to diagnosis 63 (43.75) postnatally 40 (27.7) neonatally time of surgery 51 (35.4) 1-3 month 14 (9.7) 3-6 month 15 (10.4) 6-12 month 24 (16.6) > 12 month 69 (47.9) no presence of vur 15 (10.4) left 23 (16) right 37 (25.7) both 8 (5.5) 1 vur reflux grad 10 (6.95) 2 11 (7.6) 3 19 (13.2) 4 27 (18.75) 5 30 (20.8) mild urinary bladder trabeculation 80 (55.55) moderate 34 (23.65) severe 27 (18.75) bladder diverticula 0.748 ± .618 blood creatinine level (mg/dl) 121 (84) prenatal kub sonography 31 (21.5) no presence of hydronephrosis 11 (7.6) right 20 (13.9) left 82 (57) both 31 (21.5) no degree of hydronephrosis 18 (12.5) 1 32 (22.3) 2 35 (24.3) 3 28 (19.5) 4 42 (29.2) loss of cortico-medullary differentiation 34 (23.6) < 3 mm size of bladder wall thickness 87 (60.4) 3-5 mm 23 (16) > 5 mm 140 (97.2) proteinuria in urine analysis 137 (95.1) positive urine culture 83 (57.7) renal scar in renal dmsa scan 26.80 ± 18.12 left differential function in renal dmsa scan 29.63 ± 19.75 right ap: anterior-posterior diameter; puv: posterior urethral valve, dmsa: dimercaptosuccinic acid; vur: vesicoureteral reflux; uti: urinary tract infection. archivio italiano di urologia e andrologia 2024; 96(3):12530 m. shirazi, z. jahanabadi, f. ahmed, et al. 4 three (or: 2.526; 95%ci: 1.208-7.021), presence of reflux grading four (or: 3.72; 95%ci:1.557-8.899). ann model three hundred and twenty models were fitted to the 16 structures, as shown in table 2. we selected model 7 as the best model (green row) among these models. the prediction accuracy was 90.73%, and the area under the roc curve was 0.903. the accuracy, sensitivity, and specificity of the ann system for predicting the rate of remanent valves were 90.75%, 92.73%, and 73.19%, respectively (table 5). the predictive factor for the residual valve in the ann model younger age at surgery, hyperechogenicity of the renal parenchyma, presence of vur, and grade of reflux before surgery were among the most significant characteristics that affected postoperative outcome variables, the need for repeated ablation, and were given the highest relative weight by the ann system (figure 2). discussion in this study, we developed and utilized an ann system to predict residual valve and ablation needs after endoscopic puv ablation. the accuracy and sensitivity ranged from 90.75% to 92.73%, proving that ann is a valuable table 4. descriptive statistics of postoperative characteristics of the patients n (%) variables 0.617 ± .429 blood creatinine level (mg/dl) 69 (47.9) no presence of hydronephrosis 10 (6.95) right 18 (12.5) left 47 (32.65) both 69 (48) no degree of hydronephrosis 12 (8.3) 1 21 (14.6) 2 24 (16.6) 3 18 (12.5) 4 138 (95.8) urine analysis 136 (94.4) urine culture 83 (57.6) normal blood pressure (mm hg) 4 (2.8) hight 17 (11.8) history of urinary incontinency 15 (10.4) history of enuresis 60 (41.6) 1 proteinuria in urine analysis 63 (43.7) 2 21 (14.7) 3 33 (22.91) yes remnant valve 111 (77.09) no figure 2. the ann main factors that predict the residual valve. table 5. performance of an artificial neural network system in recurrence. auc accuracy negative positive true true predictive predictive negative positive value value rate rate (specificity) (sensitivity) 0.903 90.75% 97.13% 50.69% 73.19% 92.73% recurrence auc: area under the curve. archivio italiano di urologia e andrologia 2024; 96(3):12530 5 utilizing artificial neural network system to predict the residual valve after endoscopic posterior urethral valve ablation tool for the prediction of the residual in puv patients. endoscopic primary valve ablation is the ideal initial surgical therapy for puvs; however determining the absence of remaining valve remains necessitates meticulous examination. some prescribe vcug for adequacy, while others advise cystoscopy follow-up. both procedures offer advantages and downsides, such as transitory dysuria, enuresis, hematuria, and toileting anxiety, as well as the necessity for general anesthesia for cystoscopy. the high incidence rate of remaining leaflets necessitates post-ablation assessment (18). in this study, to reduce the impact of technical aspects of the first puv ablation in the presence of remaining valves, all procedures in the research were carried out by the same surgeon with an experienced pediatric urologist with more than 20 years of experience in the pediatric urology field. additionally, as the vcug alone was insufficient to exclude residual valve tissue (positive and negative predictive values of 56% and 50%, respectively) (7), so cystoscopy was routinely performed on the patients. the reported recurrence rate of residual valves was 10%30% in most studies.13,19 in the same line with previous studies, the recurrence rate in this study was 22.91%. a higher recurrence rate was reported in some studies, such as the study carried out by nawaz et al., who reported 78% residual valves during the follow-up cystoscopy. 8 the high rate of residual valves may be attributed to the use of routine follow-up cystoscopy after primary valve ablation. previous studies have primarily examined the correlation between preoperative factors and postoperative kidney function (20, 21), with limited attention given to the risk of residual remnants valve risk in puv patients (4). in this study, factors significantly associated with residual valve and need for repeated ablation in regression analysis include younger age at operation, high initial serum creatinine, increased bladder wall thickness, higher postoperative creatinine, renal cortical thickness, severe bladder trabeculation, and advanced reflux grading (three or four). similarly, shirazi et al. evaluated the relationship between preoperative findings and residual obstructive leaflets after valve ablation. the authors found that younger age at puv ablation, increased renal echogenicity, and the high vur grade were significantly associated with the presence of residual valves (4). in nabil et al.’s study, the authors found that age at presentation and substantial post-void residual volume (pvr) were highly associated with the presence of residual valves (22). motiwala et al., in their study, recommend using the urethral ratio and bladder wall thickness to assess residual valves (23). premature birth, prenatal diagnosis, and loss of corticomedullary differentiation unilaterally or bilaterally were all associated with meaningfully higher rates of ckd, esrd, and the need for many corrective surgeries in puv patients, according to bilgutay et al. furthermore, symptomatic presentation, recurrent uti, and pre-operative and postoperative high vur were associated with the need for many corrective surgeries but not poor renal outcomes (24). in contrast, some studies mentioned that age of presentation or ablation, urinary diversion, and the bladder neck incision did not significantly affect the outcome of puv management (24, 25). nevertheless, assessing the efficacy of the puv ablation procedure is not uniform and has some drawbacks (4). additionally, bladder dysfunction after primary valve ablation is caused by the gradual deterioration of bladder contractility due to secondary lower urinary tract obstruction and eventually to myogenic bladder failure (24, 25). there is a need to develop predictive models to optimize patient selection and patient counseling and to develop further ways to determine the most likely surgical outcomes before surgery is performed. in the study, younger age at surgery, hyperechogenicity of the renal parenchyma, presence of vur, and grade of reflux before surgery were among the most significant characteristics that affected postoperative outcome variables, the need for repeated ablation and were given the highest relative weight by the ann system. the advantage of ann is that it can simply estimate and notify the relative importance of every variable on puv outcome without the use of invasive methods. the prediction accuracy of the ann model was 90.73%, and the area under the roc curve was 0.903. the accuracy, sensitivity, and specificity of the system for predicting the residual valve were 90.75%, 92.73%, and 73.19%, respectively. using a preoperative and postoperative dataset and a readily available cloudbased predictive analytical platform, we indicated that it could precisely train a model that can predict the rate of remnant leaflets valve after endoscopic valve ablation. since predicting patient outcomes based on data sets is not a novel concept, constructing and verifying these predictive models necessitates time-consuming calculations and powerful statistical techniques to be carried out by appropriately qualified professionals (26). moreover, once these calculations were completed and the result was available and ready for presentation, the statistical data set could become out of date (27). based on recent clinical data, the ann system can produce these designs in a reproducible manner a few times, allowing for continuous data entry, real-time constant model retraining, and provision of an output to influence clinical decisionmaking (28). as more input data was fed into the system (24 variables), the system innately augmented the integrated weights between the parameters. as a result, the predicted values were very close to the expected value. however, no studies have been conducted to date to compare the predictive accuracy of ann versus regression analysis methods in predicting which patients are at high risk of obstructive remnant leaflets after valve ablation in boys with puv. previous research on the outcomes of remnant leaflets after valve ablation reported the same predictive accuracy of ann systems in comparison to statistical models (4, 22, 23). the advantages of the ann model are that it is the software can be easily used and updated with more preoperative, postoperative, and intraoperative variables in future versions, and the institutes can easily add other features to their software to customize it. however, the disadvantages of the ann model include the absence of underlying causal relationships between data processing algorithms and clinical realities. few published data investigated the role of ai in puv outcomes. for example, weaver et al. used anns to predict renal failure in children with puv using a survival analysis tool. they used deep learning imaging features archivio italiano di urologia e andrologia 2024; 96(3):12530 m. shirazi, z. jahanabadi, f. ahmed, et al. 6 from us images to predict renal failure accurately. they found that the anns model could accurately predict which patients will develop renal failure (29). abdovic et al. utilized ann to predict the late presentation of puv in boys with lower urinary tract symptoms. the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of anns were 92.7%, 100.0%, 89.7%, 80.0%, and 100.0%, respectively (30). study limitation there are several limitations to the study. firstly, the retrospective nature and low sample size inherently lacked control and randomization. this approach is prone to selection bias and attrition due to loss of follow-up, potentially skewing the results. however, such surveys can aid in the development of a better methodology for the management of puvs, as well as the achievement of purposeful follow-up for high-risk patients rather than invasive procedures. the assessment of outcomes was also limited, lacking adjustments for critical factors such as depth of incision, surgeon experience, urodynamic evaluation, and needs for anticholinergic therapy. also, we do not include information on the varied outcomes, such as esrd, dialysis, and renal transplantation, which can influence the outcome. this omission could lead to an incomplete understanding of the factors influencing treatment outcomes. therefore, prospective comparative trials will be needed to confirm the predictive value of ann vs. statistical data mining models and validate the system to decide whether or not to proceed with puv ablation. conclusions in conclusion, the ann is an integrated data-gathering tool for analyzing and understanding the relationships among variables as a complex non-linear statistical model. the accuracy and sensitivity in predicting the rate of the residual valve after the endoscopic valve ablation ranged from 90.75% to 92.73%. the results indicate that ann might be a valuable tool for outcome prediction of the residual valve after endoscopic valve ablation in patients with puv. acknowledgments the authors would like to thank shiraz university of medical sciences, shiraz, iran, and also the centre for development of clinical research of nemazee hospital and dr. nasrin shokrpour for editorial assistance. references 1. krishnan a, de souza a, konijeti r, baskin ls. the anatomy and embryology of posterior urethral valves.j urol. 2006; 175:1214-20. 2. buffin-meyer b, tkaczyk m, stanczyk m, et al. a single-center study to evaluate the efficacy of a fetal urine peptide signature predicting postnatal renal outcome in fetuses with posterior urethral valves. pediatr nephrol. 2020; 35:469-75. 3. holmdahl g, sillen u. boys with posterior urethral valves: outcome concerning renal function, bladder function and paternity at ages 31 to 44 years. j urol. 2005; 174:1031-4. 4. shirazi m, 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systematic review on renal and bladder dysfunction after endoscopic treatment of infravesical obstruction in boys. plos one. 2012; 7:e44663. 26. popovics p, penniston kl. current research and future directions in non-malignant urologic research proceedings of the annual cairibu meeting. am j clin exp urol. 2022; 10:449-61. 27. checcucci e, autorino r, cacciamani ge, et al. artificial intelligence and neural networks in urology: current clinical applications. minerva urol nefrol. 2020; 72:49-57. 28. anagnostou t, remzi m, lykourinas m, djavan b. artificial neural networks for decision-making in urologic oncology. eur urol. 2003; 43:596-603. 29. weaver jk, milford k, rickard m, et al. deep learning imaging features derived from kidney ultrasounds predict chronic kidney disease progression in children with posterior urethral valves. pediatr nephrol. 2023; 38:839-46. 30. abdovic s, cuk m, cekada n, et al. predicting posterior urethral obstruction in boys with lower urinary tract symptoms using deep artificial neural network.world j urol. 2019; 37:1973-9. correspondence mehdi shirazi, md shirazim@sums.ac.ir zahra jahanabadi, md (corresponding author) z_jahanabadi@yahoo.com urology office, faghihi hospital, zand blvd., shiraz, iran faisal ahmed, md fmaaa2006@yahoo.com davood goodarzi, md gdzd32@gmail.com alimohammad keshtvarz hesam abadi, phd candidate alimohammad.keshtvarz@gmail.com mohammad reza askarpour, md askarvip2@gmail.com sania shirazi, student saniashirazi046@gmail.com conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14101 1 original paper ing day by day. the increasing demand to use rats as experimental animals has created a need for the production and preservation of transgenic and wild-type rat strains. the best way to preserve these gene resources for many years is by freezing rat embryos, sperms, and somatic cells. the successful cryopreservation of rat spermatozoa and the development of new diluents are important in biotechnology. however, compared to many species, sperm cryopreservation protocols for preserving the rat strain and protocols for in vitro fertilization of oocytes with frozen sperm remain under development. although many relevant studies have been conducted (1-4), the ultimate objective remains unachieved. therefore, successful cryopreservation of rat sperms would provide an important resource to preserve and increase the number of genetically valuable strains for research and applications. factors affecting the success of sperm cryopreservation are that the head region of rat spermatozoa is shaped in a different structure than that of mammals, the tail structure is longer than that of other animal species, and the water permeability of the plasma membrane is low (3, 5, 6). therefore, various antioxidant substances and biomolecules are supplemented to cryopreservation media for healthy storage of rat sperm. in this study, tryptophan, an aromatic amino acid, and trehalose, a disaccharide, were supplemented to the cryopreservation diluent to increase cryosurvival. amino acids are the building blocks of proteins and have important roles in various biological and physiological processes (7). their antioxidant properties provide effective primary defense for the protection of sperm plasmalemma (8). tryptophan, an essential aromatic amino acid, is the precursor of many active molecules including serotonin, melatonin, and kynurenic acid, which are antioxidants against free radicals causing oxidative stress in spermatozoa (9, 10). it is widely used in numerous research and clinical studies (9-11) and is therefore anticipated as an additive in cryopreservation protocols. sugars are large molecules that interact with the plasma membrane and energize the cell. they are widely used in cryopreservation solutions as they stabilize intracellular and extracellular osmotic pressure (12). trehalose is a background: cryopreservation of rat sperm cells and development of new diluents are very important in biotechnology. methods: in the current study, 25 mm tryptophan and 100 mm trehalose were added separately to the cryopreservation medium containing 8% lactose monohydrate, 23% egg yolk, and 10% tris aminomethane to evaluate the cryopreservation capability of rat sperms. after freeze-thawing, motility, viable spermatozoon ratio, plasma membrane integrity, abnormal acrosome ratio, and apoptotic cell ratio and levels of bax, bcl-2, and caspase-3 mrna involved in the apoptosis pathway were evaluated. results: the highest viability ratio was detected in the trehalose group (26.25 ± 3.10), which was significantly higher than that in the control group (19.62 ± 1.51) (p < 0.05). when compared to the tryptophan group (11.87 ± 3.07), plasma membrane integrity was statistically higher in the trehalose group (20.25 ± 3.65) (p < 0.05). the rate of apoptotic cells was lower in the trehalose group than in the control group. then, the effect of tryptophan and trehalose, which were added to the sperm diluent, on the expression levels of genes in the apoptosis pathway was evaluated through the rt-qpcr technique. the expression of the anti-apoptotic gene bcl-2 increased by 25 mm tryptophan and 100 mm trehalose, while the expression of the pro-apoptotic genes bax and caspase-3 decreased (p < 0.01). conclusions: as a result, it was determined that trehalose, a isaccharide sugar, added to the rat sperm diluent provided more effective protection against cryodamage in the cryopreservation process than tryptophan, an aromatic amino acid, according to the parameters evaluated. from a molecular biotechnology perspective, these findings lay a valuable foundation for research on the development of next generation media for sperm cryopreservation. key words: cryopreservation; rat; tryptophan; trehalose; gene expression. submitted 27 june 2025; accepted 27 july 2025 introduction in molecular biology and genetics, rats are used as an alternative for creating many disease models. therefore, the use of rats as experimental animals has been expandimpact of tryptophan and trehalose on post-thaw sperm quality and apoptotic gene expression in wistar albino rats firdevs yilmaz dayanc 1, oguz kaan yalcin 2, aysel eraslan sakar 3 1 hatay mustafa kemal university, department of reproduction and artificial insemination, hatay, turkey; 2 hatay mustafa kemal university, faculty of veterinary medicine, department of reproduction and artificial insemination, hatay, turkey; 3 hatay mustafa kemal university, faculty of veterinary medicine, department of genetics, hatay, turkey. doi: 10.4081/aiua.2025.14101 summary archivio italiano di urologia e andrologia 2025; 97(3):14101 f. yilmaz dayanc, o. kaan yalcin, a. eraslan sakar 2 disaccharide that alters membrane fluidity and is present in the phospholipid bilayer of membranes (13). this study aimed to evaluate the effect of the addition of the amino acid tryptophan (25 mm) and disaccharide trehalose (100 mm) to cryopreservation diluent, which have not been previously studied in rats, on the long-term cryopreservation of rat sperm. accordingly, sperm quality parameters such as motility, viability, plasma membrane integrity, acrosome morphology, and cell apoptosis ratio, and expression of certain genes involved in the apoptosis pathway (bax, bcl-2, and caspase-3) were examined to develop new and effective cryoprotectant formulations needed in the field of cryobiology. materials and methods chemicals all chemicals were purchased from sigma chemical company (st. louis, mo). humon tubal fluid (htf) was prepared according to the method of quinn et al. (14). cryopreservation agent (cpa) was prepared by modifying the method of nakatsukasa et al. (6). 23% fresh chicken egg yolk, 8% lactose monohydrate, 1 mg/ml streptomycin sulfate, and 1000 iu penicillin g potassium were added into 23% fresh chicken egg yolk in pure distilled water and mixed for 5 min at +4°c. the mixture was then centrifuged at 1600 x g for 15 min. after centrifugation, the supernatant was collected, and 0.1% atp (adenosine 5’-triphosphate) was added. the resulting diluent was partitioned, and 25 mm tryptophan (sigma-aldrich) and 100 mm trehalose (sigma-aldrich) were added to form a tryptophan (tryp) study group and a trehalose (treh) study group. a cpa group, in which no addition was made, was used as the control (c) group. lastly, the ph of the prepared study group solutions was adjusted to 7.4 with 10% tris aminomethane + distilled water solution using a ph meter (thermo scientific, usa). animals in the study, 24 adult, male wistar albino rats aged 1016 weeks were used. rats were kept at room temperature (24 ± 3°c) and a relative humidity of 60% under 12 h light:12 h dark cycle. the rats were fed rat chow (pellet feed) and tap water ad libitum. all procedures were carried out with the approval (ethical approval numbered 2024/09-01) of the animal experiments local ethics committee (hadyek) of hatay mustafa kemal university. collection and freezing/thawing of spermatozoa rats were sacrificed by cervical dislocation under anesthesia. under sterile conditions, both epididymides were removed, and both cauda epididymides were transferred into 1 ml cpa placed in 35 mm petri dishes (nunc™, massachusetts, usa) at room temperature. rat spermatozoa were reconstituted and frozen using a modified version of the protocol described by nakagata et al. (3). the cauda epididymides were immobilized using flat-tipped forceps under a stereo microscope (euromex/nexius zoom, netherlands), and 10-12 deep incisions were made in the petri dish using sharp-tipped scissors, and the spermatozoa were transferred into cpa. for the release of spermatozoa from the cauda and equilibration, the petri dishes were placed on a metal plate on ice in a styrofoam box and incubated for 10 min. after incubation, 0.25 ml straws (imv, france) were loaded with 30 µl htf, 10 mm air, 150 µl sperm suspension, 10 mm air, and 30 µl htf, respectively, and the straws were pressed. the straws were placed on a metal plate on ice and equilibrated for 30 min. the equipment used during the procedure (syringe connector, straws, and htf) was set at a temperature of 0°c. for freezing, the straws were placed in a styrofoam box (270x220x270 mm) 4 cm above the 3.5-cm liquid nitrogen level on a straw rack and kept in liquid nitrogen vapor for 10 min. the straws were then dipped in liquid nitrogen. thawing was performed by dissolving the straws in a 37°c water bath (deconjelator, cito 026897, imv, france) for 30 sec. the content of the thawed straws was transferred to 1 ml htf in a carbon dioxide incubator (37°c, 5% co2). assessment of sperm concentration sperm density was determined using a makler counting chamber (sefi-medical instruments, haifa, israel) following the guidelines of the world health organization (15). sperm samples were diluted 1:10 with phosphate buffered saline (pbs) fixation medium containing 10 mm formaldehyde and immobilized. from the fixed mixture, 10 µl was taken and the cells in 10 frames were counted under a 20x objective in olympus cx31 (japan) microscope and the density was calculated in millions/ml. each sample was measured three times, and the results were averaged. assessment of sperm motility sperm motility was analyzed using a makler counting chamber (sefi-medical instruments, haifa, israel) according to the guidelines of who (15). briefly, 20 µl of htf and sperm mixture was taken and placed on a makler slide preheated to 37°c. samples were examined under a 20x objective in a phase contrast microscope with a heating stage (olympus cx31, japan). within 100 small squares on the makler slide, the ratio of spermatozoa showing linear forward movement to spermatozoa with other types of movement (tremor, rotation, or immobility) was calculated. measurement was repeated three times for each sample, and the results were averaged. sperm motility was expressed as a percentage (%). assessment of sperm viability sperm viability was analyzed using the eosin-nigrosin staining method described by agarwal et al. (16). 10 µl of sperm samples were taken and mixed with 20 µl of 1% eosin and 10% nigrosin solutions. the mixture was swabbed onto slides and dried on a surface at 60°c for 23 sec. analyses were performed under a phase contrast microscope (olympus cx31, japan) and a 40x objective by counting at least 300 spermatozoa. spermatozoa with red or dark pink heads were classified as non-viable, while those with unstained heads were considered viable. viability ratio was calculated as percentage (%). assessment of sperm plasma membrane integrity hypo-osmotic swelling test (host) described by jeyendran archivio italiano di urologia e andrologia 2025; 97(3):14101 3 tryptophan and trehalose on post-thaw sperm et al. (17) was performed to evaluate the functional stability of the plasma membrane integrity of spermatozoa. 100 µl of host solution (1.1 g fructose + 0.55 g sodium citrate + 100 ml distilled water), of which osmotic pressure was measured with an osmometer (osmomat 3000, gonotec, usa), and 10 µl of the sperm sample were transferred into a 1.5 ml eppendorf tube. the mixture was kept in an incubator at 37°c for 45 min. after incubation, the samples were examined on a slide preheated to 37°c under a phase contrast microscope (olympus cx31, japan) and a 40x objective. spermatozoa with swelling or curling in the tail were categorized as host positive (+) and those without any morphological change were categorized as host negative (-). from each sample, a total of 200 spermatozoa were counted, and the ratio of host positive spermatozoa was recorded as percentage (%). acrosome assessment abnormal acrosome examination was performed based on the method described by somfai et al. (18). hancock’s solution (19) was used in the examination. 500 µl of hancock’s solution was transferred into an eppendorf tube, and 50 µl of sperm sample was added. 50 µl of the mixture was placed on a slide and covered with a coverslip. morphological evaluation of the slides was performed under a microscope and a 100x objective using immersion oil (20). a total of 300 spermatozoa were examined, and the ratio of spermatozoa with acrosome damage was noted as percentage (%). assessment of apoptosis annexin-v fitc/pi apoptosis kit (elabscience, e-cka211) was used for apoptosis examination. kit and staining procedures were performed according to the instructions of the manufacturer. apoptotic cells were detected with annexin v-fitc stain, while dna of necrotic cells with impaired membrane integrity was stained with propidium iodide (pi). the slides prepared for analysis were examined under a fluorescence microscope (eclipse ni, nikon) and 20x and 40x objectives using fitc/pi filters (excitation wavelength of 490 nm, emission wavelength of 520 nm). cells were classified as follows: annexin v-fitc positive (av+) and propidium iodide negative (pi-) cells (green) were defined as apoptotic cells. a total of 200 cells were counted, and apoptosis ratios were recorded as percentage (%). total rna isolation sperm suspension were washed with pbs and centrifuged at 150 × g for 10 minutes at 4°c. to eliminate somatic cell contamination, the pellets were treated with a somatic cell lysis buffer (0.05% sodium dodecyl sulfate and 0.25% triton x-100 in distilled water) and incubated on ice for 60 minutes. total rna was extracted using trizol reagent (trizol® reagent, ambion) following the manufacturer’s protocol. carefully dissected semen sample was submerged in 1 ml of trizol reagent and homogenized for 45 seconds with a homogenizer. the homogenate was incubated for 5 minutes and added 200 μl chloroform; shaken vigorously. the mixture was centrifuged at 12000 × g at 4°c for 15 minutes. following this centrifugation step, the upper aqueous layer was transferred to another nuclease-free 1.5 ml tube and added 500 μl of isopropanol; shaken vigorously. the sample was centrifuged at 12000 × g at 4°c for 10 minutes to pellet the precipitated rna. the rna-containing pellet was washed twice with 500 μl of 70% ethanol and centrifuged at 7500 × g at 4°c for 5 minutes. final rna pellet was washed with 500 μl of 99% ethanol and centrifuged at 7500 × g at 4°c for 5 minutes. the rna-containing pellet was air-dried and dissolved in 30 ml of nuclease-free water. the rna samples were stored at -80ºc for downstream application later. the concentration and purity of rna were assessed by measuring absorbance at 260/280 nm using a nanodrop™ 1000 spectrophotometer (thermo fisher scientific, usa). cdna synthesis complementary dna (cdna) was synthesized from 1 μg of total rna using the revertaid first strand cdna synthesis kit (thermo fisher scientific, usa. the reaction included 1 μl of oligo(dt) (18) primer and 1 μl of random hexamer primer, which were mixed with the rna and incubated at 65°c for 5 minutes, followed by immediate cooling on ice. subsequently, 8 μl of cdna synthesis mix (comprising 5x reaction buffer, ribolock rnase inhibitor, dntp mix, and revertaid m-mulv reverse transcriptase) was added. the reaction was incubated at 42°c for 60 minutes, followed by 25°c for 5 minutes, and terminated by heating at 70°c for 5 minutes. quantitation of gene expression by rt-qpcr reverse transcription-quantitative polymerase chain reaction (rt-qpcr) was performed using realq plus 2x master mix green (ampliqon, denmark). gene-specific primers of bax, bcl-2, and caspase-3, which involved in the apoptotic pathway, were used (table 1). a total of 100 ng of cdna was used per 25 μl reaction, which included 150 nm of each primer and 12.5 μl of realq plus master mix. reactions were run in a cfx96 system (bio-rad) with the following thermal profile: initial denaturation at 95°c for 15 minutes, followed by 40 cycles of 95°c for 30 seconds, 60°c for 60 seconds, and 72°c for 30 seconds. gene expression levels were normalized against housekeeping gene (gapdh) using the 2δδct method (21). data were reported as fold-change, with experiments conducted in two biological and technical replicates. table 1. primer sets used in the study. genes primer sequence genbank id bax f: 5′-cacgtctgcggggagtc-3′ xm_063281064.1 r: 5′-tgttgtccagttcatcgcca-3′ bcl-2 f: 5′-gggctacgagtgggatactg-3′ nm_016993.2 r: 5′-gaccccaccgaactcaaaga-3′ caspase-3 f: 5′-ggagcttggaacgcgaagaa-3′ nm_012922.3 r: 5′-ccattgcgagctgacattcc-3′ gapdh f: 5′-ctctctgctcctccctgttc-3′ nm_017008.4 r: 5′-cgacatactcagcaccagca-3′ bax, bcl-2 associated x-protein; bcl-2, b-cell leukemia/lymphoma 2; gapdh, glyceraldehyde-3-phosphate dehydrogenase. archivio italiano di urologia e andrologia 2025; 97(3):14101 f. yilmaz dayanc, o. kaan yalcin, a. eraslan sakar 4 statistical analysis the spss 22.0 software was used for statistical evaluations (ibm corporation, armonk, ny). in the evaluation of spermatological parameters, one-way analysis of variance (anova) were used to compare the significance of the difference between the groups. the results were evaluated as mean ± se and those with p < 0.05 were considered statistically significant. duncan test was used to indicate the significance of the difference between the groups as a result of the analysis. for the gene expression analysis, a one-way anova followed by a post hoc tukey test was performed using graphpad prism 9.1.1 (graphpad, san diego, ca, usa). statistical significance was considered at p < 0.05. results spermatologic parameters identified after freezing-thawing the motility, viability rate, plasma membrane integrity rates, sperm concentration, and abnormal acrosome ratio, in the study groups after post-thawing processes are presented in table 2. motility the highest motility ratio was 9.75 ± 1.33 in the control group. this ratio was 3.12 ± 1.61 in the tryptophan group, which was significantly lower compared to the control group (p < 0.05). in the group to which 100 mm trehalose was added, the motility ratio was 6.87 ± 2.48, but there was no statistically significant difference between the groups (p > 0.05). this indicates that tryptophan and trehalose supplemented to the cryopreservation diluent may not be effective on motility. viable spermatozoon ratio there were significant differences between the groups in terms of sperm viability ratio (p < 0.05). the highest viability ratio was 26.25 ± 3.10 in the trehalose group, which was significantly higher than the ratio of 19.62 ± 1.51 in the control group. in the group in which 25 mm tryptophan was added, the viability ratio was 15.00 ± 3.19, which was significantly lower than the ratios in the control and trehalose groups (p < 0.05). these findings suggest that trehalose may improve sperm viability after freezing-thawing. plasma membrane integrity ratio according to the results of host assay performed to evaluate sperm cell membrane integrity, there were significant differences between the groups (p < 0.05). the highest host positive ratio was determined in the control group with (22.87 ± 1.10) and in the trehalose group (20.25 ± 3.65). there was no statistical difference between the groups (p > 0.05). the host positive ratio was 11.87 ± 3.07 in the tryptophan group and significantly lower compared to the control group (p < 0.05). spermatozoa density spermatozoa density was determined to verify the amount of cells required for analyses to be performed after freezing-thawing and to standardize experimental procedures. sperm concentration did not differ significantly among the experimental groups (p > 0.05). abnormal acrosome ratio there was no statistically significant difference between the groups in terms of abnormal acrosome ratio (p > 0.05). the abnormal acrosome ratio was 6.37 ± 0.99 in the control group, 4.75 ± 0.75 in the tryptophan group, and 4.87 ± 0.63 in the trehalose group. apoptotic cell ratios determined with annexin v-fitc/pi staining the apoptotic cell ratios determined with annexin vfitc and pi staining are presented in figure 1. accordingly, the lowest ratio of apoptotic cells was determined in the group in which 100 mm trehalose was added (22.37 ± 2.94); however, this value was not significantly different from the ratio of 33.00 ± 4.55 determined in the control group (p > 0.05). the highest ratio was determined as 55.00 ± 3.95 in the tryptophan group, which was significantly higher than that in the control and trehalose groups (p < 0.01). effects of tryptophan and trehalose supplementation on the expression of apoptosis-related genes in frozen-thawed sperm using real-time pcr to investigate whether tryptophan and trehalose can alletable 2. spermatological findings determined after freezing-thawing in the study groups (n = 8). groups progressive motility viability intact plasma sperm concentration abnormal acrosome (%) (%) membrane integrity (%) (×10⁶ cells/ml) (%) control (c) 9.75 ± 1.33 19.62 ± 1.51 22.87 ± 1.10 221.00 ± 3.40 6.37 ± 0.99 tryptophan (tryp) (25 mm) 3.12 ± 1.61 15.00 ± 3.19 11.87 ± 3.07 245.75 ± 5.74 4.75 ± 0.75 trehalose (treh) (100 mm) 6.87 ± 2.48 26.25 ± 3.10 20.25 ± 3.65 245.5 ± 4.25 4.87 ± 0.63 c vs tryp p < 0.05 p < 0.05 p < 0.05 p < 0.05 p < 0.05 c vs treh p < 0.05 p < 0.05 p < 0.05 p < 0.05 p < 0.05 tryp vs treh p < 0.05 p < 0.05 p < 0.05 p < 0.05 p < 0.05 archivio italiano di urologia e andrologia 2025; 97(3):14101 5 tryptophan and trehalose on post-thaw sperm viate cryodamage in spermatozoa after frozen-thawed were analyzed the expression of apoptosis-related genes. addition of 25 mm tryptophan and 100 mm trehalose to the cryoprotectant agent affected bax, bcl-2, and caspase3 mrna levels in comparison to the control group (figure 2). bax gene expression was significantly downregulated in both the tryptophan and trehalose-treated groups compared to the control group (p < 0.001). furthermore, mrna expression levels in the trehalose group were significantly lower than those observed in the tryptophan group (p < 0.001). bcl-2 gene expression reached its highest level in the trehalose group when compared to the control and tryptophan groups (p < 0.001). no statistically significant difference was detected between the control and tryptophan groups in terms of bcl-2 expression (p > 0.05). these findings suggest that supplementation of the cryopreservation extender with trehalose enhances the post-thaw expression of the antiapoptotic bcl-2 gene. caspase-3 gene expression did not differ significantly between the tryptophan and trehalose groups (p > 0.05); however, when compared to the control group, both the tryptophan and trehalose groups showed a significant decrease in caspase-3 expression levels (p < 0.05). collectively, these results indicate that the figure 1. apoptotic spermatozoa evaluation. apoptosis was assessed by annexin v-fitc/pi assay in epididymal rat sperm. spermatozoa with completely green heads were early apoptotic (a), spermatozoa with green-red heads were late apoptotic (b-c), spermatozoa with completely red heads were necrotic (d), and quantification of the apoptosis index (%) of sperm cells in each group (e). data were shown as the mean ± se (n = 8 in each group). values with different superscripts differ significantly (p < 0.001). figure 2. quantitative pcr analysis of the relative expression of bax (a), bcl-2 (b), and caspase-3 genes (c) on frozen-thawed epididymal rat sperm. all data were presented as mean ± sem (n = 8 in each group). *p < 0.05, **p < 0.01, and ***p < 0.001 vs the other group. archivio italiano di urologia e andrologia 2025; 97(3):14101 f. yilmaz dayanc, o. kaan yalcin, a. eraslan sakar 6 freeze-thaw process induces apoptosis in rat spermatozoa, and the addition of amino acid (tryptophan) and disaccharide (trehalose) to the cryoprotectant medium reduces the expression levels of genes involved in the apoptotic pathway after thawing. discussion cryopreservation is known to be a more challenging process for rat sperm compared to other mammalian species (6, 22). main reason for this is that rat spermatozoa are highly sensitive to all kinds of manipulations and that these procedures constitute a significant source of stress on the cell. furthermore, the molecular structure of rat sperm is remarkably different from that of other mammalian sperm, especially due to differences in the lipid content and composition of the sperm membrane (23, 24). motility is considered a criterion of cell activity and viability after cryopreservation. in this study, motility was found to be higher in the control group (9.75 ± 1.33) compared to the trehalose group (6.87 ± 2.48), but the difference was not statistically significant (p > 0.05). interestingly, although the freezing protocol used in this study was the same as the protocol reported by nakatsukasa et al. (6), the addition of 100 mm trehalose to the diluent increased the post-thaw motility (6.87 ± 2.48), which was higher than the value reported by nakatsukasa et al. (6) (4.6 ± 0.1). moreover, in another study conducted by the same author (2), post-thaw motility ratios of rat sperm was reported to range from 2% to 12.3%. the motility observed in the present study with 100 mm trehalose falls within this range, suggesting that trehalose contributes to maintaining motility after freezing and thawing. similar stabilizing effects of trehalose have also been reported in other species, including ram (25) and goat (26) sperm. in contrast, tryptophan at 25 mm had minimal impact on motility. similar findings were reported by koçak and yıldız (27) in mouse sperm, where the same concentration had only a modest effect on motility (20.83 ± 3.96) but improved fertilization capacity. this suggests that tryptophan’s effect on motility is indirect and may depend on its antioxidant activity rather than structural stabilization (28). when viability rate was considered, the highest postthaw viability (26.25 ± 3.10) was observed in the trehalose group and was significantly higher than in the tryptophan group (p < 0.05). trehalose, as a non-permeable disaccharide, reduces osmotic stress during dehydration and stabilizes sperm cell structures, leading to better survival (29). this result is consistent with findings in pig (30), ram (31), human (32), fish (33, 34), rabbit (35), buffalo (36), and mouse (27) sperm cryopreservation, where trehalose enhanced viability. by comparison, tryptophan showed weaker effects on viability, likely because it mainly reduces oxidative stress without improving osmotic stability. since rat sperm membranes have a high lipid content and are prone to oxidative damage (28, 37), tryptophan may have more impact on dna or membrane integrity than on viability itself. plasma membrane integrity is a critical indicator for assessing sperm quality and reproductive potential after cryopreservation. the trehalose group maintained the highest membrane integrity (20.25 ± 3.65), while tryptophan had a reduced effect (p < 0.05). trehalose likely provides superior protection by stabilizing the plasma membrane bilayer and minimizing osmotic imbalance during freezing (35). this is consistent with studies on ram (25, 38), goat (26), and bull (39) sperm where trehalose preserved membrane structure more effectively than amino acids. sperm concentration did not differ significantly among the experimental groups. this was expected, as sperm concentration is determined prior to freezing and is used to confirm the amount of cells needed for post-freezethaw analyses and to standardize experimental procedures (p > 0.05). when examining the abnormal acrosome ratio, the lowest acrosome damage was found in the trehalose (4.87 ± 0.63) and tryptophan (4.75 ± 0.75) groups compared to the control (6.37 ± 0.99), although the differences were not statistically significant (p > 0.05). these findings indicate that trehalose and tryptophan have comparable cryoprotective effects in preserving acrosome integrity. trehalose stabilizes the plasma membrane by reducing osmotic stress, while tryptophan limits oxidative damage through its antioxidant properties. similar effects were reported by gholami et al. (40) for trehalose in ram sperm, and by koçak and yıldız (27), who showed that 25 mm tryptophan reduced acrosome damage in mouse sperm (11.17 ± 1.22) compared to the control (12.83 ± 1.22). the comparable outcomes in our study suggest that both additives have potential to reduce acrosomal damage, but larger sample sizes may be needed to reveal significant differences. apoptosis is a mechanism of programmed cell death, being a physiological process that eliminates cells that threaten survival, and is critical for spermatozoa (16). therefore, in this study, the annexin v-fitc/pi test was performed to determine whether tryptophan and trehalose added to the cryopreservation diluent had any effect on the apoptotic mechanism after thawing. according to the test results, spermatozoa with the head stained completely green were considered as early apoptotic, spermatozoa with green-red staining were considered as late apoptotic, and spermatozoa with red staining were considered as necrotic. when apoptotic cell ratios were evaluated together with apoptosis-related gene expression, trehalose demonstrated a clear cryoprotective advantage. the annexin v-fitc/pi assay demonstrated a significantly reduced apoptosis index (%) in the trehalose group (22.37 ± 2.94) compared with controls (33.00 ± 4.55, p < 0.01), aligning with the downregulation of proapoptotic bax (p < 0.001) and caspase-3 (p < 0.05) expression and the upregulation of anti-apoptotic bcl-2 expression (p < 0.001). these findings are consistent with previous studies (41-44). in canine sperm, trehalose supplementation during cryopreservation caused slight numerical increases in bcl-2 and decreases in bax expression (45). similarly, in rat ovaries, xie et al. (41) reported that adding trehalose to the cryoprotective agent significantly reduced the apoptotic cell ratio and suppressed bax gene expression. however, bumbat et al. (46) reported that trehalose supplementation in the cryopreservation archivio italiano di urologia e andrologia 2025; 97(3):14101 7 tryptophan and trehalose on post-thaw sperm medium of cancer cells paradoxically upregulated not only the anti-apoptotic gene bcl-2 but also the pro-apoptotic genes bax and bad, suggesting that such variations may depend on tissue type or experimental conditions. overall, trehalose consistently reduced both apoptotic cell counts and pro-apoptotic gene expression, whereas tryptophan showed more variable effects. although tryptophan also lowered bax and caspase-3 expression, the apoptosis index in the tryptophan group (55.00 ± 3.95) was unexpectedly higher than in the control, suggesting that the 25 mm concentration may not be optimal and that its effects could be dose-dependent, as reported in several sperm cryopreservation studies (27, 34, 36). in summary, trehalose provided more consistent cryoprotective benefits than tryptophan by improving viability, preserving plasma membrane integrity, reducing apoptosis, and maintaining acrosomal structure. tryptophan offered limited benefits, mainly through its antioxidant action, and its effectiveness may vary with concentration. these findings indicate that optimizing trehalose concentration is a promising approach for rat sperm cryopreservation, while further research is needed to explore the dose-response effects of tryptophan and to evaluate fertility outcomes in vivo. conclusions in conclusion, according to the parameters evaluated, the addition of the disaccharide sugar trehalose to rat sperm diluent provided more effective protection against cryodamage during cryopreservation than the aromatic amino acid tryptophan. the use of these substances may provide a significant advance in overcoming the difficulties encountered in the cryopreservation process of rat sperm and may lay a strong foundation for future studies. references 1. takeo t, nakao s, mikoda n, et al. optimized protocols for 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percoll treatment on viability and acrosome integrity of frozen-thawed bull spermatozoa. reprod domest anim. 2002; 37:285-90. declarations ethical approval: ethical approval for this study was obtained by the animal experiments local ethics committee (hadyek) of hatay mustafa kemal university, hatay, türkiye (ethical approval numbered 2024/09-01). availability of data and material: the data used in this study were generated by the author(s) and are available from the corresponding author upon reasonable request. competing interests: none of the authors have any conflicts of interest to declare that are either directly or indirectly related to the study design, execution or reporting of this work. funding: this study did not receive any financial support. authors' contributions: f.y.d., o.k.y. and a.e.ş. designed the study, performed the experiments, performed the analyses, and prepared the first drafts of the manuscript based on the data obtained. then, they made final revisions on the 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androl. 1988; 9:178-89. 24. hammerstedt rh, graham jk, nolan jp. cryopreservation of mammalian sperm: what we ask them to survive. j androl. 1990; 11:73-88. 25. tonieto ra, goularte kl, gastal gda, et al. cryoprotectant effect of trehalose and low-density lipoprotein in extenders for frozen ram semen. small rumin res. 2010; 93:206-9. 26. khalili b, farshad a, zamiri mj, et al. effects of sucrose and trehalose on the freezability of markhoz goat spermatozoa. asianaustralas j anim sci. 2009; 22:1614-9. 27. koçak g, yildiz c. the effects of ferulic acid, tryptophan, and lglutamine on the cryopreservation of mouse spermatozoa. biopreserv biobank. 2024; 22:286-93. 28. aitken rj, baker ma. oxidative stress and male reproductive biology. reprod fertil dev. 2004; 16:581-8. 29. aboagla eme, terada t. trehalose-enhanced fluidity of the goat sperm membrane and its protection during freezing. biol reprod. 2003; 69:1245-50. 30. hu jh, li qw, li g, et al. the cryoprotective effect of trehalose 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cryopreservation in a rat model. clin exp obstet gynecol. 2024; 51:90. 42. du t, chao l, zhao s, et al. successful cryopreservation of whole sheep ovary by using dmso-free cryoprotectant. j assist reprod genet. 2015; 32:1267-75. 43. izaguirre-pérez n, ligero g, aguilar-solana pa, et al. trehalose cryopreservation of human mesenchymal stem cells from cord tissue. biopreserv biobank. 2024; 22:294-302. 44. lee ya, kim yh, kim bs, et al. cryopreservation in trehalose preserves functional capacity of murine spermatogonial stem cells. plos one. 2013; 8:e54889. 45. ibrahim s, shin s, talha nah, et al. effect of trehalose supplementation in egg-yolk-free extender on conventional parameters and gene expression related to reactive oxygen species, apoptosis, and motility of frozen dog spermatozoa. biopreserv biobank. 2024; 22:395-403. 46. bumbat m, wang m, liang w, et al. effects of me2so and trehalose on the cell viability, proliferation, and bcl-2 family gene (bcl2 bax, and bad) expression in cryopreserved human breast cancer cells. biopreserv biobank. 2020; 18:33-40. correspondence firdevs yilmaz dayanc, ph.d. fiirdevsyiilmaz@gmail.com hatay mustafa kemal university, campus of tayfur sokmen, faculty of veterinary medicine, department of reproduction and artificial insemination, 31060, hatay, turkey oguz kaan yalcin okaanyalcin@gmail.com hatay mustafa kemal university, faculty of veterinary medicine, department of reproduction and artificial insemination, hatay, turkey aysel eraslan sakar ayseleraslan@gmail.com hatay mustafa kemal university, faculty of veterinary medicine, department of genetics, hatay, turkey stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11462 1 original paper introduction non-obstructive azoospermia (noa) is one of the most important causes of male infertility. it characterized by the absence of sperm in semen repeatedly (1). at present, its pathogenesis is complex and can be categorized into primary and secondary testicular failure (1). about 10-15% of people of childbearing age are infertile in the world, of which male infertility accounts for about 50% (2). noa is a type of male infertility caused by spermatogenic dysfunction of testicular tissue. patients with noa cannot produce sperm or can only produce a very small amount of sperm. in patients with noa, the structure of the seminiferous tubules in the testis is disordered, while the maturation of spermatogenic cells is blocked, and the meiosis of spermatogenic cells is arrested (3). galectins are a family of soluble carbohydrate-binding proteins that regulate cell phenotype and function in development and disease (4). galectin-1 (gal-1) and galectin-3 (gal-3) are expressed by many immune cells and receive considerable attention in the context of immunity (5, 6). gal-1 was the first member of the lectin family, reported more than 3 decades before, as a +15 kda protein existing in a noncovalent homodimer form that was previously known as electrolectin, b-galactosidebinding lectin, galaptin or l-14 (4). different organs and tissues secrete it including thymus (7), spleen (8), smooth muscle (9), colon (10), ovary (11) and also the nervous system (12). it is an endogenous introduction: galectin-1 (gal-1) and galectin-3 (gal-3) are expressed by many immune cells and receive considerable attention in the context of immunity. we aimed to compare between seminal plasma and serum levels of gal-1 and gal-3 in azoospermic patients and fertile men. materials and methods: this cross-sectional study was conducted at the andrology outpatient clinic from january (2022) to september (2022). a total of 90 participants were enrolled and divided into two equal groups: azoospermic and normal group. semen analysis was done for all participants. hormonal profile including fsh, lh, serum prolactin, total testosterone and estradiol was performed as well as assessment of serum and seminal levels of gal-1 and gal-3 by elisa commercial kits. finally, scrotal duplex was done in standing and supine position. results: serum and seminal levels of gal-1 and gal-3 were statistically significant higher in azoospermic patients compared with normal individuals (p < 0.001 for all). in addition, in healthy individuals there were statistically significant positive correlations between serum levels of gal-1 and age, fsh, lh levels (r = 0.296, p = 0.005; r = 0.333, p = < 0.001; r = 0.312, p = 0.003, respectively) and serum levels of gal-2 and fsh and lh (r = 0.436, p < 0.001; r = 0.350, p < 0.001, respectively), whereas serum gal-3 showed a borderline positive correlation with age (r = 0.2, p = 0.059). additionally, statistically significant positive correlations between seminal levels of gal-1 and gal-3 and free testosterone in healthy individuals were reported (r = 0.205, p = 0.053; r = 0.219, p = 0.038, respectively). on the other hand, there were negative correlations between serum and seminal levels of gal-1 and gal-3, total and progressive sperm motility, sperm count and abnormal sperm forms in healthy individuals (r = -0.382, p < 0.001; r = -0.405, p < 0.001; r = -0.376, p < 0.001; r = -0.364, p < 0.001) (r = -0.394, p < 0.001; r = -0.467, p < 0.001; r = -0.413, p < 0.001; r = -0.433, p < 0.001); (r = -0.372, p < 0.001; r = -0.377, p < 0.001; r = -0.317, p = 0.002; r = -0.311, p = 0.003)(r = -0.445, p < 0.001; r = -0.498, p < 0.001; r = -0.453, p < 0.001; r = -0.463, p < 0.001, respectively). furthermore, statistically significant positive correlations between serum levels of gal-1 and gal-3 and age in azoospermic patients were reported (r = 0.511, p < 0.001; r = 0.390, p = 0.008, respectively). on the other hand, there were negative correlations between seminal gal-1 and estradiol (e2) and seminal gal-3 and fsh and lh in azoospermic patients galectin-1 (gal-1) and galectin-3 (gal-3) levels in seminal plasma and serum in azoospermic patients versus fertile men: a cross-sectional study sameh fayek gamalel din 1, olfat gamil shaker 2, ahmad fawzy megawer 1, mohamed ahmed abdel salam 1, abdelhalim nabil abdelhalim 1, ahmed adel 1 1 department of andrology, sexology and stds, kasr alainy faculty of medicine, cairo university, egypt; 2 department of medical biochemistry and molecular biology, kasr alainy faculty of medicine, cairo university, egypt. doi: 10.4081/aiua.2023.11462 summary (r= -0.318, p = 0.033; r = -0.322, p = 0.031; r = -0.477, p < 0.001, respectively). also, negative correlations between serum gal-3 and total and free testosterone in azoospermic patients were detected (r = -0.396, p = 0.007; r = -0.375, p = 0.011, respectively). conclusions: elevated serum and seminal levels of gal-1 and gal-3 have detrimental effects on spermatogenesis. furthermore, the current study demonstrated potential regulatory effects of reproductive hormones on gal-1 and gal-3. thus, future studies are needed to confirm such findings. key words: gal-1; gal-3; azoospermia; normal spermatogenesis. submitted 11 may 2023; accepted 20 june 2023 archivio italiano di urologia e andrologia 2023; 95(3):11462 gamalel din s.f., shaker o.g., fawzy megawer a., et al. 2 protein that might play a key role in leydig cell biology as well as potential control of the development of normal leydig cells through autocrine and paracrine mechanisms (13). however, cells such as sertoli or peritubular cells might be responsible for gal-1 regulation in leydig cell functions (13). in contrast, gal-3 is the most commonly reported type (14). gal-3 is approximately 30kda protein that acts several roles in cell to cell interaction, cancer progression, pathogenesis of infections, and immunomodulation (15). in male reproductive tract, gal-3 is present in testes, epididymis, vas deferens, prostate, seminal vesicles and in semen (15). early reports demonstrated that extracellular gal-3 signals apoptosis via cytochrome c-release and caspase-3 activation independent of caspase-8 activation (16), with more recent data suggesting that gal-3 activates caspase9 upstream of caspase-3 through phosphorylation of extracellular signal-regulated kinase (erk) (17). differences in the pro-apoptotic signaling pathways activated by extracellular gal-1 and gal-3 may arise because they recognize different cell surface glycoproteins by way of their selectivity for different oligosaccharide ligands (18). gal-3 expression has been identified in human sertoli cells where it is under follicle stimulating hormone (fsh) control (19, 20). a potential role of gal-3 in germ cell survival/regeneration is suggested based on its increased expression one month after a transient germ cell death process (20). although luteinizing hormone (lh)/testosterone and fsh potentially exert their control on spermatogenesis via identified components, there are still other hormonally regulated sertoli cell factors which remain unknown (20). we aimed in the current study to compare between seminal plasma and serum levels of gal-1 and gal-3 in azoospermic patients and fertile men. also, we aimed to find out the potential relationships between reproductive hormones and gal-1 and gal-3. methods this cross-sectional study was conducted at the andrology outpatient clinic from january 2022 to september 2022. a total of 90 participants were enrolled and divided into two equal groups as follows: azoospermic and normal group. all participants signed an informed consent. the ethical committee approved the study that conforms to helsinki declaration (2013) (21) (ms-197-2022). inclusion criteria any azoospermic patient or fertile individual aged 20-50 years old was included. exclusion criteria any azoospermic patient with abnormal karyotyping was excluded. also, any participant with chronic medical condition was excluded. all participants were evaluated by history taking as well as general and local examinations. testicular volume (v) was calculated from measurements of length (l) and width (w) according to the formula, (v = pi/6 x l x w2) using a plastic ruler or caliper. two semen analyses with an interval of 1 month were obtained. hormonal profiles including: fsh, lh, serum prolactin, total testosterone, and estradiol were performed. scrotal duplex in standing and supine position was done. gal-1 and gal-3 were assessed in seminal plasma and serum. serum and semen were used for determination of gal-1 using elisa kit provided by bioassay technology laboratory with cat. no e2989hu (zhejiang. china). serum and semen were used for determination of gal-3 using elisa kit provided by bioassay technology laboratory with cat. no e3449hu (zhejiang. china). serum separator tubes (sst) were used, and samples were allowed to clot for 30 min at room temperature before centrifugation for 15 min at 1000 x g. serum was removed and assayed immediately or divided into aliquot and stored at ≤ -20°c. repeated freeze-thaw cycles were avoided. the ejaculates were obtained after 4 days of sexual abstinence into sterile containers for immediate analysis. semen was examined according to 5th guidelines who guidelines (2010) (22). seminal plasma was centrifuged for 15 min at 1000 x g within 30 min of collection. next, it was assayed immediately or divided into aliquot and stored at ≤ -20°c. repeated freeze-thaw cycles were avoided. statistical analysis recorded data were analyzed using the statistical package for social sciences, version 23.0 (spss inc., chicago, illinois, usa). the quantitative data were presented as mean± standard deviation and ranges. qualitative variables were presented as number and percentages. data were explored for normality using kolmogorov-smirnov and shapiro-wilk test. independent-samples t-test of significance was used when comparing between two means. mann whitney u test was used for two-group comparisons in non-parametric data. chi-square (x2) test of significance was used in order to compare proportions between qualitative parameters. spearman's rank correlation coefficient (rs) was used to assess the degree of association between two sets of variables if one or both of them was skewed. values of two variables are plotted along two axes as scatter plots showing the presence of correlations. the confidence interval was set to 95% and the margin of error accepted was set to 5%. results the current study did not reveal any statistically significant difference among participants regarding age. there were statistically significant higher means of gal-1 and gal-3 in azoospermic patients compared to healthy individuals (p < 0.001 for all) (table 1). in addition, in healthy individuals there were statistically significant positive correlations between serum levels of gal-1 and age, fsh, lh levels (r = 0.296, p = 0.005; r = 0.333, p = < 0.001; r = 0.312, p = 0.003, respectively) and serum levels of gal-2 and fsh and lh (r = 0.436, p < 0.001; r = 0.350, p < 0.001, respectively), whereas serum gal-3 showed a borderline positive correlation with age (r = 0.2, p = 0.059) (table 2). additionally, statistically significant positive correlations between seminal levels of gal-1 and gal-3 and free testosterone in healthy individuals were observed (r = 0.205, p = 0.053; r = 0.219, p = 0.038, respectively) (table 2). on the other hand, there were negative correlations archivio italiano di urologia e andrologia 2023; 95(3):11462 3 gal-1 and gal-3 and spermatogenesis and reproductive hormones between serum and seminal levels of gal-1 and gal-3, total and progressive sperm motility, sperm count and abnormal sperm forms in healthy individuals (r = -0.382, p < 0.001; r = -0.405, p < 0.001; r = -0.376, p < 0.001; r = -0.364, p < 0.001=) (r = -0.394, p<0.001; r = -0.467, p < 0.001; r = -0.413, p < 0.001; r = -0.433, p < 0.001) (r = -0.372, p < 0.001; r = -0.377, p < 0.001; r = -0.317, p = 0.002; r = -0.311, p = 0.003)(r = -0.445, p < 0.001; r = -0.498, p < 0.001; r = -0.453, p < 0.001; r = -0.463, p < 0.001, respectively) (table 2). furthermore, statistically significant positive correlations between serum levels of gal-1 and gal-3 and age in azoospermic patients were reported (r = 0.511, p < 0.001; r = 0.390, p = 0.008, respectively) (table 3). on the other hand, there were negative correlations between seminal gal-1 and estradiol (e2) and seminal gal-3 and fsh and lh in azoospermic patients (r = -0.318, p = 0.033; r = -0.322, p = 0.031; r = -0.477, p < 0.001, respectively) (table 3). also, negative correlations between serum gal-3 and total and free testosterone in azoospermic patients were detected (r = -0.396, p = 0.007; r = -0.375, p = 0.011, respectively) (table 3). discussion the current cross-sectional study was conducted at andrology outpatient clinic. the current study had shown that serum and seminal levels of gal-1 and gal-3 were statistically significant higher in azoospermic cases compared to fertile individuals. this finding is attributed to the fact that gal-3 expression and/or its subcellular localization could be modified in the human infertile testes as gal-3 immunostaining appears more intense in the infertile testes with an absence of germ cells (sertoli cell-only syndrome) (20). furthermore, animal studies on rat testes had revealed that gal3 levels are increased in severely damaged spermatogenesis (20). these findings could be seen in agreement with gamalel din et al. who evaluated seminal plasma and serum levels of gal-1 in noa patients (23). the aforementioned casecontrol study that included in total 48 noa patients and 50 age matched healthy controls demonstrated that seminal plasma levels of gal-1 were higher in noa men versus healthy controls (23). consistently, gal-3 levels are increased in oligozoospermic cases (24). in addition, there table 1. shows levels of seminal plasma and serum gal-1 and gal-3 in azoospermic cases and healthy individuals. azoospermic cases (n = 45) healthy individuals (n = 45) mean sd range mean sd range p-value serum galectin 1 (ng/ml) 13.79 ± 10.14 6.7-56 7.35 ± 1.12 5.2-9.3 < 0.001 seminal plasma gal-1 (ng/ml) 12.11 ± 6.24 3.6-27.4 7.25 ± 0.90 5.7-8.7 < 0.001 serum gal-3 (pg/ml) 402.56 ± 295.59 153.8-1300 230.11 ± 59.33 120-312.3 < 0.001 seminal plasma gal-3 (pg/ml) 404.15 ± 300.11 114.6-1230 152.77 ± 22.50 120.6-198.2 < 0.001 p value was calculated using mann-whitney test. table 2. shows correlation between gal-1 (ng/ml) and gal-3 (pg/ml) with age and different sperm parameters and reproductive hormones. parameters gal-1 (ng/ml) gal-3 (pg/ml) serum seminal plasma serum seminal plasma r p-value r p-value r p-value r p-value age (years) 0.296 0.005 0.013 0.904 0.200 0.059 -0.092 0.387 sperm count -0.382 < 0.001 -0.394 < 0.001 -0.372 < 0.001 -0.445 < 0.001 total sperm motility -0.405 < 0.001 -0.467 < 0.001 -0.377 < 0.001 -0.498 < 0.001 progressive sperm motility -0.376 < 0.001 -0.413 < 0.001 -0.317 0.002 -0.453 < 0.001 abnormal sperm forms -0.364 < 0.001 -0.433 < 0.001 -0.311 0.003 -0.463 < 0.001 fsh 0.333 < 0.001 0.319 0.002 0.436 < 0.001 0.151 0.155 lh 0.312 0.003 0.337 < 0.001 0.350 < 0.001 0.007 0.951 total testosterone -0.139 0.191 0.046 0.666 -0.184 0.082 0.054 0.614 free testosterone -0.111 0.298 0.205 0.053 -0.197 0.063 0.219 0.038 prl 0.033 0.757 0.120 0.260 0.032 0.765 0.008 0.940 e2 0.053 0.622 -0.151 0.155 0.079 0.460 -0.049 0.645 p value calculated using spearman's rank correlation coefficient. table 3. shows correlation between gal-1 (ng/ml) and gal-3 (pg/ml) with age and reproductive hormones among azoospermic patients. parameters serum gal-1 seminal plasma gal-1 serum gal-3 seminal plasma gal-3 (ng/ml) (ng/ml) (pg/ml) (pg/ml) r p-value r p-value r p-value r p-value age (years) 0.511 < 0.001 0.064 0.674 0.390 0.008 -0.102 0.505 fsh 0.077 0.615 -0.024 0.874 0.265 0.078 -0.322 0.031 lh 0.093 0.546 0.053 0.731 0.152 0.320 -0.477 < 0.001 total testosterone -0.236 0.118 0.045 0.769 -0.396 0.007 0.127 0.405 free testosterone -0.207 0.173 0.224 0.138 -0.375 0.011 0.293 0.051 prl 0.077 0.613 0.279 0.064 0.032 0.834 0.046 0.765 e2 -0.011 0.945 -0.318 0.033 0.004 0.980 -0.173 0.256 p value calculated using spearman's rank correlation coefficient. archivio italiano di urologia e andrologia 2023; 95(3):11462 gamalel din s.f., shaker o.g., fawzy megawer a., et al. 4 were statistically significant positive correlations between serum and seminal levels of gal-1 and gal-3, age, fsh, lh and abnormal sperm forms. similarly, it should be noted that fsh enhances gal-3 expression probably through the classical camp/pka/creb transducing pathway (20). furthermore, camp responsive element (cre) and activator protein complex (ap1) have been detected in gal-3 promoter, a finding which agrees with the potential direct stimulatory actions of fsh and egf, respectively. on the contrary, gal-1 has been detected in interstitial cells in mouse testis (25) where it might modulate leydig cell growth through its multivalent binding and crosslinking properties as well as its ability to interact with extra cellular matrix causing changes in cell adhesivity (26). in the same context, the same study had reported that gal-1 induces changes in leydig cell morphology and reduces cell viability and testosterone production (26). furthermore, this is the first time that an endogenous protein, gal-1, is shown to possess apoptosis-inducing activity on leydig cells. also, there were negative correlations between gal-1, gal-3, total and progressive sperm motility and sperm count. we agreed with menteşoğlu and colleagues (2021) who assessed the correlation between semen parameters and galectin-3 levels of infertile men (24). moreover, the possible role of gal-3 and sperm motility in the current study is also supported by the negative correlation between gal-3 levels and total progressive motile sperm. consistently, gal-3 levels were found to be negatively correlated with total progressive sperm count in oligozoospermic patients (24). furthermore, there was a highly statistically significant positive correlation between serum gal-1 and gal-3 and age in azoospermic patients that could be seen contradictory to the study conducted by gamalel din et al who failed to demonstrate any correlation between serum gal-1 and age in noa patients (23). furthermore, there was a statistically significant negative correlation between seminal plasma gal-1 and estradiol (e2) in azoospermic patients. similarly, perzelova et al. demonstrated an inverse relation between gal-1 and estrogen as they showed that the pharmacological activation of estrogen receptor-b led to a significant alteration in the pattern of differentiation and the proliferation activity of keratinocytes including gal-1 (27). interestingly, there were statistically significant negative correlations between serum gal-3, total testosterone and free testosterone in azoospermic patients. these findings could be seen contradictory to a recent study that was conducted on rats and revealed the favorable effect of testosterone administration to halt the progression of cavernosal fibrosis by decreasing gal-1 through enhancing the expression of mir-22-3p (28). furthermore, there were statistically significant negative correlations between seminal plasma gal-3, fsh and lh in azoospermic patients. remarkably, there are several points of strength of the current study that can be summarized as follows. it clearly demonstrates the detrimental effects of gal-1 and gal3 on spermatogenesis. also, it highlights the horizons for a potential regulatory effect of reproductive hormones on these proteins. admittedly, lack of immunohistochemistry can be seen as the major limitation of the current study. also, small sample size can be added as another limitation. finally, five cases of the healthy individuals suffering from hypothyroidism and diabetes mellitus and hypertension and disc prolapsed were included. conclusions elevated serum and seminal levels of gal-1 and gal-3 have detrimental effects on spermatogenesis. furthermore, the current study demonstrated 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zhao z, et al. the n-terminal tail coordinates with carbohydrate recognition domain to mediate galectin-3 induced apoptosis in t cells. oncotarget. 2017; 8:49824. 18. stowell sr, arthur cm, mehta p, et al. galectin-1, -2, and -3 exhibit differential recognition of sialylated glycans and blood group antigens. j biol chem. 2008a; 283:10109-10123. 19. wollina u, schreiber g, görnig m, et al. sertoli cell expression of galectin-1 and -3 and accessible binding sites in normal human testis and sertoli cell only-syndrome. histol histopathol. 1999; 14:779-84. 20. deschildre c, ji jw, chater s, et al. expression of galectin-3 and its regulation in the testes. int j androl. 2007; 30:28-40. 21. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310:2191-4. 22. world health organization (who). who laboratory manual for the examination and processing of human semen. 5th ed. geneva: who: 2010. 23. gamalel din sf, abougabal kh, saad hm, et al. estimation of serum and seminal plasma levels of glactin-1 in nonobstructive azoospermia cases and their correlations with the rate of sperm retrieval: a comparative prospective study. j reprod infertil. 2022; 23:257-263. 24. mentesoglu p, tangal s, yigman m, et al. the correlation between semen parameters and galectin-3 levels of infertile men. tjrms. 2021; 5:1-5. 25. timmons pm, rigby pwj, poirier f. the murine seminiferous ephitelial cycle is pre-figured in the sertoli cells of the embryonic testis. development. 2002; 129:635-647. 26. martinez vg, pellizzari eh, díaz es, et al. galectin-1, a cell adhesion modulator, induces apoptosis of rat leydig cells in vitro. glycobiology. 2004; 14:127-37. 27. perželová v, sabol f, vasilenko t, et al. pharmacological activation of estrogen receptors-α and -b differentially modulates keratinocyte differentiation with functional impact on wound healing. int j mol med. 2016; 37:21-8. 28. hu z, zhang y, chen j, et al. testosterone attenuates senile cavernous fibrosis by regulating tgfbr1 and galectin-1 signaling pathways through mir-22-3p. mol cell biochem.c2023; 478:1791-1802. correspondence sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg department of andrology and stds kasr al-ainy, faculty of medicine cairo university, al-saray street, el manial, cairo, 11956, egypt ahmad fawzy megawer, md mohamed ahmed abdel salam, md abdelhalim nabil abdelhalim, mbbch ahmed adel, md department of andrology, sexology and stds, kasr alainy faculty of medicine, cairo university, cairo, egypt olfat gamil shaker, md department of medical biochemistry and molecular biology, kasr alainy faculty of medicine, cairo university, cairo, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11625 1 systematic review introduction renal artery infarction (ri) describes the presence of blood clot in the main renal artery or its branches causing complete or partial obstruction of the blood supply. its etiology is either related with intrinsic disorders of the renal vasculature or with cardiovascular disorders outside the kidney (1-2). the blood perfusion impairment results in renal injury and failure, partial or total, permanent or not, though the final outcome is primarily related with the prompt diagnosis and treatment (3-5). the correct diagnosis of ri is a challenge for the physician. the disease may mimic the renal colic or other conditions such as urinary tract infection, acute abdomen, cardiac and pulmonary diseases, necessitating a multidisciplinary diagnostic work up (1-2, 6-8). several case series are referred to ri management, mainly reflecting the experience and preferences of each group, but highquality comparative series investigating the prognostic factors, the optimal diagnostic algorithm, the best treatment strategy and the role of prompt management in disease outcome are lacking. a number of different pharmaaim: renal artery infarction (ri) is the presence of blood clot in the main renal artery or its branches causing complete or partial obstruction of the blood supply. its etiology is either related with disorders of the renal vasculature or with cardiovascular diseases. recently, the sarscov-2 virus is an emerging cause of thromboembolic events and the incidence of ri is anticipated to increase after the pandemic. methods: a systematic review based on covid-19 associated ri was conducted. protocol: a systematic review of the medline/pubmed and scopus databases was conducted in accordance to the preferred reporting items for systematic reviews and meta-analyses (the prisma statement). search strategy and information sources: a hand-search was performed using the terms “sars-cov-2” or “covid-19” and “renal thrombosis” or “renal infarction” or “renal “thromboembolism”. eligibility criteria: all types of publications (case reports, case series, letters to the editor, short communications) were evaluated for relevance. inclusion criteria were: confirmed sars-cov-2 infection irrespectively of the age, diagnosis of ri during or after the onset of viral infection, and exclusion of other potential causes of thromboembolic event except of sars-cov-2. patients with renal transplantation were also considered. study criteria selection: after checking for relevance based on the title and the abstract, the full texts of the selected papers were retrieved and were further evaluated. duplicated and irrelevant cases were excluded. any disagreement was resolved by consensus with the involvement of a third reviewer. quality of studies: the assessment of the quality case reports was based on four different domains: selection, ascertainment, casualty and reporting. each paper was classified as “good”, “moderate” and “poor” for any of the four domains. data extractions: crucial data for the conduct of the study were extracted including: age, sex, time from sars-cov-2 infection till ri development, medical history, previous or current antithrombotic protection or treatment, laterality and degree of obstruction, other sites of thromboembolism, treatment for thromboembolism and sars-cov-2 and final outcome. data analysis: methods of descriptive statistics were implicated for analysis and presentation of the data. results: the systematic review retrieved 35 cases in 33 reports. in most cases, ri was diagnosed within a month from the sarscov-2 infection albeit 17 out of 35 patients were receiving or had recently received thromboprophylaxis. right, left, bilateral and allograft obstruction was diagnosed in 7, 15, 8 and 5 patients respectively. 17 cases experienced additional extrarenal thromboembolism primarily in aorta, spleen, brain and lower limbs. low molecular weight heparins (lmwh) (usually 60-80 mg enoxaparine bid) was the primary treatment, followed by combinations of unfractionated heparin and salicylic acid, apixrenal artery infarction in the sars-cov-2 era: a systematic review of case reports diomidis kozyrakis, georgios kallinikas, anastasios zarkadas, dimitrios bozios, vasileios konstantinopoulos, georgios charonis, konstantinos safioleas, athanasios filios, evangelos rodinos, despoina mytiliniou, gerasimos vlassopoulos, ioannis gkerzelis, panagiotis filios konstantopouleio general hospital of nea ionia, department of urology, nea ionia, attiki, greece. doi: 10.4081/aiua.2023.11625 summary aban and rivaraxaban, warfarin, acenocoumarol or clopidogrel. kidney replacement therapy was offered to five patients while invasive therapies with thrombus aspiration or catheter directed thrombolysis were performed in two. regarding the outcomes, five of the patients died. the total renal function was preserved in 17 cases and renal impairment with or without hemodialysis was recorded in 5 patients, two of them having lost their kidney allografts. limitations: the majority of included studies are of moderate quality. the results and the conclusions are based on case-reports only and crucial data are dissimilarly presented or missing through the relevant publications. conclusions: thromboprophylaxis may not offer adequate protection against sars-cov-2 induced thrombosis. most patients could be effectively treated with conservative measures, while in more severe cases aggressive treatment could be recommended. implications of key findings: therapeutic doses of lmwh could be considered for protection against ri in sars-cov-2 cases. interventional treatment could be offered in a minority of more severe cases after carful balancing the risks and benefits. key words: keywords: renal; artery infarction; thromboembolism; sars-cov-2; covid-19. submitted 30 july 2023; accepted 3 september 2023 archivio italiano di urologia e andrologia 2023; 95(3):11625 d. kozyrakis, g. kallinikas, a. zarkadas, et al. 2 ceutical regimens and interventional therapies have been tested in ri patients but with inconclusive results in terms of preservation of renal function (1-3, 6-10). the new sars-cov-2 infection, the etiology of the covid-19 pandemic outbreak may cause significant infection of the respiratory system and at the same time may affect multiple other organs through a prothrombotic and inflammatory effect involving the immune and vascular system albeit the mechanism of activation of the cascade of events leading to clot formation is still under investigation (11-13). the incidence of ri is anticipated to increase after the sars-cov-2 pandemic. at present, the management of post covid-19 ri is based on the experience accumulated before the pandemic onset and therefore contemporary clinical research might be beneficial. attempting to add on the existing body of evidence we conducted a review of the literature exclusively with patients who developed ri during or after the infection with sarscov-2. emphasis is given in the history, the diagnostic workup, the laboratory findings and the treatment options. a discussion regarding the role of the new virus in the development of the thrombosis is also attempted. the optimal treatment of respiratory infection due to sars-cov-2 is beyond the scope of this review. materials and methods protocol a systematic review of the medline/ pubmed and scopus databases was conducted in accordance to the preferred reporting items for systematic reviews and meta-analyses (the prisma statement) (14). search strategy and information sources the aforementioned databases were hand-searched until mid december 2022 using the terms “sars-cov-2” or “covid-19” and “renal thrombosis” or “renal infarction” or “renal “thromboembolism”. eligibility criteria based on the title and the abstract’s content all types of publications (case reports, case series, letters to the editor, short communications) were independently evaluated for relevance by two of the authors of this manuscript (dk and gk). inclusion criteria were: 1. confirmed sars-cov-2 infection irrespectively of the age, 2. diagnosis of ri during or after the onset of viral infection, and 3. exclusion of other potential causes of thromboembolic event except of sars-cov2. patients with renal transplantation or/and the co-existence of thromboembolic events outside the renal vascular system were also considered. exclusion criteria were the absence of sars-cov-2 infection or of ri, the inadequate/poor presentation of the case, included the abstractonly cases and the non-english articles. study selection after checking for relevance based on the title and the abstract, the full texts of the selected papers were retrieved and were further evaluated. duplicated and irrelevant cases were excluded. any disagreements were resolved by consensus with the involvement of a third reviewer (pf). data extraction three of the authors (dk, vk, pf) determined and extracted the crucial data for the conduct of the study: age, sex, time from sars-cov-2 infection till ri development, medical history, previous or current antithrombotic protection or treatment, laterality and degree of obstruction, other sites of thromboembolism, treatment for thromboembolism and sars-cov-2 and final outcome. figure 1. prisma flow diagram of selected cases. archivio italiano di urologia e andrologia 2023; 95(3):11625 3 renal artery infarction as a sequela of sars-cov-2 infection quality of studies two of the authors independently assessed the quality of each paper included in the study. murad et al. (15) published a guide of assessment tools of a case report quality based on four different domains: selection, ascertainment, causalty and reporting. considering that all the included papers were case report the studies were rated accordingly. each paper was classified as “good”, “moderate” and “poor” for any of the four domains. any disagreement in quality assessment was resolved with third part involvement (gv or ig). data analysis methods of descriptive statistics were applied for analysis and presentation of the demographics and clinical characteristics of the included population. results a checklist of the included items in prisma systematic review is presented in supplementary table 1. 33 papers with 35 ri cases were retrieved after the search of the databases (figure 1). an overview of the quality of the papers is provided in table 1 (12, 13, 16-46). most of the case reports were assessed with moderate risk of bias. the overview of the retrieved papers is provided in table 2. the demographics and clinical characteristics with the relevant rates are provided in table 3. all the patients except one were adults, the majority of whom were males in their sixth or seventh decade of their lives usually with a history of obesity, diabetes mellitus (dm) and/or smoking. noteworthy, 17.6% of the patients had unremarkable medical history. in most of the cases the ri event was diagnosed within a month from the sars-cov-2 infection (mean 15.3 days). it is of interest that almost half of the cases (17/35) were receiving or had recently received thromboprophylaxis. the most frequently used thromboprophylaxis was low table 1. assessment of risk of bias for each one of the included case reports for the domains of selection, ascertainment, causality and report. for each one of the four domains a classification in low (l), moderate (m) and high (h) risk is provided. author selection ascertainment causality report xu (16) h m m l acharya (17) h m h m mocerino (18) h l m l mukherjee (19) h l l l deshmukh (20) h h h m ramanathan (21) h m l m post (12) m m m l m m l l añazco (22) h m l m lushina (23) h m h m kundal (13) h m h m besutti (24) m l m h m m h h imoto (25) h m m m ammous (26) h l m l kenizou (27) h l m m webb (28) h h m l plouffe (29) m h h m singh (30) h h h m tantisattamo (31) m m h l belfort (32) m l m l topel (33) h m h m sethi (34) h m l m jentzsch (35) h m l l farias (36) h m l m al-mashdali (37) h m m l mavraganis (38) h l l l jain (39) h l m m rigual (40) h m m l huang (41) h l m l mancini (42) h l l l gjonbalaj (43) h m m l brem (44) h l l m kourien (45) h m h m veterano (46) h m h l table 2. overview of retrieved papers. author age sex days after antithrombotic/ laterality, other sites of tx for tx for outcome (y) covid-19 anti-plt tx & degree thromboembolism sars-cov-2 thromboembolism diagnosis/history before ri of obstruction xu 2020 (16) acharya 2020 (17) mocerino 2020 (18) mukherjee 2020 (19) deshmukh 2020 (20) 46 77 69 71 55 m f f m f 27/dm, kidney–pancreas transplant nd/hypothyreoidism, cad, copd, smoking, lung cancer, aortic aneurysm and bilateral renal stenting, recent embolization for leak nd/dm, ah, cad 9/unremarkable 3/recent appendicitis intermittent enoxaparin 40 mg bid asa asa, clopidogrel enoxaparin no segmental artery, incomplete bilateral incomplete left main incomplete left superior bilateral left incomplete, right complete no no no ascending aorta abdominal aorta suppl o2, azithromycin, prednisone, lopinavir/ritonavir, hclq cefuroxime nd nd suppl o2, methylprednisolone, lopinavir/ritonavir, hclq nd alive, rf nd alive, rf nd preservation rf preservation rf multiorgan dysfunction, sepsis enoxaparin 80 mg bid, at discharge apixaban 5 mg bid asa iv heparine then apixaban stop enoxaparin, heparine iv, clopidogrel then apixaban + clopidogrel nd archivio italiano di urologia e andrologia 2023; 95(3):11625 d. kozyrakis, g. kallinikas, a. zarkadas, et al. 4 ramanathan 2020 (21) post 2020 (12) añazco 2020 (22) lushina 2020 (23) kundal 2020 (13) besutti 2020 (24) imoto 2020 (25) ammous 2021 (26) kenizou 2021 (27) webb 2021 (28) plouffe 2021 (29) singh 2021 (30) tantisattamo 2021 (31) belfort 2021 (32) topel 2021 (33) sethi 2021 (34) jentzsch 2021 (35) farias 2021 (36) al-mashdali 2021 (37) mavraganis 2022 (38) jain 2022 (39) 54 62 58 41 84 39 54 53 64 62 78 49 6 32 33 28 55 62 28 37 43 64 62 m m m f m f m m m m m m m m m m m f m m m m 11/obesity 9/ah, henoch–schonlein glomerulonephritis, kidney transplantation 2/sleep apnea 3/obesity, dm 0/ah, af nd/obesity, ah, contraceptives, patent foramen ovale 9/former smoker, asthma, ulcerative colitis 6/ah, mitral valve replacement 15/gastric & duodenal ulcer 16/ah, asthma 9/obesity, pulmonary embolism, phlebitis 27/cki, kidney transplantation, rejection** 63 (suspected covid)/ unremarkable 30/unremarkable 9/obesity, dm, eskd, kidney transplantation, post-transplant aki 3/dm, heart transplantation, dyslipidemia 28/smoking, ah 5/unremarkable 0/smoking, asthma, migraines 10/na -4/type b aortic dissection, deafness, smoking 19/overweight 8/unremarkable no dalteparine 2500 u nadroparin 5700 no no no no asa no lmwh prphylaxis (stopped 2 days before rate) rivaroxaban 10 mg enoxaparin 80 mg then 40 mg no no clopidogrel, stop due to gi bleeding, heparin iv no enoxaparin stopped 14 d before rate lmwh prophylaxis no no no no no bilateral segmental allograft segmental bilateral segmental bilateral segmental massive left left upper segmental right segmental right main incomplete left segmental bilateral left segmental right main complete kidney allograft, complete right segmental incomplete right main complete allograft segment, incomplete, microangiopathy right proximal segment incomplete left segmental left segmental left segmental left main right main left anterior segmental left main complete spleen no bowel, lower limb no lung, brain, aortic arc aorta spleen spleen brain, spleen no left upper extremity, lung, brain, abdominal aorta no no no no descending thoracic aorta abdominal aorta, lower limb no no no spleen spleen, aorta descending thoracic aorta dxm, albuterol prednisone, high flow o2 non rebreathing mask o2, mechanical ventilation o2, dxm, ceftriaxone, ivermectin intubation nd lopinavir/ritonavir, hclq lopinavir/ritonavir, hclq, tocilizumab favipiravir, ciclesonide, intubation, ecmo, meropenem, steroid, teicoplanin suppl o2 cefotaxime, azithromycin prednisone, high flow o2, carbapenem ceftriaxone suppl o2 norepinephrine, levofloxacin, ceftriaxone, intubation, remdesivir, dxm prednisone, ceftriaxone, azthriomycin, hydrocortisole supp o2, azithromycin, prednisole, favipravir supp o2, methylprednisolone, lopinavir/ritonavir nd nd suppl o2 dxm, remdesivir, tocilizumab, ceftaroline, high flow nasal o2 high flow nasal o2, iv steroids, iv antibiotics preservation rf slow improvement icu, rehab center ventilation, aki, death died discharged home discharged home discharged home died preservation rf ischemic stroke, gi bleeding, death graft loss full recovery mucormycois, death cardiac arrest (survived), renal dialysis, new onset af improved improving, palpable limb pulses gi bleeding, normal rf improved na chronic renal impairment, no dialysis improving improving heparine 18u/kgr/h then apixaban 10 mg x2, shift to 5 mg x1 dalteparin 15000u then acenocoumarol heparin and nadroparin + kidney replacement therapy bowel resection enoxaparin 60 mg bid, hemodialysis thrombectomy for brain thrombus apixaban (therapeutic dose) lmwh 6,000 ui bid lmwh 6,000 ui bid enoxaparin heparin, then novel oral anticoagulant iv heparin, rivaroxaban stop, fogarty embolectomy for humeral thrombus enoxaparin 40 mg aspirine 81 mg for 6 m nephrectomy iv heparine, allograft nephrectomy enoxaparin, then warfarine thrombectomy for limb infarct, enoxaparine 0.8 mg, asa 300 mg, pentoxyfylline 600 mg renal dialysis, lmwh therapeutic dose enoxaparin 1 mg/kg bid, then asa81 mg + rivaroxaban 20 mg enoxaparin 60 mg bid, then warfarin 5 mg/d iv heparin, then warfarine 3.5 mg (target inr 2-3) enoxaparine 8000 bid + asa 80 mg, then enoxaparine replaced by fondaparinux 7.5 mg lmw heparin 80 mg bid followed by dabigatran 150 mg bid archivio italiano di urologia e andrologia 2023; 95(3):11625 5 renal artery infarction as a sequela of sars-cov-2 infection dose low molecular weight heparins (lmwh), usually enoxaparin, followed by amino-salicylic acid (asa), either as monotherapy or combined with heparin. of the 35 patients, five experienced allograft thrombosis. in the rest 30 patients, right, left and bilateral obstruction was diagnosed in 7, 15 and 8 patients respectively. in 17 cases, one or more organs outside the urinary tract were affected by the thromboembolic event with the aorta being most frequently involved (10 cases), followed by the spleen (8 cases), brain (3 cases), lower limb (3 cases), lung (3 cases) and elsewhere (2 cases). all the patients were reported to complain about pain of sudden onset in the upper lateral abdominal quadrant and/or in the costovertebral angle ipsilateral to the affected kidney. the abdomen was tender in the affected side but the guarding reflex was rarely elicited. the wbc level is frequently elevated with the reported values being mostly above 15000 wbc/μl. serum ldh and d-dimers are almost uniformly above the normal range. kidney injury is described in 12 cases while for 7 others reliable information were lacking. the mainstay of the diagnosis was the contrast-enhanced ct (cect) scan or preferably ct angiography (cta) and in only one case digital subtractive angiography (dsa) as an adjuvant diagnostic modality to the ct scans. in two other cases the diagnosis of ischemia was established with renal biopsy. massive or complete thromboembolism was revealed in eight patients. the rest of the patients had incomplete infarction of either the main artery or the segmental branches. as it is shown in table 3, the treatment for sars-cov-2 is reported for 29 patients and different combinations of drugs have been used. steroids were most frequently delivered (51.4% of patients), followed by antibiotics (37.1%) and by antiviral treatment (31.4%). hydroxychloroquine was delivered in 5 patients and monoclonal antibodies in 3. lmwh, mainly high dose enoxaparin (60-80 mg bid), was the primary treatment against thromboembolism in 19 cases, followed by therapeutic combinations containing unfractionated heparin (9 patients) and salicylic acid in dosages ranging from 81 to 300 mg/day. upfront apixaban or other antithrombotic and anti-platelet agents (rivaraxaban, warfarin, acenocoumarol or clopidogrel) have also been delivered in ri patients. kidney replacement therapy was urgently offered to only five of the cases. invasive therapies were performed in two patients. in one of them, with mid-distal segmental occlusion, aspiration and stent placement was performed and tirofiban was delivered to the thrombus site while the patient was under treatment with unfractionated heparin plus asa. the patient experienced full recovery (43). in another 56-year female with massive allograft thrombosis, history of chronic kidney disease, obesity, heart failure, diabetes type 2, arterial hypertention and lower limb rigual 2022 (40) huang 2022 (41) mancini 2022 (42) gjonbalaj 2022 (43) brem 2022 (44) kourien 2022 (45) veterano 2022 (46) nv: normal values, dm: diabetes mellitus, cad: coronary artery disease, copd: chronic obstructive pulmonary disease, rf: renal function, nd: not defined, af: atrial fibrillation, ah: arterial hypertension, icu: intensive care unit, gi: gastrointestinal, aki: acute kidney injury cki: chronic kidney injury, sc: subcutaneous, asa: acetylsalicylic acid, eskd: end stage kidney disease, lmwh: low molecular weight heparin, ckd: chronic kidney disease, hclq: hydroxychloroquine, suppl o2: supplementary oxygen, dxm: dexamethasone, ecmo: extracorporeal membrane oxygenation, iv intravenous. 53 62 43 5th decade 59 32 56 m m m m m m f 10/cerebral infarction tx with iv thrombolysis + thrombectomy 19/dm 3/mild stenosis of aortic valve, adrenal adenoma (non functioning) 60/unremarkable 14/dm 30/unremarkable 30/idiopathic ckd, kidney transplant, allograft dysfunction, obesity, heart failure, dm, ah, popliteal vein thrombosis enoxaparin 1 mg/kg, asa 100 mg no no no lmwh prophylaxis enoxaparin prophylaxis asa, enoxaparin 20 mg, prophylaxis bilateral segmental left main & posterior complete left upper, middle segmental left mid/distal segmental left bilateral segmental allograft main, quasi-complete spleen no no no spleen, lung, femoral artery thoracic aorta no no suppl o2, methylprednisolone suppl o2, methylprednisolone, ceftriaxone, antiviral piperacillin/ tazobactam nd azithromycin, ceftriaxone, hclq remdesivir, methylprednisolone, tocilizumab, positive pressure o2 dxm, o2 with nasal cannula rehab center preservation rf dmsa 28% relative renal function full recovery limb amputation, rf preservation permanent hemodialysis allograft preservation, rf improved 1 mg enoxaparin/kg, asa 100 mg, then asa 300 mg clopidogrel 75 mg, nadroparin 3800u/q12h then rivaroxaban enoxaparin 7000 ui bid, recur of thrombosis, then enoxaparin 8000 ui bid + asa 100 mg asa 100 mg/d + heparin 25,000 ui/d thrombus aspiration + tirofiban 5 ml, stent, then asa 100 mg+ clopidogrel 75 mg lmwh 60 mg bid, limb embolectomy bilateral nephrectomy, combined antfungal agents catheter directed thrombolysis (alteplase, 5cc bolus, then 0.8 mg/h + iv heparine 500u/h) for 2 days + endoprosthesis, asa 100 mg + enoxaparin 60 mg bid, then apixaban 5 mg bid archivio italiano di urologia e andrologia 2023; 95(3):11625 d. kozyrakis, g. kallinikas, a. zarkadas, et al. 6 thrombosis, the treatment consisted of catheter directed thrombolysis with alteplase combined with iv heparin, endoprothesis placement, asa and enoxaparin resulting in preservation of the transplant and improvement of renal function (46). nephrectomy was necessitated in three other cases, one bilateral one unilateral and one for allograft removal. regarding the outcomes, five of the patients died. the total renal function was preserved or improving in 16 cases, while in another one the relative function was diminished to 28% in dmsa scans without affecting though the overall renal function. renal impairment with or without hemodialysis was recorded in 5 patients, two of them having lost their kidney allografts. for 7 cases data regarding renal function outcome are inconclusive. discussion the most frequent etiologic factor for ri of any cause is table 3. patients’ demographics and clinical characteristics. epidemiology age (range) years 52.1 (6-84) male/female ratio 3.4/1 male %, female % 77%, 23% days for ri after covid-19 diagnosis 15.3 d (0-63)* history (for 34 pts) unremarkable (%) 6 (17.6) transplantation (%) 6 (17.6) heart diseases cad (%) 2 (6) chronic heart diseases (%) 4 (11.7) af (%) 1 (3) ah (%) 8 (23.5) dm (%) 7 (20.5) obesity/overweight (%) 7 (20.5) smoking (%) 4 (11.7) pulmonary diseases asthma (%) 3 (8.8) copd (%) 1 (3) sleep apnea (%) 1 (3) lung cancer (%) 1 (3) vascular diseases vasculitis/thromboembolism (%) 6 (17.7) aorta aneurysm/dissection (%) 2 (6) renal dysfunction (%) ** 4 (11.7) gastrointestinal diseases (%) 2 (6) others appendicitis (%) 1 (3) migraines (%) 1 (3) dyslipidemia (%) 1 (3) deafness (%) 1 (3) adrenal adenoma (%) 1 (3) hypothyroidism (%) 1 (3) contraceptive drug consumption (%) 1 (3) antithrombotic/anti-plt tx before ri (17 cases) lmwh (%) 11 (31.4) iv heparin (%) 1 (2.8) asa (%) 5 (14.3) clopidogrel (%) 2 (5.7) laterality right side (%) 7 (20) left side (%) 15 (42.9) bilateral (%) 8 (22.8) allograft (%) 5 (14.3) degree of obstruction segmental artery (%) 25 (58) main artery (%) 9 (21) the arterial site is not defined (%) 9 (21) incomplete *** 9 complete *** 6 massive/quasi-complete *** 2 other sites of thromboembolism aorta (%) 10 (28.6) spleen (%) 8 (22.8) lower limb (%) 3 (8.6) lung (%) 3 (8.6) brain (%) 3 (8.6) upper limb (%) 1 (2.9) bowel (%) 1 (2.9) no (%) 18 (51.4) tx for sars-cov-2 antibiotics (some pts received azithromycin 6 combinations) 13 pts (37.1%) cefuroxime 1 ceftriaxone/cefotaxime 7 ceftaroline 1 levofloxacin 1 piperacillin/tazobactam 1 meropenem/carbapenem 2 teicoplanin 1 nd antibiotics 1 steroid agents (51.4%) prednisone/methylprednisolone/dxm 18 antiviral 11 pts (31.4%) remdesivir 3 opinavir/ritonavir 5 favipiravir 2 nd antiviral 1 hclq (14.3%) hclq 5 inhaler (5.7%) albuterol 1 ciclesonide 1 mechanical ventilation/ mechanical ventilation/intubation 4 intubation (11.4%) ivermectin 1 others tocilizumab 3 ecmo 1 norepinephrine 1 o2 treatment (45.7%) positive pressure 1 nd (supplementary) 10 high flow 4 non-rebreathing 1 nd (20%) nd 7 overview of primary tx therapeutic agent in primary tx long term tx or tx after for ri (%) for ri (no of pts) discharge (no of pts) single medical tx 22 pts (62.9) lmwh (19) apixaban (5) combined medical tx 7 pts (20) asa (7) asa (5) surgical tx 2 pts (5.7) heparin iv (9) clopidogrel (2) nd 4 pts (11.4) clopidogrel (2) acenocoumarol (1) apixaban (2) oral anticoagulant (1) nd heparin (1) warfarine (2) nephrectomy (2) rivaroxaban (2) interventional/endovascular treatment (2) fondaparinux (1) nd (4) dabigatran (1) outcomes: no of pts dead: 5, alive: 30 rf preservation: 8 full recovery: 2 improved /improving: 6 multiorgan dysfunction/sepsis: 1 icu: 2 discharged home (no further info): 3 discharged to rehabilitation center: 2 renal dysfunction: 5 loss of renal unit: 1 cardiac arrest, af: 1 gi bleeding: 2 * in one case ri was diagnosed 4 days before the definite sars-cov-2 diagnosis. ** irrelevant to history of transplantation. *** rates are not displayed due to missing data. archivio italiano di urologia e andrologia 2023; 95(3):11625 7 renal artery infarction as a sequela of sars-cov-2 infection atrial fibrillation (af) encountered 25% to 75% of the patients (2, 8, 47). however, amongst patients with covid-19-induced ri, af is a rare occasion. the cytokine storm has been described in these patients predisposing to pro-inflammatory, prothrombotic and profibrotic effects induced by activated neutrophils and monocytes, as well as in causing damage to the endothelium (endothelitis) through the activation of angiotensin-converting enzyme-2 receptor. this cascade of events leads to activation and aggregation of factor vii, von willebrand factor and fibrinogen and consequently to thrombin activation and fibrin clot formation and also in aggregation of platelets resulting in multiple thrombotic events (28, 32). several other factors predispose to the onset of the ri such as diabetes mellitus, arterial hypertension, hyperlipidemia, congestive heart failure, coronary artery disease, myocardial infarction, mitral valve disease and cerebrovascular disease (10, 47, 48). a relevant history has also been recorded in many patients of this review. occasionally, in situ thrombosis may be iatrogenic in origin or traumatic (4, 49). history of a previous embolic event or thrombophilia with potential resistance of activated protein c and deficiency of protein s should also be examined (4, 5, 9). almost half of the covid-19 related ri cases were receiving or had recently received thromboprophylaxis. it seems that low dose of lmwh or asa do not offer adequate protection against ri so as to overcome the cytokine storm effect. the use of intermediate-dose enoxaparin in covid19-induced-hypoxia and before the onset of ri could be proposed as a measure to overcome the failure of throboprophylaxis attributed to high levels of factor vii, von willebrand factor and fibrinogen (28). therefore based on the results of a randomized clinical trial spyropoulos et al. recommended the administration of 1mg/kg bid of lmwh and 0.5 mg/kg bid for patients with clearance creatinine ≥ 30 and < 30 ml/min/1.73 m2 respectively for hospitalized patients. the beneficial effect of the proposed dosages was evident in non icu patients though (50). the prompt diagnosis and treatment is the cornerstone of a favorable outcome for ri of any case. 90 minutes of normothermic ischemia can lead to irreversible damage of the renal parenchyma (3, 4), albeit this threshold is not always confirmed in clinical practice. several groups have reported the preservation of renal function after many hours or even days after the onset of infarction (6, 51). in covid19-associated ri the delay in seeking for medical help cannot be evaluated because this piece of information is not reported in many of the included case reports but it seems that the degree of obstruction is more crucial than the delay in diagnosis. three out of the five deaths of the review were recorded in the 8 patients with complete or massive infarction, indicating that the high degree of obstruction might be life threatening compared with the lower degree of ri. the most frequently affected renal unit by covid-19 was the left-sided, representing a finding that is poorly understood. in most case series with ri of any etiology both sides were almost equally infracted (2, 6, 9, 51). three case series of the pre-covid-19 era demonstrated a predominance of left ri which is a finding similar to that of the present review (47, 48, 52). another paper from korea though reported a higher incidence of right-sided ri (1). domanovits et al. favor the hypothesis that the right renal artery has an acute angle of divergence with the aorta (48). in a more recent report it was revealed that the degrees of angulation were similar for both sides but the left orifice is larger than the right one and this fact may have influenced the laterality of ri (52). apart from the dimensions of the orifice, it could be speculated that the length of renal arteries as well as the distance of the branching from the orifice may also play a role in the predominance of the left side. noteworthy pulmonary embolism (pe) among sars-cov-2 patients is a usual finding with an overall incidence of 16.5% (53). in the present review however pe was a rare finding among ri patients with the aorta and spleen being most frequently affected. if pulmonary infection was the triggering event of thromboembolism through the dissemination of infection and inflammation to the adjacent lung vessels it is anticipated that the incidence of pe would be much higher. however, the figure of three pe events of this review is too low to support this assumption. it has been shown that the virus may directly attack the respiratory system causing pneumonia, while the cardio-vascular system is affected either directly from the virus or indirectly through the blood stream with activation of cytokine storm and pro-inflammatory pathways. it seems that some vessels are more vulnerable than others perhaps due to endothelitis or to increased permeability of the endothelium enhancing the clot formation and platelet aggregation (54). this might explain the higher incidence of aortic and splenic infarctions compared to pulmonary or brain embolism. moreover, in some patients the synchronous diagnosis of viral pneumonia and visceral infarction is indicative of the direct attack against the vascular system, while in others the long time interval (up to 63 days) between the covid-19 pneumonia till the onset of infarction could be associated with an indirect assault (54). in most of the cases the who definition of long post-covid-19 syndrome is met should the duration of ri symptoms lasts at least 2 months (55). in the pre-sars-cov-2 era some authors advocate the dsa as the diagnostic gold standard. the sensitivity rates are as high as 100% but at a cost of increased invasiveness (3, 4). this modality has now been broadly replaced by contrast enhanced ct (cect) imaging and ct angiography (cta) showing single or multiple wedge-shaped filling defects of the renal parenchyma or global hypo-attenuation of the affected renal unit (compared with the healthy one). the blood clots may be also revealed in the vascular system. infarcts involving greater than 50% of the renal parenchyma are considered global. smaller single or multiples lesions (less than 50% of the renal unit) are classified as focal or multifocal respectively (56). the cect/cta sensitivity ranges from 80 to 97.3%, representing a rapid, non invasive, comprehensive and informative method for the diagnosis of ri and it should be performed as early as possible should renal infarction is suspected (2, 8, 48). nephrotoxicity due to radiopaque agents is well described and acute kidney injury may occur in the grounds of an already impaired renal function (57). however, the correct diagnosis cannot be established with other means and the archivio italiano di urologia e andrologia 2023; 95(3):11625 d. kozyrakis, g. kallinikas, a. zarkadas, et al. 8 benefits from the administration of the contrast agent should be balanced against the potential risks. therefore many authors proceeded to ivc administration in patients with renal impairment even at the risk of subsequent hemodialysis (12, 16, 20, 22, 27, 34, 37, 44, 46). the treatment options against sars-cov-2 show a significant variability among the different medical centers. the combinations of regimens comprise mainly steroids plus broad spectrum antibiotics and usually antiviral treatment. due to this variability the impact of anti-sarscov-2 treatment on the natural history of thrombosis cannot not be reliably evaluated. large scale studies with meticulous designed statistical analysis models might address the question whether some medications or combinations might play a preventive role against infarction. revascularization of ri is rarely attempted (1, 6, 8). in one of the biggest series comprising 438 ri of any cause the rate of thrombolysis with urokinase and embolectomy was as low as 4.5% and 0% respectively (2). however, it could be assumed that following a prompt diagnosis and perhaps in the settings of a massive or bilateral ri, endovascular surgery or thrombolytic management may be applied despite the risks of complications (3-5, 46, 48). in the present review, revascularization techniques were applied in one case with almost complete allograft obstruction and in another with a lesser degree of occlusion both with favorable results (43, 46). mortality rate after ri of any cause ranges from 0% to 23.4% (1-3, 7-9). the total number of 5 deaths in 35 patients with post covid-19 ri corresponds to a rate of 14.3% which is reasonable for a severe disease burdened by the unfavorable prognosis of sars-cov-2. perhaps the prompt diagnosis with modern ct-scanners, the close monitoring of the patients and the availability of new generation anti-coagulative agents may all have contributed to acceptable survival rates. nevertheless, the broader use of higher dosages of thromboprophylaxis might further enhance the outcomes in post-covid-19 renal infarction (28, 50). this review has several limitations. as it is shown in table 2 the majority of included studies are of moderate quality. the results and the conclusions are based only on casereports and data are missing through the relevant publications. any treatment of ri is based upon the preferences of the responsible physicians since therapeutic and follow up protocols differ among the medical centers. the outcomes are dissimilarly presented increasing the likelihood of bias. therefore, a direct comparison of the studies or classification of the patients from different reports should be made with caution. moreover, papers published in non english language and presentations in scientific meetings were not included in this review increasing the likelihood of missing data. conclusions thromboprophylaxis may not offer adequate protection against sars-cov-2 induced thrombosis. if ri is suspected the correct diagnosis is based on cect/cta scan and it should be performed as soon as possible, even in patients with renal 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54. evans pc, rainger ge, mason jc, et al. endothelial dysfunction in covid-19: a position paper of the esc working group for archivio italiano di urologia e andrologia 2023; 95(3):11625 d. kozyrakis, g. kallinikas, a. zarkadas, et al. 10 atherosclerosis and vascular biology, and the esc council of basic cardiovascular science. cardiovasc res. 2020; 116:2177-84. 55. soriano jb, murthy s, marshall jc, et al. who clinical case definition working group on post-covid-19 condition. a clinical case definition of post-covid-19 condition by a delphi consensus. lancet infect dis. 2022; 22:e102-7. 56. suzer o, shirkhoda a, jafri sz, et al. ct features of renal infarction. eur j radiol. 2002; 44:59-64. 57. obed m, gabriel mm, dumann e, et al. risk of acute kidney injury after contrast-enhanced computerized tomography: a systematic review and meta-analysis of 21 propensity score-matched cohort studies. eur radiol. 2022; 32:8432-42. correspondence diomidis kozyrakis, md (corresponding author) dkozirakis@yahoo.gr; urology@konstatnopouleio.gr konstantopouleio general hospital of nea ionia, department of urology th. konstantopoulou 3-5 str., nea ionia, 14233, attiki, greece georgios kallinikas, md georgioskallinikas@gmail.com anastasios zarkadas, md azark13@hotmail.com dimitris bozios, md dbozios@gmail.com vasileios konstantinopoulos, md vkonstantinopoulos@yahoo.com georgios charonis, md george.xarwnhs@gmail.com konstantinos safioleas, md konstantinossafioleas@yahoo.gr athanasios filios, md athanfilios@gmail.com evangelos rodinos, md vag.international@hotmail.com despoina mytiliniou, md dmitiliniou@yahoo.gr gerasimos vlassopoulos, md vlassger@gmail.com ioannis gkerzelis, md ioannisgkerzelis@gmail.com panagiotis filios, md panosfilios@yahoo.gr konstantopouleio general hospital of nea ionia, department of urology, nea ionia, attiki, greece conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13301 1 review practice. the dj stent is the most frequently applied indwelling stent in the treatment of symptoms of upper urinary tract obstruction (1). the dj stent is essential and frequently employed in various procedures. it helps keep the ureters open, ensuring the reduction of swelling and the healing of any potential injuries. therefore, it is considered a useful tool in the postoperative therapy of patients with retroperitoneal tumours or fibrosis, ureteropelvic junction stenosis, ureteral strictures, ureteral stones, or iatrogenic ureteral injury, a dj stent is typically the preferred treatment option for patients suffering from obstructive uropathy caused by urinary tract stones. nevertheless, the use of dj stents can causes some complication (2). forgotten dj stent is one of the problems associated with the use of dj stents which have become a challenging problem for urologists. as a consequence of h widespread use of stents, in association to lack of information and compliance with routine follow up visits, patients may forget for years that they have had the placement of a dj stent in the pelvic-ureteral system. hematuria, stent occlusion, migration, fragmentation, encrustation, stone formation, recurrent urinary tract infections (uti), obstruction of the urinary tract, kidney failure, fistula formation in the iliac arteries, and even fatal complications can result from a forgotten dj stent (3). management of the forgotten dj stent varies depending on the complications experienced and differs from patient to patient (1). this management requires an individual approach in view of possible long-term and shortterm complications secondary to the use of dj stents. comparison of complications and assessment of outcomes of management in different cases can provide new insights into managing forgotten dj stents. managing a forgotten dj may be time-consuming, complex, complicated, risky, and expensive, so the treatment choice must be precise and accurate (4). methods preferred reporting items for systematic reviews and metaanalyses (prisma) were adhered to in the present study (5). background: double j stent is one of the procedures frequently performed in the field of urology. forgotten dj stent is a problem that can cause serious complications. this systematic review aims to explore complications and management of patients with forgotten double j stents. methods: scientific literature was obtained from pubmed, sciencedirect, and google scholar with a publication year limited to 2013-2023. the search string included ‘forgotten dj stent, case report, complication’. inclusion criteria were as follows: (1) case report or series, (2) available individual patient data, and (3) english language. data are presented descriptively. results: of the 210 records, 14 articles published were analyzed after the full-text assessment. forgotten dj stent sufferers vary from age 7 years to 88 years. male gender was predominant. the initial symptoms were flank pain and micturition disorders. the complications experienced were encrustation, multiple stones formation, emphysematous pyelonephritis, emphysematous perinephric abscess, fragmentation, and vesical calculus. in management, it was found that procedures were selected according to patient's situation at that time and the condition of the stent. there are case reports that report management that differed from those initially planned. all the patients were alive after treatment. conclusions: a forgotten dj stent can have serious consequences. the management approach requires a combination of various endourological procedures. in consideration of potential complications, urologists need to be careful in making decisions about the choice of technique used. key words: complication; management, forgotten double j stents; endourology. submitted 26 october 2024; accepted 9 december 2024 introduction the dj stent is one of the tools that urologists need to drain and divert upper urinary tract. over the past few decades, there have been continued advances in placement techniques and materials used for ureteral stent. this technique has gained recognition from urologists worldwide as a necessary procedure in urology surgical management of forgotten double j stents: insight from a systematic review of case reports antonius galih pranesdha putra 1*, yufi aulia azmi 2*, soetojo wirjopranoto 1, nadya rahmatika 3, agustin junior nanda de niro 1, alviano satria wibawa 1, kevin muliawan soetanto 4 1 department of urology, faculty of medicine, universitas airlangga; dr. soetomo general academic hospital, surabaya, indonesia; 2 department of health sciences, university of groningen, university medical center groningen, groningen, the netherlands; 3 faculty of medicine, universitas wijaya kusuma, surabaya, indonesia; 4 department of immunology, faculty of medicine siriraj hospital, mahidol, university, bangkok, thailand. * these authors shared first author. doi: 10.4081/aiua.2025.13301 summary archivio italiano di urologia e andrologia 2025; 97(1):13301 a. galih pranesdha putra, y. aulia azmi, s. wirjopranoto, et al. 2 ethics statement ethical approval was not crucial for this study, as it did not involve direct patients, and all included data were previously published. the protocol was registered with the international prospective register of systematic reviews (prospero) by prisma-p guidelines (prospero crd42024577367). eligibiliy a systematic search focused on case reports and a series about forgotten double j stents, which featured information on individual patients. case reports published in 2013-2023 having complete individual data, written in english, discussing appropriate topics, namely management and complications of forgotten dj stents, were included in the analysis. exclusion criteria were being not case report manuscript, lack of individual data, not written in english and not open access. article duplication were eliminated prior to the screening of titles and abstracts. search strategy and selection of studies on august 23, 2023, we performed a systematic database search in pubmed, sciencedirect, and google scholar. an exhaustive exploration was also accomplished through a manual or bibliography search of relevant papers. the keywords "forgotten/neglected double j stent, complication, case report" were used in the search. the titles and abstracts of the articles were assessed independently for prospective eligibility as studies for the full-text review. article extraction we independently extracted essential information from the included studies using a structured and standardized form. the extracted information includes author, year, country, number of patients, age, sex, symptoms, history, forgotten dj stent time duration, complication, management and outcome. quality assessment we independently assessed the risk of bias in included studies by implementing joanna briggs institute (jbi) checklist, that is used for critical appraisal of case studies. we categorized the results as 'yes, cannot tell, and no' (6). statistical analysis a meta-analysis was not feasible because this systematic review evaluated a rare condition which relies on published case reports. similar findings of variables, such as symptoms, are grouped to evaluate their frequency. results study selection ten of the 210 records returned by the search were duplicates. after sifting through titles and abstracts, we eliminated 149 articles. following the full-text assessment, we included 14 published articles in this systematic review. the prisma flow diagram (figure 1) presents the procedure for selecting studies and the exclusion justifications. quality assessment we evaluated each included case report using the jbi critical appraisal checklist (table 1). the summarized critical appraisal checklist shows that the studies were generally of moderate to good quality. study and demographic characteristics this systematic review of published cases included 14 case reports (table 2). most research was conducted in developing countries, including india (4 studies). forgotten dj stent sufferers range in age from 7 to 88. male gender predominated in most of the studies (10 studies). figure 1. flowchart study selection. archivio italiano di urologia e andrologia 2025; 97(1):13301 3 forgotten double j stent symptoms most people complain of flank pain and micturition disorders as their initial symptoms. diarrhea and nocturia are sporadic. the duration of symptoms varies depending on their appearance. history and forgotten dj stent time duration the patient's medical history varies, including procedures related to ureteric/pelvic/kidney stone treatment, ureteral stricture with uti, a surgical procedure to remove a giant uterine myoma, renal transplant, muscle-invasive bladder tumour, sigmoid colon cancer, partial resection of the bladder and nonspecific flank surgery. in addition, there were patients with a history of previously forgotten dj stent treatment. dj stents were forgotten per periods ranging from 1 to 17 years. complications the complications experienced were encrustation, multiple stones formation, emphysematous pyelonephritis, emphysematous perinephric abscess, fragmentation, and vesical calculus. table 1. article quality assessment. no author were patient’s was the patient’s was the current were diagnostic was the was the were adverse does the demographic history clearly clinical condition tests or assessment intervention(s) post-intervention events (harms) case report characteristics described of the patient on methods and the or treatment clinical condition or unanticipated provide clearly described? and presented presentation results clearly procedure(s) clearly described? events identifie akeaway as a timeline? clearly described? described? clearly described? and described? lessons? 1 aboutaleb, et al, 2021, uae (12) yes yes yes yes yes yes yes yes 2 ahmed, et al, 2021, yemen (13) yes yes yes yes yes yes yes yes 3 sigdel et al, 2021, nepal (14) yes yes yes yes yes yes yes yes 4 hee lee et al, 2022, republic of korea (15) yes yes yes yes yes yes yes yes 5 prihadi et al, 2018, indonesia (16) yes yes yes no yes yes no yes 6 alwesali et al, 2022, saudi arabia (17) yes yes yes yes yes yes yes yes 7 sharma, 2018, india (18) yes yes yes yes yes yes yes yes 8 ghorai et al, 2022, india (19) yes yes yes yes yes yes yes yes 9 kandemir et al, 2019, turkey (20) yes yes yes yes yes yes yes yes 10 nihal er et al, 2023, turkey (21) yes yes yes yes yes yes yes yes 11 aamiir, et al, 2022, india (22) yes yes yes yes yes yes yes yes 12 gupta et al, 2017, india (23) no yes yes yes yes yes yes yes 13 yan gu et al, 2016, china (24) yes yes yes yes yes yes yes yes 14 kumsa, et al, 2022, ethiopia (25) yes yes yes yes yes yes yes yes table 2. research characteristics. nauthor, year, country number age sex symptoms of patient flank ache micturition abdominal lower fever hematuria diarrhea nocturia duration of disorders pain limb swelling symptoms aboutaleb, et al, 2021, uae (12) 1 49 yo male yes yes no no no no no no 1 month ahmed, et al, 2021, yemen (13) 1 32yo male yes yes no no no no no no 3 days sigdel et al, 2021, nepal (14) 1 35 yo female no yes yes yes no no no no 3 days hee lee et al, 2022, republic of korea (15) 1 56 yo female no no yes no yes no no no 4 days prihadi et al, 2018, indonesia (16) 1 40 yo female yes yes no no no yes no no na alwesali et al, 2022, saudi arabia (17) 1 13 yo male no no yes no no no yes no 3 days sharma, 2018, india (18) 1 38 yo male yes yes no no yes, low grade no no no 1 year ghorai et al, 2022, india (19) 1 65 yo male no yes no no no no no yes 2 years kandemir et al, 2019, turkey (20) 1 30 yo male yes yes no no no no no no na nihal er et al, 2023, turkey (21) 1 7 yo female no yes no no no no no no 10 days aamiir, et al, 2022, india (22) 1 28 yo male yes no no no no no no no 5 months gupta et al, 2017, india (23) 1 32yo male yes no no no no no no no na yan gu et al, 2016, china (24) 1 88 yo male no yes no no yes no no no 1 week kumsa, et al, 2022, ethiopia (25) 1 22 yo male yes yes no no no no no no 3 years archivio italiano di urologia e andrologia 2025; 97(1):13301 a. galih pranesdha putra, y. aulia azmi, s. wirjopranoto, et al. 4 management and outcome procedures used for treatment were based on the patient's situation. sometimes procedures differed from those initially planned. for example, a percutaneous nephrolithotomy (pcnl) was performed in a patient who was originally scheduled for ureterorenoscopy lithotripsy, that was not effective in removing the dj stent. in another case, the planned cystoscopic laser lithotripsy was not feasible because the preoperative endoscopic examination showed a bladder stone with a radius of about 2 cm at the tip of the double-j catheter from the right kidney. all the patients remained alive after treatment for dj stent removal. table 3. management and outcome. history post ureteric stone treatment right open nephrolithotomy with double j stent placement due to obstructed right renal pelvis stone history of extracorporeal shock wave lithotripsy (eswl) ureteral stricture with uti surgical procedure to remove a giant uterine myoma renal transplant 13 years ago in india for end stage renal disease of unknown etiology history of right-sided laparoscopic anderson-hynes dismembered pyeloplasty with double j (dj) stenting performed for right pelviureteric junction obstruction 5 years back ureterolithotomy with left sided dj stenting elsewhere 17 years ago for a ureteral stone endoscopic stone surgery due to right ureteral stone and kidney stone 11 years ago a history of kidney stones, and a double-j catheter was placed in her right kidney as a treatment for kidney stones the stent placed 11 years back as a part of percutaneous nephrolithotomy (pcnl) for right renal stone, had forgotten forgotten dj stent timeduration 10 years 1 year 5 years 10 years 4 years 13 years 5 years 17 years 11 years 1 year complication the whole stent was covered with a thick layer of encrustation with multiple stones formation double-j stent was separated into four parts. and the stones were observed in the total parts of the right urinary tract system from the renal pelvis to the bladder with a 20 £ 15 mm stone impacting the left renal pelvis. huge radiolucent bladder stone around the double j stent emphysematous pyelonephritis encrustation, emphysematous perinephric abscess no no encrustation right dj stent without encrustation and radiopaque shadow in left renal region an abdominal x ray revealed an encrusted left sided dj stent with its lower end showing a large radio opacity suggestive of a vesical calculus fragmented and severely encrusted ureteral a bladder stone about 2 cm in size was formed around the double-j catheter large urinary baldder stone with encrusted double j stent and calculus deposits along the entire length of the stent management endorse cystolithotripsy with holmium yag laser for the bladder calculus and semirigid/flexible ureteroscopy with holmium yag laser lithotripsy for ureteral stones and encrusted stent the left ureteroscopic ureterolithomy and double j stent placement were done under spinal anesthesia during the first operation. then, right open nephroureterolithotomy with open cystolithotomy were performed after 1 month of previous surgery to remove the stone and forgotten double j stent surgical drainage to control the sepsis. few days later after control of sepsis and optimization, left nephrectomy and removal of retained dj stent was done retained djs removal and vesicolitholapaxy. a piece of fractured stent was removed via open ureterolithotomy ureterorenoscopic lithotripsy, but it failed to remove the remaining encrusted double-j stent. as a result, percutaneous nephrolithotomy was performed successfully nephrostomy was performed and antegrade pyelogram. two weeks later, the patient became hemodynamically stable and underwent a dj stent removal without any stenting due to stricture ureteric stent removal followed by placement of right-sided percutaneous nephrostomy (pcn). he underwent right nephrectomy followed by left percutaneous nephrolithotomy underwent percutaneous cystolithotomy using pneumatic lithotripsy along with removal of the forgotten dj stent under intravenous antibiotic cover cystoscopy was made under general anesthesia. the foreign object was removed with forceps. then with ureterorenoscope, the stones integrated with the stent at the end of the piece of dj stent in the ureter were fragmented with pneumolithotriptor. stone pieces and the second removed part of the stent were extracted with foreign object forceps. then using nephroscope through percutaneous intervention, the stones at the end of the third torn piece of dj stent were fragmented with pneumolithotriptor. they were extracted with forceps the patient was planned cystoscopic laser lithotripsy. after the pre-operative examinations and follow-up results came out normal, the patient was taken to operation. because a bladder stone with a radius of approximately. 2 cm on the end of a double-j catheter from the right kidney was spotted, it was decided that it was no suitable for lithotripsy because of the size of the stone. therefore, transition to open surgery was decided the patient was then managed in two sittings, as an open cystolithotomy, followed a few months later by a combination of uretroscopic lithotripsy and percutaneous lithotomy outcome alive alive alive alive alive alive alive alive alive alive alive author, year, country aboutaleb, et al, 2021, uae ahmed, et al, 2021, yemen sigdel et al, 2021, nepal hee lee et al, 2022, republic of korea prihadi et al, 2018, indonesia alwesali et al, 2022, saudi arabia sharma, 2018, india ghorai et al, 2022, india kandemir et al, 2019, turkey nihal er et al, 2023, turkey aamiir, et al, 2022, india archivio italiano di urologia e andrologia 2025; 97(1):13301 5 forgotten double j stent discussion demographic characteristics most cases were observed in developing countries, including india (4 cases). a forgotten dj stent is frequent in developing nations, with patients from lower socioeconomic classes being more susceptible (7). in fact, patients from lower socioeconomic backgrounds may have less access to quality healthcare. they need to receive adequate counselling, to avoid misunderstandings about their treatment. individuals from lower socioeconomic classes often face financial constraints that can affect their ability to seek medical care or to attend follow-up appointments. delays in stent removal can increase the risk of complications (26). the age of patients with forgotten dj stent ranged from 7 to 88. male gender predominated in most studies (10 studies). a review of hospital data from 2000 to 2013, including 28 cases of forgotten dj stents, revealed that the average age of patients was 37.7 ± 14 years (3). a retrospective study on forgotten dj stent patients between january 2009 and december 2019 reported an average age of 32.1 years (1). patil et al. reported an average age of 56.66 years 2 and adanur et al. of 38.2 ± 25.06 years (range from 2 to 86 years) (4). ali observed an average age of 59.12 ± 9.8 years, ranging from 34 to 70.8. the majority of these cases involved men. in adanur’s study, 39 out of 54 patients were men, while 15 were women (4). this contrasts with the findings on another study, where the majority were women, with 9 out of 16 patients (56.25%) (8). lin et al. observed that patients over 60 were 3.6 times more likely to forget their dj stent than younger patients (27). symptoms most patients complained of flank pain and micturition disorders as their initial symptoms. diarrhea and nocturia are sporadic. the duration of symptoms was variable. a study identified urinary irritation and hematuria as the most frequent complaints (3). in another study, pain and dysuria were the most common issues (1). patil et al. reported that patients typically presented with low back pain, dysuria, hematuria, and fever (2). additionally, another study indicated that pelvic pain with lower urinary tract symptoms were reported by most patients, with 9 out of 16 (56.25%) experiencing these symptoms. recurrent urinary tract infections were found in 2 patients (12.5%), while 4 cases (25%) showed no symptoms (8). history and forgotten dj stent time duration the medical history of patients varies, including procedures related to ureteric/pelvic/kidney stone treatment, ureteral stricture with uti, surgical removal of a giant uterine myoma, renal transplant, muscle-invasive bladder tumour, sigmoid colon cancer, partial resection of the bladder and nonspecific flank surgery. in addition, there are patients with a history of previously forgotten dj stent treatment. dj stents remained forgotten for a period ranging from 1 to 17 years. other studies reported an average stent indwelling time of 38.96 months1, 22.6 ± 30.3 (6144) months 4 and 1.73 ± 0.9 (0.11-3.4) years (8). dj stents generally must be replaced or removed within six weeks to 6 months to avoid complications (2). complications the complications observed were encrustation, multiple stones formation, emphysematous pyelonephritis, emphysematous perinephric abscess, fragmentation, and vesical calculus (1). the study of hajjaj reported several complications occurring during or after stent removal, including stent fragmentation (20%), fever (16%), sepsis (8%), and hematuria requiring a transfusion (4%) (9). in a series of 16 cases, severe stent encrustation was seen in ten cases; two cases involved urinary tract obstruction, one involved stent migration, and two involved stent fragmentation8. another study reviewed 50.000 procedures performed on 36.688 patients between 1996 and 2021. complications were related to malposition of the dj stent, migration and obstruction of the ureteral stent, and symptoms of bladder irritation; hematuria was detected in 5.213 cases, it for 6 years, underwent open cystolithotomy for the encrusted dj stent and concomitant urinary bladder stone, was again lost to follow up passage of tube like structure (lower end of right dj stent) through ileal conduit 15 days back. he had undergone radical cystectomy with ileal conduit for muscle invasive bladder tumor six years back in another hospital approximately 6 years prior, the patient had undergone simultaneous radical resection of sigmoid colon cancer and partial resection of the bladder nonspecific flank surgery 15 years ago 5 years 6 years 6 years 15 years bilateral staghorn calculus with forgotten double j stent in ileal conduit patient presence of an entire coiled double-j stent with calculi from the kidney to the bladder severe stent encrustation at the presentation. he also had a solitary bladder stone and many pelvic stones discovered patient was successfully treated with minimally invasive therapy in the form of combined bilateral pcnl (percutaneous nephrolithotomy) and eswl (extracorporeal shock wave lithotripsy) therapy a computed tomography scan revealed mild hydronephrosis of the left kidney and one j end of the stent in the bladder. the stent was removed successfully by cystourethroscopy and holmium laser lithotripsy cytolithotrity and semirigid ureteroscopy with laser lithotripsy were performed, and the encrusted stent was removed. subsequently, an open cytolitotomy was done. followed by an ultrasound-guided pcnl at which time the remaining stones were removed alive alive alive gupta et al, 2017, india yan gu et al, 2016, china kumsa, et al, 2022, ethiopia archivio italiano di urologia e andrologia 2025; 97(1):13301 a. galih pranesdha putra, y. aulia azmi, s. wirjopranoto, et al. 6 demanding blood transfusion in 7 instances 10. the severity of symptoms depends on the duration of stent indwelling time and the degree of encrustation and stone formation. longer forgotten stents are more likely to cause significant morbidity (28). the treatment of case reported in our review yielded the encouraging result that every patient survived, whereas three of the twenty-eight patients involved in another investigation passed out due to complications following the intervention for stent removal (3). management and outcomes the treatment should be multimodal and individualized and often the initial planned treatment has to be changed due to unexpected situations. sometimes the dj stent cannot be removed with the planned procedure, so a different procedure has to be performed. in addition, during the examination, other unexpected problems, such as stones, can be found requiring making adjustments. the procedure performed also depends on the patient's condition. many procedures can be performed for the removal of forgotten stents, such as cystoscopic extraction of the stent, percutaneous cystolithotomy (pclt), percutaneous nephrolithotomy (pcnl), ureterorenoscopy lithotripsy (ursl), extracorporeal shock wave lithotripsy (eswl) with cystoscopic stent removal (1). the choice of procedure depends on variables such as location and extent of calcification and associated stent injury. all patients with stents should receive counseling regarding potential longterm complications. especially if stents are forgotten for more than a year, they may have a very thick layer of deposits on their surface and may require additional procedures such as shock wave lithotripsy, ureteroscopy (urs), and pcnl, alone or in combination, with great caution to prevent related morbidities (2). the procedure to be carried out requires accurate preoperative evaluation. preoperative evaluation is critical, involving a thorough history and physical examination, evaluation through urine culture and sensitivity tests, appropriate radiological imaging, such as kidney ureter bladder (kub) x-ray, ultrasound, or non-contrast ct (ncct), and serum creatinine assessment (26-28). sohrab et al. described removal of stent using endourology techniques and extracorporeal shock wave lithotripsy (eswl) (3). mahmood et al. reported ureteroscopy as the most common primary surgery (1). another paper reported that 14 children experienced retention of dj stent retention that were removed using eswl, cystolithotripsy (clt), and pcnl (11). in nawaz ali's study, four patients underwent cystoscopic stent removal, four clt, three had clt followed by pcnl, two had their fragmented stents removed by ureteroscopy and one by open pyelolithotomy (8). prevention prevention remains a critical aspect of managing forgotten stents, emphasizing the importance of proper patient counseling regarding the stent's indwelling time and the necessity of follow-up. establishing a stent registry with patient details and scheduled removal dates coupled with automated reminders via social media to patients and healthcare providers can significantly reduce the incidence of forgotten stents. additionally, engaging patients and relatives in the follow-up process is essential to prevent complications and mitigate the associated morbidity and healthcare costs. the effective management of forgotten dj stents hinges on a comprehensive approach that integrates timely intervention, meticulous follow-up, and proactive prevention strategies (26-28). limitation of the study this review considered case report data, so further research needs to be carried out prospectively. this research also has not been able to explore long-term complications from stent removal management due to forgotten dj stent. future research is recommended to investigate complications from stent removal management. conclusions a forgotten dj stent can lead to significant consequences, necessitating a management approach that combines various endourological procedures while carefully considering potential complications. urologists must exercise caution when deciding on the appropriate technique. healthcare providers must inform all patients with an implanted stent about the long-term risks of prolonged stenting and stress the need for timely removal or replacement. references 1. mahmood k, singh kh, upadhyay r, et al. management of forgotten double-j stent in a tertiary care center with ten years of experience: a retrospective study. int surg. j 2020; 7:2615. 2. patil s, raghuvanshi k, jain dk, raval a. forgotten ureteral double-j stents and related complications: a real-world experience. african j urol. 2020; 26:8. declarations ethical approval: ethical approval was not crucial for this study, as it did not involve direct patients, and all included data were previously published. availability of data and material: availability of data and materials data and materials used in our study are open to access by request. competing interests: no conflict of interest was declared by the authors. funding: -. authors' contributions: y.a.a, s.w, n.r, a.g.p.p, a.j.n.d.n and k.m.s; methodology: y.a.a, s.w, n.r, a.g.p.p, a.j.n.d.n and k.m.s; investigation: y.a.a, s.w, n.r, a.g.p.p, a.j.n.d.n, a.s.w, and k.m.s; writing original draft: y.a.a, s.w, n.r, a.g.p.p, a.j.n.d.n, a.s.w, and k.m.s; writing review & editing: y.a.a, s.w and k.m.s; resources: y.a.a, s.w, n.r, a.g.p.p, a.j.n.d.n and k.m.s; visualization: n.r, and a.g.p.p; supervision: y.a.a and s.w. acknowledgments: none. conference presentation: this article has never been presented at any conference before. archivio italiano di urologia e andrologia 2025; 97(1):13301 7 forgotten double j stent 3. sohrab a, aneesh s, sureka sk, et al. forgotten reminders: an experience with managing 28 forgotten double-j stents and management of related complications. indian j surg. 2015; 77:1165-1171. 4. adanur s, ozkaya f. challenges in treatment and diagnosis of forgotten/encrusted double-j ureteral stents: the largest single-center experience. ren fail. 2016; 38:920-926. 5. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021; 372: n71. 6. joanna briggs institute critical appraisal tools. checklist for case reports. available from: https://jbi.global/sites/default/files/202008/checklist_for_case_reports.pdf 7. jhanwar a, bansal a, prakash g, sankhwar s. endourological management of forgotten double j ureteral stents: a single centre study. sm j urol. 2017; 3:1-3. 8. ali n, somarendra k, ali a. forgotten double-j stent: evaluation and management in a tertiary hospital in the north east india. international journal of scientific study 2021; 9:103-8 9. al-hajjaj m, alam oa, abu-hussein b, et al. forgotten double-j ureteral stent: an analysis of 25 cases in a tertiary hospital. ann med surg. 2022; 80:104223. 10. geavlete p, georgescu d, mulțescu r, et al. ureteral stent complications experience on 50,000 procedures. j med life. 2021; 14:769-775. 11. nerli rb, magdum pv, sharma v, et al. forgotten/retained double j ureteric stents: a source of severe morbidity in children. african j paediatr surg. 2016; 13:32-35. 12. aboutaleb h.. a neglected double j ureteral stent for 10 years: a rare case report. urol case reports. 2021; 36:101570. 13. ahmed f, al-wageeh s, ghabisha s, et al. a case report of forgotten double j stent with giant calculus formation from the renal pelvis to the bladder. j emerg med trauma acute care. 2021:13. 14. sigdel b, shrestha s, maskey p. forgotten dj stent presenting with emphysematous pyelonephritis: a life threatening complication. int j surg case rep. 2021; 87:106405. 15. lee ih, shin hs, ahn dj. a forgotten double-j ureteral stent resulting in an emphysematous perinephric abscess: a case report. medicine (baltimore). 2022; 101:e29418. 16. prihadi jc, kusumajaya c. double-j stents forgotten for four years: a case report. med j indones. 2019; 28:280-283. 17. alwesali sm. a long forgotten ureteral stent for 13 years post renal transplantation. urol case reports. 2022; 44:102156. 18. sharma a, garg g, sharma d, singh m. fungal bezoar in an immunocompetent patient: a rare complication of forgotten double j stent. bmj case rep. 2018; 2018:bcr2018226904. 19. ghorai rp, talwar hs, mittal a, et al. a 17-year-old indwelling ureteral stent with large vesical calculus at one end: the tombstone of a forgotten double “j” stent. j fam med prim care 2022; 11:796-798. 20. kandemir a, sönmez mg. treatment of fragmented and severely encrusted ureteral double-j stent forgotten for 11 years through multimodal endourological methods. urol ann. 2019; 11:310-313. 21. er zn, tiryaki se, erdener çeliktürk c, avlan d. forgotten double-j stent with bladder stone formation: a pediatric case. turkish med student j. 2023; 10:133-135. 22. aamir s. forgotten double j stent with maximum stone burden. j clin images med case reports. 2022; 3:128-133. 23. gupta r, dey rk, sharma r, gupta s. bilateral staghorn calculus with forgotten double j stent in ileal conduit patient a rare urological challenge. j clin diagnostic res. 2017; 11:pd9-10. 24. gu y, zhang j, wang g. use of cystourethroscopy to remove an indwelling double-j ureteral stent 6 years following simultaneous radical sigmoid colon cancer and partial bladder resection: a case report. exp ther med. 2016; 11:2467-2469. 25. kumsa id, gebreamlak al, leul mm, et al. a case report on the management of neglected and forgotten dj stent for 15 years with severe encrustation and multiple renal and bladder stones. int j surg case rep. 2023; 103:107859. 26. vajpeyi v, chipde s, khan fa, parashar s. forgotten double-j stent: experience of a tertiary care center. urol ann. 2020; 12:138143. 27. lin tf, lin wr, chen m, et al. the risk factors and complications of forgotten double-j stents: a single-center experience. j chin med assoc. 2019; 82:767-771. 28. cheng w, chiu yc, fan yh, et al. risks of forgotten double-j ureteric stents after ureterorenoscopic lithotripsy in taiwan: a nationwide population-based study. sci rep. 2020; 10:20711. correspondence soetojo wirjopranoto (corresponding author) stjowirjopranoto@gmail.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general academic hospital, jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 antonius galih pranesdha putra galihpranesdha@gmail.com agustin junior nanda de niro deniro_nanda@yahoo.co.id alviano satria wibawa alvianosw65@gmail.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general academic hospital, surabaya, indonesia yufi aulia azmi yufiazmi@gmail.com; y.aulia.azmi@umcg.nl department of health sciences, university of groningen, university medical center groningen, groningen, the netherlands nadya rahmatika nadyasaham@gmail.com faculty of medicine, universitas wijaya kusuma, surabaya, indonesia kevin muliawan soetanto kmskevinmuliawan@gmail.com department of immunology, faculty of medicine siriraj hospital, mahidol, university, bangkok, thailand stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2232 original paper no conflict of interest declared. studies have shown that ed and numbness occur, respectively in up to 24% and 61% of selected groups of riders. however, most studies were conducted on longdistance/intensive cyclists, so there is little information about the true effects of cycling in the sexual life of amateur practitioners (6-11). with this study, we aimed to evaluate the effects of amateur cycling in erectile function using a comparative athlete group and a validated sexual questionnaire. methods recruitment and sporting clubs’ outreach 199 amateur cyclists (cyclists that do not receive financial support or sponsorship) were recruited in person in several cycling meetings and completed an anonymous survey. we chose four mountain cycling events with high participation. the comparison group consisted of 43 amateur footballers (sport without perineal contact) recruited in person from two amateur clubs. institutional review board approval was obtained. survey predictor variables the two groups of athletes were characterized and compared regarding their age, body mass index, alcohol intake, smoking, medication (diuretics, high blood pressure drugs, excluding angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, anti-depressants, anti-anxiety drugs, antihistamines, parkinson’s disease medications, prostate cancer medications, 5a-reductase inhibitors, chemotherapy), comorbidities (hypercholesterolemia, hypertriglyceridemia, arterial hypertension, myocardial infarction, stroke, diabetes mellitus, chronic kidney disease, chronic liver disease, thyroid disease, hormonal disorder, neurological disease, spine injury, prostate disease, perineal radiotherapy, penile/perineal trauma, depression, anxiety disorder) and hours per week of sports practice. the cyclists (group 1) were specifically characterized in terms of road vs cross-country, rest breaks during cycling (by questionnaire), saddle, shorts, and the riding position. the effect of each of these characteristics on sexual function was assessed. survey outcome variables to evaluate ef, the international index of erectile function (iief-5) questionnaire was applied. the presence of introduction: cycling is a popular means of transport and recreational activity; bicycles are also a source of genitourinary injuries and there is the idea that cycling may have a significant impact on sexual function. the objective of this study was to evaluate the effect of amateur cycling on erectile function. methods: we used a questionnaire comparing amateur cyclists (n = 199) and footballers (n = 43), regarding sexual related comorbidities and hours of practice per week. the cyclists were also characterized in terms of road vs cross-country, breaks during cycling, saddle, and shorts. to evaluate erectile function, the international index of erectile function questionnaire was applied. results: there was no difference in international index of erectile function total score between groups. age and presence of erectile dysfunction associated comorbidity were negative factors in the international index of erectile function score in cyclists but not in the footballers. conclusions: cycling is usually associated with perineal numbness, but that numbness did not lead to lower international index of erectile function scores. in conclusion amateur cycling has no effect on ef. key words: cycling; football; erectile function; perineal numbness. submitted 9 april 2022; accepted 4 june 2022 introduction cycling is a popular means of transport and recreational activity for many people in a wide age range. it is an economical and efficient form of aerobic non-impact exercise with well-established cardiovascular beneficial effects and with a positive effect on quality of life (1, 2). bicycles are also a source of genitourinary injuries, that can be categorized into acute traumatic injuries versus chronic overuse injuries (3). exercise is a well-known preventer of erectile dysfunction, in an italian study patients with lower physical activity were associated with higher levels of erectile disfunction (4). since the 80’s, there is the idea that cycling may have a significant impact on sexual function (including erectile dysfunction (ed), perineal numbness and chronic pain) (1, 5, 6). the most frequently proposed pathophysiological mechanisms for ed in cyclists are vascular and nerve injuries (related to nerve entrapment and vascular occlusion with continuous compression of the pudendal nerve and pudendal artery) (1). erectile function in amateur cyclists duarte vieira e brito 1, mário pereira-lourenço 1, jose alberto pereira 1, miguel eliseu 2, carlos rabaça 1 1 portuguese institute of oncology, coimbra, portugal; 2 urology and renal transplantation department, coimbra university hospital centre, coimbra, portugal. doi: 10.4081/aiua.2022.2.232 summary 233archivio italiano di urologia e andrologia 2022; 94, 2 erection in cyclists numbness was also registered, although in a subjective way (“yes or no” question). statistical analysis data was analysed using spss 21. demographic and medical variables were compared across athletic groups using pearson chi-square and mann-whitney tests. the effect of cycling variables in ef was calculated with mann-whitney, pearson chi-square and kruskal-wallis tests. a p-value of ≤ 0.05 was considered statistically significant. results general characterization and comparison between the two groups is summarized in table 1. the subjects in group 1 were older (38.1 vs 30.5 years old; p = 0.001), and less individuals consumed alcoholic beverages (60% vs 79%, p = 0.018). the remaining variables did not differ between the 2 groups. there was also no difference in the iief-5 total score between groups (22.45 vs 21.70; p = 0.071). group 1 showed better results in question 3 of the iief-5, which concerns the ability to maintain erection after penetration (4.49 vs 4.14, p = 0.014). age and the presence of ed associated comorbidities were negative factors in the iief-5 total score in cyclists (p = 0.032 and p = 0.036, respectively) but not in footballers (p = 0.120 and p = 0.623, respectively). no other variables influenced iief-5 in the cycling group or in the football group when evaluated separately (table 2). the iief-5 total score ≤ 21 included 37.2% of cyclists and 26.6% of footballers (p = 0.164), with no difference regarding ed severity between the two groups (p = 0.173) (table 3). regarding cycling specific variables (table 4), there was no relation between iief-5 and number of hours per week of practice (p = 0.666), type of shorts (p = 0.254), type of saddle (p = 0.611), frequency of resting pauses (p = 0.288) and predominant position of the trunk while cycling (p = 0.371). table 1. general characterization and homogeneity. cycling (n = 199) football (n = 43) p ed associated comorbidities 76.8% 86.0% 0.208 mean age (years) 38.1 30.5 0.001 mean weight (kg) 77.3 75.1 0.157 mean bmi (kg/m2) 24.9 24.4 0.255 alcohol consumption 60.3% 79.1% 0.018 smoking 34.2% 46.5% 0.112 bmi: body mass index. table 3. erectile dysfunction severity by sport modality. ed severity (iief-5 score) cycling football p severe ed (1-7) n = 0; 0% n = 0; 0% moderate ed (8-11) n = 3; 1.5% n = 0; 0% mild-moderate ed (12-16) n = 7; 3.5% n = 3; 7.0% 0.173 moderate ed (17-21) n = 43; 21.6% n = 13; 30.2% no ed (22-25) n = 46; 73.4% n = 27; 62.8% ed: erectile dysfunction. table 4. effect of cycling related variables on erectile function. ed severity (iief-5 score) cycling football p hours per week < 5 (n = 73) 22.18 0.666 5-8 (n = 75) 21.30 > 8 (n = 51) 21.67 shorts uncoated (n = 2) 23.00 0.254 gel (n = 107) 22.40 sponge (n = 77) 22.34 saddle hard (n = 29) 22.70 0.611 gel (n = 105) 22.51 sponge (n = 55) 22.32 continuous exercise until pause * 30 min (n = 29) 21.90 0.288 60 min (n = 60) 22.49 120 min (n = 29) 23.28 no pauses (n = 92) 22.34 modality only cross-country (n = 136) 22.13 0.023 cross-country + road (n = 63) 23.13 perineal numbness yes (n = 50) 22.54 0.508 no (n = 149) 22.42 predominant position no (n = 64) 21.97 0.371 30º (n = 4) 21.75 45º-60º (n = 124) 22.77 90º (n = 7) 21.57 * time from start until stopping for rest. table 2. effect of erectile dysfunction associated variables on iief-5 total score by sport modality. cycling iief-5 p football iief-5 p bmi < 25 kg/m2 yes 22.57 (n = 119) 0.423 21.80 (n = 30) 0.759 no 22.26 (n = 80) 21.46 (n = 13) alcohol yes 22.24 (n = 119) 0.363 21.35 (n = 34) 0.200 no 22.75 (n = 80) 23.00 (n = 9) tobacco yes 22.27 (n = 67) 0.159 21.00 (n = 20) 0.081 no 22.54 (n = 132) 22.30 (n = 23) ed associated medication yes 23.00 (n = 34) 0.565 22.13 (n = 8) 0.987 no 22.30 (n = 165) 21.60 (n = 35) ed associated comorbidity yes 21.79 (n = 57) 0.036 21.73 (n = 11) 0.623 no 22.71 (n = 142) 21.69 (n = 32) age ≤ 20 22.67 (n = 9) 0.032 18.78 (n = 9) 0.120 21-30 23.08 (n = 37) 22.81 (n = 16) 31-40 22.88 (n = 78) 21.08 (n = 10) 41-50 21.67 (n = 55) 23.00 (n = 6) > 50 21.60 (n = 20) 21.50 (n = 2) bmi: body mass index; ed: erectile dysfunction. archivio italiano di urologia e andrologia 2022; 94, 2 d. vieira e brito, m. pereira-lourenço, j.a. pereira, m. eliseu, carlos rabaça 234 athletes that also practice road cycling had better iief-5 scores (p = 0.023). perineal numbness during or after exercise was present in 25.1% (n = 50) of cyclists and 7.0% (n = 3) of footballers (p = 0.009). athletes (both groups included) without perineal numbness (n = 189), with numbness during the exercise (n = 46) and with numbness only after exercise (n = 7) had an iief-5 score of 22.35, 22.46 and 20.43, respectively (p = 0.301). regarding only cyclists, athletes without perineal numbness (n=149), with numbness during exercise (n = 46) and with numbness only after exercise (n = 4) had an iief-5 score of 22.42, 22.46 and 23.5, respectively (p = 0.752). discussion we choose amateur footballers as a control group for two main reasons: 1) the aerobic metabolism is used in 90% of movements in football players and cycling is an aerobic sport (12, 13); 2) football might be the most practiced sport among portuguese males. our study shows that amateur cycling does not cause erectile dysfunction, when compared with amateur footballers. among cyclists, only age, presence of ed related comorbidities and the exclusive practice of cross-country cycling were related to lower iief-5 scores. age is strongly associated with ed, being erectile function reduced in men particularly after the age of forty due to multiple causes (14). in a study analysing a spanish population, a culturally similar population to the one in our study, higher rate of ed was found when the iief-5 score was used versus direct questioning. a rate of 8.48% and 13.72% was found for men between 25-39 and 40-49 respectively, and rate almost doubled in men between 5059 years (15). in our population with a median age difference of 8 years, the cycling group should in theory present with higher rates of ed that were not observed in our study. in the 80s, some case reports began to relate cycling with sexual dysfunction (1). in the 90s, andersen et al. showed a relation between cycling and ed (13% of 160 cyclists who rode in a 540 km touring race, but only 1.9% lasted more than a month) (8). in fact, ed and perineal numbness are the most common described bicycle related sexual symptoms in literature, occurring, respectively, in up to 24 and 61% of selected groups of riders (6). in relation to the possible pathophysiology responsible for this association, the most frequently proposed causes are vascular and nerve injuries. sommer et al. described nerve entrapment and vascular occlusion related to continuous compression (compression of the pudendal nerve and pudendal arteries through alcock’s canal) as the more plausible cause (1). rider/saddle interaction, namely the type of saddle, shorts, preferential riding position, cycling modality (low impact vs. high impact) and hours of practice can explain possible different rate of cycling related ed. we did not find ed differences between types of saddles or shorts, but we only evaluated coating. in literature, the saddle plays a major role in cycling related ed (6). the best saddle (for ed protection) seems to be a wide, unpadded, no nose saddle that allows proper placement of the sit bones (more weight on the ischial tuberosities and less on the perineal soft tissues) (1, 6, 16-21). a more horizontal or even downward-pointing position of the saddle has been associated with reduced pressure on the perineum (22). in relation to shorts, a study showed that the saddle is more important for compression than shorts pad, suggesting that cyclist should choose self-reported comfortable shorts (23). we also did not find ed differences between the rider preferential position, although there is some literature evidencing that the rider’s position influences compression on perineal structures. cycling in the seated position decreases perineal blood flow and this decrease is inversely related with body weight (1, 6, 10, 21). cycling in a reclined position reduces compression, while leaning forward in the “aero” position (as the nose of the saddle bears almost all of the rider’s weight) decreases blood flow by approximately 70% (10). adjusting the handlebars, stem length and angle, and crank, has shown to have beneficial effect on perineal pressure. related to position, riders should cycle in a more upright position and changing a seat to a “standing” position (1). in our study, cyclists that only practiced cross-country had lower iief-5 score. cross-country cycling (mountain bike) is associated with perineal numbness and incident ed, that can be explained by the vibrations associated with this modality (6, 9, 21). in our study, cyclists had more perineal numbness, but that numbness did not lead to lower iief-5 scores. numbness in perineum, penis, scrotum or buttocks, usually referred to as “genital numbness” is probably the most common and most recognized symptom of pudendal compression. most of the times it is the only symptom or the earliest one to indicate compression syndrome. genital numbness may occur unrelated to ed although cycling related ed is invariably associated with genital numbness, which may serve as a marker for increased risk for erectile dysfunction (24). as in our study, recent works failed to show cycling as a risk factor for ed. an internet survey on 3932 cyclists showed that low and high intensity cyclists had better sexual function than swimmers and runners (25). we also did not find iief-5 differences related to hours of practice per week (older studies, focused on elite longdistance riders, related intensive cycling with ed) (24). marceau et al (7) investigated ed incidence in the general population, in recreational cyclists (< 3 hours per week) and in intensive cyclists (> 3 hours per week). the ed incidence was 21%, 11% and 17%, respectively, showing that intensive cyclists may have worse erectile function than recreational riders (although both have better results than non-cyclists). a recent large-scale observational study on 5282 cyclists, also did not find differences in ed incidence between several intensity groups < 3.75, 3.75-5.75, 5.76-8.5, and > 8.5 hours/week) (26). we must understand that the practice of sport can influence sexual behaviour, interfering with the hypothalamicpituitary-testicular axis function. however, competitive sports can lead to both reproductive or sexual tract injuries, dysfunction that can be transient (genital pain, hypoesthesia of the genitalia, hypogonadism, ed, altered sexual drive, etc.) or permanent (hypogonadism, ed, 235archivio italiano di urologia e andrologia 2022; 94, 2 erection in cyclists etc.), by direct action (traumas of the external genitalia, saddle-related disorders in cyclists, etc.) or indirect (exercise-related hypogonadism, drug abuse, doping, stress, etc.) (27). a recent systematic review and meta-analysis indicates that moderate-intense physical activity improves erectile dysfunction problems (28). results of a cross-sectional study show a sexual function benefit for those exercising at least 18 metabolic equivalent (met) hours of activity weekly, an amount translating to 2 hours of strenuous exercise such as running or swimming, 3.5 hours of moderate exercise, or 6 hours of light exercise (29). our study has some limitations, namely its cross-sectional design (it does not evaluate the temporal sexual evolution of the athlete), the low number of athletes in the control group and age differences between groups with an average age difference of 8 years, as erectile disfunctions in strongly associated with age (although our older group did not present with higher rates of ed). we also did not evaluate all the important saddle characteristics (presence of nose, width, cut-outs) and we did not investigate cyclists that only practice road cycling. another limitation was the higher percentage of alcohol and tobacco consumption in the football group, although when statistically analysed no significant difference was found. the numbness outcome was self-reported and was investigated with a non-validated question. the questionnaire utilized was not validated but being the questions made in person by the researcher, the subjectivity was reduced. another possible limitation is selection bias as healthier cyclist might have been chosen as there are the ones that usually participate in competing events, having been excluded cyclist in poorer condition and with more comorbidities. a final limitation might be the lack of questioning about the use of anabolic steroids, that alter erectile function. however, the authors believe that there was no important impact on the quality of the study by this, because the use of such substances is limited in the portuguese population. conclusions amateur cycling has no effect on ef and the intensity of practice seems to have no influence on ef. however, cycling is associated with perineal numbness, but ed was not found in conjunction to this. references 1. sommer f, goldstein i, korda jb. bicycle riding and erectile dysfunction: a review. j sex med. 2010; 7:2346-58. 2. sundquist k et al. frequent and occasional physical activity in the elderly: a 12-year follow-up study of mortality. am j prev med. 2004; 27:22-7. 3. thompson mj, rivara fp. bicycle-related injuries. am fam physician. 2001; 63:2007-14. 4. parazzini f, et al. effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: results from the 2018 #controllati survey. arch ital urol androl. 2020; 91:245-250. 5. desai km, gingell jc. hazards of long distance cycling. bmj. 1989; 298:1072-3. 6. baran c, mitchell gc, hellstrom wj. cycling-related sexual dysfunction in men and women: a review. sex med rev. 2014; 2:93-101. 7. marceau l, et al. does bicycling contribute to the risk of erectile dysfunction? results from the massachusetts male aging study (mmas). int j impot res. 2001; 13:298-302. 8. andersen kv, bovim g. impotence and nerve entrapment in long distance amateur cyclists. acta neurol scand. 1997; 95:233-40. 9. dettori jr, et al. erectile dysfunction after a long-distance cycling event: associations with bicycle characteristics. j urol. 2004; 172:637-41. 10. sommer f, et al. impotence and genital numbness in cyclists. int j sports med. 2001; 22:410-3. 11. baek s, et al. bicycle riding: impact on lower urinary tract symptoms and erectile function in healthy men. int neurourol j. 2011; 15:97-101. 12. silva jf, et al. aerobic evaluation in soccer. rev. bras. cineantropom. desempenho hum. (online) 2011; p. 384-391. 13. mcmillan k, et al. lactate threshold responses to a season of professional british youth soccer. br j sports med. 2005; 39:432-6. 14. feldman ha, et al. impotence and its medical and psychosocial correlates: results of the massachusetts male aging study. j urol. 1994; 151:54-61. 15. martin-morales a, et al. prevalence and independent risk factors for erectile dysfunction in spain: results of the epidemiologia de la disfuncion erectil masculina study. j urol. 2001; 166:569-74. 16. jeong sj, et al., bicycle saddle shape affects penile blood flow. int j impot res. 2002; 14:513-7. 17. lowe bd, schrader sm, breitenstein mj. effect of bicycle saddle designs on the pressure to the perineum of the bicyclist. med sci sports exerc. 2004; 36:1055-62. 18. munarriz r, et al. only the nose knows: penile hemodynamic study of the perineum-saddle interface in men with erectile dysfunction utilizing bicycle saddles and seats with and without nose extensions. j sex med. 2005: 2:612-9. 19. schrader sm, breitenstein mj, lowe bd. cutting off the nose to save the penis. j sex med. 2008; 5:1932-40. 20. goldstein i, lurie al, lubisich jp. bicycle riding, perineal trauma, and erectile dysfunction: data and solutions. curr urol rep. 2007; 8:491-7. 21. michiels m, van der aa f. bicycle riding and the bedroom: can riding a bicycle cause erectile dysfunction? urology. 2015; 85:72530. 22. spears ir, et al. the effect of saddle design on stresses in the perineum during cycling. med sci sports exerc. 2003; 35:1620-5. 23. marcolin g, et al. biomechanical comparison of shorts with different pads: an insight into the perineum protection issue. medicine (baltimore) 2015; 94: e1186. 24. leibovitch i, mor y. the vicious cycling: bicycling related urogenital disorders. eur urol. 2005; 47:277-86. 25. awad ma, gaither tw, murphy gp, et al. cycling, and male sexual and urinary function: results from a large, multinational, cross-sectional study. j urol. 2018; 199:798-804. archivio italiano di urologia e andrologia 2022; 94, 2 d. vieira e brito, m. pereira-lourenço, j.a. pereira, m. eliseu, carlos rabaça 236 26. hollingworth m. harper s, hamer m. an observational study of erectile dysfunction, infertility, and prostate cancer in regular cyclists: cycling for health uk study. journal of men´s health. 2014; 11:75-79. 27. sgrò p, di luigi l. sport and male sexuality. j endocrinol invest. 2017; 40:911-923. 28. silva ab, et al. physical activity and exercise for erectile dysfunction: systematic review and meta-analysis. br j sports med. 2017; 51:1419-1424. 29. simon rm, et al. the association of exercise with both erectile and sexual function in black and white men. j sex med. 2015; 12:1202-10. correspondence duarte vieira e brito, md (corresponding author) duartevbrito@hotmail.com mario pereira lourenço, md mariolourenco88@gmail.com jose pereira, md joseaclpereira@gmail.com carlos rabaça carlosrabaca@gmail.com portuguese institute of oncology, coimbra (portugal) casa da aveleira, pencelo guimaraes (portugal) miguel eliseu, md duartevbrito@gmail.com urology and renal transplantation department. coimbra university hospital centre, coimbra (portugal) stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13918 1 review undescended testis (4). the mainstay of treatment for cryptorchidism is to perform the treatment as soon as possible, preferably before 12 months and no later than 18 months, to decrease the chance of testicular atrophy (1). however, fertility after orchidopexy may be adversely affected. one factor influencing fertility potential after orchidopexy is the laterality of the undescended testis. some studies indicate differences in testicular function between patients with unilateral and bilateral udt postorchidopexy, with better outcomes observed in unilateral udt (5, 6). however, another study suggests that there is no significant difference in testicular function between unilateral and bilateral udt (4, 7). as far as we know, no comparative meta-analysis regarding bilateral and unilateral udt in testicular function exists. the primary objective of our meta-analysis is to compare bilateral and unilateral udt post-orchiopexy in terms of their fsh, lh, inhibin b, and azoospermia rates. this finding will help guide clinical decision-making for surgical strategies for udt. methods study design this study is a systematic review and meta-analysis to evaluate testicular function following orchidopexy in bilateral and unilateral udt. the study followed the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines to ensure comprehensive research. the literature search was conducted using pubmed, google scholar, and science direct databases until march 2025. the search strategy for the articles included [("adult") or ("post-pubertal")] and [("orchidopexy") or ("orchiopexy")] and ("bilateral") and ("unilateral") and [("fertility") or ("testicular function") or ("semen analysis")]. all search results will be screened for duplicates and assessed based on title and abstract relevance. fulltext articles are retrieved for detailed evaluation and the references of the selected studies are manually reviewed to identify additional relevant articles. the studies comprised rcts and observational studies to assess the post-orchidopexy outcome. original research introduction: cryptorchidism, or undescended testis (udt), is a congenital anomaly linked to an increased risk of infertility. the laterality of udt, whether unilateral or bilateral, may influence post-orchidopexy outcomes. this meta-analysis compares testicular function and azoospermia rates between patients with bilateral and unilateral udt post-orchiopexy. materials and methods: a comprehensive literature search was performed using pubmed, sciencedirect, and google scholar databases up to march 2025. statistical analyses were conducted using review manager (revman). result: ten eligible studies were included in the analysis, comprising 563 bilateral udt post-orchidopexy and 1259 unilateral udt post-orchidopexy cases. populations post bilateral orchidopexy have significantly higher fsh level (md: 3.77 ui/l [95% ci: 1.65 5.89]), significantly higher lh level (md: 1.27 ui/l [95% ci: 0.27 2.26]), lower inhibin b level (md: -44.86 pg/ml [95% ci: -69.58 -20.15]), and higher frequency of azoospermia (or 2.3 [95% ci: 1.57 3.37]) compared to unilateral udt post orchidopexy. conclusions: bilateral udt post-orchidopexy exhibit poorer testicular function with significantly higher fsh and lh levels, reduced inhibin b levels, and a greater incidence of azoospermia compared to unilateral udt post-orchidopexy key words: bilateral; unilateral; undescended testis; post-orchidopexy; testicular function. submitted 21 april 2025; accepted 27 april 2025 introduction cryptorchidism or undescended testis (udt) is a common congenital malformation in pediatric urology caused by an incomplete descent of the testis. it can be divided into palpable or non-palpable testis according to the location of the testis (1). based on laterality, in one-third of cases, udt is unilateral (2).the prevalence of undescended testis is 1.6%-9% at birth and 0.9-1.8% at age 3 months (3). undescended testis is related to an increased risk of infertility associated with testicular atrophy and tumors, particularly germ cell tumors (3). standard current treatment for cryptorchidism is orchiopexy (4). early treatment by orchidopexy is the definitive procedure for cryptorchid patients with an does bilateral undescended testis have worst testicular function than unilateral cases? a meta-analysis of adult orchidopexy patients anak agung ngurah krisnanta adnyana 1, marshal harvy wicaksono pantjoro 1, gede wirya kusuma duarsa 2 1 intern doctor of urology surgery department prof. dr. i.g.n.g. ngoerah general hospital, bali, indonesia; 2 urology staff of urology surgery department prof. dr. i.g.n.g. ngoerah general hospital, bali, indonesia. doi: 10.4081/aiua.2025.13918 summary archivio italiano di urologia e andrologia 2025; 97(2):13918 a. agung ngurah krisnanta adnyana, m. harvy wicaksono pantjoro, g. wirya kusuma duarsa 2 articles were included if they met following criteria: (a) diagnosis of undescended testis that underwent orchidopexy for the definitive treatment, (b) state the bilateral or unilateral condition of the testis before orchidopexy, (c) assessesment of fsh, lh, inhibin b levels, and azoospermia rate post-orchidopexy. the exclusion criterias were: (a) review article, letter to the editor, animal study, commentary, or consensus document, (b) study not focusing on undescended testis. the study protocol was registered in the international prospective register of systematic review (prospero) to ensure transparency and adherence to established standards (prospero crd420251010333). data extraction and synthesis the data extraction was conducted with two independent reviewers. the discrepancies of the reviewers were resolved through discussion and consultation with a third reviewer. all extracted data included were extracted and pooled using the excel program, including study characteristics such as author, year of publication, sample size, laterality of udt, values of fsh, lh, inhibin b, and azoospermia rate. risk of bias was assessed using newcastel-ottawa scale. statistical analysis primary outcomes in this study are post-orchidopexy fsh, lh, inhibin b levels, and azoospermia rate, as these serve as key indicators of testicular endocrine function. we conduct the meta-analysis using review manager (revman) to synthesize the results of the included studies and, using i² statistic and chi² test, to perform the heterogeneity assessment. a fixed-effects model was used when i2 was < 50%, whereas, when i2 was > 50%, a random-effects model was chosen. in the fixedeffects model, population effect sizes were assumed to be the same for all studies. in contrast, the random-effects model attempted to generalize the results beyond the included studies by assuming that the selected studies were random samples from a larger population. if there was statistical heterogeneity in the results, a further sensitivity analysis was performed to determine the source of heterogeneity. a sensitivity analysis was performed to assess the robustness of the findings by excluding studies with a high risk of bias or those with extreme outlier results. meta-regression may also be employed to explore potential moderators affecting testicular function outcomes post-orchidopexy. results data retrieval the literature review identified 3945 studies as potentially relevant to this investigation. after removing duplicates, 1821 studies were eliminated. the titles and abstracts of 2134 studies were then screened, and 39 were selected for eligibility assessment. of these, 29 studies were excluded due to being review letter, commentary or editorial; incomplete data; not focusing on the hormonal outcome. finally 10 studies were included in this systematic review and meta-analysis. figure 1 presents the prisma flow chart for the study selection process. study characteristics data from 10 studies are summarized in table 1 and were stratified by laterality into unilateral and bilateral. there were 563 patients who underwent orchidopexy for bilateral udt and 1259 patients who underwent orchidopexy for unilateral udt. the study outcomes included in this study are follicle-stimulating hormone (fsh), luteinizing hormone (lh), inhibin b levels, and azoospermia rate. table 1. studies characteristics of bilateral and unilateral udt post-orchidopexy. figure 1. prisma flow chart. archivio italiano di urologia e andrologia 2025; 97(2):13918 3 testicular function of bilateral undescended testis risk of bias we included 10 studies in this meta-analysis, 5 of which are retrospective cohorts, 3 prospective cohorts, and 2 cross-sectional studies. each study's risk of bias assessment is presented using the newcastle ottawa scale, as shown in table 2. six studies have a low risk of bias, and the other four studies have a moderate risk of bias. follicle-stimulating hormone (fsh) nine studies were included in the meta analysis of fsh value. the forest plot revealed that post-orchidopexy fsh values in bilateral udt were significantly higher compared to fsh values after unilateral udt, with a mean difference (md) of 3.77 ui/l (95% ci: 1.65-5.89, p = 0.0005) and significant heterogeneity (i² = 86%, p < 0.00001) (figure 2). luteinizing hormone (lh) five studies were included in the meta-analysis of lh value. post-orchidopexy lh values after bilateral udt were significantly higher compared to lh values after unilateral udt, with a mean difference (md) of 1.27 ui/l figure 2. forest plot of fsh value. table 1. studies characteristics of bilateral and unilateral udt post-orchidopexy. study bilateral unilateral patients fsh lh inhibin b azoospermia patients fsh lh inhibin b azoospermia chiba et al. (2009) (8) 10 23.2 ± 5.6 6.8 ± 1.7 10 10 5 lee et al. (2001) (9) 88 17.4 ± 14.3 7.1 ± 2.4 59.8 ± 50.6 609 6.7 ± 4.6 4.6 ± 3.1 112.5 ± 57.6 trsinar et al. (2009) (7) 19 5.9 ± 3.3 119 ± 106.2 2 49 4.8 ± 3.9 164 ± 65.4 2 rusnack et al. (2003) (10) 11 10.27 ± 4.34 7.24 ± 2.93 25 5.56 ± 2.56 6.59 ± 3.2 ozan et al. (2019) (5) 86 28.19 ± 12.4 62 22.71 ± 11.86 rohayem et al. (2016) (11) 135 15.5 ± 11.9 6.3 ± 5 62 222 11.9 ± 10 5.3 ± 3.3 62 fan et al. (2024) (4) 43 7.19 ± 3.06 4.84 ± 1.74 23 56 7.15 ± 2.92 4.26 ± 1.81 19 barbotin et al. (2019) (12) 145 21.3 ± 12.1 67.0 ± 26.5 80 19.3 ± 10.5 91 ± 38.9 van brakel (2012) (6) 7 8.2 ± 7.4 182.5 ± 90.8 55 4.8 ± 3.9 288.0 ± 133.0 kraft et al. (2012) (13) 19 9.70 ± 4.19 6.35 ± 3.36 91 5.48 ± 3.58 5.17 ± 2.73 table 2. risk of bias assessment using newcastle-ottawa scale for each included study. study selection (max 4) comparability (max 2) outcome (max 3) total (max 9) risk of bias chiba et al. (2009) (8) 4 1 2 5 moderate lee et al. (2001) (9) 4 2 3 9 low trsinar et al. (2009) (7) 4 2 3 9 low rusnack et al. (2003) (10) 3 1 2 6 moderate ozan et al. (2019) (5) 3 1 2 6 moderate rohayem et al. (2016) (11) 4 2 3 9 low fan et al. (2024) (4) 4 2 3 9 low barbotin et al. (2019) (12) 4 2 3 9 low van brakel (2012) (6) 4 2 3 9 low kraft et al. (2012) (13) 3 1 2 6 moderate archivio italiano di urologia e andrologia 2025; 97(2):13918 a. agung ngurah krisnanta adnyana, m. harvy wicaksono pantjoro, g. wirya kusuma duarsa 4 (95% ci: 0.27-2.26, p = 0.01) and significant heterogeneity (i² = 81%, p = 0.0004) (figure 3). inhibin b meta analysis of inhibin b value included four studies. inhibin b levels post-orchidopexy in bilateral udt were significantly lower compared to inhibin b levels after unilateral udt, with a mean difference (md) of -44.86 pg/ml (95% ci: -69.58 -20.15, p = 0.0004) and significant heterogeneity (i² = 83%, p = 0.0006) (figure 4). azoospermia four studies were included in the meta-analysis of azoospermia rate. the frequency of azoospermia was significantly higher in post-orchidopexy after bilateral udt compared to unilateral udt, with an odds ratio (or) of 2.3 (95% ci: 1.573.37, p < 0.0001) and low heterogeneity (i² = 0%, p = 0.55) (figure 5). discussion this meta-analysis involved ten studies comprising 563 post-orchidopexy cases for bilateral udt and 1259 postorchidopexy cases for unilateral udt. it was shown that patients with bilateral undescended testis (udt) have significantly poorer post-orchidopexy testicular function compared to unilateral udt. we find significantly elevated fsh and lh, and reduced inhibin b, which suggests some degree of primary testicular failure in bilateral udt patients. these hormonal findings are backed up by significantly increased incidence of azoospermia. various other studies have found that bilateral udt has a worse outcome than unilateral udt. lee et al. found that patients with bilateral udt had significantly higher fsh and lh, and lower inhibin b than cases with unilateral udt (9). trsinar et al. and ozan et al. also found a significant difference between unilateral and bilateral udt (5, 7). our meta-analysis found that the risk of azoospermia was figure 3. forest plot of lh value. figure 4. forest plot of inhibin b value. figure 5. forest plot of azoospermia rate. archivio italiano di urologia e andrologia 2025; 97(2):13918 5 testicular function of bilateral undescended testis more than twofold higher in bilateral udt than unilateral udt (or 2.3). these findings backed up by various studies with similar results. a study by van brakel et al. found that sperm concentration is significantly lower in the bilateral udt (6). studies by rohayem et al, also find that 49% of the patients with history of bilateral udt with azoospermia and only 27% of the unilateral udt had azoospermia (11), fsh, inhibin b, and lh represent the functions of the sertoli and leydig cells, respectively. fsh enhances t action by maintaining the supporting function of sertoli cells on spermatogenesis (3). serum levels of inhibin b are strictly related to the germinative epithelium status and reflect the sertoli function (14). inhibin b and fsh are biomarkers for the integrity of the seminiferous tubules. damage to the seminiferous tubules are suggested by the elevation of fsh and low inhibin b levels (9). on the other hand, lh works in the leydig cell and helps stimulate the production of t, which is the cornerstone of effective spermatogenesis (3). earlier study found elevated fsh and decreased inhibin b are a good markers of decreased sperm production (9, 15). this is also consistent with this study, which found that the risk of developing azoospermia is significantly higher in patients with bilateral udt, who exhibit poorer results in fsh and inhibin b levels compared to those with unilateral udt. this shows that laterality of udt is one of the critical factors for testicular functions after orchidopexy, along with the timing of surgery. additionally, for adult patients presenting with infertility and a history of cryptorchidism, the laterality should be a critical component of the clinical assessment. our study has limitations inherent to retrospective data synthesis. additionally, heterogeneity was moderate to high for endocrine markers (fsh, lh, inhibin b), likely due to variation in study design, patient age at surgery, timing of hormonal assessment, and laboratory methods. although we used a random-effects model to account for this variability, residual confounding cannot be excluded. future studies should stratify outcomes based on surgical technique and pubertal status, with a focus on long-term fertility endpoints. conclusions this meta-analysis provides strong evidence that bilateral udt is associated with significantly poorer testicular function outcomes following orchidopexy compared to unilateral udt. patients with bilateral udt exhibited markedly elevated levels of fsh and lh, reduced levels of inhibin b, and a more than twofold increased risk of azoospermia. these findings suggest greater sertoli and leydig cell dysfunction in bilateral cases, highlighting the long-term implications of testicular maldescent on reproductive endocrinology. despite heterogeneity in hormone assay timing and surgical timing across studies, the consistency of trends across multiple parameters strengthens the validity of our findings. future prospective studies with standardized protocols and longer follow-up are warranted to explore the impact of laterality on fertility outcomes in greater depth, particularly when combined with variables such as age at surgery and testicular histopathology. references 1. liu j, xiu w, sui b, et al. open controversies on the treatment of undescended testis: an update. front pediatr. 2022; 10:874995. 2. averous m, lopez c. la cryptorchidie: le point de vue de l'urologue pédiatre [cryptorchidism: the point of view of a pediatric urologist]. gynecol obstet fertil. 2004; 32:813-817. 3. rodprasert w, virtanen he, toppari j. cryptorchidism and puberty. front endocrinol (lausanne). 2024; 15:1347435. 4. fan l, shi l, liu s, et al. bilateral versus unilateral orchidopexy: ivf/icsi-et outcomes. front endocrinol (lausanne). 2024; 15:1294884. 5. ozan t, karakeci a, kaplancan t, et al. are predictive factors in sperm retrieval and pregnancy rates present in nonobstructive azoospermia patients by microdissection testicular sperm extraction on testicle with a history of orchidopexy operation?. andrologia. 2019; 51:e13430. 6. van brakel j, kranse r, de muinck keizer-schrama sm, et al. fertility potential in men with a history of congenital undescended testes: a long-term follow-up study. andrology. 2013; 1:100-108. 7. trsinar b, muravec ur. fertility potential after unilateral and bilateral orchidopexy for cryptorchidism. world j urol. 2009; 27:513-519. 8. chiba k, ishikawa t, yamaguchi k, fujisawa m. the efficacy of adult orchidopexy as a treatment of male infertility: our experience of 20 cases. fertil steril. 2009; 92:1337-1339. 9. lee pa, coughlin mt. fertility after bilateral cryptorchidism. evaluation by paternity, hormone, and semen data. horm res. 2001; 55:28-32. 10. rusnack sl, wu hy, huff ds, et al. testis histopathology in boys with cryptorchidism correlates with future fertility potential. j urol. 2003;169:659-662. 11. rohayem j, luberto a, nieschlag e, et al. delayed treatment of undescended testes may promote hypogonadism and infertility. endocrine. 2017; 55:914-924. declarations ethical approval: ethical approval was not crucial for this study, as it did not involve directly patients, and all included data were previously published. availability of data and material: availability of data and materials used in our study are available to access by request. competing interests: the authors declare that they have no competing interests. funding: this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions: aanka, investigation, writing – original draft, perform statistical analysis; mhwp, investigation, writing – original draft, perform statistical analysis; gwkd, conceptualization, supervision, writing-review and editing, validation. all authors read and approved the final manuscript. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13918 a. agung ngurah krisnanta adnyana, m. harvy wicaksono pantjoro, g. wirya kusuma duarsa 6 12. barbotin al, dauvergne a, dumont a, et al. bilateral versus unilateral cryptorchidism in nonobstructive azoospermia: testicular sperm extraction outcomes. asian j androl. 2019; 21:445-451. 13. kraft kh, canning da, snyder hm, kolon tf. undescended testis histology correlation with adult hormone levels and semen analysis. j urol. 2012; 188(4 suppl):1429-1435. 14. esposito s, cofini m, rigante d, et al. inhibin b in healthy and cryptorchid boys. ital j pediatr. 2018; 44:81. 15. corinne tm, anatole pc, jeanne ny. comparison of serum inhibin b and follicle-stimulating hormone (fsh) level between normal and infertile men in yaoundé. int j reprod med. 2020; 2020:4765809. correspondence anak agung ngurah krisnanta adnyana (corresponding author) krisnanta.adnyana@gmail.com intern doctor of urology surgery department prof. dr. i.g.n.g. ngoerah general hospital, bali jalan diponegoro, kota denpasar 80113, bali, indonesia marshal harvy wicaksono pantjoro marshalharvy@gmail.com gede wirya kusuma duarsa gwkduarsa@gmail.com urology staff of urology surgery department prof. dr. i.g.n.g. ngoerah general hospital, bali, indonesia stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13194 1 original paper introduction prostate cancer (pca) is the second most common solid tumor in males worldwide and tends to be diagnosed mainly after 65 years of age (1). there is considerable variation between developed and developing countries regarding its incidence and mortality due to the hereditary component of the disease, the method of screening and diagnosis, and the involved environmental factors (2, 3). approximately 95% of tumors are adenocarcinomas and tend to be located in the peripheral zone (pz) of the prostate (4-6). pca is diagnosed via direct sampling obtained by prostate biopsy, which can be performed transperineally or transrectally, both of which are comparable in terms of tolerability and the detection rate of clinically significant pca (cspca) (7). however, the first approach is preferred due to the lower risk of infection and associated rectal bleeding and the need for prophylactic antibiotic therapy (8-12). other complications include urinary retention, haematuria, haematospermia, perineal pain, lower urinary tract symptoms, erectile dysfunction, and, very rarely, death (13). the decision to perform a prostate biopsy is not only based on a particular prostate-specific antigen (psa), but it is recommended to contextualize with psa velocity and density, free/total psa ratio, digital rectal examination (dre), and with some patient risk factors such as age, ethnicity, family history, and associated comorbidities (14, 15). the classical technique for obtaining a prostate sample is the standard ultrasound-guided double sextant prostate biopsy, where prostatic material (usually 12 samples) is randomly collected at predefined locations (10, 15-17). the limitations associated with this technique include the high rate of clinically insignificant pca (cispca) detection introduction and objectives: prostate cancer (pca) is the second most commonly diagnosed cancer in men. cognitive fusion transrectal ultrasound prostate biopsy is one of several modalities for diagnosing this disease. however, no existing studies have shown the clear superiority of one image-guided technique over another. this investigation aimed to evaluate the efficacy of targeted biopsy through cognitive guidance, as well as to assess the accuracy of multiparametric magnetic resonance imaging (mpmri) in the detection of pca compared to the specimen obtained by radical prostatectomy (rp). materials and methods: we conducted a retrospective observational single-center study approved by the ethical committee, including men with prostate-specific antigen (psa) levels between 2-10 mg/ml who underwent rp and cognitive fusion biopsy (cfb) between 2017 january and 2022 january. results: a total of 639 patients were analyzed, 83 of whom met the inclusion criteria and were enrolled in this study. the overall rate of pca detection with cfb was 79.5% (median of specific pca detection was 100%), and the rate of detecting clinically significant prostate cancer (cspca) was 74.7%. in addition, there was 42.2% agreement between the international society of urological pathology (isup) score of the cfb and the rp specimen, which increased to 56.6% when the systematic biopsy was added. regarding the accuracy of mpmri, several parameters were evaluated with respect to rp sample histology. of these, tumor location had a total match rate of 39.8% and a partial match rate of 55.4%. moreover, regarding extraprostatic extension (epe), the present study found a significant association between the rp specimen and mpmri (p = 0.002), with an agreement rate of 60% if it was present in the histology and 79.5% if it was not. additionally, larger prostates and tumors located in the transition zone were significantly associated with a lower cfb accuracy (p = 0.001 and p = 0.030, respectively). after adjusting for all variables evaluated, only prostate volume remains statistically significant (p = 0.029). conclusions: in this study, we conclude that mpmri is highly accurate, allowing good characterization of suspicious tumors and reasonably guiding cognitive biopsy. however, the use of both targeted biopsy through cognitive guidance and systematic biopsy increases the diagnostic accuracy for pca. although there is no recommendation in the current literature for one guiding technique over another, we believe that cognitive-guideffectiveness of cognitive fusion transrectal ultrasound prostate biopsy when compared with final prostatectomy histology ana sofia araújo 1, joão serra 2, sara anacleto 1, ricardo rodrigues 1, catarina tinoco 1, andreia cardoso 1, mariana capinha 1, vera marques 1, paulo mota 1, 2 1 hospital de braga, dept. of urology, braga, portugal; 2 school of medicine, university of minho, department of urology, braga, portugal. doi: 10.4081/aiua.2024.13194 summary ed biopsy should only be reserved for centers with no access to ultrasound or magnetic resonance fusion software. key words: cognitive fusion biopsy; diagnostic accuracy; image fusion prostate cancer; multiparametric magnetic resonance imaging; radical prostatectomy. submitted 2 october 2024; accepted 6 october 2024 archivio italiano di urologia e andrologia 2024; 96(4):13194 a.s. araújo, j. serra, s. anacleto, et al. 2 and the failure to detect cspca which leads to imprecision in stratifying this disease and may require a repeat of the procedure, delaying diagnosis and therapeutic decisionmaking (10, 12, 15, 16, 18). multiparametric magnetic resonance imaging (mpmri) has shown superiority over individual mri sequences, allowing the determination of a definitive correlation between the lesions identified by imaging and the tumor location in the specimens obtained from radical prostatectomy (rp) (10, 15, 19-21). mpmri sequences include high-resolution t2-weighted imaging (t2w) to describe the anatomy of the prostate, typically combined with two functional mri techniques, diffusion-weighted imaging (dwi) to display cell densities, and dynamic contrast-enhanced mri (dce-mri), which can reveal the vascularization at the suspected location (7, 22, 23). the clinical indications for prostatic imaging include detection and localization of pca, for guidance in mpmri-guided biopsy (mpmri-gb), local staging and stratification of the tumor, and assessment of pca recurrence and local treatment (12, 14). it has been demonstrated that the use of mpmri before biopsy increases the detection of cspca, and so the european association of urology (eau) recommends performing mpmri before biopsy for all eligible patients (8, 9, 15, 20, 24, 25). the ability to detect and delineate lesions strongly suggestive of pca on mpmr images has led to the development of new magnetic resonance imaging-guided biopsy (mri-gb) techniques: cognitive fusion biopsy (cfb), biopsy performed during mpmri imaging, and software fusion biopsy of the images previously obtained mpmri with the images acquired during the ultrasound (7, 8, 15, 26). cfb consists of lesion identification and delineation on previously obtained mpmri based on anatomical points that may exist near the lesion (7, 27). subsequently, through ultrasound, the operator can direct the biopsy needle to the suspected site, cognitively correlating the images obtained from mpmri and ultrasound in real time (9, 28). this is an old, fast, simple, and accessible technique that does not require additional software to merge the mpmr images with those of the ultrasound (7, 10, 15, 28). the associated disadvantages are the limited accuracy of the biopsy in the absence of reference points, especially for smaller, anterior-located lesions (7, 9). cfb seems to be more useful for larger and more aggressive lesions, as well as diffuse abnormalities located in the pz of the prostate (7, 9). the diagnostic accuracy of cfb depends on the visibility of the lesion on the ultrasound images, the position of the patient, and the location of the lesion on mpmri because ultrasound and mpmri do not employ the same exploration planes. furthermore, this technique depends on the operator and his experience in interpreting images and in transposing them to ultrasound (9, 10, 28). therefore, taking into account the associated advantages and disadvantages, the present study aims to evaluate the effectiveness of cfb in the detection of pca in terms of accuracy and diagnosis of cspca, as well as in comparison with the histological results obtained after rp; it also aims to evaluate the accuracy of mpmri as well as the parameters that influence the probability of detecting pca on mpmri with respect to cfb histology. materials and methods the present study was approved by the ethics committee of hospital de braga (cehb) (appendix i) and the department of data protection (appendix ii). the norms and recommendations of the declaration of helsinki, the convention on human rights and biomedicine, and the guidelines on good clinical practice were respected. we conducted a retrospective observational single-center study, including men who underwent rp and cfb between 2017 january and 2022 january. in addition, the inclusion criteria for this study were: first biopsy, psa levels between 2 and 10 ng/ml, and lesion categorization on mpmri according to version 2.1 of the prostate imaging-rating and data system (pi-rads) equal to or greater than 3. patients who did not meet the inclusion criteria described above, as well as those whose outcome information was not fully available, were excluded. data analysis was performed using ibm®spss® software, version 28.0. in the descriptive analyses, means (ms) and standard deviations (sds) are calculated for continuous variables with normal distributions, and medians (mdns) with percentiles (p25-p75) are calculated otherwise. the decision criteria were the skewness coefficient within the interval [-1; 1] and the analysis of the histogram. categorical variables are described with numbers (n) and percentages (%). ordinal variables are described as frequencies and percentages or as medians and percentiles, whichever was more intuitive for describing the variable. when comparing categorical variables, the chi-square test (𝝌2) was used in cases of compliance with cochran's rules; otherwise, fisher’s exact test was used. the standardized residuals, ri = (o = observed frequency in the sample, e = expected frequency), were calculated in cases in which the association was statistically significant in tables with dimension (2 + n) x (2 + n), for n > 0. the residuals were said to be statistically significant when ri ≥ |1.96|, under the assumption of a normal distribution. to assess the agreement of the evaluation methods, cohen's kappa (κ) was calculated, in which 0.01 to 0.20 was considered minimal agreement, 0.21 to 0.40 fair agreement, 0.41 to 0.60 moderate agreement, 0.61 to 0.80 substantial agreement and 0.81 to 1.00 high agreement. logistic regression was used to evaluate the association of different variables with lower detection of pca on cfb, first with univariate models and then with models adjusted to the variables with statistically significant results in the univariate analysis. the odds ratio (or) was calculated to assess the association between the variables. statistical significance was assessed using the 95% confidence interval (ci) for the or and the associated p value. statistical significance was set at a p value < 0.05. definitions we defined as a cspca when the international society of urological pathology (isup) score was greater than or equal to 2. the presence of extraprostatic extension (epe) was identified in the mpmri report and in the pathological anatomy report of the specimens obtained by rp. regarding the characteristics of the lesions on mpmri and in the histological analysis of the rp sample, 3 parameters were defined with regard to the location of the nodule archivio italiano di urologia e andrologia 2024; 96(4):13194 3 cognitive fusion biopsy with the largest dimensions: zone (peripheral/transition/ both), laterality (right, left, both) and site (apex, middle, base, middle+base, middle+apex, base+apex, > 2 sites). if the three location parameters agreed between mpmri and the rp analysis, we consider a perfect match; if one of the three parameters was not in agreement, mpmri was said to have no match. a partial match was subdivided into false-positives (all those individuals whose tumor location in the mpmri report was more extensive than that in the pathological anatomy report for the prostate specimen) and false-negatives (individuals whose imaging indicated a more restricted location than to the actual location of the tumor in the prostate). results patient selection and sample characterization the patient selection process is described in the flowchart below (figure 1). of the 639 patients initially analyzed, 83 with a mean age of 64 years were included, 34 of whom (41.0%) were suspected of pca according to the dre. the median total psa was 6.62 ng/ml (p25-p75, 4.638.99), the median free/total psa ratio was 13.00% (p25p75, 8.20%-19.00%) and the median psa density was 0.15 ng/ml/cm3 (p25-p75, 0.10-0.21). mpmri analysis showed that most patients had only 1 suspicious nodule (n = 61, 73.5%), and the mean diameter of the largest identified lesion was 14.27 mm (sd = 4.60). the median prostatic volume verified on mpmri was 40.00 cm3 (p25-p75, 32.00-52.00), and the pi-rads evaluation classified the largest nodule detected into three categories: 3 (n = 15, 18.1%), 4 (n = 36, 43.4%) and 5 (n = 32, 38.6%). in most cases, two fragments (n = 58, 69.9%) were collected by cfb, with a range between 0 (n = 17, 20.5%) and 4 (n = 1, 1.2%) samples. most patients had two positive fragments (n = 36, 43.4%), and the median number of positive samples was 2.00 (p25-p75, 1.00-2.00). regarding sb, the most common number of fragments collected was 12 (n = 76, 91.6%). the tumor was detected in 0-2 (n = 15, 18.1%), 3-5 (n = 31, 37.3%), 6-7 (n = 19, 22.9%) and ≥ 8 samples (n = 18, 21.7%), with a median of 5.00 samples (p25-p75, 3.00-7.00). on mpmri, the nodules were mostly found in the pz (n = 63, 75.9%), on the left (n = 37, 44.6%), and in the apical region (n = 23, 27.7%). in the rp sample, the tumor was detected more frequently in the pz (n = 64, 77.1%), bilaterally (n = 45, 54.2%), and in more than 2 sites (n = 22, 26.5%). the pca isup score obtained for the samples collected from sb was distributed among categories 1 (n = 12, 14.5%) to 5 (n = 11, 13.3%), with most classified as category 4 (n = 17; 20.5%).the same results were observed for the tumors detected with cfb, with isup scores from 1 (n = 20, 24.1%) to 5 (n = 6, 7.2%), with category 4 being more frequent (n = 22, 26.5%). the overall isup scores were distributed among the same categories, from 1 (n = 15, 18.1%) to 5 (n = 13, 15.7%), where the highest frequency was observed for isup category 2 (n = 24, 28.9%). for the samples obtained from rp, the isup carcinoma scores ranged from 1 (n = 4, 4.8%) to 5 (n = 19, 22.9%), with most classified into category 2 (n = 29, 34.9%). regarding the presence of epe, we found that 29 (34.9%) and 25 (30.1%) patients were positive on mpmri and post-rp, respectively. following sb, 16 individuals (19.3%) were negative for tumor detection in the collected fragments, 12 (14.5%) were classified as having cispca, and 55 individuals (66.3%) had cspca. figure 1. flowchart of the patient selection according to the inclusion and exclusion criteria for the study. archivio italiano di urologia e andrologia 2024; 96(4):13194 a.s. araújo, j. serra, s. anacleto, et al. 4 regarding the samples obtained by cfb, 20 (24.1%) and 62 men (74.7%) were said to have cispca and cspca, respectively; only 1 patient (1.2%) had no diagnosis of pca. after removal of the prostate via rp, 4 men (4.8%) were diagnosed with cispca, and 79 individuals (95.2%) had cspca (table 1). overall and specific rate of pca detection table 2 presents the results of the overall and specific rate of pca detection for cfb. the overall rate of cap detection table 1. sample characterization. parameters n = 83 age 64.40 (6.08) [49-77] digital rectal examination normal 49 (59.0%) suspected 34 (41.0%) total psa (ng/ml) 6.62 (4.63–8.99) [2.10–10.00] free/total psa ratio (%) 13.00 (8.20–19.00) [4.37–82.90] psa density (ng/ml/cm3) 0.15 (0.10–0.21) [0.05–0.42] number of nodules on mpmri 1 61 (73.5%) 2 16 (19.3%) ≥ 3 6 (7.2%) diameter of the largest nodule on mpmri (mm) 14.27 (4.60) [11.00–17.00] prostate volume (cm3) 40.00 (32.00–52.00) [18.00–97.00] pi-rads category 3 15 (18.1%) 4 36 (43.4%) 5 32 (38.6%) number of samples collected by cfb 1 3 (3.6%) 2 58 (69.9%) 3 14 (16.9%) 4 7 (8.4%) 5 1 (1.2%) number of tumor-bearing samples collected by cfb 2.00 (1.00–2.00) [0.00–4.00] 0 17 (20.5%) 1 18 (21.7%) 2 36 (43.4%) 3 11 (13.3%) 4 1 (1.2%) number of fragments collected by sb 10 5 (6.0%) 11 2 (2.4%) 12 76 (91.6%) number of tumor-bearing fragments collected by sb 5.00 (3.00–7.00) [0-12] 0–2 15 (18.1%) 3–5 31 (37.3%) 6–7 19 (22.9%) ≥ 8 18 (21.7%) location of the nodule on mpmri zone pz 63 (75.9%) tz 14 (16.9%) both (pz + tz) 6 (7.2%) laterality right 28 (33.7%) left 37 (44.6%) bilateral 18 (21.7%) site apex 23 (27.7%) middle 19 (22.9%) base 14 (16.9%) middle + apex 11 (13.3%) middle + base 5 (6.0%) base + apex 2 (2.4%) > 2 sites 9 (10.8%) location of the nodule in the rp sample zone pz 64 (77.1%) tz 12 (14.5%) both (pz + tz) 7 (8.4%) laterality right 19 (22.9%) left 19 (22.9%) bilateral 45 (54.2%) site apex 17 (20.5%) middle 14 (16.9%) base 13 (15.7%) middle + apex 11 (13.3%) middle + base 4 (4.8%) base + apex 2 (2.4%) > 2 sites 22 (26.5%) isup score from sb 1 12 (14.5%) 2 14 (16.9%) 3 13 (15.7%) 4 17 (20.5%) 5 11 (13.3%) isup score from csb 1 20 (24.1%) 2 18 (21.7%) 3 16 (19.3%) 4 22 (26.5%) 5 6 (7.2%) global isup score 1 15 (18.1%) 2 24 (28.9%) 3 19 (22.9%) 4 12 (14.5%) 5 13 (15.7%) isup score from rp 1 4 (4.8%) 2 29 (34.9%) 3 27 (32.5%) 4 4 (4.8%) 5 19 (22.9%) epe on mpmri yes 29 (34.9%) no 54 (65.1%) epe on rp samples yes 25 (30.1%) no 58 (69.9%) sb pca none 16 (19.3%) cispca 12 (14.5%) cspca 55 (66.3%) cfb pca none 1 (1.2%) cispca 20 (24.1%) pcspca 62 (74.7%) rp pca cispca 4 (4.8%) cspca 79 (95.2%) for continuous variables, the results are presented as m (sd) [min-max] for normal distributions and mdn (p25–p75) [min-max] for nonnormal distributions; categorical variables are presented as n (%). archivio italiano di urologia e andrologia 2024; 96(4):13194 5 cognitive fusion biopsy (obtained by the presence of ≥ 1 positive sample(s) in the total number of samples collected) was 79.5%. the median of the specific rate of pca detection, calculated by the formula (1 ), was 100% (p25-p75, 50.0%-100.0%). for instance, if it was collected 3 fragments and all of them were positive [1 (3 3 -3 )] = (1-0) = 1 or 100%. otherwise, if it was collected 3 fragments but none of them were positive [1 (3 3 -0)] = (1-1) = 0 or 0.0%. association of pca detection between cfb and sb the association of cancer detection between cfb and sb showed moderate agreement (κ = 0.36), with statistical significance (p < 0.001), mainly for cspca (80.6%) (table 3). the standardized residues suggested that the number of samples considered to not have tumor tissue according to cfb and to have cispca according to sb was higher than expected (n = 1, 100%, ri = 2.2%). the proportion of cispca detected by both cfb and sb was 40.0%, with a positive residue of ri = 3.0, suggesting a higher proportion than expected. in contrast, the proportion of cispca from cfb classified as cspca by sb (25.0%) was lower than expected (ri = -2.3). although significant, 4.8% of cspcas detected with cfb were considered cspca according to sb, which was lower than expected (ri = -2.0). comparison of the isup scores obtained with cfb and the global isup score with the isup score obtained with rp histology table 4 compares the isup scores obtained for the samples collected with cfb with those described in the rp histology, using the formula (isup rp-isup cfb), with total agreement observed for 35 (42.2%). the proportions of -/+1 and -/+2 errors were 45.7% (38 individuals) and 12% (10 individuals), respectively. the same analysis was performed for the global isup score, yielding a total agreement for 47 patients (56.6%), and proportions of -/+1, -/+2 and -/+3 errors of 30.1% (25 patients), 10.8% (9 patients) and 2.4% (2 patients), respectively. rate of match considering mpmri locations relative to rp histology with respect to the rp samples, mpmri had total match in tumor location in 33 patients (39.8%). partial match was achieved for 46 patients (55.4%), 40 (48.2%) with false negatives and 6 (7.2%) with false positives. no match at all was obtained for 4 patients (4.8%) (figure 2). association of laterality, tumor zone, site and epe observed in rp histology with that observed on mpmri the laterality in the rp histology was statistically significantly associated with the laterality on mpmr (p < .001). the agreement for right-, left-, and bilaterally located tumors was 73.7%, 94.7% and 28.9%, table 3. association of pca detection between cfb and sb. pca detected by cfb pca detected none cispca cspca fisher's cohen's by sb exact test κ none 0 (0.0%) 7 (35.0%) 9 (14.5%) p < 0.001 0.36 cispca 1 (100%), ri = 2.2 8 (40.0%), ri = 3.0 3 (4.8%), ri = -2.0 cspca 0 (0.0%) 5 (25.0%), ri =2.3 50 (80.6%) table 4. comparison of the isup scores obtained with cfb and the global isup score with the isup score obtained with rp histology. isup rp–isup cfb isup rp–isup global n % n % -3 0 0.0% 1 1.2% -2 2 2.4% 3 3.6% -1 9 10.8% 5 6.0% 0 35 42.2% 47 56.6% 1 29 34.9% 20 24.1% 2 8 9.6% 6 7.2% 3 0 0.0% 1 1.2% figure 2. rate of match considering mpmri locations relative to rp histology. table 2. overall and specific rate of pca detection. pca detection overall 66 (79.5%) specific 1 no. fragments collected – no. positive fragments 100% (50.0% 100%) [0.0% 100%] no. fragments collected 0.0% 17 (20.5%) 33.0% 2 (2.4%) 40.0% 1 (1.2%) 50.0% 13 (15.7%) 75.0% 2 (2.4%) 100% 48 (57.8%) continuous variables are presented as m (sd) [min-max] for normal distributions and mdn (p25–p75) [min-max] for nonnormal distributions; categorical variables are presented as n (%). archivio italiano di urologia e andrologia 2024; 96(4):13194 a.s. araújo, j. serra, s. anacleto, et al. 6 respectively. cohen's κ was 0.35, indicating slight agreement (table 5). the zone in which the tumor was found in rp histology was statistically significantly associated with that identified on mpmri (p < 0.001). the agreement for the pz, tz, and both was 95.3%, 100% and 71.4%, respectively. cohen's κ was 0.84, indicating high agreement (table 6). table 7 shows the associations of the rp histological site with that identified on mpmri. statistically significant differences were found for apical (p = 0.026), middle (p < 0.001), and basal locations (p < 0.001) and > 2 sites (p < 0.001). cohen's k showed the highest agreement for the basal location (κ = 0.80, high), with true negatives of 93.8% and true positives of 89.5%. this was followed by agreement in middle locations (κ = 0.70, substantial), which had the highest proportion of true positives (89.7%), and in > 2 sites (κ = 0.43, fair), which had the highest proportion of true negatives (98.4%). finally, apical sites had an agreement of 0.20, with 62.0% true negatives and 75.0% true positives. the association of epe assessed by rp histology with that assessed on mpmri was statistically significant (p = 0.002) (table 8). regarding positive epe as observed in rp histology, 60.0% of cases were also positive on mpmri. when epe was not detected in the rp specimen, it was also not detected in 75.9% of the cases on imaging. the agreement between the two modalities was fair (κ = 0.34). association of different variables with lower detection of pca on cfb, adjusted for covariates table 9 shows the association of different variables with no detection of pca on cfb, adjusted for covariates. in the univariate analysis, covariates referring to the presence of cspca in the rp specimen (or = 0.07 [95% ci = 0.07; 0.74], p = 0.027), a suspected tumor from dre (or table 5. association of laterality observed in rp histology with that observed on mpmri. rp histology laterality right left both fisher's cohen's exact test κ zone according to mpmri right 14 (73.7%) 0 (0.0%) 14 (31.1%) p < 0.001 0.35 left 1 (5.3%) 18 (94.7%) 18 (40.0%) both 4 (21.1%) 1 (5.3%) 13 (28.9%) table 6. association of tumor zone in rp histology with that identified on mpmri. zone according to rp histology pz tz both fisher's cohen's exact test κ zone according to mpmri pz 61 (95.3%) 0 (0%) 2 (28.6%) p < 0.001 0.84 tz 2 (3.1%) 12 (100%) 0 (0%) both 1 (1.6%) 0 (0%) 5 (71.4%) table 8. association of epe assessed by rp histology and that assessed on mpmri. epe rp histology no yes χ2 test cohen's κ epe mpmri no 44 (75.9%) 10 (40.0%) p = 0.002 0.34 yes 14 (24.1%) 15 (60.0%) table 9. association of different variables with lower detection of pca on cfb, adjusted for covariates. dependent variable: no detection of pca on cbf unadjusted models (univariate) ajusted model age or = 1.04 (p = 0.440) [95% ci = (0.95; 1.14)] suspected tumor on dre or = 0.14 (p = 0.014) [95% ci = (0.03; 0.67)] or = 0.30 (p = 0.166) [95% ci = (0.06; 1.64)] total psa or = 0.99 (p = 0.925) [95% ci = (0.79; 1.24)] free/total psa ratio or = 1.02 (p = 0.477) [95% ci = (0.97; 1.06)] psa density or = 0.001 (p = 0.033) [95% ci = (0.00; 0.51)] number of nodules or = 1.39 (p = 0.393) [95% ci = (0.66; 2.94)] size of the largest nodule or = 0.96 (p = 0.459) [95% ci = (0.85; 1.08)] prostate volume or = 1.06 (p = 0.001) [95% ci = (1.02; 1.09)] or = 1.04 (p = 0.029) [95% ci = (1.00; 1.08)] pi-rads category or = 0.46 (p = 0.045) [95% ci = (0.22; 098)] or = 0.92 (p = 0.848) [95% ci = (0.37; 2.27)] site: apex or = 0.47 (p = 0.199) [95% ci = (0.15; 1.49)] site: middle or = 0.95 (p = 0.926) [95% ci = (0.32; 2.80)] site: base or = 1.86 (p = 0.292) [95% ci = (0.59; 5.85)] > 2 sites or = 2.14 (p = 0.320) [95% ci = (0.48; 9.63)] zone: pz or = 0.25 (p = 0.017) [95% ci = (0.08-0.78)] or = 0.46 (p = 0.524) [95% ci = (0.03; 4.98)] zone: tz or = 3.96 (p = 0.030) [95% ci = (1.15; 13,66)] or = 1.11 (p = 0.936) [95% ci = (0.09; 14.61)] both (pz + tz) or = 2.07 (p = 0.426) [(95% ci = 0.35; 12,36)] cspca on rp or = 0.07 (p = 0.027) [95% ci = (0.07; 0.74)] or = 0.12 (p = 0.111) [95% ci = (0.009; 1.63)] table 7. association of tumor zone in rp histology with that identified on mpmri. apex rp histology statistical test apex mpmri no yes χ2 test cohen's κ no 44 (62.0%) 3 (25.0%) p = 0.026 0.20 yes 27 (38.0%) 9 (75.0%) middle rp histology middle mpmri no yes χ2 test no 45 (83.3%) 3 (10.3%) p < 0.001 0.70 yes 9 (16.7%) 26 (89.7%) base rp histology base mpmri no yes χ2 test no 60 (93.8%) 2 (10.5%) p < 0.001 0.80 yes 4 (6.3%) 17 (89.5%) > 2 sites rp histology > 2 sites mpmri no yes χ2 test no 60 (98.4%) 14 (63.6%) p < 0.001 0.43 yes 1 (1.6%) 8 (36.4%) archivio italiano di urologia e andrologia 2024; 96(4):13194 7 cognitive fusion biopsy = 0.14 [95% ci = 0.03; 0.67], p = 0.014) and psa density (or = 0.001 [95% ci = (0.00; 0.51)], p = 0.033) were significantly associated with detection of pca on cfb. a higher pi-rads classification (or = 0.46 [95% ci = 0.22; 098], p = 0.045) and tumor location in the pz (or = 0.25 [95% ci = (0.08-0.78)], p = 0.017) were also associated with detection of pca on cfb. however, the volume of the prostate (or = 1.06 [95% ci = 1.02; 1.09], p = 0.001) and nodule location in the tz (or = 3.96 [95% ci = 1.15; 13.66)], p = 0.030) were associated with no detection of pca on cfb. when adjusting for all statistically significant variables from the univariate analysis, only prostate volume remained significant in the multivariate analysis (or = 1.04 [95% ci = 1.01; 1.08)], p = 0.029); that is, for every 1 cm3 increase in the volume of the prostate, the odds of the cfb not hitting the mpmri site increased by 4%. the variable related to psa density was not taken into account in the multivariate model, despite having a statistically significant result in the unadjusted model, as there was a loss of statistical power due to a wide confidence interval without statistical significance. discussion the main objective of this study was to evaluate the effectiveness of cfb in the detection of pca. we observed an overall rate of pca detection of 79.5%, consistent with previous investigations. the median specific pca detection rate in our investigation was 100%, i.e., in 57.8% of the patients, all the biopsied samples were positive for the tumor. a possible explanation for this high value may be the selection of patients with imaging results suggestive of pca (pi-rads ≥ 3) and elevated psa values. dekalo et al. showed that cfb had a pca detection rate of 52% and 78% in individuals suspected only due to imaging and in men with changes in both analytical and mpmri results, respectively (29). in the study published by wang et al., there was a 67% detection rate of pca through cfb (30). a portuguese study published in the ata urologica portuguesa revealed an effectiveness of cfb of 73% in the detection of pca (15). recently, kulis et al. revealed a 52% success rate of cfb in patients with high psa levels and persistent changes on imaging despite a previous negative sb (31). additionally, it was performed sb and cfb in the same patients which allow the association of these two routes of sample collection regarding the ability to identify prostatic lesions, and statistically significant differences were found with a moderate association between the two. the two methods agreed in the detection of cspca and cispca in 80.6% and 40.0% of cases, respectively. based on the analysis of these data, cfb detected 62 cases (74.7%) of cspca, while sb only detected 55 cases (66.3%). nevertheless, we found that 9 and 3 patients classified as having no tumor and cispca, respectively, according to sb were identified as having cspca with cfb, i.e., approximately 19.3% of the patients with cspca in our sample who underwent sb only would not have been correctly identified. according to the available literature, the false-negative rate of sb is between 15.7-17%, especially for cspca, corroborating the conclusions of several studies that performing a prebiopsy mpmri allows the detection of more cases of cspca than with only sb (15, 18, 30-35). however, the 5 patients diagnosed with cspca by sb but cispca according to cfb was greater than expected. these results are in agreement with previous studies, where kulis et al. revealed that if only 5 patients (13.16%) had undergone cfb, the diagnosis would have failed; one of these patients had a gleason scale score of 8 in the anatomopathological evaluation after rp (31). thus, the data of the present study suggest that cfb could not detect all cases of cspca, which is in agreement with previous studies; therefore, we do not advise completely replacing sb with cfb, but instead, they should be used in complementarity to reduce errors in the diagnosis of cspca (10, 18, 30, 31, 35-38). based on the histology of the samples collected with cfb, the greatest gleason score in the specimen was classified according to the isup score; a similar analysis was conducted for tumor tissue present in the prostate specimen collected by rp. when comparing the differences between the isup values from rp and cfb for each patient, a total agreement of 42.2% (35 patients) was obtained. baco et al. showed that the agreement in the gleason score between sb and rp samples was 90% (20). this finding contrasts with the retrospective study by diamand et al., which showed an agreement of 51.2%; however, the combination of sb and cfb increased the agreement with the final rp histology to 63.2% (39). this conclusion was observed in our study, showing that the combination of cfb and sb increased the agreement to 56.6%, a finding that is also corroborated by multicenter studies that confirmed the benefit of concomitant sb (39, 40). another objective of this study was to evaluate the accuracy of data provided from mpmri in terms of tumor location with respect to the histology of the specimen obtained with rp. a total match between the two was obtained in 39.8% (33 cases), a partial match was achieved in 55.4% (46 cases) and no match at all was found in 4.8% (4 cases). to date, no studies have been conducted comparing the 3 location parameters between mpmri and rp specimens. when analyzing each of the specific location parameters, we found high agreement with respect to laterality (73.7% on the right and 94.7% on the left) and zone (95.3% in the pz and 100% in the tz). with regard to site, cohen's κ value showed a stronger agreement when the tumor was at the base (positive predictive value (ppv), 89.5%; negative predictive value (npv), 93.8%), followed by the middle area (ppv 89.7%; npv 83.3%). therefore, there are high values in all parameters of the location; however, the total nonagreement can be explained because radiologists and pathologists do not use the same templates to correlate the locations, in addition to the fact that the in vivo and in vitro anatomical positions of the prostate also influence the interpretation of the affected site. another way to assess the accuracy of mpmri is through epe, comparing it with that reported by the histology of the rp samples. in the present study, agreements of 75.9% and 60% were obtained in detecting the absence and presence of epe, respectively. these data allow us to infer that in the present study, mpmri had a specificity of 53% and a sensitivity of 18%. in the study by martins et al., a sensiarchivio italiano di urologia e andrologia 2024; 96(4):13194 a.s. araújo, j. serra, s. anacleto, et al. 8 tivity of 56% (ci, 39%-72%) and a specificity of 84% (ci, 75%-91%) were found. similar values were found in articles that evaluated the accuracy of mpmri regarding epe (41-44). possible explanations for this wide variation in the accuracy of mpmri in detecting mpmri include the fact that there are several classification systems with different criteria for predicting the risk of epe; however, in validation cohorts, none showed definitive superiority over others (12, 44), and therefore, different criteria can lead to different results. additionally, differences in the study design and in epe prevalences among the populations, as well as differences in the experience of the radiologists and the center where the findings are interpreted, may influence the results (43). we also intended to evaluate which factors (demographic, analytical, physical examination, mpmri, and histological data of rp) were associated with a lower pca detection on cfb. in the present study, age was not found to be a statistically significant predictor of pca detection on cfb. this can be explained by the findings of bura et al., who showed that younger men exhibit lower signal intensity on t2w imaging, lower values on dwi, and diffuse enhancement on dce-mri, making the interpretation of pca on mpmri more difficult. although we are not aware of the existence of studies that associated dre findings and the effectiveness of cfb, it is understood that there is a positive association between these two variables; therefore, when the dre suggests a mass, cfb is more likely to hit the target tumor site. we also concluded that the psa value did not affect the pca detection of the cfb, a result that is corroborated by the study by guang xu (45). possible explanations for this finding are due to the fact that larger prostates are also associated with a higher psa level and as shown below, prostate volume is associated with a lower pca detection on cfb. however, psa density was found to be a significant independent predictor of the correctness of cfb in the detection of pca in the multivariate regression analysis, as pang et al. and dekalo et al. presented in their studies (10, 29). regarding factors related to mpmri, in previous studies, it was demonstrated that for larger suspected nodules and higher values on the pi-rads scale, the lesions were more frequently detected with cfb (10, 21, 36, 38, 45). however, in our study, only higher values on the pirads scale were associated with higher pca detection on cfb. in addition, there was no preferential nodule location of the prostate with statistically significant in the univariate logistic regression model; however, it was demonstrated that malignant lesions in the anterior apical region of the prostate can be more frequently missed (46). with regard to prostate volume and the presence of cancer in the tz, they were statistically significantly associated with less pca detection on cfb. these facts are corroborated by the current literature, since for larger prostates, there is greater difficulty in performing the biopsy (36). the association of tz lesions with an inaccurate cfb may be due to the difficulty in distinguishing pca from benign hyperplasia nodules (47). in contrast to tz lesions, lesions located in the pz were an independent predictor of pca detection with cfb (36). we also concluded that the existence of cspca in the histology of rp samples was associated with a higher probability of correct pca detection on cfb, which can be explained by the fact that higher gleason scores are associated with greater tumor aggressiveness, allowing greater visibility on mpmri (21, 47, 48) and, therefore, a higher probability of cfb pca detection. this study demonstrated several limitations, including those related to its retrospective and nonrandomized nature, such as the potential bias in patient selection. in addition, the small sample size could have implications regarding the inference of the statistical results. furthermore, factors associated with the performance of the biopsy, the lack of unified criteria in imaging and histology reports, and inconsistent experience by all professionals involved could have influenced these results. conclusion the present study concludes that mpmri is highly accurate in characterizing the presence of suspicious nodules and reasonably in guiding cognitive biopsy. however, the use of both targeted biopsy through cognitive guidance and systematic biopsy increases the diagnostic accuracy for pca. although there is no recommendation in the current literature for one guiding technique over 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of prostate cancer. urologic oncology: seminars and original investigations. 2020; 38:734.e19-734.e25. 35. lim ly, tan gh, zainuddin zm, et al. prospective evaluation of using multiparametric magnetic resonance imaging in cognitive fusion prostate biopsy compared to the standard systematic 12-core biopsy in the detection of prostate cancer. urol ann. 2020; 12:276-282. 36. majchrzak n, cieslinski p, milecki t, et al. analysis of the usefulness of magnetic resonance imaging and clinical parameters in the detection of prostate cancer in the first systematic biopsy combined with targeted cognitive biopsy. cent european j urol. 2021; 74:321326. 37. oberlin dt, casalino dd, miller fh, et al. diagnostic value of guided biopsies: fusion and cognitive-registration magnetic resonance imaging versus conventional ultrasound biopsy of the prostate. urology. 2016; 92:75-9. 38. pepe p, pepe l, panella p, pennisi m. can multiparametric ultrasound improve cognitive mri/trus fusion prostate biopsy. arch ital urol androl. 2020; 92.89-92 39. diamand r, oderda m, al hajj obeid w, et al. a multicentric study on accurate grading of prostate cancer with systematic and mri/us fusion targeted biopsies: comparison with final histopathology after radical prostatectomy. world j urol. 2019; 37:2109-2117. 40. ploussard g, borgmann h, briganti a, et al.; eau-yau prostate cancer working group. positive pre-biopsy mri: are systematic biopsies still useful in addition to targeted biopsies? world j urol. 2019; 37:243-251. 41. martins m, regusci s, rohner s, et al. the diagnostic accuracy of archivio italiano di urologia e andrologia 2024; 96(4):13194 a.s. araújo, j. serra, s. anacleto, et al. 10 multiparametric mri for detection and localization of prostate cancer depends on the affected region. bjui compass. 2021; 2:178-187. 42. de rooij m, hamoen eh, witjes ja, et al. accuracy of magnetic resonance imaging for local staging of prostate cancer: a diagnostic meta-analysis. eur urol. 2016; 70:233-45. 43. dinneen e, allen c, strange t, et al. negative mpmri rules out extra-prostatic extension in prostate cancer before robot-assisted radical prostatectomy. diagnostics (basel). 2022; 12.1057 44. park kj, kim mh, kim jk. extraprostatic tumor extension: comparison of preoperative multiparametric mri criteria and histopathologic correlation after radical prostatectomy. radiology. 2020; 296:87-95. 45. xu g, xiang l, wu j, et al. the accuracy of prostate lesion localization in cognitive fusion. clinical hemorheology and microcirculation. 2020; 74:223-229. 46. rais-bahrami s, siddiqui mm, turkbey b, et al. utility of multiparametric magnetic resonance imaging suspicion levels for detecting prostate cancer. j urol. 2013; 190:1721-1727. 47. bratan f, niaf e, melodelima c, et al. influence of imaging and histological factors on prostate cancer detection and localisation on multiparametric mri: a prospective study. eur radiol. 2013; 23:2019-29. 48. girouin n, mège-lechevallier f, tonina senes a, et al. prostate dynamic contrast-enhanced mri with simple visual diagnostic criteria: is it reasonable? eur radiol. 2007; 17:1498-509. correspondence ana sofia araújo (corresponding author) ana.sofia.araujo@hb.min-saude.pt sara anacleto sara.anacleto@hb.min-saude.pt ricardo rodrigues ricardo.matos.rodrigues@hb.min-saude.pt catarina tinoco catarina.sousa.tinoco@hb.min-saude.pt andreia cardoso andreia.filipa.cardoso@hb.min-saude.pt mariana capinha mariana.dias.capinha@hb.min-saude.pt vera marques vera.p.marques@hb.min-saude.pt paulo mota paulo.mota@hb.min-saude.pt hospital de braga, dept. of urology, braga, portugal joão serra serrajoao.ricardo@gmail.com school of medicine, university of minho, dept. of urology, braga, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso 155archivio italiano di urologia e andrologia 2022; 94, 2 original paper no conflict of interest declared. after transrectal prostate biopsy, it remains higher than after transperineal approach because of bacterial resistance to antibiotics (5). in fact, in case of transrectal biopsy the risk of complications requiring hospital admission ranges from 0.1% to 2.5% (6) being in most of the cases secondary to urinary tract infection (uti), fever or sepsis. in addition, transperineal prostate biopsy improves the detection of clinically significant prostate cancer (cspca) located in the anterior zone of the gland especially in men submitted to repeated biopsies or enrolled in active surveillance (as) protocols (7, 8). in this study, the clinical complications following prostate biopsy in 8.500 patients submitted to transperineal approach in more than twenty years of clinical practice have been retrospectively evaluated. materials and methods from january 2000 to january 2022, 8.500 men aged between 38 and 96 years (median age: 62.8 years) underwent prostate biopsy under the suspicion of pca. the indications for biopsy were: abnormal digital rectal examination, psa >10 ng/ml or psa values between 4.1-10 ng/ml, and 2.6-4 ng/ml with free/total psa < 25% and < 20%, respectively; moreover, 175 men enrolled in as protocol underwent scheduled repeated biopsies. since 2011, 1.850 patients were submitted to mpmri for initial (1.100 cases) and repeated (750 cases) procedure; 5.550 (65.3%) vs. 2.950 (34.7%) men underwent initial vs. repeated prostate biopsy. after institutional review board and ethical committee approval were granted the informed consent was obtained from all individual partecipants included in the study. in the presence of a prostate imaging-reporting and data system-version 2 (pi-rads) score ≥ 3, a transperineal mpmri/trus fusion targeted biopsy (tpbx: 4 cores for each suspicious area) was added to systematic prostate biopsy (8, 9). all mpmri examinations were performed using a 1.5 or 3.0 tesla scanner (achieva 3t; philips healthcare best, the netherlands) equipped with: a 16-channel phased-array coil placed around the pelvic area with the patient in the supine position, a multi-planar turbo spin-echo t2-weighted, an axial diffusion weighted imaging and an axial dynamic contrast enhanced mri. all the data were collected using the start criteria (10). in the case of initial or repeated procedure an extended (epbx: 12-18 cores) vs. a saturation transperineal biopsy (spbx: 24 cores) was done (9). from 2002 to 2009 introduction: to evaluate clinical complications following transperineal prostate biopsy in 8.500 patients. materials and methods: from january 2000 to january 2022, 8,500 men (median age: 62.8 years) underwent transperineal prostate biopsy; since 2011, 1,850 patients were submitted to mpmri and in the presence of a pi-rads score ≥ 3, a transperineal targeted biopsy was added to systematic prostate biopsy (4 cores). all patients underwent antibiotic prophylaxis (20002011: levoxacin 500 tablet; 2012-2022: 2 grams intravenous of cefazolin). among 8.500 men 1.350 (15.8%) vs. 4.520 (53.3%) vs. 2.630 (30.9%) underwent 12 vs. 18 vs. > 24 needle cores, respectively. the prostate biopsy-related complications were evaluated within 20 days from prostate biopsy; the number of patients who needed hospital admission or emergency department visit (edv) was recorded. results: prostate cancer was found in 3.150/8.500 (37.1%) patients; overall, hospital admission and edv were equal to 1.5% and 8.9% and the side effects were directly correlated with the number of needle cores resulting equal to 17.4% (12 cores), 38.7% (18 cores) and 55.3% (> 24 cores) (p = 0.001). hospital admission and edv in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% and 7.4% vs. 1.4% and 8.7% vs. 1.7% and 10.6% (p > 0.05), respectively. conclusions: clinical complications following transperineal prostate biopsy involved 35.9% of the patients but only 1.5% of them required hospital admission; urinary tract infection with fever was the most frequent cause of hospital recovery (33.4% of the cases), but none of the patients developed sepsis. key words: prostate cancer; transperineal prostate biopsy; prostate biopsy; complications; sepsis. submitted 25 april 2022; accepted 30 april 2022 introduction prostate cancer (pca) is the most frequent tumor diagnosed in men with about 2 million procedures carried out in the united states and europe every year (1). although it has an overlapping detection rate for pca with respect to transrectal procedure, transperineal biopsy is recommended as the first-choice technique for diagnosis of prostate cancer owing to lower rates of post-procedural sepsis in comparison with transrectal approach (2-4). although the use of targeted antibiotic therapy obtained by rectal swab culture and rectal preparation with povidone-iodine decrease the risk of infections and/or sepsis morbidity following transperineal prostate biopsy: our experience in 8.500 men pietro pepe, michele pennisi urology unit cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2022.2.155 summary archivio italiano di urologia e andrologia 2022; 94, 2 p. pepe, m. pennisi 156 prostate biopsy was performed under local anesthesia (2% lidocaine 10-20 ml) and from 2010 to 2022 under sedation; spbx was always performed under sedation in surgery room. the patients underwent antibiotic prophylaxis assuming one tablet of levofloxacin (500 mg daily) for 3 days beginning the day before biopsy from 2000 to 2011; from 2012 to 2022 the patients underwent a single intravenous dose of 2 grams of cefazolin. in men with previous endocarditis or with artificial cardiac valve a single dose of penicillin plus aminoglycoside was administered before biopsy. anticoagulant drugs (i.e., dicumarol) were stopped 5-7 days before biopsy and replaced with a daily dose of low molecular weight of heparin. prostate biopsy was performed transperineally (8, 10) using a freehand technique, a tru-cut 18 gauge needle (bard; covington, ga) and a ge logiq 500 pro and p6 ecograph (general electric; milwaukee, wi) supplied with a biplanar transrectal probe (5-6.5 mhz); the tpbx was performed transperineally using using a hitachi 70 arietta ecograph, (chiba, japan) supplied with a bi-planar transrectal probe (8). the prostate biopsy scheme at 12, 18 or > 24 cores included 3 vs. 6 vs. 12 cores in the posterior zone of each lobe (apex, middle zone and base of the gland) beginning parasagittally to reach the outer edges of the gland (lateral margins); in case of repeated procedure the biopsy included 2-4 cores in the transition and anterior zone (9, 11, 12). among 8.500 men 1.350 (15.8%) vs. 4.520 (53.3%) vs. 2.630 (30.9%) were submitted to 12 vs. 18 vs. 24 or more needle cores, respectively. in detail, 1.150/1.850 (62.1%) men submitted to mpmri underwent tpbx combined with systematic biopsy for pi-rads score 3 lesions (625 cases: 54.4%) vs. 4 (370 cases: 32.1%) vs. 5 (155 cases: 13.5%); over time, the use of mpmri in clinical practice allowed to reduce the number of needle biopsy cores performed during prostate biopsy. clinical (comorbidities, drug therapy, risk factors) and laboratory data were collected from each patient’s medical record; overall, 6.595/8.500 (77.5%) patients utilized alpha blockers. overall prostate biopsy-related complications were evaluated within 20 days from prostate biopsy when the histological report was given; moreover, number of patients who needed hospital admission or emergency department visit (edv) was recorded. the patients without clinical complications following prostate biopsy did not undergo additional clinical evaluation. definition of urinary tract infection (uti) was given by presence of fever, positive urine culture and/or leucocytosis without bacteremia; moreover, in case of fever greater than 38.5°c the presence of bacteremia was investigated by blood culture. all patients were prospectively evaluated with the 5-item version of the international index of erectile function (iief-5) at time zero and at 1, 3 and 6 months from prostate biopsy (13). the clavien-dindo grading system for the classification of biopsy complications was used (14). for statistical analysis the t student’s test was used; a p value < 0.05 was considered statistically significant. results overall, pca was found in 3.150/8.500 (37.1%) patients, high grade prostatic intraepithelial neoplasia (hgpin) in 209 (2.4%), atypical small acinar proliferation (asap) in 102 (1.3%) and normal parenchyma in 5.039 (59.2%); 2.135 (67.8%) and 2.310 (73.3%) out 3,150 with pca had a psa < 10 ng/ml and a t1c clinical stage, respectively. detection rate for cspca (15) increased with the use of mpmri (pi-rads ≥ 3) reducing the risk of overdiagnosis in comparison with systematic prostate biopsy (17 vs. 28%). overall, clinical parameters and histological findings in presence of pca diagnosed at initial or repeat biopsy are listed in table 1. overall, hospital admission and edv were equal to 1.5% (129/8.500) and 8.9% (755/8.500); moreover, clinical complications of men submitted to 12 vs. 18 vs. > 24 cores are listed in table 2. overall, side effects following prostate biopsy occurred in 40.5% (3,441/8,500) of the patients (5.8% of them had two or more symptoms); in detail, overall complications were directly correlated with number of needle cores resulting equal to 17.4% (235 cases), 38.7% (1.751 cases) and 55.3% (1.455 cases) in patients who underwent 12 vs. 18 vs. > 24 cores (p = 0.001), respectively. hospital admission and edv in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% (21/1.350) and 7.4% (100/1.350) vs. 1.4% (63/4.520) and 8.7% (395/4.520) vs. 1.7% (45/2.630) and 10.6% (280/2.630) (p > 0.05), respectively. overall, the most frequent biopsy complication that needed hospital admission vs. edv was uti (73 cases: 0.8%) vs. acute urinary retention (435 cases: 5.1%), respectively (table 2). uti with fever greater than 38.5° c was the most frequent cause (43 men: 33.3%) of hospital recovery. in all the 43 men admitted to hospital for uti the blood culture was negative and a double antibiotics therapy was administered (penicillin plus aminoglycoside for 5 days) acquiring a complete remission of table 1. clinical characteristics and results in 8.500 patients (pts) who underwent 12, 18 and ≥ 24 needle cores as an initial or repeat transperineal prostate biopsy. scheme of biopsy 12 cores 18 cores ≥ 24 cores pts = 1.350 pts = 4.520 pts = 2.630 number of biopsies 1st 2nd 3d 1st 2nd 3d 1st 2nd 3d number of patients 1.350 3510 870 140 195 1978 457 median number of cores (range) 12 (10-15) 18 (16-21) 28 (24-38) median age (years; range) 68.2 (40-85) 61.8 (49-78) 63.2 (48-76) number of pts number of pts number of pts psa ≤ 2.5 ng/ml (f/tpsa ≤ 15%) 71 84 5 psa 2.6-4 ng/ml (f/tpsa ≤ 20%) 195 185 55 35 90 psa 4.1-10 ng/ml (f/tpsa ≤ 25%) 599 2479 97 65 1030 232 psa > 10 ng/ml 485 1462 158 72 841 260 abnormal dre 190 150 58 18 44 16 median prostate weight (grams) 47 (24-94) 58 (23-128) 63 (20-209) results % % % prostate cancer (pca) 39.8 47.5 13.7 48.6 28 9.3 gleason score (median) 7.3 7.2 6.4 6.75 6.3 6 clinically insignificant pca 2 8.7 34.4 18.3 36.8 38 pca ≤ 10 ng/ml 54. 68.2 77.8 77.8 63 66.7 clinical stage t1c 53.4 74.3 81.8 76 93 92 dre: digital rectal examination; f/t: percentage of free/total psa; clinically insignificant pca: ≤ 2 positive cores with percentage of cancer ≤ 50% and gleason score 6 (grade group 1) . 157archivio italiano di urologia e andrologia 2022; 94, 2 transperineal prostate biopsy complications symptoms and fever within 3 days; moreover, 3/43 (7%) patients had a positive urine culture for gram negative bacteria after the double antibiotics administration. only two patients with gross hematuria needed blood transfusion and all men with urinary retention had catheters removed within 7 days. among each complication, only hemospermia significantly correlated with the number of needle cores resulting equal to 36.5% (960/2.630) vs. 11.8% (160/1.350) (p = 0.001) in patients submitted to more than 24 vs 12 cores, respectively; moreover, urinary retention was most frequent in patients with a higher prostate weight who underwent spbx (table 1). biopsy complication rate that needed hospital admission vs edv was superimposable in presence (1.2 vs. 8.9%) and absence of pca (1.3% vs. 9.3%). hospital recovery occurred a median of 2 days (range: 1-3) after prostate biopsy for a median duration of 3 days (range: 2-6), moreover, edv was performed within 3 days (range: 1-7) from the procedure. complication rate was superimposable in patients submitted to prostate biopsy under local anesthesia office performed (2.105 cases) vs. sedation in surgery room (6.495 cases); from 2000 to 2022 uti resulted superimposable and equal to 0.6% (2002) vs 0.9% (2022), respectively, moreover, nobody had sepsis or needed recovery in intensive care unit. finally, among the patients who needed hospital admission 69 (53.4%) and 60 (46.8%) were assigned a grade ii and i of the clavien-dindo complications scale (14), respectively; moreover, all patients submitted to edv had a grade i. discussion the latest eau guidelines strongly recommend to perform transperineal approach to reduce the risk of sepsis (1) suggesting a single dose of antibiotic (i.e., cefazolin) (2) for the antibacterial prophylaxis. infections are well-established adverse events after transrectal prostate biopsy; asymptomatic bacteriuria, febrile uti, acute bacterial prostatitis, orchitis, epididymitis, and urinary sepsis represent the broad spectrum of possible infectious complications. medical comorbidities (particularly diabetes or metabolic syndrome) and older age are independent predictors increasing the risk of infections and sepsis; a previous history of prostatitis, antibiotics within 6 months before prostate biopsy, and non-adherence to antibiotic prophylaxis or resistence to antibiotics (i.e., quinolone) represent other risk factors (16, 17). whether a repeated biopsy protocol, including those done in as, could increase the risk of infection is unclear; loeb et al. (18), reported a cumulative increase in the risk of having a complication where each additional biopsy was associated with a 1.7-fold increase in overall hospitalizations, and a 1.7-fold increase in serious infectious complications. clinical complications and hospital admissions following transrectal prostate biopsy have increased during the last years primarily due to an increasing rate of infections (9); carignan et al. (20) in 5.798 submitted to transrectal prostate biopsy demonstrated an increased incidence of infections from 0.52% in 2002-09 to 2.15% in 2010-11 secondary in the 52% of the cases to pathogens (escherichia coli in the 75% of the cases) resistant to ciprofloxacin especially in patients with diabetes, chronic obstructive pulmonary disease and in those hospitalized during the precedent month. loeb et al. (21) in a random sample of medicare participants in surveillance, epidemiology and end results (seer) regions from 1991 to 2007 found that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization secondary to infections within 30 days compared to the control population; men who were hospitalized for infectious complications had a 12-fold higher 30-day mortality rate in comparison to those who were not. the use of targeted antibiotic therapy obtained from rectal swab culture combined with rectal preparation using povidone-iodine decrease the risk of infections and/or sepsis in men submitted to transrectal biopsy (22); recently, dai et al. (23) reported clinically fewer infections (1.9% vs. 2.9%) in men managed with targeted antibiotic prophylaxis, although the difference was not statistically significant (p = 0.53). transperineal prostate biopsy in comparison with transrectal approach reduce number of infections and reset sepsis rate (0-0.2%) (24), given the avoidance of bacterial contamination which is common during transrectal access (25). miller et al. (26) compared side effects following transrectal and transperineal biopsy showing a superimposable incidence of clinical complications (19.8 vs. 22.2%) but a sepsis rate equal to 1.2 vs. 0%, respectively. in a recent meta-analysis including 90 randomized controlled trials (16.941 participants) pradere et al. (27) showed that transperineal biopsy was associated with significantly reduced infectious complications as compared to transrectal biopsy; on the contrary, no difference in infectious complications/hospitalization was found for number of biopsy cores, periprostatic nerve block, number of injections for periprostatic nerve block, needle guide type, needle type and rectal preparation with enema. in addition, in table 2. complications following transperineal prostate biopsy in 8.500 patients (pts) submitted to 12 vs. 18 vs. ≥ 24 needle cores. complications 12 cores * vs 18 cores *° vs ≥ 24 cores ° 1.350 pts 4.520 pts 2.630 pts hematuria 101 (7.4%) 352 (8.4%) 235 (8.9%) urethrorrhagia 28 (2.1%) 75 (1.6%) 60 (2.2%) hemospermia 105 (10.7%) 915 (20.2%) 785 (29.8%) acute urinary retention 48 (3.5%) 285 (6.3%) 270 (10.2%) prostatitis 7 (0.5%) 29 (0.6%) 21 (0.8%) sepsis orchiepidymitis 6 (0.4%) 18 (0.4%) 16 (0.6%) urinary tract infection 16 (1.2%) 30 (0.6%) 16 (0.6%) perineal hematoma 5 (0.3%) 20 (0.4%) 18 (0.7%) vagal syndrome 9 (0.9%) erectile dysfunction** (6 months from biopsy) 3 (0.2%) 15 (0.3%) 10 (0.3%) fever 7 12 24 systemic adverse events*** 1 (0.07%) hospital admission (within 20 days) 21 (1.5%) 63 (1.4%) 45 (1.7%) emergency department visit (within 20 days) 100 (7.7%) 395 (8.7%) 280 (10.6%) * prostate biopsy performed under local anesthesia (*) or sedation (°); **transient erectile dysfunction resolved within 3-6 months from biopsy; ***acute cardiac ischemia. archivio italiano di urologia e andrologia 2022; 94, 2 p. pepe, m. pennisi 158 a systematic review and meta-analysis on 37.805 men submitted to transperineal biopsy spyridon et al. (28) showed that incidence of sepsis was similar in the patients who received antibiotics or not (0.05 vs 0.08%; p = 0.2) underlining the safety of the procedure. in our series, to our knowledge the first that evaluated transperineal prostate biopsy complications in a so high number of patients of a single center (8.500 cases), overall hospital admission and edv were equal to 1.5% (129/8.500) and 8.9% (755/8.500). overall, side effects following prostate biopsy occurred in 40.5% (3.441/8.500) of the patients (5.8% of them had two or more symptoms); in detail, side effects were directly correlated with number of needle cores resulting equal to 17.4% (235 cases), 38.7% (1.751 cases) and 55.3% (1,455 cases) in patients who underwent 12 vs. 18 vs. > 24 cores (p = 0.001), respectively. hospital admission and edv in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% (21/1.350) and 7.4% (100/1.350) vs. 1.4% (63/4.520) and 8.7% (395/4.520) vs. 1.7% (45/2.630) and 10.6% (280/2.630) (p > 0.05), respectively. overall, the most frequent biopsy complication that needed hospital admission vs. edv was uti (73 cases: 0.8%) vs. acute urinary retention (435 cases: 5.1%), respectively; 43/73 (59%) men with uti had fever greater than 38.5°c, but nobody developed sepsis or needed recovery in resuscitation department. erectile dysfunction following prostate biopsy was restored within 3-6 months irrespective of the number of needles cores obtained. some limitations and considerations of the present study deserve mention. first, we don’t know if a greater percentage of patients developed complications after our evaluation performed 20 days from prostate biopsy. second, some cases of uti could be missed because no additional clinical evaluation were required in absence of urinary symptoms. third, the reduction of needle cores following the introduction in clinical practice of mpmri could reduce prostate biopsy complications. finally, our data refer in the majority of the cases to procedures performed under sedation, but the same biopsy protocol could be office-performed under local anesthesia (29, 30). conclusions clinical complications following transperineal prostate biopsy involved 35.9% (3.050/8.500) of the patients but only 1.5% (129/8.500) of them required hospital admission; uti with fever was the most frequent cause of hospital recovery (33.4% of the cases), but none of the patients developed sepsis. finally, number of needle cores (12 vs. 18. vs. > 24) significantly correlated with increased onset of side effects, but did not significantly increased hospital admission or edv. references 1. lenfant l, barret e, rouprêt m, et al. transperineal prostate biopsy is the new black: what are the next targets? cancerology committee of association française d'urologie (ccafu). eur urol. 2022; s0302-2838(22)01602-5. 2. mottet n, cornford p, van den bergh rcn. guidelines associates. eau guideline. 2022. prostate cancer. 3. mehmood s, alothman ki, alwehaibi a, alhashim sm. diagnostic efficacy and safety of transperineal prostate targeted and systematic biopsy: the preliminary experience of first 100 cases. arch ital urol androl. 2021; 93:127-131. 4. derin o, fonseca l, sanchez-salas r, roberts mj. infectious complications of prostate biopsy: winning battles but not war. world j urol. 2020; 38:2743-2753. 5. he j, guo z, huang y, et al. comparisons of efficacy and complications between transrectal and transperineal prostate biopsy with or without antibiotic prophylaxis urol oncol 2022; s10781439(22)00004-7. 6. pinkhasov gi, lin yk, palmerola r, et al. complications following prostate needle biopsy requiring or emergency department visitsexperience from 1000 consecutive cases. bju int. 2012; 110:369374. 7. meyer ar, mamawala m, winoker js, et al. transperineal prostate biopsy improves the detection of clinically significant prostate cancer among men on active surveillance j urol. 2021; 205:1069-1074. 8. pepe p, aragona f. prostate biopsy: results and advantages of the transperineal approach--twenty-year experience of a single center. world j urol. 2014; 32:373-377. 9. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol. 2018; 200:774-778. 10. pepe p, aragona f. saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. urology. 2007; 70:1131-1135. 11. moore cm, kasivisvanathan v, eggener s, et al. standards of reporting for mri-targeted biopsy studies (start) of the prostate: recommendations from an international working group. eur urol. 2013; 64:544-552. 12. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the ra of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology. 2020; 137:133-137. 13. pepe p, m pennisi. erectile dysfunction in 1050 men following extended (18 cores) vs saturation (28 cores) vs saturation plus mritargeted prostate biopsy (32 cores). int j impot res. 2016; 28:1-3. 14. valerio m, anele c, bott sr, et al. the prevalence of clinically significant prostate cancer according to commonly used histological thresholds in men undergoing template prostate mapping bopsies. j urol. 2016; 195:1403-1408. 15. dindo d, demartines n and clavien pa. classification of surgical complications. a new proposal with evaluation in a cohort of 6336 patients and results of survey. ann surg. 2004; 2:205-213. 16. tan wp, papagiannopoulos d, latchamsetty kc, et al. predictors of fluoroquinolone-resistant bacteria in the rectal vault of men undergoing prostate biopsy. prostate cancer prostatic dis. 2019; 22:350. 17. papagiannopoulos d, abern m, wilson n, et al. predictors of infectious complications after targeted prophylaxis for prostate needle biopsy. j urol. 2018; 199:155-160. 18. loeb s, vellekoop a, ahmed hu, et al. systematic review of complications of prostate biopsy. eur urol. 2013; 64:876-892. 19. carignan a, roussy jf, lapointe v, et al. increasing risk of infectious complications after transrectal ultrasound-guided biopsies: time to reassess antimicrobial prophylaxis? eur urol. 2012; 62:453-459. 20. nam rk, saskin r, lee y, et al. increasing hospital admission 159archivio italiano di urologia e andrologia 2022; 94, 2 transperineal prostate biopsy complications rates for urological complications after transrectal ultrasound guided prostate biopsy. j urol. 2010; 183:963-969. 21. loeb s, van den heuvel s, zhu x, et al. infectious complications and hospital admissions after prostate biopsy in a european randomized trial. eur urol. 2012; 61:1110-1114. 22. pilatz a, veeratterapillay r, köves b, et al. update on strategies to reduce infectious complications after prostate biopsy. eur urol focus. 2019; 5:20-28. 23. dai j, leone a, mermel l, hwang k, et al. rectal swab culturedirected antimicrobial prophylaxis for prostate biopsy and risk of postprocedure infection: a cohort study. urology. 2015; 85:8-14. 24. pepe p, aragona f. morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. urology. 2013; 81:1142-1146. 25. berry b, parry mg, sujenthiran a, et al. comparison of complications after transrectal and transperineal prostate biopsy: a national population-based study. bju int. 2020; 126:97-103. 26. miller j, perumalla c, heap g. complications of transrectal versus transperineal prostate biopsy. anz j surg. 2005; 75:48-50. 27. pradere b, veeratterapillay r, dimitropoulos k, et al. nonantibiotic strategies for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. j urol. 2021; 205:653-663. 28. basourakos sp, alshak mn, lewicki pj, et al. role of prophylactic antibiotics in transperineal prostate biopsy: a systematic review and meta-analysis. eur urol open sci. 2022; 37:53-63. 29. stefanova v, buckley r, flax s, et al. transperineal prostate biopsies using local anesthesia: experience with 1,287 patients. prostate cancer detection rate, complications and patient tolerability. j urol. 2019; 201:1121-1126. 30. cricco-lizza e, wilcox vanden berg rn, laviana a, et al. comparative effectiveness and tolerability of transperineal mri-targeted prostate biopsy under local versus sedation. urology. 2021; 155:33-38. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com michele pennisi, md michepennisi2@virgilio.it urology unit cannizzaro hospital, via messina 829, catania (italy) stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14203 1 review many patients with various etiologies as trauma, infection, ischemia, inflammation, instrumentation, or other unknown causes (1). studies reported that it occurs in 200 in 100,000 people, with an increasing incidence rate in the last 50 years (2). the treatments recommended for patients with urethral strictures include urethrotomy, dilatation, and urethroplasty (3). internal urethrotomy is used for urethral stricture with a length of less than 1.5 cm. however, the efficacy of internal urethrotomy is still being questioned because of its high stricture recurrence rate (4). a case-control study regarding urethral stricture in indonesia by gede et al. in 2017 stated that the urethral stricture recurrence after internal urethrotomy was as high as 92.5% (5). many treatment alternatives after internal urethrotomy have been widely studied to reduce the urethral stricture recurrence rate. corticosteroid is one of the most commonly used drugs studied. it has been widely used in many centers to reduce scar formation. it is able to decrease collagen, glycosaminoglycan synthesis, and the expression of inflammatory mediators (6). among corticosteroids, triamcinolone is regularly reported. however, results of this approach are conflicting. many studies investigating the role of corticosteroids have been published (7-10). therefore, we aimed to assess the efficacy of triamcinolone following internal urethrotomy in preventing urethral stricture recurrence. materials and methods this study was a systematic review and meta-analysis performed and reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (prisma) guideline. the protocol is registered in the prospero database with the registration number crd42020202254. eligibility criteria we used the following inclusion criteria to determine the eligibility of studies: introduction: urethral stricture, characterized by urethral narrowing due to fibrosis and scar tissue, is a common urological condition. it occurs in about 200 per 100,000 people, with increasing incidence over the past 50 years. internal urethrotomy is commonly performed for short strictures, but its high recurrence rate has led to the exploration of adjunctive treatments like adjunct of triamcinolone application. this study aimed to analyze the effect of triamcinolone as adjunctive therapy for internal urethrotomy on reducing urethral stricture recurrence in urethral stricture patients. methods: a systematic search was conducted in pubmed, sciencedirect, and google scholar. this review was conducted according to the prisma guideline, and the protocol has been registered in the prospero database (crd42020202254). results: six rcts, including 373 urethral stricture patients, were eligible for this study. pooled results of the included studies showed a significant difference between the triamcinolone and control groups, indicating a lower recurrence rate in the triamcinolone group (or = 0.49 95% ci 0.31-0.77, p = 0.002). a significant difference was seen in the ointment with clean intermittent catheterization (cic) intervention subgroup (or = 0.47 ci 95% 0.26-0.82, p = 0.009), but not in the submucosal injection subgroup (p > 0.05). the treatment and control groups had similar maximum urinary flow rate (qmax) at six and twelve months (p > 0.05). conclusions: triamcinolone ointment with cic reduced urethral stricture recurrence following internal urethrotomy, whereas submucosal injection did not. both treatments do not increase the maximum urinary flow rate. key words: urethral stricture; triamcinolone; internal urethrotomy; systematic review. submitted 29 july 2025; acceptd 27 august 2025 introduction urethral stricture is one of the most commonly found urological problems, in which there is a narrowing of the urethra caused by fibrosis and scar tissue. it can occur in triamcinolone application following internal urethrotomy for reducing urethral stricture recurrence rate: a systematic review and meta-analysis of randomized controlled trials dimas panca andhika 1, 2, 3, tarmono djojodimedjo 1, 4, furqan hidayatullah 1, 4, zakaria aulia rahman 1, 4, ilham akbar rahman 1, 4, prima ardiansah surya 1, 4, mohammad ayodhia soebadi 1, 4 1 department of urology, faculty of medicine, airlangga university, surabaya, indonesia; 2 department of anatomy, histology, and pharmacology, faculty of medicine, airlangga university, surabaya, indonesia; 3 universitas airlangga hospital, surabaya, indonesia; 4 dr. soetomo general-academic hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2025.14203 summary archivio italiano di urologia e andrologia 2025; 97(3):14203 d. panca andhika, t. djojodimedjo, f. hidayatullah, et al. 2 (1) randomized controlled trial (rct) study design, (2) studies comparing triamcinolone with internal urethrotomy alone, (3) men with urethral stricture treated with internal urethrotomy. studies with the following criteria were excluded: (1) nonenglish articles, (2) animal studies, (3) unpublished articles, and (4) abstract-only articles. search strategy, study selection and data extraction we performed a systematic search in the medline, pubmed, sciencedirect and google scholar databases. we used the keyword “triamcinolone and urethra or stricture”. we used mendeley to combine the results from the databases and evaluate possible duplicates. the primary screening of the studies was performed by reading the titles and abstracts. the studies that fit the inclusion criteria based on the title and abstract were evaluated in their full-text forms during the secondary review. both the primary and secondary screenings in this systematic review were performed by three investigators. any disputes between the investigators would have been resolved in a discussion. in the screening process of this review, there weren’t any inter-rater disagreements. outcome measurement and data analysis the primary outcome was urethral stricture recurrence rate, whereas the secondary outcomes were maximum urinary flow rates examined in the 6th and 12th month after urethrotomy. the analyzed primary outcome was dichotomous and presented in an odds ratio (or) with a confidence interval (ci) of 95%. the secondary outcomes were continuous and analyzed using a mean difference (md). the heterogeneity between studies was calculated using i2. it was assumed that heterogeneity between studies was statistically high if the i2 > 50%, then the random effects model analysis would be used. otherwise, a fixed effecst model would be used. for statistical analysis revman version 5.4 (the cochrane collaboration, 2020) for windows was used, presenting results in the form of forest plots and narrative description. risk of bias assessment risk of bias was assessed using cochrane risk of bias tools for randomized trials 2 (9). two reviewers conducted an independent bias assessment, with the results of the risk of bias being low risk, some concerns, and high risk. results in the initial search, as shown in figure 1, 458 studies were obtained from the pubmed, science-direct, and google scholar databases, and three studies were obtained from the references of previous meta-analysis. a total of 26 studies were extracted from the primary screen. the full paper version of the articles was evaluated in the secondary screening to determine which studies fit the inclufigure 1. prisma flowchart of the study. archivio italiano di urologia e andrologia 2025; 97(3):14203 3 triamcinolone following internal urethrotomy sion and exclusion criteria for this review. there were six articles that could be analyzed qualitatively and quantitatively in this study. all studies were presented in the baseline characteristics table in table 1. a total of 373 patients were included in this review. there were six rct studies that met the inclusion criteria for this study. overall, each study limited the length of the stricture to below 2 or 1.5 cm. four studies evaluated the application of triamcinolone ointment with clean intermittent catheterization (cic), whereas two studies administered submucosal triamcinolone injection. the etiologies of the strictures consisted mostly of infections and traumas. the strictures mostly occurred in the bulbar area, with a few studies reporting both bulbar and penile, as well as multiple strictures. most studies excluded patients with a history of urethroplasty, except for hosseini et al. (11). complications were only found in the study by tabassi et al. (12). table 1. baseline characteristics of studies. author (year) group sample age action operator intervention previous location length of stricture complication follow up (mean + sd) urethroplasty (number stricture etiology rate (n) (months) year (n) of strictures) mazdak, (2010) triamcinolone 23 37,1 ± 20,9 20fr dviu single submucosal no previous bulbar (nr) < 1,5 trauma, no 24 (cold knife) operator triamcinolone urehtroplasty inflammatory, complications injection unknown without 22 34 ± 19,9 none triamcinolone regmi (2018) triamcinolone 27 37,2 ± 1,6 21fr dviu single 16 fr cic + no previous bulbar or < 1,5 trauma, no 12 (cold knife) operator triamcinolone urehtroplasty penile or inflammatory, complications ointment 1% both (nr) unknown without 28 36 ± 1,7 16 fr cic triamcinolone tabassi (2011) triamcinolone 34 42,38 dviu nr submucosal no previous bulbar or < 1,5 trauma, infection (1), 24 (cold knife) triamcinolone urehtroplasty penile or catheterization, bleeding (3), injection both (nr) infection, extravasation (2) unknown without 36 42 none infection (2), triamcinolone bleeding (3), extravasation (2) gucuk (2010) triamcinolone 15 33,4 ± 7,6 21fr dviu nr 18fr cic + no previous bulbar (nr) < 1,5 trauma, no 18 (cold knife) triamcinolone urehtroplasty infection, complications ointment 1% instrumentation, unknown without 15 18fr cic riamcinolone hosseini (2008) triamcinolone 30 37,7 ± 17,1 dviu multi 18fr cic + 18 multiple (nr) < 1,5 urethral no complications 12 (cold knife) operators triamcinolone distraction ointment 1% disease, straddle injury, urethral catheterization without 34 34,5 ± 13,3 18fr cic 17 triamcinolone ergun (2015) triamcinolone 30 60,7 dviu single 14fr until 20fr cic no previous bulbo< 2 iatrogenic no 24 (cold knife) operator + triamcinolone urehtroplasty membranous (endoscopic complications ointment (nr) urologic surgery, urethral catheterization), trauma, idiopathic contratubex 30 57,8 14fr until 20fr cic + contratubex ointment without 30 61,2 14fr until 20fr cic triamcinolone without 19 47 ± 8,8 18fr cic triamcinolone *dviu: direct vision internal urethrotomy; cic: clean intermittent catheterisation; sd: standard deviation; fr: french; nr: not reported. archivio italiano di urologia e andrologia 2025; 97(3):14203 d. panca andhika, t. djojodimedjo, f. hidayatullah, et al. 4 all studies included in the qualitative and quantitative analysis in this review were randomized controlled trial (rct) studies; thus the cochrane risk of bias tools for randomized trials 2 was used (13), as shown in figure 2. in this study, four studies had a low risk of bias. the studies conducted by mazdak et al. (14) and tabassi et al. (12) were at risk for randomization bias since the studies did not clearly explain the randomization process and whether the allocation process was blinded. urethral stricture recurrence rate after triamcinolone application (ointment lubrication and injection) all six studies evaluated the application of triamcinolone after urethrotomy, as shown in figure 3. the data of the studies were considered homogenous (i2 = 0%, p = 0.45). the fixed model analysis in the forest plot showed a lower urethral stricture incidence of the triamcinolone group (or = 0.49 95% ci 0.31-0.77, p = 0.002). further subgroup analyses were performed based on the methods of application, injection, and ointment. urethral stricture recurrence rate after triamcinolone ointment lubrication there were four studies evaluating the application of triamcinolone ointment lubrication in figure 3. the combined data obtained in each study was homogeneous (i2 = 0%, p = 0.45). the fixed effects model analysis in figure 3 showed that there is a significant difference in urethral stricture incidence between the treatment and control groups (or = 0.47 ci 95% 0.26-0.82, p = 0.009). figure 2. risk of bias assessment using cochrane rob tool 2. figure 3. urethral stricture recurrence rate after triamcinolone application. archivio italiano di urologia e andrologia 2025; 97(3):14203 5 triamcinolone following internal urethrotomy urethral stricture recurrence rate after submucosal triamcinolone injection there were two studies evaluating submucosal triamcinolone injection. the pooled odds ratio analysis in the subgroup of figure 3 showed that the combined data obtained from each study were homogeneous (i2 = 33%, p = 0.22). the analysis was carried out using a fixed effect models, showing an insignificant difference (or = 0.53 ci 95% 0.25-1.13, p = 0.10). urethral recurrence rate and follow-up duration figure 4 shows the visualization of the recurrence rate probability of the studies with different durations of follow-up. maximum urinary flow rate (qmax) in 6 months there were two studies reporting the mean maximum urinary flow rate after six months. the data of the studies were homogeneous with the value of (i2 = 0%, p = 0.84). the fixed effect model analysis in figure 5 showed that there was no difference in qmax between groups (md = 0.91 ci 95% -0.82-2.63, p = 0.30). maximum urinary flow rate (qmax) in 12 months there were two studies describing the mean maximum urinary flow rate after 12 months as shown in figure 6. the combined data obtained in each study were homogeneous (i2 = 0%, p = 0.52). the analysis was carried out by a fixed figure 5. maximum urinary flow rate (qmax) at 6 months. figure 6. maximum urinary flow rate (qmax) at 12 months. figure 4. recurrence rate probability of the studies with different durations of follow-up. archivio italiano di urologia e andrologia 2025; 97(3):14203 d. panca andhika, t. djojodimedjo, f. hidayatullah, et al. 6 effects model, showing no difference in qmax between groups (md = 0.77 ci 95%-1.52-3.05, p = 0.51). discussion symptomatic urethral strictures impede voiding function and may significantly impact patient’s quality of life (15). the role of corticosteroids for urethral strictures and stenoses has been studied for decades (16-18). triamcinolone is a long-acting synthetic glucocorticoid with anti-inflammatory and vasoconstricting properties. it is commonly used in many urological disorders as it is inexpensive and well-tolerated (19). many studies have been exploring the possibilities of corticosteroids after internal urethrotomy, as the procedure does not provide an epithelial approximation, but only separates the scar tissues while relying on secondary healing (20). triamcinolone is believed to be able to reduce scar formation by reducing collagen, glycosaminoglycan synthesis, and the expression of inflammatory mediators (21). a previously published meta-analysis evaluated the application of triamcinolone after internal urethrotomy (22). however, the review also evaluated a variety of other corticosteroids. this review, on the other hand, focused only on clinical trials evaluating triamcinolone as an adjunctive treatment for internal urethrotomy. urethral stricture recurrence rate after triamcinolone application (ointment lubrication and injection) the pooled results of all published rcts evaluating the application of triamcinolone as an adjunctive treatment showed a lower probability of urethral stricture recurrence (or = 0.49 95% ci 0.31-0.77, p = 0.002). in early animal studies, the application of a single dose of steroid on a wound site was shown to decrease wound contraction by up to 30% by the 28th day (23). the promising effects of corticosteroid on preventing scar tissues formation were what led to investigations regarding its effect on strictures. in this review, we discovered that there are two routes of administration used, four studies evaluated triamcinolone ointment with cic and two studies administered the steroid through a submucosal injection. dividing the analysis into two subgroups provided interesting results. urethral stricture recurrence rate after triamcinolone ointment lubrication there were four studies evaluating the use of triamcinolone ointment following internal urethrotomy, which indicated the protective effect of topical triamcinolone (or = 0.47 ci 95% 0.26-0.82, p = 0.009). regarding the route of administration, korhonen et al. reported that administering intralesional injections of steroids generated poor results compared to self-dilatation (24). selfdilatation using cic following internal urethrotomy is considered an acceptable procedure to reduce treatment failure and had been recommended in the past to be performed within three to six months following the procedure (25). the studies included in this review showed the addition of triamcinolone to cic significantly decreases the rate of stricture recurrence. urethral stricture recurrence rate after submucosal triamcinolone injection studies evaluating triamcinolone injection in urethral stricture are still limited. only two trials examined submucosal triamcinolone injection and found similar stricture probabilities (or = 0.53 ci 95% 0.25-1.13, p = 0.10). these studies also included patients with multiple urethral strictures in the bulbar and pendular areas (26, 27). these findings are similar to a study by korhonen et al. (24), who reported a higher rate of stricture recurrence in the triamcinolone injection group compared to the control group. tabasssi et al. (28) believed that the insignificant findings in their study were because their subjects were not instructed to use cic apart from given injections. even though they could not demonstrate a decrease in recurrence rate, they claimed that the recurrence of stricture after internal urethrotomy was postponed due to the injection (28). however, the other study included in this meta-analysis by mazdak et al. (14) reported favorable outcomes of triamcinolone injection. a previous study also reported the beneficial effects of circular steroid injections as opposed to applying them directly into the structure (16). the difference in findings between the studies. another evaluation in the future with more studies evaluating triamcinolone injection is warranted. maximum urinary flow rate (qmax) uroflowmetry helps diagnose stricture and monitor its recurrence. if the symptoms and uroflowmetry findings suggested urethral stricture, retrograde urethrography would be performed to make a definitive diagnosis of the stricture as it can reveal the full length of the urethra to the stricture, passing through the urethral sphincter and prostatic urethra (29). there were two studies reporting the mean maximum urinary flow rate in six and twelve months. however, the findings of both follow-up periods were insignificant (p > 0.05). gucuk et al. (30) reported that when the groups were compared with respect to qmax values, the patients undergoing self-dilatation combined with triamcinolone showed improvements, even though the difference with the patients of the control group was not statistically significant. in this paper the flow rate evaluation may suffer from selection bias since patients not treated with triamcinolone had earlier and more frequent recurrences (53% in the control group compared to 20% group) and subjectes where recurrence has occurred were excluded from the evaluation of maximum urinary flow rate. the review has several limitations. three studies evaluated multiple strictures and diverse etiologies, even though they were still within the anterior urethra. furthermore, the studies analyzed have included patients beyond the contemporary indications for direct vision internal urethrotomy, which limit its use to bulbar strictures. the different catheter sizes used by the patients were also a potential bias regarding the actual effects of the ointment combined with the dilatation caused by the clean intermittent catheterization. the study by hosseini et al. also included patients with a history of urethroplasty which could affect the outcome of the urethrotomy al. (11) studies evaluating submucosal injection were only a few archivio italiano di urologia e andrologia 2025; 97(3):14203 7 triamcinolone following internal urethrotomy with contrasting results, indicating a possible biased result. the differences in time to urethral stricture recurrence were also different among studies. as more clinical trials will become available in the future, an updated systematic review which overcome these limitations should be performed. conclusions the administration of submucosal triamcinolone injection did not improve the urethral stricture recurrence rate after internal urethrotomy, whereas the administration of triamcinolone ointment with clean intermittent catheterization could decrease urethral stricture recurrence. however, the administration of both triamcinolone ointment and injection did not improve maximum urinary flow rate. references 1. anger jt, buckley jc, santucci ra, et al. trends in stricture management among male medicare beneficiaries: underuse of urethroplasty? urology. 2011; 77:481-485. 2. hampson la, mcaninch jw, breyer bn. male urethral strictures and their management. nat rev urol. 2014; 11:43-50. 3. mcdougal w, wein aj, kavoussi lr, et al. campbell-walsh urology eleven edition review: urethral stricture disease. 2016. 4. naudé am, heyns cf. what is the place of internal urethrotomy in the treatment of urethral stricture disease? nat clin pract urol. 2005; 2:538-545. 5. sanjaya dgr, rizaldi f, renaldo j. the recurrence of stricture in postoperative patients at dr. soetomo hospital from 2013-2017: a case-control study. journal of global pharma technology 2017:711-716. 6. koc e, arca e, surucu b, kurumlu z. an open, randomized, controlled, comparative study of the combined effect of intralesional triamcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. dermatologic surgery. 2008; 34:1507-1514. 7. gupta s, roy s, pal dk. efficacy of oral steroids after optical internal urethrotomy in reducing recurrence of urethral strictures. turk j urol. 2018; 44:42. 8. ahmed m, hossain sm, islam mt, et al. use of intra-urethral steroid clobetasol cream to prevent the recurrence of urethral stricture after optical urethrotomy: randomized clinical trial. mediscope. 2019; 6:59-63. 9. bhuiyun mhk, al mamun am, belal t, et al. treatment of short segment anterior urethral stricture: optical internal urethrotomy (oiu) alone and oiu with triamcinolone. bangladesh med j. 2019; 48:31-38. 10. abdallah hm, abuelnaga m, rasmy ag. intraurethral steroid injection following visual internal uerthrotomy in the management of anterior urethral strictures. qjm: an international journal of medicine. 2020; 113(suppl 1):hcaa070-002. 11. hosseini j, kaviani a, golshan ar. clean intermittent catheterization with triamcinolone ointment following internal urethrotomy. urol j. 2008; 5:265-268. 12. tabassi kt, yarmohamadi a, mohammadi s. triamcinolone injection following internal urethrotomy for treatment of urethral stricture. urol j. 2011; 8:132. 13. sterne jac, savovic j, page mj, et al. rob 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019; 366:l4898. 14. mazdak h, izadpanahi mh, ghalamkari a, et al. internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. int urol nephrol. 2010; 42:565568. 15. benson cr, li g, brandes sb. long term outcomes of one-stage augmentation anterior urethroplasty: a systematic review and metaanalysis. international braz j urol. 2021; 47:237-250. 16. sharpe jr, finney rp. urethral strictures: treatment with intralesional steroids. j urol. 1976; 116:440-443. 17. uemura s, hutson jm, woodward aa, et al. balanitis xerotica obliterans with urethral stricture after hypospadias repair. pediatr surg int. 2000; 16:144-145. 18. castañón garcía-alix m, carrasco torrens r, muñoz fernández me, et al. treatment with triamcinolone cetonide (trigondepot) for stenosis after surgery of severe hypospadias. actas urol esp. 2000; 24:347-50. spanish. 19. jiang t, zhou x, chen z, et al. clinical efficacy of submucosal injection of triamcinolone acetonide in the treatment of type ii/iii interstitial cystitis/bladder pain syndrome. bmc urol. 2020; 20:1-6. 20. partin aw, wein aj, kavoussi lr, et al. campbell walsh wein urology, e-book. elsevier health sciences; 2020. 21. koc e, arca e, surucu b, kurumlu z. an open, randomized, controlled, comparative study of the combined effect of intralesional trideclarations ethical approval and consent for participate: no ethical review needed for this type of article. availability of data and material: the datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. competing interest: no conflict of interest was declared by the authors. conference presentation: this article was never presented in any conference before. authors' contributions: dpa: led the conceptualization of the systematic review, designed the methodology, performed the data synthesis, and drafted the manuscript, and ensured all revisions were addressed. mas: conducted the literature search, screened studies for inclusion, and contributed to data extraction and analysis. assisted in drafting and critically revising the manuscript.td: performed the data extraction, contributed to the quality assessment of included studies, and participated in manuscript writing and revisions. fh: assisted in the systematic literature search, data analysis, and contributed to manuscript drafting and revisions. zar: supported the data analysis, assisted in reviewing the included studies, and contributed to manuscript revisions. iar: contributed to the literature search, data extraction, and performed statistical analysis. also provided input on the manuscript's structure and revisions. pas: assisted in the data extraction process, contributed to the quality assessment of studies, and helped in revising the manuscript. all of the authors read and approved the final manuscript. acknowledgments: none declared. archivio italiano di urologia e andrologia 2025; 97(3):14203 d. panca andhika, t. djojodimedjo, f. hidayatullah, et al. 8 amcinolone acetonide and onion extract gel and intralesional triamcinolone acetonide alone in the treatment of hypertrophic scars and keloids. dermatologic surgery. 2008; 34:1507-1514. 22. zhang k, qi e, zhang y, et al. efficacy and safety of local steroids for urethra strictures: a systematic review and meta-analysis. j endourol. 2014; 28:962-968. 23. richters cd, paauw nj, mayen i, et al. administration of prednisolone phosphate-liposomes reduces wound contraction in a rat partial-thickness wound model. wound repair and regeneration. 2006; 14:602-607. 24. korhonen p, talja m, ruutu m, alfthan o. intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. int urol nephrol. 1990; 22:263269. 25. lawrence wt, macdonagh rp. treatment of urethral stricture disease by internal urethrotomy followed by intermittent ‘low-friction’self-catheterization: preliminary communication. j r soc med. 1988; 81:136-139. 26. tavakkoli tabassi k, mansourian e, yarmohamadi a. one-stage transperineal repair of pan-urethral stricture with dorsally placed buccal mucosal grafts: results, complications, and surgical technique. urol j. 2011; 8:307-312. 27. mazdak h, izadpanahi mh, ghalamkari a, et al. internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. int urol nephrol. 2010; 42:565568. 28. tavakkoli tabassi k, mansourian e, yarmohamadi a. one-stage transperineal repair of pan-urethral stricture with dorsally placed buccal mucosal grafts: results, complications, and surgical technique. urol j. 2011; 8:307-312. 29. mundy ar, andrich de. urethral strictures. bju int. 2011; 107:6-26. 30. gücük a, tuygun c, burgu b, et al. the short-term efficacy of dilatation therapy combined with steroid after internal urethrotomy in the management of urethral stenoses. j endourol. 2010; 24:10171021. correspondence dimas panca andhika dimaspanca26@gmail.com mohammad ayodhia soebadi (corresponding author) yodisoebadi@gmail.com department of urology, faculty of medicine, airlangga university, surabaya, indonesia department of anatomy, histology, and pharmacology, faculty of medicine, airlangga university, surabaya, indonesia universitas airlangga hospital, surabaya, indonesia tarmono djojodimedjo tar_urology@yahoo.com furqan hidayatullah furqanhidayatullah26@gmail.com zakaria aulia rahman zakariaaulia04@gmail.com ilham akbar rahman ilhamakbaarr@gmail.com prima ardiansah surya prima.ardiansah1922@gmail.com department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia universitas airlangga teaching hospital, surabaya, east java, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13870 1 letter to editor to the editor, given the strong association between metabolic bone diseases and kidney stones, we propose a new public health strategy aimed at improving the management of patients affected by these conditions. this novel diagnostic protocol is designed to ensure the most effective treatment possible. bone tissue structure and functions bone is a complex multifunctional tissue that, for many years, was considered merely a mechanical support structure with limited biological significance. however, over the last few decades, numerous experimental and clinical studies have highlighted the complexity and heterogeneity of bone’s biological functions (1). bone is the only physiologically mineralized connective tissue in the human body. it is composed of approximately 60% inorganic components – mainly hydroxyapatite – 10% water, and 30% organic components, primarily collagen proteins (2). a healthy bone turnover, characterized by continuous and finely regulated bone formation and resorption, preserves the mechanical properties of bone. the main actors involved in this dynamic process are osteoblasts and osteoclasts, which operate within the bone multicellular units (bmu) (3). osteoblasts are mononuclear cells derived from mesenchymal stem cells and play the key role in bone formation. conversely, osteoclasts are multinucleated cells originating from hematopoietic stem cells and are essential for bone resorption (4). throughout life, the balance between osteoblast and osteoclast activity ensures the maintenance and regeneration of bone mass (5). bone tissue is an endocrine organ and produces molecules with endocrine and paracrine functions, such as fibroblast growth factor 23 (fgf 23), osteopontin (opn), sclerostin (sost), and osteocalcin (6). through these bone-derived hormones, bone communicates with extra-skeletal organs and systems (7, 8). the skeletal and immune systems are intricately connected, a relationship studied under the fields of osteoimmunology (9). this interplay is achieved through several molecular mechanisms, cytokines and signaling transducers. immune and bone cells not only share a common origin and microenvironment – such as the bone marrow – but also influence each other’s activation, proliferation and senescence (9). recent evidence supports a mutual regulation between immune and bone cells. for instance, the immune system supports bone development: macrophages promote osteoblastogenesis via interleukin 18 kidney stones and metabolic bone diseases not linked to parathyroid disfunction: a proposal for an integrated management anita vergatti 1, veronica abate 1, matteo della monica 2, alfonso varriale 1, simone magelli 1, francesca garofano 1, lanfranco d’elia 1, antonio barbato 1, gianpaolo de filippo 3, domenico rendina 1 1 department of clinical medicine and surgery, federico ii university, naples, italy; 2 former head of the medical and laboratory genetic unit, cardarelli hospital, naples, italy; 3 assistance publique-hôpitaux de paris, hôpital robert-debré, service d’endocrinologie-diabétologie, paris, france. doi: 10.4081/aiua.2025.13870 nephrolithiasis (ks) and metabolic bone diseases (mbds) not linked to parathormone (osteoporosis, paget’s disease of bone and renal phosphate leak) are related as demonstrated by epidemiological and experimental data. moreover, patients affected by monogenic kidney stone disorders (idiopathic hypercalciuria, primary hyperoxaluria, hypocitraturia, cystinuria and defects in purine metabolism) showed a bone phenotype. a significant economic and social burden is associated with ks and mbds, due to high mortality and morbidity rate. concerning this point of view, an integrated screening could be a cost-saving strategy. we suggest a new clinical management for patients affected by ks and mbds. the assessment of bone mineral density by dual x-ray absorptiometry and bone turnover markers should be proposed in ks patients. on the contrary, the evaluation of ks-related metabolic risk factor and an abdomen ultrasound exam should be offered to mbd patients. moreover, in patients with early and/or recurrent ks, an extended gene-panel should be suggested. key words: nephrolithiasis; osteoporosis; paget disease of bone; osteomalacia; phosphate leak. submitted 7 april 2025; accepted 25 april 2025 summary archivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 2 (il18) (10), and t cells regulate osteoclastogenesis through il1, il6, il4 and interferon-γ (11, 12). in turn, osteoclasts can activate t-cell through receptor activator of nuclear factor kappa b (rank) rank ligand (rankl) osteoprotegerin (opg) signalling axis (13). moreover, studies suggest that osteoblasts and osteoclasts contribute to hematopoietic niche formation and mobilization respectively, although the precise mechanisms remain incompletely understood (14). bone also plays a critical role in mineral metabolism regulation. fgf23, secreted by osteoblasts and osteocytes, reduces phosphate reabsorption by inhibiting the expression of the type iia sodium-phosphate co-transporter (napi-2a) in renal proximal tubules. fgf23 also regulates calcium and sodium reabsorption, through the transient receptor potential vanilloid-5 (trpv5) channel and sodium-chloride co-transporter (ncc), respectively (15). additionally, fgf23 suppresses parathyroid (pth) hormone, which normally increases calcium release from bone and absorption from the gut and kidney, as well as the synthesis of 1,25-dihydroxy-vitamin d (15). bone health can be assessed using dual-energy x-ray absorptiometry (dxa), the gold standard for evaluating bone mineral density (bmd). dxa employs low-dose x-rays to measure the bmd in lumbar spine and total hip (16). results are reported as standard deviation (sd) from the mean bmd of healthy 30-year-old subjects of the same sex and ethnicity (tscore), or the same sex, age and ethnicity (z-score) (17). in addition to dxa, the trabecular bone score (tbs) is an indirect marker of bone microarchitecture, assessing variations in pixel gray levels in dxa image. tbs may be an independent predictor of frailty fracture (18). other diagnostic technics are represented by quantitative ultrasound (qus) and quantitative computed tomography (qtc). qus uses ultrasound waves that interact with the bone surface. the physical and mechanical bone features modify the return waves, allowing the evaluation of elasticity and strength, two bone quality parameters (19). qtc employs standard x-ray computed tomography and converts attenuation values into bmd values. it is particularly useful in patients in whom dxa in unsuitable (e.g., scoliosis) or where dxa may overestimate bmd (e.g., osteophytes, aortic calcification, arthritis) (20). a recent innovative is radiofrequency echographic multi spectrometry (rems), a non-ionizing technique that analyses raw, unfiltered ultrasound signals acquired during scans of the lumbar spine and/or femoral neck to provide dxa-equivalent bmd values (21). rems has been clinically validated through a multicentre observational trial involving 7 italian centres (22), and the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (esceo) has recognized rems as the first clinically available, non-ionized method for assessing lumbar and femoral bmd and predicting fracture risk (21). in addition to instrumental technics, bone turnover markers (btms) can be evaluated. btms are peptides produced during bone formation or reabsorption. n-terminal (p1np) and c-terminal (p1cp) propeptides are products of osteoblastderived procollagen synthesis, and their blood concentration reflect bone formation rates (23, 24). oc and bone-specific alkaline phosphatase (balp) are also produced by osteoblasts. oc is specific to bone, but it is hard to analyse, due to molecular instability and the impact of renal failure on its blood concentration (25). in contrast, balp remains a reliable marker even in chronic kidney disease and is a specific marker of bone formation (26). for bone resorption, c-terminal (ctx) and n-terminal (ntx) telopeptides, both products of collagen degradation, are the most widely used markers (27). ctx measurement is influenced by circadian rhythm and food intake, while ntx is affected by liver and renal function (28). another btm is opg, which reflects the bone microenvironment and osteocyte activity (28). kidney stones and metabolic bone disease kidney stones (ks), also known as nephrolithiasis or urolithiasis, are crystal concretions typically formed in the kidney and/or the urinary tract, including the renal pelvis, ureters, bladder, and urethra (29). ks affect approximately 13% of the population in north america, 9% in europa, and 5% in asia (30). the regional differences in prevalence and incidence worldwide are influenced by geographical, climatic, ethnic, dietary and genetic factors (31). ks have a significant economic impact, including direct treatment costs and loss of productivity. in 2021, the annual cost of treating ks in the united states was estimated at $9 billion. the global market for ks management is projected to reach $4.02 billion by 2034 (32, 33). about 85% of ks are composed of calcium oxalate and calcium phosphate salts, 10% of struvite (magnesium ammonium phosphate produced during infections by urease-producing bacteria), 9% of uric acid (ua), and the remaining 1% of cystine, ammonium acid urate, or drug-related stones (34). metabolic bone disease (mbds) are disorders affecting bone remodelling. the more common mbds include primary and secondary osteoporosis (op), paget’s disease of bone (pdb), rickets, and osteomalacia (35). the conditions carry a growing social and economic burden, especially with the aging global population (36). in italy alone, the economic burden of op is estimated at €2.2 billion, with about 80% of costs related to hospitalisations, 16% to pharmacological treatment, and about 3% to outpatient visits. these data show that op is one of the main health problems (37). since both mbds and ks are linked to the precipitation and crystallization of salts, an association between them has been hypothesized (38). osteoporosis and kidney stones op is the most prevalent mbd worldwide, affecting a large proportion of individuals over 60 years of age (39). op is characterised by a reduction in bone mass and deterioration of bone microarchitecture due to an imbalance between bone resorption and formation. this results in decreased bone strength and increased fracture risk (40). fracture prevalence in ks patients is estimated between 19-24% (41). both op and ks are multifactorial disorders with modifiable and non-modifiable risk factors (42). modifiable risk factors include high salt, protein, and sugar consumption, inadequate archivio italiano di urologia e andrologia 2025; 97(2):13870 3 kidney stones and metabolic bone diseases calcium and vitamin d intakes, smoking, and physical inactivity (43-46). non-modifiable risk factors are mainly genetic and epigenetic, although not fully understood (47). hypercalciuria (hca), defined as daily urinary calcium excretion higher than 300 mg/day in men and higher than 250 mg/day in women (48), is found in 20-30% of individuals with primary op (49, 50). hca is associated with persistent overproduction of cytokines predisposing bone loss (51), pth/calcitriol pathways (52), and disruptions in calcium-phosphate homeostasis (53). genetic variants of claudin 14 (cldn14) gene, involved inwnt signalling and osteoblast function, have been linked to both op and ks (53). unhealthy dietary habits represent a common risk factor. high salt consumption increases urinary calcium excretion (54), while low calcium and potassium intake and low physical activity contribute to the development of both conditions. the role of calcium intake and supplementation remains debated. jackson and coll. report a higher incidence of ks after calcium supplementation (55), while in his meta-analysis, heaney rp did not find differences between women with and without calcium supplementation (56). other authors showed a lower risk of ks in subjects with calcium intake > 1 g/day, due to the reduced intestinal absorption of oxalate and production of calcium-oxalate stones (57). in addition, in subjects with ks and low bmd, calcium intake through water and fibre seems to prevent ks (57). another important point is the salt dietary consumption. kleeman and coll. demonstrated that increasing salt intake, the 24h urinary calcium excretion increased (54). indeed, an increase of 6 g/day in salt consumption results in a 40 mg/day increase in 24h urinary calcium excretion (58). furthermore, nouvenne and coll. showed that high sodium intake raised ks and op risk, due to both higher calcium and lower citrate excretion (59). sugars are also involved in the pathogenesis of these conditions, causing a higher urinary calcium excretion (60, 61). overall, these data are emphasized in metabolic syndrome, a recognized risk factor for both op and ks (62). on the contrary, a diet rich in fruit and vegetables, with a low consumption of salt and animal protein and a calcium intake > 1 g/day is able to avoid ks and op (63). ks is characterized by higher levels of inflammatory markers (64), with potential role in bone resorption. in particular, elevated serum levels of il1, il-6, and tumor necrosis factor-α (tnfα) influence the osteoclasts activation and stimulate the synthesis of other bone remodelling mediators, such as prostaglandin e (65). in their meta-analysis, lucato and colleagues examined 24 case-control studies involving 1595 subjects with nephrolithiasis and 3402 healthy controls. ks formers showed lower bone mineral density (bmd), an increased risk of op, and a significantly higher risk of bone fractures compared to healthy controls (66). in a multicenter prospective study involving 107,001 women followed for 32 years and 50,982 men followed for 26 years, ks was associated with a higher risk of wrist fracture in both women and men, also correcting for race, body mass index (bmi), diet and other confounding factors (67). another study, based on veterans health administration data, found that 1 in 4 male ks formers had a history of op or frailty fractures, suggesting that the risk of op in ks is high also in men and supporting the bmd screening in all ks formers (68). furthermore, dhayat and colleagues identified ks constituents as predictors of low bmd. in particular, calcium-oxalate stones are negatively associated with bmd at the femoral neck (69). in contrast, sakhaee and colleagues (70) did not find a significant association between urinary calcium excretion and bmd in ks, in agreement with fink and coll. (71), that in a cohort of men with op and ks, did not find any relationship between op and 24h urinary calcium excretion. these results suggest that 24h urinary calcium may be a marker, but not a cause of bone loss. also, in a large cohort of multiethnic post-menopausal ks women, no significant association between ks and changes in bmd was found at multiple skeletal sites, after adjustment for confounders associated with op and/or ks (72). overall considered, data demonstrate that op is a risk factor for occurrence of ks and that ks is a risk factor for op (73). thus, we can look at op and ks as the two sides of the same coin (74). paget’s disease of bone and kidney stones paget’s disease of bone (pdb, omim 602080) is the second most common metabolic disease characterized by increased and disorganized bone turnover, involving one or more regions of the skeleton. pdb affects a significant percentage of peoples over 40 years old, with a prevalence between 1 and almost 8%. (75). the increased osteoclastic bone resorption, followed by marrow fibrosis, increased and disorganized vascularity and bone formation, represents the main pathophysiologic mechanism (75). the pdb osteoclasts show peculiar morphological and functional properties, such as hyper-responsivity to calcitriol, enhanced sensitivity to rank ligand, increased expression of il 6, il 6 receptor, and paramyxovirus transcript. pdb can evolve into malignant or non-malignant complications. in particular, ks is a non-malignant metabolic complication of pdb patients. pdb patients are at increased risk of ks independently of pdb activity or hyperparathyroidism. the involvement of multiple skeletal sites can influence the recurrence of ks. polyostotic patients have often ks and ks recurrences. in a recent study, it was demonstrated that the prevalence of ks in pdb patients without primary hyperparathyroidism is significantly higher compared with healthy control, also adjusted for age, gender, bmi, and estimated glomerular filtration rate (egfr). furthermore, pdb patients with ks showed a higher prevalence of hca, hypocitraturia, hyperoxaluria, and hyperuricuria compared with pdb patients without nephrolithiasis (76). renal phosphate leak and kidney stones the renal phosphate leaks are disorders of phosphate homeostasis with a reduced tubular reabsorption of phosphate not pth-related. it is characterized by low serum levels of phosphate (< 0.8 mmol/l or < 2.5 mg/dl), low threshold of tubuarchivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 4 lar phosphate reabsorption, and calcium, pth, 25-hydroxy vitamin d serum levels within the normal range (77). the maintenance of phosphate balance is crucial for bone health. indeed, different organs contribute to phosphate homeostasis: gut, kidney, and bone (78, 79). moreover, three main regulators of phosphate homeostasis had been identified: i) calcitriol increases phosphate absorption from the gut and bone; ii) pth increases phosphate resorption from bone and decreases its reabsorption in the proximal tubule; iii) fibroblast growth factor-23 (fgf-23) increases renal phosphate excretion (78, 80-82). notably, fgf23 controls cellular expression of type 2 sodium-phosphate cotransporter (ntp2a) in proximal renal tubule, independently from pth (83). hypophosphatemia causes osteomalacia, a clinical disorder characterised by under-mineralized soft bone. osteomalacia usually manifests with reduced bone mineral density, bone pain, frailty fractures, and muscle weakness, i.e. the osteomalacic syndrome (84). epidemiological studies indicate that 20% of patients with ks and normal level of pth show hypophosphatemia caused by renal phosphate leak, without complete phenotypic expressions of osteomalacia (85). the renal phosphate leak affects calcium salt urinary saturation and contributes to the pathogenesis of ks (86). some patients affected by ks and renal phosphate leak show genetic mutations in solute carrier family 34 member 1 (slc34a1, omim 182309), solute carrier family 34 member 3 (slc34a3, omim 609826), and sodium-hydrogen antiporter 3 regulator 1 (nherf1, omim 604990) genes (87). the identification of these gene mutations in patients with both hypophosphatemia, skeletal alterations and ks contribute to the common pathogenesis of these disorders. ks patients with renal phosphate leak show higher serum levels of fgf23 compared with ks patients without renal phosphate leak and healthy controls (88). in addition, in fgf23-dependent forms of renal phosphate leak, calcitriol can worsen ks, due to increased renal excretion of calcium (88). an isoform of fgf23, fgf23239m, occurring in 10% of caucasian population, is associated with recurrent ks in patients with phosphate renal leak. the mutant region c716t influences fgf23 biological proprieties and its interaction with fgfreceptor and klotho (89). in addition, the same allelic variant of fgf23 is involved in bone modelling in growing young children (90). bone health and monogenic kidney stones frequently, ks represents only the first symptom of an unknown disease. patients with early renal failure, severe and multiple ks, abnormal family history need to evaluate for genetic of ks, including idiopathic hca, primary hyperoxaluria (ph), hypocitraturia (hctr), cystinuria and defects in purine metabolism. moreover, these pathological conditions are associated to bone impairment. idiopathic hca (omim 143870-607258) is a metabolic condition affecting both children (91) and adult (92) with a diagnosis of ks. hca is defined as urinary calcium levels ≥ 4 mg/kg body weight/day (93). we recognized three different pathway and metabolic disorders, involving intestinal calcium absorption, renal phosphate leak, and renal calcium leak, respectively: i) absorptive hca type i; ii) absorptive hca type iii; iii) renal hca (94). different studies show the association between idiopathic hca and loss in bmd. in children, an increased bone reabsorption and a decreased bone formation cause a low bmd, while in adult, the bone reabsorption is prevalent (95). freundlich and coll. evaluated the bmd and btm in 21 children with a diagnosis oh idiopathic hca and in their mothers, founding osteopenia in 38% and 33%, respectively. furthermore, mothers with osteopenia showed an increasing in btm by 57% (96). also, garcía-nieto and coll. studied 40 girls with idiopathic hca and their pre-menopausal mothers. they found a z-score < 1 at the lumbar spine in 42.5% of girls and in 47.5% of their mothers, suggesting the necessity to measure early bmd in these patients (97). the skeletal sites involved are mainly represented by trabecular bone (98), but the mechanism causing the bone loss are poorly understood. ph are a group of autosomal recessive disorders linked to a liver overproduction of oxalate and characterized by ks (99). ph 1 (omim 259900; agxt gene mutation) is the most severe form with a higher risk of end-stage renal disease, while ph2 (omim 260000; grhpr gene mutation) and ph3 (omim 613616; hoga1 gene mutation) are less severe (99). the ph cause osteodystrophy related to chronic kidney disease, but ph patients show bone pain, fractures, bone deformations and subperiosteal tophi, independently of kidney disease (100). the exact pathophysiology remains unknown. hctr is a common risk factor for ks, with an incidence that ranges from 20% to 60% in ks formers (101). the low 24h urinary citrate excretion is a marker of acid load of the body. to maintain acid-base balance, kidney retains and bone releases alkali (citrate), causing a reduction in bmd and an increasing of btm (102). pak and coll. described a significant improvement of bmd in lumbar spine in ks formers treated with a long-term potassium citrate salt (mean 44 months), suggesting that this drug, used for ks, may prevent bone loss (103). cystinuria (omim: 220100) is a rare genetic disease caused by cystine tubular transport alteration, and it is considered as the most frequent monogenic form of ks. cystinuria is classified as: i) type a characterized by slc3a1 gene mutation; ii) type b characterized by slc7a9 gene mutation (104). cystinuric patients have a higher prevalence of chronic kidney disease and failure, caused by recurrent ks. this latter is associated to low bmd. an animal study by peters and coll., the slc3a1 gene mutation was associated to low bmd independently of renal failure, assuming a direct role of cystinuria in skeletal alteration (105). the high prevalence of low bmd in this setting was showed by bijelic and coll. compared to ks formers and healthy controls (106) and it was confirmed by d’ambrosio and coll. (107). the main defect in purine metabolism is the deficiency of hypoxanthine-guanine phosphoribosyltransferase (hprt), resulting in an accumulation of uric acid (ua) (108). ua has a double action on bone. in the normal range, it acts as an antioxarchivio italiano di urologia e andrologia 2025; 97(2):13870 5 kidney stones and metabolic bone diseases idant and reduces the incidence of op by 23-26% (109). meanwhile, elevated ua levels cause destructive effects on bone health through reactive oxygen species (ros) and increase of inflammation (110). an integrated approach to ks and mbds to reduce the financial and social burden growing epidemiological and experimental data support a non-stochastic association between idiopathic ks and common mbds, such as op, pdb and renal phosphate leak not pth related. mbds and ks share common environmental and genetic backgrounds. based on such evidence, a different clinical approach and management of ks and mbd patients should be evaluated. additionally, ks and mbds account for an increased economic burden, linked to hospitalisation and pharmacological treatment costs, and ambulatory visits (111, 112). an integrated screening protocol could be able to impact positively, reducing mortality, morbidity and overall costs. we propose the evaluation of metabolic risk factors for nephrolithiasis (measurement of 24-h urinary excretion of calcium, phosphate, citrate, magnesium and urate), and an abdomen ultrasound exam in patients with op, pdb and renal phosphate leak. on the contrary, the assessment of bone mineral density by dxa or rems, btms and threshold of tubular phosphate resorption should be evaluated in patients with nephrolithiasis. both in ks and mbd patients, the evaluation of daily calcium and salt intake, and the adherence to a balanced diet is recommended. moreover, in case of ks in young patients or recurrent ks, without any metabolic causes, it could be essential to search for gene mutations related to ks. this new diagnostic protocol guarantees the best possible treatment of any type of metabolic bone disorders, and, for this reason, it is necessary to develop a specific public health strategy. figure 1. suggested flow-chart for the management of nephrolithiasis and metabolic bone disorders. declarations ethical approval: n/a. availability of data and material: n/a. competing interests: all authors declare no conflict of interest. funding: this manuscript was supported by pnrr funding (pnrr-poc-2023-12378009). authors' contributions: conceptualization va, rd; methodology av, va, mdm, fg, gdf, rd; discussion of the findings av, va, mdm, av, sm, gdf, rd; writing original draft preparation va; final editing mdm, gdf, lde, rd; project administration and supervision mdm, gdf, rd. all authors have read and agreed to the published version of the manuscript. acknowledgments: this manuscript was supported by pnrr funding (pnrr-poc-2023-12378009). archivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 6 references 1. karsenty g. the complexities of skeletal biology. nature 2003; 423:316-318. 2. feng x. chemical and biochemical basis of cell-bone matrix interaction in health and disease. curr chem biol 2009; 3:189-196. 3. arias cf, herrero ma, echeverri lf, et al. bone remodeling: a tissue-level process emerging from cell-level molecular algorithms. plos one 2018; 13:e0204171. 4. šromová v, sobola d, kaspar p. a brief review of bone cell function and importance. cells 2023; 12:2576. 5. florencio-silva r, sasso gr, sasso-cerri e, et al. biology of bone tissue: structure, function, and factors that influence bone cells. biomed res int 2015; 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129:71-78. 109. chen f, wang y, guo y, et al. specific higher levels of serum uric acid might have a protective effect on bone mineral density within a chinese population over 60 years old: a cross-sectional study from northeast china. clin interv aging 2019; 14:1065-1073. 110. dalbeth n, becce f, botson jk, et al. dual-energy ct assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapy. rheumatology (oxford). 2022; 61:4898-4904. 111. hyams es, matlaga br. economic impact of urinary stones. transl androl urol 2014; 3:278-283. 112. marcellusi a, rotundo ma, nardone c, et al. osteoporosis: economic burden of disease in italy. clin drug investig 2020; 40:449-458. correspondence anita vergatti anita.vergatti@unina.it veronica abate veronica.abata@unina.it alfonso varriale alfonso.varriale@unina.it simone magelli simone.magelli@outlook.it francesca garofano garofanofran.1@gmail.com lanfranco d'elia lanfranco.delia@unina.it antonio barbato abarbato@unina.it domenico rendina (corresponding author) domenico.rendina@unina.it department of clinical medicine and surgery, federico ii university, naples, italy matteo della monica matteo191257@gmail.com former head of the medical and laboratory genetic unit, cardarelli hospital, naples, italy gianpaolo de filippo gianpaolo.defilippo@aphp.fr assistance publique-hôpitaux de paris, hôpital robert-debré, service d’endocrinologie-diabétologie, paris, france stesura seveso 371archivio italiano di urologia e andrologia 2022; 94, 3 letter to editor no conflict of interest declared. submitted 3 july 2022; accepted 9 july 2022 to the editor, good surgical training is essential for the formation of excellent surgeons, consequently providing the best possible care for our patients in the future. considering the increase in surgeon shortage over the last two decades (1, 2) (estimated between 14,300 and 23,400 by the year 2032 only in the us) (3), it is important for filling the national health system's needs as well. finally, respectable surgical training will allow preservation of residency programs by annually attracting more and more new candidates. every country has its' own structure of surgical training, and it differs immensely between states, sometimes even within the same country (4). in recent years, several issues were raised regarding inadequacy of surgical training in some of the most developed countries (5). resident-directed surveys, done primarily in italy, spain and germany, evaluating urological training in particular, revealed a lot of training-related concerns such as residents' low exposure to major surgeries and a lack of their active participation during them (4-10). reasons for this trend might be multiple, starting from the administrative work overload, increasing medico-legal assessments and lawsuits, development of the new, high-tech devices that do not allow both mentor and trainee working simultaneously (e.g. single-console robotic systems and novel laser techniques) and neo-specialists still in learning curve. although we have training centers with simulators dedicated to resolving these issues, concerns such as poor understanding of the skill-retention, possibility of the skill decay and scarce evidence about simulators improving clinical outcomes are often discussed (11, 12). as if that was not enough, a significant reduction in elective procedures occurred during the covid-19 pandemic. this has had a huge impact on surgical activity and residents, with 50% reduction in procedures with them as primary surgeons (1315). furthermore, the reality of many residents is a lack of time they can dedicate to simulators at their disposal (4). so, can this be mediated? what are the questions we are frequently asking our residents and ourselves? what are the most important skills a surgeon should possess before stepping in the or? a good base of the surgical anatomy, familiarity with different organ tissues, textures and resistances as well as proficiency in various methods of suturing and knot-tying. although residents have access to a lot of learning material (e.g. recordings of the operations) that might help improving their knowledge about surgical anatomy, it does not provide any practical training nor tactile experience. in some centers, residents have access to simulators or, in other cases where they do not, tutorials on how to build your own, low-cost training models1 (6, 17) are available. unfortunately, they often do not reproduce truthfully the real-life tissue consistencies. further, programs that offer training on the cadaveric models are also available (18, 20). the major problems with cadaveric models are firstly, the availability of them, secondly, they are expensive, and lastly, but maybe the most importantly, the ceased circulation, low temperature and electrolytic imbalances alter organs. so, in the end, even cadaveric models are not able to faithfully reproduce the real-life medical procedures. now, if we do not teach young surgeons today, we will not have any surgeons, or at least not capable surgeons, tomorrow, so these issues need to be addressed as soon as possible. in addition, italy is facing yet another challenge considering that, a few years back, epateam (national association for liver transplant patients) predicted shortage of transplant surgeons (21) and availability to harvest organs at late night hours. all in all, we are in a desperate need of better surgical training and in a serious need of (transplant) surgeons. one must wonder, couldn't we simply involve surgical residents in organ harvesting as a mandatory structured program during the first two years of their training? instead of two transplant surgeons, organs could be harvested (and transplanted for that matter) by one transplant surgeon and one trainee or, even, by two senior supervised trainees. why should we use cadaveric models if we have access to a living body? could this be a win-win solution? simply, it seems a nearly perfect answer to all of our problems: surgical anatomy can be mastered very well and quite organ harvesting as a mandatory training step of all pgy1 and pgy2 surgical residents rafaela malinaric 1, 2, guglielmo mantica 1-3, carlo terrone 1, 2 1 department of urology, irccs ospedale policlinico san martino, genova, italy; 2 department of surgical and diagnostic integrated sciences (disc), university of genova, genova, italy; 3 european society of residents in urology (esru), arnhem, the netherlands. doi: 10.4081/aiua.2022.3.371 archivio italiano di urologia e andrologia 2022; 94, 3 r. malinaric, g. mantica, c. terrone 372 quickly, novices could become more acquainted with organ structures, connections and textures as well as learning how to manipulate various organs without creating too much damage. moreover, during arterial or venous graft harvesting and abdominal wall closure residents could practice various types of knot-tying and improve their knowledge about suture materials, suture size, and the components of the surgical needle. the major pitfall of this proposal is the fact that not all training-centers have transplant programs. but how many surgical residency programs already include rotations in other departments or hospitals? so, couldn't this principle simply be applied to here-proposed organ-harvesting program? this would provide both, better education for the residents and could help greatly our transplant teams. it would mean night hours, and some training programs do not allow or simply do not encourage them, but this rotation could have only a three to four months duration. of course, this is just an idea that needs furnishing, thought, elaborated and structured plan, but surely worthwhile considering, at least for a discussion. references 1. stringer b, et al. trouble on the horizon: an evaluation of the general surgeon shortage in rural and frontier counties. am surg. 2020; 86:76-78. 2.van way cw jr. is there a surgeon shortage? mo med. 2010; 107:309-12. 3. https://www.aamc.org/news-insights/press-releases/new-findings-confirm-predictions-physician-shortage. 4. carrion dm et al. current status of urology surgical training in europe: an esru-esu-esut collaborative study world j urol. 2020; 38:239-246. 5. mattar sg, et al. general surgery residency inadequately prepares trainees for fellowship: results of a survey of fellowship program directors ann surg. 2013; 258:440-449. 6. borgmann h, arnold hk, meyer cp, et al. training, research, and working conditions for urology residents in germany: a contemporary survey. eur urol focus. 2018; 4:455-460. 7. rodríguez-socarrás me, et al. medical-surgical activity and the current state of training of urology residents in spain: results of a national survey' actas urol esp. 41:391-399. 8. mantica g, chierigo f, gallo f; italian residents association of the italian urology association study group. patients' perceptions of quality of care delivery by urology residents: a nationwide study. bju int. 2022. doi: 10.1111/bju.15768. 9. almannie r, et al. exposure of urology residents to the management of urethral strictures in saudi arabia: should the program for postgraduates be customized? res rep urol. 2020; 12:367-372. 10. aslam au, philipraj j, jaffrey s, buchholz n. a global snapshot of endourology residency training. arch ital urol androl. 2020; 92:219-229. 11. stefanidis d, et al. simulation in surgery what’s needed next?' ann surg. 2015; 261:846-53. 12. kozan aa, chan lh, biyani cs. current status of simulation training in urology: a non-systematic review. res rep urol. 2020; 12:111-128. 13. joint committee of surgical training, association of surgeons in training, british orthopaedics trainees’ association, confederation of postgraduate schools of surgery. maximising training: making the most of every training opportunity. 2021. https://www.jcst.org/key-documents/. 14. coleman jr, abdelsattar jm, glocker rj. ras-acs covid-19 task force. covid-19 pandemic and the lived experience of surgical residents, fellows, and early-career surgeons in the american college of surgeons. j am coll surg. 2021; 232:119-135.e20. 15. mantica g, et al. the tomato model. urology. 2021; 157:280-281; 16. leonardi r, bellinzoni p, broglia l, et al. hospital care in departments defined as covid-free: a proposal for a safe hospitalization protecting healthcare professionals and patients not affected by covid-19. arch ital urol androl. 2020; 92:67-72. 17. soriero d, et al. 'development and validation of a homemade, low-cost laparoscopic simulator for resident surgeons (labot)' int j environ res public health. 2020; 17:323. 18. huri e, et al. the novel laparoscopic training 3d model in urology with surgical anatomic remarks: fresh-frozen cadaveric tissue' turk j urol. 2016; 42:224-229. 19. mantica g, leonardi r, diaz r. cactus group. reporting characteristics of cadaver training and surgical studies: the cactus guidelines. int j surg. 2022; 101:106619. 20. mantica g, pini g, de marchi d, et al. intensive simulation training on urological mini-invasive procedures using thiel-embalmed cadavers: the iamsurgery experience. arch ital urol androl. 2020; 92:93-96. 21. https://www.repubblica.it/salute/medicina-e-ricerca/2019/02/21/news/15mila_trapianti_di_fegato_nei_prossimi_10_anni_ma_mancheranno_i_chirurghi-219733589/ correspondence rafaela malinaric, md (corresponding author) rafaela.malinaric@gmail.com san martino hospital, university of genoa, genoa, italy guglielmo mantica, md guglielmo.mantica@gmail.com carlo terrone, md carlo.terrone@med.uniupo.it stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2166 original paper no conflict of interest declared. intensity-modulated radiotherapy that has shown that increasing dose improves biochemical disease-free survival with acceptable acute and long-term complications (1, 2). recently, injection of a hydrogel spacer (space oar) between the rectum and the prostate and the use of intraprostatic fiducials have been suggested to reduce rectal toxicity and improve selective prostate radiation therapy (3-8) resulting particularly useful in men candidate to hypofractionated radiotherapy (hrt) (9-11). in this study, the incidence of ed in men with organ-confined pca submitted to hrt has been prospectively evaluated. materials and methods from april 2018 to september 2020, 56 patients (median age 70 years; range = 58-82) with organ-confined pca (ct1c stage) were treated by hrt directed to the prostate and seminal vesicle. all the patients were previously submitted to multiparametric magnetic resonance imaging (mpmri) (13) and transperineal prostate biopsy (14-15). the median psa was 8.3 ng/ml (range = 4.5-23.1); 20 patients (35.7%) were at low risk (grade group 1/gleason score 6), 28 (50%) at favorable intermediate risk (grade group 2/gleason score 3 + 4) and only 8 (22.3%) at unfavorable intermediate risk (grade group 3/gleason score 4 + 3) (6); moreover, all patients were without evidence of disease spread to the lymph nodes or the bones. all patients were selected for a hydrogel injection space oar before hrt. the injection of hydrogel was performed under sedation by transrectal ultrasound guidance, furthermore, three gold fiducials were inserted transperineally at the prostate base and mid-gland (8). patients were simulated 2 weeks after placement; ct simulation was obtained at 3 mm slice thickness using an immobilization device, extending from l1 to below the ischial tuberosities. ct-mri image registration was accomplished using the mim-software (maestro, version 7.0.5, mim software inc., cleveland, oh, usa). the whole prostate and seminal vesicle were delineated as the clinical target volume (ctv). non-uniform planning target volume (ptv) was defined by adding margins to ctv; the margin was 8 mm in the anterior, lateral, superior and inferior directions, while it was 4 mm in the posterior direction. the rectum, urinary bladder, bowel, femoral introduction: the incidence of erectile dysfunction (ed) in men with organ-confined prostate cancer (pca) submitted to hypofractionated radiotherapy (hrt) has been prospectively evaluated. materials and methods: from april 2018 to september 2020, 56 patients (median age 70 years) with ct1c pca were treated by hrt directed to the prostate and seminal vesicle. median psa was 8.3 ng/ml; 20 patients (35.7%) vs. 28 (50%) vs. 8 (22.3%) had a pca grade group 1 vs. 2 vs. 3, respectively. all patients underwent hydrogel injection of space oar and intraprostatic fiducials before hrt. the prescription dose was 60 gy in 20 fractions 5 days/week over 4 weeks. during the follow up, psa, genitourinary (gu) and gastrointestinal (gi) toxicities were evaluated. the sexual function was evaluated by international index of erectile function 5 (iief-5) before, 6 and 18 months from hrt; 32/56 (57.1%) men referred a normal sexual activity before hrt (median iief-5 score: 22). results: median psa level at median follow up of 18 months was 0.92 ng/ml and none used adjuvant therapy. one man (1.8%) referred a tardive grade 1 gu complication. at a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median iief-5 score: 21). the 12/32 men who worsened the sexual function following hrt had a median age higher than patients without ed (78 vs. 67 years). conclusions: the use of hydrogel injection and intraprostatic fiducials followed by hrt allowed to kept pretreatment sexual potency in 62.5% of the cases. key words: prostate cancer; erectile dysfunction; hypofractionated radiotherapy; intraprostatic fiducials; hydrogel injection. submitted 10 april 2022; accepted 23 april 2022 introduction prostate cancer (pca) is the most commonly diagnosed male malignancy and radical prostatectomy or external radiotherapy (rt) are currently recommended as definitive treatment alone or combination in men with a life expectancy greater than 10 years. radiation damage to neural and vascular tissue, such as the neurovascular bundles (nvbs) and internal pudendal arteries (ipas), during radiotherapy for pca may cause erectile dysfunction (ed). the advances in physics, engineering and imaging have been channeled into the development of image-guided erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: our experience in 56 cases pietro pepe 1, maria tamburo 2, paolo panella 1, ludovica pepe 1, giulia marletta 2, michele pennisi 1, francesco marletta 2 1 urology unit, cannizzaro hospital, catania, italy; 2 radiotherapy unit, cannizzaro hospital, catania, italy. doi: 10.4081/aiua.2022.2.166 summary 167archivio italiano di urologia e andrologia 2022; 94, 2 erectile dysfunction and hypofractionated radiotherapy heads and penile bulb were contoured as organs at risk. the rectum was delineated from the rectosigmoid flexure to the anus; the treatment planning system was monacoelekta (elekta ab, stockholm, sweden). the prescription dose was 60 gy in 20 fractions 5 days/week over 4 weeks, the ctv was planned to receive at least 100% of the prescription dose and the ptv at least 95% with maximum dose at ctv < 110% of the prescription dose. dose-volume constraints were: dose given to 30% of rectal volume < 46 gy, dose given to 50% of rectal volume < 37 gy, dose given to 30% urinary bladder volume < 46 gy, dose given to 30% urinary bladder volume < 37 gy, dose given to 5% left/right femoral head volume < 43 gy. patients were treated with volumetric modulated arc therapy (vmat) using the linac sinergy elekta and pretreatment verification of the prostate was conducted using a kilovoltage cone-beam ct during each treatment session. patients were followed every 3 months for 2 years, and thereafter every 6 months. psa relapse was determined according to the phoenix consensus definition (nadir psa value plus 2 ng/ml). genitourinary (gu) and gastrointestinal (gi) toxicities were evaluated following rtog/eort score. acute toxicity was defined as that occurred within 3 months after the initiation of radiotherapy, while late toxicity was observed after 3 months. the sexual function was evaluated by international index of erectile function-5 (iief-5) (12) before (baseline), 6 and 18 months from hrt. none of the patients used 5-phosphodiesterase inhibitors or prostaglandins to improve sexual activity. the median prostate volume was 69.4 cm2; clinical (comorbidities, drug therapy) and laboratory data collected before prostate biopsy are reported in table 1. thirtytwo (57.1%) men referred a normal sexual activity before hrt (median iief-5 score: 22; range 20-25) and among them 12 (37.5%) vs. 18 (56.2%) vs. 2 (6.3%) men had a pca grade group equal to 1 vs. 2 vs. 3, respectively. results all patients tolerated well the injection of space oar plus intraprostatic fiducials and completed the hrt treatment. median psa level at median follow up of 18 months was 0.92 ng/ml (range: 0.01-3.6 ng/ml) and none used adjuvant therapy. only one man (1.8%) referred a tardive grade 1 gu complication, the remain 55 (98.2%) had no tardive side effects. among the 32/56 (57.1%) men who had a normal sexual activity before hrt (median iief-5 score: 22; range 2025), at a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median iief-5 score: 21; range = 19-25) (table 2). the 12/32 men who worsened the sexual function following hrt had a median age higher than patients without de (78 vs. 67 years). discussion however the advent of modern technology using advanced prostate targeting and penile-bulb sparing techniques, ed is a prevalent side effect of pca treatment; hunt et al. (16) in a recent systematic review of the literature reported in 2,714 patients at 2-year follow-up a median increase of ed equal to 17%, 26%, 23%, and 23%, in men who underwent three-dimensional conformal radiation therapy, intensity-modulated radiotherapy, low dose rate of brachytherapy, and stereotactic body radiation therapy, respectively. goy et al. (17) reported in 1,503 men with intermediate risk pca who underwent radical prostatectomy vs. external radiotherapy vs. brachytherapy a prevalence of ed at 10 years of follow up equal to 24.3%, 6.6%, 8.2%, respectively; in addition, ed was not significantly different in men submitted to standard dose radiation therapy (38.1%) vs. dose escalated radiation therapy (49.7%) (18). recently, the introduction in clinical practice of the so-called precision medicin table 1. clinical findings and drugs therapy in the 56 patients submitted to hypofractionated radiotherapy. clinical findings no (%) of patients median age (years) 70 (range: 58-82) psa 4.1-10 ng/ml 43 psa > 10 ng/ml 13 abnormal dre luts 42 qmax 12 ipss (median) 11 (4-29) comorbidities: 35 diabetes mellitus 9 hypertension 23 gastritis 12 cardiovascular ischemic disease 6 other 9 drug therapy (overall): 495 (88.3) oral hypoglycemic 6 antihypertensive 25 antiplatelet agents 34 diuretic 10 proton pomp inhibitor 23 alfa-blockers 50 other 15 dre: digital rectal examination; luts: lower urinary tract symptoms; ipss: international prostate symptoms score. table 2. international index erectile function (iief-5) in 56 patients before (baseline) and after 6 and 18 months from hypofractionated radiotherapy. ieff-5 (score: 5-25) baseline 6 months 18 months median age: 70 years (%) (%) (%) absence of erectile dysfunction (ed) (22-25) 32 (57.1) 20 (62.5) 20 (62.5) median age: 67 years mild ed (17-21) 4 (7.1) 3 (5.3) 2 (3.5) median age: 72 years mild-moderate ed (12-16) 4 (7.1) 5 (8.9) 5 (8.9) median age moderate ed (8-11) 4 (7.1) 3 (5.3) 2 (3.5) median age: 76 years severe ed (5-7) 12 (21.5) 13 (23.2) 14 (25) median age: 78 years archivio italiano di urologia e andrologia 2022; 94, 2 p. pepe, m. tamburo, p. panella, l. pepe, g. marletta, m. pennisi, f. marletta 168 decreased the risk of complications; in fact, neurovascular-sparing magnetic resonance-guided adaptive radiotherapy seems to reduce the risk of ed following external radiotherapy (19). at the same time, ct-mri image registration using dedicated software, the use of intraprostatic fiducials and hydrogel spacer could help to better focalize radiation therapy into the prostate; therefore, these devices used before radiotherapy could better preserve neurovascular bundle reducing the risk of ed. in our series, to our knowledge the first that evaluated ed following hrt in men submitted hydrogel spacer and intraprostatic fiducials injection, we reported among 32/56 (57.1%) men who had a normal sexual activity before hrt, at a median follow up 18 months, a restored pretreatment sexual potency in 20/32 (62.5%) (median iief-5 score: 21; range = 19-25). in addition, the 12/32 men who worsened the sexual function following hrt had a median age higher than patients without de (78 vs. 67 years). regarding our results some considerations should be done. firstly, the true sexual activity of the couple administering a sexual questionnaire to the partners was not investigated. secondly, in the absence of a control group we don’t know if the onset of ed was really given by hrt; at the same time, the role of hydrogel injection in preventing ed in comparison with hrt alone can not be established. finally, a greater number of patients should be evaluated. in conclusion, in our preliminary experience, the use of hydrogel injection and intraprostatic fiducials followed by hrt allowed to kept pretreatment sexual potency in 62.5% of the cases. references 1. dearnaley dp, jovic g, syndikus i, et al. escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the mrc rt01 randomised controlled trial. lancet oncol 2014; 15:464-473. 2. aluwini s, pos f, schimmel e, et al. hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (hypro): late toxicity results from a randomised, non-inferiority, phase 3 trial. lancet oncol 2016; 17:464-474. 3. hall wa, tree ac, dearnaley d, et al. considering benefit and risk before routinely recommending spaceoar. lancet oncol 2021; 22:11-13. 4. ung m, bossi a, abbassi l, et al. [dosimetric impact of hydrogel spacer use for stereotactic body radiotherapy of localised prostate cancer]. cancer radiother 2021; 25:237-241. 5. babar m, katz a and ciatto m. dosimetric and clinical outcomes of spaceoar in men undergoing external beam radiation therapy for localized prostate cancer: a systematic review. j med imaging radiat oncol 2021; 65:384-397. 6. butler wm, kurko bs, scholl wj, et al. effect of the timing of hydrogel spacer placement on prostate and rectal dosimetry of lowdose-rate brachytherapy implants. j contemp brachytherapy 2021; 13:145-151. 7. aminsharifi a, kotamarti s, silver d, et al. major complications and adverse events related to the injection of the spaceoar hydrogel system before radiotherapy for prostate cancer: review of the manufacturer and user facility device experience database. j endourol 2019; 33:868-871. 8. pepe p, tamburo m, pennisi m, et al. clinical outcomes of hydrogel spacer injection space oar in men submitted to hypofractionated radiotherapy for prostate cancer. in vivo 2021; 35:3385-3389. 9. dearnaley d, syndikus i, mossop h, and chhip investigators: conventional versus hypofractionated high-dose intensitymodulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 chhip trial. lancet oncol 2016; 17:10471060. 10. lee wr, dignam jj, amin mb, et al. randomized phase iii noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. j clin oncol 2016; 34:23252332. 11. catton cn, lukka h, gu cs, et al. randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. j clin oncol 2017; 35:1884-1890. 12. pepe p, pennisi m: erectyle dysfunction in 1,050 men submitted to extended (18 cores) vs saturation (28 cores) vs saturation plus mri targeted prostate biopsy (32 cores). int j impot res 2016; 28:1-3. 13. pepe p, garufi a, priolo gd, et al. is it time to perform only mri targeted biopsy? our experience in 1032 men submitted to prostate biopsy. j urol 2018; 200:774-778. 14. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology 2020; 137:133-137. 15. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. clin genitourin cancer. 2021; 19:305-308. 16. hunt aa, choudhury kr, nukala v, et al. risk of erectile dysfunction after modern radiotherapy for intact prostate cancer. prostate cancer prostatic dis. 2021; 24: 128-134. 17. goy bw, burchette r: ten-year treatment complication outcomes of radical prostatectomy vs external beam radiation vs brachytherapy for 1503 patients with intermediate risk prostate cancer. brachytherapy 2021; 20:1083-1089. 18. hall wa, deshmukh s, bruner dw, et al. quality of life implications of dose-escalated external beam radiation for localized prostate cancer: results of a prospective randomized phase 3 clinical trial, nrg/rtog 0126. int j radiat oncol biol phys. 2022; 112:83-92. 19. teunissen fr, wortel rc, wessels fj, et al. interrater agreement of contouring of the neurovascular bundles and internal pudendal arteries in neurovascular-sparing magnetic resonance-guided radiotherapy for localized prostate cancer. clin transl radiat oncol. 2021; 32:29-34. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com paolo panella, md ppanella5@gmail.com ludovica pepe, md ludopepe97@gmail.com michele pennisi, md michepennisi2@virgilio.it urology unit, cannizzaro hospital, via messina 829, catania (italy) maria tamburo, md marinellatamburo@virgilio.it giulia marletta, md marlettagiulia1@gmail.com francesco marletta, md francescomarletta1@gmail.com radiotherapy unit, cannizzaro hospital, catania (italy) stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13516 1 original paper an effective alternative for advanced blca due to their better tolerance especially by older patients with more comorbidities. however, despite durable responses shown in a subset of patients with blca, the overall response rate of ici’s is only 15%~25%, which increases the demand for biomarkers of response and therapeutic strategies that can overcome resistance to icis (4, 5). lactylation modification has been well studied for its potential role in cancer progression (6-8). the tumor microenvironment is characterized by low ph, hypoxia, and increased lactate production. lactate, a product of pyruvate metabolism, is known to play an important role in promoting tumor growth and metastasis by modulating the extracellular matrix, angiogenesis, and immune evasion (9-11). lactylation has also been found to alter the activity and stability of intracellular proteins, leading to changes in certain cellular processes including glycolysis (12, 13) and apoptosis (14). in addition, lactylation can further affect the interactions between tumor cells and their microenvironment by promoting or inhibiting tumor progression (15-17). these findings suggest that lactylation may serve as a potential target for the development of novel cancer therapeutics to interfere with lactate signaling pathways and disrupt tumor progression. however, the role of lactylation in blca remains still unclear. in this present study, we aimed to identify lactylationrelated gene subtypes of blca through unsupervised clustering in order to compare clinical features, differentially expressed genes (degs), pathways and immune cell infiltration between the lactylation-related gene subtypes identified. furthermore, by establishing a special lactylation score we also aimed to predict the overall survival of blca patients. lastly, we investigated the correlation between the lactylation score and the tumor immune microenvironment, as well as the potential for immunotherapeutic efficacy. objective: lactylation is a type of chemical modification involving the introduction of lactyl groups to a molecule which can affect the interactions between tumor cells and their microenvironment. this study aims to evaluate the possible role of lactylation-related gene signature in the prediction of both prognosis and immunotherapy response in bladder cancer (blca). methods: lactylation-related genes were obtained from the published work and two subtypes (cluster a and b) were identified through unsupervised clustering. the differences including clinical features, differentially expressed genes (degs), pathways, and immune cell infiltration between these two clusters were thoroughly examined. results: by utilizing the degs between the two clusters, a lactylation score was identified to predict the overall survival status and the response of blca patients receiving immunotherapy. our results demonstrated that patients with a high lactylation score tended to have a worse survival period and increased immune cell infiltration level. further analysis showed that high lactylation score may be associated with higher sensitivity to immune checkpoint inhibitor (ici) treatment which is crucial in the identification of the suitable candidates for ici therapy. conclusions: our results emphasize the possible predictive role of lactylation-related gene signature both in the survival rates of blca and its implications for treatment strategies. key words: lactylation; gene signature; bladder cancer; prognosis; immunotherapy. submitted 22 december 2024; accepted 3 january 2025 introduction bladder cancer (blca) is one of the most common malignant pathologies of the genitourinary tract, with approximately 573,000 new cases and 212,000 deaths per year worldwide. the incidence of blca is still increasing owing to population growth and ageing (1-3). in recent years, immune checkpoint inhibitors (icis) took attention as predictive role of lactylation-related gene signature in the prognosis and immunotherapy response in bladder cancer guoyuan liu 1*, ting hong 2*, xinyu liu 2*, xuanhao lin 3, peixiu yao 3, xifeng chen 3, yonghai zhang 1, kemal sarica 4, 5, xuwei hong 1 1 department of urology, shantou central hospital, shantou, china; 2 clinical medical research center, shantou central hospital, shantou, china; 3 department of biobank, shantou central hospital, shantou, china; 4 department of urology, health sciences university, prof. dr. ilhan varank education and training hospital, istanbul, turkey; 5 department of urology, biruni university, medical school, istanbul, turkey. * these authors contributed equally to this work. doi: 10.4081/aiua.2025.13516 summary archivio italiano di urologia e andrologia 2025; 97(1):13516 g. liu, t. hong, x. liu, et al. 2 materials and methods sources of sample the cancer genome atlas urothelial bladder carcinoma (tcga-blca) is a data collection initiative that is part of a larger effort to connect cancer phenotypes to genotypes. the data includes clinical, genetic, pathological, and radiological information of 412 tumor samples and 19 normal samples. gse13507 is a public gene expression dataset that identifies prognosis-related gene signatures in blca. it contains 165 primary tumors, 23 recurrent tumors, 58 normal bladder mucosae surrounding cancer and 10 normal bladder mucosae, the clinical characteristics of included samples are attached as well. data collection the mrna expression profile and clinical data for tcgablca (412 tumor tissues) were downloaded from the university of california santa cruz (ucsc)-xena database (https://xenabrowser.net/datapages/), while gse13507 (165 tumor tissues) was obtained from the gene expression omnibus (geo) database (https://www.ncbi.nlm.nih.gov/ geo/). the clinical characteristics and survival outcomes of blca patients from these two datasets were shown in supplementary table s1. r package “limma” was executed to normalize the expression data for nonuniform matrix distribution. to improve the reliability, the two datasets were merged and batch effects were removed using the r package “sva”. the gene set for lactylation was acquired from the published work (18). online analysis the genetic alteration of selected genes, including copy number variant (cnv), methylation and mutation, were conducted using gene set cancer analysis (gsca) database (http://bioinfo.life.hust.edu.cn/gsca/#/), which is an integrated platform for genomic, pharmacogenomic, and immunogenomic gene set cancer analysis. the platform has four main functional modules for cancer gsa to explore, analyze and visualize expression, genomic variations, tumor immune infiltration, drug sensitivity and their associations with clinical outcomes. enrichment analysis gene ontology (go) analysis and kyoto encyclopedia of genes and genomes (kegg) analysis are two common functional annotation methods, which are mainly used to study the functions of genes and proteins. go analysis is performed by classifying the function of a gene or protein into three distinct levels: molecular function, cellular component and biological process to describe their different functions and interactions within cells. kegg analysis is a functional annotation method based on metabolic pathways and biological signaling networks. by correlating genes or proteins with metabolic pathways and signaling networks in kegg databases, it is possible to understand their functional roles and interrelationships in the cells. to obtain the pathways used in gene set variation analysis (gsva), the hallmark, reactome, and kegg pathways were downloaded from version 7.5.1 of the msigdb database. the r package "gsva" was used to calculate the pathway score for each sample. the r package "clusterprofiler" was used to carry out go and kegg analysis of degs. immune cell infiltration analysis the r package "estimate" was used to assess the blca samples' tumor microenvironment, including stromal score, immune score, and estimate score. in order to measure the 23 immune cell infiltrations, the gsva r package's ssgsea function was used. following that, the various groups were compared based on their immune cell level. construction of lactylation score using the r package "limma", we identified 275 degs distinguishing between cluster a and b with |logfc| > 0.5 and p < 0.05. subsequently, we conducted univariate regression analysis, which revealed 11 degs significantly associated with overall survival at p < 0.001. based on these 11 degs, we performed principal component analysis (pca). using principal components 1 and 2, we constructed the lactylation score (19). statistical analysis all data are presented as the mean ± standard deviation (sd). statistical analysis was performed using r software (https://www.r-project.org/, version:4.1.1). p < 0.05 (two-tailed) was considered statistically significant: *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. results identification of lactylation genes-related subtypes of blca the flow chart of the study is show in figure 1. at first, we combined the expression profiles of tumor tissues from tcga-blca and gse13507, and then used univariate cox regression and kaplan-meier analysis to evaluate the prognostic significance of lactylation genes (supplementary table s2). figure 2a depicts the results of univariate cox regression and correlation analysis of lactylation genes. 10 lactylation genes were revealed to have some correlation with each other. among them, 9 genes were identified as risk factors and one was favorable factor. while figure 2b illustrates 7 lactylation genes that were significantly associated with the prognosis of blca patients revealed by kaplan-meier analyses. next, we divided blca into two subtypes, cluster a and b, based on the expression pattern of lactylation genes (figure 3a), and found that there was a clear distinction between cluster a and b according to the pca plot (figure 3b). we also presented the distribution of clinical features and lactylation gene expression in each cluster (figure 3c, d). furthermore, we assessed the immune infiltration in blca samples, and found that the stromalscore, immunescore, and estimatescore were all higher in cluster a (figure 3e), and most immune cell levels were more highly infiltrated in cluster a than in cluster b (figure 3f). we also investigated the differences between the two clusters in terms of various pathways using gsva. we discovered that most of the hallmark pathways, kegg pathways, and reactome pathways had higher scores in cluster b (supplementary figure s1). for hallmark pathways, the scores tgf beta signaling pathway and mtorc1 signaling pathway were higher in cluster b. for kegg, the scores of tgf beta signaling pathway, wnt signaling archivio italiano di urologia e andrologia 2025; 97(1):13516 3 lactylation-related gene signature in bladder cancer pathway, and mtor signaling pathwaywere higher in cluster b. for reactome results, most pathways were observed to be higher in cluster b. these findings suggested that the biggest difference between the two subtypes was in the pathways associated with carcinogenesis. identification of gene subtypes and construction of lactylation score by employing the "limma" package, 275 degs were screened between cluster a and cluster b (figure 4a). the go enrichment analysis highlighted that these degs were enriched in cell growth and g1/s transition of mitotic cell cycle in biological process (bp), cell leading edge and nuclear speck in cellular component (cc), and dna−binding transcription factor binding in molecular function (mf) (figure 4b-d). in terms of kegg, the degs were predominantly enriched in cell cycle, p53 signaling pathway, and nicotinate and nicotinamide metabolism (figure 4e). furthermore, we utilized univariate cox regression analysis to determine the prognostic significance of the 275 degs and identified 11 genes associated with overall survival (p < 0.001) (figure 5a, supplementary table s3). to confirm above findings, unsupervised clustering separated patients into two subtypes based on these 11 prognostic genes, genecluster a-b (figure 5b). patients categorized in genecluster a had worse survival rates compared to those in genecluster b (figure 5c). the expression of the 11 lactylation-related genes was depicted in figure 5d, while figure 5e showed the distribution of clinical features and expression of the 11 prognostic genes in the two geneclusters. using the pca algorithm, the 11 prognostic genes were used to establish the lactyfigure 1. flow chart of the study. archivio italiano di urologia e andrologia 2025; 97(1):13516 g. liu, t. hong, x. liu, et al. 4 lation score. figure 5f suggested that patients with a high lactylation score have worse survival. the correlation between cluster, genecluster, lactylation score, and survival status is depicted in figure 5g using a sankey diagram. we analyzed the correlation of lactylation score with immune cell infiltration and found that patients with high lactylation score have elevated immune cell infiltration level (figure 5h). figure 2. correlation and prognostic value of lactylation genes in blca: a. network diagram showing the interaction of lactylation genes in blca. the line connecting the lactylation genes represents their correlation, with the line thickness indicating the strength of the correlation between lactylation genes. blue and pink represent negative and positive correlations, respectively. b. kaplan-meier analysis of indicated genes. archivio italiano di urologia e andrologia 2025; 97(1):13516 5 lactylation-related gene signature in bladder cancer figure 3. identification of lactylation genes-related subtypes of blca: a. consensus matrix heatmap defining various clusters and their correlation area. b. pca plot of blca patients in two clusters. c. distributions of clinical features and expression levels of lactylation genes between two clusters. d. the expression of lactylation genes in cluster a and cluster b. e. the tumor microenvironment difference in two clusters. f. the difference of immune cell infiltration level in two clusters. archivio italiano di urologia e andrologia 2025; 97(1):13516 g. liu, t. hong, x. liu, et al. 6 figure 4. enrichment analysis of degs between two lactylation subtypes: a. volcanic map of degs between two clusters. b-d. go enrichment analysis of degs, including bp, cc, and mf. e. the correlation of degs with top5 terms of kegg results. archivio italiano di urologia e andrologia 2025; 97(1):13516 7 lactylation-related gene signature in bladder cancer genetic alteration of prognostic genes we further explored the expression and genetic alterations of 11 prognostic genes. the snv frequency of these genes was generally low, with tbx3 having the highest snv frequency (supplementary figure s2a-b). supplementary figure s3a displays the percentage of copy number variation (cnv) for each gene. tp53inp1 had the highest amplification cnv frequency, while lgals1 showed a significant figure 5. construction of lactylation score in blca: a. forest plot presenting results of univariate cox regression analysis. b. consensus matrix heatmap defining various clusters and their correlation area. c. kaplan-meier analysis of blca patients in two geneclusters. d. the expression of indicated genes in two geneclusters. e. distributions of clinical features and expression levels of 11 degs between the two geneclusters. f. kaplan-meier analysis of lactylation score in blca. g. the sankey diagram visualized the correlation between cluster, genecluster, lactylation score, and survival status of blca patients. h. the correlation between lactylation score and immune cell infiltration. red color represents positive correlation, blue color represents negative correlation. archivio italiano di urologia e andrologia 2025; 97(1):13516 g. liu, t. hong, x. liu, et al. 8 cnv deletion. we also represented the percentage of heterozygous and homozygous cnv of each gene in blca, including heterozygous amplification, heterozygous deletion, homozygous amplification, and homozygous deletion (supplementary figure s3b). the linear cnv levels of tcirg1, tp53inp1, and tbx3 were positively correlated with their mrna expression (supplementary figure s3c). the expression of these genes was generally negatively correlated with their dna methylation level (supplementary figure s3d). the association of lactylation score with clinical features additionally, we discovered that patients who are alive have lower lactylation scores compared to those who have passed away (figure 6a). the proportion of patients who are alive in the high lactylation score group (43%) was lower than that in the low lactylation score group (63%). furthermore, a higher lactylation score was strongly associated with other clinical features, including gender, grade, who stage, n stage, and t stage in blca (figure 6b-f). the correlation of lactylation score with immune microenvironment and efficacy of immunotherapy the correlation between the immune microenvironment and lactylation score was evaluated. as illustrated in figure 7a, chemokine and receptor expression were notably elevated in the high lactylation score category. the lactylation score exhibited a favorable correlation with immune-related pathways such as inflammatory response, il6-jak-stat3 signaling pathway, il2-stat5 signaling pathway, and interferon gamma response (figure 7b). additionally, the high lactylation score group demonstrated an elevated immune checkpoint expression, including figure 6. the association of lactylation score with clinical features: a. left: the lactylation score in alive and dead groups. right: the percentage of alive and dead patients in high and low lactylation score groups. b. left: the lactylation score in various gender. right: the percentage of various gender patients in high and low lactylation score groups. c. left: the lactylation scores in highand low-grade groups. right: the percentages of highand low-grade patients in high and low lactylation score groups. d. left: the lactylation score in highand low-stage groups. right: the percentage of high and low stage patients in high and low lactylation score groups. e. left: the lactylation score in high and low n stage groups. right: the percentage of high and low n stage patients in high and low lactylation score groups. f. left: the lactylation score in high and low t stage groups. right: the percentage of high and low t stage patients in high and low lactylation score groups. archivio italiano di urologia e andrologia 2025; 97(1):13516 9 lactylation-related gene signature in bladder cancer cd274, ctla4, lag3, pdcd1, and tigit (figure 7c). moreover, the high lactylation score group presented a higher frequency of gene mutations (supplementary figure s4a-c). these findings further support the theory that cancer patients with a high lactylation score may respond well to immunotherapy. to verify our hypothesis, further analysis was performed using immunotherapy datasets. we confirmed that patients with a high lactylation score were responsive to ici treatment in the imvigor210 cohort (20) (figure 7de; urothelial carcinoma) and nct02684006 cohort (21) (figure 7f-g; renal clear cell carcinoma). figure 7. the correlation of lactylation score with immune microenvironment and efficacy of immunotherapy: a. the expression of chemokines and chemokine receptors in high and low lactylation score group in blca. b. the correlation of lactylation score with hallmark pathway scores. c. the expression of immune checkpoints in high and low lactylation score group. d. kaplan-meier analysis of patients in high and low lactylation score groups in imvigor210 cohort. e. the percentage of patients with different progress status after ici treatment in high and low lactylation score groups in imvigor210 cohort. f. kaplan-meier analysis of patients in high and low lactylation score groups in nct02684006 cohort. g. the percentage of patients with different progress status after ici treatment in high and low lactylation score groups in nct02684006 cohort. archivio italiano di urologia e andrologia 2025; 97(1):13516 g. liu, t. hong, x. liu, et al. 10 apart from immunotherapy, we also analyzed other antitumor drugs. based on the predicted results using the r package “prrophetic”, we displayed 6 commonly used chemotherapeutic agents for blca, including gemcitabine, cisplatin, vinblastine, doxorubicin, docetaxel, and paclitaxel, may be resistant to patients with a high lactylation score. furthermore, 5 targeted agents, including sunitinib, pazopanib, gefitinib, erlotinib, and tipifarnib, were also revealed to be resistance in high lactylation score group (supplementary figure s5). discussion lactylation modification seems to have an important place in cancer therapeutics research. it has been well shown that tumor cells undergo metabolic reprogramming, resulting in increased lactate production and alterations in the microenvironment (22-24). related with this issue, lactate has been shown to play a critical role in tumor growth and progression by promoting angiogenesis, immune evasion, and metastasis (25). moreover, lactylation of proteins has been found to modulate cellular processes involved in carcinogenesis regarding the survival, proliferation, and invasion status (26, 27). these findings suggest that lactylation modification may offer novel therapeutic targets in the management of cancer. however, further studies are needed to identify specific lactylated targets and explore the possible underlying mechanisms of this process in different types of tumors. in recent years, increasing attention has been focused on the possible role of lactylation modification in carcinogenesis of different tumor types such as bladder cancer (28), lung cancer (29), liver cancer (27, 30), and gastric cancer (31). a recent study indentified a unique cluster of cisplatin-resistant epithelial cells by constructing a blca single-cell atlas. the elevated lactylation was founded in the cisplatin-resistant cluster and verified in blca cell lines with cisplatin resistance. furthermore, h3k18la was up-regulated in cisplatin-resistant blca cell lines, and heightened transcription factor expression such as ybx1 and yy1, ultimately driving cisplatin resistance in blca (28). more and more studies demonstrated the emerging evidence suggesting that lactylation modification plays a critical role in the pathogenesis and progression of cancer. however, further research is certainly needed to explore the exact underlying mechanisms of lactylation in different types of tumors and to develop novel lactylation-based therapies for the treatment of cancer. in this study, firstly we evaluated 11different lactylation genes. by examining the expression of these lactylation genes, we identified two subtypes of blca (cluster a and b). additionally, we observed the difference in malignant cancer-promoting pathways and immune-related pathways between cluster a and b, such as tgf beta signaling, mtorc1 signaling, and wnt signaling pathway. based on these findings, in the second stage we investigated the immune infiltration in blca samples. the stromal, immune, and estimate scores were all higher in cluster a, and most immune cell levels were found to be highly infiltrated in cluster a than in cluster b. based on this information in our study we aimed to develop a lactylation score for quantifying patient risk. initially, we screened 275 degs across two clusters and later we conducted univariate cox regression analysis to determine the prognostic value of these 275 degs. 11 genes being identified at the last stage have been found to be correlated with overall survival period (p < 0.001). following this critical evaluation based on the pca algorithm used , we established a lactylation score depending on these 11 prognostic genes. in addition to the poorer survival rates observed in patients with high lactylation scores; the correlation between the lactylation score and immune cell infiltration suggested a positive association between these two variables. among the 11 genes included in the established lactylation score, clic3、tcirg1 、s100a8 and lgals1 were found to be related to glycolysis and lactate regulation in tumor cells. clic3 and tcirg1, as a member of the chloride intracellular channel protein family and a subunit of a large protein complex known as a vacuolar h+-atpase (v-atpase) respectively, play important roles in regulating the ph of cells and their surrounding environment (32, 33). the acidification of the tumor microenvironment (tme) can regulate glycolysis in cells and mediate the production of lactate, thereby regulating the lactylation modification of proteins (34). s100a8 is a member of the s100 family of proteins containing 2 ef-hand calcium-binding motifs. it is involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. according to a recent study, s100a8 also play a critical role in promoting macrophage perturbation and glycolysis through the tlr4/myd88/nf-κb signaling pathway (35). lgals1, also known as gal-1, is a member of the family of beta-galactoside-binding proteins implicated in modulating cell-cell and cell-matrix interactions. previous study had revealed that the tlr4/gal-1 signaling pathway could regulate lactate-mediated emt processes in crc cells (36). although no studies have revealed that the other seven genes are directly or indirectly related to lactylation modification, many studies have reported that they are closely related to the occurrence and development of bladder cancer. among them, sphk1, rcn3, cda, tbx3, aebp1 and krt16 are widely reported oncogenes. it can regulate cell apoptosis, promote cell proliferation, migration, or resist immune killing by activating stat3 and nf-κb signaling pathways, participating in collagen biosynthesis, inducing specific gene mutations, or acting as transcriptional promoters (37-43). tp53inp1 has been reported to be a tumor suppressor gene in bladder cancer, which can inhibit the migration and invasion of bladder cancer cells by inducing autophagy and inhibiting the activation of extracellular regulated kinase (erk) (44). the effectiveness of an ici treatment can be predicted by chemokines, chemokine receptors, and immune checkpoints (45, 46). chemokines are critical in directing immune cell migration necessary to mount and deliver an effective antitumor immune response. chemokine secretion is often altered in the tme, and an aberrant chemokine profile can facilitate the differentiation and infiltration of immunosuppressive pro-tumorigenic cells into the tumor, namely treg cells, mdscs and tams. due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential archivio italiano di urologia e andrologia 2025; 97(1):13516 11 lactylation-related gene signature in bladder cancer immunotherapy target (47). in addition, immune checkpoints are another key regulator of the tumour immune response. normally, the presence of immune checkpoints avoids the damage caused by excessive immune response, but tumour cells can escape from the immune system by expressing corresponding ligands that bind to them, activating inhibitory pathways or inhibitory immune checkpoints within the immune cells, inhibiting immune cell activity or mediating apoptosis of immune cells. immune checkpoint inhibitors can enhance the immune attack against tumours by blocking the interaction of these immune checkpoint proteins with their ligands and preventing the inactivation of t-cell function (48). our results reveal that high expression levels of chemokines, chemokine receptors, and immune checkpoints were observed in the group with high lactylation scores, which indicated although high lactylation score is a poor prognostic factor for blca, patients with high lactylation score may respond better to an ici treatment. this finding is highly valuable in an attempt to predict the efficacy of ici treatment in a reliable manner in cases with blca. the analysis of immunotherapy datasets confirmed that patients with high lactylation scores had positive responses to ici treatment in the imvigor210 and nct02684006 cohorts. these findings again further supported our findings. however, as a bioinformatics-based analysis, the findings of this study are subjected to several limitations. first and foremost, as research in the protein lactylation field is still in its preliminary stages, there are relatively few genes directly related to lactylation modification reported. therefore, the lactylation gene subtypes and lactylation score identified based on these genes may not be able to fully describe the characteristics of lactylationrelated gene signature. furthermore, the experimental validation of all signature genes currently faces practical difficulty due to the lack of corresponding lactylation antibodies. another potential limitation of this study is that the findings of this study rely mainly on retrospective data collected from public databases. the accuracy of the lactylation score in predicting the response to ici treatment by bca still needs to be verified by large-scale clinical trials. conclusions in the light of our findings and the limited data published so far in the literature, we may state that lactylation genes have a significant control over the immune microenvironment of tumors, clinical traits and treatment outcomes in cases with blca. moreover, a lactylation score has been well established by our group and this scoring has proven its reliability in the prediction of the prognosis and efficacy of ici treatment. all these observations 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cancer via mirna-221/tp53inp1/p-erk axis. front oncol. 2020; 10:589. 45. pinato dj, howlett s, ottaviani d, et al. association of prior declarations ethical approval: the study was approved by the institutional review board of shantou central hospital and carried out following the declaration of helsinki. availability of data and material: the data that support the findings of this study are available with the article and its supplementary material, or are available from the corresponding authors upon reasonable request. competing interests: the authors declare that there is no conflict of interest. funding: this study was supported by the national natural science foundation of china (grant no. 82372685), basic and applied basic research foundation of guangdong province (grant no. 2023a1515220213), science and technology planning projects of guangdong province (grant no. stkj202209068), science and technology program of shantou city (grant no. sfk[2023] no.68-1). authors' contributions: conceptualization: x.h and y.z.; investigation: g.l., t.h.; and x.l. data curation: t.h. and x.l.; formal analysis: g.l.; methodology: x.l.; resources: p.y.; software: x.c.; writing original draft: g.l. and t.h.; writing review & editing: x.h., k.s. and y.z. funding acquisition: x.h. and y.z. consent for publication: all authors have read and approved the content and agree to submit for consideration for publication in the journal. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(1):13516 13 lactylation-related gene signature in bladder cancer antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. jama oncol. 2019; 5:1774-8. 46. liu l, bai x, wang j, et al. combination of tmb and cna stratifies prognostic and predictive responses to immunotherapy across metastatic cancer. clin cancer res. 2019; 25:7413-23. 47. bule p, aguiar si, aires-da-silva f, dias jnr. chemokinedirected tumor microenvironment modulation in cancer immunotherapy. int j mol sci. 2021; 22. 48. peng q, qiu x, zhang z, et al. pd-l1 on dendritic cells attenuates t cell activation and regulates response to immune checkpoint blockade. nat commun. 2020; 11:4835. correspondence guoyuan liu liugyst@126.com yonghai zhang zhang_yonghai@126.com department of urology, shantou central hospital, shantou, china ting hong 695594973@qq.com xinyu liu lxy19971116@163.com clinical medical research center, shantou central hospital, shantou, china xuanhao lin stbiobank@126.com peixiu yao yaopeixiu0646@qq.com xifeng chen cxf8282@163.com department of biobank, shantou central hospital, shantou, china kemal sarica saricakemal@gmail.com department of urology, health sciences university, prof. dr. ilhan varank education and training hospital, istanbul, turkey xuwei hong (corresponding author) hong_xuwei@sina.cn shantou central hospital, 114th waima road, shantou 515031, p.r. china stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13935 1 letter to editor key words: benign prostatic hyperplasia; bladder outlet obstruction; mri; urology. submitted 29 april 2025 accepted 10 may 2025 to the editor benign prostatic hyperplasia (bph) is a highly prevalent histological condition in aging men that can commonly cause lower urinary tract symptoms (luts) due to benign prostatic obstruction (bpo). bph typically begins developing after the age of 40 and affects approximately 50-60% of men by age 60 (1). with the recent emergence of minimally invasive treatments (mits) in bpo treatment – including urolift, echolaser, rezūm, prostate artery embolization, and itind – detailed assessment of prostatic anatomy has become of paramount importance. such procedures can often be limited by factors such as prostate volume, the presence of a high bladder neck or of a median lobe (2). whilst transrectal ultrasound (trus), often combined with flexible cystoscopy, remains commonly employed in bpo evaluation, multiparametric magnetic resonance imaging (mpmri) is less invasive and can offer superior information which we believe can be beneficial to the patient. rationale for preoperative mpmri in bpo evaluation in our clinical experience, many men presenting with luts or urinary retention express concerns that they may have underlying prostate cancer. it is therefore important to exclude a prostate cancer diagnosis before considering a bpo procedure. this is particularly critical in the context of mits and vaporisation procedures, which do not yield tissue for histopathological analysis. acquiring an mri of the prostate and assessing for prostate cancer can alter the management as cancer management would take precedence over bladder outflow obstruction (boo) procedures. even in procedures that do retrieve tissue, such as transurethral resection of the prostate (turp) or enucleation techniques, a preoperative diagnosis of clinically significant prostate cancer can change the treatment plan. for example, if a patient with bpo and concomitant prostate cancer opts for a radical prostatectomy, it will address both his cancer and obstruction – thus eliminating the need for a separate boo procedure. moreover, the incidental discovery of prostate cancer on bpo histology often usually prompts a multidisciplinary team discussion (mdt) and recommendation of a delayed mpmri typically 3 to 6 months after the procedure allowing for postoperative changes to resolve in order to more easily be able to identify suspicious lesions present in the residual transitional zone or unsampled peripheral zone. this delay may be significantly stressful for some patients and, at least theoretically, could even compromise the chance of a cancer cure in those with significant prostate cancer that is underestimated by the tissue retrieved from the bpo procedure. any such delay would have been avoided if an mri had been performed preceding the bpo procedure. mri is highly accurate in terms of diagnosing locally advanced prostate cancer and can also identify suspicious lesions for subsequent targeted biopsy. it is superior to the combination of prostate specific antigen (psa) and digital rectal examination (dre) which is the only other way of screening for significant prostate cancer in the absence of mri (3). there are cases where prostate cancer can present without a raised psa. in 2004 thompson et al analysed data of nearly 10,000 men. about 3,000 of these men never had a psa level of more than 4 ng/ml. interestingly, 15% of these men should magnetic resonance imaging be considered in every patient before a bladder outflow obstruction procedure? ivo donkov 1, nikolaos chatzikrachtis 1, abhisekh chatterjee 2, tevita aho 3, mark emberton 4, panagiotis nikolinakos 1 1 department of urology, west middlesex university hospital, chelsea & westminster hospital nhs foundation trust, london, uk; 2 imperial college school of medicine, imperial college london, london sw7 5nh, uk; 3 cambridge university hospitals nhs foundation trust, cambridge, cb2 0qq, uk; 4 division of surgery & interventional science, university college london, london, wc1e 6bt, uk. doi: 10.4081/aiua.2025.13935 archivio italiano di urologia e andrologia 2025; 97(2):13935 i. donkov, n. chatzikrachtis, a. chatterjee, et al. 2 had prostate cancer, with 15% of those cancers being high grade tumours (4). current guidelines consider psa of less than 6.5 ng/ml to be in reference range for men 70 years and above, which is the usual age group of patients requiring bph surgery. we can speculate on the results of the goteborg trial, assessing the prostate cancer risk in men with psa below 3 ng/ml (5), that increase in the overall cumulative incidence may be due to performing psa screening rather than mri imaging, and a certain percentage of those patients might have already had undiscovered prostate cancers with a psa of less than 3 ng/ml, which might have been detected had an mpmri been performed. additionally, post operative psa levels may not accurately reflect the underlying cancer risk. it is well known that each gram of prostate tissue resected decreases psa by 0.15 ± 0.11 ng/ml, while 1% prostate volume resection leads to a reduction of 2.4 ± 0.4% of serum psa from its baseline (6). thus in patients with normal or borderline psa, stable grade prostate cancer can be missed if pre-treatment mpmri has not been performed, and we solely rely on post treatment psa results which will be subsequently reduced by the reduction of adenomatous tissue. the urolift procedure introduces permanent metallic implants, which create significant artifacts on mpmri. these artifacts, especially in 3.0 tesla systems using gradient echo sequences, can obscure up to 15 mm around each implant (6). moreover, ablations do create areas of necrosis that may distort the normal zonal anatomy between the peripheral and transition zones, and prostate artery embolisation can create infarcts in the transition zone. therefore, acquiring a baseline mpmri prior to these interventions can be helpful for future comparison, if another mri is indicated (7). beyond its role in cancer detection, mri offers superior anatomical evaluation of the prostate when compared to alternatives such as us and flexible cystoscopy (8). mri allows for accurate assessment of prostatic anatomy with clear distinction of the prostatic zones, median lobe configuration, volume of the prostate, intravesical component, presence of a high bladder neck, bladder diverticula, and calculi (9). pesapane et al compared conventional mpmri and the quicker and cheaper unenhanced bpmri and demonstrated similar diagnostic performance between the two modalities, and no high grade prostate cancers were missed by bpmri (10). therefore, it can be useful for assessing prostate anatomy prior to bph procedures. these anatomical features are key to selecting the most suitable surgical option for each individual patient, supporting a tailored and evidence-based approach to bpo management. conclusions current prostate imaging and reporting guidelines, including pi-rads, recommend measuring the prostate volume on t2-weighted mri using either the ellipsoid formulation or planimetric segmentation and include it in the clinical reports. with the growing clinical use of mpmri, unprecedented anatomical detail is now accessible for preoperative planning (11). naturally, an mri classification of bph has also been published detailing the same six patterns of lobar bph distribution previously described on ultrasound and their appearance on mri (11). mri lobar classification of bph has been associated with severity of luts (8). this will definitely aid in adopting the most suitable approach and choosing the most successful treatment option in every patient with bph. in light of mri’s capabilities in detecting prostate cancer and precisely characterising bph anatomy, we believe mri should more routinely integrated into the preoperative workup of patients being considered for bpo procedures. references 1. guneyli s, ward e, thomas s, et al. magnetic resonance imaging of benign prostatic hyperplasia. diagn interv radiol. 2016; 22:215-9. 2. elterman d, gao b, lu s, et al. new technologies for treatment of benign prostatic hyperplasia. urol clin north am. 2022; 49:11-22. 3. mclaughlin pw, troyer s, berri s, et al. functional anatomy of the prostate: implications for treatment planning. int j radiat oncol biol phys. 2005; 63:479-91. 4. thompson im, pauler dk, goodman pj, et al. prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0 ng per milliliter. n engl j med. 2004; 350:2239-46. declarations ethical approval: not required. availability of data and material: not applicable. competing interests: no competing interests to declare. funding: this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. authors' contributions: id, nc and pn have drafted the manuscript, ac, ta and me have critically revised the manuscript. article type: commentary. archivio italiano di urologia e andrologia 2025; 97(2):13935 3 preoperative mpmri in bpo 5. frånlund m, arnsrud godtman r, carlsson sv, et al. prostate cancer risk assessment in men with an initial p.s.a. below 3 ng/ml: results from the göteborg randomized population-based prostate cancer screening trial. scandinavian j urol. 2018; 52:256-62. 6. roehrborn cg, barkin j, gange sn, et al. five year results of the prospective randomized controlled prostatic urethral l.i.f.t. study. can j urol. 2017; 24:8802-13. 7. han ea, nandalur kr, morgan ma, et al. mri of benign prostatic hyperplasia: important preand posttherapeutic considerations. radiographics. 2023; 43:e220096. 8. wasserman nf, spilseth b, golzarian j, metzger gj. use of mri for lobar classification of benign prostatic hyperplasia: potential phenotypic biomarkers for research on treatment strategies. ajr am j roentgenol. 2015; 205:564-71. 9. yacoub jh, oto a. mr imaging of prostate zonal anatomy. radiol clin north am. 2018; 56:197-209. 10. pesapane f, acquasanta m, meo r, et al. comparison of sensitivity and specificity of biparametric versus multiparametric prostate mri in the detection of prostate cancer in 431 men with elevated prostate-specific antigen levels. diagnostics. 2021; 11:1223. 11. walker sm, turkbey b. role of mpmri in benign prostatic hyperplasia assessment and treatment. curr urol rep. 2020; 21:55. correspondence ivo donkov i.donkov@nhs.net nikolaos chatzikrachtis nick.cha@hotmail.com panagiotis nikolinakos, md, msc (corresponding author) pnikolinakos@yahoo.gr department of urology, west middlesex university hospital, chelsea & westminster hospital nhs foundation trust, tw7 6af, london, uk abhisekh chatterjee abhisekh.chatterjee20@imperial.ac.uk imperial college school of medicine, imperial college london, london sw7 5nh, uk tevita aho tev.aho@nhs.net cambridge university hospitals nhs foundation trust, cambridge, cb2 0qq, uk mark emberton mark.emberton@nhs.net division of surgery & interventional science, university college london, london, wc1e 6bt, uk stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):11206 1 original paper mation across distance” (1). telemedicine specifically refers to remote clinical services and was first adopted in the 1950’s when a closed-circuit television connected to a prison was employed by an american psychiatrist to provide mental health services (2-4). due to the covid-19 pandemic outbreak, the request for information on telemedicine activity increased exponentially (5). this phenomenon emerged in an attempt to reduce the chance of infection without compromising patients’ care (6, 7). additionally, the covid-19 pandemic has stressed the digital divide, especially in remote and rural areas (8). hence, the advantages of remote care include both a reduction of the overcrowding in health centers and solving the inequalities in health care access due to sociodemographic and economic characteristics. recently new telemedicine platforms and schedules, such as amazon care or telehealth apps, were created and more and more used by the public (7, 9-11). despite this scenario, health policymakers had to work smarter, promoting more realistic planning and interventions to standardize the information and communication technology (ict). nowadays, social media (some), are important tools for professional networking, medical education, research recruitment, and patient information (12-19). among internet sources, youtube is the second most used website and over 2.6 billion people worldwide use it once a month (17). facebook is the third most used website and counts around 2.9 billion monthly active users in the world (https://www.semrush.com/website/top/). finally, twitter is at eleventh place in the top 500 sites on the web and counts 206 million daily active users worldwide (https://www.semrush.com/website/top/). however, the material available on these platforms differs from studies published within the scientific literature community, which underwent a peer review process, whereas information on the internet is not always checked and verified. consequently, low quality information may be available on the internet and the users may acquire misleading information. the current study aims to evaluate the content type and quality of information on telemedicine available on the most clicked some platforms during the second year following the covid-19 pandemic outbreak. objective: to evaluate the telemedicine information published on the most popular social media platforms, during the second year of the covid-19 pandemic. methods: we queried the buzzsumo tool to identify relatedtelemedicine article links that were shared most on social media, from february 2021 to february 2022. the pemat-p was used for the quality assessment of the most shared links. results: 125 links were eligible for the analysis. facebook was the most used social media platform for sharing articles (median engagement: 1000). most of the articles were published by magazines (n = 82, 65.6%) and the main topic addressed was general information (n = 49, 39.2%). in the subgroup analyses of the 34 most shared articles, facebook was the most used social media platform (median engagement:1950), most of the articles were published by magazines (n = 24, 70.6%), whereas the main topic addressed was the prescription of the abortion pill (n = 9, 26.5%). according to the pemat-p tool, the median understandability and actionability score was 63.8 and 20%, respectively. conclusions: the interest in telemedicine has increased all over the world, as evidenced by the high engagement in social media articles, recorded during the last year. however, the access to digital health services is still limited, the information provided is often not verified by an official entity and unable to fill the digital divide exacerbated by covid 19 pandemic crisis. hence, health policy should be developed or modified to ensure a more egalitarian internet access for all citizens. official medical institutions should standardize telemedicine regulation and online content to reduce the widespread of misleading information. key words: telehealth; virtual healthcare; healthcare technology; covid-19. submitted 27 march 2023; accepted 6 april 2023 introduction telehealth represents a fast-developing area of contemporary medicine during the last decades. the word “telehealth” is defined by “the use of information technology and telecommunications to provide access to health assessment, consultation, diagnosis, intervention, supervision, and infortelemedicine and social media: a contemporary analysis of the most shared content by internet users vincenzo mirone 1, francesco di bello 1, simone morra 1, gianluigi califano 1, luigi cirillo 1, marco abate 1, giovanni maria fusco 1, stefano luzzago 2, claudia mirone 3, luigi napolitano 1, roberto la rocca 1, massimiliano creta 1, giuseppe celentano 1, marco capece 1, gennaro musi 2, francesco mangiapia 1, nicola longo 1, claudia collà ruvolo 1 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples “federico ii”, naples, italy; 2 urology department, istituto europeo di oncologia (i.e.o.), milan, italy; 3 multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples, italy. doi: 10.4081/aiua.2024.11206 summary archivio italiano di urologia e andrologia 2024; 96(1):11206 v. mirone, f. di bello, s. morra, et al. 2 materials and methods search strategy and links selection criteria on february 28th, 2022, from 9:00 a.m. to 6:00 p.m. utc-4, the buzzsumo online analytic tool (http://buzzsumo.com) was used in order to gather the most shared internet links regarding telemedicine. specifically, buzzsumo is an online analytic tool working as a data controller application that searches for articles based on keywords and provides data about the number of shares on the most popular social media platforms, such as facebook, twitter, reddit, and pinterest reporting the article’s engagement. engagement is defined as the total number of interactions (meaning likes, comments, or sharing) that users have with a particular article link. this tool has already been used in previous research papers, in order to collect links regarding a specific topic, also in the medical and public health field (18-21). conversely, other studies evaluated the medical content uploaded in only one of social media platforms (22, 23). for example, loeb et al. evaluated the quality of bladder cancer information on youtube™, without considering other important sharing websites (22). moreover, alex j xu et al. examined the quality of prostate cancer content only on the instagram social media platform (23). thus, in the current study, thanks to the buzzsumo tool, it was possible to explore internet content simultaneously on several and independent social media platforms. according to the buzzsumo 30-day free trial rules, only links published during the year preceding the search date (from the 28th february 2021 to the 28th february 2022) were available for consultation. only “english language” and “all country” settings were applied before searching. the buzzsumo systematic research was performed using the following four keywords: “telemedicine”, “telehealth”, “healthcare technology” and “virtual healthcare”, selected among ten keywords obtained by buzzsumo suggestions (supplementary table 1). only the keyword which provides at least 1000 results and with at least 50% of links related to the telemedicine topic were included. thus, four different searches were performed. for each keyword, the first 50 links were collected, obtaining a total of 200 links. the threshold of 50 links was since buzzsumo allowed to open only the first 100 links and that approximately over the 50th link most of those were with low engagement value and were almost off-topic. the following exclusion criteria were applied (figure 1): i) off-topic (n = 43, 21.5%), ii) duplicates (n = 14, 7.0%), iii) expired links (n = 14, 7.0%) and links with a subscription needed (n = 4, 2.0%). thus, 29, 37, 38 and 21 links (for a total of 125) were included using “telemedicine”, “telehealth”, “healthcare technology” and “virtual healthcare” keywords, respectively. for each link, the following characteristics were collected: facebook, twitter, pinterest, and reddit engagement, evergreen score (measuring the number of social engagements and backsupplementary table 1. search keywords obtained by buzzsumo analytic tool suggestions. only the keyword which provides at least 1000 results and with at least 50% of links related to the telemedicine topic were included. number of links percentage of on-topic links included keywords telemedicine 12709 80% telehealth 22908 76% virtual healthcare 5915 64% healthcare technology 1679 76% included keywords videoconsultation 9147 34% telemedicine and healthcare 920 teleconsultation 469 telemonitoring 269 healthcare on demand 205 televisit 18 figure 1. buzzsumo links identification and selection, from the 28th february 2021 to the 28th february 2022. archivio italiano di urologia e andrologia 2024; 96(1):11206 3 telemedicine and social media links an article receives 30 days after beginning publication, if an article is considered “evergreen” it has maintained it is relevance to an audience for longer) and total engagement. additionally, links’ source (defined as nonmedical informative site [such as magazines], communication channel, alternative media [such as blogs]), medical centers, hospitals or universities, youtube or official national website), topic (defined as information on the role of telemedicine through the years, obstetrics and gynecology [defined as prescription of abortion pill, contraception or pregnancy), telehealth platform, new technologies, health policy, telehealth human relationship, mental health) and country (defined as united states, asia, australia, canada, and europe) data was also collected. in the links’ quality assessment, the following tools, in their language, were used: the jama benchmark score and the patient education materials assessment tool for printable materials (pemat-p). the jama benchmark tool scores website quality based on four criteria: disclosure of authorship, attribution of sources, disclosure of commercial interest and website ownership, and currency (date of update) (24). the pemat-p is a systematic method to evaluate and compare the understandability (17 items) and actionability (7 items) of patient education materials. higher the score and more understandable or actionable is the material (25-28). the links’ content was independently assessed by two investigators (a junior and a senior resident doctor). a third investigator (an associate professor) adjudicated any differences, and a consensus was achieved among all reviewers. statistical analyses descriptive statistics were presented as means with the standard deviation (sd) and medians with the interquartile ranges (iqr) for continuously coded variables or counts and percentages for categorically coded variables. all data were collected for each link included in the analyses. subsequently, subgroup analysis was performed on the most shared links defined as links characterized by facebook, twitter engagement and evergreens score values above the respective overall median score. in all statistical analyses, the r software (www.rproject.org) environment for statistical computing and graphics (r version 4.0.0) was used. results link’s engagement of all 200 links examined, 125 were selected for the analyses (table 1). facebook was the most used some platform to share articles on telemedicine (mean: 3195.5 [sd:967.5], median: 1000 [iqr:130-220]), followed by twitter (mean: 114.8 [sd:20.5], median: 48 [iqr:6-124]), reddit (mean: 41.3 [sd: 29.3], median: 0 [iqr:0-1]) and pinterest (mean:0.4 [sd:0.1], median: 0 [iqr:0]). the mean and median evergreen score was 2.2 (sd:0.3) and 1 (iqr:0-4), respectively. finally, the mean and median total score was 3353.9 (sd:971.4) and 1200 (iqr:211-2500), respectively. link’s characteristics according to the source of the link, most of the articles were published by magazines (n = 82, 65.6%), followed by news organizations (n = 20, 16%), alternative media (n = 10, 8%), youtube (n = 6, 4.8%), medical centers, hospitals or universities (n = 4, 3.2%) and official national website (n = 3, 2.4%). the main topic addressed was information on the role of telemedicine through the years (n = 49, 39.2%), followed by obstetrics and gynecological field (n = 22, 17.6%; specifically the prescription of abortion pill [n = 20, 90.9%]), platform proposal (n = 20, 16%), new technology (n = 15, 12%), health policy (n = 9, 7.2%), mental health (n = 5, 4.0%) and human relationship (n = 4, 3.2%). finally, most of the links were published in the united states (n = 106, 84.8%) (table 2). table 1. social media engagements of 125 links on telemedicine collected with buzzsumo analytic tool, from the 28th february 2021 to the 28th february 2022. engagement is defined as the total number of interactions (meaning likes, comments, or sharing) that users have with a particular article link. overall facebook mean (sd) 3195.5 (967.5) median (iqr) 1000 (130-2200) twitter mean (sd) 114.8 (20.5) median (iqr) 48 (6-124) pinterest mean (sd) 0.4 (0.1) median (iqr) 0 (0-0) reddit mean (sd) 41.3 (29.1) median (iqr) 0 (0-1) evergreen score mean (sd) 2.2 (0.3) median (iqr) 1(0-4) total mean (sd) 3353.9 (971.4) median (iqr) 1200 (211-2500) iqr: interquartile range; sd: standard deviation. table 2. content characteristics of 125 links on telemedicine collected with buzzsumo analytic tool from the 28th february 2021 to the 28th february 2022. overall (n = 125) source number of articles (%) non-medical informative sites 82 (65.6) communication channel 20 (16.0) alternative media 10 (8.0) medical center, hospital or university 4 (3.2) youtube 6 (4.8) official national website 3 (2.4) topic number of articles (%) obstetric and gynecology 22 (17.6) prescription of abortion pill 20 (90.9) contraception 2 (9.0) pregnancy 1 (4.5) information on the role of telemedicine through the years 49 (39.2) telehealth platform 20 (16.0) new technologies 15 (12.0) health policy 9 (7.2) telehealth human relationship 4 (3.2) mental health 5 (4.0) country number of articles (%) united states 106 (84.8) asia 11 (8.8) australia 4 (3.2) canada 3 (2.4) europe 1 (0.8) archivio italiano di urologia e andrologia 2024; 96(1):11206 v. mirone, f. di bello, s. morra, et al. 4 subgroup analysis we performed a subgroup quality assessment analysis on the link characterized by the highest engagement, defined as links with a facebook and twitter engagement and evergreens score values above the respective median score recorded in the overall analyses. of all 125 links examined, 34 were selected for the analyses. as well as in the overall analyses, facebook was the most used some platform for sharing articles on telemedicine (mean:6385.3 [sd:2970.6], median:1950 [iqr:14253950]), most of the articles were published by magazines (n = 24, 70.6%) and were published in the united states (n = 31, 91.2%). differently from the overall analyses, the main topic addressed was the obstetrics and gynecological field (n = 10, 29.4%), specifically the prescription of abortion pill [n = 9, 90%]) (table 3). according to the jama benchmark score, all links respected the four criteria defined as disclosure of authorship, attribution of sources, disclosure of commercial interest and website ownership, and currency (date of update). according to the pemat-p tool, the median understandability score was 63.8% (iqr:50.7-81.2), and the median actionability score was 20% (iqr:0-50.0). discussion after the covid-19 pandemic outbreak in march 2020, the need and interest for telemedicine development increased all over the world (4, 6, 7). the current study aims to evaluate the articles and videos’ content type and quality on telemedicine uploaded on the most clicked some platforms. our analyses identified several noteworthy observations. first, from the overall analyses, it emerged that the social media platform used most to share information on telemedicine was facebook, followed by twitter. while facebook has the greatest number of active user accounts worldwide, twitter appears to be a good platform for the dissemination of scientific information and knowledge transfer. these observations may be explained by a facebook audience of a wide age group. moreover, facebook’s users are allowed to share videos and articles and fix them to posts over a long period (21). conversely, social media platforms such as pinterest or reddit have poorly used for this aim. similar observations were recorded in other studies (13, 19, 21). for example, alsyouf et al. used the buzzsumo analytic tool to gather the most shared articles on genitourinary malignancies and facebook resulted in the most used some platform (13). altogether, some had revolutionized the health information spread, communication and monitoring in health care (29). for instance, petruzzi et al. measured telemedicine impressions via whatsapp and clinical assessments that were consistent in 82% of the cases examined (30). additionally, this new form of knowledge could solve the digital divide of our society, enlightened by the covid-19 pandemic (8). indeed, it should be noted that for people who live in remote and rural areas or covid-19 infected, the access to digital technologies for diagnosis, follow-up and treatment has been a significant resource (8). moreover, telehealth and digital health had decreased the covid-19 exposure, reducing the likelihood of contamination and infection during the pandemic (31). a great contribution was also given by the physicians that started to use the internet to book an appointment, to send and receive examinations and laboratory results through a web-based portal (29). for table 3. social media engagements, content charavteristics quality assessment of 34 most shared links on telemedicine collected with buzzsumo analytic tool from the 28th february 2021 to the 28th february 2022.those links were characterized by a facebook and twitter engagements and evergreens score values above the respectively median score recorded in the overall analysis. overall (n = 34) facebook mean (sd) 6385.3 (2970.6) median (iqr) 1950 (1425-3950) twitter mean (sd) 194.9 (22.225) median (iqr) 145.5 (103.2-258.2) pinterest mean (sd) 1.1 (0.222) median (iqr) 1 (0-2) reddit mean (sd) 137.3 (106.052) median (iqr) 1.5 (0-5.8) evergreen score mean (sd) 5.4 (0.593) median (iqr) 4 (3-6.8) total mean (sd) 6705.9 (2981.643) median (iqr) 2400 (1550-4400) source, n (%) non-informative channel 24 (70.6) communication channel 6 (17.6) alternative media 2 (5.9) medical center, hospital or university 2 (5.9) youtube 0 (0) official national website 0 (0) topic, n (%) obstetrics and gynecology 10 (29.4) prescription of abortion pill 9 (90.0) contraception 1 (10.0) pregnancy 0 (0) information on the role of telemedicine through the years 9 (26.5) health policy 5 (14.7) telehealth human relationship 4 (11.8) mental health 3 (8.8) telehealth platform 3 (8.8) new technologies 0 (0) country, n (%) united states 31 (91.2) asia 1 (2.9) australia 2 (5.9) canada 0 (0) europe 0 (0) pemat-p understandability median (iqr) 63.4 (50.7-81.2) actionability median (iqr) 20 (0-50.0) jama benchmark scoring number percentage of links (1 point for each criteria, max= 4 points) of links adhering to criteria authorship authors and contributors, 34 100 affiliations, and relevant credentials attribution references and sources used 34 100 for the content and relevant copyright information disclosures ownership, sponsorship, advertising, 34 100 underwriting, commercial funding, and potential conflicts of interests currency dates of posted 34 100 and updated information archivio italiano di urologia e andrologia 2024; 96(1):11206 5 telemedicine and social media instance, the georgia health sciences university has enabled the communication between patients and their physicians through a web-based platform for asking questions or requesting prescription refills (32). as a result, both physicians and patients were willing to embrace digital tools to maintain and continue the highquality care delivery (33). in conclusion, the some should be considered as an unprecedented tool that could make evidence-based information accessible to the public and promote positive health behaviors (29). in this regard, the governments must consider telemedicine as an opportunity to facilitate access to the internet and ict for their citizens (33). thus, health policymakers and health care managers must learn about the digital divide and must plan and promote more realistic interventions to improve the access to telehealth (33). second, we recorded that most of the links (65.5%) were published on non-official websites, such as magazines. conversely, only 5% of articles were published by the official national website or medical entities, which should be considered a reliable source. in consequence, the quality content of telemedicine information on the internet is not guaranteed by medical organizations and misleading information may be widespread. in addition, more than 80% of the articles were uploaded in the united states, highlighting a higher interest in them, with respect to the rest of the world. finally, most of the articles wrote about information on the role of telemedicine through the years. for example, alena kharlamenko wrote an article on the platejoy blog describing in detail telemedicine’s definition and the different approaches providing several televisits examples. from our results, it emerged that a non-negligible part of the viewed links focused on telehealth human relationships and mental health. one of the main concerns regarding telemedicine use is the absence of physical contact between patients and physicians, which may impair the clinical evaluation and the correct patient management. the in-person visit is particularly crucial for some kind of specialty, such as psychiatry, where a simple check of laboratory blood exams or a pill prescription is not possible. however, in specific conditions, such as during a covid-19 pandemic, the application of the telemedicine is noteworthy. thus, the category of psychologists and psychiatrists could benefit from telemedicine implementation. for instance, in ireland, 92% of the psychiatrists surveyed reported a reduction in diagnostic confidence due to the absence of a visual comparison with the patients (34). the transitioning from telephone consultations to video consultations would improve to allow a better acceptance of the service and a better receptivity from the specialist physicians (34). in addition to these aspects, several other links focused the attention on the development of new technologies. specifically, mobile health applications (mhas) represent a potential educational instrument of telemedicine. the use of mhas is constantly increasing year to year, but the main concern was the lack of scientific validation (1, 911). this lack is highly restricted. indeed, the mhas could be used both to educate patients about their conditions and to promote high-quality health information. moreover, apps could become a library service accessible to everyone, from health care workers to patients. scientific society should create and validate their own mhas and then promote their use through the general population and to the patients affected by specific diseases. moreover, policymakers should have learnt from covid-19 pandemic crisis that more equal internet access should be guaranteed for the public also in normal times (8). hence, health policy should be developed or modified to ensure a more egalitarian internet access for all citizens. in addition to increasing and widening access to the internet and the health knowledge services, icts should be employed to lead towards digitization of health care (1, 8). in conclusion, several relevant topics were addressed by the link shared on the some. however, few articles better explained the traps hidden with telemedicine, such as an increased level of distrust with doctors and a higher risk of defrauding patients resulting from an absence of appropriate regulation (3). third, in the subgroup analysis, we quantified internet users’ engagement across a variety of social media platforms on the 34 most shared links on telemedicine. subsequently, we evaluated the quality of information shared on these platforms. we recorded that as well for the overall analyses, facebook resulted in the most used platform, whereas the main topic addressed was the prescription of the abortion pill through telemedicine. in december 2021, the food and drug administration permanently removed the in-person requirement for picking up abortion medication (https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/ mifeprex-mifepristone-information) and in 2022 the world health organization recommend the use of telemedicine for abortion pill prescriptions in its abortion care guidelines (world health organization 2022). however, multiple governments place limits on telehealth access to abortion care as evidenced by several articles available on the web. this topic has aroused great interest in the united states, as revealed by our analyses. it may represent a starting point to interpret telemedicine as a powerful instrument to use in several circumstances, from chronic disease management for medical advice. finally, according to the pemat-p results, we recorded a higher understandability than actionability score (median 63.8 vs 20.0%). the understandability score reflects how viewers could process and assimilate articles’ key messages, despite their cultural and medical backgrounds. the actionability score reflects how viewers could apply the information achieved. these observations confirmed what we expected since most of the articles were informative rather than instructive. taken together, telemedicine has become a hot topic during the last years, especially after the need emerged from the covid-19 outbreak, which did not allow patients to get in person visits and healthcare in general. these interests resulted in higher investments from governments all over the world (7). from our analyses emerged that the telemedicine advantages (such as lower costs, access to health care from rural areas, or fastest interaction between patients and physicians or between physicians of different specialties) and the disadvantages (such as lower control of privacy and security, lower patient engagement and the evolving patient-physician relationship, limited and fragmented insurance coverage of telemedicine) were not archivio italiano di urologia e andrologia 2024; 96(1):11206 v. mirone, f. di bello, s. morra, et al. 6 well discussed on the internet (35). in the future, a standard regulation should be promoted to increase telemedicine knowledge allowing people to properly use this essential service today. moreover, the use of mhas should be promoted both for their educational role as a telemedicine instrument and for spreading high-quality health information. our study is not devoid of limitations. first, buzzsumo tool only collected data from facebook, twitter, pinterest, reddit, and youtube. in consequence, information available on other social media platforms such as instagram and tiktok may be missed. second, facebook was the most used platform to share articles. however, we were not able to discriminate if a person sharing an article actually promoted it or warned against it. third, some reliable or unreliable articles may be missed, due to our search terms choose and to the number of links included for each term. however, we used four different keywords with the highest number and on-topic links. fourth, quality assessment videos were subjectively evaluated. however, to reduce this confounder, three investigators were involved to independently analyze video contents. finally, according to the 30-day free trial buzzsumo version, we were only able to collect the links uploaded during the last year. in consequence, our study observations represent a frame on what was mostly shared during the second year following the covid-19 outbreak. future studies should update our observations in order to confirm or reject them. regardless of these limitations, the present study can be considered as a snapshot of the latest and most shared information on telemedicine available on the internet. conclusions the interest in telemedicine has increased all over the world, as evidenced by the high engagement in social media articles, recorded during the last year. however, the access to digital health services is still limited, the information provided is often not verified by an official entity and unable to fill the digital divide exacerbated by covid 19 pandemic crisis. hence, health policy should be developed or modified to ensure a more egalitarian internet access for all citizens. in addition to increasing and widening access to the internet and the health knowledge services, icts should be employed to lead towards digitization of health care. in the future, official medical institutions should standardize telemedicine regulation, creating their own mhas and online content to reduce the widespread of misleading information. references 1. mirone v, celentano g, collà ruvolo c, et al. perceptions and attitudes toward the use of telemedicine for the postoperative outpatient urological care during the covid-19 pandemic in an academic hospital in southern italy. arch ital urol androl. 2022; 94:375-9. 2. chaet d, clearfield r, sabin je, skimming k, on behalf of the council on ethical and judicial affairs american medical association. ethical practice in telehealth and telemedicine. j gen intern med. 2017; 32:1136-40. 3. dorsey er, topol ej. state of telehealth. campion ew, editor. n engl j med. 2016; 375:154-61. 4. mirone v, creta m, capece m, et al. telementoring for communication between residents and faculty physicians: results from a survey on attitudes and perceptions in an academic tertiary urology referral department in italy. arch ital urol androl. 2021; 93:450-4. 5. creta m, sagnelli c, celentano g, et al. sars-cov-2 infection affects the lower urinary tract and male genital system: a systematic review. j med virol. 2021; 93:3133-42. 6. hollander je, carr bg. virtually perfect? telemedicine for covid19. n engl j med. 2020; 382:1679-81. 7. lukas h, xu c, yu y, gao w. emerging telemedicine tools for remote covid-19 diagnosis, monitoring, and management. acs nano. 2020; 14:16180-93. 8. samadbeik m, bastani p, fatehi f. bibliometric analysis of covid-19 publications shows the importance of telemedicine and equitable access to the internet during the pandemic and beyond. health info libr j. 2023; 40:390-399. 9. fusco gm, cirillo l, abate m, et al. male infertility, what mobile health applications ‘know’: quality analysis and adherence to european association of urology guidelines. arch ital urol androl. 2022; 94:470-5. 10. napolitano l, fusco gm, cirillo l, et al. erectile dysfunction and mobile phone applications: quality, content and adherence to european association guidelines on male sexual dysfunction. arch ital urol androl. 2022; 94:211-6. 11. napolitano l, cirillo l, fusco gm, et al. premature ejaculation in the era of mobile health application: a current analysis and evaluation of adherence to eau guidelines. arch ital urol androl. 2022; 94:328-33. 12. melchionna a, collà ruvolo c, capece m, et al. testicular pain and youtube™: are uploaded videos a reliable source to get information? int j impot res. 2023; 35:140-146. 13. alsyouf m, stokes p, hur d, et al. ‘fake news’ in urology: evaluating the accuracy of articles shared on social media in genitourinary malignancies. bju int. 2019; 124:701-6. 14. capece m, di giovanni a, cirigliano l, et al. youtube as a source of information on penile prosthesis. andrologia. 2022; 54:e14246. 15. cilio s, collà ruvolo c, turco c, et al. analysis of quality information provided by "dr. youtubetm" on phimosis. int j impot res. 2023; 35:398-403. 16. gerundo g, collà ruvolo c, puzone b, et al. personal protective equipment in covid-19: evidence-based quality and analysis of youtube videos after one year of pandemic. am j infect control. 2022; 50:300-305. 17. morra s, collà ruvolo c, napolitano l, et al. youtube™ as a source of information on bladder pain syndrome: a contemporary analysis. neurourol urodyn. 2022; 41:237-245. 18. moscadelli a, albora g, biamonte ma, et al. fake news and covid-19 in italy: results of a quantitative observational study. ijerph. 2020; 17:5850. 19. obiała j, obiała k, manczak m, et al. covid-19 misinformation: accuracy of articles about coronavirus prevention mostly shared on social media. health policy technol. 2021; 10:182-186. 20. diaz p, takele ra, thaker s, et al. kidney stone surgery: assessing public interest and evaluating social media content. j endourol. 2022; 36:954-960. archivio italiano di urologia e andrologia 2024; 96(1):11206 7 telemedicine and social media 21. zaila ke, osadchiy v, shahinyan rh, et al. social media sensationalism in the male infertility space: a mixed methodology analysis. world j mens health. 2020; 38:591. 22. loeb s, folkvaljon y, makarov dv, et al. five-year nationwide follow-up study of active surveillance for prostate cancer. eur urol. 2015; 67:233-8. 23. xu aj, myrie a, taylor ji, et al. instagram and prostate cancer: using validated instruments to assess the quality of information on social media. prostate cancer prostatic dis. 2022; 25:791-3. 24. silberg wm, lundberg gd, musacchio ra. assessing, controlling, and assuring the quality of medical information on the internet: caveant lector et viewor--let the reader and viewer beware. jama. 1997; 277:1244-5. 25. collà ruvolo c, califano g, tuccillo a, et al. "youtube™ as a source of information on placenta accreta: a quality analysis". eur j obstet gynecol reprod biol. 2022; 272:82-87. 26. di bello f, collà ruvolo c, cilio s, et al. testicular cancer and youtube: what do you expect from a social media platform? int j urol. 2022; 29:685-691. 27. the patient education materials assessment tool (pemat) and user’s guide. https://www.ahrq.gov/health-literacy/patient-education/pemat.html 28. turco c, collà ruvolo c, cilio s, et al. looking for cystoscopy on youtube: are videos a reliable information tool for internet users? arch ital urol androl. 2022; 94:57-61. 29. farsi d, martinez-menchaca hr, ahmed m, farsi n. social media and health care (part ii): narrative review of social media use by patients. j med internet res. 2022; 24:e30379. 30. petruzzi m, de benedittis m. whatsapp: a telemedicine platform for facilitating remote oral medicine consultation and improving clinical examinations. oral surg oral med oral pathol oral radiol. 2016; 121:248-54. 31. sageena g, sharma m, kapur a. evolution of smart healthcare: telemedicine during covid-19 pandemic. j inst eng india ser b. 2021; 102:1319-24. 32. chauhan b, george r, coffin j. social media and you: what every physician needs to know. j med pract manage. 2012; 28:206-9. 33. burbury k, wong zw, yip d, et al. telehealth in cancer care: during and beyond the covid-19 pandemic. intern med j. 2021; 51:125-33. 34. hincapié ma, gallego jc, gempeler a, et al. implementation and usefulness of telemedicine during the covid-19 pandemic: a scoping review. j prim care community health. 2020; 11:2150132720980612. 35. wootton r, geissbuhler a, jethwani k, et al. long-running telemedicine networks delivering humanitarian services: experience, performance and scientific output. bulletin of the world health organization. 2012; 90:341-347d. correspondence vincenzo mirone, md mirone@unina.it francesco di bello, md fran.dibello12@gmail.com simone morra, md simonemorra93@gmail.com luigi cirillo, md cirilloluigi22@gmail.com marco abate, md marcoabate5@gmail.com giovanni m. fusco, md giom.fusco@gmail.com luigi napolitano, md luiginap89@gmail.com roberto la rocca, md robertolarocca87@gmail.com massimiliano creta, md max.creta@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com marco capece, md drmarcocapece@gmail.com francesco mangiapia, md mangiapiaf@gmail.com nicola longo, md nicola.longo@unina.it claudia collà ruvolo, md c.collaruvolo@gmail.com gianluigi califano, md (corresponding author) gianl.califano2@gmail.com department of neurosciences, reproductive sciences and odontostomatology, university of naples “federico ii” via sergio pansini n°5, 80138 naples gennaro musi, md stefano luzzago, md urology department, istituto europeo di oncologia (i.e.o.), milan, italy claudia mirone, md claudia.mirone@unina.it multidisciplinary department of medical, surgical and dental sciences, university of campania "luigi vanvitelli", naples, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12984 1 meta-analysis ejaculation upon vaginal penetration and classified into lifelong and acquired pe (1, 2). pe affects about 31% of men aged 18-59, causing psychological effects such as disappointment, hopelessness, and avoidance of sexual relations (3). pe treatment usually involves multimodal therapy, including behavioral, psychological, and pharmacological approaches. ssris including dapoxetine and paroxetine are the gold standard, but their long-term use is limited due to several adverse effects, including psychiatric and neurological complications (4, 5). silodosin, an alpha-1 blocker, offers a new option for treating pe with minimal side effects (6). alpha-1 blockers, as primary treatment for benign prostatic hyperplasia, are also linked to pe treatment. recent studies show they suppress seminal emission by inhibiting smooth muscle contraction, potentially delaying ejaculation (7). limited research exists on silodosin's effectiveness in treating pe. investigating silodosin as an alternative treatment for pe is crucial. hence, we aim to assess its efficacy in treating pe. methods literature search on december 23, 2023, four reviewers (m.a., m.f., i.f., i.a) conducted a literature study using pubmed, sciencedirect, and cochrane library, including additional valid studies and screening reference lists for relevant research outside of the databases if they met the criteria. eligibility criteria the search was performed using keywords ‘(silodosin) and (premature ejaculation)’. followed the pico criteria: (1) populations with premature ejaculation; (2) silodosin therapy; (3) comparison with placebo or other therapies; (4) outcomes including intravaginal ejaculation latency time (ielt) and therapy-related adverse events; (5) randomized controlled studies; (6) published in english. introduction and objectives: premature ejaculation (pe) occurs in 31% of men aged 18-59 years, leading to disappointment and avoidance of sexual relations. the current guideline of treatment for pe is dapoxetine, which possesses several adverse effects causing the limitation of its long-term use. silodosin, an alpha-1 blocker, has been proposed as a new option for treating pe due to its minimal side effects. therefore, our study aims to assess the efficacy of silodosin in treating pe. materials and methods: this systematic review and meta-analysis was in accordance with cochrane handbook guidelines. comprehensive literature search was conducted in several databases including pubmed, sciencedirect, and cochrane central register of controlled trials. the studies were included if they met the following criteria: (1) involving premature ejaculation patients; (2) intervention using silodosin; (3) comparing placebo or other therapies for pe (4) outcome includes the intravaginal ejaculation latency time (ielt) and reported adverse events related to the therapy. study quality was assessed using cochrane risk-of-bias criteria. statistical analysis in this study was performed using review manager 5.4 results: a total of four studies were included in this meta-analysis. our study showed that patients who received silodosin had a significantly longer ielt compared to control (md: 132.54, 95% ci 51.51-213.57, p < 0.001). however, patient treated with silodosin also possessed significantly higher risk of adverse event for developing reduced semen ejaculation (or 10.79, 95% ci 3.46-33.67, p < 0.0001). conclusions: silodosin significantly increased ielt. however, it also reduced semen ejaculation as its drug adverse effect. this result supports the clinical use of silodosin as an alternative treatment for premature ejaculation. key words: silodosin; premature ejaculation; alpha blocker; retrograde ejaculation. submitted 29 august 2024; accepted 31 august 2024 introduction ejaculation involves complex physiological processes. premature ejaculation (pe) is defined as inability to delay promising selective alpha-1 blocker silodosin as a new therapeutic strategy for premature ejaculation and analysis of its drug adverse effect: a systematic review and meta-analysis of randomized controlled trials muhammad ilham fauzan 1, besut daryanto 1, taufiq nur budaya 1, moh. anfasa giffari makkaraka 2, muhammad fakhri 3, ilham akbar rahman 4 1 department of urology, faculty of medicine, universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia; 2 andi djemma masamba hospital, south sulawesi, indonesia; 3 aceh singkil hospital, aceh, indonesia; 4 department of urology, faculty of medicine, airlangga university, surabaya, indonesia. doi: 10.4081/aiua.2024.12984 summary archivio italiano di urologia e andrologia 2024; 96(4):12984 m. ilham fauzan, b. daryanto, t. nur budaya, et al. 2 selection process duplicate studies were excluded after the initial search. four independent reviewers screened titles and abstracts for eligibility, including studies that met criteria and excluding those that didn't. conflicts were resolved through discussion. the screening results follow preferred reporting items for systematic review and meta-analyses (prisma) guidelines. data collection each author independently extracted data, which was then cross-examined by others. discrepancies were resolved through discussion. authors were contacted for unclear information; non-responsive studies were withdrawn with reviewer consent. collected data include author, year, location, design, population, sample size, mean age, intervention, control, outcomes, and adverse events. quality assessment study quality was assessed using the cochrane risk-ofbias tool with review manager 5.4, classifying each point as low, high, or unclear risk. statistical analysis data were processed using review manager 5.4. two meta-analyses assessed the effect and odds of silodosin versus placebo or other therapies. the first analysed mean differences in ielt scores, and the second analysed adverse event odds ratios, both with 95% cis. heterogeneity was assessed by i2 value; a fixed-effects model was used if i2 < 50%, and a random-effects model if i2 ≥50%. results are shown in a forest plot, with significance at p < 0.05. a funnel plot was used to evaluate publication bias. asymmetrical distribution indicates high bias, while symmetrical distribution indicates low bias. results literature search and screening results using keywords, 108 studies were identified from databases, plus 5 studies outside the databases, totaling 113. after removing 22 duplicates, two reviewers screened 91 titles and abstracts, excluding 86 that didn't meet criteria. four studies met the criteria for analysis. full search and filter details are in figure 1. characteristics of eligible studies the four included rcts were conducted in three countries, with a total of 358 pe patients. most studies diagnosed pe using dsm-iv-tr and issm criteria. all studies administered 4 mg of silodosin 1-3 hours before intercourse. controls included placebo (hodeeb et al., bhat et al.), naftopidil 25 mg (sato et al.), and other alpha blockers (akin et al.). outcomes measured included ielt in all studies, cgic in three (sato, bhat, akin et al.), pe profile in two (sato, bhat et al.), and qol index in one (akin et al.). the most common side effect was reduced semen ejaculation. full study characteristics are in table 1. quality assessment result the risk of bias assessment using review manager 5.4 showed that all studies generally had a low risk of bias (figure 2). however, blinding bias was high in some studies due to the lack of double-blind procedures. figure 1. flow diagram of literature search and selection based on preferred reporting items for systematic reviews and meta-analyses (prisma). archivio italiano di urologia e andrologia 2024; 96(4):12984 3 promising selective alpha-1 blocker silodosin as a new therapeutic strategy for premature ejaculation and analysis... statistical analysis (meta-analysis) efficacy of silodosin on ielt scores meta-analysis of four rcts found that silodosin recipients had significantly longer ielt than controls (md: 132.54, 95% ci 51.51-213.57, p < 0.001). heterogeneity exceeded 50% (p < 0.00001, i2 = 98%), so the random-effects model was applied (figure 3). silodosin reported adverse event analysis all studies reported reduced semen ejaculation as an adverse event postsilodosin. figure 4 displays the pooled effect size. the forest plot indicated heterogeneity below 50% (p = 0.12, i2 = 41%), favoring the fixed-effects model. silodosin treatment significantly increased the risk of reduced semen ejaculation (or 10.79, 95% ci 3.46-33.67, p < 0.0001). funnel plot analysis the funnel plot in figures 5a and 5b shows the symmetrical shape of the study distribution, indicating a low risk of publication bias in this metaanalysis. figure 2. risk of bias assessment using the cochrane risk-of-bias tool for randomized trials. table 1. collection data of included studies. no author (year) country study population mean age (years) total samples intervention control type outcome adverse design silodosin control (silodosin vs control) assesment event reported 1 hodeeb et al. (2019) egypt db-rct pe patient 29.39 ± 7.6 30.91 ± 7.5 160 silodosin 4 mg placebo 1. ielt reduced diagnosed with (80 vs 80) (2 hours before (2 hours before 2. pe profile semen volume dsm iv-tr criteria intercourse) intercourse) 2 sato et al. (2016) usa rct pe patient 26 silodosin 4 mg naftopidil 25 mg 1. ielt reduced (1 hours before (1 hours before 2. cgic semen volum intercourse) intercourse) 3. pe profile 3 bhat et al. (2016) china rct diagnosed pe 32.6 ± 3.53 28.7 ± 3.14 64 silodosin 4 mg placebo 1. ielt 1. reduced patient reported (31 vs 33) (3 hours before (3 hours before 2. cgic semen volume unsatisfied with intercourse) intercourse) 3. pe profile 2. uncomfortably ‘on demand’ delayed ejaculation dapoxetine 3. dizziness 4. akin et al. (2013) usa rct pe patient 49.4 ± 11.8 1. 43.3 ± 8.9 108 silodosin 4mg 1. tamsulosin 0.4 mg 1. ielt reduced diagnosed with 2. 46 ± 8.6 (21 vs 23 vs 22 (2-3 hours before 2. alfuzosin 10 mg 2. cgic semen volume dsm iv-tr criteria 3. 44.5 ± 9.1 vs 21 vs 21) intercourse) 3. terazosin 5 mg 3. qol index 4. 45.7 ± 9.4 4. doksazosin 4 mg (2-3 hours before intercourse) db-rct: double blind-randomized controlled study; pe: premature ejaculation; dsm iv-tr: diagnostic and statistical manual of mental disorders iv-text revision; issm: international society of sexual medicine; ielt: intravaginal ejaculation latency time; cgic: clinical global impression of change; qol: quality of life. archivio italiano di urologia e andrologia 2024; 96(4):12984 m. ilham fauzan, b. daryanto, t. nur budaya, et al. 4 discussion pe is the most prevalent male sexual disorder, affecting 30% to 50% of men globally (8). pe is a common male sexual disorder, leads to negative effects including avoidance of sexual intimacy, frustration, reduced confidence with partners, and decreased quality of life (2, 3). pe treatments include oral medications like ssris and alpha blockers, as well as topical and behavioral therapies (9). dapoxetine, an ssri, treats pe by inhibiting the ejaculatory reflex. however, its significant adverse effects, like nausea, dizziness, and loss of libido, negatively impact patients' qol (3-5). silodosin, an alpha blocker for bph, is highly selective for α1a adrenergic receptors and effective in treating pe (10). in this meta-analysis, patients receiving silodosin before intercourse showed improved ielt compared to controls or those on placebo (md: 132.54, p < 0.001). alpha blockers, including silodosin, are gaining attention as alternative treatments for their ability to inhibit contractions of seminal vesicles, vas deferens, prostate, and assofigure 3. forest plot analysis of the silodosin effect in intravaginal ejaculation latency time (ielt). m-h: mantel–haenszel, ci: confidence interval. figure 4. forest plot analysis of reduced semen ejaculation as a silodosin adverse event. m-h: mantel–haenszel, ci: confidence interval. figure 5. funnel plot analysis: a) effect of silodosin on ielts. b) reduced semen ejaculation as silodosin adverse event. se: standard error; md: mean difference; or: odds ratio.. archivio italiano di urologia e andrologia 2024; 96(4):12984 5 promising selective alpha-1 blocker silodosin as a new therapeutic strategy for premature ejaculation and analysis... ciated muscles, peripheral effectors in ejaculation. silodosin's strong suppressive action on seminal emission, via its high α1a selectivity, may prolong ielt and improve ejaculatory control (11-13). while effective for pe, silodosin may cause mild anejaculation discomfort and reduced semen ejaculation. α1aadrenoreceptor antagonists, including silodosin, suppress seminal emission, possibly reducing semen production and prolonging ejaculation (12). roehrborn et al. discovered that 28.1% of those experiencing retrograde ejaculation during silodosin treatment showed significant symptom improvement and enhanced peak flow rate compared to those without this side effect. this suggests silodosin effectively relaxes smooth muscles in the lower urinary and genital tracts, leading to retrograde ejaculation (14). silodosin has fewer systemic adverse events and is more effective in treating pe than other alpha blockers (9). akin et al. compared pe patients given 4 mg silodosin 2-3 hours before intercourse with those on other alpha blockers: tamsulosin hydrochloride 0.4 mg, alfuzosin 10 mg, terazosin 5 mg, and doxazosin mesylate 4 mg. silodosin significantly improved qol, increased ielt, and decreased pep (9). silodosin's selectivity for alpha 1 receptors in the prostate makes it more effective in treating pe. studies by sato y et al. and hodeeb et al. support silodosin's greater improvement in pe patients, offering a promising, effective, affordable, and safe treatment avenue (11, 15) this study has several limitations. firstly, due to silodosin's novelty, relevant literature sources were still scarce. secondly, the literatures that existed did not yet compare silodosin to dapoxetine, the main therapy for premature ejaculation therefore comparison of head-tohead was not available in this study. thirdly, sample sizes varied, causing significantly high heterogeneity. conclusions silodosin significantly increased ielt. however, it causes reduced semen ejaculation as its drug adverse effect. this result supports the clinical use of silodosin as an alternative treatment for premature ejaculation. further clinical studies evaluate the comparison of silodosin and ssri are warranted. references 1. parnham a, serefoglu ec. classification and definition of premature ejaculation. transl androl urol. 2016; 5:416-23. 2. crowdis m, leslie sw, nazir s. premature ejaculation. 2023 may 30. in: statpearls (internet). treasure island (fl): statpearls publishing; 2024. 3. hatzimouratidis, k. giuliano, f. moncada, et al. eau guidelines on erectile dysfunction, premature ejaculation, penile curvature and priapism in: european association of urology guidelines, eau guidelines office, arnhem, the netherlands, published online 2019:1-28. 4. hisasue s. the drug treatment of premature ejaculation. transl urol androl 2016; 5:482-486. 5. mcmahon cg. dapoxetine: a new option in the medical management of premature ejaculation. ther adv urol. 2012; 4:233-51. 6. bhat gs, shastry a. effectiveness of 'on demand' silodosin in the treatment of premature ejaculation in patients dissatisfied with dapoxetine: a randomized control study. cent european j urol. 2016; 69:280-284. 7. martin c, nolen h, podolnick j, wang r. current and emerging therapies in premature ejaculation: where we are coming from, where we are going. int j urol. 2017; 24:40-50. 8. gao j, zhang x, su p, et al. prevalence and impact of premature ejaculation in outpatients complaining of ejaculating prematurely: using the instruments of intravaginal ejaculatory latency time and patient-reported outcome measures. int j impot res. 2014; 26:94-99. 9. akin y, gulmez h, ates m, et al. comparison of alpha blockers in treatment of premature ejaculation: a pilot clinical trial. iran red crescent med j. 2013; 15:e13805. 10. maladkar m, awate s, bramhe p. exploring alpha-blockers as an effective intervention for premature ejaculation. the indian practitioner 2024; 77:31-36. 11. sato y, otani t, amano t, et al. silodosin versus naftopidil in the treatment of premature ejaculation: a prospective multicenter trial. int j urol. 2017; 24:626-631. 12. sato y, tanda h, nakajima h, et al. silodosin and its potential for treating premature ejaculation: a preliminary report. int j urol. 2012; 19:268-72. 13. kobayashi k, masumori n, hisasue si, et al. inhibition of seminal emission is the main cause of anejaculation induced by a new highly selective α1a-blocker in normal volunteers. j sex med. 2008; 5:2185-2190. 14. roehrborn cg, lepor h, kaplan sa. retrograde ejaculation induced by silodosin is the result of relaxation of smooth musculature in the male uro-genital tracts and is associated with greater urodynamic and symptomatic improvements in men luts secondary to bph. j urol. 2009; 181:694-695. 15. mohamed y, hodeeb i, saeed m, hasan m. effectiveness and safety of silodosin in treatment of premature ejaculation : placebo double blind control study. the egyptian journal of hospital medicine 77:5482-5487. correspondence muhammad ilham fauzan ilhmfauzn18@gmail.com taufiq nur budaya taufiq_uro.fk@ub.ac.id department of urology, faculty of medicine, universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia besut daryanto (corresponding author) urobes.fk@ub.ac.id department of urology, dr. saiful anwar general hospital malang jalan jaksa agung suprapto 2, klojen, malang, east java 65112, indonesia moh. anfasa giffari makkaraka fasagifari@gmail.com andi djemma masamba hospital, south sulawesi, indonesia muhammad fakhri muhammadfakhri.md@gmail.com aceh singkil hospital, aceh, indonesia ilham akbar rahman ilhamakbaarr@gmail.com department of urology, faculty of medicine, airlangga university, surabaya, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12756 1 original paper introduction erectile dysfunction (ed) is an inability to provide adequate erection to initiate or maintain any sexual activity (1). ed prevalence in adult males is approximately 20% (2). previous studies had shown that the neutrophils/lymphocytes (nlr) and platelets/lymphocytes (plr) ratios could be used as markers of inflammatory load as well as prognostic factors in several medical conditions (3-4). the common pathophysiological conditions underlying ed, cvd and other vascular diseases included inflammation, atherosclerosis and endothelial dysfunction (5). the nlr and plr were known to be potential markers of inflammation in vascular diseases and inflammation play a critical role in the initiation and development of vascular endothelial dysfunction and atherosclerosis (6). neutrophils produce and secrete several inflammatory mediators including myeloperoxidase (mpo) and reactive oxygen species (ros) which can be responsible of myocardial and non-myocardial tissue damages (7). additionally, platelets release numerous inflammatory mediators that modify leukocyte and endothelial responses via different inflammatory stimuli (8). a modern study had revealed that nlr and plr had been proposed as biomarkers of subclinical inflammation and many studies had investigated these ratios (9). a previous study had demonstrated that onset and severity of ed had been attributed to increased levels of inflammatory biomarkers (10). in the same context, nlr and plr were used as signs of inflammation together with a significant relationship between development of ed and these inflammatory markers (11). previous studies reported a chronic effect of sildenafil and tadalafil on endothelial function and pro-inflammatory markers (12). das (2007) stated that different cohorts of ed patients were associatbackground: previous studies had shown that the neutrophils/lymphocytes (nlr) and platelets/lymphocytes (plr) ratios could be used as markers of inflammatory load as well as prognostic factors in several medical conditions. the current study aimed to compare between the effect of using daily tadalafil 5 mg/day versus daily sildenafil 25 mg/day in improving erectile function as well as their ability to reduce nlr and plr. methods: one hundred and four participants were recruited. seventy-four randomized patients with erectile dysfunction were equally divided into 2 groups. patients in group a used daily tadalafil 5 mg for 2 months while patients in group b used daily sildenafil 25 mg for 2 months. patients were collected from june 2022 to june 2023. thirty healthy individuals served as controls. all patients and controls were evaluated using the validated arabic version of the international index of erectile function (ariief-5) at baseline and after 2 months of medical treatment. five cc of venous blood sample was obtained before and after 2 months of medical treatment to compare the effect of phosphodiestrase type 5 inhibitors (pde-5is) intake for erectile dysfunction on plr and nlr before and after treatment. results: the current study showed that there were no statistically significant differences between the cases and the controls apart from the ariief-5 scores. moreover, there was no significant difference between patients in group a and those in group b regarding plr and nlr post administration of pde-5is. interestingly, patients in group a demonstrated a highly significant difference between the ariief-5 scores as well as the plr and the nlr before and 2 months after administration of daily tadalafil 5 mg. on the other hand, patients in group b who were administrated daily sildenafil 25 mg for 2 months demonstrated only a highly significant difference between the ariief-5 scores before and after administration. meanwhile, patients in group b did not reveal any statistically significant difference in the plr and the nlr before and 2 months after administration of sildenafil 25 mg. further regression analysis after adjustment of different variables of the study showed a significant correlation between ariief-5 and plr in patients who received daily tadalafil 5 mg (r = 0.430, p = 0.004). conclusions: tadalafil and sildenafil have similar clinical efficacy in treating erectile dysfunction. however, tadalafil is more effective in lowering plr and nlr compared to sildenafil. evaluation of the effect of daily tadalafil 5 mg versus daily sildenafil 25 mg on neutrophil-lymphocyte and platelet-lymphocyte ratios in patients with erectile dysfunction: a comparative randomized controlled study abdel rahman bakry 1, ali mohamed mahran 1, hisham diab gaber 1, mohamed ismail sedek 2, sameh fayek gamalel din 3, ahmad tarek motawi 3, mohamed diab mohamed 1, ahmed elshebany 1 1 department of andrology & stds, faculty of medicine, assiut university, assiut, egypt; 2 department of clinical pathology, faculty of medicine, assiut university, assiut, egypt; 3 department of andrology & stds kasr alainy faculty of medicine, cairo university, giza, egypt. doi: 10.4081/aiua.2024.12756 summary key words: erectile dysfunction; neutrophils/lymphocytes (nlr); platelets/lymphocytes (plr); tadalafil; sildenafil. submitted 27 june 2024; accepted 9 july 2024 archivio italiano di urologia e andrologia 2024; 96(4):12756 a. rahman bakry, a. mohamed mahran, h. diab gaber, et al. 2 ed with increased levels of inflammatory markers as well as the significant ability of oral phosphodiesterase-5 inhibitors (pde-5is) to decrease these markers (13). the current study aimed to compare between the effect of using daily tadalafil 5 mg/day versus daily sildenafil 25 mg/day in improving erectile function as well as their ability to reduce nlr and plr. patients and methods one hundred and four participants with erectile dysfunction (ed) were recruited. seventy-four randomized patients were equally divided into 2 groups. thirty healthy individuals served as controls. patients in group a used daily tadalafil 5 mg for 2 months while patients in group b used daily sildenafil 25 mg for 2 months. patients were collected from the andrology outpatient clinic, assiut university hospital from june 2022 to june 2023. the institutional review board approved the study (17101846) that conforms to helsiniki declaration 2013 (14). all patients signed a written informed consent after explaining the steps and the aim of the study. they were randomized by simple numbering method. inclusion criteria of the patients any male patient aged 25 to 60 years in a stable relationship and suffering from ed was included. exclusion criteria of the patients patients who suffered from severe uncontrolled medical conditions, patients under treatment with sublingual nitrate, patients with blood diseases that affect sexual function and patients using cytotoxic drugs or immunosuppressive drugs were excluded. also, patients without partners were excluded. inclusion criteria of the controls they were age matched potent controls who attended the outpatient clinic for fertility checkup. all participants were subjected to the following steps. medical as well as sexual and surgical histories were obtained. general and local examinations were done. all patients and controls were evaluated using the validated arabic version of the international index of erectile function (ariief-5) at baseline and after 2 months of medical treatment (15). five cc of venous blood sample was obtained before and after 2 months of medical treatment by using sterile 5 ml syringe then the sample poured into edta vacuum tube. then gentle mixing was performed to obtain complete blood count using cell-dyn haematology analyzer device to compare the effect of pde-5is intake for ed on plr and nlr before and after treatment. patients in group a received daily tadalafil 5 mg while patients in group b received daily sildenafil 25 mg for 2 months. statistical analysis data were fed to the computer and analyzed using ibm spss software package version 20.0 (armonk, ny: ibm corp). qualitative data were described using number and percent. the kolmogorov-smirnov test was used to verify the normality of distribution. quantitative data were described using range (minimum and maximum), mean, standard deviation, median and inter-quartile range (iqr). chi-square test was used for categorical variables, to compare between different groups. student t-test was used for normally distributed quantitative variables and to compare between two studied groups. paired t-test was used for normally distributed quantitative variables and to compare between two repeated measures. mann-whitney test was used for nonparametric quantitative variables and to compare between two studied groups. wilcoxon test was used for nonparametric quantitative variables and to compare between two repeated measures. significance of the obtained results was judged at the 5% level. results table 1 showed that there were no statistically significant differences between the cases and the controls apart from the ariief-5 scores. furthermore, the current study revealed that there was no statistically significant difference between patients in group a and those in group b regarding the ariief-5 prior to administration of pde5is (table 2). also, the current study demonstrated that there were no statistically significant differences between patients in group a and those in group b regarding plr and nlr prior to administration of pde5-is (table 2). conversely, there was no statistically significant difference between patients in group a and those in group b regarding the ariief-5 after intake of pde5-is (table 3). table 2. ariief-5 and nlr and plr among studied cases before intervention. group a tadalafil group b sildenafil p (n = 37) (n = 37) ariief-5 range 5-20 5-19 0.507 median (iqr) 9 (7-15) 8 (6-15) erectile dysfunction n % n % no 0 0 0 0 0.741 mild 7 18.9 7 18.9 moderate 17 45.9 14 37.8 severe 13 35.1 16 43.2 plr range 45.6-185 60-194 0.296 mean ± sd 126.25 ± 36.04 117.33 ± 36.91 nlr range 0.48-3.9 0.56-4.3 0.384 median (iqr) 2.1 (1-3.2) 1.8 (0.8-3.1) ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio; nlr = neutrophils/lymphocyte ratio. table 1. socio-demographic data of the participants. tadalafil sildenafil controls p-value mean sd mean sd mean sd age 44.2 ± 6.9 45.7 ± 6.1 45.1 6.5 0.602 ariief5 before 10.8 ± 4.7 10.2 ± 4.8 23.9 ± 0.9 0.000 plr before 126.3 ± 36 117.3 ± 36.9 110 ± 46.9 0.206 nlr before 2.2 ± 1.17 2 ± 1.19 1.9 ± 1.4 0.686 ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio; nlr = neutrophils/lymphocyte ratio. archivio italiano di urologia e andrologia 2024; 96(4):12756 3 evaluation of the effect of daily tadalafil 5 mg versus daily sildenafil 25 mg on neutrophil-lymphocyte and platelet-lymphocyte ratios... moreover, there was no significant difference between patients in group a and those in group b regarding plr and nlr post administration of pde5-is (table 3). interestingly, patients in group a demonstrated a highly significant difference between the ariief-5 scores as well as the plr and the nlr before and 2 months after administration of daily tadalafil 5 mg (table 4). on the other hand, patients in group b who were administrated daily sildenafil 25 mg for 2 months demonstrated only a highly significant difference between the ariief-5 scores before and after administration (table 5). meanwhile, patients in group b did not reveal any statistically significant difference in the plr and the nlr before and 2 months after administration of sildenafil 25 mg (table 5). further regression analysis after adjustment of different variables of the study showed a significant correlation between ariief-5 and plr in patients in group a who received daily tadalafil 5 mg (r = 0.430, p = 0.004) (table 6). it should be mentioned that no other correlation was observed (table 6). discussion the current study demonstrated that baseline plr and nlr were higher in the patients compared to the controls. however, they did not show any significant difference. consistently, demirci and ozgur (2019) found that the median nlr level and plr level were higher when compared to controls in mild-moderate ed and severe ed groups (16). similarly, aslan et al. (2019) found that nlr was higher in the patients compared to the controls (17) and that it also predicted ed and it might be helpful in diagnosing ed (17). zhang et al. (2022) reported that nlr and plr were significantly higher in ed patients compared with healthy controls (18) and ventimiglia et al. (2018) determined that nlr was 3 times higher in severe ed patients and that they were independent predictors (19). a modern retrospective study conducted by akbaş et al. (2016) showed that the plr value increased proportionately with the severity of ed (20). our study did not show any statistically significant difference between the studied groups regarding plr and nlr post-intervention. kilic et al. (2023) reported that there was no significant difference in nlr or plr between ed patients who did not respond to pde5i treatment and controls who responded to treatment (21) and that there was a highly significant difference between ariief-5 scores before and after intervention in the studied groups who received daily tadalafil 5 mg and daily sildenafil 25 mg. similarly, gong et al. (2017) revealed that sildenafil and tadalafil had equivalent abilities to improve iief table 3. ariief-5 and nlr and plr among studied cases post intervention. group a tadalafil group b sildenafil p (n = 37) (n = 37) ariief-5 range 5-24 5-24 0.102 median (iqr) 20 (17-22) 18 (10-22) erectile dysfunction n % n % no 17 45.9 11 29.7 0.323 mild 12 32.4 11 29.7 moderate 4 10.8 7 18.9 severe 4 10.8 8 21.6 plr range 31.6-148 43.8-182.5 0.197 mean ± sd 99.73 ± 24 108.58 ± 33.69 nlr range 0.38-3.52 0.56-4.5 0.523 median (iqr) 1.1 (1-1.4) 1.1 (0.7-1.9) ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio; nlr = neutrophils/lymphocyte ratio; iqr: interquartile range. table 4. ariief-5 and nlr and plr pre and post-intervention in group a. group a who received pre-intervention post-intervention p tadalafil 5 mg (n = 37) (n = 37) ariief-5 range 5-20 5-24 < 0.001* median (iqr) 9 (7-15) 20 (17-22) erectile dysfunction n % n % no 0 0 17 45.9 < 0.001* mild 7 18.9 12 32.4 moderate 17 45.9 4 10.8 severe 13 35.1 4 10.8 plr range 45.6-185 31.6-148 < 0.001* mean ± sd 126.25 ± 36.04 99.73 ± 24 nlr range 0.48-3.9 0.38-3.52 < 0.001* median (iqr) 2.1 (1-3.2) 1.1 (1-1.4) ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio; nlr = neutrophils/lymphocyte ratio; iqr: interquartile range. table 5. ariief-5 and plr and nlr pre and post-intervention in group b. group b who received pre-intervention post-intervention p tadalafil 25 mg (n = 37) (n = 37) ariief-5 range 5-19 5-24 < 0.001* median (iqr) 8 (6-15) 18 (10-22) erectile dysfunction n % n % no 0 0 11 29.7 < 0.001* mild 7 18.9 11 29.7 moderate 14 37.8 7 18.9 severe 16 43.2 8 21.6 plr range 60-194 43.8-182.5 0.229 mean ± sd 117.33 ± 36.91 108.58 ± 33.69 nlr range 0.56-4.3 0.56-4.5 0.368 median (iqr) 1.8 (0.8-3.1) 1.1 (0.7-1.9) ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio; nlr = neutrophils/lymphocyte ratio; iqr: interquartile range. table 6. plr and nlr and smoking in both groups and tadalafil and sildenafil post intervention. ariief-5 plr nlr smoking tadalafil pearson correlation 0.430 0.029 0.072 p value 0.004 0.433 0.336 sildenafil pearson correlation 0.168 -0.066 0.061 p value 0.161 0.349 0.360 ariief5 = the validated arabic version of the international index of erectile function; plr = platelets/lymphocyte ratio. archivio italiano di urologia e andrologia 2024; 96(4):12756 a. rahman bakry, a. mohamed mahran, h. diab gaber, et al. 4 scores (22). however, rubio-aurioles et al. (2012) revealed that the time concerns domain score of the psychological and interpersonal relationship scales (pairs) was significantly lower for daily tadalafil 5 mg compared with sildenafil on demand treatment (23) showing that tadalafil improves sexual confidence more efficiently than sildenafil (23). interestingly, our patients in group a who received daily tadalafil 5 mg for 2 months showed a high statistically significant difference between pre and post-intervention plr and nlr. meanwhile, patients in group b who received daily sildenafil 25 mg for 2 months did not show any statistically significant difference between pre and post-intervention plr and nlr. consistently, la vignera et al. (2014) showed that tadalafil has a preventive effect on both endothelial apoptosis and excessive platelet adhesion in ed patients (24). furthermore, a recent egyptian study demonstrated that daily tadalafil 5 mg supplementation lowers these markers with significant improvement in the erectile function (25). the superiority of tadalafil versus sildenafil in lowering plr and nlr in the current study might be explained by the shorter half-life of sildenafil but no available data support this hypothesis that needs further investigations. although tadalafil and sildenafil showed significant improvement in improving the ariief-5 scores, yet, tadalafil was superior to sildenafil in lowering the studied inflammatory markers. a previous systematic review conducted by mirone et al. (2008) stated that tadalafil was preferred by the patients compared to sildenafil for several reasons (26). firstly, patients preferred tadalafil owing to its flexibility (27). secondly, tadalafil was also preferred owing to its better tolerance (28). finally, tadalafil was preferred by the patients for its higher efficacy (28-29). to the best of our knowledge, the current study is one of the first to demonstrate higher efficacy of tadalafil compared to sildenafil in lowering nlr and plr. however, there were several limitations of the current study that should be acknowledged. the sample size was relatively small and the patients were followed up for short duration. conclusions tadalafil and sildenafil have similar clinical efficacy in treating ed. however, tadalafil is more effective in lowering plr and nlr compared to sildenafil. future studies are required to replicate this finding as it may add superiority to tadalafil compared to sildenafil. references 1. impotence nih consensus development panel on impotence. jama1993; 270:83-90. 2. burnett al. evaluation and management of erectile dysfunction. in kavoussi lr, novick ac, partin aw, & peters içinde ca (eds.), campell-walsh urology. philadelphia, pa: elsevier. 2012; pp. 721748. 3. bhat t, teli s, rijal j, et al. neutrophil to lymphocyte ratio and cardiovascular diseases: a review. expert rev cardiovasc ther. 2013; 11:55-9. 4. feng jr, qiu x, wang f, et al. diagnostic value of neutrophil-tolymphocyte ratio and platelet-to-lymphocyte ratio in crohn's disease. gastroenterol res pract. 2017; 2017:3526460. 5. zhang y, feng x, wu x, et al. a systematic review and metaanalysis of the relationship between erectile dysfunction and the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. andrologia. 2022; 54:e14337. 6. liao z, tang y, li x, li d. the relationship between hematologic parameters and erectile dysfunction. sex med. 2021; 9:100401. 7. winterbourn cc, kettle aj, hampton mb. reactive oxygen species and neutrophil function. annu rev biochem. 2016; 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28:642-3. 14. world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013; 310: 2191-2194. 15. shamloul r, ghanem h, abou-zeid a. validity of the arabic version of the sexual health inventory for men among egyptians. int j impot res. 2004; 16:452-5. 16. demirci a, ozgur bc. the effect of using tadalafil 5 mg/day on neutrophil-lymphocyte and platelet-lymphocyte ratios in mild-medium and severe erectile dysfunction patients; and comparison of clinical response. andrologia. 2019; 51:e13347. 17. aslan a, kaya y, cirakoglu a, et al. neutrophil-lymphocyte ratio could be a marker for erectile dysfunction. urol j. 2019; 16:216-20. 18. zhang y, feng x, wu x, et al. a systematic review and metaanalysis of the relationship between erectile dysfunction and the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios. andrologia. 2022; 54:e14337. 19. ventimiglia e, cazzaniga w, pederzoli f, et al. the role of neutrophil-to-lymphocyte ratio in men with erectile dysfunction—preliminary findings of a real-life cross-sectional study. andrology. 2018; 6:559-63. 20. akbas a, gulpınar mt, sancak eb, et al. the relationship between platelet-lymphocyte ratio and severity of erectile dysfunction. kaohsiung j med sci. 2016; 32:91-5. 21. kilic m, erkan a, zengin s, et al. inflammatory biomarkers may predict response to phosphodiesterase type 5 inhibitor treatment in patients with erectile dysfunction. investig clin urol. 2023; 64:404-411. 22. gong b, ma m, xie w, et al. direct comparison of tadalafil with archivio italiano di urologia e andrologia 2024; 96(4):12756 5 evaluation of the effect of daily tadalafil 5 mg versus daily sildenafil 25 mg on neutrophil-lymphocyte and platelet-lymphocyte ratios... sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis. int urol nephrol. 2017; 49:1731-40. 23. rubio-aurioles e, porst h, kim ed, et al. a randomized openlabel trial with a crossover comparison of sexual self-confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on-demand in men with erectile dysfunction. j sex med. 2012; 9:1418-29. 24. la vignera s, condorelli ra, burgio g, et al. functional characterization of platelets in patients with arterial erectile dysfunction. andrology. 2014; 2:709-15. 25. gamalel din sf, nabil ismail n, moawad hh, et al. evaluation of tadalafil supplementation on the neutrophil/lymphocyte and the platelet/lymphocyte ratios in patients with erectile dysfunction: a prospective study. urologia. 2024; 91:598-603. 26. mirone v, fusco f, rossi a, et al. tadalafil and vardenafil vs sildenafil: a review of patient-preference studies. bju int. 2009; 103:1212-7. 27. von keitz a, rajfer j, segal s, et al. a multicenter, randomized, double-blind, crossover study to evaluate patient preference between tadalafil and sildenafil. eur urol 2004; 45:499-509 28. eardley i, montorsi f, jackson g, et al. factors associated with preference for sildenafil citrate and tadalafil for treating erectile dysfunction in men naive to phosphodiesterase 5 inhibitor therapy: post hoc analysis of data from a multicentre, randomized, open-label, crossover study. bju int 2007; 100:122-9. 29. eardley i, mirone v, montorsi f, et al. an open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. sex med 2005; 96:1323-32. 30. rodriguez tolra jr, cuadrado campaña jm, fumadó ciutat l, franco miranda e. prospective, randomized, open-label, fixed dose, crossover study to establish preference of patients with erectile dysfunction after taking the three pde-5 inhibitors. j sex med 2006; 3:901-9. correspondence abdel rahman bakry, md ali mohamed mahran, md hisham diab gaber, md mohamed diab mohamed, msc ahmed elshebany, md department of andrology & stds, faculty of medicine, assiut university, assiut, egypt mohamed ismail sedek, md department of clinical pathology, faculty of medicine, assiut university, assiut, egypt ahmad tarek motawi, md sameh fayek gamalel din, md (corresponding author) samehfayek@kasralainy.edu.eg department of andrology & stds kasr al-ainy, faculty of medicine cairo university, al-saray street, el manial, cairo, 11956, egypt conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12944 1 meta-analysis tion (1). its prevalence varies worldwide, starting from 15% in asia, 5-9% in europe, and 7-13% in north america (2). the global morbidity and disability-adjusted life years (dalys) of nephrolithiasis increased substantially between 1990 and 2019 (3). the majority of kidney stones are composed of calcium, primarily in the form of calcium oxalate or calcium phosphate stones (2). nephrolithiasis is often symptomatic (4). percutaneous nephrolithotomy (pcnl) is the primary treatment in patients with symptomatic nephrolithiasis larger than 2 cm (5). over time, pcnl has been through many alterations in patient positioning. the first ever pcnl was done by fernström et al. in prone position, back in 1976. the prone position was believed to be safely avoiding vital organs, such as the colon (6). later, the first report of supine pcnl was introduced by valdivia et al. in 1990 (7) and further elaborated in 1998 (8). since then, the supine position has undergone variable modifications. this includes the flank roll position, galdakaomodified valdivia position, crossed-leg supine position, complete supine position, and the most recent barts ffms position (9). all of them have been reported to decrease the duration of pcnl procedures by eliminating the need for patient repositioning and allowing quick airway access (10). barts flank-free modified supine (ffms) position is a newly enhanced version of the traditional supine position, with better access to the kidney (10). it offers several advantages compared to the prone position, including easier fluoroscopy access, more comfortable patient positioning, simpler tract dilation, reduced kidney pressure, improved fragment clearance, and easier transition to rirs (11). given these potential benefits, it is crucial to determine whether barts ffms is superior to the prone position in terms of clinical outcomes. this study aims to compare the barts ffms and prone positions in pcnl, focusing on key clinical outcomes such as stone-free rates, complications, and surgery duration. by identifying the optimal patient positioning for pcnl, this study seeks to contribute to the improvement of patient care and surgical efficiency in the treatment of nephrolithiasis. introduction: percutaneous nephrolithotomy (pcnl) has been performed in various positions, including prone position and several modifications of supine position. the barts flank-free modified supine (ffms) position is a newly enhanced version of the supine positions. this study aims to compare the outcomes of barts ffms and prone position in pcnl. methods: this study followed prisma 2020 guideline and was registered to prospero crd42024530426. comprehensive search in pubmed, sciencedirect, and scopus was conducted until may 2024. stone-free rates, complications, surgery duration, fluoroscopy duration, use of nephrostomy, and length of stay were collected. data were analyzed using revman 5.4. results: a total of 4 studies were included in this review. there was no significant difference in stone-free rates between barts ffms and prone positions (or = 1.12, 95% ci 0.64-1.95, p = 0.70). there were no significant difference in incidence of fever (or = 0.91, 95% ci 0.38-2.18, p = 0.84), need for blood transfusion (or = 0.46, 95% ci 0.11-1.88, p = 0.28), and urine leakage (or = 0.41, 95% ci 0.16-1.05, p = 0.06). the surgery duration was significantly shorter in barts ffms position than in prone position (md = -15.48, 95% ci [(-26.42)-(-4.55)], p = 0.006). there was no significant difference in patients requiring nephrostomy (or = 0.19, 95% ci 0.01-3.75, p = 0.28). there were no significant difference in fluoroscopy duration (md = 0.27, 95% ci [(-6.85)-7.40], p = 0.94) and the length of hospital stay (md = -0.20, 95% ci [(-0.74)-0.33], p = 0.46). conclusions: the surgery duration was significantly shorter in barts ffms position than in prone position. there were no significant differences regarding stone-free rates, complications, fluoroscopy duration, use of nephrostomy, and length of hospital stay. this indicates that neither barts ffms nor prone position is superior, and the choice should be based on the surgeon's preference and the patient's clinical status. key words: barts; flank-free; supine; prone; pcnl. submitted 19 august 2024; accepted 31 august 2024 introduction nephrolithiasis is among the most prevalent urological conditions, impacting around 12% of the global populabarts flank-free modified supine position vs prone position in percutaneous nephrolithotomy: systematic review and meta analysis i gede yogi prema ananda 1, kadek budi santosa 1, 2, i wayan yudiana 1, 2, pande made wisnu tirtayasa 1, 3, ida bagus putra pramana 1, 3, nyoman gede prayudi 1, 2, gede wirya kusuma duarsa 1, 2 1 department of urology, faculty of medicine, universitas udayana, denpasar, bali, indonesia; 2 prof. dr. i.g.n.g. ngoerah hospital, denpasar, bali, indonesia; 3 universitas udayana teaching hospital, badung, bali, indonesia. doi: 10.4081/aiua.2024.12944 summary archivio italiano di urologia e andrologia 2024; 96(4):12944 i gede yogi prema ananda, k. budi santosa, i w. yudiana, et al. 2 methods study design this systematic review and meta-analysis followed prisma 2020 guidelines and was registered to prospero crd42024530426. search strategy comprehensive search by the authors in scientific databases such as pubmed, sciencedirect, and scopus was conducted until may 2024. the keywords used were "pcnl" and ("flank-free" or "barts"). the authors engaged in discussions to settle any disagreements. eligibility criteria inclusion criteria cover studies in english, rct or cohort studies, and adult patients who had undergone standard pcnl in barts ffms compared to prone position. the definition of barts ffms position included in this study is a supine position with a 15° tilt of the ipsilateral flank, achieved by placing a 3-liter saline bag under the rib cage and a gel pad under the pelvis, thus creating the 'flankfree' position (8). stone-free rates, postoperative complications, and duration of surgery were the expected primary outcomes, while fluoroscopy duration, need for nephrostomy, and length of stay were chosen as secondary outcomes. exclusion criteria cover non-english articles, study designs other than rcts or prospective studies, non-standard pcnl procedures, and pcnl positions other than barts ffms and prone position. data extraction information was systematically collected using a structured format as first author, publication year, study design, sample size, age, body mass index (bmi), stone size, stone-free rates, complications, duration of surgery, duration of fluoroscopy, number of patients needing nephrostomy, and length of hospital stay. data analysis the analysis for this study was conducted using review manager version 5.4 (the cochrane collaboration, the nordic cochrane centre, copenhagen, denmark). for continuous data, the mean difference (md) was utilized, while dichotomous data were analyzed using the odds ratio (or). meta-analysis was performed when two or more studies provided the same type of data. to assess the heterogeneity among the included studies, cochran’s q and i² statistics were employed. a fixedeffects model was used when there was statistical homogeneity (defined as pvalue > 0.1 and i² < 50%). in cases where heterogeneity was present (p-value ≤ 0.1 or i² ≥ 50%), a random-effects model was applied. statistical significance was determined with a threshold of p < 0.05. quality appraisal to assess the selected studies, we utilized two different tools. we utilized two different tools: the jadad score for randomized controlled trials (rcts) and the newcastleottawa scale (nos) for cohort studies. if any discrepancies arose in bias assessments or justifications, they will be resolved through discussions among the authors until a consensus was reached. results study selection the search yielded 263 results, with 231 records removed due to duplicates and irrelevance. after this removal, 32 potentially relevant articles remained. a thorough examination of the full texts resulted in 4 studies meeting the inclusion criteria for this review. the process is illustrated in the prisma flow chart (figure 1). figure 1. prisma flowchart. archivio italiano di urologia e andrologia 2024; 96(4):12944 3 barts flank-free modified supine vs prone position in pcnl study assessment two rcts were included, assessed using the jadad score and classified as poor quality. two cohort studies were assessed using the newcastle-ottawa scale, all rated as good quality. the assessment details are presented in table 1. study characteristics there were 4 studies with a total of 228 pcnl patients operated in the barts ffms position and 285 patients in the prone position. the data in table 2 provides a summary of the subject's baseline characteristics. from the 4 studies, only 3 of them showed proper data to account for the mean age of the patients. one study by zanaty et al. lacked the standard deviation (sd) in mean age data. the baseline characteristics such as the sample size, mean age, bmi, stone size, stone-free rate, the definition of stone-free status, and follow up time were available in table 2. stone-free rates based on the forest plot presented in figure 2, which included all 4 studies, there was no significant difference in the stone-free rate between barts ffms and the prone position (or = 1.12, 95% ci 0.64-1.95, p = 0.70). complications (clavien-dindo) fever (clavien-dindo grade 1) all studies reported fever as a postoperative complication. figure 3 indicates that the incidence of fever did not differ significantly between barts ffms and the prone position (or = 0.91, 95% ci 0.38-2.18, p = 0.84). blood loss requiring transfusion (clavien-dindo grade 2) only 3 studies reported blood transfusion. forest plot in figure 4 demonstrates that there was no significant difference in the incidence of blood loss requiring transfusion between patients in the barts ffms and prone positions (or = 0.46, 95% ci 0.11-1.88, p = 0.28). urine leakage (clavien-dindo grade 3) figure 5 illustrates that the incidence of urine leakage was not significantly different between the barts ffms and prone position groups, as shown in the forest plot of 3 studies (or = 0.41, 95% ci 0.16-1.05, p = 0.06). surgery duration the duration of surgery was significantly shorter in barts table 1. assessment of the studies included. author study design assessment jadad score newcastle-ottawa scale mulay et al., 2022 (12) rct 1 míçooğullari et al., 2021 (13) cohort 7 sohail et al., 2017 (14) cohort 7 zanaty et al., 2022 (15) rct 2 figure 2. stone-free rates. table 2. baseline characteristics of the studies included. study pcnl sample size mean age bmi stone size stone-free rate definition of follow-up position (n) (years) (kg/m2) (cm) (%) stone-free status time mulay et al. (2022) barts ffms 50 40.16 n/a 2.43 ± 1.23 96 residual stones < 4 mm 1 month prone 50 42.80 2.6 ± 1.23 94 zanaty et al. (2022) barts ffms 30 47.40 ± 7.89 32.55 ± 8.98 4.56 ± 1.51 80 n/a n/a prone 30 47.67 ± 8.82 31.21 ± 5.48 4.05 ± 1.21 90 sohail et al. (2017) barts ffms 96 38.9 ± 10.1 27.9 ± 7.2 2.99 ± 1.26 85 -no residual stones, 1-3 months prone 101 45.2 ± 9.5 28.7 ± 6.5 2.97 ± 1.51 79 or -residual stones < 5 mm míçooğullari et al. (2021) barts ffms 52 43.9 ± 16.2 24.4 ± 2.9 3.21 ± 0.73 92 residual stones < 3 mm 1 month prone 104 40.8 ± 14.6 24.8 ± 2.9 3.27 ± 0.82 94 archivio italiano di urologia e andrologia 2024; 96(4):12944 i gede yogi prema ananda, k. budi santosa, i w. yudiana, et al. 4 ffms position than in prone position, as indicated in figure 6 (md = -15.48, 95% ci [(-26.42)-(-4.55)], p = 0.006). it also showed the studies were heterogeneous. use of nephrostomy in figure 7, the forest plot of 3 studies displayed that the use of nephrostomy after pcnl did not differ significantfigure 4. blood loss requiring transfusion. figure 5. urine leakage. figure 6. duration of surgery. figure 3. fever. archivio italiano di urologia e andrologia 2024; 96(4):12944 5 barts flank-free modified supine vs prone position in pcnl ly in barts ffms and prone position (or = 0.19, 95% ci 0.01-3.75, p = 0.28). the studies were heterogeneous. fluoroscopy duration only 2 studies reported the duration of fluoroscopy used in pcnl, and they were heterogeneous. as shown in figure 8, the duration of fluoroscopy did not significantly differ between the barts ffms and prone position groups (md = 0.27, 95% ci [(-6.85)-7.40], p = 0.94). length of hospital stay the included studies in this outcome were heterogeneous. there was no significant difference between patients in the barts ffms and prone positions, as shown in figure 9 (md = -0.20, 95% ci [(-0.74)-0.33], p = 0.46). discussion when choosing between the barts ffms and prone positions, it is important to note that all supine positions, regardless of the modification, offer several advantages over the prone position. these include easier positioning for anesthesia, reduced risk of nervous system injury, and suitability for patients with comorbidities such as cardiovascular disease, risk of infection, and obesity (16). additionally, the total cost of supine pcnl is lower than that of prone pcnl, due to savings on surgical equipment and anesthesia expenses (17). to determine whether the barts ffms or prone position is superior, this review focused on stone-free rates, complications, and surgery duration as primary outcomes. the stone-free rates were not significantly different between the barts ffms and prone positions. while a meta-analysis by birowo et al. (18) found higher stonefree rates for supine positions in general, li et al. (19) reported no significant difference between supine and prone positions. complications were classified using the clavien-dindo system: fever as grade 1, blood loss requiring transfusion as grade 2, and urine leakage as grade 3. the incidences of fever, transfusion due to blood loss, and urine leakage figure 8. duration of fluoroscopy. figure 9. length of hospital stay. figure 7. nephrostomy. archivio italiano di urologia e andrologia 2024; 96(4):12944 i gede yogi prema ananda, k. budi santosa, i w. yudiana, et al. 6 were not significantly different between the barts ffms and prone positions. however, li et al. (19) found no significant difference in complication rates between supine and prone positions, while birowo et al. (18) reported significantly lower major complications in supine positions. these discrepancies may be due to inconsistencies in outcome reporting, as not all studies used the clavien-dindo classification. in this review, the duration of pcnl was significantly shorter in the barts ffms position compared to the prone position. this aligns with li et al. (19), who also found shorter durations in supine positions, but contrasts with birowo et al. (18) who reported no significant difference. literature suggests that supine positions should reduce operation time by eliminating the need for patient repositioning and allowing quick airway access (10). additionally, supine positions facilitate easier anesthesia, further shortening the duration of surgery (16). the insertion of a nephrostomy tube after pcnl remains as a standard procedure. it served as drainage, a means to tamponade bleeding after surgery, and an access for a second exploration if necessary (20). in this review, the use of nephrostomy was reported in three articles and showed no significant difference between the barts ffms and prone positions. the use of fluoroscopy is a crucial step in pcnl, allowing urologists to guide the needle to a safe location. the imaging helps them to navigate into brodel’s line of bloodless incision, minimizing the probability of bleeding (21). fluoroscopy duration was reported in only two studies in this review, showing no significant difference between barts ffms and prone patients. in this study, the length of hospital stay did not significantly differ between the barts ffms and prone positions. this is consistent with meta-analyses by birowo et al. (18) and li et al. (19). this review article provides valuable information to assist surgeons in choosing between the two positions. however, this study has limitations, including a small number of included studies, inconsistencies in outcome reporting, and high heterogeneity in some outcomes. future research should explore the cost-benefit analysis and potential advantages of the barts ffms position to optimize pcnl procedures. conclusions the surgery duration was significantly shorter in barts ffms position than in prone position. there were no significant differences regarding stone-free rates, complications, fluoroscopy duration, use of nephrostomy, and length of hospital stay. overall, the barts ffms position was not superior to the prone position. it offers a viable alternative to the prone position in pcnl, with no significant differences in clinical outcomes. therefore, the choice of patient position should be based on the surgeon's preference and the patient's clinical condition. acknowledgments we would like to thank all the staff at the department of surgery, urology division, prof. dr. i.g.n.g ngoerah general hospital for their support. references 1. alelign t, petros b. kidney stone disease: an update on current concepts. adv urol. 2018; 2018:3068365. 2. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017 sep; 35(9):1301-1320. 3. zhang l, zhang x, pu y, et al. global, regional, and national burden of urolithiasis from 1990 to 2019: a systematic analysis for the global burden of disease study 2019. clin epidemiol. 2022; 14:971-983. 4. edvardsson vo, indridason os, haraldsson g, et al. temporal trends in the incidence of kidney stone disease. kidney int. 2013; 83:146-52. 5. assimos d, krambeck a, miller n. surgical management of stones: aua/endourology society guideline (2016), part ii. journal of urology 2016; 196: 1-50. 6. fernström i, johansson b. percutaneous pyelolithotomy. scand j urol nephrol 1976; 10:257-9 7. valdivia jg, valer j, villarroya s, et al. why is percutaneous nephroscopy still performed with the patient prone? journal of endourology 1990; 4: 269-277. 8. valdivia uría j g, valle gerhold j, lópez lópez ja, et al. technique and complications of percutaneous nephroscopy: experience with 557 patients in the supine position. j urol 1998; 160:1975-1978. 9. karaolides t, moraitis k, bach c, et al. positions for percutaneous nephrolithotomy: thirty-five years of evolution. arab journal of urology 2012; 10: 307-316. 10. kumar p, bach c, kachrilas s, et al. supine percutaneous nephrolithotomy (pcnl): ’in vogue’ but in which position? bju international 2012; 110: 1-4. 11. bach c, goyal a, kumar p, et al. the barts 'flank-free' modified supine position for percutaneous nephrolithotomy. urol int. 2012; 89:365-8. 12. mulay a, mane d, mhaske s, et al. supine versus prone percutaneous nephrolithotomy for renal calculi: our experience. curr urol. 2022; 16:25-29. 13. miçoogulları u, kamacı d, yıldızhan m, et al. prone versus barts “flank-free” modified supine percutaneous nephrolithotomy: a match-pair analysis. turk j med sci. 2021; 51:1373-1379. 14. sohail n, albodour a, abdelrahman km. percutaneous nephrolithotomy in complete supine flank-free position in comparison to prone position: a single-centre experience. arab j urol. 2016; 15:42-47. 15. zanaty f, mousa a, elgharabawy m, et al. a prospective, randomized comparison of standard prone position versus flank-free modified supine position in percutaneous nephrolithotomy: a singlecenter initial experience. urol ann. 2022; 14:172-176. 16. proietti s, rodríguez-socarrás me, eisner b, et al. supine percutaneous nephrolithotomy: tips and tricks. transl androl urol. 2019; 8(suppl 4):s381-s388. 17. satyagraha p, alluza hhd, daryanto b, nurhadi p. prone vs supine pcnl: what about the cost?. j med clin res & rev. 2018; 2: 1-6. https://doi.org/10.33425/2639-944x.1067 18. birowo p, tendi w, widyahening is, et al. supine versus prone archivio italiano di urologia e andrologia 2024; 96(4):12944 7 barts flank-free modified supine vs prone position in pcnl position in percutaneous nephrolithotomy: a systematic review and meta-analysis. f1000res. 2020; 9:231. 19. li j, gao l, li q, et al. supine versus prone position for percutaneous nephrolithotripsy: a meta-analysis of randomized controlled trials. int j surg. 2019; 66:62-71. 20. türk c, petrík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-82. 21. sharma gr, maheshwari pn, sharma ag, et al. fluoroscopy guided percutaneous renal access in prone position. world journal of clinical cases 2015; 3: 245-264. correspondence i gede yogi prema ananda (corresponding author) yogiprema16@gmail.com department of urology, faculty of medicine, universitas udayana, denpasar, bali, indonesia kadek budi santosa busanbsa@gmail.com i wayan yudiana yanyud@yahoo.com nyoman gede prayudi prayudi_blonx@yahoo.com gede wirya kusuma duarsa gwkduarsa@yahoo.com prof. dr. i.g.n.g. ngoerah hospital, denpasar, bali, indonesia pande made wisnu tirtayasa wisnu.tirtayasa@gmail.com ida bagus putra pramana bagusputra@unud.ac.id universitas udayana teaching hospital, badung, bali, indonesia conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 65archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. potential candidates. in the most important pp market, the usa, it is estimated that no more than 3% of the patients with erectile dysfunction (ed) will finally undergo pp surgery to treat the condition (3). there is a lack of information about pp implantation trends in south american countries. the main reason is that the number of devices sold annually is extremely low compared with bigger markets such as the usa. particularly in chile, the trends in pp implantation and other available treatments for ed are unknown. chile has a population of 18.7 million people as of 2019 (4) and the second highest growth domestic product per capita (gdppc) of south america (us $16,280 us) after uruguay (us $17,870) (for reference, gdppc is us $62,794 in the usa) (5). according to the world health organization (who), male life expectancy in chile is 76.5 years (6). among chilean men over 50 years old, the prevalence of any degree of ed is 58% (7-9). during the last decade, the available treatments for ed in chile have been phosphodiesterase 5 inhibitors (pd5is) (sildenafil, vardenafil, tadalafil), intracavernosal vaso-active agents, and pp (malleable and 3-piece inflatable). neither public nor private insurance covers any pharmacological treatment for ed. some health insurances partially cover hospital stay and operation costs including surgeon's fee for pp. however, the device must always be paid by the patient, with prices ranging from us $1,000 for a malleable pp to us $10,000 for a 3-piece inflatable pp. the aim of this study is to evaluate the trends in chile over a 10-year period in regard to the available treatments for ed with special focus on pp. it also estimates the potential number of candidates for pp according to population demographics, sexually active men, and ed prevalence. materials and methods for our analysis we considered chilean ed patients over 50 years old. we estimated the total number of this group by crossing demographic and clinical data. demographic information was obtained from the chilean national institute of statistics (4). annually, male populations older than 50 years old examined from january 1, 2010 to objectives: evidence regarding demand trends for erectile dysfunction (ed) treatments are scarce in south america. this study aims to evaluate trends in ed treatments in chile over a 10-year period (20102020) and estimate the potential number of candidates for penile prosthesis. materials and methods: sales trends of pharmacological treatments and penile prosthesis were obtained from market studies. the potential number of candidates for penile prosthesis implantation was calculated by crossing epidemiological data with previously reported ed prevalence, proportion of sexually active men, percentage of men seeking medical assistance for ed, and the proportion of patients who are non-responders to ed oral drug therapies results: in the 10-year studied period, the chilean male population older than 50 years increased 34.7%, with an average annual variation (aav) of 3.4%. for the same period, the sales of oral drug therapies for ed increased by 71.3% (aav 6.2%), the sales of intracavernosal vasoactive agents (icva) decreased by 0.4% (aav -0.2%), and penile prosthesis sales increased by 113% (aav 6.7%). we estimated that only 0.05% of sexually active men older than 50 years old with ed who sought medical assistance finally had a penile prosthesis implanted to manage their condition. conclusions: demand for ed oral drug therapies significantly increased in chile during the last decade, while icva remained stable. the annual rate of penile prosthesis implantation increased. however, the gap between the potential penile prosthesis candidates and the actual number of devices implanted is suspected to remain extremely high. key words: erectile dysfunction treatment; pharma-trends; penile prosthesis. submitted 17 december 2021; accepted 26 january 2022 introduction worldwide, penile prosthesis (pp) implantation has increased annually by an average of 8.1% in the period 2006-2011 and is expected to have a compound annual growth rate (cagr) of 2.1% in the period 2017-2023 (1, 2). despite this constant increase, the annual number of devices sold is still considered extremely low compared to the number of trends in treatments for erectile dysfunction in chile between 2010 and 2020 with special focus on penile prostheses marcelo marconi 1, cristian palma 2, sergio moreno 3, jose miguel flores 4, santiago escobar-urrejola 5 1 andrology unit, department of urology, pontificia universidad católica de chile, santiago, chile; 2 department of urology, clínica las condes, santiago, chile; 3 department of urology, clínica santa maria, santiago, chile; 4 sexual and reproductive medicine fellowship at memorial sloan kettering cancer center, new york, usa; 5 emergency department, complejo asistencial sótero del río, puente alto, chile. doi: 10.4081/aiua.2022.1.65 summary archivio italiano di urologia e andrologia 2022; 94, 1 m. marconi, c. palma, s. moreno, j.m. flores, s. escobar-urrejola 66 january 1, 2020 were considered for analysis. the proportion of sexually active men and the ed prevalence were obtained from previous chilean surveys (7-10). to calculate the number of chilean men who could be potential candidates to receive a pp to treat their ed, we estimated the proportion of men who would suffer severe ed, defined as patients who are pd5is non-responders. this population was calculated by crossing the number of sexually active chilean ed patients and the internationally reported percentage of men with ed who seek medical assistance (11, 12) and the estimated proportion of men with ed who are pd5is non-responders (13, 14). finally, we compared the estimated number of potential candidates for pp implantation to the actual number of chilean men who finally had a pp implanted in the same period. for the period of 2010-2020, the sales trends of pharmacological ed treatments were obtained from pharma-market studies performed annually (15). this information includes the sales of the generic and labeled drugs per unit of sildenafil, vardenafil, tadalafil, and intracavernosal vasoactive agents. for pp, six companies represented 100% of the chilean market: boston scientific®, (marlborough, massachusetts, usa), previously named american medical system® (minnetonka, minneapolis, usa), coloplast® (humlebaek, denmark), promedon® (cordoba, argentina), zephyr® (geneva, switzerland), and rigicon® (ronkonkoma, new york, usa). all companies shared their unit sales data for the study period. with this information we calculated average annual variations (aav) of ed drugs and pp, and modeled growth trends for the study period. data were analyzed using the statistical software graphpad® prism 8.0 (graphpad software, san diego, california, usa). descriptive statistics are reported as percentages and frequencies for categorical variables. ethical and regulatory approvals were obtained from the ethical committee of the faculty of medicine of pontificia universidad católica de chile. results in the 10-year period (january 1, 2010, to january 1, 2020) the chilean male population older than 50 years old increased by 34.7% (figure 1) with an aav of 3.4%. the total sales of pd5is (sildenafil, vardenafil, tadalafil) in the same period increased by 71.3% with an aav of 6.2% (figure 1). for the study period the mean market shares for each drug were: sildenafil 71,9%, tadalafil 28%, vardenafil 0,1%. the sales trends of intracavernosal vasoactive agents for the same period time were negative (-0.4%) with an aav of -0.2% (figure 1). during the study period, a total of 1087 pp were implanted, 68% were malleable, while 32% were 3-piece inflatable pp (figure 1). the 10-year increase was 113% (year 2010: 59 implants; year 2019: 126 implants) with an aav of 6.7% per year. for the study period, we estimated the annual number of men affected with severe ed by crossing the demographic data with the percentage of sexually active men older than 50 years old and the ed prevalence, reported in chile (7,8,9). in 2019, chile had 2,569,856 men older than 50 years old, of which 77% declared being sexually active (n = 1,978,789), and 58% of these men report some degree of ed (n = 1,147,698). according to international data (11, 12), 22.5% of such men would seek medical assistance or treatment (n = 258.232). figure 1. a) annual growth of men older than 50 years old in chile. ten-year variation 34.7%; average annual variation (aav) 3.4%. b) annual growth sales of pd5is in units of sildenafil, vardenafil, tadalafil. ten-year variation 71.3%; aav 6.2%. c) annual sales growth of intracavernosal prostaglandin (units). ten-year variation -0.4%, aav -0.2%. d) annual growth of pp implantation (units). ten-year variation 113%, aav 6.7%. 67archivio italiano di urologia e andrologia 2022; 94, 1 ed treatment trends in chile: focus on penile prostheses finally, according to previous reports (13, 14), 30% of these patients would not respond to pd5is and become potential candidates for pp implantation (n = 77.470). in figure 2, the estimated prevalence of ed and potential pp candidates are presented for each year of the study. if we consider that all potential pp candidates were willing to receive an implant during the study period, the estimated gap between this number (net pp candidates) and the actual number of implanted units is 99.83% (figure 3). in order to perform a more realistic analysis, we considered an alternative scenario where only 1% of the pp potential candidates would be willing to undergo surgery. even in this theoretical setting, the gap between the number of pp actually implanted and the potential demand was 83% (figure 3). finally, using the same methodology, we estimated that only 0.05% of sexually active men older than 50 years old with ed who sought medical assistance finally had a pp procedure to manage the ed. discussion according to the organization for economic cooperation and development, chile is an aging country in south america, and it is expected that age-related conditions such as ed will significantly increase in the next decades (16). this epidemiological data is consistent with the observed 10-year growth in the number of men older than 50 years old (34.7%). the combination of this fact with the proportion of them who declare being sexually active (77%) and the high prevalence of ed (58%), we believe explains the constant annual rate of increase in the sales of pd5is. interestingly, the 10-year growth observed in the sales of figure 2. estimation of net pp candidates in chile according to demographic data, percentage of sexually active men, ed prevalence, ed patients who seek medical assistance, and estimated proportion of patients who are pd5is non-responders. figure 3. a) estimated uncovered gap between all (100%) potential pp candidates and devices actually implanted in the 10-year study period. b) estimated uncovered gap considering a scenario where only 1% of potential pp candidates would be willing to undergo surgery versus the devices actually implanted. archivio italiano di urologia e andrologia 2022; 94, 1 m. marconi, c. palma, s. moreno, j.m. flores, s. escobar-urrejola 68 pd5is (71.3%) and its aav (6.2%) almost doubled the growth rates observed for the population of men older than 50 in the same period (10-year variation 34.7%; aav 3.4%). this difference may be explained by three reasons. first, a significant number of pd5i consumers might be men under 50 years old (11, 12). second, in chile, pd5is are over-the-counter medicines (no prescription needed), with multiple new generic low-price drugs, which facilitates its access. finally, as recently reported by dogan and madendere (17), chile is in the top five worldwide for pd5is search trends on the internet, specifically for sildenafil, which confirms the fact that these drugs are extremely well known in this country. in the last two decades, similar annual growth rates of pd5is sales have also been reported in other countries, and the worldwide market is expected to grow 6.5% annually by 2023 (7, 11), being sildenafil the most prescribed drug by physicians, particularly among andrologists (18). for clinicians who treat ed patients regularly, it is not surprising to observe that the annual sales trends of intracavernosal vasoactive agents have remained stable or were even slightly negative in the study period (aav -0.2%). a lack of spontaneity, pain, and risk of priapism, among others, may explain why the demand for intracavernosal vasoactive agents has remained unchanged in the last 10 years in chile. combining our clinical experience and results, we believe that intracavernosal vasoactive agents still have a role in the management of moderate/severe ed. however, in the whole spectrum of ed treatments available, it seems to occupy a specific niche without potential for growth. penile prosthesis have been an option to treat ed for the last 40 years and are available in almost all countries around the world. recently, in the period 2006-2010, bass et al. reported an aav of 8.1% in pp sales worldwide, which was based on information given by two companies: american medical system® (minnetonka, minneapolis, usa) and coloplast® (humlebaek, denmark) (1). in this study, the usa represented 85.9% of the worldwide market, followed by germany (2.3%), the united kingdom (2.1%), and italy (2.0%). in the last two decades, other countries such as france and saudi arabia have reported aavs of 4.9% and 31.3% respectively (19, 20). compared to the global tendencies, our study shows a similar trend in the last decade (6.7%). regarding the type of implant, we observed that 68% were malleable and 32% were 3-piece inflatable implants, which are similar to other countries where pp are not covered by either public or private insurance (20). on the other hand, in the usa, where most pp devices are covered by insurance, 90% of implanted pp were inflatable, and only 10% were malleable (21). this reveals that when it comes to choosing the type of pp, costs and insurance coverage play an important role. high satisfaction rates have been reported for pp (90%) (22), and the number of candidates for this treatment are presumed to have significantly increased in the last two decades. nevertheless, the gap between the number of pp implanted annually and the net number of potential candidates remains extremely high. only around 3% of ed patients finally undergo surgery in the usa, the country with the highest number of pp implanted and with a high percentage of patients who have insurance coverage (3). according to our data, this proportion in chile would be 0.05%, and the potential uncovered gap between the net pp candidates and the actual number of implanted devices ranges from 99.83% (considering 100% of the net potential demand) to an extremely conservative 83% (considering 1% of the net potential demand). it is a fact that the number of ed patients has constantly increased worldwide in the last 40 years, the gdppcs of developed and emerging economies have also increased constantly, the pp satisfaction rates are extremely high, and the costs have decreased. thus, considering our results and the available information in peer-reviewed journals, it is worth examining why the implantation of pp has not increased substantially, as well as why the gap between potential candidates and actual pp implanted remains extremely high worldwide. we believe that the answers to this question are beyond the scope of this paper. however, considering our results, it is worth proposing some possible explanations. first, it may be that the number of men with severe ed who are sexually active and seek treatment is overestimated, which would make the estimated number of potential candidates for pp wrong. however, the rising demand for pd5is is evidence against this argument because even if we consider that a high proportion of men who consume pd5is do not suffer from ed, the remaining proportion still represents a high volume of men worldwide (11, 12). second, it may be that the calculated proportion of ed patients who do not respond to pd5is might be overestimated (30%), meaning that there would be much fewer net pp candidates. however, our own clinical experience and the published evidence consistently indicate that 30% of men with ed will not experience clinical significant improvements in their erections (13, 14). considering this analysis, it seems that our estimation of the net pp candidates comes from robust data. third, as demonstrated by pescatori et al. (23), oral drugs (pd5is) are extensively known in the general population as a treatment alternative for ed; however, second and third line treatments, such as pp are known by a minority of men (22.2-27.9%) and women (19.2-20.2%). the same study evaluated the attitude towards pp revealing that 50,7% of men and 48,4% of women would be willing to choose (men) or support (women) pp as a treatment option for severe ed. this evidence supports the idea that the low awareness that the general population and particularly men have about pp, may be one of most important facts behind the huge uncovered demand. if we consider the gap between the potential and the actual demand to be real (83 to 99.83%), we believe there is an important issue to address: how pp technology can be more efficiently provided to men who do not have other suitable treatment options? strategies to improve transfer from manufacturers to the community could be, among others; increasing access through insurance coverage for devices in countries that still do not have them, such as chile; lower device prices and finally, educating urologists and patients about the benefits of pp in order to increase awareness about this treatment option for patients with ed. our study has several limitations. first, it is a retrospective study; second, the number of men with ed and severe ed (pp candidates) were estimated from previous reports that may not strictly represent all chilean men; 69archivio italiano di urologia e andrologia 2022; 94, 1 ed treatment trends in chile: focus on penile prostheses third, the proportion of men that consume pd5is and do not have ed is unknown, which may have impacted the annual sales trend results significantly; fourth, the number of pp that were re-operations is unknown, meaning that the number of men who actually received a pp as treatment for severe ed could be lower; finally, as mentioned, the actual proportion of men who are pp candidates but would be really willing to undergo the procedure is unknown; for the aim of the research, this number was estimated by crossing the available data. conclusions in the 10-year period (2010-2020), pd5is significantly increased in demand, while intracavernosal injections of vasoactive agents remained stable. the average annual variation of pp in chile is comparable to the rest of the world. however, the gap between potential pp candidates and the actual number of devices implanted is suspected to be extremely high. this phenomenon seems to be present worldwide, even in countries where the device is covered by insurance. the reasons behind this gap may be addressed by taking actions to increase the access to pp to treat patients with ed worldwide. references 1. baas w, o'connor b, welliver c, et al. worldwide trends in penile implantation surgery: data from over 63,000 implants. transl androl urol. 2020; 9:31-37. 2. penile implants or penile prosthesis market global industry analysis, size, share, trends and forecast, 2015-2023. https://www. researchandmarkets.com/. id: 4209017, report, march 2017. 3. lee dj, najari bb, davison w, et al. trends in the utilization of penile prostheses in the treatment of erectile dysfunction in the united states. j sex med. 2015; 12:1638-45. 4. instituto nacional de estadística de chile. www.ine.cl 5. world bank national accounts data, and oecd national accounts data files. gdp per capita (current us$). https://data.worldbank.org/. 6. world health statistics 2020: monitoring health for the sdgs, sustainable development goals. geneva: world health organization; 2020. www.who.org 7. venegas ja, baeza r. prevalencia de disfunción eréctil en chile. rev chil urol. 2004; 69:199-202. 8. acuña ji, marió c, salazar i, et al. prevalence of erectile dysfunction in men screened for prostate cancer. abstracts from the 36th congress of the société internationale d'urologie, buenos aires, argentina. world j urol. 2016; 34 (suppl 1):1-248. 9. santibañez c, anchique c, herdy a, et al. prevalencia de disfunción eréctil y factores asociados en pacientes con indicación de rehabilitación cardíaca. rev chil cardiol. 2016; 35:216-221. 10. la sexualidad de lo chilenos. encuesta gfk adimark, año 2017. https://www.gfk.com/es/ 11. nicolosi a, buvat j, glasser db, et al. sexual behaviour, sexual dysfunctions and related help seeking patterns in middle-aged and elderly europeans: the global study of sexual attitudes and behaviors. world j urol. 2006; 4:423-8. 12. moreira ed, glasser db, gingell c, et al. sexual activity, sexual dysfunction and associated help-seeking behaviours in middle-aged and older adults in spain: a population survey. world j urol .2005; 6:422-9. 13. mcmahon c, smith c, shabsigh r. treating erectile dysfunction when pde5 inhibitors fail. bmj. 2006; 332:589-92. 14. goldstein i, tseng l-j, creanga d, et al. efficacy and safety of sildenafil by age in men with erectile dysfunction. j sex med. 2016; 13:852-59. 15. consultora-iqvia. informe de evolución del mercado farmacéutico chileno. santiago, chile; 2020. www.iqvia.com 16. old-age dependency ratio. in pensions at a glance 2017: oecd and g20 indicators, oecd publishing, paris. doi: https://doi.org/ 10.1787/pension_glance-2017-22-en 17. deger md, madendere s. erectile dysfunction treatment with phosphodiesterase-5 inhibitors: google trends analysis of last 10 years and covid-19 pandemic. arch ital urol androl. 2021; 93:361-365. 18. palmieri a, silvani m, giammusso b, et al. a "real life" investigation on the prescriptive habits among italian andrologists: the "conser" survey from italian society of andrology (sia) on sildenafil oral film. arch ital urol androl. 2019; 91:115. 19. léon p, seisen t, mozer p, et al. trends in the placement of penile prosthesis over the last 17 years in france. asian j androl. 2015; 17:337-8. 20. alwaal a, al-sayyad a. utilization of penile prosthesis and male incontinence prosthetics in saudi arabia. j urol ann. 2017; 4:353-356. 21. kashanian ja, golan r, sun t, et al. trends in penile prosthetics: influence of patient demographics, surgeon volume, and hospital volume on type of penile prosthesis inserted in new york state. j sex med. 2018; 15:245-250. 22. vakalopoulos i, kampantais s, ioannidis s, et al. high patient satisfaction after inflatable penile prosthesis implantation correlates with female partner satisfaction. j sex med. 2013; 10:2774-81. 23. pescatori es, baldini a, parazzini f, et al. how much do people know about male sexual problems? a survey in a selected population sample. arch ital urol androl. 2019; 91:182. correspondence marcelo marconi, md (corresponding author) mmarconi@andro.cl andrology unit, department of urology, pontificia universidad católica de chile cruz del sur 177, santiago (chile) cristian palma, md palmaceppi@gmail.com department of urology, clínica las condes estoril 450, las condes, santiago (chile) sergio moreno, md sergiomorenof@gmail.com department of urology, clínica santa maria avenida santa maría 500, providencia, santiago (chile) jose miguel flores, md floresmartinezjm@gmail.com sexual and reproductive medicine fellowship at memorial sloan kettering cancer center 1275 york avenue, new york (usa) santiago escobar-urrejola, md sescobar3@uc.cl emergency department, complejo asistencial sótero del río, puente alto garcía moreno 1439, ñuñoa (chile) stesura seveso archivio italiano di urologia e andrologia 2023; 95, 1 note on surgical technique operative efficiency. we hereby describing our novel technique of penile tourniquet application using a silicone penrose tube designed as a strap. this technique increases the operative efficiency and simplifies the application of a tourniquet for any type of penile surgery. technique this technique was designed by an experienced penile reconstructive surgeon who performed and tested various tourniquet techniques. our technique consists of the application of sterile penrose silicone tube drain (medline® ref.dynd50427, size: 45.72 cm x 0.64 cm). in this purpose, we utilize all penrose length (45.72 cm) without shortening the tube. first, we create the tourniquet part of the tube by using about 15 cm of the tube length as a loop. then, we create a small 0.8 cm through and through hole in the 15 cm point using a surgical mayo scissors. the extremity of the drain is then passed through this small window. we apply then the tourniquet loops around the base of the penis and secure the loop by pulling away both extremities to create the desired compression on the corporal bodies. the tourniquet will be self-retained, anti-slip through the silicone surface characteristics and the hole resistance. additional clamping may be beneficial to increase or to maintain the exerted pressure. lastly, releasing the tourniquet will be achieved by removing the clamp if present or simply by untightening both penrose tube extremities. this maneuver can be repeated several times during the surgery without removing the tourniquet from the base of the penis. the tension exerted through the tourniquet is adjustable according to the pressure desired. in our experience, no complications, failures nor difficulties were encountered, and the application of this novel technique is reproducible and easy to perform (figure 1). discussion to our knowledge, this is the first article describing this technique. there is a paucity of data regarding the various tourniquet types and safety use guidelines for penile surgery. gupta et al. (6), studied the different type of penile tourniquet with an author’s design of silicone strip tourniquet secured by tubectomy ring. introduction: penile compression using a tourniquet is common with several materials and designs that have been previously described. the objective of the tourniquet is to induce an artificial erection through corporal occlusion for intra-operative penile curvature assessment or to obtain a clear visible bloodless surgical field. objective: we sought to describe our novel step-by-step technique of applying penile tourniquet using silicone penrose drain tube designed as a strap by creating a small hole on the side of the tube to obtain a loop at the base of the penis conclusions: this novel technique is simple, effective and requires no additional materials nor special equipment, and facilitates the application and release of a tourniquet during penile surgery. key words: penis; penile surgery; tourniquet; penoplasty, surgical technique. submitted 21 january 2023; accepted 17 february 2023 introduction penile surgery is common in general and reconstructive urology. frequently, surgeons apply intra-operative penile compression called tourniquet – derived from the french verb ‘’to turn’’ – at the base of the penis to induce an artificial arterial erection to assess penile curvature. furthermore, tourniquet use allows a bloodless surgical field and an adequate hemostatic control in either emergency or elective settings. the aim of the tourniquet in penile surgery is to compress and constrict distal penile blood outflow by corporal body occlusion (1). routine use of a tourniquet is safe respecting occlusion time and the exerted pressure to avoid complications (2). there is no standardized penile tourniquet design nor specific material recommendation. several material types have been used (for example silicone, rubber, and latex) in numerous forms such as catheters, bands, rolled gloves and drains secured either by a simple knot tie or by a two-turn loop fashion by clamping in order to maintain the pressure inside both corpora cavernosa (3-5). in an attempt to respect the recommended occlusive compression time of less than 30-40 minutes 2, surgeons may require to release and to reapply the tourniquet several times during the surgery. in contrast, repeating tourniquet applications and releasing could decrease the intranovel penile compression technique of penile surgeries ‘’penile strap’’ abdulghani khogeer 1, 2, abdullah alzahrani 1, 3, ahmed ibrahim 1, melanie aubé-peterkin 1, serge carrier 1 1 department of surgery, division of urology, mcgill university health center, montreal qc, canada; 2 department of surgery, faculty of medicine, rabigh, king abdulaziz university, jeddah, saudi arabia; 3 department of urology, college of medicine, imam abdulrahman bin faisal university, dammam, saudi arabia. doi: 10.4081/aiua.2023.11201 summary archivio italiano di urologia e andrologia 2023; 95, 1 a. khogeer, a. alzahrani, a. ibrahim, m. aubé-peterkin, s. carrier in our center, we examined the application of silicone penrose drain tube designed intra-operatively as a selfgripped strap with or without additional securing clamp to maintain the pressure. furthermore, we found that this technique helps to maintain the tourniquet at the base of the penis all over the surgery in either released or tightened fashion. tightening or un-tightening the tourniquet is achieved by simply pulling or releasing both extremities respectively. this technique doesn’t require any additional materials or resources and require exclusively a silicone penrose tube and surgical mayo scissors to create the small window. penrose drain is widespread available and currently used by many urologists as a tourniquet in several forms. we modified the usage of silicone penrose for this indication by inventing this strap-like tourniquet design. the aim of our study is to describe an effective technical surgical step that could interest current and future reconstructive urologist that we perceive as simple and easy to perform. however, our study is limited by its descriptive non-comparative design with no intention to prove superiority among other tourniquet techniques in terms of either facility or functional outcomes. we found this technique is easy with similar satisfactory operative objectives in terms of bleeding control and corporal occlusion. in addition, the use of tourniquet is advantageous during penile curvature surgery in order to achieve best results notably in cases of solitary saline infusion or vasoactive agents injection failure. surgeon should consider that penile tourniquet could compromise precise assessment of penile curvature through penile geometrical alteration especially in the presence of penile deformities at the base of the penis (hour-glass deformity, indentations). however, this technical field needs further studies to assess and to compare different tourniquet designs and to evaluate the exerted local mechanical pressure effects on the penile tissues and vascularity (dorsal penile arteries) and glandular supply. our future suggestion is to create a penile tourniquet inspired by our design with either selflocked strap or buckle band (e.g., tongue/button and holes) with a pressure graduation measurement. conclusions this novel technique of penile tourniquet is effective, reproducible and easy to perform to achieve complete corporal bodies occlusion for various penile surgery. further studies are warranted to compare different tourniquet designs with penile mechanical pressure evaluation. references 1. klenerman l. the tourniquet in surgery. j bone joint surg br. 1962; 44-b:937-943. 2. parsons ba, kalejaiye o, mohammed m, persad ra. the penile tourniquet. asian j androl. 2013; 15:364-367. figure 1. step-by-step technique (a-f). measuring 15 cm from one extremity. marking the hole window at the 15 cm creating the hole using the mayo point. scissors. (a) (b) (c) passing the extremity of the tube applying pressure by pulling away both securing the loop by using a surgical through the hole created. extremities. clamp. (d) (e) (f) archivio italiano di urologia e andrologia 2023; 95, 1 penile strap for penile surgery 3. redman jf. tourniquet as hemostatic aid in repair of hypospadias. urology. 1986; 28:241. 4. barnett a, pearl rm. readily available, inexpensive finger tourniquet. plast reconstr surg. 1983; 71:134-135. 5. obaidullah, aslam m. ten-year review of hypospadias surgery from a single centre. br j plast surg. 2005; 58:780-789. 6. gupta dk, devendra s. a simple and safe penile tourniquet. indian j plast surg. 2015; 48:93-95. correspondence abdulghani khogeer, md dr-abdulghani@hotmail.com melanie aubé-peterkin, md melanie.aube-peterkin@mcgill.ca abdullah alzahrani, md abdullah.alzahrani2@mail.mcgill.ca ahmed ibrahim, md eldemerdash90@gmail.com department of surgery, division of urology, mcgill university health center, montreal qc, canada serge carrier, md, frcs (c), mmmgt, professor of urology (corresponding author) serge.carrier@mcgill.ca mcgill university health centre 1001 boul decarie, suite d05.5331, montreal, quebec h4a 3j1 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13954 1 review 2021, with approximately 123,436 cases worldwide. in indonesia, there were 1,829 reported cases, highlighting the growing concern for pediatric kidney stone disease (1). urolithiasis in children warrants great attention, particularly considering the potential long-term impacts on renal function and quality of life for affected children. pediatric stone formers differ from adults. for instance, calcium oxalate (caox) stones, which are more prevalent in adults, are less commonly seen in children, who more frequently present with uric acid or ammonium acid stones, particularly in regions such as southeast asia and the middle east (2). the proportion of calcium oxalate stones will increase with age as that of carbapatite stones will decrease. in contrast with adult urolithiasis formation, which is more often idiopathic or diet-induced, pediatric urolithiasis necessitates a more nuanced understanding of the factors that influence biomarker profiles in this population (3). the pathogenesis of urolithiasis in children is complex, involving both genetic and environmental factors. over time, the primary causes of stone formation have shifted from being predominantly infectious to metabolic (4). in particular, kidney stone formation is closely associated with metabolic abnormalities, including calcium, oxalate, and urate dysregulation (5). urine sampling is a widely used clinical tool for diagnosing diseases due to its non-invasive nature, cost-effectiveness, and reliability (6). urinary risk factors such as calcium, creatinine, and uric acid, detectable through urine sampling, have been implicated in the pathogenesis of kidney stones and offer potential diagnostic and prognostic value in clinical practice (7). the exploration of urinary biomarkers as predictors of urolithiasis in children demonstrates significant variability of research findings. a study identified increased urinary levels of cystatin c and ngal as potential indicators of early kidney tubular dysfunction in children with urolithiasis, even when serum creatinine remained normal (8). in contrast, another study stated that these biomarkers were less reliable for assessing renal injury due to urinary stone in pediatric populations (9). the inconsistent results highlight the complexity of using urinary biomarkers in pediatric urolithiasis, indicating a critical need for larger, standardized research to establish their clinical utility. introduction: urolithiasis in children has become a clinical concern because of its longterm impact on kidney function and quality of life. in previous studies, the role of urinary biomarkers in predicting the risk of urolithiasis in children was still unclear due to inconsistent findings. this meta-analysis aimed to evaluate the diagnostic potential of various urinary risk factors in children with urolithiasis. methods: a systematic review and meta-analysis was performed based on prisma 2020 guidelines, registered in prospero (crd42025644893). a total of six studies (1 cohort and 5 casecontrol) involving 2,060 pediatric patients (817 with urolithiasis; 1,243 controls) were analyzed. urinary risk factors including citrate/creatinine (cit/cr), oxalate/creatinine (ox/cr), calcium/creatinine (ca/cr), phosphorus/creatinine (p/cr), magnesium/creatinine (mg/cr), and urea/creatinine (ur/cr) were examined. standard mean differences (smd) were calculated, and heterogeneity was assessed using the i² statistic. results: significant differences were obtained in the cit/cr, ca/cr, ox/cr, and mg/cr ratios between children with urolithiasis and controls. hypocitraturia (cit/cr smd: -0.60, 95% ci: -0.90 to -0.30, p = 0.0001), hyperoxaluria (ox/cr smd: 0.76, 95% ci: 0.37-1.16, p = 0.0001), hypercalciuria (ca/cr smd: 0.55, 95% ci: 0.10-1.01, p = 0.02), and hypomagnesuria (smd -0.13 (95% ci: -0.24 to -0.01), p = 0.03) were significantly associated with the formation of stones in the urinary tract. on the contrary, there were no significant relationships for p/cr and ur/cr ratios. conclusions: this meta-analysis highlights cit/cr, ox/cr, and ca/cr ratios as potential urinary biomarkers to identify the risk of urolithiasis in pediatric patients. hypocitraturia, hyperoxaluria, and hypercalciuria are the main metabolic abnormalities that contribute to urinary tract stone formation. future studies with standardized methodology are essential to confirm these findings and guide clinical management strategies. key words: urolithiasis; urinary risk factor; pediatric kidney stones. submitted 20 may 2025; accepted 1 june 2025 introduction urolithiasis, the formation of calculi in the urinary tract, is a significant clinical condition that can affect children of all ages. the global prevalence of urolithiasis in children under 20 years of age was estimated at 0.01% in urinary risk factors for urolithiasis in children: a systematic review and meta-analysis derryl rasad texaga 1, saskia ratna desita 1, nadira muthi tsania 1, junjungan nismasratu rahmatsani 1, kevin yuwono 1, i gede yogi prema ananda 2, radika naufal hadi surya 2, dimas panca andhika 2, 3, 4 1 faculty of medicine, airlangga university, surabaya, indonesia; 2 department of urology, faculty of medicine, airlangga university, surabaya, indonesia; 3 department of anatomy, histology, and pharmacology, faculty of medicine, airlangga university, surabaya, indonesia; 4 universitas airlangga hospital, surabaya, indonesia. doi: 10.4081/aiua.2025.13954 summary archivio italiano di urologia e andrologia 2025; 97(3):13954 d. rasad texaga, s. ratna desita, n. muthi tsania, et al. 2 methods this meta-analysis was performed according to the 2020 preferred reporting items for systematic review and metaanalysis (prisma) guideline and has been registered to prospero database (https://www.crd.york.ac.uk/prospero/) with a registration number crd42025644893. eligibility criteria inclusion criteria for this study were: (1) patients under 18 years old with urolithiasis; (2) study that examines urinary risk factor of stone formation; (3) written full-text in english. the exclusion criteria were: (1) the type of studies being review, case-report, meeting report, comments and other unrelated studies; (2) non-human studies; (3) studies that focus only on healthy children. selection of the study was demonstrated on the prisma diagram (figure 1). data selection, search strategy, and selection of studies a comprehensive literature research was conducted in several databases including medline, science direct, springer, and plos one from the initial period of the study until january 2025. the following keywords were used as follows [(“nephrolithiasis”) or (“urolithiasis”)] and [(“pediatric”) or (“infant”) or (“children”)] and [(“risk factor”) or (“dietary”)]. studies retrieved were exported into rayyan.ai–intelligent systematic review for article screening and duplication removal. two authors (d.r.t and s.r.d) screened the literature and extracted the data independently. disagreements between two authors were discussed until agreement was established. the following data were collected: (1) information of the study: first author, publication year, country; (2) basic study characteristics: sample size, patient’s age of enrollment; (3) study findings including key risk factors of urolithiasis, methods of diagnosis, and biochemical measurement. quality assessment three authors (j.n.r., r.n.h.s, and i.y.p.a) independently assessed the risks of bias (rob) from selected studies using newcastle ottawa scale (nos) assessment tool for cohort and case-control studies. statistical analysis the study was analyzed using review manager 5.4 (cochrane collaboration). the standard mean differences (smds) were calculated as effect sizes using inverse variance methods for continuous outcomes. for dichotomous outcomes, pooled risk ratios (rrs) were computed using mantel-haenszel methods. heterogeneity across the included studies was assessed using the i² statistic. a random-effects model was applied if the i² value was greater than 50%, indicating moderate-tohigh heterogeneity. conversely, a fixed-effects model was used if the i² value was less than 50%. statistical significance was determined with a p-value of less than 0.05. begg’s funnel plots were employed to evaluate potential publication bias, and the trim-and-fill method was applied if any publication bias was detected. results study selection from four databases, a total of 274 studies were retrieved. after the removal of duplicates and irrelevant studies, 191 studies remained for screening. following the inclusion and exclusion criteria, 42 studies were assessed eligible. upon fulltext review, 6 studies were included in this study. the study selection process is summarized in the prisma flowchart. figure 1. flow of literature search and selection based on preferred reporting items for systematic reviews and meta-analyses (prisma). archivio italiano di urologia e andrologia 2025; 97(3):13954 3 urinary risk factors for urolithiasis in children: a systematic review and meta-analysis the six studies included in this study included 5 casecontrol studies, and 1 cohort study. quality assessment for case-control and cohort study using the nos assessment tool revealed that 2 studies were classified as very good, while 4 were assessed as good quality. study characteristics in our review, we analyzed a total cohort of 2,060 pediatric patients, consisting of 817 subjects with urolithiasis, and 1243 controls. out of the six studies included, five were case-control studies and one is cohort studies. two of the studies were conducted in poland, one in turkey, while the remaining three were done in hungary, germany, and spain respectively. we examined multiple urinary biomarkers and their relationship to the incidence of urolithiasis. to diagnose urolithiasis, the studies used a range of methods, including standard ultrasound, intravenous urography, plain x-rays, infrared spectroscopy, and surgical intervention. detailed biochemical urinary measurements and additional study details are presented in table 1. urinary risk factors cit/cr citrate/creatinine ratios were evaluated using 24-hour urinary samples and urine spot samples. four studies examined a total of 1769 subjects (717 with urolithiasis, 1052 controls). the meta-analysis demonstrated there was a sigtable 2. quality assessment. study representativeness sample size non-respondents ascertainment comparability of subjects in assessment statistical total result of the sample of the exposure different outocome groups on of outcome test score (risk factor) the basis of design or analysis. confounding factors controlled tekin et al., 2001 1 0 0 2 2 2 1 8 good reustz et al., 1995 1 1 0 2 2 2 1 9 very good kuroczycka-saniutycz et al., 2015 1 1 0 2 2 2 1 9 very good mir et al., 2020 1 1 0 1 1 1 1 6 good sikora et al., 2008 1 1 0 1 1 1 1 6 good porrowski et al., 2013 1 1 0 1 1 1 1 6 good table 1. characteristics of the study. study study type enrollment participants mean age at enrollment male (n) key risks factor outcomes methods of diagnosis biochemical measurement tekin et al., 2001 reustz et al., 1995 kuroczycka-saniutycz et al., 2015 sikora et al, 2008 mir et al, 2020 porowski et al, 2013 retrospective cohort case-control study case-control study case-control study case-control study case-control study turkey hungary poland germany spain poland intervention 90 children with normal anatomy and urolithiasis 27 with renal stones 478 children with urolithiasis 60 patients with idiopathic calcium oxalate urolithiasis 13 patients with primary hyperoxaluria 26 stone-forming children 123 stone-formers with hypocitraturia control 24 healthy children 156 healthy children 517 healthy children 35 healthy children 87 healthy children 424 healthy children intervention 7.70 ± 10.45 years 6–16 years 14.19 ± 4.16 years 13.3 ± 4.1 years 12 ± 4 years 13.30 ± 8.06 years control 7.8 ± 6.3 years 1–14.5 years 13.9 ± 4.43 years 11.1 ± 3.6 years 12 ± 3 years 12.3 ± 8.67 years intervention na na 205 41 15 66 control na na 219 23 50 212 hypocitraturia hyperoxaluria hyperoxaluria hypercalciuria hyperuricemia obesity intestinal hyperabsorption of oxalate 12 hour daytime 12 hour overnight 24 hour hypercalciuria hypocitraturia urinary ph ca2⁺/citrate ratio incidence of nephrolithiasis in children with upper tract anatomy anomalies calcium, oxalate excretion, activity product (measurement of ca/cr and ox/cr in first-morning urine samples is suitable for screening for hypercalciuria and hyperoxaluria) incidence of urolithiasis incidence of idiopathic calcium oxalate urolithiasis diagnosis of lithiasis diagnosis of lithiasis intravenous urography and ultrasonography intravenous urography and sonography ultrasonography x-ray infrared spectroscopy na ultrasonography x-ray 24-hour-urine excretion serum biochemistry urine samples blood sample urine sample [13c2] oxalate absorption test 24-hour-urine excretion 12-hour-day-urine excretion 12-hour-overnight-urine excretion 24-hour-urine collection archivio italiano di urologia e andrologia 2025; 97(3):13954 d. rasad texaga, s. ratna desita, n. muthi tsania, et al. 4 nificant decrease of citrate in children with urolithiasis compared to controls (smd -0.60 (95% ci: -0,90 to -0.30), p = 0.0001) with moderate effects. the heterogeneity test showed a statistically significant high heterogeneity (i2 = 81%, p = 0.0001) indicating the use of a random-effect model. ox/cr six studies with a total of 2060 patients (817 with urolithiasis, 1243 controls) measured oxalate/creatinine ratios in 24-hour urinary and urine spot samples. this study found children with urolithiasis have significantly higher ox/cr ratios compared to controls (smd 0.76 (95% ci: 0.37 to 1.16, p = 0.0001), with moderate to large effect. the heterogeneity test showed a statistically significant high heterogeneity (i2 = 91%, p = 0.0001) indicating the use of a random-effect model. ca/cr calcium/creatinine ratios were measured in 1952 subjects consisting in 744 patients with urolithiasis and 1208 controls using 24-hour urinary and urine spot samples. the meta-analysis revealed children with urolithiasis have a higher ca/cr ratios compared to controls (smd 0.55 (95% ci: 0.10 to 1.01), p = 0.02, i2 = 93%), with a moderate effect. the i2 tests showed a high heterogeneity test, resulting in random-effect models methods. p/cr three studies with a total of 1232 patients examined phosphorus/creatinine ratios of 24 hour urinary and urine spotsamples, respectively. the meta-analysis demonstrated there was no significant difference in children with urolithiasis compared to controls (smd -0.11 (95% ci: -0.23 to 0.01), p = 0.06, i2 = 0%), with low effect. a fixed-effect model was applied since the low heterogeneity test. mg/cr magnesium/creatinine ratios were evaluated using 24 hour urinary and urine spot samples respectively. three studies with a total of 1222 patients were examined. the studies figure 2. forest plot of cit/cr biomarker in urolithiasis vs healthy children. figure 3. forest plot of ox/cr biomarker in urolithiasis vs healthy children. figure 4. forest plot of ca/cr biomarker in urolithiasis vs healthy children. archivio italiano di urologia e andrologia 2025; 97(3):13954 5 urinary risk factors for urolithiasis in children: a systematic review and meta-analysis have low heterogeneity (i2 = 0%) and a fixed-effect was applied. meta-analysis demonstrated there was a statistically significant difference in children with urolithiasis compared to controls (smd -0.13 (95% ci: -0.24 to -0.01), p = 0.03). ur/cr uric acid/creatinine ratios were evaluated using 24-hour urinary excretions. four studies with a total of 1222 patients examined 24-hour urinary excretions. the metaanalysis demonstrated there was no significant relationship in children with urolithiasis compared to controls (smd 0.04 (95% ci: -0.07 to 0.16), p = 0.47, i2 = 0%). a fixed-effect was applied since the study had low heterogeneity (i2 = 0%). discussion this study's findings demonstrate significant differences in urinary biomarkers cit/cr, ca/cr, ox/cr, and mg/cr -between pediatric patients with urolithiasis and those without. among children diagnosed with urolithiasis, the ca/cr ratio was markedly elevated in comparison to the controls (smd 0.55, 95% ci: 0.10-1.01, p = 0.02). of the five studies that reported ca/cr data, four studies identified statistically significant different levels of ca/cr between stone-forming children and healthy children.1013 hypercalciuria is one of the most prevalent metabolic disorders associated with pediatric urolithiasis, affecting approximately 30% to 50% of patients (2, 14). idiopathic hypercalciuria is the most frequent etiology of calciumstone (15). several studies shown that hypercalciuria was found in nine of 74 children with recurrent unilateral stones (16). this study was similar to a prior study by kamel et al. (17) that found 22% of children with urolithiasis had hypercalciuria based on their laboratory findings. similarly, another study by kovacevic et al. (18) found that hypercalciuria was the most common risk factor in pediatric urolithiasis. as most urinary stones are composed of calcium, hypercalciuria is the major risk factor for calcium stone. kidney stones, particularly those composed of calcium oxalate, often originate from calcium deposits known as randall's plaques. these plaques form in the renal papilla's interstitial tissue and can serve as a nidus for stone development. when the urothelium's integrity is compromised, regions of the plaque become exposed to urine and crystallization begin (19). several factors contribute to hypercalciuria and the role of dietary supplementation of calcium or vitamin d had conflicting results towards the risk of urolithiasis. a meta-analysis revealed that patients undergoing long-term vitamin d figure 6. forest plot of mg/cr biomarker in urolithiasis vs healthy children. figure 7. forest plot of ur/cr biomarker in urolithiasis vs healthy children. figure 5. forest plot of p/cr biomarker in urolithiasis vs healthy children. archivio italiano di urologia e andrologia 2025; 97(3):13954 d. rasad texaga, s. ratna desita, n. muthi tsania, et al. 6 supplementation experienced an increased risk of hypercalciuria, though the risk of kidney stone disease remained unaffected (20). other conditions that predispose individuals to hypercalciuria include hyperparathyroidism, metabolic bone diseases, renal calcium leak, and diets that impose a high renal acid load (21). hyperoxaluria plays a crucial role in the pathogenesis of crystallization and stone formation (15). urinary oxalate excretion is an important determinant in the development of calcium oxalate (caox) urolithiasis, the most common type of kidney stone (22). this meta-analysis revealed that ox/cr levels were significantly elevated in stone-forming children compared to controls (smd 0.76, 95% ci: 0.37-1.16, p = 0.0001). among the six studies providing ox/cr data, five studies demonstrated a significant difference in ox/cr levels between the stone-forming and control groups (10-12, 22, 23). prior studies found that hyperoxaluria was found in children with multiple and single kidney stones (24). this study align with a previous study by issler et al. (25) that showed as 37 children with renal stone disease had hyperoxaluria as their metabolic abnormality. this study was similar with another study by placzynska (26) that found hyperoxaluria in children with different composition of renal stones, such as weddellite, whewellite, and non-calcium oxalate. hyperoxaluria is also another major risk factor for stone formation, as calcium oxalate is the most common composition of urinary stones. an in vitro study demonstrated that elevated levels of oxalate boost the ability of renal epithelial cells to adhere to calcium oxalate monohydrate (com) crystals. this increased binding capability is facilitated by a rise in the surface expression of α-enolase, a protein that binds to com crystals.21 the concentration of urinary oxalate is primarily affected by the intake of dietary oxalate and its precursors, and the absorption rate from the gastrointestinal tract. therefore, consumption of oxalate-rich foods and increased absorption of oxalate from the intestine (eg. in bypass/bariatric surgery patients) is associated with hyperoxaluria and kidney stones formation (27, 28). the decrease of urinary stone inhibitors increases the risk of urolithiasis, with citrate being a key inhibitory factor (29). this meta-analysis found that cit/cr levels were significantly lower in the urolithiasis group compared to the control group (smd -0.60, 95% ci: -0.90 to -0.30, p = 0.00001). among the four studies providing cit/cr, three studies showed statistically significant results (10, 12, 23). citrate mitigates stone formation by binding calcium ions in urine, thereby reducing calcium supersaturation and preventing crystallization (30). another inhibitor, urinary magnesium (mg), also showed a significant negative association with stone formation in this study (smd = -0.13; 95% ci: -0.24 to -0.01; p = 0.03). interestingly, none of the three studies that separately analyzed mg/cr ratio demonstrated a significant association. hypocitraturia was found frequently in pediatric kidney stones (31). velasquez et al. (29) found that hypocitraturia was the main risk factors among children with urolithiasis, which aligns with our meta-analysis. on the contrary, a study by lee et al. (32) reported that hypocitraturia was the less frequent risk factor of urolithiasis in children. hypocitraturia has long been linked to the development of kidney stones, especially to calcium stone formation. the mechanisms by which citrate inhibits crystal formation are thought to be mediated by its ability to form soluble complexes with calcium, which significantly lowers urinary calcium supersaturation and helps prevent the nucleation of both calcium oxalate and calcium phosphate crystals (33). additionally, citrate can directly prevent the attachment of calcium oxalate crystals to renal epithelial cells by adsorbing onto the surfaces of the crystals (34). an in vivo study involving genetically hypercalciuric stone-forming rats demonstrated that administering potassium citrate resulted in elevated urinary citrate levels and reduced urinary calcium concentrations in addition to urine alkalinization (35). in children, hypocitraturia has been commonly defined as 24-h citrate excretion of < 400 mg/g creatinine or < 180 mg/g creatinine. however, other proposed definitions exist, and factors such as age and gender also influence them, making interpretation rather difficult (33). magnesium also acts as an inhibitor by preventing the crystallization of calcium oxalate and calcium phosphate. it binds to oxalate, which may reduce intestinal absorption of oxalate and lower the supersaturation of calcium oxalate in urine. some studies have shown that magnesium supplementation may benefit children with secondary hyperoxaluria (2). urolithiasis in children is predominantly linked to metabolic abnormalities, which are identified in approximately 30% to 84% of cases. among these, hypomagnesiuria is one of the contributing conditions, although idiopathic hypercalciuria remains the most commonly observed metabolic disorder (36). in identifying children at high risk of urolithiasis, these findings strengthen the potential use of urinary biomarkers, particularly hypocitraturia and hyperoxaluria. hypocitraturia in children with urolithiasis can be used as a benchmark for administering potassium citrate that can reduce stone size and recurrence rate (37). hyperoxaluria can be managed by eating a diet low in oxalate precursors that can help prevent the formation of declarations ethical approval: not applicable, since this is a systematic review and meta-analysis. availability of data: available data are open for researchers and the corresponding author will provide it by request. competing interests: the authors state no conflict of interest. funding: not applicable. authors' contributions: concept, design, and methodology: d.r.t, s.r.d, d.p.a; literature search: d.r.t., s.r.d., n.m.t., k.y., j.n.r, i.y.p.a, r.n.h.s; data analysis: d.r.t, s.r.d, n.m.t, k.y, d.p.a; statistical analysis: d.r.t, s.r.d, d.p.a; manuscript writing: d.r.t., s.r.d., n.m.t., k.y., j.n.r, i.y.p.a, r.n.h.s; suprvision: d.p.a. acknowledgments: these authors would like to thank to department of urology, faculty of medicine, universitas airlangga; dr. soetomo general academic hospital, surabaya, indonesia. archivio italiano di urologia e andrologia 2025; 97(3):13954 7 urinary risk factors for urolithiasis in children: a systematic review and meta-analysis kidney stones (38). a long-term normal intake of dietary calcium can decrease numbers of stone recurrences due to idiopathic hypercalciuria (39). conclusions this meta-analysis highlights the important role of urinary biomarkers, especially cit/cr, ox/cr, and ca/cr ratios, in predicting the risk of urolithiasis in children. hypocitraturia, hyperoxaluria, and hypercalciuria emerged as important risk factors, supporting their clinical relevance in assessing and managing urinary tract stone formation in children. these findings suggest that targeted interventions, such as administration of potassium citrate for hypocitraturia and dietary modification for hyperoxaluria and hypercalciuria, may be effective in preventing recurrence of urinary tract stones. however, the high heterogeneous and limited data on certain biomarkers indicate the need for further standardized and large-scale studies to establish definitive clinical guidelines. references 1. murray cjl; 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80:1278-91. 16. tasian ge, ziemba j, casale p. unilateral hypercalciuria: a stealth culprit in recurrent ipsilateral urolithiasis in children. j urol. 2012; 188:2330-5. 17. kamel as, al-gameel a, mahmoud m, et al. role of urinary calcium/creatinine ratio in diagnosis of hypercalciuria in children with urolithiasis in fayoum, egypt. al-azhar journal of ped. 2022; 25:3034-3049 18. kovacevic l, wolfe-christensen c, edwards l, et al. from hypercalciuria to hypocitraturia--a shifting trend in pediatric urolithiasis? j urol. 2012; 188:1623-7. 19. chung hj. the role of randall plaques on kidney stone formation. transl androl urol. 2014; 3:251-4. 20. malihi z, wu z, stewart aw, et al. hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin d supplementation: a systematic review and meta-analysis. am j clin nutr. 2016; 104:1039-51. 21. peerapen p, thongboonkerd v. kidney stone proteomics: an update and perspectives. expert rev proteomics. 2021; 18:557-69. 22. sikora p, von unruh ge, beck b, et al. 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2014:cd006022. correspondence dimas panca andhika (corresponding author) dimaspanca26@gmail.com department of urology, faculty of medicine, universitas airlangga; dr. soetomo general academic hospital, surabaya, indonesia jl. mayjend. prof. dr. moestopo no. 6-8, surabaya, east java, indonesia, 60286 stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12108 1 original paper erogeneity of the definitions applied, the follow-up time and the way it is diagnosed. clinical parastomal hernia (cph) is defined as peristomal protrusion through a wall defect detected by physical examination, with the patient in the supine or standing position. one of the most frequently used classifications to define radiological ph (rhp) is the one proposed by moreno-matías and serra-aracil et al. in 2009 (figure 1), creating three different categories according to the relationship between the hernia sac and the bowel forming the stoma. although most patients remain asymptomatic, up to one third may require surgical repair (4), in most cases due to pain, skin irritation, leakage and, in a small percentage, bowel obstruction. most of the information dedicated to ph research comes from the colorectal literature, and there is little data about the natural history and risk factors associated with the development of ph in bricker-type urinary diversions. the aim of our study was to analyze the incidence of ph after radical cystectomy with ileal conduit and to describe the evolution and predictive factors. patients and methods patients the files of 125 consecutive patients undergoing open or lap radical cystectomy and bricker urinary diversion at our institution (january 2006-january 2021) were retrospectively reviewed. patient records were reviewed to gather any information suggesting the development of ph. time since the cystectomy, presence of symptoms, and the requirement for surgery and surgical outcome were also gathered. demographic data were collected, including age, gender, bmi, ht, dm, copd, chronic kidney disease, smoking, preoperative hemoglobin and albumin, and history of previous pelvic radiotherapy, abdominal surgery and neoadjuvant chemotherapy. we also documented the approach (open or laparoscopic), stoma fixation to the rectus aponeurosis, surgical time, days of hospitalization and the application of fasttrack protocol. purpose: parastomal hernia (ph) is one of the most frequent complications after stoma creation. our objective was to analyze the incidence, evolution and predictive factors of ph in bricker-type urinary diversion. patients and methods: case series analysis of 125 patients submitted to radical cystectomy and ileal conduit diversion for cancer in a single center during 2006-2021. patient’s record and imaging tests were reviewed to identify those suffering ph. moreno-matías classification was used to define radiological ph (rph). demographic and preoperative characteristics of the patients, surgical details and postoperative complications were recorded. univariate and multivariate analyses were conducted to determine the effect of each predictive variable on the development and progression of ph. results: 21.6% of patients developed ph (median follow-up 37 months). incidence increased with follow-up time (15.2% at 1 year, 20.8% at 2 years). bmi ≥ 25 (expβ 8.31, 95% ci 1.0665.18, p = 0.04), previous midline laparotomy (expβ 6.74, 95% ci 1.14-39.66, p = 0.04) and wound infection (expβ 3.87, 95% ci 1.21-12.33, p = 0.02) were significantly associated with ph. half of the patients with hernia had symptoms, 25.9% requiring surgical correction. 46% of type 1 hernias and 40% of type 2 hernias progressed to grade 3 with a median of 11 months. no variable was associated with radiological progression. conclusions: this study proved 3 independent factors (overweight, laparotomy and wound infection) that increase the risk of developing ph. key words: parastomal hernia; radical cystectomy; ileal conduit; risk factors; natural history. submitted 19 november 2023; accepted 28 november 2023 introduction bricker ileal conduit is one of the most commonly used urinary diversions in radical cystectomy. stoma-related complications, with a reported incidence of up to 60% (1), are a major problem because of their negative impact on patients' quality of life (2). parastomal hernia (ph), defined as an incisional hernia associated with a stoma in the abdominal wall, is one of the most frequent complications following bricker urinary diversion (3). its incidence varies widely depending on the series (4-65%) (4, 5), as a consequence of the hetparastomal hernia after radical cystectomy. incidence, natural history and predictive factors – a single center study maría alonso grandes, josé antonio herranz yagüe, rocío roldán testillano, alfonso maría márquez negro, casilda cernuda pereira, emilio andrés ripalda ferretti, álvaro páez borda university hospital of fuenlabrada, department of urology, fuenlabrada, madrid, spain. doi: 10.4081/aiua.2023.12108 summary archivio italiano di urologia e andrologia 2023; 95(4):12108 m. alonso grandes, j.a. herranz yagüe, r. roldán testillano, et al. 2 additionally, we analyzed the effect of the following complications on the development of ph: evisceration, paralytic ileus, wound infection, transfusion, intestinal and urinary fistula, pelvic abscess and intensive care unit (icu) admission. statistical analysis uniand multivariate logistic regression analyses were performed to determine the effect of each predictive variable on the development and progression of ph. patients with radiological follow-up shorter than 12 months and those with incomplete clinical data were excluded. statistical analysis was performed using the ibm spss statistics version 20. results patient characteristics 125 patients undergoing radical cystectomy and bricker urinary diversion were included in the study. average age (84.8% male) was 66.2 years (sd 9.4). table 1 shows the main patients characteristics and univariate and multivariate analyses. multivariate analysis detected a significant association between ph and bmi ≥ 25 (expβ 8.31, 95% ci 1.065.18, p = 0.04) and previous abdominal surgery with previous midline laparotomy (expβ 6.74, 95% ci 1.1439.66, p = 0.04). variable overall (n = 125) univariate analysis multivariate analysis hr (95% ci) p hr (95% ci) p age, years 66.2 (de 9.4) 0.97 (0.95-1.05) 0.34 gender, n (%) male 106 (84.8) reference female 19 (15.2) 0.72 (0.21-2.99) 0.78 bmi, n (%) normal (bmi < 25) 32 (25.6) reference overweight and obesity (bmi ≥ 25) 93 (74.4) 10.18 (1.31-78.98) 0.026 8.31 (1.06-65.18) 0.04 diabetes, n (%) 29 (23.2) 1.18 (0.42-3.41) 0.75 hypertension, n (%) 72 (57.6) 1.14 (0.46-2.83) 0.77 smoking, n (%) 53 (42.4) 1.59 (0.66-3.86) 0.30 copd, n (%) 27 (21.6) 0.45 (0.12-1.72) 0.23 chronic kidney disease, n (%) 23 (18.4) 0.58 (016-2.15) 0.42 previous midline laparotomy, n (%) 8 (6.4) 9.30 (1.60-54.34) 0.023 6.74 (1.14-39.66) 0.04 previous hernioplasty, n (%) 17 (13.6) 2.10 (0.65-6.92) 0.21 pelvic radiotherapy, n (%) 8 (6.4) 0.75 (0.10-6.71) 0.97 anemia (female hb < 12. male hb < 13.8), n (%) 70 (56) 0.59 (0.24-1.44) 0.25 hypoalbuminemia (< 3.5 g/dl), n (%) 27 (21.6) 0.65 (0.19-2.15) 0.48 pathological stage, n (%) ≤ t2. n0 50 (40) > t2. n0 50 (40) any t, n+ 25 (20) bmi body mass index, copd chronic obstructive pulmonary disease. values in bold indicate a p-value < 0.05. figure 1. radiological classification of ph. a) type 1: hernia sac contains prolapsed bowel forming the stoma. b) type 2: ph contains abdominal fat or omentum herniating through the abdominal wall defect created by the stoma. c) type 3: hernial sac contains bowel loops. table 1. univariate and multivariate cox regression analyses of the predictive factors for the development of ph (patient characteristics). a. b. c. archivio italiano di urologia e andrologia 2023; 95(4):12108 3 parastomal hernia after radical cystectomy surgery-related characteristics and postoperative complications open approach was the technique of choice (82.4% of the patients). mean operative time was 322 min (sd 60). mean hospital stay was 15.9 days [sd 16.7, r (5-122)]. 43.2% (54/125) of the patients presented severe postoperative complications (score 3 or higher on the claviendindo scale), the most frequent being paralytic ileus. the main postoperative complications and their effect on the development of ph are described in table 2. univariate analysis showed a significant association between ph and two different variables: prolonged surgical time and surgical wound infection, but only wound infection was confirmed in the multivariate analysis (expβ 3.87, 95% ci 1.21-12.33, p = 0.02). ph: diagnosis, symptoms and natural history 21.6 % (27/125) of patients developed ph, with a median follow-up of 37 months (sd 37). median time to diagnosis was 7 months (sd 6.4). the incidence increased with follow-up time, with an incidence of 15.2% one year after surgery, and 20.8% at two years. radiological detection rate was more frequent than the detection after clinical examination (21.6% vs. 11.2%, respectively) (figure 2). approximately half of the patients with ph (48.2%, 13/27) presented symptoms (table 3). 76.8% (10/13) of these symptomatic patients, corresponded to grade 2 and 3 hernias, while only 23.2% (3/13) of grade 1 hernias caused symptoms. 7 patients (25.9%) underwent ph correction, surgical repair being significantly higher in patients with grade 3 rph (hr 4.4, 95% ci 1.06-18.33, p = 0.04). pain was the main indication for surgery, except in one patient who required emergent surgical intervention due to bowel obstruction. open approaches were the rule. in 85.7% (6/7) of the patients, a mesh was placed during the repair, while in one case primary closure was performed, with early recurrence at 2 months. one patient required stoma relocation. regarding natural history, 46% (5/11) of type 1 hernias and 40% of type 2 (4/10) progressed to type 3 at a median time of 11 months (sd 9.4) (figure 3). none of the previously described variables were significantly associated with ph progression. discussion the european hernia society (ehs) defines ph as an abnormal protrusion of the contents of the abdominal cavity through an abdominal wall defect created during placement of a colostomy, ileostomy, or ileal conduit stoma (6). this term does not include protrusions caused by atony or paresis of the abdominal wall muscles, but rather true peritoneal sac hernias (3). ph is the most frequent complication after stoma placement, to the point that many authors consider it an evolutionary consequence and part of the natural history of the stoma (3). its incidence is difficult to estimate and varies widely in the series [incidence described as 4-65% (4, 5)], due to the heterogeneity in the definition used, the table 3. reported symptoms in 27 patients with clinical or radiological ph. patients with ph n = 27 (%) asymptomatic patients 14 (51.8) symptomatic patients 13 (48.2) pain 10 (37) device-related problems (leak, poor adjustment) 4 (14.8) skin irritation 3 (11.1) aesthetic problems 4 (14.8) bowel obstruction 1 (3.7) variable overall (n = 125) univariate analysis multivariate analysis hr (95% ci) p hr (95% ci) p neoadjuvant chemotherapy, n (%) 49 (39.2) 0.67 (0.26-1.72) 0.41 fast-track protocol, n (%) 48 (38.4) 1.41 (0.57-3.44) 0.45 approach, n (%) open 103 (82.4) reference laparoscopy 22 (17.6) 1.33 (0.43-4.11) 0.61 aponeurosis attachment, n (%) 97 (77.6) 0.63 (0.15-3.52) 0.60 operating time (> 6h), n (%) 36 (28.8) 2.57 (1.02-6.47) 0.04 2.38 (0.92-6.17) 0.07 long length of stay (> 15 days), n (%) 43 (34.4) 1.26 (0.49-3.18) 0.62 postoperative complications (first 90 days) evisceration, n (%) 26 (20.8) 1.92 (0.68-5.35) 0.21 paralytic ileus, n (%) 58 (46.4) 0.48 (0.19-1.22) 0.12 wound infection, n (%) 18 (14.4) 3.72 (1.22-11.28) 0.02 3.87 (1.21-12.33) 0.02 intestinal fistula, n (%) 11 (8.8) 2.00 (0.46-8.63) 0.35 urinary fistula, n (%) 22 (17.6) 0.94 (0.28-3.11) 0.92 pelvic abscess, n (%) 34 (27.2) 1.15 (0.43-3.09) 0.78 icu admission, n (%) 30 (24) 0.56 (0.18-1.81) 0.33 polytransfusión (> 5 rbc concentrates), n (%) 23 (18.4) 0.77 (0.23-2.55) 0.67 parenteral nutrition, n (%) 62 (49.6) 0.41 (0.16-1.03) 0.06 clavien complication ≥ 3, n (%) 54 (43.2) 1.62 (0.67-3.93) 0.28 icu intensive care unit, rbc red blood cells. values in bold indicate a p-value < 0.05. table 2. univariate and multivariate cox regression analyses of the predictive factors for the development of ph (surgery-related characteristics). archivio italiano di urologia e andrologia 2023; 95(4):12108 m. alonso grandes, j.a. herranz yagüe, r. roldán testillano, et al. 4 follow-up time and the way of diagnosis. the type of ostomy also has an important impact on the incidence of ph. thus, terminal colostomy is the one with the highest rates of hernia, while bowel-dependent ostomies, whether terminal ileostomies, loop ostomies or bricker-type urinary diversions, are those with the lowest incidence of ph (7). most of them develop in the first two years following surgery (4, 8-9), but presentation can be delayed up to 20 or 30 years (10). diagnosis of ph can be clinical or radiological. most clinical definitions are based on the finding of a protrusion close to the stoma, but studies differ considerably as how the clinical examination is performed: supine vs. standing, and with or without valsalva maneuvers. the use of physical examination as a diagnostic tool, especially in retrospective studies underestimates the number of ph, mainly at the expense of low-grade hernia. radiological evaluation of the stoma aids the clinical examination improving the detection rate of ph. radiographic criteria have the advantage of being more objective and less influenced by the patient's body habitus (4). in addition, imaging allows measurement of the size of stoma and hernia sac over time, which is essential in the study of the natural history of ph. cingi et al. (11) described a radiographic ph rate (rph) of 78% and a clinical ph rate (cph) of 52% in a series of 23 patients evaluated by computed tomography (ct) and physical examination, supporting the hypothesis that imaging is superior to clinical examination in detecting ph. dechao feng et al. (12) performed a meta-analysis involving a total of 1878 patients with ph. in this case, the radiological incidence of ph was 23%, while the incidence of clinical ph was 15%. these data agree with those obtained in our series, where radiological detection of ph with ct was higher than those obtained by physical examination (21.6% vs. 11.2% respectively). a frequent concern arising from the increased use of imaging tests is the detection of a higher number of clinically insignificant hernias. although data are limited, there appears to be good correlation between radiologic diagnosis and symptoms resulting from ph (4). seo et al. (13) described the rates of cph and rph in 83 patients with terminal colostomy. all patients with type 3 ph had ph on clinical examination and all of them were symptomatic; 80% of type 2 ph were clinically detectable and 75% were symptomatic; and 60% of type 1 ph were detectable on physical examination, with 63% showing symptoms. figure 2. ph detected by physical examination. figure 3. ph type 2 with radiological progression to type 3 during follow-up. archivio italiano di urologia e andrologia 2023; 95(4):12108 5 parastomal hernia after radical cystectomy in our experience, more than one third (76.8%) of the 13 patients developing symptoms corresponded to grade 2-3 hernias, while only 23.2% of grade 1 hernias were symptomatic. also, surgical repair, motivated in most cases by pain, was significantly higher in patients with radiological grade 3 ph (hr 4.4, 95% ci 1.06-18.33, p = 0.04). the etiology of ph is multifactorial, and determined by factors related to the patient and the surgical technique (4-7, 14-15). donahue et al. performed a retrospective study of 386 patients undergoing radical cystectomy and ileal diversion (15), with female gender (hr 2.25), bmi (1.08) and preoperative hypoalbuminemia (hr 0.4) accounting for a significant association with the development of ph. in another study involving 58 patients with ph after cystectomy, previous median laparotomy (hr 1.98) and severe obesity bmi > 40 (hr 4) were identified as independent risk factors for ph (5). dm (hr 1.81), chronic obstructive pulmonary disease (hr 1.78) (16) and long operative time (17) have also been shown to predispose to the development of this complication. the most important modifiable risk factor for ph is obesity, contributing to the weakening of the abdominal wall and thus to the formation of hernias through several mechanisms such as increased intra-abdominal pressure, seroma development, necrosis and wound infection (5, 16). regarding technical factors, size and location of the stoma and preoperative stoma site marking by certified ostomy nurse, have been described in the literature as factors that may influence the development of ph after stoma creation (3-5, 15). the size of the cutaneous and aponeurotic orifice should be wide enough to allow passage of the bowel, but not too large, to avoid the risk of herniation. several studies have described the correlation between larger stoma diameter and the risk of developing symptomatic ph. for instance, seo et al. (13) reported significant differences in the diameter of the stoma fascial defect in symptomatic versus asymptomatic patients (76.45 mm vs. 49.41 mm, p = 0.00) and, furthermore, they observed a significant correlation between the size of the opening and the type of rhp (rhp type 2, 62.69 mm, rhp type 3, 81.01; p = 0.003). despite this, there is insufficient evidence to define an ideal size preventing the development of hernias. traditionally, it is estimated that the orifice should not exceed 3 cm in colostomies and 2.5 cm in ileostomies (18), since fascial defects larger than this size can multiply the risk of developing a ph by up to five times (17). the use of fascial support sutures is a procedure routinely performed in clinical practice despite the lack of evidence of any effect in reducing ph rates. pisters et al. (19) described the impact of anterior fascial fixation sutures in 496 patients undergoing radical cystectomy with ileal conduit at the md anderson cancer center, with a median follow-up of 16 months. sixty-one patients (12.2%) developed ph. the rate of cph was significantly higher in patients who had anterior fascial sutures placed compared to those who did not (15.3% vs. 7.3%, p = 0.02). furthermore, they observed that the use of these sutures was an independent risk factor in multivariate analysis for the development of ph (or 2.3 ci95%, 1.03-5.14; p = 0.04), so they discouraged their use in radical cystectomy with ileal diversion. moreover, multiple studies in the colorectal literature also advise against facial support sutures, since they have not been shown to reduce ph rates in this type of stoma (15, 20, 21). our series confirmed the association between ph and obesity, and previous midline laparotomy, two factors that contribute to weakening the abdominal wall and promote herniation. the other factors previously mentioned as predisposing the development of ph (female sex, dm, hypoalbuminemia, prolonged surgical time, etc. [4-7, 14-17)] did not show a significant association in our series, probably as a consequence of the limited number of cases. we also observed that ph was significantly more frequent in patients with postoperative surgical wound infection. although studies in the colorectal literature have previously described this association (20, 21), to our knowledge, this is the first study in the field of urology to link surgical wound infection with ph. this could be explained by the tissue damage and necrosis produced by the infection, which contributes to the weakening of the abdominal wall and therefore to the development of ph. the pathophysiology and natural history of ph is a poorly studied subject, and most of the available data is derived from the colorectal literature. radiographic classifications are indispensable, as they provide insight into its evolution, especially regarding changes in size and time to progression to a higher grade in the classification. in our series, radiological progression occurred in 46% of type 1 and 40% of type 2 hernias, with a median time of 11 months (sd 9.4). as in other previously reported studies (16), we found no predictive factors for progression, although the small number of events could also affect the results. despite this, only 25.9% of our patients with ph required surgical repair, and only one patient underwent emergency surgery due to intestinal obstruction, a figure similar to the previously reported (9-30%) (4, 5, 15-17). in general, ph surgical correction tends to be postponed due to its extreme complexity and high recurrence rate. primary repair and stoma relocation have traditionally been associated with unacceptably high hernia recurrence rates (up to 76%) (10, 20, 21). this figure drops to 10% (21) when a mesh is placed during the surgery, making this procedure the preferred choice. the two main techniques described so far are the sugarbaker technique (reduction of the contents of the hernial sac and placement of intraperitoneal mesh covering the aponeurotic orifice and the bowel forming the stoma) and the keyhole technique (creation of a hole in the mesh through which the stoma passes). in the colorectal literature, the first one has shown lower recurrence rates (18), although data are limited in patients with ileal diversion. the high prevalence of ph along with the negative impact on patients' quality of life, morbidity of surgical repair, and high recurrence rates have encouraged urologists to attempt to prevent its development by prophylactic mesh placement at the time of stoma creation. recently, three prospective randomized trials have demonstrated a significant reduction in the rate of ph by more than 50% with no differences in postoperative complications or mesh-related complications (infection) (22-24). the only difference between the two groups lies in surgical time (median 50 archivio italiano di urologia e andrologia 2023; 95(4):12108 m. alonso grandes, j.a. herranz yagüe, r. roldán testillano, et al. 6 min more in patients with mesh placement). prospective trials with longer follow-up time are needed, as well as cost-effectiveness studies to evaluate the role of prophylactic mesh in cystectomy and to determine if it should be placed systematically in all patients or only in those with a higher risk of ph (obese patients, female sex, copd...). the main limitation of our study lies in its retrospective nature, which may lead to underdiagnosis of clinical ph, mainly low-grade ph (i and ii). conclusions parastomal hernia is a common complication following radical cystectomy and bricker-type urinary diversion, and can be considered as part of natural evolution after stoma creation. consideration of the predictive factors can help for patient preoperative optimization and in the planning of surgery. obesity, wound infection and a history of midline laparotomy represent independent risk factors. references 1. caricato m, ausania f, ripetti v, et al. retrospective analysis of long-term defunctioning stoma complications after colorectal surgery. colorectal dis. 2007; 9:559-61. 2. gerharz ew, mansson a, hunt s, skinner ec, månsson w. quality of life after cystectomy and urinary diversion: an evidencebased analysis. j urol 2005; 174:1729-36. 3. uriarte vergara b, gutiérrez ferreras ai, pérez de villarreal amilburu p, et al. guía para el manejo actualizado de la hernia paraestomal. rev hispanoam hernia 2021; 9:126-130. 4. donahue tf, bochner bh, sfakianos jp, et al. risk factors for the development of parastomal hernia after radical cystectomy. j urol 2014; 191:1708-13. 5. liu nw, hackney jt, gellhaus pt, et al. incidence and risk factors of parastomal hernia in patients undergoing radical cystectomy and ileal conduit diversion. j urol 2014; 191:1313-8. 6. muysoms f, campanelli g, champault gg. eurahs: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair. hernia. 2012; 16:239-250. 7. martínez lahoz y, casas sicilia e, castán villanueva n, et al. hernias paraestomales. revisión de la literatura. revista sanitaria de investigación 2022; 3 (8). 8. martin l, foster g. parastomal hernia. ann r coll surg engl 1996; 78:81-4. 9. marimuthu k, vijayasekar c, ghosh d, mathew g. prevention of parastomal hernia using preperitoneal mesh: a prospective observational study. colorectal dis 2006; 8:672-5. 10. ripoche j, basurko c, fabbro-perray p, prudhomme m. parastomal hernia. a study of the french federation of ostomy patients. j visc surg 2011; 148:e435-41. 11. cingi a, cakir t, sever a, aktan ao. enterostomy site hernias: a clinical and computerized tomographic evaluation. discolon rectum 2006; 49:1559-63. 12. feng d, wang z, yang y, et al. incidence and risk factors of parastomal hernia after radical cystectomy and ileal conduit diversion: a systematic review and meta-analysis. transl cancer res. 2021; 10:1389-1398. 13. seo sh, kim hj, oh sy, et al. computed tomography classification for parastomal hernia. j korean surg soc 2011; 81:111-4. 14. aquina ct, iannuzzi jc, probst cp, et al. parastomal hernia: a growing problem with new solutions. digsurg. 2014; 31:366-76. 15. donahue tf, bochner bh. parastomal hernias after radical cystectomy and ileal conduit diversion. investig clin urol. 2016; 57:240-8. 16. ghoreifi a, allgood e, whang g, et al. risk factors and natural history of parastomal hernia after radical cystectomy and ileal conduit. bju int. 2022; 130:381-388. 17. hussein aa, ahmed ye, may p, et al. natural history and predictors of parastomal hernia after robot-assisted radical cystectomy and ileal conduit urinary diversion. j urol. 2017; 199:766-773. 18. pallisera a, serra x, mora l, et al. actualización de las hernias paraestomales: diagnóstico, tratamiento y prevención parastomal. rev hispanoam hernia. 2017; 5:3-12. 19. pisters al, kamat am, wei w, et al. anterior fascial fixation does not reduce the parastomal hernia rate after radical cystectomy and ileal conduit. urology 2014; 83:1427-31. 20. israelsson la. parastomal hernias. surg clin north am 2008; 88:113-25. 21. carne pw, frye jn, robertson gm, frizelle fa. parastomal hernia. br j surg. 2003; 90:784-93. 22. janes a, cengiz y, israelsson la. randomized clinical trial of the use of a prosthetic mesh to prevent parastomal hernia. br j surg 2004; 91:280. 23. liedberg f, kollberg p, allerbo m, et al. preventing parastomal hernia after ileal conduit by the use of a prophylactic mesh: a randomised study. eur urol. 2020; 78:757-63. 24. hammond tm, huang a, prosser k, et al. parastomal hernia prevention using a novel collagen implant: a randomised controlled phase 1 study. hernia. 2008; 12:475. correspondence maría alonso grandes, md (corresponding author) marialonsograndes@gmail.com university hospital of fuenlabrada, department of urology, camino del molino 2, 28942, fuenlabrada, madrid, spain josé antonio herranz yagüe, md jherranz@salud.madrid.org rocío roldán testillano, md rocio.roldan@salud.madrid.org alfonso maría márquez negro, md alfonsomaria.marquez@salud.madrid.org casilda cernuda pereira, md casilda.cernuda@salud.madrid.org emilio andrés ripalda ferretti, md emilio.ripalda@salud.madrid.org álvaro páez borda, md alvaro.paez@salud.madrid.org conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12369 1 original paper introduction although kidney stones are less common in children compared to adults, their recurrence rate is higher (1,2). therefore, in this age group, complete removal of stones with a less traumatic method is important for future kidney health. in the past, pediatric kidney stones were treated with open surgery. however, today, extracorporeal shock wave lithotripsy (swl) treatment is widely used for most pediatric kidney stones (3). the main disadvantages of the swl method are that it is performed under general anesthesia and requires a high number of sessions (4). percutaneous nephrolithotomy (pcnl) is a frequently used treatment method, especially for the treatment of large and complex stones (3). eau guidelines recommend pcnl as the first treatment option for pediatric kidney stones larger than 2 cm and stones larger than 1 cm in the lower calyx. however, the possibility of bleeding requiring transfusion increases as the sheath diameter, number of punctures, and surgery time increase in pcnl (5, 6). this is why mini-pcnl has become popular today. with the mini-pcnl method, it is expected that there will be less renal parenchymal damage and fewer complications since the working channel is smaller. because pediatric kidneys are small and mobile, have thin parenchyma, and the pelvicalyceal area has small volume, the large instruments used in standard pcnl can be traumatic (7). therefore, the importance of mini-pcnl increases for these patients. our study aimed to compare the results of mini and standard pcnl, along with their morbidity and success rates, for pediatric kidney stones. materials and methods the data for 128 patients < 18 years of age who underwent pcnl for pediatric kidney stones between june 2013 and december 2022 were retrospectively examined. patients who had previously undergone pcnl, had chronic kidney disease, were operated for ureteral stones in the same session, had skeletal anomalies, and with missing postoperative follow-up data were excluded from the study. patients were divided into two groups: mini-pcnl objective: in this study, the aim was to compare the results of mini and standard percutaneous nephrolithotomy (pcnl) for the treatment of pediatric kidney stones. materials and methods: data for 128 patients < 18 years of age who underwent mini and standard pcnl due to pediatric kidney stones were retrospectively examined. patients were divided into two groups: mini-pcnl (16-20 fr) and standard pcnl (26 fr). surgery time, number of punctures to the pelvicalyceal system, hospital stay, postoperative hemoglobin drop, complications and stone-free status (sfr) were compared between the groups. additional surgical intervention (double-j stent, ureterorenoscopy, secondary pcnl) performed after the surgery was recorded. the absence of residual stones or < 3 mm residual stones on kidney, ureter and bladder radiography (kub) and ultrasonography (usg) performed in the third postoperative month were accepted as success criteria. results: there were 32 (43.8%) patients in the mini-pcnl group and 41 (56.2%) patients in the standard pcnl group. the mean age was 9.3 ± 4.1 years in the mini-pcnl group and 10.1 ± 5.4 years in the standard pcnl group. mean stone size in the mini-pcnl group was 2.1 ± 1.2; while for standard pcnl it was 2.3 ± 1.4. the mean surgery time was statistically significantly higher in the mini-pcnl group (p = 0.005). there was no difference between the groups in terms of intraoperative double j stent use, postoperative complications and sfr. a double j stent was inserted in two patients in the mini-pcnl group and in one patient in the standard pcnl group due to urine leakage from the nephrostomy tract in the postoperative period. although the postoperative hemoglobin drop was found to be significantly higher in standard pcnl (p = 0.001), hematuria and blood transfusion rates were low in both groups. mean hospital stay was shorter in the mini-pcnl group compared to standard pcnl (3.6 ± 1.2 days vs. 2.5 ± 1.1; p = 0.018). conclusions: although mini-pcnl has longer surgery time compared to standard pcnl, it should be preferred for the treatment of pediatric kidney stones due to advantages such as similar success and complication rates to standard pcnl, short hospital stay and less postoperative hemoglobin drop. key words: mini percutaneous nephrolithotomy; standard percutaneous nephrolithotomy; pediatric kidney stones. submitted 8 february 2024; accepted 17 february 2024 comparison of two percutaneous nephrolithotomy methods for the treatment of pediatric kidney stones: mini-percutaneous nephrolithotomy and standard percutaneous nephrolithotomy kadir karkin 1, mubariz aydamirov 2, buğra aksay 1, eyüp kaplan 3, güçlü gürlen 1, adem altunkol 1, ferhat ortaoğlu 1, ömer faruk akgün 1, ediz vuruşkan 1, zafer gökhan gürbüz 1 1 health sciences university, adana city training and research hospital urology clinic, adana, turkey; ² başkent university, alanya application and research center, alanya, turkey; ³ abdulkadir yüksel state hospital urology clinic, gaziantep, turkey. doi: 10.4081/aiua.2024.12369 summary archivio italiano di urologia e andrologia 2024; 96(2):12369 k. karkin, m. aydamirov, b. aksay, et al. 2 (16-20 fr) and standard pcnl (26 fr). preoperatively, urinalysis, urine culture, complete blood count, kidney and liver function tests, coagulation tests, urinary ultrasonography (usg), kidney, ureter and bladder radiography (kub) and non-contrast whole abdominal computed tomography (ncct) were performed on all patients. those with active urinary tract infection were treated with appropriate antibiotics, and those with no growth in the control urine culture were taken for surgery. stone size was defined as the maximum diameter of the stone. in the presence of multiple stones, the sum of the longest diameter of each stone was accepted as the stone size. in both groups, the surgeries were performed in prone position under general anesthesia and with antibiotic (cephalosporin) prophylaxis. previously, a 4-6 fr ureteral catheter was inserted in patients in the lithotomy position. diluted opaque material was administered through the ureteral catheter to visualize the collecting system. then, after determining the appropriate calyx under fluoroscopy, entry was made with a two-piece needle with an 18-gauge trocar tip (cook urological, bloomington, in, usa). when necessary, additional entries were made before dilation began. a 0.035 inch hydrophilic nitinol (terumo, tokyo, japan) guide wire was sent through the needle to the collector system. in the mini-pcnl group, 16-20 fr dilatation was performed over the guide wire with the help of amplatz dilators and a sheath was placed. the kidney was entered with a 15 fr rigid nephroscope (olympus), and a pneumatic lithotripter was used when necessary, along with a holmium laser, to break up the stones. the broken stone pieces were removed by washing, using forceps and a basket. patients in the standard pcnl group underwent 26 fr dilation and surgeries were performed with a 24 fr nephroscope. a pneumatic lithotripter was used to break up the stones. at the end of the procedures, the presence of residual stones was checked with fluoroscopy. if no residual stone could be seen during both fluoroscopy and endoscopic examination, the operation was considered completed. double-j stents were emplaced antegradely in those who were thought to have infection stones, with injuries in the renal pelvis, and stenosis in the ureteropelvic junction. at the end of the procedure, a 12-14 fr foley catheter was inserted as a nephrostomy tube. on the first postoperative day, all patients underwent kub and their urethral catheters were removed; the nephrostomy tube was removed on the first or second day. patients who had no fever, hematuria, or discharge from the nephrostomy tract during follow-up were discharged. surgery time, number of punctures to the pelvicalyceal system, hospital stay, postoperative hemoglobin drop, complications and stone-free status (sfr) were compared between the groups. in both groups, the duration of surgery was defined as the time from the first puncture of the pelvicalyceal system until the placement of the nephrostomy catheter. the first follow-up after discharge was performed two weeks later (those with a dj stent had their stents removed). the success criteria were defined as no additional postoperative surgical intervention (double-j stent, ureterorenoscopy, secondary pcnl), no residual stones or < 3 mm stones at kub and usgs performed 3 months later. statistical analysis data were analyzed using spss. the chi-square test was used to compare proportions. fisher's exact test was used when the expected number of > 20% of cells in the table fell below five. student t test was used to compare the means of two groups. a p value of 0.05 was considered statistically significant. univariate analyses were performed to detect a significant relationship between each of the dependent and independent variables. a 95% confidence interval was also calculated. results a total of 73 pediatric patients were included in the study. there were 32 (43.8%) patients in the mini-pcnl group and 41 (56.2%) patients in the standard pcnl group. the mean age was 9.3 ± 4.1 years in the mini-pcnl group and 10.1 ± 5.4 years in the standard pcnl group. mean stone size for mini-pcnl was 2.1 ± 1.2; for standard pcnl it was 2.3 ± 1.4. there were no differences between the groups in terms of demographic, clinical and radiological stone characteristics of the patients (table 1). the mean surgery time was statistically significantly higher in the mini-pcnl group (p = 0.005). there was no difference between the groups in terms of intraoperative double j stent use, postoperative complications and sfr. the overall sfr was 81.2% in mini-pcnl and 85.4% in standard pcnl. complications were generally managed with medical treatment. a double j stent was placed in two patients in the mini-pcnl group and in one patient in the standard pcnl group due to urine leakage from the nephrostomy tract in the postoperative period. although puncture rates were slightly higher in the minipcnl group, this was not statistically significant (p = 0.076). although postoperative hemoglobin drop was found to be significantly higher in standard pcnl (p = 0.001), hematuria and blood transfusion rates were low in both groups. blood transfusion was performed in one patient in the mini-pcnl group and in two patients in the standard pcnl group. the mean hospital stay was table 1. comparison of patients' demographic, clinical and radiological parameters. variables mini pcnl (n = 32) standard pcnl (n = 41) p age (mean ± sd) 9.3±4.1 10.1±5.4 0.105 sex, n (%) 0.196 male 19 (59.3) 29 (70.7) female 13 (40.7) 12 (29.3) bmi (mean ± sd) 19.0±3.6 20.2±3.9 0.388 stone side, n (%) 0.383 right 17 (53.1) 24 (58.5) left 15 (46.9) 17 (41.5) stone size (mm), (mean ± sd) 2.1±1.2 2.3±1.4 0.211 stone complexity, n (%) 0.622 single stone 11 (34.4) 14 (34.1) multiple stone 16 (50) 17 (41.5) partial staghorn 3 (9.4) 4 (9.8) complete staghorn 2 (6.2) 6 (14.6) pcnl: percutaneous nephrolithotomy, bmi: body mass index. archivio italiano di urologia e andrologia 2024; 96(2):12369 3 comparison of two percutaneous nephrolithotomy methods for the treatment of pediatric kidney stones shorter in the mini-pcnl group compared to standard pcnl (3.6 ± 1.2 days vs. 2.5 ± 1.1; p = 0.018) (table 2). discussion in this study, it was planned to compare the results of standard and mini-pcnl for pediatric kidney stones. although the surgery time was longer in mini-pcnl, the hospital stay and average postoperative hemoglobin drop were less. sfr and complication rates were similar between the groups. the prevalence of pediatric kidney stones with high recurrence rates is increasing day by day (8). pcnl is a standard treatment method in this age group, especially for the treatment of large kidney stones. mini-pcnl is the most popular technique in recent times. with this technique, the aim is to cause less damage to the kidney parenchyma, reduce complications, and achieve high sfr by using small-diameter sheaths (9-11). in many studies, the sfr in standard pcnl is 50-98% (5, 10-14). in minipcnl, this rate was reported to be 80-85% (5, 8, 14). in similar literature studies comparing mini and standard pcnl in the pediatric population, there was no significant difference between the two techniques in terms of sfr (1517). if we look at the sfr in our study, it was similar to the literature with rates of 81.2% in the mini-pcnl group and 85.4% in the standard pcnl group. many studies showed that the operation time in minipcnl is longer than standard pcnl (13, 18, 19). in our study, the operation time was longer in the mini-pcnl group. we think that surgery times are prolonged in minipcnl due to reasons such as the slow flow of irrigation fluid due to the use of small-diameter instruments, the limited visual field due to the use of miniaturized endoscopic devices, and the preference for stones to be broken into smaller pieces for removal or grinding, instead of active stone crushing. one of the complicated situations in studies comparing both standards in the literature is the length of hospital stay. although some studies showed that the postoperative hospital stay is similar for both methods (13, 18-20), some reported that the length of stay is shorter for mini-pcnl (15). in our study, the length of stay after mini-pcnl was found to be significantly shorter. we think that the smaller size of the nephrostomy tract and the resulting reduction in postoperative pain and bleeding result in a shorter hospital stay. after pcnl surgery, patients may experience complications such as fever, urinary tract infection and bleeding. complication rates in the literature vary between 15-25% (21-26). although some studies say that complication rates are similar (19, 20), there are also studies showing that intraoperative bleeding, postoperative hemoglobin drop and blood transfusion rates are significantly higher in standard pcnl (13, 18). in our study, although the number of punctures seemed to be slightly higher with mini-pcnl, the postoperative hemoglobin drop was found to be significantly higher with standard pcnl. however, there was no statistically significant difference between the groups in terms of general postoperative complications. our study has some limitations. firstly, our study was a retrospective study and the number of patients was small. secondly, no subgroup analysis was performed according to stone complexity. thirdly, due to the small number of patients, analysis was not made according to age groups. additionally, computed tomography could not be used in follow-up imaging to avoid further radiation exposure. conclusions although mini-pcnl has a longer surgery time compared to standard pcnl, it has similar success and complication rates. in addition, it is a safe and effective method that should be preferred for the treatment of pediatric kidney stone patients due to important advantages such as short hospital stay and less postoperative hemoglobin drop. references 1. smaldone mc, docimo sg, ost mc. contemporary surgical management of pediatric urolithiasis. urol clin north am. 2010; 37:253-67. 2. veeratterapillay r, shaw mb, williams r, et al. safety and efficacy of percutaneous nephrolithotomy for the treatment of paediatric urolithiasis. ann r coll surg engl. 2012; 94:588-92. 3. tekgül s, stein r, bogaert g, et al. european association of urology and european society for paediatric urology guidelines on paediatric urinary stone disease. eur urol focus. 2022; 8:833-39. 4. zeren s, satar n, bayazit y, et al. percutaneous nephrolithotomy in the management of pediatric renal calculi. j endourol. 2002; 16:75-8. 5. guven s, istanbulluoglu o, gul u, et al. successful percutaneous nephrolithotomy in children: multicenter study on current status of its use, efficacy and complications using clavien classification. j urol. 2011; 185:1419-24. 6. onal b, dogan hs, satar n, et al. factors affecting complication table 2. comparison of intraoperative and postoperative data. variables mini pcnl standart pcnl p operative duration (min), (mean ± sd) 85.4 ± 18.8 71.7 ± 11.6 0.005 punctures, n (%) 0.076 single 24 (75) 37 (90.2) multiple 8 (25) 4 (9.8) intraoperative double j stent insertion, n (%) 5 (15.6) 9 (21.9) 0.225 hospital stay (days), (mean ± sd) 2.5 ± 1.1 3.6 ± 1.2 0.018 postoperative complications 0.159 clavien grade 1 4 (12.5) 7 (17) clavien grade 2 3 (9.3) 5 (12.2) clavien grade 3 2 (6.2) 1 (2.4) clavien grade 4 0 0 postoperative fever, n (%) 5 (15.6) 8 (19.5) postoperative transient hematuria, n (%) 1 (3.1) 2 (4.9) blood transfusion, n (%) 1 (3.1) 2 (4.9) urinoma 0 0 prolonged urine leakage (≥ 24 hours) 2 (6.2) 1 (2.4) pleural injury 0 0 colon injury 0 0 sepsis 0 0 mortality 0 0 postoperative hb (g/dl) drop, (mean ± sd) 0.9 ± 0.3 1.6 ± 0.5 0.001 sfr, n (%) 26 (81.2) 35 (85.4) 0.487 pcnl: percutaneous nephrolithotomy, sfr: stone-free rate. archivio italiano di urologia e andrologia 2024; 96(2):12369 k. karkin, m. aydamirov, b. aksay, et al. 4 rates of percutaneous nephrolithotomy in children: results of a multiinstitutional retrospective analysis by the turkish pediatric urology society. j urol. 2014; 191:777-82. 7. kapoor r, solanki f, singhania p, et al. safety and efficacy of percutaneous nephrolithotomy in the pediatric population. j endourol. 2008; 22:637-40. 8. hesse a, brändle e, wilbert d, et al. study on the prevalence and incidence of urolithiasis in germany comparing the years 1979 vs. 2000. eur urol. 2003; 44:709-13. 9. samad l, aquil s, zaidi z. paediatric percutaneous nephrolithotomy: setting new frontiers. bju int. 2006; 97:359-63. 10. jackman sv, hedican sp, peters ca, et al. percutaneous nephrolithotomy in infants and preschool age children: experience with a new technique. urology. 1998; 52:697-701. 11. dogan b, atmaca af, canda ae, et al. efficiency of percutaneous nephrolithotomy in pediatric patients using adult-type instruments. urol res. 2012; 40:259-62. 12. salah ma, tóth c, khan am, et al. percutaneous nephrolithotomy in children: experience with 138 cases in a developing country. world j urol. 2004; 22:277-80. 13. unsal a, resorlu b, kara c, et al. safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. urology. 2010; 76:247-52. 14. goyal nk, goel a, sankhwar sn, et al. a critical appraisal of complications of percutaneous nephrolithotomy in paediatric patients using adult instruments. bju int. 2014; 113:801-10. 15. mahmood sn, aziz bo, tawfeeq hm, et al. miniversus standard percutaneous nephrolithotomy for treatment of pediatric renal stones: is smaller enough? j pediatr urol. 2019; 15:664.e1-664.e6. 16. mahajan ad, mahajan sa. comparison of mini-percutaneous nephrolithotomy by standard and miniperc instruments in pediatric population: a single-center experience. j pediatr urol. 2021; 26:37479. 17. kumar n, yadav p, kaushik vn, et al. mini-versus standard percutaneous nephrolithotomy in pediatric population: a randomized controlled trial. j pediatr urol. 2023; 19:688-95. 18. bilen cy, koçak b, kitirci g, et al. percutaneous nephrolithotomy in children: lessons learned in 5 years at a single institution. j urol. 2007; 177:1867-71. 19. celik h, camtosun a, dede o, et al. comparison of the results of pediatric percutaneous nephrolithotomy with different sized instruments. urolithiasis. 2017; 45:203-208. 20. altintas r, oguz f, tasdemir c, et al. the importance of instrument type in paediatric percutaneous nephrolithotomy. urolithiasis. 2014; 42:149-153. 21. ozden e, mercimek mn, yakupoglu yk, et al. modified clavien classification in percutaneous nephrolithotomy: assessment of complications in children. j urol. 2011; 185:264-68. 22. zeng g, zhao z, zhao z, et al. percutaneous nephrolithotomy in infants: evaluation of a single-center experience. urology. 2012; 80:408-11. 23. resorlu b, unsal a, tepeler a, et al. comparison of retrograde intrarenal surgery and mini-percutaneous nephrolithotomy in children with moderate-size kidney stones: results of multi-institutional analysis. urology. 2012; 80:519-23. 24. yan x, al-hayek s, gan w, et al. minimally invasive percutaneous nephrolithotomy in preschool age children with kidney calculi (including stones induced by melamine-contaminated milk powder). pediatr surg int. 2012; 28:1021-24. 25. izol v, satar n, bayazit y, et al. which factors affect the success of pediatric pcnl? single center experience over 20 years. arch ital urol androl. 2020; 18:345-49. 26. eslahi a, ahmed f, hosseini mm, et al. minimal invasive percutaneous nephrolithotomy (mini-pcnl) in children: ultrasound versus fluoroscopic guidance. arch ital urol androl. 2021; 28:173-77. correspondence kadir karkin, md, febu (corresponding author) kadir_karkin@msn.com department of urology, health sciences university, adana city training and research hospital, adana, türkiye mubariz aydamirov, md aydemirov.89@mail.ru başkent university, alanya application and research center, alanya, türkiye buğra aksay, md bgraksay@gmail.com güçlü gürlen, md guclugurlen@hotmail.com adem altunkol, md ademaltunkol@hotmail.com ferhat ortoglu, md ferhatort@hotmail.com ömer faruk akgün, md dromerfarukakgun@gmail.com ediz vuruşkan, md evuruskan@hotmail.com zafer gökhan gürbüz, md zafergokhangurbuz@yahoo.com eyüp kaplan, md dreyup001@hotmail.com abdulkadir yüksel state hospital urology clinic, gaziantep, türkiye conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13760 1 original paper introduction bladder cancer posed a significant epidemiological concern in the arab world, as evidenced by the 2019 global burden of disease data. in yemen, the age-standardized incidence rate (asir) was recorded at 4.374 per 100,000, amounting to a total of 535.947 cases. gender-specific analysis revealed asirs of 7.003 for males and 4.584 for females, with corresponding age-standardized death rates (asdr) of 1.863 for males and 1.433 for females. the age-standardized disability-adjusted life years (asdalys) attributed to bladder cancer in yemen reached approximately 7,400.041, resulting in 57.819 deaths and a mortality-incidence ratio (mir) of 2.95 (1). in 2020, the incidence of bladder cancer among males was estimated at 4.0 per 100,000, with a mortality rate of 1.6 per 100,000, underscoring the public health challenge presented by this disease in the region (2). muscle-invasive bladder cancer (mibc) represents a significant global health challenge, necessitating complex, multidisciplinary therapeutic approaches (3). standard treatment protocols typically involve radical cystectomy with pelvic lymph node dissection, often integrated with neoadjuvant or adjuvant chemotherapy (ac) to improve oncological outcomes (3, 4). indeed, radical cystectomy has been widely recognized as the gold standard treatment, demonstrating superior survival rates and reduced recurrence compared to less aggressive modalities (5, 6). prognostic factors, including advanced age, non-urothelial variant histology, a reduced number of lymph nodes removed, lymph node status, tumor stage, and surgical margin status, are critical determinants of long-term survival following radical cystectomy for mibc (7, 8). bladder cancer mortality remains a substantial concern, particularly in advanced disease stages, underscoring the imperative for effective interventions (9). however, the successful implementation of these guidelines is contingent upon the availability of robust diagnostic pathways and therapeutic infrastructure (6). in resource-constrained settings such as yemen, the management of mibc presents considerable obstacles. these regions often face limitations in essential resources, including diagnostic imaging modalities, specialized surbackground: the lack of a cohesive diagnostic and therapeutic framework for muscleinvasive bladder cancer (mibc) in yemen has resulted in significant variability in patient care. this study evaluates oncological outcomes and survival rates after radical cystectomy (rc) for mibc patients in yemen. methods: we conducted a retrospective analysis of 300 mibc patients who underwent rc between 2006 and 2020. demographics, histopathological findings, and survival data were meticulously collected. kaplan-meier survival analysis estimated survival probabilities, while prognostic factors were evaluated using the log-rank test. results: the median patient age was 67 years (iqr 65-70), with a male predominance (n = 184, 61.3%). ileal loop reconstruction was the primary method of urinary diversion (n = 234, 78.0%). urothelial carcinoma was the predominant diagnosis (n = 246, 82.0%), followed by squamous cell carcinoma (n = 42, 14.0%). postoperative complications occurred in 93 patients (31.0%), primarily grade i (n = 61, 20.3%). overall survival was 71.7% (n = 215), with 28.3% mortality due to non-cancer-related (n = 43, 14.3%) and bladder cancer-related causes (n = 35, 11.7%). the median overall survival was 191 months, with 1-year, 3-year, 5-year, and 10-year survival rates of 99%, 93%, 88%, and 82%, respectively. in the multivariate analysis, non-ileal conduit diversion (hazard ratio [hr] 5.21, 95% confidence interval [ci]: 1.80-15.00, p = 0.003), stage iv disease (hr 2.76, 95% ci: 1.01-7.61, p = 0.050), lymph node positivity (hr 2.92, 95% ci: 1.15-7.42, p = 0.022), and squamous cell carcinoma (hr 3.09, 95% ci: 1.25-7.63, p = 0.022) were identified as predictors of mortality. conclusions: this study highlights the urgent need for improved bladder cancer care in yemen. late-stage diagnosis and suboptimal surgical methods critically affect survival. addressing these issues requires prioritizing early detection and standardized surgical techniques to develop effective care pathways for mibc patients. key words: muscle-invasive bladder cancer; cystectomy; yemen; disease-free survival; mortality; oncological outcomes. submitted 20 february 2025; accepted 24 february 2025 current status of management and outcomes of muscle-invasive bladder cancer in yemen: a retrospective observational study khaled al-kohlany 1, amal al-maleki 2, majdi al-shami 3, hani hussein 4, faisal ahmed 5 1 department of urology, general military hospital, sana'a, yemen; 2 department of obstetrics and gynecology, palestine hospital for motherhood and childhood, sana'a, yemen; 3 department of urology, general military hospital, sana'a, yemen; 4 department of urology, 22 may typical specialized surgical center, sana'a, yemen; 5 department of urology, school of medicine, ibb university, ibb, yemen. doi: 10.4081/aiua.2025.13760 summary archivio italiano di urologia e andrologia 2025; 97(2):13760 k. al-kohlany, a. al-maleki, m. al-shami, h. hussein, f. ahmed 2 gical equipment, and access to systemic therapies (10, 11). moreover, limited access to trained urologic oncologists and comprehensive supportive care services can adversely affect patient outcomes. the absence of standardized protocols, compounded by these resource constraints, can lead to heterogeneous patient management and potentially compromise treatment efficacy. therefore, this study seeks to investigate the current status of mibc management and the associated oncological outcomes and survival rates following radical cystectomy in yemen, a resource-limited environment. we present a retrospective analysis of oncological outcomes and survival following radical cystectomy for mibc performed by a single surgeon at tertiary referral centers. by characterizing the experiences of patients undergoing surgical treatment for mibc in yemen, this study aims to identify areas for improvement in the diagnosis, treatment, and ultimately, survival of this vulnerable patient population. this study is crucial, as it not only provides insight into existing practices but also highlights gaps in the healthcare system. these insights may be used to inform the development of evidence-based national guidelines and recommendations for bladder cancer treatment in yemen. patients and methods study design this retrospective observational study analyzed data from approximately 300 patients diagnosed with mibc who underwent radical cystectomy at various governmental and private healthcare facilities in sana'a, yemen, between january 2006 and march 2020. the study adhered to the principles outlined in the declaration of helsinki and received ethical approval from the ethics research committees of the general military hospital in sana'a. given the retrospective nature of the study, the ethics committee waived the requirement for individual patient consent for chart review. all patient data were encrypted and anonymized to ensure confidentiality. inclusion criteria patients diagnosed with mibc who underwent radical cystectomy were included in the study, irrespective of tumor behavior or histology, with the exception of those diagnosed with lymphomas or small cell carcinomas. all included patients were managed by a single urologist with over five years of experience in oncologic surgery (k. a-k.). exclusion criteria patients were excluded from this analysis for the following reasons: failure to undergo radical cystectomy; presence of documented clinical metastatic disease or noninvasive disease; a history of multiple primary cancers; a follow-up duration of less than six months; or treatment conducted by a different urologic team. treatment and follow-up preoperative staging comprised abdominal and pelvic computed tomography (ct) scans, chest x-rays, and transurethral resection of bladder tumors (turbt). radical cystectomy (rc) was performed, which included either bilateral or limited pelvic lymph node dissection (plnd), with prostatectomy and seminal vesiculectomy conducted for male patients. female patients also underwent hysterectomy, anterior vaginal wall resection, and bilateral salpingo-oophorectomy, as dictated by the presence of involvement in these organs. the execution and extent of lymph node dissection, along with the choice of urinary diversion, were determined based on patient preferences and the recommendations of the department’s specialists. post-cystectomy follow-up involved clinical examination, laboratory studies, chest radiography, and abdominal/pelvic ct scans, with follow-up appointments scheduled every two months during the first year, semi-annually during the second year, and annually thereafter. treatment failure was defined as radiological evidence of tumor relapse, categorized as either local recurrence or distant metastasis. neoadjuvant chemotherapy (nac) was administered to selected patients with clinically localized urothelial tumors. ac was offered to patients with pathological stage t3 or greater and/or node-positive disease unless medically contraindicated or declined by the patient; this regimen was initiated within three months of surgery. data collection comprehensive data were meticulously extracted from patient charts and compiled into a microsoft excel database. the collected data included demographic information (age, sex, smoking status) and key clinicopathological variables such as the date of diagnosis, tumor histology and behavior, date of last follow-up or date of death, and cause of death (whether bladder cancer-related or due to other causes). tumors were classified pathologically using the 2002 tnm system established by the international union against cancer and graded according to the world health organization system from 2004 (12, 13). additional noteworthy factors were documented, including the american society of anesthesiologists (asa) classification, type of urinary diversion, and any postoperative complications or mortality. duplicate records and cases with implausible dates of diagnosis (e.g., incidence date after the date of death or less than two weeks from death for patients undergoing radiotherapy and/or chemotherapy) were excluded from analysis. postoperative complications occurring within 30and 90-days following surgery were classified according to the clavien-dindo grading system, categorized as overall (any grade), minor (grades 1-2), and major (grades 3-5) (14). postoperative ileus was defined as the inability to tolerate oral alimentation after cystectomy or the occurrence of nausea, emesis, and abdominal distension that necessitated gastrointestinal decompression or nutritional support at any point during the postoperative period. furthermore, data concerning complications specifically attributable to radical cystectomy were also collected. study outcomes the primary outcome of this study was the association of bladder cancer treatment with overall survival (os) and cancer-specific survival (css). progression-free survival (pfs) was also assessed, defined as the interval from the index date to either the date of progression or death from archivio italiano di urologia e andrologia 2025; 97(2):13760 3 bladder cancer management in yemen any cause, or the initiation of a new treatment regimen, with patients who were alive and did not experience progression censored at their last visit date. median pfs (mpfs) was estimated, along with 95% confidence intervals (cis), measured in months using the kaplan-meier method. css was defined as the duration from rc to cancer-related death, while os was defined as the duration from rc to any cause of death. the secondary outcome involved the identification of factors associated with mortality among patients undergoing radical cystectomy. statistical analysis data were analyzed using spss statistics version 24 (ibm corp., armonk, ny). descriptive statistics summarized patient characteristics and tumor features, using mean ± standard deviation for continuous variables and frequency and percentage for categorical variables. the chi-squared test compared categorical variables, while survival analyses were conducted using kaplan-meier methods and cox proportional hazards models to assess recurrence-free survival (rfs), disease-free survival (dfs), and overall survival (os). the log-rank test was applied to compare survival distributions, with a p-value of less than 0.05 considered statistically significant. survival time was calculated from the date of diagnosis to either the date of death or the last follow-up, with patients who were alive and without clinical evidence of disease at the last follow-up censored. the proportional hazards assumption was evaluated for each covariate in the cox regression models, with covariates selected for the final regression model based on the likelihood ratio test. included covariates were ecog performance status, type of urinary diversion, tumor grade, pathological stage, lymph node status, histological type, gender, smoking status, gender, and age. results baseline patient, operative details, and tumor characteristics the patient cohort consisted of 300 individuals, with a mean age of 67.6 ± 4.8 years and a median age of 67.0 years (iqr 65.0, 70.0). the majority of patients were male (n = 184, 61.3%), and a substantial proportion reported a history of tobacco use (n = 186, 62.0%). curative radical cystectomy was the most common surgical intervention, performed in 272 patients (90.7%), followed by palliative cystectomy in 22 (7.3%) and salvage cystectomy in 6 (2.0%). ileal loop urinary diversion was the most frequently employed reconstruction technique, used in 234 patients (78.0%). other reconstruction techniques included ileal w neobladder (53 patients, 17.7%), ureterosigmoidostomy (5 patients, 1.7%), cutaneous ureterostomy (3 patients, 1.0%), indwelling pcn (1 patient, 0.3%), and studer pouch (4 patients, 1.3%). urothelial carcinoma was the predominant pathological diagnosis, observed in 246 patients (82.0%). squamous cell carcinoma, mixed carcinoma, and adenocarcinoma were also identified in 42 (14.0%), 7 (2.3%), and 5 (1.7%) patients, respectively. the majority of tumors were classified as high grade (n = 270, 90.0%). stage ii disease was the most frequently observed pathological stage (n = 131, 43.7%). stage iii and stage iv disease were observed in 42 (14.0%) and 33 (11.0%) patients, respectively. lymph node involvement was documented in a significant proportion of the cohort (n = 98, 32.7%) (table 1). postoperative and survival outcomes postoperative complications were documented in 93 patients (31.0%). grade i complications were the most common (n = 61, 20.3%). grade ii complications occurred in 21 patients (7.0%), while grade iii to v (major complications) were observed in 6 (2.0%) and 7 (2.3%) patients, respectively. the mean follow-up duration was 102.1 months (sd 52.0), with a range of 1.0 to 227.0 months and a median of 111 months (iqr: 62, 141). table 1. baseline patient, operative details, and tumor characteristics in muscle-invasive bladder cancer patients undergoing radical cystectomy. characteristic n (%) age (years), mean ± sd 67.6 ± 4.8 gender female 116 (38.7%) male 184 (61.3%) smoking status no 114 (38.0%) yes 186 (62.0%) ecog performance status 0 131 (43.7%) 1 110 (36.7%) 2 59 (19.7%) operative type radical cystectomy 272 (90.7%) palliative cystectomy 22 (7.3%) salvage cystectomy 6 (2.0%) urinary diversion type ileal loop 234 (78.0%) ileal w neobladder 53 (17.7%) ureterosigmoidostomy 5 (1.7%) cutaneous ureterostomy 3 (1.0%) indwelling pcn 1 (0.3%) studer pouch 4 (1.3%) pathology type urothelial carcinoma 246 (82.0%) squamous cell carcinoma 42 (14.0%) mixed carcinoma 7 (2.3%) adenocarcinoma 5 (1.7%) tumor stage tis 57 (19.0%) i 37 (12.3%) ii 131 (43.7%) iii 42 (14.0%) iv 33 (11.0%) tumor grade high 270 (90.0%) low 30 (10.0%) lymph node status negative 202 (67.3%) positive 98 (32.7%) archivio italiano di urologia e andrologia 2025; 97(2):13760 k. al-kohlany, a. al-maleki, m. al-shami, h. hussein, f. ahmed 4 the overall survival rate was 215 (71.7%), with 85 (28.3%) cases resulting in death. specifically, 7 (2.3%) cases were mortality-related deaths that occurred during postoperative hospital admission within 30 days of the operation. significantly, a substantial fraction of the cohort experienced mortality attributed to non-cancer causes (n = 43, 14.3%) or bladder cancer-related causes (n = 35, 11.7%). at the time of data analysis, among patients who were alive, 184 (61.3%) were alive free of disease, and 31 (10.3%) were alive with disease (table 2). survival analysis single-arm survival analysis of 293 patients with bladder cancer demonstrated a median overall survival (mos) of 191 months (95% ci: 116-267 months) (figure 1). kaplan-meier estimates indicated 1-year, 3-year, 5-year, and 10-year survival probabilities of 99% (95% ci: 97%-100%), 93% (95% ci: 90%-96%), 88% (95% ci: 84%92%), and 82% (95% ci: 78%-87%), respectively. factors associated with mortality univariate cox regression analysis revealed that ecog performance status (2 vs. 0: hr 5.29, p < 0.001; 1 vs. 0: hr 3.80, p < 0.001), non-ileal conduit urinary diversion (hr 4.21, p < 0.001), high-grade tumors (hr 9.50, p < 0.001), advanced stage (stage ii vs. tis: hr 5.16, p < 0.001; stage iv vs. tis: hr 6.10, p < 0.001), lymph node positivity (hr 11.95, p < 0.001), and squamous cell carcinoma histology (hr 16.78, p < 0.001) were significantly associated with increased mortality (table 3). however, multivariate cox regression analysis demonstrated that only non-ileal conduit urinary diversion (hr 5.21, p = 0.003), stage ii (hr 2.56, p = 0.047), stage iv figure 1. kaplan-meier estimates of overall survival for yemeni patients who underwent radical cystectomy. table 2. oncological outcomes and postoperative complications in muscle-invasive bladder cancer patients undergoing radical cystectomy. characteristic n (%) follow-up duration (months) mean ± sd 102.1 ± 52.0 range 1.0 to 227.0 median 111 (iqr: 62, 141) outcome alive without disease 184 (61.3%) non-cancer mortality 43 (14.3%) cancer mortality 35 (11.7%) died early 7 (2.3%) alive with disease 31 (10.3%) progression-free survival (pfs) median pfs, 95% ci (months) 155 (143-191) any complication no 207 (69.0%) yes 93 (31.0%) complication grade grade 1 61 (20.3%) grade 2 21 (7.0%) grade 3 6 (2.0%) grade 4 7 (2.3%) table 3. univariate cox regression analysis of factors associated with overall survival in muscle-invasive bladder cancer patients undergoing radical cystectomy. variable subgroup n (%) hazard ratio (95% ci) p-value ecog performance status 0 131 (43.7) ref 1 110 (36.7) 3.80 (1.89-7.64) < 0.001 2 59 (19.7) 5.29 (2.58-10.85) < 0.001 urinary diversion type ileal conduit diversion 287 (95.7) ref non-ileal conduit diversion 13 (4.3) 4.21 (2.31-7.67) < 0.001 tumor grade low grade 270 (90.0) ref high grade 30 (10.0) 9.50 (5.87-15.37) < 0.001 pathological stage tis 57 (19.0) ref i 37 (12.3) 0.03 (0.00-0.27) 0.002 ii 131 (43.7) 5.16 (2.24-11.90) < 0.001 iii 42 (14.0) 2.28 (0.87-5.99) 0.095 iv 33 (11.0) 6.10 (2.64-14.13) < 0.001 lymph node status negative 202 (67.3) ref positive 98 (32.7) 11.95 (7.11-20.08) < 0.001 histological type urothelial carcinoma 246 (82.0) ref squamous cell carcinoma 42 (14.0) 16.78 (10.09-27.91) < 0.001 other 12 (4.0) 4.00 (1.99-8.03) < 0.001 gender female 116 (38.7) ref male 184 (61.3) 0.95 (0.61-1.46) 0.800 smoking status no 114 (38.0) ref yes 186 (62.0) 0.86 (0.55-1.33) 0.496 age (year) mean (sd) 67.6 (4.8) 0.97 (0.93-1.01) 0.159 ecog = eastern cooperative oncology group; hr = hazard ratio; ci = confidence interval; sd = standard deviation. ref = reference. "other" in histological type includes adenocarcinoma and mixed carcinoma. archivio italiano di urologia e andrologia 2025; 97(2):13760 5 bladder cancer management in yemen (hr 2.76, p = 0.050), lymph node positivity (hr 2.92, p = 0.022), and squamous cell carcinoma histology (hr 3.09, p = 0.022) remained significantly associated with overall mortality. while ecog performance status and high-grade tumors did not achieve statistical significance in the multivariate model, the aforementioned factors demonstrated a significant independent impact on patient mortality (table 4) (figure 2 a-f). discussion the study provides a comprehensive evaluation of the management and outcomes of mibc in yemen over a period of 16 years. the data collected from patients indicate a median overall survival of 191 months, with 1-year, 3-year, 5-year, and 10-year survival probabilities of 99%, 93%, 88%, and 82%, respectively. additionally, the result identified non-ileal conduit diversion, advanced stages of disease, lymph node positivity, and squamous cell carcinoma histology as significant independent predictors of overall mortality in bladder cancer patients. in contrast to studies in western countries, which have reported 5-year survival rates of 54.5%-68% in bladder cancer patients who underwent radical cystectomy (15, 16), the current study achieved a 5-year survival rate of 88%. this suggests that appropriate patient selection and surgical interventions can lead to comparable outcomes in diverse healthcare settings, despite geographical and infrastructural challenges. in general, findings indicate that rc demonstrates efficacy in controlling local recurrence, evidenced by a five-year dfs rate of 74% (17). conditional survival analysis revealed that a figure 2. kaplan-meier analysis of overall survival probability in yemeni patients undergoing radical cystectomy, stratified by: (a) ecog performance status; (b) urinary diversion type; (c) tumor grade; (d) histological type; (e) pathological stage; (f) lymph node status. table 4. multivariate cox regression analysis of factors associated with overall mortality in muscle-invasive bladder cancer patients undergoing radical cystectomy. variable subgroup hazard ratio (95% ci) p-value ecog performance status 0 ref 1 1.95 (0.79-4.83) 0.148 2 1.75 (0.72-4.26) 0.217 urinary diversion type ileal conduit diversion ref non-ileal conduit diversion 5.21 (1.75-15.47) 0.003 tumor grade low grade ref high grade 0.60 (0.29-1.25) 0.175 pathological stage tis ref i 0.02 (0.00-0.23) 0.001 ii 2.56 (1.01-6.48) 0.047 iii 2.58 (0.95-7.00) 0.062 iv 2.76 (1.00-7.61) 0.050 lymph node status negative ref positive 2.92 (1.17-7.31) 0.022 histological type urothelial carcinoma ref squamous cell carcinoma 3.09 (1.18-8.10) 0.022 other 0.09 (0.03-0.29) < 0.001 ecog = eastern cooperative oncology group; hr = hazard ratio; ci = confidence interval; sd = standard deviation. ref = reference. archivio italiano di urologia e andrologia 2025; 97(2):13760 k. al-kohlany, a. al-maleki, m. al-shami, h. hussein, f. ahmed 6 longer survivorship after surgery leads to an increase in os and csm-free survival probability in patients with mibc. for instance, patients who were alive at 1 year after rc had 70% and 74% 5-year conditional os and csm-free survival rates, respectively, whereas patients who survived 5 years after surgery had 85% and 92% 5year conditional os and csm-free survival rates (18, 19). these findings underscore the importance of optimizing surgical management in mibc to improve patient prognosis in diverse healthcare settings. radical cystectomy remains the gold standard for mibc treatment due to its association with improved survival outcomes (5). however, the results of this study suggest that appropriate surgical interventions can lead to comparable outcomes in diverse healthcare settings, despite geographical and infrastructural challenges. our study conducted in yemen elucidates the significant prevalence of squamous cell carcinoma (scc), which can be attributed to the country's high rates of schistosomiasis. among the cases analyzed, urothelial carcinoma emerged as the most prevalent pathology, accounting for 82.5% of all instances, thereby corroborating findings from global studies that consistently identify urothelial carcinoma as the predominant variant of bladder cancer (9). nonetheless, the 13.5% prevalence of scc within our cohort warrants attention, particularly in the context of research emerging from regions with endemic schistosomiasis, a well-established risk factor for scc. notably, alsamawi et al. (10) reported that 17% of bladder cancer cases in yemen were classified as scc. furthermore, the literature indicates that scc of the bladder is associated with increased aggressiveness and inferior survival outcomes, including diminished progression-free and cancerspecific survival, when compared to the urothelial histological subtype (20-22). furthermore, metastatic scc is observed to respond inadequately to systemic treatments and radiotherapy (22). concordant with previous findings, the scc histopathological subtype in our study was significantly associated with elevated overall mortality. these observations underscore the pressing imperative for the development of targeted screening and management strategies aimed at addressing the distinct risk factors endemic to regions affected by schistosomiasis. while our study demonstrates promising overall and dfs rates, the reported 31.2% post-operative complication rate, including 7 cases of 30-day post-operative mortality, underscores the imperative for enhanced post-operative care and monitoring. this complication rate is consistent with findings from other reports, such as a systematic review by novara et al., which reported a post-rc complication range of 20% to 30% (23). similarly, katsimperis et al. identified gastrointestinal (20%), infections (17%), and ileus (14%) complications as the most frequent, with the majority classified as clavien i-ii (45%) (24). zakaria et al. reported an overall complication rate of 30.6%, encompassing both early and late events, with a 90-day (clavien grade iii-iv) complication rate of 20.9% (25). these elevated complication rates may stem from disparities in healthcare infrastructure, patient management protocols, and adherence to surgical guidelines. addressing these issues through refined surgical techniques, optimized pre-operative patient preparation, and improved post-operative care has the potential to reduce the complication rate in yemeni patients. while numerous studies have investigated the impact of orthotopic neobladder (on) and ileal conduit (ic) diversions on health-related quality of life (hrqol) in bladder cancer patients, the influence of orthotopic neobladder on cancer control remains less defined. a systematic review found no significant difference in quality of life between continent and incontinent urinary diversions. however, orthotopic neobladder may offer hrqol advantages through the preservation of body image (26). in contrast, the impact of orthotopic neobladder on survival outcomes has been less extensively studied. yossepowitch et al. (27) reported improved cancer-specific and overall survival with orthotopic neobladder compared to ileal conduit, though this significance was not maintained after stratification by disease stage (confined vs. non-confined). in contrast to this finding, su et al. observed superior 5-year survival rates with orthotopic neobladder across all and specific t stages (28). after employing propensity score matching to mitigate baseline differences, orthotopic neobladder was identified as a protective factor for overall survival; however, subgroup analysis revealed that this benefit was primarily observed in patients with pathological t2 stage disease (28). consistent with previous research, non-ileal conduit diversion was associated with increased overall mortality in our study. our findings underscore the significance of certain prognostic factors in bladder cancer patients. specifically, advanced tumor stage, lymph node involvement, and squamous cell carcinoma histology emerged as independent predictors of overall mortality. these factors likely contribute to a poorer prognosis through several mechanisms. advanced stage disease often indicates a more extensive local invasion and a higher likelihood of distant metastasis, rendering curative treatment more challenging. moreover, lymph node positivity signifies regional spread of the malignancy, further decreasing the likelihood of successful local control and increasing the risk of systemic dissemination. notably, squamous cell carcinoma is a less common histological subtype of bladder cancer that is frequently associated with more aggressive biological behavior and a decreased responsiveness to standard platinum-based chemotherapy regimens, contributing to its association with increased mortality. these results align with prior reports (29-32); and further emphasize the critical role of accurate staging, comprehensive pathological assessment, and individualized treatment strategies that consider the unique characteristics of each patient's disease. implications for future care the substantial morbidity associated with mibc, coupled with the challenges identified in this study, highlights the need for a comprehensive cancer management program in yemen. interdisciplinary collaboration among urologists, medical oncologists, and primary care providers is essential to optimize treatment pathways and improve patient outcomes. furthermore, enhanced public health education focusing on early detection and timely intervention may significantly improve survival rates. archivio italiano di urologia e andrologia 2025; 97(2):13760 7 bladder cancer management in yemen study limitations this study is subject to several limitations. the singlesurgeon design potentially restricts the generalizability of the findings. the retrospective methodology introduces inherent selection bias and the potential for data inconsistencies. the relatively small sample size limits statistical power and the feasibility of conducting robust subgroup analyses. variability in follow-up duration may impact the assessment of long-term outcomes. the absence of standardized treatment protocols could contribute to variability in post-operative results, while reliance on clinical documentation for complication reporting may lead to underreporting. finally, the lack of comparative data from other institutions and the absence of several factors that may affect survival, such as chemotherapy, limits the contextualization of these findings within the broader landscape of bladder cancer management. future multi-center, randomized controlled trials incorporating diverse treatment protocols are recommended to address these limitations and further refine our understanding of mibc management in this context. conclusions this study highlights the urgent need for improved bladder cancer care in yemen. late-stage diagnosis and suboptimal surgical methods critically affect survival. addressing these issues requires prioritizing early detection and standardized surgical techniques to develop effective care pathways for mibc patients. references 1. al saidi i, mohamedabugroon a, sawalha a, sultan i. epidemiology of bladder cancer in the arab world: 2019 global burden of disease data. asian pac j cancer prev. 2022; 23:2907-19. 2. ibrahim a, el baldi m, mohammed s, et al. cancer statistics in yemen: incidence and mortality, in 2020. bmc public health. 2024; 24:962. 3. ariafar a, zeighami s, salehipour m, ahmed f, et al. an investigation of the pathology report of bladder cancer patients with radical cystectomy in southern iran, 2013-2018: a cross-sectional study. med j islam repub iran. 2021; 35:176. 4. gómez caamaño a, garcía vicente am, maroto p, et al. management of localized muscle-invasive bladder cancer from a multidisciplinary perspective: current position of the spanish oncology genitourinary (sogug) working group. curr oncol. 2021; 28:5084-100. 5. yafi fa, kassouf w. radical cystectomy is the treatment of choice for invasive bladder cancer. can urol assoc j. 2009; 3:409-12. 6. abdel-rahman o. bladder cancer mortality after a diagnosis of nonmuscle-invasive bladder carcinoma. future oncol. 2019; 15:2267-75. 7. aglamis e, toktas g, unluer e, et al. prognostic factors in radical cystectomy affecting survival. arch med sci. 2012; 8:650-4. 8. kim h, kim m, kwak c, et al. prognostic significance of lymphovascular invasion in radical cystectomy on patients with bladder cancer: a systematic review and meta-analysis. plos one. 2014; 9:e89259. 9. dobruch j, oszczudłowski m. bladder cancer: current challenges and future directions. medicina (kaunas). 2021; 57:749. 10. al-samawi as, aulaqi sm. urinary bladder cancer in yemen. oman med j. 2013; 28:337-40. 11. abbas nf, aoude mr, kourie hr, al-shamsi ho. uncovering the epidemiology of bladder cancer in the arab world: a review of risk factors, molecular mechanisms, and clinical features. asian j urol. 2024; 11:406-22. 12. o'sullivan b, brierley j, byrd d, et al. the tnm classification of malignant tumours-towards common understanding and reasonable expectations. lancet oncol. 2017; 18:849-51. 13. epstein ji, amin mb, reuter vr, mostofi fk. the world health organization/international society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. bladder consensus conference committee. am j surg pathol. 1998; 22:1435-48. 14. inoue t, kato m, sasaki t, et al. postoperative complications and determinant of selecting non intracorporeal urinary diversion in patients undergoing robot-assisted radical cystectomy: an initial experience. transl cancer res. 2024; 13:46-56. 15. zhang zl, dong p, li yh, et al. radical cystectomy for bladder cancer: oncologic outcome in 271 chinese patients. chin j cancer. 2014; 33:165-71. 16. nieuwenhuijzen ja, pos f, moonen lm, et al. survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience. eur urol. 2005; 48:239-45. 17. manoharan m, ayyathurai r, soloway ms. radical cystectomy for urothelial carcinoma of the bladder: an analysis of perioperative and survival outcome. bju int. 2009; 104:1227-32. 18. ploussard g, shariat sf, dragomir a, et al. conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. eur urol. 2014; 66:361-70. 19. kang m, kim hs, jeong cw, et al. prognostic factors for conditional survival in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy. sci rep. 2015; 5:12171. declarations ethical approval: the study was conducted in accordance with the declaration of helsinki and received ethical approval from the ethics research committees of the general military hospital, sana'a, yemen, with id: 0015, on april 15, 2024. due to the retrospective nature of the study, the ethics committee did not require patient consent for chart review, and all data were encrypted and kept anonymous. availability of data and material: all the data was included in this study. competing interests: the author declares no potential conflict of interest. funding: none. authors' contributions: all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13760 k. al-kohlany, a. al-maleki, m. al-shami, h. hussein, f. ahmed 8 20. banek s, hoeh b, cano garcia c, et al. metastatic squamous cell carcinoma of the urinary bladder: urgent call for new therapies. urol int. 2024; 108:1-8. 21. sefik e, celik s, basmaci i, et al. effect of variant histology presence and squamous differentiation on oncological results and patient's survival after radical cystectomy. arch ital urol androl. 2018; 90:172-5. 22. pereira jn, reis jd, braga i, et al. variant histologies of urothelial carcinoma: does it change the survival outcomes in patients managed with radical cystectomy? arch ital urol androl. 2022; 94:138-43. 23. novara g, de marco v, aragona m, et al. complications and mortality after radical cystectomy for bladder transitional cell cancer. j urol. 2009; 182:914-21. 24. katsimperis s, tzelves l, tandogdu z, et al. complications after radical cystectomy: a systematic review and meta-analysis of randomized controlled trials with a meta-regression analysis. eur urol focus. 2023; 9:920-9. 25. zakaria as, santos f, dragomir a, et al. postoperative mortality and complications after radical cystectomy for bladder cancer in quebec: a population-based analysis during the years 2000-2009. can urol assoc j. 2014; 8:259-67. 26. yang ls, shan bl, shan ll, et al. a systematic review and metaanalysis of quality of life outcomes after radical cystectomy for bladder cancer. surg oncol. 2016; 25:281-97. 27. yossepowitch o, dalbagni g, golijanin d, et al. orthotopic urinary diversion after cystectomy for bladder cancer: implications for cancer control and patterns of disease recurrence. j urol. 2003; 169:177-81. 28. su x, wu k, wang s, et al. the impact of orthotopic neobladder vs ileal conduit urinary diversion after cystectomy on the survival outcomes in patients with bladder cancer: a propensity score matched analysis. cancer med. 2020; 9:7590-600. 29. zhang l, wu b, zha z, et al. clinicopathological factors in bladder cancer for cancer-specific survival outcomes following radical cystectomy: a systematic review and meta-analysis. bmc cancer. 2019; 19:716. 30. martin jw, vernez sl, lotan y, et al. pathological characteristics and prognostic indicators of different histopathological types of urinary bladder cancer following radical cystectomy in a large singlecenter egyptian cohort. world j urol. 2018; 36:1835-43. 31. wang sd, ge cg, zhang jy. incidence, prognostic factors and survival in bladder cancer patients: a population-based study. transl cancer res. 2022; 11:2742-56. 32. chen c, hu l, chen y, hou j. the prognostic value of histological subtype in patients with metastatic bladder cancer. oncotarget. 2017; 8:28408-17. correspondence khaled al-kohlany kalkohlani@gmail.com majdi al-shami majedialshami@gmail.com department of urology, general military hospital, sana'a, yemen amal al-maleki majdi.alshami@yahoo.com department of obstetrics and gynecology, palestine hospital for motherhood and childhood, sana'a, yemen hani hussein drhani01@gmail.com department of urology, 22 may typical specialized surgical center, sana'a, yemen faisal ahmed (corresponding author) fmaaa2006@yahoo.com department of urology, school of medicine, ibb university, ibb, yemen stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12623 1 original paper a separate condition, defining chronic primary pain as any pain without a clear cause (2). an estimated 4% to 16% of women worldwide (3, 4) are thought to experience chronic pelvic pain in their lives, which is also known as persistent noncancer pelvic discomfort. this condition frequently results in discomfort during sex (dyspareunia), orgasmic dysfunction, and decreased desire, arousal, and lubrication in addition to producing pain in or perceived to be in the pelvic tissues (5). pelvic discomfort and symptoms of the lower urinary tract are the two main clinical hallmarks of chronic pelvic pain syndrome (cpps). different aspects of the cpp have been investigated through the years. according to scientific research in the literature, compared to women without chronic pelvic pain, women with chronic pelvic pain exhibited increased pelvic floor muscular tone, stronger resistance to pressure application, and slower stretching of the pelvic floor muscles by the index finger (6, 7). additionally, they demonstrated lower pelvic floor muscular flexibility and increased pelvic floor muscle stiffness. finally, electromyography (emg) analysis revealed that the women with persistent pelvic discomfort had increased myoelectrical activity in both the superficial and deep pelvic floor muscles (6, 8). although there are many theories on the aetiology of myofascial pain, none of them have been proven in the literature. according to one idea, metabolic alterations at the level of the motor endplate that result in muscular hyperactivity or microscopic muscle injury are the source of myofascial pain (9, 10). additionally, it has been postulated that myofascial pain involves alterations in the central nervous system, such as glial cell proliferation and neuronal cell death, which could account for the referred pain patterns observed in myofascial pain pathologies (9, 11). finally, it has been proposed that the persistent muscle spasm and contraction associated with myofascial pain represents a compensating strategy for pelvic floor dysfunction or defects in the design of the levator ani muscle (9, 10). background: the increased hypertonicity or activity of pelvic floor muscles can lead to chronic pelvic pain (cpp). it represents an aspecific and persistent pain with no apparent clinical reason, affecting an estimated 6% to 16% of women worldwide. this study aimed to evaluate with validated questionnaires the efficacy and the safeness of a new device that uses top flat magnetic stimulation for the management of muscular hypertonia in women with ccp. methods: all patients underwent 8 sessions of treatment with a non-invasive electromagnetic therapeutic device. the device produces a top flat magnetic stimulation with a uniform profile so, the muscle work aims to reduce pain while also inhibiting muscle activity. the pisq-12 questionnaire was used for the evaluation of improvements. side effects were monitored. results: the pisq-12 total mean score decreases from 29.2 (± 3.3) to 17 (± 2). regarding the behavioural-emotive items (1-4), a decrease from 12 (± 2) to 7 (± 0.9) was observed. physical items (5-9) decrease from 10.6 (± 1.8) to 6 (± 1.4) and the partner related items (10-12) from 6.6 (± 1.6) to 3.9 (± 0.4). conclusions: the device we used in this research demonstrated to be a valid tool for the treatment of chronic pelvic pain in female patients. key words: electromagnetic stimulation; pelvic floor hypertonia; chronic pelvic pain; women. submitted 30 april 2024; accepted 5 may 2024 introduction the increased hypertonicity or activity of pelvic floor muscles can lead to chronic pelvic pain (cpp) or myofascial syndrome when the type of pelvic floor dysfunction called pelvic floor tension myalgia (pftm) occurs (1). cpp management is a tremendous concern for healthcare professionals and a significant financial burden for healthcare systems because it represents an aspecific and persistent pain with no apparent clinical reason. the world health organisation (who) has lately recognised chronic pain as electromagnetic stimulation to reduce the hypertonia of the pelvic floor muscles and improve chronic pelvic pain in women nicola mondaini 1, mauro gacci 2, tommaso cai 3, francesco lotti 4, vincenzo li marzi 2, fabio crocerossa 1, francesco cantiello 1, sara tanguenza 5, alessandra comito 6, irene fusco 6, beatrice marina pennati 6, rocco damiano 1 1 department of urology, magna graecia university of catanzaro, catanzaro, italy; 2 department of minimally invasive and robotic urologic surgery and kidney transplantation, university of florence, florence, italy; 3 department of urology, santa chiara regional hospital, trento, italy; 4 sexual medicine and andrology unit, department of experimental and clinical biomedical sciences, university of florence, florence, italy; 5 pelvic pain centre, florence, italy; 6 el.en. group, 50041 calenzano, italy. doi: 10.4081/aiua.2024.12623 summary archivio italiano di urologia e andrologia 2024; 96(3):12623 n. mondaini, m. gacci, t. cai, et al. 2 myofascial pain is the most common symptom in patients with cpp and it can be the primary source of pain, unrelated to organ disease, or it can be a secondary source of pain elicited by a reflex response (visceral-muscle reflex) (3). trigger points often develop in the affected muscles. trigger points are specific areas of tenderness that develop in the muscle wall and can begin as just a symptom of pelvic pain, or they can be the main source of the pain. for this reason, treating trigger points can significantly reduce pain. in addition, it has been noted that it is a very common finding that the origin of the pain area was previously affected by gynaecological (ovarian cysts, endometriosis, dyspareunia, vulvodynia, recurrent candidiasis), or urological (interstitial cystitis/painful bladder syndrome, urgency/frequency, urge incontinence), or colorectal (constipation, proctalgia fugax, irritable bowel syndrome), or tissue adherence (scarring following surgery) disorders, or other musculoskeletal or neural (pudendal neuralgia, coccygodynia, post-surgical or postnatal pelvic pain) conditions (12). however, there is currently no standardized and reliable technique for evaluating myofascial pain. an evidencebased physical examination for myofascial pain is required considering the mounting evidence linking myofascial pain to chronic pelvic pain syndromes and new information pointing to a connection between subclinical myofascial pain and lower urinary tract symptoms (luts). in addition, although some aspects of the pelvic floor myofascial evaluation may be the same in men and women, the method used to access these muscles differs, hence for the purposes of this research study, we chose to concentrate on examination techniques in women (13, 14). there are numerous treatment methods for managing pftm and cpp, including pharmaceutical (analgesics and muscle relaxants) and non-pharmacological therapies. between these, there are high-voltage electro-galvanic stimulation (hvgs), transcutaneous electrical nerve stimulation (tens) devices, ultrasound, short wave diathermy, massages, posture training and strengthening exercises, biofeedback, botulin toxin injections, hydrotherapy, and sitz baths seem to be the most effective treatments. nevertheless, some women do not react to conventional treatments such as medical/pharmacological management, physical therapy methods or surgery (15, 16). it is important to remember that all these levels of pain should be treated together with a multidisciplinary therapy approach to be effective. the treatment can therefore include, in addition to the rehabilitation treatment with a midwife, also a psychological, and medical consultation and/or the use of supplements or drugs. it may happen that it is not possible to completely solve the pain. an effective treatment means that the pain has decreased to a level where you can once again enjoy your life and the activities you did before the pain began (17, 18). in this study, we explored the effectiveness of extracorporeal top flat magnetic stimulation (fms) for improving chronic pelvic pain conditions. after its approval by the fda in 1998, fms is now mostly used for the treatment of urge urinary incontinence (uui). it is a viable option with the significant advantage of letting patients remain comfortable in their clothes throughout a procedure. depending on the protocol, the fms technology allows the improvement of muscle mass by neuromuscular stimulation since it depolarizes motor neurons, inducing large and deep muscle contractions. on the other hand, it can help in the treatment of muscular hypertonia inducing fibres relaxation while maintaining a uniform profile and preventing any areas of irregular stimulation intensity (19). moreover, because magnetic stimulation has no impact on cutaneous receptors, the discomfort associated with electrostimulation is also avoided. this study aimed to evaluate with validated questionnaires the efficacy and the safeness of a new device that uses top flat magnetic stimulation for the management of muscular hypertonia in women with ccp. materials and methods a retrospective evaluation study was conducted at the pelvic pain centre, florence, italy between january, and september 2023. study population patients presenting secondary chronic pelvic pain due to cystitis, endometriosis or vulvodynia, and non-responders to the current available pharmacological or physical solutions, were considered in this study. to make a precise diagnosis of chronic pelvic pain, we have ruled out all other pathologies that might be causing the same kind of excruciating symptoms. these conditions included menopause, pelvic organ prolapses, genital infections, menstruation, malignant tumours, severe neurological diseases, pregnancy, obesity, and those who had metal implants or pacemakers. patients with hypertonicity of the pelvic floor and persistent pelvic discomfort met the inclusion criteria. an experienced gynaecologist manually evaluated the pelvic floor muscles in all patients to diagnose hypertonic pelvic floor (19). also, any previous gynaecological surgery was considered as an exclusion criterion for enrolment in the investigation. lastly, patients were asked to avoid any other pharmacological (also painkillers) and non-pharmacological medications from 15 days before the study began and for the whole duration of the study. other contraindications include the presence of cardiac pacemakers, implanted defibrillators/ table 1. baseline characteristics of the study participants (n = 40). no characteristics frequency (n) proportion (%) 1 age (mean ± sd) (years) 34.7 ± 8.1 18-30 12 30 31-50 28 60 2 marital status married 33 82.5 single 7 17.5 3 education level primary 9 22,5 higher education 31 77.5 4 past medical/surgical history yes 34 85 no 6 15 5 family history of pelvic inflammatory disease (pid) yes 18 45 no 22 55 archivio italiano di urologia e andrologia 2024; 96(3):12623 3 electromagnetic stimulation to reduce the hypertonia of the pelvic floor muscles and improve chronic pelvic pain in women neurostimulators, electronic or metal implants, bleeding conditions, cardiac diseases, pulmonary deficiency, malignant cancerous lesions, pregnancy, severe inflammatory conditions, fever and weight over 160 kilograms. study device for this study, was used a non-invasive electromagnetic therapeutic device (dr arnold, deka m.e.l.a. calenzano, italy) with a chair applicator and a main unit. the chair has a coil in the centre of the seat to target the deep pelvic floor area. before each session, a gynaecologist set the patient's position to guarantee the best result. the patient's legs are set up perpendicularly so that the thighs are parallel to the floor and the feet are flat. patients should bend their knees to a 90-degree angle or slightly higher. this way, the perineum of the patient is perfectly aligned with the centre of the seat, and the local stimulation of the sphincter muscles and pelvic floor is at maximum. the device produces a top flat magnetic stimulation electromagnetic field with a uniform profile. the magnetic fields transmit current directly to the muscle tissue in-, contracting or relaxing it. the electromagnetic stimulation's spatial profile (figure 1) distinguishes dr arnold from other devices. it covers a larger area, is uniformly dispersed. because of this configuration, electromagnetic radiation can be distributed deeply, symmetrically, and uniformly, reaching deep neural areas inside the pelvis without dispersing superficially. study protocols procedure protocols for reducing hypertonicity with lowfrequency stimulations (around 10 hz), were used. a total of 8 treatment sessions for every patient were performed. sessions were held twice weekly for 4 weeks in a row, lasting ca 30 minutes depending on the patient's muscle condition. after the first two minutes of warm-up for all patients, the overtone/pain protocol was chosen (19). the warm-up phase is a gentle muscle activation; it is a preparation step in which blood circulation is increased with low frequencies (about 5 hz). using frequencies of about 10 hz, the overtone/pain protocol produces low-level electric currents on neuromuscular tissue, which depolarizes neurons and causes decontraction of the pelvic floor muscles. so, the muscle work aims to reduce pain (hyperactivity and hypertonia) while also inhibiting muscle activity. data were gathered at the beginning of the study, at the end of each treatment session, and three months later. potential side effects and adverse events such as muscle soreness, momentary muscle spasms, joint/tendon pain, or local erythema/skin redness were monitored throughout the treatment period. validated questionnaires cpp was assessed using the pelvic organ prolapse/urinary incontinence sexual function questionnaire (pisq-12) (20). it is a test of sexual function and a condensed version of the pisq-31 (21). the pisq-12 has three domains: partnerrelated (items 10-12), physical (items 5-9), and behavioural-emotive (items 1-4). lower scores imply enhanced sexual function. scores are calculated by totalling the scores for each question, going from 0-never to 4-always. reverse scoring is used for items 1, 2, 3 and 4 (20). it was administered before the first treatment and right after the last session. moreover, a visual analogue scale (vas) was used to collect information from every patient about the pain intensity perceived before and after the last treatment. the scores ranged from 0 (no pain) to 10 (very painful, not bearable). figure 1. spatial profile of the uniform distribution of flat magnetic stimulation. courtesy of deka m.e.l.a company. archivio italiano di urologia e andrologia 2024; 96(3):12623 n. mondaini, m. gacci, t. cai, et al. 4 statistical analysis the statistical analysis was performed with spss (ibm corp., new york, usa). specifically, the student t-test (p < 0.05 for significance) was conducted (means and ± sds). results in total, 40 women presenting secondary chronic pelvic pain were considered. some general demographic information is reported in table 1. the population median age was 34.7± 8.1 year (from the youngest, 19 years old, to the eldest, 45 years old). the great majority of the subjects were married (82.5%) and with a higher education (77.5%). moreover, most of them have had surgical events in the past. generally, no side effects were observed during the study. when the results of the questionnaires are considered, the pisq-12 total mean score proved to be statistically significant different (p < 0.05) and decreases from 29.2 (± 3.3) to 17 (± 2) at the end of the study. the same statistical significance is found when analysing the single items. regarding the behavioural-emotive items (1-4), a decrease from 12 (± 2) to 7 (± 0.9) was observed. physical items (5-9) decrease from 10.6 (± 1.8) to 6 (± 1.4) and the partner related items (10-12) from 6,6 (± 1.6) to 3.9 (± 0.4) (see table 2 and figure 2). the vas questionnaire scores were collected by every patient at baseline (before the first treatment) and right after the last treatment. the mean score decreased from 8 (± 1.3) to 3 (± 0.6) with statistical significance (p < 0.05) (see table 3 and figure 3). figure 2. graphical representation of the pisq-12 questionnaire: mean results divided by different items (behavioural–emotive (items 1-4), physical (items 5-9), and partner-related (items 10-12) at baseline (pre-first treatment) and after the last treatment. figure 3. graphical representation of the vas questionnaire for the pain intensity evaluation. the mean results preand post-treatment are shown. table 2. pisq-12 questionnaire mean results divided by different items (behavioural-emotive (items 1-4), physical (items 5-9), and partner-related (items 10-12) preand post-treatments. pisq-12 questionnaire baseline post-treatments significance mean (± sd) mean (± sd) total score 29.2 (± 3.3) 17.0 (± 2.0) p < 0.05 behavioural-emotive items (1-4) 12.0 (± 2.0) 7.0 (± 0.9) p < 0.05 physical items (5-9) 10.6 (± 1.8) 6.0 (± 1.4) p < 0.05 partner related items (10-12) 6.6 (± 1.6) 3.9 (± 0.4) p < 0.05 vas questionnaire baseline post-treatments significance mean (± sd) mean (± sd) score 8.0 (± 1.3) 3.0 (± 0.6) p < 0.05 table 3. vas questionnaire mean results at baseline (before the first treatment) and after the last treatment are reported. vas questionnaire baseline post-treatments significance mean (± sd) mean (± sd) score 8.0 (± 1.3) 3.0 (± 0.6) p < 0.05 archivio italiano di urologia e andrologia 2024; 96(3):12623 5 electromagnetic stimulation to reduce the hypertonia of the pelvic floor muscles and improve chronic pelvic pain in women no correlation between the patient’s age and different pisq12 item score results was remarkable (see figure 4). magnetic stimulation appears to be effective in the observed improvement of sexual function and health regardless of patient age as shown by the consistent reduction of the pisq-12 questionnaire scores. discussion in women, when the pelvic floor muscles show an increased hypertonicity or activity, it can lead to cpp. the magnetic stimulation technique deeply interests the muscles of the pelvic floor, restoring neuromuscular control (22). the interaction with the tissue can result in muscle contraction or relaxation, depolarization of neuronal cells, and changes to the blood circulation system. according to the scientific literature (23-27), this technology may have an impact on the sexuality and health of a large patient population. based on the subjective assessment, patients also reported additional therapeutic advantages, such as improved urine control (28-30) and higher sexual satisfaction (31). in fact, the overtone/pain protocol for hypertonic management may use lower frequencies (around 10 hz) to produce an electromagnetic field distribution that is homogeneous and does not produce regions of different stimulation intensity, preventing overstimulation of the already hypersensitive receptors and sensory nerves typical of chronic pelvic pain. because no probe is placed into the vaginal channel during muscle stimulation, the device we employed is considered non-invasive. thanks to the steady emission of energy that is progressively given, patients can continue to be fully clothed in a comfortable and supportive chair and resume their daily activities straight immediately following sessions. the dr arnold system can also be seen as an "educator" system because it enables the patient to sense the relaxation of the treated muscles, allowing them more autonomy and awareness to choose when to repeat the next treatment session. furthermore, the use of this novel technology can be combined with existing pharmacological or physical methods (32). the etiopathology of cpp is not fully understood. indeed, genito-pelvic pain/penetration disorders, vulvodynia, interstitial cystitis/bladder pain syndrome and endometriosis, are just a few of the illnesses that can produce cpp. however, it's possible that women with any of these diseases have identical pelvic floor muscle tone and functionality. studying the correlation between personal and social characteristics such as the marital status or the education level and the presence of cpp, was not matter of this research study. but, according to other investigation in literature, pelvic floor muscle strength (pfms) declines with age and ageing increases the likelihood of incontinence and genital organ prolapses and also cpp development (33, 34). furthermore, a number of studies have demonstrated a strong correlation between pelvic floor diseases and educational attainment [34-36). similar findings were made by gümüssoy et al. (2021) [37), where it was discovered that as women's educational levels rose, so did their pfms values. this finding implies that women's awareness of pfms is raised by education. according to the results of this study, women with lower income levels or without employment had lower pfms values. overholt et al. (2019) (38) described a clinical case providing support to evaluate the efficacy of pulsed electromagnetic field therapy for the management of chronic pelvic pain in interstitial cystitis/bladder pain syndrome. indeed, for urinary incontinence higher frequencies (frefigure 4. graphical representation of the correlation between the patient’s age and different pisq-12 item score results. archivio italiano di urologia e andrologia 2024; 96(3):12623 n. mondaini, m. gacci, t. cai, et al. 6 quencies ≥ 20 hz) are needed to target the muscles and improve muscular tone. in this study, device protocols with a low-frequency (10hz) emission were used. by using the top fms technology, the distribution of the magnetic vibrations is homogeneous in the treated area. indeed, these low frequencies are able to create a homogeneous distribution of the electromagnetic field that does not create regions of different stimulation intensity avoiding an overstimulation/overactivation of the pelvic floor muscles. in this way, no energy-peak can be produced. this is important because, in patients presenting ccp, these energy-peaks can cause opposite outcomes, resulting in the worsening of the pain feeling due to an overactivation of the pelvic floor muscles. with this study we wanted to evaluate with validated questionnaires the efficacy and the safeness of a new device that uses top flat magnetic stimulation for the management of muscular hypertonia in women with ccp. our results indicated that the patient's symptoms of muscular hypertonia and chronic pelvic pain were improved. as support, the pisq-12 questionnaire was used because of its internal consistency, test-retest reliability, and validity. after the final therapy, we have seen a considerable decrease in the pisq12 mean score. when the single items are considered, the trend is comparable. also, results from the vas questionnaires revealed a statistically significant reduction of the patient pain perception after the conclusion of the treatment cycle. no correlation between the patient’s age and different pisq-12 item score results was remarkable probably indicating the wide efficacy of the magnetic stimulation regardless the age of the patient. study limitations our long-term objective is to register additional patients to further examine this novel, non-invasive approach to treating complex illnesses such as chronic pelvic pain without sex distinction. moreover, the number of patients enrolled should be increased and a control group should be included for better completeness. lastly, it would be interesting to evaluate the short-term and long-term improvement of the symptoms following the patients after the conclusion of the treatment cycle. conclusions the device we used in this research demonstrated to be a valid tool for the treatment of chronic pelvic pain in female patients. further studies are needed to have a deeper knowledge about the electromagnetic stimulation activity in reducing the hypertonia of the muscles since it could be the right strategy to improve the quality of life of the patients affected. references 1. grimes wr, stratton m. pelvic floor dysfunction’, in statpearls, treasure island (fl): statpearls publishing, 2023. accessed: dec. 14, 2023. 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sci. 2015; 27:2133-2137. 35. braekken ih, majida m, engh me, bø k. are pelvic floor muscle thickness and size of levator hiatus associated with pelvic floor muscle strength, endurance and vaginal resting pressure in women with pelvic organ prolapse stages i-iii? a cross sectional 3d ultrasound study. neurourol urodyn. 2014; 33:115-120. 36. nygaard i, barber md, burgio kl, et al. prevalence of symptomatic pelvic floor disorders in us women. jama. 2008; 300:13111316. 37. gümüssoy s, öztürk r, kavlak o, et al. investigating pelvic floor muscle strength in women of reproductive age and factors affecting it. clin nurs res. 2021; 30:1047-1058. 38. overholt tl, ross c, evans rj, walker sj. pulsed electromagnetic field therapy as a complementary alternative for chronic pelvic pain management in an interstitial cystitis/bladder pain syndrome patient. case rep urol. 2019; 2019:5767568. correspondence nicola mondaini, md n.mondaini@unicz.it fabio crocerossa, md crocerossa@unicz.it francesco cantiello, md cantiello@unicz.it rocco damiano, md damiano@unicz.it department of urology, magna graecia university of catanzaro, catanzaro, italy mauro gacci, md maurogacci@gmail.com vincenzo li marzi, md vlimarzi@hotmail.com department of minimally invasive and robotic urologic surgery and kidney transplantation, university of florence, florence, italy tommaso cai, md ktommy@libero.it department of urology, santa chiara regional hospital, trento, italy francesco lotti, md francesco.lotti@unifi.it sexual medicine and andrology unit, department of experimental and clinical biomedical sciences, university of florence, florence, italy sara tanguenza, md saratanguenza@gmail.com pelvic pain centre, florence, italy alessandra comito, md a.comito@elen.it irene fusco, md (corresponding author) i.fusco@deka.it beatrice marina pennati, md b.pennati@deka.it el. en. group, 50041 calenzano, italy conflict of interest: bmp, if and ac are employed at el. en. group. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. institutional review board statement: all the authors declare that the procedures followed were in accordance with the declaration of helsinki. informed consent statement: informed consent was obtained from all subjects involved in the study. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 61 original paper inflammatory features common to two pathologies: pd and cp in both diseases, there is a chronic inflammatory process in which pro-inflammatory cytokines and oxygen and nitrogen reactive species (ros/rns) play an important role (6-10). furthermore, there are studies in the literature that have confirmed the therapeutic efficacy of the use of antioxidant substances in both diseases (10-15). we also know that pro-inflammatory cytokines, tumor necrosis factor (tnf), and interleukin 1 and 6 (il-1 and il-6) are present at high levels in the inflammatory process of pd and chronic prostatitis (cp) (6, 7). in both diseases, as well as in other chronic inflammatory diseases, the circulating levels of cytokines are increased; therefore, these can act systemically in other organs, including the nervous system (16-19). it has been ascertained that pro-inflammatory cytokines can determine various effects at this level and particularly by reducing serotonin levels. this mechanism, as is known, is also strongly involved in the development of depression. pro-inflammatory cytokines are also capable of causing an additional pro-depression effect as they cause changes in glucocorticoid function via the hypothalamicpituitary-adrenal axis (20). cytokines are also capable of having effects on the amygdala and hippocampus, which are areas widely involved in stress and anxiety (21, 22). thanks to this knowledge from the literature, we can better understand the causes of anxious-depressive symptoms in patients with pd and cp. pro-inflammatory cytokines are also involved in neurogenic inflammation causing pelvic pain in patients with prostatitis/chronic pelvic pain syndrome (cpps) (22). pelvic pain in cp is therefore the consequence of neurogenic inflammation in the nervous system (central and peripheral). an important signaling molecule implicated in neurogenic inflammation is nerve growth factor neurotrophin (ngf). neurotrophins are proteins that determine the survival, development, and function of neurons. ngf is a signaling molecule that is produced in the case of neuronal suffering, which in our case is caused by inflammation. ngf appears to be induced by il-10, a cytokine that possesses anti-inflammatory activity by inhibiting the synthesis of pro-inflammatory cytokines (23-25). several studies have demonstrated that ngf together with some cytokines (il-6 and il-10) that regulate inflammaobjective: this study aims to investigate a possible relationship between chronic prostatitis (cp) and peyronie's disease (pd) and to characterize the psychological profile of patients suffering from pd, with or without concomitant cp. methods: we included 539 patients with pd, of which 200 were found to have underlying cp. as a comparator population, we selected 2201 patients without pd, referring to our tertiary care clinic. in this population, we detected 384 subjects with cp. all 539 pd patients underwent photographic documentation of the penile deformation, and dynamic penile eco-color doppler with plaque and volume measurements and answered the following questionnaires: the generalized anxiety disorder-7, the patient health questionnaire-9, the visual analog scale for penile pain measurements, the international index of erectile function (iief), and the nih-chronic prostatitis symptom index. results: the overall prevalence of chronic prostatitis in pd patients was 37.1% compared to a prevalence of 17.4% in the non-pd control population (or = 2.79 and p < 0.0001). the severity of cp symptom total scores (nih-cpsi) correlated significantly with the severity of erectile dysfunction (p < 0.0001). significant anxiety was present in 89.2% of pd patients and it is more prevalent in pd patients with cp than in pd patients without cp (93.0% vs. 87.0%, respectively; p = 0.0434). significant depression was detected in 57.1% of pd patients and it is more prevalent in pd patients with cp than in pd patients without cp (64.0% vs. 53.09%, respectively; p = 0.0173). conclusion: chronic prostatitis (cp) and peyronie's disease (pd) are frequently associated. our results demonstrate the strong impact of chronic prostatitis on the mental status of pd patients. anxiety and depression were significantly more pronounced in pd patients with cp than in pd patients without cp. key words: chronic prostatitis; peyronie’s disease; risk factors. submitted 12 april 2023; accepted 11 may 2023 introduction prostatitis is a pathological condition that is often observed in patients with peyronie's disease (pd). this clinical association is often present in specialist outpatient practice and is also described in the literature (15). with this study, we set out to ascertain whether there are common factors between the two pathologies that could justify this relationship. chronic prostatitis as possible risk factor for peyronie's disease: psychological, sexual and prostatitis-like symptoms in patients with pd gianni paulis 1, andrea paulis 2 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy. doi: 10.4081/aiua.2023.11406 summary archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 62 tion can play a role in the pain of patients with cpps; furthermore, ngf directly correlates with pain severity (2325). we also know that il-10 is a known inducer of ngf and a suppressor of il-6 and il-8 expression (23, 25). the association of increased levels of ngf in other inflammatory states (inflammatory bowel disease and arthritis) has also been demonstrated (25). although no studies exist in the literature, it is likely that ngf also plays a role in pd and associated erectile dysfunction, since some studies demonstrate a protective role of this neurotrophin on erectile function (26-28). kalisch et al., in one of their studies, demonstrated that the ngf neurotrophin increases nos activity expression (in all three of its isoforms: nnos, enos, and inos) and nitric oxide (no) production, the principal mediator of penile erection (29). in an experimental study on diabetic rats, the induction of igc (anti-ngf) was detected with related erectile dysfunction caused by a decrease in the tissue level of ngf (neutralizing effect of anti-ngf) (26). it is in fact known that in patients with diabetes mellitus, the incidence of erectile dysfunction is significantly higher than in the general male population. in another experimental study on diabetic rats with erectile dysfunction, the presence of high concentrations of ngf was found in the penis, and the authors hypothesized that the significant presence of ngf, in the presence of erectile nerves that are severely damaged by diabetes, would not be sufficient to compensate for the reproductive needs of nerve fibers (27). another study found elevated concentrations of ngf in urine in patients with type 2 diabetes mellitus and associated erectile dysfunction (28). considering that several pro-inflammatory biological factors and other signaling molecules are present in cp, it may be hypothesized that cp could represent a risk factor for pd. the present study aimed at studying the relationship between a history of cp and pd. the psychological impact of pd, in the presence or absence of concomitant cp, was also investigated in depth. psychological consequences of pd and cp the penile deformation present in patients with pd inevitably determines a significant impact on the psychic sphere of these patients, their quality of life (qol), and their psycho-social relationships. in fact, these patients show depressive symptoms in about 48% of cases (30). in these patients, bowing can frequently lead to a loss of personal body image, lower self-esteem, and a lower ability to achieve satisfactory sexual intercourse; furthermore, sexual performance anxiety with secondary psychogenic erectile dysfunction is often present (31). other possible consequences are as follows: the tendency to lose confidence in their sexual abilities; decreased sex drive or even sexual aversion; concern about further sexual trauma; and curtailing or canceling appointments with prospective sexual partners (32-34). although there is no specific incidence of anxiety symptoms in pd in the literature, some studies report the presence of "emotional difficulties" and "distress" in about 80-81% of cases (34, 35). in our recent study, we found that moderate-to-severe anxiety was present in 89.4% of pd patients (36). chronic prostatitis such as pd is characterized by a strong component of frustration with related anxious-depressive symptoms (21). depression and catastrophizing about pain are often present; in this regard, some authors believe that depression and catastrophism represent a strong factor in the development, prolongation, and perpetuation of prostatic symptoms and, particularly, chronic pelvic pain (37, 38). patients who have more pain tend to amplify it and have more catastrophic thoughts, resulting in a poorer physical qol and a tendency towards depression (39). in their recent study, bai et al. found a higher incidence of depression, anxiety, somatization disorder, and obsessive-compulsive behavior in patients with ed associated with cp/cpps (40). the literature is quite scarce regarding the incidence of anxiety and depression in patients with cp/cpss; however, in the few studies analyzed, the incidence of anxiety symptoms in patients with cp/cpps was found in about 60-90% of cases (41, 42), while with respect to the incidence of depressive symptoms, these were found to be present in approximately 27-90% of cases in patients with cp/cpps (42-44). this study aims to investigate a possible relationship between cp and pd and to characterize the psychological profile of patients suffering from pd, with or without concomitant cp. in the supplementary materials we published an "addendum"" as a deeper insight into the two diseases cp and pd. patients and methods study design we performed a retrospective analysis of the clinical database of a single andrology clinic. from the database, we considered two separate cohorts of patients observed between january 2013 and january 2023. in this study, one cohort included 539 patients diagnosed with pd. as a comparator population, we considered a cohort of 2201 urological patients referred to our clinic for any disease but not pd. among our cohorts of patients, we identified patients with a diagnosis of long-standing cp (cp, category ii chronic bacterial prostatitis or category iii chronic prostatitis/chronic pelvic pain syndrome, nih criteria). all data were obtained from patient records. this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki ; all study subjects were contacted and provided informed consent for the study. sensitive data were anonymized to warrant patients’ privacy according to legislative decree 10 august 2018, n. 101, published in the official gazette of the italian republic, general series, issue 205, 09/04/2018. inclusion criteria the inclusion criteria for both groups were as follows: age between 18 and 75 years and availability of data that report the results of thorough clinical history examination (comprising all diseases, including prostatitis). the diagnosis of pd was made as follows: performing penile palpation for all pd patients and by a (i) photoarchivio italiano di urologia e andrologia 2023; 95, 2 63 chronic prostatitis as possible risk factor for peyronie's disease graphic documentation of the penile deformation (according to kelâmi) with a goniometric measurement of the angulation and evaluation with respect to the possible presence of the multiplanarity of the curvature (29) and a (ii) dynamic penile eco-color doppler ultrasound with plaque measurements and volume calculation (in the three dimensions) using an ellipsoid formula (volume = 0.524 x width x length x thickness) (45, 46). exclusion criteria the exclusion criteria were as follows: – for both groups, pd patients and non-pd patients an age under 18 years and over 75 years; – for the comparison control cohort (2201 non-pd patients) a diagnosis of pd, without excluding all other associated diseases including a possible erectile dysfunction. clinical data patients with pd were asked to complete of the following questionnaires: (i) the visual analog scale (vas) for penile pain measurement, (ii) the international index of erectile function (iief), (iii) the nih-chronic prostatitis symptom index (nih-cpsi), (iv) the generalized anxiety disorder-7 (gad-7, focusing on anxiety), and (v) the patient health questionnaire-9 (phq-9, focusing on depression) (4751). the vas score range varies from 0 (no pain) to 10 (most intolerable pain) (48). the iief score interpretation is as follows: severe ed = from 0 to 10; moderate ed = from 11 to 16; mild-tomoderate ed = from 17 to 21; mild ed = from 22 to 25; no ed, from 26 to 30 (49). the gad-7 score interpretation is as follows: minimal anxiety = 0-4; mild anxiety = 5-9; moderate anxiety = 1014; and severe anxiety = 15-21 (50). we considered the presence of significant anxiety when gad-7 score > 9. the phq-9 score interpretation is as follows: minimal depression = 0-4; mild depression = 5-9; moderate depression = 10-14; moderately severe depression = 1519; and severe depression = 20-27 (51). we considered significant depression when phq-9 score > 9. nih-cpsi is assessed in 3 domains with the following severity levels: pain (from 0 to 21), urinary symptoms (from 0 to 10), and impact on qol (from 0 to 12) (47). chronic prostatitis was diagnosed in patients with prostatitis-like symptoms according to the following examinations: clinical history, thorough physical examination, including the digital rectal exam, prostate ultrasound, and microbiological assessment (preand post-massage urine and sperm cultures). study endpoints the primary endpoint of the study was the association between a diagnosis of cp and the occurrence of pd in a patient population referring to a single tertiary care andrology center. the secondary endpoints are as follows: – the impact of prostatitis on the psychological status of patients and, particularly, on anxiety, which was assessed with the gad-7 test, and depression which was assessed with the phq-9 test; – the impact of prostatitis on the presence and severity of erectile dysfunction; – the impact of prostatitis on the presence and severity of penile pain; – the impact of prostatitis on the severity of penile curvature; – the impact of prostatitis on the pd plaque volume; – the impact of prostatitis on the multiplanarity of penile curvature; – the impact of prostatitis on plaque multifocality; – the impact of prostatitis on plaque calcification. statistical analysis the central tendency and dispersion data for continuous or interval variables were expressed as means and standard deviations (sds) or medians and interquartile ranges (iqrs), respectively. intergroup unpaired comparisons for continuous or interval variables were performed using a 2-tailed t-test (heteroscedastic) or a 2-tailed mann–whitney–wilcoxon (rank-sum) test, respectively. differences between proportions in unpaired groups were analyzed by both a z-test and pearson’s chi-square test. correlations between questionnaire scores were analyzed by non-parametric tests (spearman’s rho and kendall’s tau). analyses were performed in the “r” environment for statistical computing. we planned a post hoc analysis of the statistical power achieved for the crude odds ratio calculation using the g*power 3.1 software (52). a 5% threshold for the alpha error was used to define statistical significance (significant p-value < 0.05). results a table (supplementary materials) summarizes the clinical characteristics of the two groups (pd patients and non-pd control population) and the relative statistical study. cases and controls did not differ in age, and most associated pathologies. however, for some associated diseases such as diabetes mellitus, erectile dysfunction, hypertension, benign prostatic hyperplasia (bph), and cp, there was a statistically significant difference between the two groups. prevalence of cp in pd patients from our general patient database, we extracted a cohort of 539 pd patients, with a mean age of 49.68 years (± 12.16 sd), that met our inclusion criteria. within this cohort, 200 patients (37.1%) were diagnosed with cp. the median total score of the nih-cpsi test in this cohort was 9 (iqr = 10). the cohort of urological patients without pd meeting our inclusion criteria consisted of 2201 subjects, with a mean age of 50.53 years (± 12.04 sd), of which 384 (17.4%) were diagnosed with cp. the statistical comparison between the mean age of the two patient cohorts (unpaired t test) was not significant (p value = 0.1088). the difference between the proportions of cp patients in the two cohorts is statistically significant (p < 0.0002, two-tailed z-test: p < 0.0001 and two-tailed chi-square test; chi-square = 98.6). we generated a contingency archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 64 table comparing the presence/absence of a history of prostatitis in patients diagnosed or not with pd. the resulting significant crude odds ratio (or) for prostatitis was 2.79 (95% ci, 2.27 to 3.43, p < 0.0001) (see table 1). the post hoc analysis showed an achieved power equal to 0.99 for the magnitude of effect (odds ratio) and 95% ci. assessment of prostatitis symptoms (nih-cpsi test) in pd patients with or without pc median nih-cpsi scores were significantly higher in pd patients with cp (n = 200) (median nih-cpsi = 9, iqr = 10) compared to pd patients without cp (n = 339) (median nih-cpsi = 2, iqr=2; p = < 0.0001, two-tailed mann-whitney-wilcoxon test). psychological profiling of pd patients with or without cp all included pd patients completed the generalized anxiety disorder-7 questionnaire. median anxiety scores of gad-7 in patients with or without cp were identical and not significantly different at the statistical level (cp = 14, iqr = 7; no-cp = 14, iqr = 7, p = 0.21, two-tailed mann-whitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test correlated positively and significantly with gad-7 anxiety scores (spearman’s rho, 0.21, p = 0.0031; kendall’s tau, 0.163, p = 0.018). phq-9 depression scores were significantly higher in cp patients (median = 14; iqr = 4) compared to patients without cp (median = 12.5; iqr = 4, p = 0.0017, twotailed mann-whitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test did not significantly correlate with phq-9 depression scores (spearman’s rho, 0.072, p = 0.309; kendall’s tau, 0.054, p = 0.28). table 2 summarizes data of gad-7, phq-9, nih-cpsi, and iief in pd patients with and without prostatitis. erectile dysfunction in pd patients with or without cp we evaluated the median scores of the iief test in pd patients with erectile dysfunction with or without prostatitis. in these patients, erectile dysfunction developed concomitantly with pd. median iief scores were not significantly different in pd patients with (median iief = 23, iqr = 4.5) or without cp (median iief = 23, iqr = 5; p = 0.98, two-tailed mannwhitney-wilcoxon test). however, the severity of total cp symptom scores assessed with the nih-cpsi test correlated significantly and inversely with iief scores (spearman’s rho, -0.9, p < 0.0001; kendall’s tau, -0.77, p < 0.0001). penile pain assessments in pd patients with or without cp we evaluated the median vas scores in pd patients with penile pain with or without prostatitis. median vas scores were not significantly different in patients with (median vas = 2, iqr = 5) or without cp (median vas = 1, iqr = 4; p = 0.784, two-tailed mannwhitney-wilcoxon test) (see table 2). severity of the penile curve and fibrotic plaque in pd patients with or without cp patients with prostatitis showed a less pronounced penile curve (29 ± 34 degrees) compared with patients without cp (34 ± 21 degrees, p = 0.0066, two-tailed t-test). no significant differences were found between the mean volumes of fibrotic plaques in pd patients with (809.6 ± 563.9 mm^3) or without cp (mean = 908.4 ± 618.6 mm^3; p = 0.063, twotailed t-test). characteristics of pd in patients with or without cp table 3 summarizes the findings relative to plaque calcification and plurifocal lesions and relative to curve complexity (multiplanar curve deformity). no significant differences were found in any of the considered findings between patients with or without cp. psychological profile (anxiety and depression) of pd patients the results showing the psychological profile (anxiety and depression) of pd table 1. prevalence of cp in pd patients compared to the non-pd control population. cohort of patients with non-pd control statistical analysis peyronie's disease (pd) population odds ratio (or) p value chronic prostatitis (cp) 200 384 no chronic prostatitis (cp) 339 1817 total 539 2201 prevalence of cp (%) 37.1 17.4 or = 2.79 p < 0.0001 table 2. summary of data of gad-7, phq-9, nih-cpsi, iief and vas in pd patients with and without chronic prostatitis. questionnaire score pd patients with prostatitis (cp) pd patients without prostatitis (cp) mann-whitney test (n cases = 200) (n cases = 339) median score median score p value nih-cpsi 9 2 < 0.0001 iief 23 23 0.98 gad-7 14 14 0.21 phq-9 14 12.5 0.0017 vas 2 1 0.784 nih-cpsi = national institutes of health chronic prostatitis symptom index is assessed in 3 domains with the following severity levels: pain (from 0 to 21), urinary symptoms (from 0 to 10), and impact on quality of life (qol) (from 0 to 12) (47). iief = international index of erectile function (iief) questionnaire, score range = 0-30. interpretation: severe erectile dyisfunction (ed) = from 0 to 10; moderate ed = from 11 to 16; mild-to-moderate ed = from 17 to 21; mild ed = from 22 to 25; no ed, from 26 to 30 (49). gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). vas = visual analog scale questionnaire for pain measurement. score range = 0-10. interpretation: 1-5, mild–moderate pain; 6-7, severe pain; 8-10, very severe pain (48). archivio italiano di urologia e andrologia 2023; 95, 2 65 chronic prostatitis as possible risk factor for peyronie's disease patients are illustrated in table 4. notably, “significant anxiety” is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (93.0% vs. 89.2%, respectively). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (43.5% vs. 39.3%, respectively) (see table 5). it should be also noted that “significant depression” is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (64.0% vs. 57.1%, respectively). we also found that severe depression is more prevalent in pd patients showing the concomitant presence of cp compared to patients with pd alone (6.5% vs. 4.6%, respectively) (see table 5). discussion the scientific literature is rich in studies that have demonstrated the presence of numerous risk factors able to favor the onset of pd. these studies include the following risk factors: penile trauma, erectile dysfunction, congenital penile curvature, dupuytren's disease, diabetes mellitus, dyslipidemia, obesity, hypertension, smoking, alcohol consumption, rheumatoid arthritis, psoriasis, and psoriatic arthritis (36, 53-58). this is the first study that specifically investigates the association between pd and cp. our results show that the overall prevalence of cp in patients with pd was significantly higher (37.1%) compared to the prevalence in a non-pd control population (17.4%). our data suggest that cp and pd are frequently associated. another study on this topic identified pd as a risk factor for prostatitis (3). in our study, median iief scores were not significantly different in pd patients with or without cp although the severity of cp symptom total scores (nih-cpsi) correlated significantly with the severity of erectile dysfunction (p < 0.0001). some studies published in the literature have already argued or demonstrated the correlation between prostatic symptoms and erectile dysfunction (59-65). in our study, median vas scores were not significantly different in pd patients with or without cp. furthermore, the presence of cp in patients with pd does not affect the following: severity of penile curvature, complexity of penile curvature (multiplanarity), penile plaque volume, plaque plurifocality, and plaque calcification presence. in their study, smith and colleagues reported that 81% of pd patients suffered from "emotional difficulties" (35). our results revealed that “significant anxiety” was present in 89.2% of pd patients. furthermore, our study found that “significant anxiety” is more prevalent in pd patients showing the concomitant table 3. summary of findings related to plaque calcification and multifocal lesions and curve complexity (multiplanar curve deformity). prostatitis (n = 200) no prostatitis (n = 339) p, fisher’s exact test p, pearson’s chi-square no. of patients with a complex (multiplanar) curve 62 (31%) 105 (31%) 0.99 0.99 number of patients with multifocal plaque 46 (23%) 58 (17%) 0.11 0.094 number of patients with calcifications 61 (30.5%) 81 (24%) 0.105 0.092 table 4. psychological profile of 539 patients with peyronie’s disease. psychological questionnaire mental state n. cases prevalence (%) mean test score gad-7 minimal anxiety 6 1.1 2.5 mild anxiety 52 9.6 6.7 moderate anxiety 269 49.9 13.06 severe anxiety 212 39.3 19.7 “significant anxiety” 481 89.2 15.9 total 539 14.9 phq-9 minimal depression 62 11.5 3.3 mild depression 169 31.3 7.08 moderate depression 194 35.9 12.1 moderately severe depression 89 16.5 16.6 severe depression 25 4.6 21.64 “significant depression” 308 57.1 14.19 total 539 10.7 gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). table 5. psychological profile of pd patients with or without chronic prostatitis (pc). psychological mental state pd patients with cp pd patients without cp statistical analysis questionnaire n. cases out 200 cases n. cases out 339 cases p-value (χ2 test ) prevalence (%) prevalence (%) gad-7 “significant anxiety” 186 (93.0) 295 (87.0) 0.0434 severe anxiety 87 (43.5) 125 (36.8) 0.1526 phq-9 “significant depression” 128 (64.0) 180 (53.09) 0.0173 severe depression 13 (6.5) 25 (7.3) 0.8344 cp = chronic prostatitis. gad-7 = generalized anxiety disorder-7 questionnaire, score range = 0-21. interpretation: 0-4, minimal anxiety; 5-9, mild anxiety; 10-14, moderate anxiety; 15-21, severe anxiety. “significant anxiety” (moderate-to-severe anxiety) when gad-7 score > 9 (50). phq-9 = patient health questionnaire-9, score range = 0-27. interpretation: 1-4, minimal depression; 5-9, mild depression; 10-14, moderate depression; 15-19, moderately severe depression; 20-27, severe depression. “significant depression” (moderate to severe depression) when phq-9 score > 9 (51). archivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 66 presence of cp compared to pd alone (93% vs. 89.2%, respectively). we also found that severe anxiety is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (43.5% vs. 39.3%, respectively). our findings show that prostatitis symptomatology affects pd patients' anxiety status; in fact, the severity of total cp symptom scores, assessed with the nih-cpsi test, correlates positively and significantly with gad-7 anxiety scores (p < 0.05). these results demonstrate the strong impact of cp on the anxiety state of pd patients. nelson and coworkers, in their study about depression in men with pd, demonstrated that 48% of patients show clinically meaningful depression (30). in our study “significant depression” was reported in a higher fraction of patients (57.1%). furthermore, our study found that “significant depression” is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (64.0% vs. 57.1%, respectively). we also found that severe depression is more prevalent in pd patients showing the concomitant presence of cp compared to pd alone (6.5% vs. 4.6%, respectively). overall, our results demonstrate the strong impact of pd and cp on the mental status of patients. conclusions chronic prostatitis (cp) and pd are frequently associated. although the present study has the limitations of a retrospective analysis performed on a patient database, the size of the odds ratio (= 2.79), and its statistical significance (p < 0.0001) support the relative certitude of our results. patients with pd and cp showed a significantly higher prevalence of more severe depression and anxiety. in urological and andrological clinical practice, the involvement of psychologists is desirable in order to provide the patient with psychological support treatment and to mitigate the psychological impact of these two physically and psychologically devastating diseases (pd and cp). our study suggests that patients with pd and/or cp should always be studied by administering specific 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disease: prevalence and association with cigarette smoking. a multicenter population-based study in men aged 50-69 years. eur urol. 2001; 40:525-530. 56. tal r, heck m, teloken p, et al. peyronie's disease following radical prostatectomy: incidence and predictors. j sex med. 2010; 7:1254-1261. 57. el-sakka ai. prevalence of peyronie's disease among patients with erectile dysfunction. eur urol. 2006; 49:564-569. 58. ventimiglia e, capogrosso p, colicchia m, et al. peyronie's disarchivio italiano di urologia e andrologia 2023; 95, 2 g. paulis, a. paulis 68 ease and autoimmunity—a real-life clinical study and comprehensive review. j sex med. 2015; 12:1062-1069. 59. brookes st, link cl, donovan jl, mckinlay jb. relationship between lower urinary tract symptoms and erectile dysfunction: results from the boston area community health survey. j urol. 2008; 179:250-255. 60. magri v, perletti g, montanari e, et al. chronic prostatitis and erectile dysfunction: results from a cross-sectional study. arch ital urol androl. 2008; 80:172-1755. 61. hao zy, li hj, wang zp, et al. the prevalence of erectile dysfunction and its relation to chronic prostatitis in chinese men. j androl. 2011; 32:496-501. 62. shoskes da. the challenge of erectile dysfunction in the man with chronic prostatitis/chronic pelvic pain syndrome. curr urol rep. 2012; 13:263-267. 63. zhang z, li z, yu q, et al. the prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction in chinese men. andrology. 2015; 3:1119-1124. 64. zhang y, zheng t, tu x, et al. erectile dysfunction in chronic prostatitis/chronic pelvic pain syndrome: outcomes from a multicenter study and risk factor analysis in a single center. plos one. 2016; 11:e0153054. 65. magri v, boltri m, cai t, et al. multidisciplinary approach to prostatitis. arch ital urol androl. 2019; 90:227-248. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis, md andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13277 1 review the elimination half-life of theobromine is between 6 and 8 hours. the primary metabolites of theobromine are 3-methylxantine, 7-methylxantine, 7-methyluric acid and 3,7-dimethyluric acid, with 18-21% of theobromine excreted unchanged in the urine (3-5). theobromine also derives from caffeine that is metabolized in the liver into paraxanthine (84%), theobromine (12%), and theophylline (4%). for this reason, individuals that non ingest theobromine (or chocolate) could have low, though detectable, urinary levels of theobromine (6, 7). theobromine has stimulating action on the central nervous system by intervening on the synapses, but this effect is weaker than caffeine (8). it has negligible toxicity in humans, because it is metabolized very quickly. in other mammals, such as dogs and cats, it becomes toxic because they metabolize theobromine very slowly. the symptoms of intoxication are excitation, lowered heart rate, convulsions and in the most serious cases death (9). theobromine has several various pharmacological applications including cough suppression, increase of plasma hdl cholesterol and decrease of plasma ldl cholesterol, protection of enamel surface (10-13). a derivative of theobromine, 7-methylxanthine, has been used for the treatment of myopia (14). theobromine should be administered as extract of cocoa beans rather than chocolate that contains large amounts of sugar and oxalate, that should be avoided in subjects with diabetes type 2 or metabolic syndrome and calcium oxalate renal stone formers. treatment and prevention of uric acid stones uric acid urinary stones account for about 10% of all the urinary stones although it is predictable an increase of their prevalence because of demographic and climate changes (15, 16). uric acid stones form by crystallization of urinary uric acid when its concentration is above the threshold of solubility which depends on ph. it ranges from 110 mg/l for urinary ph below 5.0 to 250 mg/l for ph 5.5 and up to 600 mg for a ph over 6.0. urinary saturation for uric acid depends on urinary ph and urinary uric acid concentration (17-19). when urine is supersaturated with respect to uric acid, crystal formation is possible, although above this threshold there is an interval of saturation values at which the solution is theobromine (or 3,7-dimethylxanthine) is a natural alkaloid present in cocoa plant and its derivatives, such as chocolate. about 20% of ingested theobromine is excreted unchanged in the urine. theobromine also derived from caffeine that is metabolized into theobromine by 12%. the primary metabolites of theobromine are 3-methylxantine, 7-methylxantine, 7-methyluric acid and 3,7-dimethyluric acid. theobromine has an inhibitory activity of uric acid crystallization, because it has a structural pattern very similar to uric acid and can substitute uric acid molecules in the corresponding uric acid crystals, making them longer and thinner and decreasing their growth rate. theobromine also favors the dissolution of crystals by decreasing supersaturation of uric acid by forming aggregates with uric acid through hydrogen bonds and aromatic stacking interactions (-stacking bonds) increasing urinary solubility of uric acid. theobromine can be used for uric acid stone dissolution in combination with alkalinization to reduce the dose of citrate, thus preventing excessive alkalinization and the risk of formation of sodium urate crystals. theobromine could also be used to treat patient with xanthine stones that cannot be dissolved by alkalinization because the solubility of xanthine is relatively independent of urinary ph. a metabolite of theobromine, 7-methylxanthine, has the potential to be used for the prevention of the formation of sodium urate crystals in the synovial fluid of gouty patients. key words: theobromine; uric acid; urinary calculi; xanthine; gout. submitted 21 october 2024; accepted 24 october 2024 introduction theobromine (or 3,7-dimethylxanthine) is a natural alkaloid present in theobroma cacao (cocoa plant) and its derivatives. it is found in chocolate, and it is also present in small quantities in tea leaves (1, 2). chemically it is a xanthine, a derivative of purine, whose related compounds include theophylline, caffeine, paraxanthine, and 7-methylxanthine, each of which differ in the number or placement of the methyl groups. theobromine is derived from the nucleoside xanthosine by cleavage of the ribose and n-methylation to 7-methylxanthosine. theobromine is slightly water-soluble but more fat-soluble, therefore requires 2-3 hours to peak, while caffein is highly water-soluble and peaks after only 30 minutes. in the liver, it is metabolized into xanthine and subsequently into methyluric acid. theobromine for treatment of uric acid stones and other diseases alberto trinchieri c.d.c. ambrosiana, cesano boscone, milan, italy. doi: 10.4081/aiua.2024.13277 summary archivio italiano di urologia e andrologia 2024; 96(4):13277 a. trinchieri 2 metastable that means that preformed crystals can grow but there is no formation of new crystals. above the upper limit of the metastable zone of saturation crystals form spontaneously. other factors can interfere with uric acid crystallization in the urine as the presence of heterogeneous nuclei that can facilitate crystal formation or inhibitors of crystallization. uric acid stones can be dissolved when urinary saturation is under the threshold of supersaturation. alkalinization alkalinization by high doses of citrate and bicarbonate is commonly used for uric acid dissolution (20). urinary ph should be raised over 6, although higher values are not recommended because a urinary ph above 6.2 can cause the formation of an outer shell of insoluble calcium phosphate salts that are less soluble for higher ph values. furthermore, in the presence of hyperuricosuria, deposits of sodium and/or potassium urate can form, because of reduced solubility of such urate salts at higher ph values (contrary to what happens for uric acid). finally, long-term treatment with citrate can cause gastrointestinal disturbances. other substances n-acetylcysteine (nac) has been proposed for its alkalinizing and mucolytic effect due to the cleavage of disulfide bridges of mucoproteins contained in the deposits of organic matter covering stone crystals (21, 22). in vitro studies suggested the use of some glycosaminoglycans, glycoproteins and saponins (such as ginseng extract) to interfere with crystallization of uric acid (23). however, these substances are not properly inhibitors because they act by modifying the surface tension of water and do not show dose-response relationships. theobromine more recently, in vitro studies showed that theobromine is a very effective inhibitor of uric acid crystallization (24, 25). this effect is clinically significant for urinary concentration over 15 mg/l or higher, although higher concentrations (80 mg/l) provided no additional benefit. urinary concentrations in the therapeutical range are obtained after oral administration of 300 mg of theobromine with approximately 60 mg excreted unchanged in the urine. caffeine, theophylline and paraxanthine showed no similar effects. in fact, they had a structure very similar to theobromine, but minimal modification of their chemical structure makes them ineffective as inhibitors. theobromine inhibits nucleation of uric acid crystals being absorbed onto the faces of the crystals and modifying their morphology making them longer and thinner. in particular, theobromine may inhibit growth at only one of the faces of the crystal (210), but not at the others (001 and 201). because uric acid and theobromine molecules have very similar structural patterns, theobromine can substitute uric acid molecules in the corresponding uric acid crystals. the incorporation of this molecule to the uric acid crystal lattice modifies the structure of some layers so increasing their energy and decreasing their growth rate. in the presence of theobromine crystals formed on the surface of the uric acid were smaller. thus, theobromine may be clinically useful in preventing the regrowth of uric acid calculi fragments. theobromine also favors the dissolution of crystals by decreasing supersaturation of uric acid (26). the velocity of stone dissolution depends on the size and location of the stone and on flow of irrigation. furthermore, the microstructure of the stone, as observed at scanning electronic microscopy can influence the process of dissolution. in fact, stones that appeared macroscopically similar, may have major differences in microstructure by the presence of porosities, the distribution of organic matter and the size of crystals. the dissolution can be made difficult by the presence of shells of sodium/potassium urate or apatite as consequence of very high ph (above 7) and high uric acid concentration (27). combined treatment the combination of alkalization with citrate and theobromine patented and commercialized by the company devicare in its lit-control ph up treatment (28, 29), allows to use lower doses of citrate, thus preventing excessive alkalinization to avoid formation of sodium urate crystals (30). furthermore, the reduced dose of potassium citrate administration decreases the risk of hyperkaliemia in patients with kidney failure or heart disease. theobromine and xanthinuria xanthinuria is a rare hereditary disorder related to a deficiency of xanthine dehydrogenase/oxidase (xdh/ox) causing an accumulation of hypoxanthine and xanthine due to a reduced degradation of these two precursors to uric acid. this results in hypouricemia, hypouricosuria, xanthinuria and formation of xanthine urinary stones (31, 32). there are different types of xanthinuria due to mutations of different genes (33-35). the classical type i is caused by a mutation in xdh/xo gene mapped to chromosome 2p23.1. type ii depends on mutations in molybdenum cofactor sulfurase gene (mocos) localized on chromosome 18q12.2 that cause a defect of xdh/ox and aldehyde oxidase (ao). triple deficiency of xdh, aox and sulfite oxidase is caused by molybdenum cofactor deficiency type a (omim 252150) due to mutations in mocs1 gene (6p21.1). the classical presentation occurs at any age with renal colic, hematuria and urinary tract infection associated to xanthine stones. less frequently the presentation is more severe with renal failure, muscle-skeletal and gastrointestinal symptoms. traditional diagnosis with allopurinol loading test or liver biopsy has been replaced by genetic testing in stone patients with extremely low serum and low urinary uric acid replaced by xanthine. the treatment for patients with xanthinuria is a low purine diet and high intake of fluids. in contrast to patients with uric acid stones, urine alkalinization is not effective because the solubility of xanthine is relatively independent of urinary ph. a recent study showed that 1-methylxanthine (1-mx), 7-methylxanthine (7-mx), and 3-methylxanthine (3-mx) significantly inhibited xanthine crystallization in vitro in a concentration dependent manner (36). archivio italiano di urologia e andrologia 2024; 96(4):13277 3 theobromine and uric acid stones two of these molecules are major metabolites of theobromine whereas the third is a metabolite of caffeine. in fact, after theobromine ingestion, 20% is excreted as theobromine, 21.5% as 3-mx, and 36% as 7-mx and after consumption of caffeine, 19% of it is excreted as 1-mx. hypoxanthine (hx), theophylline (tp), paraxanthine (px), theobromine (tb), caffeine (cf), 1-methyluric acid (1-mu), and 1,3-dimethyluric acid (1,3-dmua) showed no significant inhibitory effect on xanthine crystallization because only methyl derivatives of xanthine can be incorporated into the xanthine crystal lattice modifying its structure and slowing crystal growth (by increasing gibbs free energy). however, even if theobromine did not inhibit xanthine crystallization by itself, it could be used for prevention of xanthine stones by the effects of its metabolites. theobromine and gout gout is a rheumatic disease presenting with pain, swelling, and redness in the peripheral joints, especially in the metatarsophalangeal joint in the big toe and other joints in the feet and hands (37). the disease is due to accumulation of monosodium urate (nau) needle-shaped crystals in the affected joints. synovial fluid is an ultrafiltrate from plasma with a ph of 7.4 and a sodium level of about 150 mmol/l. at a ph of 7.4 most uric acid is present as univalent anionic urate, whereas at serum urate level below 6 mg/dl sodium urate crystals do not form because sodium urate solubility threshold is 6.6 mg/dl. when urate levels are over the solubility limit of 6.6 mg/dl sodium urate crystals start to form. furthermore, solubility of sodium urate is related to temperature and tends to decrease at temperature lower than 37°c, being only 3.7 mg/dl at 26°c. this explains why crystal formation is more common in the joints of the hands and feet where temperature tends to be lower (38). the pathophysiology of crystal formation in synovial fluids is peculiar because the circulation of fluids in the cavities of synovial joints is quite limited with a much slower renewal of fluids compared to urinary tract where the flow of urine is continuous and relatively fast. consequently, inhibitors that can prevent crystal formation for a period up to 30-40 minutes can be useful in continuous flow of urine, but they are ineffective in absence of renewal of fluid as in the joint cavities. treatment of gout is based on anti-inflammatory drugs and the reduction of serum urate levels by a low purine diet, or drugs decreasing the production of uric acid, as allopurinol and febuxostat or drugs increasing the urinary excretion of uric acid, such as probenecid. an alternative approach could be increasing urate solubility or inhibit sodium urate crystallization. some in vitro studies demonstrated that the combination of arginine-rich peptide and copper ions was able to delay the crystallization of sodium urate (39, 40). similarly, the addition of trimethoprim to urate solutions delayed sodium urate crystallization because trimethoprim acted as competing binding agent forming a more soluble co-crystal with sodium urate (41). theobromine can form aggregates with uric acid through hydrogen bonds and aromatic stacking interactions (-stacking bonds) increasing urinary solubility of uric acid (42). similarly, the solubility of uric acid increased in the presence of vitamin c (43). furthermore, theobromine is also able to interact with uric acid crystals changing their morphology. epidemiological studies demonstrated that coffee and chocolate consumption decreased the risk of gout (44, 45). an in vitro study suggested that 7-methylxanthine, a metabolite of theobromine, has the potential to be used for the prevention of gout (46). the same study found that 3-methylxanthine also prevented crystallization, although this happens at a four-fold-greater concentration than with 7-methylxanthine; 7-methyluric acid has a slightly stronger effect than 3-methylxanthine, but its plasma levels are negligible. for this reason, consumption of 7-methylxanthine (or theobromine) has the potential for preventing the crystallization of sodium urate and the development of gout. regarding the safety of the treatment of 7-methylxanthine, studies documented that it has no toxic effects up to an oral dose of 1000 mg/kg of weight indicating that the consumption of 400 mg three times per day that should be requested to 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hereditary xanthinuria. urolithiasis. 2015; 43:61-67. 36. grases f, costa-bauza a, roig j, rodriguez a. xanthine urolithiasis: inhibitors of xanthine crystallization. plos one. 2018; 13:e0198881. 37. archer he, rhoden e. uric-acid levels in blood and plasma. br med j. 1951; 2:947. 38. kippen i, klinenberg jr, weinberger a, wilcox wr. factors affecting urate solubility in vitro. ann rheum dis. 1974; 33:313-317. 39. liu y, zhang q, du j, guo r. arginine-rich peptides as crystallization inhibitors for sodium urate. j mater chem b. 2023; 11:73897400. 40. liu y, zhang q, li n, et al. efficient synergistic cooperation of an arginine-rich peptide and copper ions in sodium urate crystallization inhibition. langmuir. 2023; 39:9942-9951. 41. hall vm, thornton a, miehls ek, et al. uric acid crystallization interrupted with competing binding agents. cryst. growth des. 2019; 19:7363-7371. 42. chattaraj kg, paul s. appraising the potency of small molecule inhibitors and their graphene surface-mediated organizational attributes on uric acid-melamine clusters. phys chem phys. 2022; 24:1029-104. 43. chattaraj kg, paul s. the miscibility and solubility of uric acid and vitamin c in the solution phase and their structural alignment in the solid-liquid interface. phys chem chem phys. 2021; 23:1516915182. 44. choi hk, curhan g. coffee consumption and risk of incident gout in women: the nurses’ health study. am j clin nutr. 2010; 92:922-927. 45. dillinger tl, barriga p, escárcega s, et al. food of the gods: cure for humanity? a cultural history of the medicinal and ritual use of chocolate. j nutr. 2000; 130(suppl. s8):2057s-2072s. 46. costa-bauza a, grases f. 7-methylxanthine inhibits the formation of monosodium urate crystals by increasing its solubility. biomolecules. 2023; 13:1769. correspondence alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com c.d.c. ambrosiana, cesano boscone, milan, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12531 1 original paper approach, which allowed for nerve-sparing, that the procedure gained popularity (4). the retropubic open approach was considered the gold standard for more than two decades, until about 25 years ago when the first laparoscopic radical prostatectomy was performed (5). further innovations were to follow, and soon after, in 2002, the first reports of robot-assisted procedures started to emerge (6). since then, the surgical management of prostate cancer has changed drastically. nevertheless, the uptake of robotic systems varies even today from country to country and mostly depends on cost, insurance coverage, and government healthcare approval (7). still, the market share of rarp is extremely high, with up to 85% in the usa and more than 92% in england (8), which does not leave much room for orp. considering the immense expansion of robotics in urology, justified questions emerged: should this open surgical technique be performed at all in the robotics era? while rarp is generally accepted to have a shorter hospital stay, there is conflicting evidence regarding functional outcomes and no reliable data on oncological outcomes (9) when the two techniques are compared. the main goal of this prospective study was to assess the safety, functional outcomes, and oncological outcomes after orp and rarp performed by two experienced surgeons at one institution. methods we prospectively analyzed the records of patients who underwent radical prostatectomy at our institution between august 2021 and july 2023. the ethics committee of the state medical chamber of baden-württemberg approved the project (f-2023-120). the data were obtained from the patient data management software (cgm clinical®), in which all relevant data such as preoperative staging, external imaging findings, therapy-relevant parameters, and complication rates are prospectively updated. the main criterion for surgical technique selection was patient preference. patients were informed about the available surgical options for their condition during their preoperative consultations with their respective referring urologists. during these consultations, patients were provided with comprehensive information about each surgical approach, including its benefits, risks, and potential outcomes. patients were introduction: to determine the very early functional as well as oncological outcomes after robot-assisted radical prostatectomy (rarp) and open radical prostatectomy (orp) at a single institution. methods: we identified patients who underwent rarp or orp at our institution between august 2021 and july 2023. the main criterion for surgical technique selection was patient preference. primary endpoints included anastomosis leakage rate, very early continence rate reported by standardized pad-test, and positive surgical margin rate. furthermore, we analyzed operation time, hospital stay, postoperative analgesia, and complication rates. results: in this prospective study, we analyzed data from 222 radical prostatectomies (111 rarp and 111 orp). there were no significant differences in preoperative age, prostate size, and risk stratification among the groups. patients who underwent rarp had lower anastomosis leakage rates (8.1% vs. 18.9%) and slightly lower early continence rates (76.6% vs. 78.4%) when compared to patients who underwent orp. positive surgical margin rates were similar, and complication rates were also comparable. operation time was similar for both techniques, but the hospital stay was significantly shorter in the rarp group (6.3 vs. 9.1 days, p = 0.03). the orp group experienced significantly higher opioid administration postoperatively (p < 0.001). conclusions: from a functional and oncological point of view, both techniques are safe and provide excellent outcomes when performed by experienced surgeons. nevertheless, patients are likely to benefit from a shortened hospital stay and reduced postoperative pain after rarp. key words: robot-assisted radical prostatectomy; open radical prostatectomy; functional outcomes; oncological outcomes. submitted 1 april 2024; accepted 11 april 2024 introduction prostate cancer is a major health concern and represents the second most commonly diagnosed cancer in men, with an estimated 1.4 million new cases worldwide in 2020; incidence is mainly dependent on age (1). the main goal of radical prostatectomy by any approach is the eradication of cancer while, whenever possible, preserving pelvic organ function (2). the initial transperineal open technique was described more than 100 years ago (3), but it was not until the '80s with the retropubic the impact of surgical technique on very early functional outcomes after radical prostatectomy mladen stankovic department of urology, salem hospital, academic hospital, university of heidelberg, heidelberg, germany. doi: 10.4081/aiua.2024.12531 summary archivio italiano di urologia e andrologia 2024; 96(3):12531 m. stankovic 2 encouraged to express their preferences based on their individual medical history, personal preferences, and understanding of the procedures. we obtained data from 263 patients but excluded 41 to standardize surgical variables, resulting in a final cohort of 222 patients treated by two highly experienced surgeons, each having performed over 2000 procedures in representive technique. during orp, the retropubic access was used, the endopelvic fascia was incised, and the prostate dissected in ascending order. the vesicourethral anastomosis was performed using six independent single sutures. during rarp, the transperitoneal approach was used, the endopelvic fascia was also incised, but the prostate was dissected in descending order. the vesicourethral anastomosis was performed using one running suture with two needles. standard lymphadenectomy was performed using anatomical landmarks, regardless of the surgical approach. the catheter was removed directly after the cystography was performed (day 5-6 after rarp and day 7-8 after orp) given no urinary leakage was evident. in case of leakage, the catheter remained for another 1-2 days, depending on the leakage severity. upon catheter removal, patients had one day for pelvic floor muscle exercises, explained and taught by a physical therapist. the very early continence was then documented using a standardized pad test. this test measures the amount of involuntary urine loss while performing predefined physical activities with a full bladder within 1h. the urine pad was weighed before and after the test. full continence was defined as urine loss of 0-10g and one urine pad per day. mild urinary incontinence grade i and grade ii were defined as urine loss of 10-25 g and 25-50 g, respectively. urine loss of > 50 g represented severe incontinence. the pathologist graded the tumors according to the gleason system (10), analyzing the entire prostate including every tumor focus. the complication rates were documented using the clavien-dindo classification (11). the statistics were performed using spss software v23. the significance level was set at 0.05. results between august 2021 and july 2023, 222 men with histologically proven prostate cancer underwent radical prostatectomy, of whom 111 underwent orp and 111 underwent rarp. the main patient characteristics are listed in table 1. there were no significant differences in preoperative age, psa, and ipss between the rarp and orp groups. based on d’amico's (12) risk classification of prostate cancer, 13 patients (11.7%) had intermediaterisk and 98 patients (88.3%) had high-risk cancer in the orp group, as represented in figure 1. in the rarp group, 6 patients (5.4%) and 105 patients (94.6%) had intermediateand high-risk cancer, respectively. figures 2 and 3 show the disease spread and gleason score among the groups. most of the patients had a preoperative prostate volume of ≤ 70 ml on the transrectal ultrasound (rarp 84.6% vs. orp 86.1%) as shown in figure 4. nerve sparing was able to be performed on 37.8% of patients in the rarp group and on 39.6% of patients in the orp group. pelvic lymph node dissection (plnd) was performed on all patients. the duration of figure 1. d’amico risk stratification. table 1. patient characteristics. variable rarp n, (%) orp n, (%) p value age (median, years) 69.9 70.3 0.24 ppsa (median, ng/ml) 7.2 7.7 0.66 iief 5 (median) 12.2 11.8 0.71 ipss(median) 18.5 19.1 0.69 trus (median, cm3) 45.1 46.3 0.81 pt stage 0.16 pt2 69 (62.2) 79 (71.2) pt3a 29 (26.1) 21 (18.9) pt3b 13 (11.7) 11 (9.9) nerve sparing 0.64 unilateral 19 (17.1) 18 (16.2) bilateral 23 (20.7) 26 (23.4) without 69 (62.2) 67 (60.4) positive surgical margins 15 (13.6) 17 (15.3) 0.54 clavien dindo 0.74 n.a. 104 (93.7) 101 (91) 2 6 (5.4) 5 (4.5) 3a 1 (0.9) 3 (2.7) 3b n.a. 1 (0.9) 4 n.a. 1 (0.9) gleason score 0.27 ≤ 7 96 (86.5) 89 (80.2) ≥ 8 15 (13.5) 22 (19.8) lymph nodes removed (median) 16.1 15.4 0.36 leakage at contrast cystography 9 (8.1) 21 (18.9) 0.59 very early full continence rate 85 (76.6) 87 (78.4) 0.72 operation time (median, minutes) 141.3 151.9 0.79 hospital stay (median, days) 6.3 9.1 0.03 epidural analgesia 1 (0.9) 81 (72.9) < 0.001 overlapping opioids 1 (0.9) 72 (64.9) < 0.001 patient-controlled analgesia pump 4 (3.6) 18 (16.2) < 0.001 archivio italiano di urologia e andrologia 2024; 96(3):12531 3 functional outcomes after radical prostatectomy the procedure was similar among the groups, as were the positive surgical margin rates (13.6% rarp vs. 15.3% orp). patients who underwent rarp had lower anastomosis leakage rates (8.1% vs. 18.9%) and slightly lower early full continence rates (76.6% vs. 78.4%) when compared to patients who underwent orp, though the differences were not significant (figure 5). nevertheless, the hospital stay was significantly shorter in the rarp group (6.3 vs. 9.2 days, p = 0.03) and the orp group experienced significantly higher opioid administration rates postoperatively (1 vs. 81 patients, p < 0.001). finally, the complication rates were assessed and the vast majority of patients in both groups (93.7% for rarp and 91% for orp) did not experience any deviation from the normal postoperative course. discussion despite the paucity of data on anastomosis leakage rates following radical prostatectomy due to many institutions no longer performing contrast cystography, our department remains one of the few that continues this practice. additionally, we have consistently employed a standardized pad test for the past two decades. this allows us to confidently present our radiologically obtained leakage figure 2. diasease spread. figure 4. distribution of prostate size among groups. figure 3. distribution of gleason score among groups. figure 5. early continence rates based on standardized pad-test. archivio italiano di urologia e andrologia 2024; 96(3):12531 m. stankovic 4 results as a reliable measure. contrary to a prominent meta-analysis suggesting superior early functional outcomes for rarp compared to orp (13), our research did not corroborate this. we discovered no significant discrepancies regarding the early continence rate between the two procedures. continence is typically evaluated 12 months post-surgery, with average late continence rates generally being around 80% (14, 15). however, our findings demonstrate exceptionally high early continence rates upon catheter removal of 76.6% for rarp and 78.4% for orp (16). furthermore, our severe early incontinence rates barely reached 6% for both techniques, markedly lower than the average 15% cited in existing literature (17, 18). mirroring another meta-analysis (19), our study detected no significant divergence in positive surgical margin rates between the two techniques. notably, surgical margin status is a crucial prognostic indicator for biochemical recurrence (20), and positive surgical margin rates can fluctuate considerably, from 7% to 44%, depending on the surgeon's experience (2123). regardless of factors such as patient and tumour characteristics and the size of lymph node packets removed, which influence the number of lymph nodes reported in histology (24, 25), our study found an insignificant difference in the number of lymph nodes removed per procedure (median 15.4 vs. 16.1; orp vs. rarp). all patients underwent the same tissue processing and blocking procedures in the same laboratory. the disparity in preoperative prostate size, which can act as a predictive factor for functional outcomes, was not a concern as the majority of patients exhibited a preoperative prostate volume of ≤ 70 ml on transrectal ultrasound (rarp 84.6% vs. orp 86.1%). additionally, both procedures consumed similar operative time. hospital stay was significantly shorter after rarp and orp group experienced significantly higher opioid administration rates postoperatively, our data showed that patients undergoing rarp had a significantly shorter hospital stay and fewer postoperative opioid requirements than the orp group, proving the benefit of minimally invasive surgical approach, as already in literature reported (26). nonetheless, the vast majority of patients in both groups did not experience any deviation from the normal postoperative course. we acknowledge that our study has its limitations. single centre study with just two surgeons evaluated and lack of randomisation being some of them, so that the results might not generalise to other settings. lack of intraoperative blood loss data and missing potency data being the other limitations. it should be mentioned that no patient required an intraoperative blood transfusion in either group. however, despite these limitations, our study has its strengths. we were able to prospectively analyse two almost identical patient groups who underwent two different surgical techniques. furthermore, in addition to minimising variability by having standardised procedures, we were also able to have somewhat of a surgeon heterogenity by having one expert in the respective surgical approach, performing all the procedures. as some authors have already stated, the patients should be ancouraged to choose an experianced surgen rather that a specific surgical approach (27). our study can be interpreted as a small contribution to a never ending-debate. conclusions the two techniques yield very similar early functional and oncological outcomes when performed by very experienced surgeons. orp will probably continue to be performed in institutions with financial limitations and limited access to robotics. nevertheless, patients are likely to benefit from a shortened hospital stay and reduced postoperative pain after rarp. references 1. culp mb, soerjomataram i, efstathiou ja, et al. recent global patterns in prostate cancer incidence and mortality rates. eur urol. 2020; 77:38-52. 2. adolfsson j. watchful waiting and active surveillance: the current position. bju int. 2008; 102:10-14. 3. hatzinger m, hubmann r, moll f, sohn m. die geschichte der prostatektomie von den anfängen bis davinci (the history of prostate cancer from the beginning to davinci). aktuelle urol. 2012; 43:228-230. 4. walsh pc, donker pj. impotence following radical prostatectomy: insight into etiology and prevention. j urol. 1982; 128:492-497. 5. schuessler ww, schulam pg, clayman rv, kavoussi lr. laparoscopic radical prostatectomy: initial short-term experience. urology. 1997; 50:854-857. 6. binder j, jones j, bentas w, et al. roboterunterstützte laparoskopie in der urologie. radikale prostatektomie und rekonstruktive retroperitoneale eingriffe (robot-assisted laparoscopy in urology. radical prostatectomy and reconstructive retroperitoneal interventions). urologe a. 2002; 41:144-149. 7. chandrasekar t, tilki d. robotic-assisted vs. open radical prostatectomy: an update to the never-ending debate. transl androl urol 2018; 7(suppl 1):s120-s123. 8. luciani lg, mattevi d, cai t, malossini g. robotics in urology: no more shadows? uro 2021; 1: 254-265. 9. novara g, ficarra v, rosen rc, et al. systematic review and meta-analysis of perioperative outcomes and complications after robot-assisted radical prostatectomy. eur urol 2012; 62:431-52. 10. gleason df, mellinger gt. prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. j urol. 1974; 111:58-64. 11. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 12. d'amico av, whittington r, malkowicz sb, et al. pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. j clin oncol. 1999; 17:168-172. 13. ficarra v, novara g, rosen rc, et al. systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. eur urol 2012; 62: 405-17. 14. haglind e, carlsson s, stranne j, et al. urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: archivio italiano di urologia e andrologia 2024; 96(3):12531 5 functional outcomes after radical prostatectomy a prospective, controlled, nonrandomised trial. eur urol. 2015; 68:216-225. 15. gresty h, walters u, rashid t. post-prostatectomy incontinence: multimodal modern-day management. br j community nurs. 2019; 24:154-159. 16. theissen l, preisser f, wenzel m, et al. very early continence after radical prostatectomy and its influencing factors. front surg. 2019; 6:60. 17. hoeh b, preisser f, wenzel m, et al. correlation of urine loss after catheter removal and early continence in men undergoing radical prostatectomy. curr oncol. 2021; 28:4738-4747. 18. heidenreich a, fossati n, pfister d, et al. cytoreductive radical prostatectomy in men with prostate cancer and skeletal metastases. eur urol oncol. 2018; 1:46-53. 19. novara g, ficarra v, mocellin s, et al. systematic review and meta-analysis of studies reporting oncologic outcome after robotassisted radical prostatectomy. eur urol 2012; 62: 382-404. 20. meeks jj, eastham ja. radical prostatectomy: positive surgical margins matter. urol oncol 2013; 31: 974-79. 21. yossepowitch o, briganti a, eastham ja, et al. positive surgical margins after radical prostatectomy: a systematic review and contemporary update. eur urol 2014; 65: 303-13. 22. eastham ja, kattan mw, riedel e, et al. variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. j urol 2003; 170: 2292-95. 23. suardi n, delloglio p, gallina a, et al. evaluation of positive surgical margins in patients undergoing robot-assisted and open radical prostatectomy according to preoperative risk groups. urol oncol 2016; 34: 57. 24. liss ma, palazzi k, stroup sp, jabaji r, et al. outcomes and complications of pelvic lymph node dissection during robotic-assisted radical prostatectomy. world j urol 2013; 31: 481-88. 25. jung jh, seo jw, lim ms, et al. extended pelvic lymph node dissection including internal iliac packet should be performed during robot-assisted laparoscopic radical prostatectomy for highrisk prostate cancer. j laparoendosc adv surg tech a 2012; 22: 785-90. 26. gandaglia g, sammon jd, chang sl, et al. comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. j clin oncol 2014; 32: 1419-26. 27. yaxley jw, coughlin gd, chambers sk, et al. robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. lancet. 2016; 388:1057-1066. correspondence mladen stankovic, md (corresponding author) mladen.stankovic@stadtmission-hd.de zeppelinstraße 11-33, 69121, heidelberg, germany conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12997 1 original paper 5% to 10% of the population, leading many individuals to seek medical care for stone-related problems in emergency and general outpatient departments. the lifetime possibility of experiencing urolithiasis is estimated to be around 13% for males and 7% for females. the incidence of urolithiasis is highest for males between the ages of 40 and 60, whereas for females, it peaks in the late 20s (1-3). a ureteric stone accounts for 20% of stones in the urinary tract, with 70% of these stones typically situated in the distal part of the ureter (3). major complaints such as urinary tract infection, vomiting, renal obstruction, nausea, hematuria (bloody urine), and abdominal or back pain in ureteral calculi can be noticed (4). a non-contrast computed tomography (ncct) scan is the most preferred imaging technique for urolithiasis diagnosis in symptomatic patients. the sensitivity and specificity of this diagnostic method were found to be approximately 100%, making it an extremely reliable diagnostic tool (4). regarding the management of stone passage, a considerable number of ureteral stones have the potential to pass on their own (5). per the european urological association's and american urological association's recommendations, medical expulsive therapy (met) is considered the primary treatment for ureteral stones measuring less than 10 mm (6). not all patients taking met can achieve spontaneous stone passage. the key factors influencing predictability include the stone's size and its location. as indicated by the american urological association, 68% of stones measuring less than 5 mm and 47% of stones exceeding 5 mm in size were noted to pass spontaneously (7). in cases where the stone cannot pass naturally, treatment alternatives such as extracorporeal shockwave lithotripsy (eswl), ureteroscopy, and open surgery may be considered (4). inflammatory markers are indicators of an inflammatory response in the human body. the level of inflammation can be detected by various markers, such as serum procalcitonin, c-reactive protein (crp), and others (8). elevated levels of these markers are observed in various conditions, including covid-19, cancer, and inflammaintroduction: in ureterolithiasis, the prediction of spontaneous passage poses a challenge for urologists. moreover, there is controversy surrounding the preferred management approach, whether medical or surgical, as each approach has its disadvantages. procalcitonin and other inflammatory markers were studied for predicting stone passage spontaneously, but their significance remains controversial. this study aims to assess the association between these markers, especially procalcitonin, and spontaneous ureteral stone passage. materials and methods: in this multicenter prospective cohort study from march 2022 to october 2023, consecutive patients with a single unilateral distal ureteric stone less than 10 mm were enrolled. exclusion criteria were specified. patients underwent medical expulsive therapy (met) and were monitored for stone passage. the significance level was set at p < 0.05. results: out of 94 patients enrolled, 72.3% were male and 27.7% were female, with a mean age of 38.84± 10.41 years. stone sizes varied, with the most common range being 4 mm5.9 mm. participants were categorized based on spontaneous stone passage as spontaneous stone passage (ssp) and non-ssp. no significant differences were observed in most demographic and laboratory variables. however, serum procalcitonin and c-reactive protein showed significant differences between the ssp and non-ssp groups. conclusions: although several inflammatory markers were studied to predict the spontaneous passage of the ureteral stone, the current study concluded that only elevated procalcitonin, c-reactive protein, and large stone diameter decrease the chance of spontaneous ureteral stone passage. key words: nephrolithiasis; spontaneous stone passage; inflammatory marker; procalcitonin level; renal stone surgery. submitted 1 september 2024; accepted 9 september 2024 introduction nephrolithiasis is a common urinary tract disease, ranking third in terms of prevalence after urinary tract infection and benign prostate obstruction. it affects around role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm ismaeel aghaways 1, rawa bapir 2-4, nabaz s. siwaily 2, ahmed mohammed abdalqadir 2, shakhawan hamaamin said 1, ayman m. mustafa 3, bryar othman muhammed 5, hawbash m. rahim 4, 6, berun a. abdalla 3, 4, fahmi h. kakamad 1, 3, 4, shvan h. mohammed 4 1 college of medicine, university of sulaimani, madam mitterrand street, sulaimani, kurdistan, iraq; 2 department of urology, sulaymaniyah surgical teaching hospital, sulaymaniyah, iraq; 3 smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq; 4 kscien organization, hamdi str, azadi mall, sulaimani, kurdistan, iraq; 5 smart health tower (raparin branch), karukh street, ranya, sulaymaniyah, kurdistan, iraq; 6 medical laboratory science department, college of health sciences, university of human development, sulaymaniyah, kurdistan region, iraq; doi: 10.4081/aiua.2024.12997 summary archivio italiano di urologia e andrologia 2024; 96(4):12997 i. aghaways, r. bapir, n.s. siwaily, et al. 2 tory bowel disease (9). newly conducted research has been released, demonstrating that biochemical indicators of inflammation can function as predictors for the spontaneous passage of stones (10). the relevance of inflammatory markers in the spontaneous passage of ureteral stones is a subject of debate among various studies (11). the current study aims to assess the association between serum procalcitonin, crp, and other inflammatory markers with the possibility of passing stones spontaneously. materials and methods study design and setting this prospective observational cohort study was conducted from march 2022 to october 2023. ethical approval was secured by the ethics committee with a degree no. 53. and both written and informed consent were obtained from each participant. inclusion and exclusion criteria the study focused on patients aged between 18 and 64 years, including both genders. it only included patients diagnosed through a non-contrast-enhanced ct scan with single unilateral stones less than 10mm in size and located in the distal ureter below the lower border of the sacroiliac joint. individuals with a single functioning kidney, more than 1 stone in the same ureter, bilateral ureteric and/or concurrent renal stones, severe hydronephrosis [defined as grade 4 hydronephrosis based on the onen classification systemwhich characterizes severe hydronephrosis as greater than 50% loss of renal parenchyma or a cyst-like kidney with no significant visible renal parenchyma (12)], impaired renal function, congenital or acquired anatomical anomaly of the urinary tract, pregnant patients, history of ureteral stenosis or reconstructive ureteral surgery, previous intervention for a stone or any other operation (within 2 months of inclusion in the study), or individuals who had eswl and stent or nephrostomy insertion for a stone in the same ureter were not included. furthermore, exclusion criteria were patients with diabetes, thyroid or hepatic disease, active malignancy, active inflammatory bowel disease, active infectious disease, immunological diseases, active chronic inflammatory disease, or patients who used antibiotic, steroid, nsaids, or immune suppressant medicines (within 2 weeks of inclusion in the study) or patients with documented infection clinically (fever > 38) or via investigations (positive urine culture) or patients who were also unable to comply with met or had contraindications to met therapy or side effects of the medications or patients who preferred immediate active treatment of stones, or who were lost follow-up during the study. sample and data collection upon admission and throughout the acute phase, demographic information such as age, gender, body weight, and height were obtained from all patients. this information was obtained as part of the initial assessment to characterize the study population. body mass index (bmi) was computed as the ratio of height in meter square to weight in kilogram and expressed as kg/m2. a medical history and thorough physical examination were conducted on each participant to assess their overall health and identify any clinical signs. as part of the initial assessment, inflammatory markers were measured, including complete blood count (white blood cells (wbcs), neutrophils (ncs), lymphocytes, neutrophil-to-lymphocyte ratio (nlr), platelet-tolymphocyte ratio (plr), serum procalcitonin, c-reactive protein, and serum creatinine to evaluate disease severity. all patients underwent ncct scans of the kidney, ureter, and bladder. axial ncct images with a slice thickness of 5 mm were obtained, utilizing specific imaging parameters such as a soft-tissue window with a width of 360, a pitch of 1.5, a tube voltage of 120 kv, and a tube current ranging from 70 to 90 mas. radiological findings included a detailed analysis of stone characteristics, determining stone side (right versus left), site (proximal, mid, and distal), size (defined by the stone’s greatest diameter), and density measured in hounsfield units. in terms of hydronephrosis grading, the study utilized the onen classification system. this system categorized grades 0 and 1 as indicating no-to-mild hydronephrosis. conversely, grades 2, 3, and 4 were grouped to represent moderateto-severe hydronephrosis. this classification allowed for a concise and clinically relevant assessment of the degree of hydronephrosis in the study population, providing a more detailed analysis of renal conditions and their implications (12). concerning the anatomical position, the distal ureter was specified as the segment extending from the lower boundary of the sacroiliac joint to the bladder. stone size calculations were performed using both coronal and axial images obtained through cross-sectional imaging. finally, all the obtained data were recorded for further analysis. follow-up patients without indications for interventional treatment underwent observation and met, which involved a prescription of diclofenac sodium (75 mg/day) and tamsulosin (0.4 mg/day) for four weeks, along with a recommended daily fluid intake of 2-3 liters. those on met attended weekly outpatient controls, excluding emergencies. during these visits, patients were asked about the stone passage and any renal colic incidents. for those unable to pass the stone, confirmation was sought through ultrasound/plain kidney-ureter-bladder at weeks one, two, and three, and at the fourth week using noncontrast abdominal ct. individuals failing to pass the stone were categorized as passage negative (no ssp), while those successful were grouped as passage positive (ssp). failure of passage was defined as the stone's presence on ncct after four weeks or urgent intervention within the period due to stone-related complications, such as drainage, shockwave lithotripsy, or ureteroscopy (urs). inflammatory markers were not reassessed during the follow-up period; instead, the follow-up focused on monitoring stone passage and patient progress. statistical analysis the acquired data were analyzed via statistical package for the social sciences software 25.0. quantitative variables were analyzed by using an independent sample t-test and archivio italiano di urologia e andrologia 2024; 96(4):12997 3 role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm chi-square; additionally, these data were presented in the form of means and standard deviations. qualitative data were presented as proportions and percentages. in this study, a p-value of < 0.05 was considered significant. results demographic characteristics of the total patients enrolled in this study (n = 94), 68 (72.3%) were male and 26 (27.7%) were female. they had a mean age of 38.84 ± 10.41 years (19-64 years), with the majority of the patients (33%) being between 29 and 38 years old. the mean bmi of the participants was 26.3 ± 4.638, with the majority of participants falling within the normal range (18.5-24.9). stone sizes were further classified into different classes; the most common stone size falls within the 4 mm-5.9 mm range, comprising the largest percentage of the sample (39.36%). further characteristics of the enrolled participants are given in table 1. clinical characteristics and statistical analysis the individuals enrolled in this study were divided into two main groups depending on whether they experienced spontaneous passage of stones or non-spontaneous passage of stones, with a mean age of 39.4 ± 10.8 and 37.78 ± 9.73, respectively. the mean stone size ± sd in ssp was 5.41 ± 1.6, while the size of the stone in non-ssp was 6.37 ± 1.76. inflammatory markers are regarded as predictive factors for the evaluation of spontaneous stone passage. in this study, several demographics, laboratory, and radiological variables were analyzed to investigate their association with spontaneous stone passage. no statistically significant differences among several variables between the no ssp and ssp groups were found, including age, bmi, side (right or left) of the kidney stone, serum creatinine, plr, white blood cells, granulocytes, and platelets. regarding the association between inflammatory markers and the possibility of stone passage spontaneously, a high statistically significant difference in serum procalcitonin levels was found between the no ssp and ssp groups (p < 0.001), with the mean of procalcitonin being higher (0.14 ± 0.089) among the no ssp groups compared to the ssp group (0.05 ± 0.027). crp, as another inflammatory marker, was found to have statistical significance between the no ssp and ssp groups (p < 0.001), with the mean of crp being lower among the ssp group (5.55 ± 5.06) compared to the no ssp group (12.63 ± 11.03). additionally, nlr and lymphocytes were found to have statistical significance difference between the no ssp and ssp groups with a p-value of (0.032, and 0.032), respectively (table 2). accordingly, the size of the stone also showed a statistically significant difference between the no ssp and ssp groups (p-value = 0.009), with the mean stone size being higher among the no ssp group (6.37 ± 1.76) compared to the ssp group (5.41 ± 1.6). which indicated that larger stone sizes have less possibility of passing spontaneously. additionally, stone sizes were grouped into 2 major groups and analyzed table 1. baseline characteristics. variables frequency percentage (%) gender male 68 72.3 female 26 27.7 age 19-28 17 18.1 29-38 31 33 38-47 27 28.7 above 47 19 20.2 stone size (longest diameter) 2 mm-3.9 mm 13 13.82 4 mm-5.9 mm 37 39.36 6 mm-7.9 mm 28 29.8 8 mm-9.9 mm 16 17.02 side right 48 51.06 left 46 48.94 bmi < 18.5 3 3.2 18.5-24.9 33 35.1 25-29.9 41 43.6 > 30 17 18.1 hydronephrosis grade mild 68 72.3 moderate 26 27.7 table 2. analyzing demographic, laboratory, and radiological variables for predicting passage of stones spontaneously. variable total no ssp ssp p-value age (mean ± sd) 38.84 ± 10.41 37.78 ± 9.73 39.4 ± 10.8 0.474 gender male (n, %) 68 (72.3%) 19 (61.2%) 49 (77.8%) 0.018 female (n, %) 26 (27.7%) 12 (38.7%) 14 (22.2%) bmi (mean ± sd) 26.3 ± 4.638 26.05 ± 4.38 26.44 ± 4.8 0.695 side right (n, %) 48 (51.06%) 16 (48.48%) 32 (52.46%) 0.717 left (n, %) 46 (48.94%) 17 (51.52%) 29 (47.54%) size (mean ± sd) 5.7 ± 1.7 6.37 ± 1.76 5.41 ± 1.6 0.009 serum procalcitonin (mean ± sd) 0.083 ± 0.072 0.14 ± 0.089 0.05 ± 0.027 < 0.001 crp (mean ± sd) 8.04 ± 8.36 12.63 ± 11.03 5.55 ± 5.06 < 0.001 serum creatinine (mean ± sd) 0.88 ± 0.22 0.92 ± 0.21 0.86 ± 0.22 0.197 nlr (mean ± sd) 3.39 ± 2.186 2.74 ± 1.61 3.75 ± 2.37 0.032 plr (mean ± sd) 126.62 ± 86.66 112.78 ± 86.78 134.1 ± 86.38 0.257 white blood cells (mean ± sd) 9.73 ± 2.9 9.01 ± 2.77 10.12 ± 2.92 0.078 hydronephrosis grade mild (n, %) 68 (72.3%) 19 (57.6%) 49 (80.3%) 0.018 moderate (n, %) 26 (27.7%) 14 (42.4%) 12 (19.7%) size group (n, %) < 6 mm 62 (65.96%) 17 (51.5%) 45 (73.77%) 0.022 > 6 mm 32 (34.04%) 16 (48.5%) 16 (26.23%) granulocyte (mean ± sd) 7.68 ± 2.51 7.26 ± 2.45 7.91 ± 2.53 0.233 lymphocyte (mean ± sd) 3.16 ± 3.38 4.17 ± 5.38 2.61 ± 1.20 0.032 platelets (mean ± sd) 276.21 ± 73.12 275.5 ± 71.3 276.59 ± 74.67 0.946 archivio italiano di urologia e andrologia 2024; 96(4):12997 i. aghaways, r. bapir, n.s. siwaily, et al. 4 statistically to demonstrate their association with stone passage; a statistically significant difference was also found (p-value = 0.022). hydronephrosis grade was determined for all the patients and further classified into mild and moderate to determine its association with the spontaneous passage of stones. this variable was also found statistically significant (p-value = 0.018). another factor that should be taken into account in this study is the significant difference in gender distribution between the no ssp and ssp groups (p = 0.018). the ssp group had a higher percentage of males (77.8%) (table 2). regarding the association between procalcitonin level at admission with the weeks of stone passage and hydronephrosis grade, it was found that procalcitonin levels vary significantly across different weeks of stone passage (p < 0.001). procalcitonin levels were lowest at week 0 (0.021 ± 0.002) and increased progressively in subsequent weeks: week 1 (0.038 ± 0.016), week 2 (0.049 ± 0.022), week 3 (0.077 ± 0.013), and week 4 (0.084 ± 0.059). however, no significant difference in procalcitonin levels between different hydronephrosis grades was found (p = 0.093) (table 3). receiver operating characteristic (roc) for the association between procalcitonin and stone passage showed an area of 0.925 (%95 c.i. 0.866-0.984) with a cut-off value of 0.076, a sensitivity of 82%, a specificity of 88%, and a p-value < 0.001 (figure 1) (table 4). discussion nephrolithiasis is a commonly occurring urinary tract condition, which is the third most prevalent disease after infections in the urinary tract and benign obstruction in the prostate (1). various therapeutic approaches and treatment methods exist for the management of stones in the ureter, depending on factors such as the size of the stone, location, composition, and clinical aspects (11). these treatment options range from conservative treatment or non-surgical treatment (with analgesics with or without met to assist spontaneous stone passage) to invasive treatments such as eswl and ureteroscopy (urs-l) (flexible or semi-rigid) (6, 13, 14). medical treatment is considered cost-effective, alleviating the need for surgical procedures and leading to minimal complications. potential disadvantages of met may include recurring colic and urinary tract infections (11). conversely, invasive procedures lead to a safer and more efficient stone removal rate, with a higher cost compared to medical treatment. furthermore, potential complications in the urinary system, such as the formation of hematomas, urinary infections, and urinary extravasation, should be taken into account as adverse effects of this treatment approach (15). the success of eswl and urs-l treatments depends on the stone's location and size, with reported success rates ranging from 68% to 90% for eswl and 80% to 97% for urs-l (6). likewise, delaying surgical intervention until medical therapy fails can be stressful for the patient and increase treatment costs compared to the immediate surgical removal of a stone (11). these controversies about choosing the management method have led many researchers to study inflammatory markers. these markers can help clinicians decide on the most effective treatment method for patients. medical expulsive therapy (met) involves the administration of medications to facilitate the expulsion of ureteric stones. various drugs, including alpha-blockers, calcium channels blockers, corticosteroids, and phosphodiesterase-5 inhibitors, have undergone thorough examination. recent guidelines recommend alpha-blockers as an effective standalone therapy for the medical removal of stones in the ureter. on the other hand, there isn't enough evidence to consider other drugs mentioned as table 3. association between procalcitonin level at admission and weeks of stone passage and hydronephrosis grade. parameters procalcitonin level p value week of stone passage (mean ± sd) week 0 0.021 ± 0.002 < 0.001 week 1 0.038 ± 0.016 week 2 0.049 ± 0.022 week 3 0.077 ± 0.013 week 4 0.084 ± 0.059 hydronephrosis grade (mean ± sd) mild 0.075 ± 0.07 0.093 moderate 0.103 ± 0.077 table 4. receiver operating characteristic (roc) for the association between procalcitonin and stone passage. parameters area 95% confidence cut off p-value under curve interval value procalcitonin 0.925 0.866-0.984 0.076 < 0.001 roc sensitivity 82% specificity 87.9% figure 1. receiver operator curve analysis for association between serum procalcitonin and stone passage. archivio italiano di urologia e andrologia 2024; 96(4):12997 5 role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm standalone therapies (14). according to the recent guidelines from the european association of urology (eau), for distal ureteric stones larger than 5 mm, alpha-blockers are recommended as met (15, 16). most studies in the literature assess met outcomes over a four-week duration, and there is no data available to support other time intervals currently. in the present study, patients were given diclofenac sodium (75 mg/day,) as an analgesic to reduce pain and tamsulosin (0.4 mg/day) for four weeks, along with a daily fluid intake of 2-3 liters. the possibility of passing ureteral stones naturally is highly influenced by two crucial factors, its size and location. the relationship between stone size and spontaneous stone passage (ssp) is inversely proportional. stones measuring less than 5 mm have a 75% chance of passing naturally, with the possibility of passage decreasing as the size increases. for ureteral stones between 5 and 10 mm, the chance of spontaneous passage ranges from 25 to 46%. additionally, it has been reported that for stones less than 4mm, there is a 95% possibility of spontaneous passage within 40 days (1, 11, 17). the european association of urology and american urological association (eau/aua) panel examined spontaneous passage rates through a recent meta-analysis, revealing rates of 68% for stones smaller than 5 mm and 48% for stones ranging from 5 to 10 mm (18). one study by demehri et al. classified patients into 3 groups based on stone sizes, groups were less than or equal to 5 mm, between 5 and 10 mm, and greater than 10 mm. a spontaneous passage rate of 92% for stones less than 5 mm and 9.1% for stones larger than 10 mm was observed (19). the current study revealed an overall ssp rate of 67%; additionally, the mean size of the stone was 5.41 ± 1.6 among ssp groups and 6.37 ± 1.76 among no ssp groups, with a p-value of 0.009, which indicates a statistically significant difference between the two groups in terms of stone size. likewise, patients in this study were classified into two groups based on stone size, and statistical analysis showed a pvalue of 0.022 with the highest rate of ssp (73.77%) for stones less than 6mm. several studies have consistently demonstrated that demographic characteristics do not exert a significant influence on the probability of ureteral stones passage spontaneously. a study conducted by mohammad et al. involving 73 patients with distal ureteric stones sized 4-8 mm revealed no significant difference in age, bmi, or gender between the ssp and non-ssp groups statistically (3). in another study, which was conducted on 54 patients with single ureteral stones, no significant difference was found in demographic characteristics between the ssp and no ssp groups (1). however, according to a study conducted by puntub et al., which included 139 patients with ureteral stones < 10 mm, demographic characteristics such as age and gender showed statistically significant differences between the ssp and no ssp groups. the study found that individuals with ssp had a mean age of 44.53 years, while those with no ssp had an average age of 52.62 years. the study also observed that males had a better chance of ssp than females. the statistical analysis showed a significant relationship between age, gender and stone passage with a p-value of 0.003 and 0.031, respectively (4). in the present study, considering various demographic characteristics, only gender exhibited a statistically significant difference between the ssp and nonssp groups. the incidence of ssp was significantly higher among males (77.8%) compared to females (22.2%), and this was found to be statistically significant with a pvalue of 0.018. regarding the side of the stone, in one study by jain et al. conducted on 185 patients with stones in the ureter, the side of the stone showed no significant difference among the ssp and no spp groups (20). in another study in which 156 patients enrolled, the side of the stone showed no statistically significant difference among the ssp and no ssp groups with a p-value of 0.1 (7). in this study, statistical analysis showed no significant difference in the spontaneous passage of ureteral stones between leftand right-sided stones with a p-value of 0.717. regarding the association between inflammatory markers and ureteral stone passage, several inflammatory markers have been studied. in a study involving 156 patients conducted by sfoungaristos et al., elevated levels of wbcs and nc during the acute phase of renal colic were linked to an elevated possibility of ureteral stones passing spontaneously (7). likewise, in another study by özcan et al., which was conducted on 251 renal colic patients, statistical analysis showed a significant difference in wbcs and neutrophils among groups that pass their stones spontaneously and those that do not pass their stones, with the level being higher among no ssp groups compared to ssp groups (21). in another study, which was performed on 192 patients, wbcs and ncs were decreased among ssp groups compared to no ssp groups, with a p-value of 0.0005 for both markers (14). additionally, in a study by park et al., in which a total of 182 patients were enrolled, it was reported that an elevated level of nc percentage leads to a spontaneous decrease in the rate of ureteral stone passage (22). a possible causation for this finding is that ureteral stone presence leads to swelling of the ureteral mucosa, ultimately resulting in obstruction. these interactions may contribute to increased inflammatory reactions and an elevated percentage of neutrophils and white blood cells (4). the neutrophil-to-lymphocyte ratio (nlr) and platelet-tolymphocyte ratio (plr) are other markers that can be used as predictors of ureteral stone passage. different studies suggested that elevated nlr and plr are associated with a decreased possibility of spontaneous ureteral stone passage. statistical analysis showed that there is an inverse relationship between nlr and plr levels and the spontaneous passage of ureteral stones, as indicated by a p-value of less than 0.005 in various studies (5, 8, 11, 23). however, in contrast to the above-mentioned studies, according to a study by ahmed et al., which was performed on 163 patients for spontaneous passage prediction of stones less than 10 mm, it was reported that serum wbcs did not show a significant difference between ssp and non-ssp groups (12). likewise, in a retrospective study performed on 279 patients, it was found that inflammatory markers, particularly wbcs, nc, and nlr, do not serve as meaningful parameters for passage prediction of ureteral stones as they did not show any difference between both groups significantly (24). additionally, in a prospective study that was performed archivio italiano di urologia e andrologia 2024; 96(4):12997 i. aghaways, r. bapir, n.s. siwaily, et al. 6 to find the relationship between stone passage and inflammatory markers, in which 139 patients were enrolled, it was concluded that both wbcs and ncs did not play a role in predicting the passage of stones spontaneously, with a p-value of 0.97 and 0.58, respectively (4). the current study findings are in contrast with these studies. we observed elevated nlr and decreased lymphocyte count among patients who pass their stones spontaneously (ssp), with mean values of 3.75 ± 2.37 and 2.61 ± 1.20, respectively, compared to no ssp groups with mean values of 2.74 ± 1.61 and 4.17 ± 5.38, respectively. the statistical analysis of both variables showed a pvalue of 0.032. additionally, the current study findings did not show any statistically significant differences in wbcs, plr, ncs, and platelets among the ssp and no ssp groups. another inflammatory parameter that serves as a meaningful parameter for predicting ureteral stone passage is crp, which is primarily produced by the liver in response to tissue damage and serves as a sensitive indicator of inflammation (25). previous studies have established associations between crp and various inflammatory conditions, including diabetic nephropathy (26), subacute thyroiditis (27), and hepatitis (28). in numerous studies, the serum crp level appeared as a significant predictor for the spontaneous passage of ureteral stones. these studies consistently observed a significant elevation in serum crp levels among patients who did not experience spontaneous ureteral stone passage (2-4, 20-22). one potential explanation of the mentioned results could be that the rise in these levels reflects the extent of inflammation induced in the ureteral mucosa as a stone passes through. this is supported by the observation that the interaction between the mucosa of the ureter and the stone leads to inflammation at the site where the stone is located (29). however, in contrast to these findings, a study conducted by hassan et al., in which 195 patients were enrolled, reported that the spontaneous passage rate of ureteral stones among individuals with high crp levels was higher, with a statistically significant p-value of less than 0.05 (30). the current study reported that crp is a strong inflammatory marker to predict spontaneous passage of ureteral stones, with the level being elevated among those who did not pass their stones spontaneously (12.63 ± 11.03), compared to ssp groups (5.55 ± 5.06) with a p-value of < 0.001. apart from stone size, location, wbc indices, and crp, to our knowledge, there are limited studies in genuine literature that examine the effects of procalcitonin on stone passage (31). procalcitonin is a peptide composed of 116 amino acids, possessing a molecular weight of approximately 13 kilodaltons. ghillani et al. initially characterized this hormone in 1989 as a precursor to calcitonin, a thyroid gland-produced hormone consisting of 32 amino acids (32). the normal range for procalcitonin in the general population is recognized as being below 0.05 ng/ml. during systemic infections, it may elevate to levels of 2 ng/ml, and in cases of sepsis, it can reach levels higher than 10 ng/ml (33). likewise, procalcitonin has been identified as useful in establishing a relationship between infections in the urinary tract and obstructed ureteral stones. according to papa giannopoulos et al., they found that procalcitonin levels exceeding 100 pg/ml (0.1 ng/ml) were observed in 18% of patients treated with medical expulsive therapy (met), 45% of those had undergone procedures such as ureteroscopy with laser lithotripsy (ursl) or the placement of a ureteral stent (34). in a study conducted by cilesiz et al. to examine the role of procalcitonin in predicting the possibility of spontaneous passage of ureteral stones, in which 54 patients were enrolled, it was reported that the procalcitonin levels were significantly elevated in groups that did not experience spontaneous stone passage (0.207 ± 0.145 ng/ml) compared to those with successful spontaneous stone passage (0.133 ± 0.028 ng/ml) with a p-value of < 0.001 (1). in the current study, in which 94 patients were involved, it was found that procalcitonin levels were significantly higher among groups failing to pass their stones spontaneously (0.14 ± 0.089) compared to those who passed their stones spontaneously (0.05 ± 0.027), with a p-value of < 0.001. in this study, the determined cutoff value for procalcitonin in predicting stone passage was established at 0.076 ng/ml with an auc of 0.925, a sensitivity of 82%, and a specificity of 88% (95% ci 0.8660.984). the possible explanation for elevated procalcitonin among no ssp groups is linked to an excess of mucosal inflammation. this excess mucosal inflammation might have increased the possibility of stone impaction in the future, making their passage more challenging (1). in this study, the association between procalcitonin levels and weeks of passage among ssp groups was examined at the time. patients were classified based on weeks of stone passage into five groups. statistical analysis showed that procalcitonin levels vary significantly across different weeks of stone passage (p < 0.001). procalcitonin levels are lowest at week 0 (0.021 ± 0.002) and increase progressively in subsequent weeks: week 1 (0.038 ± 0.016), week 2 (0.049 ± 0.022), week 3 (0.077 ± 0.013), and week 4 (0.084 ± 0.059). the association between stone passage and hydronephrosis grade is a subject of controversy, yet individuals with no or mild hydronephrosis were more likely to pass their stones spontaneously than those with moderate hydronephrosis, according to a study conducted on 163 patients (13). in contrast, in a study by jendeberg et al., which was performed on 392 patients retrospectively, it was reported that stones inducing moderate to significant hydronephrosis exhibited a greater likelihood of spontaneous passage compared to stones causing either no hydronephrosis or only mild hydronephrosis, with a pvalue of 0.002 (35). in the present study, hydronephrosis grade was significantly different among ssp and no ssp groups. statistical analysis showed an increased chance of ssp when dealing with mild hydronephrosis (80.3%) compared to moderate hydronephrosis (19.7%), with a p-value of 0.018. a notable limitation of this study is that we did not assess the time length from the onset of symptoms to the first admission. consequently, we did not analyze how this time interval might relate to inflammatory markers. future research should consider evaluating this aspect to provide further insights into the progression of inflammation and its impact on inflammatory indexes. archivio italiano di urologia e andrologia 2024; 96(4):12997 7 role of inflammatory markers in predicting spontaneous passage of ureteral stones less than 10 mm conclusions the findings suggest that elevated levels of procalcitonin may be a contributing factor in complicating the stone's passage and lengthening the duration of the stone passage. likewise, elevated crp and larger stones were found to decrease the chance of ssp. the validity and confirmation of the current findings require further studies. references 1. çilesiz nc, arslan b, balcı mb, et al. the role of procalcitonin and other markers of inflammation in predicting spontaneous passage of ureteral stones. journal of academic research in medicine 2021; 11:179-18. 2. hada a, yadav ss, tomar v, et al. assessment of factors affecting the spontaneous passage of lower ureteric calculus on the basis of lower ureteric calculus diameter, density, and plasma c-reactive protein 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aykanat ic, asfuroglu a, et al. what is the role of inflammatory markers in predicting spontaneous ureteral stone passage? aktuelle urologie. 2022; 53:448-53. 25. wang l, li y, wang c, et al. c-reactive protein, infection, and outcome after acute ischemic stroke: a registry and systematic review. curr neurovasc res. 2019; 16:405-15. 26. bilgin s, kurtkulagi o, tel bm, et al. does c-reactive protein to serum albumin ratio correlate with diabetic nephropathy in patients with type 2 diabetes mellitus? the care time study. prim care diabetes. 2021; 15:1071-4. 27. baruah mp, bhattacharya b, baruah um. c-reactive protein level can be a better indicator than erythrocyte sedimentation rate in assessing the severity of inflammation and guiding glucocorticoid therapy in subacute thyroiditis. indian j endocrinol metab. 2022; 26:328. 28. demirkol me, aktas g, bilgin s, et al. c-reactive protein to lymphocyte count ratio is a promising novel marker in hepatitis c infection: the clear hep-c study. rev assoc med bras (1992) 2022; 68:838-841 29. nuss gr, rackley jd, assimos dg. adjunctive therapy to promote stone passage. rev urol. 2005; 7:67. 30. hassan m, hayat s, shahzad m. frequency of spontaneous expulsion of lower ureteric stones in patients with raised c-protein. kjms 2019; 12:469. 31. abdullah ho, abdalla ba, kakamad fh, et al. predatory publishing lists: a review on the ongoing battle against fraudulent actions. barw med j. 2024; 2:26-30. archivio italiano di urologia e andrologia 2024; 96(4):12997 i. aghaways, r. bapir, n.s. siwaily, et al. 8 32. ghillani pp, motté p, troalen f, et al. identification and measurement of calcitonin precursors in serum of patients with malignant diseases. cancer res. 1989; 49:6845-51. 33. claeys r, vinken s, spapen h, et al. plasma procalcitonin and c-reactive protein in acute septic shock: clinical and biological correlates. inadvances in critical care testing: the 2002 ifcc-roche diagnostics award 2004, springer berlin heidelberg, pp. 17-31. 34. papagiannopoulos d, whelan p, ahmad w, et al. procalcitonin is a strong predictor of urine culture results in patients with obstructing ureteral stones: a prospective, pilot study. urol ann. 2016; 8:277-80. 35. jendeberg j, geijer h, alshamari m, et al. size matters: the width and location of a ureteral stone accurately predict the chance of spontaneous passage. eur radiol. 2017; 27:4775-85. correspondence ismaeel aghaways ismaeelagha@hotmail.com shakhawan hamaamin said shakhwan.said@gmail.com college of medicine, university of sulaimani, madam mitterrand street, sulaimani, kurdistan, iraq rawa bapir dr.rawa@yahoo.com nabaz s. siwaily nabaz@gmail.com ahmed mohammed abdalqadir ahmed.abdalqadir@gmail.com department of urology, sulaymaniyah surgical teaching hospital, sulaymaniyah, iraq ayman m. mustafa aymanmajid75@gmail.com berun a. abdalla berun.anwer95@gmail.com smart health tower, madam mitterrand street, sulaimani, kurdistan, iraq bryar othman muhammed muhammed.ali@gmail.com smart health tower/raparin, madam mitterrand street, sulaimani, kurdistan, iraq hawbash m. rahim hawbash.mhamad96@gmail.com shvan h. mohammed shvanh80@gmail.com kscien organization, hamdi str, azadi mall, sulaimani, kurdistan, iraq fahmi hussein kakamad (corresponding author) fahmi.hussein@univsul.edu.iq doctor city, building 11, apartment 50, sulaimani, kurdistan, iraq conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12181 1 original paper considering the urolithiasis-related epidemiological factors as an important parameter, gender-based prevalence has been subjected to several studies where the male-tofemale ratio ranged from 1.3 to 3 (3). on the other hand, as a precious predictive factor, positive family history is a significant risk factor for stone formation in individuals with family members suffering from urolithiasis (4). geographic conditions are also important, and factors including climate, socioeconomic status, diet, and comorbidities may further affect the prevalence of stone formation (2, 5). components of metabolic syndrome like diabetes mellitus, hypertension, or obesity have also been implicated in constituting an additional risk for urinary stone formation (6). related to metabolic problems, in addition to less fluid intake, hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia are the most common urinary stone-forming risk factors identified, particularly in recurrent cases (7, 8). the dietary habits of the community, both in developing countries and in developed ones, are essential in stone formation by altering urine composition and increasing relevant risk status (9, 10). lastly, despite some contradictory reports, education might play a role in urolithiasis. some studies show that a lower education level may be a possible reason for stone formation (11, 12). in this present study, we aimed to assess certain clinical and metabolic factors to update epidemiological risk factors in the turkish population in a regional evaluationbased manner. methods ethics committee approval was obtained for the study from the local ethics committee with the number 2023/4203 on 17 february 2023. while conducting this study, the declaration of helsinki and international ethical standards were taken into consideration at every stage. a total of 2348 adult patients referring to the urology departments of different hospitals in the same region with sonography and/or computed tomography-proven stones were included in the study program. following close collaborative work with epidemiologists, our team designed a simple questionnaire and conducted a face-to-face survey. staff nurses and resident doctors in urology wards objective: to evaluate the metabolic and clinical characteristics of adult cases with stone disease from a regional part of turkey. methods: the study included 2348 adult patients with sonography and/or computed tomography-proven urinary stones. all cases were given a questionnaire about the epidemiological features of urolithiasis. aside from the type and severity of stoneforming risk factors, both patient (age, gender, bmi, associated comorbidities, first onset of stone disease, positive family history, educational level) and stone-related (size, number, location, chemical composition, previous stone attacks) factors have been thoroughly assessed. the data were evaluated in multiple aspects to outline the epidemiological features. results: the overall mean age value of the cases was 43.3 years, and the m/f ratio was 1.34. the first onset of the disease was found to vary between 15-57 years, with a mean value of 32.4 years. while most of the stones were located in kidney and ureter, calcium-containing stones constituted the most common type (caox 69%, caoxpo4 7%). more than 42% of the cases suffered from multiple stone attacks; positive family history waspresent in 31.6%. among the associated comorbidities, hypertension was the most common pathology (45.8%), and the bmi index value was > 30 in 31.3% of the cases. 57.7% of the patients had just one stone attack, and 42.2% had recurrent stone formation. conclusions: our findings clearly show that important implications may be extracted from epidemiologic data acquired from local scale research to implement an effective preventative program and closely monitor the patients. key words: urinary stones; epidemiology; kidney stones. submitted 11 december 2023; accepted 25 december 2023 introduction as an endemic problem in certain parts of the world, urolithiasis constitutes an evident risk to the healthcare system and a certain burden on the economy. the etiology of the disease is multifactorial, and an increase in incidence and prevalence ranging from 7% to 13% in north america, 5-8 % in europe, and 1-5% in asia has been reported (1). environmental and dietary factors, lifestyle, and some individual personal factors, such as age, gender, body mass index (bmi), and familial anamnesis, seem to play a critical role in the course of the disease (2). clinical characteristics of adult cases with urolithiasis from turkey: a regional epidemiological study mehmet ezer 1, rasim güzel 2, mehmet uslu 1, selçuk güven 3, kemal sarica 4, 5 1 department of urology, kafkas university, kars, turkey; 2 department of urology, medistate kavacık hospital, istanbul, turkey; 3 department of urology, necmettin erbakan university, konya, turkey; 4 department of urology, sancaktepe şehit prof. dr. ilhan varank training and research hospital, istanbul, turkey; 5 department of urology, biruni university medical school, istanbul, turkey. doi: 10.4081/aiua.2024.12181 summary archivio italiano di urologia e andrologia 2024; 96(1):12181 m. ezer, r. güzel, m. uslu, s. güven, k. sarica 2 completed each form after interviewing study participants prior to medical or surgical management of stones. regarding the questions with respect to the established epidemiological features of urinary calculi, in addition to the type and severity of stone-forming risk factors, both patient-related factors (such as age, gender, bmi, associated comorbidities, the first onset of stone disease, positive family history, educational level) and stone related factors (such as size, number, location, chemical composition, previous stone attacks) have all been evaluated and recorded. obtained data were assessed from multiple aspects to outline the epidemiological features in our patients. results evaluation of our data revealed the following findings. the mean age value of the 2348 adult cases was 43.3 years (15-69), and the gender distribution was 1346 males and 1002 females with an m/f ratio of 1.34. the first onset of the disease was found to vary between 15-57 years, with a mean value of 32.4 years (table 1). the majority of the stones were located in the kidney (62.3%) and ureter (35.2%), and calcium-containing stones constituted the most common type (caox 69%, caoxpo4 7%) (table 2). on referral, 57.7% of the cases had the first stone attack; 42.2% had recurrent stone formation. regarding the previous interventions for stone removal, pyelolithotomy was present in 12 patients (0,5%), cystolithotomy in 14 (0,6%), pcnl in 108 (4,6%), ureterorenoscopy in 213 (9%), and lastly swl in 284 cases (12 %) (table 2). a positive family history was present in 743 patients (31.6%) (table 2). positive family history was strongly associated with the mean age of the cases at first presentation and the disease's number of stone attacks (recurrence). stones are formed at younger ages in these cases, with more recurrent stone formation than those with no family history. of the clinical presentation symptoms noted, while the majority of the cases referred with colic pain (n:1902, 81%), 50.3% (n:1181) of the patients had microscopic hematuria, and 7.2% (n:169) presented with macroscopic hematuria. high-grade hydronephrosis (grade 3-4) was present at first presentation in 14.2% of the cases, and 53.3% had no dilatation (table 3). among the associated comorbidities evaluated, while hypertension was present in 45.8% of the cases, diabetes was present in 2.8%, hypercholesterolemia in 27.6%, and obesity in 31.3% (in 735 cases, bmi index value was 3035). while the mean bmi was 25.7 ± 8.8 in male patients, this value was 26.8±9.2 in female cases (table 3). table 1. evaluation of the patient characteristics and stone-related factors by gender. male female total number of cases (n) 1346 1002 mean age of the cases (years) 42.6 ± 9.8 44.3 ± 11.3 first onset of the disease (years) 31.7 ± 10.2 33.5 ± 12.8 stone size (mm) 1.3 ± 0.8 1.1 ± 0.6 height (cm) 170.1 ± 9.7 165.7 ± 10.2 body weight (kg) 75.0 ± 9.4 79.2 ± 10.2 body mass index (bmi) (kg/m2) 25.7 ± 8.8 26.8 ± 9.2 table 2. urolithiasis characteristics of the patients at first presentation. total male female n % n % n % stone analysis data 1945 82.8 981 72.9 964 96.2 calcium oxalate 1342 69 703 71.7 639 66.3 calcium phosphate 136 7 74 7.5 62 6.4 infection stones 233 12 86 8.8 147 15.2 uric acid 156 8 83 8.5 73 7.6 cystine 78 4 35 3.5 43 4.5 number of stone episodes one episode 1355 57.7 731 54.3 624 62.3 2-4 episodes 647 27.6 388 28.8 259 25.8 5 and more 346 14.7 227 16.9 119 11.9 stone localization at the first presentation kidney 1463 62.3 786 58.4 677 67.5 single 696 29.6 372 27.6 324 32.3 multiple 767 32.7 414 30.8 353 35.2 ureter 826 35.2 437 32.5 389 38.8 bladder 59 2.5 59 4.4 0 0 previous interventions pyelolithotomy 12 0.5 7 0.5 5 0.5 uretrorenoscopy 213 9 134 10 79 7.9 pcnl 108 4.6 53 3.9 55 5.5 cystolithotomy 14 0.6 14 1 0 0 swl 284 12 123 9.1 161 16.1 family history positive 743 31.6 331 24.5 412 41.1 table 3. clinical characteristics of the patients at first presentation. total male female n % n % n % total number of cases 2348 100 1346 57.9 1002 42.1 associated morbidities hypertension 1075 45.8 623 46.3 452 45.1 diabetes mellitus 66 2.8 29 2.2 37 3.7 hypercholesterolemia 648 27.6 403 29.9 245 24.5 obesity (bmi of > 30) 735 31.3 347 25.8 388 38.7 presence of urinary tract infection (uti) 802 34.2 114 8.5 688 68.6 presence of obstruction (sonographic findings) none 1252 53.3 883 65.6 369 36.8 grade i 356 15.2 124 9.2 232 23.2 grade ii 406 17.3 226 16.8 180 18 grade iii 187 8 52 3.9 135 13.5 grade iv 147 6.2 61 4.5 86 8.5 presence of hematuria microscopic 1181 50.3 671 49.9 510 50.9 macroscopic 169 7.2 87 6.5 82 8.2 presence of pain * no 446 18.9 253 18.8 193 19,3 mild (vas 1-3) 680 29 408 30.3 272 27,1 moderate (vas 4-6) 483 20.6 267 19.8 216 21,6 severe (vas ≥ 7) 739 31.5 418 31.1 321 32 * evaluation according to visual analogus sclala 0-10. archivio italiano di urologia e andrologia 2024; 96(1):12181 3 clinical characteristics of adult cases with urolithiasis from turkey when the education level of the cases was evaluated, 36.4% (n = 856) were primary school graduates, 14.3% (n = 335) were secondary school graduates, 34.5% (n = 810) were high school graduates, and 14.8% (n = 347) were college graduates. discussion urinary system stone disease is an endemic pathology in many parts of the world, which poses an evident risk to the healthcare system with a significant burden on the economy. the etiology of the disease is multifactorial, consisting of several risk factors evaluated in detail so far. regarding the evident differences among several regions and countries of the world, variations in specific etiologic parameters like age, gender, dietary preferences, fluid consumption, the climate they live in, their occupation, level of education, socioeconomic status, and genetic and metabolic factors have been considered to be responsible (2, 9). on the other hand, the formation of new stones based on the present metabolic and other risk factors is commonly observed, particularly in recurrent stone-forming cases. studies on this aspect have revealed that after the initial stone passage, the rate of stone recurrence in patients with previous urolithiasis was reported to be 40% at five years and 75% at 20 years, respectively (13). considering all these facts, it is clear that data from regional epidemiological studies will help us assess the prevalence and underlying etiological factors, which will support developing policies for effective metaphylaxis and treatment of the disease appropriately. in other words, in light of reported evident geographic differences in the prevalence of urolithiasis, well-conducted local/regional studies may provide a detailed understanding of the disease nationwide. when we look at the studies examining the effect of gender on kidney stone formation, several gender-based studies have shown that although infection stones were more commonly reported in women, the general incidence of urinary calculi tends to be more frequent in men (14, 15). statistics show that males tend to indulge in higher amounts of alcohol and coffee as well as meat consumption compared to females. moreover, it has been observed that testosterone can increase the likelihood of stone formation, whereas estrogen plays a role in inhibiting stone formation by regulating the synthesis of 1.25dihydroxy-vitamin d (5). stone formation is often linked to anatomical factors, with infravesical obstruction being a common risk factor. this obstruction is usually caused by benign prostatic hyperplasia or urethral stricture (16). in many countries, it has been observed that the ratio in favor of females is increasing while the ratio in favor of males is decreasing. changes observed in the living standards resulting in the differences in diet, lifestyle, and occupations of the female population could be responsible for the decreased ratio (17). as another important factor affecting the prevalence of stone disease, geographic conditions may also affect the occurrence of urolithiasis (2, 5). differences in factors such as climate, socioeconomic status, race, genetics, dietary habits, and the presence of other medical conditions may contribute to significant variations in the prevalence of kidney stone formation in a particular geographic or regional area. this scenario has the potential to mirror the urolithiasis problem at a national and even global level. apart from commonly diagnosed urinary tract infections, patients with urolithiasis frequently present with the component pathologies of metabolic syndrome like diabetes mellitus, hypertension, or obesity, which could potentially be another factor that increases the risk for urinary stone formation (2, 18). the involved patients' associated comorbidities and metabolic factors play a specific role in the presence and severity of urinary stoneforming risk factors. related to this important subject, in addition to reduced fluid intake, decreased urine output, hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia are the most commonly reported risk factors for stone formation in adults and children (7, 8). based on this fact, a comprehensive metabolic evaluation seems mandatory in risk group cases prone to form recurrent stones requiring interventional procedures for a stone-free status. considering the formation of metabolic risk factors in these cases, apart from the lifestyle playing a significant role in the formation of stones, the dietary habits of the community have a more critical role. while cereals and vegetables contain high levels of oxalate and its precursors are widely consumed in developing countries, in the western part of the world, a westernized diet containing excessive protein, lipid, calcium, and sodium is also important in stone formation, changing the urine composition and increasing the associated risk status (9, 19). among the dietary risk factors evaluated so far, in addition to excessive calcium and oxalate-rich food consumption, a high sodium intake may increase calcium absorption into the blood or decrease absorption from urine into renal tubular cells, resulting in hypercalciuria. on the other hand, higher consumption of animal protein can also lead to urine acidification (10). last but not least, education might play a role in urolithiasis. in support of this, data from studies in iran and turkey suggest that lower education levels may contribute to kidney stone formation (11, 20). however, some studies also show a negative relationship between the incidence of stone disease and the education level or occupation (12, 21). taking all the above facts, we believe that significant implications could be derived from the epidemiologic data obtained from local scale studies. with this aim to update urolithiasis epidemiological data by examining certain epidemiological risk factors in the turkish population, we conducted this study. our findings revealed valuable data showing useful clinical implications that could be derived from our trial. the majority of the stones were located in the upper tract and were calcium-containing stones. the number of stone attack episodes was an important issue, and most cases did present with the first attack (57.7%), where a limited percentage had high recurrence rates with more than five attacks (14.7%). men were affected by the disease at relatively younger ages than women. hypertension was the most common co-morbidity. additionally, as another important component of metabolic syndrome, bmi values archivio italiano di urologia e andrologia 2024; 96(1):12181 m. ezer, r. güzel, m. uslu, s. güven, k. sarica 4 were well evaluated, and 31.3% of the cases had severe obesity with bmi values of > 30. on the first presentation, most cases presented with persistent microscopic hematuria (50.3%), and recurrent infection, colic pain were the other presenting symptoms. 26.8% of the patients have a previous stone-related intervention. a considerable percentage of the cases have severe (grade iii-iv) obstruction at first evaluation. last but not least, positive family history was a critical and predictive parameter noted where 1/3 of all cases did have this history, and men were more likely to have this anamnesis. this parameter affected the course of the disease, and mean age at first onset was less in these cases. also, stone attacks were higher in these cases than in patients without family history. our study is not free of limitations. the number of patients evaluated may be limited, and the need for a control group may constitute another critical drawback. however, taking limited information regarding the epidemiological data on stone disease, particularly in a regional evaluation-based manner, we believe our findings will be contributive to a greater extent. additionally, taking the endemic nature of the stone disease in our country, these values coming from a regional part of the country will give further insights into the epidemiologic features of the disease. conclusions in light of the data published so far and our findings obtained in adult cases with urinary stones, we may say that local and regional epidemiological studies focusing on personal, environmental, and metabolic risk factors could be critical. these data can be used to derive practical, predictive clinical implications from limiting the risk of stone recurrence, lowering the economic burden of the disease, and outlining the most rational treatment alternative. references 1. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol 2017; 35:1301-20. 2. stamatelou k, goldfarb ds. epidemiology of kidney stones. healthcare 2023; 11:424 3. worcester em, coe fl. clinical practice. calcium kidney stones. n engl j med 2010; 363:954-63. 4. huang wy, chen yf, carter s, et al. epidemiology of upper urinary tract stone disease in a taiwanese population: a nationwide, population based study. j urol 2013; 189:2158-63. 5. marya rk, dadoo rc, sharma nk. genetic predisposition to renal stone disease in the first-degree relatives of stone-formers. urol int 1981; 36:245-7. 6. trinchieri a. epidemiological trends in urolithiasis: impact on our health care systems. urol res 2006; 34:151-6. 7. soligo m, morlacco a, zattoni f, et al. metabolic syndrome and stone disease. panminerva med 2022; 64:344-58. 8. chandrajith r, wijewardana g, dissanayake cb, abeygunasekara a. biomineralogy of human urinary calculi (kidney stones) from some geographic regions of sri lanka. environ geochem health 2006; 28:393-9. 9. yasui t, iguchi m, suzuki s, kohri k. prevalence and epidemiological characteristics of urolithiasis in japan: national trends between 1965 and 2005. urology 2008; 71:209-13. 10. trinchieri a. diet and renal stone formation. minerva med 2013; 104:41-54. 11. nasir sj. the mineralogy and chemistry of urinary stones from the united arab emirates. qatar univ sci j 1999; 18:189-202 12. muslumanoglu ay, binbay m, yuruk e, et al. updated epidemiologic study of urolithiasis in turkey. i: changing characteristics of urolithiasis. urol res 2011; 39:309-14. 13. lee yh, huang wc, tsai jy, et al. epidemiological studies on the prevalence of upper urinary calculi in taiwan. urol int. 2002; 68:172-7. 14. scales jr. cd, curtis lh, norris rd, et al. changing gender prevalence of stone disease. j urol 2007; 177:979-82. 15. strope sa, wolf jr. js, hollenbeck bk. changes in gender distribution of urinary stone disease. urology 2010; 75:543-6, 546.e1. 16. sierakowski r, finlayson b, landes rr, et al. the frequency of urolithiasis in hospital discharge diagnoses in the united states. invest urol 1978; 15:438-41. 17. silva gr, maciel lc. epidemiology of urolithiasis consultations in the paraíba valley. rev col bras cir 2016; 43:410-5. 18. shastri s, patel j, sambandam kk, lederer ed. kidney stone pathophysiology, evaluation and management: core curriculum 2023. am j kidney dis 2023; 82:617-634 19. yitgin y, asrak h, tefik t. role, importance and assessment of dietary habits in urolithiasis patient. world j urol 2023; 41:1229-33. 20. basiri a, shakhssalim n, khoshdel ar, et al. the demographic profile of urolithiasis in iran: a nationwide epidemiologic study. int urol nephrol 2010; 42:119-26. 21. abomelha ms, al-khader aa, arnold j. urolithiasis in saudi arabia. urology 1990; 35:31-4. correspondence mehmet ezer, md (corresponding author) mehmetezer@gmail.com department of urology, kafkas university, kars, turkey, 36100 mehmet uslu, md dr.mhmtuslu@gmail.com department of urology, kafkas university, kars, turkey rasim güzel, md rasimguzel@hotmail.com department of urology, medistate kavacık hospital, istanbul, turkey selçuk güven, md selcukguven@hotmail.com department of urology, necmettin erbakan university, konya, turkey kemal sarıca, md saricakemal@gmail.com department of urology, sancaktepe şehit prof. dr. ilhan varank training and research hospital, istanbul, turkey department of urology, biruni university medical school, istanbul, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14172 1 review introduction lower urinary tract symptoms (luts), including urgency, frequent urination, urinary incontinence (ui), and nocturia, whether occurring individually or as part of a syndrome known as overactive bladder (oab), are prevalent and distressing conditions that affect millions of individuals worldwide (1-3). epidemiological studies reveal that these symptoms impact 12% to 18% of communitydwelling men, with incidence increasing with age (2-4). initial therapies for ui and oab include non-invasive behavioral approaches and/or pharmacological treatments, tailored to the patient’s goals and preferences. pharmacologic interventions are frequently commenced for particular oab symptoms, such as urgency (with or without ui), frequency, and nocturia. however, recent findings indicate that pharmaceutical interventions, including anticholinergic bladder relaxants, are frequently abandoned due to unpleasant side effects or perceived ineffectiveness (4). moreover, growing concerns have emerged regarding their potential long-term adverse effects on cognitive function (5). as a result, there is a clear need to develop alternative strategies that promote prevention and early intervention, particularly for men affected by ui and oab. vitamin d supplementation has been proposed as a simple and potentially effective strategy for alleviating luts, especially storage problems associated with oab. vitamin d receptors are present in the detrusor muscle of the bladder and the prostate (6, 7), and vitamin d administration may enhance smooth and skeletal muscle performance while decreasing prostate growth (8, 9). thus, vitamin d may contribute to improved bladder control by directly enhancing detrusor smooth muscle activity and reducing the sensation of urgency. however, the relationship between vitamin d and ui remains unclear, as research findings have been contradictory. background: urinary incontinence (ui) and overactive bladder (oab) are common lower urinary tract symptoms that significantly impact quality of life. conventional pharmacologic treatments are often associated with side effects and limited efficacy, highlighting the need for alternative therapies. vitamin d, known for its role in muscle function and its presence in the receptors of the bladder and prostate, has been proposed as a potential non-invasive intervention. this study aimed to evaluate the effectiveness of vitamin d supplementation in the management of ui and oab. methods: a systematic review and meta-analysis were conducted in accordance with the prisma guidelines. twelve studies (six rcts and six cohort studies) were included. study quality was assessed using the newcastle-ottawa scale (nos) and the cochrane risk of bias tool. statistical analysis was conducted using review manager 5.4. standardized mean differences (smds) and risk ratios (rrs) were used to compare outcomes. a meta-analysis was performed using a random-effects model, which was applied due to heterogeneity, as assessed by the i² statistic. sensitivity analysis was performed using the leaveone-out method. results: no significant difference was found between the vitamin d and control groups in improving ui scales (smd = -1.04; 95% ci: -2.35 to 0.27, p = 0.12) with an i² of 94%. there were no significant effects on the risk of oab (rr = 1.03, p = 0.16) or ui (rr = 0.88, p = 0.59), nor on ui improvement or worsening. the sensitivity analysis revealed that excluding one unusual study resulted in more consistent results and confirmed similar patterns. conclusions: i no substantial advantage of vitamin d was observed in ui or oab patients compared to the control groups. key words: vitamin d; urinary incontinence; overactive bladder. submtted 24 july 2025; accepted 1 august 2025 effectiveness of vitamin d supplementation in managing urinary incontinence and overactive bladder: a systematic review and meta-analysis saad thamer alshahrani 1, naif alamri 2, mohammad dhafer asiri 3, meshal omar albabtain 4, raed alwadai 5, hassan m. assiri 1, saleh alghamdi 1, ali thamer alshahrani 6, mohanad jebril bosily 7, hussain munyif 8, omar safar 1 1 urology department, armed forces hospital southern region, khamis mushayt, saudi arabia; 2 urology department, saudi german hospital, asir, saudi arabia; 3 urology department, health cluster 1, riyadh, saudi arabia; 4 urology department, king saud medical city, riyadh, saudi arabia; 5 urology department, king abdullah hospital, bisha, asir, saudi arabia; 6 college of medicine, king khalid university, abha, saudi arabia; 7 ministry of health, aseer health cluster, asir, saudi arabia; 8 urology department, king khalid hospital, najran city, saudi arabia. doi: 10.4081/aiua.2025.14172 summary archivio italiano di urologia e andrologia 2025; 97(3):14172 s. thamer alshahrani, n. alamri, m. dhafer asiri, et al. 2 vitamin d is a lipophilic molecule mostly acquired by solar exposure or dietary consumption. vitamin d attaches to vitamin d-binding protein in the body and is metabolized to 25-hydroxyvitamin d [25(oh)d] by 25-hydroxylase in the liver; its concentration is typically utilized to evaluate an individual's vitamin d status. in primary cultures of satellite cells, 1,25-dihydroxyvitamin d3 was observed to enhance myogenic differentiation and myotube formation by elevating the expression of myogenic regulatory proteins, including myogenin (10). the research conducted by van der meijden et al. (11) further demonstrated that higher levels of vitamin d support the differentiation and maturation of skeletal muscle cells, leading to increased myotube fiber diameter and enhanced muscle performance. these findings suggest a potential novel approach for treating ui. however, the relationship between vitamin d levels and urinary symptoms remains unclear, with studies showing conflicting results. therefore, this systematic review aims to evaluate the effectiveness of vitamin d supplementation in the management of oab and ui. methods study design the systematic review adhered to the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines (12). the prospero registration number was given to the protocol of this systematic review [crd420251107352]. definition of inclusion criteria and targeted outcomes the inclusion criteria focused on studies evaluating the effectiveness of vitamin d supplementation in managing overactive bladder (oab) and urinary incontinence (ui). eligible study designs included randomized controlled trials (rcts) and cohort studies. the review was guided by the pico framework, where the population consisted of patients with oab or ui, the intervention involved vitamin d supplementation, and the comparator included placebo, no intervention, or lower doses of vitamin d, where applicable. the outcomes of interest were efficacy measures, particularly improvements in urinary symptoms. studies were excluded if they presented insufficient or unclear outcome data, or if they were laboratory-based studies, posters, study protocols, case studies, case series, case reports, abstract-only publications, reviews, or articles not published in english. search strategy a comprehensive search for systematic reviews was conducted across the following electronic databases for articles published from inception to march 2025: pubmed, cochrane library, scopus, and web of science. the search strategy employed a combination of keywords and medical subject headings (mesh) related to the pico framework. terms such as "urinary incontinence", "overactive bladder", and "vitamin d" were combined using boolean operators (and/or) to capture relevant studies. filters were applied to include only english-language studies from the last 10 years and focus on specific study types, such as clinical trials, rcts, and retrospective studies, ensuring relevance to the research question. additionally, reference lists of relevant articles were reviewed to ensure thorough coverage of the available evidence. screening and extraction initially, articles with irrelevant titles were excluded. in the subsequent phase, both the full text and abstracts of papers were meticulously reviewed to determine their compliance with the inclusion criteria. to streamline the process, titles and abstracts were organized and screened using endnote version 8, and duplicate records were removed. the titles and abstracts were independently screened by two reviewers, followed by a full-text assessment based on predefined inclusion and exclusion criteria. full-text articles meeting the inclusion criteria undergo further assessment. baseline characteristics and outcome data were extracted in excel sheets. any differences of opinion were resolved by consensus or by referring them to a senior author. quality assessment the newcastle-ottawa scale (nos) was used for non-randomized studies, including retrospective or prospective cohort designs. scores were interpreted as low quality if they received 0-3 stars, moderate quality if they received 4-6 stars, and high quality if they received 7-9 stars (13). for randomized controlled trials (rcts), the cochrane risk of bias tool was used. this tool systematically evaluated various domains of bias, including selection bias, performance bias, detection bias, attrition bias, and reporting bias. each study was carefully reviewed to determine whether the authors had implemented adequate measures to minimize these biases. statistical analysis the statistical analysis was done using review manager 5.4 software. we compared the continuous outcomes using the standardized mean difference (smd), given the difference in measurement scales. we compared the dichotomous data using the risk ratio (rr). heterogeneity was assessed using i², with a p-value of 0.05. a randomeffects model was used to account for the heterogeneity among the outcomes. sensitivity analysis using the leaveone-out method was used to resolve the heterogeneity. all the steps were done at 95% confidence intervals (ci), and p-values were considered significant if they were less than or equal to 0.05. results search results the searching process resulted in a total of 221 articles from the included databases. these encompassed 123 duplicates, so we conducted title and abstract screening on the remaining 98 articles. in this phase, 81 articles were excluded, and 17 were included for full-text screening, resulting in 12 articles archivio italiano di urologia e andrologia 2025; 97(3):14172 3 vitamin d in urinary incontinence and overactive bladder being selected for the current systematic review and meta-analysis (figure 1). results of quality assessment the quality of the six included cohort studies was assessed using nos, which evaluates studies based on three domains: selection of study groups (maximum four stars), comparability of groups (maximum two stars), and ascertainment of either the exposure or outcome (maximum three stars). three studies vaughan (2021), markland (2020), and vaughan (2022) received the highest overall rating of 9 stars, indicating strong methodological quality across all domains. these studies achieved full scores in selection and outcome/exposure, and were rated with two stars in comparability, suggesting robust control of confounding variables. özçift and micoogullari (2022) and yoo (2018) scored seven stars each, reflecting slightly lower quality due to limited comparability and fewer stars in the outcome domain. aydogmus (2023) received the lowest rating of 5 stars, with limited strength in both selection and comparability domains. overall, the majority of studies included in the review demonstrated moderate to high methodological quality, with careful selection and adequate outcome assessment; however, variation in the control for confounding was noted (table 1). the risk of bias across the six included rcts was evaluated using the cochrane risk of bias tool, covering seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. shahraki (2022) demonstrated the highest methodological rigor, with a low risk of bias across all domains, indicating strong internal validity. markland (2023) and markland (2022), although showing figure 1. prisma flow diagram of searching and screening processes. archivio italiano di urologia e andrologia 2025; 97(3):14172 s. thamer alshahrani, n. alamri, m. dhafer asiri, et al. 4 low risk in most categories, exhibited high risk of bias in selective reporting and other biases, potentially affecting the reliability of their outcomes. markland (2019) showed a low risk in most areas, but allocation concealment was unclear, which slightly weakened its overall robustness. arjmand (2023) had unclear risk in three domains – allocation concealment, blinding of participants and personnel, and outcome assessment – raising concerns about potential performance and detection bias. the oberg (2017) study had multiple areas of concern, including unclear randomization, allocation, and performance blinding, as well as a high risk of bias in outcome assessment, indicating a greater potential for bias. overall, while several studies were methodologically sound, a few showed risks, particularly in blinding and reporting, that should be considered when interpreting their findings (table 2). baseline characteristics the baseline characteristics of the included studies reveal a diverse representation of populations across various countries and age groups, focusing on the relationship between vitamin d supplementation and ui or oab symptoms. six studies were rcts and six were cohort studies. study populations ranged from children [mean age 7.71 years (14)] to older adults [mean age 71.6 years (15)], with sample sizes varying widely from small randomized controlled trials [e.g., 30 participants per arm (16)] to large cohort studies [e.g., 59355 participants (17)]. most studies focused on women, with several targeting postmenopausal women or those with specific ui subtypes, while a few included men (18, 19). the interventions involved varying doses and forms of vitamin d, from low daily doses to high-dose regimens such as 50,000 iu weekly (20) or a single intramuscular dose of 200,000 iu (21). control groups primarily received placebos, no intervention, or lower doses of vitamin d. collectively, the baseline characteristics underscore substantial heterogeneity in study design, intervention protocols, control group, and target demographics (table 3). statistical analysis no significant difference was observed between vitamin d and the control groups regarding the effect on ui scales with smd = -1.04 (95% ci: -2.35, 0.27, p = 0.12) and i2 = 94%, p < 0.00001 (figure 2). no significant difference was observed between vitamin d and controls regarding the risk of oab (rr: 1.03; 95% ci: 0.99 to 1.07, p = 0.16, and i2 = 45%, p = 0.16) and ui (rr: 0.88; 95% ci: 0.57 to 1.37, p = 0.59, and i2 = 93%, p < 0.00001) (figures 3, 4). no significant difference was observed between vitamin d and control in ui improvement (rr: 1.57, 0.31, 7.78, p = 0.58, and i2 = 76%, p = 0.04) or worsening (rr: 1.37; 95%ci: 0.82, 2.3, p = 0.23, and i2 = 96%, p < 0.00001) (figures 5, 6). sensitivity analysis sensitivity analysis using the leave-one-out method revealed that removing shahraki 2022 (4) (high control values) resolved the heterogeneity in the ui scales, with smd = -0.34 (95% ci: -0.9, 0.21, p = 0.23) and i² = 55%, p = 0.14. (figure 7). table 2. the cochrane risk of bias assessment for rct. study random allocation blinding blinding incomplete selective other sequence concealment of participants of outcome outcome reporting bias generation and personnel assessment data arjmand 2023 (7) low unclear unclear unclear low low low markland 2023 (8) low low low low low high high shahraki 2022 (9) low low low low low low low markland 2019 (10) low unclear low low low low low oberg 2017 (11) unclear unclear unclear high low low unclear markland 2022 (12) low low low low low high high table 1. the nos quality assessment for non-randomized studies. studies selection comparability exposure/outcome overall star rating aydogmus 2023 (1) ** * ** 5 vaughan 2021 (2) **** ** *** 9 markland 2020 (3) **** ** *** 9 özçift and micoogullari 2022 (4) **** * ** 7 yoo 2018 (5) *** ** ** 7 vaughan 2022 (6) **** ** *** 9 archivio italiano di urologia e andrologia 2025; 97(3):14172 5 vitamin d in urinary incontinence and overactive bladder table 3. baseline characteristics of the included studies. study id study population country study intervention control sample size mean age, (sd) male, n (%) dose of design period intervention control intervention control intervention control vitamin d arjmand 2023 (7) rct postmenopausal women iran 2019–2020 vitamin d placebo 45 45 58 (5) 57 (5) 0 (0) 0 (0) vitamin d3 with urgency urinary (50,000 iu) tablets incontinence weekly for 8 weeks aydogmus 2023 (1) cohort postpartum urinary pelvic floor incontinence belgium nr vitamin d muscle 29 28 27.8 (5.9) 27.4 (4.6) 0 (0) 0 (0) 1200 iu daily training group vitamin d for 12 weeks markland 2023 (8) rct older men with overactive usa between november vitamin d placebo 2823 2830 68 (7) 68 (7) 2823 (100) 2830 (100) vitamin d3 2000 iu bladder and urinary 2011 and march incontinence symptoms 2014 shahraki 2022 (9) rct premenopausal women iran 2020 and 2021 vitamin d placebo 30 30 44.53 (2.5) 44.23 (2.4) 0 (0) 0 (0) 5000 iu vitamin d with stress urinary incontinence weekly for 3 months and vitamin d insufficiency markland 2019 (10) rct women with urgency usa from 2013–2017 vitamin d placebo 28 28 61.4 (7.1) 59.5 (9.2) 0 (0) 0 (0) weekly oral 50,000 urinary incontinence iu vitamin d3 for 12 weeks vaughan 2021 (nhs-i) (2) cohort women with urinary usa 2004–2012 >=1000 iu 0–<200 iu vitamin d 2213 3063 71.6 (6.78) 70.72 (7) 0 (0) 0 (0) 0-200 iu or >=1000 iu incontinence vitamin d intake intake daily vitamin d intake vaughan 2021 (nhs-ii) (2) cohort women with urinary usa 2005–2013 >=1000 iu 0–<200 iu vitamin d 1082 2669 52.97 (4.09) 50.53 (4.53) 0 (0) 0 (0) 0-200 iu or incontinence vitamin d intake intake >=1000 iu daily vitamin d intake markland 2020 (nhs-i) (3) cohort women with urgency urinary usa 2004–2012 >=1000 iu 0–<200 iu vitamin d 3912 6472 68 (7) 67 (7) 0 (0) 0 (0) 0-200 iu or >=1000 iu daily incontinence vitamin d intake intake vitamin d intake markland 2020 (nhs-ii) (3) cohort women with urgency urinary usa 2005–2013 >=1000 iu vitamin d 0–<200 iu vitamin d 2956 7555 52 (4) 49 (5) 0 (0) 0 (0) 0-200 iu or >=1000 iu daily incontinence intake intake vitamin d intake oberg 2017 (11) rct postmenopausal women norway 2007-2010 high dose vitamin d standard dose 134 139 62.8 (7.5) 63.4 (6.9) 0 (0) 0 (0) 20000 iu daily in the high with lower urinary tract symptoms vitamin d dose group and 400 iu of vitamin d3 twice daily in the standard dose group özçift and micoogullari 2022 (4) cohort children with overactive bladder turkey between may vitamin d na 34 na 7.71 (2.66) na 16 (48) na oral vitamin d3 2000 iu/day related urinary incontinence 2017 and july 2021 was pres cribed for 8 weeks yoo 2018 (5) cohort men with lower urinary tract korea between march 2014 vitamin d na 255 na 59.4 (11.4) na 255 (100) na intramuscular injection symptoms and april 2017 of 200000 iu in a single dose vaughan 2022 (6) cohort women from mid-life through usa nr vitamin d (>=1000 iu) no vitamin d 36789 22566 67 (6.5) 67 (6.9) 0 (0) 0 (0) >=1000 iu older ages with overactive bladder markland 2022 (12) rct older women with urinary usa 2011 to 2018 vitamin d placebo 5213 5222 70 (7) 70 (7) 0 (0) 0 (0) 2000 iu/day incontinence na: not applicable; rct: randomized controlled trial. figure 2. comparison between vitamin d and controls in their effect on urinary incontinence scales. archivio italiano di urologia e andrologia 2025; 97(3):14172 s. thamer alshahrani, n. alamri, m. dhafer asiri, et al. 6 figure 3. comparison between vitamin d and controls in the risk of overactive bladder. figure 4. comparison between vitamin d and controls in the risk of urinary incontinence. figure 5. comparison between vitamin d and controls in urinary incontinence improvement. figure 6. comparison between vitamin d and controls in urinary incontinence worsening. figure 7. leave-one-out analysis of the comparison between vitamin d and controls in their effect on urinary. archivio italiano di urologia e andrologia 2025; 97(3):14172 7 vitamin d in urinary incontinence and overactive bladder discussion summary of findings this systematic review and meta-analysis examined the potential effect of vitamin d supplementation in alleviating symptoms of ui and oab. the study encompassed a diverse population, including children, postpartum women, postmenopausal women, and elderly individuals of both genders. this demonstrated the diversity of the impacted groups. in the comparison of vitamin d supplementation against a placebo or other control circumstances for its effect on urinary symptoms, no statistically significant changes were observed. nonetheless, an examination of scores before and during therapy revealed a persistent tendency toward enhancement among the intervention groups. the analysis of risk ratios did not demonstrate that vitamin d supplementation significantly decreased or increased the likelihood of developing ui or oab. the comparisons of the improvement or worsening of symptoms revealed no significant differences between the vitamin d group and the control group. nonetheless, considerable variability existed among the studies, likely because of the extensive range of dosages, methods of administration, study populations, baseline vitamin d levels, and procedures employed to assess outcomes. sensitivity analysis elucidated the conclusions by highlighting which studies exerted a disproportionate influence on the outcomes and the variations among them. the research indicates that vitamin d supplementation may not consistently outperform control therapies across all parameters. clinical implications and investigation with current literature current evidence does not support routine vitamin d screening or supplementation solely for ui/oab in the general older adult population. major trials (e.g., vital ancillary studies) found no improvement in oab or ui prevalence/incidence with vitamin d3 2000 iu/day over several years (8, 12). however, vitamin d deficiency is common in certain high-risk groups (e.g., older adults with pelvic floor disorders, pregnant/postpartum women, and children with oab (4, 13). in these subpopulations, clinicians might consider checking vitamin d levels. several observational studies and a systematic review and meta-analysis reported associations between low vitamin d and worse lower urinary tract symptoms (luts)/ui (5, 14-16). for example, pregnant women in late gestation with vitamin d deficiency had higher ui prevalence and severity (13). in children with oab, deficiency was far more common than in healthy controls (4). thus, assessing vitamin d status is reasonable in treatment-refractory ui/oab, particularly if other deficiency risk factors are present (e.g., limited sun exposure, malabsorption, darker skin) (4, 13). a previous systematic review by bapir et al. (17) also evaluated treatments for urge incontinence in postmenopausal women and identified limited but suggestive evidence for vitamin d efficacy in selected cases. for patients with confirmed vitamin d deficiency and symptoms of ui/oab, supplementation may be considered as an adjunct. small trials suggest benefits in specific contexts: for example, in premenopausal women with stress ui and vitamin d insufficiency, 8-12 weeks of highdose vitamin d3 (5,000 iu weekly) significantly reduced leakage scores vs placebo (9). in children with oab, an 8week regimen of vitamin d3 2,400 iu/day, combined with standard urotherapy, resulted in greater improvements in voiding frequency, urgency, nocturia, and quality of life compared to urotherapy alone(18). similarly, postpartum women with ui who received vitamin d replacement showed greater increases in pelvic floor strength (oxford score) and larger decreases in incontinence questionnaire scores than those doing pelvic-floor exercises alone (1). in sum, when deficiency is documented, supplementation (often at higher-than-routine doses) might improve symptoms. nevertheless, vitamin d should not replace guideline-based ui/oab care (such as behavioral therapy, pelvic floor training, and pharmacotherapy) but can be an adjunct for patients with deficiency. adequate dietary calcium and monitoring of serum 25(oh)d are advised if high-dose regimens are used. regarding the dosing of vitamin d, typical large trials used moderate doses (e.g. 2000 iu/day), which did not improve ui/oab (8, 12). in contrast, trials that reported benefit used higher dosing. one rct administered 5,000 iu of vitamin d3 once weekly for 3 months to premenopausal women (9). the pediatric trial used 2,400 iu daily for 8 weeks (18). these regimens quickly raised 25(oh)d levels above 30 ng/ml. thus, when considering vitamin d therapy for ui/oab, clinicians might aim for a serum 25(oh)d level in the sufficient range (≥ 30 ng/ml) using adequate dosing; treatment durations in studies have ranged from 8 weeks to 5 years. however, the optimal dose and duration remain uncertain. careful monitoring is warranted to avoid hypervitaminosis d. strengths and limitations this review provides a comprehensive synthesis of available rcts and cohort studies evaluating the impact of vitamin d supplementation on ui and oab. a key strength lies in the inclusion of diverse populations spanning multiple age groups, from children to older adults, and various clinical subtypes of ui. additionally, the employment of sensitivity analyses, including leave-oneout testing, strengthened the robustness of findings and helped identify sources of heterogeneity across studies. this systematic approach enables a more accurate interpretation of both between-group and within-group effects of vitamin d supplementation. the findings are limited by significant heterogeneity across included studies in terms of population demographics, vitamin d dosages, treatment durations, baseline vitamin d status, and outcome assessment tools. many studies had small sample sizes or short follow-up periods, which may reduce statistical power and limit the generalizability of results. the meta-analysis included both randomized and observational studies, which, while increasing data breadth, introduces potential biases such as confounding and selection bias. moreover, few studies have stratified participants based on baseline vitamin d levels, making it difficult to isolate the effects of repletion in individuals with deficient versus sufficient levels. archivio italiano di urologia e andrologia 2025; 97(3):14172 s. thamer alshahrani, n. alamri, m. dhafer asiri, et al. 8 recommendations the findings of this review suggest that while vitamin d supplementation does not consistently demonstrate superiority over control interventions for ui or oab. clinicians should consider assessing vitamin d status in individuals presenting with persistent or treatment-resistant ui or oab, especially among high-risk groups such as postmenopausal women, older adults, postpartum women, and children with oab. these populations are more likely to exhibit vitamin d insufficiency, which may influence pelvic floor muscle function and bladder detrusor activity. vitamin d supplementation may be used as an adjunct to standard ui/oab management in patients with confirmed deficiency. although its use should not replace evidence-based first-line treatments such as pelvic floor muscle training, bladder retraining, or pharmacologic therapy, supplementation may help enhance therapeutic outcomes. higher-dose regimens, such as weekly or daily supplementation for short durations, appear to be more effective in improving urinary symptoms than low-dose maintenance therapy. however, individualization and monitoring are essential to prevent hypervitaminosis d. for researchers, future clinical trials should adopt standardized definitions of ui and oab, utilize validated outcome measures, and stratify participants according to baseline serum vitamin d levels. longer follow-up durations and adequately powered sample sizes are necessary to evaluate the sustained effects of supplementation. studies should also focus on identifying specific subgroups, such as those with stress incontinence, postpartum incontinence, or pediatric oab, that may benefit most from vitamin d therapy. conclusions the results of this meta-analysis reveal that vitamin d supplementation does not produce a statistically significant improvement in ui or oab symptoms when compared directly with control groups. no meaningful differences were found in the risk of developing ui or oab, nor in the likelihood of symptom improvement or worsening between intervention and control arms. the included studies exhibited considerable heterogeneity in terms of populations, dosing regimens, and outcome measures, which likely contributed to inconsistent findings across the analyses. sensitivity analyses helped identify specific studies that disproportionately influenced the overall heterogeneity. further high-quality, targeted research is needed to determine which patient subgroups are most likely to benefit and to establish optimal dosing strategies. references 1. aydogmus s, aydogmus h, gul s, et al. is vitamin d replacement effective in the treatment of postpartum urinary incontinence? int urogynecol j. 2023; 34:1103-8. 2. vaughan cp, markland ad, huang aj, et al. vitamin d intake and progression of urinary incontinence in women. urology. 2021; 150:213-8. 3. markland ad, vaughan c, huang a, et al. vitamin d intake and the 10-year risk of urgency urinary incontinence in women. j steroid biochem mol biol. 2020; 199:105601. 4. özçift b, micoogullari u. the effect of vitamin d deficiency in children with overactive bladder related urinary incontinence. int braz j urol. 2022; 48:316-25. 5. yoo s, oh s, kim hs, et al. impact of serum 25-oh vitamin d level on lower urinary tract symptoms in men: a step towards reducing overactive bladder. bju int. 2018; 122:667-72. 6. vaughan cp, markland ad, huang aj, et al. vitamin d supplements and prevalent overactive bladder in women from midlife through older ages. menopause. 2022; 29:1399-403. 7. arjmand m, abbasi h, behforouz a. the effect of vitamin d on urgent urinary incontinence in postmenopausal women. int urogynecol j. 2023; 34:1955-60. 8. markland ad, vaughan cp, huang aj, et al. effect of vitamin d supplementation on overactive bladder and urinary incontinence symptoms in older men: ancillary findings from a randomized trial. j urol. 2023; 209:243-52. 9. shahraki sk, emadi sf, salarfard m, et al. effect of vitamin d supplementation on the severity of stress urinary incontinence in premenopausal women with vitamin d insufficiency: a randomized controlled clinical trial. bmc womens health. 2022; 22:431. 10. markland ad, tangpricha v, mark beasley t, et al. comparing vitamin d supplementation versus placebo for urgency urinary incontinence: a pilot study. j am geriatr soc. 2019; 67:570-5. 11. oberg j, verelst m, jorde r, et al. high dose vitamin d may improve lower urinary tract symptoms in postmenopausal women. j steroid biochem mol biol. 2017; 173:28-32. 12. markland ad, vaughan c, huang a, et al. effect of vitamin d supplementation on urinary incontinence in older women: ancillary findings from a randomized trial. am j obstet gynecol. 2022; 226:535.e1-.e12. 13. gul s, aydogmus h, keles c, et al. the effect of vitamin d defideclarations ethical approval and consent for participate: the prospero registration number was given to the protocol of this systematic review [crd420251107352]. consent for publication: not applicable. availability of data and material: the data supporting this study's findings are available from the corresponding author upon reasonable request. competing interests: the authors declare no competing interest. funding: none. authors' contributions: s.t. alshahrani: protocol development, manuscript writing, manuscript review. n. alamri: protocol development, manuscript writing, manuscript review. m.d. asiri: data collection and manuscript review. m.o. albabtain: data analysis, manuscript writing. r. alwadai: data collection and manuscript review. h.m. assiri: data collection and manuscript review. s. alghamdi: manuscript review, editing, and senior author. a.t. alshahrani: data collection and manuscript review., m.j. bosily: data collection and manuscript review. h. munyif: data collection and manuscript review. o. safar: protocol development, manuscript writing, editing, manuscript review, and senior author. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):14172 9 vitamin d in urinary incontinence and overactive bladder ciency on urinary incontinence during third trimester pregnancy. medicine (baltimore). 2023; 102:e36044. 14. yuan p, wang t, li h, et al. systematic review and metaanalysis of the association between vitamin d status and lower urinary tract symptoms. j urol. 2021; 205:1584-94. 15. vaughan cp, tangpricha v, motahar-ford n, et al. vitamin d and incident urinary incontinence in older adults. eur j clin nutr. 2016; 70:987-9. 16. zhang w, zheng x, wang y, xiao h. vitamin d deficiency as a potential marker of benign prostatic hyperplasia. urology. 2016; 97:212-8. 17. bapir r, bhatti kh, eliwa a, et al. treatment of urge incontinence in postmenopausal women: a systematic review. arch ital urol androl. 2023; 95:11718. 18. chen h, zhang z, wu s, et al. efficacy and safety of high-dose vitamin d supplementation vs solifenacin or standard urotherapy for overactive bladder dry in children: a randomized clinical trial. j urol. 2024; 211:26-36. correspondence omar safar (corresponding author) omar2725@hotmail.com urology department, armed forces hospital southern region, khamis mushayt, saudi arabia saad thamer alshahrani saadkkumed@gmail.com hassan m. assiri dr.assiri2020@gmail.com saleh alghamdi alobead@hotmail.com urology department, armed forces hospital southern region, khamis mushayt, saudi arabia naif alamri drnaifalamri@hotmail.com urology department, saudi german hospital, asir, saudi arabia mohammad dhafer asiri asirimohd2030@gmail.com urology department, health cluster 1, riyadh, saudi arabia meshal omar albabtain meshal_al_babtain@hotmail.com urology department, king saud medical city, riyadh, saudi arabia raed alwadai ri_mw@hotmail.com urology department, king abdullah hospital, bisha, asir, saudi arabia ali thamer alshahrani alithamer798@gmail.com college of medicine, king khalid university, abha, saudi arabia mohanad jebril bosily dr.bosily@gmail.com ministry of health, aseer health cluster, asir, saudi arabia hussain munyif hussainmunief@gmail.com urology department, king khalid hospital, najran city, saudi arabia stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12374 1 original paper introduction ureteroscopy is increasingly chosen as a treatment of choice for patients with kidney stone disease (ksd) (1). multiple national registries have recorded that it is the surgical intervention for ksd, which has seen the greatest uptake in recent years (2, 3). a key reason for this shift in practice pattern has been the advancements related to the energy source employed for intracorporal endoscopic stone lithotripsy and more specifically, the advent of laser (light amplification by stimulated emission of radiation) to urological practice (4-6). the manufacturer user and facility device experience (maude) database is a registry in the united states that catalogues failures including damages related to surgical devices (7). this database, which is essentially a library of adverse events can therefore be examined to gain understanding in surgical fields (8). to date, and in contrast to other areas of urology, little has been explored in the area of lasers used in urs and stone lithotripsy (9). our aim was to analyse this database and evaluate the events recorded with the principal purpose of evaluating its safety, insights and lessons learned from it relevant to laser machines and fibers. materials and methods search was performed of the maude database for all events related to holmium laser fibers and laser machines between january 1st 2012 to december 31st 2021 (10). search terms used were “laser”, “laser fiber”, “holmium laser”, “ureteroscopy” and “laser machine”. this yielded 5450 events. event reports combine the information given by health professional as well as a manufacturer summary and verdict on root cause. each report was individually reviewed, and the following information was collected: problem related to the event, timing, prolonged anaesthesia, early termination of procedure, patient injury, surgeon introduction: ureteroscopy has become increasingly chosen as a treatment of choice for patients with kidney stone disease and laser as the energy source for stone lithotripsy is a key part of this. our aim was to analyse a national database to evaluate the burden of adverse events related to laser fibers and laser machines. methods: search was performed of the manufacturer user and facility device experience (maude) database in the united states for all events related to holmium laser fibers and holmium laser machines during ureteroscopy between 2012-2021. information collected included the following: problem, timing, prolonged anaesthesia, early termination of procedure, injury and retained parts. results: 699 holmium laser fiber events were reported and these had been manufactured by 13 different companies. the commonest problems were breakage outside the patient while in use (26.3%) and breakage of the laser fiber tip (21.2%). manufacturers concluded root cause to be device failure in 8.9%. 29% of issues occurred before the laser had been activated. 5.2% of cases had to be cancelled as a result of an event. significantly more injuries were sustained intra-operatively by operating staff compared to patients (6% vs. 0.2%, p < 0.001). all these injuries were superficial burns to the skin with the hand being the most affected body part (88.1%). zero ocular injuries were reported. only eight events were related to laser machines and all involved sudden hardware failure but no patient injury. conclusions: laser fibers are fragile. most adverse events are due to operator error. direct patient injury from laser fiber is scarce but operating staff should be aware of the risk of sustaining minor burns. laser machines rarely incur problems and, in this study, did not result in any safety issues beyond need to abort the procedure due to lack of spare equipment. key words: ureteroscopy; urolithiasis; laser; injury. submitted 9 february 2024; accepted 15 february 2024 adverse events related to laser fibers and laser machines during ureteroscopy and stone lithotripsy: insights from an updated 10-year analysis of the us maude database patrick juliebø-jones 1, 2, 7, mathias sørstrand æsøy 1, christian beisland 1, 2, vincent de coninck 3, 7, etienne xavier keller 4, 7, lazaros tzelves 5, 7, peder gjengstø 1, christian arvei moen 1, bhaskar k. somani 6, øyvind ulvik 1, 2 1 department of urology, haukeland university hospital, bergen, norway; 2 department of clinical medicine, university of bergen, bergen, norway; 3 department of urology, az klina, brasschaat, belgium; 4 department of urology, university hospital zurich, university of zurich, zurich, switzerland; 5 second department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens, greece; 6 department of urology, university hospital southampton, uk; 7 eau yau urolithiasis group. doi: 10.4081/aiua.2024.12374 summary archivio italiano di urologia e andrologia 2024; 96(3):12374 p. juliebø-jones, m. sørstrand æsøy, c. beisland, et al. 2 injury, retained parts and manufacturers´ final verdict on root cause. reports were excluded if there was insufficient information (n = 37) and/or where the wording lacked clarity (n = 9). this also applied to any duplicates (n = 59). all information in this particular database is unrestricted and freely available to the public worldwide and completely anonymised. as such, ethical approval was not deemed necessary. data was collected and analysed using spss statistics v.26 (ibm, armonk, ny). where deemed appropriate, categorical variables were compared using chi-square test with p-values < 0.05 considered to be statistically significant. results laser fibers over the study period, 699 were events reported related to laser fibers manufactured by 13 different companies (table 1). the commonest problems were inadvertent breakage outside the patient while in use (26.3%), breakage of the laser fiber tip inside the patient´s body (21.2%) and laser fiber that suddenly stopped working (16.7%). when laser fibers were reported to suddenly stop working, the cause was found to be micro cracks. if overheating of the laser fiber was reported (3.9%), the underlying cause was also found to be micro cracks. manufacturers reported the laser fiber problem to have been caused by manufacturing fault, in 8.9% of the events. in that latter group, two skin burns to staff were recorded but no patient injuries. none of the procedures had been terminated but two had incurred prolonged anaesthesia. while most issues arose while the laser had been activated and in use, 29% occurred before this happened. the most frequently reported reasons for the latter were either the laser being broken in the packaging (16.6%) or inadvertently broken by the assistant during preparation or assembly. while more than 9 in 10 of these events did not affect the procedure being successfully completed, it remained the case that 5.2% had to be cancelled and 14.7% required prolonged anaesthesia. the latter was typically due to the additional time required for basket retrieval of the detached laser fiber tip, which is not always straightforward. overall, 5% of patients had a fiber fragment retained in the urinary system at the end of the case. onward treatment plan for this issue appeared to come down to surgeon preference. while 60% of these retained fragments led to the patients being re-listed for elective urs and active retrieval, the remainder were left to pass spontaneously. in 10% of the latter group, a supplementary report had been filed to provide an update that the patient had been re-admitted with pain and required emergency urs and retrieval of the residual fragment. details were not available to provide a further update on whether surgery to remove residual fragments was successful. in 4.7% of the events, the ureteroscope was damaged. cases were terminated early to insufficient spare equipment being readily available at the time of surgery rather than safety concerns except for one case. that particular event involved the surgical drapes catching fire while the laser fiber was resting against them while in use and was found to be broken. limited details beyond this were available but it was confirmed that it was successfully extinguished, and no injury was sustained to the patient or staff. significantly more injuries were sustained intra-operatively by operating staff compared to patients (6% vs. 0.2%, p < 0.001) (table 2). the distribution of injuries to surgeon and assistant/nurse was 45.2% and 54.8%, respectively. all these injuries were superficial burns to the skin with the hand being the most affected body part (88.1%). no ocular injuries were reported. only two intra-operative injuries were recorded in patients. these consisted of a superficial skin burn to their leg and a case of thermal injury to the ureteric mucosa resulting in stenting. laser machines there were few events related specifically to the holmium laser machine itself. in total, there were eight reported, and all involved a sudden shut down of the machine. these occurred after laser activation had been commenced. these all related in prolonged anaesthesia. while no patient or operating staff injuries were recordtable 1. summary of events. characteristic frequency number of laser fibers 699 problem broken outside patient while in use 184 (26.3%) broken laser fiber tip 148 (21.2%) stopped working 117 (16.7%) broken in packaging 112 (16%) broken in preparation or assembly 67 (9.6%) overheating 27 (3.9%) broken on entry to scope 21 (3%) broken within body of scope 16 (2.3%) not registering 3 (0.4%) broken after reported stuck in machine 3 (0.4%) misfiring 1 (0.1%) visible location of laser fiber breakage while in use distal section 169 (45.4%) middle section (i.e., within scope) 16 (4.3%) proximal section (i.e., outside patient) 187 (50.3%) damage to ureteroscope yes 33 (4.7%) timing of problem before laser used 203 (29%) during laser use 488 (69.8%) after completion laser usage 8 (1.2%) successful completion of procedure yes 662 (94.8%) prolonged anaesthesia yes 103 (14.7%) lost laser fiber tip left in patient at end of the case yes 35 (5%) management: conservative 14 (40%) re-listed for planned urs and removal 21 (60%) archivio italiano di urologia e andrologia 2024; 96(3):12374 3 safety of laser machines and fibers ed as a result, six out of eight of these cases had to be cancelled as no spare laser machine was available. manufacturer claimed responsibility for this issue in only two cases. reasons given by the manufacturer as to why responsibility could not be accepted in the other cases included previous repair having been performed by an external company and failure to service the machine in a timely manner. discussion this study has found that the safety profile related to use of laser fibers is favourable. risk of intra-operative injury to a patient related to a laser fiber problem seems to be a rare event. the risk for injury to operating staff is higher in comparison, but still relatively low. likelihood of manufacturing failure is low, and most problems are the result of user error including mishandling of the fiber. while more than one in ten cases incurred prolonged anaesthesia, over 90% of cases were completed successfully despite the event. lack of spare equipment being readily available leads to cancellation of cases mid procedure. our study revealed limited results for laser machines, which would suggest that in comparison, that such hardware problems are rare and while they do not result in patient injury, having spare laser unit would prevent aborting the operation. these findings from the maude database confirm the fragility of laser fibers. surgeons and operating staff alike should invest time in learning how to use and handle them safely and appropriately (11). key points include being gentle when feeding the fiber into the scope as well as securing the fiber with a damp swab rather than with a glove or instrument (table 3) (12). awareness of risk factors for fiber fracture can help minimise the risk of occurrence. these include increased angle of deflection, shorter pulse duration, higher core diameter and higher pulse energy (11). the soft, polytetrafluoroethylene lining of the flexible ureteroscope is extremely sensitive to damage such as by uncontrolled energy loss occurring during fiber fracture or the silicate tip itself. relevant to this, is observing the safety distance concept of the laser tip in relation to the ureteroscope tip to prevent iatrogenic damage from the laser´s cavitation bubble or direct laser energy impact. it is worth noting a relatively low rate of damages to the ureteroscope in our analysis (4.7%), compared to a fourfold higher rate of breakage of the laser fiber tip (21.2%). this observation suggests that the laser fiber tip may have broken relatively far away from the instrument in most cases, an event known to happen when working with a transparent fiber tip. interestingly, a theme from the reports of the maude database was that if the glass tip had not been clipped beforehand, identification and retrieval was more difficult. this is precisely the reason why some authors have suggested to cut the fiber tip though the coloured plastic jacket, discarding the transparent fiber tip and its risk of breakage and retainment (11). note the laser pilot beam can be activated prior to use to help identify coating damage. management of broken laser fiber tip appears to vary and indeed there is no precedent in terms of evidence to really guide how this should be. while this study has not compared single use and re-usable fibers, when using the latter, these should be carefully inspected and checked for cracks or damages, which can cause subsequent energy leakage (13). in this regard, single-use fibers may lower the risk of unintended laser energy leakages compared to re-usable fibers and would be readily available in case of fiber failure. our findings serve as a reminder that damage can occur outside the operating theatre such as during packaging and sterilisation process. while this remains an area where there is limited research to guide clinical practice, the authors recommend implementation of safety training courses locally for dedicated personnel training as well as hospital protocols for safe use of laser. a previous survey of endourologists revealed that institutional laser safety training was only present among 63% of the respondents´ hospitals and likewise, a formal committee was only found in 34% (14). the potential for ocular injuries attracts a lot of attention and had led to continued debate regarding the absolute table 2. intra-operative injuries. frequency operating staff injury yes 42 (6%) staff member: surgeon 19 (45.2%) nurse/assistant 23 (54.8%) injury type: superficial skin burn 42 (100%) anatomical location of burn: hand 37 (88.1%) elbow 2 (4.8%) shoulder 2 (4.8%) abdomen 1 (2.4%) patient injury yes 2 (0.2%) injury type: superficial skin burn 1 (0.1%) ureteric thermal injury (stented) 1 (0.1%) table 3. summary of prevention strategies for laser machine and fiber failure. problem prevention machine failure laser machine testing prior to procedure spare machine (if available) regular servicing and testing of machine laser fiber failure careful removal from packagiung to acoid breakage careful insertion of fiber into the scope secure fiber on outside with wet swab cutting the distal tip of the fiber after use (for resuable fiber) laser fibers should not be wrapped too tight. if a lesion is detected, cut the fiber proximal to this lesion activate laser pilot beam prior to use to help identify coating damage archivio italiano di urologia e andrologia 2024; 96(3):12374 p. juliebø-jones, m. sørstrand æsøy, c. beisland, et al. 4 need for protective eyewear (14). operating staff injuries were mostly limited to skin burns, with no eye injury at all. this data adds to the evidence supporting the possibility of omitting wearing protective glasses for laser interventions in urology, except for greenlight laser where the risk of injury to the retina remains a safety hazard. similarly, a previous review has found that no injuries of this kind related to ho:yag have ever been reported in the literature over the past 20 years (15). villa et al. found the critical laser fiber tip to eye distance for injury to be 5 cm when using ho:yag (16). limitations there are drawbacks to acknowledge in this study. firstly, the total number of cases performed over this study period is not known and therefore the incidence of these events cannot be calculated. given manufacturers were providing evaluations on their own equipment, inherent bias can be present. there was only one case of thermal injury to the ureter reported, which is acknowledged to not be representative of its true burden. similarly, late complications such as ureteral stricture, which can occur because of thermal injury have not been captured in this data set and this is also a limitation. the data in maude is added prospectively, however, the intention for its use is not primarily for academic research purposes. research groups wishing to study this data are reliant on trusting the quality of information provided. in this regard, we were strict to exclude events where information was limited or deemed of insufficient quality. the database also does not register certain parameters such as hospital setting (e.g., community versus academic), surgeon experience nor any information regarding patient characteristics such as comorbidities, stone burden or anticoagulation status (17). also, specific details on prolonged anaesthesia such as precise timings were not available. however, there are valuable insights that arise from reviewing this database, which is relatively unique in nature and the largest of its kind globally. our study sheds light on events that while they may have been heard of or reported in individual case reports, such data lies outside the standard parameters that are recorded in clinical studies. moreover, nearly all studies that evaluate the intricacies of laser properties are exclusively performed in the pre-clinical setting. a strength of databases such as maude is that they are well suited for reporting events that are often related to user error as the information can be shared anonymously. it is such that authors rarely strive to publish results, which could potentially place their own reputation and their hospital´s in an unfavourable light, which may in turn lead to underreporting go these events. conclusions laser fibers are fragile, and the vast majority of adverse events related to them are not caused by a manufacturing fault, but rather operator and handling errors. damage to a patient specifically from the physical laser fiber is very seldom but operating staff should be aware of the risk of sustaining minor burns when handling the laser fiber while in use. laser machines rarely incur problems intraoperatively and in this study did not result in any safety issues beyond the need to abort the procedure due to lack of spare equipment. references 1. herout r, baunacke m, groeben c, et al. contemporary treatment trends for upper urinary tract stones in a total population analysis in germany from 2006 to 2019: will shock wave lithotripsy become extinct? world j urol. 2022; 40:185-91. 2. jour i, lam a, turney b. urological stone disease: a 5-year update of stone management using hospital episode statistics. bju int. 2022; 130:364-9. 3. geraghty rm, jones p, somani bk. worldwide trends of urinary stone disease treatment over the last two decades: a systematic review. j endourol. 2017; 31:547-56. 4. staehler g, hofstetter a, gorisch w, et al. endoscopy in experimental urology using an argon-laser beam. endoscopy. 1976; 8:1-4. 5. kronenberg p, cerrato c, juliebo-jones p, et al. advances in lasers for the minimally invasive treatment of upper and lower urinary tract conditions: a systematic review. world j urol. 2023; 41:381727. 6. juliebø-jones p, keller ex, haugland jn, et al. advances in ureteroscopy: new technologies and current innovations in the era of tailored endourological stone treatment (test). journal of clinical urology. 0(0):20514158221115986. 7. gurtcheff se. introduction to the maude database. clin obstet gynecol. 2008; 51:120-3. 8. lee j, kaplan-marans e, jivanji d, et al. post-cystoscopy infections and device malfunctions in reprocessed flexible cystoscopes in a national database. can j urol. 2022; 29:11361-5. 9. althunayan am, elkoushy ma, elhilali mm, andonian s. adverse events resulting from lasers used in urology. j endourol. 2014; 28:256-60. 10. administration ufad. maude manufacturer and user facility device experience 2023 [available from: https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/textsearch.cfm. 11. keller ex, kronenberg p, tailly t, et al. laser accessories: surgical fibers, strippers, cleavers, and protective glasses. curr opin urol. 2022; 32:330-338. 12. talso m, emiliani e, haddad m, et al. laser fiber and flexible ureterorenoscopy: the safety distance concept. j endourol. 2016; 30:1269-74. 13. juliebo-jones p, somani bk, gjengsto p, et al. holmium and thulium fiber laser safety in endourological practice: what does the clinician need to know? curr urol rep. 2023; 24:409-15. 14. paterson nr, fitzpatrick r, blew b, et al. perceptions and practice patterns of holmium laser goggles in endourological procedures: an unnecessary evil? j endourol. 2019; 33:146-50. 15. bhojani n, andonian s, watterson jd, et al. canadian urological association best practice report: holmium:yag laser eye safety. can urol assoc j. 2020; 14:380-2. 16. villa l, cloutier j, comperat e, et al. do we really need to wear proper eye protection when using holmium:yag laser during endourologic procedures? results from an ex vivo animal model on pig eyes. j endourol. 2016; 30:332-7. archivio italiano di urologia e andrologia 2024; 96(3):12374 5 safety of laser machines and fibers 17. gopal n, long b, phillips j, eshghi m. endovascular stapler complications during minimally invasive nephrectomy: an updated review of the fda maude database from 2009-2019. urology. 2021; 153:181-4. correspondence patrick juliebø-jones, md (corresponding author) jonesurology@gmail.com resident department of urology, haukeland university hospital, bergen, norway mathias sørstrand æsøy, md mathias.asoy@gmail.com peder gjengstø, md peder.gjengsto@helse-bergen.no christian arvei moen, md christian.arvei.moen@gmail.com consultant urological surgeon department of urology, haukeland university hospital, bergen, norway christian beisland, md christian.beisland@helse-bergen.no consultant urological surgeon, professor of urology department of urology, haukeland university hospital, bergen, norway vincent de coninck, md vdconinck@gmail.com consultant urologist department of urology, az klina, brasschaat, belgium etienne xavier keller, md etienne.xavier.keller@gmail.com consultant urological surgeon department of urology, university hospital zurich, university of zurich, zurich, switzerland lazaros tzelves, md lazarostzelves@gmail.com consultant urologist second department of urology, national and kapodistrian university of athens, sismanogleio general hospital, athens, greece bhaskar k. somani, md bhaskarsomani@yahoo.com consultant urological surgeon, professor of urology dept of urology, university hospital southampton, uk øyvind ulvik, md doc.ulvik@online.no consultant urological surgeon, associate professor of urology department of urology, haukeland university hospital, bergen, norway conflict of interest: øyvind ulvik has acted as a consultant for olympus. the other authors have nil to declare. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13163 1 original paper stents (1). an encrusted stent is defined as one that cannot be removed simply by cystoscopy due to calcification or stone formation around the stent (1, 2). several risk factors have been described, namely indwelling time and bacterial colonization, as well as patient specific factors and the physical characteristics of the stent (3). el-faqih et al. proved that the incidence of stent encrustation increases with indwelling time, reporting 9.2% of stents removed before 6 weeks were encrusted compared to 47.5% removed between 6 to 12 weeks (4). nowadays there is no consensus around the best management of this type of complication. its approach depends on the severity and location of the encrustation. some classification for the encrusted stents (ess) had been published in the last years, namely the kub score and the forgotten, encrusted and calcified (fecal) grading system. the first one, kub system is based on the degree of encrustation of the stent in the kidney, ureter and bladder, grading it from 1 to 5, and it’s supposed to identify those that will be surgically challenging to remove (5). the later, is based on the stone size, location and degree of stent encrustation, and graded from 1 to 5, proposing also a treatment algorithm (2, 6). in 2021, manzo et al. proposed a novel system, the v-gues, which aims to propose a visual classification for ess that help to guide the choice of the appropriate treatment. this system is based on visual interpretation of ct scans and divides it into 4 categories: group a includes distal calcification, sparing the ureteral and proximal portions of the stent; group b includes calcification of the distal and ureteral portions of the stent, sparing the proximal loop; group c includes proximal calcification, with or without calcification of the distal portion, but sparing the ureteral portion of the stent; and finally group d includes calcification of the proximal and ureteral portions of the stent, with or without calcification of the distal portion. the authors advocate that their classification system is associated with the number of procedures required for a patient to be stent-free, stone-free rate and complications. they suggested that this classification will allow urologist to choose the most reliable intervention (1). based on the aforementioned studies, the authors intended to prove that the endoscopic combined intra-renal surgery (ecirs) is the best choice when there’s an encrusted proximal loop of a ureteral stent. background: ureteral stents are one of the most used devices in urology, allowing drainage of the upper urinary system, and can be used either in elective or emergency procedures. however, as a foreign body inside the urinary system, they are subject to encrustation. encrustation is one of the burdens seen with double-j stents and, to date, there is no consensus about its best management. this study aims to prove that endoscopic combined intra-renal surgery (ecirs) is the best choice when there’s an encrusted proximal loop of a ureteral stent. methods: the authors conducted a retrospective cohort study of patients with an encrusted proximal loop of the ureteral stent who underwent surgery at a single center, comparing ecirs with other procedures. results: between july 2011 and june of 2024, 33 patients (18 females and 15 males) were submitted to surgery. the median indwelling time of the stent was 11 (8-19) months and a stentfree rate of 100% was achieved. the authors demonstrated a significant stone-free rate of 61.1% following ecirs compared to merely 20% with other procedures (p = 0.023). notably, while the complication rate was low across all procedures, the ecirs group exhibited fewer complications (5.6%) than those undergoing alternate techniques (13.3%), though this difference was not statistically significant (p = 0.439). conclusions: our study advocates for ecirs as the preferred initial treatment for encrusted proximal ureteral stents, as it facilitates superior stone clearance, minimizes complications, and maintains comparable operative efficiency. this research contributes valuable insights into the management of challenging cases involving encrusted ureteral stents, calling for future studies to further validate these findings. key words: encrusted stent; lithiasis; endoscopic combined intra-renal surgery. submitted 26 september 2024; accepted 27 september 2024 introduction ureteral stents are one of the most used devices in urology. they allow the drainage of the upper urinary system and are a powerful tool to use either in elective or emergency procedures. however, as a foreign body inside the urinary system, they are subject to encrustation. encrustation is one of the burdens seen with double-j should patients with encrusted jj stents involving the proximal/renal loop undergo primarily endoscopic combined intrarenal surgery? alexandra rocha, gonçalo mendes, sofia mesquita, mariana madanelo, joão vital, miguel marques-monteiro, nuno vinagre, martinha magalhães, beatriz oliveira, guilherme gonçalves, vítor cavadas, avelino fraga urology department, centro hospitalar e universitário de santo antónio, unidade local de saúde de santo antónio, porto, portugal. doi: 10.4081/aiua.2024.13163 summary archivio italiano di urologia e andrologia 2024; 96(4):13163 a. rocha, g. mendes, sofia mesquita, et l. 2 materials and methods we conducted a retrospective cohort study of all patients who were found to have an encrusted jj stent and underwent surgical procedures for its removal in our center between july 2011 and june of 2024 (54 patients). from this group of patients, the ones with proximal loop encrustation were selected, based on preoperative ct scans and the v-gues classification. the patients selected belonged to the c and d groups from this classification. all patients without a preoperative ct scan were excluded. all clinical and surgical data were collected from patients' files, focusing on age, sex, height and weight and renal function (serum creatinine levels). we also gathered information about the procedure during which the stent was initially placed, the time of diagnosis of the encrustation and the duration of the catheterization. we registered the type and number of procedures needed to achieve a stone free status, that was defined as the absence of any fragments in the postoperative imaging studies, and a stent-free status. all patients underwent surgery in our hospital, by a single surgeon. treatment decisions were based on the surgeon’s preference. the surgeries performed were semirigid ureteroscopy (srurs), flexible ureteroscopy (furs), percutaneous nephrolithotomy (pcnl) and endoscopic combined intrarenal surgery (ecirs). all patients with positive cultures were treated with antibiotics before the surgery, and all were given perioperative antibiotic prophylaxis. other data collected included the postoperative complications, including the first 30 days, and classified according to the clavien-dindo classification. data was collected in a spss file. we conducted descriptive statistics for all the variables, presenting their means or median according to the presence (or not) of a normal distribution. the categorical and nominal variables are presented in frequency tables. to compare means between variables we used a t-sample test. the correlation between variables was ascertained using pearson correlation and logistic regression was made to obtain odds ratio of the variables, were applicable. differences were considered statistically significant if p < 0.05. the study was made in were in accordance with the helsinki declaration. results between july 2011 and june of 2024, 33 patients with an encrusted proximal/kidney loop of a ureteral stent were submitted to surgery in our centre. there were 18 females and 15 males, with a mean age of 53.9 (± 19.0) years. the mean height and weight were 1.62 (± 0.1) m and 74.1 (± 19.4) kg, respectively. the mean bmi was 27.8 (± 6.0). in 11 cases the encrusted jj stent was on the left and in 20 cases on the right; we had 2 cases of encrusted stents in a renal transplant. the preoperative serum creatinine levels were 1.1 (± 0.6) mg/dl and the postoperative was 1.1 (± 0.4) mg/dl. we found no statistically significant difference in the creatinine levels preand post-operatively (p = 0.961) preoperative urine cultures were also taken, with a positive result in 10 cases and negative in 9. in 12 cases the lab was not able to isolate the bacteria probably due to contamination of the sample. in the other 2 cases the preoperative urine culture was not available. the isolated strain was escherichia coli in 6 patients, followed by proteus mirabilis in 3 cases, and 1 case of candida albicans. these results can be consulted on table 1. the median indwelling time of the stent was 11 (8-19) months, varying between 5 and 71 months. we found no correlation between indwelling time and the occurrence of complications (p = 0.830) or the stone-free rate (p = 0.423). regarding surgical approach, the most performed surgery was endoscopic combined intrarenal surgery in 18 cases of 35 (54.5%), as can be seen on table 2. in 8 patients (24.2%) the surgery chosen was pcnl, 6 patients (18.2%) underwent furs and 1 patient (3%) underwent srurs. the mean time of procedure was 121.1 (± 44.3) min. when comparing ecirs with other procedures, the authors found a mean time for combined surgery of 123.6 (± 50.9) min and a mean time a 118.1 (± 36.5) min for other surgeries. there was no statically significant difference between the groups (p = 0.727). we also found no difference between the procedure time and the occurrence of complications (p = 0.523) and the stone-free rate (p = 0.487). in all the cases (100%) the encrusted stent was removed in the first procedure. regarding the stone-free state, 14 patients (42.4%) were stone free after the first procedure, with 19 (57.6%) patients not achieving this state. comparing the ecirs procedure with the other surgeries performed, a stone-free rate of 61.1% was achieved with the ecirs procedure, while other procedures resulted in a 20% stone-free rate. comparing these rates, we found a correlation between the choice of ecirs and the stone-free rate (p = 0.023, or 6.3, 95% ci:1.3-30.5). this data can be seen on table 3. table 1. results of urine cultures. urine culture frequency (%) e. coli 6 (60.7%) p. mirabilis 3 (30%) c. albicans 1 (10%) table 2. frequency table of the surgeries performed. surgery frequency (%) combined access 18 (54.5%) pcnl 8 (24.2%) flexible ureteroscopy 6 (18.2%) semirigid ureteroscopy 1 (3%) table 3. comparing ecirs with other procedures regarding stent-free, stone-free and complication rate. combined procedure other procedures p stent-free after one procedure 18 (100%) 15 (100%) n/a stone-free after one procedure 11 (61.1%) 3 (20%) 0.0023 complication rate 1 (5.6%) 2 (13.3%) 0.439 archivio italiano di urologia e andrologia 2024; 96(4):13163 3 should patients with encrusted jj stents involving the proximal/renal loop undergo primarily endoscopic combined intrarenal surgery? the median hospital stay was 3 (2-3) days. overall, there were 3 cases (9.1%) of postoperative complications in the first 30 days. two cases of fever with urinary tract infection (uti) and 1 case of urinary leakage. regarding the clavien-dindo classification, all fall into the ii classification. comparing ecirs with other procedures, we found a complication rate of 5.6% with ecirs and a 13.8% rate with other procedures; we found no statistically significant correlation between these variables (p = 0.439). the complications and its frequencies can be seen on table 4. regarding the necessity of a second procedure, 2 patients needed other surgery 1 patient a furs (first procedure was a mini-pcnl), 1 mini-pcnl (first procedure was furs). no complication was reported on these cases. discussion encrusted ureteral stents are a complex problem to manage and it may be difficult and risky to treat it (7, 8). classification systems appear to facilitate the approach of this type of patients. according to juliebø-jones et al. (7), it is recommended to use one of the classification systems available. in this study, the authors chose to use the vgues classification system as it appears as the most reliable and useful. the kub system is based on x-ray images alone, which may render some limitations. the fecal system, despite its more broaden classification, it is only based on 9 patients. (1, 2). the classification was used to select patients to enter the study, and only the ones categorized as c or d were selected which means with the presence of encrusted proximal loop of the stent was the selection criteria. some authors already proposed that the location of the encrustation will determine the surgical modality required for the management of the ureteral stent, and the authors from v-gues already suggest that combined surgery was associated with best stone-free and stent-free rate (1, 2). the main objective of this study is to propose ecirs, with combined percutaneous surgery and retrograde endoscopic surgery, as the best first approach to managed encrusted proximal loops of ureteral stents. this study harbours some limitations inherent to its retrospective design and relatively small patient cohort. however, due to the nature of this type of cases and its relative scarcity, the authors believe that a prospective study is not feasible. the cases were all performed by the same surgeon, with plenty of experience in lithiasis surgery, which could help to explain the good results. the data collected gathered information from patients with an encrusted proximal/kidney loop of a ureteral stent that were submitted to surgery in our centre for a period of roughly 13 years. the sample obtained was 33 patients, with 18 women and 15 men. given the scarcity of reports on these subject, and its relative infrequent occurrence, this number are in line with other single center reports. the median indwelling time of the stent was 11 (8-19) months it is known that the prolonged indwelling time of stents increases the prevalence and severity of all complications (8). however, we could not find a correlation between the occurrence of complications or stonefree rate and the indwelling time of the ureteral stent. we hypothesize that this could be explained by the low level of complications present in the sample. the mean time of procedure for ecirs was 123.6 (± 50.9) min, that was not statistically significantly different from the mean time of the other procedures (p = 0.727). this shows that, even when comparing operative time, the use of a more complex surgery, like the combined approach, does not imply longer operative times, advocating for its use. there was a 100% rate of stent-free patients after the first procedure, independently of the procedure used. this excellent stent-free rate can be explained by the relative short number of cases and the experience of the surgeon. when focusing on the stone-free state, 42.4% of the patients achieved this state after the first procedure. when comparing the two groups, we found a higher stone-free rate when using ecirs comparing to other procedures (61.1% vs 20%, respectively). in this case, we found a positive correlation between the use of ecirs and the stone-free status, with a or of 6.3 (p = 0.023, 95% ci:1.3-30.5). this shows that ecirs is a more effective procedure comparing to the other procedures, in cases of encrusted stent, namely with proximal loop encrustation. some authors already proposed that pcnl should be used in encrusted proximal loops stent. pais et al. state that only 8% of the stents could be removed by pcnl alone, suggesting that additional procedures may be needed (9). our results show that in proximal loops, ecirs should be preferred as first-line as it is the most successful surgery. when looking at the complications rate, the group had a very low complication rate and only with clavien-dindo ii. once again, this could probably be explained by the experience of the surgeon and the limited number of cases analysed. despite not being statistically significant, the complication rate was lower when using the combined approach, supporting its primary use. there was need for a second procedure in 2 patients. all the patients needed at least one procedure with a percutaneous access and others with retrograde endoscopic surgery. this is also in favour with the proposed theory (all needed combined surgery), even if it was in two separate procedures. this supports the theory of using combined approach as the first choice in this type of patients. in the remaining patients, the residual stone burden was very little and didn’t need other procedure. weeding et al. reported that patient with proximal encrusted stents required more procedures to remove the stent and the stone burden (10). our study group reports that table 4. description of complications. procecure type of management clavien-dindo complication classification complication nº1 ecirs uti antibiotics ii complication nº2 other uti antibiotics ii complication nº3 other urinary leakage vesical cathetherization ii + antibiotics archivio italiano di urologia e andrologia 2024; 96(4):13163 a. rocha, g. mendes, sofia mesquita, et l. 4 the used of combined surgery approach can improve outcomes and reduce the number of surgeries needed to treat this type of patients. conclusions encrusted ureteral stents poses a significant challenge for urologist. there is a lack of standardized treatment in this area. the authors propose combined surgery as the first choice for the treatment of encrusted proximal loops of ureteral stents, as it is associated with better stone-free rate and fewer complications, while not increasing operative time. references 1. manzo bo, alarcon p, lozada e, et al. a novel visual grading for ureteral encrusted stent classification to help decide the endourologic treatment. j endourol. 2021; 35:1314-9. 2. acosta-miranda am, milner j, turk tmt. the fecal double-j: a simplified approach in the management of encrusted and retained ureteral stents. j endourol. 2009; 23:409-15. 3. tomer n, garden e, small a, palese m. ureteral stent encrustation: epidemiology, pathophysiology, management and current technology. j urol. 2021; 205:68-77. 4. el-faqih sr, shamsuddin ab, chakrabarti a, et al. polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. j urol. 1991; 146:1487-91. 5. arenas jl, shen jk, keheila m, et al. kidney, ureter, and bladder (kub): a novel grading system for encrusted ureteral stents. urology. 2016; 97:51-5. 6. guner e, gokhan seker k. comparison of two different scoring systems in encrusted ureteral stent management: a single-center experience. urol j. 2020; 17:248-251. 7. juliebø-jones p, pietropaolo a, sørstrand æsøy m, et al. endourological management of encrusted ureteral stents: an up-todate guide and treatment algorithm on behalf of the european association of urology young academic urology urolithiasis group. cent european j urol. 2021; 74:571-8. 8. adanur s, ozkaya f. challenges in treatment and diagnosis of forgotten/encrusted double-j ureteral stents: the largest single-center experience. ren fail. 2016; 38:920-6. 9. pais vm, chew b, shaw o, et al. percutaneous nephrolithotomy for removal of encrusted ureteral stents: a multicenter study. j endourol. 2014; 28:1188-91. 10. weedin jw, coburn m, link re. the impact of proximal stone burden on the management of encrusted and retained ureteral stents. j urol. 2011; 185:542-7. correspondence maria alexandra ferreira rocha (corresponding author) marialexandrarocha@gmail.com gonçalo mendes goncalo.grilomendes@gmail.com sofia mesquita sofiaoplmesquita@gmail.com mariana madanelo marianacmadanelo@gmail.com joão vital joaopvital@gmail.com miguel marques-monteiro mmonteiro.iam@gmail.com nuno vinagre nunomrvinagre@gmail.com martinha magalhães martinha.a.magalhaes@gmail.com beatriz oliveira ana.bia.5@hotmail.com guilherme gonçalves guilha.gon@gmail.com vitor cavadas vcavadas@gmail.com avelino fraga avfraga@gmail.com urology department, centro hospitalar e universitário de santo antónio, unidade local de saúde de santo antónio, porto, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13708 1 editorial comment on key words: female and male; medical student; lady urologist; male patient; self-respecting man. submitted 12 january 2025; accepted 13 january 2025 as a member of the editorial board and a pioneering woman in the world of urology, i would like to make some comments on the letter from prof. montironi and his team published in the present issue of archivio italiano di urologia e andrologia (1) about suzanne koven's book published in 2021 (2). after her internship and medical residency at johns hopkins hospital, suzanne koven joined the harvard medical school and practiced basic internal medicine at massachusetts general hospital for more than 30 years. of particular interest is her “letter to a young woman physician,” an essay describing the challenges faced by women physicians, including her personal struggle with “imposter syndrome,” a long-held secret belief that she is not smart or good enough to be a “real” doctor. consulted by thousands of readers around the world, koven's “letter” turned into a heartfelt reflection on her medical career. montironi's letter focused on 4 points, which i commented on separately 1) male and female medical students and residents in italy, the admission tests for medicine and especially for graduate school have changed things a lot. if we look at the entrance exams today, we do not find big gender differences; in fact, perhaps it is women who get in more easily. it used to be that before entering resident schools it was almost mandatory to attend the department in which one then wanted to attend resident school for a certain period of time; and in that case female students were discriminated against in that they did not always get in by simple “choice”of the committee. in some urology schools they were known to be asked not to show up. i entered in resident school in 1987 and the opinion of all my colleagues was that i could never become a surgeon, at best i could be an instrumental nurse in the operating room or alternatively i could only do urodynamic examinations or work on prostate biopsy slides. today, in fact, the situation has changed, and the real first obstacle for women is to establish themselves in the world of work in the surgical environment, and this is mainly because mentoring is practically exclusively male. female residents are hardly trained in the operating room, as being often more precise and willing than male residents they are mostly employed in the outpatient setting. in academia, especially in the surgical branches, there are no women full professors except in negligible numbers. in urology today, 2024, we have only one female full professor out of more than 40 men. therefore, in urology the pyramid is extremely gender biased, with few female researchers and very few female associate professors who are often unfairly denied academic progression even with impeccable curricula. the fact that the authors state that in their realities “both women and men have the same chances to succeed in their future professional and academic careers and with patients” shows a new and certainly promising opening for a better future for women uropathologists, but i do not see the same situation in the surgical branches. 2) women urologists it is evident that the percentage of women in urology services, academic and otherwise, has been lower than that of male urologists. why? the decision to become a urologist today is a difficult and not very popular choice. in general, the number of students enrolled in surgical residence schools is lower than in medical schools, and the reasons may be different. surgery involves specific and more complex reasons, first and foremost the risks, including medico-legal and well known to all, inherent in the profession that are undoubtedly higher and the training that is often difficult. the choice to become a surgeon today is often uneconomical, and many students prefer branches that allow for greater profits even in private freelancing. currently, students in the period of the competition for admission to resident schools, no longer attend the hospital ward and the operating room. the student goes from being a “medical student” to a “resident,” without knowing the realities of the department, much less the operating room. being a resident in a surgical branch means having different goals and expectations. many come “lady urologist and male patients with prostate cancer” elisabetta costantini, ester illiano andrological and urogynecological clinic, santa maria terni hospital, university of perugia, terni, italy. doi: 10.4081/aiua.2025.13708 archivio italiano di urologia e andrologia 2025; 97(1):13708 e. costantini, e. illiano 2 to resident school without knowing their aptitudes; academia does not always help the resident discover them and understand what their practical skills are. women residents, for the most part, have little opportunity to experience the operating room and are often referred to super-specialties that involve a more clinical than surgical approach. this makes it increasingly difficult for women urologists to get a grip on and demonstrate surgical skills, if any, once they enter the workforce. montironi et al. reported mayer's statement (3), “relatively few women hold leadership positions in the session, and this reflects an old approach of a fundamentally male profession, an approach that has changed rapidly over time.” it is not yet clear to me how it is changing. my experience is similar to that of suzanne koven, reported in her book “letter to a young woman physician, notes from a medical life.” we are of the same generation, and i can only agree with at least some of what she says. i too have experienced many of her difficulties, although we probably have different characters, and i never felt like an impostor and always believed in myself. in some ways my situation was even worse because in the urological world, when i started working, i was the “only” woman, unlike in internal medicine or gynecology where sometimes women outnumber men. the urological world was, moreover, one of the most difficult for a woman to experience: all the colleagues were men and most of the patients were also men. in addition to this, the real discrimination was the fact that surgery was almost always precluded to women. surgery was always reserved for men. the reasons? they are unclear. for a long time, optimistically, i thought the reason was mainly based on the long-standing belief that long and sometimes demanding open surgery was not suitable for the female physique: surgeries that were too long and tiring. unfortunately, however, the reality, also based on my personal history, was more discriminatory, and the male belief was that women did not have the surgical ability in their hands. today, however, many women are proving that this ability is not exclusive to the male gender. today, many women urologists are unable to understand some of suzanne's considerations because they experience a different situation. two elements are turning the tables on women in urology and in surgical branches in general. the first is the introduction of new technologies and the robotic surgical approach that are completely changing the scenario. surgeries are no longer so physically strenuous and the ability to maneuver the robot is proving that the female gender has capabilities equal to those of the male gender, and i don't want to say better because i would discriminate in the opposite sense. on the other hand, it is true that in both gender surgical skill is related to individual factors. just as we are not all inclined to play the violin, so we are not all predisposed to surgery, as well as to mathematics, singing, or dancing. the second factor is the increase in jobs where women have somehow managed to emerge, which has prompted many more women to become urologists and follow suit. almost as if to say that if one did it, so can others. that's why today's new generations do not feel the gender difference significantly, and this is especially true where there is female leadership. finally, regarding wallis's study (4), it is interesting because it shows that empathy, which is considered a predominant female characteristic, can improve outcomes after surgery. this is important because it underscores the importance of shared decision making as part of the physician-patient relationship and how today this approach should be considered a must for any therapeutic approach. 3) male patients both male and female patients can decide which physician to follow. i think it is important that in every field there are specialists of both genders, so that each patient can choose the gender he or she feels comfortable with. i think the patient is sovereign in his or her choice. in my opinion, the fact that men do not want to be seen by women has been used, in an exaggerated way, as a discriminatory element. actually, i don't think any particular comments are necessary. we found this news in the newspapers, but no one ever wrote that some women do not want to be visited by men. yet it happens and it is not news. a few years ago, there were no women urologists. it was normal for the male patient to find it strange to be seen by a woman, just as it was normal for a woman to be seen by a male gynecologist because there was no alternative. today, patients consciously choose the specialist physician based on their professional considerations and preferences. to find many women in urology clinics today means that the population is adapting, and fortunately this is no longer new. so today everything is changing for the better and it is nice to have the opportunity to choose freely. i don't see why i should be offended if a man prefers not to be seen by me. the important thing is that in the end the patient finds the right solution to his urological problem. perhaps i am a bit presumptuous to think that those who choose differently will not necessarily choose the best! 4) self-respecting man i agree with montironi (1) of course patients are treated equally both for regardless of gender and social class.i think this has always been the case, independent of the historical era and the gender of the physician. references 1. montironi r, lopez-beltran a, wasserman mc, et al. lady urologist and male patients with prostate cancer. arch ital urol androl. 2025; 97:13343. archivio italiano di urologia e andrologia 2025; 97(1):13708 3 editorial comment on lady urologist 2. koven s. letter to a young female physician: thoughts on life and work (notes from a medical life). new york, ny: w.w. norton & company, inc; 2022. 3. mayer en, lenherr sm, hanson ha, et al. gender differences in publication productivity among academic urologists in the united states. urology. 2017; 103:39-46. 4. wallis cjd, jerath a, aminoltejari k, et al. surgeon sex and long-term postoperative outcomes among patients undergoing common surgeries. jama surg. 2023; 158:1185-1194. correspondence elisabetta costantini (corresponding author) elisabetta.costantini@unipg.it professor of urology chief of andrological and urogynecological clinic aou terni chief of department of surgery and surgical specialty president of bachelor's degree in midwifery dept of medicine and surgery university of perugia italy andrological and urogynecological clinic, santa maria terni hospital, university of perugia 05100 terni (italy) ester illiano, md, phd ester.illiano@inwind.it andrological and urogynecological clinic,santa maria terni hospital, university of perugia 05100 terni (italy) declarations ethical approval: not applicable. availability of data and material: not applicable. competing interests: the authors have nothing to disclose. funding: the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors' contributions: author alb and author lc have given substantial contributions to the conception or the design of the manuscript, author mw and author ac to acquisition, analysis and interpretation of the data. all authors have participated in drafting the manuscript, author rm revised it critically. all authors read and approved the final version of the manuscript. acknowledgments: not applicable. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12869 1 original paper introduction benign prostatic hyperplasia (bph) is a common urological disease among older men. it consists of a progressive enlargement of the prostatic tissue, especially its central portion. the resulting bladder outlet obstruction, coupled with increased muscle tone of the bladder and secondary dysfunction of the detrusor, produce lower urinary tract symptoms (1). medical treatment is the first-line therapeutical option for this condition. commonly administered drugs are alphablockers, 5-alpha reductase inhibitors (5-aris) and phosphodiesterase 5-inhibitors (pde5-i). if men have persistent irritative storage symptoms after first line bph therapy then overactive bladder (oab) medications can be added or used as a replacement. combination therapies usually allow to increase the efficacy of medical treatments and delay the need for corrective surgery (2, 3). most said drugs, however, show a consistent rate of side effects in those who use them. this is why there is a massive increase of interest for herbal and nutraceutical treatments. serenoa repens, for instance, is one of the oldest and most effective nutraceutical drugs used to treat bph-related symptoms. in vitro, serenoa repens extract (320 mg once a day) has demonstrated anti-inflammatory, antiandrogenic, and estrogenic effects along with a decrease in sexual hormone-binding globulin; inhibition of 5α-reductase, muscarinic cholinoreceptors, dihydropyridine receptors, and vanilloid receptors; neutralization of free radicals. as of today, serenoa repens is considered introduction: the aim of our study was to treat 2 similar groups of patients suffering from benign prostatic hyperplasia (bph): one group with a complex of phytochemicals based on phycocyanin, palmitoylethanolamide (pea) and selenium; the other group with dutasteride. the effectiveness of these treatments was checked, especially regarding the improvement of lower urinary tract symptoms (luts) and the reduction of prostatic specific antigen (psa) and prostate volume. materials and methods: we included 104 patients in the study. all patients were aged between 50 and 70 years, with psa values between 4 and 10 ng/ml, prostate volume, as calculated by transrectal ultrasound between 50 and 70 cc, maximum flow value greater than or equal to 10 ml/s at flowmetry, no suspicious nodules on difital rectal examination (dre), no suspicious lesions on magnetic resonance imaging mri (pi-rads 1-2), negative previous prostatic biopsies or never biopsied, moreover absence of diabetes mellitus or chronic renal failure (blood creatinine > 2 mg/dl). we considered: group a of 54 men who used the complex of phytochemicals; group b of 50 patients treated with dutasteride. we followed all the patients for 6 months after starting therapy, considering the following parameters: psa, prostate volume, and flowmetry. results: our results showed that both dutasteride and the phytochemicals complex decreased psa levels (p < 0.0001 for both), with a more significant effect of dutasteride (mean decrease of -2.743 ng/ml vs -0.971 ng/ml). uroflowmetry also improved in both groups ( p < 0.0001) with a mean increase in maximum flow of urine of + 3.03 ml/min for the dutasteride group and + 13.02 ml/min for phytochemicals complex group. lastly, dutasteride proved to be highly effective on reducing the prostate volume on transrectal ultrasound (trus) (-22.14 ml, p < 0.0001) compared to the complex of phytochemicals, which showed a mean decrease of -10.04 ml (p < 0.0001). moreover, the reduction in prostate volume obtained through the use of dutasteride proved to be more consistent than the one obtained by using the complex of phytochemicals even at statistical analysis (p < 0.0001). conclusions: both the complex of phytochemicals and dutasteride showed reduction of psa values after 6 months of treatment. the complex based on phycocyanin, pea and selenium showed a statistically significant improvement in urinary flow, while dutasteride acted more on the volume of the prostate. prospective observational study on the efficacy and tolerability of a complex of phytochemicals versus dutasteride in the treatment of lower urinary tract symptomps due to benign prostatic hyperplasia giuseppe saitta 1, franco a. mantovani 1, benedetto calabrese 1, 2, camilla aliboni 1, 2, giuseppe di paola 1, attilio l. meazza 1, mauro seveso 1 1 iccs istituto clinico città studi, milan, italy; 2 humanitas university, pieve emanuele, milan, italy. doi: 10.4081/aiua.2024.12869 summary however, the natural complex is a product with good efficacy on the phlogistic component and does not have the side effects of dutasteride (eg gynecomastia, reduced libido). therefore, we believe it can be used by a large part of the population with bph, in order to reduce luts and psa and improve urinary flow, without side effects. key words: benign prostatic hyperplasia; lower urinary tract symptoms; prostate specific antigen; prostate volume; urinary flow. submitted 5 august 2024; accepted 12 september 2024 archivio italiano di urologia e andrologia 2024; 96(3):12869 g. saitta, f.a. mantovani, b. calabrese, et al. 2 equally effective compared to the alphablocker tamsulosin for what concerns the improvements on international prostate symptom score (ipss), quality of life (qol), maximum urinary flow rate, postvoid residual volume and prostate specific antigen (psa) levels (4, 5). combination therapy of alpha-blockers and serenoa repens, furthermore, proved even more effective than monotherapy (6). palmitoylethanolamide (pea) is an endogenous fatty acid amide-signaling molecule with anti-inflammatory and neuroprotective effects that has an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain (7). pea exerts its clinical effects through different mechanisms: the down-regulation of mast cell activation; the direct activation at least two different receptors: the peroxisome proliferator-activated receptors-alfa (ppar-α) and the orphan g-protein coupled receptors 55 (gpcr 55): gpr55; more recently, it has also been demonstrated that pea can activate transient receptor potential vanilloid 1 (trpv1) channels or increase the expression of cannabinoid receptor 2 (cb2) receptors, of which pea has been demonstrated to be a weak agonist, via ppar-α receptors. this results in a neuroprotective and anti-nociceptive effect of pea, decreasing hyperalgesic responses in the chronic constriction injury (cci) model of neuropathic pain (8, 9). in a female rat model of cyclophosphamideinduced cystitis, it has been reported that pain behavior, bladder inflammation and voiding dysfunction were associated with increased bladder levels of pea, up-regulation of cannabinoid receptor 1 (cb1) receptor expression and down-regulation of ppar-α expression. oral administration of ultra micronized pea produced both anti-inflammatory and analgesic effects (10). such results suggest that pea could also be used in bph-related voiding dysfunctions and irritative lower urinary tract symptoms (luts). in fact, d’amico et al. demonstrated that daily administration of pea in bph-affected rats considerably reduced the levels of testosterone and dihydroetestosterone (dht), main characters of bph. also, it substantially reduced 5α-reductase-2 expression and obtained a significant decrease in tumor growth factor-beta (tgf-b) expression, leading to a better cellular growth/apoptosis ratio (11). phycocyanin (pc) is a protein that derives from spirulina. it has been widely demonstrated that pc exerts its antiinflammatory and antioxidant activity through the inhibition of cyclooxygenase-2 (cox-2) enzymatic activity. the same inhibitory effect of cox-2 was observed in the model of human prostate epithelial cells, in which pc also showed a synergic effect with pea by abating the synthesis of prostaglandin e2 (pge2) (12, 13). selenium (se) and tomato extracts (te) are important trace elements in health, and their role has been widely evaluated even for bph and prostate cancer. se may be able to prevent, inhibit or reverse the transition of the epithelial cells to the mesenchymal phenotype. both se and te proved to modify anatomopathological results when comparing a hyperplastic hypertrophic prostate treated with both elements and a healthy one. in particular, mild hyperplasia with predominance of no presence of glandular hyperplasia and stromal restructuring and decrease in the thickness of the epithelium was observed. furthermore, the combination on se and te proved to be synergic. in the oxidative stress markers of the bph group, there was a significant increase in malondialdehyde (mda) and nitrites (no2) with respect to the control group. oral administration of se and te, especially when combined, proved to significantly decrease the levels of those markers, thus showing an antioxidant effect (14, 15). the aim of our study was to compare two groups of patients affected by bph: the first was treated with the 5ari dutasteride, the second, instead, with a combination of nutraceuticals: palmitoylethanolamide (200 mg), phycocianin (250 mg) and selenium (55 mcg). although synergic effects between such elements have been hypothesized and, to some extent, demonstrated, our aim is to contribute to the present literature by describing the results in this cohort of patients. material and methods we included in the study 104 patients who presented to the istituto clinico città studi (iccs) in milan, italy, complaining of symptoms related to bph. all patients were aged between 50 and 70 years, with prostate specific antigen (psa) values between 4 and 10 ng/ml, prostate volume, calculated through transrectal ultrasound (trus), between 50 and 70 ml, a maximum flow of urine value greater than or equal (4) to 10 ml/s at uroflowmetry, no suspicious nodules on digital rectal examination (dre), no suspicious lesions on mri (prostate imaging reporting and data system score: 1-2), negative previous prostatic biopsies or never biopsied. patients with diabetes mellitus or chronic renal failure were excluded. we divided our patients into two groups: group a including 54 men who were treated using a complex containing phycocyanin, palmitoylethanolamide and selenium [ficoxpea (f), by kura®], and group b including 50 men who were treated using dutasteride alone (d). we re-evaluated all patients after 6 months of therapy, considering the following parameters: psa levels, uroflowmetry (ufm), prostate volume. statistical analysis data were collected using microsoft excel (v. 12.2.4) and analyzed using the spss statistics v.29 software (ibm corporation new york, usa). statistical analysis of data was performed using anova test with tukey’s post-hoc correction. p values < 0.05 were considered significant. all data are expressed as mean ± structural equation models (sem). results our results showed a significant decrease in psa value both for the dutasteride (-2.743 ng/ml after 6 months of treatment) and phytochemicals complex (-0.9712 ng/ml after 6 months of treatment) groups (figure 1). there was a significant difference among the psa values between the two groups after 6 months of treatment (+1.865 ng/ml higher for the phytochemicals complex group) (figure 1). regarding ufm, there was a slight but significant increase in the flow of urine (ml/s) for the dutasteride group (mean increase of +3.029 ml/s after 6 months of treatarchivio italiano di urologia e andrologia 2024; 96(3):12869 3 phytochemicals versus dutasteride for luts due to bph ment). the phytochemicals complex group, on the other hand, showed a greater improvement after the administration of the complex with a mean increase of +13.03 ml/s (p < 0.001) after 6 months of treatment (figure 2). the improvement in the flow of urine was statistically higher than that of the dutasteride group (+13.03 ml/s vs +3.029 ml/s, p < 0.001) (figure 2). the mean voided volume (vv) was greater than 150 ml (154-347 ml) at the first observation and also after the medical therapy (157-418 ml). the post void residual (pvr) volume was greater than 50 ml (55-165 ml) before treatment and slightly decreased in both groups after 6 months (45-150 ml). no particular differences were found between the 2 groups regarding these parameters. lastly, prostate volume evaluated through trus showed significant improvements in both groups. for the dutasteride group, a mean volume decrease of -22.14 ml (p < 0.001) after 6 months of treatment was found; for the phytochemicals complex group, despite being still significant from a statistical point of view, the mean decrease was much lower: -10.04 ml (p < 0.001) after 6 months of treatment (figure 3). the difference in mean volume decrease was much higher in the dutasteride group, when compared to the phytochemicals complex group (-22.14 ml vs -10.04 ml, p < 0.001) (figure 3). discussion the efficacy of nutraceuticals for the treatment of bphrelated urinary symptoms is a wide field of interest in urology. our study aims to enriching the present literature for what concerns the comparison between commonly used drugs, like 5-ari dutasteride, and a combination of nutraceuticals like palmitoylethanolamide, selenium and phycocianin. our results show that both the alternatives are valid for the treatment of such symptoms and suggest that treating bph does not necessarily require the administration of drugs, such as 5-aris, that usually heavily impact the qol because of their side effects. 5-ari dutasteride is well-known for its capability in reducing psa values, the prostate volume and improving ufm parameters and our results agree with this. however, 5α-reductases (5α-rs), a family of several isozymes whose activity is inhibited by the administration of 5-aris, play an important role in human physiology by figure 1. difference of basal and 6-month follow up psa values in dutasteride and phytochemical complex groups: significant decrease in both groups *. lower mean psa in dutasteride group at 6 month follow up. figure 3. difference of basal and 6-month follow up prostate volume values in dutasteride and phytochemical complex groups: significant decrease in both groups *. lower mean volume in dutasteride group at 6-month follow up #. figure 2. difference of basal and 6-month follow up uroflowmetry values in dutasteride and phytochemical complex groups: significant improvement in both groups *. higher mean qmax values in the phytochemical complex group at 6-month follow up #. archivio italiano di urologia e andrologia 2024; 96(3):12869 g. saitta, f.a. mantovani, b. calabrese, et al. 4 regulating cellular metabolism of androgens, glucocorticoids and other steroids. along with hypoactive sexual desire, erectile dysfunction, gynecomastia and psychiatric side effects such as a higher risk of major depression, some studies suggest that such treatments may result in development of non-alcoholic fatty liver diseases (nafld), insulin resistance (ir), type 2 diabetes (t2dm), dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions (16, 17). not many studies in literature have evaluated the role of less known nutraceuticals in the treatment of bph (pea, selenium, phycocyanin, etc.). however, based on the biochemical activities of such molecules, it is reasonable to suppose that their main action is towards inflammation and its pathways. today, it is only possible to estimate the effects of such chemicals on the prostate function. for instance, pea has been demonstrated to play a significant neuroprotective effect on chronic pelvic pain, but it may also play an important role in reducing inflammation by interfering with the androgenic pathways. as previously said, daily administration of pea is capable of reducing the levels of testosterone, dht and decreasing the expression of markers like psa and 5αreductases in the prostate tissue (11). this mechanism may lead to the reduction in prostate weight and inflammation markers that eventually is responsible for the improvement of bph-related luts that we have observed in our results. according to our data, even if analysis is biased by the low number of patients taken into consideration, our results show that the complex was able to improve the maximum flow of urine by +13.03 ml/s after 6 months of treatment without dramatically reducing the prostate volume in the meantime. not only is this evidence significant, but it is also very puzzling when compared to the +3.029 ml/s increase in patients treated with dutasteride. even though this result may be paradoxical to some extent, it is possible to deduce that this combination of nutraceuticals may have a stronger impact on ufm parameters than on prostate weight or psa serum levels, where dutasteride seemed to perform better, because of their effect on inflammation. this result supposedly highlights the importance of inflammation pathways in determining urinary symptoms and the fact that such combination of nutraceuticals may have an equal or even slightly stronger anti-inflammatory effect compared to that of 5-ari dutasteride in bph, thus undermining the importance of the absolute value of the prostate volume, main target of 5-aris, in causing bph-related luts. however, it is important to acknowledge the intrinsic limits of this study. the limited number of patients, and the fact that most of them had seen a urologist prior to the inclusion in the study, hence probably being exposed to serenoa repens and/or modifications of their lifestyle, could have affected the astonishing result that we have obtained regarding the ufm parameters. the role of prostate inflammation in determining bphrelated luts is controversial and many studies are being conducted as to explain its exact role in the pathophysiology of bph. it is well known that prostate tissue affected by bph carries a particular kind of inflammatory infiltrate (cd3+ t lymphocytes, cd19 or cd20 b lymphocytes, and macrophages). most t cells in the inflammatory areas are cd4+ that are not present in normal prostate tissue (scattered stromal and intraepithelial t, 70% of which are cd8+, and b lymphocytes, macrophages, and mast cells). however, the stimulus for an inflammatory response in the prostates of older males is not fully understood and it is likely to be multifactorial (18). in an interesting clinical study, kwon et al. observed that in patients with high-grade prostatic inflammation, the use of ablockers with 5-aris can be insufficient to reduce symptom severity. patients with highgrade chronic inflammation reported significantly lower changes in ipss and storage symptom scores compared to patients with lowgrade inflammation (19). a meta-analysis of three randomized controlled trials showed that non-steroidal antiinflammatory drugs (nsaids), when given over periods of 4-24 weeks, improved symptoms by 2.9 ipss points and flow by 0.89 ml/second (20). these studies suggest the need to treat inflammation accordingly, a field in which nutraceuticals seem to have convincing possibilities. conclusions both nutraceutical complex and dutasteride showed reduction of psa values after 6 months of treatment. the complex based on phycocyanin, pea and selenium showed a statistically significant improvement in urinary flow, while dutasteride acted more on the volume of the prostate. however, the natural complex is a product with good efficiency on the phlogistic component and does not have the side effects reported for dutasteride (such as gynecomastia, reduced libido). therefore, we believe it can be used by a large part of the bph population, in order to reduce luts and psa and improve urinary flow, without side effects. acknowledgements first of all, we thank the patients who participated giving us the possibility to observe and analyze the effects of the therapies. we are grateful to all the staff of our institute for the support in the successful completion of this study. of course we appreciate who provide financial support to publish this manuscript. declaration the introduction of ficoxpea® in the commerce was ethically approved and officially notified at the italian ministry of health on 16th october 2020. all patients followed by us accepted anonymous data collection and agreed on its possible use for scientific purposes. references 1. gbd 2019 benign prostatic hyperplasia collaborators. the global, regional, and national burden of benign prostatic hyperplasia in 204 countries and territories from 2000 to 2019: a systematic analysis for the global burden of disease study 2019. lancet healthy longev. 2022; 3:e754-e776. archivio italiano di urologia e andrologia 2024; 96(3):12869 5 phytochemicals versus dutasteride for luts due to bph 2. blankstein u, van asseldonk b, elterman ds. bph update: medical versus interventional management. can j urol. 2016; 23(suppl 1):10-5. 3. van asseldonk b, barkin j, elterman ds. medical therapy for benign prostatic hyperplasia: a review. can j urol. 2015; 22 suppl 1:7-17. 4. alcaraz a, rodríguez-antolín a, carballido-rodríguez j, et al. efficacy and tolerability of the hexanic extract of serenoa repens compared to tamsulosin in moderate-severe luts-bph patients. sci rep. 2021; 11:19401. 5. cai t, cui y, yu s, et al. comparison of serenoa repens with tamsulosin in the treatment of benign prostatic hyperplasia: a systematic review and meta-analysis. am j mens health. 2020; 14:1557988320905407. 6. alcaraz a, rodríguez-antolín a, carballido-rodríguez j, et al. the qualiprost study group obo. clinical benefit of tamsulosin and the hexanic extract of serenoa repens, in combination or as monotherapy, in patients with moderate/severe luts-bph: a subset analysis of the qualiprost study. j clin med. 2020; 9:2909. 7. cicero afg, allkanjari o, busetto gm, et al. nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. arch ital urol androl. 2019; 91:139 8. petrosino s, di marzo v. the pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. br j pharmacol. 2017; 174:1349-1365. 9. loverme j, russo r, la rana g, et al. rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. j pharmacol exp ther. 2006; 319:1051-61. 10. pessina f, capasso r, borrelli f, et al. protective effect of palmitoylethanolamide in a rat model of cystitis. j urol. 2015; 193:1401-8. 11. d'amico r, genovese t, cordaro m, et al. palmitoylethanolamide/ baicalein regulates the androgen receptor signaling and nf-κb/nrf2 pathways in benign prostatic hyperplasia. antioxidants 2021; 10:1014. 12. bergandi l, apprato g, silvagno f. antioxidant and antiinflammatory activity of combined phycocyanin and palmitoylethanolamide in human lung and prostate epithelial cells. antioxidants 2022; 11:201. 13. cordaro m, impellizzeri d, siracusa r, et al. effects of a comicronized composite containing palmitoylethanolamide and polydatin in an experimental model of benign prostatic hyperplasia. toxicol appl pharmacol. 2017; 329:231-240. 14. arias-chávez dj, mailloux-salinas p, ledesma aparicio j, et al. selenium in combination with a tomato lipid extract as a therapy for benign prostatic hyperplasia and its alterations in rats with induced bph. j cell mol med. 2023; 27:3147-3156. 15. kok de, kiemeney la, verhaegh gw, et al. a short-term intervention with selenium affects expression of genes implicated in the epithelial-to-mesenchymal transition in the prostate. oncotarget. 2017; 8:10565-10579. 16. traish am. health risks associated with long-term finasteride and dutasteride use: it's time to sound the alarm. world j mens health. 2020; 38:323-337 17. garcia-argibay m, hiyoshi a, fall k, montgomery s. association of 5α-reductase inhibitors with dementia, depression, and suicide. jama netw open. 2022; 5:e2248135. 18. ficarra v, rossanese m, zazzara m, et al. the role of inflammation in lower urinary tract symptoms (luts) due to benign prostatic hyperplasia (bph) and its potential impact on medical therapy. curr urol rep. 2014; 15:463. 19. kwon yk, choe ms, seo kw, et al. the effect of intraprostatic chronic inflammation on benign prostatic hyperplasia treatment. korean j urol. 2010; 51:266-70. 20. kahokehr a, vather r, nixon a, hill ag. non-steroidal antiinflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. bju int. 2013; 111:304-11. correspondence giuseppe saitta, md (corresponding author) gsaitta@hotmail.it iccs istituto clinico città studi, milan (italy) viale sabotino 19, 20135, milan (italy) franco a mantovani, md mantovanifranco@yahoo.it benedetto calabrese, md calabrese.benedetto98@gmail.com camilla aliboni, md camilla.aliboni@gmail.com giuseppe di paola, md giuseppe.dipaola@ic-cittastudi.it attilio l meazza, md attilio.meazza@ic-cittastudi.it mauro seveso, md mauro.seveso@ic-cittastudi.it iccs istituto clinico città studi, milan (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13596 1 original paper els across numerous domains of medicine, including clinical data analysis, diagnostic support, and treatment planning. among these models, openai's chat generative pretrained transformer (chatgpt) has emerged as a leading large language model (llm), capable of generating humanlike responses based on extensive textual data training. although primarily designed for natural language processing tasks, chatgpt’s potential extends beyond its original scope, raising the question of its applicability in clinical data analysis and decision-making processes (1-3). recent advancements in ai-driven models such as chatgpt have demonstrated potential in supporting systematic reviews and meta-analyses by automating literature screening, data extraction, and bias assessment processes, thus streamlining evidence synthesis in clinical research (4). in clinical practice, analyzing patient data to identify prognostic and predictive factors is critical for improving therapeutic strategies and outcomes. traditional statistical methods such as logistic regression, survival analysis, and multivariable modeling have been the gold standard for data interpretation. however, these techniques often require specialized statistical expertise and are susceptible to human error during data management, analysis, and interpretation (5). beyond its analytical potential, chatgpt appears oòito be promising in automating repetitive, standardized, and compilative tasks, reducing the time and effort required in such activities. for instance, a study by aykut demirci in 2024 compared the performance of chatgpt with humans in completing validated quality assessment questionnaires (6), including the discern-5 and global quality scale (gqs), which have also been used in the past by other authors for similar analyses but without the use of ai (7), for evaluating audio-video materials on youtube. the findings revealed no statistically significant differences in median scores (iqr) for both discern-5 and gqs when comparing chatgpt to human assessments, suggesting that chatgpt can deliver comparable results in such tasks while enhancing efficiency (8). objective: to compare statistical outputs from chatgpt 4.0 and human experts in both comparative and correlation analyses in the evaluation of multiparametric mri/ultrasound fusion-targeted biopsy plus random biopsy versus standard random biopsy alone, in terms of upstaging. methods: authors performed a retrospective evaluation on 101 patients undergoing robot-assisted radical prostatectomy (rarp) between 2021 and 2023. patients were divided in two groups, according to the type of prostatic biopsy received: combined fusion (mri/us) targeted and random biopsy versus standard random biopsy. clinical and histological data were anonymized and analyzed using logistic regression models, anova, and chi-square tests. analysis generated by chatgpt and by an experienced human statistician were compared. the q-eval and q-eva tools were used to assess the quality of user-formulated questions and ai-generated answers, respectively.results: results revealed high concordance between statistical outputs generated by ai and expert human statistician with perfect concordance using cohen’s kappa coefficient (κ = 1.0). logistic regression analysis demonstrated that fusion biopsy was associated with a reduced likelihood of upstaging, a consistent finding across statistical evaluations. additionally, user interaction assessments indicated high-quality in question formulation. conclusions: chatgpt (version 4.0) proved reliable for statistical analysis, showing strong concordance with human statisticians (κ = 1.0) in performing logistic regression, chi-square, and anova tests. the q-eval tool could reduce query errors, though chatgpt's lack of automatic citations remains a limitation. fusion biopsy significantly lowered upstaging risk after rarp. in conclusion, chatgpt is a valuable assistive tool but further research is required to optimize human-ai collaboration in clinical research. key words: prostate cancer; chatgpt; artificial intelligence; upstaging; robot-assisted radical prostatectomy; fusion biopsy. submitted 7 january 2025; accepted 29 march 2025 introduction the rapid advancement of artificial intelligence (ai) technologies has led to the integration of machine learning modchatgpt artificial intelligence in clinical data analysis: an example comparing standard vs fusion prostate biopsy outcomes after robotic-assisted radical prostatectomy (rarp) pier paolo prontera 1, francesca romana prusciano 1, 2, marco lattarulo 1, arman tsaturyan 3, 4, francesco addabbo 5, carmine sciorio 6, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto, italy; 2 division of urology, hospital “valle d’itria”, martina franca (ta), italy; 3 department of urology, yerevan state medical university after mkhitar, heratsi, yerevan, armenia; 4 department of urology erebouni medical center, yerevan, armenia; 5 unit of statistics and epidemiology, local health authority of taranto, taranto, italy; 6 department of urology, “alessandro manzoni” hospital, lecco, italy. doi: 10.4081/aiua.2025.13596 summary archivio italiano di urologia e andrologia 2025; 97(2):13596 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 2 postoperative management following robot-assisted radical prostatectomy (rarp) presents a complex clinical challenge, particularly regarding upstaging (identification of more advanced cancer than initially assessed) and upgrading (identification of more aggressive cancer types than initially expected). these factors significantly affect postoperative management, including the need for adjuvant therapy and closer follow-up (3). the clinical management of prostate cancer has seen notable advances in biopsy techniques, specifically the comparison between standard systematic biopsy (sbx) and multiparametric mri/ultrasound fusion-targeted biopsy (tbx). systematic biopsy has historically been the standard method, offering spatially distributed sampling of the prostate gland. however, sbx has notable limitations, including, higher rates of false-negative, frequent under detection of aggressive tumors and over detection hof clinically insignificant cancers, potentially leading to overtreatment (9). recent studies have highlighted a persistent risk of diagnostic misclassification in low-risk prostate cancer patients, with 10.5% experiencing pathological upstaging at radical prostatectomy, including 6.3% with gleason grade group (ggg) 2 and 1.6% with ggg ≥ 3. studies have consistently shown that tbx improves the detection of clinically significant cancers while reducing unnecessary diagnoses of indolent tumors (10). research comparing these two methods indicates that tbx more accurately identifies prostate cancer’s gleason scores, leading to lower rates of undergrading and overgrading when compared to sbx alone (11). additionally, the combination of sbx and tbx provides the highest cancer detection rates, supporting a multimodal approach to minimize the risk of misclassification. studies highlight the significant upstaging and upgrading observed when combining these methods, which is essential for surgical planning and long-term patient management (12). the increased accuracy in detecting more aggressive lesions through tbx has been particularly evident in identifying high-risk prostate cancer types with higher gleason scores and larger tumor volumes (13). given this background, the expanding role of ai in medical research and its increasing accessibility, this study aims to explore whether chatgpt can support clinical data analysis in urological field. materials and methods a retrospective evaluation was conducted on 153 patients who underwent robot-assisted radical prostatectomy (rarp) between 2021 and 2023, in a single center. 101 patients were enrolled in the study based on specific inclusion and exclusion criteria. patients with previous negative prostate biopsies or histological diagnoses performed at external institutions were excluded. all enrolled patients underwent robot-assisted radical prostatectomy using the davinci xi (intuitive) multiport robotic system. techniques and histopathology prostate biopsy histological diagnosis was performed using either standard trans-perineal prostate biopsy (sbx) or mri/us fusion combined trans-perineal biopsy (tbx+sbx); both procedures were performed under transrectal ultrasound guidance. fifty patients underwent a combined fusion biopsy, while 51 patients received a standard random biopsy. all procedures were performed by a highly experienced operator. fusion biopsy was indicated for patients presenting with clinically significant pirads lesions (pirads ≥ 3) and included both targeted cores (based on the number and size of regions of interest (roi)) and 12 to 16 systematic cores according a prostatic template including base, mid-gland, and apex on both sides. when multiparametric mri (mpmri) was unavailable or no significant pirads lesions were detected, a standard 16-core trus guided trans-perineal biopsy was performed following the institutional template, sampling the base, mid-gland, apex, and transition zones bilaterally. staging and surgery all patients underwent staging with contrast-enhanced total-body ct scan and total-body bone scintigraphy scan. subsequently, they underwent robot-assisted radical prostatectomy (rarp) at the same center, performed by two different surgeons. forty-seven procedures were conducted by one surgeon and fifty-four by the other, both highly experienced in robotic prostate cancer surgery. the surgical specimens were examined by an expert pathologist. statistical analysis data collection clinical and laboratory data related to the sample of 101 patients enrolled in the study were collected by two urologists and recorded in a database using microsoft excel (version 2013). the database comprehensively collects data on patients undergoing robot-assisted radical prostatectomy (rarp). it includes demographic information such as patient age, weight, height, bmi, and waist circumference. preoperative clinical parameters include family history of prostate cancer (firstor second-degree relatives), preoperative psa levels, clinical staging, biopsy gleason score, and eau 2024 risk classification. intraoperative variables include the surgeon’s experience, operative time (minutes), blood loss, intraoperative complications, and nerve-sparing approach. postoperative outcomes cover hospitalization duration, final pathological staging, postoperative gleason score, lymph node involvement, surgical margins, and recalculated eau 2024 risk classification based on definitive histology. functional outcomes include continence status, calculated by using a continence score based on three levels (2 full continence, 1 stress incontinence and 0 complete incontinence), and by evaluating the variation in the number of pads used per day at 3, 6, 9 and 12 months, erectile function recovery (iief score at 3, 6, 9 and 12 months), and psa levels at 3, 6, 9 and 12 months. the database also records perioperative complications, reintervention rates, oncological outcomes (biochemical recurrence and survival), as well as patient-reported satisfaction scores, including ratings for the hospital facility and nursing staff. additionally, the geographical distance traveled by patients to reach the hospital is documented. archivio italiano di urologia e andrologia 2025; 97(2):13596 3 chatgpt for analysis of outcomes of prostate biopsy the excel sheet was designed to use a binary coding system exclusively ("0": negative variable, "1": positive variable). column nomenclature was simplified as much as possible. both urologists independently reviewed the database in order to avoid potential structural and errors. to ensure patient confidentiality, all data were fully anonymized before analysis, with no personally identifiable information retained in the dataset. the dataset included patient records with relevant clinical variables, such as biopsy type (standard = 0, fusion = 1) and upstaging outcome (no = 0, yes = 1). the dataset was sufficiently large to ensure robust regression model fitting. prostate volume data were collected to categorize patients into three preoperative risk groups: low, intermediate, and high. the dataset included a sufficient sample size for each group to ensure the validity of the anova assumptions. the dataset was used to conduct statistical analyses independently by: 1) an expert human statistician, 2) a user with limited statistical knowledge utilizing chatgpt (user a), 3) a user with limited statistical knowledge utilizing chatgpt (user b). evaluation criteria for questions and answers both users (user a and user b) independently formulated questions to the ai. questions formulated by both users a and b and answers provided by the chatgpt platform were subsequently evaluated using two non-validated tools specifically developed by the authors of the study: the "q-eval" tool (quality evaluation for verification and assessment of language-based queries) and the "q-eva" tool (quality evaluation of answers). both tools assess a total score (ranging from 0 to 100) for each question formulated by the user and to each answer generated by the ai. both q-eval and q-eva evaluates four items, each of them scored either 0 (if not met) or 25 (if met). q-eval assesses four key items related to the quality of user-formulated questions. the first criteria is minimum length, requiring questions to contain at least 10 characters. the second is specificity, emphasizing the use of action verbs to clearly define the intent of the query. the third criterion involves the absence of ambiguity, ensuring that unclear terms are avoided. lastly, context presence is evaluated, requiring the use of complete sentences to provide clarity and context. q-eva evaluates four parameters of ai-generated answers. the first criterion is the presence of citations, ensuring that sources are appropriately referenced. internal consistency is the second aspect, requiring logically coherent responses structured with complete sentences. the third criterion focuses on the use of technical terms, verifying the inclusion of relevant keywords in the answer. finally, the absence of opinion ensures that responses remain objective, avoiding personal judgments or subjective interpretations. openai's chatgpt (user a and user b) analysis users a and b used chatgpt (version 4.0), developed by openai, under the intermediate subscription tier. this version supports advanced natural language processing, context-aware responses, and statistical query handling. key features included extended context retention and improved reasoning capabilities, though limitations such as the lack of real-time database access and automatic source citation, were recognized. statistical analyses were conducted to evaluate the association between clinical variables and patient outcomes. a logistic regression analysis was performed using the independent variable "fusion" (biopsy type: 0 = standard, 1 = fusion) to predict the likelihood of upstaging (0 = no, 1 = yes). additionally, a one-way anova was conducted to compare prostate volumes across three preoperative risk classes, according to d’amico classification (14). pairwise comparisons using independent samples t-tests were performed among the three risk classes (low vs. intermediate, low vs. high, and intermediate vs. high), assuming unequal variances. all statistical analyses were performed using python, employing libraries such as pandas, scipy, and scikitlearn. data visualization and graphical outputs were generated using matplotlib to provide clear and interpretable representations of the results. the process of submitting data to chatgpt for analysis follows a structured yet intuitive workflow. users can upload data by either clicking the “+” button in the chat interface or simply dragging and dropping the file into the conversation. in this case, the file was uploaded by dragging and dropping it directly onto the search bar and was an excel spreadsheet (.xlsx), but other commonly used formats such as csv, json, and txt are also supported. to initiate an analysis, users provide instructions in natural language, in this case in italian language, specifying the tasks they need, such as data cleaning, statistical analysis, or visualization. for example, a user typed, “analyze the patient dataset and provide a summary of the main variables.” context and specific objectives can also be outlined, making it easier for chatgpt to tailor the analysis. a more detailed instruction was, “this dataset contains information on patients undergoing prostatectomy. please summarize key variables such as age, bmi, and psa levels.” once instructions are provided, chatgpt first cleans the data by handling missing values, renaming columns if necessary, and ensuring proper formatting. it then performs the requested analysis by interpreting the instructions and converting them into python scripts, which are executed in a built-in python environment. the results are then returned in user-friendly formats, such as tables, figures, and summaries. for example, when a user asks, “show me the average bmi of patients in the dataset”, chatgpt will read the excel file, extract the relevant column, calculate the mean bmi using python, and display the result either as a numerical output or as a graphical representation. the final results are presented in natural language, ensuring accessibility even for users without technical expertise. an example output could be: “the average bmi of patients in the dataset is 27.5”, accompanied by a chart showing the bmi distribution. this process makes data analysis efficient and accessible, allowing users to gain insights without needing programming knowledge while still leveraging the power of python for advanced computations. archivio italiano di urologia e andrologia 2025; 97(2):13596 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 4 experienced human statistician analysis statistical analyses were performed using the chi-squared test and logistic regression to evaluate the association between type of biopsy and upstaging. the statistical computations were carried out using the online platform "statistics kingdom" (https://www.statskingdom.com/ 180anova1way.html). the platform facilitated the implementation of the anova test, the validation of assumptions using the shapiro-wilk test, and the assessment of homogeneity of variances using levene's test. effect size calculations, including the eta-squared (η²) statistic, were also generated. additionally, one-way analysis of variance (anova) was conducted using the f distribution to determine whether significant differences existed between prostate volumes emerged among the evaluated risk classes, according to d’amico classification (14). post hoc comparisons were performed using tukey's honest significant difference (hsd) test to identify pairwise differences between group means. comparison of statistical analyses to comprehensively evaluate the agreement between chatgpt-driven analyses and those performed by a human statistician, a dual-approach methodology was applied. first, standard statistical metrics such as f-statistics, regression coefficients, p-values, and model fit indicators were computed for both anova and logistic regression analyses. absolute and percentage differences in these key parameters were calculated. secondly, to quantitatively assess the agreement between chatgpt-generated results and human expert analyses, cohen's kappa statistics were employed. this metric measures inter-rater reliability and accounts for agreement occurring by chance. the comparison focused on two key clinical outcomes: biopsy type classification and upstaging detection. for biopsy type, the variable 'fusion' from the dataset was compared with ai-predicted biopsy classifications. for upstaging, preoperative and postoperative risk classifications were used to determine whether upstaging occurred, and these results were cross-referenced with aigenerated outputs. cohen's kappa coefficients were computed for both variables, yielding values of 1.0 for both biopsy type and upstaging detection. graphical representations were generated to highlight the results. a p-value less than or equal to 0.05 was considered statistically significant. results this retrospective study included 101 patients who underwent robot-assisted radical prostatectomy (rarp) between 2021 and 2023, in a single center. none of the patients undergoing rarp developed significant perioperative complications. the cohort had a mean age of 68.6 years, with a mean preoperative psa level of 9.23 ng/ml and an average prostate volume of 54.4 ml. the distribution of patients according to preoperative risk class showed that 24.757% were classified as low risk, 48.51% as intermediate risk, and 26.73% as high risk. regarding preoperative clinical stages, the most frequent stages were t2b (40.59%), t2a (24.75), t1c (17.82%), t2c (10.89%) and t3b (5.94) (table 1). the evaluation process revealed that both users, a and b, consistently formulated well-defined questions, receiving perfect q-eval scores of 100 points across all queries (table 2). in addition to statistical accuracy, chatgpt's response quality was evaluated using q-eva scoring criteria. despite the absence of automatically generated citations, chatgpt's responses demonstrated high internal consistency, appropriate use of technical terminology, and objectivity, yielding a consistent q-eva score of 75 points (table 3). this underscores its reliability as a research tool when complemented by human validation. however, the responses provided by chatgpt received a consistent q-eva score of 75 points due to the lack of citations, despite excelling in internal consistency, technical accuracy, and objectivity. the combined use of these evaluation tools highlighted the effectiveness of chatgpt as a support system for clinical data analysis. the relationship between biopsy type and upstaging was assessed using a logistic regression and chi-square test, both indicated a statistically significant association (pvalue < 0.05). chi-square tests shows the following findings: chi-square value 4.48 and p-value 0.034 for user table 1. patient demographics, pre-operative clinical features, and risk classifications according to d’amico criteria are summarized. mean age, total preoperative psa levels, and prostate volume are presented with ranges. pre-operative staging is reported in absolute numbers and percentages. risk classification includes low, intermediate, and high-risk categories based on clinical assessment prior to surgery. the distribution of these variables highlights differences between patients undergoing fusion biopsy and those managed through standard random biopsy. clinical and pathological characteristics of enrolled patients undergoing rarp fusion-combined biopsy random biopsy tot. mean age, y (range) 67.7 (55-76) 69.5 (54-75) 68.6 (54-76) mean pre-operative total psa, ng/ml (range) 8.46 (3.9-13.5) 10 (3.54-31.5) 9.23 (3.54-31.5) mean prostate volume, ml (range) 48.3 (20-142) 54.4 (25-120) 51.4 (20-142) pre op. staging, n° (%) t1c 12 (24) 6 (11.76) 18 (17.82) t2a 15 (30) 10 (19.6) 25 (24.75) t2b 16 (32) 25 (49) 41 (40.59) t2c 4 (8) 7 (13.72) 11 (10.89) t3b 3 (6) 3 (5.88) 6 (5.94) pre op. risk classification (acc. d’amico) low, n° (%) 15 (30) 10 (19.6) 25 (24.75) intermediate n° (%) 22 (44) 27 (52.94) 49 (48.51) high n° (%) 13 (26) 14 (27.45) 27 (26.73) archivio italiano di urologia e andrologia 2025; 97(2):13596 5 chatgpt for analysis of outcomes of prostate biopsy a; chi-square 4.48 and p-value 0.034 for users b. logistic regression analysis confirmed this finding: intercept -0.783 (p-value 0.009) and fusion biopsy coefficient -1.210 (p-value 0.022) for user a; intercept -0.78 (pvalue 0.0095) and fusion biopsy coefficient -1.21 (pvalue 0.0224) for user b. both users obtained consistent results indicating a significant relationship between biopsy type and the likelihood of upstaging, with fusion biopsy being associated with a lower probability of upstaging compared to standard biopsy. the one-way anova comparing prostate volumes across preoperative risk classes (low, intermediate, high) revealed no statistically significant differences (f-value = 0.73 and p-value = 0.485 for user a; f-value 0.7294 anche p-value 0.4848 for user b). post-hoc tukey hsd comparisons confirmed the lack of significance, with all pairwise comparisons yielding p-values greater than 0.05 for both analysis, with no statistically significant differences in prostate volumes among the evaluated risk classes. additionally, an experienced human statistician performed statistical analysis, using the same dataset. to evaluate the association between type of biopsy and upstaging, statistical analyses were conducted using the chi-squared test and logistic regression. chi-square test shows the following results: chi-square stat 4.9629, pvalue 0.0259, freedom degrease 1, phi 0.22167 and cramer’s v 0.22167. from logistic regression emerged a correlation coefficient -0.121. overall, both statistical tests reinforce the presence of a meaningful relationship, with the chi-square test highlighting statistical significance and the logistic regression supporting the clinical relevance of the association. one-way analysis of variance (anova) was conducted comparing prostate volumes across preoperative risk classes (low, intermediate, high) revealed no statistically significant differences (f-statistic 0.7673, p-value 0.4656, effect size 0.088). a detailed comparison was conducted between the results obtained by a human statistician and those generated by operators a and b, independently, using chatgpt 4.0. a dual-approach methodology was applied to compare statistical results from an expert statistician, operator a, and operator b. standard statistical metrics were computed for anova, logistic regression, and chi-square analyses (figure 1). for anova analysis, f-statistic values were 0.7673 (expert), 0.73 (operator a), and 0.73 (operator b), with p-values of 0.4656, 0.485, and 0.485, respectively, indicating no statistically significant differences in prostate volume across risk classes. for logistic regression, regression coefficients for biopsy type ("fusion") were -0.121 (expert) versus -1.210 (operators a and b), with p-values of 0.0259 (expert) and 0.022/0.0224 (operators a/b). these differences suggest methodological variations in model specification. for chi-square test, chi-square statistics were 4.9629 (expert) versus 4.48 (operators a/b), with p-values of 0.0259 (expert) and 0.034 (operators a/b), confirming similar statistical significance despite slight numerical discrepancies (table 4). agreement was assessed using cohen's kappa, yielding perfect scores of 1.0 for both biopsy type classification and upstaging detection, indicating full concordance between human and ai-driven analyses (figure 2). these results suggest high reliability and comparable accuracy across all tested methods. these comparisons underscore the high concordance between ai-supported analyses and expert-driven statistical evaluations. despite different methodological table 2. quality assessment of user-formulated questions using the q-eval tools. user a user b question 1: length (at least 10 characters) 25 25 assess of statistically significant differences in upstaging between patients undergoing specificity (use of action verbs) 25 25 standard biopsy and those undergoing fusion biopsy un-ambiguous (absence of vague or unclear terms) 25 25 clarity and context 25 25 question 2: length (at least 10 characters) 25 25 correlation between prostate volume and preoperative risk categories specificity (use of action verbs) 25 25 un-ambiguous (absence of vague or unclear terms) 25 25 clarity and context 25 25 table 3. quality assessment of ai-generated answers using the q-eva tools. user a user b question 1: presence of citations 0 0 assess of statistically significant differences in upstaging between patients undergoing internal consistency (logical coherence) 25 25 standard biopsy and those undergoing fusion biopsy use of technical terms 25 25 absence of opinion 25 25 answer 2: presence of citations 0 0 correlation between prostate volume and preoperative risk categories internal consistency (logical coherence) 25 25 use of technical terms 25 25 absence of opinion 25 25 archivio italiano di urologia e andrologia 2025; 97(2):13596 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 6 table 4. detailed statistical comparison of anova, logistic regression, and chi-square tests: expert statistician vs. user a vs. user b: the table presents a detailed comparison of key statistical metrics, including f-statistics, p-values, regression coefficients, and chi-square statistics. results from the expert statistician, operator a, and operator b are presented, highlighting areas of agreement and statistical differences observed during the analyses. metric expert statician user a user b anova f-statistic 0.7673 0.73 0.73 anova p-value 0.4656 0.485 0.485 logistic regression coefficient (fusion) -0.121 -1.21 -1.21 logistic regression p-value (fusion) 0.0259 0.022 0.0224 chi-square statistic 4.9629 4.48 4.48 chi-square p-value 0.0259 0.034 0.034 figure 1 detailed statistical comparison of anova, logistic regression, and chi-square tests: expert statistician vs. operator a vs. operator b: the chart presents a comparative analysis of key statistical metrics obtained from analyses conducted by the expert statistician, operator a, and operator b. metrics include f-statistics and p-values for anova, regression coefficients and p-values for logistic regression, and chi-square statistics with corresponding p-values. the comparison highlights areas of agreement and methodological differences across the three analytical approaches. archivio italiano di urologia e andrologia 2025; 97(2):13596 7 chatgpt for analysis of outcomes of prostate biopsy approaches, chatgpt delivered reliable statistical results consistent with the expert’s interpretations. discussion the use of artificial intelligence platforms, such as the chatgpt 4.0 tool, in the clinical field is a highly relevant topic and the application of such tools in clinical research represents a field that is not yet fully explored. nowadays, a comprehensive review of the updated literature revealed only one published study evaluating the effectiveness of chatgpt in performing clinical statistical analyses, compared to a human statistician (5). this finding highlights a significant research gap and underscores the novelty of investigating chatgpt's potential as a reliable analytical tool in clinical research settings. the integration of artificial intelligence (ai) into clinical practice has become increasingly relevant, as demonstrated by numerous studies exploring ai-driven tools, such as chatgpt. in this context, our study provides compelling evidence of chatgpt's capability to perform accurate and consistent statistical analyses in clinical research, particularly in evaluating the impact of biopsy methods on prostate cancer upstaging. this aligns with findings from the mritargeted biopsy study, which demonstrated how advanced imaging-guided biopsies improved diagnostic precision and incorporating ai-driven analyses into such protocols could further streamline clinical decision-making processes (9). our findings resonate with broader research on ai applications in healthcare, highlighting both the strengths and limitations of such technologies. for instance, other studies found that chatgpt could assist in generating diagnostic insights in urology, providing context-aware responses based on clinical scenarios (8). this demonstrates how ai-driven models can augment diagnostic accuracy when integrated with standard medical protocols (3). moreover, chatgpt has been employed in medical research tasks such as systematic reviews, significantly reducing the time required for literature screening and data extraction, as shown in cardiology-focused ai research tutorials (13). several studies emphasize the advantages of using chatgpt in clinical data analysis. showing that chatgpt-4 could achieve analytical efficiency and user-friendliness comparable to traditional statistical software like sas, spss, and r. (5). this evidence aligns with our results, showing a strong agreement between chatgpt and human-driven analyses in logistic regression, anova, and chi-square tests. its ability to generate accurate statistical outputs, without requiring complex coding, underscores its potential as a valuable analytical tool in clinical research, even for users with limited statistical expertise. in the clinical domain, chatgpt has also turned out to be a decision-support tool. it has been noted that while chatgpt is not a substitute for clinical judgment, it can enhance decisionmaking by providing up-to-date medical research and clinical guidelines (5). similarly, chatgpt's effectiveness in producing radiology reports with clarity and precision was highlighted in a review of its clinical application. this endorses our findings, where chatgpt consistently produced statistical summaries comparable to those generated by experienced statisticians. however, our study also reveals inherent limitations. chatgpt's lack of automatic citation generation was a notable drawback, reflected in lower evaluation scores in our study (q-eva). this issue has been widely discussed, particularly regarding the risk of academic misconduct and the spread of misinformation. the need for human oversight in interpreting aigenerated results is thus critical, especially in high-stakes clinical research and decision-making environments. a 2023 review highlights similar concerns, stressing how, while ai tools like chatgpt can automate complex data analyses, transparent reporting and human verification remain essential to prevent errors and maintain clinical figure 2. cohen's kappa agreement analysis for biopsy type and upstaging detection: the bar chart displays cohen's kappa scores for biopsy type classification and upstaging detection, comparing the results obtained by operator a and operator b. both operators achieved perfect agreement (cohen's kappa = 1.0) across all evaluated metrics, indicating complete concordance with the expert statistician's analysis. archivio italiano di urologia e andrologia 2025; 97(2):13596 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 8 integrity (15). similarly, it is crucial to standardize the formulation of queries submitted to the ai platform, in order to minimize result variability caused by potential system misinterpretations. the q-eval tool was designed for this purpose, although further studies are required to evaluate its effectiveness and explore its potential implementation. from a clinical perspective, our study established the superiority of fusion combined (mri/us) target and random biopsy over random biopsy alone in reducing post-operative upstaging for prostate cancer, in accordance with findings reported in the literature (16). the protective effect of fusion biopsy in reducing upstaging risk, confirmed through logistic regression, aligns with these clinical outcomes. this highlights the potential of combining ai-driven analytics with advanced diagnostic techniques for improved patient management. looking ahead, the integration of chatgpt into clinical workflows could enhance productivity, reduce human error, and lower the operational threshold for performing complex analyses. additionally, research about prostate cancer diagnostics suggests that combining ai-assisted analyses with mri-trus fusion techniques could further enhance the precision of tumor localization and reduce unnecessary biopsies (10). as a.i. technologies continue to evolve, addressing issues such as source transparency, data privacy, and interpretability will be essential. future research should explore hybrid models that combine a.i. capabilities with human expertise, promoting data-driven decision-making in clinical practice, refine and standardize querying methods for interrogation of a.i. systems in the medical-scientific field. in this evolving landscape, chatgpt and similar a.i. tools hold significant promise as supportive technologies in medical research and clinical care. the integration of chatgpt as an analytical tool demonstrated significant potential for supporting clinical research by providing accurate statistical analyses comparable to those of expert statisticians. these results suggest that ai-powered tools could streamline future clinical research workflows, enhancing efficiency without compromising analytical accuracy. conclusions this study demonstrates how chatgpt (version 4.0) is a reliable and consistent tool for statistical analysis in clinical research, showing high concordance with human statisticians across both correlation analyses (e.g., logistic regression) and comparative tests (e.g., chi-square, anova). statistical agreement was confirmed by p-values < 0.05, with logistic regression for biopsy type yielding chi-square tests. cohen's kappa coefficients for biopsy type and upstaging reached 1.0, indicating perfect alignment between ai-driven and human analyses. qeval tool can reduce inaccuracies and errors related to poorly formulated user queries, although further studies are needed to explore this hypothesis. application of qeva tools highlighted chatgpt's capacity for logical and technically sound responses, though its inability to generate automatic source citations underscores a key limitation requiring future improvement. regarding the secondary objective, fusion biopsy significantly reduced the risk of upstaging after rarp. while chatgpt shows strong analytical potential, it should currently be viewed as an assistive tool complementing human expertise rather than replacing it. future research should explore ai’s analytical boundaries and the dynamics of human-ai collaboration to enhance the integration of ai-powered tools into clinical research workflows. references 1. qin s, chislett b, ischia j, et al. chatgpt and generative ai in urology and surgery a narrative review. bjuicompass. 2024; 5:813-21. 2. mu y, he d. the potential applications and challenges of chatgpt in the medical field. int j gen med. 2024; 17:817-826. 3. lazaros t, konstantinos k, georgios f, et al. chatgpt in clinical medicine, urology and academia: a review. arch. esp. urol. 2024; 77: 708-717. 4. teperikidis l, boulmpou a, papadopoulos c, et al. using chatgpt to perform a systematic review: a tutorial. minerva cardiology and andrology. 2024; 72:547-67. 5. huang y, wu r, he j, et al. evaluating chatgpt-4.0’s data anadeclarations ethical approval: this study was approved by the local ethics committee of bari (ba), irccs oncological institute "gabriella serio" (protocol number: 2112/cel study “propt”). availability of data and material: the datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. competing interests: the authors declare no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions (according to http://www.icmje.org/ #author): 1: pier paolo prontera author corresponding substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 2: francesca romana prusciano, francesco saverio grossi: substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 3: marco lattarulo, arman tsaturyan; francesco addabbo, carmine sciorio: substantial contributions to the interpretation of data for the work. reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13596 9 chatgpt for analysis of outcomes of prostate biopsy lytic proficiency in epidemiological studies: a comparative analysis with sas, spss, and r. j glob health 2024; 14:04070. 6. aykut d. a comparison of chatgpt and human questionnaire evaluations of the urological cancer videos most watched on youtube. clinical genitourinary 2024; 22:102145. 7. prontera pp, prusciano fr, lattarulo m, et al. quality of bladder cancer treatment information on youtube: may the user’s profile affect the quality of results? arch ital urol androl 2024; 96:12179. 8. braga martinelli avn, nunes nc, santos en, et al. use of chatgpt in urology and its relevance in clinical practice: is it useful? int braz j urol 2024; 50:192-198. 9. kasivisvanathan v, rannikko as, borghi m, et al. mri-targeted or standard biopsy for prostate-cancer diagnosis. n engl j med 2018; 378:1767-77. 10. baco e, ukimura o, rud e, et al. magnetic resonance imagingtransectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. eur urol 2014; 67:787-794. 11. porpiglia f, de luca s, passera r, et al. multiparametric-magnetic resonance/ultrasound fusion targeted prostate biopsy improves agreement between biopsy and radical prostatectomy gleason score. anticancer res. 2016; 36:4833-9. 12. borkowetz a, platzek i, toma m, et al. direct comparison of multiparametric magnetic resonance imaging (mri) results with final histopathology in patients with proven prostate cancer in mri/ultrasonography-fusion biopsy. bju int. 2016; 118:213-20. 13. lanz c, cornud f, beuvon f, et al. gleason score determination with transrectal ultrasound-magnetic resonance imaging fusion guided prostate biopsies are we gaining in accuracy? j urol. 2016; 195:88-93. 14. d’amico av, whittington r, malkowicz sb, et al. biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. ama. 1998; 280:969-74. 15. dave t, athaluri sa, singh s. chatgpt in medicine: an overview of its applications, advantages, limitations, future prospects, and ethical considerations. front. artif. intell. 2023; 6:1169595. 16. flammia rs, hoeh b, hohenhorst l, et al. adverse upgrading and/or upstaging in contemporary low-risk prostate cancer patients. int urol nephrol. 2022; 54:2521-2528. correspondence pier paolo prontera, md (corresponding author) pierpaolo.prontera@asl.taranto.it lattarulo marco, md marco.lattarulo@asl.taranto.it francesco saverio grossi, md, phd francescos.grossi@asl.taranto.it department of urology, “s.s. annunziata” hospital, via bruno francesco 1 74010 taranto (italy) francesca romana prusciano, md francescaprusciano@gmail.com division of urology, hospital “valle d’itria”, martina franca (ta), italy arman tsaturyan, md, phd tsaturyanarman@yahoo.com department of urology, yerevan state medical university after mkhitar and department of urology erebouni medical center, heratsi, yerevan, armenia francesco addabbo, md, phd francesco.addabbo@asl.taranto.it unit of statistics and epidemiology, local health authority of taranto, taranto (italy) carmine sciorio, md carmine.sciorio@gmail.com department of urology, “alessandro manzoni” hospital of lecco, 23900 (italy) stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13750 1 review infertility is caused by defective sperm parameters (spermatogenic failure), including total absence (azoospermia), low count (oligozoospermia), abnormal morphology (teratozoospermia), and/or impaired motility (asthenozoospermia). the failure in dealing with male infertility is mostly because of the multifaceted etiology that arises from the interaction of genetics, lifestyle choices, environmental influences, and concomitant conditions (2). reactive oxygen species (ros) are normal products of cellular metabolism, mainly produced in the mitochondria during oxidative phosphorylation. free radicals form during oxygen reduction for energy production. when oxidants increase, the balance shifts toward oxidative stress, which is linked to over 100 disorders, including infertility. ros can induce protein degradation, lipid peroxidation, dna damage and apoptosis. evidence indicates that ros-mediated damage to sperm significantly contributes to 30%-80% of all cases (3, 4). n-acetyl-cysteine (nac) is a dietary supplement and mucolytic drug utilized in the treatment of acetaminophen and paracetamol overdoses. as a thiol-based derivative of the amino acid l-cysteine and a precursor to glutathione peroxidase, it has potent anti-inflammatory, mucolytic, and antioxidant properties. numerous studies indicate that nac supplementation can elevate sperm counts, improve motility, diminish abnormal morphology, minimize dna fragmentation, promote acrosomal activity, and function as a potent semen antioxidant (5). this review investigates the potential of nac supplementation in the latest studies on seminal parameters and its safety in male with infertility or impaired semen parameters. method search strategy two authors independently searched for and reviewed all randomized controlled trial describing the efficacy and safety of nac in male with infertility or impaired semen parameters from inception until february 21, 2024 from several databases comprised of pubmed, sciencedirect, introduction and objectives: n-acetyl-cysteine (nac) is one of the oldest and most powerful antioxidants used to treat various diseases. it plays an important role in protecting cells against oxidative damage and has the potential to improve seminal parameters in male with infertility. this systematic review and meta-analysis aim to comprehensively evaluate the efficacy and safety profile of antioxidant supplementation with nac in male with infertility or impaired semen parameters. materials and methods: this systematic review and meta-analysis adhered to cochrane handbook guidelines. a literature search across pubmed, sciencedirect, cochrane library and scopus on february 21, 2024 of studies evaluating nac supplementation for male infertility or impaired semen parameters was conducted. study quality was assessed using revised cochrane's risk of bias (rob 2.0) and revman 5.4 was used for meta-analysis. results: search yielded 1.106 articles and 5 studies were included in this meta-analysis. our study showed that patients who received nac had statistically significant results in improving sperm volume [md: 0.69 (0.26-1.12), p = 0.002], sperm concentration [md: 4.43 1.50-7.36), p = 0.003], sperm total motility [md: 9.69 (6.61-12.77), p < 0.00001], and normal sperm morphology [md: 1.36 (0.70-2.03), p < 0.0001] compared to control. additionally, patients given nac had no reported side effects based on our included studies. conclusions: we found nac supplementation significantly improves seminal parameters and has a favorable safety profile. these findings highlight the potential role of nac as a safe supplementation for male with infertility or in male with impaired semen parameters. key words: antioxidant; sperm parameters; safety; meta-analysis; n-acetylcysteine. submitted 18 february 2025; accepted 24 february 2025 introduction the male component significantly accounts for around 50% of all infertility cases (1). male fertility is primarily influenced by spermatogenesis, the process of spermatozoa formation from spermatogonia within the testes. male unlocking the potential of antioxidant supplementation with n-acetylcysteine to improve seminal parameters and analysis of its safety: a systematic review and meta-analysis of randomized controlled trials syarif 1, moh. anfasa giffari makkaraka 2, ahmad taufik fadillah zainal 2, ponco birowo 3, widi atmoko 3 1 division of urology, department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia; 2 faculty of medicine, hasanuddin university, makassar, indonesia; 3 department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia. doi: 10.4081/aiua.2025.13750 summary archivio italiano di urologia e andrologia 2025; 97(1):13750 syarif, m.a. giffari makkaraka, a. taufik fadillah zainal, et al. 2 scopus and cochrane library. the subsequent keywords were generated by integrating several terms, including “n-acetyl-cysteine” and “semen quality” or “seminal parameters” or “semen”. this study applied no restrictions regarding country or publication year. the protocol of this meta-analysis was registered in prospero (crd42024516001). this study also followed the guideline of prisma 2020 (6). eligibility criteria this systematic review and meta-analysis examined studies of randomized controlled trials that met the specified criteria. the studies were included into this meta-analysis if they fulfilled the following criteria. (1) evaluated nac supplementation for male with infertility or impaired semen parameters; (2) each article provided precise data, mostly involving the subject count and indicator outcomes of: semen volume, sperm concentration, total motility, normal sperm morphology and adverse event (ae) reported; and (3) full-text article in english language and related data can be obtained. studies presented as abstracts, review articles, and case reports were removed. selection process duplicate studies were identified and excluded after the initial search. the titles and abstracts of the remaining literature were screened by at two independent reviewers to determine eligibility. studies meeting the criteria were included, while those not meeting requirements were excluded. conflicts in study classification were resolved through group discussion. the results of the literature screening adhere to the preferred reporting items for systematic review and meta-analyses (prisma guidelines). data extraction the following data were collected for each study by different reviewers: (1) first author’s name; (2) published time; (3) the type of study design; (4) patients description; (5) patient’s received therapy, dosage and treatment period; (6) number of patients in each group; (7) age, and (8) data on semen volume (ml), sperm concentration (106/ml), total motility (%), normal sperm morphology (%) and ae reported. quality assessment two authors independently assessed all identified inclusion studies, and any disagreements that emerged were addressed with the input of a third reviewer. cochrane risk of bias (rob) tools 2 was used to assess the quality of each study. rob 2 instrument was utilized to assess the risk of bias in randomized controlled trials (rcts), focusing on five domains (7). overall risk-of-bias judgement of these instruments was classified into 3 groups which low risk of bias (if the study is judged to be at low risk of bias for all domains for this result), some concerns (if there is some concern at least in one domain) and high risk of bias (if the study is judged to be at high risk of bias in at least one domain for this result). risk-of-bias visualization (robvis) was used for the visualization of risk of bias graph (8). statistical analysis the acquired data was analyzed with review manager 5.4. (cochrane collaboration, uk). variations between baseline (study entrance) and study completion (end-point measure) were utilized to indicate changes in the results. mean difference (md) was used to explain continuous data and odds ratio (or) for dichotomous results with the corresponding 95% confidence interval (ci). i2 value refers to statistical analysis of heterogeneity. the fixed-effects model is used if i2 < 50%, while the random-effects model is used if i2 ≥ 50%. the results will be presented in a forest plot, and the overall effect is considered significant if p < 0.05. asymmetry tests, including egger’s test for assessing potential publication bias via funnel plots, will not be performed if the meta-analysis comprises fewer than 10 studies due to their restricted reliability (9). furthermore, subgroup analysis and sensitivity analysis will also not be conducted if there is a small number of studies (10). results literature search, screening results and characteristic of studies from various databases, 1.106 studies were initially identified using keywords. after excluding 82 duplicates, two reviewers independently screened the remaining 1.024 study titles and abstracts, which excluded 1.015 articles according to the inclusion and exclusion criteria. after reviewing only nine full texts, we excluded four studies because they lacked sufficient data or did not meet our study criteria. finally, 5 rct studies (11-15) were included in our analysis with a total of 666 patients. full details of the search and selection process are presented in the prisma flow diagram (figure 1) and the characteristics of these studies are stated in table 1. quality assessment result three studies (11-13) raised concerns regarding the randomization process (domain 1), while one study (11) indicated issues related to the lack of personnel and patient blinding, which pertains to deviations from intended interventions (domain 2) and bias in outcome measurement (domain 4). additionally, one study (13) expressed concerns about missing outcome data due to a significant number of patient withdrawals, resulting in an imbalance in sample sizes between groups (domain 3). four studies (11, 12, 14, 15) raised concerns about bias in the selection of reported results due to the absence of a published protocol (domain 5). a detailed assessment of the risk of bias is presented in figure 2. sperm volume sperm volume from two studies assessing the efficacy of nac showed a marked improvement of sperm volume (md: 0.69; 95% ci: 0.26-1.12; p = 0.002), nac demonstrated a markedly larger enhancement in sperm volume in relation to the control group (figure 3a). sperm concentration five studies evaluating the efficacy of nac exhibited that the nac group had a significant improvement (md: 4.43; 95% ci: 1.50-7.36; p = 0.003) (figure 3b), it archivio italiano di urologia e andrologia 2025; 97(1):13750 3 n-acetylcysteine to improve seminal parameters demonstrated that nac is more effective in increasing sperm concentration compared to the control (figure 3b). total sperm motility four studies revealed that patients who received nac intervention had a significant improvement in total sperm motility (md: 9.69; 95% ci: 6.61-12.77; p < 0.00001) (figure 4a), which shown that nac was more effective in enhancing sperm motility than the control (figure 4a). normal sperm morphology there were four studies that assessed normal sperm morphology. the random effects model showed that there was significant increase in normal sperm morphology in the nac group (md: 1.36; 95% ci: 0.70-2.03; p < 0.0001), which demonstrated that nac resulted in a much higher enhancement in sperm normal morphology relative to the control (figure 4b). safety profile the included studies reported that patient receiving nac supplementation at a dosage of 600 mg/day for twelve weeks or 26 weeks, resulted in improved sperm quality without any reported side effects. discussion the results of this meta-analysis showed that nac supplementation significantly increased sperm volume, sperm concentration, total sperm motility and normal sperm morfigure 1. flow of literature search and selection based on preferred reporting items for systematic reviews and meta-analyses (prisma). archivio italiano di urologia e andrologia 2025; 97(1):13750 syarif, m.a. giffari makkaraka, a. taufik fadillah zainal, et al. 4 figure 2. risk of bias assessment using the revised cochrane risk-of-bias tool algorithm for randomized trials (rob 2.0). rct: randomized controlled trial; nac: n-acetylcystein. table 1. characteristics data of included studies. archivio italiano di urologia e andrologia 2025; 97(1):13750 5 n-acetylcysteine to improve seminal parameters phology in male with infertility or impaired semen parameters. wei et al. previously carried out a meta-analysis assessing the effectiveness of l-carnitine/l-acetyl-carnitine (lc/lac) and nac in males with idiopathic asthenozoospermia. the findings indicated that supplementation with lc/lac and nac significantly enhanced sperm motility, normal morphology, sperm concentration, and ejaculate volume (16). different from that study, this metaanalysis included 5 rct studies evaluating nac supplementation and providing new insights into the effectivefigure 3. forest plots of seminal parameters of (a) semen volume. (b) sperm concentration. ci: confidence interval; iv: inverse variance; sd: standard deviation. figure 4. forest plots of seminal parameters of (a) total motility. (b) normal sperm morphology. ci: confidence interval; iv: inverse variance; sd: standard deviation. archivio italiano di urologia e andrologia 2025; 97(1):13750 syarif, m.a. giffari makkaraka, a. taufik fadillah zainal, et al. 6 ness of nac for improving semen parameters. several previous studies have shown that around 30-80% of male infertile patients have increased ros in their semen (17). an increase in ros that surpasses the antioxidant capacity in semen leads to an imbalance between pro-oxidants and antioxidants, resulting in oxidative stress (os) conditions that damage the spermatozoa plasma membrane and sperm dna. this explains why increased ros can have a negative impact on sperm parameters and cause infertility in men (18). one way to prevent os is to increase the antioxidant capacity of semen by providing antioxidant supplements. nac is a derivative of the natural amino acid l-cysteine, which has an important role in cellular protection against oxidative damage (19). nac is one of the oldest and most powerful antioxidants in treating several diseases, including its application in decreasing the viscosity and flexibility of mucus due to its capacity to break disulfide bonds. in addition, nac has the potential to interact directly with oxidants and with some thiols, which are excellent hydroxyl radical scavengers (20). the results of this metaanalysis show that nac administration can improve the quality of sperm parameters. this is thought to be related to the main role of nac as a stem-form antioxidant, which has the ability to increase intracellular glutathione concentration, the most crucial biothiol responsible for cellular redox imbalance (21). nac administration can also increase the total antioxidant capacity (tac) in semen fluid (20). increased tac will prevent os due to overproduction of ros. this is proven by the study of barekat et al., who reported that patients given nac reduced the percentage of ros in semen (13). preventing os in semen can prevent damage to spermatozoa and enhance the integrity of sperm dna, leading to a significant increase in the number of sperm in the semen (19). several studies have reported that the antioxidant effect in semen can also increase the mitochondrial function of spermatozoa, thereby providing more energy and increasing their motility (22). jannatifar et al. indicated that following nac administration, the levels of seminal malondialdehyde (mda) drastically reduced. mda served as a particular indicator of lipid peroxidation, whereas tac exhibited a considerable rise. nac mitigates the intensity of oxidative stress, therefore diminishing lipid peroxidation (12). the theoretical basis and mechanisms explain the results of this meta-analysis, which show that nac is effective and safe in improving sperm parameters. in addition, nac is relatively safe and well tolerated, even at high doses (21). of all the included studies, none reported any significant side effects of nac administration on male with infertility or impaired semen parameters. the primary goal of infertility therapy is to achieve pregnancy. in a study conducted by barekat et al., nac was administered to men following varicocelectomy, leading to significant improvements in semen quality and a higher reported clinical pregnancy rate in the nac group compared to the control group. this indicates a notable enhancement in fertility outcomes associated with nac supplementation (13). unfortunately, our analysis could not assess pregnancy rates because the studies we included did not provide sufficient data for further evaluation.the dosage and duration of nac supplementation have been extensively evaluated in studies related to male fertility. most studies have administered nac at a dosage of 600 mg each day for three months, which has consistently resulted in significant improvements in sperm quality and oxidative stress markers. jannatifar et al. reported enhanced sperm parameters following this regimen (12), while rafiee et al. observed similar benefits in men with impaired semen parameters (11). in a larger trial by safarinejad et al., participants received 600 mg of nac daily for 26 weeks, leading to significant improvements in multiple semen parameters (15). comhaire et al. also noted improvements in sperm concentration and acrosome reaction at similar dosages (23). these studies suggest that nac supplementation at dose of 600 mg each day for durations of three to six months should be preferred for enhance seminal parameters. several studies have reported on the safety profile of nac supplementation. erkkilä et al. found no cytotoxic effects of nac on human male germ cells in vitro, supporting its safety for reproductive health applications (24). a systematic review by zafarullah et al. highlighted that nac is also safe in various clinical applications, being generally well-tolerated even at higher doses used for treating conditions such as chronic obstructive pulmonary disease and acetaminophen overdose (25). this study suggests that nac is a safe and effective antioxidant supplement for enhancing male fertility parameters without a significant risk of adverse events. declarations ethical approval: this study did not need ethical approval. availability of data and material: all data and materials from this research are available to the researcher and we will provide it upon request if the researcher needs it. competing interests: the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. funding: all funding for this research comes from researchers without receiving reimbursement of research costs or research grants from third parties. authors' contributions: contribution details (to be ticked marked as applicable): ss mag atf concepts √ √ √ design √ √ √ definition of intellectual content √ literature search √ √ data acquisition √ √ √ data analysis √ √ √ statistical analysis √ √ √ manuscript preparation √ √ √ manuscript editing √ manuscript review √ √ √ guarantor √ acknowledgments: we as authors would like to thank all parties involved in this study, including the department of urology, faculty of medicine, hasanuddin university and also hasanuddin university hospital. conference presentation: this article has been oral presented in the 21st urological association of asia congress (uaa) on september 7th 2024. archivio italiano di urologia e andrologia 2025; 97(1):13750 7 n-acetylcysteine to improve seminal parameters we need to acknowledge some limitations of this study. first, there are only a few trials included in our study. however, all studies used in this research are randomized controlled trials, hence augmenting the robustness of the findings. in addition, bias due to deviations from intended interventions may affect the final results of this study. secondly, this meta-analysis is limited by the limited number of rct studies. based on these limitations, it is important to interpret the findings of this review cautiously, as they may warrant further studies. additionally, future studies should analyze and compare the combination of nac and other types of antioxidant supplements to improve sperm parameters. based on our analysis, we recommend nac supplementation for males experiencing impairment of semen parameters, either at a dose of 600 mg or at a dose of 200 mg nac three times a day for a minimum of 12 weeks, and up to 26 weeks. conclusions a significantly improvement of seminal parameter was found in male with infertility or impaired semen parameters who received nac supplementation. nac supplementation has also been proven to be safe. these findings highlight the potential role of nac as a safe supplementation for males with infertility or impaired semen parameters. references 1. schlegel pn et al. diagnosis and treatment of infertility in men: aua/asrm guideline part i. j urol. 2021; 205:36-43. 2. assidi m. infertility in men: advances towards a comprehensive and integrative strategy for precision theranostics. cells. 2022; 11:1711. 3. o’flaherty c. reactive oxygen species and male fertility. antioxidants. 2020; 9:287. 4. agarwal a et al. male oxidative stress infertility (mosi): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. world j mens health. 2019; 37:296-312. 5. tenório mcds, graciliano ng, moura fa, et al. n-acetylcysteine (nac): impacts on human health. antioxidants (basel). 2021; 10:967. 6. page mj, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. the bmj 2021; 372:n71. 7. sterne jac, et al. rob 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019; 366:l4898. 8. mcguinness la, higgins jpt. risk-of-bias visualization (robvis): an r package and shiny web app for visualizing risk-of-bias assessments. res synth methods. 2021; 12:55-61. 9. egger m, smith gd, schneider m, minder c. bias in meta-analysis detected by a simple, graphical test. bmj. 1997; 315:629-634. 10. higgins jpt. cochrane handbook for systematic reviews of interventions. https://training.cochrane.org/handbook (2024). 11. rafiee b, bagher tabei sm. the effect of n-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of covid-19 in the last three months. arch ital urol androl. 2021; 93:465-467. 12. jannatifar r, parivar k, roodbari nh, nasr-esfahani mh. effects of n-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. reprod. biol. endocrinol. rbe. 2019; 17, 24 13. barekat f, et al. a preliminary study: n-acetyl-l-cysteine improves semen quality following varicocelectomy. int j fertil steril. 2014; 10:120-126. 14. ciftci h, verit a, savas m, et al. effects of n-acetylcysteine on semen parameters and oxidative/antioxidant status. urology. 2009; 74:73-76. 15. safarinejad mr, safarinejad s. efficacy of selenium and/or nacetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. j urol. 2009; 181:741-751. 16. wei g, et al. a meta-analysis of the efficacy of l-carnitine/lacetyl-carnitine or n-acetyl-cysteine in men with idiopathic asthenozoospermia. am j mens health. 2021; 15:15579883211 011371. 17. agarwal a, et al. male oxidative stress infertility (mosi): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. world j. mens health. 2019; 37:296-312. 18. bui ad, sharma r, henkel r, agarwal a. reactive oxygen species impact on sperm dna and its role in male infertility. andrologia. 2018; 50:e13012. 19. rafiee b, bagher tabei sm. the effect of n-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of covid-19 in the last three months. arch ital urol androl. 2021; 93:465-467. 20. ciftci h, verit a, savas m, et al. effects of n-acetylcysteine on semen parameters and oxidative/antioxidant status. urology. 2009; 74:73-76. 21. tenório mcds, graciliano ng, moura fa, et al. n-acetylcysteine (nac): impacts on human health. antioxidants (basel). 2021; 10:967. 22. hirata s, hoshi k, shoda t, mabuchi t. spermatozoon and mitochondrial dna. reprod med biol. 2002; 1:41-47. 23. comhaire fh, et al. the effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. prostaglandins leukot. essent. fatty acids. 2000; 63:159-165. 24. erkkilä k, hirvonen v, wuokko e, et al. n-acetyl-l-cysteine inhibits apoptosis in human male germ cells in vitro. j. clin. endocrinol. metab. 1998; 83:2523-2531. 25. zafarullah m, li wq, sylvester j, ahmad m. molecular mechanisms of n-acetylcysteine actions. cell mol life sci cmls. 2003; 60:6-20. correspondence syarif syarif (corresponding author) syarifbakri@hotmail.com perintis kemerdekaan st. km. 10, tamalanrea, makassar, indonesia (postal code: 90245) moh. anfasa giffari makkaraka fasagifari@gmail.com ahmad taufik fadillah zainal ahmadtaufik2014004@gmail.com faculty of medicine, hasanuddin university, makassar, indonesia ponco birowo ponco.birowo@gmail.com widi atmoko dr.widiatmoko@yahoo.com department of urology, faculty of medicine, universitas indonesia, jakarta, indonesia stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11672 1 systematic review nephrectomy techniques according to the staging of the disease (2, 3). despite the fact that surgical resection of tumors in localized disease can be curative, disease progression and mortality could be up to 20% of patients after primary treatment, and therefore any intervention to improve the oncological outcomes would be considered a significant benefit (4). several variables including age, race, gender, stage, grade, tumor size, performance status, and blood type, have been found as independent predictors of mortality after nephrectomy for locoregional rcc. although these risk variables may provide useful prognostic information, they typically offer limited opportunity for intervention to modify the disease's trajectory (5, 6).unlike in metastatic rcc, targeted therapy and immunotherapy such as vascular endothelial growth factor (vegf) or mammalian-target of rapamycin (mtor) inhibitor are shown to have minimal benefits in an adjuvant treatment scenario for localized rcc after surgery and a high-risk profile for disease recurrence (7-9). given the high costs and limited availability of pharmacological development and clinical implementation of targeted therapies, the technique of drug repositioning (dr) of selected non-anticancer drugs is being investigated (10). various concomitant medications in rcc patients undergoing surgery are investigated to explore the potential for improving survival and preventing disease recurrence, including insulin, beta-blockers, metformin, statins, and other therapies (11). statins are the most widely used drugs for the treatment of hypercholesterolemia, and several authors discovered the anti-tumor activities in this medication. these drugs have been observed to induce apoptosis, thereby inhibiting tumor growth and angiogenesis (12). even though the exact mechanism is still unclear, clinical trials have been conducted to explore the potential benefits of statin in several cancers such as lung cancer, liver cancer, and colorectal cancer (13-15). several cohorts are also currently being conducted to evaluate the impact of statins on the oncological outcomes of rcc patients having surgery (5, 1619). the results are encouraging but often conflicting, and there are currently no strong recommendations regarding the use of statins as either neo-adjuvant or adjuvant therapy in rcc. therefore, we aimed to perform a systematic introduction: renal cell carcinoma (rcc) is regarded as one of the most common malignant tumors. various concomitant medications in rcc patients undergoing surgery are investigated to explore the potential for improving survival and preventing disease recurrence, including statin. it has been observed that these drugs induce apoptosis, thereby inhibiting tumor growth and angiogenesis. we aimed to perform a systematic review and meta-analysis to enhance the level of evidence for statin in rcc. methods: a systematic literature search was conducted in several online databases, including pubmed, scopus, and sciencedirect, using terms relevant to the use of statins in rcc patients undergoing nephrectomy for publications published up to july 2023, according to a registered review procedure (crd42023452318). the newcastle-ottawa scale (nos) was used to assess the risk of bias of the included study. review manager 5.4 was used for all analyses. results: seven articles was eligible for our study. the analysis revealed that patients receiving statin had a better overall survival compared to patients who does not receive statin (hr 0.71, 95% ci 0.51-0.97, p = 0.03, i2 = 76%). however, there was insignificant difference in terms of css, dfs, and pfs between rcc patients receiving statin and without statin. conclusions: statin has substantial benefits for improving os. even though the outcomes for css, dfs, and pfs were insignificant, the potential role of statins as a supplementary therapy in surgically treated rcc still requires further investigation. key words: statin; renal cell carcinoma; nephrectomy; survival rate; outcome. submitted 24 august 2023; accepted 31 august 2023 introduction renal cell carcinoma (rcc) is regarded as one of the most common malignant tumors, accounting for approximately 2% of all tumors and 90% of all kidney malignancies. renal cancer is expected to remain a major threat to global health as the global incidence of this disease has been steadily growing in recent decades (1). in order to manage the disease, surgical resection of the tumor is the cornerstone treatment. as a curative or palliative treatment, surgical therapy is performed using either partial or radical impact of statin on renal cell carcinoma patients undergoing nephrectomy. does it affect cancer progression and improves survival? a systematic review and meta-analysis ghazian adli 1, 2, niwanda yogiswara 1, 2, ida bagus gde tirta yoga yatindra 1, 2, rheza maulana putra 1, 2, wahjoe djatisoesanto 1, 2 1 department of urology, faculty of medicine, universitas airlangga, indonesia; 2 dr. soetomo general-academic hospital, surabaya, east java, indonesia. doi: 10.4081/aiua.2023.11672 summary archivio italiano di urologia e andrologia 2023; 95(3):11672 g. adli, n. yogiswara, i. bagus gde tirta yoga yatindra, r. maulana putra, w. djatisoesanto 2 review and meta-analysis to enhance the level of evidence for statin in rcc. methods review protocol and search strategy this study evaluates the impact of statin on rcc patients who underwent nephrectomy on the oncological outcomes through systematic review and meta-analysis design (20), following the latest preferred reporting items for systematic reviews and meta-analyses (prisma) statement in pubmed, science-direct, and scopus. the literature search followed medical subject headings (mesh®) terms related to the use of statin in rcc patients who underwent nephrectomy for articles published up to july 2023. the protocol has been registered in prospero (crd42023452318). eligibility criteria for review the inclusion criteria are (1) observational studies (2) evaluation of rcc patients who underwent open or laparoscopic. nephrectomy diagnosed with histopathological examination, (3) compare patients who receive statin and without statin (4) and reporting the outcome. the outcomes analysed in this study were overall survival (os), cancerspecific survival (css), disease-free survival (dfs), and progression-free survival (pfs). we excluded nonenglish studies, studies without full text, and duplicate studies. data extraction and risk of bias assessment baseline characteristics of the study were extracted by two independent authors, while the third author resolved all disagreements through a discussion. the extracted data consisting of publication details as first author name and year of publication, study design, sample size, and sample characteristics such as age, rcc grade, cell type, stage of rcc, and surgical methods were collected in spreadsheet software microsoft excel® 2021. the risk of bias was assessed with the newcastle-ottawa scale (nos), which has the domain of selection, comparison, and exposure. data analysis and presentation the analysis effect size was estimated in a forest plot with a hazard ratio (hr) with a 95% confidence interval (95% ci) and a p-value below 0.05 was considered statistically significant using the software review manager 5.4 (cochrane collaboration). heterogeneity between studies was evaluated using i2, where an i2 value above 50% indicated high heterogeneity and a random-effects model was applied for pooled analysis. results study search our preliminary search found 298 results. twenty-five full articles were retrieved for eligibility. following the assessment of the full-text articles, sixteen were eliminated for several reasons, including differences in intervention, population, and incomplete data. the remaining seven publications were investigated further, as shown in figure 1. the clinical characteristics of the included participants are described in table 1. baseline characteristics and quality assessment all of the included studies were retrospective cohorts. the majority of the populations of the included studies were american, ranging from 55-66 years. the type of statins that were used in the study comprised atorvastatin, figure 1. identification of included studies. archivio italiano di urologia e andrologia 2023; 95(3):11672 3 statin affecting survival in surgically treated rcc simvastatin, lovastatin, pravastatin, rosuvastatin, fluvastatin, and cerivastatin. the techniques used for surgical resection were varied such as open, laparoscopic, and robotic approach. the follow-up of the studies ranged from 25 to 93 months. the risk of bias assessed using nos revealed a moderate score ranging from 5 to 9, with a median of 7 as presented in table 2. impact of statin on overall survival six articles were included in the analysis of overall survival using the random-effect model, as presented in figure 2. table 2. quality assessment using newcastle-ottawa scale. author selection comparability exposure score berquist, 2017 *** ** *** 8 haddad, 2015 **** ** ** 8 choi, 2012 *** * * 5 hamilton, 2013 **** ** ** 8 kaffenberger, 2014 *** ** *** 8 nayan, 2016 **** ** **** 9 neumann, 2019 *** ** *** 8 viers, 2015 *** ** *** 8 haide, 2019 *** ** *** 8 table 1. baseline characteristics of the included study. author country study sample intervention n age follow up nephrectomy cancer outcome adjusted variable type size (n) (years) (month) (n) histology analyzed in multivariate median (iqr) analysis choi, 2012 korea retrospective 115 statin 21 58.95 ± 12.33 40 radical and clear cell, papillary, pfs, rfs age, gender, bmi cohort non statin 94 65.24 ± 6.82 partial (115) chromophobe, collecting duct, sarcomatoid hamilton, 2013 america retrospective 2608 statin 708 66 (59-72) 36 radical (1580) clear cell, papillary, progression, age, gender, race, cohort non statin 1900 59 (50-68) partial (1028) chromophobe, overall mortality type of surgery, commorbidity, unclassified renal function, tumor stage, year of surgery, local and systemic symptoms kaffenberg, 2014 america retrospective 916 statin 270 60.8 (51.3–69.3) 42.5 (19.1–67.1) radical (584) clear cell, dss, os age, asa score, staging, nodes, cohort non statin 646 partial (332) non-clear cell metastatic status, blood group, corrected hypercalcemia viers, 2015 america retrospective 2357 statin 630 66 (59–73) 93.6 (63.6-134.4) radical (1727) clear cell, papillary, pfs, css, os age, gender, type of surgery, cohort non statin 1727 61 (52–70) partial (630) chromophobe, clear cell, smoking status, tumor stage, mucinous-spindle cell. tumor grade, sarcomatoid translocation-associated differentiation collecting duct, nos haddad, 2015 america retrospective 850 statin 342 62 (19-92) 25 (7.8-52.3) radical (384) clear cell, non-clear cell rfs,os tumor stage, tumor grade, cohort non statin 508 55 (20-87) partial (466) lymphovascular invasion, ldl, tg nayan, 2016 canada retrospective 839 statin 259 66 ± 16 47 (20-80) radical (477) clear cell, papillary, dfs, css, os age, gender, type of surgery, cohort non statin 634 57 ± 18 partial (259) chromophobe, tumor stage unclassified berquist, 2017 america retrospective 283 statin 180 57.5 ± 15 68 (50-90) radical (204) clear cell, papillary, dfs tumor stage and grade cohort non statin 103 partial (77) chromophobe rcc, other histology neumann, 2019 germany retrospective 388 statin 207 64.26 (17.12–90.32) 57.93 (0–237.18) radical clear cell os commedication, tumor stage, cohort non statin 39 partial haide, 2019 germany retrospective 104 statin 41 62 (53-70 35.4 (12.3-73.3) radical clear cell, non-clear cell css tumor stage, hypertension cohort non statin 63 partial figure 2. impact of statin on overall survival. archivio italiano di urologia e andrologia 2023; 95(3):11672 g. adli, n. yogiswara, i. bagus gde tirta yoga yatindra, r. maulana putra, w. djatisoesanto 4 the meta-analysis revealed that rcc patients receiving statin had better overall survival compared to patients who did not receive statin (hr 0.71, 95% ci 0.51-0.97, p = 0.03, i2 = 76%). impact of statin on cancer-specific survival, disease-free survival, and progression-free survival four studies were included in the analysis of css. the meta-analysis using the random-effects model in figure 3 revealed that there was an insignificant difference in terms of css between rcc patients receiving statin and those without statin (hr: 0.85 95% ci 0.541.33, p = 0.47, i2 = 55%). analysis of dfs was performed using two studies. the meta-analysis result using the random-effects model in figure 4 showed that there was an insignificant difference in terms of dfs between rcc patients receiving statin and without statin (hr: 0.76 95% ci 0.38-1.52; p = 0.44, i2 = 73%). based on the result from the forest plot shown in the figure 5, there was an insignificant difference in pfs between rcc patients receiving statin and those without statin (hr: 0.92 95% ci 0.51-1.65; p = 0.77, i2 = 86%). discussion this meta-analysis includes seven retrospective cohorts investigating oncological outcomes in the form of os, dfs, css, and pfs in statin administration in surgically treated rcc patients (5, 11, 16-19, 21). the pooled analysis revealed that rcc patients receiving statin had a better os compared to patients who did not receive statin, while there are no differences in dfs, css, and pfs. overall survival is a critical parameter for evaluating the efficacy, safety, and clinical benefits of a cancer intervention. the effect of statins on improving os has been explored in many tumors in urology, including patients with rcc, although investigations in rcc patients having nephrectomy were limited to a retrospective cohort and the results were contradictory. based on the results of combined observational studies, we discovered higher overall survival in rcc patients who received statin therapy compared to those without statins. the results of this meta-analysis are consistent with the previous metaanalysis by nayan et al. which reported that statins were significantly associated with an improvement in os in all patients kidney cancer patients with hr of 0.74 (22). our finding also aligns with a recent meta-analysis conducted figure 3. impact of statin on cancer-specific survival. figure 4. impact of statin on disease-free survival. figure 5. impact of statin on progression-free survival. archivio italiano di urologia e andrologia 2023; 95(3):11672 5 statin affecting survival in surgically treated rcc by luo et al. (23), who incorporated 35 studies to evaluate on the beneficial effects of statins in various urological cancers and discovered a significant improvement in os in patients with rcc and bladder cancer. however, wu et al. (24) observed no significant difference in os in rcc patients, but their analysis only included american cohorts, which can be biased if generalized in the global population. the strength of the current analysis is that this review mainly focused on rcc patients undergoing surgical treatment, whereas prior meta-analyses included all rcc patients, surgical or non-surgical (22). statin improves the os of rcc patients undergoing surgery by several mechanisms. one possible mechanism of statins in improving the os of cancer patients is by inhibiting the proliferation and progression of rcc and inducing apoptosis of cancer cells thereby directly improving os (11). another possible mechanism is lowering cholesterol levels by blocking the active site of the hmg-coa reductase enzyme, reducing the risk of coronary artery blockage and deadly cardiovascular events such as myocardial infarction or stroke which indirectly improves os (17). tumor cells can activate the coagulation process by releasing procoagulants, tissue factors, and fibrinolytic proteins, or by invading the vessel wall. in cancer patients including rcc, increased blood hypercoagulation can occur which causes an increased risk of arterial thrombosis and thromboembolic events, whereas one of the ways statins reduce death is by preventing thrombosis (17). furthermore, our study tried to evaluate comprehensively the synergistic effect of statin in rcc patients receiving targeted therapy. mckay et al. (25) discovered that patients who had targeted therapies and concomitant statins had improved os compared to non-statin patients (25.6 versus 18.9 months, respectively) with insignificant differences in drug-related toxicity. although statin has been proven to improve the os, this parameter has a weakness because it can be affected by bias from external factors and confounding factors. there is currently no high level of evidence demonstrating the advantage of adjuvant radiation therapy, vegfr, or mtor inhibitors for improving survival, and these treatments are not recommended in adjunctive contexts due to unfavorable tolerability. given that a third of rcc patients will develop recurrence or advancement after nephrectomy, any adjunctive therapies to reduce the progression and improve cancer-related survival were considered a substantial benefit. in this study, we assessed the effects of statin as adjunctive therapy on several other oncology outcomes including pfs, dfs, and css. based on the results of the combined analysis, we found that statins had an insignificant effect on css in rcc patients undergoing nephrectomy procedures (p = 0.47). these results differ from a metaanalysis study by nayan et al., which found that statins were significantly associated with improved cancer-specific survival (hr 0.67) (26). the discrepancy could be attributed to several factors, including the inclusion of non-surgically treated rcc in the earlier review. according to the literature, the outcome of css in patients with surgically treated and non-surgically treated rcc differs, therefore combining the populations may have resulted in bias. after performing a combined analysis using forest plots, we found that statins had no significant effect on dfs and pfs in rcc patients undergoing nephrectomy. these results are in accordance with a meta-analysis by nayan et al. which included 2 studies, with the result that there was no relationship between statin administration in pfs and dfs in rcc patients in general (22). various statin mechanisms for reducing cancer progression and death in rcc patients have been discussed in the literature. statins have previously been proven in vitro and in vivo to reduce proliferation, angiogenesis, and tumor invasion, thereby reducing cancer growth (27). data suggests that in general statin reduces cancer growth by two possible mechanisms, including cholesterol-dependent and cholesterol-independent pathways. statins limit mevalonate production and the generation of downstream lipid isoprenoid intermediates in the hmgcoa pathway. the latter chemical regulates angiogenesis, apoptosis, and inflammation. in the cholesterol-independent process, interactions with proteasomes and lymphocyte-function antigen 1 agents have impacts on invasion, cell adhesion, inflammation, and proliferation. the latest evidence suggests that statins can decrease rcc cell growth by prompting cell cycle arrest and apoptosis in a dose and time-dependent manner. furthermore, statins suppress the phosphorylation of akt, mtor, and erk, resulting in decreased rcc cell motility (28). although there are various mechanisms through which statins have been shown to prevent cancer progression, in this meta-analysis, we discovered that statins did not provide substantial benefits in preventing cancer progression. the insignificant results in this study could be attributed to lower statin bioavailability due to liver metabolism and variations in lipid metabolism in rcc (29). statins are selectively absorbed by the liver, with less than 5% of the provided dose reaching the systemic circulation, resulting in limited statin penetrating rcc cells (28). furthermore, lipid metabolism in rcc differs from that of other cancers. rcc has much lower expression of cholesterol synthase proteins including hmg-coa reductase (hmgcr) than adjacent normal tissues (30). in fact, the major mechanism of statins is hmgcr downregulation. this might explain the reason that statins have a lower impact on rcc than on other forms of cancer. statin plasma levels depend on dose, statin type, and liver function. the higher the dose the higher level of statin in the plasma. lipophilic statin (atorvastatin, simvastatin, lovastatin, fluvastatin, and pitavastatin) tends to have higher uptake in the liver than hydrophilic statin (pravastatin and rosuvastatin) which can affect the liver function and rising the creatinine kinase level (28). statin plasma levels are higher in altered liver function patients due to reduced statin metabolism and transport activities (31). in general, this review provided evidence of the beneficial effect of statin on improving the os of surgically treated rcc patients. despite the insignificant result of css, dfs, and pfs, the potential role of statins as adjunctive therapy in surgically treated rcc still needs to be explored. this meta-analysis provides support for future prospective and randomized controlled studies to evaluate the potential benefit of statins in extending the survival of surgically treated rcc patients, especially when archivio italiano di urologia e andrologia 2023; 95(3):11672 g. adli, n. yogiswara, i. bagus gde tirta yoga yatindra, r. maulana putra, w. djatisoesanto 6 considering the limited efficacy and toxicity of targeted therapies in adjunctive settings. there are several limitations to this review. this review was confined only to retrospective cohort studies, which cannot establish causality. furthermore, there was significant heterogeneity among the studies due to variation of histological subgroups, surgical technique, intervention protocol, and rcc stage, which we could not further analyze using subgroups analysis due to the lack of data. moreover, the several included studies were conducted on small sample size and in a single institution. therefore, larger cohorts, and multi-institutional or population-based research are necessary. conclusions in the context of limited recommendations for adjunctive immunotherapy or targeted therapy for improving os of surgically treated rcc patients, the present review highlights the substantial benefits of statin for improving os in this population. even though the outcomes for css, dfs, and pfs were insignificant, the potential role of statins as a supplementary therapy in surgically treated rcc still requires further investigation. to confirm the beneficial effects of statin on surgically treated rcc more evidence from prospective and clinical studies may be required. references 1. bray f, ferlay j, soerjomataram i, siegel rl, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin 2018; 68:394-424. 2. hanna n, sun m, meyer cp, et al. survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a national cancer data base study. j clin oncol. 2016; 34:3267-75. 3. krabbe lm, bagrodia a, margulis v, wood cg. surgical management of renal cell carcinoma. semin intervent radiol 2014; 31:27. 4. teloken pe, thompson rh, tickoo sk, et al. prognostic impact of histological subtype on surgically treated localized renal cell carcinoma. j urol 2009; 182:2132-6. 5. heide j, ribback s, klatte t, et al. evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients. world j urol. 2020; 38:1525-33. 6. brierley j, gospodarowicz md, wittekind ct. tnm classification of malignant tumors international union against cancer. 8th. oxford, england: wiley; 2017. wiley 2017 7. larkin jmg, eisen t. kinase inhibitors in the treatment of renal cell carcinoma. crit rev oncol hematol 2006; 60:216-26. 8. rini bi, escudier b, tomczak p, et al. comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (axis): a randomised phase 3 trial. lancet 2011; 378:1931-9. 9. sternberg cn, davis id, mardiak j, et al. pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase iii trial. j clin oncol 2010; 28:1061-8. 10. li x, shong k, kim w, et al. prediction of drug candidates for clear cell renal cell carcinoma using a systems biology-based drug repositioning approach. ebiomedicine 2022; 78:1039633. 11. neumann e, klaiber p, freitag k, et al. assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation. j cancer res clin oncol 2019; 145:1835-43. 12. santoni m, monteiro fsm, massari f, et al. statins and renal cell carcinoma: antitumor activity and influence on cancer risk and survival. crit rev oncol hematol. 2022; 176:103731. 13. seckl mj, ottensmeier ch, cullen m, et al. multicenter, phase iii, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in smallcell lung cancer (lungstar). j clin oncol. 2017; 35:1506-14. 14. kawata s, yamasaki e, nagase t, et al. effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. a randomized controlled trial. br j cancer 2001; 84:886-91. 15. alarfi h, youssef la, salamoon m. a prospective, randomized, placebo-controlled study of a combination of simvastatin and chemotherapy in metastatic breast cancer. j oncol. 2020; 2020:4174395. 16. nayan m, finelli a, jewett mas, et al. statin use and kidney cancer outcomes: a propensity score analysis. urol oncol. 2016; 34:487.e1-487.e6. 17. viers br, houston thompson r, psutka sp, et al. the association of statin therapy with clinicopathologic outcomes and survival among patients with localized renal cell carcinoma undergoing nephrectomy. urol oncol. 2015; 33:388.e11-8. 18. kaffenberger sd, lin-tsai o, stratton kl, et al. statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma. urol oncol. 2015; 33:21.e11-21.e17. 19. hamilton rj, morilla d, cabrera f, et al. the association between statin medication and progression after surgery for localized renal cell carcinoma. j urol 2014; 191:914-9. 20. higgins jp, green s. cochrane handbook for systematic reviews of interventions®. 21. haddad aq, jiang l, cadeddu ja, et al. statin use and serum lipid levels are associated with survival outcomes after surgery for renal cell carcinoma. urology. 2015; 86:1146-52. 22. nayan m, punjani n, juurlink dn, et al. statin use and kidney cancer survival outcomes: a systematic review and meta-analysis. cancer treat rev 2017; 52:105-16. 23. luo y, she dl, xiong h, et al. the prognostic effect of statin use on urologic cancers: an updated meta-analysis of 35 observational studies. medicine (baltimore). 2015; 94:e1523. 24. wu p, xiang t, wang j, et al. statin use and the overall survival of renal cell carcinoma: a meta-analysis. clin invest med. 2020; 43:e17-23. 25. mckay rr, lin x, albiges l, et al. statins and survival outcomes in patients with metastatic renal cell carcinoma. eur j cancer. 2016; 52:155-62. 26. nayan m, hamilton rj, finelli a, et al. the value of complementing administrative data with abstracted information on smoking and obesity: a study in kidney cancer. can urol assoc j 2017; 11:167-71. 27. di bello e, zwergel c, mai a, valente s. the innovative potential of statins in cancer: new targets for new therapies. front chem. 2020; 8:516. archivio italiano di urologia e andrologia 2023; 95(3):11672 7 statin affecting survival in surgically treated rcc 28. petyaev im. improvement of hepatic bioavailability as a new step for the future of statin. arch med sci. 2015; 11:406-10. 29. petyaev im. improvement of hepatic bioavailability as a new step for the future of statin. arch med sci 2015; 11:406. 30. stepanovska tanturovska b, manaila r, fabbro d, huwiler a. lipids as targets for renal cell carcinoma therapy. int j mol sci. 2023; 24:3272. 31. calderon rm, cubeddu lx, goldberg rb, schiff er. statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. mayo clin proc 2010; 85:349. correspondence ghazian adli ghazianadli@gmail.com niwanda yogiswara niwandayogiswara@gmail.com ida bagus gde tirta yoga yatindra tirtayogastudi@gmail.com rheza maulana putra putrarhe@gmail.com wahjoe djatisoesanto (corresponding author) djatisoe@gmail.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general-academic hospital, surabaya, east java, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12382 1 original paper complications from pcnl can arise due to various factors. stone characteristics are among the factors contributing to complications. in fact, size, location, and complexity of the kidney stones can increase the risk of complications during pcnl. larger stones may require more extensive procedures, increasing the chances of complications. other risk factors are related to patient characteristics, such as obesity, older age, or pre-existing medical conditions like diabetes or hypertension, that can increase the risk of complications during pcnl (5, 6). bleeding is still one of the most common and significant morbidities, with reports showing an average hemoglobin drop ranging from 2.1 to 3.3 g/dl (7-12). bleeding complications are one of the potential risks associated with pcnl. sources of bleeding during pcnl can be multifactorial including injury to the renal vessels during the procedure, bleeding at the puncture site, trauma to surrounding tissue when crushing and removing kidney stones. it is important to identify the factors associated to intraoperative bleeding and massive post-operative hemoglobin reduction so that transfusion therapy can be prepared if necessary (5, 6, 13). in this study, we aim to determine the factors associated with pcnl-related hemoglobin decrease. materials and methods this research is a retrospective analytical observational study of patients undergoing pcnl at siloam hospital makassar, south sulawesi, indonesia. this study used secondary electronic medical records on patients who underwent pcnl from january 2018 to december 2022. the inclusion criteria in this study were being patients aged 23-78 years who underwent unilateral pcnl and had complete medical record data, while the exclusion criteria were being patients with complete staghorn stones, chronic kidney disease, anatomical or functional abnormalities of the urinary tract system, receiving a transfusion before or during the surgical procedure, being on anti-coagulant therapy, being submitted another surgical procedure or to bilateral pcnl surgery in the same session. all patients who met the exclusion criteria were removed from the research sample. all pcnl procedures in this study sample were performed using a 24 f amplatz sheath for renal calculi; surgery was objective: this study aims to determine the preoperative and perioperative risk parameters associated with a decrease in hemoglobin (hb) in patients undergoing percutaneous nephrolithotomy (pcnl). methods: we collected prospective data of consecutive patients who underwent pcnl from january 2018 to december 2022. the median decrease in post-operative hemoglobin levels compared to pre-operative was found to be 1.5 g/dl. this value was the cut-off value that divided the sample into two groups. group 1 has a decrease in hb levels that is higher or equal to the cutoff, group 2 has a decrease in hb levels that is lower than the cut-off. all preoperative, stone characteristics and perioperative factors were recorded. results: a total of 273 patients were included in the study, 141 in group 1 and 132 in group 2. the mean age of group 1 was significantly higher (55.48 ± 8.73 vs 45.9 ± 10.75 years, p < 0.05). the mean bleeding of group 1 was significantly higher (285.85 ± 113.68 vs 135 ± 77.54 ml, p < 0.05). there was a significant difference in mean operation time between groups (86.35 ± 32.05 vs 64.89 ± 27.83 min, p < 0.05). multivariate analysis showed that the variables age, comorbid diabetes mellitus, intraoperative bleeding amount, and operation time had a significant relationship with hb reduction in patients undergoing pcnl (p < 0.05). conclusions: older age, comorbid diabetes mellitus, large amounts of intraoperative bleeding, and longer operating time are factors associated with pcnl-related postoperative hemoglobin decrease. key words: bleeding; hemoglobin; stone; percutaneous nephrolithotomy (pcnl). submitted 13 february 2024; accepted 24 february 2024 introduction percutaneous nephrolithotomy (pcnl) is an effective, safe, and minimally invasive treatment method with low rate of renal and ureteral calculi complications (1, 2). indications for pcnl were determined as the presence of larger than 2 cm stones in the upper urinary tract or stones larger than 1.5 cm in the renal lower pole resistant to extracorporeal shock wave lithotripsy (3). high success rates that exceed 90% have been reported with percutaneous nephrolithotomy. however, despite the high success rate, several complications still often occur due to pcnl procedures (4). factors associated to hemoglobin decrease after percutaneous nephrolithotomy: a retrospective study syarif 1, abdul azis 1, saidah rahmat a. 2, ahmad taufik fadillah zainal 3, ade nusraya 3 1 division of urology, department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia; 2 faculty of medicine, muhammadiyah malang university, malang, indonesia; 3 faculty of medicine, hasanuddin university, makassar, indonesia. doi: 10.4081/aiua.2024.12382 summary archivio italiano di urologia e andrologia 2024; 96(2):12382 syarif, a. azis, s. rahmat a., et al. 2 performed in complete supine position under subarachnoid spinal block; the tract was dilatated using serial metallic dilatators and stone fragmentation was done by lithoclast® master (ems, nyon, switzerland); residual fragments were cleared using a flexible nephroscope; experience of surgeons was more than five year. at the end of the procedure, a 18 fr foley urethral catheter with the balloon inflated was placed. operative time was considered from the beginning of the cystoscopy for ureteral catheter insertion to the end of the placement of nephrostomy catheter. a non-contrast computerized tomography (ct scan) and routine serum exams were performed during the first postoperative day in all cases. the success rate was defined as the absence of residual symptomatic fragments > 4 mm in the ct of the first postoperative day. characteristic data collected included age, gender, body mass index (bmi) (normal value: 18.5-25.0), stone characteristics (stone side and location, degree of hydronephrosis, stone burden, and stone complexity using guy's stone score (gss) based on preoperative ct scan analysis). intraoperative factors include operative time and amount of bleeding. the amount of bleeding was calculated by the anesthesiologist team from the initial flank incision to access the kidney to the closure of the incision site with sutures or adhesive strips. the amount was calculated by the total blood volume collected in the suction canister (taking into account the fluid used for irrigation) and the estimated bleeding from the gauze/sponge used during the operation. comorbidities including hypertension and diabetes mellitus were also registered. hemoglobin (hb) levels (normal value: male 13-17 g/dl; female 12-16 g/dl) of all patients were tested 3-5 days before the surgery. after pcnl is carried out, hemoglobin measurement was carried out again 2 hours after surgery. the decrease in hemoglobin levels was assessed by the difference between hemoglobin before and after surgery. the median reduction of hemoglobin level was 1.5 g/dl; this value was accepted as the cut-off value. patients were divided into two groups based on the threshold value. patients with reductions in hemoglobin levels by more than 1.5 g/dl were assigned to group 1, and patients with reductions by less than the cut-off value were assigned to group 2. statistics variables with categorical data are reported as frequencies and percentages. meanwhile, continuous data variables are reported in the form of mean and standard deviation. the data normality test was carried out using the kolmogorov-smirnov test. the chi-square test was performed to assess the association of categorical variables. alternatively, fisher's exact test was used if chi-square requirements were not met. to test comparisons of numerical data, an independent t test was carried out for normally distributed data and the mann-whiteney test for non-normally distributed data. the pearson correlation test was carried out if the data were normally distributed, while the spearman correlation test was carried out if the data were not normally distributed. ethical approval this research has received ethical approval from the health research ethics committee siloam hospital, makassar (no. 068/ke-rs/shmk/ix/2023). results a total of 368 electronic medical records were collected, 95 of which met one of the exclusion criteria, leaving 273 samples who met the criteria and were included in this study. of the 273 samples, 141 samples were in group 1 and 132 samples were in group 2. the average decrease in post-operative hb in the total study sample was 1.5 g/dl. the average age in the total study sample was 50.85 years. the majority of patients were males (74.4%). a total of 37.4% of patients had comorbid hypertension and 9.2% diabetes mellitus. the average body mass index (bmi) was 26.45 kg/m2. the average total bleeding during surgery was 212 ml and the average operative time was 75.97 minutes. data characteristics of this research sample are available in table 1. several variables were found to have a significant relationship with post-operative hb reduction, namely age, comorbid diabetes mellitus, comorbid hypertension, intraoperative amount of bleeding and operation time. the mean age of group 1 was significantly higher than in group 2 (55.48 ± 8.73 vs 45.9 ± 10.75 years, p < 0.001). mean bleeding amount in group 1 was significantly higher than group 2 (285.85 ± 113.68 vs 135 ± 77.54 ml, p < 0.001). there was a significant difference also in mean operation time between groups (group 1 86.35 ± 32.05 vs group 2 64.89 ± 27.83 minutes, p < 0.001). the characteristics of stones and their distribution are presented in table 2. most stones were found in the right urinary tract (56%) and the majority of patients were accompanied by moderate hydronephrosis (41.4%). stone location was most commonly reported at the lower pole (42.9%). in most patients, stone burden was around 30-50 mm2 (58.2%). stone complexity was most commonly reported as grade 2 (51.6%). bivariate analysis showed that of all stone characteristics, only stone burden was reported table 1. clinical characteristics of patients and distribution according to decreases of hb. parameters total group 1 group 2 p-value (mean ± sd) (n = 273) (n = 141) (n = 132) decrease in hb (g/dl) 1.5 ± 1.24 2.3 ± 1.10 0.8 ± 0.35 < 0.001 * age (year) 50.85 ± 10.85 55.48 ± 8.73 45.9 ± 10.75 < 0.001 * gender (male) 203 (74.4%) 105(74.46%) 98 (74.24%) 1.000 * comorbidities ht 102 (37.4%) 61 (43.26%) 41 (31.06%) 0.045 # dm 25 (9.2%) 19 (13.47%) 6 (4.54%) 0.012 # ht + dm 12 (4.4%) 8 (5.67%) 4 (3.03%) 0.380 # bmi (kg/m2) 26.45 ± 4.62 26.18 ± 4.49 26.73 ± 4.76 0.391 * bleeding amount (ml) 212 ± 123.49 285.85 ± 113.68 135 ± 77.54 < 0.001 * operation time (min) 75.97 ± 31.89 86.35 ± 32.05 64.89 ± 27.83 < 0.001 * *t-independent test; #chi-square test. sd: standard deviation; hb: hemoglobin; dm: diabetes mellitus; ht: hypertension; bmi: body mass index. archivio italiano di urologia e andrologia 2024; 96(2):12382 3 factors associated to hemoglobin decrease after percutaneous nephrolithotomy: a retrospective study to have a significant relationship with post-operative hb reduction, because patients with a higher stone burden tended to have a greater decrease in hb (p < 0.05). the results of multivariate analysis showed that the variables age, comorbid dm, bleeding amount, and operation time significantly influenced the reduction in post-operative hb (p < 0.05) (table 3). next, a correlation test was carried out to assess the strength and direction of the correlation between hb decrease and age, intraoperative bleeding amount and operation time. the results showed that age had a weak positive correlation with decrease in hb (r: 0.337, p < 0.001), intraoperative bleeding amount had a strong positive correlation with decrease in hb (r: 0.669, p < 0.001), and operation time had a moderate positive correlation. with decrease in hb (r: 0.432, p < 0.001) (table 4). these results show that older age, greater amount of bleeding, and longer operation time are associated with a higher decrease in post-operative hb levels. discussion despite the efficacy of percutaneous nephrolithotomy (pcnl), bleeding complications remain a concern, leading to decreased hemoglobin levels. factors associated with bleeding consist of age, diabetes mellitus, operation time and intraoperative bleeding amount (14). a study by taylot et al. found that patients with diabetes mellitus had a higher risk of bleeding complications during pcnl due to impaired platelet function and altered coagulation factors (15). the significant association between diabetes mellitus and increased blood loss during pcnl leads to a greater decrease in hemoglobin level. furthermore, diabetes mellitus affects the entire vascular system, causing microangiopathies and an increased tendency for bleeding. in univariate analyses in their study, tefekli et al. found that diabetes mellitus and hypertension correlated with decreased hemoglobin levels (14, 16). the multivariate regression analysis revealed that diabetes mellitus is an independent risk factor for bleeding. our study also found diabetes mellitus as a significant risk factor in multivariate regression analysis. significant correlations were found between advanced age and increased risk of bleeding complications and subsequent hemoglobin decrease in pcnl procedures (14). reduced ability to recover after injury and changes in cardiovascular system may be possible mechanisms for increased bleeding (17). therefore, age has to be considered an high-risk factor for decreasing hemoglobin after pcnl. there are several studies indicating that stone burden is another risk factor for decreasing hemoglobin after pcnl. in their study, kukreja et al. demonstrated that a larger stone burden was associated with an increased risk of bleeding complications during pcnl, resulting in a greater decrease in hemoglobin levels. syahputra et al., suggested that the size of the kidney stone positively correlated with the amount of blood loss during pcnl (18, 19). however, in our study, multivariate regression showed no significant correlation between stone burden and decrease of hemoglobin. a study by wilson et al. found that longer operation table 3. multivariate analysis of factors associated with hemoglobin decrease. multivariate exp (b) 95% ci p-value age 0.923 0.889 0.958 < 0.001 ht 1.454 0.706 2.994 0.309 dm 3.574 1.089 11.728 0.036 stone burden 0.232 0.034 1.579 0.136 bleeding amount (ml) 0.986 0.982 0.990 < 0.001 operation time (min) 0.985 0.974 0.996 0.011 ci: confidence interval; dm: diabetes mellitus; ht: hypertension. table 4. correlation analysis between factors associated with hemoglobin decrease. variable mean ± sd pearson correlations r p-value age 50.85 ± 10.85 0.337 < 0.001+ bleeding amount (ml) 212 ± 123.49 0.669 < 0.001+ operation time (min) 75.97 ± 31.89 0.432 < 0.001+ + pearson correlations; r: correlation coefficient. table 2. stone characteristics and distribution according to decreases of hb. parameters total group 1 group 2 p-value (mean ± sd) (n = 273) (n = 141) (n = 132) laterality (n; %) 0.179 # right 153 (56%) 85 (60.28%) 68 (51.51%) left 120 (44%) 56 (39.72%) 64 (48.49%) hydronephrosis (n; %) 0.847 # none 11 (4%) 5 (3.55%) 6 (4.54%) mild 90 (33%) 47 (33.34%) 43 (32.57%) moderate 113 (41.4%) 61 (43.26%) 52 (39.39%) severe 59 (21.6%) 28 (19.85%) 31 (23.48%) stone location (n; %) 0.082 # upper pole 14 (5.1%) 12 (8.51%) 2 (1.51%) mid pole 5 (1.8%) 4 (2.83%) 1 (0.75%) lower pole 117 (42.9%) 54 (38.29%) 63 (47.7%) pelvic-ureteric junction 12 (4.4%) 6 (4.25%) 6 (4.54%) pelvic 44 (16.1%) 22 (15.6%) 22 (16.67%) multiple location 81 (29.7%) 43 (30.5%) 38 (28.78%) stone burden (n; %) < 0.001 # < 30 mm2 47 (17.2%) 14 (9.93%) 33 (25%) 30-50 mm2 159 (58.2%) 76 (53.9%) 83 (62.8%) > 50 mm2 67 (24.5%) 51 (36.17%) 16 (12.2%) stone complexity (gss grade) 0.384 # grade 1 94 (34.4%) 54 (38.3%) 40 (30.3%) grade 2 141 (51.6%) 69 (48.9%) 72 (54.5%) grade 3 38 (13.9%) 18 (12.8%) 20 (15.2%) grade 4 # chi-square test. sd: standard deviation; gss: guy’s stone score. archivio italiano di urologia e andrologia 2024; 96(2):12382 syarif, a. azis, s. rahmat a., et al. 4 times were associated with a higher risk of bleeding complications during pcnl, leading to a more significant decrease in hemoglobin levels. chen et al. reported a positive correlation between operation duration and blood loss during pcnl (20, 21). and lee et al. demonstrated a significant correlation between the amount of blood loss during pcnl and the decrease in hemoglobin levels postoperatively. kumar et al. also reported that higher blood loss during pcnl was associated with a greater decrease in hemoglobin levels (22, 23). the analysis of the selected studies revealed several significant findings. firstly, advanced age was consistently associated with an increased risk of bleeding complications and subsequent hemoglobin decrease in pcnl procedures. secondly, patients with a history of hypertension demonstrated a higher incidence of bleeding and greater hemoglobin decrease than normotensive individuals. furthermore, diabetes mellitus was found to be an independent risk factor for bleeding complications. stone size, operative duration, and blood loss significantly influenced bleeding in pcnl procedures. the present research has several advantages, including a fairly large sample size and an analysis which was carried out comprehensively and sequentially. however, apart from that, this study also has limitations, including using secondary data from medical records and considering pcnl carried out by different surgeons with different experience so that this could be a confounding factor in this study. conclusions this comprehensive study highlights the importance of considering various factors associated with bleeding complications and hemoglobin reduction in pcnl procedures. older age, comorbid diabetes mellitus, more perioperative bleeding, and long operative time are significantly associated with decreasing hb post-pcnl surgery. these findings emphasize the need for careful patient selection, careful surgical technique, and appropriate precautions to minimize bleeding complications in pcnl procedures. references 1. yu j, park hk, kwon hj, et al. risk factors for acute kidney injury after percutaneous nephrolithotomy: implications of intraoperative hypotension. medicine (baltimore). 2018; 97:e11580. 2. batagello ca, vicentini fc, monga m, et al. tranexamic acid in patients with complex stones undergoing percutaneous nephrolithotomy: a randomised, double-blinded, placebo-controlled trial. bju int. 2022; 129:35-47. 3. de la rosette jjmch, opondo d, daels fpj, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 4. sharma a, parab s, goyal g, et al. comparison of single-step renal dilatation and serial renal dilatation in percutaneous nephrolithotomy: a retrospective case-control study. urol ann. 2021; 13:374-7. 5. türk c, petrík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-82. 6. skolarikos a, gross aj, krebs a, et al. outcomes of flexible ureterorenoscopy for solitary renal stones in the croes urs global study. j urol. 2015; 194:137-43. 7. alken p, hutschenreiter g, günther r. percutaneous kidney stone removal. eur urol. 1982; 8:304-11. 8. segura jw, patterson de, leroy aj, et al. percutaneous removal of kidney stones: review of 1,000 cases. j urol. 1985; 134:1077-81. 9. tiselius hg, ackermann d, alken p, et al. guidelines on urolithiasis. eur urol. 2001; 40:362-71. 10. matlaga br, kim sc, lingeman je. improving outcomes of percutaneous nephrolithotomy: access. eau update series. 2005; 3:37-43. 11. davidoff r, bellman gc. influence of technique of percutaneous tract creation on incidence of renal hemorrhage. j urol. 1997; 157:1229-31. 12. michel ms, trojan l, rassweiler jj. complications in percutaneous nephrolithotomy. eur urol. 2007; 51:899-906. 13. stoller ml, wolf js, st lezin ma. estimated blood loss and transfusion rates associated with percutaneous nephrolithotomy. j urol. 1994; 152:1977-81. 14. eksi m, ozlu dn, kargi t, et al. pre-operative parameters predicting hemoglobin decline related to percutaneous nephrolithotomy. sisli etfal hastan tip bul. 2022; 56:70-6. 15. taylor e, miller j, chi t, stoller ml. complications associated with percutaneous nephrolithotomy. transl androl urol. 2012; 1:223-8. 16. tefekli a, ali karadag m, tepeler k, et al. classification of percutaneous nephrolithotomy complications using the modified clavien grading system: looking for a standard. eur urol. 2008; 53:184-90. 17. du n, ma jq, luo jj, et al. the efficacy and safety of transcatheter arterial embolization to treat renal hemorrhage after percutaneous nephrolithotomy. biomed res int. 2019; 2019:6265183. 18. kukreja r, desai m, patel s, et al. factors affecting blood loss during percutaneous nephrolithotomy: prospective study. j endourol. 2004; 18:715-22. 19. syahputra fa, birowo p, rasyid n, et al. blood loss predictive factors and transfusion practice during percutaneous nephrolithotomy of kidney stones: a prospective study. f1000res. 2016; 5:1550. 20. wilson r, et al. predictors of blood loss during percutaneous nephrolithotomy. journal of endourology. 2015; 29:402-6. 21. chen q, et al. risk factors for bleeding during percutaneous nephrolithotomy: a retrospective study. j endourol. 2017; 31:581-6. 22. lee c, et al. predictors of postoperative hemoglobin decrease and blood transfusion in percutaneous nephrolithotomy. world j urol. 2018; 36:263-9. 23. kumar a, et al. predictors of blood transfusion in percutaneous nephrolithotomy: a prospective study. j urol. 124:153-9. correspondence syarif, md syarifbakri@hotmail.com division of urology, department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia perintis kemerdekaan st. km. 10, tamalanrea, makassar, indonesia (postal code: 90245) abdul azis, md saidah rahmat a., md faculty of medicine, muhammadiyah malang university, malang, indonesia ahmad taufik fadillah zainal, md ade nusraya, md faculty of medicine, hasanuddin university, makassar, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2138 original paper no conflict of interest declared. ness for the identification of those variants on pathology specimens and, in that way, better understand its clinical and therapeutic impact. vh have been reported in 7-81% (3) and, although the presence of vh has been associated with a more aggressive behavior, conclusive data on their effect on survival outcomes are currently not well stablished. the optimal therapeutic management of this patients is based in expert opinion and so, no strong recommendations in this respect can be done. therefore, this is the first portuguese-based cohort to report the oncological and survival outcomes after radical cystectomy (rc) in patients with vh, comparing against patients with pure urothelial carcinoma (puc). materials and methods a retrospective review was done using an electronic data search of all patients submitted to radical cystectomy (rc) between january 2013 and december 2019 in our institution. the procedures were approved by the institutional internal review board. overall, 240 consecutive patients were identified. exclusion criteria were: lymph node or distant metastasis on initial staging (n = 43), pure non-urothelial carcinomas (n = 8), no transurethral resection of bladder tumor prior to rc (n = 5) and lost in follow-up or insufficient data (n = 3). a multidisciplinary team reviewed all patients preoperatively with chest, abdominal and pelvic computed tomography (ct) or magnetic resonance imaging (mri) if tc was contraindicated. open rc with pelvic node dissection was performed by a team of urologists using standard techniques. all rc specimens were assigned by genitourinary dedicated pathologists and histological type was classified according to the 2004 who classification of tumors of the urinary system (2). pathological stages were classified according to 2010 american joint committee on cancer (ajcc)/union international contre le cancer (uicc) tumor, node, metastasis (tnm) staging classification (7th edition) (4). only vh on rc specimens were included. for the purpose of this study, we didn’t discriminate the amount of vh on the specimen and assumed that any component of vh would drive outcomes. vh with less than 10 cases were classified as other variants and more than one vh on the rc specimen as mixed variants. objective: to investigate the impact of variant histologies (vh) of urothelial carcinoma (uc) on survival outcomes after radical cystectomy (rc). materials and methods: data from 181 patients with uc treated with rc between january 2013 and december 2019 at a single tertiary care referral center were retrospectively accessed. all rc specimens were assigned by genitourinary dedicated pathologists. overall survival (os), disease-specific survival (dss) and recurrence-free survival (rfs) were evaluated using the kaplan-meier methodology and the cox proportional hazards regression. results: of 181 patients, 43.1% (n = 78) had vh, with the most common being squamous differentiation (n = 29), followed by mixed variants (n = 18), micropapillary variant (n = 10) and other subtypes (n = 21). the median (range) follow-up was 35 (18-59) months. kaplan-meier survival analysis shows that median os and ds were significantly worse for vh patients (78 vs 31 months, p = 0.038; not reached vs 42 months; p = 0.016). at 5 years, vh was associated with a 12% and 14% decrease in os and dss, respectively. no significant statistical difference between the two groups was reached regarding rfs. however, after adjusting for confounders, such as, demographics characteristics, comorbidities and pathological features, vh were not associated with any survival outcomes. conclusions: our study evidenced the high incidence of bladder cancers with vh. although clearly associated with features of more aggressive behavior, vh had not any significant impact in survival expectancies when all confounders are adjusted in multivariate analyses. key words: urothelial carcinoma; variant histology; radical cystectomy. submitted 2 april 2022; accepted 16 april 2022 introduction bladder cancer is the tenth most common cancer worldwide, accounting for 3% of all new cases worldwide (1). urothelial carcinoma (uc) is the commonest histology of bladder cancer. however, due to its known propensity for divergent differentiation, the 2004 world health organization (who) classification of tumors of the urinary system recognized a wider spectrum of variant histologies (vh) (2). one of its aims was increase the awarevariant histologies of urothelial carcinoma: does it change the survival outcomes in patients managed with radical cystectomy? joão nuno pereira 1, joão duarte reis 2, isaac braga 1, rui freitas 1, vitor moreira da silva 1, sanches magalhães 1, francisco lobo 1, antónio morais 1 1 department of urology, portuguese institute of oncology, oporto, portugal; 2 mathematics department, university of aveiro, portugal. doi: 10.4081/aiua.2022.2.138 summary 139archivio italiano di urologia e andrologia 2022; 94, 2 variant histologies and survival after radical cystectomy patients were followed-up, at least, every 6 months for the first 2 years and then yearly with a clinical review, complete blood count and serum chemistry evaluation and ct or abdominal and pelvic ultrasonography plus chest x-ray. additional investigation (e.g., bone scan, petct, urine cytology, neocystoscopy) was performed when clinically indicated. we aimed to prove that patients with vh had worst survival outcomes, defined as overall survival (os), diseasespecific survival (dss) and recurrence-free survival (rfs), in comparison with patients with puc. recurrence was defined as the evidence of any locoregional or distant metastasis on imaging follow-up. evidence of disease progression in patients with positive surgical margins was not consider as recurrence, rather persistence of disease. descriptive statistical analysis was performed using pearson chi-square test to compare categorical variables and mann-whitney-u (2 categories) or kruskal-wallis (3 or more categories) tests to compare continuous variables. the kaplan-meier method was used to estimate os, dfs and rfs and differences between groups were assessed using log-rank test. multivariable cox proportional hazards regression analysis tested the effect of vh on recurrence, disease specific (dsm) and overall (om) mortality after adjustment for age, gender, body mass index (bmi), estimated 10-year survival according to charlson comorbidity index (cci), time to rc, neoadjuvant chemotherapy (nac), pathological t and n stage, positive surgical margins (psm) and lymph vascular invasion (lvi). all models were tested for concordance probability using wald and score tests. schoenfield residual plots were used to test the proportional hazards assumption. statistical significance was considered as p < 0.05. statistical analyses were conducted using spss statistics® v. 24.0 (ibm corp., armonk, new york, united states of america) and rstudio v. 1.4.1 (integrated development for r. rstudio, pbc, boston, united states of america). results in total, 181 patients were included after meeting inclusion/exclusion criteria. median age was 69 years [interquartile range (iqr): 62-75)] and 86% (n = 155) were male. table 1. clinicopathological characteristics of cohort. puc vh p-value (n = 103; 57%) (n = 78; 43%) age. median. range (years) 69 (62-74) 69 (62-75) 0.659 male gender 88 (85%) 67(86%) 0.930 bmi ≥ 25 58 (56%) 38 (49%) 0.311 estimated 10-year survival according cci 21% (2-53) 21% (2-53) 0.220 turbt muscle invasive 79 (76.7%) 65 (83.3%) 0.542 nac 44 (42.7%) 20 (25.3%) 0.017 time to rc. median. range (weeks) 19 (10-27) 16 (10-22) 0.094 pathological stage t0 22 (21.3%) 5 (6.4%) < 0.0001 pta-t1-cis 31 (30.1%) 4 (5.1%) t2 15 (14.6%) 11 (14.1%) t3-t4 35 (34.0%) 58 (74.4%) pn+ 24 (23.3%) 29 (37.2%) 0.042 psm 7 (6.8%) 14 (17.9%) 0.020 lvi 34 (33.0%) 47 (60.3%) < 0.0001 bmi: body mass index; cci: charlson comorbidity index; lvi: lymphvascular invasion; nac: neoadjuvant chemotherapy; psm: positive surgical margins; puc: pure urothelial carcinoma; rc: radical cystectomy; vh: variant histology. median (months) 2-years os 5-years os puc 78 0.72 0.54 vh 31 0.63 0.42 figure 1. the kaplan meier analysis assessing overall survival (a), disease-specific survival (b) and recurrence-free survival (c). nr – not reached; puc – pure urothelial carcinoma; vh: variant histology. median (months) 2-years dss 5-years dss puc nr 0.76 0.63 vh 42 0.64 0.49 median (months) 2-years rfs 5-years rfs puc nr 0.70 0.63 vh nr 0.70 0.63 a overall ssurvival b disease-specific survival c recurrence-free survival archivio italiano di urologia e andrologia 2022; 94, 2 j. nuno pereira, j. duarte reis, i. braga, r. freitas, v. moreira da silva, s. magalhães, f. lobo, a. morais 140 regarding histology, 57% (n = 103) patients had puc, whereas 43% (n = 78) patients had vh. squamous cell differentiation (sqd; n = 29, 16.0%) was the commonest vh, followed by mixed vh (n = 18; 9.9%), micropapillary vh (mpv; n = 10, 5.5%) and others vh (n = 21; 11.6%), which comprise nested vh (n = 7; 3.9%), glandular vh (n = 5; 2.8%), sarcomatoid vh (n = 4; 2.2%), plasmacytoid (n = 3; 1.7%), microcystic (n = 1; 0.5%) and poorly differentiated (n = 1; 0.5%). table 1 shows clinicopathological characteristics of the cohort. patients with vh had a significantly higher pathological stage, regional lymph node metastasis, psm and lvi, comparing to puc patients. the median follow-up was 35 (iqr: 18-59) months for all cases. over that period, 50.3% (n = 91) of patients died and cancer related mortality was 40.3% (n = 73). disease recurrence occurred in 35.4% (n = 64) of all patients. kaplan-meier survival analysis shows that median os (figure 1a) and dss (figure 1b) were significantly worse for vh patients (78 vs 31 months, p = 0.038; not reached vs 42 months; p = 0.016). at 5 years, vh was associated with a 12% and 14% decrease in os and dss, respectively. no significant statistical difference between the two groups was reached regarding rfs (figure 1c). multivariable cox regression analyses predicting the risk of om, dsm and recurrence are represented in table 2. no differences were seen in these endpoints between puc and vh patients. on the other hand, higher pathological stage, regional lymph node metastasis and psm were all independent predictors for om, dsm and recurrence. a significant higher proportion of patients with puc were submitted to nac as opposite to patients with vh (42.7% vs 25.3%, p = 0.017). when we looked for the effects of nac in survival outcomes, although no statistically significant difference was seen, patients submitted to nac of both groups had better os, dss and rfs compared to patients undergoing rc only (figure 2). table 2. multivariable cox regression analyses predicting de risk of overall mortality (om), disease-specific mortality (dsm) and recurrence. om dsm recurrence hr [95% ci] p-value hr [95% ci] p-value hr [95% ci] p-value age 0.99 [0.95; 1.03] 0.55 0.99 [0.95; 1.04] 0.76 0.98 [0.93; 1.02] 0.34 gender (male ref.) 0.74 [0.37; 1.50] 0.41 0.86 [0.41; 1.79] 0.68 0.92 [0.39; 2.16] 0.85 bmi ≥ 25 (< 25.0 ref.) 0.65 [0.42; 1.02] 0.06 0.63 [0.38; 1.04] 0.07 0.71 [0.42; 1.24] 0.23 time to rc 1.00 [0.99; 1.01] 0.18 1.00 [0.99; 1.01] 0.65 1.00 [0.99; 1.01] 0.79 nac 0.76 [0.45; 1.30] 0.32 0.80 [0.44; 1.46] 0.47 0.95 [0.51; 1.80] 0.88 estimated 10-y survival cci 0.99 [0.98; 1.01] 0.27 0.99 [0.98; 1.01] 0.69 0.99 [0.98; 1.01] 0.26 ≥ pt3 (pt0-t2 ref) 3.30 [1.81; 6.01] < 0.001 4.67 [2.24; 9.78] < 0.001 3.51 [1.77; 6.93] < 0.001 pn+ 1.97 [1.16; 3.34] 0.01 1.93 [1.07; 3.47] 0.03 32.54 [1.41; 4.60] < 0.001 psm 1.99 [1.10; 3.61] 0.02 2.35 [1.26; 4.39] 0.007 0.08 [0.01; 0.61] 0.01 lvi 1.54 [0.88; 2.68] 0.13 2.03 [1.17; 3.71] 0.02 1.93 [1.05; 3.55] 0.03 puc (ref) vh 0.83 [0.52; 1.33] 0.44 0.91 [0.54; 1.53] 0.72 0.75 [0.42; 1.35] 0.33 squamous 0.68 [0.36; 1.31] 0.25 0.77 [0.38; 1.56] 0.47 0.72 [0.32; 1.59] 0.41 micropapillary 0.58 [0.24; 1.42] 0.23 0.63 [0.25; 1.58] 0.32 0.78 [0.28; 2.18] 0.64 mixed 0.86 [0.41; 1.81] 0.69 1.01 [0.46; 2.24] 0.97 0.66 [0.35; 2.14] 0.38 others 1.24 [0.64; 2.41] 0.52 1.40 [0.46; 2.24] 0.39 0.66 [0.26; 1.69] 0.75 concordance (se): 0.761 (0.026) concordance (se): 0.795 (0.026) concordance (se): 0.779 (0.031) likelihood ratio test: p < 0.001 likelihood ratio test: p < 0.001 likelihood ratio test: p < 0.001 wald test: p < 0.001 wald test: p < 0.001 wald test: p < 0.001 score test: p < 0.001 score test: p < 0.001 score test: p < 0.001 bmi: body mass index; cci: charlson comorbidity index; lvi: lymphvascular invasion; nac: neoadjuvant chemotherapy; psm: positive surgical margins; puc: pure urothelial carcinoma; rc: radical cystectomy; vh: variant histology. median (months) 2-years os 5-years os rc only 49 0.66 0.49 nac prior to rc nr 0.80 0.61 figure 2. the kaplan meier analysis assessing os (a), dss (b) and rfs (c) in patients with puc and vh stratified for nac. nr – not reached; puc – pure urothelial carcinoma; vh: variant histology. median (months) 2-years os 5-years os rc only 28 0.59 0.39 nac prior to rc 72 0.75 0.53 a overall survival puc a overall survival vh 141archivio italiano di urologia e andrologia 2022; 94, 2 variant histologies and survival after radical cystectomy discussion over the last decade, an increasing number of studies has been published about vh and its clinical significance. this trend is not the result of an increase in true prevalence of vh, but rather the result of a growing awareness and recognition of vh after the 2004 who classification of urothelial carcinomas, updated in 2016 (2, 5). as an example, linder et al. re-reviewed all pathological specimens of patients submitted to rc between 1980 and 2005 and concluded that, of 1211 patients initially diagnosed with puc, 33% were reclassified as vh (6). similarly, shah et al. reported that 44% of vh weren’t documented by referral institutions, being then recognized by central pathology rereview (7). we report that 43% of patients had vh, with sqd (16%), mixed vh (9.9%) and mpv (5.5%) being the most common variants. although the frequency of vh reported in our cohort is superior of those reported in largest series published in the past few years, which have found prevalences of vh between 17-32%, vh subtypes proportions is in concordance, being sqd and mpv between the most common variants reported (8-11). in our study, vh were significantly associated with predictors of more aggressive disease comparing with puc, such as, higher pathological stages, higher rates of regional nodal involvement, higher rates of lvi and psm. the key question is to know if whether these vh pathological findings translate in worse survival outcomes. for the entire cohort, the 5-year os and dss were 49% and 57%, respectively, which were in line with a recent review, where the 5-year os is between 36-48% for patients with non-metastatic muscle-invasive disease (12). when we looked for survival differences between vh and puc patients, we found that patients with vh had significantly worst os and dss in comparison with puc patients, with a decrease of 12 and 14% in 5 yearos and dss, respectively. however, after adjusting for cofounders, such as, demographics characteristics, comorbidities and pathological features, vh didn’t reach statistical significance to infer it as a predictor of survival, namely, om and dsm. the same results in multivariate cox analyses continued to be truth when we stratified vh into subgroups, such as, sqd, mpv, mixed vh and other vh. we also didn’t find any differences in unior multivariate analyses regarding recurrences when comparing both groups. median (months) 2-years dss 5-years dss rc only nr 0.70 0.57 nac prior to rc nr 0.84 0.72 median (months) 2-years dss 5-years dss rc only 42 0.61 0.48 nac prior to rc 72 0.75 0.53 median (months) 2-years rss 5-years rss rc only 65 0.66 0.57 nac prior to rc nr 0.75 0.72 median (months) 2-years rss 5-years rss rc only nr 0.67 0.62 nac prior to rc 65 0.70 0.65 b disease-specific survival puc c recurrence-specific survival puc c recurrence-specific survival vh b disease-specific survival vh archivio italiano di urologia e andrologia 2022; 94, 2 j. nuno pereira, j. duarte reis, i. braga, r. freitas, v. moreira da silva, s. magalhães, f. lobo, a. morais 142 it probably contributes the fact that we didn’t consider as recurrence patients with psm (significantly higher in vh group) that had disease progression over the follow-up period. to date, the evidence with regard to survival outcomes in this subset of patients is based in retrospective series, with heterogenous results in stablish if whether or not vh is a true predictor of worse survival outcomes. xylinas et al. reported that vh were significantly associated with more advanced tumor stages, lymph node metastasis, lvi and psm, which as a negative effect in univariate analyses of dss and rfs of patients with non-puc and non-sqd variants. however, no differences were seen in multivariate cox regression analyses (8). soave et al. stated identical results, with higher diseasespecific mortality in vh patients in univariate analyses, but no differences when adjusting for cofounders (13). sefik et al. concluded, in a study with nearly the size of ours, that, although patients with variant histology (especially sqd variant) have proportionally higher t stage compared to non-vh, there weren’t significant differences for dss and os (14). in contrast, stroman et al found that patients with vh had higher probability of death of all and disease-related causes, even after adjusting for cofounders, with hr 1.86 (95% ci: 1.21-2.85) and hr 1.89 (1.91-3.01), respectively. a recent meta-analysis, which include 20544 patients of 39 studies, has concluded that patients with vh have worse os (pooled hr 1.44; 95% ci 1.26-1.65; significant heterogeneity), dss (pooled hr 1.37; 95% ci 1.24-1.50; no significant heterogeneity) and rfs (pooled hr 1.32; 95% ci 1.20-1.45; no significant heterogeneity). furthermore, the subgroup analyses showed that the variants with worst os were small cell (pooled hr 3.32; 95% ci 1.98-5.59; no significant heterogeneity), plasmacytoid (pooled hr 2.03; 95% ci 1,17-3,52; significant heterogeneity) and micropapillary vh (pooled hr 1.20; 95% ci 1.02-1.41; no significant heterogeneity) (15). the 2020 european urology association guidelines strongly recommends to offer neoadjuvant cisplatin-based combination therapy to patients with muscle-invasive bc prior to rc, based in a 8% improve on 5-year os (16). however, this survival benefit of nac was mostly seen in patients with uc histology. at the best of our knowledge, the available evidence regarding the added benefit of nac for patients with vh is limited due to the lack of rct. in a retrospective study, vetterlein et al. evaluated the benefit of nac in patients with muscle-invasive vh and concluded that nac lowered the rates of non-organ-confined disease at the time of rc in patients with neuroendocrine, micropapillary, sarcomatoid and adenocarcinoma differentiation tumours. however, that pathological benefit only translates in better os for neuroendocrine patients (hr 0.49; 95% ci 0.33-0.74; p = 0.01) (17). in our study, patients of both groups had better os, dss and rfs in univariate analyses when stratified for nac, although no statistical difference was seen. furthermore, the potential negative effect of delayed cystectomy due to nac was not seen in multivariate cox analyses, as time to cystectomy was not a predictor of worst survival outcomes. there are several limitations that worth mention. first and foremost, it was a retrospective single-center study and our findings should be interpreted in this context. second, rc specimens weren’t re-review and so pathological findings are unified in two dedicated genitourinary pathologists. third, the small proportions of vh limited the subanalyses and conclusions in this regard. fourth, there were more rc specimens with pt0 and pta-t1-cis in the puc group (51.4%) comparing with vh group (11.5%). for this, probably contributes the higher rate of puc patients submitted to nac prior to cystectomy and although it was accounted for multivariate cox analyses, this may contribute to worse survival outcomes for vh patients. conclusions our study evidenced the high incidence of bladder cancers with variants histologies. although clearly associated with features of more aggressive behavior, there was not any significant impact in survival expectancies when all cofounders are adjusted in multivariate analyses. more than large prospective studies assessing outcomes of different morphology variants, we believed that the future directions are in treatment modalities targeting molecular subtypes of bladder cancer. references 1. sung h, ferlay j, siegel rl, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021; 71:209-49. 2. montironi r, lopez-beltran a. the 2004 who classification of bladder tumors: a summary and commentary. int j surg pathol. 2005; 13:143-53. 3. chalasani v, chin jl, izawa ji. histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. can urol assoc j. 2009; 3:193. 4. edge s, compton c. the american joint committee on cancer: the 7th edition of the ajcc cancer staging manual and the future of tnm. in ann surg oncol; 2010. p. 1471-4. 5. humphrey pa, moch h, cubilla al, et al. the 2016 who classification of tumours of the urinary system and male genital organs— part b: prostate and bladder tumours. eur urol. 2016; 70:106-19. 6. linder bj, boorjian sa, cheville jc, et al. the impact of histological reclassification during pathology re-review— evidence of a will rogers effect in bladder cancer? j urol. 2013; 190:1692-7. 7. shah rb, montgomery js, montie je, kunju lp. variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. urol oncol semin orig investig. 2013; 31:1650-5. 8. xylinas e, rink m, robinson bd, et al. impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. eur j cancer. 2013; 49:1889-97. 9. monn mf, kaimakliotis hz, pedrosa ja, et al. contemporary bladder cancer: variant histology may be a significant driver of disease. urol oncol semin orig investig. 2015; 33:18.e15-18.e20. 10. moschini m, dell’oglio p, luciano’ r, et al. incidence and effect of variant histology on oncological outcomes in patients with bladder 143archivio italiano di urologia e andrologia 2022; 94, 2 variant histologies and survival after radical cystectomy cancer treated with radical cystectomy. urol oncol semin orig investig. 2017; 35:335-41. 11. stroman l, nair r, russell b, et al. the impact of non-urothelial variant histology on oncological outcomes following radical cystectomy. bju int. 2019; 124:418-23. 12. lenis at, lec pm, chamie k, mshs m. bladder cancer: a review. jama. 2020; 324:1980. 13. soave a, schmidt s, dahlem r, et al. does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? urol oncol semin orig investig. 2015; 33:21.e1-21.e9. 14. sefik e, celik s, basmaci i, et al. effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy. arch ital urol androl. 2018; 90:172-5. 15. mori k, abufaraj m, mostafaei h, et al. a systematic review and meta-analysis of variant histology in urothelial carcinoma of the bladder treated with radical cystectomy. j urol. 2020; 204:1129-40. 16. witjes ja, bruins hm, cathomas r, et al. european association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. eur urol. 2021; 79:82-104. 17. vetterlein mw, wankowicz sam, seisen t, et al. neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology: neoadjuvant ctx and bladder cancer variants. cancer. 2017; 123:4346-55. correspondence joão nuno pereira, md (corresponding author) joao.pereira@ipoporto.min-saude.pt jnp.urologia@gmail.com isaac braga, md isaac.braga@ipoporto.min-saude.pt rui freitas, md antoniofreitas@ipoporto.min-saude.pt vitor moreira da silva, md i11074@ipoporto.min-saude.pt sanches magalhães, md i10997@ipoporto.min-saude.pt francisco lobo, md i2045@ipoporto.min-saude.pt antónio morais, md i1900@ipoporto.min-saude.pt department of urology, portuguese institute of oncology, oporto (portugal) joão duarte reis, md jduarte.reis@ua.pt mathematics department, university of aveiro (portugal) stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12627 1 review introduction advancing into 3rd decade of the new millennium, progress of organ replacement care is rapidly evolving due to its promising prospect as the next definitive treatment for degenerative and chronic diseases. kidney transplantation (ktx) is currently the state-of-art procedure to attenuate symptoms of end-stage kidney disease (eskd), offering nearly “permanent” restoration despite requiring long-term close observation on the recipients (1, 2). the etiologies of eskd are diverse, often resulted from multisystem damage and longstanding pathologic involvement of the kidney as observed in systemic lupus erythematosus (sle) (3). immune-complex deposition plus abnormal interplay of immune cells’ response in sle may cause persistent kidney damage termed lupus nephritis (ln), which is clinically confirmed by laboratory and biopsy evaluation (4). the prevalence of sle among the global population is estimated to be between 48 to 366.6 per 100.000 individuals, with at least 50% of cases developing ln at some point, and 10-30% progressing further into eskd (5, 6). eskd is the most aggravating complication of ln, that primarily affects young female population (mean diagnosis age of 31.2 years old) and has a 10-20% probability to progress into eskd within 15 years from diagnosis (7). as a kidney replacement therapy, ktx offers major prospects on treatment’s effect longevity, although individuals with sle/ln might possess higher risk for developing worse prognostic value. although outcomes of ktx had been generally associated to other factors as ethnic/racial differences, related to the genetical susceptibility and local lifestyle, the apparent influence on ktx outcome of prior ln diagnosis, as the underlying etiology, remains questionable, specifically in the last couple of decades with some remarkable breakthroughs in transplant-molecular science (8, 9). regardless its distinctive autoimmune origin and subsebackground: the actual prognostic impact of prior lupus nephritis (ln) diagnosis on end-stage kidney disease (eskd) patients remains questionable, especially in relation to outcomes of kidney transplantation (ktx) we aim to determine the survival of the graft and recipient after the ktx procedure among patients with eskd due to ln in comparison to non-ln. methods: this meta-analysis included retrospective studies from the last two decades, focusing on the ktx’s outcomes among eskd due to ln in comparison to non-ln. we establish the graft/recipient survival rate at different follow-up intervals as the primary outcome, and acute graft rejection and pooled graft failure rate as secondary outcomes. all analyses were performed with the random-effect model (rem) and were presented as odd ratio (or; within 95% confidence interval (ci)). the protocol of this study was registered in prospero: crd42023394310. results: a total of 1,299 ktx (368 ln patients) from 10 studies with >10 years of follow-up were thoroughly reviewed. all checkpoints (at 1-, 5-, 10, and 15-year post-ktx) on graft survival rate demonstrated comparable outcomes in either ln or non-ln (e.g., at 10-year follow up (or, 1.08 [0.40, 2.91]; p = 0.88). similar findings at all checkpoints for recipient survival rate were also observed without statistically significant difference between ln and non-ln arm (e.g., at 10-year checkpoint; or, 0.99 [0.68, 1.46]; p = 0.98). both of our secondary analyses also presented insignificant differences (p = 0.70 and = 0.16, respectively). conclusions: our findings suggested that prognosis of eskd due to complicated ln is equal compared to eskd associated with non-ln etiologies, suggesting the impact of ln as the inducing cause of eskd on ktx outcome is relatively neglectable. key words: graft survival; kidney transplantation; lupus nephritis; systemic lupus erythematosus; recipient survival. submitted 30 april 2024; accepted 2 june 2024 redefining kidney transplantation procedure among adult lupus nephritis: expedient review approach and meta-analysis from the last couple of decades syah mirsya warli 1, 2, andi raga ginting 3, naufal nandita firsty 4, adrian joshua velaro 5, stephani clarissa sembiring 6, 7, dewi masyithah darlan 8, zaimah zulkarnaini tala 9 1 department of urology, universitas sumatera utara hospital, universitas sumatera utara, medan, indonesia; 2 division of urology, department of surgery, faculty of medicine, universitas sumatera utara haji adam malik general hospital, medan, indonesia; 3 division of rheumatology, department of internal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia; 4 general practitioner, putri hijau level ii military hospital, medan, indonesia; 5 general practitioner, djasamen saragih hospital, pematang siantar, indonesia; 6 general practitioner, sipirok hospital, south tapanuli regency, indonesia; 7 department of pediatrics, faculty of medicine, universitas sumatera utara, medan, indonesia; 8 department of parasitology, faculty of medicine, universitas sumatera utara, medan, indonesia; 9 department of nutrition, faculty of medicine, universitas sumatera utara, medan, indonesia doi: 10.4081/aiua.2024.12627 summary archivio italiano di urologia e andrologia 2024; 96(3):12627 s. mirsya warli, a. raga ginting, n. nandita firsty, et al. 2 quent requirement of systemic management, should the general transplant care be extended to ln-related ktx? is the outcome of ktx recipients remarkably worse than general population, hence requiring early robust observation? should the current research progress be focused on preventing sle-related flare after ktx? this review is aimed to define the prognostic aspect of kidney-transplanted individuals after eskd following complicated ln in comparison with non-ln etiologies, by focusing on the grafts and recipients’ survival plus the overall rejection status. materials and methods registration and protocol the protocol of this review had been approved and registered in prospero: international prospective register of systematic reviews under issue id crd42022376362. study design, search strategy, and eligibility criteria we conducted this study based on the preferred reporting items for systematic reviews and meta-analysis (prisma) protocol to address our main clinical question on whether the ktx’s outcomes among individuals with ln with eskd are different to those of eskd due to other etiologies. online electronic databases e.g., pubmed, sciencedirect, cochrane library and proquest were thoroughly searched to retrieve all eligible literatures (in english) until november 2022. we employed boolean method to connect the keywords on abstract/title-based identification i.e. (“lupus nephritis”) and (“systemic lupus erythematosus”) and (“kidney transplantation”). each keywords derivatives or synonyms e.g., ‘renal transplantation’ for the ‘kidney transplantation’ phrase was also included through “or” keywords in between. duplicate documents were automatically identified by using mendeley (version 1.19.8) software, and subsequently removed. the literatures were initially screened by two authors (s.m.w. and n.n.f.) through relevant abstractto-full text identification, followed by group discussion with other co-authors for any identified discrepancies. to date, most of the studies investigating ktx were designed as either cohort or case-control analysis, considering that the procedure itself is a “personalized approach” for both donor (either living or deceased) and recipient, therefore assumption to organize a trial-based investigation is impractical in this case. consequently, the reviewed literatures mainly consisted of studies with aforementioned designs (cohort and/or case-control), covering an adequate period of time (≥ 10 years of coverage from either singleor multi-centre records) in a geographical region (or nation), but not restricted to specific continent or race. studies older than a decade are included in this review since we aimed to synthesize reliable evidences from previous years (or the new millennia i.e., > year 2000), capturing how the progress had evolved over time. however, we also excluded nationwide cohort, which might solely rely on medical records and were often conducted by independent investigators (outside of the ktx-eligible centres) to reduce “gap” in population size and avoid potential statistical bias. risk of bias assessment and data extraction the risk-of-bias (rob) were collectively assessed by three authors (n.n.f., a.j.v., and s.c.s.), using a criteria appraisal tools by joanna briggs institute (jbi), each specifically designed for estimating the bias level of both cohort and case-control studies (10, 11). discrepancies between each interpretation were resolved through a re-assessment of respective studies in an internal discussion with the first author (s.m.w.). to systematically summarize our finding, we extracted the following information from each study: its design, region and period, diagnosis of included patients and controls, both arm’s characteristics (age, donor status, pretransplant dialysis status, and pretransplant dialysis duration (in months)). in the quantitative analysis, we applied proportional-odds model to compare each group which focused on graft and patient survival analysis as the primary outcomes. we also secondarily investigate the acute graft rejection (< 1 month) to represent short-term graft-host interaction and overall graft-failure, accumulated throughout the fullduration of cohort and case-control studies. effect measures and statistical analysis variations might be observed considering both cohort and case-control studies were included in the final analysis (as indicated by i square (i2) value). therefore, this meta-analysis will be conducted by a random-effect model (rem) to reduce the heterogeneity’s impact on the final estimation. the statistical analysis was performed by review manager (revman) 5.4 to capture our review model on forest plots whilst estimating odd-ratio (or) value in 95% confidence interval (ci; p value of < 0.05 was considered to be statistically significant). this review also attempted to conduct sub-group analysis on graftand patient-survival based on time-point of follow-up (e.g., 1-year, 5-year, 10-year, and 15-year after ktx.). however, it should be noted that not all studies provide complete reports from the aforementioned checkpoints due to limitations in the observation period and reporting model. we prefer or over risk ratio (rr) parameter since our review also comprised of case-control study, in which the latter study model is basically tracking the exposure from cases and controls populations (rather than identifying the exposure, then analyzing the subsequent outcomes); thus or is more preferrable in this situation (12). inclusion of case-control study in this review is justifiable, considering ktx procedure among ln patients are relatively uncommon requiring an individualized care, hence we prioritize to synthesize as much evidence as possible. a meta-epidemiological study by lanza et al. suggested that meta-analysis with both cohort and casecontrol studies included might possess no statistically significant difference in estimating treatment effects, which can be applied as well in our study (13). a set of sensitivity analysis was conducted as well by restricting the analysis to investigations which included only adult age populations (> 18 years old), performed the ktx from living donor source > 50.0% of the total, cohort-only analysis, and applying leave-one-out approach by removing individual studies one at a time to confirm its overall influence in pooled estimation. archivio italiano di urologia e andrologia 2024; 96(3):12627 3 kidney transplantation in adult lupus nephritis results after thorough identification of studies from literature (figure 1), we included 10 studies (8 retrospective cohorts) from multiple regions with at least 10 years of investigation period (table 1). uncontrolled studies, nationwide investigations, studies that included general rheumatic diseases other than slelns, and those with different aims (e.g., focusing on ethnic/race influence, re-transplantation, etc.) were excluded from the final analysis (figure 1). all patients were diagnosed with eskd due to ln’s complication following sle diagnosis, and were compared to a control group (i.e., eskd resulting from any other disease except for ln or sle’s kidney manifestation). all studies enlisted > 50 individuals in total, though the participant’s distributions were not always in 1:1 ratio and the study population might be compared to a control group twice it size (e.g., 25 vs. 50 individuals) (14-23). a total of 368 ktx procedure from ln arm were compared to 931 controls, with majority of studies consisting of females (mostly > 70.0% of the total study size), except for a cohort by pampa-saico in 2019. the mean ages (or median) of the populations were relatively homogenous, ranging from 3rd to 5th decade of life. though variability in population’s age occurred, inclusion of all the cohorts is still within our review scope since specific limitation on studied population’s age was not applied. the donor status of the transplanted kidney included both living (either related or unrelated donor) and deceased donor. five studies (ghafari et al., horta-baas et al., lionaki et al., park et al., ramirez-sandoval et al., and roozbeh et al.) reported living donors to be > 50.0% of organ source. pretransplant dialysis method and duration were also provided on table 1 though significant difference on baseline characteristics was not observable. the rob assessment results in table 2 demonstrated the majority of confounding aspects in our studies were completely reported based on the jbi-based quality scoring. figure 1. process of identifying the eligible studies by utilizing prisma 2020 flow diagram. archivio italiano di urologia e andrologia 2024; 96(3):12627 s. mirsya warli, a. raga ginting, n. nandita firsty, et al. 4 graft and recipients’ survival our first primary analysis on graft survival demonstrated that there was not any statistically meaningful difference between the two arms based on the modelled proportional-odd estimation (figure 2). on sub-group analysis at 1-year post-ktx, the estimated or value was 0.79 [0.38, 1.62] in 95% ci (p > 0.05), slightly favouring ln population though statistical difference was not significant. however, analysis at the following checkpoint (5year post-ktx) revealed a lower or of 0.74 [0.41, 1.32] in 95% ci (p = 0.31). the latter results represent a lower possibility of longer surviving grafts among non-ln population despite this change does not directly translate into a significant finding upon 95% ci estimation. further analysis on 10and 15-year post-ktx demonstrated that the long-term follow-up of graft survival does not show any difference between the two groups. moreover, our analysis also depicted a progressively reduced graft survival rate throughout the observation period (only 46.8% vs. 28.2% of the transplanted kidney will survive after 10 years in ln vs. non-ln etiology, respectively). comparison of those rates with those observed at earlier checkpoints (e.g., 1st year (89.7% vs. 86.9; p = 0.52, and 5th year 62.3% vs. 63.5%; p = 0.31) revealed consistent reductions on graft survival, which even lower rates at 15th year with only 42.4% (ln) vs. 38.2% (non-ln); p = 0.83. those percentages were congregated from the figure 2 by calculating the event-to-total rate in each arm (i.e., grafts’ survival rate per total ktx performed). overall analysis on the recipient survival comparison demonstrated similar outcomes to the corresponding graft status after several years of follow-up (figure 3). on 1-year table 2. risk of bias assessment by checklists provided by joanna-briggs institute (10, 11). table 1. summary of the included studies of this review. ln/non-ln ktx characteristics study design, region, study size (n) age (years) living donor (%) pretransplant dialysis % (hd, pd) pre-transplant dialysis and studied period and female duration (months) percentage (%) ln non-ln ln non-ln ghafari 2008 retrospective cohort, 23(78.2)/60(81.6) 22.5 ± 16.0 26.2 ± 18.0 (77 a/23b)/(40 a/60 b) na na iran (sc; 1989-2006) horta-baas 2018 retrospective cohort, 25(76.0)/50(74.0) 20.5 (10-50) (84 a/8b)/(43 a/3 b) 36/48/12 c 22/62/6 c na mexico (sc; 2003-2014) lionaki 2008 case-control, (26/26; 89.0) 34.4 ± 9.2 36.9 ± 10.5 54 a/54 a na 30.0 ± 29.0/42.7 ± 48.7 greece (sc; 1985-2005) moroni 2005 retrospective cohort, 33(78.8)/70(80.0) 34.6 ± 9.9 35.8 ± 9.8 26/26 73/27 83/17 42.0 ± 38.4/47.6 ± 45.9 italy (sc; 1982-2004) naranjo-escobar 2017 case-control, 65(85.0)/65(85.0) 34 (27-43) 31/25 48/15/31 c/6d 49/22/18 c/11 d 35 (16-62)/31 (20-49) colombia (sc; 1996-2014) pampa-saico 2019 retrospective cohort, 47(39.5)/367(36.2) 38.5 ± 13.4 44.0 ± 14.0 * na na 30.1 ± 27.7/30.8 ± 31.5 mexico (sc; 1980-2014) park 2017 retrospective cohort, (19/18; 100.0) 43.5 ± 10.2 43.6 ± 10.5 (79 a/5b)/(39 a/6 b) * 74/21/5d 43.3 ± 47.9/50.3 ± 43.8 korea (sc 2005-2016) ramirez-sandoval 2018 retrospective cohort, 74(83.0)/148(80.0) 31.5 ± 10.2 32.1 ± 10.4 66/65 na na usa (sc 1979-2015) roozbeh 2011 case-control, 33(na)/33(na) 26.8 ± 8.0 26.7 ± 8.0 (18 a/45 b; both arm) na 24.3 ± 24.0/14.3 ± 8.9 iran (sc; 1990-2004) yu 2008 retrospective cohort, 23(87.3)/94(81.7) 33.7 ± 10.3 33.6 ± 11.6 4/7 70/30 78/22 29.7 ± 28.4/26.1 ± 32.2 taiwan (sc; 1984-2007) a living-related donor; b living-unrelated donor; c both hd-pd; d no pretransplant dialysis at all; * significant baseline difference (p < 0.05). esrd: end-stage renal disease; gn: glomerulonephritis; ln: lupus nephritis; na: not available. archivio italiano di urologia e andrologia 2024; 96(3):12627 5 kidney transplantation in adult lupus nephritis post-ktx, the estimated or value was 0.94 [0.26, 3.43] in 95% ci (p > 0.05). conversely to the previous analysis, we observe that after 5 years of ktx the or value of recipient survival is slightly favouring non-ln population (1.52 [0.72, 3.21] in 95% ci (p = 0.27)). nevertheless, this finding does not possess any significance in our estimation model though the findings are interesting to be elaborated further. further analysis on 10and 15-year post-ktx disclosed similar results with those observed for graft, as this analysis failed to show any difference (both p > 0.05). additionally, we observed a remarkable challenge of transplantation care in relation to the progressively reduced recipient survival rate after years of observation. in comparison, the 1st year survival rate was 96.3% vs. 95.7% (p = 0.93) in ln and non-ln arm, respectively. however, the patients’ survival rate was massively affected throughout the years with reduced values at 5th year (80.8% vs. 74.0%; p = 0.27), 10th year (69.3% vs. 59.6%; p = 0.98), and 15th year (65.1% vs. 61.8%; p = 0.75). acute and chronic graft rejection status secondary investigation was conducted on the recorded figure 2. graft survival after 1, 5, 10, and 15 years of follow-up post-kidney transplantation. archivio italiano di urologia e andrologia 2024; 96(3):12627 s. mirsya warli, a. raga ginting, n. nandita firsty, et al. 6 rejection rate within acute graft reaction period (< 1 month) and pooled graft failure during each complete study period (figure 4). the estimation of acute rejection demonstrated an or value of 1.06 [0.77, 1.47] in 95% ci (p = 0.70). the following analysis on pooled graft failure disclosed similar outcomes which delineated insignificant difference among both groups, as represented by a or value of 1.48 [0.86, 2.55]; 95% ci (p = 0.16). for that reason, our results concluded that the etiology of ln hardly influence the grafts’ reaction rate in both shortand long-term observation. sensitivity analysis the influence of living-donor graft status was not observed on all analysis, since most of the sub-group estimation remain statistically insignificant. however, at 5-year postktx checkpoint of grafts’ survival analysis, we observe a significant finding (p < 0.05) with the or value at 0.41 [0.24, 0.69] in 95% ci, favouring the ln arm by only including studies with > 50.0% living-donor percentage. further sensitivity analysis on pooled rejection status also demonstrated similar outcomes to our primary report, with neither ln nor non-ln having better estimation on both acute rejection (or 1.01 [0.61, 1.68]; p = 0.98) and graft figure 3. recipient survival after 1, 5, 10, and 15 years of follow-up post-kidney transplantation. archivio italiano di urologia e andrologia 2024; 96(3):12627 7 kidney transplantation in adult lupus nephritis figure 4. meta-analysis of graft’s reaction on acuteand chronic-phase post-renal transplantation after maximum follow-up period in each study. failure variable (or 1.97 [0.84, 4.60]; p = 0.12) in 95% ci. those sensitivity analysis draw a confounding question on ln-etiology influence; how does the population has better grafts’ survival in 5-year post-ktx checkpoint, but also possess similar pooled graft failure risk? (the forest plot outcomes of these sensitivity analysis are available on supplementary data). discussion current research in transplantation care is focused on improving the prognosis, by avoiding graft rejection or subsequent organ failure. the transplant procedure is a demanding task in modern medicine, and issues need to be addressed beforehand, as donor organ shortage and preservation, recipients’ compatibility, technological limitation, and the main issue reviewed in this study that was graft and recipient survival in a special population (2, 24, 25). the role of other renal replacement therapy (rrt) is considered to be pivotal and often deemed to be the only regular eskd ‘treatment’ option available in remote regions. both haemodialysis and peritoneal dialysis hold much advantages in early-cost effectiveness and are relatively “attainable” in short-term, yet their advantages remain controversial in continuous and long-term run (26). the patient may discontinue the dialysis and proceed to ktx option since its overall outcomes are significantly better than prolonged and routine dialysis, which eventually involves pitfalls on the individuals’ quality of life (1, 27). however, transplantation may involves the risk of early (< 1 month) or longer-term host-graft reaction, though it is generally accepted that the patient may achieve high survival rate in case of minimal rejection event (28). moreover, chronic graft rejection will eventually lead into lower graft survival, creating the necessity to identify the outcome-influencing factors. donor transplantation procedure requires a complex collaboration to establish recipient eligibility and organ availability. eligible recipients are placed on a “waiting list” and selected based on several “qualifications” related to life expectancy (26, 29). the statement “different eskd’s etiology might manifest unique outcomes” is related to the personalized medicine program, based on the theoretically reasonable idea that a pathology might induce a specific reaction in a specific patient. though the recurrence-related concern is relatively rare among ln, it was presumed to be correlated with high-titers of anti-phospholipid antibodies, therefore the immunosuppressive options of post-ktx care may significantly reduce its impact (30, 31). the 2020 clinical guideline by kidney disease improving global outcomes (kdigo) placed the recommendation “not excluding” for selection of ln patients to ktx but also assessed that minimal disease activity should be achieved prior to the procedure (32). even though the recommended waiting time to transplant among ln patients is ideally as short as possible, european league against rheumatism and european kidney association-european dialysis and transplant association (eular/era-edta) suggested that the patients should achieve controllable disease for at least 3-6 months prior archivio italiano di urologia e andrologia 2024; 96(3):12627 s. mirsya warli, a. raga ginting, n. nandita firsty, et al. 8 to be eligible for ktx (33). considering its autoimmune course, combination of the underlying dysfunctional immune reaction plus expected host-graft’ reaction could theoretically drive the prognostication of much worse outcomes of rtx for ln patients. requirements of standardized induction and maintenance therapy for both ln and transplantation procedures is another issue to be resolved. performing ktx on serologically active sle might involve an higher risk of subsequent recurrence and lower graft/recipient survival, thus, apart from its complicated ln, the underlying lupus should be quiescent or stable within minimal or no immunosuppressive influence (34, 35). the main objective of our study was to determine whether ln may significantly influence ktx outcomes, so we solely scoped the survival-related outcomes without describing much of its influencing factors from each study. to our knowledge, this is the first systematic review and meta-analysis to compare ln versus non-ln etiology among eskd patients which received ktx. revisiting the outcomes of this demanding procedure is unquestionably essential to establish the impact of this variable in patients who underwent ktx. this review basically concluded that there are no significant differences (p > 0.05) between ln versus non-ln arm, according to proportional-odds estimation at different timing of follow-up (1-, 5-, 10-, and 15-years postktx). the results are relatively consistent throughout each observation period, though the latter checkpoint only involved 3-4 studies at the most. if the analysis was aimed solely to or values, fluctuations at each checkpoint, were statistically inconsistent. throughout each checkpoint estimation, our analysis was unable to observe even a slightest suggestion to differentiate the outcomes, excluding the hypothesis that ln might negatively influence the graft/recipient survival. this lack of differences might be originated from diverse etiologies included in non-ln population or other factors such race/ethnicity or others, although our simplified conclusion is that ln might, in fact, did not involve a worse prognostic value compared to ktx procedures in general. several controversies around possible factors influencing graft and patients’ survival after ktx had been elaborated, and yet, the most commonly described variables are the absence of induction treatment, multiple immunosuppressant medication, pre-existing comorbidities, higher body mass index, donor/recipient of afro-american race, non-living donor, longer dialysis time, prior dialysis figure s1. graft’s survival after 1, 5, 10, and 15 years of follow-up post-renal transplantation limited to studies which included 50.0% living-donor. archivio italiano di urologia e andrologia 2024; 96(3):12627 9 kidney transplantation in adult lupus nephritis figure s2. meta-analysis of recipients’ survival after 1, 5, 10, and 15 years of follow-up post-renal transplantation limited to studies which included 50.0% living-donor. figure s3. meta-analysis of graft’s reaction on acuteand chronic-phase post-renal transplantation after maximum follow-up period in each study; limited to studies which included 50.0% living-donor. archivio italiano di urologia e andrologia 2024; 96(3):12627 s. mirsya warli, a. raga ginting, n. nandita firsty, et al. 10 method, lower adherence to treatment or routine control, and delayed graft function (36-38). it is highly perceivable that the concomitant sle might theoretically worsen outcome of ktx procedures considering the similarity of risk factors between graft loss and the sle (37, 39, 40). specific evaluation on the causes of graft loss was not performed in this study, even though chronic graft nephropathy was the most common etiology, followed by thrombotic events which are related to anti-phospholipid antibody (apa) positivity or pregnancy. the population age was younger in ln arm, raising the hypothesis that this might affect the outcome of the procedure. did it favour the survival or early onset translated into more severe course of disease? another issue is the statistical design of the studies which estimated the prognosis by hazard-ratio (hr) value in kaplan-meier curve. since not all studies provided those details, we adapted our approach to the proportionalodds model evaluating values corresponding to each checkpoint of follow-up, although this choice is our main limitation in providing more accurate estimation in survival rate, our review primarily consisted of retrospective studies that lack the advantages of randomization and all the benefits of trial-investigation. we incorporated both case-control and cohorts into the same pooling of analysis because of the scarcity of the included studies that obliged us to perform a meta-analysis of all the studies available at that point. only 3 casecontrol studies (lionaki et al., naransjo-escobar et al., and roozbeh et al.) were included in the final analysis (16, 18, 22), however it should be underlined that differences in design compared to other retrospective cohorts may act as an important selection bias (originated from case-control studies) in this review (41). nevertheless, our primary outcome was statistical confirmation of ktx outcome to justify ktx among lns, since it might offer better quality of life or superior survival rate compared to individuals in routine dialysis schedule. we encourage future original studies on ln-eskd-ktx subjects to be focused on identifying factors preceding grafts loss and subsequent recipient mortality in order to evaluate not only grafts rejection rate but also the best modality of control of sle activity and prevention of ln recurrence by managing the most appropriate immunosuppressants. conclusions ktx procedure in eskd with ln etiology is equally beneficial in shortand long-term outcomes compared to procedure in patients with non-ln etiologies since no statistically significant difference of outcomes were observed. hence no special care was practically required on the ln population. recommendation to perform ktx among eligible participants including individuals with sle should be advocated considering that current transplantation care had progressed into more specific and personalized approach. therefore, this review is expected to assist global transplant community in tailoring better strategies and preventing ktx’s-related pitfall among complicated-ln patients. references 1. wang jh, skeans ma, israni ak. current status of kidney transplant outcomes: dying to survive. adv chronic kidney dis 2016; 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79:s713-23. 34. wilhelmus s, bajema im, bertsias gk, et al. lupus nephritis management guidelines compared. nephrol dial transplant. 2016; 31:904-13. 35. morales e, galindo m, trujillo h, praga m. update on lupus nephritis: looking for a new vision. nephron. 2021; 145:1-13. 36. rodelo j, gonzález la, ustáriz j, et al. kidney transplantation outcomes in lupus nephritis: a 37-year single-center experience from latin america. lupus. 2021; 30:1644-59. 37. legendre c, canaud g, martinez f. factors influencing long-term outcome after kidney transplantation. transpl int. 2014; 27:19-27. 38. albuquerque bc, salles vb, tajra rdp, rodrigues cem. outcome and prognosis of patients with lupus nephritis submitted to renal transplantation. sci rep. 2019 aug 12; 9(1):11611. 39. gergianaki i, bortoluzzi a, bertsias g. update on the epidemiology, risk factors, and disease outcomes of systemic lupus erythematosus. best pract res clin rheumatol 2018; 32:188-205. 40. nee r, jindal rm, little d, et al. racial differences and income disparities are associated with poor outcomes in kidney transplant recipients with lupus nephritis. transplantation. 2013; 95:1471-8. 41. palumbo sa, robishaw jd, krasnoff j, hennekens ch. different biases in meta-analyses of case-control and cohort studies: an example from genomics and precision medicine. ann epidemiol. 2021; 58:38-41. correspondence syah mirsya warli, md, phd warli@usu.ac.id department of urology, universitas sumatera utara hospital, universitas sumatera utara, medan, indonesia division of urology, department of surgery, faculty of medicine, universitas sumatera utara haji adam malik general hospital, medan, indonesia jl. dr. mansyur, no.66, medan, north sumatera, 20154, indonesia andi raga ginting andi.raga@usu.ac.id division of rheumatology, department of internal medicine, faculty of medicine, universitas sumatera utara, medan, indonesia naufal nandita firsty acnaufal06@gmail.com general practitioner, putri hijau level ii military hospital, medan, indonesia adrian joshua velaro ajoshuav@gmail.com general practitioner, djasamen saragih hospital, pematang siantar, indonesia stephani clarissa sembiring stephaniclarissas@gmail.com general practitioner, sipirok hospital, south tapanuli regency, indonesia department of pediatrics, faculty of medicine, universitas sumatera utara, medan, indonesia dewi masyithah darlan dewi2@usu.ac.id department of pediatrics, faculty of medicine, universitas sumatera utara, medan, indonesia zaimah zulkarnaini tala zaimah@usu.ac.id department of nutrition, faculty of medicine, universitas sumatera utara, medan, indonesia conflict of interest: the authors declare no potential conflict of interest. the initial version of this study has been presented as poster presentation session of world congress of nephrology (wcn) 2023 by the international society of nephrology (isn) from march 30th to april 2nd, 2023 in bangkok, thailand. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 51 original paper inflammation is involved in carcinogenesis (1, 2). in the field of prostate diseases, recent studies have shown that patients with chronic inflammation of the prostate are at greater risk of more severe voiding symptoms, acute urinary retention and prostate surgery (3, 4). the gold standard for the diagnosis of tissue inflammation is represented by histological examination of tissue specimen. a biopsy cannot always be performed for both ethical and procedural issues (5). for this reason, in recent years, several studies attempted to identify a serological marker of inflammation for the various neoplastic and benign urological pathologies (6). however, most of the markers used at preclinical and in vitro levels have poor diagnostic specificity, significant variability over time or high costs. in recent years, several authors have shown how some laboratory tests (complete blood count/cbc, albumin, fibrinogen, c-protein reactive/pcr and procalcitonin/pct), that are routinely performed in preparation for various urological surgeries, can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (7). in particular, these markers can be considered as proxies of inflammation of the organism and are related to an increased risk of mortality in numerous diseases. the role of these inflammation markers in urology is still unclear today and the scientific evidence comes mainly from retrospective studies (8). there is currently no consensus on the pharmacological management of inflammatory prostatic diseases in a unique way. nonsteroidal anti-inflammatory drugs (nsaids) are typically prescribed together with antibiotics without clear evidence. the use of herbal remedies is very common, but the clinical evidence remains scarce (9). above all, it remains unclear whether the use of such preparations can affect the reduction of the inflammatory state inferred on blood chemistry tests. the primary purpose of this multicenter study is to describe the variation in subjective, objective and biochemical inflammatory indexes in men affected by chronic abacterial prostatitis, treated with herbal extracts, containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg, for each administration, as described in the manufacturer’s instructions (naturneed, macerata, italy). introduction: inflammation is a highly prevalent finding in the prostate. men with inflammation have higher ipss score and increased prostate size. for men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease. some laboratory tests (i.e. fibrinogen, c-reactive protein), can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery. there have been several experiences exploring the role of nutraceutical approach to the prostate inflammation. aim of our study were to describe the variation in symptoms and inflammatory indexes in men affected by chronic abacterial prostatitis, treated with an herbal extract containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg. materials and methods: a prospective multicenter study was conducted from february 2021 and march 2022. one hundred patients, with a diagnosis of chronic prostatitis were enrolled in a multicentric phase iii observational study. they were treated with the herbal extract, one capsule per day, for 60 days. no placebo arm was included. in each patient, inflammatory indexes, psa, prostate volume, iief-5, puf, uroflowmetry (qmax), ipss-qol, nih-cpps were registered and statistically compared at baseline and at the follow up visit. results: the variation obtained on the inflammation indexes showed a global improvement after treatment, including the psa reduction. we also recorded a significant improvement on ipss-qol, nih-cpps, puf and qmax scores. conclusions: the herbal extract considered in our study may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, and could be used in the treatment of prostatitis and benign prostatic hyperplasia. key words: nutraceuticals; inflammation; inflammatory indexes; psa. submitted 1 may 2023; accepted 11 may 2023 introduction in recent years many authors highlighted the central role of inflammation in the pathogenesis of urological diseases. in particular, in patients with some neoplastic diseases, it has been shown that the presence of locoregional chronic variation of inflammatory indexes in patients with chronic abacterial prostatitis treated with an herbal compound/extract luca cindolo 1, andrea fabiani 2, daniele vitelli 1, filippo cianci 1, lorenzo gatti 1, nicola ghidini 1, nikolas niek ntep 1, rosario calarco piazza 1, alessandra filosa 3, giovanni ferrari 1 1 cure group, hesperia hospital, modena, italy; 2 urology unit, surgical dpt, ast macerata, macerata hospital, macerata, italy; 3 pathological anatomy, politechnic university of marche region, ancona, italy. doi: 10.4081/aiua.2023.11441 summary archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 52 materials and methods from february 2021 and march 2022, all 100 consecutive patients, with prostatitis-like symptoms (10) attending each one of participating urologic centers, were enrolled in a multicentric phase iii observational study. the patients were treated with an herbal extract, containing curcuma longa 500 mg, boswellia 300 mg, urtica dioica 240 mg, pinus pinaster 200 mg and glycine max 70 mg (prostaflog®), taking one capsule at bedtime every 24h for 60 days. no placebo arm was included. the demographic characteristics were studied using descriptive analysis tables and the calculation on the sample size has not been determined because the sample will be a "convenience sample". inclusion criteria were: age more than 18 years, diagnosis of diagnosis of chronic abacterial prostatitis, any prostatic volume, qmax between 11 and 25, post voiding volume < 50 ml. exclusion criteria were patient under 18 years old, history of neurological or psychiatric disorders which may impair evaluation of urinary symptoms, patients with urethral stricture or history of bladder or prostatic cancer or concomitant bladder stones, previous pelvic radiation therapy, inability to assess urinary symptoms, chronic opioid or opioid derivatives (for any reason) or cortisone therapy, alpha blockers or 5-alpha-reductase therapies, phosphodiesterase-5 inhibitors (pde5i) or nsaids assumption during the study period, intolerance/allergies to the ingredients of the herbal extracts. after the diagnosis of chronic prostatitis, all patients who met the inclusion criteria signed a written informed consent and underwent baseline questionnaires: international prostatic symptoms score-quality of life (ipss-qol), national institutes of health chronic prostatitis symptom index (nih-cpsi), pelvic pain and urgency/frequency (puf) patient symptom scale, international index of erectile function-5 (iief-5) (11, 14). a urological examination using the expressed prostatic secrete (eps) culture or seminal fluid culture and a prostatic transrectal ultrasound (trus) were performed. uroflowmetry, cbc, inflammation indices (erythrocyte sedimentation rate/esr; pcr; prothrombin time/pt; partial thromboplastin time/ptt; fibrinogen; psa) were tested. the first follow-up visit was scheduled at 2 months from starting therapy, with a urological and microbiological examination, questionnaire collection, transrectal ultrasound (trus), treatment benefit scale (tbs) questionnaire compilation (15). the softwares used for statistical analyses were excel 2019, statplus pro 7.6.5 (med calc to confirm). mean, standard deviation, median, differences were calculated for the quantitative variables interquartile. the scores obtained in the responses to the ipss, nih cpsi, puf and iief 5 questionnaires were assimilated to variables quantitative, but ipss and iief 5 were also evaluated based on the frequency distribution for expected score ranges, which is perhaps a more correct way of considering them, since there is a division into interpretation classes. for the qol questionnaire, the frequency distributions recorded in the baseline versus follow up visit were evaluated, for the 5 scheduled answers. for tbs, the distribution of frequencies recorded in each of the 4 responses was equally evaluated as provided in the questionnaire. for each quantitative variable examined, the normality of the distribution of data was preliminarily evaluated, using shapiro wilk's test. in case of confirmed h0 and of normal distribution, parametric tests were used in the evaluation of the statistical significance of the differences between the different variables at baseline and after follow up (anova within subjects). in case of data non-normally distributed, the evaluation of the differences between the variables (baseline vs follow-up) was performed using nonparametric tests (wilcoxon signed rank test). the differences between the frequency distributions were evaluated by pearson's chi-square test. results one hundred patients were included in the study. the main characteristics were: mean age 52.1 ± 12.0 yeras, mean body mass index 25.5 ± 2.8. essential systemic arterial hypertension, dyslipidemia and diabetes mellitus occurred in 37%, 37% and 13%, respectively. the changes in baseline vs follow up clinical and biochemical variables were reported in table 1 and 2. these changes between visit 1 and visit 2 were significant for prostate volume, qmax and for all the questionnaires but the iief score variation which showed was not significant (table 1). the tbs score revealed an interesting improvetable 1. the clinical variables at baseline visit and follow-up. baseline follow-up variable mean ± sd median mean ± sd median baseline vs follow-up (p) prostate volume (ml) 35.58 ± 15.98 33.50 33.82 ± 15.64 30.00 < 0.001 uroflowmetry qmax (ml/s) 17.74 ± 5.40 17.00 19.00 ± 5.41 18.00 < 0.001 ipss 15.94 ± 5.01 17.5 13.78 ± 4.89 14.00 < 0.001 qol 2.60 ± 0.89 3.00 2.16 ± 0.94 2.00 0.003 nih cpsi 17.34 ± 5.43 18.00 14.56 ± 5.83 14.00 < 0.001 puf 12.77 ± 4.36 15.00 10.74 ± 4.8 10.00 < 0.001 iief 5 18 ± 4 19 18 ± 4 19 0.909 table 2. variation of inflammation indices. baseline follow-up variable mean ± sd median mean ± sd median baseline vs follow-up (p) wbc (10^3/ml) 6.36 ± 1.76 6.17 6.02 ± 1.30 5.80 0.0039 lymphocyte count (10^3/ml) 2.08 ± 0.55 2.05 1.96 ± 0.53 1.95 < 0.001 neutrophil count (10^3/ml) 3.97 ± 1.25 3.86 3.64 ± 0.90 3.60 < 0.001 esr (mm/h) 7.76 ± 7.99 6.00 5.98 ± 5.40 5.00 < 0.001 crp 2.40 ± 2.92 0.80 2.22 ± 2.90 0.50 < 0.001 fibrinogen (mg/dl) 261.33 ± 57.28 246.00 250.56 ± 57.27 230.00 < 0.001 total serum psa (ng/ml) 3.57 ± 3.70 2.80 2.37 ± 1.73 2.20 < 0.001 archivio italiano di urologia e andrologia 2023; 95, 2 53 herbal compound/extract in chronic abacterial prostatitis ment of perceived clinical status. at follow up visit, the patients declared an improvement (great also) in 76% of cases. no changes were declared in 22% and a worsened situation only in 2% (figure 1). for the iief-5 questionnaire the differences are not significant both if we evaluate the scores or if we consider it a quantitative variable dividing the patients into categories based on the score intervals (figure 2a, b). the variation obtained on the biochemical inflammation indexes was reported in table 2, showing a global improvement of all parameters at follow-up visit, including a significant reduction in psa as proxy of inflammatory status. discussion inflammation is a highly prevalent finding in the prostate, both at histological and biochemical level. men with inflammation have higher ipss scores and increased prostate size, even if these differences appear to be imperceptibly small. for men with prostatic inflammation, there is a significantly increased risk of developing acute urinary retention and the need of a surgical approach to the disease (4). in recent years, several authors have shown how some laboratory tests (cbc, albumin, esr, fibrinogen, pcr) that are routinely performed in preparation for various urological surgeries can play a role in identifying patients at greatest risk of complications and adverse outcomes after surgery (6). the effects of systemic inflammatory conditions, most notably metabolic syndrome, and their role in lower urinary tract symptoms (luts) have also been examined. when the data are examined at a clinically relevant level, we must take into high consideration that inflammation is a common process in the prostate and that the clinically significant impact of ingland inflammation is variable and difficult to define. for a long time, we know that the location of inflammation is important and that there are subsets of inflammation that are more frequently associated with the development of urinary symptoms or the prostate growth (16). in recent years, there was several experiences exploring the role of nutraceutical approach to the prostate inflammation. in particular, cai and co-workers (17) evaluated the efficacy of a combination of soyabean extracts associated with curcuma longa, boswellia, pinus pinaster and urtica dioica (prostaflog®) in patients affected by cp/cpps, through the evaluation of interleukin-8 (il-8) plasma seminal levels. all patients diagnosed with cp/cpps, attending the same urologic center, were enrolled in this randomized, controlled phase iii study. participants were randomized to receive oral capsules of prostaflog® (two capsules at bedtime every 24 h) or ibuprofen 600 mg (1 tablet daily), lasting for a period of four weeks. nihcpsi and sf-36 questionnaires in association with urological evaluations with trus, meares-stamey test, and il-8 dosage in seminal plasma were performed at baseline and at 3 months follow-up. a total of 77 patients were enrolled [prostaflog® (n = 39); ibuprofen (n = 38)] in the study and followed for 3 months. in the prostaflog® series, 69.2% of patients showed a significant reduction in the nih-cpsi score, compared with 34.2% in the ibuprofen group (p < 0.0001). the mean il8 levels were significantly lower in the prostaflog® figure 1. treatment benefit scale (tbs) after therapy. figure 2a, b. no improvement of iief score after therapy. a. b. archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 54 cohort compared with the ibuprofen series (p < 0.0001), while a significant reduction in the il-8 level between the enrollment and last follow-up evaluation was also observed in this group (p < 0.0001). additionally, a significant reduction in the volume of the seminal vesicles assessed by trus was also found in the prostaflog® series during the observational timeframe. the authors concluded that prostaflog® significantly improves the qol in patients affected by cp/cpps and provides a significant reduction in il-8 seminal levels as the overall seminal vesicles volume. in our present study, the same observation in terms of qol improvement was made (figure 3). especially in case of moderate qol alteration, patients declared a positive impact from therapy on symptoms. these data are confirmed at the follow up evaluation with tbs questionnaire. the 20% of population studied reported a great improvement after treatment. the rate moves to 76% considering improvement to any extent. the statistically significant amelioration recorded at the follow-up visit after two months of therapy in ipss, nih cpps and puf scores (figures 4a-b, 5, 6) confirms how the control of prostatic inflammation is correlated closely with a better perception of urinary symptoms characteristic of chronic prostatitis. the iief-5 scores registered before treatment did not improve. this finding could be related to the markedly multifactorial nature of the etiology of erectile dysfunction (ed). given the age of the patients figure 3. qol improvement after therapy. figure 4a, b. ipss global score improvement at follow up visit, but not in cases with severe basal symptoms. figure 5. nih-cpsi score improvement at follow up visit. a. b. archivio italiano di urologia e andrologia 2023; 95, 2 55 herbal compound/extract in chronic abacterial prostatitis enrolled and the presence of known risk factors for ed, such as systemic hypertension and diabetes mellitus, the lack of improvement after treatment is not surprising as the therapy is aimed at the management of the prostatic inflammatory process which is only one of the possible causative factors of ed. considering inflammation indicators, we preferred to investigate laboratory tests more accessible in daily clinical practice than seminal il-8 levels. the routinely determined markers of inflammation showed a statistically significative improvement between the first visit and the visit performed at the follow-up. this clearly depends on prostatic inflammation etiology and confirm the anti-inflammatory role of the nutraceutical product. the first experience with prostaflog® was by fabiani et al. (18). they described their real-life experience with this anti-inflammatory mixture on psa levels and, in a prospective mono-institutional study of 50 patients, admitted for a first psa raising, reported a lowered psa value in 80% of cases, with a mean of reduction of 2.94 ng/ml (0.26-16.2 ng/ml) in one month therapy (two pill per day). no differences were reported in term of prostate volume variation. they concluded that prostaflog® use was able to lower the value of psa, inviting to evaluate in appropriate studies the nutraceuticals products use in the treatment of prostatic pathology. in our present experience, we can confirm the lowering effect on psa value by the prostaflog® administration. after 60 days of treatment, with one pill per day, we observed, at followup visit, a mean psa levels of 2.74 ng/ml, starting from a 4.63 ng/ml mean value (figure 7). moreover, in our results, we reported a statistically significant reduction on prostate volume (38.01 ml vs 35.86 ml), presumably linked to the anti-inflammatory effect of prolonged administration (figure 8). from a functional point of view, we found a significant improvement on flow parameters (figure 9). the qmax registered at the enrollment visit was significantly increased after prostaflog® treatment. this is evidently the effect induced by the reduction of the static and dynamic factors which underlie the typical symptoms of bph (9). conclusions prostaflog® treatment employed in case of chronic prostatitis may significantly increase qol, providing a significant improvement of symptomatic scores. a critical reduction in psa level may be eventually take into account in clinical decision making. prostaflog® may represent a promising and safe therapeutic agent leading to a reduction of inflammation markers, able to interrupt the pathophysiological mechanism of benign prostatic hyperplasia. references 1. lloyd gl, marks jm, ricke wa. benign prostatic hyperplasia and lower urinary tract symptoms: what is the role and significance of inflammation? curr urol rep. 2019; 20:54. 2. vasavada sr, dobbs rw, kajdacsy-balla aa, et al. inflammation on prostate needle biopsy is associated with lower prostate cancer risk: a meta-analysis. j urol. 2018; 199:1174-1181. figure 7. decreased psa level from baseline after 2 months of treatment. figure 8. prostate volume decrease after therapy. figure 9. qmax improvement at follow up visit. figure 6. puf score improvement after therapy. archivio italiano di urologia e andrologia 2023; 95, 2 l. cindolo, a. fabiani, d. vitelli, et al. 56 3. de nunzio c, voglino o, cicione a, et al. ultrasound prostate parameters as predictors of successful trial without catheter after acute urinary retention in patients ongoing medical treatment for benign prostatic hyperplasia: a prospective multicenter study. minerva urol nephrol. 2021; 73:625-630. 4. gandaglia g, briganti a, gontero p, et al. the role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (bph). bju int. 2013; 112:432-41. 5. vela-navarrete r, alcaraz a, rodríguez-antolín a, et al. efficacy and safety of a hexanic extract of serenoa repens (permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (luts/bph): systematic review and metaanalysis of randomised controlled trials and observational studies. bju int. 2018; 122:1049-1065. 6. wang q, zhu sr, huang xp, et al. prognostic value of systemic immune-inflammation index in patients with urinary system cancers: a meta-analysis. eur rev med pharmacol sci. 2021; 25:1302-1310. 7. alazawi w, pirmadjid n, lahiri r, bhattacharya s. inflammatory and immune responses to surgery and their clinical impact. ann surg. 2016; 264:73-80. 8. paulis g. inflammatory mechanisms and oxidative stress in prostatitis: the possible role of antioxidant therapy. res rep urol. 2018; 10:75-87. 9. cicero afg, allkanjari o, busetto gm, et al. nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. arch ital urol androl. 2019; 91. 10. krieger jn, nyberg l jr, nickel jc. nih consensus definition and classification of prostatitis. jama. 1999 jul; 282:236-7. 11. hopland-nechita fv, andersen jr, beisland c. ipss "bother question" score predicts health-related quality of life better than total ipss score. world j urol. 2022; 40:765-772. 12. giubilei g, mondaini n, crisci a, et al. the italian version of the national institutes of health chronic prostatitis symptom index. eur urol. 2005; 47:805-11. 13. brewer me, white wm, klein fa, et al. validity of pelvic pain, urgency, and frequency questionnaire in patients with interstitial cystitis/painful bladder syndrome. urology. 2007; 70:646-9. 14. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 199; 11:319-26. 15. viktrup l, hayes rp, wang p, shen w. construct validation of patient global impression of severity (pgi-s) and improvement (pgii) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. bmc urol. 2012; 12:30. 16. kohnen pw, drach gw. patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. j urol. 1979; 121:755-60. 17. cai t, anceschi u, tamanini i, et al. soybean extracts (glycine max) with curcuma, boswellia, pinus and urtica are able to improve quality of life in patients affected by cp/cpps: is the proinflammatory cytokine il-8 level decreasing the physiopathological link? uro 2022; 2:40-48. https://doi.org/10.3390/ uro2010006 18. fabiani a, morosetti c, filosa a, et al. effect on prostatic specific antigen by a short time treatment with a curcuma extract: a real life experience and implications for prostate biopsy. arch ital urol androl. 2018; 90:107-111. correspondence luca cindolo, md, phd lucacindolo@virgilio.it daniele vitelli, md doc.vitelli@gmail.com filippo cianci, md filippocianci3p@hotmail.com lorenzo gatti, md dottor102@gmail.com nicola ghidini, md info@nicolaghidini.it nikolas niek ntep, md nicolas22it@yahoo.fr rosario calarco piazza, md iaiiopiazza@gmail.com giovanni ferrari, md giogioferrari@yahoo.it cure group, hesperia hospital, modena, italy andrea fabiani, md (corresponding author) andreadoc1@libero.it surgery dpt, section of urology asur marche area vasta 3, macerata hospital, italy via santa lucia, 2; 62100 macerata (italy) alessandra filosa, md phd alessandrafilosa@yahoo.it pathology unit, asur marche area vasta 5, ascoli piceno (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12389 1 original paper the disease in children is more complex than in adults, leading to specific challenges such as poor growth, cognitive problems, bladder dysfunction, and special dietary needs, which profoundly impact their quality of life (1, 2). despite the availability of renal replacement therapy (rrt), children with severe renal failure face a significantly increased risk of mortality, approximately 30 times higher compared to their peers of the same age. furthermore, children with hemodialysis experience low self-esteem, loss of identity, compromised body integrity, diminished control, and reduced independence (2). kidney transplantation (ktx) remains the preferred treatment for both adults and children with esrd. it offers reduced morbidity and mortality rates along with enhanced quality of life compared to rrt. however, despite ktx being a well-established procedure for adults, it is relatively rare in children (3). even though there have been significant improvements in graft and patient outcomes, ktx remains a challenging procedure for pediatric patients. this is primarily due to factors like smaller recipients, congenital anomalies, and donorrecipient mismatches that lead to an increased risk of postoperative complications (3). it has also been reported that long-term graft survival rates in the pediatric population have not shown significant improvement, primarily due to factors like infections, episodes of acute rejection, and suboptimal adherence to medication regimens (4). the existing literature on pediatric ktx predominantly focuses on long-term outcomes for grafts and patients. however, there is a scarcity of data regarding the impact of pre-transplantation factors, donor-recipient mismatching, and the occurrence and consequences of surgical complications (3, 5). the present study is a case series aimed to show the experience of the city of sulaymaniyah regarding pediatric renal transplantation. methods study design a retrospective single-group case series study was conducted on children with esrd who were planned to undergo ktx from living donors between 2015 and introduction: the rising prevalence of global end-stage renal disease (esrd) is a significant health concern, especially among children. although renal replacement therapy is available, children with esrd are at an increased risk of mortality. kidney transplantation is the preferred modality of treatment and surpasses renal replacement therapy in terms of survival. however, pediatric renal transplantation could prove difficult due to factors like smaller recipients and donor-recipient mismatches leading to higher complications. materials and methods: a retrospective single-group case series study was conducted on children with esrd who were planned to undergo kidney transplantation from living donors between 2015 and 2021. the data was collected from two centers in the city of sulaymaniyah. results: the study comprised a predominantly male patient population, with a total of 39 individuals (n = 39) and 13 female patients. the donors were mostly males between 25-40 years old. the majority of participants were 15-18 years old. in majority of the patients thymoglobulin was the immunosuppressive agent used in induction. the most common etiology for renal failure was reflux nephropathy and artery anastomosis was performed to the external iliac artery in the majority of patients. only 9 patients had complications following the transplantation and 3 patients had an episode of acute rejection. conclusions: renal transplantation is the preferred treatment of renal failure in pediatric patients in the city of sulaymaniyah. the most common etiology for pediatric renal failure was reflux nephropathy which was different from the findings of north american pediatric renal trials and collaborative studies. key words: kidney; graft; end-stage renal disease; pediatric renal transplantation. submitted 15 february 2024; accepted 22 february 2024 introduction the global incidence of end-stage renal disease (esrd) is currently escalating and posing a significant health concern worldwide. chronic kidney disease (ckd) is a condition characterized by irreversible injury to the kidneys that can advance to esrd, the final stage of renal deterioration. esrd is a devastating disorder associated with high mortality rates and cardiovascular complications. pediatric renal transplantation: a single center experience shakhawan hama amin said 1, saiwan hayas agha 1, goran fryad abdulla 1, mzhda sahib jaafar 1, rawa bapir 2-4, nali h. hama 1, 2, ismaeel aghaways 1, aso omer rashid 1, berun a. abdalla 2, 4, fahmi h. kakamad 1, 2, 4 1 college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq; 2 smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq; 3 department of urology, sulaymaniyah teaching hospital, sulaymaniyah, kurdistan, iraq; 4 kscien organization, hamdi street, azadi mall, sulaymaniyah, kurdistan, iraq. doi: 10.4081/aiua.2024.12389 summary archivio italiano di urologia e andrologia 2024; 96(2):12389 s. hama amin said, s. hayas agha, g. fryad abdulla, et al. 2 2021. the consent for participation and publication of data was obtained from the parents of patients. ethical approval of the study was provided by the ethical committee of the university of sulaimani. inclusion criteria all children younger than 18 years who underwent renal transplantations from living donors due to esrd. exclusion criteria renal transplant cases older than 18 years old. data collection the data was collected from two centers, shar hospital and faruk medical city, by reviewing the medical records of patients or filling out a specific questionnaire form by patients or their families. the extracted variables were patient demographics, etiology of renal failure, history of dialysis before transplantation, donor characteristics, the surgical technique of renal transplantation including the type of vascular and ureteric reconstruction, ischemia time, patient and graft survival, acute rejection episodes, reasons for graft failure, and cause of death. doppler ultrasound of the graft had been performed within 24 hours of transplantation. graft function had been monitored daily using plasma creatinine levels. the applied immunosuppression protocol (induction drugs and maintenance therapy) had been documented. operative and postoperative adverse events had been graded using the modified clavien dindo scale of complication severity (6). graft failure was defined as the failure of a renal transplant with a return to dialysis or the performance of a second preemptive transplant. acute rejection episode was defined as a rise in serum creatinine of at least 30% from baseline levels, accompanied by clinical symptoms and signs (fever, oliguria), and pathologic proof with a renal biopsy. data analysis data entry and coding were done using microsoft excel (version 2010). data analysis was performed using statistical package for the social sciences (spss) version 24. standard descriptive statistics, including percentages and mean ± standard deviation, were performed to analyze the data. results our patients were grouped into 3 age categories. only 9 (17.3%) of them were younger than 10 years old while the majority 31 patients 59.6% were between 15-18 years old. the remaining 12 (23.1%) patients were between 11-14 years old. thirty-nine patients were male and constituted 75% of our data while the remaining 25% (13 patients) were females. the mean body mass index (bmi) of our patients was 21.3 ± 1.69. the immunosuppressive pharmacologic agents used for induction were thymoglobulin (used in 88.5% of our patients) and basiliximab (used in only 6 patients). only two patients had a history of previous transplantation and the other 50 patients were having their first attempt at renal transplantation. the majority of the donors were 25-40 years old and a minority of 5 donors were older than 40 years old. the majority (42, 80.8%) of the donors were male and the rest were female. only 8 of the donors were related to the patients and the other 44 donors were non-related. the most common etiology for renal failure was reflux nephropathy which accounted for 21.2% of the patients. this was followed by focal segmental glomerulosclerosis which accounted for 17.3% of the patients. forty-six patients had a single graft artery which accounted for 88.5% of the cases. the rest of the patients had double artery grafts. artery anastomosis was performed to the external iliac artery in the majority of the patients, accounting for 63.5% of them, and in the remaining patients it was anastomosed to the common iliac artery. thirty-eight patients had the venous anastomosis done with the external iliac vein and in only 2 patients the anastomosis was performed with the inferior vena cava (ivc). post-operative evaluation of our patients showed only 9 patients had complications following the transplantation and 3 patients had an episode of acute rejection. table 1 shows the recipient characteristics, etiologies of renal failure, surgical techniques and post-operative data. table 1. recipient and donor characteristics, etiology of renal failure, surgical technique. recipient characteristics no. (%) age group (years) < 10 9 (17.3) 11-14 12 (23.1) 15-18 31 (59.6) gender male 39 (75) female 13 (25) duration of dialysis < 1 37 (71.2) 1-3 4 (7.7) > 3 1 (1.9) no dialyzed 10 (19.2) agent of induction thymoglobulin 46 (88.5) basiliximab 6 (11.5) number of transplantations first 50 (96.2) second 2 (3.8) bmi (mean ± sd) 21.3 ± 1.69 donor characteristics age group < 25 17 (32.7) 25-40 30 (57.7) > 40 5 (9.6) male 42 (80.8) female 10 (19.2) donors related 8 (15.4) non-related 44 (84.6) etiology of renal failure urological causes reflux nephropathy 11 (21.2) posterior urethral valve 2 (3.8) archivio italiano di urologia e andrologia 2024; 96(2):12389 3 pediatric renal transplantation discussion renal transplantation is the preferred modality for the treatment of esrd. if possible, pre-emptive renal transplantation, which is transplantation before the need for dialysis, shows better results than early renal transplantation. the analysis of our pediatric renal transplant patient data reveals a predominant demographic within the age bracket of 15-18 years, comprising 59.6% of the data. subsequently, the following demographic consists of patients aged between 11-14 years, representing 23.1% of the total, while those under 10 years old account for 17.3%. this distribution of age segments aligns with the conclusions drawn from a study conducted by chacko and colleagues. their findings similarly underscore a prevalence of older pediatric recipients in renal transplantation, with a mean age of 15 years. consequently, it suggests a propensity for renal transplantation among older children and adolescents (7). in terms of gender distribution, our data showed that 75% of the patients (n = 39) were male while only 25% were female (n = 13). in accordance with the data recorded in the north american pediatric renal trials and collaborative studies (naprtcs) registry, it has been observed that there exists an inverse correlation between the age group of patients and the male-to-female ratio. specifically, as the age group of patients advances, the ratio of male to female patients tends to decrease. during infancy, the male patients made up 70% of the naprtcs data. at ≥ 18-year-old, this ratio decreases to 54.3% for males and 45.7% for female (8). chacko et al. also found a disparity in male to female ratio in pediatric renal transplantation, where 65% of the patients in their study were male and only 35% were female (7). this was in contrast to a study by barlas et al., in which a gender disparity was not as obvious and only 51.2% of their data were male (9). also, in a paper by kavas and colleagues, out of 37 patients, 20 of them were male and 17 were female (10). in a study conducted by hogan and colleagues that investigated gender disparities in access to pre-emptive pediatric renal transplantation in europe, revealed a significant gender disparity, indicating that girls were 23% less likely to undergo a pre-emptive renal transplant when compared to boys. this outcome underscores the existence of genderrelated discrepancies in the accessibility of pre-emptive renal transplantation within the pediatric population in europe, warranting further exploration into the factors contributing to this observed disparity (11). the most common cause of renal failure in our patients was reflux nephropathy which accounted for 21.2% of the patients. while the second most common cause was focal segmental glomerulosclerosis (fsgs) which accounted for 17.3% of the patients. in accordance with the naprtcs registry, it is noteworthy to underscore that renal dysplasia in infants emerges as the predominant etiology of renal failure within the pediatric age group. however, as age advances, the probability of renal dysplasia serving as the primary causative factor for renal failure diminishes. notably, upon reaching the age of 18 years and beyond, focal segmental glomerulosclerosis (fsgs) emerges as the predominant cause of renal failure. subsequently, obstructive uropathy ranks second in prevalence, while renal dysplasia occupies the third position in the hierarchy of causative factors for renal failure (8). our findings were in contrast to a paper by kavaz et al. where the most common cause of esrd was juvenile nephronophthisis (n = 11 out of 37 patients). reflux nephropathy was found to be the cause of renal failure in only 2 patients and focal segmental glomerulosclerosis was determined to the cause in 4 patients (10). in the study conducted by barlas and colleagues, it was identified that vesicoureteral reflux and primary glomerular disease were the predominant etiologies leading to esrd (9). the similarity in our findings prompts questions regarding whether the high prevalence of reflux nephropathy and primary glomerular disease as primary causes of esrd is attributable to a smaller sample size within our centers, or if it is a consequence of the geographic proximity of the two centers, where both are located in neighboring countries. while most of our patients had no complication post-operatively, the most common complication in our data proved to be urinary tract infection which accounted for 9.6% (n = 5) of our complications. the most common complications in a study by beetz et al. were vascular complications for which 34 (15.4%) patients needed surgical revision of their transplantations. also, urinary tract infections accounted for 6.3% of their overall complications (3). hemorrhage non-urological causes alport syndrome 4 (7.7) b.k. nephropathy 1 (1.9) fsgs 9 (17.3) iga nephropathy 5 (9.6) minimal change disease 5 (9.6) nephronophthisis 3 (5.8) nephrotic syndrome 1 (1.9) primary hyperoxaluria 2 (3.8) renal dysplasia 3 (5.8) wegner granulomatosis 1 (1.9) unknown cause 5 (9.6) surgical technique number of arteries graft kidney single 46 (88.5) double 6 (11.5) artery anastomosis external iliac end to side 33 (63.5) common iliac end to side 19 (36.5) vein anastomosis external iliac end to side 38 (73.1) common iliac end to side 12 (23.1) ivc end to side 2 (3.8) ureter anastomosis lich gregoir 52 (100) post-operative data poc urinary tract infection 5 (9.6) cmv colitis 2 (3.8) bleeding 2 (3.8) drug-induced press 1 (1.9) chest infection 1 (1.9) no significant complication 41 (79) rejection one episode of rejection 3 (5.8) no rejection 49 (94.2) archivio italiano di urologia e andrologia 2024; 96(2):12389 s. hama amin said, s. hayas agha, g. fryad abdulla, et al. 4 accounted for 3.8% of our complications. this goes in line with the complications of a study done by irtan et al., where only 2 out of 202 patients had hemorrhage (12). the difference among these numbers could be explained by the difference in sample size, where beetz et al. had a larger sample size of 221 patients and irtan et al. had a sample size of 202 patients (3, 12). the main limitation of our study was a lack of a comparison group, hence correlating the preoperative variables to graft survival could not be done appropriately and establishing causations was not possible. the sample size was small and cannot be generalized for the whole population. also, the retrospective nature of the study is another limitation. conclusions renal transplantation is the preferred treatment of renal failure in pediatric patients in the city of sulaymaniyah. the most common etiology for pediatric renal failure was reflux nephropathy which was different from the findings of naprtcs. references 1. ghelichi-ghojogh m, mohammadizadeh f, jafari f, et al. the global survival rate of graft and patient in kidney transplantation of children: a systematic review and meta-analysis. bmc pediatr 2022; 22:503. 2. agerskov h, thiesson hc, pedersen bd. everyday life experiences in families with a child with kidney disease. j ren care. 2019; 45:205-211. 3. beetz o, weigle ca, nogly r, et al. surgical complications in pediatric kidney transplantation-incidence, risk factors, and effects on graft survival: a retrospective single-center study. pediatr transplant. 2021; 25:e13871. 4. naderi g, latif a, karimi s, et al. the long-term outcome of pediatric kidney transplantation in iran: results of a 25-year single-center cohort study. int j organ transplant med. 2017; 8:85-96. 5. loes oomen, huib de jong, antonia hm bouts, et al. a pre-transplantation risk assessment tool for graft survival in dutch pediatric kidney recipients. clin kidney j. 2023; 16:1122-1131. 6. clavien pa, barkun j, de oliveira ml, et al. the clavien-dindo classification of surgical complications: five-year experience. ann surg. 2009; 250:187-96. 7. chacko b, rajamanickam t, neelakantan n, et al. pediatric renal transplantation--a single center experience of 15 yr from india. pediatr transplant. 2007; 11:844-9. 8. chua a, cramer c, moudgil a, et al. naprtcs investigators. kidney transplant practice patterns and outcome benchmarks over 30 years: the 2018 report of the naprtcs. pediatr transplant. 2019; 23:e13597. 9. barlas is, demir m, akin eb. a single-center nine-year experience in pediatric kidney transplantation. cumhuriyet medical journal. 2020; 42:126-35. 10. hogan j, couchoud c, bonthuis m, et al. espn/era-edta registry. gender disparities in access to pediatric renal transplantation in europe: data from the espn/era-edta registry. am j transplant. 2016; 16:2097-105. 11. kavaz a, özçakar zb, bulum b, et al. pediatric renal transplantation: a single center experience. transplant proc. 2008; 40:1095-8. 12. irtan s, maisin a, baudouin v, et al. renal transplantation in children: critical analysis of age related surgical complications. pediatr transplant. 2010; 14:512-9. correspondence shakhawan said, md shakhwan.said@gmail.com saiwan agha, md saiwan.agha@gmail.com goran abdullah, md goran.abdullah@gmail.com mzhda jafaar, md mzhda.jafaar@gmail.com nali hama, md nali.hama12@gmail.com ismaeel aghaways, md ismaeelagha@hotmail.com aso rashid, md aso.rashid@univsul.edu.iq fahmi kakamad, md (corresponding author) fahmi.hussein@univsul.edu.iq college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq doctors city, building 11, apartment 50, sulaimani, 46001 iraq rawa bapir, md dr.rawa@yahoo.com berun abdalla, md berun.anwer95@gmail.com smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq conflict of interest: the authors declare no potential conflict of interest. stesura seveso 515archivio italiano di urologia e andrologia 2022; 94, 4 letter to editor no conflict of interest declared. key words: pediatric urology; urology; children; italy; position paper. submitted 4 april 2022; accepted 6 april 2022 to the editor, the aim of this “position paper” is to describe the discipline of pediatric urology with its clinical and cultural competencies, represent the reasons for legitimizing its existence, and reinforce its importance in the “scenario” of the national italian healthcare system. the requisites and the educational requirements were defined by both the italian ministry of health with the state-regions conference, and the european union. definition and requirements pediatric urology (discipline code 48 ministerial decree 05 december 2006) deals with the congenital and acquired diseases and disorders of the urinary and genital systems, at every pediatric age, from the fetal and neonatal age as far as the adolescence. in collaboration and synergy with adult specialties, pediatric urology continues to deal with the assistance of the patients “becoming adults”, in their process of “transitional care” and thereafter long-life (1). the national needs for pediatric urology services in italy have been defined in the ministerial decree of 02 april 2015 (italian official gazette n. 70 of 04 june 2015) (2): it was recognized as “medium” level of healthcare regarding the allocation of human resources (doctors, nurses), similarly to others surgical specialties. it was also calculated a population basin of 4-6 millions of inhabitants for each pediatric urology unit, therefore a total of 10-15 units nationwide, a parameter that substantially matches the current existing situation (16 units). the same 2015 ministerial document indicates the need for pediatric surgery units, which are currently twice as many as expected. a further consideration comes from the international definitions of the pediatric networks, and of the pathways to treat uro-genital malformations by reconstructive/substitution surgery. there is a tendency to refer the complex and “rare” conditions to a few “hub” centers, which are able to provide the needed specialized services and reference sub-disciplines. this trend has been acknowledged by the italian state-regions conference (agreement of december 21, 2017 guidelines to promote and ameliorate the quality, security, and appropriateness of treatment interventions in the pediatric-adolescent area). pediatric urology as a sub-specialty the origin of pediatric urology is traced back to great britain during the 1960s, while a more structured development occurred also in north america and northern europe during the seventies (3). at that time, the necessities were mainly dictated by the young age of the patients (children and newborns), requiring expertise in working with fragile structures, the discipline of pediatric urology: prerogatives and necessities “position paper” written by the italian society urology (società italiana urologia, siu) and the italian society pediatric urology (società italiana urologia pediatrica, siup) walter artibani 1, luca carmignani 2, giuseppe carrieri 3, marco castagnetti 4, giuseppe cretì 5, mario de gennaro 6, gianantonio manzoni 7, lorenzo masieri 8, francesco porpiglia 9, roberto m. scarpa 10 1 segretario generale siu 2018-2021; 2 comitato esecutivo siu 2018-2021, responsabile ufficio ricerca; 3 comitato esecutivo siu 2018-2021, responsabile ufficio educazionale; 4 gdl siu urologia pediatrica 2018-2021 e consiglio direttivo siup 2020-21; 5 consiglio direttivo siup, presidente eletto 2022-23; 6 coordinatore gdl siu urologia pediatrica 2018-2021; 7 presidente siup 2020-21; 8 gdl siu urologia pediatrica 2018-2021 e consiglio direttivo siup 2020-21; 9 comitato esecutivo siu 2018-2021, responsabile ufficio scientifico; 10 presidente siu 2021. doi: 10.4081/aiua.2022.4.515 archivio italiano di urologia e andrologia 2022; 94, 4 w. artibani, l. carmignani, g. carrieri, m. castagnetti, g. cretì, m. de gennaro, g. manzoni, l. masieri, f. porpiglia, r.m. scarpa 516 in “small” surgical fields, using “small” instruments; while another limitation was the high risk for general anesthesia. furthermore, the principle to be followed was the correction of any congenital malformations, at any age, thus falling under the competence of general pediatric surgeons. they were the experts of embryology (the fetus), of neonatal and pediatric development, of changes at adolescence. moreover, pediatric surgeons had also greater support from advanced neonatal/pediatric anesthesia and specialized radiology, and availability of miniaturized instruments. but, newborns and children’s survival was, at that time, the only (or main) objective when correcting congenital anomalies: little consideration was given to the dysfunction of a malformed organ and system, which on the contrary could result in clinical complications, impairments (even fatal in the long-term) and disabilities leading to poor quality of life. more recently, gradually the various pediatric surgical specialists were able to benefit from more specific training, coupled with the advent of advanced technologies within their “parent” specialties (i.e. cardiac surgery, neurosurgery, orthopedics, plastic surgery, urology, etc.). regarding urology, in parallel, some medical pediatric specialties related to urology (i.e nephrology, endocrinology) grew up, and supported pediatric urology itself by their specific competencies, as for renal transplant and the disorders of gender differentiation. thus, in the end, pediatric urology separated from pediatric surgery, to become a subspecialty in its own right, similarly to the previous development of urology as a specialty distinct from general surgery (4). by this way, most pediatric urologists could fully work with pediatric patients, paying attention to the emerging necessities of the affected children and adolescents, who legitimately were looking for a reasonable quality of life. in general, patients with congenital anomalies aspire to achieve a “normal” life, playing sports, having fun with friends and getting a fulfilling job. conversely those with genito-urinary malformations disabilities, also, wish a reasonable urinary (and fecal) continence, a regular sexual activity, sufficient fertility, and adequate maternity and paternity. for the above reasons, nowadays, the surgical correction of malformations of the genital and urinary systems has to firmly take into account the preservation of affected organs and functions. the initial purpose of saving life has changed into the perspective of the adulthood, in view of lifelong maintenance of the primary functions and continuous management of the condition itself. clinical pathways and regular follow-up toward adulthood are of paramount importance and should be shared among the different pediatric and adult specialists. this process of moving from pediatric to adult healthcare, known as “transition of care”, is even more compelling, as is the training of general urologists in the reconstructive and corrective surgery of malformations in functional terms (5, 6). related disciplines the principal relationship of pediatric urology is with urology, due to technological innovations and for the competence in adults looking at the transitional care; while the collaboration with pediatric surgery relates to the association between genito-urinary and other apparatus malformations, such as anorectal anomalies. furthermore, clinical relationships with the following medical sub-specialties are required, to obtain a complete and firstclass assistance: – pediatric nephrology, for renal function aspects and kidney replacement therapy (transplant) – neonatology, for specific neonatal assistance of patients with complex anomalies – fetal medicine, for antenatal diagnosis/counselling and selective fetal interventions – pediatric endocrinology, for genital diseases in general, and especially for differences of sex development (dsd) the advanced center of pediatric urology should also offer availability for some specialized activities and procedures which are very common for adults but rarely used for children: they should have easy and structured access to endourology (stone centers), neuro-urology (spinal units, incontinence referral centers), robotic surgery, interventional radiology. uro-genital diseases and malformations the urinary and genital malformations are the most frequent (3.1 0/00 live births), following cardiac (6.5 0/00) and limbs (3.8 0/00) defects [data from the eurocat 2010 study, conducted on 1.5 million of births in 22 european countries]. they may affect continence and fertility. the most complex anomalies are exstrophy-epispadias, posterior urethral valves, neurogenic bladder, ano-rectal malformations, all affecting continence; while the most frequent are hypospadias and cryptorchidism, potentially affecting fertility. surgical correction should save functions of the patient becoming adult, who has the hope to enjoy his/her own social, sportive, working, procreative and emotional life. other fields of interest are the not-malformative urinary and genital diseases: neuropathic bladder and neurogenic dysfunction, urinary calculi, tumors of urogenital tracts, vesicoureteral reflux, vesical and perineal dysfunctions, urinary incontinence, nocturnal enuresis. guidelines for principal and more frequent diseases pertinent to pediatric urology are jointly elaborated by the european association of urology (eau) and the european society for pediatric urology (espu), and are published on the website of both siu e siup. pediatric urology in italy in italy, the development of pediatric urology began in the 1980s within the fields of general urology (i.e. padua, florence, varese) and pediatric surgery (i.e. vicenza, bologna, rome), and this led to the subsequent establishment of the first autonomous pediatric urology departments in children's hospitals, and also in general and teaching hospitals. 517archivio italiano di urologia e andrologia 2022; 94, 4 the discipline of pediatric urology: prerogatives and necessities results of the siu/siup census (2021) the italian society of urology, in collaboration with the italian society of pediatric urology in 2020 and 2021 conducted a census of the pediatric urology units in the nation, taking into consideration their assignment to general urology and/or pediatric surgery divisions, or if they were independent and affiliated to general departments, as surgery or pediatrics. the results showed a sufficient yet in-homogeneous distribution across italy. of the 16 formal departments, 10 are located in the north of the country, while 11 regions are totally devoid of a service. the majority of the pediatric hospitals have a department of pediatric urology, specifically eight out of the eleven ones nationwide (turin, milan, alessandria, trieste, florence, rome, naples, bari), with the exclusion of genoa, one of the largest pediatric institutions. of the aforementioned 16 pediatric urology departments, 11 are autonomous and 5 are divisions of pediatric surgery (3) or general urology (2) departments. there are only 4 units (milan, padua, turin, rome) offering renal transplantation within a context of tertiary care (table 1). organization and education in italy and european union organization since 2013, with the objective of reducing healthcare inequalities for everyone with rare and complex diseases, the european reference networks of centers of expertise (ern) has been identifying centers of excellence (hcp), primarily those with larger case-loads including the more complex cases. the ern on uro-recto-genital diseases and conditions, eurogen, comprises three workstreams with their own disease areas (malformative, reconstructive/functional, oncological) and provides pathways of clinical care from birth to adulthood; workstream 1 focuses on rare congenital urogenital anomalies. these centers of excellence have been recognized due to their experience, expertise, and volume of activity within the urological area, and area quite distinct from pediatric surgery. education the european union of medical specialists (uems), jointly with urologists and pediatric surgeons, has established a qualification in pediatric urology, which involves a biennial period of training in european board pediatric urology (ebpu) accredited training centers, and fellowships in european pediatric urology academy (feapu). in italy, we have 2 of the above accredited centres: the bambino gesù children hospital in rome and the foundation irccs cà granda policlinico maggiore hospital in milan. in addition, several academic schools of urology provide brief educational programs in pediatric urology inside the entire general urology program, involving periods of active training in pediatric urology departments. and the universities of milan and florence provided a professional master’s course in pediatric nephron-urology. it would be desirable that the urological society contributes to the development of the international fellowship ebpu and feapu programs. the desire is to reinforce the educational academic offer in general, in order to ensure that in italy, as in other european countries, will be possible to obtain a more structured educational program in the field of pediatric urology and transitional urological care. table 1. formalized units of pediatric urology in italy january 2022. city institution unit department/division name of the unit hosp head padova university hospital * uoc dep surgery pediatric urology gen prof f. del moro (int) torino “regina margherita” hospital * uoc dep pediatrics pediatric urology ped drsa s. gerocarni nappo milano foundation “cà granda maggiore” hospital * uoc maternal pediatric dep pediatric urology gen dr g.a. manzoni firenze “meyer” pediatric hospital uoc multidisciplinary dep pediatric urology ped prof l. masieri roma ”bambino gesù” children hospital * uoc dep surgery pediatric urology ped prof m. castagnetti roma-palidoro ”bambino gesù” children hospital * uoc dep surgery continence surgery and neurourology ped dr g. mosiello napoli “santobono” hospital uoc dep surgery pediatric urology ped dr g. di iorio bari “papa giovanni xxiii” pediatric hospital uoc pediatric surgical sciences dep pediatric surgery urological ped dr n. laricchiuta trieste “burlo garofalo” pediatric hospital uosd maternal pediatric dep pediatric surgery and urology ped dr j. schleef (int) bolzano “centrale” hospital uos urology division pediatric urology gen drsa e. comploj varese “del ponte” hospital uosd maternal pediatric dep pediatric urology gen drsa l. reali vicenza “san bortolo” hospital uos pediatric surgery div pediatric mini-invasive urology gen dr f. chiarenza (int) alessandria “arrigo” pediatric hospital uos pediatric surgery div pediatric urology ped dr l. sangiorgio milano “buzzi” pediatric hospital uos pediatric surgery div pediatric urology ped dr g. selvaggio milano “san raffaele” hospital uos urology division pediatric urology gen drsa a. lesma s. giovanni rotondo (fg) “casa sollievo sofferenza” hospital uosd dep surgery pediatric urology gen dr g. cretì uoc = complex operative unit; uos = simple operative unit; uosd = simple departmental unit; dep = department; div = division; hosp = hospital; gen = general hospital; ped = pediatric hospital; (int) = ad interim. * neonatology, pediatric nephrology and renal transplant available at the institution. archivio italiano di urologia e andrologia 2022; 94, 4 w. artibani, l. carmignani, g. carrieri, m. castagnetti, g. cretì, m. de gennaro, g. manzoni, l. masieri, f. porpiglia, r.m. scarpa 518 conclusions this document was designed looking at the following objectives: – maintain and sustain the italian pediatric urology credit, on a national and international level – clarify the affinity of the sub-specialty pediatric urology with the discipline general urology and also its proximity to the pediatric surgery discipline, even emphasizing its own autonomy – defend the existence and operativity of the already formalized pediatric urology units, its diffusion nationwide, and natural placement in children’s hospitals; and promote the institution of other units where required, on a regional and national basis – implement the educational offer, according to european standards, and encourage and help international attendance at accredited training centers in italy – promote a culture of the "referral center” for rare pathologies (e.g. bladder exstrophy) and for advanced technologies (robotic surgery, neuromodulations) – contribute to the identification of "hubs" to refer for more complex pathologies (e.g. north, centre, south), with their requirements. references 1. lambert sm. transitional care in pediatric urology. seminars in pediatric surgery. 2015; 24:73-78. doi:10.1053/j.sempedsurg.2015.01.004. 2. d.m. 70/02.04.2015: regolamento recante definizione degli standard qualitativi, strutturali, tecnologici e quantitativi relativi all’assistenza ospedaliera. venerdì 5 giugno 2015. 3. innes williams d. the history of paediatric urology: personal recollections 1948-1978. bju int. 2003; 92(suppl 1):1-3. doi:10.1046/j.1464410x.92.s1.7.x. 4. lebowitz rl. paediatric urology and uroradiology: changes in the last 25 years: paediatric urology and uroradiology. bju international. 2003; 92:7-9. doi:10.1046/j.1464-410x.92.s1.3.x. 5. ritchey ml. pediatric urology: a “grown-up” subspecialty. journal of urology. 2012; 187:7-8. doi:10.1016/j.juro.2011.10.050. 6. van batavia jp, shukla ar, joshi rs, reddy pp. pediatric urology and global health. urologic clinics of north america. 2018; 45:623-631. doi:10.1016/j.ucl.2018.06.009. correspondence walter artibani, md prof.artibani@gmail.com luca carmignani, md luca.carmignani@unimi.it giuseppe carrieri, md giuseppe.carrieri@unifg.it francesco porpiglia, md francesco.porpiglia@unito.it roberto mario scarpa, md r.scarpa@unicampus.it società italiana di urologia, via giovanni amendola 46, 00185 roma giuseppe cretì, md urologia@operapadrepio.it gianantonio manzoni, md gianantonio.manzoni@policlinico.mi.it lorenzo masieri, md lorenzo.masieri@meyer.it marco castagnetti, md marco.castagnetti@unipd.it mario de gennaro, md (corresponding author) dott.mariodegennaro@gmail.com società italiana urologia pediatrica stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14047 1 original paper detection rates for pca were overlapping, transperineal biopsy is recommended as the first-choice technique for diagnosis of prostate cancer owing to lower rates of postprocedural sepsis in comparison with transrectal approach (2); in fact, in case of transrectal biopsy the risk of complications requiring hospital admission ranges from 0.1% to 2.5% (3) in most of the cases secondary to urinary tract infection (uti), fever or sepsis. in addition, transperineal prostate biopsy improves the detection of clinically significant prostate cancer (cspca) located in the anterior zone of the gland (4) especially in men submitted to repeated biopsies or enrolled in active surveillance (as) protocols (5, 6). in men without rectum because submitted to proctocolectomy for benign or malignant diseases, prostate biopsy cannot be performed under transrectal ultrasound guidance (7, 8), moreover, transurethral prostate resection to perform pca diagnosis is not accurate and/or recommended as prostate biopsy especially for lesions located in the peripheric zone of the gland. in fact, patients presenting at an earlier stage, due to increased psa testing combined with multiparametric magnetic resonance imaging (mpmri) suspicious for pca, need systematic combined with targeted needle cores. in these cases, transperineal ultrasound-guided prostate biopsy has emerged as an alternative and unique approach (9). in this retrospective study we report the use of transcutaneous transperineal ultrasound to guide prostate biopsy in men previously submitted to pancolectomy with rectal amputation. materials and methods from january 2018 to january 2025, 10 men aged between 47 and 76 years (median age: 56 years) previously submitted to proctocolectomy (7 men for rectum cancer and 3 men for benign disease) were evaluated for the suspicion of pca. the study is retrospective and informed consent to publish was obtained before the procedure by each subject whose data were anonymized; moreover, the study was performed according to the ethical principles of the declaration of helsinki. the indications for biopsy were psa > 10 ng/ml or psa values between 4.1-10 ng/ml with free/total psa < 25% (10, 11) introduction: to evaluate the use of transcutaneous perineal ultrasound to guide prostate biopsy in men previously submitted to rectal amputation. materials and methods: from january 2018 to january 2025, 10 men aged between 47 and 76 years (median age: 56 years) previously submitted to proctocolectomy (7 men for rectum cancer and 3 men for benign disease) were evaluated for the suspicion of prostate cancer (pca). the indications for biopsy were psa > 10 ng/ml or psa values between 4.1-10 ng/ml with free/total psa < 25% and/or psa density > 0.20. all the patients submitted for the first time to biopsy underwent extended scheme (epbx: 12-18 cores); in addition, all the patients underwent multiparametric magnetic resonance (mpmri) and in the presence of a prostate imaging-reporting and data system-version 2 (pi-rads) score ≥ 3 a cognitive targeted biopsy (tpbx: 4 cores) was added to systematic prostate biopsy. biopsies were freehand using 18-gauge automatic biopsy needles under perineal real-time ultrasound guidance (3.5 mhz convex probe). results: median psa was 9.7 (range: 4.8-27 ng/ml); in 1/10 (10%) patient mpmri was negative, conversely in 3 (30%) vs. 3 (30%) vs. 3 (30%) men pirads score was 3 vs. 4 vs. 5, respectively. overall, a cspca (isupgrade group > 2/gleason score > 3+4) was found in 5/10 (50%) patients; pca was located in the peripheric zone in 4 (80%) cases and 1 (20%) case in the anterior zone of the gland. in detail, epbx vs. tpbx biopsies diagnosed 5/5 (100%) and 4/5 (90%) cspca. one patient diagnosed with cspca had negative mpmri, 1 and 3 men had pirads score 4 and 5, respectively. none had clinical complications that needed hospital admission. conclusions: transcutaneous perineal ultrasound-guided prostate biopsy allows to perform accurate systematic and targeted biopsies in men with suspicious pca previously submitted to rectal amputation. key words: prostate cancer; transcutaneous perineal ultrasound guided prostate biopsy; abdominoperineal resection; prostate biopsy. submitted 1 june 2025; accepted 5 june 2025 introduction prostate cancer (pca) is the most frequent tumor diagnosed in men with about 2 million procedures carried out in the united states and europe every year (1). although transcutaneous perineal-ultrasound guided prostate biopsy in men with rectal amputation pietro pepe 1, ludovica pepe 2, vincenzo fiorentino 2, mara curduman 3, filippo fraggetta 4 1 urology unit, cannizzaro hospital, catania, italy; 2 department of human pathology in adult and developmental age “gaetano barresi”, university of messina, messina, italy; 3 pathology unit, cannizzaro hospital, catania, italy; 4 pathology unit, gravina and s. pietro hospital, caltagirone (ct), italy. doi: 10.4081/aiua.2025.14047 summary archivio italiano di urologia e andrologia 2025; 97(3):14047 p. pepe, l. pepe, v. fiorentino, m. curduman, f. fraggetta 2 and/or psa density > 0.20 (12). all the patients underwent mpmri evaluation, moreover, in all cases digital rectal examination was not performed because rectum amputation. all mpmri examinations were performed using a 1.5 or 3.0 tesla scanner, (achieva 3t; philips healthcare best, the netherlands) equipped with a 16channel phased-array coil placed around the pelvic area with the patient in the supine position; a multi-planar turbo spin-echo t2-weighted, an axial diffusion weighted imaging and an axial dynamic contrast enhanced mri were obtained (13). all the patients submitted for the first time to biopsy underwent extended scheme (epbx: 12-18 cores) (14); in addition, in the presence of a prostate imaging-reporting and data system-version 2 (pi-rads) score ≥ 3, a cognitive targeted biopsy (tpbx: 4 cores) was added to systematic prostate biopsy (15). all the patients underwent biopsy under sedation and antibiotic prophylaxis (a single intravenous dose of 2 grams of cefazolin). the perineal skin was disinfected using iodophor, the prostate was examined to determine the puncture sites and paths using transperineal ultrasound. biopsies were performed using 18-gauge automatic biopsy needles (figure 1) under perineal real-time ultrasound guidance by a 3.5 mhz convex probe. results median psa was 9.7 (range: 4.8-27 ng/ml); in 1/10 (10%) patient mpmri was negative, conversely in 3 (30%) vs. 3 (30%) vs. 3 (30%) men pirads score was 3 vs. 4 vs. 5, respectively. overall, a cspca (grade group 2/gleason score ≥ 3 + 4) was found in 5/10 (50%) patients, whereas 5 (50%) men had a normal parenchyma. overall, clinical parameters and histological findings in presence of pca are listed in table 1; 4/5 (80%) cspca were located in peripheric zone and 1 (20%) in the anterior zone of the gland. in detail, epbx vs. tpbx biopsies diagnosed 5/5 (100%) and 4/5 (90%) cspca. one patient with cspca had negative mpmri, one had pirads score 4 and 3 men pirads score 5 (100%), respectively. none had clinical complications that needed hospital admission. discussion in the last years, with the use of psa and derivatives (11) combined with mpmri (16), psma pet/ct (17-19) or genetic (20-24) evaluation the necessity to improve the accuracy of prostate biopsy and to reduce the number of unnecessary procedures has increased (25, 26). the management of the patient with an elevated psa and no recfigure 1. transcutaneous perineal ultrasound-guided prostate biopsy. a convex probe (3.5 mhz) is located upon perineal skin to guide transperineal biopsy (white arrow) of the left prostatic lobe (a: anterior biopsy; b: peripheric biopsy). table 1. clinical and histological characteristics of prostate cancer in 5 patients submitted to transcutaneous perineal ultrasound-guided prostate biopsy. clinical parameters 5 cases median psa (range) 15.2 ng/ml (7.4-27) isup gg3/gleason score 4+3 (1 case) pi-rads score 2 isup gg3/gleason score 4+3 (1 cases) pi-rads score 4 isup gg3/gleason score 4+5 (3 cases) pi-rads score 5 median mpmri index lesion diameter 12 millimeter (range) (7-20) detection of cspca (isup gg > 2) 5 (100%) systematic prostate biopsy 5/5 (100%) tpbx 4/5 (80%) median number of positive cores (range) 6 (4-9) tpbx 2 (0-4) systematic biopsy 5 (5-7) median gpc (range) 65% tpbx 60% (0-100%) systematic biopsy 70% (50-100%) psa density (range) 0.21 (0.16-0.26) psa free/total (range) 12% (7-31%) median prostate weight (grams) 45 (20-115 grams) psa: prostate specific antigen; tpbx: targeted cognitive fusion biopsy; pi-rads (prostate imaging-reporting and data system); gg: grade groups isup (international society of urological pathology); cspca: clinically significant prostate cancer. a. b. archivio italiano di urologia e andrologia 2025; 97(3):14047 3 transcutaneous perineal-ultrasound guided prostate biopsy tum is challenging for the urologist; few authors have reported different approaches in obtaining prostate biopsy specimens in patients post abdominoperineal resection such as ct guided random or transgluteal targeted biopsies (27), transurethral ultrasound or transabdominal ultrasound guidance. mcnhicolas et al. (10) reported their technique to perform prostate biopsy in men submitted to panproctocolectomy: after patient catheterization and by using anatomical surface landmarks, placing traction on the catheter to bring the balloon to the level of the bladder neck and using fluoroscopy, the distance to the apical prostate was estimated and transperineal prostate biopsies were performed. amin et al. (28) used in one patient an endocavitary biplane ultrasound transducer with a transperineal biopsy grid with the ultrasound placed at a 45° angle to the patient invaginating the patients perineum, such that ultrasound images were able to capture the prostate; park et al. (29) in 9 men with pirads score 5 performed transperineal cognitive targeted biopsies guided by endfire endo-cavity transducer placed on perineum diagnosing pca in 7/9 (77.8%) cases. on the other hand, transabdominal ultrasound biopsy of prostate could be associated to the risks injury of the bowel and/or dorsal vein complex and may miss peripheral zone tumours (30). in our series, we used convex probe located upon perineal skin surface to guide transperineal biopsies and the detection rate for cspca was equal to 50% of the cases; in detail, systematic vs. tpbx diagnosed 100 vs. 80% of the cancers without clinical complications that needed hospitalization. the approach allowed, at the same time, to perform accurate peripheric vs. anterior biopsies; moreover, in men with cspca, median psa was 15.2 ng/ml and the better biopsy accuracy was achieved in men with pirads score 5 (100% of the cases). some limitations and considerations of the present study deserve mention. first, the detection rate for pca was evaluated in biopsy specimen and not in the entire gland; secondly, the biopsy accuracy, probably, might have been lower in the presence of earlier pca stage characterized by smaller cancer volume. third, systematic or perilesional prostate biopsy should be always combined with targeted cores to improve the diagnosis of cspca (31). four, in the next future, the use of artificial intelligence programs (32, 33) combined with genetic evaluation (34, 35) and more accurate imaging (18, 36-38) could better select men at risk for cspca and improve prostate biopsy procedure. finally, the number of patients evaluated in our series is low. in conclusion, transcutaneous perineal ultrasound-guided prostate biopsy allows to perform accurate systematic and targeted biopsies in men with suspicious pca previously submitted to rectal amputation. references 1. bergengren o, pekala kr, matsoukas k, et al. update on prostate cancer epidemiology and risk factors-a systematic review. eur urol 2023; 84:191-206. 2. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8.500 men. arch ital urol androl 2022; 94:155-159. 3. derin o, fonseca l, sanchez-salas r, roberts mj. infectious complications of prostate biopsy: winning battles but not war. world j urol 2020; 38:2743-2753. 4. pepe p, dibenedetto g, pennisi m, et al. detection rate of anterior prostate cancer in 226 patients submitted to initial and repeat transperineal biopsy. urol int 2014; 93:189-192. 5. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsies in men enrolled in active surveillance protocols? j clin med. 2022; 11:3473. 6. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol 2017; 51:260-263. 7. filderman ps, jacobs sc. prostatic ultrasound in the patient without a rectum. urology 1994; 43:722-724. 8. schapira he: prostatic needle biopsy in patients after abdominoperineal resection. urology 1982; 20:76-77. 9. mcnicholas dp, parr nj. image intensifier-guided transperineal prostate biopsy for patients without a rectum: novel technique. bju int 2024; 133:487-490. 10. aragona f, pepe p, motta m, et al. incidence of prostate cancer in sicily: results of a multicenter case-findings protocol. eur urol 2005; 47:569-74. 11. pepe p, aragona f. incidence of insignificant prostate cancer using free/total psa: results of a case-finding protocol on 14,453 patients. prostate cancer prostatic dis. 2010; 13:316-319. 12. roscigno m, stabile a, lughezzani g, et al the use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. 13. pepe p, d'urso d, garufi a, et al. multiparametric mri apparent diffusion coefficient (adc) accuracy in diagnosing clinically significant prostate cancer. in vivo 2017; 31:415-418. declarations ethical approval: institutional review board and ethical committee approval were granted and the informed consent was obtained from all individual participants included in the study. consent for publication: all authors have read and approved the content and agree to submit for consideration for publication in the journal. availability of data and material: the data that supports the findings of this study are available from the corresponding author upon reasonable request. competing interests: the authors declare that there is no conflict of interest. funding: none. authors' contributions: conceptualization: p.p., p.l., f.v; investigation: p.p., p.l., f.v; data curation: p.p., p.l., f.v.; formal analysis: p.p., p.l., f.v; methodology: p.p., p.l., f.v, c.m., f.f.; resources: p.p., p.l., f.v, c.m., f.f.; software: p.p., p.l., f.v; writing original draft: v.s.,p.p., p.l.; writing review & editing: p.p., p.l., f.v, c.m., f.f. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):14047 p. pepe, l. pepe, v. fiorentino, m. curduman, f. fraggetta 4 14. pepe p, aragona f. prostate needle biopsy: 12 vs. 18 cores is it necessary? urol int 2005; 74:19-22. 15. pepe p, pennisi m, fraggetta f. how many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? experience in 875 patients submitted to repeat prostate biopsy. urology 2020; 137:133-137. 16. pepe p, dibenedetto g, pepe l, pennisi m. multiparametric mri versus selectmdx accuracy in the diagnosis of clinically significant pca in men enrolled in active surveillance. in vivo 2020; 34:393396. 17. pepe p, pennisi m. targeted biopsy in men high risk for prostate cancer: 68ga-psma pet/ct versus mpmri. clin genitourin cancer 2023; 21: 639-642. 18. pepe p, pepe l, tamburo m, et al. 68ga-psma pet/ct and prostate cancer diagnosis: which suvmax value? in vivo 2023; 37:1318-1322. 19. pepe p, pepe l, tamburo m, et al. 68ga-psma pet/ct evaluation in men enrolled in prostate cancer active surveillance. arch ital urol androl. 2023; 95:11322. 20. pepe p, fraggetta f, galia a, et al. pca3 score and prostate cancer diagnosis at repeated saturation biopsy. which cut-off: 20 or 35? int braz j urol 2012; 38:489-995. 21. pepe p, aragona f. pca3 score vs psa free/total accuracy in prostate cancer diagnosis at repeat saturation biopsy. anticancer res 2011; 31:4445-4449. 22. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl 2020; 92:209-210. 23. fiorentino v, pepe l, pizzimenti c, et al. pd-l1 expression in prostate cancer and gleason grade group: is there any relationship? findings from a multi-institutional cohort. pathol res pract. 2025; 269:155916. 24. fiorentino v, martini m, dell'aquila m, et al. histopathological ratios to predict gleason score agreement between biopsy and radical prostatectomy. diagnostics (basel). 2020; 11:10. 25. pepe p, pepe l, panella p, pennisi m. can multiparametric ultrasound improve cognitive mri/trus fusion prostate biopsy. arch ital urol androl. 2020; 92:89-92. 26. pepe p, pepe l, tamburo m, et al. targeted prostate biopsy: 68ga-psma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl 2022; 94:274-277. 27. patel n, coakley fv, foster br. performance of transgluteal ctguided biopsy of prostate lesions in men without rectal access: a retrospective study. clin imaging 2021; 79:225-229. 28. amin a, blazevski a, scheltema m, stricker p. transperineal biopsy of the prostate in a patient post abdominoperineal resection. urol case rep. 2019; 28:101055. 29. park bk, chung jh, song w, et al. new transperineal ultrasound-guided biopsy for men in whom psa is increasing after miles' operation. insights imaging. 2023; 14:42. 30. seaman ek, sawczuk is, fatal m, et al. transperineal prostate needle biopsy guided by transurethral ultrasound in patients without a rectum. urology 1996; 47:353-355. 31. pepe p, pepe l, fiorentino v, et al. multiparametric mri targeted biopsy: when omit systematic biopsy? arch ital urol androl 2024; 96:12992. 32. caputo a, maffei e, gupta n, et al. computer-assisted diagnosis to improve diagnostic pathology: a review. indian j pathol microbiol. 2025; 68:3-10. 33. ström p, kartasalo k, olsson h, et al. artificial intelligence for diagnosis and grading of prostate cancer in biopsies: a populationbased, diagnostic study. lancet oncol. 2020; 21:222-232. 34. vatrano s, pepe p, pepe l, et al. brca mutations and prostate cancer: should urologist improve daily clinical practice? arch ital urol androl. 2025:13635. 35. pecci v, troisi f, aiello a, et al. targeting of h19/cell adhesion molecules circuitry by gsk-j4 epidrug inhibits metastatic progression in prostate cancer. cancer cell int. 2024; 24:56. 36. kinnaird a, luger f, cash h, and optimum investigators. microultrasonography-guided vs mri-guided biopsy for prostate cancer diagnosis: the optimum randomized clinical trial. jama. 2025; 333:1679-1687. 37. fandella a, scattoni v, galosi a, et al. italian prostate biopsies group: 2016 updated guidelines insights. anticancer res. 2017; 37:413-424. 38. xiao y, zeng y, han l, et al. a novel simplified transperineal prostate biopsy guided by perineal ultrasound. br j radiol 2024; 97:1351-1356. correspondence pietro pepe, md (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital, via messina 829, catania (italy) ludovica pepe, md ludopepe97@gmail.com vincenzo fiorentino, md vincenzo.fiorentino@unime.it department of human pathology in adult and developmental age “gaetano barresi”, university of messina, messina, (italy) mara curduman, md mara.curduman@aoec.it pathology unit, cannizzaro hospital, catania (italy) filippo fraggetta, md filippofra@hotmail.com pathology unit, gravina and s. pietro hospital, caltagirone (ct), italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12704 1 original paper tries (1, 2). this procedure can be performed by patients, non-professionals, or medical personnel and can present severe consequences in cases of complications (3), including penile deformity, skin necrosis, limited erection due to pressure, and pain during sex (4). the definitive therapy is to remove the entire skin and subcutaneous tissue and resurface the penile shaft (5). the technique can be single-staged (simple excision and primary closure, bilateral scrotal flap, one-sheet spiraling full-thickness skin graft, scrotal tunnel + inverted v incision and anastomosis inverted y technique), or multistaged (6-8). erectile function is assessed by measuring erection hardness using the erection hardness score (ehs), which provides specific and readily monitored results (9). in this study, we report our experience in performing treatment on penile paraffinoma patients using the scrotal tunnel + ventral inverted v incision + anastomosis inverted y technique, along with the esthetics and functional outcome of the procedure. materials and methods we performed a single-center retrospective descriptive study using data collected from january 2013 to december 2023 from patients who underwent single-stage scrotal tunnel + ventral inverted v-incision and anastomosis inverted y-shape procedures (figure 1). figure 2 provides a conceptual illustration of the technique. data on the chief complaint, reason for the injection, type of fluid injected, duration of surgery, duration of hospitalization, length of follow-up, and results after surgery were collected. the inclusion criteria were as follows: [1] new patient and [2] penile paraffinoma performed in a single stage. exclusion criteria were [1] penile paraffinoma that affected the skin of the penis and greater than half of the skin of the scrotum, [2] presence of malignancy, and [3] penile paraffinoma coexisting with diabetes mellitus. introduction and objective: penis enlargement through substance injection is common in many countries of southeast asia and eastern europe. the definitive therapy involves removing the entire skin and the subcutaneous tissue and resurfacing the penile shaft via a singlestage or multi-staged procedure. this study aimed to report the functional outcome and esthetics of treating penile paraffinoma patients using the scrotal tunnel + ventral inverted v incision + anastomosis inverted y technique. materials and methods: this study was a single-center retrospective descriptive analysis of patients who underwent onestage scrotal tunnel + ventral inverted v incision and inverted y-shaped anastomosis procedures from january 2013 to december 2023. the following data were collected: chief complaint, reason for the injection, type of fluid injected, duration of surgery, duration of hospitalization, length of follow-up, and results after surgery. results: of the 32 patients included in the study, 78% injected liquids in the form of oil and the goal of the majority of patients was penis enlargement (71%). the average age was 36.84 years, and the main complaint was pain in the penis during erection (53%). the average operation time was 130 minutes, hospitalization duration was 2.21 days, primary wound healing was 91%, patient satisfaction level was 97%, and scale 4 erection hardness was 91%. conclusions: one-stage surgery for penile paraffinoma produced promising results when the granuloma was limited to the penis and healthy scrotal skin was available to cover the penis. key words: penile paraffinoma; surgery; one stage; scrotal flap; functional outcome. submitted 2 june 2024; accepted 11 july 2024 introduction penis enlargement through the injection of substances (paraffin, oil, cod liver oil, petroleum jelly, silicone, methacrylates, hyaluronic acid, or collagen patches) is common in southeast asian and eastern european counfunctional outcome of the one-stage scrotal tunnel + ventral inverted v incision + inverted y anastomosis technique to treat penile paraffinoma: a single center retrospective study muhammad asykar palinrungi 1, syakri syahrir 2, syarif 1, andhini l.r. palinrungi 3, muhammad faruk 4 1 department of urology, faculty of medicine, hasanuddin university hasanuddin university hospital, makassar, south sulawesi, indonesia; 2 department of urology, faculty of medicine, hasanuddin university dr. wahidin sudirohusodo hospital, makassar, south sulawesi, indonesia; 3 department of surgery, akademis jaury jusuf putra hospital, makassar, south sulawesi, indonesia; 4 department of surgery, faculty of medicine, hasanuddin university hasanuddin university hospital, makassar, south sulawesi, indonesia. doi: 10.4081/aiua.2024.12704 summary archivio italiano di urologia e andrologia 2024; 96(3):12704 m. asykar palinrungi, s. syahrir, syarif, et al. 2 figure 1. step-by-step representation of the operative stage. onestage surgical excision steps with scrotal tunnel + ventral inverted v-incision and anastomosis inverted y-shape. a) after the skin of the penis is removed, b) the creation of the tunneling exit hole, c) after the penis is passed under the skin and the glans protrudes from the prepared hole (penile scrotal invagination), d) appearance after suturing, e) inverted v-incision, and f) after suturing into inverted y-shape. figure 2. a conceptual illustration of the one-stage surgical excision steps with scrotal tunnel + ventral inverted v-incision and inverted y-shaped anastomosis. a) paraffinoma in the shaft of the penis, b) excision of the entire paraffinoma in the penile shaft, c) naked penile shaft after the skin is excised, d) measurement of the scrotal tunnel for scrotal flap creation, e) creation of a hole in the scrotum, f) insertion of the penis into the scrotum hole to cover the penis with the skin of the scrotum (penile scrotal invagination), g) inverted v-incision on the ventral penis, and h) inverted y-shaped suture. archivio italiano di urologia e andrologia 2024; 96(3):12704 3 technique to treat penile paraffinoma this study followed the strengthening the reporting of observational studies in epidemiology (strobe) reporting guideline. informed consent was obtained from all patients and this study was approved by the ethics committee of hasanuddin university, makassar, indonesia (no. 304/un4.6.4.5.31/pp36/2024) with protocol no. uh24040277. the five-grade ehs was used to assess erection rigidity [grade 0 (no enlargement of the penis), grade 1 (penis enlarges but does not become firm), grade 2 (penis is hard, but not hard enough to penetrate), grade 3 (penis is hard enough for penetration but not completely hard), and grade 4 (penis is completely stiff and firm)]. a score of two or less was considered an abnormal ehs (10). results the 32 patients included in this study had an average age of 36.84 years and an average length of hospital stay of 2.21 days. most patients had a history of silicone, oil, or paraffin injections with the main aim of enlarging the penis. the characteristics of the data are listed in table 1. discussion the outcomes we obtained from the 32 patients were positive, whereby 29 patients recovered completely, 2 patients experienced wound infection, and 1 patient presented contractures, which we successfully excised several months later. no erection problems were noted according to the ehs, and no sexual activity issues were reported after surgery. a one-stage penile paraffinoma excision is faster and easier than a two-stage procedure (requires only one operation, which generally reduces the time for recovery and degree of pain). in addition, this method is more cost-effective (the cost is usually more affordable than a two-stage surgery), has less risk of complications (fewer incisions and tissue manipulations), and allows for a thorough evaluation (the surgeon can perform a comprehensive assessment of the penile tissue during surgery to evaluate any other problems that need to be addressed). the disadvantages of the one-stage technique are long recovery times (despite only requiring one surgery), swelling and bruising (swelling and bruising are common side effects after surgery), infection (infection is a minor but serious risk after any surgery), nerve damage (nerve damage may occur, which can cause numbness or tingling of the penis), and penile deformity (particularly when the silicone implant is large or has been in place for many years). granulomatous reactions resulting from the injection of a foreign body can accumulate in parts of the penis or spread to the entire penile shaft, supra-pubic area, and scrotum (11, 12). when complications occur, the entire foreign object and related skin should be removed to prevent the recurrence or graft loss that can occur if some residue remains (13). simple excision and primary suturing may be performed in selected cases (14); however, if the penile paraffinoma involves the entire penile shaft without extension to the suprapubic area (84% of the cases in this study) or a small amount of the scrotal area (3% of our cases), then the treatment therapy should involve a radical excision of the fibrotic tissue and the associated skin and the use of scrotal skin to close the open area. the skin of the scrotum has high elasticity, which makes it suitable for covering the penis, despite the presence of hair. most of the surgeries are successful without any complications, and the reconstructed penis has an immediate post-operative tactile sensibility (1, 2, 6, 13). the two-stage procedure for paraffinoma involves exposing the penis and inserting it into the previously created scrotal tunnel while leaving the glans exposed for urination. after a few weeks, the penis is removed from the scrotum (13). in all our cases, we performed a single-stage scrotal tunnel and inverted v incision + inverted y anastomosis after removing all parts of the penile skin along with the underlying granulomatous tissue (figure 1). this action is possible because sufficient skin in the scrotum is available to cover the penis. the average time required for this procedure is 130 minutes, while the average length of hospital stay is 2.21 days and the average follow-up is 3.4 months. lumbiganon et al. found no significant difference in surgical wound infection, wound dehiscence, or reoperation rate in the one-stage group compared to the two-stage table 1. clinical characteristics of patients. characteristic n (%) patient (n) 32 mean age (y) 36.84 reason for injection (n) enlarge the penis 23 (71) increase self-confidence 5 (16) satisfy sexual partner 4 (13) foreign body type (n) vaseline 3 (9) oil 25 (78) paraffin 4 (13) location the entire shaft of the penis 27 (84) part of the shaft of the penis 4 (13) the entire shaft of the penis + a small part of the scrotum 1 (3) reason for treatment pain during erection 17 (53) chronic wound 5 (16) difficulty during sex 7 (22) phimosis 2 (6) penile deformity 1 (3) mean operation time (min) 130 mean length of stay (d) 2.21 mean follow-up period (mo) 3.4 results after operation (n) good healing 29 (91) wound infection 2 (6) scar contracture 1 (3) satisfaction status satisfied 31 (97) not satisfied 1 (3) ehs 3 3 (9) 4 29 (91) ehs: erection hardness score. archivio italiano di urologia e andrologia 2024; 96(3):12704 m. asykar palinrungi, s. syahrir, syarif, et al. 4 group; however, the two-stage group had a longer length of stay and lower complication rate. therefore, these two techniques can be considered for reconstruction in penile paraffinoma cases (15). in addition, dellis et al. recommended one-stage surgery after the procedure was performed on 10 patients with safe and effective results (16). this study had several limitations. as a retrospective cohort study, it was subject to inherent selection and information biases. in addition, the study was conducted at a single center, which may limit the generalizability of the findings. further multicenter, prospective studies are required to validate these results and confirm whether the one-stage scrotal tunnel + ventral inverted v incision + inverted y anastomosis technique is safe and effective and can provide the appropriate functional and esthetic outcome post-surgery. conclusions single-stage surgery on penile paraffinoma can be effective when the granuloma is limited to the penis and healthy scrotal skin is available to cover the penis. acknowledgments we acknowledge ashy amelia arista for her help in providing us with the conceptual illustration of the one-stage surgical excision steps for this study. references 1. mahadewa aw, marinta y, nugraha p, lukman k. candlenut oilinduced sclerosing lipogranuloma of the penis: a case report. int j surg case rep. 2023; 110:108673. 2. marín-martínez fm, guzmán martínez-valls pl, dekalo s, et al. aesthetic and functional results after singleand two-stage resection and reconstruction of penile paraffinomas experience from two tertiary centers and a surgical management algorithm. urology. 2023; 171:227-35. 3. dellis ae, nastos k, mastorakos d, et al. minimal surgical management of penile paraffinoma after subcutaneous penile paraffin injection. arab j urol. 2017; 15:387-90. 4. shin ys, zhao c, park jk. new reconstructive surgery for penile paraffinoma to prevent necrosis of ventral penile skin. urology. 2013; 81:437-41. 5. kim js, shin ys, park jk. penile skin preservation technique for reconstruction surgery of penile paraffinoma. investig clin urol. 2019; 60:133-7. 6. dunev vr, kolev nh, genov pp. late results of bilateral scrotal flap. urol case rep. 2019; 27:100920. 7. ismy j, amirsyah m, palgunadi in, et al. one-stage reconstruction of penile paraffinoma using spiral stitches ftsg and evaluation of sexual function. plast reconstr surg glob open. 2022; 10:e4048. 8. prasetyono toh. one-sheet spiraling full thickness skin graft for penile resurfacing after paraffinoma excision. medical journal of indonesia 2011; 20: 222. 9. mulhall jp, goldstein i, bushmakin ag, et al. validation of the erection hardness score. j sex med. 2007; 4:1626-34. 10. silva ac, silva cm, morgado a. erection hardness score or penile doppler ultrasound: which is a better predictor of failure of nonsurgical treatment of erectile dysfunction? sex med. 2023; 11:qfad009. 11. downey ap, osman ni, mangera a, et al. penile paraffinoma. eur urol focus. 2019; 5:894-8. 12. svensøy jn, travers v, osther pjs. complications of penile selfinjections: investigation of 680 patients with complications following penile self-injections with mineral oil. world j urol. 2018; 36:13543. 13. putra ibow, wahyudi i, rodjani a. penile paraffinoma reconstruction with scrotal flap and surgical outcome: a case report. indonesian journal of urology. 2019; 26(1). 14. khairudin ma, salauddin sa, ghazali h. scrotal bridge flap reconstructive surgery for extensive penile paraffinoma: steps and outcomes from a single center: a case series. african journal of urology 2021; 27:113. 15. lumbiganon s, pachirat k, sirithanaphol w, et al. surgical treatment of penile foreign body granuloma: penile shaft reconstruction with singleversus two-stage scrotal flap techniques. int j urol. 2023; 30:681-7. 16. dellis ae, arkoumanis t, kyprianou c, papatsoris ag. paraffinoma, siliconoma and co: disastrous consequences of failed penile augmentation-a single-centre successful surgical management of a challenging entity. andrologia. 2018; 50:e13109. correspondence muhammad asykar palinrungi (corresponding author) apalinrungi@yahoo.com department of urology, faculty of medicine, hasanuddin university – hasanuddin university hospital, makassar, south sulawesi, indonesia jalan perintis kemerdekaan km 11, makassar, 90245, south sulawesi, indonesia syakri syahrir drsyakrisyahrir@gmail.com department of urology, faculty of medicine, hasanuddin university – dr. wahidin sudirohusodo hospital, makassar, south sulawesi, indonesia syarif syarifbakri@hotmail.com department of urology, faculty of medicine, hasanuddin university – hasanuddin university hospital, makassar, south sulawesi, indonesia andhini l. r. palinrungi dnypalinrungi@gmail.com department of surgery, akademis jaury jusuf putra hospital, makassar, south sulawesi, indonesia muhammad faruk muhammadfaruk@unhas.ac.id department of surgery, faculty of medicine, hasanuddin university – hasanuddin university hospital, makassar, south sulawesi, indonesia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12186 1 original paper world health organization (who) ejaculate analysis laboratory guidelines 2021, each standard ejaculate analysis test takes about 60 minutes, so the timing to test fructose is extended, which may affect the measurement of the level of fructose in ejaculate (3). in fact, when fructose is tested in this way, the fructose level obtained will differ from the real fructose level because the fructose in the ejaculate will undergo fructolysis. nonspecific and sensitive test results will inevitably influence the diagnosis. there are several methods to test for fructose, including colorimetric, enzymatic, and chromatographic methods (4). who used karvonen and malm's modified methods to test the amount of fructose in ejaculation (3). the manual fructose testing method has disadvantages, such as a complicated procedure with a long waiting time. since 1981, the use of semiautomatic or automatic machines for testing fructose began to develop (5). the semiautomatic machine can shorten the time to test the fructose level. the advantages of the semiautomatic fructose method include easy reagent preparation, minimal reagent use, minimal error, reduced human resources, and easy calibration and quality control processes (6). there is no standardized time and method for semi-automated fructose testing, so the researchers felt it was necessary to research to find the best timing for testing fructose in order to obtain results close to real fructose levels. in this study, we carried out the process using a bts-350 semiautomatic machine. the method used was an enzymatic method using hexokinase and phosphoglucoisomerase enzymes and then switching to a colorimetric method. the method used in bts-350 semiautomatic machines makes the processing time much faster. methods this was an observational analytic study using the ejaculates of infertile men who visited the policlinic andrology outpatient general hospital, dr. soetomo surabaya. the study was approved by the ethics committee of rsud dr. soetomo with no. 0669/kepk/v/2023. based on the sample calculation, 13 ejaculates from different men were included in this study. objective: various factors, such as obstructive azoospermia, cause infertility in men. biochemical examination of ejaculate, especially measurement of fructose, can be an additional investigation that can be used for this diagnosis in reproductive health. examination of fructose is carried out after routine ejaculate analysis, resulting in prolonging the examination time so that it will affect the measurement of fructose level in the ejaculate and the accuracy of the diagnosis. this study aims to determine the best timing and procedure for measurement of fructose using a semiautomatic method. methods: this research is an analytic observational study conducted at dr. soetomo general hospital, surabaya. a total of 13 ejaculate samples from infertile male patients who met the inclusion criteria were evaluated. each ejaculate was divided into eight aliquots that were examined for fructose using a semiautomated method after different intervals of time and centrifugation modalities. results: this study showed a significant difference in fructose levels when aliquots were centrifuged and examined immediately or after different interval of time (p = 0.036). in addition, aliquots left standing for more than 60 minutes (p = 0.012) and 120 minutes (p < 0.001) before centrifugation, showed significantly lower levels compared to aliquots that were centrifuged and then immediately examined. conclusions: we suggest that measuring fructose immediately after centrifugation is more reliable than measuring fructose left standing before or after centrifugation. leaving the ejaculate standing will reduce the fructose level so that it does not resemble its real level. key words: infertile; fructose; semiautomatic; time; centrifugation; reproductive health. submitted 13 december 2023; accepted 4 january 2024 introduction the fructose examination is one of the biochemical tests used to diagnose the cause of male infertility (1). it is not a routine test, but it is a useful supplemental test to provide information on specific clinical conditions, that is done after routine testing ejaculate analysis (2). according to examination of ejaculate fructose levels on male infertility patients at various times and centrifugation using semiautomatic method hermansyah hermansyah 1, 3*, muhammad fadhli abdullah 1, 3*, cennikon pakpahan 1, 2, 3*, reny i’tishom 1, 2, supardi supardi 1, 3, ilhamsyah ilhamsyah 1, 3 1 andrology study program, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia; 3 andrology outpatient clinic, general academic dr. soetomo hospital, surabaya, indonesia. * these authors contributed equally to this paper. doi: 10.4081/aiua.2024.12186 summary archivio italiano di urologia e andrologia 2024; 96(1):12186 h. hermansyah, m. fadhli abdullah, c. pakpahan, et al. 2 inclusion criteria were samples from men aged 18-50 years old, with ejaculate volume > 2 ml, and willing to participate in the study by signing informed consent; we exclude men with anejaculation, haematospermia, hyperviscosity, and men with reproductive infection. each man who meets the criteria was explained about the procedures and objectives of the study and signed an informed consent if he was willing to participate to the research with his sample. then, the participant was asked to masturbate and collect ejaculate into a non-toxic container. after that, each ejaculate was divided into eight aliquots which were managed in different ways after ejaculate liquefaction. k1: the aliquot was immediately examined for fructose content; k2: the aliquot was centrifuged, then the supernatant was taken, and fructose content was examined; k3: the aliquot was centrifuged and allowed to stand for 30 minutes, then the supernatant was taken and examined for fructose; k4: the aliquot was centrifuged, then was left standing for 60 minutes and examined for fructose; k5: the aliquot was centrifuged, left for 120 minutes and then the supernatant was taken and examined for fructose; k6: the aliquot was allowed to stand for 30 minutes, then centrifuged, and the supernatant was examined for fructose content; k7: the aliquot was allowed to stand for 60 minutes, then centrifuged, and supernatant examined for fructose content; k8: the aliquot after standing for 120 minutes was centrifuged and supernatant examined for fructose content. fructose was examined using a semi-automated method. the procedure of fructose test with semi-automated method using the bts-350 semiautomatic machine, a colorimetric procedure followed an enzymatic process involving phosphoglucoisomerase and hexokinase enzymes. a spectrophotometer was used to detect nadph. to measure fructose with the bts 350 semiautomatic device, the reagent mixture reagent a (pipes 70 mmol/l, nadp+ 1.2 mmol/l, hexokinase > 15 u/ml, phosphoglucose isomerase > 10 u/ml, preservative, ph 7), reagent b (atp > 15 mmol/l, glucose-6-phosphate dehydrogenase > 10 u/ml, preservative, ph 9), and fructose standard (d-fructose 75 mg/dl equivalent to 375 mg/dl or 28 mmol/l fructose according to the sample dilution factor) were used. samples were added to reagents and put in a unique tube made of teflon to be sucked automatically by the machine until, within a few minutes, the value of fructose content will appear. after that, the fructose concentration needs to be calculated manually. statistical analysis the data obtained were analyzed statistically with the graph pad prism 10 software package. data normality test was conducted with the shapiro wilk test, and comparative analysis between variables was tested with the wilcoxon sign rank test for non-normally distributed data, and paired t-test for normally distributed data. results the results of this study were obtained from samples of 13 subjects divided into eight aliquots. the general characteristics of the study participants and observational data of macroscopic analysis of ejaculate are shown in table 1. in this study, the results of ejaculate ejaculate of infertile men with azoospermia criteria were 8%, severe oligozoospermia 23%, oligoteratozoospermia 23%, asthnezoospermia 31%, and teratozoospermia 15%. table 2 shows no significant difference between fructose levels measured in the aliquot that was immediately examined after centrifugation compared to fructose levels measured in aliquots that were left standing after centrifugation for 30 (p = 0.100) and 60 (p = 0.133) minutes. however, there was a significant difference between the level measured immediately after centrifugation compared to the level measured in the aliquot left for 120 minutes (p = 0.036). these results suggest that 60 minutes may be the recommended most extended time limit for measurement of fructose after centrifugation, as after that time, fructose levels may drop not resembling real levels. in the comparison between fructose levels that are left standing before centrifugation, there was a significant difference between immediate measurement and measurements aliquots that are left standing for 60 minutes (p = 0.012) and 120 minutes (p < 0.001) before centrifugation. the decrease in fructose levels between direct examination and 120 minutes was highly significant. this finding indicates that leaving samples for more than 60 minutes before centrifugation significantly decreases the measurement of the level of fructose content (table 3). the results of the measurements of fructose in the different eight aliquots were plotted on a graph, showing that aliquots that were left standing for a period of time and table 1. the general characteristics of the study participants and observational data of macroscopic analysis of ejaculate. general characteristics of participants mean ± sd median and results of macroscopic ejaculate analysis (min-max) age (years old) 32.69 ± 4.76 abstinence (day) 4 (2-7) volume (ml) 3.39 ± 1.31 liquefaction (minute) ph 7.5 (7-8,1) viscosity (cm) < 2 table 2. comparison of fructose concentrations (mean ± sd) in seminal plasma standing for 0, 30, 60, or 120 minutes after centrifugation of ejaculate. aliquot n fructose (mmol/l) 0 minutes 13 15.77 ± 4.81 30 minutes 13 15.18 ± 5.34 a 60 minutes 13 14.87 ± 5.47 b 120 minutes 13 14.23 ± 5.76 c a p = 0.100; b p = 0.133; c p = 0.036. archivio italiano di urologia e andrologia 2024; 96(1):12186 3 semen fructose levels and semiautomatic method then centrifuged showed a more significant decrease in fructose levels than measurement in aliquots that were centrifuged and then left standing for a period of time. our findings suggest that the best procedure for fructose examination is immediate centrifugation with measurement within 60 minutes. levels of fructose in samples left standing before centrifugation tend to be lower than real levels (figure 1). discussion the results showed that there was a significant difference in fructose levels in the aliquots that were immediately centrifuged after liquefaction and then immediately checked compared to the aliquots that, after centrifugation, were allowed to stand for 120 minutes before measurement (p = 0.036). there is a significant difference in fructose levels in the aliquots immediately checked compared to those allowed to stand 60 minutes and 120 minutes after liquefaction, then centrifuged and checked (p = 0.012 and p < 0.001). the difference in results in the present study for the aliquots that were allowed to stand 120 minutes after centrifugation compared to the results of lu et al. may be due to different centrifugation speeds and the number of samples measured. the present study used a centrifugation speed of 4000 rpm for 30 minutes, while the research conducted by lu et al. used a centrifugation speed of 3000 x g for 15 minutes. although research conducted by lu et al. showed that different centrifugation speeds have little effect on fructose levels, remaining spermatozoa or non-cellular components (7, 8), including zinc, alpha-glucosidase, citric acid may mildly affect the fructose level (9). the difference may also be due to differences in sample size being the sample size in the present study was 13 people, while the study research by lu et al. included 20 subjects. the data from the aliquots examined directly after centrifugation compared to those examined after a standing period before centrifugation showed no significant difference after a 30-minute standing (15.78 mmol/l and 15.30 mmol/l), but after 60and 120-minute standing the fructose levels decreased significantly (14.25 mmol/l and 10.51 mmol/l). the finding of no difference of fructose level after 30 minutes standing align with the research of elzanaty and malm although they found no significant difference between ejaculate fructose levels examined also 60 minutes, and 90 minutes after ejaculation (10). the fructose levels of the aliquots that were allowed to stand for 60 and 120 minutes before centrifugation were significantly lower than those allowed to stand for only 30 minutes. this is in line with research conducted by lu et al., although the method used is different. lu et al. used the resorcinol method, while this study used the enzymatic method. they reported a difference in the fructose content of ejaculate that was allowed to stand for 2 hours compared to those directly examined, and fructose levels significantly lower after 4 hours with table 3. comparison of fructose concentrations (mean ± sd) in seminal plasma obtained from centrifuged ejaculate after standing for 0, 30, 60, or 120 minutes. aliquot n fructose (mmol/l) 0 minutes 13 15.77 ± 4.81 30 minutes 13 15.30 ± 5.64 a 60 minutes 13 14.25 ± 5.84 b 120 minutes 13 10.51 ± 7.21 c a p = 0.294; b p = 0.012; c p = < 0.001. figure 1. comparison of mean fructose levels measured in aliquots immediately centrifugated and then allowed to stand compared to levels measured in aliquots allowed to stand before centrifugation. archivio italiano di urologia e andrologia 2024; 96(1):12186 h. hermansyah, m. fadhli abdullah, c. pakpahan, et al. 4 respect to 0 or 2 hours. in other words, the fructose concentration decreased with the length of standing time (7). the results in this study are also in line with the research conducted by andrade-rocha, in which fructose concentration was significantly lower in the samples examined after 120 minutes of liquefaction (11). the process of fructolysis causes a decrease in fructose levels in ejaculate. this process is influenced by many factors such as concentration, motility and metabolism of spermatozoa, temperature, ph, and other substances in the ejaculate (9). an increase in spermatozoa concentration requires more fructose, which decreases fructose levels in ejaculate and vice versa (12). increased fructose levels due to decreased fructose utilization can be caused by reduced spermatozoa, abnormal spermatozoa morphology, and decreased spermatozoa activity. low fructose levels can be caused by good spermatozoa motility (13). there is a positive correlation between the motility rate of spermatozoa and the fructolysis rate in human ejaculation (9). very low temperatures can stop all spermatozoa metabolic activity, affecting fructose utilization and resulting in a slow decline in fructose levels (14). references 1. trang nt. seminal fructose concentration in man infertility and the fructose test’s meaning in diagnosis reason of azoospermia man. biomed j sci tech res. 2018; 8:11-3. 2. baskaran s, finelli r, agarwal a, henkel r. diagnostic value of routine ejaculate analysis in clinical andrology. andrologia. 2021; 53:1-12. 3. world health organization. who laboratory manual for examining and processing human ejaculate sixth edition [internet]. vol. edition, v, world health organization. 2021. 286 p. available from: http://whqlibdoc.who.int/publications/2010/9789241547789_eng.pdf 4. tanga bm, qamar ay, raza s, et al. ejaculate evaluation: methodological advancements in sperm quality-specific fertility assessment a review. anim biosci. 2021; 34:1253-70. 5. s.s v. male infertility: a clinical approach. in: male infertility: a clinical approach. 2016, p. 55-83. 6. aucky hinting, agustinus a. technology updates in male infertility management. indones androl biomed j. 2021; 2:63-7. 7. lu jc, chen f, xu hr, et al. standardization and quality control for determination of fructose in seminal plasma. j androl. 2007; 28:207-13. 8. feng rx, lu jc, zhang hy, lü nq. a pilot comparative study of 26 biochemical markers in seminal plasma and serum in infertile men. biomed res int. 2015; 2015. 9. a gs and k. basics of human andrology. in: basics of human andrology. new delhi: springer nature singapore pte ltd; 2017, p. 163-70. 10. elzanaty s, malm j. effects of ejaculation-to-analysis delay on levels of markers of epididymal and accessory sex gland functions and sperm motility. j androl. 2007; 28:847-52. 11. andrade-rocha ft. physical analysis of ejaculate to evaluate the secretory activity of the seminal vesicles and prostate. clin chem lab med. 2005; 43:1203-10. 12. kataria j, gill gk, cojandaeaj l. relationship of seminal fructose and serum prolactin levels in infertile men. asian j pharm clin res. 2021; 14:85-7. 13. toragall mm, satapathy sk, kadadevaru gg, hiremath mb. evaluation of seminal fructose and citric acid levels in men with fertility problem. j hum reprod sci. 2019; 12:199-203. 14. srivastava n, pande m. protocols in semen biology (comparing assays). springer, singapore, 2017; p. 1-288. correspondence hermansyah hermansyah drherman09@gmail.com muhammad fadhli abdullah muhammad.fadhli.abdullah-2021@fk.unair.ac.id cennikon pakpahan cennikon.pakpahan@fk.unair.ac.id reny i’tishom (corresponding author) ritishom@fk.unair.ac.id department of biomedical sciences, faculty of medicine, universitas airlangga, surabaya, indonesia supardi supardi supardi.unair@gmail.com ilhamsyah ilhamsyah ilhamsyah-2021@fk.unair.ac.id conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12682 1 original paper approaches being adopted by clinicians (5). histological examination of the vasa is not commented upon by the uk guidelines. the aua guidelines state that although histological evaluation is unlikely to cause harm it is not recommended as pvsa is preferred (6). the faculty of sexual & reproductive healthcare guidelines are more categorically against histology evaluation stating that “routine histology on vasectomy specimens represents an unacceptable burden on both laboratory staff and time and is expensive” (7). however, there is likely variation in practice here too (8), perhaps out of caution or fear of litigation. pvsa makes the pathological examination of the vasa redundant, as the identification of two vasa specimens does not preclude the possibility of vasa duplications or division of the vas on the same side twice (9-12). it has been our own practice to submit the vasa specimens for pathological evaluation.perhaps the greatest pitfall of vasectomy evaluation is the low compliance with pvsa which has generally been documented to be between 30% and 80% (8, 13-17). addressing this realworld problem has a greater potential to strengthen vasectomy evaluation, than any further refinement of guidance on the timing and interpretation of the semen analysis. poor compliance presents a real challenge; on the one hand there is increased risk of an unwanted pregnancy, litigation, and unclear appropriation of responsibility; on the other hand, unnecessary resources may be squandered chasing up men who will ultimately never carry out a pvsa. the aim of this study was to evaluate the utility of the vasectomy histology in determining the need for revision vasectomy, in a retrospective cohort of patients who underwent vasectomy between 2018 and 2022 inclusive. material and methods an nhs health research authority evaluation questionnaire was completed which determined that ethical approval was not required for the study as only routine health data was evaluated in a retrospective manner. the coding department provided a list of all vasectomies undertaken between 2018 and 2022, including patient age and anaesthetic modality. the histology, pvsa and f/u appointment records were extracted from contemporaneous electronic records. procedures were carried out after written consent and appropriate counselling, under local anaesthetic, general anaesthetic, spinal anaesthetic or sedation. in all cases the vasa were excised diathermised and ligated. the excised vasa were placed in formalin in sperate pots, labelled objectives: to determine if histological evaluation of the vasa is useful when post-vasectomy semen analysis (pvsa) compliance is low and to determine whether compliance could be predicted. methods: a retrospective evaluation of patients undergoing vasectomy between 2018 and 2022 was undertaken. a comparison of the pvsa between three vasa histological categorisations was made: complete divisions, incomplete division(s), absent vas(a). a multivariate model was constructed to predict pvsa compliance. results: from 388 patients, 191 (49.2%) undertook pvsa. four patients had a revision of vasectomy. on 3 occasions this was due to the histology findings and once from semen analysis with normal histology. there was no significant difference in the number of azoospermic samples (95.4% vs 91.2%, ns), of samples with presence of rare non-motile sperm (rnms) (2.6% vs 8.8%, ns) and those with sperm present (2.0 vs 0%, ns), between patients with complete division of the vasa on both sides and those with incomplete division on one side respectively. there was no difference in patient characteristics between those who complied with pvsa and those who did not. conclusions: this paper suggests that there is a role for histological evaluation of the vasa when pvsa compliance is poor. incompletely divided vasa on histology are not associated with an adverse pvsa. key words: vasectomy; histology; semen analysis; pvsa; sterility; patient compliance. submitted 21 may 2024; accepted 13 june 2024 introduction vasectomy is a commonly undertaken and effective form of contraception. 8.531 vasectomies were performed in the uk in 2021/22, which is 30% below the last pre-pandemic total for 2019/20 (12.157) (1). it is estimated that it is the primary form of contraception for 42 million couples worldwide (2). updated vasectomy guidelines for the uk were introduced in 2016, advocating the use of a single post vasectomy semen analysis (pvsa) at 3 months to determine clearance (3). this represents a welcome change in reducing the number of necessary semen analyses. however, the need for two pvsas to determine special clearance has been challenged (4). there is likely to be variation in the management of patients with low numbers of nonmotile sperm present in pvsa, as demonstrated by a recent international survey which highlighted a range of vasectomy histology: is it still useful? anthony sim 1, panagiotis nikolinakos 2, konstantinos charitopoulos 2, ivo donkov 2, samuel bishara 2 1 imperial college london, uk; 2 department of surgery west middlesex hospital, twickenham road, isleworth, london tw7 6af. doi: 10.4081/aiua.2024.12682 summary archivio italiano di urologia e andrologia 2024; 96(3):12682 a. sim, p. nikolinakos, k. charitopoulos, et al. 2 according to side, and sent to the pathology laboratory for evaluation. semen analysis was requested, and patients were provided with written instructions on how to organise a pvsa at 3 months after the surgery. the histology outcome of the vasectomy was classified as either 2 vasa present and divided, 2 vasa present and one or more incompletely divided, or one or more vasa absent from each side. the semen analysis was conducted according to the 2016 british association of urology guidelines. the semen analysis outcome, as per guidelines were classified, as present (any motile sperm or > 100,000 immotile sperm), rare non-motile sperm (< 100,000 immotile sperm) or azoospermia (no sperm detected). rare non-motile sperm is believed to carry no greater risk of paternity than absent sperm, and its persistence may be reflective of sperm that’s had previously refluxed in the seminal vesicles or the ampulla of the vas (4, 18). when more than one semen analysis was carried out the final semen analysis was regarded as definitive and utilised in this analysis. the demographic details of the patient and procedure were recorded including age, asa and anaesthetic type. a comparison of these demographics was made between those who did and did not undertake a pvsa. differences between these two groups were assessed by an unpaired t-test for age, the mann whitney u test for asa grade, and by the chi squared test for anaesthetic type. a binary logistic regression was carried out to ascertain whether a predictive model using the patient and operative demographics could determine whether pvsa compliance could be predicted. the proportion of semen analysis outcomes between the different histological categories were compared and evaluated using the fisher test. statistical significance was taken as p < 0.05 (two tailed). statistical analyses were carried out using minitab statistical software. results 388 vasectomies were carried out between 2018 to 2022 and were include in this study. for 385 vasectomies, histological evaluation of the vasa took place and in 3 cases this was absent. 191 patients (49.2%) undertook semen analysis at 12 weeks or later, 6 patients repeated pvsa once (1.5%) and 197 (50.8%) did not carry out a follow up pvsa. the outcome of pvsa according to the histological classification of the vasa is shown in table 1. four patients (1.0%) underwent revision vasectomy. three of these patients were identified through the histology, as they had an absent vas on one side. one was identified through the pvsa, which demonstrated sperm though they had 2 vasa histologically confirmed as divided. 2 of these 3 patients identified from histology proceeded to revision vasectomy without pvsa. one of these 3 patients had a pvsa prior to revision which demonstrated the presence of sperm. all the patients who had a revision vasectomy were histologically confirmed to have had 2 vasa present after the revision procedure. one of the 4 patients who had an absent vas on histology, had only one vas identified at the time of an open procedure and was therefore likely to have ipsilateral absence of the vas, however they did not undertake a follow up pvsa. the semen parameters when two completely identified vasa were compared to when the pathologist flagged one of the sides, though present as being incompletely divided. there is no significant difference in the number of azoospermia samples (95.4% vs 91.2%, ns), those with rare non-motile sperm (rnms) (2.6% vs 8.8%, ns) and those with sperm present (2.0 vs 0%, ns) between these two groups respectively. incomplete division of the vasa demonstrated a 0% positive predictive power for determining the presence of spermatozoa on pvsa. the demographic details for the study patients are shown in table 2. there is some incomplete data. asa class was electronically recorded in 360 patients and the anaesthetic modality in 366 patients. ga was the most common anaesthetic (218 patients), followed by la (141 cases), sedation (6 cases) and spinal anaesthetic (1 case). there table 2. characteristic of vasectomy patients according to pvsa compliance. pvsa no pvsa probability age 41.4 40.9 ns α (5.6, n = 191) (6.3, n = 197) asa 1.3 1.3 ns b (0.5, n = 180) (0.5, n = 180) anaesthetic type: ns † general 112 106 la 68 73 sedation 3 3 spinal 0 1 total (n = 183) (n = 183) α: unpaired t-test, b: mann-whitney u test, †: chi square test. table 1. semen analysis according to histological report. histology number semen azoospermia rnms spermatozoa revision analysis present vasectomy 2 divided vasa 306 154 147 (95.5%) 4 † 3 1 (2.6%) (1.9%) (0.3%) 2 vasa present but possible incomplete division 75 34 31 (91.2%%) 3 † 0 0 (8.8%) (0%) (0%) absent vas on one side 4 1 0 0 1 (100%) 3 (0%) (0%) (75%) no histology 3 2 1 1 0 0 (50%) (50%) (0%) (0%) total 388 191 179 8 4 4 (93.7%) (4.2%) (2.1%) (1.0%) †: not significant difference by fisher test. archivio italiano di urologia e andrologia 2024; 96(3):12682 3 vasectomy histology is no significant difference in age, asa, or anaesthetic modality between the two groups. theses variables were used to generate a multivariate model to determine if pvsa could be predicted. none of these parameters achieved statistical significance. the area under the roc curve was 0.54 for the prediction of pvsa compliance. discussion this paper accords with many others, highlighting the low follow up rate for pvsa that is typical across many practices, with just under 50% of patients complying with follow up. several have investigated the reasons for this, with men citing travel and time constraints (14) and embarrassment (15) as reasons for this. others have looked at strategies for improving follow up including home test kits (19-21), which have yielded variable results and postal notification strategies (22), which improved pvsa compliance. revision of the baus guidelines, to reduce the number of pvsa mandated form two to one is a step in the right direction, and one likely to facilitate compliance, however it seems that we will always be a long way from 100% compliance with pvsa. whilst pvsa will always remain the gold standard, the question remains how we best manage non-compliance and does pvsa alone remain the optimal strategy when there is poor compliance and limited healthcare resources? if there is 100 percent compliance with pvsa then clearly histology would be completely unnecessary, however, in this study more patients underwent redo vasectomy because of the histopathological findings than from the pvsa. only one patient underwent redo vasectomy through the pvsa alone and three underwent redo vasectomy from the pathology findings. the pathological findings are pertinent to the pvsa if no evidence of vasal tissue can be identified on one or more side. from this study, incomplete division of the vasa on one or both sides does not seem to have any impact on the pvsa, and largely reflects the difficulty in obtaining thin perpendicular sections through the vasa for pathological analysis. the paper suggests that there may still be a role for vasa histology when the compliance rate is low as it picked up 75% of the known failures. lack of compliance and inefficiency of follow up remain a problem, one option would be to shift the responsibility for follow up to the patient by requesting a patient initiated follow up appointment (pifu), so that a follow up appointment is generated if and when the patient carries out a semen analysis. patients should be informed clearly, whilst a system is in place to make pvsa possible, they are responsible for making sure this takes place and if they do not undertake pvsa, then they take responsibility for a having a lower level of certainty, for the success of their procedure, at 99.0% (form the histology alone) rather than 99.95% (through pvsa). it may be some men feel that the 1.0% risk is not worth the hassle of a further semen analysis, or by having already undergone a vasectomy, they have already gone above and beyond to provide contraception for themselves and their partner. histology is relatively expensive and costs £95 per case in our institution. the cost effectiveness of histology is dependent on the compliance rate and the failure rate of vasectomy. excluding consultation cost, the estimated cost of histology per failed vasectomy detected is £95/(failure rate x compliance rate). e.g., if the failure rate is 1% and the pvsa compliance rate is 50%, then histological cost per additional failed vasectomy detected is £95/(0.01 x 0.5) = £19000. in this study the actual cost was £12192 per failed vasectomy detection. exploration of alternatives to histology which may provide similar diagnostic information is worthy of further evaluation. the statistical risk of litigation from patients as a result vasectomy is low. a review found 67 cases over 28 years from the westlaw database of us cases (23), though not all us cases may have been captured in this study. the simplest approach would be to follow the faculty of sexual & reproductive healthcare guidelines and abandon the histology, however we feel that under the circumstances of low pvsa compliance retaining the histology facilitates greater stewardship of our patients albeit at a financial cost. there was no significant difference in the demographic factors between those who undertook a pvsa and those who did not. likewise, a predictive model utilising binary logistic regression did not achieve statistical significance for any of the parameters and was only of low predictive power. the number of children that patients had previously was not universally recorded and therefore not utilised in this study. some studies have demonstrated that fatherhood is associated with increased compliance with pvsa (14). previous studies have demonstrated that increased age was associated with better pvsa compliance, but we did not find that to be the case in this study (13). conclusions this paper suggests that there is a role for histological evaluation of the vasa when pvsa compliance is poor, which is likely to be the case in many centres. references 1. nhs england. part 4: sterilisations and vasectomies. available from: https://digital.nhs.uk/data-and-information/publications/statistical/sexual-and-reproductive-health-services/2021-22/sterilisationsand-vasectomies. 2. haldar n, cranston d, turner e, et al. how reliable is a vasectomy? long-term follow-up of vasectomised men. lancet. 2000; 356:43-4. table 3. binary logistic regression of variables hypothesised to predict compliance with pvsa. area under roc curve 0.54. term coefficient se coefficient z-value p-value constant -0.570 0.755 -0.75 0.451 age 0.0186 0.0175 1.07 0.287 asa_class -0.242 0.225 -1.08 0.282 ga 0.178 0.229 0.78 0.437 archivio italiano di urologia e andrologia 2024; 96(3):12682 a. sim, p. nikolinakos, k. charitopoulos, et al. 4 3. hancock p, woodward bj, muneer a, brown jck. laboratory guidelines for postvasectomy semen analysis: association of biomedical andrologists, the british andrology society and the british association of urological surgeons. j clin pathol. 2016; 69:655-60. 4. beder d, chitale s. the clinical impact of british guidelines on post-vasectomy semen analysis. cent european j urol. 2020; 73:558-562. 5. agarwal a, gupta s, sharma rk, et al. post-vasectomy semen analysis: optimizing laboratory procedures and test interpretation through a clinical audit and global survey of practices. world j mens health. 2022; 40:425-41. 6. sharlip id, belker am, honig s, et al. vasectomy: aua guideline. j urol. 2012; 188:2482. 7. fsrh. clinical guideline: male and female sterilisation (september 2014). available from: https://www.fsrh.org/standardsand-guidance/documents/cec-ceu-guidance-sterilisation-cpd-sep2014/ 8. katsoulis ie, walker sr. vasectomy management in morecambe bay nhs trust. ann r coll surg engl. 2005; 87:131. 9. miller s, couture s, james g, et al. unilateral absence of vas deferens: prevalence among 23,013 men seeking vasectomy. int braz j urol. 2016; 42:1010-7. 10. carr r. apparent bilateral duplication of the vas deferens. br j urol. 1993; 71:354. 11. erdemir f, parlaktas bs, yasar a, uluocak n. duplicated vas deferens: a rare congenital abnormality. kaohsiung j med sci. 2008; 24:210-1. 12. karaisli s, ezer m. duplicated vas deferens: a case report and comprehensive review of the literature. andrologia. 2021; 53:e13896. 13. christensen re, maples dc. postvasectomy semen analysis: are men following up? j am board fam pract. 2005; 18:44-7. 14. bradshaw a, owusu r, ballon-landa e, et al. poor compliance with post-vasectomy semen analysis: analysis of factors and barriers. j urol. 2019; 201:e685. 15. diederichs j, mcmahon p, tomas j, muller aj. reasons for not completing postvasectomy semen analysis. available from: https://www.cfp.ca/content/cfp/65/9/e391.full.pdf 16. maatman tj, aldrin l, george bgs, car-others g. patient noncompliance after vasectomy. fertil steril. 1997; 68:552-5. 17. derosa r, lustik mb, stackhouse da, mcmann lp. impact of the 2012 american urological association vasectomy guidelines on postvasectomy outcomes in a military population. urology. 2015; 85:505-10. 18. philp t, guillebaud j, budd d. late failure of vasectomy after two documented analyses showing azoospermic semen. br med j. 1984; 289:77. 19. kiessling rj, hauser a, eyre rc, kiessling aa. a new approach to postvasectomy semen analyses eliminates the need to evaluate a fresh specimen. andrology. 2023; 11:464-70. 20. welliver c, zipkin j, lin b, et al. factors affecting post-vasectomy semen analysis compliance in homeand lab-based testing. can urol assoc j. 2023; 17:e189-92. 21. trussler j, browne b, merino m, et al. post-vasectomy semen analysis compliance with use of a home-based test. can j urol 2020; 27:10388-93. 22. atkinson m, james g, bond k, et al. comparison of postal and non-postal post-vasectomy semen sample submission strategies on compliance and failures: an 11-year analysis of the audit database of the association of surgeons in primary care of the uk. bmj sex reprod health. 2022; 48:54-9. 23. blazek aj, belle jd, deibert mp, deibert cm. legal review of vasectomy litigation and the variables impacting trial outcomes. urology. 2019; 131:120-4. correspondence anthony sim, md anthony.sim21@imperial.ac.uk imperial college london, uk panagiotis nikolinakos, md panagiotis.nikolinakos@nhs.net konstantinos charitopoulos, md k.charitopoulos@nhs.net ivo donkov, md i.donkov@nhs.net department of surgery west middlesex hospital, twickenham road, isleworth, london tw7 6af samuel bishara, md (corresponding author) samuel.bishara2@nhs.net department of urology, west middlesex university hospital, chelsea & westminster hospital nhs foundation trust, london, united kingdom conflict of interest: the authors declare no potential conflict of interest. cop+ed+fisse 2006 1archivio italiano di urologia e andrologia 2022; 94, 1 original paper no conflict of interest declared. patients with tumor stage 1 (t1) and has been shown to be comparable to rn in terms of oncologic outcomes (3). although there is no prospective randomized study comparing nss with rn in terms of oncological and renal functions in t2 patients, there are retrospective studies conducted to date (4). according to the current european urology association guideline, the standard approach in patients with ≥ t2 is rn (5). pre-operative clinical staging is performed with computed tomography (ct) or magnetic resonance imaging (mri), and patients may develop local recurrence despite surgical procedures based on clinical stage (6). in clinical practice, pre-operative ct and mri provide information about tumor size, tumor localization, presence of tumor invasion into vascular structures and adjacent organs (7). however, apart from these frequently reported findings, there are ct and mri findings that can be used to predict advanced disease. according to 2017 tumor, node, and metastasis (tnm) classification, invasion of the pelvicalyceal system, perirenal or renal sinus fat invasion has been included in the t3a category (8). there are studies evaluating predictive value of ct to indicate renal sinus fat or perirenal fat invasion (9). although not included in the standard tnm classification, it has been shown that renal capsule invasion is an independent prognostic variable for advanced disease and can be detected on ct (10, 11). on the other hand, it has been indicated that thickening of the gerota’s fascia, the presence of enlarged collateral vessels, and the presence of intra-tumoral necrosis may be imaging findings that can be used to predict advanced disease (12). we also think that these markers can be used in prediction of advanced disease in rcc. although renal capsule invasion and perirenal fat invasion has been considered reliable markers in advanced disease, additional markers can make imaging more reliable. consequently, in our study we decided to investigate these markers that could be used for prediction of ≥ pt3a disease. we also think that the predictive value of mri may be higher than ct. therefore, in this study we evaluated the role of some features (renal capsule invasion, perirenal fat invasion, thickening of the gerota’s fascia, presence of enlarged collateral vessels, tumor necrosis, perinephric stranding) of pre-operative computed tomography and magnetic objective: we evaluated predictive features of pre-operative computed tomography and magnetic resonance imaging for advanced disease in renal cell carcinoma. materials and methods: 92 patients with pathologically confirmed diagnosis of renal cell carcinoma were included in our study. patients were divided into two groups according to preoperative imaging as computed tomography (ct) (55 patients) and magnetic resonance imaging (mri) (37 patients). within the imaging groups, the patients were divided into two groups according to pathological tumor stage: 1-2 (pt1-2) versus ≥ pt3a. it was evaluated whether there was a difference between the two groups in terms of the presence of pre-operative imaging (ct and mri) features. predictive value of these features for ≥ pt3a disease was evaluated both for ct and mri. results: the cut-off value for the gerota’s fascia thickness in predicting ≥ pt3a disease was calculated as 0.205 cm. positive predictive value (ppv) for gerota's fascia thickness was 52.4% (31.0-73.7) and 66.7% (40.0-93.3) for ct and mri respectively. the ppv value for renal capsule invasion was 75.0% (53.8-96.2) and 90.0% (71.4-108.6) for ct and mri respectively. ppv of perirenal fat invasion for ct and mri was 69.2% (44.1-94.3) and 81.8% (59.0-104.6) respectively. conclusion: renal capsular invasion and perirenal fat invasion are reliable signs for locally advanced (≥ pt3a) renal cell carcinoma both in ct and mri. gerota’s fascia thickness has relatively low ppv value for prediction of locally advanced disease. presence of enlarged collateral vessels, tumor necrosis, perinephric stranding are not reliable signs. for all predictors mri seems more reliable than ct. key words: renal cell carcinoma; computed tomography; magnetic resonance imaging; predictive features. submitted 9 december 2021; accepted 18 january 2022 introduction renal cell carcinoma (rcc) is one of the most common urinary system cancers and accounts for 3% of all cancers (1). with the frequent use of imaging methods most renal masses are detected when localized (2). the standard treatment option in localized rcc is radical nephrectomy (rn) or nephron-sparing surgery (nss). nss is preferred in predictive features of pre-operative computed tomography and magnetic resonance imaging for advanced disease in renal cell carcinoma musab ali kutluhan 1, selman unal 1, serhan eren 2, asim ozayar 1, emrah okulu 1, hüseyin cetin 3, onder kayigil 1 1 department of urology, yildirim beyazit university, school of medicine, ankara, turkey; 2 department of radiology, university of health sciences, etlik zubeyde hanım research and training hospital, ankara, turkey; 3 department of radiology, yildirim beyazit university, school of medicine, ankara, turkey. doi: 10.4081/aiua.2022.1.1 summary archivio italiano di urologia e andrologia 2022; 94, 1 m. ali kutluhan, s. unal, s. eren, a. ozayar, e. okulu, h. cetin, o. kayigil 2 resonance imaging for predicting advanced disease in renal cell carcinoma. materials and methods study design and patient selection after local ethics committee approval (26379996/58), patients who had rn or nss operation due to renal mass in our clinic were retrospectively screened. in total, 92 patients with pathologically confirmed diagnosis of rcc and pre-operative ct or mri images were included in our study. patients who had metastatic rcc, who had unclear ct or mri images, who had undergone surgery on the same side before the onset of kidney mass due to other urological pathologies, and who had pathology results other than rcc (oncocytoma, etc.) were excluded from the study. patients were divided into two groups according to pre-operative imaging as ct (55 patients) and mri (37 patients). pre-operative ct and mri images were evaluated by a dedicated blinded radiologist. postoperative pathology results of the patients were screened. within the imaging groups, the patients were divided into two groups according to pathological tumor stage as 1-2 (pt1-2) (group 1) and ≥ pt3a (group 2). it was evaluated whether there was a difference between the two groups in terms of the presence of pre-operative imaging (ct and mri) features (renal capsule invasion, perirenal fat tissue invasion, thickening of the gerota’s fascia, presence of enlarged collateral vessels, intra-tumoral necrosis, perinephric stranding). predictive value of these features for ≥ pt3a disease was evaluated both for ct and mri. radiological evaluation ct acquisition ct examination was performed using a 128-slice multidetector ct scanner (ge, revolution evo, usa). the ct parameters and scanning sequence were as follows: 1:1 pitch, 200-250 mas, 120 kvp, and 0.5-0.625 isotropic spatial resolution, window width 250~450 hu, and window level 30-50 hu; for cortical phase, medullary phase, and excretion phase, the duration of scanning was 30-35, 50-60, and 180 s after the injection of contrast agent, respectively. 100 ml of non-ionic intravenous contrast agent was administered through antecubital veins with an automated injector at 3 ml/sec (ulrich medizin version, 2004, germany). all patients were examined in a supine position with 6-8 hours fasting. mri acquisition mri examinations were performed with 1.5-tesla mri (signa, ge medical systems) with 5 mm slice thickness and 2.0 mm gap spacing by using surface phased array coil. mri sequence parameters were coronal t2-weighted halffourier single-shot fast spin-echo (tr/te msec 8001100/60; slice thickness 4 mm; gap 1 mm; matrix size 192 × 256; flip angle 130°-155°), axial t1-weighted inphase and opposed-phase gradient-echo (180-205/2.22.7, 4.5-5.2; flip angle, 80°; slice thickness, 6-8 mm; gap, 1 mm; matrix, 160 × 256), and 3d t1-weighted liver imaging with volume acceleration (lava) with fat suppression (tr/te msec 1.4/4.3; slice thickness 2.5 mm; matrix size 132x320; flip angle, 10-12°; fov 25x35 cm). in dynamic imaging, the delay time was 20 seconds for corticomedullary phase, 60 seconds for nephrographic phase, and 120 seconds for the coronal delayed phase after the intravenous injection of 15 ml of magnevist (0.1 mmol/kg; bayer schering, pharma ag, berlin, germany) at a rate of 2 ml/s. diffusion weighted imaging (dwi) was performed with two b values (0 and 600 mm2/s). image analysis one dedicated radiologist for abdominal radiology reviewed all images in archiving system blinded to histopathologic information. imaging features of perinephric fat tissue, perinephric stranding, perinephric vascularity, and irregular contours was evaluated both in ct (figure 1) and mri. tumor margins were identified as smooth or lobulated for evaluation of capsule invasions (figure 2). in quantitative measurements, gerota’s fascia thickness was measured in magnified images of ct and mri (figure 3). presence of tumor necrosis and collateral vessels were also evaluated both in mri and ct. statistical analyzes statistical analyses of the study were performed using spss 23.0 program (spss, version 23.0; ibm corp, armonk, ny). number, percentage, mean and standard deviation were used for descriptive statistics. analyses of differences between groups were performed with t-test and chi-square test in independent groups as significance tests. crosstabs were used for sensitivity, specificity, and predictive value calculations. the diagnostic value of gerota’s fascia thickness in predicting cancer stage was analyzed by roc curve by considering 0.05 as the significance threshold for p-value. figure 1. a 50-year-old woman with high-grade clear cell rcc (fuhrman grade iv) in left kidney. axial contrast-enhanced computed tomography image shows a 15-cm hyper vascular centrally necrotic renal mass. gerota.s fascia (anterior perirenal fascia) thickness was 0.41 cm. 3archivio italiano di urologia e andrologia 2022; 94, 1 predictive imaging features in renal cell carcinoma in addition, there was a statistically significant difference between the groups in terms of perinephric stranding and perirenal fat invasion (p = 0.04, p < 0.001). comparison of ct predictors according to groups was summarized in table 2. when the groups were compared in terms of pre-operative mri features, the mean gerota’s fascia thickness of group 2 was statistically significantly thicker than group 1 (0.38 ± 0.24 vs 0.13 ± 0.06 cm, p < 0.001). there was a statistically significant difference between the groups in terms of the presence of collateral vessels and intratumoral necrosis (p = 0.015, p = 0.015). there was a statistically significant difference between the groups in terms of renal capsule invasion (p < 0.001). in addition, there was a statistically significant difference between the groups in terms of perinephric stranding and perirenal fat table 1. characteristics of the patients. figure 3. a 58-year-old man with 8 cm high-grade clear cell rcc (fuhrman grade iii) in left kidney. axial t2 weighted fat saturated images show heterogenous ill-defined tumor in left kidney. gerota fascia was thickened and measured 0.3 cm. figure 2. a 62-year-old man with high-grade clear cell rcc (fuhrman grade iv) in left kidney. axial computed tomography image shows lesion margin was ill-defined and lobulated. the tumor showed invasion of the renal capsule and perirenal fat. perirenal fat stranding was prominent. number of patients 92 mean age (years) 58.08 ± 11.58 n (%) pre-operative imaging ct 55 (59.8) mri 37 (40.2) tumor side right 50 (54.3) left 42 (45.7) operation radical nephrectomy 42 (45.7) partial nephrectomy 50 (54.3) pathological t stage t1a 37 (40.2) t1b 17 (18.5) t2a 7 (7.6) t2b 6 (6.5) t3a 16 (17.4) t3b 6 (6.5) t4 3 (3.3) pathological type clear cell rcc 71 (77.2) papillary rcc 12 (13.0) chromophobe rcc 9 (9.8) ct: computed tomography; mri: magnetic resonance imaging; t: tumor; rcc: renal cell carcinoma. table 2. comparison of ct predictors according to pt stage. pre-operative ct predictors pt stage p-value group 1 = group 2 = < t3a (n = 40) ≥ t3a (n = 15) gerota’s fascia thickness mean sd (cm) 0.15 ± 0.01 0.30 ± 0.12 < 0.001 presence of enlarged collateral vessels 0.008 positive 19 (47.5%) 13 (86.7%) negative 21 (52.5%) 2 (13.3%) tumor necrosis 0.078 positive 19 (47.5%) 11 (73.3%) negative 21 (52.5%) 4 (26.7%) renal capsule invasion < 0.001 positive 5 (10.3%) 12 (80.0%) negative 35 (89.7) 3 (20.0%) perirenal fat invasion < 0.001 positive 4 (10.0%) 9 (60.0%) negative 36 (90.0%) 6 (40.0%) perinephric stranding 0.040 positive 17 (42.5%) 11 (73.3%) negative 23 (57.5%) 4 (26.7%) ct: computed tomography; pt: pathological tumor. results the mean age of the patients included in the study was 58.08 ± 11.58. 59.8% of patients had ct as pre-operative imaging, while 40.2% had mri. the clinical features of the patients are summarized in table 1. when the groups were compared in terms of pre-operative ct features, the mean gerota’s fascia thickness of group 2 was statistically significantly thicker than group 1 (0.15 ± 0.01 vs 0.30 ± 0.12 cm p < 0.001). there was a statistically significant difference between the groups in terms of the presence of collateral vessels (p = 0.008). there was a statistically significant difference between the groups in terms of renal capsule invasion (p < 0.001). archivio italiano di urologia e andrologia 2022; 94, 1 m. ali kutluhan, s. unal, s. eren, a. ozayar, e. okulu, h. cetin, o. kayigil 4 invasion (p < 0.001, p < 0.001). comparison of mri predictors according to groups was summarized in table 3. the diagnostic value of gerota's fascia thickness in estimating pathological stage was evaluated with the roc curve. according to this evaluation, the cut-off value for the gerota’s fascia thickness in predicting ≥ pt3a disease was calculated as 0.205 cm. sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv) of ct and mri predictors was summarized in table 4. accordingly, the ppv value for gerota's fascia thickness was 52.4% (31.0-73.7) and 66.7% (40.0-93.3) for ct and mri respectively. the ppv value for renal capsule invasion was 75.0% (53.896.2) and 90.0% (71.4-108.6) for ct and mri respectively. ppv of perirenal fat invasion for ct and mri was 69.2% (44.1-94.3) and 81.8% (59.0-104.6) respectively. discussion in patients with renal mass, tumor stage is important for the prognosis of the disease. perirenal fat invasion, renal sinus fat invasion, renal capsule invasion and renal vein invasion are important factors that may affect the prognosis. in a study conducted on 563 patients with pt3a tumor and negative node (n0), shah et al. demonstrated that although there was no difference between perirenal fat invasion, renal sinus fat invasion and renal vein invasion in terms of the prognosis of the disease, the combination of these factors could negatively affect the prognosis of the disease (13). in another multicentric study by brookmanmay et al., it was shown that perirenal fat invasion may be an independent prognostic factor for cancer specific survival (14). it has also been shown that renal capsule invasion may be an independent prognostic factor for rcc (10). pre-operative detection of prognostic factors has recently become more important for the management of the disease, with the increase in neo-adjuvant and adjuvant treatment modalities. in a study conducted by renard et al., the predictive value of ct for pt3a disease was evaluated and the ppv values of perirenal fat invasion, renal sinus fat invasion and venous invasion were detected to be 49%, 68% and 90%, respectively (15). in another study by el-hefnawy et al. including 693 patients, the ppv value of ct in predicting pt3a disease was reported as 43.7% (16). in our study, ppv of perirenal fat invasion in predicting ≥ pt3a was 69.2% and 81.8% in ct and mri respectively. when compared to literature (15, 16), ppv of perirenal fat invasion seems to be higher according to ct. in addition, mri seems to be more reliable for detecting perirenal fat invasion. although it is thought that it is difficult to detect renal capsule invasion in pre-operative imaging, it has been reported in studies that some ct findings may indicate renal capsule invasion (11). in addition, in a study conducted by nazım et al. ppv of renal capsule invasion in ct was 75.3% in predicting local advanced rcc (17). in our study ppv of renal capsule invasion was 75.0% (53.8-96.2) and 90.0 (71.4-108.6) for ct and mri respectively. our results demonstrated that ppv value of renal capsule invasion on ct in predicting t3a and above table 4. ct and mri predictions for pt stage > pt3a. predictors sensitivity (%) specificity (%) ppv (%) npv (%) bt (ci) mr (ci) bt (ci) mr (ci) bt (ci) mr (ci) bt (ci) mr (ci) gerota’s fascia thickness 0.205 cm < 73.3 (51.0-95.7) 80.0 (55.2-104.8) 75.0 (61.6-88.4) 85.2 (71.8-98.6) 52.4 (31.0-73.7) 66.7 (40.0-93.3) 88.2 (77.4-99.1) 92.0 (81.4-102.6) presence of enlarged collateral vessels positive 86.7 (69.5-103.8) 80.0 (55.2-104.8) 52.5 (37.0-67.8) 66.7 (48.9-84.4) 40.6 (23.6-57.6) 47.1 (23.3-70.8) 91.3 (79.8-102.8) 90.0 (76.9-103.1) tumor necrosis positive 73.3 (51.0-95.7) 80.0 (55.2-104.8) 52.5 (37.0-68.0) 66.7 (48.9-84.4) 36.7 (19.4-53.9) 47.1 (23.3-70.8) 84.0 (69.6-98.4) 90.0 (76.9-103.1) renal capsule invasion positive 80.0 (59.8-100.2) 90.0 (71.4-108.6) 89.7 (80.2-99.3) 96.3 (89.2-103.4) 75.0 (53.8-96.2) 90.0 (71.4-108.6) 92.1 (83.5-100.6) 96.3 (89.2-103.4) perinephric stranding positive 73.3 (50.1-95.7) 100.0 57.5 (42.2-72.8) 74.1 (57.5-90.6) 39.3 (21.2-57.4) 58.8 (35.4-82.2) 85.2 (71.8-98.6) 100.0 perirenal fat invasion positive 60.0 (35.2-84.8) 90.0 (71.4-108.6) 90.0 (80.7-99.3) 92.6 (82.7-102.5) 69.2 (44.1-94.3) 81.8 (59.0-104.6) 85.7 (75.1-96.3) 96.2 (88.8-103.5) ct: computed tomography, mri: magnetic resonance imaging, pt: pathological tumor, ppv: positive predictive value, npv: negative predictive value. table 3. comparison of mri predictors according to pt stage. pre-operative mri predictors pt stage p-value group 1 = group 2 = < t3a (n = 27) ≥ t3a (n = 10) gerota’s fascia thickness mean sd (cm) 0.13 ± 0.06 0.38 ± 0.24 < 0.001 presence of enlarged collateral vessels 0.015 positive 9 (33.3%) 8 (80.0%) negative 18 (66.6%) 2 (20.0%) tumor necrosis 0.015 positive 9 (33.3%) 8 (80.0%) negative 18 (66.6%) 2 (20.0%) renal capsule invasion < 0.001 positive 1 (3.7%) 9 (90.0%) negative 26 (96.3%) 1 (10.0%) perirenal fat invasion < 0.001 positive 2 (7.4%) 9 (90.0%) negative 25 (92.6%) 1 (10.0%) perinephric stranding < 0.001 positive 7 (25.9%) 10 (10.0%) negative 20 (74.1%) 0 (0.0%) mri: magnetic resonance imaging; pt: pathological tumor. 5archivio italiano di urologia e andrologia 2022; 94, 1 predictive imaging features in renal cell carcinoma disease is similar to the literature. in addition, mri seems to be more reliable for detecting renal capsule invasion. in locally advanced rcc, thickening of the gerota's fascia adjacent to the tumor may be expected due to the spread of the tumor. however, increase in the thickness of gerota's fascia may also develop due to other reasons such as infectious pathologies. in a study by bradley et al., it was stated that the gerota’s fascia thickness on ct has 90% specificity and 81% ppv for t3a and above disease, and it has been shown that gerota’s fascia thickness is a reliable predictor of locally advanced disease (12). in our study, we measured the thickness of the gerota’s fascia adjacent to the tumor for the first time in the literature, and in our roc analysis, we determined that the cut-off value for the gerota’s fascia thickness in predicting advanced disease was 0.205 cm. according to this cut-off value, the specificity of the gerota’s fascia thickness in predicting a stage > t3a is 75% and 85% for ct and mri respectively. we also determined that the ppv value was 52% and 66% for ct and mri respectively. according to our results, we think that the gerota’s fascia thickness has less predictive value for locally advanced disease in contrast to literature and that mri is more reliable than ct. presence of enlarged collateral vessels and tumor necrosis are thought to be predictive markers for advanced rcc. in meta-analyses, indication of tumor necrosis as a factor that adversely affects prognosis in rcc makes the predictive value of the presence of necrosis in advanced stage disease more important in pre-operative imaging (18). there are studies indicating that tumor necrosis on ct has high specificity and ppv in predicting t3a disease (12). in our study, even though there was a significant difference between the groups in terms of the presence of necrosis, we found that the presence of necrosis had a low predictive value for advanced disease in both ct and mri (ppv= 37% and 47% respectively). however, the absence of tumor necrosis indicates that pathological stage could be < t3a (npv= 84% and 90% for ct and mri). on the other hand, in a study conducted by suo et al., it was shown that patients with collateral vessel diameter > 0.2 cm had a higher pt stage than patients with < 0.2 cm. they also showed that the presence of a collateral vessel is an independent prognostic factor for overall survival in rcc (19). in another study, the presence of enlarged collateral vessels was shown to have an 88% ppv value in predicting > pt3a disease (12). in our study, there was a significant difference between the groups in terms of the presence of enlarged collateral vessels on ct and mri (p = 0.008 and p = 0.015 respectively). however, although the npv value of the presence of enlarged collateral vessels in both ct and mri was high in predicting > pt3a disease (91% and 90% respectively), the ppv value was low (41% and 47% respectively). in contrast to literature, we don’t think that presence of enlarged collateral vessels can predict locally advanced disease in rcc. perinephric fat stranding develops mostly due to pyelovenous or pyelolymphatic backflow due to acute ureteral obstruction (20). studies have shown that perinephric fat stranding has a low predictive value for locally advanced disease in rcc (10, 14). in our study, we found that the power of perinephric fat standing to predict local advanced disease was low in both ct and mri (ppv = 39% and 58% respectively). on the other hand, mri seems more reliable than ct. nevertheless, our study has some limitations. firstly, our study is retrospective and the number of patients in the groups is limited. secondly, the patients in the mri and ct groups were different, and not every patient had both ct and mri as imaging so ct and mri were not statistically compared for predictive values of preoperative imaging markers. however, it can be said that mri may be more reliable because it has higher ppv values than ct for all predictors. thirdly, we did not measure the diameter of the collateral vessels. we considered patients with significant enlarged collateral vessels to be positive. conclusions in conclusion, renal capsular invasion, perirenal fat invasion are reliable signs for locally advanced (> pt3a) renal cell carcinoma both in ct and mri. gerota’s fascia thickness has relatively low ppv value for prediction of locally advanced disease. presence of enlarged collateral vessels, tumor necrosis, perinephric stranding are not reliable signs. on the other hand, for all predictors mri seems more reliable than ct. prospective large cohort studies are needed for more defined conclusions. references 1. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j. clin 2018; 68:394-424. 2. novara g, ficarra v, antonelli a, et al. validation of the 2009 tnm version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? eur urol, 2010; 58:588-95. 3. van poppel h, da pozzo l, albrecht w, et al. a prospective, randomised eortc intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. eur urol, 2011; 59:543-52. 4. mir mc, derweesh i, porpiglia f, et al. partial nephrectomy versus radical nephrectomy for clinical t1b and t2 renal tumors: a systematic review and meta-analysis of comparative studies. eur urol, 2017; 71:606-617. 5. ljungberg b, albiges l, abu-ghanem y, et al. european association of urology guidelines on renal cell carcinoma: the 2019 update. eur. urol.2019; 75:799-810. 6. antonelli a, furlan m, tardanico r, et al. features of ipsilateral renal recurrences after partial nephrectomy: a proposal of a pathogenetic classification. clin genitourin cancer 2017; 15:540-547. 7. hotker am, karlo ca, zheng j, et al. clear cell renal cell carcinoma: associations between ct features and patient survival. ajr am. j. roentgenol. 2016; 206:1023-1030. 8. amin mb, greene fl, edge sb, et al. the eighth edition ajcc cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. ca cancer j clin. 2017; 67:93-99. 9. sokhi hk, mok wy, patel u. stage t3a renal cell carcinoma: staging accuracy of ct for sinus fat, perinephric fat or renal vein invasion. br j radiol 2015; 88:20140504 archivio italiano di urologia e andrologia 2022; 94, 1 m. ali kutluhan, s. unal, s. eren, a. ozayar, e. okulu, h. cetin, o. kayigil 6 10. ha u-s, lee kw, jung j-h, et al. renal capsular invasion is a prognostic biomarker in localized clear cell renal cell carcinoma sci rep 2018; 8:202. 11. zhang y, tian h, zhang s, et al. multislice spiral computed tomography signs of invasion of the renal capsule by renal cell carcinoma medicine 2018; 97:e13075. 12. bradley aj, macdonald l, whiteside s, et al. accuracy of preoperative ct t staging of renal cell carcinoma: which features predict advanced stage? clin radiol 2015; 70:822-9. 13. shah ph, lyon td, lohse cm, et al. prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage t3a clear-cell renal cell carcinoma bju int 2019; 123:270-276. 14. brookman-may sd, may m, wolff i, et al. evaluation of the prognostic significance of perirenal fat invasion and tumor size in patients with pt1-pt3a localized renal cell carcinoma in a comprehensive multicenter study of the corona project. can we improve prognostic discrimination for patients with stage pt3a tumors? eur urol 2015; 67:943-51. 15. renard as, nedelcu c, paisant a, et al. is multidetector ct-scan able to detect t3a renal tumor before surgery? scand j urol 2019; 53:350-35. 16. el-hefnawy as, mosbah a, el-diasty t, et al. accuracy of multidetector computed tomography (mdct) in staging of renal cell carcinoma (rcc): analysis of risk factors for mis-staging and its impact on surgical intervention world j urol 2013; 31:887-91. 17. nazım sm, ather mh, hafeez k, et al. accuracy of multidetector ct scans in staging of renal carcinoma int j surg 2011; 9:86-90. 18. zhang l, zha z, qu w, et al. tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis bmc cancer 2018; 18:870. 19. suo x, chen j, zhao y, et al. clinicopathological and radiological significance of the collateral vessels of renal cell carcinoma on preoperative computed tomography sci rep 2021; 11:518. 20. farrell mr, papagiannopoulos d, ebersole j, et al. perinephric fat stranding is associated with elevated creatinine among patients with acutely obstructing ureterolithiasis. j endourol 2018; 32:891-89. correspondence musab ali kutluhan, md dr.musab151@gmail.com selman unal, md (corresponding author) drselmanunal@gmail.com universiteler district bilkent avenue no: 1 ankara, 06800 (turkey) serhan eren, md serhanerenhu@gmail.com etlik avenue no: 55 kecioren/ankara, 06010 (turkey) asim ozayar, md aozayar@gmail.com emrah okulu, md eokulu@yahoo.com huseyin cetin, md hcetinrad@gmail.com onder kayigil, md kayigilo@yahoo.com.tr universiteler district bilkent avenue no: 1 ankara, 06800 (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11481 1 letter to editor key words: benign prostatic obstruction; peyronie’s disease; mental health. submitted 27 june 2023; accepted 14 july 2023 to the editor, our study aimed to investigate a possible relationship between benign prostatic obstruction (bpo) and peyronie's disease (pd) and to characterize the psychological profile of patients affected by peyronie's disease, with or without concomitant bpo. in this study, we have investigated whether there is a relationship between the two diseases. the typical symptoms of pd are as follows: penile deformation, local pain, erectile dysfunction (ed), and anxious-depressive state. benign prostatic hyperplasia (bph) causes symptoms only in the case of urinary obstruction (benign prostatic obstruction/bpo). bpo is an emotionally stressful condition, but any type of treatment, such as surgery, by significantly decreasing luts, can significantly improve the general well-being of the affected patient (1). we performed a retrospective analysis of the clinical database of a single uro-andrology clinic. from the database, we considered two separate cohorts of patients observed between january 2013 and february 2023. the first cohort included 539 patients diagnosed with peyronie's disease. as a comparator population, we considered a cohort of 2208 outpatients referred to our clinic for any disease, but not peyronie's disease. in the two cohorts, we identified patients with a diagnosis of long-standing bpo. all data were obtained from patient records. this retrospective observational study was conducted in compliance with the principles contained in the declaration of helsinki (fortaleza, 2013); all study subjects were contacted and provided informed consent for study inclusion. sensitive data were anonymized to warrant patients’ privacy according to legislative decree 10 august 2018, n. 101, published in the official gazette of the italian republic, general series, issue 205, 09/04/2018. all 539 pd patients underwent photographic documentation of the penile deformation and dynamic penile eco-color doppler with plaque and volume measurements and answered the following questionnaires: the generalized anxiety disorder-7, the patient health questionnaire-9, the visual analog scale for penile pain measurements, the international index of erectile function (iief), and the international prostate symptom score (ipss). in the cohort of 539 pd patients and in a cohort of 2208 outpatients (comparator population), bpo was diagnosed in patients with urinary symptoms according to the following examinations: clinical history, thorough physical examination, including a digital rectal exam, prostate ultrasound, and microbiological assessment (preand post-massage urine and sperm cultures) to exclude concomitant chronic bacterial prostatitis, and the compilation of the international prostate symptom score (ipss). the primary endpoint of the study was the association between a diagnosis of bpo and the occurrence of pd in a single outpatient center patient population. the secondary endpoints were as follows: the impact of pd on the psychological status of patients with or without bpo; the impact of bpo in pd patients on the severity of penile curvature, on the multiplanarity of penile curvature, on plaque volume, on plaque multifocality, on plaque calcification, on the presence and severity of ed, and on presence and severity of penile pain. to investigate an association between pd and a history of bpo, we calculated the odds ratio (or) test. we completed a post hoc analysis of the statistical power obtained by calculating the crude odds ratio. our findings show that cases (pd patients) and controls (comparator population) did not differ in age and most associated pathologies. however, for some associated diseases such as diabetes mellitus, erectile dysfunction, hypertension, bpo, and chronic prostatitis (cp), there was a statistically significant difference between the two groups. clinical features and basic demographics of the patients in the two groups, as well as the results for the primary and secondary endpoints of the study, are shown in table 1. although many studies indicate some risk factors that influence the appearance of peyronie’s disease (penile trauma, diabetes mellitus, dupuytren’s disease, erectile dysfunction, congenital penile curvature, hypertension, obesity, smoking, benign prostatic obstruction (bpo) as a possible risk factor for peyronie's disease (pd). the influence of bpo and pd on mental health gianni paulis 1, andrea paulis 2 1 peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy; 2 neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy. doi: 10.4081/aiua.2023.11481 archivio italiano di urologia e andrologia 2023; 95(3):11481 g. paulis, a. paulis 2 hypertension, rheumatoid arthritis, psoriatic arthritis, psoriasis, dyslipidemia, and alcohol consumption), studies on bpo as a risk factor for pd are unfortunately lacking. our results show that the overall prevalence of benign prostatic obstruction in patients with peyronie’s disease is significantly higher (22.07%) than the prevalence in a non-pd control population (13.49%). the resulting significant crude odds ratio for bpo was 1.81 (p < 0.0001). our data suggest that bpo and pd are frequently associated. we have also ascertained that in pd patients, there is no impact of bpo on the psychological status of patients, on the severity of penile curvature, on the multiplanarity of penile curvature, on plaque volume, on plaque multifocality, on plaque calcification, on the presence and severity of ed, or on the presence and severity of penile pain. nevertheless, the severity of bpo symptom scores (ipss) correlated significantly with the severity of erectile dysfunction (p < 0.0001). furthermore, in peyronie's disease patients, we ascertained the presence of significant depressive symptoms in 57.1% of cases in contrast to the lower percentages documented in nelson's studies (48%) (2, 3). additionally, the prevalence of significant anxiety symptoms that we found in peyronie's disease patients (89.2%) appears to be higher when compared to the findings of other studies that generically refer to “distress” and “emotional” difficulties (80-81%) (4, 5). our findings indicate that bpo and pd are often associated. although our study has the limitations of being a retrospective analysis based on patient medical records, the the size of the odds ratio (or = 1.81) and its statistical significance (p < 0.0001) support our conclusions sufficiently. nevertheless, we believe that more studies are needed to confirm bpo as a risk factor for pd. our study confirms that bpo affects the severity of ed in patients with peyronie's disease, and this suggests that bpo should be treated early and efficiently to hinder the onset and progression of ed in these patients. table 1. clinical features and basic demographics of patients in the two groups, and results for the primary and secondary endpoints of the study. clinical features and basic demographics of patients in the two groups (pd patients and non-pd patients) variable pd patients non-pd control population statistical analysis (539 cases) (2208 cases) p-value (t-test) mean age 49.6 (± 12.16 sd) 50.5 (± 12.04 sd) 0.120 variable pd patients non-pd control population statistical analysis n. cases (%) n. cases (%) p-value (𝝌2-test) varicocele 13 (2.4) 62 (2.8) 0.720 hydrocele 6 (1.1) 23 (1.04) 0.884 hypercholesterolemia 48 (8.9) 151 (6.8) 0.117 thyroid disease 27 (5.00) 111 (5.02) 0.986 history of myocardial infarction 13 (2.4) 50 (2.2) 0.964 history of malignant urological neoplasm 43 (7.97) 176 (7.97) 0.995 history of non-urological malignancy 11 (2.04) 48 (2.17) 0.979 history of urinary stones 52 (9.6) 207 (9.37) 0.910 urogenital infections 19 (3.5) 120 (5.4) 0.088 diabetes mellitus 32 (5.9) 77 (3.48) 0.0128 hypertension 101 (18.7) 299 (13.5) 0.0027 erectile dysfunction (ed) 216 (40.07) 529 (23.95) < 0.0001 chronic prostatitis (cp) 200 (37.1) 384 (17.39) < 0.0001 benign prostatic obstruction (bpo) 119 (22.07) 298 (13.49) < 0.0001 primary endpoints cohort of patients with non-pd control statistical analysis peyronie's disease (pd) population odds ratio (or) p-value benign prostatic obstruction (bpo) 119 298 no benign prostatic obstruction (bpo) 420 1910 total 622 2208 prevalence of bpo (%) 22.07 13.49 or = 1.81 p < 0.0001 secondary endpoints impact statistical analysis yes or no p-value the impact of benign prostatic obstruction on the presence and severity of anxiety no < 0.05 * presence and severity of depression no < 0.05 * presence and severity of penile curvature no > 0.05 penile curvature multiplanarity no > 0.05 plaque volume no > 0.05 plaque multifocality no > 0.05 plaque calcification no > 0.05 presence and severity of erectile dysfunction no < 0.05 ** presence and severity of penile pain no < 0.05 *** * although the p-value was found to be significant, this must be interpreted in favor of cases without bpo. note that median anxiety and depression scores were found to be higher in pd patients without bpo. consequently, no positive impact of bpo on presence of anxiety or depression in patients with pd was found. ** although the p-value was found to be significant, this must be interpreted in favor of cases without bpo, in fact, the severity of total bpo symptom scores assessed with the ipss test correlated significantly and inversely with iief scores. these results indicate that, in pd patients, no positive impact of bpo on presence and severity of erectile dysfunction was found. *** although the p-value was found to be significant, the trend line of the logistic regression test indicated that the vas score is higher in pd patients without bpo than the vas score in bpo patients. these results indicate that, in pd patients, no positive impact of bpo on pain severity was found. archivio italiano di urologia e andrologia 2023; 95(3):11481 3 bemign prostatic obstruction and peyronie’s disease our results also revealed an important prevalence of anxiety and depression in pd patients; furthermore, we are especially concerned about the high percentages of “severe” anxiety (39.3%) present in the course of pd. consequently, we believe that simultaneous psychological therapy is highly desirable in these patients, both to improve their quality of life and to avoid a drop-out of medical treatments. references 1. anderson d, kumar d, divya d, et al. mental health in non-oncologic urology patients. health psychol res. 2022; 10:38352. 2. nelson cj, diblasio c, kendirci m, et al. the chronology of depression and distress in men with peyronie's disease. j sex med. 2008; 5:19851990. 3. nelson cj, mulhall jp. psychological impact of peyronie's disease: a review. j sex med. 2013; 10:653-660. 4. terrier je, nelson cj. psychological aspects of peyronie's disease. transl androl urol. 2016; 5:290-295. 5. smith jf, walsh tj, conti sl, et al. risk factors for emotional and relationship problems in peyronie’s disease. j sex med. 2008; 5:2179-2184. correspondence gianni paulis, md (corresponding author) paulisg@libero.it peyronie’s care center, department of uro-andrology, castelfidardo clinical analysis center, rome, italy andrea paulis andrea.fx.94@gmail.com neurosystem center for applied psychology and neuroscience, janet clinical centre, rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13257 1 original paper ment has advanced over time, radical prostatectomy (rp) continues to be the standard surgical treatment for localized cases (2). over the past two decades, the surgical management of localized prostate cancer has undergone substantial changes. open radical prostatectomy (orp) has been largely replaced by laparoscopic radical prostatectomy (lrp) and robot-assisted laparoscopic radical prostatectomy (ralp) in many parts of the world (3). ralp, in particular, has emerged as the leading surgical technique, accounting for over 61% of rp cases in some regions (4). despite these technological advancements, orp remains a crucial procedure in regions with limited access to robotic surgical systems, such as azerbaijan, where ralp is not yet available. the outcomes of orp and minimally invasive techniques have been extensively studied. generally, ralp is associated with reduced blood loss and shorter hospital stays but incurs higher costs compared to orp. both lrp and ralp have demonstrated favorable perioperative outcomes compared to orp, with comparable long-term oncologic control (4). however, comprehensive studies examining orp outcomes in the azerbaijani population are lacking, and the effectiveness of this approach in early-stage prostate cancer within our region is not well documented. in light of the absence of robot-assisted surgical methods in azerbaijan and the scarcity of academic literature on prostatectomy outcomes for early-stage prostate cancer patients in this country, it is crucial to explore the experiences of surgeons proficient in the orp technique. this study aims to address this gap by providing insights from the perspective of an experienced surgeon on orp outcomes in azerbaijan. we believe that sharing this experience will not only contribute valuable data to the limited academic literature on prostate cancer treatment in azerbaijan but will also serve as a foundation for comparisons with international outcomes in prostate cancer surgery. methods study population and data collection this study included men diagnosed with non-metastatic prostate cancer patients with t1-t3 tumors with or without lymph node involvement who underwent extraperiobjective: prostate cancer is a significant health concern worldwide and ranks as the 4th most frequent cancer among men in azerbaijan. while robot-assisted laparoscopic radical prostatectomy is the preferred surgical technique in many countries, open retropubic radical prostatectomy (orp) remains the primary treatment option in azerbaijan due to limited access to robotic surgical systems. this study aims to analyze the outcomes of orp in patients with local and locally advanced prostate cancer. methods: we retrospectively evaluated 95 men who underwent extraperitoneal retropubic orp for prostate cancer at our center between may 2020 and december 2023. comprehensive data on patient demographics, preoperative parameters, surgical details, and postoperative outcomes were collected. statistical analyses were conducted using ibm spss 27.0 software. results: the mean age of the patients was 65.9 years. the median preoperative psa level was 14.8 ng/ml, and lymph node enlargement was identified in 29.5% of patients. a rectal injury occurred in one patient (1.1%) as the only intraoperative complication. the mean intraoperative blood loss was 330 ml, and the median hospital stay was 6 days. a positive surgical margin was observed in 38.9% of cases. diabetes mellitus and higher intraoperative blood loss were associated with prolonged hospital stays (≥ 7 days). erectile dysfunction was reported in 52.6% of patients 6 months postoperatively, while urinary incontinence was observed in 2.2%. conclusions: orp outcomes in azerbaijan are comparable to those reported for laparoscopic and robot-assisted techniques in terms of perioperative and oncological results. despite the absence of advanced surgical technology, orp remains an effective treatment option for prostate cancer when performed by experienced surgeons. key words: prostate cancer; open radical prostatectomy; azerbaijan. submitted 15 october 2024; accepted 21 october 2024 introduction prostate cancer is a major health concern for men worldwide, remaining one of the most prevalent malignancies affecting this population. in azerbaijan, prostate cancer has become increasingly common, ranking as the 4th most frequent cancer among men in 2022, with an incidence rate of 5.7% (1). although prostate cancer treatradical prostatectomy outcomes of prostate cancer cases: insights from a leading surgeon's experience in azerbaijan rashad sholan scientific research center, state security service military hospital, baku, azerbaijan; department of kidney diseases and organ transplantation, republican diagnostic center, baku, azerbaijan. doi: 10.4081/aiua.2024.13257 summary archivio italiano di urologia e andrologia 2024; 96(4):13257 r. sholan 2 toneal retropubic orp at our centers between may 2020 and december 2023. all procedures performed in the study involving human participants were in accordance with the 1964 helsinki declaration and its later amendments. the study was approved by state security service scientific research center ethics board (decision no: etek: 24/03). we collected comprehensive data on patients' baseline characteristics, including age, body mass index (bmi), comorbid diseases, smoking status, and family history of prostate cancer. preoperative parameters such as serum prostate-specific antigen (psa) levels, prostate volume (measured via transrectal ultrasound or magnetic resonance imaging), imaging results, and needle biopsy findings were recorded. surgical technique all surgeries were performed using the open extraperitoneal retropubic approach, aiming to preserve urinary continence. this technique was performed by an experienced surgeon following the standardized procedure described in the literature (5). after placing the patient in the supine position, a midline incision was made from the pubic symphysis to the umbilicus. the extraperitoneal space was developed, and the prostate was carefully dissected, with an emphasis on preserving the neurovascular bundles whenever feasible, depending on the tumor's location and size. hemostasis was meticulously maintained throughout the procedure, and the dorsal vein complex was controlled using ligatures and sutures. the bladder neck was dissected carefully to maintain its integrity, and the prostate was removed en bloc. bilateral pelvic lymph node dissection was performed in patients with a higher risk of lymph node involvement. the urethrovesical anastomosis was completed using interrupted sutures. a drain was placed in the pelvic cavity, and a urinary catheter was left in place for postoperative management. intraoperative and postoperative data during the surgery, data on the anesthesia method, duration of the operation, and estimated intraoperative blood loss were recorded. any intraoperative complications were documented. postoperative follow-up included monitoring for complications, such as bleeding, infection, or urinary leakage, as well as the duration of the hospital stay. all prostatectomy specimens were examined by experienced pathologists, and pathological parameters such as gleason score, surgical margin status, lymphovascular and/or perineural invasion, and lymph node involvement were assessed. serum psa levels were measured at 3 months to evaluate early biochemical recurrence. erectile dysfunction (ed) was assessed six months postoperatively using an azerbaijani translation of the third question from the international index of erectile function, which inquired, “in the past 6 months, how often was your erection firm enough for penetration during sexual activity?”. erectile function was considered adequate if erections were sufficient for intercourse more than 50% of the time. statistical analysis statistical analyses were performed using ibm spss 27.0 software. descriptive characteristics were presented as frequency (%), mean ± sd, or median (range). normal distribution of continuous variables was assessed using visual and analytical methods. chi-square or fisher's exact test compared categorical groups. student t-test or mann-whitney u test compared independent continuous variables, while paired sample t-test or wilcoxon test analyzed dependent variables. a p-value < 0.05 was considered statistically significant. results the mean age of the 95 patients included in the study was 65.9 ± 6.4 years (range: 52-83). the basic clinical characteristics of the patients are summarized in table 1. the preoperative median psa level was 14.8 ng/ml (range: 0.2-145), and the prostate volume was 55 ml (range: 28table 1. baseline patient characteristics. characteristics total 95 patients * age (years) 65.9 ± 6.4 bmi (kg/m2) 26.7 ± 1.7 comorbidities diabetes mellitus 34 (35.8) coronary artery disease 29 (30.5) cholelithiasis 7 (7.4) artificial mitral valve 6 (6.3) asthma 5 (5.3) renal stone 4 (4.2) heart failure 3 (3.2) copd 3 (3.2) inguinal hernia 3 (3.2) others 12 (12.6) smoking 37 (38.9) family history of prostate cancer 31 (32.6) * findings are presented as n (%) or mean ± standard deviation. bmi: body mass index; copd: chronic obstructive pulmonary disease. table 2. preoperative characteristics. characteristics total 95 patients * psa (ng/ml) 14.8 (0.2-145) prostate volume (ml) 55 (28-110) lymph node enlargement 28 (29.5) needle biopsy results asap 22 (23.2) adenocarcinoma 73 (76.8) gleason score 4 (2+2) 4 (5.5) 5 (2+3) 2 (2.7) 6 (3+3) 33 (45.2) 7 (3+4) 4 (5.5) 7 (4+3) 13 (17.8) 8 (4+4) 16 (21.9) 9 (4+5) 1 (1.4) hemoglobin level (g/dl) 14.6 ± 1.6 * findings are presented as n (%), mean ± standard deviation or median (min-max). asap: atypical small acinar proliferation, psa: prostate-specific antigen. archivio italiano di urologia e andrologia 2024; 96(4):13257 3 radical prostatectomy experience from azerbaijan 110). lymph node enlargement was detected on imaging in 28 patients (29.5%). prostate needle biopsy identified atypical small acinar proliferation (asap) in 22 patients (23.2%) and prostate adenocarcinoma in 73 patients (76.8%). among those with prostate adenocarcinoma, the gleason score on preoperative biopsy was ≤ 6 in 53.4% of cases, 7 in 23.3%, and ≥ 8 in 23.3% (table 2). intraoperative parameters and postoperative short-term surgical outcomes are presented in table 3. one patient experienced a rectal injury, which was repaired intraoperatively; this patient was monitored in the icu for one day. no other postoperative complications or deaths occurred. postoperative hemoglobin levels showed a significant decrease compared to preoperative levels (14.6 ± 1.6 g/dl vs. 13.1 ± 0.9 g/dl; p < 0.001). the median hospital stay was 6 days (range: 5-14). a comparison between patients with a hospital stay of < 7 days (n = 49) and those with a stay of ≥ 7 days (n = 46) is shown in table 4. patients with a hospital stay of ≥ 7 days had a higher incidence of diabetes mellitus (47.8% vs. 24.5%; p = 0.018) and greater median intraoperative blood loss (345 ml [range: 150600] vs. 310 ml [range: 150-510]; p = 0.004). in the postoperative pathological examination, a positive surgical margin was observed in 37 patients (38.9%), and the gleason score was ≤ 6 in 27.4%, 7 in 55.8%, and ≥8 in 16.8% of cases. for patients with a preoperative asap diagnosis (n = 22), the postoperative gleason score was ≤6 in 63%, 7 in 27.3%, and ≥ 8 in 9.1% (figure 1). regarding those with a preoperative gleason score ≤ 6, 23.1% remained at ≤ 6 postoperatively; for patients with a preoperative gleason score of 7, 64.7% retained a score of 7; and for those with a preoperative gleason score of ≥ 8, 47.1% remained at ≥ 8 postoperatively (figure 2). lymph node metastasis was confirmed in 40.9% of patients with preoperative lymph node enlargement, compared to 6.6% of those without lymph node enlargement (p < 0.001). detailed postoperative pathological outcomes table 4. comparison of baseline and perioperative characteristics of patients with and without a hospital stay of ≥ 1 week. hospital stay * < 7 days (n = 49) ≥ 7 days (n = 46) age (years) 66.6 ± 6.2 65.1 ± 6.6 0.267 bmi (kg/m2) 26.5 ± 1.5 27.0 ± 1.8 0.202 comorbidities diabetes mellitus 12 (24.5) 22 (47.8) 0.018 coronary artery disease 13 (26.5) 16 (34.8) 0.383 cholelithiasis 4 (8.2) 3 (6.5) 1.000 artificial mitral valve 3 (6.1) 3 (6.5) 1.000 asthma 1 (2.0) 4 (8.7) 0.195 renal stone 3 (6.1) 1 (2.2) 0.618 heart failure 1 (2.0) 2 (4.3) 0.609 copd 2 (4.1) 1 (2.2) 1.000 inguinal hernia 2 (4.1) 1 (2.2) 1.000 others 6 (12.2) 6 (13.0) 0.907 smoking 20 (40.8) 17 (37.0) 0.700 preoperative hemoglobin level (g/dl) 14.9 ± 1.8 14.4 ± 1.4 0.101 anesthesia method 0.477 general 46 (93.9) 41 (89.1) epidural 3 (6.1) 5 (10.9) duration of surgery (min) 160 (120-220) 160 (130-230) 0.067 intraoperative blood loss (ml) 310 (150-510) 345 (150-600) 0.004 intraoperative complication 0 (0.0) 1 (2.2) 0.484 postoperative hemoglobin level (g/dl) 13.3 ± 1.0 12.9 ± 0.8 0.138 * findings are presented as n (%), mean ± standard deviation or median (min-max). bmi: body mass index; copd: chronic obstructive pulmonary disease. table 3. intraoperative parameters and postoperative surgical outcomes. parameters total 95 patients * anesthesia method general 87 (91.6) epidural 8 (8.4) duration of surgery (min) 160 (120-230) intraoperative blood loss (ml) 330 (150-600) intraoperative complication 1 (1.1) ** icu admission 1 (1.1) ** postoperative hemoglobin level (g/dl) 13.1 ± 0.9 postoperative complication 0 (0.0) hospital stay (days) 6 (5-14) * findings are presented as n (%), mean ± standard deviation or median (min-max). ** a patient experienced a rectal injury, which was repaired intraoperatively, and was subsequently monitored in the icu for one day. icu: intensive care unit. figure 1. distribution of postoperative gleason scores among patients initially diagnosed with atypical small acinar proliferation based on preoperative needle biopsy. figure 2. comparison of preoperative and postoperative gleason scores in patients diagnosed with prostate adenocarcinoma via preoperative needle biopsy. archivio italiano di urologia e andrologia 2024; 96(4):13257 r. sholan 4 are provided in table 5. the preoperative median psa level of 14.8 ng/ml (range: 0.2-145) decreased to 0.0030 ng/ml (range: 0.0001-0.34) at the first postoperative month and remained stable at 0.0032 ng/ml (range: 0.0001-0.3) by the third postoperative month (figure 3). while ed was present in 21.1% of patients before surgery, it was detected in 52.6% of patients 6 months after surgery. two (2.2%) patient developed urinary incontinence during postoperative follow-up. discussion our study provides a comprehensive analysis of the outcomes of orp in men with local and locally advanced prostate cancer, offering valuable insights into the experiences of a high-volume center in azerbaijan. while the adoption of lrp and ralp has grown rapidly worldwide, orp continues to be a relevant surgical option, especially in settings where advanced technology is not available. our study showed a median operative time of 160 minutes, comparable to the duration observed in lrp as reported by çelen et al. (6), where experience contributed to reduced operative times. our study had only one intraoperative complication (1.1%), which involved a rectal injury, consistent with the low complication rates reported in experienced centers performing orp (7). studies involving large orp series have reported that mean intraoperative blood loss can range from 500 ml to over 2 liters (8). this variation is influenced by factors such as the surgical technique, whether nerve-sparing procedures are performed, the surgeon's level of experience, and the duration of the surgery (9). the intraoperative blood loss in our study was 330 ml, which was reported as 372 ml in a 2-year prospective lrp series by leitao et al. (10). this suggests that while minimally invasive techniques offer some perioperative advantages, orp remains a viable option, particularly when performed by an experienced surgeon. the mean hospital stay for orp in our cohort was comparable to that reported for minimally invasive techniques in other studies (10). our analysis revealed that patients with diabetes mellitus and those with higher intraoperative blood loss experienced prolonged hospital stays. therefore, meticulous perioperative management is essential to minimize complications and optimize recovery following orp. the positive surgical margin rate in our study was 38.9%, which is somewhat higher than the 23.7% reported by çelen et al. (6) for lrp but comparable to the rates reported in other orp studies (3, 7). in comparing orp outcomes with lrp and ralp, several studies have reported similar oncological results (11, 12). for instance, ficarra et al. (13) found no significant differences in positive surgical margin rates between orp, lrp, and ralp, suggesting that all three techniques can provide effective cancer control when performed by experienced surgeons. furthermore, the positive surgical margin rates in our study were comparable to those reported for minimally invasive techniques (14). this indicates that with adequate surgical expertise, orp can achieve effective oncologic control, even in the absence of advanced technology. the median life expectancy after curative treatment for prostate cancer exceeds 10 years (15). as a result, it is vital to optimize long-term functional outcomes to enhance the postoperative quality of life for these men. the most frequent long-term complications following surgery are ed and urinary incontinence, both of which can significantly diminish patients' quality of life. pompe et al. (16) found that the rate of functional erections significantly decreased after orp. while 78.4% of patients had functional erections at baseline, this dropped to 33.6% at 3 months post-surgery. gradual improvement was seen, reaching 44.7% at 12 months, 51.1% at 24 months, and 52.6% at 36 months. while 78.9% of our patients described effective erection before the operation, this rate decreased to 47.4% 6 months after the operation. incontinence is often the most challenging and disfigure 3. changes in prostate-specific antigen (psa) levels measured preoperatively, as well as at the 1st and 3rd months postoperatively. table 5. postoperative pathological outcomes. parameters total 95 patients * surgical margin positivity 37 (38.9) proximal 10/37 (27.0) distal 12/37 (32.4) both 15/37 (40.5) gleason score 4 (2+2) 2 (2.1) 6 (3+3) 24 (25.3) 7 (3+4) 30 (31.6) 7 (4+3) 23 (24.2) 8 (4+4) 7 (7.4) 8 (5+3) 1 (1.1) 9 (4+5) 7 (7.4) 9 (5+4) 1 (1.1) lymphovascular invasion 57 (60.0) perineural invasion 72 (75.8) number of lymph nodes removed 8 (2-15) metastatic lymph node 15 (15.8) number of metastatic lymph nodes (n = 15) 2 (1-11) * findings are presented as n (%) or median (min-max). archivio italiano di urologia e andrologia 2024; 96(4):13257 5 radical prostatectomy experience from azerbaijan tressing complication associated with rp for both patients and clinicians. studies have reported postoperative continence rates ranging from 80% to 97% in contemporary surgical cases (7). in our series postoperative continence rate was 97.8%. when considering cost-effectiveness, orp continues to have an advantage over ralp, particularly in lowresource settings. therefore, in countries like azerbaijan, where robotic technology is not yet available, orp remains an essential, effective, and cost-efficient option. however, to ensure access to modern medical practices, companies offering robot-assisted surgical technologies should actively collaborate with our country. the expanding comprehensive health insurance system aims to enhance patient access to advanced treatments and improve overall health outcomes. a preoperative diagnosis of asap is known to be associated with varying rates of postoperative prostate cancer detection. in one study, 42% of cases with a pathological diagnosis of asap were later confirmed to have prostate cancer (17). in another sudy, among 71 patients diagnosed with asap, 25 underwent pelvic bilateral lymphadenectomy and nerve-sparing rp immediately after the diagnosis (18). remarkably, all 25 were confirmed to have adenocarcinoma in the final pathology, as verified by an independent review pathologist. in our cohort, 22 patients (23.2%) had preoperative needle biopsy results consistent with asap, with the diagnosis confirmed through repeat biopsies. the decision to perform radical prostatectomy in these cases was driven by suspicious rectal exam findings and rising psa levels. radical surgery was undertaken after detailed discussions with patients about the potential benefits and risks. interestingly, all of these cases resulted in a postoperative diagnosis of prostate cancer. in cases where asap is detected on biopsy, a comprehensive assessment that includes clinical, laboratory, and radiological findings is crucial. additionally, treatment decisions should take into account patient preferences, life expectancy, quality of life, and the psychological burden of the diagnosis. an important point to mention is that more than half of the patients in our cohort diagnosed with prostate cancer through preoperative biopsy had a gleason score of 6 or lower. however, due to the widespread negative perception of a cancer diagnosis in our society, active surveillance is not commonly accepted. it also lacks sufficient support within the ministry of health's regulations. this explains why rp was performed in these patients, despite their low gleason scores. furthermore, the european association of urology (eau) guidelines for active surveillance are somewhat limited due to the lack of data from prospective randomized controlled trials (19). when deciding between active surveillance and radical surgery, it's crucial to consider the patient's psychosocial status, anxiety levels, and societal views. conclusions in conclusion, our study provides valuable insights into the outcomes of orp for prostate cancer in a setting without access to advanced laparoscopic or robotic techniques. the findings underscore the importance of surgeon experience in achieving favorable outcomes and demonstrate that orp remains a viable, effective, and potentially cost-efficient treatment option for prostate cancer. references 1. ferlay j, ervik m, lam f, et al. (2024). global cancer observatory: cancer today. lyon, france: international agency for research on cancer. available from: https://gco.iarc.who.int/today. accessed [30.09.2024]. 2. costello aj. considering the role of radical prostatectomy in 21st century prostate cancer care. nat rev urol. 2020; 17:177-88. 3. loeb s, catalona wj. open radical retropubic prostatectomy. urol oncol. 2007; 25:494-8. 4. healy ka, gomella lg. retropubic, laparoscopic, or robotic radical prostatectomy: is there any real difference? semin oncol. 2013; 40:286-96. 5. lepor h. radical retropubic prostatectomy. urol clin north am. 2001; 28:509-19, viii. 6. çelen s, özlülerden y, mete a, et al. laparoscopic radical prostatectomy: a single surgeon’s experience in 80 cases after 2 years of formal training. african j urol. 2021; 27:57. 7. pereira r, joshi a, roberts m, et al. open retropubic radical prostatectomy. transl androl urol. 2020; 9:3025-35. 8. yaxley jw, coughlin gd, chambers sk, et al. robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. lancet. 2016; 388:1057-66. 9. djavan b, agalliu i, laze j, et al. blood loss during radical prostatectomy: impact on clinical, oncological and functional outcomes and complication rates. bju int. 2012; 110:69-75. 10. leitão tp, papatsoris ag, mandron e. extraperitoneal laparoscopic radical prostatectomy: a prospective 2-year single-surgeon experience with 171 cases. arab j urol. 2012; 10:347-52. 11. lantz a, bock d, akre o, et al. functional and oncological outcomes after open versus robot-assisted laparoscopic radical prostatectomy for localised prostate cancer: 8-year follow-up. eur urol. 2021; 80:650-60. 12. coughlin gd, yaxley jw, chambers sk, et al. robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study. lancet oncol. 2018; 19:1051-60. 13. ficarra v, novara g, fracalanza s, et al. a prospective, nonrandomized trial comparing robot-assisted laparoscopic and retropubic radical prostatectomy in one european institution. bju int. 2009; 104:534-9. 14. ficarra v, novara g, artibani w, et al. retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. eur urol. 2009; 55:1037-63. 15. tward jd, lee cm, pappas lm, et al. survival of men with clinically localized prostate cancer treated with prostatectomy, brachytherapy, or no definitive treatment: impact of age at diagnosis. cancer. 2006; 107:2392-400. 16. pompe rs, tian z, preisser f, et al. shortand long-term functional outcomes and quality of life after radical prostatectomy: archivio italiano di urologia e andrologia 2024; 96(4):13257 r. sholan 6 patient-reported outcomes from a tertiary high-volume center. eur urol focus. 2017; 3:615-20. 17. mallén e, gil p, sancho c, et al. atypical small acinar proliferation: review of a series of 64 patients. scand j urol nephrol. 2006; 40:272-5. 18. brausi m, castagnetti g, dotti a, et al. immediate radical prostatectomy in patients with atypical small acinar proliferation. over treatment? j urol. 2004;172:906-8. 19. cornford p, van den bergh rcn, briers e, et al. eau-eanmestro-esur-isup-siog guidelines on prostate cancer-2024 update. part i: screening, diagnosis, and local treatment with curative intent. eur urol. 2024; 86:148-63. correspondence rashad sholan md, phd, dsci (corresponding author) sholanrashad@gmail.com scientific research center, state security service military hospital, baku, azerbaijan az1000, baku city, badamdar, mektebli street, 1 conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13695 1 original paper for treating ureteric strictures by utilizing buccal mucosa grafts (bmg) in conjunction with omental wrapping. implementing onlay bmg during ureteral reconstruction eliminates the necessity for extensive ureterolysis, reducing disruption to the peri-ureteral blood supply. furthermore, the bmg can be customized to accommodate the dimensions of the ureteral defect, ensuring a tension-free anastomosis (3). although bmg ureteroplasty for long-segment ureteral strictures was developed long ago, evidence is still restricted to case series in the literature. the current study aims to evaluate outcomes of onlay bmg ureteroplasty for recurrent, long-segment proximal ureteric strictures and recurrent uretero-pelvic junction obstruction (upjo). patients and methods study design and patient selection the present study is a prospective trial conducted at the urology department, faculty of medicine, al-azhar university in cairo, egypt, from january 2022 to september 2024. following approval from the local institutional review board, the study was duly registered on clinicaltrials.gov, with a registration id of nct05928364. the cohort comprised patients with recurrent long proximal and middle ureteric strictures and recurrent upjo not amenable to primary anastomosis due to stricture length or extensive fibrosis. before surgical intervention, all patients underwent comprehensive medical history assessments, physical examinations, and standard laboratory investigations. for preoperative imaging, abdominal ultrasound and renal isotope scans were conducted for all participants. antegrade pyelography was performed in cases with a fixed percutaneous nephrostomy (pcn) tube. computed tomography (ct) urogram was requested when clinically indicated. all enrolled patients underwent open ureteroplasty utilizing onlay bmg and omental wrapping. operative technique under general anesthesia, retrograde ureteropyelography was performed for all cases to assess the exact stricture objectives: to evaluate the outcomes of oral buccal mucosa graft (bmg) ureteroplasty in managing recurrent long-segment proximal ureteric strictures and recurrent uretero-pelvic junction obstruction (upjo). methods: a single-centre prospective study included patients with recurrent long-segment proximal ureteric strictures and recurrent upjo treated with open onlay bmg ureteroplasty from january 2022 to september 2024. patient demographics, intraoperative and postoperative characteristics, and the percentage of stricture-free status at the last visit were documented. complication rates were categorized according to the modified clavien-dindo grading system. results: the study included 21 patients, 11 males (52.4%) and 10 females (47.6%), with a mean age ± sd of 45.8 ± 13.7 years. regarding the stricture etiology, ten patients (47.6%) had previously undergone complicated endoscopic stone surgeries, seven patients (33.3%) had a history of open surgery for stone disease, while the remaining four (19%) had undergone previously failed pyeloplasty for congenital upjo. the mean operative time was 145 minutes, the mean stricture length ± sd was 3.94 ± 1.4 cm, and the mean harvested bmg length ± sd was 7.6 ± 1.1 cm. six patients (28.6%) developed postoperative complications of clavien ii and iii grade. the follow-up duration ranged from 9 to 24 months, with a mean duration of 16.3 months. at the last follow-up visit, 18 out of 21 patients (85.7%) were stricture-free. conclusions: buccal mucosa graft for onlay ureteroplasty represents an effective surgical intervention for managing recurrent, long-segment proximal ureteric strictures and recurrent cases of ureteropelvic junction obstruction. key words: stricture; ureter; buccal mucosa, proximal. submitted 6 february 2025; accepted 6 february 2025 introduction surgical management of long proximal ureteral strictures presents significant challenges in clinical practice. surgical options, such as ileal ureter replacement and renal autotransplantation, can be considered for addressing these conditions. however, both procedures are associated with complexities and a substantial risk of morbidity (1). in 1999, naude (2) introduced an alternative and innovative technique buccal mucosal graft for onlay ureteroplasty in the management of proximal ureteral stricture. single centre, prospective trial ahmed salah nasef, ibrahim alaa eldin tagrida, mohamed fawzy salman, adel elatreisy, sabry mahmoud khaled urology department, faculty of medicine, al-azhar university, cairo, egypt. doi: 10.4081/aiua.2025.13695 summary archivio italiano di urologia e andrologia 2025; 97(2):13695 a. salah nasef, i. alaa eldin tagrida, m. fawzy salman, a. elatreisy, s. mahmoud khaled 2 length, and combined antegrade and retrograde ureteropeylography were used in patients with fixed pcn. patients were placed in the lateral lumbar position, and the incision was performed to access the affected site of the ureter. the diseased ureteral segment was identified and longitudinally incised from the lateral side. after incising the stricture segment, we kept it as a plate, and the exact length of the defect was measured. the bmg was harvested from the inner cheek after identification of the stensen duct. each graft had a varying length that followed the size of the ureteral defect. the harvested mucosal graft was laid on the incised ureters as an onlay graft (figure 1) and sutured with vicryl 4/0 with antegrade 6 fr double-j (dj) ureteric stent. the omentum was then mobilized and wrapped around the reconstructed site of the ureter. follow up patients were monitored for blood tests and drain output during the early postoperative period. as part of their treatment regimen, they received anti-inflammatory and antibacterial therapy and were discharged after the drain was removed. the foley catheter was removed once the drain output was nil for 48 hours. the drain was also removed if there was no output for 24 hours following the removal of the foley catheter. for patients with a fixed pcn, it was closed for 48 hours once the drain output was nihil and removed if there was no pain or fever. the dj ureteral stent was scheduled for cystoscopy and was removed approximately six to eight weeks postoperatively. the hydronephrosis grade was assessed according to the society of fetal urology (sfu) classification, and renal function was evaluated with a renal isotope scan 3 to 6 months after surgery. outcomes the analysis will encompass patient demographics, intraoperative data, perioperative complications as classified by the modified clavien-dindo grading system (5), duration of follow-up, and the percentage of patients remaining free of strictures at the final assessment. a good postoperative outcome was considered being asymptomatic, the absence of hydronephrosis or grade 1, a patent ureter on contrast study after removal of the ureteric stent (figures 2-4), and a non-obstructed curve in the diuretic renogram. statistical analysis statistical analysis was conducted using spss statistical software version 29.0 (ibm, chicago, usa). continuous data are presented as means and standard deviations. nominal data are reported in terms of counts and perfigure 1. opened ureter in the site of stricture, buccal mucosa graft was sutured to the ureteral defect with a double-j ureteric stent. figure 2. a: preoperative retrograde uretero-pyelography revealed recurrent long-segment stricture of the proximal right ureter. b: post onlay buccal mucosa graft ureteroplasty with antegrade nephrostogram showing patent right ureter. archivio italiano di urologia e andrologia 2025; 97(2):13695 3 buccal mucosal graft for onlay ureteroplasty in the management of proximal ureteral stricture centages. depending on the data type, the paired-sample t-test was utilized to compare preoperative and postoperative parameters. differences were considered statistically significant at a threshold of p < 0.05. results twenty-one patients were included, comprising 11 males (52.4%) and 10 females (47.6%). the mean age of the cohort was 45.8 years. eleven (52.4%) were found to have dj stents, five (23.8%) had fixed percutaneous nephrostomy (pcn) tubes, and the remaining five presented solely with loin pain without any fixed catheters or tubes. regarding the etiology of the stricture, ten patients (47.6%) had complicated endoscopic ureteric stone surgeries, including four patients (19%) who underwent semirigid ureteroscopy (urs), and six patients (28.6%) who underwent retrograde intrarenal surgery. seven patients (33.3%) had a history of open surgery for stone disease, while the remaining four (19%) had undergone pyeloplasty for upjo. the mean stricture length ± sd was 3.94 ± 1.4 cm, and the mean harvested bmg length ± sd was 7.6 ± 1.1 cm. patients' demographic data are demonstrated in table 1. the operative time ranged from 105 to 205 minutes, with a mean duration of 145.71. estimated blood loss (ebl) during surgery varied between 50 and 300 ml, with an average of 157.14 ml (table 2). the average length of hospital stay (los) was 4.28 days. figure 3. a: preoperative retrograde uretero-pyelography revealed a 3 cm recurrent stricture of the proximal right ureter. b: post buccal mucosa graft onlay ureteroplasty with rgp showing patent right ureter and wide graft area. figure 4. a: preoperative retrograde pyelography (rgp) revealed a 2 cm recurrent stricture of the proximal left ureter and failed previous four times ureteroplasty procedures. b: post onlay buccal mucosa graft ureteroplasty with rgp showing patent left ureter and wide graft area. table 1. demographic data of the study cohort. parameter value age, mean ± sd 45.76 ± 13.7 sex, n (%) male 11 (52.4) female 10 (47.6) bmi, mean ± sd 30 ± 3.8 stricture location, n (%) upj 4 (19%) proximal 14 (66.7%) middle 3 (14.3%) laterality, n (%) right 12 (57.1%) left 9 (42.9%) stricture length (cm), mean ± sd, (range) 3.94 ± 1.4 (2–6.5) etiology of the ureteric stricture, n (%) complicated ureteral stone surgery by rirs using laser 6 (28.6%) complicated ureteral stone surgery by urs 4 (19%) iatrogenic during open surgery 7 (33.3%) congenital upjo 4 (19%) previous open ureteroplasty procedures for the same stricture pathology, n (%) one time 9 (42.6%) two times 4 (19.1%) three times 6 (28.6%) four times 1 (4.8%) five times 1 (4.8%) preoperative urinary drain, n (%) double-j ureteric stent 11 (52.4%) nephrostomy 5 (23.8%) no diversion of urine 5 (23.8%) sd: standard deviation; bmi: body mass index; upj: ureteropelvic junction; rirs: retrograde intrarenal surgery; urs: ureteroscopy; upjo: ureteropelvic junction obstruction. archivio italiano di urologia e andrologia 2025; 97(2):13695 a. salah nasef, i. alaa eldin tagrida, m. fawzy salman, a. elatreisy, s. mahmoud khaled 4 no intraoperative complications were observed. however, six patients (28.6%) developed postoperative complications. two patients experienced urinary tract infections, requiring additional antibiotics (grade ii), and two patients developed wound infections that needed further systemic and local antibiotic treatment (grade ii). one patient developed leakage at the anastomosis site due to migration of dj stent and was managed with percutaneous nephrostomy tube drainage (grade iiia complication). another patient developed an incisional hernia at the surgical site, which was later surgically repaired (grade iiib). there was no complication related to the graft harvested site. as regards to post ureteroplasty ipsilateral renal function compared to preoperative values, the mean glomerular filtration rate (gfr) improved from 36 to 38.7 ml/min, and the split renal function (srf) improved from 44.5% to 47.4% with insignificant p-value as depicted in table 3. the follow-up duration ranged from 9 to 24 months, with a mean duration of 16.3 months. at the last follow-up visit, 18 out of 21 patients (85.7%) were stricture-free, while three (14.3%) had failed ureteroplasty and were kept on permanent dj-ureteric stents to be exchanged annually. discussion proximal long ureteric strictures are complex and challenging to treat in reconstructive urology. such complex cases require major urologic procedures to treat, including ileal ureter replacement and renal autotransplantation. onlay bmg ureteroplasty is a less morbid operative technique to treat these conditions (6). intestinal interposition carries risks such as bowel anastomosis leakage, impaired bowel movement, urinary tract obstruction, and recurrent utis. prolonged urine exposure to ileal mucosa may also lead to metabolic acidosis (7). kidney autotransplantation for ureteric strictures is a complex procedure; complication rates range from 33% to 46%, with a transplantation failure rate of about 11%. common complications include issues with vascular anastomosis, such as thrombosis and hemorrhages (8). alternative surgical options for proximal ureteric strictures include the utilization of appendiceal onlay or tubularized bladder flaps. however, there are notable drawbacks associated with appendiceal interposition, particularly regarding the availability of the appendix and its significant variability in length, which may result in a 1020% incidence of insufficiency. furthermore, a transperitoneal approach is required for the implementation of appendiceal interposition. in contrast to bladder flaps or transposition techniques, bmg ureteroplasty preserves the natural vesicoureteral anti-reflux mechanism (9). the eau guidelines recommend bmg as an option for long-segment ureteral stricture, especially after a previous failed reconstruction, with an average overall success rate of 90%, but experience is limited (10). the buccal mucosa is readily accessible for harvesting, exhibits lower susceptibility to immune responses, and can withstand urinary tract pathogens. while buccal mucosa grafting is extensively employed in reconstructive urethral surgery, bmg ureteroplasty is also gaining popularity, particularly in cases where achieving a tensionfree anastomosis proves challenging through ureteroureterostomy. this technique is especially beneficial for patients experiencing recurrent ureteral strictures who have previously undergone unsuccessful ureteroplasty characterized by peri-ureteral scarring and inadequate ureteral vascularization (11). our study included 21 patients, 17 with recurrent long segment upper ureteral stricture and 4 with prior failed repair for upjo treated with on lay bmg ureteroplasty. we reported a high success rate of 85.7%. no intraoperative complications were observed. heijkoop and kahokehr carried out a systematic literature review of surgical outcomes in 72 patients with ureter strictures who underwent bmg ureteroplasty (including 34 open and 38 robotic) from 15 articles. the overall success rate was reported as 91.6%, and the rate of complications, with clavien grades ≥ 3, was 5% (12). our results are comparable to the results of these trials. in the present study, six patients (28.6%) experienced minor postoperative complications classified as clavien grades ii and iii, with no instances of complications rated at clavien grade ≥ 3. this indicates a low morbidity rate associated with this procedure, particularly in comparison to the complications associated with alternative treatment options for this condition, such as ileal transposition. table 2. operative and postoperative characteristics of the study cohort. parameter value bmg length (cm), mean ± sd, (range) 7.6 ± 1.1 (5.2-10) operative time (min), mean (range) 145.71 (105-205) estimated blood loss (ml), mean (range) 157.14 (50-300) length of hospital stay (days), mean (range) 4.28 (4-5) follow-up duration (months), mean (range) 16.3 (9-24) stricture free at last visit, n (%) 18 (85.7 %) complication rate according to the modified clavien-dindo grading system, n (%) total 6 (28.6%) grade ii 4 (19%) grade iiia 1 (4.8%) grade iiib 1 (4.8%) bmg: buccal mucosa graft. table 3. comparison between preoperative and postoperative renogram findings and split renal function in the study cohort. preoperative postoperative p-value serum creatinine, mean ± sd 1.31 ± 0.41 1.13 ± 0.26 0.19 gfr, ml/min 36.1 ± 11.28 38.65 ± 12.19 0.48 split renal function, % 44.53 ± 23.52 47.4 ± 22.83 0.69 sfu grade of hydronephrosis, n (%) no hn 0 13 (61.9%) grade 1 0 5 (23.8%) grade 2 14 (66.7%) 0 < 0.001 grade 3 6 (28.6%) 3 (14.3%) grade 4 1 (4.7%) 0 sd: satndared deviation, gfr: glomerular filteration rate; sfu: society of fetal urology. archivio italiano di urologia e andrologia 2025; 97(2):13695 5 buccal mucosal graft for onlay ureteroplasty in the management of proximal ureteral stricture using the omentum to wrap the grafted area gives the confidence that the augmented area is more supported and postoperative leakage may be minimized. engelmann and his colleagues performed 14 cases of ureteroplasty with bmg without omental wrap, and 13 cases (92.9%) were stricture-free; their findings indicate that the perirenal and retroperitoneal fat surrounding the bmg is an adequate substitute for this mechanism. the omission of omental wrapping facilitates a strictly extraperitoneal approach, which spares the intestines and decreases the risk of impaired bowel function or ileus (9). in all cases, we utilized the omentum to encase the grafted region; however, the observed success rate was 87.5%, slightly lower than that reported in previous studies. all cases in the current study involved recurrent strictures that had undergone failed surgical interventions up to four to five times in certain instances. the presence of severe fibrosis in several cases contributed to these failures. nonetheless, our findings indicate a commendable success rate. cases of recurrent upjos after prior failed pyeloplasty are another challenging condition due to increased periureteral and peri pelvic scarring and fibrosis in the previous surgical area. most studies in the literature describe the utilization of a dismembered (transecting) pyeloplasty in cases of recurrent upjo setting (13-15). bmg ureteroplasty avoids complete transection of the ureter, which may help avoid devascularization of the ureteral blood supply and reduces the need for significant ureterolysis in such cases. the published data regarding the use of bmg ureteroplasty in managing recurrent upjos are limited (16). our study included four patients with secondary upjo. the four cases were non-obstructed at the last follow-up (100% success rate). a report of 10 cases of seccondary upjo repaired via robotic bmg ureteroplasty showed an 80 % success rate (8 out of 10 cases) with a low complication rate (16). in summary, we present the findings of the first prospective study assessing the outcomes of bmg ureteroplasty with omental wrap in cases of recurrent long-segment ureteric strictures and recurrent ureteropelvic junction obstruction (upjo). our results indicate a success rate of 85.7% and a postoperative complication rate of 28.6%, primarily involving low clavien grades ii and iii. study limitations the present study acknowledges several limitations. firstly, it is not a comparative analysis; the procedures used open surgical techniques. notably, current practices in bmg ureteroplasty increasingly incorporate laparoscopic and robotic methodologies. furthermore, a critical need exists for direct prospective randomized studies featuring a substantial sample size to compare bmg ureteroplasty with alternative treatment options for long-segment ureteral strictures. conclusions our study indicates that onlay buccal mucosa graft ureteroplasty represents an effective and safe surgical intervention for managing recurrent, long-segment ureteral strictures and recurrent cases of ureteropelvic junction obstruction. references 1. yang k, fan s, li z, et al. lingual mucosa graft ureteroplasty for ureteral stricture: a narrative review of the current literature. ann palliat med. 2021; 10:4840-4845. 2. naude jh. buccal mucosal grafts in the treatment of ureteric lesions. bju int. 1999; 83:751-754. 3. lee z, keehn ay, sterling me, et al. a review of buccal mucosa graft ureteroplasty. cur urol rep. 2018; 19:1-6. 4. yang ch, lin ys, weng wc, et al. validation of robotic-assisted ureteroplasty with buccal mucosa graft for stricture at the proximal and middle ureters: the first comparative study. j robot surg. 2022; 16:1009-17. 5. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 6. sahay sc, kesarwani p, sharma g, and tiwari a. buccal mucosal graft ureteroplasty: the new normal in ureteric reconstructive surgery our initial experience with the laparoscopic and robotic approaches. j minim access surg. 2024:10-4103. 7. kocot a, kalogirou c, vergho d, and riedmiller h. long-term results of ileal ureteric replacement: a 25-year single-centre experience. bju int. 2017; 120:273-279. 8. ruiz m, hevia v, fabuel jj, et al. kidney autotransplantation: long-term outcomes and complications. experience in a tertiary hospital and literature review. int urol nephrol. 2017; 49:1929-1935. 9. engelmann su, yang y, pickl c, et al. ureteroplasty with buccal mucosa graft without omental wrap: an effective method to treat ureteral strictures. world j urol. 2024; 42:116. 10. eau guidelines. edn. presented at the eau annual congress milan march 2023. pp 17-19. isbn 978-94-92671-19-6. 11. guliev bg, komyakov b, avazkhanov z, et al. laparoscopic vendeclarations ethical approval and consent for participate: this study was conducted by the principles outlined in the declaration of helsinki. approval was obtained from the local institutional review board of the urology department at the faculty of medicine, al-azhar university, located in cairo, egypt. all participants provided their informed consent by signing the necessary forms. the methods employed adhered strictly to the relevant guidelines and regulatory standards. availability of data and material: available from the corresponding author on a reasonable request. competing interests: there are no conflicts of interest involving any of the authors in relation to the subject matter discussed in this article. funding: no funding was received. authors' contributions: a.s.n and i.a.t. conceptualized the article; m.f.s. wrote the initial manuscript; and a.e and s.m.k. reviewed and edited the main manuscript. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13695 a. salah nasef, i. alaa eldin tagrida, m. fawzy salman, a. elatreisy, s. mahmoud khaled 6 tral onlay ureteroplasty with buccal mucosa graft for complex proximal ureteral stricture. int braz j urol. 2023; 49:619-627. 12. heijkoop b, kahokehr aa. buccal mucosal ureteroplasty for the management of ureteric strictures: a systematic review of the literature. int j urol. 2021; 28:189-195. 13. sundaram cp, grubb rl, rehman j, et al. laparoscopic pyeloplasty for secondary ureteropelvic junction obstruction. j urol. 2003; 169:2037-2040. 14. hammady a, elbadry ms, rashed en, et al. laparoscopic repyeloplasty after failed open repair of ureteropelvic junction obstruction: a case-matched multi-institutional study. scand j urol. 2017; 51:402-406. 15. atug f, burgess sv, castle ep, thomas r. role of robotics in the management of secondary ureteropelvic junction obstruction. int j clin pract. 2006; 60:9-11. 16. lee m, nagoda e, strauss d, et al. role of buccal mucosa graft ureteroplasty in the surgical management of pyeloplasty failure. asian j urol. 2024; 11:373-376. correspondence ahmed salah nasef drahmedmero@gmail.com ibrahim alaa eldin tagrida itagreda@yahoo.com mohamed fawzy salman (corresponding author) prof_mohamed_fawzy@yahoo.com adel elatreisy adel.elatreisy@azhar.edu.eg sabry mahmoud khaled sabri.moussa@azhar.edu.eg lecturer of urology, faculty of medicine, al-azhar university, cairo, egypt stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13933 1 original paper introduction in recent years, prostate cancer (pca) management has undergone significant advancements in both diagnostic and therapeutic fields (1-2). innovations in diagnosis and staging, including the widespread adoption of multiparametric magnetic resonance imaging (mpmri) and prostatespecific membrane antigen positron emission tomography (psma-pet), have markedly improved disease detection and characterization (3). moreover, the development and integration of clinical tools such as nomograms and dedicated applications have enhanced risk stratification and individualized treatment planning (4-6). therapeutic strategies have also evolved, with refinements in surgical techniques and the emergence of new systemic therapies, offering a broader range of tailored options for patients across different stages of the disease (7). mpmri has significantly transformed the diagnostic pathway for the management of pca. due to its superior ability to detect clinically significant pca (cspca) compared to traditional methods, mri/ultrasound (us) fusion biopsy has gained a pivotal role, including in contexts such as active surveillance (8). nevertheless, the diagnostic performance of this technique can be affected by various factors, notably the operator’s level of expertise (9). interpreting mpmri scans remains challenging for both radiologists and urologists, often leading to discrepancies between readers (10). this, combined with the technical skills required for proficient ultrasound use, underscores the complexity of the fusion biopsy technique. as a result, relatively few surgeons are adequately trained in this method, potentially impacting cspca detection rates, particularly in the early stages of the learning curve (11-12). to date, only a limited number of studies have explored the learning curve for transperineal mri/us fusion prostate biopsy, yielding inconsistent findings. reported introduction: this study aimed to evaluate the learning curve of transperineal magnetic resonance imaging (mri)/ultrasound (us) fusion biopsy performed by a multidisciplinary team comprising a single urologist, radiologist, and pathologist. we analyzed the temporal changes in overall prostate cancer detection rates and clinically significant prostate cancer (cspca) detection rates. methods: we retrospectively enrolled consecutive patients with clinically suspected prostate cancer (pca) who underwent mri/us fusion prostate biopsy at a single center from january 2019 to december 2022. the patients were divided into four cohorts based on the year of biopsy to assess temporal variations in the outcomes. univariate and multivariate analyses were performed to model detection rate curves. results: overall, 291 patients underwent targeted biopsy (tbx) and standard biopsy (sbx) during the study period. multivariate analysis showed that the overall pca diagnosis was significantly higher when prostate biopsy was performed after the first year (2019; 74 patients), particularly in 2022 (or 11.68, ci 3.0849.1). the cspca detection rate increased significantly from 13.5% to 40.0%, p = 0.03). conclusions: cumulative experience and teamwork may increase the overall pca detection rate, specifically cspca detection rate. transperineal mri fusion-guided biopsies combined with a standard template provided a higher overall cancer and cspca detection rate than the standard template or targeted biopsy alone. multidisciplinary team meetings and procedure standardization are key factors in overcoming the learning curve. key words: image-guided; magnetic-resonance imaging; ultrasonography; prostatic neoplasms; transperineal biopsy; learning curve. submitted 28 april 2025; accepted 21 july 2025 learning curve of a multidisciplinary team for magnetic resonance imaging/transperineal ultrasonography fusion prostate biopsy marcello scarcia 1, vincenzo andracchio 2, alberto piana 3, roberto calbi 4, michele zazzara 1, francesco chiaradia 2, antonio greco 2, flavio sidoti 2, gianluca scarpelli 2, pierluigi rizzo 1, guglielmo mantica 5, alessandro calarco 6, rosario leonardi 7, giuseppe mario ludovico 1, stefano alba 2 1 division of urology, ente ecclesiastico ospedale generale regionale "miulli" 70021acquaviva delle fonti (ba), italy; 2 department of urology, romolo hospital, rocca di neto, italy; 3 division of urology, department of oncology, school of medicine, university of turin, san luigi hospital, turin, italy; 4 division of radiology, ente ecclesiastico ospedale generale regionale "miulli", acquaviva delle fonti (ba), italy; 5 department of surgical and diagnostic integrated sciences (disc), university of genoa, genoa, italy; 6 department of urology, san carlo di nancy hospital, rome, italy; 7 division of urology, school of medicine, university of kore, enna (en), italy. doi: 10.4081/aiua.2025.13933 summary archivio italiano di urologia e andrologia 2025; 97(3):13933 m. scarcia, v. andracchio, a. piana, et al.. 2 case numbers required to achieve proficiency range from 52 to 156 procedures (13-14). however, just one study has assessed the learning curve for an established multidisciplinary team specialized in prostate biopsy (15). the main aim of this study was to investigate how the overall detection rate of pca evolved over time in patients undergoing transperineal fusion biopsy at a high-volume institution. a secondary aim was to analyze trends in cspca detection rates in relation to the accumulating experience of both the operators performing the fusion biopsies and the radiologists preparing the imaging. materials and methods we analyzed data from a prospectively maintained database of consecutive patients who underwent transperineal fusion biopsy between january 2019 and december 2022. all patients provided informed consent for the use of data obtained from clinical records after anonymization. all the procedures complied with the ethical principles for biomedical research outlined in the declaration of helsinki. this study was approved by the institutional ethics committee of the hospital of bari (decision n°6331). we included men aged over 18 years with clinical suspicion of pca, based on elevated prostate-specific antigen (psa) levels, abnormal digital rectal examination (dre) findings, clinical suspicion, and/or a family history of prostate cancer. radiological protocol all patients who underwent prostatic mpmri (< 90 days) with at least one lesion with a pi-rads v2 score of ≥ 3 were considered for this study. all mpmri examinations were performed using a 1.5 t scanner with a 32-channel phased-array surface coil. a morphological study of the prostate was performed using t2-weighted turbo spinecho (tse) sequences in the sagittal, axial, and coronal planes, including the prostate gland and seminal vesicles. functional studies were performed using diffusion-weighted imaging (dwi) and dce. all patients underwent the same mpmri protocol. the mri scans were reviewed by the same expert uroradiologist. procedure details each patient underwent targeted (tbx) and standard (sbx) biopsies in the same session, performed by a single operator with extensive experience in fusion biopsy (> 100 procedures). similarly, the same pathologist and radiologist were involved in the procedures. tbx and sbx sample numbers were performed according to current european guidelines for pca and antibiotic prophylaxis (16). for sbx, 10-14 biopsy fragments were collected from the peripheral prostate zones, including the base, central gland, and apex. for tbx, 3-7 biopsy fragments were obtained per patient; the transition zone was biopsied only if mpmri indicated suspicious areas. all biopsies were performed transperineally under local anesthesia using the biopsee system® from medcom gmbh, which integrates mri and us images to provide accurate 3d mapping and real-time guidance during biopsy. biopsy samples were analyzed by the same dedicated uropathologist and reported according to isup 2014 guidelines (17). cspca was defined as an isup score of ≥ 2, whereas clinically insignificant pca (cipca) was defined as an isup score of 1. multidisciplinary team the multidisciplinary team for prostate biopsy consisted of urologists, pathologists, and radiologists. the team met bimonthly to evaluate the results and re-evaluate, discuss, and improve the protocol to reduce possible complications and improve outcomes. statistical analysis the baseline characteristics of patients who underwent fusion prostate biopsy were compared by year (2019 vs. 2020 vs. 2021 vs. 2022). continuous variables are expressed as median and interquartile range (iqr) and compared using the anova test, while categorical variables are presented as counts and percentages and compared using a proportion test. an estimated annual percentage change (eapc) analysis was conducted to evaluate the trends in pca detection rates over the years for both overall and cspca. multivariate logistic regression analysis was performed to determine predictive factors for pca detection, both overall and cspca, including the year of biopsy, pre-biopsy psa levels, prostate volume on mpmri, pi-rads score, target area location and volume, number of previous biopsies, and number of sbx and tbx samples. statistical significance was set at p < 0.05, and analyses were conducted using the r software (www.rproject.org, version 4.0.0). results a total of 291 patients underwent tbx and sbx. the clinical, radiological, and pathological characteristics of the patients are presented in table 1. of these, 246 (84.6%) were biopsy-naïve, and 45 (15.4%) had previously negative biopsies. the median age was 64.5 years (range 59-70), with a median psa level of 6 ng/ml (range 4.3-8). the median prostate volume detected on mpmri is 53 ml, with a decreasing trend from 2019 (60 ml) to 2022 (45 ml). pi-rads score distributions were as follows: 42 patients (14.3%) scored pi-rads 3, 221 (75.4%) scored pi-rads 4, and 28 (9.6%) scored pi-rads 5, with an increasing trend in pi-rads 5 cases over the years (6 in 2019 to 12 in 2022). the median number of biopsy cores was 16 (range 1622), with a significant decrease over time (22 in 2019 vs. 16 in 2022), reflecting both reduced prostate volume and increased operator confidence. the median number of standard biopsy cores decreased from 12 in 2019 to 10 in 2022, while the target biopsy cores remained consistent (range 4-7 based on pi-rads lesion size). overall, pca was detected in 137 of 291 patients (47.1%), of whom 76 had cspca (26.1%) and 61 had cipca (21%) (table 2). the highest pca detection rate (67.7%) was observed in 2022 among 65 patients. in 2021, 52.2% of 92 patients were positive for pca. in 2020, 41.7% of 60 patients tested positive, and in 2019, 27% of 74 patients tested positive. cspca detection increased over the years, from 13.5% in 2019 to 40% in 2022. tbx detected cspca in 35.4% and cipca in 24.6% of cases in 2022. sbx pca archivio italiano di urologia e andrologia 2025; 97(3):13933 3 multidisciplinary team for fusion prostate biopsy detection rate rose from 20.4% in 2019 to 58.5% in 2022; for cspca, detection rates increased from 10.9% in 2019 to 35.4% in 2022 (figures 1-3). multivariate analysis showed significantly higher pca detection rates after the first year (2019), particularly in 2022 (or 11.68, ci 3.08-49.1). pca detection was positively correlated with higher psa levels (or 1.08, ci 1.01-1.17), lower prostate volume (< 60 ml, or 0.97, ci 0.95-0.98), target lesions in the peripheral zone (or 0.39, 0.18-0.79), higher lesion volume (or 5.81, ci 2.60-13.8), and biopsy-naïve status (or 2.98, ci 1.17-7.78). cspca detection was similarly associated with table 1. characteristics of patients participating in the study. characteristics prostate biopsy year overall 2019 2020 2021 2022 p-value (n = 291) (n = 74, 25.4%) (n = 60, 20. 6%) (n = 92, 31.6%) (n = 65,22. 4%) age median (iqr) 64.5 (59-70) 64 (58-70.8) 64 (61-69.5) 65 (61.8-68.2) 65 (58-70) 0.4 psa median (iqr) 6 (4.3-8) 6 (5-8) 6 (4-8) 5 (4-7) 6 (4.7-7.9) 0.8 prostate volume at mri median (iqr) 53 (40-70) 60 (45-70.8) 54 (44-70.2) 50.5 (40-74.2) 45 (31-59) 0.001 lesion volume 1 median (iqr) 0.7 (0.5-1.1) 0.8 (0.6-1.2) 0.5 (0.4-1) 0.6 (0.5-0.8) 0.9 (0.6-1.2) 0.2 zone lesion 1 zp 204 (70.1) 51 (68.9) 36 (60) 63 (68.5) 54 (83.1) 0.04 cz/tz 85 (29.2) 23 (31.1) 23 (38.3) 28 (30.4) 11 (16.9) 0.06 highest pirads 3 42 (14.3) 10 (13.5) 6 (10) 18 (19.6) 8 (12.3) 0.4 4 221 (75.4) 58 (78.4) 50 (83.3) 68 (73.9) 45 (69.2) 0.3 5 28 (9.6) 6 (8.1) 4 (6.7) 6 (6.5) 12 (18.5) 0.05 number of lesions at mri 1 221 (75.4) 54 (73.0) 45 (75.0) 70 (76.1) 51 (78.5) 0.9 2 63 (21.5) 17 (23.0) 15 (25.0) 17 (18.5) 13 (20.0) 0.8 3 9 (3.1) 3 (4.1) 0 (0) 5 (5.4) 1 (1.5) 0.2 number of previous biopsy 0 248 (84.6) 59 (79.7) 41 (68.3) 85 (92.4) 61 (93.8) 0.001 1 42 (14.3) 13 (17.6) 18 (30.0) 7 (7.6) 4 (6.2) 0.001 2 3 (1) 2 (2.7) 1 (1.7) 0 (0) 0 (0) 03 total number of biopsy cores median (iqr) 16 (16-21) 22 (20-24) 21 (16-22.2) 16 (16-16) 16 (16-16) 0.001 number of systematic biopsy cores median (iqr) 12 (10-16) 16 (16-16) 16 (12-16) 10 (9-12) 10 (10-10) 0.001 number of target biopsy cores median (iqr) 6 (4-7) 6 (4-8) 6 (4.8-7) 6 (4-7) 6 (6-8) 0.2 * total number of positive biopsy cores median (iqr) 5 (3-8) 6.5 (3.8-12.2) 5 (3-7) 5 (2.8-6) 6 (3.8-8) 0.1 * number of positive systematic biopsy cores median (iqr) 3 (2-4) 3.5 (2-5) 3 (1-3) 3 (2-4) 3 (2-5) 0.7 * number of positive target biopsy cores median (iqr) 2 (1-4) 2.5 (0.8-8.2) 3 (2-4) 1.5 (1-3) 2.5 (1-4) 0.2 * overall core ratio median (iqr) 27.8 (18.2-38.9) 26.5 (17.4-52.5) 22.2 (18.2-36.4) 31.2 (16.1-37.5) 37.5 (19.7-47.8) 0.2 * standard coreratio median (iqr) 18.8 (9.1-33.3) 14.6 (4.7-51.6) 18.8 (12.5-25) 16.2 (8.3-30) 27.5 (10-40) 0.4 * target core ratio median (iqr) 45.5 (25-75) 47.7 (33.3-71.9) 40 (25-60) 50 (25-80) 45 (28.8-76.2) 0.9 table 2. gleason grade group distribution. prostate biopsy year overall 2019 2020 2021 2022 p-value (n = 291) (n = 74, 25.4%) (n = 60, 20.6%) (n = 92, 31.6%) (n = 65, 22.4%) no pca 154 (52.9) 54 (73) 35 (58.3) 44 (47.8) 21 (32.3) 0.001 gleason grade 1 61 (21.0) 10 (13.5) 7 (11.7) 26 (28.3) 18 (27.7) 0.01 group overall 2 46 (15.8) 4 (5.4) 11 (18.3) 17 (18.5) 14 (21.5) 0.04 3 21 (7.2) 3 (4.1) 4 (6.7) 5 (5.4) 9 (13.8) 0.1 4 7 (2.4) 3 (4.1) 3 (5) 0 (0) 1 (1.5) 0.2 5 2 (0.7) 0 (0) 0 (0) 0 (0) 2 (3.1) 0.1 no pca 180 (61.9) 59 (79.7) 39 (65.0) 55 (59.8) 27 (41.5) 0.001 gleason grade 1 59 (20.3) 7 (9.5) 13 (21.7) 24 (26.1) 15 (23.1) 0.05 group of target biopsy cores 2 32 (11.0) 3 (4.1) 6 (10.0) 10 (10.9) 13 (20.0) 0.03 3 14 (4.8) 3 (4.1) 1 (1.7) 3 (3.3) 7 (10.8) 0.1 4 4 (1.4) 2 (2.7) 1 (1.7) 0 (0) 1 (1.5) 0.5 5 2 (0.7) 0 (0) 0 (0) 0 (0) 2 (3.1) 0.1 overall detection rates 137 (47.1) 20 (27) 25 (41.7) 48 (52.2) 44 (67.7) 0.001 archivio italiano di urologia e andrologia 2025; 97(3):13933 m. scarcia, v. andracchio, a. piana, et al.. 4 figure 1. ggg found over the years in patients undergoing target biopsy and standard biopsy. figure 2. ggg found over the years considering only target biopsy. figure 3. ggg found over the years considering only standard biopsy. archivio italiano di urologia e andrologia 2025; 97(3):13933 5 multidisciplinary team for fusion prostate biopsy the biopsy year (especially in 2022), low prostate volume, pi-rads 5 score, peripheral zone lesion location, and biopsy-naïve status (table 3). discussion the accuracy of pathological diagnosis in pca, particularly for tumors classified as clinically significant (18), remains crucial for appropriate therapeutic decisionmaking (19-20). siddiqui et al. previously demonstrated that mri-targeted fusion biopsies preferentially detect high-grade gleason score tumors, thus reducing the diagnosis of clinically insignificant pca, as confirmed by two systematic reviews (21-22). in our experience, close collaboration among the urologist performing the biopsy, the radiologist interpreting the mpmri, and the pathologist evaluating the biopsy cores led to a progressive improvement in overall pca detection rates, with particular attention to clinically significant disease. over the 4-year study period, the detection rate for pca significantly increased from 27% to 67.7% (p = 0.001) when comparing the first and last year of analysis (figure 4a). similarly, the cspca detection rate rose from 13.5% to 40% (p = 0.01) (figure 4b). figure 4. (a) detecton rate pca over the years, (b) detecton rate cspca over the years. table 3. multivariate logistic regression analysis. multivariable lrm predicting prostate cancer multivariable lrm predicting clinically significant overall detection rate prostate cancer detection rate or (95% ci) p-value or (95% ci) p-value prostate biopsy year, 2019 ref 2020 5.09 (1.83-15.0) 0.01 4.6 (1.46-15.79) 0.01 2021 15.45 (4.38-62.4) 0.001 6.87 (1.64-33.6) 0.01 2022 11.68 (3.08-49.1) 0.001 7.15 (1.66-35.6) 0.01 psa 1.08 (1.01-1.17) 0.02 1.04 (0.98-1.18) 0.1 mri prostate volume 0.97 (0.95-0.98) 0.001 0.96 (0.95-0.98) 0.001 pira ds, 3 ref 4 1.29 (0.52-3.28) 0.5 2.02 (0.67-7.57) 0.2 5 2.35 (0.51-12.24) 0.2 4.58 (1.03-23.67) 0.05 zone lesion 1, zp ref cz/tz 0.39 (0.18-0.79) 0.01 0.35 (0.14-0.83) 0.02 lesion volume 1 5.81 (2.60-13.8) 0.001 3. 05 (1.43-6.70) < 0.01 number of previous bioosy, 0 ref 1 2.98 (1.17-7.78) 0.02 8.22 (3.01-23.9) 0.001 number of targetbiopsy cores 1.21 (1.03-1.43) 0.01 1.06 (0.88-1.29) 0.5 number of standard biopsy cores 1.12 (0.82-0.95) 0.18 1.05 (0.87-1.29) 0.5 archivio italiano di urologia e andrologia 2025; 97(3):13933 m. scarcia, v. andracchio, a. piana, et al.. 6 our findings further support the combined use of systematic biopsy (sb) and targeted biopsy (tb) to enhance cspca detection (23), in line with results reported by ahdoot et al. (24), and reinforce the value of performing systematic 12-core biopsies (25-26). nonetheless, the learning curve (lc) for transperineal (tp) fusion biopsy appears to be slower than that for transrectal (tr) fusion biopsy. approximately 52 cases were required to reach a stable pca and cspca detection rate with tr fusion biopsy, comparable to outcomes achieved by experienced urologists (27). prostate biopsy strategies should therefore be adapted based on local expertise, available resources, and institutional needs. although targeted biopsy improves the ratio of cspca to insignificant cancer diagnoses, some cspca cases may still be missed. software-based tbx offers greater precision, particularly for less experienced operators, but its higher costs may not always be justified. the tp approach offers advantages in terms of infection prevention, although it requires greater resource allocation (28). in patients with suspicious mpmri findings, combining tp mri fusion-guided biopsy with systematic template biopsy provides higher overall and cspca detection rates compared to either approach alone (29). therefore, in the presence of mpmri-detected lesions, both targeted and systematic biopsies should be included in the tp procedure (30). the improvement in detection rates, particularly for cspca, can also be attributed to the progressive completion of the learning curve by both urologists and radiologists. hsieh et al. reported similar findings, demonstrating that multidisciplinary collaboration significantly increased cspca detection rates using transperineal mri/us fusion tbx over a four-year period (from 35.3% to 60.0%, p = 0.01). combining tbx and sbx consistently yielded the highest cspca detection rates annually. furthermore, with increasing experience, detection rates for small (≤ 1 cm) and anterior lesions improved (from 41.2% to 51.6%, p = 0.5 and from 54.5% to 88.2%, p = 0.8, respectively), while the percentage of positive cores on tbx significantly increased (from 18.1% to 44.2%, p = 0.001). notably, the rate of gleason score upgrading after radical prostatectomy decreased over time (from 22.2% to 11.1%, p = 0.4) (15). the progressive improvement in detection rates likely reflects not only the growing experience of the urologist, but also the stable collaboration within the multidisciplinary team, including consistent radiological and pathological evaluation throughout the study period. when evaluating learning curves in surgical and interventional procedures, it is essential to consider multiple factors, including technological advancements, institutional characteristics, patient populations, and operator experience. moreover, in prostate biopsy, the absence of a definitive gold standard for cancer detection introduces variability influenced by disease prevalence and distribution within the study cohort (31). recent developments have emphasized the potential of artificial intelligence (ai) to further enhance the detection of clinically significant tumors. integration of ai with mri fusion tbx could offer a more comprehensive assessment of prostate cancer aggressiveness, analyzing lesion size, location, and mpmri features. ai-driven analysis of large imaging and clinical datasets may facilitate the identification of predictive biomarkers and disease progression patterns. the combination of ai technologies with mri fusion biopsy represents a significant advancement, enhancing diagnostic accuracy, informing therapeutic strategies, and broadening access for clinicians. these innovations offer substantial benefits for both patients and healthcare providers (32). similarly, a better and standardized training using simulators and cadaveric models (33) may improve outcomes and learning curves. in conclusion, our study suggests that establishing a multidisciplinary team involving urologists, radiologists, and pathologists can minimize procedural variability and improve clinical outcomes. our study has several limitations that must be acknowledged. first, it was a retrospective analysis, which inherently introduces the potential for selection and information biases. second, this study was conducted in a single high-volume academic center with a dedicated multidisciplinary team, regular clinical meetings, and standardized mpmri and biopsy protocols. while these factors likely contributed to the observed improvements in diagnostic performance, they may not reflect the reality of lower-volume institutions or settings without structured multidisciplinary collaboration. therefore, the external validity of our findings may be limited, and caution is warranted when extrapolating these results to different clinical environments with varying levels of experience, infrastructure, or workflow integration. third, although the sample size was adequate to detect significant trends, it remains relatively modest, potentially limiting the power to explore certain subgroups or rare outcomes in greater depth. fourth, the performance of the operators (both urologists and radiologists) progressively improved over time, but we did not formally assess individual learning curves or account for potential variations in performance among different operators. fifth, no external validation cohort was included, and our findings should therefore be interpreted cautiously until confirmed by larger, prospective multicenter studies. in addition, we acknowledge that the observed improvement in prostate cancer detection over time may not be solely attributed to the procedural learning curve. a significant factor may have been the evolution in patient selection criteria over the study period. while biopsy referrals were initially accepted from outside urologists based on basic clinical suspicion (elevated psa or abnormal dre), the multidisciplinary team (mdt) gradually introduced a more selective triage approach. from the second year onward, indications for biopsy were reviewed by the mdt and cases with low psa density (< 0.15 ng/ml²) or non-suspicious mri findings (pi-rads < 3) were progressively excluded. this strategy likely contributed to the decrease in prostate volume observed over the years and may have impacted the increase in overall and cspca detection rates, independently of operator experience. consequently, this change in selection policy represents a potential confounding factor and should be considered a limitation of our study. archivio italiano di urologia e andrologia 2025; 97(3):13933 7 multidisciplinary team for fusion prostate biopsy furthermore, we acknowledge that we did not use a formal statistical model, such as cusum, to define the learning curve. due to the retrospective nature of the study we based our conclusions on year-by-year trends. therefore, we describe a progressive improvement over time rather than a formally modeled learning curve. finally, although biopsy outcomes were rigorously assessed, no long-term follow-up data (such as radical prostatectomy pathology or oncologic outcomes) were available to further validate the accuracy of the fusion biopsy findings. conclusions mpmri fusion biopsy for pca diagnosis may be considered a relatively simple procedure. however, several factors appeared to significantly affect procedure accuracy. along with the learning curve of the surgeon, the procedure is safe and effectiveness of the procedure (8). however, in our experience, the detection rate continued to increase until the fourth year of life. in our experience, the performance of radiologists seems to improve over time, which has played a key role in increasing the detection rate. moreover, a low prostate volume (< 60 ml), a pirads score of 5 in the target area, a target area located in the peripheral zone, a higher lesion volume, and a biopsy-naive patient appeared to increase the diagnosis of cspca, while the number of target biopsy cores harvested did not correlate with cspca diagnosis. references 1. maclennan s, azevedo n, duncan e, et al. 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transl androl urol 2021; 10:1956-65. 28. marra g, ploussard g, futterer j, valerio m, eau-yau prostate cancer working party. controversies in mr targeted biopsy: alone or combined, cognitive versus software-based fusion, transrectal versus transperineal approach? world j urol 2019; 37:277-87. 29. porpiglia f, checcucci e, de cillis s, et al. a prospective randomized controlled trial comparing target prostate biopsy alone approach vs. target plus standard in naïve patients with positive mpmri. minerva urol nephrol 2023; 75:31-41. 30. kim mm, wu s, lin sx, et al. transperineal multiparametric magnetic resonance imaging-ultrasound fusion targeted prostate biopsy combined with standard template improves prostate cancer detection. j urol 2022; 207:86-94. 31. calleris g, marquis a, zhuang j, et al. impact of operator expertise on transperineal free-hand mpmri-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve. world j urol 2023; 41:3867-76. 32. lenfant l, seisen t, rouprêt m, et al. unleashing the power of artificial intelligence and fusion magnetic resonance imagingtargeted biopsy: transforming prostate cancer diagnosis. eur urol oncol 2023; 6:541-2. 33. mantica g, leonardi r, diaz r, et al. reporting characteristics of cadaver training and surgical studies: the cactus guidelines. int j surg. 2022; 101:106619. correspondence marcello scarcia scarciam@hotmail.com michele zazzara michele.zazzara@miulli.it pierluigi rizzo pierluigirizzo@miulli.it giuseppe mario ludovico g.ludovico@miulli.it division of urology, ente ecclesiastico ospedale generale regionale "miulli" 70021 acquaviva delle fonti (ba), italy vincenzo andracchio urologoandracchio@gmail.com francesco chiaradia francescochiaradia@pec.omceo.bari.it antonio greco antonio.greco992@miulli.it flavio sidoti flavio.sidoti@miulli.it gianluca scarpelli g.scarpelli@magnagrecia.it stefano alba stefanoalba78@gmail.com department of urology, romolo hospital 88821 rocca di neto, italy alberto piana alb.piana@gmail.com division of urology, department of oncology, school of medicine, university of turin, san luigi hospital, 10043 turin, italy roberto calbi calbi.roberto@gmail.com division of radiology, ente ecclesiastico ospedale generale regionale "miulli" 70021 acquaviva delle fonti (ba), italy guglielmo mantica (corresponding author) guglielmo.mantica@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genova, genoa, italy alessandro calarco alecalarco@gmail.com department of urology, san carlo de nancy, rome, italy. rosario leonardi rosario.leonardi@unikore.it division of urology, school of medicine, university of kore, enna (en), italy stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4450 original paper no conflict of interest declared. sidered to be under the umbrella of telehealth and refers specifically to remote clinical services (2). remote care provides the advantage of reducing the use of resources in health centers, improving access to care, and minimizing the risk of direct transmission of the infectious agent (3). the adoption of telemedicine was first described in the 1950’s when a nebraska psychiatrist connected to a prison over 150 miles through a closed-circuit television to provide mental health services (4). in recent years, with the advancement of mobile technologies, telemedicine is more accessible than ever before. in the usa the percentage of us hospitals that connect with patients through the use of video and other technology has increased from 35% in 2010 to 76% in 2017 (1). available literature indicates that telemedicine has been adopted successfully in patients with common clinical urological conditions, including prostate cancer, uncomplicated urinary stones, uncomplicated urinary infections, urinary incontinence, or pelvic organ prolapse and hematuria (5). moreover, literature on the use of telemedicine in medical education, called telementoring, is increasing and results underline the facilitation of the learning process while increasing motivation and enabling instant communication and discussion at a distance due to the possibility of sharing multimedia contents (6). the aim of the present study was to explore attitudes and perceptions by urology residents toward the use of telementoring in the context of residentsfaculty physicians communication for patient-related care in a large academic tertiary urology referral department in italy. methods questionnaire an online survey consisting of 19 multiple choice questions (formulated in italian with the aim of increasing the response rate) was designed using the google form application included in the google drive office suite introduction: telemedicine has been adopted successfully in various urological scenarios. the aim of the present study was to explore attitudes and perceptions by urology residents toward the use of telementoring in the context of residents-faculty physicians communication for patient-related care. methods: an online survey consisting of 19 multiple choice questions was designed including three sections: respondents’ demographics, attitudes and perceptions towards the use of telementoring. invitations to participate in this anonymous survey were e-mailed to urology residents at university of naples federico ii. results: in total 60 responses were received (participation rate 86%). the frequency of telementoring use was described as occasional, frequent, very frequent, and rare by 51,3%, 41.0%, 5,1%, and 2,6% of respondents, respectively. whatsapp messenger was used by 89.5% of respondents and photos were the most common type of media content shared (73.7%). most of respondents declared a moderate and a strong agreement with respect to the utility of telementoring in improving the communication in relation to the interpretation of clinical, radiological, endoscopic, and functional findings. overall, 78% of participants individuated risks of information flow distortions and misinterpretations as the major limit of telementoring. conclusions: the use of telementoring is widespread and perceived as useful by urology residents in the context of residentsfaculty physicians communication in multiple settings of patientrelated care. key words: telementoring; telemedicine; urology; bladder cancer; patient-related care; survey; pandemic; covid-19: medical informatics. submitted 15 july 2021; accepted 2 august 2021 introduction telehealth, defined as the use of information technology and telecommunications to provide access to health assessment, consultation, diagnosis, intervention, supervision and information across distance, represents a rapidly evolving field of medicine (1). telemedicine is contelementoring for communication between residents and faculty physicians: results from a survey on attitudes and perceptions in an academic tertiary urology referral department in italy vincenzo mirone 1, massimiliano creta 1, marco capece 1, giuseppe celentano 1, gianluigi califano 1, claudia collà ruvolo 1, lorenzo spirito 1, giovanni maria fusco 1, luigi cirillo 1, nicola longo 1, ferdinando fusco 2, claudia mirone 3, roberto la rocca 1, luigi napolitano 1 1 department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", naples, italy; 2 department of woman, child and general and specialized surgery, urology unit, university of campania “luigi vanvitelli'” naples, italy; 3 multidisciplinary department of medical, surgical and dental sciences, university of campania “luigi vanvitelli”, naples, italy. doi: 10.4081/aiua.2021.4.450 summary 451archivio italiano di urologia e andrologia 2021; 93, 4 telementoring in urology residency (google llc). the questionnaire was composed of three sections: a first one to assess respondents’ demographics (age, sex, year of residency) a second one to evaluate their attitudes, and a third to evaluate perceptions. questions about attitudes toward use of telementoring during the residency program and in the context of resident to faculty physicians communication for patientrelated care investigated the following settings: frequency, duration, and temporal trend of telementoring adoption, tools adopted (telephone call, e-mails, whatsapp, others) clinical context in which telementoring was used (ward, ambulatory care, referral activities), type of findings whose interpretation made use of telementoring (findings from physical examination, findings from radiological imaging, findings from endoscopy, findings from functional investigations), type of shared data (text, video, audio, photos), content of multimedia data shared (reports, radiological images, drainages, findings from physical examination, endoscopic findings, intraoperative findings). questions about perceptions investigated the perceived usefulness of telementoring in improving resident to faculty physicians communication for patient-related care in various clinical settings (ward, ambulatory care, referral activities) and in relation to various clinical and instrumental findings (findings from physical examination, endoscopy, radiological imaging, functional investigations). respondents were invited to "strongly agree", "moderately agree", "slightly agree", "strongly disagree", "moderately disagree", "slightly disagree" with a series of statements about perceptions. a question was designed to investigate how often the use of telementoring was able to change the diagnostic and/or therapeutic decision-making process. question about the perceived limits of telementoring investigated: medico-legal issues, risk of distortion of the information flow, risk of receiving incomplete data, risk of providing incomplete data. some questions required a single answer while others gave the respondents the choice to select as many answers as they felt appropriate. data collection invitations to participate in this anonymous survey were e-mailed on 1 february 2021 to current urology residents and to urology residents who attended the urology residence program in the last three years at university of naples federico ii and who gave the approval to the use of their e-mail address. for those who had not completed the survey, four follow-up reminder e-mail invitations were sent over the following 2 weeks. the survey was closed on 28 february 2021. all respondents had to fully complete the questionnaire before submission since all questions were flagged as mandatory. after submission, users could not review neither amend their answers. both personal contact information and data collected were not accessible to third parties. data analysis data were expressed as mean (standard deviation) and raw numbers and percentages of survey answers. statistical analyses were two-sided using a significance level of 0.05. all statistical analyses were performed with spss version 17.0 (spss, inc., chicago, il) software. results in total 60 responses were received (participation rate 86%). fifty-seven residents (95%) were male and 3 (5%) were female. mean age was 31.36 (3.16). overall, 23.33% were 1st years residents, 16.6 2nd year, 10 % 3rd year, 15% 4th year, 23.3% 5th year and 11.67% were specialist less than two year. the frequency of telementoring use in the context of resident to faculty physicians communication for patient-related care was described as occasional, frequent, very frequent, and rare by 51.3%, 41.0%, 5.1%, and 2.6%, respectively. figure 1 shows the setting of utilization of telementoring use by urology residents. figure 2 describes the percentage of utilization by residents of the different tools of telementoring in the context of resident to faculty physicians communication for patient-related care. figure 1. setting of telementoring use in the context of resident to faculty physicians communication for patient-related care and relative percentage of use in the various settings. figure 2. percentage of residents using different tools of telementoring in the context of resident to faculty physicians communication for patient-related care. archivio italiano di urologia e andrologia 2021; 93, 4 v. mirone, m. creta, m. capece, et al. 452 figure 3 shows the percentage of residents sharing different types of media contents in the context of resident to faculty physicians communication for patient-related care. figure 4 shows the percentage of residents sharing different types of information as media contents in the context of resident to faculty physicians communication for patient-related care. table 1 describes the perceptions about the usefulness of telementoring in improving resident to faculty physicians communication for patient-related care in various clinical settings and in relation to various clinical and instrumental findings. finally, regarding perception of telementoring limitation, 78% of participants individuated risks of information flow distortions and misinterpretations, 56.4%found limits for a complete information collection, 35.9% risks of flow distortions to give information, and 28.2% legal risk. discussion remote communication between members of a medical staff has always been the key element in any part of patients’ care (7). of note, poor communication was considered by the 2011 joint commission sentinel event report as the main root cause of delays in patient treatment and the second leading cause of operative and post-operative complications (8). interprofessional communication has a critical role mainly in university hospitals, where residents are involved in the management of patients. indeed, ineffective communication between residents and attending surgeons has been reported to be a significant contributor to figure 3. percentage of residents sharing different types of media contents in the context of resident to faculty physicians communication for patient-related care. figure 4. percentage of residents sharing different types of information as media contents in the context of resident to faculty physicians communication for patient-related care. table 1. perceptions about the usefulness of telementoring in improving resident to faculty physicians communication for patient-related care in various clinical settings and in relation to various clinical and instrumental findings. agree strongly agree moderately agree slightly disagree slightly disagree moderately disagree strongly n (%) n (%) n (%) n (%) n (%) n (%) telementoring is useful in improving resident to faculty physicians communication for patient-related care in the ward setting 14 (23.3) 35 (58.3) 11 (18.3) 0 (0) 0 (0) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care in the ambulatory setting 14 (23.3) 36 (60.0) 8 (13.3) 0 (0) 2 (3.3) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care in the referral activity setting 17 (28.3) 32 (53.3) 9 (15.0) 2 (3.3) 0 (0) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of radiological imaging interpretation 17 (28.3) 32 (53.3) 8 (13.3) 3 (5.0) 0 (0) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of endoscopic findings interpretation 14 (23.3) 27 (45.0) 17 (28.3) 2 (3.3) 0 (0) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of interpretation of findings from physical examination 14 (23.3) 35 (58.3) 11 (18.3) 0 (0) 0 (0) 0 (0) telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of functional findings interpretation 6 (10.0) 30 (50.0) 14 (23.3) 10 (16.6) 0 (0) 0 (0) 453archivio italiano di urologia e andrologia 2021; 93, 4 telementoring in urology residency medical errors, patient injury, and malpractice claims (9). verbal report via telephones has represented the traditional method of communication for years (10). however, although rapid, this method of communication can be inadequately objective and precise (10). since the late 1990’s telemedicine gained popularity and clinical photographs taken by digital cameras were transmitted as downloadable files between computers having modem and telephone link to improve communication flow (10). initially, several technological limitations including the lack of digitalization of medical records, the inability to send images quickly, and limited internet lines strongly limited the use of telemedicine. in recent years, advances in information technology have driven dramatic changes in several aspects of human behavior and communication. audiovisual communication in health care supported by smartphone apps is a novel concept that is rapidly gaining interest in all areas of medicine and surgery (11). implementation of telemedicine is currently encouraged and supported by both states and multiple medical associations worldwide (12). to the best of our knowledge, we investigated for the first-time attitudes and perceptions about the use of telementoring in the context of resident to faculty physicians communication for patient-related care in an academic tertiary urology referral department in italy. most urology residents participating in the present survey declared to utilize telementoring for patient-related care and that the use of telementoring increased over time. this finding is in line with available evidence demonstrating the expanding role of telehealth (1). whatsapp messenger was reported as the most commonly used tool for communication. whatsapp is a method of sending and receiving messages to and from individuals or groups with additional features of sending images, videos, and links (13). whatsapp has been evaluated in numerous subspecialties in both undergraduate and postgraduate settings and current available literature suggests it is an effective tool for medical learning (14). some authors also consider whatsapp as an effective telemedicine tool in many different fields of health care (11). photos followed by text messages were the most common type of data shared by the respondents in present survey. in details, the main contents of photos were medical reports followed by radiological images and pictures of drainages. accordingly, sener et al. suggest that whatsapp can be used to share photos of cases of hematuria to determine the severity of cases, and thereby discriminate whether active treatment is required (15). urology residents are commonly involved in multiple activities characterized by increasing complexity. most of respondents in the present survey perceived telementoring e as a useful communication tool in several aspects of patient care. indeed, the majority of them declared a moderate and a strong agreement towards the utility of telementoring in improving resident to faculty physicians communication for patient-related care in the context of ambulatory care, ward, and urology referral consultation. in details, most declared a moderate and a strong agreement with respect to the utility of telementoring in improving the communication in relation to the interpretation of clinical, radiological, endoscopic, and functional findings. interestingly, a high percentage of residents declared that the use of telementoring in the context of resident to faculty physicians communication for patientrelated care contributed to change the diagnostic and/or therapeutic decision making process. taken together, results from the present survey underline the increasing and relevant role of telementoring as an additional tool in the context of resident to faculty physicians communication in several settings of patient-related care. however, telementoring is still in its infancy and a number of potential drawbacks still exist. these include mainly limitations with performing comprehensive medical history and physical examination and security breaches (2). distortion of the medical information and limits in acquiring complete information were perceived by the participants in the present survey as the major drawbacks of telementoring in the context of resident to faculty physicians communication for patient-related care. the major limitation of this survey includes the small number of participants. although respondents are not fully representative of the overall community of italian urology residents, currently the school of urology of the university of naples federico ii represents the largest of the southern italy in terms of number of residents and one of the largest in italy. moreover, like any survey, participant responses were limited to the available choices. a further limit of the study is the lack of data about the feedback of faculty physicians. further studies are needed to investigate the usefulness of telementoring by residents in relation to specific diseases (16). conclusions results from the present survey demonstrate that the use of telementoring is widespread and perceived as useful by urology residents in the context of resident to faculty physicians communication in multiple settings of patientrelated care and its use has increased over time. whatsapp messenger is the most common tool adopted for remote communication with text and photos of reports and drainages being the most common data shared. references 1. kichloo a, albosta m, dettloff k, et al. telemedicine, the current covid-19 pandemic and the future: a narrative review and perspectives moving forward in the usa. fam med community health. 2020; 8:e000530. 2. gajarawala sn, pelkowski jn. telehealth benefits and barriers. j nurse pract jnp. 2021; 17:218-221. 3. wittson cl, affleck dc, johnson v. two-way television in group therapy. ment hosp. 1961; 12:22-3. 4. monaghesh e, hajizadeh a. the role of telehealth during covid19 outbreak: a systematic review based on current evidence. bmc public health. 2020; 20:1193. 5. novara g, checcucci e, crestani a, et al. telehealth in urology: a systematic review of the literature. how much can telemedicine be useful during and after the covid-19 pandemic? eur urol. 2020; 78:786-811. 6. mazzuoccolo ld, esposito mn, luna pc, et al. whatsapp: a realtime tool to reduce the knowledge gap and share the best clinical archivio italiano di urologia e andrologia 2021; 93, 4 v. mirone, m. creta, m. capece, et al. 454 practices in psoriasis. telemed j e-health off j am telemed assoc. 2019; 25:294-300. 7. haykal t, al-dulaimi r, sidahmed s, et al. understanding the means of communication between nurses and resident physicians in the modern world: a community-based university hospital survey results. j community hosp intern med perspect. 2020; 10:107-110. 8. commission tj. tj commission. sentinel event data root causes by event type 2004-third quarter 2011. washington, dc: the joint commission; 2011. 9. senders zj, aeder m, semrau s, et al. improving resident-toattending communication: implementing a tool to facilitate attending notification of critical patient events at a single academic institution. am surg. 2019; 85:663-670. 10. wani sa, rabah sm, alfadil s, et al. efficacy of communication amongst staffcmembers at plastic and reconstructive surgery section using smartphone and mobile whatsapp. indian j plast surg off publ assoc plast surg india. 2013; 46:502-5. 11. giordano v, koch h, godoy-santos a, et al. whatsapp messenger as an adjunctive tool for telemedicine: an overview. interact j med res. 2017; 6:e11. 12. becker cd, dandy k, gaujean m, et al. legal perspectives on telemedicine part 1: legal and regulatory issues. perm j. 2019; 23:18-293. 13. bakshi sg, bhawalkar p. role of whatsapp-based discussions in improving residents’ knowledge of post-operative pain management: a pilot study. korean j anesthesiol. 2017; 70:542-549. 14. coleman e, o’connor e. the role of whatsapp® in medical education; a scoping review and instructional design model. bmc med educ. 2019; 19:279. 15. sener te, butticè s, sahin b, et al. whatsapp use in the evaluation of hematuria. int j med inf. 2018; 111:17-23. 16. ambrosini f, di stasio a, mantica g, cavallone b, serao a. covid-19 pandemic and uro-oncology follow-up: a "virtual" multidisciplinary team strategy and patients' satisfaction assessment. arch ital urol androl. 2020; 92:78-79.. correspondence vincenzo mirone, md mirone@unina.it massimiliano creta, md, phd (corresponding author) max.creta@gmail.com marco capece, md drmarcocapece@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com gianluigi califano, md gianl.califano2@gmail.com claudia collà ruvolo, md c.collaruvolo@gmail.com lorenzo spirito, md lorenzospirito@msn.com giovanni maria fusco, md giom.fusco@gmail.com luigi cirillo, md cirilloluigi22@gmail.com nicola longo, md nicola.longo@unina.it roberto la rocca, md robertolarocca87@gmail.com luigi napolitano, md luiginap89@gmail.com department of neurosciences, reproductive sciences and odontostomatology, university of naples "federico ii", 80131 naples (italy) ferdinando fusco, md ferdinando-fusco@libero.it department of woman, child and general and specialized surgery, urology unit, university of campania “luigi vanvitelli'” 80131 naples (italy) claudia mirone, md claudiamirone@outlook.it multidisciplinary department of medical, surgical and dental sciences, university of campania “luigi vanvitelli”, 80131 naples (italy) stesura seveso archivio italiano di urologia e andrologia 2021; 93, 3326 original paper no conflict of interest declared. us (3, 4). technological advances have contributed to the development of new technologies and techniques, that play a major role in the management of this disease. semirigid and flexible ureteroscopes constitute a basic component of endourologist armamentarium. after the first appearance of digital technology in ureteroscopes in 2004 (5) many more followed. reusable instruments offer repeatability but with uncertain endurance. legemate et al. (6) report that shaft bending, kinking and dent of coating is an issue that appears not seldom in everyday use. moreover sterilization procedures that apply for reusable instruments are accompanied by increased costs, necessary time intervals between operations and trained staff members (7). the first single-use digital flexible ureteroscope, was launched back in 2015 (8). equipped with a tip diameter of 7.7 fr, outer diameter of 9.5 fr, a wide enough working channel for baskets and laser fibers (3.6 fr), digital imaging and deflection angle up to 270 degrees, it is a great aid for the endourologist 8. a wide variety of movements, such as pronation/ supination, downward and upward deflection, along with back and forth movements, offers a great degree of freedom for the operator (8). literature search revealed data of in vitro/in vivo studies (8) and cadavers (9), while initial results on comparison with reusable fiberoptic ureteroscope showed better results in the single-use group regarding procedural time, failure of procedure and complications. despite the convincing results more studies should be conducted to reach safe conclusions. the aim of this study is to compare intraand postoperative complications and parameters while using a single-use, digital flexible ureteroscope, in comparison with a reusable fiberoptic ureteroscope in a prospective cohort of matched population for their baseline characteristics and their disease. patients and methods study design data collection was performed from an ongoing prospective database regarding patients treated for urolithiasis with a single-use, digital or reusable fiberoptic ureteroscope. objectives: ureteroscopy is one of the commonest procedures performed to manage urolithiasis. flexible ureteroscopy has been traditionally based on reusable, fiber-optic ureteroscopes. technology advancements permitted the development of single-use scopes with digital image. the aim of this study is to compare efficacy and safety between a reusable, fiberoptic ureteroscope with a single-use, digital scope. patients and methods: we collected data based on chart review from a prospectively collected database on a tertiary, high-volume hospital in greece. baseline, perioperative and postoperative data were gathered and analyzed. chi-square and fisher's exact test was used to compare qualitative data and unpaired t-test for continuous data, with a statistical significance set at a = 0.05. results: 40 patients underwent flexible ureteroscopy with a single-use digital scope, while 37 with the reusable scope. the two groups were matched regarding baseline characteristics and stone-related parameters. after data analysis, a shorter operative time in favor of single-use flexible ureteroscope was detected (45 vs 65 min, p = 0.001), while safety was also in favor of this type of scope with a significantly higher immediate stonefree rate (70% vs 43%, p = 0.005). overall complications did not differ between the two groups, although a lower sepsis rate was detected in patients treated with single-use scope. conclusions: our findings indicate that single-use, digital ureteroscopes are a viable alternative for flexible ureteroscopy and management of urolithiasis, especially in centers with deficient facilities for sterilization and ensured funds for more expensive reusable scopes. key words: urolithiasis; flexible ureteroscope; kidney stone disease; digital ureteroscope; single-use ureteroscope; fiber-optic ureteroscope; reusable ureteroscope. submitted 11 july 2021; accepted 25 july 2021 introduction geography and climatic changes along several regions affect kidney stone disease prevalence. in greece, urolithiasis is found to affect around 15% of population (1), while in contrast us citizens suffer from kidney stones to a lesser extent of around 9% (2). the total annual cost directed to this condition reaches around 5.3 billion $ in comparison of a single-use, digital flexible ureteroscope with a reusable, fiberoptic ureteroscope for management of patients with urolithiasis panagiotis mourmouris 1, lazaros tzelves 1, grigorios raptidis 2, marinos berdempes 1, titos markopoulos 1, grigorios dellis 2, ioannis siafakas 2, andreas skolarikos 1 1 national and kapodistrian university of athens, 2nd university department of urology, sismanoglio hospital, athens, greece; 2 251 airforce general hospital, urology department, athens, greece. doi: 10.4081/aiua.2021.3.326 summary 327archivio italiano di urologia e andrologia 2021; 93, 3 single-use, digital versus reusable, fiberoptic ureteroscope chart review for patient demographic characteristics, stone disease parameters and perioperative details was performed. cross-match of patients for confounders was also performed (stone disease parameters, age, asa score). settings data were derived from second urology department in sismanoglio, a tertiary hospital in greece, which is considered a reference center for stone disease, between a 12month period (06/2017-06/2018). a high volume of furs cases is performed yearly at out center (> 100). participants inclusion criteria were: patients older than 18 y/o with diagnosed stone disease based on imaging studies (ultrasound, ct scan or x-ray). patients with non-radiopaque stone disease, history of urinary tract neoplasm or those undergoing a diagnostic workup for hematuria were excluded. the ethics committee of hospital approved study protocol and patients were informed about inclusion and signed informed consent in case of participation. the study was conducted according to the principles of helsinki declaration. assignment to the specific treatment arm was done according to patient choice after being informed for the potential choices and availability of equipment. variables the demographic profile of patients was based on collection of data like age, gender, american society of anesthesiologists (asa) score according to anesthesiologic evaluation, side of disease, presence of bacteriuria and potential anatomic malformation of kidneys. perioperative variables like operation room time, technique and equipment used during ureteroscopy, complications and duration of hospital stay, stone free rates, as well as stone disease characteristics were also gathered (stone location, maximum diameter, and total burden). data sources and measurements in the study six experienced urologists performed the total number of cases either with lithovuetm (boston scientific) single-use, digital ureteroscope or the flex x2 (karl storz) fiberoptic, reusable fiberoptic ureteroscope. the exact same equipment was used between the two groups concerning laser fiber, baskets and other retrieval devices, as well as access sheaths in order to minimize confounding effect. antibiotic prophylaxis was administered to all patients according to existing eau guidelines and preoperative urine culture results. data regarding perioperative details were recorded by the urologist, the residents who were present in the operating room or by scrub nurses. the total operative time was defined as the length of time from ureteroscope entry until completion of stone pulverization. the patient stone burden was determined based on the most accurate imaging modality, while in order to categorize a patient stone free, no fragments of residual stone disease or clinically insignificant fragments < 2 mm (cifrs) should have been identified during patient follow-up with imaging tests. bias in order to limit confounding bias, we performed a crossmatching of cases regarding baseline characteristics and stone disease parameters. statistical methods categorical variables are described as proportions, while fisher’s exact test or chi-square test were used for comparing them. continuous data are presented as mean ± standard deviation or medians and analyzed using unpaired student’s t-test or mann-whitney u test. the choice of mann-whitney or t-test according to normal distribution was determined based on assessment of q-q plots and shapiro-wilk test. statistical significance was set at a = 0.05. all analyses were done with ibm spss statistics 25.0 software (spss inc., chicago, il.). results during the study recruitment period, 77 patients were treated, including 40 in the single-use scope group and the rest 37 in reusable scope group. the two groups were balanced with respect to mean age (55.73 ± 13.47 vs 55 ± 11.2, p = 0.797), use of access sheath (88% vs 92%, p = 0.713) and semirigid ureteroscope (60% vs 59%, p > 0.99) but more men (55% vs 38%) and more patients with positive urine culture preoperatively (23% vs 11%) were included in the single-use scope group, although this did not reach statistical significance (table 1). maximum stone size didn’t differ between the groups (12.63 vs 12.52 mm, p = 0.914), while the most common stone location was renal pelvis and lower pole calyces. ct scan was used more frequently for diagnosis in the singleuse scope group (78% vs 57%, p = 0.087) and hydronephrosis was more frequent, but this didn’t reach statistical significance (table 2). regarding the laser fiber used from stone fragmentation, in single-use scope group the 270 μm was more frequently used (57.5% vs 30%, p = 0.092) but results didn’t differ significantly. all patients received post-operative insertion of a double-j stent and a similar proportion in both groups was pre-stented. ancillary use of basket for stone removal and laser setting use for stone fragmentation were also similar between the two groups (table 3). median operative time (45 vs 65 min, p < 0.001), sepsis rate (0% vs 11%, p = 0.049) and stone free rate at day one after surgery (78% vs 43%, p < 0.001) favored use of single-use scope. no intraoperative complications were observed in both groups. finally, length of hospital stay and rates of table 1. baseline demographic characteristics of patients. characteristic single-use, reusable, fiber-optic p-value digital (n = 40) ureteroscope (n = 37) mean age ± sd 55.73 ± 13.47 55 ± 11.2 0.797 male sex no. (%) 22 (55) 14 (38) 0.172 asa score ≤ 2 no. (%) 39 (98) 34 (22) 0.441 positive urine culture no. (%) 9 (23) 4 (11) 0.228 kidney laterality left no. (%) 19 (47) 17 (46) > 0.999 present renal anomaly no. (%) 4 (10) 1 (3) 0.359 use of semirigid ureteroscope no. (%) 24 (60) 22 (59) > 0.999 use of access sheath no. (%) 35 (88) 34 (92) 0.713 archivio italiano di urologia e andrologia 2021; 93, 3 p. mourmouris, l. tzelves, g. raptidis, m. berdempes, t. markopoulos, g. dellis, i. siafakas, a. skolarikos 328 post-operative fever and macroscopic hematuria didn’t differ significantly between the two groups (table 4). discussion innovations in equipment technology resulted in improvement of clinical outcomes and rendered endoscopic management of stone disease the gold-standard (10). in this study we performed a comparison of clinical outcomes with the use of a disposable, single-use and digital flexible ureteroscope or a re-usable, fiber-optic flexible ureteroscope. the single-use ureteroscope performance in animal studies showed promising results regarding its efficacy and safety. the risk of transmitting potentially fatal infections with repeated use of duodenoscopes (11) or ureteroscopes (12), along with the associated costs for sterilization and maintenance, favor the adoption of single-use scopes, when efficacy is similar. a mean maximum deflection of 270 degrees when used with an empty working channel was found by winship (13), while after insertion of a laser fiber, an 8.3 degrees reduction in deflection angle was noted. duration of this type of scope proved satisfying since after 200 full deflections, a mean 21.8 degrees loss was detected, thus maintaining the desired deflection of > 250 degrees (13). this bench-top study also indicates no distortion of digital imaging after laser insertion through the working channel (13). in our study, we found a significant reduction in operative time equal to 20 minutes, although the two groups were similar in term of demographic characteristics, stone size and location. the reduction of operative time by 30% can save time for completion of further cases, reduce the physical burden of staff and the total associated costs. the lower weight of the single-use scope, which adds dexterity to the operator and reduces physical strain during ureteroscopy can be a possible explanation for these findings (6). endourologists frequently suffer from orthopedic problems in wrists/upper arms, as reported by healy et al. (14) in their survey, where 32% of urologists performing furs responded dealing with such issues. proietty et al. (15) reported that such a single-use scope is 10-300% lighter with camera head and light cable attached when compared to its counterpart reusable digital/fiberoptic scopes. less physical strain of endourologist might contribute to reduced operating time detected to our study. improved visual field during use of digital imaging also contributes to reduction of operative time and increases safety intraoperatively, according to somani et al. (16). another important advantage offered by the single use nature is that inexperienced users like residents, can handle it without the excess fear of scope breakage. according to mager et al. (17) and kam et al. (18), low-volume centers (< 51-60 furs yearly) might benefit from establishing a single-use scope based program, while high-volume centers (> 10/month) are more likely to save costs with reusable scopes, especially when they are handled properly. of course, current local market prices in each country may dictate different adaptations in a case-specific scenario. to ensure the superiority of a single-use scope regarding cost-effectiveness, further dedicated studies are needed. results of the croes global study (19) imply an 80% stone-free rate (sfr) for stones < 15 mm after a single furs, which is comparable with the 78% sfr found in this study sample when using a single-use scope, for a median stone size of 12.63 mm. of course, the several definitions used for stone-free rate across studies, may weaken these results, but the increased sfr seems promising, since this is the main primary outcome and the main determining factor to guide future management of table 2. stone characteristics. parameter single-use, reusable, fiber-optic p-value digital (n = 40) ureteroscope (n = 37) median number of stones (mm) 1.07 1.65 0.625 median maximum stone diameter (mm) 12.63 12.52 0.914 median total stone burden (mm) 17.36 15.22 0.284 present pre-operative hydronephrosis no. (%) 20 (50) 15 (41) 0.494 use of ct scan for diagnosis no. (%) 31 (78) 21 (57) 0.087 pelvicalyceal location of stones no. (%) 0.698 upper ureter 2 (5) 7 (19) renal pelvis 16 (40) 10 (27) middle renal pole 2 (5) 2 (5) lower renal pole 5 (12.5) 4 (11) renal pelvis/upper pole 1 (2.5) 1 (3) renal pelvis/middle pole 2 (5) 11 (30) renal pelvis/lower pole 10 (25) 0 (0) multiple calyces 1 (2.5) 1 (3) table 3. procedural characteristics. characteristic single-use, reusable, fiber-optic p-value digital (n = 40) ureteroscope (n = 37) use of basket for remaining stone fragments no. (%) 12 (30) 13 (35) 0.902 pre-operative jj stent no. (%) 14 (35) 13 (35) > 0.999 post-operative jj stent no. (%) 40 (100) 37 (100) size of laser fiber used for stone fragmentation no. (%) 0.092 270 μm 23 (57.5) 11 (30) 365 μm 9 (22.5) 15 (41) 270 & 365 μm 6 (15) 8 (20) laser settings used no. (%) 0.092 dusting 25 (62.5) 14 (38) chipping 2 (5) 2 (5) dusting & popcorn 6 (15) 9 (24) chipping & popcorn 5 (12.5) 10 (27) table 4. intraoperative and postoperative outcomes. outcome single-use, reusable, fiber-optic p-value digital (n = 40) ureteroscope (n = 37) median operative time (min) 45.00 65.00 < 0.001 mean length of stay in hospital ± sd (days) 1.75 (1.96) 1.38 (0.64) 0.261 immediate stone free status no. (%) 28 (70) 16 (43) < 0.005 stone free status 24 hours postoperatively no. (%) 31 (78) 16 (43) < 0.001 intraoperative complications no. (%) 0 (0) 0 (0) postoperative complications no. (%) 2 (5) 6 (16) 0.144 postoperative fever no. (%) 2 (5) 6 (16) 0.144 postoperative hematuria no. (%) 2 (5) 3 (8) 0.667 postoperative sepsis no. (%) 0 (0) 4 (11) 0.049 329archivio italiano di urologia e andrologia 2021; 93, 3 single-use, digital versus reusable, fiberoptic ureteroscope patients with urolithiasis. the fact that this a relatively new equipment and learning curve did not negatively impact perioperative results, further strengthens its use. post-operative fever shows a reported incidence equal to 0-10.8% (20-23) after operating in the urinary tract for stones less than 20 mm, using furs. the main contributing factors are female gender, increased body mass index, positive pre-operative urine culture, increased operative time and increased renal pelvic pressure. in our study we detected a rate of 5% in single-use scope group, which lies in agreement with existing literature. the reduction in operative time can be a protective factor for post-operative fever and sepsis when using single-use scopes, mainly due to less extend increase of renal pelvic pressure. patients in single-use scope group also suffered less hematuria and sepsis, which is quite important considering morbidity and mortality of urosepsis. this study has certain limitations. since this is not a randomized controlled trial, there is the possibility for selection bias, which we tried to minimize by cross-matching the groups for baseline demographic characteristics and stone disease parameters. the learning curve and the limited follow-up could also obscure the results regarding stone-free rates. conclusions this study compares a single-use, digital flexible ureteroscope with a re-usable, fiber-optic flexible ureteroscope for treatment of stone disease. the fact that single-use scope significantly decreases procedural duration and sepsis rates, while increased immediate-stone free rates, makes it a viable option for management of stone disease. further randomized trials and cost-effectiveness studies are needed to confirm these results. references 1. stamatiou k, karanasiou vi, lacroix r et al. prevalence of urolithiasis in rural thebes, greece. rural remote health. 2006; 6:610. 2. scales cd j, smith ac, hanley jm, saigal cs. prevalence of kidney stones in the united states. eur urol. 2012; 62:160-165. 3. ghani kr, sammon jd, karakiewicz pi, et al. trends in surgery for upper urinary tract calculi in the usa using the nationwide inpatient sample: 1999-2009. bju international. 2013; 112:224-230. 4. saigal cs jg, timilsina ar. direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? kidney int. 2005; 68:1808-1814. 5. shah k mm, knudsen b. prospective randomized trial comparing 2 flexible digital ureteroscopes: acmi/olympus invisio dur-d and olympus urf-v. urology. 2015; 85:1267-1271. 6. legemate jd, kamphuis, g. m., freund, j. e., et al. durability of flexible ureteroscopes: a prospective evaluation of longevity, the factors that affect it, and damage mechanisms. eur urol focus. 2019; 5:1105-1111. 7. semins mj gs, allaf me, matlaga br. ureteroscope cleaning and sterilization by the urology operating room team: the effect on repair costs. j endourol. 2009; 23:903-905. 8. dale j, kaplan ag, radvak d, shin r, et al. evaluation of a novel single-use flexible ureteroscope. j endourol. 2021; 35:903-907. 9. proietti s dl, molina w, doizi s, et al. comparison of new single-use digital flexible ureteroscope versus nondisposable fiber optic and digital ureteroscope in a cadaveric model. j endourol. 2016; 30:655-659. 10. kartal i, baylan b, cakici mc, et al. comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones. arch ital urol androl. 2020; 92:39-44. 11. epstein l, hunter jc, arwady ma, et al. new delhi metallo-�lactamase-producing carbapenem-resistant escherichia coli associated with exposure to duodenoscopes. jama. 2014; 312:1447-1455. 12. chang cl sl, lu cm, et al. outbreak of ertapenem-resistant enterobacter cloacae urinary tract infections due to a contaminated ureteroscope. j hosp infect. 2013; 85:118-24. 13. winship b wd, carlos e, li j, et al. avoiding a lemon: performance consistency of single-use ureteroscopes. j endourol. 2019; 33:127-131. 14. healy ka pr, cleary rc, colon-herdman a, bagley dh. hand problems among endourologists. j endourol. 2011; 25:1915-1920. 15. proietti s, somani b, sofer, et al. the "body mass index" of flexible ureteroscopes. j endourol. 2017; 31:1090-1095. 16. somani bk, al-qahtani sm, de medina sd, traxer o. outcomes of flexible ureterorenoscopy and laser fragmentation for renal stones: comparison between digital and conventional ureteroscope. urology. 2013; 82:1017-1019. 17. mager r km, höfner t, frees s, et al. clinical outcomes and costs of reusable and single-use flexible ureterorenoscopes: a prospective cohort study. urolithiasis. 2018; 46:587-593. 18. kam j, yuminaga y, beattie k, et al. single use versus reusable digital flexible ureteroscopes: a prospective comparative study. int j urol. 2019; 26: 999-1005. 19. skolarikos a, gross aj, krebs a, et al. outcomes of flexible ureterorenoscopy for solitary renal stones in the croes urs global study. j urol. 2015; 194:137-143. 20. kourambas j df, munver r, preminger gm. nitinol stone retrieval-assisted ureteroscopic management of lower pole renal calculi. urology. 2000; 56:935-939. 21. hollenbeck bk st, faerber gj, wolf js. flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi. urology. 2001; 58:859-863. 22. jung h nb, osther pj. retrograde intrarenal stone surgery for extracorporeal shock-wave lithotripsy-resistant kidney stones. scand j urol nephrol. 2006; 40:380-384. 23. el-nahas ar ih, youssef rf, sheir kz. flexible ureterorenoscopy versus extracorporeal shock wave lithotripsy for treatment of lower pole stones of 10-20 mm. bju international. 2012; 110:898-902. correspondence panagiotis mourmouris, md thodoros13@yahoo.com lazaros tzelves, md, msc (corresponding author) lazarostzelves@gmail.com andreas skolarikos, md andskol@yahoo.com 2nd university department of urology, sismanoglio hospital, sismanogliou 37, athens (greece) grigorios raptidis, md gregrapt@otenet.gr marinos berdempes, md marinosberdebes@hotmail.com titos markopoulos, md titosmark@gmail.com grigorios dellis, md grdellis@yahoo.gr ioannis siafakas, md sfksgnns@yahoo.com 251 airforce general hospital, urology department, athens (greece) stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12367 1 original paper der outlet obstruction (boo) are two main pathologies involved in the etiology of luts (2). luts is often associated with boo caused by prostate enlargement in men. moderate and severe luts are reported as 26% in men aged 40-49, while this rate doubles in the group aged 70 and older (3). the international prostate symptom score (ipss) from 8 to 19 indicates moderate luts (4), while a maximum flow (qmax) of less than 15 ml/sec in uroflowmetry has 82% sensitivity for boo (5). according to european association urology (eau) guidelines (6), alpha blockers are recommended as the first-line medical treatment in patients clinically diagnosed with boo (7). in recent years, many studies have been published on the relationship of urinary biomarkers with luts. nerve growth factor and brain derived neurotrophic factor, which are among most studied markers, have been shown to be closely associated with neurogenic or nonneurogenic detrusor overactivity and significant improvements were observed after treatment (8-11). the relationship between urinary glycosaminoglycan (gag) and overactive bladder (oab) has been demonstrated and it has been reported that the values have decreased after treatment (12). men with prostate enlargement (pe) and luts often have symptoms of overactive bladder. however, to our knowledge, there is no previous study in the literature examining the utility of urinary gag levels in this patient group. the aim of this study was to investigate the relationship between urinary gag levels and patients with luts. materials and methods patients who were seen in the outpatient clinic due to luts and diagnosed as clinically boo due to pe were included in the study. ethical approval was obtained from the local ethics committee (2018/53). the study was designed prospectively and submitted to clinicaltrials.gov (identifier: nct03955484). before starting an alphablocker medication, patients were enrolled to the study. all patients were evaluated under the guidance of eau guideobjective: the aim of this study was to investigate whether urinary glycosaminoglycans (gag) levels reflect clinical status in men with lower urinary tract symptoms and if they could be used as a marker in management of overactive bladder (oab). methods: a total of 34 patients were recruited who were admitted with luts and diagnosed as having clinically bladder outlet obstruction (boo) due to prostate enlargement. these newly diagnosed, never treated patients underwent routine investigation, consisting of history, physical examination, psa, ultrasound, uroflowmetry, assessment of symptoms scored by both international prostate symptom score (ipss) and marmaraoveractive bladder questionnaire (m-obq). the patients were divided into two groups as those with an initial m-obq score < 12 (group 1) and ≥ 13 (group 2). alfa blocker was initiated in eligible patients. further evaluations included prostate volume measurement, preand post-treatment urinary gag levels, ipss and m-qaob values and maximum urine flow rate (qmax). results: before treatment, urinary gag level was 21.5 mg/gcr (6.1-45.5) in group 1, and 23.35 mg/gcr (15.6-32.6) in group 2 (p =0.845). after the treatment, the gag level in group 1 and group 2 were found to be 19.8 mg/gcr (7.4-70.5) and 18 (7.641.7), respectively (p = 0.511). no difference in gag levels was found in subgroup analysis for patients with or without oab. conclusions: in recent years, there have been many studies investigating the relationship between luts and urinary markers. however, in our prospective study, no relationship was found between preand posttreatment urinary gag levels in patients with luts with or without oab. key words: gag; bladder outlet obstruction; overactive bladder; biomarker. submitted 2 february 2024; accepted 18 february 2024 introduction lower urinary tract symptoms (luts) are one of the most common conditions in the urology clinic, affecting at least one in four men after 40 years of age (1). bladder dysfunction (detrusor overactivity or underactivity) and bladrole of urine glycosaminoglycan levels in the diagnosis and follow-up in men with lower urinary tract symptoms hasan riza aydin 1, cagri akin sekerci 2, huseyin kocakgol 3, banu isbilen basok 4, fevzi bedir 3, ahmet ozgur guctas 5, firat akdeniz 6, hamit zafer aksoy 1, mehmet akif ramazanoglu 7, yiloren tanidir 2 1 department of urology, trabzon faculty of medicine, university of health sciences, trabzon, turkey; 2 department of urology, school of medicine, marmara university, istanbul, turkey; 3 department of urology, erzurum training and research hospital, erzurum, turkey; 4 department of biochemistry, tepecik training and research hospital, university of health sciences, izmir, turkey; 5 department of urology, marmara pendik training and research hospital, istanbul, turkey; 6 medical park hospital, trabzon turkey; 7 department of urology, trabzon kanuni training and research hospital, trabzon, turkey. doi: 10.4081/aiua.2024.12367 summary archivio italiano di urologia e andrologia 2024; 96(2):12367 h. riza aydin, c. akin sekerci, h. kocakgol, et al. 2 lines (6). patients received routine investigation, consisting of medical history taking, physical examination including digital rectal examination, prostate-specific antigen (psa), urinalysis and urine culture, ultrasound imaging, and uroflowmetric study, measurement of post void residual urine (pvr) assessment of symptoms scored by both international prostate symptom score (ipss) and marmaraoveractive bladder questionnaire (m-oabq) (13). male patients who applied to the urology outpatient clinic with luts, and had an ipss of 8 and above, and a prostate volume greater than 40 ml and a maximum flow of less than 15 ml/sec, were diagnosed with clinically boo due to prostate enlargement. of these patients, those who did not receive any medical and/or surgical treatment for luts were found to be eligible for the study. patients with a history of medical and/or surgical treatment for luts, or with a diagnosis of urethral stenosis, prostate cancer, neurologic diseases, spinal cord trauma or an absolute indication for surgical treatment at first admission (macroscopic hematuria, bladder stones, urinary retention, upper urinary tract dilatation) were excluded from the study. also, patients who required prostate biopsy according to rectal examination and psa were not included the study. in the initial evaluation, those who were not suitable for alpha-blocker treatment and needed urodynamic examination were excluded from the study. apart from the study group, 10 healthy adult males were selected as the controls for the assessment of baseline urinary gag levels. the study group were divided into two subgroups, according to m-oabq score before the alpha-blocker medication: a score of 12 and less (group 1) and a score of 13 and higher (group 2). the m-oabq is a tool to assess oab symptoms. m-oab questionnaire consists of eight questions and it has the highest sensitivity (97%) and specificity (94%) for the diagnosis of oab when a cut off value of 12.5 for the total score is used (13). after one month of alpha blocker treatment, all patients underwent re-evaluated with uroflowmetry, pvr, ipss, m-oabq. preand post-treatment urinary gag values, prostate volumes, ipss and moabq values and qmax were compared. biochemical analysis midstream morning urine samples were collected into sterile urine collection tubes and each urine sample was centrifuged at 5000 g for 10 minutes, the supernatant was aliquoted in 1.5-ml microcentrifuge tubes and stored at -800c until further analysis. total gag levels in supernatants were determined using the blyscan sulfated glycosaminoglycan assay (blyscan assay, biocolor ltd., northern ireland, uk) according to the manufacturer’s instructions (14). the blyscan assay as a direct colorimetric method quantifying urinary glycosaminoglycan excretion exploits the specific binding of 1,9-dimethylmethylene blue that provides a specific label for the sulfated polysaccharide component of proteoglycans or the protein-free sulfated glycosaminoglycan chains (15). the detection limit of assay was 2.5 µg/ml. urinary creatinine (cr) concentration was determined on each sample using the kinetic jaffe method in the au5800 clinical chemistry system (beckman coulter inc., ca, usa). the urinary concentrations of gag were normalized to the concentration of urinary cr and results were expressed as, milligram per gram of cr. statistical analysis data were analyzed using the ibm statistical package for the social sciences version 22 (ibm spss statistics for windows, chicago, il, usa). the normality of the distribution of the variables was evaluated using the shapirowilk test. as the distribution of continuous variables did not show a normal distribution, continuous data were presented with median, minimum and maximum. comparison of independent and dependent groups were done with mann-whitney u test and wilcoxon signed ranks test, respectively. the p value < 0.05 was accepted as statistically significant. results thirty-four patients with a median age of 59.5 (42-74) years were included in the study. there were 22 patients in group 1 and 12 patients in group 2. the median age of the control group was 44.5 (44-52) years. the median age of group 1 was 60 (48-72) years, and of group 2 was 58 (54-74) (p = 0.845). pre-treatment normalized urinary gag level was found to be 20.8 (6.1-45.5) mg/gcr in study group and 17.8 (11.5-22.26) mg/gcr in control group (p = 0.183). the normalized urinary gag level of the study group after the treatment was found to be 19.7 (7.53-70.5) mg/gcr and did not show a statistical difference compared to the pre-treatment level (p = 0.530). initial normalized urinary gag value of group 1 and 2 were as 21.5 (6.1-45.5) mg/gcr and 23.35 (15.6-32.6) mg/gcr, respectively (p = 0.845) (table 1). both ipss and m-obq score were found to be higher in group 2 compared to group 1 (p = 0.009, p < 0001, respectively) (table 1). baseline prostate volume (ml), psa (mg/dl), pvr (ml), qmax (ml/sec) were found to be similar in both groups (p = 0.136, p = 0.383, p = 0.276, p = 0.790, respectively) (table 1). table 1. comparison of age, prostate volume, symptom scores, pvr, qmax and urinary gag values between the two groups before medical treatment. pre-treatment group 1 (n: 22) group 2 (n: 12) p value median (min-max) median (min-max) age (year) 60 (48-72) 58 (54-74) 0.845 prostate (ml) 47.5 (30-102) 40 (23-93) 0.136 psa (ng/ml) 1.45 (0.6-40) 1.1 (0.5-13) 0.383 ipss 11 (5-25) 17.5 (10-30) 0.009 ipss-ql 3 (0-5) 4 (2-6) 0.037 m-oabq 6.5 (1-12) 17.5 (14-32) < 0.001 pvr (ml) 120 (30-350) 76 (14-278) 0.276 qmax (ml/sec) 9 (2-14) 9.5 (4-13) 0.790 gag (mg/g cr) 21.55 (6.1-45.5) 23.25 (15.6-32.6) 0.845 psa: prostate specific antigen; ipss: international prostate symptom score; ql: quality of life; m-oabq: marmara-overactive bladder questionnaire; pvr: post void residual urine volume; qmax: maximum urine flow rate; gag: glycosaminoglycan. archivio italiano di urologia e andrologia 2024; 96(2):12367 3 urinary gag levels in men with luts after the alpha-blocker treatment, the normalized urinary gag levels in group 1 and 2 was found to be statistically similar as 19.8 (7.4-70.5) mg/gcr and 18 (7.6-41.7) mg/gcr, respectively (p = 0.511) (table 2). interestingly, only m-obq score was still found to be higher in group 2 compared to group 1 (p < 0.0001), but ipss, pvr and qmax were found to be statistically similar (p=0.204, p = 0.309, p = 0.245, respectively) (table 2). discussion recently, several urinary biomarkers have been frequently studied in the assessment of luts. in general, urinary biomarker levels are frequently studied in various disease as they can be measured both noninvasively and easily. gags, a polysaccharide molecule produced in every cell in the human body, exist in two main structures as sulfated and non-sulfated (16, 17). non-sulfated gag contains hyaluronic acid, while sulfated gags include chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin. gags are in the structure of the basal lamina of the urethra, and damage to the gag layer can affect the basal functions of the urothelium (17, 18). this process may result in the bladder surface being exposed to microcrystals, proteins, calcium, toxic metabolic products, and carcinogens of the urine (19). thus, gags have been studied in overactive bladder (oab) and found to have an association with oab (12). intriguingly, urinary gag levels are affected differently in patients with luts symptoms. in a study conducted with 45 patients with oab, urinary gag levels were found to be higher in the patients with oab compared to the healthy subjects. one month of solifenacin treatment did help to decrease gag levels but no significant difference was found between responders and non-responders (12). yet, in another study involving 25 patients with luts (mean age 65.75 years) and urodynamically proven detrusor overactivity, urinary gag values were shown to be low compared to the healthy control group (20). in interpreting this finding, the authors speculated that high-amplitude and prolonged overactive detrusor contractions may be associated with the ischemic process in the bladder epithelium, which in turn could reduce urinary gag excretion. the relationship between interstitial cystitis (ic), another pathology, and urinary gag level has also been studied. like in oab, levels of urinary gag were differently reported. lokeshwar et al. reported urinary gag levels to be higher in patients with ic compared to healthy controls and even higher in patients with severe ic symptoms compared to those with mild symptoms (21). controversially, lucon et al. reported urinary gag levels to be low in patients with ic compared to patients with stress urinary incontinence. however, these authors also evaluated gag in tissue samples and could not show a decrease in the gag content of the urothelium in any groups (22). nocturnal enuresis appears to be another pathology associated with changes of urinary gag values. researchers have shown that urinary gag excretion is increased in children with nocturnal enuresis compared to healthy children (23, 24). urinary gag has also been reported to be associated with other urological pathologies such as renal cell carcinoma, acute renal failure, and bladder cancer, apart from lower urinary tract pathologies. in the current study, no significant difference was found between urinary gag values in boo patients with and without oab symptoms. most significant limitation of our prospective study is the small sample size; it could be responsible for the failure to show statistical difference in various situations. another limitation is the lack of urodynamics to diagnose detrusor over activity and boo. additionally, the control group was younger and was not formally assessed as the study group with medical history taking, physical examination including digital rectal examination, psa, ultrasound imaging, and uroflowmetric study, measurement of pvr and assessment of symptoms by ipss and m-oabq. conclusions no potential role of measurement of urinary gag was found in the evaluation of patients with luts in this study. we consider that this result may have been affected by the small number of the sample of patients and should be confirmed by studies with a higher number of subjects. references 1. robertson c, link cl, onel e, et al. the impact of lower urinary tract symptoms and comorbidities on quality of life: the bach and urepik studies. bju int. 2007; 99:347-54. 2. chapple cr, wein aj, abrams p, et al. lower urinary tract symptoms revisited: a broader clinical perspective. eur urol. 2008; 54:563-9. 3. speakman m, kirby r, doyle s, ioannou c. burden of male lower urinary tract symptoms (luts) suggestive of benign prostatic hyperplasia (bph) focus on the uk. bju int. 2015; 115:508-19. 4. barry mj, fowler fj, jr., o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549-57. 5. reynard jm, yang q, donovan jl, et al. the ics-'bph' study: uroflowmetry, lower urinary tract symptoms and bladder outlet obstruction. br j urol. 1998; 82:619-23. 6. cornu jn, gacci m, hashim h, et al. eau guidelines on nontable 2. comparison of symptom scores, pvr, qmax and urinary gag values between the two groups after medical treatment. post-treatment group 1 (n: 22) group 2 (n: 12) p value median (min-max) median (min-max) ipss 8 (1-16) 10 (3-30) 0.204 ipss-ql 2 (0-5) 3 (0-5) 0.631 m-oabq 5 (1-13) 12 (5-27) < 0.0001 pvr (ml) 43 (6-300) 77 (0-177) 0.309 qmax (ml/sec) 10.5 (4-17) 9.5 (4-13) 0.245 gag (mg/g cr) 19.8 (7.4-70.5) 18 (7.6-41.7) 0.511 ipss: international prostate symptom score; ql: quality of life; m-oabq: marmara-overactive bladder questionnaire; pvr: post void residual urine volume; qmax: maximum urine flow rate; gag: glycosaminoglycan. archivio italiano di urologia e andrologia 2024; 96(2):12367 h. riza aydin, c. akin sekerci, h. kocakgol, et al. 4 neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). eau guidelines. edn. presented at the eau annual congress milan march 2023, eau guidelines office, arnhem, the netherlands. 7. gravas s, cornu j, gacci m, et al. management of non-neurogenic male lower urinary tract symptoms (luts), incl. benign prostatic obstruction (bpo). 2019. https://uroweb.org/guidelines/management-of-non-neurogenic-male-luts 8. suh ys, ko kj, kim th, et al. urinary nerve growth factor as a potential biomarker of treatment outcomes in overactive bladder patients. int neurourol j. 2017; 21:270-81. 9. cekerci ç a, isbilen b, isman f, et al. urinary ngf, tgf-b1, timp-2 and bladder wall thickness predict neurourological findings in children with myelodysplasia. j urol. 2014; 191:199-205. 10. wang lw, han xm, chen ch, et al. urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. int urol nephrol. 2014; 46:341-7. 11. sekerci ca, tanidir y, toprak t, et al. value of urinary brainderived neurotrophic factor levels on the assessment of botulinum toxin type a treatment for neurogenic detrusor overactivity in children with myelodysplasia. j urol. 2019; 201:174-80. 12. alkis o, zumrutbas ae, toktas c, et al. the use of biomarkers in the diagnosis and treatment of overactive bladder: can we predict the patients who will be resistant to treatment? neurourol urodyn. 2017; 36:390-3. 13. mesane maa, formunun s. constitution and validation of a new symptom assessment tool for overactive bladder: marmara overactive bladder questionnaire (m-obq). journal of urological surgery. 2014; 1:24-7. 14. mashima r, sakai e, tanaka m, et al. the levels of urinary glycosaminoglycans of patients with attenuated and severe type of mucopolysaccharidosis ii determined by liquid chromatography-tandem mass spectrometry. mol genet metab rep. 2016; 7:87-91. 15. whitley cb, ridnour md, draper ka, et al. diagnostic test for mucopolysaccharidosis. i. direct method for quantifying excessive urinary glycosaminoglycan excretion. clin chem. 1989; 35:374-9. 16. gandhi ns, mancera rl. the structure of glycosaminoglycans and their interactions with proteins. chem biol drug des. 2008; 72:455-82. 17. ustundag y, huysal k, guzelsoy m, et al. urine and serum glycosaminoglycan levels in the diagnosis of urological diseases and conditions: a narrative review of the literature. urologia. 2021; 88:103-9. 18. costantini e, lazzeri m, porena m. gags and gags diseases: when pathophysiology supports the clinic. urologia. 2013; 80:173-8. 19. nickel jc, emerson l, cornish j. the bladder mucus (glycosaminoglycan) layer in interstitial cystitis. j urol. 1993; 149:716-8. 20. siracusano s, cucchi a, ciciliato s, et al. urinary levels of glycosaminoglycans in patients with idiopathic detrusor overactivity. int urogynecol j pelvic floor dysfunct. 2009; 20:1477-80. 21. lokeshwar vb, selzer mg, cerwinka wh, et al. urinary uronate and sulfated glycosaminoglycan levels: markers for interstitial cystitis severity. j urol. 2005; 174:344-9. 22. lucon m, martins jr, leite kr, et al. evaluation of the metabolism of glycosaminoglycans in patients with interstitial cystis. int braz j urol. 2014; 40:72-9. 23. ferrara p, rigante d, lambert-gardini s, et al. urinary excretion of glycosaminoglycans in patients with isolated nocturnal enuresis or combined with diurnal incontinence. bju int. 2000; 86:824-5. 24. budak yu, huysal k, guray a. urinary glycosaminoglycan excretion in patients with primary nocturnal enuresis. ital j pediatr. 2010; 36:13. correspondence hasan riza aydin, md (corresponding author) hrizaaydin@gmail.com hamit zafer aksoy, md hamitzaferaksoy@hotmail.com department of urology, trabzon faculty of medicine, university of health sciences, trabzon, turkey cagri akin sekerci, md cagri_sekerci@hotmail.com yiloren tanidir yiloren@yahoo.com department of urology, school of medicine, marmara university, istanbul, turkey huseyin kocakgol, md hsynkocakgl@gmail.com fevzi bedir, md fevzibedir84@gmail.com department of urology, erzurum training and research hospital, erzurum, turkey banu isbilen basok, md drisbilen@yahoo.com department of biochemistry, tepecik training and research hospital, university of health sciences, izmir, turkey ahmet ozgur guctas, md aoguctas@gmail.com department of urology, marmara pendik training and research hospital, istanbul, turkey firat akdeniz, md dr.frt5535@gmail.com medical park hospital, trabzon turkey mehmet akif ramazanoglu, md maramazanoglu@hotmail.com department of urology, trabzon kanuni training and research hospital, trabzon, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso 425archivio italiano di urologia e andrologia 2021; 93, 4 original paper no conflict of interest declared. gery and percutaneous nephrolithotomy (pcnl) especially for avoidance of accessing to the renal cavities through the kidney cortex. therefore, rirs stands out as a better treatment option especially in avoiding some important complications such as bleeding and risk of injury of adjacent organs. however, minimally invasive stone surgery has potential problems, such as radiation exposure, for both the patient and the surgical team (1). krup et al. reported their radiation exposure hypotheses according to a linear ‘‘non-threshold’’ model and estimated that one of every 1000 adult patients undergoing endoscopic stone surgery using fluoroscopy could experience secondary skin malignancy due to radiation exposure (2). the present study, aimed to investigate the factors affecting the outcome of rirs and stone-free rate in fluoroscopy-free technique setting. materials and methods after obtaining local ethics committee approval (ethics committee decision no: 1050), the charts of patients at the university of health sciences trabzon kanuni training and research hospital, who underwent flouroscopy-free retrograde intrarenal surgery (ffrirc) between january 2017 and august 2019 were reviewed retrospectively. patients with missing preoperative non-contrast computed tomography (ncct) and/or congenital kidney anomalies were excluded from the study. computed tomography (ct) scans of the patients were performed with a siemens somatom emotion 16 detector device. shooting protocol was in 1.5 mm axial sections with 110 kv and 90 mas energy and images obtained in coronal and sagittal planes. the ct sections were evaluated in the window settings l300/w1120 and maximum stone length was measured in axial, coronal and sagittal axis. the stone burden was calculated with formula of the ellipsoid volume (π/6 × d1xd2xd3) (3). a stone burden of 520 mm3 (when stone diameter was taken as 10 mm in all three planes) was used for comparison. stone density was measured three times by taking more than 50% of the stone size from the center of the stone. the average objective: to evaluate the outcomes of flouroscopy-free retrograde intrarenal surgery (ffrirs) and to investigate the factors that may affect stone-free rate. materials and methods: the charts of patients who underwent ffrirs between january 2017 and august 2019 were reviewed retrospectively. patients with missing preoperative imaging and patients with kidney anomalies were excluded from the study. age, gender, stone size, stone localization, stone density, laterality, operation time, stone-free rate, complications and auxiliary procedures were recorded and analyzed. results: study group involved 44 (43.1%) female and 58 (56.8%) male patients. stone-free rate in a single-session ffrirs were found to be correlated with stone localization (p = 0.003), stone volume (p = 0.004), and stone density (p = 0.009) but not with age (p = 0.950). patients with multiple calyceal stones and a stone burden over 520 mm3 were found to be less stone-free. the complication rate in female gender (n = 7) was significantly higher compared to male (n = 1) (p = 0.011). no major complications such as ureteral injury or avulsion were observed. overall, 13 patients (12.7%) needed auxiliary procedures. the operation time seemed to be affected by stone size and gender (p = 0.005; p = 0.044, respectively). conclusions: stone-free rate in ffrirs were found to be affected by stone density, size, and localization. patients with multiple caliceal stones and high stone burden (< 520 mm3) have been found to have low stone-free rate, so one can speculate that having fluoroscopy assistance in rirs might help us to improve surgical success. key words: kidney stones; rirs; fluoroscopy free; stone free; stone density. submitted 12 august 2021; accepted 28 october 2021 introduction in recent years, technological advances have provided us with important facilities in the surgical treatment of urinary tract stone diseases (utsd). open surgery has been largely replaced by minimally invasive urological procedures. retrograde intrarenal surgery (rirs), which is one of the minimally invasive techniques, differs from open suroutcomes of fluoroscopy-free retrograde intrarenal surgery and predictive factors of stone-free huseyin kocakgol 1, hasan riza aydin 2, ahmet ozgur guctas 3, cagri akin sekerci 4, deniz ozturk kocakgol 5, hamit zafer aksoy 2, yiloren tanidir 6 1 department of urology, university of health sciences, erzurum regional training and research hospital, erzurum, turkey; 2 department of urology, university of health sciences, kanuni training and research hospital, trabzon, turkey; 3 department of urology, marmara university training and research hospital, istanbul, turkey; 4 department of urology, division of pediatric urology, school of medicine, marmara university, istanbul, turkey; 5 department of radiology, maresal cakmak state hospital, erzurum, turkey; 6 department of urology, school of medicine, marmara university, istanbul, turkey. doi: 10.4081/aiua.2021.4.425 summary archivio italiano di urologia e andrologia 2021; 93, 4 h. kocakgol, h. riza aydin, a. ozgur guctas, et al. 426 hounsfield unit of three measurements was recorded as stone density (4). stone density above and below 1000 hu was compared (5). the “stone-free” condition was defined as absence of residual stones or presence of stone fragments less than 2 mm. stone features, demographic features, and surgical findings of patients like age, gender, stone size, stone localization, stone density, residual stone size and number, complications, operation time, stone-free rate, number and type of auxiliary procedures were analyzed and compared. surgical technique all patients were evaluated preoperatively with physical examination, routine blood tests, urine test and culture, kidney-ureter-bladder x-ray, and ncct. the operation was performed when the urine culture was sterile and parenteral antibiotic prophylaxis was administered to all patients before the procedure. no medical expulsive treatment was given after the procedure. all patients were operated with the following standard equipment: 6/7.5 fr wolf® semirigid ureterorenoscope (urs), storz® flex-x 2s flexible ureterorenoscope (f-urs), wolf® mega pulse tower 30+ laser device and cooks medical® 10.7 fr ureteral access sheath (uas). all operations were done under the general anesthesia. initially a ureteroscopy was done in the dorsal lithotomy position with a semi-rigid urs with the aid of a guidewire. semi-rigid ureteroscopy helped the passive dilation of the ureteral orifice and assessed the calibration and patency of the ureter. a 10.7 fr hydrophilic ureteral access sheath was gently advanced over the guidewire through the urethra into the ureters that look convenient for the uas insertion. fluoroscopyfree advancement of the uas continue until any resistance was felt. in such cases, the guidewire was left on the patient and the uas was taken out, and the lumen of the ureter was investigated with semi-rigid urs to assess the cause of resistance and possible ureter injury. in cases where uas could not be placed, a double j stent was placed, and the procedure was terminated and postponed to another session. after placing the uas, the collecting system of the kidney was inspected with the f-urs and laser lithotripsy was performed. laser settings were modified according to the efficiency of lithotripsy. following lithotripsy, collecting system of the kidney was inspected for residual stones. furs was carefully taken out of the body with the access sheath simultaneously and the guidewire was left within the ureter, so that the ureter was re-observed against any risk of injury. a double j stent was routinely placed into the renal pelvis in each patient. on the first postoperative day, a kub x-ray was obtained, and the uneventful patients were discharged. patients were re-evaluated by either ultrasonography (us) (n: 64) or ncct (n:38) in the first postoperative month. patients with significant residual stones or hydronephrosis were scheduled for auxiliary interventions. statistical analysis statistical analysis was done using international business machines (ibm) statistical package for social sciences (spss) statistics for windows (ibm corp. released 2017, version 25.0. armonk, ny: ibm corp). shapiro-wilk test was used to evaluate the distribution of variables. categorical variables were presented as numbers and percentages, and continuous variables as means and standard deviations. categorical variables were analyzed using chi-square test. statistical analyses of the means of continuous variables were performed using student’s t-test and analysis of variance. a p-value of less than 0.05 was considered statistically significant. results a total of 102 patients, 44 female (43.1%) and 58 male (56.9%), were included in our study. the mean age of the study group was 48.4 ± 14.4 years. in the primary procedure, rirs was performed by placing a urethral sheath in 57 (55.8%) patients. a double j stent was placed in the remaining 45 patients and rirs was performed in the next session. almost half of the patients had stones in renal pelvis (n = 55, (53.9%) (table 1). mean stone volume of patients were found to be 428 ± 405 mm3. of all patients treated with ffrirs, stone-free status was achieved in 69 (67.6%). the mean age of these patients was similar to patients with residual stones (48.3 ± 14.4 years vs 48.5 ± 14.7 years; p = 0.950). interestingly, stone free patients had a shorter operative time (62.8 ± 23.1 minutes vs 80.5 ± 24.5 minutes; p = 0.001). also, some stone characters were found to be significantly different in stone-free patients like stone localization (p = 0.003), size (p = 0.004) and density (p = 0.009) (table 1). no perioperative complications were found but eight patients (7 female, 1 male) suffered from postoperative complications. majority of these patients (n = 4) had febrile urinary tract infection. only one patient, required double j stent replacement in the postoperative early period. three patients need a second look with urs/rirs during stent removal due to high volume residual stones. overall, a total of 13 patients underwent urs or rirs as table 1. demographic features and parameters of stones (p values are for comparison of patients with and without residual stones). all patients stone-free patients with residual p value (n = 102) patients (n = 69) stones (n = 33) age (years) 48.4 ± 14.4 48.3 ± 14.4 48.5 ± 14.7 0.950 gender female 44 (43.1%) 33 (47.8%) 11 (33.3%) 0.167 male 58 (56.8%) 36 (52.1%) 22 (66.7%) side right 58 (56.8%) 42 (60.9%) 16 (48.5%) 0.237 left 44 (43.1%) 27 (39.1%) 17 (51.5%) stone localization upper pole 7 (0.68%) 3 (4.3%) 4 (12.1%) 0.003 middle pole 19 (18.6%) 14 (20.3%) 5 (15.2%) pelvis 55 (53.9%) 43 (62.3%) 12 (36.4) lower pole 13 (12.7%) 8 (11.6%) 5 (15.2%) multiple 8 (0.78%) 1 (1.4%) 7 (21.2%) stone volume < 520 mm³ 77 (75.4%) 58 (84.1%) 19 (57.6%) 0.004 > 520 mm³ 25 (24.6%) 11 (15.9%) 14 (42.4%) stone density < 1000 hu 53 (%51.9) 42 (60.9%) 11 (33.3%) 0.009 > 1000 hu 49(%48) 27(39.1%) 22 (66.7%) 427archivio italiano di urologia e andrologia 2021; 93, 4 outcomes of ff rirs an auxiliary intervention. there was no statistically significant difference between the demographic or stone parameters of the patient who needed additional surgery (p > 0.05). discussion the main goal of the treatment of utsd is to provide stone-free with minimum harm and maximum benefit. therefore, predictive factors are important in the selection of the treatment procedure. in this study, we investigated the need for fluoroscopy and predictive factors of rirs. it is a fact that fluoroscopy at many stages in the treatment of utsd provides us with a roadmap function. however, ionizing radioactivity emitted from the x-ray device carries a potential risk for both the patient and the surgical team. unfortunately, exposure to radioactivity does not have an exact threshold because the radioactive effect occurs in two ways with deterministic and stochastic effects. the detrimental effect occurs at radioactive exposure on the threshold dose. the stochastic effect is the mutations caused by the effect of radiation on dna and it is thought that there is no threshold value for this effect (6). today, technological developments enable us to work with tools that provide smaller diameter and higher quality images in endourological interventions. in addition, ureteral injuries are more rare complications due to high-quality guide wires and ureteral access sheaths and expertise gained by urologists in endourological interventions. placing uas during ffrirs is one of the critical stages of the process. uas provides direct access to the kidney during rirs. however, it has been reported that it increases the susceptibility to urinary infection as well as ureteral injury (7). during uas insertion, ureter damage may occur. various techniques have been developed for the uas placement procedure to prevent ureteral injury. some authors recommend performing the procedure without uas insertion, and others suggested placing uas in pre-stented patients (8-10). boulalas et al. evaluated ureteral compliance with a 9.5 fr semi-rigid ureterorenoscopy routinely prior to 12/14 fr uas insertion in their prospective study. in patients with unsuitable small-diameter ureters, they continued the procedure with smaller-diameter instruments. in this series of 100 patients, uas were successfully placed in the first session with this technique in 77 patients (77%), but ureteral complications were reported in 10%. eight of these were reported as grade i secondary to 3 fr guide wire induction, and the remaining two as grade i and grade iii ureteral injuries secondary to uas procedure (11). in our study, uas could be placed in 57 (55.8%) patients at the first session in primary cases. we did not observe any complications related to ureteral injury. routinely use of hydrophilic guidewire and a smaller diameter of 10.7 fr uas could explain this result. in addition, some authors described the technique of wearing uas on semi-rigid or flexible urs (12-13). the benefits of performing sheath placement under fluoroscopy are controversial, because fluoroscopy without the administration of opaque material has no ability to show strictures, kinks, or non-opaque stones in the ureter. wearing a uas on the urs allows direct visualization of the ureter during the procedure. however, using the ureteroscope instead of the access sheath mandrel may cause the loss of the protection of the ureteral wall due to the mandrel that is a "non-traumatic, round structure that completely covers the sheath mouth". in our study, ffrirs was applied to eligible patients in the first session, whereas non eligible patients were treated in a second session after double j stent. various studies have been conducted on the treatment of ffrirs. in a series of 100 patients, 33 patients underwent the procedure with fluoroscopy, while in 67 patients the procedure was done without fluoroscopy and no statistically significant difference was reported between the two groups in terms of perioperative complications. in the same study, there were no major complications such as ureter perforation, and no statistically significant difference was reported between stone-free rates (14). in another study in which rirs was performed without using fluoroscopy a total of 5 complications (5 fever, 1 hematuria) in 140 patients were reported and a high stone-free rate of 95.7% was reported (6). when we searched the literature about rirs, we did not find a study in which age, gender and side factor were found to be significant in providing stone free. in the study of resorlu et al., patients were evaluated in four different age groups as ≤ 7, 8-17, 18-60, and > 60 years old and there was no statistically significant difference in stone-free rates between patient groups (15). similarly, soo hyun lim et al. did not report age and gender as a predictive factor in their study (16). in our study, the mean age of patients without residual stones was 48.3 ± 14.4 years, and the mean age of patients with residual was 48.5 ± 14.7 years (p = 0.950). although our stone free rate was 75% in females and 62.1% in males, there was no statistically significant difference (p = 0.121). in many studies, stone size has been reported as an important predictive factor of success of rirs (15, 16). however, the fact that the stone-free ratio tend to be lower with the increase in stone size does not mean that rirs can be completely avoided in these patient groups. in eau guidelines, total stone-free rates of 91% have been reported with 1.45 procedures in patients with stones over 2 cm (1719). we calculated stone size as mm³ aiming to have a more accurate evaluation of stone size. in our study, the rate of stone-free after one session was 75.2% in the patient group with a stone size < 520 mm³, while it was 44% in the group > 520 mm³ (p = 0.005). stone localization and infundibulo-pelvic angle have been reported as important predictive factors in the rirs procedure. resorlu et al. reported that stone-free ratio was statistically decreased in lower pole stones, multi-calyceal stones and in patients with infundibulo-pelvic angle < 45° (15). sung yong cho et al. reported that stone-free rates in multiple stones were statistically lower than in single stone in their study (p = 0.005) (20). the results of our study were compatible with the literature. our stone-free rates were 73.7% and 78.2% in the middle pole and pelvis stones and were 61.5%, 42.9% and 12.5% in the lower pole, upper pole and multiple stones, respectively (p = 0.003). archivio italiano di urologia e andrologia 2021; 93, 4 h. kocakgol, h. riza aydin, a. ozgur guctas, et al. 428 stone density was another important parameter in treatment of renal stones. this parameter has found its place in many studies especially on extracorporeal lithotripsy (21, 22). kim et al. reported that stone density did not affect the endoscopic treatment of ureteral stones (23). in the treatment of ureteral stones, it should be considered that a thicker laser probe can be used with the semirigid urs and that it can be easily manipulated. predictive effect of the stone density in rirs is controversial and there are a limited number of studies in the literature. gucuk et al. found stone density to be insignificant as a predictive factor in rirs treatment (p = 0.22). in this article, unlike the present study, the stones were divided as below and above 677 hu (24). in another study, stone density was evaluated in groups of patients with and without stone free and it was found to be higher in patients with residual stone (p < 0.001) but a density limit was not specified (25). in our study, stone density was found to be a predictive factor in stone-free when patients who underwent rirs were evaluated according to two different categories of stone density (< 1000 hu and > 1000 hu): stone-free rate was 55.1% in patients with stone density above 1000 hu and 79.2% in the group below 1000 hu (p = 0.009). in our study, the gender was found to be a significant factor in the development of complications. no statistically table 2. the comparison of studies with fluoroscopy assisted retrograde intrarenal surgery and present study author/year lim s.h. et al. 2010 (16) resorlu et al. 2012 (15) ito h. et al. 2014 (27) erbin a. et al. 2016 (28) xiao et al. 2017 (25) present study study design retrospective retrospective retrospective retrospective retrospective retrospective number of patients (n) 66 207 310 339 382 102 stone free rate (%) 72.7% (46/66) %86 (178/207) 59.6% (185/310) 70.1% (238/339) 73.6% (281/382) 67.6% (69/102) stone localization upper-middle pole or pelvis: upper-middle pole: lower pole stone presence: upper calyx: inferior pole stone group: upper pole sfr: 94.2% (17/18) sfr: 92.7% (51/55) sf group: 53.5% (99/185) sfr: 72.2% (26/36) sf group: 47.6% (69/145) sfr: 42.8% (3/7) lower pole: pelvis: non-sf group: middle calyx: non-inferior pole stone free group: middle pole sfr: 60.4% (29/48) sfr: 90.6% (58/64) 85.6% (107/125) sfr: 92.9% (13/14) 89.5% (212/237) sfr: 73.6% (14/19) (p: 0.007) (p < 0.001) (p < 0.001) lower pole: pelvis: single stone group: pelvis: sfr: 78.4% (69/88) sfr: 73.1% (76/104) sfr: 85.8% (200/233) sfr: 78.1% (43/55) (p: 0.025) lower calyx: multiple calyces stone group: lower pole: sfr: 65.5% (91/139) sfr: 54.4% (81/149) sfr: 61.5% (8/13) (p < 0.001) multiple calyces: multiple: sfr: 69.6% (32/46) sfr: 12.5% (1/8) (p: 0.247) (p: 0.003) lower pole infindibulopelvic angle: sf group: 49.5°± 12.3° non-sf group: 44.1°± 11.3° (p: 0.004) stone size ≤ 150 mm2 0-10 mm sfr: 88.9% (8/9) sf group: 15.88 mm sf group: 13.6 ± 4.7 mm mean stone size: 14 mm < 520 mm³ sfr: 83.7% (41/49) 11-20 mm non-sf group: non-sf group: 16.4 ± 6.5 mm sf group: 12 mm (9-17) sfr: 75.3% (58/77) > 150 mm2 sfr: 93.3% (153/164) 32.79 mm (p: 0.000) non-sf group: 25 mm (18-29) > 520 mm³ sfr: 29.4% (5/17) > 20 mm sfr: 50% (17/50) p < 0.001 (p < 0.001) sfr: 44% (11/25) (p < 0.001) (p < 0.001) (p: 0.004) sf group: 12 mm (9-17) stone density (hu) na na sf group: na sf group: < 1000 hu 944.49 (373.52) hu 1022.59 ± 342.97 hu sfr: 79.2% (42/53) non-sf group: 1099.73 non-sf group: > 1000 hu (335.46) hu 1193.43 ± 285.44 hu sfr: 55.1% (27/49) (p < 0.001) (p < 0.001) (p: 0.009) operation time (min) na 52 (15-95) na na sf group: 64.7 ± 23.2 50 (60–40; 20) min. non-sf group: 60 (85–50; 35) min. (p < 0.001) complication rate (%) 4 (6%) 20 (9.66%) 18 (5.8%) 18 (5%) 27 (7.1%) 8 (7.8%) type of intraoperative minor ureteral perforation (1) high-grade postoperative clavien grade i na clavien grade i: complication cases (n) ureter injury (1) abdominal pain (4) fever (16) or ii complication (12) febrile urinary febrile urinary tract infection (2) voiding disturbances (4) postoperative ureteric clavien grade iiia tract infection (4) postoperative paralytic ileus (1) hematuria (4) stricture (2) complication (urosepsis) (7) clavien grade iiib: postoperative fever urs was performed or infection (5) due to a residual urosepsis (1) ureter stone that could not pass (4) crirs: retrograde intrarenal surgery; urs: ureterorenoscopy; sf: stone free; sfr: stone free rate; hu: hounsfield unit; min: minute; mm: millimeter; na: not available. 429archivio italiano di urologia e andrologia 2021; 93, 4 outcomes of ff rirs significant difference was observed in other parameters. seven of our 8 patients who developed complications were women (p = 0.04). febrile urinary tract infection developed in 4 patients (clavien grade i) and they were treated with appropriate antibiotics and antipyretic therapy. all the patients with febrile urinary infection were female. we think that this finding may be related to the fact that women are more prone to urinary tract infection (26). complications requiring surgical intervention (clavien grade 3b) developed in 4 patients and urs was performed due to a residual ureter stone that could not pass. a total of 13 patients underwent urs/rirs as an additional intervention. 4 of them were secondary to complications, and the remaining 9 patients received rirs treatment as second session. the 18 of the remaining patients who were not stone free were included in the follow-up protocol. in 11 of 13 patients who needed additional treatment, stone density was > 1000 hu (p = 0.08). in our study, the operation time was found to be significantly longer in high stone volume and men. while mean operation time was 64.7 ± 23.2 minutes in the patient group with stone burden < 520 mm³, it was 80.4 ± 26.6 minutes in the patient group with > 520 mm³ (p = 0.005). similarly, the operation time was found to be longer in the non-stone free group (p = 0.001). operation time in females was 62.8 ± 19.6 minutes and 72.8 ± 27.6 minutes in males (p = 0.044). it is not surprising that the operation time is longer in high stone volume. however, it is noteworthy that the duration of the operation in women is shorter. in our study, we think that the short female urethra and the low number of female patients with a stone size > 520 mm³ (n: 8) are an explanation of this result. the operation time was found to be 64.3 ± 25.5 minutes in patients with < 1000 hu, 73.1 ± 23.6 minutes in patients with > 1000 hu (p = 0.07). we summarized the results of some fluoroscopy assisted rirs studies and our findings in table 2. we choose these studies as the stone burden seemed to be similar to ours. our stone-free rates are lower than those observed in these studies although complication rates were similar or lower. as an exception, ito et al. reported worse stone free rates and almost similar complication rates, but in this series the majority of stones were in the lower pole (15, 16, 25, 27, 28). a randomized comparison should be necessary to confirm that fluoroscopy-free rirs can obtain the same results of conventional rirs with the use of fluoroscopy. the study has some limitations. this was a retrospective study, and all controls were not performed with ct. our study has no control group, so it lacks the comparison with data of fluoroscopy assisted rirs. we tried to get rid of this limitation by comparing our study with historical fluoroscopy assisted rirs studies as shown in table 2. conclusions although fluoroscopy is not protective against major complications such as ureteral injury, it may increase success in multiple calyx and large stones. stone density, size, and localization were observed to affect the success of treatment. particularly, stone density occurred as an important predictive factor for rirs in this study. we hope that our study will make an important contribution to the literature, evaluating ffrirs and stone density as predictive factor. references 1. olgin g, smith d, alsyouf m, et al. ureteroscopy without fluoroscopy: a feasibility study and comparison with conventional ureteroscopy. j endourol. 2015; 29:625-9. 2. krupp n, bowman r, tenggardjaja c, et al. fluoroscopic organ and tissue-specific radiation exposure by sex and body mass index during ureteroscopy. j endourol. 2010; 24:1067-73. 3. park j, kang m, jeong cw, et al. external validation and evaluation of reliability and validity of the modified seoul national university renal stone complexity scoring system to predict stone-free status after retrograde intrarenal surgery. j endourol. 2015; 29:888-93. 4. foda k, abdeldaeim h, youssif m, assem a. calculating the number of shock waves, expulsion time, and optimum stone parameters based on noncontrast computerized tomography characteristics. urology. 2013; 82:1026-31. 5. cakiroglu b, eyyupoglu se, tas t, et al. are hounsfield densities of ureteral stones a predictive factor for effectiveness of extracorporeal shock wave lithotripsy? int j clin exp med. 2014; 7:1276. 6. peng y, xu b, zhang w, et al. retrograde intrarenal surgery for the treatment of renal stones: is fluoroscopy-free technique achievable? urolithiasis. 2015; 43:265-70. 7. karaaslan m, tonyali s, yilmaz m, et al. ureteral access sheath use in retrograde intrarenal surgery. arch ital urol androl. 2019; 91:112-114 8. emiliani e, motta g, llorens e, et al. totally fluoroless retrograde intrarenal surgery technique in prestented patients: tips and tricks. j pediatr urol. 2019; 15:570-3. 9. tepeler a, armagan a, akman t, et al. is fluoroscopic imaging mandatory for endoscopic treatment of ureteral stones? urology. 2012; 80:1002-6. 10. hein s, schoenthaler m, wilhelm k, et al. ultralow radiation exposure during flexible ureteroscopy in patients with nephrolithiasis—how far can we go? urology. 2017; 108:34-9. 11. boulalas i, de dominicis m, defidio l. semirigid ureteroscopy prior retrograde intrarenal surgery (rirs) helps to select the right ureteral access sheath. arch ital urol androl. 2018; 90:20-4. 12. ekici m, özgür bc, şentürk ab, et al. all-seeing-access sheath: a novel fluoroscopy-free placement technique in retrograde intrarenal surgery. j coll physicians surg pak. 2019; 29:263-267. 13. sönmez mg, kara c. a new approach in ureteral access sheath locating in retrograde intrarenal surgery (rirs) by endovisional technique. arch ital urol androl. 2015; 87:286-90. 14. manzo bo, lozada e, manzo g, et al. radiation-free flexible ureteroscopy for kidney stone treatment. arab j urol. 2019; 17:200205. 15. resorlu b, unsal a, gulec h, oztuna d. a new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the “resorlu-unsal stone score”. urology. 2012; 80:512-8. 16. lim sh, jeong bc, seo si, et al. treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stonefree. korean j urol. 2010; 51:777-82. 17. wendt-nordahl g, mut t, krombach p, et al. do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? urol res. 2011; 39:185-8. archivio italiano di urologia e andrologia 2021; 93, 4 h. kocakgol, h. riza aydin, a. ozgur guctas, et al. 430 18. geraghty r, abourmarzouk o, rai b, et al. evidence for ureterorenoscopy and laser fragmentation (ursl) for large renal stones in the modern era. curr urol rep. 2015; 16:54. 19. binbay m, yuruk e, akman t, et al. is there a difference in outcomes between digital and fiberoptic flexible ureterorenoscopy procedures? j endourol. 2010; 24:1929-34. 20. cho sy, choo ms, jung jh, et al. cumulative sum analysis for experiences of a single-session retrograde intrarenal stone surgery and analysis of predictors for stone-free status. plos one. 2014; 9:e84878. 21. wang l-j, wong y-c, chuang c-k, et al. predictions of outcomes of renal stones after extracorporeal shock wave lithotripsy from stone characteristics determined by unenhanced helical computed tomography: a multivariate analysis. eur radiol. 2005; 15:2238-43. 22. el-nahas ar, el-assmy am, et al. a prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. eur urol. 2007; 51:1688-94. 23. kim jw, chae jy, kim jw, et al. computed tomography-based novel prediction model for the stone-free rate of ureteroscopic lithotripsy. urolithiasis. 2014; 42:75–79. 24. gucuk a, yilmaz b, gucuk s, uyeturk u. are stone density and location useful parameters that can determine the endourological surgical technique for kidney stones that are smaller than 2 cm? a prospective randomized controlled trial. urol j. 2019; 16:236-41. 25. xiao y, li d, chen l, et al. the r.i.r.s. scoring system: an innovative scoring system for predicting stone-free rate following retrograde intrarenal surgery. bmc urology. 2017; 17:105. 26. harrington rd, hooton tm. urinary tract infection risk factors and gender. the journal of gender-specific medicine: jgsm: the official journal of the partnership for women's health at columbia. 2000; 3:27-34. 27. ito, h, sakamaki k, kawahara t, et. al. development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones. bju international. 2015; 115: 446-451. 28. erbin a, tepeler a, buldu i, et al. external comparison of recent predictive nomograms for stone-free rate using retrograde flexible ureteroscopy with laser lithotripsy. j endourol. 2016, 30: 1180-1184. correspondence huseyin kocakgol, md (corresponding author) hsynkocakgl@gmail.com department of urology, university of health sciences, erzurum regional training and research hospital, adnan menderes mahallesi şehit burak karakuş sokak al-furkan sitesi a blok kat:1 no:8 palandöken/erzurum (turkey) hasan riza aydin, md hasanriza.aydin.61@gmail.com hamit zafer aksoy, md hamitzaferaksoy@hotmail.com department of urology, university of health sciences, kanuni training and research hospital, trabzon (turkey) ahmet ozgur guctas, md aoguctas@gmail.com department of urology, marmara university training and research hospital, istanbul (turkey) cagri akin sekerci, md cagri_sekerci@hotmail.com department of urology, division of pediatric urology, school of medicine, marmara university, istanbul (turkey) deniz ozturk kocakgol, md dr.denizz@hotmail.com department of radiology, maresal cakmak state hospital, erzurum (turkey) yiloren tanidir, md yiloren@yahoo.com department of urology, school of medicine, marmara university, istanbul (turkey) stesura seveso archivio italiano di urologia e andrologia 2023; 95(3):11494 1 original paper (1). in africa, circumcisions are often not carried out in hospital settings and are typically performed by lesstrained nurses and traditional practitioners. circumcision complications can range from minor to major, impacting patients' vital or functional prognosis. this study aimed to review clinical presentations and evaluate the management and outcomes of circumcision at souro sanou university teaching hospital in burkina faso. patients and methods this retrospective descriptive study examined all circumcision complications collected between january 1, 2014 and december 31, 2018, at the urology division in souro sanou university hospital. all patients admitted to the urology division with circumcision complications were included. variables considered included age, reason for visit, reason for circumcision, place of residence, admission delay, qualification of the practitioner who performed the circumcision, clinical presentation upon admission, medication, surgical revision technique, voiding quality, and aesthetic appearance of the penis for each subject included in this study. all patients or their parents or legal guardian when they are minor consent for the publication of chosen images to illustrate our clinical presentation. the study obtain the approval of the local ethical committee of the department of surgery of souro sanou university hospital registered under the number n°007/2018. results we documented a total of 23 circumcision complications, averaging 4.6 cases per year. the patients' mean age was 8.33 years ± 3.5 years, with a range spanning from 18 months to 65 years. among the 23 patients, 22 underwent circumcision without medical indication, while one case involved circumcision for medical reasons due to phimosis. we identified three cases of hemophilia and one case of hiv infection. most patients (60.87%) lived in rural areas and worked in agriculture, compared to 39.13% who resided in urban areas. nurses performed 52% of the circumcisions, while objective: to report the clinical presentation of circumcision complications encountered at our center and evaluate their management and outcomes. patients and methods: a retrospective and descriptive study was conducted at souro sanou university hospital between january 1, 2014, and december 31, 2018. all patients presenting with circumcision complications were included. parameters related to clinical aspects of circumcision complication, their management and outcomes were studied. results: during the study period, 23 cases of circumcision complications were reported. the average age of patients with circumcision complications was 8.3 years ± 3.5 years, with ages ranging from 18 months to 65 years old. circumcision was performed by nurses in 12 cases and traditional practitioners in 11 cases. observed complications included post-circumcision bleeding and hematoma (n = 8), leading to surgical exploration and hemostasis; total or partial amputation of the glans (n = 4), requiring regularization and meatoplasty; infectious complications (n = 3), managed with combined resuscitation, antibiotic administration, and penile debridement; penile urethra-cutaneous fistulas (n = 2), which were repaired; and stenosis of the external urethral meatus (n = 2), treated by meatoplasty. no deaths were reported. conclusions: circumcision complications presented various clinical manifestations, including hemorrhagic complications, glans amputation, infection, penile fistulas, and meatal stenosis. these complications were effectively managed from a functional perspective; however, aesthetic issues may persist. emphasis should be placed on preventing these complications by ensuring circumcisions are performed by appropriately trained medical professionals. key words: circumcision; complications; hemorrhage; amputation; prevention. submitted 30 may 2023; accepted 18 june 2023 introduction circumcision involves the partial or complete removal of the foreskin. it is not only a religious requirement for israelites, a custom for muslims, and a rite of passage into adulthood for many africans, but also a common surgical procedure used to treat various balanopreputial diseases complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes about 23 cases and literature review adama ouattara 1, abdoul-karim paré 1, delphine yé 1, ali sherazi 2, mohamed simporé 1, mickael rouamba 1, aristide f. kaboré 3, timothée kambou 1 1 urology division, souro sanou university teaching hospital, bobo-dioulasso, burkina faso; 2 department of medicine, dalhousie medicine new brunswick, saint john, new brunswick, canada; 3 urology division, yalgado ouedraogo university teaching hospital, ouagadougou, burkina faso. doi: 10.4081/aiua.2023.11494 summary archivio italiano di urologia e andrologia 2023; 95(3):11494 a. ouattara, a.-k. paré, d. yé, et al. 2 traditional practitioners conducted 48%. the average consultation delay was 12 ± 8.5 hours, with a range between 2 hours and 15 days. according to patients or their relatives, all circumcisions took place without anesthesia. however, we could not determine if the general rules of asepsis were adhered to when nurses performed the circumcision. consultation reasons included urine leakage through a urethrocutaneous fistula for two patients (n = 2), local hemorrhage with blood loss for patients with partial or complete glandular section or hematoma (n = 8), dysuria with urine retention for patients with external urethral stenosis or incomplete circumcision, and local signs of suppuration for patients. table 1 lists the main consultation reasons that prompted patients to seek emergency care. nurses employed the classic guillotine method for foreskin removal, a technique commonly used by various professionals. this method involves removing the foreskin by placing forceps over the glans and cutting it flat. techniques performed by traditional practitioners are not described. the study reported various types of complications, including hemorrhages (n = 8), penile amputations (n = 4), incomplete circumcisions (n = 3), external urethral stenosis (n = 3), urethrocutaneous fistulas (n = 2), and infections (n = 3). these complications are detailed in table 2. figures 1 through 7 illustrate the different complications observed in this study. all patients admitted due to complications underwent both medical and surgical management. this comprehensive approach included medical resuscitation, antibiotic administration, tetanus prevention and serotherapy, as well as surgical treatments tailored to the specific complication. among patients with bleeding complications (n = 8), seven required an isogroup isorhesus blood transfusion to address anemia with signs of hypovolemic shock and hemoglobin levels below 7 g/dl. additionally, three patients (n = 3) with hemorrhagic complications related to hemophilia necessitated collaborative management with hematologists. the various surgical management methods for circumcision complications are outlined in table 3. table 1. main reasons of consultation. reasons of consultation frequency (n) percentage (%) local bleeding 10 26.08 amputation of glans 4 17.39 dysuria 3 13.04 urinary leakage from fistula 3 13.04 tumefaction of the penis 3 13.04 local infection 2 8.69 acute urinary retention 2 8.69 figure 1. total amputation of the glans. figure 2. post-circumcision infection. figure 3. gangrene of external genitalia. table 2. circumcision complications reported. type of complication frequency (n) percentage (%) post-circumcision bleeding 6 26.08 total amputation of the glans 3 13.04 incomplete circumcision 3 13.04 external urethral stenosis 3 13.04 urethro-cutaneous fistula 2 8.69 gangrene of external genitalia 2 8.69 post-circumcision hematoma 2 8.69 necrosis of the glans 1 4.34 partial amputation of the glans 1 4.34 total 23 100 table 3. distribution of patients by type of surgery. type of surgery frequency (n) percentage (%) revision of circumcision with hemostasis 6 26.08 regularisation of the glans stump 4 13.04 revision of circumcision/posthectomy 3 13.04 meatoplasty 3 13.04 cure of penile fistula 2 8.69 gangrene of external genitalia 2 8.69 evacuation of penile hematoma 2 8.69 glanduloplasty 1 4.34 total 23 100 archivio italiano di urologia e andrologia 2023; 95(3):11494 3 complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes in general, the management of circumcision complications led to delayed healing for the three patients (n = 3) experiencing infectious complications. the four patients (n = 4) who underwent glans amputations exhibited functional sequelae and an unaesthetic appearance of the glans, although they maintained good voiding quality. psychological trauma was not assessed in this study, and no deaths were reported. figure 8 and figure 9 provide an example of re-circumcision following an incomplete procedure and the final appearance after the procedure's revision. discussion in 1997, bankolé et al. (1) reported 22 cases of traditional circumcision and excision sequelae in abidjan. sylla et al. (2) documented 63 cases of circumcision complications in dakar in 2003, while dieth et al. (3) recorded 35 cases of circumcision accidents in abidjan in 2008. kimassoum et al. (4) reported 28 cases of circumcision complications in chad in 2016. in the west, gross et al. (5) studied ritual circumcision complications in paris in 1986. many authors argue that circumcision reduces the risk of urinary tract infections in children, helps prevent penile cancer in adults, and plays a significant role in preventing sexually transmitted infections, including hiv (6, 7, 9, 11). in muslim and jewish communities, circumcision is practiced as a religious rite, while in others (particularly traditional ones), it is performed for sociocultural or initiation reasons, with fewer than 10% having a medical indication (6, 7, 3, 9). in our series, the mean age of patients was 8.33 years, with a range between 1 month and 65 years. sylla et al. (2) reported a mean age of 10.5 ± 6.7 years in their dakar figure 4. huge penile hematoma extended to perineum figure 5. incomplete circumcision. figure 6. urethro-cutaneous fistula with glans penis buria. figure 7. incomplete circumcision with phimosis. figure 8. revision of circumcision figure 9. final appearance of glans after revision. archivio italiano di urologia e andrologia 2023; 95(3):11494 a. ouattara, a.-k. paré, d. yé, et al. 4 series, while gross et al. (5) in paris published a mean age of under 16 months. this age variability can be attributed to the fact that in african countries, the age at which circumcision is performed depends on the sociocultural and ritual practices of the populations. in our work environment, circumcision is practiced in early childhood and represents a sacred act that confirms a child's male identity and anticipates flawless sexuality in adulthood. however, with the increasing influence of muslim culture, neonatal circumcision is becoming more popular. in our study, only complications requiring surgical management were referred to hospitals. this was the case for the 23 circumcision complications we collected over five years. in côte d'ivoire, dieth et al. (3) reported 35 circumcision complications over 14 years, while in senegal, sylla et al. (2) had already reported 63 complications over 11 years. numerous factors contribute to these complications, and they largely depend on the operator. in our cases, 47.82% of patients were circumcised by traditional practitioners. this can be attributed to the influence of tradition, poverty, insufficient and inaccessible healthcare structures, and low education levels. circumcision is primarily a surgical procedure performed by a doctor, requiring knowledge of contraindications, adherence to rigorous asepsis during the procedure, understanding of anatomy, and expertise in circumcision techniques. failing to meet these requirements can result in complications and does not guarantee safety in terms of infectious risks and iatrogenic injuries. in our study, 52.17% of patients had their circumcision performed by a nurse. this highlights the need for improved training, especially since studies (11) have shown that the prevalence of circumcision complications increases when the procedure is performed by untrained individuals. in burkina faso and many other sub-saharan african countries, there is a shortage of urologists. considering these observations, it may be worthwhile to explore proposals from authors like dieth et al. (2) and okeke et al. (12), which suggest integrating circumcision into medical student curricula and training nurses to perform the procedure with minimal risk. in africa, nurses are often the only healthcare workers available in remote rural areas. the average consultation time in our department was 11.89 days. kimassoum et al. (4) in chad reported an average consultation time of 896 days. this difference in average consultation time can be attributed to the higher representation of late complications in their series. in our series, hemorrhage was due to a hemostasis defect (n = 3) or a hemostasis disorder, specifically hemophilia (n = 3). hemorrhage is a common complication in countries where ritual circumcision is performed by nurses or traditional practitioners and often leads to early consultation due to parental concern. three of our patients were hemophiliacs, emphasizing the importance of performing a coagulation test before any circumcision. glans amputation, one of the most horrifying aspects of circumcision accidents, occurred in 13.04% (n = 3) of our patients. diabaté et al. (10) in senegal found similar results in 2016. in contrast, kimassoum et al. (4) in chad reported a significant number of amputation cases in their series (n = 10). this reflects the incompetence of the practitioner and is sometimes a direct consequence of poor child immobilization during foreskin removal, lack of general anesthesia, and inadequate knowledge of the procedure. in the cases we collected, patients were seen late (more than 12 hours after the accident), making reimplantation impossible due to microvascular anastomosis challenges and insufficient technical resources. in our series, treatment consisted of a meatoplasty with satisfactory results in terms of urination but poor aesthetic outcomes, leading to an unfavorable social prognosis in a context where respecting the body's integrity is sacred. we report one case of penile denudation in our study, with similar results found in the literature (4, 10). this injury occurs after excessive removal of penile skin due to exaggerated traction of the skin covering the glans. retraction of the proximal part leaves a completely exposed penile area. treatment involved debridement and a wet oily dressing for healing, although other authors opt for a skin graft. some studies rank infectious complications as the second most common issue after hemorrhage (2, 10). these complications result from inadequate asepsis and the presence of skin flora (8). locally, at the circumcision wound site, they cause delayed healing. although rare, we observed two cases of necrotizing cellulitis of the external genitalia and perineum. treatment for these cases required debridement, resuscitation with antibiotic therapy, and local care. urethrocutaneous penile fistulas were the most frequent complication in kimassoum et al. (4) series; however, in our study, we only recorded two cases. these fistulas are located in the balanopreputial groove where the urethra is more superficial, and adhesions increase its vulnerability. inadequate hemostasis of the frenulum artery can also lead to urethral injury and subsequent fistula formation. clinically, urine passes through the fistula during urination, negatively affecting body image. the urethrocutaneous splitting technique with separate suturing of the two planes was most commonly used in our series, yielding good results. stenosis of the external urethral meatus has a traumatic and/or infectious origin, with ligation of the frenulum artery implicated as well (8). the main symptom is dysuria, and rarely, urinary retention. it occurs at varying times after the healing process. a meatotomy is usually sufficient to remove the stenosis, but recurrences are frequent. unsightly, incomplete circumcision was noted in one of our patients. kimassoum et al. (4) reported six cases in their series. this issue highlights the importance of anatomical knowledge and mastery of the learning curve before performing circumcisions. in our series, this patient underwent laborious adhesion lysis to expose the glans up to the balanopreputial groove before proceeding with the circumcision. conclusions accidents resulting from ill-timed and imprudent circumcision practices can sometimes be serious enough that this surgical procedure should either be reserved for expert hands or, at the very least, supervised. the challenge now lies in raising public awareness and providing appropriate training for everyone involved in circumcision practice, from medical students to doctors and even nurses, who remain the most widely distributed healthcare personnel in remote areas of the country. archivio italiano di urologia e andrologia 2023; 95(3):11494 5 complications of non-medical assisted circumcision in burkina faso. clinical presentation, management, and outcomes references 1. bankole sanni r, coulibaly b, nandiolo r, et al. sequelae of traditional circumcision and excision. med afr noire. 1997; 44:239-41. 2. sylla c, diao b, diallo ab, et al. complications of circumcision. about 63 cases. prog urol. 2003; 13:266-72. 3. dieth ag, moh-elloh n, fiogbe m, et al. circumcision accidents in children in abidjan, ivory coast. bull soc path exo. 2008; 101:314-5. 4. kimassoum r, franklin ds, arya zat, mignagnal k. epidemiological, anatomoclinical and therapeutic characteristics of circumcision complications. uro'andro. 2016; 1:218-224. 5. gross ph, pages r, bourdelat d. complications of ritual circumcision. chir pediatr. 1986; 27:224-5. 6. ceylan k, burhan k, yılmaz y, et al. severe complications of circumcision: an analysis of 48 cases. j pediatr urol. 2007; 3:32-5. 7. chaim jb, livne pm, binyamini j, et al. complications of circumcision in israel: a one-year multicentre survey. isr med assoc j. 2005; 7:368-70. 8. krill aj, palmer ls, palmer js. complications of circumcision. sciworld j. 2011; 11:2458-68. 9. moses s, bailey rc, ronald ar. male circumcision: assessment ofhealth benefits and risks. sex transm infect. 1998; 74:368-73. 10. diabaté i, et al. management of complications of circumcision. sexologies. 2017; 3:169-175. 11. muula as, prozesky hw, mataya rh, ikechebelu ji. prevalence of complications of male circumcision in anglophone africa: a systematic review. bmc urol. 2007; 7:4. 12. okeke li, asinobi aa, ikuerowo os. epidemiology of complications of male circumcision in ibadan, nigeria. bmc urol. 2006; 6:21. correspondence adama ouattara, md (corresponding auhor) adamsouat1@hotmail.com urologist, associate professor of urology division of urology, souro sanou university teaching hospital bp: 676 bobo-dioulasso, burkina faso abdoul-karim paré boupare@yahoo.fr delphine yé delphineye73@gmail.com mohamed simporé mohamedsimpore25@hotmail.com mickael rouamba rouambami@yahoo.com timothée kambou tkambou@hotmail.com division of urology, souro sanou university teaching hospital, bobo-dioulasso, burkina faso ali sherazi, bmsc ali.sherazi@dal.ca department of medicine, dalhousie medicine new brunswick, saint john, new brunswick, canada aristide f. kaboré urology division, yalgado ouedraogo university teaching hospital, ouagadougou kaborefamd@icloud.com conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 91 original paper sive techniques (laparoscopic, robotic prostatectomy) and endoscopic interventions. first resectoscope and the first transurethral resection of prostate (turp) procedure was introduced by maximilian stern in 1926 (4). with technological advances, turp became more and more popular and has been considered the reference technique for the surgical management of bph. despite the decline in the rate of turp for bph surgery due to development of various alternative techniques such as holmium laser enucleation of prostate (holep), turp is still the most frequently taught and performed surgical technique for bph (5). the internet's baby steps began to be taken in the 1960’s and accelerated in the 80’s (6). nowadays, 60% of the world’s population has access to internet (7). with portable electronic devices online resources have become an important part of education in general. videos are easily accessible, allow creating personal time and space for learning. by watching videos online, one can learn different techniques from various surgeons, interact with colleagues around the world, exchange ideas and improve skills. with fewer opportunities being found lately by trainees in the operating rooms due to work hour restrictions, high costs, patient safety measures (8), videos became a crucial learning method in surgical training. many surgical videos are avaliable online and advantages of these videos in surgical education have been shown in various studies (9, 10). youtube™ (google, llc) which was founded on 2005, is the second most popular website in the world with over 33 billion total visits in june 2022 (11) and the biggest source of videos on the internet. studies showed that youtube™ is the most widely used platform by both residents and surgeons for surgical education (12, 13). there is a great opportunity to learn about surgical techniques and improving skills with watching videos on youtube™. however, since there is lack of professional peer review and quality check of the videos on youtube™, surgical videos may be untrustworthy. in this study we aimed to evaluate the educational quality of turp videos on youtube™. materials and methods in this study we evaluated turp surgery videos which are avaliable for the public. therefore, no ethical approval is background: our aim was to evaluate the educational value of transurethral resection of prostate (turp) videos on youtube. methods: a comprehensive search was conducted for turp videos on youtube. based on the laparoscopic surgery video educational guidelines we created a checklist which includes 20 items for evaluation of the videos. ibm spss statistics was used for analysis. results: a total of 104 surgical videos were assessed. the mean view count was 15647.3 (21-324.522, sd 47556.4). video image quality found as low for 57.7% of videos. both staff (76%) and resident (75%) rated most of the videos low educational quality. no statistically significant difference was found between staff’s total points (mean 4.35 ± sd 2.9) and resident’s total points (mean 4.63 ± sd 3.3) (p: 0.761). positive correlation was found between view count and staff’s total points (r: 0.242 p < 0.05), resident’s total points (r: 0.340 p < 0.01). there was also positive correlation between number of likes and staff’s total points (r: 0.375 p < 0.01) and resident’s total points (r: 0.466 p < 0.01). conclusions: most turp surgical videos on youtube are low quality. higher educational quality videos with detailed explanation of the procedure are needed on this subject. we believe this study could be a guide for future high quality turp videos. key words: transurethral resection of prostate; benign prostatic hyperplasia; social media; video recording; data quality. submitted 11 april 2023; accepted 27 april 2023 introduction benign prostatic hyperplasia (bph) is a histologic diagnosis which is characterized by proliferation of smooth muscle and epithelial cells of the periurethral prostatic tissue. its prevalance increases with age reaching 90% by the ninth decade of life at autopsy studies (1). bph is the leading cause of male lower urinary tract symptoms (luts) (2). most men after 45 suffer at least one component of luts and symptoms are mostly mild (3). with aging global population and high prevelance of luts especially in elderly men, treatment of male luts will become even more important in the future. treatment options for bph related male luts are conservative treatment, pharmacotherapy and surgery. surgical management of bph can basically divided into three main groups; open prostatectomy, minimally invaanalysis of transurethral resection of prostate videos on youtube™: educational quality assessment yavuz karaca 1, emre burak sahinler 1, didar ilke karaca 2, orhun sinanoglu 1 1 department of urology, sancaktepe sehit prof. dr. ilhan varank research and training hospital, istanbul, turkey; 2 department of public health, marmara university school of medicine, istanbul, turkey. doi: 10.4081/aiua.2023.11404 summary archivio italiano di urologia e andrologia 2023; 95, 2 y. karaca, e. burak sahinler, d. ilke karaca, o. sinanoglu 92 required. a comprehensive search was performed in october 31, 2022 on youtube™ (https://www.youtube.com) using the search terms “tur prostate”, “tur prostatectomy”, “tur p”, “monopolar tur p”, “bipolar tur p” seperately. the videos were selected by the first author based on following criterias: traditional resection of the prostate must be performed either with monopolar or bipolar systems, live surgery recorded by endoscopic camera systems, videos made by professionals and videos in english language. videos including multiple surgeries, externally recorded videos, commercial videos, slide based presentation videos and animation videos and nonenglish videos were excluded from the study. 104 videos met these criterias and were included the study (figure 1). characteristics of the videos were view count, number of likes, days online, video length, region, video image quality (480p resolution: low, 720p resolution: medium, 1080p resolution: high). there are several reports assessing youtube™ videos from patient’s perspective, rating their understandibility and patient educational value (14, 15). in this report, we tried to evaluate turp videos on youtube™ as tools for surgical education. no guideline for assessing the educational value of turp videos were present. first author which is a junior staff urologist and the third author which is a senior staff urologist created a video quality checklist based on the checklist that was developed for the evaluation of laparoscopic surgery videos (16). the checklist included five major categories which were author’s information, case presentation, critical steps of the procedure, outcomes of the procedure, supplementary contents with a total of 20 items. each item represented one point (table 1). first author and second author which was a junior restable 1. the checklist for the evaluation of turp surgical videos' educational quality. items of checklist author’s information 1. author’s information 2. title of the video including the procedure 3. conflict of interest disclosure case presentation 4. patient privacy protection 5. patient characteristics 6. preoperative work-up 7. prostate volume critical steps of the procedure 8. introduction of the equipments 9. setting of cut and coagulation 10. anatomic demonstration 11. step by step explanation 12. explanation of the critical steps outcomes of the procedure 13. operating time 14. volume of resected specimen 15. length of hospitalization 16. intraoperative and postoperative complications 17. functional outcomes supplementary contents 18. educational tables and photos 19. audio commentary 20. video commentary figure 1. prisma diagram showing the selection of the videos. archivio italiano di urologia e andrologia 2023; 95, 2 93 quality evaluation of turp videos on youtube™ ident evaluated the videos and scored each video from 1 to 20. videos were divided into 4 educational quality groups according to their total score; low quality (0-5 points), medium quality (6-10 points), high quality (1116 points) and very high quality (16-20 points). with scoring videos separately by a staff surgeon and a resident we aimed to not only evaluate the educational quality of the videos but to determine if there is a difference between a resident’s and a surgeon’s evaluation. statistical analysis statistical analysis was performed with ibm spss software (version 26 for macos, ibm corporation, ny, usa). the characteristics of the videos were presented as mean, median, ranges, standard deviation (sd). the distribution of the variables was measured by kolmogorovsmirnov test. mann whitney u test was used for the comparison of two reviewers mean points. pearson’s correlation coefficient was used to evaluate the correlations between variables. p < 0.05 was considered statistically significant. results total of 104 videos were evaluated. the mean view count was 15647.3 (range 21-324.522, sd 47556.4). mean like count was 30.8 (range 0-285, sd 54.7). the median days avaliable online was 1856.5 (137-5943) (table 2). videos were sourced from asia (65.3%), europe (15.3%), unknown region (14.4%), usa (2.8%) and australia (1.9%). 73 (70.1%) videos were uploaded by private users, 15 (14.4%) videos by medical organizations and 16 (15.3%) videos by unknown users. video image quality was found as low for 60 (57.7%), medium for 25 (24%) and high for 19 (18.3%) videos. no statistically significant difference was found between staff’s total points (mean 4.35 ± sd 2.9) and resident’s total points (mean 4.63 ± sd 3.3) for the evaluation of the videos (p: 0,761) (table 3). no video received full points from the checklist. both staff urologist (79/104, 76%) and resident (78/104, 75%) rated most of the videos low educational quality. resident rated 8 (7.7%) videos high quality while staff urologist rated 5 (4.8%). only one video rated very high quality and it was by the staff urologist. the correlation test showed positive correlation between view count and number of likes (r: 0.787 p < 0.01), staff’s total points (r: 0.242 p < 0.05), resident’s total points (r:0.340 p < 0.01) and days online (r: 0.477 p < 0.01). there was also positive correlation between number of likes and staff’s total points (r: 0.375 p < 0.01) and resident’s total points (r: 0.466 p < 0.01). there was a positive correlation between staff’s total points and resident’s total points (r: 0.887 p < 0.01). negative correalation was found between days online and video lenght (r: 0.207 p < 0.05) and staff’ total points (r: 0.195 p < 0.05) (table 4). discussion in this study our purpose was to evaluate turp videos on youtube™ to estimate their educational value, define the pros and cons of the videos and try to set a standard for future high quality videos. to our knowledge, this is the first report to review the quality of turp videos on youtube™. in this report we demostrated that most of the turp videos on youtube™ have low educational quality. in the majority of videos; there was limited information regarding patient’s data. most videos consisted of edited or unedited footage of the surgery and did not include any explanation of the critical steps regarding the procedure. very few of the videos have mentioned outcomes of the procedure. additionally image quality were low in most videos. these major defects resulted in videos that were not suitable for educational purpose. there are several studies in the literature assessing surgery videos on youtube™. a study on videos about surgical treatment of luts/bph indicated low quality content in the vast majority of the videos (17). yang et al. evaluated 70 thulep videos on youtube™ and concluded that there is lack of high educational valued videos on this topic (18). a review of 32 mid urethral sling videos on youtube™ showed that none of the videos demonstrated the complete list of critical steps of the procedure (19). loeb et al. reported that overall information quality was moderate to poor in 67% of 150 bladder cancer videos on youtube™ and moderate to high misinformation was present in 21% of the videos (20). haslam et al. assessed 23 robotic pyeloplasty videos on youtube™ and found out that only 6 videos included all critical steps of the procedure (21). these studies along with our’s outlined that, although table 3. comparison of staff’s and residents' mean points. staff urologist’s points resident’s points p-value mean ± sd 4.35 ± 2.9 4.63 ± 3.3 0.761 median (min-max) 3 (2-16) 3 (2-15) table 2. characteristics of the videos. mean ± sd median (min-max) view count (n) 15647.3 ± 47556.4 894 (21-324522) video length (m) 864 ± 988.6 528 (77-6236) like (n) 30.8 ± 54.7 7 (0-285) days online (d) 1961.1 ± 1297.4 1856.5 (137-5943) number (n); minute (m); days (d). table 4. correlation analysis of between video features and scores. 1 2 3 4 5 6 1. view count 1 2. video lenght 0.150 1 3. like 0.787** 0.190 1 4. point 1 0.242* -0.072 0.375** 1 5. point 2 0.340** 0.004 0.466** 0.887** 1 6. days online 0.477** -0.207* 0.086 -0.195* -0.134 1 * correlation is significant at the 0.05 level (2-tailed). ** correlation is significant at the 0.01 level (2tailed). archivio italiano di urologia e andrologia 2023; 95, 2 y. karaca, e. burak sahinler, d. ilke karaca, o. sinanoglu 94 youtube™ has a wide variety of medical videos, there are great heterogeneity in their quality. great care must be taken when using youtube™ videos as a source of information, because most of the videos contain inaccurate and incomplete information about the procedures, which may prove to be harmful than educational, especially for inexperienced learners. videos from academic institutions tend to be more high quality than videos from single users (22). sources with rigorous review processes like official websites of urological associations (i.e. american urological association, european association of urology) or video sections of certain urology journals may be used for more credible information. our study has limitations. firstly, we evaluated videos on youtube™ solely hence more websites should be included for more comprehensive view of the quality of turp videos. but since youtube™ is the most popular source for surgical videos we believe these results have great value. secondly, the fact that one of the reviewer was a junior resident with little experience on turp could have introduced bias into the study. however no statistically significant difference was found between two reviewers evaluations thus this suggests that his inexperience did not have any effects on our findings and our findings are reliable. lastly we were obligated to create a checklist for evaluation of turp videos because no other study has addressed this subject before. more studies are needed to develop a standardizied and validated checklist. conclusions youtube™ lacks high educational quality videos of transurethral resection of the prostate. it is important to detect high quality videos and verify the information with multiple sources. we believe that this study can guide future high educational quality videos. references 1. berry sj, coffey ds, walsh pc, ewing ll. the development of human benign prostatic hyperplasia with age. j urol. 1984; 132:474-9. 2. parsons jk. benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors. curr bladder dysfunct rep. 2010; 5:212-218. 3. mcvary kt. bph: epidemiology and comorbidities. am j manag care. 2006; 12(5 suppl):s122-8. 4. https://www.baus.org.uk/_userfiles/pages/files/museum/20%20%20turp.pdf 5. malaeb bs, yu x, mcbean am, elliott sp. national trends in surgical therapy for benign prostatic hyperplasia in the united states (2000-2008). urology. 2012; 79:1111-6. 6. https://www.britannica.com/story/who-invented-the-internet. 7. https://data.worldbank.org. 8. pugh cm, watson a, bell rh jr, et al. surgical education in the internet era. j surg res. 2009; 156:177-82. 9. friedl r, höppler h, ecard k, et al. development and prospective evaluation of a multimedia teaching course on aortic valve replacement. thorac cardiovasc surg. 2006; 54:1-9. 10. pape-koehler c, immenroth m, sauerland s, et al. multimediabased training on internet platforms improves surgical performance: a randomized controlled trial. surg endosc. 2013; 27:1737-47. 11. https://www.similarweb.com/top-websites/ 12. rapp ak, healy mg, charlton me, et al. youtube is the most frequently used educational video source for surgical preparation. j surg educ. 2016; 73:1072-1076. 13. mota p, carvalho n, carvalho-dias e, et al. video-based surgical learning: improving trainee education and preparation for surgery. j surg educ. 2018; 75:828-835. 14. shoemaker sj, wolf ms, brach c. development of the patient education materials assessment tool (pemat): a new measure of understandability and actionability for print and audiovisual patient information. patient educ couns. 2014; 96:395-403. 15. morra s, napolitano l, collà ruvolo c, et al. could youtube™ encourage men on prostate checks? a contemporary analysis. arch ital urol androl. 2022; 94:285-290. 16. celentano v, smart n, mcgrath j, et al. lap-vegas practice guidelines for reporting of educational videos in laparoscopic surgery: a joint trainers and trainees consensus statement. ann surg. 2018; 268:920-926. 17. betschart p, pratsinis m, müllhaupt g, et al. information on surgical treatment of benign prostatic hyperplasia on youtube is highly biased and misleading. bju int. 2020; 125:595-601. 18. yang k, meng y, zhang k. educational value of youtube surgical videos of thulium laser enucleation of the prostate (thulep): the quality assessment. transl androl urol. 2021; 10:2848-2856. 19. larouche m, geoffrion r, lazare d, et al. mid-urethral slings on youtube: quality information on the internet? int urogynecol j. 2016; 27:903-8. 20. loeb s, reines k, abu-salha y, et al. quality of bladder cancer information on youtube. eur urol. 2021; 79:56-59. 21. haslam re, seideman ca. educational value of youtube surgical videos of pediatric robot-assisted laparoscopic pyeloplasty: a qualitative assessment. j endourol. 2020; 34:1129-1133. 22. sahin y, paslanmaz f, ulus i, et al. quality and content analysis of female urethroplasty videos on youtube. low urin tract symptoms. 2023; 15:24-30. correspondence yavuz karaca, md mdyavuzkaraca@gmail.com emre burak sahinler, md emre.sahinler@yahoo.com orhun sinanoglu, md orhundr@hotmail.com department of urology, sancaktepe sehit prof. dr. ilhan varank research and training hospital, istanbul, turkey didar ilke karaca, md karacailke@yahoo.com department of public health, marmara university school of medicine, istanbul, turkey conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 95 original paper progression, intravesical bacillus calmette-guérin (bcg) is the gold standard adjuvant therapy (4). the use of intravesical instillation of bcg for high risk nmibc demonstrates a role for immunotherapy in uc. bcg, originally used as a vaccine against tuberculosis (tb), contains live-attenuated mycobacterium bovis (4). the specific mechanism of bcg in nmibc treatment continues to be studied, however, its role is attributed to both local immunological efforts and systemic immune responses (5). some work has suggested that bcg vaccination may be associated with a lower rate of bladder cancer incidence (6). despite this relationship, research on bcg immunization as a possible predictive factor in nmibc has been limited. in the present study, we evaluated the relationship between history of infantile bcg vaccination with the depth of invasion and the grade in patients with nmibc. methods data were retrospectively collected between 2017 and 2022. inclusion criteria included all patients with a new diagnosis of nmibc at the thunder bay regional health sciences centre (tbrhsc), for whom complete clinical, lab, and pathological data could be retrieved. data collected included the history of infantile bcg as well as the patients’ age, sex, comorbid status, cbc, vaccination, history of intravesical bcg instillation, pathological data, recurrence, and progression. vaccination status was correlated with these variables. institutional ethical approval was obtained from the tbrhsc research ethics board (rp741). correlations between continuous variables were done using student’s t-test. categorical variables were compared using fisher exact test. a p-value of < 0.05 was used to define significance. results a total of 188 patients met the inclusion criteria for our study. no patients were lost to follow up. the mean follow-up time was 26 ± 7 months. of the 188 individuals meeting the eligibility criteria, 113 individuals had received the infantile bcg immunization and 75 did not. objective: to evaluate the utility of infantile bcg vaccination history in predicting stage and grade of tumours in non-muscle invasive bladder cancer (nmibc). materials and methods: we retrospectively analyzed data from patients from a single center who were diagnosed with new nmibc and underwent transurethral resection of bladder tumour (turbt) between 2017 and 2022. we assessed bcg immunization status with various demographics and comorbidities, as well as tumour recurrence, progression, stage, and grade. results: a total of 188 patients met the inclusion criteria for our study. the mean age of patients at the time of diagnosis was significantly lower in those that had been immunized with bcg (71 ± 9) than those who had not (77 ± 10) (p < 0.0001). history of bcg immunization did not correlate with sex, history of diabetes mellitus (dm), prior history of intravesical bcg treatment, and tumour recurrence, progression, stage, and grade. conclusions: history of infantile bcg vaccination did not correlate with the depth of invasion and/or the grade in patients with non-muscle invasive bladder cancer. patients that received infantile bcg vaccination were significantly younger at the time of diagnosis of nmibc. key words: bcg; non-muscle invasive bladder cancer (nmibt); bladder cancer. submitted 11 april 2023; accepted 26 may 2023 introduction bladder cancer is the tenth most common malignancy worldwide, with increasing incidence, particularly in developed nations (1). approximately 80% of bladder cancers arise in individuals aged 65 or older with the mean age being 73 years old (2, 3). this is thought to reflect a disease process requiring many decades of development following exposure to risk factors, such as tobacco (2). urothelial carcinoma (uc) accounts for 90% of bladder cancers (4). at the time of presentation, approximately 70% of uc cases are non-muscle invasive (nmibc), while 30% are muscle invasive (mibc) (4). initial management of nmibc is transurethral resection of bladder tumor (turbt) (4). for those with nmibc who are deemed to be at high risk for history of infantile bcg immunization did not predict lamina propria invasion and/or high-grade in patients with non-muscle invasive bladder cancer anastasia macdonald 1, vahid mehrnoush 1, asmaa ismail 1, livio di matteo 2, ahmed zakaria 1, waleed shabana 1, ashraf shaban 1, mohammed bassuony 1, hazem elmansy 1, walid shahrour 1, owen prowse 1, ahmed kotb 1 1 northern ontario school of medicine, thunder bay, on, canada; 2 department of economics, lakehead university, thunder bay, on, canada. doi: 10.4081/aiua.2023.11380 summary archivio italiano di urologia e andrologia 2023; 95, 2 a. macdonald, v. mehrnoush, a. ismail, et al. 96 a statistically significant difference was identified between the age of individuals who had received the immunization and those who did not (p < 0.0001). the mean age at the time of diagnosis for those immunized was 71 ± 9 years, and 77 ± 10 in the non-immunized group. there was no statistically significant difference found between immunization status and other patient characteristics including sex, history of diabetes mellitus (dm), or history of intravesical bcg treatment. history of immunization did not correspond with tumour recurrence, progression, stage, or grade in this population. the results are summarized in table 1. discussion studies assessing the relationship between nmibc and bcg immunization have been limited. one scoping literature review identified a 35-37% lower age-standardized rate of bladder cancer incidence in individuals with bcg immunizations, suggesting an association between the two (6). we demonstrated that bcg immunization did not correlate with tumour characteristics in nmibc, including stage, grade, and risk stratification. this may be explained by the routes of administration and subsequent immune responses elicited. the anti-tumour activity of intravesical bcg therapy is attributed to non-specific immune mechanisms related to the direct interaction with urothelial cells, as well as a contribution of systemic immune response, though specific mechanisms have yet to be fully elucidated (7). bcg immunization is also associated with non-specific immune mechanisms that provide protection against tuberculosis, however, given the nature of vaccinations, this response is exclusively systemic (8). interestingly, this generalized immune response from immunization has been shown to confer protection against other respiratory infections through a mechanism referred to as trained immunity (ti) (8, 9). it was demonstrated that bcg immunotherapy in nmibc patients induced ti and provided protection against respiratory infections (9). this suggests that intravesical bcg therapy can produce similar systemic immune responses as the bcg vaccination. given that our data demonstrated that immunization status did not impact the tumour progression characteristics and risk stratification, this may suggest increased importance in the role of the local immune response in intravesical bcg in preventing the progression of nmibc. our findings may also be explained by the waning protection from immunization over time. while bladder cancer incidence increases in the elderly (10), individuals immunized with bcg are typically immunized as infants. it has been well documented that protection from this immunization against tb infections wanes over time (7). studies have identified that a positive purified protein derivative (ppd) skin test, an indication of bcg immunity, was associated with a better response to intravesical bcg therapy than those with a negative reaction (11, 12). niwa et al. (2017) demonstrated that the recurrence-free survival (rfs) in patients with a slightly positive or negative ppd skin test reaction was significantly diminished compared to the rfs in those with a strongly positive response. this may suggest that a reduced immune response from bcg immunization does not generate the same benefit in bcg treatment. given that the mean age of those vaccinated with bcg in our study was 71 years, and our study specifically looked at infantile bcg immunization, this may also explain why individuals with waning immunity from remote immunization did not influence tumour characteristics or risk stratification in patients with nmibc. in our study, the mean age of patients diagnosed with new nmibc was significantly lower in individuals who received the infantile bcg vaccination (71 ± 9) compared to those who did not (77 ± 10) (p < 0.0001). increased age is a risk factor for developing uc, largely attributed to a disease course that develops decades after exposure to risk factors (2). countries with the lowest incidence of bladder cancer are typically those found to be below average on the human development index (hdi), which may be attributable to less industrial chemical exposure and access to tobacco, major risk factors for uc (1). interestingly, such countries tend to have a higher incidence of tuberculosis and subsequently higher rates of infantile bcg immunization (13). this may imply that non-immunized individuals were likely raised in countries with low tb incidence, yet above-average hdi. such individuals would likely have had a higher risk of exposure to industrial chemicals and tobacco, leading to the slow development of bladder cancer and presentation at a later age. those immunized and likely raised in countries with less exposure to common risk factors may have developed uc earlier on due to other reasons, such as genetics, diets, or other lifestyle factors. older age at presentation has been shown to be a poor prognostic factor in nmibc (4). consequently, the older age of presentation with nmibc in non-immunized individuals poses a significant healthcare concern. the incidence of bladder cancer has been steadily increasing, particularly in developed countries (1). such countries do not tend to implement routine immunization against tb table 1. correlation of clinical and tumour data with history of infantile bcg immunization. no infantile bcg infantile bcg p value age (mean + sd) 77 + 10 71 + 9 0.0001 sex males 60 77 0.09 females 15 36 recurrence no 34 57 0.5 yes 41 56 progression no 72 108 1 yes 3 5 intravesical bcg no 44 68 0.9 yes 31 45 dm no 61 86 0.5 yes 14 27 stage ta 58 86 1 t1 17 27 grade low 54 81 1 high 21 32 sd: standard deviation. bcg: bacillus calmette–guérin. dm: diabetes mellitus. archivio italiano di urologia e andrologia 2023; 95, 2 97 infantile bcg vaccination in patients with nmibc given the low incidence. consequently, there is a growing population of non-immunized individuals presenting with nmibc and potentially at older ages. this may result in overall more complicated patients with poorer prognostics. further research in this area would be of utility given the growing aging population and potentially increased demands on healthcare systems. there are several limitations to our study. first, it is a retrospective study completed at a single center. therefore, selection bias was inevitable, and our study represents a relatively small sample size of patients. this study also limited by the relatively short follow up period (26 + 7 months) for assessing recurrence and progression. additionally, we did not account for the various demographic factors that may influence the risk factors for developing nmibc. conclusions infantile bcg immunization was not associated with higher risk stratification in patients with nmibt. the mean age of patients diagnosed with nmibc was significantly lower in patients who received the infantile bcg vaccination. references 1. bray f, ferlay j, soerjomataram i, et al. global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries ca cancer j clin. 2018; 68:394. 2. mushtaq j, thurairaja r, nair, r. bladder cancer surgery (oxf). 2019; 37:529. 3. siegel rl, miller kd, jemal a. cancer statistics, 2019 ca cancer j clin. 2019; 69:7. 4. saginala k, barsouk a, aluru js, et al. epidemiology of bladder cancer med sci. 2020; 8:15. 5. taniguchi k, koga s, nishikido m, et al. systemic immune response after intravesical instillation of bacille calmette-guérin (bcg) for superficial bladder cancer clin exp immunol. 1999; 115:131. 6. trigo s, gonzalez k, di matteo l, et al. bacillus calmette-guerin vaccine and bladder cancer incidence: scoping literature review and preliminary analysis arch ital urol. 2021; 93:1. 7. mukherjee n, julián e, torrelles jb, svatek rs. effects of mycobacterium bovis calmette et guérin (bcg) in oncotherapy: bladder cancer and beyond vaccine. 2021; 39:7332. 8.covián c, fernández-fierro a, retamal-díaz a, et al. bcginduced cross-protection and development of trained immunity: implication for vaccine design front immunol. 2019; 10:2806. 9. van puffelen j h, novakovic b, van emst l, et al. intravesical bcg in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections j immunother cancer. 2023; 11:e005518. 10. martinez l, cords o, liu q, et al. infant bcg vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data metaanalysis lancet glob health. 2022: 10:e1307. 11. niwa n, kikuchi e, matsumoto k, et al. purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus calmette-guérin therapy urol oncol. 2018; 36e15. 12. biot c, rentsch ca, gsponer jr, et al. preexisting bcg-specific t cells improve intravesical immunotherapy for bladder cancer sci transl med. 2012; 4:72. 13. centers for disease control and prevention. bcg vaccine fact sheet. 2016. retrieved from https://www.cdc.gov/tb/publications/ factsheets/prevention/bcg.htm correspondence anastasia macdonald, md anamacdonald@nosm.ca vahid mehrnoush, md vahidmehrnoush7@gmail.com asmaa ismail, md asmaaismail0782@gmail.com ahmed zakaria, md aszakaria81@yahoo.com waleed shabana, md waleed.shabana@gmail.com ashraf shaban, md ashraf.shaban@tbh.net mohammed bassuony, md mohammed.bassuony@tbh.net hazem elmansy, md hazem.elmansy@tbh.net walid shahrour, md walid.shahrour@tbh.net owen prowse, md owen.prowse@tbh.net ahmed kotb, md, phd, frcsc, frcs urol, febu (corresponding author) associate professor drahmedfali@gmail.com northern ontario school of medicine (nosm) and thunder bay regional health research institute (tbrhri) thunder bay, on, canada livio di matteo, md ldimatte@lakeheadu.ca department of economics, lakehead university, thunder bay, on conflict of interest: the authors declare no potential conflict of interest. stesura seveso 251archivio italiano di urologia e andrologia 2021; 93, 3 original paper no conflict of interest declared. ment outcome and survival (2, 3). it is possible therefore that age and comorbidities rather than the tumor itself may be the primary cause of death (3, 4). comorbidity is defined as “any co-existing disease or condition that can affect the diagnosis, treatment, and prognosis for an index disease under study” and is used for assessing fitness for surgery (5). furthermore, its prognostic effect has been present in various cancers including urological cancers such as prostate, bladder and renal cancer (6-8), the effect being more prominent in indolent tumors. comorbidity should not be confused with quality-of-life scales such as the karnofsky and eastern cooperative oncology group scales, or functionality scales. comorbidity can be represented by a mathematical index; one of them is the charlson comorbidity index (cci) that was developed in 1987 as a prognostic taxonomy for 19 medical conditions, each with its own associated weight, which singly or in combination might alter the risk of short-term mortality for patients enrolled in longitudinal studies. the total score ranges from 0-37 and reflects the cumulative likelihood of one-year mortality (9). the cci was further adapted to include increasing age (age-adjusted charlson comorbidity index-acci) (8, 10). both indices are easy to use and have shown good reliability (11), while kutikov et al. (12) recently incorporated patient comorbidity, as measured by cci, into a nomogram in addition to age, race, gender, and tumor size. this instrument calculates the probability of kidney cancer death compared to death from other causes and helps in selecting those who could really benefited from surgical intervention. complication rates have been mainly used in comparing surgical techniques as well as surrogate markers of health care quality. however, this is hampered by the lack of standardized methodology in reports of surgical complications. in 2012 an ad hoc european association of urology (eau) guidelines panel (13) recommended the preferential use of the clavien-dindo system that classifies complications assigning a severity grade according to the type of the intervention needed to resolve them (14). this system has been developed for use in general surgery but has also been validated to be used in urological procedures (15). while preoperative nomograms and comorbidity indices have been widely used to assess short-and long-term mortality following surgical interventions for kidney tumors, there are only scares reports of objective predicobjectives: comorbidity along with tumor and patient characteristics is taken into account when deciding for the surgical treatment of renal cell carcinoma (rcc). comorbidity has also been used as an independent predictive factor for postoperative complications of several major urological procedures including radical nephrectomy for rcc. the aim of the present study was to objectively evaluate the association between comorbidity and postoperative complications after radical nephrectomy for rcc, using standardized systems to grade both comorbidity and severity of postoperative complications. materials and methods: clinicopathological data of 171 patients undergoing open radical nephrectomy for lesions suspected of rcc were prospectively recorded for a period of 3 years. comorbidity was scored using the charlson comorbidity index (cci) while postoperative complications were graded according to the clavien-dindo system. results: patients were predominantly males (59.1%); their age ranged from 35 to 88 years (mean ± sd: 63.6 ± 11.9 yrs) with 50.8% of them being ≤ 65 yrs. cci ranged from 0 to 8 with the majority (85.3%) scoring ≤ 2. the procedure was uncomplicated in 57.3% cases; 10 patients suffered major (grade iii/iv) complications and 4 patients died within the 40 days postoperative period. cci correlated with the manifestation of any postoperative complication, clavien ≥ 1, or (95% ci): 1.47 (1.09-1.96), p = 0.011 and the occurrence of severe complications, clavien > 2. or (95% ci): 1.29 (1.01-1.63), p = 0.038. conclusions: the present prospective study showed that considerable complications occur in patients with major comorbidities. cci is easily calculated and should be incorporated in preoperative consultation especially in cases of elder patients with severe comorbidity and favorable tumor characteristics where less invasive interventions or even active surveillance could be applied. key words: nephrectomy; complications; comorbidity; clavien dindo; charlson. submitted 29 july 2021; accepted 22 august 2021 introduction surgery (radical or partial nephrectomy using an open, laparoscopic or robotic-assisted approach) is traditionally the preferred treatment for renal cell carcinoma (rcc) (1). both tumor(i.e., clinical stage) and patient-related (i.e., physical status and comorbidities) characteristics evaluated preoperatively are important prognosticators of treatprediction of post radical nephrectomy complications based on patient comorbidity preoperatively evangelos fragkiadis, christos alamanis, constantinos a. constantinides, dionysios mitropoulos 1st urology department univesity of athens laiko hospital, athens, greece. doi: 10.4081/aiua.2021.3.251 summary archivio italiano di urologia e andrologia 2021; 93, 3 e. fragkiadis, c. alamanis, c.a. constantinides, d. mitropoulos 252 tion of postoperative morbidity using standardized comorbidity assessment and complication grading (1619), often with contradicting results. we present a singlecenter experience of open radical nephrectomies for rcc evaluating the association between preoperative comorbidity and the severity of postoperative complications using standardized systems (cci and clavien-dindo, respectively). materials and methods this was an analysis of data gathered prospectively over a period of 3 years. we included all patients undergoing radical nephrectomy for suspected rcc. our study was approved by the scientific and ethics committee of our hospital. cases of nonmalignant final pathology such as oncocytoma, mimicking renal tumors and treated by radical nephrectomy, were also included in the study. patients treated with partial nephrectomy and patients with vena cava infiltration were excluded, due to different surgical approach. all operations were performed under general anesthesia with standard retroperitoneal open approach, by experienced surgeons. data included gender, age, clinical tumor size (largest diameter at computed tomography or magnetic resonance imaging), pathological stage (tnm-uicc 2002), comorbidity (cci) and postoperative complications within 40 postoperative days. complications were graded according to clavien-dindo by an independent researcher not involved in medical decisions. a drainage was left indwelling in all cases, typically removed on 3rd postoperative day and patients were discharged on 5th postoperative day. patients hospitalized more than the 6th postoperative day were considered as having a prolonged hospital stay. complications with a severity grade of > 2 were considered as “major”. in case of multiple complications in the same patient, only the highest grade was used for the analysis. the prognostic value of each variable for clavien, was primarily assessed by univariate logistic regression analysis. variables that exhibit significant association with the outcome were included in the multivariate logistic regression model in a stepwise method (p for entry 0.05, p for removal 0.10), in order to identify independent factors, associated with clavien results. results table 1 shows the characteristics of the 171 patients included in the study. of the total group, 10 patients (5.8%) present with nodal disease and 17 (9.9%) with metastases at time of diagnosis. cci ranged from 0 to 8. eighty seven patients (50.8%) had no comorbidities at all, while 59 patients (34.5%) had mild (cci 1 or 2) comorbidities and only 25 patients (14.6%) had considerable (cci ≥ 3) comorbidities. no notable complications were recorded in most of the cohort (98 patients, 57.3%); the overall postoperative complication rate was 42.6% (73 of 171 patients). most patients suffered minor complication of clavien i (35 pts 20.5%) and clavien ii (14pts 8.2%). major complications (grade ≥ iii) occurred in 14 patients (postoperative ileus, pneumonia, respiratory insufficiency after pneumonia, postoperative bleeding requiring intervention; of which 4 cases were fatal (grade v). univariate logistic regression analyses for the occurrence of any complication (clavien ≥ i) showed that: increased cci was associated with increased likelihood for the manifestation of clavien ≥ i with an or (95% ci) of 1.45 (1.18-1.79), p < 0.001. univariate logistic regression analyses for major complication (clavien ≥ iii) indicated that increased cci was associated with increased odds for the occurrence of clavien ≥ iii with an or (95% ci) of 1.35 (1.08-1.7) and p = 0.01. when multiple logistic regression analysis was applied for any complication (clavien ≥ i) in a stepwise method, it was found that cci was independently associated with complications. specifically for one unit increase of cci the likelihood for clavien ≥ i increases 47% with a p value of 0.011. multiple logistic regression analysis for major complications of clavien ≥ iii showed that cci was also an independent predictor and for one unit increase of cci the likelihood for clavien ≥ iii increases 29% with a p value of 0.038. table 1. characteristics of the study population. patients, n (%) 171 (%) age, years 63.6 ± 11.7 yrs (35-88) ≤ 65 years 87 (50.8) > 65 years 84 (49.2) gender female 70 (40.9) male 101 (59.1) tumor size 5.8 ± 3.2 cm (4.4-8.2 cm) tumor stage t1a 21 (12.2) t1b 38 (22.2) t2a 24 (14.0) t2b 4 (2.3) t3a 57 (33.3) t3b 3 (1.7) t4 12 (7.0) n+ 10 (5.8) m+ 17 (9.9) cci o 87 (50.8) 1 38 (22.2) 2 21 (12.2) 3 8 (4.6) 4 4 (2.3) 5 1 (0.5) 6 8 (4.6) 7 2 (1.2) 8 2 (1.2) ≤ 2 86 (47.3) complications none 98 (57.3) minor (grade ≤ ii) 49 (28.6) major (grade ≥ iii) 14 (8.2) grade i 35 (20.4) grade ii 14 (8.1) grade iii 4 (2.3) grade iv 6 (3.5) grade v 4 (2.3) 253archivio italiano di urologia e andrologia 2021; 93, 3 radical nephrectomy complications and preoperative comorbidity discussion treatment decisions in oncology patients are based on cancer type and stage, the assessment of life-expectancy and the treatment benefits against treatment-related adverse events. while age is the main determinant of lifeexpectancy, comorbidity, physical and mental functioning may also play a critical role. rcc patients may have significant comorbidities at diagnosis. an analysis of 47 studies where cci was used (references on demand) revealed that at least 20% of the patients had significant comorbidity at diagnosis. in our cohort of patients, considerable (cci ≥ 3) comorbidity was observed in 14.6% of them. several studies have shown a significant correlation of cci with cancer-specific and overall survival (3, 19, 20) this demonstrates that survival in rcc is dependent on not only tumor-related variables but also patient-related variables. recording comorbidity with a validated instrument like cci may even be incorporated into nomograms (11) to provide useful prognostic information. in cases of competing causes of death, a more conservative management (i.e., active surveillance) could be advocated, especially for t1a renal masses. the relationship between comorbidity and postoperative complications using standardized indices (cci) and systems (clavien-dindo), accordingly, has not been studied appropriately. hennus et al. (8) studied 198 patients with lesions suspected of rcc who underwent partial or radical nephrectomy. the complication rate was 34% while preoperative comorbidities were present in 51% of all patients. there were significantly more major complications (> grade ii) in patients with major comorbidities (cci > 2). watanabe et al. (17) studied 62 patients ≥ 65 years old who underwent open partial or radical nephrectomy. significant comorbidity (cci ≥ 3) and grade ≥ ii complications was observed in 9.7% and 17.7% of patients, respectively. the relationship between comorbidity and postoperative complications was statistically insignificant. lue et al. (18) studied 144 patient who underwent nephrectomy along with excision of vena cava thrombus. the complication rate was 50% and comorbidity was significantly correlated with complication rate in multivariate analysis. trudeau et al. (19) studied patients who underwent percutaneous or laparoscopic tumor ablation (289 and 227 patients, respectively). while median cci was significantly different (2.1 vs 2.7, p = 0.03), postoperative complication rates were similar (21% vs 25%, p = 0.3). in both groups the complication rate was independent of comorbidity in multivariate analysis. in our study the overall postoperative complication rate was 24.2% and cci was significantly correlated to the severity of postoperative complications. conclusions although no definite conclusions can be drawn, our results along with those of hennus and lue are useful in considering how to prevent complications or take proactive action, when possible, in patients with considerable comorbidity and rcc. for example, in patients with chronic obstructive pulmonary disease postponing surgery to give time for pulmonary rehabilitation and systematic postoperative physiotherapy may help to avoid postoperative pneumonia or respiratory distress that could require admission to intensive care. moreover, complication rate reports should be adjusted for comorbidity to allow fair comparisons of quality of care and performance among individual surgeons, different techniques, urology departments and hospitals. references 1. ljungberg b, albiges l, abu-ghanem y, et al. european association of urology guidelines on renal cell carcinoma: the 2019 update. eur urol. 2019; 75:799-810. 2. heng dy, xie w, regan mm, et al. prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. j clin oncol. 2009; 27:5794-9. 3. santos arrontes d, fernandez acenero mj, garcia gonzalez ji, et al. survival analysis of clear cell renal carcinoma according to the charlson comorbidity index. j urol. 2008; 179:857-61. 4. kutikov a, egleston bl, wong yn, uzzo rg. evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. j clin oncol. 2010; 28:311-7. 5. thomas m, george na, gowri bp, et al. comparative evaluation of asa classification and ace-27 index as morbidity scoring systems in oncosurgeries. indian j anaesth. 2010; 54:219-25. 6. post pn, hansen be, kil pj et al. the independent prognostic value of comorbidity among men aged < 75 years with localized prostate cancer: a population-based study. bju int. 2001; 87:821826. 7. svatek rs, fisher mb, matin sf, et al. risk factor analysis in a contemporary cystectomy cohort using standardized reporting methodology and adverse event criteria. j urol. 2010; 183:929-34. 8. hennus pml, kroeze sgc, bosch jlhr, jans jjm. impact of comorbidity on complications after nephrectomy: use of the clavien classification of surgical complications. bju int. 2012; 110:682-687. 9. charlson me, pompei p, ales kl, mackenzie cr. a new method of classifying prognostic comorbidity in longitudinal studies: development and validation. j chron dis. 1987; 40:373-383. 10. charlson m, szatrowski tp, peterson j, gold j. validation of a combined comorbidity index. j clin epidem. 1994; 47:1245-1251. 11. de groot v, beckerman h, lankhorst g, bouter l. how to measure comorbidity: a critical review of available methods. j clin epidemiol. 2003; 56:221-229. 12. kutikov a, egleston bl, canter d, et al. competing risks of death in patients with localized renal cell carcinoma: a comorbidity based model. j urol. 2012; 188:2077-2083. 13. mitropoulos d, artibani w, graefen m, et al. european association of urology guidelines panel. reporting and grading of complications after urologic surgical procedures: an ad hoc eau guidelines panel assessment and recommendations. eur urol. 2012; 61:341-9. 14. clavien pa, barkun j, de oliveira ml, et al. the claviendindoclassification of surgical complications: five-year experience. ann surg. 2009; 250:187-196. 15. mitropoulos d, artibani w, biyani cs, et al. validation of the archivio italiano di urologia e andrologia 2021; 93, 3 e. fragkiadis, c. alamanis, c.a. constantinides, d. mitropoulos 254 clavien-dindo grading system in urology by the eau guidelines ad hoc panel. european urology focus. 2018; 4:608-613. 16. watanabe d, miura k, yamashita a, et al. a comparison of the predictive role of the geriatric nutritional risk index and immunonutritional parameters for postoperative complications in elderly patients with renal cell carcinoma. j invest surg. 2020; 1-6. 17. lue k, russell cm, fisher j, et al. predictors of postoperative complications in patients who undergo radical nephrectomy and ivc thrombectomy: a large contemporary tertiary center analysis. clinical genitourinary cancer. 2016; 14:89-95. 18. trudeau v, larcher a, boehm k, et al. comparison of postoperative complications and mortality between laparoscopic and percutaneous local tumor ablation for t1a renal cell carcinoma: a population-based study. urology. 2016; 89:63-7. 19. lund l, jacobsen j, norgaard m, et al. the prognostic impact of comorbidities on renal cancer, 1995 to 2006: a danish population based study. j urol. 2006; 182:35-40. correspondence evangelos fragkiadis, md (corresponding author) e.fragkiadis@gmail.com christos alamanis, md constantinos a constantinides, md dionysios mitropoulos, md 1st urology department univesity of athens laiko hospital athens greece stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13798 1 review more frequently affected than women. this disparity is reflected in significant differences in the urinary excretion of potassium, oxalate, citrate, uric acid, sodium, magnesium, and phosphate, as well as lower urine volume and urine ph in men compared to women (2). despite these physiological differences, common dietary habits may serve as a shared risk factor between genders. in both men and women, fluid and animal protein intake influence the risk of developing kidney stones (3). given these influences, factors that mediate the relationship between diet, fluid intake, and lithogenesis must be considered. studies advise that enhanced purine metabolism due to high consumption of meat and increased acid load can lead to uric acid kidney stones. the likely mechanism involves a reduction in urine ph and an increase in urinary excretion of uric acid, particularly in individuals with metabolic syndrome and diabetes (4). conversely, alkalization of urine has been demonstrated as pivotal in the dissolution of existing and prevention of recurrent uric acid stones (5). in calcium stones, and particularly in calcium oxalate stones, which represent most kidney stones, the role of urine ph is controversial but still under investigation (6). persistent urine ph less than 5.5 on at least two occasions daily has been noted in 14.6% of stone formers, following the most common abnormality of hypercalciuria (46%) (7). moreover, low urine ph, as part of metabolic acidosis, has been associated with insulin resistance, implying that the body does not use insulin properly when urine becomes acidic. this inverse relationship has been noticed in healthy individuals and those forming uric acid stones, and therefore, urine ph could be considered a marker of overall metabolic health (8). furthermore, the reduced ability to acidify urine can lead to recurrent nephrolithiasis, and refractory alkaline urine ph associated with renal tubular acidosis (rta) is a key factor in the formation of calcium phosphate stones (9). understanding the complex interplay between these factors is essential for developing more effective strategies for the prevention and managekidney stone disease, or nephrolithiasis, is a prevalent urological condition with variable pathogenesis. among various factors, urine ph is not only considered to be a more influential factor in stone formation, aiding in the early diagnosis and management of specific stone types such as uric acid, cystine, calcium phosphate and struvite stones, but the role of urine ph in calcium oxalate stones, which comprise most cases, is more complex. hypocitraturia in routine evaluation is another recognizable factor in lithogenesis, and administration of citrate, a widely used agent in the conservative management of stones, corrects hypocitraturia. citrate also alkalizes the urine and can therefore be used to dissolve and prevent uric acid stones. however, citrate can induce the formation of insoluble calcium phosphate salts, such as brushite and hydroxyapatite, which can lead to mixed stones and the development of nephrocalcinosis. to address this complexity, innovative treatments that focus on a broader inhibition of lithogenesis with ph-modifying strategies may allow for more comprehensive management. in addition, modern technological tools such as ph meters and ph-tracking mobile applications can offer personalized treatment plans, potentially improving patient outcomes. the current lack of consensus on the standard and optimal management of ph measurement and modification underscores the need for further research and greater collaboration among experts. the development of evidence-based strategies will be essential to improve the prevention and management of nephrolithiasis. key words: kidney stones; citrate; phytate; urine ph. submitted 5 march 2025; accepted 24 march 2025 introduction kidney stone disease or nephrolithiasis represents a significant global health burden due to the increasing prevalence of kidney stones worldwide, affecting approximately 10-15% of the population over a lifetime (1). gender may be pivotal in the clinical presentation, as men are urine ph, citrate, and beyond: challenges of pharmaceutical stone management in daily urological practice georgios tsampoukas 1, mohammad ferdous hossain 1, antigoni katsouri 2, alisha pati-alam 1, evangelos n symeonidis 3, mohammad moussa 4, murtadha almusafer 5, mohammed alameedee 6, athanasios papatsoris 7 1 department of urology, homerton healthcare nhs foundation trust, homerton, london, united kingdom; 2 department of pharmacy, princess alexandra hospital, harlow, united kingdom; 3 department of urology ii, european interbalkan medical center, 55535 thessaloniki, greece; 4 department of urology, al zahraa hospital, university medical center, lebanese university, beirut, lebanon; 5 department of urology, college of medicine, university of basrah, basrah, iraq; 6 department of urology, diwaniya teaching hospital, ad diwaniyah, al-qadisiyah governorate, iraq; 7 department of urology, university hospital of athens, athens, greece. doi: 10.4081/aiua.2025.13798 summary archivio italiano di urologia e andrologia 2025; 97(2):13798 g. tsampoukas, m. ferdous hossain, a. katsouri, et al. 2 ment of nephrolithiasis, highlighting the need for individualized approaches based on metabolic and dietary assessments. in this review, we discuss the role of ph in lithogenesis, explore strategies to measure and modify urinary ph, discuss the limitations of citrate as a treatment, and present novel molecules to improve patient outcomes. materials and methods we performed a comprehensive pubmed review in june 2024, covering the period from 2000 to date. our search string was ("urine ph"[mesh terms] or "urine ph"[all fields]) and ("lithiasis"[mesh terms] or "lithiasis"[all fields] or "kidney stones"[mesh terms] or "kidney stones"[all fields] or "nephrolithiasis"[mesh terms] or "nephrolithiasis"[all fields] or "urolithiasis"[mesh terms] or "urolithiasis"[all fields]). we selected studies examining the influence of ph on kidney stones, including mechanisms, ph level effects on various stone types, and ph modification for dissolution and prevention through dietary and pharmacological interventions, commercial products, and patient compliance. additionally, we evaluated treatment recommendations from the european association of urology (eau) and the national institute for health and care excellence (nice) regarding urine ph. link of urine ph on kidney stones formation calcium oxalate and calcium phosphate stones constitute most kidney stones, accounting for up to 80% of all cases (10). urine ph has an impact on the formation of various types of calcium-based kidney stones, influencing both the crystallization process and the metabolic environment within the urinary tract. evidence highlights the role of urine ph modulation in the management of calcium oxalate stones, suggesting that raising urine ph with alkaline agents has a significant impact on reducing urinary calcium excretion and calcium oxalate saturation (11). however, the role of urine ph is also significant in the formation of idiopathic calcium phosphate stones, where elevated urine ph favours the precipitation of calcium phosphate crystals, leading to the formation of these stone – a process linked to defects in bicarbonate reabsorption in the kidneys (12). in patients with brushite stones, increased urine ph is a significant metabolic abnormality, observed in 61.5% of cases, along with a high prevalence of absorptive hypercalciuria and distal renal tubular acidosis (13). high urine ph is of particular interest, as it is linked to the transformation from calcium oxalate to calcium phosphate stones. one study suggests that high urine ph may be a key factor in predisposing certain individuals to this transformation, possibly due to dietary influences, hereditary factors, or the use of alkaline agents such as citrate. this underscores the importance of proactively monitoring urine ph to prevent the progression to calcium phosphate stones (14). finally, higher urine ph has been positively associated with an increased calcium oxalate dihydrate to monohydrate crystal ratio, which possibly reflects underlying urinary metabolic risk factors, warranting further evaluation (15). given the significant impact of urine ph on calcium stone formation, proactive management and monitoring of ph levels are essential components of effective prevention and treatment strategies for calcium-based nephrolithiasis. while high urine ph is a risk factor for some types of calcium stones, it appears to have a protective effect against uric acid stones, highlighting the unique association between urine ph and the pathogenesis of different types of urinary stones (16). uric acid stones account for approximately 10% of all kidney stones, making them the second most common type of urinary stone after calcium oxalate and calcium phosphate stones (17). the main defects leading to uric acid stones include hyperuricosuria, low urine ph – identified as the most common and significant factor – and low urine volume, with possible mechanisms involving insulin resistance, which can impair ammonia production in the renal proximal tubule (18). as a result, uric acid, a weak organic acid with low solubility and high ph dependence, can lead to kidney stone formation due to supersaturation when urine ph is less than 5.5. within the ph range of 6.0 to 6.5, uric acid deprotonates to its more soluble form, urate, which is crucial for the effective dissolution of existing stones (19). understanding uric lithiasis is essential for effective prevention and treatment, ultimately reducing the burden of this condition. in addition to calcium and uric acid stones, there is a diverse group of non-calcium stones that present unique challenges, such as cystine and struvite stones. cystinuria is the most common monogenic disorder leading to nephrolithiasis, characterized by the recurrent formation of cystine stones due to the poor solubility of cystine at urine ph levels below 7, and is often associated with a higher prevalence of chronic kidney disease (20). mutations in genes encoding subunits of a transporter have been identified as responsible for cystinuria, and thus, diagnosis is usually made early in life, although late diagnosis is not uncommon. management of cystinuria remains challenging, with patients often at risk of multiple surgical procedures due to recurrent cystine stone formation (21). on the other hand, infectious stones such as struvite, which account for less than 10% of kidney stone cases and are characterized by a female gender predominance, can lead to the development of large kidney stones such as staghorn calculi. despite their infectious aetiology, metabolic abnormalities are highly prevalent in patients with staghorn stones, with conditions such as hypercalciuria and hypocitraturia observed in over 50% of cases (22). bacteria that hydrolyse urea, such as proteus mirabilis, raise urine ph levels above 7.2, creating an alkaline environment that promotes the crystallization of minerals, particularly magnesium ammonium phosphate, leading to the formation of large, capacious renal stones. these stones are associated with serious complications, including recurrent urinary tract infections, urinary obstruction, renal failure, and septicaemia (23). understanding this pathogenic mechanism has driven experimental research efforts, such as the development of vaccines to prevent these infections and mitigate their severe consequences (24). finally, it has been reported that certain populations, such as patients who have undergone bladder replacement or reservoir procedures, have significantly lower urinary citrate excretion and significantly higher urine ph (due to the altered archivio italiano di urologia e andrologia 2025; 97(2):13798 3 pharmaceutical stone management urine handling by the intestinal segment) compared to healthy controls, even in the absence of an active urinary infection. this leads to higher urinary supersaturation with respect to calcium phosphate, brushite, and magnesium ammonium phosphate, indicating that stone formation in these patients can be driven by altered urine ph and metabolic factors, rather than by infection alone (25). urinary ph modification strategies dietary interventions water intake is the most easily modifiable factor in urinary health, as both its volume and acidity can be adjusted, thus influencing urine ph and potentially altering the risk of lithogenesis. in a study of young athletes, low urine volume and low ph, together with increased uric acid and calcium concentrations, may increase the risk of lithogenesis. therefore, preventing dehydration could be a strategy to balance urine ph and reduce the risk of kidney stones (26). regarding the influence of the ph levels of drinking water on urine ph, a study involving wistar albino rats over a 13-day period, in which rats were given water with ph levels of 5.5, 7, and 8.2, showed statistically significant changes in urine ph on different days between groups. specifically, the urine ph of the group given water with ph 7 was significantly lower on the first day and higher on the fourth day compared to the other groups. on the seventh day, the group given water with ph 8.2 had higher urine ph compared to the other groups. the authors concluded that the ph of drinking water is associated with fluctuations in urine ph over time (27). the mechanism may involve the buffer system, renal function, and other haemostasis procedures. moreover, while the market for alkaline water is growing, the efficacy of water alone as a treatment to alter urine ph is questionable. a chemical analysis of various brands of alkaline water shows that, despite their high ph levels, they have negligible alkali content, calling into question the ability of these products to achieve therapeutic goals, and patients should consider adhering to established treatments such as potassium citrate (28). on the other hand, a study investigating the potential role of acidic sports drinks in lithogenesis did not show dramatic changes in ph, but a higher concentration of citrate in a sports drink may correlate with an increase in ph and increased citrate excretion, which may be a preventive strategy against some types of kidney stone formation (29). therefore, effective prevention of kidney stones requires a multifaceted approach that focuses on adequate hydration and established treatments such as potassium citrate, rather than relying solely on the ph of drinking water. pharmacological interventions alkalizing agents urine alkalization with citrate is the most widely used approach for both the prevention and dissolution of uric and cystine stones (30). potassium citrate is the most commonly used, although sodium bicarbonate, magnesium bicarbonate, or sodium-potassium citrate or magnesiumpotassium salts have also been suggested (31, 32). citrate is a tricarboxylic acid and an important intermediate in the krebs cycle, which is filtered and partially reabsorbed in the kidney, where it prevents nephrolithiasis by binding to calcium to form soluble complexes, thereby inhibiting crystal formation. additionally, citrate raises urine ph by being metabolized in the liver to bicarbonate, which is then excreted in the urine, creating a more alkaline environment that reduces the likelihood of stone formation (33). citrate therapy is reported to be highly effective for uric acid stones, with complete resolution in up to 70% of cases. furthermore, in populations with suspected (radiolucent) ureteral uric acid stones, citrate therapy may result in a nearly 90% stone-free status (34). in terms of prevention, despite the lack of standardization in optimal administration, citrate-based alkalization can offer a stonefree status for several years, whether used frequently or on demand and with the option of troubleshooting dissolution therapy (31). as cystine stones also respond to alkalization, potassium or sodium bicarbonate, with or without penicillamine, is often used alongside surgical treatment. however, to be effective, the ph needs to be raised above 7.0-7.5, and this is very difficult to achieve in a sustained manner, so reoperation rates for recurrence or regrowth remain high (35). a recent systematic review highlighted that gastrointestinal disturbances, such as nausea and vomiting, were common side effects leading to discontinuation; non-compliance, failure, and non-adherence were also implicated (32). to avoid intolerance and discontinuation, dose reduction may be beneficial while still effective and can be achieved in combination with other agents such as theobromine, a novel inhibitor of uric acid crystallization. hernandez et al. reported that the combination of citrate and theobromine (lit-control® ph up) can reduce the risk of uric acid stone formation and may serve as an additional, more effective, more tolerable, and safer strategy in clinical practice (36). acidifying agents l-methionine is a known acidifying agent recognized for its role in lowering urinary ph through the metabolic production of sulphuric acid during its breakdown. by creating an acidic environment, it can effectively counteract conditions that favour the crystallization of certain urinary stones, such as struvite and calcium phosphate stones, which thrive in alkaline urine. the use of a single dose of 1500 mg of l-methionine has been shown to reduce struvite supersaturation by 34% and brushite by 25%, while leaving calcium oxalate stone risk and urinary calcium excretion unaffected, emphasizing its use in stone cases associated with high urinary ph (37). in a 10year study of former struvite stone formers treated with lmethionine to acidify the urine, a significant decrease in urinary ph from 7.5 to 5.5 was observed, along with an increase in the excretion of citrate, magnesium, potassium, and uric acid, with only 10% of patients developing new stones (38). ammonium chloride, another urinary acidifier, effectively lowers urine ph by enhancing renal hydrogen ion excretion, creating a more acidic urinary environment. this mechanism disrupts the favourable conditions for the formation and growth of struvite stones. therefore, l-methionine or ammonium chloride archivio italiano di urologia e andrologia 2025; 97(2):13798 g. tsampoukas, m. ferdous hossain, a. katsouri, et al. 4 in combination with antibiotics plays a crucial role not only in reducing stone formation but also in preventing recurrent infections, making it a key component in the comprehensive management of struvite nephrolithiasis (39). however, both l-methionine and ammonium chloride are still weak recommendations in the eau guidelines as part of a broader strategy for the prevention and management of struvite stones, mainly due to the lack of randomized clinical trials (40). agents with no effect on ph for calcium stones, the benefits of ph modification are less well established, but evidence in healthy volunteers suggests that potassium citrate can raise ph and reduce both urinary calcium excretion and calcium oxalate saturation. on the other hand, magnesium treatment may also be beneficial (11), by reducing oxalate absorption and forming soluble complexes with oxalate in the urine. in a prospective double-blind study, the administration of potassium-magnesium citrate for up to 3 years effectively prevented recurrent calcium oxalate stones, with a reduction in the risk of recurrence by 85% (41). zerwekh et al. conducted a study in 20 normocalciuric subjects randomized to receive either placebo or potassium-magnesium citrate and reported that the latter significantly reduced the relative saturation of calcium oxalate (42). in patients with enteric hyperoxaluria due to previous bowel surgery, potassium citrate therapy may be beneficial against stone formation, as it binds urinary calcium and reduces the formation of insoluble calcium oxalate crystals, providing a valuable adjunct to the primary focus of dietary oxalate management (43). in these cases, the addition of magnesium may also provide additional benefit, as pairing magnesium with oxalate-containing meals can reduce oxalate absorption (44). however, although potassium citrate effectively increases urinary citrate levels, the associated rise in urine ph, oxalate, and phosphate levels leads to increased calcium phosphate supersaturation, which may inadvertently contribute to calcium phosphate stone formation (45), or even to infection and struvite stones. as noted in the previous section, these stones should be treated with acidifying agents such as l-methionine. this challenge has been highlighted by researchers such as siener et al. (46), who, after analysing 42,519 stones, concluded that new agents with no effect on urine ph are needed to treat calcium stones. grases and costa-bauzà have been working for many years on the use of phytate, a safe natural ingredient approved by the us fda, with strong inhibitory capacity on calcium oxalate and calcium phosphate crystallization and no effect on ph (47). other authors have shown that phytate intake is associated with a lower risk of stone formation, can bind calcium, and reduce urinary calcium excretion in patients with hypercalciuria (48-50). in a study conducted on 74 active calcium oxalate stone formers divided into three groups – no treatment, potassium citrate at a dose of 6,480 mg, and phytate at a dose of 120 mg – the risk of calcium stone formation was eliminated in both the potassium citrate and phytate groups. moreover, the authors demonstrated for the first time that phytate could achieve similar efficacy at a significantly lower dose than citrate (51). subsequently, other authors have shown that only 1.5 mg of phytate, versus 800 mg of citrate, is required to prevent calcium oxalate nucleation in synthetic urine (52). with this superior inhibitory capacity and no effect on ph, phytate appears to be a promising treatment for calcium stone patients. finally, grases et al. recently demonstrated a surprising and highly significant synergistic effect between phytate and magnesium in the inhibition of calcium oxalate crystallization (53). a combination of magnesium and phytates is currently used in clinical practice (lit-control ph® balance). urine ph as a marker of early stone diagnosis in addition to its established association with stone risk, urine ph plays a critical role in the assessment of possible nephrolithiasis at all levels of patient care and may be valuable in certain populations. an association between bmi and urine ph has been reported, suggesting that diet and lifestyle modifications may be beneficial in reducing the risk of stone formation and potentially improving overall kidney health. a decrease in urine ph with increasing bmi is associated with a higher prevalence of urate and calcium oxalate stones (54). moreover, higher bmi and lower urine ph have been reported as significant predictors of asymptomatic renal stones ultimately requiring surgical treatment. early detection by assessing urine ph may be crucial in identifying asymptomatic stones that may eventually require surgical intervention (55). in diabetic patients, lower urine ph (or 0.500, 95% ci 0.043-0.581) is associated with a higher likelihood of stone recurrence, particularly for calcium oxalate and uric acid stones. as urine ph is a modifiable factor, targeted therapy to modify it could potentially reduce the incidence of recurrent stones in type 2 diabetic patients (56). the pathophysiology in diabetic patients appears to be complex, as both lower urine ph and higher urine oxalate levels have been reported compared to non-diabetic individuals (57). this requires specific dietary advice, medical management, and tailored stone prevention strategies to effectively manage nephrolithiasis in this population. furthermore, sleep apnoea has been associated with lower urine ph even after adjustment for bmi, age, and gender, and the fact that this risk appears to be independent of obesity suggests that populations with sleep apnoea may be candidates for screening for ph alterations and potential stone risk (58). urine ph monitoring and adherence to treatment measurement of urinary ph is a critical aspect of monitoring alkalization therapy in the management of uric acid, cystine, and struvite stones, yet there is considerable variability in the methods (ph meter, reagent strips, or not disclosed), timing, and frequency used among researchers (31). the study by de coninck et al. demonstrates that medical-grade portable electronic ph meters outperform reagent strips in terms of resolution, consistency, and reliability for urine ph measurement. unlike strips, which rely on subjective colour interpretation prone to user error, the portable electronic ph meter provides precise numerical readings with the highest correlation to the gold standard, superior ability to classify ph archivio italiano di urologia e andrologia 2025; 97(2):13798 5 pharmaceutical stone management within target ranges, and better results in sensitivity, specificity, ppv, npv, and accuracy (59). other researchers have also suggested that the colorimetric method is not reliable for assessing urinary ph in patients receiving citrate treatment (60). in addition, the timing and frequency of urine ph measurement is another area that lacks standardization, with studies varying between spot collection of freshly voided urine and 24-hour urine collection (31). regarding the optimal time of collection, it is important to note that ph changes with increasing storage time and temperature. therefore, prolonged storage or elevated temperatures should be avoided, as they may alter the results. in terms of frequency, murayama et al. found that uric acid stone formers have a consistently low urinary ph throughout the day, whereas calcium phosphate stone formers have a consistently high urine ph during the day, and calcium oxalate stone formers have a typical diurnal pattern, with low ph in the early morning, rising during the day, and falling again at night (61). overall, ph monitoring needs standardization, but in the meantime, it seems that the most efficient approach to urine ph measurement is to use a portable medical-grade electronic ph meter with freshly voided spot urine samples several times a day. this can be a challenge for adherence in stone patients; therefore, the development of new digital technologies such as the mylit-control® app is needed to educate patients, change poor behaviours, and increase adherence. medical societies recommendations to assess clinicians’ access to guidance on the role of ph, we evaluated the guidelines from the european association of urology (eau) and the national institute for health and care excellence (nice), due to their prominence and influence in europe and the uk, respectively. the 2024 eau guidelines recommend urine ph measurement as a basic laboratory test and as part of a specific metabolic assessment. a 24-hour urine collection is recommended to differentiate between renal tubular acidosis, infections, or acidic arrest, while dipstick or ph-meter measurements on freshly voided urine collected at different times of the day are suggested to monitor alkalization therapy. the guidelines also recognize the role of ph alkalization with agents such as citrate in the prevention and dissolution of uric acid stones (40). in contrast, the nice guideline on urolithiasis (ng118), published in 2019, provides limited information on urinary ph and makes no recommendations on stone dissolution therapy. although the guideline mentions lemon juice as a lifestyle modification and the use of citrate for calcium oxalate stones, it does not emphasize the role of urine ph (62). although the exact role of urinary ph in the management of all kidney stones remains unclear, there are efficient strategies for uric acid, cystine, calcium phosphate, and struvite stones. discrepancies between medical guidelines highlight the need for collaboration to improve the credibility of evidence and to consider cost-effectiveness. cross-referencing between guidelines could improve clinical practice while awaiting further evidence. limitations our work has several limitations. this is not a systematic review, so relevant studies may have been omitted, while research into the influence of urine ph on lithogenesis is constantly evolving and new findings may alter current knowledge and recommendations. conclusions urine ph plays a crucial role in the management of kidney stone disease, particularly for uric acid, cystine, and struvite stones, although its influence on calcium stones is less clear and should be an area for future research. in addition, urine ph may mask underlying stone disease and could be used for early diagnosis in selected populations. in the treatment landscape, although effective ph modification should be an integral part of stone management, challenges remain in the standardization of measurement and monitoring. advances in technology, such as ph meters and mobile apps, can provide valuable tools for patients and clinicians, improving adherence and promoting patient-centred, personalized care. finally, discrepancies in clinical guidelines highlight the need for further research and collaboration to establish standardized ph management strategies in nephrolithiasis. references 1. stamatelou k, goldfarb ds. epidemiology of kidney stones. healthcare (basel). 2023 feb 2; 11:424. 2. ferraro pm, taylor en, curhan gc. factors associated with sex differences in the risk of kidney stones. nephrol dial transplant. 2023; 38:177-183. 3. 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allie-hamdulay s, jackson ge, sutton ral. enteric hyperoxaluria secondary to small bowel resection: use of computer declarations ethical approval: ethics committee (ec) was not required for a review of papers. availability of data and material: n/a. competing interests: the authors declare that they have no conflict of interest to disclose regarding the publication of this manuscript. no financial, commercial, or personal relationships exist that could be perceived as influencing the content or conclusions of this work. no external or departmental funding was provided. funding: no external or departmental funding was provided. authors' contributions: 1. georgios tsampoukas: conception, study design, manuscript drafting, literature review, supervision of the project. 2. mohammad ferdous hossain: study design, manuscript drafting, literature review, critical reviewing. 3. antigoni katsouri: literature search, manuscript drafting, reviewing and editing. 4. alisha pati-alam: literature search, manuscript writing, reviewing and editing. 5. evangelos n symeonidis: literature search, manuscript reviewing. 6. mohammad moussa: literature search, manuscript reviewing and editing. 7. murtadha almusafer: manuscript reviewing, reference management. 8. mohammed alameedee: reviewing and editing, final manuscript approval. 9. athanasios papatsoris: supervision of the project, final approval, and critical reviewing. acknowledgments: n/a. archivio italiano di urologia e andrologia 2025; 97(2):13798 7 pharmaceutical stone management simulation to characterize urinary risk factors for stone formation and assess potential treatment protocols. j endourol. 2014; 28:985-94. 44. zimmermann dj, voss s, von unruh ge, hesse a. importance of magnesium in absorption and excretion of oxalate. urol int. 2005; 74:262-7. 45. krieger ns, asplin jr, frick kk, et al. effect of potassium citrate on calcium phosphate stones in a model of hypercalciuria. j am soc nephrol jasn. 2015; 26:3001-8. 46. 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crystallization inhibitors (citrate and phytate). arch esp urol. 1999; 52:305-10. 52. hsu y-c, lin y-h, shiau l-d. effects of various inhibitors on the nucleation of calcium oxalate in synthetic urine. crystals. 2020; 10:333. https://doi.org/10.3390/cryst10040333 53. grases f, rodriguez a, costa-bauza a. j urol. 2015; 194:812-9. 54. najeeb q, masood i, bhaskar n, et al. effect of bmi and urinary ph on urolithiasis and its composition. saudi j kidney dis transplant 2013; 24:60-6. 55. park dj, kim bs, kwon so, et al. clinical characteristics of surgically managed patients with asymptomatic renal stones: comparison of patients with symptomatic renal stones. investig clin urol. 2023; 64:161-7. 56. prasanchaimontri p, monga m. predictive factors for kidney stone recurrence in type 2 diabetes mellitus. urology. 2020; 143:85-90. 57. eisner bh, porten sp, bechis sk, stoller ml. diabetic kidney stone formers excrete more oxalate and have lower urine ph than nondiabetic stone formers. j urol. 2010; 183:2244-8. 58. tallman je, stone bv, sui w, et al. association between obstructive sleep apnea and 24-h urine chemistry risk factors for urinary stone disease. urolithiasis. 2023; 51:46. 59. de coninck v, keller ex, rodríguez-monsalve m, et al. evaluation of a portable urinary ph meter and reagent strips. j endourol. 2018; 32:647-52. 60. da silva ibl, amaro cp, amaro jl, et al. fasting and 24-h urine ph in patients with urolithiasis using potassium citrate. am j clin exp urol. 2022; 10:188-93. 61. murayama t, sakai n, yamada t, takano t. role of the diurnal variation of urinary ph and urinary calcium in urolithiasis: a study in outpatients. int j urol off j jpn urol assoc. 2001; 8:525-31. 62. https://www.nice.org.uk/guidance/ng118/chapter/recommendations #medical-expulsive-therapy 2019. nice guideline ng118. urolithiasis: assessment and management. national institute for health and care excellence, 2019. correspondence dr georgios tsampoukas (corresponding author) tsampoukasg@gmail.com consultant urologist, ph.d., febu, certified radiographer (eaa) homerton healthcare nhs foundation trust mohammad ferdous hossain mohammad.hossain10@nhs.net alisha pati-alam alisha.patialam@nhs.net department of urology, homerton healthcare nhs foundation trust, homerton, london, united kingdom antigoni katsouri a.katsr@gmail.com department of pharmacy, princess alexandra hospital, harlow, united kingdom evangelos n symeonidis evansimeonidis@gmail.com department of urology ii, european interbalkan medical center, 55535 thessaloniki, greece mohammad moussa mohamadamoussa@hotmail.com department of urology, al zahraa hospital, university medical center, lebanese university, beirut, lebanon murtadha almusafer dralmusafer@yahoo.com department of urology, college of medicine, university of basrah, basrah, iraq mohammed alameedee mohammedalameedee@yahoo.com department of urology, diwaniya teaching hospital, ad diwaniyah, al-qadisiyah governorate, iraq athanasios papatsoris agpapatsoris@yahoo.gr department of urology, university hospital of athens, athens, greece stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13336 1 original paper introduction around 5-10% of the general population suffer from urolithiasis (1, 2). majority of the cases presenting with obstructive ureteral calculi require a prompt management to preserve functional and structural status of the involved kidneys which may cause some irreversible changes if not removed on time (3-5). regarding the management of such cases, ureteroscopy (urs) with laser lithotripsy and percutaneous nephrolithotomy (pnl) are the available options applied in the management of obstructing large ureteral calculi (6). antegrade percutaneous approach is being applied in a certain per cent of the cases with the complete removal of all stone(s) in a single session. however, this procedure is more invasive than other endourological approaches for the risk of certain severe complications (bleeding, perforation, infection, etc) even in experienced hands. in the objective: to compare the safety and efficacy of retrograde intrarenal surgery (rirs) versus minimally invasive percutaneous nephrolithotomy (mpcnl) in the minimal invasive management of impacted upper ureteral stones along with the evaluation of predictive radiological parameters. patients and methods: a retrospective analysis was done in 124 patients, undergoing rirs (n:61) and mpcnl (n:63) for the management of impacted upper ureteral stones. both operative (success and complication rates, operative time, postoperative hospital stay) and radiological (ureteral wall thickness (uwt), stone volume (sv), and stone density (hounsfield unit, hu) factors were all evaluated and recorded. comparative evaluation of stone free status in both groups was done following 72 hours and 4-weeks after the procedures to calculate the primary stone-free as well as final stone clearance rates. additionally, the outcomes of rirs group were categorized based on the intraoperative findings (presence or absence of stone encasement by a polyp) and preoperative radiological parameters. all data were well analyzed for statistical significance. a significance level of p<0.05 was considered statistically significant. results: baseline patient and stone related characteristics were similar in two groups. the success rates after a single session for rirs and mpcnl were 73.77% and 93.65%, respectively (p = 0.003), indicating a significantly higher success rate for mpcnl. however the final stone clearance rates were 96.72% and 100.00%, respectively (p = 0.147), with no significant difference observed among the groups. the rirs group demonstrated higher rate of need for auxiliary treatments (p < 0.001), shorter hospital stay (p < 0.001) and lower incidence of bleeding (p < 0.001). radiological evaluation showed no significant differences in stone volume, hu and uwt values between patients with and without residual stones after rirs (pstone volume = 0.151, phu = 0.451, puwt = 0.083). similarly, no significant differences were observed with respect to these values also in mpcnl patients, (pstone volume = 0.532, phu = 0.455, puwt = 0.658). however, a significant difference has been noted regarding the mean value of uwt between the stones surroundcomparative evaluation of the efficacy and safety of antegrade minimally percutaneous nephrolithotomy (mpcnl) and retrograde intrarenal surgery (rirs) in the treatment of upper ureteral impacted stones: a retrospective cohort study kequan cheng 1, 2*, xuwei hong 1*, gang wang 1, 2, zepai chi 1, kemal sarica 3, 4, guoyuan liu 1, yonghai zhang 1 1 department of urology, shantou central hospital, shantou, guangdong, p.r. china; 2 department of urology, sun yat-sen memorial hospital, sun yat-sen university, guangzhou, guangdong, p.r. china; 3 department of urology, health sciences university, prof. dr. ilhan varank education and training hospital, istanbul, turkey; 4 department of urology, biruni university, medical school, istanbul, turkey. * these authors contributed equally to this work. doi: 10.4081/aiua.2025.13336 summary ed by a polypoid alterations and the ones without such changes with values 5.23 ± 0.65 mm, to 4.10 ± 0.82 mm respectively (p = 0.001). conclusions: our results demonstrated that antegrade mpcnl achieves faster stone clearance and a lower re-treatment rate without serious complications in impacted upper ureteric stones. however, rirs could be a valuable and safe alternative with comparable success rates particularly in cases with contraindications to or unwillingness for mpcnl. preoperative assessment of ureteral wall thickness (uwt) value may be a good predictor for the possible tissue changes in ureteral wall at stone site to guide the decision making of the most appropriate surgical approach. key words: percutaneous nephrolithotomy; retrograde intrarenal surgery; ureteral impacted stones; retrospective study. submitted 4 november 2024; accepted 28 november 2024 archivio italiano di urologia e andrologia 2025; 97(1):13336 k. cheng, x. hong, g. wang, et al. 2 light of the risk for such complications endourologists began to use smaller instruments in an attempt to limit both the extent of renal injury and also the risk of above mentioned complications (7, 8). miniaturized pcnl techniques are being utilized with higher success and limited complications in the majority of cases presenting with large upper tract stones (9). on the other hand, based on its less invasive nature and successful outcomes compared with pcnl, flexible ureteroscopic management gained more popularity in the last 2-3 decades as a result of the evident advances in instrument technology. based on these improvements and acceptable outcomes obtained the joint clinical guidelines of the aua and the eau nephrolithiasis panel on the management of ureteral calculi recommend urs in patients with proximal ureteral stones smaller than 2 cm (10). additionally, the most recent eau and aua guidelines also recommend urs as the primary modality for stones > 10 mm (1, 11). this modality may serve as a viable alternative treatment particularly in patients with contraindications to pcnl or whom do not prefer to undergo such a more invasive intervention (12). however, accumulated data have shown that despite its evident minimally invasive nature, ureteroscopic manipulation may be associated with certain complications such as ureteral injuries and subsequent ureteral stricture formation (13). additionally, relatively lower stone-free rates (sfr) and the need for additional auxiliary procedures (14, 15) remain significant challenges for this technique when particularly dealing with large stones. some stone related parameters have been identified and used to predict the outcomes of retrograde intrarenal surgery (rirs) in the management of large, impacted ureteral stones causing certain degree of obstruction. related with this issue in addition to the size, volume, density and chemical composition of the stones treated, the thickness of the ureteric wall surrounding the impacted stone(s) have been used with great success to predict both the success as well as complications of rirs in such cases (16). taking the advantages and disadvantages of both modalities into account, in this study we aimed to compare the clinical results of rirs and mpcnl in the management of single impacted upper ureteral stones less than 2 cm in diameter. also, the potential value of some radiological parameters in the prediction of success after rirs were evaluated to select the most appropriate surgical method in these stones. patients and methods a retrospective analysis was conducted in 124 patients with upper ureteral impacted stones (< 2 cm) admitted to our urology department from april 2020 to december 2023. based on the type of intervention applied, patients were divided into two groups: group 1 (n:61) including patients undergoing rirs with laser lithotripsy and group 2 (n:63) including patients undergoing mpcnl. an informed consent was obtained in all cases undergoing both interventions. inclusion criteria were unilateral single upper ureteral stones (< 2 cm) confirmed by non-contrast computed tomography (ncct). exclusion criteria included patients with active urinary tract infections, previous renal-ureteral interventions, renal functional deterioration and anatomical abnormalities contraindicating surgery. in addition to a detailed history and through urogenital examination, blood/urine analyses were done in all patients. patients with urinary tract infections were previously treated according to the outcomes of culture-sensitivity tests. radiological evaluation consisted of kidney-ureter-bladder (kub) film, sonography and ncct in all cases. an intravenous urography was performed in cases requiring further anatomical information for making a proper decision. demographic data, including age and sex, medical history, and stone side, size, and location, were recorded (see table 1). surgical duration, length of hospital stays, perioperative complications, and treatment outcomes were evaluated and compared between groups. additionally, hounsfield units (hu) value of the stone, ureteral wall thickness (uwt) and maximum transverse and longitudinal diameter of the stones were measured on ncct and noted. kub x-ray was obtained within 72 hours of post-operative period to confirm the correct placement of double-j stents and to assess residual stone status. surgical success was defined as the absence of fragment or presence of residual stone fragments smaller than 3 mm following the procedures. residual stones were treated with extracorporeal shock wave lithotripsy (eswl) or external physical vibration lithotripsy (epvl). dj stents were removed after two weeks, and all patients were followed up one month postoperatively in the outpatient or inpatient department to outline the status of final stone clearance. definitions of outcome measures surgical efficacy: assessed the results of 72-hour and onemonth follow-up, including technical success rate and stone-free rate. operative time: for rirs, timing commenced with the placement of the flexible ureteroscope sheath, or the guidewire passing the stone and concluded with the successful placement of the ureteral stent. for mpcnl, timing began with the percutaneous puncture and ended with the successful placement of the nephrostomy tube. postoperative hospital duration: the duration from the day of surgery until discharge. postoperative auxiliary treatment rate: number of cases requiring eswl and epvl based on follow-up kub results. postoperative complications: postoperative complications were classified according to the clavien-dindo system, including the number of cases requiring hemostatic agents, those with postoperative fever, and those needing pain medication within 24 hours of surgery. surgical procedure rirs: the procedure was performed in the lithotomy position under general or combined spinal-epidural anesthesia. a 0.035-inch wolf guidewire was passed into the ureter through the rigid fr 8.0 to 9.8 wolf ureteroscope was and stone localization was confirmed by using low-pressure irrigation. fragmentation of the stone was performed with the help of either holmium laser or pneumatic ballistic lithotriparchivio italiano di urologia e andrologia 2025; 97(1):13336 3 mpcnl vs rirs for upper ureteral impacted stones sy. the holmium laser settings were arranged with a frequency value of 10 hz, energy value of 800 j, and pressure value of 14 kpa. while larger fragments were extracted with the help of stone forceps, dust and smaller fragments were flushed out. the procedure was finished with the routine placement of a 5-fr double-j stent in the affected ureter. a urethral catheter was left in place for 1 to 2 days. mpcnl: following the placement of a 5fr open end ureteral catheter during cystoscopic evaluation in lithotomy position under general anesthesia, later the patient was turned into prone position and renal puncture was performed with a 18-gauge puncture needle under ultrasound guidance. upon achieving puncture to the dependant calyx, a 0.035-inch guidewire was inserted into the collecting system whit following a 1 cm skin incision, fascial dilation and placement of a 18-fr working sheath. a 17-fr nephroscope was introduced through the working sheath for stone fragmentation. stones were disintegrated using either a holmium laser or pneumatic ballistic lithotripsy and all fragments were removed. a nephrostomy tube was inserted if necessary. following the removal of all stone fragments a 5-french double-j stent was placed antegradely into the affected ureter. a urethral catheter was placed and retained for 1 to 2 days as needed. radiologic evaluation of the stones and relevant parameters ncct images were analyzed by two radiologists to measure the ureteral wall thickness (uwt) at the stone location by taking the maximum value from cross-sectional images. hounsfield unit (hu) value of the stone was measured at the stone's central region, avoiding the boundary with surrounding soft tissue. maximum longitudinal and transverse diameter of the stones were measured in coronal and transverse planes. stone surface area (sa) and volume (v) were estimated using the following formulas based on eau guidelines (10): sa (mm²) = l × w × π × 0.25 (formula 3-1) v (mm³) = 0.6 × sa1.27 (formula 3-2) (l = maximum longitudinal diameter, w = maximum transverse diameter) degree of hydronephrosis was classified based on preoperative ultrasound or ct measurements of renal pelvis separation as mild, moderate, or severe. statistical analysis data were analyzed using spss 26.0 software. for quantitative data, independent samples t-tests were used for normally distributed data, and wilcoxon rank-sum tests for non-normally distributed data. categorical data were analyzed using chi-square tests. statistical significance was set at p < 0.05. results comparative evaluation of the efficacy rates a total of 124 adult patients were included in the study. there were no statistically significant differences between the two groups in terms of demographic characteristics such as sex, age, medical history, stone side, location, and size (table 1). comparative evaluation of the periand postoperative parameters are given in table 2. although there was a significant difference in the operative success rates between the two groups (p < 0.05), no significant difference could be noted in the stone-free rates of two groups. of the 61 cases in rirs group, 14 required additional procedures (eswl or epvl) to achieve a complete stone-free status. the auxiliary treatment rate was higher in the rirs group compared to the mpcnl group (p < 0.05). table 1. preoperative baseline characteristics of patients in the mpcnl and rirs groups. rirs (n = 61) mpcnl (n = 63) χ2/t p sex/cases (%) female 25 (40.98) 22 (34.92) 0.48 0.487 male 36 (59.02) 41 (65.08) age (mean sd) 53.82 (14.61) 54.68 (13.05) -0.35 0.729 side of the stone/cases (%) left 38 (62.29) 32 (50.79) 1.67 0.197 right 23 (37.71) 31 (49.21) medical history/cases (%) diabetes 6 (9.84) 12 (19.05) 2.12 0.145 coronary heart disease 4 (6.56) 1 (1.59) 1.98 0.160 hypertension 19 (31.15) 19 (30.16) 0.01 0.905 copd1 0 (0.00) 1 (1.59) 0.98 0.323 bph2 9 (14.75) 7 (11.11) 0.37 0.545 operational history/cases (%) eswl 7 (11.48) 3 (4.76) 1.88 0.170 rirs 4 (6.56) 1 (1.59) 1.98 0.160 pcnl 0 (0.00) 1 (1.59) 0.98 0.323 imaging characteristics (mean sd) uwt/mm 4.23 (0.88) 4.02 (0.90) 1.30 0.196 hu 1150.38 (258.18) 1158.81 (263.38) -0.18 0.857 transverse diameter/mm 11.25 (2.37) 10.81 (1.82) 1.16 0.247 longitudinal diameter/mm 14.45 (3.80) 14.48 (3.21) -0.04 0.966 hydronephrosis/cases (%) mild 26 (42.62) 20 (31.75) 3.95 0.139 moderate 20 (32.79) 17 (26.98) severe 15 (24.59) 26 (41.27) mean sd: mean standard deviation; 1 chronic obstructive pulmonary disease; 2 benign prostatic hyperplasia. table 2. postoperative efficacy and safety outcomes of rirs and mpcnl. rirs (n = 61) mpcnl (n = 63) χ2/t p operation success rate (%) 45 (73.77) 59 (93.65) 9.05 0.003 stone clearance rate (%) 59 (96.72) 63 (100.00) 2.10 0.147 postoperative adjunctive therapy (%) 14 (22.95) 1 (1.59) 13.30 ＜0.001 operation time/min (mean ± sd) 69.41 (36.11) 72.33 (29.93) -0.49 0.624 hospital stay/days (mean ± sd) 2.98 (1.58) 4.76 (2.32) -5.01 ＜0.001 infection case (%) 8 (13.11) 3 (4.76) 2.67 0.102 bleeding/case (%) 1 (1.63) 19 (30.16) 18.63 ＜0.001 analgesic use/case (%) 49 (80.33) 50 (79.37) 0.02 0.894 mean (sd) indicates the mean (standard deviation). archivio italiano di urologia e andrologia 2025; 97(1):13336 k. cheng, x. hong, g. wang, et al. 4 complications were classified by using the clavien-dindo grading system and no grade iv complication was noted in any case of this study. there was no statistically significant difference regarding the postoperative pain between the two groups. however, use of the hemostatic drugs was more frequent (30.16%) in the mpcnl group where one patient received blood transfusion and one underwent interventional treatment for bleeding demonstrating a statistically significant difference (p < 0.05) between two groups with respect to this complication. there was no significant difference between the two techniques regarding the postoperative need for pain medication within 24 hours and infective complication rates. last but not least, the average hospital stay was 2.98 ± 1.58 days in the rirs group and 4.76 ± 2.32 days for the mpcnl group respectively, indicating a relatively longer recovery time observed in the mpcnl group (p < 0.05). evaluation of the radiological parameters comparative analysis of the possible relationship between treatment outcomes and mean stone related parameters (volume and hu) as well as mean uwt values revealed no statistically significant differences between two group of cases (prirs-stone volume = 0.151 > 0.05, prirs-hu = 0.451 > 0.05, prirs-uwt = 0.083 > 0.05; pmpcnlstone volume = 0.532 > 0.05, pmpcnl-hu = 0.455 > 0.05, pmpcnl-uwt = 0.658 > 0.05) (tables 3, 4). a retrospective analysis of our data revealed that the rirs group had a lower success rates in a single session compared to the mpcnl group, often requiring additional eswl or epvl. further analysis of success rates in rirs group demonstrated that stone free rates were significantly affected by the changes in the ureteral wall characteristics (table 5). while 36 out of 61 cases in this group had inflammatory polyps noted during the procedure, 6 had strictures and 7 had stones encased by polyps, which could complicate guidewire placement, increase the risk of intraoperative bleeding, and necessitate multiple ureteroscope manipulations causing additional trauma. based on this fact, further detailed analysis on the preoperative imaging findings and the presence of intraoperative polyps encasing stones was conducted, as demonstrated in table 5. the mean preoperative uwt value detected in ncct imaging was significantly higher in cases with stones encased by polyps (5.23 ± 0.65 mm), (p_uwt = 0.001). in contrast, there was no statistically significant difference in the mean stone volume and mean hu values (p_stone volume = 0.441, p_hu = 0.711). discussion currently both anterograde pcnl and rirs are acceptable options for the minimal invasive management of impacted proximal ureteral stones with varying rates of success and complications in different series (17). each modality has its own advantage and disadvantages and accumulated experience so far demonstrated that despite its higher stone free rates in a single session, even minipcnl could be associated with severe complications (1820). on the other hand, with the use new generation flexible scopes with ho-yag laser technology, rirs was found to reveal comparable stone free rates with limited rate of complications particularly in risk group of cases for pcnl (21). taking all these facts into account, in this present study we aimed to evaluate the efficacy and safety of both modalities in the management of impacted upper ureteral stones causing obstruction. additionally, we evaluated the some certain radiological parameters in an attempt to predict the outcomes of rirs in such stones and their possible role in the preoperative decision making phase to outline the best modality. evaluation of our obtained data revealed the following findings. evaluation of success rates and the need for auxiliary treatment our results demonstrated a significant difference between success rates in terms of stone free status during short term evaluation between the two modalities where rirs approach seemed to be less effective. additionally, table 3. comparison of imaging data of residual stones after rirs surgery. no residual stones residual stones (n = 59) (n = 4) t p stone volume/mm3 (mean ± sd) 92.30 (30.19) 124.27 (83.00) -2.23 0.151 hu (mean ± sd) 1135.38 (279.19) 1192.56 (188.15) -0.76 0.451 uwt/mm (mean sd) 4.12 (0.84) 4.56 (0.94) -1.76 0.083 hu stands for hounsfield units, a measure used in ct scans; uwt stands for ureteral wall thickness; mean sd indicates the mean standard deviation. table 5. comparison of imaging data for cases with and without polyp encapsulation in rirs group. stone stone t-value p-value without polyp with polyp encapsulation encapsulation (n = 54) (n = 7) stone volume/mm3 (mean sd) 102.51 (53.45) 86.61 (20.52) 0.78 0.441 hu (mean sd) 1154.83 (266.86) 1116.00 (189.54) 0.37 0.711 ureteral wall thickness/mm 4.10 (0.82) 5.23 (0.65) -3.48 0.001 hu stands for hounsfield units, a measure used in ct scans; uwt stands for ureteral wall thickness; mean sd indicates the mean standard deviation. table 4. comparison of imaging data of residual stones after mpcnl surgery. no residual stones residual stones (n = 45) (n = 16) t p stone volume/mm3 (mean ± sd) 93.33 (29.36) 118.96 (72.48) -0.70 0.532 hu (mean ± sd) 1152.29 (265.82) 1255.00 (233.13) -0.75 0.455 uwt/mm (mean sd) 4.01 (0.90) 4.22 (0.94) -0.04 0.658 hu stands for hounsfield units, a measure used in ct scans; uwt stands for ureteral wall thickness; mean sd indicates the mean standard deviation. archivio italiano di urologia e andrologia 2025; 97(1):13336 5 mpcnl vs rirs for upper ureteral impacted stones patients undergoing rirs procedure required higher need for adjunctive treatments to achieve outcomes similar to mpcnl. as a certain advantage, mpcnl was associated with the advantage of effective fragmentation of the stones from above enabling rapid expulsion of residual fragments under high-pressure irrigation coupled with the enhanced clarity. despite marked advances in rirs technology, such as improved irrigation systems and larger working channels, flexible ureteroscopy technique remains less effective in stone fragmentation compared to mpcnl (22). related with this issue, faruk et al., found that flexible ureteroscopic management is effective for upper ureteral stones (average size of 1.24 cm), with a 96.4% single-session success rate (23). however, flexible ureteroscopic stone management was found to exhibit promising results in challenging cases such as obese and pediatric patients. in their original study best et al. were able to demonstrate a single-session success rate of 91% obese patients undergoing flexible ureteroscopic lithotripsy (24). regarding the disadvantages of rirs compared to mini-pcnl, the complex nature of the procedure with its high equipment costs and maintenance expenses seemed to limit the widespread use of rirs (25). stone fragmentation and removal may also be less practical and effective during rirs compared to mpcnl where dust forming during the procedure can cause blurred vision making the identification of small fragments hard for the surgeon. however, recent technological advancements with the introduction of new effective laser types and suction device will certainly help to improve the success rates of rirs, as in studies indicating good results for relatively larger stones (26). in fact mulţescu et al. and cho et al. were able to demonstrate that stones larger than 1 cm could be well pulverized in a successful manner with flexible ureteroscopic approach (27). evaluation of the procedure related complications complications with mpcnl are primarily linked to puncture and stone fragmentation, including severe risks like bleeding, upper urinary tract perforation, renal function deterioration and injury to adjacent organs.(28, 29) in the retrospective study of 10.413 cases of f-url treatment patients by xu et al. (30) the incidence rate of complications with electronic ureteroscopy soft mirrors did not exceed 1%. in our study, 8 patients in the rirs group experienced postoperative infective problems, which were well treated with appropriate antibiotic treatment. among these, 3 cases experienced fever possibly due to bacteremia from stone fragmentation. regarding the bleeding complication while postoperative hematuria generally improved well within one day after the procedure in rirs cases, cases in mpcnl group required more hemostatic drugs, with one case requiring interventional treatment for severe bleeding. thus, mpcnl generally involves more postoperative complications and higher management demands. evaluation of ureteral wall thickness value on the outcomes of rirs mean ureteral wall thickness (uwt) values did not show any statistically significant difference between the two groups with or without residual stones for either specific technique. possible reasons include: 1) uwt measurements can be influenced by factors such as the surgeon’s experience, scan thickness, and ct image quality; (31) 2) large stones are frequently associated with ureteral anomalies, which can lead to measurement errors. in this study, 5 cases in the rirs group exhibited significant ureteral tortuosity, necessitating image aggregation from three planes to achieve more accurate uwt values. subgroup analysis revealed that stones encased by polyps in the rirs group had significantly mean higher uwt values, indicating that preoperative measurement of uwt may be an effective predictor for the presence of polyps encasing stones. elevated uwt was found to be associated with ureteral inflammatory proliferation.(16) our results indicate that measurement of uwt value may help to predict stone related ureteral changes and guide urologists in decision making phase to choose the most appropriate option for a successful and complication free procedure. mini pcnl approach could be a reasonable alternative in such cases by avoiding rirs for polyp-encased stones to minimize the risk of procedure related complications. limitations our study is not free of limitations. first of all the retrospective, single-center nature of the study design could be stated as the main limitations. additionally, relatively small size of the sample along with a shorter follow-up period (one month) are additional limitations. we believe that further randomized controlled trials would further support the validity of these findings. clinical observations indicate that impacted stones are often accompanied by varying degrees of ureteral tortuosity, which may introduce measurement errors. additionally, inflammatory reactions leading to congestion and edema can cause the ureteral wall to have a density similar to surrounding soft tissues, resulting in measurement bias. utilizing imaging techniques to accurately measure ureteral wall area (uwa) and extract imaging features could provide new insights for developing individualized treatment plans for patients with upper ureteral impacted stones (32). conclusions our findings demonstrated that mini-pcnl could provide higher stone free rates and lower need for auxiliary treatments compared to rirs in the management of impacted upper ureteral stones. however, rirs was found to be safer with limited rate of complications associated with faster postoperative recovery. our findings did also point out the predictive role of uwt value on the presence and severity of polypoid formation surrounding the stones. thus, this radiological parameter may be helpful for the endourologists during decision making phase to choose the appropriate modality for the management of such stones to limit procedure related complications and increase the stone free rates. references 1. türk c, petrík a, sarica k, et al. eau guidelines on interventional treatment for urolithiasis. eur urol. 2016; 69:475-82. archivio italiano di urologia e andrologia 2025; 97(1):13336 k. cheng, 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29. de la rosette jj, opondo d, daels fp, et al. categorisation of declarations ethical approval: the study was approved by the institutional review board of shantou central hospital. availability of data and material: the datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. competing interests: these authors declare that they have no conflict of interest. funding: this study was supported by the special fund project for science and technology innovation strategy of guangdong province (grant no. stkj202209068). authors' contributions: conception and design: yz, ks and gl; data analysis and interpretation: kc and gw; data acquisition: xh and zc; critical revision of the manuscript: yz, ks and gl; drafting the manuscript: kc and xh; statistical analysis: kc, xh; supervision: yz. all authors read and approved the final version of the manuscript. acknowledgments: not applicable. consent for publication: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13336 7 mpcnl vs rirs for upper ureteral impacted stones complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 30. xu g-b, li x-z, he y-z, et al. ten years experience in treatment of upper urinary calculi withrirs: clinical analysis of 10 413 cases in single center. chin j endosc. 2020; 26:64-8. 31. popiolek m, lidén m, georgouleas p, et al. radiological signs of stone impaction add no value in predicting spontaneous stone passage. urolithiasis. 2024; 52:114. 32. yamashita s, kohjimoto y, iguchi t, et al. ureteral wall volume at ureteral stone site is a critical predictor for shock wave lithotripsy outcomes: comparison with ureteral wall thickness and area. urolithiasis. 2020; 48:361-8. correspondence kequan cheng, md chengkq2021@163.com xuwei hong, md hong_xuwei@sina.cn gang wang, md 1031020787@qq.com zepai chi, md zepaichist@126.com guoyuan liu, md liuguoyuan91@sohu.com department of urology, shantou central hospital, shantou, guangdong, p.r. china kemal sarica, md saricakemal@gmail.com department of urology, health sciences university, prof. dr. ilhan varank education and training hospital, istanbul, turkey yonghai zhang, md (corresponding author) zhang_yonghai@126.com department of urology, shantou central hospital 114th waima road, shantou, guangdong, p.r. china stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12617 1 original paper dence of kss is influenced by multiple factors, including environmental factors, gender, race, geographical location, occupation, exposure to hot climates, family history, unhealthy diet, obesity, smoking, alcohol consumption, and low fluid intake (5). additionally, comorbid metabolic disorders, such as hypertension, diabetes mellitus, cardiovascular disease, and chronic kidney disease can be associated with an elevated risk (3, 4, 6, 7). the symptoms of kss exhibit variability based on their location—whether within the kidney, ureter, or urinary bladder (8). common sites for stone dislodgement include the vesicoureteric junction, mid-ureter, and pelvoureteric junction (9). clinical presentations encompass renal colic and flank pain, often accompanied by gross hematuria, a burning sensation during urination, nausea, vomiting, and fever (9-11). over the last three decades, there have been notable advancements in ks treatment. currently, treatment options include minimally invasive methods such as extracorporeal shock wave lithotripsy (eswl), percutaneous nephrolithotomy (pcnl), and retrograde intrarenal surgery (rirs), as opposed to conventional open surgery (12). the applications of rirs in treating kss have expanded significantly due to recent advances in endoscopic technology (13). although the efficacy of flexible ureterorenoscopy (urs) in managing solitary ks is widely acknowledged in the literature, its effectiveness in treating multiple stones has scarcely been investigated (14). the present study aims to assess the effectiveness and safety of rirs utilizing flexible urs and laser lithotripsy in the management of multiple kss. methods setting and design this single-group cohort study was carried out on patients with multiple kss who underwent treatment with rirs with flexible urs and laser lithotripsy at a single center between september 2020 and july 2023. the iraqi council for medical specializations granted ethical approval for the study. patients underwent comprehensive counseling concerning various treatment approaches, the risk of complications, and the potential necessity for introduction: while the efficacy of flexible ureterorenoscopy (urs) in managing solitary kidney stones (kss) is widely acknowledged, its effectiveness in treating multiple stones has scarcely been investigated. this study aims to assess the effectiveness and safety of retrograde intrarenal surgery (rirs) utilizing flexible urs and laser lithotripsy in the management of multiple kss. methods: this study was a single-group cohort study conducted on patients with multiple kss who underwent treatment with rirs using flexible urs and laser lithotripsy. stone-free status was considered as the lack of residual stone fragments or any residual stone of any size. the first follow-up appointment was arranged 3-4 weeks following the procedure. if significant residual stones were present, patients underwent reintervention within 2-4 weeks. results: a total of 110 patients with multiple kss were included. the mean stone burden was 27.5 ± 7.9 mm, and the mean duration of the operation was 54.9 ± 19.7 minutes. seven cases (6.3%) experienced intraoperative complications, while postoperative complications were found in eight cases (7.3%). after four weeks, a stone-free rate (sfr) was documented in 80.9% of the cases, and this rate increased to 93.6% after three months. the sfr after three months was significant with guy’s stone score (p < 0.001); however, it did not reach a significant level with any other parameters. conclusions: the rirs with flexible urs may be an effective and potentially safe procedure for treating multiple kss. it may yield a favorable sfr with an acceptable complication rate. key words: kidney stone; urinary tract; retrograde intrarenal surgery; ureterorenoscopy; nephrolithiasis. submitted 29 april 2024; accepted 4 july 2024 introduction nephrolithiasis, also known as kidney stone (ks), is a common condition with a global concern (1). following urinary tract infections and prostate diseases, ks is the most presented urinary tract disease. regarding epidemiology, kss affect about 5% of females and 12% of males over their lifetimes (2, 3). variations in risk factors for kss can be observed among different population groups (4). the inciefficacy of flexible ureterorenoscopy in treating multiple renal stones: a cohort study sarwar noori mahmood 1, 2, rawa bapir 3, 4, 5, khoshbin faeq mustafa 4, ahmed mohammed abdalqadir 4, shakhawan hama amin said 1, nali h. hama 1, 3, hiwa o. abdullah 3, 5, berun a. abdalla 3, 5, fahmi h. kakamad 1, 3, 5 1 college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq; 2 mercy medical city, malik mahmood street, sulaymaniyah, kurdistan, iraq; 3 smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq; 4 department of urology, sulaymaniyah teaching hospital, sulaymaniyah, kurdistan, iraq; 5 kscien organization for scientific research, hamdi street, azadi mall, sulaymaniyah, kurdistan, iraq. doi: 10.4081/aiua.2024.12617 summary archivio italiano di urologia e andrologia 2024; 96(3):12617 s, noori mahmood, r, bapir, k, faeq mustafa, et al. 2 a staged or auxiliary procedure to ensure an optimal stone-free rate. eligibility criteria the inclusion criteria comprised the following: 1) patients aged ≥ 18, presenting with multiple kss sized between 11 and 30 mm. 2) stones distributed anywhere within the pelvicalyceal system. 3) conducting rirs was based on patient preference and several characteristics, such as morbid obesity, congenital renal anomalies, coagulopathy, and treatment failure with pcnl or eswl. patients with calyceal diverticular stones, ipsilateral ureteric stones or strictures, staghorn stones, pelvic-ureteric junction obstruction, or a medullary sponge kidney were excluded. patient examination and data collection patients underwent preoperative assessment through noncontrast computed tomography (ct). stone sizes were determined by calculating the sum of the greatest dimensions of each stone observed on non-contrast ct scans. the collected data encompassed patients’ demography, family history for ks, history of ks intervention, comorbidities, renal ultrasonography (u/s), non-contrast ct kidney-ureterbladder (kub), the indication of rirs, stone parameters (laterality, number, size), operation time, complications, and stone-free status. complications were classified based on the modified clavien classification system (mccs) (15). stone-free status was considered as the lack of residual stone fragments or any residual stone of any size, as determined by u/s and kub imaging. the outcomes of interest encompassed stone-free rate (sfr) and complication rates. stones exceeding the 400-600 hu threshold were more likely classified as radiopaque, whereas those falling below were considered radiolucent, although assessment based solely on hu values may have limitations and clinical correlation with additional imaging modalities or stone analysis was often necessary for accurate characterization. intervention under either general or spinal anesthesia and with patients positioned in lithotomy, a semi-rigid ureteroscope (8-9.5f, karl storz endoscopy, tuttlingen, germany) was utilized for all procedures. this facilitated the passive dilation of the ureter, enabling the evaluation of the presence of concurrent ureteral stones or strictures. a zebra nitinol guidewire (0.032/0.035 inches) (boston scientific, usa) was threaded into the pelvicalyceal system through the ureteroscope. following this, a 7.5 fr flexible urs (storz flex-x2s, tuttlingen, germany), or a digital singleuse ureteroscope (hu32, shenzhen huge med medical technical development, china), was advanced along the guidewire in a monorail manner. in patients pre-stented, a ureteral access sheath (uas) was placed over the guidewire, followed by the advancement of the flexible urs through the uas. stone fragmentation was achieved using either the holmium: yag laser (cyber-ho 60 holmium laser system, quanta system, milan, italy) or the calculase iii (storz, tuttlingen, germany). this involved applying 0.5-0.8 j power at a frequency of 15-30 hz through a 200 μm fiber. to obviate the necessity for stone retrieval, a stone dusting technique was utilized, fragmenting the stones into minuscule pieces or fine powder. following the completion of lithotripsy, a visual assessment of the pelvicalyceal system was conducted to detect any residual stone fragments. to prevent overlooking substantial pieces or fragments, fluoroscopy was utilized. under direct endoscopic vision, the guidewire was carefully inserted into the renal pelvis or collecting system. following this, the flexible ureteroscope was gradually retracted, allowing for a thorough examination of the entire ureter to identify larger calculi, fragments, and any instances of significant ureteral damage. subsequent to the procedure, a double-j (dj) stent with dimensions 5-6 f and a length of 26 cm was inserted in all cases. additionally, an indwelling foley catheter was left in place for approximately 6-12 hours. if the postoperative course was uncomplicated, patients were discharged on the postoperative day with prescribed oral antibiotics. follow-up the first follow-up appointment was arranged 3-4 weeks after the procedure. the kub examination was conducted, and the dj stent was removed in the absence of any complications. in the presence of significant residual stones and substantial complications, patients underwent reintervention within 2-4 weeks. conversely, patients without complications but with residual stones remained under observation for three months. subsequent evaluations, utilizing renal u/s and kub x-ray, took place three months after the intervention. ct scans were excluded from the diagnostic protocol to minimize expenses and reduce radiation exposure. at the three-month mark following the intervention, the sfr was determined. this categorization included either complete stone-free status, indicating the lack of residual stone fragments, or the presence of residual stones, identified through u/s and kub x-rays. statistical analysis the data were organized in microsoft excel (2019). subsequently, they were analyzed using the statistical package for the social sciences (spss) (version 22, ibm spss statistics inc., usa). the data are presented as frequency, percentage, range, mean, and standard deviation. the chi-square test and independent samples t-test were employed to identify significant relationships between the sfr and other variables. statistical significance was defined as p-values less than 0.05. results a total of 110 patients with multiple kss were included, with a mean age of 45 ± 13.82 years and a mean bmi of 25 ± 3.39 kg/m2. the majority of the cases (66.4%) were male. a positive history of ks intervention was found in 26.4% of cases. hypertension was the most common comorbidity (74.5%). ten patients (9.1%) had a history of ischemic heart disease, and nine of them were receiving anticoagulant medications. the degree of hydronephrosis was commonly distributed between mild (39.1%) and moderate (31.8%). renal malformation was present in 18.2% of the patients, while renal malfunction was observed in 20%. the indication for rirs was predomiarchivio italiano di urologia e andrologia 2024; 96(3):12617 3 furs for multiple renal stones nantly primary (80.9%). half of the cases (50%) presented with two stones, 38 (34.5%) with three stones, and 17 cases (15.5%) had more than three stones. the mean stone burden was 27.5 ± 7.9 mm and the majority of them were unilateral (91.8%). radiopaque was the prevalent radiologic characteristic of the stones (74.5%). according to guy’s stone score (gss), the majority of the stones were categorized as grade 2 (87.3%). intraoperative fluoroscopy was utilized in 52 (47.3%) patients. the mean duration of the operation and laser operating time were 54.9 ± 19.7 minutes and 31.8 ± 15.8 minutes, respectively. seven cases (6.3%) experienced intraoperative complications, including bleeding in four cases (3.6%) and ureteral injury in three cases (2.7%). postoperative complications were urinary tract infection (5.5%) and hematuria (1.8%), of which seven cases (6.4%) were re-admitted to the hospital and managed conservatively. five cases (4.5%) needed the second stage of rirs due to residual stones. after four weeks, stone free status was achieved in 80.9% of the cases, and this increased to 93.6% after three months (table 1). the sfr after three months was significant with gss; however, it did not reach a significant level with any other parameters (tables 2 and 3). discussion renal stones have several treatment options, each with its advantages and drawbacks. pcnl is a method known for effectively treating large kss (16). however, it involves accessing the kidney through the renal parenchyma. furthermore, the widely used prone position during the procedure may increase the risks associated with anesthesia and result in a decline in oxygen saturation levels, especially in patients who are obese or elderly and already have respiratory disorders (17). complications, including hemorrhage, hydrothorax, septicemia, bowel and major vessel injuries, and renal collecting system perforation, pose significant risks during and after this procedure. this has driven heightened interest in alternative treatment modalities (18, 19). recently, there has been a growing discussion about using rirs for multiple kss. several studies have investigated the feasibility and effectiveness of rirs in treating the issue (20, 21). çakıcı et al. compared the efficacy of rirs and pcnl in treating multicalyceal stones. pcnl was the preferred treatment modality unless patients had comorbidities such as anesthesia risk, bleeding diathesis, or anatomical issues where pcnl was unsuitable (20). alazaby et al. assessed rirs for the treatment of multiple kss and reached a positive conclusion regarding its efficacy. they recommended the utilization of rirs for patients with multiple kss, especially in cases where prior treatments such as eswl and pcnl have been unsuccessful (21). in the present study, the results indicated a favorable outcome, with the sfr reaching 93.6% at 3 months postoperatively. the mean operation time was 54.9 ± 19.7 minutes. no significant correlations were identified between the mean operation time and the sfr at both 4 weeks and 3 months postoperatively. ozgor et al. reported a mean operation time of 47.8 ± 22.2 minutes. also, they reported no significant correlation between it and sfr (22). in contrast, demirbas et al. reported a mean operative time of 62.8 ± table 1. baseline characteristics of the patients. variables frequency/percentage demographics mean age, year ± sd 45 ± 13.82 mean bmi, kg/m2 ± sd 25 ± 3.39 gender male 73 (66.4%) female 37 (33.6%) family history for ks yes 8 (7.3%) no 102 (92.7%) history of ks intervention yes 29 (26.4%) no 81 (73.6%) comorbidities diabetes mellitus 15 (13.6%) hypertension 82 (74.5%) ischemic heart disease 10 (9.1%) degree of hydronephrosis none 28 (25.5%) mild 43 (39.1%) moderate 35 (31.8%) severe 4 (3.6%) renal malformation yes 20 (18.2%) no 90 (81.8%) renal malfunction yes 22 (20%) no 88 (80%) indication of rirs * primary 89 (80.9%) secondary 21 (19.1%) number of stones two 55 (50%) three 38 (34.5%) more than three 17 (15.5%) stone burden, mm (mean ± sd) 27.5 ± 7.9 stone laterality right side 46 (41.8%) left side 55 (50%) bilateral 9 (8.2%) x-ray characteristics of stone 50 (21.9%) radiopaque 82 (74.5%) radiolucent 28 (25.5%) guy’s stone score grade 2 96 (87.3%) grade 3 14 (12.7%) use of fluoroscopy yes 52 (47.3%) no 58 (52.7%) operation time, min (mean ± sd) 54.9 ± 19.7 laser operating time, min (mean ± sd) 31.8 ± 15.8 intraoperative complication bleeding # 4 (3.6%) ureteral injury # 3 (2.7%) postoperative complication urinary tract infection # 6 (5.5%) hematuria# 2 (1.8%) re-admission to hospital 7 (6.4%) re-intervention (second stage rirs) 5 (4.5%) stone free after 4 weeks 89 (80.9%) stone free after 3 months 103 (93.6%) sd: standard deviation; ks: kidney stone; min: minute. * a primary indication means that the patient underwent rirs for the first time, while a secondary indication means the patient had a positive history of rirs. # grade ii according to modified clavien classification system. archivio italiano di urologia e andrologia 2024; 96(3):12617 s, noori mahmood, r, bapir, k, faeq mustafa, et al. 4 17.57 minutes and identified a highly significant correlation between the procedure time and sfr (23). a mean operation time of 51.97 ± 20.18 minutes has also been reported (24). variations in the duration of procedures among different studies may reflect the overall proficiency and the inherent complexities of the surgical tasks. it is crucial to recognize that these differences may also arise from varying methodologies used to estimate operative time. notably, some practitioners begin their time assessment with the initiation of cystoscopy, while others commence the measurement at the start of urs. the sfr in the current study was similar to that alazaby et al. reported (92.8%) (21). the similarity may be attributed to the close resemblance in mean stone burden. our reported stone burden was 27.5 mm, and alazaby et al. reported a mean stone burden of 25.7 mm (21). in the present study, although sfr was higher with fewer stones per renal unit, the difference was not statistically significant when comparing two stones with three or more at three months post-procedure. this contrasts with alazaby et al., who reported significant differences: 100% sfr for two stones, 77.7% for three, and 50% for four stones. in our cohort, sfr was 98.2% for two stones, 86.8% for three stones, and 94.1% for more than three stones. this discrepancy may be attributed to the larger sample size in this study and differences in the definition of sfr. the current study considered patients as stone-free when no stone fragments were detected by us and kub, while alazaby et al. considered sfr when fragments of 3 mm or less detected in ct-kub (21). the current study unveiled a significant correlation between the sfr observed three months post-operation and the gss. this may suggest that as the complexity of stones increases, the probability of achieving stone-free status diminishes within the three months following the operation. this aligns with the conclusions drawn by karsiyakali et al., who also found a significant correlation between sfr and gss grade 3 (25). notably, their study questioned the gss scoring system's effectiveness in predicting sfr after rirs. this is due to the reduced utility for gss grade 1 and grade 4 stones, making the system less effective across the entire stone complexity spectrum. as a result, their findings highlight the necessity for a nuanced approach to predict sfr post-rirs (25). in this study, the assessment of radiopacity in stones showed no significant correlation with sfr at four weeks and three months postoperation. this aligns with lim et al.'s findings on the relationship between stone radiopacity and sfr after rirs procedures (26). ozgor et al. similarly concluded that there was no significant correlation between these parameters (22). these outcomes emphasize the need for a nuanced consideration of factors influencing sfr beyond focusing solely on stone radiopacity in the postoperative context. with decreased instrument size, potential complications like ureteral avulsion are now extremely rare. our study found no major complications, but 15 patients (13.6%) experienced manageable minor complications—seven intraoperative and eight postoperative. this aligns with alazaby et al., reporting 16.6% minor complications (21). in contrast, atis et al. documented 3.4% minor complications in their rirs group; this variance may be due to varying sample sizes, and notably, our cohort included intraoperative complications (27). this research is subject to several limitations, including the study's small sample size, which limits its generalizability. the definition of stone burden varies, introducing potential inconsistencies. additionally, the absence of a comparison with alternative stone treatment methods hinders a comprehensive assessment. the study's short follow-up duration restricts the evaluation of long-term outcomes. to avoid citing nonpeer-reviewed data, the authors ensured the credibility of the referenced studies (28). table 2. correlation of sfr with rirs indication, stone characteristics, stent placement, and ureteric access sheath. variable no. stone free after 4 weeks p-value * stone free after 3 months p-value * iindication of rirs primary 89 72 (80.9%) 0.63 84 (94.4%) 0.40 secondary 21 17 (81%) 19 (90.5%) number of stones 2 55 48 (87.3%) 0.14 54 (98.2%) 0.08 3 38 27 (71.1%) 33 (86.8%) > 3 17 14 (82.4%) 16 (94.1%) pre-operative stent placement yes 23 18 (78.3%) 0.46 21 (91.3%) 0.45 no 87 71 (81.6%) 82 (94.3%) x-ray characteristics radio-opaque 82 67 (81.7%) 0.45 77 (93.9%) 0.57 radiolucent 28 22 (78.6%) 26 (92.9%) use of ureteric access sheath yes 80 66 (82.5%) 0.33 75 (93.8%) 0.61 no 30 23 (76.7%) 28 (93.3%) guy’s stone score g2 96 77 (80.2%) 0.068 90 (93.8%) < 0.001 g3 14 13 (92.9%) 14 (100%) * chi-square test. sfr: stone-free rate; rirs: retrograde intrarenal surgery. table 3. correlation of stone burden and operation time with sfr. variable sfr after 4 weeks p-value ** sfr after 3 months p-value ** yes (89) no (21) yes (103) no (7) mean stone burden (mm) 27.10 ± 8.44 29.09 ± 4.97 0.15 27.40 ± 8.0 29.30 ± 4.85 0.26 mean operation time (min) 54.40 ± 20.36 57.14 ± 16.77 0.39 54.94 ± 19.70 55 ± 21 0.82 ** independent t-test. archivio italiano di urologia e andrologia 2024; 96(3):12617 5 furs for multiple renal stones in conclusion, rirs with flexible urs may be an effective and potentially safe procedure for treating multiple kss. it may yield an excellent sfr with an acceptable complication rate. references 1. said sh, al kadum hassan ma, ali rh, et al. percutaneous nephrolithotomy; alarming variables for postoperative bleeding. arab j urol. 2017; 15:24-29. 2. bhatti kh, bapir r, bhatti ws, et al. efficacy of sexual intercosurse in the spontaneous passage of distal or intramural ureteral stones: a randomsized controlled trial. ann med surg (lond). 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nephrolithometric scoring systems to predict outcomes of retrograde intrarenal surgery. urol j. 2020; 17:352-7. 26. lim sh, jeong bc, seo si, et al. treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stone-free. korean j urol. 2010; 51:777. 27. atis g, culpan m, pelit es, et al. comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery in treating 20-40 mm renal stones. urol j 2017; 14:2995-9. 28. muhialdeen as, ahmed jo, baba ho, et al. kscien’s list; a new strategy to discourage predatory journals and publishers (second version). barw med j.2023; 1:24-26. correspondence sarwar noori mahmood, md shakhawan hama amin said, md nali h. hama, md college of medicine, university of sulaimani, sulaymaniyah, kurdistan, iraq rawa bapir, md hiwa o. abdullah, md berun abdalla, md berun.anwer95@gmail.com smart health tower, madam mitterrand street, sulaymaniyah, kurdistan, iraq khoshbin faeq mustafa, md ahmed mohammed abdalqadir, md department of urology, sulaymaniyah teaching hospital, sulaymaniyah, kurdistan, iraq fahmi hussein kakamad, md (corresponding author) fahmi.hussein@univsul.edu.iq doctors city, building 11, apartment 50, sulaimani, iraq conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11852 1 original paper preserving the affected kidney, this established surgical treatment aims at optimal oncological outcomes while maintaining normal renal function and avoiding chronic kidney disease (3, 4). in recent years, minimally invasive techniques have dominated the surgical field, especially in urology. consequently, laparoscopic surgery has been widely utilized. however, the steep learning curve and the advanced technical skills, which are associated with laparoscopic surgery, contribute to the underperformance of demanding laparoscopic procedures such as partial nephrectomy (pn) (5). in particular, the restricted motion of laparoscopic instruments can compromise the surgeon’s effort to accomplish tumor resection and hemostatic renorrhaphy in limited warm ischemic time (wit) (6). robotic assistance is an established trend in surgery providing high-definition, three-dimensional imaging, along with better articulation of the wristed instruments, there wise, making demanding surgeries like partial nephrectomy more easily feasible (7). the use of robotic surgery in urology is growing exponentially, thus many novel robotic systems have been introduced in the last decade (8). a novel robotic system is a new suggestion and it consists of two main components; the surgical robot with four robotic arms in which the endoscope and the instruments are mounted, and a separate console unit for the surgeon with multiple adjustments for the eyepiece, the seat, and the handling mechanism. as the eyepiece offers a high-resolution image and does not cover the surgeon’s ears and mouth, the cooperation over team members is optimized (9). four instruments are provided: bipolar metzenbaum scissors for cutting and coagulation, atraumatic grasper for holding and grasping tissue, bipolar maryland dissector for dissecting and coagulating tissue and needle holder for suturing. all instruments are compatible with 5 mm trocars (9). unlike other robotic systems, the single-use instruments minimize the sterilization costs and eliminate any risk of cross-contamination (9). the aim of the present study is to highlight the feasibility purpose: to evaluate the safety and feasibility of partial nephrectomy with the use of the novel robotic system in an in vivo animal model. methods: right partial nephrectomy was performed in female pigs by a surgical team consisting of one surgeon and one bedside assistant. both were experienced in laparoscopic surgery and trained in the use of the novel robotic system. the partial nephrectomies were performed using four trocars (three trocars for the robotic arms and one as an assistant trocar). the completion of the operations, set-up time, operation time, warm ischemia time (wit) and complication events were recorded. the decrease in all variables between the first and last operation was calculated. results: in total, eight partial nephrectomies were performed in eight female pigs. all operations were successfully completed. the median set-up time was 19.5 (range, 15-30) minutes, while the estimated median operative time was 80.5 minutes (range, 59-114). the median wit was 23.5 minutes (range, 17-32) and intraor postoperative complications were not observed. all variables decreased in consecutive operations. more precisely, the decrease in the set-up time was calculated to 15 minutes between the first and third attempts. the operative time was reduced by 55 minutes between the first and last operation, while the wit was decreased by 15 minutes during the consecutive attempts. no complications were noticed in any operation. conclusions: using the newly introduced robotic system, all the advantages of robotic surgery are optimized and incorporated, and partial nephrectomies can be performed in a safe and effective manner. key words: robot-assisted surgery; avatera system; partial nephrectomy; kidney cancer; animal model. submitted 20 september 2023; accepted 23 october 2023 introduction renal cell carcinoma is the 13th most common malignancy worldwide and the 10th most identified cancer in europe (1). the gold-standard treatment for small renal masses (< 4 cm) is currently the nephron-sparing surgery (2). by feasibility study of a novel robotic system for transperitoneal partial nephrectomy: an in vivo experimental animal study solon faitatziadis 1, vasileios tatanis 1, paraskevi katsakiori 1, angelis peteinaris 1, kristiana gkeka 1, athanasios vagionis 1, theodoros spinos 1, arman tsaturyan 1, 2, theofanis vrettos 3, panagiotis kallidonis 1, jens-uwe stolzenburg 4, evangelos liatsikos 1, 5 1 department of urology, university of patras, patras, greece; 2 department of urology, erebouni medical center, yerevan, armenia; 3 department of anesthesiology and icu, university of patras, patras, greece; 4 department of urology, university hospital of leipzig, leipzig, germany; 5 department of urology, medical university of vienna, vienna, austria. doi: 10.4081/aiua.2023.11852 summary archivio italiano di urologia e andrologia 2023; 95(4):11852 s. faitatziadis, v. tatanis, p. katsakiori, et al. 2 of partial nephrectomy with this novel robotic system in an in vivo animal model. materials and methods compliance with ethical standards ethics approval was obtained from the corresponding state services and eight female pigs, approximately 30 kg each, were used. the study has been carried out in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. the experiments were carefully designed and preapproved by the veterinary administration of the prefecture of western greece and conducted according to directive 2010/63/eu (http: //eurlex.europa.eu/lexuriserv/lexuriserv.do?uri= oj:l:2010:276:0033:0079:en: pdf). preparation of the pigs the pigs were kept unfed 12 hours prior to the procedure. ketamine, atropine sulfate and xylazine were used for initiating the anesthesia. following intubation, the pigs were connected to the ventilator and anesthesia was maintained using propofol 5%. surgical team each operation was performed by two surgeons: the primary surgeon (with experience of more than 100 laparoscopic and robotic surgeries) and the bedside assistant surgeon (with experience of more than 100 laparoscopic and robotic surgeries as assistant). the primary surgeon performed the operation via the control console, and the bedside assistant surgeon was standing next to the patient and the robot. the assistant surgeon, familiar with all surgical steps of partial nephrectomy, assisted with dissection and operated the suction, changed the surgical instruments, passed and retrieved sutures and was competent in laparoscopy or capable of converting to open surgery, if necessary. prior to the study, both surgeons participated in a training program on the use of this novel robotic system. surgical technique after anesthesia was initiated, the pig was placed in a lateral position. all partial nephrectomies were performed at the right kidney. three of the four robotic arms were used, and the procedure was performed through four ports. a 10 mm port for the camera was placed in the midclavicular line at the same level as the umbilicus. two 5 mm ports were placed at approximately 4 mm laterally from the camera trocar, one above and one below the level of the umbilicus. a 12 mm assistant port was placed at the midline, between the umbilicus and the xiphoid, for the assistant’s instruments and the suction. all the currently provided surgical instruments were utilized: the bipolar metzenbaum scissors, the atraumatic grasper, the bipolar maryland dissector, and the needle holder. the primary surgeon seated in the console unit and was not scrubbed in, while the assistant surgeon was set at the operating table (figure 1). after the placement of the trocars and the achievement of pneumoperitoneum, the procedure was initiated. the peritoneum surrounding the right kidney was incised and pulled medially with the use of grasper, exposing the kidney. holding the grasper on the left arm and the bipolar dissector on the right arm, further mobilization of the kidney was performed, and the renal hilum was identified. a bulldog clamp was placed at the renal artery and the period of warm ischemia was initiated (figure 2). afterwards, the excision of a small part of the lower or upper pole of the kidney (the supposed tumor) was performed with the use of bipolar scissors. the specimen was put in a laparoscopic bag and removed from the assistant’s 12 mm port. renorraphy followed using a running suture and placement of hem-o-lok clips to keep tension (figure 3). when renorraphy was completed, the bulldog clamp was removed from the renal artery and the blood flow to figure 1. a) control console unit b) surgical robot (the fourth robotic arm is not being used). archivio italiano di urologia e andrologia 2023; 95(4):11852 3 novel robotic system for partial nephrectomy the kidney was restored. a thorough inspection for bleeding took place. upon completion of the partial nephrectomy, all the ports were removed, and the abdomen was deflated. lastly, the fascia and the skin were sutured. immediately after finalizing the procedure, sedation was discontinued, and all pigs were extubated and monitored postoperatively. data collection the collected intra and postoperative data included the set-up time, the operative time, the wit, and the presence of complications. the set-up time was defined as the time between the incision for the first trocar and the application of the last robotic arm. the time between the first robotic maneuver and the suture of the trocar incisions was considered as the operative time. wit was defined as the time between the placement and removal of the bulldog clamp. the recorded complications were stratified into systemrelated or not. the decrease in every variable between the first and last operation was also evaluated. results in total, eight partial nephrectomies were performed in eight female pigs. all operations were successfully completed. the estimated median set-up time was 19.5 minutes (range, 15-30), while the median operative time was calculated to 80.5 minutes (range, 59-114). the median needed wit was 23.5 minutes (range, 17-32). regarding the complications, major or system-related ones were not recorded. the improvement during the consecutive attempts was also evaluated. more precisely, during the first attempt, the set-up, operation and warm ischemia times were 30, 114 and 32 minutes, respectively. on the eighth operation, the set-up and the operation were completed in 15 and 59 minutes, respectively, while the estimated needed wit was 17 minutes. the decrease in the set-up time was calculated to 15 minutes between the first and third attempt. the operative time was reduced by 55 minutes between the first and last operation, while the wit was decreased by 15 minutes during consecutive attempts. all the results are summarized in table 1. discussion nowadays, minimally invasive techniques are well-established in urology. robotic assistance is increasingly adopted in the urological field and adjusted in a variety of surgical procedures (10). the idea of robotic surgery is to perform minimally invasive procedures without the technical difficulties of laparoscopy (11). major benefits of the robotic approach are the high-resolution stereoscopic image and the fully articulating instruments, which allow precise control (6). in the case of partial nephrectomy, precise control helps surgeons to carry out more difficult cases and approach hilar or large endophytic tumors (12-15). compared to laparoscopic pn (lpn), the robotic pn (rpn) offers better outcomes. in particular, recent data suggest that rpn is associated with reduced wit, fewer complications, lower conversion rates to open surgery, better postsurgery renal function, and reduced hospitalization time (16, 17). furthermore, a remarkable benefit of robotic surgery is the minimization of the learning curve. it has been shown that rpn’s learning curve is steeper than the learning curve of lpn, having an immediate impact on the operative times, wits and blood loss (18, 19). in the present study, the feasibility and safety of rpn with the use of a novel robotic system were investigated on a porcine in vivo model. the transperitoneal access was used although the retroperitoneal access has been also utilized in the literature (20). the duration of the surgery was significantly reduced within only eight operations, an indicator of a steep learning curve in the use of this novel robotic system. the set-up time was considerably different between the first and the last surgeries, as it was the first setting and docking of the novel robotic system in our department after initial basic training, and all the new elements had to be assimilated. this important step was easily improved, as mentioned in the results section. especially, the simplified controlling mechanisms of the novel robotic system can table 1. the outcomes of the investigated variables in the first and the eighth operation. set-up time operative time warm ischemia time complications median (range) (minutes) 19.5 (15-30) 80.5 (59-114) 23.5 (17-32) no 1st operation 30 min 114 min 32 min no 8th operation 15 min 59 min 17 min no decrease (1st to 8th operation) 15 min 55 min 15 min min: minutes. figure 2. a) identification of renal artery and veins (left instrument → bipolar maryland dissector, right instrument → bipolar metzenbaum scissors). b) bulldog clamp on renal artery and initiation of warm ischemia time. figure 3. a) suturing and clip placement of renal parenchyma. b) final look of the kidney with clips after partial nephrectomy. archivio italiano di urologia e andrologia 2023; 95(4):11852 s. faitatziadis, v. tatanis, p. katsakiori, et al. 4 make any surgeon proficient in setting up the robot easily and in a short time. wit is of utmost importance in partial nephrectomy and this step was significantly improved during consecutive operations. prolonged wit is associated with acute or chronic renal dysfunction, thus it has to be maintained to a minimum (21). the precise time limit is still controversial. more dated studies showed that renal damage may be reversible when wit is less than 30 minutes (22). contemporary studies set a goal of 20 minutes (21, 23). in our study, this goal was achieved, as the median wit was 23.5 minutes. in comparison with laparoscopy, robotic assistance has decreased the technical complexity of tumor excision and intracorporeal suturing by providing articulated instruments and consequently more angles for the surgeon. therefore, as mentioned above, robotic surgery has better outcomes concerning wit than laparoscopy (17). this is supported by large comparison studies. particularly, wang et al. compared 199 rpn with 176 lpn noticing a significant difference in mean ischemia time between rpn (19.7 min) and lpn (35.2 min) (24). in the study of benway et al., wit favored robotic surgery. 129 rpn and 188 lpn were compared and the difference was almost 9 minutes (19.7 min of wit for robotic and 28.4 min for laparoscopic approach) (25). besides the superiority of rpn compared to lpn, open pn (opn) is associated with significantly lower wit (8.7 vs 15.4 minutes, p = 0.001), as presented by kowalewski et al. (26). the feasibility of rpn has been evaluated using various novel robotic platforms. fan et al. investigated the successful completion of rpn using the novel kangduo surgical robot-01 (kd-sr-01) system (suzhou kang duo robot co., ltd., suzhou, china). one rpn was performed on a 60 kg female porcine. the estimated operative time was 94 minutes, while the set-up time was 4.5 minutes. no complications were reported (27). in our study, the median operative and set-up times were 80.5 and 19.5 minutes, respectively. the feasibility and safety of rpn with kd-sr-01 were also investigated in a clinical study conducted by xu et al. in total, 17 rpn were performed with a mean operative time of 110.5 ± 37.6 minutes. the median set-up time was calculated to 3.3 minutes (range, 2.2-6.3), while the mean ischemia time was 16.9 ± 9.0 minutes (28). the performance of rpn using the versius (cmr, cambridge, uk) robot was investigated in a study conducted by hussein et al. six rpn were performed with a median operative time of 170 minutes and without reported malfunctions of the robotic system (29). hugo ras system (medtronic, minneapolis usa) was also evaluated on both cadaveric and live cases. three rpn (one on the right and two on the left side) were performed in cadavers. the recorded mean operative and docking times were 98 minutes and 7 minutes, respectively, while no major complications or clashing of the arms occurred (30). additionally, gallioli et al. presented their initial experience in 10 cases of rpn using the hugo ras system. the median docking time was 9.5 minutes (range, 914) and the median console time was 138 minutes (range, 124-162). the estimated, median wit was 13 minutes (range, 10-14), whereas one case was completed clampless. one postoperative pseudoaneurysm bleeding was treated by selective embolization (31). in the present study, this novel robotic system, which gathers all the advantages of a robotic system trying to maximize them and simplify its use, was utilized. highdefinition 3-d vision and wristed instrumentation are the main elements. easy handling of the robot and console helps to minimize the set-up time and learning curve. many safety mechanisms ensure that the operation will be carried out without any risks for the patients. moreover, all instruments are for single use which neutralizes the possibility of contamination and infections. unfortunately, this new system has some disadvantages that can be improved. at the time of the study, the singleuse instruments have a life span of one hour of continuous usage which means that during surgery they must be exchanged, most probably more than once. another disadvantage is the lack of haptic feeling, which, nevertheless, characterizes all robotic systems (9). despite the encouraging results of the present study, there are some limitations and weaknesses that should be addressed in future studies. firstly, this is an in vivo experiment, but still, surgical times and difficulties will be different in human operations. most notably, the intraperitoneal space differs, and the softer tissue of a pig’s renal parenchyma makes it harder to suture. however, the instruments used and the procedure followed were almost identical to clinical practice. secondly, a small number of partial nephrectomies were performed and strong conclusions with regard to the learning curve cannot be driven. nevertheless, our institution’s recent experience with this novel robotic system let us anticipate a steep learning curve with this robot as we have already performed several urological procedures. to the best of our knowledge, this is the first time that this novel robotic system has been tested in a complex surgical procedure like partial nephrectomy and we tried to evaluate all its elements. conclusions minimally invasive approaches have emerged and been adopted in urology. robotic assistance has helped surgeons to overcome the technical challenges and disadvantages of laparoscopic surgery and make demanding procedures such as rpn even more feasible. using this novel robotic system, all the advantages of robotic surgery are optimized and incorporated, and partial nephrectomies can be performed in a safe and effective manner. references 1. ljungberg b, campbell sc, choi hy, et al. the epidemiology of renal cell carcinoma. eur urol. 2011; 60:615-21. 2. van poppel h, becker f, cadeddu ja, et al. treatment of localised renal cell carcinoma. eur urol. 2011; 60:662-72. 3. fergany af, hafez ks, novick ac. long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. j urol. 2000; 163:442-5. 4. tan hj, norton ec, ye z, et al. long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. jama. 2012; 307:1629-35. 5. hollenbeck bk, taub da, miller dc, et al. national utilization archivio italiano di urologia e andrologia 2023; 95(4):11852 5 novel robotic system for partial nephrectomy trends of 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fifth-generation and wired networks: an animal experiment and clinical study. eur urol open sci. 2023; 49:6-9. 28. xu w, dong j, xie y, et al. robot-assisted partial nephrectomy with a new robotic surgical system: feasibility and perioperative outcomes. j endourol. 2022; 36:1436-43. 29. hussein aa, mohsin r, qureshi h, et al. transition from da vinci to versius robotic surgical system: initial experience and outcomes of over 100 consecutive procedures. j robot surg. 2023; 17:419-26. 30. prata f, ragusa a, tempesta c, et al. state of the art in robotic surgery with hugo ras system: feasibility, safety and clinical applications. j pers med. 2023; 13:1233. 31. gallioli a, uleri a, gaya jm, et al. initial experience of robotassisted partial nephrectomy with hugo ras system: implications for surgical setting. world j urol. 2023; 41:1085-91. correspondence solon faitatziadis, md solonasfait@gmail.com vasileios tatanis, md tatanisbas@gmail.com paraskevi katsakiori, md vkatsak@upatras.gr angelis peteinaris, md peteinarisaggelis@gmail.com kristiana gkeka, md kristianagkeka@gmail.com athanasios vagionis, md thanos_vagionis@hotmail.gr theodoros spinos, md thspinos@otenet.gr arman tsaturyan, md tsaturyanarman@yahoo.com panagiotis kallidonis, md pkallidonis@yahoo.com department of urology, university of patras, patras, greece theofanis vrettos, md greece teovret@gmail.com department of anesthesiology and icu, university of patras, patras, greece jens-uwe stolzenburg, md jens-uwe.stolzenburg@medizin.uni-leipzig.de department of urology, university hospital of leipzig, leipzig, germany evangelos liatsikos, md (corresponding author) liatsikos@yahoo.com department of urology, university of patras medical school, rio, patras, 26500, greece conflict of interest: jens-uwe stolzenburg is co-founder, shareholder and medical advisor of avateramedical gmbh. evangelos liatsikos is medical advisor of avateramedical gmbh. the rest of the authors have no relevant financial or non-financial interests to disclose. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12957 1 original paper pain. men with pd are most commonly present in their sixth decade of life, with a mean age of 52-57 years old (2-5). pd impacts sexual function and is also associated with psychosocial distress in patients and their partners. once thought to be rare, pd now has a reported prevalence of up to 20.3% in adult men (6) whose conservative treatment is usually successful during the active phase (7). treatment of pd utilizes both medical and surgical approaches and includes a diverse group of systemic and locally administered drugs. approaches to pd have included observation, small molecule and biologic drugs administered orally, topically, and intralesionally, mechanical therapies, and surgery. counseling and observation alone may be appropriate for patients with minimal curvature that does not impede sexual intercourse and with no erectile dysfunction (ed) (8); other patients will elect to proceed with treatment. if the curve in the penis continues during the stable phase and plaques are completely stabilized, surgery is generally the best treatment, mainly if there are problems with having sexual intercourse (9) . orally treatments with vitamin e, potassium para-aminobenzoate and tamoxifen have been used in the initial phase with low success rates (10). penile shortening procedures are used when the curvature is less severe and include the nesbit wedge resection and the plication techniques performed on the convex unaffected side of the penis. penile lengthening procedures are performed on the concave side of the penis and require the use of a graft (11-14). altieri modified nesbit corporoplasty avoids intraoperative use of tourniquet without risk of bleeding, to reduce penile ischemic anatomical and functional damages such as long-term erectile dysfunction (15). surgical procedures can be performed under local block anesthesia, general, or regional anesthesia. the choice of anesthetic technique has a major impact on how the patient responds during the postoperative period. local anesthesia is cheaper, avoids the hazards of general or spinal anesthesia, and may be the only option in patients in whom general/spinal anesthesia is deemed too objective: to compare the safety profile and clinical outcomes of altieri-modified nesbit corporoplasty using two different anesthesia methods including spinal anesthesia and local anesthesia. materials and methods: a total of 40 patients with congenital penile curvature (cpc) and peyronie’s disease (pd) underwent altieri-modified nesbit corporoplasty. group 1 (n = 20) received spinal anesthesia, and group 2 (n = 20) received local anesthesia. the patients were categorized into age groups (< 30 years, 31-45 years, 46-60 years, and 61-75 years) for analysis. clinical outcomes, post-operative complications, hospital stay, pain levels, and other parameters were assessed. results: the results showed that 2 patients (10%) reported postoperative complications, including headache, arterial hypotension, and penile foreskin necrosis from the spinal anesthesia group. whereas, in the local anesthesia group, 1 patient (5%) reported scar phimosis. further, post-operative pain was predominantly very mild, with 16 patients (80%) in the spinal anesthesia group and 14 patients (70%) in the local anesthesia group experiencing minimal discomfort. age did not significantly impact hospital stay, post-operative intestinal disorders, constipation, lower urinary tract symptoms, voiding burning, or dysuria. conclusions: spinal anesthesia may lead to more post-operative complications and longer hospital stays compared to local anesthesia. age does not significantly affect most clinical outcomes but can influence post-operative pain in patients receiving local anesthesia. key words: penile curvature; altieri-modified nesbit corporoplasty; spinal anesthesia; local anesthesia; peyronie's disease. submitted 22 august 2024; accepted 31 august 2024 introduction congenital penile curvature (cpc) is a rare condition with an incidence of less than 1% (1). peyronie’s disease (pd) is a fibrotic disorder of the tunica albuginea of the penis characterized by the presence of fibrotic plaques often leading to penile deformity, with or without concomitant altieri modified nesbit corporoplasty for the treatment of penile curvature: comparison of local anesthesia vs loco-regional anesthesia on the clinical outcomes vincenzo maria altieri 1, 2, pietro saldutto 2, vittore verratti 3, roberto la rocca 4, ernesto di mauro 4, giuseppe celentano 4, marco capece 4, vincenzo morgera 4, gianluigi cacace 4, walter vena 2, francesco mastrangelo 4, luigi napolitano4, fabrizio iacono 1 1 department of medicine and health sciences "v. tiberio", university of molise, campobasso, italy; 2 department of urology, humanitas gavazzeni, bergamo, italy; 3 department of psychological, health and territorial sciences, university "g. d'annunzio" chieti-pescara, chieti, italy; 4 unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii”, naples, italy. doi: 10.4081/aiua.2024.12957 summary archivio italiano di urologia e andrologia 2024; 96(4):12957 v.m. altieri, p. saldutto, v. verratti, et al. 2 risky. regional anesthesia has been increasingly employed in the outpatient setting, given its unique characteristics of selectivity and efficacy in the control of acute postoperative pain. outpatient regional anesthesia economic externalities have been investigated by some studies, which have associated its systematic adoption with a decrease in anesthesia-controlled operating room time and thus in the operating room fixed costs, potentially translating into a significant increase in patient turnover and ultimately hospital revenues (16, 17). however, some patients may not get complete pain relief from local block anesthesia. spinal anesthesia has been shown to decrease postoperative pain after inguinal herniorrhaphy when compared with general anesthesia; local anesthesia has been shown to reduce hospital time, lower the cost of treatment, and has no or fewer side effects compared with spinal and general anesthesia (19, 20). little information is available on the use of local anesthesia and loco-regional anesthesia on the clinical outcomes of peyronie’s disease and congenital penile curvature. therefore, present study, was to compare the safety profile and the outcomes of spinal and local anesthesia for surgical treatment of peyronie’s disease and congenital penile curvature. methods study design the present study compared the clinical outcomes of two groups of patients undergoing altieri-modified nesbit corporoplasty for the treatment of penile curvature using local vs loco-regional anesthesia. group 1 consists of 20 patients with an age ranging from 17 to 71 years who underwent surgery under spinal anesthesia between january 2010 and march 2019. while group 2 consists of 20 patients with an age range from 18 to 68 years who underwent surgery under local anesthesia between january 2010 and march 2019. the comparison of patients’ clinical outcomes was also studied based on different age groups (< 30 years, 3145 years, 46-60 years, 61-75 years) and with respect to local vs loco-regional anesthesia. all patients underwent surgery using the same adapted nesbit method and had a year-long following evaluation. a short-term post-operative assessment was performed every week to look for any early complications until the incision had fully healed. inclusion and exclusion criteria in this research, patients with peyronie's disease and congenital penile curvature were included. patients who didn't improve after taking their medications were treated with prosthesis insertion and were left out of the research. another criteria for exclusion was the existence of complex penile curvatures (pc) in patients, which required elongation operations involving plaque incision and bovine pericardial grafting to fill the albugineal defect. additionally, patients with follow-ups of less than 12 months were excluded from the study. ethical approval the "g. d'annunzio" university of chieti and pescara (01/26-01-2017) and the ethics committee for biomedical research of the districts of chieti and pescara authorized the research, which was carried out in line with the declaration of helsinki (revised in 2013). all patients provided documented, fully informed consent. clinical outcomes following a year of monitoring, a thorough physical examination was conducted among both the treatment groups, including assessments of the degree of full straightness, remaining curvature (> 15°), penile shortening, and a visible suture knot. additionally, patient happiness, erectile performance as measured by the iief-5, and penile doppler ultrasonography were also assessed. we used five questions to gauge patient happiness, asking respondents to indicate their degree of satisfaction on a scale from "very dissatisfied" to "very satisfied"(21). clinical outcome was evaluated by the change in ed and penile vibratory stimulation (pvs) along with the severity at the baseline and the end of the study. the comparison of clinical outcomes among local vs loco-regional anesthesia groups was done through post-operative complications, along with hospital stay, post-operative pain, constipation, intestinal disorders, bladder catheterization, lower urinary tract symptoms, voiding burning and dysuria. statistical analysis the clinical outcomes for both groups were analyzed considering p ≤ 0.05 as statistical significance and analyzing the results with the spss software (version 25.0, spss inc., chicago, il, usa). results the evaluation of patients undergoing altieri-modified nesbit corporoplasty for the treatment of penile curvature in spinal anesthesia and local anesthesia groups showed that 2 patients who were given spinal anesthesia and 4 patients who were given local anesthesia were in a group with less than 30 years of age. three patients for each type of anesthesia were found in the age group of 31-45 years. in the age group 46-60 years, six and seven patients were given spinal and local anesthesia respectively. in the age group 61-75 years, nine and six patients were given spinal and local anesthesia respectively. data are presented in figure 1. figure 1. age distribution of patients with penile curvature in spinal anesthesia and local anesthesia groups, archivio italiano di urologia e andrologia 2024; 96(4):12957 3 different anesthesia in corporoplasty two of the patients in the spinal anesthesia group reported post-operative complications, one had headache and arterial hypotension while the second had penile foreskin necrosis. only one patient in the local anesthesia group reported scar phimosis as post-operative complication. the results showed only one patient from each group was somewhat dissatisfied with the procedure, while 2 from the spinal anesthesia group and 5 from the local anesthesia group were neither satisfied nor dissatisfied. on the other hand, 17 from the spinal anesthesia group and 14 from the local anesthesia group were somewhat satisfied with the procedure as presented in the figure 2. however, pearson chi-square showed a non-significant difference (p = 0.455) among the treatment groups. the results also showed that one patient from the local anaesthesia group and two patients from spinal anaesthesia group showed noticeable and distracting pain, while, 2 from the spinal anesthesia group and 5 from the local anesthesia group showed minor pain. on the other hand, 16 from the spinal anesthesia group and 14 from the local anesthesia group were having very mild pai as presented in figure 3. however, pearson chi-square showed a nonsignificant difference (p = 0.416) among the treatment groups. other clinical outcomes were not significantly different between spinal and local anesthesia groups, including penile shortening, post-operative intestinal disorders, postoperative constipation, post-operative lower urinary tract symptoms, voiding burning, and dysuria. hospital stay and post-operative bladder catheterization showed significant differences between spinal anesthesia and local anesthesia groups as shown in table 1. there was a non-significant difference (p = 0.964) in penile shortening when spinal and local anesthesia groups were compared. there was no shortening in 35% and 30% of the patients given local anesthesia and spinal anesthesia, respectively. only 5% of the patients from each group showed 0.5 cm shortening in penile length. in the spinal anesthesia group, 30%, 20%, and 15% of patients showed penile shortening of 1.0, 1.5, and 2.0 cm, respectively. similarly, 20%, 25%, and 15% of patients in the local anesthesia group showed penile shortening of 1.0, 1.5, and 2.0 cm, respectively (table 1). there was a significant difference (p = 0.000) in length of hospital stay when comparing spinal and local anesthesia groups, as 100% of the patients had to stay in the hospital after the procedure in the spinal anesthesia group while none after the procedure in local anesthesia group (table 1). the chi-square test showed non-significant difference (p = 0.147) in post-operative intestinal disorders and post-operative constipation when comparing patients in spinal and local anesthesia groups. only 10% of the patients who showed post-operative intestinal disorders and post-operative constipation were given spinal anestable 1. clinical outcomes among patients with congenital penile curvature in spinal anesthesia and local anesthesia groups. variables frequency (%) p-value** spinal anesthesia local anesthesia penile shortening (cm) 0.964 0.0 6 (30%) 7 (35%) 0.5 1 (5%) 1 (5%) 1.0 6 (30%) 4 (20%) 1.5 4 (20%) 5 (25%) 2.0 3 (15%) 3 (15%) hospital stay 0.000 yes 20 (100%) 0 (0%) no 0 (0%) 20 (100%) post-operative intestinal disorders 0.147 yes 2 (10%) 0 (0%) no 18 (90%) 20 (100%) post-operative constipation 0.147 yes 2 (10%) 0 (0%) no 18 (90%) 20 (100%) post-operative bladder catheterization 0.000 yes 20 (100%) 0 (0%) no 0 (0%) 20 (100%) post-operative lower urinary tract symptoms 0.147 yes 2 (10%) 0 (0%) no 18 (90%) 20 (100%) voiding burning 0.311 yes 1 (5%) 0 (0%) no 19 (95%) 20 (100%) dysuria 0.311 yes 1 (5%) 0 (0%) no 19 (95%) 20 (100%) ** pearson chi-square. figure 2. the satisfaction rate of patients with penile curvature in spinal anesthesia and local anesthesia groups. *satisfaction was self-assessed by patients using a 5-point rating scale, with a score of 1 indicating very dissatisfied and 5 indicating very satisfied. figure 3. post-operative pain among patients with penile curvature in spinal anesthesia and local anesthesia groups. archivio italiano di urologia e andrologia 2024; 96(4):12957 v.m. altieri, p. saldutto, v. verratti, et al. 4 thesia while none of the patients showed any intestinal disorder from local anesthesia group (table 1). there was a significant difference (p = 0.000) in postoperative bladder catheterization rate when comparing spinal and local anesthesia groups, as 100% of the patients had post-operative bladder catheterization in the spinal anesthesia group while none of the patients had it in local anesthesia group (table 1). the results showed non-significant difference (p = 0.147) in post-operative lower urinary tract symptoms when comparing patients in spinal and local anesthesia groups. only 10% of the patients in the spinal anesthesia group showed post-operative lower urinary tract symptoms while none of the patients showed post-operative lower urinary tract symptoms in the local anesthesia group (table 1). the results showed also non-significant difference (p = 0.311) in burning at voiding and dysuria when comparing patients in spinal and local anesthesia groups. only 5% of the patients in the spinal anesthesia group showed burning at voiding and dysuria while none of the patients showed such symptoms in the local anesthesia group (table 1). the age group comparison of the length of hospital stay showed that among patients of spinal anaesthesia group having age less than 30 only two had to stay in hospital while in age group 31-45 years, three patients had a hospital stay. in group 46-60 years, six patients have hospital stay while, in group 61-75 years, nine patients have a hospital stay. on the other hand, none of the patients from local anaesthesia group stay in the hospital. there was a non-significant difference (p = 0.719) among age groups for hospital stay as shown in table 2. in the age group less than 30 years given spinal anaesthesia, only 2 patients had very mild post-operative pain, whereas, in group 31-45 years, three patients had very mild pain. similarly, in age group 46-60 years, four patients had very mild pain, one had minor, and one had noticeable and distracting pain. in group 61-75 years, seven patients had very mild pain, one had minor pain, and one had noticeable and distracting pain. there was non-significant (p = 0.925) difference among the age groups. on the other hand, among age group less than 30 years given local anaesthesia, four patients had very mild pain and in age group 31-45 years, three patients had minor pain. in age group 46-60 years, six patients had very mild pain and one had minor pain. in age group 6175 years, four patients had very mild pain, one patient had minor pain and one had noticeable and distracting pain. there was a significant difference (p = 0.037) among age groups given local anaesthesia for post-operative pain (table 3). the results of age group comparison for the post-operative intestinal disorder in patients given spinal anaesthesia showed that there were only two patients in age group 61-75 years had post-operative intestinal disorder. none of the patients in other age groups have such disorder. on the other hand, there was no patients having post-operative intestinal disorder in local anaesthesia group. the pearson chi-square test showed a non-significant (p = 0.438) difference for post-operative intestinal disorder by type of anaesthesia and age (table 4). the results of age group comparison for the post-operative constipation in patients given spinal anaesthesia showed that there were only two patients in age group 61-75 years who were having post-operative constipation however, none of the patients in other age group have such disorder. on the other hand, there was no patients having post-operative constipation in local anaesthesia group. the pearson chi-square test showed a non-significant (p = 0.438) difference among anaesthesia, age groups and post-operative intestinal disorder (table 5). the results of age group comparison for post-operative bladder catheterization rate in patients given spinal anaesthesia showed that 2, 3, 6 and 9 patients in age groups < 30 years, 31-45 years, 46-60 years and 61-75 table 2. pearson chi-square test for the relation of age groups with anaesthesia types and hospital stay. anesthesia type age group hospital stay pearson no yes chi-square spinal anesthesia < 30 years 0 2 0.719 31-45 years 0 3 46-60 years 0 6 61-75 years 0 9 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 table 3. pearson chi-square test for the relation of age groups with anaesthesia types and post-operative pain. anesthesia type age group post-operative pain pearson very mild minor noticeable chi-square and distracting spinal anesthesia < 30 years 2 0 0 0.925 31-45 years 3 0 0 46-60 years 4 1 1 61-75 years 7 1 1 local anesthesia < 30 years 4 0 0 0.037 31-45 years 0 3 0 46-60 years 6 1 0 61-75 years 4 1 1 table 4. pearson chi-square test for the relation of age groups with anesthesia types and post-operative intestinal disorder. anesthesia type age group post-operative intestinal disorder pearson no yes chi-square spinal anesthesia < 30 years 2 0 31-45 years 3 0 46-60 years 6 0 61-75 years 7 2 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 archivio italiano di urologia e andrologia 2024; 96(4):12957 5 different anesthesia in corporoplasty years respectively, had post-operative bladder catheterization. none of the patients in the local anaesthesia group have post-operative bladder catheterization. there was non-significant (p = 0.719) difference for post-operative bladder catheterization by type of anaesthesia and age (table 6). the results of age group comparison for the post-operative lower urinary tract symptoms in patients given spinal anaesthesia showed that there was only one patient in age group 31-45 years and one patient in age group 46-60 years showing post-operative lower urinary tract symptoms. none of the patients in the local anaesthesia group have post-operative lower urinary tract symptoms. there was non-significant (p = 0.343) difference for lower urinary tract symptoms by type of anaesthesia and age (table 7). the results of age group comparison for burning at voiding in patients given spinal anaesthesia showed that there was only one patient in age group 46-60 years who showed symptoms of burning. none of the patients in the local anaesthesia group had burning at voiding there was non-significant (p = 0.438) difference of burning at voiding by type of anaesthesia and age (table 8). the results of age group comparison for the dysuria in patients given spinal anaesthesia showed that there was only one patient in age group 31-45 years who showed symptoms of dysuria. none of the patients in the local anaesthesia group had dysuria. there was non-significant (p = 0.113) difference for dysuria by type of anaesthesia and age (table 9). discussion altieri modified nesbit corporoplasty for the treatment of penile curvature utilizes surgical approaches in patients with cpc or pd that are naïve to treatment or have previously used locally or systemic and drugs. the choice of anesthetic technique to perform altieri modified nesbit corporoplasty has a major impact on how the patient responds during the postoperative period (22). in the present study, we compared the safety profile and the outcomes of local anesthesia vs loco-regional anesthesia for surgical treatment of penile curvature. the distribution of patients by age groups in the present study showed that most of the patients were in the elderly age group (61-75 years) which might be due to the reason that elderly population is at a high risk of diseases (23). table 5. pearson chi-square test for the relation of age groups with anesthesia types and post-operative constipation. anesthesia type age group post-operative constipation pearson no yes chi-square spinal anesthesia < 30 years 2 0 0.438 31-45 years 3 0 46-60 years 6 0 61-75 years 7 2 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 table 6. pearson chi-square test for the relation of age groups with anaesthesia types and post-operative bladder catheterization. anesthesia type age group post-operative bladder catheterization pearson no yes chi-square spinal anesthesia < 30 years 0 2 0.719 31-45 years 0 3 46-60 years 0 6 61-75 years 0 9 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 table 7. pearson chi-square test for the relation of age groups with anesthesia types and post-operative lower urinary tract symptoms. anesthesia type age group post-operative lower urinary pearson tract symptoms chi-square no yes spinal anesthesia < 30 years 2 0 0.343 31-45 years 2 1 46-60 years 5 1 61-75 years 9 0 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 table 8. pearson chi-square test for the relation of age groups with anaesthesia types and voiding burning. anesthesia type age group voiding burning pearson no yes chi-square spinal anesthesia < 30 years 2 0 0.438 31-45 years 3 0 46-60 years 5 1 61-75 years 9 0 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 table 9. pearson chi-square test for the relation of age groups with anesthesia types and dysuria. anesthesia type age group dysuria pearson no yes chi-square spinal anesthesia < 30 years 2 0 0.113 31-45 years 2 1 46-60 years 6 0 61-75 years 9 0 local anesthesia < 30 years 4 0 31-45 years 3 0 46-60 years 7 0 61-75 years 6 0 archivio italiano di urologia e andrologia 2024; 96(4):12957 v.m. altieri, p. saldutto, v. verratti, et al. 6 additionally, our results also showed that more patients showed only mild pain in the spinal anesthesia group compared to the local anesthesia group which should be due to the section in the ligaments, fascia, or bone with localized bleeding (24). in the present study, the comparison of spinal and local anesthesia in the context of post-operative outcomes reveals that local anesthesia appears to be associated with a shorter hospital stay, potentially making it a more favorable choice for this particular procedure. there was a non-significant difference in penile shortening when it was compared in spinal and local anesthesia groups. these findings are consistent with the study conducted by ana et al. who reported that surgical treatment of penile curvature under local anesthesia improves the cost-effectiveness ratio with the same quality of care, degree of satisfaction and postoperative functional results, maintaining a similar rate of intra/postoperative complications (25). similarly, the results showed that 10% of patients in the spinal anesthesia group showed post-operative intestinal disorders and post-operative constipation compared to the local anesthesia group which might be due to the shorter time needed to return of bowel function (26). these results are in-line with the previous studies reporting post-operative constipation (27-28). our results also showed a significant difference in post-operative bladder catheterization time when comparing spinal and local anesthesia groups as 100% of the patients had post-operative bladder catheterization in the spinal anesthesia group while none of the patients had post-operative bladder catheterization in local anesthesia group. need of post-operative bladder catheterization after spinal anesthesia was due to the urinary retention (29). in the present study, due to the urinary retention, patients who had spinal anesthesia also showed signs of post-operative lower urinary tract symptoms. these findings are consistent with the previously reported studies (30, 31). similarly, patients after surgery conducted by using spinal anesthesia also showed signs of voiding burning and dysuria. it has been reported that spinal anesthesia commonly leads to urinary retention because the patient is unable to feel the bladder sensation and to initiate voiding after the surgery. bladder and sphincter muscles are unable to respond for voiding reflex (32, 33). altieri-modified nesbit corporoplasty and minimally invasive techniques can offer effective solutions for penile curvature with high patient satisfaction rates and minimal complications (34). however, it has to be considered the specific patient population, the severity of the curvature, and the desired outcomes when choosing the most appropriate surgical technique and anesthesia type. the choice of anesthesia, whether spinal or local, should also consider the potential post-operative complications and the patient's overall health status. further, the results of present study also showed that most patients in age group 61-75 years who were given spinal anaesthesia had hospital stay due to the deep sedation during spinal anaesthesia in older age group (35, 36). furthermore, noticeable and distracting post-operative pain was observed among higher age group patients who were given spinal anesthesia that might be due to numbness, and motor weakness among older patients (37). similarly, age group comparison for the post-operative intestinal disorders showed more intestinal disorders among 61-75 years age group patients who were given spinal anaesthesia which could be due to increased colonic transit time among older patients (38). our results also showed that patients in age group 61-75 years had post-operative constipation with spinal anaesthesia. these findings are consistent with previously reported studies (39). our findings showed that post-operative lower urinary tract symptoms were observed in patients with age groups 31-45 years and 46-60 years given spinal anaesthesia. symptoms of voiding burning were observed in patients with age group 46-60 years wereas dysuria was observed in patients with age group 31-45 years. these findings are comparable to the previously reported studies (41, 42). in conclusion, the choice of anesthesia technique for surgical treatment of penile curvature, particularly utilizing the altieri modified nesbit corporoplasty method, plays a pivotal role in determining postoperative outcomes. our findings also support the preference for local anesthesia in terms of shorter hospital stays and less post-operative complications. particularly, spinal anesthesia was associated with a higher risk of post-operative complications such as urinary retention and constipation. in summary, the choice of anesthesia method should be a well-considered decision that considers the individual patient's characteristics, the surgical technique to be employed, and the potential implications for postoperative outcomes, making it essential for healthcare professionals to make informed choices in the best interest of their patients. moreover, long-term follow-up studies are required for making informed decisions about the choice of anesthesia. future research should focus on collecting patientreported outcomes to assess quality of life, psychological well-being, and sexual function after surgery. additionally, as surgical techniques and technology advance, the potential for minimally invasive procedures and innovations in anesthesia protocols may provide safer and more efficient options for patients. collaboration through multi-center studies and international comparisons will help identify best practices and regional variations, ultimately leading to more personalized, effective, and globally accessible care for individuals seeking treatment for penile curvature. conclusions this study comparing altieri-modified nesbit corporoplasty outcomes with spinal anesthesia and local anesthesia for congenital penile curvature and peyronie's disease with spinal anesthesia and local anesthesia confirms the effectiveness of the surgical procedure and demonstrates that both approaches yield high patient satisfaction and minimal post-operative pain. however, spinal anesthesia was associated with a slightly higher rate of post-operative complications and significantly longer hospital stays compared to local anesthesia. importantly, age did not significantly influence most clinical outcomes, except for post-operative pain, where older patients in the local anesthesia group reported slightly more discomfort. these findings provide valuable insights for clinicians, archivio italiano di urologia e andrologia 2024; 96(4):12957 7 different anesthesia in corporoplasty aiding in the selection of anesthesia methods to optimize patient outcomes and enhance their overall surgical experience. references 1. montag s, palmer ls. abnormalities of penile curvature: chordee and penile torsion. scientificworldjournal. 2011; 11:1470-8. 2. el-sakka ai. prevalence of peyronie's disease among patients with erectile dysfunction. eur urol. 2006; 49:564-9. 3. spirito l, manfredi c, la rocca r, et al. daily low-dose tadalafil may reduce the penile curvature progression rate in patients with acute peyronie's disease: a retrospective comparative analysis. int j impot res. 2024; 36:129-134. 4. spirito l, manfredi c, la rocca r, et al. long-term outcomes of extracorporeal shock wave therapy 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adults. n engl j med. 2021; 385:2025-2035. 37. bafna u, rajarajeshwaran k, khandelwal m, verma ap. a comparison of effect of preemptive use of oral gabapentin and pregabalin for acute post-operative pain after surgery under spinal anesthesia. j anaesthesiol clin pharmacol. 2014; 30:373-7. archivio italiano di urologia e andrologia 2024; 96(4):12957 v.m. altieri, p. saldutto, v. verratti, et al. 8 38. tu c-p, tsai c-h, tsai c-c, et al. postoperative ileus in the elderly. international journal of gerontology 2014; 8:1-5. 39. lang-illievich k, bornemann-cimenti h. opioid-induced constipation: a narrative review of therapeutic options in clinical management. korean j pain. 2019; 32:69-78. 40. yılmaz e, arı m. impact of pre-operative anxiety on postoperative constipation. turk j colorectal dis 2016; 26:39-46. 41. basques ba, bohl dd, golinvaux ns, et al. general versus spinal anaesthesia for patients aged 70 years and older with a fracture of the hip. bone joint j. 2015; 97-b:689-95. 42. hernandez ns, wang ay, kanter m, et al. assessing the impact of spinal versus general anesthesia on postoperative urinary retention in elective spinal surgery patients. clin neurol neurosurg. 2022; 222:107454. correspondence vincenzo maria altieri, md vincenzomaria.altieri@gmail.com fabrizio iacono, md info@fabrizioiacono.it department of medicine and health sciences "v. tiberio", university of molise, 86100 campobasso, italy pietro saldutto, md pietro.saldutto@gavazzeni.it walter vena, md walter.vena@gavazzeni.it department of urology, humanitas gavazzeni, 24125 bergamo, italy vittore verratti vittore.verratti@unich.it department of psychological, health and territorial sciences, university "g. d'annunzio" chieti-pescara, 66100 chieti, italy roberto la rocca, md robertolarocca87@gmail.com giuseppe celentano, md dr.giuseppecelentano@gmail.com marco capece, md drmarcocapece@gmail.com ernesto di mauro, md ernesto.dimauro@unina.it vincenzo morgera, md vincemorgera87@gmail.com gianluigi cacace, md cacace.gianlu@gmail.com francesco mastrangelo, md fmastrangelo91@gmail.com unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii”, naples, italy luigi napolitano, md (corresponding author) dr.luiginapolitano@gmail.com unit of urology, department of neurosciences, reproductive sciences, and odontostomatology university of naples “federico ii” via sergio pansini 5, 80131 naples, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 96(1):13353 1 original paper oping effective therapeutic strategies (3). the development of prostate tumors has been linked to a range of factors, including race, age, heredity, diet, and environment. recent research suggests that prostatic inflammation may play a key role in both pca and bph (4-6), highlighting the need for further investigation into this connection (5, 6). the hypothesis that inflammation can drive cancer cell proliferation has been explored for over 150 years. recent preclinical research supports the idea that inflammation plays a role in the development and progression of pca. the correlation between prostatic inflammation and bph has been recognized since as early as 1937 (7). despite these historical and preclinical insights, there remains a scarcity of comprehensive clinical data directly linking prostatic inflammation with tumor development and progression. understanding the immune pathways associated with prostate tumors could lead to novel therapeutic strategies (3,8). the inflammatory infiltrates found in prostate glands differ in type, intensity, and location, indicating the participation of various molecular processes (9). pathological research is particularly valuable in this context, as it can provide more reliable insights into the association between inflammation and prostate tumors compared to epidemiological studies alone (5, 10). recent studies have identified inflammatory cytokines such as fibroblast growth factor-2 (fgf2) interleukin (il)-8, and il-6 as potential contributors to prostate tumor development (11, 12). fgf2 is known for its role as a potent growth factor, promoting abnormal prostate growth and the proliferation of basal epithelial cells, thus contributing to the pathogenesis of both pca and bph. il-6 and il-8 are also critical in stromal growth associated with bph and cancer progression (11, 13). this study aims to explore the correlation between inflammation and prostate tumor development and progression by investigating these inflammatory markers and their roles in both pca and bph. methods study population and tissue collection a cross-sectional study was carried out to examine the introduction: chronic inflammation is associated to the pathogenesis of prostate cancer (pca) and benign prostatic hyperplasia (bph). this study evaluated the correlation between inflammatory markers fibroblast growth factor-2 (fgf2), interleukin (il)-8, and il-6 in pca and bph tissues to understand their involvement in disease progression. methods: a cross-sectional investigation was carried out, examining prostate specimens from 62 male patients diagnosed with pca or bph. specimens were taken via transurethral resection of the prostate (turp) and stained with hematoxylin and eosin to look for inflammatory infiltrates and aggressiveness. the levels of fgf2, il-8, and il-6 were evaluated using elisa. chi-square and logistic regression tests were used in the statistical analysis. results: high-grade inflammation was found in all bph cases (100%), but not in pca cases. in bph tissues, elevated levels of il-8 and il-6 had a significant correlation with high-grade inflammation (p < 0.05). on the other hand, pca tissues had considerably greater fgf2 levels than benign tissues (p < 0.05). elevated fgf2 levels and the lack of high-grade inflammation in pca tissues point to different pathogenic processes in pca and bph. conclusions: this study emphasizes the importance of chronic inflammation in bph development, with il-8 and il-6 playing essential roles. the results imply that treating bph by focusing on il-8 and il-6 may be beneficial. increased levels of fgf2 in pca tissues suggest that this protein may be used as a biomarker and therapeutic target for pca. these findings highlight the importance of targeting both inflammatory and growth factor pathways for treating prostatic disorders. key words: prostatic inflammation; prostate cancer; inflammatory markers; benign prostatic hyperplasia. submitted 6 november 2024; accepted 27 january 2025 introduction prostate cancer (pca) and benign prostatic hyperplasia (bph) are increasingly significant health issues, with their prevalence likely to rise due to an aging population (1, 2). a deeper understanding of the natural history of prostate tumors is crucial for improving early detection and develthe impact of inflammation on prostate tumor dynamics: a pathological perspective on prostate cancer and benign prostatic hyperplasia syakri syahrir 1, 2, muhammad asykar palinrungi 1, mochammad hatta 3, khoirul kholis 1, 2, syarif 1, abdul azis 1, muhammad faruk 4 1 division of urology, department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia; 2 dr. wahidin sudirohusodo hospital, makassar, indonesia; 3 department of clinical microbiology, faculty of medicine, hasanuddin university, makassar, indonesia; 4 department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia. doi: 10.4081/aiua.2025.13353 summary archivio italiano di urologia e andrologia 2025; 96(1):13353 s. syahrir, m. asykar palinrungi, m. hatta, et al. 2 association between prostatic inflammation and the development of tumors. the study involved 62 prostate samples from patients with symptoms of obstruction who were diagnosed with either pca and bph. these samples were acquired during turp procedures between april and september 2018. participants were recruited from four major hospitals in makassar: universitas hasanuddin hospital, ibnu sina hospital, awal bros hospital, and wahidin sudirohusodo hospital. the investigation was granted authorization by the institutional review board, and informed consent was gathered from all individuals prior to their participation in the study. prostate processing and histological analysis all collected prostate specimens were processed and subjected to histological analysis. hematoxylin and eosin staining was performed on all samples. a qualified pathologist examined the specimens to assess the presence and extent of inflammatory infiltrations and their aggressiveness. degree of inflammation morphological description (typical inflammatory cell density, cells/mm2) was classified as low grade (individual inflammatory cells, most of which separated by distinct intervening spaces [< 100]), moderate grade (confluent sheets of inflammatory cells with no tissue destruction or follicle formation/ lymphoid nodule [100-500]), and high grade (confluent sheets of inflammatory cells with tissue destruction or follicle/nodule formation [> 500]) (14). inflammatory aggressiveness inflammation was assessed using a 4-point scale: grade 0 indicates no interaction between glandular epithelium and inflammatory cells; grade 1 denotes contact between glandular epithelium and inflammatory cells, with minimal epithelial dissociation present; grade 2 involves interstitial inflammatory infiltration with limited glandular epithelium disruption (less than 25%); grade 3 reflects glandular epithelium disruption exceeding 25% of the examined material (15). in this study, grades 0 and 1 were classified as having no glandular disruption, and grades 2 and 3 were classified as glandular disruption groups. inflammatory location stromal inflammatory cells are located in the prostatic stroma, distant from prostatic glands. periglandular inflammatory infiltrates are centered around glands and ducts, approaching glands and ducts closely. glandular inflammatory infiltrates are found within the epithelium and/or lumens of glands and ducts (14). inflammatory markers evaluation the inflammatory cytokines fgf2, il-8, and il-6 levels in prostate samples were quantified using elisa kits from r&d systems (minneapolis, mn). the procedure followed the manufacturer’s instructions. in summary, 100 μl of each sample was added in duplicate to the wells and incubated at room temperature for 1.5 hours. subsequently, 100 μl of biotinylated antibodies was added to each well and incubated for one hour at 37°c. after this step, streptavidin-horseradish peroxidase was applied for 45 minutes, followed by a 30-minute incubation with 3,3’,5,5’tmb. the reaction was terminated with sulfuric acid, and absorbance was recorded at 450 nm using a pherastar microplate reader (bmg labtech, durham, nc). fgf2, il-8, and il-6 concentrations were quantified in ng/ml. prostate-specific antigen (psa) examination a 3 cc blood sample was taken from the vein, then centrifuged to take the blood serum. then, the blood serum was examined by the architech plus device from abbott (chicago, illinois, usa) using a monoclonal antibody psa reagent from meridian bioscience (memphis, tn, usa) with catalog #m86806m. the psa concentrations was quantified in ng/ml. statistical analysis the data were evaluated to distinguish bph from pca based on their pathological characteristics. the chi-square test was utilized to evaluate the correlation between inflammatory infiltrates and the presence of prostate diseases. to examine the association between inflammatory infiltrates and prostate diseases aggressiveness, the kruskal-wallis test was conducted. additionally, spearman correlation test was performed to determine the correlation between psa, inflammatory markers and age. a p-value of less than 0.05 was deemed statistically significant, with a confidence interval set at 95%. all statistical analyses were conducted using spss software. results baseline characteristics of patients the study included 62 prostate glands from male subjects (table 1), with 51 glands (82.3%) diagnosed as bph and 11 glands (17.7%) as prostate cancer. the average age of the patients was 69 ± 9 years, while the median volume of the glands measured 65 ± 35 cm³. inflammatory aggressiveness showed glandular disruption in 49 glands (79%) and no glandular disruption in 13 glands (21%). the mean psa level for pca was 92.16 ± 39.35. table 1. characteristics of participants. variables n (%) age (years), mean (± sd) 69 (± 9) glands benign prostate hyperplasia 51 (82.3) prostate carcinoma 11 (17.7) degree of inflammation low grade 45 (72.6) moderate grade 0 (0) high grade 17 (27.4) inflammatory aggressiveness no glandular disruption 13 (21) with glandular disruption 49 (79) psa level (ng/ml), mean (± sd) pca 92.16 (± 39.35) bph 20.54 (± 24.53) prostate volume (cc), mean (± sd) 65 (± 35) psa: prostate specific antigen; pca: prostate cancer; bph: benign prostatic hyperplasia. archivio italiano di urologia e andrologia 2025; 96(1):13353 3 the impact of inflammation on prostate tumor dynamics... pathological features of inflammation table 2 summarizes the pathological features of inflammation in the prostate glands as observed in patients with pca and bph. out of the 62 patients, 45 exhibited low-grade inflammation (low-grade inflammation was present in 34 [75.6%] bph glands and 11 [24.4%] pca glands). in contrast, all 17 cases of high-grade inflammation were found in bph glands, showing significant difference (p < 0.05). regarding inflammation location and aggressiveness, 13 glands had stromal-only inflammation (9 in bph and 4 in pca), and 49 glands had glandular involvement (42 in bph and 7 in pca). the differences in inflammation locations were not statistically significant (p > 0.05). classification and degree of inflammation figure 1 illustrates the classification and degree of inflammation. low-grade inflammation was the most prevalent pattern, characterized by a scattered infiltrate of inflammatory cells within the stroma. it was found in 34 (75.6%) bph glands and 11 (24.4%) pca glands. in contrast, high-grade inflammation, involving extensive areas of confluent infiltrate, was less common and observed in 17 (100%) bph glands. a significant correlation was observed between the degree of inflammation and prostate diseases aggressiveness (rho = 0.786, p < 0.05). high-grade inflammation was linked to glandular disruption, whereas low-grade inflammation was associated with the absence of glandular disruption. comparison of clinical data and inflammatory markers table 3 compares clinical data and inflammatory markers between patients experiencing low-grade and high-grade inflammation. patients with high-grade inflammation exhibited higher serum psa levels than those with lowgrade inflammation (114 vs. 38), this difference was statistically significant (p < 0.05). association between inflammatory markers (il-6, il-8, and fgf-2) and age with serum psa levels in table 4, no correlation was shown between the inflammatory markers (il-6, il-8, and fgf-2) and serum psa table 2. pathological features of inflammation in 62 prostate glands. variables bph pca p-value degree of inflammation low grade 34 (75.6) 11 (24.4) 0.026 moderate grade 0 (0) 0 (0) high grade 17 (100) 0 (0) inflammatory location stromal 9 (69.2) 4 (30.8) 0.22 periglandular 0 (0) 0 (0) glandular 42 (85.7) 7 (14.3) pca: prostate cancer; bph: benign prostatic hyperplasia. figure 1. degree of inflammation based on histopathological examination: a. low-grade inflammation [presence of scattered inflammatory cells (arrow)] (he staining, magnification 10x); b. high-grade inflammation [extensive areas of inflammation with the formation of lymphoid nodules (arrow)] (he staining, magnification 4x). table 4. correlation between psa, inflammatory markers and age. variable variables statistics psa il-6 correlation coefficient 0.157 p-value 0.322 il-8 correlation coefficient 0.113 p-value 0.475 fgf-2 correlation coefficient -0.077 p-value 0.630 age correlation coefficient -0.52 p-value 0.742 spearman correlation test. table 3. the comparison of clinical data and inflammatory marker between patients with low and high grade of inflammation. variable degree of inflammation p-value low grade high grade serum psa levels (ng/ml), mean (± sd) 38 (42) 114 (334) 0.992 age (years), mean (± sd) 70 (9) 66 (8.4) 0.145 prostate volume (cc), mean (± sd) 67 (36) 57 (28) 0.394 il-6 (ng/ml), mean (± sd) 382 (207) 638 (205) 0.000298 il-8 (ng/ml), mean (± sd) 99 (43) 149 (41) 0.000149 fgf-2 (ng/ml), mean (± sd) 190 (43) 94 (67) 0.000074 psa: prostate specific antigen; il-6: interleukin-6; il-8: interleukin-8; fgf: fibroblast growth factor-2. archivio italiano di urologia e andrologia 2025; 96(1):13353 s. syahrir, m. asykar palinrungi, m. hatta, et al. 4 levels (rho = 0.157, p = 0.322; rho = 0.113, p = 0.475; and rho = -0.077, p = 0. 630, respectively). additionally, serum psa levels did not show a correlation with the patients' age (rho = 0.069, p = 0.626). increased inflammatory marker concentration in prostate diseases tissue the levels of fgf2, il-8, and il-6 were measured in prostate diseases samples. patients with high-grade inflammation had significantly higher concentrations of il-6 compared to those with low-grade inflammation (638 vs. 382, p < 0.05). the mean il-6 concentration in benign tissues was recorded at 493 pg/ml, whereas in cancerous tissues, it was 264 pg/ml, indicating a significant difference (p < 0.05; figure 2). likewise, il-8 levels were found to be greater in highgrade inflammation cases compared to low-grade inflammation (149 vs. 99, p < 0.05). the mean il-8 concentration was 120 pg/ml in benign tissues and 83 pg/ml in cancer tissues (p < 0.05; figure 3). figure 2. the comparison of il-6 tissue levels between prostate diseases (p-value < 0.05). figure 3. the comparison of il-8 tissue levels between prostate diseases (p-value < 0.05). archivio italiano di urologia e andrologia 2025; 96(1):13353 5 the impact of inflammation on prostate tumor dynamics... interestingly, fgf2 concentration was higher in lowgrade inflammation compared to high-grade inflammation (190 vs. 94, p < 0.05). the mean fgf2 concentration was higher in cancer tissues compared to benign tissues (238 vs. 148, p < 0.05; figure 4). discussion chronic inflammation is associated to the development of various prostatic conditions, but the precise roles and mechanisms of inflammatory markers like fgf2, il-8, and il-6 are still not well understood. in this study, prostate samples from patients with pca and bph were examined, with a focus on inflammation presence and severity, and the concentrations of fgf2, il-8, and il-6. high-grade inflammation was found in all bph cases, but not in pca cases. elevated il-8 and il-6 levels were detected in bph tissues with high-grade inflammation, while fgf2 concentrations were significantly higher in cancerous tissues compared to benign tissues. the presence of high-grade inflammation in all bph cases and its absence in pca cases suggest a strong link between inflammation and bph pathogenesis. chronic inflammation appears to be a critical driver of hyperplastic growth in the prostate, as indicated by the elevated levels of il-8 and il-6 in inflamed tissues. this finding implies that targeting inflammatory pathways could be a potential therapeutic strategy for bph. one potential reason for the lack of significant inflammation in pca tissues is that inflammation's role in pca may be intricate and influenced by the context. in the initial phases of pca, inflammation may be a key factor in fostering carcinogenesis. however, as the cancer advances, elements like genetic mutations and epigenetic alterations may take precedence in facilitating tumor growth. according to de marzo et al., inflammation may trigger the onset of cancer, but further oncogenic developments are necessary for the progression to full malignancy (16). il-6 and il-8 levels the elevated levels of il-8 and il-6 in bph tissues highlight their significant role in promoting an inflammatory microenvironment. il-6 is known for its multifunctional role in immune response and cell proliferation, while il8 is involved in the recruitment of inflammatory cells and angiogenesis. these findings indicate that il-8 and il-6 are key mediators in the inflammatory processes contributing to bph development. the heterogeneity of inflammatory responses might also influence the overall impact of inflammation on prostate disease progression (17). as the inflammatory infiltrates in prostate tissues are heterogeneous in nature, severity, and location hence it is a possible explanation to why the elevated il-6 and il-8 are significant in bph but not uniformly present in pca tissues (17, 18). fgf2 levels the markedly elevated levels of fgf2 found in pca tissues compared to benign tissues suggest that growth factors could be more critical in the advanced stages of cancer development. fgf2 contributes to cell growth, differentiation, and angiogenesis, all of which are vital processes for tumor progression and metastasis (19). this finding suggests that fgf2 could be a potential biomarker for pca and a target for therapeutic interventions. the elevated levels of fgf2 in pca tissues support the idea that as pca progresses, growth factors like fgf2 become more critical in sustaining tumor growth and promoting metastasis (20-22). figure 4. the comparison of fgf-2 tissue levels between prostate diseases (p-value < 0.05). archivio italiano di urologia e andrologia 2025; 96(1):13353 s. syahrir, m. asykar palinrungi, m. hatta, et al. 6 inflammation’s role in bph vs pca: where are we now? in their study, inamura and terada highlighted the roles of il-8 and il-6 in benign prostatic hyperplasia (bph), explaining how these cytokines facilitate tissue remodelling and smooth muscle contraction, which can affect the progression of the disease. this finding aligns with our results, which demonstrate elevated levels of il-8 and il6 in bph tissues with marked inflammation (23). based on our observations, it seems likely that these cytokines are key players in the inflammatory process, acting as the molecular pathways through which chronic inflammation influences prostatic diseases. other research has also pointed to this, linking it to the pro-inflammatory environment created by increased levels of il-8 and il-6 (10, 24). we also found in our observation that high-grade inflammation is found predominantly in bph cases, as proposed by kramer et al. who stated bph might be an immune inflammatory disease, validating the association between inflammation and prostatic diseases. they found that inflammatory infiltrates are common in bph tissues and are associated with disease severity (24, 25). robert et al. also found that inflammatory infiltrates are common in bph tissues and are associated with disease severity (26). further reinforcing the idea that inflammation plays a crucial role in the severity and progression of bph. de marzo et al. discussed how chronic inflammation in the onset and progression of prostate cancer. they emphasized that chronic inflammation could foster a microenvironment conducive to cancer development, which aligns with our findings of increased fgf2 levels in prostate cancer tissues (16). their study suggested that inflammation could drive genetic and epigenetic changes that promote malignancy, aligning with our findings regarding the role of inflammatory markers. bridging the current gap our findings further reinforce the theory that chronic inflammation is a key factor in the development of bph. the significant association between high-grade inflammation and bph also supports the idea that targeting specific inflammatory pathways could be a potential therapeutic strategy. increased levels of il-8 and il-6 suggest these cytokines are critical mediators of the inflammatory processes driving bph, providing a deeper explanation of the disease's pathogenesis. the inflammation-driven model of disease was also proposed by as kramer et al. who suggested that bph might be fundamentally an immune inflammatory disease (25). moreover, the absence of high-grade inflammation in pca tissues, contrasted with the higher levels of fgf2, indicating that different mechanisms may be at play in pca and bph. this supports the hypothesis that while inflammation initiates bph, other factors such as growth factors like fgf2 become more critical in later stages of pca (5, 16, 27). the differential expression of fgf2, il-8, and il-6 in pca and bph and tissues has significant clinical implications. anti-inflammatory treatments targeting il-6 and il-8 may offer therapeutic benefits for patients with bph by mitigating the inflammatory processes that drive hyperplasia. for instance, agents that block il-6 signalling, such as tocilizumab, have shown efficacy in treating inflammatory diseases and might be repurposed for bph treatment (28, 29). furthermore, the elevated fgf2 levels in pca suggest that therapies aimed at inhibiting fgf2 could be more relevant for managing pca. anti-fgf2 therapies, such as the use of fgfr inhibitors, are being explored in various cancers and could potentially be adapted for pca (30). these targeted approaches could lead to more effective treatments tailored to the underlying pathophysiology of each condition (31). overall, our findings suggest that a dual approach targeting both inflammation and growth factors might be necessary to effectively manage prostatic diseases, aligning with the multiple approaches for the treatment strategies proposed by recent clinical (31, 32). a limitation of this study is that it included only 62 prostate glands, with 51 diagnosed with bph and 11 with pca. this relatively small sample size may limit the generalizability of the findings to a broader population. the study found no high-grade inflammation in pca tissues, which raises questions about the role of inflammation in the later stages of cancer. this absence may indicate that other factors, such as genetic mutations, play a more significant role in pca progression, but the study does not explore these factors in depth. conclusions this study deepens our understanding of the distinct roles of fgf2, il-8, and il-6 in pca and bph. a significant correlation was observed between high-grade inflammation and bph, characterized by increased levels of il-8 and il-6, while such inflammation was not present in pca tissues. conversely, fgf2 levels were found to be notably elevated in pca tissues. these findings suggest different pathogenic mechanisms in bph and pca, with growth factors like fgf2 becoming more prominent in cancer progression. future studies should focus on longitudinal designs to clarify the causal correlation between inflammation and prostate disease progression. investigating the molecular mechanisms underlying the differential expression while exploring other inflammatory cytokines. conducting multicenter studies could be highly beneficial for several reasons: multicenter studies can recruit participants from various geographical locations and demographics, leading to a more diverse patient population. this diversity can help ensure that the findings are generalizable across different groups, which is crucial for understanding the broader implications of inflammation in prostate diseases. researchers can significantly increase the sample size by pooling data from multiple centers. a larger sample size enhances the study's statistical power, allowing for more robust conclusions regarding the associations between inflammatory markers and prostate conditions. references 1. tang j, yang j. etiopathogenesis of benign prostatic hypeprlasia. indian j urol. 2009; 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participants were performed in accordance with the ethical standards of the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent was obtained from all participants included in the study. availability of data and material: the datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. competing interests: the authors declare that they have no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not forprofit sectors. authors' contributions: all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 96(1):13353 s. syahrir, m. asykar palinrungi, m. hatta, et al. 8 31. schaeffer em, srinivas s, adra n, et al. prostate cancer, version 3.2024 featured updates to the nccn guidelines. j natl compr canc netw. 2024; 22:140-150. 32. schaeffer e, srinivas s, antonarakis es, et al. nccn guidelines insights: prostate cancer, version 1.2021. j natl compr canc netw. 2021; 19:134-143. correspondence syakri syahrir (corresponding author) drsyakrisyahrir@gmail.com division of urology, department of surgery, faculty of medicine, hasanuddin university dr. wahidin sudirohusodo hospital, makassar, indonesia jalan perintis kemerdekaan km 11, makassar, 90245, south sulawesi, indonesia muhammad asykar palinrungi apalinrungi@yahoo.com khoirul kholis khoirulkholis@yahoo.com syarif syarif syarifbakri@unhas.ac.id abdul azis abdul.azis031@gmail.com division of urology, department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia mochammad hatta hattaram@yahoo.com department of clinical microbiology, faculty of medicine, hasanuddin university, makassar, indonesia muhammad faruk muhammadfaruk@unhas.ac.id department of surgery, faculty of medicine, hasanuddin university, makassar, indonesia stesura seveso archivio italiano di urologia e andrologia 2024; 96(2):12387 1 original paper fournier’s gangrene severity index (sfgsi), laboratory risk indicator for necrotizing fasciitis (lrinec), neutrophil-tolymphocyte ratio (nlr), and platelet-to-lymphocyte ratio (plr), have been formulated to estimate the mortality risk in fg patients (2-6). these predictive instruments are invaluable for healthcare professionals, especially urologists and surgeons, as they enable the initiation of more aggressive interventions at an early stage. some of these indicators, engineered for ease of use and practicality, rely solely on laboratory data (sfgsi, lrinec, nlr, and plr), while others are more sophisticated, amalgamating both laboratory and clinical data (fgsi and ufgsi). in the quest for an indicator that harmonizes precision and simplicity, a comparative evaluation of these indicators is indispensable. however, the sensitivity and specificity of these scoring systems remain undetermined. this study seeks to assess the efficacy of fgsi, ufgsi, sfgsi, lrinec, nlr, and plr at the point of admission in forecasting mortality outcomes in fg patients. materials and methods a retrospective cross-sectional study from january 2014 to december 2020 was conducted following approval from the hospital review board (no. 0528/loe/301.4.2/vii/ 2021). the study included all patients with fg admitted to dr. soetomo hospital. patient data was retrieved from the hospital's electronic medical records system. all participants provided written informed consent for the use of their clinical information for research purposes. the study included patients diagnosed with fg by a urologist, excluding those with incomplete data. scoring was done at admission, reflecting the emergency assessment when the patient arrived at the hospital. if a patient had test results from another healthcare institution, these tests were repeated. the data examined included demographics (age, sex, etiology, comorbidities, and wound culture results) and parameters (fgsi, ufgsi, sfgsi, lrinec, plr, and nlr). participants were segregated into two categories: those who survived and those who did not. a comparative analysis was conducted between these groups conbackground: fournier's gangrene scoring index (fgsi), simplified fgsi (sfgsi), uludag fgsi (ufgsi), laboratory risk indicator for necrotizing (lrinec), neutrophil-lymphocyte ratio (nlr), and platelet-lymphocyte ratio (plr) have been devised to assess the risk of mortality in fournier's gangrene (fg) patients. however, the effectiveness of these indicators in predicting mortality at the time of admission remains uncertain. the aim of this study is to assess the prognostic efficacy of fg’s various indicators on in-hospital mortality. methods: this study analyzed 123 patients from dr. soetomo general hospital’s emergency department in indonesia from 2014 to 2020. data included demographics, wound cultures, and parameters like fgsi, ufgsi, sfgsi, nlr, plr, and lrinec. in-hospital mortality status was also recorded. the data was subjected to comparative, sensitivity, specificity and regression analyses. results: in our study of 123 patients, the median age was 52, with a mortality rate of 17.9%. the majority of patients were male (91.1%) and the most common location was scrotal (54.5%). non-survivors had a shorter median stay (6.5 days) compared to survivors (14 days). diabetes was the most prevalent comorbidity (61.8%). the highest sensitivity and specificity were found in fgsi and ufgsi indicators. multivariate logistic regression identified los and fgsi as independent predictors of mortality. conclusions: fgsi and ufgsi, upon admission, demonstrated the highest sensitivity and specificity, with hospital stay duration and fgsi as key mortality determinants. key words: fournier's gangrene; indicator; neutrophil/lymphocyte ratio (nlr); platelet to lymphocit ratio. submitted 14 january 2024; accepted 19 february 2024 introduction despite significant strides in technological advancement, fournier’s gangrene (fg) continues to pose a formidable challenge with mortality rates oscillating between 5% and 65% (1). an array of prognostic indicators, encompassing fournier’s gangrene severity index (fgsi), uludag fournier’s gangrene severity index (ufgsi), simplified evaluating prognostic indicators for in-hospital mortality in fournier's gangrene: a 7-year study in a tertiary hospital soetojo wirjopranoto 1, 2*, mohammad reza affandi 1*, faisal yusuf ashari 3, 4, yufi aulia azmi 2, 5, kevin muliawan soetanto 6 1 faculty of medicine, universitas airlangga, surabaya, indonesia; 2 department of urology, faculty of medicine, universitas airlanggadr. soetomo general academic hospital, surabaya, indonesia; 3 department of biomedical sciences, faculty of medicine universitas airlangga, surabaya, indonesia; 4 faculty of biology, medicine and health, university of manchester, manchester, united kingdom; 5 department of health sciences, university of groningen, university medical center groningen, groningen, netherlands; 6 department of immunology, faculty of medicine siriraj hospital, mahidol university, bangkok, thailand. * these authors equally contributed as first co-authors. doi: 10.4081/aiua.2024.12387 summary archivio italiano di urologia e andrologia 2024; 96(2):12387 s. wirjopranoto, m. reza affandi, f. yusuf ashari, y. aulia azmi, k. muliawan soetanto 2 cerning demographic information and scoring. the fgsi, ufgsi, sfgsi, lrinec, nlr, and plr were calculated using various parameters (5, 7, 8). statistical analysis group comparisons were performed using chi-square and mann whitney u test as appropriate. the area under the receiver operating characteristic (roc) curve was used to assess sensitivity and specificity, and the youden index was used to determine the optimal cutoff value. multivariable logistic regression models were constructed using the stepwise backward lr method. a significance level of p < 0.05 was considered statistically significant. data analyses were performed using ibm spss statistics for windows version 24.0 (ibm corp., armonk, ny, usa). results throughout the period under investigation, spanning from january 2014 to december 2020, the emergency department received a total of 135 patients with fg. however, the analysis only incorporated 123 patients (figure 1). the patients had a median age of 52 (44-61), and the mortality rate was recorded at 17.9%. the study population was predominantly male (91.1%), and the most common location was scrotal (54.5%). non-survivors had a shorter median duration of stay compared to survivors, with lengths of 6.5 (3-14) days and 14 (7-21) days, respectively (table 1). diabetes was identified as the most prevalent comorbidity, present in 61.8% of patients. table 1. prognostic correlation with demographic and clinical features. variable total survivor non-survivor p value 101 (82.1%) 22 (17.9%) age 52 (44-61) 52 (44-60) 55.5 (44-63) 0.328 sex male 112 (91.1%) 93 (92.1%) 19 (86.4%) 0.413 female 11 (8.9%) 8 (7.9%) 3 (13.6%) etiology penoscrotal 18 (14.6%) 16 (15.8%) 2 (9.1%) 0.714 perineum 38 (30.9%) 31 (30.7%) 7 (31.8%) scrotum 67 (54.5%) 54 (53.5%) 13 (59.1%) los 12 (5-20) 14 (7-21) 6.5 (3-14) 0.009 comorbidities diabetes mellitus 76 (61.8%) 65 (64.4%) 11 (50.0%) 0.23 hypertension 31 (25.2%) 29 (28.7%) 2 (9.1%) 0.06 chronic kidney disease 11 (8.9%) 8 (7.9%) 3 (13.6%) 0.41 *los = length of stay. figure 1. algorithm for the inclusion and exclusion of patients. figure 2. the roc curve for fgsi, sfgsi, nlr, plr, and lrinec. the microorganisms most frequently encountered in our study population were pseudomonas spp., klebsiella pneumonia, e. coli, and acinetobacter spp. (table 2). as illustrated in figure 2, the roc analysis unveiled cutoff values (sensitivity, specificity) for fgsi, sfgsi, ufgsi, nlr, plr, and lrinec predicting mortality as follows: 9 (100%, 83.2%), 2.5 (50%, 74.3%), 10.5 (100%, 83.2%), 7.5 (95.5%, 47.5%), 264.69 (68.2%, 57.4%), and 3.5 (50%, 56.4%), respectively. to identify independent predictors of mortality, a multivariate logistic regression analyarchivio italiano di urologia e andrologia 2024; 96(2):12387 3 prognostic indicators of fournier's gangrene sis was conducted, including variables that were significantly associated with mortality in the univariate analysis (p < 0.05) (table 3). among these variables, only length of stay (los) and fgsi remained significant predictors of mortality in the multivariate analysis (table 4). discussion during the study interval, it was observed that the majority of patients were male, with the scrotum being the most frequent site of origin. the length of hospital stay, prevalence of diabetes, and incidence of pseudomonas spp. were also noteworthy among patients. an analysis of sensitivity, specificity, and independent risk factors for mortality revealed that both fgsi and ufgsi demonstrated the highest sensitivity and specificity. furthermore, the length of hospital stay and fgsi were identified as independent prognostic value. despite significant advancements, the mortality associated with fg remains alarmingly high (9-11). our study, conducted at a tertiary hospital in indonesia's secondlargest city, yielded a mortality rate of 17.9%, which could be attributed to the availability of advanced medical facilities and expertise. notably, the demographics between groups were comparable, with the exception of los, which was significantly lower among non-survivors. in this study, we investigated established indicators employed at admission to predict fg mortality, including fgsi, sfgsi, nlr, plr, and lrinec. fgsi, recognized as the earliest and most frequently utilized indicator, is designed to assess the likelihood of mortality in fg patients (12). our findings indicated that individuals who did not survive exhibited elevated fgsi values compared to those who did. the optimal cut-off for fgsi, along with its sensitivity and specificity, was identified as 9, 100%, and 83.2%, respectively. these results outperformed those of previous studies, which reported sensitivity range of 69% to 100% and specificity range of 57% to 97% (4, 7, 13). the established cut-off of 9 at admission aligns with the accepted threshold for mortality prediction. therefore, fgsi with this recognized cut-off can be effectively utilized for early assessment and aggressive intervention. an analysis of the sfgsi, a simplified version of the fgsi that utilizes only three variables, revealed no differences between groups. the optimal cut-off, sensitivity, and specificity for sfgsi were determined to be 2.5, 50%, and 74.3%, respectively. the cut-off was similar to the consensus, which considered values above 2 as indicating a high risk of mortality (4). however, the reliability of sfgsi on admission to predict mortality in fg patients could not be confirmed. the ufgsi, a version of fgsi that includes age and disease extent, was studied. ufgsi values were found to be table 2. findings from the wound culture analysis. variable total survivor non-survivor p value acinetobacter 18 (14.6%) 13 (12.9%) 5 (22.7%) 0.31 candida 6 (4.9%) 3 (3.0%) 3 (13.6%) 0.07 e.coli 18 (14.6%) 15 (14.9%) 3 (13.6%) 1.00 pseudomonas 23 (18.7%) 19 (18.8%) 4 (18.2%) 1.00 clostridium 5 (4.1%) 4 (4.0%) 1 (4.5%) 1.00 streptococcus 4 (3.3%) 4 (4.0%) 0 (0.0%) 1.00 streptococcus bovis 1 (0.8%) 1 (1.0%) 0 (0.0%) 1.00 fusobacterium 11 (8.9%) 8 (7.9%) 3 (13.6%) 0.41 staphylococcus 3 (2.4%) 3 (3.0%) 0 (0.0%) 1.00 gamella 1 (0.8%) 1 (1.0%) 0 (0.0%) 1.00 klebsiella p 20 (16.3%) 18 (17.8%) 2 (9.1%) 0.52 sterile 13 (10.6%) 12 (11.9%) 1 (4.5%) 0.46 table 3. evaluation of the predictive capacity of fgsi, sfgsi, ufgsi, nlr, plr, and lrinec through univariate analysis. variable total survivor non-survivor p value fgsi 6 (4-10) 5 (4-8) 10.5 (10-11) 0.0001 sfgsi 1 (0-3) 1 (0-3) 2.5 (0-4) 0.085 ufgsi 8 (5-11) 7 (5-9) 12 (11-13) 0.0001 nlr 10 (4-16) 8 (4-15) 13 (10-19) 0.008 plr 252.53 243.53 289.035 0.611 (164.62-358.97) (164.62-359.85) (165.07-358.65) lrinec 3 (2-5) 3 (2-5) 3.5 (2-5) 0.859 table 4. outcomes of the multivariate logistic regression analysis. variable β se or (95% ci) p value los -0.105 0.039 0.9 (0.83-0.97) 0.008 fgsi 0.618 0.127 1.856 (1.45-2.38) 0.0001 supplementary table 1. measured parameters and cut-off score of each scoring system from the literature. scoring system number of parameters parameters cut-off score fgsi 9 temperature, heart rate, respiratory rate, serum sodium, potassium, serum creatinine, hematocrit, leucocyte counts, and serum bicarbonate > 9 (13) ufgsi 11 age and dissemination score in addition to the measured parameters from fgsi ≥ 9 (7) sfgsi 3 serum creatinine, hematocrit, and serum potassium > 2 (4) nlr 1 the ratio was calculated by dividing the number of neutrophils by the number of lymphocytes. > 8 (14) plr 1 the ratio was calculated by dividing the number of platelets by the number of lymphocytes. > 140 (14) lrinec 6 c-reactive protein, white blood cell counts, hemoglobin, serum sodium, serum creatinine, and blood glucose ≥ 6 (17) fgsi: fournier’s gangrene severity index; ufgsi: uludag fournier’s gangrene severity index; sfgsi: simplified fournier’s gangrene severity index; nlr: neutrophil-to-lymphocyte ratio (nlr); plr: platelet-to-lymphocyte ratio (plr); lrinec: laboratory risk indicator for necrotizing fasciitis. archivio italiano di urologia e andrologia 2024; 96(2):12387 s. wirjopranoto, m. reza affandi, f. yusuf ashari, y. aulia azmi, k. muliawan soetanto 4 higher in non-survivors. the optimal cut-off, sensitivity, and specificity for ufgsi were identified as 10.5, 100%, and 83.2%, respectively. these values were similar to those of the fgsi. while previous research suggested that ufgsi performs better than fgsi, the difference in our findings could be due to the lack of pelvic and beyond involvement in our study population (3). nlr and plr have been used as mortality predictors in fg patients in previous studies (5, 6, 14). high nlr and plr have been linked with mortality predictors in fg patients (5, 14). one study found nlr and plr to be better than fgsi (14), while another found nlr to be better than plr (6). however, our study showed significantly higher nlr levels in non-survivors compared to survivors. despite this, neither nlr nor plr predicted inhospital mortality in our study. nlr and plr are known markers of inflammation and infection (15). the divergence in results suggests that nlr and plr may be influenced by the disease phase, whether acute or chronic, a distinction challenging to ascertain in a tertiary hospital setting primarily consisting of referred patients (16). the lrinec score, which overlaps with fgsi in some variables, is a laboratory-centric indicator employed to evaluate mortality in patients suffering from fg. while certain studies have identified a significant correlation between elevated lrinec scores and mortality (5, 17), our research did not discern a notable difference between survivors and non-survivors, nor could it prognosticate in-hospital mortality for fg. these findings may be profoundly influenced by the specific laboratory equipment utilized and the disease’s stage at the time of examination. given the inconsistent results obtained using laboratorybased indicators like sfgsi, lrinec, nlr, and plr, employing a scoring system (fgsi and ufgsi) at the time of admission could potentially provide a more accurate prediction of mortality for fg patients. despite its strengths, this study has certain limitations. first, it utilized a retrospective design, which restricted to influence the laboratory blood draws. second, the study analysed data from a single tertiary referral center, potentially leading to a sample population skewed towards more severe cases. thirdly, each patient may have been in a distinct disease stage upon admission, given our hospital's tertiary status and frequent intake of referred patients. lastly, despite the confirmation of all fg cases through a thorough review of medical and surgical records, some positive cases might have been missed due to the absence of comprehensive retrospective records. future prospective studies involving multiple centers are imperative to identify the most sensitive parameters for predicting patient mortality. conclusions in this study, it was observed that fgsi and ufgsi showed the highest sensitivity and specificity among the current indicators upon admission. the duration of hospital stay and fgsi were recognized as independent determinants of mortality. these indicators could potentially offer a more accurate prediction of mortality. however, it is essential to exercise caution when interpreting laboratory-only indicators in a tertiary hospital setting due to possible biases arising from disease stage. to validate these results, a multicenter prospective study is recommended. this would aid in verifying the reliability and applicability of these indicators across various settings and patient demographics. acknowledgments all medical recors staff’s of soetomo general academic hospital and faculty of medicine, universitas airlangga. references 1. sorensen md, krieger, jn, rivara fp, et al. fournier's gangrene: management and mortality predictors in a population based study. j urol 2009; 182:2742-2747. 2. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier's gangrene. j urol 1995; 89-92. 3. yilmazlar t, ozturk e, ozguc h, et al. fournier's gangrene: an analysis of 80 patients and a novel scoring system. tech coloproctol 2010; 14:217-223. 4. lin ty, ou ch, tzai ts, et al. validation and simplification of fournier's gangrene severity index. int j urol 2014; 21:696-701. 5. bozkurt o, sen v, demir o, esen a. evaluation of the utility of different scoring systems (fgsi, lrinec and nlr) in the management of fournier’s gangrene. int urol and neph 2015; 47:243-248. 6. wirjopranoto s. comparison between neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as predictors of mortality on fournier's gangrene cases. indian j urol 2023; 39:121-125. 7. ureyen o, acar a, gokcelli u, et al. usefulness of fgsi and ufgsi scoring systems for predicting mortality in patients with fournier's gangrene: a multicenter study. ulus travma acil cerrahi derg 2017; 23:389-394. 8. tutino r, colli f, rizzo g, et al. which role for hyperbaric oxygen therapy in the treatment of fournier's gangrene? a retrospective study. front surg 2022; 9:850378. 9. rieger c, huber m, kastner l, et al. center-based first-line therapy is a significant predictor for mortality of fournier gangrene. ju open plus 2023; 1. 10. bermani bf, rizaliyana s, handriani i. predisposition factors analysis for fournier’s gangrene defects closure complication. j rekon est 2021; 5:13 11. radcliffe rs, khan ma. mortality associated with fournier's gangrene remains unchanged over 25 years. bju int 2020; 125:610616. 12. laor e, palmer ls, tolia bm, et al. outcome prediction in patients with fournier's gangrene. j urol 1995; 154:89-92. 13. noegroho bs, siregar s, mustafa a, rivaldi ma. validation of fgsi scores in predicting fournier gangrene in tertiary hospital. res rep urol 2021; 13:341-346. 14. yim su, kim sw, ahn jh. et al. neutrophil to lymphocyte and platelet to lymphocyte ratios are more effective than the fournier's gangrene severity index for predicting poor prognosis in fournier's gangrene. surg infect 2016; 17:217-223. 15. kosidlo jw, wolszczak-biedrzycka b, matowicka-karna j, et al. clinical significance and diagnostic utility of nlr, lmr, plr and sii in the course of covid-19: a literature review. j inflamm res 2023; 16:539-562. archivio italiano di urologia e andrologia 2024; 96(2):12387 5 prognostic indicators of fournier's gangrene 16. kose n, yildirim t, akin f, et al. can nlr, plr and lmr be used as prognostic indicators in patients with pulmonary embolism? author's reply on commentary. bosn j basic med sci 2021; 21:502. 17. kincius m, telksnys t, trumbeckas d, et al. evaluation of lrinec scale feasibility for predicting outcomes of fournier gangrene. surg infect 2016; 17:448-453. correspondence prof. soetojo wirjopranoto, md (corresponding author) stjowirjopranoto@gmail.com department of urology, faculty of medicine, universitas airlangga dr. soetomo general academic hospital, surabaya, indonesia mohammad reza affandi, md rezaaffandi@outlook.com faculty of medicine, universitas airlangga, surabaya, indonesia faisal yusuf ashari, md faisal.ashari@postgrad.manchester.ac.uk department of biomedical sciences, faculty of medicine universitas airlangga, surabaya, indonesia jl. mayjen prof. dr. moestopo no.6-8, surabaya, east java, indonesia, 60286 faculty of biology, medicine and health, university of manchester, manchester, uk yufi aulia azmi, md yufiazmi@gmail.com; y.aulia.azmi@umcg.nl department of urology, faculty of medicine, universitas airlangga dr. soetomo general academic hospital, surabaya, indonesia department of health sciences, university of groningen, university medical center groningen, groningen, netherlands kevin muliawan soetanto, md kmskevinmuliawan@gmail.com department of immunology, faculty of medicine siriraj hospital, mahidol university, bangkok, thailand conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14296 1 original paper disorders, and a consequent reduction in quality of life (6-8). benign prostatic hyperplasia (bph) is one of the most prevalent conditions in aging men, with a significant impact on the quality of life and often significant lower urinary tract symptoms (luts), impaired voiding efficiency, and associated complications such as acute or chronic urinary retention and recurrent urinary tract infections (utis). surgical management is recommended when conservative or pharmacological treatments fail (5). the transurethral resection of the prostate (turp) has historically represented the gold standard. over the last years, endoscopic enucleation techniques using different energy sources (holmium, thulium, green laser, diode lasers) are progressively replacing turp in the management of medium and large prostates (9-13). in parallel, the last decades have also witnessed the incredibly rapid expansion of robotic surgery, progressing up to single-site platforms, which now provide additional minimally invasive options for the surgical management of bph (14, 15). however, one of the main issues of endoscopic enucleation of the prostate is the significant risk of loss of antegrade ejaculation, reported in up to 70% of patients after some endoscopic procedures (16, 17). the ejaculatory dysfunction has a substantial impact on patients’ sexual satisfaction and quality of life. the fear of postoperative sexual side effects is one of the leading reasons why many men delay or refuse surgical intervention for bph. in the contemporary medical practice, which is patient-centered, techniques that ensure both effective relief of obstruction and preservation of sexual function are increasingly demanded. the leonardi ejaculation-sparing technique (lest), previously described in 2019 (18), was specifically developed to preserve the anatomical structures involved in the ejaculatory mechanism, including the verumontanum, genital sphincter, and selected bladder neck fibers, allowing, at the same time, complete adenoma enucleation using diode laser and a dedicated fiber (twister). initial feasibility reports suggested promising results, with high rates of preservation of antegrade ejaculation without compromising voiding outcomes. however, evidence introduction: benign prostatic hyperplasia (bph) significantly impairs quality of life and may lead to complications such as urinary retention and recurrent infections. while endoscopic enucleation techniques provide effective relief, they are frequently associated with loss of antegrade ejaculation. the leonardi ejaculation-sparing technique (lest) was developed to preserve ejaculatory function during diode laser enucleation of the prostate (dilep). methods: we conducted an observational, retrospective analysis of 99 men undergoing dilep with lest between january 2018 and june 2020. inclusion criteria were symptomatic bph refractory to medical therapy, prostate volume ≥ 40 ml, and suitability for endoscopic surgery. functional outcomes (ipss, qmax, pvr), erectile function (iief-5), and ejaculatory status (mshqejd) were assessed preoperatively and at 6 months. patient satisfaction was evaluated with a dedicated 5-item questionnaire. results: mean age was 48.1 years, and median prostate volume was 67 ml. at 6 months, ipss decreased from 21.6 to 3.8, qmax improved from 9.1 to 25.7 ml/s, and pvr decreased from 103 to 6.8 ml (all p < 0.01). erectile function showed modest improvement (iief-5: 14.4 to 16.2; p < 0.01). antegrade ejaculation was preserved in 94.1% of patients. satisfaction was high, with > 80% willing to repeat the procedure and denying regret. no major complications occurred. conclusions: dilep with lest provides excellent functional results with high rates of ejaculatory preservation and patient satisfaction. this technique may represent a patient-centered alternative for bph surgery, especially in younger men prioritizing sexual function. key words: dilep; bph; ejaculation sparing surgery; antegrade ejaculation; prostate. submitted 1 september 2025; accepted 3 september 2025 introduction the management of prostatic diseases, whether malignant (1-3) or benign (4, 5), medical or surgical, is not only crucial for reduce urinary symptoms and the related complications but also has a significant impact on men’s sexual health, often leading to erectile dysfunction, ejaculatory diode laser enucleation prostate for benign prostatic hyperplasia: outcomes of the leonardi ejaculation sparing technique rosario leonardi 1, guglielmo mantica 2, francesca ambrosini 3, antonio tufano 4, gabriele iacona 5, alessandro calarco 4 1 department of medicine and surgery, university of enna "kore", enna, italy; 2 department of surgical and diagnostic integrated sciences (disc), university of genoa, genoa, italy; 3 irccs san martino polyclinic hospital, genoa, italy; 4 department of urology, san carlo di nancy hospital, rome, italy; 5 casa di cura musumeci gecas, gravina di catania (ct), italy. doi: 10.4081/aiua.2025.14296 summary archivio italiano di urologia e andrologia 2025; 97(3):14296 r. leonardi, g. mantica, f. ambrosini, et al. 2 is still limited, particularly in men with very large middle lobes and very high-volume prostates, where surgical dissection is more challenging and the risk of functional impairment is higher. in this light, the aim of the present study is to report the outcomes of a larger size cohort of men undergoing diode laser enucleation with the lest approach. we aimed to evaluate standard functional outcomes but also ejaculatory preservation and patient-reported satisfaction at 6 months, using a dedicated questionnaire. this represents one of the largest and most comprehensive cohorts of lest-treated patients reported to date, providing important insights into the feasibility, safety, and patient-centered value of this novel approach. materials and methods study design and patients’ selection this was an observational, retrospective study based on prospectively collected data of patients undergoing diode laser enucleation of the prostate using the lest between january 2018 and june 2020. inclusion criteria for lest were: men with symptomatic bph refractory to medical therapy, prostate volume ≥ 40 ml, and suitability for endoscopic surgical management. exclusion criteria included: prior prostate or urethral surgery, known prostate cancer, neurogenic bladder dysfunction, or incomplete follow-up data at 6 months. all patients included were highly motivated to undergo a procedure with the potential advantage of preserving antegrade ejaculation. they were informed, however, that the technique could not guarantee complete (100%) preservation of ejaculation (19). preoperatively, all patients underwent a psa assessment. while in the past elevated psa levels might have led to non-invasive testing such as pca3 3 or even random biopsy, current practice involves routine multiparametric mri. in cases where cancer was suspected, a targeted fusion biopsy was performed prior to surgery. surgical technique and equipment all interventions were carried out by a single experienced surgeon (r.l.), with extensive expertise in laser prostate surgery. the procedures were performed using a highpower diode laser platform with dual wavelengths (980 and 1470 nm) in combination with dedicated “twister” quartz contact fibers, specifically designed to allow precise tissue vaporization and enucleation while minimizing collateral damage to ejaculatory structures. the standard lest technique has been performed (19). outcomes and follow-up preoperative assessment included general data such as age, prostate-specific antigen (psa), prostate volume (measured by ultrasound), maximum urinary flow rate (qmax), post-void residual urine volume (pvr), international prostate symptom score (ipss), and erectile function assessed with the 5-item international index of erectile function (iief-5). ejaculatory function was assessed using the mshq-ejd short form. at 6-month follow-up, the same functional outcomes were reassessed, including ipss, qmax, pvr, iief-5, and ejaculatory status. prostate volume reduction was also recorded (measured by ultrasound). in addition, patient-reported satisfaction was evaluated using a dedicated 5-item decisional satisfaction questionnaire (see supplementary file). patient satisfaction questionnaire the questionnaire explored agreement or disagreement with five key statements regarding surgical decision-making and postoperative outcomes, using a 5-point likert scale (from “strongly agree” to “strongly disagree”). items included willingness to repeat the procedure, absence of regret, and perceived benefits versus harms. statistical analysis continuous variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate. comparisons between preoperative and postoperative outcomes were performed using paired t-tests or wilcoxon signed-rank tests, depending on data distribution. categorical variables were summarized as frequencies and percentages, and differences were assessed with the χ² or fisher’s exact test. a p-value < 0.05 was considered statistically significant. statistical analyses were performed using spss v.25 (ibm corp., armonk, ny, usa). results a total of 99 patients were included in the study. the mean age was 48.1 ± 3.5 years, reflecting a relatively young surgical population, and therefore a group in which preservation of sexual function may be particularly relevant. the median prostate volume was 67 ml [57.578.5], with a mean of 68.2 ± 17.6 cc. mean psa was 2.2 ± 1.4 ng/ml. at baseline, patients presented with a high symptom burden, as reflected by a mean ipss of 21.5 ± 5.1, low qmax (9.1 ± 2.8 ml/s), and significant pvr (102.3 ± 46.1 ml). the baseline erectile function assessed with iief-5 averaged 14.4 ± 5.5 (table 1). at a median follow-up of 6 months, all functional outcomes demonstrated marked improvement. ipss decreased from 21.6 to 3.8 (p < 0.01), reflecting a substantial reduction in luts. qmax improved almost threefold from 9.1 to 25.7 ml/s (p < 0.01). pvr decreased dratable 1 descriptive characteristics of 99 patients who underwent lest between january 2018 and june 2020. parameter cohort (n = 99) age at surgery (yr), mean ± sd 48.1 ± 3.5 bmi (kg/cm2), median (iqr) 25.5 (24, 28) psa level (ng/ml), mean ± sd 2.2 ± 1.4 prostate volume (ml), median (iqr) 67 (57.5-78.5) preoperative ipss, mean ± sd 21.5 ± 5.1 preoperative iief-5, mean ± sd 14.4 ± 5.5 qmax (ml/s), mean ± sd 9.1 ± 2.8 pvr (ml), mean ± sd 102.3 ± 46.1 archivio italiano di urologia e andrologia 2025; 97(3):14296 3 laser enucleation prostate with ejaculation sparing technique matically from 103 to 6.8 ml (p < 0.01), indicating effective bladder emptying (table 2, figures 1-3). these improvements were not only statistically significant but also clinically meaningful, with the majority of patients reaching values within the normal or near-normal range. regarding sexual function, the iief-5 scores increased modestly but significantly, from 14.4 to 16.2 (p < 0.01), suggesting stability or mild improvement in erectile function. importantly, antegrade ejaculation was preserved in 94.1% of the 85 patients with available data. figure 1. box plot showing the distribution of international prostate symptom score (ipss) values before and 6 months after surgery. figure 2. box plot of postvoid residual urine volume (pvr) at baseline and 6 months after surgery. pvr decreased markedly following the procedure. table 2. functional results of 99 patients who underwent lest between january 2018 and june 2020 at a median follow up of 6 months. parameter cohort (n = 99) p value* 6 months ipss, mean ± sd 3.8 ± 3.1 < 0.01 6 months iief-5, mean ± sd 16.2 ± 4.5 < 0.01 qmax (ml/s), mean ± sd 25.7 ± 3.1 < 0.01 pvr (ml), mean ± sd 6.8 ± 10.3 < 0.01 archivio italiano di urologia e andrologia 2025; 97(3):14296 r. leonardi, g. mantica, f. ambrosini, et al. 4 responses to the 5-item decisional satisfaction questionnaire demonstrated consistently high satisfaction levels. over 80% strongly agreed that they had made the right choice and would undergo the procedure again, while nearly all denied regret or harm from the decision. specifically, for the statement “i would make the same choice”, 78.4% strongly agreed and 20.7% agreed. for negatively framed items such as “i regret my choice” and “the choice caused me damage”, approximately 80% of patients strongly disagreed. collectively, these findings highlight that the combination of functional efficacy and ejaculatory preservation translated into exceptionally high patient-perceived value. although detailed perioperative morbidity data were limited, the overall safety profile was favorable. no transfusions or re-interventions were required, and minor complications were rare, consistent with the expected profile of diode laser enucleation. discussion the present study demonstrates that diode laser enucleation using the lest provides excellent functional outcomes while achieving great preservation of antegrade ejaculation and very high patient satisfaction. the improvement in ipss, qmax, and pvr observed in this series is comparable to results historically reported for holep, thulep, greenlep in medium-large prostates (20-23). for example, large multicenter holep series have reported ipss reductions of about 17-20 points and qmax increases of 12-16 ml/s at 6-12 months (24-25). our improvements (ipss -18, qmax +16.5 ml/s, pvr -95 ml) fall squarely within these ranges, supporting the efficacy of the lest approach. crucially, this suggests that sparing key anatomical structures does not compromise the deobstructive effect of the surgery. conventional endoscopic enucleation is associated with rates of retrograde ejaculation > 70%, largely due to disruption of the ejaculatory hood, bladder neck fibers, and verumontanum. 16-18 this adverse effect, although not directly harmful, may significantly reduce patient satisfaction, particularly in young men. many strategies to mitigate this problem have been described, including “ejaculation hood sparing” turp and modified holep techniques, with high reported ejaculatory preservation rates. some of these approaches have consistently achieved rates > 80% (26-31). in our cohort, preservation reached 94.1% among respondents, a significant result that underscores the technical validity of lest. this outcome is particularly relevant given the relatively young mean age of our patients, highlighting the role of lest in a population with high expectations for preserved sexual function. the importance of patient satisfaction is of mandatory importance. increasingly, surgical success is defined not only by objective functional metrics but also by alignment with patient priorities. in our series, decisional satisfaction was extremely high, with most patients affirming they made the right choice and would repeat the procedure. the congruence between objective functional efficacy and subjective patient satisfaction strengthens the external validity of the findings. our results suggest that lest maintains the favorable safety profile of diode laser enucleation, with very low perioperative morbidity and no transfusion requirement. although complication details were limited, the absence of major adverse events further supports the feasibility of the technique. in order to optimize surgical outcomes, particularly the preservation of antegrade ejaculation, it is essential for surgeons to gain a thorough understanding of the prostatic anatomy and the genital sphincter complex. adequate anatomical knowledge allows precise dissection while minimizing the risk of functional compromise. to achieve this level of proficiency, structured training on synthetic models and cadaveric dissection should be undertaken figure 3. box plot illustrating maximum urinary flow rate (qmax) before and after surgery. archivio italiano di urologia e andrologia 2025; 97(3):14296 5 laser enucleation prostate with ejaculation sparing technique before performing such procedures independently on patients, thereby ensuring both safety and functional preservation (32-35). this study is not without limitations. its retrospective design, despite prospective data collection, introduces inherent biases. the absence of a control group undergoing standard procedures or other ejaculation-sparing technique precludes direct comparison of ejaculation rates and functional improvements. the follow-up period of 6 months, while adequate to assess early outcomes, is relatively short; durability of the antegrade ejaculation beyond 1-2 years remains to be demonstrated. in addition, questionnaire response rates were incomplete for some items, and the mshq-ejd was underutilized, limiting detailed assessment of sexual function domains. the size is based on a single surgeon, highly expert for this procedure, therefore, his results may be reproducible by every surgeon after an adequate learning curve. all advanced surgery techniques (robot assisted simple prostatectomy, lest, etc.) require a learning curve to get the best out of the technique used. furthermore, in some settings, the culture traditionally tied to values of masculinity, virility, and modesty persists. this may translate into greater difficulty in admitting sexual problems such as erectile dysfunction, reduced libido, or ejaculatory disorders, compared to more urbanized or culturally liberalized contexts. this may be one of the reasons for obtaining such high rates of ejaculatory preservation. finally, the study was conducted in a single center with experienced surgeons, potentially limiting generalizability. despite these limitations, our findings have clear clinical implications. lest represents a viable surgical option for men with symptomatic bph, especially those with large prostates who also prioritize sexual function preservation. its near-complete preservation of ejaculation may reduce patient reluctance to undergo surgery, thus improving treatment uptake and quality of life. future studies should aim to validate these findings in randomized controlled designs, with longer follow-up and broader assessment of sexual and psychosocial outcomes. multicenter collaboration will be essential to confirm generalizability and to establish lest as a standard technique within guidelines. conclusions diode laser enucleation with lest combines the efficacy of complete enucleation with the advantage of consistent ejaculatory preservation. for younger men and those concerned about sexual side effects, it offers a truly patient-centered surgical solution. if validated by larger prospective trials, lest may represent a paradigm shift in the surgical management of bph. references 1. maclennan s, azevedo n, duncan e, et al. mapping european association of urology guideline practice across europe: an audit of androgen deprivation therapy use before prostate cancer surgery in 6598 cases in 187 hospitals across 31 european countries. eur urol. 2023; 83:393-401. 2. stanford jl, feng z, hamilton as, et al. urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the prostate cancer outcomes study. jama. 2000; 283:354-60. 3. galasso f, giannella r, bruni p, et al. pca3: a new tool to diagnose prostate cancer (pca) and a guidance in biopsy decisions. preliminary report of the urop study. arch ital urol androl. 2010; 82:5-9. 4. donkov i, chatzikrachtis n, chatterjee a, et al. should magnetic resonance imaging be considered in every patient before a bladder outflow obstruction procedure? arch ital urol androl. 2025; 97:13935. 5. mantica g, ambrosini f, drocchi g, et al. non-surgical management of bph: an updated review of current literature and state of the art on natural compounds and medical therapy. arch ital urol androl. 2024; 96:13098. 6. bruskewitz rc. quality of life and sexual function in patients with benign prostatic hyperplasia. rev urol. 2003; 5:72-80. 7singh d, nguyen t, burnam p, et al. benign prostatic hyperplasia and sexual dysfunction: review of the impact of new medical and surgical therapies on sexual health. curr urol rep. 2025; 26:49. 8. gacci m, eardley i, giuliano f, et al. critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. eur urol. 2011; 60:809-25. 9. spirito l, capra m, sciorio c, et al. long-term functional outcomes and predictors of efficacy in thulium laser enucleation of the prostate (thulep) for benign prostatic hyperplasia (bph): a retrospective observational study. j basic clin physiol pharmacol. 2024; 35:169-174. 10. macdonald a, fathy m, nikoufar p, et al. safety and clinical outcomes of greenlight laser prostatectomy in octogenarians. can urol assoc j. 2024; 18:e65-e72. 11. tricard t, xia s, xiao d, et al. outcomes of holmium laser enudeclarations ethical approval and consent for participate: this study was conducted in accordance with the declaration of helsinki. it is a retrospective analysis involving standard clinical practices, including diode laser enucleation of the prostate (dilep) with the leonardi ejaculation sparing technique (lest), which are part of routine care according to current clinical guidelines for the management of benign prostatic hyperplasia (bph). for this reason, and considering that in our institution patients routinely provide written consent for the use of their anonymized clinical data for research purposes, specific ethical committee approval was not required. consent for publication: all patients provided informed consent for the surgical procedure, data collection and publication. availability of data and material: on demand to the main author r.l. competing interests: the authors declare that they have no competing interests. funding: none. authors' contributions: rosario leonardi: ideation, data collection and analysis; guglielmo mantica and francesca ambrosini: writing of the manuscript, other authors: revision and validation. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):14296 r. leonardi, g. mantica, f. ambrosini, et al. 6 cleation of the prostate (holep) for very large-sized benign prostatic hyperplasia (over 150 ml): open simple prostatectomy is dead. world j urol. 2023; 41:2249-2253. 12. dimitri m, calarco a, filippi b, et al. i-tind for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: mid-term outcomes from a multicenter cohort. urologia. 2025 aug 4:3915603251360530. 13. cakiroglu b, acar ic, uyanık bs. outcomes of rezum water vapor therapy for benign prostate obstruction with 1-year follow-up: largest real-world data from turkey. cent european j urol. 2025; 78:144-150. 14. de marchi d, mantica g, tafuri a, et al. robotic surgery in urology: a review from the beginning to the single-site. ame med j 2022; 7:16. 15. kim hj, hong sk. application of robotics in the treatment of benign prostatic hyperplasia: a narrative review. prostate int. 2025; 13:74-80. 16. couteau n, duquesne i, frédéric p, et al. ejaculations and benign prostatic hyperplasia: an impossible compromise? a comprehensive review. j clin med. 2021; 10:5788. 17. konstantinidis c, zachariou a, evgeni e, et al. recent advances in the diagnosis and management of retrograde ejaculation: a narrative review. diagnostics (basel). 2025; 15:726. 18. leonardi r. the lest technique: treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. arch ital urol androl. 2019; 91:35-42. 19. leonardi r. preliminary results on selective light vaporization with the side-firing 980 nm diode laser in benign prostatic hyperplasia: an ejaculation sparing technique. prostate cancer prostatic dis. 2009; 12:277-80. 20. luo f, sun hh, su yh, et al. greenlight laser photoselective vaporization of the prostate for treatment of benign prostate hyperplasia/lower urinary tract symptoms in patients with different postvoid residual urine. lasers med sci. 2017; 32:895-901. 21. enikeev d, taratkin m, morozov a, et al. long-term outcomes of holmium laser enucleation of the prostate: a 5-year singlecenter experience. j endourol. 2020; 34:1055-1063. 22. kim hw, lee jz, kim tn, shin dg. holmium laser enucleation of the prostate for advanced prostate cancer-related bladder outlet obstruction: assessing effectiveness and unraveling factors impacting postoperative urinary incontinence. world j mens health. 2024; 42:650-657. 23 kang sh, choi ys, kim sj, et al. long-term follow-up results of photoselective vaporization of the prostate with the 120 w greenlight hps laser for treatment of benign prostatic hyperplasia. korean j urol. 2011; 52:260-4. 24. klein c, marquette t, capon g, et al. implementing holep in an academic department with multiple surgeons in training: mentoring is the key for success. société internationale d’urologie journal. 2023; 4:11-18. 25. droghetti m, porreca a, bianchi l, et al. long-term outcomes of holmium laser enucleation of prostate and predictive model for symptom recurrence. prostate. 2022; 82:203-209. 26. ramachandran a, chavannavar km, thiruvengadam g, et al. ejaculation preserving turp (ep-turp): a viable alternative in sexually active males with boo-a single centre prospective randomized study. world j urol. 2024; 42:567. 27. eliwa a, aldarraji a, abdelwahab k, salem e. randomized prospective trial comparing ejaculatory preservation holep versus standard holep: the other face of the coin. world j urol. 2025; 43:145. 28. trama f, lauro gd, illiano e, et al. ejaculation sparing thulium laser enucleation of the prostate: an observational prospective study. j clin med. 2022; 11:6365. 29. perri d, besana u, mazzoleni f, et al. ejaculation-sparing enucleation of the prostate with thulium: yag laser (es-thulep) versus thulium fiber laser (es-thuflep): outcomes on sexual function. world j urol. 2025; 43:92. 30. bozzini g, berti l, maltagliati m, et al. ejaculation-sparing thulium laser enucleation of the prostate (es-thulep): outcomes on a large cohort. world j urol. 2021; 39:2029-2035. 31. busetto gm, lombardo r, de nunzio c, et al. ejaculation sparing of classic and minimally invasive surgical treatments of luts/bph. prostate cancer prostatic dis. 2025; 28:37-44. 32. tunc l, bozzini g, scoffone cm, et al. determination of face and content validity of cadaveric model for holmium anatomic endoscopic enucleation of the prostate training: an esut aeep group study. eur urol open sci. 2021; 32:28-34. 33. jang t, kong hj, baek c, et al. effect of self-training using virtual reality head-mounted display simulator on the acquisition of holmium laser enucleation of the prostate surgical skills. int neurourol j. 2024; 28:138-146. 34. mantica g, leonardi r, diaz r, et al. reporting characteristics of cadaver training and surgical studies: the cactus guidelines. int j surg. 2022; 101:106619. 35. luu t, gonzalez rr. residency surgical bph training paradigms from mist to holep. curr urol rep. 2023; 24:261-269. correspondence rosario leonardi rosario.leonardi@unikore.it division of urology, school of medicine, kore university of enna, enna, italy guglielmo mantica (corresponding author) guglielmo.mantica@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genoa, largo rosanna benzi 10, 16132, genoa, italy francesca ambrosini f.ambrosini1@gmail.com department of surgical and diagnostic integrated sciences (disc), university of genoa, largo rosanna benzi 10, 16132, genoa, italy antonio tufano antonio.tufano91@gmail.com urology unit, san carlo di nancy hospital, roma, italy gabriele iacona gabriele.iacona@grupposamed.com casa di cura musumeci gecas, gravina di catania (ct) alessandro calarco alecalarco@gmail.com urology unit, san carlo di nancy hospital, roma, italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12613 1 original paper have been associated with an increased risk of morbidity and mortality in males with esrd (5, 6). kidney transplantation (kt) has been reported to improve sexual function and sex hormone profiles (7-10). however, there are few studies concerning serum pituitary-gonadal hormones and sexual dysfunction during dialysis and post-kt in saudi populations. this study aimed to evaluate sex hormonal profile and sexual function status in patients with erectile dysfunction (ed) after two treatment modalities for esrd, including kt and peritoneal/hemodialysis (pd/hd) in southern saudi arabia. patients and methods a non-concurrent cohort study included esrd patients associated with ed after two treatment modalities, including kt and peritoneal/hemodialysis (pd/hd). the study was conducted at the armed forces hospitals southern region, ksa, from september 2017 to january 2023. the local institutional ethical committee approved the protocol, and all enrolled patients signed an informed consent form. inclusion criteria the study included all married male patients with ed associated with esrd aged 18-60; in group a, 40 and 10 patients were on hd and pd, respectively. in group b, all patients underwent kt between september 2017 and september 2023 and had stable graft function. exclusion criteria primary hypogonadism, hemochromatosis, history of cancer treatment (chemotherapy and radiotherapy), pituitary tumors, hypopituitarism of any etiology, and inflammatory diseases such as tuberculosis and sarcoidosis. moreover, patients having second kt, rejection within three months after transplantation, unstable postoperative graft function with serum creatinine over 20 mg/l, and sirolimus as part of the immunosuppressive regimen. background: erectile dysfunction (ed) and sex hormone profile disturbances are common in esrd patients. objective: to assess the effect of kidney transplant (kt) and hemodialysis/peritoneal dialysis (hd/pd) on the serum sex hormone profile and sexual functions in esrd patients with ed. patients and methods: a single-center, nonconcurrent cohort study included a hundred esrd patients with ed, on regular hd/pd (group a, n = 50) and after kt (group b, n = 50) at armed forces hospitals southern region, ksa. results: the mean age of patients was 47.3 ± 7.01 and 56.8 ± 9.6 years in groups a and b, respectively. the cohorts were comparable regarding patient demographics, apart from a higher incidence of comorbidities in group b. after kt the mean testosterone level was higher in group b (13.64 ± 3.21 nmol/l vs 10.26 ± 3.26 nmol/l, p < 0.001). similarly, lh and prolactin levels were lower in group b than in group a (p < 0.05). as regards sexual function, ed was reported in 92% of patients in group a compared to 42% in group b (p < 0.001). in groups a and b, mild ed was found in 48% and 14% of patients, while moderate ed was found in 16% and 8%, respectively. the mean total iief-15 score was 36.42 ± 9.33 and 43.87 ± 9.146 in groups a and b, respectively (p = 0.0001). sexual desire and orgasm were significantly better in group b. conclusions: our study showed that kidney transplantation could improve erectile function and restore normal sex hormone levels in esrd male patients with ed, with better outcomes compared to hd/pd. key words: sex hormones profile; erectile dysfunction; kidney transplantation. submitted 27 april 2024; accepted 13 june 2024 introduction hormonal disturbances such as luteinizing hormone (lh), follicle-stimulating hormone (fsh), and prolactin increase, and decreased testosterone levels are associated with endstage renal disease (esrd) (1-3). these hormonal changes may lead to sexual dysfunction, especially disorder in sexual arousal (4). in addition, low testosterone levels kidney transplantation restores sex hormone profile and improves sexual function in esrd patients with erectile dysfunction hany m. el hennawy 1, omar safar 2, abdullah s. al faifi 1, osama shalkamy 2, 3, mahmoud z. el madawie 2, saad thamer 2, muath almurayyi 2, abdullah mohammed alqarni 4, sami saleh amri 4, ali abdullah hawan 4, adel elatreisy 3, 5 1 surgery department, section of transplantation, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia; 2 urology department, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia; 3 urology department, faculty of medicine, al azhar university, cairo, egypt; 4 laboratory department, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia; 5 urology department, king fahd armed forces hospital, jeddah, saudi arabia. doi: 10.4081/aiua.2024.12613 summary archivio italiano di urologia e andrologia 2024; 96(3):12613 h.m. el hennawy, o. safar, a.s. al faifi, o. shalkamy, et al. 2 in addition, patients receiving medication or herbal compounds to restore erectile function or underwent testosterone replacement therapy. during the pre-kidney transplant (kt) evaluation, 50 patients presenting with ed were selected from the urology clinic (group a). in comparison, an additional 50 patients with ed were chosen from the dialysis unit (group b) based on predefined inclusion and exclusion criteria. in all transplanted patients, the kidney graft was placed extraperitoneal in the right/left iliac fossa, the renal artery was anastomosed to the common or external iliac artery, and the vein was anastomosed to the common or external iliac vein. the ureter was anastomosed to the recipient’s bladder using the lich-gregoire technique over a doublej ureteric stent. we usually remove the ureteric stent after six weeks. immunosuppression for all patients consisted of a triple regimen including tacrolimus, mycophenolate mofetil or mycophenolic acid, and prednisolone. all patients were subjected to a complete medical history through medical examination and routine laboratory investigation. in addition, gonadal hormone levels (lh, fsh, free testosterone, prolactin [prl]) and the international index of erectile function (iief5-15) questionnaire were assessed pretransplant and 6 months after renal transplantation. major drugs causing ed, such as beta-blockers, alpha-blockers, spironolactone, and thiazide diuretics, were withdrawn six months before starting the study. measurements serum pituitary-gonadal hormones were measured as follows: all blood samples were drawn in the morning (7.00-9.00 a.m.) after an overnight fast (12 h). venous blood samples of the patients with ed were collected during dialysis and 1-2 and 3-4 months postoperatively, respectively. serum prolactin (prl), follicle-stimulating hormone (fsh), lh, and testosterone levels were measured immediately by electrochemiluminescence immunoassay (elecsys system, roche diagnostics gmbh, mannheim, germany) according to the manufacturer’s instructions. all blood samples were measured in duplicate (11). moreover, we reported sexual activity after transplantation, sexual desire, degree of erection, satisfaction with sexual activities, frequency of sexual activities, and iief5-15 score for all patients. comparison between the study groups included patient demographics, sex hormone levels, and sexual function status. statistical analysis we analyzed the data using the statistical package for social science (spss) software, version 29 (spss inc., chicago, il). we presented the numeric variables as a mean and standard deviation, while categorical variables were presented as a frequency and percentage. we tested the association between nominal variables using the chi-square test. at the same time, the student’s t-test was applied to define the difference between the means of continuous variables for different groups. we used the mannwhitney u test to compare the ordinal variables in two groups. a paired-sample t-test was used to detect the significance level between pre-transplant and post-transplant values. results group a included 50 patients with ed on hd/pd, and group b included 50 patients with ed who underwent living-related donor kt. the cohorts were comparable in terms of patient demographics, including smoking history, duration of peritoneal/hemodialysis, and body mass index. nevertheless, the prevalence of comorbidities, including diabetes mellitus, hypertension, ischemic heart disease, and dyslipidemia, was significantly higher in group b, as shown in table 1. the median duration of peritoneal/hemodialysis in group a was 4 years, while the median duration of hemodialysis before kt in group b was 2 years, with an average of (4 and 3 years), in groups a and b, respectively table 1. table 2 displays the serum sex hormone levels for the study groups at 6-month follow up after kt.. in group a, fsh, prolactin, and lh levels were significantly higher, and serum testosterone levels were significantly lower than average range values. the mean testosterone level was 13.64 ± 3.21 nmol/l in group b compared to 10.26 ± 3.26 nmol/l in group a with a statistically significant difference (p = 0.0001). similarly, lh and prolactin levtable 1. demographic data of the study groups. parameter group a group b p-value (dialysis patients = 50) (kt patients, n = 50) total (n) patients 50 50 age in years, mean ± sd 47.32 ± 7.013 56.87 ± 9.612 0.0001 dm, % (n) 22% (11) 100% (50) 0.00001 htn, % (n) 100% (50) 100% (50) n/a ihd, % (n) 6% (3) 54% (27) 0.00001 dyslipidemia, % (n) 22% (11) 72% (36) 0.00001 pvd, % (n) 0% (0) 18% (9) 0.00001 smoking, % (n) 18% (9) 28% (14) 0.234 neuropathy, % (n) 0% (0) 0% (0) n/a psychological disease, % (n) 0% (0) 0% (0) n/a cause of esrd, % (n) 0.00001 dm 22% (11) 8% (4) htn 76% (32) 28% (14) dm, htn 14% (7) 64% (32) mood of dialysis, % (n) n/a pd 20% (10) 0% (0) hd 80% (40) 100% (50) previous transplant 2% (n = 1) 0% (0) n/a duration of peritoneal/hemodialysis before kt, median (iqr) in years 4 (4) 2 (3) n/a bmi, mean ± sd 24.68 ± 1.42 24.41 ± 3.62 0.630 follow up serum creatinine mean ± sd in µmol/l 976.96 ± 204.1 83.26 ± 19.44 0.0001 archivio italiano di urologia e andrologia 2024; 96(3):12613 3 kidney transplantation and sexual function els were lower in group b than in group a (p < 0.05). there was no significant difference in the fsh levels, as shown in table 2. as regards sexual function, ed was reported in 92 % of patients in group a compared to 42% in group b (p < 0.001). in groups a and b, mild ed was found in 48% and 14% of patients, while moderate ed was found in 16% and 8%, respectively, as detailed in table 3. in group a, the mean iief5-15 score was 18.4/30 ± 5.4 (range, 7-30), and the mean total iief-15 score was 46.8/75 ± 12.7 (range, 19-75). in group b, one year after successful kt, the mean iief5-15 score was significantly higher than group a; it was 22.3 ± 5.7 (p < .001). similarly, the mean total iief-15 score was 55.5 ±13 (p < .001), as depicted in table 4. sexual desire and orgasm were significantly better in group b compared to group a; similarly, sexual intercourse satisfaction and overall patient sexual satisfaction were significantly higher in group b, as demonstrated in table 4. in group b, patients who had improved erectile function post-transplant (n = 34), mean serum testosterone level increased by 48% compared with an 18% increase in patients who reported no change in erectile function (n = 16) (p = 0.001). discussion erectile dysfunction is defined as the persistent incapability to attain or maintain a penile erection sufficient for satisfactory sexual activity. in endstage renal disease, incidence is 50-70% (2). significant hormonal changes, such as lh, fsh, and prolactin elevation, as well as declines of testosterone and anti-müllerian hormone (amh) levels, are the most prominent effects of a decrease in kidney function levels (3, 8). likewise, our study found similar changes in sex hormone levels in dialysis patients (table 3). total testosterone was inversely associated with ed after adjusting for shbg. men with both low free testosterone and high shbg had the highest ed risk (12-14). in addition, high testosterone levels independently predicted a decreased risk of ed in young men (12). moreover, the duration of dialysis was more than fifty months, and the fsh level was higher in subjects with longer period of dialysis than that in those dialyzed for a shorter period or not dialyzed (15). hyperprolactinemia commonly occurs in ckd, with a prevalence of 30-65% (16) due to declines in excretion and to increased synthesis (17). clinical features may include ed, decreased libido, infertility, gynecomastia, and reduced skeletal mass (18). cardiovascular events in men with ed are associated with elevated plasma prolactin levels (17, 18). in addition, the impairment of testicular function seen in advanced uremia is not reversible by maintenance hemodialysis (19). several studies have demonstrated restoration of pituitary-gonadal axis dysfunction and improved hormonal profile, clinical sexual profile, and fertility after kt (11, 20, 21). it was found that pituitary-gonadal function was nearly restored to the normal range in most recipients about four months postkt (3, 12). similarly, in our study, normal sex hormone levels were restored within six months post-kt.our study reported that serum testosterone levels were higher in the post-kt group in association with lower plasma prolactin and lh levels. there was no noticeable difference in plasma fsh levels between the two groups. these results are comparable to the findings of rahman et al. (22). in agreement with several studies (23), during the serial baseline and follow-up assessments, we discovered a significant increase in testosterone levels in the post-kt (p < 0.008). furthermore, serum testosterone levels were restored to the normal range 3-4 months post-kt in male recipients. consequently, sexual activities and iief-15 scores improved markedly post-kt (11, 22). similarly, our study restored total testosterone levels within six months after kt. in our study, we found that patients table 2. comparison in sex hormones serum levels between the study groups. serum levels of sex hormones group a group b p-value mean ± sd (dialysis patients = 50) (kt patients, n = 50) before kidney transplant • testosterone (nmol/l) 10.25 ± 3.32 10.11 ± 3.23 0.76 • lh (miu/ml) 15.52 ± 17.56 15.87 ± 4.81 0.58 • fsh (miu/ml) 11.08 ± 20.21 11.9 ± 12.96 0.98 • prolactin (ng/ml) 23.98 ± 16.46 23.22 ± 1.71 0.26 6 months after kidney transplant • testosterone (nmol/l) 10.26 ± 3.26 13.64 ± 3.21 0.0001 • lh (miu/ml) 15.49 ± 17.64 5.66 ± 4.76 0.0001 • fsh (miu/ml) 11.11 ± 20.39 11.07 ± 13.95 0.993 • prolactin (ng/ml) 24.12 ± 16.57 9.19 ± 1.63 0.0001 table 3. degree of erectile dysfunction in the study groups. serum levels of sex hormones group a group b p-value mean ± sd (dialysis patients = 50) (kt patients, n = 50) no ed 4 (8%) 29 (58%) <0.001 mild ed 24 (48%) 7 (14%) mild to moderate ed 10 (20%) 9 (18%) moderate ed 8 (16%) 4 (8%) sever ed 4 (8%) 1 (2%) table 4. the iief-15 score in transplant group before & after transplant. the score group a group b p-value mean ± sd (dialysis patients = 50) (kt patients, n = 50) iief5-15 (ed) 13.94 ± 3.941 17.03 ± 3.719 0.0001 iief 9-10 (orgasm) 4.90 ± 1.469 5.84 ± 1.369 0.001 iief 11-12 (sexual desire) 5.10 ± 1.62 5.81 ± 1.515 0.026 iief 6-8 (intercourse satisfaction) 7.42 ± 2.233 9.16 ± 2.311 0.0001 iief 13-14 (overall satisfaction) 5.06 ± 1.526 6.03 ± 1.581 0.002 total iief-15 score 36.42 ± 9.330 43.87 ± 9.146 0.0001 archivio italiano di urologia e andrologia 2024; 96(3):12613 h.m. el hennawy, o. safar, a.s. al faifi, o. shalkamy, et al. 4 with an increase in the iief score post-kt showed a rise in mean testosterone levels by 48% compared with an 18% increase in patients with a decrease in the iief score post-kt (p = 0.366). this corresponds to an increase in potency. during the serial baseline and follow-up assessments, we discovered a significant decrease in prolactin levels in the post-kt group (p 0.006) compared with the other group. similarly, in a study by reinhardt et al., they reported that prolactin levels fell immediately post-kt and were constant until the end of follow-up (10). our findings contradicted those of sikora-grabka et al. (24), who found that both lh and fsh levels decreased significantly during the observation period. successful kt could improve gonadal function, but immunosuppressive medications could also impair it. it remains controversial whether kt could improve gonadal, sexual, and reproductive functions, especially in the long follow-up (11). glucocorticoids affect gonadal function at several levels in the hypothalamic-pituitary-gonadal axis: 1) decreasing the release and synthesis of gnrh by the hypothalamus; 2) decreasing the release and synthesis of lh and fsh by the pituitary gland; 3) modulating of steroidogenesis and/or gametogenesis directly by the testis/ovary (25). furthermore, several studies found that plasma testosterone levels were lower in fsh and lh in sirolimustreated recipients than in non-sirolimus-treated controls, although the two groups showed no significant difference in serum prolactin levels in another study (21, 26, 27). several studies show post-kt recipients’ improvement in the iief score (28-30). the impact of kt on ed is controversial. many studies show successful kt may play an essential role in ed improvement (23), (22), which aligns with the current study's findings. in our study, ed was reported in 42 % of patients after kt compared to 92 % in patients on regular hd/pd. sexual desire and orgasm were significantly better in post-kt patients. furthermore, the mean total iief-15 score was significantly higher in the post-kt group (p < .001). nevertheless, other studies have suggested that ed may persist in 20%-50% of patients (31, 32). alternatively, it may worsen in patients younger than 45 years post-kt but is unaffected in patients older than 45 years (33). the study has limitations due to its small sample size, singlecenter nature, and retrospective design with data recall bias. future research could consider a prospective randomized trial. conclusions our study showed that kidney transplantation could improve erectile function and restore normal sex hormone levels in esrd male patients with ed. we demonstrated a significantly higher serum testosterone level and lower levels of luteinizing hormone and prolactin after renal transplantation compared to regular hd/pd. references 1. anantharaman p, schmidt rj. sexual function in chronic kidney disease. adv chronic kidney dis. 2007; 14:119-25. 2. bailie gr, elder sj, mason na, et al. sexual dysfunction in dialysis patients treated with antihypertensive or antidepressive medications: results from the dopps. nephrol dial transplant. 2007; 22:1163-70. 3. eckersten d, giwercman a, pihlsgård m, et al. impact of kidney transplantation on reproductive hormone levels in males: a longitudinal study. nephron. 2018; 138:192-201. 4. anastasiadis ag, davis ar, salomon l, et al. hormonal factors in female sexual dysfunction. curr opin urol. 2002; 12:503-7. 5. elsafty me, hasan fh, rashed am. effect of renal transplantation on gonadal hormones in male patients with end stage renal disease. al-azhar international medical journal. 2022; 3:82-6. 6. bello ak, stenvinkel p, lin m, et al. serum testosterone levels and clinical outcomes in male hemodialysis patients. am j kidney dis. 2014; 63:268-75. 7. procci wr, goldstein da, adelstein j, massry sg. sexual dysfunction in the male patient with uremia: a reappraisal. kidney int. 1981; 19:317-23. 8. eckersten d, giwercman a, christensson a. male patients with terminal renal failure exhibit low serum levels of antimüllerian hormone. asian j androl. 2015; 17:149-53. 9. akbari f, alavi m, esteghamati a, et al. effect of renal transplantation on sperm quality and sex hormone levels. bju int. 2003; 92:281-3. 10. reinhardt w, kübber h, dolff s, et al. rapid recovery of hypogonadism in male patients with end stage renal disease after renal transplantation. endocrine. 2018; 60:159-66. 11. wang g chun, zheng j hua, xu l gen, et al. measurements of serum pituitary-gonadal hormones and investigation of sexual and reproductive functions in kidney transplant recipients. int j nephrol. 2010; 2010:1-6. 12. luo y, zhang h, liao m, et al. sex hormones predict the incidence of erectile dysfunction: from a population-based prospective cohort study (famhes). j sex med. 2015; 12:1165-74. 13. liao m, huang x, gao y, et al. testosterone is associated with erectile dysfunction: a cross-sectional study in chinese men. plos one. 2012; 7:e39234. 14. antonucci m, palermo g, recupero sm, et al. male sexual dysfunction in patients with chronic end-stage renal insufficiency and in renal transplant recipients. arch ital urol androl. 2016; 87:299. 15. starzyk j, grzeszczak w, kowalski d. effect of many years of hemodialysis therapy on fsh secretion induced by luliberin in men with chronic renal failure. wiad lek. 1993; 46:286-91. 16. yavuz d, topçu g, özener ç, et al. macroprolactin does not contribute to elevated levels of prolactin in patients on renal replacement therapy. clin endocrinol (oxf). 2005; 63:520-4. 17. carrero jj, kyriazis j, sonmez a, et al. prolactin levels, endothelial dysfunction, and the risk of cardiovascular events and mortality in patients with ckd. clinical journal of the american society of nephrology. 2012; 7:207-15. 18. corona g, rastrelli g, boddi v, et al. prolactin levels independently predict major cardiovascular events in patients with erectile dysfunction. int j androl. 2011; 34:217-24. 19. prem ar, punekar sv, kalpana m, et al. male reproductive function in uraemia: efficacy of haemodialysis and renal transplantation. br j urol. 1996; 78:635-8. 20. pietrzak b, cyganek a, jabiry-zieniewicz z, et al. function of the ovaries in female kidney transplant recipients. transplant proc. 2006; 38:180-3. archivio italiano di urologia e andrologia 2024; 96(3):12613 5 kidney transplantation and sexual function 21. fritsche l, budde k, dragun d, et al. testosterone concentrations and sirolimus in male renal transplant patients. am j transplant. 2004; 4:130-1. 22. rahman ia, rasyid n, birowo p, atmoko w. effects of renal transplantation on erectile dysfunction: a systematic review and meta-analysis. int j impot res. 2022; 34:456-66. 23. kang j, tian j, lu y, et al. erectile function after kidney transplantation: a meta-analysis. transl androl urol. 2020; 9:1967-79. 24. sikora-grabka e, adamczak m, kuczera p, wiecek a. serum sex hormones concentrations in young women in the early period after successful kidney transplantation. endokrynol pol. 2018; 69:150-5. 25. whirledge s, cidlowski ja. glucocorticoids, stress, and fertility. minerva endocrinol. 2010; 35:109-25. 26. huyghe e, zairi a, nohra j, et al. gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. transpl int. 2007; 20:305-11. 27. tondolo v, citterio f, panocchia n, et al. gonadal function and immunosuppressive therapy after renal transplantation. transplant proc. 2005; 37:1915-7. 28. teng lc, wang cx, chen l. improved erectile function and sex hormone profiles in male chinese recipients of kidney transplantation. clin transplant. 2011; 25:265-9. 29. nassir a. sexual function in male patients undergoing treatment for renal failure: a prospective view. j sex med. 2009; 6:3407-14. 30. pourmand g, emamzadeh a, moosavi s, et al. does renal transplantation improve erectile dysfunction in hemodialysed patients? what is the role of associated factors? transplant proc. 2007; 39:1029-32. 31. rebollo p, ortega f, valdés c, et al. factors associated with erectile dysfunction in male kidney transplant recipients. int j impot res. 2003; 15:433-8. 32. malavaud b, rostaing l, rischmann p, et al. high prevalence of erectile dysfunction after renal transplantation. transplantation. 2000; 69:2121-4. 33. mirone v, longo n, fusco f, et al. renal transplantation does not improve erectile function in hemodialysed patients. eur urol. 2009; 56:1047-53. correspondence hany m. el hennawy, md hennawyhany@hotmail.com abdullah s. al faifi, md surgery department, section of transplantation, armed forces hospitals southern region khamis mushayte, 101, saudi arabia omar safar, md mahmoud z. el madawie, md saad thamer, md muath almurayyi, md urology department, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia osama shalkamy, md urology department, faculty of medicine, al azhar university, cairo, egypt urology department, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia abdullah mohammed alqarni, md sami saleh amri, md ali abdullah hawan, md laboratory department, armed forces hospitals southern region, khamis mushayte, 101, saudi arabia adel elatreisy, md urology department, faculty of medicine, al azhar university, cairo, egypt urology department, king fahd armed forces hospital, jeddah, saudi arabia conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13869 1 original paper end anastomosis to reconstruction with intestinal interposition and auto-transplantation (1). these procedures result in significant morbidity and mortality, especially in patients with major comorbidities or advanced cancer. traditionally, two primary options exist for managing these cases. ureteral stents or double-j stents can be inserted retrograde or antegrade. however, inserting a ureteral stent is not always feasible due to complete ureteral lumen occlusion. furthermore, stents may fail to adequately drain the upper urinary tract in almost half of the cases due to tumor progression, extreme compression, or invasion of the ureter (2). complications such as pain, lower urinary tract symptoms (luts), hematuria, encrustation, urinary tract infections (uti), and impairment of kidney function are common. additionally, stents are temporary and require regular replacement in the operating room based on stent type and patient characteristics (3). an alternative is the placement of a percutaneous nephrostomy tube with an external collection device. while it ensures urinary drainage, it is associated with a significant reduction in quality of life due to discomfort, skin erosion, complex management requirements, limitations on daily and social activities, risk of obstruction and accidental removal, utis, and the need for frequent substitutions (4). in this setting the extra-anatomical urinary diversion (eaud) with detour® (coloplast, humlebaek, denmark) seems to confer an acceptable approach (5, 6). this involves a specially designed reinforced silicone tube with a 27 fr (9 mm) external and 17 fr (5.8 mm) internal diameter, connecting the renal cavities to the bladder. the detour bypass is inserted into the kidney through a small flank incision, runs subcutaneously, and is connected to the bladder dome through a small hypogastric incision. eaud is extra-anatomical as it avoids the abdominal cavity and can be placed irrespective of ureter patency. eaud is primarily indicated for palliative urinary diversion in selected oncologic patients requiring a percutaneous tube. remarkable are the results of a series of terminally ill patients, where eaud provided better quality of the patients’ life than traditional percutaneous nephrostomy (7). additionally, it may be considered in cases of stent failure, complications, or intolerance, where external diversion with a percutaneous tube is the only viable introduction and objectives: ureteral stenosis and upper urinary tract obstruction present significant clinical challenges, especially in cases involving complex, long strictures. traditional management options like ureteral stents and percutaneous nephrostomy tubes often result in complications and diminished quality of life. extra-anatomical urinary diversion (eaud) offers an alternative approach, particularly for oncologic patients requiring palliative care. materials and methods: from 2015 to 2019, eight patients with cancer-related ureteral strictures underwent eaud. in all patients cancer-specific prognosis exceeded one year. the procedure was performed using a standard surgical technique. results: the mean patient age was 62.5 years, ranging from 22 to 82 years. the mean follow-up duration was 62.8 months. improvement in renal function was observed in some patients, while the early complication rate was 62.5%. notable complications included infections and encrustation of the prosthesis. two patients experienced multiple infections of the overlying skin and soft tissue necessitated the dislodgement of the prothesis after 38 and 101 months, respectively. conclusions: extra-anatomical stent placement constitutes a somewhat effective and safe option in the context of complex ureteral obstruction management in oncologic patients. the lack of external devices and its longer duration without the need for substitution compared with conventional double j stents can theoretically assure a better quality of life. however, a careful patient selection is needed in order to maximize the patients' benefit. key words: ureteric obstruction; extra-anatomical urinary diversion; detour bypass. submitted 4 april 2025; accepted 25 april 2025 introduction ureteral stenosis and resulting upper urinary tract obstruction can manifest with symptoms such as pain, infections, and diminished kidney function. managing ureteral stenosis poses a challenge, especially in cases with complex long stenosis. according to eau guidelines, endourological treatment, such as dilatation, is safe and effective for small strictures (1). on the other hand, recurrent and long strictures require a more aggressive approach, ranging from end-toextra-anatomical urinary diversion for malignant ureteric obstruction: our clinical experience napoleon moulavasilis 1, konstantinos douroumis 1, konstantinos kotrotsios 1, periklis anastasiou 2, panagiotis levis 1, evangelos fragkiadis 1, ioannis anastasiou 1 1 first department of urology, national and kapodistrian university of athens, medical school, goudi, athens, greece; 2 faculty of medicine, school of health sciences, university of ioannina, bizani, ioannina, greece. doi: 10.4081/aiua.2025.13869 summary archivio italiano di urologia e andrologia 2025; 97(2):13869 n. moulavasilis, k. douroumis, k. kotrotsios, et al. 2 solution. furthermore, eaud can serve as a definitive option in selected patients with complex ureteral stenosis of benign origin when stent insertion is not feasible, has failed, or when reconstructive surgery is not indicated or has proven unsuccessful (5). finally, eas placement has been reported in patients with ureteric stricture after renal transplantation (8). we present our series with treatment of ureteral strictures with detour eaud. materials and methods between 2015 and 2019, our experience involved eight cases of extra-anatomical urinary diversion (eaud) with detour, each performed on a different patient. patients with ureteral obstruction secondary to advanced abdominal or pelvic malignancy were included. the datasets used and analyzed during the current study are available upon reasonable request from the corresponding author. we decided to include only patients with malignancyrelated obstruction due to the ambiguous results regarding eaud efficiency in ureteral strictures of benign descent deriving from relevant published literature. (9, 10) all the patients were informed about the study and the study was approved by the scientific and ethics committee of our hospital. the subcutaneous bypass was introduced as an alternative to a permanent percutaneous nephrostomy after either a failed attempt or a patient’s denial to undergo double-j stent placement. all patients were discussed in a multidisciplinary tumor board meeting, and cancer-specific survival was evaluated based on the stage of the malignant disease. only patients with over 1 year cancer-specific survival were included. also, patients over 70 years old were evaluated using the geriatric 8 screening tool (11). the follow-up was performed in an outpatient setting once every 6 months, where urine culture was obtained, the functionality of the detour prothesis was assessed and the satisfaction of the patients was reported through a non-structured interview. the bypass-related complications’ severity was classified using the clavien dindo scale of surgical complications (12). results the mean age of the patients in our experience was 62.5±18.4 years, with a range of 22 to 82 years and a median age of 64.5. among the eight cases, four had colorectal cancer, two had cervical or ovarian cancer, one had retroperitoneal sarcoma and one suffered from cholangiocarcinoma. in all oncologic patients, the prognosis was more than 1 year, as indicated by the geriatricscore. prior to the eaud procedure, all patients had a nephrostomy tube, and five of them had previously undergone a failed or intolerable double-j (dj) stent placement. a list of all cases treated with detour stent is presented in table i. the mean follow-up duration was 62.8 ± 34.8 months, ranging from 13 to 112 months, with a median duration of 65 months. interestingly, many cases exhibited positive urine cultures, and three of them had symptomatic utis before undergoing eaud. in those cases empiric antibiotic therapy was administered and subsequently was modified based on the antimicrobial susceptibility testing results. the early complication rate during the first 90 days postoperatively was 62.5%, with 37.5% experiencing no complications, 60% classified as clavien i, 20% as clavien ii and 20% as clavien iiib. no patients reported luts during the whole follow-up period. improvement in renal function was observed in two patients during their hospital stay the mean decrease in hb was 1.14 ± 0.576, while the mean cr decrease was 0.416 ± 0.79. mean length of stay was as high as 4.57 ± 1.72. however, during follow-up period three patients experienced multiple infections of the overlying skin and soft tissue requiring surgical debridement and dislodgement of the prothesis in two cases. also, one of the patients presented with encrustation of the prothesis’ vesical end, which subsequently necessitated endourological management. additionally, one patient suffered from recurrent utis during the 31 month follow-up, which ended due to the patient’s cancer related death. on the other hand, it is important to highlight that three of the patients experienced a complication free post-implantation course for 13, 72 and 106 months. table 1. cases treated with detour stent. patient gender age malignant hb decrease cr decrease urine length clavien dindo follow-up complications disease (24h) (24h) culture of stay (days) (first 90 days) (months) during follow-up 1 female 66 ovarian 0.9 0.2 positive 3 31 multiple utis 2 male 82 colorectal 2.0 -0.1 negative 4 72 3 male 63 colorectal 0.6 1.72 positive 6 38 multiple skin and soft tissue infections 4 male 22 retroperitoneal 0.8 0 positive 6 i 67 abscess formation along sarcoma the course of the ureter 5 female 57 cholangiocarcinoma 2.1 0.3 positive 7 ii 13 6 female 75 cervical 0.8 -0.1 positive 3 i 112 prothesis encrustation 7 female 75 colorectal 1.0 1.6 positive i 106 8 male 60 colorectal 0.9 -0.29 positive 3 iiib 101 multiple skin and soft tissue infections archivio italiano di urologia e andrologia 2025; 97(2):13869 3 extra-anatomical urinary diversion a summary of the results of eaud in the included patients is provided in table ii. discussion the indication for performing a diversion, such as detour, is a common consideration in a diverse group of oncologic patients with substantial variations in treatment options and prognosis. within this population, there is a distinct subset facing untreatable malignancies, characterized by a grim prognosis where ureteral obstruction is just one aspect of a more complex manifestation of metastatic disease. these patients often exhibit poor performance status and immunosuppression. some studies suggest that urinary diversion in such cases might be considered overtreatment, as there is no clear clinical benefit in terms of survival (13). moreover, urinary diversion can lead to a significant reduction in quality of life, with many spending a substantial portion of their remaining time postintervention in the hospital (14). conversely, other patients experiencing ureteral obstruction have a more favorable prognosis. in many instances, ureteral stenosis is a consequence of the disease itself, surgical procedures, or systemic radiotherapy or chemotherapy. those in this latter group who undergo urinary diversion often experience longer lifespans and may even achieve a cancer-free status (15). recent epidemiological studies highlighting declining mortality rates in colorectal and cervical cancer, frequently associated with ureteral obstruction, contribute to the increasing number of chronic oncologic patients requiring permanent urinary diversion (16, 17). in cases with a focus on quality of life, particularly in younger patients with a more extended life expectancy, the concept of palliative treatment for ureteral obstruction needs reconsideration. the psychological burden of longterm nephrostomy or ureteral stent use, with associated discomfort, challenging management, potential complications, and frequent substitutions, becomes particularly challenging for patients who have already overcome the adversities of cancer treatments. additionally, patients often feel a sense of abandonment when told there are no alternatives, and they must continue living with nephrostomies or stents (18, 19). within this context, the treatment of ureteral stenosis with a permanent extra-anatomical stent emerges as an option to enhance the quality of life and preserve kidney function (20). however, due to the heterogeneity of these patients, the complexity of their medical history, and the uncertainty of prognosis, the decision is challenging and needs to be personalized. eaud involves surgical implantation rather than endoscopic stent insertion (1). the first extra-anatomical stent devices developed consisted of a single lumen rigid stent with an internal diameter between 7 and 11 fr and a length of 50 to 70 centimeters. however, given that the small diameter was a risk factor for stent encrustation a minimum diameter of 17 fr was proposed (21-24). despite the wider diameter, there is a risk of encrustation and infection, potentially requiring explantation or substitution through further surgical procedures (25). although rare, severe complications have been reported (26). factors such as previous multiple surgeries, especially those associated with radiotherapy, and a history of symptomatic utis with sepsis may contribute as potential risk factors. therefore, patients must be thoroughly informed, prepared, and undergo regular follow-up evaluations. despite these risks, our experience and that of other groups indicate that, in selected patients, the benefits of extra-anatomical stents in terms of significant improvement in quality of life outweigh the potential risks. this study has several limitations. first of all, its retrospective nature constitutes a potential source of selection bias. also, its small sample size cannot allow the extraction of reliable conclusions and restricts the external validity of the results. moreover, given that only creatinine levels were provided and that chemotherapy can significantly affect creatinine levels in oncological patients, improvement in renal function cannot be accurately evaluated. more on that, the assessment of the device placement in the context of quality of life advancement was not performed through a structured tool potentially leading to reporting bias. last but not least, the lack of a control group does not allow the provision of some valuable insights on which management option is optimal for patients with chronic upper urinary tract obstruction. table 2. summary of results. patient features age (mean ± sd) 62.5±18.4 gender, n (%) female 4 (50%) male 4 (50%) complications, n (%) 5 (62.5%) i 3 (60%) ii 1 (20%) iii 1 (20%) hb decrease (mean ± sd) 1.14 ± 0.576 cr decrease (mean ± sd) 0.416 ± 0.79 los in days (mean ± sd) 4.57 ± 1.72 follow-up in months (mean ± sd) 62.8 ± 34.8 declarations competing interests: the authors declare that they have no competing interests. funding: no source of funding was received for this study. authors' contributions: mn: study concept, data acquisition, contribution to manuscript writing and editing; dk: ethics committee approval, manuscript original drafting; kk: data analysis and interpretation, manuscript original drafting; ap: data extraction, contribution to manuscript writing and editing; lkp: data acquisition, manuscript reviewing; fe: data acquisition, manuscript reviewing; ai: project supervision, manuscript reviewing.all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13869 n. moulavasilis, k. douroumis, k. kotrotsios, et al. 4 conclusions the detour extra-anatomical stent constitutes a somewhat effective and safe option in the context of complex ureteral obstruction management. the lack of external devices and its longer duration without the need of substitution compared with conventional double j stents can theoretically promise a better quality of life. however, a more careful patient selection is needed in order to maximize the patients’ benefit. references 1. eau guidelines. edn. presented at the eau annual congress milan 2023. isbn 978-94-92671-19-6. 2. tlili g, ammar h, dziri s, et al. antegrade double-j stent placement for the treatment of malignant obstructive uropathy: a retrospective cohort study. ann med surg (lond). 2021; 69:102726. 3. hepperlen tw, mardis hk, kammandel h. the pigtail ureteral stent in the cancer patient. j urol 1979; 148:17-8. 4. young m, leslie sw. percutaneous nephrostomy. 2023 jun 26. in: statpearls (internet). treasure island (fl): statpearls publishing; 2024; pmid: 29630257. 5. lloyd sn, tirukonda p, biyani cs, et al. the detour extra-anatomic stent--a permanent solution for benign and malignant ureteric obstruction? eur urol. 2007; 52:193-8. 6. chong jjy, kum f, hadjipavlou m, et al. extra-anatomic stents in ureteric obstruction: our experience. j endourol. 2019; 33:242-247. 7. desgrandchamps f, leroux s, ravery v, et al. subcutaneous pyelovesical bypass as replacement for standard percutaneous nephrostomy for palliative urinary diversion: prospective evaluation of patient's quality of life. j endourol. 2007; 21:173-6. 8. tahir w, hakeem a, white a, et al. extra-anatomic stent (eas) as a salvage procedure for transplant ureteric stricture. am j transplant. 2014; 14:1927-30. 9. azhar ra, hassanain m, aljiffry m, et al. successful salvage of kidney allografts threatened by ureteral stricture using pyelovesical bypass. am j transplant. 2010; 10:1414-9. 10. muller co, meria p, desgrandchamps f. long-term outcome of subcutaneous pyelovesical bypass in extended ureteral stricture after renal transplantation. j endourol. 2011; 25:1389-92. 11. boyle hj, alibhai s, decoster l, et al. updated recommendations of the international society of geriatric oncology on prostate cancer management in older patients. eur j cancer. 2019; 116:116-136. 12. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-213. 13. tatenuma t, tsutsumi s, yasui m, et al. outcome of palliative urinary diversion and observation for malignant extrinsic ureteral obstruction. j palliat med. 2020; 23:254-258. 14. lapitan mc, buckley bs. impact of palliative urinary diversion by percutaneous nephrostomy drainage and ureteral stenting among patients with advanced cervical cancer and obstructive uropathy: a prospective cohort. j obstet gynaecol res. 2011; 37:1061-1070. 15. cordeiro md, coelho rf, chade dc, et al. a prognostic model for survival after palliative urinary diversion for malignant ureteric obstruction: a prospective study of 208 patients. bju int. 2016; 117:266-271. 16. perri t, meller e, ben-baruch g, et al. palliative urinary diversion in patients with malignant ureteric obstruction due to gynaecological cancer. bmj support palliat care. 2022; 12:e855-e861. 17. heo je, jeon dy, lee j, et al. clinical outcomes after urinary diversion for malignant ureteral obstruction secondary to nonurologic cancer: an analysis of 778 cases. ann surg oncol. 2021; 28:2367-2373. 18. joshi hb, adams s, obadeyi oo, rao pn. nephrostomy tube or 'jj' ureteric stent in ureteric obstruction: assessment of patient perspectives using quality-of-life survey and utility analysis. eur urol. 2001; 39:695-701. 19. zhang kp, zhang y, chao m. which is the best way for patients with ureteral obstruction? percutaneous nephrostomy versus double j stenting. medicine (baltimore). 2022; 101:e31194. 20. heidenreich a, ohlmann c, braun m. palliative subkutane harnableitung bei maligner ureterobstruktion (detour-system) (palliative subcutaneous urinary diversion in malignant ureteral obstruction (detour system)). aktuelle urol. 2004; 35:429-441. 21. andonian s, zorn kc, paraskevas s, anidjar m. artificial ureters in renal transplantation. urology. 2005; 66:1109. 22. lingam k, paterson pj, lingam mk, et al. subcutaneous urinary diversion: an alternative to percutaneous nephrostomy. j urol. 1994; 152:70-72. 23. ahmadzadeh m. clinical experience with subcutaneous urinary diversion: new approach using a double pigtail stent. br j urol. 1991; 67:596-9. 24. nakada sy, gerber aj, wolf js jr, et al. subcutaneous urinary diversion utilizing a nephrovesical stent: a superior alternative to long-term external drainage?. urology. 1995; 45:538-541. 25. wrona aj, zgajewski j, kopec n, et al. subcutaneous pyelovesical bypass detour bypass as a solution for ureteric obstruction. cent european j urol. 2017; 70:429-433. 26. nouaille a, descazeaud a, desgrandchamps f, et al. morbidity and long-term results of subcutaneous pyelovesical bypass in chronic ureteral obstruction. prog urol. 2021; 31:348-356. correspondence napoleon moulavasilis napomoul@hotmail.com konstantinos douroumis kostasdour@hotmail.com konstantinos kotrotsios (corresponding author) kotrwtsiosk@gmail.com panagiotis levis panagiotislevis@yahoo.com evangelos fragkiadis e.fragkiadis@gmail.com ioannis anastasiou ekati2@otenet.gr first department of urology, national and kapodistrian university of athens, medical school, agiou thoma 17, goudi, athens, 11527, greece periklis anastasiou grrlol13@gmail.com faculty of medicine, school of health sciences, university of ioannina, bizani, ioannina, 45500, greece stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12833 1 meta-analysis introduction parkinson's disease (pd) is one of the most common neurodegenerative diseases, primarily caused by the degeneration of dopamine-producing neurons and α-synuclein accumulation in the substantia nigra and the formation of lewy bodies. however, various mechanisms and pathway dysfunctions contribute to parkinson's disease pathogenesis, including oxidative stress, malfunctioning mitochondria, cellular calcium imbalance, neuroinflammation, and other neurotransmitter system abnormalities (1, 2). the main symptoms of this disease include bradykinesia, rigidity, tremors, and postural instability (3). the risk of pd increases almost exponentially with age, with most patients being over 65 years old. globally, the incidence and prevalence of this disease from 1990 to 2019 have been reported to be 13.43 and 106.28 per 100.000 population, respectively, with a rising global trend in the burden of pd (4). since there is currently no definitive cure for pd, symptom control – primarily through dopamine agonists and dopamine replacement therapy – remains the only treatment approach (5). levodopa is one of the most effective drugs, having been used in pd treatment for over five decades (6). the metabolism of this drug occurs through four pathways: decarboxylation, o-methylation, transamination, and oxidation (7). seventy percent of oral levodopa is metabolized by the enzyme aaad (aromatic amino-acid decarboxylase) in the gut and liver (8). to increase the drug's half-life and concentration levels, dopa decarboxylase inhibitors (dci) such as carbidopa and benserazide are prescribed alongside levodopa (9). the main side effects of pd medications include gastrointestinal issues like nausea and psychiatric disorders such as psychosis and dyskinesia (10). a recent retrospective study by gremke et al. indicated that the incidence of urinary tract infection (uti) during one year of treatment with dci drugs exceeds ten percent (11). urinary tract infection (uti) is a common factor in worsening the neurological status of patients with pd. uti can be one of the leading causes of delirium, decreased functionalobjectives: parkinson’s disease is the most common neurodegenerative disease. combining levodopa with other drugs, including decarboxylase inhibitors (dci) is its most effective treatment. urinary tract infection (uti) is the most common cause of hospitalization in parkinson’s patients, making it crucial to find an appropriate treatment to reduce the incidence of this complication. this study aimed to investigate utis in parkinson’s patients using levodopa with dci supplements. methods: in this systematic review and meta-analysis, databases such as pubmed, scopus, embase, cochrane, and web of science were searched up to march 2024. only randomized controlled trials involving parkinson’s patients were included in the present study. parkinson’s patients who used levodopa along with carbidopa or benserazide were considered the intervention group, while those who used levodopa with another drug were considered the control group. results: nine interventional studies were ultimately analyzed. the relative risk (rr) of uti in patients taking dci was 26% lower than those who did not (rr treatment/control = 0.74, 95% ci: 0.58-0.95, p = 0.019). furthermore, observations at different times of follow-up showed that at 13-24 weeks and at > 24 weeks of treatment with dci, there was a reduction in the incidence of uti (rr = 0.68, 95% ci: 0.46-1.01 and rr = 0.77, 95% ci: 0.58-1.0, respectively). on the contrary, there was an increase of the risk of uti in the first 12 weeks of treatment with dci (rr = 1.11, 95% ci: 0.37-3.33). conclusions: the results of this study indicated that using dci drugs is associated with a reduced relative risk of developing utis. the beneficial effect of the drug showed after 12 weeks of treatment after an initial negative effect on the risk of uti. key words: parkinson’s disease; urinary tract infections; carbidopa; beneserazide; dopa-decarboxylase inhibitors; systematic review; meta-analysis. submitted 22 july 2024; accepted 2 august 2024 effect of dopa decarboxylase inhibitor supplements on the incidence of urinary tract infections in parkinson’s disease patients: a systematic review and meta-analysis of randomized controlled trials ismaeel alshoaibi 1, basheer abdo 1, mohammed abdullah 1, khaled alzanen 1, mohammed alhakamy 1, mamoon al-namer 1, abdulghani al-hagri 2, morshed salah 3, afrah salem 1, mohammed almogahed 1, ibrahim alnadhari 4, faisal ahmed 5 1 department of internal medicine, school of medicine, ibb university, ibb, yemen; 2 student research committee, faculty of medicine and health sciences, sana'a university, sana'a, yemen; 3 urology section, surgery department, hazm mebaireek general hospital, hamad medical corporation, doha, qatar. 4 department of surgery, school of medicine, qatar university, doha, qatar; 5 department of urology, school of medicine, ibb university, ibb, yemen. doi: 10.4081/aiua.2024.12833 summary archivio italiano di urologia e andrologia 2024; 96(4):12833 i. alshoaibi, b. abdo, m. abdullah, et al. 2 ity, falls, and hospitalizations in these patients (12). various clinical features of pd, including autonomic dysfunction, urodynamic changes, weakness, cognitive impairment, and the need for bladder catheterization, contribute to the increased risk of uti (13). moreover, untreated uti can lead to urosepsis, a major complication in pd. the use of clean methods for catheterization when requested, antibiotics, and supplements are among the preventive strategies for uti in pd patients (13). various studies have reported uti as a side effect of dci drugs in parkinson's patients (1416). however, given that this significant complication has not been addressed explicitly in different studies, we aimed to conduct a systematic review and meta-analysis to investigate and compare the incidence of uti due to dci drugs with other parkinson's medications. materials and methods research design this systematic review and meta-analysis were registered with prospero (registration number: crd42024560930) and were done according the prisma (preferred reporting items for systematic reviews and meta-analyses) guidelines (17). additionally, this study was reported in compliance with the amstar (a measurement tool to assess systematic reviews) methodological quality guidelines. research question does the incidence of uti in patients treatment with dci drugs differ compared to patients on other parkinson's medications? research criteria and study selection two researchers independently imported the search results from each database into endnote software. using endnote, duplicates were identified and removed. subsequently, two researchers screened all remaining articles to identify eligible studies. a third researcher reviewed and resolved any controversies between the two researchers. this study's inclusion criteria were randomized clinical trials (rcts) published as full articles. exclusion criteria included reviews, book chapters, conference abstracts, in vivo and in vitro studies, cross-sectional, case-control, and cohort studies. additionally, studies with a lack of full text and unclear data, including patients with prostate carcinoma or uncontrolled diabetes, patients with other urinary problems, or studies with small sample size (n < 20), were excluded. the relative risk (rr) was calculated as the effect size based on the reported incidence of uti in the intervention and control groups. the intervention group comprised pd patients who received dci drugs (carbidopa or benserazide) alongside levodopa. the control group included pd patients who took levodopa with other medications (e.g., rotigotine, safinamide, or entacapone). we labeled them as "other" to indicate the use of drugs other than the intervention drugs. search strategy data sources we researched the pubmed/medline, scopus, embase, cochrane library, and web of science databases up to march 2024. gray literature was also reviewed to identify additional relevant studies. the search was performed without any time or language restrictions. the mesh (medical subject heading) and non-mesh keywords used included: “parkinson's disease, parkinson, parkinsonism, carbidopa, benserazide, aromatic amino acid decarboxylase inhibitors, dopa decarboxylase inhibitor, dci, urinary tract infections, cystitis, pyelonephritis, lower urinary tract symptoms, urinary, and urosepsis”. a multi-stage process was employed to determine the search keywords and design the search syntax, utilizing common free-text keywords and mesh terms. data extraction the outcome was the incidence of uti complications in the intervention and control groups. data extracted from each study included the first author's name, publication date, start date of data collection, intervention or control designation, form of drug administration, collaborating countries in data collection, sample size, and incidence of uti in both groups. quality assessment (risk of bias assessment) a systematic assessment of bias in the included rcts was conducted using the cochrane rob 2.0 tool (introduced in 2016 and last revised on august 22, 2019) to assess the risk of bias in randomized trials (18). the following domains were used to evaluate each study: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. studies were categorized as low risk of bias, high risk of bias, or with some concerns. two researchers independently performed screening, study selection, validation, data extraction, and methodological quality assessment, with any disagreements resolved by a third reviewer. publication bias publication bias was assessed using funnel plots and eggar's weighted regression (19). a p-value greater than 0.05 indicated no publication bias. subgroup and sensitivity analysis sensitivity analysis was conducted using a leave-one-out approach to assess the impact of individual studies on the overall effect size. subgroup analysis was performed based on variables such as follow-up duration and type of treatment. statistical analyses data were entered into a statistical program and analyzed using stata 17.0 (stata corporation, college station, tx). a random effects model was used to account for heterogeneity between studies. heterogeneity was assessed using cochran’s test and the higgins i2 test, and the differences between studies by the researchers were evaluated using qualitative evaluation. forest plots were used to display the effect size of each study and pooled estimates. a p-value of less than 0.05 was considered statistically significant. results study selection and characteristics after searching all international databases, 1407 articles archivio italiano di urologia e andrologia 2024; 96(4):12833 3 dopa decarboxylase inhibitors and risk of urinary tract infections in parkinson’s disease were found. after removing duplicate articles, 1328 were screened for title and abstract review. following the screening phase, 150 articles were selected for the next phase, where full-text articles were assessed, and nine articles were included in the final analysis (20-28). additionally, the references of the included articles were examined to identify and include related studies. the study selection process is illustrated in figure 1. the included studies were up to march 2024. nine studies comprising 18 records within the time frame were eligible, and they specifically addressed uti as a side effect of dci use in parkinson's disease patients. descriptive data of these studies are presented in table 1 (20-28). risk of bias assessment figure 2 shows the quality assessment results. based on the quality evaluation checklist used, 7 articles were of good quality (low risk), 2 articles had some concerns, and none were of poor quality (high risk). it is noteworthy that all the reviewed studies were randomized trials. in 7 studies, blindness was double-masked, and five studies were phase 3 trials. heterogeneity the results of the chi-squared test and the i2 index indicated no heterogeneity regarding side effects among the studies (i2 = 7.52%, q-value = 14.07, p = 0.661). however, due to the inherent qualitative differences between the studies, a random effects model was used for the analyses. the results of the fixed effects model were also reported. the relative risk of uti side effects based on the random effects model, the relative risk (rr) of uti in patients taking dci (carbidopa) was 26% lower than in patients not taking it, and this reduction was statistically significant (rr treatment/control = 0.74, 95% ci: 0.58-0.95, p = 0.019) (figure 3). similarly, based on the fixed effects model, the results were consistent, showing a 25% lower relative risk of uti in patients taking dci (carbidopa) compared to those not taking it (rr treatment/control = 0.75, 95% ci: 0.60-0.94, p = 0.012) (appendix 1). subgroup analysis the subgroup analysis results based on the type of intervention (dci group vs. other groups) were consistent. in the dci group, the relative risk of uti was 26% lower (rr = 0.74, 95% ci: 0.54-1.03), and in the other group, it was 24% lower (rr = 0.76, 95% ci: 0.56-1.03) (appendix 2). however, the results varied based on the follow-up duration. for follow-ups from 13 to 24 weeks and over 24 weeks, the relative risk was 32% lower (rr = 0.68, 95% ci: 0.46-1.01) and 23% lower (rr = 0.77, 95% ci: 0.58-1.02), respectively. for follow-ups up to 12 weeks, the relative risk was 11% higher (rr = 1.11, 95% ci: 0.37-3.33) (appendix 3). sensitivity analysis the sensitivity analysis showed that the effect size did not change significantly after excluding any individual study, and the results remained statistically significant (appendix 4). figure 1. preferred reporting items for a systematic review and meta-analysis (prisma) 2020 flow diagram for new systematic reviews, including database, registers, and other source searches. archivio italiano di urologia e andrologia 2024; 96(4):12833 i. alshoaibi, b. abdo, m. abdullah, et al. 4 table 1. demographic characteristics of the included studies in the systematic review. d author year of year of starting intervention consumption country sample follow-up publication data collection or control form size time 1 chung, et al (20) 2022 levadopa+carbidopa intestinal gel 9 sites in spain, 8 sites in the united states, 7 sites in italy, 87 26 weeks 4 sites in australia, 3 sites in canada, 3 sites in the republic of korea, 2 sites in greece, 1 site in germany, 1 site in sweden 1 chung, et al (20) 2022 other tablet or capsule 9 sites in spain, 8 sites in the united states, 7 sites in italy, 87 26 weeks 4 sites in australia, 3 sites in canada, 3 sites in the republic of korea, 2 sites in greece, 1 site in germany, 1 site in sweden 2 fahn, et al (21) 2004 1998 levadopa+carbidopa tablet 33 sites in the united states and 5 sites in canada 361 40 weeks 2 fahn, et al (21) 2004 1998 other tablet 33 sites in the united states and 5 sites in canada 361 40 weeks 3 freire-alvarez, et al (22) 2021 levadopa+carbidopa intestinal gel 9 sites in spain, 5 sites in italy, 4 sites in slovakia, 3 sites 61 12 weeks in hungary, 3 sites in greece, 2 sites in the united states, 2 sites in finland 3 freire-alvarez, et al (22) 2021 other tablet or capsule 9 sites in spain, 5 sites in italy, 4 sites in slovakia, 3 sites 61 12 weeks in hungary, 3 sites in greece, 2 sites in the united states, 2 sites in finland 4 hauser, et al (23) 2013 2009 levadopa+carbidopa tablet 35 sites in the united states, 7 sites in ukraine, 7 sites 393 22 weeks (extended-release) in poland, 6 sites in spain, 6 sites in germany, 5 sites in france, 4 sites in romania, 3 sites in canada 4 hauser, et al (23) 2013 2009 levadopa+carbidopa tablet 35 sites in the united states, 7 sites in ukraine, 393 22 weeks (immediate release) 7 sites in poland, 6 sites in spain, 6 sites in germany, 5 sites in france, 4 sites in romania, 3 sites in canada 5 hauser, et al (24) 2023 2018 levadopa+carbidopa tablet 56 sites in the united states, 15 sites in spain, 8 sites 506 20 weeks (extended-release) in germany, 8 sites in italy, 7 sites in poland, 7 sites in poland, 6 sites in czechia, 6 sites in germany, 5 sites in france, 3 sites in the united kingdom 5 hauser, et al (24) 2023 2018 levadopa+carbidopa tablet 56 sites in the united states, 15 sites in spain, 8 sites 506 20 weeks (immediate release) in germany, 8 sites in italy, 7 sites in poland, 7 sites in poland, 6 sites in czechia, 6 sites in germany, 5 sites in france, 3 sites in the united kingdom 6 olanow, et al (25) 2004 levadopa+carbidopa tablet multicenter 750 26 weeks 6 olanow, et al (25) 2004 other tablet multicenter 750 26 weeks 7 rascol, et al (26) 2016 2012 levadopa+carbidopa tablet 10 sites in the united states, 3 sites in poland, 2 sites 68 12 weeks in slovakia, 1 site in germany 7 rascol, et al (26) 2016 2012 other tablet 10 sites in the united states, 3 sites in poland, 2 sites 68 12 weeks in slovakia, 1 site in germany 8 schapira, et al (27) 2017 2009 levadopa+carbidopa tablet / tablet 28 sites in the united states, 12 sites in germany, 12 sites 549 24 weeks and/or in hungary, 8 sites in india, 6 sites in israel, 6 sites in slovakia, levadopa+ benserazide 6 sites in canada, 6 sites in belgium, 5 sites in thailand, 5 sites in the united kingdome, 5 sites in france, 4 sites in spain, 3 sites in the republic of korea, 3 sites in taiwan, 3 sites in new zealand, 2 sites in australia, 2 sites in austria, 2 sites in malaysia, 2 sites in switzerland, 1 site in estonia, 1 site in the netherlands 8 schapira, et al (27) 2017 2009 other tablet 28 sites in the united states, 12 sites in germany, 12 sites 549 24 weeks in hungary, 8 sites in india, 6 sites in israel, 6 sites in slovakia, 6 sites in canada, 6 sites in belgium, 5 sites in thailand, 5 sites in the united kingdome, 5 sites in france, 4 sites in spain, 3 sites in the republic of korea, 3 sites in taiwan, 3 sites in new zealand, 2 sites in australia, 2 sites in austria, 2 sites in malaysia, 2 sites in switzerland, 1 site in estonia, 1 site in the netherlands 9 stocchi, et al (28) 2010 levadopa+carbidopa tablet 31 sites in the united states, 6 sites in italy, 5 sites in germany, 744 134 weeks 5 sites in finland, 4 sites in sweden, 4 sites in france, 4 sites in the united kingdom, 4 sites in canada, 2 sites in greece, 2 sites in belgium, 2 sites in spain, 2 sites in switzerland, 1 site in australia, 1 site in turkey 9 stocchi, et al (28) 2010 other tablet 31 sites in the united states, 6 sites in italy, 5 sites in germany, 744 134 weeks 5 sites in finland, 4 sites in sweden, 4 sites in france, 4 sites in the united kingdom, 4 sites in canada, 2 sites in greece, 2 sites in the belgium, 2 sites in the spain, 2 sites in the switzerland, 1 site in the australia, 1 site in the turkey archivio italiano di urologia e andrologia 2024; 96(4):12833 5 dopa decarboxylase inhibitors and risk of urinary tract infections in parkinson’s disease figure 2. risk of bias assessment: (a) risk of bias summary of all included randomized clinical trials (rcts); (b) detailed risk of bias. figure 3. meta-analysis of the relative risk of urinary tract infection complications in parkinson's disease patients; ci: confidence interval. archivio italiano di urologia e andrologia 2024; 96(4):12833 i. alshoaibi, b. abdo, m. abdullah, et al. 6 appendix 1. meta-analysis of the relative risk of urinary tract infection in parkinson’s disease patients using decarboxylase inhibitors (carbidopa); ci: confidence interval. appendix 2. subgroup meta-analysis of the relative risk of urinary tract infection in parkinson’s disease patients using decarboxylase inhibitors (carbidopa) based on type of intervention; ci: confidence interval. appendix archivio italiano di urologia e andrologia 2024; 96(4):12833 7 dopa decarboxylase inhibitors and risk of urinary tract infections in parkinson’s disease appendix 3. subgroup meta-analysis of the relative risk of urinary tract infection in parkinson’s disease patients using decarboxylase inhibitors (carbidopa) based on treatment duration; ci: confidence interval. appendix 4. sensitivity analysis results of the studies included in the meta-analysis with the exclusion of one study; ci: confidence interval. archivio italiano di urologia e andrologia 2024; 96(4):12833 i. alshoaibi, b. abdo, m. abdullah, et al. 8 publication bias finally, a funnel plot was created to assess publication bias for the uti complication of dci. egger's test results did not confirm the presence of publication bias for uti complications (bias: -0.19, se = 0.48, p = 0.693) (figure 4). discussion our study results indicated that the use of dci drugs in pd patients is a protective factor against uti. furthermore, the duration of treatment is significantly essential, because dci use for less than 12 weeks is associated with an increased relative risk of developing uti in pd patients whereas long-term use has shown a protective effect against uti. findings from a prospective cross-sectional study by chaudhuri et al. indicated that the occurrence of uti in pd patients using carbidopa gel is 3% (20). additionally, a cross-sectional survey by fernandez et al. reported a uti incidence of 11.4% due to levodopa-carbidopa intestinal gel use in pd patients (21). another study by fernandez et al. reported that the occurrence of uti in carbidopa users was 7.8% (29). different results regarding uti incidence have been obtained in randomized and controlled studies. a 134-week prospective double-blind trial by stocchi et al. (28) reported that uti occurrence in patients using levodopa and carbidopa was 1% higher than in the control group. conversely, in a prospective, double-anonymized, placebo-controlled trial, olanow et al. (25) reported that uti occurrence was half as frequent in the levodopa and carbidopa group compared to the control group. both studies compared entacapone in pd patients using levodopa and carbidopa, but differences in sample size, length of follow-up, and the duration of parkinson's disease may explain the divergent results. our study demonstrated that although levodopa with dci was associated with a reduced incidence of uti, it did not significantly differ from other drugs used with levodopa in reducing uti occurrence. mechanistically, carbidopa increases the conversion of levodopa to dopamine in the central nervous system (cns), reducing peripheral side effects during pd treatment (30). although the effects of levodopa on urinary infections are not well-defined, some previous animal and human studies have shown that acute activation of d2 receptors worsens bladder function (31, 32). conversely, a survey of parkinsonian monkeys demonstrated that tonic activation of d1 receptors prevents bladder voiding (33). residual urine can be associated with urinary infections (34, 35). therefore, by preventing the peripheral conversion of levodopa, carbidopa causes a greater amount of levodopa to reach the brain, and as a result, the dose of levodopa consumed is reduced and its side effects are avoided (36). another mechanism suggests that inflammatory genes are expressed in pd, leading to immune cell infiltration into the brain and increased activated/memory t cells (37). in a laboratory study by zhu et al. (30), carbidopa was shown to inhibit t cell responses and autoimmunity in two animal models of parkinson's, potentially increasing infection risk. they concluded that this indicates the immunosuppressive activity of this dci. further studies are needed to better understand the relationship between carbidopa and urinary tract infection. a cross-sectional study by gremke et al. (11) used another dci, benserazide, instead of carbidopa. the study (11) did not show a significant relationship between the two dci drugs, but benserazide had better protective effects compared to carbidopa. due to a lack of studies for comparison, we did not focus on benserazide, and most of our results pertain to carbidopa. nonetheless, we recommend future studies to investigate urinary complications, particularly uti, in pd patients using benserazide. a phase 3 interventional study by freire-alvarez et al. (22) reported that uti occurrence in pd patients was 7% figure 4. funnel plot for the studies assessing urinary tract infection complication of carbidopa; ci: confidence interval. archivio italiano di urologia e andrologia 2024; 96(4):12833 9 dopa decarboxylase inhibitors and risk of urinary tract infections in parkinson’s disease higher in the group treated with carbidopa-levodopa for 12 weeks compared to the control group. fernandez et al. also noted an increasing trend in uti occurrence up to week 13, followed by a decreasing trend until week 54 (29). our study also found that treatment with levodopa and dci (carbidopa) increased the risk of uti within 12 weeks, while the risk decreased in the 13-24 week and ¬> 24-week periods. an open-label phase 3b study by standaert et al., examining non-motor symptoms in pd patients using carbidopa gel over 60 weeks, reported a significant reduction in urinary symptoms up to week 12, but this reduction was not sustained. they used the nonmotor symptoms scale (nmss) scoring system, which only assesses urgency, frequency, and nocturia, whereas our study focused solely on uti occurrence. uti is a significant cause of hospitalization and mortality in pd patients. management strategies for uti in pd patients mainly involve preventive measures, including vitamin supplements, estrogen supplements, prophylactic antibiotics, and hygiene practices in catheterization cases (38). given our study's finding of a 32% relative risk reduction in uti occurrence in pd patients using dci (carbidopa) during weeks 13-24, we recommend future studies focus on dci drugs in patients with parkinson's disease who suffer from urinary symptoms, especially uti, in this treatment period so that they can benefit from the maximum protective effects of dci drugs, especially carbidopa. further research is necessary to optimize pd treatment, considering the associated urological complications and infections. limitations and strengths: this study is the first systematic review and meta-analysis examining uti occurrence in pd patients using dci drugs. however, it has some limitations. firstly, many studies were excluded due to the need of randomization and control groups. secondly, control groups in the studies were highly heterogeneous, potentially affecting the comparison of dci drug effects. thirdly, not all studies provided detailed information on specific variables, so the intended outcome in this study was not reported in terms of the dosage of the drugs used, and it was impossible to estimate the relative risk based on the dosage. conclusions our study showed that dci use, along with levodopa in pd patients, is associated with a reduced relative risk of uti occurrence. however, this reduction was not specific to dci drugs, as other medications used with levodopa also reduced uti occurrence. subgroup analysis indicated that the relative risk of uti significantly decreased starting from the 13 to 24-week treatment period with dci. these findings can help researchers better manage the primary cause of hospitalization and mortality in pd patients that is uti. additionally, researchers can use these findings to design future studies more effectively, focusing on the type of drug and treatment duration with dci drugs, especially carbidopa. acknowledgments the authors would like to thank the general manager of althora general hospital, ibb, yemen, dr. abdulghani ghabisha, for editorial assistance. references 1. demaagd g, philip a. parkinson's disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. p t. 2015; 40:504-32. 2. aarsland d, batzu l, halliday gm, et al. parkinson disease-associated cognitive impairment. nat rev dis primers. 2021; 7:47. 3. bloem br, okun ms, klein c. parkinson's disease. lancet. 2021; 397:2284-303. 4. ou z, pan j, tang s, et al. global trends in the incidence, prevalence, and years lived with disability of parkinson's disease in 204 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disease medication and the risk of lower urinary tract infection (luti): a retrospective cohort study. j clin med. 2022; 11:7077 12. okunoye o, kojima g, marston l, et al. factors associated with hospitalisation among people with parkinson's disease a systematic review and meta-analysis. parkinsonism relat disord. 2020; 71:66-72. 13. hogg e, frank s, oft j, et al. urinary tract infection in parkinson's disease. j parkinsons dis. 2022; 12:743-57. 14. fernandez hh, boyd jt, fung vsc, et al. long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced parkinson's disease. mov disord. 2018; 33:928-36. 15. espay a, hauser r, dhall r, et al. long-term safety and efficacy of ipx203 in parkinson’s disease patients with motor fluctuations: a 9-month open-label extension trial (s32.006). neurology. 2023; 100(17 suppl 2):2472. 16. boyd jt, zadikoff c, benesh ja, et al. a post hoc comparison of levodopa-carbidopa intestinal gel daytime monotherapy vs polytherapy safety and 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disease. n engl j med. 2004; 351:2498-508. 22. freire-alvarez e, kurca e, lopez manzanares l, et al. levodopacarbidopa intestinal gel reduces dyskinesia in parkinson's disease in a randomized trial. mov disord. 2021; 36:2615-23. 23. hauser ra, hsu a, kell s, et al. extended-release carbidopa-levodopa (ipx066) compared with immediate-release carbidopa-levodopa in patients with parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. lancet neurol. 2013; 12:346-56. 24. hauser ra, espay aj, ellenbogen al, et al. ipx203 vs immediate-release carbidopa-levodopa for the treatment of motor fluctuations in parkinson disease: the rise-pd randomized clinical trial. jama neurol. 2023; 80:1062-9. 25. olanow cw, kieburtz k, stern m, et al. double-blind, placebocontrolled study of entacapone in levodopa-treated patients with stable parkinson disease. arch neurol. 2004; 61:1563-8. 26. rascol o, zesiewicz t, chaudhuri kr, et al. a randomized controlled exploratory pilot study to evaluate the effect of rotigotine transdermal patch on parkinson's disease-associated chronic pain. j clin pharmacol. 2016; 56:852-61. 27. schapira ah, fox sh, hauser ra, et al. assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with parkinson disease and motor fluctuations: a randomized clinical trial. jama neurology. 2017; 74:216-24. 28. stocchi f, rascol o, kieburtz k, et al. initiating levodopa/carbidopa therapy with and without entacapone in early parkinson disease: the stride-pd study. ann neurol. 2010; 68:18-27. 29. fernandez hh, vanagunas a, odin p, et al. levodopa-carbidopa intestinal gel in advanced parkinson's disease open-label study: interim results. parkinsonism relat disord. 2013; 19:339-45. 30. zhu h, lemos h, bhatt b, et al. carbidopa, a drug in use for management of parkinson disease inhibits t cell activation and autoimmunity. plos one. 2017; 12:e0183484. 31. uchiyama t, sakakibara r, hattori t, yamanishi t. short-term effect of a single levodopa dose on micturition disturbance in parkinson's disease patients with the wearing-off phenomenon. mov disord. 2003; 18:573-8. 32. brusa l, petta f, pisani a, et al. central acute d2 stimulation worsens bladder function in patients with mild parkinson's disease. j urol. 2006; 175:202-6 33. yoshimura n, mizuta e, yoshida o, kuno s. therapeutic effects of dopamine d1/d2 receptor agonists on detrusor hyperreflexia in 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys. j pharmacol exp ther. 1998; 286:228-33. 34. byron jk. urinary tract infection. vet clin north am small anim pract. 2019; 49:211-21. 35. storme o, tiran saucedo j, garcia-mora a, et al. risk factors and predisposing conditions for urinary tract infection. ther adv urol. 2019; 11:1756287218814382. 36. gilbert ja, frederick lm, ames mm. the aromatic-l-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. clin cancer res. 2000; 6:4365-72. 37. tan ek, chao yx, west a, et al. parkinson disease and the immune system associations, mechanisms and therapeutics. nat rev neurol. 2020; 16:303-18. 38. aslam s, albo m, brubaker l. recurrent urinary tract infections in adult women. jama. 2020; 323:658-9. correspondence ismaeel alshoaibi, md drismsho@gmail.com basheer abdo abdobasheer500@gmail.com mohammed abdullah, md dr.moh.moqbel@gmail.com khaled alzanen, md khaledhamoud409@gmail.com mohammed alhakamy, md wwkkh2018@gmail.com mamoon al-namer, md m_namer@yaho.com afrah salem, md salemafrah111@gmail.com mohammed almogahed, md mugahedmoham123@gmail.com department of internal medicine, school of medicine, ibb university, ibb, yemen abdulghani al-hagri, md alhagriabdulghani@gmail.com student research committee, faculty of medicine and health sciences, sana'a university, sana'a, yemen urology office, althora general hospital, alodine street, ibb (yemen) morshed salah, md morshed.salah@gmail.com urology section, surgery department, hazm mebaireek general hospital, hamad medical corporation, doha, qatar. ibrahim alnadhari, md ibrahimah1978@yahoo.com department of surgery, school of medicine, qatar university, doha, qatar al wakra hospital, hamad medical corporation, al wakra, (qatar) faisal ahmed, md (corresponding author) fmaaa2006@yahoo.com department of urology, school of medicine, ibb university, ibb, yemen conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):14085 1 review the formation of kidney stones is a complex biologic process involving interactions among genetic, anatomic, dietary, and environmental factors. traditional lithogenic models were based on urine supersaturation in relation to the activity of crystallization promoters and inhibitors. however, modern research has added new principles such as the “renal epithelial cell response” and the role of inflammation and oxidative stress leading to the development of a “multi-hit hypothesis”. a strong correlation between urinary stones and kidney damage has been well demonstrated by both cohort and case-control studies. the main contributors to chronic kidney damage associated with urinary stones include crystal deposition within the renal parenchyma, associated comorbidities, repeated obstructive and infectious episodes, as well as the potential adverse effects of stone removal procedures. most hereditary stones may management of urinary stones by experts in stone disease (esd 2025) athanasios papatsoris 1, bogdan geavlete 2, george daniel radavoi 3, mohammed alameedee 4, murtadha almusafer 5, m. hammad ather 6, alberto budia 7, alin adrian cumpanas 8, murat can kiremit 9, athanasios dellis 10, mohamed elhowairis 11, juan antonio galán-llopis 12, petrisor geavlete 13, jordi guimerà garcia 14, bernat isern 15, viorel jinga 3, juan manuel lopez 16, juan antonio mainez 17, iraklis mitsogiannis 1, jorge mora christian 18, mohammad moussa 19, razvan multescu 2, yusuf oguz acar 20, kremera petkova 21, adria pinero 22, elenko popov 23, maria ramos cebrian 24, stefan rascu 3, roswitha siener 25, petros sountoulides 26, kyriaki stamatelou 27, jaffry syed 28, alberto trinchieri 29 1 national kapodistrian university of athens, 2nd university urology clinic, sismanoglio hospital, athens, greece; 2 “carol davila” university of medicine and pharmacy, "saint john" emergency clinical hospital, bucharest, romania; 3 clinical hospital of urology prof. dr. theodor burghele, bucharest, romania; 4 diwaniya teaching hospital, diwaniyah, iraq; 5 university of basrah, college of medicine, basrah, iraq; 6 urology department at the aga khan university, karachi, pakistan; 7 urology department la fe university and polytechnic hospital, valencia, spain; 8 department of urology, victor babeş university of medicine and pharmacy, timisoara, romania; 9 koç university school of medicine, department of urology, istanbul, turkey; 10 2nd department of surgery, aretaieion academic hospital, school of medicine, national and kapodistrian university of athens athens, greece; 11 london clinic, london (uk); 12 department of urology, general university hospital dr balmis, isabial, alicante, spain; 13 romanian academy of medical sciences; 14 lithiasis unit, urology department, son espases university hospital, palma, spain; 15 renal lithiasis and pathological calcification group (lircap), research institute of health sciences (iunics), university of the balearic islands, spain & health research institute of the balearic islands (idisba), spain; 16 urology department, icnu barcelona university clinic hospital, barcelona, spain; 17 urologist, la paz university hospital, madrid, spain; 18 urologia clínica bilbao, imq zorrotzaurre university hospital and deusto university, bilbao, spain; 19 faculty of medicine at lebanese university, beirut, lebanon; 20 liv vadistanbul hospital, istanbul, turkey; 21 department of urology and nephrology, military medical academy, sofia, bulgaria; 22 urology department, hospital del mar, barcelona, spain; 23 medical university sofia, department of urology, umhat “tzaritza yoanna-isul”, bulgaria; 24 renal transplant unit hospital universitari i politècnic la fe, renal lithiasis, valencia, spain; 25 university stone center, department of urology and pediatric urology, university hospital bonn, bonn, germany; 26 1st urology department, aristotle university of thessaloniki, greece; 27 “mesogeios” nephrology center, athens, greece; 28 university college hospital, galway clinic and bons secours hospital, galway, ireland; 29 cdc ambrosiana, cesano b, milan, italy. doi: 10.4081/aiua.2025.14085 summary cause high urinary saturation levels promoting obstruction of the bellini ducts and consequent glomerulosclerosis and interstitial fibrosis in the cortex. these include hereditary hypercalciurias, primary hyperoxalurias, cystinuria, adenine phosphoribosyltransferase (aprt) deficiency (associated with 2,8-dihydroxyadenine lithiasis) and xanthinuria. complete distal renal tubular acidosis occurs in childhood and presents deafness, rickets, and a short life expectancy. the incomplete form usually manifests in adulthood, primarily with recurrent urinary lithiasis, and less frequently with nephrocalcinosis. in all stone formers stone analysis and a basic metabolic evaluation, including blood biochemistry, urine sediment examination, urinary ph and culture are mandatory, in contrast high-risk stone formers require a more specific metabolic evaluation, including a 24-hour urine sample to measure calcium, phosphate, citrate, archivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 2 oxalate, uric acid, magnesium, sodium and proteinuria. the morpho compositional analysis of kidney stones offers essential insights beyond merely identifying their predominant chemical component. this approach reveals key aspets of the stone formation, such as nucleation sites, crystal growth patterns, and the presence of specific lithogenic processes. the ideal analytical protocol combines stereoscopic microscopy (stm), scanning electron microscopy with energy-dispersive x-ray spectroscopy (sem-eds), and, when necessary, fourier-transform infrared spectroscopy (ftir). recurrence prevention and managing residual fragments require complementary strategies such as lifestyle modifications, dietary interventions, and pharmacological therapies. among pharmacological options, alkaline citrate salts, particularly potassium citrate, are widely used due to their ability to modify urinary chemistry and inhibit stone formation. recently, novel molecules have been introduced into the management of renal stone disease. phytate a naturally occurring polyphosphorylated carbohydrate, exibits a potent inhibitory effect on calcium salt’s nucleation, growth, and aggregation. theobromine, another natural compound, has been shown to effectively inhibit uric acid crystallization. the co-administration of urinary alkalinizing agents, such as potassium citrate, alongside theobromine has been proposed as a therapeutic strategy to optimize uric acid solubility and to reduce the risk of excessive alkalinization and subsequent sodium urate precipitation. struvite stones are caused by urinary tract infection with urease-producing microorganisms. their treatment requires specific measures including complete surgical stone removal, short or long-term antibiotic treatment, to maintain urinary acidification to a ph below 6.2, and a urine volume of at least 2 litres/24 hours. l-methionine has been shown to effectively lower urine ph and the relative supersaturation of struvite. an essential aspect of medical management of urinary stone disease is treatment adherence, which depends on perceived benefit, treatment duration, and side effect profile. the side effects of citrate treatment are mild gastrointestinal disorders whereas thiazide diuretics tend to cause hypokalemia-related symptoms and less frequent metabolic and dermatologic side effects. urease inhibitors for struvite stones and drugs used to enhance cystine solubility are more frequently associated with side effects. the use of smartphone applications can support patients by promoting adequate hydration, adherence to dietary recommendations, and compliance with prophylactic medication. endoscopic techniques currently play a prevalent role in the removal of renal stones, while extracorporeal shock wave lithotripsy is today marginally used for specific indications. different technical modalities can be used for percutaneous nephrolithotomy (pcnl), each with its own advantages and disadvntages (standard vs. mini, prone vs. supine, fluoroscopic vs ultrasound-guided). flexible ureteroscopy or retrograde intrarenal renal surgery (rirs) has extended its indications due to technological advancements in endoscopes and their accessories. the availability of new laser technologies (thulium fiber laser and pulse-modulated ho:yag laser) has enhanced stone fragmentation and dusting capabilities. however, their use exposes the renal parenchyma to high temperatures and pressures which could potentially contribute to renal damage. factors influencing heat release include laser type and settings, exposure time, stone location, fiber-to-stone distance, irrigation volume and fluid circulation. reduction of heat release can be achieved by limiting the laser settings to reasonable values or by improving fluid circulation with use of ureteral access sheaths, especially those navigable and equipped with suction. high intrarenal pressure is also closely associated with renal damage. sustained high pressure or even pressure spikes may increase this risk, highlighting the importance of real-time pressure monitoring through sensors integrated on guidewires, scopes, access sheath and use of innovative platforms regulating irrigation/suction systems. direct in-scope suction (diss) system was developed to control intrarenal pressure and facilitate the removal of residual fragments. flexible and navigable suction ureteral access sheath (fans-uas) is a flexi-bendable uas equipped with suction capabilities combining mechanical flexibility with continuous irrigation management and stone clearance mechanisms. ultra-thin scopes (7.5 f) make it easy to perform rirs without the need for pre-placed double-j stents or with a 9 f sheath achieving more space for stone fragments expulsion or infusion. all these technological advancements have enhanced the efficacy of furs or rirs which can be an alternative treatment (salvage furs) when standard stone management techniques, such as percutaneous nephrolithotomy (pcnl), are contraindicated or fail. salvage furs has shown favorable outcomes in complex or high-risk cases, including patients with coagulopathies, morbid obesity, renal anatomical abnormalities (e.g., horseshoe or pelvic kidneys), urinary diversion, calyceal diverticula, and altered urinary tracts. in such scenarios it demonstrated favorable outcomes with stone-free rates ranging from 55.6% to 64% for stones > 2 cm. although non-invasive, extracorporeal and endoscopic treatments for renal and ureteral stones carry a risk of complications that can be classified according to the clavien-dindo system. the complication rate after swl was estimated at 18.43% for clavien grade i-ii complications (pain, hematuria) and 2.48% for clavien iii-iv complications (hematoma, sepsis). the most frequent complication after rirs is fever or urinary tract infection observed in 0.2-15% (with 0.1-4.3% of cases of urinary sepsis). complications after pcnl are more frequent and may include moderate events (hemorrhage requiring transfusion 2-7%, urosepsis 1-2%, bowel injury < 1%) as well as severe events (arteriovenous fistula 0.5-1%, thoracic complications < 1% , loss of access tract 1-3%, death < 0.5%). the risk of bleeding complications is significantly increased in patients on antithrombotic therapy. a personalized, interdisciplinary approach enables optimal decision-making in balancing antithrombotic therapy with surgical safety during urological stone interventions finally, it must be considered that endourological procedures can be harmful to the surgeons themselves and their team due to exposure to ionizing radiation. for this reason, procedures must be carried out in strict accordance with safety guidelines and regulations to minimize radiation exposure. safety is vital in any surgical intervention, with efficacy being the next most critical consideration. however, cost-effectiveness should be also considered. endourology involves high costs largely due to the use of sophisticated equipment that requires frequent renewal due to the continuous rapid technological evolution. using disposable devices brings numerous benefits but also leads to a further increase in costs. finally, in the cost-benefit assessment, the rate of reintervention associated with some types of procedures must be considered. key words: urinary calculi; citrate; phytate; theobromine; shock wave lithotripsy; retrograde intrarenal lithotripsy; percutaneous nephrolithotomy; direct scope suction; flexible and navigable suction ureteral access sheath. submitted 19 june 2025; accepted 27 june 2025 archivio italiano di urologia e andrologia 2025; 97(2):14085 3 management of urinary stones introduction (almusafer m, geavlete b, geavlete p, jinga v, mitsogiannis i, moussa m, oguz acar y, papatsoris a, radavoi d) the experts in stone disease (esd) conference was founded with a clear purpose: to bring together experts worldwide, foster collaboration, and drive innovation in stone disease treatment. over the years, esd has become a recognized global platform for exchanging knowledge, combining traditional and emerging treatment approaches, and advancing technology and pharmacology. just as importantly, it continues to inspire and educate the next generation of urologists. the 7th edition of the esd conference was held in bucharest on 11-12 april 2025 under the presidency of professors thanos papatsoris, bogdan geavlete and daniel radavoi in conjunction with the 10th romanian nephro-urology conference. etiopathogenesis lithogenesis processes (kyriaki stamatelou) the formation of kidney stones is a complex biologic process involving interactions of genetic, anatomic, dietary, and environmental factors. the traditional lithogenesis models emphasize 1. urine supersaturation, 2. the role of crystallization promoters and inhibitors, and 3. randall’s plaques, as the primary pathophysiologic stone formation mechanisms (1, 2). modern research has added the “renal epithelial cell response” and the pivotal role of inflammation and oxidative stress to form a “multi-hit hypothesis” (3, 4). the scheme describing the physicochemical mechanisms of stone formation has evolved to a multiple-step sequential process involving: supersaturation, oxidative stress, cell apoptosis and/or necrosis, cell injury, crystal nucleation, crystal growth, crystal aggregation, crystal cell interaction, crystal adhesion and stone formation. an imbalance between stone inhibitors (magnesium, citrate, pyrophosphate, phytate, uromodulin, osteopontin, nephrocalcin, etc) and stone promoters (calcium, sodium, oxalate, uric acid, etc) precedes and triggers supersaturation. in the “supersaturation zone of urine” the formation of new crystals occurs spontaneously, the pre-existing crystals may grow, and crystal aggregation is more likely. the pathogenic components of lithogenesis include: • the urinary solute supersaturation that provides the necessary milieu for stone formation. • the nucleus that provides a substrate for crystal growth in supersaturated urine. injured epithelial cells may serve as nuclei. nucleation occurs on randall’s plaques. • the plaques of randall and plugs which are no longer considered as mere incidental findings but as active pathologic features that act as initiators of calciumbased stones. chronic inflammation is increasingly viewed as a trigger and amplifier in the lithogenesis. it influences crystal adhesion, growth, and retention in renal tissue: • crystals induce localized inflammation and oxidative stress, leading to renal epithelial injury. epithelial injury induces the production of 1.pro-inflammatory cytokines (e.g., il-6, il-1β, tnf-α), 2. mineralization modulators (e.g. osteopontin, inter-α-trypsin inhibitor, fibronectin, matrix gla protein) and 3. promotes osteogenic changes in epithelial cells. • reactive oxygen species are produced in response to intratubular crystals and induce the expression of molecules known to promote calcification. oxidative stress and the production of caspases and inflammatory cytokines further promote mitochondrial changes and macrophage infiltration. • exposure to crystals favors the expression of the proinflammatory m-1 phenotype of macrophages thus perpetuating the inflammatory response. • injured cells promote crystal adhesion and aggregation. finally, the urinary and gut microbiomes have recently been recognized as pathogenetic elements and modulators of stone risk: oxalate-degrading bacteria (e.g., oxalobacter formigenes) reduce urinary oxalate, and “dysbiosis” is considered to promote lithogenesis. research is focusing on probiotic or microbiome-modifying therapies as potential treatments. a better understanding of inflammation activation and modulation of the immune response to urine supersaturation and crystal deposition, as well as effective targeting of inflammatory pathways may provide promising new therapeutic options to reduce lithogenesis and kidney stone recurrence. renal impairment and eskd in stone patients (alberto trinchieri) the correlation between urinary stones and kidney damage has been well described since the beginning of the last century with the description of single cases or small series up to the most recent cohort and case-control studies. vupputuri et al. (5) demonstrated that a history of kidney stones was more frequent in a large series of patients with chronic kidney disease compared to controls matched for sex and age. the or for ckd of patients with a history of kidney stones was 1.9. a meta-analysis of seven studies confirmed that the history of kidney stones was associated with an increased adjusted risk estimate for ckd (rr 1.47, ci1.23-1.76) (6). the causes of chronic kidney damage associated with urinary stones include crystal deposition in the renal parenchyma, related comorbidities, repeated obstructive and infectious episodes and the effect of treatments for stone removal. in very high urinary saturation levels, obstruction of the bellini ducts may occur due to crystal plugs with consequent glomerulosclerosis and interstitial fibrosis in the cortex. these conditions are created in the case of most hereditary stones such as hereditary hypercalciurias (e.g. dent’s disease), primary hyperoxalurias, deficiency of adenine-phospho-ribosyl transferase (2,8 hydroxyadenine) and, to a lesser extent, cystinuria. plugging of the bellini ducts can also be observed in some forms of acquired stones such as brushite stones which are often associated with high levels of calciuria and are resistant to swl. ckd can also be caused by comorbidities frequently associated with renal stone formation, such as type 2 diabetes. the effects of ureteral obstruction are well demonstrated by experimental studies of ureteral ligation in rats. in clinical conditions, obstruction is incomplete and interarchivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 4 mittent, still, repeated and prolonged episodes without relief of the obstruction can be associated with a loss of functional nephrons with hyperfiltration and overload of the residual nephrons resulting in the onset of chronic kidney disease over time. for this reason, urinary tract decompression or treatment of ureteral stones should be timely, especially in case of severe obstruction. the maximum waiting time is not well defined by the guidelines, although the aua recommends definitive stone treatment after conservative treatment of 4-6 weeks (7). studies on urinary excretion of renal tubular damage markers have shown that open renal stone surgery causes significant renal tubular damage, especially in treating staghorn renal stones with nephrotomies with temporary clamping of the renal artery (8). however, even noninvasive treatment can cause transient renal damage. extracorporeal shock wave lithotripsy induces a measurable alteration of urinary renal tubular enzymes related to the number and energy of shock waves which is due to renal vasoconstriction and hemorrhagic microlesions. these renal “bioeffects” after swl are even slightly higher than those observed after percutaneous nephrolithotomy (pcnl) and retrograde intrarenal surgery (rirs). in contrast, the bioeffects of pcnl are higher than those of rirs. long-term studies after swl have not shown significant gfr alterations or unexpected blood pressure increases. however, it must be considered that all these forms of treatment can cause obstructive or vascular complications that can cause renal damage in a single case, so their use must be carefully planned to minimize the potential risks of iatrogenic damage. finally, the recent use of new technologies for intracorporeal lithotripsy potentially exposes the kidney to risks related to high intrarenal pressures or temperatures. these potential causes of morbidity must be carefully evaluated to define better protocols ensuring the safety of the treatment. rare stones (maria ramos) these stones are not prevalent, accounting for just 1-3%. many have a genetic basis and a high recurrence rate (9-11). cystinuria is considered one of the most complex conditions to treat and is suspected in young patients with a high recurrence rate and weakly radiopaque, bilateral stones. the diagnosis can be made by analysing kidney stones, observing cystine crystals (pathognomonic) in the urinary sediment, or detecting an abnormal excretion of cystine and dibasic amino acids in the urine. genetic analysis is not mandatory, and the incidence of end-stage kidney disease remains relatively low. treatment consists of increasing fluid intake, modifying the diet and taking citrate to increase cystine solubility and maintain urine ph at 7-7.5. we use d-penicillamine and tiopronin to bind cystine in the urine in refractory cases. however, they have serious side effects and are often poorly tolerated, which is why some alternative drugs have been investigated, such as tolvaptan, alpha-lipoic acid and isglt2, but the results are not conclusive. adenine phosphoribosyltransferase (aprt) deficiency is an inherited disorder that leads to 2,8-dihydroxyadenine lithiasis. it can present as urolithiasis or crystalline nephropathy, and the stones are radiolucent with no metabolic alterations in urine or blood. these stones do not respond to alkali therapy. the treatment consists of high fluid intake and allopurinol. hereditary xanthinuria is caused by a xanthine oxidase deficiency, resulting in hypouricaemia and hypouricosuria. since the solubility of xanthine is unaffected by urinary ph, alkalisation is ineffective. distal tubular acidosis in idiopathic stone patients (jordi guimerà garcia) distal renal tubular acidosis (drta) has two clinical forms: complete and incomplete. the complete form mainly occurs in childhood and presents deafness, rickets, and a short life expectancy. the incomplete form generally occurs in adulthood and presents recurrent urinary lithiasis, and, sometimes, nephrocalcinosis. the etiopathogenesis of incomplete drta is the partial inability to excrete acid (h+) into the urine. incomplete drta has the following biochemical characteristics: normal serum ph, alkaline urinary ph (ph > 6), hypercalciuria, and hypocitraturia. hypercalciuria is due to elevated bone resorption; the patient does not have metabolic acidosis because they compensate with calcium from the bone (buffer effect) (12). renal stones commonly associated with incomplete drta are calcium oxalate dihydrate, hydroxyapatite, and brushite. the diagnosis of incomplete drta can be made using the furosemide test or the acid overload test (gold standard). if the furosemide test is performed on patients with the aforementioned characteristics, it has a specificity and sensitivity equivalent to the gold standard (13). treatment for incomplete drta is not well established. traditionally, treatment involved alkalizing the patient to offset the buffering effect and reduce bone resorption. a recent study demonstrated the efficacy of phytate (300400 mg every 12 hours) as an inhibitor of bone resorption and reduction of hypercalciuria in patients with incomplete drta (14). diagnostics metabolic workup (maria ramos) metabolic studies are necessary to diagnose and evaluate the response to preventive measures (15-17). the lithogenic risk of a patient is determined by metabolic disturbances, as well as urine ph and volume. urine ph is critical in cystinuria, uric acid stones and infectious stones. changes in urine composition can be caused by increasead crystallization promoters (such as calcium, phosphate, oxalate, uric acid or cystine) or a deficit of crystallization inhibitors (such as citrate, magnesium and phosphate). stone analysis and basic metabolic evaluation are mandatory for all stone formers. crystalluria is valuable in assessing the probability of stone recurrence and indicating treatment efficacy. adult patients who have had a single episode of calcium lithiasis require a basic evaluation including blood tests for glucose, urea, creatinine, sodium, potassium, magnesium, chloride, uric acid, calcium, phosphate, bicarbonate, parathyroid hormone (pth) and vitamin d, as well as urine tests for sediment, ph and culture. high-risk stone formers (those with recurrent nephrolithiasis, persistent residual lithiasis or nephocalcinosis, as well as children and young adults) require a more specific metaarchivio italiano di urologia e andrologia 2025; 97(2):14085 5 management of urinary stones bolic evaluation, which also includes a 24-hour urine sample to measure calciuria, phosphaturia, citraturia, oxaluria, uricosuria, magnesiuria, natriuresis and proteinuria. alternatively, spot urine samples can be used, particularly when a 24-hour urine collection is difficult. the first follow-up 24-hour urine measurement should be taken eight to twelve weeks after starting pharmacological prevention of stone recurrence. once urinary parameters have normalized, an evaluation every twelve months is sufficient. stone analysis (bernat isern) the morpho-compositional analysis of kidney stones offers essential insights beyond merely identifying their predominant chemical component (18). this type of analysis reveals crucial information about the conditions of stone formation, including nucleation, growth patterns, and the presence of specific lithogenic processes. it reconstructs the patient’s lithiasis history sequentially evaluating the stone from nucleus to surface, guiding tailored diagnostic and therapeutic decisions. while metabolic analyses are helpful, they often provide only a snapshot of current urinary conditions, which may not reflect the original lithogenic environment. in contrast, the stone itself serves as a record of past events, making morpho-compositional analysis a more reliable approach to understanding stone formation (19). the ideal analytical protocol combines stereoscopic microscopy (stm), scanning electron microscopy with energydispersive x-ray spectroscopy (sem-eds), and, when necessary, fourier-transform infrared spectroscopy (ftir) (20). stm is used first to assess external and internal morphology. sem-eds provides highly detailed information about elemental composition and minor components often missed by other methods. ftir complements the analysis in complex or drug-induced stones, though it is limited in detecting minor components and lacks structural context. the renal lithiasis research laboratory at the university of the balearic islands has conducted over 15,000 such analyses, delivering dual reports: one for clinicians with specific therapeutic recommendations, and a simplified version for patients. in conclusion, morphocompositional analysis should be routine practice. it significantly enhances diagnostic accuracy, explains stone etiology, and informs more precise treatment strategies, far surpassing the capabilities of traditional chemical or infrared-only methods. medical treatment and prevention dietary measures (mohamed elhowairis) kidney stone formation is a prevalent and recurrent condition influenced significantly by dietary and lifestyle factors. evidence-based dietary strategies for preventing stones, with a focus on calcium oxalate stones, include increasing fluid intake to achieve optimal urine dilution, maintaining adequate dietary calcium, reducing sodium and animal protein intake, and limiting oxalate-rich foods. additional emphasis should be placed on enhancing citrate intake through citrus fruits, avoiding excess vitamin c and sugars, and promoting a balanced, plant-rich diet. special attention is given to patients with malabsorption syndromes or gastrointestinal surgeries, who are at heightened risk for enteric hyperoxaluria. emerging therapies are microbiome-targeted probiotics, oxalate-degrading bacteria, and precision nutrition. these comprehensive, personalized nutritional interventions aim to reduce stone recurrence and improve patient outcomes through non-pharmacological means. citrates (m. can kiremit) active treatment modalities remain the cornerstone in the comprehensive management of urinary system stone disease. however, recurrence prevention and managing of residual fragments also require complementary strategies such as lifestyle modifications, dietary interventions, and pharmacological therapies. among these, alkaline citrate salts (ac), particularly potassium citrate, are widely used due to their ability to alter urinary chemistry and inhibit stone formation (21). the efficacy and safety of ac therapy has been demonstrated in various age groups, including pediatric population (22-24) and therefore it is recommended in the current eau guidelines (25) for the management of calcium oxalate stones associated with hypocitraturia, hypercalciuria, hyperoxaluria, or distal renal tubular acidosis, as well as in the management of uric acid and cystine stones. however, there are certain limitations to their use. although generally well tolerated and associated with minimal side effects, gastrointestinal intolerance may reduce patient adherence. additionally, regular monitoring of serum electrolytes is necessary, to prevent the development of hyperkalemia, particularly in patients with chronic kidney disease or those receiving potassium-sparing medications. moreover, monitoring urine ph regularly to adjust the dosage properly is another aspect that might reduce patient compliance. if adherence is lacking, the treatment may become ineffective or the risk of uncontrolled urinary ph elevation (≥ 7.5) by over-alkalinization, particularly if sustained over time, may increase the risk of calcium phosphate stone formation. in conclusion, given its dual role in preventing recurrence and managing residual disease, citrate supplementation is a valuable adjunct to active stone treatment. its efficacy in stone prevention is well demonstrated, but careful patient selection, individualized dosing, and appropriate monitoring are essential in optimizing therapeutic outcomes and minimizing adverse effects. novel molecules (adrià pinero) phytate (myo-inositol hexakisphosphate, insp 6 ) is a naturally occurring polyphosphorylated carbohydrate in seeds, legumes, nuts, and whole grains. in vitro studies have demonstrated that both insp 6 and its lower phosphorylated derivatives (insps) exhibit a potent inhibitory effect on the nucleation, growth, and aggregation of calcium salts, particularly calcium oxalate and calcium phosphate crystals (26). epidemiological evidence from a large-scale, prospective cohort study involving 96,245 women over eight years revealed that higher dietary phytate intake is significantly associated with a reduced risk of developing symptomatic kidney stones (27). furthermore, experimental data indicate a synergistic interaction between phytate and magnesium, enhancing the inhibitory effect on crystal formation (28). archivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 6 theobromine, a naturally occurring dimethylxanthine abundant in cocoa beans, has been shown to effectively inhibit uric acid crystallization (29, 30). due to its structural similarity to uric acid, theobromine can integrate into forming crystals, altering their morphology by producing longer and thinner structures with reduced growth kinetics. unlike calcium-containing stones, pharmacological options for preventing uric acid crystallization remain limited. upon ingestion, theobromine is metabolized and excreted in the urine primarily as 7methylxanthine (36%), unchanged theobromine (21%), 3-methylxanthine (21%), and 3,7-dimethyluric acid (1.3%), all of which retain inhibitory activity against uric acid crystallization. the co-administration of urinary alkalinizing agents, such as potassium citrate, alongside theobromine has been proposed as a therapeutic strategy to optimize uric acid solubility. this combination allows for lower citrate dosages, reducing the risk of excessive alkalinization and subsequent sodium urate precipitation. additionally, minimizing citrate dosage decreases the risk of hyperkalemia, particularly in patients with impaired renal function or cardiovascular comorbidities. management of struvite stones (roswitha siener) struvite (magnesium-ammonium-phosphate-hexahydrate) stones can grow rapidly to large sizes. struvite stone formers are at high risk for chronic kidney disease and end-stage renal disease. a study of 45,783 stones revealed that 2.1% contained struvite (31). struvite stones were three times more common in women than men and were most frequent in the youngest and oldest age groups. factors predisposing to urinary tract infections include vesicoureteral reflux in children and indwelling urinary catheters in the elderly. struvite stones are always caused by a urinary tract infection with ureaseproducing microorganisms. the bacterial enzyme urease splits urea to form ammonium and bicarbonate, leading to high urinary ammonium concentrations and ph values above 7.0. specific measures include complete surgical stone removal, short or long-term antibiotic treatment, urinary acidification to a ph below 6.2, and a urine volume of at least 2 litres/24 hours. urinary acidification can be achieved with l-methionine. l-methionine is effective in physiologically lowering urine ph and the relative supersaturation of struvite (32). a recent analysis of 1,231 stones containing struvite revealed that only 6% were pure (33). the most common components in mixed struvite stones were carbonate apatite, ammonium urate, calcium oxalate monoand dihydrate, uric acid and cystine. a previous study found metabolic abnormalities in 57% of patients with pure struvite stones and in 81% of patients with mixed stones (34). therefore, the search for metabolic abnormalities in 24-hour urine after stone removal and infection control is suggested. side effects of stone medications (alberto budia) patient adherence is one of the most critical aspects of medical treatment for urinary stone disease. if the five dimensions of adherence in these treatments are analyzed (social-economic, healthcare system, condition-related, therapy-related and patient-related), the leading causes of low adherence are a lack of perceived benefit from treatment (e.g. lack of symptoms after an acute episode), long duration of therapy and side effects (35, 36). the most common side effects of citrates are gastrointestinal disorders, such as nausea, diarrhea and abdominal distension. diuretics can cause weakness, headaches, muscle pain, insomnia and muscle cramps, and longterm thiazide treatment has been associated with nonmelanocytic skin cancer. neurogenic effects (headache and myalgia) have been observed with acetohydroxamic acid and pyridoxine. specific therapies for cystinuria are associated with a high percentage of side effects (20-30% early and late toxicity). therefore, to increase adherence to specific treatments for metabolic disorders in stone disease, we must provide accurate information to our patients about the benefits and recommend the use of medical devices such as ph meters or apps that provide immediate feedback on long-term treatment efforts and, of course, ensure continuity of care. smart apps for stone patients (juan a. galán-llopis) challenges faced in managing urolithiasis include problems in maintaining adequate hydration tracking, adherence to specific diets, and prophylactic medication. mobile apps have also been changing the management scenario of this disease, and long lists of apps for urolithiasis, including those for patient information, dietary recording tools, and herbal and drug remedies and advice, have been reported (37). coaching patients towards maintaining a high compliance to a low-risk lifestyle is a key factor to prevent stone recurrence, and the new eand m-health apps may provide the additional coaching needed (38). these apps may help calculate stone risk, plan specific diets, offer personalized dietary recommendations and hydration advice, a ph diary, and reminders for stent removal. the lito diagnostic app allows for precise identification of stone types through the analysis of data on renal stone composition and patient urinary biochemistry, automatically generating a report. the mylit-control app provides monitoring of urine ph, fluid and medication intake, helps patients learning about kidney stones and how to prevent them, and enables a safe and private connection to the patient’s portable ph meter. nevertheless, the stone apps need scientific validation to ensure high-quality content and should adhere to clinical guidelines. recently, the latter app was deemed valid and acceptable by urolithiasis patients as a portable tool for urine ph monitoring at home with high usage compliance and satisfaction rates (39). future research should explore long-term outcomes and strategies to enhance patient adherence, ensuring effective integration of digital health tools in routine clinical practice (40). percutaneous nephrolithotomy (pcnl) supine pcnl (jorge mora) (41-43) the supine position offers advantages in anesthetic management, reduced operative time, and lower complication rates, making it suitable for high-risk or pediatric patients. the choice between positions should be individualized based on patient and stone characteristics, surgeon experience and surgical goals (table 1). archivio italiano di urologia e andrologia 2025; 97(2):14085 7 management of urinary stones table 1. advantages or disadvantages of supine pcnl. advantages of supine pcnl anesthetic management easier airway access; reduced cardiopulmonary risks; beneficial for high-risk patients operative time generally shorter due to elimination of patient repositioning and easier stone retrieval stone-free rate (sfr) slightly better sfr complication rate lower major complication rates; less bleeding and infection risk radiation exposure reduced exposure for the surgeon due to lateral puncture site access access to every calyx. allows access to upper pole patient positioning no need for repositioning; facilitates simultaneous retrograde or contraleteral procedures hospital stay shorter hospital stay ideal candidates high-risk patients, combined endoscopic procedures, pediatrics disadvantages of supine pcnl surgical team requires more than one urologist if the combined approach is used access longer tract can reduce instrument maneuverability, specially in obese patients more expensive due to more personnel and usage of more instrument and materials * * probably cost/effective due to reduction in time, complications and hospital stay but needs to be proven. table 2. advantages and disadvantages of prone pcnl. advantages of prone pcnl better access to the posterior calyces larger working space for instrument manipulation lower risk of bowel injury due to retroperitoneal location disadvantages of prone pcnl requires repositioning under anesthesia (increased time and complexity) less favorable for obese patients or those with respiratory compromise reduced cardiovascular monitoring access during surgery table 3. advantages and disadvantages of standard pcnl. advantages of standard pcnl good visualization low intrarenal pressure low risk of bacterial spread/risk of sepsis effectiveness/speed of the procedure disadvantages of standard pcnl hard access in narrow intrarenal spaces (calycean infundibulum, complete staghorn stone) – lower intrarenal mobility table 4. advantages and disadvantages of mini pnl. advantages of mini-pnl higher stone-free rates and shorter operating times compared to rirs similar stone-free rates compared to standard pcnl stone-free rates not affected by stone size and composition reduced overall complication rates compared to standard pcnl reduced blood loss compared to standard pcnl reduced pain compared to standard pcnl suitable for: • small and medium sized stones up to 30 mm • lower pole stones • stones resistant to swl • failed furs • special situations (e.g. stones in calyx diverticula) • additional nephrostomy tracts during a multi-tract pcnl • pediatric patients disadvantages of mini-pnl increased morbidity compared to rirs longer hospital stay compared to rirs longer convalescence period compared to rirs longer or times compared to standard pcnl inability to retrieve larger fragments compared to standard pcnl concerns about raised intrarenal pressures compared to standard pcnl difficulties in the use of the nephroscopic graspers compared to standard pcnl table 5. advantages of fluoroscopy vs. ultrasound guided renal puncture. in favour of fluoroscopy-guided access comparable results in favour of ultrasound-guided access radiation exposure needle puncture time atone clearance rate single needle puncture success rate puncture time operation time access to complicated anatomy intraoperative bleeding rate blood transfusion requirement fever/urosepsis rates prone pcnl (george daniel radavoi) (44-46) (table 2) fluoroscopy guided renal puncture (petros sountoulides) (table 5) standard pcnl (alin adrian cumpanas) (table 3) mini pcnl (kremera petkova) (47-51) (table 4) archivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 8 ultrasound guided renal puncture (mohammed alameedee) (52-53) (table 6) retrograde intrarenal surgery (rirs) high power holmium:yag laser (stefan rascu) (54-57) high power (hp) ho:yag machines represent an improvement over standard ho:yag units, allowing a wider variety of settings, with energy settings as low as 0.2 j and frequencies up to 100 hz. the higher frequencies on high-power holmium devices help achieve faster dusting, smaller fragments and a decrease of 50% in lasing time over the standard machines. pulse modulation on some hp units (moses technology®, vapour tunnel and virtual basket®) allows for decreased stone movement, improved dusting efficiency and more fragmentation at distance, according to clinical and benchtop studies. while thulium fibre laser (tfl) possesses low peakpower, high-power ho:yag benefits from high peakpower. according to my experience, high peak-power matters as laser lithotripsy is not only about dusting. a higher-peak power allows you to fragment stones more efficiently, making the hp unit adequate for all scenarios and locations (embedded, impacted, mobile, small, large, ureteral, kidney or bladder stone). i genuinely believe modern urologists should not be keen on using only one laser device but rather consider each device’s advantages and disadvantages for the case they are facing. hence, in the following tables, i tried to summarize a few scenarios for using each laser in my daily practice in table 7 a/b. table 7a. scenarios for using each laser: kidney stones. hp ho:yag tfl large volume > 2 cm3 small size < 1 cm uas – fans no uas high-power settings low-power settings high-flow irrigation low-flow irrigation jj stent no stent table 7b. scenarios for using each laser: ureteral stones. hp ho:yag tfl impacted non-impacted low-power settings low-power settings p < 10w, frequency < 10 hz p < 10w, frequency < 10 hz table 6. zero radiation ultrasound-guided pcnl advantages and disadvantages. advantages 1 no radiation 2 imaging of structures between skin and kidney, depth of access needle, prevent organ injury (colon, pleura, liver, spleen …etc.). 3 no need for contrast media (in azotemia pt., contrast allergy). 4 avoids renal vascular injury (color doppler u/s). 5 used in failed retrograde pyelogram during failure of ureteric catheterization. 6 safe in pediatric and pregnant patients can performed in supine position. 7 cost effective (using a portable ultrasound). 8 no need for lithotomy position and ureter stent fixation. 9 used even in perinephric extravasated fluid. 10 use hydro dissection to dissect and separate the colon from the lower pole of the kidney, and early diagnoses of colonic injury especially in obese patients. 11 use optical hydro dissection in ectopic pelvic kidney to prevent bowel injury. 12 facilitate reentry to the collecting system in case of tangential entry out of the collecting system. 13 used in prone, supine, semi prone, semi supine and lateral positions. 14 all the abdomen is the field of entrance from posterior axillary line to the umbilicus. 15 use the doppler study to detect the residual stones and also the edges of colon. disadvantages 1 difficult identification of the access needle. 2 technical difficulty in non-dilated pcs. 3 difficult visualization and manipulation of guide wire and dilaters, especially the nonmetallic dilators. 4 long learning curve. archivio italiano di urologia e andrologia 2025; 97(2):14085 9 management of urinary stones thulium laser (juan manuel lopez) (58-60) (table 8) impact of intrarenal pressure and temperature (razvan multescu) (61-63) flexible ureteroscopy is generally a procedure with low morbidity and mild complications. however, while performing it we are altering pyelocaliceal system conditions, sometimes with significant clinical consequences. elevated temperature may impair cell viability and renal function. many papers are using the critical threshold of 43°c. however, dewey and sapareto arbitrarily chose this value and reported it as dangerous if the renal cells were exposed for 120 minutes (61). factors influencing heat release include laser type and settings, exposure time, stone location, fiber-to-stone distance, irrigation volume, fluid circulation. efficient irrigation and use of ureteral access sheaths, especially those navigable and with suction (fans), help temperature control by improving fluid circulation. limiting the laser settings to reasonable values may also prevent such significant lesions. however, experimental in vivo porcine models demonstrated that although laser induced thermal lesions were still severe at one week, they may improve by healing in a short period (62). high intrarenal pressure (irp) is closely associated with septic complications, pain or bleeding. while normal irp ranges from 0-20 cm h2o, pyelovenous backflow occur beyond 41 cm h2o and fornix ruptures above 81 cm h2o (63). sustained high pressures or even pressure spikes may increase risk, suggesting importance of realtime monitoring. innovations include pressure sensors on wires, scopes, uas and innovative platforms with ai-regulated irrigation/suction systems. fans and direct inscope suction help maintaining a low irp. understanding and controlling time-dependent changes in temperature and pressure can enhance procedural safety and efficacy. direct in-scope suction (diss) (bogdan geavlete) flexible ureteroscopy (furs) utilization is increasing, surpassing shock wave lithotripsy (swl), with experience of over 1,500 procedures a year, worldwide. eau guidelines suggest percutaneous nephrolithotomy for stones > 20 mm and retrograde renal surgery is not recommended as a first-line treatment for stones > 20 mm (25). however, it may be a first-line option in patients where pcnl is not an option or contraindicated or in selected patients. technical improvements and disposable tools have increased urs use. miniaturization of flexible ureteroscopes improves access. single-use scopes enhance safety, though cost and sustainability remain concerns. the goal is to minimize residual fragments, aiming for < 63 µm. suction techniques like irrigation/suctioning systems and direct in scope suction (diss) are being developed to control pressure and remove the residual fragments (64-66). table 8. comparison of lasers for stone treatment. technical specifications ho:yag tfl p-tm:yag magneto wavelength ~2100 nm ~1940 nm 2013 nm ~2100 nm max power 100–150 w 50–60 w 100 w 100–150 w frequency 5–80 hz 10–2400 hz 5–300 hz 5–100 hz peak power up to 10 kw ~0.5 kw ~3.7 kw up to 10 kw tissue penetration ~0.3 mm ~0.08 mm ~0.15–0.2 mm ~0.3 mm design and operational characteristics electrical needs 16–20 a standard 15 a standard 15 a 16–20 a cooling water cooling air/water cooling closed-loop water cooling size/weight >100 kg ~50–60 kg ~97 kg >100 kg fiber size ≥200 μm 50–150 μm ≥200 μm 200–1000 μm noise loud (~70 db) quiet mid ≤65 db loud lithotripsy performance feature ho:yag tfl p-tm:yag magneto retropulsion significant minimal low low-minimal * fragmentation excellent low excellent excellent dusting moderate excellent excellent excellent predominant effect photomechanical photothermal mixed adjustable soft tissue surgery feature ho:yag tfl p-tm:yag magneto coagulation moderate excellent good improved dissection blunt/pulsed smooth smooth versatile char low hi medium low visibility (bleeding) good excellent very good excellent * based on technical characteristics. archivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 10 advantages of suction during furs include lower intrarenal temperature and pressure, reduced infection risk, and improved visibility. pusen offers single-use furs with suction (diss) that can provide low intrarenal pressure and better vision. diss can be combined with flexible-tip suction uas. finally, recent studies support diss, showing it could be more efficient and helps improve stone-free rates. large, randomized, multicenter studies are now needed to standardize the results and draw definite conclusions regarding the benefit of these procedures. the true practical impact over the mediumand long-term success rates of the procedure still needs to be further studied. flexible and navigable suction ureteral access sheaths uas (fans-uas) (petros sountoulides) retrograde intrarenal surgery (rirs) has evolved into a cornerstone of modern endourological management for renal calculi, especially for patients with anatomical constraints or those at higher surgical risk. a pivotal component facilitating rirs is the ureteral access sheath (uas), which enables repeated scope access, improves irrigation outflow, and contributes to procedural safety and efficacy. the latest advancements have introduced flexi-bendable uas equipped with suction capabilities – flexible and navigable suction uas (fans-uas) – which combine mechanical flexibility with continuous irrigation management and stone clearance mechanisms (67). the advantages of flexi-bendable uas are: – enhanced navigation and access: traditional uas are limited by rigidity, potentially restricting access to the lower pole or extreme calyces. flexi-bendable sheaths feature a soft, passively bendable distal tip that can follow the ureteroscope's movement into difficult-to-reach areas, significantly improving navigation and clinical access in complex renal anatomies (68). – suction capability and improved visualization: fansuas incorporate a vacuum-assisted side port, allowing active removal of stone dust, blood clots, and irrigation fluid during lithotripsy. this functionality creates a clear operative field (avoiding the 'snow globe' effect), enhancing stone visualization and procedural control. improved vision correlates with better fragmentation accuracy and shorter operative times (68). – reduced intrarenal pressure (irp): elevated irp during rirs is associated with pyelovenous backflow, increased risk of urosepsis, and renal injury (69). fans-uas have demonstrated the ability to maintain irp under 20-30 cm h2o, particularly with larger sheaths (> 12/14 fr) and effective suction mechanisms. real-time digital ureteroscopes monitoring confirms safer pressure profiles than non-suction approaches (68, 70). higher stone-free rates (sfr): clinical trials and multicenter studies show that bendable suction uas significantly outperform traditional sheaths in achieving stone-free status. one study reported an 81.3% immediate and 87.5% threemonth sfr for fans-uas compared to 49.4% and 70% for standard sheaths (70). real-world data echo these findings, with a 30-day sfr of 86.8% across 25 centers. decreased postoperative complications: continuous suction and pressure control reduce the risk of infectious complications, including postoperative fever and sepsis. the use of fans-uas also minimizes the need for stenting and auxiliary procedures, thus decreasing the overall healthcare burden. clinical utility and expanded indications flexi-bendable suction uas are particularly useful in scenarios involving: – large stone burdens (> 2 cm) – pus or turbid urine with infection risk – solitary kidneys or cases with impaired renal function – same-session bilateral ureteroscopy (rirs) – challenging lower pole stone access. for large stones, fans-uas have shown comparable effectiveness to mini-percutaneous nephrolithotomy (mini-pcnl), with lower complication rates and potential for single-session clearance (71). despite their many advantages, flexi-bendable uas are not without limitations. maneuvering the flexible tip requires frequent adjustments, particularly in narrow calyceal infundibula. fragment removal may still require basketing for stones in the lower calyx due to limited deflection angles (68). additionally, operator training, cost, and the need for more robust data on long-term outcomes and equipment durability remain essential considerations for widespread clinical adoption. in conclusion, fans-uas represent a transformative step in endourology, combining flexibility, suction, and safety. they improve access, visibility, pressure control, and stone-free rates, while minimizing complications and intervention times. while further research is needed to optimize design and validate cost-effectiveness, these systems have the potential to redefine standard rirs protocols. slim disposable furs (athanasios papatsoris) flexible ureteroscopy (furs) has been increasingly used as the first-line treatment for urolithiasis (72,73). disposable (single-use) furs has enormously progressed because novel slimmer scopes provide both safety and cost/efficacy in retrograde intrarenal surgery (rirs) (74). the slimmest diameter of most commercially available models is 7.5 fr (e.g. the endoview hu-30s by hugemed). hugemed was the first to launch the 6.3 fr furs in the global market which has already received clinical praise from many colleagues (75). the ultra-thin hu-30s makes it easy to perform rirs without pre-placed double-j stents (avoidance of another procedure) and insertion of ureteral access sheaths (avoidance of ureteral injury), resulting in lower costs. if a ureteral access sheath is used the hu-30s is easily manipulated through a slim 9 fr sheath and more stone expelling space is achieved. moreover, the ultra-thin hu30s, provides greater infusion space between the scope and the ureter. this will prevent temperature rise during laser (i.e. thulium) lithotripsy, relieve renal pressure and improve the stone-clearance rate and reduce the likelihood of post op steinstrasse. weighing less than 300g, the hu-30m effectively prevents the operator’s fatigue during longstanding surgeries. its standard parameters, including an adjustable angle knob, the 285° bending range in both directions, the 1080p optimization algorithm, and the passive bending function, support surgeons in efficiently tackling even the most demanding surgical cases. a unique characteristic of the hu-30m is archivio italiano di urologia e andrologia 2025; 97(2):14085 11 management of urinary stones that the scope is produced with a 3 or 9 o’clock working channel for right and left furs, respectively. additionally, there is no time limit in working with the hu-30m; therefore, the term disposable is preferred over single use. having been one of the first endourologists to use the hu-3om in recent years, it’s my first choice for furs even for large stones. once the wire is inserted in the kidney the scope can be easily advanced over it just as we advance a 6 fr jj stent. with the hu-30m, i’ve stopped pre-stenting patients, and i’ve minimized the use of ureteral access sheaths. i found it ideal for impacted ureteral and lower pole stones, special populations (i.e. children, anatomical anomalies) while slimmer size does not obscure vision or irrigation. salvage flexible urs, pushing the boundaries (syed jaffry) salvage flexible ureterorenoscopy (furs) is a minimally invasive endourological approach used when standard stone management techniques, such as percutaneous nephrolithotomy (pcnl), are contraindicated or fail. it has become a key alternative in complex or high-risk cases, including patients with coagulopathy, morbid obesity, renal anatomical abnormalities (e.g., horseshoe or pelvic kidneys), urinary diversion, calyceal diverticula, and altered urinary tracts. in salvage scenarios, furs demonstrates favorable outcomes with stone-free rates (sfrs) ranging from 55.6% to 64% for stones > 2 cm, reaching up to 90% for fragments < 2 mm when multiple sessions are utilized (average 1.6 sessions). studies show safety and effectiveness across challenging patient groups, with no major intraoperative complications or mortality reported (25). technological advancements have enhanced the efficacy of salvage furs. high-powered holmium:yag lasers, particularly systems featuring vapor tunnel™ and masterpulse™, allow customization of lithotripsy based on stone composition and size. short pulses deliver aggressive fragmentation for hard stones, while long pulses enable controlled ablation with minimal retropulsion. suction access sheaths further optimize outcomes by facilitating fragment evacuation and maintaining clear visualization. these tools are particularly advantageous in salvage procedures involving large or multiple stones. salvage furs provides a safe, repeatable, and effective option in modern stone management. are we truly seeing the end of an era, or are we simply witnessing a redefinition of indications? with salvage furs and suctionenabled rirs pushing boundaries, perhaps the question is no longer ‘can we do pcnl?’, but rather ‘do we need to? complications of stone treatment classification & reporting (elenko popov) surgical procedures carry intraoperative or postoperative complications risks, which can have significant outcomes. therefore, accurate documentation of adverse events and thorough preoperative assessments are crucial. these practices help identify systematic errors and improve patient care. unfortunately, inaccuracies in reporting complications are common among surgeons. a consistent and precise classification system for complications is essential and can only be achieved through a reliable and validated reporting and grading system recognized in clinical practice. the clavien-dindo classification system (cdc) classifies complications based on the interventions required for treatment. its strengths include applicability across various surgical contexts (76). however, a key limitation is that it only considers the highest-grade complication, potentially underestimating overall patient morbidity. modifications such as the memorial sloan-kettering cancer centre secondary events system (77) and the accordion severity grading system (78) have been introduced. yet they do not fully address the conceptual challenges of the cdc. each classification and reporting approach has advantages and disadvantages. cdc is the central system for documenting complications due to its ease of use; however, it offers a broad overview of surgical adverse events, creating new reporting frameworks. a urology-specific complication reporting system is needed to monitor complications in urological procedures, facilitating better data collection and analysis and enhancing patient safety. the system should be comprehensive and replicable, ensuring accuracy and reliability. improving the complication reporting system is essential for urologists to enhance surgical outcomes. swl (athanasios dellis) the advent of shockwave lithotripsy (swl) in the 1980s revolutionized the management of kidney stones, replacing open surgery and its associated risks of morbidity and mortality. however, it became evident that swl was not universally effective for all stone types and carried its own risks and potential complications. as retrograde intrarenal surgery (rirs) and percutaneous nephrolithotomy (pcnl) advanced, the scope of swl applications narrowed. according to the european association of urology (eau) guidelines, swl remains a first-line treatment for proximal or distal ureteral stones smaller than 1 cm, renal stones up to 2 cm, and lower pole stones in patients with suitable anatomical conditions (25). swl has fewer overall complications compared to pcnl and ureteroscopy (urs) (table 9) (25). table 9. complications of swl. complications of swl regrowth of residual fragments 21–59% dysrhythmia 11–59% bacteriuria in non-infection stones 7.7–23% macroscopic haematuria 17.2% pain 12.1% auxiliary procedure 6.9% steinstrasse 4% renal colic 2–4% haematoma, asymptomatic (renal) 1.2% haematoma, symptomatic (renal) 0.21% sepsis 0.15% morbid cardiac events case reports liver, spleen haematoma case reports bowel perforation case reports archivio italiano di urologia e andrologia 2025; 97(2):14085 a. papatsoris, b. geavlete, g.d. radavoi, et al. 12 a meta-analysis of 115 rcts reported 18.43% clavien i-ii and 2.48% clavien iii-iv complications (79). the connection between swl and conditions like hypertension or diabetes remains uncertain. while published data are inconsistent, no conclusive evidence suggests swl leads to longterm adverse effects. management of swl complications involves monitoring and addressing adverse events such as pain, hematuria, or infection. pain is managed with analgesics, while infections require antibiotics. persistent obstruction or fragments may need auxiliary procedures like ureteroscopy or nephrostomy placement. severe complications, including hematoma, require close observation or intervention based on the patient’s clinical stability. rirs (elenko popov) the ongoing advancements in endoluminal endourology in the upper urinary tract have considerably broadened the applicability of retrograde intrarenal surgery (rirs) within clinical practice. rirs has transitioned from serving as an alternative modality to a primary intervention for treating renal stones measuring up to 20 mm in maximum diameter, as stated in both the european and american association of urology guidelines. nonetheless, this technique can be associated with various potential complications akin to any surgical procedure. the most frequently cited complications include discomfort associated with a ureteral stent, injury to the ureteral wall, and the migration of residual stone fragments (1). among the early and most serious postoperative complications, fever is identified as the most prevalent, closely followed by urinary tract infections, which exhibit an incidence range of 0.2% to 15% (80). a particularly alarming complication is sepsis, with an incidence rate fluctuating between 0.1% and 4.3% (81). in rare instances, sepsis may become life-threatening and is recognized as a primary contributor to postoperative mortality, alongside other significant complications such as cardiac events, respiratory distress, multiorgan failure, and haemorrhagic incidents (80). table 10. complications of retrograde intrarenal surgery (rirs). complication incidence potential risk factors preventive strategies ureteral injury 0.5% 5% previous surgeries, anatomical anomalies preoperative imaging, proper surgical technique hemorrhage 0.5% 3% coagulopathy, significant stone burden, prolonged operative time monitor operative time and intrarenal pressure infection 1% 10% preexisting urinary tract infections, diabetes, significant stone burden, prophylactic antibiotics, proper sterile technique, prolonged operative time control of intrarenal pressure and operative time urinary leakage 1% 4% preexisting urinary conditions, increased intrarenal pressure, forceful technique control of intrarenal pressure postoperative pain 30% 70% individual pain threshold, complications, jj stent adequate analgesia, multimodal pain management residual stone fragments 5% 10% large stone size, inadequate clearance thorough exploration of renal collecting system, use of adjunctive techniques (eswl, ecirs, second stage rirs) table 11 complications of percutaneous nephrolithotomy (pcnl). complication estimated rate (%) notes mild fever 10–30% usually self-limited; related to systemic inflammatory response bleeding (self-limited) 5–10% minor hematuria, no transfusion required pain requiring analgesia 10–20% often resolves within 24–48 hours urinary leakage (self-limited) 2–5% usually resolves with conservative management moderate hemorrhage requiring blood transfusion 2–7% due to vascular injury or significant bleeding urosepsis 1–2% may require icu admission if not promptly managed prolonged urinary leakage 1–2% may require stenting or nephrostomy reinsertion injury to collecting system requiring repair < 1% includes pelvic perforation bowel injury < 1% requires early detection; may need surgical intervention severe arteriovenous fistula/pseudoaneurysm 0.5–1% may require angioembolization thoracic complications (e.g., pneumothorax) < 1% especially in supracostal access loss of access tract < 1–3% may necessitate re-puncture or conversion death < 0.5% rare; usually related to sepsis or massive hemorrhage pcnl (george daniel radavoi) (25, 82, 83) archivio italiano di urologia e andrologia 2025; 97(2):14085 13 management of urinary stones perioperative management of antithrombotic therapy in urological stone surgery (jaffry syed) (84-86) the management of anticoagulant and antiplatelet therapy in patients undergoing urological stone procedures presents a complex balance between minimizing bleeding risk and preventing thromboembolic events. as the prevalence of cardiovascular disease and anticoagulant use increases with an aging population, stone complexity and associated interventions also grow. commonly used agents include antiplatelets (e.g., aspirin, clopidogrel) for arterial thrombosis and anticoagulants (e.g., warfarin, direct-acting oral anticoagulants or doacs) for venous thromboembolism and atrial fibrillation. procedural bleeding risk varies, with low risk for cystoscopy, moderate for ureteroscopy, and high for pcnl. thrombotic risk is stratified based on clinical history, such as mechanical valves or recent venous thromboembolism (vte). bridging therapy typically using low molecular weight heparin (lmwh) is now limited to high thrombotic risk patients due to increased perioperative bleeding and limited efficacy in thrombosis prevention, as shown in recent studies and the bridge trial. doacs are generally stopped 48-72 hours preoperatively without bridging; warfarin is stopped 5 days prior, with or without bridging depending on risk. aspirin is usually continued, while clopidogrel requires cessation 5-7 days before surgery, especially if part of dual antiplatelet therapy (dapt). multidisciplinary collaboration with cardiology and hematology is advised for complex cases. evidence-based guidelines, such as those from the eau and american college of clinical pharmacy (accp), emphasize individualized risk assessment, procedure-specific planning, and structured resumption of therapy postoperatively. for safe outcomes, institutional protocols, pre-assessment planning, and patient education are critical. a personalized, interdisciplinary approach enables optimal decision-making in balancing antithrombotic therapy with surgical safety during urological stone interventions. protection and economic issues radiation protection (juan antonio mainez) we know that exposure to ionizing radiation is widespread in endourology. it’s also known that exposure to high levels of ionizing radiation is associated with an increased risk of cancer and other adverse health effects (87). it’s for this reason that the urologist involved in the care of lithiasis patients should be educated on the safe use of radiation, because the urolithiasis patients will need a multitude of diagnostic and follow-up tests, and surgical interventions (eswl, urs and fluoroscopy-guided pcnl) in their lives (88). different international organisms regulate radiation doses and limits. different countries have been adapting their laws to meet the requirements of the european directive which was published in february 2018. the legislation sets the limits to which healthcare personnel can be exposed annually, regulates how to carry out the records and finally indicates how professionals should be trained. healthcare personnel should be aware of the different individual protection systems available to reduce the radiation they receive, such as using aprons and glasses, keeping a distance from the source of the radiation, and reducing the time of use (89). all these recommendations are based on the alara principle: as low as reasonably achievable. many studies are being published in which endourological interventions are performed without the use of ionizing radiation to reduce exposure (patient and urologist). i believe that these x-ray-free procedures can be carried out with the idea of never subjecting the patient to extra risk by not using fluoroscopic support (90). laser protection in endourology (alin adrian cumpanas) the urologists must have a core knowledge about the laser system – both for patients and staff members protection – before starting to use it in a clinical setting. personnel working in an endourology environment using ho:yag, tm:yag, or tfls face minimal ocular risks (if distance from the laser tip to the cornea < 5 cm): safety goggles are optional. safety goggles are mandatory for nd:yag, ktp (green light), diode lasers (visible/near infrared < 1400 nm wavelength). patient complications: the injury is more laser user dependent than laser type dependent. setting up a cost-effective endourology service (hammad ather) at the turn of the century, the endourological revolution swept the most formidable invention in urology, extracorporeal shock wave lithotripsy (eswl). surgical interventions are assessed on efficacy, safety, and cost-effectiveness. endourology is superior to eswl in terms of efficacy; however, eswl is a truly minimally invasive modality with a better safety profile. in terms of cost-effectiveness, the jury is still out. konnopka et al. (91) recently reported that in a german set-up, in 7 years of follow-up, reintervention was needed in 15, 23, and 26% of patients undergoing urs, pcnl, and eswl, respectively. the cost for the primary procedure and reintervention was highest for pcnl (5783€), followed by eswl (3240€) and urs (2979€). in a recent systematic review by ghorai and kumar (92), the authors noted that reusing single-use devices in endourology has financial, environmental, and practical advantages. safety is vital in any surgical intervention, and efficacy is the second most important consideration. however, the value of cost-effectiveness cannot be underscored. the measures described can significantly reduce the cost of most endourology interventions. conclusions (geavlete b, papatsoris a, radavoi d) the 2025 esd conference held special significance as a tribute to the late noor buchholz (13.02.2024), whose vision and dedication laid the foundation for esd. alongside pioneering colleagues, he established an enduring legacy that we honor through our shared commitment to excellence and progress. archivio italiano di urologia e andrologia 2025; 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validation, a.p., b.g., g.d.r.; formal analysis, a.t.; investigation, a.t.; resources, n/a.; data curation, a.t.; writing, a.p., b.g., g.d.r., m.a., m.a., h.a., a.b., a.a.c., m.c.k., a.d., j.a.g.l., p.g., j.g.g., b.i., v.j., j.m.l., j.a.m., i.m., j.m., m.m., r.m., y.o.a., k.p., a.p., e.p., m.r..c., s.r., r.s., p.s., j.s., k.s., a.t.; writing-review and editing, a.t.; visualization, a.t.; supervision a.p.; project administration, n/a; funding acquisition, n/a. all authors have read and agreed to the published version of the manuscript. acknowledgments: we thank vicky nickolopoulou of insession events who helped to superbly organize all the editions of esd, and we thank devicare sl for its unconditioned support of the esd conference in bucharest. archivio italiano di urologia e andrologia 2025; 97(2):14085 15 management of urinary stones 31. siener r, herwig h, rüdy j, et al. urinary stone composition in germany: results from 45,783 stone analyses. world j urol 2022; 40:1813-1820. 32. siener r, struwe f, hesse a. effect of l-methionine on the risk of phosphate stone formation. urology 2016; 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40:3021-3027. 92. ghorai rp, kumar r. reuse of single-use devices in endourology: a review. j endourol. 2024; 38:68-76. correspondence athanasios papatsoris md, msc, msc, phd, febu, fes, fpua agpapatsoris@yahoo.gr full professor of urology, university department of urology, sismanoglio hospital, national and kapodistrian university of athens, greece bogdan geavlete, md, phd bogdan_geavlete@yahoo.com professor of urology “carol davila” university of medicine and pharmacy medical director “saint john” emergency clinical hospital, president of the urological committee romanian ministry of health, bucharest, romania george daniel radavoi, md radadaniel@yahoo.com clinical hospital of urology “prof. dr. theodor burghele”, bucharest, romania mohammed al-ameedee, md mohammedalameedee@yahoo.com consultant urologist, diwaniya teaching hospital, iraq murtadha almusafer, md dralmusafer@yahoo.com prof. & consultant of urology, university of basrah, college of medicine, basrah, iraq m. hammad ather, md hammadather@gmail.com consultant urologist, professor and head of urology department at the aga khan university, karachi, pakistan archivio italiano di urologia e andrologia 2025; 97(2):14085 17 management of urinary stones alberto budia alba, md alberto.budia@hotmail.com associate professor, valencia university, head of urology department la fe university and polytechnic hospital, spain murat can kiremit, md mckiremit@gmail.com koç university, school of medicine, department of urology, istanbul, turkey alin adrian cumpanas, md, phd, febu alincumpanas@hotmail.com professor and chairman, department of urology, victor babeş university of medicine and pharmacy, timisoara, romania athanasios e. dellis md, phd, febu aedellis@gmail.com professor of urology, 2nd department of surgery, aretaieion academic hospital school of medicine, national and kapodistrian university of athens, athens, greece mohamed elhowairis londonclinic1@gmail.com consultant urologist, london, uk juan antonio galán-llopis, md jagalanllopis@gmail.com department of urology, general university hospital dr balmis, isabial, alicante, spain petrisor geavlete, md geavlete@gmail.com professor emeritus of urology, academician (romanian academy of medical sciences), board member of the romanian association of urology, bucharest, romania jordi guimerà garcia, md jordi_guime@hotmail.com urologist, lithiasis unit, urology department, son espases university hospital, palma, spain bernat isern, phd bernat.isern@uib.cat associate professor, renal lithiasis and pathological calcification group (lircap), research institute of health sciences (iunics), university of the balearic islands, spain health research institute of the balearic islands (idisba), spain viorel jinga, md vioreljinga@yahoo.com professor of urology, head and chairman of clinical department of urology, “theodor burghele” clinical hospital, rector of the university carol davila of medicine and pharmacy, bucharest, romania juan manuel lopez, md urodrlopez@gmail.com urology department, icnu barcelona university clinic hospital, barcelona, spain juan antonio mainez, md urologist, la paz university hospital, madrid, spain drmainez@gmail.com iraklis mitsogiannis, md imitsog@med.uoa.gr professor of urology, national & kapodistrian university of athens medical school, greece jorge mora christian, md jorgemora@urologiaclinica.biz; jmorach2210@gmail.com urologia clínica bilbao, imq zorrotzaurre university hospital and deusto university, blbao, spain mohammad moussa, md mohamadamoussa@hotmail.com; mohamad.moussa.1@ul.edu.lb professor of urology and former dean of the faculty of medicine at lebanese university, lebanon razvan multescu ,md, phd razvanmultescu@yahoo.com assoc.professor of urology, university of medicine and pharmacy “carol davila” department of urology “saint john” emergency clinica hospital, romania yusuf oguz acar, md oguz.acar@livhospital.com.tr urologist, liv vadistanbul hospital, istanbul, turkey kremera petkova, md dr_petkova@yahoo.com associate professor, department of urology and nephrology, military medical academy, sofia, bulgaria adrià piñero, md adria.pinero@gmail.com urology department, hospital del mar, barcelona, spain elenko popov, md shennyp@yahoo.com associate professor in urology, medical university sofia, department of urology, umhat “tzaritza yoannaisul”, bulgaria maria ramos cebrian, md ramos_marceb@gva.es nephrologist, renal transplant unit hospital universitari i politècnic la fe, renal lithiasis, valencia, spain stefan rascu, md, phd stefanrascu.sr@gmail.com urology consultant, lecturer urology discipline, “carol davila” university of medicine and pharmacy, urology clinic “prof. dr. th. burghele” clinical hospital, bucharest, romania roswitha siener, phd roswitha.siener@ukbonn.de professor, university stone center, department of urology and pediatric urology, university hospital bonn, bonn, germany petros sountoulides, md psountoulidis@auth.gr associate professor of urology, 1st urology department, aristotle university of thessaloniki, greece kyriaki stamatelou, md dr.stamatelou@gmail.com nephrologist, mba scientific director, “mesogeios” nephrology center, athens, greece jaffry syed, md jaffrysyed@gmail.com consultant urological surgeon, university college hospital, galway clinic and bons secours hospital, ireland alberto trinchieri, md (corresponding author) alberto.trinchieri@gmail.com cdc ambrosiana, cesano b., milano, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14264 1 original paper tomy (rc) with lymph node dissection, that is the cornerstone of curative treatment (1). to improve oncological outcomes, neoadjuvant chemotherapy (nac) has become the standard of care for eligible patients, providing a 5-8% increase in survival benefit at five years (2, 3). beside this, before surgery, more patients can receive chemotherapy, as post-operative status and complications may preclude adjuvant chemotherapy (4). however, not all patients respond to neoadjuvant treatment. identifying those most likely to benefit remains a critical challenge, as no validated score currently exists to accurately predict response (5). it is estimated that following nac, 20-40% of patients have no residual tumor on histological examination of the rc specimen representing a pathologically complete response (2, 6, 7). these patients tend to have excellent outcomes with reported 5-year os rates of 80-85% (7). it is even hypothesized that patients with a pathologically complete response after nac might not benefit from concurrent rc. this hypothesis is being tested in the ongoing pre-prevencys trial (8). tumor regression grade (trg) aims to quantify the extent of histological response to chemotherapy by assessing the relative proportion of residual viable tumor cells and treatment-related changes, such as fibrosis or necrosis. although its importance has been well established for other malignancies, like rectal and esophago-gastric cancers (9-11), no standardized grading system has been created for bladder cancer. research has been conducted to validate trg-based classifications and to demonstrate their association with oncologic outcomes, showing additional prognostic value when combined with standard tnm staging (12-14). fleischmann et al. introduced a trg classification and concluded that trg determination in neoadjuvant treated bladder cancer predicts survival independently and better than ypt and ypn stages (12). since then, other studies have evoked the role of trg predicting oncological outcomes in mibc treated with nac followed by surgery, and its additional value when combined with standard tnm staging (13-15). introduction: tumor regression grade (trg) is a recognized prognostic marker in several solid tumors treated with neoadjuvant therapy, but its clinical relevance in muscle-invasive bladder cancer (mibc) remains under investigation. this study aimed to evaluate the prognostic value of trg and its integration with pathological tnm staging in patients with mibc treated with neoadjuvant chemotherapy (nac) followed by radical cystectomy (rc). materials and methods: we conducted a retrospective analysis of 51 patients with mibc who received platinum-based nac followed by rc and lymphadenectomy between 2013 and 2024. trg was assessed according to the fleischmann classification and combined with yptnm stage to categorize patients as complete, partial or non-responders. overall survival (os) and disease-free survival (dfs) were estimated using kaplan–meier analysis, and independent prognostic factors were identified through cox regression models. results: complete response (ypt≤1, ypn0, trg1) was observed in 43.1% of patients. median os was 19 months, with 3and 5-year os rates of 28.6% and 14.3%, respectively. complete responders demonstrated significantly improved os and dfs (p < 0.001). on multivariable analysis, absence of nodal involvement (p = 0.047) and complete response (p = 0.012) were independently associated with better os. negative surgical margins showed a trend toward improved survival (p = 0.064). conclusions: trg is a reproducible and clinically meaningful histopathologic scoring system that enhances prognostic stratification when combined with pathological tnm staging. its integration into routine post-nac assessment may improve postoperative decision-making and help identify patients who could benefit from tailored surveillance or adjuvant strategies. key words: tumor regression grade; muscular-invasive bladder cancer; neoadjuvant chemotherapy; radical cystectomy. submitted 20 august 2025; accepted 30 august 2025 introduction patients with muscle-invasive bladder cancer (mibc) have a 5-year overall survival (os) of 40-60% after radical cystecprognostic value of combined tumor regression grade and tnm stage in muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy manuel lopes 1, 2, josé pereira 3, maria josé temido 2, 4, joão gama 5, edgar silva 1, 2, vasco quaresma 1, 2, joão lorigo 1, rui pedrosa 1, joão pedroso lima 1, 2, henrique dinis 1, 2, lorenzo marconi 1, 2, vítor sousa 2, 5, arnaldo figueiredo 1, 2 1 urology and renal transplantation department, hospitais da universidade de coimbra, portugal; 2 faculty of medicine, university of coimbra, portugal; 3 urology department, instituto português de oncologia coimbra, portugal; 4 gastroenterology department, hospitais da universidade de coimbra, portugal; 5 pathology department, hospitais da universidade de coimbra, portugal. doi: 10.4081/aiua.2025.14264 summary archivio italiano di urologia e andrologia 2025; 97(3):14264 m. lopes, j. pereira, m.j. temido, et al. 2 we thus aim to evaluate trg of patients with mibc who underwent nac before rc and lymphadenectomy and to assess its prognostic role in combination with tnm staging classification as predictors of os and disease-free survival (dfs). material and methods study design this is a retrospective cohort study conducted in a tertiary hospital. from a total of 307 patients who underwent rc for bladder cancer between january 2013 and december 2024, the study included a consecutive series of 51 patients with mibc treated with platinum-based nac followed by rc with lymphadenectomy. inclusion criteria were (1) histologically confirmed urothelial carcinoma (uc) of the bladder (pure or predominant histology); (2) clinical stage t2-t4a, n0-3, m0 prior to nac; (3) completion of at least two cycles of chemotherapy; and (4) availability of full pathological specimens for review. patients were excluded if they had (1) pure nonurothelial histology, (2) ≤pt1/tis stage disease on initial histology, (3) completed less than two cycles of nac, or (4) missing clinical or histopathological data. initial diagnosis and staging were established after transurethral resection of the bladder (turb) and chest, abdominal and pelvic computed tomography (ct). followup after surgery was based on chest, abdominal and pelvic ct or 18f-fdg (fluordesoxiglicose) positron emission tomography/ct. last follow-up was performed in july 2025. neoadjuvant chemotherapy the decision of nac was made after discussion at a multidisciplinary tumor board involving urologists and oncologists. standard treatment included a platin-based combination of drugs [gemcitabine and cisplatin (gemcis); gemcitabine and carboplatin (gemcarbo), methotrexate, vinblastine, doxorubicin and cisplatin (mvac); or cisplatin and etoposide (ciseto)] depending on patient and tumor features. surgical procedure after nac all patients were submitted to open rc and bilateral lymphadenectomy in the same procedure. standard lymph node dissection was generally carried out. extended or super-extended templates were used depending on preoperative staging results (16). in two cases, lymphadenectomy could not be performed due to intraoperative or anatomical limitations. intraoperative frozen section analysis of the urethra and ureters was routinely performed. histopathological analysis turb and rc specimens were analyzed by two dedicated genitourinary pathologists blinded to outcomes. trg was evaluated in the primary tumor site using the system proposed by fleischmann et al. (12), described in table 1. if multiple areas with varying response were present, the dominant trg pattern was recorded. discrepancies between reviewers were resolved by joint consensus. residual pathological staging (yptnm) was assigned according to ajcc 8th edition criteria (17). lymph nodes were examined separately and classified as invaded (pn≥1) or not (pn0). trg classification and yptnm stage were combined in treatment response evaluation categories, adapted from the criteria introduced by voskuilen c. et al. (13). patients were classified as complete, partial or nonresponders (table 2). data collection and statistical analysis data was analyzed with stata (statacorp lp® version 16.0). descriptive statistics were used for clinical and analytical data description. continuous variables were described with median and interquartile range (iqr) and categorical variables with frequencies. os was defined as the time from rc to death from any cause or last known followup. dfs was measured from the date of rc to the first evidence of recurrence, disease progression, or death. kaplan-meier analysis was used to estimate os and dfs, with group comparisons performed using the log-rank test. independent predictors of survival were assessed through multivariate cox proportional hazards regression, with backward selection. variables with a p-value < 0.1 in the univariate analysis were included in the multivariable model. a p-value of < 0.05 was considered statistically significant. ethical considerations the project was conducted in accordance with good clinical practice and adhered to the ethical principles of the declaration of helsinki. informed consent was obtained prior to inclusion in the study. all data were anonymized before the analysis. results study’s population characteristics a total of 51 patients were included, the majority of whom (76.5%) were male. the median age at diagnosis was 66 years (iqr 60-76) and 42 patients (82.3%) had previous or concurrent history of smoking. demographic, clinical and histopathological characteristics are detailed table 1. tumor regression grade classification. trg1 complete regression (no viable tumor) trg2 > 50% regression (predominantly therapy-induced changes, sparse viable tumor) trg3 ≤ 50% regression (predominantly viable tumor with limited regression) trg: tumor regression grade. table 2. patients classification according to neoadjuvant chemotherapy response. complete responder ypt≤1 and ypn0 and trg1 partial responder ypt≥2 or ypn1-3 and trg1 or trg2 non-responder ypt≥2 or ypn1-3 and trg3 trg: tumor regression grade. archivio italiano di urologia e andrologia 2025; 97(3):14264 3 prognostic value of combined tumor regression grade and tnm in table 3. figure 1 illustrates tumor regression grades. median time from turb to nac and from nac to rc were 55 days (iqr 35-78) and 100 days (iqr 80-142), respectively. majority of patients (86.3%) received gemcis, 4 patients had dense-dose mvac, 1 patient had gemcarbo due to renal function impairment and 2 patients received ciseto figure 1. tumor regression grade (trg) (hematoxylin and eosin). a – trg1, no histologically detectable residual cancer cells, with extensive fibrosis present in the tumor bed. b – trg2, the tumor bed is predominantly fibrotic, with residual cancer cells comprising less than 50% of the area. c – trg3, residual cancer cells dominate over fibrosis, occupying 50% or more of the tumor bed area, or there are no signs of regression. table 3. clinicopathologic data of the study population (n = 51 patients undergoing neoadjuvant chemotherapy followed by radical cystectomy). parameter n (%) age, median (iqr) 66 (60-76) gender male 39 (76.5) female 12 (23.5) smoking history yes 42 (83.4) no 9 (17.6) ct stage t2 39 (76.5) t3 5 (9.8) t4 7 (13.7) cn stage n0 38 (74.5) n+ 13 (25.5) nac scheme gemcis 44 (86.3) mvac 4 (7.8) ciseto 2 (3.9) gemcarbo 1 (2.0) no. of nac cycles, median (iqr) 4 (3-4) 2 10 (19.6) 3 13 (25.5) 4 24 (47.1) 6 4 (7.8) radical cystectomy specimen no tumor present 12 (23.5) tumor present 39 (76.5) pure urothelial carcinoma/cis 25 (64.1) variant histology 14 (35.9) squamous cell 4 (7.8) micropapillary 4 (7.8) adenocarcinoma 2 (3.9) neuroendocrine 2 (3.9) sarcomatoid 2 (3.9) pt stage t0 12 (23.5) tis 11 (21.6) t1 3 (5.9) t2 3 (5.9) t3 14 (27.5) t4 8 (15.7) residual tumor dimension (cm), median (iqr) 3.25 (2.0-5.5) pn stage nx 2 (3.9) n0 36 (70.6) n1 1 (2.0) n2 12 (23.5) no. of positive lymph nodes if n1-3, median (iqr) 4.5 (2-8) surgical margins negative 41 (80.4) positive 10 (19.6) tumor regression grade trg1 23 (45.1) trg2 9 (17.7) trg3 19 (37.2) type of responder complete responder 22 (43.1) partial responder 10 (19.6) non-responder 19 (37.2) gemcis: gemcitabine/cisplatin; gemcarbo: gemcitabine/carboplatin; cis: carcinoma in situ; ciseto: cisplatin/etoposide; mvac: methotrexate/vinblastine/doxorubicin/cisplatin; nac: neoadjuvant chemotherapy; trg: tumor regression grade. archivio italiano di urologia e andrologia 2025; 97(3):14264 m. lopes, j. pereira, m.j. temido, et al. 4 because of poorly differentiated neuroendocrine variant present in > 10% of turb specimen. regarding response to neoadjuvant treatment, trg was closely correlated with response classification. all non-responders (n = 19) exhibited trg3. among the 23 patients with trg1, 22 were classified as complete responders, while one was a partial responder. in this particular case, complete tumor regression was observed in the bladder, but residual uc was identified in the prostate (pt4a, n0, trg1). finally, nine patients were assigned trg2, contributing to a total of 10 patients categorized as partial responders. overall and disease-free survivals the median follow-up period was 16.7 months (iqr 9.947.3), and the 3and 5-year os rates were 28.6% and 14.3%, respectively (figure 2a). the median os was 19 months (iqr 9.9-47.3). four patients survived for more than eight years after rc. the 3and 5-year dfs rates were 28.6% and 14.3%, respectively (figure 2b). progression of disease was diagnosed in 23 patients (46.9%), with non-regional lymph nodes in 4 (17.4%), visceral lesions in 4 (17.4%), bone metastasis in 2 (8.7%), pelvic mass in 2 (8.7%) and in multiple locations in 11 (47.8%) patients. three patients had metastatic disease based on rc specimen analysis: (1) peritoneal implant, (2) ovarian metastasis and (3) non-regional lymph nodes metastasis. figure 2. kaplan-meier curves of overall survival (a) and disease-free survival (b) in 51 patients undergoing neoadjuvant chemotherapy followed by radical cystectomy. figure 3. kaplan-meier curves of overall survival (os) in 51 patients undergoing neoadjuvant chemotherapy followed by radical cystectomy. (a) os according to surgical margins (log rank p < 0.001). (b) os according to pn stage (log rank p < 0.001). (c) os according to treatment response (log rank p < 0.001). a. a. b. c. b. archivio italiano di urologia e andrologia 2025; 97(3):14264 5 prognostic value of combined tumor regression grade and tnm impact of clinical and histopathological factors in the disease-free and overall survival univariate analysis identified several predictors of longer os, including tumor type in the rc specimen (p = 0.04), with pure uc showing better outcomes compared to variant histology (p = 0.008), as well as pathological stage ypt≤1 (p < 0.001), node-negative status (p < 0.001), negative margins (p < 0.001), lower trg (p < 0.001), and complete response (p < 0.001) (figure 3 and supplementary table). these same predictors were also associated with improved dfs (p < 0.05) (supplementary table). independent predictive factors of survival on multivariable analysis, the absence of nodal involvement and complete response (defined as ypt≤1, ypn0, trg1) were identified as independent predictors of improved os (p = 0.047 and p = 0.012, respectively). negative surgical margins demonstrated a trend toward significance as an independent prognostic factor for os (p = 0.064) (table 4). discussion in this retrospective cohort of 51 patients with mibc treated with nac followed by rc, we observed that trg was significantly associated with both os and dfs. the median os in our cohort was 19 months, with 3and 5-year os rates of 28.6% and 14.3%, respectively. these are lower rates than those reported in large multicenter trials (2, 3), likely reflecting differences in patient selection, disease burden, and histological subtypes. despite this, a small subset of patients achieved long-term survival beyond eight years, reinforcing the potential of nac followed by rc to provide durable benefit in well-selected individuals. consistent with prior studies (12, 13, 18) we found that better trg scores (trg1-2), node-negative status, and lower pathological stage (ypt≤1) were associated with prolonged survival. importantly, being a complete responder emerged as a strong prognostic factor on both univariate and multivariate analyses, supporting trg classification utility in stratifying patients beyond conventional tnm staging. while pathologic complete response (pt0n0) is the most widely used surrogate endpoint in nac trials, our findings are aligned with the literature in showing that patients with near-complete response (trg1 and pt≤1n0) also derive substantial benefit (13). variant histology was significantly associated with worse survival, consistent with previous evidence suggesting that non-pure uc is less responsive to nac and associated with more aggressive behavior (19). additionally, positive surgical margins – despite of not being independently predictive in multivariable analysis – were associated with decreased os on univariate analysis, highlighting the importance of surgical quality and local tumor control (1). nearly half of the cohort (46.9%) experienced disease progression, with distant metastases to lymph nodes, viscera, and bone as the most common. the detection of metastatic disease in three patients at the time of cystectomy highlights limitations in current preoperative staging and supports the need for better diagnostic tools to identify occult disease prior to surgery. our results reinforce the prognostic value of trg after nac in mibc and the importance of its integration with standard tnm classification to improve postoperative risk stratification. patients with poor trg scores, positive nodes, or incomplete response may benefit from more intensive surveillance or consideration for adjuvant therapies, including immune checkpoint inhibitors, as it is being practiced (20). conversely, identification of complete or partial responders may support the emerging supplementary table. clinical and pathological characteristics of the study population (n = 51 patients undergoing neoadjuvant chemotherapy followed by radical cystectomy) and predictors of overall and disease-free survival (log rank) (p < 0.05). parameters no. of overall disease-free patients (%) survival survival gender male 39 (76.5%) 0.436 0.5 female 12 (23.5%) age ≤ 65 14 (73.7%) 0.61 0.65 > 65 5 (26.3%) history of smoking yes 42 (82.4%) 0.333 0.587 no 9 (17.7%) rc specimen no tumor present 12 (23.5%) 0.04 0.026 tumor present 39 (76.5%) rc specimen with tumor pure urothelial carcinoma/cis 25 (64.1%) 0.008 0.004 variant histology 14 (35.9%) ypt t≤1 7 (36.8%) < 0.001 < 0.001 t≥2 12 (63.2%) ypn n0 16 (84.2%) < 0.001 < 0.001 n1-3 3 (15.8%) surgical margins negative 41 (80.4%) < 0.001 < 0.001 positive 10 (19.6%) tumor regression grade trg 1 23 (45.1%) < 0.001 < 0.001 trg 2 9 (17.7%) trg 3 19 (37.2%) type of responder complete 22 (43.1%) < 0.001 < 0.001 partial 9 (17.7%) non-responder 20 (39.2%) hr: hazard ratio; 95% ci: 95% confidence interval. table 4. independent predictors of overall survival (cox regression). hr 95% ci p value surgical margins (negative) 2.72 0.94-7.84 0.064 pn stage (n0) 2.59 1.01-6.62 0.047 type of responder (complete responder) 2.19 1.18-4.06 0.012 hr: hazard ratio; 95% ci: 95% confidence interval. archivio italiano di urologia e andrologia 2025; 97(3):14264 m. lopes, j. pereira, m.j. temido, et al. 6 bladder-sparing approaches in carefully selected cases. on the behalf of this, the pre-prevencys trial showed that the absence of residual disease after nac in patients with mibc is accurately predicted, and so a randomized controlled trial is scheduled for comparing os after nac plus rc versus nac and close surveillance in patients with a clinically complete response (8). additionally, the value of circulating tumor dna holds promise as a biomarker in the perioperative treatment of mibc and the integration of both markers may be an enthusiastic area of research in the upcoming years (21). this study is limited by its retrospective, single-center design and relatively small sample size, which may impact statistical power and generalizability. in addition, variations in chemotherapy regimens and timing between turb, nac, and rc may introduce heterogeneity. nevertheless, the strong association observed between response categories and survival outcomes adds a robust role for trg as a clinically meaningful criterion. conclusions trg system is a reproducible and clinically relevant method for assessing histological response to nac in bladder cancer. when combined with yptnm staging, it enhances prognostic stratification and may inform postoperative management decisions. future studies should focus on standardizing these scoring systems and evaluating their role in prospective treatment algorithms. references 1. stein j, lieskovsky g, cote r, et al. radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. clin oncol. 2001; 19:666-675. 2. grossman h, natale r, tangen c, et al. neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. n engl j med. 2003; 349:859-66. 3. collaboration. abcm. neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. lancet. 2003; 361:1927-1934. 4. van der heijden a, bruins h, carrion a, et al. european association of urology guidelines on muscle-invasive and metastatic bladder cancer. eur assoc urol. 2025; 87:582-600. 5. motterle g, andrews jr, morlacco a, karnes rj. predicting response to neoadjuvant chemotherapy in bladder cancer. eur urol focus. 2020; 6:642-649. 6. yuh b, ruel n, wilson t, et al. pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer. j urol. 2013; 189:1682-1686. 7. rosenblatt r, sherif a, rintala e, et al. pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. eur urol. 2012; 61:1229-1238. 8. hinsenveld fj, noordman bj, boormans jl, et al. prediction of pathological response following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: the pre-prevencys trial. bmc cancer. 2021; 21:1-11. 9. morgan m, koorey d, painter d, et al. histological tumour response to pre-operative combined modality therapy in locally advanced rectal cancer. color dis. 2002; 4:177-183. 10. becker k, langer r, reim d, et al. significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. ann surg. 2011; 253:934-939. 11. fareed k, ilyas m, kaye p, et al. tumour regression grade (trg) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy. histopathology. 2009; 55:399-406. 12. fleischmann a, thalmann gn, perren a, seiler r. tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy. a novel and successful strategy to predict survival. am j surg pathol. 2014; 38:325-332. 13. voskuilen cs, oo hz, genitsch v, et al. multicenter validation of histopathologic tumor regression grade after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma. am j surg pathol. 2019; 43:1600-1610. 14. gronostaj k, czech ak, fronczek j, et al. the prognostic value of tumor regression grades combined with tnm classification in patients with muscle-invasive bladder cancer who underwent neoadjuvant chemotherapy followed by radical cystectomy. clin genitourin cancer. 2019; 17:e1203-e1211. 15. seiler r, oo hz, todenhöfer t, et al. tumor regression grading after neoadjuvant chemotherapy in bladder cancer: validation in an independent cohort. eur urol suppl. 2017; 16:e685. 16. nakagawa t. lymph node dissection for bladder cancer: current standards and the latest evidence. int j urol. 2021; 28:7-15. 17. amin mb, greene fl, edge sb, et al. the eighth edition ajcc cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. ca cancer j clin. 2017; 67:93-99. declarations ethical approval and consent for participate: ethics approval statement was waived. informed consent was obtained from all patients, or a representant in case of incapability or death, prior to inclusion in this study. consent for publication: not applicable. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: no funding was necessary for this study. authors' contributions: ml, study concepts, methodology, data acquisition, analysis and interpretation, manuscript original drafting and edition; jp, manuscript drafting and review; mjt, data analysis and interpretation and manuscript review; jg, histopathological analysis and manuscript review; es, study concepts and manuscript review; vq, manuscript edition and review; jl, manuscript review; rp, manuscript review; jpl, manuscript review; hd, manuscript review; lm, manuscript review; vs, histopathological analysis and manuscript review; af, manuscript review and supervision. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: the authors are grateful to the staff of urology and renal transplantation department and pathology department of coimbra university hospital for their support in data collection and specimen processing. archivio italiano di urologia e andrologia 2025; 97(3):14264 7 prognostic value of combined tumor regression grade and tnm 18. zargar h, espiritu pn, fairey as, et al. multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. eur urol. 2015; 67:241-249. 19. veskimäe e, espinos el, bruins hm, et al. what is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? a european association of urology mus. eur urol oncol. 2019; 2:625-642. 20. mamede i, silva c, alves ac, et al. adjuvant immunotherapy in high-risk muscle-invasive urothelial cancer: an updated metaanalysis of randomized controlled trials. clin genitourin cancer 2025; 23:102288. 21. crupi e, de padua tc, marandino l, et al. circulating tumor dna as a predictive and prognostic biomarker in the perioperative treatment of muscle-invasive bladder cancer: a systematic review. eur urol oncol. 2024; 7:44-52. correspondence manuel antónio ferreira malheiro lopes (corresponding author) manuel11070@gmail.com serviço de urologia e transplantação renal, hospitais da universidade de coimbra rua praceta professor mota pinto 3000-075 coimbra, portugal josé pereira joseaclpereira@gmail.com instituto português de oncologia, coimbra, portugal maria josé temido mariajosetemido@gmail.com joão gama joaomartinsgama@gmail.com edgar silva edsilva.elv@gmail.com vasco quaresma vpdquaresma@gmail.com joão lorigo joaolorigo@gmail.com rui pedrosa rui.mdp93@gmail.com joão pedroso lima joaopedrosolima@gmail.com henrique dinis hdinis@gmail.com lorenzo marconi lorenzooliveiramarconi@gmail.com arnaldo figueiredo ajcfigueiredo@gmail.com hospitais da universidade de coimbra, portugal stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13955 1 review rcc is highly immunosuppressive and inflammatory, with cytokines playing a pivotal role in disease progression and treatment resistance (3). among these cytokines, interleukin-6 (il-6) has emerged as a key mediator of tumorigenesis, angiogenesis, and immune evasion, making it a promising candidate for prognostic evaluation (4). il-6 is a pleiotropic cytokine involved in acute and chronic inflammation, with well-documented roles in cancer progression (4). in rcc, elevated il-6 levels have been associated with advanced disease stage, poor survival, and resistance to systemic therapies (5). preclinical studies demonstrate that il-6 promotes tumor growth by activating the jak/stat3 pathway, enhancing angiogenesis through vegf upregulation, and suppressing antitumor immune responses (6). clinically, serum il-6 levels correlate with tumor burden, metastatic potential, and adverse outcomes, suggesting its utility as a non-invasive biomarker (7). however, existing studies on il-6 in rcc have produced heterogeneous results, likely due to variations in assay methods, patient populations, and treatment modalities. a comprehensive synthesis of these findings is therefore necessary to clarify the prognostic value of il-6 in rcc. this meta-analysis aims to evaluate the prognostic significance of il-6 in rcc by synthesizing data from published studies, specifically overall survival (os) and progression-free survival (pfs). methods eligibility criteria this meta-analysis will include studies that evaluate the association between preoperative serum il-6 levels and clinical outcomes in rcc patients. inclusion criteria comprise: (1) original research articles with full-text availability in english; (2) studies measuring serum il-6 levels prior to surgical intervention or systemic therapy; (3) studies reporting correlations between il-6 and survival outcomes (os and pfs). exclusion criteria are: (1) non-english publications; (2) review articles, editorials, case reports, conference abstracts, or duplicate studies; (3) studies involving patients who received neoadjuvant chemotherapy before il-6 measurement, as these treatments may confound cytokine levels. additionally, studies lacking sufficient statistical data for meta-analysis will be excluded. introduction & objectives: renal cell carcinoma (rcc) represents the majority of kidney malignancies and is characterized by variable outcomes, even with current systemic therapies. interleukin-6 (il-6), a proinflammatory cytokine implicated in tumor progression and immune suppression, has been proposed as a prognostic biomarker in rcc. however, the evidence remains inconsistent due to methodological heterogeneity across studies. therefore, our study aims to evaluate the prognostic significance of il-6 in rcc by synthesizing data from published studies, specifically overall survival (os) and progression-free survival (pfs). methods: a systematic meta-analysis was conducted to evaluate the prognostic significance of il-6 in rcc. eligible studies were identified through pubmed, sciencedirect, and proquest up to march 2025. inclusion criteria encompassed original articles measuring pre-treatment serum il-6 levels in rcc patients and reporting associations with overall survival (os) or progressionfree survival (pfs). random-effects models were used to compute pooled hazard ratios (hrs) and survival differences. results: nine studies comprising 702 rcc patients were included. patients with low il-6 levels had significantly longer os (difference: 5.36 months; 95% ci: 2.2-8.53; p < 0.001; i² = 0%) and pfs (difference: 6.41 months; 95% ci: 1.3-11.53; p = 0.01; i² = 48.5%) compared to those with high il-6. the pooled hr for survival associated with elevated il-6 was 2.06 (95% ci: -0.23-4.36), with considerable heterogeneity (i² = 89.19%) and borderline statistical significance (p = 0.08). despite variations in study design, sample size, and il-6 detection methods, elevated il-6 consistently predicted worse clinical outcomes. conclusions: il-6 is a promising prognostic biomarker in rcc, with elevated levels associated with significantly poorer os and pfs. key words: renal cell carcinoma; interleukin-6; prognosis; survival; biomarker submitted 10 may 2025; accepted 17 may 2025 introduction renal cell carcinoma (rcc) accounts for approximately 90% of all kidney cancers and remains a significant cause of cancer-related morbidity and mortality worldwide (1). despite advancements in targeted therapies and immune checkpoint inhibitors, patient outcomes vary widely (2), underscoring the need for reliable prognostic biomarkers to guide clinical decision-making. the tumor microenvironment in circulating il-6 and survival outcomes in renal cell carcinoma: a systematic review and meta-analysis haryo nindito wicaksono 1, taufiq nur budaya 2, kurnia penta seputra 2, aulia rahman putra 2 1 general practicioner, intern at department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia; 2 department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2025.13955 summary archivio italiano di urologia e andrologia 2025; 97(3):13955 h. nindito wicaksono, t. nur budaya, k. penta seputra, a. rahman putra 2 literature search a systematic search will be conducted in pubmed/medline, science direct, and proquest, from inception to the present, using predefined search terms: − population: ("renal cell carcinoma" or "rcc" or "kidney cancer") − intervention/exposure: ("interleukin-6" or "il-6" or "serum cytokine") − outcome: ("prognosis" or "survival") − study design: ("cohort" or "prospective" or "retrospective"). the search strategy will combine mesh terms and freetext keywords with boolean operators. two independent reviewers will perform the search, remove duplicates, and screen titles/abstracts. full texts of potentially eligible studies will be assessed for final inclusion, with discrepancies resolved by consensus or a third reviewer. data analyses extracted data will include: (1) study characteristics (author, year, country, design); (2) patient demographics (sample size, age, sex); (3) il-6 measurement methods; (4) clinical outcomes [os, pfs, and hr with 95% confidence intervals (cis)]. statistical analysis will be performed using stata. pooled os, pfs, and hr will be calculated using random-effects models. heterogeneity will be assessed via i² statistics (i² > 50% indicating substantial heterogeneity). the quality of each study assessed using newcastle-ottawa scale. results this meta-analysis incorporated nine studies investigating the prognostic role of il-6 in renal cell carcinoma (rcc), comprising a total of 702 patients. full search and filter details are in figure 1. the studies were predominantly retrospective (n = 6), with one prospective cohort and two clinical trial analyses. patient cohorts varied in size from 19 to 217 individuals, with median/mean ages ranging from 55.5 to 64.5 years where reported. females constituted 32-42% of participants in studies documenting sex distribution. most studies focused on metastatic or advanced rcc (n = 7), while two included localized disease. il-6 measurement methods differed across studies: two used immunoassay (without specifying the method), three used serum/plasma elisa, one used immunoenzymatic or immunoradiometric assay, one used immunohistochemistry (ihc), one directly measured the level of il6 in the serum, and one analyzed tcga rna-seq data. cutoffs for "high il-6" were heterogeneous, ranging from > 5 pg/ml to ≥ 35 pg/ml in serum assays or quartile-based thresholds in transcriptomic studies. methodological variability was evident, with serum/plasma il-6 levels spanning 6.9-48.2 pg/ml across cohorts. key findings consistently associated elevated il-6 with adverse outcomes: five studies reported significantly worse os or pfs with high il-6 levels, while two noted trends toward poorer survival. despite differing assays and cutoffs, all studies supported il-6 as a negative prognostic marker. full study characteristics are in table 1. figure 1. prisma diagram. archivio italiano di urologia e andrologia 2025; 97(3):13955 3 circulating il-6 and survival outcomes in renal cell carcinoma: a systematic review and meta-analysis meta-analysis results demonstrated significant associations between il-6 levels and survival outcomes in rcc patients as showed in figures 2-4. patients with low il6 levels exhibited 5.36 months longer os compared to those with high il-6 levels (95% ci: 2.2-8.53; p < 0.001), with no observed heterogeneity (i² = 0%) across all nine studies. similarly, progression-free survival (pfs) was 6.41 months longer in the low il-6 group (95% ci: 1.3-11.53; p = 0.01), though moderate heterogeneity was noted (i² = 48.5%) among the four studies analyzed. figure 2. overall survival difference low vs high il-6. table 1. characteristics of each study. first author pilskog et al. (8) negrier et al. (9) pilskog et al. (5) tran et al. (10) thiounn et al. (11) stadler et al. (12) costes et al. (13) akdogan et al. (14) kays et al. (15) country of study norway france norway usa france argentina france turkey usa study design open-label, single-arm phase ii study retrospective analysis of a randomized multicentric trial retrospective analysis of a single-arm phase ii study retrospective analysis of phase 2 and phase 3 clinical trials retrospective study analysis of patients in a phase i evaluation retrospective analysis prospective observational cohort study retrospective analysis of tcga data total number of patients 46 138 46 129 19 22 38 23 (rcc subgroup of 85 total cancer patients) 217 (ccrcc) average age median 63.1 years median 56 years median 63.1 years not stated mean 55.5 years not stated 61.2 years median 64.5 years (overall cohort) 59.65 years percentage of women 37.0% 28.3% 37.0% not stated 42.1% not stated 28.9% 32% (overall cohort) not stated cancer stage metastatic or non-resectable clear cell renal cell carcinoma (ccrcc) metastatic renal cell carcinoma (mrcc) metastatic or non-resectable clear cell renal cell carcinoma (ccrcc) metastatic renal-cell carcinoma metastatic renal cell carcinoma metastatic kidney cancer primary renal cell carcinoma (stages i-iv) advanced renal cell carcinoma (part of a cohort with nsclc and melanoma) clear cell renal cell carcinoma (ccrcc) il-6 detection method elisa (plasma il-6 pil6) immunoassay (serum il-6) immunohistochemistry (ihc) (tumour tissue il-6 expression) multiplex assay, protein array, and elisa (plasma il-6) assay (serum il-6) measured levels of il-6 in serum immunoenzymatic or immunoradiometric assay (serum il-6) elisa (baseline serum il-6) rnaseq (tumour il-6 gene expression) il-6 cutoff (high/low) low pil6 at baseline associated with improved response and pfs; median baseline pil6 was 6.90 pg/ml (implied cutoff around this value) high il-6 (≥ 35 pg/ml) associated with worse overall survival (cutoff determined by quartile method) low vs. high expression in tumour cells based on staining index (si 0-2 vs 3-9), low expression associated with improved pfs low (relative to median) il-6 correlated with increased tumour shrinkage and prolonged pfs; high levels were negative prognostic factors (median not specified in excerpt) greater or less than 15 pg/ml; high il-6 correlated with shorter survival abnormal il-6 (>5 pg/ml) associated with worse prognosis detectable serum il-6 (presence vs. absence) correlated with worse survival; mean serum il-6 was 8.32 pg/ml in il-6r -ve and 48.2 pg/ml in il-6r +ve tumours stratified by median il-6 level (20.0 pg/ml); higher levels showed a trend towards shorter os (not statistically significant) high vs. low il-6 expression in tumour, correlated with survival based on quartiles of expression; high expression associated with decreased survival archivio italiano di urologia e andrologia 2025; 97(3):13955 h. nindito wicaksono, t. nur budaya, k. penta seputra, a. rahman putra 4 the pooled hazard ratio (hr) for survival further supported these findings, with high il-6 levels correlating with a 2.06-fold increased risk of poor outcomes (95% ci: -0.23-4.36), albeit with substantial heterogeneity (i² = 89.19%) and borderline statistical significance (p = 0.08). these results collectively underscore il-6 as a robust prognostic biomarker in rcc, where elevated levels consistently predict shorter survival and disease progression, despite variability in study methodologies. discussion the present meta-analysis, comprising nine studies and a total of 702 patients with rcc, consolidates robust evidence that elevated il-6 levels are significantly associated with poorer survival outcomes. this finding aligns with prior review by wang et al. (2019), which demonstrated a strong correlation between high il-6 levels and worse overall os, reporting an hr of 3.03 (95% ci: 2.37-3.70) (16). however, our study extends this understanding by quantifying the prognostic advantage associated with low il-6 levels: a 5.36-month os benefit (95% ci: 2.2-8.53; p < 0.001) and a 6.41-month improvement in progression-free survival (pfs) (95% ci: 1.3-11.53; p = 0.01). notably, our analysis yielded a lower degree of heterogeneity (i² = 0% for os) compared to that of wang et al., which reported a markedly high heterogeneity (i² = 98%). this consistency across diverse methodologies and patient populations underscores il-6’s biological role as a key driver of rcc progression, plausibly through mechanisms of angiogenesis, immune evasion, and resistance to therapy, as previously postulated (17-19). from a biological and clinical standpoint, the prognostic relevance of il-6 is mechanistically plausible. preclinical data have demonstrated that il-6 activates the jak/stat3 pathway, which fosters tumor proliferation while concurrently impairing anti-tumor immunity (6). our pooled hr of 2.06 (95% ci: -0.23 to 4.36), while not statistically significant (p = 0.08), is consistent with the trends previously reported (9), who observed that elevated serum il-6 levels were associated with diminished os in metastatic rcc. furthermore, the well-documented correlation between il-6 and c-reactive protein (crp) suggests crp may function as a surrogate biomarker (16). however, our findings support the notion that il-6 itself plays a more direct and pivotal role in rcc biology. importantly, the consistent association between elevated il-6 levels and advanced tumor stage (which documented in seven of nine included studies) reinforces its potential utility as a biomarker for prognostication and risk stratification. this is particularly relevant in the context of il-6-targeting therapeutic agents such as siltuximab and tocilizumab (20). one notable strength of our meta-analysis lies in its refined precision. by focusing exclusively on pre-treatment il-6 measurements, we reduced the confounding figure 3. progression free survival difference low vs high il-6. figure 4. hazard ratio for poor survival. archivio italiano di urologia e andrologia 2025; 97(3):13955 5 circulating il-6 and survival outcomes in renal cell carcinoma: a systematic review and meta-analysis influence of systemic therapies, particularly immunotherapy, which affected a substantial proportion (60%) of patients in wang et al.’s cohort (16). in terms of methodological rigor, our use of a random-effects model appropriately accounted for heterogeneity in il-6 cutoffs (ranging from > 5 pg/ml to ≥ 35 pg/ml) and assay techniques, yet still yielded consistent os and pfs differences. the observed 6.41 month pfs advantage is not only statistically significant but also clinically meaningful, suggesting that il-6 may serve as a stratifying tool in selecting patients for adjuvant or intensified therapy, especially within the metastatic setting. nonetheless, several limitations must be acknowledged. the high heterogeneity observed in the hr analysis (i² = 89.19%) reflects substantial methodological variation among the included studies, including differences in detection platforms (elisa versus immunohistochemistry), biological samples (serum versus tumor tissue), and patient populations (localized versus metastatic rcc). additionally, the small sample sizes in some included studies raise concerns about potential effect size inflation. publication bias, although not formally detected due to the small number of included studies (n = 9), cannot be definitively ruled out. the clinical implications of our findings are considerable. integrating il-6 into existing prognostic frameworks, such as the international metastatic rcc database consortium (imdc) model, may enhance risk stratification and inform therapeutic decisions. patients with elevated il-6 may benefit from risk-adapted surveillance protocols and may represent an ideal target population for clinical trials evaluating the efficacy of il-6 blockade. preclinical studies have shown promising synergy between il-6 inhibition and vegf-tkis (19, 21), thus warrants further clinical exploration. looking forward, prospective trials should prioritize the standardization of il-6 assays (ideally through centralized elisa platforms) and establish consensus on clinically actionable cutoffs. given the dual biological and prognostic roles of il-6 in rcc, its integration into both biomarker-driven clinical trials and real-world prognostic models may represent the next advance in personalized therapy for this aggressive malignancy. conclusions elevated il-6 levels are significantly associated with poorer overall and progression-free survival in patients with renal cell carcinoma, confirming its role as a negative prognostic biomarker. these findings support the integration of il-6 measurement into clinical risk stratification and therapeutic decision-making in rcc management. references 1. hsieh j, purdue m, signoretti s, et al. renal cell carcinoma. nat rev dis prim 2018; 9:1-42. 2. petrelli f, vavassori i, rossitto m, dottorini l. management of metastatic renal cell carcinoma following first-line immune checkpoint therapy failure: a systematic review. cancers (basel) 2024; 16:2598-610. 3. heidegger i, pircher a, pichler r. targeting the tumor microenvironment in renal cell cancer biology and therapy. front oncol 2019; 9:1-11. 4. zhao h, wu l, yan g, et al. inflammation and tumor progression: signaling pathways and targeted intervention. signal transduct. target. ther.2021; 6:263-308. 5. pilskog m, bostad l, edelmann rj, et al. tumour cell expression of interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. j pathol clin res 2018; 4:114-23. 6. jian shi, wang k, xiong z, et al. impact of inflammation and immunotherapy in renal cell carcinoma (review). oncol. lett.2020; 20:272-84. 7. gudbrandsdottir g, aarstad hh, bostad l, et al. serum levels of the il-6 family of cytokines predict prognosis in renal cell carcinoma (rcc). cancer immunol immunother 2021; 70:19-30. 8. pilskog m, nilsen gh, beisland c, straume o. elevated plasma interleukin 6 predicts poor response in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. cancer treat res commun 2019; 19:1-5. 9. negrier s, perol d, menetrier-caux c, et al. interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6 from the groupe français d’immunothérapie. j clin oncol 2004; 22:2371-8. 10. tran ht, liu y, zurita aj, et al. prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. lancet oncol 2012; 13:827-37. 11. thiounn n, pages f, flam t, et al. rapid note: il-6 is a survival prognostic factor in renal cell carcinoma. immunol lett 1997; 58:121-4. 12. stadler wm, richards jm, vogelzang nj. serum interleukin-6 levels in metastatic renal cell cancer: correlation with survival but not an independent prognostic indicator. j. natl. cancer inst.1992; 84:1835-6. 13. costes v, liautard j, picot mc, et al. expression of the interleukin 6 receptor in primary renal cell carcinoma. j clin pathol 1997; 50:835-40. 14. akdogan o, turkmen s, uyar g, et al. impact of serum gdf-15 and il-6 on immunotherapy response in cancer: a prospective study. cancers (basel) (internet) 2024; 16:41-6. 15. kays jk, koniaris lg, cooper ca, et al. the combination of low skeletal muscle mass and high tumor interleukin-6 associates with declarations ethical approval and consent: not applicable. consent for publication: not applicable. availability of data and materials: all data generated or analyzed during this study are included in this published article. competing interests: the authors declare no potential conflict of interest. funding: the authors report no funding. authors' contributions: conception or design: tnb, kps; acquisition, analysis, or interpretation of data: hnw, arp, tnb, kps; drafting the work or revising: hnw, arp, tnb, kps; final approval of the manuscript: hnw, arp, tnb, kps. archivio italiano di urologia e andrologia 2025; 97(3):13955 h. nindito wicaksono, t. nur budaya, k. penta seputra, a. rahman putra 6 decreased survival in clear cell renal cell carcinoma. cancers (basel) 2020; 12:1605-15. 16. wang y, zhang y. prognostic role of interleukin-6 in renal cell carcinoma: a meta-analysis. clin transl oncol 2020; 22:835-43. 17. gopinathan g, milagre c, pearce omt, et al. interleukin-6 stimulates defective angiogenesis. cancer res 2015; 75:3098-107. 18. jian y, yang k, sun x, et al. current advance of immune evasion mechanisms and emerging immunotherapies in renal cell carcinoma. front. immunol. 2021; 12:1-21. 19. ishibashi k, koguchi t, matsuoka k, et al. interleukin-6 induces drug resistance in renal cell carcinoma. fukushima j. med. sci. 2018; 64:103-10. 20. soler mf, abaurrea a, azcoaga p, et al. new perspectives in cancer immunotherapy: targeting il-6 cytokine family. j. immunother. cancer 2023; 11:1-13. 21. sweeney pl, suri y, basu a, et al. mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma. cancer drug resist.2023; 6:858-73. correspondence haryo nindito wicaksono (corresponding author) wicaksonoharyo123@gmail.com general practicioner, intern at department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia aulia rahman putra taufiq nur budaya kurnia penta seputra department of urology, faculty of medicine, universitas brawijaya, saiful anwar general hospital, malang, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13999 1 original paper recommends the dorsal slit incision technique, which is widely used and valued for its safety as it is performed under direct observation (3, 4). this approach allows for the immediate identification and resolution of any intraoperative issues. however, despite its prevalence and established techniques, there remains an acknowledged potential for improvement. existing methods are associated with several complications, including anatomic abnormalities, patient comorbidities, surgeon’s technique and skill, and age (5). complications include hemorrhage, which is the most common with an incidence of up to 1% (6), infection, excessive or inadequate skin excision, and unsatisfactory cosmetic outcomes that may necessitate surgical revision (7, 8). the incidence of these complications can increase when the procedure is performed by less experienced surgeons or during mass circumcision events, underscoring the need for techniques that are simpler and more easily reproducible. this context highlights a clear gap in current practice. while the conventional dorsal slit method is safe, there is a need for a modification that enhances operative efficiency without compromising safety or cosmetic results. a technique that is faster, equally safe, and easier to perform consistently would be a valuable addition to the field, particularly in high-volume clinical settings. to address this gap, this study introduces and evaluates a novel modification called the "dorsal buttonhole slit" circumcision. the objective was to assess the safety and efficacy of this new technique. the evaluation compared its operative time, healing time, complication rates, and parental satisfaction against the conventional dorsal slit method. materials and methods this retrospective, descriptive study was conducted at a single center and designed to align with the principles of the strengthening the reporting of observational studies in epidemiology (strobe) guidelines. the study retrospecintroduction and objective: circumcision is the most frequently performed surgical procedure worldwide. the world health organization recommends that circumcisions should be performed by dorsal slit incision. this study introduces the dorsal buttonhole slit, a novel modification of the conventional dorsal slit technique, and aims to evaluate its clinical outcomes and safety in a pediatric cohort. material and methods: this retrospective descriptive study was conducted on 107 pediatric patients aged 1-10 years who underwent circumcision for religious reasons or phimosis between january 2022 and december 2023. patients were divided into two groups based on the surgical technique used: dorsal buttonhole slit (n = 56) versus conventional dorsal slit (n = 51). the assessment parameters included intra-operative hemorrhage, operating time, healing time, postoperative complications, and parental satisfaction. results: the mean operative time was significantly shorter in the dorsal buttonhole slit group compared to the conventional group (293.79 vs. 320.67 seconds, respectively; p = 0.028). there was no significant difference in wound healing time between the two groups. no postoperative complications, such as hemorrhage or need for revision, were observed in any patient during the 1-month follow-up period. all parents reported satisfaction with the functional and cosmetic results conclusions: the dorsal buttonhole slit technique was associated with a shorter operative time and excellent safety outcomes. while these results are promising, prospective randomized trials are required to definitively confirm the efficacy and safety of this method. the technique shows potential as a reproducible and reliable alternative for pediatric circumcision. key words: circumcision; male; phimosis; child; postoperative complications; operative time. submitted 17 may 2025; accepted 21 june 2025 introduction circumcision is a common surgical procedure performed worldwide (1) for medical and traditional cultural or religious purposes (2). the world health organization (who) comparison of novel dorsal buttonhole slit versus conventional dorsal slit circumcision: efficacy, safety, and parents’ satisfaction muhammad asykar palinrungi 1, 2, 3, muhammad faruk 4, muhammad rum marewa 5, andi makkawaru chairul 6, ashy amelia arista 4, nurnaningsi thalib 4, abdul azis 1, 2 1 division of urology, department of surgery, faculty of medicine, universitas hasanuddin, makassar, indonesia; 2 department of urology, universitas hasanuddin hospital, makassar, indonesia; 3 department of surgery, akademis jaury jusuf putera hospital, makassar, indonesia; 4 department of surgery, faculty of medicine, universitas hasanuddin, makassar, indonesia; 5 konawe utara hospital, north konawe, indonesia; 6 department of physiology, faculty of medicine, universitas negeri makassar, pare-pare, indonesia. doi: 10.4081/aiua.2025.13999 summary archivio italiano di urologia e andrologia 2025; 97(3):13999 m. asykar palinrungi, m. faruk, m. rum marewa, et al. 2 tively analysed the medical records of paediatric patients who underwent circumcision between january 2022 and may 2022. study population patients included in this study were identified from medical records and met the following criteria: pediatric patients aged between 1 and 10 years who underwent circumcision for either religious reasons or a diagnosis of phimosis. the cohort consisted of all patients who met these criteria within the specified timeframe. patients were then allocated into one of two groups for comparative analysis based on the surgical technique they had received: the conventional dorsal slit technique or the dorsal buttonhole slit technique. outcomes and definitions the following outcome variables were retrospectively collected and assessed: operative time: defined as the interval in seconds from the initial skin incision to the application of the final suture. healing time: defined as the number of days until the wound was considered fully healed upon assessment at the 1-month follow-up visit. complications: the presence of any of the following prespecified adverse events, assessed during the 1-month follow-up period: frenulum haemorrhage, painful postoperative erection, chordae, meatal stenosis, the presence of residual preputial skin requiring revision, or urethral cutaneous fistula. parents’ satisfaction: this was assessed during the followup visit. for this retrospective analysis, satisfaction was recorded as a binary outcome (satisfied or not satisfied) based on direct parental reporting noted in the clinical records. a specific, validated assessment tool for cosmetic satisfaction was not utilized in the routine data collection for these procedures. the assessment included intra-operative hemorrhage, operation time, wound healing, satisfaction with penile appearance, and the impact of side effects. procedure conventional circumcision method was performed using dorsal slit technique as described in previous studies (911). the following describes the surgical procedure used for dorsal buttonhole slit circumcision: the patients were under local or general anesthesia; the attachment and smegma in the coronary sulcus were cleaned, after which a mark was made on the skin at the border of the coronary sulcus; the frenulum was clamped and traction was applied; a mosquito clamp was inserted between the skin and the glans of the penis at twelve o'clock (figure 1a); then, a buttonhole slit was made at the lower limit of the clamp using metzenbaum scissors (figure 1b); then, circumcision was carried out according to the marker (figure 1c); bleeding control was then performed, and then the skin and the inner layer of the prepuce were sutured (figure 1d). statistical analysis all statistical analyses were performed to compare the outcomes between the dorsal buttonhole slit and conventional dorsal slit groups. a p-value of less than 0.05 was considered statistically significant. continuous variables with normal distribution, including patient age and operative time, were compared using an independent samples t-test. categorical variables, such as the indication for surgery (phimosis vs. religious reasons), were compared using the chi-squared test. to assess for baseline comparability and potential confounding, patient age and indication for surgery were compared between the two groups. data are presented as mean ± standard deviation for continuous variables and as frequency (percentage) for categorical variables. figure 1. the attachment and smegma in the coronary sulcus were cleaned, after which a mark was made on the skin at the border of the coronary sulcus. the frenulum was clamped, and traction was applied. a) a mosquito clamp was inserted between the skin and the glans of the penis at twelve o’clock. b) a buttonhole slit was made at the lower limit of the clamp using metzenbaum scissors. c) circumcision was carried out according to the marker. d) bleeding was controlled, and the skin and inner layer of the prepuce were sutured. archivio italiano di urologia e andrologia 2025; 97(3):13999 3 dorsal buttonhole slit circumcision results the demographic characteristics were comparable between the two groups (table 1). there was no statistically significant difference in the mean age of patients between the dorsal buttonhole slit and conventional dorsal slit groups (p > 0.05). the primary outcome of operative time showed a statistically significant difference between the techniques. the mean operative time was significantly shorter for the dorsal buttonhole slit group (293.79 ± 46.71 seconds) compared to the conventional dorsal slit group (320.67 ± 44.64 seconds). this represented a mean difference of 26.88 seconds. the finding was statistically significant (p = 0.028). there were no statistically significant differences observed in the average healing time between the two groups (3.6 days vs. 3.7 days, p > 0.05). furthermore, no postoperative complications were recorded in either group, and parental satisfaction was 100% for both techniques. all patients’ surgeries were successful, and the outcomes were satisfactory. all parents were satisfied with the results of the operations. no significant complications, such as frenulum hemorrhage, painful postoperative erection, chordae, meatal stenosis, residual preputial skin, or urethral cutaneous fistula, were observed in any patient after a 1-month follow-up. the cosmetic results were satisfactory. discussion this study showed that the dorsal buttonhole slit technique had a significantly shorter operative time compared to the conventional technique (p = 0.028). these findings indicate that the dorsal buttonhole slit technique may be more efficient in terms of operative time, which may be an important consideration in clinical practice, especially in settings with high patient volumes. although there was a significant difference in operative time, there was no significant difference in healing time between the two groups (p > 0.05). both techniques showed similar mean healing time of 3.7 days, with a range of 3-5 days. this suggests that although the dorsal buttonhole slit technique is faster in terms of operative time, there is no difference in the rate of wound healing compared to the conventional technique. one of the most important findings of this study is that there were no complications reported in either group. this suggests that both circumcision techniques are safe and well tolerated by patients. in addition, parental satisfaction rates reached 100% in both groups, indicating that both techniques produce satisfactory cosmetic and functional results. male circumcision is the surgical removal of some or the entire foreskin of the penis. it is one of the most commonly performed procedures (12). lei et al. (2016) reported that phimosis is the main indication beyond non-medical, social, ethnic, and religious reasons (3). in this study, religious reasons were the most common indication for parents to request circumcision for their child. there are many methods of circumcision. the dorsal slit incision technique is recommended by the who and is the most commonly used method of circumcision. this technique is effective and safe because it is done by direct observation; any damage that occurs can be immediately identified and resolved intra-operatively, and the results are satisfactory (3, 4). the dorsal buttonhole slit technique slightly modifies this technique by cutting a buttonhole in the dorsal frenulum with mosquito clamps from the gap between the glans and the inner side of the frenulum. complications of circumcision are reported to be nearly 5%; complications increase when the surgery is performed by inexperienced surgeons or during mass circumcision events (13). the most common complication is hemorrhage (14). in this study, there were no visible hemorrhage complications owing to the careful inspection and hemotable 1. patient characteristic. variable dorsal buttonhole slit conventional p-value n (%) n (%) participant 56 (100) 51 (100) age (years) 5.03 (1-10) 5.33 (1-10) > 0.05 * indication phimosis 23 (41 ) 25 (49 ) > 0.05 religious 33 (59) 26 (51) operative time (seconds) 293.79 + 46.71 320.67 + 44.64 0.028 * healing time (days) 3.6 (3-5) 3.7 (3-5) > 0.05 * complication 0 (0) 0 (0) parents’ satisfaction 56 (100) 51 (100) * independent samples t-test. ** chi-squared test; a p-value < 0.05 was considered statistically significant. declarations ethical approval and consent for participate: the authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. all patients included in this study were provided with informed consent prior to participation, which was carried out in accordance with the principles of the declaration of helsinki. this study was approved by the ethics committee of hasanuddin university (no. 209/un4.6.4.5.31/pp36/2023) with protocol no. uh23030185 on april 4, 2023. availability of data and material: the data that support the findings of this study are available from the corresponding author upon reasonable request. competing interests: the authors declare no conflict of interest. funding: this research received no specific grant from any funding agency in the public, commercial, or not forprofit sectors. authors' contributions: study concept and design: map and mf; data acquisition: mrm, amc, aas, and nt: drafting of manuscript: mrm, amc, aaa, and nt; critical revision of the manuscript: map, mf, and aa. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):13999 m. asykar palinrungi, m. faruk, m. rum marewa, et al. 4 stasis that were performed during circumcision. another complication that can occur is redundant foreskin, owing to the prepuce skin being too short or too long, which may require revision (15). severe problems, such as partial amputation of the glans, complete loss of the penis, sepsis, or fournier's gangrene, can also occur (16). this study has several clinical implications. first, there was no difference in healing time and no complications were reported, and the dorsal buttonhole slit technique was shown to be as safe as the conventional technique. second, the dorsal buttonhole slit technique can be an effective alternative to the conventional technique in circumcision, especially when efficiency of surgical time is a major consideration. third, the high level of parental satisfaction in both groups suggests that both techniques produce satisfactory results. this study has several limitations. first, the sample size was relatively small, which may limit the generalizability of the findings. further studies with larger sample sizes are needed to confirm these results. second, this study was conducted in a single center, which may not reflect the broader population. multicenter studies are needed to increase the external validity of the findings. future studies should focus on long-term comparisons of the two techniques, including evaluation of long-term cosmetic and functional outcomes. in addition, cost-effectiveness studies may help determine which technique is more efficient in different clinical settings. conclusions the dorsal buttonhole slit technique is a novel procedurally straightforward method for paediatric circumcision with excellent clinical outcomes. our findings indicate a favourable clinical outcome, including a significantly shorter operative time compared to the conventional method and a notable absence of postoperative complications. furthermore, the procedure was associated with high levels of parental satisfaction regarding functional and cosmetic results, with no need for surgical revision. while promising, claims regarding the definitive safety and efficacy of this technique cannot be firmly established from this study alone. therefore, future prospective, randomized controlled trials are warranted to confirm these preliminary results and to rigorously evaluate the safety and efficacy of the dorsal buttonhole slit technique against standard procedures. references 1. shenoy sp, marla pk, sharma p, et al. frenulum sparing circumcision: step-by-step approach of a novel technique. j clin diagn res jcdr 2015; 9:pc01-3. 2. jiang z-l, sun c-w, sun j, et al. subcutaneous tissue-sparing dorsal slit with new marking technique. medicine (baltimore) 2019; 98:e15322. 3. lei j-h, liu l-r, wei q, et al. circumcision with “no-flip shang ring” and “dorsal slit” methods for adult males: a single-centered, prospective, clinical study. asian j androl 2016; 18:798-802. 4. lukong cs. dorsal slit-sleeve technique for male circumcision. j surg tech case rep 2012; 4:94-7. 5. krill aj, palmer ls, palmer js. complications of circumcision. sci world j 2011; 11:2458-2468. 6. talini c, antunes la, carvalho bcn de, et al. circumcision: postoperative complications that required reoperation. einstein são paulo 2018; 16:eao4241. 7. weiss ha, larke n, halperin d, et al. complications of circumcision in male neonates, infants and children: a systematic review. bmc urol 2010; 10:2. 8. roth jd, keenan ac, carroll ae, et al. readmission characteristics of elective pediatric circumcisions using large-scale administrative data. j pediatr urol 2016; 12:27.e1-6. 9. warees wm, anand s, leslie sw, rodriguez am. circumcision. 2024. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2025. 10. abdulwahab-ahmed a, mungadi i. techniques of male circumcision. j surg tech case rep 2013; 5:1. 11. azizoglu m, risteski t, klyuev s. alisklamp versus conventional dorsal slit circumcision: a multicentric randomized controlled trial. j clin med 2024; 13:4568. 12. abdullah l, mohammad a, anyanwu l, et al. outcome of male circumcision: a comparison between plastibell and dorsal slit methods. niger j basic clin sci 2018; 15:5. 13. atikeler mk, geçit i, yüzgeç v, et al. complications of circumcision performed within and outside the hospital. int urol nephrol 2005; 37:97-9. 14. ozkan a, ozorak a, oruc m. retrospective investigation complications in nineteen hundred cases of circumcision. konuralp med j 2012; 4:8-12. 15. brisson pa, patel hi, feins nr. revision of circumcision in children: report of 56 cases. j pediatr surg 2002; 37:1343-1346. 16. niku sd, stock ja, kaplan gw. neonatal circumcision. urol clin north am 1995; 22:57-65. correspondence muhammad asykar palinrungi (corresponding author) apalinrungi@yahoo.com division of urology, department of surgery, faculty of medicine, universitas hasanuddin, makassar, indonesia jalan perintis kemerdekaan km 11, makassar, sulawesi selatan, 90245, indonesia muhammad faruk muhammadfaruk@unhas.ac.id ashy amelia arista ashyamelia@gmail.com nurnaningsi thalib ningsi.t.thalib@gmail.com department of surgery, faculty of medicine, universitas hasanuddin, makassar, indonesia muhammad rum marewa marewa21@gmail.com konawe utara hospital, north konawe, indonesia andi makkawaru chairul drandimakkawaru@gmail.com department of physiology, faculty of medicine, universitas negeri makassar, pare-pare, indonesia abdul azis abdul.azis031@gmail.com division of urology, department of surgery, faculty of medicine, universitas hasanuddin, makassar, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13492 1 original paper introduction external beam radiotherapy is used as a treatment for several pelvic cancers, such as prostate cancer, rectal cancer and gynecological cancers. the main objective of radiation therapy is to deliver high doses of radiation to target organs while reducing to the least possible, the injury to surrounding organs. radiation-induced hemorrhagic cystitis is a well-known complication of pelvic radiation, affecting 5-10% of patients submitted to pelvic radiotherapy. this late complication can appear after 6 months and up to 20 years after radiation (1). nevertheless, severe hematuria occurs in less than 5% of cases (2). radiation induces mucosal edema and inflammation, leading to telangiectasias, submucosal hemorrhage and interstitial fibrosis. subendothelial proliferation, edema and medial thickening progressively deplete blood supply to urothelium, resulting in endarteritis obliterans causing acute and chronic ischemia. these changes promote the development of revascularization with superficial, fragile vessels that have an increased tendency to bleed, being responsible for uncontrollable hematuria. hemorrhagic cystitis is defined by the presence of hematuria, lower urinary tract symptoms and cystoscopy findings indicative of underlying urothelial damage, such as erythema, edema or telangiectasias (3, 4). despite being a known entity, its treatment remains a challenge for most urologists, mainly because of the lack of clear guidelines and the multiple comorbidities of these patients. several treatments have been proposed, such as bladder irrigation, transurethral bladder fulguration, intravesical instillations, hyperbaric oxygen therapy, internal iliac embolization and, in extreme/refractory cases, cystectomy with urinary diversion (3, 5). in addition to bladder injury, the desmoplastic reaction of the surrounding tissues and organs, a consequence of preintroduction: hemorrhagic cystitis is defined by the presence of hematuria, lower urinary tract symptoms and cystoscopy findings indicative of underlying urothelial damage. it is common in patient with prior radiotherapy for pelvic malignancies. the severity of the bleeding can vary from a mild to a severe hematuria refractory to conservative therapy and with a continuous need for transfusions. treatment can be challenging not only by the lack of clear guidelines but also the multiple comorbidities of these patients. urinary diversion with or without cystectomy should be reserved for those who failed all the previously available therapy, because of the morbidity/mortality associated with this type of procedure. supratrigonal cystectomy can be an option in patients with intense fibrosis of the pelvic region. the purpose of this article is to present the results of our institution with supratrigonal cystectomy with urinary diversion as a last line treatment for radiation-induced hemorrhagic cystitis. materials and methods: we retrospectively analyzed 17 patients who underwent supratrigonal cystectomy and bladder mucosa fulguration with urinary diversion for refractory radiationinduced hemorrhagic cystitis in our institution from january 2010 to december 2020. results and discussion: median patient age at time of cystectomy was 69 years and 64.7% (11) were females. the most common etiology was prior radiation therapy for gynecologic malignancies (11-64.7%). all the patients had prior therapy with bladder irrigation and fulguration. besides that, 29.4% (n = 5) received intravesical therapy with formalin, 11.8% (n = 2) hyperbaric oxygen therapy and 5.9% (n = 1) prior urinary diversion. median time between radiation therapy and cystectomy was 65 months. median asa score of 3, median preoperative hemoglobin was 9,6mg/dl and 10.5 mg/dl at time of discharge after surgery. ileal conduit was used in 52.9% (9), cutaneous ureterostomy in 41.2% (7) and ureterosigmoidostomy in 5.9% (1). majority of patients (10-58.8%) did not require any blood transfusion during surgery or during their stay. clavien-dindo complications grade iii or higher occurred in 29,4% (5). median hospital stay postoperative was 12 days. no mortality was reported in the 30 days after surgery. median follow-up after cystectomy was 28 months, with a 1-year survival of 93.3% (14 of 15) and 3-year survival of 83.3% (10 of 13). there was no difference in the presence of postoperative complications or overall survival between the types of urinary diversion. conclusions: this represents one of the largest series on cystectomy in hemorrhagic cystitis, that we found to this date. supratrigonal cystectomy is a valid option as a last line treatment for radiation-induced hemorrhagic cystitis, reducing the supratrigonal cystectomy: last line treatment for radiation-induced hemorrhagic cystitis josé alberto pereira, duarte vieira-brito, mário lourenço, paulo conceição, ricardo godinho, pedro peralta, bruno jorge pereira, carlos rabaça urology department, portuguese institute of oncology coimbra, coimbra, portugal. doi: 10.4081/aiua.2025.13492 summary risks associated with simple cystectomy in patients with prior pelvic radiation. key words: radiotherapy; supratrigonal cystectomy; cystitis; ileal conduit; hematuria. submitted 16 december 2024; accepted 3 february 20 archivio italiano di urologia e andrologia 2025; 97(2):13492 j.a. pereira, d. vieira-brito, m. lourenço, et al. 2 vious radiation, renders surgical planes challenging to identify and dissect, increasing the risks of involuntary damage to adjacent organs. furthermore, ureteral and bowel segments affected by radiation can increase the risks and possible complications associated with urinary diversion (6). the usage of supratrigonal cystectomy can be a valid solution in patients where the dissection of the posterior plane of the bladder cannot be safely achieved (7, 8). there is a lack of data on the outcomes of these patients when submitted to cystectomy, and even fewer report the outcomes of supratrigonal cystectomy (8, 9). consequently, the aim of our study was to evaluates the clinical outcomes, complications, and efficacy of supratrigonal cystectomy in managing refractory hematuria associated with radiation-induced hemorrhagic cystitis at our center. materials and methods we conducted a retrospective observational single-center study, including 17 patients who underwent supratrigonal cystectomy for radiation-induced hemorrhagic cystitis at our institution from january 2010 to december 2020. all patients underwent supratrigonal cystectomy with urinary diversion after the failure of conservative measures. patient charts were reviewed, and clinicopathological variables recorded included age at cystectomy, etiology for hemorrhagic cystitis, previous therapies, asa score, hemoglobin value pre-operative and at time of discharge, operative time, intraoperative blood loss, length of postoperative hospitalization, perioperative (within 30 days of surgery) complications, 30 and 90-day mortality and overall survival. postoperative complications were graded according to the clavien-dindo classification (10). survival was estimated as the time from cystectomy to death using the kaplan-meier method. data analysis was performed using spss® software version 25.0 (ibm corp., armonk, ny, usa) and a p-value < 0.05 was considered statistically significant. results after screening for the patients submitted to cystectomy after radiotherapy, we identified 17 patients who had a supratrigonal cystectomy for intractable hematuria associated with radiation-induced hemorrhagic cystitis. the median age of the patients at the time of cystectomy was 67 years (iqr 58.5, 82.5), 11 (64.7%) patients were females and the median time between radiotherapy and cystectomy was 65 months (iqr 35, 182). the most common cause of hemorrhagic cystitis was radiotherapy for gynecological cancer (64.7%), followed by radiotherapy for prostate cancer (23.5%). all the patients had previous treatment with bladder irrigation and endoscopic fulguration. in addition, (29.4%) received intravesical treatment with formalin, hyperbaric oxygen therapy (11.8%), and previous urinary diversion with bilateral nephrostomy tubes (5.9%). the median asa was 3 and the median preoperative hemoglobin was 9,6 g/dl (iqr 9, 10.55) (table 1). all the patients underwent a supratrigonal cystectomy with urinary diversion, with bricker ileal conduit being the most used in 52.9% (9 out of 17), followed by cutaneous ureterostomy in 41.2% (7 out of 17) and one patient had a ureterosigmoidostomy. at least 7 patients (41.2%) required one or more blood transfusions, during surgery or during their postoperative hospital stay. median intraoperative blood loss was 300 ml (iqr 125, 500) and the median time from surgery to discharge from the hospital was 12 days (iqr 10, 17.5), with a median hemoglobin of 10.5 g/dl (iqr 10.15, 10.85) at the last blood sample during hospitalization. in terms of complications, 5 (29.4%) patients presented with a clavien-dindo complication grade iii or higher in the first 30 days after surgery. the most common complications of any grade were gastrointestinal, namely, ileus requiring a nasogastric tube insertion and wound infections. the patient with a complication grade iv had abdominal abscess and kidney failure, requiring surgical drainage and transfer to an intensive care unit. there were no deaths in the first 30 days after surgery (table 2). table 1. clinical and demographic features of patients undergoing supratrigonal cystectomy. median age (iqr) years 67 (58.5, 82.5) gender • female 11 (64.7%) • male 6 (35.3%) etiology • external beam radiotherapy for prostate cancer 4 (23.5%) • radiotherapy for gynecological cancer 11 (64.7%) • radiotherapy rectum cancer 2 (11.8%) median time between radiotherapy and cystectomy (iqr), months 65 (35-182) months previous treatment • bladder irrigation 17 (100%) • endoscopic fulguration 17 (100%) • formalin 5 (29.4%) • hyperbaric oxygen therapy 2 (11.8%) • urinary diversion 1 (5.9%) median asa 3 median hemoglobin pre operation (iqr), g/dl 9.6 (9 , 10.55) table 2. perioperative outcomes. median intraoperative blood loss (iqr), ml 300 (125 , 500) median length of stay (iqr) days 12 (10.0 , 17.5) median hemoglobin at time of discharge (iqr), g/dl 10.5 (10.15 , 10.85) median follow-up after cystectomy (iqr), months 28 (16 , 36) urinary diversion • bricker ileal conduit 9 (52.9%) • cutaneous ureterostomy 7 (41.2%) • ureterosigmoidostomy 1 (5.9%) complications • gastrointestinal (ileus, intestinal anastomosis dehiscence) 4 (23.5%) • urinary (urinary leak, stenosis urinary anastomosis) 3 (17.7%) • infectious (wound infection, abdominal collection, sepsis) 3 (17.65%) clavien dindo – grade iii or higher • iiia 1 (5.9%) • iiib 3 (17.7%) • iv 1 (5.9%) archivio italiano di urologia e andrologia 2025; 97(2):13492 3 supratrigonal cystectomy median follow-up after surgery was 28 months (iqr 16, 36), with a 93.3% (14/15) and 83.3% (10/13) survival rate, at one and three years of follow-up, respectively (figure 1). the sole first-year mortality occurred 36 days postoperatively due to sepsis. subgroup analysis comparing ileal conduits to cutaneous ureterostomies revealed no statistically significant differences in complication rates (p = 0.64), length of hospitalization (p = 0.81), or overall survival (p = 0.96) (figure 2). discussion our study sought to evaluate the results of supratrigonal cystectomy in patients with refractory radiation-induced hemorrhagic cystitis. we considered refractory hematuria as gross hematuria that did not respond to conservative measures and first-line treatments, and with constant need for blood transfusions. we were able to identify 17 patients who underwent supratrigonal cystectomy over a ten-year span in our institution. hemorrhagic cystitis is a well-known adverse effect of pelvic radiation, despite this, its management is still a challenge. patients presenting with macroscopic hematuria after any form of radiation treatment should undergo a diagnostic evaluation, to rule out other causes. a population-based study compared the incidence of bladder cancer in a group of patients with localized prostate cancer that underwent external beam radiotherapy or radical prostatectomy, and the results show that patients treated with radiotherapy are at an increased risk of developing a bladder cancer (11). radiation-induced hemorrhagic cystitis should initially be managed with conservative measures, such as hydration and, when needed, catheterization with a large-bladder catheter to treat possible retention and allow clot evacuation. in refractory cases, cystoscopy with electrofulguration or laser therapy can be used to control suspected hemorrhagic lesions. when the previous procedures were not successful in controlling the hematuria several intravesical agents have been studied such as, alum salts, aminocaproic acid, hyaluronic acid, and formalin. the latter presents high treatment efficacy with a single instillation but at cost of significant morbidity. in line with the intravesical agents, hyperbaric oxygen therapy has been intensively studied, showing a high percentage of complete responses with a low rate of complications (12, 13). a phase ii/iii clinical trial (rich-art) also reported improvement in other urinary symptoms related with radiation and an improvement in bladder tissues changes induced by radiotherapy, after hyperbaric oxygen therapy (14). in cases of severe and life-threatening hematuria transarterial embolization provides an alternative to more invasive procedures, mainly in older and frailer patients, showing a success rate above 80% (15, 16). urinary diversion without cystectomy has also been proposed, with the objective of avoiding contact of urine components with the bladder mucosa, however, this raises concerns about the leftover bladder, with up to 50% of the patients experiencing complications and 25% requiring cystectomy (17, 18). a recent study comparing urinary diversion alone against urinary diversion with supratrigonal cystectomy in benign diseases did not identify concomitant cystectomy as a predictor of increased morbidity, discouraging the use of urinary diversion alone in patients with increased risk of bleeding or infection of the remaining bladder (19). linder et al. published the biggest series on cystectomies on patients with hemorrhagic cystitis, reporting severe complications (clavien iii or iv) in 42% and 16% 90-day mortality rate. one and three-year survival rates of the remaining patients were 84% and 52%, respectively (8). series accounting for cystectomies for bladder cancer report 1.5% and 2.7% mortality rates at 30 and 90-day, respectively figure 2. overall survival of patients undergoing cystectomy with urinary diversion for refractory hemorrhagic cystitis stratified by usage or not of ileal conduit. figure 1. overall survival of patients undergoing cystectomy with urinary diversion for refractory hemorrhagic cystitis. archivio italiano di urologia e andrologia 2025; 97(2):13492 j.a. pereira, d. vieira-brito, m. lourenço, et al. 4 (20). in our series we found 5 (29.4%) patients with severe complications (clavien iii or iv) and no fatalities in 30days after surgery. survival outcomes of our cohort showed 93.3% survival one year and 83.3% three years after surgery. in our series the population was younger, and no patients underwent surgery in an emergency setting, nevertheless, the median hemoglobin was lower (9.6 vs 10.2 g/dl) and the median asa scores were the same. urinary diversion alone (nephrostomy, intestinal conduit or cutaneous ureterostomy) is one of the possibilities of treatment in patients with hemorrhagic cystitis, working by preventing bladder distension and rupture of vessels, as well as, decreasing the exposure of the bladder urothelium to urokinase, increasing the possibility of successful hemostasis (2, 21). bilateral nephrostomies are valid options, considering the advanced age, comorbidities and past radiotherapy of these patients, all factors that can affect the outcomes of more invasive procedures. nevertheless, up to 25% will need further cystectomy, for complications associated with the leftover bladder or for intractable symptoms (17). in our series, only 5.9% (1) of our patients had nephrostomies tubes placed before cystectomy, possibly because of the elective setting the procedures were done and concomitant complaints such as fistula and pain. when deciding the type of urinary diversion in patients who underwent cystectomy for radiation cystitis, one of the main problems is the tissue devascularization related to radiotherapy, increasing the risk of complications with uretero-enteric anastomosis (8, 22). while ileal conduits remain the standard, cutaneous ureterostomy emerges as a viable option in these frail population. a systematic review comparing ileal conduit and cutaneous ureterostomy in bladder cancer patients published by korkes et al. showed that cutaneous ureterostomy was associated with a reduction in surgery time, lower transfusion rate, less blood loss, shorter hospital stay and reduced intra and pos-operative complications (23). suzuki et al. reported similar perioperative results between ileal conduit and cutaneous ureterostomy, however the latest was associated with an increased risk of pyelonephritis and renal deterioration (24). in our series we found no significant difference in early complications, length of stay or mortality when comparing ileal conduit and cutaneous ureterostomy. the type of urinary diversion should be carefully chosen for each patient and according to surgeon experience and intraoperative findings. radiotherapy is responsible for inducing fibrosis and extensive adhesions, between the bladder and the rectum, but also between the bladder and the symphysis and pubic rami, increasing the difficulty of the surgery. kim and steinberg reported an increased risk of complications in patients who had cystectomy after pelvic radiation, with 39% of the patients in the irradiated group having complications that required an invasive surgical or radiologic intervention, compared with 9% of the group without previous radiotherapy (22). similar results were reported in other studies (8). in our series, the severe complications requiring intervention had a lower incidence (29.4%), possibly because of the less complexity of the surgery, requiring less dissection and mobilization of structures, thereby slightly reducing operative time and blood loss. when the dissection of posterior planes is difficult due to fibrosis, we chose to use a supratrigonal approach with fulguration of the remaining bladder, with the objective of decreasing the morbidity of this surgery in such a frail population, by decreasing dissection and slightly reducing operative times (25). in these situations, it is important to exclude the presence of urothelial neoplasm, not only due to the risk of seeding after opening of the bladder, but also for the sub-optimal oncological treatment. our study should be viewed in the context of certain limitations. it was conducted in a single institution and had a small sample size. as well as, the retrospective nature of this study impacts the risk of underreporting, mainly minor complications. as such, the number of complications after discharge could be underreported. nevertheless, with the paucity of data on patients submitted to cystectomy for hemorrhagic cystitis our study represents one of the largest series published, providing important insights into the management of this challenging condition (8, 26, 27). despite the encouraging results compared with previous studies, this procedure should remain a last resort for patients with intractable hematuria. the decision between the type of procedure and urinary diversion should be made by the surgeon and according to the intraoperative findings. conclusions radiation-induced hemorrhagic cystitis is a severe complication of pelvic radiation that often necessitates invasive interventions. in cases of intractable hematuria unresponsive to conservative treatments, immediate and effective management is crucial. our findings support supratrigonal cystectomy as a viable last resort option, with acceptable perioperative morbidity and, possibly, reduced risks compared with simple cystectomy in patients with prior pelvic radiation. this approach provides a practical solution for declarations ethical approval and consent for participate: not applicable. consent for publication: not applicable. availability of data and material: the datasets used and analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions: jap, study concept, data analysis and interpretation, manuscript original drafting; dvb, data collection and interpretation, manuscript drafting; ml, study concept, data analysis and manuscript reviewing; pc, data interpretation and manuscript reviewing; rg, data interpretation and manuscript reviewing; bjp, manuscript drafting and reviewing; pp, data collection and interpretation, manuscript drafting; cr, study conception and design, data analysis and manuscript reviewing. all the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13492 5 supratrigonal cystectomy managing this challenging condition while balancing safety and efficacy. future studies with larger cohorts and prospective designs are needed to further optimize management strategies for this challenging condition. references 1. smit sg, heyns cf. management of radiation cystitis. nat rev urol. 2010; 7:1-15. 2. crew jp, jephcott cr, reynard jm. radiation-induced haemorrhagic cystitis. eur urol. 2001; 40:111-23. 3. goucher g, saad f, lukka h, kapoor a. canadian urological association best practice report: diagnosis and management of radiation-induced hemorrhagic cystitis. can urol assoc j. 2019; 13:15-23. 4. martin se, begun em, samir e, et al. incidence and morbidity of radiation-induced hemorrhagic cystitis in prostate cancer. urology. 2019; 131:190-5. 5. ju z, yu w, li y, et al. the clinical research of 5 steps sequential method for whole treatment of hemorrhagic radiation cystitis in china. int j med sci. 2021; 18:756-62. 6. eisenberg ms, dorin rp, bartsch g, et al. early complications of cystectomy after high dose pelvic radiation. juro. 2010; 184:2264-9. 7. rowley mw, clemens jq, latini jm, cameron ap. simple cystectomy: outcomes of a new operative technique. j urol. 2011; 78:942-5. 8. linder bj, tarrell rf, boorjian sa. cystectomy for refractory hemorrhagic cystitis: contemporary etiology, presentation and outcomes. j urol. 2014; 192:1687-92. 9. tachibana i, calaway ac, abedali z, et al. definitive surgical therapy for refractory radiation cystitis: evaluating effectiveness, tolerability, and extent of surgical approach. urol oncol. 2021; 39:789.e1-789.e7. 10. dindo d, demartines n, clavien p. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 11. moschini m, zaffuto e, karakiewicz pi, et al. external beam radiotherapy increases the risk of bladder cancer when compared with radical prostatectomy in patients affected by prostate cancer: a population-based analysis. eur urol. 2019; 75:319-28. 12. pereira d, ferreira c, catarino r, et al. oxígeno hiperbárico para la cistitis inducida por radioterapia: un seguimiento a largo plazo. actas urológicas españolas. 2020; 44:561-7. 13. ribeiro de oliveira tm, carmelo romão aj, simões de oliveira pm, et al. oxigenoterapia hiperbárica na cistite rádica hemorrágica. acta urológica port. 2016; 33:1-5. 14. oscarsson n, müller b, rosén a, et al. radiation-induced cystitis treated with hyperbaric oxygen therapy (rich-art): a randomised, controlled, phase 2-3 trial. lancet oncol. 2019; 20:1602-14. 15. korkmaz m, åžanal b, aras b, et al. the short-and long-term effectiveness of transcatheter arterial embolization in patients with intractable hematuria. diagn interv imaging. 2016; 97:197-201. 16. mohan s, kumar s, dubey d, et al. superselective vesical artery embolization in the management of intractable hematuria secondary to hemorrhagic cystitis. world j urol. 2019; 37:2175-82. 17. fazili t, bhat tr, masood s, et al. fate of the leftover bladder after supravesical urinary diversion for benign disease. j urol. 2006; 176:620-1. 18. chong jt, dolat mt, klausner ap, et al. the role of cystectomy for non-malignant bladder conditions: a review. can j urol. 2014; 21:7433-41. 19. vetterlein mw, buhné mj, yu h, et al. urinary diversion with or without concomitant cystectomy for benign conditions: a comparative morbidity assessment according to the updated european association of urology guidelines on reporting and grading of complications. eur urol focus. 2022; 8:1831-9. 20. shabsigh a, korets r, vora kc, et al. defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. eur urol. 2009; 55:164-76. 21. pascoe c, duncan c, lamb bw, et al. current management of radiation cystitis: a review and practical guide to clinical management. bju int. 2019; 123:585-94. 22. kim hl, steinberg gd. complications of cystectomy in patients with a history of pelvic radiation. urology. 2001; 58:557-60. 23. korkes f, fernandes e, gushiken fa, et al. bricker ileal conduit vs. cutaneous ureterostomy after radical cystectomy for bladder cancer: a systematic review. int braz j urol. 2022; 48:18-30. 24. suzuki k, hinata n, inoue ta, et al. comparison of the perioperative and postoperative outcomes of ileal conduit and cutaneous ureterostomy: a propensity score-matched analysis. urol int. 2020; 104:48-54. 25. linn jf, hohenfellner m, roth s, et al. treatment of interstitial cystitis: comparison of subtrigonal and supratrigonal cystectomy combined with orthotopic bladder substitution. j urol. 1998; 159:774-8. 26. osborn dj, dmochowski rr, kaufman mr, et al. cystectomy with urinary diversion for benign disease: indications and outcomes. urology. 2014; 51590:1-5. 27. tachibana i, calaway ac, abedali z, et al. definitive surgical therapy for refractory radiation cystitis: evaluating effectiveness , tolerability, and extent of surgical approach. urol oncol semin orig investig. 2021; 39:1-7. correspondence josé alberto pereira (corresponding author) joseaclpereira@gmail.com duarte vieira-brito duartevbrito@gmail.com mário lourenço mariolourenco88@gmail.com paulo conceição pjcconceicao@hotmail.com ricardo godinho ricardogodinhoandrade@gmail.com pedro peralta joaopedroperalta@gmail.com bruno jorge pereira brunoalexpereira@gmail.com carlos rabaça carlosrabaca@gmail.com urology department, portuguese institute of oncology coimbra, coimbra, portugal rua antónio jardim, nº 398, lote 21, 3000-038 stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12138 1 original paper introduction persistent urinary incontinence (ui) after radical prostatectomy (rp), commonly referred to as post-prostatectomy incontinence (ppi), is an adverse event that leads to significant distress. ficarra et al. (1) found that for a "no pad" definition of ui, rates ranged from 4% to 31%, with a mean of 16%. the ppi is influenced by muliple elements, anatomic components and biological factors (2). the anatomic components that influence on urinary continence, after rp, are the urethral sphincter complex, the supporting structures of the membranous urethra (3), the fibrosis after surgery (4), the neural components (5-8), the zone of urothelium coaptation. the biological factors contributing to ppi are the age (9), the functional bladder changes (10), the body mass index (11), pre-existing low urinary tract symptoms (12), turp before rp (13), the prostate size (14) and the membranous urethral length (15). the urethral sphincter complex consists of two functionally independent components, an internal or lissosphincter of smooth muscle and an outer or external rhabdosphincter of skeletal muscle, that are thought to be responsible for passive and active continence, respectively (16). the internal sphincter maintains continence during normal activity when there is little stress on the bladder outlet. its smooth muscle maintains tone for long periods with minimal exertion. the external urethral sphincter is a muscle that is very strong but becomes fatigued very quickly. the urothelium is surrounded by elastic tissue and fibers introduction: the post-prostatectomy incontinence is influenced by multiple elements, anatomic components and biological factors. the bladder neck preservation, more accurate during robot assisted radical prostatectomy, works on two anatomic components responsible for post-prostatectomy continence. the bladder neck preservation spares the internal sphincter, which is responsible for passive continence, and results in earlier return to continence and lower rates of post-prostatectomy incontinence. moreover, this surgical technique spares the zone of urothelium coaptation and provides primary resistance to the urine to maintain postprostatectomy continence. the potential risk of bladder neck positive surgical margins (psm) may prevent the usage of the bladder neck preservation. aim: the purpose of this study is to evaluate the surgical and pathological outcome in prostate cancer patients underwent robot assisted radical prostatectomy with bladder neck preservation. materials and methods: prospectively, we have collected demographic, clinical, surgical and pathological data of prostate cancer patients underwent robot assisted radical prostatectomy with bladder neck preservation, from january 2014 to december 2016, in urological clinic of the university of padua. moreover, it was valued the presence of alterations or continuous solutions of specimen external capsule, attributable to the surgical technique of bladder neck preservation, by microscopic and macroscopic pathological analysis. results: according to d'amico risk classification, 40 patients (45.4%) had a low risk neoplasia, 35 patients (39.8%) had an intermediate risk neoplasia, 13 patients (14.8%) had an high risk neoplasia. the median prostatic volume, valued on specimen, was 30.84 cc (21.5-44.75 cc). the median prostatic weight, valued on specimen, was 51 gr (36-67 gr). the pathological stage of disease was pt2a in 11 cases (12.5%), pt2b in 37 cases (42.1%), pt3a in 28 cases (31.8%), pt3b in 12 cases (13.6%). the pathological stage of lymph node involvement was pnx in 17 cases (19.3%), pn0 in 66 cases (75%), pn1 in 5 cases (5.7%). the prostate cancers diagnosed had a gleason score at specimen of 6 in 10 cases (10.4%), 7 (3+4) in 30 cases (34.1%), 7 (4+3) in 20 cases (22.7%), 8 in 19 cases (21.6%) and 9 in 9 cases (10.2%). the prostatic base was involved by neoplasia in 14 patients (15.9%); of these, 5 patients (35.7%) had bladder neck psm. the patients with bladder neck psm had: a pathological stage of disease as pt3a in 2 cases (40%) and pt3b in 3 cases (60%); a pathological stage of lymph node involvement as pn0 in 2 cases (40%) and pn1 in 3 cases (60%); a gleason score at specimen of 8 in 3 cases (60%) and 9 in 2 cases (40%); the bladder neck preservation in robot assisted radical prostatectomy: surgical and pathological outcome michele zazzara 1, marina p. gardiman 2, fabrizio dal moro 1 1 urology clinic, department of surgical oncological and gastroenterological sciences, university of padua, padua, italy; 2 surgical pathology and cytopathology unit, department of medicine, university of padua, padua, italy. doi: 10.4081/aiua.2023.12138 summary multiple psm. nobody had alterations or continuous solutions of specimen external capsule, attributable to surgical technique of bladder neck preservation. conclusions: the bladder neck preservation, during robot assisted radical prostatectomy, is a safe oncological procedure resulting in a good functional outcome, about post-prostatectomy continence, working on two anatomic components responsible for post-prostatectomy continence. the bladder neck psm are linked to neoplasia with adverse pathological features, rather than the bladder neck preservation. key words: rarp; bladder neck sparing surgery; prostate cancer. submitted 27 november 2023; accepted 30 november 2023 archivio italiano di urologia e andrologia 2023; 95(4):12138 m. zazzara, m.p. gardiman, f. dal moro 2 of smooth and striated muscle. at the junction of the inferior bladder and the proximal urethra, the urothelium becomes a key component of sphincter function. the elastic components of the proximal urethral wall are responsible for coaptation of the urothelium (zone of coaptation). this proper adhesion of the urethral wall provides primary resistance to the urine to maintain continence (17). little is known about the optimal length of the zone of coaptation. it is hypothesized that it should be at least 5-10 mm to ensure continence (18). the bladder neck preservation (bnp), more accurate during robot assisted radical prostatectomy (rarp), works on these two anatomic components responsible for post-prostatectomy continence influencing ppi. the potential risk of bladder neck psm may prevent the usage of the bnp. the current study investigates the surgical and pathological outcome of bnp in prostate cancer patients treated with rarp. materials and methods between january 2014 and december 2016, 88 patients with prostate cancer underwent davinci® rarp with bnp at the urology department of the university of padua. we prospectively collected demographic data including age, body mass index, comorbidities, previous surgery, erectile function as per the international index of erectile function 5 (iief-5) questionnaire (19), and lower urinary tract symptoms as per the international prostate symptom score (ipss) questionnaire (20), as well as clinical data including prostate-specific antigen status, clinic stage according to tumor, node, and metastasis staging (21), bioptic gleason score (22) and d’amico risk classification (23) for each patient. surgical data including total operative duration, blood loss, whether a transfusion was performed, time to drain removal, time to cystography and time to catheter removal were also recorded. the bnp was considered reached when the diameter of the bn was adequate to the diameter of the urethra, not requiring bn neck reconstruction before anastomosis. all surgical procedures were performed by the same expert surgeon. the prostate specimen was formalin fixed in the standard manner; the paraffin-embedded specimen was examined histologically in the form of 4-mm, whole mount, haematoxylin and eosin stained sections. therefore, the specimen was examined in its entirety in every case. a positive surgical margin was defined as the presence of tumour at the inked margin (24). therefore, for each patient we evaluated the following pathological parameters: site and side of the tumour, definitive gleason score, pathological extension of the primary tumour and the lymph node involvement. moreover, it was valued the presence of alterations or continuous solutions of specimen external capsule, attributable to the surgical technique of bladder neck preservation, by microscopic and macroscopic pathological analysis. a single expert uro-pathologist reviewed all rp specimens. this study did not receive any funding. all patients provided written informed consent for the procedures described herein. descriptive data are presented as the mean ± standard deviation or median (interquartile range). results table 1 summarizes patient demographic and clinical data. the mean patient age was 64.77 ± 6.75 years and the mean body-mass index was 26.73 ± 3.04 kg/m2. the median ipss score was 9 (4,5-14) and the median iief-5 score was 17 (11-23). the median prostate-specific antigen value was 6.09 ng/ml (4.92-8.01 ng/ml). the median prostatic volume was 40 cc (38.75-50 cc). clinical staging was ct1c in 51 patients (58%), ct2a in 26 patients (29.5%), ct2b in 8 patients (9.1%), ct2c in 2 patients (2.3%) and ct3a in 1 patient (1.1%). the bioptic gleason score was 6 in 48 patients (54.6%), 7 [3 + 4] in 27 patients (30.7%), 7 [4 + 3] in 3 patients (3.4%), 8 in 9 patients (10.2%), 9 in 1 patient (1.1%). as per the d'amico risk classification, 40 patients (45.4%) had lowrisk prostate cancer, 35 patients (39.8%) had intermediate-risk prostate cancer, and 13 patients (14.8%) had high-risk prostate cancer. table 2 summarizes pathological data. the median prostatic volume, valued on specimen, was 30.84 cc (21.5-44.75 cc). the median prostatic weight, valued on specimen, was 51 gr (36-67 gr). pathological stage was pt2a in 11 cases (12.5%), pt2b in 37 cases (42.1%), pt3a in 28 cases (31.8%), pt3b in 12 cases (13,6%). the pathological stage of lymph node involvement was pnx in 17 cases (19.3%), pn0 in 66 cases (75%), pn1 in 5 cases (5.7%). the prostate cancers diagnosed had a gleason score at specimen of 6 in 10 cases (10.4%), 7 (3+4) in 30 cases (34.1%), 7 (4+3) in 20 cases (22.7%), 8 in 19 cases (21.6%) and 9 in 9 cases (10.2%). the prostatic base was involved by neoplasia in 14 patients (15.9%); of these, 5 patients (35.7%) had bladder neck psm. the patients with bladder neck psm had: a pathological stage of disease as pt3a in 2 cases (40%) and pt3b in 3 cases (60%); a pathological table 1. patient demographic and clinical data. parameter value age (years) (64.77 ± 6.75) bmi (kg/m2) (26.73 ± 3.04) ipss score (9; 4.5-14) iief-5 score (17; 11-23) prostatic volume (cc) (40; 38.75-50) psa (ng/ml) (6.09; 4.92-8.01) bioptical gleason score 6 48 (54.6%) 7 (3+4) 27 (30.7%) 7 (4+3) 3 (3.4%) 8 9 (10.2%) 9 1 (1.1%) ct ct1c 51 (58%) ct2a 26 (29.5%) ct2b 8 (9.1%) ct2c 2 (2.3%) ct3a 1 (1.1%) d'amico risk classification low risk 40 (45.4%) intermediate risk 35 (39.8%) high risk 13 (14.8%) archivio italiano di urologia e andrologia 2023; 95(4):12138 3 bladder neck preservation in robot assisted radical prostatectomy stage of lymph node involvement as pn0 in 2 cases (40%) and pn1 in 3 cases (60%); a gleason score at specimen of 8 in 3 cases (60%) and 9 in 2 cases (40%); multiple psm. nobody had alterations or continuous solutions of specimen external capsule, attributable to surgical technique of bladder neck preservation. the median time to cystography was 6 days (4.5-14). in one case, there was anastomosis urinary leakage at cystography (1.13%). discussion the bladder neck preservation spares the internal sphincter, which is responsible for passive continence, and results in earlier return to continence and lower rates of post-prostatectomy incontinence (25-27). moreover, this surgical technique spares the zone of urothelium coaptation and provides primary resistance to the urine to maintain post-prostatectomy continence (17). thus, the bnp is a surgical factor contributing to ppi, acting on two anatomic components influencing ppi. the other anatomic components are the targets of several surgical procedure, as supporting structures of the membranous urethra are the targets of anterior fixation or posterior reconstruction, as the neural components are the targets of nerve-sparing surgery. therefore, the continence recovery after rp is multifactorial and its achievement is due to several surgical approaches and not exclusively to a single surgical procedure. for this reason, in our study, it was not investigated the continence outcome. the current study investigates the surgical and pathological outcome of bnp during rarp. in fact, the potential risk of bladder neck psm may prevent the usage of the bnp. nowadays, this topic is controversial; some authors support that bnp may raise the bladder neck psm (8, 29), contrarily, a meta-analysis (30) and other studies (31-36), support that the bnp would not compromise the oncological control of disease and that the mini-invasive approach, in particular rarp, and the best imaging diagnostic tools may allow a more safe procedure. to address this controversy, we have evaluated in our study the presence of alterations or continuous solutions of specimen external capsule, attributable to the surgical technique of bnp, by microscopic and macroscopic pathological analysis. in our series, no specimen exhibited alterations or continuous solutions of specimen external capsule, referring to the surgical technique of bnp. however, in 5 of the 14 cases (35.7%) with basal tumor, there were bladder neck psm. evaluating the pathological features of these cases, it was shown an extraprostatic extension of disease (pt3a-3b), a low grade of disease differentiation (g.s. 8-9), a lymph node involvement in more part of them, multiple psm and not exclusive of bn; therefore, all patients with bladder neck psm showed unfavorable pathological features. according to golabeck (34), the potential risk of bladder neck psm would be linked to neoplasia with extraprostatic extension and a low grade of disease differentiation. our study shows that bnp during rarp doesn't cause alterations or continuous solutions of specimen external capsule, attributable to the surgical technique of bladder neck preservation, by microscopic and macroscopic pathological analysis, and that the bladder neck psm are linked to neoplasia with adverse pathological features, rather than the bnp. moreover, all case with bladder neck psm showed multiple psm, and, therefore, the psm would be present regardless of bnp. there are several limitations to this study. although the data on our patients are collected prospectively, there isn't a control group, the patients are not randomized, and the number of patients is weak. moreover, the bn approach was decided intraoperatively. thus, it is possible that patients were selected according to individual features and technical considerations encountered intraoperatively. cases of large prostate, prominent middle lobe or more difficult dissection would likely be spared the bnp approach. conclusions the bnp during rarp is a safe oncological procedure resulting in a good functional outcome, about post-prostatable 2. patient pathological data. parameter value prostatic volume (cc) (30.84; 21, 5-44, 75) prostatic weight (gr) 51; 36-67) pt pt2a 11 (12.5%) pt2b 37 (42.1%) pt3a 28 (31.8%) pt3b 12 (13.6%) pn pnx 17 (19.3%) pn0 66 (75%) pn1 5 (5.7%) gleason score 6 10 (10.4%) 7 (3+4) 30 (34.1%) 7 (4+3) 20 (22.7%) 8 19 (21.6%) 9 9 (10.2%) tumor site base 14 (15.9%) other sites 74 (84.1%) basal psm present 5 (35.7%) absent 9 (64.3%) pt in patients with basal psm pt3a 2 (40%) pt3b 3 (60%) pn in patients with basal psm pn0 2 (40%) pn1 3 (60%) gleason score in patients with basal psm 8 3 (60%) 9 2 (40%) multiple psm in patients with basal psm present 88 (100%) absent 0 (0%) continuous solutions of specimen external capsule due to surgery present 0 (0%) absent 88 (100%) archivio italiano di urologia e andrologia 2023; 95(4):12138 m. zazzara, m.p. gardiman, f. dal moro 4 tectomy continence, working on two anatomic components responsible for post-prostatectomy continence. the bladder 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16. koraitim mm. the male urethral sphincter complex revisited: an anatomical concept and its physiological correlate. j urol. 2008; 179:1683-9. 17. sacco e, prayer-galetti t, pinto f, et al. urinary incontinence after radical prostatectomy: incidence by definition, risk factors and temporal trend in a large series with a long-term follow-up. bju int. 2006; 97:1234-41. 18. de ridder d, rehder p. the advance male sling: anatomic features in relation to mode of action. eur urol suppl 2011; 10:383-9. 19. rosen rc, cappelleri jc, smith md, et al. development and evaluation of an abridged, 5-item version of the international index of erectile function (iief-5) as a diagnostic tool for erectile dysfunction. int j impot res. 1999; 11:319. 20. barry mj, fowler fj jr, o'leary mp, et al. the american urological association symptom index for benign prostatic hyperplasia. the measurement committee of the american urological association. j urol. 1992; 148:1549. 21. sobin lh, compton cc. tnm seventh 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2010; 85:135-8. 26. soljanik i, bauer rm, becker aj, et al. is a wider angle of the membranous urethra associated with incontinence after radical prostatectomy? world j urol. 2014; 32:1375-83. 27. selli c, de antoni p, moro u, et al. role of bladder neck preservation in urinary continence following radical retropubic prostatectomy. scand j urol nephrol. 2004; 38:32-7. 28. srougi m, nesrallah lj, kauffmann jr, et al. urinary continence and pathological outcome after bladder neck preservation during radical retropubic prostatectomy: a randomized prospective trial. j urol. 2001; 165:815-8. 29. zakri rh, vedanayagam m, john b, et al. bladder neck sparing (bns) robot assisted laparoscopic prostatectomy (ralp): does it improve continence? eur urol. suppl. 2016; 15:ev20. 30. ma x, tang k, yang c, et al. bladder neck preservation improves time to continence after radical prostatectomy: a systematic review and meta-analysis. oncotarget. 2016; 7:67463-67475. 31. nyarangi-dix jn, radtke jp, hadaschik b, et al. impact of complete bladder neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomized, controlled, single blind trial. j urol. 2013; 189:891-8. 32. friedlander df, alemozaffar m, hevelone nd, et al. stepwise description and outcomes of bladder neck sparing during robot-assisted laparoscopic radical prostatectomy. j urol. 2012; 188:1754-60. archivio italiano di urologia e andrologia 2023; 95(4):12138 5 bladder neck preservation in robot assisted radical prostatectomy 33. golabek t, jaskulski j, jarecki p, et al. laparoscopic radical prostatectomy with bladder neck preservation: positive surgical margin and urinary continence status. wideochir inne tech maloinwazyjne. 2014; 9:362-70. 34. gomez ca, soloway ms, civantos f, hachiya t. bladder neck preservation and its impact on positive surgical margins during radical prostatectomy. urology. 1993; 42:689-93. 35. bianco fj, grignon dj, sakr wa, et al. radical prostatectomy with bladder neck preservation: impact of a positive margin. eur urol. 2003; 43:461-6. 36. gawlas w, golabek t, hessel t, et al. bladder neck preservation and the risk of positive surgical margins after laparoscopic radical prostatectomy. eur urol, suppl. 2014; 13:e1275. correspondence michele zazzara, md michele.zazzara@gmail.com fabrizio dal moro, md urology clinic, department of surgical oncological and gastroenterological sciences, university of padua, padua, italy marina p. gardiman, md surgical pathology and cytopathology unit, department of medicine, university of padua, padua, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13867 1 original paper introduction urolithiasis represents a significant public health concern, affecting millions globally, with an estimated prevalence of 2-3%, and a recurrence rate of 50% (1). the existing literature delineates various treatment modalities for renal and ureteral stones, including conservative management, endourological procedures, and open surgery (2). extracorporeal shock wave lithotripsy has evolved considerably since its inception, establishing itself as a pivotal treatment option for renal and ureteral stones (3). the dornier compact delta® iii pro optimizes the latest advancements in eswl technology, featuring enhanced shock wave generation, improved imaging capabilities, and refined patient positioning systems (4). these innovations contribute to increased treatment efficacy, reduced procedural pain, and minimized recovery time, thereby solidifying eswl's role in contemporary urological practice (3, 4). numerous studies have identified various predictive factors influencing complications and the stone-free rate (sfr) following eswl for renal and ureteral stones. among these, stone characteristics, such as size, density, location, shape, and degree of impaction, are critical determinants for treatment efficacy (5, 6). for instance, larger, denser stones, particularly those located in anatomically challenging areas like the lower pole of the kidney with steep infundibulopelviceal angle, are associated with lower sfrs and higher treatment failures. moreover, patient-related factors, including age, comorbidities, congenital anomalies, the degree of obstruction, infection status, body mass index (bmi), skin to stone distance can further alter treatment outcomes (5-7). despite these advancements, there is a notable lack of studies about the latest, new generation lithotripters (8). understanding the factors influencing sfrs is essential for optimizing patient selection and treatment strategies. in this context, the present study aims to assess sfrs and identify major negative predictive factors, influencing the success of eswl utilizing the dornier compact delta® iii pro, based on a retrospective analysis of our first 1000 patients treated at a secondary hospital. background: the dornier compact delta® iii pro is a next-generation extracorporeal shock wave lithotripter featuring flat-panel detector technology for enhanced imaging and a compact modular design. this study evaluates treatment outcomes and predictors of failure for this system, representing the first published clinical experience. methods: we retrospectively analyzed the first 1,000 consecutive patients treated with the dornier compact delta® iii pro for renal or ureteric stones between may 2022 and november 2023 at a secondary hospital. stone-free status was assessed via radiography, ultrasonography, or computed tomography (ct) within three months post-treatment. predictive factors for treatment failure were identified through univariate and multivariate logistic regression analyses. results: the cohort had a median age of 37 years (iqr: 3244.2) and a body mass index (bmi) of 26 kg/m² (iqr: 24-29). key characteristics included: prior urologic interventions in 36.6% of patients, single stones in 79.8% (median size 9 mm, iqr: 7-10), a median stone density of 1000 hounsfield units (hu) (iqr: 760-1200), and hydronephrosis observed in 55.3% of cases. initial eswl success was achieved in 80.5% of cases, increasing to 87.5% following repeat sessions (mean treatments: 1.2). multivariate analysis identified four independent predictors of treatment failure: prior urologic intervention (adjusted odds ratio [aor] 2.64, 95% ci 1.75-4.00, p < 0.001), multiple stones (aor 0.45, 95% ci 0.24-0.77, p = 0.011), increased skin-to-stone distance (per cm: aor 1.18, 95% ci 1.06-1.30, p < 0.001), and higher stone density (per 100 hu: aor 1.12, 95% ci 1.06-1.18, p < 0.001). conclusions: the dornier compact delta® iii pro achieved an 87.3% stone-free rate with failure predictors consistent with established lithotripsy literature. these findings support the adoption of this device as an effective eswl system, particularly for institutions prioritizing advanced imaging and a spaceefficient design. key words: urolithiasis; eswl; dornier; predictive factors; stone-free rate. submitted 2 april 2025; accepted 25 april 2025 predictors of treatment failure and outcome assessment of extracorporeal shock wave lithotripsy with the dornier compact delta®iii pro: experience from the first 1000 treatments morshed salah 1, 2, maged al-ghashmi 1, bela tallai 1, 2, abu baker 1, mohammed ibrahim 1, 2, tawiz gul 1, 2, hatem kamkoum 1, salvan alhabash 1, hossameldin alnawasra 1, abdoulhafid elmogassabi 1, maged alrayashi 1, mohammed ebrahim 1, mohamed abdelkareem 1, faisal ahmed 3 1 urology section, hazm mebaireek general hospital, hamad medical corporation, doha, qatar; ² college of medicine, qatar university, doha, qatar; ³ department of urology, school of medicine, ibb university, ibb, yemen. doi: 10.4081/aiua.2025.13867 summary archivio italiano di urologia e andrologia 2025; 97(2):13867 m. salah, m. al-ghashmi, b. tallai, et al. 2 patients and methods study design this retrospective study was conducted at hazm mebaireek general hospital, hamad medical corporation, doha, qatar, between may 2022 and november 2023. a total of 1,000 adult patients (≥ 16 years) with renal collecting system and ureteric stones (≤ 25 mm) underwent extracorporeal shock wave lithotripsy (eswl) using the dornier compact delta® iii pro lithotripter (dornier medtech gmbh, germany). the study was performed in accordance with the ethical principles outlined in the declaration of helsinki and received approval from the medical research center of the institution (id mrc-01-25-167). due to the retrospective nature of the study, the ethics committee waived the requirement for patient consent while ensuring that patient confidentiality and data protection measures were strictly adhered to. inclusion criteria adult patients (≥ v16 years) with ureteral and/or renal stones with a maximum diameter less than 25 mm were included. exclusion criteria – active urinary tract infection (uti) or urosepsis, – active anticoagulation, – pregnancy, – untreated coagulopathies, – poorly controlled hypertension, – aortic aneurysms, – bilateral ureteric stone, – solitary kidney, and – renal insufficiency. pre-treatment assessment all patients underwent comprehensive assessment, including complete medical history, physical examination, laboratory analyses (urine analysis, urine culture and/or sensitivity analysis, complete blood count, coagulation profile, blood urea nitrogen analysis, and serum creatinine levels), and radiological examinations (plain abdominal radiograph, ultrasonography, and computed tomography scan). eswl procedure the extracorporeal shock wave lithotripsy procedure was conducted using the dornier compact delta® iii pro lithotripter (dornier medtech gmbh, germany) at a maximal intensity of 15 kv. patients were positioned in a supine position and received sedation and analgesia throughout the procedure. a low initial power setting of 8 kv was employed, with sequential voltage ramping to maximize patient comfort. for kidney stones ultrasound imaging was conducted to localize stone fragments and monitor fragmentation in real-time, while fluoroscopy was used for targeting ureteric stones. post-treatment and outcome patients were assessed for the first time 2 weeks following the initial session using a plain radiograph. repeat treatment was instituted in 66 cases where fragmentation was deemed inadequate (defined as either no fragmentation or stone fragments exceeding 4 mm in size). successful eswl was defined as the absence of any visible stones on radiological images within a 3-month post-treatment period either on plain radiograph, us, or ct scan ordered based on the practitioner’s preference. stones with no change or the presence of fragments larger than 4 mm beyond 3 months were considered as failure. data collection a self-constructed questionnaire was developed for the purpose of data collection. information was obtained from participants through structured interviews and examinations of their medical records. independent, validated chart reviews facilitated the collection of data. patient characteristics recorded included age, gender, body mass index (bmi), comorbidities, prior radiologic interventions, and the use of anticoagulants. stone characteristics documented encompassed size, location, skinto-stone distance (ssd), density measured in hounsfield units (hu), and the presence of hydronephrosis. additionally, details regarding the eswl treatment were captured, including the number of shock waves delivered, required power, frequency, analgesia usage, pain tolerance, fluoroscopy time and dosage, treatment duration, and the total number of sessions. treatment outcomes measured included stone clearance, any postoperative emergencies, complications, and the necessity for further procedures. all data collected were assessed for accuracy, completeness, and consistency. two independent reviewers achieved an inter-rater agreement of 98.2% on key variables, with any discrepancies addressed by a senior consultant urologist. statistical analysis statistical analyses were performed using spss v22 (spss inc., chicago, illinois, usa). descriptive statistics were utilized to characterize the study population, with continuous variables reported as means ± standard deviation (sd) for normally distributed data or as medians interquartile range (iqr) for non-normally distributed data. categorical variables were presented as frequencies (%). bivariable analyses involved chi-square or fisher's exact tests for categorical variables, and t-tests or mannwhitney u tests for continuous variables. multivariable logistic regression models were employed to identify independent predictors of eswl treatment failure, incorporating variables with p-values < 0.2 from the bivariable analysis or those deemed clinically relevant. model fit was assessed using the hosmerlemeshow test, with p-values > 0.05 indicating adequate fit. discrimination was evaluated using the area under the receiver operating characteristic (roc) curve. variables exhibiting multicollinearity (variance inflation factor [vif] ≥ 5), sparse data (cell counts < 5), or excessive missingness (> 15%) were excluded from the final models. the final analysis considered variables with p-values < 0.05 and adjusted odds ratios (aor) with corresponding 95% confidence intervals (cis) as statistically significant. archivio italiano di urologia e andrologia 2025; 97(2):13867 3 predictors of treatment failure and outcome assessment of extracorporeal shock wave lithotripsy... results patient and stone characteristics table 1 presents the demographic and clinical characteristics of 1,000 patients undergoing extracorporeal shock wave lithotripsy (eswl). the median age was 37.0 years (iqr: 32.0-44.2), with a male predominance (99.7%). left-sided stones were more common (54.7%) than right-sided stones (45.3%). the median bmi was 26.0 kg/m² (iqr: 24.029.0), and the majority of patients (79.0%) had no comorbidities; 7.5% had diabetes mellitus (dm), 9.6% had hypertension (htn), and 0.3% had coronary artery disease (cad). prior urologic interventions (e.g., percutaneous nephrolithotomy [pcnl], ureteroscopy [urs], or previous eswl) were reported in 36.6% of patients, while 10.8% had undergone previous double-j (dj) stenting (28 patients [2.8%] for ureteric stones and 80 patients [8.0%] for renal stones). single stones predominated (79.8%), with a median size of 9.0 mm (iqr: 7.0-10.0) and density of 1,000.0 hounsfield units (hu) (iqr: 760.0-1,200.0). hydronephrosis was present in 55.3% of cases. laboratory results included median creatinine levels of 86.0 µmol/l (iqr: 77.0-97.0), blood urea nitrogen (bun) of 4.2 mmol/l (iqr: 3.4-5.1), and hemoglobin of 14.8 g/dl (iqr: 14.0-15.5). preoperative urine cultures were negative in 97.4% of cases. stones were primarily renal (59.1%) or ureteral (40.7%), with a median stone-to-skin distance of 9.0 cm (iqr: 8.0-11.0). eswl procedure details the mean power delivered was 6.6 ± 1.2 kv (range: 2.010.0), with an average of 3,314.1 ± 517.2 shocks per session (range: 900.0-4,200.0). procedures lasted an average of 44.0 ± 5.1 minutes (range: 15-57), with 96.0% utilizing a frequency of 80 shocks per minute. guidance was provided via ultrasound (50.3%) or fluoroscopy (49.7%). analgesia included midazolam/morphine (61.2%) or fentanyl (37.2%). most patients (89.6%) tolerated the procedure well; 8.0% reported mild pain, while 2.4% had low tolerance for the procedure. treatment outcomes initial eswl success was achieved in 80.5% of cases, table 1. patient and stone characteristics of individuals who underwent extracorporeal shock wave lithotripsy. characteristic subgroup total (n = 1000) stone clearance p-value yes (n = 875) no (n = 125) age (years) median (iqr) 37.0 (32.0–44.2) 37.0 (32.0–44.0) 38.0 (30.0–45.0) 0.951 gender male 997 (99.7%) 870 (99.7%) 127 (100%) 1.000 female 3 (0.3%) 3 (0.3%) 0 (0%) laterality left 547 (54.7%) 484 (55.4%) 63 (49.6%) 0.255 right 453 (45.3%) 389 (44.6%) 64 (50.4%) body mass index (kg/m2) median (iqr) 26.0 (24.0–29.0) 26.0 (24.0–29.0) 27.0 (24.0–30.0) 0.099 comorbidities none 790 (79.0%) 685 (78.5%) 105 (82.7%) 0.571 diabetes mellitus 75 (7.5%) 68 (7.8%) 7 (5.5%) hypertension 96 (9.6%) 85 (9.7%) 11 (8.7%) cad 3 (0.3%) 2 (0.2%) 1 (0.8%) others* 36 (3.6%) 33 (3.8%) 3 (2.4%) previous dj stenting no 892 (89.2%) 781 (89.5%) 111 (87.4%) 0.585 yes 108 (10.8%) 92 (10.5%) 16 (12.6%) previous urologic intervention no 634 (63.4%) 570 (65.3%) 64 (50.4%) 0.002 yes 366 (36.6%) 303 (34.7%) 63 (49.6%) stone number single 798 (79.8%) 687 (78.7%) 111 (87.4%) 0.030 multiple 202 (20.2%) 186 (21.3%) 16 (12.6%) stone size (mm) median (iqr) 9.0 (7.0–10.0) 9.0 (7.0–10.0) 9.0 (7.0–11.0) 0.052 stone density (hu) median (iqr) 1000.0 (760.0–1200.0) 980.0 (750.0–1200.0) 1100.0 (911.5–1250.0) < 0.001 hydronephrosis no 447 (44.7%) 387 (44.3%) 60 (47.2%) 0.602 yes 553 (55.3%) 486 (55.7%) 67 (52.8%) creatinine (µmol/l) median (iqr) 86.0 (77.0–97.0) 86.0 (77.0–97.0) 86.0 (78.5–94.5) 0.787 blood urea nitrogen (mmol/l) median (iqr) 4.2 (3.4–5.1) 4.3 (3.4–5.2) 4.0 (3.2–5.1) 0.122 white blood cells (mcl) median (iqr) 7.7 (6.6–9.2) 7.8 (6.6–9.2) 7.5 (6.8–9.1) 0.525 hemoglobin (g/dl) median (iqr) 14.8 (14.0–15.5) 14.8 (14.0–15.5) 14.8 (14.0–15.5) 0.734 preoperative urine culture negative 974 (97.4%) 847 (97.0%) 127 (100%) 0.094 positive 26 (2.6%) 26 (3.0%) 0 (0%) stone-to-skin distance (cm) median (iqr) 9.0 (8.0–11.0) 9.0 (8.0–11.0) 10.0 (9.0–12.0) < 0.001 stone location kidney 591 (59.1%) 523 (59.7%) 68 (54.4%) 0.034 ureter 407 (40.7%) 350 (40.1%) 57 (45.6%) bladder 2 (0.2%) 2 (0.2%) 0 (0%) iqr: interquartile range; cad: coronary artery disease; hu: hounsfield units. * others: includes chronic kidney disease, asthma, etc. bold p-values: statistically significant (p < 0.05). archivio italiano di urologia e andrologia 2025; 97(2):13867 m. salah, m. al-ghashmi, b. tallai, et al. 4 increasing to 87.5% following repeat sessions (mean treatments: 1.2). success rates varied by stone location: – renal stones: 78.2% (lower calyx: 76.0%, mid calyx: 80.6%, upper calyx: 81.3%, renal pelvis: 82.4%). – ureteral stones: 83.1% (proximal ureter: 82.0%, distal ureter: 83.7%). treatment failure occurred in 12.5% (n = 125), necessitating additional interventions: semirigid urs (5.4%), flexible urs (0.7%), or pcnl (0.4%). postoperative complications arose in 4.6% (n = 46), primarily renal colic (4.2%). rare complications included bowel perforation (0.1%, n = 1), urosepsis (0.1%), and pyelonephritis (0.1%). bowel perforation details (n = 1): a 36-year-old male with a history of recurrent renal stones and prior eswl treatments developed acute abdominal pain 4 hours after eswl for an 8mm right upper ureteral stone. preoperative evaluation revealed leukocytosis (wbc 13×10³/μl) with 80% neutrophils. ct imaging demonstrated pneumoperitoneum and mesenteric stranding. during emergent laparoscopy, purulent intraperitoneal fluid was noted along with a 6-mm small bowel perforation 120 cm distal to the duodenojejunal flexure with adhesions. due to limited space and adhesions the procedure was converted to open. the patient underwent primary repair with peritoneal lavage and concurrent double-j stent placement for persistent ureteral obstruction. the presence of purulent fluid during exploration suggested early localized peritonitis. the patient made a full recovery postoperatively, highlighting the importance of prompt surgical intervention in such rare complications. predictors of eswl failure univariate analysis identified significant predictors of eswl failure, including prior urologic intervention (17.2% vs. 10.1%; p = 0.002), multiple stones (7.9% vs. 13.9%; p = 0.030), higher stone density (1100.0 vs. 980.0 hu; p < 0.001), and increased stone-to-skin distance (10.4 vs. 9.6 cm; p < 0.001). however, multivariate analysis confirmed significant predictors of eswl failure, including prior intervention (aor 2.64; 95% ci: 1.75-3.99; p < 0.001), multiple stones, which were associated with reduced odds of clearance (or 0.45; 95% ci: 0.24-0.77; p = 0.003), increased stone density, where each 100-hu increase raised the risk of failure (or 1.00; 95% ci: 1.00-1.00; p < 0.001), and stoneto-skin distance, where each 1-cm increase elevated failure odds by 18% (or 1.18; 95% ci: 1.06-1.30; p = 0.002). stone location (kidney vs. ureter) was found to be non-significant (p = 0.547) (table 2). discussion the present study aimed to provide significant insights into the efficacy and predictive factors associated with extracorporeal shock wave lithotripsy utilizing the dornier compact delta® iii pro for the management of renal and ureteric stones. the results indicate an overall stone-free rate that increased from 80.7% following the initial eswl procedure to 87.3% after repeat treatments. this progressive improvement underscores the potential of the dornier compact delta® iii pro to enhance treatment efficacy, marking a noteworthy presence in the contemporary stone management practice. the demographic characteristics of our cohort provide valuable details into the patient population underwent eswl. the median age of participants was 37 years, with a substantial predominance of males (99.7%) and a high prevalence of single stones (79.8%). although these findings corroborate results from previous studies that underscore the male predominance in urolithiasis (9-11), our situation is different, as the area covered by our facility, is mainly occupied by male labor population. a pivotal finding of our multivariate analysis was the identification of specific predictors for treatment failure following eswl, with a history of previous urologic intervention emerging as the most significant factor, reflected by an odds ratio of 2.64 (95% ci: 1.75-4.00). this underscores the challenges posed by altered renal anatomy or scarring from prior procedures, aligning with findings from gültekin et al., which demonstrated that overall stone-free rates after eswl treatment were significantly lower in patients with a history of prior ureteroscopy or stone surgery, particularly for stones in the lower calix (12). additionally, repeated eswl may contribute to long-term fibrotic degeneration of the collecting system, thereby complicating subsequent eswl treatment efforts (13). the impact of patient characteristics on the success rate table 2. predictive factors for extracorporeal shock wave lithotripsy failure in multivariate analysis. characteristic stone clearance multivariate logistic regression subgroup yes (n = 873) no (n = 127) crude or (95% ci) p-value adjusted or (95% ci) p-value previous urologic intervention no 570 (89.9%) 64 (10.1%) ref ref < 0.001 yes 303 (82.8%) 63 (17.2%) 1.87 (1.30–2.69) < 0.001 2.64 (1.75–3.99) < 0.001 stone number single 687 (86.1%) 111 (13.9%) ref ref 0.006 multiple 186 (92.1%) 16 (7.9%) 0.53 (0.31–0.91) 0.021 0.45 (0.24–0.77) 0.003 hounsfield unit (hu) (per 100-unit increase) 1.12 (1.06–1.18) < 0.001 1.00 (1.00–1.00) * < 0.001 stone-to-skin distance (cm) (per 1 cm increase) 1.15 (1.05–1.26) 0.002 1.18 (1.06–1.30) 0.002 stone location kidney 523 (88.5%) 68 (11.5%) ref ref 0.241 ureter 350 (86.0%) 57 (14.0%) 1.25 (0.86–1.81) 0.241 1.17 (0.70–1.97) 0.548 bladder 2 (100%) 0 (0%) ior = odds ratio; ci = confidence interval; ref = reference category. statistically significant values (p < 0.05) are in bold. *hu was modeled as a continuous variable; or represents per 100-unit increase for clinical interpretability. multivariate logistic regression: adjusted for all significant variables from univariate analysis. hosmer-lemeshow goodness-of-fit test: p = 0.42 (indicating good fit); area under the roc curve (auc): 0.72 (95% ci: 0.67–0.77), suggesting moderate discrimination. archivio italiano di urologia e andrologia 2025; 97(2):13867 5 predictors of treatment failure and outcome assessment of extracorporeal shock wave lithotripsy... of eswl remains a subject of debate in literature. previous studies, such as those by shinde et al., have indicated that female gender may be a significant negative predictor for stone clearance due to lower pain thresholds in women, which can impact their tolerance to higher energy shock waves, potentially leading to complications (7). other studies, such as those by el-nahas et al. (14), have identified bmi as a significant factor influencing stone clearance, while alharbi et al. noted that stone location and laterality significantly affected eswl efficacy (15). they also found that stones in patients with diabetes mellitus and hypertension exhibited lower fragmentation rates (15). in our study, the median age across gender groups was relatively consistent at 37.0 years (iqr: 32.0 to 44.2), suggesting that age-related effects on eswl outcomes may be negligible within this range. furthermore, the gender distribution was predominantly male (99.7%), limiting the applicability of gender as a predictive factor. the distribution of comorbidities, particularly diabetes mellitus and hypertension, did not exhibit significant discrepancies, indicating minimal influence on stone clearance. although our median bmi was 26.0 kg/m² (iqr: 24.0 to 29.0), which is within typical ranges, we acknowledge that previous reports suggest a relationship between bmi and successful stone fragmentation (16). the discrepancies between our findings and past literature highlight the need for future investigations with larger, more diverse cohorts to explore the impact of a broader range of patient characteristics on eswl success rates. comprehensive methodologies, including multi-center studies, may better delineate these relationships, ultimately enabling refinement of patient selection criteria for eswl. in our report, the influence of stone characteristics on treatment outcomes in eswl is pronounced, with multiple stones and increased stone density, measured in hu, identified as key predictors of treatment failure. specifically, stones with higher hu values (mean 1074.2 ± 303.2 in non-clearance cases) correlate with diminished eswl efficacy, indicating that denser stones are more resistant to shock wave fragmentation (17, 18). furthermore, an increased ssd negatively affected clearance rates, with failed cases exhibiting a mean distance of 10.4 ± 2.3 cm compared to 9.6 ± 2.1 cm in successful cases. conversely, our report found the presence of multiple stones to be a significant predictive factor for eswl failure. in contrast, stone location and size did not achieve statistical significance in multivariate analysis, with kidney and ureter stone locations yielding similar outcomes (upper: 88.46% clearance; lower: 86% clearance, p = 0.241). median stone sizes demonstrated marginal significance (median size: 9.0 mm, p = 0.052). factors such as hydronephrosis also showed no significant influence on treatment outcomes (p = 0.602). these individual results may be attributed to the use and technical characteristics of the new dornier compact delta®iii pro eswl machine resulting in enhanced fragmentation efficacy. comparative performance of modern eswl systems in different reports are mentioned in table 3 (8, 19-24). table 3. comparative performance of modern extracorporeal shock wave lithotripsy (eswl) systems. system sample size initial final sfr follow-up auxiliary major key additional (study, year) (n) stone-free period procedures complications* technological significant findings rate (sfr) features storz modulith slx-f2 474 82.7% 77% 3 months 14.7% 0.8% dual-focus • lower pole stones had 12% (elkoushy et al., 2011) (19) (subcapsular hematoma) electromagnetic lower success rate (p = 0.03) • stented patients showed 14.5% reduced efficacy storz modulith slx-f2 361 eq** = 0.646 22% 1.7% adjustable • standard focus (6 mm) improved (suzuki et al., 2010) (20) (hematoma) focal zones (6-9 mm) ureteral stone outcomes by 17% • smli*** > 0.65 correlated with complications siemens lithoskop 183 91% 3 months 7.1% 0.5% acoustic pressure • pediatric sfr = 94% (n = 13) (neisius et al., 2013) (8) (hematoma) monitoring • no difference by stone location (p = 0.41) dornier compact delta ii 336 78.2% (renal) 3 months 11.5-14% none reported optical coupling control • occ improved sfr by 15.4% (lv et al., 2016) (21) (occ) (p < 0.01) 81.7% (ureteral) • reduced skin ecchymosis by 60% edap-sonolith praktis 703 95.3% 4 weeks 30.6% none major ultrasound • efficiency quotient (eq) = 0.71 (lee et al., 2005) (22) localization • treatment time < 45 mins for 89% cases dornier mfl 5000 347 82.4% 4 weeks 51.6% 4% (steinstrasse) electrohydraulic source • 23% longer treatment time (sheir et al., 2003) (23) vs electromagnetic • higher re-treatment rate for > 10 mm stones dornier compact delta 614 95.9% 6 weeks 18% 26.4% hematuria electromagnetic • 37% faster than (yang & hyun, 2007) (24) with ultrasound electroconductive models • better for obese patients (bmi > 30) * major complications defined as: steinstrasse requiring intervention, subcapsular hematoma > 2 cm, or sepsis; ** eq (efficiency quotient) = [% stone-free/(100 + % re-treatment + % auxiliary procedures)] × 100; *** smli (storz medical lithotripsy index) = energy × number of shocks/1000. archivio italiano di urologia e andrologia 2025; 97(2):13867 m. salah, m. al-ghashmi, b. tallai, et al. 6 technological advancements in shock wave technology have positioned eswl as the primary treatment for most renal and ureteric stones (3). the dornier compact delta® iii pro exemplifies these innovations, featuring enhanced shock wave generation and dual imaging systems that enable precise targeting while minimizing radiation exposure (4). with the capability to deliver up to 1000000 shock waves, this device surpasses the efficiency of ordinary lithotripters, facilitating outpatient procedures with reduced analgesia requirements and lower morbidity. additionally, the dornier compact delta® iii pro integrates advanced imaging, maximal energy delivery, and improved operational efficiency, supporting urologists to achieve effective stone management. recent developments in lithotripters, such as the modularis vario, have further optimized key components, enhancing patient comfort and imaging quality (4). these technological advancements not only improve stone comminution but also elevate success rates in treating renal and ureteric stones, consequently decreasing the need for auxiliary interventions. notably, the dornier compact delta®iii pro's superior capabilities contribute to increased sfrs and lower complication rates, as demonstrated by a low postoperative emergency rate of only 4.6%. future research is warranted with this device and compare its efficacy and outcome measures across various clinical settings. clinical implications the results of this study provide valuable insights into the efficacy of the newly introduced eswl machine, the dornier compact delta®iii pro, highlighting its significant role in the management of renal and ureteric stones, as evidenced by a commendable stone-free rate of 87.3%. the identification of critical predictors of treatment failure, including prior urologic interventions, the presence of multiple stones, increased stone-to-skin distance (ssd), and stone density, enables clinicians to conduct more nuanced preoperative evaluations and implement tailored therapeutic strategies. however, it is important to note that these findings align with those already described in the existing literature and are well-established within the international medical community. limitations of the study this study acknowledges several limitations that may impact the interpretation of the findings. firstly, the moderate sample size, monocentric design, and retrospective nature of the investigation present inherent challenges, as reliance on secondary data may introduce variability due to inconsistencies in documentation and the potential for bias in the results. additionally, technical limitations in the methodologies employed to define stone clearance could affect the accuracy and reliability of the findings. the single-center design further restricts the generalizability of the results to broader populations, and the three-month follow-up duration may not adequately capture delayed treatment failures that could occur over an extended period. despite these challenges, this investigation represents the inaugural report correlating stone clearance with the newly launched eswl machine, the dornier compact delta® iii pro, at our institution. consequently, our results underscore the critical need for further research involving larger sample sizes and, ideally, multicentric approaches that incorporate institutions utilizing and operating the same machine. such studies would enhance the robustness of the findings and contribute to a more comprehensive understanding of the effectiveness of this eswl system in diverse clinical settings. conclusions the dornier compact delta® iii pro has demonstrated considerable efficacy in the treatment of renal and ureteric stones, achieving a stone-free rate of 87.3%. this study identified several key predictors of treatment failure, including prior urologic interventions, the presence of multiple stones, increased skin-to-stone distance, and higher stone density. these findings affirm the continued relevance of eswl as a mainstay in the contemporary management of renal and ureteral stones. future multicenter randomized controlled trials are warranted to validate these preliminary results and further evaluate the performance of the dornier compact delta® iii pro lithotripter in diverse clinical settings. references 1. stamatelou k, goldfarb ds. epidemiology of kidney stones. healthcare (basel, switzerland) 2023; 11(3). 2. sarier m, duman i, callioglu m, et al. outcomes of conservative management of asymptomatic live donor kidney stones. urology 2018; 118:43-46. 3. mosquera seoane l, ortiz salvador jb, budia alba a, perez fentes da. technological innovations in shock wave lithotripsy. actas urol esp (engl ed) 2024; 48:105-10. 4. dornier medtech. dornier delta iii. secondary dornier medtech. dornier delta iii 2023. https://www.dornier.com/products-item/dornier-delta-iii/. 5. lee sm, collin n, wiseman h, philip j. optimisation of shock wave lithotripsy: a systematic review of technical aspects to improve outcomes. transl androl urol 2019; 8(suppl 4):s389-s97. 6. wagenius m, oddason k, utter m, et al. factors influencing stone-free rate of extracorporeal shock wave lithotripsy (eswl); a cohort study. scandinavian journal of urology 2022; 56:237-43. declarations ethical approval: the study adhered to the principles of the helsinki declaration and was approved by the ethics committee of hazm mebaireek general hospital, hamad medical corporation, doha, qatar (id mrc-01-25-167). availability of data: data is available upon request. competing interests: the authors declare no conflicts of interest. funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13867 7 predictors of treatment failure and outcome assessment of extracorporeal shock wave lithotripsy... 7. shinde s, al balushi y, hossny m, et al. factors affecting the outcome of extracorporeal shockwave lithotripsy in urinary stone treatment. oman medical journal 2018; 33:209-17. 8. neisius a, wöllner j, thomas c, et al. treatment efficacy and outcomes using a third generation shockwave lithotripter. bju int 2013; 112:972-81. 9. campbell mf, walsh pc, wein aj, et al. campbell-walsh-wein urology. 12th ed. / editor-in-chief, alan w. partin; editors, roger r. dmochowski, louis r. kavoussi, craig a. peters ed: elsevier, 2021. 10. al-zubi m, al sleibi a, elayan bm, et al. the effect of stone and patient characteristics in predicting extra-corporal shock wave lithotripsy success rate: a cross sectional study. ann med surg 2021; 70:102829. 11. fisang c, anding r, müller sc, et al. urolithiasis--an interdisciplinary diagnostic, therapeutic and secondary preventive challenge. dtsch arztebl int. 2015; 112:83-91. 12. gültekin mh, türegün fa, ozkan b, et al. does previous open renal stone surgery affect the outcome of extracorporeal shockwave lithotripsy treatment in adults with renal stones? j endourol 2017; 31:1295-300. 13. abdel-khalek m, sheir kz, mokhtar aa, et al. prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. scand j urol nephrol 2004; 38:161-7. 14. el-nahas ar, el-assmy am, mansour o, sheir kz. a prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. eur urol 2007; 51:1688-93. 15. alharbi as, gameraddin m, gareeballah a, et al. assessment of hounsfield units and factors associated with fragmentation of renal stones by extracorporeal shock wave lithotripsy: a computerized tomography study. tomography 2024; 10:90-100. 16. abou-farha m, el-abd a, gameel t, et al. efficacy of extracorporeal shockwave lithotripsy, with modified position of the machine head in the treatment of lower calyceal stones in obese patients. urol ann 2022; 14:81-84. 17. garg m, johnson h, lee sm, et al. role of hounsfield unit in predicting outcomes of shock wave lithotripsy for renal calculi: outcomes of a systematic review. curr urol rep 2023; 24:173-85. 18. abdelaziz h, elabiad y, aderrouj i, et al. the usefulness of stone density and patient stoutness in predicting extracorporeal shock wave efficiency: results in a north african ethnic group. can urol assoc j. 2014; 8:e567-9. 19. elkoushy ma, hassan ja, morehouse dd, et al. factors determining stone-free rate in shock wave lithotripsy using standard focus of storz modulith slx-f2 lithotripter. urology 2011; 78:759-63. 20. suzuki k, yamashita y, yoshida m, matuzaki j. a single center experience with a lithotripsy machine "modulith slx-f2" : evaluation of dual focus system and clinical results. hinyokika kiyo 2010; 56:81-6. 21. lv jl. a new optical coupling control technique and application in swl. urolithiasis 2016; 44:539-44. 22. lee ch, koh sk, kim hj. experience of extracorporeal shock wave lithotripsy with electroconductive lithotriptor (ecl, edapsonolith praktis) in 703 patients with urinary calculi. korean j urol 2005; 46:375-81. 23. sheir kz, madbouly k, elsobky e. prospective randomized comparative study of the effectiveness and safety of electrohydraulic and electromagnetic extracorporeal shock wave lithotriptors. j urol 2003; 170:389-92. 24. kim yh, kim hj, oh js. comparative study of the results of electromagnetic (eml dornier compact delta®) and electroconductive (ecl, edap-sonolith praktis) extracorporeal shock wave lithotriptors. korean j urol 2007; 48:1027-34. correspondence morshed salah (corresponding author) msalah1@hamad.qa; morshed.salah@gmail.com urology section, hazm mebaireek general hospital, hamad medical corporation, doha, qatar maged al-ghashmi majidghashmi2013@gmail.com bela tallai belatallai@gmail.com abu baker abu_kmcite@yahoo.com mohammed ibrahim mibrahim26@hamad.qa salvan alhabash salwansaad@gmail.com hatem kamkoum hatemkamkoum@gmail.com tawiz gul tawizgul@yahoo.com; tgulistan@hamad.qa hossameldin alnawasra halnawasra@hamad.qa abdoulhafid elmogassabi aelmogssabi@hamad.qa maged alrayashi malrayashi@hamad.qa mohammed ebrahim mebrahim2@hamad.qa; mohammed.alezi@gmail.com mohamed abdelkareem m.a.alkareem@gmail.com faisal ahmed fmaaa2006@yahoo.com stesura seveso archivio italiano di urologia e andrologia 2025; 96(1):13709 1 editorial comment on submitted 6 february 2025; accepted 6 february 2025 in arch ital urol androl, zeki bayraktar presented the results of a review of all published research on the quality of life, satisfaction, patient-reported outcomes, and shortand long-term problems of patients who had gender-affirming surgery (gas) (1). according to the author, transgender people who have gas virtually completely lose their sexual function and irreversibly lose their reproductive function, and their urinary function is also severely compromised (1). according to the diagnostic and statistical manual of mental disorders, fifth edition, text revision (dsm-5-tr), gender dysphoria has been defined as a marked incongruence between one’s experienced/expressed gender and their assigned gender, lasting at least 6 months (2). strong desires to be of the other gender and to be treated as such (or any alternative gender different from one's assigned gender) are linked to gender dysphoria (2). on the basis of these considerations, is clear that transgender people experience an impairment in quality of life in terms of clinically significant distress or impairment in social, occupational, or other important areas of functioning (3, 4). gender dysphoria-related distress might include anxiety, sadness, low self-esteem, self-harm, suicidality, or trauma reactions, including hypervigilance, brought on by social mistreatment. these facts make it abundantly evident that gender dysphoria is a mental illness that needs specialized care because it has a major detrimental influence on social and familial life. gender dysphoria is not only a psychological issue but is a complicated mental illness that typically affects individuals and their families. transgender individuals may need genderaffirming surgery in a number of situations to enhance their overall quality of life. all urologists certified to do this type of surgery must attend to these patients' requirements and works to enhance their quality of life. these crucial aspects of treating gender dysphoria are not included in zeki bayraktar's paper. 1) the lack of recognition of high volume and highly qualified centres; 2) the lack of agreement among surgeons regarding surgical procedures and the management of complications; and 3) the absence of a long-lasting and beneficial partnership between patient associations and the uro-andological scientific society are the unmet needs for bettering the care of transgender individuals who need gender-affirming surgery. in conclusion, it is clear that gender dysphoria is a complicated mental illness that requires specific treatment such as several times gender-affirming surgery. the question not is: “so, what is the reason for this insistence on gas?” but “how we can improve the management of gender-affirming surgery in terms of quality of care, patients’ satisfaction and quality of life?” references 1. bayraktar z. urogenital and extra genital mutilation in gender-affirming surgery: are we violating primum non nocere?. arch ital urol androl 2025; 97:13324. 2. diagnostic and statistical manual of mental disorders, fifth edition, text revision (dsm-5-tr). american psychiatric association. 2022. 3. turban jl, beckwith n, reisner sl, keuroghlian as. association between recalled exposure to gender identity conversion efforts and psychological distress and suicide attempts among transgender adults. jama psychiatry 2020; 77:68-76. 4. cai t, verze p, bjerklund johansen te. the quality of life definition: where are we going? uro. 2021; 1:14-22. urogenital and extra genital mutilation in gender-affirming surgery: are we violating primum non nocere? tommaso cai 1, 2, alessandro palmieri 3 on behalf of italian society of andrology 1 department of urology, santa chiara regional and teaching hospital, trento, italy; 2 institute of clinical medicine, university of oslo, oslo, norway; 3 department of neurosciences and reproductive and odontostomatological sciences, urologic unit, università federico ii, naples, italy. doi: 10.4081/aiua.2025.13709 declarations ethical approval: not applicable. availability of data and material: not applicable. competing interests: none. funding: not applicable. authors' contributions: t.c and a.p. writing. acknowledgments: not applicable. correspondence tommaso cai ktommy@libero.it department of urology, santa chiara regional hospital, trento, italy alessandro palmieri info@alessandropalmieri.it department of urology, federico ii university, naples, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11830 1 original paper introduction the implementation of multiparametric prostate magnetic resonance imaging (mpmri) prior to prostate biopsy led to an improvement of clinically significant prostate cancer (cspca) diagnosis, contributing to the reduction of unnecessary biopsies and over-diagnosis of clinically insignificant prostate cancer and resultant overtreatment (1-4). in the setting of primary diagnosis, mpmri was interpreted according to the prostate imaging reporting and data system (pirads), created by the european society of urogenital radiology (esur) to standardize radiologic reports and improve the diagnostic quality of prostate mpmri exams (5). in 2021 a new pirads version 2.1 replaced the previous 2.0 version published in 2015 (6). the pi-rads score report the likelihood of a cspca based on various mpmri characteristics. categories pi-rads 1 or 2 indicate (very) low likelihood of cspca, whereas categories 4 or 5 indicate (very) high likelihood of cspca. the european association of urology recommends performing a prostate biopsy when mpmri shows lesions with pi-rads ≥ 3 (7). however, the pi-rads category 3 is an intermediate status, with an equivocal risk of malignancy (8). a metanalysis with 17 studies reported a cancer detection rate of 16% (7-27%) in patients with pi-rads category 3 lesions. (9) the psa density (psad) has been proposed as a tool to facilitate biopsy decisions on pi-rads categoric 3 lesions. a recent study on biopsy naive patients with pi-rads 3 lesions and low psad (<0.10 ng/ml/ml) reported a low risk of sigintroduction and objectives: the prostate imaging reporting and data system (pi-rads) score reports the likelihood of a clinically significant prostate cancer (cspca) based on various multiparametric prostate magnetic resonance imaging (mpmri) characteristics. the pi-rads category 3 is an intermediate status, with an equivocal risk of malignancy. the psa density (psad) has been proposed as a tool to facilitate biopsy decisions on pi-rads category 3 lesions. the objective of this study is to determine the frequency of cspca, assess the diagnostic value of targeted biopsy and identify clinical predictors to improve the cspca detection rate in pi-rads category 3 lesions. methods: between 1st january 2017 and 31st december 2022, a total of 1661 men underwent a prostate biopsy at our institution. clinical and mpmri data of men with pi-rads 3 lesions was reviewed. the study population was divided into two groups: target group, including those submitted to systematic plus targeted biopsy versus non-target group when only systematic or saturation biopsy were performed. patients with pi-rads 3 lesions were divided into three categories based on pathological biopsy results: benign, clinically insignificant disease (score gleason = 6 or international society of urologic pathologic (isup) 1) and clinically significant cancer (score gleason ≥ 7 (3+4) or isup ≥ 2) according to target and non-target group. univariate and multivariate analyses were performed to identify clinical predictors to improve the cspca detection rate in pi-rads category 3 lesions. results: a total of 130 men with pirads 3 index lesions were identified. pathologic results were benign in 77 lesions (59.2%), 19 (14.6%) were clinically insignificant (gleason score 6) and 34 (26.2%) were clinically significant (gleason score 7 or higher). eighty-seven of the patients were included in the target group (66.9%) and 43 in the non-target group (33.1%). the cspca detection was higher in the non-target group (32.6%, n = 14 vs 23.0%, n = 20 respectively). when systematic and target biopsies were jointly performed, if the results of systematic biopsies are not considered and only the results of target biopsies are taken into account, a cspca diagnosis would be missed on 9 patients. the differences of insignificant cancer and cspca rates among the target or non-target group were not statistically significant (p = 0.50 and p = 0.24, respectively). on multivariate analysis, the abnormal dre and lesions localized in peripheral zone (pz) were significantly associated with a presence of cspca in pi-rads 3 lesions (or = 3.61, 95% ci [1.22,10.72], p = 0.02 and or = 3.31, 95% ci [1.35, 8.11], p = 0.01, respectively). a higher median psad significantly predisposed for predictors of prostate cancer cetection in mri pi-rads 3 lesions – reality of a terciary center débora araújo 1, alexandre gromicho 2, jorge dias 1, samuel bastos 1, rui miguel maciel 1, ana sabença 1, luís xambre 1 1 urology department, centro hospitalar vila nova de gaia/espinho epe, vila nova de gaia, portugal; 2 urology department, centro hospitalar do funchal, madeira, portugal. doi: 10.4081/aiua.2023.11830 summary cspca on univariate analyses (p = 0.05), however, was not significant in the multivariate analysis (p = 0.76). in our population, using 0.10 ng/ml/ml as a cut-off to perform biopsy, 41 patients would have avoided biopsy (31.5%), but 5 cases of cspca would not have been detected (3.4%). we could not identify any statistical significance between other clinical and imagiological variables and cspca detection. conclusions: pi-rads 3 lesions were associated with a low likelihood of cspca detection. a systematic biopsy associated or not with target biopsy is essential in pi-rads 3 lesions, and targeted biopsy did not demonstrate to be superior in the detection of cspca. the presence of abnormal dre and lesions localized in pz potentially predict the presence of cspca in biopsied pi-rads 3 lesions. key words: prostate cancer; pi-rads category 3 lesions; prostate multiparametric mri. submitted 17 september 2023; accepted 2 november 2023 archivio italiano di urologia e andrologia 2023; 95(4):11830 d. araújo, a. gromicho, j. dias, s. bastos, r. miguel maciel, a. sabença, l. xambre 2 nificant disease (4%) suggesting that biopsies could be avoided. nevertheless, pi-rads 3 scores in patients with high psad (> 0.20 ng/ml/ml) should be offered targeted and systematic biopsies due to the higher risk of significant disease (29%) (10). the objective of this study is to determine the frequency of cspca, assess the diagnostic value of targeted biopsy and identify clinical predictors to improve the cspca detection rate in pi-rads category 3 lesions. materials and methods between 1st january 2017 and 31st december 2022, a total of 1661 men underwent a prostate biopsy at our center due to altered prostate-specific antigen (psa) and/or abnormal digital rectal examination (dre). the inclusion criteria were: mpmri with a pi-rads 3 lesion followed by prostate biopsy. these patients could be biopsy naive, with previous negative biopsies or in active surveillance protocol. the exclusion criteria were absence of mpmri before prostate biopsy, mpmri without pi-rads classification, having a scored lesion other than pi-rads 3 or only having performed target biopsy. a flowchart with study inclusion criteria is presented in figure 1. a total of 130 patients with pi-rads 3 index lesions were retrospectively reviewed. all patients were treatment naive and clinical, mpmri and pathologic data were collected for each patient. clinical data included age, total psa, ratio free to total psa and dre results (normal and abnormal findings). abnormal findings were areas of localized or diffuse firmness, induration, irregularity or nodularity suggestive of a ct2 lesion. prostate volume, number of target lesions, maximum lesion diameter and location (peripheral, transitional, or anterior zone and the base, middle or apex) were examined on mpmri. psad was calculated using pre-biopsy psa and mpmri-derived volume. all patients were submitted to a transrectal ultrasound (trus)-guided biopsy performed by an urologist (6 urologists, with a median 6.5 years of experience (range, 3-10 years)). before the prostate biopsy, mpmri was reviewed and analysed, identifying the presence of any pi-rads lesion. the mpmri was performed and reported by different radiologists but every mpmri protocol included multiplanar t2-weighted imaging, diffusion weighted imaging (dwi), and dynamic contrast-enhanced mri (dcemri). the study population was divided into two groups to assess the diagnostic value of targeted biopsy: target group, including those submitted to systematic plus targeted biopsy versus non-target group when only systematic or saturation biopsy were performed. the patients were distributed according to physician’s preference, and the two groups’ pathological results were compared. the mpmri-targeted biopsy was performed through cognitive guidance. three to 5 cores were obtained from each target lesion. the histopathology of the prostate biopsies was reported as a gleason score and according to the 2014 international society of urologic pathologic (isup) guidelines. patients with pi-rads 3 lesions were divided into three categories based on pathological biopsy results: benign, clinically insignificant disease (score gleason = 6 or isup 1) and clinically significant cancer (score gleason ≥ 7 (3+4) or isup ≥ 2) according to target and non-target group. figure 1. flowchart for study inclusion among patients with pi-rads 3 index lesions with clinical suspicion of prostate cancer. dre: digital rectal examination; mpmri: multiparametric magnetic resonance imaging; psa: prostate-specific antigen. archivio italiano di urologia e andrologia 2023; 95(4):11830 3 mri pi-rads 3 lesions statistical analyses were performed using ibm spss statistics software version 25. categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations, or medians and interquartile ranges for variables with skewed distributions. pearson's chi-squared or fisher's exact test were used to test for associations in categorical variables. continuous variables were compared with the t-test student and mann-whitney u test. simple and multiple logistic regression were performed to determine clinical predictors of cspca. a p-value ≤ 0.05 was considered statistically significant. results one thousand six hundred sixty-one men were submitted to prostate biopsy for altered psa or/and abnormal dre over the last 6 years. patients without a pre-biopsy mpmri (n = 840), without a pi-rads classification in mpmri (n = 41) and patients submitted to a target biopsy alone (n = 80) were excluded. one hundred and twenty-two patients with a pi-rads category 5 lesions (17.4%), 330 with a pi-rads category 4 lesions (47.1%) and 118 with pi-rads category 2 lesions (16.9%) were not included in the cohort. the detailed patient inclusion and exclusion flow charts are presented in figure 1. a total of 130 men (18.5%) with pi-rads 3 index lesions were biopsied and included in this study. one hundred fifty-three pi-rads 3 index lesions were observed. general characteristics of the pi-rads 3 lesions and patients are summarized in table 1. the mean age was 65.2 ± 6.9 years. median total psa was 7.7 ng/dl (iqr 5.43-9.77), with a median of free/total psa of 14.6% (iqr 11.0-18.9). seventeen of 121 patients had an abnormal dre (14.0%). mean prostate size on mpmri was 60.1 ± 22.6 ml. when calculated, median psad was 0.12 ng/ml/ml (iqr 0.09-0.18). median maximum lesion diameter was 10.0 mm (iqr 7.0-13.0). the majority of the lesions were located on the peripheral zone (pz) (64.9%) followed by transitional (tz) and anterior zone (33.1% and 1.9%, respectively). regarding prostatic location, most were in the middle of prostate (54.3%). one hundred and eight men had prostates with only one targeted lesion (83.1%) and 22 patients had more than one pi-rads 3 lesion (16.9%). the number of pi-rads 3 lesions in the prostate ranged from 1 to 4 lesions. pathologic results in this cohort were benign in 77 lesions (59.2%), 19 (14.6%) were clinically insignificant (gleason score 6 or isup 1) and 34 (26.2%) were cspca (more than gleason score 7 or above isup 2). of the 34 patients with cspca, 30 patients had a gleason score of 7 (3+4), 3 patients had a gleason score of 7 (4+3) and one patient had a gleason score 9 (5+4). eighty-seven of the patients were included in the target group (66.9%) and 43 in the non-target group (33.1%). the pathologic outcomes of pirads 3 lesions, considering the clinical data and target and non-target group, are described in figure 2. the presence of benign histology was the most common result in both groups. the cspca detection in patients with previous negative biopsy was inferior compared to naive or active surveillance patients. the difference in cspca rates among the three clinical scenarios was not statistically significant (p = 0.32). the cspca detection was higher in the non-target group (32.6%, n = 14 vs 23.0%, n = 20 respectively). regarding the target group, 11 patients with pirads 3 lesions had cspca in both systematic and target biopsy (55.0%). nine patients had a positive systematic and negative target biopsy. no case of a positive target biopsy and a negative systematic biopsy was identified. in all patients, the presence of positive pathologic findings in systemic and target biopsy, equivalent histological results for both specimens were found. when systematic and target biopsies were jointly performed, if the results of systematic biopsies are not considered and only the results of target biopsies are taken into account, a cspca diagnosis would be missed on 9 patients. the difference of insignificant cancer and cspca rates among the target or non-target group was not statistically significant (p = 0.50 and p = 0.24, respectively). psad, abnormal dre and peripheral target lesion location were significantly associated with cspca in pi-rads 3 lesions (p = 0.05, 0.01 and 0.01, respectively). clinical, mpmri and pathologic findings on cspca lesions are reported in table 3. on multivariate analysis, the abnormal dre and lesions localized in peripheral zone (pz) were significantly associated with a presence of cspca in pirads 3 lesions (or = 3.61, 95% ci [1.22, 10.72], p = 0.02 and or = 3.31, 95% ci [1.35, 8.11], p= 0.01, respectively). the frequency of abnormal dre was superior in the group of cspca patients (29.0% vs 14.0%, respectively). the median psad was similar in cspca positive patients and the overall pi-rads 3 lesions group. a higher median psad significantly predisposed for cspca on table 1. clinical and imagiological characteristics of the pi-rads categoric 3 cohort population. variables no. (%) age (years) [mean ± sd] 65.2 ± 6.9 total psa (ng/dl) [median (iqr)] 7.7 (5.43-9.77) free/total psa (%) [median (iqr)] 14.6 (11.0-18.9) prostate volume (ml) [mean ± sd] 60.1 ± 22.6 psa density (ng/ml/ml) [median (iqr)] 0.12 (0.09-0.18) abnormal dre (n, %) 17 (14.0) clinical scenario (n, %) – biopsy naive 84 (64.6) – previous negative biopsy 34 (26.2) – active surveillance 12 (9.2) maximum lesion diameter (ml) [median (iqr)] 10.0 (7.0-13.0) number of pi-rads 3 index lesions (n, %) – single 108 (83.1) – multiple 22 (16.9) target lesion zonal location (n = 154) (n, %) – peripheral zone 100 (64.9) – transition/central zone 51 (33.1) – anterior fibromuscular stroma 3 (1.9) target lesion quadrantal location (n = 140) (n, %) – base 30 (21.4) – middle 76 (54.3) – apex 34 (24.3) dre: digital rectal examination; iqr: interquartile range; sd: standard deviation; psa: prostate-specific antigen. archivio italiano di urologia e andrologia 2023; 95(4):11830 d. araújo, a. gromicho, j. dias, s. bastos, r. miguel maciel, a. sabença, l. xambre 4 univariate analyses (p = 0.05) but was not significant in the multivariate analysis (p = 0.76). in our population, using 0.10 ng/ml/ml as a cut-off to perform biopsy, 41 patients would have avoided biopsy (31.5%), but 5 cases of cspca would not have been detected (3.4%). we could not identify statistical significance between others clinical and imagiological variables and cspca detection. discussion the evaluation of pi-rads 3 lesions does not represent the primary endpoint in most studies of prostate cancer diagnosis, and, currently, the quality of the studies focusing on this pi-rads subset remains low. pi-rads classification was designed to reduce the mpmri inter-reader reproducibility, however, it does not provide a specific management algorithm for each category (11). concerning the pi-rads 3 lesions, there is no agreement on the best clinical management biopsy or clinical surveillance (12, 13). prostate biopsy is the standard recommendation, however, in some cases a follow-up strategy could be an acceptable option (10, 11). in our institution, the prevalence of pi-rads 3 lesions was 18.5%. maggi et al., in a review of 23 studies, reported a prevalence of pi-rads 3 cases of 17.3% (range 6.445.7%) (11). given the incidence of these lesions, choosing the best approach is essential. we demonstrated that pi-rads 3 lesions were associated with a low risk of prostate cancer (40.8%), especially when considering cspca. in our study, most pi-rads 3 lesions were benign (59.2%) and only 26.2% were cspca. the most common gleason scored diagnosed was score 7 (3+4) or isup 2 (30/34). regarding the diagnosis of isup 4 or higher, only one case was identified on pi-rads 3 lesions. the cspca rate was significantly variable between published studies. this can be explained based on the population heterogeneity, mri protocols, type of mpmri-targeted biopsy (cognitive guidance, ultrasound or mri fusion software or direct in-bore guidance) and cspca definitions. oerther et al. reported a cancer detection rate of 16% (7-27%) in patients with pi-rads 3 lesions (9). schoots et al. reviewed 3006 biopsy-naive men in five studies and found the percentage of isup ≥ 2 detection rate in lesions pirads 3 was 16% (10). in a review of thirteen prospective studies of pi-rads 3 lesions, the overall pca detection rate was 37%, while for cspca it was 21% (14). magui et al., in a systematic review of 28 studies with a total of 1759 cases of pirads 3 lesions, reported a prostate cancer detection rate of 36% (range 10.3-55.8%) and cspca rate of 18.5% (range 3.4-46.5%) (11). the best biopsy strategy also remains controversial. the inclusion of the mri previously to prostate biopsy increased the number of cspca detected and reduced the number of insignificant cancer. however, omitting systematic biopsy would miss approximately 16% and 10% of all detected isup grade ≥ 2 in biopsy-naive and repeatbiopsy patients, respectively (1-4) in our population, the cspca rate was slightly higher in non-target group (32.6 vs. 23%, respectively); and paradoxically, insignificantly cancer rate was slightly higher in the target group (16.1 vs. 11.6%, respectively). however, both results were not statistically significant (p = 0.50 and p = 0.24, respectively). nevertheless, a cspca diagnosis would be missed in 9 patients if targeted biopsy was performed alone, confirming the importance of not omitting the systematic biopsy in this setting. in our cohort, the value of the systematic biopsy was demonstrated. no case of histological upgrading or only positive pathological results on target biopsies were reported. in our opinion, the target biopsy could be omitted in pi-rads 3 lesions, however the systematic biopsy should always be performed if cspca is suspected. the importance of the systematic biopsies in cspca detection in pi-rads 3 lesions can be explained due to mri interpretation and mistargeting issues (i.e., the lesion has been correctly identified by mpmri but missed by mpmri-targeted biopsy and detected by systematic sampling), especially in non-peripheral zones and smaller lesions. some authors advocate a saturation targeted approach or increasing the number of cores taken by target to raise the cspca detection (15, 16). we believe that in reference centers with large number of patients, experienced teams with dedicated radiologists and urologists, well-defined protocols and newer technologies or softwares, the target biopsy may be crucial in pi-rads 3 lesions. however, in tertiary centers like ours, there are some disadvantages smaller number of patients, interpretation of mpmri by different radiologists and different urologists with different levels of experience. our targeted biopsies were obtained by cognitive guidance. the current literature does not show superiority or inferiority of the cognitive technique compared with us/mr fusion software or direct in-bore guidance (17). regarding the pathology analyses, the most common result was benign histology in both groups. the cspca detection in patients with previous negative biopsy was lower comparative to naive or active surveillance patients. the difference of cspca rates among the three groups was not statistically significant (p = 0.32). given the high variability of the published studies, it is difficult to decide to perform prostate biopsy in case of pi-rads 3 lesions independently of clinical scenario (naive patient, or with previous negative biopsy, or active surveillance) (11). many studies tried to identify clinical and imagiological findings that can help to identify which patients can be selected for surveillance. psad is the most frequently investigated clinical predictor. recently, a risk-adapted biopsy decision was proposed, based on psad and mpmri report. concerning the pi-rads 3 lesions, patients with high-risk psad (> 0.20 ng/ml/ml) should be offered targeted and systematic biopsies as they have a higher risk for significant disease (29%). on the other hand, patients with low risk psad (< 0.10 ng/ml/ml) have a low risk of significant disease (4%) and biopsies could be avoided (10). in our study, the median psad was similar in cspca positive patients and the general pi-rads 3 lesions cases. a higher median psad significantly predisposed for cspca on univariate analyses (p = 0.05) but not significant in the multivariate analysis (p = 0.76). in our population, using 0.10 ng/ml/ml as a cut-off to perform biopsy, 41 patients would have avoided biopsy (31.5%), but 5 cases of cspca would not have been detected (3.4%). venderink et al. demonstrated that biopsying only pi-rads 3 cases with a psad of ≥ 0.15 ng/ml/ml resulted in 42% of cases who would avoid biopsy, thus missing 6% archivio italiano di urologia e andrologia 2023; 95(4):11830 5 mri pi-rads 3 lesions of cspca cases. lowering the cut-off value to 0.12 ng/ml/ml resulted in 26% of cases that would have avoided biopsy without missing any cspca (18). an abnormal dre (p = 0.02) and a peripheral target lesion (p = 0.01) significantly predisposed for cspca in multivariate logistic regression. the frequency of abnormal dre was higher in the cspca patients group comparatively to general pi-rads 3 cases (29.0% vs 14.0%, respectively). sheridan et al. calculated risks factors of cspca in pi-rads 3 lesions in their multivariate analyses and demonstrated that an abnormal dre was a significant predictor of cspca (or.3.92, p = 0.03), as was advanced age (≥ 70 years) and smaller prostates (≤ 36cc) (19). radtle et al. showed that a higher psa level (or, 2.08), a smaller gland size (or, 0.81), abnormal dre findings (ct2 or more lesion, or, 4.09) and advanced age (or, 1.09) were independently associated with cspca in pirads 3 lesions. (20) abnormal dre is a strong predictor of advanced pca that is associated with an increasing risk of higher isup and, despite being a subjective test, is an important tool in our population to decide who should underwent biopsy. most of the pi-rads 3 lesions in our cohort were located in the peripheral zone, independently of cspca results. liddell et al. showed that pi-rads 3 lesions within the pz were more likely to be associated with malignant disease compared with lesions identified within tz (10.8% vs. 3.8%) (21). yang et al. demonstrated in his study that pirads 3 lesions were most frequent in tz than pz (n = 67 and n = 54, respectively), however the cspca rate was superior in pz (18.5% vs. 6.0%, respectively) (22). galosi et al. defended a low risk of cancer in pi-rads 3 lesions located in tz; they concluded that biopsy could be omitted in same patients considering a nomogram with pca risk, psad, and lesion location (23). a systematic review and meta-analyses of a total of 17 articles showed no systematic difference of cancer detection rate between pz lesions and tz lesions in different pi-rads classifications (24). schoots et al. explain that mpmri interpretation of tz is more challenging comparative to pz because the tz shows heterogeneous signal intensities due to presence of nodules of benign prostatic hyperplasia while a normal pz is brightly hyperintense on t2 images and hypointense abnormalities can be easily identified. in case of pi-rads 3 lesions, the overlapping with benign situations often interpreted as false-positive mpmri findings (benign prostate hyperplasia, inflammation or fibrosis) are more common (25). this can explain the higher frequency of pi-rads 3 lesions on tz, however, it was not observed in our cohort. our study has several limitations. it is a retrospective study, from a single institution and with limited pi-rads 3 lesions enrolled which may have resulted in possible risk of selection bias. it included patients from 2017 to 2022 and some lesions were classified as intermediate probability using criteria from version 2 and others with version 2.1. therefore, the possibility of a bias of interpretation is higher given that the mpmri reports are reviewed by multiple readers, with an interobserver variability of identification and classification of the lesions. biopsies were also performed by different urologists with different experience and biopsy specimens were evaluated by multiple pathologists. it was not possible to compare the results with other approaches, namely transperineal biopsy or fusion guided software, to analyse differences in cspca detection. our definition of cspca considered only the gleason/isup score without any interpretation on basis in lesion volume. larger studies, prospective and randomized, are required to evaluate the reproducibility of our results. conclusions we have demonstrated in our cohort that prostate lesions characterized as pi-rads 3 lesions, according to the current prevalent scoring systems, were associated with a low likelihood of the cspca detection. a systematic biopsy associated or not with a target biopsy is essential in pirads 3 lesions, and targeted biopsy did not demonstrate to be superior in the detection of cspca. the presence of abnormal dre and lesions localized in pz potentially predict the presence of cspca in biopsied pi-rads 3 lesions. references 1. ahmed hu, el-shater bosaily a, brown lc, et al. diagnostic accuracy of multi-parametric mri and trus biopsy in prostate cancer (promis): a paired validating confirmatory study. the lancet. 2017; 389:815-22. 2. rouvière o, puech p, renard-penna r, et al. use of prostate systematic and targeted biopsy on the basis of multiparametric mri in biopsy-naive patients (mri-first): a prospective, multicentre, paired diagnostic study. lancet oncol. 2019; 20:100-9. 3. van der leest m, cornel e, israël b, et al. head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study. eur urol. 2019; 75:570-8. 4. drost fjh, osses df, nieboer d, et al. prostate mri, with or without mri-targeted biopsy, and systematic biopsy for detecting prostate cancer. cochrane database syst rev. 2019; 4:cd012663. 5. barentsz jo, richenberg j, clements r, et al. esur prostate mr guidelines 2012. eur radiol. 2012; 22:746-57. 6. turkbey b, rosenkrantz ab, haider ma, et al. prostate imaging reporting and data system version 2.1: 2019 update of prostate imaging reporting and data system version 2. eur urol. 2019; 76:340-51. 7. eau guidelines. edn. presented at the eau annual congress milan 2023. isbn 978-94-92671-19-6. 8. weinreb jc, barentsz jo, choyke pl, et al. pi-rads prostate imaging reporting and data system: 2015, version 2. eur urol. 2016; 69:16-40. 9. oerther b, engel h, bamberg f, sigle a, gratzke c, benndorf m. cancer detection rates of the pi-radsv2.1 assessment categories: systematic review and meta-analysis on lesion level and patient level. prostate cancer prostatic dis. 2022; 25:256-63. 10. schoots ig, padhani ar. risk-adapted biopsy decision based on prostate magnetic resonance imaging and prostate-specific antigen density for enhanced biopsy avoidance in first prostate cancer diagnostic evaluation. bju int. 2021; 127:175-8. 11. maggi m, panebianco v, mosca a, et al. prostate imaging archivio italiano di urologia e andrologia 2023; 95(4):11830 d. araújo, a. gromicho, j. dias, s. bastos, r. miguel maciel, a. sabença, l. xambre 6 reporting and data system 3 category cases at multiparametric magnetic resonance for prostate cancer: a systematic review and meta-analysis. eur urol focus. 2020; 6:463-78. 12. maggi m, panebianco v, mosca a, et al. prostate imaging reporting and data system 3 category cases at multiparametric magnetic resonance for prostate cancer: a systematic review and meta-analysis. eur urol focus. 2020; 6:463-78. 13. ullrich t, quentin m, arsov c, et al. risk stratification of equivocal lesions on multiparametric magnetic resonance imaging of the prostate. j urol. 2018; 199:691-8. 14. park kj, choi sh, lee js, et al. risk stratification of prostate cancer according to pi-rads® version 2 categories: meta-analysis for prospective studies. j urol. 2020; 204:1141-9. 15. hansen nl, barrett t, lloyd t, et al. optimising the number of cores for <scp>magnetic resonance imaging</scp> guided targeted and systematic transperineal prostate biopsy. bju int. 2020; 125:260-9. 16. cash h, günzel k, maxeiner a, et al. prostate cancer detection on transrectal ultrasonography-guided random biopsy despite negative real-time magnetic resonance imaging/ultrasonography fusionguided targeted biopsy: reasons for targeted biopsy failure. bju int. 2016; 118:35-43. 17. wegelin o, exterkate l, van der leest m, et al. the future trial: a multicenter randomised controlled trial on target biopsy techniques based on magnetic resonance imaging in the diagnosis of prostate cancer in patients with prior negative biopsies. eur urol. 2019; 75:582-90. 18. venderink w, van luijtelaar a, bomers jgr, et al. results of targeted biopsy in men with magnetic resonance imaging lesions classified equivocal, likely or highly likely to be clinically significant prostate cancer. eur urol. 2018; 73:353-60. 19. sheridan ad, nath sk, syed js, et al. risk of clinically significant prostate cancer associated with prostate imaging reporting and data system category 3 (equivocal) lesions identified on multiparametric prostate mri. ajr am j roentgenol. 2018; 210:347-57. 20. radtke jp, wiesenfarth m, kesch c, et al. combined clinical parameters and multiparametric magnetic resonance imaging for advanced risk modeling of prostate cancer—patient-tailored risk stratification can reduce unnecessary biopsies. eur urol. 2017; 72:888-96. 21. liddell h, jyoti r, haxhimolla hz. mp-mri prostate characterised pirads 3 lesions are associated with a low risk of clinically significant prostate cancer a retrospective review of 92 biopsied pirads 3 lesions. curr urol. 2015; 8:96-100. 22. yang s, zhao w, tan s, et al. combining clinical and mri data to manage pi-rads 3 lesions and reduce excessive biopsy. transl androl urol. 2020; 9:1252-61. 23. galosi ab, palagonia e, scarcella s, et al. detection limits of significant prostate cancer using multiparametric mr and digital rectal examination in men with low serum psa: up-date of the italian society of integrated diagnostic in urology. arch ital urol androl. 2021; 93:92-100. 24. oerther b, engel h, bamberg f, et al. cancer detection rates of the pi-radsv2.1 assessment categories: systematic review and metaanalysis on lesion level and patient level. prostate cancer prostatic dis. 2022; 25:256-63. 25. schoots ig. mri in early prostate cancer detection: how to manage indeterminate or equivocal pi-rads 3 lesions? transl androl urol. 2018; 7:70-82. correspondence débora araújo, md deboracerqueiraaraujo@gmail.com jorge dias, md josh_dias@hotmail.com samuel bastos, md samuel.sbastos@hotmail.com rui miguel maciel, md rui.painhas.maciel@chvng.min-saude.pt ana sabença, md anasofiassg@gmail.com luís xambre, md xambreluis@gmail.com urology department, centro hospitalar vila nova de gaia/espinho epe, vila nova de gaia, portugal alexandre gromicho, md alexandrepgromicho@gmail.com urology department, centro hospitalar do funchal, madeira, portugal conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12661 1 original paper impairment of the external urethral sphincter, predominantly resulting from radical prostate cancer treatment (2). irrespective of its underlying causes, sui significantly diminishes the quality of life for those who experience it (3-9). the primary approach for managing male sui involves pelvic floor muscle training, biofeedback, and electrical stimulation. if these conservative methods prove ineffective, surgical interventions are the only available alternative (1-16). in 1973, the artificial urinary sphincter (aus) was initially developed to address male moderate-to-severe sui, eventually establishing itself as the preferred treatment for this pathology (17-19). however, the process of inserting an aus remains intricate and carries the potential for complications such as erosion, infection, and mechanical failure. introduced in 1983, the last version of american medical systems (ams) 800 device stands as the gold standard of aus and continues to be utilized to this day (4, 5, 9, 12). while it has demonstrated favorable long-term outcomes, it is important to note that the preparation and execution of the procedure remain intricate, carrying a potential risk of complications. in instances of postoperative urethral atrophy, it is not feasible to readjust the cuff, and once activated, there are no available options to modify the pressure of the device (4, 5, 9, 13-16, 20). the success of the procedure relies heavily on the meticulous preparation of the sphincter, proper connection of its components, and the surgeon's expertise, considering the lengthy learning curve. the majority of aus insertions are performed by surgeons who only conduct a few procedures (between 1 and 3) per year. less than 10% of aus insertions in the usa are carried out by surgeons who have completed at least 100 procedures, which indicates a lower level of experience (21). as a result, the likelihood of requiring additional surgery increases from 13% to 24% (22). the purpose of designing zephyr surgical implants (zsi) 375 is to simplify the process of inserting the aus. the first implantation of zsi 375 took place in march 2009, making it a relatively recent innovation (23). the cuff is adaptable and placed around the urethra, already connected beforehand. additionally, zsi 375 eliminates the need for an abdominal reservoir, leading to reduced operating time and avoiding the requirement for abdominal purpose: radical prostate cancer treatment is the predominant cause of iatrogenic stress urinary incontinence (sui) in men, significantly impacting their quality of life (qol). this prospective single-center study in portugal aimed to evaluate the outcomes of men with moderateto-severe sui treated with a single-component artificial urinary sphincter (aus). materials and methods: male patients with iatrogenic moderateto-severe sui, determined by a 24-hour pad weight test, were included. the single-component device comprises a cuff linked to a pump unit through a kink-resistant tube. the implantation involved perineal incision for cuff placement and an inguinal incision for pump and tank positioning within the scrotum. complications, pad usage, perioperative complications (claviendindo classification), and quality of life assessment using the international consultation on incontinence questionnaire-short form (iciq-sf) questionnaire were documented. results: between may 2021 and march 2023, 20 consecutive single-component aus insertions were conducted at a portuguese urology department. follow-up concluded in july 2023, with a mean follow-up duration of 15 months (range: 5-27). four patients experienced complications necessitating device revision or removal (erosion = 2, infection = 1, mechanical failure = 1). social continence (0/1 pad/day) was achieved in 70% (14/20 patients), while 30% (6/20 patients) experienced incontinence. perioperatively, one patient was classified as grade 2, while the remaining were grade 0/1 in the claviendindo classification. the mean iciq-sf score reduction was 10.5 points. conclusions: the single-component aus shows promising efficacy in managing moderate-to-severe male sui, offering a good success rate, acceptable complications, improved qol, and a straightforward surgical procedure. key words: artificial urinary sphincter; zephyr surgical implants 375; male stress urinary incontinence; radical prostatectomy; quality of life. submitted 13 may 2024; accepted 6 june 2024 introduction the prevalence of urinary incontinence (ui) in men can reach up to 39% and tends to rise with advancing age (1). the primary cause of stress urinary incontinence (sui) among adult men is commonly attributed to iatrogenic single-component artificial urinary sphincter: outcomes from one centre in portugal joão aragão vital 1, miguel marques monteiro 1, bernardo lobão teixeira 1, gonçalo grilo mendes 1, alexandra rocha 1, mariana madanelo 1, sofia mesquita 1, nuno vinagre 1, beatriz oliveira 1, martinha magalhães 1, ana isabel lopes 1, carlos ferreira 2, paulo príncipe 1, avelino fraga 1 1 centro hospitalar universitário de santo antónio (chudsa), porto, portugal; 2 centro hospitalar universitário de são joão (chusj), porto, portugal. doi: 10.4081/aiua.2024.12661 summary archivio italiano di urologia e andrologia 2024; 96(3):12661 j. aragão vital, m. marques monteiro, b. lobão teixeira, et al. 2 incision and dissection in previously scarred retroperitoneum. by increasing the pressure, it enhances the patient's continence (10, 24). we conducted an analysis of the outcomes of the aus zsi 375 implantation for stress urinary incontinence in 20 male patients, and its influence on the individual's quality of life (qol). materials and methods patients the study employed a prospective, non-randomized design and was conducted at a single urological department in portugal. between may 2021 and march 2023, 20 consecutive placements of the aus zsi 375 were performed in male patients presenting iatrogenic moderate to severe sui as determined by the 24-hour pad weight test. the procedures were carried out by two experienced surgeons. prior to surgery, the pre-operative protocol encompassed patient history assessment, physical examination, urinalysis, cystoscopy to rule out stenosis, a 24hour pad weight test, and urodynamics to exclude overactive bladder. all patients had previously undergone pelvic floor muscle training. in preparation for the surgical procedures, all patients completed the international consultation on incontinence questionnaire-short form (iciq-sf questionnaire). the study was approved by the ethical committee of our center. all study participants provided written informed consent. zsi 375 device the zsi 375 is a single-component device made up of a cuff linked to a pump unit through a kink-resistant tube. the adaptable cuff is designed in a curved shape to prevent creasing. it is positioned around the urethra, while the pump unit, which includes a pressure-regulating tank and pump, is situated within the scrotum, specifically in the subdartos pouch. it has no abdominal reservoir. once activated, the hydraulic circuit's pressure can be adjusted up or down to enhance the patient's continence (25). the improved hydraulic system of the zsi 375 pf (pre-filled) has been in use since march 2015, and it is anticipated that the reduced operating time will lead to decreased infection and mechanical failure rates (25). surgical procedure the implantation surgical procedure was carried out under general anesthesia with the patient in the lithotomy position. the surgical technique consists in a perineal incision for cuff placement and an inguinal incision for pump and tank placement in the scrotum. a 14 fr foley urethral catheter is placed for guidance and was removed by routine in the day after surgery. the device was activated six weeks later. follow-up after implantation the scheduled appointments occurred at intervals of 1, 3, and 6 months following device activation, with subsequent annual appointments. patients documented their daily pad usage in a 7-day diary prior to each visit. the follow-up process was concluded in july 2023. total continence was defined as the absence of any pad usage, while social continence was characterized by the use of 1 pad per day. incontinence was ascribed to individuals who required > 1 pad per day. success was defined as achieving social continence, which encompassed the range of pad usage from 0 to 1 per day. perioperative complications were classified using the clavien-dindo classification system. the quality of life was evaluated by means of the iciq-sf questionnaire, administered both before the surgical procedure and during the follow-up period subsequent to device activation. additionally, a subjective assessment of patient satisfaction was documented. results patient characteristics a total of 20 patients had the zsi 375 device implanted, with a mean (range) follow-up of 15 (5-27) months. the averaged (range) patient age was 71.5 (62-80) years old. the indications were incontinence following radical prostatectomy (rp, n = 11), rp and radiotherapy (n = 8) and transurethral resection of prostate (turp, n = 1). five (25%) patients with a 24h pad weight test between 200-400g and 15 (75%) > 400g. the mean (range) iciqsf score before surgery was 20,8 (17-21) points. the mean (range) operative time was 69 (35-100) minutes, and the mean hospital stay was 1 day with catheter removal on the same day. the device was activated six weeks later by routine. complications complications leading to a revision or permanent device removal arose in 4 patients: 2 erosions of the urethra with device explantation, 1 infection and 1 mechanical failure both with device re-implantation. perioperatively, one patient was classified as grade 2, while the remaining were classified as grade 0 or 1 in the clavien-dindo classification (table 1). pressure adjustment in 5 (25%) patients, there was a need for device pressure adjustment under radiographic control, in an outpatient setting, to improve continence. efficacy three (15%) patients achieved total continence (0 pads per day), 11 (55%) social continence (1 pad per day), and table 1. the aetiology of the incontinence and complications. aetiology infections urethral erosions mechanical complications of incontinence n (%) n (%) n (%) rp (11 patients) 0 1 (9.1) 1 (9.1) rp+rt (8 patients) 1 (12.5) 1 (12.5) 0 turp (1 patients) 0 0 0 total (20 patients) 1 (5) 2 (10) 1 (5) rp: radical prostatectomy; rt: radiotherapy; turp: transurethral resection of prostate. archivio italiano di urologia e andrologia 2024; 96(3):12661 3 single-component artificial urinary sphincter 6 (30%) experienced incontinence (> 1 pad per day), resulting in an overall success rate of 70% (total and social continence). the mean (range) iciq-sf score after surgery was 10,5 (0-18) points with a mean reduction of 10,3 points in a scale from 0-21. the grade of satisfaction with the device was 75% (table 2). discussion in this study, we present our short-term experience with 20 patients who received the zsi 375 aus. over a median follow-up period of 15 months, the overall success rate, encompassing total and social continence, reached 70%. while the aus ams 800 currently stands as the gold standard therapy for moderate to severe sui in men, concerns regarding its complexity, time-consuming nature, inability to adjust device pressure, and the challenge of cuff readjustment in cases of postsurgical urethral atrophy have arisen (4). the zsi 375 device represents a relatively recent addition to this field. our study highlighted the simplicity of the surgical procedure, even during the early stages of the learning curve, with notably short surgical times. one significant advantage of this device lies in its capacity to adjust internal pressures using the in situ trans-scrotal applicator within an office outpatient setting, offering the potential for improved outcomes post-surgery. enhanced management of pressure escalation following activation is expected to reduce the incidence of urethral erosion (25). in our study, this procedure was necessary for five patients. regrettably, as of the conclusion date, it has not been possible to assess post-adjustment outcomes. the most frequent complication observed was urethral erosion, which affected 2 (10%) of the patients, a rate comparable to that of ams 800 (11, 16, 24, 26, 27). notably, one of these two patients had undergone previous radiotherapy, a well-recognized adverse factor for sphincter insertion (28). the second patient was catheterized in primary healthcare following a suspected episode of urinary retention, indicating a potential iatrogenic cause. mechanical failure necessitating device re-implantation occurred in 1 (5%) patient during the early stages of the study, likely attributed to the surgeons' relative inexperience with implanting this new device. this rate is also in line with that reported for the ams 800 (12, 24, 27). our overall complication rate aligns with that of other reported series involving zsi 375 implantations (10, 23-25, 29, 30). assessment of qol using the iciq-sf questionnaire revealed a significant improvement, and a high level of patient satisfaction with the device was noted, possibly attributable to its simplicity. finally, this study has limitations, including a short follow-up duration and a small patient cohort. some patients with prior ams 800 aus procedures underwent surgery, and the study was conducted during the early stages of the surgical learning curve. additionally, utilizing the weight pad test after device activation may offer a more accurate measure for assessing real improvements in incontinence. conclusions in this short-term follow-up study, the zsi 375 aus demonstrated effectiveness in the management of moderate to severe male sui, exhibiting a commendable success rate while maintaining a low incidence of complications. the qol was evaluated using the iciq-sf questionnaire, revealing a significant improvement. notably, the surgical procedure proved to be straightforward with a brief learning curve. in conclusion, the zsi 375 aus emerges as a promising treatment option for moderate to severe sui in male patients. references 1. bauer rm, gozzi c, hübner w, et al. contemporary management of postprostatectomy incontinence. eur urol. 2011; 59:985-996. 2. shamliyan ta, wyman jf, ping r, et al. male urinary incontinence: prevalence, risk factors, and preventive interventions. rev urol. 2009; 11:145-165. 3. park hk, chang s, palmer mh, et al. assessment of the impact of male urinary incontinence on health-related quality of life: a population based study. low urin tract symptoms. 2015; 7:22-26. 4. ostrowski i, sledz e, ciechan j, et al. current interventional management of male stress urinary incontinence following urological procedures. cent european j urol. 2015; 68:340-347. 5. james mh, mccammon ka. artificial urinary sphincter for postprostatectomy incontinence: a review. int j urol. 2014; 21:536-543. 6. sousa-escandón a, cabrera j, mantovani f, et al. adjustable suburethral sling (male remeex system) in the treatment of male stress urinary incontinence: a multicentric european study. eur urol. 2007; 52:1473-1479. 7. leruth j, waltregny d, de leval j. the inside-out transobturator male sling for the surgical treatment of stress urinary incontinence after radical prostatectomy: midterm results of a single-center prospective study. eur urol. 2012; 61:608-615. 8. kim sw, walsh r, berger y, kim jh. male readjustable sling (mrs) system for postprostatectomy incontinence: experiences of 2 centers. urology. 2016; 88:195-200. 9. van der aa f, drake mj, kasyan gr, et al. young academic urologists functional urology group. the artificial urinary sphincter after a quarter of a century: a critical systematic review of its use in male non-neurogenic incontinence. eur urol. 2013; 63:681-689. 10. ostrowski i, blewniewski m, neugart f, et al. multicentre experience with zsi 375 artificial urinary sphincter for the treatment of stress urinary incontinence in men. urologia. 2017; 84:148-152. table 2. the efficacy after the implantation of the zsi 375. total continence social continence incontinence 0 pads per day (%) 1 pad per day (%) > 1 pad per day (%) moderate sui (5 patients) 1 (20) 3 (60) 1 (20) 200-400g 24h pad weight test severe sui (15 patients) 2 (13.3) 8 (53.3) 5 (33.3) > 400g 24h pad weight test total (20 patients) 3 (15) 11 (55) 6 (30) overall success 14 (70) archivio italiano di urologia e andrologia 2024; 96(3):12661 j. aragão vital, m. marques monteiro, b. lobão teixeira, et al. 4 11. hajivassiliou ca. a review of the complications and results of implantation of the ams artificial urinary sphincter. eur urol. 1999; 35:36-44. 12. herschorn s, bruschini h, comiter c, et al. surgical treatment of stress incontinence in men. neurourol urodyn. 2010; 29:179-190. 13. clemens jq, schuster tg, konnak jw, et al. revision rate after artificial urinary sphincter implantation for incontinence after radical prostatectomy: actuarial analysis. j urol. 2001; 166:1372-5. 14. petrou sp, elliott ds, barrett dm. artificial urethral sphincter for incontinence. urology. 2000; 56:353-359. 15. elliott ds, barrett dm. mayo clinic long-term analysis of the functional durability of the ams 800 artificial urinary sphincter: a review of 323 cases. j urol. 1998; 159:1206-8. 16. lai hh, hsu ei, teh bs, et al. 13 years of experience with artificial urinary sphincter implantation at baylor college of medicine. j urol. 2007; 177:1021-1025. 17. scott fb, bradley we, timm gw. treatment of urinary incontinence by an implantable prosthetic urinary sphincter. j urol. 1974; 112:75-80. 18. lucas mg, bosch rj, burkhard fc, et al. eau guidelines on surgical treatment of urinary incontinence. eur urol. 2012; 62:11181129. 19. herschorn s. the artificial urinary sphincter is the treatment of choice for post-radical prostatectomy incontinence. can urol assoc j. 2008; 2:536-539. 20. vakalopoulos i, kampantais s, laskaridis l, et al. new artificial urinary sphincter devices in the treatment of male iatrogenic incontinence. adv urol. 2012; 2012:439372. 21. wilson sk, aliotta pj, salem ea, mulcahy jj. new enhancements of the scrotal one-incision technique for placement of artificial urinary sphincter allow proximal cuff placement. j sex med. 2010; 7:3510-3515. 22. sandhu js, maschino ac, vickers aj. the surgical learning curve for artificial urinary sphincter procedures compared to typical surgeon experience. eur urol. 2011; 60:1285-1290. 23. ostrowski i, golabek t, ciechan j, et al. preliminary outcomes of the european multicentre experience with the zsi 375 artificial urinary sphincter for treatment of stress urinary incontinence in men. cent european j urol. 2019; 72:263-269. 24. staerman f, g-llorens c, leon p, leclerc y. zsi 375 artificial urinary sphincter for male urinary incontinence: a preliminary study. bju int. 2013; 111:e202-e206. 25. ostrowski i, ciechan j, sledz e, et al. four-year follow-up on a zephyr surgical implants 375 artificial urinary sphincter for male urinary incontinence from one urological centre in poland. cent european j urol. 2018; 71:320-325. 26. venn sn, greenwell tj, mundy ar. the long-term outcome of artificial urinary sphincters. j urol. 2000; 164:702-707. 27. kim sp, sarmast z, daignault s, et al. long-term durability and functional outcomes among patients with artificial urinary sphincters: a 10-year retrospective review from the university of michigan. j urol. 2008; 179:1912-1916. 28. queissert f, huesch t, kretschmer a, et al. artificial urinary sphincter cuff size predicts outcome in male patients treated for stress incontinence: results of a large central european multicenter cohort study. int neurourol j. 2019; 23:219-225. 29. llorens c, pottek t. urinary artificial sphincter zsi 375 for treatment of stress urinary incontinence in men: 5 and 7 years follow-up report. urologia. 2017; 84(4):263-266. 30. ostrowski i, sledz e, wilamowski j, et al. patients' quality of life after implantation of zsi 375 artificial urinary sphincter due to stress urinary incontinence. cent european j urol. 2020; 73:178-186. correspondence joão aragão vital, md joaopvital@gmail.com miguel marques monteiro, md mmonteiro.iam@gmail.com bernardo lobão teixeira, md bernardolat@gmail.com gonçalo grilo mendes, md goncalo.grilomendes@gmail.com alexandra rocha, md marialexandrarocha@gmail.com mariana madanelo, md marianacmadanelo@gmail.com sofia mesquita, md sofiaoplmesquita@gmail.com nuno vinagre, md nunomrvinagre@gmail.com beatriz oliveira, md ana.bia.5@hotmail.com martinha magalhães, md martinha.a.magalhaes@gmail.com ana isabel lopes, bsc analopes.urodinamica@chporto.min-saude.pt paulo príncipe, md paulo.principe@gmail.com avelino fraga, md phd avfraga@gmail.com urology department, santo antónio university hospital center largo do prof. abel salazar, 4099-001 porto, portugal carlos ferreira, md carlosferreira.esr@gmail.com centro hospitalar universitário de são joão (chusj) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(1):12179 1 original paper information on youtube about some urological pathologies. in particular, the quality of information about neoplastic bladder disease has been evaluated (2, 3). bladder cancer is the 10th most frequent cancer in the world (4). a high number of patients with this disease use social media for information and support (5). the quality of information available on youtube about this disease appears mostly moderate or poor (2) and this leads to a high risk of disinformation for users. other social media, such as twitter, also collect information about this disease (6). the therapeutic opportunities and the possible surgical indication determine a strong emotional impact for these patients, for instance, the possible urinary diversion after radical cystectomy. the possibility of obtaining reliable information about these aspects, using social tools such as youtube, therefore, appears an important factor in the path of understanding and acceptance of the pathology by these patients. youtube platform is very dynamic with thousands of hours of contents up-loaded per second. deep learning has recently had a huge impact on the youtube video recommendations system, therefore, youtube’s algorithm selects output based on different factors like user’s history and context (7, 8). nowadays, the absence of information about the characteristics of youtube users has not allowed authors who investigated this field to evaluate the impact of these videos on patient’s decision making (2), furthermore we have no data about the quality of information related to youtube user’s profile. the primary end point of this paper is to evaluate quality of informations available on the youtube platform in 2023, with focus on informations about the bladder cancer treatment, evaluating the relation between numbers of views and other point of interest, such as age of the videos, level of misinformation, discern score and pemat-av score. authors also wanted to explore a secondary endpoint in order to evaluate the differences in term of quality of information and level of disinformation of contents background: social media are widely used information tools, including the medical/health field. unfortunately, the levels of misinformation on these platforms seem to be high, with a medium-low quality of the proposed content, as evidenced by previous studies. you tube is one of the most important platforms for audio/video content. it shows content to users through a recommendation algorithm system. materials and methods: we have classified in two cohorts the first results obtained by researching "bladder tumor treatment" on you tube through two different user profiles: "cohort a" with a not logged-in session in incognito mode (46 videos enrolled) and "cohort b" with a logged-in session with a physician profile (50 videos enrolled). the videos were evaluated using validated instruments such as discern and pemat-av furthermore, we used a likert’s scale for the evaluation of levels of misinformation. results: overall quality of information was moderate to poor (discern 3) in 54% of cohort a and 24% of cohort b. moreover, a high degree of misinformation (likert score 3) was found in 52% of cohort a cases and 32% of cohort b. conclusions: levels of misinformation in both cohorts are positively correlated to the number of views per month. globally, the levels of information quality, understandability and actionability are lower for the results obtained from searches performed with anonymous user profile (cohort a). key words: bladder cancer; youtube; misinformation; social media; bladder. submitted 11 december 2023; accepted 24 december 2023 introduction since youtube platform was established, on february 14th 2005, the world of information and communication has been revolutionized. this social media is a widely used tool, with more than 1.5 billion users (1), allowing to find information on many areas of interest. the quality of information available on youtube is evoking considerable interest in scientific literature in recent years. several authors have already assessed the reliability of the quality of bladder cancer treatment information on youtube: may the user’s profile affect the quality of results? pier paolo prontera 1, francesca romana prusciano 2, marco lattarulo 1, emanuele utano 1, francesco schiralli 1, carmine sciorio 3, lorenzo romano 4, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto, italy; 2 department of emergency and organ transplantation-urology, andrology and kidney transplatation unit, university of bari, bari, italy; 3 department of urology, “alessandro manzoni” hospital of lecco, lecco, italy; 4 department of neurosciences, reproductive sciences and odontostomatology, university of naples “federico ii”, naples, italy. doi: 10.4081/aiua.2024.12179 summary archivio italiano di urologia e andrologia 2024; 96(1):12179 p. paolo prontera, f. romana prusciano, m. lattarulo, et al. 2 emerged from researches made by different user’s profile (in particular comparing the results obtained using a logged-in session with a physician profile (urologist) with those obtained using a not logged-in session (in incognito mode). materials and methods youtube algorithm was queried independently of the two different authors, on november 19th, 2023, at 10 o'clock. the keywords used were: "bladder tumor treatment". authors used two different user setting: a logged-in session with a physician profile (urologist) and a not loggedin session in incognito mode. we decided to exclude from the analysis advertising video and ten "very short videos", which by definition can be a maximum of 60 seconds long and should be a minimum of 15 seconds long, without any information about number of views and comments. we received first 60 videos for both cohorts so we enrolled 50 videos in the first cohort (logged-in session with physician profile) and 46 videos in the second cohort (not logged-in session in incognito mode). were excluded ten and fourteen videos respectively in the two groups, given the exclusion criteria. all contents enrolled were analysed using validate instruments: the patient education materials assessment tool for audio-video (pemat-av) and discern quality criteria for consumer health information (9, 10). the patient education materials assessment tool (pemat) is a systematic method to evaluate and compare the understandability and actionability of patient education materials. it is designed as a guide to help determine whether patients will be able to understand and act on information. separate tools are available for use with print and audiovisual materials (11). discern is a brief questionnaire which provides users with a valid and reliable way of assessing the quality of written information on treatment choices for a health problem. discern can also be used by authors and publishers of information on treatment choices as a guide to the standard which users are entitled to expect (12). moreover, we rated the level of misinformation using a likert scale (13). we also evaluated other parameters according to other authors (2): length of video (less than 4 minutes, 4 to 20 minutes, or more than 20 minutes), presence of advertising during viewing, age of video, number of views, type of publisher (academic journal/company, commercial/industrial, consumer/patient, physician, foundation, health/wellness channel, hospital/clinic, medical education, news, source/media outlet, professional society, university, other), number of thumbs-up and thumbs-down, audience (anyone/public, medical education), audience (any/general public, patients, healthcare providers, caregivers), characters in the video (animation/drawing, celebrity/public figure, doctor/healthcare professional, patient, other). we also assessed the relation between numbers of views (globally and per months) and other variables using pearson correlation coefficients. we also evaluated the total number of comments per video. analysis for both cohorts lasted twelve days. results from now on the group of videos searched using the user profile not logged-in and with session in incognito mode will be called "cohort a", and the group of videos obtained using logged-in physician user profile will called "cohort b" (table 1). the total length of videos was 271.31 minutes (median length of 5.51 minutes) for the cohort a and 268.45 minutes (with a median length of 5.35 minutes) for cohort b. the majority of the videos was less than 4 minutes in both cohorts (43.5% and 56% respectively). the median numbers of views for both groups were respectively 19.6k and 57.5k for cohort a and cohort b, with a median age of each videos calculated of 5.21 and 3.66 years respectively. a median of 111.65k thumbs up were found in the cohort a and 545.24k in cohort b. while no thumbs down were funded in both cohorts. most of the contents in cohort a was aimed at anyone (83%) and to healthcare providers (15%). only 1% of contents of the cohort a was specifically for patients. table 1. property of the analysed youtube® videos. value cohort a cohort b lenght of video total lenght 271.31 268.45 median lenght (h:min:sec) (range) 5.51 (0.49-51.04) 5.36 (48.3-0.52) less than 4 min. (n°) 20 (43.5%) 28 (56%) 4-20 min. (n°) 19 18 more than 20 min., n° (%) 6 4 views, median (range) 19.6k (26-247k) 57.5k (0-362k) thumbs up, median (range) (tot) 111.65 (0-2.39k) (4801k) 545,24 (0-3.58k) (27.26k) thumbs down, median (range) 0 (0) 0 (0) comment, median (range) (tot) 35.3 (0-196) (1658) 43.4 (0-242) (2040) intended audience, n° (%) anyone 38 (83%) 37 (74%) specifically for patients 1 (2%) 12 (24%) healtcare providers 7 (15%) 1 (2%) caregivers 0 0 (0) others 0 0 (0) publisher type, n° (%) academic journal/company 6 (13%) 0 (0) commercial/industry 1 (2%) 4 (8%) consumer/patient 0 (0) 0 (0) doctor 11 (24%) 4 (8%) foundation 2 (4%) 9 (18%) healt/wellness channel 15 (33%) 11 (22%) hospital/clinic 5 (11%) 6 (12%) medical/education 0 (0) 8 (16%) news source/media 1 (2%) 2 (4%) professional society 4 (9%) 3 (6%) university 0 (0) 2 (4%) others 1 (2%) 1 (2%) who is in?, n° (%) doctor/healthcare professional 40 (87%) 34 (68%) others 6 (13%) 16 (32%) presence of advertising, n° (%) 18 (39%) 13 (26%) presence of “very short videos” 4 (9%) 3 (6%) median age of the videos (years) 5.21 3.66 archivio italiano di urologia e andrologia 2024; 96(1):12179 3 bladder cancer treatment information on youtube similar results emerged from the analysis of cohort b with the 74% of contents directed to anyone, but with an inversion of proportion regarding healthcare providers and patients (2% and 24% respectively). doctors or health care professional were the most frequent characters in the contents in both cohorts (87% for cohort a and 68% for cohort b). the presence of advertisements that interrupted the viewing of the video was found in 39% of cases in cohort a and in 26% of cases in cohort b. according to the discern score, the quality of information was moderate to poor for the cohort a (median range 42.4) and moderate to high for the cohort b (median range 59.56), and the score 1 appears in 13% of the cohort a while it was never present in the cohort b. moreover, in both groups the discern most representative score was 4 with a prevalence of 64% for the cohort b instead of the 29% for the cohort a. in the cohort a the understandability score and the actionability score, calculated using pemat-av tool, were median to poor (respectively 49% and 44%), whereas the same parameters were evaluated moderate to high for the cohort b (respectively 76% and 77.7%). the application of a likert scale revealed a low level of misinformation in cohort b if compared with cohort a. in particular, we found 28% vs 6% of score 5 and 0% vs 27% of score 1, in cohort b and a respectively (table 2). application of pearson correlation coefficients highlighted a moderate positive correlation between overall views and the level of misinformation, considering cohort b, and a weak negative correlation considering cohort a for the same factors. the relation between overall views and pemat-av score (understandability and actionability both) was weakly positive for both groups, while we discovered a weak negative correlation between overall views and discern score for the cohort b versus a weak positive correlation found for the cohort a (table 3). investigating relationships of discern score, pemat-av score and misinformation levels to the views per months, we found a strong negative correlation between discern score and views per months in cohort b and a weak positive correlation in cohort a (table 4). these findings are in line with the results of other authors (2, 3). discussion social media today represent a mass information tool also regarding the demand for information in the healthcare sector. the same health professionals (healthcare professionals) use social media for scientific dissemination. unfortunately, the massive presence of disinformation on the web is a serious social problem (2, 14), which, in our opinion, can have an impact both on the psychological sphere of the patient undergoing medical treatment, especially if it is invasive, and on the ability of the professional to convey the appropriate information in the most correct way. in recent years several authors have investigated the quality and levels of misinformation present in content published on various social media, through the use of validated tools (9, 10, 13], showing a high percentage of erroneous content in the publications (2, 3, 14). youtube is one of the leading platforms for visual audio content and uses a search algorithm that, thanks to deep learning, offers results selected according to the characteristics of the user and his activity on the site (8). therefore, we decided to evaluate the results obtained from the research of "bladder tumor treatment" performed through two different user accounts: cohort a and cohort b. overall, the quality of the contents obtained in cohort b was higher (96% of medium-high quality compared to 69% obtained in cohort a). on average the contents of cohort b have higher levels of understandability and table 2. results of analysis with validated tools (discern, pemat-av). value cohort a cohort b discern overall rating, n° (%) 1 6 (13%) 0 (0) 2 8 (17%) 2 (4%) 3 11 (24%) 10 (20%) 4 13 (29%) 32 (64%) 5 8 (17%) 6 (12%) discern sum (median range) 42.4 (19-78) 59.56 (22-76) pemat-av, median (range) understandability 49% (0-100) 76% (0-100%) actionability 44% (0-100) 77.7% (0-100%) misinformation score (likert scale) no. (%) 1 3 (6%) 14 (28%) 2 15 (32%) 20 (40%) 3 10 (22%) 10 (20%) 4 6 (13%) 6 (12%) 5 12 (27%) 0 (0%) table 3. correlation between the number of total views and the variables examined. tot view variables pearson index (r) (n°) cohort a cohort b * age of the video 0.144 (weak) 0.25 (weak) * misinformation (likert scale) -0.028 (weak) 0.400 (moderate) * discern score 0.166 (weak) -0.252 (weak) * pemat-av understandability 0.009 (weak) 0.150 (weak) * pemat-av actionability 0.031 (weak) 0.170 (weak) * rounded to the three decimal places. table 4. correlation between the number of views/month and the variables examined. view per variables pearson index (r) month (n°) cohort a cohort b * age of the video -0.26 (weak) 0.25 (weak) * misinformation (likert scale) 0.012 (weak) 0.007 (weak) * discern score 0.153 (weak) -0.75 (strong) * pemat-av understandability -0.004 (very weak) -0.550 (moderate) * pemat-av actionability 0.073 (weak) 0.097 (weak) * rounded to the three decimal places. archivio italiano di urologia e andrologia 2024; 96(1):12179 p. paolo prontera, f. romana prusciano, m. lattarulo, et al. 4 actionability (76% and 77.7% respectively compared to 49% and 44% observed in cohort a) (table 5). this data seems to confirm that the same search performed by a user profile closely related to the field of interest of the search, returns results of higher quality and with higher level of understandability and actionability. however, this could be a contradiction because if on the one hand it is logical for the algorithm to propose higher quality videos based on the level of affinity of the user profile to the search, on the other hand it seems controversial to show videos with a lower level of understandability and actionability to an average user not associated with a health profile and therefore potentially with a lower ability to understand the content. as for the level of misinformation, obtained through the use of a likert scale, our data are almost in line with previous published studies. in fact, the calculation of the linear correlation coefficient shows a positive correlation between the number of views of the videos and their degree of misinformation; this is particularly evident and relevant if we look at the results obtained by relating the number of total views and the degree of misinformation in cohort b, which is associated with the average health profile. this correlation becomes weakly negative if we consider the results obtained with the same variables in cohort a. this might seem like a paradox since from this data we could deduce that the videos with more views proposed by the youtube algorithm to a health profile are at the same time those with a higher degree of misinformation. if instead we consider as variable the visualizations for month this correlation becomes weakly positive in both cohorts. it is also interesting to note that there is a strong negative correlation between the number of views per month and the discern score in cohort b, unlike a weak positive correlation present in cohort a. from this, we could then deduce that the videos proposed to the user with health profile with a higher number of views per month are actually those with lower quality. on average, enlisted videos have a medium-low quality level of 30% and 4% in cohorts a and b respectively. this figure is apparently not in line with the findings of other authors (2, 3) who report a low average quality level of about 67% (2) and 66,7% (3). this discrepancy, however, could be linked to different research criteria: in the study of garcía cano fernández et al. videos were enlisted exclusively in spanish and with a duration of less than four minutes, which instead represent 43,5% and 56% of cohorts a and b respectively in our paper. in the paper by loeb at al. videos with a range of duration from 21 seconds to 76 minutes were enlisted. however, in both papers, the type of user profile from which the search was made has not been specified and this, in our opinion, represents an important limitation. the limitations of this study are linked to the exclusive use of youtube, and not of other social media, although this platform represents the mainly used. another limit, as probably for all the studies presented on this issue to date, is intrinsically related to the huge number of variables that affect the results offered by youtube’s algorithm. the evaluation of the results obtained by two profiles with deeply different characteristics (medical profile and anonymous profile) is a first step in the understanding and interpretation of the health information offered to users on social media, and the consequent impact on the clinical practice of these instruments. conclusions according to our study, in accordance with the literature data available today, the level of misinformation of the youtube’s contents about bladder cancer treatment is positively related to the number of views per month. the same search performed by a user profile related to the field of interest of the search itself offers higher quality results. the quality of information provided by youtube regarding bladder cancer therapy, as well as levels of understandability and actionability, is, in general, medium-low if the research is performed with anonymous profile (cohort a), while such results are reversed if the research is performed by a profile with high level of affinity with the field of interest of the research. this could be an important step in better understanding the correlation between the results suggested by youtube's video recommendation algorithm and the characteristics of the user profile from which the search is performed. we also hope that future studies will investigate the positive correlation that appears to exist between higher levels of misinformation and more views. references 1. borgmann h, cooperberg m, murphy d, et al. online professionalism— 2018 update of european association of urology (@uroweb) recommendations on the appropriate use of social media. eur urol 2018; 74: 644-50. 2. loeb s, reines k, abu-salha y, et al. quality of bladder cancer information on youtube. eur urol. 2021; 79:56-59. 3. garcía-cano-fernández am, szczesniewski-dudzik jj, garcíatello a, et al. quality of bladder cancer information on youtube. cent european j urol. 2022; 75:248-251. 4. international agency for research on cancer. bladder cancer globocan. in: https://gco.iarc.fr/today/data/factsheets/cancers/30-bladder-fact-sheet.pdf2018. 5. kamat am, agarwal p, bivalacqua t, et al. collaborating to move research for-ward: proceedings of the 10th annual bladder cancer think tank. bladder cancer 2016; 2:203-13. 6. tariq a, khan sr, vela i, williams ed. assessment of the use of the internet and social media among people with bladder cancer and their carers, and the quality of available patient-centric online. bju int. 2019; 123(suppl 5):10-18. table 5. spread of contents about treatment of bladder tumor on youtube®. cohort a cohort b moderate to poor quality (discern ≤ 3) 54% 24% high misinformation (likert score ≥ 3) 52% 32% high understandability (> 50%) 49% 76% high actionability (> 50%) 44% 77.7% archivio italiano di urologia e andrologia 2024; 96(1):12179 5 bladder cancer treatment information on youtube 7. covington c, adams j, sargin e. deep neural networks for youtube recommen-dations. recsys '16: proceedings of the 10th acm conference on recom-mender systems 2016; pp. 191-198. 8. davidson j, liebald b, liu j, et al. the youtube video recommendation system. in proceedings of the fourth acm conference on recommender sys-tems, recsys’10, pages 293-296, new york, ny, usa, 2010. acm. 9. ahrq. the patient education materials assessment tool (pemat) and user’s guide. https://www.ahrq.gov/professionals/preventionchronic-care/improve/self-mgmt/pemat/pemat-av.html. 10. charnock d, shepperd s, needham g, gann r. discern: an instrument for judging the quality of written consumer health information on treatment choices. j epidemiol commun health 1999; 53:105-11. 11. available from: http://www.ahrg.gov/healt-literacy/patient-education/pemat.html 12. available from: http://www.discern.org.uk 13. herbert as, nemirovsky a, hess ds, et al. pelvic organ prolapse on youtube: evaluation of consumer information. bju int. 2020; 125:759-760. 14. fode m, jensen cfs, østergren pb. how should the medical community respond to the low quality of medical information on social media? eur urol. 2021; 79:60-61. correspondence pier paolo prontera, md (corresponding author) pierpaolo.prontera@asl.taranto.it marco lattarulo, md marco.lattarulo@asl.taranto.it emanuele utano, md emanuele.utano@asl.taranto.it francesco schiralli, md francesco saverio grossi, md, phd grossifs@libero.it department of urology, “s.s. annunziata” hospital, taranto (italy) via bruno francesco 1 74010 taranto (italy) francesca romana prusciano, md department of emergency and organ transplantation, urology, andrology and kidney transplantation unit, university of bari, 70124 bari (italy) carmine sciorio, md carminesciorio@gmail.com department of urology, “alessandro manzoni” hospital of lecco, lecco (italy) lorenzo romano, md loryromano@hotmail.it department of neurosciences, reproductive sciences and odontostomatology, university of naples “federico ii”, 80131 naples (italy) conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14129 1 original paper introduction urinary tract infections (utis) are among the most common bacterial infections globally, with over 150 million cases reported annually (1, 2). they impose a significant clinical and economic burden on healthcare systems, ranging from uncomplicated cystitis to severe conditions such as pyelonephritis and urosepsis (1). the severity of clinical presentation often reflects the extent of disease progression (3). gram-negative bacteria, particularly escherichia coli (e. coli), remain the predominant uropathogens worldwide. however, recent epidemiological trends indicate a growing prevalence of non-e. coli organisms, including klebsiella pneumoniae (k. pneumoniae), pseudomonas aeruginosa (p. aeruginosa), and staphylococcus aureus (s. aureus), which complicates empirical treatment decisions and highlights the need for continuous surveillance (4, 5). the emergence of antimicrobial resistance (amr), especially multidrug-resistant (mdr) and extensively drug-resistant (xdr) strains, has further complicated the management of utis (6). mdr is defined as resistance to at least three antimicrobial classes, while xdr refers to resistance to all but two or fewer antimicrobial classes (7). these resistance patterns are particularly concerning in resource-limited settings, where inadequate antimicrobial stewardship and limited diagnostic infrastructure contribute to the rapid dissemination of resistant organisms (7). key molecular mechanisms underlying resistance include the production of extended-spectrum β-lactamases (esbls), carbapenemases (e.g., kpc and ndm), and the overexpression of efflux pumps. these mechanisms are associated with treatment failure, prolonged hospital stays, increased healthcare costs, and higher mortality rates (8). background: urinary tract infections (utis) are a major global health concern, particularly in resource-limited regions where antimicrobial resistance (amr) is increasingly prevalent. this study aimed to describe the demographic characteristics, pathogen distribution, and antimicrobial resistance patterns among uti patients, and to identify clinical predictors of multidrug-resistant (mdr) and extensively drug-resistant (xdr) infections. methods: a retrospective analysis was conducted on 216 clinically confirmed uti cases processed at the infectious bacteriology and biochemistry laboratory affiliated with ibb university between january 2023 and september 2024. data collected included patient demographics, clinical symptoms, comorbidities, bacterial isolates, and antimicrobial susceptibility profiles. mdr and xdr were classified according to internationally recognized definitions. univariate and multivariate logistic regression analyses were performed to identify independent predictors of mdr/xdr infections. results: the majority of patients were adults aged 15-65 years (83.3%, n = 180), with a slight male predominance (53.2%, n = 115). escherichia coli was the most frequently isolated pathogen (29.6%, n = 64), followed by staphylococcus aureus (19.0%, n = 41) and pseudomonas aeruginosa (6.0%, n = 13). a substantial proportion of isolates exhibited mdr or xdr phenotypes (80.1%, n = 173). among e. coli isolates, resistance rates to ciprofloxacin and ceftriaxone exceeded 60%. notably, all klebsiella pneumoniae isolates were mdr (100%), and 92.3% of p. aeruginosa isolates were mdr. nitrofurantoin and carbapenems demonstrated relatively higher susceptibility rates. multivariate analysis identified prior hospitalization (adjusted odds ratio [aor] = 3.15; 95% ci: 1.50-6.60; p = 0.002) and e. coli infection (aor = 2.41; 95% ci: 1.02–5.70; p = 0.04) as significant predictors of mdr/xdr infections. conclusions: the high prevalence of mdr and xdr uropathogens, particularly e. coli, underscores the urgent need for sustained antimicrobial resistance surveillance and stewardship programs in resource-limited settings. identifying key clinical predictors can inform empirical treatment strategies, improve patient outcomes, and help contain the spread of resistant organisms. epidemiology and antimicrobial resistance of uropathogens in a tertiary care setting in yemen: a retrospective study faisal ahmed 1, ennayyat alhamdani 1, saleh al-wageeh 2, qasem alyhari 2, saif ghabisha 2, ahmed ateik 3, khalil al-naggar 1, ibrahim alnadhari 4, 5, abdulghani al-hagri 6 1 department of urology, school of medicine, ibb university, ibb, yemen; 2 department of general surgery, school of medicine, ibb university, ibb, yemen; 3 department of general surgery, school of medicine, 21 september university, sana'a, yemen; 4 al wakra hospital, hamad medical corporation, al wakra, qatar; 5 department of surgery, college of medicine, qatar university, doha, qatar; 6 student research committee, faculty of medicine, sana'a university, sana'a, yemen. doi: 10.4081/aiua.2025.14129 summary key words: urinary tract infections; uropathogenic escherichia coli; antimicrobial resistance; multidrug resistance (mdr); extensively drug-resistant (xdr); yemen; resource-limited setting. submitted 10 july 2025; accepted 27 july 2025 archivio italiano di urologia e andrologia 2025; 97(3):14129 f. ahmed, e. alhamdani, s. al-wageeh, et al. 2 in yemen, the inappropriate use of antibiotics is a major driver of amr. a prior study in aden reported that antibiotics were prescribed in 84.2% of outpatient cases, a rate far exceeding world health organization (who) recommendations (9). this issue is compounded by the widespread availability of counterfeit and substandard medicines. it is estimated that up to 80% of pharmaceuticals entering yemen are distributed through unregulated channels, with approximately 40% being of poor quality or counterfeit (10). according to who analyses, 43% of counterfeit antibiotics contain no active ingredient, 24% fail to meet quality standards, 21% contain subtherapeutic concentrations, and 7% contain incorrect substances (11). the combination of irrational prescribing practices and the proliferation of ineffective antimicrobials creates a conducive environment for the emergence and spread of resistant uropathogens. patients exposed to subtherapeutic or inactive treatments are at increased risk of treatment failure, facilitating the persistence and transmission of resistant strains in the community (12). despite national efforts to monitor amr, there remains a significant gap in data regarding the distribution and resistance profiles of uropathogens in yemen, particularly in tertiary care settings. this lack of local evidence limits the development of context-specific treatment guidelines and infection control strategies. understanding the demographic and clinical factors associated with mdr and xdr utis – such as prior hospitalization, comorbidities, and healthcare exposure – is essential for improving patient outcomes and informing antimicrobial stewardship programs (12). this study aimed to describe the demographic characteristics, pathogen distribution, and antimicrobial resistance patterns among uti cases at a tertiary referral laboratory in ibb, yemen. additionally, it sought to identify clinical predictors of mdr and xdr infections to support evidence-based prescribing and enhance regional amr surveillance. patients and methods study design and setting this retrospective observational study was conducted at the infectious bacteriology and biochemistry (ibb) laboratory, affiliated with ibb university, located in ibb city, yemen. the ibb laboratory functions as a tertiary referral center, receiving clinical specimens from diverse patient populations across multiple healthcare facilities. the study period spanned from january 1, 2023, to september 12, 2024. study population the study included all patients with clinically confirmed utis whose urine samples were processed at the ibb laboratory during the specified timeframe. a uti was defined as the presence of typical clinical symptoms – such as dysuria, urinary frequency, and urgency – accompanied by a positive urine culture yielding ≥ 105 colonyforming units per milliliter (cfu/ml) of a single uropathogen. this definition aligns with internationally recognized diagnostic criteria for uti (e.g., ema and fda guidelines) (13). patients with contaminated samples (mixed flora), or duplicate isolates from the same infection episode were excluded. consecutive sampling was employed to minimize selection bias, resulting in a final sample of 216 eligible cases. sample collection and microbiological analysis midstream urine specimens were collected using standardized aseptic techniques to reduce contamination risk. initial screening was performed using urine dipstick tests to detect leukocyte esterase and nitrites, which are suggestive of infection. however, dipstick results were not used as diagnostic criteria. samples were inoculated onto cled agar, blood agar, and macconkey agar and incubated aerobically at 35-37°c for 18-24 hours. bacterial growth was quantified, and isolates with ≥ 105 cfu/ml were considered clinically significant. bacterial identification was performed using a combination of conventional biochemical tests and automated systems, including vitek 2 (biomérieux, durham, nc, usa) (14). where available, matrix-assisted laser desorption/ionization time-of-flight (maldi-tof) mass spectrometry was used for confirmatory identification. antimicrobial susceptibility testing antimicrobial susceptibility testing (ast) was conducted in accordance with the clinical and laboratory standards institute (clsi) guidelines (31st edition) (15). the kirbybauer disk diffusion method and/or broth microdilution techniques were used to determine susceptibility to a panel of antibiotics commonly used in uti treatment, including fluoroquinolones, β-lactams, aminoglycosides, nitrofurantoin, and carbapenems. minimum inhibitory concentrations (mics) were interpreted using clsi clinical breakpoints. mdr was defined as resistance to at least one agent in three or more antimicrobial classes, while xdr was defined as resistance to all but two or fewer antimicrobial classes, based on international consensus definitions (7). quality control was maintained by including reference strains such as e. coli atcc 25922 in each testing batch to ensure the validity and reproducibility of results. data collection and management relevant demographic, clinical, and microbiological data were extracted from the laboratory information system and patient medical records using a standardized data collection form. double data entry and cross-validation were performed to ensure accuracy and minimize transcription errors. all data were anonymized prior to analysis. patient confidentiality was maintained throughout the study in accordance with institutional ethical standards and the principles of the declaration of helsinki. statistical analysis data were analyzed using ibm spss statistics version 23 (ibm corp., armonk, ny, usa). descriptive statistics were used to summarize demographic, clinical, and microbiological variables. categorical variables were expressed as frequencies and percentages, while continuous variables were reported as means ± standard deviations (sd) or medians with interquartile ranges (iqr), depending on archivio italiano di urologia e andrologia 2025; 97(3):14129 3 uropathogens in yemen data distribution. group comparisons were performed using the chi-square (χ²) test or fisher’s exact test for categorical variables, and the student’s t-test or mannwhitney u test for continuous variables, following normality assessment using the shapiro-wilk test. variables with a p-value < 0.20 in univariate analysis were included in a multivariable logistic regression model to identify independent predictors of mdr/xdr utis. adjusted odds ratios (aor) with 95% confidence intervals (ci) were calculated. multicollinearity was assessed using the variance inflation factor (vif), with values > 5 indicating significant collinearity. model calibration was evaluated using the hosmer-lemeshow goodness-of-fit test, with a p-value > 0.05 indicating adequate fit. discriminatory ability was assessed using the area under the receiver operating characteristic curve (auc), with values between 0.7 and 0.8 considered acceptable. a two-tailed p-value < 0.05 was considered statistically significant for all analyses. ethical considerations the study protocol was reviewed and approved by the institutional ethics committee of ibb university (approval no. ibbuni.ac.yem.2024.79). given the retrospective nature of the study and the use of anonymized data, the requirement for informed consent was waived. all procedures were conducted in accordance with the ethical standards of the institutional research committee and the declaration of helsinki. results demographic and clinical characteristics a total of 216 patients with clinically confirmed utis were included in the study. the majority were adults aged 15-65 years, comprising 180 patients (83.3%). pediatric patients aged 1-14 years accounted for 24 patients (11.1%), while geriatric patients over 65 years represented 12 patients (5.6%) (table 1). males slightly outnumbered females, with 115 (53.2%) and 101 (46.8%) patients, respectively. most patients presented with symptomatic utis (91.7%, n = 198), while 8.3% (n = 18) had asymptomatic bacteriuria. comorbidities were present in 32.4% of patients. diabetes mellitus was the most common (19.4%, n = 42), followed by other chronic conditions such as hypertension, chronic kidney disease, or immunosuppression (13.0%, n = 28). the remaining 67.6% (n = 146) had no documented comorbidities. a history of prior hospitalization within the last six months was reported in 26.9% (n = 58) of cases. the prevalence of mdr or xdr infections was high across all age groups: 75.0% (18/24) in pediatric patients, 81.1% (146/180) in adults, and 83.3% (10/12) in geriatric patients. however, these differences were not statistically significant (p = 0.12). similarly, no significant difference in mdr/xdr prevalence was observed between males (79.1%, 91/115) and females (82.2%, 83/101) (p = 0.45). symptomatic patients had an mdr/xdr prevalence of 80.8% (160/198), compared to 77.8% (14/18) in those with asymptomatic bacteriuria (p = 0.62). patients with diabetes mellitus exhibited a higher mdr/xdr prevalence (88.1%, 37/42) compared to those without comorbidities (78.1%, 114/146), though this difference was not statistically significant (p = 0.08). in contrast, prior hospitalization was significantly associated with mdr/xdr utis (89.7% vs. 77.2%, p = 0.02), highlighting its importance as a risk factor (table 1). pathogen distribution and resistance profiles a total of 216 bacterial isolates were identified. e. coli was the most frequently isolated pathogen (29.6%, n = 64), followed by s. aureus (19.0%, n = 41), p. aeruginosa (6.0%, n = 13), and k. pneumoniae (5.6%, n = 12) (table 2). other gram-negative organisms accounted for 24.1% (n = 52) of isolates, while other gram-positive species represented 15.7% (n = 34). overall, 56.0% (n = 121) of isolates were classified as mdr, and 25.9% (n = 56) as xdr. the highest mdr rates were observed in k. pneumoniae (100.0%, 12/12), followed by p. aeruginosa (92.3%, 12/13), e. coli (81.3%, 52/64), and s. aureus (73.2%, 30/41). xdr rates were also notable in k. pneumoniae (50.0%, 6/12), p. aerugitable 1. demographic and clinical characteristics of patients with urinary tract infections and their association with multidrug-resistant/extensively drug-resistant status (n = 216). characteristic category n (%) mdr/xdr cases n (%) p-value age group pediatric (1–14 years) 24 (11.1) 18 (75.0) 0.12 * adult (15–65 years) 180 (83.3) 146 (81.1) geriatric (> 65 years) 12 (5.6) 10 (83.3) sex male 115 (53.2) 91 (79.1) 0.45 * female 101 (46.8) 83 (82.2) clinical presentation symptomatic uti 198 (91.7) 160 (80.8) 0.62 * asymptomatic bacteriuria 18 (8.3) 14 (77.8) comorbidities diabetes mellitus 42 (19.4) 37 (88.1) 0.08 * hypertension 15 (6.9) 12 (80.0) 0.83 * chronic kidney disease 8 (3.7) 7 (87.5) 0.50 ** immunocompromised 5 (2.3) 4 (80.0) 1.00 ** none (reference) 146 (67.6) 114 (78.1) — prior hospitalization yes 58 (26.9) 52 (89.7) 0.02 * no 158 (73.1) 122 (77.2) * chi-square test; ** fisher’s exact test (used for small cell counts). mdr/xdr percentages represent the proportion of resistant cases within each subgroup. archivio italiano di urologia e andrologia 2025; 97(3):14129 f. ahmed, e. alhamdani, s. al-wageeh, et al. 4 nosa (38.5%, 5/13), s. aureus (24.4%, 10/41), and e. coli (18.8%, 12/64) (table 2). antimicrobial resistance patterns antibiotic susceptibility testing revealed high resistance rates to several commonly used agents (table 3). ciprofloxacin resistance was observed in 64.8% (140/216) of isolates, with particularly high rates among e. coli (78.1%, 50/64) and p. aeruginosa (84.6%, 11/13). ceftriaxone resistance was detected in 75.9% (164/216) of isolates, especially among k. pneumoniae (91.7%, 11/12). gentamicin resistance was present in 52.8% (114/216) of isolates, with the highest rate observed in p. aeruginosa (76.9%, 10/13). nitrofurantoin resistance was relatively low, affecting 28.8% (57/198) of tested isolates. enterococcus faecalis demonstrated the lowest nitrofurantoin resistance (12.0%, 3/25). meropenem resistance was observed in 13.4% (29/216) of isolates, with a notably higher rate among k. pneumoniae (33.3%, 4/12) (table 3). resistance phenotype classification based on resistance phenotypes, 17.6% (n = 38) of isolates were non-mdr, 56.0% (n = 121) were mdr, 25.9% (n = 56) were xdr, and 0.5% (n = 1) were pandrugresistant (pdr) (table 4). among e. coli isolates, 18.8% (12/64) were non-mdr, 62.5% (40/64) were mdr, and 18.8% (12/64) were xdr. for s. aureus, 26.8% (11/41) were non-mdr, 48.8% (20/41) were mdr, and 24.4% (10/41) were xdr. p. aeruginosa isolates were predominantly mdr (53.8%, 7/13) or xdr (38.5%, 5/13). no pdr isolates were identified among these species, with the exception of one acinetobacter baumannii isolate (table 4). predictors of mdr/xdr urinary tract infections multivariable logistic regression analysis identified two independent predictors of mdr/xdr utis (table 5). infection with e. coli was significantly associated with an increased risk of mdr/xdr status aor = 2.41; 95% ci, 1.02-5.70; p = 0.04). prior hospitalization within the last six months was also a strong predictor (aor = 3.15; 95% ci, 1.50-6.60; p = 0.002). in contrast, age over 65 years (aor = 1.82; 95% ci, 0.388.72; p = 0.45) and female sex (aor = 0.91; 95% ci, 0.44-1.89; p = 0.80) were not significantly associated table 3. antimicrobial resistance profiles of uropathogens (n = 216 isolates). antibiotic (class) resistant isolates overall pathogens with n (%) resistance rate high resistance (>75%) ciprofloxacin (fluoroquinolone) 140 (64.8) 64.8% escherichia coli ceftriaxone (3rd-gen cephalosporin) 164 (75.9) 75.9% klebsiella pneumoniae gentamicin (aminoglycoside) 114 (52.8) 52.8% pseudomonas aeruginosa nitrofurantoin (nitrofuran) 57/198 (28.8) 28.8% enterococcus faecalis (low resistance) meropenem (carbapenem) 29 (13.4) 13.4% klebsiella pneumoniae 3rd-gen = third-generation cephalosporin. high resistance defined as > 75% resistance rate among isolates tested. nitrofurantoin was not tested against pseudomonas spp. (n = 13) and non-uti pathogens (n = 5). table 2. frequency and resistance patterns of uropathogens isolated from patients with urinary tract infections (n = 216 isolates). pathogen frequency n (%) mdr cases n (%) xdr cases n (%) escherichia coli 64 (29.6) 52 (81.3) 12 (18.8) staphylococcus aureus 41 (19.0) 30 (73.2) 10 (24.4) pseudomonas aeruginosa 13 (6.0) 12 (92.3) 5 (38.5) klebsiella pneumoniae 12 (5.6) 12 (100.0) 6 (50.0) other gram-negative spp. * 52 (24.1) 38 (73.1) 14 (26.9) other gram-positive spp. ** 34 (15.7) 22 (64.7) 9 (26.5) mdr = resistance to ≥ 3 antimicrobial classes; xdr = resistance to all but ≤ 2 classes. * includes proteus spp. (n = 9), enterobacter spp. (n = 8), citrobacter spp. (n = 6), and others (n = 29). ** includes enterococcus spp. (n = 17), streptococcus spp. (n = 5), and other species (n = 12). overall mdr rate = 56.0% (121/216); xdr rate = 25.9% (56/216). table 4. resistance phenotypes of major uropathogens isolated from patients with utis (n = 216 isolates). pathogen non-mdr n (%) mdr n (%) xdr n (%) pdr n (%) escherichia coli 12 (18.8) 40 (62.5) 12 (18.8) 0 (0.0) staphylococcus aureus 11 (26.8) 20 (48.8) 10 (24.4) 0 (0.0) pseudomonas aeruginosa 1 (7.7) 7 (53.8) 5 (38.5) 0 (0.0) klebsiella pneumoniae 0 (0.0) 6 (50.0) 6 (50.0) 0 (0.0) total 38 (17.6) 121 (56.0) 56 (25.9) 1 (0.5) mdr = resistance to ≥3 antimicrobial classes; xdr = resistance to all but ≤ 2 classes; pdr = resistance to all tested agents. one acinetobacter baumannii isolate was classified as pandrug-resistant (pdr). archivio italiano di urologia e andrologia 2025; 97(3):14129 5 uropathogens in yemen with mdr/xdr status. diabetes mellitus showed a nonsignificant elevation in odds (aor = 1.95; 95% ci, 0.824.65; p = 0.13), which should be interpreted cautiously. model diagnostics indicated adequate fit (hosmerlemeshow test, p = 0.62) and moderate discriminative ability (area under the curve = 0.72; 95% ci, 0.65-0.79) (table 5). discussion pathogen distribution and resistance trends this study reveals a high prevalence of mdr and xdr uropathogens among patients with utis, consistent with emerging trends in both regional and global contexts (2, 16). e. coli was the most frequently isolated pathogen, accounting for 29.6% of cases, which aligns with data from across africa and other lowand middle-income countries (lmics) (17-19). the predominance of e. coli as a uropathogen is well-documented, and its high rates of mdr (81.3%) and xdr (18.8%) phenotypes in this study mirror findings from sub-saharan africa and other resource-constrained settings (10, 18-20). this trend is largely driven by the global spread of extended-spectrum beta-lactamase (esbl)-producing strains, which significantly limit therapeutic options and complicate clinical management (21, 22). similarly, the elevated resistance observed in k. pneumoniae (100% mdr, 50% xdr) and p. aeruginosa (92.3% mdr, 38.5% xdr) reflects a broader pattern of increasing antimicrobial resistance among gram-negative pathogens in utis (10, 23-25). the universal resistance of k. pneumoniae to ampicillin is consistent with its intrinsic resistance mechanisms, including chromosomal beta-lactamase production and the acquisition of plasmid-mediated esbls and carbapenemases (23). these enzymatic defenses severely restrict antibiotic choices and underscore the need for enhanced surveillance and stewardship. resistance to commonly prescribed antibiotics such as ciprofloxacin (64.8%) and ceftriaxone (75.9%) was notably high, consistent with reports from saudi arabia, iran, and other parts of africa, where fluoroquinolone and third-generation cephalosporin resistance often exceed 60% (2, 3, 17, 26, 27). in contrast, nitrofurantoin and carbapenems retained relatively higher susceptibility rates (71.2% and 86.6%, respectively), supporting their continued use as empirical treatment options in selected cases (28, 29). however, the emergence of carbapenem resistance – particularly among k. pneumoniae isolates (33%) – is concerning and highlights the urgent need for judicious use of last-resort antibiotics. risk factors for mdr/xdr infections multivariate analysis identified prior hospitalization (aor = 3.15; 95% ci: 1.50-6.60; p = 0.002) and e. coli infection (aor = 2.41; 95% ci: 1.02-5.70; p = 0.04) as independent predictors of mdr/xdr utis. these findings are consistent with existing literature that links healthcare exposure to increased risk of resistant infections due to selective antibiotic pressure and nosocomial transmission (30, 31). the association between e. coli and mdr/xdr status may reflect the widespread dissemination of esblproducing strains in both community and hospital settings. this pathogen’s genetic adaptability and frequent exposure to antibiotics make it a key driver of resistance in utis (25). these findings emphasize the importance of targeted diagnostic approaches and tailored empirical therapy, particularly in high-risk populations. demographic and clinical characteristics although age and gender were not identified as a statistically significant predictor of mdr/xdr urinary tract infections in this study, the majority of patients were adults aged 15-65 years (83.3%), with a slight male predominance (53.2%). this contrasts with many regional studies that report a higher uti prevalence among females (26, 27, 32). the observed male predominance may be attributable to differences in healthcare-seeking behavior, referral patterns, or underlying comorbidities in this setting. notably, khanal et al. reported higher mdr rates among males, possibly due to increased antibiotic exposure in this group (33). these sex-specific trends warrant further investigation and should inform future risk stratification strategies. moreover, our findings align with regional epidemiological data from the middle east and north africa. amiri et al. reported that uti incidence peaked in younger adults, particularly females aged 20-24 and males aged 35-39, followed by a gradual decline with age (2). while our study did not observe a significant difference in mdr/xdr prevalence across age groups, the concentration of cases in the 15-65 age range is consistent with these regional patterns (2). this suggests that while age remains a key factor in uti epidemiology, the emergence of resistance may be influenced more by healthcare exposure and antibiotic use than by age alone. table 5. multivariable logistic regression analysis of predictors for multidrug-resistant and extensively drug-resistant urinary tract infections. predictor reference unadjusted or p-value adjusted or p-value vif category (95% ci) (95% ci) age > 65 years ≤ 65 years 1.42 (0.51–3.95) 0.50 1.82 (0.38–8.72) 0.45 1.12 female sex male 0.84 (0.45–1.56) 0.58 0.91 (0.44–1.89) 0.80 1.04 escherichia coli other pathogens 2.15 (1.12–4.13) 0.02 2.41 (1.02–5.70) 0.04 1.32 prior hospitalization no hospitalization 3.40 (1.78–6.50) < 0.001 3.15 (1.50–6.60) 0.002 1.18 diabetes mellitus no diabetes 2.01 (0.93–4.35) 0.08 1.95 (0.82–4.65) 0.13 1.21 model diagnostics: • hosmer-lemeshow test: p = 0.62 (indicating good model fit). • area under the curve (auc): 0.72 (95% ci: 0.65–0.79), indicating moderate discriminatory ability.. • variance inflation factor (vif): all values < 5, suggesting no significant multicollinearity. archivio italiano di urologia e andrologia 2025; 97(3):14129 f. ahmed, e. alhamdani, s. al-wageeh, et al. 6 although several factors previously reported to be associated with mdr urinary tract infections – such as prior antibiotic use, duration of catheterization, urological procedures and the presence of comorbidities – were not fully captured in our analysis due to the retrospective nature of the study, their role in the development of resistance remains well established (34-38). these patient-specific factors, along with broader determinants such as healthcare exposure and environmental influences, significantly contribute to the emergence and persistence of mdr and xdr uropathogens. in our study, a notably high proportion of patients with diabetes mellitus (88.1%) were affected by resistant infections, a finding that aligns with existing literature linking diabetes to increased susceptibility to complicated and antimicrobial-resistant utis (39). the underlying pathophysiology includes immune dysfunction due to chronic hyperglycemia, urinary stasis, and frequent healthcare contact, all of which facilitate bacterial colonization and the selection of resistant strains (40). these findings underscore the importance of targeted infection control measures and individualized antimicrobial strategies in high-risk populations, particularly those with chronic comorbidities such as diabetes mellitus. clinical and public health implications the findings of this study have important implications for clinical practice and public health policy. the high prevalence of mdr and xdr uropathogens – particularly e. coli – highlights the urgent need for continuous antimicrobial resistance surveillance and the implementation of stewardship programs in resource-limited settings. empirical treatment guidelines should be updated regularly to reflect local resistance patterns and minimize the risk of treatment failure. moreover, the emergence of carbapenem resistance in klebsiella spp. and other gram-negative pathogens signals a critical threat to available treatment options. this trend necessitates the development of novel therapeutic strategies and the reinforcement of infection prevention and control measures in both hospital and community settings. study limitations several limitations should be considered when interpreting the results of this study. first, its retrospective design limits the ability to control for confounding variables, and some clinical data may be incomplete or inconsistently documented. second, variations in uti definitions across studies may affect comparability. although our use of clinical symptoms combined with culture results aligns with current guidelines, misclassification – particularly in cases of asymptomatic bacteriuria – cannot be ruled out (41, 42). third, while antimicrobial susceptibility testing followed clsi guidelines, we did not systematically investigate specific resistance mechanisms such as esbl or carbapenemase production. this limits the depth of our resistance analysis and may obscure important epidemiological trends. fourth, the study was conducted at a single tertiary care center, which may limit the generalizability of the findings to primary care or community settings. finally, the study did not assess patient outcomes or treatment efficacy, which are essential for linking resistance patterns to clinical impact and guiding therapeutic decisions. conclusions in summary, this study highlights a high burden of mdr and xdr uropathogens in a resource-limited setting, with e. coli playing a central role in resistance dissemination. prior hospitalization and e. coli infection were identified as key predictors of resistant infections. these findings underscore the need for ongoing resistance monitoring, antimicrobial stewardship, and context-specific treatment guidelines to improve patient outcomes and curb the spread of antimicrobial resistance. references 1. mancuso g, midiri a, gerace e, et al. urinary tract infections: the current scenario and future prospects. pathogens. 2023; 12:623. 2. amiri f, safiri s, aletaha r, et al. epidemiology of urinary tract infections in the middle east and north africa, 1990-2021. trop med health. 2025; 53:16. 3. fakhri-demeshghieh a, shokri a, bokaie s. antibiotic resistance of uropathogenic escherichia coli (upec) among iranian pediatrics: a systematic review and meta-analysis. iran j public health. 2024; 53:508-23. 4. kapesa c, mumbula em, kwenda hc. prevalence of gram-negative bacterial causes of urinary tract infection and their antimicrobial susceptibility profile at the university teaching hospitals in lusaka, zambia. scientific african. 2025; 27:e02558. declarations ethical approval and consent for participate: the study protocol was reviewed and approved by the institutional review board (irb) of ibb university (approval code: ibbuni.ac.yem.2024.79, dated february 3, 2024). due to the retrospective nature of the study and the use of anonymized data, the requirement for informed consent was waived. the study was conducted in accordance with the principles of the declaration of helsinki. availability of data and material: the datasets analyzed during the current study are available in the mendeley data repository and can be accessed via the following doi: 10.17632/26hn6wmb8x.1. competing interests: the authors declare no conflicts of interest. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions: all authors contributed substantially to the conception, design, data acquisition, analysis, interpretation, and manuscript preparation. each author reviewed and approved the final version for submission and agreed to be accountable for all aspects of the work. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):14129 7 uropathogens in yemen 5. mouanga-ndzime y, bisseye c, longo-pendy nm, et al. trends in escherichia coli and klebsiella pneumoniae urinary tract infections and antibiotic resistance over a 5-year period in southeastern gabon. antibiotics (basel). 2024; 14:14. 6. prestinaci f, pezzotti p, pantosti a. antimicrobial resistance: a global multifaceted phenomenon. pathog glob health. 2015; 109:309-18. 7. magiorakos ap, srinivasan a, carey rb, et al. multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. clin microbiol infect. 2012; 18:268-81. 8. muteeb g, kazi rna, aatif m, et al. antimicrobial resistance: linking molecular mechanisms to public 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associated factors of urinary tract infection among patients attending nekemte comprehensive specialized hospital, western ethiopia, 2024: a cross-sectional study. bmc infect dis. 2025; 25:474. 19. que at, tran ad, trang thn, et al. epidemiology and antimicrobial resistance patterns of urinary tract infection: insights and strategies from a 5-year serial cross-sectional study in vietnam. ther adv infect dis. 2025; 12:20499361251315346. 20. ngai pv, dat th, nhi ly, et al. distribution and antifungal susceptibility of candida species causing vulvovaginal candidiasis and urinary tract infection in medlatec healthcare system, ha noi city, vietnam in 2023. ther adv infect dis. 2025; 12:20499361241311465. 21. farag pf, albulushi ho, eskembaji mh, et al. prevalence and antibiotic resistance profile of uti-causing uropathogenic bacteria in diabetics and non-diabetics at the maternity and children hospital in jeddah, saudi arabia. front microbiol. 2024; 15:1507505. 22. zhanel gg, pozdirca m, golden ar, et al. sulopenem: an intravenous and oral penem for the treatment of urinary tract infections due to multidrug-resistant bacteria. drugs. 2022; 82:533-57. 23. li j, shi y, song x, et al. mechanisms of antimicrobial resistance in klebsiella: advances in detection methods and clinical implications. infect drug resist. 2025; 18:1339-54. 24. pitout jd, laupland kb. extended-spectrum beta-lactamaseproducing enterobacteriaceae: an emerging public-health concern. lancet infect dis. 2008; 8:159-66. 25. l b, priya b, a e, p shenoy r. isolation and molecular characterization of multi-drug resistant uropathogenic escherichia coli from urine samples: insights into urinary tract infection management. the microbe. 2024; 5:100185. 26. mohanna ma, raja'a ya. frequency and treatment of urinary tract infection in children subjected to urine culture, in sana'a, yemen. j ayub med coll abbottabad. 2005; 17:20-2. 27. nasher ma, nasher tm, gunaid aa. etiologies of the urinary tract infections in a yemeni city. saudi med j. 2001; 22:599-602. 28. nakandi rm, kakeeto p, kihumuro rb, et al. antibiotic susceptibility patterns of bacterial uropathogens at a private tertiary hospital in uganda: a retrospective study. bmc infect dis. 2025; 25:605. 29. naidoo a, kajee a, mvelase nr, swe-han ks. antimicrobial susceptibility of bacterial uropathogens in a south african regional hospital. afr j lab med. 2023; 12:1920. 30. barré sl, weeda er, matuskowitz aj, hall ga, weant ka. risk factors for antibiotic resistant urinary pathogens in patients discharged from the emergency department. hosp pharm. 2022; 57:462-8. 31. rossignol l, maugat s, blake a, vaux s, heym b, le strat y, et al. risk factors for resistance in urinary tract infections in women in general practice: a cross-sectional survey. j infect. 2015; 71:302-11. https://doi.org/10.1016/j.jinf.2015.05.012. 32. ku jh, bruxvoort kj, salas sb, et al. multidrug resistance of escherichia coli from outpatient uncomplicated urinary tract infections in a large united states integrated healthcare organization. open forum infect dis. 2023; 10:ofad287. 33. khanal n, cortie ch, story c, et al. multidrug resistance in urinary e. coli higher in males compared to females. bmc urol. 2024; 24:255. 34. wright sw, wrenn kd, haynes m, haas dw. prevalence and risk factors for multidrug resistant uropathogens in ed patients. am j emerg med. 2000; 18:143-6. 35. mohamed ah, sheikh omar nm, osman mm, et al. antimicrobial resistance and predisposing factors associated with catheter-associated uti caused by uropathogens exhibiting multidrug-resistant patterns: a 3-year retrospective study at a tertiary hospital in mogadishu, somalia. trop med infect dis. 2022; 7(3). 36. alrasheedy m, abousada hj, abdulhaq mm, et al. prevalence of urinary tract infection in children in the kingdom of saudi arabia. arch ital urol androl. 2021; 93:206-10. archivio italiano di urologia e andrologia 2025; 97(3):14129 f. ahmed, e. alhamdani, s. al-wageeh, et al. 8 37. el-agamy ei, elhelaly ma, abouelgreed ta, et al. randomized comparison of effect of standard antibiotic prophylaxis versus enhanced prophylactic measures on rate of urinary tract infection after flexible ureteroscopy. arch ital urol androl. 2023; 95:11084. 38. cai t, tamanini i, kulchavenya e, et al. the role of nutraceuticals and phytotherapy in the management of urinary tract infections: what we need to know? arch ital urol androl. 2017; 89:1-6. 39. nitzan o, elias m, chazan b, saliba w. urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. diabetes metab syndr obes. 2015; 8:129-36. 40. chen sl, jackson sl, boyko ej. diabetes mellitus and urinary tract infection: epidemiology, pathogenesis and proposed studies in animal models. j urol. 2009; 182(6 suppl):s51-6. 41. bilsen mp, jongeneel rmh, schneeberger c, et al. definitions of urinary tract infection in current research: a systematic review. open forum infect dis. 2023; 10:ofad332. 42. nelson z, aslan at, beahm np, et al. guidelines for the prevention, diagnosis, and management of urinary tract infections in pediatrics and adults: a wikiguidelines group consensus statement. jama netw open. 2024; 7:e2444495. correspondence faisal ahmed (corresponding author) fmaaa2006@yahoo.com ennayyat alhamdani enayatalhamdani@gmail.com khalil al-naggar alnajjarkh1234@gmail.com department of urology, school of medicine, ibb university, ibb, yemen saleh al-wageeh alwajihsa78@gmail.com qasem alyhari qalyhary@hotmail.com saif ghabisha saifalighabisha@yahoo.com department of general surgery, school of medicine, ibb university, ibb, yemen ahmed ateik drahmedatik@gmail.com department of general surgery, school of medicine, 21 september university, sana'a, yemen ibrahim alnadhari ibrahimah1978@yahoo.com al wakra hospital, hamad medical corporation, al wakra, qatar & department of surgery, college of medicine, qatar university, doha, qatar abdulghani al-hagri alhagriabdulghani@gmail.com student research committee, faculty of medicine, sana'a university, sana'a, yemen stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12856 1 original paper sive, and there is a lack of well-defined strategies for patients whose metastatic penile carcinoma progresses or recurs after front-line cisplatin-based chemotherapy (4). the ability of tumor cells to evade the immune system is one of the many characteristics of tumor cells recognized as a hallmark of cancer (5). the programmed cell death 1 and its ligand (pd-1/pd-l1) pathway is one of the primary immune checkpoint targets that has been extensively studied in clinical research in recent years (6). pd-l1 acts as a co-stimulatory ligand, which, upon binding with its receptor pd-1, functions as a negative regulator of t-cell-mediated antitumor immunity (7). although pd-l1 expression is typically induced in cells of the macrophage lineage and t cells, abnormal pd-l1 expression has been detected in various types of cancer. this has led to the hypothesis that pd-l1 expression in either tumor cells or tumor-infiltrating immune cells (tiics) might facilitate tumor progression by inhibiting the antitumor immune response (7). currently, several clinical studies evaluating pd-1/pd-l1 inhibitors have been conducted in several different tumor types including melanoma, breast cancer, non-small-cell lung cancer, and head and neck cancer. pd-l1 expression has also been extensively studied in a number of urological malignancies such as bladder, kidney, and prostate cancer. however, there have been relatively few studies on pd-l1 expression in penile squamous cell carcinoma (8-10). given the aforementioned difficulty in treating recurrent and/or metastatic penile sqcc, the targeting of pd-l1 may offer a novel therapeutic avenue for those patients who exhibit pd-l1 expression upon recurrence or progression after first-line chemotherapy. the aim of our study is to investigate the association between pd-l1 immunoexpression as a combined positive score and clinical outcomes in penile squamous cell carcinoma. methods patients and samples we retrospectively reviewed all penile sqcc cases treated in our institution between 2018 and 2023. tumors were classified according to the 5th edition of the world health organization urinary and male genital tumors 2004 tnm classification. exclusion factors included a non-squamous cell carcinoma diagnosis and cases without available purpose: our objective was to investigate the association between programmed death-ligand (pd-l1) immunoexpression measured as a combined positive score and clinical outcomes in penile sqcc. materials and methods: we retrospectively reviewed all penile sqcc cases diagnosed in our institution between 2018 and 2023. pd-l1 immunohistochemistry was performed as a qualitative assay. immunoexpression in both tumor and immune cells equal or superior to 1 was considered positive. results: a total of 34 patients with conventional penile sqcc were included. eleven cases were hpv-associated (32.4%). twelve cases were pd-l1 cps < 1 and twenty-two were pd-l1 cps ≥ 1. nine cases (32.4%) were pd-l1 cps ≥ 1 and p16 positive, but this did not translate in worse clinicopathological features. larger tumors (3.0 cm in pd-l1 cps ≥ 1 vs 2.5 cm in pd-l1 cps < 1; p = 0.662), vascular invasion (36.4% in pd-l1 cps ≥ 1 vs. 25.0% in pd-l1 cps < 1; p = 0.705) and perineural invasion (40.9% in pd-l1 cps≥1 vs. 16.7% in pd-l1 cps < 1; p = 0.252) were associated with pd-l1 expression. among the high-risk features, only lymph node involvement had statistical significance, with 14 out of 22 pd-l1 cps ≥ 1 patients (63.6%) having lymph node metastases when lymphadenectomy was performed (p = 0.031). with a median follow-up of 16 months (iqr 27.5), pd-l1 cps ≥ 1 patients had worse overall survival (53.4 months vs 75.9 months), but no statistical significance could be inferred (p = 0.188). conclusions: it is noteworthy the clinical significance of lymph node involvement in pd-l1 cps ≥ 1 cases and a trend towards worse overall survival in this group of patients. key words: pd-l1; penile carcinoma; lymph node involvement; prognostic biomarker. submitted 25 july 2024; accepted 2 august 2024 introduction penile cancer (pc) is a rare form of cancer in western nations, with squamous cell carcinoma (sqcc) being the most common type, accounting for around 95% of cases (1) the global incidence of pc varies due to differences in socioeconomic and religious factors, representing less than 1% of all malignancies in western europe (2). regions with high rates of human papillomavirus (hpv) infection are most affected by penile cancer, with approximately one third to half of cases attributed to hpv-related causes (3). the management of penile cancer presents a significant challenge for clinicians. this malignancy is highly aggresprogrammed death-ligand expression and lymph node involvement in penile squamous cell carcinoma ines peyroteo 1, filipa santos 2, celso marialva 1, rodrigo ramos 1 1 portuguese institute of oncology in lisbon, urology, lisbon, portugal. 2 portuguese institute of oncology in lisbon, pathology, lisbon, portugal. doi: 10.4081/aiua.2024.12856 summary archivio italiano di urologia e andrologia 2024; 96(3):12856 i. peyroteo, f. santos, c. marialva, r. ramos 2 material for additional immunohistochemistry studies and without clinical follow-up. baseline patient and disease characteristics were assessed for the selected patients. all penile specimens were reviewed by a pathologist specialized in genitourinary pathology. all research was performed in accordance with relevant national and international regulations and informed consent to use the pathology material was obtained from all participants. the research was performed in accordance with the declaration of helsinki. immunohistochemistry pd-l1 expression was assessed by immunohistochemistry (ihc) in formalin-fixed, paraffin-embedded (ffpe) tumor samples at our institution. pd-l1 ihc 22c3 pharmdx assay was performed using a monoclonal mouse anti-pdl1 clone 22c3 and a validated protocol for ventana benchmark ultra platform. pd-l1 protein expression was determined by using a combined positive score (cps), counting the number of pd-l1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100 (e.g. if 1 staining cell was found out of 100 viable cells the score was 1/100 x 100 = 1). a minimum of 100 viable tumor cells was present in each stained slide for adequate pd-l1 evaluation. pd-l1 staining was evaluated as membranous tumor cell staining and membranous/cytoplasmic staining of mononuclear inflammatory cells (mics) within tumor nests and adjacent supporting stroma. pd-l1 cps ≥ 1 cases were considered when cps ≥ 1. also, in all cases before 2021 ihc for p16 was performed on ventana® benchmark ultra equipment with the ventana® optview dab ihc detection kit (ref 760-700). cc1 was used for antigen retrieval (ar) and anti-p16 (roche ventana® clone e6h4) was used. positive cases were considered if a strong block positivity for p16 was observed. statistical analysis continuous data were described by median and interquartile range (iqr). categorical data were presented by counts and percentages. comparisons between continuous data were performed by the mann-whitney u test and categorical data by pearson's chi-squared or fisher's exact test, accordingly. kaplan-meier curves were obtained to estimate the survival rates with statistical significance evaluated by the log-rank test. a p < 0.05 was defined as statistically significant. data was processed and analysed with ibm-spss software version 22.0. results patient characteristics a total of 34 patients were eligible for analysis in this study. the median age at diagnosis was 67 years (iqr 20). the median size of the tumor was 3.0 cm (iqr 3.3). among the patients, 11 were classified as hpv-associated (p16 positive). twenty-two cases were considered to be pd-l1 cps ≥ 1. the study uniformly recorded cases across all grades. regarding pathological stages, no pt1b tumors were observed, but all other stages were represented. a partial penectomy was performed in the majority of the cases (70.6%) and none of the patients had adjuvant treatments. clinicopathological and demographic characteristics of the cohort are presented in table 1. association of pd-l1 expression with clinicopathological features larger tumors (3.0 cm in pd-l1 cps ≥ 1 vs 2.5 cm in pdl1 cps < 1; p = 0.662), vascular invasion (36,4% in pdl1 cps ≥ 1 vs. 25,0% in pd-l1 cps < 1; p = 0.705) and perineural invasion (40.9% in pd-l1 cps ≥ 1 vs. 16,7% in pd-l1 cps < 1; p = 0.252) were associated with pdl1 expression, but with no statistical significance. twenty-three patients underwent lymphadenectomy, with lymph node involvement detected in 17 of them. among those with lymph node involvement, 16 patients were found to be pd-l1 cps ≥ 1. among the high-risk features, only lymph node involvement had statistical significance, with 14 out of 22 pd-l1 cps ≥ 1 patients (63.6%) having lymph node metastases when lymphadenectomy was performed (p = 0.031). these associations are presented in table 2. association of pd-l1 expression with survival outcomes: with a median follow-up of 16 months (iqr 27.5), pdl1 cps ≥ 1 patients had worse overall survival (53.4 table 1. clinical and pathological characteristics. characteristic total sample (n = 34) median age at surgery, yr 67 (iqr 20) high-risk hpv status, n (%) negative 23 (67.6%) positive 11 (32.4%) pd-l1 status, n (%) cps < 1 12 (35.3%) cps ≥ 1 22 (64.7%) median tumor size, cm 3 (iqr 3.3) tumor grade, n (%) 1 11 (32.4%) 2 14 (41.2%) 3 8 (23.5%) 4 1 (2.9%) vascular invasion, n (%) no 23 (67.6%) yes 11 (32.4%) perineural invasion, n (%) no 23 (67.6%) yes 11 (32.4%) pt stage, n (%) 1a 9 (26.5%) 2 11 (32.4%) 3 14 (41.2%) lymph node involvement, n (%) no 17 (50.0%) yes 17 (50.0%) treatment, n (%) glansectomy 6 (17.6%) partial penectomy 24 (70.6%) total penectomy 4 (11.8%) archivio italiano di urologia e andrologia 2024; 96(3):12856 3 programmed death-ligand expression and lymph node involvement in penile squamous cell carcinoma months vs 75.9 months), but statistical significance could not be inferred (p = 0.188). the survival curves are presented in figure 1. discussion the rarity of penile cancer in western countries poses challenges in understanding its biology and optimal management strategies. our study aimed to find an association between pd-l1 status and clinicopathological characteristics of penile sqcc, as well as associated prognostic implications. in fact, our results showed a trend towards worse clinical features and worse survival in pdl1 cps ≥ 1 patients, as well as a significant association between pd-l1 status and lymph node involvement. the association between pd-l1 expression and clinicopathological features observed in our study is consistent with previous research in various cancer types, including studies conducted in penile cancer (9, 10). we found a trend towards larger tumor size, vascular invasion, and perineural invasion in patients with pd-l1 cps ≥ 1 tumors, although statistical significance was not achieved, probably due to the low number of patients in our cohort. these findings are consistent with the largest cohort, to our knowledge, published by sabina davidsson and colleagues, who analysed 222 cases of penile squamous cell carcinoma (sqcc) (8). this suggests a potential link between pd-l1 expression and aggressive tumor behaviour, which poses the question regarding the need for a different treatment pathway in these patients. a novel observation in our study is the significant association between pd-l1 expression and lymph node involvement. we found that a higher proportion of patients with pd-l1 cps ≥ 1 tumors had lymph node metastases upon lymphadenectomy compared to those with pd-l1 cps < 1 tumors, with 14 out of 22 pd-l1 cps ≥ 1 patients (63.6%) having lymph node metastases when lymphadenectomy was performed (p = 0.031) and only 3 out of 12 pd-l1 cps < 1 patients having lymph node involvement. these findings are in line with those from udager and colleagues that were among the first to investigate pd-l1 expression in a cohort of 37 patients with penile sqcc. they discovered that pd-l1 expression was detected in 62.2% of penile sqcc. despite the limited sample size, they noted a trend towards worse clinical clinicopathological features and worse overall survival but, at least to our knowledge, no statistically significant association has been established yet (9). this finding suggests a potential table 2. association of pd-l1 expression with clinicopathological features. pd-l1 in tumor cells, n (%) cps < 1 cps ≥ 1 tumor size (median, cm) 2.5 (iqr 2.5) 3.0 (iqr 3.4) p = 0.662 p16 immuno-expression, n (%) p = 0.252 negative 10 (83.3%) 13 (59.1%) positive 2 (16.7%) 9 (32.4%) histological grade, n (%) p = 0.360 grade 1 5 (41.7%) 6 (27.3%) grade 2 6 (50.0%) 8 (36.4%) grade 3 1 (8.3%) 7 (31.8%) grade 4 0 (0.0%) 1 (4.5%) vascular invasion, n (%) p = 0.705 no 9 (75.0%) 14 (63.6%) yes 3 (25.0%) 8 (36.4%) perineural invasion, n (%) p = 0.252 no 10 (83.3%) 13 (59.1%) yes 2 (16.7%) 9 (40.9%) pt stage, n (%) p = 0.989 pt1a 3 (25.0%) 6 (27.3%) pt2 4 (33.3%) 7 (31.8%) pt3 5 (41.7%) 9 (40.9%) lymph node involvement, n (%) p = 0.031 no 9 (75.0%) 8 (50.0%) yes 3 (25.0%) 14 (63.6%) figure 1. overall survival stratified by pd-l1 status. archivio italiano di urologia e andrologia 2024; 96(3):12856 i. peyroteo, f. santos, c. marialva, r. ramos 4 role for pd-l1 expression in promoting tumor metastasis and aggressiveness. however, the underlying mechanisms driving this association remain unclear and warrant further investigation through mechanistic studies. the lack of a standard second-line treatment for patients with metastatic penile scc underscores the urgent need for novel therapeutic strategies. the emergence of immune checkpoint inhibitors targeting the pd-1/pd-l1 pathway has revolutionized cancer treatment across various tumor types. our study adds to the growing body of evidence supporting the clinical relevance of pd-l1 expression as a potential biomarker for immunotherapy response in penile sqcc. in our study, we observed a high proportion of patients with pd-l1 cps ≥ 1 (64,7%), which is in line with the current literature (8, 9). until now, the main focus has been on hpv related penile carcinoma that in our sample was only 32,4%, which is also in line with the current evidence (3). given the much higher prevalence of pd-l1 expression there is potential for identifying a novel therapeutic target since the literature indicates that tumors expressing high levels of pd-l1 are more likely to respond to immunotherapy. additionally, in the future, it will be of interest to observe the potential impact of male hpv vaccination on the incidence and oncological outcomes of penile cancer. hpvrelated penile cancers are believed to have better outcomes (3). if the incidence of hpv-related cancers decreases as a result of vaccination efforts, we may encounter a higher proportion of aggressive cases. therefore, the importance of novel strategies will become even more significant. furthermore, many patients become ineligible for chemotherapy over time, yet they may still be suitable candidates for immunotherapy. offering such patients an alternative treatment could prevent disease progression. if clinical benefits are demonstrated in this advanced setting, there is potential to pursue approval for this therapy in earlier stages as an adjuvant treatment for tumors with high-risk features, similar to current discussions regarding kidney cancer treatment protocols. despite the promising role of pd-l1 expression as a prognostic biomarker, our study did not find a statistically significant association between pd-l1 expression and overall survival. this may be attributed to the relatively small sample size and short follow-up duration. the survival curves show a trend towards separation, suggesting that with a larger sample size, the survival outcomes would likely achieve statistical significance. larger studies with longer follow-up periods are warranted to validate our findings and assess the impact of pd-l1 expression on survival outcomes in penile sqcc. several limitations should be considered when interpreting our results. first, our study was retrospective and conducted at a single institution, which may introduce selection bias and limit generalizability. second, the assessment of pd-l1 expression was based on immunohistochemistry, which has inherent variability and subjectivity. future studies incorporating more robust techniques, such as rna sequencing or multiplex immunofluorescence, could provide deeper insights into the tumor microenvironment and immune landscape in penile sqcc. despite de low number of cases, reflecting the rarity of this tumor, our data comes from a tertiary cancer center in portugal, where all decisions are based on multidisciplinary tumor boards. besides this, we exclusively analysed conventional squamous cell carcinoma and omitted other histologies to avoid confounding the results with histologies known to have a different prognosis. conclusions our study highlights the association between pd-l1 expression and worse clinical outcomes in penile sqcc. it is noteworthy the clinical significance of lymph node involvement in pd-l1 cps ≥ 1 cases, suggesting a potential role of pdl1 as a predictive biomarker for metastatic disease. references 1. eau guidelines (2024). edn. presented at the eau annual congress paris 2024. 2. bleeker mcg, heideman dam, snijders pjf, et al. penile cancer: epidemiology, pathogenesis and prevention. world j urol 2009; 27:141-150. 3. backes dm, kurman rj, pimenta jm, smith js. systematic review of human papillomavirus prevalence in invasive penile cancer. cancer causes control 2009; 20:449-457. 4. brouwer or, rumble rb, ayres b, et al. penile cancer: eauasco collaborative guidelines update q and a. jco oncol pract 2024; 20:33-37. h 5. topalian sl, hodi fs, brahmer jr, et al. safety, activity, and immune correlates of anti-pd-1 antibody in cancer. n engl j med 2012; 366:2443-2454. 6. brahmer jr, tykodi ss, chow lqm, et al. safety and activity of anti-pd-l1 antibody in patients with advanced cancer. n engl j med 2012; 366:2455-2465. 7. el-mouallem n, paul ak. immune checkpoint inhibitors for urothelial cancer: an update on new therapies. fed pract 2018; 35:s62. 8. davidsson s, carlsson j, giunchi f, et al. pd-l1 expression in men with penile cancer and its association with clinical outcomes. eur urol oncol 2119; 2:214-221. 9. u udager am, liu ty, skala sl, et al. frequent pd-l1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. ann oncol. 2016; 27:1706-12. 10. bacco mw de, carvalhal gf, macgregor b, et al. pd-l1 and p16 expression in penile squamous cell carcinoma from an endemic region. clin genitourin cancer 2020; 18:e254-e259. correspondence inês peyroteo (corresponding author) ipeyroteo@gmail.com celso marialva rodrigo ramos portuguese institute of oncology in lisbon, urology, lisbon, portugal filipa santos portuguese institute of oncology in lisbon, pathology, lisbon, portugal conflict of interest: the authors declare no potential conflict of interest. this work was presented at american association of urology congress in 2024. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13938 1 original paper been found in about 15% of the general male populations (3-5). men with varicoceles typically seek medical assistance when they encounter symptoms such as pain or a dragging sensation in the scrotum. it's notable that up to 40% of men assessed at subfertility clinics are diagnosed with varicocele (6). numerous theories have been proposed to explain the relationship between varicocele and infertility, with the primary factors including sperm damage due to increased scrotal temperature, accumulation of waste products in the sluggish blood flow of the pampiniform plexus, and elevated concentrations of testosterone and other hormones within these vessels (7-11). various surgical methods are available for varicocele management, aiming to alleviate pain, remove the mass, and enhance semen parameters. however, despite varicocele being considered one of the most treatable causes of male infertility, debates and uncertainties persist regarding its treatment (12). a common abnormality observed in individuals with varicocele is a reduction in sperm motility, present in approximately 90% of patients (13). moreover, abnormalities in sperm morphology are also prevalent. currently, there is no established correlation between the grade of varicocele, testicular pathology, and abnormalities in semen parameters (14). patients and methods this study was carried out from february 2021 to august 2024 on 162 patients who presented at thumbay university hospital seeking advice for infertility (primary or secondary). the patients were subjected to history taking, clinical examination, semen analysis, colour doppler ultrasonography (scrotal). patients with recurrent varicocele, azoospermia or have cause of infertility other than varicocele were excluded from the study. at least 2 semen analyses were done for all patients before operation and 3 objectives: to assess the effectiveness of laparoscopic varicocelectomy in patients with clinical versus subclinical varicocele concerning preoperative and postoperative seminal parameters. patients and methods: between february 2021 and august 2024, a total of 162 patients diagnosed with varicocele (72 with subclinical and 90 with clinical presentation) seeking infertility advice (primary or secondary) at the author's institution underwent laparoscopic varicocelectomy and were enrolled in the study. all patients underwent history taking, clinical examination, semen analysis, and scrotal colour doppler ultrasonography. patients with recurrent varicocele, azoospermia, or infertility due to causes other than varicocele were excluded from the study. semen analysis was conducted for all patients before laparoscopic varicocelectomy and 3 to 6 months after varicocelectomy. results: significant improvements in seminal parameters were observed in patients with clinical varicocele (p < 0.05). bilateral and right-sided varicoceles were more prevalent in patients with subclinical varicocele. additionally, the incidence of secondary infertility was higher in patients with subclinical varicocele compared to those with clinical varicocele (p < 0.05). conclusions: our study indicates favourable outcomes of laparoscopic varicocelectomy in patients with clinical varicocele. regarding the effects of varicocelectomy in patients with subclinical varicocele, we recommend avoiding varicocelectomy in subclinical group of patients unless no identifiable causes of semen abnormality. key words: semen; subclinical varicocele; infertility. submitted 30 april 2025; accepted 1 june 2025 introduction varicocele is a state of dilated, elongated and tortuous veins of the pampiniform plexus of the spermatic cord (1, 2). varicoceles typically develop during adolescent and have the changes of semen parameters of patients with clinical versus subclinical varicocele managed by laparoscopic varicocelectomy: observational study tamer a. abouelgreed 1, 2, mohamed a. abdelaal 1, mohamed a. amer 3, hassan mamdouh 3, ahmed f. el-sherbiny 4, emad elrewiny 3, ahmed e. elsaadany 3, waleed a. mahmoud 5, mohamed s. hasan 3, mostafa t. eldestawy 3, hazem b. zakaria 3, shaimaa h. mohamed 6, mosab f. alassal 7, hany elsegeay 8, mohamed y. elamir 9 1 department of urology, faculty of medicine, al-azhar university, cairo, egypt; 2 department of urology, faculty of medicine, gulf medical university, ajman, uae; 3 department of dermatology, venereology & andrology, faculty of medicine, al-azhar university, cairo, egypt; 4 department of andrology, international islamic centre for population studies and research, al-azhar university, cairo, egypt; 5 department of dermatology, venereology & andrology, faculty of medicine, al-azhar university, asyut, egypt; 6 department of dermatology & venerology, faculty of medicine for girls, al-azhar university, cairo, egypt; 7 department of vascular surgery, lister hospital, stevenage, united kingdom; 8 department of urology, faculty of medicine, al-azhar university, asyut, egypt; 9 department of andrology, faculty of medicine, cairo university, cairo, egypt. doi: 10.4081/aiua.2025.13938 summary archivio italiano di urologia e andrologia 2025; 97(2):13938 t.a. abouelgreed, m.a. abdelaal, m.a. amer, et al. 2 to 6 months after operation. the patients were divided into 2 groups according to the degree of varicocele. group a (90 patients with clinical varicocele) and group b (72 patients with subclinical varicocele). the seminal parameters before and after the operation were compared among patients of each group. in both groups, varicocelectomy was done using laparoscopic approach for all patients by a single surgeon. clinical varicocele was classified according to dubin system into three grades. grade i: small, palpable with only valsalva manoeuvre; grade ii: moderate, palpable with patient standing and grade iii: large, visible through scrotal skin, and palpable with patient standing. subclinical varicoceles are not palpable on physical examination but rather are diagnose radiographically. after obtaining informed consent and performing clinical evaluation, for each patient a questionnaire regarding demographic features, marital situation, type of varicocele, genital evaluation and type of infertility (primary or secondary) was filled out. to ensure the accuracy of the study, a single medical technologist performed all laboratory experiments and a single urologist performed all operations. the spermiogram results pre and post-operative were compared among individuals of each group. statistical analysis statistical analysis was performed using the ‘statistical package for the social sciences’ software for windows (version 26.0; spss inc.). for all comparisons, p < 0.05 was considered statistically significant. results in our study we select a total of 162 men, suffering from varicocele. their mean age was 28.7 ± 3.9 years. the largest age group belonged to those who were 40 years and younger, making up 94.64 % of group a patients and 94.5% of group b (table 1). the affected side in the patients is shown in table 2. in patients of group a, 21 (23.33%) had grade i, 41 (45.56%) had grade ii and 28 (31.11%) hade grade iii varicocele. among patients of our study, the period of time from marriage to the first visit to the urology clinic regarding infertility was 3.4 ± 1.2 years in group a patients and 1.6 ± 1.9 years in group b patients, with a significant p value of < 0.001. in group a patients, 78.2% had primary and 21.8% had secondary infertility. among group b patients, 25.3% had primary infertility, 74.7% had secondary infertility. comparison of spermiogram parameters before and after varicocelectomy between individuals of each group is shown in table 3. the main complications after operation in both groups were testicular pain and sensitivity in 19 patients (14 group a and 5 group b), mild hydrocele in 17 (6 group a and 11 group b), testicular atrophy in 3 (all of group b) and recurrence of varicocele in 8 (3 group a and 5 group b). discussion primary infertility remains a major challenge facing the world today. studies have shown that approximately 15% of married couples suffer from infertility, with male causes, especially varicocele, accounting for 20% to 50% of cases (15, 16). in men with secondary infertility, this proportion increases to 80% (17). there is evidence that men with normospermic varicocele respond differently to varicocele resection than patients with preoperative oligozoospermia due to different pathophysiological mechanisms (18). two important studies examined outcomes after varicocele repair in patients with normal sperm count. in one case, isolated teratozoospermia showed no significant improvement after varicocele resection; in another case, neither teratozoospermia nor asthenozoospermia showed any improvement (19, 20). furthermore, the authors claimed that undergoing varicocele resection puts this group of patients at risk for oligozoospermia. the approach to treating varicocele has changed significantly since tulloch first proposed the association between varicocele and infertility in 1952 (21). scott's 1961 study of 108 patients with varicocele concluded that larger varicoceles cause greater damage (22). despite advances in imaging and understanding over the past six decades, the treatment of non-palpable varicocele remains controversial. although there are sevtable 3. comparing the semen parameters between the groups of patients. sperm parameters groups preoperative postoperative p value values values total sperm count (million per ml) a-i 21.61 ± 22.75 49.65 ± 16.95 < 0.05 a-ii 19.8 ± 33.2 47.4 ± 15.92 < 0.05 a-iii 16.1 ± 28.1 37.23 ± 18.7 < 0.05 b 20.9 ± 15.6 22.7 ± 12.8 ns percentage of motile sperms a-i 48.75 ± 23.85 53.85 ± 21.07 ns a-ii 40.27 ± 19.25 63.6 ± 19.9 < 0.05 a-iii 38.7 ± 16.2 71.45 ± 12.25 < 0.05 b 58.4 ± 11.2 59.6 ± 8.9 ns percent of sperm with normal morphology a-i 57.75 ± 19.45 58.35 ± 13.51 ns a-ii 52.76 ± 18.35 53.7 ± 17.4 ns a-iii 50.21 ± 19.46 50.16 ± 18.65 ns table 1. age distribution between patients of both groups. age group a (n = 90) group b (n = 72) t < 20 14 (15.6%) 7 (9.7%) 21-30 63 (70%) 56 (77.8%) 31-40 8 (8.8%) 5 (7%) > 40 5 (5.6%) 4 (5.5%) table 2. side distribution of varicocele between patients of both groups. side of varicocele group a (n = 90) group b (n = 72) right 9 (10%) 16 (22.2%) left 5 (5.6%) 24 (33.3%) bilateral 78 (84.4%) 32 (44.5%) archivio italiano di urologia e andrologia 2025; 97(2):13938 3 semen parameters after laparoscopic varicocelectomy eral grading systems, the dublin grading system, which takes into account visibility and palpability, is widely accepted and classifies varicocele into three grades: grade 1 (palpable during valsalva manoeuvre), grade 2 (palpable in upright position) and grade 3 (visible and palpable at rest) (23). research indicates that varicoceles, regardless of their size, are associated with changes in semen parameters (24, 25). however, urologists need to consider sub-clinical varicocele (scv), which cannot be detected through visual or tactile examination but requires doppler ultrasound for identification (26). since the majority of studies focus on varicoceles diagnosed clinically, there is ongoing debate regarding the optimal management of scv. this study deals into the prevalence of infertility, the impact of scv, and the controversies surrounding its diagnosis and treatment within our community. while varicocele represents a significant and common factor in male infertility, clinical varicoceles can fortunately be effectively treated following certain paraclinical diagnoses such as abnormalities in sperm analysis and/or sonogram results. various publications express many different views regarding surgical outcomes in patients with subclinical varicocele (27-29). in our research, varicocelectomy did not show favorable outcomes among patients with subclinical varicocele. this finding aligns with the results reported by bsat and masabni, who similarly observed no positive outcomes following varicocelectomy in patients with subclinical varicocele (30). conversely, pierik et al., in their study involving patients with both clinical and subclinical varicocele, demonstrated that surgical intervention yielded consistent positive outcomes irrespective of the type of the condition (31). many studies have sought to evaluate the impact of varicocelectomy on patients with subclinical varicocele. among these studies, unal et al. conducted a comparison of two treatment methods for patients with subclinical varicocele: prescribing clomiphene to one group and performing varicocelectomy on the other group. they observed improvements in spermiogram parameters in both groups, with no significant difference between the two treatment methods (32). in our study, bilateral or left-sided varicoceles were relatively more common in group b compared to the clinical group, and baseline spermiograms of subclinical patients were less abnormal than those of patients in group a. based on our findings and those of previous studies, it can be inferred that the underlying mechanisms and pathogenesis of leftsided subclinical varicoceles, as well as those with severe spermiogram abnormalities (similar to clinical varicocele), resemble those of clinical varicocele, suggesting that surgery may yield better outcomes. however, in our study, a majority of the patients were affected on the left or both sides, indicating that other mechanisms may have influenced their sperm parameters. conclusions laparoscopic varicocelectomy shows favourable outcome in patients with clinical varicocele, while in patients with subclinical varicocele there was no significant effect of varicocelectomy, so, we recommend avoiding varicocelectomy in patients with subclinical varicocele to avoid the possible complications that might be occur from such surgery. references 1. baazeem a, belzile e, ciampi a, et al. varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. eur urol. 2011; 60:796-808. 2. kupis ł, dobroński pa, radziszewski p. varicocele as a source of male infertility current treatment techniques. central eur j urol. 2015; 68:365-370. 3. razi m, tavalaee m, sarrafzadeh-rezaei f, et al. varicocele and oxidative stress: new perspectives from animal and human studies. andrology. 2021; 9:546-558. 4. kohn tp, kohn jr, pastuszak aw. varicocelectomy before assisted reproductive technology: are outcomes improved? fertil steril. 2017; 108:385-391. 5. peter c. fretz, jay i. sandlow. varicocele: current concepts in pathophysiology, diagnosis and treatment. urol clin n am 2002; 29:921937. 6. dubin l, amelar rd. varicocelectomy: 986 cases in a twelve-year study. urology. 1977; 10:446-449. 7. kim hj, seo jt, kim kj, et al. clinical significance of subclinical varicocelectomy in male infertility: systematic review and metaanalysis. andrologia. 2016; 48:654-661. 8. merla a, ledda a, di donato l, et al. use of infrared functional imaging to detect impaired thermoregulatory control in men with asymptomatic varicocele. fertil steril. 2002; 78:199-200. 9. hauser r, paz g, botchan a, et al. varicocele: effect on sperm functions. hum reprod update. 2001; 7:482-485. declarations ethical approval and consent for participate: all procedures performed in this study complied with institutional and/or national research council ethical standards as well as the 1964 declaration of helsinki and its subsequent amendments or similar ethical standards. protocols and written informed consent for all participants were approved by the research ethics committee of thumbay university hospital (affiliated with gulf medical university, rec #: 152/2021). consent for publication: not applicable. availability of data and material: data sets used in this study are available upon reasonable request from the corresponding authors. competing interests: the authors declare no conflicts of interest. funding: the authors did not receive any financial support for the research, authorship and/or publication of this article. authors' contributions: ta, ma, ma, hm, af: manuscript preparation, protocol, data collection and management, manuscript editing; ee, ae, wa, ms, mt: data acquisition, data analysis and management, manuscript editing; hb, sh, mf, he, my: manuscript editing, project development; data analysis, project development. all authors have read and approved the manuscript acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13938 t.a. abouelgreed, m.a. abdelaal, m.a. amer, et al. 4 10. blumer cg, fariello rm, restelli ae, et al. sperm nuclear dna fragmentation and mitochondrial activity in men with varicocele. fertil steril. 2008; 90:1716-1722. 11. sakamoto y, ishikawa t, kondo y, et al. the assessment of oxidative stress in infertile patients with varicocele. bju int. 2008; 101:1547-1552. 12. khera m, lipshultz li. evolving approach to the varicocele. urol clin north am. 2008; 35:183-9. 13. will ma, swain j, fode m, et al. the great debate: varicocele treatment and impact on fertility. fertil steril. 2011; 95:841-852. 14. zini a, buckspan m, berardinucci d, jarvi k. loss of left testicular volume in men with clinical left varicocele: correlation with grade of varicocele. arch androl. 1998; 41:37-41. 15. jarow jp. effects of varicocele on male fertility. hum reprod update. 2001; 7:59-64. 16. kroese ac, de lange nm, collins j, evers jl. surgery or embolization for varicoceles in subfertile men. cochrane database syst rev. 2012. 17. meacham rb, townsend rr, rademacher d, drose ja. the incidence of varicoceles in the general population when evaluated by physical examination, gray scale sonography and color doppler sonography. j urol. 1994. 18. okeke l, ikuerowo o, chiekwe i, et al. is varicocelectomy indicated in subfertile men with clinical varicoceles who have asthenospermia or teratospermia and normal sperm density? int j urol. 2007; 14:729-32. 19. blumer cg, restelli ae, giudice pt, et al. effect of varicocele on sperm function and semen oxidative stress. bju int 2012; 109:25965. 20. maciejko a, kim p, jang t, et al. isolated teratospermia: is varicocelectomy indicated? j urol. 2005; 173:369. 21. tulloch ws. a consideration of sterility factors in the light of subsequent pregnancies ii. sub fertility in the male. (tr. edinburgh obst. soc. session 104). edinb med j. 1951; 59:29-34. 22. scott ls. varicocele: a treatable cause of subfertility. br med j. 1961; 1:788-90. 23. dubin l, amelar rd. etiologic factors in 1294 consecutive cases of male infertility. fertil steril. 1971; 22:469-474. 24. silber sj. the varicocele dilemma. hum reprod update. 2001; 7:70-77. 25. redmon jb, carey p, pryor jl. varicocele-the most common cause of male factor infertility. hum reprod update. 2002; 8:53-58. 26. pauroso s, di leo n, fulle i, et al. varicocele: ultrasonographic assessment in daily clinical practice. j ultrasound. 2011; 14:199-204. 27. muthukumar a, sekar h, krishnamoorthy s, kumaresan n. subclinical varicocele (scv): what the urologists need to know? world journal of surgery and surgical research. 2021; 1281:1-4. 28. schauer i, madersbacher s, jost r, et al. the impact of varicocelectomy on sperm parameters: a meta-analysis. j urol. 2012; 187:1540-1547. 29. birowo p, tendi w, widyahening is, et al. the benefits of varicocele repair for achieving pregnancy in male infertility: a systematic review and meta-analysis. heliyon. 2020; 6:e05439. 30. bsat fa. & masabni r. effectiveness of varicocelectomy in varicoceles diagnosed by physical examination versus doppler studies. fertil steril. 1988; 50:321-323. 31. pierik fh, vreeburg jt, stijnen t, et al. improvement of sperm count and motility after ligation of varicoceles detected with colour doppler ultrasonography. int j androl. 1998; 21:256-260. 32. unal d, yeni e, verit a, karatas of. clomiphene citrate versus varicocelectomy in treatment of subclinical varicocele: a prospective randomized study. int j urol. 2001; 8:227-230. correspondence tamer a. abouelgreed (corresponding author) dr_tamer_ali@yahoo.com; tamerali.8@azhar.edu.eg department of urology, al-azhar university, cairo, egypt, & gulf medical university, ajman, uae mohamed a. abdelaal maal_uro@yahoo.com department of urology, faculty of medicine, al-azhar university, cairo, egypt mohamed a. amer amerrom@yahoo.com hassan mamdouh hsdermaclinic@yahoo.com emad elrewiny emad.elrewiny@yahoo.com ahmed e. elsaadany drhousesaadany@gmail.com mohamed s. hasan mohamed.saeed80@gmail.com mostafa t. eldestawy mostafa.eldestawy@azhar.edu.eg hazem b. zakaria hazem.basuny.1988@gmail.com department of dermatology, venereology & andrology, faculty of medicine, al-azhar university, cairo, egypt ahmed f. el-sherbiny ahmed_derma@yahoo.com department of andrology, international islamic center for population studies and research, al-azhar university, cairo, egypt waleed a. mahmoud waleedderma44@gmail.com department of dermatology, venereology & andrology, faculty of medicine, al-azhar university, asyut, egypt shaimaa h. mohamed shaimaadiab08@gmail.com department of dermatology & venerology, faculty of medicine for girls, al-azhar university, cairo, egypt mosab f. alassal mosabalassal32@gmail.com department of vascular surgery, lister hospital, stevenage, united kingdom hany elsegeay docterhany53@gmail.com department of urology, faculty of medicine, al-azhar university, asyut, egypt mohamed y. elamir yousry82@kasralainy.edu.eg department of andrology, faculty of medicine, cairo university, cairo, egypt stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12951 1 original paper tion (1). postoperative pain control after ipp surgery can be enhanced by targeting nerve endings and receptors in penile tissues. the dorsal penile nerve, formed by converging nerve fibers, carries signals through the pudendal nerve to the spinal cord (s2-s4), then to the thalamus and sensory cortex. anesthesia can be applied at various points along this pathway, including the dorsal nerve, perineal nerve, pudendal nerve, and s2-s4 nerve roots (2). several studies explored intraoperative analgesia for postoperative pain control. raynor et al., for instance, found that the dorsal penile nerve block (dpnb) reduced early postoperative pain but did not impact postoperative narcotic use (3). additionally, xie et al. studied the effectiveness of a combination of penile dorsal nerve and ring blocks, while hsu et al. investigated the efficacy of a crural block. both studies noted a decrease in early postoperative pain, although rates of postoperative narcotic use were not reported (4, 5). the opioid fentanyl, possessing lipophilic properties, exhibits rapid onset and demonstrates up to 20 times greater potency when administered via the intrathecal route in comparison to the intravenous route (6). however, the use of intrathecal fentanyl has been linked to an increase in intravenous opioid requirement during the postoperative period, potentially attributable to subtle opioid tolerance or opioid-induced hyperalgesia (7). additionally, it has been noted that intrathecal fentanyl doses exceeding 0.25 µg/kg may reach a "ceiling effect," indicating that higher doses do not enhance intraoperative analgesia and may amplify adverse effects (8). our study compares intrathecal fentanyl and dorsal penile nerve block for controlling postoperative pain in patients undergoing insertion of an inflatable penile prosthesis. patients and methods a concurrent cohort study was conducted at the urology and anesthesia departments, faculty of medicine, al-azhar university, cairo, egypt. the study spanned from february 2022 to february 2024 and included 80 eligible patients objectives: to compare the efficacy of intrathecal fentanyl and dorsal penile nerve block for postoperative pain management in patients undergoing inflatable penile prosthesis (ipp). patients and methods: a prospective single-center study included 80 patients amenable to ipp. patients were divided equally into two groups. group i included 40 patients who were managed with spinal anesthesia with intrathecal fentanyl before undergoing ipp. group ii comprised 40 patients who received spinal anesthesia with dorsal penile block before ipp. study groups were compared regarding postoperative vas (visual analog scale) scores, total narcotics consumption, patient satisfaction levels, and perioperative complications. results: the study groups were comparable regarding baseline patients’ criteria. the operative time was comparable between the study groups, with group i and group ii having respective median times of 64 minutes (interquartile range: 55-78) and 67 minutes (interquartile range: 56-81) (p = 0.65). additionally, both groups demonstrated similar distributions in ipp implant cylinder and reservoir size (p = 0.9). postoperative pain was higher in group i, with a statistically significant difference (p < 0.001). eight patients in group i (20%) called the physician’s office asking for pain medication, compared to two patients in group ii (5%) (p = 0.04). 85% of patients in group ii were highly satisfied compared to 50 % in group i (p = 0.003). we reported a 5% complication rate in group i compared to 2.5% in group ii (p = 0.6). conclusions: the present study found that the dorsal penile nerve block offers superior postoperative pain control and patient satisfaction compared to intrathecal fentanyl for patients undergoing inflatable penile prosthesis insertion. key words: penile prosthesis; penile block; intrathecal fentanyl; postoperative pain. submitted 21 august 2024; accepted 31 august 2024 introduction inflatable penile prosthesis (ipp) represents a gold-standard surgical treatment for medically refractory erectile dysfunccomparative study between intrathecal fentanyl and dorsal penile nerve block for controlling postoperative pain after inflatable penile prosthesis implantation adel elatreisy 1, 2, yasser ahmed 1, ahmed elgarhy 3, mohamed hindawy 1, tamer abouelgreed 1, ismail ahmed 3, abdalla abdalla 3, hany ramadan 3, mohamed aboelsuod 3, khaled shrief 3, ayman mohamed 3, wael ibrahim 3, saeed abdelhameed 3, mohammad alghamdi 2, mohammed alzahrani 2, hamada youssof 4 1 urology department, faculty of medicine, al-azhar university, cairo, egypt; 2 urology department, king fahd armed forces hospital, jeddah, saudi arabia; 3 anesthesia department, faculty of medicine, al-azhar university, cairo, egypt; 4 urology department, faculty of medicine, fayoum university, fayoum, egypt. doi: 10.4081/aiua.2024.12951 summary archivio italiano di urologia e andrologia 2024; 96(4):12951 a. elatreisy, y. ahmed, a. elgarhy, et al. 2 for elective inflatable penile prosthesis implantation with asa i, ii, and iii at the facility. the study protocol received approval from the institutional review board. informed written consent was obtained from all participants in compliance with ethical guidelines and regulations to ensure patient safety and confidentiality. inclusion criteria ipp was considered for patients with ed after the failure of conservative therapy, including phosphodiesterase inhibitors, alprostadil urethral suppositories, vacuum erection devices, and intracavernosal injections. exclusion criteria patients with asa iv and coagulopathy were excluded from the study. the study cohort was divided into two equally sized groups. the patients were prospectively allocated to treatment groups without randomization. the choice between intrathecal fentanyl or dpnb was made through mutual agreement by the patients and physicians. group i consisted of 40 patients who underwent spinal anesthesia with intrathecal fentanyl before undergoing ipp. in comparison, group ii comprised 40 patients who received spinal anesthesia with dpnb before ipp. anesthesia technique upon establishing an intravenous (iv) line, a pre-load of normal saline was administered before the initiation of spinal anesthesia. cardiorespiratory monitoring, including heart rate (hr), peripheral oxygen saturation (spo2), and blood pressure (bp), was commenced for all patients. in the case of group, i, spinal anesthesia was induced using a 25-gauge bd quinck spinal needle following the sterilization of the back and identification of the anatomical landmark. the needle was then inserted using a paramedian approach at the l3-4 intervertebral lumbar space level. upon successful confirmation of cerebrospinal fluid (csf) flow, a combination of 15 mg (3 ml) of heavy bupivacaine and 0.25 mcg/kg (0.5 ml) of fentanyl was intrathecally injected. for group ii, spinal anesthesia induction involved the use of 3.5 ml (3 ml heavy bupivacaine plus 0.5 ml water for injection), followed by a dorsal penile nerve block performed by inserting an 18-gauge needle connected to a 20 cc syringe between the suspensory ligament and the base of the penis. a total volume of 20 bupivacaine was injected at the 2and 10-o'clock positions (10 ml for each side) for the right and left dorsal penile nerves. all penile implant procedures were conducted by a single surgeon using a penoscrotal approach, employing coloplast titan and rigicon prostheses. postoperative pain assessment was conducted using a visual analog scale (vas) after the ipp surgeries at 2, 4, 8, 12, 16, 20, 24 and 36 hours. patient satisfaction was evaluated using the 5-point likert scale, ranging from dissatisfied (1) to completely satisfied (5). outcome in the comparative analysis of the study groups, the parameters considered encompassed patients' demographics, postoperative visual analog scale (vas) scores, total narcotics consumption, patient satisfaction levels regarding postoperative pain management, and perioperative complications according to modified clavien classification system (mccs) (9). statistical analysis we analyzed the data using the statistical package for social science (spss) software, version 29 (spss inc., chicago data. the descriptive statistics included percentages, frequencies, means, and medians. we compared categorical variables between the two groups using the fisher exact test. additionally, for normally and abnormally distributed continuous variables, we used the student’s t-test or the mann-whitney u test, respectively. statistical significance was defined as a two-tailed p-value of less than 0.05. results group i included 40 patients who underwent spinal anesthesia with intrathecal fentanyl before undergoing ipp, while group ii included 40 patients who received spinal anesthesia with dorsal penile block before ipp. the study groups were comparable regarding baseline patients’ criteria, as depicted in table 1. the smoking status and prevalence of prior prostatectomy, pelvic radiation therapy, peyronie’s disease, diabetes, and hypertension were similar across the study groups (p = 0.87). the operative time was comparable between the study groups, with group i and group ii having respective median times of 64 minutes (interquartile range: 55-78) and 67 minutes (interquartile range: 56-81); the between-group difference was not statistically significant (p = 0.65). additionally, both groups demonstrated similar distributions in implant cylinder size and reservoir size (p = 0.9), as shown in table 1. as measured with the vas score, post-operative pain was higher in group i, with a statistically significant difference table 1. comparison between the study groups regarding baseline patients’ criteria. parameter group i group ii p-value (n = 40) (n = 40) age, median (iqr) 59 (51-72) 59 (52-70) 0.72 bmi, median (iqr) 29 (24-32) 29 (23-33) 0.62 etiology/comorbidities, n (%) 0.87 dm 33 (82.5%) 35 (87.5%) htn 21 (52.5%) 20 (50%) smoking 18 (45%) 19 (47.5%) peyronie’s disease 6 (15%) 5 (12.5%) prostatectomy 1 (2.5%) 1 (2.5%) radiotherapy 1 (2.5%) 0 implant cylinder size (cm), n (%) 0.93 < 18 4 (10%) 5 (12.5%) 18-19 13 (32.5%) 11 (27.5%) 20-21 15 (37.5%) 17 (42.5%) ≥ 22 8 (20%) 7 (17.5%) reservoir size ≥ 100cc 13 14 0.91 operative time (minutes), median (iqr) 61 (45-80) 63 (45-76) 0.65 archivio italiano di urologia e andrologia 2024; 96(4):12951 3 comparative study between intrathecal fentanyl and dorsal penile nerve block... (p < 0.001), as shown in table 2. eight patients in group i (20%) called the physician’s office asking for pain medication, compared to two patients in group ii (5%) with a statistically significant difference (p = 0.04). regarding patients’ satisfaction with post-surgery pain control, 85% of patients in group ii were highly satisfied compared to 50 % in group i. on the other hand, 25% of group i reported low satisfaction on the 5-point likert scale compared to 5% in group ii, with a significant p-value (p = 0.003) (table 2). the 90-day perioperative complication rates were comparable between the study groups, as shown in table 2. we reported a 5% complication rate in group i compared to 2.5% in group ii (p = 0.6). discussion pain control after ipp surgery has been well studied and includes a multimodal analgesic approach that utilizes combinations of different non-opioid analgesics (10). given the significant impact of the opioid epidemic, there is a growing emphasis on reducing narcotic use in postoperative care. consequently, nerve blocks are increasingly employed in urological procedures as an essential strategy for achieving this goal (11). there are multiple studies about the intra-operative use of local anesthesia to improve pain control during penile prosthesis surgery. nagao and colleagues studied the utilization of dorsal penile nerve block with 10 ml of bupivacaine as a single pain control approach during noninflatable prosthesis insertion in 20 patients at a mean follow-up of 3.4 years; they did not report any patient with chronic penile pain (12). ghanem and fouad reported a series of 159 patients who received a dorsal penile nerve block for anesthesia during implantation of a penile prosthesis; additional general anesthesia was reported in 1.8%, and 5% of their cohort required additional local anesthesia (13). however, they did not report postoperative pain control. raynor and colleagues investigated the efficacy of dorsal penile block in pain control compared to placebo after 30 penile prosthesis implants; they found that vas scores were significantly lower in patients with penile block (14). in their study, gürkan and colleagues compared an ultrasound-guided penile nerve block administered to patients undergoing implantation under spinal anesthesia and a control group who did not receive local anesthesia. the results indicated that patients who received the penile nerve block exhibited lower vas scores and reduced opioid consumption during all observed time intervals up to 24 hours (15). numerous studies have indicated that the use of intrathecal fentanyl in combination with bupivacaine results in reduced requirements for intraoperative supplemental analgesia, a decreased incidence of intraoperative nausea/vomiting, and an extended duration until the first analgesic request (30). the aggregated data from 14 studies revealed an 8% incidence of pruritus in patients administered intrathecal fentanyl, in contrast to 0.6% in the placebo cohort (30). in the present study, we conducted a comparative analysis of the effectiveness of dorsal penile block and intrathecal fentanyl in managing postoperative pain among patients undergoing inflatable penile prosthesis insertion. our findings indicate that dpnb demonstrated superior efficacy in pain reduction, accompanied by a significant decrease in postoperative narcotic usage and greater overall patient satisfaction. there were no adverse events with intrathecal fentanyl, and the incidence of perioperative morbidities was comparable to dpnb. limitations of the study the current study introduces a novel prospective comparison between dorsal penile block and intrathecal fentanyl. however, it is essential to note that the study has certain limitations, such as the absence of randomization and a relatively small sample size. conclusions our research illustrates that the dorsal penile block offers superior postoperative pain management and patient satisfaction compared to intrathecal fentanyl for patients undergoing inflatable penile prosthesis insertion. ethical approval all procedures conducted in this study complied with the institution and national research committee's ethical standards, the 1964 declaration of helsinki, and its subsequent amendments or equivalent ethical standards. the institutional review board approved the protocol for the current study of the anesthesia department at the faculty of medicine, al-azhar university hospital. informed written consent was obtained from all participating patients. table 2. comparison between the study groups regarding postoperative outcomes. parameter group i group ii p-value (n = 40) (n = 40) vas score, mean ± sd 2 hours 1.8 ± 0.52 1.73 ± 0.59 0.55 4 hours 3.7 ± 0.76 1.85 ± 0.62 < 0.001 8 hours 4 ± 0.72 3 ± 0.64 < 0.001 12 hours 5.3 ± 1.6 3.6 ± 1 < 0.001 16 hours 6.2 ± 1.8 2.8 ± 1 < 0.001 20 hours 7.5 ± 1 3.9 ± 0.6 < 0.001 24 hours 7.5 ± 0.9 4 ± 0.7 < 0.001 36 hours 6.4 ± 1 3.8 ± 0.5 < 0.001 post operative calls for pain meds, n (%) 8 (20%) 2 (5%) 0.04 hospital stay in hours, median (iqr) 35 (34-39) 35 (33-38) 0.82 patients satisfaction with 5-point likert scale, n (%) 0.003 low satisfaction (1-2) 10 (25%) 2 (5%) intermediate satisfaction (3) 10 (25%) 4 (10%) high satisfaction 20 (50%) 34 (85%) 90-days complications according to mccs, n (%) 0.6 total 2 (5%) 1 (2.5%) wound seroma (iiib) 1 (2.5%) 0 device infection (iiib) 1 (2.5%) 1 (2.5%) mccs: modified clavien classification system. archivio italiano di urologia e andrologia 2024; 96(4):12951 a. elatreisy, y. ahmed, a. elgarhy, et al. 4 references 1. burnett al, nehra a, breau rh, et al. erectile dysfunction: aua guideline. j urol 2018; 200:633-41. 2. zhu m, labagnara k, loloi j, et al. pudendal nerve block decreases narcotic requirements and time spent in post-anesthesia care units in patients undergoing primary inflatable penile prosthesis implantation. int j impot res 2024; 1-6. 3. raynor mc, smith a, vyas sn, et al. dorsal penile nerve block prior to inflatable penile prosthesis placement: a randomized, placebo-controlled trial. j sex med. 2012; 9:2975-9. 4. xie d, nicholson m, azaiza m, et al. effect of operative local anesthesia on postoperative pain outcomes of inflatable penile prosthesis: prospective comparison of two medications. int j impot res 2018; 30:93-96. 5. hsu gl, hsieh ch, wen hs, et al. outpatient penile implantation with the patient under a novel method of crural block. int j androl 2004; 27:147-51. 6. uppal, vishal frca, retter, susanne md, casey, margaret md, et al. efficacy of intrathecal fentanyl for cesarean delivery: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. anesthesia & analgesia 2020; 130:111-125. 7. carvalho b, drover dr, ginosar y, et al. intrathecal fentanyl added to bupivacaine and morphine for cesarean delivery may induce a subtle acute opioid tolerance. int j obstet anesth. 2012; 21:29-34. 8. belzarena sd. clinical effects of intrathecally administered fentanyl in patients undergoing cesarean section. anesth analg. 1992; 74:653-657. 9. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg 2004; 240:205-213. 10. lucas j, gross m, yafi f, et al. a multiinstitutional assessment of multimodal analgesia in penile implant recipients demonstrates dramatic reduction in pain scores and narcotic usage. j sex med. 2020; 17:518-25. 11. garcía rojo e, garcíia gómez b, manfredi c, al. efficacy and safety of dorsal penile nerve block before collagenase of clostridium histolyticum injections in peyronie’s disease patients: results from a prospective pilot study. andrologia. 2020; 52:e13740. 12. nagao k, ishii n, miura k, et al. one-day penile prosthesis surgery by penile block. int j urol 2000; 7:s56-60. 13. ghanem h, fouad g. penile prosthesis surgery under local penile block anaesthesia via the infrapubic s space. int androl 2000; 23:357-9. 14. raynor mc, smith a, vyas sn, et al. dorsal penile nerve block prior to inflatable penile prosthesis placement: a randomized, placebo-controlled trial. j sex med 2012; 9:2975-9. 15. gürkan y, kuş a, aksu c, et al. ultrasonographyguided penile block for adult penile surgery. can j anesth 2016; 63:780-81. 16. uppal, vishal, retter, susanne, casey margaret, et al. efficacy of intrathecal fentanyl for cesarean delivery: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. anesthesia & analgesia 2020; 130:111-125. correspondence adel elatreisy, md, msc, phd (urol), frcs (urol) (corresponding author) dr_adelelatreisy@yahoo.com adel.elatreisy@azhar.edu.eg urology department, faculty of medicine, al-azhar university, cairo, egypt urology department, king fahd armed forces hospital, jeddah, saudi arabia flat 1, 3245 manazil aleuzama’ street, ar ruwais dist, jeddah, saudi arabia postal code: 23211 yasser ahmed dryasserbadran@gmail.com mohamed hindawy hindawy78@gmail.com tamer abouelgreed dr_tamer_ali@yahoo.com urology department, faculty of medicine, al-azhar university, cairo, egypt ahmed elgarhy elgarhy_79@yahoo.com ismail ahmed ismailabdelgawad.623@azhar.edu.eg abdalla abdalla abdalla201@yahoo.com hany ramadan hanysaid.icu@gmail.com mohamed aboelsuod abosoad.mohamed2017@gmail.com khaled shrief khaledshrief2@gmail.com ayman mohamed ayman_icu@yahoo.com wael ibrahim waelelmahdy@gmail.com saeed abdelhameed dr_said_mostafaa@yahoo.com dr_said_mostafaa@yahoo.com anesthesia department, faculty of medicine, al-azhar university, cairo, egypt mohammad alghamdi mmss.19903@hotmail.com mohammed alzahrani mohdsaleh9@hotmail.com urology department, king fahd armed forces hospital, jeddah, saudi arabia hamada youssof hay02@fayoum.edu.eg urology department, faculty of medicine, fayoum university, fayoum, egypt conflict of interest: the authors declare no potential conflict of interest. archivio italiano di urologia e andrologia 2025; 97(1):13396 1 review histopathological tests. invasive tests include cystoscopy and fluorescence cystoscopy which remain the gold standard for detecting bladder cancer. non-invasive tests include urine cytology (a standard test with high specificity but low sensitivity especially for low-grade cancers) (13). urine-based tests are the most common non-invasive methods for detecting bladder cancer, including protein, transcriptomic, and epigenetic markers. multiple studies have assessed cell-free dna, dna mutation, methylated dna, circulating tumour cells, mirna, mrnas, cell-free proteins and peptides in urine specimens and blood (4). circulating urinary tumour dna (utdna) has shown a major sensitivity over traditional urine cytology and offers genomic and epigenetic insights (5). four urinary biomarkers have fda approval, but they have not replaced cystoscopy and cytology due to limitations in sensitivity and specificity (6). several studies have identified several proteins in urinary extracellular vehicles (evs) that show potential, such as masp2, c3, a2m, chmp2a, and nherf1 (7). advances in next-generation sequencing have highlighted genomic, transcriptomic, and epigenetic markers as promising candidates (8). furthermore, in the current literature, multitarget biomarker panels offer better diagnostic accuracy compared with single biomarkers (9, 10). research has focused on identifying new biomarkers capable of reducing the use of invasive diagnostic methods or to be complements of traditional methods (1-3), however, their clinical utility is still under investigation due to varying sensitivity and specificity. for this reason, the aim of our work is, through a bibliometric analysis of the literature, to evaluate the typology, methods, diffusion, and evolution of published papers to orient towards more aware research of the available material. currently, bibliometric analysis has turned into an accepted method to present the research patterns of scientific literature (11). it provides evidence regarding the progress of a specific domain, accentuating the most relevant country, journals, authors, and institutes involved in background/objectives: bladder cancer is a multifactorial disease, ranking as the 10th most common cancer globally and the fourth most common cancer in men and the ninth in women in the western world. this bibliometric analysis aims to identify and evaluate scientific literature addressing new biomarkers for bladder cancer diagnosis, as well as to identify the most prolific organizations, authors, journals, countries, and keywords within this research domain. methods: an electronic search was conducted using elsevier's scopus database. from a total of 940 retrieved papers (published between 2019 and 2024), 493 were selected. for data analysis and visualization, the titles of articles, year of publication, countries, authors, journals, articles, and keywords were analyzed using microsoft excel, vosviewer, and biblioshiny. results: china published the most papers (200 articles) and received the highest number of citations, followed by the usa. while some countries, such as egypt and india, published exclusively single country publications (scps), others demonstrated a higher level of international collaboration, with at least half of their publications being multi-country publications (mcps). countries with higher rates of mcps were greece (66.6%), italy (53.8%), korea, and france (50%). the journals that produced the most publications and received the highest number of citations were cancers, international journal of molecular sciences, and frontiers in oncology, confirming their role in producing high-impact research. conclusions: the consistent distribution of publications over the years considered indicates a sustained interest in this field. key words: bladder cancer; biomarkers; diagnosis; screening; bibliometric analysis. submitted 17 november 2024; accepted 13 december 2024 introduction bladder cancer (bc) diagnosis has traditionally relied upon different diagnostic tests, both invasive and non-invasive, including imaging-based, molecular, urine-based, and new biomarkers for diagnosis of bladder cancer: a bibliometric analysis roberto falabella 1, valentina de simone 2, felice crocetto 3, francesco del giudice 4, angelo porreca 5, nazario foschi 6, biagio barone 7, luca di gianfrancesco 5, 6, valentina di pasquale 2, vincenzo francesco caputo 1 1 unit of urology, san carlo hospital, potenza, italy; 2 department of industrial engineering, university of salerno, italy; 3 unit of urology, department of neurosciences, reproductive science and odontostomatology, university of naples federico ii, naples, italy; 4 department of maternal infant and urological sciences, sapienza university rome, policlinico umberto 1 hospital, rome, italy; 5 oncological urology, veneto institute of oncology (iov), irccs, padua, italy; 6 department of urology, fondazione policlinico universitario agostino gemelli irccs, università cattolica del sacro cuore, rome, italy; 7 department of urology, p.o. san paolo, asl na1 centro, naples, italy. doi: 10.4081/aiua.2025.13396 summary archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 2 the research area (12, 13). during these years, the results of bibliometric analyses were used in orthopaedics, gynaecology, and other medical fields (14-17), providing a guide for further research on disease prevention and treatment (18, 19). however, there is a paucity of bibliometric studies examining biomarkers in bladder cancer. therefore, this study systematically analyzed the research of biomarkers in bc, to assess frontiers and hotspots in this field. in summary, the aim of this study was to analyze global developments in biomarker studies, providing a valid analysis that projects the researcher towards new directions such as personalized medicine, liquid biopsy or the use of combinations of markers to improve diagnostic accuracy, sensitivity and specificity of tests and personalized treatment of the patient. materials and methods the overall methodology followed to perform the bibliometric analysis has been reported in figure 1. data collection the scopus database, one of the largest peer-reviewed databases of multidisciplinary research publications, was used to search for the relevant literature related to the research topic of this study. the search was conducted in august 2024 and the search string was developed using terms in line with the aim of this research study. search terms associated with (1) bladder cancer, (2) biomarkers, and (3) diagnosis have been combined using boolean operators (“or”, “and”). the overall string developed is reported below. title-abs-key( ["bladder cancer" or "bladder carcinoma") and (biomarkers or markers) and (diagnosis)]. the preferred reporting items for systematic reviews and meta-analysis (prisma), i.e., a technique that provides a roadmap to study systematic reviews objectively, clearly, and transparently, has been adopted in this research study for the establishment of an eligible set of articles to analyze (20). all articles related to the use of biomarkers for diagnosis of bladder cancer have been considered relevant if they met the following criteria: (1) written in the english language, (2) focused on bladder cancer (3) involving biomarkers for diagnosis and not follow up of bladder cancer. the authors decided to include only research articles from peer-reviewed journals. this choice was mainly related to the quality of publications. the timespan was limited to the last six years (2019-2024). the period has been chosen to provide a detailed analysis of the topic focusing on the most recent publications trying to highlight how the research topic is changing. two authors conducted the screening process following the prisma method as reported in figure 2 following the inclusion criteria just discussed. in the analysis of the searched works, the following were excluded from the analysis: articles not relevant to bladder cancer (233 articles), articles related to gallbladder pathologies (43 articles), case reports (23 articles), articles dedicated to the analysis of new biomarkers only for the follow up of bladder cancer (148 articles). finally, data from the selected articles were gathered and stored in **.csv formats. analysis after having defined the final set of articles, the bibliometric analysis was carried out using microsoft excel and two bibliometric tools biblioshiny and vosviewer. biblioshiny is an r statistical programming language tool developed by aria and cuccurullo (2017) (21) and designed for quantitative evaluation. the user-friendly interface of biblioshiny makes it simple for users to import, modify, and generate interactive visualizations of data. also, vosviewer, freely available software developed for constructing and viewing bibliometric maps with significant attention to graphical representation, was employed for some of the analyses carried out. figure 1. research methodology. archivio italiano di urologia e andrologia 2025; 97(1):13396 3 new biomarkers for diagnosis of bladder cancer as reported in figure 1, a descriptive and performance analysis was defined. this analysis, focused on the publications and their main characteristics, aimed to examine the contribution of researchers in a given field (22). the most relevant authors, sources, affiliations, articles, etc. have been identified objectively. subsequently, a more detailed analysis in the field of science mapping was performed. focusing on keywords as a unit of analysis, the existing and possible future relationships between the topics were investigated. keywords and their trends revealed the main themes on which researchers have focused over the years and that dominate the research landscape. results figure 3 shows the annual change of studies from 2019 to 2024. the number of papers remains stable overall, highlighting a constant attention to the topic. the 493 publications identified are distributed across 253 different sources. figure 4 exhibits the top 10 journals that contributed to the domain of bladder cancer biomarkers and in figure 5 the citations received are reported. cancers, international journal of molecular sciences and frontiers in oncology published the highest number of articles (17 in the first 2 and 15 in the third), that received a high number of citations (respectively 213, 122 and 174). urologic oncology: figure 2. prisma flow chart for the screening process. 493 included articles from a starting value of 4270 papers. figure 3. distribution of the number of papers per year. archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 4 seminars and original investigations is the first journal in the purely urological sector for the number of papers published, that is 13 with 147 citations. with 104 total publications, the top 10 journals published 21% of all publications identified in the last 5 years. figure 6, instead, shows the evolution over time of publications on leading sources. figure 4. journals number of publications over the last 5 years. figure 6. distribution of sources over the last 5 years. figure 5. journals number of citations over the last five years. archivio italiano di urologia e andrologia 2025; 97(1):13396 5 new biomarkers for diagnosis of bladder cancer performance of countries/regions on global output table 1 and figure 7 show the leading countries (the first 15) that published the highest number of papers related to bladder cancer biomarkers based on the nationality of the corresponding author. all articles were analyzed also considering the difference between scp (single country publication) and mcp (multi country publication) to indicate in addition to the corresponding authors also the other authors belong to the identified country. china published the highest number of papers (200) which represents 40.6% of all the articles identified, followed by the usa which published 41 articles (8.3% of the sample), although this primacy goes to greece, followed by poland, korea, and italy considering the ratio between the articles published and the population (expressed in millions of inhabitants) of the countries considered. some countries, such as egypt and india, published exclusively scp-type articles. the countries with at least half of mcp articles and therefore greater collaboration at an international level are greece (66.6%), italy (53.8%), korea (50%), and france (50%). with respect to collaborations between authors from different countries, figure 8 highlights the collaboration network identified in the selected papers. the different colors highlight the main clusters of co-authorship collaborations identified. it is clear that there are countries that have numerous collabtable 1. number of country publications and distribution of scp and mcp articles in percentage. country articles* % articles on the total sample scp %scp mcp %mcp article/population** china 200 40.6% 178 89% 22 11% 0.14 usa 41 8.3% 31 75.6% 10 24.4% 0.12 egypt 22 4.5% 22 100% 0 0% 0.20 japan 22 4.5% 20 90.9% 2 9.1% 0.18 germany 16 3.2% 13 81.2% 3 18.8% 0.19 india 14 2.8% 14 100% 0 0 0.01 iran 14 2.8% 11 78.6% 3 21.4% 0.16 united kingdom 14 2.8% 8 57.1% 6 42.9% 0.20 italy 13 2.6% 6 46.2% 7 53.8% 0.22 korea 12 2.4% 6 50% 6 50% 0.23 poland 12 2.4% 10 83.3% 2 16.7% 0.33 turkey 11 2.2% 10 90.9% 1 9.1% 0.13 spain 9 1.8% 8 88.9% 1 11.1% 0.19 france 8 1.6% 4 50% 4 50% 0.12 greece 6 1.2% 2 33.3% 4 66.7% 0.58 * number of articles based on the corresponding authors. ** population in millions of inhabitants. figure 7. journals number of citations over the last five years. archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 6 orations (china, usa, italy, germany, japan) and others with very limited collaborations (egypt only with jordan; india only with china; iraq only with iran; taiwan only with canada). the country scientific production (figure 9 and table 2) was also calculated by measuring the total number of authors by country affiliation. the number was obtained by considering the number of corresponding authors plus the number of co-authors of the same nationality who authored each paper. as a result, the sum of values of scientific production of all the countries is higher than the total number of papers considered (each paper contributing with more authors apart from papers with a single authorship). the results obtained numerically for the first 20 countries are reported in table 2, where the overall production and total number of citations were also related to the population of the countries (millions of inhabitants in the year 2023). china and the usa are the top countries with respectively 1660 and 430 authors identified, however, figure 9. country scientific production. the highest saturation for the major number of publications. figure 8. clusters of international collaborations. archivio italiano di urologia e andrologia 2025; 97(1):13396 7 new biomarkers for diagnosis of bladder cancer table 2. results of top ten countries based on the country scientific production. # country overall total citations/ country scientific production citations overall production/ production population * 1 china 1660 2278 1.37 1.18 2 usa 430 612 1.42 1.28 3 japan 263 347 1.32 2.11 4 united kingdom 203 193 0.95 2.97 5 germany 187 219 1.17 2.21 6 italy 171 135 0.79 2.91 7 egypt 120 201 1.68 1.06 8 turkey 107 39 0.36 1.25 9 france 101 594 5.88 1.48 10 korea 101 102 1.01 1.95 11 spain 86 80 0.93 1.78 12 india 84 40 0.48 0.06 13 iran 77 198 2.57 0.86 14 poland 71 90 1.27 1.94 15 netherlands 54 185 3.43 3.02 16 canada 47 39 0.83 1.17 17 greece 45 40 0.89 4.34 18 tunisia 43 8 0.19 3.45 19 denmark 41 9 0.22 6.89 20 romania 39 58 1.49 2.05 * population in millions of inhabitants. figure 10. countries scientific production over time. considering the country scientific production per million inhabitants, denmark, greece, tunisia, netherlands, uk, and italy are the countries with the highest scientific production. figure 10 shows the trend of publications over time, showing strong growth for china and much slower growth for the remaining countries. focusing, instead, on the citations received by the different countries (figure 11 and table 2), a different trend is noted. china, the usa and japan maintain the first positions, followed by countries such as france, or iran which obtained a high number of citations despite a lower production. this aspect could depend on numerous factors: a greater or lesser quality of the published papers, different possibilities of access to the papers (open access or subscription), or a different temporal distribution of the works with relative impact on the recorded citations. table 3 analyses the results of the different countries compared to european and non-european countries. although with a lower overall number, 94 corresponding authors and 921 country scientific production for eucountries and 380 and 3300 for the others, the works published at the european level show a higher ratio between the citations received and the works published (respectively 1.69 versus 1.31). furthermore, as also highlighted in table 2 considering table 3. results of the eucountries and no eu-countries. articles country scientific citation average citations/country average production articles/population* scientific production country scientific production/population* eu-countries 94 921 1554 0.29 1.69 2.19 no eu-countries 380 3300 4321 0.17 1.31 1.33 * population in millions of inhabitants. archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 8 the overall population of the countries considered, at the european level the number of publications and citations received per million inhabitants is higher. affiliations performance analysis going into the details of the authors’ affiliations, 1011 affiliations were identified for the 493 papers. figure 12. most relevant affiliations. figure 11. country distribution of the number of citations. table 4. affiliations’ publications over time details. figure 12 displays findings of the most relevant institutes, based on the corresponding authors, that are published the most within the field. peking university shenzhein hospital published 71 papers, followed by zhongnan hospital of wuhan university and shangai jiao tong university school of medicine with 38 and 37 papers respectively. these main institutes also show (figure 13) an increase in publications in the last 5 years. extending the evaluation to all the authors of the papers, the first five institutes are reported in table 4, with evidence also of the increase over time. affiliation country 2019 2020 2021 2022 2023 2024 tot peking university shenzhen hospital china 0 8 10 31 2 20 71 zhongnan hospital of wuhan university china 8 9 9 0 0 12 38 shanghai jiao tong university school of medicine china 5 2 0 20 10 0 37 international agency for research on cancer (iarc) france 0 26 0 5 0 0 31 central south university china 9 0 4 8 9 0 30 osaka university graduate school of medicine japan 0 16 0 14 0 0 30 total 22 61 23 78 21 32 * population in millions of inhabitants. archivio italiano di urologia e andrologia 2025; 97(1):13396 9 new biomarkers for diagnosis of bladder cancer authors performance analysis for 493 papers, a total of 3373 different authors were identified with an average of 9.42 authors per paper. only 3 articles are published by a single author. furthermore, the international co-authorship is equal to 20.08%. table 5 identifies the leading authors who published papers related to bladder cancer biomarkers in the last 5 years. li x. published 21 papers, followed by wang l, wang x. wang, y and zhang y, who published 17 articles each. li x. was the highest cited author (345), followed by wang c figure 13. affiliations’ production over time. figure 14. most relevant authors based on the number of. document over times. and wang y, who received 336 and 333 citations, respectively (table 5, figure 14). the co-occurrence of authors is shown in figure 15. documents performance analysis table 6 displays the highly cited papers on bladder cancer biomarkers. among these, a paper alix-panabieres c. et al. published in 2021, received the highest citation (457). the subsequent most highly cited articles were by usuba w et al.'s paper, which was published in 2019 and received 174 citations (table 6). archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 10 keywords performance analysis in the present analysis, various keywords were used in the domain of bladder cancer diagnostic biomarkers. keyword performance analysis was carried out excluding the keywords used for primary research for example bladder cancers, biomarker, and all similar. the keywords related to the methods applied in the papers identified (for example review, meta-analysis) were excluded. in this way, the top relevant keywords found in this analysis, according to the level of occurrence, were urine (34 papers), liquid biopsy (18 papers), urothelial carcinoma (16 papers), dna methylation (13 papers) and mirna (13 papers) (figure 16). considering the frequency over the years considered, there is a growing use of the world urine, liquid biopsy, methylation, and mirna that confirm the interest in mini-invasive research of novel biomarkers for the diagnosis of bc (figure 17). figure 15. co-authorship distribution. figure 16. most relevant keywords. table 5. most leading authors (number of papers and citations). author number of documents total citations li x. 21 345 wang l. 17 261 wang x. 17 139 wang y. 17 333 zhang y. 17 278 li y. 15 249 wang z. 15 164 li j. 14 294 wang j. 14 206 wang h. 13 262 zhang c. 13 91 zhang j. 13 257 li h. 12 124 liu x. 12 141 zhang x. 12 259 zhao y. 12 229 chen j. 11 311 chen x. 11 295 liu s. 11 167 liu y. 11 90 yang y. 11 221 chen y. 10 67 wang c. 10 336 archivio italiano di urologia e andrologia 2025; 97(1):13396 11 new biomarkers for diagnosis of bladder cancer table 6. the top ten most cited papers. authors alix-panabières c., pantel k. usuba w., urabe f., yamamoto y., matsuzaki j., sasaki h., ichikawa m., takizawa s., aoki y., niida s., kato k., egawa s., chikaraishi t., fujimoto h., ochiya t. chen x., zhang j., ruan w., huang m., wang c., wang h., jiang z., wang s., liu z., liu c., tan w., yang j., chen j., chen z., li x., zhang x., xu p., chen l., xie r., zhou q., xu s., irwin d.l., fan j.-b., huang j., lin t. zhang s., du l., wang l., jiang x., zhan y., li j., yan k., duan w., zhao y., wang l., wang y., shi y., wang c. fest j., ruiter r., mulder m., groot koerkamp b., ikram m.a., stricker b.h., van eijck c.h.j. huang j., jiang y., li j., he s., huang j., pu k. mi x., zou b., zou f., hu j. wang y., li z., lin q., wei y., wang j., li y., yang r., yuan q. yu c., longfei l., long w., feng z., chen j., chao l., peihua l., xiongbing z., hequn c. laukhtina e., shim s.r., mori k., d'andrea d., soria f., rajwa p., mostafaei h., compérat e., cimadamore a., moschini m., teoh j.y.-c., enikeev d., xylinas e., lotan y., palou j., gontero p., babjuk m., witjes j.a., kamat a.m., roupret m., shariat s.f., pradere b., european association of urology-young academic urologists (eau-yau): urothelial carcinoma working group years 2021 2019 2020 2019 2020 2020 2021 2019 2019 2021 ref. (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) source title cancer discovery cancer dcience journal of cinical investigation journal of cellular and molecular medicine international journal of cancer angewandte chemie international edition nature communications acs sensors journal of cellular physiology european urology oncology total citation (tc) 485 174 139 103 95 78 68 61 50 49 tc per year 121,25 29 27,8 17,17 19 15,6 17 10,17 8,33 12,25 title liquid biopsy: from discovery to clinical application circulating mirna panels for specific and early detection in bladder cancer urine dna methylation assay enables early detection and recurrence monitoring for bladder cancer evaluation of serum exosomal lncrna-based biomarker panel for diagnosis and recurrence prediction of bladder cancer the systemic immune-inflammation index is associated with an increased risk of incident cancer – a population-based cohort study a renal-clearable macromolecular reporter for near-infrared fluorescence imaging of bladder cancer permutation-based identification of important biomarkers for complex diseases via machine learning models highly sensitive detection of bladder cancer-related mirna in urine using time-gated luminescent biochip lncrna pvt1 regulates vegfc through inhibiting mir-128 in bladder cancer cells diagnostic accuracy of novel urinary biomarker tests in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis figure 17. keywords frequency over time. archivio italiano di urologia e andrologia 2025; 97(1):13396 r. falabella, v. de simone, f. crocetto, et al. 12 discussion to the best of the authors’ knowledge, this is the first bibliometric analysis focusing on research based on new biomarkers in the diagnosis of bladder cancer from 2019 to 2024 over the last 6 years. the scopus database was used to generate an eligible set of articles related to the topic field including only research articles from peer-reviewed journals to guarantee the high level of the publications analyzed. the six-year time interval taken into consideration was chosen with the aim of evaluating how research has evolved in the last period, how it is changing, and which are the most important and recent results. several parameters have been taken into consideration such as journals, the contribution of nations and organizations, citations, leading countries, author’s contributions and keywords. with the support of the bibliometric analysis and mapping a better visualization of organizations and dynamics of science domains have been done to make a deep description of this scientific field and to provide predictions for future trends. the analysis revealed that the distribution of publications over the 6-year interval remained almost constant, highlighting an ever-present interest in the field under study. an interesting finding of this bibliometric analysis was that most of the papers were published in the most influential and pertinent journals, having a high impact factor, this underlining that the papers published are characterized by a lot of citations. even if some countries, like egypt and india, published exclusively scp-type articles, other nations showed at least half of mcp-articles showing greater collaborations at an international level. this is the case of greece with 66.6%, italy with 53.8%, and korea and france with 50% of mcp article. the number of citations of these mcp articles underlined also the strong value of the publications on the field in analysis and the high impact on research. the main clusters of international collaborations and coauthorship were shown in figure 8 and underlined how nations like italy, the usa, china, germany, and japan had numerous collaborations while egypt, taiwan, iraq, and india showed limited collaborations, this confirming the results of our analysis on their propension to scparticles. the journals which produced the greatest number of works were cancers, international journal of molecular sciences, and frontiers in oncology and they received a high number of citations, confirming their role in producing highly impactful publications. urologic oncology: seminars and original investigations was the first purely urological journal for publications in this field, with 13 works and 147 citations. it should be noted that the top ten journals published 21% of all publications identified by our analysis. considering the number of national publications (figure 9), china was the best publisher, with the highest number of papers in this field (200), representing the 40% of all articles. the second country for the number of publications was the usa with 41 articles (8.3%). considering the pure number of citations, china is in the first place, but considering the country's production over time, figure 10 showed how china, the usa, and japan were the first publishers with a growing interest, followed by france and iran that on the contrary obtained a high number of citations despite a lower production of articles. the explanation for this phenomenon is probably linked to different factors including, better or worse quality of the works, the different possibilities of accessing these works or the different temporal distribution of the articles with a consequent different impact on citations. however, considering the overall population of the different countries, it is above all the european countries that have the greatest scientific production and also the greatest capillarity and resonance of the published works, as evidenced by the greater number of citations received. affiliation performance analysis details on author’s affiliations and most relevant institutes involved in the research. peking university shenzhein hospital was the first publisher with 71 papers, followed by zhongnan hospital of wuhan university and shangai jiao tong university school of medicine with respectively 38 and 37 papers, thus confirming that the main institutes correspond to the main country publisher (china). the analysis also confirmed the growing trend of publications of these institutes over the last 5 years, confirming the constant interest in the field of study. the authors performance analysis showed the highest cited authors, underlining how there was a correspondence between the author with the greatest number of publications and the one with the greatest number of citations, as shown in table 5. a piece of fundamental importance in our research is represented by document performance analysis which showed the most cited works. in the study of alix-panabierès c et al. (2021), enormous attention was given to the role of circulating tumor cells (ctc) and circulating tumor dna (ctdna) as new biomarkers with clinical application in early cancer detection, improved cancer staging, detection of relapse and monitoring of therapeutic efficacy (23). usuba w et al. (2019) underlined the role of mirna profiles as a tool for liquid biopsy in bladder cancer screening and performed a global mirna profiling of 392 serum samples of bladder cancer patients with 100 non-cancer samples and 480 samples of other cancers as controls, thus demonstrating that the 7-mirna panel could be a biomarker for the specific and early detection of bladder cancer (24). in this research study, a careful choice of keywords (bladder cancer; circulating microrna; diagnosis; early detection; liquid biopsy) has shown the real importance and great impact of the topic of work. in the third most cited paper, chen x et al. (2020) developed a diagnostic model capable of identifying bca-specific methylation markers and compared it with cytology and fish (25). with this model, they showed how urine tumor dna methylation assessment for early diagnosis but also for minimal residual tumor detection and surveillance in bca could be proposed as a rapid, noninvasive, and promising approach to reduce the burden of invasive methods. the keyword performance analysis showed the most relevant words used in the papers and their frequency over time. considering also the frequency over the years, there was a growing use of the words urine, liquid biopsy, archivio italiano di urologia e andrologia 2025; 97(1):13396 13 new biomarkers for diagnosis of bladder cancer methylation, and mirna that confirm that the research hotspots are supported by the interest in novel biomarkers for the diagnosis of bc. in this analysis, the choice to exclude the keywords used in the first search was dictated by the desire to increase the appropriateness of the article selection. in this way, it was possible to highlight keywords such as liquid biopsy, mirna, and urine, useful for understanding which type of research the various authors were leaning towards. these results have underlined the trend of research towards non-invasive diagnostic approaches such as urinalysis and liquid biopsy. the growing use of these words is also confirmed by the analysis of the frequency of their use in literature over the years, thus underlining that the research hotspots are supported by the interest in identifying new diagnostic methods and new biomarkers in the diagnosis of bc. conclusions this bibliometric analysis demonstrated that research on biomarkers in bc is in rapid evolution. nonetheless, this study has limitations, since we have used only one database, namely the scopus database which does not represent the entire literature, and some articles not indexed could not be included. however, bibliometric analyses are a precise instrument in the field of medicine, giving us the possibility to better understand the evolution of literature, the collaborations, and the value of the papers published. furthermore, it highlighted the links between the various nations, institutes, and authors, bringing to light the great value of collaboration between the different structures. from a clinical point of view, this bibliometric analysis has shown, through the articles taken into consideration, the propensity of the research towards non-invasive methods of diagnosis of bladder carcinoma that could support or replace conventional diagnostic methods. it has also underlined the possibility that the combination of different biomarkers could potentially improve diagnostic accuracy and contribute to increasing the accuracy (sensitivity and specificity) of the tests. although large-scale clinical trials are necessary to validate the effectiveness of these biomarkers and also evaluation of the costs of developing urinary biomarkers tests should be taken into account. references 1. karam ja, lotan y, shariat sf. urine cytology and commercially available urine-based markers for monitoring of bladder urothelial carcinoma. lab med. 2007; 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109:103516. 23. alix-panabières c, pantel k. liquid biopsy: from discovery to clinical application. cancer discov. 2021; 11:858-73. 24. usuba w, urabe f, yamamoto y, et al. circulating mirna panels for specific and early detection in bladder cancer. cancer sci. 2019; 110:408-19. 25. chen x, zhang j, ruan w, et al. urine dna methylation assay enables early detection and recurrence monitoring for bladder cancer. j clin invest. 2020; 130:6278-89. 26. zhang s, du l, wang l, et al. evaluation of serum exosomal lnc rna-based biomarker panel for diagnosis and recurrence prediction of bladder cancer. j cell mol med. 2019; 23:1396-405. 27. fest j, ruiter r, mulder m, et al. the systemic immune-inflammation index is associated with an increased risk of incident cancer— a population-based cohort study. int j cancer. 2020; 146:692-8. 28. huang j, jiang y, li j, et al. a renal-clearable macromolecular reporter for near-infrared fluorescence imaging of bladder cancer. angew chem int ed. 2020; 59:4415-20. 29. mi x, zou b, zou f, hu j. permutation-based identification of important biomarkers for complex diseases via machine learning models. nat commun. 2021; 12:3008. 30. wang y, li z, lin q, et al. highly sensitive detection of bladder cancer-related mirna in urine using time-gated luminescent biochip. acs sens. 2019; 4:2124-30. 31. yu c, longfei l, long w, et al. lncrna pvt1 regulates vegfc through inhibiting mir-128 in bladder cancer cells. j cell physiol. 2019; 234:1346-53. 32. laukhtina e, shim sr, mori k, et al. diagnostic accuracy of novel urinary biomarker tests in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. eur urol oncol. 2021; 4:927-42. correspondence roberto falabella, md rfalabella@libero.it vincenzo francesco caputo, md (corresponding author) vincitor@me.com unit of urology, aor san carlo, potenza, italy via potito petrone 85100 potenza, italy valentina de simone vadesimone@unisa.it valentina di pasquale vdipasquale@unisa.it department of industrial engineering, university of salerno, italy felice crocetto, md felice.crocetto@unina.it unit of urology, department of neurosciences, reproductive science and odontostomatology, university of naples federico ii, naples, italy francesco del giudice, md francesco.delgiudice@uniroma1.it department of maternal infant and urological sciences, sapienza university rome, policlinico umberto 1 hospital, rome, italy angelo porreca, md angeloporreca@gmail.com oncological urology, veneto institute of oncology (iov). irccs, padua, italy biagio barone, md biagio.barone@aslnapoli1centro.it department of urology, p.o. san paolo, asl na1 centro, 80125, naples, italy nazario foschi, md nazario.foschi@policlinicogemelli.it luca di gianfrancesco, md dr.lucadigianfrancesco@gmail.com department of urology, fondazione policlinico universitario agostino gemelli, irccs, università cattolica del sacro cuore, rome, italy stesura seveso archivio italiano di urologia e andrologia 2023; 95, 2 57 original paper was a significant risk factor (7, 8). however, the results of multivariable analyses assessing the prognostic significance of type2 prcc histological subtype are incoherent (9, 10). in this context, outcomes may vary depending on the prcc type and tumor stage. the aim of this study was to compare os, css and rfs of patients diagnosed with prcc and ccrcc and define the factors affecting survival in the patient population with localized disease. materials and methods patients with renal cell carcinoma (rcc), who underwent radical or partial nephrectomy due to renal tumors, whose data were obtained from a series of 5300 patients with kidney tumors included in the urologic cancer database kidney (urocad-k) of turkish urooncology association (tuoa) were evaluated retrospectively. pathological stage and grade were determined according to the 2002 union internationale contre le cancer tnm classification, and fuhrman classification (g1-g4), respectively. tumor size was measured using the computed tomography (ct) and taking the largest diameter. histological subtypes were classified according to the heidelberg classification (1): ccrcc, prcc, chromophobe, bellini duct, and unclassified rcc. patients from urocad-k database, who had pathological t1-t2 ccrcc and prcc were evaluated in the study. according to the two histological subtype, recurrence and mortality status, recurrence free survival (rfs), overall survival (os) and cancer-specific survival (css) data were analyzed. the follow-up protocol of the patients was arranged according to the eau-rcc guideline. statistical analysis analyses were performed by the using of statistical package for the social sciences (spss) version 22.0. chiobjectives: to compare overall survival (os), recurrence free survival (rfs), and cancer-specific survival (css) in the long-term follow-up of t1 and t2 clear-cell-renal cell carcinoma (ccrcc) and papillary renal cell carcinoma (prcc) patients, as well as to determine the risk factors for recurrence and overall mortality. material and method: data of patients with kidney tumors obtained from the urologic cancer database kidney (urocad-k) of turkish urooncology association (tuoa) were evaluated retrospectively. out of them, patients who had pathological t1-t2 ccrcc and prcc were included in the study. according to the two histological subtype, recurrence and mortality status, rfs, os and css data were analyzed. results: rfs, os and css of prcc and ccrcc were found to be similar. radiological local invasion was shown to be a risk factor for recurrence in prcc, and age was the only independent factor affecting overall mortality. conclusions: there were no differences in survivals (rfs, os and css) of patients with localized papillary and clear cell rcc. while age was the only factor affecting overall mortality, radiological local invasion was a risk factor for recurrence in papillary rcc. key words: kidney cancer; renal cell carcinoma; clear cell rcc; papillary type rcc; recurrence, survival. submitted 26 january 2023; accepted 17 february 2023 introduction almost twenty years ago the heidelberg classification system recognized the histological subtypes of renal cell carcinoma (rcc) as clear cell (cc)-rcc, with a frequency of 70-88% in most series, papillary (p)-rcc accounting for 10-15% and other rcc accounting for less than 10% (1, 2). several studies have uniformly reported that a prcc histology is associated with a favorable prognosis compared with clear cell rcc (ccrcc) (3-6). in other studies, prcc oncological outcomes of papillary versus clear cell renal cell carcinoma in pt1 and pt2 stage: results from a contemporary turkish patient cohort taha cetin 1, serdar celik 1, sinan sozen 2, bulent akdogan 3, volkan izol 4, guven aslan 5, evren suer 6, yildirim bayazit 4, nihat karakoyunlu 7, haluk ozen 3, sumer baltaci 6, fatih gokalp 8, ilker tinay 9, members of turkish urooncology association 1 izmir bozyaka research and training hospital urology department, izmir, türkiye; 2 gazi university faculty of medicine urology department, ankara, türkiye; 3 hacettepe university faculty of medicine urology department, ankara, türkiye; 4 cukurova university faculty of medicine urology department, adana, türkiye; 5 dokuz eylul university faculty of medicine urology department, izmir, türkiye; 6 ankara university faculty of medicine urology department, ankara, türkiye; 7 university of health sciences dıskapi yildirim beyazit research and training hospital urology department, ankara, türkiye; 8 mustafa kemal university tayfur ata sokmen medicine faculty urology department, hatay, türkiye; 9 marmara university faculty of medicine urology department, istanbul, türkiye. doi: 10.4081/aiua.2023.11218 summary archivio italiano di urologia e andrologia 2023; 95, 2 t. cetin, s. celik, s. sozen, et al. 58 square and student t-tests were used to compare categorical and continuous data, respectively. the relationship between tumor size and histological subtype was analyzed with logistic regression models. the kaplan-meier method was used to estimate tumor specific survival, and comparison was performed by the log-rank test. multivariate cox proportional hazard models were used to detect independent variables with a p < 0.05 considered to indicate statistical significance. results the clinical, pathological and oncological data of the patients are shown in table 1. among 5300 patients, 2129 patients who had pathological t1-t2 ccrcc and prcc were included in the study. the mean age was 57.7 ± 11.8 years and two-thirds of the patients were male. there were 1700 patients with ccrcc, while the prcc was observed in 429 patients. patients in the ccrcc group were younger and had a higher bmi. (p values were < 0.001 and 0.004, respectively). radiological tumor size was statistically found to be smaller in prcc than ccrcc group (mean size were 4.7 cm vs 5cm, p = 0.001). we detected that radiologically < 4 cm tumors were more frequent in the prcc group that ccrcc (p = 0.034). the finding of radiological local invasion was also more common in ccrcc, but there was no statistically difference (5.4% vs 3.5%). there was no statistically difference between the groups when we evaluated them in terms of pathological tumor size and fuhrman grade. considering the postoperative follow-up periods, the mean follow-up time for ccrcc and prcc were 25.2 months and 26.1 months, respectively (p = 0.613). pathological t stage and radiological local invasion were found to be risk factors for recurrence in ccrcc. age, radiological local invasion and fuhrman grade 3-4 were found to be independent risk factors affecting overall mortality in patients with ccrcc. in prcc patients, radiological local invasion was found to be an independent risk factor for recurrence and age was a risk factor for overall mortality (table 2). in addition, rfs, os and css were not statistically different between the groups (figure 1). discussion we aimed to discuss os, css and rfs of patients diagnosed with prcc and ccrcc and define the factors affecting survival in patient population with pt1 and pt2 disease. it was observed that ccrcc was seen in younger patients and in patients with higher bmi, and that prcc was more common in males. papillary type pathology was radiologically smaller and was more frequently evaluated as pt1a than clear cell type. radiological local invasion and age were found to be independent risk factors for recurrence and overall mortality, respectively for both groups. pathological stage was also a risk factor for recurrence in ccrcc. in addition, during the follow-up, os, css and rfs were not statistically different for both groups in pt1 and pt2 disease. the two most important factors determining the outcome of rcc are nuclear grade and tumor stage (11). according to some authors, apart from these two factors, histological subtype was also an independent prognostic factor (12). table 1. clinical, pathological and oncological data of the patients. ccrcc (n = 1700) prcc (n = 429) p age (year) 56.7 ± 12 59.6 ± 11.8 < 0.001 sex, n (%) female 641 (37.9) 72 (16.8) < 0.001 male 1048 (62.1) 356 (83.2) bmi (kg/m2) 28.3 ± 5 27 ± 4 0.004 radiological tumor size (cm) 5 ± 3 4.7 ± 3 0.001 tumor diameter, n (%) < 4 cm 787 (46.4) 226 (52.6) 0.034 4-7 cm 626 (36.8) 126 (29.4) 7-10 cm 209 (12.3) 55 (12.8) > 10 cm 77 (4.5) 22 (5.2) radiological organ confined, n (%) localized 1609 (94.6) 414 (96.5) 0.114 locally invasive 91 (5.4) 15 (3.5) pathological tumor size (cm) 5±2.8 5.2±3.2 0.155 pathological t stage, n (%) t1a 806 (37.1) 216 (43.4) 0.05 t1b 606 (28.4) 129 (25.7) t2a 214 (10.9) 55 (11.6) t2b 74 (4.1) 29 (6.3) fuhrman grade, n (%) 1-2 986 (70.4) 177 (67.8) 0.385 3-4 413 (29.6) 70 (32.2) relapse, n (%) 33 (1.94) 10 (2.33) 0.608 overall mortality, n (%) 37 (2.17) 11 (2.6) 0.629 cancer specific mortality, n (%) 10 (0.6) 2 (0.5) 0.556 mean follow-up time (months) 25.2 ± 30.3 26.1 ± 30.7 0.613 table 2. factors affecting recurrence and overall mortality in ccrcc and prcc groups. histologic subtype recurrence overall mortality univariate multivariate univariate multivariate p value or (ci) p value or (ci) ccrcc • age 0.958 0.002 1.056 (1.023-1.090) • sex 0.370 0.084 • bmi 0.279 0.471 • pathological tumor size 0.071 0.105 • pathological stage 0.044 1.447 (1.006-2.081) 0.091 • radiological local inv. 0.007 4.136 (1.663-10.287) 0.044 • fuhrman 3-4 0.952 0.033 prcc • age 0.444 0.026 1.066 (1.009-1.127) • sex 0.069 0.128 • bmi 0.270 0.131 • pathological tumor size 0.776 0.275 • pathological stage 0.423 0.474 • radiological local inv. 0.044 7.808(1.507-40.450) 0.673 • fuhrman 3-4 0.406 0.681 archivio italiano di urologia e andrologia 2023; 95, 2 59 papillary clear cell carcinoma outcomes type 1 prcc is associated with met alteration or trisomy of chromosome 7 where the met gene is located, while type2 prcc shows allelic imbalance on chromosomes 1p, 3p, 5, 6, 8, 9p, 10, 11, 15, 18 and 22 (13, 14). according to the study shared by waldert et al. 5-year css was 94% in type 1 prcc and 74% in type 2 prcc (p = 0.027). during the follow-up, the overall css for m0 patients with prcc and ccrcc (90% vs 84% respectively) was not significantly different). steffens et al. evaluated long-term survival of prcc versus ccrcc. in this series, patients with prcc had significantly higher 5-yr css rate (85.1% vs 76.3%; p = 0.001). notably, at multivariable analysis, the papillary subtype was significantly associated with favorable oncologic outcome in localized rcc but was an independent negative prognostic factor in metastatic patients. these results could be evaluated separately for papillary type 1 and type 2, but this was not evaluated in the study (14). in addition, authors have shown that type 1 and type 2 rcc have similar clinical and histopathological features, but lymphovascular invasion (lvi) in type 2 prcc worsened css rate, compared to type1 prcc (5). in a multicenter study involving more than four thousand patients from eight international centers, patients with prcc had better 5-year css than patients with ccrcc in univariate analysis (73% versus 79% respectively). in multivariate analysis, the histological subtype was not an independent prognostic factor (15). five studies with 32.158 patients indicated that prcc had a better prognosis than ccrcc (3, 6, 16-18), while other 5 studies including 3674 patients showed that prcc was an independent predictor of poor outcomes (4, 7, 8, 19, 20). according to the results of the metaanalysis including these studies, prcc was associated with better outcomes than ccrcc in patients with nonmetastatic disease, but not in patients with metastatic disease. type 2 prcc had worse prognosis than ccrcc, but no significant difference was found with type 1 prcc. in this study, it was observed that the tumor size was smaller in prcc. in the study of waldert et al. tumor size was also smaller in prcc (mean 4.5 cm) compared to ccrcc (mean 5.5 cm) (p = 0.013) (14). traditionally, p-rcc is divided into 2 types: type 1 is characterized by a basophilic cytoplasm and is classified as a low-grade tumor, while type 2 displays a bulky eosinophilic cytoplasm and pseudostratified tumor cell nuclei and is considered a high-grade tumor (3). compared to type 1 p-rcc, type 2 p-rcc presents more frequently as a locally advanced disease and is associated with more aggressive clinicopathologic features and significantly worse outcome (9, 10, 14, 21). our study had some limitations. most important limitations are the retrospective analysis and the multi-centered design with pathological evaluation not performed in a single centre. evaluation of the patients by experts in urooncology may reduce the disadvantage of multi-center data analysis. in addition, not taking into the account the prcc subtypes can be considered among the limitations of the study. conclusions in conclusion, rfs, os and css were similar between prcc and ccrcc patients with localized disease. although it was not statistically significant, it is obvious that the histopathological and therefore cancer biology of the most common rcc subtypes are different. the management of patients should be planned according to the stage and subtype of the disease. references 1. kovacs g, akhtar m, beckwith bj, et al. the heidelberg classification of renal cell tumours. j pathol. 1997; 183:131-3. 2. pantuck aj, zisman a, belldegrun as. the changing natural history of renal cell carcinoma. j urol 2001; 166:1611-1623. 3. wagener n, edelmann d, benner a, et al. european association of urology (eau) young academic urologists (yau) kidney cancer group. outcome of papillary versus clear cell renal cell carcinoma varies significantly in non-metastatic disease. plos one. 2017; 12:e0184173. 4. nguyen dp, vertosick ea, corradi rb, et al. histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy. urol oncol. 2016; 34:259.e1-8. figure 1. kaplan-meier survival analysis of recurrence-free survival (rfs), overall survival (os), cancer specific survival (css) between pathological t1-t2 ccrcc and prcc. archivio italiano di urologia e andrologia 2023; 95, 2 t. cetin, s. celik, s. sozen, et al. 60 5. steffens s, janssen m, roos fc, et al. incidence and long-term prognosis of papillary compared to clear cell renal cell carcinoma--a multicentre study. eur j cancer. 2012; 48:2347-52. 6. teloken pe, thompson rh, tickoo sk, et al. prognostic impact of histological subtype on surgically treated localized renal cell carcinoma. j urol. 2009; 182:2132-6. 7. yoo s, you d, jeong ig, et al. histologic subtype needs to be considered after partial nephrectomy in patients with pathologic t1a renal cell carcinoma: papillary vs. clear cell renal cell carcinoma. j cancer res clin oncol. 2017; 143:1845-1851. 8. kondo t, ikezawa e, takagi t, et al. negative impact of papillary histological subtype in patients with renal cell carcinoma extending into the inferior vena cava: single-center experience. int j urol. 2013; 20:1072-7. 9. delahunt b, eble jn, mccredie mr, et al. morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. hum pathol. 2001; 32:590-5. 10. pignot g, elie c, conquy s, et al. survival analysis of 130 patients with papillary renal cell carcinoma: prognostic utility of type 1 and type 2 subclassification. urology. 2007; 69:230-5. 11. gudbjartsson t, hardarson s, petursdottir v, et al. histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients. eur urol. 2005; 48:593-600. 12. cheville jc, lohse cm, zincke h, et al. comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. am j surg pathol. 2003; 27:612-24. 13. jiang f, richter j, schraml p, et al. chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. am j pathol. 1998; 153:1467-73. 14. antonelli a, tardanico r, balzarini p, et al. cytogenetic features, clinical significance and prognostic impact of type 1 and type 2 papillary renal cell carcinoma. cancer genet cytogenet. 2010; 199:128-33. 15. waldert m, haitel a, marberger m, et al. comparison of type i and ii papillary renal cell carcinoma (rcc) and clear cell rcc. bju int. 2008;102:1381-4. 16. patard jj, leray e, rioux-leclercq n, et al. prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. j clin oncol. 2005; 23:2763-71. 17. lee wk, lee se, hong sk, et al. characteristics and prognostic value of papillary histologic subtype in nonmetastatic renal cell carcinoma in korea: a multicenter study. urol j. 2014; 11:1884-90. 18. keegan ka, schupp cw, chamie k, et al. histopathology of surgically treated renal cell carcinoma: survival differences by subtype and stage. j urol. 2012; 188:391-7. 19. beck sd, patel mi, snyder me, et al. effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. ann surg oncol. 2004; 11:71-7. 20. simone g, tuderti g, ferriero m, et al. papillary type 2 versus clear cell renal cell carcinoma: survival outcomes. eur j surg oncol. 2016; 42:1744-1750. 21. kim kh, you d, jeong ig, et al. type ii papillary histology predicts poor outcome in patients with renal cell carcinoma and vena cava thrombus. bju int. 2012; 11:e673-8. correspondence taha cetin, md, febu (corresponding author) tahacetin88@gmail.com serdar celik, md serdarcelik84@hotmail.com izmir bozyaka research and training hospital urology department, izmir, türkiye sinan sozen, md sinansozen@usa.net gazi university faculty of medicine urology department, ankara, türkiye bulent akdogan, md blntakdogan@yahoo.com haluk ozen, md drhalukozen@gmail.com hacettepe university faculty of medicine urology department, ankara, türkiye volkan izol, md volkanizol@yahoo.com yildirim bayazit, md ybayazit@yahoo.com cukurova university faculty of medicine urology department, adana, türkiye guven aslan, md drguvenaslan@gmail.com dokuz eylul university faculty of medicine urology department, izmir, türkiye evren suer, md drevrensuer@gmail.com sumer baltaci, md baltacisumer@gmail.com ankara university faculty of medicine urology department, ankara, türkiye nihat karakoyunlu, md nkarakoyunlu@gmail.com university of health sciences dıskapi yildirim beyazit research and training hospital urology department, ankara, türkiye fatih gokalp, md fatihgokalp85@gmail.com mustafa kemal university tayfur ata sokmen medicine faculty urology department, hatay, türkiye ilker tinay, md ilker_tinay@yahoo.com marmara university faculty of medicine urology department, istanbul, türkiye conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12899 1 original paper penis in relation to the scrotum (1). it is categorized as complete or incomplete variants based on the location of the penis. in incomplete pst, the more common variant, the penis, lies in the middle of the scrotum, while in complete pst, the penis emerges from the perineum and is covered by the scrotum entirely (2). pst is rarely isolated and frequently occurs with a broad spectrum of malformations, including a strong association with severe hypospadias and chordee (3). surgery is the gold standard of pst management, with various surgical techniques utilized for pst correction, including reorienting the scrotum inferiorly with limited rotational flaps, inguinal-based groin flaps, or transposing the penis superiorly (4). this study aimed to evaluate our experience and longterm results with pst correction using a modified glennanderson technique. materials and methods study population following institutional board approval (shaare zedek medical center helsinki committee approval number 030322-szmc), we have conducted a retrospective cohort study by collecting data on all patients with pst who underwent surgical repair in our department between 2004 to 2022. a single pediatric urologist (bc) performed all surgeries. patients were categorized into three groups: in the first group, pst repair was an integral part of one-stage male genitoplasty; in the second group, pst repair was a separate last stage of the staged hypospadias repair; and the third group consisted of patients without hypospadias. only patients with recent follow-ups entered the study, including patients who attended an office visit or provided a recent photographic image of the operative site and answered questions regarding satisfaction with the surgery, lower urinary function, and curvature status. additional information included age at the time of surgery, preoperative chordee and hypospadias severity, other genital anomalies and congenital malformations, type of operation, and postoperative complications. the surgical technique briefly, all patients were considered for surgery after the age of six months. hormonal supplementation was given objective: penoscrotal transposition (pst) is a rare anomaly of the external genitalia characterized by malposition of the penis in relation to the scrotum. this transposition may be partial or complete and may be associated with hypospadias, chordee, and other anomalies. we have reviewed our experience with the surgical repair of pst utilizing a modified glenn-anderson technique. materials and methods: twenty-nine patients with a median age of 5.6 years (8 months-15 years) underwent surgical repair of pst at our institution between 2004-2022. of those, 20 (69%) had complete pst, while 9 (31%) had partial pst. all children were divided into three groups. in the first group of 8 (28%) children, repair of pst was an integral part of one-stage male genitoplasty; in the second group of 18 (62%) children, repair of pst was an isolated last stage of the staged hypospadias repair, and the remaining 3 (10%) children underwent pst repair without the presence of hypospadias. all patients underwent modification of the glenn-anderson technique involving utilization of bilateral rotational advancement scrotal flap, complete de-tethering of the testis from the internal part of the scrotum when indicated, and relocation of the scrotal compartment in a normal dependent position. the follow-up ranged from 6 months to 18 years. results: in the first group, five children (62%) underwent onlay prepucial island pedicle flap (oif) hypospadias repair, and three (38%) underwent long tubularized incised plate repair (tip). in the second group, 8 (44%) underwent oif hypospadias repair, 2 (12%) had long tip repair, and the remaining 8 (44%) underwent staged hypospadias repair. post-operative clavien dindo grade iii complications presented in three patients in group i and only one patient in group ii. in the third group, no postoperative complications were observed. conclusions: our data show that penoscrotal transposition correction utilizing the glenn-anderson technique is a reliable and durable surgery in the pediatric population. these children require careful monitoring till adolescence to ensure that no reoperation is needed. key words: glenn-anderson technique; hypospadias; penoscrotal transposition; transverse island flap onlay; tubularized incised plate repair. submitted 4 august 2023; accepted 31 august 2023 introduction penoscrotal transposition (pst) is a rare anomaly of the external genitalia, characterized by malposition of the penoscrotal transposition: long-term outcome in 29 patients dolev perez 1, stanislav kocherov 2, gaudat jaber 2, galiya raisin 2, boris chertin 1, 2 1 departments of urology and 2 pediatric urology, shaare zedek medical center, jerusalem, israel. doi: 10.4081/aiua.2024.12899 summary archivio italiano di urologia e andrologia 2024; 96(3):12899 d. perez, s. kocherov, g. jaber, g. raisin, b. chertin 2 to those with a small phallus, with the utilization of topical testosterone cream twice daily before surgery for one month to accomplish penile lengthening with the avoidance complication of hypothalamus pituitary-testicular axis, as we recently reported (5). in patients where pst repair was performed as a separate procedure, the first step was to draw lines of an incision around the root of the penis to elevate the transposed scrotum as rotational advancement flaps leaving the dorsal penile skin connected to the skin of mons pubis (figure 1). compared to the other surgical techniques, the incision does not meet in the midline as in glennanderson. still, it leaves a skin bridge of about 5-10 mm, separating the two incisions and connecting the penile skin to the skin of the mons pubis (figure 2). the second step included a complete de-tethering of the testis from the internal part of the scrotum when indicated, and the relocation of the scrotal compartment to a typical dependent position (figure 3). the two scrotal wings were then rotated inferomedially behind the penis (figure 4). in patients who underwent penoscrotal transposition repair as an integral part of a hypospadias repair, we followed the steps above: full penile degloving and penile curvature correction. in these cases, a tunica vaginalis flap was harvested from the testis and spread over the neourethra when indicated as part of the hypospadias repair. figure 5 presents the final result at the end of surgery. all patients had one routine follow-up visit six months and one year after surgery. subsequently, those without complications were advised to return to the clinic at age 12 to 13 years and at age 18 years upon the completion of adolescence or before recruitment into the army unless there were urological problems or dissatisfaction with the surgical or functional outcome. figure 6 shows long-term follow-up after penoscrotal transposition repair. statistical analysis qualitative variables are presented as frequencies and percentages, while quantitative variables are presented as means ± standard deviation (sd). all data were analyzed using the statistical package for social sciences (spss) by ibm software version 26.0. figure 1. drawing surgical landmark on external genitalia before surgery, lines of an incision around the root of the penis to elevate the transposed scrotum. figure 6. an 18-year-old patient who underwent multiple surgeries with a long-term follow-up for 14 years post-operative. figure 2. designing the scrotal rotational flaps. figure 4. scrotal flap rotated inferomedially. figure 5. appearance of the scrotum at the end of surgery. figure 3. complete dissection of scrotal flaps. archivio italiano di urologia e andrologia 2024; 96(3):12899 3 penoscrotal transposition results a total of 29 patients who underwent pst repair using the glenn-anderson technique were included. of those, 20 (69%) had complete spt, while 9 (31%) had incomplete spt variants. demographic and patient characteristics by group are presented in table 1. in group i (n = 8), five patients (62%) underwent oif hypospadias, and 3 (38%) had long tip urethroplasty. two clavien dindo grade ii complications were observed in this group; both cases developed wound infections which were treated by intravenous antibiotics. three patients (38%) required re-operation for pst due to unsatisfactory cosmetic results at an average of two years after the first operation. in group ii (n = 18), eight patients (44%) underwent oif repair, two (12%) had long tip urethroplasty, and the remaining eight (44%) underwent staged hypospadias repair. two patients with clavien dindo grade ii complications were observed in this group; both have had wound infections treated by intravenous antibiotics. six patients presented with late complications secondary to urethral repair, including a buried penis in two patients (50%), urethercutaneus fistula in three (33%), and meatal stenosis in two patients (17%). only one patient (5.5%) required secondary pst repair due to unsatisfactory cosmetic results two years following the original procedure. in group iii (n = 3), no postoperative complications were observed, and no additional procedures were required (table 2). according to severity of malformation, one (5%) patient with complete penoscrotal transposition had clavien dindo grade iii following staged hypospadias repair; three (33%) patients with partial penoscrotal transposition had clavien dindo grade iii following oif hypospadias repair. during a median follow-up of 13 years, satisfactory anatomical, cosmetic, and functional results were obtained in all patients, excluding a single post-pubertal patient from group ii awaiting a re-do pst repair. discussion pst describes an improper anatomical relationship between the penis and the scrotum, in which the scrotum is viewed as being improperly positioned in reference to the penis. the surgical correction of pst is a very complex one. although one of the most popular surgical techniques for pst repair is the glenn and anderson technique, data goes back to the seventies, and the medical literature on its usage and long-term results is scarce (6). in addition, the recent evolution in hypospadias surgical techniques has greatly influenced the approach to penoscrotal hypospadias repair and, as a result, pst surgery. at the beginning of our learning curve, most patients (group i) underwent long tip hypospadias repair combined with penile curvature repair and simultaneous reconstruction of pst. a third of the patients in this group required re-intervention due to unsatisfactory cosmetic results. in the second and third groups, patients underwent pst repair as a separate step of hypospadias repair or as an isolated condition, resulting in a better outcome than patients from the first group. we have attributed this to the fact that the repair of pst was carried out as a stand-alone procedure, and nowadays, therefore, we do recommend proceeding with pst reconstruction as a separate last stage of male genitoplasty following curvature repair and urethroplasty. as we have aforementioned, it is essential to perform a meticulous dissection of the rotational advancement flaps of the scrotum, leaving the dorsal penile skin connected to the skin of the mons pubis. in some cases, complete detachment of the testis on both sides is essential to reach full mobility of the scrotal flaps and to bring them into regular dependent positions below the penile shaft. by using this technique as a separate step of male genitoplasty, we preserve the blood supply to the urethra and do not jeopardize the blood supply of the penile shaft skin. being penile edema, one of the most common complications of pst repair (7), we recommend reserving a bridge of the dorsal penile skin during a single and staged repair procedure. we believe this maneuver avoids the development of penile edema, speeds overall recovery, and enhances early hospital discharge. we have previously published data on the re-intervention rates in post-pubertal patients after pre-pubertal hypospadias repair (8). approximately 5% of all patients with satisfactory outcomes of hypospadias surgery during childhood required re-intervention after they reached puberty. one of the major drawbacks of all studies on pst repair is a lack of long-term data. in this study, 21 patients (72%) have reached puberty, and 16 (55%) comtable 1. patients characteristics. group i group ii group iii (n = 8) (n = 18) (n = 3) median age at 1st surgery (months) 18 ± 10 79 ± 48 78 ± 51 preoperative testosterone, %(n) 12.5 % (1) 44.4% (8) 0% additional anomalies, %(n): 62.5% (5) 44.4% (8) 66.6% (2) undescended testis (rt /lt /bilateral) 3/0/2 2/0/6 1/0/1 inguinal hernia 11.1% (2) 25% (2) 100% (3) chordee 87.5% (7) 66.6% (12) 0% micropenis 0% 5.5% (1) 0% heart anomalies 0% 5.5% (1) 0% kidney anomalies 0% 0% 0% chromosomal anomalies, %(n) 12.5% (1) 11.1% (2) 0% table 2. operation type and post-operative complication (clavien-dindo classification). group i group ii group iii (n = 8) (n = 18) (n = 3) 1. onlay prepucial island pedicle flap %(n) 62% (5) 44% (8) 0% 2. long tip hypospadias %(n) 38% (3) 12% (2) 0% 3. staged hypospadias %(n) 0% 44 % (8) 0% complication %(n) 62.5% (5) 16.6% (3) 0% grade i 0% 0% grade ii 25% (2) 11% (2) grade iii 37.5% (3) 5.5% (1) archivio italiano di urologia e andrologia 2024; 96(3):12899 d. perez, s. kocherov, g. jaber, g. raisin, b. chertin 4 pleted their puberty period with sufficient post-pubertal follow-up. of those, one patient from group ii is waiting for re-intervention due to poor functional results. we believe that our modification of the glenn anderson technique, allowing an extensive dissection of the scrotal folds without jeopardizing blood supply and preserving skin integrity, as well as the separation of pst surgery from hypospadias and curvature repair, provides the best solution for pst patients with durable long-term results. this surgical approach is entirely different from another popular technique for pst repair, proposed by mark and his colleagues, stating that the penis and not the scrotum were mispositioned (9). in their technique, after penile straightening, the penis is transferred into a button-hole designed in the skin of the mons-pubis. we have had minimal experience with this technique at the beginning of our learning curve and have witnessed tethering of the scrotum to the ventral penile surface in one case and buried penis in the second case. therefore, we have omitted this technique from our surgical armamentarium. since our experience with this technique is very limited, we have not found it appropriate to compare both methods, but only to mention it for the sake of discussion. our study is not without limitations, which need to be mentioned. this a retrospective observation that suffers all the flaws of this kind of study. we have reported our outcome only on a single surgical technique and mentioned our dissatisfaction with other techniques in the discussion section. however, we do report one of the longest follow-ups on pst repair in the literature with durable post-pubertal data. we could not provide any data on the sexual function of our patients following pst repair. still, we do believe that will not be different from our previously published data regarding the sexual and voiding status of the patients who underwent hypospadias repair (10). we did not use any validated questionnaire or objective criteria for cosmetic appearance after surgical correction. however, 55% of our patients are capable of expressing their own satisfaction with the appearance of external genitalia, and the success of the operation was defined based on the patients and not the surgeons' or parents’ satisfaction with the surgical outcome. of course, missing data on the sexual and voiding status of these patients will be a subject of our future studies. conclusions pst is a rare genital anomaly with a broad spectrum of presentation, often associated with other anomalies, mainly undescended testis and hypospadias. surgically correcting these anomalies required a complex learning curve with different practice methods. our data show that penoscrotal transposition correction utilizing the modified glenn-anderson technique is a reliable and durable surgery in the pediatric population. these children require careful monitoring even in adolescence to ensure that no re-operation is needed. the sexual function and voiding status in these patients should be an objective of future studies. references 1. boddepalli y, kota m, banavath a. correction of penoscrotal transposition with hypospadias—single stage repair. indian j surg 2020; 82:1176-1178. 2. fahmy ma, el shennawy aa, edress am. spectrum of penoscrotal positional anomalies in children. int j surg. 2014; 12:983-8. 3. somoza i, palacios mg, mednez r, vela d. complete penoscrotal transposition: a three-stage procedure. indian j surg. 2012; 28:450452. 4. pinke la, rathbun sr, husmann da, kramer sa. penoscrotal transposition: review of 53 patients. j urol. 2001; 166:1865-8. 5. chertin b, natsheh a, ben-zion i, et al. objective and subjective sexual outcomes in adult patients after hypospadias repair performed in childhood. j urol. 2013; 190(4 suppl):1556-60. 6. glenn jf, anderson ee. surgical correction of incomplete penoscrotal transposition. j urol. 1973; 110:603-5. 7. khan m, majeed a, hayat w, et al. hypospadias repair: a single centre experience. plast surg int. 2014; 2014:453039. 8. chertin b, prat d, shenfeld oz. outcome of pediatric hypospadias repair in adulthood. open access j urol. 2010; 2:57-62. 9. dresner ml. surgical revision of scrotal engulfment. urol clin north am. 1982; 9:305-10. 10. mureau ma, slijper fm, van der meulen jc, et al. psychosexual adjustment of men who underwent hypospadias repair: a norm-related study. j urol. 1995; 154:1351-5. correspondence dolev perez, md (corresponding author) drdolevperez@gmail.com department of urology, shaare zedek medical center jerusalem, 91031, p.o.b 3235, israel stanislav kocherov, md kocherovs@szmc.org.il gaudat jaber, md jawdat@szmc.org.il galiya raisin, md rgal@szmc.org.il department of pediatric urology, shaare zedek medical center, jerusalem, israel boris chertin, md dechertinb@szmc.org.il departments of urology and pediatric urology, shaare zedek medical center, jerusalem, israel conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13820 1 original paper introduction renal cell carcinoma (rcc) with a tumor thrombus (rcctt) carries a high morbidity and mortality. incidence is estimated around 4-10%, and it is well-established that patients with a tumor thrombus tend to have poor prognosis (1, 2). survival of these patients ranges at five years from 18%-57% depending on the study and patient characteristics being examined (3). there has recently been an important renewed focus on disparities in health access and survival outcomes in urology. race has been studied for its association with inequities for rcc. strong evidence exists that black race predisposes patients to worse treatment outcomes, and this research has highlighted the need for more equitable treatment in rcc to ensure the best outcomes for all patients (4, 5). while the impact of race is undoubtedly an area that necessitates further research for rcc, global disparities in presentation, management, and outcomes also exist and have lacked the appropriate attention in the literature currently. it is estimated that there will be nearly 400,000 new cases of rcc worldwide and 175,000 deaths in the year 2024 (6). current evidence shows that rcc incidence is higher in north america (na) and europe relative to other continents, and this has been theorized to be due to greater rates of abdominal imaging in these areas (7, 8). nevertheless, purpose: with multi-institutional collaboration, the purpose of this study was to analyze geographical differences of renal cell carcinoma with tumor thrombus between patients in north america, central/south america, and south korea. materials and methods: patients with renal cell carcinoma and a tumor thrombus who underwent nephrectomy plus thrombectomy were retrospectively analyzed. patients were from north america, central/south america, and south korea. all comparisons were done based on the region where a patient had their surgery and follow-up. chi-squared test, analysis of variance, kaplan-meier survival with log-rank test, and cox regression analysis were used. results: a total of 478 patients were included, 212 from north america, 209 from central/south america, and 57 from south korea. of note, thrombus level was different using the neves classification system between regions (p < 0.001), with a greater thrombus level in central/south america. surgical approach differed, with laparoscopic cases done most often in central/south america and robotic in north america (p < 0.001). tumor grade was lowest in south korea (p < 0.001) and stage (p < 0.001) greatest in central/south america. overall survival was greater in south korea compared to central/south america (p = 0.026). cancer-specific survival was greater in south korea relative to north america and central/south america (p = 0.026). conclusions: patients from north america, central/south america, and south korea diagnosed with renal cell carcinoma and tumor thrombus do not present the same and have different outcomes peri-/post-operatively. this includes important variables which have impacts on patient morbidity and mortality. considering increased efforts on health equity in urology, the causes of these differences call for further investigation. a comparison of renal cell carcinoma with tumor thrombus across north america, central/south america, and south korea maxwell sandberg 1, rachel vancavage 2, claudia marie-costa 3, emily ye 3, mitchell hayes 4, justin miller 5, reuben ben david 6, kartik patel 7, kimberly waggener 1, brejjette aljabi 7, seoksoon byun 8, patricio garcía marchiñena 9, thiago mourao 10, charles peyton 7, reza mehrazin 6, philippe spiess 4, rafael zanotti 10, steven chang 11, stenio de casio zequi 10, diego abreu 12, alejandro rodriguez 1 1 atrium health wake forest baptist medical center, winston salem, nc, usa; 2 albany medical college, albany, ny, usa; 3 wake forest university school of medicine, winston salem, nc, usa; 4 moffitt cancer institute, tampa bay, fl, usa 5 university of south florida school of medicine, tampa bay, fl, usa; 6 icahn school of medicine at mount sinai, new york, ny, usa; 7 university of alabama birmingham school of medicine, birmingham, al, usa; 8 seoul bundang university hospital, seoul, south korea; 9 hospital italiano, buenos aires, argentina; 10 ac camargo cancer institute, sao paulo, brazil; 11 harvard medical school, dana-farber cancer institute, brigham and women's hospital, division of urology, boston, usa; 12 paseur hospital, division of urology, montevideo, uruguay. doi: 10.4081/aiua.2025.13820 summary key words: renal cell carcinoma; thrombus; continental; equity; disparities. submitted 13 march 2025; accepted 5 april 2025 archivio italiano di urologia e andrologia 2025; 97(2):13820 m. sandberg, r. vancavage, c. marie-costa, et al. 2 regions like latin america and asia, who historically have had a lower incidence of rcc, are expected to mirror that of na and europe in the coming years (9). though there are few studies, survival from rcc has been examined across the world with results tending to point towards equivalent overall survival (os) with worse cancer-specific survival (css), access to clinical trials, and/or guidelinebased care in lower-income countries and regions of the world (6, 9). perhaps most importantly, despite strong evidence that rcc is a cause for significant inequitable outcomes globally and is estimated to be responsible for approximately 2.5% of all cancer-related deaths across the world yearly, there is a paucity of research examining rcctt worldwide as most publications lack analysis on this important patient population (6, 7, 9, 10). over the last two years, a joint collaborative project was started to address global disparities in rcc-tt between institutions in na, central/south america (csa) (via the latin american renal cell group), and south korea known as the intercontinental collaboration on renal cell carcinoma (icorcc). the purpose of this study was to compare pre-, peri-, and post-operative management along with survival of patients with rcc-tt between na, csa, and south korea using the icorcc database. we hypothesized that no difference in presentation, operative management, or survival outcomes would exist by geography. materials and methods this was a multi-institutional study conducted under institutional review board number irb00096722 across na, csa, and south korea. data was retrospectively collected from 1999-present and stored on a master database as part of the icorcc project. participating institutions were from the united states of america, mexico, peru, uruguay, bolivia, chile, argentina, brazil, and south korea. all patients required both a diagnosis of rcc-tt on computerized tomography (ct) and/or magnetic resonance imaging (mri) and had to have undergone radical nephrectomy with tumor thrombectomy for inclusion. a variety of preoperative variables were collected including patient age, gender, race, diabetes mellitus (dm), chronic kidney disease (ckd), symptoms at presentation (local and metastatic), karnofsky performance status, charlson comorbidity index (cci), preoperative ct chest scan, preoperative tumor size, and presence of preoperative metastasis. perioperative variables were surgical approach, operative time, tumor grade, tumor stage, tumor pathologic characteristics (necrosis, sarcomatoid, rhabdoid), lymph node (ln) dissection, and soft tissue margin positivity. postoperative variables were metastasis after surgery, metastasis-free survival (mfs), follow-up time, os, and css. local symptoms were defined as flank pain and/or palpable abdominal or flank mass. metastatic symptoms were shortness of breath, chest pain, hemoptysis, bone pain/swelling, jaundice, seizures, fever, weight loss, or dizziness. for patients with preoperative metastatic location information available, locations were defined as the lungs, bone, liver, brain, retroperitoneum, regional lymph nodes, adrenal gland, and “other regions”. thrombus level was classified according to the neves classification system (11). preoperative tumor size was taken as the greatest dimension of tumor size on ct or mri imaging as closest to the date of surgery. systemic therapy was defined as any use/combination of chemotherapy (chemo), immunotherapy (immuno), or targeted therapy (targeted) for treating rcc-tt either before or after surgery. a minority of patients did not have complete data on the specific systemic therapeutic used and were defined as “unknown”. surgical approach was classified as either open, laparoscopic (pure or hand-assist), or robotic. tumors were staged according to the tnm classification system and graded according to the international society of urological pathology grading system (12, 13). patients were classified according to geographic location where they underwent primary surgery for their rcc-tt and received most of their postoperative care (na, csa, or south korea). analysis of variance (anova) was run to compare continuous variables by geographic location. chi-squared test was used to compare categorical variables by geographic location. kaplan-meier survival curves with log-rank test were used to compare os, mfs, and css by geographic location. additionally, a coxregression analysis model for os and css was also performed using variables with p < 0.05 and/or clinical relevance. patients with missing values for a particular variable were excluded from that analysis. significance was set to p < 0.05 and conducted using spss statistics version 28 (armonk, ny). results a total of 478 patients were included in the study, 212 from na, 209 from csa, and 57 from south korea (table 1; table 1. geographical comparisons for renal cell carcinoma with tumor thrombus. the following table compares pre-, peri-, and postoperative outcomes between each geographical region in the study. continuous variables are reported as means with standard deviations in parentheses aside from variable na csa south korea p-value n 212 209 57 age (years) 63.1 (10.9) 61.3 (12.4) 61.1 (10.9) 0.282 bmi 29.3 (6.6) 27.3 (4.7) 23.4 (3.4) < 0.001 female 64 (30.2) 52 (24.9) 12 (21.1) 0.273 race caucasian 163/208 (78.4) 70/169 (41.4) 0 < 0.001 black 24/208 (11.5) 7/169 (4.1) 0 hispanic 0 84/169 (49.7) 0 asian 12/208 (5.8) 8/169 (4.7) 57 (100) other 9/208 (4.3) 0 0 active smoker 32 (15.1) 24 (11.5) 6 (10.5) 0.612 former smoker 97/205 (47.3) 75 /172 (43.6) 12 (21.1) 0.002 archivio italiano di urologia e andrologia 2025; 97(2):13820 3 renal cell carcinoma with tumor thrombus karnofsky performance status, charlson comorbidity index, and the number of positive and negative lymph nodes which are medians with interquartile ranges in parentheses. categorical variables are reported as total numbers with percentage of the cohort in parentheses. associated p-values for each comparison are also provided. dm 65 (30.7) 39 (18.7) 15 (26.3) 0.021 hypertension 153 (72.2) 82 (39.2) 33 (57.9) < 0.001 ckd 39 (18.4) 13 (6.2) 3 (5.3) < 0.001 karnofsky 90 (80-90) 90 (80-97.5) 90 (90-90) 0.692 cci 6 (4-8) 5 (3-6) 1 (0-6) < 0.001 local symptoms at diagnosis 147 (69.3) 98 (46.9) 30 (52.6) 0.020 metastatic symptoms at diagnosis 19 (9) 25 (12) 0 0.007 preoperative chest ct 167 (78.8) 81 (38.8) 34 (59.6) < 0.001 preoperative tumor size (cm) 9.1 (3.3) 9.8 (3.6) 8.4 (3) 0.021 thrombus level i 109/204 (53.4) 29/93 (31.2) 32 (56.1) < 0.001 ii 45/204 (22.1) 25/93 (26.9) 7 (12.3) iii 24/204 (11.8) 26/93 (28) 16 (28.1) iv 26/204 (12.7) 13/93 (14) 2 (3.5) metastatic before surgery 80/122 (65.6) 36/94 (38.3) 20/39 (51.3) 0.002 multiple metastatic sites at presentation 27/80 (33.4) 24/36 (66.7) 8/20 (40) 0.128 preoperative metastatic locale lung 15 13 0 bone 10 5 1 liver 8 12 0 brain 3 0 0 retroperitoneum 16 16 3 nodal 1 5 4 adrenal 9 3 2 other 10 1 7 approach open 107/211 (50.7) 107/185 (57.8) 50 (87.7) < 0.001 laparoscopic 13/211 (6.2) 65/185 (35.1) 5 (8.8) robotic 91/211 (43.1) 13/185 (7) 2 (3.5) operative time (minutes) 290.8 (122.7) 285.6 (138.3) 265 (121.1) 0.422 length of stay (days) 6.6 (6) 15.5 (76.3) 12.3 (7.1) 0.199 stage t3a 63/182 (34.6) 40/153 (26.1) 0 < 0.001 t3b 80/182 (44) 74/153 (48.4) 49 (86) t3c 25/182 (13.7) 23/153 (15) 8 (14) t4 14/182 (7.7) 16/153 (10.5) 0 grade 1 7/202 (3.5) 2/155 (1.3) 0 < 0.001 2 36/202 (17.8) 17/155 (11) 2 (3.5) 3 101/202 (50) 54/155 (34.8) 33 (57.9) 4 58/202 (28.7) 82/155 (53) 22 (38.6) sarcomatoid 28 (13.9) 82 (39.2) 9 (15.8) < 0.001 rhabdoid 24 (11.3) 9 (4.3) 0 0.371 necrosis 119/201 (59.2) 112/166 (67.5) 43 (75.4) 0.048 subtype clear cell 162/205 (79) 166/188 (88.3) 50 (87.7) 0.071 papillary 17/205 (8.3) 12/188 (6.4) 4 (7) other 26/205 (12.7) 10/188 (5.3) 3 (5.3) lymph node dissection 100 (47.2) 67 (32.1) 25 (43.9) 0.004 lymph nodes positive 0 (0-1) 0 (0-1) 0 (0-1) 0.123 lymph nodes negative 2 (0-4) 2 (0-5) 5 (2-14.5) 0.003 soft tissue margin positive 58 (27.4) 34 (16.3) 1 (1.8) < 0.001 systemic therapy 92 (43.3) 56 (26.8) 30 (52.6) < 0.001 systemic therapy type chemo 6 7 0 immuno 16 10 0 targeted 26 34 12 chemo and immuno 6 1 2 chemo and targeted 3 0 0 immuno and targeted 21 4 0 chemo, immuno, targeted 1 0 3 unknown 13 0 13 postoperative tumor size (cm) 9.6 (3.7) 9.7 (3.5) 9.3 (3.2) 0.768 metastatic after surgery 42/122 (34.4) 58/94 (61.7) 19/39 (48.7) < 0.001 metastatic ever 122/211 (57.8) 94/181 (51.9) 39 (68.4) 0.075 initial number of metastatic sites 1.5 (1.1) 2.2 (1.2) 1.1 (0.6) < 0.001 metastasis-free survival (months) 15.5 (25.8) 15.4 (21.9) 17.8 (23.7) 0.938 overall survival (years) 1.9 (2.1) 1.3 (2) 3 (2.9) 0.012 cancer-specific survival (years) 1.5 (1.5) 1.5 (1.3) 2.9 (2.9) 0.014 dead 70 (33) 67 (32.1) 26 (45.6) 0.207 cancer-specific death 46/53 (86.8) 28/54 (51.9) 21/26 (80.8) < 0.001 follow-up (years) 3.9 (6.4) 2.7 (3.5) 3.4 (5.4) 0.023 archivio italiano di urologia e andrologia 2025; 97(2):13820 m. sandberg, r. vancavage, c. marie-costa, et al. 4 figure 1). mean age at surgery, gender, active smoking status, and karnofsky performance status were not significantly different between the geographical regions (p > 0.05). cci was greatest in na patients (median-6) compared to both csa (median-5) and south korea (median-1; p < 0.001). bmi was significantly greater in na patients compared to csa and south korean patients (29.3 versus 27.3 versus 23.4; p < 0.001). race of the patients from each geographical region also was significantly different (p < 0.001). a greater percentage of patients were former smokers in na (47.3%) and csa (43.6%) in comparison to south korea (21.1%; p = 0.002). dm was less prevalent in csa patients (18.7%) relative to na (30.7%) and south korea (26.3%; p = 0.021). hypertension was more prevalent in na patients (72.2%) compared to csa and south korea (p < 0.001). ckd was also more likely in na patients (18.4%) compared to csa and south korea (p < 0.001). at diagnosis local symptoms were more likely in na (69.3%) in comparison to csa (46.9%) and south korea (52.6%; p = 0.020). metastatic symptoms were more common in na (9%) and csa (12%) relative to south korea (0%; p = 0.007). patients from na (78.8%) and south korea (59.6%) were more likely to undergo a preoperative chest ct scan compared to csa (38.8%; p < 0.001). preoperative tumor size was significantly smaller in south korea (8.4 cm) relative to na (9.1 cm) and csa (9.8 cm; p = 0.021). thrombus level also differed by region, with a greater average thrombus level in csa (p < 0.001). na had the greatest percentage of patients metastatic at diagnosis (65.6%; p = 0.002). the most common location of metastases seen preoperatively was the retroperitoneum for na (n = 16) and csa (n = 16), and “other regions” for south korea (n = 7). no difference existed in the number of patients with multiple metastatic sites at presentation (p > 0.05). operative approach also differed, with a significantly greater proportion of robotic cases in na (43.1%) and a greater proportion of laparoscopic cases in csa (35.1%) (figure 2; figure 1. geographical differences. the following figure shows each geographical region in the study: north america, central/south america, and south korea. patients from the united states of america were labeled as “north america” in red, patients from south korea were labeled as “south korea” in blue, and all other regions were labeled as “central/south america” in green. relevant demographic, peri-, and post-operative differences are shown. the most common thrombus level, tumor stage, and tumor grade are provided for each region. the total number of metastatic patients preand post-operatively are also shown. means for overall survival and cancer specific survival are represented with standard deviation in parentheses. figure 2. operative approach by geographical region. the following figure shows all operations performed in each of the three geographical regions: north america, central/south america, and south korea. each bar represents a specific operative approach, which was either open, laparoscopic, or robotic. number of operations is on the y-axis and geographical region is on the x-axis. archivio italiano di urologia e andrologia 2025; 97(2):13820 5 renal cell carcinoma with tumor thrombus p < 0.001). operative time and length of stay were similar (p > 0.05). tumor stage was different by geographic region, with a greater percentage of t3b patients (86%) in south korea (p < 0.001). tumor grade was also different by region, with a greater proportion of grade 4 rcc in csa (p < 0.001). on pathology, sarcomatoid variants were significantly more prevalent in csa (39.2%), compared to na and south korea (p < 0.001). tumor necrosis was most prevalent in na patients (59.2%; p = 0.048). tumor subtype was not different (p > 0.05). csa had the lowest percentage of ln dissections performed (23.1%; p = 0.004). the median number of lns positive for cancer were similar (p > 0.05), and the median number of negative lns was greatest in south korea (median-5; p = 0.003). soft tissue margin positivity was least likely in south korean patients (1.8%; p < 0.001). csa patients were significantly less likely to receive systemic therapy (26.8%) in comparison to na (43.3%) and south korean patients (52.6%; p < 0.001). the most common regimen was targeted therapy in na (n = 24), csa (n = 34), and south korea (n = 12). postoperative tumor size on gross specimen was similar by geographical region (p > 0.05). the percentage of patients metastatic at any time in the study window and mfs was not different (p > 0.05). the percentage of patients who went on to develop metastasis after surgery was highest in csa (61.7%; p < 0.001). csa patients had a greater number of initial metastatic sites (2.1) compared to the na (1.5) and south korea (1.1; p < 0.001). os favored south korean patients (3 years) in comparison to csa (1.9 years) and on log-rank test this was significantly different (figure 3; p = 0.026). no os survival difference existed between south korea and na, nor na and csa (p > 0.05). css favored south korean patients (2.9 years) compared to both na (1.5 years) and csa (1.5 years) and on log-rank test this was significantly different (figure 3; p = 0.026). on cox regression analysis for os no significant differences were seen (table 2 and figure 4; p > 0.05) and for css, csa patients had a significantly greater hazard (hr) of cancerspecific death (table 3 and figure 4; hr = 0.44; p = 0.015). figure 3. kaplan-meier survival analysis by geographical region. the following figure represents a kaplan-meier survival analysis comparison between north american patients, central/south american patients, and south korean patients in the study for (a) overall survival and (b) cancer-specific survival, and (c) metastasis-free survival. the proportion of patients surviving at each time interval is shown on the y-axis and time is represented on the x-axis in years or months. log-rank significance p-values are shown below the figure legends. number at risk tables of all patients experiencing the event of interest during the study are also provided below the graphs with censored patients in parentheses. table 2. cox regression analysis for overall survival. the following table is a cox regression analysis with death as the outcome of interest. s.e. is standard error, b represents the predicted hazard of the terminal event (death) and exp(b) is the hazard ratio for each variable in the model. for geographical region, south korea is the reference category and for approach, robotic surgery is the reference category. associated p-values for each variable are also provided. variable b s.e p-value exp(b) confidence interval upper lower geographical region 0.14 north america 0.16 0.42 0.7 1.2 0.52 2.64 central/south america -0.45 0.27 0.1 0.64 0.38 1.1 thrombus level 0.29 0.11 0.008 1.3 1.08 1.67 approach 0.83 open 0.08 0.42 0.85 1.1 0.48 2.44 laparoscopic 0.18 0.3 0.55 1.2 0.67 2.17 tumor stage -0.01 0.16 0.95 1 0.73 1.34 tumor grade 0.22 0.19 0.25 1.2 0.86 1.8 sarcomatoid pathology 0.37 0.32 0.26 1.4 0.77 2.71 metastatic anytime 0.37 0.31 0.23 1.4 0.79 2.66 systemic therapy -0.8 0.27 0.003 0.45 0.27 0.77 archivio italiano di urologia e andrologia 2025; 97(2):13820 m. sandberg, r. vancavage, c. marie-costa, et al. 6 discussion several important differences were identified in how patients presented prior to surgery with rcc-tt. bmi was greater in the na cohort, which has been linked to an increased likelihood of rcc, but results are mixed with respect to survival, as some studies show a protective effect (14). unsurprisingly, race differed by geographical region, and as stated it is also known to impact patient outcomes for rcc and rcc-tt (4, 15). patients from na and csa were more likely to be former smokers, which is a well-established factor predisposing to poor survival in rcc (16). despite a variety of comorbidities differing by region, karnofsky performance status was equivalent, and is known to correlate with poor outcomes for rcc-tt (17). interestingly, csa patients had the lowest prevalence of local symptoms at diagnosis but the highest rate of metastatic symptoms. this may indicate that these patients are more likely to present later in their disease course and fits with some publications showing a high rate of metastatic presentation for rcc in csa countries (18). nevertheless, na patients had the highest percentage of metastasis at presentation. csa patients had a significantly lower likelihood of undergoing a chest ct preoperatively, which should be done prior to surgery and is well-supported in the literature (19). this is of concern and the disparity is difficult to ascertain by current access to care alone. ct chest omission could be due in part to the large time span of the study including cases from 1999 onward where ct scan access and care guidelines were not as ubiquitous. additionally, patients without a ct chest did have a chest x-ray in most instances. nevertheless, this is one of the most significant discrepancies we identify in our study and requires additional investigation as to its causes. while the prognostic significance of thrombus level remains controversial, na and south korea had the most patients with a level i thrombus, and it has been shown that rates of abdominal imaging differ worldwide, potentially catching the thrombus before further spread to a higher level (7, 8). peri-operative management/outcomes also differed by region. na had the greatest percentage of robotic surgery and csa had the greatest percentage of laparoscopic. while the open approach has traditionally been employed for rcc-tt, a robotic approach has been described with equivalent to superior postoperative outcomes (20). with the ubiquitous use of robotic access across academic centers in na, it is unsurprising this region had the greatest rate of robotic surgery. pure/handassist laparoscopy has also been reported on for rcc-tt, but its use may be greater and success better than what is figure 4. cox regression analysis for overall survival and cancer-specific survival. the following figure represents the survival curve from the cox regression model for (a) overall survival and (b) cancer-specific survival. the proportion of patients surviving at each time interval based on the mean of covariates in the model is shown on the y-axis and time is represented on the x-axis in years. table 2. cox regression analysis for cancer-specific survival. the following table is a cox regression analysis with cancer-specific death as the outcome of interest. b represents the predicted hazard of the terminal event (death) and exp(b) is the adjusted hazard ratio for each variable in the model. for geographical region, south korea is the reference category and for approach, robotic surgery is the reference group. associated p-values for each variable are also provided. variable b s.e p-value exp(b) confidence interval upper lower geographical region 0.053 north america -0.29 0.47 0.54 0.75 0.3 1.9 central/south america -0.82 0.34 0.015 0.44 0.23 0.86 thrombus level 0.003 0.13 0.98 1 0.77 1.3 approach 0.98 open -0.08 0.49 0.86 0.92 0.35 2.4 laparoscopic 0.01 0.36 0.98 1 0.5 2.03 tumor stage 0.19 0.18 0.3 1.2 0.84 1.73 tumor grade 0.38 0.23 0.1 1.5 0.92 2.23 sarcomatoid pathology -0.01 0.39 0.97 0.99 0.46 2.13 metastatic anytime -0.81 0.42 0.06 0.45 0.2 1.02 systemic therapy -0.95 0.31 0.002 0.39 0.21 0.71 archivio italiano di urologia e andrologia 2025; 97(2):13820 7 renal cell carcinoma with tumor thrombus currently accepted, especially in csa countries (21). a lower tumor stage was more prevalent in south korea relative to both na and csa. it is worth noting that css was greatest in south korean patients and tumor stage is associated with poor survival for rcc and rcc-tt (22). tumor grade was highest in csa, a poor prognostic factor for rcc-tt (23). similarly, sarcomatoid variants were most common in csa, which is linked to poor outcomes in patients treated surgically for rcc-tt (24). rates of ln dissection were lowest in csa, but the number of positive nodes on pathology was similar by region. this is relevant as research shows the number of positive lns after radical nephrectomy and tumor thrombectomy is independently associated with worse css (25). multiple postoperative and survival outcomes differed by geography. the overall number of patients metastatic in the study window was similar, but there was a greater number of patients metastatic at presentation in na and a greater number of metastatic sites at presentation in csa. further, csa had the highest proportion of patients who developed metastasis after surgery. despite these differences, mfs was similar amongst each region. this is particularly relevant as mfs has been shown to predict os for rcc (26). in our population though, os was not equivalent on primary analysis, and patients from south korea had a significantly greater os relative to csa. css was also greatest in south korean patients but whereas os was greater only compared to csa, css was greater than both csa and na. tian et al. published on prognostic indicators for os and css in rcc-tt patients, noting that lower tumor grade, lower tumor stage, lower thrombus level, and the use of systemic therapy predicted better outcomes (23). south korean patients had lower tumor stages in the study, and csa patients had greater tumor grades and thrombus level, which appears to fall in line with tian et al.’s findings. moreover, systemic therapy utilization was not equivalent across each region, with csa patients having the lowest usage. importantly, access to systemic therapy clinical trials in rcc differs across the world, and patients with higher risk rcc are not as well represented in these trials in csa (6, 9, 10). on cox regression analysis, when controlling for variables like tumor stage, grade, and metastasis, most survival differences disappeared, unsurprisingly showing that survival is multifactorial and additional factors besides geography are clearly at play. however, css was still worse in csa, which is concerning and calls for further investigation. several limitations are worth acknowledging in our analysis. while the multi-continental and diverse nature of our cohort is a strength, we rely on the fact that the medical records at each participating institution are correct and up to date with patient information. further, our findings are subject to the inherent biases of any retrospective review, and every patient in the study did not necessarily have a complete set of data to include in statistical analysis. while the cox regression attempted to control for confounding variables, we cannot fully control for the fact that each geographical regions’ demographic characteristics were not equivalent at baseline. in addition, na, csa, and south korea are not homogeneous regions and there is variability in patient management within regions which we did not assess in this study. despite using the same staging and grading systems for rcc, pathologist evaluation could have varied by both institution and geographical region and may account for some of the differences seen in sarcomatoid, rhabdoid, and necrotic tumor features. we also recognize that the external validity of our results is limited by the institutions that submitted data to participate in this study, all of which are tertiary academic centers. nevertheless, we feel most cases of rcc-tt end up being referred to high-volume academic centers for definitive management and thus still see utility in our results. conclusions this is one of the largest series of patients with rcc-tt in the literature, and one of the only publications to focus on geographical differences in presentation, management, and outcomes using collaboration via the icorcc database. given the need for stronger emphasis on health equity worldwide, our findings are particularly timely. while multiple studies have examined demographics such as race, gender, and functional status in rcc-tt, few have recognized how patient geography plays into this. a multifaceted approach should be taken to address the disparities we identify. there is no single fix to this complex patient population. however, what we do feel is that a global health emphasis on funding and investment in csa is required to improve access to optimal patient care like systemic therapy, surgical robots, and the like. moreover, new clinical trials need to be better about inclusion of patients and healthcare centers around the globe, rather than just the united states. we hope this study sheds light on important regional differences in the interest of narrowing worldwide gaps in healthcare and achieving more equitable outcomes in rcc-tt for all. declarations ethical approval: the following study was approved by an institutional review board on 5/16/2023 under irb00096722. availability of data and material: the data sets generated during and/or analyzed during the current study are not publicly available due patient privacy, but are available from the corresponding author on reasonable request. competing interests: none. funding: none. authors' contributions: project design: ms, rv, cmc, ey, mh, jm, rbd, kp, kw, ba, sb, pm, tm, cp, rm, ps, rz, sc, sz, da, ar. data collection: ms, rv, cmc, ey, mh, jm, rbd, kp, kw, ba, sb, pm, tm, rm, rz, sc. visualization: ms, rv, cmc, ey, mh, sb, pm, tm, cp, rm, ps, rz, sc, sz, da, ar. statistical analysis: ms, rv, cp, ps, rz, sc, sz, da, ar. validation: ms, cp, ps, sc, ar. drafting manuscript original draft: ms, rv, cmc, ey, cp, ps, sz, ar. drafting manuscript editing draft: ms, rv, cmc, ey, mh, jm, rbd, kp, kw, ba, sb, pm, tm, cp, rm, ps, rz, sc, sz, da, ar. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13820 m. sandberg, r. vancavage, c. marie-costa, et al. 8 references 1. almatari al, sathe a, wideman l, et al. renal cell carcinoma with tumor thrombus: a review of relevant anatomy and surgical techniques for the general urologist. urol oncol 2023; 41:153-165. 2. tilki d, hu b, nguyen hg, et al. impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy. j urol. 2015; 193:436-42. 3. tang q, song y, li x, et al. prognostic outcomes and risk factors for patients with renal cell carcinoma and venous tumor thrombus after radical nephrectomy and thrombectomy: the prognostic significance of venous tumor thrombus level. biomed res int. 2015; 2015:163423. 4. anastos h, martini a, waingankar n, et al. black race may be associated with worse overall survival in renal cell carcinoma patients. urol. oncol. 2020; 38:938.e9-938.e17. 5. gupta a, roy am. racial and ethnic disparities in survival outcomes of metastatic renal cell carcinoma patients receiving immunotherapy. clin genitourin cancer. 2024; 22:102104. 6. cirillo l, innocenti s, becherucci f. global epidemiology of kidney cancer. nephrol dial transplant. 2024; 39:920-928. 7. bukavina l, bensalah k, bray f, et al. epidemiology of renal cell carcinoma: 2022 update. eur urol. 2022; 82:529-542. 8. capitanio u, bensalah k, bex a, et al. epidemiology of renal cell carcinoma. eur urol. 2019; 75:74-84. 9. padala sa, barsouk a, thandra kc, et al. epidemiology of renal cell carcinoma. world j oncol. 2020; 11:79-87. 10. fay ap, mckay rr, lin x, et al. impact of geographic regions on overall survival in patients with metastatic renal cell carcinoma: results from an international clinical trials database. j glob oncol. 2018; 2018:1-14. 11. neves rj, zincke h. surgical treatment of renal cancer with vena cava extension. br j urol. 1987; 59:390-5. 12. brierley j.d., gospodarowicz m.k., wittekind c. tnm classification of malignant tumours, 8th edition. union for international cancer control. published online 2017. https://www. uicc.org/resources/tnm-classification-malignant-tumours-8th-edition. 13. delahunt b, cheville jc, martignoni g, et al. the international society of urological pathology (isup) grading system for renal cell carcinoma and other prognostic parameters. am j surg pathol. 2013; 37:1490-504. 14. goebell pj, müller l, hübner a, et al. body mass index as independent predictor of overall survival in patients with advanced renal cell carcinoma at start of systemic treatment—analyses from the german clinical rcc-registry. urol oncol 2018; 36:433-472. 15. dursun f, patel r, hui d, et al. the latinx disparity in surgery for kidney cancer: data from the south texas region. kidney cancer j. 2022; 20:6-13. 16. xu y, qi y, zhang j, et al. the impact of smoking on survival in renal cell carcinoma: a systematic review and meta-analysis. tumor biol. 2014; 35:6633-40. 17. kaptein fhj, van der hulle t, braken sje, et al. prevalence, treatment, and prognosis of tumor thrombi in renal cell carcinoma. jacc cardiooncol. 2022; 4:522-531. 18. soares a, monteiro fsm, da trindade km, et al. advanced renal cell carcinoma management: the latin american cooperative oncology group (lacog) and the latin american renal cancer group (larcg) consensus update. j cancer res clin oncol. 2024; 150:183. 19. woodruff dy, van veldhuizen p, muehlebach g, et al. the perioperative management of an inferior vena caval tumor thrombus in patients with renal cell carcinoma. urol. oncol. 2013; 31:517-21. 20. garg h, psutka sp, hakimi aa, et al. a decade of robotic-assisted radical nephrectomy with inferior vena cava thrombectomy: a systematic review and meta-analysis of perioperative outcomes. j urol. 2022; 208:542-560. 21. sun y, de castro abreu al, gill is. robotic inferior vena cava thrombus surgery: novel strategies. curr opin urol. 2014; 24:140-7. 22. pandey j, syed w. renal cancer. treasure island, fl:statpearls publishing; 2024. https://www.ncbi.nlm.nih.gov/books/nbk558975/. accessed september 14, 2024 23. tian j, zeng x, guan w, et al. prognostic indicators for survival in renal cell carcinoma with venous thrombus and development of predictive nomograms. transl androl urol. 2022; 11:1374-1388. 24. yang b, xia h, xu c, et al. impact of sarcomatoid differentiation and rhabdoid differentiation on prognosis for renal cell carcinoma with vena caval tumour thrombus treated surgically. bmc urol. 2020; 20:14. 25. tilki d, chandrasekar t, capitanio u, et al. impact of lymph node dissection at the time of radical nephrectomy with tumor thrombectomy on oncological outcomes: results from the international renal cell carcinoma-venous thrombus consortium (ircc-vtc). urol oncol. 2018; 36:79.e11-79.e17. 26. smith mr, mehra m, nair s, et al. relationship between metastasis-free survival and overall survival in patients with nonmetastatic castration-resistant prostate cancer. clin genitourin cancer. 2020; 18:e180-e189. correspondence maxwell sandberg (corresponding author) maxwellsandberg@msn.com 950 n trade street, winston salem, nc, 27101, usa rachel vancavage vancavr@amc.edu albany medical college, albany, ny, usa claudia marie-costa cmcosta@wakehealth.edu emily ye ewye@wakehealth.edu alejandro rodriguez alrrodri@wakehealth.edu wake forest baptist medical center, winston salem, nc, usa, 27157 mitchell hayes mitchell.hayes@moffitt.org moffitt cancer institute, tampa bay, fl, usa justin miller justinmiller1@usf.edu university of south florida school of medicine, tampa bay, fl, usa reuben ben david reuben.bendavis@mountsinai.org reza mehrazin reza.mehrazin@mountsinai.org icahn school of medicine at mount sinai, new york, ny, usa kartik patel kartikp@uab.edu brejjette aljabi bnaljabi@uab.edu archivio italiano di urologia e andrologia 2025; 97(2):13820 9 renal cell carcinoma with tumor thrombus charles peyton cpeyton@uabmc.edu university of alabama birmingham school of medicine, birmingham, al, usa kimberly waggener kwaggene@wakehealth.edu atrium health wake forest baptist medical center, winston salem, nc, usa, 27157 seoksoon byun seoksoo.byeon@gmail.com seoul bundang university hospital, seoul, south korea patricio garcía marchiñena patricio.garcia@hospitalitaliano.org.ar hospital italiano, buenos aires, argentina thiago mourao thiago.mourao@accamargo.org.br rafael zanotti rafael.zannotti@accamargo.org.br stenio de casio zequi stenio.zequi@accamargo.org.br ac camargo cancer institute, sao paulo, brazil philippe spiess philippe.spiess@moffitt.org moffitt cancer institute, tampa bay, fl, usa steven chang slchang@bwh.harvard.edu harvard medical school, dana-farber cancer institute, brigham and women's hospital, division of urology, 45 francis street, boston, ma 02115, usa. diego abreu die.abreu@gmail.com paseur hospital, division of urology, montevideo, uruguay stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13903 1 review still a concern. we found that some articles analyze the mtese success with orchidopexy, but none analyze the outcomes in relation to the location of the udt. this meta-analysis aims to compare the testicular function of palpable udt and non-palpable udt post-orchidopexy using hormonal markers such as fsh, lh, and testosterone in order to provide valuable information for clinical decisions and information on long-term effects for post-orchidopexy patients. methods study sesign this study is a systematic review with meta-analysis to evaluate the testicular function following orchidopexy in palpable and non-palpable udt. the study followed the preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines to ensure comprehensive research. the literature search was conducted using pubmed, google scholar, science direct, and scopus databases. the search strategy for the articles included [("orchidopexy") or ("orchiopexy")] and [("undescended testis") or ("udt") or ("cryptorchidism")] and ("location") and [("testosterone") or ("fsh") or ("lh") or ("infertility")]. all search results will be screened for duplicates and assessed based on title and abstract relevance. full-text articles are retrieved for detailed evaluation, and the references of the selected studies are manually reviewed to identify additional relevant articles. original research articles were included if they met the following criteria: (a) diagnosis of undescended testis that underwent orchidopexy for the definitive treatment, (b) stated the location of the testis before orchidopexy, (c) assessed the fsh, lh, and testosterone post-orchidopexy. we excluded animal studies, review articles, and consensus documents. the exclusion criteria were as follows: (a) the study was a review article, letter to the editor, animal study, commentary, or consensus document, (b) the study did not focus on undescended testis. the study protocol was registered in the international prospective register of systematic reviews (prospero) to ensure transparency and adherence to established standards: prospero crd420251015285. introduction: cryptorchidism or undescended testis (udt) is one of the most common congenital anomalies in male infants. based on the physical examination, udt can be classified into palpable and non-palpable. however, despite successful repositioning, the long-term function of the testis is still a concern. this meta-analysis aims to compare the testicular function of palpable udt and non-palpable udt post-orchidopexy using hormonal markers such as fsh, lh, and testosterone. materials and methods: a comprehensive literature search was performed using pubmed, sciencedirect, and google scholar databases up to march 2025. statistical analyses were conducted using review manager (revman). result: four eligible studies were included in the analysis, involving 207 patients who underwent orchidopexy for udt, including 160 with palpable udt and 47 with non-palpable udt. there is no significant difference between palpable compared to non-palpable in terms of fsh (md 0.78 iu/l [95% ci: -0.34 to 1.90], p = 0.14); lh (md -0.17 iu/l [95% ci: -0.45 to 0.12], p = 0.25); and testosterone (-0.08 iu/l [95% ci: -0.64 to 0.48], p = 0.78). conclusions: testicular functions, including fsh, lh, and testosterone, in palpable udt did not differ significantly from those in non-palpable udt. key words: palpable; nonpalpable; undescended testis; post-orchidopexy; testicular function. submitted 17 april 2025; accepted 25 april 2025 introduction cryptorchidism or undescended testis (udt) is one of the most common congenital anomalies in male infants. based on the physical examination, udt can be classified into palpable and non-palpable. palpable udt can be detected in clinical assessment, typically in the inguinal region, and non-palpable udt is not detected by palpation, which can be intra-abdominal or atrophied (1). the prevalences of undescended testis are 1.6%9% at birth and 0.9-1.8% at 3 months (2). orchidopexy is the standard management for patients with udt. its aim is to reposition the testis into the scrotum and preserve the testicular functions (1). however, despite successful repositioning, the long-term function of the testis is evaluating hormonal differences in post-orchidopexy patients: a meta-analysis of palpable vs. nonpalpable undescended testis marshal harvy wicaksono, anak agung ngurah krisnanta adnyana, gede wirya kusuma duarsa surgery department prof. dr. i.g.n.g. ngoerah general hospital, bali, indonesia. doi: 10.4081/aiua.2025.13903 summary archivio italiano di urologia e andrologia 2025; 97(2):13903 m. harvy wicaksono, a. agung ngurah krisnanta adnyana, g. wirya kusuma duarsa 2 data extraction and synthesis the data extraction was conducted by two independent reviewers. the discrepancies of the reviewers were resolved through discussion and consultation with a third reviewer. all extracted data included were extracted and pooled using the excel program, including study characteristics such as author, year of publication, sample size, age, palpability of udt, and outcome such as fsh, lh, and testosterone levels. risk of bias was assessed using newcastle-ottawa scale (nos). statistical analysis primary outcomes in this study are post-orchidopexy fsh, lh, and testosterone levels, as these serve as key indicators of testicular endocrine function. we conduct the meta-analysis using review manager (revman) to synthesize the results of the included studies and using i² statistic and chi² test to perform the heterogeneity assessment. a fixed-effects model was used when i2 was < 50%, and when i2 was > 50%, a random-effects model was chosen. in the fixed-effects model, population effect sizes were assumed to be the same for all studies. in contrast, the random-effects model attempted to generalize the results beyond the included studies by assuming that the selected studies were random samples from a larger population. if there was statistical heterogeneity in the results, a further sensitivity analysis was performed to determine the source of heterogeneity. a sensitivity analysis was performed to assess the robustness of the findings by excluding studies with a high risk of bias or those with extreme outlier results. meta-regression was also employed to explore potential moderators affecting testicular function outcomes post-orchidopexy resuls the search strategy identified 2,978 studies. following a full-text evaluation of 12 studies that potentially met the criteria, 4 studies were included in the systematic review and metaanalysis (figure 1). the basic characteristics of the included studies are presented in tables 1, 2. this meta-analysis includes four studies with 207 patients who underwent orchiopexy for undescended testis (udt). 160 patients had palpable udt, and 47 had non-palpable udt. the study outcomes included in this meta-analysis are follicle-stimulating hormone (fsh), luteinizing hormone (lh), and testosterone. the included study consisted of three retrospective cohorts and one prospective cohort. the quality assessment and risk of bias were evaluated figure 1. prisma flow chart. table 1. study characteristic for palpable undescended testis. author n age fsh lh testosterone mean/sd mean/sd mean/sd mean/sd chiba (2009) (3) 12 29.6 ± 3.08 24.23 ± 16.1 8.57 ± 4.31 4.5 ± 1.78 lee (2000) (4) 64 n/a 7.15 ± 1.46 4.21 ± 0.77 5.68 ± 0.68 jedrzejowska (2025) (5) 78 4.12 ± 2.3 1.28 ± 0.78 0.42 ± 0.34 0.2 ± 0.19 sangster (2019) (6) 6 26.5 ± 5.96 21.33 ± 10.33 n/a 13.36 ± 2.53 table 2. study characteristic for non-palpable undescended testis. author n age fsh lh testosterone mean/sd mean/sd mean/sd mean/sd chiba (2009) (3) 8 32.57 ± 2.9 24.97 ± 9.89 9.68 ± 4.63 3.46 ± 1.41 lee (2000) (4) 21 n/a 5.4 ± 2.75 3.9 ± 1.83 6.39 ± 1.87 jedrzejowska (2025) (5) 12 1.4 ± 0.4 1.0 ± 0.5 0.65 ± 0.52 0.22 ± 0.02 sangster (2019) (6) 6 32.16 ± 4.9 24.18 ± 10.38 n/a 14.6 ± 7.02 archivio italiano di urologia e andrologia 2025; 97(2):13903 3 hormonal differences in post-orchidopexy patients using the newcastle-ottawa scale in four studies (table 3). none of the studies was categorized as having a high risk of bias; two were categorized as having a low risk of bias, and two were categorized as having a moderate risk of bias. the forest plot revealed that fsh levels were higher in non-palpable udt compared to palpable udt, with a mean difference (md) of 0.78 iu/l (95% ci: -0.34 to 1.90, p = ns). this result suggests potential testicular dysfunction in non-palpable udt. however, the result was not statistically significant. moderate heterogeneity (i² = 45%) indicated some variability between studies (figure 2). the result for the lh levels did not significantly differ between palpable and non-palpable udt, with an md of -0.17 iu/l (95% ci: -0.45 to 0.12, p = 0.25). the heterogeneity was low (i² = 0%), suggesting high consistency across studies, indicating that leydig’s cell function is comparable between palpable and non-palpable udt (figure 3). testosterone levels also showed no significant difference between palpable and non-palpable udt, with a mean difference of -0.08 iu/l (95% ci: -0.64 to 0.48, p = 0.78). moderate heterogeneity was also observed (i² = 41%), suggesting some variability across studies. these findings indicate that serum testosterone does not significantly impact in palpable and non-palpable testis (figure 4). discussion our meta-analysis involved four studies and 207 patients and revealed no significant differences in fsh, lh, and testosterone levels between palpable and non-palpable patients post-orchidopexy. fsh results were slightly higher in non-palpable udt, but difference was not statistically significant. lh and testosterone levels showed no significant difference between palpable and non-palpable udt. this result suggests that leydig and sertoli cell functions are comparable regardless of the testicular location. non-palpable udts may be more susceptible to testicufigure 2. forest plot for follicle-stimulating hormone (fsh) levels in palpable and non-palpable udt post orchidopexy. figure 3. forest plot for luteinizing hormone (lh) levels in palpable and non-palpable udt post orchidopexy. figure 4. forest plot for testosterone levels in palpable and non-palpable udt post orchidopexy. table 3. risk of bias in included studies based on the newcastle-ottawa scale. author selection comparability outcome total risk of bias lee et al., 2000 (4) 4 2 3 8 low sangster et al., 2019 (6) 3 1 3 6 moderate walczak-jędrzejowska et al., 2024 (5) 4 2 3 9 low chiba et al., 2009 (3) 2 1 2 5 moderate archivio italiano di urologia e andrologia 2025; 97(2):13903 m. harvy wicaksono, a. agung ngurah krisnanta adnyana, g. wirya kusuma duarsa 4 lar atrophy because of intra-abdominal exposure. jedrzejowska et al. compared canalicular and intraabdominal udts and found no significant differences in hormone levels between the udt groups (5). another study by lee et al. (2000) shows that there are no statistical differences in fsh, lh, and testosterone levels between the different testis locations (4). however, various studies have found that the laterality of udt can affect the fertility outcome. trsinar et al. found that bilateral udt has a worse fertility prognosis than unilateral udt (7). an older study by brakel et al. also found that bilateral udt had significantly lower sertoli function, represented by high fsh and low inhibin b. trsinar et al. also show that the age of orchidopexy is critical to fertility outcomes for udt patients (7). they found significant differences between orchidopexy for children under 8 years and those over 8 years. international guidelines also agree that early orchidopexy had its benefit, the american urological association (aua) recommends orchidopexy at the age of 6 months to 1 year (8). the european association of urology also recommends orchidopexy at the age of 1 year to 18 months (9). these results reinforce the clinical notion that early orchidopexy and laterality, regardless of udt location, are critical for optimizing hormonal function. however, future research should aim to expand on these findings by incorporating long-term follow-up data, including semen analysis and fertility outcomes, to further assess the functional integrity of orchidopexy-treated testes. conclusions this meta-analysis provides evidence that the testicular endocrine function, as evaluated by serum levels of fsh, lh, and testosterone, does not significantly differ between palpable and non-palpable undescended testes following orchidopexy. from a clinical standpoint, these results highlight the importance of early diagnosis and timely orchidopexy as endorsed by both the aua and eau guidelines. these insights are vital in guiding parental counselling and surgical planning and support the current standards of care, emphasizing early intervention. references 1. liu j, xiu w, sui b, et al. open controversies on the treatment of undescended testis: an update. front pediatr. 2022; 10:874995. 2. rodprasert w, virtanen he, toppari j. cryptorchidism and puberty. front endocrinol (lausanne). 2024; 15:1347435. 3. chiba k, ishikawa t, yamaguchi k, fujisawa m. the efficacy of adult orchidopexy as a treatment of male infertility: our experience of 20 cases. fertil steril. 2009; 92:1337-9. 4. lee pa, coughlin mt, bellinger mf. paternity and hormone levels after unilateral cryptorchidism: association with pretreatment testicular location. j urol. 2000; 164:1697-701. 5. walczak-jedrzejowska r, niedzielski j, slowikowska-hilczer j, et al. hormonal function of undescended testes before orchidopexy in prepubertal boys. j clin med. 2024; 14:73. 6. sangster p, alnajjar hm, ahmed k, et al. microdissection tese (mtese) following adult orchidopexy for undescended intra-abdominal and inguinal testicles – surgical techniques and outcomes from a single-centre cohort. andrology. 2020; 8:166-70. 7. trsinar b, muravec ur. fertility potential after unilateral and bilateral orchidopexy for cryptorchidism. world j urol. 2009; 27:513-9. 8. evaluation and treatment of cryptorchidism (2018) american urological association [internet]. 2018 [cited 2025 mar 25]. available from: https://www.auanet.org/guidelines-and-quality/ guidelines/cryptorchidism-guideline. 9. eau guidelines on paediatric urology uroweb [internet]. 2025 [cited 2025 mar 25]. available from: https://uroweb.org/guidelines/paediatric-urology/chapter/citation-information. declarations ethical approval: ethical approval was not crucial for this study, as it did not involve direct patients, and all included data were previously published. availability of data and material: availability of data and materials used in our study are available to access by request. competing interests: the authors declare that they have no competing interests. funding: this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions: mhwp, investigation, writing original draft, perform statistical analysis; aanka, investigation, writing original draft, perform statistical analysis; gwkd, conceptualization, supervision, writing-review and editing, validation. all authors read and approved the final manuscript. acknowledgments: not applicable. correspondence marshal harvy wicaksono pantjoro (corresponding author) marshalharvy@gmail.com anak agung ngurah krisnanta adnyana krisnanta.adnyana@gmail.com gede wirya kusuma duarsa gwkduarsa@gmail.com intern doctor of urology surgery department prof. dr. i.g.n.g. ngoerah general hospital, jalan diponegoro, kota denpasar 80113, bali, indonesia stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2186 original paper no conflict of interest declared. (sgw) present during ureteroscopy to ease the management of possible complications (2, 3). with the development of small flexible ureteroscopes and the improvement of laser lithotripsy, ureteroscopy has become the standard of care for treating urolithiasis less than 2 cm (4, 5). should we still use the sgw? does the use of a ureteral access sheath (uas) alter the results or increase the complications? the goal of this study was to assess the success rate of flexible ureterorenoscopy (f-urs) in patients with renal stones with or without ureteral stones using uas without a safety guide wire. to our knowledge, there are no articles discussing the use of uass without guide wires present in upper urinary tract (uut) stones. patients and methods between april 2010 and march 2022, 464 renal units in patients with renal stones with and without concomitant ureteral stones, underwent ureterorenoscopy by one surgeon, and uas was used in all of them. a guide wire was used just to place the uas and during insertion of ureteral double-j stent. no sgw was used inside or outside the uas during the operation. the uas was always placed below the ureteral stone and moved up to the middle or proximal ureter for renal stone treatment. all the patients were included in the study after they matched our inclusion criteria. the inclusion criteria were as follows: 1. upper tract stones, renal stones with or without ureteral stones. 2. the same flexible ureteroscope (flexible uretero-renoscope flexx2s (karl stortz & co. kg, tuttlingen, germany) was used. 3. the holmium yag laser energy was used (fibres 272 µ, 200 µ and 230 µ). 4. the laser generator sphinx jr 30 watt (lisa laser products gmbh, germany) or mega plus 15 watt (richard wolf gmbh, knittlingen, germay) or luminis 120 watt (luminis, yokneam, israel) was used. 4. a ureteral access sheath (flexor ureteral access sheath 12/14f, 28, 35, 45 cm; fuscook medical, bloomington, in, usa) was used. 5. all data recorded. 6. adults aged 18 years and older. objectives: to assess the success rate and intraoperative complications of flexible ureterorenoscopy (f-urs) in patients with upper urinary tract (uut) stones using a ureteral access sheath (uas) without a safety guide wire (sgw). patients and methods: between april 2010 and march 2022, 464 renal units in patients with renal stones with and without concomitant ureteral stones (uut), underwent ureterorenoscopy by one surgeon, and uas was used in all of them. the primary endpoint was the stone-free rate (sfr). sfr was defined as no residual fragments at all. the following characteristics were examined: age, sex, laterality, renal/ureteral stones, stone diameter, sfr, hounsfield unit, auxiliary procedures, double-j stent insertion, and intraoperative complications. this study was retrospective, with all the data recorded prospectively. patients with residual stones were scheduled for the 2nd rirs. the clavien-dindo classification was used to report complications. results: the mean patient age was 52.9 years. the mean stone size was 13.1 mm. lower pole, upper and middle calyces, renal pelvis and ureteral stones were found in 51.5% (239), 34.9% (162), 18.3% (85) and 46.9% (218) of cases, respectively. the mean diameter was 8.1 mm, 8 mm, 12.5 mm and 8.1 mm for the lower pole, upper and middle calyces, renal pelvis and ureteral stones, respectively. the singleand second-session sfrs were 90% and 100%, respectively. the mean number of procedures per renal unit was 1.1. ureteral double-j stents were inserted in 45.7% (212) of patients. in 96 cases, a stent was placed before surgery. postoperative complications were minor, with no avulsion or perforation of the ureters; readmission and insertion of a dj stent occurred in one patient. ureteral stricture developed in one patient (0.2%) and needed treatment with laser ureterotomy. conclusions: f-urs is a safe and effective mode of surgical management of renal and simultaneous renal and ureteral calculi using the ureteral access sheath without a safety guide wire. a guide wire should not be routinely used in these cases. key words: rirs; retrograde intrarenal surgery; safety guide wire; ureteral access sheath; renal stones; ureteroscopy. submitted 5 may 2022; accepted 27 may 2022 introduction nephrolithiasis is a common disease in asia with a rate of 1-5% (1). for decades, it was advised to have a safety guide wire sheathed flexible retrograde intrarenal surgery without safety guide wire for upper urinary tract stones murad asali urology department, barzilai medical center, ben gurion university of the negev, beer sheva, israel; assuta medical center, beer sheva, ramat hyal, ben gurion university of the negev, beer sheva, israel. doi: 10.4081/aiua.2022.2.186 summary 187archivio italiano di urologia e andrologia 2022; 94, 2 rirs without safety guide wire the exclusion criteria were as follows: 1. using other flexible ureteroscopes. 2. comorbidities that interfered with the completion of the study included severe. systemic disease, congestive heart failure, pregnancy, and severe chronic lung disease. 2. missed data. 3. no or other access sheath used. 4. patients with non-compliant ureters. 5. using rigid ureteroscope. the primary endpoint was the stone-free rate (sfr). stone-free status was defined as no residual fragments at all. at the end of the operation, a triple test was done for all the calyces, using a plain abdominal radiograph of the kidneys, ureter and bladder, using the scope and the carm while injecting contrast intraoperatively as a retrograde pyelography and screening every calyx using the endoscope and simultaneously following the anatomy on the c-arm screen. we evaluated 464 consecutive renal units that underwent f-urs for uut stones (table 1). in all patients, the following characteristics were examined: age, sex, laterality, renal/ureteral stones, stone diameter, hounsfield unit, stone-free rate, auxiliary procedures per renal unit, double-j stent insertion, length of hospital stay, and any perioperative complications. stone-free status was defined as complete stone removal. this study was retrospective, and all the data (demographic data, stone characteristics, operative and postoperative data) were recorded prospectively. postoperative follow-up was scheduled at one month later with renal scan dtpa, urine culture, and renal function. patients with residual stones were scheduled for a 2nd rirs (retrograde intrarenal surgery). the clavien-dindo classification was used to report complications (6). results the mean patient age was 52.9 years. the mean maximum stone diameter was 13.1 mm. lower pole, upper and middle calyces, and renal pelvis stones were in 51.5% (239), 34.9% (162), and 18.3% (85), respectively. ureteral stones were associated to renal stones in 46.9% (218) of cases. the mean diameter was 8.1 mm, 8 mm, 12.5 mm and 8.1 mm of the lower pole, upper and middle calyces, renal pelvis and ureteral stones, respectively. the renal and ureteral stone characteristics are shown in table 2. as shown in table 3, the single-session sfr was 90% (418/464), and the two-stage procedure sfr was 100%. the mean number of procedures per renal unit was 1.1. ureteral double-j stents were inserted 45.7% (212) postoperatively. in 96 cases, a stent was placed before surgery. the mean hospital stay was one day. intraand postoperative complications were minor, as shown in table 4. there was no avulsion of the ureters, no need for conversion to open surgery, no ureteral perforation; there was readmission and insertion of an a-dj stent in one patient (0.2%). in the follow up ureteral stricture developed in one patient that needed treatment with laser ureterotomy (0.2%). table 1. patient demographics and stone characteristics. patients 423 gender m/f 266/157 renal units (kidney +/ureter) 464 male 0.63 age (years) 52.9 hounsfield unit 880.1 mean maximum stone diameter (mm) 13.1 lateralization r/l 210/254 table 2. renal and ureteral stone location and diameter. no % total stone diameter (mm) renal and ureter 464 100 13.1 lower pole 239 51.5 8.1 upper and middle calyx 159 34.3 8 renal pelvis 85 18.3 12.5 upper ureter 98 21.1 8.9 middle ureter 46 9.9 7.3 lower ureter 74 15.9 7.4 table 3. stone-free rate/auxiliary f-urs. no % renal units 464 100 sf1st session 418 90 sf2nd session 464 100 auxiliary f-urs 46 9.9 laser frequency (hz) 31.3 ** energy (joule) 0.54 ** sf = stone free; f-urs = flexible ureteroscopy; hz = hertz. table 4. complications. no % renal units 464 100 renal colic needs im/iv* treatment 13 2.8 haematuria 1 0.2 insetion of stent due to pain 1 0.2 fever 2 0.4 ureteral stricture 1 0.2 ureteral avulsion 0 0 ureteral perforation 0 0 claviendindo classification i 16 3.4 claviendindo classification iii 2 0.4 claviendindo classification ii, iv, v 0 0 *im = intramuscular, iv = intravenous. archivio italiano di urologia e andrologia 2022; 94, 2 m. asali 188 discussion rirs is a safe and valuable alternative option for the management of renal stones. it is a well-established procedure under constant evolution with advances in technique and technology. it has gained worldwide popularity due to its minimal invasiveness and satisfactory outcomes (7). with the development of small flexible ureteroscopes and the improvement of laser lithotripsy, ureteroscopy has become the standard of care for treating urolithiasis less than 2 cm (4, 5). the stone-free rate (sfr) is higher in percutaneous nephrolithotomy-pcnl, but rirs is also an option for large renal stones larger than 2.5 cm with low morbidity (8). ho et al. published their review highlighting the expanding role of urs for the management of more complex stones and patients with good outcomes (9). advances in flexible ureteroscope design and accessory instrumentation and new laser generators have allowed for more challenging cases to be treated ureteroscopically. a safety guide wire is still used during ureteroscopy or rirs to ease the management of possible complications (2, 3). there is a belief that the use of a safety guide wire could help when prompt stent placement is needed in the event of a major ureteral perforation or bleeding precluding continuing urs (3, 10). patel et al. showed that the flexible ureteroscope itself could be used as a safe guide wire and that working without sgw facilitates access, scope manipulation and stone basketing. there is less friction passing the ureteroscope alongside a guide wire (11). in their retrospective study, johnson et al. treated renal stones with wireless and sheathless flexible urs. there were no false passages or ureteral perforations secondary to ureteroscope placement (12). eandi et al. also reported no intraoperative complications related to lack of a safety wire in semirigid and flexible urs for the treatment of urolithiasis (13). using the uas makes it easier to enter and exit the ureter, renal pelvis and calyces during the operation and even more so when handling large stones. moran and bratslavsky studied a single urologist’s experience with flexible ureteroscopic laser lithotripsy without the use of an sgw, and the stone-free rate was 96% (326/340) for those who did not use an sgw compared to a contemporary, large single-centre experience with eleven treating urologists (table 5). there were no complications in the group without a safety wire secondary to loss of upper tract access (14). ulvik et al. compared the results of urs for the treatment of ureteral stones at two different hospitals where the sgw was either routinely used or omitted. both groups had 500 patients each. pre-treatment stone status differed in many aspects between groups. there was no significant difference in the overall intraoperative complication rates at the two hospitals. the overall stone-free rates were 77.1% and 85.9% with and without the sgw, respectively (p = 0.001). a significant increase in the number of patients (14 patients, 3.4%) with post-endoscopic ureteral stenosis was found at the hospital where the sgw was routinely used compared to the hospital where an sgw was omitted (six patients, 1.2%), p = 0.039 (15). uas was not routinely used in the different studies dealing with wireless f-urs, so it is hard to make a comparison between these series (11-13, 16-17). in the moran and bratslavsky comparative study, there was no information about the uas (14). molina et al., in their review, showed a lack of relevant data supporting the use of sgw during retrograde urs (18). eandi et al. concluded that the presence of a safety guide wire adjacent to the endoscope inhibits passage of the ureteroscope in an in vitro animal model. technologic advancements in ureteroscope design and use of the holmium laser lithotrite minimize ureteral trauma and obviate the need for routine use of a safety wire during ureteroscopy (13). dutta et al., in their article titled "death of the safety guide wire", concluded that a safety guide wire served an important function in providing safer percutaneous and ureteroscopic procedures during the initial endourological history score. however, the decrease in the size of today’s ureteroscopes coupled with the advent of effective ureteral access sheaths and the evolution of endoscopic percutaneous renal access has largely eliminated the need for safety guide wires in both ureteroscopic and percutaneous procedures. they argued that what was once a “help” had become an inhibitor and a nuisance, as recent studies have shown that the safety guide wire increases the resistance to passage of the ureteroscope (19). to our knowledge, there are no articles dealing with the use of uas without guide wires present in upper urinary tract stones. table 5 summarizes some of the results of this study compared to other studies and shows that this study had the greatest number of cases with uas and without sgw simultaneously, with success similar to other studies and no major complications. the uniqueness of the current study is that similar components were used in all the patients. in all patients we used uas without sgw, a holmium laser, fibres (200 µ, 230 µ and 272 µ) with the same ureteroscope (karl-stortz flex-x2s), access sheaths (12/14 28, 35, or 45 cm) from the same company, and the same surgeon. we showed that f-urs was successful in 90% of cases in table 5. current study/other series. sgw no. mean renal stone mean ureteral stone sfr uas ureteral ureteral diameter (mm) diameter (mm) (%) (n) perforation avulsion patel et al. (11) no 268 12 ** n/a 40 0 0 eandi et al. (13) no 322 n/a n/a n/a 0 0 0 moran & bratslavsky (14) no 340 n/a n/a 96 n/a 0 0 ulvik et al. [15] no 500 n/a 8.8 85.9 1 6 1 yes 480 n/a 7.9 77.1 158 11 1 dickstein et al. (16) no 270 9.1 ** 88.9 0 0 0 current study no 464 8.8 8.1 90 464 0 0 sgw: safety guide wire; sfr: stone-free rate; uas: ureteral access sheath. 189archivio italiano di urologia e andrologia 2022; 94, 2 rirs without safety guide wire a single session and 100% in the second session. the mean number of procedures per renal unit was 1.1. according to the clavien-dindo classification, no major complications were observed. we achieved good results, although there were more lower pole stones (239/464). conclusions f-urs is a safe and effective mode of surgical management of renal and simultaneous renal and ureteral calculi using the ureteral access sheath without a safety guide wire. a guide wire should not be routinely used in these cases. acknowledgements thanks to aje for their editing services. references 1. sorokin i, mamoulakis c, miyazawa k, et al. epidemiology of stone disease across the world. world j urol. 2017; 35:1301-1320. 2. sprunger jk, herrell sd 3rd. techniques of ureteroscopy. urol clin north am. 2004; 31:61-9. 3. bagley dh, kuo rl, zeltser is. an update on ureteroscopic instrumentation for the treatment of urolithiasis. curr opin urol. 2004; 14:99-106. 4. de la rosette j, denstedt j, geavlete p, et al. croes urs study group. the clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. .j endourol. 2014; 28:131-9. 5. kılıç ö, akand m, van cleynenbreugel b. retrograde intrarenal surgery for renal stones part 2. turk j urol. 2017; 43:252-260. 6. dindo d, demartines n, clavien pa. classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. ann surg. 2004; 240:205-13. 7. sanguedolce f, bozzini g, chew b, et al. the evolving role of retrograde intrarenal surgery in the treatment of urolithiasis. eur urol focus. 2017; 3:46-55. 8. breda a, angerri o. retrograde intrarenal surgery for kidney stones larger than 2.5 cm. curr opin urol. 2014; 24:179-83. 9. ho a, sarmah p, bres-niewada e. ureteroscopy for stone disease: expanding roles in the modern era. cent european j urol. 2017; 70:175-178. 10. kumar pv, keeley fx, timoney ag. safe flexible ureterorenoscopy with a dual lumen access catheter and a safety guide wire. bju int. 2001; 88:638-9. 11. patel sr, mclaren id, nakada sy. the ureteroscope as a safety wire for ureteronephroscopy. j endourol. 2012; 26:351-4. 12. johnson gb, portela d, grasso m. advanced ureteroscopy: wireless and sheathless. j endourol. 2006; 20:552-5. 13. eandi ja, hu b, low rk. evaluation of the impact and need for use of a safety guide wire during ureteroscopy. j endourol. 2008; 22:1653-8. 14. moran me, bratslavsky g. changing paradigm during routine flexible ureteroscopy and holmium: yag laser lithotripsy: need for safety wires? j endourol. 2003; 17:a225. 15. ulvik ø, rennesund k, gjengstø p, et al. ureteroscopy with and without safety guide wire: should the safety wire still be mandatory? j endourol. 2013; 27:1197-202. 16. dickstein rj, kreshover je, babayan rk, wang ds. is a safety wire necessary during routine flexible ureteroscopy? j endourol. 2010; 24:1589-92. 17. ulvik ø, wentzel-larsen t, ulvik nm. a safety guide wire influences the pushing and pulling forces needed to move the ureteroscope in the ureter: a clinical randomized, crossover study. j endourol. 2013; 27:850-5. 18. molina wr junior, pessoa rr, silva rdd, et al. is a safety guide wire needed for retrograde ureteroscopy? rev assoc med bras (1992). 2017; 63:717-721. 19. dutta r, vyas a, landman j, clayman rv. death of the safety guide wire. j endourol. 2016; 30:941-4. correspondence murad asali, md (correspnding author) dr.muradasali@gmail.com department of urology, barzilai medical center ben gurion university, beer sheva, sokolov 26/99, 8430905 stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13870 1 letter to editor to the editor, given the strong association between metabolic bone diseases and kidney stones, we propose a new public health strategy aimed at improving the management of patients affected by these conditions. this novel diagnostic protocol is designed to ensure the most effective treatment possible. bone tissue structure and functions bone is a complex multifunctional tissue that, for many years, was considered merely a mechanical support structure with limited biological significance. however, over the last few decades, numerous experimental and clinical studies have highlighted the complexity and heterogeneity of bone’s biological functions (1). bone is the only physiologically mineralized connective tissue in the human body. it is composed of approximately 60% inorganic components – mainly hydroxyapatite – 10% water, and 30% organic components, primarily collagen proteins (2). a healthy bone turnover, characterized by continuous and finely regulated bone formation and resorption, preserves the mechanical properties of bone. the main actors involved in this dynamic process are osteoblasts and osteoclasts, which operate within the bone multicellular units (bmu) (3). osteoblasts are mononuclear cells derived from mesenchymal stem cells and play the key role in bone formation. conversely, osteoclasts are multinucleated cells originating from hematopoietic stem cells and are essential for bone resorption (4). throughout life, the balance between osteoblast and osteoclast activity ensures the maintenance and regeneration of bone mass (5). bone tissue is an endocrine organ and produces molecules with endocrine and paracrine functions, such as fibroblast growth factor 23 (fgf 23), osteopontin (opn), sclerostin (sost), and osteocalcin (6). through these bone-derived hormones, bone communicates with extra-skeletal organs and systems (7, 8). the skeletal and immune systems are intricately connected, a relationship studied under the fields of osteoimmunology (9). this interplay is achieved through several molecular mechanisms, cytokines and signaling transducers. immune and bone cells not only share a common origin and microenvironment – such as the bone marrow – but also influence each other’s activation, proliferation and senescence (9). recent evidence supports a mutual regulation between immune and bone cells. for instance, the immune system supports bone development: macrophages promote osteoblastogenesis via interleukin 18 kidney stones and metabolic bone diseases not linked to parathyroid disfunction: a proposal for an integrated management anita vergatti 1, veronica abate 1, matteo della monica 2, alfonso varriale 1, simone magelli 1, francesca garofano 1, lanfranco d’elia 1, antonio barbato 1, gianpaolo de filippo 3, domenico rendina 1 1 department of clinical medicine and surgery, federico ii university, naples, italy; 2 former head of the medical and laboratory genetic unit, cardarelli hospital, naples, italy; 3 assistance publique-hôpitaux de paris, hôpital robert-debré, service d’endocrinologie-diabétologie, paris, france. doi: 10.4081/aiua.2025.13870 nephrolithiasis (ks) and metabolic bone diseases (mbds) not linked to parathormone (osteoporosis, paget’s disease of bone and renal phosphate leak) are related as demonstrated by epidemiological and experimental data. moreover, patients affected by monogenic kidney stone disorders (idiopathic hypercalciuria, primary hyperoxaluria, hypocitraturia, cystinuria and defects in purine metabolism) showed a bone phenotype. a significant economic and social burden is associated with ks and mbds, due to high mortality and morbidity rate. concerning this point of view, an integrated screening could be a cost-saving strategy. we suggest a new clinical management for patients affected by ks and mbds. the assessment of bone mineral density by dual x-ray absorptiometry and bone turnover markers should be proposed in ks patients. on the contrary, the evaluation of ks-related metabolic risk factor and an abdomen ultrasound exam should be offered to mbd patients. moreover, in patients with early and/or recurrent ks, an extended gene-panel should be suggested. key words: nephrolithiasis; osteoporosis; paget disease of bone; osteomalacia; phosphate leak. submitted 7 april 2025; accepted 25 april 2025 summary archivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 2 (il18) (10), and t cells regulate osteoclastogenesis through il1, il6, il4 and interferon-γ (11, 12). in turn, osteoclasts can activate t-cell through receptor activator of nuclear factor kappa b (rank) rank ligand (rankl) osteoprotegerin (opg) signalling axis (13). moreover, studies suggest that osteoblasts and osteoclasts contribute to hematopoietic niche formation and mobilization respectively, although the precise mechanisms remain incompletely understood (14). bone also plays a critical role in mineral metabolism regulation. fgf23, secreted by osteoblasts and osteocytes, reduces phosphate reabsorption by inhibiting the expression of the type iia sodium-phosphate co-transporter (napi-2a) in renal proximal tubules. fgf23 also regulates calcium and sodium reabsorption, through the transient receptor potential vanilloid-5 (trpv5) channel and sodium-chloride co-transporter (ncc), respectively (15). additionally, fgf23 suppresses parathyroid (pth) hormone, which normally increases calcium release from bone and absorption from the gut and kidney, as well as the synthesis of 1,25-dihydroxy-vitamin d (15). bone health can be assessed using dual-energy x-ray absorptiometry (dxa), the gold standard for evaluating bone mineral density (bmd). dxa employs low-dose x-rays to measure the bmd in lumbar spine and total hip (16). results are reported as standard deviation (sd) from the mean bmd of healthy 30-year-old subjects of the same sex and ethnicity (tscore), or the same sex, age and ethnicity (z-score) (17). in addition to dxa, the trabecular bone score (tbs) is an indirect marker of bone microarchitecture, assessing variations in pixel gray levels in dxa image. tbs may be an independent predictor of frailty fracture (18). other diagnostic technics are represented by quantitative ultrasound (qus) and quantitative computed tomography (qtc). qus uses ultrasound waves that interact with the bone surface. the physical and mechanical bone features modify the return waves, allowing the evaluation of elasticity and strength, two bone quality parameters (19). qtc employs standard x-ray computed tomography and converts attenuation values into bmd values. it is particularly useful in patients in whom dxa in unsuitable (e.g., scoliosis) or where dxa may overestimate bmd (e.g., osteophytes, aortic calcification, arthritis) (20). a recent innovative is radiofrequency echographic multi spectrometry (rems), a non-ionizing technique that analyses raw, unfiltered ultrasound signals acquired during scans of the lumbar spine and/or femoral neck to provide dxa-equivalent bmd values (21). rems has been clinically validated through a multicentre observational trial involving 7 italian centres (22), and the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (esceo) has recognized rems as the first clinically available, non-ionized method for assessing lumbar and femoral bmd and predicting fracture risk (21). in addition to instrumental technics, bone turnover markers (btms) can be evaluated. btms are peptides produced during bone formation or reabsorption. n-terminal (p1np) and c-terminal (p1cp) propeptides are products of osteoblastderived procollagen synthesis, and their blood concentration reflect bone formation rates (23, 24). oc and bone-specific alkaline phosphatase (balp) are also produced by osteoblasts. oc is specific to bone, but it is hard to analyse, due to molecular instability and the impact of renal failure on its blood concentration (25). in contrast, balp remains a reliable marker even in chronic kidney disease and is a specific marker of bone formation (26). for bone resorption, c-terminal (ctx) and n-terminal (ntx) telopeptides, both products of collagen degradation, are the most widely used markers (27). ctx measurement is influenced by circadian rhythm and food intake, while ntx is affected by liver and renal function (28). another btm is opg, which reflects the bone microenvironment and osteocyte activity (28). kidney stones and metabolic bone disease kidney stones (ks), also known as nephrolithiasis or urolithiasis, are crystal concretions typically formed in the kidney and/or the urinary tract, including the renal pelvis, ureters, bladder, and urethra (29). ks affect approximately 13% of the population in north america, 9% in europa, and 5% in asia (30). the regional differences in prevalence and incidence worldwide are influenced by geographical, climatic, ethnic, dietary and genetic factors (31). ks have a significant economic impact, including direct treatment costs and loss of productivity. in 2021, the annual cost of treating ks in the united states was estimated at $9 billion. the global market for ks management is projected to reach $4.02 billion by 2034 (32, 33). about 85% of ks are composed of calcium oxalate and calcium phosphate salts, 10% of struvite (magnesium ammonium phosphate produced during infections by urease-producing bacteria), 9% of uric acid (ua), and the remaining 1% of cystine, ammonium acid urate, or drug-related stones (34). metabolic bone disease (mbds) are disorders affecting bone remodelling. the more common mbds include primary and secondary osteoporosis (op), paget’s disease of bone (pdb), rickets, and osteomalacia (35). the conditions carry a growing social and economic burden, especially with the aging global population (36). in italy alone, the economic burden of op is estimated at €2.2 billion, with about 80% of costs related to hospitalisations, 16% to pharmacological treatment, and about 3% to outpatient visits. these data show that op is one of the main health problems (37). since both mbds and ks are linked to the precipitation and crystallization of salts, an association between them has been hypothesized (38). osteoporosis and kidney stones op is the most prevalent mbd worldwide, affecting a large proportion of individuals over 60 years of age (39). op is characterised by a reduction in bone mass and deterioration of bone microarchitecture due to an imbalance between bone resorption and formation. this results in decreased bone strength and increased fracture risk (40). fracture prevalence in ks patients is estimated between 19-24% (41). both op and ks are multifactorial disorders with modifiable and non-modifiable risk factors (42). modifiable risk factors include high salt, protein, and sugar consumption, inadequate archivio italiano di urologia e andrologia 2025; 97(2):13870 3 kidney stones and metabolic bone diseases calcium and vitamin d intakes, smoking, and physical inactivity (43-46). non-modifiable risk factors are mainly genetic and epigenetic, although not fully understood (47). hypercalciuria (hca), defined as daily urinary calcium excretion higher than 300 mg/day in men and higher than 250 mg/day in women (48), is found in 20-30% of individuals with primary op (49, 50). hca is associated with persistent overproduction of cytokines predisposing bone loss (51), pth/calcitriol pathways (52), and disruptions in calcium-phosphate homeostasis (53). genetic variants of claudin 14 (cldn14) gene, involved inwnt signalling and osteoblast function, have been linked to both op and ks (53). unhealthy dietary habits represent a common risk factor. high salt consumption increases urinary calcium excretion (54), while low calcium and potassium intake and low physical activity contribute to the development of both conditions. the role of calcium intake and supplementation remains debated. jackson and coll. report a higher incidence of ks after calcium supplementation (55), while in his meta-analysis, heaney rp did not find differences between women with and without calcium supplementation (56). other authors showed a lower risk of ks in subjects with calcium intake > 1 g/day, due to the reduced intestinal absorption of oxalate and production of calcium-oxalate stones (57). in addition, in subjects with ks and low bmd, calcium intake through water and fibre seems to prevent ks (57). another important point is the salt dietary consumption. kleeman and coll. demonstrated that increasing salt intake, the 24h urinary calcium excretion increased (54). indeed, an increase of 6 g/day in salt consumption results in a 40 mg/day increase in 24h urinary calcium excretion (58). furthermore, nouvenne and coll. showed that high sodium intake raised ks and op risk, due to both higher calcium and lower citrate excretion (59). sugars are also involved in the pathogenesis of these conditions, causing a higher urinary calcium excretion (60, 61). overall, these data are emphasized in metabolic syndrome, a recognized risk factor for both op and ks (62). on the contrary, a diet rich in fruit and vegetables, with a low consumption of salt and animal protein and a calcium intake > 1 g/day is able to avoid ks and op (63). ks is characterized by higher levels of inflammatory markers (64), with potential role in bone resorption. in particular, elevated serum levels of il1, il-6, and tumor necrosis factor-α (tnfα) influence the osteoclasts activation and stimulate the synthesis of other bone remodelling mediators, such as prostaglandin e (65). in their meta-analysis, lucato and colleagues examined 24 case-control studies involving 1595 subjects with nephrolithiasis and 3402 healthy controls. ks formers showed lower bone mineral density (bmd), an increased risk of op, and a significantly higher risk of bone fractures compared to healthy controls (66). in a multicenter prospective study involving 107,001 women followed for 32 years and 50,982 men followed for 26 years, ks was associated with a higher risk of wrist fracture in both women and men, also correcting for race, body mass index (bmi), diet and other confounding factors (67). another study, based on veterans health administration data, found that 1 in 4 male ks formers had a history of op or frailty fractures, suggesting that the risk of op in ks is high also in men and supporting the bmd screening in all ks formers (68). furthermore, dhayat and colleagues identified ks constituents as predictors of low bmd. in particular, calcium-oxalate stones are negatively associated with bmd at the femoral neck (69). in contrast, sakhaee and colleagues (70) did not find a significant association between urinary calcium excretion and bmd in ks, in agreement with fink and coll. (71), that in a cohort of men with op and ks, did not find any relationship between op and 24h urinary calcium excretion. these results suggest that 24h urinary calcium may be a marker, but not a cause of bone loss. also, in a large cohort of multiethnic post-menopausal ks women, no significant association between ks and changes in bmd was found at multiple skeletal sites, after adjustment for confounders associated with op and/or ks (72). overall considered, data demonstrate that op is a risk factor for occurrence of ks and that ks is a risk factor for op (73). thus, we can look at op and ks as the two sides of the same coin (74). paget’s disease of bone and kidney stones paget’s disease of bone (pdb, omim 602080) is the second most common metabolic disease characterized by increased and disorganized bone turnover, involving one or more regions of the skeleton. pdb affects a significant percentage of peoples over 40 years old, with a prevalence between 1 and almost 8%. (75). the increased osteoclastic bone resorption, followed by marrow fibrosis, increased and disorganized vascularity and bone formation, represents the main pathophysiologic mechanism (75). the pdb osteoclasts show peculiar morphological and functional properties, such as hyper-responsivity to calcitriol, enhanced sensitivity to rank ligand, increased expression of il 6, il 6 receptor, and paramyxovirus transcript. pdb can evolve into malignant or non-malignant complications. in particular, ks is a non-malignant metabolic complication of pdb patients. pdb patients are at increased risk of ks independently of pdb activity or hyperparathyroidism. the involvement of multiple skeletal sites can influence the recurrence of ks. polyostotic patients have often ks and ks recurrences. in a recent study, it was demonstrated that the prevalence of ks in pdb patients without primary hyperparathyroidism is significantly higher compared with healthy control, also adjusted for age, gender, bmi, and estimated glomerular filtration rate (egfr). furthermore, pdb patients with ks showed a higher prevalence of hca, hypocitraturia, hyperoxaluria, and hyperuricuria compared with pdb patients without nephrolithiasis (76). renal phosphate leak and kidney stones the renal phosphate leaks are disorders of phosphate homeostasis with a reduced tubular reabsorption of phosphate not pth-related. it is characterized by low serum levels of phosphate (< 0.8 mmol/l or < 2.5 mg/dl), low threshold of tubuarchivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 4 lar phosphate reabsorption, and calcium, pth, 25-hydroxy vitamin d serum levels within the normal range (77). the maintenance of phosphate balance is crucial for bone health. indeed, different organs contribute to phosphate homeostasis: gut, kidney, and bone (78, 79). moreover, three main regulators of phosphate homeostasis had been identified: i) calcitriol increases phosphate absorption from the gut and bone; ii) pth increases phosphate resorption from bone and decreases its reabsorption in the proximal tubule; iii) fibroblast growth factor-23 (fgf-23) increases renal phosphate excretion (78, 80-82). notably, fgf23 controls cellular expression of type 2 sodium-phosphate cotransporter (ntp2a) in proximal renal tubule, independently from pth (83). hypophosphatemia causes osteomalacia, a clinical disorder characterised by under-mineralized soft bone. osteomalacia usually manifests with reduced bone mineral density, bone pain, frailty fractures, and muscle weakness, i.e. the osteomalacic syndrome (84). epidemiological studies indicate that 20% of patients with ks and normal level of pth show hypophosphatemia caused by renal phosphate leak, without complete phenotypic expressions of osteomalacia (85). the renal phosphate leak affects calcium salt urinary saturation and contributes to the pathogenesis of ks (86). some patients affected by ks and renal phosphate leak show genetic mutations in solute carrier family 34 member 1 (slc34a1, omim 182309), solute carrier family 34 member 3 (slc34a3, omim 609826), and sodium-hydrogen antiporter 3 regulator 1 (nherf1, omim 604990) genes (87). the identification of these gene mutations in patients with both hypophosphatemia, skeletal alterations and ks contribute to the common pathogenesis of these disorders. ks patients with renal phosphate leak show higher serum levels of fgf23 compared with ks patients without renal phosphate leak and healthy controls (88). in addition, in fgf23-dependent forms of renal phosphate leak, calcitriol can worsen ks, due to increased renal excretion of calcium (88). an isoform of fgf23, fgf23239m, occurring in 10% of caucasian population, is associated with recurrent ks in patients with phosphate renal leak. the mutant region c716t influences fgf23 biological proprieties and its interaction with fgfreceptor and klotho (89). in addition, the same allelic variant of fgf23 is involved in bone modelling in growing young children (90). bone health and monogenic kidney stones frequently, ks represents only the first symptom of an unknown disease. patients with early renal failure, severe and multiple ks, abnormal family history need to evaluate for genetic of ks, including idiopathic hca, primary hyperoxaluria (ph), hypocitraturia (hctr), cystinuria and defects in purine metabolism. moreover, these pathological conditions are associated to bone impairment. idiopathic hca (omim 143870-607258) is a metabolic condition affecting both children (91) and adult (92) with a diagnosis of ks. hca is defined as urinary calcium levels ≥ 4 mg/kg body weight/day (93). we recognized three different pathway and metabolic disorders, involving intestinal calcium absorption, renal phosphate leak, and renal calcium leak, respectively: i) absorptive hca type i; ii) absorptive hca type iii; iii) renal hca (94). different studies show the association between idiopathic hca and loss in bmd. in children, an increased bone reabsorption and a decreased bone formation cause a low bmd, while in adult, the bone reabsorption is prevalent (95). freundlich and coll. evaluated the bmd and btm in 21 children with a diagnosis oh idiopathic hca and in their mothers, founding osteopenia in 38% and 33%, respectively. furthermore, mothers with osteopenia showed an increasing in btm by 57% (96). also, garcía-nieto and coll. studied 40 girls with idiopathic hca and their pre-menopausal mothers. they found a z-score < 1 at the lumbar spine in 42.5% of girls and in 47.5% of their mothers, suggesting the necessity to measure early bmd in these patients (97). the skeletal sites involved are mainly represented by trabecular bone (98), but the mechanism causing the bone loss are poorly understood. ph are a group of autosomal recessive disorders linked to a liver overproduction of oxalate and characterized by ks (99). ph 1 (omim 259900; agxt gene mutation) is the most severe form with a higher risk of end-stage renal disease, while ph2 (omim 260000; grhpr gene mutation) and ph3 (omim 613616; hoga1 gene mutation) are less severe (99). the ph cause osteodystrophy related to chronic kidney disease, but ph patients show bone pain, fractures, bone deformations and subperiosteal tophi, independently of kidney disease (100). the exact pathophysiology remains unknown. hctr is a common risk factor for ks, with an incidence that ranges from 20% to 60% in ks formers (101). the low 24h urinary citrate excretion is a marker of acid load of the body. to maintain acid-base balance, kidney retains and bone releases alkali (citrate), causing a reduction in bmd and an increasing of btm (102). pak and coll. described a significant improvement of bmd in lumbar spine in ks formers treated with a long-term potassium citrate salt (mean 44 months), suggesting that this drug, used for ks, may prevent bone loss (103). cystinuria (omim: 220100) is a rare genetic disease caused by cystine tubular transport alteration, and it is considered as the most frequent monogenic form of ks. cystinuria is classified as: i) type a characterized by slc3a1 gene mutation; ii) type b characterized by slc7a9 gene mutation (104). cystinuric patients have a higher prevalence of chronic kidney disease and failure, caused by recurrent ks. this latter is associated to low bmd. an animal study by peters and coll., the slc3a1 gene mutation was associated to low bmd independently of renal failure, assuming a direct role of cystinuria in skeletal alteration (105). the high prevalence of low bmd in this setting was showed by bijelic and coll. compared to ks formers and healthy controls (106) and it was confirmed by d’ambrosio and coll. (107). the main defect in purine metabolism is the deficiency of hypoxanthine-guanine phosphoribosyltransferase (hprt), resulting in an accumulation of uric acid (ua) (108). ua has a double action on bone. in the normal range, it acts as an antioxarchivio italiano di urologia e andrologia 2025; 97(2):13870 5 kidney stones and metabolic bone diseases idant and reduces the incidence of op by 23-26% (109). meanwhile, elevated ua levels cause destructive effects on bone health through reactive oxygen species (ros) and increase of inflammation (110). an integrated approach to ks and mbds to reduce the financial and social burden growing epidemiological and experimental data support a non-stochastic association between idiopathic ks and common mbds, such as op, pdb and renal phosphate leak not pth related. mbds and ks share common environmental and genetic backgrounds. based on such evidence, a different clinical approach and management of ks and mbd patients should be evaluated. additionally, ks and mbds account for an increased economic burden, linked to hospitalisation and pharmacological treatment costs, and ambulatory visits (111, 112). an integrated screening protocol could be able to impact positively, reducing mortality, morbidity and overall costs. we propose the evaluation of metabolic risk factors for nephrolithiasis (measurement of 24-h urinary excretion of calcium, phosphate, citrate, magnesium and urate), and an abdomen ultrasound exam in patients with op, pdb and renal phosphate leak. on the contrary, the assessment of bone mineral density by dxa or rems, btms and threshold of tubular phosphate resorption should be evaluated in patients with nephrolithiasis. both in ks and mbd patients, the evaluation of daily calcium and salt intake, and the adherence to a balanced diet is recommended. moreover, in case of ks in young patients or recurrent ks, without any metabolic causes, it could be essential to search for gene mutations related to ks. this new diagnostic protocol guarantees the best possible treatment of any type of metabolic bone disorders, and, for this reason, it is necessary to develop a specific public health strategy. figure 1. suggested flow-chart for the management of nephrolithiasis and metabolic bone disorders. declarations ethical approval: n/a. availability of data and material: n/a. competing interests: all authors declare no conflict of interest. funding: no funding was used for this manuscript.. authors' contributions: conceptualization va, rd; methodology av, va, mdm, fg, gdf, rd; discussion of the findings av, va, mdm, av, sm, gdf, rd; writing original draft preparation va; final editing mdm, gdf, lde, rd; project administration and supervision mdm, gdf, rd. all authors have read and agreed to the published version of the manuscript. acknowledgments: n/a. archivio italiano di urologia e andrologia 2025; 97(2):13870 a. vergatti, v. abate, m. della monica, et al. 6 references 1. karsenty g. the complexities of skeletal biology. nature 2003; 423:316-318. 2. feng x. chemical and biochemical basis of cell-bone matrix interaction in health and disease. curr chem biol 2009; 3:189-196. 3. arias cf, herrero ma, echeverri lf, et al. bone remodeling: a tissue-level process emerging from cell-level molecular algorithms. plos one 2018; 13:e0204171. 4. šromová v, sobola d, kaspar p. a brief review of bone cell function and importance. cells 2023; 12:2576. 5. florencio-silva r, sasso gr, sasso-cerri e, et al. biology of bone tissue: structure, function, and factors that influence bone cells. biomed res int 2015; 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347:983-991. 88. rendina d, mossetti g, de filippo g, et al. fibroblast growth factor 23 is increased in calcium nephrolithiasis with hypophosphatemia and renal phosphate leak. j clin endocrinol metab 2006; 91:959-963. 89. rendina d, esposito t, mossetti g, et al. a functional allelic variant of the fgf23 gene is associated with renal phosphate leak in calcium nephrolithiasis. j clin endocrinol metab 2012; 97:e840-e844. 90. enlund-cerullo m, holmlund-suila e, valkama s, et al. variation in the fibroblast growth factor 23 (fgf23) gene associates with serum fgf23 and bone strength in infants. front genet 2023; 14:1192368. 91. van't hoff wg. aetiological factors in paediatric urolithiasis. nephron clin pract 2004; 98:c45-c48. 92. worcester em, coe fl. new insights into the pathogenesis of idiopathic hypercalciuria. semin nephrol 2008; 28:120-132. 93. sargent jd, stukel ta, kresel j, klein rz. normal values for random urinary calcium to creatinine ratios in infancy. j pediatr 1993; 123:393397. 94. pak cy, britton f, peterson r, et al. ambulatory evaluation of nephrolithiasis. classification, clinical presentation and diagnostic criteria. am j med 1980; 69:19-30. 95. heller hj, zerwekh je, gottschalk fa, pak cy. reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria. kidney int 2007; 71:808-815. 96. freundlich m, alonzo e, bellorin-font e, weisinger jr. reduced bone mass in children with idiopathic hypercalciuria and in their asymptomatic mothers. nephrol dial transplant 2002; 17:1396-1401. archivio italiano di urologia e andrologia 2025; 97(2):13870 9 kidney stones and metabolic bone diseases 97. garcía-nieto v, navarro jf, monge m, garcía-rodríguez ve. bone mineral density in girls and their mothers with idiopathic hypercalciuria. nephron clin pract 2003; 94:c89-c93. 98. caudarella r, vescini f, buffa a, et al. bone mass loss in calcium stone disease: focus on hypercalciuria and metabolic factors. j nephrol 2003; 16:260-266. 99. cochat p, rumsby g. primary hyperoxaluria. n engl j med 2013 28; 369:2168 100. bacchetta j, boivin g, cochat p. bone impairment in primary hyperoxaluria: a review. pediatr nephrol 2016; 31:1-6. 101. zuckerman jm, assimos dg. hypocitraturia: pathophysiology and medical management. rev urol 2009; 11:134-144. 102. frassetto l, banerjee t, powe n, sebastian a. acid balance, dietary acid load, and bone effects-a controversial subject. nutrients 2018; 10:517. 103. pak cy, peterson rd, poindexter j. prevention of spinal bone loss by potassium citrate in cases of calcium urolithiasis. j urol 2002; 168:31-34. 104. prot-bertoye c, lebbah s, daudon m, et al. ckd and its risk factors among patients with cystinuria. clin j am soc nephrol 2015; 10:842-851. 105. peters t, thaete c, wolf s, et al. a mouse model for cystinuria type i. hum mol genet 2003; 12:2109-2120. 106. bijelic r, milicevic s, balaban j. incidence of osteoporosis in patients with urolithiasis. med arch 2014; 68:335-338. 107. d’ambrosiov, capolongo g, caletti c et al. bone mineral density assessment in patients with cystinuria 2023. 108. sampat r, fu r, larovere le, et al. mechanisms for phenotypic variation in lesch-nyhan disease and its variants. hum genet 2011; 129:71-78. 109. chen f, wang y, guo y, et al. specific higher levels of serum uric acid might have a protective effect on bone mineral density within a chinese population over 60 years old: a cross-sectional study from northeast china. clin interv aging 2019; 14:1065-1073. 110. dalbeth n, becce f, botson jk, et al. dual-energy ct assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapy. rheumatology (oxford). 2022; 61:4898-4904. 111. hyams es, matlaga br. economic impact of urinary stones. transl androl urol 2014; 3:278-283. 112. marcellusi a, rotundo ma, nardone c, et al. osteoporosis: economic burden of disease in italy. clin drug investig 2020; 40:449-458. correspondence anita vergatti anita.vergatti@unina.it veronica abate veronica.abata@unina.it alfonso varriale alfonso.varriale@unina.it simone magelli simone.magelli@outlook.it francesca garofano garofanofran.1@gmail.com lanfranco d'elia lanfranco.delia@unina.it antonio barbato abarbato@unina.it domenico rendina (corresponding author) domenico.rendina@unina.it department of clinical medicine and surgery, federico ii university, naples, italy matteo della monica matteo191257@gmail.com former head of the medical and laboratory genetic unit, cardarelli hospital, naples, italy gianpaolo de filippo gianpaolo.defilippo@aphp.fr assistance publique-hôpitaux de paris, hôpital robert-debré, service d’endocrinologie-diabétologie, paris, france stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13318 1 review introduction benign prostatic hyperplasia (bph) is the most common cause of lower urinary tract symptoms (luts) in men due to bladder outlet obstruction (1). symptoms range from increased urinary hesitancy, urgency, and frequency to acute urinary retention. histologic bph is found in approximately 50% of men aged 50 years, and its prevalence increases about 10% each subsequent decade (2). likewise, significant luts are documented to occur in about 10%20% of men aged 50-59 and increase to one-third of men by ages 70-79. in parallel, prostate volume increases between age 40 and age 79, with the greatest increases appearing in the sixth and seventh decades of life (3). recent studies have uncovered several genes linked to both bph and prostate cancer. for instance, li et al. (4) investigated the v89l and a49t srda52 polymorphisms, while zhang et al. expanded the search by examining genotype distributions of srd5a2, cyp17, cyp19, and vdr genes in chinese populations (4, 5). additionally, choubey et al. (5) focused on polymorphisms at the (ta)n locus. together, these investigations, alongside others exploring correlations across diverse populations, significantly enhanced our understanding of the genetic factors that may impact the development of bph and prostate cancer. previous researchers have noted the presence of alleles with low catabolic activity including two polymorphic sites: an alanine to threonine substitution at codon 49 (a49t) and a valine to leucine substitution at codon 89 (v89l) (6). the v89l polymorphism correlates with reduced concentrations of androstanediol glucuronide, free testosterone, and testosterone (7). individuals with the “ll” genotype exhibit a slight, nonsignificant, decrease in androstanediol glucuronide concentrations compared to those with the “vv” genotype. the l allele's moderate reduction in srd5a2 activity results in lower dihydrotestosterone (dht) levels, although the biological mechanism behind this genotype's connection with decreased dht production remains unclear (4). however, dht levels in the prostate are influenced by various factors, including testosterone metabolism and dht inactivation. testosterone, not dht, appears to be the primary androgen promoting prostate introduction and objectives: being the most common disease in aged men, the etiology of benign prostatic hyperplasia (bph) is not fully defined. recent studies have reported that the association between benign prostate hyperplasia and metabolic genes is still inconsistent. a gene connected with bph is srd5ar2, whose polymorphisms, a49t and v89l, have distinct enzyme activity. this systematic review examines srd5ar2 polymorphisms within two alleles (a49t and v89l), assessing their roles as prognostic indicators of malignancy, and response to medication. materials and methods: we conducted a search on six different databases, including pubmed, scopus, wiley, proquest, cochrane central, and science direct using as string of keywords (bph) and [(rs523349) or (v89l)] and [(rs9282858) or (a49t)]. we finally selected seven articles to be extracted. quality appraisal of clinical trials was evaluated using the joanna briggs institute approach for systematic reviews. results: we sorted nine clinical studies from various countries examining srda52 polymorphism and its association of bph and prostate cancer. about v89l we found that the "ll" genotype, indicating reduced 5α-reductase activity, is linked to a lower bph risk, while the "vv" genotype may slightly increase bph risk. about a49t, compared to “aa” genotype, “at” tends to be associated to higher risk in developing prostate cancer. a49t polymorphism does not show any effect on medical treatment while v89l showed a protective effect on the clinical progression of bph when treated with 5a-reductase inhibitors, aadrenergic receptor antagonists, and alpha blockers. conclusions: srd5a2 polymorphisms could be a good indicator for prognostic malignancy and a potential tool for personalized medicine of bph. the findings strongly support the recommendation for further study about srd5ar2 to enhance its use for screening and prevention and to optimize the medical treatment of benign prostatic hyperplasia. key words: benign prostatic hyperplasia; prostate cancer; genetic polymorphism; prognosis; personalized medicine. submitted 30 october 2024; accepted 5 december 2024 a comprehensive systematic review of studies on the potential of a49t and v89l polymorphism in srd5ar2 as high susceptibility gene association with benign prostate hyperplasia and prostate cancer revina maharani 1, hotma lestari 1, putra mahakarya dewa 1, dewangga yudisthira 1, nasim amar 1, besut daryanto 2 1 medical faculty, universitas brawijaya, malang, indonesia; 2 urology department, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia. doi: 10.4081/aiua.2025.13318 summary archivio italiano di urologia e andrologia 2025; 97(1):13318 r. maharani, h. lestari, p. mahakarya dewa, et al. 2 carcinogenesis (8). in addition to the v89l polymorphism, the srd5a2 a49t is linked to a significantly lower concentration of androstanediol glucuronide, indicating its impact on androgen metabolism (9). the srd5a2 polymorphism likely represents a crucial point in dht metabolism, possibly explaining its association with prostate cancer risk. this underscores the complexity of genetic factors influencing prostate cancer susceptibility. both polymorphisms likely contribute to variations in androgen levels, potentially influencing prostate cancer development (10). to the best of our knowledge, there has been limited research about a49t and v89l polymorphisms of srd5ar2 as bph risk factor. considering the role in benign prostatic hyperplasia and in the risk of malignancy and in their treatment, the authors were interested in reviewing evidence about srd5ar2 polymorphisms a49t and v89l, in order to assess their roles as prognostic indicators for malignancy and response to medication. materials and methods data sources and search strategy the systematic review was carried out based on the preferred reporting items for systematic reviews and meta analysis (prisma) guidelines by utilizing the pubmed, scopus, wiley, proquest, cochrane central, and science direct. article search for papers in english was done using boolean operators with the following keywords: [(benign prostatic hyperplasia) or (bph) or (prostate cancer)] and [(rs523349 or v89l) and (rs9282858 or a49t)]. the inclusion criteria were: case-control or cohort study; study investigating gene polymorphisms a49t and v89l in srd5ar2 and their association with bph and prostate cancer; written in english. quality appraisal of clinical trials was evaluated using the joanna briggs institute approach for systematic reviews. selection process the authors individually evaluated findings of literature search, beginning with the titles and abstracts of papers which passed eligibility criteria screening. any disagreement was freely discussed with one senior author to settle them. the entire text was then examined to weed out research that were not relevant. data extraction the selected articles were extracted by the authors, who then assessed their suitability. disagreements were discussed and ultimately settled after each author reviewed the articles on his own. name of the author, year of publication, country, study design, number of samples, sample characteristics, intervention, comparison, length of followup, and desired outcomes were taken from eligible studies. results study selection after the literature search, 116 articles were retrieved by the six databases. several articles were excluded due to duplication of studies (n = 29). some papers were excluded because they did not adhere to inclusion criteria (n = 36). there were 41 articles excluded due to ineligible data, such as review articles and books, and inaccessible articles due to subscriptions. finally, nine articles were included in the systematic review to be analysed qualitatively and quantitatively. figure 1 shows the prisma flowchart. study design this review consists of 9 clinical studies with varying designs: 1 cross-sectional, 3 case-control, 2 cohort studies, and 3 clinical trials. the total number of participants across all studies includes 1,226 individuals, comprising prostate cancer patients, bph patients, and healthy controls. methods of diagnosis and assessment included blood diagnostic criteria, prostate-specific antigen (psa) testing, digital rectal examination (dre), and biopsy results. the geographic distribution of the studies includes bulgaria, china, japan, the usa, india, and sweden. the review emphasizes the impact of gene polymorphism and its associations with prostate diseases, explores and discusses their implications for personalized medicine. risk of bias summary the risk of bias for various study designs; case-control, cohort, and cross-sectional was evaluated using the jbi critical appraisal tools. according to the risk of bias assessment, three studies were found to have a moderate risk of bias, primarily due to ambiguous statements in areas such as the identification of confounding factors and the strategies used to address them, as well as incomplete data throughout the studies. the remaining studies (n = 6) were classified as having a low risk of bias (see figure 2). despite the varying levels of bias across the included studies, most of the data have been thoroughly examined and discussed. the reviewers concluded that, overall, the studies are sufficiently suitable for analysis. study result summary gene polymorphism results for v89l variant of srd5a2 are reported in table 1. for the a49t, men with the at/tt genotypes were at increased risk for bph, asymptomatic, and symptomatic bph and prostate cancer compared to men with the aa genotype, although none of the or reached statistical significance. association to malignancy based on the studies on v89l polymorphism that were evaluated, it was shown that “ll” allele, that confers a low activity of 5 alpha reductase, was less common in patients with prostate cancer. on the other hand, “vv” locus, which is commonly found in the hispanic population, is associated with a higher risk of bph. the a49t gene consists of “aa” locus and “tt” locus producing “aa”, “at”, and “tt” genotypes. all of the genotypes mentioned have no statistically significant correlation to malignancy, although “at” and “tt” genotypes have a higher risk of developing prostate cancer. “at” archivio italiano di urologia e andrologia 2025; 97(1):13318 3 srd5ar2 gene association with benign prostate hyperplasia and prostate cancer figure 1. prisma flowchart of the literature selection. figure 2. risk of bias assessment archivio italiano di urologia e andrologia 2025; 97(1):13318 r. maharani, h. lestari, p. mahakarya dewa, et al. 4 variants were more frequently found among prostate cancer patients while “aa” variants were least likely to be found on patients with prostate cancer and bph. response to drugs both genes demonstrated a protective effect against the clinical progression of bph when treated with 5α-reductase inhibitors, α-adrenergic receptor antagonists, and alpha blockers. populations with the “ll” genotype were likely more suitable to have a standard or herbal treatment for bph. discussion the results of the present study, when contextualized with previous research (11-16), provide a deeper understanding of the role of genetic polymorphisms in the srd5a2 gene, particularly v89l and a49t, in the development and progression of prostate pathological conditions like bph and prostate cancer (pca). the associations between these polymorphisms and disease risk highlight the genetic mechanisms that may influence prostate enlargement and malignancy, as well as the potential for personalized treatment strategies based on these genetic markers. our findings on the v89l polymorphism align with previous studies showing that the srd5a2 gene encoding an enzyme responsible for converting testosterone into dihydrotestosterone (dht), plays a key role in prostate growth. the activity of this enzyme also known as 5-alpha reductase type 2 is linked to the severity of bph. the v89l polymorphism shows distinct enzyme activity variations that influence androgen levels and drive prostate growth, potentially leading to prostate cancer. our review found that the "ll" genotype is less common in prostate cancer patients, suggesting that this allele may have a protective effect by lowering 5-alpha reductase activity and, consequently, dht production. table 1. gene polymorphism. archivio italiano di urologia e andrologia 2025; 97(1):13318 5 srd5ar2 gene association with benign prostate hyperplasia and prostate cancer table 2. prognostic to malignancy archivio italiano di urologia e andrologia 2025; 97(1):13318 r. maharani, h. lestari, p. mahakarya dewa, et al. 6 these results are consistent with a study by konwar et al. (17), which reported that the ll genotype is associated with lower androstanediol glucuronide concentrations, thereby reducing free testosterone and dht levels. this may explain the reduced prostate volume and lower cancer risk in individuals with the "ll" genotype compared to those with the "vv" genotype. furthermore, the higher risk of bph associated with the "vv" allele was also supported by lunn et al. (18) research, which indicated ethnic differences in v89l polymorphism prevalence. in asian populations, such as those in india and japan, the polymorphism was found at higher rates, contributtable 3. response to medical treatment. archivio italiano di urologia e andrologia 2025; 97(1):13318 7 srd5ar2 gene association with benign prostate hyperplasia and prostate cancer ing to an increased risk of bph. this suggests that the genetic impact of the v89l variant may vary across different ethnicities, with certain populations exhibiting a higher predisposition to prostate diseases. regarding the a49t polymorphism, our review found no statistically significant association with malignancy, though the "at" and "tt" genotypes tended to be associated with a higher risk of developing prostate cancer compared to the "aa" genotype. this aligns with giwerchman et al. (15), who estimated that the a49t polymorphism could be found in approximately 8% of prostate cancer patients and 6.3% of bph patients, indicating its role in increasing the probability of developing bph and prostate cancer. although not as prominent in asian populations, this polymorphism is commonly observed in hispanic populations, as well as in certain countries like turkey and china. while the statistical significance of the a49t polymorphism in relation to malignancy remains inconclusive in our review, these findings emphasize its potential importance as a genetic marker for prostate cancer susceptibility. this warrants further research, especially in nonhispanic populations, to determine whether the a49t variant can be used as a predictive tool for prostate disease risk in other ethnic groups. the study findings on gene polymorphisms in the srd5a2 gene also underscore the potential for personalized medicine in treating prostate-related conditions. according to li et al. (14), the srd5a2 gene regulates critical hormonal pathways, influencing prostate growth and function. this insight into the biochemical pathways driven by v89l and a49t polymorphisms supports the idea of genotype-driven therapeutic approaches. both v89l and a49t polymorphisms demonstrated protective effects against the clinical progression of bph when treated with 5-alpha reductase inhibitors and αadrenergic receptor antagonists. these findings imply that personalized treatment strategies based on genetic markers could optimize therapeutic outcomes and reduce the likelihood of disease progression, offering a more tailored approach to managing bph and prostate cancer. a study by daryanto et al. (19) showed that combination of dutasteride with tamsulosin could give a more significant effect in terms of lowering the contractility of prostate smooth muscle. while the findings of this review are compelling, they also reveal the need for further research. the prevalence of v89l and a49t polymorphisms in hispanic populations has been well-documented, but additional studies in asian populations are necessary to understand their role in diverse genetic backgrounds. for example, as noted by lunn et al. (18), the v89l polymorphism shows high prevalence in india and japan, suggesting a population-specific effect. expanding genetic studies to include other asian regions may yield valuable insights into the global relevance of these polymorphisms. additionally, larger cohort studies and more diverse population sampling are needed to strengthen the associations between these polymorphisms and prostate cancer or bph risk. a more detailed exploration of the mechanistic pathways involved in dht production and androgen activity, particularly in relation to the srd5a2 gene, will be essential for translating these genetic insights into clinical practice. this study confirms the significant role of the srd5a2 gene and its v89l and a49t polymorphisms, in influencing the risk of prostate disease and its progression. both variants have distinct effects on the enzyme activity and androgen levels, impacting on prostate growth and the likelihood of developing bph or prostate cancer. ethnic differences in polymorphism prevalence further highlight the importance of population-specific genetic research. by integrating genetic profiling into clinical practice, personalized medicine approaches may offer more effective and targeted treatment options for prostate-related conditions, improving patient outcomes while minimizing unnecessary interventions. conclusions in conclusion, this systematic review proves that srd5a2 is a high susceptibility gene that is linked to bph. a49t and v89l are the polymorphism of the gene involved. ninboth polymorphism varies in different ethnic populations. further studies are required to evaluate different risk factors and outcomes after medical treatment in different geographical situation in order to provide a better theoretical basis to study the role of genetic in the pathogenesis of bph and prostate cancer. references 1. roehrborn cg. benign prostatic hyperplasia: an overview. rev urol. 2005; 7(suppl 9):s3-s14. 2. goodarzi d, cyrus a, khoddami vishteh hr, et al. effect of celecoxib on benign prostatic hyperplasia: results of a preliminary study. urological science. 2011; 22:147-150. 3. middleton lw, shen z, varma s, et al. genomic analysis of benign prostatic hyperplasia implicates cellular re-landscaping in disease pathogenesis. jci insight. 2019; 5:e129749. 4. li q, zhu y, he j, et al. steroid 5-alpha-reductase type 2 (srd5a2) declarations ethical approval: not applicable. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the authors declare that they have no competing interests. funding: the authors report no funding. authors' contributions: rm: conceptualization, methodology, writing-original draft, data curation, visualization, project administration; hl: conceptualization, methodology, writingoriginal draft; pmd: conceptualization, methodology, writingoriginal draft, investigation; dy: conceptualization, formal analysis, na: methodology, writing review & editing, methodology; bd: writing review & editing, supervision, validation. acknowledgments: not applicable. consent for publication: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13318 r. maharani, h. lestari, p. mahakarya dewa, et al. 8 v89l and a49t polymorphisms and sporadic prostate cancer risk: a meta-analysis. molecular biology reports 2013; 40:3597-3608. 5. choubey vk, sankhwar sn, carlus sj, et al. srd5a2 gene polymorphisms and the risk of benign prostatic hyperplasia but not prostate cancer. asian pac j cancer prev. 2015; 16:1033-1036. 6. salam mt, ursin g, skinner ec, et al. associations between polymorphisms in the steroid 5-alpha reductase type ii (srd5a2) gene and benign prostatic hyperplasia and prostate cancer. urol oncol. 2005; 23:246-253. 7. zeng xt, su xj, li s, et al. association between srd5a2 rs523349 and rs9282858 polymorphisms and risk of benign prostatic hyperplasia: a meta-analysis. front physiol. 2017; 8:688. 8. price dk, chau ch, till c, et 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cancer risk: a meta-analysis. prostate. 2010; 70:170-8. 14. li j, coates rj, gwinn m, khoury mj. steroid 5-α-reductase type 2 (srd5a2) gene polymorphisms and risk of prostate cancer: a huge review. am j epidemiol. 2010; 171:1-13. 15. giwercman yl, abrahamsson pa, giwercman a, et al. the 5alpha-reductase type ii a49t and v89l high-activity allelic variants are more common in men with prostate cancer compared with the general population. eur urol. 2005; 48:679-85. 16. tekin neijmann s, kural a, tinay i, et al. association of missense substitution of a49t and v89l in the srd5a2 gene with prostate cancer in turkish patients. turkish journal of biochemistry. 2017; 42:37-43 17. konwar r, chattopadhyay n, bid hk. genetic polymorphism and pathogenesis of benign prostatic hyperplasia (bph). bju international. 2008; 5:536-44. 18. lunn rm, bell da, mohler jl, taylor ja. prostate cancer risk and polymorphism in 17 hydroxylase (cyp17) and steroid reductase (srd5a2). carcinogenesis. 1999; 20:1727-31. 19. daryanto b, naim hy, budaya tn. the effect of tamsulosin, dutasteride monotherapy and tamsulosin-dutasteride combination on prostate smooth muscle contractility in bph model wistar strain rattus novergicus. medical archives. 2023; 77:13. correspondence revina maharani 10maharanirevina@gmail.com hotma lestari hotlesmo67@gmail.com putra mahakarya dewa putramahakaryadewa25@gmail.com dewangga yudisthira dewanggay369@gmail.com nasim amar nasemamar2003@gmail.com medical faculty, universitas brawijaya, malang, indonesia besut daryanto (corresponding author) urobes.fk@ub.ac.id urology department, faculty of medicine universitas brawijaya, dr. saiful anwar general hospital, malang, indonesia stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13036 1 original paper introduction spinal cord injury (sci) is a life-changing event, associated with a significant impact on patients’ lives and healthcare systems (1). sci is provoked by traumas in more than 90% cases, presenting a male-to-female ratio of 2:1 and a bimodal age distribution with the involvement of young adults and adults over the age of 60 (2). therefore, sci may involve young men at the peak of their reproductive needs (3). indeed, fertility issues represent a significant need to address for all healthcare professionals involved with sci (4). this population may experience different-graded alterations in sexual and reproductive functions, presenting with a combination of erectile dysfunction (ed), ejaculatory dysfunction and abnormal semen parameters (5). the literature about the fertility of men with sci has not showed univocal data concerning sperm quantitative and/or qualitative alterations (6). moreover, the effect of time since sci is controversial. in the case of retrograde ejaculation or anejaculation, a condition that leads to a functional obstructive azoospermia (oa), a stepwise approach of penile vibratory stimulation (pvs), followed by electroejaculation (eej) may achieve ejaculation in most patients (7). in the rest of cases, a testicular sperm extraction (tese) may be performed to diagnose spermatogenic failure and/or extract spermatozoa for cryopreservation (8). the aim of our study was to report the data from our sci patients undergoing tese, focusing on the effects of time since sci in tese outcomes. methods this study was designed as cross-sectional, retrospective, multicentric. it was conducted in accordance with the background: people with spinal cord injury (sci) may suffer from anejaculation due to functional obstructive azoospermia (oa). testicular sperm extraction (tese) may successfully overcome this problem, even if the optimal timing is controversial. objectives: the primary aim of this study was to report our experience with tese in sci, focusing on the effect of time since sci event on the tese outcomes. materials and methods: we included all consecutive people with sci and functional oa undergoing tese between january 2011 and december 2021 in four italian tertiary referral centers. we recorded tese sample parameters, sperm retrieval rate (srr) and intracytoplasmic sperm injection (icsi) outcomes. logistic regression analysis was performed to assess whether time since sci was significantly associated with these outcomes. the time since sci was considered in three different ways: (1) continuously; (2) ≤ 9 years vs. > 9 years; (3) ≤ 5 years, > 5 and ≤ 10 years, > 10 years. results: we included 32 patients with tetraplegia and 75 with paraplegia, undergoing 107 tese procedures. the median age at surgery and time since sci were 33 years (iqr 29-38) and 9 years (iqr 3-14), respectively. the srr was 81.3%. thirty-three out of 87 patients underwent icsi, achieving pregnancy in 63.6% after one cycle. the final live birth rate was 90.5%. logistic regression analyses outlined that the srr was not affected by considered variables, including time since sci, considered both continuously and categorically. conclusions: our srr did not prove to be negatively affected by all considered variables, specially by the time since sci. clinicians should not deter sci patients with functional oa from undergoing tese after long time since sci. key words: infertility; ejaculatory dysfunction; testicular sperm extraction; spinal cord injury. submitted 6 september 2024; accepted 26 september 2024 does the time from spinal cord injury affect the sperm retrieval rate in testicular sperm extraction? a multicenter cross-sectional study michele morelli 1, michele spinelli 1, paolo geretto 2, chiara stefania guerrer 1, carmine sciorio 3, lorenzo spirito 4, lorenzo romano 4, felice crocetto 4, biagio barone 4, luca gemma 5, luca frediani 6, michele sica 2, giulio del popolo 5, alberto manassero 2, santo lupo 7, roberta de stefano 7, giuseppe fallara 8, ottavio de cobelli 8, gianluca sampogna 1 1 unit of neuro-urology, unipolar spinal unit, niguarda hospital, university of milan, milan, italy; 2 unit of neuro-urology, città della salute e della scienza, university of turin, turin, italy; 3 unit of urology, manzoni hospital, lecco, italy; 4 unit of urology, department of neurosciences, reproductive sciences, and odontostomatology, university of naples "federico ii", naples, italy; 5 unit of neuro-urology, careggi university hospital, florence, italy; 6 neurocenter of southern switzerland, ente ospedaliero cantonale, lugano, switzerland; 7 unit of urology, ospedale maggiore, bologna; 8 unit of urologic surgery, european institute of oncology, university of milan, milan, italy. doi: 10.4081/aiua.2025.13036 summary archivio italiano di urologia e andrologia 2025; 97(3):13036 m. morelli, m. spinelli, p. geretto, et al. 2 declaration of helsinki through all phases. the authors retrospectively collected data from different italian tertiary referral centers: 1) unit of neuro-urology, unipolar spinal unit, niguarda hospital, milan, italy; 2) unit of neuro-urology, città della salute e della scienza, university of turin, turin, italy; 3) unit of neuro-urology, careggi university hospital, florence, italy; 4) unit of urology, department of neurosciences, reproductive sciences, and odontostomatology, university of naples "federico ii", naples, italy. we included all patients who underwent tese from january 1st, 2011, to december 31st, 2021. the biologists of each fertility center analyzed all testicular samples, while assisted reproductive technology (art) was not always realized by the same hospital. inclusion and exclusion criteria, data collection, variable and outcome definition we included all consecutive patients with sci aged more than 18 years old, affected by oa and requiring tese. most of them were refractory to pvs. we excluded cases with anemia, immunological and/or coagulation disorders, infections by human immunodeficiency virus (hiv), hepatitis c virus (hcv), hepatitis b virus (hbv), and treponema pallidum to avoid possible confounding biases. all patients underwent scrotal ultrasound (us) and blood test to assess hormonal profile, evaluating total testosterone, folliclestimulating hormone, luteinizing hormone and prolactin. we included only cases with normal testis volumes and with hormonal values within the laboratory-specific normal ranges to exclude potential biases. two authors independently collected the data; each conflict was solved by a senior author. we included couples with only male factor infertility, after a comprehensive gynecological assessment of the female partner. we collected the following pre-operative parameters: sci level, age at surgery, time since sci, bladder management, other genitourinary (gu) pathologies, smoking status. we also collected data on bladder management screening for clean intermittent catheterizations (cics), antimuscarinic therapy (amt), periodical detrusor muscle injections of botulinum toxin-a (btx-a) (9). we defined bladder management as “not optimal” in case of recurrent urinary tract infections (utis), male accessory gland infections (magis), urine leakages, vesicoureteral reflux (vur) or other possible complications related to the gu system. we collected data on any surgical procedures involving gu system (10). we collected data on the presence of grade iii varicocele, which was defined as “visible and palpable at rest” according to the standard clinical classification by the examining physician (11). our aim primary endpoint was to analyze the effect of time since sci on tese outcomes. time since sci was defined as time from sci event to the tese date. we reported the testicular sample descriptive parameters at tese: number of frozen straws retrieved, number of spermatozoa per high power field (hpf), motility and morphology (12). the sperm retrieval rate (srr) was defined as the retrieval rate of spermatozoa suitable for intracytoplasmic sperm injection (icsi). on may 2022, one author performed a phone interview to assess the number of patients who underwent art up to december 2021, collecting the number of icsi cycles, the pregnancy rate (pr) per couple, and the live birth rate (lbr) (13). surgical procedure all patients underwent a conventional tese, without the use of operating microscope (14). the procedure was performed under general or local anesthesia with lidocaine 1%. all surgeries were carried out by the experienced surgeon. we performed a small horizontal incision in the median part of the scrotum on the side decided pre-operatively according to dimensions and us evaluations (e.g., vascularization, preserved parenchymal architecture). the skin, dartos muscle, and tunica vaginalis were opened. once exposed, we performed a 5 mm incision of the tunica albuginea at the middle of the testis. multiple testicular specimens were excised and sent to our embryologists. we excised very small portions of testicular parenchyma to decrease morbidity in our frail patients, so we sent just the material necessary for art, and no tissue specimens for histopathological examination (15). absorbable sutures were later performed to close tunica albuginea, tunica vaginalis and dartos, while the skin was sutured with silk or absorbable thread. sperm identification procedure sperm identification procedures were very similar across considered centers. by way of example, we reported the procedure at the niguarda hospital, milan. all the testicular samples were preliminarily comminuted with folded needles of tuberculin syringes and then resuspended with 5 ml human serum albumin (hsa) and recombinant human insulin medium (origio®, måløv, denmark) in the laboratory. subsequently all testicular samples were subjected to centrifugation at 300 g for 8-10 minutes. our embryologists carefully examined the samples under the optic microscope to determine the presence of spermatozoa in the pellet (16). in most cases, positive research was completed in about 60 minutes, while extra time was necessary in case of unsuccessful retrieval. the sample was subjected to 1000 iu collagenase (gynemed®, lensahn, germany) if spermatozoa were not found immediately. the small sample allowed just a brief description, reporting the number of spermatozoa for 400-fold magnification fields of view (hpf) with microscope and the evaluation of spermatozoa morphology and motility. the collected paillettes were cryopreserved in origio® medium after freezing with static liquid nitrogen vapor. statistical analysis data were stored anonymously using microsoft excel, version 15 (microsoft corporation, redmond, wa, usa). another author performed blindly statistical analyses using statistical package for social science (spss), version 28 (ibm corporation, armonk, ny, usa). we estimated the median and interquartile range (iqr) for each quantitative variable when non-normally distributed, while we reported the frequencies for categorical variables. patients were stratified into two groups according to the median time between sci and tese. time since sci was considered continuously and categorically to improve the consistency of our analyses regarding the effects of time since sci. initially, we divided our cohort into 3 groups: group a (≤ 5 years), group b (> 5 and ≤ 10 years) and group c (> 10 years). later, we divided our population into 2 groups based on the median, group d and group archivio italiano di urologia e andrologia 2025; 97(3):13036 3 time from spinal cord injury and sperm retrieval rate e. differences between the groups were analyzed using the chi-squared for the categorical variables and the mann-whitney u test for continuous variables. univariable logistic regression analysis was used to assess the impact of time since sci on tese outcomes. statistical significance level was determined at p value < 0.05. results we analyzed data from 107 patients (table 1), affected by tetraplegia (n = 32) and paraplegia (n = 75). the median age at surgery was 33 years (iqr 29-38, range 19-55), while the median time since sci was 9 years (iqr 3-14, range 0-45). as for bladder management, all patients underwent cics, 85 (79.4%) took amt, while 49 (45.8%) patients underwent periodical btx-a injections into the detrusor muscle. one tetraplegic patient did not tolerate amt and btx-a bladder injections. we considered bladder management as not optimal in 39/107 (36.4%) cases. ten out of 107 patients (9.3%) reported other gu surgeries in the past: vasectomy (n = 3, 2.8%), hydrocelectomy (n = 2, 1.9%), implantation of adjustable continence therapy (proact™) system (n = 1, 0.9%), and endoscopic treatment of vesicoureteral reflux (n = 2, 1.9%) and of stress urinary incontinence with urethral bulking agents (n = 2, 1.9%). we identified (n = 2, 1.9%) cases with severe varicocele. ten (9.3%) patients reported history of surgery for cryptorchidism. the rate of current smokers was 49.5%. no intra-operative complications occurred in all 107 teses. all procedures were performed under local anesthesia but one where general anesthesia was used in a tetraplegic patient suffering from autonomic dysreflexia. no post-operative complications were observed during the considered follow-up. the overall srr was 81.3% and we depicted graphically the correlation between the sperm retrieval outcome and the time since sci by percent stacked barplots (figure 1). one paraplegic patient was monorchid due to a testicular abscess and the sperm retrieval was unsuccessful. another tetraplegic patient presented bilateral testicular microlithiasis and the sperm retrieval was successful. after dividing our population into 3 groups based on time since sci, we detected no statistically significant differences (p > 0.05) for all considered baseline characteristics, except for age at surgery (p < 0.001). later, we divided our population into 2 groups based on the median of time since sci: group d (≤ 9 years) and group e (> 9 years). we outlined no statistically significant differences, except for age at surgery (p < 0.001) and cryptorchidism (p = 0.023). in table 2 we reported the features in tese samples and the art outcomes in case of positive sperm retrieval (n = 87). spermatozoa presented progressive motility in 31 (35.6%) cases. we observed a normal sperm morphology in 40/87 (46%) samples. considering a median follow-up of 76 months (iqr: 57.5-85.5), 33 couples started art, by use of icsi. the pr per couple was 63.6% after a single cycle. table 1. characteristics and descriptive statistics of patients according to the time since sci, whose median was 9 years (range: 3-14). we divided patients into different groups based on time since spinal cord injury: group a (≤ 5 years), group b (> 5 and ≤ 10 years) and group c (> 10 years), besides group d (≤ 9 years) and group e (> 9 years). we estimated statistically significant differences among groups a, b and c, and between groups d and e. variable overall time since sci (n = 107) group a group b group c p value group d group e p value (n = 38) (n = 28) (n = 41) (n = 58) (n = 49) level of injury 0.292 0.261 tetraplegia no. (%) 32 (29%) 12 (31.6%) 11 (39.3%) 9 (22.0%) 20 (34.5%) 12 (24.5%) paraplegia no. (%) 75 (70.1%) 26 (68.4%) 17 (60.7%) 32 (78.0%) 38 (65.5%) 37 (75.5%) age at surgery years < 0.001 < 0.001 median 33 30 32 36 31 35 iqr 29-38 24.5-36.75 28.25-34.25 33-41 27.25-36 32-41 range 19-55 19-48 20-45 26-55 19-48 26-55 antimuscarinic therapy no. (%) 85 (79.4%) 29 (76.3%) 23 (82.1%) 33 (80.5%) 0.827 45 (77.5%) 40 (81.6%) 0.606 detrusor injections of btx no. (%) 49 (45.8%) 19 (50%) 8 (28.5%) 22 (53.7%) 0.098 23 (39.7%) 26 (53%) 0.166 other gu surgery* no. (%) 10 (9.3%) 3 (78.9%) 3 (10.7%) 4 (9.8%) 0.921 5 (8.6%) 5 (8.3%) 0.779 history of recurrent utis and/or magis no. (%) 24 (22.4%) 5 (13.1%) 8 (28.5%) 11 (26.8%) 0.230 9 (15.5%) 15 (10.2%) 0.062 not optimal bladder management no. (%) 39 (36.4%) 17 (44.7%) 9 (32.1%) 13 (31.7%) 0.417 25 (43.1%) 14 (28.6%) 0.120 cryptorchidism no. (%) 10 (9.3%) 2 (5.2%) 3 (10.7%) 5 (12.2%) 0.548 2 (3.5%) 8 (16.3%) 0.023 varicocele – grade iii** no. (%) 2 (1.9%) none 1 (3.6%) 1 (2.4%) 0.538 none 2 (4.1%) 0.120 current smokers no. (%) 53 (49.5%) 16 (42.1%) 15 (53.5%) 22 (53.7%) 0.522 26 (44.8%) 27 (55.1%) 0.290 sperm retrieval + no. (%) 87 (81.3%) 29 (76.3%) 22 (78.6%) 36 (87.8%) 0.387 46 (79.3%) 41 (20.7%) 0.564 bm: bladder management; btx: botulinum toxin; gu: genitourinary; iqr: interquartile range; magi: male accessory gland infection; sci: spinal cord injury; sr: sperm retrieval; uti: urinary tract infection. * other gu surgeries were the following: vasectomy (n = 3, 2.8%), hydrocelectomy (n = 2, 1.9%), implantation of adjustable continence therapy (proact™) system (n = 1, 0.9%), and endoscopic treatment of vesicoureteral reflux (n = 2, 1.9%) and of stress urinary incontinence with urethral bulking agents (n = 2, 1.9%). ** varicocele defined as grade iii was visible and palpable at rest. archivio italiano di urologia e andrologia 2025; 97(3):13036 m. morelli, m. spinelli, p. geretto, et al. 4 table 2. analysis of the biological reports in case of positive sperm retrieval, besides the outcomes of assisted reproductive technology. we divided patients into different groups based on time since spinal cord injury: group a (≤ 5 years), group b (> 5 and ≤ 10 years) and group c (> 10 years), besides group d (≤ 9 years) and group e (> 9 years). we estimated statistically significant differences among groups a, b and c, and between groups d and e. variable overall time since sci (n = 87) group a group b group c p value group d group e p value (n = 30) (n = 22) (n = 35) (n = 46) (n = 41) frozen straws 0.308 0.394 median 4 3 4 4 4 4 iqr 3-4 2-4 2-4 3-4 2-4 3-4 range 1-6 1-6 1-4 1-6 1-6 1-6 mobility no. (%) 0.004 0.004 not progressive 56 (64.4%) 22 (75.9%) 18 (81.8%) 16 (44.4%) 36 (78.3%) 20 (48.8%) progressive 31 (35.6%) 8 (26.7%) 4 (18.2%) 19 (54.3%) 10 (21.7%) 21 (51.2%) morphology no. (%) 0.051 0.074 not optimal 47 (54.0%) 17 (56.7%) 16 (72.7%) 14 (40.0%) 29 (63.0%) 18 (43.9%) normal 40 (46.0%) 13 (43.3%) 6 (27.3%) 21 (60.0%) 17 (37.0%) 23 (56.1%) icsi no. (%) 33 (37.9%) 5 (16.7%) 6 (27.3%) 22 (62.9%) < 0.001 10 (21.7%) 23 (56.1%) < 0.001 pregnancy rate no. (%) 21 (63.6%) 3 (60.0%) 4 (66.7%) 14 (63.6%) 0.974 7 (70.0%) 14 (60.9%) 0.616 lbr no. (%) 19 (90.5%) 3 (100%) 3 (75%) 13 (92.9%) 0.917 6 (85.7%) 13 (92.9%) 0.853 icsi: intracytoplasmic sperm injection; iqr: interquartile range; lbr: live birth rate. figure 1. percent stacked barplots depicting the relationship between the sperm retrieval after testicular sperm extraction and the time since spinal cord injury, considered continuously and categorically. we assessed no statistically significant statistical differences (p value > 0.05) with each approach. a. the time since sci was considered as a continuous variable. b. our cohort was divided into group a (≤ 5 years), group b (> 5 years and ≤ 10 years) and group c (> 10 years). c. the considered population was divided based on the median time since sci into group d (≤ 9 years) and group e (> 9 years). archivio italiano di urologia e andrologia 2025; 97(3):13036 5 time from spinal cord injury and sperm retrieval rate the final lbr was 90.5%. neither complications nor multiple gestations were reported following art. considering the groups based on the previously described different clusters of time since sci, we observed statistically significant differences (p < 0.05) in terms of motility and icsi. at univariate logistic regression analysis (table 3), the following parameters were not associated with positive srr in a statistically significant way: level of injury (p = 0.582), age at surgery (p = 0.776), amt (p = 0.587), detrusor injections of btx-a (p = 0.061), other gu surgeries (p = 0.911), recurrent utis and/or magis (p = 0.382), not optimal bladder management (p = 0.508), history of cryptorchidism (p = 0.083), varicocele (p = 0.999), and smoking habit (p = 0.653). similarly, we considered time since sci as both continuous and categorical variable without detecting any effects on predicting srr (p > 0.05). discussion most patients with sci may experience different-graded alterations in sexual and reproductive functions (17). the fertility assessment should start from evaluating the erectile function. ed may be treated successfully with phosphodiesterase-5 inhibitors (ipde-5) and, in case of failure, intracavernous injections (icis) of prostaglandins (pge), reaching satisfactory sexual intercourses in 76% cases with sci (18). patients with sci may experience anejaculation or retrograde ejaculation. there are several strategies to obtain spermatozoa for art. the harvest of spermatozoa from the urine may be considered, with an average lbr per transfer equal to 28% (19). according to an 18 year single center experience of 500 men with sci undergoing pvs, the success rates were 86 and 15% when the patient’s level of injury was t10 or rostral, and t11 or caudal, respectively (20). in pvs-refractory cases, eej may achieve success in up to 100%, but the equipment is expensive, the procedure is complex, healthcare professionals’ training is lacking, and conscious sedation or general anesthesia may be needed because of significant discomfort or pain (21, 22). for all these reasons, surgical sperm retrieval is usually performed after unsuccessful pvs. various surgical techniques have been described over the years, like tese, percutaneous epididymal sperm aspiration (pesa), microsurgical epididymal sperm aspiration (mesa), and microsurgical tese (mtese) (23, 24). surgical sperm retrieval combined with in vitro fertilization (ivf) icsi is usually suggested as the first line for infertility in sci. indeed, the pr after intravaginal insemination, performed mostly at home, resulted 37.8% in selected couples, so that ivf-icsi is largely considered in this population (25). the above-mentioned strategies may lead to obtain lowquality samples because of alterations induced by sci: production of reactive oxygen species, leucocytospermia with activated t cells secreting inflammatory cytokines (e.g., interleukin-1β, interleukin-12, and tumor necrosis factor-α), antisperm antibodies, derangement in energy substrates and enzymes (e.g., seminal plasma fructose, albumin, glutamic oxaloacetic transaminase, alkaline phosphatase) (26). sci may severely modify the testicular trophism, decreasing sperm quality at the early post traumatic phase with lower spermatozoid vitality (necrospermia) and reduced motility (asthenospermia) (27). indeed, a comparison against non-sci control group suggested that sperm concentration, motility and morphology were significantly decreased in sci group (p < 0.05) (28). however, the pr proved to be not statistically significant different among sci and oa, but higher with fresh testicular sperm over frozen-thawed sperm for icsi in sci (14/22 versus 4/16) (29). in literature, no high level of evidence (le) is available in neurourological patients concerning the efficacy and side effects across different medications (dosages and formulations), procedures and surgical techniques (30). this lack highlights the importance of high-quality studies to draw strong recommendations in an under-represented population, whose prevalence is growing thanks to medical advancements (31). table 3. univariate logistic regression models predicting positive sperm retrieval. variable or (95% ci) p value level of sci tetraplegia reference paraplegia 0.749 (0.267-2.097) 0.582 age at surgery years 0.991 (0.929-1.057) 0.776 time since sci years 1.053 (0.981-1.131) 0.154 time since sci ≤ 9 years reference > 9 years 1.337 (0.497-3.593) 0.565 time since sci ≤ 5 years reference > 5 and ≤ 10 years 0.448 (0.135-1.482) 0.188 > 10 years 0.509 (0.139-1.869) 0.309 antimuscarinic therapy no reference yes 0.729 (0.232-2.284) 0.587 detrusor injections of btx-a no reference yes 2.631 (0.955-7.246) 0.061 other gu surgical procedures * no reference yes 1.097 (0.215-5.610) 0.911 recurrent utis and/or magis no reference yes 0.555 (0.148-2.080) 0.382 not optimal bladder management no reference yes 0.701 (0.245-2.004) 0.508 cryptorchidism no reference yes 3.375 (0.854-13.336) 0.083 varicocele – grade iii ** no reference yes 0.999 current smokers no reference yes 0.800 (0.301-2.122) 0.653 btx-a: botulinum toxin-a; ci: confidence interval; gu: genitourinary; magis: male accessory gland infections; or: odds ratio; utis: urinary tract infections. * other gu surgeries were the following: vasectomy (n = 1), endoscopic treatment of vesicoureteral reflux (n = 2) and of stress urinary incontinence with urethral bulking (n = 2). ** varicocele defined as grade iii was visible and palpable at rest. archivio italiano di urologia e andrologia 2025; 97(3):13036 m. morelli, m. spinelli, p. geretto, et al. 6 we reported our experience with tese in patients with sci affected by anejaculation in different italian tertiary referral centers. tese resulted in a safe procedure with no intraand post-operative complications reported in our frail patients with sci. the different groups based on time since sci did not differ in terms of baseline characteristics (p > 0.05), except for age at surgery and cryptorchidism (in this case, only considering population divided into two groups). as for age at surgery, people with inveterate sci – obviously – presented as older cases at tese than patients with recent sci, justifying this statistical significance. in table 2, tese samples did not differ in terms of number of frozen straws and morphology, but progressive motility appeared to be found more frequently in people with longer times since sci compared to shorter ones. this data is interesting, as everyone could expect to find worse motility in inveterate sci. the authors believe that this result is confounding and probably due to a casual accumulation of people with improved motility in groups with longer time since sci. icsi proved to be performed in people with older sci, as over the years it is more likely to find a partner and start art compared to young people just after sci, when tese is performed to collect and freeze sperm in case of need in the future. our study highlighted that none of the variables considered proved to negatively affect the srr; in particular, the time since sci did not decrease the srr. this data is clinically important, specially for infertility counselling, as most patients require tese as soon as possible after sci for the risk of future low srr. an early tese after sci is sometimes performed to anticipate the detrimental effect of time since sci. however, this issue is not supported by strong-rated scientific evidence (table 4). there is a void on this issue on current guidelines about this aspect. we performed a literature review looking for studies assessing the effect of time since sci on spermatogenesis in sci (32-38). most studies were characterized by a low le according to the oxford centre for evidence-based medicine (39). sánchez-ramos et al. prospectively studied 28 men by a fine needle aspiration (fna) biopsy of the testis at 1-, 3and 6months following sci (38). spermatogenesis was normal in 39, 48 and 80% cases, respectively, at 1, 4 and 6 months after injury, highlighting an early recovery of spermatogenesis. iwahata et al. reported the srr at tese was significantly table 4. studies assessing the impact of time since the spinal cord injury on sperm quality and quantity. the level of evidence of each study was assessed according to the oxford centre for evidence-based medicine (ocem). reference (year) study design (le) population intervention outcomes brackett et al. (1998) (34) retrospective analysis 125 men examined at 2-year pvs, eej no difference in any semen parameters of cross-sectional data (4) intervals sci occurred and masturbation was found as a function of time post injury 6 weeks to 26 years earlier celigoj et al. (2012) (35) retrospective case series (4) 7 patients pvs or eej three patients injured before age 9 years: azoospermic age at injury: 4.4-11.9 years one patient injured at age 10 years: subnormal total sperm count age at first evaluation: 24.4-38.1 years two subjects injured at age 11.9 years: normal total sperm counts level of injury: t6-l3 elliot et al. (2000) (3) prospective cohort study (3) 50 men testicular biopsy spermatogenesis was normal in 28 patients logistic regression analyses revealed no variable (in particular, post-injury years) was predictive of testis biopsy outcome huang et al. (1998) (36) prospective case-control study (2) 75 rat models of sci killed by testicular histology normal spermatogenesis seen in 30% rats at 3 months decapitation 2 weeks-6 months compared to 47% at 6 months after laminectomy failure to prevent such effects by exogenous testosterone suggests that nonendocrine factors are involved in the sci effects on spermatogenesis iwahata et al. (2016) (37) retrospective case series (4) 52 men with pvs-refractory tese srr = 80.7%, ejaculation dysfunction pr = 86.5% lbr = 86.5% srr was significantly better in patients injured within the previous 12 years mallidis et al. (1994) (38) prospective longitudinal study (3) 7 men eej sperm motility and viability decreased towards the pattern of chronic sci by day 16, so semen storage within the first 2 weeks is recommended ohl et al. (2001) (39) prospective case-control study (2) 7 dog models of sci + eej and fna significant changes in sperm at 3 weeks after injury: decreased 6 dogs as controls sperm motility (62.9% to 20.1%), and mean number of spermatids on cross section of the testis decreased compared to controls (13.6 versus 43.9) sánchez-ramos prospective longitudinal study (3) 28 male patients with complete fna defective spermatogenesis was found at 1 (61%), 3 (52%) et al. (2017) (40) sci who were evaluated at 1, 3 and 6 (20%) months after sci, suggesting an improvement and 6 months after the injury over time eej: electroejaculation; fna: fine needle aspiration; lbr: live birth rate; le: level of evidence; pr: pregnancy rate; pvs: penile vibratory stimulation; sci: spinal cord injury; srr: sperm retrieval rate; tese: testicular sperm extraction. archivio italiano di urologia e andrologia 2025; 97(3):13036 7 time from spinal cord injury and sperm retrieval rate better in patients injured within the preceding 12 years than those injured longer (p = 0.045).35 their srr was 80.7%, and pregnancy was achieved in 32/37 (86.5%) cases undergoing icsi. we reported similar outcomes, while we did not identify a statistically significant correlation between the srr and the time since sci, assessed both continuously and categorically. indeed, our patients with dated sci (> 10 years) presented a high srr (87.8%). despite different methodologies, most studies, involving both humans and animal models, reported a rapid decline of spermatogenesis during the first weeks after sci, followed by its early recovery in the subsequent months. sperm retrival with a high srr within the first two weeks after sci was suggested by mallidis et al. (36). however, surgery is logistically and technically complex when the patient is not completely stabilized in terms of respiratory and/or cardiovascular functions. therefore, we advocate sperm retrieval after 6 months. most patients with sci were born with a normal gu system and underwent a physiological development, so sperm parameters before the injury were usually comparable to that of the non-sci population. the real causes of decreased sperm parameters over the years since sci had not been fully explained, but chronic infections are supposed to play a key role, as they are associated with infiltrating leucocytes producing noxious cytokines (40). in this scenario, testicular sperm is the best candidate for icsi, as it is protected by testis-blood barrier. this issue highlights the key role of an optimal bladder and bowel management to reduce the risk for utis and magis, preserving testicular parenchyma over the years (41). our sample included a sci population followed by tertiary referral centers for rehabilitation. a coordinated, multidisciplinary approach to the sci rehabilitation was acknowledged as a crucial achievement in outcome improvements (42). an optimal bladder and bowel management is mandatory to slow the deterioration of testicular parenchyma, favoring improved srrs and art outcomes. the cohort described by iwahata et al. included patients not uniformly treated in terms of bladder and/or bowel management (35). according to authors, the described declined in srr could also be a result of chronic infections over time due to inappropriate bladder and/or bowel management, which is the most important aspect to stress with patients during infertility counselling. limitations of the study our study is not devoid of limitations. to start with, it included case series coming from different centers with a retrospective design (le = 4), even if the sample was not small, but significantly large considering previous studies concerning patients with sci. the histology was not collected for most patients by all centers, so we could not consider this data in our study. this is a significant limitation, especially considering the reduced srr compared to other series with patients affected by functional oa. indeed, unsuccessful teses could be due with spermatogenesis regression due to different histology modifications (e.g., alterations in sertoli cells) (43). we analyzed several outcomes related to art, because of possible biases due to the modest sample size (n = 33) and different involved centers adopting dissimilar protocols. some technical features, like ovulation stimulation protocols, were investigated by previous studies, which did not find a statistically significant difference in pregnancy outcomes, supporting the consideration of low-cost protocols for cycle management (44). all these issues should be investigated through future multi-center, long-term studies. future directions our study represents a contribution to the definition of the effect of time since sci in the tese outcomes. our findings might help other colleagues in the treatment of – usually unfamiliar – patients with sci and address further research. besides an optimal bladder and bowel management, some medicines may improve sperm quality at tese (45-47). a recent study acknowledged the 4-week-long oral administration of probenecid (known to interfere with the pannexin-1 cellular membrane channel) improved the mean percent of sperm with progressive and rapid linear motility, respectively, from 19% to 26% (p < 0.05) and from 5% to 17% (p < 0.001) (48). its role is still controversial and further studies are mandatory to recommend its routine use. each attempt of improving srr should be tested in patients with sci, as fertility concerns proved to significantly impact their health status and should be considered for the management of individuals living in the community (49, 50). conclusions our experience proved the safety and efficacy of tese in sci with a valid srr, pr and lbr. we highlighted the srr was not negatively affected by the baseline characteristics, especially by the time since sci, considered both continuously and categorically. previously published papers supported early sperm cryopreservation during declarations ethical approval and consent for participate: all authors have read and agreed to the published version of the manuscript. availability of data and material: the data from this study are not publicly available and are subject to privacy restrictions. summary data may be provided on reasonable request to the corresponding author. competing interests: the authors declare no conflict of interest. funding: no authors have received any funding or support for this study. authors' contributions: conceptualization: mm, ms, and gs; methodology: mm, csg, and gs; validation: mm, ms, pg, gdp, odc, and gs; formal analysis: mm, pg, fc, lg, and gs; investigation: mm, ms, pg, csg, ls, lg, lf, msica, and gs; resources: mm, ms, csg, lr, lg, lf, msica, am, and gs; data curation: mm, pg, bb, and gs; writing-original draft preparation: mm, cs, and gs; writing-review and editing: mm, ms, gf, and gs; visualization: mm, gf, and gs; supervision: ms, gdp, am, odc. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(3):13036 m. morelli, m. spinelli, p. geretto, et al. 8 the first two weeks or after 6 months from the sci, highlighting the risk of low srr over the years. according to our experience, clinicians should not deter sci patients with functional oa from undergoing tese after long time since sci. however, they should encourage an appropriate bladder and bowel management to reduce the risk of utis and/or magis, which should damage the testicular parenchyma. references 1. alizadeh a, dyck sm, karimi-abdolrezaee s. traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. front neurol. 2019; 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19:72-80. 44. ohl d, wolf l, menge a, et al. electroejaculation and assisted reproductive technologies in the treatment of anejaculatory infertility. fertil steril. 2001; 76:1249-1255. 45. emmanuel a, krogh k, kirshblum s, et al. creation and validation of a new tool for the monitoring efficacy of neurogenic bowel dysfunction treatment on response: the mentor tool. spinal cord. 2020 jul; 58:795-802. 46. spinelli m, guerrer c, zanollo l, et al. 305 effects of anticholinergic agents on efficacy of penile vibratory stimulation to obtain ejaculation in spinal cord injured males. eur urol suppl. 2013; 12:e305. 47. przydacz m, chlosta p, corcos j. recommendations for urological follow-up of patients with neurogenic bladder secondary to spinal cord injury. int urol nephrol. 2018; 50:1005-1016. 48. ibrahim e, aballa tc, lynne cm, brackett nl. oral probenecid improves sperm motility in men with spinal cord injury. j spinal cord med. 2018; 41:567-570. 49. park se, elliott s, noonan vk, et al. impact of bladder, bowel and sexual dysfunction on health status of people with thoracolumbar spinal cord injuries living in the community. j spinal cord med. 2017; 40:548-559. 50. anderson k. targeting recovery: priorities of the spinal cordinjured population. j neurotrauma. 2004; 21:1371-83. correspondence michele morelli, md (corresponding author) michelemorelli4@gmail.com michele spinelli chiara stefania guerrer gianluca sampogna unit of neuro-urology, unipolar spinal unit niguarda hospital piazza ospedale maggiore, 3, 20162, milan, italy paolo geretto michele sica alberto manassero unit of neuro-urology, città della salute e della scienza, university of turin, turin, italy carmine sciorio unit of urology, manzoni hospital, lecco, italy lorenzo spirito lorenzo romano felice crocetto biagio barone unit of urology, department of neurosciences, reproductive sciences, and odontostomatology, university of naples "federico ii", naples, italy luca gemma giulio del popolo unit of neuro-urology, careggi university hospital, florence, italy luca frediani neurocenter of southern switzerland, ente ospedaliero cantonale, lugano, switzerland santo lupo roberta de stefano unit of urology, ospedale maggiore, bologna giuseppe fallara ottavio de cobelli unit of urologic surgery, european institute of oncology, university of milan, milan, italy stesura seveso archivio italiano di urologia e andrologia 2024; 96(3):12153 1 review ed by an increase in the glomerular filtration rate, which leads to higher urinary calcium and uric acid concentrations. however, urolithiasis prevalence is similar in pregnant and non-pregnant women, mostly due to the simultaneous increase in inhibitory factors (such as citrate, magnesium, and glycoproteins) (1). one large cohort study demonstrated an incidence of 0.2% of symptomatic urolithiasis in pregnancy (2). nevertheless, renal colic is the most common non-obstetric cause of abdominal pain and subsequent hospitalization during pregnancy, especially in the second and third trimesters (1), and it is associated with a higher risk of complications, such as premature rupture of membranes, spontaneous abortion, preterm labor, and preterm birth (2). most cases of symptomatic urolithiasis are non-complicated and can be managed conservatively with vigilance, hydration, and analgesia. this is successful in 70-80% of cases with spontaneous stone passage (2, 3). invasive treatment should be considered within a multidisciplinary discussion in cases of persistent pain or vomiting, signs of infection, decline in renal function, obstructive stones in solitary kidney, bilateral obstruction, or obstetric complications (4). the different available procedures are temporary drainage with a percutaneous nephrostomy (pcn) or a double-j stent insertion (jj), or definite treatment with ureteroscopy (urs) (4). if fever or other signs of infection are present, ureteroscopy is contraindicated and urgent temporary drainage is required. temporary drainage is also usually preferred in cases of large stone burden, complex anatomy, bilateral stone disease, obstetric complications, or presentation in the first trimester or near full term. ureteral stenting or percutaneous nephrostomy placement are usually fast procedures, require minimal anesthesia, and can be radiation-free, but they require a second definitive intervention postpartum to treat the stone, often need multiple catheter exchanges during pregnancy, and are poorly tolerated (4). consequently, definitive treatment with ureteroscopy started becoming the firstline procedure, when possible. our main objective with this systematic review is to evaluate the safety and efficacy of ureteroscopy, double-j stent insertion, and percutaneous nephrostomy in the treatment of renal colic during pregnancy. introduction: renal colic is the most common non-obstetric cause of abdominal pain during pregnancy and is associated with a higher risk of complications in these women. when invasive treatment is required, options are temporary drainage with ureteral stent (jj) or percutaneous nephrostomy (pcn), or immediate definitive treatment with ureteroscopy (urs). our goal was to review the safety and efficacy of these procedures in treating urolithiasis during pregnancy. methods: adhering to the prisma checklist guidelines, we searched pubmed, embase, and scopus databases for articles on the efficacy and complications of the three procedures in pregnant women. the quality of evidence and risk of bias were evaluated using the critical appraisal skills programme and the institute of health economics tools. results: we included 45 articles, totaling 3424 interventions in pregnant women 2188 urs, 719 jj, and 517 pcn. urs was the most assessed procedure, with stone-free rates comparable to the non-pregnant patients. the most frequent complications were lower urinary symptoms and infections independently of the intervention. obstetric complications for all interventions included 167 cases of preterm labor, resulting in 24 premature births. no statistically significant differences in post-operative complications were reported between the procedures in the few comparative studies. conclusions: despite the absence of high-quality studies, current evidence suggests that urs, jj, and pcn are all safe and effective during pregnancy. as most patients submitted to temporary drainage require a second procedure post-delivery, primary urs appears more efficient. therefore, it is the preferred option unless there are indications for temporary drainage. key words: urolithiasis; pregnancy; ureteroscopy; ureteral stent; percutaneous nephrostomy. submitted 30 march 2024; accepted 21 april 2024 introduction pregnancy induces anatomic, metabolic, and chemical changes in the urinary tract that would predispose pregnant women to stone formation: both uterine extrinsic compression and progesterone’s relaxing effect on ureteral smooth muscle cause physiologic hydronephrosis in 90% of pregnant women, especially on the right side, exacerbatsurgical management of obstructing ureteral stones during pregnancy: a systematic review of different techniques catarina laranjo-tinoco 1, maria joão oliveira 2, ana sofia araújo 1, andreia cardoso 1, carlos oliveira 1, 2, paulo mota 1, 2, joão pimentel torres 1, 2 1 hospital de braga, urology department, braga, portugal; 2 university of minho, school of medicine, braga, portugal. doi: 10.4081/aiua.2024.12153 summary archivio italiano di urologia e andrologia 2024; 96(3):12153 c. laranjo-tinoco, m.j. oliveira, a.s. araújo, et al. 2 methods we elaborated the present review according to the preferred reporting items for systematic reviews and metaanalyses (prisma) 2020 checklist (5). search strategy the primary search was conducted using the pubmed, embase, and scopus databases, for articles published before november 2021. our query was “(pregnancy or pregnant) and (renal colic or urolithiasis) and (nephrostomy) and (ureteral stent or jj) and (ureteroscopy) and (drainage or urinary diversion or urinary catheterization)”. additionally, we used the “snowball” method, tracking references and citations of found articles to identify additional relevant studies. the search results were organized using endnote with identification and removal of duplicates. two independent researchers (clt and mjo) screened the titles and abstracts of the search results against the inclusion criteria. subsequently, the same two researchers analyzed full-text reports for eligibility. any disagreement was solved through discussion and consensus. a third reviewer (jpt) resolved any disagreement during report selection and did the final review. eligibility criteria our picos definition was: participants: pregnant women with urolithiasis; intervention: ureteroscopy (or double-j stent insertion or percutaneous nephrostomy placement when no ureteroscopy was performed); comparators: double-j stent insertion or percutaneous nephrostomy placement or conservative treatment; outcomes: procedure efficacy or intervention success, perioperative and postoperative complications, and obstetric complications; study design: this systematic review included randomized controlled trials, cohort studies (prospective or retrospective), case-control studies, and case series. the articles were considered when they fulfilled the following inclusion criteria: pregnant women; treatment, including ureteroscopy, ureteral stent insertion, and/or nephrostomy; english language. the exclusion criteria were: non-pregnant; other types of treatment; other languages; grey literature; full text not available; reviews and case reports; animal studies. data extraction and management the following data was collected from each study: author’s names; country and year of publication; study duration, design, and objective; sample characteristics (sample number, mean age, mean gestational age or trimester); inclusion and exclusion criteria; type of treatment; intervention success; perioperative, postoperative, and obstetric complications; imaging considerations; relevant conclusion and limitations. critical appraisal of included studies the quality assessment and risk of bias were carried out by figure 1. prisma methodology flowchart for article selection. archivio italiano di urologia e andrologia 2024; 96(3):12153 3 surgical management of obstructing ureteral stones during pregnancy... two independent reviewers using the critical appraisal skills programme (casp) checklist (6) for cohort studies and the institute of health economics checklist (7) for case series studies. any disagreement was solved by discussion and consensus or by the involvement of the third reviewer. evidence synthesis study selection the flowchart in figure 1 describes in detail the implemented search method. critical appraisal the quality assessment of the studies included in this review is presented in figure 2 and figure 3. within the cohort studies, the most failed criteria were related to the recruitment of the cohort in an acceptable way, since some articles did not mention the exclusion criteria (3, 8-33) and to the identification and the consideration of confounding factors in the design. within the case series, all articles failed to meet the followfigure 2. critical appraisal skills programme checklist for cohort studies. 1) did the study address a clearly focused issue? 2) was the cohort recruited in an acceptable way? 3) was the exposure accurately measured to minimize bias? 4) was the outcome accurately measured to minimize bias? 5a) have the authors identified allimportant confounding factors? 5b) have they taken account of the confounding factors in the design and/or analysis? 6a) was the follow-up of subjects complete enough? 6b) was the follow-up of subjects long enough? 7) what are the results of this study? 8) how precise are the results? 9) do you believe the results? 10) can the results be applied to the local population? 11) do the results of this study fit with other available evidence? 12) what are the implications of this study for practice? green circles (+) represent low risk of bias, red circles (-) represent high risk of bias; yellow circles (?) indicate unclear risk of bias. figure 3. institute of health economics quality appraisal checklist for case series studies. 1) was the hypothesis/aim/objective of the study clearly stated? 2) was the study conducted prospectively? 3) were the cases collected in more than one center? 4) were patients recruited consecutively? 5) were the characteristics of the patients included in the study described? 6) were the eligibility criteria for entry the study clearly stated? 7) did patients enter the study at a similar point in the disease? 8) was the intervention of interest clearly described? 9) were additional interventions (co-intervention) clearly described? 10) were relevant outcome measures established a priori? 11) were outcomes assessors blinded to the intervention that patients received? 12) were the relevant outcomes measured using appropriate objective/subjective methods? 13) were the relevant outcome measures made before and after the intervention? 14) were the statistical tests used to assess the relevant outcomes appropriate? 15) was follow-up long enough for important events and outcomes to occur? green circles (+) represent low risk of bias, red circles (-) represent high risk of bias; yellow circles (?) indicate unclear risk of bias. archivio italiano di urologia e andrologia 2024; 96(3):12153 c. laranjo-tinoco, m.j. oliveira, a.s. araújo, et al. 4 ing criteria: cases collected in more than one center, presentation of eligibility criteria for entering the study since none of them presented exclusion criteria, and use of statistical tests to assess the relevant outcomes. characterization of the studies a summary of the main characteristics and conclusions of each article included in our systematic review is presented in table 1. a rti cl e c ou nt ry s tu dy d es ig n an d m et ho ds p re gn an t p at ie nt s w ho u nd er we nt i nt er ve nt io n, n m ea n ge sta tio na l a ge (w ee ks ) o r t rim es te r u rs , n j j, n p cn , n p ro ce du re e ffi ca cy p er io pe ra tiv e co m pl ica tio ns p os to pe ra tiv e co m pl ica tio ns o bs te tri c ou tc om es abdel-kader et al. (2013) 34 egypt retrospective cohort study 23 25 17 6 0 urs stone-free rate: 100% all jj stents needed postpartum definitive treatment all patients delivered at term without adverse fetal outcomes adanur et al. (2014) 9 turkey retrospective cohort study 9 24.8 9 0 0 stone-free rate: 100% uti (n=1) pre-term uterine contractions (n=1). all patients delivered at term without adverse fetal outcomes akpinar et al. (2006) 20 turkey retrospective cohort study 7 1st t: 14.3% 2nd t: 71.4% 3rd t: 14.3% 7 0 0 not specified intense pain (n=2) all patients delivered at term without adverse fetal outcomes atar et al. (2012) 35 turkey prospective cohort study 17 24 17 0 0 not specified ureteral perforation (n=1); ureteral mucosal injury (n=2) dysuria and pain (n=5); uti (n=1) all patients delivered at term without adverse fetal outcomes bayar et al. (2015) 36 turkey retrospective cohort study 70 23.4 41 29 0 urs stone-free rate: 87% higher need of postpartum additional interventions in the jj group. ureteral lesions (n=4) urs: stone could not be reached (n=2), stone migration (n=3), ureteral laceration (n=3), partial perforation (n=1) urs: acute pyelonephritis (n=5), urosepsis (n=1) jj: acute pyelonephritis (n=1), lower urinary tract symptoms (n=17), lumbar pain (n=13) no statistically significant differences in complication frequency or severity between groups. urs: pre-term delivery (n=15) jj: premature contractions (n=2), pre.term delivery (n=7), in-utero fetal death (n=1, complicated twin pregnancy). no statistically significant differences. bozkurt et al. (2012) 37 turkey retrospective cohort study 27 24 27 0 0 not specified ureteric laceration (n=2) dysuria and pelvic pain (n=2), uti (n=4), urosepsis (n=1) all patients delivered at term without adverse fetal outcomes bozkurt et al. (2013) 38 turkey retrospective cohort study 41 23.2 41 (+62 in non pregnant patients) 0 0 no statistically significant differences in stone-free rate. ureteric laceration (pregnant n=3; non-pregnant n=10) ureteric perforation (pregnant n=1; non-pregnant n=3) no statistically significant differences uti (pregnant n=4, non-pregnant n=5), dysuria (pregnant n=6, non-pregnant n=16), urosepsis (pregnant n=1, non-pregnant n=1) no statistically significant differences all patients delivered at term without adverse fetal outcomes butticè et al. (2017) 28 italy retrospective cohort study 133 2nd t: 26.1 weeks 3rd t: 31.8 weeks 133 0 0 not specified stone migration (n=10) urs: pre-term labor (8.7%) table 1. summary of included studies. ar tic le co un try st ud y d es ig n an d m et ho ds pr eg na nt p at ie nt s wh o un de rw en t in te rv en tio n, n m ea n ge st at io na l a ge (w ee ks ) or tr im es te r ur s, n jj , n pc n, n pr oc ed ur e ef fic ac y pe rio pe ra tiv e co m pl ic at io ns po st op er at ive c om pl ic at io ns ob st et ric o ut co m es archivio italiano di urologia e andrologia 2024; 96(3):12153 5 surgical management of obstructing ureteral stones during pregnancy... choi et al. (2016) 39 korea retrospective cohort study 14 1st t: 10.2% 2nd t: 74.4% 3rd t: 20.4% 0 13 1 all procedures were effective all patients delivered at term without adverse fetal outcomes cocuzza et al. (2010) 29 brazil retrospective cohort study 8 29.2 7 1 0 stone-free rate: 100% dysuria (n=1) all patients delivered at term without adverse fetal outcomes denstedt et al. (1992) 49 canad a case series 13 2nd: 41.4% 3rd: 58.6% 3 8 2 not specified jj: bladder irritability (n=8) pre-term labor after pcn (n=1); all other patients delivered at term without adverse fetal outcomes drescher et al. (2019) 3 usa retrospective cohort study 111 5 1st t: 5% 2nd t: 30% 3rd t: 65% 803 312 not specified utis: urs and/or jj (n=70 / 8.7%), pcn (n=61 / 19.6%) pre-term labor (urs and/or jj n=90 / 11.2%, pcn n=61 / 19.5%) dumitrache et al. (2013) 30 roma nia retrospective cohort study 23 25.3 11 10 2 not specified all patients delivered at term without adverse fetal outcomes elgamasy et al. (2009) 50 egypt case series 15 25.9 0 15 0 not specified distal stent migration (n=1) pre-term labor (n=1) all patients delivered at term without adverse fetal outcomes fathelbab et al. (2016) 40 egypt prospective cohort study 41 1st t: 9.8% 2nd t: 56.1% 3rd t: 34.1% 41 0 0 stone-free rate: 89.7% stone migration (n=3) dysuria and urgency (n=12), hematuria (n=5) all patients delivered at term without adverse fetal outcomes georgescu et al. (2014) 31 roma nia retrospective cohort study 54 1st t: 11.1% 2nd t: 59.3% 3rd t: 29.6% 44 9 1 semirigid urs successful in 87.5%, improving to 93.75% with flexible urs. ureteric edema, minor laceration or bleeding (n=5); stone migration (n=2), stone not reached (n=2) uti (n=4), renal colic (n=2), prolonged hematuria (n=1), bladder irritability (n=4) uterine contractions (n=1); all patients delivered at term without adverse fetal outcomes haghpanah et al. (2018) 32 iran prospective cohort study 23 1st t: 69.5% 0 11 12 not specified jj: uti (n=1), stent-related symptoms (n=4) pcn: uti (n=2) no statistically significant differences all patients delivered at term without adverse fetal outcomes haller et al. (1993) 33 croati a retrospective cohort study 4 >20 weeks: 90% 0 3 1 1 pcn placement after failure of jj insertion. 1 nephrectomy due to chronic pyelonephritis in an excluded kidney. all patients delivered at term without adverse fetal outcomes hoscan et al. (2012) 10 turkey retrospective cohort study 34 26 29 5 0 stone-free rate: 85.3% ureteric edema, minor ureteric laceration or bleeding (n=5); stone migration (n=3), stone not reached (n=2) uti (n=3); bladder irritability (n=3) uterine contractions (n=1); all patients delivered at term without adverse fetal outcomes isen et al. (2012) 11 turkey retrospective cohort study 12 23.8 8 3 1 jj was tried initially in 6 patients but was only successful in 50%. all patients delivered at term without adverse fetal outcomes archivio italiano di urologia e andrologia 2024; 96(3):12153 c. laranjo-tinoco, m.j. oliveira, a.s. araújo, et al. 6 jarrard et al. (1993) 41 usa retrospective cohort study 5 17.8 0 5 0 2 jj exchanges after 10-12 weeks bladder irritability (n=2); uti (n=1) all patients delivered at term without adverse fetal outcomes johnson et al. (2012) 12 usa retrospective cohort study 39 24.7 39 0 0 stone-free rate: 86% pre-term labor (n=2), pre-term delivery (n=1) obstetric complications 4.3% juan et al. (2007) 42 taiwan retrospective cohort study 8 1st t: 11.1% 2nd t: 33.3% 3rd t: 55.5% 3 4 1 failure of jj insertion in 3 patients, then treated with urs. all patients delivered at term without adverse fetal outcomes kavoussi et al. (1992) 51 usa case series 6 26.8 0 0 6 not specified fever and persistent pain (n=1) – submitted to a percutaneous nephrolithotomy; tube obstruction (n=4), asymptomatic bacteriuria (n=6) all patients delivered at term without adverse fetal outcomes khoo et al. (2004) 48 united kingdo m case series 4 not specified 0 0 4 not specified urosepsis (n=1), tube obstruction (n=1) pre-term delivery (n=1), all other patients delivered at term without adverse fetal outcomes lee et al. (1997) 13 korea retrospective cohort study 4 1st t: 18.8% 2nd t: 62.5% 3rd t: 81.3% 1 3 0 not specified incrustation (n=1) all patients delivered at term without adverse fetal outcomes lemos et al. (2002) 14 brazil retrospective cohort study 18 18 14 4 0 all procedures were effective all patients delivered at term without adverse fetal outcomes li et al. (2021) 15 china retrospective cohort study 101 26 101 0 0 26 patients without improvement in pain complaints sirs (n=11) regular contractions in the post-operative period (12h) (n=46) all patients delivered at term without adverse fetal outcomes lifshitz et al. (2002) 16 israel retrospective cohort study 10 1st t: 10% 2nd t: 60% 3rd t: 30% 7 3 0 not specified all patients delivered at term without adverse fetal outcomes ngai et al. (2013) 17 china prospective cohort study 30 1st t: 17% 2nd t: 50% 3rd t: 33% 0 30 0 100% successful insertion 67% with pain improvement 10% without symptom improvement 23% with symptom worsening distal stent migration needing surgery (n=3); stent incrustation (n=3, 10%); hematuria and lower urinary tract symptoms (n=5) not specified ordon et al. (2020) 2 canad a population based matched retrospective cohort study 755 1st t: 15.9% 2nd t: 48.5% 3rd t: 35.6% 379 473 152 not specified pregnancies with a nephrostomy tube or stent had the largest magnitude of risk for an adverse birth outcome. archivio italiano di urologia e andrologia 2024; 96(3):12153 7 surgical management of obstructing ureteral stones during pregnancy... polat et al. (2011) 43 turkey retrospective cohort study 11 30 11 0 0 stone-free rate: 73% no adverse fetal outcomes rana et al. (2009) 18 pakist an retrospective cohort study 19 20 19 0 0 stone-free rate: 79% stone migration (n=3) jj incrustation (n=2) no adverse fetal outcomes rashid et al. (2021) 44 iraq prospective cohort study 26 28.38 26 0 0 flexible urs stone-free rate: 100% semirigid urs stone-free rate: 72.7% urs with stone extraction stone-free rate: 100% minor ureteric lesions only in semirigid urs and urs with stone extraction flexible urs: hematuria (n=5), stent-related symptoms (n=9), fever (n=3) semirigid urs: hematuria (n=7), stent-related symptoms (n=10), fever (n=3) urs with stone extraction: hematuria (n=4), stent-related symptoms (n=3) all patients delivered at term without adverse fetal outcomes rivera et al. (2014) 45 usa retrospective cohort study 26 jj: 36.5 urs: 37.8 11 15 0 6 patients needed multiple jj stent exchanges urs: 0 complications jj: multiple hospitalizations for pain management (n=1) jj: induction of labor due to inability to tolerate the jj stent (n=7) scarpa et al. (1996) 19 italy retrospective cohort study 15 not specified 15 0 0 not specified all patients delivered at term without adverse fetal outcomes shirvan et al. (2013) 46 iran prospective cohort study 44 24 44 0 0 stone-free rate: 91% stone migration (n=4) all patients delivered at term without adverse fetal outcomes shokeir et al. (1998) 21 saudi arabia retrospective cohort study 10 24 10 0 0 not specified uti (n=2); dysuria (n=1) all patients delivered at term without adverse fetal outcomes song et al. (2013) 47 china retrospective cohort study 54 26.5 21 17 16 18/21 successful urs (85.7%), 16/16 pcn successfully placed, 12/17 jj successfully placed. urs – stone migration (n=3) urs: bladder irritability (n=1), hematuria (n=2) pcn: local cutaneous infection (n=2), pain and hematuria (n=1), tube obstruction (n=4) jj: incrustation (n=4), pain and bladder irritability (n=6), stent migration (n=1) pre-term labor (n=1) tan et al. (2018) 22 china retrospective cohort study 53 jj: 27.5 urs: 25.9 23 30 0 successful urs: 86.9% successful jj insertion: 83.3% urs: stone migration (n=1) urs: bladder irritability (n=1), hematuria (n=1) jj: bladder irritability (n=2), jj distal migration (n=1), incrustation (n=1) all patients delivered at term without adverse fetal outcomes archivio italiano di urologia e andrologia 2024; 96(3):12153 c. laranjo-tinoco, m.j. oliveira, a.s. araújo, et al. 8 regarding the study design, we included 41 cohort studies (2, 3, 9-47) and 4 cases series (48-51). five (11.1%) of the cohort studies analyzed had a prospective design (17, 32, 35, 40, 44). there were no randomized controlled trials. a total of 3424 interventions in pregnant patients were evaluated. the studies reported a mean age varying from 22 to 30, with a total age range between 16 and 42. the second trimester was the most common timing of presentation and treatment of renal colic. gestational age range varied from 8 to 38 weeks (8, 10,11, 15, 18, 19, 21, 24, 25, 27, 31, 34, 36, 38, 43, 44, 50, 51), and 24 studies reported treatment in the three trimesters (2, 3, 9, 11-13, 16, 17, 20, 22, 23, 25-27, 31, 32, 36, 40-42, 44, 46, 47, 51). results of included studies type of treatment ureteroscopy was performed in all studies when there were indications for interventional treatment and no indications for temporary drainage (fever, large stone burden, complex anatomy, bilateral stone disease, obstetric complications, presentation in the first trimester or near fullterm) were present. a total of 2188 ureteroscopies were performed. most studies included only semirigid ureteroscopies, but flexible ureteroscopy was also used in 9 studies (12, 16, 20, 26, 27, 29, 31, 44, 45). stone management was either with lithotripsy (pneumatic or laser) (10, 11, 18, 20, 22, 25, 27, 28, 36, 42-44, 47,52), with stone extraction with baskets or forceps (16, 24, 45, 49) or using both approaches in different patients (9, 14, 15, 19, 21, 23, 29, 31, 34, 35, 37, 38, 40, 46). five studies, with a total of 1233 ureteroscopies, did not specify the stone management technique used during the procedure (2, 3, 12, 13, 30). seventeen studies reported double-j stenting at the end of the procedure when needed (9, 11, 19-23, 25, 27-29, 31, 35, 37, 38, 40, 47). temporary drainage was reported in every study when the indications mentioned before were present, fever being the most common trigger. a total of 719 double-j stents were inserted and 517 percutaneous nephrostomy tubes were placed. perioperative complications sixteen articles reported perioperative complications (2, 10, 15, 18, 22, 25, 27, 28, 31, 35-38, 40, 44, 47). concerning ureteroscopies, bozkurt et al. found no statistically significant differences between pregnant and nonpregnant women (38). the other articles reported the complications without comparing groups. most studies reported minor ureteral injuries including edema, small lacerations or perforations, or bleeding, in a total of 33 events (10, 25, 31, 35-37, 44). only rashid et al. used the satava classification (52) and reported 5 intraoperative g1 ureteral injuries in semirigid ureteroscopy (44). stone migration during ureteroscopy happened 64 times (18, 22, 25, 27, 28, 30, 31, 36, 40, 46, 47) and the stone could not be reached in 9 cases (10, 25, 31, 36). specific perioperative complications for jj and pcn were not reported. among 19 articles with 138 double-j stent insertions (2, 3, 11, 13, 14, 16, 17, 24, 26, 29, 30, 32-34, 39, 42, 45, 49, 50), and 11 articles with 344 pcn (3, 11, 26, 30-33, 39, 48, 49, 51), no perioperative complications were reported. perioperative complications were not specified at all in 2 articles (2, 15). tawfiek (2009) 23 egypt prospective cohort study 26 1st t: 11.5% 2nd t: 57.7% 3rd t: 30.8% 26 0 0 successful urs in all patients dysuria/urgency (n=2), hematuria (n=2), uti (n=1) all patients delivered at term without adverse fetal outcomes travassos et al. (2009) 24 brazil retrospective cohort study 10 19 9 1 0 not specified all patients delivered at term without adverse fetal outcomes wang et al. (2014) 25 china retrospective cohort study 87 29 64 19 4 52/64 successful urs, 4/4 pcn successfully placed, 17/19 jj successfully placed. urs: ureteric laceration (n=1), bleeding (n=5), stone migration (n=9), unreachable stone (n=3) jj: stent replacement (n=4), uti (n=4), bladder irritation (n=12), hematuria (n=7) urs: premature uterine contractions with threatened abortion (n=1) all patients delivered at term without adverse fetal outcomes watterson (2003) 26 canad a retrospective cohort study 14 22 10 2 2 urs stone-free rate: 89% successful removal of 2/2 incrusted jj stents all patients delivered at term without adverse fetal outcomes zhang et al. (2016) 27 china retrospective cohort study 117 not specified 117 0 0 stone migration (n=13) urosepsis (n=1), lower urinary tract symptoms (n=21), fever (n=5), hematuria (n=116), leukocyturia (n=37), positive urine culture (n=13) unconfirmed abortion suspicion (n=12) all patients delivered at term without adverse fetal outcomes jj: ureteral double-j stent; pcn: percutaneous nephrostomy; urs: ureteroscopy; usa: united states of america; uti: urinary tract infection. archivio italiano di urologia e andrologia 2024; 96(3):12153 9 surgical management of obstructing ureteral stones during pregnancy... postoperative complications postoperative complications were compared between the different procedures in 4 studies (3, 32, 36, 47). song et al. reported that the double-j stent group had the highest rate of complications (52.9%) compared to the ureteroscopy and percutaneous nephrostomy groups but without a statistically significant difference (47). one retrospective cohort revealed no significant difference in complications between primary ureteroscopy and ureteral stent placement; while moderate or severe lower urinary tract symptoms (luts) were significantly lower in the ureteroscopy group, flank pain was not (36). no difference between ureteral stent and percutaneous nephrostomy complications was also noted in a prospective study (32). regarding urinary tract infections (utis), drescher et al. presented an infection rate of 8.7% in patients treated with ureteroscopy and/or ureteral stent placement and 19.6% in patients who received percutaneous nephrostomies (3). in a retrospective cohort, ureteroscopy complications were compared between 41 pregnant patients with 62 non-pregnant women who also underwent surgery, revealing no higher complication rate in the pregnant population (38). concerning complications related to each procedure type, in patients submitted to urs, 97 utis were reported in 12 articles (3, 9, 10, 21-23, 25, 31, 35, 36, 38), and urosepsis was diagnosed 13 times (15, 36, 37). irritative lower urinary tract symptoms such as dysuria, pain, bladder irritability, and urgency were observed 45 times in 6 studies (29, 31, 35, 38, 40, 49). colicky pain was reported in 5 patients (20, 31, 45), and hematuria was observed 10 times (23, 31, 40, 47). eleven studies did not observe any ureteroscopy postoperative complications (11, 12, 14, 16, 19, 24, 26, 30, 34, 42, 46). the most frequently reported postoperative complication associated with ureteral stents was bladder irritability. this complication was observed 28 times (8, 10, 22, 25, 47, 49), and rivera et al. reported one case of multiple hospitalizations for pain control (45). other complications related to ureteral stents were stent encrustation or migration, documented 16 times (17, 22, 25, 47, 50, 53). rivera et al. reported that 6 patients required multiple stent exchanges (45). 7 urinary tract infections were reported in 3 studies (22, 25, 32) and luts and hematuria were observed 13 times (17, 25, 29). no postoperative complications associated with ureteral stent insertion were reported in 10 studies (11, 14, 16, 24, 26, 30, 33, 34, 39, 42). in reference to pcn complications, 10 nephrostomy tube obstructions were described,47,48,51 some requiring tube exchanges. there were 2 cases of localized skin infections (47), 61 cases of uti,3 and 1 case of sepsis after pcn placement (48). persistent pain was reported in 2 articles (47, 51). no complications were observed after pcn on 6 articles (11, 26, 30, 33, 39, 42). obstetric complications all studies followed the pregnancies until term. obstetric outcomes were evaluated and managed by obstetricians. twenty-three articles did not mention any adverse obstetric outcome (8, 10, 11, 14, 16, 18, 20, 23, 24, 26, 29-34, 37-40, 42, 44, 51) and all patients from these studies delivered at term without adverse fetal outcomes. furthermore, shirvan et al. followed the children up to the age of 5 with no evidence of mental or physical development alterations (46). the most frequent obstetric complications reported were preterm uterine contractions and preterm labor. premature uterine contractions were reported 52 times in 6 studies: 50/288 (17.4%) ureteroscopies and 2/62 (3.2%) double-j insertion (9, 10, 15, 25, 31, 36). one retrospective study focused specifically on this topic, and while reporting the largest frequency of uterine contractions during the first 12 hours after ureteroscopy (45.54%), there were no severe maternal or fetal complications or premature deliveries. the authors propose some measures to reduce the odds of uterine contractions: shorten the surgical time, use phloroglucinol after the procedure, treat pain and infection, and monitor the multiparas more closely, as they seem to have a higher risk of contractions (15). the selected articles reported a total of 167 cases of preterm labor and 24 premature deliveries (3, 12, 28, 36, 47-50). a population-based retrospective cohort observed that when compared to conservative management, ureteral stent/ureteroscopy patients had higher rates (n = 90, 11.2%) of preterm labor while percutaneous nephrostomy patients had the highest rate (n = 61, 19-5%). urologic intervention with ureteral stent and/or ureteroscopy, and pcn each independently increased the risk of preterm delivery (3). ordon et al. further concluded that stone disease during pregnancy significantly increased the risk of an adverse birth outcome. the risk was higher if the stones required intervention, compared with conservative treatment, and temporary drainage (nephrostomy tubes or stents) had the largest magnitude of risk for an adverse birth outcome (2). another cohort study documented 7 cases of induction of labor before term due to stent intolerability, concluding that patients who were treated with temporary stents were significantly more likely to be induced before spontaneous labor when compared with ureteroscopy patients (45). contradicting this evidence, bayar et al. compared the number of preterm births between ureteroscopy (n = 15, 36%) and double-j stent insertion (n = 7, 24%), reporting no significant differences between them (36). there was only one case of in-utero fetal mortality one week after a double-j stent was placed but it was not due to urological reasons (36). obstetric outcomes were not mentioned in 2 articles (17, 43). procedure efficacy stone-free rate of urs was between 73% and 100% (9, 10, 12, 18, 23, 26, 29, 31, 34, 36, 40, 43, 44, 46). one study that compared urs stone-free rates between pregnant and non-pregnant women showed no statistically significant differences (38). however successful, a study with 101 ureteroscopies performed reported that 26 patients showed incomplete pain relief immediately after urs, but improved with painkillers in the following 12h (15). only 3 studies reported unsuccessful ureteroscopies, mainly due to ureteral stenosis or stone migration, in 13-19% of the cases (22, 25, 47). most temporary drainage procedures were successful. there were no reported failures in nephrostomy tube placement. in regard to ureteral stents, placement failure archivio italiano di urologia e andrologia 2024; 96(3):12153 c. laranjo-tinoco, m.j. oliveira, a.s. araújo, et al. 10 occurred at varying rates (12-75%), requiring drainage with pcn or ureteroscopy (11, 25, 33, 42, 47). in one study with 30 double-j stents successfully placed, 67% of the patients had a clinical improvement in pain relief immediately and soon after surgery, but 10% reported no difference and 23% had a worsening of symptoms, with either an increased analgesic requirement or the development of new symptoms related to stent placement (17). procedure efficacy was not mentioned in 17 studies (2, 3, 13, 16, 19-21, 24, 27, 28, 30, 32, 35, 37, 48, 50, 51). radiation exposure pre-operative imaging was mainly acquired with ultrasound. mri was used in selected cases with questionable ultrasound (12, 14, 25, 34, 47). plain x-ray, intravenous urography and computed tomography was rarely used (12, 16, 18, 26, 33, 41, 51). most surgical procedures were performed under direct vision and ultrasound guidance; intra-operative fluoroscopy was reported in 8 studies (12, 14, 16, 26, 29, 45, 48, 49). radiation doses were inconsistently reported. discussion ureteroscopy was the most reported procedure, totaling 2188 interventions. temporary drainage procedures amounted to 1236 interventions. procedures were not specified by trimester, but most were performed in the second and third trimesters. urs was performed in all trimesters, and 2 studies used flexible ureteroscopes only in the third trimester (27, 31). song et al. suggested that double-j stents should be preferentially placed in third trimester pregnant patients, due to the frequent need for replacement after 4-6 weeks (47). densted et al. recommended pcn placement before 22 weeks of gestation, and jj subsequently (49). conversely, there are descriptions of jj placement in the first trimester without adverse outcomes (17, 32, 36, 41). most procedures did not cause any type of perioperative or postoperative complications. when perioperative complications occurred, they were minor, like minimal ureteral injuries during ureteroscopy. a total of 106 perioperative complications were documented out of 2188 ureteroscopies performed (overall rate of 4.84%); the most common were stone migration, ureteral injury, and bleeding. the only comparative study between ureteroscopy in pregnant and non-pregnant women did not report significant differences (38). it is noteworthy that only one article used the satava classification for ureteral injury (44). this classification enables the classification of ureteral injuries and could be an important tool for standardizing such complications. standardization is important when comparing the results of different studies, which would have been of value to this review. specific perioperative complications for jj and pcn were not reported. postoperative complications were also mostly minor. there were few comparative studies: two did not report statistically significant differences in postoperative complications between procedures (32, 47), but bayar et al. described a lower rate of moderate or severe luts in urs (with double-j stent insertion when needed) than in those treated only with jj insertion (36), and one study revealed a higher rate of uti with nephrostomies (3). studies have described that the most common postoperative complications after ureteroscopy are fever, uti, and bleeding, after double-j stent insertion are stent-related discomfort, infection, and encrustation and after percutaneous nephrostomy are sepsis, local bleeding, and tube obstruction (53). the same conclusions could be assessed by this review. the overall documented complication rate for urs was 7.7%. the most frequent complications were lower urinary symptoms and urinary infections, with 13 cases of urosepsis (0.5%). according to a worldwide multicenter study that analyzed peri and postoperative complications associated with ureteroscopy, the most common perioperative complications were bleeding, perforation, and failed access and it happened in 4.2% of cases (53). this study represented a non-pregnant population, so the evidence presented in our systematic review shows a marginally higher rate of complications in pregnant patients. ureteral stenting complications were bladder irritability in most patients, encrustation, and stent migration, in a total of 8.2% complications. pcn had the highest rate of complications (14.8%), and they were fever, bacteriuria, tube obstruction, and hematuria. regarding obstetric complications, premature contractions were mostly reported for ureteroscopies. the rate of reported preterm labor was 4.8%, with 0.7% premature births considering all procedures. a comparative study showed no statistically significant differences in preterm labors between urs and jj patients (36), while another reported a higher rate of preterm induction of labor in jj patients due to catheter intolerability (45). two studies reported that percutaneous nephrostomy had the highest rate of adverse birth outcomes (2, 3). in terms of procedure efficacy, the mentioned stone-free rate varied from 73% to 100%, with no differences between pregnant and no pregnant women (38). ureteral dilation in pregnancy helps the insertion of the ureteroscopes, enhancing the success of this procedure (47). besides primary urs decision, urs was also the procedure of choice when temporary drainage failed. radiation exposure is a concern during pregnancy. consequently, ultrasound was the most used pre-operative and intra-operative imaging modality. however, fluoroscopy was still used in some studies (12, 14, 16, 26, 29, 45, 48, 49) with descriptions of low dose settings, protection equipment and pulsed imaging to reduce exposure. the validity of this systematic review depends largely on the quality of the available evidence. we included predominantly retrospective case series and cohort studies, typically conducted in single-center settings without a comparative design, which results in an absence of high-quality study designs. the lack of explicitly defined exclusion criteria in several studies raises the possibility of selection bias. additionally, samples were chosen by convenience, which compromises the external validity of the results. noteworthy limitations within this review encompass heterogeneity in both sample characteristics and outcome measurement. variability in sample sizes across studies introduces a notable source of potential bias, influencing the generalizability of conclusions. furthermore, the absence of standardization in outcome measurement, with divergent approaches to measuring the same outcome archivio italiano di urologia e andrologia 2024; 96(3):12153 11 surgical management of obstructing ureteral stones during pregnancy... across studies, hinders the comparability and correlation of reported results. in conclusion, there is a lack of well-designed high-quality studies on the effect of stone surgical treatments in the pregnant population. future studies should consider the inclusion of larger sample sizes, multiple centers, and randomized patient assignment to ensure homogeneous sample characteristics. despite these limitations, this systematic review summarizes the available evidence on a challenging topic, hence its value. conclusions invasive treatment may be required for the treatment of urolithiasis during pregnancy, so it is important to assess which procedures are suitable for this population. based on the findings of this systematic review, ureteroscopy, double-j stent insertion, and percutaneous nephrostomy are safe and effective treatment options in this setting, with minor complications and no severe adverse obstetric or fetal outcomes. since all three procedures are considered 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ureteral calculi in pregnancy. afr j urol. 2021; 27:46. 45. rivera me, mcalvany kl, brinton ts, et al. anesthetic exposure in the treatment of symptomatic urinary calculi in pregnant women. urology. 2014; 84:1275-8. 46. keshvari shirvan m, darabi mahboub mr, rahimi hr, seyedi a. the evaluation of ureteroscopy and pneumatic lithotripsy results in pregnant women with urethral calculi. nephrourol mon. 2013; 5:874-8. 47. song y, fei x, song y. diagnosis and operative intervention for problematic ureteral calculi during pregnancy. int j gynaecol obstet. 2013; 121:115-8. 48. khoo l, anson k, patel u. success and short-term complication rates of percutaneous nephrostomy during pregnancy. j vasc interv radiol. 2004; 15:1469-73. 49. denstedt jd, razvi h. management of urinary calculi during pregnancy. j urol. 1992; 148:1072-4. 50. elgamasy a, elsherif a. use of doppler ultrasonography and rigid ureteroscopy for managing symptomatic ureteric stones during pregnancy. bju int. 2010; 106:262-6. 51. kavoussi lr, albala dm, basler jw, et al. percutaneous management of urolithiasis during pregnancy. j urol. 1992; 148:106971. 52. tepeler a, resorlu b, sahin t, et al. categorization of intraoperative ureteroscopy complications using modified satava classification system. world j urol. 2014; 32:131-6. 53. somani bk, giusti g, sun y, et al. complications associated with ureterorenoscopy (urs) related to treatment of urolithiasis: the clinical research office of endourological society urs global study. world j urol. 2017; 35:675-81. correspondence catarina sousa laranjo tinoco (corresponding author) cat.tinoco@gmail.com sete fontes são victor, 4710-243 braga, portugal maria joão oliveira mariajboliveira3110@gmail.com ana sofia araújo anasofiaparaujo94@gmail.com andreia cardoso afds.cardoso@gmail.com carlos oliveira carlos.oliveira81@gmail.com paulo mota damota.paulo@gmail.com joão pimentel torres joaonunobpt@gmail.com conflict of interest: the authors declare no potential conflict of interest. this article was previously presented as a meeting abstract at the 40th world congress of endourology on september 27, 2023. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13642 1 review dition continues to increase. according to the recent epidemiologic studies, the incidence of urolithiasis increased from 77.78 million incident cases in 1990 to 115.55 million in 2019 (1). highest incidence rate of kidney stones were reported in saudi arabia, kuwait, south korea, china, thailand, spain, greece and the united states of america which raise concerns about the cause of kidney stone and whether it is linked to certain foods, faulty habitats and the nature of these countries (2, 3). medical treatment of kidney stones includes life style modification, high water intake, weight reduction and exercise (4). oral or intravenous non-steroidal anti-inflammatory drugs (nsaids) may be used to relieve pain. medical expulsive therapy (met) with alpha blockers has showed promising results on stone expulsion with tamsulosin being the most commonly used of this family of drugs (5). silodosin is a selective alpha blocker drug that works by binding to the extracellular domain of the alpha receptors, which inhibits activation of g protein and prevents phosphorylation of phospholipase c, giving a net result of smooth muscle relaxation (6). silodosin is 50 times more potent and selective on alpha 1 receptors than tamsulosin, which made most urologists and researchers believe that it might be more useful than tamsulosin considering the specifically high density of alpha 1 receptors in the lower ureter (7). tadalafil also is a promising drug for met that acts by inhibiting the phosphodiesterase-5 enzyme (pde-5) leading to accumulation of cyclic guanosine mono phosphate and subsequent smooth muscle relaxation (8). although the exact mechanism of tadalafil on lower ureter relaxation is not yet fully understood, it has proven to be a considerable option for met especially in patients with erectile dysfunction (9). natural stone passage is enabled with tadalafil by ureter lumen dilation, whereas alpha-1 adrenergic receptor antagonists induce stone passage by reducing muscle spasms (10, 11). in this study we aimed to compare tadalafil and silodosin for met in lower ureter stones below 10 mm through a comprehensive systematic review and meta-analysis and to assess the incidence of any adverse effects for each drug. objective: this meta-analysis aims to compare the efficacy and safety of tadalafil and silodosin as medical expulsive therapy (met) for lower ureteric stones below 10mm. the study also assesses the incidence of adverse effects associated with each drug. methods: a comprehensive search of electronic databases was conducted up to october, 2024. the study included randomized controlled trials (rcts) and cohort studies that compared tadalafil and silodosin in patients with lower ureteric stones (5-10 mm). the primary outcomes assessed were stone expulsion time (set), stone expulsion rate (ser), and adverse effects. data were analyzed using a random-effects model for heterogeneity and a fixed-effect model for non-heterogeneity. results: eight studies involving 797 patients were included. the pooled analysis showed no significant difference in set between tadalafil and silodosin (md = 0.15, 95% ci [-0.28, 0.57], p = 0.50), with significant heterogeneity. similarly, the pooled analysis showed no significant difference in ser between the two drugs (rr = 0.92, 95% ci [0.80 to 1.05], p = 0.22), with heterogeneity. however, after excluding one study, silodosin was favored over tadalafil for ser (rr 0.88, 95% ci [0.79 to 0.98], p = 0.02). there were no significant differences in headache, backache, or dizziness. silodosin was associated with a higher incidence of orthostatic hypotension, but this was resolved by excluding one study. a significant difference for abnormal ejaculation favored tadalafil (rr = 0.16, 95% ci [0.09 to 0.29], p = 0.01). conclusions: while the pooled results initially showed no significant difference in set and ser, silodosin demonstrated a superior stone expulsion rate after adjusting for heterogeneity silodosin showed a trend towards shorter set. however, silodosin was associated with a higher risk of orthostatic hypotension and abnormal ejaculation. further high-quality rcts with larger sample sizes are needed to confirm these findings. key words: ureter stones; tadalafil; silodosin; alpha blockers; medical expulsive therapy. submitted 17 january 2025; accepted 6 february 2025 introduction despite recent advances of endoscopic techniques for management of urinary stones, the prevalence of this conis silodosin better than tadalafil as a medical expulsive therapy in lower ureter stones? mohab alsaid saad abdalaziz 1, yousif ahmad hanafi 1, belal mohamed hamed 1, omar fayez abbas 1, khaled omar mahmoud khader 2, mohammad kh. alzawahreh 3, hesham ghzayel 4, rashed yousef al sharqi 5, zaid f. altawallbeh 6 1 faculty of medicine, al-azhar university, cairo, egypt; 2 internship at specialty hospital, jordan; 3 urology, department of special surgery, ministry of health, saudi arabia; 4 urology and andrology, department of special surgery, ministry of health, sultanate of oman; 5 urology department, al nadeem hospital, ministry of health, jordan; 6 internship at al nadeem hospital, madaba, jordan. doi: 10.4081/aiua.2025.13642 summary archivio italiano di urologia e andrologia 2025; 97(2):13642 m. alsaid saad abdalaziz, y. ahmad hanafi, b. mohamed hamed, et al. 2 materials and methods we adhered to the preferred reporting items for systematic reviews and meta-analyses (prisma statement) (12). all steps were completed per the cochrane handbook of systematic reviews and meta-analysis (13). this study was prospectively registered on prospero with the study id (crd42024597302). search strategy and data collection a search of electronic databases including pubmed, scopus, cochrane, science direct, embase, web of science, ebsco and google scholar has been performed until 01/10/2024 using the following keywords (“silodosin” or “alpha blocker” or “adrenergic alpha antagonists” or "adrenergic alphaantagonists" [mesh] or “antihypertensive”) and (“tadalafil” or “phosphodiesterase 5 inhibitor” or “pde5 inhibitors”) and (“ureteric stones” or “distal ureter stones” or "lower ureter stones" [mesh]). selection criteria to screen the results of the literature search, we used rayyan software (14). two stages of screening were used for studies. title and abstract screening was the initial stage. the second stage involved screening the chosen abstracts for full-text articles and resolving discrepancies through discussion. cohort studies and rcts that were reported on our pico model as follows. p (patient/problem): patients with lower ureteric stones 5 to 10 mm in size; i (intervention): studies where tadalafil was administered; c (comparator): studies where silodosin was administered; o (outcome): stone size, stone expulsion time (set), stone expulsion rate (ser), pain episodes, and side effects; s (study design): randomized control clinical trials (rcts) and cohort studies. studies with inadequate or deficient data for extraction were not included. studies with overlapping datasets, case-control studies, non-clinical studies, reviews, book chapters, case reports, case series, theses, editorials, letters, conference papers, and non-english studies were excluded. additionally, non-randomized controlled trials were not included. data extraction we used google spreadsheets for data extraction. the spreadsheet file was accessible to all authors. all authors took part in data extraction. extracted data were mainly divided into four domains: 1) study characteristics, 2) characteristics of the included studies' population, 3) risk of bias domains, and 4) study outcomes. summary: study id (first author-publication year), study design, location, year, population, intervention, comparator, outcome, key findings baseline: study arms, age (years), stone size (mm), body mass index (kg/m²), side (n (%), stone expulsion time (days), stone expulsion rate (%), analgesic dose (mb). outcomes: set, ser, headache, backache, dizziness, orthostatic hypotension, abnormal ejaculation, pain episodes. quality assessment the cochrane risk of bias (rob 2) tool was used to assess the quality of the studies that were part of this systematic review (15). there are seven study domains in the cochrane rob: 1) random sequence generation, 2) allocation concealment, 3) blinding of the investigators and patients, 4) blinding of the outcome assessors, 5) incomplete outcome data, 6) selective outcome reporting, and 7) other sources of bias. the study was classified as "low risk," "high risk," or "unclear" in each domain; disagreements were settled through discussion. newcastle-ottawa scale (nos) was used for observational cohort studies. statistical analysis we carried out statistical analysis of the included studies using an online website called “metaanalysisonline” with random effect model for the heterogeneity results and a fixed effect for non-heterogeneity results. continuous data were exhibited as mean difference (md) and 95% confidence interval (ci), while dichotomous data was exhibited as risk ratio (rr) and 95% ci. heterogeneity evaluated using i-squared (i2) and chi-square (chi2) tests (16). we considered heterogeneity significant if i2 was more than (45) % and the p-value of chi2 was less than 0.1. the random-effect model and sensitivity analysis were used for significant heterogeneity. results literature search results and characteristics of the included studies we identified 176 studies through a database search. following the removal of duplicates, 96 articles proceeded to the next review stage. our meta-analysis included 8 studies after screening abstracts and full texts; this process is depicted in the prisma flow diagram figure 1. three observational studies and five randomized controlled trials (rcts) formed the basis of our meta-analysis. these studies compared tadalafil and silodosin to determine how they affected the rate and time of stone expulsion. table 1 (see supplementary material) provides details on the studies included in this analysis, which were carried out between 2014 and 2024 across egypt, india, tunisia, and turkey. a total of 797 patients with lower ureteric stones was included in these eight studies. the mean age of participants was 40.20 years for the tadalafil groups and 39.6 years for the silodosin groups, with a mean stone size of 6.7 mm. the intervention lasted between three and six weeks. table 2 (see supplementary material) presents the characteristics of the study populations. table 3 (see supplementary material) summarizes characteristics of adverse events. risk of bias in the included studies the assessment of the quality of the included studies is demonstrated in figure 2. we utilized the cochrane risk of bias 2 (rob2) tool for randomized trials and the newcastle-ottawa scale (nos) for observational cohort studies. our assessment revealed that two rcts had a low risk of bias, while three studies showed some concerns. the three observational cohort studies were rated 7 points, and one was rated 8 points indicating a low risk of bias (table 4, see supplementary material). archivio italiano di urologia e andrologia 2025; 97(2):13642 3 tadalafil and silodosin in ureter stones figure 1. prisma flow diagram. figure 2. risk of bias assessment. archivio italiano di urologia e andrologia 2025; 97(2):13642 m. alsaid saad abdalaziz, y. ahmad hanafi, b. mohamed hamed, et al. 4 set eight studies reported on set comparing tadalafil to silodosin, as shown in figure 3. the pooled analysis of these studies showed no statistically significant difference, with the overall mean difference (md) = 0.15 (95% ci [-0.28, 0.57], p = 0.50). a random-effects model was applied due to significant heterogeneity (chi-square p < 0.01, i² = 87%). we used sensitivity analyses but did not identify any study that significantly affected the pooled estimate, and we could not resolve the heterogeneity. ser eight studies reported on stone expulsion rate (ser) comparing tadalafil to silodosin (17-24). the pooled analysis showed no significant difference between tadalafil and silodosin in the incidence of stone expulsion rate (rr = 0.92, 95% ci [0.80 to 1.05], p = 0.22), with heterogeneity (p = 0.01). to resolve the heterogeneity, we conducted a sensitivity analysis in multiple scenarios, excluding one study in each scenario. heterogeneity was best resolved by excluding the study of abdelaal et al. (20) (p = 0.14, isquare = 38%). after removing abdelaal et al. from the meta-analysis model, the overall rr favored silodosin over tadalafil (rr 0.88, 95% ci [0.79 to 0.98], p = 0.02), as shown in figure 3. headache six studies reported headache as a side effect, as shown in figure 4a. the pooled analysis showed no significant diffigure 3. a: stone expulsion time. b: stone expulsion rate. archivio italiano di urologia e andrologia 2025; 97(2):13642 5 tadalafil and silodosin in ureter stones ference between tadalafil and silodosin in the incidence of headache (rr = 1.16, 95% ci [0.77 to 1.73], p = 0.48), with no heterogeneity. backache five studies reported backache as a side effect, as shown in figure 4b. the pooled rr was 1.36 (95% ci [0.84 to 2.20], p = 0.21), with no significant difference between the two groups and no heterogeneity. dizziness five studies reported dizziness as a side effect, as shown in figure 4c. the pooled analysis indicated no significant difference in dizziness rates between tadalafil and figure 4. adverse effects. aheadache. b: backache. c: dizziness. d: orthostatic hypotension. e: abnormal ejaculation. archivio italiano di urologia e andrologia 2025; 97(2):13642 m. alsaid saad abdalaziz, y. ahmad hanafi, b. mohamed hamed, et al. 6 silodosin (rr = 0.99, 95% ci [0.59 to 1.64], p = 0.96), with no heterogeneity observed. orthostatic hypotension six studies reported on orthostatic hypotension comparing tadalafil to silodosin. the pooled analysis showed no significant difference between tadalafil and silodosin in the incidence of orthostatic hypotension (rr = 0.69, 95% ci [0.29 to 1.68], p = 0.42), with heterogeneity (p = 0.09). to resolve the heterogeneity, we conducted a sensitivity analysis in multiple scenarios, excluding one study in each scenario. heterogeneity was best resolved by excluding the study of kumar et al. (24) (p = 0.54, i-square = 0%). after removing kumar et al. from the meta-analysis model, the overall rr depicts that silodosin causes more orthostatic hypotension than tadalafil (rr 0.45, 95% ci [0.22 to 0.91], p = 0.03), as shown in figure 4d. abnormal ejaculation six studies reported abnormal ejaculation as a side effect of treatment. as shown in figure 4e the pooled analysis showed a significant difference between tadalafil and silodosin (rr = 0.16, 95% ci [0.09 to 0.29], p = 0.01), favoring silodosin, with no heterogeneity. archivio italiano di urologia e andrologia 2025; 97(2):13642 7 tadalafil and silodosin in ureter stones discussion in 2006, silodosin was first released in the japanese market as the newest generation of alpha blockers as a promising treatment in voiding dysfunction (25). since 2010, there has been a new emerging debate about using tadalafil and silodosin as a met in lower ureter stones. kumar et al. (24) was the first to put both drugs in direct comparison with each other for met of lower ureter stones through a double blind randomized control trial, showing that both drugs are effective with few and tolerable adverse effects. this led to further studies and clinical trials which demonstrated that they were comparable to other drugs used for met (5). the first and only meta-analysis comparing tadalafil and silodosin was delivered by ebrahimpour et al. (7), with a total of five studies included in the meta analysis. since then several high-quality studies were published, allowing for a more robust evidence synthesis. our metaanalysis adds evaluation of adverse events and solving of the heterogeneity which wasn’t taken care of in the previous meta-analysis. this broader approach provides a more comprehensive view of treatment effects beyond the scope of the previous analysis, enabling a more detailed comparison of treatment efficacy and adverse events. to our knowledge, this is the most comprehensive systematic review and meta-analysis comparing tadalafil and silodosin. pooled results of our study showed that silodosin and tadalafil had no significant difference on stone expulsion rate, however after solving high heterogeneity by deleting the study of abdelaal et al. (20) it was shown a statistically significant difference between silodosin and tadalafil favoring silodosin. we believe that abdelaal et al. study (20) was a poorly controlled clinical trial, with relatively high risk of bias. the study didn’t mention the type of randomization and modality of allocation, and the materials and method section was brief, blurry, with weak writing skills. abdelaal et al. was the only study among all the eight studies that pointed towards the use of tadalafil (5 mg) as a met with a high significant difference between it and the silodosin, which raised a lot of concern about the methodology of the study. although silodosin and tadalafil had no significant difference in terms of set, silodosin showed positive trends towards set without reaching significance level. results of the adverse effects showed that patients on silodosin had a relatively higher chance for orthostatic hypotension and abnormal ejaculation (e.g. loss of seminal emission) than patients on tadalafil as shown by the significant difference between the two drugs. the mechanism of orthostatic hypotension is due to the natural effect of silodosin on alpha receptors which are extensively located on blood vessels (particularly alpha-1 receptors) (26). abnormal ejaculation caused by silodosin is related to decreased number of bulbocavernous floor muscle contractions, thus decreasing semen discharge (27). kumar et al. (24) and sharma et al. (19) were the only two studies that used oral tablets with 10 mg tadalafil, unlike the rest of the studies, however no statistical difference was observed even after the administration of 10 mg tadalafil. furthermore tadalafil group in kumar et al. (24) was associated with a higher incidence of adverse events including hypotension and abnormal ejaculation witch raise concerns and question about dose related adverse effects of tadalafil as a met. huang et al. (28) demonstrated that patients with distal ureteric stones who were treated with silodosin had an expulsion rate of 83.5% and a mean expulsion time of 11 days. this was significantly better than the results for tamsulosin, which had an expulsion rate of 66.9% and a mean expulsion time of 14 days, along with a notable reduction in pain episodes. combination of silodosin and tadalafil have showed positive results on set and ser when used as a medical expulsive therapy, with variations between the studies about how tolerated is the combination by the patients (29). strength and limitations a major strength of this study is the exhaustive inclusion of all available clinical trials that directly compare tadalafil and silodosin treatment for distal ureter stones below 10 mm. our team conducted an extensive search across all major databases to ensure a comprehensive dataset; moreover, the study solved the heterogeneity that came across the results using random effect model and sensitivity analysis; finally, an extensive analysis of all the possible adverse effects of both drugs was done. despite adhering to prisma guidelines, our study has limitations that must be acknowledged. first, the heterogeneity found upon analysis of stone expulsion time couldn’t be solved by any method: random effect model; sensitivity analysis and selective regression were all useless. second, the high risk of bias in some studies should be taken into account when interpreting their results. further high-quality rcts with larger sample sizes and longer follow-up periods are needed to further support our results. conclusions silodosin has shown better results in terms of stone expulsion rate, together with positive trends towards stone expulsion time making it a valued drug than tadalafil as a met despite the fact that no significant differences were observed. however, assessment of adverse effects while giving the patients silodosin should be taken in account as, especially, orthostatic hypotension and abnormal ejaculation. further high-quality rcts with larger sample sizes and longer follow-up periods are needed to further support our results. references 1. qian x, wan j, xu j, et al. epidemiological trends of urolithiasis at the global, regional, and national levels: a population-based study. int j clin pract. 2022; 2022:6807203. 2. stamatelou k, goldfarb ds. epidemiology of kidney stones. healthcare 2023; 11:424 3. osther pjs. epidemiology of kidney stones in the european union. in: talati j. tiselius hg, albala d, ye z. (eds) urolithiasis. springer, london 2012. archivio italiano di urologia e andrologia 2025; 97(2):13642 m. alsaid saad abdalaziz, y. ahmad hanafi, b. mohamed hamed, et al. 8 4. thakore p, liang th. urolithiasis. [updated 2023 jun 5]. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2025 jan-. available from: https://www.ncbi.nlm.nih.gov/books/nbk559101/ 5. bos d, kapoor a. update on medical expulsive therapy for distal ureteral stones: beyond alpha-blockers. can urol assoc j. 2014; 8:442-5. 6. voznesensky i, shaw e, delay kj, et al. benign prostatic hyperplasia treatment options and their effects on sexual function. sexual medicine reviews. 2017, 5: 87-102. 7. ebrahimpour s, kargar m, balvardi m, et al. comparing the efficacy and safety of monotherapy and combination therapy with tadalafil, tamsulosin, and silodosin for distal ureteral stones: a systematic review and meta-analysis, asian journal of urology 2024 available from https://doi.org/10.1016/j.ajur.2024.05.003. 8. fahmy g, hess j. tadalafil. [updated 2024 mar 20]. in: statpearls [internet]. treasure island (fl): statpearls publishing; 2025 jan-. available from: https://www.ncbi.nlm.nih.gov/books/ nbk603743/ 9. kc hb, shrestha a, acharya gb, et al. tamsulosin versus tadalafil as a medical expulsive therapy for distal ureteral stones: a prospective randomized study. investig clin urol. 2016; 57:351-6. 10. liu z, su j, yuan d, et al. original article efficacy and safety of pde5-is and α-1 blockers for treating distal ureteral calculi: a mixed treatment comparison network meta-analysis of randomized controlled clinical trials [internet]. int j clin exp med. 2019; 12 available from: www.ijcem.com/ 11. sakhaee k, maalouf nm, sinnott b. kidney stones 2012: pathogenesis, diagnosis, and management. j clin endocrinol metab. 2012; 97:1847-60. 12. page mj, mckenzie je, bossuyt pm, et al. the prisma 2020 statement: an updated guideline for reporting systematic reviews. bmj 2021; 372: n71. 13. higgins jpt, thomas j, chandler j, et al. cochrane handbook for systematic reviews of interventions version 6.5 (updated august 2024). cochrane, 2024. available from www.training.cochrane.org/ handbook. 14. ouzzani m, hammady h, fedorowicz z, elmagarmid a. rayyan-a web and mobile app for systematic reviews. syst rev. 2016; 5:210. 15. sterne jac, savovic j, page mj, et al. rob 2: a revised tool for assessing risk of bias in randomised trials. bmj 2019; 366:l4898. 16. https://metaanalysisonline.com/ 17. diab t, fathi a, el-dakhakhny as, abou elezz a. efficacy of silodosin and tadalafil monotherapy versus combination of both drugs as met for distal ureteric stones: a prospective, double blinded, randomized clinical trial. arab journal of urology 2024; 1-7. available from https://doi.org/10.1080/20905998.2024.2403274. 18. ahmed ao, elsalhy ma, ahmed ya. efficacy and safety of silodosin, mirabegron, and tadalafil as medical expulsive therapy for lower ureteric stones: a prospective, randomized, comparative study. al-azhar international medical journal. 2023; 4:8. 19. sharma v, thakur aps, patel p, et al. comparison of synergistic action of alpha blockers and tadalafil in the management of lower ureteric stones as medical expulsive therapy: a prospective cohort study. j clin of diagn res. 2023; 17:oc37-oc41. 20. abdelaal ma, el-dydamony em. comparative study between tamsulosin, silodosin and tadalafil as a medical expulsive therapy for lower ureteral stones. arch ital urol androl. 2023; 95:10849. 21. gur m, ulu mb, caliskan st, et al. dexketoprofen vs. tamsulosin vs. silodosin vs. tadalafil as medical expulsive therapy for distal ureteral stones in men. j coll physicians surg pak 2021; 31:947-952. 22. khereddine md, tieoule tm, aziz k, et al. medical expulsive therapy (met) for large distal ureteral stones: a prospective study comparing three drugs. open journal of urology. 2020; 10:152-157. 23. çelik s, akdeniz f, afsar yildirim m, et al. tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for < 10 mm distal and proximal ureteral stones. arch ital urol androl. 2018; 90:117-122. 24. kumar s, jayant k, agrawal mm, et al. role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). urology. 2015; 85:59-63. 25. shimizu t, miyashita i, matsubara y, et al. pharmacokinetic profile of silodosin in clinical practice. yakugaku zasshi. 2006; 126:257-63. 26. osman ni, chapple cr, cruz f, et al. silodosin: a new subtype selective alpha-1 antagonist for the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia. expert opin pharmacother. 2012; 13:2085-96. 27. shimizu f, taguri m, harada y, et al. impact of dry ejaculation caused by highly selective alpha1a-blocker: randomized, doubleblind, placebo-controlled crossover pilot study in healthy volunteer men. j sex med. 2010; 7:1277-83. 28. huang w, xue p, xong h, zhang y. efficacy and safety of silodeclarations registration: study was registered on prospero carrying the id number (crd42024597302). availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author (yousif a.hanafi). competing interests: the authors declare that there is no conflict of interest regarding the publication of this paper. all research was conducted in accordance with ethical standards and without any financial or personal relationships that could influence or affect the results. funding: none to be reported. authors' contributions: conception: ms and yh; design: ms; data acquisition: ms,yh and km; data analysis: ms, yh, oa, za and ma; interpretation of data: hg, bh, ra, ma and oa; drafting of manuscript: bh, yh, km, hg and ms; critical revision of the manuscript: bh, ms, hg and yh. all authors confirm that have approved the submitted version of the paper and have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13642 9 tadalafil and silodosin in ureter stones dosin in medical expulsive therapy of distal ureteral calculi. br j clin pharmacol. 2016; 81:13-22. 29. el hadj sidi a, diab t, el-shazly a, et al. efficacy of silodosin versus sildosin plus tadalafil as medical expulsive therapy for lower ureteric stones: a prospective randomized placebo controlled study. benha medical journal, 2023; 40: 254-263. doi: 10.21608/bmfj.2023. 201688.1786. correspondence mohab alsaid saad abdalaziz mohabsaad955@gmail.com orcid: 0009-0000-0802-4240 faculty of medicine, al-azhar university, cairo, egypt yousif ahmad hanafi (corresponding author) yousiffahmed3@gmail.com orcid: 0009-0002-4678-4878 belal mohamed hamed bm030637@gmail.com orcid: 0009-0003-8049-5209 omar fayez abbas omarfayez0007@gmail.com orcid: 0009-0003-5255-892x al-azhar university faculty of medicine, postal code 11884, cairo, egypt khaled omar mahmoud khader dr.khaledomar2000@gmail.com orcid: 0009-0002-9203-3418 intern doctor at specialty hospital, jordan mohammad kh. alzawahreh moh.khader_zh@hotmail.com orcid: 0000-0001-7698-4120 urology, department of special surgery, ministry of health, saudi arabia hesham ghzayel surgeon1130@yahoo.com orcid: 0009-0003-6294-0604 urology and andrology, department of special surgery, ministry of health, sultanate of oman rashed yousef al sharqi rashedmed_91@yahoo.com orcid: 0009-0000-1001-4340 urology department, al nadeem hospital, ministry of health, jordan zaid f. altawallbeh zaidtawalbeh25@gmail.com orcid: 0009-0004-6130-3379 internship at al nadeem hospital, madaba, jordan stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):11723 1 original paper the last 15 years (7, 8). the scoring system may be beneficial to in patients’ counselling about complexity of surgery and the anticipated success/ failure rate of pn. in daily practice, pn is attempted as the standard of care for small renal masses, regardless of the tumour’s complexity. the aim of this study is to look for the endophytic to total tumour volume ratio as an added variable to study the complexity of partial nephrectomy to patients with t1b/t2 renal tumours. methods retrospective data collection for patients managed by partial nephrectomy, by a single surgeon (ak) for clinically t1b/t2 renal in 2018-2020. radiologists were provided with the patients’ list for the aim of the study and calculation of the tumour endophytic volume and the percentage of the endophytic volume to the total volume was calculated. the whole tumor volume was calculated by using this equation: antero-posterior x transverse x craniocaudal dimensions multiplied by 0.52. the area tool was then used to calculate the total tumor as well as to calculate the endophytic tumor component which lies within the kidney. the ratio endophytic to total tumor ratio was calculated by dividing the endophytic component to the whole tumor area. the endophytic component was identified by drawing a line through the tumour to complete the border of the kidney. figure 1 illustrates the markings. institutional ethical approval was obtained. patients’ consent for publishing was obtained as well. surgery was always started by full mobilization of the kidney and dissection of the renal pedicle regardless of the tumour location. tumour was identified. fat covering the tumour was left intact but margins of the tumour at contact with the kidney was cleared of fat. fat in this region was always sent separately for pathological analysis. after tumour edges are all clearly seen, monopolar cautery was used on the renal capsule 5-10 mm beyond the tumour edge for marking without cutting deeply into the kidney parenchyma. after that, the vascular clamp was used over the artery and vein and deep cutting with the monopolar introduction: partial nephrectomy is the standard of care to patients with small renal masses. it is still encouraged to larger tumours whenever feasible. the aim of this study is to look for the endophytic to total tumour volume ratio as an added variable to study the complexity of partial nephrectomy to patients with t1b/ t2 renal tumours. methods: retrospective data collection of patients that had partial nephrectomy for t1b/t2 renal tumours by a single surgeon was done. radiological re-assessment for the ct images to measure the endophytic to total tumour volume ratio was done. results: the mean age of the patients was 63 years. the study included 25 males and 11 females. all cases were managed by open surgery using retroperitoneal transverse lateral lumbotomy and warm ischemia was used in all patients. the mean tumour volume was 74 cc, the mean endophytic tumour volume was 29 cc. the mean percentage of endophytic to total tumour volume was 42%. conclusions: partial nephrectomy is safe for most of the patients with good performance status, having large renal masses. more complex surgery can be predicted in patients with endophytic to total tumour volume greater than 42%. key words: rcc; partial nephrectomy; tumour volume. submitted 6 september 2023; accepted 28 september 2023 introduction partial nephrectomy (pn) is currently accepted as the standard of care for most localized kidney cancer. the american society of clinical oncology defines partial nephrectomy as the standard of care for patients with t1a kidney mass (1). american urology association guidelines (2021) confirm pn to be the preferred treatment for patients with t1a solid/complex cystic renal tumours (2). canadian urology association guidelines recommend partial nephrectomy for treatment of tumours 2-4 cm in diameter (3). most recent european guidelines (2022) (4) recommend pn whenever feasible for t1 tumours, raising the bar to tumours up to 7 cm in diameter. some studies did show the feasibility of pn for t2 renal tumours (5, 6). renal scoring systems were emerged and validated over endophytic to total tumour volume ratio: an added variable to patients with t1b/t2 renal tumours undergoing partial nephrectomy asmaa ismail 1, vahid mehrnoush 1, amer alaref 2, radu rozenberg 2, hazem elmansy 1, walid shahrour 1, nishigandha burute 2, anatoly shuster 2, owen prowse 1, ahmed zakaria 1, walid shabana 1, ahmed kotb 1 1 urology department, tbrhsc, northern ontario school of medicine university, thunder bay, on, canada; 2 radiology department, tbrhsc, northern ontario school of medicine university, thunder bay, on, canada. doi: 10.4081/aiua.2023.11723 summary archivio italiano di urologia e andrologia 2023; 95(4):11723 a. ismail, v. mehrnoush, a. alaref, et al. 2 cautery mixed with mobilizing the wedge having the tumour away with an empty blade handle till tumour with normal parenchymal margin was completely removed. we repair collecting system if encountered. we then use the monopolar cautery spray to cauterize the parenchymal edges before repair. vicryl 0 was then used to take multiple deep interrupted transverse mattress sutures. once satisfied, the whole sutures are tied and the vascular clamp is removed. we usually cover the renorrhaphy with a large piece of surgicel leave a drain for 48 hours. the patient was usually discharged on the morning of the third postoperative day. results thirty-six patients were identified fulfilling our criteria. the mean age of the patients was 63 years. the study included 25 males and 11 females. all cases were managed by open surgery using retroperitoneal transverse lateral lumbotomy (9). warm ischemia was applied to all cases, clamping both the renal artery and the vein. the mean ischemic time was 9 minutes. no case required intra or postoperative blood transfusion. no case was changed to radical nephrectomy. thirty-two cases had solid tumour and 4 had bosniak 3/4 renal cysts. the mean tumour diameter was 5.5 cm, ranging from 4.2 to 10 cm. the mean tumour volume was 74 cc, the mean endophytic tumour volume was 29 cc. the mean percentage of endophytic to total tumour volume was 42%. endophytic to total tumour volume of > 42% was found to be associated with longer mean operative time (90 minutes versus 50 minutes. p 0.01) and more mean blood loss (200 versus 50 ml. p 0.02). renal cell carcinoma (rcc) was the pathological diagnosis of all patients, but one case had angiomyolipoma (aml). fortunately, positive surgical margin was only seen in the patient having aml. pathological t3 was identified in 5 patients. over a median follow up of 3 years, disease and recurrence free survival was 100%. figure 2 shows a case with a tumour diameter of 4.2 cm involving the right lower renal pole. the endophytic to total tumour volume was 39%. the case was successfully managed by pn, under warm ischemic time of 10 minutes. single patient had significant hematuria and drop in hgb few weeks after surgery. pseudoaneurysm was identified and clamping by the interventional radiology team was safely done. that patient had endophytic to total tumour volume of 79%. discussion in patients with adequate performance status, pn should be always attempted. all guidelines agree on that for t1a tumours, and some guidelines and many publications extend the recommendation to t1b/ t2 tumours. scoring systems were introduced and validated to help the decision making and patients’ counselling. efforts were ongoing to identify adding parameters to predict the success of pn. sciorio et al. (2020) identified mic (surgical margin, ischemic time, and complications) as a parameter that could mark the success of the surgery. in their study. low mic was correlated to high padua score and large tumour diameter (10). tumour volume and specifically the endophytic tumour volume was not widely studied. tiwari et al. (11) studied 87 patients that underwent pn for t1a renal mass and found a positive correlation between the endophytic tumour volume and nephrometry score. mohammadi et al. (12) published a case report for a successful pn to 17 cm renal mass. while they did not measure the tumour volume in their study, the ct images they published clearly showed very low ratio of endophytic to total tumour volume. to our knowledge, this is the first study looking for the percentage of endophytic to total tumour volume in patients that underwent pn for t1b/t2 renal masses. in our hands, pn was safe for such large renal tumours in figure 1. calculation of the tumour endophytic volume and the percentage of the endophytic volume to the total volume. the endophytic component was identified by drawing a line through the tumour to complete the border of the kidney. figure 2. figure shows a case with a tumour diameter of 4.2 cm involving the right lower renal pole. the endophytic to total tumour volume was 39%. archivio italiano di urologia e andrologia 2023; 95(4):11723 3 endophytic to total tumour volume ratio medically fit patients. we must disclose that this study did not include patients with similar or smaller tumour mass that we elected to do radical nephrectomy because of their poor performance status that we felt pn may be an added risk to them. in our experience, the patients’ performance status and comorbidities were the main factors we consider when offering partial versus radical nephrectomy. while all cases that had pn for large renal masses were successful, cases that had larger endophytic to total tumour volume had significantly longer operative time and blood loss. conclusions partial nephrectomy is a safe treatment option that should be attempted in most of the patients with good performance status regardless of the tumour size. endophytic to total tumour volume is an added parameter to consider for surgical planning. endophytic to total tumour volume ratio of greater than 0.42 was associated with longer operative time and more blood loss in patients with t1b/t2 tumours undergoing partial nephrectomy. references 1. finelli a, ismaila n, bro b, et al. management of small renal masses: american society of clinical oncology clinical practice guideline. j clin oncol. 2017; 35:668-680. 2. campbell sc, clark pe, chang ss, et al. renal mass and localized renal cancer: evaluation, management, and follow-up: aua guideline: part i. j urol. 2021; 206:199-208. 3. richard po, violette pd, bhindi b, et al. canadian urological association guideline: management of small renal masses full-text. can urol assoc j. 2022; 16:e61-e75. 4. ljungberg b, albiges l, abu-ghanem y, et al. european association of urology guidelines on renal cell carcinoma: the 2022 update. eur urol. 2022; 82:399-410. 5. nahar b, gonzalgo ml. what is the current role of partial nephrectomy for t2 tumors? can j urol. 2017; 24:8698-8704. 6. sharafeldeen m, sameh w, mehrnoush v, et al. partial nephrectomy for t1b/t2 renal mass: an added shift from radical nephrectomy. j kidney cancer vhl. 2022; 9:1-5. 7. kutikov a, uzzo rg. the r.e.n.a.l. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. j urol. 2009; 182:844-53. 8. kriegmair mc, mandel p, moses a, et al. defining renal masses: comprehensive comparison of renal, padua, nephro, and cindex score. clin genitourin cancer. 2017; 15:248-255.e1. 9. ismail a, oquendo f, allard-ihala e, et al. transverse lumbotomy for open partial/radical nephrectomy: how i do it. urol int. 2020; 104:131-134. 10. sciorio c, prontera pp, scuzzarella s, et al. predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy. arch ital urol androl. 2020; 92:165. 11. tiwari rv, ho cm, huang hh, et al. role of computed tomography-calculated intraparenchymal tumor volume in assessment of patients undergoing partial nephrectomy. int j urol. 2018; 25:436441. 12. mohammadi a, aghamir smk. partial nephrectomy of a huge solid-cystic renal mass with final pathology of renal cell carcinoma. j surg case rep. 2022; 2022:rjab622. correspondence asmaa ismail, md asmaaismail0782@gmail.com vahid mehrnoush, md vahidmehrnoush7@gmail.com hazem elmansy, md hazem.mansy@rocketmail.com walid shahrour, md walid.shahrour@gmail.com owen prowse, md owen.prowse@tbh.net ahmed zakaria, md aszakaria81@yahoo.com walid shabana, md waleed.shabana@gmail.com ahmed kotb, md, frcsc, frcs urol, febu (corresponding author) associate professor drahmedfali@gmail.com urology department, tbrhsc, northern ontario school of medicine university 980 oliver road, thunder bay, on, canada. p7b 6v4 amer alaref, md amer.alaref@tbh.net radu rozenberg, md radu.rozenberg@tbh.net nishigandha burute, md nishirad@gmail.com anatoly shuster, md shustera@tbh.net radiology department, tbrhsc, northern ontario school of medicine university, thunder bay, on, canada conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2022; 94, 2190 original paper no conflict of interest declared. metabolic disorders, anatomical anomalies and infection should be investigated in pediatric stone disease and failure to evaluate these causes will lead to higher stone recurrence after treatment (2). the european guidelines on the management of pediatric stones recommend extracorporeal shockwave lithotripsy (eswl) or percutaneous nephrolithotomy (pcnl) for the treatment of renal and upper ureteric calculi in the pediatric age group based on stone location, volume and density but with increasing evidence on the outcome of flexible ureterorenoscopy (furs), it has been added to the armamentarium to treat upper urinary tract stones in children (3). with the miniaturization of endourological instruments, retrograde intrarenal surgery (rirs) has advantages over eswl and pcnl due to its high stonefree rate (sfr) which is usually achieved in a single sitting with acceptable efficacy and low morbidity in pediatric patients. there are very few studies done to evaluate the efficacy of this method in pediatric patients. hence in our study, we evaluated the efficacy of rirs among children up to 12 years of age. the primary objective of our study is to evaluate the sfr with rirs for upper urinary tract stones in pediatric patients. the secondary objectives were the evaluation of post-procedure complications, radiation time, pain score, and duration of hospital stay. materials and methods this is an observational retrospective study done at a tertiary care centre. the study was conducted from february 2019 to november 2021 and the data was collected from the hospital records. all pediatric patients aged 12 years and below with renal and upper ureteric stones of size less than 1.5 cm treated with rirs were included. children with genetic disorders, medical renal disease and previous stone treatment on the same side were excluded. fifteen children met the inclusion criteria and demographic data and laboratory investigations were collected from hospital records. all patients had xray of kidneyureter-bladder (xray-kub) and ultrasongraphy of kidneyureter-bladder (usg-kub) and those with normal serum objective: retrograde intra renal surgery (rirs) is a minimally invasive surgical modality for the treatment of renal stones. we evaluated the efficacy of rirs in children below aged 12 years of age in the form of stone-free rate (sfr), complications and the feasibility of the procedure. materials & methods: this retrospective study included all children ≤ 12 years of age, with upper urinary tract stones single or multiple ≤ 15 mm in size who underwent rirs between february 2019 to november 2021. rirs was performed with 7.5 fr flexible ureterorenoscope over the guidewire, the stones were dusted with laser and the ureteral stent was left after rirs. all patients had the post-procedure stent removed within 3 weeks after checking for residual stones with x-ray and ultrasonography of kidney-ureter-bladder (usg-kub). follow-up usg kub was done at 4 months. results: 15 patients included in our study met the inclusion criteria. the mean age was 8.7 ± 2.8 years, the mean stone size was 11.26 ± 2.14 mm and 26.6 % had multiple stones. retrograde access failure was noted in 36.3 % in non stented patients. the mean operative time was 72.6 ± 20 minutes, fluoroscopy time was 4.4 ± 0.9 minutes and the mean laser time was 26 ± 3.9 minutes. the mean hospital stay was 2.8 ± 0.9 days. ureteral access sheath (uas) was used in one patient. conversion to mini pcnl was done in one pre stented patient due to access failure and one patient had a second look rirs for residual stone. no major complications were noted except onr patient who had sepsis. the stone-free rates were 93.3% after primary rirs and 100% after second look rirs. conclusions: rirs is a feasible, safe procedure for pediatric upper urinary stones with excellent stone-free rates and a low rate of complications. key words: rirs; laser lithotripsy; flexible ureterorenoscopy; pediatric upper urinary stones. submitted 9 may 2022; accepted 20 may 2022 introduction there is a global increase in the prevalence of urolithiasis in children attributed to lifestyle changes, dietary habits, climate changes, childhood obesity and the wider availability of ultrasonography (1). underlying causes such as retrograde intrarenal surgery (rirs) for upper urinary tract stones in children below 12 years of age: a single centre experience mohanarangam thangavelu 1, ajit sawant 2, ali abbas sayed 2, praksah pawar 2, mohamed hamid 2, sunil patil 2, vikas bhise 2, jeni mathews 2, raunak shewale 2, mohan gadodia 2 1 department of urology, ysbyty gwynedd, bangor ll57 2pw, united kingdom; 2 department of urology, ltmc & general hospital, sion, mumbai 400022, india. doi: 10.4081/aiua.2022.2.190 summary 191archivio italiano di urologia e andrologia 2022; 94, 2 rirs for upper urinary tract stones in children creatine underwent computed tomography (ct) urography. those patients who already had non-contrast ct kub underwent dtpa renogram to assess the renal functional status. all procedures were performed under general anaesthesia after confirming a sterile urine culture. patients have been given prophylactic antibiotic ceftriaxone 100 mg/kg iv at the time of induction of anaesthesia. patients were positioned in lithotomy position and cystourethroscopy was performed using a 6.5 fr storz semirigid ureteroscope and a 0.032-inch guidewire was inserted into the ureter. balloon dilatation of the ureteric orifice was done over the guidewire followed by semirigid ureteroscopy to assess the distensibility of the ureter. after this, under fluoroscopic and visual supervision, a 7.5 fr furs (storz flex x2) was placed into the ureter over the guidewire without the use of an access sheath. if the furs could not be negotiated, the ureteral stent was inserted for passive dilatation and rirs was performed later in 2 weeks. the complete pelvicalyceal system was examined with the furs. stone dusting was done using 272 microns holmium laser fibre with a power of 0.2-0.6 j and 10-20 hz frequency. this ensured that the stone was dusted and not fragmented. visual inspection of the pelvicalyceal system and fluoroscopy was done to look for any residual stone fragments after surgery and the ureter was evaluated while removal of furs to detect any potential ureteral trauma. a 5 fr ureteral stent was routinely placed at the end of the rirs and was left in place between 1 to 3 weeks. per urethral foleys catheter was removed on the first post-operative day. we used the visual analog scale for postoperative pain assessment. the children went home with prophylactic antibiotics for 5 days and oxybutynin till the stent removal. xray and usg kub were done before the stent removal between 1 to 3 weeks after rirs to assess any residual calculi. the presence of any calculi ≥ 3 mm was considered treatment failure in calculating sfr. after confirming the absence of residual calculi, the ureteral stent was removed under general anesthesia. follow-up usg kub was performed at 4 months to assess the stone recurrence. the statistical investigation was performed using microsoft excel. the collected data was evaluated and presented as a range, mean, standard deviation, and percentages. results in our study, 15 children with upper urinary tract stones met the inclusion criteria. four patients had multiple stones in the kidney. demographics shown in table 1. out of 15 patients, four patients had elective ureteral stenting before the rirs procedure and 11 patients were not pre-stented. retrograde access failed in 36.3% of nonstented patients requiring a second attempt after a 2 week stenting period. conversion to mini pcnl was necessary in one of the patients who had elective pre-stenting due to access failure. ureteral access sheath (uas) (9/11 fr 25 cm) was used only in one patient due to higher stone volume and capacious ureter. all patients were discharged on the second postoperative day, except one patient who had a postoperative fever – grade 2 on the clavien dindo scale – and required high dose antibiotics with a longer hospital stay of 6 days. one patient with 14 mm lower pole calculi was found to have residual calculi of 7 mm in the lower pole three weeks after rirs due to migration of the fragment which was not identified during the initial procedure. redo rirs was done for this patient with complete clearance. the average fluoroscopy time was 4.4 ± 0.9 minutes. the stone-free rate was 93.3% after primary rirs and 100% after a second look rirs. the operative and post-operative are shown in table 2. table 1. demographic details. variables number of patients (%) mean range age-years 0-4 years 2 8.73 ± 2.81 years 3-12 years 5-8 years 4 9-12 years 9 sex male 7 female 8 side right 9 left 6 stone location upper ureter 2 (13.3 %) renal pelvis 6 (40 %) upper calyx 3 (20 %) mid calyx 2 (13.3 %) lower calyx 2 (13.3 %) multiple stones 4 (26.6 %) stone size mm 11.26 ± 2.15 mm 7 to 14 mm hounsfield units (hu) 1132 ± 234.37 hu 720-1432 hu table 2. operative and post operative details. variables number of patients (%) mean range elective ureteral stent 4 /15 (26.6%) ureteral access sheath used 1 (6.6%) access failure during first rirs in non stented patients 4 /11 (36.3%) total number of access failure (with & without ureteral stent) 1 / 15 (6.6%) operative time (minutes) 72.6 ± 20 50 to 120 laser time (minutes) 26.07 ± 3.9 15 to 30 radiation time (minutes) 4.4 ± 0.9 3 to 6 hospital stay (days) 2.8 ± 0.9 2 to 6 conversion to mini pcnl 1 (6.6%) residual stone 1 (6.6%) redo rirs for residual stone 1 (6.6%) post-operative complications clavien didno – grade 2 1 (6.6%) pain score (visual analog scale) 1.2 ± 0.9 0 to 2 stone free rate after primary rirs 93.3% final 100% archivio italiano di urologia e andrologia 2022; 94, 2 m. thangavelu, a. sawant, a. abbas sayed, p. pawar, m. hamid, s. patil, v. bhise, j. mathews, r. shewale, m. gadodia 192 discussion management of urolithiasis in children poses a challenge because of smaller size kidneys with a small collecting system, and a small-caliber ureter. ferretti et al. (4) in their study noted that an high proportion of children with stones was associated with comorbidities like urologic malformations (42.8%), urinary infections (25%), metabolic disorders (17.8%) and non-urologic diseases (25%). this study demonstrates the need for thorough investigations in pediatric stone patients to reduce the chances of recurrent stone formation and to reduce the complications of the surgical treatment. eswl has been one of the standard treatment methods for renal stones up to 2 cm however it has its own disadvantages. the stone-free rates depend upon the stone volume, density, location, caliceal anatomy, and renal function. the overall stone-free rates of 79.9%, clinically insignificant residual fragments in 13.2% at 3 months, retreatment rate of 53.9%, and complication rate of 9.69% were observed in a large retrospective study by muslumangolu et al. (5) the need for general anesthesia, multiple sessions, pre eswl stenting for larger stones, post-procedure steinstrasse, technical difficulties in stone localization and unknown long term effects on renal parenchyma are the drawbacks of eswl. pcnl is a more invasive method reserved for larger and complex renal stones. unsal et al. (6) in their study of pcnl in children below 18 years divided into 3 groups based on their age and reported overall average stone-free rates of 82.3% after the primary procedure and 93.1% after the adjunctive procedure. they noted more bleeding and a drop in hemoglobin in children between 8 to 16 years which also depended upon the size of the instruments. the most frequently reported complication is bleeding requiring blood transfusion in less than 10% and others are postoperative infection, pain, and fever. the average hospital stay was between 3 to 4 days for pcnl. with the miniaturization of furs and the availability of efficient energy sources, rirs for upper urinary tract stones has become a safe option. a systematic review of studies between 1990 to 2014 by ishii et al. (7) on the safety and efficacy of flexible ureterorenoscopy and lasertripsy (fursl) in children with a mean age of 7.3 years reported mean stone-free rates of 85.5% and complication rate of 12.4% for the size of the stone varied from 1 to 30 mm. kim et al. (8) reported in their study of 170 furs procedures in children with a mean age of 5.2 years, stone-free rates of 100% for stones burden < 10 mm and 97% for stones > 10 mm after a single rirs procedure. a study by unsal et al. (9) reported a series of rirs in 16 children below 7 years of age with a stone-free rate of 100% for stones below 10 mm and 81.8% for stones > 10 mm in size with one complication of ureteral perforation occurring after balloon dilatation of ureteric orifice. ferretti s et al. (4) reported in their study of 28 children with a mean age of 8 years with urinary tract stones achieved stone free rate of 76.6% after first procedure and 93.3% after redo surgery with no major complications. in their study the stone size ranged from 5 to 24 mm with a mean stone area of 1.15 cm2 and they used rigid urs, rirs and combination of both procedures to treat the stone. in our study the stone-free rate observed was 93.3%, with no major complications for the mean stone size of 11.2 ± 2.15 mm after a single rirs procedure. as rirs procedure is done through a natural orifice (urethra) without any need for a puncture in the kidney which causes minimal post-procedure pain, low requirement of analgesics, faster recovery, and shorter hospital stay. complications like bleeding, clot retention, and need for blood transfusion are rare with this procedure (9) we used balloon dilatation of the ureteric orifice in all cases but kim et al. (8) did not use active ureteric dilatation with good stone-free rates and other studies mention hydrodistension is equally effective (3). we did not routinely perform pre-procedure ureteral stenting and our retrograde access failure rate was 36.3% for primary rirs in non stented patients. chandramohan et al. (10) in their study of rirs of 67 preschool children aged < 5 years for pediatric renal stones reported routine pre-procedure stenting in all their patients and reported only a 5.98 % retrograde access failure rate. corcoran et al. (11) mention that routine placement of a pre-procedure ureteral stent for passive ureteral dilatation is not required for successful ureteroscopic access to the renal pelvis in prepubertal age group children. if the initial attempt of ureteroscopy is unsuccessful then placement of a ureteral stent decreases the number of procedures while maintaining a low complication rate. in our experience, we did not routinely use uas except in one patient due to larger stone volume and a capacious ureter. we did not use the basket for stone retrieval as the stone was dusted with laser energy and it was not necessary for the repeated passage of furs to retrieve the stone fragments which increases the chance of ureteral trauma. in a study (10) of rirs for renal stones in preschool children only in 63.5 % of the cases, uas could be safely used even though all of the patients had undergone prerirs stenting and in the study are reported 2 ureteral injuries of grade 1 and grade 2 according to the traxer and thomas classification (12) which were managed by post-procedure stenting for 4 weeks with no long term complications like ureteral stricture. they have also noted lower success rate of placing uas in children less than 4 years old in spite of pre-rirs ureteral stent insertion for passive ureteral dilatation. anbarasan et al. (13) reported the results of rirs using 9.5 fr uas in 21 pediatric patients with a mean age of 11.8 years with a mean follow-up of 26 months with no long-term complications. in their study, only 8 patients had pre-procedure stenting. berrettini et al. (14) performed rirs for stones in 13 preschool children with body weight < 20 kg, and all of them had pre-procedure stenting. they concluded that the use of uas is safe and effective with no long term complications. mosquera et al. (15) reported from the data collected from 48 patients with a mean age of 10.7 years mention that use of uas was safe with excellent outcomes, especially for large and multiple stones. they noticed grade 1 ureteric injury in one patient and suggest to use the smallest size uas. all our patients had post-procedure stenting and most of the studies advocate post-procedure stenting or ureteral catheter drainage with variable duration. chen y et al. (16) did a systematic review on the safety and 193archivio italiano di urologia e andrologia 2022; 94, 2 rirs for upper urinary tract stones in children efficacy of pcnl versus rirs for pediatric upper urinary stones and noted significantly shorter hospital stay and fluoroscopy time for rirs than pcnl. the overall minor and major complication rates were higher in pcnl but not statistically significant. rirs benefits from the significantly lesser requirement of blood transfusion. they also found no significant differences in the stone-free rates and operative times. bas o et al. (17) reported that for stones between 10-20 mm, rirs has similar success and complication rates with shorter hospital stay and low radiation exposure when compared to micro-pcnl. for stones larger than 2 cm, saad ks et al. (18) reported that rirs monotherapy has lower stone-free rates than mini-pcnl but with the advantages of decreased radiation exposure, fewer complications, and shorter hospital stay. mokhless et al. (19) in their prospective study compared eswl versus rirs for 10 to 20 mm stones and found that stone free rate after a single session was 70% and 86.6% and overall stone-free rate at 3 months was 93.3% and 96% with no major complications in both the groups. ergin et al. (20) did a retrospective study that reported similar stonefree rates for eswl and rirs for pediatric renal stones between 10 to 20 mm with no complications seen in either modality. eswl had longer fluoroscopy time and shorter hospital stay but rirs had a higher cost per patient. the mean fluoroscopy time in our study was 4.4 ± 0.9 minutes and the lower radiation is beneficial for pediatric patients when additional procedures are required for stone clearance. he qing et al. (21) in their systematic review of three modalities of treatment – eswl, pcnl and rirs – for pediatric upper urinary tract stones concluded that eswl provides shorter hospital stay and operative time, lower sfr, higher auxiliary procedure rate with relatively lower effectiveness quotient (eq). pcnl is associated with higher sfr than eswl, but has longer fluoroscopy time, operative time, and highest eq when compared to rirs and eswl. rirs offers higher sfr after a single session, a lower retreatment rate than eswl, a shorter hospital stay than pcnl, and lower eq. complication rates were comparable among the three modalities however higher complication rates were found in subgroups of pcnl. there was no major post-operative complication in our study, only one patient had sepsis requiring high dose antibiotics and a longer hospital stay. mosquera et al. (22) reviewed the data of 57 children who underwent fursl for lower pole stones from two large european tertiary endourology centers and reported initial and final stonefree rates of 82.4% and 98.2% respectively; 1.19 procedures per patient were required to be stone free. despite the advantages of rirs, there are certain drawbacks associated with this procedure. pre-procedure ureteral stent under general anesthesia for passive ureteral dilatation may be required especially in children below 5 years of age. it has lower stone-free rates for stones sizes more than 2 cm and may require additional procedures. there are chances of ureteral injury during placement of uas and sometimes the uas could not be safely used in spite of pre-procedure stenting. most of the patients require ureteral stent insertion after rirs which requires another procedure under general anesthesia for stent removal. these additional procedures could influence the eq of rirs. with increasing expertise, rirs has become a good option over eswl for upper urinary stones of 10 to 20 mm size in children as it has higher stone-free rates which are usually achieved in a single sitting, and also over pcnl as it has lower morbidity and low post-operative complications with faster recovery. our study suggests that rirs is a feasible and safe alternative to pcnl for pediatric patients with upper urinary stones in selected cases with lower complication rates and a faster recovery period. conclusions pediatric rirs requires expertise and to be carried out in tertiary centers. routine pre-procedure ureteral stenting and use of ureteral access sheath are not required; however, a randomized prospective study with multivariate analysis would be helpful. rirs is a safe endourological procedure with high stone-free rates, low complication rate for the treatment of pediatric upper urinary tract stones less than 2 cm in size. references 1. clayton db, pope jc. the increasing pediatric stone disease problem. ther adv urol 2011; 3:3-12. 2. copelovitch l. urolithiasis in children: medical approach. pediatr clin north am 2012; 59:881-96. 3. eau-guidelines-on-paediatric-urology-2022.pdf. https://d56bo chluxqnz.cloudfront.net/documents/full-guideline/eau-guidelineson-paediatric-urology-2022.pdf 4. ferretti s, cuschera m, campobasso d, et al. rigid and flexible ureteroscopy (urs/rirs) management of paediatric urolithiasis in a not endemic country. arch ital urol androl. 2021; 93:26-30. 5. muslumanoglu ay, tefekli a, sarilar o, et al. extracorporeal shock wave lithotripsy as first line treatment alternative for urinary tract stones in children: a large scale retrospective analysis. j urol. 2003; 170:2405-8. 6. unsal a, resorlu b, kara c, et al. safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. urology. 2010; 76:247-52. 7. ishii h, griffin s, somani bk. flexible ureteroscopy and lasertripsy (fursl) for paediatric renal calculi: results from a systematic review. j pediatr urol. 2014; 10:1020-5. 8. kim ss, kolon tf, canter d, et al. pediatric flexible ureteroscopic lithotripsy: the children's hospital of philadelphia experience. j urol. 2008; 180:2616-9. 9. unsal a, resorlu b. retrograde intrarenal surgery in infants and preschool-age children. j pediatr surg. 2011; 46:2195-9. 10. chandramohan v, siddalingaswamy pm, ramakrishna p, et al. retrograde intrarenal surgery for renal stones in children < 5 years of age. indian j urol 2021; 37:48-53. 11. corcoran at, smaldone mc, mally d, et al. when is prior ureteral stent placement necessary to access the upper urinary tract in prepubertal children? j urol. 2008; 180(4 suppl):1861-3. 12. traxer o, thomas a. prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. j urol. 2013; 189:580-4. archivio italiano di urologia e andrologia 2022; 94, 2 m. thangavelu, a. sawant, a. abbas sayed, p. pawar, m. hamid, s. patil, v. bhise, j. mathews, r. shewale, m. gadodia 194 13. anbarasan r, griffin sj, somani bk. outcomes and long-term follow-up with the use of ureteral access sheath for pediatric ureteroscopy and stone treatment: results from a tertiary endourology center. j endourol. 2019; 33:79-83. 14. berrettini a, boeri l, montanari e, et al. retrograde intrarenal surgery using ureteral access sheaths is a safe and effective treatment for renal stones in children weighing < 20 kg. j pediatr urol. 2018; 14:59.e1-59.e6. 15. mosquera l, pietropaolo a, brewin a, et al. safety and outcomes of using ureteric access sheath (uas) for treatment of pediatric renal stones: outcomes from 2 tertiary endourology centers. urology. 2021; 157:222-226. 16. chen y, deng t, duan x, et al. percutaneous nephrolithotomy versus retrograde intrarenal surgery for pediatric patients with upper urinary stones: a systematic review and meta-analysis. urolithiasis. 2019; 47:189-199. 17. baş o, dede o, aydogmus y, et al. comparison of retrograde intrarenal surgery and micro-percutaneous nephrolithotomy in moderately sized pediatric kidney stones. j endourol. 2016; 30:765-70. 18. saad ks, youssif me, al islam nafis hamdy s, et al. percutaneous nephrolithotomy vs retrograde intrarenal surgery for large renal stones in pediatric patients: a randomized controlled trial. j urol. 2015; 194:1716-20. 19. mokhless ia, abdeldaeim hm, saad a, zahran ar. retrograde intrarenal surgery monotherapy versus shock wave lithotripsy for stones 10 to 20 mm in preschool children: a prospective, randomized study. j urol. 2014; 191(5 suppl):1496-9. 20. ergin g, kirac m, kopru b, et al. shock wave lithotripsy or retrograde intrarenal surgery: which one is more effective for 10-20-mm renal stones in children. ir j med sci. 2018; 187:1121-1126. 21. he qing, xiao k, chen y, et al. which is the best treatment of pediatric upper urinary tract stones among extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy and retrograde intrarenal surgery: a systematic review. bmc urol. 2019; 19:98. 22. mosquera l, pietropaolo a, madarriaga yq, et al. is flexible ureteroscopy and laser lithotripsy the new gold standard for pediatric lower pole stones? outcomes from two large european tertiary pediatric endourology centers. j endourol. 2021; 35:1479-1482. correspondence mohanarangam thangavelu, mbbs, febu, frcs (urology) (corresponding author) drtmohan@hotmail.com consultant urology, ysbyty gwynedd, bangor, ll57 2pw, united kingdom ajit sawant, mbbs, ms, mch (urology) drajitsawant@gmail.com ali abbas sayed, mbbs, ms, mch (urology) draliabbas09@gmail.com prakash pawar, mbbs, ms, mch (urology) praxpawar@gmail.com mohamed hamid, mbbs, ms, mch (urology) khanmohdhamid@gmail.com sunil patil, mbbs, ms, mch (urology) sunil7887@gmail.com vikas bhise, mbbs, ms, mch (urology) drvikasbhisegsmc@gmail.com jeni mathews, mbbs, ms, mch (urology) mathewjeni25@gmail.com raunak shewale, mbbs, ms, mch (urology) raunakshewale91@gmail.com department of urology, room number 219, college building, lokmanya tilak municipal medical college and general hospital, sion, mumbai 400022 (india) stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12990 1 original paper laparoscopic pyeloplasty was initially proposed for the treatment of ureteropelvic junction (upj) obstruction, with a success rate of over 90%. besides, laparoscopic pyeloplasty is associated with reduced hospital stay and postoperative complications compared to the open approach (5). however, intracorporeal suturing remains a technical challenge in the laparoscopic approach and may increase the operative time. the tedious learning curve of laparoscopic pyeloplasty constitutes another limitation (6). in this regard, robot-assisted pyeloplasty (rap) has emerged as a feasible alternative to overcome the technical difficulties of conventional laparoscopic pyeloplasty (7). the rap coveys all the advantages of conventional laparoscopic pyeloplasty while also decreasing the technical difficulties with intracorporeal suturing and shortening the operative time (8). it was reported that the high incidence of upj obstruction, which leads to a higher volume of cases, and the previous experience with laparoscopic surgery have improved the learning curve and outcomes of rap (6). the present study aimed to evaluate the learning curve of novice surgeons performing robotic-assisted pyeloplasty using a recently introduced robotic system on an ex-vivo porcine model. patients and methods study participants and robotic system we conducted a prospective ex-vivo model study that enrolled residents in the last year or new urologists. all participants were required to pass the european training in basic laparoscopic urological skills (e-blus) training program or to achieve the goals in its four tasks in a similar dry lab. we limited the participation in the present study to novice surgeons who did not have any prior experience with robotic surgery to perform four consecutive raps using the avatera system (avateramedical gmbh, germany). the avatera system is a robotic system that is based on activated robotic force feedback. the robotic cart is a four-arm component of the system that can be controlled by the surgeon and consists of three arms for controlling introduction: despite the increasing trend of utilizing robotic techniques in pyeloplasty, little is known about the learning curve for robot-assisted pyeloplasty (rap) amongst urologists with no prior robotic experience. therefore, the present study aimed to evaluate the learning curve of residents in the last year or recently appointed urologists performing rap using an ex-vivo model. methods: a prospective ex-vivo model study was conducted including participants who were either residents in the last year or recently appointed urologists. all participants had obtained the e-blus certification, or they were able to complete its 4 tasks successfully in a dry lab, without prior robotic experience. each participant performed four consecutive raps using the avatera system on an ex-vivo porcine model. the primary endpoint of the present study was the change in the average time to complete the anastomosis from the first to the fourth attempt. results: nine urologists and 8 residents were enrolled in this study. each surgeon demonstrated a reduction in the time to complete anastomosis from the 1st to 4th attempt with an average of value of 4.41 ± 1.06 minutes (p = 0.003). the decrease in time was statistically significant in both urologists and residents subgroups (4.5 ± 1.41 minutes p = 0.049 and 4.33 ± 0.71 minutes p = 0.035 respectively). conclusions: the training on the ex-vivo model could lead, in only a few attempts, to a significant improvement in skills and in the required time of experienced-naïve surgeons to complete an rap. key words: learning curve; pyeloplasty; robotic-assisted; robotics; avatera system. submitted 30 august 2024; accepted 6 september 2024 introduction the use of robotics in medical procedures has already been implemented in various medical specialties, including neuronavigation and stereotactic neurosurgery (1-3). in urology, applications of robotic systems have included laparoscopic camera control, percutaneous renal access, prostate biopsy, and transurethral resection of the prostate (4). the learning curve for robotic-assisted pyeloplasty in urologists with no prior robotic experience using an ex-vivo model: a prospective, controlled study abdullah ayed 1, panagiotis kallidonis 2, vasileios tatanis 2, angelis peteinaris 2, evangelos liatsikos 2, 3, gilles natchagande 4 1 department of surgery, university of bisha, bisha, saudi arabia; 2 department of urology, university hospital of patras, patras, greece; 3 medical university of vienna, vienna, austria; 4 university clinic of urology andrology, national university hospital center, hubert koutoukou maga of cotonou, benin. doi: 10.4081/aiua.2024.12990 summary archivio italiano di urologia e andrologia 2024; 96(4):12990 a. ayed, p. kallidonis, v. tatanis, et al. 2 the instruments (in a one-to-one master-slave fashion) and one arm to hold and control the endoscope. the second component of the system is a separate control unit for the operating surgeon. because of this, it is easily adaptable to the majority of operating rooms. it is equipped with a camera that has a resolution of full hd, while the single-use instruments are entirely articulated and can move in a range of 7 degrees of freedom. since the instruments are disposable, the possibility of crosscontamination is minimal, without the need for sterilization. the special shape of the eyepiece, which leaves the surgeon's ear and mouth uncovered, is an additional advantage that has been developed. this design makes it easier for the surgeon to communicate clearly with the operating team during surgical procedures (9). ethical standards the study has been carried out in accordance with the ethical standards laid down in the 1964 declaration of helsinki and its later amendments. the experiments were carefully designed and preapproved by the veterinary administration of the prefecture of western greece and conducted according to directive 2010/63/eu (http:// eurlex.europa.eu/lexuriserv/lexuriserv.do?uri= oj:l:2010: 276:0033:0079:en: pdf). animal model and experiment the assessment of the learning curve was based on conducting four consecutive ex-vivo anastomoses on a porcine model, with strict compliance to relevant guidelines for the use of laboratory animals. the porcine model consisted of the urinary bladder and both ureters, as described by sanchez hurtado et al. (10). it was placed upside-down, while the bladder was considered as a dilated pelvis and the ureter as the proximal part of it (figure 1). the normal ureterovesical junction (uvj) was considered as a stenotic ureteropelvic junction (upj). the supply of porcine urinary bladders was performed by a slaughterhouse. a 4-hour theoretical educational training course was performed to all the participants by the avateramedical, presenting the use and care of the robotic system. afterward, each participant completed a 2-hour e-blus task-based training to familiarize themselves with the instruments and the function of the robotic system. three trocars were placed in an artificial insufflated abdominal model based on the set-up of the conventional robotic pyeloplasty, followed by the application of three robotic arms; one for the endoscope, one for the metzenbaum scissors and the needle holder (the two instruments were exchanged during the procedure), and one for the atraumatic grasper (figure 2). the three ports were used as none of the participants have previous experience with rap. the ureter was resected horizontally in proximity to the renal hilum, followed by spatulation of its tip (figure 3). the anastomosis was performed using a vicryl 4-0 suture in a running way (figure 4). afterward, a 4f ureteral catheter was inserted from the distal part of the ureter, and indigo carmine (5 ml) was injected to ensure the patency and the water-tightness of the anastomosis. the time between the first incision and the completion of the indigo carmine test was recorded as the time needed to complete the up anastomosis. the anastomosis leakage events were also recorded. after the completion of the fourth attempt, the participants filled out a likert-scaled questionnaire figure 1. exvivo pyeloplasty model set-up. figure 2. incision of the ureteropelvic junction. figure 3. spatulation of the ureter. figure 4. ureteropelvic anastomosis. archivio italiano di urologia e andrologia 2024; 96(4):12990 3 robotic-assisted ureteropelvic anastomosis learning curve evaluating the vision, comfort and confidence to perform rap after the training. the overall questionnaire score ranged from 3-15 (1-5 points per question) (table 1). statistical analysis data were analyzed using the prism (graphpad, boston, usa) version 9. the time to complete the anastomosis and the reduction in time were described using mean, standard deviation (sd), median and range, while the percentage of change was calculated. the overall questionnaire rating was described using mean, sd, median and range. the trend of change in the time to complete the anastomosis was analyzed using paired t-test. a twotailed p-value < 5% was considered statistically significant. the learning curve factor (b factor) and the learning percentage (p percentage) is calculated based on the cumulative average model (wright model) (11, 12). results in total 9 urologists and 8 residents on the final year of residency were included into the study. the urologists had a competency of basic laparoscopic operations (including laparoscopic varicocelectomy, laparoscopic hernia repair and laparoscopic nephrectomy), while the residents had a prior experience of participation in at least 20 laparoscopic operations (including radical nephrectomies, partial nephrectomies, radical prostatectomies and pyeloplasties). each participant successfully completed the four attempts of rap. each surgeon demonstrated a reduction in the time to complete anastomosis from the 1st to 4th attempts, as shown in figure 5. there was a significant improvement, as demonstrated by the significant decrease in the average time to complete the anastomosis from 33.41 ± 3.8 minutes at the first attempt to 29 ± 4.2 minutes at the fourth attempt (p = 0.003). the mean reduction in the time to complete the pyeloplasty was 4.412 (4.96 to 3.87) minutes, with a percentage reduction of 13.5% (table 2). among the 1st attempt of all the participants, 4 events of anastomosis leakage occurred, while 2 events of anastomosis leakage were noticed among the 2nd attempts. on the 3rd and 4th attempts, no anastomosis leakage was observed. the mean overall score in the postoperative evaluation questionnaire was 11.94 ± 1.09 (median value: 12, range 10-14). in detail, the mean vision score, the mean comfort score and the mean confidence score were 4.41 ± 0.62, 4.18 ± 0.64 and 3.35 ± 0.49 respectively. the b factor of the overall learning curve was -0.965 and the p learning percentage is 1.95. a stratification of the participants was performed into urologists and residents groups based on prior laparoscopic experience. in both groups, the reduction in time was achieved at a statistically significant level. in urologist groups, the 1st and 4th rap was completed in a mean value of 32.89 ± 3.79 minutes and 28.56 ± 4.19 minutes respectively (p = 0.0351). the time to accomplish the anastomosis was diminished by a mean value of 13.44%, as it needed 4.33 ± 0.71 fewer minutes (table 3). the mean overall score of the table 1. postoperative evaluation questionnaire (1 being the lowest and 5 being the highest score). parameter scores vision 1 2 3 4 5 comfort 1 2 3 4 5 confidence 1 2 3 4 5 figure 5. the trend of change in time required to complete the pyeloplasty between the 1st and 4th attempts. table 2. the required time to complete the pyeloplasty in the 1st and 4th attempts (paired t-test). variables 1st anastomosis 4th anastomosis p value time to complete the pyeloplasty (min) mean ± sd 33.41 ± 3.8 29 ± 4.2 < 0.003* median (range) 34 (28-39) 30 (23-36) time reduction (min) mean ± sd 4.41 ± 1.06 median (range) 4 (3-7) % of reduction 13.47% table 3. the required time to complete the pyeloplasty in the 1st and 4th attempts in urologists group (paired t-test). variables 1st anastomosis 4th anastomosis p value time to complete the pyeloplasty (min) mean ± sd 32.89 ± 3.79 28.56 ± 4.19 < 0.0351* median (range) 33 (29-39) 28 (25-35) time reduction (min) mean ± sd 4.33 ± 0.71 median (range) 4 (3-5) % of reduction 13.44% archivio italiano di urologia e andrologia 2024; 96(4):12990 a. ayed, p. kallidonis, v. tatanis, et al. 4 postoperative questionnaire was 12.33 ± 1.12 (vision 4.44 ± 0.73, comfort 4.44 ± 0.53 and confidence 3.44 ± 0.53). the b factor of the urologists subgroup’s learning curve was -2.90. in the residents group, the time needed to perform the 1st and 4th pyeloplasty was 34 ± 3.89 minutes and 29.5 ± 4.47 minutes respectively (p = 0.0497). the mean difference in time between the two attempts was 4.5 ± 1.41 minutes leading to a mean reduction ratio of 13.50% (table 4). the mean postoperative questionnaire score was 11.50 ± 0.93 (vision 4.38 ± 0.52, comfort 3.88 ± 0.64 and confidence 3.25 ± 0.46). the b factor of the residents subgroup’s learning curve was -2.89. discussion the results of the current study showed that the time of anastomosis reduced by 7.7% to 20.7%, with an average reduction of 13.5%, after four pyeloplasties. a pilot study by sung et al., compared robotic-assisted and laparoscopic pyeloplasty. based on the results, no significant difference in total surgical time (115.2 minutes for robotic and 94.5 minutes for laparoscopic, p = 0.2), anastomosis time (75.7 minutes for robotic and 64.3 minutes for laparoscopic, p = 0.3), and the number of suture bites per ureter (13.0 for robotic and 12.5 for traditional, p = 0.8) was noticed. five out of 6 robotic and 3 out of 4 laparoscopic pyeloplasties presented with immediate watertight anastomosis (13). lorincz et al. conducted a study to investigate the feasibility of robot-assisted minimally invasive pyeloplasty in piglets. all seven piglets underwent the procedure without complications, and the results showed that robotic assistance enhanced surgical dexterity and precision. the mean setup and anastomosis times were 19 minutes and 51 minutes, respectively. the results demonstrated that robot-assisted pyeloplasty is a technically feasible procedure with acceptable morbidity in an animal model (14). chammas jr. and his colleagues conducted a study to assess the learning curve for robotic pyeloplasty. the study included in total 100 procedures performed on 127 patients and divided them into three groups (open pyeloplasty, laparoscopic pyeloplasty, and rap) to analyze the learning curve. the results showed a significant decrease in surgical time and hospital stay after 25 cases. the median anastomosis time and operative time were decreased in the rap as the number of procedures were increased, without significant difference (p > 0.05) (15). the reduction in anastomosis time in our study was observed earlier, indicating that using the avatera system could be associated with a shorter learning curve. the ex-vivo training model consisted of a porcine urinary bladder accompanied by both ureters. this model was evaluated in details by sanchez-hurtado and his colleagues (10). the authors conducted the evaluation of face and content validity and enrolled 127 urologists who performed various laparoscopic ureteric reconstructive techniques. afterward, the participants fulfilled a likertscaled questionnaire. the final rating range could be 1-10 points. the mean rating was 9.19 ± 0.82, while the comments performed by the expert urologists who participated were positive. in robotic pyeloplasty, the learning curve is particularly important as the procedure is technically demanding and requires a high level of dexterity and precision (16). the results of the study indicate that residents and new urologists can achieve a reduction in the time of anastomosis after four attempts at ex vivo robotic pyeloplasty using the avatera system. the reduction in the time of anastomosis suggests that the participants were able to improve their proficiency in the performance of the procedure, resulting in a reduction in the overall time required to complete the anastomosis. this improvement may be translated into ameliorated surgical outcomes, such as reduced complication rates and improved patient outcomes. in contrast, in a retrospective study conducted by sorensen et al., 33 children, who underwent rap between 2006 and 2009, were compared to a matched group who underwent open pyeloplasty. the results showed that the mean overall operative time was 90 minutes longer (38%) for the rap arm. after 15 to 20 robotic cases, the overall operative time was consistently within 1 sd of the average open pyeloplasty time with no significant difference in overall operative time. the decrease in overall operative time was due to a decrease in anastomosis time rather than access time (17). the learning curve in robot-assisted laparoscopic pyeloplasty is influenced not only by individual surgical experience but also by the experience of the surgical team. sampinato et al. reported that junior surgeons were associated with a more rapid learning process with an earlier inflection point and comparable levels of expertise as senior surgeons after seven procedures (18). in our study, the progress of the less experienced residents’ group was greater than the urologists’ group. more precisely, the mean decrease in time was 4.33 ± 0.71 minutes and 4.5 ± 1.41 minutes for the residents’ and urologists’ groups respectively. it is also worth noting that all participants in the study obtained the e-blus certification or could complete the four tasks in the dry lab, indicating that they had a basic level of proficiency in the use of laparoscopic surgery. the certification and dry lab experience likely provided a foundation for the participants to build upon during the ex vivo pyeloplasty procedure, contributing to the observed reduction in the time of anastomosis. dothan et al. reported that previous experience in open and laparoscopic pyeloplasty was associated with a shorter learning curve in the robotic approach (15). we acknowledge the existence of some limitations in the present study. the present study was based on ex-vivo models, which are limited in replicating the complexities of human anatomy, including blood flow, tissue response, table 4. the required time to complete the pyeloplasty in the 1st and 4th attempts in residents group (paired t-test). variables 1st anastomosis 4th anastomosis p value time to complete the pyeloplasty (min) mean ± sd 34 ± 3.89 29.5 ± 4.47 < 0.0498* median (range) 35 (29-39) 30 (23-36) time reduction (min) mean ± sd 4.5 ± 1.41 median (range) 4 (3-7) % of reduction 13.50% archivio italiano di urologia e andrologia 2024; 96(4):12990 5 robotic-assisted ureteropelvic anastomosis learning curve and variability among patients. as a result, the learning experience may not accurately reflect the challenges a surgeon would face during an actual procedure. besides, exvivo models do not allow for the possibility of encountering intraoperative complications, such as bleeding or unexpected anatomical variations. this limits the urologist's ability to gain experience in managing these challenges in a real-life setting. lastly, in our study, all the participants had obtained or were capable to obtain the eblus certification. thus, the results of the ex-vivo study may not be generalizable to all urologists, as individual learning curves can vary based on prior experience, skill level, and other factors. conclusions in conclusion, our study demonstrates that ureteropelvic anastomosis was precisely, effectively, and comfortably performed using the robotic system. owing to its simplicity, residents and new urologists can improve their competency in the performance of robotic-assisted pyeloplasty using a porcine ex-vivo model. acknowledgement the authors are thankful to the deanship of graduate studies and scientific research at university of bisha for supporting this work through the fast-track research support program. references 1. mao jz, agyei jo, khan a, et al. technologic evolution of navigation and robotics in spine surgery: a historical perspective. world neurosurg. 2021; 145:159-67. 2. stumpo v, staartjes ve, klukowska am, et al. global adoption of robotic technology into neurosurgical practice and research. neurosurg rev. 2021; 44:2675-87. 3. qureshi ya, mohammadi b. robotic oesophago-gastric cancer surgery. ann r coll surg engl. 2018; 100(6_sup):23-30. 4. thaly r, shah k, patel vr. applications of robots in urology. j robot surg. 2007; 1:3-17. 5. atalla ma, dovey z, kavoussi lr. laparoscopic versus robotic pyeloplasty: man versus machine. expert rev med devices. 2010; 7:27-34. 6. morales-lopez ra, perez-marchan m, perez brayfield m. current concepts in pediatric robotic assisted pyeloplasty. frontiers in pediatrics. 2019; 7:4. 7. kearns jt, gundeti ms. pediatric robotic urologic surgery-2014. j indian assoc pediatr surg. 2014; 19:123-8. 8. howe a, kozel z, palmer l. robotic surgery in pediatric urology. asian j urol. 2017; 4:55-67. 9. liatsikos e, tsaturyan a, kyriazis i, et al. market potentials of robotic systems in medical science: analysis of the avatera robotic system. world j urol. 2022; 40:283-9. 10. sanchez hurtado ma, diaz-guemes martin-portugues i, correa martin l, et al. development and assessment of an ex-vivo bench model aimed at laparoscopic ureteric reconstructive techniques. j pediatr urol. 2021; 17:753-5. 11. wright tp. factors affecting the cost of airplanes. journal of the aereonautical science 1936; 3:122. 12. tilindis j, kleiza v. learning curve parameter estimation beyond traditional statistic. applied mathematical modelling 2017; 45:768783. 13. sung gt, gill is, hsu th. robotic-assisted laparoscopic pyeloplasty: a pilot study. urology. 1999; 53:1099-103. 14. lorincz a, knight cg, kant aj, et al. totally minimally invasive robot-assisted unstented pyeloplasty using the zeus microwrist surgical system: an animal study. j pediatr surg. 2005; 40:418-22. 15. dothan d, raisin g, jaber j, kocherov s, chertin b. learning curve of robotic-assisted laparoscopic pyeloplasty (ralp) in children: how to reach a level of excellence? j robot surg. 2021; 15:93-7. 16. pakkasjärvi n, krishnan n, ripatti l, anand s. learning curves in pediatric robot-assisted pyeloplasty: a systematic review. j clin med. 2022; 11:6935. 17. sorensen md, delostrinos c, johnson mh, et al. comparison of the learning curve and outcomes of robotic assisted pediatric pyeloplasty. j urol 2011; 185(6 suppl):2517-22. 18. spampinato g, binet a, fourcade l, et al. comparison of the learning curve for robot-assisted laparoscopic pyeloplasty between senior and junior surgeons. j laparoendosc adv surg tech a. 2021; 31:478-483. correspondence abdullah ayed, md (corresponding author) aayed@ub.edu.sa department of surgery, college of medicine, university of bisha, bisha 61922, p.o box 551, saudi arabia panagiotis kallidonis, md vasileios tatanis, md angelis peteinaris, md department of urology, university hospital of patras, patras, greece evangelos liatsikos, md department of anesthesiology and icu, university hospital of patras, patras, greece medical university of vienna, vienna, austria natchagande gilles, md university clinic of urology andrology, national university hospital center, hubert koutoukou maga of cotonou, benin conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12829 1 original paper abdominoperineal or transperineal approach. all vuas treatment may aggravate existing urinary incontinence or cause one to occur de novo which patients should always be informed about before undergoing any vuas-related surgery. following that, by consenting to the treatment of vuas, the patient should be prepared for the necessity of further treatment for urinary incontinence. the aim of our study was to retrospectively evaluate the outcomes of transperineal reanastomosis (tpra) as a salvage treatment option for a selected group of patients who still suffer from vuas after either repeated, unsuccessful endoscopic procedures or the recurrence of vuas after prior reanastomosis. methods the study was designed as a retrospective case series study. we searched our medical records database for patients who underwent tpra between 2016 and 2022. then, we collected the data regarding their medical history as well as cancer treatment history. follow up included evaluation of continence, sustenance of patency, and need for additional procedures. all patients were treated with a transurethral procedure at least once prior to trpa. all patients had been informed and fully accepted the possibility of subsequent urinary incontinence after trpa. patency was evaluated with retrograde urethrogram (rug) and voiding cystourethrogram (vcug). in case of any doubt, endoscopic evaluation of lower urinary tract was performed. surgical technique patient is placed in a lithotomy position. through a median perineal incision the bulbous urethra is visualized. bulbocavernosus muscles are cut, and the bulb is mobilized both distally and proximally. both arteries of bulb of penis (if still existing) are cut and ligated. the urethra is cut off at the distal end of stenosis at the line between bulbous and membranous urethra, at the level of the diaphragm of pelvis. a flexible cystoscope is inserted through the cystostomy into the bladder neck. the scar tissue is incised under visual guidance of the cystoscope light. all fibrous tissue is dissected, and the patency of the newly formed vesical orifice is tested with 30fr bougie. the scar tissue purpose: to evaluate transperineal reanastomosis (trpa) combined with incontinence surgery as a complex treatment for recurring vesicourethral anastomosis stenosis (vuas) after radical prostatectomy (rp). methods: retrospective analysis of 8 patients who underwent trpa for recurring vuas. detailed preoperative and follow up data were assessed. results: mean follow up lasted 47 months (range 17-77) with mean age being 63.4 years (range 61-70). all patients achieved patency and 87.5% (7/8) maintained it to the end of follow up. however, four of them required additional procedures to retain patency. six underwent incontinence surgery – artificial urinary sphincter (aus) implantation – after which one cuff erosion occurred. in the end 62.5% (5/8) of patients achieved patent urethra and continence. conclusions: trpa combined with incontinence surgery is a reasonable treatment for patients with recurrent vuas. nonetheless, this is a set of difficult surgeries that may ultimately end in failure, i.e. the inability to restore urethral patency, urinary incontinence or urinary diversion, hence they should be performed by experienced surgeons. key words: transperineal reanastomosis; vesicourethral anastomosis stenosis; radical prostatectomy complications. submitted 18 july 2024; accepted 25 july 2024 introduction prostate cancer is the second most common cancer in men worldwide (1). with the rise of robot-assisted laparoscopic approach to radical prostatectomy (rp), the frequency of complications has been declining, one of them being vesicourethral anastomosis stenosis (vuas) (2). though rare, it is a serious condition of complicated nature. patients usually seek medical help upon having problems with micturition post-prostatectomy. in more severe cases it may lead to acute urinary retention and require urgent care. endoscopic procedures remain first line treatment that can be repeated if needed. according to a recently published meta-analysis by delchet et al. their overall success rate is between 62.9% and 72.8% with a negative influence on the outcomes of previous radiotherapy (3). if the transurethral approach fails, the next line is open de novo reconstruction (reanastomosis) which can be performed via abdominal, outcomes of transperineal reanastomosis as a salvage treatment for recurrent vesicourethral anastomosis stenosis after radical prostatectomy piotr gwara, łukasz białek, marta rydzińska, jakub dobruch, michał skrzypczyk department of urology, centre of postgraduate medical education, independent public hospital of prof. w. orlowski, warsaw, poland. doi: 10.4081/aiua.2024.12829 summary archivio italiano di urologia e andrologia 2024; 96(4):12829 p. gwara, ł. białek, m. rydzińska, j. dobruch, m. skrzypczyk 2 around the bulbous urethra is dissected as well. eight polysorb (5/0) sutures are placed on the bladder and the urethra, and the knots are tied tension-free. after checking for leaks the 16fr foley transurethral catheter is placed. via a separate incision a redon drain is installed with the end close to the anastomosis. the wound is closed in three layers with absorbable, running 3/0 suture. the skin is closed using absorbable, interrupted 3/0 sutures. finally, a 16fr suprapubic catheter is placed (2, 4). after three to four weeks rug and vcug are performed and, if there is no leakage, both catheters are removed. results eight patients underwent trpa between 02/2016 and 05/2022, all performed by the same surgeon (ms). patients’ detailed overview is presented in table (1). all patients received previous vuas treatment with two having undergone open reanastomosis via abdominal approach. all of them suffered from complete erectile dysfunction. one patient underwent artificial urethral sphincter (aus) placement before trpa, which was complicated by cuff erosion and later aus removal. all patients presented with a patent anastomosis in rug and vcug post-trpa. all patients had a history of previous treatment with multiple transurethral procedures, including direct visual internal urethrotomy (dviu), urethral dilatation, which were all failed. the median stenosis length estimated in urethrography was 28 mm. table (2) presents detailed overview of each patient’s treatment history and follow up. all patients were incontinent after tpra which was to be expected. half of them needed additional intervention due to stricture, after which all of them but one are stricture-free. out of seven patients with patent urethra six were willing to treat urinary incontinence and were treated with aus implantation. there was one case of urethral erosion and required aus removal. he is scheduled for another aus to be implanted. the remaining 5 patients are socially continent. one patient after table 1. patients' characteristics. number of patients 8 mean age (years) 63.4 (range 61-70) mean follow up time (months) 47 (range 17-77) approach of rp open 5 laparoscopic 3 history of radiotherapy 2 t staging 2a 1 2c 5 3a 1 3c 1 gleason score 5 (2+3) 2 6 (2+4) 1 6 (3+3) 3 7 (3+4) 1 7 (4+3) 1 mean length of defect (cm) 2.8 (range 2-5) vuas character non-obliterative 1 obliterative 7 mean vesical capacity (ml) 225 (range 180-300) mean urethral rest (months) 14.9 (range 6-23) mean time between rp and tpra (months) 46 (range 28-84) patients with cystostomy before tpra 8 comorbidities hypertension 6 diabetes mellitus 2 mean number of prior endoscopic procedures 4.9 (range 1-15) history of previous open reanastomosis 2 mean bleeding volume (ml) 250 (range 100-500) rp: radical prostatectomy; tpra: transperineal reanastomosis. table 2. detailed patients’ treatment history and follow up. patient 1 2 3 4 5 6 7 8 age (years) 70 63 71 64 61 69 61 64 previous vuas treatment 5x tur, 10x ud 10x tur, trpa dviu, tur 2x dviu, tur tui 5x tur aus, 2x dviu trapa, dviu time of follow up (months) 76 64 77 44 47 28 17 22 vuas characteristics obliterative obliterative non-obliterative obliterative obliterative obliterative obliterative obliterative time from rp 32 30 44 42 32 77 84 28 prior radiotherapy n n y n n n y n stenosis length (mm) 20 40 20 25 20 20 30 50 blood loss (ml) 500 150 400 500 100 100 150 100 postoperative complications none acs, dvt none none none none urethrocutaneous fistula, hematoma osteitis pubis additional treatment none 2x dviu, tur dviu none dviu none bricker ileal conduit tpra incontinence treatment aus (zsi375*) refuses aus (zsi375*) aus (zsi375*) aus (ams 800**) aus (ams 800**) aus (ams 800**) time between vuas and incontinence treatment (months) 24 12 16 26 16 20 incontinence treatment complications none none none none none cuff erosion continence (0-1 pads) at the end of follow up continent incontinent continent continent continent continent incontinent daily pad use 0 5 1 0 1 1 4 tur: transurethral resection; ud: urethral dilatation; tpra: transperineal reanastomosis; dviu: direct vision internal urethrotomy; tui: transurethral incision; trapa: transabdominoperineal reanastomosis; aus: artificial urinary sphincter; acs: acute compartment syndrome; dvt: deep venous thrombosis; *zephyr surgical implants, geneva, swittzerland; **boston scientific, malborough; massachusetts, united states of america. archivio italiano di urologia e andrologia 2024; 96(4):12829 3 transperineal reanastomosis for vesicourethral anastomosis stenosis trpa developed urethrocutaneous fistula which was later complicated by osteitis pubis. eventually he underwent urinary diversion with bricker ileal conduit. discussion vuas is a complication of rp that is recently observed rarer. after open rp its incidence has been reported to be between 2.6% (5) and 26% (6) but with the emergence of robot-assisted laparoscopic approach the incidence has declined to 0.2% (7)-1.6% (8). britton et al. (9) have found a positive correlation between vuas frequency and adjuvant radiation, bmi, prostate volume, urine leak, blood transfusion and nonnerve-sparing technique. they have also reported robot assistance and complete nerve sparing to be related to lower occurrence of stenosis (or 0.39, p < 0.01 and or 0.63, p < 0.01, respectively). a mean time of vuas occurrence after rp is considered to be 3.4 months (9). although rare, management of vuas remains a significant surgical dilemma and substantially affect patients quality of life. it also should be noted the treatment of vuas affects continence in most patients, thus it is crucial to appropriately inform patients about possible consequences of treatment (10). endoscopic procedures remain a first line treatment for patients with non-obstructive vuas. it offers varied results with overall success rate between 13 and 73 (3, 11). its low invasiveness and possible repeated nature are the reason for its wide acceptance by patients. open reanastomosis remains a treatment option in the cases of recurrent stenosis after failed multiple endoscopic interventions. transperineal approach offers the best results with success rate of 93%, reaching 100% after a subsequent endoscopic procedure (12), compared to 60% (95% after subsequent endoscopic procedure) for abdominal (retropubic) approach (10) and 83% for abdominoperineal approach (13). while operating by retropubic access, one must manoeuvre in scar tissue after rp which hinders preparing the anastomosis. moreover, transperineal approach is much less invasive than retropubic approach or combined abdominoperineal approach. the concept of trpa is similar to that of elaborate pelvic fracture urethral injury (pfui) repair, involving complete mobilization of the bulbar urethra, crura separation, and in some cases inferior partial pubectomy for bladder neck access. nonetheless, mundy and andrich characterize trpa as far more challenging than standard pfui repair, necessitating a surgeon with substantial experience in complex pfui procedures and the skill to employ various supplementary techniques when needed (4). unfortunately, mobilization of the urethra during the surgery usually leads to damaging the sphincter which typically leads to incontinence. thus, this access is commonly utilized in patients with preoperative urinary incontinence. favourably the incontinence can be treated afterwards with good effect with sling or aus implantation (14). ullate et al. demonstrated that implanting the adjustable trans-obturator male system (atoms) in patients with urinary incontinence who were previously treated due to urethral stricture or bladder neck stenosis is not related with higher rate of complications such us surgical revision, device explantation or overactive bladder syndrome symptoms de novo. they observed, however, that 38% of the patients with treated stricture achieved continence (≤ 20 ml 24-h pad test) compared to 83% of those without. moreover, multivariate analysis revealed that previous stricture was one of the predictive factors of failure (15). the aus implantation may come with a range of complications. however, with proper technique and surgical experience its risk can be significantly lowered. mechanical complications, regarding the device itself, occur at overall rate of 6.2% with the most susceptible part being cuff. among nonmechanical complications cuff erosion is the one requiring most consideration. it is most frequent during first two years after aus implantation with overall prevalence of 8.5% (16). the available literature data does not provide a clear answer to the question of optimal urethral management during aus explantation, and the options include urinary diversion by transurethral and/or suprapubic catheterization, urethrorraphy, and in situ urethroplasty (17). there are conflicting data on the safety of aus implantation in patients who have had transperineal surgery in the past. it seems that previous unsuccessful sling procedure does not increase the risk of complications e.g. urethral injury or erosion (18, 19). on the other hand previous urethroplasty or aus explantation due to erosion seems to negatively impact the risk of failure (20, 21). this could also be the reason for cuff erosion in the patient in our case series, who previously had three transperineal procedures. in our series 62.5% (5/8) of patients with refractory vuas have fully achieved the goal of treatment continence with patent urethra. in addition, even a higher percentage of patients in our study declare satisfaction with the results of the treatment carried out. this is in concordance with the study by reiss et al. (12), in which good results regarding quality of life after trpa despite aggravation of incontinence in 60% of patients have been noted. extended follow-up also shows high success rate of tpra and high percentage of aus implantation (22). nikolavsky et al. (23) have reported a case series of 12 patients who underwent open reanastomosis with a patency rate of 93% (11/12) and continence in 72.7% (8/11) of the patients at the end of follow-up with a median time of 75.5 months. immediately after reconstruction only 33.3% (4/12) of patients were continent whereas 75% (6/8) were continent at the end of follow up, if incontinent patients had undergone incontinence treatment. however, having used different approaches abdominal, abdominoperineal and perineal, with only 25% (3/12) being perineal their results are not easily compared to ours. there are also descriptions in the literature of case series in which buccal mucosa graft (bmg) was used in the treatment of vuas. shahrour et al. presented a series of 4 patients who underwent dorsal bmg urethroplasty for vuas (24). dolezel et al. recently published descriptions of the treatment of vuas via ventral bmg urethroplasty and endourethroplasty with bmg (25). these techniques are, however, reserved for the patients with non-obliterative strictures and the capability of its usage still needs confirmation. limitations of this case series are its retrospective character as well as relatively small number of cases. however, with vuas being a rare condition, and compared to the available literature, such a small number is to be expected. archivio italiano di urologia e andrologia 2024; 96(4):12829 p. gwara, ł. białek, m. rydzińska, j. dobruch, m. skrzypczyk 4 conclusions trpa is a valid treatment option for patients with obstructive, recurrent vuas. it offers satisfactory success rates and, at the same time, provides surgeons with optimal field visualisation and access unhindered by scar tissue. however, achieving a patent urethra is only one step in vuas treatment since reconstruction usually causes incontinence de novo or aggravates one existing prior. with that in mind, patients should always be informed to expect two-step treatment firstly open reconstruction and afterwards incontinence surgery (aus or sling implantation, depending on patient’s preference and device availability). this way we limit patients’ dissatisfaction and improve their adherence. what deserves to be emphasized, however, is that even for an experienced surgeon, this is a set of difficult surgeries that may ultimately end in failure, i.e. the inability to restore urethral patency, urinary incontinence or urinary diversion. references 1. bergengren o, pekala kr, matsoukas k, et al. 2022 update on prostate cancer epidemiology and risk factors-a systematic review. eur urol. 2023; 84:191-206. 2. rosenbaum cm, fisch m, vetterlein mw. contemporary management of vesico-urethral anastomotic stenosis after radical prostatectomy. front surg. 2020; 7:587271. 3. delchet o, nourredine m, gonzález serrano a, et al. post-prostatectomy anastomotic stenosis: systematic review and meta-analysis of endoscopic treatment. bju int. 2024; 133:237-45. 4. mundy ar, andrich de. posterior urethral complications of the treatment of prostate cancer. bju int. 2012; 110:304-25. 5. breyer bn, davis cb, cowan je, et al. incidence of bladder neck contracture after robot-assisted laparoscopic and open radical prostatectomy. bju int. 2010; 106:1734-8. 6. hu jc, gold kf, pashos cl, et al. role of surgeon volume in radical prostatectomy outcomes. j clin oncol off j am soc clin oncol. 2003; 21:401-5. 7. carlsson s, nilsson ae, schumacher mc, et al. surgery-related complications in 1253 robot-assisted and 485 open retropubic radical prostatectomies at the karolinska university hospital, sweden. urology. 2010; 75:1092-7. 8. parihar js, ha ys, kim iy. bladder neck contracture-incidence and management following contemporary robot assisted radical prostatectomy technique. prostate int. 2014; 2:12-8. 9. britton cj, sharma v, fadel ae, et al. vesicourethral anastomotic stenosis following radical prostatectomy: risk factors, natural history, and treatment outcomes. j urol. 2023; 210:312-22. 10. pfalzgraf d, beuke m, isbarn h, et al. open retropubic reanastomosis for highly recurrent and complex bladder neck stenosis. j urol. 2011; 186:1944-7. 11. labossiere jr, cheung d, rourke k. endoscopic treatment of vesicourethral stenosis after radical prostatectomy: outcomes and predictors of success. j urol. 2016; 195:1495-500. 12. reiss cp, pfalzgraf d, kluth la, et al. transperineal reanastomosis for the treatment for highly recurrent anastomotic strictures as a last option before urinary diversion. world j urol. 2014; 32:1185-90. 13. theodoros c, katsifotis c, stournaras p, et al. abdomino-perineal repair of recurrent and complex bladder neck-prostatic urethra contractures. eur urol. 2000; 38:734-740. 14. flynn bj, webster gd. evaluation and surgical management of intrinsic sphincter deficiency after radical prostatectomy. rev urol. 2004; 6:180-6. 15. ullate a, arance i, virseda-chamorro m, et al. atoms (adjustable trans-obturator male system) in patients with postprostatectomy incontinence and previously treated urethral stricture or bladder neck contracture. j clin med. 2022; 11:4882. 16. van der aa f, drake mj, kasyan gr, et al. . the artificial urinary sphincter after a quarter of a century: a critical systematic review of its use in male non-neurogenic incontinence. eur urol. 2013; 63:681-9. 17. białek ł, frankiewicz m, adamowicz j, et al. urethral management after artificial urinary sphincter explantation due to cuff erosion. cent eur j urol. 2023; 76:322-4. 18. lentz ac, peterson ac, webster gd. outcomes following artificial sphincter implantation after prior unsuccessful male sling. j urol. 2012; 187:2149-53. 19. fisher mb, aggarwal n, vuruskan h, singla ak. efficacy of artificial urinary sphincter implantation after failed bone-anchored male sling for postprostatectomy incontinence. urology. 2007; 70:942-4. 20. lai hh, boone tb. complex artificial urinary sphincter revision and reimplantation cases--how do they fare compared to virgin cases? j urol. 2012; 187:951-5. 21. mcgeady jb, mcaninch jw, truesdale md, et al. artificial urinary sphincter placement in compromised urethras and survival: a comparison of virgin, radiated and reoperative cases. j urol. 2014; 192:1756-61. 22. schuettfort vm, dahlem r, kluth l, et al. transperineal reanastomosis for treatment of highly recurrent anastomotic strictures after radical retropubic prostatectomy: extended follow-up. world j urol. 2017; 35:1885-90. 23. nikolavsky d, blakely sa, hadley da, et al. open reconstruction of recurrent vesicourethral anastomotic stricture after radical prostatectomy. int urol nephrol. 2014; 46:2147-52. 24. shahrour w, hodhod a, kotb a, et al. dorsal buccal mucosal graft urethroplasty for vesico-urethral anastomotic stricture postradical prostatectomy. urology. 2019; 130:210. 25. doležel j, hrabec r, uher m, et al. substitution urethroplasty with buccal mucosal graft in the management of stricture of vesicourethral anastomosis or membranous urethra: single-institution long-term experience with perineal approach and endourethroplasty. urology. 2024; s0090-4295(24)00418-7. correspondence piotr gwara, md p.gwara@wp.pl łukasz białek, md lukaszbtm@gmail.com marta rydzińska, md martaaga.drazkiewicz@gmail.com jakub dobruch, md jdobruch@cmkp.edu.pl michał skrzypczyk, md, phd (corresponding author) michalskrzypczyk@gmail.com department of urology, centre of postgraduate medical education, independent public hospital of prof. w. orlowski, czerniakowska street 231, 00-416 warsaw, poland conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13759 1 original paper classifying it as a urological emergency (1, 2). recent global estimates highlight the prevalence of urolithiasis, emphasizing the increasing need for efficient and safe treatment strategies (1). as the incidence of ureteral stones varies, the need for emergency intervention due to acute obstruction becomes a consistent clinical challenge. advances in endourological techniques, particularly emergency ureteroscopy (urs) using semirigid ureteroscopes, have revolutionized the management of ureteral stones (3, 4). emergency urs, defined by the immediate intervention required to address acute ureteral obstruction and its associated complications, has become a primary modality for diagnosis and treatment, including ureteroscopic lithotripsy (3, 5). this shift towards minimally invasive approaches has improved patient outcomes; however, it is crucial to acknowledge and address the potential for adverse events, especially in emergency settings where patient acuity, the degree of obstruction, and resource availability may impact outcomes (3). the use of pneumatic lithotripsy is a common method for stone fragmentation. the spectrum of adverse events associated with emergency urs ranges from minor, such as mucosal abrasions and stone migration, to more severe events like ureteral perforation or avulsion (3, 4). while advancements in urs technology and surgical techniques have improved stone-free rates (approaching 90-97%), the emergency nature of the procedure can influence the incidence and severity of complications (4-6). specifically, in the setting of acute obstruction, challenges include increased tissue edema, altered ureteral anatomy, and the potential for infection, which may affect the surgeon's ability to manage the stones. prior research has identified several factors associated with adverse events in urs for ureteral stone treatment (4, 6-9). these include stone characteristics (size, density, location), patient-specific variables (age, comorbidities, and anatomy), and procedural factors (instrument type, surgical experience, and the presence of infection). in the context of emergency urs, the interplay of these factors requires specific investigation to optimize patient care. despite the importance of this topic, there is a relative lack of research focusing on adverse events in emergency urs settings, particularly within the context of resource-limited environments. this study aims to anabackground: data on complications associated with emergency ureteroscopy for ureteral stones are limited, particularly in developing countries. this study investigates factors contributing to complications in emergency ureteroscopy utilizing a pneumatic semirigid ureteroscope (urs). materials and methods: this retrospective analysis included 266 patients with ureteral stones who underwent emergency ureteroscopy using a pneumatic semirigid urs from 2018 to 2023. we extracted comprehensive data on patient demographics, stone characteristics, intraoperative and postoperative complications, and stone-free rate (sfr) from medical records, subsequently subjected to statistical analysis. factors linked to complications were explored through univariate and multivariate analyses. results: the mean stone size was 9.1 ± 4.9 mm, with the majority (n = 181, 71.3%) located in the mid-ureter. the mean operative duration was 57.7 ± 7.3 minutes. the overall complication rate was 10.2%, with intraoperative complications in 16 patients (6.0%), including mucosal damage (3.4%), stone up-migration (3.0%), and one ureteral perforation (0.4%). postoperative complications occurred in 13 patients (4.9%), primarily fever (2.6%), followed by hematuria (1.1%). additional complications included febrile urinary tract infections (utis), pyelonephritis, and one mortality. the overall sfr was 85.3%, with 39 patients (14.7%) demonstrating residual stones. significant predictive factors for complications included larger stone size (adjusted odds ratio [aor]: 1.3; 95% confidence interval [ci]: 1.15-1.39, p < 0.0001) and proximal ureteral stones (aor: 4.9; 95% ci: 1.3118.23, p = 0.0182). conclusions: emergency ureteroscopy using a semirigid urs demonstrated favorable outcomes in treating ureteral stones, characterized by minimal complications and an acceptable sfr. emphasizing appropriate instrument selection, surgical expertise, and technique is crucial in minimizing adverse events, particularly for large and upper ureteral stones. key words: emergency ureteroscopy, pneumatic semirigid ureteroscope, surgical complications, ureteral stones, urolithiasis. submitted 24 february 2025; accepted 25 february 2025 introduction ureteral stones represent a significant and growing public health burden, necessitating timely and effective interventions due to the acute pain associated with ureteric colic, complications in emergency ureteroscopy for ureteral stone treatment: a retrospective study khalil al-naggar 1, faisal ahmed 1, khaled al-kohlany 2, ibrahim alnadhari 3, 4 1 department of urology, school of medicine, ibb university, ibb, yemen; 2 department of urology, college of medicine, sana'a university, sana'a, yemen; 3 urology section, department of surgery, al wakra hospital, hamad medical corporation, al wakra, qatar; 4 department of surgery, college of medicine, qatar university, doha, qatar. doi: 10.4081/aiua.2025.13759 summary archivio italiano di urologia e andrologia 2025; 97(2):13759 k. al-naggar, f. ahmed, k. al-kohlany, i. alnadhari 2 lyze the adverse events and predictive factors associated with emergency ureteroscopy using a pneumatic semirigid urs for ureteral stones, with the goal of improving treatment efficacy, enhancing patient safety, and developing targeted strategies to mitigate the risk of complications. the findings of this study may inform clinical practice guidelines, improve patient counseling, and optimize resource allocation in emergency urological care. materials and methods study design and setting this retrospective study was conducted at ibb university hospitals, ibb, yemen. the study cohort comprised 266 patients who underwent emergency transurethral ureterolithotripsy (tul) using semirigid ureteroscopes from november 2018 to september 2023. emergency urs was defined as a procedure performed for acute ureteral obstruction due to symptomatic stones in patients presenting with: (1) severe ureteric colic unresponsive to conservative management; (2) acute renal impairment, indicated by a serum creatinine increase of ≥ 0.5 mg/dl or a calculated egfr decrease of ≥ 15 ml/min within 24-48 hours; or (3) symptoms suggestive of urinary tract infection with systemic inflammatory response syndrome or suspected pyonephrosis requiring urgent intervention. ethical approval was obtained from the ibb university ethics committee, following the principles of the helsinki declaration, with a waiver for individual patient consent due to the study's retrospective nature. this investigation focused on emergency urs as a firstline treatment for ureteral stones that were refractory to conservative management or complicated by severe conditions. additionally, patients with severe uremia or sepsis due to obstruction who underwent urinary decompression via percutaneous nephrostomy or ureteral stenting prior to definitive urs were included in the analysis. inclusion criteria participants included adult patients (aged 18 years and older) presenting with symptomatic ureteral calculi and subsequently undergoing emergency semirigid urs at our facility. all patients in the cohort presented with acute symptoms requiring emergent intervention, as defined above. exclusion criteria patients were excluded if they met any of the following criteria: (1) established ureteral strictures precluding safe urs access; (2) active utis (requiring initial treatment and exhibiting clinical signs of sepsis that were not directly related to the acute obstruction); (3) pregnancy; (4) severe orthopedic deformities that would have made proper positioning for urs impossible; (5) documented coagulation disorders that could not be medically corrected prior to intervention; or (6) those undergoing urs for non-emergency indications (e.g., elective stone removal, diagnostic ureteroscopy). patients with documented prior urs or other ureteral interventions were included as long as they met inclusion criteria. preoperative assessment comprehensive preoperative assessments were meticulously conducted to gauge the severity of the patients' acute presentation and guide treatment decisions. this included a detailed review of medical and surgical histories, including medication use (especially anticoagulants), prior urologic interventions, and comorbid conditions (diabetes, hypertension, cardiovascular disease). clinical examinations focused on assessing vital signs (temperature, heart rate, blood pressure, respiratory rate) and signs of systemic illness, and thorough abdominal examinations. investigations included: (1) renal function tests (blood urea nitrogen, creatinine); (2) complete blood count with differential; (3) urinalysis with microscopic examination to assess for the presence of hematuria, pyuria, and bacteriuria; and (4) urine culture and sensitivity if a uti was suspected. imaging evaluation comprised: (1) urinary tract ultrasound to assess for hydronephrosis, stone presence/location, and any evidence of renal abscess; (2) plain radiography (kub) to assess for radiopaque stones; and (3) non-contrast computed tomography (ncct) scans of the abdomen and pelvis to accurately characterize the stone, assess the degree of hydronephrosis, and evaluate for other potential etiologies. stone characteristics, including dimensions (in mm), location (proximal, mid, or distal ureter), and hounsfield units (hu) were evaluated using ncct. the degree of hydronephrosis was graded based on the society of urodynamics, female urology, and urogenital reconstruction (sufu) guidelines (mild, moderate, severe). surgical procedure all tul procedures were performed by experienced urologists with a minimum of 10 years of experience in endourology, including urs. the tul procedure was performed under either general or regional anesthesia based on patient and surgeon preference and clinical assessment. a single intravenous dose of prophylactic antibiotics (ceftriaxone) at a dose of one gram was administered before the induction of anesthesia and continued for 24-48 hours postoperatively, based on institutional protocols. patients were positioned in the standard dorsal lithotomy position. the procedure commenced with rigid cystoscopy to visualize the bladder and identify the ureteral orifice. a hydrophilic guidewire was then advanced into the ureter under direct vision. a semirigid ureteroscope (6-fr, karl storz, tuttlingen, germany) was employed, and stone fragmentation was accomplished using a swiss lithoclast® pneumatic lithotriptor. ureteroscopic procedures were performed by the experienced urologists. retrieval of stone fragments was attempted with a retrieval basket or grasping forceps, especially for larger fragments. smaller fragments (< 2 mm) were often left to pass spontaneously if it was deemed safe (absence of significant obstruction, no evidence of severe ureteral injury). doublej (dj) ureteral stents were placed at the discretion of the operating surgeon based on the clinical scenario, which was the presence of edema, anticipated difficulty with stone passage, or ureteral injury and were usually left in situ for 5-10 days unless complications arose. the reasons for stent placement were documented in the patient charts. for patients with significant hydronephrosis, impacted stones, solitary kidney, or those with pre-operaarchivio italiano di urologia e andrologia 2025; 97(2):13759 3 emergency ureteroscopy tive uremia, the dj stent was retained for 4-6 weeks to facilitate optimal healing and prevent obstruction. indwelling urethral catheters were not routinely inserted, except in cases where significant bleeding was expected, or for patients with comorbidities that required it. operative time was recorded, defined as the time from insertion of the cystoscope to the completion of the procedure and removal of instruments. fluoroscopy was used during the procedure. postoperative assessment postoperatively, patients received appropriate analgesics (non-steroidal anti-inflammatory drugs, opioids) and antiemetics as required. alpha-blockers were administered as per clinical needs. most patients were discharged within 24 hours, contingent on a stable clinical condition, absence of significant complications, and adequate pain control. uremic patients were discharged only after laboratory and clinical parameters were normalized and after consultation with a nephrologist. pain was assessed using a validated pain scale (e.g., visual analog scale). all patients were instructed to report any symptoms of fever, persistent pain, or changes in urinary function. all patients underwent plain radiography (kub) and abdominal ultrasound two days after surgery. success was defined as the absence of residual stones larger than 2 mm, resolution of symptoms (colic), and improvement in renal function in patients presenting with renal impairment, or in the absence of complications. an additional ultrasound was conducted three months after the procedure. stone clearance was confirmed by the absence of residual stones on radiological imaging, including radiography, ultrasound, or non-contrast ct scans within the first three months following urs. follow-up imaging was based on clinical need and according to the established protocol. intraoperative complications were assessed using a modified version of the satava classification system (10), specifically adapted for urs. grade 1 complications were considered minor and did not negatively impact patient outcomes. this category included: (1) minimal mucosal injuries (observed only); (2) mild bleeding that was selflimited or easily controlled with irrigation; (3) instrument malfunctions that were easily and quickly resolved (e.g., guidewire issues, irrigation problems); and (4) proximal stone migration that could be managed with a change in technique or observation. grade 2 complications necessitated some form of medical intervention. these were further subdivided into: grade 2a, which included complications managed intraoperatively through endoscopic techniques (e.g., additional stone manipulation, repeat lithotripsy, stent placement due to ureteral injury), and grade 2b, requiring subsequent endoscopic re-treatment within the same hospital admission. examples included: (1) difficulties in accessing the ureter requiring use of alternative techniques (e.g., change of guidewire); (2) significant bleeding requiring prolonged irrigation, the use of hemostatic agents (e.g., topical thrombin); (3) extraureteral stone migration; (4) mucosal injuries such as false passages or thermal injuries (requiring stent placement); and (5) ureteral perforation requiring stent placement or other interventions, but without the need for open or laparoscopic surgery. grade 3 complications were considered more severe and required open or laparoscopic surgical intervention. this category comprised: (1) severe bleeding requiring blood transfusion or surgical exploration; (2) persistent instrument malfunctions that prevented completion of the procedure; (3) inability to access the ureter or stone despite multiple attempts and the use of various techniques; (4) ureteral perforation with extravasation requiring open or laparoscopic repair; (5) ureteral intussusception; and (6) ureteral avulsion. postoperative complications were systematically classified by the operating surgeon using the modified clavien classification system (mccs) (11). each complication was evaluated according to the modified clavien grading scale. in instances where patients experienced multiple complications, each was graded individually based on its severity. main outcomes the primary outcome of this study was the prevalence of intraoperative and postoperative adverse events, while the secondary outcome aimed to identify factors associated with these complications. data collection data collected included: (1) patient demographics [age, gender, body mass index (bmi)]; (2) comorbidities (diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, etc.) were recorded using the charlson comorbidity index; (3) previous treatments such as extracorporeal shock wave lithotripsy (eswl) and other prior interventions for ureteral stones; (4) radiological characteristics of stones [hounsfield units (hus), size (in mm), location (proximal, mid, distal ureter), number of stones, laterality (left/right), and degree of hydronephrosis (sufu grading)]; (5) presenting symptoms (colic, infection, renal insufficiency), including the duration of symptoms before the presentation; (6) treatment outcomes; (7) intraoperative and postoperative complications (classified as described above); and (8) stone-free rates (sfr) at 2 days and 3 months. the s.t.o.n.e. scoring system was calculated based on preoperative non-contrast ct findings, incorporating size, topography, obstruction, number, and evaluation of hounsfield units (hu) (12). data was extracted from electronic medical records and from the patient's medical chart. statistical analysis statistical analyses were conducted using spss version 22 (ibm, armonk, ny). continuous variables are presented as means ± standard deviations or medians with interquartile ranges (iqr) and compared using the student’s t-test for normally distributed data and the mann-whitney u-test for non-normally distributed data. categorical variables are reported as frequencies and percentages and analyzed using pearson's chi-square test or fisher's exact test, where appropriate. univariate analysis was performed to identify potential risk factors associated with intraoperative and postoperative complications. variables with a p-value < 0.2 in univariate analysis were then considered for inclusion in a multivariate logistic regression model to identify independent predicarchivio italiano di urologia e andrologia 2025; 97(2):13759 k. al-naggar, f. ahmed, k. al-kohlany, i. alnadhari 4 tors of complications. the multivariate model included variables that were clinically relevant to the outcome. results were reported as adjusted odds ratios (aors) with 95% confidence intervals (cis). a p-value < 0.05 was considered statistically significant. results this study included a total of 266 patients, with a mean age of 47.7 ± 15 years and a median age of 44 years (range: 18 to 91 years). the cohort was predominantly male, comprising 192 individuals (72.2%). the mean weight of the patients was 72.7 ± 9.8 kg, with a median of 72 kg (range: 46 to 110 kg). the most common presenting symptom was acute flank pain, reported by 168 patients (63.2%), followed by fever in 60 patients (22.6%) and hematuria in 38 patients (14.3%). the majority of stones were located on the right side (n = 141, 53.0%), and a history of prior eswl was noted in 31 patients (11.7%). comorbid conditions included diabetes in 13 patients (4.9%) and hypertension in 10 patients (3.8%) (table 1). preoperative ct scans indicated a mean stone size of 9.1 ± 4.9 mm and a median size of 8 mm (range: 4 to 24 mm). multiple stones were identified in 132 patients (52.0%), with an average of 1.6 ± 0.6 stones per patient and a median of 2 stones (range: 1 to 3). the mean stone density was measured at 523.4 ± 281.4 hu, with a median of 458.5 hu (range: 0 to 1351 hu). hydronephrosis severity was classified as mild in 188 patients (74.0%), moderate in 52 patients (20.5%), and severe in 14 patients (5.5%). the majority of ureteral stones were located in the midureter (n = 181, 71.3%), while distal and proximal ureteral stones were present in 68 patients (26.8%) and 5 patients (2.0%), respectively. all patients underwent urgent ureteroscopy utilizing semirigid ureteroscopes; however, the procedure was unsuccessful in 7 patients (2.63%), resulting in the placement of a double j stent, with successful completion of the procedure one week later. the mean operative time was 57.7 ± 7.3 minutes, with a median of 55 minutes (range: 45 to 77 minutes) (table 2). table 1. patients demographic characteristics. variable a subgroup total (266) complications or (95% ci) p-value b no (239) yes (27) age (year) mean ± sd 47.7 ± 15.0 47.4 ± 15.0 50.0 ± 15.2 1.01 (0.99-1.04) 0.386 gender male 192 (72.2) 170 (71.1) 22 (81.5) ref 0.362 female 74 (27.8) 69 (28.9) 5 (18.5) 0.56 (0.18-1.43) weight (kg) mean ± sd 72.7 ± 9.8 72.9 ± 9.6 71.0 ± 10.9 0.98 (0.94-1.02) 0.343 history of diabetes no 253 (95.1) 230 (96.2) 23 (85.2) ref 0.040 yes 13 (4.9) 9 (3.8) 4 (14.8) 4.44 (1.13-14.85) history of hypertension no 256 (96.2) 230 (96.2) 26 (96.3) ref 1.000 yes 10 (3.8) 9 (3.8) 1 (3.7) 0.98 (0.05-5.54) history of previous eswl no 235 (88.3) 213 (89.1) 22 (81.5) ref 0.392 yes 31 (11.7) 26 (10.9) 5 (18.5) 1.86 (0.59-5.01) symptoms at presentation acute flank pain 168 (63.2) 151 (63.2) 17 (63.0) ref hematuria 38 (14.3) 36 (15.1) 2 (7.4) 0.49 (0.08-1.83) 0.359 fever 60 (22.6) 52 (21.8) 8 (29.6) 1.37 (0.53-3.27) 0.495 sd: standard deviation; eswl: extracorporeal shock wave lithotripsy; or: odds ratio, ci: confidence interval. a data were presented as count (percentage) or mean (standard deviation). b p-valus of < .05 were blooded and considered statistically significant and analyzed by student’st-test and chi-square test. table 2. radiologic and operative characteristics. variable a subgroup total (266) complications or (95% ci) p-value b no (239) yes (27) stone size (mm) mean ± sd 9.1 ± 4.9 8.4 ± 4.4 15.5 ± 5.1 1.31 (1.20-1.44) < 0.001 stone density (hu) mean ± sd 523.4 ± 281.4 517.4 ± 286.7 577.0 ± 226.6 1.00 (1.00-1.00) 0.297 hydronephrosis degree mild 195 (73.3) 177 (74.1) 18 (66.7) ref 0.712 moderate 55 (20.7) 48 (20.1) 7 (25.9) 1.43 (0.53-3.50) 0.447 severe 16 (6.0) 14 (5.9) 2 (7.4) 1.40 (0.21-5.58) 0.669 stone location distal 70 (26.3) 68 (28.5) 2 (7.4) ref middle 188 (70.7) 169 (70.7) 19 (70.4) 3.82 (1.07-24.40) 0.077 proximal 8 (3.0) 2 (0.8) 6 (22.2) 102.00 (14.77-1188.43) < 0.001 operative time (min) mean ± sd 55.7 ± 8.9 55.9 ± 9.0 53.6 ± 8.5 0.97 (0.92-1.02) 0.208 s.t.o.n.e. score mean ± sd 8.0 ± 1.8 7.8 ± 1.7 10.0 ± 1.2 2.43 (1.77-3.55) < 0.001 stone number single 122 (45.9) 120 (50.2) 2 (7.4) ref < 0.001 multiple 144 (54.1) 119 (49.8) 25 (92.6) 12.61 (3.65-79.44) hu: hounsfield units; sd: standard deviation; or: odds ratio, ci: confidence interval. a data were presented as count (percentage) or mean (standard deviation). b p-valus of < .05 were blooded and considered statistically significant and analyzed by student’st-test and chi-square test. archivio italiano di urologia e andrologia 2025; 97(2):13759 5 emergency ureteroscopy the overall complication rate was 10.2%. intraoperative complications were observed in 16 patients (6.0%), primarily consisting of mucosal damage (n = 9, 3.4%), stone up-migration or retropulsion (n = 8, 3.0%), and ureteral perforation (n = 1, 0.4%). postoperative complications occurred in 13 patients (4.9%), with fever being the most prevalent (n = 7, 2.6%), followed by hematuria in 3 patients (1.1%). additional complications included febrile urinary tract infection, pyelonephritis, and one case of mortality (n = 1, 0.4%). importantly, there were no significant intraoperative complications, such as ureteral avulsion. among the postoperative complications, two notable cases emerged: one patient developed pyelonephritis and was treated with intravenous antibiotics, while another patient succumbed to diabetic ketoacidosis compounded by emphysematous pyelonephritis, sepsis, and multiorgan failure. the overall sfr at follow-up was 85.3%, as verified by postoperative radiographic examinations; however, 39 patients (14.7%) exhibited residual stones and required additional endourological interventions (table 3). factors associated with complications univariate analysis identified several factors significantly associated with complications, including a history of diabetes (p = 0.040), larger stone size (p < 0.001), presence of multiple stones (p < 0.001), s.t.o.n.e. score (p < 0.001), and stones located in the proximal ureter (p < 0.001). in multivariate analysis, the key predictive factors for complications included large stone size aor: 1.3; 95% confidence interval (ci): 1.15-1.39, p < 0.0001) and the proximal ureter location of stones (aor: 4.9; 95% ci: 1.31-18.23, p = 0.0182) (table 4). discussion urs has seen significant advancements, establishing itself as a safer and more effective approach for the management of urinary tract stones. innovations in smaller ureteroscopes and the development of advanced instruments and energy sources have improved procedural outcomes; however, complications remain a concern, emphasizing the need to identify predictive factors associated with these risks (4, 5). this study examines the complications and outcomes associated with emergency semirigid urs in managing ureteral calculi within a resource-limited setting. our findings show that semirigid urs yields excellent outcomes, exhibiting high stone clearance rates and minimal complications, with larger stone sizes and proximal stone locations identified as significant predictors of adverse events. the variability in intraoperative complication rates among studies can be attributed to several factors, including differences in study design, patient demographics, stone characteristics, surgical techniques, and the expertise of the surgical teams. our investigation revealed an overall intraoperative complication rate of 6.0%, comprising mucosal damage (3.4%), stone upward migration (3.0%), and ureteral perforations (0.4%). for comparison, geavlete et al. reported an intraoperative complication rate of 3.6% in a cohort of 98 cases, highlighting mucosal injuries and stone migrations (13). tanriverdi et al. documented a higher complication rate of 8%, which included transient hematuria, mucosal erosion, and ureteral perforations (4). the lower complication rate observed in our study may reflect the experience of the surgical team, as more complex cases are frequently table 3. intraoperative and postoperative complications characteristics. complication * n (%) intraoperative 16 (6.0%) mucosal damage 9 (3.4%) stone up-migration or retropulsion 8 (3.0%) ureteral perforations 1 (0.4%) postoperative 13 (4.9%) fever (grade i) 7 (2.6%) hematuria (grade i) 3 (1.1%) febrile uti (grade ii) 1 (0.4%) pyelonephritis (grade iii) 1 (0.4%) death (grade ⅴ) 1 (0.4%) uti: urinary tract infection. * some patients had multiple complication. table 4. predictive factors for complications in multivariate regression analysis. variable a subgroup no (239) yes (27) cured or p-value adjusted p-value b (95% ci) or (95% ci) history of diabetes no 230 (90.9) 23 (9.1) ref 0.235 yes 9 (69.2) 4 (30.8) 2.80 (0.46-14.61) stone size (mm) mean ± sd 8.4 ± 4.4 15.5 ± 5.1 1.18 (1.05-1.35) 0.007 1.3 (1.15-1.39) < 0.0001 stone number single 120 (98.4) 2 (1.6) ref 0.918 multiple 119 (82.6) 25 (17.4) 1.12 (0.15-11.70) stone location distal 68 (97.1) 2 (2.9) ref mid 169 (89.9) 19 (10.1) 1.03 (0.23-7.18) 0.973 proximal 2 (25.0) 6 (75.0) 10.97 (1.18-150.52) 0.046 4.9 (1.31-18.23) 0.0182 s.t.o.n.e. score mean ± sd 7.8 ± 1.7 10.0 ± 1.2 1.54 (0.90-2.65) 0.113 sd: standard deviation; ci: confidence interval; or: odds ratio. a data were presented as count (percentage) or mean (standard deviation). b p-valus of < .05 were blooded and considered statistically significant and analyzed by multivariate regression analysis test. archivio italiano di urologia e andrologia 2025; 97(2):13759 k. al-naggar, f. ahmed, k. al-kohlany, i. alnadhari 6 referred to the capital city, where a specialized urology team with advanced equipment operates. among intraoperative complications, ureteral mucosal injury was the most commonly reported, consistent with findings from previous studies (4, 14). such injuries often occur during the introduction of operative instruments, including the ureteroscope and guide wires. importantly, all complications were managed conservatively, avoiding the need for open surgery and resulting in favorable outcomes. the upward migration of stones, observed in 3.0% of cases, is often linked to larger stones during urs, particularly when using pneumatic lithotripsy. proximal ureteric stones exhibit migration rates approaching 30%, underscoring the importance of anti-retropulsion devices (4, 14). the advent of devices like the stone cone and various entrapment nets aims to mitigate the risk of stone migration during ureteroscopic procedures (8). importantly, our study noted a low incidence of ureteral perforations at 0.4%. these perforations typically arise due to excessive force during the advancement of the ureteroscope. the incorporation of smaller-caliber ureteroscopes can facilitate safer navigation through narrowed regions of the ureter (9, 15). predicting complications, particularly in urgent cases, necessitates consideration of potential anatomical variations, such as constricted ureteric lumens, prevalent in a significant percentage of patients undergoing urological procedures (15, 16). postoperative complication rates are notably variable in the literature. recent reviews, including a study by de coninck et al., reported that postoperative febrile events and urinary tract infections (utis) can vary from 0.2% to 15%, with renal colic rates ranging from 1.1% to 10.2%. in our cohort, the overall postoperative complication rate was 4.9%. fever was the most common complication (2.6%), followed by hematuria (1.1%), with isolated cases of febrile uti, pyelonephritis, and mortality (0.4%). these results resonate with findings from perez et al., who similarly identified fever as the predominant postoperative complication (17). despite these occurrences, we did not document any severe postoperative complications aside from one case of urosepsis requiring hospitalization and another involving a patient with diabetes who succumbed to multiorgan failure. the risk of severe outcomes, particularly those associated with urosepsis, remains a critical concern, reinforcing the necessity for adherence to safety protocols and effective management strategies during interventions (3). overall, practical experience, judicious patient selection, thorough preoperative assessment, and close follow-up for high-risk patients likely contribute to the low incidence of complications observed in our study. our findings reported an overall stone-free rate (sfr) of 85.3% post-urs, consistent with results from other studies, including alameddine et al. (89.0%), shrestha et al. (80.5%), kim et al. (85.7%), and sirirak et al. (89.68%) (18-21). conversely, a study conducted in ethiopia revealed a notably lower sfr of 54.7%, attributed to limited experience among surgical staff and less advanced equipment (22). the inconsistency in the definition of sfr across studies raises questions about the comparability of reported outcomes, as divergent imaging techniques can yield varied results. the report identifies a mean patient age of 47.7 ± 15 years, with a male predominance, reflecting trends observed in other geographic regions such as ethiopia, iraq, and egypt (22-25). notably, our analysis revealed no significant correlation between age and complication rates, aligning with observations from mustafa et al. (26). while some studies suggest an increased risk of complications with advancing age (27, 28), our findings indicate that age alone may not serve as a critical determinant of adverse outcomes. regarding gender, we found no statistically significant correlation with complications in our study, although previous research suggests gender may influence stone clearance rates and complication risks (7, 29). comorbid conditions, particularly diabetes mellitus, were identified as contributing factors to postoperative complications. this aligns with historical data suggesting that diabetes increases the risk of adverse outcomes following urs (3, 30, 31). however, the small sample size limits our ability to draw definitive conclusions regarding these associations. moreover, our findings support the notion that stone characteristics – such as size, location, and density – serve as predictors of complications. larger stone size and proximal location were shown to be significant predictors in our multivariate analysis, corroborating previous literature (22, 24, 32, 33). the rationale for this association is that larger stones necessitate longer operative times and greater irrigation volumes, increasing the likelihood of complications. interestingly, we found no statistical correlation between stone density and complications, potentially due to the limited sample size available for analysis. while the american urological association recommends flexible urs for larger upper ureteric calculi, evidence suggests that semirigid urs can effectively treat upper ureteric stones, including larger and impacted stones (24, 34). our study reinforced the importance of considering stone location as a predictive factor for complications – echoing findings from prior studies (22, 25). the presence of multiple stones was also evaluated; while we observed some association, it was statistically significant only in univariate analyses. in line with our findings, mustafa et al. did not find a correlation between stone number and complications (26). other reports indicate the number of stones is an independent predictor of low stone clearance, higher retreatment rates, and longer operative times, although they did not report an increase in complications (35, 36). conversely, perez et al. noted that having multiple stone locations was linked to higher postoperative complications (17). additional factors potentially impacting urs complications may include the surgeon's experience, the use of auxiliary equipment, and different lithotripsy devices; however, these factors were not analyzed in our study due to the absence of laser lithotripters and the decision to avoid basket retrieval methods during most ureteroscopic procedures. study limitations this study has several notable limitations. the primary constraints include a low sample size and a retrospective design, which may affect the robustness of our findings. relying on secondary data introduces variability in data archivio italiano di urologia e andrologia 2025; 97(2):13759 7 emergency ureteroscopy quality, potentially due to inconsistencies in documentation practices. the retrospective nature may also introduce selection and recall biases that could influence outcomes; the limited sample size restricts the ability to perform comprehensive statistical analyses. additionally, all procedures were conducted by experienced urologists, which might skew results toward more favorable outcomes. the presence of ureteral stents may impede the detection of minor stone fragments after removal, potentially contributing to increased postoperative complications. however, this study is the first systematic evaluation of complications associated with semirigid ureteroscopy in patients with ureteral stones at our center, yet its findings should be interpreted with caution. the single-center nature of this research limits the generalizability of the results to other populations and settings. future research with larger sample sizes and multicenter designs is essential to enhance understanding of the unique challenges and opportunities for treatment in resource-limited environments. conclusions emergency ureteroscopy with a semirigid ureteroscope has shown promising outcomes in managing ureteral stones. this approach is associated with minimal intraoperative and postoperative complications, as well as satisfactory stone-free rates. key factors in optimizing these outcomes include careful instrument selection, the surgical team's expertise, and adherence to meticulous surgical techniques. attention to these details is especially critical in complex cases involving larger stones or those positioned in the proximal ureter, where procedural challenges may increase. prioritizing these aspects can significantly reduce the risks of adverse events during emergency ureteroscopy. references 1. the global, regional, and national burden of urolithiasis in 204 countries and territories, 2000-2021: a systematic analysis for the global burden of disease study 2021. e clinical medicine. 2024; 78:102924. 2. yoo mj, pelletier j, koyfman a, et al. high risk and low prevalence diseases: infected urolithiasis. am j emerg med. 2024; 75:137-142. 3. de coninck v, keller ex, somani b, et al. complications of ureteroscopy: a complete overview. world j urol. 2020; 38:21472166. 4. tanriverdi o, silay ms, kadihasanoglu m, et al. revisiting the predictive factors for intra-operative complications of rigid ureteroscopy: a 15-year experience. urol j. 2012; 9:457-64. 5. wason se, monfared s, ionson a, et al. ureteroscopy. 2024 apr 20. in: statpearls (internet). treasure island (fl): statpearls publishing; 2025. 6. kaczmarek k, jankowska m, kalembkiewicz j, et al. assessment of the incidence and risk factors of postoperative urosepsis in patients undergoing ureteroscopic lithotripsy. cent european j urol. 2024; 77:122-128. 7. fuganti pe, pires s, branco r, et al. predictive factors for intraoperative complications in semirigid ureteroscopy: analysis of 1235 ballistic ureterolithotripsies. urology. 2008; 72:770-4. 8. farahat ya, elbahnasy ae, elashry om. a randomized prospective controlled study for assessment of different ureteral occlusion devices in prevention of stone migration during pneumatic lithotripsy. urology. 2011; 77:30-5. d 9. francesca f, scattoni v, nava l, et al. failures and complications of transurethral ureteroscopy in 297 cases: conventional rigid instruments vs. small caliber semirigid ureteroscopes. eur urol. 1995; 28:112-5. 10. tepeler a, resorlu b, sahin t, et al. categorization of intraoperative ureteroscopy complications using modified satava classification system. world j urol. 2014; 32:131-6. 11. mandal s, goel a, singh mk, et al. clavien classification of semirigid ureteroscopy complications: a prospective study. urology. 2012; 80:995-1001. 12. molina wr, kim fj, spendlove j, et al. the s.t.o.n.e. score: a new assessment tool to predict stone free rates in ureteroscopy from pre-operative radiological features. int braz j urol. 2014; 40:23-9. 13. geavlete p, georgescu d, nita g, et al. complications of 2735 retrograde semirigid ureteroscopy procedures: a single-center experience. j endourol. 2006; 20:179-85. 14. zheng j, wang y, chen b, et al. risk factors for ureteroscopic lithotripsy: a case-control study and analysis of 385 cases of holmium laser ureterolithotripsy. wideochir inne tech maloinwazyjne. 2020; 15:185-191. 15. gaizauskas a, markevicius m, gaizauskas s, et al. possible complications of ureteroscopy in modern endourological era: two-point or "scabbard" avulsion. case rep urol. 2014; 2014:308093. 16. fathelbab tk, abdelhamid am, anwar azm, et al. prevention of stone retropulsion during ureteroscopy: limitations in resources invites revival of old techniques. arab j urol. 2020; 18:252-256. 17. perez castro e, osther pj, jinga v, et al. differences in ureteroscopic stone treatment and outcomes for distal, mid-, proximal, or multiple ureteral locations: the clinical research office of the endourological society ureteroscopy global study. eur urol. 2014; 66:102-9. declarations ethical approval: availability of data and material: all the data was included in this study. competing interests: the author declares no potential conflict of interest. funding: none. authors' contributions: all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13759 k. al-naggar, f. ahmed, k. al-kohlany, i. alnadhari 8 18. alameddine m, azab mm, nassir aa. semi-rigid ureteroscopy: proximal versus distal ureteral stones. urol ann. 2016; 8:84-6. 19. shrestha b, koju r, makaju shrestha s, et al. predictors of stone free rate and application of the size, topography, obstruction, number and evaluation of hounsfield units (s.t.o.n.e) scoring system in predicting the outcome in patients undergoing semi-rigid ureteroscopic lithotripsy for ureteric calculi at a university hospital of nepal. kathmandu univ med j (kumj). 2024; 22:31-35 20. kim jw, chae jy, kim jw, et al. computed tomography-based novel prediction model for the stone-free rate of ureteroscopic lithotripsy. urolithiasis. 2014; 42:75-9. 21. sirirak n, sangkum p, phengsalae y, et al. external validation of the s.t.o.n.e. score in predicting stone-free status after rigid ureteroscopic lithotripsy. res rep urol. 2021; 13:147-154. 22. mohammed s, redi s, berhe t, et al. ureteroscopy outcome and its determinants in a resource-limited setting. ethiop j health sci. 2022; 32:947-954. 23. el-qadhi m. outcome of ureteroscopy for the management of distal ureteric calculi: 5-years’ experience. african journal of urology. 2015; 21:67-71. 24. mursi k, elsheemy ms, morsi ha, et al. semi-rigid ureteroscopy for ureteric and renal pelvic calculi: predictive factors for complications and success. arab j urol. 2013; 11:136-41. 25. almusafer m, jawad al-tawri a. complications of ureteroscopic stone lithotripsy: a multicentre local study. hamdan med j. 2019; 12. 26. mustafa m, al zabadi h, mansour s, et al. endoscopic management of upper and lower ureteric stones using pneumatic lithotripter: a retrospective medical records review. res rep urol. 2023; 15:77-83. 27. wagenius m, rydberg m, popiolek m, et al. ureteroscopy: a population based study of clinical complications and possible risk factors for stone surgery. cent european j urol. 2019; 72:285-295. 28. bhojani n, miller le, bhattacharyya s, et al. risk factors for urosepsis after ureteroscopy for stone disease: a systematic review with meta-analysis. j endourol. 2021; 35:991-1000. 29. daly kf, mac curtain bm, collins e, et al. an analysis of the predictive factors for stone clearance at primary ureteroscopy. ir j med sci. 2024; 193:2531-2535. 30. waseda y, takazawa r, kobayashi m, et al. risk factors and predictive model for incidence of difficult ureter during retrograde ureteroscopic lithotripsy. int j urol. 2022; 29:542-546. 31. bin x, friedlander ji, chuang kw, et al. predictive factors for intraoperative balloon dilation in semirigid ureteroscopic lithotripsy. j endourol. 2012; 26:988-91. 32. osther pjs, osther ss, hesselholt mp, et al. understanding intrarenal backflow: intrarenal pressure during ureteroscopy and beyond. asian j urol. 2024; 11:139-142. 33. kim jw, lee yj, ha ys, et al. secondary signs on preoperative ct as predictive factors for febrile urinary tract infection after ureteroscopic lithotripsy. bmc urol. 2020; 20:131. 34. elganainy e, hameed da, elgammal m, et al. experience with impacted upper ureteral stones; should we abandon using semirigid ureteroscopes and pneumatic lithoclast? int arch med. 2009; 2:13. 35. kurahashi t, miyake h, oka n, et al. clinical outcome of ureteroscopic lithotripsy for 2,129 patients with ureteral stones. urol res. 2007; 35:149-53. 36. pace kt, kroczak t, wijnstok nj, et al. same session bilateral ureteroscopy for multiple stones: results from the croes urs global study. j urol. 2017; 198:130-137. correspondence khalil al-naggar alnajjarkh1234@gmail.com orcid: 0000-0001-9955-4537 faisal ahmed (corresponding author) fmaaa2006@yahoo.com orcid: 0000-0001-7188-2715 department of urology, school of medicine, ibb university, ibb, yemen khaled al-kohlany kalkohlani@gmail.com department of urology, college of medicine, sana'a university, sana'a, yemen ibrahim alnadhari ibrahimah1978@yahoo.com orcid: 0000-0003-3371-2285 urology section, department of surgery, al wakra hospital, hamad medical corporation, al wakra, qatar department of surgery, college of medicine, qatar university, doha, qatar stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13848 1 original paper introduction the metastatic spread to the penis from distant primary sites is a very rare phenomenon accounting for approximately 600 cases in the literature. while the management of primary tumors in the penis is rather well-defined, its involvement by metastatic lesions originating from other organs poses unique diagnostic and therapeutic dilemmas. in fact, the metastasis to the penis are generally associated with disseminated disease and poor prognosis (12). understanding the different primary tumor origins, the pathogenetic mechanisms and the clinical implications of penile metastasis is necessary for healthcare professionals involved in the management and treatment of these patients. more frequently, penile metastasis has been associated with primary tumors originating from urogenital cancers (69%) (2). however, metastasis from more unusual primary sites have been reported such as gastrointestinal tract (19%), kidney, lung and skin (2-6). the aim of this paper was to show the clinical and the oncologic data of a multi institutional series of 31 patients affected by penile metastatic cancer in order to enhance the knowledge and the management of this condition and improve patients’ care and outcomes. materials and methods patient population we retrospectively analyzed electronic medical records of 31 consecutive patients diagnosed with metastatic cancer to the penis and treated at eight ligurian urological departments between january 2014 and january 2024. clinical characteristics, including age, prior history of malignancy, metastasis at other sites, interval time between primary tumor and metastasis, presenting symptoms and physical examination findings were analyzed. introduction: the metastatic spread of cancer to the penis is a very rare clinical entity generally associated with disseminated disease and poor prognosis. the aim of this paper was to show the outcomes of a series of patients treated for metastatic cancer to the penis and enhance the understanding and the management of penile metastasis in order to improve patients’ care and outcomes. methods: we retrospectively analyzed the medical records of 31 patients diagnosed with metastatic cancer to the penis and treated at eight ligurian urological departments between january 2014 and january 2024. clinical characteristics, physical examination findings, diagnostic evaluations, treatment options and follow-up data were assessed. results: 27 (87%) patients had a prior history of malignancy with a metachronous metastasis. the most common primary site of malignancy was the genitourinary tract (71.1%) followed by the gastrointestinal tract (16.1%). the time interval from the diagnosis of the primary tumour to the detection of the penile metastasis was 36.0 months. the penile metastasis generally appeared with a mass (54.8%) and pain (29%), more rarely with priapism (6.5%), oedema (6.5%) and hematuria/urinary disorders (3.2%). the metastatic lesion required a total penectomy in 17 (54.8%) patients and a partial penectomy in 8 patients (25.8%). at a follow-up of 15.9 (1-75) months, 4 (18.2%) patients were still alive with disease. conclusions: our data confirmed penile metastasis as a rare entity usually associated with clinical symptoms involving the penis in the context of a known primary malignancy, mainly from the neighboring pelvic organs, with a poor prognosis. the majority of our patients required a total penectomy with a negative impact on their quality of life. these aspects highlighted the importance of a penile examination and an early diagnosis of a penile metastasis during the follow-up schedule of many patients with a history of previous oncologic disease. key words: penis; penis cancer; neoplasm metastasis; metachronous neoplasm; synchronous neoplasm. submitted 25 march 2025; accepted 29 march 2025 metastatic cancer to the penis: a multi-institutional comprehensive analysis of 31 patients aldo franco de rose 1, fabrizio gallo 2, francesca ambrosini 3, guglielmo mantica 3, tommaso saccucci 3, nataniele piol 4, bruno spina 4, franco bertolotto 5, carlo ambruosi 6, marco ennas 7, luca timossi 8, elisa melani 9, paola baccini 1, carlo introini 7, maurizio schenone 2, carlo terrone 3 1 villa montallegro private hospital, genoa, italy; 2 department of urology, san paolo hospital, savona, italy; 3 department of surgical and diagnostic integrated sciences (disc), irccs ospedale policlinico san martino, university of genoa, genoa, italy; 4 department of pathology, policlinico san martino hospital, university of genoa, genoa, italy; 5 department of urology, imperia hospital, imperia, italy; 6 department of urology, villa scassi hospital, genova, italy; 7 department of urology, galliera hospital, genova, italy; 8 department of urology, international evangelical hospital, genova, italy; 9 department of urology, sant’andrea hospital, la spezia, italy. doi: 10.4081/aiua.2025.13848 summary archivio italiano di urologia e andrologia 2025; 97(2):13848 f. de rose aldo, f. gallo, f. ambrosini, et al. 2 diagnostic evaluations, such as imaging studies and histopathological examinations, were assessed to confirm the presence of metastatic disease and determine the primary tumor origin. the pathology reports were carried out by individual dedicated pathologists. details regarding the management of penile metastasis were collected and analyzed. treatment options included surgical and non-surgical interventions (lesion excision, partial or total penectomy, radiotherapy), systemic therapies (chemotherapy, targeted therapy, immunotherapy), and palliative interventions (pain management, supportive care). patient follow-up data, including disease progression, response to treatment, and survival outcomes, were documented. statistical analysis descriptive statistics were used to summarize the demographic and clinical characteristics of the patient series. continuous variables were expressed as means. categorical variables were presented as frequencies and percentages. the descriptive statistical analysis was performed using r software environment for statistical computing and graphics (version 4.1.2). results table 1 showed the demographics, oncological and clinical data of the patients. thirty-one patients with metastatic cancer to the penis were included in the study. the mean age at diagnosis was 72.3 years (range 21-83 years). as regards the oncological history, twenty-seven (87%) patients had a known prior malignancy with a metachronous presentation of penile metastasis; in the remaining four (13%), the penile involvement was synchronous with the initial clinical manifestation of the disease and the diagnosis of the primary cancer was achieved during the follow-up. among these four patients, two were affected by bladder cancer, one by colorectal adenocarcinoma and another one by pancreatic carcinoma. concerning the primary sites of malignancy, the most common was the genitourinary tract (71.1%) followed by the gastrointestinal tract (16.1%). other uncommon primary sites included skin (9.6%), and bone marrow (3.2%). in particular, within the genitourinary system, the most recurring primary organ was the bladder (48.5%), followed by the prostate (9.6%), the kidney (6.5%) and the urethra (6.5%). within the gastrointestinal tract, the most recurring primary location was the colon/rectum (12.9%), followed by the pancreas (3.2%) (table 2). microscopic images of metastatic solid tumors to the penis from urothelial carcinoma, colorectal adenocarcinoma and cutaneous melanoma are represented in figure 1-3, respectively. regarding the staging of the primary tumor at diagnosis, it was pt3 and pt4 in twenty-one (67.7%) and ten (32.3%) patients respectively. nodal involvement was assessed in twenty-three (74.1%) patients. metastasis at other sites of primary cancer were assessed in six (19.3%) patients. seventeen (54.8%) patients underwent an adjuvant therapy after the treatment of the primary cancer (hormonal therapy, radiotherapy and/or chemotherapy). the mean time interval from the diagnosis of the primary tumour to the detection of the penile metastasis was 36.0 months (range 0-240 months). in particular, the twentyseven metachronous metastatic lesions developed within the first, third, fifth and tenth year since the initial diagnosis in seven (22,6%), ten (32.3%), four (12.9%), and three (9.6%) patients, respectively, and over the tenth year in the remaining three (9.6%) patients (table 3). as concerns the clinical presentation of the penile metastasis, seventeen (54.8%) patients showed a bothersome mass or nodule. in particular this lesion was localized into the corpus cavernosum in twelve (70.5%) patients while in the glans in five (29.5%) patients. furthermore, the penile lesions produced pain in nine (29%) patients, priapism in two (6.5%) patients, oedema in two (6.5%) patients and hematuria/urinary disorders in one (3.2%) patient. regarding sexual activity, seven (22.5%) patients reported sexual intercourses, often occasionally, and rarely with the help of phosphodiesterase inhibitors. table 1. demographics, oncological and clinical characteristics of the patients. n° of pts 31 age (ys) 72.3 (21-83) previous history of cancer (n %) yes 27 (87%) no 4 (13%) staging of primary cancer (n %) pt3 21 (67.7%) pt4 10 (32.3%) nodal involvement of primary cancer (n %) yes 23 (74.1%) no 8 (25.9%) metastasis at other sites of primary cancer (n %) yes 6 (19.3%) no 26 (80.7%) adjuvant therapy after primary cancer treatment (n %) yes 17 (54.8%) no 14 (45.2) interval time between primary tumor and metastasis (months) 36.0 (0-240) clinical manifestation of disease (n %) mass/nodule 17 (54.8%) pain 9 (29%) priapism 2 (6.5%) edema 2 (6.5%) hematuria/urinary disorders 1 (3.2%) table 2. primary sites of metastatic solid tumors to the penis (n = 31). n° of pts (%) 31 bladder 15 (48.5) colon/rectum 4 (12.9) kidney 2 (6.5) skin 3 (9.6) pancreas 1 (3.2) urethra 2 (6.5) prostate 3 (9.6) bone marrow 1 (3.2) archivio italiano di urologia e andrologia 2025; 97(2):13848 3 metastatic cancer to the penis the metastatic lesion required a penectomy in the majority of the patients. in particular. total penectomy was performed in seventeen (54.8%) patients and a partial penectomy (nodule excision or glandulectomy) in eight patients (25.8%) followed by local radiotherapy in four of them. among the remaining six patients, the diagnosis was performed with an excisional biopsy and not followed by any treatment procedure due to the poor patients’ clinical conditions. follow-up data were available for twenty-two (70.9%) patients. among these, at a mean follow-up of 15.9 (175) months, fifteen (68.2%) patients died of disease, four (18.2%) patients were alive with disease, three (13.6%) patients died for other causes. discussion the aim of this paper was to show the clinical and oncologic data of a multi institutional series of 31 patients affected by penile metastatic cancer in order to enhance the knowledge and the management of this condition and improve patients’ care and outcomes. the metastatic spread of cancer to the penis is a very rare clinical entity with about 600 cases reported to date worldwide (1, 7-8). this aspect has been recently confirmed in the largest paper available in literature on this topic by nova-camacho et al. who described the data of 108 patients collected at twenty-two pathology departments from eight countries on three continents (8). the relatively small number of patients collected in our study resulted substantially in line with the outcomes reported by these authors. actually, our data look rather more remarkable considering that they referred to only an italian regional experience. as regards the oncologic aspects, penile metastases are commonly identified in patients with known malignancies and an advanced disease (7-11). accordingly, 87% of the patients of our series showed a metachronous metastasis, whereas the penile metastasis occurred synchronously with the primary tumour only in the remaining 13% of patients. concerning these primary tumors, although we assessed different forms in terms of origins and hystopathological characteristics, as expected, they were high stage primary cancers with nodal and metastatic involvement at diagnosis respectively in 74.1% and 19.3% respectively, which often required an extended surgery followed by an adjuvant treatment. based on these aspects, also in our experience the penile metastasis generally occurred in a setting of advanced metastatic diseases. regarding the physiopathology of penile metastasis, the discrepancy between the relative blood supply and the rarity of the penis as site of secondary malignancy has been already reported. in particular, the retrograde venous route is thought to be the main way by which tumor cells from pelvic organs (prostate, urinary bladder, rectosigmoid) reach the corpus cavernosa and the glans, as the dorsal venous system of the penis has communication with the venous plexus system of the pelvis. similarly, the retrograde lymphatic route seems to be the way by which tumor cells reach the penile skin via lymphatics that drain the pelvic organs, passing through the iliac and inguinal nodes (7-8). less commonly, arterial spread, direct extension or iatrogenic spread by instrufigure 1-3. microscopic images of metastatic solid tumors to the penis from urothelial carcinoma, colorectal adenocarcinoma and cutaneous melanoma. table 3. time interval between the primary tumor and penile metastasis (n = 31). months n (%) 0 (synchronous) 4 (12.9%) 1-12 7 (22.6%) 13-36 10 (32.4%) 37-60 4 (12.9%) 61-120 3 (9.6%) > 120 3 (9.6%) 1. 2. 3. archivio italiano di urologia e andrologia 2025; 97(2):13848 f. de rose aldo, f. gallo, f. ambrosini, et al. 4 ments, could explain metastasis from closer or distant organs as the kidneys, the hematologic system, the liver and the lungs or other organs (12-16). according to the seed/soil hypothesis and to the fact that the site of metastasis is determined not only by the characteristics of the neoplastic cells but also by the microenvironment of the host tissue, the penis probably does not provide the perfect environment (soil) for neoplastic seeding. furthermore, the rich communications between arterial inflow and venous outflow could explain the difficulty in cell seeding in normal conditions. however, when the outflow is impaired by venous or lymphatic occlusions, such as in the presence of a tumor in the neighboring genito-urinary organs or in massive pelvic disease, the process of seeding could be facilitated (7). our data showed that 80% of the metastatic lesions originate from the neighboring genito-urinary and pelvic organs, mainly bladder, prostate and rectum-sigmoid confirming the more validated hypothesis that the venous or lymphatic flows could be the routes by which tumor cells reach the penis from these organs. regarding the interval time between the primary tumor and the development of metachronous metastasis, it was 3 years in our series. this period of time looks rather surprisingly and longer than expected considering the high risk of the primary tumors. however, a similar time interval between the primary diagnosis and the occurrence of the penile metastasis has been already reported in literature and probably explained by the effect of the adjuvant treatments on patients’ surveillance (8). as concerns the clinical presentation of the metastasis, our data confirmed that the majority of the patients (84%) showed symptoms associated with penile nodules and pain. this aspect highlighted the importance that physicians become worried of an eventual penile metastasis in case of a known history of primary tumors and clinical symptoms involving the penis, especially following previous pelvic tumors diagnosed even some years before considering also the documented patients’ tendency to delay the presentation and diagnosis of penile lesions. in case of penile pain, particular attention should be paid at the differential diagnosis between penile metastasis and peyronie’s disease, especially when the pain is reported also in flaccidity (17). regarding the management of penile metastasis, there is no consensus in literature regarding the best treatment to choose. this aspect is likely due to insufficient data available and the worse prognosis for these patients. in particular, the decision between radical or partial penectomy and/or radiation therapy is balanced considering the primary tumor, the size, location and number of metastatic lesions, patient’s age, performance status and motivation [1, 7-10, 18-20]. in our experience, the majority of patients (80%) required a penectomy which was mainly a total penectomy. in fact, a partial penectomy (nodule excision or glandulectomy) was feasible only in 25.8% of patients. although the mean age of our study population was rather old (72 years) and the prognosis of these patients rather poor, we can neglect that 22.5% of them still reported a sexual activity and that an earlier diagnosis and treatment of the metastasis could allow a less invasive surgery with a less impact on function (sexual, urinary or sensory), genital appearance, quality of life and psychological well-being, especially in younger patients. in fact, negative impact on quality of life has been described in some studies following penile cancer surgery, variably correlated with aggressiveness of penile surgery. furthermore, anxiety, depression, and reduced self-esteem have been reported in penile cancer survivors (20-22). these aspects highlight again the importance of a penile examination and an early diagnosis of penile metastasis during the follow-up schedule of many patients with a history of previous oncologic disease. finally, in our experience 68.2% of patients died of disease and a very low cancer specific surveillance (18.2%) was assessed at 16 months follow-up. this is also in accordance with the previous data that show poor prognoses for these patients due to a disseminated disease and a poor general health which cause death generally within a year from the presentation (7-9). the retrospective nature of this study may be subject to inherent limitations, such as missing data, incomplete documentation, and potential selection bias. additionally, the generalizability of the findings may be influenced by the specific characteristics of the patient population treated at different participating institutions. conclusions our data confirmed penile metastasis as a rare entity usually associated with clinical symptoms involving the penis in the context of a known primary malignancy, mainly from the neighboring genito-urinary and pelvic organs, with a poor prognosis. the majority of our patients required a declarations ethical approval: the authors declared that the study was performed in accordance with the ethical standards as laid down in the 1964 declaration of helsinki and its later amendments or comparable ethical standards. informed consent was obtained from all individual participants included in the study. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the author has no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. all authors declared that all data and materials as well as software application or custom code support their published claims and comply with field standards. funding: no specific funding was obtained for this study. authors' contributions: authors' contributions: d.r. a.f.: conception and design of the work, supervision, final approval of the version; g.f., a.f., g.m.: drafting and writing the paper, final approval of the version; t.s., b.f., a.c., e.m., t.l., m.e., b.p., i.c.: acquisition, analysis and interpretation of the data, final approval of the version; s.m., t.c.: supervision, final approval of the version. acknowledgments: none. archivio italiano di urologia e andrologia 2025; 97(2):13848 5 metastatic cancer to the penis total penectomy with a negative impact on their quality of life. these aspects highlighted the importance of a penile examination and an early diagnosis of a penile metastasis during the follow-up schedule of many patients with a history of previous oncologic disease in order to allow more effective and less invasive management strategies for alleviating the symptoms, preserving the sexual function, and improving the overall quality of life. overall, our study on penile metastasis not only enhances our understanding of cancer systemic development and progression but also remarks the importance of a multidisciplinary collaboration among urologists, oncologists, radiologists, and pathologists. continuous research and clinical investigations, should allow us to optimize diagnostic accuracy, improve treatment approaches, and enhance the overall care of the patients affected by this rare metastatic disease. references 1. cocci a, hakenberg ow, cai t, et al. prognosis of men with penile metastasis and malignant priapism: a systematic review. oncotarget 2018; 9:2923-30. 2. zhang k, da j, yao h jun, et al. metastatic tumors of the penis: a report of 8 cases and review of the literature. medicine (baltimore). 2015; 94:e132. 3. de rose af, vecco f, gallo f, et al. penile metastasis of colorectal cancer; case report and discussion on this rare clinical entity. annals of case reports 2023; 8:1-4. 4. zou q, jiao j, zou m hong, et al. diffuse metastases in bilateral penile corpus cavernosum from renal cancer diagnosed by 18ffdg pet/ct. clin nucl med. 2020; 45:451-2. 5. guo lc, li g, wang xm, et al. penile metastases from primary lung cancer: case report and literature review. medicine (baltimore). 2017; 96:e7307. 6. maruyama y, sadahira t, mitsui y, et al. red nodular melanoma of the penile foreskin: a case report and literature review. mol clin oncol. 2018; 9:449-452. 7. mearini l, colella r, zucchi a, et al. a review of penile metastasis. oncol rev. 2012; 6:e10. 8. nova-camacho lm, acosta am, trpkov k, et al. metastatic solid tumors to the testis: a clinicopathologic evaluation of 157 cases from an international collaboration. hum pathol. 2023; 139:37-46. 9. cherian j, rajan s, thwaini a, et al. secondary penile tumours revisited. int. semin. surg. oncol 2006; 3:33. 10. dust n, bates aw, baithun si. secondary neoplasms of the male genital tract with different patterns of involvement in adults and children. histopathology 2000; 37:323-331. 11. morichetti d, mazzucchelli r, lopez-beltran a, et al. secondary neoplasms of the urinary system and male genital organs. bju int. 2009; 104:770-776. 12. hizli f, berkmen f. penile metastasis from other malignancies. a study of ten cases and review of the literature. urol int. 2006; 76:118-121. 13. chaux a, amin m, cubilla al, et al. metastatic tumors to the penis: a report of 17 cases and review of the literature. int j surg pathol. 2011; 19:597-606. 14. eberth cj. krebsmetastasen des corpus cavernosum penis. archiv f. pathol anat 1870; 51: 145-146. 15. giunchi f, vasuri f, valerio v, et al. unusual asymptomatic presentation of bladder cancer metastatic to the penis. pathol. res. pract. 2017; 213:717-720. 16. ellis cl, epstein ji. metastatic prostate adenocarcinoma to the penis: a series of 29 cases with predilection for ductal adenocarcinoma. am. j. surg. pathol. 2015; 39:67-74. 17. de rose af, mantica g, gallo f, et al. risk factors for the delay in the diagnosis of penile lesions: results from a single center in italy. minerva urol nefrol. 2019; 71:258-263. 18. brouwer or, albersen m, parnham a, et al. european association of urology-american society of clinical oncology collaborative guideline on penile cancer: 2023 update. eur urol. 2023; 83:548560. 19. simon n, atiq s, sonpavde g, et al. new therapeutic horizons for advanced or metastatic penile cancer. urol clin north am. 2024; 51:367-376. 20. croghan sm, cullen im, raheem o. functional outcomes and health-related quality of life following penile cancer surgery: a comprehensive review. sex med rev. 2023; 11:441-459. 21. pérez j, chavarriaga j, ortiz a, et al. oncological and functional outcomes after organ-sparing plastic reconstructive surgery for penile cancer. urology. 2020; 142:161-165. 22. croghan sm, compton n, daniels ae, et al. phallus preservation in penile cancer surgery: patient-reported aesthetic & functional outcomes. urology. 2021; 152:60-66. correspondence aldo franco de rosealdofdr@libero.it paola baccini pbaccini@montallegro.it villa montallegro private hospital, genoa, italy maurizio schenone m.schenone@asl2.liguria.it fabrizio gallo (corresponding author) fabriziogallo.sv@gmail.com department of urology, san paolo hospital, via genova 30, savona, italy francesca ambrosini f.ambrosini1@gmail.com guglielmo mantica guglielmo.mantica@gmail.com tommaso saccucci 5729023@studenti.unige.it carlo terrone carlo.terrone@med.uniupo.it department of surgical and diagnostic integrated sciences (disc), irccs ospedale policlinico san martino, university of genoa, genoa, italy nataniele piol nataniele.piol@hsanmartino.it bruno spina bruno.spina@hsanmartino.it department of pathology, policlinico san martino hospital, university of genoa, genoa, italy franco bertolotto francobertolotto.ge@gmail.com department of urology, imperia hospital, imperia, italy carlo ambruosi carloambruosi1@libero.it department of urology, villa scassi hospital, genova, italy marco ennas marco.ennas@gmail.com carlo introini cintroini@gmail.com department of urology, galliera hospital, genova, italy luca timossi luca.timossi@gmail.com department of urology, international evangelical hospital, genova, italy elisa melani elisa.melani@asl5.liguria.it department of urology, sant’andrea hospital, la spezia, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13639 1 original paper introduction robotic-assisted radical prostatectomy (rarp) has emerged as a gold standard for the surgical management of localized prostate cancer, offering superior oncological outcomes and reduced perioperative morbidity compared to traditional open surgery, confirming the advantages of minimally invasive techniques compared to traditional surgery, as in the case of laparoscopic radical prostatectomy (1). however, the procedure often results in significant postoperative complications, including erectile dysfunction (ed) and urinary incontinence, which can profoundly impact patients' quality of life (2). the pathophysiological mechanisms underlying these complications include cavernosal hypoxia, structural changes in penile tissue, and neurovascular injury (3, 4). early penile rehabilitation protocols employing vacuum devices have been shown to counteract these effects by improving cavernosal oxygenation and reducing fibrosis (4, 5). studies also suggest that vacuum therapy can preserve penile length and stimulate tissue remodeling, mitigating the adverse effects of extended hypoxia (5, 6). erectile dysfunction, a common consequence of rarp, stems from intraoperative injury to the neurovascular bundles, cavernosal hypoxia, and fibrosis. histopathological studies reveal that post-rarp penile tissue undergoes significant degenerative changes, including fibrosis and smooth muscle atrophy, primarily due to reduced oxygenation and extended denervation. this fibrosis is marked by an upregulation of pro-fibrotic cytokines, such as transforming growth factor-beta (tgf-β), which leads to an irreversible loss of elasticity and compliance in the cavernosal tissue (7). as djavan et al. (2011) highlighted, these pathological changes compromise the structural integrity of penile tissue, necessitating early and effective intervention (8). the pathogenesis of post-operative ed involves a multifaceted interplay of neurogenic, vascular, and psychological factors. neurovascular bundle injury, even in nerve-sparing surgeries, can lead to axonal degeneration, impairing the signalling required for erectile function. additionally, reduced endothelial nitric oxide (no) production exacerbates cavernosal vasoconstriction and hypoxia, further fuelling the cycle of fibrosis (9). objective: this study evaluated the primary efficacy of vacuum therapy combined with phosphodiesterase type 5 inhibitors (pde5i) versus pde5i alone in improving erectile function recovery, assessed via the international index of erectile function (iief) questionnaire, after robotic-assisted radical prostatectomy (rarp). a secondary objective was to assess the impact of the combined therapy on continence outcomes, including pad usage and continence scores. the study also explored predictors of rehabilitation success and the potential synergistic effects of the combined approach. materials and methods: a retrospective analysis of 101 patients who underwent rarp (2021-2023) was conducted. patients were divided into group 1 (pde5i only, n = 70) and group 2 (pde5i + vacuum therapy, n = 31). vacuum therapy was started within 20 days postoperatively and performed daily under specialist supervision. all data were completely anonymous. primary outcomes included iief-5 scores for erectile function and continence recovery (pad usage, continence scores based on three levels: 0 complete incontinence, 1 stress incontinence and 2 full continence). predictive factors were analysed using repeated measures anova and multivariate regression. results: group 2 showed significantly higher mean iief-5 scores at 12 months (10.2 vs. 2.5, p < 0.001) and earlier continence recovery, with better scores at 3 and 6 months (p < 0.05). vacuum therapy and pde5i accelerate continence recovery during the early postoperative period, with fewer pads required, compared with patients treated with pde5i alone, at 6 months (1.32 vs. 1.62; p = 0.358) and 9 months (0.54 vs. 1.08; p = 0.034). key predictors of recovery included age, bmi, nerve-sparing status, and preoperative continence levels. conclusions:this study demonstrates the benefits of combining vacuum therapy with pde5i for improving erectile function and early continence recovery after rarp, highlighting the importance of early, individualized rehabilitation. vacuum therapy enhances oxygenation, reduces fibrosis and complements pde5i effects. further research is needed to refine predictive factors for success and explore the impact of intraoperative blood loss on erectile recovery, enabling optimized, tailored strategies for post-rarp rehabilitation. key words: prostate cancer; urinary continence; erectile dysfunction; iief; robot-assisted radical prostatectomy; functional outcomes. submitted 16 january 2025; accepted 30 march 2025 recovery of functional outcomes after robot assisted radical prostatectomy (rarp): impact of vacuum therapy compared to pde5 inhibitors alone pier paolo prontera 1, francesca romana prusciano 2, 1, marco lattarulo 1, arman tsaturyan 3, 4, carmine sciorio 5, francesco saverio grossi 1 1 department of urology, “s.s. annunziata” hospital, taranto, italy; 2 division of urology, hospital “valle d’itria”, martina franca (ta), italy; 3 department of urology, yerevan state medical university after mkhitar, heratsi, yerevan, armenia; 4 department of urology erebouni medical center, yerevan, armenia; 5 department of urology, “alessandro manzoni” hospital of lecco, italy. doi: 10.4081/aiua.2025.13639 summary archivio italiano di urologia e andrologia 2025; 97(2):13639 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 2 the effectiveness of phosphodiesterase type 5 inhibitors (pde5i) lies in their ability to enhance and restore normal erectile physiology by targeting the no-cyclic guanosine monophosphate (cgmp) pathway. during sexual stimulation, nitric oxide is released from endothelial cells and nonadrenergic, non-cholinergic neurons, activating guanylate cyclase in the smooth muscle cells of the corpus cavernosum. this leads to increased cgmp levels, resulting in smooth muscle relaxation and subsequent cavernosal blood engorgement. pde5i, such as tadalafil or sildenafil, inhibit the breakdown of cgmp by phosphodiesterase type 5, prolonging its vasodilatory effects and improving erectile function (7, 8). furthermore, the synergistic use of pde5i and vacuum therapy has demonstrated promising outcomes in enhancing erectile recovery. the combined approach optimizes penile hemodynamics and structural integrity, facilitating a faster return to spontaneous erections compared to monotherapy (4-6). the role of patient-specific factors, including baseline erectile function and metabolic health, highlights the need for individualized rehabilitation strategies (4, 5). vacuum therapy complements the action of pde5i by directly addressing cavernosal hypoxia and structural changes. by creating negative pressure around the penis, vacuum devices induce blood flow into the corpus cavernosum, counteracting ischemia and promoting oxygenation. enhanced cavernosal oxygenation mitigates the risk of fibrosis and preserves smooth muscle integrity. additionally, repeated mechanical stretching through vacuum use stimulates angiogenesis and tissue remodeling, which are critical for long-term recovery of erectile function.the role of vacuum in reducing oxidative stress and enhancing endothelial repair was elucidated, further supporting its application in post-rarp rehabilitation (9, 10). rarp nerve-sparing techniques aim to preserve the integrity of the neurovascular bundles, mitigating the severity of ed. these techniques can be classified into full, partial, or minimal nerve-sparing approaches, each varying in the degree of tissue preservation. patel et al. (2015) demonstrated that bilateral full nerve-sparing rarp significantly improves postoperative erectile function outcomes compared to unilateral or non-nerve-sparing procedures. however, the success of nerve-sparing also depends on preoperative factors, including patient age, baseline erectile function, and tumor location (7). urinary incontinence, another debilitating consequence of rarp, arises primarily from sphincteric dysfunction and pelvic floor weakness. the intricate balance between the internal and external urinary sphincters is disrupted during prostatectomy, leading to stress incontinence. additionally, detrusor overactivity due to denervation may further exacerbate urinary symptoms. studies, including those by preisser et al. in 2019, have emphasized the role of meticulous surgical technique and early pelvic floor muscle rehabilitation in facilitating continence recovery (11). the role of vacuum therapy in this context remains underexplored but holds potential due to its capacity to enhance pelvic floor vascularization and support tissue regeneration (10). the combined use of pde5i and vacuum device has shown promising results in enhancing erectile function recovery. in 2018, salciccia et al. demonstrated that patients undergoing integrated rehabilitation protocols experienced a significant improvement in international index of erectile function-5 (iief-5) scores, with outcomes superior to those achieved with pde5 inhibitors alone (2). similarly, preisser et al. emphasized the role of multimodal approaches, particularly the synergistic effects of pharmacological and mechanical interventions, in accelerating functional recovery post-rarp (11). while erectile function recovery has been the primary focus of most studies, urinary incontinence remains another prevalent and debilitating postoperative challenge. existing evidence suggests that factors influencing continence recovery are multifactorial, involving age, surgical technique, and baseline pelvic floor function. pde5 inhibitors are not directly related to continence outcomes, vacuum therapy may offer indirect benefits. du et al. highlighted the potential of vacuum in promoting pelvic floor vascularization, which could facilitate faster continence recovery (10). however, systematic reviews, such as those conducted by califano et al. (2021), have noted limited data directly addressing vacuum’s role in continence improvement, pointing to a critical gap in literature (12). furthermore, systematic reviews and trials have consistently highlighted the multifactorial nature of recovery following rarp. a review by preisser et al. highlighted the importance of tailoring rehabilitation strategies based on individual patient profiles, including age, preoperative iief scores, and surgical complexity (11). trials such as protect-t have also emphasized the need for early intervention and consistent adherence to rehabilitation protocols to optimize outcomes (13). this study aims to evaluate the comparative efficacy of pde5 inhibitors alone versus pde5 inhibitors combined with vacuum therapy in the context of andrological rehabilitation post-rarp. specifically, it focuses on primary endpoints, such as improvement in erectile function (assessed through iief-5 scores), and secondary endpoints, including the impact of vacuum on continence recovery. by leveraging statistical analyses and insights from the literature, this work seeks to contribute to the optimization of rehabilitation strategies following radical prostatectomy. moreover, it addresses critical gaps identified in previous research, providing a comprehensive assessment of the benefits and limitations of combined rehabilitation protocols. materials and methods a total of 153 patients who underwent robotic-assisted radical prostatectomy (rarp) at our institution between 2021 and 2023 were evaluated. of these, 101 patients met specific inclusion and exclusion criteria and were enrolled in the study. eligible patients had localized prostate cancer (pca), were ≤ 75 years old, exhibited good performance status, and were either not suitable candidates for or not motivated toward active surveillance. patients were excluded if they had a history of deprivation hormonal therapy, prior pelvic surgery or radiotherapy, or histological diagnoses performed at external institutions. this study employed a retrospective design to evaluate the outcomes of patients who underwent radical prostatectoarchivio italiano di urologia e andrologia 2025; 97(2):13639 3 vacuum therapy compared to pde5i my and subsequent andrological rehabilitation using either pde5 inhibitors (pde5i) alone or pde5i combined with vacuum therapy. a total of 101 patients were included, divided into two treatment groups: group 1 (pde5i only, n = 70) and group 2 (pde5i + vacuum, n = 31). patients in the vacuum therapy group (group 2) performed vacuumgymnastics under specialist guidance, dedicating at least 20 minutes daily to the therapy to ensure proper use of the device and adherence to the protocol. both rehabilitation therapies were started within 45 days of surgery, with a mean start time of 20 days postoperatively. the primary endpoints were improvements in erectile function, measured through iief-5 scores and continence recovery. histological diagnosis was obtained via standard transrectal ultrasound-guided trans-perineal prostate biopsy (trussbx) or mri/ultrasound fusion-guided trans-perineal biopsy (tbx+sbx). fifty patients underwent fusion-guided biopsy, while 51 received a standard biopsy. all procedures were performed by an experienced operator. fusion biopsy was indicated for patients with clinically significant pirads lesions (pirads ≥ 3) and included both targeted cores [based on the number and size of regions of interest (roi)] and 12-16 systematic cores from a prostatic template covering the base, mid-gland, and apex bilaterally. when multiparametric mri (mpmri) was unavailable or no significant pirads lesions were identified, a standard 16-core trusguided trans-perineal biopsy was performed according to institutional protocol, systematically sampling the base, mid-gland, apex, and transition zones bilaterally. preoperative staging was performed for all patients using contrast-enhanced total-body ct and total-body bone scintigraphy. all patients subsequently underwent rarp using the da vinci xi (intuitive) multiport robotic system. the procedures were performed by two surgeons, both employing the same standardized surgical technique, which included an anterograde extraperitoneal approach and a double-layer running anastomosis with posterior plate reinforcement using a 2-0 barbed suture. when indicated, a nerve-sparing technique was performed. histopathological analysis of surgical specimens was performed by an expert pathologist. catheter removal was performed on the seventh postoperative day, only after excluding active peri-anastomotic urinary leakage through retrograde and voiding cystourethrography. all patients, after hospital discharge, underwent pelvic floor rehabilitation under the guidance of an experienced physiotherapist. data collected included demographics (age, height, weight, waistline, bmi), preoperative factors (preoperative total psa, plasma levels of total cholesterol, hdl, triglycerides, and glucose, preoperative iief-5, preoperative ipss-qol, risk of extracapsular extension calculated with the memorial sloan kettering cancer center (mskcc) nomogram) (table 1), perioperative metrics (operative time, estimated blood loss, white blood cell changes up to 24 hours after surgery, nerve-sparing rates, pre-operative and post-operative gleason score, pre-operative and post operative isup grade) (tables 2-4), oncological outcomes (positive surgical margins, postoperative psa levels at 3, 6, 9, and 12 months), and postoperative functional outcomes. urinary continence was evaluated at 3, 6, 9, and 12 months using a continence score based on three levels (0 complete incontinence, 1 stress incontinence table 1. pre-operative characteristics of patients: pde5i alone vs. pde5i combined with vacuum: comparison of preoperative demographic, clinical, and biochemical characteristics between patients treated with pde5 inhibitors (pde5i) alone and those treated with pde5i combined with vacuum therapy. data are presented as median (range), and p-values indicate statistical comparisons between the two groups. pde5i pde5i + vacuum p value age (years) 68 (54-75) 69.7 (63-76) 0.07 height (mt) 1.73 (1.65-1.88) 1.77 (1.7-1.9) 0.29 weight (kg) 81.7 (56-105) 71 (60-97) 1.96 waist circumference (cm) 90.9 (70-110) 86.25 (78-94) 0.0004 bmi 27.2 (19.52-35.3) 23.34 (20.8-29.76) 1.41 prostate volume (ml) 53.96 (20-142) 45.6 (27-85) 0.08 pre-operative total psa (ng/ml) 9.4 (5.5-31.5) 8.86 (5-13.5) 0.50 total cholesterol (mg/dl) 180.7 (112-263) 179.6 (101-269) 0.89 hdl (mg/dl) 51.27 (35-104) 48.6 (40-75) 0.24 triglycerides (mg/dl) 111.34 (56-371) 120.5 (58-169) 0.20 glycemia (mg/dl) 100.22 (78-172) 100.1 (73-141) 0.88 pre-operative iief5 score 13 (0-25) 15 (2-24) 0.14 pre-operative ipss voiding score 6 (0-14) 7 (2-13) 0.12 pre-operative ipss storage score 4 (0-12) 4 (0-11) 0.79 pre-operative qol score 4 (0-10) 3 (0-8) 0.02 risk of extracapsular invasion (mrkcc score) 52.5 (11-98) 49.6 (15-90) 0.58 table 2. intraoperative and pathological outcomes: pde5i vs pde5i plus vacuum groups: comparison of operative time and pathological outcomes, including positive surgical margins, nerve-sparing rates, and incidences of perineural and vascular invasion, between patients treated with pde5 inhibitors (pde5i) alone and those treated with pde5i combined with vacuum therapy. data are presented as median (range) or percentages, with p-values indicating statistical significance. pde5i pde5i + vacuum p value operative time (min), mean (range) 205 (130-365) 200 (110-290) 0.62 positive surgical margins (%) 32.86 3.39 0.0029 nerve sparing procedures (%) 35.71 19.35 0.158 neural invasion (%) 71.43 51.61 0.087 vascular invasion (%) 10 35.48 0.005 archivio italiano di urologia e andrologia 2025; 97(2):13639 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 4 iief-5 scores and continence recovery at multiple time points. multivariate analyses utilizing a random forest regression model assessed the predictive significance of variables such as age, bmi, psa levels, and nerve-sparing status. a significance level of p < 0.05 was applied. results a total of 101 patients were analysed, divided into group 1 (pde5i only, n=70) and group 2 (pde5i + vacuum, n = 31). baseline characteristics, including age, bmi, preoperative iief-5 scores, and psa levels, were comparable between the two groups. the mean age of participants was 68 years (range: 54-76), with a median bmi of 26.7 kg/m² (iqr: 24.5-28.3). preoperatively, group 2 exhibited a slightly higher median iief-5 score compared to group 1 (15 vs. 13; p = 0.14), but this difference was not table 3. comparison of preoperative and postoperative gleason scores in pde5i vs. pde5i combined with vacuum therapy groups: distribution of gleason scores from preoperative biopsy and postoperative robotic-assisted radical prostatectomy (rarp) specimens in patients treated with pde5 inhibitors (pde5i) alone and those treated with pde5i combined with vacuum therapy. data are presented as the number of patients (n) and percentages (%). pre operative gleason (biopsy) post operative gleason (rarp) gleason, n°(%) pde5i pde5i + vacuum pde5i pde5i + vacuum 6 (3+3) 32 (45.71) 14 (45.16) 21 (30) 6 (19.35) 7 (3+4) 18 (25.71) 7 (22.58) 35 (50) 11 (35.48) 7 ( 4+3) 13 (18.57) 4 (12.9) 10 (14.29) 8 (25.81) 8 (4+4) 6 (8.57) 3 (9.68) 3 (4.29) 3 (9.68) 8 (3+5) 3 (9.68) 8 (5+3) 1 (1.43) 3 (9.68) 9 (5+4) 1 (1.43) table 4. comparison of preoperative and postoperative isup grades in both pde5i vs. pde5i combined with vacuum therapy groups: distribution of international society of urological pathology (isup) grades from preoperative biopsy and postoperative roboticassisted radical prostatectomy (rarp) specimens in patients treated with pde5 inhibitors (pde5i) alone and those treated with pde5i combined with vacuum therapy. data are expressed as percentages (%), with chi-squared statistics and p-values provided for comparisons: no significant differences were found. pre operative gleason (biopsy) post operative gleason (rarp) isup grade (%) pde5i pde5i + vacuum pde5i pde5i + vacuum 1 45.71 45.16 27.14 19.35 2 21.43 22.58 55.71 64.52 3 22.86 19.35 14.29 6.45 4 1.43 12.9 2.86 9.68 chi2 statistic: 3.635 chi2 statistic: 3.940 p value: 0.457 p value: 0.268 table 5. comparison of iief scores between 'pde5i + vacuum' and 'solo pde5i' groups: this table compares the mean iief scores and ranges (min-max) between the two treatment groups at each time point. p-values indicate the statistical significance of differences, with values below 0.05 considered significant. pde5i pde5i + vacuum p value pre-operative iief 13.16 (0-25) 15.1 (0-22) 0.148 post-operative iief 1 month, mean score (range) 1.1 (0-12) 4.4 (0-23) 0.012 post-operative iief 3 months, mean score (range) 2.5 (0-16) 7.4 (0-23) 0.0001 post-operative iief 6 months, mean score (range) 3.3 (0-16) 10.2 (0-25) 0.000 post-operative iief 9 months, mean score (range) 2.5 (0-15) 10.2 (0-25) 0.000 post-operative iief 12 months, mean score (range) 2.5 (0-15) 10.2 (0-25) 0.000 table 6. comparison of pad usage between pde5i + vacuum and solo pde5i groups: this table presents the mean number of pads used daily at various time points (1, 3, 6, 9, and 12 months post-operatively) for each treatment group. p-values indicate the statistical significance of group differences. pde5i pde5i + vacuum p value pad used at 1 month, mean number 3.32 3.87 0.410 pad used at 3 months, mean number 2.67 2.54 0.813 pad used at 6 months, mean number 1.62 1.32 0.358 pad used at 9 months, mean number 1.08 0.54 0.034 pad used at 12 months, mean number 0.55 0.38 0.413 and 2 full continence). the variation in the number of daily pads used over the same time period was also calculated. erectile function was assessed by the iief-5 at 3, 6, 9, and 12 months) (tables 5, 6) (figures 1, 2). statistical analyses were conducted using systematically collected and recorded data. anthropometric parameters, biopsy types, prostate volumes, clinical stages, comorbidities, preand postoperative blood levels (including psa and hemoglobin), operative times, histopathological findings, oncological and functional outcomes were included. functional outcomes evaluated total psa levels, urinary continence, and sexual potency at 1, 3, 6, 9, and 12 months post-procedure. comparative analyses included t-tests or welch’s t-tests for continuous variables and chi-squared or fisher’s exact tests for categorical data. repeated measures anova and linear regression models were used to analyse trends in archivio italiano di urologia e andrologia 2025; 97(2):13639 5 vacuum therapy compared to pde5i statistically significant. similarly, no significant differences were observed in psa levels (9.4 vs. 8.86 ng/ml; p = 0.50) or mskcc-calculated extracapsular extension risk (52.5% vs. 49.6%; p = 0.58) (table 1). postoperative erectile function recovery, as measured by iief-5 scores, demonstrated a marked improvement in group 2 across all time points. at 12 months, the mean iief-5 score was significantly higher in group 2 (10.2 vs. 2.5; p < 0.001). early recovery trends were also more favorable in group 2, with significant differences at 3 months (4.4 vs. 1.1; p = 0.012) and 6 months (10.2 vs. 3.3; p < 0.001) (table 6, figure 1). continence recovery, as assessed by the number of daily pads used and continence scores, showed earlier improvements in group 2 compared to group 1. at 3 and 6 months, continence scores were significantly higher in group 2 (1.58 vs. 1.28; p = 0.025 and 1.58 vs. 1.21; p = 0.004, respectively). pad usage trends mirrored these results, with fewer pads required in group 2 at 6 months (1.32 vs. 1.62; p = 0.358) and 9 months (0.54 vs. 1.08; p = 0.034). by 12 months, no significant differences were observed between the groups in continence scores (1.14 vs. 1.26; p = 0.239) or pad usage (0.38 vs. 0.55; p = 0.413) (tables 7, figure 2). figure 1. iief trend comparison: pde5i + vacuum vs. pde5i. this line graph compares the mean iief scores of the 'pde5i + vacuum' group and the 'pde5i' group at six time points. statistical significance is evident at multiple intervals, highlighting the superiority of combined treatment. figure 2. pad usage over time in pde5i + vacuum and pde5i groups. this line graph depicts the mean number of pads used daily by patients in each group across 12 months post-operatively, highlighting differences in recovery trajectories.combined treatment. archivio italiano di urologia e andrologia 2025; 97(2):13639 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 6 multivariate analysis using random forest regression identified several factors influencing postoperative recovery. for erectile function, postoperative hemoglobin levels, age, nerve-sparing status, and bmi were the most significant predictors (tables 7, 8). on the other hand, preoperative bmi, mskcc-calculated extracapsular extension risk, and baseline continence scores primarily influenced continence recovery. pre-operative metabolic markers (e.g., triglycerides, glucose) and hemoglobin levels are strong determinants of continence recovery and pad reduction (table 9). the combination of pre-operative hemoglobin and postoperative hemoglobin shows a notable negative interaction coefficient (-0.322). this suggests that patients with lower pre-operative hemoglobin but better recovery post-operatively may benefit more in terms of pad usage. the regression models incorporating interaction terms achieved an r^2 of approximately 0.37, indicating that these interactions moderately explain the variance in recovery outcomes. negative interaction coefficients imply counteracting effects, where the combined influence of two factors on pad usage diminishes their individual impacts. recovery outcomes like pad usage are influenced not just by individual factors but also by their interplay (e.g., metabolic health and peri-operative recovery (table 9). postoperative psa levels and operative time had limited impact on both outcomes. overall, the combination of pde5 inhibitors with vacuum therapy resulted in significant improvements in erectile function recovery and earlier continence recovery. these benefits were particularly pronounced during the intermediate postoperative period, highlighting the potential of combined therapy to optimize functional outcomes following robotic-assisted radical prostatectomy. discussion the early initiation of vacuum therapy has demonstrated a significant advantage in enhancing the recovery of erectile function. patients who began vacuum therapy within a median of 20 days postoperatively exhibited superior iief-5 scores at all evaluated time points compared to those treated with pde5i alone. this finding highlights the potential synergistic effect of combining pharmacological and mechanical interventions. moreover, the combination of vacuum therapy with pde5i addresses both the structural and physiological facets of ed recovery. clinical trials have consistently highlighted the efficacy of multimodal approaches in improving both iief scores and the rate of spontaneous erections (6-14). vacuum therapy likely exerts its benefits by improving cavernosal oxygenation and reducing oxidative stress, thereby mitigating fibrosis risk and promoting endothelial repair (9, 10). the protective effects of vacuum therapy, mediated through antihypoxic and antifibrotic mechanisms, have been substantiated in both clinical and preclinical studies (4, 5). the findings of this study align with existing literature on table 7. feature importance analysis for iief recovery at 12 months using random forest: this table presents the relative importance of various pre-operative and peri-operative factors in predicting iief recovery at 12 months postoperatively. feature importance was calculated using a random forest model, which accounts for non-linear relationships and interactions among variables. feature importance fasting blood glucose 0.307 total colesterol 0.169 prostatic volume 0.102 post-operative hb 0.064 pre-operative psa 0.061 pre-operative hb 0.043 qol score 0.043 triglyceridemia 0.039 hdl 0.037 ipss storage score 0.032 ipss voiding score 0.029 operative time 0.028 statin therapy 0.019 age (years) 0.016 therapy for hypertension 0.007 table 8. partial regression analysis results for iief recovery at 12 months: this table presents the results of partial regression analysis, showing the unique contribution of the top five most important factors identified by the random forest model. partial 𝑅2 values indicate the proportion of variance in iief recovery at 12 months that can be attributed to each factor, independent of the others. feature partial r^2 post-operative hb (12 h) 0.029 prostatic volume 0.026 fasting blood glucose 0.021 pre-operative psa 0.011 total colesterol 0.002 table 9. most significant factors influencing continence and pad recovery: this table highlights the most significant factors based on their unique contributions (max partial r2) and interaction effects (max interaction coefficient) on continence recovery and pad usage. factors with high partial r2 explain a larger portion of the outcome variance, while significant interaction coefficients indicate combined effects with other variables. factor max partial r^2 max interaction coefficient fasting blood glucose (mg/dl) 0.113 0.008 post-operative hb (entro 12 h) 0.057 triglyceridemia (mg/dl) 0.114 0.003 antihypertensive therapy 0.191 hdl (mg/dl) 0.156 operative time (min.) 0.204 pre-operative hb (mg/dl) 0.057 archivio italiano di urologia e andrologia 2025; 97(2):13639 7 vacuum therapy compared to pde5i the benefits of early initiation of penile rehabilitation. as demonstrated by kohler et al., early use of ved therapy post-rarp significantly improves iief scores and prevents penile shortening (5). the observed correlation between intraoperative blood loss and iief-5 recovery underscores the interplay of perioperative factors and functional outcomes. patients with significant blood loss experienced greater reductions in hemoglobin levels, potentially impairing tissue oxygenation and delaying neurovascular recovery. hypoxia, known to suppress nitric oxide (no) synthesis and reduce cyclic guanosine monophosphate (cgmp)-mediated vasodilation, further compromises erectile function. these findings emphasize the importance of minimizing blood loss during surgery and ensuring optimal postoperative hemoglobin levels (7, 8). regarding continence recovery, vacuum therapy facilitated earlier improvements, particularly within the first six months postoperatively. enhanced vascularization and tissue remodelling, as described by du et al. (2018), likely contributed to accelerated healing of sphincteric and periurethral tissues. however, by 12 months, continence outcomes were comparable between groups, suggesting that vacuum therapy’s primary benefit lies in promoting early recovery (10-12). the timing of intervention plays a critical role, with studies indicating that early initiation within one month postsurgery yields superior outcomes compared to delayed protocols (5, 6). conversely, some studies have questioned the direct impact of vacuum therapy on continence, attributing outcomes primarily to factors such as preoperative bmi, baseline continence status, and surgical technique. this perspective underscores the multifactorial nature of continence recovery and highlights the need for comprehensive patient assessments and individualized rehabilitation strategies (7-13). the neuroprotective role of vacuum therapy is further corroborated by animal studies, which demonstrated its capacity to enhance enos expression, reduce apoptosis, and preserve smooth muscle integrity (4, 5). these findings suggest that vacuum therapy not only facilitates functional recovery but also contributes to long-term preservation of penile tissue architecture. additionally, patient satisfaction and adherence are critical for the success of rehabilitation protocols. studies have noted that the empowerment derived from active participation in therapy, such as vacuum use, enhances patient compliance and psychological well-being (5-14). future research should explore the integration of emerging modalities, such as low-intensity extracorporeal shockwave therapy (lieswt), alongside established therapies to further optimize recovery (4-14). according to literature evidences, this study shows that early introduction of vacuum therapy in association to ped5i administration improves erectile function recovery and facilitating early continence restoration. older patients and those with metabolic disorders may derive particular benefit from this approach due to their predisposition to slower recovery. while the physiological mechanisms underlying these benefits align with current evidence on cavernosal and pelvic floor rehabilitation, additional investigations are necessary to clarify the connection between perioperative factors and long-term functional outcomes, with particular attention to the correlation between intraoperative blood loss and the recovery of functional outcomes. a comprehensive, multimodal rehabilitation strategy tailored to individual patient profiles remains paramount in addressing the multifaceted challenges of post-rarp recovery. conclusions this study highlights the significant benefits of combining vacuum therapy with pde5i in the rehabilitation of functional outcomes following rarp. the findings underscore that early initiation of this multimodal approach facilitates improved recovery of erectile function, as evidenced by higher iief-5 scores, and accelerates continence recovery during the early postoperative period. vacuum therapy enhances cavernosal oxygenation, reduces fibrosis, and promotes endothelial repair, complementing the pharmacological effects of pde5 inhibitors. the study also identifies critical factors influencing recovery, such as age, metabolic health, and perioperative varideclarations ethical approval: this study was approved by the local ethics committee of bari (ba), irccs oncological institute "gabriella serio" (protocol number: 2112/cel study “propt”). availability of data and material: the datasets generated and analysed during the current study are available from the corresponding author upon reasonable request. competing interests: the authors declare no competing interests. funding: this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. authors' contributions (according to http://www.icmje.org/ #author): 1: p.p. prontera author corresponding substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 2: f.r. prusciano, f.s. grossi: substantial contributions to the conception, design of the work, acquisition, analysis and interpretation of data for the work. drafting the work, reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; 3: m. lattarulo, a. tsaturyan, f. addabbo, c. sciorio: substantial contributions to the interpretation of data for the work. reviewing it critically for important intellectual content. final approval of the version to be published. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13639 p.p. prontera, f.r. prusciano, m. lattarulo, et al. 8 ables, emphasizing the importance of individualized rehabilitation protocols. while the combined therapy demonstrates clear advantages in improving functional outcomes, the results also reveal the importance of early intervention to optimize recovery trajectories. despite these promising findings, further research is warranted to strengthen the evidence regarding the predictive factors for the success of vacuum therapy, enabling a more tailored approach to treatment. additionally, future studies should delve deeper into the correlation between intraoperative blood loss and delays in the recovery of erectile function, as measured by the iief-5, to optimize postoperative rehabilitation strategies further. in conclusion, the synergistic effects of vacuum therapy and pde5i provide a robust foundation for developing tailored, evidence-based strategies that address the multifaceted challenges of functional recovery post-rarp. this multimodal approach not only improves patient outcomes but also fosters greater satisfaction and adherence to rehabilitation, ultimately enhancing quality of life. references 1. grossi fs, utano e, minafra p, et al. oncological and functional outcomes of extraperitoneal laparoscopic radical prostatectomy: an 18-years, single-center experience. arch ital urol androl 2021; 93:3. 2. salciccia s, rosati d, viscuso p, et al. influence of operative time and blood loss on surgical margins and functional outcomes for laparoscopic versus robotic-assisted radical prostatectomy: a prospective analysis. cent european j urol. 2021; 74:503-515 3. quin f, wang s, li j, et al. the early use of vacuum therapy for penile rehabilitation after radical prostatectomy: systematic review and meta-analysis. am j mens health 2018; 12:2136-2143. 4. yuan j., lin h, li p, et al. molecular mechanisms of vacuum therapy in penile rehabilitation: a novel animal study. eur urol 2010; 58:773-780. 5. kohler ts, pedro r, hendlin k, et al. a pilot study on the early use of the vacuum erection device after radical retropubic prostatectomy. bju international 2007; 100:858-862. 6. soderdahi dw, thrasher jb, hansberry k. intracavernosal druginduced erection therapy versus external vacuum devices in the treatment of erectile dysfunction. bju 1997; 79:952-957. 7. patel hr, ilo d, shah n, et al. effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy: quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized, placebo-controlled phase iv study. bmc urology 2015; 15:31. 8. djavan b, agalliu i, laze j, et al. blood loss during radical prostatectomy: impact on clinical, oncological and functional outcomes and complication rates. bju int. 2012; 110:69-75. 9. lin h, wang r. the science of vacuum erectile device in penile rehabilitation after radical prostatectomy. transl androl urol 2013; 2:61-66. 10. du y, long q, guan b, et al. robot-assisted radical prostatectomy is more beneficial for prostate cancer patients: a system review and meta-analysis. med sci monit, 2018; 24:272-287. 11. preisser f, pompe rs, salomon g, et al. impact of the estimated blood loss during radical prostatectomy on functional outcomes. urol oncol. 2019; 37:298.e11-298.e17. 12. schoentgen n, califano g, manfredi c, et al. is it worth starting sexual rehabilitation before radical prostatectomy? results from a systematic review of the literature. front surg. 2021 8:648345. 13. lane j.a., donovan j.l., young g.j., et al. functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment (protect) study) bju int 2022; 130: 370-380. 14. nicolai m., urkmez a., sarikaya s. et al. penile rehabilitation and treatment options for erectile dysfunction following radical prostatectomy and radiotherapy: a systematic review. front. surg. 2021; 8:636974. correspondence pier paolo prontera, md (corresponding author) pierpaolo.prontera@asl.taranto.it marco lattarulo, md marco.lattarulo@asl.taranto.it francesco saverio grossi, md, phd francescos.grossi@asl.taranto.it department of urology, “s.s. annunziata” hospital via bruno francesco, 1 street 74010 taranto (italy) francesca romana prusciano, md francescaprusciano@gmail.com division of urology, hospital “valle d’itria”, martina franca (ta), italy arman tsaturyan, md, phd tsaturyanarman@yahoo.com department of urology, yerevan state medical university after mkhitar, heratsi, yerevan, armenia carmine sciorio, md carmine.sciorio@gmail.com department of urology, “alessandro manzoni” hospital of lecco, 23900 (italy) stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):13295 1 original paper introduction percutaneous nephrolithotomy (pcnl) is the gold standard procedure to treat relatively large renal stones (> 2 cm) with a high success rate but still with significant morbidity despite technical advances. there is no consensus on an ideal predictive model of morbidity outcomes following pcnl. available predictive tools aim at assessing the kidney stone complexity to predict the stone-free rate. they include the guy’s stone score, the croes nomogram, s.t.o.n.e. nephrolithometry, seoul national university renal stone complexity (s-resc) score, and the simple stone score (sss) (1-5). in our opinion, the risk of surgical complications is an important variable that should guide clinical decision-making. in comparative studies, none of the available scoring systems was fully satisfactory in predicting surgical complications (6). considering the deficient literature in assessing post-pcnl morbidity, this study was conducted to develop a widely applicable, simple disease stratification tool that will greatly improve patient counseling, surgical planning, evaluation of outcomes, and academic reporting. methods patient data a total of 631 patients who underwent pcnl at the collaborating centers were retrospectively analyzed. the prointroduction: a model to predict the risk of surgical complications following percutaneous nephrolithotomy (pcnl) could be a useful tool to guide clinical decision-making. the aim of this study was to develop a simple and widely applicable stratification tool to be used for patient counseling, surgical planning, evaluation of outcomes, and academic reporting. methods: data of patients who underwent pcnl were retrieved from the database of the collaborating centers including demographics of patients, characteristics of their stones and urinary tracts, and perioperative data. the primary outcome was the development of postoperative complications. data were randomly split into a training dataset (85%) and a validation dataset (15%). a univariate and multivariate logistic regression analysis of the training dataset was performed to identify independent predictors of postoperative complications. model variables were used to construct a nomogram that was internally validated on the testing dataset by measuring calibration, discrimination, and plotting the decision curve. results: six hundred thirty one patients (245 males) with a median (iqr) age of 49 (37-56) years were included. post-operative complications occurred in 147 (23.3%) patients. significant predictors of complications included preoperative urine culture (p < 0.001), largest stone diameter (p = 0.02), and intraoperative blood loss (p = 0.002). a nomogram was developed from the predictors and applied to the validation dataset showing an area under the curve (95%ci) of 66.4% (52.2;80.6). conclusions: this new scoring system emphasized patient characteristics and operative details rather than stone characters to predict the morbidity of pcnl. furthermore, it should facilitate risk adjustment, enabling physicians to better define the nephrolithiasis disease continuum and identify patients who should be referred to tertiary care centers. development and internal validation of el-shazly-buchholz’s nomogram to predict postoperative complications after pcnl: a multicenter study rawa bapir 1, 2, kamran bhatti 3, mohamed el-shazly 4, juan antonio galan 5, ahmed m. harraz 6, 7, sarwar noori mahmood 8, renato n. pedro 9, pablo vargas 10, athanasios papatsoris 11, 12, alberto trinchieri 12, noor buchholz 12 1 department of urology, sulaymaniyah surgical teaching hospital, sulaymaniyah, iraq; 2 smart health tower, madam mitterrand street, sulaymaniyah, iraq; 3 hmc medical corporation, al khor, qatar; 4 menoufia university, shebin elkom 32714, egypt; 5 department of urology, dr. balmis general university hospital, alicante institute for health and biomedical research (isabial), alicante, spain; 6 mansoura university urology and nephrology center, mansoura, egypt; 7 farwaniya hospital and sabah al ahmad urology center, kuwait city, kuwait; 8 department of surgery, college of medicine, university of sulaymaniyah, sulaymaniyah, iraq; 9 division of urology, faculdade de medicina são leopoldo mandic de campinas, sao paulo, brazil; 10 marina baixa hospital. la vila joiosa. alicante. spain; 11 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens; 12 u-merge scientific office. doi: 10.4081/aiua.2024.13295 summary key words: percutaneous nephrolithotomy; complications; urine culture; stone diameter; intraoperative blood loss. submitted 24 october 2024; accepted 28 october 2024 archivio italiano di urologia e andrologia 2024; 96(4):13295 r. bapir, k. bhatti, m. el-shazly, et al. 2 cedures used in this study adhere to the tenets of the declaration of helsinki (as revised in 2013). approval was obtained from the research ethics committees of medical research center hmc (mrc-01-20-385). because of its retrospective nature, the consent was waived from the participants. all the information collected during the research project remained confidential to the extent required and provided by law. patient data were anonymized, coded, and kept by the principal investigator. the preoperative clinical data included age, gender, body mass index (bmi), recurrent stone status, previous renal surgery in the ipsilateral kidney, associated comorbidities, the american society of anesthesia (asa) score, preoperative urine culture, and diagnostic imaging (modality). stone characteristics were the stone diameter, burden, density (hounsfield unit), and the number of involved calyces. intraoperative documented data included pcnl position, operative time, number of tracts, size of the tract, intraoperative blood loss (hb loss > 2 gr/dl), pus on the puncture, residual fragments size and number, exit strategy, combination with retrograde intrarenal surgery (rirs), and the caseload of surgeon per year. postoperatively, collected data were fever, urine culture, sepsis, bleeding, postoperative transfusion, length of hospital stay, and stone-free status/residual fragments. study outcome the primary outcome was the development of postoperative complications by clavien-dindo system (7). a secondary outcome was the development of postoperative infectious complications. statistical analysis the data were randomly split into a training dataset (85%) and a validation dataset (15%). in the training dataset, a univariate and multivariate logistic regression analysis was performed to identify independent predictors of the occurrence of any postoperative complication. statistical significance was determined using the chisquare or fischer's exact tests for categorical variables whenever appropriate. mann-whitney u or student ttests were used for non-parametric and parametric variables, respectively. model variables were used to construct a nomogram. the nomogram was internally validated by measuring calibration, discrimination, and plotting the decision curve. a calibration plot was generated to identify how much predicted nomogram probabilities match the actual post-operative complications values. the discrimination was evaluated by calculating the area under the curve (desired when more than 50%). decision curve analysis reveals the net benefit of using the model to detect postoperative complications. the decision curve compares the ability of the nomogram to distinguish the occurrence or absence of complications according to a range of threshold probabilities. if the decision curve shows a higher net benefit, it is clinically beneficial. statistical analysis was performed using r programming language version 4.1.2. with p-value less than 0.05 was considered statistically significant. results patients’ demographics a total of 631 patients with a median (iqr) age of 49 (37:56) years were included. female patients constituted 38.83% while obese patients (> 30 bmi) accounted for 43.26%. four institutions contributed to the current study [j: 100 (15.85%), m: 99 (15.69%), r: 332 (52.61%), and u: 100 (15.85%) patients]. postoperative complications occurred in 147 (23.3%) patients. after random splitting, there was no significant difference between both groups. the difference between both groups is shown in table 1. table 1. comparison between training and validating datasets for patients who underwent percutaneous nephrolithotomy in 4 institutions. parameter train validate p-value institutions 0.3 j 79 (14.74%) 21 (22.11%) m 83 (15.49%) 16 (16.84%) r 287 (53.54%) 45 (47.37%) u 87 (16.23%) 13 (13.68%) age median (iqr) 50 (38:56) 47 (34.5:55) 0.09 gender 0.6 female 205 (38.25%) 40 (42.11%) male 331 (61.75%) 55 (57.89%) bmi, median (iqr) 29.31(26.1:32.1) 28.5 (26.7:32.8) 0.9 obesity 0.2 non-obese 298 (55.6%) 60 (63.16%) obese 238 (44.4%) 35 (36.84%) recurrent one 0.7 no 375 (69.96%) 64 (67.37%) yes 161 (30.04%) 31 (32.63%) previous one surgery 0.6 no 380 (70.9%) 64 (67.37%) yes 156 (29.1%) 31 (32.63%) diabetes mellitus 0.7 no 474 (88.43%) 86 (90.53%) yes 62 (11.57%) 9 (9.47%) hypertension 0.3 no 444 (82.84%) 83 (87.37%) yes 92 (17.16%) 12 (12.63%) asa score 0.5 i 310 (57.84%) 54 (56.84%) ii 194 (36.19%) 38 (40%) iii 32 (5.97%) 3 (3.16%) preoperative urine culture 0.7 negative 490 (91.42%) 85 (89.47%) positive 46 (8.58%) 10 (10.53%) lsd, mm, median (iqr) 30 (20:41) 32 (25:40) 0.2 number of involved calyces 0.5 0 103 (19.22%) 16 (16.84%) 1 196 (36.57%) 31 (32.63%) 2 102 (19.03%) 24 (25.26%) 3 135 (25.19%) 24 (25.26%) hu, mean (sd) 1037 (312.9) 971.2 (325.5) 0.07 sheath size 0.1 mini 164 (30.6%) 21 (22.11%) standard 372 (69.4%) 74 (77.89%) or time, min, median (iqr) 70 (35:120) 80 (45:130) 0.07 intraoperative blood loss 0.5 no 494 (92.16%) 90 (94.74%) yes 42 (7.84%) 5 (5.26%) residual fragment 0.1 no 424 (79.1%) 68 (71.58%) yes 112 (20.9%) 27 (28.42%) los, days, median (iqr) 1 (1:2) 1 (1:3) 0.2 archivio italiano di urologia e andrologia 2024; 96(4):13295 3 development and internal validation of el-shazly-buchholz’s nomogram to predict postoperative complications after pcnl... predictors of complications in the training dataset significant variables include preoperative urine culture [positive: 24 (5.78%) versus 22 (18.18%), p < 0.001], median (iqr) largest stone diameter [30 (20:40) versus 35 (22:48), p = 0.02], intraoperative blood loss [24 (5.78%) versus 18 (14.88%), p = 0.002]. data are displayed in table 2. on multivariate logistic regression analysis, independent predictors were intra-operative blood loss [odds ratio (or) and 95% confidence interval (ci): 2.5 (1.2:4.9), p = 0.007], preoperative urine culture [or (95%ci): 3.2 (1.6:6), p < 0.001] (table 3). nomogram development and validation a nomogram was developed from the predictors and is displayed in figure 1. the nomogram is applied to the validation dataset. the area under the curve (95%ci) was 66.4 (52.2; 80.6). regarding calibration, the nomogram's predicted probabilities slightly overestimated the post-operative complications' actual occurrence. the calibration plot is displayed in figure 2a. the decision curve shows a higher net benefit of the model in a wide range of thresholds (25%-75%). therefore, the model is performing better in this range of thresholds than if treatment of complications is considered in all patients or in none of the patients. results are displayed in figure 2b. table 2. univariate and logistic regression analysis for predictors of post-pcnl complications. parameter complications p-value no yes age median (iqr) 49 (38:56) 51 (37:62) 0.2 gender 1 female 158 (38.07%) 47 (38.84%) male 257 (61.93%) 74 (61.16%) bmi median (iqr) 29.3 (26.1:32.1) 29.3 (25.3:31.9) 0.5 recurrent stone 0.5 no 294 (70.84%) 81 (66.94%) yes 121 (29.16%) 40 (33.06%) diabetes mellitus 0.3 no 363 (87.47%) 111 (91.74%) yes 52 (12.53%) 10 (8.26%) hypertension 0.05 no 336 (80.96%) 108 (89.26%) yes 79 (19.04%) 13 (10.74%) preoperative urine culture < 0.001 negative 391 (94.22%) 99 (81.82%) uti 24 (5.78%) 22 (18.18%) lsd, mm, median (iqr) 30 (20:40) 35 (22:48) 0.02 number of involved calyces 0.07 0 89 (21.45%) 14 (11.57%) 1 150 (36.14%) 46 (38.02%) 2 73 (17.59%) 29 (23.97%) 3 103 (24.82%) 32 (26.45%) hu, mean (sd) 1038.7 (319.3) 1031(291) 0.8 sheath size 1 mini 127 (30.6%) 37 (30.58%) standard 288 (69.4%) 84 (69.42%) intraoperative blood loss 0.002 no 391 (94.22%) 103 (85.12%) yes 24 (5.78%) 18 (14.88%) no. of punctures 0.5 single 362 (87.23%) 102 (84.3%) multiple 53 (12.77%) 19 (15.7%) rf number, median (iqr) 1 (1:2) 1 (1:2) 0.3 drainage 0.08 jj 11 (2.65%) 9 (7.44%) jj and pcn 304 (73.25%) 81 (66.94%) pcn 60 (14.46%) 16 (13.22%) tubeless 40 (9.64%) 15 (12.4%) bmi: body mass index; lsd: largest stone diameter; hu: hounsfield units; or: operation; los: length of stay. * mode of drainage after the procedures. table 3. multivariate logistic regression analysis for predictors of postoperative complications after percutaneous nephrolithotomy. b or (95% ci) p-value (intercept) -1.807 0.164 (0.09:0.2) < 0.001 intraoperative blood loss (yes) 0.925 2.521 (1.2:4.9) 0.007 preoperative urine culture (positive) 1.168 3.215 (1.6:6.1) < 0.001 largest stone diameter, mm 0.01 1.01 (0.9:1.02) 0.1 b: regression coefficient; or: odds ratio; ci: confidence interval. figure 1. nomogram for the evaluation of the risk of complications after pcnl. parameter train validate p-value stone free status 0.2 no 106 (19.78%) 25 (26.32%) yes 430 (80.22%) 70 (73.68%) no. of punctures 0.07 single 464 (86.57%) 75 (78.95%) multiple 72 (13.43%) 20 (21.05%) rf number, median (iqr) 1 (1:2) 1 (1:2) 0.9 pcn only * 0.3 f no 21 (4.36%) 1 (1.32%) yes 461 (95.64%) 75 (98.68%) jj only * 0.6 yes 405 (84.02%) 66 (86.84%) no 77 (15.98%) 10 (13.16%) pcn and jj * 0.3 no 97 (20.12%) 11 (14.47%) yes 385 (79.88%) 65 (85.53%) postoperative complications 0.4 no 415 (77.43%) 69 (72.63%) yes 121 (22.57%) 26 (27.37%) infectious complications 0.3 no 432 (80.6%) 72 (75.79%) yes 104 (19.4%) 23 (24.21%) bmi: body mass index; asa: american society of anesthesiology; lsd: largest stone diameter; hu: hounsfield units; or: operation; los: length of stay. * mode of drainage after the procedures. archivio italiano di urologia e andrologia 2024; 96(4):13295 r. bapir, k. bhatti, m. el-shazly, et al. 4 discussion literature exhibits multiple stone scoring systems for evaluating outcomes of percutaneous nephrolithotomy including the guy’s stone score, the clinical research office of the endourological society (croes) nomogram, the s.t.o.n.e. score, and the s-resc score (1-5). the pivotal variables in all the scoring systems are stone location, stone number, and the presence of staghorn calculi. the guy’s stone score stratifies patients into four grades, where grade i indicates a solitary stone with simple anatomy (mid-lower pole or renal pelvis), grade ii a solitary stone in the upper pole or multiple stones with simple anatomy or a solitary stone with abnormal anatomy, grade iii multiple stones with abnormal anatomy or stones in a calyceal diverticulum or partial staghorn stone, and grade iv staghorn stone or any stone in a patient with spina bifida or spinal injury. the s.t.o.n.e. score classifies patients into low-, moderate-, and highrisk groups according to stone size (s), tract length (t), obstruction (o), number of involved calyces (n), and essence (e) (composition or stone density). the croes nomogram grades risk across a continuous scale considering the stone burden, location, number, and surgical volume. the s-resc scoring system subdivides the pelvicaliceal system in nine locations and the score is the cumulative sum of the locations involved by the stone. several studies evaluated the efficacy of these stone-scoring systems in predicting the stone-free status and the incidence of complications after percutaneous nephrolithotomy. a systematic review (6) of ten studies (8-17) with metanalysis compared the efficacy of the stone scoring systems in predicting stone-free rate after pcnl most of them confirming their equal predictive efficacy of the stone-free rate. stone free status was negatively related to guy’s (wmd = -0.64, p < 0.0001) and s.t.o.n.e. score (wmd = -1.23, p < 0.0001) and positively to the score of croes nomogram (wmd = 29.48, p = 0.003). no significant difference between the three stone scoring nomogram was found at comparison of area under curves (auc) of predicting stone free rate. a secondary outcome of the systematic review of jiang et al. (6) was the comparison of the efficacy of the stone score systems in predicting complications after pcnl. tailly et al. (16) and sfoungaristos et al. (15) did not find correlation between stone scores and complication rates. similarly, noureldin et al. (14) and kocaaslan et al. (12) observed no significant correlation of guy score and s.t.o.n.e. score with complications after pcnl. only bozkurt et al. (8) observed a correlation of guy’s score and the croes nomogram with complication rates after pcnl. in addition, choi et al. (10) compared the predictability of the outcomes of tubeless pcnl using the guy score, croes nomogram, and s.t.o.n.e. score showing that only the guy score was able to predict the complication rate after pcnl. the metanalysis showed that only the guy’s score was able to predict complications after pcnl (wmd = 0.29, 95% ci: -0.57 to -0.02, p = 0.03). a systematic review (18) specifically focused on the correlation between stone scoring systems and postoperative complications after pcnl in adult patients adding six studies (19-24) to the 5 studies (9, 10, 13, 16, 17) previously considered by the systematic review of jiang et al. (6). a significant correlation with complications was obtained with guy’s stone score in 6 out 9 studies, with s.t.o.n.e. nephrolithometry score in 4 out 11 studies, with croes score in 3 out 9 studies and with s-resc score in one of two studies, respectively. other studies (16, 19-21) showed no correlation between nomograms and post-surgical complications graded using the clavien-dindo (cd) classification system modified for pcnl (8). biswas et al. (22) found significative correlations between gss, s.t.o.n.e. nephrolithometry score, and croes score with post-operative complications including ebl. labadie et al. (13) reported no significant correlation at logistic regression analysis of gss, s.t.o.n.e. nephrolithometry score and croes score with most post-operative complications, although gss and s.t.o.n.e. nephrolithometry were corfigure 2. calibration plot (a) and range of threshold. archivio italiano di urologia e andrologia 2024; 96(4):13295 5 development and internal validation of el-shazly-buchholz’s nomogram to predict postoperative complications after pcnl... related with ebl. choi et al. (9) found a correlation between gss and post-operative complications, while s.t.o.n.e. nephrolithometry score and croes score were not correlated. similar results were obtained by the same authors in a cohort of tubeless pcnl (10). al adl et al. (23) evaluated the correlation between all four nomograms and complications observing a modest correlation of s.t.o.n.e. nephrolithometry score, gss, s-resc score, and croes score with complications according to cd, although only gss, s-resc score and croes score correlated with ebl. khan et al. (24) reported significant correlation between both s.t.o.n.e. nephrolithometry score and gss with overall complication rates at multivariate analysis. overall results demonstrated that stone morphology, as accurately described by the stone scoring systems, seemed to be not sufficient by itself to accurately predict the risk of complications after pcnl. our nomogram adds to a measure of stone size, as stone diameter, other two easily obtained measures as positivity of preoperative urine culture and intraoperative blood loss. preoperative urine culture is mandatory before pcnl although it was well demonstrated that a negative midstream urine culture cannot exclude the presence of infection in the stone or the urinary tract upstream of the stone (25). a systematic review of 19 studies demonstrated that positivity of stone culture was associated with higher odds of developing a systemic inflammatory response syndrome (sirs) after pcnl in comparison with preoperative midstream urine culture (pmuc), although the odds of developing sepsis were not significantly different between positivity of stone culture or pmuc (26). in another study, high procalcitonin (pct) values, il-6 (> 264 pg/ml), sirs score (> 2.5), national early warning score (news) (> 2.5), quick sequential organ failure assessment (qsofa) (> 0.50) and surgical time were independent risk factors for septic shock (27). finally, at multivariate analysis, renal pelvic pressure ≥ 30 mmhg during pcnl procedure was included among the more relevant risk factors for urosepsis together with operative time, bladder urine culture and hydronephrosis (28). intraoperative blood loss is a parameter that can be only obtained at the end of the procedure therefore it cannot be used in the choice and the planning of the treatment although it can be useful to identify those patients that are at higher risk of complications requiring a strict followup for prevention and early treatment of complication. the strength of this study is the homogeneity of the series that was analyzed, which comes from only 4 centres that contributed at least 100 cases each. the number of cases studied is relatively high although for the prediction of less frequent and more serious complications it could be even too small. furthermore, the retrospective design constitutes another limitation. finally, for the prediction of infectious complications, some microbiological parameters were not available (culture of the pelvic urine and of the stone) as well as some laboratory tests (c-reactive protein, procalcitonin) and symptomatic scores predictive of the systemic inflammatory response or sepsis. for these reasons, the efficacy of the nomogram will have to be confirmed by prospective studies of larger series. conclusions this new scoring system (the el-shazly-buchholz’s nomogram) emphasized on patient characteristics and operative details rather than stone features as in previous scores. it should allow reliable and accurate comparisons of treatment efficacy and quality of surgical care by predicting the morbidity of pcnl. furthermore, it should facilitate risk adjustment, enabling physicians to better define the nephrolithiasis disease continuum and identify patients who should be referred to tertiary care centers. acknowledgments this study was designed by noor buchholz who organized its initial phase and contributed an important surgical case series. after he passed away on february 13, 2024, his collaborators and friends wanted to complete his work so that the memory of his enthusiastic activity in the study and treatment of kidney stones is maintained over time. references 1. thomas k, smith nc, hegarty n, glass jm. the guy's stone score—grading the complexity of percutaneous nephrolithotomy procedures. urology. 2011; 78:277-81. 2. okhunov z, friedlander ji, george ak, et al. s.t.o.n.e. nephrolithometry: novel surgical classification system for kidney calculi. urology. 2013; 81:1154-9. 3. smith a, averch td, shahrour k, et al. a nephrolithometric nomogram to predict treatment success of percutaneous nephrolithotomy. j urol. 2013; 190:149-56. 4. jeong cw, jung jw, cha wh, et al. seoul national university renal stone complexity score for predicting stone-free rate after percutaneous nephrolithotomy. plos one 2013; 8:e65888 5. harraz am, el-nahas ar, nabeeh ma, et al. development and validation of a simple stone score to estimate the probability of residual stones prior to percutaneous nephrolithotomy. minerva urol nephrol. 2021; 73:525-531. 6. jiang k, sun f, zhu j, et al. evaluation of three stone-scoring systems for predicting sfr and complications after percutaneous nephrolithotomy: a systematic review and meta-analysis. bmc urol. 2019; 19:57. 7. de la rosette jj, opondo d, daels fp, et al. categorisation of complications and validation of the clavien score for percutaneous nephrolithotomy. eur urol. 2012; 62:246-55. 8. bozkurt ih, aydogdu o, yonguc t, et al. comparison of guy and clinical research office of the endourological society nephrolithometry scoring systems for predicting stone-free status and complication rates after percutaneous nephrolithotomy: a single centerstudy with 437 cases. j endourol. 2015; 29:1006-10. 9. choi sw, baewj, ha us, et al. prognostic impact of stone-scoring systems after percutaneous nephrolithotomy for staghorn calculi: a single center's experience over 10 years. j endourol. 2016; 30:97581. 10. choi sw, bae wj, ha us, et al. prediction of stone-free status and complication rates after tubeless percutaneous nephrolithotomy: a comparative and retrospective study using three stone-scoring systems and preoperative parameters. world j urol. 2017; 35:449-457. 11. jaipuria j, suryavanshi m, sen tk. comparative testing of reliability and audit utility of ordinal objective calculus complexity archivio italiano di urologia e andrologia 2024; 96(4):13295 r. bapir, k. bhatti, m. el-shazly, et al. 6 scores. can we make an informed choice yet? bju int. 2016; 118:958-68. 12. kocaaslan r, tepeler a, buldu i, et al. do the urolithiasis scoring systemspredict the success of percutaneous nephrolithotomy in cases with anatomical abnormalities? urolithiasis. 2016; 45:305-10. 13. labadie k, okhunov z, akhavein a, et al. evaluation and comparison of urolithiasis scoring systems used in percutaneous kidney stone surgery. j urol. 2015; 193:154-9. 14. noureldin ya, elkoushy ma, andonian s. which is better? guy's versus s.t.o.n.e. nephrolithometry scoring systems in predicting stone-free status postpercutaneous nephrolithotomy. world j urol. 2015; 33:1821-5. 15. sfoungaristos s, gofrit on, pode d, et al. percutaneous nephrolithotomy for staghorn stones: which nomogram can better predict postoperative outcomes? world j urol. 2016; 34:1163-8. 16. tailly to, okhunov z, nadeau br, et al. multicenter external validation and comparison of stone scoring systems in predicting outcomes after percutaneous nephrolithotomy. j endourol. 2016; 30:594-601. 17. yarimoglu s, polat s, bozkurt ih, et al. comparison of s.t.o.n.e and croes nephrolithometry scoring systems for predicting stone-free status and complication rates after percutaneous nephrolithotomy: a single center study with 262 cases. urolithiasis. 2017; 45:489-494. 18. mazzon g, choong s, celia a. stone-scoring systems for predicting complications in percutaneous nephrolithotomy: a systematic review of the literature. asian j urol. 2023; 10:226-238. 19. ozgor f, yanaral f, savun m, et al. comparison of stone, croes and guy’s nephrolithometry scoring systems for predicting stone-free status and complication rates after percutaneous nephrolithotomy in obese patients. urolithiasis 2018; 46:471-7. 20. farhan m, nazim sm, salam b, ather mh. prospective evaluation of outcome of percutaneous nephrolithotomy using the ‘stone’ nephrolithometry score: a single-centre experience. arab j urol 2015; 13:264-9. 21. yarimoglu s, bozkurt ih, aydogdu o, et al. external validation and comparisons of the scoring systems for predicting percutaneous nephrolithotomy outcomes: a single center experience with 506 cases. j laparoendosc adv surg tech 2017; 27:1284-9. 22. biswas k, gupta sk, tak gr, et al. comparison of stone score, guy’s stone score and clinical research office of the endourological society (croes) score as predictive tools for percutaneous nephrolithotomy outcome: a prospective study. bju int 2020; 126:494-501. 23. al adl am, mohey a, abdel aal a, et al. percutaneous nephrolithotomy outcomes based on s.t.o.n.e., guy, croes, and s-resc scoring systems: the first prospective study. j endourol 2020; 34:1223e8. 24. khan n, nazim sm, farhan m, et al. validation of s.t.o.n.e nephrolithometry and guy’s stone score for predicting surgical outcome after percutaneous nephrolithotomy. urol ann 2020; 12:324e30. 25. mariappan p, smith g, bariol sv, et al. stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. j urol. 2005; 173:1610-4. 26. li y, xie l, liu c. prediction of systemic inflammatory response syndrome and urosepsis after percutaneous nephrolithotomy by urine culture, stone culture, and renal pelvis urine culture: systematic review and meta-analysis. heliyon 2024; 10:e33155. 27. yuxin liu y, sun q, long h, et al. the value of il-6, pct, qsofa, news, and sirs to predict septic shock after percutaneous nephrolithotomy. bmc urology 2024; 24:116. 28. haoxiang xu h, wang k, cao z, et al. nomogram including renal pelvic pressure to predict the occurrence of urosepsis following percutaneous nephrolithotomy: a dual center retrospective study of 1,448 patients. transl androl urol 2024; 13:667-678. correspondence rawa bapir, md dr.rawa@yahoo.com department of urology, sulaymaniyah surgical teaching hospital, sulaymaniyah, iraq smart health tower, madam mitterrand street, sulaymaniyah, iraq kamran bhatti, md, ms, facs kamibhatti92@gmail.com hmc medical corporation, al khor, qatar assistant professor of urology, qatar university, qatar specialist urology, hmc medical corporation, al khor, qatar mohamed el-shazly, md mshazly2001@yahoo.com assistant professor of urology, menoufia university, shebin elkom 32714, egypt juan antonio galan, md jagalanllopis@gmail.com department of urology, dr. balmis general university hospital, alicante institute for health and biomedical research (isabial), alicante, spain ahmed m. harraz, md, ms, frcs, ebu ahmed.harraz@hotmail.com professor, urology and nephrology center, mansoura university, mansoura, egypt consultant, farwaniya hospital and sabah al ahmad urology center, kuwait city, kuwait sarwar noori mahmood, md sarwarchalabi@yahoo.com department of surgery, college of medicine, university of sulaymaniyah, sulaymaniyah, iraq renato n. pedro, md rnpedro@gmail.com division of urology, faculdade de medicina são leopoldo mandic de campinas, sao paulo, brazil pablo vargas, md pavaran5@gmail.com marina baixa hospital, la vila joiosa, alicante, spain athanasios papatsoris, md agpapatsoris@yahoo.gr 2nd department of urology, school of medicine, sismanoglio hospital, national and kapodistrian university of athens, u-merge scientific office alberto trinchieri, md alberto.trinchieri@gmail.com noor buchholz, md u-merge, scientific office conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13762 1 review introduction prostate cancer (pca) is the most prevalent form of cancer among men in the european union, the usa and israel (1). alongside factors such as age, diet and lifestyle, heritability has emerged as a significant determinant of pca risk (2). epidemiological and genetic studies indicate a hereditary predisposition in approximately 5-10% of all pca cases (3). first-degree relatives of affected individuals have a relative risk of developing pca ranging from 1.65 to 3.3, the risk increasing for those with an earlier diagnosis or multiple affected family members. specifically, having one, two, or three affected first-degree relatives progressively increases the risk ratio for pca by 2.2, 4.9, and 10.9 times, respectively (4). twin studies suggest that approximately 40% of pca cases may have a hereditary component (5), while meta-analyses indicate that having an affected brother or father increases the risk of developing the disease by 2.9-fold or 2.12-fold, respectively. the risk for firstand second-degree relatives is increased by 2.2-fold and 1.8-fold, respectively (6, 7). notably, pca has been observed with increased frequency in families affected by the hereditary breast and ovarian cancer (hboc) syndrome. additionally, a family history of prostate cancer among first-degree relatives has been correlated with an elevated risk of breast cancer in women (8). if familial clustering is recognized as a critical risk factor for pca, genetic bottlenecks might further enhance the likelihood of transmitting mutations within specific genes within a population. populations with high levels of endogamy, resulting from consanguineous unions or marriages among relatives, exhibit a greater propensity for developing autosomal recessive non-cancer diseases and cancers, compared to non-endogamous populations. for example, in the icelandic population, historically characterized by significant kinship, the 999del5 founder mutation in the brca2 gene, which accounts for 7-8% of female breast cancers and 40% of male breast cancers, is strongly associated with a highly aggressive form of lethal prostate cancer (hazard ratio, 3.64, 95% ci, 2.29-5.78) (9). ashkenazi jews (aj), or ashkenazim, are a diaspora population that consolidated toward the end of the first milbackground: prostate cancer (pca) is the most prevalent cancer among men in the european union, the usa and israel, with heritability being a key risk factor. endogamy and kinship are known to increase the likelihood of transmitting genetic mutations associated with various cancers, as seen in populations with high levels of consanguinity, such as ashkenazi jews. the ashkenazi jewish population, with a history of genetic bottlenecks and selective migrations, has a higher prevalence of inherited mutations that predispose individuals to various diseases including cancer. this article reviews the literature examining the potential effects of founder mutations specific to ashkenazi jews, in enhancing the genetic risk of prostate cancer in this population. methods: we searched for english-language articles on dna mutations in ashkenazi jewish patients of any age with prostate cancer of any grade, including various study types, using pubmed and other databases with relevant keywords, and confirmed the search was up-to-date as of january 31st, 2025. results: while the overall burden of pca may not be higher than in european non-jews, certain founder mutations in ashkenazi jews, especially 6174delt in brca2, are linked to increased risk and aggressive forms of pca. further research is needed to ascertain unequivocally the potential predisposing role of mutations such as 185delag in brca1 or 471delaaag in rnasel. conclusions: overall, genetic screening for pca risk in ashkenazi jewish men, particularly within high-endogamy subgroups (haredim), may be beneficial. increasing awareness of familial hereditary prostate cancer among ashkenazi men and healthcare providers is also crucial for early detection and better management of the condition. the complexity of pca genetics in ashkenazim, including the influence of multiple low-penetrance mutations, the possible confounding factor of phenocopies, and the need for larger, more diverse studies, underscores the challenges in identifying definitive genetic risk factors. further studies are awaited investigating in-depth the aggressiveness and response to treatment of pc among ashkenazi jews. key words: prostate cancer; breast cancer; ovarian cancer; dna mutation; jews; ashkenazi jews; endogamy. submitted 5 march 2025; accepted 24 march 2025 genetic determinants of prostate cancer predisposition in ashkenazi jews gianpaolo perletti 1, daniel cohen hattab 2, sergio dellapergola 3, ofer gofrit 4, vittorio magri 5, alberto trinchieri 6 1 department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy; 2 faculty of medicine, the hebrew university of jerusalem, israel; 3 the harman institute of contemporary jewry, the hebrew university of jerusalem, israel; 4 department of urology, hadassah hebrew university hospital, jerusalem, israel; 5 urology clinic, asst fatebenefratelli sacco hospitals, milan, italy; 6 former lecturer, school of urology, university of milan, milan, italy. doi: 10.4081/aiua.2025.13762 summary archivio italiano di urologia e andrologia 2025; 97(2):13762 g. perletti, d. cohen hattab, s. dellapergola, et al. 2 lennium c.e., historically inhabiting regions of central and eastern europe. some of the founders were jewish migrants from southern european regions, namely from southern italy, some of whom in turn had more ancient middle eastern origins (10, 11). bottlenecks were periodically generated due to selective migrations and to repeated cases of drastic jewish population reductions following massacres of entire communities. these reductions were followed by periods of rapid expansion due to high fertility and sometimes higher-than-average life expectancies among jewish populations (12-14). the ashkenazi population, initially estimated to number a few tens of thousands at the end of the 12th century, grew to over 9.5 million by 1939. following the killing of approximately 6 million ashkenazim during world war ii, an estimated 56 million ashkenazim currently reside in the usa, over 3 million in israel, and over a million in europe, south america, and other regions worldwide (15). the high degree of endogamy historically prevalent among ashkenazim has significantly contributed to elevated rates of genetically transmitted diseases, including tay-sachs disease, familial dysautonomia, gaucher's disease, bloom syndrome, cystic fibrosis and others (16, 17). with respect to neoplastic diseases, non-hodgkin's lymphoma, as well as ovarian, pancreatic, and stomach cancers, exhibit higher incidence rates among ashkenazim compared to non-jewish populations (18, 19). in relation to breast cancer, one in ten ashkenazi jewish women diagnosed at any age carries brca1 or brca2 inherited mutations, which are comparatively less frequently found in the general population (approximately 1 in 50) (20). the role of inherited mutations predisposing ashkenazim to pca remains controversial. whereas it is becoming increasingly evident that mutations that predispose aj to various cancers (e.g., breast cancer) may also increase susceptibility to prostate cancer, it is unclear whether ashkenazim have a higher burden of pca than non-jewish populations. additionally, it is uncertain whether pcapredisposing mutations demonstrate increased penetrance in this population. the objective of this article is to systematically review the existing literature on established and potential prostate cancer predisposition genes in aj, with the goal of clarifying the genetic underpinnings and implications for risk stratification in this unique population. methods inclusion criteria for literature search we included full-text articles published in english that reported studies evaluating the prevalence of dna mutations in cohorts of ashkenazi jewish patients of any age diagnosed with prostate cancer, regardless of grade, including both lethal and nonlethal forms. our selection encompassed a variety of study designs, including casecontrol studies, single-cohort studies, case series, systematic reviews and meta-analyses. the search strategy performed in pubmed utilized a combination of keywords and mesh terms to retrieve relevant literature. key search terms included: "prostate," "cancer/ carcinoma," "ashkenazi," "jew/jews/jewish," "mutation*/ polymorphism*/deletion*/insertion*”, “linkage" and others. all searches were confirmed to be up to date as of january 31st, 2025. filters were applied to limit results to human studies. additional databases (e.g., scopus, embase) were searched with similar strategies. articles written in hebrew were also hand-searched and translated for a total of 69 records which were retrieved and are reviewed in this article. results studies on genetic loci linked to prostate cancer evidence emerging from research on genetic loci linked to pca has provided important insights into the molecular underpinnings of disease susceptibility. genome-wide linkage studies have identified over 140 variants of susceptibility loci that may confer an increased risk of pca in certain chromosomal regions (21, 22). a summary of the loci investigated up to year 2016 has been published by lynch and colleagues (23). hpc1 at 1q24, pcap at 1q42, hpcx at xq27, capb at 1p36, hpc20 at 20q13, and elac2 at 17p11 are among the most investigated genetic loci (24). xu et al. conducted linkage studies to investigate the genetic factors contributing to prostate cancer susceptibility in 159 aj families with multiple affected members, focusing on the short arm of chromosome 8 (25). they identified evidence of linkage with pca at the 8p22-23 locus (logarithm of the odds [lod] = 1.84, p = 0.004), which includes genes such as zbtb7a/lrf (a transcription factor involved in cell proliferation and differentiation) and various genes with putative tumor-suppressor activity, like the n33 macrophage-scavenger receptor, the nat1/2 n-acetyltransferases, lzts1 (a gene frequently mutated in prostate cancer cell lines), and deleted in liver cancer-1 (dlc1). linkage analysis revealed that specific microsatellite markers were associated with prostate cancer across multiple familial lines. a study by alanee and coworkers investigated the prevalence of the rare missense variant g84e in the homeobox b13 (hoxb13) gene, a known familial pca-predisposing gene located at the 17q21-22 region (26). in a prior study performed in the general population, the carrier frequency of the variant was found to be 1.4% in men affected by pca, compared to 0.1% in individuals without the disease (odds ratio [or] = 20.1, 95% confidence interval [ci] = 3.5-803.3) (27). the alanee study included 889 selfreported aj men and 920 non-aj men. four patients were heterozygous for the g84e variant, all of whom were of non-aj descent. therefore, the g84e variant does not appear to show increased prevalence in aj. in a genome-wide linkage analysis of ashkenazi families, friedrichsen et al. identified a prostate cancer susceptibility locus on chromosome 7q11-21, characterized by a nonparametric linkage score of 3 (lod = 1.14; p = 0.0013) (28). notably, they could not replicate the significant findings of xu et al. regarding the 8p22 locus, as no significant linkage was observed at 8p22 (allele sharing lod = 0.01). in a cohort of 963 aj cases and 613 aj controls, vijai and coworkers genotyped 29 single nucleotide polymorphisms archivio italiano di urologia e andrologia 2025; 97(2):13762 3 genetic of prostate cancer (snps) previously linked to pca risk (29). they found that a number of candidate snps (rs7008482, rs1016343, rs13254738, rs6983267, rs7000448, rs4242382, rs7931342, rs10896449, rs4430796, and rs5945572) did not show significant differences in frequency compared to prior studies conducted on subjects of european nonjewish ancestry (age-unadjusted analysis). it was concluded that there is no evidence of major differences between aj individuals and non-jewish europeans regarding the association between these mutations and pca. however, in a separate investigation, the same group found that the a/a genotype of snp rs10486567 in the 7jazf1 gene (chromosome 7) and the rs7008482 snp (g/g) in the 8q24 locus were significantly associated with biochemical recurrence (30). additionally, the 7jazf1 rs10486567 snp (c/c) was linked to castration-resistant metastases. notably, the 7jazf1 gene is a transcriptional repressor of the nr2c2 nuclear receptor, which is expressed in the prostate and interacts with the androgen receptor. two additional snps, rs4962416 (c/c genotype, in the 10q26 locus) and rs6465657 (c/c genotype, in the 7q21 locus), were significantly associated with metastatic disease, while rs2735839 (a/a in the 19q13 locus) was associated with pca-specific mortality. the authors suggested that their results warrant validation in larger cohorts. mutations in the y-chromosome have been linked to various cardiological and neurological diseases, as well as to male-specific neoplasia such as pca (31). loss of the y chromosome is frequently observed in prostate cancer and may serve as an early marker of prostate carcinogenesis. wang et al. identified a significant association between specific y chromosome haplogroups and pca susceptibility (32). in particular, the e1b1b1c haplogroup (located in the last intron of the taxilin gamma 2 pseudogene in the yq11.222 locus) was significant in overall pca groups, with some evidence suggesting a protective effect. interestingly, this haplogroup is found at a higher frequency in aj (10-11%) compared to men of european, non-jewish ancestry (1-2%). however, the authors cautioned that the statistical power of some analyses was insufficient, and thus refrained from making definitive conclusions. in jewish populations of non-ashkenazi ancestry, a study by álvarez-topete et al. examined y-chromosomal haplogroups prevalent in a cohort of mexican pca patients. their findings revealed a significant association between haplogroups such as r1a (age-adjusted or, 7.4, 95% ci, 1.3-42.1) and increased susceptibility to pca. the authors hypothesize that these lineages may reflect a founder effect associated with converso heritage, specifically sephardic jews who converted to christianity during the spanish inquisition (33). interestingly, the r1a haplogroup is also found frequently in aj (34), suggesting that historical intermixing of jewish populations may have contributed to the persistence of certain y-chromosomal lineages predisposing individuals to pca. this raises the question of whether the association reflects sephardic ancestry or the presence of aj in spain. a more radical hypothesis could suggest that the mutation predates the sephardic-ashkenazi division; however, this theory would likely predict higher rates of pca in contemporary sephardic populations, which is not observed. therefore, the hypothesis of an external genetic introduction appears more plausible. germline variants in hpc1 and hpcx loci approximately 25 years ago, susceptibility loci for hereditary prostate cancer (hpc) were identified at 1q24-31 (hpc1) and at xq27-28 (hpcx) through linkage analysis of families with a high prevalence of pca (35-37). within the hpc1 region, the rnasel gene (1q25), which encodes the 2’5’-oligoadenylate-dependent ribonuclease l, a protein involved in the interferon-regulated 2-5a pro-apoptotic pathway, was identified as a candidate for hereditary pca due to its tumor suppressor activity (38). in a japanese case-control study, the asp/asp phenotype of the asp541glu rnasel variant was associated with a 6.9-fold increased odds of pca compared to controls (95% ci, 3.9-12.1). in contrast, the gln/gln phenotype of the arg462gln variant appeared to offer protection against pca (or, 0.06, 95% ci, 0.035-0.11) (39). additionally, the a/a genotype of the rs12757998 snp of rnasel was linked to a 1.63 odds ratio for pca compared to controls (95% ci, 1.18-2.25), and a 1.9 odds ratio for high-grade disease in individuals of northern/western european ancestry (gleason > 7, 95% ci, 1.252.89) (40). in addition, a glu265x truncating variant of rnasel was found to be expressed in pca patients from finland (or, 4.56; p = 0.04) (41). a potentially pathogenic rnasel splice site mutation (ivs5+1delg) was identified in a study performed on ashkenazi jewish individuals by orr-urteger et al. (42). additionally, a novel ashkenazi founder mutation was reported by rennert and colleagues in two siblings affected by pca, where loss of heterozygosity (loh) of the wildtype allele occurred in the cancer cells. this mutation consists of a four-base deletion at nucleotide 471 in exon 1 (471delaaag), resulting in premature truncation at codon 164 (43). the authors observed an increased, though not statistically significant, frequency of this deletion in pca patients of aj descent, compared to aj controls (or, 3; 95% ci, 0.6-15.3). notably, among ashkenazim mutation carriers were diagnosed at a significantly younger age compared to non-carriers (65 vs. 74.4 years, respectively; p < 0.001). subsequent studies produced inconclusive results. a single carrier of the 471delaaag mutation was identified among 122 aj pca patients in canada (44). similarly, one deletion carrier was found among 190 ashkenazi pca patients in israel, with no carriers identified among nonashkenazi patients (45). in a large aj population study (979 pca cases and 1250 controls), agalliu and colleagues could not confirm a significant effect of the 471delaaag mutation on pca risk, citing insufficient power to detect modest associations. in contrast to the earlier japanese study, this research identified an inverse association between the a/a genotype (rs486907) of the arg462gln variant and pca in patients diagnosed before age 65 (or, 0.47; 95% ci, 0.23-0.96) (46). furthermore, the study examined five microsatellite markers on the hpcx locus and found positive associations with low-grade pca (gleason score ≤ 6) for allele archivio italiano di urologia e andrologia 2025; 97(2):13762 g. perletti, d. cohen hattab, s. dellapergola, et al. 4 135 of microsatellite str b97 and allele 188 of the str marker dxs1205 (or, 1.77; 95% ci, 1.15-2.71 and or, 1.65; 95% ci, 1.08-2.54, respectively). however, no significant associations were observed for high-grade pca. in conclusion, additional evidence is awaited before drawing a conclusive statement about pca risk conferred by 471delaaag in rnasel. germline variants in brca1 and brca2 genes the brca1 (chromosome 17, 17q21.31) and brca2 (chromosome 13, 13q13.1) gene products play a critical role in dna damage detection, checkpoint arrest, doublestrand break repair, and chromatin remodeling (47). additionally, brca1 regulates the androgen receptor and may be implicated in the pathogenic mechanisms of pca associated with it (48). germline mutations in these genes are responsible for the majority of hereditary breast and ovarian cancers. these mutations typically consist of small deletions or insertions and are inherited in an autosomal dominant fashion with incomplete penetrance. interestingly, in certain brca family clusters, the inheritance pattern of pca also resembles autosomal dominant inheritance. for example, in a swedish family carrying the brca2 6051dela truncating mutation, a father and his four sons were diagnosed with early-onset pca, while three daughters developed breast cancer (49). in the nonjewish population, it has been demonstrated that men with a brca1 mutation have a lifetime 7-26% risk of developing pca (50), while individuals with a brca2 mutation exhibit a 3-8fold increased risk of pca compared to non-carriers (51). approximately one in 40 aj carries a brca mutation, to 1 in 400 in the general population. the brca1 185delag and brca2 6174delt founder mutations are the most common deleterious variants predisposing to breast cancer in ashkenazim (52), though 185delag has been also genotyped in a small group of jews of confirmed moroccan origin (53). among ashkenazi men diagnosed with breast cancer, about 1 in 5 carries a brca1/brca2 inherited gene mutation. in addition to their established role in breast cancer, brca1 and brca2 founder mutations have been associated with reduced life expectancy in aj, even in the absence of cancer (54). a 1995-1996 study conducted at the department of oncogenetics at the israeli sheba ramat gan hospital tested 292 women for mutations associated with breast and ovarian cancers. among women with cancer, 45% carried a founder mutation in brca1/2, compared to 25% of healthy individuals. specific mutations included 185delag and 5385insc in brca1 (74.5% and 4.5%, respectively), and 6174delt in brca2 (13%). notably, 80% of the tested families had first-degree relatives diagnosed with other cancers, including prostate, colon, and lung cancers. moreover, ten close relatives of affected patients were diagnosed with prostate cancer (55). brca1 and prostate cancer a significant breakthrough in understanding the relationship between brca mutations and prostate cancer was provided by struewing and colleagues, who studied a population of 5318 ashkenazi jewish women and men (56). the study identified 120 carriers of brca1 (185delag, 5382insc) and brca2 (6174delt) founder mutations. women with brca1 and brca2 mutations had an estimated lifetime breast cancer risk of approximately 56-87% and 45-84%, respectively. the risk of ovarian cancer for brca1 carriers was estimated at 16-54%, while for brca2 carriers it ranged between 10 and 30%. in men, carriers of any brca1 or brca2 founder mutation exhibited a significantly higher prevalence of prostate cancer (14% vs. 8% in noncarriers, p < 0.01). this study concluded that specific brca1 and brca2 mutations can significantly increase the risk of breast, ovarian, and prostate cancers in aj. giusti and colleagues examined medical records of pca patients from 23 israeli hospitals during the early psa era (1994-1995). by combining this israeli dataset (n = 940) with data from the washington ashkenazi study (n = 872), the authors calculated a significant odds ratio of 2.18 for prostate cancer in carriers of any brca founder mutation (95% ci, 1.09-4.43). however, the odds ratios for individual brca1 or brca2 mutations were not statistically significant (57). in a separate study on the impact of brca1 5382insc on prostate cancer, vazina and colleagues assessed a subset of 95 ashkenazi patients (58). the authors found that the detection rate of 5382insc among pca patients was significantly higher than in the general population analyzed in the study by struewing et al. (3.3% vs. 0.37%, p = 0.02). despite the limitations due to its small sample size and to the use of external controls (59), this study supports the hypothesis that brca1 5382insc may contribute to prostate cancer risk. a key question is whether somatic mutations in oncogenes or tumor suppressor genes can modulate the phenotype of prostate cancer in individuals harboring brca mutations. nickerson and colleagues examined the molecular makeup of metastatic castration-resistant prostate cancer (crpc) in an ashkenazi carrier of brca1 185delag. notably, all metastases analyzed (n = 11) showed somatic loss of heterozygosity. the study also reported 62 somatic non-synonymous mutations in genes implicated in cancer progression and metastasis, including tp53 (frequently altered in metastatic crpc), pten (whose loss is associated with tumor aggressiveness), the androgen receptor (whose mutations and amplifications are crucial for castration resistance), kmt2c (playing a role in crpc progression), and fat1 (linked to the metastatic phenotype). the tet2 gene, whose loss of function is associated with epigenetic changes in cancer, was also altered (60). these findings suggest that somatic mutations may play a crucial role in crpc in ashkenazi individuals with brca1 founder mutations. if confirmed by larger studies, these results could provide valuable insights into the molecular mechanisms driving hereditary prostate cancer and suggest potential diagnostic or therapeutic targets. brca2 and prostate cancer brca2 harbors a pca cluster region containing two separate domains linked to increased risk of pca, namely the ob1 oligonucleotide-olisaccharide binding domain and the ob2 tower dna binding domain (61). kirchhoff and colleagues compared the prevalence of the three ashkenazi founder mutations -185delag and 5382insc in brca1, and 6174delt in brca2among 251 unselected ashkenazi men with pca and 1472 archivio italiano di urologia e andrologia 2025; 97(2):13762 5 genetic of prostate cancer healthy ashkenazi controls. the age-adjusted odds ratio for pca in carriers of any mutation was 3.41 (95% ci, 1.64-7.06). statistical significance was primarily driven by carriers of the brca2 6174delt mutation, whose odds of developing pca were nearly five times greater compared to controls (or, 4.78; 95% ci, 1.87-12.25). in contrast, the odds ratio for a brca1 mutation did not reach statistical significance (or, 2.2; 95% ci, 0.72-6.7) (62). in a subsequent study by gallagher and colleagues, comparing 832 aj pca patients with 454 healthy aj controls, the odds ratio for pca in carriers of brca2 6174delt was 3.10 (95% ci, 1.52-6.66), while the odds ratio for carriers of brca1 185delag was not significant (or, 0.38; 95% ci, 0.05-2.75) (63). notably, a significantly higher proportion of brca2 6174delt carriers had high-grade pca (gleason score > 7) compared to non-carriers (85% vs. 50%, respectively; p = 0.0002), while brca1 185delag carriers were evenly distributed between highand low-grade disease (50% vs. 50%). both brca1 185delag and brca2 6174delt carriers had significantly higher hazards of biochemical recurrence (hazard ratio [hr] for 185delag, 4.32; 95% ci, 1.31-13.62; hr for 6174delt, 2.41; 95% ci, 1.23-4.75) and prostate cancer death (hr for 185delag, 5.16; 95% ci, 1.09-24.53; hr for 6174delt, 5.48; 95% ci, 2.03-14.79) compared to non-carriers. additionally, carriers of brca2 6174delt, but not brca1 185delag, exhibited a significantly higher hazard for castration-resistant metastatic disease (hr,3.01; 95% ci, 1.26-7.14). in 2009, agalliu and colleagues compared 979 ashkenazi pca cases with 1251 healthy aj controls. the odds of high-grade pca (gleason score > 7) were significantly higher in carriers of both brca1 185delag (or, 3.54; 95% ci, 1.22-10.31) and brca2 6174delt (or, 3.18; 95% ci, 1.37-7.34) compared to non-carrier patients. however, the proportion of mutation carriers in this study was lower than that reported by gallagher et al. (64). additionally, significantly higher odds ratios for pca were observed in patients of all ages carrying 185delag or 6174delt brca mutations (or, 1.91; 95% ci, 1.05-3.48). high and significant odds ratios were also found for patients over 65 years of age carrying the 185delag mutation (or, 6.91; 95% ci, 1.37-34.87), or any of the 185delag or 6174delt mutations (or, 3.69; 95% ci, 1.47-9.29). consistent with these observations, in a cohort of 146 ashkenazi men from canada diagnosed exclusively with metastatic pca, hamel and colleagues identified two carriers of the brca2 6174delt mutation (65). however, this was a single-cohort study and the authors compared their data with those of other studies to attempt statistical inference. at the hadassah medical center in jerusalem, israel, hubert et al. compared 87 aj men with pca to 87 healthy ashkenazi controls. they identified three mutation carriers in the pca cohort: two with brca1 185delag and one with brca2 6174delt, while three healthy carriers were found in the control group. despite the small sample size, the fact that all three mutation carrier patients had been diagnosed at stage b with gleason scores of 7, 8, and > 8 -higher than the average for noncarriers at stage b and similar to the average at stage dsupports the findings of gallagher et al. and agalliu et al. regarding the increased likelihood of mutation carriers of being affected by high-grade pca (66). kwon et al. analyzed genetic and clinical data from a cohort of 1351 men of various ethnicities diagnosed with pca, including 150 ashkenazi patients (11%). they found that ashkenazim were more likely than caucasian men to carry pathogenic mutations in brca2 or chek2 (6.7% vs. 2.8%, p = 0.01, and 5.3% vs. 2.8%, respectively), while pathogenic or likely pathogenic brca1 mutations were similar in ashkenazi men compared to caucasians (0.7% vs. 0.8%). unexpectedly, ashkenazi mutation carriers were diagnosed at an older age compared to caucasians (66.6 vs. 60.5 years, p < 0.01) (67). the significant findings summarized above could not be replicated in studies performed on smaller cohorts of patients. for instance, lehrer and colleagues did not detect any carriers of brca1 or brca2 founder mutations in a cohort of 60 ashkenazi pca patients (68), and wilkens et al. identified a single healthy carrier of brca2 6174delt in a study of 18 aj families with at least three first-degree relatives affected by pca (69). other studies, such as the 1995 study by friedman et al., which examined 37 aj families with a high prevalence of familial breast cancer, found no cases of prostate cancer among deletion carriers (70). similarly, nastiuk et al. found that brca1-185delag and brca2-6174delt deletions were present in only 1 and 2 patients, respectively, out of 83 pca cases. the authors concluded that the study was only powered to detect a 4-5-fold increase in prostate cancer risk associated with these mutations and recommended larger studies to investigate smaller but statistically significant increases in relative risk (71). in conclusion, ensuring adequate statistical power is essential in clinical studies to reliably detect true associations between genetic variants and cancer outcomes, minimizing the risk of false negatives and ensuring that observed results reflect genuine associations rather than random variation. meta-analyses as shown in the preceding section, studies conducted on small cohorts of patients have failed to provide conclusive evidence regarding the risk and frequency of prostate pca in ashkenazi carriers of brca1 or brca2 mutations. in such cases, meta-analyses, which combine data from smaller studies with those that have sufficient statistical power, offer a more robust understanding of statistical trends and provide clinically relevant insights. several meta-analyses have examined the association between germline founder mutations – including 185delag or 5382insc in brca1, and 6174delt in brca2 – and pca risk in aj. a 2019 study by oh et al. found that the odds ratio for pca in carriers of brca1 and/or brca2 mutations across all populations (both jewish and non-jewish) was 1.90 (95% ci, 1.58-2.29). in an ashkenazi subgroup, the unadjusted event rate (er) for pca among carriers of any brca founder mutation was 1.7% (95% ci, 1.5-2.1), with specific event rates of 1.4% for brca1 and 2.1% for brca2 founder mutations (95% ci, 1.0-1.8 and 1.6-2.6, respectively) (72). a subsequent meta-analysis by nyberg et al. differed from the oh study, as it excluded the 2019 case series by nastiuk archivio italiano di urologia e andrologia 2025; 97(2):13762 g. perletti, d. cohen hattab, s. dellapergola, et al. 6 et al. (71). in men of ashkenazi jewish ancestry, the risk ratio (rr) for pca was statistically non-significant for brca1 founder mutation carriers (rr, 1.12; 95% ci, 0.552.31), while the risk in carriers of the 6174delt mutation in brca2 was twofold and statistically significant (rr, 2.08; 95% ci, 1.38-3.12) (73). risk ratios for aj were consistently lower compared to non-ashkenazi men of european ancestry (e.g., rr for brca2 6174delt in europeans: 4.07; 95% ci, 3.45-4.80). however, the metaanalysis including non-jewish europeans showed substantial heterogeneity (i² = 66%), which was absent from the analysis including aj (i² = 0). a 2023 meta-analysis investigated the prevalence of both germline founder and non-founder mutations in brca1 and brca2 among ashkenazi versus non-ashkenazi pca patients (74). the study found that ashkenazi jewish men had a higher prevalence of brca1 variants (0.9% vs. 0.5%, p = 0.09) and a lower prevalence of brca2 variants [1.5% vs. 3.5%, p = 0.08] compared to non ashkenazi patients, though the p values do not reach statistical significance. figure 1 presents a pooled summary of the evidence emerging from case-control studies showing similar designs. this summary specifically excludes case series, single-cohort studies, research comparing data to external population estimates, and studies utilizing controls from either (i) cohorts published by different research groups or (ii) cohorts including healthy women. although these findings are not part of a comprehensive meta-analysis (currently in preparation), the data indicate a significantly increased odds ratio for harboring the brca2 6147delt mutation in prostate cancer cases (odds ratio 2.3, 95% ci 1.59-3.43) compared to controls. these findings align with those of previous meta-analyses, which reported a 2.1 risk rate (95% ci 1.6-2.6) and a 2.08 risk ratio (95% ci 1.38-3.12) for brca2 ashkenazi mutation carriers (72, 73). in conclusion, the evidence derived from case series, cohort studies, and meta-analyses suggests that the rate of brca mutations associated with prostate cancer in ashkenazi jewish men may not differ significantly from that in the general population. however, founder mutations in brca2, and to a lesser extent in brca1 are likely linked to the development of prostate cancer among aj. germline apc variants familial adenomatous polyposis (fap) is an autosomal dominant inherited disorder responsible for up to 5% of colorectal cancer (crc) cases. truncating mutations in the apc tumor suppressor gene, which encodes a protein involved in regulating β-catenin via the wnt-ctnnb1 signaling pathway, lead to heterozygous germline loss-offunction alterations in fap families, resulting in the onset of forms of polyposis which can ultimately progress to crc. two case series have reported loh at the apc locus, detected in 3 out of 7 and 3 out of 15 metastatic prostate cancer cases, respectively (75, 76). in the late 1990s, a tto-a transversion at nucleotide 3920 of apc, present in 10% of ashkenazim and 2.7% of sephardic jews, causing an isoleucine-to-lysine substitution at codon 1307 was described. this alteration creates a genetically unstable and hypermutable region of the gene, and was found to be highly prevalent (28%) among aj with a family history of crc (77-79). case studies indicated that relatives of crc patients carrying the i1307k substitution had family histories of various cancers, including pca (80). woodage and colleagues investigated a cohort of 5081 ashkenazim carrying either a homoor heterozygous i1307k substitution. the odds ratio for pca was 2.0, but the wide confidence interval (0.81-4.7) precluded statistical significance (81). a 2006 kin-cohort study comparing relatives of i1307k carriers with non-carriers observed a higher incidence of pca in relatives of i1307k carriers over the age of 80, compared to non-carriers, although the difference was not statistically significant (82). conclusive evidence of an association between i1307k and pca is still to be confirmed. conversely, a 2023 case series demonstrated that, compared to non-carrier cancer patients with somatic frameshift mutations of apc (n = 20), carriers of the germline i1307k substitution (n = 18) had a significantly increased odds of presenting with the severe and untreatable "aggressive variant of prostate cancer" (avpc, odds ratio: 7.2; 95% ci: 1.3-40.7) (83), defined as an androgen receptor independent neoplasia characterized by a unique array of genetic (e.g., rb1, tp53, or pten mutations) and cellular characteristics (e.g., small cell histology), making the disease virtually untreatable. among the i1307k carriers (100% aj, personal communication from the corresponding author), five patients had somatic alterations in one or more of the rb1, tp53, or pten tumor suppressors, and two exhibited the aj founder mutation s1982fs*22 (6147delt) in brca2. in summary, while increased odds ratios suggest a potential association between i1307k and pca, small sample sizes and/or the limited number of mutation carriers resulted in large confidence intervals preventing the confirmation of statistical significance. studies conducted on larger patient populations are required to provide data for a more conclusive assessment of this association. pca incidence in lynch syndrome patients lynch syndrome (ls), also known as hereditary non-polyposis colorectal cancer, is an autosomal dominant genetic disorder caused by mutations in specific dna mismatch repair (mmr) genes, including mlh1, msh2, msh6, and pms2. pathogenic mutations in these genes increase the risk of several cancers, notably colorectal and endometrial cancers, as well as ovarian, stomach, renal pelvis, and ureteral cancers. a 2014 study by haraldsottir which involved 188 ls men from the us, demonstrated a significantly higher incidence of pca in these individuals compared to the general population, with a standardized rate ratio of 4.87 (95% ci, 2.43-8.71) (84). mutations were identified in all aforementioned mmr genes. in the same year, a meta-analysis, which included both molecular studies and family/population risk studies, confirmed the findings of haraldsdottir, despite his study being excluded from the meta-analysis. the meta-analysis revealed a 2.13-fold increased risk of prostate cancer in mutation carriers from clinic-based retrospective cohorts (95% ci, 1.45-2.80), a 2.11-fold risk (95% ci, 1.27-2.95) for male mutation carriers with a prior diagnosis of colorectal cancer, and a 2.28-fold risk (95% ci, 1.37-3.19) for men from mutation-carrying families, when compared to archivio italiano di urologia e andrologia 2025; 97(2):13762 7 genetic of prostate cancer the general population (85). the study also highlighted variations in prostate cancer risk, with msh2 mutation carriers exhibiting a higher frequency of prostate cancer than carriers of other mmr genes. despite potential recall and detection biases associated with retrospective studies, the authors concluded that prostate cancer may be considered part of the spectrum of ls associated neoplasms. to date, three founder mutations linked to ls have been identified in the ashkenazi jewish population. foulkes et al. characterized the c.1906g>c (ala636pro) mutation in msh2, which has a prevalence of 0.6% among aj with colorectal cancer (86). additionally, the founder truncating mutations c.3984_3987dup-gtca (p.leu1330valfsx12) and c.3959_3962delcaag in the msh6 gene have been identified in ashkenazi populations (87,88). recombination analysis suggests that both mutations likely originated in the 6th and 7th centuries c.e., respectively, during the early formation of the ashkenazi population in the rhineland through a trickle of immigration from the south (87, 12). goldberg and colleagues reported that while mutations in msh2 and msh6 are found in 38% and 14% of ls patients in the general population, the frequencies among ashkenazim are 74% and 18%, respectively (88). importantly, co-inheritance of brca mutations and mmr gene mutations linked to lynch syndrome has been reported in several studies (reviewed in: 88). for instance, a study by laish and colleagues identified eleven double-heterozygote mutation carriers in four unrelated israeli ashkenazi families. all carriers had a brca founder mutation (brca2 5946delt/c.6174delt, n = 10; brca1 185delag, n = 1) and an mmr aj founder mutation (msh2 1906g>c, msh6 3984_3987dupgtca, or msh6 3956_3957duppv). among these carriers, one patient was diagnosed with prostate cancer (89). further studies are required to evaluate whether the simultaneous presence of brca1/brca2 founder mutations and lynch-linked mmr mutations exerts a deleterious effect in the ashkenazi jewish population. germline mutations in various genes a 2008 study conducted in north america explored the role of seven newly identified snps in the chek2 gene (located on chromosome 22q) among aj men with prostate cancer (90). of these snps, the 1270t>c variant in exon 11, which causes the missense y242h substitution, was identified in three affected men from one family and four affected men from another. however, the mutation did not consistently segregate with the disease. it was found in 4 out of 85 families with affected probands, but in none of 136 pca cases from montreal, none of 221 aj controls, and in 8 out of 740 unselected pca cases. the authors concluded that the y242h variant is unlikely to play a major role in pca predisposition, though it may represent a mild predisposition allele in aj men. at the genetic institute of the tel aviv sourasky medical center, a study screened 188 aj and 112 non-aj pca patients for mutations in three candidate genes implicated in prostate cancer: phosphatase and tensin homolog (pten), kruppel-like factor 6 (klf6), and macrophage scavenger receptor 1 (msr1) (91). controls included 200 healthy aj women and 100 non-aj women. among the mutations examined, the g160x variant (478c>t) in klf6 was found in one pca patient but not in any of the controls. however, the premature stop codon generated by this variant did not result in reduced gene expression at the rna level, suggesting that loss of the wild-type allele did not occur in this case. interestingly, the intronic ivs1-27g>a mutation in klf6, which generates a novel splice variant, was detected in a significantly larger fraction of controls (17.3%) than in pca patients (11.9%, p = 0.043). additionally, the ivs1-27a allele was significantly less frequent in aj pca patients compared to aj controls (5.6% vs. 9%, respectively, p = 0.047), and was also significantly less present in all pca patients compared to all controls (6.1% vs. 9.2%, respectively, p = 0.03). the authors concluded that the negative association between the ivs1-27a allele and pca risk may be attributed to its significantly lower frequency in aj patients. protection of telomeres 1 (pot1) is a component of the six-membered shelterin complex that plays a critical role in telomere length regulation and protection. the p.(i78t) variant in pot1 has been identified as a founder pathogenic mutation in aj. a 2024 database review detected cases of pca among carriers and advocated for the inclusion of pot1 in germline screening panels for cancer (92). extensive studies are required to further elucidate the pathogenic role of pot1 mutations in pca among ashkenazim. genetic screening, diagnosis and counseling genetic screening while the role of certain genetic determinants of pca in aj still remains to be fully confirmed, ashkenazi ancestry is included among the eligibility criteria for germline testing in the framework for prostate cancer genetic evaluation and management algorithm established at the 2019 philadelphia prostate cancer consensus conference. key eligibility criteria also include a strong family history (two or more male relatives diagnosed with pca before age 60 or who died from it), specific pathological features (e.g., intraductal pathology or advanced disease), ashkenazi ethnicity, and a family history of cancers associated with hereditary syndromes, such as hboc or lynch syndrome (93). the inclusion of ashkenazi ethnicity in these criteria reflects the growing body of evidence regarding certain predisposing mutations, such as brca2, which informs decision-making in the philadelphia guidelines. additional guidelines recommend germline testing for patients of aj ancestry. these include the american urological association 2022 advanced prostate cancer guidelines, the australian eviq prostate cancer panel testing guides, and the us national comprehensive cancer network clinical practice guidelines in oncology (94). importantly, the national health service of the united kingdom has recently initiated a special jewish brca testing program aimed at identifying jewish carriers of deleterious mutations at risk for breast, ovarian and prostate cancer. testing is available to individuals over the age of 18 with jewish ancestry documented by at least one jewish grandparent (95). in israel, patients with metastatic prostate cancer have access to a comprehensive sequencing panel through the public health services basket, which provides essential healthcare services to all citizens. major hospital institutions, such as the hadassah archivio italiano di urologia e andrologia 2025; 97(2):13762 g. perletti, d. cohen hattab, s. dellapergola, et al. 8 medical center in jerusalem, offer tests comparable to the foundationone® cdx test (96). these include a dedicated prostate cancer panel that assesses genetic alterations in key genes, such as brca1, brca2, atm, bard1, brip1, cdk12, chek1, chek2, fancl, palb2, rad51b, rad51c, rad51d, and rad54l. sequencing for the mlh1, msh2, msh3, and msh6 mmr genes is also available. other israeli hospitals provide tests that analyze mutation burdens and microsatellite instability across panels of approximately 400-500 genes, including brca1 and brca2. this multifaceted approach to genetic testing enhances the ability to tailor surveillance and treatment strategies for patients at increased risk of prostate cancer. diagnosis a study by tamir et al. examined age-related changes in the prostate through magnetic resonance imaging among brca mutation carriers. the study revealed significant quantitative alterations, including changes in prostate volume, as well as qualitative variations in tissue characteristics, such as lesions and fluctuations in signal intensity. these findings have important implications for brca mutation carriers, highlighting the potential benefits of tailored mri screening for early prostate cancer detection and ongoing monitoring (97). counseling genetic counseling is a cornerstone in the prevention, diagnosis, and treatment of familial cancers. counseling about the implications of specific mutations and the importance of surveillance should be routinely implemented for men with a family history of cancer. for informed decisionmaking in pca, specific algorithms are used, such as the one described by russo and coworkers (figure 1 in: 98). a 2008 article by mohamad and apffelstaedt emphasized the importance of counseling for male brca mutation carfigure 1. summary of studies included in this review, comparing the prevalence of accepted or putative predisposing mutations in cohorts of ashkenazi prostate cancer cases and healthy ashkenazi male controls. controlled studies showing sufficient design and accrual similarities were included and pooled. data to the right of the no-effect line represent increased odds of finding a specific mutation in brca1 (panels a and b), brca2 (panel c) or rnasel (panel d) in prostate cancer patients compared to controls. overall effect sizes (odds ratios) extending to the upper and lower limits of the 95% confidence intervals, the significance of the pooled effect sizes (z statistics) and heterogeneity data (i^2) are shown. mantel-haenszel weighting method, random effects model. software: meta-essentials excel workbook 1.5 (erim, erasmus university, rotterdam, the netherlands). archivio italiano di urologia e andrologia 2025; 97(2):13762 9 genetic of prostate cancer riers, particularly regarding their elevated risk for prostate, pancreatic and breast cancers (99). it recommends tailored counseling for male brca carriers, as they are often unaware of their increased risks and may not seek genetic testing or appropriate surveillance. in the context of comprehensive counseling, discussions about lifestyle modifications may empower patients to take an active role in managing their health. for example, charred meat byproducts, particularly polycyclic aromatic hydrocarbons and heterocyclic amines such as 2-amino-1-methyl6-phenylimidazo (4,5-b) pyridine (phip), have been implicated in prostate cancer risk. (100, 101). this observation is significant, as high-risk dietary and lifestyle behaviors may compound the genetic predisposition, contributing to the development of neoplasia in at-risk populations. therapy and chemoprevention clinical trials have investigated the impact of various prostate cancer therapies in brca mutation carriers. gallagher and colleagues studied whether brca1 or brca2 mutations could affect the sensitivity to taxane-based chemotherapy. their study found that 57% of brca mutation carriers responded to chemotherapy, compared to 72% of non-carriers (n = 81). the difference between the groups was not statistically significant, suggesting that brca mutation carriers are indeed responsive to chemotherapy (102). poly (adp-ribose) polymerase (parp), which plays a crucial role in dna repair and apoptosis, is targeted by inhibitors such as olaparib, rucaparib, niraparib and talazoparib. these drugs are used in the treatment of her2-negative, familial metastatic breast cancer in women with brca1 or brca2 mutations. given that these inhibitors also suppress the function of the androgen receptor, their use has been explored in clinical trials for crpc patients carrying mutations in brca1, brca2, and atm. the profound phase iii trial demonstrated that progression-free survival was significantly prolonged in patients treated with olaparib compared to untreated controls (103). similarly, the triton2 and galahad phase ii trials, which included patients with crpc carrying brca1/2 mutations as well as mutations in other pca predisposing genes, showed that rucaparib and niraparib significantly increased both objective (triton2, 46% for brca mutation carriers vs. 0% for carriers of other mutations) and composite response rates in treated subjects (galahad, 57.7% in brca mutation carriers vs. 14.8% in non-carriers), compared to untreated patients (104, 105). thus, parp inhibitors show promising clinical efficacy in treating metastatic crpc in patients with mutations in brca1/2. further investigation is needed to determine whether patient responses are associated with specific classes of mutations or if they can be generalized to all types of pathogenic brca variants, including ashkenazi founder mutations. additionally, the impact of tumor resistance to parp inhibitors should be evaluated as the use of these agents becomes more widespread in prostate cancer treatment. conclusions the genetic identity of aj has been shaped over centuries by strict endogamy and high reproductive rates, factors which have been further potentiated by genetic bottlenecks (106). these historical phenomena have contributed to the emergence of hereditary diseases, including familial forms of cancer such as prostate cancer. this review article summarized the available evidence linking specific genetic mutations, expressed by aj, to the heritability, onset, and progression of prostate cancer. from the evidence produced so far, it appears that the overall burden of prostate cancer may not be considerably higher in aj compared to european non-jewish populations (107). furthermore, ashkenazi founder mutations do not appear to be strongly associated with early-onset prostate cancer. however, substantial evidence supports a link between certain founder mutations and an increased risk of developing prostate cancer. notably, the 6174delt ashkenazi founder deletion in brca2 has been consistently associated with an elevated susceptibility to prostate cancer. carriers of this mutation also face an increased risk of high-grade pca (gleason score > 7), as well as higher rates of castration-resistant metastatic disease, biochemical recurrence, and mortality when compared to non-carriers. mutations in brca1 also appear to be linked to pca, albeit to a lesser extent. several findings reviewed in this article underscore the potential benefit of genetic screening for prostate cancer risk in ashkenazi jewish men, especially considering the high degree of endogamy observed within certain subgroups of this population, such as the “haredim” (a hebrew term for the “fearful”, i.e. the very religious communities) (108). on the other side, contemporary israeli society and diaspora jewish communities have experienced growing intermarriage rates—both among ashkenazim and non-aj in israel, and between jews and non-jews in the diaspora (109). this trend may serve to “dilute” the negative effects of endogamy over time, potentially reducing the long-term risk of hereditary diseases. however, within the highly segregated “haredi” communities in israel and in the diaspora, strict endogamy is maintained not only within the jewish religious-cultural group at large, but more specifically within smaller ashkenazi subgroups (“hatzerot”) which are linked by specific extended families or geographical ancestries. in these cases, the risks of genetic disease transmission may tend to substantially increase. public health implications and further research the clinical implications of identifying cancer-predisposing mutations for patient prognosis and treatment remain an open question. further research is needed to explore the potential applications of genetic information for personalized therapeutic strategies and risk stratification. as a general caveat, we caution against over-interpreting variations in cancer rates between ethnic groups, emphasizing the need for careful consideration of public health implications. in this respect, the possible presence of diagnostic bias in populations with high rates of familial cancers should be considered, as increased preventive screening may lead to the detection of previously undiagnosed, low-risk or indolent prostate cancers. given the indolent and often asymptomatic nature of certain forms of prostate cancer, it is essential to raise awareness among ashkenazi men and healthcare providers, as early detection through proactive screening is crucial in contrast to other tumors, such as bladder cancer, that tend to present with more symptomatic features at earlier stages. archivio italiano di urologia e andrologia 2025; 97(2):13762 g. perletti, d. cohen hattab, s. dellapergola, et al. 10 unresolved issues the role of non-brca mutations contributing to pca in aj remains unclear and demands further investigation. additional evidence is needed before drawing definitive conclusions about the risks associated with mutations such as 471delaaag in rnasel or i1307k in apc. as noted by agalliu et al. (46, 64), inconsistent results across studies may be attributed to factors such as small sample sizes, low statistical power, false-positive findings, genetic heterogeneity in prostate cancer, or errors in distinguishing hereditary, familial, and sporadic forms of the disease. the identification of highly penetrant genetic markers for prostate cancer is more complex than for other common cancers due to a variety of factors. prostate cancer is often diagnosed at an older age, compared – for instance – to early-onset, brca-linked breast cancer, making it difficult to obtain multi-generational dna samples from affected individuals. furthermore, the diversity of mutations observed in ashkenazi populations also complicates our understanding of how these genetic variants influence prostate cancer biology and patient outcomes. variability in mutations and their functional consequences underscores the complexity of prostate cancer in this population. in addition, high-risk pedigrees may include phenocopies, i.e., sporadic pca cases that may act as confounders and complicate the distinction between familial and non-hereditary forms. it should also be taken into consideration that certain mutations may act as risk modifiers, contributing to disease susceptibility in combination with other genetic factors rather than as dominant determinants. in families with a strong history of prostate cancer, the disease may result from a combination of multiple mutations with moderate/low penetrance rather than a single high penetrance mutation. the presence of a combination of multiple risk alleles may thus increase the likelihood of developing prostate cancer more than any individual mutation. seibert and colleagues demonstrated that when the penetrance of mutations is plotted against their frequency in a given population, low-penetrance prostate cancer risk variants -when combined into polygenic risk scorescan have a net effect comparable to that of rare pathogenic mutations with modest-to-intermediate penetrance (110). moreover, many linkage analyses in studies examining prostate cancer among aj are limited by small sample sizes and lack of cohort diversity. simard and colleagues suggested that association studies should ideally be based on at least one thousand blood samples from prostate cancer cases, compared to ethnically matched controls (24). therefore, adequately powered studies are necessary to provide more definitive insights into prostate cancer susceptibility conferred by low-penetrance genes. references 1. https://www.gov.il/blobfolder/reports/prostate2022/en/files_publications_units_icdc_prostate20 22.pdf. 2. alanee s, shah s, vijai j, schrader k, et al. prevalence of hoxb13 mutation in a population of ashkenazi jewish men treated for prostate cancer. fam cancer 2013; 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83:241-248. correspondence gianpaolo perletti (corresponding author) gianpaolo.perletti@uninsubria.it department of biotechnology and life sciences, section of medical and surgical sciences, university of insubria, varese, italy daniel cohen hattab daniel.cohen-hatta@mail.huji.ac.il faculty of medicine, the hebrew university of jerusalem, israel sergio dellapergola sergio.dellapergola@mail.huji.ac.il the harman institute of contemporary jewry, the hebrew university of jerusalem, israel ofer gofrit ogofrit@gmail.com department of urology, hadassah hebrew university hospital, jerusalem, israel vittorio magri vmdoctor26@gmail.com urology clinic, asst fatebenefratelli sacco hospitals, milan, italy alberto trinchieri alberto.trinchieri@gmail.com former lecturer, school of urology, university of milan, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13445 1 original paper introduction premature ejaculation (pe) is a common sexual dysfunction that significantly impacts individuals' sexual experiences and overall well-being (1-3). pe is traditionally categorized into lifelong and acquired forms, with definitions often revisited by the scientific community. according to the current definition by the international society for sexual medicine (issm), acquired and lifelong pe are male sexual dysfunctions characterized by: (i) an intravaginal ejaculatory latency time (ielt) that always or nearly always is about one minute of vaginal penetration from the first sexual experience (lifelong pe), or a clinically significant and bothersome reduction in latency time, often to about three minutes or less (acquired pe); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy (4). the true prevalence of pe remains ambiguous, evidenced by a wide range of different multinational studies (5-8). numerous studies have evaluated satisfaction with sexual life, considering both patients and their partners, in cases of sexual dysfunctions such as pe or erectile dysfunction (ed), as well as in the general population, underscoring the adverse effects of pe on relationships and sexual satisfaction (9-11). the primary aim of this study is to assess the ejaculatory latency time with a focus on the prevalence of pe in a large cohort of young patients, to background: premature ejaculation is a sexual dysfunction that can impact both men and women. this study aimed to shed light on this condition within a cohort as extensive as possible. materials and methods: we conducted an online open survey, distributed via social media, proposing a questionnaire regarding various aspects including the duration of ejaculatory latency, perceptions of premature or delayed ejaculation, as well as lifestyle and psychological aspects of sexuality. the questionnaire comprised 77 questions for male participants and 16 for female participants, with responses structured on a likert scale ranging from 1 to 5. results: a total of 1300 men and 1197 women participated in the survey, completing the entire questionnaire.the median age (iqr) of male participants was 27 (23-32) years, while that of female participants was 22 (19-35) years. men reported a median (iqr) ejaculatory latency time of 17 (8-20) minutes during sexual intercourse, compared to 20 (15-20) minutes reported by women. only 7.5% (98) of men and 5% (60) of women reported an ejaculatory latency time of less than 3 minutes in their last five sexual encounters (p = 0.0001). twelve percent (160) of men believed they consistently experienced premature ejaculation, whereas only 3% (41) of women reported this sensation (p = 0.0001). regarding satisfaction with ejaculatory latency time, 7% of men (85) expressed dissatisfaction, whereas only 2% of women (28) reported the same (p = 0.0001). conversely, only 12% of men (160) considered themselves completely satisfied, compared to 30% of women (358) (p = 0.0001). conclusions: these analyses highlight a dissonance between male and female perceptions of premature ejaculation, not only in terms of actual intercourse duration but also in terms of psychological perception and sexual well-being. this should suggest a need to increase awareness among the population regarding the contrast between idealized sexual experiences and reality. discrepancy between male and female perceptions of ejaculation latency and sexual satisfaction: results from an online open survey andrea cocci 1, marta pezzoli 1,2, arturo lo giudice 3, gaia polloni 4, giorgio ivan russo 3, leonardo gajo 1, 2, daniel giunti 5, michele di dio 6, borja garcia gòmez 7, manuel alonso isa 8, agustin fraile poblador 9, javier romero otero 10, andrea minervini 1, mattia lo re 1, 2 1 unit of oncologic minimally invasive urology and andrology, university of florence, careggi hospital, florence, italy; 2 department of experimental and clinical medicine, university of florence, florence, italy; 3 urology section, department of surgery, university of catania, catania, italy; 4 centre of psychology, como, italy; 5 centro integrato di sessuologia il ponte, florence, italy; 6 department of surgery, division of urology, ss annunziata hospital, cosenza, italy; 7 hospital universitario 12 octubre, instituto de investigación sanitaria hospital 12 de octubre, madrid, spain; 8 department of urology, hospital universitario hm puerta del sur, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain; 9 department of urology, hospital universitario hm rivas, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain; 10 department of urology, hospital universitario hm sanchinarro, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain. doi: 10.4081/aiua.2025.13445 summary key words: premature ejaculation; delayed ejaculation; sexual satisfaction. submitted 1 december 2024; accepted 13 december 2024 archivio italiano di urologia e andrologia 2025; 97(1):13445 a. cocci, m. pezzoli, a. lo giudice, et al. 2 understand how it affects satisfaction with sexual intercourse for both males and their partners. secondary objectives include evaluating factors that may influence pe and examining behaviors adopted by the population in reallife experiences to enhance their quality of sexual life. materials and methods study population participants were recruited via nonpaid posts of a survey link on instagram, facebook and telegram, correlated to the webpage “sessuologia” of daniel giunti (https://www. instagram.com/sessuologia/?hl=it). no advertising campaigns or giveaway incentives were utilized for patient recruitment, and all responses were kept completely anonymous. inclusion criteria included being 18 years of age or older, proficiency in the italian language, and providing informed consent before accessing the survey, with the explicit option to terminate participation at any time by closing the webpage. data from participants who did not complete the survey were omitted from the analysis. additionally, measures were implemented to prevent individuals from participating in the survey more than once. a completed checklist following the cherries criteria (12) is provided as supplementary material 1. questionnaire institutional review board (irb) approval was not required from our center for this kind of survey, but an informed consent was provided before the start of the questionnaire with information on the topics of the survey, the anonymity of the responses and the possibility to terminate participation at any time by closing the webpage. the survey encompassed a variety of questions, and two models were developed (refer to supplement material 2): one targeting the male population, comprising 77 questions that were more complex and detailed regarding aspects of masturbation (age of onset, frequency, ejaculation latency), lifestyle (consumption of alcohol, drugs, and their influence on ejaculation time), and psychological aspects of sexuality; the other tailored to the female population, consisting of 16 questions, primarily addressing the frequency and duration of sexual intercourse and its impact on sexual life satisfaction. ejaculatory latency time was documented as the average duration across the last five penetrative and masturbatory episodes. pe patients were identified as individuals with an ielt of less than three minutes and who exhibited distress related to this condition, as evidenced in the psychological questions. statistical analysis descriptive statistics were utilized to examine the responses from the questionnaire. the sample was one of convenience, without the conduct of a power analysis. the estimations of ielts did not follow a normal distribution; therefore, summarized data are presented as medians and interquartile ranges. response frequencies were compared between male and female groups using the chi-square test. a multivariate logistic regression was employed to analyze the association between the condition of pe and factors such as abnormal sexual habits or trauma, lifestyle, and psychic dysfunction. statistical analyses were performed using stata (statacorp. 2023. stata statistical software: release 18. college station, tx: statacorp llc). results demographic characteristics a total of 2,497 respondents were included in this study, with 1,300 men and 1,197 women. the male sample comprised individuals who identified as heterosexual straight table 1. demographic characteristics. male, n = 1300 female, n = 1197 age, median (iqr) 27 (23-32) 22 (19-35) ethnia caucasic 1091 83.9% 1010 83.4% ispanic 39 3.1% 24 2.0% asian 3 0.2% 5 0.4% other/unspecificed 167 12.8% 158 13.2% bmi, median (iqr) 24 (21-27) na smoker, n (%) 537 na antidepressive user, n (%) 38 2,9 na recreational drugs use never, n (%) 1015 78% na sometimes, n (%) 228 17.5% na regularly, n (%) 57 4.4% na alcohol assumption never, n (%) 145 11.1% na sometimes, n (%) 953 73.3% na regularly, n (%) 202 15.5% na sexual orientation heterosexual, n (%) 1148 88.3% na homosexual, n (%) 65 5% na bisexual, n (%) 74 5.7% na other, n (%) 13 1% na stable relation, n (%) yes 1083 83.8% 1002 83.1% no 217 16.2% 195 16.9% sexual intercourse frequency, n (%) < 1 month 177 13.6% 51 4.3% 1-2 month 294 22.6% 238 19.9% 1-2 weekly 566 43.5% 695 58.1% 4-5 weekly 153 11.8% 178 14.9% daily 19 1.5% 35 2.9% foreplay, n (%) never 20 1.5% 23 1.9% less than half the time 28 2.2% 43 3.6% half the time 59 4.5% 77 6.4% more than half the time 185 14.2% 129 10.8% everytime 1008 77.5% 925 77.3% foreplay time, n (%) none 12 0.9% 11 0.9% < 5 minutes 169 13.0% 183 15.3% 5-15 minutes 805 61.9% 692 57.8% 15-30 minutes 276 21.2% 267 22.3% 30-60 minutes 31 2.4% 38 3.2% > 60 minutes 0 0.0% 0 0.0% time until ejaculation minutes, median (iqr) 17 (8-20) 20 (15-20) n: number; iqr, interquartile range. archivio italiano di urologia e andrologia 2025; 97(1):13445 3 perceptions of ejaculation latency and sexual satisfaction (n = 1,148, 88.3%), homosexual gay (n = 65, 5.0%), bisexual (n = 74, 5.7%), and other or unspecified orientations (n = 13, 1.0%). we included female participants who had sexual intercourses with male subjects, independently from their sexual orientation. the median age (iqr) for the two groups was 27 (23-32) for men and 22 (19-35) for women. the participation of principally young subjects was probably due to the use of social media. at the time of the survey, 83.3% (n = 1083) of men and 83.7% (n = 1002) of women reported being in a stable relationship. the most frequent rate of sexual intercourse reported was 1-2 times per week by 43.5% (n = 566) of men and 58.1% (n = 695) of women. median (iqr) ejaculatory latency time (elt) declared by men during sexual intercourse was 17 (8-20) minutes versus 20 (15-20) minutes by women. additional demographic and sexual life-related characteristics are reported in table 1. regarding the perception of suffering from delayed ejaculation, 44.5% (n = 578) of men and 52.3% (n = 626) of women declared that they had never experienced it (table 2). conversely, 8.3% (n = 108) of men believed they always suffered from delayed ejaculation, while only 2.1% (n = 25) of women reported that they partners never suffered if it (p < 0.01). in terms of perceived suffering from pe, 36.3% (n = 472) of men reported never experiencing it, in contrast to 60.9% (n = 730) of women who reported that they partners never suffered if it (p < 0.01). while 12.3% (n = 160) of men believed they always suffered from pe, only 3.4% (n = 41) of women reported this feeling (p < 0.01) (figure 1). however, only 7.5% (n = 98) of men and 5% (n = 60) of women declared an ejaculatory latency time of under 3 minutes in their last five sexual encounters (p < 0.01). regarding satisfaction with ejaculatory latency time, 6.5% (n = 85) of men considered themselves unsatisfied, compared to 2.3% (n = 28) of women (p < 0.01). moreover, only 12.3% (n = 160) of men reported being fully satisfied, versus 29.9% (n = 358) of women (p < 0.01) (figure 2). in terms of overall sexual satisfaction, only 25.9% (n = 337) of men considered themselves fully satisfied, compared with 43.5% (n = 521) of women (p < 0.01) (figure 3). figure 1. feeling premature ejaculation. figure 2. satisfaction with ejaculatory latency time. figure 3. overall sexual satisfaction. table 2. male and female response comparison by m f p value feeling delayed ejacuation p = 0.0001 never 578 44.5% 626 52.3% rarely 387 29.8% 339 28.3% sometime 126 9.7% 124 10.4% often 101 7.8% 83 6.9% everytime 108 8.3% 25 2.1% feeling premature ejacuation p = 0.0001 never 472 36.3% 730 61.0% rarely 307 23.6% 246 20.6% sometime 181 13.9% 107 8.9% often 180 13.8% 73 6.1% everytime 160 12.3% 41 3.4% time satisfaction p = 0.0001 unsatisfied 85 6.5% 28 2.3% quite unsatisfied 227 17.5% 107 8.9% unmoved 272 20.9% 170 14.2% quite satisfied 556 42.8% 534 44.6% satisfied 160 12.3% 358 29.9% importance of foreplay for lasting p = 0.0001 none 55 4.2% 33 2.8% little 281 21.6% 215 18.0% much 649 49.9% 540 45.1% very much 315 24.2% 409 34.2% satisfaction overall p = 0.0001 unsatisfied 68 5.2% 16 1.3% quite unsatisfied 102 7.8% 56 4.7% unmoved 185 14.2% 90 7.5% quite satisfied 608 46.8% 514 42.9% satisfied 337 25.9% 521 43.5% m = male; f = female; comparison between two groups were performed by chi-square test. archivio italiano di urologia e andrologia 2025; 97(1):13445 a. cocci, m. pezzoli, a. lo giudice, et al. 4 finally, most men often or always use expedients to delay ejaculation, most used the "stop and start" technique, and the change of intercourse position (table 4) (figure 4). factors associated with premature ejaculation in table 3 we reported the result of the multivariate logistic regression analysis. in the analysis, the odds ratio in predicting pe during sexual intercourse for "age", "substance abuse" and "porn use frequency” was 1.00 (p = 0.46) 0.76 (p = 0.24) and 0.88 (p = 0.66), respectively. the odds ratio in predicting pe for "masturbation frequency", "penetrating frequency" and "erection quality" was 0.76 (p = 0.02), 0.75 (p < 0.01) and 0.73 (p < 0.01). the odds ratio in predicting pe during sexual intercourse for "premature ejaculation during masturbation" was 6.74 (p < 0.001). the odds ratio for "alcohol abuse" is 1.60 (p = 0.019), suggesting that alcohol use has a positive effect, increasing the risk of pe. the odds ratio for "sex desire" is 1.02 (p = 0.903), indicating that sexual desire does not significantly affect pe. discussion here, we presented our work in which we subjected the largest population cohort presented in a study from a single center to the best of our knowledge, to a questionnaire regarding the sexual life of both men and women. in this study, the ielt reported by male patients was a median (iqr) of 17 (8-20) minutes. this finding is corroborated by female partners, who reported a median ielt of 20 (15-20) minutes, indicating an increased duration of intercourse compared to that reported in the literature. for instance, nguyen et al. (13) recently observed a perceived ielt of 6.09 (± 6.59) minutes (median 3 minutes, range 0.5-45 minutes), which was 2.01 (± 1.21) minutes for the pe-affected group and 11.69 (± 6.83) minutes for the control group, in a population with a mean age of 30.9 (±6.84) years, similar to our study's population (median 27 (23-32) years). conversely, giuliano et al. (14), in a multicentric study, reported a median ielt in the group of italian subjects not affected by pe of 15.0 (1.5-45.0) minutes, more in line with our data, although our series did not differentiate between patients affected by pe and those who were not. moreover, patrick et al. (15), in a study of a large population sample (1,587 patients), noted a median ielt of 1.8 (range, 0-41) minutes for pe subjects and 7.3 (range, 0-53) minutes for table 3. multiple logistic regression of factors associated with premature ejaculation. or 95% ci p age 1.01 0.98-1.03 0.457 substance abuse 0.76 0.48-1-03 0.239 porn use frequency 0.88 0.51-1.53 0.659 masturbation frequency 0.76 0.61-0.95 0.017 penetration frequency 0.75 0.63-0.90 0.002 erection quality 0.73 0.62-0.87 < 0.001 premature ejaculation during masturbation 6.74 4.42-10.30 < 0.001 alcohol abuse 1.60 1.08-2.38 0.019 sex desire 1.02 0.73-1.43 0.903 figure 4. graphical representation of most used expedients for retarding ejaculation. archivio italiano di urologia e andrologia 2025; 97(1):13445 5 perceptions of ejaculation latency and sexual satisfaction non-pe subjects, with a mean age of 35.4 (± 10.7) years. our results, therefore, offer an update on the average ielt among the population, particularly in younger individuals. regarding the prevalence of pe, we observed a global prevalence of 7.5% in our study population, which aligns with the results of two large observational studies included in the issm evidence-based definition of pe, where the prevalence of lifelong and acquired pe was 6.2% and 8.0%, respectively (2, 3). the implementation of multivariate logistic regression analysis enabled the assessment of predictive factors for pe. factors such as masturbation frequency, penetration frequency, and quality of erections were identified as having a negative impact on pe. the association between penetration frequency and pe is well-documented in the literature. this was highlighted in a study by verze et al. (16), which found that italian men with pe experienced a significant reduction in sexual intercourse attempts. a comparable decline in sexual frequency was observed among men with pe versus non-pe men in a study based on the korean general population (17). consistently, the current study found an inverse correlation, indicating that a higher frequency of sexual intercourse was associated with a reduced probability of experiencing pe (table 3). the correlation between ed and pe is equally evident, with a higher incidence of pe noted in patients with ed (18-20), a finding that is consistent with observations from the current research (table 3). concerning sexual desire, our results were contrasting. while the study was based on the korean general population (17), low libido was more frequent in men with pe compared to men without, we did not find those association. our questionnaire incorporated five questions related to potential pe prevention techniques (male questionnaire, questions 58-62, supplementary material 2). behavioral therapy is recognized as a critical component in the management of pe (21-24). as indicated in table 4, the "start and stop" method, along with "changing position," emerged as the most frequently utilized technique in our sample, reported as sometimes or often by 40% and 30% for the former, and 38% and 23% for the latter, respectively. given that "changing position" could be considered another variant of the "start and stop" method, a considerable segment of the population employs these techniques. this suggests that a majority of the population, even those not diagnosed with pe, use behavioral strategies to extend the duration of sexual encounters, which in turn indicates a high prevalence of subjective pe. on one hand, this finding may explain the higher ielt observed in our cohort compared to that documented in the literature; on the other hand, it could imply a degree of discomfort with the duration of intercourse, despite exceeding the 3-minute threshold defined by the issm. concerning the latter point, this study facilitates the assessment of both men's and their partners' satisfaction with sexual activity and their expectations. the link between pe and personal distress is well-established (25), with varying impacts on men and their partners. patrick et al. (15) reported that partners' perceptions of pe are typically less problematic than those of the affected individuals. this was also supported by verze et al. (16), although a significantly higher proportion of partners of men with pe reported personal distress (44% vs. 3%) and interpersonal difficulties (25% vs. 2%) compared to partners of non-pe men. graziottin & althof (10), in a 2011 review, identified significantly greater sexual problems, decreased satisfaction, and heightened distress and interpersonal difficulties among partners of men with pe than those of non-pe men. in our dataset, as depicted in table 2, there is a notable disparity in terms of satisfaction between men and women concerning the duration of intercourse and related sensations. specifically, only 26% of men reported full satisfaction, compared to 44% of women. this discrepancy, alongside the fact that the study involved a younger population with fewer comorbidities that could impair sexual activity, should prompt reflection on the psychological pressures faced by young men regarding sexual performance and may direct educational interventions toward a more accurate understanding of sexual realities and the adjustment of expectations to prevent a dysfunctional misperception of sexual life. this research offers a fresh outlook on the perception of elts among the young, male and female, population, and its influence on the behavioral and emotional facets of sexual life, and encompasses the largest mixed cohort yet assessed with this method, to the best of our knowledge. the substantial case series also enabled us to evaluate various factors associated with pe, corroborating existing literature (26, 27). additionally, through the questionnaire focused on the psychological domain, this study offers a preliminary view into the perceived differences in sexual life satisfaction between men and women. the interpretations of our findings must consider the study's limitations. primarily, the employed questionnaire is not internationally validated, though it is akin to other instruments, such as the scs-m (28) or the female sexual distress scale-revised-premature ejaculation (fsds-r-pe) devised by limoncin et al. (29). nonetheless, the use of a multi-item questionnaire enabled us to explore various aspects not assessable by any single questionnaire available in the literature to date. secondly, it should be acknowledged that the study relies on voluntary participation in a questionnaire disseminated by a page addressing these types of issues. consequently, it must be recognized that there is no explicit distinction between users who actively seek out the page, presumably for concerns pertaining to the sexual sphere, and those who encounter the page through sponsored content without perceiving themselves table 4. most used expedients for retarding ejaculation. never rarely sometime often everytime reducing foreplay 585 (45%) 312 (24%) 273 (21%) 104 (8%) 26 (2%) masturbating before 403 (31%) 442 (34%) 364 (28%) 78 (6%) 13 (1%) abuse of substances 1157 (90%) 76 (6%) 52 (4%) 13 (1%) 2 (0%) stop and restart 132 (10%) 145 (11%) 524(40%) 392 (30%) 101 (8%) changing position 210 (16%) 223 (17%) 498 (38%) 300 (23%) 69 (5%) retarding condoms 1092 (84%) 117 (9%) 65 (5%) 12 (1%) 14 (1%) archivio italiano di urologia e andrologia 2025; 97(1):13445 a. cocci, m. pezzoli, a. lo giudice, et al. 6 to have such issues. additionally, due to the specific clinical setting we employed, we did not differentiate whether the subjects had lifelong or acquired pe. since the different clinical expressions of pe rarely require different treatment strategies, this bias does not significantly impact our results. an additional significant limitation is that the study participants were not evaluated by a professional, such as a sexologist or psychosexologist, which would have permitted a more precise objectification of the feelings described by the population. regrettably, this limitation is intrinsic to the study design, which was structured as a survey. the inclusion of a predominantly young sample may introduce biases, especially concerning the prevalence of ed and its impact on pe (30). conclusions in conclusion, our findings, given the extensive sample size and the range of assessed items, provide new insights into the prevalence of subjective premature ejaculation and its psychological consequences for both patients and their partners within the italian population. moreover, these results affirm the documented correlations between pe and its risk factors. references 1. rosen rc, althof s. impact of premature ejaculation: the psychological, quality of life, and sexual relationship consequences. j sex med. 2008; 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6:e34. 13. nguyen hb, nguyen ct, pham mq, et al. perceived intravaginal ejaculation latency time: the diagnosis of premature ejaculation among vietnamese men. andrology. 2024; 12:618-623. 14. giuliano f, patrick dl, porst h, et al. premature ejaculation: results from a five-country european observational study. eur urol. 2008; 53:1048-1057. 15. patrick dl, althof se, pryor jl, et al. premature ejaculation: an observational study of men and their partners. journal of sexual medicine. 2005; 2:358-367. 16. verze p, arcaniolo d, imbimbo c, et al. general and sex profile of women with partner affected by premature ejaculation: results of a large observational, non-interventional, cross-sectional, epidemiological study (iper-f). andrology. 2018; 6:714-719. 17. lee sw, lee jh, sung hh, et al. the prevalence of premature ejaculation and its clinical characteristics in korean men according to different definitions. int j impot res. 2013; 25:12-7. 18. corona g. erectile dysfunction and premature ejaculation: a continuum movens supporting couple sexual dysfunction. j endocrinol invest. 2022; 45:2029-2041. 19. moussa m, papatsoris ag, chakra ma, et al. erectile dysfunction in common neurological conditions: a narrative review. arch ital urol androl. 2020; 92:371-385. declarations ethical approval: this research has been conducted in the public arena using only publicly available or accessible records without contact with the individual/s and it does not require ethics reviews according to tri-council policy statement: ethical conduct for research involving humans articles 2.2 to 2.4. availability of data and material: the datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors' contributions: ac and mlr have given substantial contributions to the conception and the design of the manuscript. alg, mp, gp, mdd, mai, afp, gl and dg to the acquisition of the data; mlr and alg to the analysis and interpretation of the data. mlr, ac, alg have participated to drafting the manuscript, bgg, jro, am revised it critically. all authors read and approved the final version of the manuscript. acknowledgments: not applicable. consent for publication: not applicable. archivio italiano di urologia e andrologia 2025; 97(1):13445 7 perceptions of ejaculation latency and sexual satisfaction 20. metz me, pryor jl. premature ejaculation: a psycho physiological approach for assessment and management. j sex marital ther. 2000; 26:293-309. 21. ia ah, naggar e, gilany ah el. assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. int j impot res. 2001; 13:41-5. 22. yuan p, dai j, yang y, et al. a comparative study on treatment for premature ejaculation: citalopram used in combination with behavioral therapy versus either citalopram or behavioral therapy alone 2008; pp 35-38 https://www.researchgate.net/publication/ 292872130 _a_comparative_study_on_treatment_for_premature_ejaculation_ci talopram_used_in_combination_with_behavioral_therapy_versus_eit her_citalopram_or_behavioral_therapy_alone. 23. dogan k, keçe c. comparison of the results of stop-start technique with stop-start technique and sphincter control training applied in premature ejaculation treatment. plos one. 2023; 18:e0283091. 24. cooper k, james mms, kaltenthaler e, et al. interventions to treat premature ejaculation: a systematic review short report. health technol assess (rockv). 2015; 19:1-180. 25. russo gi, cocci a. do we have put a new cornerstone for the correspondence andrea cocci, md (corresponding author) cocci.andrea@gmail.com unit of oncologic minimally invasive urology and andrology, university of florence, careggi hospital, 50100 florence, italy marta pezzoli marta.pezzoli@unifi.it leonardo gajo leonardo.gajo@unifi.it unit of oncologic minimally invasive urology and andrology, department of urology, university of florence, careggi hospital, 50100 florence, italy arturo lo giudice arturologiudice@gmail.com giorgio ivan russo giorgioivan.russo@unict.it urology section, department of surgery, university of catania, catania 95131, italy gaia polloni info@gaiapolloni.com centre of psychology, via cadorna, 22100 como, italy daniel giunti danielgiunti@gmail.com centro integrato di sessuologia il ponte, 50100 florence, italy. michele di dio m.didio@aocs.it department of surgery, division of urology, ss annunziata hospital, cosenza, italy borja garcia gòmez borjagarciagomez@gmail.com hospital universitario 12 octubre, instituto de investigación sanitaria hospital 12 de octubre, madrid 28041, spain manuel alonso isa manuel.alonso@rocclinic.com department of urology, hospital universitario hm puerta del sur, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain agustin fraile poblador agustin.fraile@rocurologia.com department of urology, hospital universitario hm rivas, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain javier romero otero jromerootero@rocclinic.com department of urology, hospital universitario hm sanchinarro, instituto investigación sanitaria hm hospitales and roc clinic, madrid, spain andrea minervini andrea.minervini@unifi.it mattia lo re mattialore1994@gmail.com unit of oncologic minimally invasive urology and andrology, university of florence, careggi hospital, 50100 florence, italy treatment of premature ejaculation? int j impot res. 2018; 30:272273. 26. ventus d, jern p. lifestyle factors and premature ejaculation: are physical exercise, alcohol consumption, and body mass index associated with premature ejaculation and comorbid erectile problems? j sex med. 2016; 13:1482-1487. 27. herkommer k, meissner vh, dinkel a, et al. prevalence, lifestyle, and risk factors of erectile dysfunction, premature ejaculation, and low libido in middle-aged men: first results of the bavarian men’s health-study. andrology. 2024; 12:801-808. 28. gündüz a, sertçelik s, gündogmus i, et al. turkish validity and reliability of the sexual complaints screener for men turkish validity and reliability of the sexual complaints screener for men. psychiatry and clinical psychopharmacology 2018; 29:1-6. 29. limoncin e, tomassetti m, gravina gl, et al. premature ejaculation results in female sexual distress: standardization and validation of a new diagnostic tool for sexual distress. j urol. 2013; 18:1830-1835. 30. jannini ea, lombardo f, lenzi a. correlation between ejaculatory and erectile dysfunction. int j androl. 2005; 28(suppl 2):40-45. stesura seveso archivio italiano di urologia e andrologia 2025; 97(2):13856 1 original paper stage chronic kidney disease (ckd)(1). it is defined as the inability to attain and maintain an erection of sufficient duration and rigidity for satisfactory sexual intercourse (2, 3). end-stage ckd requires renal replacement therapy, such as kidney transplantation or dialysis. these therapies are expected to improve both the general condition and erectile function of patients. hemodialysis is one form of dialysis therapy (1, 4). the prevalence of ed in patients undergoing hemodialysis reaches 90% (5). it is therefore important to consider ed in the care of hemodialysis patients, as it significantly affects their quality of life (6). this study aims to determine changes in erectile function in end-stage ckd patients who underwent hemodialysis, focusing on changes in laboratory parameters. materials and methods this is a cross-sectional study conducted from march to april 2024 at the hemodialysis unit of wangaya general hospital, denpasar bali. subjects were male patients with end-stage ckd who underwent hemodialysis twice a week. inclusion criteria were being male patients with end-stage (ckd), aged 45-65 years, being married and having sexual partners, undergoing hemodialysis for at least 3 months, and consenting to participate in the study. exclusion criteria were use of sexual performance enhancing drugs, history of genital surgery, history of neurological disease such as stroke, history of benign prostatic hyperplasia. based on this criteria, 22 subjects were included in this study. data were collected through interviews and from medical records. subjects were assessed for erectile function using the 5-item version of international index of erectile function (iief-5) and the erection hardness score (ehs). subjects were given iief-5 and ehs questionnaires to assess erectile function before the first session of hemodialysis and after the last session of routine hemodialysis 8at least 3 months). laboratory parameters were collected from medical records during hemodialysis, and included hemoglobin, hematerectile dysfunction (ed) is one of the complications in male patients with end-stage chronic kidney disease (ckd). renal replacement therapy may improve general conditions and thus improve erectile function. this study aims to determine changes in erectile dysfunction in end stage ckd patients who underwent hemodialysis, focusing on changes in laboratory parameters. this cross-sectional study was conducted from march to april 2024 at the hemodialysis unit of wangaya general hospital. the subjects were male patients with end-stage chronic kidney disease (ckd) who were undergoing hemodialysis and met the specific inclusion and exclusion criteria. erectile function was assessed using the international index of erectile function (iief5) and the erection hardness score (ehs). laboratory parameters, including hemoglobin, hematocrit, neutrophil count, neutrophil-to-lymphocyte ratio (nlr), and platelet-to-lymphocyte ratio (plr) were recorded. twenty-two subjects were included in this study. the prevalence of ed before starting hemodialysis and after a period of at least 3 months of hemodialysis was 28.3% and 86.4% respectively. a statistically significant difference was observed in the iief-5 scores of patients before and after hemodialysis (p = 0.001). significant differences were observed in the erection degree before and after hemodialysis based on iief-5 (p = 0.001) and ehs (p = 0.001). there was a significant correlation between erection degree assessed by iief-5 and hemoglobin, hematocrit, nlr and plr; and erection degree assessed by ehs and hemoglobin, hematocrit, and plr, (all p < 0.05). in conclusion, there is a deterioration in erectile function in patients undergoing hemodialysis compared to their condition before hemodialysis. there was significant correlation between hemoglobin, hematocrit, nlr, and plr and erectile dysfunction. key words: erectile dysfunction; erection hardness score; hemodialysis; international index of erectile function-5; laboratory parameters. submitted 1 april 2025; accepted 25 april 2025 introduction erectile dysfunction (ed) is a common sexual dysfunction that occurs as a complication in male patients with endexploring the association between hemoglobin, hematocrit, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with erectile dysfunction in chronic kidney disease patients undergoing hemodialysis: a cross-sectional study anak agung ngurah krisnanta adnyana 1, i wayan suarsana 2, anak agung patriana puspaningrat 2, ida bagus oka widya putra 2 1 general practitioner, wangaya general hospital, denpasar, bali, indonesia; 2 departement of urology, wangaya general hospital, denpasar, bali, indonesia. doi: 10.4081/aiua.2025.13856 summary archivio italiano di urologia e andrologia 2025; 97(2):13856 a. agung ngurah krisnanta adnyana, i wayan suarsana, a. agung patriana puspaningrat, i. bagus oka widya putra 2 ocrit, neutrophil count, neutrophil-to-lymphocyte ratio (nlr), and platelet-to-lymphocyte ratio (plr). the neutrophil-to-lymphocyte ratio (nlr) and platelet-tolymphocyte ratio (plr) were utilized as biomarkers to assess systemic inflammation. inflammation is known to impair endothelial function and promote prothrombotic events. given that endothelial dysfunction is a key factor in the pathogenesis of erectile dysfunction, these inflammatory markers were evaluated to investigate their potential association. wilcoxon sign-rank was used to compare difference erectile function (score and degree of erection) before the first session of hemodialysis and after undergoing routine hemodialysis for at least 3 months. given that the normality assumption was found to be violated in the distribution of our data, spearman’s rho test was used to analyse correlation of erection degree (based on iief-5 and ehs) and laboratory parameters (hemoglobin, hematocrit, neutrophil count, nlr, and plr). a p value of < 0.05 was considered statistically significant. all data analyses were performed using statistical package for the social sciences (spss version 27.0; armonk, ny: ibm corp). results the characteristics of the 22 subjects included in this study were presented in table 1. the mean age of the participants was 52.77 years, and the mean duration of hemodialysis was 39.4 months. the comorbid condition found in the majority of participants was hypertension. the average iief-5 score was 21.7 before hemodialysis and 14.09 during hemodialysis. a significant difference (p = 0.001) was observed between the iief-5 score before and during hemodialysis. based on iief-5, there were 6 participants (27.3%) who had erectile dysfunction before hemodialysis and 19 participants (86.4%) who had erectile dysfunction during hemodialysis, as shown in table 2. there was a significant difference between the erection degree before and during hemodialysis based on iief-5, with p = 0.001. table 3 displays erection degree based on ehs. based on ehs, there were 14 participants (63.6%) with score 4 before hemodialysis and there were 9 participants (40.9%) with score 2 during hemodialysis. there was a significant difference between the erection degree before and during hemodialysis, as measured by the erection hardness score (ehs), with p = 0.001. there was a significant correlation between the erection degree during hemodialysis based on iief-5 and hemoglobin (p = 0.013, r = 0.518), hematocrit (p = 0.016, r = 0.508), nlr (p = 0.038, r = -0.444), plr (p = 0.041, r = -0.439) (table 4). there was a significant correlation between the degree of erection during hemodialysis based on ehs and hemoglobin (p = 0.013, r = 0.522), hematocrit (p = 0.012, r = 0.523), plr (p = 0.017, r = -0.502) (table 4). table 2. comparation of erection degree before and after hemodialysis based on iief-5. erection degree before hemodialysis after hemodialysis p value (based on iief-5) n (%) n (%) no ed 16 (72.7%) 3 (13.6%) 0.001 mild 3 (13.6%) 6 (27.3%) mild-moderate 2 (9.1%) 5 (22.7%) moderate 0 1 (4.5%) severe 1 (4.5%) 7 (31.8%) table 1. characteristics of participants. characteristic mean ± sd age 52.77 ± 5.50 hemodialysis period (months) 39.41 ± 47.46 iief-5 scorea 14.09 ± 7.02 erection degree (iief-5)a no erectile dysfunction 3 (13.6%) mild 6 (27.3%) mild-moderate 5 (22.7%) moderate 1 (4.5%) severe 7 (31.8%) erection degree (ehs) * 0 3 (13.6%) 1 2 (9.1%) 2 9 (40.9%) 3 7 (31.8%) 4 1 (4.5%) hypertension yes 20 (90.9%) no 2 (9.1%) diabetes mellitus yes 9 (40.9%) no 13 (59.1%) cardiovascular disease yes 9 (40.9%) no 13 (59.1%) laboratory values hemoglobin (g dl-1) 10.39 ± 1.52 hematocrit (%) 31.76 ± 5.05 neutrophil count (103 ul-1) 6.12 ± 4.13 neutrophil to lymphocyte ratio (103 ul-1) 4.06 ± 4.20 platelet to lymphocyte ratio (103 ul-1) 134.76 ± 63.58 * score and degree of erection after patients underwent routine hemodialysis. table 3. comparation of erection degree before and after hemodialysis based on erection hardness score (ehs). ehs before hemodialysis after hemodialysis p value n (%) n (%) 0 1 (4.5%) 3 (13.6%) 0.001 1 0 2 (9.1%) 2 2 (9.1%) 9 (40.9%) 3 5 (22.7%) 7 (31.8%) 4 14 (63.6%) 1 (4.5%) archivio italiano di urologia e andrologia 2025; 97(2):13856 3 erectile dysfunction in ckd patients undergoing hemodialysis discussion the prevalence of erectile dysfunction (ed) in patients before hemodialysis was 28.3%, which increased to 86.4% after hemodialysis. this rise in prevalence is consistent with the finding of gorsane et al., who reported an increased from 8.4% to 91.6%(5). similarly, warli et al., found a high prevalence of ed, with 90.5% of patients undergoing hemodialysis experiencing the condition (1). in this study, there was a significant difference in the iief5 scores of patients before and after hemodialysis (p value = 0.001), which were lower after hemodialysis (14.09 ± 7.02) compared to before hemodialysis (21.77 ± 4.86). additionally, significant difference was observed between the degree of erection based on ehs, with p-values of 0.001. gorsane et al. found that 79.1% of participants experienced reduced erectile function during hemodialysis, and noted that patients with preserved diuresis were able to maintain better erectile function (5). similarly, the study by stolic et al. reported a significant difference in iief-5 scores between patients with preserved diuresis, who had better scores compared with those without preserved diuresis (7). endothelial dysfunction due to vascular problems explains the worsening of erectile dysfunction in hemodialysis patients (5). the presence of residual renal function in dialysis patients can help reduce the risk of cardiovascular disease, and control blood pressure and anemia. additionally, preserved residual kidney function is known to enhance the effectiveness of dialysis (7). different results were reported in a study by savadi et al., which found an increase in erectile function scores in patients before their first hemodialysis session compared to after 6 months of hemodialysis (8). conversely, the study by duarsa et al, observed an increase in the iief-5 score in patients before and after hemodialysis, although he found no significant difference in the degree of erectile dysfunction (9). the causes of erectile dysfunction are not solely vascular. erectile dysfunction in hemodialysis patients can also result from psychological effects (9, 10). there is a positive correlation between anxiety and the incidence of ed in both hemodialysis and capd patients (1). in addition, depression has also been identified as a risk factor for ed in hemodialysis patients (11). in end-stage ckd, the causes of depression are often related to multiple losses, such as the loss of kidney function, diminished wellbeing, changes in family and work role, and concerns about the future (10). depression can lead to decreased sexual desire, lowered self-esteem, and reluctance to engage in pleasurable activities, so it may be a psychological cause of erectile dysfunction (11). this study did not address psychogenic factors, which could be a limitation. in this study, there was a significant correlation between haemoglobin and haematocrit and erectile dysfunction based on iief-5 and ehs scores (hb: p = 0.013 and p = 0.013; hct: p = 0.016 and p = 0.012). the correlation between haemoglobin and haematocrit and erectile dysfunction was also found in other studies(12-14). this may be because anemia can worsen the general condition and cause asthenia in patients with end-stage ckd (10, 13). however, there was no association between haematocrit and erectile dysfunction in other studies(15, 16). erectile dysfunction is an early sign of systemic problems that can lead to cardiovascular disease. exposure to atherogenic risk factors leads to endothelial dysfunction and contributes to the development of atherosclerosis. atherosclerosis affects all vessels, but the onset of symptoms varies depending on the diameter of the affected artery. inflammation plays an important role in the initiation and progression of atherosclerosis. endothelial dysfunction is also a key factor in the pathogenesis of erectile dysfunction. low-degree subclinical inflammation can impair endothelial function and induce prothrombic events. in recent years, nlr and plr have been utilized as biomarkers of subclinical inflammation (17, 18). this study also found correlation between erection degree to nlr and plr levels. these results are consistent with studies by pakpahan et al. and sambel et al. (17, 19). table 4. correlation of erection degree before and after hemodialysis (based on iief-5 and ehs) and laboratory values. laboratory erection degree (based on iief-5) erection degree (based on ehs) values correlation p value correlation p value coefficient coefficient hemoglobin 0.518 0.013 0.522 0.013 hematocrit 0.508 0.016 0.523 0.012 neutrophil -0.196 0.383 -0.144 0.523 nlr -0.444 0.038 -0.419 0.052 plr -0.439 0.041 -0.502 0.017 nlr: neutrophil-to-lymphocyte ratio; plr: platelet-to-lymphocyte ratio. declarations ethical approval: we obtained ethical approval for this study from health research ethics committee wangaya general hospital, bali, indonesia. the study was conducted in accordance with the declaration of helsinki. written informed consent was obtained from all participants. availability of data and material: the datasets during the current study are available from the corresponding author on reasonable request. due to privacy concerns, individual participant data cannot be made publicly available. however, aggregated data supporting the findings of this study are included within the article. competing interests: the authors declare that they have no competing interests. funding: this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors' contributions: aanka, investigation, writing – original draft, perform statistical analysis, writing – review and editing; iws, conceptualization, validation, writing – review and editing; aapp, conceptualization, methodology, validation; ibowp, conceptualization, methodology, supervision, writingreview and editing, validation. all authors read and approved the final manuscript. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(2):13856 a. agung ngurah krisnanta adnyana, i wayan suarsana, a. agung patriana puspaningrat, i. bagus oka widya putra 4 in conclusion, erectile function deteriorates in patients undergoing hemodialysis compared to their condition before starting treatment. there is correlation between hemoglobin, hematocrit, nlr, and plr and erectile dysfunction. anemia may contribute to erectile dysfunction, and endothelial dysfunction due to inflammation (as measured by inflammatory biomarkers) may associate to erectile dysfunction in hemodialysis patients and has the potential to be used as a biomarker. references 1. warli sm, alamsyah mt, nasution at, et al. the assessment of male erectile dysfunction characteristics in patients undergoing continuous ambulatory peritoneal dialysis and hemodialysis using the international index of erectile function (iief-5) combined with hospital anxiety and depression scales. int j nephrol renovasc dis. 2023; 16:155-61. 2. muneer a, kalsi j, nazareth i, arya m. erectile dysfunction. bmj. 2014 jan 27; 348. 3. nih consensus conference. impotence. nih consensus development panel on impotence. jama. 1993; 270:83-90. 4. chen l, shi gr, huang dd, et al. male sexual dysfunction: a review of literature on its pathological mechanisms, potential risk factors, and herbal drug intervention. biomed pharmacother. 2019; 112:108585. 5. gorsane i, amri n, younsi f, et al. erectile dysfunction in hemodialysis patients. saudi j kidney dis transpl. 2016; 27:23-8. 6. edey mm. male sexual dysfunction and chronic kidney disease. front med (lausanne). 2017; 4:1-10. 7. stolic rv, bukumiric zm, jovanovic an, et al. residual renal function and erectile dysfunction in patients on hemodialysis. int urol nephrol. 2012; 44:891-5. 8. savadi h, khaki m, javnbakht m, pourrafiee h. the impact of hemodialysis on sexual function in male patients using the international index of erectile function questionnaire (iief). electron physician. 2016; 8:2371-7. 9. duarsa gwk, kandarini y, winarta gk, et al. a comparison of erectile dysfunction improvement between patients with regular hemodialysis and patients with continuous ambulatory peritoneal dialysis. j sex med. 2021; 18:920-5. 10. el-assmy a. erectile dysfunction in hemodialysis: a systematic review. world j nephrol. 2012; 1:160-5. 11. fernandes gv, dos santos rr, soares w, et al. the impact of erectile dysfunction on the quality of life of men undergoing hemodialysis and its association with depression. j sex med. 2010; 7:4003-10. 12. ali mem, abdel-hafez hz, mahran am, et al. erectile dysfunction in chronic renal failure patients undergoing hemodialysis in egypt. int j impot res. 2005; 17:180-5. 13. tsai wk, chiang pk, chen m, yang s. prevalence and correlates of erectile dysfunction among end-stage renal disorder patients on hemodialysis. hypertension. 2008; 52:49-1. 14. neto af, de freitas rodrigues ma, saraiva fittipaldi ja, moreira ed jr. the epidemiology of erectile dysfunction and its correlates in men with chronic renal failure on hemodialysis in londrina, southern brazil. int j impot res. 2002; 14:19-26. 15. cerqueira j, moraes m, glina s. erectile dysfunction: prevalence and associated variables in patients with chronic renal failure. int j impot res. 2002; 14:65-71. 16. messina le, claro ja, nardozza a, et al. erectile dysfunction in patients with chronic renal failure. int braz j urol. 2007; 33:673-8. 17. sambel m, kilic m, demirbas m, et al. relationship between erectile dysfunction and the neutrophil to lymphocyte and platelet to lymphocyte ratios. int j impot res. 2018; 30:27-35. 18. aslan a, kaya y, çırakoglu a, et al. neutrophil-lymphocyte ratio could be a marker for erectile dysfunction. urol j. 2019; 16:216-20. 19. pakpahan c, ilhamsyah i, supardi s, et al. the interplay between neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, erectile dysfunction, and peyronie’s disease: a meta-analysis of observational studies. arch ital urol androl. 2023; 95:11162. correspondence anak agung ngurah krisnanta adnyana krisnanta.adnyana@gmail.com general practitioner, wangaya general hospital, denpasar, bali, indonesia i wayan suarsana suarsanawayan6@gmail.com anak agung patriana puspaningrat patriana.ptty@yahoo.com ida bagus oka widya putra (corresponding author) ibokawp@gmail.com department of urology, wangaya general hospital, denpasar, bali, indonesia jalan kartini no. 133 denpasar 80231, bali, indonesia stesura seveso archivio italiano di urologia e andrologia 2021; 93, 4468 original paper no conflict of interest declared. coccal urethritis (gu), caused by neisseria gonorrhoeae, or non-gonococcal urethritis (ngu), caused by other aetiological agents, such as chlamydia trachomatis, mycoplasma genitalium or ureaplasma urealyticum (1). however, it is estimated that the aetiology remains unknown in up to 30%-40% of cases of ngu (2). in recent years, new microorganisms have been described as aetiological agents for ngu, with bacteria of the genus haemophilus taking on special importance (3, 4). sexual transmission to the urethra via insertive oral sex is recognized as a potential mode of transmission (5). however, this mechanism has not been fully proven. we conducted a retrospective study to describe the epidemiological, clinical and laboratory characteristics of male patients diagnosed with urethral infections due to haemophilus spp. and to compare these characteristics with those observed in male patients diagnosed with urethral infections due to n. gonorrhoeae, c. trachomatis, m. genitalium and u. urealyticum. materials and methods inclusion criteria the study population comprised all male patients who attended our department of sexually transmitted infections (sti) between january 2018 and february 2019 and underwent conventional bacteriological and multiplex pcr studies in the urethra at the same time. the study was approved by our institutional medical and research ethics committee. demographic, behavioural, clinical and laboratory data were obtained by reviewing medical charts. the different parameters under study were defined as follows: • sexual orientation. • type of sexual partner. • number of sexual partners during the 90 days prior to the infection. • type of unprotected sex during the 90 days prior to the infection. • history of stis: all patients were asked about their sti history. objective: to describe the epidemiological, clinical and laboratory characteristics of male patients diagnosed with haemophilus spp. urethral infection and to compare them with the characteristics of male patients diagnosed with n. gonorrhoeae, c. trachomatis, m. genitalium and u. urealyticum urethral infection. over the past 2 years, an increase in urethral infections due to haemophilus spp. was observed. materials and methods: all male patients who attended our department of sexually transmitted infections between january 2018 and february 2019 were retrospectively studied; they underwent conventional bacteriological and multiplex pcr studies in the urethra at the same time. results: of the 86 patients studied, a unique microorganism was detected in 76 cases, n. gonorrhoeae in 24, haemophilus spp. in 21 (16 h. parainfluenzae and 5 h. influenzae), c. trachomatis in 19, m. genitalium in 8 and u. urealyticum in 4; 10 cases presented more than one microorganism. in case of multiple aetiological agents, sexual partnership was multiple. in the haemophilus group, 81% reported only unprotected oral insertive sex; symptoms lasted for more than one week in 62% of the patients. conclusions: haemophilus is an aetiological agent of non-gonococcal urethritis whose incidence is clearly increasing; the main route of transmission is oral sex. the most common reason for consultation is dysuria and testicular pain, while urethral discharge was predominant for the other causes of urethral infection. due to the high frequency of antibiotic resistance in the haemophilus group, it is necessary to confirm eradication by performing a test of cure. key words: haemophilus spp.; neisseria gonorrhoeae; chlamydia trachomatis; mycoplasma genitalium; ureaplasma urealyticum; urethral infections; males; sexually transmitted infections. submitted 15 august 2021; accepted 7 october 2021 introduction one of the most common presentations of sexually transmitted infections (sti) among men is acute urethritis. classically, cases of sexually transmitted urethritis have been classified according to their aetiology, as either gonoepidemiological, clinical and laboratory differences between male urethral infections due to haemophilus spp. and those due to neisseria gonorrhoeae, chlamydia trachomatis, mycoplasma genitalium and ureaplasma urealyticum: a descriptive study alvaro vives, marco cosentino, lluis bassas, carles alonso, felix millan sexually transmitted infection department, andrology service, fundació puigvert, universitat autònoma de barcelona, barcelona, spain. doi: 10.4081/aiua.2021.4.468 summary 469archivio italiano di urologia e andrologia 2021; 93, 4 differences between male urethral infections • hiv status. • recreational drugs during the past year. • main reason for consultation. • duration of symptoms. • presence of leukocytes. • types of treatment • test of cure: this consists in the performance of a conventional bacteriological and/or multiplex pcr study 3 weeks after the end of the treatment. • clinical cure: in our sti department patient is seen again 3 weeks after the end of the treatment. all patients without signs and symptoms at that time are considered clinically cured. • partner notification and treatment: we considered a positive result for partner notification when at least one of the sexual partners from the last 90 days had been advised and treated correctly. according to the cdc sti guidelines, urethritis can be documented on the basis of any of the following signs or laboratory tests: 1) mucoid, mucopurulent, or purulent discharge on examination. 2) gram stain of urethral secretions exist that demonstrate ≥ 2 wbcs per oil immersion field. 3) positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun first-void urine demonstrating ≥ 10 wbcs/hpf. men evaluated in settings in which gram stain or mb or gv smear is unavailable who meet at least one criterion for urethritis (i.e., urethral discharge, positive leukocyte esterase test on first void urine, or microscopic examination of first-void urine sediment with ≥ 10 wbcs/hpf) should be tested for c. trachomatis and n. gonorrhoeae by naats. laboratory studies only urethral samples were obtained: the first sample for culture and leukocyte counting while the second for multiple pcr. conventional bacteriological study included direct examination by gram stain of the sample smear under 100× and 1000× magnification, and culture. petri dishes of chocolate agar (bd), martin-lewis agar (bd), gardnerella agar (bd) and sabouraud with gentamicin and chloramphenicol (bd) were used. chocolate agar, martin-lewis agar and gardnerella agar were incubated at 35°c with enriched 7% co2 atmosphere for 3 days (chocolate and martin-lewis agar) or 2 days (gardnerella agar). sabouraud was incubated at 35°c for 2 days at room air. n. gonorrhoeae and haemophilus strains were identified by api nh test (biomérieux). multiplex pcr was performed by anyplextm ii sti-7 assay (seegene), which detects five microorganisms in a single reaction: chlamydia trachomatis, neisseria gonorrhoeae, trichomonas vaginalis, mycoplasma genitalium, ureaplasma urealyticum. leukocytes and other elements were looked for in lpf microscopy (100x). then, leukocytes in 20 fields of these areas were observed at 1000x and the average was calculated. the antimicrobial susceptibility of n. gonorrhoeae and haemophilus spp. strains was analyzed according to 2015 clsi guidelines (6). statistical analysis statistical analysis was conducted using statistical product and service solutions version 18.0 (spss). descriptive statistics were used to evaluate the study outcomes. mean values and ranges are presented for continuous measurements. frequencies and percentages were reported for dichotomous and ordinal variables. differences of discrete variables were analysed with unpaired two-tailed student’s t test. comparisons of proportions were performed with fisher’s exact test. statistical significance was set at p < 0.05. multivariate binary logistic regressions were used to search for the better combination of variables to predict the aetiology of haemophilus spp, and the accuracy of the model was measured as the area under the roc curve (auc). results in total, 158 patients met the inclusion criteria, all had symptoms except for 5 who attended for screening. the screening cases were men to whom a sexual partner of the last 90 days had warned a positive result for: n. gonorrhoeae, c. trachomatis, m. genitalium, u. urealyticum. we obtained 86 (54%) positive results for the microortable 1. reasons for consultation. reason for consultation total positive cases * urethral secretion 69 55 (86.2%) dysuria 47 20 (42.5%) testicular pain 9 6 (66.7%) balanitis 12 0 (0%) meatitis 9 2 (22.2%) screening 5 2 (40%) hematospermia 6 1 (16.7%) urethrorrhagia 1 0 (0%) total 158 86 (54.4%) * positive results for any of the following microorganisms: haemophilus, neisseria gonorrhoeae, chlamydia trachomatis, mycoplasma genitalium or ureaplasma urealyticum. table 2. classification of the isolated microorganisms. microorganism number haemophilus spp. haemophilus parainfluenzae 16 21 haemophilus influenzae 5 neisseria gonorrhoeae 24 chlamydia trachomatis 19 mycoplasma genitalium 8 ureaplasma urealyticum 4 c. trachomatis + m. genitalium 1 c. trachomatis + n. gonorrhoeae 1 c. trachomatis + h. parainfluenzae 3 c. trachomatis + h. influenzae 2 u. urealyticum + h. parainfluenzae 1 u. urealyticum + gardnerella vaginalis 1 n. gonorrhoeae + m. genitalium + u. urealyticum 1 archivio italiano di urologia e andrologia 2021; 93, 4 a. vives, m. cosentino, l. bassas, c. alonso, f. millan 470 ganisms under study however, when we focused the main reason for consultation. in patients with urethral discharge the percentage of positives increased to 86.2% (55 cases) (table 1). regarding the 86 positive results, a single microorganism was detected in 76 cases; 24 cases of n. gonorrhoeae, 21 cases of haemophilus spp. (16 h. parainfluenzae and 5 h. influenzae), 19 cases of c. trachomatis, 8 cases of m. genitalium and 4 cases of u. urealyticum. ten cases presented with more than one microorganism, being c. trachomatis the most frequent, followed by haemophilus spp. (table 2). in table 3 we described the demographic, behavioural, clinical and laboratory data according to the germ obtained or multiple infection. demographic and behavioural differences age: the mean age of the patients included in the study was 31.6 years (range 16-74). the lowest mean age (24.5 years) was observed in patients with infection by u. urealyticum while the highest was seen in those with n. gonorrhoeae infection (37.5 years); haemophilus cases displayed the second highest mean age. sexual orientation: for all microorganisms, including multiple infections, most cases occurred in males having sex table 3. reasons for consultation. aetiology haemophilus neisseria chlamydia mycoplasma ureaplasma multiple p * spp gonorrhoeae trachomatis genitalium urealyticum infection number of cases 21 24 19 8 4 10 mean age (years) 35.6 (20–52) 37.5 (21–74) 29.8 (16–57) 32.6 (21–47) 24.5 (16–38) 30.1 (18–46) p = 0.315 sexual orientation msw 13 (62%) 14 (58%) 16 (84%) 7 (88%) 4 (100%) 7 (70%) p = 0.459 msm 7 (33%) 10 (42%) 3 (16%) – – 1 (10%) p = 0.616 bsm 1 (5%) – – 1 (12%) – 2 (20%) p = 0.560 type of sexual partner single 5 (24%) 8 (33%) 9 (47%) 4 (50%) – 2 (20%) p = 0.381 multiple 16 (76%) 16 (67%) 10 (53%) 4 (50%) 4 (100%) 8 (80%) p = 0.381 number of sexual partners 3.5 (1–20) 2.5 (1–10) 2.4 (1–10) 3.,6 (1–20) 2.2 (1–4) 8.4 (1–20) p = 0.336 type of unprotected sex durings uois 21 (100%) 24 (100%) 18 (95%) 8 (100%) 4 (100%) 10 (100%) p = 0.676 the past 90 day uvs 4 (19%) 9 (38%) 14 (74%) 7 (88%) 3 (75%) 7 (70%) p = 0.004 uais 1 (5%) 4 (17%) – 1 (12%) – 1 (10%) p = 0.922 previous history of sti 9 (43%) 7 (29%) 8 (42%) 2 (22%) – 5 (50%) p = 0.477 hiv status positive 2 (10%) – 2 (11%) – – 1 (10%) p = 0.651 negative 14 (66%) 21 (87%) 16 (84%) 8 (100%) 3 (75%) 9 (90%) p = 0.081 not available 5 (24%) 3 (13%) 1 (5%) – 1 (25%) – p = 0.182 recreational drugs alcohol 18 (86%) 22 (92%) 18 (95%) 8 (100%) 4 (100%) 8 (80%) p = 0.398 tobacco 14 (66%) 11 (46%) 12 (63%) 5 (63%) 2 (50%) 6 (60%) p = 0.546 other drugs 3 (14%) 3 (13%) 3 (16%) – 1 (25%) 4 (40%) p = 0.794 main reason for consultation discharge 7 (33%) 23 (96%) 13 (68%) 4 (50%) 1 (25%) 8 (80%) p = 0.003 dysuria 8 (38%) 1 (4%) 4 (21%) 3 (38%) 2 (50%) 1 (10%) p = 0.132 testicular pain 4 (19%) – 2 (11%) – – – p = 0.096 meatitis 1 (5%) – – – – 1 (10%) haematospermia 1 (5%) – – – – – screening – – – 1 (12%) 1 (25%) – duration of symptoms < 1 week 8 (38%) 22 (92%) 11 (58%) 6 (75%) 2 (50%) 8 (80%) p = 0.006 > 1 week 13 (62%) 2 (8%) 8 (42%) 1 (12%) 1 (25%) 2 (20%) p = 0.002 not available – – – 1 (12%) 1 (25%) – presence of leukocytes 5 (24%) 18 (75%) 8 (42%) – – 4 (40%) p = 0.124 treatments ceftriaxone (ceft.) – 4 – – – – ceft. + doxycycline 2 16 8 – 2 4 ceft. + azithromycin 1 4 2 – – 1 doxycycline 2 – 4 – 2 4 azithromycin, single 1 g oral dose – – 5 – – – azithromycin 5-day course 3 – – 4 – 1 moxifloxacin – – – 4 – – other 13 – – – – – clinical cure yes 19 (90%) 23 (96%) 17 (89%) 8 (100%) 3 (75%) 10 (100%) p = 0.968 not known 2 (10%) 1 (4%) 2 (11%) – 1 (25%) – p = 0.968 culture/pcr control 19 (90%) – – 8 (100%) – 10 (100%) partner notification and treatment – 23 (96%) 18 (95%) 8 (100%) 3 (75%) 10 (100%) uois: unprotected oral insertive sex; uvs: unprotected vaginal sex; uais: unprotected anal insertive sex. hiv status: at the time of the consultation or during the 3 months preceding the consultation. treatments: ceftriaxone 500 mg single intramuscular dose. ceftriaxone 500 mg single intramuscular dose + doxycycline 100 mg every 12 h, orally, for 7 days. ceftriaxone 500 mg single intramuscular dose + azithromycin 1 g single dose, orally. doxycycline 100 mg every 12 h, orally, for 7 days. azithromycin 1 g orally, single dose. azithromycin 5-day course: 500 mg–250 mg–250 mg–250 mg–250 mg orally. moxifloxacin 400 mg oral single dose daily for 7 days. other treatments: ciprofloxacin, levofloxacin, amoxicillin and clavulanic acid. * p: comparison of the most important aspects between single infections by haemophilus spp and the other single infections combined (excluding multiple infections). fisher test for comparison of proportions. 471archivio italiano di urologia e andrologia 2021; 93, 4 differences between male urethral infections with women (msw). of the cases of haemophilus spp. and n. gonorrhoeae, 33% and 42% respectively occurred in males having sex with males (msm). no cases of infection by u. urealyticum or m. genitalium were found in msm. type of sexual partner: for most aetiological agents, the type of sexual partner was multiple; an exception was m. genitalium infection, for which 50% of patients reported a single partner and 50% multiple partners. number of sexual partners: the highest mean number of sexual partners in the last 90 days was observed in the multiple infection group (8.4), followed by m. genitalium (3.6) and haemophilus spp. (3.5), with a range from 1 to 20. type of unprotected sex: between 95 and 100% of all patients had unprotected oral insertive sex, being the most frequent risk sexual practice, without differences between the different germs. on the other hand, only 19% of the haemophilus spp reported unprotected vaginal sex, which is statistically significant in relation to the other germs (p = 0.004) (table 3). history of stis: between 22% and 50% of the patients had a history of stis, without significant differences according to the microorganism, with the exception of patients with u. urealyticum infection, who had no history of stis. hiv status: in 76 of the 86 cases (88%) the hiv status was known; only 5 patients were hiv+, and all of them were under treatment with negative viral load. recreational drugs: between 80% and 100% of the patients consumed alcohol on a regular basis and between 46% and 66% used tobacco, without significant differences between the various groups. use of other drugs ranged between 13% and 40%, being higher in patients with multiple infections. clinical differences main reason for consultation: of the 158 cases analysed, all were symptomatic except for 5 who consulted for screening. among patients with single infections other than haemophilus spp., urethral discharge was the main reason for consultation with a statistically significant difference observed in relation to the haemophilus spp. group (p = 0.003); dysuria was the main reason for consultation in 38%, urethral discharge in 33%, testicular pain in 19%, meatitis and haematospermia in 5%. the haemophilus spp. group showed greater variability in the reasons for consultation. of the 5 asymptomatic patients who consulted for screening, in one case we found m. genitalium and in another, u. urealyticum. duration of symptoms: the duration of the symptoms was less than 1 week for the majority of infections (n. gonorrhoeae, m. genitalium, u. urealyticum and multiple infections). for c. trachomatis, the distribution was more homogeneous. in case of haemophilus spp. infection, the duration was more than 1 week in the majority of cases, with statistically significant differences compared with the other infections (p = 0.002). type of treatment: the type of treatment was empirical, before cultures or pcr results (46 of 86 cases, 53%), or based on the antibiogram for the isolated microorganism which usually became available after 4 days (40 of 86 cases, 47%). clinical cure: globally we achieved a high percentage of clinical cures, without significant differences between the microorganisms. in 6 cases (2 haemophilus spp., 2 c. trachomatis, 1 n. gonorrhoeae and 1 u. urealyticum) patients went lost at follow up. test of cure: pcr was done in all m. genitalium infections, as stated in the guidelines (7), and in all the results were negative. bacteriological study (gram stain and culture) was done in 90% of the cases of haemophilus spp. infection cases, and in all the results were negative. we also performed a pcr test in all cases of multiple infections, and they were also all negative. partner notification and treatment: we carried out the notification and treatment of sexual partners between 75 and 100% of the cases (7). laboratory differences presence of leukocytes: we observed the presence of leukocytes in 75% of n. gonorrhoeae infections, in 42% of c. trachomatis infections and in 40% of multiple infections, but in only 24% of haemophilus spp. infections; the differences were not statistically significant. we did not observe leukocytes in any m. genitalium or u. urealyticum infections. antibiotic resistance antibiotic resistance was analysed only in cases in which the cultures were positive for n. gonorrhoeae or haemophilus spp. of the 26 cases positive for n. gonorrhoeae (24 single infections plus 2 multiple infections), we did not observe any case of resistance to ceftriaxone. of the 27 cases positive for haemophilus spp. (including those with multiple infections), 20 were positive for h. parainfluenzae, of which 70% were resistant to cotrimoxazole, 60% resistant to tetracyclines and 40% resistant to azithromycin. by comparison, among the 7 cases positive for haemophilus influenzae we found 43% resistance to cotrimoxazole, 29% to tetracyclines and rifampicin and 14% to azithromycin. we observed a 20% resistance to quinolones in cases of haemophilus parainfluenzae, without such resistance in haemophilus influenzae (table 4). multivariate analysis multivariate logistic regression was used to build a predictive model of assignment to the haemophilus group, table 4. antibiotic resistance in patients with h. parainfluenzae and h. influenzae infections. antibiotic h. parainfluenzae * h. influenzae ** cases sensitive resistant cases sensitive resistant ampicillin 20 13 (65%) 7 (35%) 7 7 (100%) – amoxicillin + clavulanic ac 20 18 (90%) 2 (10%) 7 7 (100%) – cefuroxime 20 16 (80%) 4 (20%) 7 7 (100%) – cefotaxime 20 20 (100%) – 7 7 (100%) – meropenem 20 20 (100%) – 7 7 (100%) – cipro/levoflox 20 16 (80%) 4 (20%) 7 7 (100%) – cotrimoxazole 20 6 (30%) 14 (70%) 7 4 (57%) 3 (43%) azithromycin 20 12 (60%) 8 (40%) 7 6 (86%) 1 (14%) tetracyclines 20 8 (40%) 12 (60%) 7 5 (71%) 2 (29%) rifampicin 20 17 (85%) 3 (15%) 7 5 (71%) 2 (29%) * h. parainfluenzae: 16 cases of single and 4 of multiple infections. ** h. influenzae: 5 cases of single and 2 of multiple infections. archivio italiano di urologia e andrologia 2021; 93, 4 a. vives, m. cosentino, l. bassas, c. alonso, f. millan 472 using a combination of clinical variables. a backward stepwise (conditional) method was used to drop insignificant terms. the final model included as significant predictors the type of unprotected sex being exclusively oral, the main reasons for consultation (testicular pain, no urethral discharge), the duration of symptoms more than one week, and the lack of leukocytes in the urethral sample. the accuracy of the logistic function, measured as the calculated auc on a roc curve was 0.834 (0.7170.951), and or of 8.076 (3.391-19.234), showing a sensitivity of 76% and a specificity of 90%. discussion to our knowledge this is the first study to compare the characteristics of haemophilus infections with those of the other sexually transmitted urethral infections. limitations of this study can be the small sample size and the lack of a representative control group. over the past 2 years we have observed an increase in urethral infections due to haemophilus spp. in our sti department for men, in keeping with other published reviews (8). motivated by this, we decided to perform a retrospective study to identify the epidemiological, clinical and laboratory characteristics of these infections and to compare them with urethral infections by n. gonorrhoeae, c. trachomatis, m. genitalium and u. urealyticum. all male patients who underwent conventional bacteriological and multiplex pcr studies in the urethra at the same time between january 2018 and february 2019 were selected for inclusion in the study, yielding a total of 158 cases. of these, 86 tested positive for one or more of these microorganisms, including 76 (88%) with infections by a single microorganism and 10 (12%) with multiple infections. this is consistent with the literature, where dual infections have been identified in up to 10% of men in some studies, expecially among c. trachomatis and m. genitalium (9, 10). taking into account that (a) all 27 haemophilus infections were symptomatic; (b) in 21 of the 27 cases a single microorganism was identified and; (c) all of these patients (except for 2 lost at follow up) had remission of symptoms and negative cultures at control, our first conclusion is that haemophilus spp. are a sexually transmitted source of symptomatic urethral infection in men. supporting this, we did not find any cases of haemophilus infection in the 5 asymptomatic patients who attended for screening. füzi was the first to report, in 1980, that haemophilus could be a cause of sexually transmitted urethritis (11). the 2016 european guideline on the management of ngu also refers to the fact that haemophilus spp. are responsible for a small proportion of cases of ngu (7). in our study, haemophilus spp. were responsible for at least 24.4% (21/86) of the cases and were the second most frequent microorganism to be isolated alone, behind n. gonorrhoeae but ahead of c. trachomatis and m. genitalium. this result does not match previous reports, where c. trachomatis was the most frequent microorganism, followed by n. gonorrhoeae and, thirdly, by m. genitalium (1, 12). in a cross-sectional study conducted by orellana et al. (13), in which they analyzed 1248 male urethral samples over 3 years, h. parainfluenzae was isolated in 1.76% and h. influenzae in 1.12% of the samples. probably the frequency of infection by haemophilus spp. must be related to the sexual habits of the population, and the increasing practice of unprotected oral sex potentially explains these differences in incidence. in our series, h. parainfluenzae was more frequent than h. influenzae (74% vs 26%), which is in concordance with the literature review (4, 8, 14). another discrepant finding in comparison to previously published studies, such as rane’s review in 2014, which showed a higher prevalence of haemophilus urethritis in msm, is that in our series most infections were in msw (62%), with only 33% in msm (15). this may be because in our city msm have access to regular screening and treatment in specific community settings. in our series, c. trachomatis, m. genitalium and u. urealyticum were less common in msm than msw with ngu, which is consistent with the literature (15). all of the haemophilus group reported unprotected oral insertive sex and 81% of them denied having had another kind of unprotected sex, which was statistically significantly different compared with the other causes of urethritis. these results were similar to the findings of deza et al. (2015), who reported that all cases in their series had practiced unprotected insertive oral sex (4). therefore, it seems clear that the main route of transmission of haemophilus is via this route (16). these data support the contribution of oropharyngeal exposure to this syndrome. colonization of the oral cavity by h. parainfluenzae and h. influenzae in different amounts in healthy individuals is very frequent (17). one aspect that we did not evaluate in men with recurrences, was the need to study partner’s oral flora in order to establish a direct relation with oral sex and, also, to determine whether it is necessary to treat sexual partners. in cases of haemophilus infection the main reason for consultation varied being the most common dysuria; the difference was statistically significant compared with the other causes of urethritis, for which urethral discharge was the main reason for consultation. in comparison, in the study by deza et al. the most common clinical presentation among cases of haemophilus infection was mucopurulent urethral discharge, suggesting potential difficulty in distinguishing causes of urethritis based on symptomatology (4). we did not find any cases of haemophilus infection in the 5 asymptomatic patients who consulted for screening. regarding the duration of the symptoms, it was longer than one week in the haemophilus group but usually less than one week in the other groups, the statistical difference being significant. leukocytes were frequently present in infections due to n. gonorrhoeae and c. trachomatis as well as multiple infections, but less frequent in infections due to haemophilus and absent in infections due to u. urealyticum and m. genitalium. in this regard it should be noted that there is significant interand intra-observer error in counting polymorphonuclear leukocytes, especially in samples with low-grade inflammation (18). an interesting finding was the multiple resistances to antibiotics in the haemophilus group, which suggests a need to reconsider which is the best empirical treatment as adjuvant to intramuscular ceftriaxone in patients consulting for urethritis. the most striking finding was that 473archivio italiano di urologia e andrologia 2021; 93, 4 differences between male urethral infections 60% of h. parainfluenzae and 29% of h. influenzae infections were resistant to doxycycline and 40% of h. parainfluenzae and 19% of h. influenzae infections were resistant to azithromycin, both of which are recommended firstline drugs for the treatment of ngu (19). these percentages are similar to those described in other areas of the world such as east asia (20). among the h. parainfluenzae cases there was also a 20% rate of resistance to quinolones, which exclude them as a therapeutic option. another drug that may be of special interest in usual practice is amoxicillin in combination with clavulanic acid, since we observed resistance to this combination in only 10% of h. parainfluenzae and none of h. influenzae infections. in view of these findings and the high prevalence of resistance either present prior to treatment or developing during treatment, it is important to perform a test of cure to confirm microbiological healing, as recommended in all guidelines for m. genitalium (21). we performed a test of cure in 100% of cases of m. genitalium and multiple infection, with clinical and microbiological cure confirmed in all cases. we also performed a test of cure in 90% (19/21) of the cases of single haemophilus infection and in all of them we were able to confirm clinical and microbiological cure. an explanation for this high percentage of clinical cures could be that not all the positive cases were treated empirically; in 40 of the 86 cases, we waited for the results, which normally took about 4 days, and then adjusted the antibiotic depending on the antibiogram of the microorganism isolated. there is good evidence that u. urealyticum causes urethritis in some but not all men, the problem being that even the pcr test cannot distinguish between asymptomatic carriers and possible causality (22-24). on the other hand, there are reports of patients with persistent or recurrent ureaplasma-positive urethritis who have been cured only after their sexual partner received appropriate treatment (23). there is some controversy over the timing of treatment of u. urealyticum, especially in asymptomatic patients. in our series, of the 7 positive patients, 6 had symptoms; in addition, all were msw, with the exception of a single patient with multiple infections who was bsm, and their mean age of 24.5 years was lower than for all other microorganisms. taking all of this into account, as well as the fact that there is clear evidence that u. urealyticum can affect seminal parameters (25-27), we decided to treat all patients with u. urealyticum immediately. to break the chain of transmission, we undertook partner notification and treatment in a large majority of cases, including 75% of u. urealyticum, 100% of m. genitalium and multiple infection and 95% of n. gonorrhoeae and c. trachomatis. multivariate logistic regression model confirmed that patients having mainly oral sex, showing testicular pain but not no urethral discharge neither leukocytes in the urethra, and displaying symptoms for more than one week, were up to eight times more likely to have an haemophilus as the cause of their urethritis. finally, in relation to patients with multiple infections, it is of note that they had the highest mean number of sexual partners, the highest rate of drug use other than alcohol and tobacco and the highest rate of a history of sti. main limitation of the study is represented by the retrospective nature of the paper and the absence of a control group; another is the number of patients of our study that, even if it is high for a single centre in one year, could be implemented to increase statistical significance. finally, our diagnostic work out was focused on the diagnosis of urethritis not including a screening for concomitant prostatic infections. conclusions to our knowledge, this is the first study to compare the characteristics of haemophilus infections with those of the other sexually transmitted urethral infections. haemophilus seems to be an aetiological agent of nongonococcal urethritis whose incidence is clearly increasing. oral insertive sex is the main route of acquisition of haemophilus urethral infection. in the haemophilus group the main reason for consultation varied; this could make diagnosis difficult and the duration of symptoms was clearly longer than for other microorganisms. it is necessary to confirm eradication of infection due to the high rate of antibiotic resistance, for this reason, in the future we should update the guidelines for empirical treatment of urethritis. finally, it would be interesting, in cases of recurrence, to detect haemophilus spp. in the couple’s oral cavity and to compare whether the strain coincides with that of the urethra, in order to ascertain whether it is necessary to treat sexual partners. references 1. ito s, hanaoka n, shimuta k, et al. male non-gonococcal urethritis: from microbiological etiologies to demographic and clinical features. int j urol. 2016; 23: 325-331. 2. janier m, lassau f, casin i, et al. male urethritis with and without discharge: a clinical and microbiological study. sex transm dis. 1995; 22:244-52. 3. bradshaw cs, tabrizi sn, read trh, et al. etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. j infect dis. 2006; 193: 336-345. 4. deza g, martin-ezquerra g, gómez j, et al. isolation of haemophilus influenzae and haemophilus parainfluenzae in urethral exudates from men with acute urethritis: a descriptive study of 52 cases. sex transm infect. 2015; 92: 29-31. 5. hsu ms, wu my, lin th, et al. haemophilus parainfluenzae urethritis among homosexual men. j microbiol immunol infect. 2012; 48: 450-452. 6. clinical and laboratory standards institute (clsi). performance standards for antimicrobial susceptibility testing; twenty-fifth informational supplement. clsi document m100-s25 (isbn 156238-990-4). clinical and laboratory standards institute, 950 west valley road, suite 2500, wayne, pennsylvania 19087. usa, 2015. 7. horner pj, blee k, falk l, et al. european guideline on the management of non-gonococcal urethritis. int j std aids. 2016; 27:928-37. 8. vázquez f, andrés mt, palacio v. isolation of haemophilus influenzae and haemophilus parainfluenzae in genitourinary infections: a 4year review. enferm infec microbiol clin. 1996; 14:181-185. archivio italiano di urologia e andrologia 2021; 93, 4 a. vives, m. cosentino, l. bassas, c. alonso, f. millan 474 9. wetmore cmp, manhart lep, lowens msp, et al. demographic, behavioral, and clinical characteristics of men with nongonococcal urethritis differ by etiology: a case comparison study. sex transm dis. 2011; 38:180-6. 10. gaydos c, maldeis ne, hardick a, et al. mycoplasma genitalium compared to chlamydia, gonorrhoea and trichomonas as an aetiological agent of urethritis in men attending std clinics. sex transm infect. 2009; 85:438-40. 11. füzi m. haemophili in sexually transmitted diseases. lancet. 1980; 2:476. 12. manhart le, holmes kk, hughes jp, et al. mycoplasma genitalium among young adults in the united states: an emerging sexually transmitted infection. am j public health. 2007; 97:1118-25. 13. orellana ma, gómez ml, teresa sánchez m, fernándezchacón t. microbiological diagnosis of urethritis in men. 3 years review. rev esp quimioter. 2009; 22:83. 14. sturm aw. haemophilus influenzae and haemophilus parainfluenzae in nongonococcal urethritis. j infect dis. 1986; 153:165-7. 15. rane vs, fairley ck, weerakoon a, et al. characteristics of acute nongonococcal urethritis in men differ by sexual preference. j clin microbiol. 2014; 52:2971-2976. 16. bradshaw cs, tabrizi sn, read trh, et al. etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. j infect dis. 2006; 193:336-45. 17. gonzalez md, ledeboer na haemophilus. chapter 38. manual of clinical microbiology, 12th edition. 18. smith r, copas aj, prince m, et al. poor sensitivity and consistency of microscopy in the diagnosis of low grade non-gonococcal urethritis. sex transm infect. 2003; 79:487-90. 19. cdc sexually transmitted diseases treatment guidelines. 2021. 20. deguchi t, ito s, hatazaki k, et al. antimicrobial susceptibility of haemophilus influenza strains isolated from the urthra of men with acute urethritis and/or epididymitis. j infect chemother. 2017; 23:804-7. 21. horner p, blee k, o'mahony c, et al. clinical effectiveness group of the british association for sexual health and hiv. 2015 uk national guideline on the management of non-gonococcal urethritis. int j std aids. 2016; 27:85-96. 22. zhang n, wang r, li x, liu x, tang z, liu y. are ureaplasma spp. a cause of nongonococcal urethritis? a systematic review and meta-analysis. plos one. 2014; 9: e113771. 23. magri v, boltri m, cai t, et al. multidisciplinary approach to prostatitis. arch ital urol androl. 2019; 90:227-248. 24. stamatiou k, magri v, perletti g, et al. chronic prostatic infection: microbiological findings in two mediterranean populations. arch ital urol androl. 2019; 91:177-181. 25. ford dk,henderson e. non-gonococcal urethritis due to tmycoplasma (ureaplasma urealyticum) serotype 2 in a conjugal sexual partnership. br j venereal dis. 1976; 52:341-342. 26. lee js, kim kt, lee hs, et al. concordance of ureaplasma urealyticum and mycoplasma hominis in infertile couples: impact on semen parameters. urology. 2013; 81:1219-24. 27. ma xp, gao xq. the effect of ureaplasma urealyticum on the level of p34h expression, the activity of hyaluronidase, and dna fragmentation in human spermatozoa. am j reprod immunol. 2017; 77. doi: 10.1111/aji.12600. correspondence alvaro vives, md avives@fundacio-puigvert.es marco cosentino, md (corresponding author) doccosentino@gmail.com lluis bassas, md lbassas@fundacio-puigvert.es carles alonso, md calonso@fundacio-puigvert.es felix millan fmillan@fundacio-puigvert.es fundacio puigvert, barcelona, spain stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):13859 1 letter to editor key words: malakoplakia; giemsa; papanicolaou; von hansemann. submitted 1 april 2025; accepted 25 april 2025 to the editor more than a century has passed since 1903, when professor david von hansemann described the presence of macrophages deposited in the form of a soft plaque and coined the term of greek origin, malakoplakia (mlp). a year later, the morphology of this cell with its own name was completed by the contribution of michaelis and gutmann, who pointed out the inclusions in its cytoplasm (1). since then, these aggregates of soft plaques have been found in various tissues such as the thyroid gland, brain, adrenal gland, lung, gastrointestinal tract (2), and especially the bladder. in all these cases, the definitive diagnosis is the presence of macrophage deposits in the corresponding biopsies, known as von hansemann cells, with inclusions in the form of a bird's eye (michaelis-gutmann bodies) (3). the origin of this pathology is still unclear. in 90% of patients it is an e. coli infection, but it could also be caused by other bacteria (4). an intrinsic failure of macrophages caused by several factors has also been proposed: a deficiency of cyclic gmc, which is necessary for the formation of clathrin-coated vesicles; another possibility is a low synthesis of tumor necrosis factor (tnf) and a third theory is that beta-glucuronidase is not fully effective (5). perhaps there is a combination of these three deficiencies that results in the cell having poor bactericidal function and that the noxious agent remains in the michaelis-gutmann bodies. this could explain why there are patients who have recurring urinary tract infections. the bacteria are not killed and return after some time and are even resistant to the same antibacterial treatment (6, 7). there are many reports of single or a few cases of mlp in different organs, with the bladder being perhaps the most common. years after our first publication, we trained many biochemistry students and interns and repeatedly received smears in which we observed von hansemann cells in fresh urine sediments (8). therefore, we decided to investigate the actual prevalence of this disease in our hospital and whether it is as rare as reported or whether it is a misinterpretation of the cells in the sediment. materials and methods samples from january to october 2023, we detected 45 fresh urine sediments suspected of containing von hansemann cells in our cytology service at the clinical hospital “josé de san martín”, buenos aires, argentina. they all came from hospitalized and outpatients. these were selected to be stained with giemsa and papanicolau, as previously reported. staining techniques giemsa the smear was air-dried on a microscope slide. it was then soaked in methanol for 5 minutes and then in 1/10 diluted giemsa for 15 minutes and washed off with distilled water. papanicolaou the study was carried out according to carson and hladik, 2009 (9). microscopic visualization the diagnosis was made by two cytologists examining the same sample. first, the fresh urine sediment was centrifuged at 2000 rpm and the pellet was isolated and viewed on 6 slides, two for direct observation and the others for appropriate staining. malakoplakia: a rare pathology? fernando guerra, cintia giménez, luis palaoro, adriana rocher, gabriela mendeluk cytology laboratory, department of clinical biochemistry, hospital de clinicas josé de san martín, university of buenos aires, “instituto de fisiopatología y bioquímica clínica infibioc faculty of pharmacy and biochemistry”, university of buenos aires, argentina. doi: 10.4081/aiua.2025.13859 archivio italiano di urologia e andrologia 2025; 97(3):13859 f. guerra, c. giménez, l. palaoro, et al. 2 results over a period of 10 months, we observed 45 samples in fresh urine sediments suspected of containing von hansemann cells. these patients had symptoms of urinary tract infection or were hospitalised for follow-up. the patients were 19 men and 26 women, with an average age of 49 years and a range of 5 to 85 years (figure 1). the smears stained with giemsa or papanicolaou were examined by two cytologists. 27 of 45 had von hansemann cells in one or both staining techniques (figure 2). these cells can be identified as macrophages with birefringent inclusions in their cytoplasm (figures 3a, b), which in most cases may be round. on staining, these inclusions are recognised as pale vesicles in giemsa, similar to biopsies, in the form of a “bird's eye” or “targettoid" (figures 3c, d) and as a red spot in papanicolaou (figures 3e, f). it could be a single or multiple inclusions. discussion the term malakoplakia is not well known among physicians, not even among biochemists. pathologic urine can be very challenging for those who are not cytologists, as many different cells can indicate numerous and complex diseases, such as viral and bacterial infections, lithiasis, renal abnormalities, and of course bladder cancer. this is the main reason why it is important to stain each sample and perform a cytological analysis, althoughstaining these smears is not always possible in many emergency laboratories. in 2019, our group published a report of 6 cases confirming the correlation between the biopsy and the presence of hansemann cells in fresh urine stained with giemsa and papanicolaou. since then, we have received many consultations because these cells were observed in several hospitals by our students, and that was the reason why we thought that it was not a rare pathology. this study shows that in 10 months we found several patients with pathologic urine figure 1. distribution of patients by gender. figure 2. after suspicious von hansemann cells were detected in the fresh smear, 45 urine samples were selected for staining, and in 27 of them (60%) these particular cells were confirmed by giemsa or/and papanicolaou. figure 3. a and b show the suspect cells, macrophages with birefringent inclusions (direct observation, 400x, zoom); four different samples confirming the presence of von hansemann cells in c and d (giemsa, 400x, zoom) and e and f (papanicolaou, 400x, zoom). archivio italiano di urologia e andrologia 2025; 97(3):13859 3 malakoplakia that had suspicious cells, which we could confirm after staining that they were von hansemann cells. the presence of 27 randomly selected patients may indicate that this disease is more common than reported. the other 18 patients who were negative did not show the cells in the giemsa or papanicolaou test or the smear was insufficient. it is thought this finding is more common in women, causing recurrent urinary tract infections, possibly due to the michaelis-gutmann corpuscles carrying the resistant bacteria remaining in the pathognomonic cells, but we had almost 40% males and even three infants (two of 5 and one of 7 years), although the staining was negative. vesical malacoplakia is the most commonly publicised form of the disease, but it has been found in many different organs. this could indicate a phagocytosis deficit in all macrophages, but this is not yet entirely clear, and two main mechanisms have been proposed: a deficiency of cgmp, which contributes to the formation of clathrin-coated vesicles or an insufficient amount or inefficient activity of beta-glucuronidase, an intracellular enzyme that is crucial for the clearance of microorganisms. either or both malfunctions lead to poor bactericidal activity, and this is why vitamin c and betanechol are important as treatment (both increase cgmp levels) and cell-penetrating antibiotics are necessary (10-12). the soft plates diagnosed in the colon (13), brain (14), lung (15, 16), thyroid (17), kidney (18), skin (19, 20) and cervix (21), although most of them are found at necropsy, may indicate that the disease is silent until a symptom such as urine infection occurs. during our research on this topic, we came across a genetic disorder that is associated with a defect in the same enzyme, beta-glucuronidase. this is mucopolysaccharidosis type vii or sly syndrome, and among the symptoms reported we find recurrent ear and respiratory infections (22). this hereditary alteration is also described as rare (ultra-rare), but more than 30 mutations have been identified in the gene, affecting a variety of phenotypes: indeterminate, attenuated and severe (23). we propose the theory that malacoplakia may be an unknown phenotype of sly syndrome or mucopolysaccharidosis vii. conclusions we found 27 cases of malakoplakia in a 10-month period, which could mean that this disease is more common than reported. confirmation was possible by staining the fresh urine sediments with giemsa and papanicolaou, which allowed us to observe the von hansemann cells with the michaelis-gutmann bodies. the etiology of this pathology is not entirely clear, but it shares the deficiency of the enzyme beta-glucuronidase with sly syndrome or mucopolysaccharidosis vii, and we propose that malakoplakia may be an undetermined phenotype of this genetic disorder. references 1. velásquez lópez jg, vélez hoyos a, uribe arcila jf. malacoplaquia en urología: aportación de seis casos y revisión de la literatura. actas urol esp 2006; 30:610-618. 2. lee m, ko hm, rubino a, et al. malakoplakia of the gastrointestinal tract: clinicopathologic analysis of 23 cases. diagn pathol 2020; 15:97. 3. wang hk, hang g, wang yy, et al. bladder malacoplakia: a case report. world j clin cases 2022; 10:8291-8297. 4. fatola a, johnson bc, walsh l, et al. a very complicated uti: malakoplakia following e. coli urinary tract infection. bmc nephrol. 2024; 25:200. 5. daghdagh y, razzouki i, moataz a, et al. a case of extremely rare pathology: renal malakoplakia. urol case rep. 2024; 54:102737. 6. stamatiou k, chelioti e, tsavari a, et al. renal failure caused by malakoplakia lesions of the urinary bladder. nephrourol mon. 2014; 6:e18522. 7. triozzi jl, rodriguez jv, velagapudi r, et al. malakoplakia of the kidney transplant. kidney int rep. 2022; 8:680-684. 8. guerra f, rocher ae, angeleri a, et al. von hansemann cells from fresh urine sediment samples in the diagnosis of malakoplakia. j cytol. 2019; 36:165-168. declarations ethical approval and consent for participate: not applicable. consent for publication: not applicable. availability of data and material: the datasets used and analyzed during the current study are available upon reasonable request from the corresponding author. competing interests: the authors declare that they have no competing interests. funding: the funds have been used from the hospital de clínicas josé de san martín itself. authors' contributions: fernando guerra: samples recollection, diagnosis and paper writing; cintia gimenez: diagnosis; luis palaoro: diagnosis and paper writing; adriana rocher: diagnosis and paper editing; gabriela mendeluk: paper editing. acknowledgments: not applicable. archivio italiano di urologia e andrologia 2025; 97(3):13859 f. guerra, c. giménez, l. palaoro, et al. 4 9. carson fl, hladik, ch. histotechnology: a self-instructional text. 3rd ed. hong kong, american society for clinical pathology press, 2009. 10. meredith t, dharan n, killen l, et al. colonic malakoplakia in a dual stem cell and cardiac transplant recipient: a case report and literature review. transpl infect dis. 2021; 23:e13488. 11. pastena d, giambusso m, castri f, et al. malakoplakia of the appendix in a young healthy adult: a case report and literature review. j surg case rep. 2022; 2022:rjac357. 12. velásquez lópez juan g, vélez hoyos a, uribe arcila jf. malacoplaquia en urología: aportación de seis casos y revisión de la literatura. actas urol esp [internet]. 2006; 30:610-618. 13. yared ra, badran ha, kamareddine mh, et al. colonic malakoplakia: a rare finding in a healthy male. case rep gastroenterol. 2018; 12:453-456. 14. toubes-klingler e, prabhu vc, bernal k, et al. malacoplakia of the cranium and cerebrum in a human immunodeficiency virus-infected man. case report. j neurosurg 2006; 104: 432–435. 15 . corrêa lf, da silva tkb, camargo sm, furian bc. pulmonary malakoplakia associated with peripheral cysts in an immunocompetent patient: a case report. j chest surg. 2022; 55:422-424. 16. narwani p, rajendran i, lewington a, et al. malakoplakia presenting as pleuropulmonary masses: a rare clinical, radiological and histopathological diagnosis. radiol case rep. 2021; 16:3859-3863. 17. vitkovski t, costales c, chen s, et al. malakoplakia of the thyroid gland: a case report and review of literature. int j surg pathol. 2015; 23:308-12. 18. daghdagh y, razzouki i, moataz a, et al. a case of extremely rare pathology: renal malakoplakia. urol case rep. 2024; 54:102737. 19. gerard a, mesa h, danziger-isakov l, et al. successful treatment of malakoplakia of the liver and skin in a pediatric liver transplant patient. pediatr transplant. 2023; 27:e14492. 20. whittington cp, saleh js, schadler e, et al. cutaneous malakoplakia arising on the ankle of a patient with pyoderma gangrenosum. j cutan pathol. 2023; 50:942-946. 21. li j, mi j, wang j, zhuo z. case report: a rare case of malacoplakia resembling a malignant tumor of the cervix: a case report and review of the literature. front med (lausanne). 2024; 11:1409239. 22. morrison a, oussoren e, friedel t, et al. pathway to diagnosis and burden of illness in mucopolysaccharidosis type vii a european caregiver survey. orphanet j rare dis. 2019; 14:254. 23. tomatsu s, montaño am, dung vc, et al. mutations and polymorphisms in gusb gene in mucopolysaccharidosis vii (sly syndrome). hum mutat. 2009; 30:511-9. correspondence fernando guerra (corresponding author) fer.rguerra@gmail.com cytology laboratory, department of clinical biochemistry, hospital de clinicas josé de san martín, university of buenos aires, argentina billinghurst 1333 9c pc 1425, buenos aires, argentina cintia giménez cintialgimenezbq@gmail.com luis palaoro luispalaoro47@gmail.com adriana rocher adrianarocher60@gmail.com gabriela mendeluk gabrielamendeluk@gmail.com cytology laboratory, department of clinical biochemistry, hospital de clinicas josé de san martín, university of buenos aires, argentina stesura seveso archivio italiano di urologia e andrologia 2023; 95(4):12155 1 original paper izens (2). the cost of working days lost due to illness must be added to these costs. hospitals can take care of the surgical treatment of the disease and the diagnosis of diseases associated with urinary stones, but they are not able to provide follow-up and secondary and primary prevention of the disease on their own. collaboration between gps and hospitals is crucial to achieve these objectives (3-7). for this reason, a shared guideline between the associations of gps and clinicians of academic and hospital structures is necessary to define the methods of intervention and tasks assignment. methods a panel composed of 4 general practitioners from the società italiana di medicina generale (simg) and 8 academic and hospital clinicians expert in the treatment of urinary stones from the club litiasi urinaria (clu) met with the aim of identifying the activities that require the participation of the gp in the management process of the patient with kidney stones. the panel met for the first time to read the index of the guidelines for urinary stones of the european association of urology (8) with the aim of identifying the topics of greatest interest for collaboration between gps and hospitals. each topic was assigned to a team made up of a gp and two hospital doctors who had the task of drafting a text illustrating the role of the gp and the method of collaboration with the hospital. the texts were circulated for corrections and modifications. the panel met a second time to approve the final text in italian which was published on www.simg. finally, a short version in english language was written to be published after approval of the panel. prevalence, etiology, risk of recurrence epidemiology of urolithiasis in italy the prevalence of urinary calculi has been evaluated in background: the prevalence of kidney stones tends to increase worldwide due to dietary and climate changes. disease management involves a high consumption of healthcare system resources which can be reduced with primary prevention measures and prophylaxis of recurrences. in this field, collaboration between general practitioners (gps) and hospitals is crucial. methods: a panel composed of general practitioners and academic and hospital clinicians expert in the treatment of urinary stones met with the aim of identifying the activities that require the participation of the gp in the management process of the kidney stone patient. results: collaboration between gp and hospital was found crucial in the treatment of renal colic and its infectious complications, expulsive treatment of ureteral stones, chemolysis of uric acid stones, long-term follow-up after active treatment of urinary stones, prevention of recurrence and primary prevention in the general population. conclusions: the role of the gp is crucial in the management and prevention of urinary stones. community hospitals which are normally led by gps in liaison with consultants and other health professional can have a role in assisting multidisciplinary working as extended primary care. key words: urinary calculi; general practice; renal colic; diagnosis; treatment; prevention; primary care; recommendation. submitted 2 december 2023; accepted 19 december 2023 introduction urinary stones are a very common disease that causes patients to suffer due to its painful symptoms and the repeated surgical procedures necessary to remove stones from the urinary tract. in some cases it can cause renal failure and, albeit rarely, mortality (1). the management of urinary stones involves the use of considerable economic resources at the expense of health services and citthe role of the general practictioner in the management of urinary calculi domenico prezioso 1, gaetano piccinocchi 2, veronica abate 3, michele ancona 2, antonio celia 4, ciro de luca 1, riccardo ferrari 5, pietro manuel ferraro 6, stefano mancon 7, giorgio mazzon 4, salvatore micali 5, giacomo puca 1, domenico rendina 3, alberto saita 7, salvetti andrea 2, andrea spasiano 8, elisa tesè 2, alberto trinchieri 9 1 dipartimento neuroscienze, scienze della riproduzione ed odontostomatologia università federico ii, naples, italy; 2 società italiana di medicina generale, florence, italy; 3 department of clinical medicine and surgery, federico ii university, naples, italy; 4 s.c. urologia ulss 7 pedemontana, bassano del grappa (vi), italy; 5 department of urology, university of modena and reggio emilia, baggiovara (mo), italy; 6 sezione di nefrologia, dipartimento di medicina, università degli studi di verona, verona, italy; 7 department of urology, irccs humanitas research hospital, rozzano, milan, italy; 8 università cattolica del sacro cuore, roma, italy; 9 urology school, university of milan, milan, italy. doi: 10.4081/aiua.2023.12155 summary archivio italiano di urologia e andrologia 2023; 95(4):12155 d. prezioso, g. piccinocchi, v. abate, et al. 2 some studies in italy, ranging between 1.7 and 7.5%, depending on the population studied and the period of the study (9-13). a study (14) based on the health search/csd longitudinal patient database (hs) compiled by 650 general practitioners demonstrated in the italian adult population in 2012 a prevalence of urolithiasis of 4.14% and an incidence of 0.323%. the prevalence was higher in males (4.53% versus 3.78%). regional differences were demonstrated with higher prevalence in southern regions and islands (4.26-6.08%) than in central (3.75-5.35%) and northern regions (2.62-3.71%) in southern regions and islands the male to female ratio (m/f) was in favor of females while in central and northern cities it was in favor of males. some studies have demonstrated seasonal variations in the incidence of cases of renal colic observed in the emergency department of hospitals in various italian cities. in padua (15) an association was demonstrated between the date of presentation for renal colic and higher environmental temperature and humidity, in particular higher rates of presentations for renal colic were observed when temperature was > 27°c and relative humidity > 45%. similar observations on the relationship between environmental temperature and rate of renal colic were made in parma, cuneo, and rome (16-18). in one study (19) the age of patients with renal colic in the summer period was higher than in the rest of the year, probably due to a greater number of patients with uric acid stones who tend to be older. finally, another study carried out in ferrara (20) on data from the period 1990-96, demonstrated that renal colic occurs with a circadian rhythm which has a peak in the early morning and a minimum in the afternoon. other studies have shown that the epidemiological characteristics of urinary calculi in italy have varied over time. the prevalence of urinary stones increased from 1986 to 1998 by 40% in males and by 20% in females (10). from 2001-2003 to 2016-18, the mean age of patients increased from 45.8+/15.4 years to 57.9+/14.8 years and the frequency of calcium oxalate monohydrate stones increased from 44 to 51% (21). from 1986-1998 to 2005-2010, a change of the urinary biochemical characteristics of renal stone formers patients in italy was observed. patients observed in 2005-2010 showed higher urinary volume, lower urinary sodium, and lower urinary saturation for calcium oxalate and uric acid (22) than those observed in 1986-1998. in parallel, they have higher levels of physical activity and lower blood pressure levels. in conclusion, the general increase in the prevalence of stones appears to be linked to an increase of patients forming a single stone or presenting low stone recurrence in association with a lower urinary biochemical risk. finally, in italy some studies have demonstrated the correlation between urinary stones and some chronic diseases such as arterial hypertension and osteoporosis. in about 700 workers of a factory in pozzuoli, in the suburban area of naples, the prevalence of stones was evaluated in normotensive subjects (13.4%), in untreated hypertensive patients (20.3%) and in treated hypertensive patients (32.8 %) demonstrating an independent association between arterial hypertension and the prevalence of urolithiasis (23). in a case-control study, patients with kidney stones demonstrated increased vascular stiffness and decreased bone density (24). in a study carried out in naples in a population of over 12.000 women aged over 40 who had performed dexa bone densitometry: incident nephrolithiasis was evaluated in the months following the examination, demonstrating an increased lithiasis risk (hr = 1.33) in patients with osteoporosis (25). similarly, a study of more than 7,000 ultrasound bone densitometries demonstrated that urolithiasis is an additional risk factor for osteoporosis (26). recurrence urinary calculi tend to recur. after 7 years from the first stone episode 27% of patients presented one or more recurrent episodes (27). cystine, struvite, uric acid, brushite and apatite stones are at higher risk compared with calcium oxalate stones (28). classification of urinary stones urinary stones are classified according to: • composition and etiology; • site; • size; • radiological characteristics. composition and etiology according to etiology they can be divided into stones from infectious causes, stones from non-infectious causes, stones from genetic defects, and drug-related stones (table 1). calcium oxalate stones are the most common. the main metabolic abnormalities associated with calcium oxalate stones are hypercalciuria (30-60%) and hyperoxaluria (26-67%), followed by hyperuricosuria (15-46%), hypomagnesiuria (7-23%) and hypocitraturia (5-29%) (29). calcium phosphate stones can present as carbonate apatite which can be associated with urinary tract infections (uti) or brushite which crystallizes in the presence of high concentrations of calcium and phosphate, regardless of uti. possible causes of calcium phosphate stones include hyperparathyroidism, renal tubular acidosis, and utis. calcium stones can be secondary to some specific pathologies including primary hyperparathyroidism, sarcoidosis, primary hyperoxaluria, enteric hyperoxaluria, distal renal tubular acidosis. table 1. classification according to etiology and stone composition. from non-infectious causes calcium oxalate calcium phosphate uric acid from infectious causes ammonium magnesium phosphate carbonate apatite ammonium urate genetic causes cystine xanthine 2.8-di-hydroxyadenine drug-related archivio italiano di urologia e andrologia 2023; 95(4):12155 3 urinary calculi in general practice primary hyperparathyroidism (hpt) causes approximately 5% of urinary calcium (calcium oxalate and/or calcium phosphate) stones. in fact, the increase in parathormone (pth) induces hypercalcaemia, hypercalciuria, hypophosphatemia and renal phosphate loss. the laboratory diagnosis is implemented by ultrasound of the neck and scintigraphy of the parathyroid glands, and by computerized bone densitometry to assess the presence of osteoporosis. primary hyperparathyroidism complicated by kidney stones or osteoporosis may require surgical treatment (30). granulomatous diseases, such as sarcoidosis, may be complicated by hypercalcemia and hypercalciuria because of overproduction of calcitriol with increased intestinal calcium absorption and pth suppression (31). primary hyperoxaluria (ph) is a rare hereditary genetic disease with increased endogenous production of oxalate, renal stone formation and nephrocalcinosis which can lead to end stage renal failure requiring kidney-liver transplantation (32). enteric hyperoxaluria occurs in patients with intestinal fat malabsorption, such as in cases of intestinal resection, bariatric surgery, crohn's disease, or pancreatic insufficiency. increased fatty acids link to calcium in the intestinal lumen reducing availability of calcium to form insoluble complexes with oxalate and causing intestinal hyperabsorption of free oxalate (33). renal tubular acidosis occurs due to impaired tubular reabsorption of protons (type 1) or bicarbonates (type 2) in the nephron. it can be acquired (e.g. in the case of recurrent pyelonephritis, acute tubular necrosis, autoimmune diseases, drugs, etc.) or hereditary. especially in the type 1 form, where urine ph is always > 5.8, there is a high probability of calcium phosphate stone formation (34, 35). uric acid stones account for 10% of kidney stones and have a high risk of recurrence (36). they are mainly caused by undue low urinary ph, decreased excretion of ammonia in the urine (e.g. gout), increased endogenous production of acids (e.g. metabolic syndrome) or increased loss of bases (diarrhoea). another risk factor is hyperuricosuria, secondary to dietary excess (high dietary intake of animal proteins), excessive endogenous production, myeloproliferative disorders, gout, drug intake (in particular chemotherapy, thiazides and loop diuretics) and tumor cell lysis or catabolic processes. ammonium urate stones are rare, accounting for less than 1% of all forms of kidney stones, and are associated with urinary tract infection or intestinal malabsorption, hypokalemia, and malnutrition. finally, some drugs can promote the formation of kidney stones by various mechanisms: drug crystallization in the urinary tract as a consequence of overdosage and/or dehydration (allopurinol, ceftriaxone, quinolones, sulfonamides, etc.); alteration of metabolism with increased risk of urinary saturation (acetazolamide, topiramate, furosemide, laxatives, excess of vitamin d or calcium supplements between meals, etc.) (37, 38). stone size size of urinary stones is crucial for treatment planning. it is usually expressed according to the largest diameter and stratified in the following groups: up to 5 mm, 5-10, 1020 and larger than 20 mm. the size of the stones should be considered in association with stone location, presence and degree of hydronephrosis, clinical symptoms and signs. stone location stones can be classified according to their anatomical location as kidney, ureteral and bladder stones. renal stones can be further divided as upper, middle or lower caliceal stones and renal pelvic stones; ureteral stones as proximal, mid or distal ureteral stones. different locations, in association with the other characteristics of urinary stones, require different therapeutic approaches. stone location is associated with specific clinical presentation requiring a differential diagnosis. radiological characteristics urinary stones can also be classified according to their radiodensity at plain abdomen x-ray (rx) as radiopaque or radiolucent (39). radiolucent are not demonstrated on x-ray. non-enhanced computed tomography (ct) can be also used to classify stones according to their density, measured in hounsfield units (hu) (40). weakly radio-opaque and radio-lucent stones at x-ray can be well demonstrated on non-enhanced ct. clinical presentation urinary stones can present with different symptoms and signs. renal colic is a characterized by acute flank pain, often radiating to the groin, and associated with hematuria and dysuria. microhematuria and episodes of urinary tract infection associated with chronic low back pain and/or evening fever can also be associated with kidney stones. asymptomatic urinary stones can be diagnosed during investigations for other pathologies. gp and hospital should collaborate in the diagnosis and treatment of patients with renal colic according to shared protocols (7, 8, 41, 42). statement 1 the role of gp the gp has a role in initial diagnosis and monitoring of patients with renal colic, management of analgesic therapy and prevention of obstructive and infectious complications. the patient with symptoms of renal colic often firstly refers to the gp, who has an important role in the emergency management. clinical evaluation is crucial for differential diagnosis between renal colic and acute low back pain of other causes. when office ultrasound is available, diagnosis can be facilitated by demonstration of direct (urinary table 2. classification of urinary stones by their radiodensity. radio-opaque weakly radio-opaque radio-lucent calcium oxalate monohydrate (com) ammonium magnesium phosphate (struvite) uric acid calcium oxalate dihydrate (cod) cystine calcium phosphate archivio italiano di urologia e andrologia 2023; 95(4):12155 d. prezioso, g. piccinocchi, v. abate, et al. 4 stone) or indirect (urinary tract dilatation/hydronephrosis) signs. the initial step is pain treatment: the first choice are nonsteroidal anti-inflammatory drugs (nsaids); opioids are more frequently associated with side effect as vomiting and stunning, and risk of dependence; antispasmodics are not suitable. if pain is not controlled, the gp must advise access to the emergency room for further diagnostic investigations. when pain is associated with fever, the gp should administer parenteral antibiotics plus antipyretics. respiratory rate (=/> 22), systolic blood pressure (=/< 100 mmhg) and state of consciousness must be evaluated. if these parameters are altered and sepsis is suspected, the gp must advise immediate access to the emergency room for diagnostics (ultrasonography, ct) and emergency treatment (stenting, nephrostomy). in the suspect of urinary stones because of the presence of other symptoms, as microhematuria and episodes of urinary tract infection associated with chronic low back pain or fever, abdominal ultrasound should be performed. expulsive therapy after the resolution of the acute symptomatology, the patient with ureteral calculi can be followed up with a treatment aimed at the spontaneous stone passage. in presence of risk factors (severe hydronephrosis, long-lasting hydronephrosis, large stones, infection resistant to antibiotic treatment, recurrent pain) or in case of prolonged observation without stone passage, surgical treatment for the removal of the stone must be planned (43-47). statement 2 the role of gp the gp has a role in the management of expulsive and analgesic therapy and in the prevention of obstructive and infectious complications. obstructive and infectious complications are renal failure, pyelonephritis, and urosepsis. there is no validated protocol that defines the necessary diagnostic tests and their timing in the followup of patients with ureteral stones treated conservatively or with medical expulsive therapy, but only the opinion of experts and the results of some systematic reviews. based on these observations a moderate increase in water intake should be suggested. observation or medical expulsive therapy should not be prolonged beyond 4 weeks. patients should be monitored for infectious complication (white blood count, c-reactive protein, urinalysis, and urine sediment) and promptly referred to the emergency department in case of systemic inflammatory response syndrome (sirs). analgesic therapy has to be monitored in order to prevent digestive complications of nsaids (gastroprotection) and risk of prolonged opioids (addiction). patients should be informed of off-label use of alpha-blockers (especially in young men and in women where use is not justified by concomitant benign prostatic hyperplasia) and of the side effects of alpha-blockers (anejaculation for tamsulosin and silodosin, syncope). chemolysis uric acid stones can be dissolved with chemolytic therapy. pure uric acid stones can be suspected in case of age onset > 50 years, male sex, and diabetes mellitus. uric acid composition can be predicted from stone radiodensity on ct (hu < 500) and low urine ph values (ph < 5.2). demonstration of the stone on ultrasound in the absence of radiopaque images on the abdominal x-ray may be an alternative to ct (48). undersaturation of the urine with respect to uric acid causes the dissolution of uric acid stones and can be achieved by alkalizing the urine with citrate or bicarbonate, increasing urine volume and reducing the excretion of uric acid (allopurinol) (49-54). statement 3 the role of gp the oral chemolytic treatment of pure uric acid stones with oral administration of alkalizing agents can be performed on the recommendation of the urologist or nephrologist (or directly from the gp). the gp has a very important role in increasing treatment compliance and follow-up. the success of the therapy depends on the patient's compliance which can be increased with selfmeasurement of urine ph several times a day and weekly checks to evaluate the diary of ph values and urine volumes. stone size should be monitored frequently (every two weeks) until the stone has dissolved. treatment should be ended after three months if the stone has not reduced in size. extracorporeal and endoscopic therapy the modern treatment of urinary stones is based on extracorporeal or endoscopic lithotripsy (8). stone fragments are eliminated through the urinary tract or suctioned through endoscopic instruments. the choice of treatment depends on location, size and composition of the stone, morphology of the urinary tract, renal function, possible presence of urinary tract infection, any anticoagulant therapy and general conditions of the patient the treatment is chosen by the urologist according to the aforementioned characteristics of the stone and his personal experience. at the end of the treatment, the patient is discharged with indications on the management of residual fragments and possible complications. followup of actively treated patients for urinary stones should be under the responsibility of the urologist who performed the treatment. statement 4 the role of gp the gp must be aware of the complications that can arise in the post-operative period in the patient undergoing lithotripsy. the main complications are represented by infections/sepsis, obstruction of the urinary tract (hydronephrosis), and hemorrhage (for percutaneous lithotripsy). the gp must recognize the early onset of complications and send the patient to the emergency department, as these complications cannot be treated at home and require rapid management by an expert team. in the case of post-operative nephrostomy and/or ureteral stent placement, the management of these devices is demanded to urologists and hospitals. stones in pregnancy urinary calculi in pregnancy are a rare event which nevertheless requires careful management to avoid damage to the mother and the unborn child (55). ultrasonography is archivio italiano di urologia e andrologia 2023; 95(4):12155 5 urinary calculi in general practice the first-line method of diagnostic imaging in pregnant women. magnetic resonance imaging (mri) is a second-line procedure used to define the level of the obstruction and to visualize the stones. radiography and ct, due to the use of ionizing radiation, should be avoided. the recommended initial treatment is conservative with hydration and analgesics, if necessary, with the addition of antibiotics (56), since in 75% of cases there is a resolution of the symptoms and in 40-80% spontaneous expulsion. in symptomatic cases refractory to medical therapy or in the presence of infection or persistent obstruction, it is advisable to place a double j stent or alternatively a nephrostomy, under local anesthesia and if possible, under ultrasound control. however, both the stent and the nephrostomy are a potential risk of infection, and require periodic replacements, especially if the placement is performed in the first or second trimester of pregnancy. therefore, some authors suggest performing a first-line rigid or flexible ureteroscopy as an effective procedure not burdened by obstetric complications. despite the studies performed on some cell lines, the effects of shock waves on the fetus are not fully known at present and therefore shock wave lithotripsy (swl) is not indicated during pregnancy and the reported cases generally refer to accidental treatments. statement 5 the role of gp the gp has a role in patient monitoring, in the prevention of obstructive and infectious complications and in the management of analgesic therapy. the choice of analgesic therapy must be careful, avoiding nsaids, which are associated with pulmonary hypertension and premature closure of the ductus arteriosus, and codeine. paracetamol is an option (category b according to the fda) for analgesic and antipyretic treatment. morphine must be used in low doses and for limited periods of time (category c). beta-lactam antibiotics and fosfomycin are generally considered safe and effective in pregnancy. the use of fluoroquinolones and tetracyclines is not recommended. in the event that the pain symptomatology is refractory to medical therapy or pain symptomatology is associated with hyperpyrexia or in the suspicion of urosepsis, the gp must advise immediate access to the emergency department. stones in the renal transplant recipient kidney transplant recipients may suffer from calculi both due to the presence of calculi in the kidney already at the time of transplantation, and due to the greater risk of de novo lithiasis due to various risk factors: recurrent urinary tract infections due to immunosuppressive therapy, tendency to alkalize the urine, hyperfiltration, renal tubular acidosis, serum hypercalcaemia due to tertiary hyperparathyroidism (57). statement 6 the role of gp the gp must be aware of the greater risk of stones in patients with renal transplants, must contribute to an early diagnosis by means of abdominal ultrasound (and possibly non-enhanced ct) and guide the patient towards an adequate therapeutic procedure, reserving conservative treatment under close follow up to only asymptomatic and highly compliant patients with small stones. general advice for the prevention of recurrence all patients with kidney stones should follow general prophylaxis measures in order to reduce the risk of recurrence. general measures can be associated with a targeted pharmacological treatment based on the chemicalphysical analysis of the stone in patients classified as high risk (7). statement 7 the role of gp the gp has an important role in advising on an adequate diet and lifestyle. a constant intake of at least 2.5-3 liters of liquids per day should be recommended to guarantee a diuresis of at least 2.5 liters of clear urine in 24 hours. the patient should prefer water intake. consumption of soda and sugary drinks is associated with a higher risk of urinary stones, while the intake of water, coffee, tea, beer, wine and orange juice are associated with a lower risk of urinary stones. the patient must be instructed to consume a varied and balanced diet, following the recommendations of mediterranean diet. should be recommended: • increased intake of fruit and vegetables, at least 5 servings a day (alkaline content of the vegetarian diet increases the urinary ph); • avoiding intake of foods high in oxalate and vitamin c (especially in patients who show high oxalate excretion); • limiting the intake of animal proteins (maximum 0.81 g/kg of body weight)(as they favor hypocitraturia, lowering of urinary ph, hyperoxaluria and hyperuricuria); • not limiting calcium intake but ensuring an intake at least equal to the daily calcium requirement of 10001200 mg per day (to promote the formation of nonabsorbable calcium-oxalate salts in the intestinal lumen and reduce intestinal absorption of oxalate); • not exceeding 3-5 g of sodium per day (as a higher intake is associated with increased calcium excretion, reduced citrate excretion and greater risk of sodium urate crystal formation); • limiting the intake of foods rich in purines (no more than 500 mg/day) in patients with hyperuricuric calcium oxalate and uric acid stones. adequate physical activity should be recommended. for adults over the age of 18, at least 150 minutes of moderate-intensity physical activity per week, especially walking, cycling, or playing a sport at a non-competitive level is recommended. finally, the maintenance of a normal body mass index, i.e. less than 30 kg/m2 and correct control of blood pressure with systolic blood pressure values below 135 mm hg and diastolic blood pressure values below 85 mm hg must be recommended. metabolic evaluation the chemical composition of the stone should always be identified, preferably by infrared spectroscopy or x-ray diffraction (7, 8). in patients at high risk of recurrence, an individualized metabolic assessment is required, including: measurements of blood levels of creatinine, sodium, archivio italiano di urologia e andrologia 2023; 95(4):12155 d. prezioso, g. piccinocchi, v. abate, et al. 6 potassium, chloride, calcium (ionized or total corrected for albumin), phosphate and uric acid; measurement of urine ph and urine specific gravity; 24-hour urine collection with measurement of urine volume and concentration of calcium, oxalate, uric acid, citrate, sodium and magnesium (7, 8). in case of hypercalcemia, determination of blood parathyroid hormone (pth) and vitamin d levels is recommended to rule out hyperparathyroidism. in case of struvite or ammonium urate stones, urine culture is recommended. pharmacological prevention in patients at high risk of recurrence, drug therapy should be considered. alkaline citrates (5-12 g per day) in case of calcium oxalate or uric acid stones. thiazide diuretics at a dosage of between 25 and 50 mg per day in case of oxalate and/or calcium phosphate stones (monitoring blood pressure, advising the execution of a densitometric examination and of periodic dermatological visits). magnesium at a dosage between (200 and 400 mg per day) in case of calcium oxalate stones associated with hypomagnesiuria or enteric hyperoxaluria (taking care not to induce diarrhea). allopurinol (100-300 mg/day) in case of uric acid or calcium oxalate stones associated with hyperuricemia/hyperuricuria or of ammonium urate stones (alternatively febuxostat at 80-120 mg/day). calcium supplements (up to 2000 mg) 20 minutes before meals in case of enteric hyperoxaluria, to reduce intestinal absorption of oxalate. tiopronine (800 and 2000 mg per day) in case of cystine stones, to reduce the urinary excretion of cystine, in combination with alkalizing citrates to increase the solubility of cystine (as a second-line drug to reduce the excretion of cystine, captopril at a dose between 75 and 150 mg). primary prevention primary prevention is mainly entrusted to the gp and to the media (newspapers, tv, books, internet). statement 8 the role of gp the gp should suggest measures to prevent the risk of stone formation to her/his patients who have not formed stones, particularly in those with a family history of the disease or other risk factors. risk factors can be highlighted by a thorough medical history: • familiarity; • dietary habits (energy intake, quantity and type of fluids, intake of salt, animal proteins, calcium, oxalate, carbohydrates, and potassium); • lifestyle; • urological pathologies: bladder diverticula, renal cysts, urethral strictures, horseshoe kidney, upj stenosis, ureterocele, etc. • non-urological pathologies that can cause urinary stones: obesity, diabetes, dyslipidemia, arterial hypertension, ibd (crohn's disease and rectocolitis), hyperparathyroidism; • recurring urinary tract infections (utis); • drugs with potential lithogenic effect: cortisone, laxatives, some antibiotics, topiramate; • previous urological procedures. gp should encourage to modify risky dietary habits as: • reduced calcium intake (which can cause hyperoxaluria); • low fruit consumption; • reduced fluid intake. physical activity should be encouraged in conjunction with increased fluid intake to compensate for sweating losses. finally, it is useful to correct excess weight, sedentary lifestyle, arterial hypertension, and metabolic pathologies predisposing to stone formation (dyslipidemia, hyperuricemia, diabetes, etc.). follow up after treatment for urinary stones, patients without residual stones should be monitored for no less than 2 years in the case of radio-opaque stones and no less than 3 years in the case of radiolucent stones. a 5-year follow-up window allows for a greater margin of safety that can be evaluated on the basis of cost-effectiveness (58, 59). in patients with residual stones no greater than 4mm, disease progression and need for intervention are reported in less than 40%. stones are expelled spontaneously within the fourth year in 25-33% of cases. an instrumental follow-up window of 48 months is therefore recommended in these patients. residual stones greater than 4 mm in diameter should require retreatment unless there are contraindications suggesting conservative follow-up. populations of patients diagnosed with metabolic abnormalities undergoing medical therapy require monitoring and follow-up for adverse reactions and compliance for a period of 4 years. in patients diagnosed with metabolic abnormalities not undergoing specific medical therapy, an extension of the follow-up window to at least 10 years is strongly recommended. the reference imaging method for follow up is plain x-ray and renal ultrasound for patients with radiolucent stones. computed tomography should be avoided as a first-line follow-up method to minimize patient exposure to ionizing radiations. in the presence of residual fragments, the follow-up must be extended for 4-5 years by alternating ultrasound and ct (considering the risk of exposure to ionizing radiation). statement 9 the role of gp the gp who identifies a progression in the size of the stone should refer the patient to the urologist to evaluate the need of active therapeutic intervention. in patients with metabolic abnormalities on drug treatment, the gp should monitor any adverse reactions and help increase patient compliance with medical therapy. the gp can intercept patients who may have missed follow-up and, conversely, discourage the use of opportunistic diagnostic procedures outside the follow-up windows, illustrating the lack of evidence of the benefit of monitoring procedures after an adequate recurrence-free period. archivio italiano di urologia e andrologia 2023; 95(4):12155 7 urinary calculi in general practice references 1. 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pregnancy: diagnostic and therapeutic aspects. literature review. cent european j urol. 2017; 70:93-100. 56. bookstaver pb, bland cm, griffin b, et al. a review of antibiotic use in pregnancy. pharmacotherapy. 2015; 35:1052-62. 57. piana a, basile g, masih s, et al. en representación del grupo de trabajo de trasplante renal de la sección de jóvenes urólogos académicos (yau) de la asociación europea de urología (eau). kidney stones in renal transplant recipients: a systematic review. actas urol esp (engl ed). 2023:s2173-5786(23)00101-4. 58. tzelves l, geraghty r, lombardo r, et al. duration of followup and timing of discharge from imaging follow-up, in adult psatients with urolithiasis after surgical or medical intervention: a systematic review and meta-analysis from the european association of urology guideline panel on urolithiasis. eur urol focus. 2022: s2405-4569(22)00146-8. 59. skolarikos a, laguna mp, alivizatos g, et al. the role for active monitoring in urinary stones: a systematic review. j endourol. 2010; 24:923-30. correspondence domenico prezioso, md dprezioso@libero.it giacomo puca, md giacomopuca40@gmail.com ciro de luca, md cirodeluca96@libero.it dipartimento neuroscienze, scienze della riproduzione ed odontostomatologia, università federico ii napoli, naples, italy gaetano piccinocchi, md società italiana di medicina generale, florence, italy piccinocchi.gaetano@simg.it veronica abate, md veronica.abate@unina.it domenico rendina, md domenico.rendina@unina.it department of clinical medicine and surgery, federico ii university, naples, italy michele ancona, md mich.ancona@gmail.com simg regione puglia antonio celia, md antonio.celia@aulss7.veneto.it giorgio mazzon, md giorgiomazzon83@gmail.com s.c. urologia ulss 7 pedemontana, bassano del grappa (vi). italy riccardo ferrari, md richiferrari91@gmail.com università modena e reggio emilia, modena, italy pietro manuel ferraro, md pietromanuel.ferraro@univr.it sezione di nefrologia, dipartimento di medicina, università degli studi di verona, verona, italy stefano mancon, md stefano.mancon@humanitas.it resident humanitas university, rozzano (mi), italy salvatore micali, md salvatore.micali@unimore.it università modena e reggio emilia, baggiovara (mi), italy alberto saita, md alberto.saita@humanitas.it responsabile endourologia istituto clinico humanitas, via manzoni 56, 20089 rozzano (mi) andrea salvetti, md dr.andreasalvetti@gmail.com segretario simg toscana coordinatore aft_sud ausl sud est regione toscana andrea spasiano, md andrea.spasiano01@icatt.it department of translational medicine and surgery, università cattolica del sacro cuore, rome, italy alberto trinchieri, md alberto.trinchieri@gmail.com urology school, university of milan, via commenda 15, milan, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14069 1 original paper since then, the assessment of nocturnal penile tumescence has become a valuable diagnostic tool in evaluating ed. this method was first implemented by karacan in 1970 (4). building on previous techniques, timm et al and bradley et al. (5-7) introduced the use of npt test software to monitor nocturnal erections. subsequently, levine (8) developed a new approach in which the data were analysed and presented both graphically and numerically. npt test consists of a small, computerized device, equipped with two small cables with loops capable of measuring the circumference of the penis and the degree of tumescence-rigidity obtained over a period of 10 hours (one night) for 3 nights (figure 1). the npt test is user friendly, and can be comfortably used by patients, during the physiological periods of sleep, at home and in bed, without interfering with sleep and it is capable of effectively distinguishing whether nocturnal erections exhibit normal characteristics or are altered. in this way, the presence of an organic dysfunction within the erectile system can be identified and graphically differentiated from a condition primarily of psychogenic origin. in men presenting with ed, it is essential to distinguish between a possible psycho-emotional or anxiety-related component that may inhibit adequate erections during sexual activity, and an underlying neurovascular impairment. penile erections during sleep are a physiological phenomenon observed in all males from childhood onward. these erections occur during a specific phase of sleep known as rem sleep, which is characterized by elevated blood levels of the neurotransmitter acetylcholine and a marked reduction in histamine, serotonin, and norepinephrine (9). this phase is also associated with distinctive physiological changes: heart rate and respiration slow down, muscle tone decreases, skin temperature drops, and brain waves become slower. during rem sleep, the penile arteries dilate, leading to increased blood flow, penile enlargement, tumescence, and often sufficient rigidity for penetration. in practical terms, if the penis becomes and remains rigid for some minutes during sleep, it can be inferred that the vascular structures of the corpora cavernosa, including arteries and veins, are functioning properly in response to neurogenic stimuli originating from the brain (a normal physiological condition). conversely, irregular rem sleep introduction: the authors report their 38year experience with the use of nocturnal penile tumescence (npt) testing. methods: among over 46,000 patients evaluated for andrological issues since 1980, the npt test was selectively proposed in cases of suspected psychogenic erectile dysfunction, as part of a standardized diagnostic workup, which included medical history, physical and genital examination, blood tests, and hormonal evaluation. the test aimed to assess nocturnal erectile function and support differential diagnosis. results: from june 20, 1986, to december 31, 2024, a total of 1,587 npt recordings were performed in patients aged 16 to 90 years. among these, 992 tests were conducted over three nights, 486 over two nights, and 109 for a single night. the majority of tests were completed without major issues and provided interpretable data. overall, the test was well tolerated, with good patient compliance and minimal technical difficulties. in many cases, the recordings allowed useful diagnostic insights into the nature of erectile dysfunction. in nearly all cases, patients exhibited varying degrees of anxiety concerning their ed, often interpreted as a consequence rather than the cause of an underlying organic condition. conclusions: after nearly four decades of clinical use, npt testing has proven to be a reliable and informative component of the diagnostic approach to erectile dysfunction. its ability to offer objective data in a home setting, with minimal discomfort and high patient compliance, makes it a useful adjunct in distinguishing psychogenic from etiologies. key words: npt test; erectile dysfunction; nocturnal erections; rigiscan. submitted 11 june 2025; accepted 14 june 2025 introduction the nocturnal penile tumescence (npt) test, also known as rigiscan, a computerized instrument capable of monitoring the variations in penile circumference and consistency that occur in all men during the rem phases of sleep, has represented a great step forward in the diagnostic approach of erectile dysfunction (ed). karacan et al. (1-3) were the first to report that penile erections naturally occur 3 to 5 times during sleep, typically coinciding with the rapid eye movement (rem) phase. nocturnal penile tumescencetest, revaluation of its utility after 1587 exams recorded from 1986 to 2024 diego pozza 1, andrea marcantonio 1, gabriele savarese 1, mariangela pozza 1, carlotta pozza 2 1 studio di andrologia e di chirurgia andrologica, rome, italy; 2 dipartimento di medicina sperimentale, “sapienza” università di roma. doi: 10.4081/aiua.2025.14069 summary archivio italiano di urologia e andrologia 2025; 97(3):14069 d. pozza, a. marcantonio, g. savarese, m. pozza, c. pozza 2 cycles associated with inadequate erectile responses, such as insufficient rigidity, poor maintenance, or abnormal duration may indicate an underlying organic cause of ed. the npt test is relatively simple to use. it is first initialized with the patient's data and then provided to the patient, who must follow specific instructions to ensure accurate results. these include abstaining from sexual activity on the days of recording, avoiding strenuous physical activity, refraining from the use of tranquilizers and phosphodiesterase-5 inhibitors, limiting the intake of caffeine, tea, and alcohol, urinating before going to bed, and maintaining typical daily habits without engaging in unusual physical or discretionary activities. the goal is to capture the patient’s normal nocturnal physiological patterns. material and methods since 1980, our andrological center has evaluated over 46,000 male patients, aged 12 to 90 years, for a wide range of concerns, including urological disorders, infertility, ed, hypogonadism, pubertal development issues, testicular pain and preventive andrological check-ups. all patients underwent clinical examination by the same physician (dp), who consistently applied a standardized diagnostic approach. this included a thorough medical history, physical and genital examination, blood tests, and hormonal assessments. when indicated, further investigations such as x-rays, basal and duplex ultrasound, or mri were performed. among the various reasons for consultation, ed represented one of the most common and complex issues. in most cases, patients reported some degree of anxiety related to their ed, often perceived as consequence of an underlying organic condition. when a psychological or anxiety-related component was suspected, npt testing was recommended to better characterize the nature of the dysfunction. the nocturnal penile tumescence test our first npt test device (rigiscan) utilized since in 1986, is still in operation. over the years, we have used one device for 28 years, two devices for 18 years, and three devices for the past 9 years (10-11). maintenance is relatively straightforward: recalibration is recommended every 2-3 years, and the tension guides (base and tip) typically require replacement every 50-60 uses. the cover rings, although designed as disposable components, can be washed, sterilized, and reused for multiple nocturnal recordings. multipurpose elastic bands are used to secure the device to the patient’s thigh, allowing for freedom of movement during sleep (figure 1). the npt test is initialized with the patient's data using windows-compatible software, which enables data from each night’s recording to be downloaded and converted into numerical values and graphs that are easily interpretable by both physician and patient. initially, the npt test operated using the dos 3.2 system, with data stored on floppy disks (figure 2). later, the system was upgraded to a windows-based platform, which significantly improved data management and usability. in addition to monitoring nocturnal erections, the npt test can be employed to assess erectile responses during diagnostic procedures such as the audio-visual sexual stimulation test (avsst) or following intracavernosal drug injections, helping to clarify the nature of the erectile response to various stimuli (12-18) (figure 3). whenever possible, we prefer to deliver the npt test to the patient in person, providing detailed instructions and troubleshooting guidance for figure 2. examples of original npt test software boot and data diskettes from the dacomed corporation, dating back to the system’s introduction in 1986. figure 3. nocturnal npt test recording. the pattern shows preserved erectile episodes with both tip and base rigidity exceeding 60% and tumescence exceeding 3 cm, consistent with normal erectile physiology. figure 1. the nocturnal penile tumescence test device. archivio italiano di urologia e andrologia 2025; 97(3):14069 3 nocturnal penile tumescence test common issues that may arise during the recordings (e.g., replacing cover rings, delayed activation, or battery problems). alternatively, the device can be shipped to the patient’s home, pre-initialized with their data, along with instructions to view an instructional youtube video. after completing three nights of recording, the patient returns the device either in person or via courier which typically ensures return within 1-2 days. the results, including graphs, numerical data, and interpretation, are processed the day after return and sent to the patient and their referring physician via email (figures 4-7). real time npt test monitoring with avsst real-time npt test monitoring can be performed along with an avsst in a private setting (14-16). during the procedure, patients wear headphones that deliver audio from a sequence of erotic audiovisual stimuli while the npt test device is active. a baseline penile duplex ultrasound is performed prior to stimulation. the stimulation protocol consists of six explicit erotic contents of increasing intensity (each lasting 3 minutes), interspersed with 30-second neutral segments (nature or landscape scenes), for a total of 12 clips (24 minutes). in openly homosexual patients, samesex content is provided. following the audiovisual stimulation, penile doppler ultrasound is repeated, both immediately after the test and after intracavernosal administration of pge1, to evaluate the vascular response of cavernous vessels, in a setting that stimulates physiological conditions. this approach may help identification of artefigure 4. audio visual sexual stimulation test (avsst). representative recordings from 1998 demonstrating poor erectile response (a, b), partial rigidity without full tumescence (c), and complete erectile cycles (d, e) as recorded by early npt test software. screen width: 1 hour. figure 5. nocturnal penile tumescence and rigidity tracing form. the trace shows multiple erectile events with sustained rigidity and tumescence, indicating preserved neurovascular function. figure 6. example of a modern nocturnal penile tumescence test plus recording (2020), showing nocturnal erectile activity. the graphs display tip rigidity (%), tip tumescence (cm), base rigidity (%), and base tumescence (cm) over a 10-hour recording window. figure 7. recent npt plus output illustrating three distinct erectile events with sufficient rigidity and tumescence, interpreted as physiologically normal responses. archivio italiano di urologia e andrologia 2025; 97(3):14069 d. pozza, a. marcantonio, g. savarese, m. pozza, c. pozza 4 riogenic erectile dysfunction in patients with borderline or inconclusive rigiscan results, or in those who do not respond adequately to standard npt monitoring. use of npt before the recording night, two 9-volt batteries must be inserted into the device. fabric bands are attached to secure the instrument to the inner thigh. the measuring rings are gently expanded and positioned around the base of the penis (base ring) and just below the glans (tip ring). once the device is activated using the side button, the rings automatically adjust to their correct positions. importantly, even if one of the rings shifts or opens during the night, the recording is still considered valid. in the morning, the patient presses the side button to stop the recording and removes the rings. the used batteries should be discarded, and new ones inserted before the next session. the same rings and bands can be reused for subsequent nights. special problems during the night, the patient may need to get up to urinate, defecate, drink, or answer the phone. these actions can be performed while the npt test remains securely attached to the thigh, without interrupting the recording. alternatively, the patient may pause the recording by pressing the side button, gently remove the rings and release the bands to leave the bed and then reapply the device. it is important that the npt test, rings, and bands are correctly repositioned, and the recording restarted within 15 minutes to ensure data validity. in some cases, a ring may come undone. if this occurs, the patient is instructed on how to reconnect it using a silicone guide that allows the metal cable to be reinserted into the cover ring, thus enabling the continuation of the recording. the npt test can be used for up to three nights, which do not need to be consecutive. after completing the recordings, the device, along with the rings and bands, should be returned to the studio, either by the patient or another person, or shipped via courier (e.g., dhl or ups) with delivery expected within 2-3 days. once the device is returned, the data are downloaded, and graphs, numerical recordings, and a final report are generated. these can be provided directly to the patient or sent to the referring physician via email. results between june 20, 1986, and december 31, 2024, we performed a total of 1,587 npt test recordings in patients aged 16 to 90 years (tables 1, 2). of these, 992 were conducted over three nights, 486 over two nights, and 109 for a single night only. in the initial phase of our experience, local patients were asked to return after the first night of recording to allow early evaluation of the erectile activity recorded. if enough adequate erections were observed, further testing on subsequent nights was deemed unnecessary. however, to ensure diagnostic reliability, the npt test was repeated in 78 cases: 52 patients underwent a second night of recording, and 26 proceeded to a third night. in 123 cases, we encountered complications during nocturnal recordings. among these, 32 patients reported being unable to sleep with the device applied to the penis. in 36 cases, the tip ring, and in 42 cases, the base ring, detached during the night, and the patients were unable to reconnect them. additionally, 46 recordings were repeated due to irregularities in the output graphs, while in 29 cases, the discomfort caused by the rings led to premature interruption of the recording (table 3). sleep duration was assessed in a subgroup of 200 patients. on average, sleep lasted: – 5 hours and 32 minutes during the first night (range: 45 minutes to 10 hours); – 5 hours and 45 minutes during the second night (range: 137 minutes to 10 hours); – 6 hours and 45 minutes during the third night (range: 224 minutes to 10 hours). the mean sleep duration across all nights was 6 hours and 25 minutes. patients generally slept longer on the third night, likely due to increased adaptation to the device. erections were considered "valid for penetration" when rigidity exceeded 80% and was sustained for more than 5 minutes. the number of erectile episodes recorded per night ranged from 1 to 9, regardless of their intensity. valid erections (> 80% rigidity) were observed in 23% of the patients. all patients evaluated in our outpatient clinic completed vascular investigations to determine the aetiology of their table 1. distribution of npt test recordings performed since 1986, categorized by number of recording nights. number of nights n. of patients 3 992 2 486 1 109 table 3. age range of patients who performed npt test since 1986. age (years) n. of patients < 20 92 21-40 615 41-60 436 61-90 444 table 2. number of npt test recording nights and corresponding number of patients, grouped by period (1986–2024). period number of nights n. of patients 1986-1999 612 247 2000-2009 934 467 2010-2019 1498 548 2020-2024 852 325 1986-2024 3896 1587 archivio italiano di urologia e andrologia 2025; 97(3):14069 5 nocturnal penile tumescence test ed. an additional 350 patients were referred by other specialists and underwent diagnostic workups externally; therefore, final diagnoses for these individuals are not available. in 48 cases, npt test was repeated after a course of therapy to assess treatment efficacy. a subset of 176 patients underwent real-time npt test monitoring, performing a avsst in a private room (14-16). based on the erectile response obtained during the test, we categorized patients into five groups (figure 3): a. absent response a) the patient reported discomfort with the stimuli or didn’t enjoy porn b) the patient engaged with the content but showed no response due to severe vasculopathy b. mild response with confirmed vascular impairment c. mild response with good arterial inflow but insufficient rigidity d. consistent and lasting erectile response during stimulation. indicating normal vascular function e. initial erectile response during erotic videos followed by detumescence during neutral segments, suggestive of corporal veno occlusive dysfunction (cvod). discussion in many cases, the rigiscan can differentiate ed primarily caused by organic factors from that arising due to psycho-emotional components. while the device cannot replace the role of a psychologist (16), it offers unique advantages: it can be performed at home, during sleep, in complete privacy, and without interfering with daily activities or requiring the involvement of others. the resulting data, presented as easily interpretable graphs, allow the patient to understand potential alterations in erectile function, even without medical or psychological expertise. moreover, the cost of a npt test assessment is significantly lower than that of multiple psychodiagnostics sessions, making it a cost-effective option in the initial diagnostic workup. patients often seek specialist consultation for ed in clinical contexts where no overt psychological factors, such as emotional distress, uncertainty, or performance anxiety, are initially apparent. in these cases, organic causes are presumed to be predominant or exclusive (17, 18). however, some patients do exhibit psychological comorbidities, including anxiety, depression, or even manic features, making it difficult to determine whether these are the cause or the consequence of ed. when psycho-emotional factors are clearly present, a psychological assessment is advisable. psychological counselling and psychotherapy can be often difficult to access in everyday clinical practice. patients may struggle to find a trusted therapist, to attend sessions regularly around work and personal obligations, and may face the additional burden of cost, especially when only private care is available. furthermore, the duration of psychological assessment and treatment can be lengthy, and the final reports sent to the referring andrologist are often not easily understood by patients, particularly those without a medical background. based on our long-standing experience, we believe that collaboration between the andrologist and psychologist is essential in both diagnostic and therapeutic phases. however, it is not uncommon for patients to abandon the psychological path if they perceive slow or unclear progress, especially after having waited a considerable time before seeking medical help. many patients expect a clear diagnosis and a concrete therapeutic plan in a short time frame. conclusions in the diagnostic workup of ed, some tests offer more diagnostic value than others. a comprehensive assessment, including physical, metabolic, and hormonal evaluation, is essential to define an accurate diagnosis and initiate appropriate treatment. within this framework, npt testing has confirmed to be a particularly useful tool. it is typically proposed by the andrologist after the initial clinical assessment and is often well accepted even by the patient’s partner, who tends to appreciate the patient's proactive engagement in addressing the issue. in our experience, partner refusal to the examination is rare, except in a few cases where the patient had not engaged in sexual activity within the relationship for an extended period and was experiencing ed only in extramarital encounters unknown to the partner. even in such situations, many men have justified undergoing testing as a step toward restoring intimacy within the relationship, often citing fatigue, relational difficulties, or long-standing ed as contributing factors to the sexual distance. declarations ethical approval: this study is a retrospective collection of case reports from our clinical practice. all procedures were performed in accordance with the ethical standards of the declaration of helsinki. informed consent for the procedure and for the use of anonymized data for publication was obtained from each patient prior to testing. availability of data and material: the datasets generated and analyzed during the current study are not publicly available due to the inclusion of sensitive patient information and privacy regulations. competing interests: the authors declare that they have no competing interests. funding: this research received no external funding. authors' contributions: diego pozza: conceptualization and design of the study, clinical evaluation and management of all patients, interpretation of npt results, and final approval of the manuscript; andrea marcantonio and gabriele savarese: data collection; mariangela pozza: statistical analysis; carlotta pozza: study supervision, critical revision of the manuscript, and contribution to data interpretation and discussion. all authors have read and approved the final version of the manuscript. acknowledgments: the authors would like to thank all patients who participated in the diagnostic process and acknowledge the support of the entire clinical team in data management over the years. archivio italiano di urologia e andrologia 2025; 97(3):14069 d. pozza, a. marcantonio, g. savarese, m. pozza, c. pozza 6 references 1. karacan i, salis pj, williams rl. clinical disorders of sleep. psychosomatics. 1973; 14:77-88. 2. karacan i, williams rl, thornby ji, salis pj. sleep-related penile tumescence as a function of age. am j psychiatry. 1975; 132:932-7. 3. beutler le, scott fb, karacan i. psychological screening of impotent men. j urol. 1976; 116:163-71. 4. karacan i, aslan c, hirshkowitz m. erectile mechanism in man. science, 1983; 220:1080-2. 5. timm gw. the performance of the rigiscan in the measurement of penile tumescence and rigidity. int j impot res, 1994; 6:43-6. 6. bradley w, timm g, gallagher j, johnson b. new method for continuous measurement of nocturnal penile tumescence and rigidity. urology. 1985; 26:4-9. 7. dacomed corporation, minneapolis, minnesota, usa (1986). ambulatory rigidity and tumescence system. selected cases studies. farm number 7501560486. 8. levine la, lenting ei. use of nocturnal penile tumescence and rigidity in the evaluation of male erectile dysfunction. urol clin north am. 1995; 22:755-8. 9. giesbers aagm, bruinss jk, kramer aejl, jonas u, new method in the diagnosis of impotence: rigiscan penile tumescence and rigidity monitoring and diagnostic papaverindehydrochloride injection. world j urol. 1987; 5:173-6. 10. pozza d, ossanna p, marchionni l. can rigiscan nocturnal monitoring reveal the etiology of organic impotence?. int j impot res. 1990; 21; 105-6. 11. cilurzo p, canale d, turchi p, et al. the rigiscan system in the diagnosis of male sexual impotence. arch ital urol nefrol androl. 1992; 64(suppl 2):81-5. 13. karacan i, karatas m. erectile dysfunction in sleep apnea and response to cpap. j sex marital ther. 1995; 21:239-47. 12. nehra a, goldstein i, pabby a, et al. mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. j urol. 1996; 156:1320-9. 14. pozza d, ossanna p, marchionni. nocturnal and real-time rigiscan monitoring in patients with venous incompetence. arch esp urol. 1996; 49:217-20. 15. martins fe, reis jp. visual erotic stimulation test for initial screening of psychigenuc erectile dysfunction: a reliable noninvasive alternative? j urol. 1997; 157:134-9 16. djamilian m, stief cg, hartmann u, jonas u. predictive value of real-time rigiscan monitoring for the etiology of organogenic impotence. j urol. 1993; 149:1269-71. 17. yannakoyorgos k, dimitriadis g, kalinderis a. nocturnal penile tumescence and rigidity monitoring in young potent volunteers: reproducibility, evaluation criteria and the effect of sexual intercourse. j urol. 1998; 159:1921-6. 18. jannini ea, granata am, hatzimouratidis k, goldstein i. use and abuse of rigiscan in the diagnosis of erectile dysfunction. j sex med. 2009; 6:1820-9. correspondence diego pozza (corresponding author) diegpo@tin.it via b.gozzoli, 62h, 00142 roma, italy andrea marcantonio md.andreamarcantonio@gmail.com gabriele savarese gabriel.savarese@gmail.com mariangela pozza mariangela.pozza@gmail.com studio di andrologia e di chirurgia andrologica, rome, italy carlotta pozza dipartimento di medicina sperimentale, “sapienza” università di roma, rome, italy stesura seveso archivio italiano di urologia e andrologia 2025; 97(3):14094 1 original paper introduction diabetes mellitus (dm) has emerged as a global health crisis, with the number of affected individuals rising dramatically from 108 million in 1980 to 422 million in 2014, accompanied by an increase in global adult prevalence from 4.7% to 8.5% (1). this metabolic disorder is associated with severe complications, including cardiovascular, renal, ocular, and neural impairments, which significantly reduce functional capacity and quality of life (2, 3). among these complications, erectile dysfunction (ed) is a prevalent yet often overlooked condition in diabetic males, with incidence rates two to three times higher than in the general population (4, 5). the pathophysiology of ed in diabetes is multifactorial, involving central or autonomic neuropathy, endothelial and smooth muscle dysfunction in the corpus cavernosum, and hypogonadism (6). hyperglycemia-driven mechanisms, such as the accumulation of advanced glycation endproducts (ages), oxidative stress, and reactive oxygen species (ros), play pivotal roles in vascular and neural damage (7). ages impair endothelial nitric oxide synthase (enos) activity, reduce nitric oxide (no) bioavailability, and promote collagen cross-linking, leading to vascular stiffness and compromised erectile function (8, 9). additionally, ages exacerbate oxidative stress by upregulating nadph oxidase and downregulating antioxidant enzymes like mnsod, further diminishing endothelial-dependent vasodilation (10). while pharmacological interventions exist, non-pharmacological approaches, such as moderate-intensity aerobic exercise, have shown promise in mitigating diabetic complications. as demonstrated in hypercholesterolemic animal models, exercise enhances enos activity, no synthesis, and endothelial function (9). however, the specific effects of aerobic exercise on molecular markers of erectile function, such as enos and α-smooth muscle actin (α-sma) in diabetic corpus cavernosum, remain underexplored. this study aims to investigate the impact of moderateintensity aerobic exercise on enos and α-sma expresbackground: diabetes mellitus (dm) is a chronic disease with globally increasing prevalence, significantly impacting quality of life, including erectile dysfunction (ed). moderate-intensity aerobic exercise has been shown to improve metabolic and cardiovascular parameters, yet limited studies have examined its effect on erectile function. this study aimed to explore the effect of aerobic exercise on the expression of alpha-smooth muscle actin (α-sma) and endothelial nitric oxide synthase (enos) in the penile tissue of diabetic rat models. methods: this true-experimental study used 24 male rattus norvegicus (wistar), aged 12 weeks, randomly assigned to three groups: control (c), diabetic without intervention (ne), and diabetic with aerobic exercise (e). the aerobic exercise was performed for 60 minutes per session, 5 days a week, for 10 weeks. the expression of enos and α-sma in penile tissues was analysed by immunohistochemistry and quantified by image j software version 1.54p. statistical analysis was performed using spss software version 29.0, including tests for homogeneity and normality, followed by one-way anova with lsd or tukey post hoc tests for normally distributed data, or the kruskal wallis test for non-normal distributions. results: there was no significant difference in enos expression among the three groups (p > 0.05). however, α-sma expression showed a significant difference among the three groups (p < 0.05). group e showed a significant increase in α-sma expression compared to group ne (p = 0.034). conclusions: moderate-intensity aerobic exercise improves αsma expression in the penile tissue of diabetic rats, contributing to better erectile function. although it did not affect enos expression, this finding supports the potential of exercise-based non-pharmacological therapy for managing ed in diabetic patients. key words: diabetes mellitus; erectile dysfunction; aerobic exercise; alpha-smooth muscle actin; enos. submitted 24 june 2025; accepted 21 july 2025 effect of moderate-intensity aerobic exercise on penile α-sma and enos expression in diabetes mellitus rats model: a non-pharmacological approach to diabetic erectile dysfunction adelia anggasta adzhani 1, 2, johan renaldo 1, 2, mohammad ayodhia soebadi 1, 3, anny setijo rahaju 2, 4 1 department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia; 2 dr. soetomo general-academic hospital, surabaya, indonesia; 3 department of urology, universitas airlangga teaching hospital, surabaya, indonesia; 4 department of pathology anatomy, faculty of medicine, universitas airlangga, surabaya, indonesia. doi: 10.4081/aiua.2025.14094 summary archivio italiano di urologia e andrologia 2025; 97(3):14094 a. anggasta adzhani, j. renaldo, m. ayodhia soebadi, a. setijo rahaju 2 sion in the penile tissue of diabetes mellitus rats model. by addressing this gap, we seek to elucidate exerciseinduced mechanisms that may counteract ed progression in diabetes, offering a foundation for non-pharmacological therapeutic strategies. materials and methods study design this study was true experimental research with a posttest-only control group design. animals were randomly assigned into three groups: c: non-diabetic control group (no treatment) ne: diabetic model group without exercise e: diabetic model group with moderate-intensity aerobic exercise intervention. the intervention consisted of swimming for 60 minutes per session, 5 days a week, for 10 consecutive weeks. this study obtained ethical clearance for animal research under ethical number 66/ec/kepk/fkua/2025. animal model and sample size the study utilized organ samples from a parallel project involving male rattus norvegicus (wistar strain), aged 12 weeks, weighing 140-180 grams, and meeting the following inclusion criteria: healthy, never used in prior experiments, and physically active. animals were excluded if they became ill, died (not due to treatment), or failed three consecutive exercise sessions (11). the sample size was calculated using the formula for comparing two means, with an effect size (d) of 1.8, α = 0.05, and β = 0.05 (power = 95%). a minimum of 8 rats per group was obtained, resulting in a total of 24 rats randomly assigned to 3 groups. experimental procedures acclimatization and induction of diabetes mellitus rats underwent a 7-day acclimatization period under standard laboratory conditions (temperature 21-25°c, 12-hour light/dark cycle). diabetes mellitus was induced using a single intraperitoneal injection of streptozotocin (stz) at 40 mg/kg body weight dissolved in citrate buffer (ph 4.5). fasting blood glucose was measured via the tail vein using a glucometer (accu-chek instant), and rats with fasting glucose > 150 mg/dl were classified as diabetic (12). table 1 presents the baseline and final characteristics of the rats, including body weight and fasting glucose levels, before and after the streptozotocin induction. exercise protocol rats in the e group performed swimming exercises in a cylindrical tank (diameter 45 cm, water depth 55 cm) for 60 minutes/day, 5 days/week (monday-friday) for 10 weeks. swimming was supervised, and sessions were terminated if rats could not keep their heads above water for more than 3 seconds without effort. non-compliance in three consecutive sessions led to exclusion. euthanasia and tissue collection at 24 hours following the completion of the 10-week intervention, all rats were anaesthetized with intraperitoneal injections of ketamine (300 mg/kg) and xylazine (30 mg/kg), followed by cervical dislocation and decapitation. penile tissues were collected and preserved in formaldehyde for histological analysis. histological and immunohistochemical analysis enos and α-smooth muscle actin (α-sma) expression penile tissue was processed into paraffin blocks, sectioned at 5 µm thickness, and mounted on slides. immunohistochemical staining was performed using monoclonal anti-enos (#bsm-33176m, bioss) and polyclonal anti-α-sma antibodies (#bsm-33188m, bioss). slides were processed via xylene and graded alcohol series, antigen retrieval, and incubation with antibodies, followed by chromogen development and counterstaining. slides were scanned using a high-resolution digital slide scanner, and representative images from the corpus cavernosum were selected for analysis. image analysis was performed using imagej software version 1.54p to determine the area fraction of positive staining. thresholding was used to identify and isolate the positively stained regions, and the area fraction of positive staining was calculated by dividing the stained area by the total area of the corpus cavernosum within the same field. measurement and all quantification were performed by a blinded observer to reduce bias. data were reported as mean percentage area of positive staining per group. instruments and materials this study utilized a range of instruments and materials tailored to each phase of the experimental protocol. for the aerobic exercise intervention, a circular swimming tank with a diameter of 75 cm was employed to facilitate moderate-intensity swimming exercises in rats. each session was monitored using a stopwatch to ensure consistent exercise duration, and a towel was used to dry the animals post-exercise before returning them to their cages. penile tissues were fixed in formalin, embedded in paraffin, and sectioned at 5 µm. immunohistochemistry was performed using bioss antibodies against enos and α-sma. sections were processed with xylene, alcohol series, hydrogen peroxide, and chromogen substrates, then incubated for antibody binding. stained tissues were scanned, and immunoreactive areas were quantified using imagej v1.54p to assess enos and α-sma expression in erectile tissue after aerobic exercise in diabetic rats. table 1. animal characteristics before and after induction. c (mean ± sd) ne (mean ± sd) e (mean ± sd) initial body weight 154.14 ± 10.88 150.29 ± 10.14 153.71 ± 9.84 final body weight 235.71 ± 52.05 238.29 ± 24.79 187 ± 18.48 initial fasting glucose 456.14 ± 137.001 382.57 ± 136. 15 final fasting glucose 108.29 ± 9.84 490.43 ± 107.35 381.42 ± 138.12 archivio italiano di urologia e andrologia 2025; 97(3):14094 3 moderate-intensity aerobic exercise and penile α-sma and enos expression study site and duration the research was conducted over a period of six months in the biochemistry laboratory and anatomical pathology laboratory, faculty of medicine, universitas airlangga. data processing and statistical analysis data analysis was conducted using spss software version 29.0. homogeneity and normality tests were performed initially. one-way anova was used to compare normally distributed data between groups, followed by lsd or tukey post hoc tests, while the kruskal wallis test was used for non-normally distributed data. a p-value < 0.05 was considered statistically significant. results the basic data for this study were obtained from the rat penis preparations of male wistar strain rats (rattus norvegicus) aged 12 weeks from a previous study. all rats included in the previous study had their body weight measured at the beginning of stz injection and at the end of the treatment before termination, along with fasting blood glucose measurements taken at both the beginning and end of the intervention. the c group received no treatment, ne group was the diabetic model group without treatment, e group received moderate-intensity aerobic exercise until the age of 22 weeks. for the expression of enos in the corpus cavernosum smooth muscle, the immunohistochemical examination was performed using imagej software to assess the surface area of staining in the preparations. homogeneity tests were conducted for all groups, and normality tests were performed on each group. enos expression was found to be homogeneous and generally distributed in the smooth muscle of the cavernosum penis, allowing for analysis using a one-way anova. the results indicated no significant differences between groups (p > 0.05). table 2 and figure 1 show the mean enos expression, the results of the normality test, and the one-way anova test across three groups: c, ne, and e. in group c, the mean enos expression was 0.115 ± 0.058, with a normality test p-value of figure 1. expression of enos in the smooth muscle of the corpus cavernosum penis, a. group c, b. group ne, c. group e, d. mean ± sd of enos expression in the smooth muscle of the penile cavernosum. table 2. mean, normality test, and one-way anova test on enos expression in the smooth muscle of the corpus cavernosum penis. group mean ± sd normality test p value c 0.115 ± 0.058 0.200 0.888 ne 0.099 ± 0.065 0.200 e 0.108 ± 0.063 0.200 archivio italiano di urologia e andrologia 2025; 97(3):14094 a. anggasta adzhani, j. renaldo, m. ayodhia soebadi, a. setijo rahaju 4 0.200, indicating that the data follows a normal distribution. in group ne, mean enos expression was 0.099 ± 0.065, with a normality test p-value of 0.200, indicating a normal distribution. similarly, group e showed a mean enos expression of 0.108 ± 0.063, with a normality test p-value of 0.200, again indicating normal distribution. the one-way anova test resulted in a p-value of 0.888, suggesting no statistically significant difference in enos expression between the groups (since the p-value is greater than 0.05). table 3 and figure 2 shows mean α-sma expression, normality test, and one-way anova test across three groups: c, ne, and e. for group c, the mean α-sma expression was 0.118 ± 0.053. the normality test p-value for this group was 0.200, indicating that the data follow a normal distribution. in group ne, the mean α-sma expression was 0.048 ± 0.031, with a normality test pvalue of 0.200, also indicating normal distribution. group e showed a mean α-sma expression of 0.106 ± 0.059 with a normality test p-value of 0.167, indicating the data also follows a normal distribution. the anova test yielded a p-value of 0.030, suggesting a statistically significant difference among the groups regarding α-sma expression. post hoc lsd analysis of α-sma expression between groups revealed significant differences between c and ne (p = 0.013) as well as between ne and e (p = 0.034). in contrast, no significant difference was found between c and e (p = 0.641). the results of post hoc lsd analysis are shown in table 4. table 3. mean, normality test, and one-way anova test on α-sma expression in the smooth muscle of the corpus cavernosum penis. group mean ± sd normality test p value c 0.118 ± 0.053 0.200 0.030 ne 0.048 ± 0.031 0.200 e 0.106 ± 0.059 0.167 figure 2. expression of α-sma in the smooth muscle of the corpus cavernosum penis in group c, group ne, and group e. as mean ± sd of α-sma expression in the smooth muscle of the corpus cavernosum penis. * significant difference in post hoc lsd analysis of α-sma expression at p < 0,05. table 4. post hoc lsd test analysis of α-sma expression between groups in the smooth muscle of the penile cavernosum. group c ne e c 0.013 0.641 ne 0.013 0.034 e 0.641 0.034 archivio italiano di urologia e andrologia 2025; 97(3):14094 5 moderate-intensity aerobic exercise and penile α-sma and enos expression discussion diabetes mellitus is a chronic metabolic disease with rising global prevalence, increasing from 108 million in 1980 to 422 million in 2014.1 one notable complication is erectile dysfunction (ed), which is 2-3 times more common in diabetic men (13). the multifactorial pathophysiology involves vascular damage, neuropathy, and hormonal imbalances. chronic hyperglycemia leads to oxidative stress and accumulation of advanced glycation end-products (ages), contributing to endothelial dysfunction by decreasing enos and α-sma (14-16). moderate-intensity aerobic exercise has been shown to improve endothelial function, enhance enos expression, and reduce ages (17, 18). this study examined the effect of moderate-intensity swimming exercise on the expression of enos and α-sma in the corpus cavernosum of diabetic wistar rats. tissues were obtained from a previous study and divided into three groups: healthy control (c), diabetic without intervention (ne), and diabetic with exercise intervention (e). immunohistochemical analysis was used to assess biomarker expression. the study found no significant difference in enos expression between groups, although the highest expression was in the control group (c), suggesting diabetes impairs enos levels and potentially contributes to ed. this aligns with previous studies showing exercise alone may not restore enos levels in diabetic models (16, 19) though conflicting evidence exists in other tissues like the heart (20, 21). conversely, α-sma expression showed significant differences between groups. diabetic rats (ne) had lower αsma expression than controls (c), indicating structural deterioration of smooth muscle. moderate-intensity exercise (e) increased α-sma levels in diabetic rats, suggesting partial restoration, although not to control levels. this supports the potential of exercise to reverse structural changes in penile tissue (22). while the observed increase in α-sma expression in the exercise group may suggest a beneficial effect of moderate-intensity aerobic activity on smooth muscle preservation in diabetic penile tissue, it is important to note that α-sma is also a marker of myofibroblast activation involved in early fibrotic processes. therefore, the elevation in α-sma could reflect either tissue restoration or the onset of fibrosis. without the inclusion of additional fibrosis-specific markers – such as tgf-β1 or collagen subtypes – it is difficult to fully interpret the nature of these changes. future studies are recommended to incorporate a broader panel of fibrosis biomarkers and histological analyses to distinguish between adaptive remodelling and pathological fibrosis, thereby providing a more comprehensive understanding of exercise-induced tissue changes in diabetic erectile dysfunction (23-25). limitations of this study include the use of archived tissue samples, which may have undergone some degree of degradation, and the assessment of only two biomarkers (enos and α-sma), limiting the scope of molecular insights. additionally, the exercise protocol employed was limited to a single intensity and duration (moderateintensity swimming for 10 weeks), without comparisons to other intensities or frequencies. as a result, it remains unclear whether lower or higher-intensity activity, or different training frequencies, could elicit more pronounced or distinct effects on penile tissue markers. although the 10-week intervention yielded some molecular changes, it may still represent a relatively short duration for modelling chronic conditions such as diabetes. longer-term interventions may be necessary to observe more sustained or significant endothelial and smooth muscle improvements. future research should incorporate a range of exercise intensities and durations and assess a broader spectrum of molecular markers such as reactive oxygen species (ros), advanced glycation end-products (ages), and inflammatory cytokines to more comprehensively elucidate the therapeutic potential of exercise in diabetic erectile dysfunction. conclusions this study demonstrated that moderate-intensity aerobic exercise did not significantly affect enos expression in the corpus cavernosum of diabetic rats. however, moderate-intensity aerobic exercise was associated with a significant increase in α-sma expression compared to the untreated diabetic group, suggesting restoration of smooth muscle integrity. these findings support the potential of aerobic exercise in mitigating structural deterioration in diabetic erectile dysfunction, although further research with additional biomarkers and longer intervention durations is warranted to clarify the underlying mechanisms. declarations ethical approval: this study has been ethically approved and registered under 66/ec/kepk/fkua/2025. availability of data and material: all data generated or analyzed during this study are available upon request. competing interests: the authors declare that they have no competing interests. funding: this article receives no financial support. authors' contributions: aaa: conceptualization, methodology, and supervision of the study. jr: data collection, analysis, and manuscript drafting. mas: data collection, analysis, and manuscript drafting. asr: data analysis, manuscript drafting, and review. acknowledgments: the authors sincerely thank all the staff of the department of urology and the department of anatomical pathology of the universitas airlangga, for their invaluable assistance throughout this study. we also thank the laboratory technicians and research assistants for their dedicated work in data collection and preparation. archivio italiano di urologia e andrologia 2025; 97(3):14094 a. anggasta adzhani, j. renaldo, m. ayodhia soebadi, a. setijo rahaju 6 references 1. world health organization. global report on diabetes. 2016. 2. deshpande ad, harris-hayes m, schootman m. epidemiology of diabetes and diabetes-related complications. phys ther. 2008; 88:1254-1264. 3. shlomai g, neel b, leroith d, gallagher ej. type 2 diabetes mellitus and cancer: the role of pharmacotherapy. journal of clinical oncology. 2016; 34:4261-4269. 4. lizza ef, rosen rc. definition and classification of erectile dysfunction: report of the nomenclature committee of the international society of impotence research. int j impot res. 1999; 11:141-143. 5. gur s, c peak t, j kadowitz p, et al. review of erectile dysfunction in diabetic animal models. curr diabetes rev. 2014; 10:61-73. 6. kyprianou n, benning cm. suppression of human prostate cancer cell growth by α1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis. cancer res. 2000; 60:4550-4555. 7. su j, lucchesi pa, gonzalez-villalobos ra, et al. role of advanced glycation end products with oxidative stress in resistance artery dysfunction in type 2 diabetic mice. arterioscler thromb vasc biol. 2008; 28:1432-1438. 8. du xl, edelstein d, dimmeler s, et al. hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the akt site. j clin invest. 2001; 108:1341-1348. 9. neves d. advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction. free radic res. 2013; 47(suppl 1):49-69. 10. christ m, bauersachs j, liebetrau c, et al. glucose increases endothelial-dependent superoxide formation in coronary arteries by nad(p)h oxidase activation. diabetes. 2002; 51:2648-2652. 11. fauzi mf, djojodimedjo t, soebadi ma, rahaju as. effects of telmisartan and moderated-intensity aerobic exercise on collagen type i expression in a diabetes melitus model. south east eur j public health 2025:2242-2252. 12. fatahajjad hh, soebadi ma, putra rm, et al. effect of moderate-intensity aerobic exercise on bladder tgf-β1 and type i collagen expressions in diabetic rat model. narra j. 2024; 4:e1110-e1110. 13. rajkovic j, gostimirovic m, bukarica a. resveratrol and gut microbiota synergy: preventive and therapeutic effects’. int j mol sci. 2023; 24:17573. 14. kaushal k, sharma r, patel a. molecular mechanisms of erectile dysfunction in diabetes: focus on oxidative stress and endothelial dysfunction. int j impot res. 2024; 36:45-52. 15. goncharov n v, lokhmatova ey, avdonin pv. endothelial dysfunction in diabetes: the role of ages and no signaling. journal of vascular biology. 2024; 56:22-30. 16. wang t, liu y, wang y, et al. irreversible erectile dysfunction in long-term diabetic rats: failure of pharmacotherapy to reverse fibrosis and smooth muscle loss’. andrology. 2024; 8:1234-1242. 17. shanaida m, lysiuk r, mykhailenko o. alpha-lipoic acid: an antioxidant with anti-aging properties for disease therapy’. curr med chem. 2025; 25:3708. 18. kulawik t, nowacki m, dabrowski m. moderate aerobic training prevents endothelial dysfunction and enhances enos expression in diabetic models. diab vasc dis res. 2024; 21:112-120. 19. li z, yan z. effects of aerobic exercise on nitric oxide synthase and apelin in abdominal aorta of rats with type 2 diabetes mellitus’. asian sports science. 2014; 3:104-110. 20. hicks s, grijalva j, zhao x, medikayala s. exercise training enhanced myocardial endothelial nitric oxide synthase (enos) function in diabetic goto-kakizaki (gk) rats’. cardiovasc res. 2008; 7:112-118. 21. zago as, reis silveira l, kokubun e. effects of aerobic exercise on the blood pressure, oxidative stress and enos gene polymorphism in pre-hypertensive older people’. eur j appl physiol. 2010; 9:99-106. 22. yin gn, kim dk, lee sh. treadmill exercise prevents fibrosis and increases α-sma in the corpora cavernosa of diabetic rats. andrologia. 2018; 50:12805. 23. liu g, wang b, wang l. upregulation of tgf-β1 and α-sma in diabetic cavernosal tissue: indicators of fibrosis. journal of sexual medicine. 2014; 11:2343-2351. 24. tao m, tasdemir c, tasdemir s, et al. penile alterations at early stage of type 1 diabetes in rats’. international brazilian journal of urology. 2017; 43:753-761. 25. wang w, liu y, zhu zb, et al. research advances in stem cell therapy for erectile dysfunction. biodrugs. 2024; 38:353-367. correspondence adelia anggasta adzhani adeliadzhani21@gmail.com johan renaldo (corresponding author) johanrenaldo@fk.unair.ac.id mohammad ayodhia soebadi mohammad-a-s@fk.unair.ac.id department of urology, faculty of medicine, universitas airlangga, surabaya, indonesia anny setijo rahaju anny_sr@fk.unair.ac.id department of pathology anatomy, faculty of medicine, universitas airlangga, surabaya, indonesia stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12975 1 letter key words: pelvic reflex; male sexual response; male genital response; pelvic floor; neurological reflex; genital excitatory response; genital perception; ejaculatory urgency. submitted 26 august 2024; accepted 31 august 2024 to the editor, what are the male anatomical structures that trigger the so-called "desire" to have sex? what are the male anatomical structures that determine the perception of arousal in men? the most prevalent models of male sexuality to date, those of masters w, johnson ve (1) and kaplan hs (2), while revolutionary for their time and introducing important physiological concepts, begin the entire process with erection and its perception as the first anatomical sign of male arousal and desire. however, erection as the first response of male reactivity does not always coincide with arousal, understood as the psychological and physiological arousal that a male experiences in response to sexual stimuli. it also does not always coincide with the perception of arousal, meaning the perception of occurrence of an erection, or more accurately, the excitatory response of the genitals. in fact, the subjective perception of the excitatory response of the genitals does not always correspond simultaneously with the actual genital response, such as an increase in penile volume and rigidity (3, 4). for instance, a study by rieger (5) reported that some men without erectile dysfunction, when asked to perform mathematical calculations during visual erotic stimulation, experienced a reduction in erection but not in self-reported arousal. in other situations, the opposite was found: a genital excitatory response, such as an erection, occurred without a subjective state of arousal. this is what happens during nocturnal erections in the rem phase of sleep, which are not always associated with erotic dreams or arousal states (6, 7). another example where erection does not lead to subjective arousal and its perception is the phenomenon of priapism, which is characterized by an erection without arousal (8). the same phenomenon can be observed during cavernous pharmacological infusion with papaverine, as occurred during virag's experiment, in which an erection was obtained under general anesthesia without the subject being aroused or aware of it (9). this lack of simultaneous correspondence, at least in men, may be due to the fact that the perception of the genital response after visual or psycho-sensory stimulation may not be a simple perception of erection, but rather a consequence of the involvement of another structure, which, according to my hypothesis, is the pelvic floor. there are three clues that have led me to hypothesize that the first response to psycho-sensory stimulation, understood as all visual or mental erotic stimuli, could involve an initial response mediated through pelvic floor contraction, making the male subject aware of the genital excitatory response. the first clue arises from the negative consequences on sexuality following radical prostatectomy for cancer. this “experimental model”, which i place in quotation marks out of respect for the patients who have undergone cancer surgery, highlights two phenomena that have so far only been described as contemporaneous but not yet proven to be in a cause-andeffect relationship: damage to the pelvic floor (10) with static alterations due to vesicourethral anastomosis (11) and a decrease in libido by 50% (12), even when erection is restored postoperatively (13). the second clue that supports my hypothesis is based on studies by shafik published in 2001 (14), in which the author demonstrated that both the bladder and rectum exhibit an excitatory reflex involving the levator ani muscle and an inhibitory reflex involving the pubo-rectalis muscle, which regulates the perception of urgency and the mechanism of evacuation and urination. this study raises the question: if the bladder, rectum, and penis share common nerve bundles and blood vessels, and if these structures are all traversed by the pelvic floor muscles, why should these same muscles not play a similar role in male arousal, not just in erection and ejaculation, as has been demonstrated so far? (15-17). the third piece of evidence for this new theory on male sexual response is based on research conducted by la pera (18) and colleagues, in which 270 subjects, responding to a questionnaire that evoked an erotic image, highlighted a correlation between initial arousal and pelvic floor contraction. the purpose of this work is to propose a new pathophysiology of the male sexual response, integrating the model of masters the psycho-sensory pelvic reflex: a new paradigm in the model of male sexual response giuseppe la pera consultant urologist, rome, italy. doi: 10.4081/aiua.2024.12975 archivio italiano di urologia e andrologia 2024; 96(4):12975 giuseppe la pera 2 and johnson, which includes excitement, plateau, orgasm, and resolution. in this new hypothesis, their model is complemented by a fifth step represented by the psycho-sensory pelvic reflex, mediated by the contraction of the pelvic floor. pathophysiology of the male sexual response to illustrate the proposal of this new model, which integrates the pioneering work of masters and johnson, we analyze two aspects that have not been considered until now and which, in our opinion, although not yet demonstrated, could be fundamental to the first male sexual response: the psycho-sensory sexual reflex and the perception of the male genital response. the psycho-sensory sexual pelvic reflex the hypothesis proposed here is based on the reflexive involvement of the pelvic floor in response to psycho-sensory erotic stimulation. this reflex response, in my view, consists in the contraction of the pelvic floor, which makes the subject aware of the excitatory response. according to this new model, when a man receives visual or imagined erotic stimulation, a reflexive contraction of the pelvic floor occurs. this reflex not only causes the contraction of the levator ani muscle, but also triggers the contraction of the bulbourethral, bulbocavernosus, and ischiocavernosus muscles. in this proposal, following psycho-sensory stimulation, the contraction of these muscles results in the compression of the intra-abdominal part of the penis, increasing the pressure within the corpus spongiosum and corpus cavernosum. furthermore, this increase in pressure within the corpus spongiosum of the urethra is transmitted to the glans and its receptors, resulting in the perception of the genital response. according to this hypothesis, the psychophysiological reflex is the missing link – the mechanism – in the sequence of events that leads from visual or imagined erotic stimulation to a genital response and its perception. the perception of the male genital response if the sequence of events is as described above, we should ask ourselves how the perception of the sensation of the first genital excitatory response occurs and how we should define this initial genital excitatory response. continuing with this hypothesis, the perception of this genital excitatory response – the process through which we interpret, organize, and give meaning to the sensations originating from the genitals – occurs because the pelvic floor muscles, including the bulbourethral, bulbocavernosus, and ischiocavernosus muscles, reflexively contract in response to a psycho sensorial stimulus, causing a “compression” of the internal part of the penis, consisting of the corpus cavernosum and the corpus spongiosum of the urethra. the contraction of these muscles increases pressure within the penis, corpus cavernosum and corpus spongiosum of the urethra, and is transmitted to the receptors of the glans. this contraction and increase in pressure inside the penis determine the perception of the genital response. from this psycho-physiological mechanism, we can deduce how to define the first genital excitatory response, which should therefore be defined as the contraction of the pelvic floor muscles and increase in pressure within the corpus cavernosum and corpus spongiosum of the urethra in response to psycho-sensory erotic stimulation. discussion once the perception of the contraction of the pelvic floor and increase in pressure within the corpus cavernosum and corpus spongiosum of the urethra becomes conscious, there is a need to engage in sex and seek mechanical genital stimulation that leads to orgasm. this need constitutes an “ejaculatory urgency”, similar to the sensation experienced when the bladder is full and there is an urgency to find an appropriate place to void the bladder and relieve the sensation of urgency. the antagonist of this psycho-sensory sexual pelvic reflex could be the pubo-rectalis muscle, which, similar to how it inhibits contraction for urination and defecation, inhibits the sensation of urgency to evacuate (14). when such a “need” becomes conscious through this sensation, the brain decides case-by-case how to proceed to find a solution to satisfy this need, using the tools at its disposal. the contraction of the pelvic floor, generating the sensation of genital response, would signal the need to "take action" and engage in behaviors that enable mechanical stimulation of the genitals – in other words, to have sex. the perception of the contraction of the pelvic floor and the increase in pressure within the corpus cavernosum and corpus spongiosum initiates a series of behaviors aimed at achieving mechanical stimulation of the genitals that lead to ejaculation. this is a “cascade” of events that begins with the psycho-sensory pelvic reflex and ends with ejaculation. the perception of this contraction, due to the psycho-sensory pelvic reflex, as reconstructed here, could be one of the triggers or one of the possible motivations that initiates the search for sexual activity. the new five-phase model of male sexual response the sequence of events describing the new model of the male sexual response consists of five phases. at present, it is not known how much each of these phases may overlap with the previous one and continue subsequently after the end of its action. according to this proposal, the classic masters and johnson model is supplemented by a preliminary phase called the phase of reflex and perception. phase of the psycho-sensory sexual pelvic reflex and its perception the phase of reflex and perception that precedes the four stages of the male sexual response described by masters and johnson consists of the following six moments: archivio italiano di urologia e andrologia 2024; 96(4):12975 3 psycho-sensory pelvic reflex 1. trigger phase: the subject has a thought or sees an erotic image capable of eliciting a genital excitatory response. 2. phase of the psycho-sensory pelvic reflex: in this phase, the erotic stimulus triggers a neurological reflex that leads to an involuntary contraction of the pelvic floor, particularly the levator ani, bulbourethral, bulbocavernosus, and ischiocavernosus muscles. 3. compression phase: the intra-abdominal part of the penis and urethra, where the bulbourethral, bulbocavernosus, and ischiocavernosus muscles insert, are compressed by the contraction of these muscles. 4. pressure increase phase: following the compression in the previous phase, an increase in pressure occurs within the corpus cavernosum and corpus spongiosum. 5. perception phase: the increase in pressure in the corpus cavernosum and corpus spongiosum of the urethra, the stimulation of the receptors of the glans, and the contraction of the pelvic floor are consciously perceived. 6. trigger phase: once it is perceived that a genital response has occurred, the subject begins to feel the need to have sex and engages in behaviors aimed at achieving the mechanical stimulation necessary for a full erection, to then progress to the plateau phase, and subsequently to orgasm with ejaculation. conclusions in this article, a new paradigm for the male sexual response is proposed and hypothesized, integrating a fifth step into the masters and johnson model. this new model consists of the psycho-sensory sexual pelvic reflex and perception of pelvic floor contraction, which triggers the “cascade” of the subsequent four phases of the male sexual response: excitement, plateau, orgasm, and resolution. in this model, the subjective perception of pelvic floor contraction could be the trigger that initiates the motivation to seek mechanical genital stimulation to achieve ejaculation. acknowledgments i thank martha b. scherr for her help in translating the text into english. references 1. masters wh, johnson ve. human sexual response. little, brown and company, new york, 1966. 2. kaplan hs. the new sex therapy. brunner/mazel, 1974. 3. janssen e. sexual arousal in men: a review and conceptual analysis. hormones and behavior.2011; 59:708-716. 4. van lankveld j, van den hout ma. increasing neutral distraction inhibits genital but not subjective sexual arousal of sexually functional and dysfunctional men. archives of sexual behavior 2004; 33:549-558. 5. rieger g, chivers ml, bailey jm. sexual arousal patterns of bisexual men. psychological science 2005; 16:579-584. 6. bach ak, brown ta, barlow dh. the effects of false negative feedback on efficacy expectancies and sexual arousal in sexually functional males. behavior therapy 1999; 30:79-95. 7. janssen e, everaerd w. determinants of male sexual arousal. annual review of sex research 1993; 4:211-246. 8. silberman m, stormont g, leslie sw, hu ew. priapism. statpearls [internet]. treasure island (fl): statpearls publishing 2023; 30:1-11. 9. porst h, lewis r, virag r, goldstein i. a comprehensive history of injection therapy for erectile dysfunction, 1982-2023. sexual medicine reviews 2024; 12:419-433. 10. cui j, guo h, li y, chen s, et al. pelvic floor reconstruction after radical prostatectomy: a systematic review and meta-analysis of different surgical techniques. scientific reports 2107; 7:2737. 11. kadono y, nohara t, kawaguchi s, et al. impact of pelvic anatomical changes caused by radical prostatectomy. cancers (basel) 2022;14:3050. 12. messaoudi r, menard j, parquet h, et al. modification of sexual desire and orgasm after radical prostatectomy for prostate cancer. progrès en urologie 2011; 21:48-52. 13. dalkin bl, christopher ba. potent men undergoing radical prostatectomy: a prospective study measuring sexual health outcomes and the impact of erectile dysfunction treatments. urologic oncology 2008; 26:281-285. 14. shafik a. effect of pelvic floor muscles contraction on vesical and rectal function with identification of puborectalis-rectovesical inhibitory reflex and levator rectovesical excitatory reflex. world journal of urology 2001;19:278-284. 15. shafik a. response of the urethral and intracorporeal pressures to cavernosus muscle stimulation: role of the muscles in erection and ejaculation. urology 1995; 46:85-88. 16. gerstenberg tc, levin rj, wagner g. erection and ejaculation in man: assessment of the electromyographic activity of the bulbocavernosus and ischiocavernosus muscles. british journal of urology 1990; 65:395-402. 17. de groat wc, booth am. physiology of male sexual function. annals of internal medicine 1980; 92:329-331. 18. la pera g, anticoli s, mangiardi m, livi s. pelvic floor contraction as an initial response to psycho-sensory sexual stimulation in men and a trigger for male sexual behaviour. arch ital urol androl 2024; 96:13119. correspondence giuseppe la pera md (corrisponding author) – dr.giuseppelapera@gmail.com via delle mura gianicolensi 67 c/o upmc salvator mundi international hospital, rome, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2024; 96(4):12992 1 original paper tematic prostate biopsy in diagnosing cspca and reducing unnecessary biopsies; the detection rate for cspca is correlated with prostate imaging-reporting and data system (pi-rads) score and in selected cases systematic biopsies could be omitted without harbor pca diagnosis. in this study we have prospectively evaluated the detection rate for pca performing only mpmri/fusion targeted biopsy combined with ipsilateral systematic prostate biopsy. materials and methods from january 2023 to december 2023, we prospectively evaluated 495 men with clinical suspicion of pca underwent transperineal systematic (spbx: 20 cores in both prostatic lobes plus anterior zone) plus mpmri/transrectal ultrasound (trus) fusion biopsy in the presence of pirads score lesions ≥ 3 (tpbx: 4 cores) (11, 12). clinical criteria for prostate biopsy were: psa values > 4 ng/ml and/or suspicion digital rectal examination (dre) or revaluation (scheduled biopsy) of men enrolled in as protocol. after institutional review board and ethical committee approval were granted, the informed consent was obtained from all individual participants included in the study. median psa was 7.3 ng/ml (range: 3.8-152 ng/ml), digital rectal examination (dre) was suspicion for pca in 58/495 (11.7%) cases, 295 vs. 200 underwent initial vs. repeated biopsy, 48 men were enrolled in as protocol for very low/low risk pca (13). all the mpmri index lesions characterized by a pi-rads (version 2) ≥ 3 underwent targeted cores (tpbx: 4 cores); the procedure was performed transperineally using a tru-cut 18 gauge needle (bard; covington, ga, usa) under sedation and antibiotic prophylaxis. the tpbx was done using an hitachi 70 arietta ecograph, chiba, japan) supplied by a bi-planar trans-rectal probe (14, 15). the detection rate for pca of spbx in the controlateral “negative” mpmri prostatic lobe of men has been evaluated; in detail, the opportunity to omit systematic biopsy in the hemigland without suspicion mpmri lesions was evaluated. results none had significant complications (clavien-dindo grade i) from prostate biopsy that needed hospital admission; introduction: to evaluate the detection rate for prostate cancer (pca) performing multiparametric magnetic resonance imaging (mpmri) fusion targeted biopsy (tpbx) combined only with ipsilateral systematic prostate biopsy (spbx). materials and methods: from january 2023 to december 2023, 495 men with clinical suspicion of pca underwent transperineal spbx plus tpbx in the presence of pi-rads score lesions ≥ 3. results: in 250/495 men (50.5%) a pca was found, while 36/250 (14.4%) men had negative mpmri. in comparison to tpbx, spbx diagnosed a higher number of indolent pca, 38.5 vs. 5.8%, respectively; conversely, spbx demonstrated a higher detection rate for clinically significant pca (97.3 vs. 85.4%) in the presence of isup grade group 2 (gg2). in details, rates were higher in the presence of gg2 (100 vs. 76%), gg3 (85.7 vs. 75.8%) and gg4 (100 vs. 86.4%) tumors. however, in gg5, both spbx and tpbx diagnosed 100% of cspca. furthermore, 89.4% of the cases showed cspca on the negative mpmri side. conclusions: spbx combined with tpbx maximized cspca diagnosis; the use of reduced biopsy scheme limited to ipsilateral side of mpmri lesion plus tpbx missed 11.6% cspca. only in the presence of pi-rads score 5 spbx and tpbx diagnosed both 100% of cspca. key words: prostate cancer; mpmri; targeted biopsy; systematic biopsy; gleason score. submitted 30 august 2024; accepted 16 september 2024 introduction prostate cancer (pca) is the most frequent tumor worldwide in the male population (1), with a high estimated risk of overdiagnosis and overtreatment for men enrolled in psa screening. in the last years, the use of multiparametric magnetic resonance imaging (mpmri) combined with risk calculator including more clinical parameters allowed to improve the diagnosis of clinically significant pca (cspca) (2-7). in this respect, the diagnosis and treatment of pca should be tailored for each patient to balance oncological and functional outcomes. although active surveillance (as) protocols (8) have reduced overtreatment of low risk pca and, in well informed patients, favorable intermediate risk (9, 10) pca, the necessity of definitive treatment (radical prostatectomy or external radiotherapy) results to worse the quality of life. multiparametric mri has improved the accuracy of sysmultiparametric mri targeted prostate biopsy: when omit systematic biopsy? pietro pepe 1, ludovica pepe 2, vincenzo fiorentino 2, mara curduman 3, filippo fraggetta 4 1 urology unit, cannizzaro hospital, catania, italy; 2 department of human pathology in adult and developmental age “gaetano barresi”, university of messina, messina, italy; 3 pathology unit, cannizzaro hospital, catania, italy; 4 pathology unit, asp catania, "gravina" hospital, caltagirone, italy. doi: 10.4081/aiua.2024.12992 summary archivio italiano di urologia e andrologia 2024; 96(4):12992 p. pepe, l. pepe, v. fiorentino, et al. 2 no patient had bilateral suspicious lesions at mpmri. in 250/495 (50.5%) men a pca was diagnosed: 100 (40%) had an international society of urological pathology (16) grade group 1 (isup gg1)/gleason score 6, 50 (20%) a gg2/gleason score 3+4, 28 (21.4%) a gg3/gleason score 4+3, 26 (15.4%) a gg4/gleason score 8 and 46 (18.4%) a gg5/gleason score 9. 36/250 (14.4%) men had negative mpmri (pi-rads score < 2): 38.9% (14 cases) were gg1, 33.3% (12 cases) gg2, 16.7% (6 cases) gg3, 11.1% (4 cases) gg4, and 0% gg5. spbx in comparison with tpbx diagnosed a greater number of indolent pca equal to 96/250 (38.5%) vs. 14/250 (5.8%) men; on the contrary, spbx showed an higher detection rate for cspca (97.3 vs. 85.4%). in details, rates were higher in the presence of gg2 (100 vs. 76%), gg3 (85.7 vs. 78.5%) and gg4 (100 vs. 84.6%), whereas in gg5 spbx vs. tpbx diagnosed both 100% of cspca (table 1). spbx in comparison with tpbx diagnosed 146/150 (97.3%) vs. 128/150 (85.4%) cspca, respectively. in total 16/150 (10.6%) men with cspca had positive systematic cores located only in the ipsilateral side of suspicious mpmri. out of them, 2/50 (4%) men with gg2 had pi-rads 3; 10/28 (35.8%) with gg3 had pi-rads score 3 (2 cases), 4 (6 cases) and 5 (2 cases), respectively; 2/26 (7.7%) and 2/46 (4.3%) with gg4 and gg5 had lesions pi-rads score 4, respectively (table 1). performing only tpbx would have spared 14.4% (36/250) biopsies and adding systematic cores in the ipsilateral side of tpbx 11.6% cspca located in the controlateral prostatic lobe with negative mpmri would have missed. discussion the use of mpmri has increased the diagnosis of cspca with a false negative rate equal to 15-20% of the cases; therefore, systematic biopsies, still today, should be combined with targeted cores to improve pca diagnosis (17). it remains unknown whether cspca is missed due to the limited sensitivity of mri, the suboptimal image fusion, the biopsy technique and strategy, expertise of the surgeon or a combination of these. if the diagnosis of pca is based on “mri pathway” (18) the patients should be advised of false negative rate for cspca but, at the same time, the morbidity of the procedure could result less invasive because the lower number of needle cores. recently, a reduced-core prostate biopsy strategy confined to the ipsilateral emigland of suspicious mpmri including “perilesional cores” has been proposed to decrease the number of systematic cores, but, still today, the literature data are not in agreement and the detection rate for cspca is correlated to different pi-rads scores (19). bourgeno et al. (20) in 2.387 men submitted to different prostate biopsy schemes reported that the added value of contralateral systematic biopsy was negligible in terms of cancer detection (6.1% of the cases) and upgrading rates. hegens et al. (21) reported in 235 patients that tpbx plusperilesional biopsy approach detected 96.8% cspca reducing the diagnosis of indolent pca in 12.8% of the cases. deniffel et al. (22) in 745 men submitted to mpmri tpbx plus systematic biopsy reported that standard cores could be avoided only in men with pi-rads score 5 and/or previous negative biopsy, missing 1 vs. 2% of cspca and avoiding 27 vs. 58% of systematic procedures. on the other hand, sawhney et al. (23) reported in 490 men that about 20% of men with unilateral mri lesions and cspca on targeted biopsy were found to have controlateral cspca on systematic biopsies. phelps et al. (24) in 212 men with mpmri-visible intraprostatic lesions demonstrated that tpbx alone diagnosed 81.5% pca, on the contrary 7.6% had controlateral involvement and 10.9% had bilateral pca and concluded that tpbx combined with systematic biopsies maximizes cspca diagnosis. hou et al. (25) in 229 patients showed that the benefit of systematic biopsy added to tpbx was restricted to smaller pi-rads score 3-4 resulting not useful for the diagnosis of cspca in the presence of pi-rads score lesions 5 and larger (> 1 cm) pi-rads score 3-4 allowing to reduce systematic biopsies in 44.5% of the cases without compromising cspca diagnosis. the discordant data reported in literature are, probably, correlated with the clinical parameters (dre, clinical stage, psa values), pirads score values and number of needle cores performed by systematic prostate biopsy; in general, only in the presence of pi-rads score 5 controlateral spbx could be omitted. anyway, omitting controlateral spbx a relevant number of cspca could be definitively missed especially in men candidate to radiotherapy. recently, new prostate targeted strategies have been proposed; the use of transrectal microultrasound (26) and psma pet/ct (2730) demostrated good accuracy in diagnosing cspca performing targeted biopsy when compared with mpmri accuracy, but the results were obtained in men enrolled in clinical trials and/or in limited number of cases. in our series, among 250/495 (50.5%) pca 150 (60%) where cspca and 36 (14.4%) had negative mpmri (pirads score ≤ 2). spbx in comparison with tpbx diagnosed a greater number of indolent pca (38.5 vs. 5.8%); table 1. biopsy findings in the 250 men with prostate cancer (pca) submitted to systematic (spbx) and targeted biopsy (tpbx). overall pca pi-rads ≤ 2 positive positive pca only number of median gpc 250 36 (14.4%) tpbx spbx in ipsilateral side positive cores psa median gg1/gs 6 14 (39%) 54 (54%) 96 (96%) 0 2 4.2 25% 100 cases gg2/gs 3+4 12 (33.3%) 38 (76%) 50 (100%) 2/50 (4%) 8 5.9 40% 50 cases gg3/gs 4+3 6 (16.6%) 22 (78.5%) 24 (85.7%) 10/28 (35.7%) 10 8.6 55% 28 cases gg4/gs 8 4 (11.1%) 22 (84.6%) 26 (100%) 2/26 (7.7%) 15 12.5 60% 26 cases gg5/gs 4+5 0 100% 100% 2/46 (4.3%) 18 19.2 85% 46 cases gs: gleason score; psa: prostate specific antigen; gpc: greatest percentage of cancer; pi-rads: prostate imaging-reporting and data system; gg: isup grade group; mpmri: multiparametric magnetic resonance image archivio italiano di urologia e andrologia 2024; 96(4):12992 3 targeted vs. systematic prostate biopsy on the ther hand, spbx showed an higher detection rate for cspca (97.3 vs. 85.4%). in detail, only 16/150 (10.6%) men with cspca had positive cores located only in the ipsilateral side of suspicious mpmri: 2/50 (4%) men with gg2; 10/28 (35.8%) with gg3; 2/26 (7.7%) and 2/46 (4.3%) with gg4 and gg5, respectively. only men with pi-rads score 5 had a detection rate for cspca equal to 100% performing tpbx vs. spbx (table 1). tpbx combined with ipsilateral spbx alone would have missed 27.2% of pca irrispective of pirads score and 11.6% were cspca; in addition, quantitative histological findings useful for local staging of pca and planification of definitive treatment (i.e. nerve sparing prostatectomy; intensity modulated radiotherapy) would have missed. finally, performing only tpbx would have spared 14.4% biopsies missing the presence of cspca also in the negative mpmri side in 89.4% of the cases. regarding our results, some consideration should be done. first, pca diagnosis has been evaluated in biopsy finding and not in the entire prostate specimen; secondly, many patients had an indolent pca because included in as protocol and in these cases spbx combined with tpbx is highly recommended. finally, a greater number of patients should be evaluated. conclusions spbx combined with tpbx maximized cspca diagnosis; the use of reduced biopsy scheme limited to tpbx plus ipsilateral systematic cores missed 11.6% of cspca; only in the presence of pi-rads score 5 spbx and tpbx diagnosed all cspca. references 1. bergengren o, pekala kr, matsoukas k, et al. 2022 update on prostate cancer epidemiology and risk factors-a systematic review. eur urol 2023; 84:191-206. 2. pepe p, garufi a, priolo gd, et al. is it time to perform only magnetic resonance imaging targeted cores? our experience with 1,032 men who underwent prostate biopsy. j urol 2018; 200:774778. 3. roscigno m, stabile a, lughezzani g, et al. the use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. can psa density discriminate patients at different risk of reclassification? clin genitourin cancer. 2020; 18:e698-e704. 4. pepe p, d'urso d, garufi a, et al. multiparametric mri apparent diffusion coefficient (adc) accuracy in diagnosing clinically significant prostate cancer. in vivo 2017; 31:415-418. 5. salemi m, pettinato a, fraggetta f, et al. expression of mir-132 and mir-212 in prostate cancer and metastatic lymph node: case report and revision of the literature. arch ital urol androl 2020; 92. 6. fiorentino v, martini m, dell'aquila m, et al. histopathological ratios to predict gleason score agreement between biopsy and radical prostatectomy. diagnostics (basel). 2020; 11:10. 7. pecci v, troisi f, aiello a, et al. targeting of h19/cell adhesion molecules circuitry by gsk-j4 epidrug inhibits metastatic progression in prostate cancer. cancer cell int. 2024; 24:56. 8. pepe p, cimino s, garufi a, et al. confirmatory biopsy of men under active surveillance: extended versus saturation versus multiparametric magnetic resonance imaging/transrectal ultrasound fusion prostate biopsy. scand j urol 2017; 51:260-263. 9. russell jr, siddiqui mm. active surveillance in favorable intermediate risk prostate cancer: outstanding questions and controversies. curr opin oncol 2022; 34:219-227. 10. pepe p, pepe l, pennisi m, fraggetta f. oncological outcomes in men with favorable intermediate risk prostate cancer enrolled in active surveillance. in vivo 2024; 38:1300-1305. 11. pepe p, pennisi m. morbidity following transperineal prostate biopsy: our experience in 8.500 men. arch ital urol androl 2022; 94:155-159. 12. pepe p, candiano g, pepe l, et al. mpmri pi-rads score 3 lesions diagnosed by reference vs affiliated radiological centers: our experience in 950 cases. arch ital urol androl 2021; 93:139-142. 13. pepe p, pepe l, pennisi m, fraggetta f. which prostate biopsy in men enrolled in active surveillance? experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. clin genitourin cancer 2021; 19:305-308. 14. pepe p, garufi a, priolo g, pennisi m. transperineal versus transrectal mri/trus fusion targeted biopsy: detection rate of clinically significant prostate cancer. clin genitourin cancer. 2017; 15:e33-e36. 15. pepe p, aragona f. prostate needle biopsy: 12 vs. 18 cores -is it necessary? urol int 2005; 74: 19-22. 16. offermann a, hupe mc, sailer v, et al. the new isup 2014/ who 2016 prostate cancer grade group system: first résumé 5 years after introduction and systemic review of the literature. world j urol 2020; 38:657-662. 17. pepe p, garufi a, priolo g, pennisi m. can mri/trus fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? world j urol 2016; 34:1249-1253, 2016. 18. chang sd, ghai s, kim ck, et al. mri targeted prostate biopsy techniques: ajr expert panel narrative review. ajr am j roentgenol 2021; 217:1263-1281. 19. yusim i, mazor e, frumkin e, et al. evaluation of the optimal strategy in men with a single unilateral suspicious lesion on mri undergoing transperineal mri/ultrasound fusion prostate biopsy. prostate 2023; 83:1255-1262. 20. bourgeno ha, jabbour t, baudewyns a, et al. the added value of side-specific systematic biopsy in patients diagnosed by magnetic resonance imaging-targeted prostate biopsy. eur urol oncol 2024:s2588-9311(24)00031-2. 21. hagens mj, noordzij ma, mazel jw, et al. an magnetic resonance imaging-directed targeted-plus-perilesional biopsy approach for prostate cancer diagnosis: "less is more". eur urol open sci 2022; 43:68-73. 22. deniffel d, perlis n, ghai s, et al. prostate biopsy in the era of mritargeting: towards a judicious use of additional systematic biopsy. eur radiol 2022; 32:7544-7554. 23. sawhney v, huang r, huang wc, et al. predictors of contralateral disease in men with unilateral lesions on multiparametric mri. urology. 2024:s0090-4295(24)00564-8. 24. phelps te, yilmaz ec, harmon sa, et al. ipsilateral hemigland prostate biopsy may underestimate cancer burden in patients with unilateral mpmri-visible lesions. abdom radiol (ny) 2023; 48:1079-1089. archivio italiano di urologia e andrologia 2024; 96(4):12992 p. pepe, l. pepe, v. fiorentino, et al. 4 25. hou y, jiang kw, zhang j, et al. a clinical available decision support scheme for optimizing prostate biopsy based on mpmri. prostate cancer prostatic dis. 2022; 25:727-734. 26. avolio pp, lughezzani g, anidjar m, et al. the diagnostic accuracy of micro-ultrasound for prostate cancer diagnosis: a review. world j urol 2023; 41:3267-3276. 27. pepe p, pepe l, tamburo m, et al. targeted prostate biopsy: 68gapsma pet/ct vs. mpmri in the diagnosis of prostate cancer. arch ital urol androl 2022; 94:274-277. 28. pepe p, pennisi m. targeted biopsy in men high risk for prostate cancer: 68ga-psma pet/ct versus mpmri. clin genitourin cancer 2023; 21:639-642. 29. pepe p, pepe l, cosentino s, et al. detection rate of 68ga-psma pet/ct vs. mpmri targeted biopsy for clinically significant prostate cancer. anticancer res 2022; 42:3011-3015. 30. pepe p, roscigno m, pepe l, et al. could 68ga-psma pet/ct evaluation reduce the number of scheduled prostate biopsies in men enrolled in active surveillance protocols? j clin med. 2022; 11:3473. correspondence pepe pietro, md (corresponding author) piepepe@hotmail.com urology unit, cannizzaro hospital, 95126 catania, italy ludovica pepe, md ludopepe97@gmail.com vincenzo fiorentino, md vincenzo.fiorentino@unime.it department of human pathology in adult and developmental age “gaetano barresi”, university of messina, 98125 messina, italy mara curduman, md mara.curduman@aoec.it pathology unit, cannizzaro hospital, 95126 catania, italy filippo fraggetta, md filippofra@hotmail.com pathology unit, asp catania, "gravina" hospital, 95041 caltagirone, italy conflict of interest: the authors declare no potential conflict of interest. stesura seveso archivio italiano di urologia e andrologia 2025; 97(1):13412 1 original paper α1-blockers and 5α-reductase inhibitors are established therapies, yet their impact on erectile and ejaculatory function can be bothersome (3, 4). consequently, there is a growing interest in nutraceutical agents for managing bph. within this context, xipag® (idi integratori dietetici italiani s.r.l., aci bonaccorsi, ct, italy), formulated with pollen extract (graminex® g96®; 500 mg) and teupolioside (teupol 25p; 60 mg), has emerged as a promising bph treatment, supported by research into its key components (5). graminex®, derived from secale cereale, has demonstrated anti-inflammatory, anti-edema, and antioxidant effects in ex vivo studies on rat prostate specimens, owing to its complex composition rich in amino acids, enzymes, minerals, and bioactive compounds (6). pollen extracts have been researched for their efficacy in managing prostatitis and pelvic pain, with animal models showing effectiveness in reducing stromal proliferation and glandular inflammation (7, 8). furthermore, clinical trials have highlighted significant improvements in chronic pelvic pain and luts with pollen extract, often surpassing the efficacy of tadalafil (9). teupolioside, derived from ajuga reptans cell cultures, has shown promise in preliminary in vitro studies by reducing dihydrotestosterone (dht) production through nadph oxidation and exhibiting notable anti-inflammatory properties (5). this combined approach offers a novel therapeutic strategy for alleviating luts in bph patients, targeting both inflammation and dht production. this study aims to assess the efficacy of xipag® in managing luts among bph patients. materials and methods study design and protocol this single-center observational study was conducted from march to september 2024. background: benign prostatic hyperplasia (bph) is a common condition in men over 50, leading to lower urinary tract symptoms (luts). a nutraceutical containing pollen extract (graminex® g96®) and teupolioside has shown potential in alleviating luts by targeting inflammation and dihydrotestosterone production. this prospective, monocentric study enrolled 60 patients with mild to moderate luts due to bph. methods: participants received one tablet daily for three months. assessments included the international prostate symptom score (ipss), quality of life (qol), uroflowmetry, postvoid residual (pvr), and sexual function (iief-5, mshq ejd). results: fifty-three patients completed follow-up. significant improvements were observed in ipss and qol (p < 0.001), with scores decreasing from 14 (11-16) at baseline to 10 (8-12) at three months and decreasing from 3 (2-3) to 2 (2-2), respectively. uroflowmetry parameters (qmax and pvr) improved, increasing from 12 (11-16) ml/s to15 (11-17) ml/s and decreasing from 50 (30-55) ml to 35 (25-45) ml, respectively, without statistical significance (p > 0.05). sexual function and psa levels remained stable, with no significant adverse effects reported. conclusion: the combination of pollen extract and teupolioside effectively alleviates luts in bph patients with a favorable safety profile, particularly in avoiding sexual dysfunction. key words: benign prostatic hyperplasia; nutraceutical; lower urinary tract symptoms. submitted 21 nvember 2024; accepted 12 december 2024 introduction benign prostatic hyperplasia (bph) is a prevalent condition among men over 50 years old, often leading to lower urinary tract symptoms (luts) (1). chronic inflammation is pivotal in the pathogenesis and progression of bph, where immune cells in the prostate release pro-inflammatory cytokines and free radicals, exacerbating the inflammatory process (2). discovering a new nutraceutical based on pollen extract and teupolioside: a prospective monocentric study evaluating its role in alleviating lower urinary tract symptoms in benign prostatic hyperplasia patients mattia lo re 1, 2*, marta pezzoli 1, 2*, anna cadenar 1, 2, elettra fuligni 1, 2, leonardo gajo 1, 2, andrea minervini 1, andrea cocci 1, 2 1 unit of oncologic minimally invasive urology and andrology, university of florence, careggi hospital, florence, italy; 2 department of experimental and clinical medicine, university of florence, florence, italy. * these authors contributed equally to this work. this study was awarded at the 97th siu congress in bari on october 11th-13th, 2024. doi: 10.4081/aiua.2025.13412 summary archivio italiano di urologia e andrologia 2025; 97(1):13412 m. lo re, m. pezzoli, a. cadenar, et al. 2 patients presenting mild or moderate luts related to bph were enrolled after signing a written informed consent. all enrolled patients completed three baseline (t0) questionnaires: the international prostatic symptoms scorequality of life (ipss-qol), the male sexual health questionnaire ejaculatory dysfunction (mshq ejd short form), and the international index of erectile function-5 (iief-5). additionally, patients underwent a blood examination to evaluate prostate-specific antigen (psa) levels and performed uroflowmetry with post-void residual (pvr) evaluation. patients who consented to participate in the study received one tablet per day of xipag® for three months. clinical evaluations, using the same four baseline questionnaires, psa dosage, and uroflowmetry with pvr assessment, were conducted at one month (t1) and three months (t2) after the start of the treatment. at t2, patients were also asked about their willingness to continue the use of xipag®. the study was conducted in line with good clinical practice guidelines and with the ethical principles of the declaration of helsinki. before the beginning of the study, all participants signed the written informed consent. no placebo run-in period was performed. inclusion and exclusion criteria inclusion criteria were age over 40 years, diagnosis of luts related to bph, mild to moderate luts (ipss score 819), sexually active patients (iief-5 score ≥ 17) and any prostate volume. exclusion criteria included clinical suspicion of prostatic cancer (based on rectal examination or suspicious elevation of psa levels) or bladder cancer, neurological bladder, urethral stricture, bacterial prostatitis or recurrent urinary tract infections, previous pelvic radiation therapy, use of alpha-blockers, 5-alphareductase inhibitors, or phosphodiesterase-5 inhibitors (pde5i), and allergies to components of xipag®. outcomes the primary objective was to evaluate the efficacy of xipag® in improving urinary symptoms and function, as measured by ipss, maximum urinary flow rate (qmax), and pvr. the secondary objective was to assess changes in sexual function, using iief-5 and mshq-ejd scores, and analyze any changes in psa levels. statistical analysis values for quantitative variables are expressed as median and interquartile range (iqr). comparisons between pairs of values (baseline each time point) were performed using a wilcoxon signed rank test, with a p-value < 0.05 deemed to be statistically significant. all statistical analyses were conducted using spss 21.0 (ibm corporation, armonk, ny, usa). results a total of 60 patients were consecutively enrolled in this study. of these, 6 were lost to follow-up and 1 was excluded due to starting alpha-blocking therapy on his family doctor's advice. consequently, 53 patients completed both the 1 and 3-month follow-ups. the age of participants was 55 (45-64) years, with a body mass index (bmi) of 24.5 (23.2-26.3). significant improvements in urinary symptoms were observed at both time points (p < 0.001) (table 1). ipss score decreased from 14 (11-16) at baseline to 11 (9-13) at 1 month and 10 (8-12) at 3 months. ipss quality of life (qol) parameter also improved, decreasing from 3 (2-3) at t0 to 2 (2-2) at t1 and 2 (2-2) at t2. uroflowmetry parameters improved, even without a statistical significance (p < 0.05): qmax increased from 12 (11-16) ml/s at t0 to 14 (11-16) ml/s at t1 and 15 (11-17) ml/s at t2 meanwhile pvr decreased from 50 (30-55) ml at t0 to 35 (25-40) ml at t1 and 35 (25-45) ml at t2 (figure 1). table 1. functional outcomes at different timepoints. baseline, n = 60 1 month, n = 53 3 months, n = 53 p ipss, median (iqr) 14 (11-16) 11 (9-13) 10 (8-12) 0.001 ipss qol, median (iqr) 3 (2-3) 2 (2-2) 2 (2-2) 0.001 qmax (ml/s), median (iqr) 12 (11-16) 14 (11-16) 15 (11-17) > 0.05 pvr (ml), median (iqr) 50 (30-55) 35 (25-40) 35 (25-45) 0.001 psa (ng/ml), median (iqr) 1.54 (1.34-2.35) 1.35 (1.22-2.12) 1.34 (1.12-2.30) > 0.05 iqr: interquartile range; qmax: maximum flow rate; pvr: post-void residual; ipss: international prostatic symptoms score; qol: quality of life; mshq: men sexual health questionnaire. figure 1. graphical representation of functional outcomes over different time points. qmax: maximum flow rate; pvr: post-void residual; ipss: international prostatic symptoms score; qol: quality of life. archivio italiano di urologia e andrologia 2025; 97(1):13412 3 discovering a new nutraceutical based on pollen extract and teupolioside regarding sexual function, there was a slight increase in both iief5 and mshq ejd scores, though these changes were not statistically significant (p > 0.05). psa levels remained stable at t1 and showed a slight decrease at t2, but no statistically significant changes were detected (p > 0.05). after 3 months of treatment, 44 patients (83.2%) expressed their willingness to continue. three patients (5.7%) reported no significant improvement in luts and expressed the desire to switch to another therapy. six patients (11.3%) with initially mild luts experienced intolerance to daily therapy, leading them to want to discontinue the treatment, with the possibility of reevaluation if symptoms worsened. overall, no adrs were recorded. after three weeks of using xipag®, one patient developed a mild skin rash, which was resolved spontaneously. the patient continued the treatment, and no similar events occurred, suggesting that the rash was not likely an adr related to the nutraceutical. discussion in this study, we evaluated the efficacy and safety of a novel nutraceutical, xipag®, which contains teupolioside (teupol 60 mg) and pollen extract (graminex® g96® 500 mg), for the treatment of luts associated with bph. as previously documented in the literature, the effectiveness of teupolioside in addressing prostatic hypertrophy and that of pollen extract in alleviating symptoms such as chronic pelvic pain and irritation are well established (10), making this product particularly promising for managing moderate luts. our findings offer several insights into the potential utility of this product. first, only three patients (5.7%) reported no significant improvement in luts and expressed a desire to switch to alternative therapies. conversely, all other participants experienced a significant improvement in symptoms as measured by the international prostate symptom score (ipss), alongside a non-significant improvement in urinary flow rate (qmax). our study corroborates the findings of muraca et al., who first demonstrated the potential benefits of xipag® in a pilot study (11), noting an ipss improvement from a mean baseline score of 13.3 ± 6.1 to a 3-month decrease of 22.7-88.9% (mean 55.2 ± 23.6%). this consistency with prior research bolsters the credibility of our results and suggests that xipag® may represent an effective therapeutic option for patients with bph. secondly, while nutraceuticals have garnered attention in the management of bph, their efficacy remains a subject of debate. a recent systematic review by franco et al. (12) did not find significant evidence supporting the efficacy of nutraceuticals in various trials. however, another systematic review by novara et al. (13) reported significant efficacy on outcomes such as ipss, ipss qol, and qmax in patients treated with permixon, which also exhibited a favorable safety profile. in this context, our study demonstrates that a phytotherapeutic agent like xipag® can achieve symptom improvements in selected patients, comparable to those observed in studies of nutraceuticals like serenoa repens. thirdly, although the symptom relief observed with xipag® was less pronounced than that reported in studies of alphablockers, our study is noteworthy for the absence of adverse effects on sexual function, as we do not detect a significant change in the iief and mshq ed questionnaire. this is a considerable advantage, as conventional alphablocker treatments are often associated with side effects, such as ejaculatory dysfunction, which can lead to therapy discontinuation (14, 15). the tolerability of xipag® thus positions it as an attractive option for patients seeking symptom relief – particularly those with mild symptoms – without the risk of side effects. nonetheless, our study is not devoid of limitations. one notable limitation is the relatively short follow-up period of three months. while significant improvements were observed within this timeframe, longer follow-up is necessary to assess the sustainability of xipag®'s effects. additionally, the observational nature of our study introduces potential biases, as it lacks the rigor of a randomized controlled trial (rct). future research should aim to utilize rct methodologies to further validate the efficacy of xipag® and compare its performance against placebo and established bph treatments in a controlled environment. conclusions in conclusion, this study represents the largest cohort to date evaluating the effects of xipag® on bph-related symptoms, with 53 patients completing the study. the size of our cohort enables a more robust analysis and provides valuable data to the limited existing literature on xipag® and contributes to the growing body of evidence supporting the use of nutraceuticals in managing bphrelated symptoms, particularly in cases where conventional therapies may lead to undesirable side effects. declarations ethical approval: the procedures used in this study adhere to the tenets of the declaration of helsinki. the patients/participants provided their written informed consent to participate in this study. availability of data and material: all inquiries can be directed to the corresponding author. competing interests: the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. funding: the authors report no involvement in the research by the sponsor that could have influenced the outcome of this work. authors' contributions: mlr and mp have given substantial contributions to the conception and the design of the manuscript. ac, lg and ef to the acquisition of the data; 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2:553-561. 14. cindolo l, pirozzi l, fanizza c, et al. drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. eur urol. 2015; 68:418-425. 15. bapir r, bhatti kh, eliwa a, et al. effect of alpha-adrenoceptor antagonists on sexual function. a systematic review and meta-analysis. arch ital urol androl. 2022; 94:252-263. correspondence mattia lo re, md mattialore1994@gmail.com marta pezzoli, md (corresponding author) marta.pezzoli@unifi.it university of florence, careggi hospital, 50100 florence, italy anna cadenar, md anna.cadenar@unifi.it elettra fuligni, md elettra.fuligni@unifi.it leonardo gajo, md leonardo.gajo@unifi.it andrea minervini, md andrea.minervini@unifi.it andrea cocci, md cocci.andrea@gmail.com